PMID- 21521642 TI - A large liver tumor in a 3-month-old girl. Diagnosis: GLUT1-negative hepatic vascular malformation with capillary proliferation. PMID- 21521641 TI - Colonoscopy and optical biopsy: bridging technological advances to clinical practice. PMID- 21521644 TI - Up-regulation of FSHR expression during gonadal sex determination in the frog Rana rugosa. AB - In vertebrates, gonadal production of steroid hormones is regulated by follicle stimulating hormone (FSH) and luteinizing hormone (LH) via their receptors designated FSHR and LHR, respectively. We have shown recently that steroid hormones are synthesized in the differentiating gonad of tadpoles during sex determination in the frog Rana rugosa. To elucidate the role of gonadotropins (GTHs) and their receptors in the production of gonadal steroid hormones during sex determination, we isolated the full-length FSHbeta, LHbeta, FSHR and LHR cDNAs from R. rugosa and determined gonadal expression of FSHR (FSH receptor) and LHR (LH receptor) as well as brain expression of FSHbeta and LHbeta during sex determination in this species. The molecular structures of these four glycoproteins are conserved among different classes of vertebrates. FSHbeta expression was observed at similar levels in the whole brain (including the pituitary) of tadpoles, but it showed no sexual dimorphism during gonadal sex determination. By contrast, LHbeta mRNA was undetectable in the whole brain of tadpoles. FSHbeta-immunopositive cells were observed in the pituitary of female tadpoles with a differentiating gonad. Furthermore, FSHR expression was significantly higher in the gonad of female tadpoles during sex determination than in that of males, whereas LHR was expressed at similar levels in males and females. The results collectively suggest that FSHR, probably in conjunction with FSH, is involved in the steroid-hormone production during female-sex determination in R. rugosa. PMID- 21521645 TI - Identification and gene expression analysis of three GnRH genes in female Atlantic cod during puberty provides insight into GnRH variant gene loss in fish. AB - Gonadotropin releasing hormone (GnRH) is a key regulator of sexual development and reproduction in vertebrates. Fish have either two or three pre-pro-GnRH genes, encoding structurally distinct peptides. We identified three pre-pro-GnRH genes in Atlantic cod (Gadus morhua, gmGnRH) using RT-PCR, RACE-PCR and BAC DNA library clone sequencing based on synteny searching. Gene identity was confirmed by sequence alignment and subsequent phylogenetic analysis. The expression of these genes was measured by quantitative PCR in the brain and pituitary of female cod throughout their reproductive cycle and in peripheral tissues. All three gmGnRH genes have highly conserved deduced decapeptide sequences, but sequence and phylogenetic data for gmGnRH1 suggest that this is a pseudogene. gmGnRH1 shares low identity with all fish GnRH variants and grouped with the GnRH3 clade. Although gmGnRH1 is a putative pseudogene, it is transcribed in multiple tissues but at low levels in the brain, indicating the loss of conserved hypophysiotrophic function. Phylogenetic analysis reveals that gmGnRH2 and gmGnRH3 variants are located in variant-specific clades. Both gmGnRH2 and gmGnRH3 transcripts are most abundant in the brain, with lower expression in pituitaries and ovaries. Brain gmGnRH3 gene expression increases in spawning fish and is expressed in the pituitary during puberty. Brain gmGnRH2 transcripts are highly expressed relative to gmGnRH3 before and during spawning. Sequence and expression data suggest that gmGnRH1 is a pseudogene and that gmGnRH3 is likely the hypophysiotrophic form of GnRH in Atlantic cod. PMID- 21521646 TI - Differential effects of NMDA antagonists on high frequency and gamma EEG oscillations in a neurodevelopmental model of schizophrenia. AB - Neuroanatomical, electrophysiological and behavioural abnormalities following timed prenatal methylazoxymethanol acetate (MAM) treatment in rats model changes observed in schizophrenia. In particular, MAM treatment on gestational day 17 (E17) preferentially disrupts limbic-cortical circuits, and is a promising animal model of schizophrenia. The hypersensitivity of this model to the NMDA receptor antagonist-induced hyperactivity has been proposed to mimic the increase in sensitivity observed in schizophrenia patients following PCP and Ketamine administration. However, how this increase in sensitivity in both patients and animals translates to differences in EEG oscillatory activity is unknown. In this study we have shown that MAM-E17 treated animals have an increased response to the hyperlocomotor and wake promoting effects of Ketamine, PCP, and MK801 but not to the competitive antagonist SDZ 220,581. These behavioural changes were accompanied by altered EEG responses to the NMDAR antagonists, most evident in the gamma and high frequency (HFO) ranges; altered sensitivity of these neuronal network oscillations in MAM-exposed rats is regionally selective, and reflects altered interneuronal function in this neurodevelopmental model. PMID- 21521648 TI - Effects of the filamentous cyanobacterium Nodularia on fitness and feeding behavior of young-of-the-year (YOY) Eurasian perch (Perca fluviatilis). AB - This study reveals that both cyanobacterial toxicity and turbidity have the potential to reduce the growth and energy storage of young-of-the-year (YOY) perch and thereby influence survival rates. During the 1990's a reduction in recruitment of YOY perch (Perca fluviatilis) occurred along the Swedish East coast. Concurrently, large blooms of filamentous cyanobacteria have increased in the Baltic Proper and in coastal waters. This study examined whether extended exposure to toxic and non-toxic filamentous cyanobacterium Nodularia affect YOY perch growth and feeding behavior under simulated bloom conditions (30 days at 50 MUg Chl a L(-1)). Specific growth rate (SGR), the somatic condition index (SCI) and the lipid content of YOY perch (10-12 weeks old) were significantly lower in perch exposed to Nodularia compared to fed controls (no Nodularia). YOY perch exposed to non-toxic Nodularia displayed a higher attack rate than perch living in Nodularia free controls in 2 out of 3 trials. Reductions in growth and energy storage, mediated by cyanobacteria, increase the risk of starvation and predation and could locally influence recruitment of YOY perch. PMID- 21521647 TI - Differential effects of cocaine and MDMA self-administration on cortical serotonin transporter availability in monkeys. AB - Cocaine self-administration alters brain dopaminergic and serotonergic function primarily in mesolimbic and prefrontal brain regions whereas 3,4 methylenedioxymethamphetamine (MDMA) self-administration predominately alters brain serotonergic function in a more widespread distribution across cortical regions. We previously reported that, compared to drug-naive rhesus monkeys, self administration of cocaine but not MDMA was associated with increased serotonin transporter (SERT) availability in two mesolimbic regions, the caudate nucleus and putamen, as measured by positron emission tomography (PET) using the SERT specific ligand [(11)C]-3-amino-4(2-dimethylamino-methyl-phenylsulfanyl) benzonitrile ([(11)C]DASB). The goal of the present study was to extend this comparison between cocaine and MDMA self-administration to SERT availability in cortical regions, which have been shown previously to be affected in human drug abusers and are associated with executive function. PET studies using [(11)C]DASB were conducted in adult male rhesus monkeys with a history of cocaine (mean intake = 742.6 mg/kg) or MDMA (mean intake = 121.0 mg/kg) self-administration, and drug-naive controls (n = 4/group). Regions of interest were drawn for several cortical (prefrontal, temporal, parietal, occipital and midcingulate) and subcortical (thalamus, amygdala and hippocampus) areas. Cortical SERT availability was significantly higher in monkeys with a cocaine self administration history compared to controls whereas MDMA self-administration resulted in lower levels of SERT availability. These data extend our previous findings indicating that cocaine and MDMA self-administration differentially alter SERT availability in subcortical and cortical regions, which may have implications for development of treatment drugs. PMID- 21521650 TI - Rostroventral medulla-mediated biphasic modulation of the rat cardiosomatic motor reflex. AB - The purpose of the present study was to examine whether the rostroventral portion of the medulla oblongata (RVM) exerts descending modulation on the cardiosomatic motor reflex (CMR) in rats. Capsaicin (1 MUg/ml, 0.2 ml) was injected into the pericardial sac as an algesic substance to induce the CMR, which was monitored via electromyogram (EMG) responses of dorsal spinotrapezius muscle to the noxious cardiac stimulus. Descending modulation of the CMR was observed by electrical or chemical stimulation of RVM. Specifically, electrical stimulation of RVM produced facilitatory, inhibitory or biphasic effects on the CMR evoked by noxious cardiac stimulation, depending on stimulation intensity. In addition, glutamate receptor activation in RVM replicated the effects of electrical stimulation. Lidocaine interruption of the ventrolateral funiculus/ventral funiculus (VLF/VF) or transection of the dorsolateral funiculus (DLF) revealed that the descending facilitatory and inhibitory influences from RVM were conveyed via the VLF/VF and DLF, respectively. Furthermore, intrathecal administration of naloxone or yohimbine partly reversed the inhibitory effect of RVM electrical stimulation, suggesting that opioid and noradrenergic systems are involved in descending RVM modulation of the CMR. PMID- 21521652 TI - Increased serum osteopontin levels in autistic children: relation to the disease severity. AB - Autoimmunity to brain may play an etiopathogenic role in autism. Osteopontin is a pro-inflammatory cytokine that has been shown to play an important role in various autoimmune neuroinflammatory diseases. Osteopontin induces IL-17 production by T-helper 17 lymphocytes, the key players in the pathogenesis of autoimmune disorders. Anti-osteopontin treatment reduces the clinical severity of some autoimmune neuroinflammatory diseases by reducing IL-17 production. We are the first to measure serum osteopontin levels, by ELISA, in 42 autistic children in comparison to 42 healthy-matched children. The relationship between serum osteopontin levels and the severity of autism, which was assessed by using the Childhood Autism Rating Scale (CARS), was also studied. Autistic children had significantly higher serum osteopontin levels than healthy controls (P<0.001). Increased serum osteopontin levels were found in 80.95% (34/42) of autistic children. Children with severe autism had significantly higher serum osteopontin levels than patients with mild to moderate autism (P=0.02). Moreover, serum osteopontin levels of autistic patients had significant positive correlations with CARS (P=0.007). In conclusions, serum osteopontin levels were increased in many autistic children and they were significantly correlated to the severity of autism. Further wide-scale studies are warranted to shed light on the etiopathogenic role of osteopontin in autism and to investigate its relation to IL-17 and brain-specific auto-antibodies, which are indicators of autoimmunity, in these patients. The therapeutic role of anti-osteopontin antibodies in amelioration of autistic manifestations should also be studied. PMID- 21521651 TI - Neuronal Fc-gamma receptor I mediated excitatory effects of IgG immune complex on rat dorsal root ganglion neurons. AB - Pain often accompanies antigen-specific immune-related disorders though little is known of the underlying neural mechanisms. A common feature among these disorders is the elevated level of antigen-specific immunoglobulin (Ig) G in the serum and the presence of IgG immune complex (IC) in the affected tissue. We hypothesize that IC may directly activate the Fc-gamma receptor type I (FcgammaRI) expressed in nociceptive dorsal root ganglion (DRG) neurons and increase neuronal excitability thus potentially contributing to pain. Immunofluorescent labeling indicated that FcgammaRI, but not FcgammaRIIB or FcgammaRIII, was expressed in a subpopulation of rat DRG neurons including those expressing nociceptive markers. Calcium imaging revealed that the IC, but neither of the antibody (IgG) or antigen alone, produced an increase in intracellular calcium. This effect was abolished by the removal of the IgG Fc portion in the IC or the application of an anti-FcgammaRI antibody, suggesting a key role of the FcgammaRI receptor. Removal of extracellular calcium or depletion of intracellular calcium stores prevented the IC-induced calcium response. In whole-cell current-clamp recordings, IC depolarized the resting membrane potential, decreased the rheobase, and increased the number of action potentials evoked by a depolarizing current at 2* rheobase. In about half of the responsive neurons, IC evoked action potential discharges. These results suggest that a subpopulation of nociceptive neurons expresses functional FcgammaRI and that the activation of this receptor by IC increases neuronal excitability. PMID- 21521653 TI - Acute amygdaloid response to systemic inflammation. AB - The amygdala, a group of nuclei located in the medial temporal lobe, is a key limbic structure involved in mood regulation, associative learning, and modulation of cognitive functions. Functional neuroanatomical studies suggest that this brain region plays also an important role in the central integration of afferent signals from the peripheral immune system. In the present study, intracerebral electroencephalography and microdialysis were employed to investigate the electrophysiological and neurochemical consequences of systemic immune activation in the amygdala of freely moving rats. Intraperitoneal administration of bacterial lipopolysaccharide (100 MUg/kg) induced with a latency of about 2 h a significant increase in amygdaloid neuronal activity and a substantial rise in extracellular noradrenaline levels. Activated neurons in the amygdaloid complex, identified by c-Fos immunohistochemistry, were mainly located in the central nucleus and, to a lesser extent, in the basolateral nucleus of the amygdala. Gene expression analysis in micropunches of the amygdala revealed that endotoxin administration induced a strong time-dependent increase in IL-1beta, IL 6, and TNF-alpha mRNA levels indicating that these cytokines are de novo synthesized in the amygdala in response to peripheral immune activation. The changes in amygdaloid activity were timely related to an increase in anxiety-like behavior and decreased locomotor activity and exploration in the open-field. Taken together, these data give novel insights into different features of the acute amygdaloid response during experimental inflammation and provides further evidence that the amygdala integrates immune-derived information to coordinate behavioral and autonomic responses. PMID- 21521654 TI - Crystal structures of the free and inhibited forms of plasmepsin I (PMI) from Plasmodium falciparum. AB - Plasmepsin I (PMI) is one of the four vacuolar pepsin-like proteases responsible for hemoglobin degradation by the malarial parasite Plasmodium falciparum, and the only one with no crystal structure reported to date. Due to substantial functional redundancy of these enzymes, lack of inhibition of even a single plasmepsin can defeat efforts in creating effective antiparasitic agents. We have now solved crystal structures of the recombinant PMI as apoenzyme and in complex with the potent peptidic inhibitor, KNI-10006, at the resolution of 2.4 and 3.1A, respectively. The apoenzyme crystallized in the orthorhombic space group P2(1)2(1)2(1) with two molecules in the asymmetric unit and the structure has been refined to the final R-factor of 20.7%. The KNI-10006 bound enzyme crystallized in the tetragonal space group P4(3) with four molecules in the asymmetric unit and the structure has been refined to the final R-factor of 21.1%. In the PMI-KNI-10006 complex, the inhibitors were bound identically to all four enzyme molecules, with the opposite directionality of the main chain of KNI 10006 relative to the direction of the enzyme substrates. Such a mode of binding of inhibitors containing an allophenylnorstatine-dimethylthioproline insert in the P1-P1' positions, previously reported in a complex with PMIV, demonstrates the importance of satisfying the requirements for the proper positioning of the functional groups in the mechanism-based inhibitors towards the catalytic machinery of aspartic proteases, as opposed to binding driven solely by the specificity of the individual enzymes. A comparison of the structure of the PMI KNI-10006 complex with the structures of other vacuolar plasmepsins identified the important differences between them and may help in the design of specific inhibitors targeting the individual enzymes. PMID- 21521656 TI - Microbiological quality and related factors of sheep milk produced in farms of NE Greece. AB - Sheep herds are a significant capital of dairy industry in Greece, but as dairy farming becomes more complex and intense the need to provide assistance to dairy producers on milk quality is critical. In this study, the quality of raw milk produced in sheep farms of NE Greece was surveyed and the role of various factors was explored. In total, 21 dairy ewe's farms from the regions of Xanthi and Evros, in the north-eastern Greece were monitored. Milk samples were sampled after the morning milking every 15 days throughout the dairy period (March-June). For the study, a questionnaire was also filled by personal interview with the owners in order to collect information about herd characteristics, health status, handling practices etc. From each farm, air was also sampled for microbiological analysis. Milk samples were examined for chemical components: fat content, protein, lactose, non-fat dry matter (NFDM) and somatic cells count (SCC). Microbiological examination involved the estimation of Total Bacterial Counts (TBC), coliform count (CC), Staphylococcus aureus, Streptococcus sp., and preliminary incubation count (PIC). The possible correlation among different bacterial species and their interaction with SCC and chemical components of milk was also considered. It was examined whether farm management practices could influence the hygiene and the quality of milk. Our results show that as an average TBCs were 5.48 log cfu/ml, SCC: 6.05 log cells/ml, CC: 4.49 log cfu/ml, S. aureus: 3.94 log cfu/ml, Streptococcus sp.: 4.95 log cfu/ml and PIC: 5.7 log cfu/ml. The mean fat, protein, lactose and NFDM were 6.17%, 5.28%, 4.73% and 10.95% respectively. The study revealed significant positive correlation between TBC and PIC (0.825), while SCC was marginally positive correlated with protein and NFDM. No statistically significant correlations observed among SCC with any of the bacterial species. Herd size and farm management practices had considerable influence on SCC and bacterial species. PMID- 21521655 TI - HDAC3 and the molecular brake pad hypothesis. AB - Successful transcription of specific genes required for long-term memory processes involves the orchestrated effort of not only transcription factors, but also very specific enzymatic protein complexes that modify chromatin structure. Chromatin modification has been identified as a pivotal molecular mechanism underlying certain forms of synaptic plasticity and memory. The best-studied form of chromatin modification in the learning and memory field is histone acetylation, which is regulated by histone acetyltransferases and histone deacetylases (HDACs). HDAC inhibitors have been shown to strongly enhance long term memory processes, and recent work has aimed to identify contributions of individual HDACs. In this review, we focus on HDAC3 and discuss its recently defined role as a negative regulator of long-term memory formation. HDAC3 is part of a corepressor complex and has direct interactions with Class II HDACs that may be important for its molecular and behavioral consequences. And last, we propose the "molecular brake pad" hypothesis of HDAC function. The HDACs and associated corepressor complexes may function in neurons, in part, as "molecular brake pads." HDACs are localized to promoters of active genes and act as a persistent clamp that requires strong activity-dependent signaling to temporarily release these complexes (or brake pads) to activate gene expression required for long term memory formation. Thus, HDAC inhibition removes the "molecular brake pads" constraining the processes necessary for long-term memory and results in strong, persistent memory formation. PMID- 21521657 TI - Antibacterial activities of essential oils from eight Greek aromatic plants against clinical isolates of Staphylococcus aureus. AB - Aromatic plants have been used widely to extend the shelf life of foods but at the same time research is undergoes for their properties as antibacterial agents in clinical use. Although there are promising results for the antimicrobial properties of various essential oils against environmental or food-isolated strains of Staphylococcus aureus, limited work has been done concerning these properties against clinical isolates of this pathogen. S. aureus is responsible for an increase number of nosocomial infections and at the same time exhibits increased resistance to synthetic agents. In this study, essential oils from eight aromatic plants common in Greece were isolated by hydrodistillation, analyzed by gas chromatography (GC) and GC/mass spectrometry (GC/MS) for their chemical components and tested for their antimicrobial activities against 24 clinical isolates of S. aureus. The methods used were disk diffusion and broth dilution in order to determine the Minimum Inhibitory Concentration (MIC). Our results showed that essential oils from Origanum vulgare and Origanum dictamnus were active against S. aureus when tested by disk diffusion, but exhibited increased MIC values (>256 mg/L) with the dilution method. In contrast, the reference strain NCTC 6571 showed to be extremely sensitive in most of the oils tested (MICs 0.25-32.0 mg/L) and resistant only to the essential oil from Ocimum basilicum. Therefore, there is no evidence of a potential clinical use for those essential oils and further research is needed in order to determine if they could substitute efficiently synthetic antibiotics or, perhaps be used in combination. PMID- 21521658 TI - Combined effects of Gm or Km immunoglobulin allotypes and age on antibody responses to Plasmodium falciparum VarO rosetting variant in Benin. AB - Clinical protection of Beninese children against Plasmodium falciparum malaria was shown to be influenced by immunoglobulin (IG) Gm and Km allotypes, and related to seroreactivity with the rosette-forming VarO-antigenic variant. IgG to the VarO-infected erythrocyte surface, IgG1 and IgG3 to PfEMP1-NTS-DBL1alpha(1) VarO were higher in the under 4-year-old children carrying the Gm 5,6,13,14;1,17 phenotype. In contrast, surface-reactive IgG, total IgG, IgG1 and IgG3 to NTS DBL1alpha(1)- and DBL2betaC2-VarO domains were lower in the above 4-year-old children harbouring the Km1 allotype. These data outline an age-related association of antibodies against malaria antigens and IG allotype distribution. PMID- 21521659 TI - Increasing capillary diameter and the incorporation of gelatin enhance axon outgrowth in alginate-based anisotropic hydrogels. AB - Substantial recovery of function following peripheral and central nervous system (CNS) injury critically depends on longitudinally directed axon regeneration across the injury site, which requires a mechanical guidance providing scaffold. We have previously shown that anisotropic alginate-based hydrogels with a defined capillary diameter (25 MUm), which form via a self-organizing process driven by unidirectional diffusion of divalent cations into sodium alginate sols, promoted longitudinally oriented elongation of CNS axons in vitro and in vivo. In the present study the influence of various capillary diameters and the incorporation of gelatin to promote directed axon outgrowth and Schwann cell migration were assessed in a dorsal root ganglion outgrowth assay in vitro. Superimposing an alginate sol with Cu(2+), Sr(2+), or Zn(2+) ion containing solutions allowed the creation of hydrogels with capillaries 18, 25 and 55 MUm in diameter, respectively. Axon outgrowth and Schwann cell migration were analyzed in terms of axon length/density and Schwann cell density within the capillary structures. Axon ingrowth into capillary hydrogels, which was always accompanied by Schwann cells, was enhanced with increasing capillary diameter. The incorporation of gelatin did not influence overall axon density, but promoted the length of axon outgrowth within the hydrogels. The longitudinal orientation of axons decreased in wider capillaries, which suggests that medium-sized capillaries are the optimal substrate to elicit substantial axon growth and longitudinal orientation after axon injury. PMID- 21521660 TI - The evolution of laparoscopic surgery for rectal prolapse. AB - External rectal prolapse is defined as a full thickness extrusion of the rectum outside of the anus. In patients who are fit enough, it is usually treated with surgical intervention. The surgical focus has traditionally been on reduction of the prolapse, rather than improvement in function. Internal rectal prolapse is also well recognised, being a folding of the full thickness of the rectal wall that occurs on straining to defecate, but that does not protrude outside of the anus. It may present with either obstructed defecation or faecal incontinence.(1,2) In contrast to external prolapse surgery for internal rectal prolapse has enjoyed a poor reputation, in part due to the poor results of surgery in the late 1980s(3,4) but also because of the suggestion that internal prolapse is an incidental finding.(5) The introduction of surgical techniques that focus on functional outcomes in external prolapse surgery have led to a re appraisal of the treatment of internal rectal prolapse.(6) This coupled with new evidence regarding the morphology of symptomatic internal prolapse has quashed the concept of internal prolapse as an untreatable and incidental phenomenon.(7,8) This article will outline the evolution of surgery for rectal prolapse, the use of laparoscopic ventral rectopexy in external prolapse and the evaluation and treatment of patient with internal rectal prolapse. PMID- 21521661 TI - Conjugation of quantum dots and JT95 IgM monoclonal antibody for thyroid carcinoma without abolishing the specificity and activity of the antibody. AB - Among the immunoglobulins, IgM class-antibodies are now considered to be potent immunological reagents for anticancer remedies. However, only a few reports are available about the effective labeling of IgM with enzymes, fluorescence, or other bioreactive reagents. Here, we report an effective application of luminescent semiconductive nanoparticles, quantum dots (QDs), as a labeling material of the IgM antibody. The CdSe carboxyl QDs were reacted with 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysulfo- succinimide in 2-(morpholino) ethanesulfonic acid. The reacted QDs were then coupled to JT95 IgM antibody, which recognizes thyroid carcinoma associated antigen. The specificity and activity of the conjugates were tested by immunoblot, immunoquantitive assay and immunohistological imaging. The QDs were firmly conjugated with JT95 IgM monoclonal antibody. In immunoblot assay, QD-JT95 conjugates directly detected the target molecules without obstructing the binding site. In immunoquantitive assay, the conjugates could quantify the antigen in the range of 1.56-100 MUg/mL. Also, QDs-labeled antibody detected the antigen on plasma membrane. Our results demonstrate that labeling of JT95 and other IgM class antibodies with QDs is feasible. This approach may be an important method for the medical application of IgM in the diagnosis and treatment of cancers. PMID- 21521662 TI - Organ surface deformation measurement and analysis in open hepatic surgery: method and preliminary results from 12 clinical cases. AB - The incidence of soft tissue deformation has been well documented in neurosurgical procedures and is known to compromise the spatial accuracy of image guided surgery systems.Within the context of image-guided liver surgery (IGLS), no detailed method to study and analyze the observed organ shape change between preoperative imaging and the intra-operative presentation has been developed. Contrary to the studies of deformation in neurosurgical procedures, the majority of deformation in IGLS is imposed prior to resection and due to laparotomy and mobilization. As such, methods of analyzing the organ shape change must be developed to use the intra-operative data (e.g. laser range scan (LRS) surfaces) acquired with the organ in its fully deformed shape. To achieve this end we use a signed closest point distance deformation metric computed after rigid alignment of the intra-operative LRS data with organ surfaces generated from the preoperative tomograms. The rigid alignment between the intra-operative LRS surfaces and pre-operative image data was computed with a feature weighted surface registration algorithm. In order to compare the deformation metrics across patients, an inter-patient non-rigid registration of the pre-operative CT images was performed. Given the inter-patient liver registrations, an analysis was performed to determine the potential similarities in the distribution of measured deformation between patients for which similar procedures had been performed. The results of the deformation measurement and analysis indicates the potential for soft tissue deformation to compromise surgical guidance information and suggests a similarity in imposed deformation among similar procedure types. PMID- 21521663 TI - Robotic ICSI (intracytoplasmic sperm injection). AB - This paper is the first report of robotic intracytoplasmic sperm injection (ICSI). ICSI is a clinical procedure performed worldwide in fertility clinics, requiring pick-up of a single sperm and insertion of it into an oocyte (i.e., egg cell). Since its invention 20 years ago, ICSI has been conducted manually by a handful of highly skilled embryologists; however, success rates vary significantly among clinics due to poor reproducibility and inconsistency across operators. We leverage our work in robotic cell injection to realize robotic ICSI and aim ultimately, to standardize how clinical ICSI is performed. This paper presents some of the technical aspects of our robotic ICSI system, including a cell holding device, motion control, and computer vision algorithms. The system performs visual tracking of single sperm, robotic immobilization of sperm, aspiration of sperm with picoliter volume, and insertion of sperm into an oocyte with a high degree of reproducibility. The system requires minimal human involvement (requiring only a few computer mouse clicks), and is human operator skill independent. Using the hamster oocyte-human sperm model in preliminary trials, the robotic system demonstrated a high success rate of 90.0% and survival rate of 90.7% (n=120). PMID- 21521664 TI - Magnetic resonance electrical impedance tomography for monitoring electric field distribution during tissue electroporation. AB - Electroporation is a phenomenon caused by externally applied electric field of an adequate strength and duration to cells that results in the increase of cell membrane permeability to various molecules, which otherwise are deprived of transport mechanism. As accurate coverage of the tissue with a sufficiently large electric field presents one of the most important conditions for successful electroporation, applications based on electroporation would greatly benefit with a method of monitoring the electric field, especially if it could be done during the treatment. As the membrane electroporation is a consequence of an induced transmembrane potential which is directly proportional to the local electric field, we propose current density imaging (CDI) and magnetic resonance electrical impedance tomography (MREIT) techniques to measure the electric field distribution during electroporation. The experimental part of the study employs CDI with short high-voltage pulses, while the theoretical part of the study is based on numerical simulations of MREIT. A good agreement between experimental and numerical results was obtained, suggesting that CDI and MREIT can be used to determine the electric field during electric pulse delivery and that both of the methods can be of significant help in planning and monitoring of future electroporation based clinical applications. PMID- 21521665 TI - Simultaneous multi-scale registration using large deformation diffeomorphic metric mapping. AB - In the framework of large deformation diffeomorphic metric mapping (LDDMM), we present a practical methodology to integrate prior knowledge about the registered shapes in the regularizing metric. Our goal is to perform rich anatomical shape comparisons from volumetric images with the mathematical properties offered by the LDDMM framework. We first present the notion of characteristic scale at which image features are deformed. We then propose a methodology to compare anatomical shape variations in a multi-scale fashion, i.e., at several characteristic scales simultaneously. In this context, we propose a strategy to quantitatively measure the feature differences observed at each characteristic scale separately. After describing our methodology, we illustrate the performance of the method on phantom data. We then compare the ability of our method to segregate a group of subjects having Alzheimer's disease and a group of controls with a classical coarse to fine approach, on standard 3D MR longitudinal brain images. We finally apply the approach to quantify the anatomical development of the human brain from 3D MR longitudinal images of pre-term babies. Results show that our method registers accurately volumetric images containing feature differences at several scales simultaneously with smooth deformations. PMID- 21521666 TI - Discriminant independent component analysis. AB - A conventional linear model based on Negentropy maximization extracts statistically independent latent variables which may not be optimal to give a discriminant model with good classification performance. In this paper, a single stage linear semisupervised extraction of discriminative independent features is proposed. Discriminant independent component analysis (dICA) presents a framework of linearly projecting multivariate data to a lower dimension where the features are maximally discriminant with minimal redundancy. The optimization problem is formulated as the maximization of linear summation of Negentropy and weighted functional measure of classification. Motivated by independence among extracted features, Fisher linear discriminant is used as the functional measure of classification. Experimental results show improved classification performance when dICA features are used for recognition tasks in comparison to unsupervised (principal component analysis and ICA) and supervised feature extraction techniques like linear discriminant analysis (LDA), conditional ICA, and those based on information theoretic learning approaches. dICA features also give reduced data reconstruction error in comparison to LDA and ICA method based on Negentropy maximization. PMID- 21521667 TI - Blind image quality assessment: from natural scene statistics to perceptual quality. AB - Our approach to blind image quality assessment (IQA) is based on the hypothesis that natural scenes possess certain statistical properties which are altered in the presence of distortion, rendering them un-natural; and that by characterizing this un-naturalness using scene statistics, one can identify the distortion afflicting the image and perform no-reference (NR) IQA. Based on this theory, we propose an (NR)/blind algorithm-the Distortion Identification-based Image Verity and INtegrity Evaluation (DIIVINE) index-that assesses the quality of a distorted image without need for a reference image. DIIVINE is based on a 2-stage framework involving distortion identification followed by distortion-specific quality assessment. DIIVINE is capable of assessing the quality of a distorted image across multiple distortion categories, as against most NR IQA algorithms that are distortion-specific in nature. DIIVINE is based on natural scene statistics which govern the behavior of natural images. In this paper, we detail the principles underlying DIIVINE, the statistical features extracted and their relevance to perception and thoroughly evaluate the algorithm on the popular LIVE IQA database. Further, we compare the performance of DIIVINE against leading full reference (FR) IQA algorithms and demonstrate that DIIVINE is statistically superior to the often used measure of peak signal-to-noise ratio (PSNR) and statistically equivalent to the popular structural similarity index (SSIM). A software release of DIIVINE has been made available online: "http://live.ece.utexas.edu/research/quality/DIIVINE_release.zip" xmlns:xlink="http://www.w3.org/1999/xlink">http://live.ece.utexas.edu/research/qu lity/DIIVINE_release.zip for public use and evaluation. PMID- 21521668 TI - Memory-efficient architecture for hysteresis thresholding and object feature extraction. AB - Hysteresis thresholding is a method that offers enhanced object detection. Due to its recursive nature, it is time consuming and requires a lot of memory resources. This makes it avoided in streaming processors with limited memory. We propose two versions of a memory-efficient and fast architecture for hysteresis thresholding: a high-accuracy pixel-based architecture and a faster block-based one at the expense of some loss in the accuracy. Both designs couple thresholding with connected component analysis and feature extraction in a single pass over the image. Unlike queue-based techniques, the proposed scheme treats candidate pixels almost as foreground until objects complete; a decision is then made to keep or discard these pixels. This allows processing on the fly, thus avoiding additional passes for handling candidate pixels and extracting object features. Moreover, labels are reused so only one row of compact labels is buffered. Both architectures are implemented in MATLAB and VHDL. Simulation results on a set of real and synthetic images show that the execution speed can attain an average increase up to 24* for the pixel-based and 52* for the block-based when compared to state-of-the-art techniques. The memory requirements are also drastically reduced by about 99%. PMID- 21521669 TI - Pose-free structure from motion using depth from motion constraints. AB - Structure from motion (SFM) is the problem of recovering the geometry of a scene from a stream of images taken from unknown viewpoints. One popular approach to estimate the geometry of a scene is to track scene features on several images and reconstruct their position in 3-D. During this process, the unknown camera pose must also be recovered. Unfortunately, recovering the pose can be an ill conditioned problem which, in turn, can make the SFM problem difficult to solve accurately. We propose an alternative formulation of the SFM problem with fixed internal camera parameters known a priori. In this formulation, obtained by algebraic variable elimination, the external camera pose parameters do not appear. As a result, the problem is better conditioned in addition to involving much fewer variables. Variable elimination is done in three steps. First, we take the standard SFM equations in projective coordinates and eliminate the camera orientations from the equations. We then further eliminate the camera center positions. Finally, we also eliminate all 3-D point positions coordinates, except for their depths with respect to the camera center, thus obtaining a set of simple polynomial equations of degree two and three. We show that, when there are merely a few points and pictures, these "depth-only equations" can be solved in a global fashion using homotopy methods. We also show that, in general, these same equations can be used to formulate a pose-free cost function to refine SFM solutions in a way that is more accurate than by minimizing the total reprojection error, as done when using the bundle adjustment method. The generalization of our approach to the case of varying internal camera parameters is briefly discussed. PMID- 21521670 TI - Joint registration and super-resolution with omnidirectional images. AB - This paper addresses the reconstruction of high-resolution omnidirectional images from multiple low-resolution images with inexact registration. When omnidirectional images from low-resolution vision sensors can be uniquely mapped on the 2-sphere, such a reconstruction can be described as a transform-domain super-resolution problem in a spherical imaging framework. We describe how several spherical images with arbitrary rotations in the SO(3) rotation group contribute to the reconstruction of a high-resolution image with help of the spherical Fourier transform (SFT). As low-resolution images might not be perfectly registered in practice, the impact of inaccurate alignment on the transform coefficients is analyzed. We then cast the joint registration and super resolution problem as a total least-squares norm minimization problem in the SFT domain. A l(1)-regularized total least-squares problem is considered and solved efficiently by interior point methods. Experiments with synthetic and natural images show that the proposed methods lead to effective reconstruction of high resolution images even when large registration errors exist in the low-resolution images. The quality of the reconstructed images also increases rapidly with the number of low-resolution images, which demonstrates the benefits of the proposed solution in super-resolution schemes. Finally, we highlight the benefit of the additional regularization constraint that clearly leads to reduced noise and improved reconstruction quality. PMID- 21521671 TI - Computation of level-set components from level lines. AB - We present an algorithm to compute the connected components of upper or lower level sets from level lines. The running time is O (n + |tau|), where n is the size of the image and |tau| is the number of level lines. PMID- 21521672 TI - Atrial myxomas: a single unit's experience in the modern era. AB - BACKGROUND: Although an atrial myxoma is the commonest cardiac tumor, it is still relatively rare, with an annual incidence of approximately 0.5 per million. In our unit, which performs 1000 major cardiac procedures per year, this equates to approximately 3 patients annually. We therefore sought to evaluate our experience of managing this type of tumor over the last 5 years. METHODS: A retrospective review was performed of prospectively collected data from the departmental database. We analyzed consecutive patients who were operated upon between 2002 and 2007. Three patients with a papillary fibroelastoma on histological examination were excluded from this study. RESULTS: We have performed excision of atrial myxoma in 18 patients. Twelve patients (66%) were female; the median age was 64 years (range, 35-80 years), and the median logistic euroSCORE was 5.22% (range, 1.51-27.82%). Fifteen patients (83%) were deemed urgent, 2 elective, and 1 emergency. Sixteen tumors (89%) were left sided. Symptoms attributable to the tumor were found in 16 of the 18 patients (embolic, n = 9; chest pain, n = 3; palpitations, n = 2; incidental finding, n = 2, others n = 4), and the mean time from diagnosis to operation was 3 days (range, 0-22 months). The median cardiopulmonary bypass time was 87 minutes (range, 28-228 minutes), with the median aortic cross clamp time being 61 minutes (16-175 minutes).The approaches used were transeptal via right atriotomy (n = 8), biatrial/Dubost (n = 4), left atrial (n = 4), and right atrial (n = 2); the interatrial septum was involved in 14 patients. The resultant defect was closed using a pericardial (n = 8) or prosthetic patch (n = 5) or directly sutured (n = 5). Concomitant procedures were performed in 8 patients (coronary artery bypass graft [CABG], n = 4; mitral valve replacement [MVR], n = 2; valve + grafts, n = 2). All tumors were completely excised.Postoperatively there were no deaths within 30 days of the procedure. Indeed, only 2 patients have died at 4 and 25 months postoperatively, respectively, both of unrelated causes. Median intensive therapy unit (ITU) stay was 2 days (range, 1-9 days), and median hospital stay was 10 days (range, 5-20 days). A permanent pacemaker was required in only 1 patient, and median blood loss was 340 mL (range, 140-1760 mL). Atrial fibrillation was the commonest complication affecting 6/18 patients (33%). CONCLUSIONS: Excision of atrial myxoma can be performed using a variety of intraoperative approaches and closure techniques, all with acceptable postoperative morbidity and low mortality rates. To date, no recurrences have been found at median 2-year follow-up. PMID- 21521673 TI - A transapical or transluminal approach to aortic valve implantation does not attenuate the inflammatory response. AB - BACKGROUND: Cardiopulmonary bypass (CPB) and cardiac surgery cause an inflammatory response, as measurable by an increase in the concentration of C reactive protein (CRP), a nonspecific inflammation marker. Previous publications have demonstrated typical perioperative CRP concentration profiles in cases of uncomplicated aortic valve replacement (AVR) with CPB. A regression analysis for modifying factors showed that chronic disease (heart failure, diabetes, and pulmonary disease), along with obesity and sex, all tend to influence the CRP response. We analyzed the inflammatory response to aortic valve implantation (AVI) with interventional techniques, mainly transapical but also transfemoral and transaxillary approaches, in a retrospective case-control study design. METHODS: Sixty-eight patients who underwent AVI by the transapical (59 patients), transfemoral (7 patients), or transaxillary (2 patients) approach were matched by age, sex, body mass index (BMI), and chronic-disease state (absence or presence of diabetes, pulmonary disease, and renal impairment) with 68 patients who underwent conventional AVR with CPB. We compared the 2 groups with respect to perioperative CRP concentration, EuroSCORE, and outcome data (time to extubation and 30-day mortality). All data were collected prospectively and analyzed retrospectively. RESULTS: The 2 groups-the study population (interventional) and the control population (conventional)-were similar in age, sex distribution, BMI, and chronic-disease status. As expected, the study population had a significantly higher median EuroSCORE. The 2 groups had similar postoperative CRP profiles over time, but the interventional group had significantly higher peak concentrations on days 2, 3, and 4. The short-term outcomes, as assessed by ventilation time and 30-day mortality, were similar for the 2 groups. CONCLUSIONS: Using an interventional transcatheter approach to AVI (thereby eliminating CPB from the procedure and reducing surgical trauma) does not attenuate the patient's innate inflammatory response. PMID- 21521674 TI - Congenital mitral valve regurgitation in adult patients. AB - OBJECTIVE: Congenital mitral valve regurgitation (MVR) is a rare disease found in adults. We report on our 5-year surgical experience with congenital MVR in adults. METHODS: We reviewed the data for 48 consecutive patients (26 men), aged >18 years (median, 42 years; range, 18-78 years) who underwent operations for severe congenital MVR between June 2005 and May 2010. Patients with atrioventricular septal defect were excluded. RESULTS: Congenital MVR was preoperatively diagnosed in 28 cases (58%). The lesions consisted of annular dilation (100%), valvular cleft (58%), prolapsed leaflet (40%), papillary muscle abnormality (5%), commissure fusion (2%), and leaflet deficiency (2%). Mitral valve repair was performed in 42 cases (88%) by means of Carpentier techniques. The other 6 patients underwent mitral valve replacement; one of these patients died of ventricular fibrillation 2 days after surgery. There were no other hospital deaths or late mortality. At the last follow-up (median, 38 months; range, 2-50 months), all 47 patients were in New York Heart Association functional class I or II. Echocardiography evaluations for the 42 patients who underwent the repairs revealed that 32 (76%) of the patients had no or trivial MVR and 10 patients (24%) had mild MVR. No patient underwent reoperation. CONCLUSION: Congenital MVR is rare and often misdiagnosed in adults. Mitral valve repair is feasible in the majority of patients, with excellent immediate and medium-term results. PMID- 21521676 TI - Leiomyosarcoma protruding into the left ventricle during diastole: report of a case. AB - Cardiac leiomyosarcoma is a rare tumor with poor survival prospects. Surgery prolongs survival, but the tumor often recurs early after surgery. The diagnosis is often made by transthoracic echocardiography. Magnetic resonance imaging and computed tomography are required to characterize the location and extent of cardiac masses. In this report, we present a patient with a leiomyosarcoma that was resected completely. The tumor was located in the left atrium, mimicked a myxoma, and protruded into the left ventricle during diastole. PMID- 21521677 TI - Pericardial tamponade due to perforation of a posterolateral branch of the circumflex artery caused by a perforating edge of a resected rib following orthopedic surgery in a 14-year-old patient. AB - A 14-year-old female patient with Marfan syndrome was resuscitated because of pericardial tamponade following orthopedic surgery to correct scoliosis. The emergency sternotomy revealed injury to a posterolateral branch of the circumflex artery caused by pericardial perforation by the stump of a previously resected rib. Cardiopulmonary bypass immediately restored the circulation, and the primarily dilated, noncontractile heart regained its contractile function. The small posterolateral branch was sewn over, and the sharp edge of the rib stump was smoothed by abrasion and covered with a Gore-Tex membrane. The patient recovered completely during the remainder of her postoperative stay. PMID- 21521678 TI - Aortic dissection caused by giant cell arteritis. AB - Aortic dissection is a very serious condition mainly caused by degenerative diseases of the connective tissue and hypertension. Ascending aortic dissection as a consequence of aortitis in association with giant cell arteritis is very rarely seen. In this article we report on the successful surgical repair of a Stanford type A aortic dissection caused by giant cell arteritis in a 74-year-old patient. We could visualize this dissection via echocardiography and computed tomography. Histopathology confirmed this rare complication of giant cell aortitis. PMID- 21521679 TI - Aortic valve endocarditis with splenic and brain abscesses: difficult management issues. AB - Staphylococcus aureus endocarditis is associated with a high incidence of complications, a poor prognosis, and high operative mortality. We present a complex case of aortic valve endocarditis in a critically ill patient, highlight the difficult management issues, and report a good outcome. PMID- 21521680 TI - Process review of a departmental change from conventional coronary artery bypass grafting to totally arterial coronary artery bypass and its effects on the incidence and severity of postoperative stroke. AB - BACKGROUND: We evaluated the process of changing from conventional coronary artery bypass grafting (CABG) to totally arterial off-pump coronary artery bypass (TOPCAB) at a single heart center in Germany. METHODS: We (1) used multivariate statistical methods to assess real-time monitoring of OPCAB effects, (2) conducted a case review to assess preventable deaths and identify areas of improvement, (3) conducted a team survey, and (4) evaluated benchmarking results. RESULTS: All surgeons and assistants (n = 18) at this center were involved and were guided by the department head and one of the consultants, who was trained in this procedure in 2004 at the Leuven OPCAB school. The frequency of OPCAB operations increased abruptly in 2005 from 5% to 43% and then increased gradually to 67% (n = 546) by 2008 (total, 1781 OPCAB cases and 1563 on-pump cases). The in hospital and 30-day mortality rates for OPCAB surgeries (n = 10 [0.6%] and 21 [1.2%], respectively) were lower than for on-pump surgeries (n = 27 [1.7%] and 26 [1.7%], respectively). Stroke rates were also lower for OPCAB surgeries (7 cases [0.4%] versus 15 cases [1%]). The lower risk of stroke in the OPCAB group was significant (P < .05) after risk adjustment. Monitoring curves and case reviews demonstrated a preventable death percentage of at least 30%. The attitude of the team was mostly positive because of the promising results (eg, fewer strokes, increasing TOPCAB popularity, and a top national rank). CONCLUSIONS: The change from conventional CABG to TOPCAB was effective in decreasing the incidence and severity of stroke, in developing a team routine and a positive team attitude, and in producing excellent benchmarking results. The presence of a training and communication deficiency at the beginning of the study suggested an area for further improvement. After 6 years TOPCAB had largely replaced conventional CABG. PMID- 21521681 TI - Resource utilization in off-pump versus conventional coronary artery bypass grafting in a community hospital: a comparative analysis using propensity scoring. AB - BACKGROUND: At a time when cost containment in health care is under increased scrutiny, coronary artery bypass grafting remains the most widely performed cardiac surgical procedure in the world. This study compares 30-day mortality, morbidity, and resource use for off-pump coronary artery bypass (OPCAB) versus conventional coronary artery bypass (CCAB) revascularization. METHODS: From January 2000 through December 2008, 1003 patients underwent OPCAB grafting by a single surgeon (S.C.S.). Data were prospectively collected, entered into a Society of Thoracic Surgeons adult cardiac surgery database, and analyzed retrospectively. We used propensity-matching techniques to match this cohort to a group of 1003 patients who underwent CCAB. RESULTS: The hospital mortality rate was lower for the OPCAB patients than for the CCAB patients: 2.0% (20/1003) versus 2.8% (28/1003). Predictors of hospital mortality for the entire cohort included age (P = .001), cardiogenic shock (P = .001), congestive heart failure (P = .019), history of myocardial infarction (P = .001), and reoperation (P = .007). The overall incidence of morbidity was lower for the OPCAB patients (reoperation for bleeding, P = .011; prolonged ventilation, P = .035; stroke, P = .045; cardiac arrest, P = .004). OPCAB patients experienced significantly reduced procedure times (P = .001), postoperative ventilation times (P = .035), post operative lengths of stay (P = .035), and blood product use (intraoperative, P = .001; postoperative, P = .001). CONCLUSION: These outcomes clearly demonstrate that OPCAB is a safe and effective procedure for myocardial revascularization. This retrospective, nonrandomized observational study has shown that the patients who underwent OPCAB had reduced morbidity and mortality, as well as decreased resource use, compared with those who underwent CCAB. PMID- 21521682 TI - Comparison of fibrinolytic versus surgical therapy in the treatment of obstructive prosthetic valve thrombosis: a single-center experience. AB - OBJECTIVE: Prosthetic heart valve thrombosis (PVT) is a rare but severe cardiac condition. There are only a few data regarding comparison of the fibrinolytic and surgical approaches for the treatment of PVT. In this study, we compared the results of fibrinolytic therapy versus surgery in patients who presented to our institution with a diagnosis of obstructive-type PVT. METHODS: From January 2001 to August 2008 in our institution, 33 patients who met clinical and echocardiographic criteria for obstructive-type PVT were included in the study. Fifteen of these patients underwent fibrinolytic treatment with streptokinase, which consisted of an initial bolus of 250,000 U followed by 100,000 U/h. Eighteen patients were treated with surgery. RESULTS: The 2 groups had similar baseline characteristics, including New York Heart Association functional status, types and positions of prosthetic valves, international normalized ratio values, and presentation symptoms. Full hemodynamic success was achieved in 12 patients who underwent fibrinolytic therapy and in 15 patients in the surgery group. The mean (+/-SD) streptokinase infusion time was 17.8 +/- 11.1 hours. Two major hemorrhages and 2 cases of systemic embolism were observed in the fibrinolytic group. The 2 groups did not differ with respect to mortality rate (P = .79). The duration of hospitalization was longer in the fibrinolytic group than in the surgery group (10.7 +/- 6.6 days versus 6.9 +/- 6.7 days, P = .045). CONCLUSIONS: Although fibrinolytic therapy is generally recommended for the treatment of PVT for specific patient groups, our results suggest that it may be as efficacious and safe as surgery, depending on patient selection. PMID- 21521683 TI - Dexmedetomidine in cardiac surgery patients who fail extubation and present with a delirium state. AB - BACKGROUND: We evaluated the use of dexmedetomidine to facilitate the weaning of delirious postoperative patients from mechanical ventilation. METHODS: We included 72 consecutive patients who underwent elective cardiac surgery in this prospective observational study. Each patient had failed at least 1 trial of continuous positive airway pressure (CPAP) and had agitation. Patients were assessed with the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the Intensive Care Unit (CAMICU) 12 to 18 hours after their admission to the ICU. Midazolam and fentanyl were then given to all patients according to the sedation protocol. At 36 hours in the ICU, patients who had agitation and an inability to wean were randomly divided into 2 groups: group M, 34 patients who continued to follow the routine sedative protocol; and group D, 38 patients who were given dexmedetomidine. Arterial blood gas measurements, hemodynamic parameters, and time to extubation were recorded. Statistical analysis was performed with GraphPad InStat (version 2.02 for DOS). RESULTS: All patients tested positive in the CAM-ICU assessment, and all had a delirium diagnosis. The 38 patients in group D tolerated a spontaneous breathing trial with CPAP and were extubated after a mean (+/-SD) of 49.619 +/- 6.96 hours. The 2 groups had significantly different extubation times (58.389 +/- 3.958 hours versus 49.619 +/- 6.96 hours). The 2 groups had significantly different RASS scores at 48 and 60 hours and significantly different heart rates and PO2 values at 12 and 24 hours. The 2 groups showed no significant differences with regard to hemodynamic parameters. CONCLUSIONS: Dexmedetomidine may help to eliminate the emergence of agitation and can be a good treatment choice for the delirium state after cardiac surgery. PMID- 21521684 TI - Airway management issues in the intensive care unit: revisiting old paradigms and broadening our horizons. AB - Airway management in the intensive care setting provides unique challenges that can be quite daunting, even for the most experienced practitioner. Airways are usually intubated for long periods, multiple comorbidities often interfere with "routine" airway management practices, and patients are often physiologically disadvantaged or hemodynamically unstable. Strapped with this calamity, the first responder to a patient with an acutely compromised airway is often someone less experienced with global airway management skills. As anesthesiologists, we are very familiar with the skill sets necessary to handle these predicaments, and as intensivists, we have the fortunate opportunity to share that wealth of information and experience. Airway care in the intensive care unit is a continuum from elective or emergent intubation, to airway preservation and hygiene, to elective or unintentional extubation. Thus, familiarization with the basics of airway management in routine and "first responder" settings should bolster confidence and greatly improve patient safety and outcomes. PMID- 21521685 TI - HSP70 protein promotes survival of C6 and U87 glioma cells by inhibition of ATF5 degradation. AB - Although both the heat shock protein 70 (HSP70) and the activating transcription factor 5 (ATF5) have been shown to promote cell survival of transformed cells but not survival of non-transformed cells, the relationship of the two molecules is unknown. Here we show that HSP70 and ATF5 are concomitantly up-regulated upon transient but down-regulated over prolonged cellular stress and apoptotic stimulation in the rat C6 glioma and human U87 glioma cells. HSP70 interacts strongly with the N-terminal activation domain of ATF5, which is expected to be rigid and uniquely structured under physiological conditions because of extraordinary high concentration (over 25%) of proline residues. Binding of HSP70 to ATF5 is an ATP-driven process and requires functional ATPase on the nucleotide binding domain of the HSP70 molecule. Overexpression of HSP70 dramatically stabilizes the ATF5 protein, which is otherwise subject to rapid degradation, facilitated by both proteasome-dependent and caspase-dependent processes, whereas HSP70 depletion leads to acceleration of ATF5 degradation and transcription repression of Bcl-2 and Egr-1, which are downstream targets of ATF5 in C6 and U87 glioma cells. Our data reveal an essential role for HSP70 in maintaining high levels of ATF5 expression in glioma cells and support the conclusion that ATF5 is an important substrate protein of HSP70 that mediates HSP70-promoted cell survival in glioma cells. PMID- 21521686 TI - Quantitative analyses of cryptochrome-mBMAL1 interactions: mechanistic insights into the transcriptional regulation of the mammalian circadian clock. AB - The mammalian cryptochromes mCRY1 and mCRY2 act as transcriptional repressors within the 24-h transcription-translational feedback loop of the circadian clock. The C-terminal tail and a preceding predicted coiled coil (CC) of the mCRYs as well as the C-terminal region of the transcription factor mBMAL1 are involved in transcriptional feedback repression. Here we show by fluorescence polarization and isothermal titration calorimetry that purified mCRY1/2CCtail proteins form stable heterodimeric complexes with two C-terminal mBMAL1 fragments. The longer mBMAL1 fragment (BMAL490) includes Lys-537, which is rhythmically acetylated by mCLOCK in vivo. mCRY1 (but not mCRY2) has a lower affinity to BMAL490 than to the shorter mBMAL1 fragment (BMAL577) and a K537Q mutant version of BMAL490. Using peptide scan analysis we identify two mBMAL1 binding epitopes within the coiled coil and tail regions of mCRY1/2 and document the importance of positively charged mCRY1 residues for mBMAL1 binding. A synthetic mCRY coiled coil peptide binds equally well to the short and to the long (wild-type and K537Q mutant) mBMAL1 fragments. In contrast, a peptide including the mCRY1 tail epitope shows a lower affinity to BMAL490 compared with BMAL577 and BMAL490(K537Q). We propose that Lys-537(mBMAL1) acetylation enhances mCRY1 binding by affecting electrostatic interactions predominantly with the mCRY1 tail. Our data reveal different molecular interactions of the mCRY1/2 tails with mBMAL1, which may contribute to the non-redundant clock functions of mCRY1 and mCRY2. Moreover, our study suggests the design of peptidic inhibitors targeting the interaction of the mCRY1 tail with mBMAL1. PMID- 21521687 TI - Liver-enriched inhibitory protein (LIP) actively inhibits preadipocyte differentiation through histone deacetylase 1 (HDAC1). AB - The CCAAT/enhancer-binding protein beta (C/EBPbeta) is expressed as three isoforms (LAP*, liver-enriched activating protein (LAP), and liver-enriched inhibitory protein (LIP)) that differentially regulate gene expression. The interplay between LAP*, LAP, and LIP in regulating cellular processes is largely unknown, and LIP has been largely regarded to repress transcription through a passive heterodimerization-dependent mechanism. Recently, we have shown that p300/GCN5 and mSin3A/HDAC1 differentially regulate the ability of C/EBPbeta to stimulate preadipocyte differentiation through activation of C/ebpalpha transcription. Here, we have mapped requirements for binding of mSin3A/HDAC1 to LAP/LAP* and LIP to a 4-amino acid motif in the central region of LAP/LAP* (residues 153-156) and the N terminus of LIP. Reducing mSin3A/HDAC1 binding to LAP/LAP* and LIP through deletion of this motif reduced the recruitment of HDAC1 to the C/ebpalpha promoter and increased preadipocyte differentiation stimulated by insulin and 1-methyl-3-isobutylxanthine. Additional studies showed that the interaction of HDAC1 with LIP provides for active repression of C/ebpalpha transcription and is largely responsible for the ability of LIP and HDAC1 to repress preadipocyte differentiation. Thus, although mSin3A/HDAC1 interacted readily with LAP/LAP* in addition to LIP and that expression of LAP/LAP* was sufficient to recruit HDAC1 to the C/ebpalpha promoter, mutations in C/ebpbeta that abrogated HDAC1 association to LAP/LAP* in the absence of LIP provided no additional stimulation of differentiation or transcription beyond the deletion of LIP alone. The implication of these results for the interaction between p300/GCN5 and mSin3A/HDAC1 in regulating C/EBPalpha transcription and preadipocyte differentiation are discussed. PMID- 21521688 TI - Caloric restriction mimetic 2-deoxyglucose antagonizes doxorubicin-induced cardiomyocyte death by multiple mechanisms. AB - Caloric restriction (CR) is a dietary intervention known to enhance cardiovascular health. The glucose analog 2-deoxy-D-glucose (2-DG) mimics CR effects in several animal models. However, whether 2-DG is beneficial to the heart remains obscure. Here, we tested the ability of 2-DG to reduce cardiomyocyte death triggered by doxorubicin (DOX, 1 MUm), an antitumor drug that can cause heart failure. Treatment of neonatal rat cardiomyocytes with 0.5 mm 2 DG dramatically suppressed DOX cytotoxicity as indicated by a decreased number of cells that stained positive for propidium iodide and reduced apoptotic markers. 2 DG decreased intracellular ATP levels by 17.9%, but it prevented DOX-induced severe depletion of ATP, which may contribute to 2-DG-mediated cytoprotection. Also, 2-DG increased the activity of AMP-activated protein kinase (AMPK). Blocking AMPK signaling with compound C or small interfering RNA-mediated knockdown of the catalytic subunit markedly attenuated the protective effects of 2-DG. Conversely, AMPK activation by pharmacological or genetic approach reduced DOX cardiotoxicity but did not produce additive effects when used together with 2 DG. In addition, 2-DG induced autophagy, a cellular degradation pathway whose activation could be either protective or detrimental depending on the context. Paradoxically, despite its ability to activate autophagy, 2-DG prevented DOX induced detrimental autophagy. Together, these results suggest that the CR mimetic 2-DG can antagonize DOX-induced cardiomyocyte death, which is mediated through multiple mechanisms, including the preservation of ATP content, the activation of AMPK, and the inhibition of autophagy. PMID- 21521689 TI - The yeast plasma membrane ATP binding cassette (ABC) transporter Aus1: purification, characterization, and the effect of lipids on its activity. AB - The ATP binding cassette (ABC) transporter Aus1 is expressed under anaerobic growth conditions at the plasma membrane of the yeast Saccharomyces cerevisiae and is required for sterol uptake. These observations suggest that Aus1 promotes the translocation of sterols across membranes, but the precise transport mechanism has yet to be identified. In this study, an extraction and purification procedure was developed to characterize the Aus1 transporter. The detergent solubilized protein was able to bind and hydrolyze ATP. Mutagenesis of the conserved lysine to methionine in the Walker A motif abolished ATP hydrolysis. Likewise, ATP hydrolysis was inhibited by classical inhibitors of ABC transporters. Upon reconstitution into proteoliposomes, the ATPase activity of Aus1 was specifically stimulated by phosphatidylserine (PS) in a stereoselective manner. We also found that Aus1-dependent sterol uptake, but not Aus1 expression and trafficking to the plasma membrane, was affected by changes in cellular PS levels. These results suggest a direct interaction between Aus1 and PS that is critical for the activity of the transporter. PMID- 21521690 TI - Relevance of the branch point adenosine, coordination loop, and 3' exon binding site for in vivo excision of the Sinorhizobium meliloti group II intron RmInt1. AB - Excision of the bacterial group II intron RmInt1 has been demonstrated in vivo, resulting in the formation of both intron lariat and putative intron RNA circles. We show here that the bulged adenosine in domain VI of RmInt1 is required for splicing via the branching pathway, but branch site mutants produce small numbers of RNA molecules in which the first G residue of the intron is linked to the last C residue. Mutations in the coordination loop in domain I reduced splicing efficiency, but branched templates clearly predominated among splicing products. We also found that a single substitution at the EBS3 position (G329C), preventing EBS3-IBS3 pairing, resulted in the production of 50 to 100 times more RNA molecules in which the 5' and 3' extremities were joined. We provide evidence that these intron molecules may correspond to both, intron circles linked by a 2' 5' phosphodiester bond, and tandem, head-to-tail intron copies. PMID- 21521691 TI - Regulation of sialyl Lewis antigen expression in colon cancer cells by sialidase NEU4. AB - Sialyl Lewis antigens, sialyl Lewis a and sialyl Lewis x, are utilized as tumor markers, and their increase in cancer is associated with tumor progression by enhancement of cancer cell adhesion to endothelial E-selectin. However, regulation mechanisms are not fully understood. We previously demonstrated that NEU4 is the only sialidase efficiently acting on mucins and it is down-regulated in colon cancer. To elucidate the significance of NEU4 down-regulation, we investigated sialyl Lewis antigens as endogenous substrates for the sialidase. NEU4 was found to hydrolyze the antigens in vitro and decrease cell surface levels much more effectively than other sialidases. Western blot, thin layer chromatography, and metabolic inhibition studies of desialylation products revealed NEU4 to preferentially catalyze sialyl Lewis antigens expressed on O glycans. Cell adhesion to and motility and growth on E-selectin were significantly reduced by NEU4. E-selectin stimulation of colon cancer cells enhanced cell motility through activation of the p38/Hsp27/actin reorganization pathway, whereas NEU4 attenuated the signaling. On immunocytochemical analysis, some NEU4 molecules were localized at cell surfaces. Under hypoxia conditions whereby the antigens were increased concomitantly with several sialyl- and fucosyltransferases, NEU4 expression was markedly decreased. These results suggest that NEU4 plays an important role in control of sialyl Lewis antigen expression and its impairment in colon cancer. PMID- 21521692 TI - Cell cycle-dependent phosphorylation and ubiquitination of a G protein alpha subunit. AB - A diverse array of external stimuli, including most hormones and neurotransmitters, bind to cell surface receptors that activate G proteins. Mating pheromones in yeast Saccharomyces cerevisiae activate G protein-coupled receptors and initiate events leading to cell cycle arrest in G(1) phase. Here, we show that the Galpha subunit (Gpa1) is phosphorylated and ubiquitinated in response to changes in the cell cycle. We systematically screened 109 gene deletion strains representing the non-essential yeast kinome and identified a single kinase gene, ELM1, as necessary and sufficient for Gpa1 phosphorylation. Elm1 is expressed in a cell cycle-dependent manner, primarily at S and G(2)/M. Accordingly, phosphorylation of Gpa1 in G(2)/M phase leads to polyubiquitination in G(1) phase. These findings demonstrate that Gpa1 is dynamically regulated. More broadly, they reveal how G proteins can simultaneously regulate, and become regulated by, progression through the cell cycle. PMID- 21521693 TI - Loss of mitogen-activated protein kinase phosphatase-1 protects from hepatic steatosis by repression of cell death-inducing DNA fragmentation factor A (DFFA) like effector C (CIDEC)/fat-specific protein 27. AB - The integration of metabolic signals required for the regulation of hepatic lipid homeostasis is complex. Previously, we showed that mice lacking expression of the mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) have increased fatty acid oxidation and are protected from the development of hepatic steatosis. Here, we show that leptin receptor-deficient (db/db) mice lacking MKP-1 are also resistant to the development of hepatic steatosis. Microarray analyses of livers from db/db mice lacking MKP-1 showed suppression of peroxisome proliferator activated receptor gamma (PPARgamma) target genes. We identified the fat-specific protein 27 (Fsp27), which promotes PPARgamma-mediated hepatic steatosis, as repressed in livers of both db/db and high fat diet-fed mice lacking MKP-1. Hepatocytes from MKP-1-deficient mice exhibited reduced PPARgamma-induced lipid droplet formation. Mechanistically, loss of MKP-1 inhibited PPARgamma function by increasing MAPK-dependent phosphorylation on PPARgamma at its inhibitory residue of serine 112. These results demonstrate that in addition to inhibiting hepatic fatty acid oxidation, MKP-1 promotes hepatic lipogenic gene expression through PPARgamma. Hence, MKP-1 plays an important role in MAPK-mediated control of hepatic lipid homeostasis. PMID- 21521694 TI - Streptococcus pyogenes M49 plasminogen/plasmin binding facilitates keratinocyte invasion via integrin-integrin-linked kinase (ILK) pathways and protects from macrophage killing. AB - The entry into epithelial cells and the prevention of primary immune responses are a prerequisite for a successful colonization and subsequent infection of the human host by Streptococcus pyogenes (group A streptococci, GAS). Here, we demonstrate that interaction of GAS with plasminogen promotes an integrin mediated internalization of the bacteria into keratinocytes, which is independent from the serine protease activity of potentially generated plasmin. alpha(1)beta(1)- and alpha(5)beta(1)-integrins were identified as the major keratinocyte receptors involved in this process. Inhibition of integrin-linked kinase (ILK) expression by siRNA silencing or blocking of PI3K and Akt with specific inhibitors, reduced the GAS M49-plasminogen/plasmin-mediated invasion of keratinocytes. In addition, blocking of actin polymerization significantly reduced GAS internalization into keratinocytes. Altogether, these results provide a first model of plasminogen-mediated GAS invasion into keratinocytes. Furthermore, we demonstrate that plasminogen binding protects the bacteria against macrophage killing. PMID- 21521695 TI - Sortilin associates with transforming growth factor-beta family proteins to enhance lysosome-mediated degradation. AB - Transforming growth factor (TGF)-beta family proteins are synthesized as precursors that are cleaved to generate an active ligand. Previous studies suggest that TGF-beta activity can be controlled by lysosomal degradation of both precursor proteins and ligands, but how these soluble proteins are trafficked to the lysosome is incompletely understood. The current studies show that sortilin selectively co-immunoprecipitates with the cleaved prodomain and/or precursor form of TGF-beta family members. Furthermore, sortilin co-localizes with, and enhances accumulation of a nodal family member in the Golgi. Co-expression of sortilin with TGF-beta family members leads to decreased accumulation of precursor proteins and cleavage products and this is attenuated by lysosomal, but not proteosomal inhibitors. In Xenopus embryos, overexpression of sortilin leads to a decrease in phospho-Smad2 levels and phenocopies loss of nodal signaling. Conversely, down-regulation of sortilin expression in HeLa cells leads to an up regulation of endogenous bone morphogenic protein pathway activation, as indicated by an increase in phospho-Smad1/5/8 levels. Our results suggest that sortilin negatively regulates TGF-beta signaling by diverting trafficking of precursor proteins to the lysosome during transit through the biosynthetic pathway. PMID- 21521696 TI - TNO1 is involved in salt tolerance and vacuolar trafficking in Arabidopsis. AB - The Arabidopsis (Arabidopsis thaliana) soluble N-ethylmaleimide-sensitive factor attachment protein receptor SYP41 is involved in vesicle fusion at the trans Golgi network (TGN) and interacts with AtVPS45, SYP61, and VTI12. These proteins are involved in diverse cellular processes, including vacuole biogenesis and stress tolerance. A previously uncharacterized protein, named TNO1 (for TGN localized SYP41-interacting protein), was identified by coimmunoprecipitation as a SYP41-interacting protein. TNO1 was found to localize to the TGN by immunofluorescence microscopy. A tno1 mutant showed increased sensitivity to high concentrations of NaCl, KCl, and LiCl and also to mannitol-induced osmotic stress. Localization of SYP61, which is involved in the salt stress response, was disrupted in the tno1 mutant. Vacuolar proteins were partially secreted to the apoplast in the tno1 mutant, suggesting that TNO1 is required for efficient protein trafficking to the vacuole. The tno1 mutant had delayed formation of the brefeldin A (BFA) compartment in cotyledons upon application of BFA, suggesting less efficient membrane fusion processes in the mutant. Unlike most TGN proteins, TNO1 does not relocate to the BFA compartment upon BFA treatment. These data demonstrate that TNO1 is involved in vacuolar trafficking and salt tolerance, potentially via roles in vesicle fusion and in maintaining TGN structure or identity. PMID- 21521697 TI - A conserved, Mg2+-dependent exonuclease degrades organelle DNA during Arabidopsis pollen development. AB - In plant cells, mitochondria and plastids contain their own genomes derived from the ancestral bacteria endosymbiont. Despite their limited genetic capacity, these multicopy organelle genomes account for a substantial fraction of total cellular DNA, raising the question of whether organelle DNA quantity is controlled spatially or temporally. In this study, we genetically dissected the organelle DNA decrease in pollen, a phenomenon that appears to be common in most angiosperm species. By staining mature pollen grains with fluorescent DNA dye, we screened Arabidopsis thaliana for mutants in which extrachromosomal DNAs had accumulated. Such a recessive mutant, termed defective in pollen organelle DNA degradation1 (dpd1), showing elevated levels of DNAs in both plastids and mitochondria, was isolated and characterized. DPD1 encodes a protein belonging to the exonuclease family, whose homologs appear to be found in angiosperms. Indeed, DPD1 has Mg2+-dependent exonuclease activity when expressed as a fusion protein and when assayed in vitro and is highly active in developing pollen. Consistent with the dpd phenotype, DPD1 is dual-targeted to plastids and mitochondria. Therefore, we provide evidence of active organelle DNA degradation in the angiosperm male gametophyte, primarily independent of maternal inheritance; the biological function of organellar DNA degradation in pollen is currently unclear. PMID- 21521698 TI - Arabidopsis thaliana high-affinity phosphate transporters exhibit multiple levels of posttranslational regulation. AB - In Arabidopsis thaliana, the PHOSPHATE TRANSPORTER1 (PHT1) family encodes the high-affinity phosphate transporters. They are transcriptionally induced by phosphate starvation and require PHOSPHATE TRANSPORTER TRAFFIC FACILITATOR (PHF1) to exit the endoplasmic reticulum (ER), indicating intracellular traffic as an additional level of regulation of PHT1 activity. Our study revealed that PHF1 acts on PHT1, upstream of vesicle coat protein COPII formation, and that additional regulatory events occur during PHT1 trafficking and determine its ER exit and plasma membrane stability. Phosphoproteomic and mutagenesis analyses revealed modulation of PHT1;1 ER export by Ser-514 phosphorylation status. Confocal microscopy analysis of root tip cells showed that PHT1;1 is localized to the plasma membrane and is present in intracellular endocytic compartments. More precisely, PHT1;1 was localized to sorting endosomes associated with prevacuolar compartments. Kinetic analysis of PHT1;1 stability and targeting suggested a modulation of PHT1 internalization from the plasma membrane to the endosomes, followed by either subsequent recycling (in low Pi) or vacuolar degradation (in high Pi). For the latter condition, we identified a rapid mechanism that reduces the pool of PHT1 proteins present at the plasma membrane. This mechanism is regulated by the Pi concentration in the medium and appears to be independent of degradation mechanisms potentially regulated by the PHO2 ubiquitin conjugase. We propose a model for differential trafficking of PHT1 to the plasma membrane or vacuole as a function of phosphate concentration. PMID- 21521699 TI - Improving surgical outpatient efficiency through mobile phone text messaging. AB - INTRODUCTION: Currently, 175,000 people are on outpatient waiting lists in Irish hospitals. Many clinic slots are taken by patients returning for routine review postoperatively. METHODS: A Nokia mobile phone was used to send an outpatient text (OPT) to patients 2 weeks postdischarge. Patients replying that they were well were discharged. If no reply after 2 attempts was received, they were scheduled for the next outpatient clinic. RESULTS: Overall, 55 patients were offered the service over a 4-month period. Of these, 74.5% of patients were discharged from follow-up using text message surveillance. Patients were surveyed regarding their perception of the surveillance model, with all respondents ranking OPT surveillance as their preferred method of follow-up. There was a 13.6% decrease in outpatient visits over the study period. In addition, 6 emergency department visits were also avoided. CONCLUSION: Text message surveillance decreases outpatient waiting times and increases quality of care. PMID- 21521700 TI - Emergency transumbilical single-incision laparoscopic splenectomy for the treatment of traumatic rupture of the spleen: report of the first case and literature review. AB - AIM: The authors report 1 case of emergency splenectomy for the treatment of traumatic rupture of the spleen where a laparoendoscopic single-site surgery technique was performed. METHOD: A 17-year-old male with a diagnosis of traumatic rupture of the spleen underwent emergency transumbilical single-incision laparoscopic splenectomy. Three ports, including 5 mm and 10 mm ports, were placed through a transumbilical incision for the procedure. RESULTS: Intraoperative and postoperative courses were uneventful. The patient was discharged home 8 days after the surgery in a stable condition. Discussion. The Laparoendoscopic single site surgery technique is still in its infancy, but because of its reduced invasion and ideal aesthetic results, it is well received by patients. Improvements are needed to widen its application. CONCLUSION: To the authors' knowledge, this is the first report where an emergency laparoendoscopic single site surgery technique has been used in the management of a ruptured spleen. PMID- 21521701 TI - Understanding early functional recovery after robotic prostatectomy. AB - OBJECTIVES: The time to regain urinary control and sexual function after robotic assisted prostatectomy varies widely. The authors performed a study to prospectively assess relationships between intraoperative processes and early functional recovery after surgery. METHODS: Prostate cancer patients undergoing robotic prostatectomy prospectively completed questionnaires (Expanded Prostate Cancer Index Composite-Short Form, Sexual Health Inventory for Men) preoperatively and at 3 months postoperatively. Relationships between intraoperative processes and early recovery were measured using multiple logistic regression. RESULTS: At 3 months, 73.9% and 29.7% of patients had recovered urinary and sexual function, respectively. Bladder neck preservation was associated with early recovery of both urinary and sexual function (P < .01). The quality of nerve sparing (P = .01), seminal vesicle sparing (P = .03), and the use of urethral suspension (P = .04) were associated with early recovery of sexual function. CONCLUSIONS: Early functional recovery for patients undergoing robotic-assisted prostatectomy varies by both patient characteristics and process measures. The causal link between intraoperative processes and patient outcomes merits further study through quality improvement collaboratives. PMID- 21521702 TI - Transumbilical single-incision laparoscopic resection of ileocecal junction for benign disease: first report of two cases. AB - BACKGROUND: Transumbilical single-incision laparoscopic surgery (TUSILS) has emerged as an advanced technique for minimally invasive surgery. Recently, the authors performed TUSIL resection of the ileocecal junction for benign lesions. METHODS: The authors report the surgical technique and clinical effect of TUSIL resection of the ileocecal junction in 2 patients. RESULTS: The 2 operations were completely successful with satisfactory and scarless recovery. No postoperative complications occurred. CONCLUSIONS: TUSIL resection of the ileocecal junction was feasible and safe in the 2 patients and might lead to an expansion of the indications for TUSILS. PMID- 21521703 TI - Clinical activity of anti-Gram-positive agents against methicillin-resistant Staphylococcus aureus. AB - Current concerns about multiresistance and a diminishing antibiotic pipeline are mainly addressed to Gram-negative bacteria. The greatest fear within the Gram positive arena is vancomycin-resistant Staphylococcus aureus. Its epidemiology and clinical presentation give cause for concern, but so far its impact has been strictly limited. While this may change, the loss of glycopeptides as a treatment option may not, in fact, be all bad news. PMID- 21521704 TI - Clinical experience with linezolid in infants and children. AB - The worldwide spread of multidrug-resistant organisms has required the development of new antimicrobials. Linezolid, the first oxazolidinone, has a broad spectrum of activity against Gram-positive bacteria, including resistant strains. Although approved by the Food and Drug Administration in 2002, the clinical experience with linezolid in the paediatric population is still limited, also given the fact that in most European countries the paediatric use of linezolid is off-label. In this paper we summarize the actual evidence on both licensed and off-label clinical uses of linezolid in children, including efficacy, safety and tolerability issues. Taking into account the potential bias in comparing heterogeneous clinical trials and reports, the available literature data suggest that linezolid is a safe and effective agent for the treatment of serious Gram-positive bacterial infections in neonates and children. At present, linezolid is reserved for those children who are intolerant to or fail conventional agents. A linezolid-containing regimen can be a valuable option for treating multidrug-resistant and extensively drug-resistant tuberculosis in children as well as disseminated non-tuberculous mycobacterial infections. Given the rare occurrence of serious side effects, careful monitoring of haematological parameters, possible drug interactions and neurological manifestations is recommended in linezolid-treated children, especially in case of prolonged treatments. Appropriate linezolid dosage and hospital infection control measures are essential to avoid the spread of linezolid resistance. Further studies are needed to establish novel paediatric indications for linezolid use and to assess the tolerability of long-term treatments. PMID- 21521705 TI - Linezolid: safety and efficacy in special populations. AB - Linezolid has been in general use in the UK since 2000. Although toxicity, particularly haematological and neurological, has been an issue, linezolid has proved to be an effective alternative to glycopeptides in the treatment of Gram positive infections. Since its original licence for the treatment of skin and soft tissue infections and pneumonia, there have been reports of its successful use in the treatment of bone and joint infections, endocarditis, and other difficult-to-treat infections. PMID- 21521706 TI - Methicillin-resistant Staphylococcus aureus: the European landscape. AB - Pan-European surveillance of bacteraemia caused by methicillin-resistant Staphylococcus aureus (MRSA) shows it to be a problem affecting all European countries, although there is marked geographical variation in prevalence. Although the proportion of S. aureus bacteraemia due to MRSA is declining in many countries, data from the European Antimicrobial Resistance Surveillance System (EARSS) for 2008 showed that in more than one-third of countries the proportion remained >25%. In contrast to bacteraemia, community-associated MRSA infection in Europe remains relatively uncommon. However, there appears to be an increasing problem involving transmission of MRSA (particularly sequence type 398) from colonized livestock, particularly pigs, to farm workers, abattoir workers and veterinarians who are in contact with such animals. Molecular analysis of isolates of MRSA has shown that there has been spread of only a limited number of MRSA clones in Europe and that many of these clones show geographical clustering due to dissemination through regional healthcare networks. Despite our increasing understanding of the epidemiology of MRSA in Europe, MRSA infections continue to pose a significant public health challenge. PMID- 21521707 TI - Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. AB - Linezolid has been widely used in the treatment of Gram-positive infections for more than a decade. It is unique amongst antibiotics active against most multiply resistant Gram-positive bacteria in that there is an oral preparation with 100% bioavailability and an extensive volume of distribution. This review examines pharmacokinetic data relating to linezolid use in different patient groups (obesity, enteral feeding, renal failure, neonates, and paediatrics) and in different clinical conditions (sepsis syndrome, skin and soft tissue infection, diabetic foot infection, pneumonia, bone and joint infection, infection of the central nervous system, eye infection, and neutropenic sepsis). PMID- 21521708 TI - Active commuting to and from school among Swedish children--a national and regional study. AB - BACKGROUND: Active commuting to school by walking or cycling can have positive impact on children's health and development. The study investigates the prevalence of active commuting to school in Sweden, a setting where it is facilitated and promoted; and how active commuting varies according to socio demographic and socio-economic characteristics. METHODS: Self-reports from a national sample of Swedish children (11- to 15-year-olds, n = 4415) and a regional one from Stockholm County (13-year-olds, n = 1008) on transport to school were compared. The association that active commuting has with socio demographic (gender, school grade, Swedish origin, type of housing, urbanicity in the local area), and socio-economic characteristics (household socio-economic status, family car ownership) was studied using logistic regression, controlling for car ownership and urbanicity, respectively. RESULTS: Active commuting was high (62.9% in the national sample) but decreased with age-76% at the age of 11 years, 62% at the age of 13 years and 50% at the age of 15 years-whereas public transport increased (19-43%). Living in an apartment or row-house (compared with detached house) and living in a medium-sized city (compared with a metropolitan area) was associated with active commuting. In urban areas, active commuting was more common in worker households compared with intermediate- to high-level salaried employees. CONCLUSION: Active commuting is common but decreases with age. Active commuting differed based on housing and urbanicity but not based on gender or Swedish origin, and impact of socio-economic factors differed depending on level of urbanicity. PMID- 21521709 TI - Managing unused pharmaceuticals in a hospice setting: a pilot study. AB - With the escalating use of pharmaceuticals in health care, there has been increasing anxiety over the potential health risks associated with pharmaceutical waste accumulating in the environment. This research provided nurses in a hospice care facility in Concord, California, with education and training to offer patients a medication disposal service through the use of mail-back envelopes. Over the 6-month study period, 160 of the 400 distributed mailers were returned for disposal. The total weight of pharmaceuticals diverted for incineration was 107 pounds, with an average weight of 0.66 pounds per mailer. This study suggests that the mailer system and proper education of medical staff have the potential to improve medical waste management, but alternative approaches may be necessary to increase the rate of envelop return. PMID- 21521710 TI - Taking care of a dying grandparent: case studies of grandchildren in the hospice caregiver role. AB - This study aims to provide insight into the role of grandchildren as informal hospice caregivers. It presents 4 cases that highlight the challenges and perceptions of grandchildren who care for a grandparent at the end of life. A researcher met regularly with family caregivers to discuss the problems or challenges during hospice caregiving. Although each caregiver presented unique individual experiences, several themes are common among the family caregivers including fatigue, stress, guilt, and loss of the "grandchild" identity. Grandchildren caregivers often take care of 3 generations (grandparents, parents, and children) and in many cases need additional assistance to help them overcome the challenges associated with managing a household, career, family, and caregiving roles. PMID- 21521711 TI - Naturally occurring, tumor-specific, therapeutic proteins. AB - The emerging approach to cancer treatment known as targeted therapies offers hope in improving the treatment of therapy-resistant cancers. Recent understanding of the molecular pathogenesis of cancer has led to the development of targeted novel drugs such as monoclonal antibodies, small molecule inhibitors, mimetics, antisense and small interference RNA-based strategies, among others. These compounds act on specific targets that are believed to contribute to the development and progression of cancers and resistance of tumors to conventional therapies. Delivered individually or combined with chemo- and/or radiotherapy, such novel drugs have produced significant responses in certain types of cancer. Among the most successful novel compounds are those which target tyrosine kinases (imatinib, trastuzumab, sinutinib, cetuximab). However, these compounds can cause severe side-effects as they inhibit pathways such as epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor, which are also important for normal functions in non-transformed cells. Recently, a number of proteins have been identified which show a remarkable tumor-specific cytotoxic activity. This toxicity is independent of tumor type or specific genetic changes such as p53, pRB or EGFR aberrations. These tumor-specific killer proteins are either derived from common human and animal viruses such as E1A, E4ORF4 and VP3 (apoptin) or of cellular origin, such as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and MDA-7 (melanoma differentiation associated-7). This review aims to present a current overview of a selection of these proteins with preferential toxicity among cancer cells and will provide an insight into the possible mechanism of action, tumor specificity and their potential as novel tumor-specific cancer therapeutics. PMID- 21521712 TI - Vascular rhexis in mice subjected to non-sustained myocardial ischemia and its therapeutic implications. AB - We previously described the death of vascular cells (vascular rhexis) following persistent coronary occlusion. The present study was designed to determine whether non-sustained ischemia can initiate vascular rhexis and if so, whether relatively brief ischemic insults are sufficient. C57BL6 mice were subjected to coronary ligation for 15 min or 3 h followed by reperfusion. Soluble fractions of left ventricular (LV) homogenates were obtained 48 h after the onset of transitory coronary occlusion. They were assayed by Western blotting for quantification of alpha smooth muscle actin (alpha-SMA) and smooth muscle myosin heavy chain (SM-MHC) that we have shown reflect vascular rhexis delineated immunohistochemically. Non-sustained coronary occlusion for 3 h initiated vascular rhexis evident 45 h after reperfusion, but not earlier, as judged from Western blotting of alpha-SMA and SM-MHC. The number of small- and medium-sized vessels in the previously ischemic zones was reduced at 45 h after reperfusion as well. Thus, vascular rhexis occurs after ischemia as brief as 3 h but evolves slowly and is not evident for 45 h. The delayed disintegration of the vasculature makes it likely that it can be ameliorated by interventions initiated after non sustained ischemia, rendering it an attractive target for diminution of phenomena such as late negative LV remodeling, and 'no reflow.' PMID- 21521713 TI - Adiponectin reduces proteinuria in streptozotocin-induced diabetic Wistar rats. AB - The aim of the paper is to investigate the effects of adiponectin in diabetic nephropathy; we used an adenovirus to over-express adiponectin (Ad-Adipo) in streptozotocin (STZ)-induced diabetic rats. Animals were injected with either Ad Adipo or control Ad-lacZ at 10 weeks after STZ treatment, and at two weeks postadenovirus injection, renal function was assessed. The degree of proteinuria was significantly reduced in Ad-Adipo rats compared with Ad-lacZ rats. Consistent with this, the mRNA expression levels of nephrin and transforming growth factor beta (TGF-beta) were significantly increased and decreased in the renal cortex of Ad-Adipo rats, respectively. Moreover, adiponectin over-expression in STZ rats decreased markers of endothelial dysfunction, a feature of diabetic nephropathy disease progression. Endothelin 1 (ET-1), plasminogen activator inhibitor 1 (PAI 1) and inducible nitric oxide synthase (iNOS) mRNA expression levels were significantly reduced in the renal cortex of Ad-Adipo rats, respectively. Concurrently, mRNA expression levels of endothelial nitric oxide synthase (eNOS), a positive regulator of endothelial function, were significantly increased in the renal cortex of Ad-Adipo rats. We have shown that chronic hyperadiponectinemia significantly alleviated the progression of proteinuria in early stage diabetic nephropathy. The mechanism whereby adiponectin decreases proteinuria involves an increase in nephrin expression, and an improvement of the endothelial dysfunction due to decreases in ET-1 and PAI-1, and an increase in eNOS expression in the renal cortex. Thus, over-expression of adiponectin has beneficial effects on early stage diabetic nephropathy. PMID- 21521714 TI - Premature aging with impaired oxidative stress defense in mice lacking TR4. AB - Early studies suggest that TR4 nuclear receptor is a key transcriptional factor regulating various biological activities, including reproduction, cerebella development, and metabolism. Here we report that mice lacking TR4 (TR4(-/-)) exhibited increasing genome instability and defective oxidative stress defense, which are associated with premature aging phenotypes. At the cellular level, we observed rapid cellular growth arrest and less resistance to oxidative stress and DNA damage in TR4(-/-) mouse embryonic fibroblasts (MEFs) in vitro. Restoring TR4 or supplying the antioxidant N-acetyl-l-cysteine (NAC) to TR4(-/-) MEFs reduced the DNA damage and slowed down cellular growth arrest. Focused qPCR array revealed alteration of gene profiles in the DNA damage response (DDR) and anti reactive oxygen species (ROS) pathways in TR4(-/-) MEFs, which further supports the hypothesis that the premature aging in TR4(-/-) mice might stem from oxidative DNA damage caused by increased oxidative stress or compromised genome integrity. Together, our finding identifies a novel role of TR4 in mediating the interplay between oxidative stress defense and aging. PMID- 21521715 TI - Secretoneurin stimulates the production and release of luteinizing hormone in mouse L{beta}T2 gonadotropin cells. AB - Secretoneurin (SN) is a functional secretogranin II (SgII)-derived peptide that stimulates luteinizing hormone (LH) production and its release in the goldfish. However, the effects of SN on the pituitary of mammalian species and the underlying mechanisms remain poorly understood. To study SN in mammals, we adopted the mouse LbetaT2 gonadotropin cell line that has characteristics consistent with normal pituitary gonadotrophs. Using radioimmunoassay and real time RT-PCR, we demonstrated that static treatment with SN induced a significant increment of LH release and production in LbetaT2 cells in vitro. We found that GnRH increased cellular SgII mRNA level and total SN-immunoreactive protein release into the culture medium. We also report that SN activated the extracellular signal-regulated kinases (ERK) in either 10-min acute stimulation or 3-h chronic treatment. The SN-induced ERK activation was significantly blocked by pharmacological inhibition of MAPK kinase (MEK) with PD-98059 and protein kinase C (PKC) with bisindolylmaleimide. SN also increased the total cyclic adenosine monophosphate (cAMP) levels similarly to GnRH. However, SN did not activate the GnRH receptor. These data indicate that SN activates the protein kinase A (PKA) and cAMP-induced ERK signaling pathways in the LH-secreting mouse LbetaT2 pituitary cell line. PMID- 21521716 TI - Protection from diabetes development by single-chain antibody-mediated delivery of a NF-kappaB inhibitor specifically to beta-cells in vivo. AB - Recently, we reported the generation of single-chain antibodies (SCAs) highly specific for rodent and human beta-cells. Our current report describes the generation of a fusion protein of one of these SCAs (SCA B1) with a NF-kappaB essential modifier (NEMO)-binding domain (NBD) peptide, thereby creating a selective inhibitor of NF-kappaB activation in beta-cells. The SCA B1-NBD fusion protein was cloned in the pIRES-EGFP, expressed in bacteria, and purified by metal affinity chromatography; the newly generated complex was then administered intravenously to rodents and evaluated for its ability to protect beta-cells against cytokines in vitro and diabetogenic agents in vivo. First, it was shown clearly that our SCA B1-NBD fusion protein binds highly selective to CD rat beta cells in vivo. Second, we observed that SCA B1-mediated in vivo delivery of the NBD peptide completely blocked IL-1beta + IFNgamma- and TNFalpha + IFNgamma mediated induction of NF-kappaB as well as islet dysfunction in culture. Finally, repeated intravenous injection of SCA B1-NBD prior to multiple low-dose administration of streptozotocin in CD mice not only induced a striking resistance to diabetes development but also preserved beta-cell mass. In conclusion, our data show for the first time that a SCA B1-NBD fusion peptide reliably protects beta-cells against cytokines in vitro and allows protection from diabetes development in CD mice in vivo. PMID- 21521717 TI - Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. AB - Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance. PMID- 21521718 TI - Liver X receptors regulate de novo lipogenesis in a tissue-specific manner in C57BL/6 female mice. AB - The liver X receptors (LXRs) play a key role in cholesterol and bile acid metabolism but are also important regulators of glucose metabolism. Recently, LXRs have been proposed as a glucose sensor affecting LXR-dependent gene expression. We challenged wild-type (WT) and LXRalphabeta(-/-) mice with a normal diet (ND) or a high-carbohydrate diet (HCD). Magnetic resonance imaging showed different fat distribution between WT and LXRalphabeta(-/-) mice. Surprisingly, gonadal (GL) adipocyte volume decreased on HCD compared with ND in WT mice, whereas it slightly increased in LXRalphabeta(-/-) mice. Interestingly, insulin stimulated lipogenesis of isolated GL fat cells was reduced on HCD compared with ND in LXRalphabeta(-/-) mice, whereas no changes were observed in WT mice. Net de novo lipogenesis (DNL) calculated from Vo(2) and Vco(2) was significantly higher in LXRalphabeta(-/-) than in WT mice on HCD. Histology of HCD-fed livers showed hepatic steatosis in WT mice but not in LXRalphabeta(-/-) mice. Glucose tolerance was not different between groups, but insulin sensitivity was decreased by the HCD in WT but not in LXRalphabeta(-/-) mice. Finally, gene expression analysis of adipose tissue showed induced expression of genes involved in DNL in LXRalphabeta(-/-) mice compared with WT animals as opposed to the liver, where expression of DNL genes was repressed in LXRalphabeta(-/-) mice. We thus conclude that absence of LXRs stimulates DNL in adipose tissue, but suppresses DNL in the liver, demonstrating opposite roles of LXR in DNL regulation in these two tissues. These results show tissue-specific regulation of LXR activity, a crucial finding for drug development. PMID- 21521719 TI - Salt sensitivity in experimental thyroid disorders in rats. AB - This study assessed salt sensitivity, analyzing the effects of an increased saline intake on hemodynamic, morphological, and oxidative stress and renal variables in experimental thyroid disorders. Six groups of male Wistar rats were used: control, hypothyroid, hyperthyroid, and the same groups treated with salt (8% via food intake). Body weight, blood pressure (BP), and heart rate (HR) were recorded weekly for 6 wk. Finally, BP and HR were recorded directly, and morphological, metabolic, plasma, and renal variables were measured. High-salt intake increased BP in thyroxine-treated rats but not in control or hypothyroid rats. High-salt intake increased cardiac mass in all groups, with a greater increase in hyperthyroid rats. Urinary isoprostanes and H(2)O(2) were higher in hyperthyroid rats and were augmented by high-salt intake in all groups, especially in hyperthyroid rats. High-salt intake reduced plasma thyroid hormone levels in hyperthyroid rats. Proteinuria was increased in hyperthyroid rats and aggravated by high-salt intake. Urinary levels of aminopeptidases (glutamyl-, alanyl-, aspartyl-, and cystinylaminopeptidase) were increased in hyperthyroid rats. All aminopeptidases were increased by salt intake in hyperthyroid rats but not in hypothyroid rats. In summary, hyperthyroid rats have enhanced salt sensitivity, and high-salt intake produces increased BP, cardiac hypertrophy, oxidative stress, and signs of renal injury. In contrast, hypothyroid rats are resistant to salt-induced BP elevation and renal injury signs. Urinary aminopeptidases are suitable biomarkers of renal injury. PMID- 21521720 TI - Highlighting relatedness promotes prosocial motives and behavior. AB - According to self-determination theory, people have three basic psychological needs: relatedness, competence, and autonomy. Of these, the authors reasoned that relatedness need satisfaction is particularly important for promoting prosocial behavior because of the increased sense of connectedness to others that this engenders. In Experiment 1, the authors manipulated relatedness, autonomy, competence, or gave participants a neutral task, and found that highlighting relatedness led to higher interest in volunteering and intentions to volunteer relative to the other conditions. Experiment 2 found that writing about relatedness experiences promoted feelings of connectedness to others, which in turn predicted greater prosocial intentions. Experiment 3 found that relatedness manipulation participants donated significantly more money to charity than did participants given a neutral task. The results suggest that highlighting relatedness increases engagement in prosocial activities and are discussed in relation to the conflict and compatibility between individual and social outcomes. PMID- 21521721 TI - Humor in romantic contexts: do men participate and women evaluate? AB - Several lines of research illustrate that humor plays a pivotal role in relationship initiation. The current article applies sexual selection theory to argue that humor production is a fitness indicator, allowing men to transmit information tacitly about their underlying qualities. And whereas prior research has emphasized women's appreciation of humor as a signal of interest, the focus here is on how women evaluate prospective suitors' humorous offerings. Two studies, including an ecologically valid study of online dating advertisements, provided evidence for men's production and women's evaluation of humor in romantic contexts. A third study revealed that women's evaluations of potential mates' humor are predictive of their romantic interest. Moreover, this article shows that preferences for and perceptions of humor are associated with preferences for and perceptions of intelligence and warmth, consistent with the argument that one function of humor is as a fitness indicator that provides information about underlying mate quality. PMID- 21521723 TI - Taking the gonococcus-human relationship to a whole new level: implications for the coevolution of microbes and humans. AB - While horizontal gene transfer occurs frequently among bacterial species, evidence for the transfer of DNA from host to microbe is exceptionally rare. However, the recent report by Anderson and Seifert [mBio 2(1):e00005-11, 2011] provides evidence for such an event with the finding that 11% of Neisseria gonorrhoeae strains harbor a 685-bp sequence that is 98 to 100% identical to the human long interspersed nuclear element L1. While the function of this element in gonococci remains unclear, this finding significantly impacts our consideration of the coevolution of hosts and microbes, particularly that of humans and pathogens. PMID- 21521724 TI - Oropharyngeal cancer: clinical implications of the HPV connection. PMID- 21521725 TI - Reply to Benefit of cytoreductive nephrectomy in metastatic RCC: do we learn from retrospective studies and small prospective studies? PMID- 21521726 TI - Coronary heart disease and cerebrovascular disease mortality in young adults: recent trends in Europe. AB - BACKGROUND: Over the last two decades, mortality from coronary heart disease (CHD) and cerebrovascular disease (CVD) declined by about 30% in the European Union (EU). DESIGN: We analyzed trends in CHD (X ICD codes: I20-I25) and CVD (X ICD codes: I60-I69) mortality in young adults (age 35-44 years) in the EU as a whole and in 12 selected European countries, over the period 1980-2007. METHODS: Data were derived from the World Health Organization mortality database. With joinpoint regression analysis, we identified significant changes in trends and estimated average annual percent changes (AAPC). RESULTS: CHD mortality rates at ages 35-44 years have decreased in both sexes since the 1980s for most countries, except for Russia (130/100,000 men and 24/100,000 women, in 2005-7). The lowest rates (around 9/100,000 men, 2/100,000 women) were in France, Italy and Sweden. In men, the steepest declines in mortality were in the Czech Republic (AAPC = 6.1%), the Netherlands (-5.2%), Poland (-4.5%), and England and Wales (-4.5%). Patterns were similar in women, though with appreciably lower rates. The AAPC in the EU was -3.3% for men (rate = 16.6/100,000 in 2005-7) and -2.1% for women (rate = 3.5/100,000). For CVD, Russian rates in 2005-7 were 40/100,000 men and 16/100,000 women, 5 to 10-fold higher than in most western European countries. The steepest declines were in the Czech Republic and Italy for men, in Sweden and the Czech Republic for women. The AAPC in the EU was -2.5% in both sexes, with steeper declines after the mid-late 1990s (rates = 6.4/100,000 men and 4.3/100,000 women in 2005-7). CONCLUSIONS: CHD and CVD mortality steadily declined in Europe, except in Russia, whose rates were 10 to 15-fold higher than those of France, Italy or Sweden. Hungary and Poland, and also Scotland, where CHD trends were less favourable than in other western European countries, also emerge as priorities for preventive interventions. PMID- 21521727 TI - Penetration of a fractured Bird's Nest filter strut into the liver parenchyma: report of two cases. AB - This report deals with two rare but similar cases of asymptomatic fracture of a Bird's Nest inferior vena cava (IVC) filter strut, penetrated into the liver parenchyma. Follow-up over 4 and 6 years, respectively, could not reveal any changes in the position of the fragmented strut in the liver parenchyma or any evidence of clinical symptoms owing to the migrated strut fragment. PMID- 21521728 TI - Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials. AB - OBJECTIVES: To evaluate the cardiovascular outcomes and other outcomes associated with angiotensin receptor blockers. DESIGN: Systematic review of randomised controlled trials with meta-analysis and trial sequential analysis (TSA). DATA SOURCES AND STUDY SELECTION: Pubmed, Embase, and CENTRAL searches for randomised clinical trials, until August 2010, of angiotensin receptor blockers compared with controls (placebo/active treatment) that enrolled at least 100 participants and had a follow-up of at least one year. DATA EXTRACTION: Myocardial infarction, death, cardiovascular death, angina pectoris, stroke, heart failure, and new onset diabetes. RESULTS: 37 randomised clinical trials included 147,020 participants and had a total follow-up of 485,166 patient years. When compared with controls (placebo/active treatment), placebo, or active treatment, angiotensin receptor blockers were not associated with an increase in the risk of myocardial infarction (relative risk 0.99, 95% confidence interval 0.92 to 1.07), death, cardiovascular death, or angina pectoris. Compared with controls, angiotensin receptor blockers were associated with a reduction in the risk of stroke (0.90, 0.84 to 0.98), heart failure (0.87, 0.81 to 0.93), and new onset diabetes (0.85, 0.78 to 0.93), with similar results when compared with placebo or with active treatment. Based on trial sequential analysis, there is no evidence even for an average 5.0-7.5% (upper confidence interval 5-11%) relative increase in myocardial infarction (absolute increase of 0.3%), death, or cardiovascular death with firm evidence for relative risk reduction of stroke (at least 1%, average 10%) (compared with placebo only), heart failure (at least 5%, average 10%), and new onset diabetes (at least 4%, average 10%) with angiotensin receptor blockers compared with controls. CONCLUSIONS: This large and comprehensive analysis produced firm evidence to refute the hypothesis that angiotensin receptor blockers increase the risk of myocardial infarction (ruling out even a 0.3% absolute increase). Compared with controls, angiotensin receptor blockers reduce the risk of stroke, heart failure, and new onset diabetes. PMID- 21521730 TI - Hysterectomy, endometrial ablation, and levonorgestrel releasing intrauterine system (Mirena) for treatment of heavy menstrual bleeding: cost effectiveness analysis. AB - OBJECTIVE: To undertake a cost effectiveness analysis comparing first and second generation endometrial ablative techniques, hysterectomy, and the levonorgestrel releasing intrauterine system (Mirena) for treating heavy menstrual bleeding. DESIGN: Model based economic evaluation with data from an individual patient data meta-analysis supplemented with cost and outcome data from published sources taking an NHS (National Health Service) perspective. A state transition (Markov) model was developed, the structure being informed by the reviews of the trials and clinical input. A subgroup analysis, one way sensitivity analysis, and probabilistic sensitivity analysis were also carried out. POPULATION: Four hypothetical cohorts of women with heavy menstrual bleeding. INTERVENTIONS: One of four alternative strategies: Mirena, first or second generation endometrial ablation techniques, or hysterectomy. MAIN OUTCOME MEASURES: Cost effectiveness based on incremental cost per quality adjusted life year (QALY). RESULTS: Hysterectomy is the preferred strategy for the first intervention for heavy menstrual bleeding. Although hysterectomy is more expensive, it produces more QALYs relative to other remaining strategies and is likely to be considered cost effective. The incremental cost effectiveness ratio for hysterectomy compared with Mirena is L1440 (?1633, $2350) per additional QALY. The incremental cost effectiveness ratio for hysterectomy compared with second generation ablation is L970 per additional QALY. CONCLUSION: In light of the acceptable thresholds used by the National Institute for Health and Clinical Excellence, hysterectomy would be considered the preferred strategy for the treatment of heavy menstrual bleeding. The results concur with those of other studies but are highly sensitive to utility values used in the analysis. PMID- 21521731 TI - Chernobyl 25 years on. PMID- 21521732 TI - Food price crises and health. PMID- 21521736 TI - FatJ acts via the Hippo mediator Yap1 to restrict the size of neural progenitor cell pools. AB - The size, composition and functioning of the spinal cord is likely to depend on appropriate numbers of progenitor and differentiated cells of a particular class, but little is known about how cell numbers are controlled in specific cell cohorts along the dorsoventral axis of the neural tube. Here, we show that FatJ cadherin, identified in a large-scale RNA interference (RNAi) screen of cadherin genes expressed in the neural tube, is localised to progenitors in intermediate regions of the neural tube. Loss of function of FatJ promotes an increase in dp4 vp1 progenitors and a concomitant increase in differentiated Lim1(+)/Lim2(+) neurons. Our studies reveal that FatJ mediates its action via the Hippo pathway mediator Yap1: loss of downstream Hippo components can rescue the defect caused by loss of FatJ. Together, our data demonstrate that RNAi screens are feasible in the chick embryonic neural tube, and show that FatJ acts through the Hippo pathway to regulate cell numbers in specific subsets of neural progenitor pools and their differentiated progeny. PMID- 21521735 TI - Principles of planar polarity in animal development. AB - Planar polarity describes the coordinated polarisation of cells or structures in the plane of a tissue. The patterning mechanisms that underlie planar polarity are well characterised in Drosophila, where many events are regulated by two pathways: the 'core' planar polarity complex and the Fat/Dachsous system. Components of both pathways also function in vertebrates and are implicated in diverse morphogenetic processes, some of which self-evidently involve planar polarisation and some of which do not. Here, we review the molecular mechanisms and cellular consequences of planar polarisation in diverse contexts, seeking to identify the common principles across the animal kingdom. PMID- 21521737 TI - Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by a Gata3-Raldh2-Ret molecular network in mice. AB - Urinary tract development depends on a complex series of events in which the ureter moves from its initial branch point on the nephric duct (ND) to its final insertion site in the cloaca (the primitive bladder and urethra). Defects in this maturation process can result in malpositioned ureters and hydronephrosis, a common cause of renal disease in children. Here, we report that insertion of the ND into the cloaca is an unrecognized but crucial step that is required for proper positioning of the ureter and that depends on Ret signaling. Analysis of Ret mutant mice at birth reveals hydronephrosis and defective ureter maturation, abnormalities that our results suggest are caused, at least in part, by delayed insertion of the ND. We find a similar set of malformations in mutants lacking either Gata3 or Raldh2. We show that these factors act in parallel to regulate ND insertion via Ret. Morphological analysis of ND extension in wild-type embryos reveals elaborate cellular protrusions at ND tips that are not detected in Ret, Gata3 or Raldh2 mutant embryos, suggesting that these protrusions may normally be important for fusion with the cloaca. Together, our studies reveal a novel Ret dependent event, ND insertion, that, when abnormal, can cause obstruction and hydronephrosis at birth; whether ND defects underlie similar types of urinary tract abnormalities in humans is an interesting possibility. PMID- 21521738 TI - p120 catenin is required for normal renal tubulogenesis and glomerulogenesis. AB - Defects in the development or maintenance of tubule diameter correlate with polycystic kidney disease. Here, we report that absence of the cadherin regulator p120 catenin (p120ctn) from the renal mesenchyme prior to tubule formation leads to decreased cadherin levels with abnormal morphologies of early tubule structures and developing glomeruli. In addition, mutant mice develop cystic kidney disease, with markedly increased tubule diameter and cellular proliferation, and detached luminal cells only in proximal tubules. The p120ctn homolog Arvcf is specifically absent from embryonic proximal tubules, consistent with the specificity of the proximal tubular phenotype. p120ctn knockdown in renal epithelial cells in 3D culture results in a similar cystic phenotype with reduced levels of E-cadherin and active RhoA. We find that E-cadherin knockdown, but not RhoA inhibition, phenocopies p120ctn knockdown. Taken together, our data show that p120ctn is required for early tubule and glomerular morphogenesis, as well as control of luminal diameter, probably through regulation of cadherins. PMID- 21521739 TI - Flt1 acts as a negative regulator of tip cell formation and branching morphogenesis in the zebrafish embryo. AB - Endothelial tip cells guide angiogenic sprouts by exploring the local environment for guidance cues such as vascular endothelial growth factor (VegfA). Here we present Flt1 (Vegf receptor 1) loss- and gain-of-function data in zebrafish showing that Flt1 regulates tip cell formation and arterial branching morphogenesis. Zebrafish embryos expressed soluble Flt1 (sFlt1) and membrane bound Flt1 (mFlt1). In Tg(flt1(BAC):yfp) * Tg(kdrl:ras-cherry)(s916) embryos, flt1:yfp was expressed in tip, stalk and base cells of segmental artery sprouts and overlapped with kdrl:cherry expression in these domains. flt1 morphants showed increased tip cell numbers, enhanced angiogenic behavior and hyperbranching of segmental artery sprouts. The additional arterial branches developed into functional vessels carrying blood flow. In support of a functional role for the extracellular VEGF-binding domain of Flt1, overexpression of sflt1 or mflt1 rescued aberrant branching in flt1 morphants, and overexpression of sflt1 or mflt1 in controls resulted in short arterial sprouts with reduced numbers of filopodia. flt1 morphants showed reduced expression of Notch receptors and of the Notch downstream target efnb2a, and ectopic expression of flt4 in arteries, consistent with loss of Notch signaling. Conditional overexpression of the notch1a intracellular cleaved domain in flt1 morphants restored segmental artery patterning. The developing nervous system of the trunk contributed to the distribution of Flt1, and the loss of flt1 affected neurons. Thus, Flt1 acts in a Notch-dependent manner as a negative regulator of tip cell differentiation and branching. Flt1 distribution may be fine-tuned, involving interactions with the developing nervous system. PMID- 21521740 TI - Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity. AB - The facial branchiomotor neurons (FBMNs) undergo a characteristic tangential migration in the vertebrate hindbrain. We previously used a morpholino knockdown approach to reveal that zebrafish prickle1b (pk1b) is required for this migration. Here we report that FBMN migration is also blocked in a pk1b mutant with a disruption in the consensus farnesylation motif. We confirmed that this lipid modification is required during FBMN migration by disrupting the function of farnesyl biosynthetic enzymes. Furthermore, farnesylation of a tagged Pk1b is required for its nuclear localization. Using a unique rescue approach, we have demonstrated that Pk1b nuclear localization and farnesylation are required during FBMN migration. Our data suggest that Pk1b acts at least partially independently of core planar cell polarity molecules at the plasma membrane, and might instead be acting at the nucleus. We also found that the neuronal transcriptional silencer REST is necessary for FBMN migration, and we provide evidence that interaction between Pk1b and REST is required during this process. Finally, we demonstrate that REST protein, which is normally localized in the nuclei of migrating FBMNs, is depleted from the nuclei of Pk1b-deficient neurons. We conclude that farnesylation-dependent nuclear localization of Pk1b is required to regulate REST localization and thus FBMN migration. PMID- 21521741 TI - The nucleoporin Seh1 forms a complex with Mio and serves an essential tissue specific function in Drosophila oogenesis. AB - The nuclear pore complex (NPC) mediates the transport of macromolecules between the nucleus and cytoplasm. Recent evidence indicates that structural nucleoporins, the building blocks of the NPC, have a variety of unanticipated cellular functions. Here, we report an unexpected tissue-specific requirement for the structural nucleoporin Seh1 during Drosophila oogenesis. Seh1 is a component of the Nup107-160 complex, the major structural subcomplex of the NPC. We demonstrate that Seh1 associates with the product of the missing oocyte (mio) gene. In Drosophila, mio regulates nuclear architecture and meiotic progression in early ovarian cysts. Like mio, seh1 has a crucial germline function during oogenesis. In both mio and seh1 mutant ovaries, a fraction of oocytes fail to maintain the meiotic cycle and develop as pseudo-nurse cells. Moreover, the accumulation of Mio protein is greatly diminished in the seh1 mutant background. Surprisingly, our characterization of a seh1 null allele indicates that, although required in the female germline, seh1 is dispensable for the development of somatic tissues. Our work represents the first examination of seh1 function within the context of a multicellular organism. In summary, our studies demonstrate that Mio is a novel interacting partner of the conserved nucleoporin Seh1 and add to the growing body of evidence that structural nucleoporins can have novel tissue-specific roles. PMID- 21521742 TI - Acupuncture does not influence brainstem auditory evoked potentials: a volunteer crossover study. AB - BACKGROUND: Although acupuncture is effective for treating several conditions, its site specificity is questionable. OBJECTIVE: To investigate whether acupuncture influences the brainstem auditory evoked potentials (BAEP). METHODS: 10 healthy volunteers were enrolled according to inclusion criteria. One of four acupuncture points-TE3, GB43 (both auditory system-specific, according to traditional Chinese medicine) and non-specific acupuncture points HT7 and ST44 was needled during each session. Each volunteer received four sessions of acupuncture, with a 1-week interval between the sessions. RESULTS: Peak latencies and amplitudes of the BAEP were registered before and during each session of acupuncture. Pain intensity and the incidence of paraesthesia (Qi sensation) during acupuncture were also registered. The peak latencies and amplitudes of the BAEP registered during acupuncture had not changed from the baseline levels. Needling of acupoint HT7 was most painful and induced the maximal incidence of Qi sensation. CONCLUSIONS: Findings suggest that monitoring the BAEP is not a suitable technique for studying the immediate effects of acupuncture. PMID- 21521743 TI - A role for the cysteine-rich 10 kDa prolamin in protein body I formation in rice. AB - The rice prolamins consist of cysteine-rich 10 kDa (CysR10), 14 kDa (CysR14) and 16 kDa (CysR16) molecular species and a cysteine-poor 13 kDa (CysP13) polypeptide. These storage proteins form protein bodies (PBs) composed of single spherical intracisternal inclusions assembled within the lumen of the rough endoplasmic reticulum. Immunofluorescence and immunoelectron microscopy demonstrated that CysR10 and CysP13 were asymmetrically distributed within the PBs, with the former concentrated at the electron-dense center core region and the latter distributed mainly to the electron-lucent peripheral region. These results together with temporal expression data showed that the formation of prolamin-containing PB-I in the wild-type endosperm was initiated by the accumulation of CysR10 to form the center core. In mutants deficient for cysteine rich prolamins, the typical PB-I structures containing the electron-dense center core were not observed, and instead were replaced by irregularly shaped, electron lucent, hypertrophied PBs. Similar, deformed PBs were observed in a CysR10 RNA interference plant line. These results suggest that CysR10, through its formation of the central core and its possible interaction with other cysteine-rich prolamins, is required for tight packaging of the proteins into a compact spherical structure. PMID- 21521744 TI - Pharmacologic inhibition of ALK5 causes selective induction of terminal differentiation in mouse keratinocytes expressing oncogenic HRAS. AB - TGFbeta has both tumor suppressive and oncogenic roles in cancer development. We previously showed that SB431542 (SB), a small molecule inhibitor of the TGFbeta type I receptor (ALK5) kinase, suppressed benign epidermal tumor formation but enhanced malignant conversion. Here, we show that SB treatment of primary K5rTA/tetORASV12G bitransgenic keratinocytes did not alter HRASV12G-induced keratinocyte hyperproliferation. However, continuous SB treatment significantly enhanced HRASV12G-induced cornified envelope formation and cell death linked to increased expression of enzymes transglutaminase (TGM) 1 and TGM3 and constituents of the cornified envelope small proline-rich protein (SPR) 1A and SPR2H. In contrast, TGFbeta1 suppressed cornified envelope formation in HRASV12G keratinocytes. Similar results were obtained in HRASV12G transgenic mice treated topically with SB or by coexpressing TGFbeta1 and HRASV12G in the epidermis. Despite significant cell death, SB-resistant HRASV12G keratinocytes repopulated the primary culture that had overcome HRas-induced senescence. These cells expressed reduced levels of p16(ink4a) and were growth stimulated by SB but remained sensitive to a calcium-induced growth arrest. Together these results suggest that differential responsiveness to cornification may represent a mechanism by which pharmacologic blockade of TGFbeta signaling can inhibit the outgrowth of preneoplastic lesions but may cause a more progressed phenotype in a separate keratinocyte population. PMID- 21521745 TI - Phosphoproteomic screen identifies potential therapeutic targets in melanoma. AB - Therapies directed against receptor tyrosine kinases are effective in many cancer subtypes, including lung and breast cancer. We used a phosphoproteomic platform to identify active receptor tyrosine kinases that might represent therapeutic targets in a panel of 25 melanoma cell strains. We detected activated receptors including TYRO3, AXL, MERTK, EPHB2, MET, IGF1R, EGFR, KIT, HER3, and HER4. Statistical analysis of receptor tyrosine kinase activation as well as ligand and receptor expression indicates that some receptors, such as FGFR3, may be activated via autocrine circuits. Short hairpin RNA knockdown targeting three of the active kinases identified in the screen, AXL, HER3, and IGF1R, inhibited the proliferation of melanoma cells and knockdown of active AXL also reduced melanoma cell migration. The changes in cellular phenotype observed on AXL knockdown seem to be modulated via the STAT3 signaling pathway, whereas the IGF1R-dependent alterations seem to be regulated by the AKT signaling pathway. Ultimately, this study identifies several novel targets for therapeutic intervention in melanoma. PMID- 21521746 TI - Impaired CNS leptin action is implicated in depression associated with obesity. AB - Recent epidemiological studies indicate that obesity increases the incidence of depression. We examined the implication of leptin for obesity-associated depression. Leptin induced antidepressive behavior in normal mice in a forced swimming test (FST), and leptin-overexpressing transgenic mice with hyperleptinemia exhibited more antidepressive behavior in the FST than nontransgenic mice. In contrast, leptin-deficient ob/ob mice showed more severe depressive behavior in the FST than normal mice, and leptin administration substantially ameliorated this depressive behavior. Diet-induced obese (DIO) mice fed a high-fat diet showed more depressive behavior in the FST and in a sucrose preference test compared with mice fed a control diet (CD). In DIO mice, leptin induced neither antidepressive action nor increment of the number of c-Fos immunoreactive cells in the hippocampus. Diet substitution from high-fat diet to CD in DIO mice ameliorated the depressive behavior and restored leptin-induced antidepressive action. Brain-derived neurotrophic factor concentrations in the hippocampus were significantly lower in DIO mice than in CD mice. Leptin administration significantly increased hippocampal brain-derived neurotrophic factor concentrations in CD mice but not in DIO mice. The antidepressant activity of leptin in CD mice was significantly attenuated by treatment with K252a. These findings demonstrated that leptin induces an antidepressive state, and DIO mice, which exhibit severe depressive behavior, did not respond to leptin in both the FST and the biochemical changes in the hippocampus. Thus, depression associated with obesity is due, at least in part, to impaired leptin activity in the hippocampus. PMID- 21521747 TI - Glucose regulates cyclin D2 expression in quiescent and replicating pancreatic beta-cells through glycolysis and calcium channels. AB - Understanding the molecular triggers of pancreatic beta-cell proliferation may facilitate the development of regenerative therapies for diabetes. Genetic studies have demonstrated an important role for cyclin D2 in beta-cell proliferation and mass homeostasis, but its specific function in beta-cell division and mechanism of regulation remain unclear. Here, we report that cyclin D2 is present at high levels in the nucleus of quiescent beta-cells in vivo. The major regulator of cyclin D2 expression is glucose, acting via glycolysis and calcium channels in the beta-cell to control cyclin D2 mRNA levels. Furthermore, cyclin D2 mRNA is down-regulated during S-G(2)-M phases of each beta-cell division, via a mechanism that is also affected by glucose metabolism. Thus, glucose metabolism maintains high levels of nuclear cyclin D2 in quiescent beta cells and modulates the down-regulation of cyclin D2 in replicating beta-cells. These data challenge the standard model for regulation of cyclin D2 during the cell division cycle and suggest cyclin D2 as a molecular link between glucose levels and beta-cell replication. PMID- 21521748 TI - Insulinotropic and antidiabetic effects of 17beta-estradiol and the GPR30 agonist G-1 on human pancreatic islets. AB - We have recently shown that 17beta-estradiol (E2) and the synthetic G protein coupled receptor 30 (GPR30) ligand G-1 have antiapoptotic actions in mouse pancreatic islets, raising the prospect that they might exert beneficial effects also in human islets. The objective of the present study was to identify the expression of GPR30 in human islets and clarify the role of GPR30 in islet hormone secretion and beta-cell survival. GPR30 expression was analyzed by confocal microscopy, Western blot, and quantitative PCR in islets from female and male donors. Hormone secretion, phosphatidylinositol hydrolysis, cAMP content, and caspase-3 activity in female islets were determined with conventional methods and apoptosis with the annexin-V method. Confocal microscopy revealed GPR30 expression in islet insulin, glucagon, and somatostatin cells. GPR30 mRNA and protein expression was markedly higher in female vs. male islets. An amplifying effect of G-1 or E2 on cAMP content and insulin secretion from isolated female islets was not influenced by the E2 genomic receptor (ERalpha and ERbeta) antagonists ICI 182,780 and EM-652. Cytokine-induced (IL-1beta plus TNFalpha plus interferon-gamma) apoptosis in islets cultured for 24 h at 5 mmol/liter glucose was almost abolished by G-1 or E2 treatment and was not affected by the nuclear estrogen receptor antagonists. Concentration-response studies on female islets from healthy controls and type 2 diabetic subjects showed that both E2 and G-1 displayed important antidiabetic actions by improving glucose-stimulated insulin release while suppressing glucagon and somatostatin secretion. In view of these findings, we propose that small molecules activating GPR30 could be promising in the therapy of diabetes mellitus. PMID- 21521749 TI - Active and total transforming growth factor-beta1 are differentially regulated by dopamine and estradiol in the pituitary. AB - Dopamine, acting through the dopamine type 2 receptor (Drd2), is the main inhibitor of pituitary prolactin (PRL) secretion and lactotroph proliferation. TGF-beta1 is involved, at least in part, in mediating these actions. It was described that TGF-beta1 synthesis in rat pituitary lactotrophs is up-regulated by dopamine and down-regulated by estradiol. TGF-beta1 is secreted as a large latent complex. The local regulation of cytokine activation in the pituitary has not yet been explored. In this work, we studied pituitary active and total TGF beta1 content, as well as TGF-beta1 mRNA, and the in vivo role of dopamine and estradiol on pituitary TGF-beta1 levels. Adult female mice (wild type), and female mice with a null mutation in the Drd2 (Drd2(-/-)), were used. The loss of dopaminergic tone induced a decrease in TGF-beta1 mRNA expression, in active and total cytokine content, and in TGF-beta type II receptor expression. Dopamine regulation of pituitary TGF-beta1 activation process was inferred by the inhibition of active cytokine by in vivo sulpiride treatment. Interestingly, in the absence of dopaminergic tone, estradiol induced a strong increase in active TGF-beta1. PRL secretion correlated with active, but not total cytokine. TGF beta1 inhibitory action on lactotroph proliferation and PRL secretion was decreased in Drd2(-/-) pituitary cells, in correlation with decreased TGF-beta type II receptor. The study of the TGF-beta1 activation process and its regulation is essential to understand the cytokine activity. As an intermediary of dopamine inhibition of lactotroph function, TGF-beta1 and local activators may be important targets in the treatment of dopamine agonist-resistant prolactinomas. PMID- 21521750 TI - Oxytocin and dopamine stimulate ghrelin secretion by the ghrelin-producing cell line, MGN3-1 in vitro. AB - To understand the physiological role of ghrelin, it is crucial to study both the actions of ghrelin and the regulation of ghrelin secretion. Although ghrelin actions have been extensively revealed, the direct factors regulating ghrelin secretion by ghrelin-producing cells (X/A-like cells), however, is not fully understood. In this study, we examined the effects of peptide hormones and neurotransmitters on in vitro ghrelin secretion by the recently developed ghrelin producing cell line MGN3-1. Oxytocin and vasopressin significantly stimulated ghrelin secretion by MGN3-1 cells. Because MGN3-1 cells express only oxytocin receptor mRNA, not vasopressin receptor mRNA, oxytocin is the likely regulator, with the effect of vasopressin mediated by a cross-reaction. We also discovered that dopamine stimulates ghrelin secretion from MGN3-1 cells in a similar manner to the previously known ghrelin stimulators, epinephrine and norepinephrine. MGN3 1 cells expressed mRNA encoding dopamine receptors D1a and D2. The dopamine receptor D1 agonist fenoldopam stimulated ghrelin secretion, whereas the D2, D3 agonist bromocriptine did not. Furthermore, the D1 receptor antagonist SKF83566 attenuated the stimulatory effect of dopamine. These results indicate that the stimulatory effect of dopamine on ghrelin secretion is mediated by the D1a receptor. In conclusion, we identified two direct regulators of ghrelin, oxytocin and dopamine. These findings will provide new direction for further studies seeking to further understand the regulation of ghrelin secretion, which will in turn lead to greater understanding of the physiological role of ghrelin. PMID- 21521751 TI - Metabolic sensing and the brain: who, what, where, and how? AB - Unique subpopulations of specialized metabolic sensing neurons reside in a distributed network throughout the brain and respond to alterations in ambient levels of various metabolic substrates by altering their activity. Variations in local brain substrate levels reflect their transport across the blood- and cerebrospinal-brain barriers as well as local production by astrocytes. There are a number of mechanisms by which such metabolic sensing neurons alter their activity in response to changes in substrate levels, but it is clear that these neurons cannot be considered in isolation. They are heavily dependent on astrocyte and probably tanycyte metabolism and function but also respond to hormones (e.g. leptin and insulin) and cytokines that cross the blood-brain barrier from the periphery as well as hard-wired neural inputs from metabolic sensors in peripheral sites such as the hepatic portal vein, gastrointestinal tract, and carotid body. Thus, these specialized neurons are capable of monitoring and integrating multiple signals from the periphery as a means of regulating peripheral energy homeostasis. PMID- 21521753 TI - Increased hepatic insulin sensitivity in mice lacking inhibitory leptin receptor signals. AB - Leptin regulates food intake and energy expenditure by activating the long form of the leptin receptor (LepRb). Leptin also regulates glucose homeostasis by improving whole-body insulin sensitivity, but the mechanism remains undefined. Leptin action is mediated by phosphorylation of several tyrosine residues on LepRb. LepRb-Tyr985 plays an important role in the attenuation of LepRb signaling. We determined the contribution of LepRb-Tyr985-mediated signals to leptin action on insulin sensitivity using LepRb-Tyr985 mutant mice (l/l mice). Glucose tolerance and whole-body insulin-mediated glucose utilization were determined in wild-type (+/+) and l/l mice. Glucose tolerance was unaltered between female +/+ and l/l mice but enhanced in the male l/l mice. Serum insulin concentration was decreased at baseline and 15 min after a glucose injection in female l/l vs. +/+ mice (P < 0.05) but unaltered in the male l/l mice. However, basal and insulin-stimulated glucose transport in isolated soleus and extensor digitorum longus muscle was similar between +/+ and l/l mice, indicating skeletal muscle insulin sensitivity in vitro was not enhanced. Moreover, euglycemic hyperinsulinemic clamps reveal hepatic, rather than peripheral, insulin sensitivity is enhanced in female l/l mice, whereas male l/l mice display both improved hepatic and peripheral insulin sensitivity. In conclusion, signals emanating from leptin receptor Tyr985 control hepatic insulin sensitivity in both female and male l/l mice. Lack of LepRb-Tyr985 signaling enhances whole-body insulin sensitivity partly through increased insulin action on the suppression of hepatic glucose production. PMID- 21521752 TI - Ambient temperature and 17beta-estradiol modify Fos immunoreactivity in the median preoptic nucleus, a putative regulator of skin vasomotion. AB - Estrogen has pronounced effects on thermoregulation, but the anatomic sites of integration between the reproductive and thermoregulatory axes are unknown. In this study, we tested whether estradiol-17beta (E(2)) treatment would alter the activity of thermoregulatory brain regions responding to mild changes in ambient temperature (T(AMBIENT)). Core and tail skin temperatures were recorded at the ambient temperatures of 20, 24, or 31 C in ovariectomized (OVX) rats with and without E(2). Neuronal activity was evaluated by counting the number of Fos immunoreactive cells in the brains of rats killed 90 min after exposure to one of the three ambient temperatures. Of 14 brain areas examined, the median preoptic nucleus (MnPO) was the only site that exhibited increased Fos immunoreactivity at the high T(AMBIENT) of 31 C. At 24 C, OVX rats exhibited increased numbers of MnPO Fos-immunoreactive cells, compared with OVX + E(2) rats. Interestingly, tail skin vasomotion and MnPO Fos expression were affected in a similar manner by T(AMBIENT) and E(2) treatment. In the arcuate nucleus and anteroventral periventricular nucleus (AVPV), Fos immunoreactivity was highest at the low T(AMBIENT) of 20 C, with inhibitory (arcuate nucleus) and stimulatory (AVPV) effects of E(2). No other areas responded to both T(AMBIENT) and E(2) treatment. These results implicate the MnPO, the arcuate nucleus, and the AVPV as sites of integration between the reproductive and thermoregulatory axes. Combined with studies showing the importance of MnPO neurons in heat-defense pathways, the MnPO emerges as a likely site for E(2) modulation of thermoregulatory vasomotion. PMID- 21521754 TI - Presentation of lipopeptide by dendritic cells induces anti-tumor responses via an endocytosis-independent pathway in vivo. AB - Cross-presentation by DCs is the major mechanism by which exogenous antigens activate CTLs. However, the mechanisms of entry and presentation of vaccine peptides by DCs remain unclear. In this study, we determined that the mechanisms of antigen presentation differed between nonlipidated and monopalmitoylated peptide antigens. We found that a nonlipidated long peptide could be taken up by DCs and that the peptide could be colocalized with early endosomes. The uptake of nonlipidated peptides by DCs was inhibited at low temperatures or by the depolymerization of actin filaments or microtubules. In contrast, lipidated peptides were internalized by DCs at low temperatures, and internalization was not inhibited when actin filaments or microtubules were depolymerized. Moreover, lipidated peptide, but not nonlipidated peptide, was internalized by nonphagocytic Jurkat cells. The endosomal/lysosomal and proteasomal degradation pathways were necessary for nonlipidated presentation leading to the activation of CD8(+) T cells, but the proteasomal degradation pathway alone was sufficient to process lipidated peptides for MHC class I presentation. We further found that lipidated peptides could enhance peptide-specific T cell responses in vitro and in vivo and induced stronger antitumor responses than nonlipidated peptides. Taken together, our results demonstrate that DCs present lipidated peptides through an endocytosis-independent pathway to promote strong anti-tumor effects in vivo. PMID- 21521755 TI - Interleukin-17A differentially modulates BCG induction of cytokine production in human blood macrophages. AB - The pathogenesis of Mtb depends in part on cytokine cross-regulation between macrophages and T cells in host immunity. Th17 cells produce IL-17A to induce granuloma formation and to restrict mycobacterial dissemination. IL-17A also mediates cytokine responses induced by proinflammatory cytokines such as TNF alpha. Our previous results showed that BCG induces IL-6, IL-10, and TNF-alpha via activity of protein kinases, including dsRNA-activated serine/threonine protein kinase and glycogen synthase kinase-3 in primary human monocytes. Therefore, we investigated whether IL-17A, upon its induction by BCG, plays an additional role to aid the production of downstream proinflammatory cytokines in macrophages. Here, we showed that IL-17A enhanced IL-6 mRNA and protein levels inducible by BCG in a time- and dose-dependent manner, whereas it had no effect on IL-10 and TNF-alpha production. We also demonstrated that IL-17A activated the phosphorylation of ERK1/2 triggered by BCG. With the use of a specific chemical inhibitor of a MAPK/ERK-activating kinase (MEK1/2), we confirmed the correlation between the enhanced ERK1/2 activation and augmented IL-6 production. Additionally, we revealed that IL-17A acts in concert with BCG-induced TNF-alpha to enhance the level of IL-6 synthesis. Taken together, our results suggest a significant role of IL-17A to serve as a modulator of cytokine expression in innate immune response during mycobacterial infection. PMID- 21521756 TI - The fusimotor and reafferent origin of the sense of force and weight. AB - Signals associated with the command the brain sends to muscles are thought to create the sensation of heaviness when we lift an object. Thus, as a muscle is weakened by fatigue or partial paralysis (neuromuscular blockade), the increase in the motor command needed to lift a weight is thought to explain the increasing subjective heaviness of the lifted object.With different fatiguing contractions we approximately halved the force output of the thumb flexor muscles, which were then used to lift an object. For two deafferented subjects the perceived heaviness of the lifted object approximately doubled, in keeping with the central signal theory. However, for normal subjects this resulted in objects feeling the same or lighter, inconsistent with the central-signal theory but consistent with the expected effects of the conditioning contractions on the sensitivity of peripheral receptors. In separate experiments we subjected the forearm muscles to complete paralysis with a non-depolarising neuromuscular blocking agent and then allowed them to recover to approximately half-force output. This also resulted in objects feeling lighter when lifted by the semi-paralysed thumb, even though the motor command to the motoneurons must have been greater. This is readily explained by reduced lift-related reafference caused by the prolonged paralysis of muscle spindle intrafusal fibres.We conclude that peripheral signals, including a major contribution from muscle spindles, normally give rise to the sense of exerted force. In concept, however, reafference from peripheral receptors may also be considered a centrally generated signal that traverses efferent and then afferent pathways to feed perceptual centres rather than one confined entirely to the central nervous system. These results therefore challenge the distinction between central- and peripheral-based perception, and the concept that muscle spindles provide only information about limb position and movement. PMID- 21521757 TI - Brain glycogen decreases during prolonged exercise. AB - Brain glycogen could be a critical energy source for brain activity when the glucose supply from the blood is inadequate (hypoglycaemia). Although untested, it is hypothesized that during prolonged exhaustive exercise that induces hypoglycaemia and muscular glycogen depletion, the resultant hypoglycaemia may cause a decrease in brain glycogen. Here,we tested this hypothesis and also investigated the possible involvement of brain monoamines with the reduced levels of brain glycogen. For this purpose,we exercised male Wistar rats on a treadmill for different durations (30-120 min) at moderate intensity (20 m min-1) and measured their brain glycogen levels using high-power microwave irradiation (10 kW). At the end of 30 and 60 min of running, the brain glycogen levels remained unchanged from resting levels, but liver and muscle glycogen decreased. After 120 min of running, the glycogen levels decreased significantly by ~37-60% in five discrete brain loci (the cerebellum 60%, cortex 48%, hippocampus 43%, brainstem 37% and hypothalamus 34%) compared to those of the sedentary control. The brain glycogen levels in all five regions after running were positively correlated with the respective blood and brain glucose levels. Further, in the cortex, the levels of methoxyhydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA), potential involved in degradation of the brain glycogen, increased during prolonged exercise and negatively correlated with the glycogen levels. These results support the hypothesis that brain glycogen could decrease with prolonged exhaustive exercise. Increased monoamines together with hypoglycaemia should be associated with the development of decreased brain glycogen, suggesting a new clue towards the understanding of central fatigue during prolonged exercise. PMID- 21521758 TI - The cerebrovascular response to carbon dioxide in humans. AB - Carbon dioxide (CO2) increases cerebral blood flow and arterial blood pressure. Cerebral blood flow increases not only due to the vasodilating effect of CO2 but also because of the increased perfusion pressure after autoregulation is exhausted. Our objective was to measure the responses of both middle cerebral artery velocity (MCAv) and mean arterial blood pressure (MAP) to CO2 in human subjects using Duffin-type isoxic rebreathing tests. Comparisons of isoxic hyperoxic with isoxic hypoxic tests enabled the effect of oxygen tension to be determined. During rebreathing the MCAv response to CO2 was sigmoidal below a discernible threshold CO2 tension, increasing from a hypocapnic minimum to a hypercapnic maximum. In most subjects this threshold corresponded with the CO2 tension at which MAP began to increase. Above this threshold both MCAv and MAP increased linearly with CO2 tension. The sigmoidal MCAv response was centred at a CO2 tension close to normal resting values (overall mean 36 mmHg). While hypoxia increased the hypercapnic maximum percentage increase in MCAv with CO2 (overall means from76.5 to 108%) it did not affect other sigmoid parameters. Hypoxia also did not alter the supra-threshold MCAv and MAP responses to CO2 (overall mean slopes 5.5% mmHg-1 and 2.1 mmHg mmHg-1, respectively), but did reduce the threshold (overall means from 51.5 to 46.8 mmHg). We concluded that in the MCAv response range below the threshold for the increase of MAP with CO2, the MCAv measurement reflects vascular reactivity to CO2 alone at a constant MAP. PMID- 21521759 TI - Carbon monoxide: an emerging regulator of ion channels. AB - Carbon monoxide is rapidly emerging as an important cellular messenger, regulating a wide range of physiological processes. Crucial to its role in both physiology and disease is its ability differentially to regulate several classes of ion channels, including examples from calcium-activated K(+) (BK(Ca)), voltage activated K(+) (K(v)) and Ca(2+) channel (L-type) families, ligand-gated P2X receptors (P2X2 and P2X4), tandem P domain K(+) channels (TREK1) and the epithelial Na(+) channel (ENaC). The mechanisms by which CO regulates these ion channels are still unclear and remain somewhat controversial. However, available structure-function studies suggest that a limited range of amino acid residues confer CO sensitivity, either directly or indirectly, to particular ion channels and that cellular redox state appears to be important to the final integrated response. Whatever the molecular mechanism by which CO regulates ion channels, endogenous production of this gasotransmitter has physiologically important roles and is currently being explored as a potential therapeutic. PMID- 21521760 TI - SK2 channel expression and function in cerebellar Purkinje cells. AB - Small-conductance calcium-activated K(+) channels (SK channels) regulate the excitability of neurons and their responsiveness to synaptic input patterns. SK channels contribute to the afterhyperpolarization (AHP) following action potential bursts, and curtail excitatory postsynaptic potentials (EPSPs) in neuronal dendrites. Here we review evidence that SK2 channels are expressed in rat cerebellar Purkinje cells during development and throughout adulthood, and play a key role in diverse cellular processes such as the regulation of the spike firing frequency and the modulation of calcium transients in dendritic spines. In Purkinje cells as well as in other types of neurons, SK2 channel plasticity seems to provide an important mechanism allowing these cells to adjust their intrinsic excitability and to alter the probabilities for the induction of synaptic learning correlates, such as long-term potentiation (LTP). PMID- 21521761 TI - The mysterious microcircuitry of the cerebellar nuclei. AB - The microcircuitry of cerebellar cortex and, in particular, the physiology of its main element, the Purkinje neuron, has been extensively investigated and described. However, activity in Purkinje neurons, either as single cells or populations, does not directly mediate the cerebellar effects on the motor effector systems. Rather, the result of the entire cerebellar cortical computation is passed to the relatively small cerebellar nuclei that act as the final, integrative processing unit in the cerebellar circuitry. The nuclei ultimately control the temporal and spatial features of the cerebellar output. Given this key role, it is striking that the internal organization and the connectivity with afferent and efferent pathways in the cerebellar nuclei are rather poorly known. In the present review, we discuss some of the many critical shortcomings in the understanding of cerebellar nuclei microcircuitry: the extent of convergence and divergence of the cerebellar cortical pathway to the various cerebellar nuclei neurons and subareas, the possible (lack of) conservation of the finely-divided topographical organization in the cerebellar cortex at the level of the nuclei, as well as the absence of knowledge of the synaptic circuitry within the cerebellar nuclei. All these issues are important for predicting the pattern-extraction and encoding capabilities of the cerebellar nuclei and, until resolved, theories and models of cerebellar motor control and learning may err considerably. PMID- 21521762 TI - Robust L-type calcium current expression following heterozygous knockout of the Cav1.2 gene in adult mouse heart. AB - Mechanisms that contribute to maintaining expression of functional ion channels at relatively constant levels following perturbations of channel biosynthesis are likely to contribute significantly to the stability of electrophysiological systems in some pathological conditions. In order to examine the robustness of L type calcium current expression, the response to changes in Ca2+ channel Cav1.2 gene dosage was studied in adult mice. Using a cardiac-specific inducible Cre recombinase system, Cav1.2 mRNA was reduced to 11 +/- 1% of control values in homozygous floxed mice and the mice died rapidly (11.9 +/- 3 days) after induction of gene deletion. In these homozygous knockout mice, echocardiographic analysis showed that myocardial contractility was reduced to 14 +/- 1% of control values shortly before death. For these mice, no effective compensatory changes in ion channel gene expression were triggered following deletion of both Cav1.2 alleles, despite the dramatic decay in cardiac function. In contrast to the homozygote knockout mice, following knockout of only one Cav1.2 allele, cardiac function remained unchanged, as did survival.Cav1.2mRNAexpression in the left ventricle of heterozygous knockout mice was reduced to 58 +/- 3% of control values and there was a 21 +/- 2% reduction in Cav1.2 protein expression. There was no significant reduction in L-type Ca2+ current density in these mice. The results are consistent with a model of L-type calcium channel biosynthesis in which there are one or more saturated steps, which act to buffer changes in both total Cav1.2 protein and L-type current expression. PMID- 21521763 TI - Lymphatic fluid: exchange mechanisms and regulation. AB - Regulation of fluid and material movement between the vascular space of microvessels penetrating functioning organs and the cells therein has been studied extensively. Unanswered questions as to the regulatory mechanisms and routes remain. Significantly less is known about the lymphatic vascular system given the difficulties in seeing, no less isolating, these vessels lying deeper in these same tissues. It has become evident that the exchange microvasculature is not simply a passive biophysical barrier separating the vascular and interstitial compartments but a dynamic, multicellular structure subject to acute regulation and chronic adaptation to stimuli including inflammation, sepsis, diabetes, injury, hypoxia and exercise. Similarly lymphatic vessels range, in their simplest form, from lymphatic endothelium attached to the interstitial matrix, to endothelia and phasic lymphatic smooth muscle that act as Starling resistors. Recent work has demonstrated that among the microvascular lymphatic elements, the collecting lymphatics have barrier properties similar to venules, and thus participate in exchange. As with venules, vasoactive agents can alter both the permeability and contractile properties thereby setting up previously unanticipated gradients in the tissue space and providing potential targets for the pharmacological prevention and/or resolution of oedema. PMID- 21521764 TI - Mechanisms underlying a life-threatening skeletal muscle Na+ channel disorder. AB - Myotonia is an intrinsic muscular disorder caused by muscle fibre hyperexcitability, which produces a prolonged time for relaxation after voluntary muscle contraction or internal mechanical stimulation. Missense mutations in skeletal muscle genes encoding Cl- or Na+ channels cause non-dystrophic myotonias.Mutations of the SCN4A gene that encodes the skeletal voltage-gated Na+ channel Nav1.4 can produce opposing phenotypes leading to hyperexcitable or inexcitable muscle fibres. Nav1.4 mutations result in different forms of myotonias that can be found in adults. However, the recently reported myotonic manifestations in infants have been shown to be lethal. This was typically the case for children suffering from severe neonatal episodic laryngospasm (SNEL). A novel Nav1.4 channel missense mutation was found in these children that has not yet been analysed. In this study, we characterize the functional consequences of the new A799S Na+ channel mutation that is associated with sodium channel myotonia in newborn babies. We have used mammalian cell expression and patch clamp techniques to monitor the channel properties.We found that the A799S substitution changes several biophysical properties of the channel by causing a hyperpolarizing shift of the steady-state activation, and slowing the kinetics of fast inactivation and deactivation. In addition, the single channel open probability was dramatically increased, contributing hence to a severe phenotype. We showed that substitutions at position 799 of the Nav1.4 channel favoured the channel open state with sustained activity leading to hyperexcitability of laryngeal muscles that could be lethal during infancy. PMID- 21521765 TI - Proprioceptive signals contribute to the sense of body ownership. AB - The sense of body ownership, knowledge that parts of our body 'belong' to us, is presumably developed using sensory information. Cutaneous signals seem ideal for this and can modify the sense of ownership. For example, an illusion of ownership over an artificial rubber hand can be induced by synchronously stroking both the subject's hidden hand and a visible artificial hand. Like cutaneous signals, proprioceptive signals (e.g. frommuscle receptors) exclusively signal events occurring in the body, but the influence of proprioceptors on the sense of body ownership is not known. We developed a technique to generate an illusion of ownership over an artificial plastic finger, using movement at the proximal interphalangeal joint as the stimulus. We then examined this illusion in 20 subjects when their index finger was intact and when the cutaneous and joint afferents from the finger had been blocked by local anaesthesia of the digital nerves. Subjects still experienced an illusion of ownership, induced by movement, over the plastic finger when the digital nerves were blocked. This shows that local cutaneous signals are not essential for the illusion and that inputs arising proximally, presumably from receptors in muscles which move the finger, can influence the sense of body ownership. Contrary to other studies, we found no evidence that voluntary movements induce stronger illusions of body ownership than those induced by passive movement. It seems that the congruence of sensory stimuli ismore important to establish body ownership than the presence of multiple sensory signals. PMID- 21521766 TI - Inhibition of synaptic transmission and G protein modulation by synthetic CaV2.2 Ca2+ channel peptides. AB - Modulation of presynaptic voltage-dependent Ca2+ channels is a major means of controlling neurotransmitter release. The CaV2.2Ca2+ channel subunit contains several inhibitory interaction sites for Gbetagamma subunits, including the amino terminal (NT) and I-II loop. The NT and I-II loop have also been proposed to undergo a G protein-gated inhibitory interaction, whilst the NT itself has also been proposed to suppress CaV2 channel activity. Here, we investigate the effects of an amino terminal (CaV2.2[45-55]) 'NT peptide' and a I-II loop alpha interaction domain (CaV2.2[377-393]) 'AID peptide' on synaptic transmission, Ca2+ channel activity and G protein modulation in superior cervical ganglion neurones (SCGNs). Presynaptic injection of NT or AID peptide into SCGN synapses inhibited synaptic transmission and also attenuated noradrenaline-induced G protein modulation. In isolated SCGNs, NT and AID peptides reduced whole-cell Ca2+ current amplitude, modified voltage dependence of Ca2+ channel activation and attenuated noradrenaline-induced G protein modulation. Co-application of NT and AID peptide negated inhibitory actions. Together, these data favour direct peptide interaction with presynaptic Ca2+ channels, with effects on current amplitude and gating representing likely mechanisms responsible for inhibition of synaptic transmission. Mutations to residues reported as determinants of Ca2+ channel function within the NT peptide negated inhibitory effects on synaptic transmission, Ca2+ current amplitude and gating and G protein modulation. A mutation within the proposed QXXER motif for G protein modulation did not abolish inhibitory effects of the AID peptide. This study suggests that the CaV2.2 amino terminal and I-II loop contribute molecular determinants for Ca2+ channel function; the data favour a direct interaction of peptides with Ca2+ channels to inhibit synaptic transmission and attenuate G protein modulation. PMID- 21521767 TI - Sarcoplasmic reticulum and L-type Ca2+ channel activity regulate the beat-to-beat stability of calcium handling in human atrial myocytes. AB - Irregularities in intracellular calcium on a beat-to-beat basis can precede cardiac arrhythmia, but the mechanisms inducing such irregularities remain elusive. This study tested the hypothesis that sarcoplasmic reticulum (SR) and L type calcium channel activity determine the beat-to-beat response and its rate dependency. For this purpose, patch-clamp technique and confocal calcium imaging was used to record L-type calcium current (ICa) and visualize calcium in human atrial myocytes subjected to increasing stimulation frequencies (from 0.2 to 2 Hz). The beat-to-beat response was heterogeneous among a population of 133 myocytes, with 30 myocytes responding uniformly at all frequencies, while alternating and irregular responses were induced in 78 and 25 myocytes, respectively. Myocytes with uniform responses had the lowest frequency of calcium wave-induced transient inward currents (ITI; 0.4 +/- 0.2 min-1), ICa density (1.8 +/- 0.3 pA pF-1) and caffeine-releasable calcium load (6.2 +/- 0.5 amol pF-1), while those with alternating responses had the highest ITI frequency (1.8 +/- 0.3 min-1,P =0.003) and ICa density (2.4 +/- 0.2 pA pF-1, P =0.04). In contrast, the calcium load was highest in myocytes with irregular responses (8.5 +/- 0.7 amol pF-1, P =0.01). Accordingly, partial ICa inhibition reduced the incidence (from 78 to 44%, P <0.05) and increased the threshold frequency for beat-to-beat alternation (from 1.3 +/- 0.2 to 1.9 +/- 0.2 Hz, P <0.05). Partial inhibition of SR calcium release reduced the ITI frequency, increased calcium loading and favoured induction of irregular responses, while complete inhibition abolished beat-to-beat alternation at all frequencies. In conclusion, the beat-to-beat response was heterogeneous among human atrial myocytes subjected to increasing stimulation frequencies, and the nature and stability of the response were determined by the SR and L-type calcium channel activities, suggesting that these mechanisms are key to controlling cardiac beat-to-beat stability. PMID- 21521768 TI - Longitudinal attentional engagement rescues mice from age-related cognitive declines and cognitive inflexibility. AB - Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm maze task that required the mice to remember and operate on two sets of overlapping guidance (spatial) cues. As previously reported, this training resulted in an immediate (at 4 mo of age) improvement in the animals' aggregate performance across a battery of five learning tasks. Subsequently, these animals received an additional 3 d of working memory training at 3-wk intervals for 15 mo (totaling 66 training sessions), and at 18 mo of age were assessed on a selective attention task, a second set of learning tasks, and variations of those tasks that required the animals to modify the previously learned response. Both attentional and learning abilities (on passive avoidance, active avoidance, and reinforced alternation tasks) were impaired in aged animals that had not received working memory training. Likewise, these aged animals exhibited consistent deficits when required to modify a previously instantiated learned response (in reinforced alternation, active avoidance, and spatial water maze). In contrast, these attentional, learning, and perseverative deficits were attenuated in aged animals that had undergone lifelong working memory exercise. These results suggest that general impairments of learning, attention, and cognitive flexibility may be mitigated by a cognitive exercise regimen that requires chronic attentional engagement. PMID- 21521769 TI - Orientation of MU-conotoxin PIIIA in a sodium channel vestibule, based on voltage dependence of its binding. AB - Mutant cycle analysis has been used in previous studies to constrain possible docking orientations for various toxins. As an independent test of the bound orientation of MU-conotoxin PIIIA, a selectively targeted sodium channel pore blocker, we determined the contributions to binding voltage dependence of specific residues on the surface of the toxin. A change in the "apparent valence" (zdelta) of the block, which is associated with a change of a specific toxin charge, reflects a change in the charge movement within the transmembrane electric field as the toxin binds. Toxin derivatives with charge-conserving mutations (R12K, R14K, and K17R) showed zdelta values similar to those of wild type (0.61 +/- 0.01, mean +/- S.E.M.). Charge-changing mutations produced a range of responses. Neutralizing substitutions for Arg14 and Lys17 showed the largest reductions in zdelta values, to 0.18 +/- 0.06 and 0.20 +/- 0.06, respectively, whereas unit charge-changing substitutions for Arg12, Ser13, and Arg20 gave intermediate values (0.24 +/- 0.07, 0.33 +/- 0.04, and 0.32 +/- 0.05), which suggests that each of these residues contributes to the dependence of binding on the transmembrane voltage. Two mutations, R2A and G6K, yielded no significant change in zdelta. These observations suggest that the toxin binds with Arg2 and Gly6 facing the extracellular solution, and Arg14 and Lys17 positioned most deeply in the pore. In this study, we used molecular dynamics to simulate toxin docking and performed Poisson-Boltzmann calculations to estimate the changes in local electrostatic potential when individual charges were substituted on the toxin's surface. Consideration of two limiting possibilities suggests that most of the charge movement associated with toxin binding reflects sodium redistribution within the narrow part of the pore. PMID- 21521770 TI - Substrate specificity and ligand interactions of CYP26A1, the human liver retinoic acid hydroxylase. AB - All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. atRA is also used as a drug, and synthetic atRA analogs and inhibitors of retinoic acid (RA) metabolism have been developed. The hepatic clearance of atRA is mediated primarily by CYP26A1, but design of CYP26A1 inhibitors is hindered by lack of information on CYP26A1 structure and structure-activity relationships of its ligands. The aim of this study was to identify the primary metabolites of atRA formed by CYP26A1 and to characterize the ligand selectivity and ligand interactions of CYP26A1. On the basis of high-resolution tandem mass spectrometry data, four metabolites formed from atRA by CYP26A1 were identified as 4-OH-RA, 4 oxo-RA, 16-OH-RA and 18-OH-RA. 9-cis-RA and 13-cis-RA were also substrates of CYP26A1. Forty-two compounds with diverse structural properties were tested for CYP26A1 inhibition using 9-cis-RA as a probe, and IC(50) values for 10 inhibitors were determined. The imidazole- and triazole-containing inhibitors [S-(R*,R*)]-N [4-[2-(dimethylamino)-1-(1H-imidazole-1-yl)propyl]-phenyl]2-benzothiazolamine (R116010) and (R)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2 benzothiazolamine (R115866) were the most potent inhibitors of CYP26A1 with IC(50) values of 4.3 and 5.1 nM, respectively. Liarozole and ketoconazole were significantly less potent with IC(50) values of 2100 and 550 nM, respectively. The retinoic acid receptor (RAR) gamma agonist CD1530 was as potent an inhibitor of CYP26A1 as ketoconazole with an IC(50) of 530 nM, whereas the RARalpha and RARbeta agonists tested did not significantly inhibit CYP26A1. The pan-RAR agonist 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 propenyl]benzoic acid and the peroxisome proliferator-activated receptor ligands rosiglitazone and pioglitazone inhibited CYP26A1 with IC(50) values of 3.7, 4.2, and 8.6 MUM, respectively. These data demonstrate that CYP26A1 has high ligand selectivity but accepts structurally related nuclear receptor agonists as inhibitors. PMID- 21521771 TI - The weather dependence of particle size distribution of indoor radioactive aerosol associated with radon decay products. AB - This study was performed to measure the activity size distribution of aerosol particles associated with short-lived radon decay products in indoor air at Nagoya University, Nagoya, Japan. The measurements were performed using a low pressure Andersen cascade impactor under variable meteorological conditions. The results showed that the greatest activity fraction was associated with aerosol particles in the accumulation size range (100-1000 nm) with a small fraction of nucleation mode (10-100 nm). Regarding the influence of the weather conditions, the decrease in the number of accumulation particles was observed clearly after rainfall without significant change in nucleation particles, which may be due to a washout process for the large particles. PMID- 21521772 TI - Type 1 diabetes-induced hyper-responsiveness to 5-hydroxytryptamine in rat pulmonary arteries via oxidative stress and induction of cyclooxygenase-2. AB - Recent epidemiological data suggest that diabetes is a risk factor for pulmonary arterial hypertension. The aim of the present study was to analyze the link between type 1 diabetes and pulmonary arterial dysfunction in rats. Male Sprague Dawley rats were randomly divided into a control group (saline) and a diabetic group (70 mg/kg streptozotocin). After 6 weeks, diabetic animals showed a down regulation of the lung bone morphogenetic protein receptor type 2, up-regulation of 5-hydroxytryptamine (5-HT) 2A receptors and cyclooxygenase-2 (COX-2) proteins as measured by Western blot analysis, and increased contractile responses to 5-HT in isolated intrapulmonary arteries. The hyper-responsiveness to 5-HT was endothelium-independent and unaffected by inhibition of nitric-oxide synthase but prevented by indomethacin, the selective COX-2 inhibitor N-[2-(cyclohexyloxyl)-4 nitrophenyl]-methane sulfonamide (NS-398), superoxide dismutase, and the NADPH oxidase inhibitor apocynin or chronic treatment with insulin. However, diabetic rats at 6 weeks did not develop elevated right ventricular pressure or pulmonary artery muscularization, whereas a longer exposure (4 months) to diabetes induced a modest, but significant, increase in right ventricular systolic pressure. In conclusion, type 1 diabetes mellitus in rats induces a number of changes in lung protein expression and pulmonary vascular reactivity characteristic of clinical and experimental pulmonary arterial hypertension but insufficient to elevate pulmonary pressure. Our results further strengthen the link between diabetes and pulmonary arterial hypertension. PMID- 21521773 TI - Antiarthritis effect of a novel Bruton's tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy. AB - Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation, and proliferation of B-lineage cells, making it an attractive target for the treatment of rheumatoid arthritis. The objective of this study was to evaluate the antiarthritis effect of GDC-0834 [R-N-(3-(6-(4-(1,4-dimethyl-3 oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2 methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], a potent and selective BTK inhibitor, and characterize the relationship between inhibition of BTK phosphorylation (pBTK) and efficacy. GDC-0834 inhibited BTK with an in vitro IC(50) of 5.9 and 6.4 nM in biochemical and cellular assays, respectively, and in vivo IC(50) of 1.1 and 5.6 MUM in mouse and rat, respectively. Administration of GDC-0834 (30-100 mg/kg) in a rat collagen-induced arthritis (CIA) model resulted in a dose-dependent decrease of ankle swelling and reduction of morphologic pathology. An integrated disease progression pharmacokinetic/pharmacodynamic model where efficacy is driven by pBTK inhibition was fit to ankle-diameter time course data. This model incorporated a transit model to characterize nondrug related decreases in ankle swelling occurring at later stages of disease progression in CIA rats. The time course of ankle swelling in vehicle animals was described well by the base model. Simultaneous fitting of data from vehicle- and GDC-0834-treated groups showed that overall 73% inhibition of pBTK was needed to decrease the rate constant describing the ankle swelling increase (k(in)) by half. These findings suggest a high degree of pBTK inhibition is required for maximal activity of the pathway on inflammatory arthritis in rats. PMID- 21521774 TI - Enhanced sensitivity to afferent stimulation and impact of overactive bladder therapies in the conscious, spontaneously hypertensive rat. AB - The spontaneously hypertensive rat (SHR) has been proposed as an overactive bladder model, driven, at least partially, by alterations in bladder innervation. To assess the functional role of sensory bladder afferents we evaluated the conscious cystometric response to prostaglandin E(2) (PGE(2)) or acetic acid (AA) bladder infusion. SHR demonstrated a hypersensitivity to PGE(2) and AA, as indicated by a greater reduction in both void volume (VV) and micturition interval (MI) compared with Sprague-Dawley controls. The heightened PGE(2) and AA responses in the SHR were inhibited by capsaicin desensitization, supporting a role for bladder afferents in facilitating the hypersensitivity. Furthermore, we characterized the SHR pharmacologically using overactive bladder therapeutic agents. In the SHR, both darifenacin and oxybutynin (M(3)-selective and nonselective muscarinic antagonists, respectively) reduced micturition pressure (MP) and functional bladder capacity (VV and MI). In sharp contrast, functional bladder capacity was significantly enhanced by beta(3)-adrenoceptor agonism [5 [(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole 2,2-dicarboxylate (CL316243)], and by gabapentin, without effect on MP. These data provide the first functional evidence for hypersensitive bladder afferents in the SHR and provide a pharmacological benchmark in this model for overactive bladder therapeutics. These data also support the idea that beta(3)-adrenoceptor agonism and gabapentin may provide a more effective overactive bladder therapy than muscarinic antagonism. PMID- 21521775 TI - FGFR3 is overexpressed waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis and overcomes stroma-induced proliferation. AB - PURPOSE: There is no standard of therapy for the treatment of Waldenstrom macroglobulinemia (WM), therefore there is a need for the development of new agents. Fibroblast growth factor receptor 3 (FGFR3) was shown to play a major role in several types in cancer. Dovitinib, an inhibitor of FGFR3, was effective in hematologic malignancies. In this study, we tested FGFR3 as a therapeutic target in WM and tested the effect of dovitinib on cell proliferation and apoptosis of WM cells in the context of BM microenvironment. METHODS: The expression of FGFR3 in WM cells was tested using immunofluorescence and flow cytometry. Cell signaling in response to stimulation with FGF3 and stromal cells, and its inhibition by dovitinib was performed using immunoblotting. Cell survival and cell proliferation were assessed by MTT and BrdU assays. Apoptosis was measured by detection of APO-2.7 and cleavage of caspase-3 using flow cytometry. Cell cycle was performed by PI staining of cells and flow cytometry. The combinatory effect of dovitinib with other drugs was analyzed using Calcusyn software. The effect of dovitinib was tested in vivo. RESULTS: FGFR3 was overexpressed in WM cells and its activation induced cell proliferation. Inhibition of FGFR3 with dovitinib decreased cell survival, increased apoptosis, and induced cell cycle arrest. Inhibition of FGFR3 by dovitinib reduced the interaction of WM to bone marrow components, and reversed its proliferative effect. Dovitinib had an additive effect with other drugs. Moreover, dovitinib reduced WM tumor progression in vivo. CONCLUSION: We report that FGFR3 is a novel therapeutic target in WM, and suggest dovitinib for future clinical trial the treatment of patients with WM. PMID- 21521776 TI - Genomic profiles specific to patient ethnicity in lung adenocarcinoma. AB - PURPOSE: East-Asian (EA) patients with non-small-cell lung cancer (NSCLC) are associated with a high proportion of nonsmoking women, epidermal growth factor receptor (EGFR)-activating somatic mutations, and clinical responses to tyrosine kinase inhibitors. We sought to identify novel molecular differences between NSCLCs from EA and Western European (WE) patients. EXPERIMENTAL DESIGN: A total of 226 lung adenocarcinoma samples from EA (n = 90) and WE (n = 136) patients were analyzed for copy number aberrations (CNA) by using a common high-resolution SNP (single nucleotide polymorphism) microarray platform. Univariate and multivariate analyses were carried out to identify CNAs specifically related to smoking history, EGFR mutation status, and ethnicity. RESULTS: The overall genomic profiles of adenocarcinomas from EA and WE patients were highly similar. Univariate analyses revealed several CNAs significantly associated with ethnicity, EGFR mutation, and smoking, but not to gender, and KRAS or p53 mutations. A multivariate model identified four ethnic-specific recurrent CNAs significantly higher rates of copy number gain were observed on 16p13.13 and 16p13.11 in EA tumors, whereas higher rates of genomic loss on 19p13.3 and 19p13.11 were observed in tumors from WE patients. We identified several potential driver genes in these regions, showing a positive correlation between cis-localized copy number changes and transcriptomic changes. CONCLUSION: 16p copy number gains (EA) and 19p losses (WE) are ethnic-specific chromosomal aberrations in lung adenocarcinoma. Patient ethnicity should be considered when evaluating future NSCLC therapies targeting genes located on these areas. PMID- 21521777 TI - Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts. AB - PURPOSE: The success of immunotoxin therapy of cancer is limited by host production of neutralizing antibodies, which are directed toward the Pseudomonas exotoxin A (PE) component. In this proof-of-principle study using a well established murine model, we hypothesized that a newly developed immune depletion regimen consisting of pentostatin plus cyclophosphamide would abrogate anti immunotoxin reactivity. EXPERIMENTAL DESIGN: BALB/c hosts were injected weekly with recombinant immunotoxin (RIT) SS1P, which is an antimesothelin Fv antibody fragment genetically fused to a 38 kDa portion of PE, and has been evaluated in clinical trials. Experimental cohorts received induction chemotherapy consisting of pentostatin (P) plus cyclophosphamide (C) prior to initial RIT exposure; some cohorts received further maintenance PC therapy of varying intensity just prior to each weekly RIT challenge. Cohorts were monitored for T, B, myeloid cell depletion, and for total anti-SS1P antibody (Ab) formation. RESULTS: Controls uniformly developed anti-SS1P Ab after the third RIT exposure. Induction PC therapy reduced the frequency of hosts with anti-SS1P Ab. Abrogation of antibody generation was improved by maintenance PC therapy: nearly 100% of recipients of intensive PC maintenance were free of anti-SS1P Ab after 9 weekly RIT doses. The most effective PC regimen yielded the greatest degree of host B-cell depletion, moderate T-cell depletion, and minimal myeloid cell depletion. CONCLUSIONS: Induction and maintenance PC chemotherapy safely prevented anti-immunotoxin antibody formation with uniform efficacy. These data suggest that immunotoxin therapy might be used in combination with pentostatin plus cyclophosphamide chemotherapy to improve the targeted therapy of cancer. PMID- 21521778 TI - Characterization of the genomic structure and function of regions influencing renin and angiogenesis in the SS rat. AB - Impaired regulation of renin in Dahl salt-sensitive rats (SS/JRHsdMcwi, SS) contributes to attenuated angiogenesis in this strain. This study examined angiogenic function and genomic structure of regions surrounding the renin gene using subcongenic strains of the SS and BN/NHsdMcwi (BN) rat to identify important genomic variations between SS and BN involved in angiogenesis. Three candidate regions on Chr 13 were studied: two congenic strains containing 0.89 and 2.62 Mb portions of BN Chr 13 that excluded the BN renin allele and a third strain that contained a 2.02 Mb overlapping region that included the BN renin allele. Angiogenesis induced by electrical stimulation of the tibialis anterior muscle was attenuated in the SS compared with the BN. Congenics carrying the SS renin allele had impaired angiogenesis, while strains carrying the BN renin allele had angiogenesis restored. The exception was a congenic including a region of BN genome 0.4 Mb distal to renin that restored both renin regulation and angiogenesis. This suggests that there is a distant regulatory element in the BN capable of restoring normal regulation of the SS renin allele. The importance of ANG II in the restored angiogenic response was demonstrated by blocking with losartan. Sequencing of the 4.05 Mb candidate region in SS and BN revealed a total of 8,850 SNPs and other sequence variants. An analysis of the genes and their variants in the region suggested a number of pathways that may explain the impaired regulation of renin and angiogenesis in the SS rat. PMID- 21521779 TI - Gene expression variation between African Americans and whites is associated with coronary artery calcification: the multiethnic study of atherosclerosis. AB - Coronary artery calcium (CAC) is a strong indicator of total atherosclerosis burden. Epidemiological data have shown substantial differences in CAC prevalence and severity between African Americans and whites. However, little is known about the molecular mechanisms underlying initiation and progression of CAC. Microarray gene expression profiling of peripheral blood leucocytes was performed from 119 healthy women aged 50 yr or above in the Multi-Ethnic Study of Atherosclerosis cohort; 48 women had CAC score >100 and carotid intima-media thickness (IMT) >1 mm, while 71 had CAC <10 and IMT <0.65 mm. When 17 African Americans were compared with 41 whites in the low-CAC group, 409 differentially expressed genes (false discovery rate <5%) were identified. In addition, 316 differentially expressed genes were identified between the high- and low-CAC groups. A substantial overlap between these two gene lists was observed (148 genes, P < 10( 6)). Furthermore, genes expressed lower in African Americans also tend to express lower in individuals with low CAC (correlation 0.69, P = 0.002). Ontology analysis of the 409 race-associated genes revealed significant enrichment in mobilization of calcium and immune/inflammatory response (P < 10(-9)). Of note, 25 of 30 calcium mobilization genes were involved in immune/inflammatory response (P < 10(-10)). Our data suggest a connection between immune response and vascular calcification and the result provides a potential mechanistic explanation for the lower prevalence and severity of CAC in African Americans compared with whites. PMID- 21521780 TI - Gatt ME, Zhao JJ, Ebert MS, Zhang Y, Chu Z, Mani M, Gazit R, Carrasco DE, Dutta Simmons J, Adamia S, Minvielle S, Tai Y-T, Munshi NC, Avet-Loiseau H, Anderson KC, Carrasco DR. MicroRNAs 15a/16-1 function as tumor suppressor genes in multiple myeloma [published online ahead of print October 20, 2010]. Blood. doi:10.1182/blood-2009-11-253294. PMID- 21521781 TI - Depletion of CD25+ T cells from hematopoietic stem cell grafts increases posttransplantation vaccine-induced immunity to neuroblastoma. AB - A multifaceted immunotherapeutic strategy that includes hematopoietic stem cell (HSC) transplantation, T-cell adoptive transfer, and tumor vaccination can effectively eliminate established neuroblastoma tumors in mice. In vivo depletion of CD4+ T cells in HSC transplantation recipients results in increased antitumor immunity when adoptively transferred T cells are presensitized, but development of T-cell memory is severely compromised. Because increased percentages of regulatory T (Treg) cells are seen in HSC transplantation recipients, here we hypothesized that the inhibitory effect of CD4+ T cells is primarily because of the presence of expanded Treg cells. Remarkably, adoptive transfer of presensitized CD25-depleted T cells increased tumor vaccine efficacy. The enhanced antitumor effect achieved by ex vivo depletion of CD25+ Treg cells was similar to that achieved by in vivo depletion of all CD4+ T cells. Depletion of CD25+ Treg cells resulted in elevated frequencies of tumor-reactive CD8 and CD4+ T cells and increased CD8-to-Treg cell ratios inside tumor masses. All mice given presensitized CD25-depleted T cells survived a tumor rechallenge, indicating the development of long-term CD8+ T-cell memory to tumor antigens. These observations should aid in the future design of immunotherapeutic approaches that promote the generation of both acute and long-term antitumor immunity. PMID- 21521782 TI - TIMP-1 deficiency subverts cell-cycle dynamics in murine long-term HSCs. AB - In addition to the well-recognized role in extracellular matrix remodeling, the tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested to be involved in the regulation of numerous biologic functions, including cell proliferation and survival. We therefore hypothesized that TIMP-1 might be involved in the homeostatic regulation of HSCs, whose biologic behavior is the synthesis of both microenvironmental and intrinsic cues. We found that TIMP-1(-/ ) mice have decreased BM cellularity and, consistent with this finding, TIMP-1(-/ ) HSCs display reduced capability of long-term repopulation. Interestingly, the cell cycle distribution of TIMP-1(-/-) stem cells appears distorted, with a dysregulation at the level of the G(1) phase. TIMP-1(-/-) HSCs also display increased levels of p57, p21, and p53, suggesting that TIMP-1 could be intrinsically involved in the regulation of HSC cycling dynamics. Of note, TIMP 1(-/-) HSCs present decreased levels of CD44 glycoprotein, whose expression has been proven to be controlled by p53, the master regulator of the G(1)/S transition. Our findings establish a role for TIMP-1 in regulating HSC function, suggesting a novel mechanism presiding over stem cell quiescence in the framework of the BM milieu. PMID- 21521783 TI - DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. AB - Chromosomal translocations of the mixed lineage leukemia (MLL) gene are a common cause of acute leukemias. The oncogenic function of MLL fusion proteins is, in part, mediated through aberrant activation of Hoxa genes and Meis1, among others. Here we demonstrate using a tamoxifen-inducible Cre-mediated loss of function mouse model that DOT1L, an H3K79 methyltransferase, is required for both initiation and maintenance of MLL-AF9-induced leukemogenesis in vitro and in vivo. Through gene expression and chromatin immunoprecipitation analysis we demonstrate that mistargeting of DOT1L, subsequent H3K79 methylation, and up regulation of Hoxa and Meis1 genes underlie the molecular mechanism of how DOT1L contributes to MLL-AF9-mediated leukemogenesis. Our study not only provides the first in vivo evidence for the function of DOT1L in leukemia, but also reveals the molecular mechanism for DOT1L in MLL-AF9 mediated leukemia. Thus, DOT1L may serve as a potential therapeutic target for the treatment of leukemia caused by MLL translocations. PMID- 21521784 TI - Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model. AB - The clinical outcome of granulocyte transfusion therapy is often hampered by short ex vivo shelf life, inefficiency of recruitment to sites of inflammation, and poor pathogen-killing capability of transplanted neutrophils. Here, using a recently developed mouse granulocyte transfusion model, we revealed that the efficacy of granulocyte transfusion can be significantly increased by elevating intracellular phosphatidylinositol (3,4,5)-trisphosphate signaling with a specific phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670. Neutrophils treated with SF1670 were much sensitive to chemoattractant stimulation. Neutrophil functions, such as phagocytosis, oxidative burst, polarization, and chemotaxis, were augmented after SF1670 treatment. The recruitment of SF1670-pretreated transfused neutrophils to the inflamed peritoneal cavity and lungs was significantly elevated. In addition, transfusion with SF1670-treated neutrophils led to augmented bacteria-killing capability (decreased bacterial burden) in neutropenic recipient mice in both peritonitis and bacterial pneumonia. Consequently, this alleviated the severity of and decreased the mortality of neutropenia-related pneumonia. Together, these observations demonstrate that the innate immune responses can be enhanced and the severity of neutropenia-related infection can be alleviated by augmenting phosphatidylinositol (3,4,5)-trisphosphate in transfused neutrophils with PTEN inhibitor SF1670, providing a therapeutic strategy for improving the efficacy of granulocyte transfusion. PMID- 21521785 TI - Inhibition of beta-TrcP-dependent ubiquitination of p53 by HIV-1 Vpu promotes p53 mediated apoptosis in human T cells. AB - HIV-1 viral protein U (Vpu) is involved in ubiquitination and degradation of BM stromal cell Ag 2 and surface receptor CD4 through their recruitment to SCF(beta TrcP) (Skp1/Cul1/F-box) ubiquitin ligase (SCF) complex. Here, we show that specific interaction of wild-type Vpu protein with SCF complex leads to inhibition of ubiquitination and proteasomal degradation of p53 protein in a beta TrcP-dependent manner. Successful interaction of SCF(beta-TrcP) complex with beta TrcP binding motif (DS(52)GNES(56)) present in Vpu is essential because mutant Vpu possessing specific alanine substitutions (DA(52)GNEA(56)) in the beta-TrcP binding motif not only failed to stabilize p53 protein but was also unable to inhibit ubiquitination of p53 protein. Furthermore, Vpu competes efficiently with the interaction of p53 protein with the beta-TrcP subunit of the SCF complex and inhibits subsequent ubiquitination of p53 proteins in a dose-dependent manner. We also observed potent apoptotic activity in a p53 null cell line (H-1299) that was cotransfected with p53 and Vpu-expressing plasmids. Furthermore, MOLT-3 (human T lymphoblast) cells when infected with vesicular stomatitis virus glycoprotein pseudotypic HIV-1 possessing wild-type vpu gene exhibited maximum activation of p53/Bax proteins and p53-mediated cell death. These findings establish a novel function of Vpu in modulating the stability of p53 protein that correlates positively with apoptosis during late stages of HIV-1 infection. PMID- 21521786 TI - DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer. AB - Candidate gene-based studies have identified a handful of aberrant CpG DNA methylation events in prostate cancer. However, DNA methylation profiles have not been compared on a large scale between prostate tumor and normal prostate, and the mechanisms behind these alterations are unknown. In this study, we quantitatively profiled 95 primary prostate tumors and 86 benign adjacent prostate tissue samples for their DNA methylation levels at 26,333 CpGs representing 14,104 gene promoters by using the Illumina HumanMethylation27 platform. A 2-class Significance Analysis of this data set revealed 5912 CpG sites with increased DNA methylation and 2151 CpG sites with decreased DNA methylation in tumors (FDR < 0.8%). Prediction Analysis of this data set identified 87 CpGs that are the most predictive diagnostic methylation biomarkers of prostate cancer. By integrating available clinical follow-up data, we also identified 69 prognostic DNA methylation alterations that correlate with biochemical recurrence of the tumor. To identify the mechanisms responsible for these genome-wide DNA methylation alterations, we measured the gene expression levels of several DNA methyltransferases (DNMTs) and their interacting proteins by TaqMan qPCR and observed increased expression of DNMT3A2, DNMT3B, and EZH2 in tumors. Subsequent transient transfection assays in cultured primary prostate cells revealed that DNMT3B1 and DNMT3B2 overexpression resulted in increased methylation of a substantial subset of CpG sites that showed tumor-specific increased methylation. PMID- 21521787 TI - Association studies for next-generation sequencing. AB - Genome-wide association studies (GWAS) have become the primary approach for identifying genes with common variants influencing complex diseases. Despite considerable progress, the common variations identified by GWAS account for only a small fraction of disease heritability and are unlikely to explain the majority of phenotypic variations of common diseases. A potential source of the missing heritability is the contribution of rare variants. Next-generation sequencing technologies will detect millions of novel rare variants, but these technologies have three defining features: identification of a large number of rare variants, a high proportion of sequence errors, and a large proportion of missing data. These features raise challenges for testing the association of rare variants with phenotypes of interest. In this study, we use a genome continuum model and functional principal components as a general principle for developing novel and powerful association analysis methods designed for resequencing data. We use simulations to calculate the type I error rates and the power of nine alternative statistics: two functional principal component analysis (FPCA)-based statistics, the multivariate principal component analysis (MPCA)-based statistic, the weighted sum (WSS), the variable-threshold (VT) method, the generalized T(2), the collapsing method, the CMC method, and individual tests. We also examined the impact of sequence errors on their type I error rates. Finally, we apply the nine statistics to the published resequencing data set from ANGPTL4 in the Dallas Heart Study. We report that FPCA-based statistics have a higher power to detect association of rare variants and a stronger ability to filter sequence errors than the other seven methods. PMID- 21521788 TI - Tour of bordered Floer theory. AB - Heegaard Floer theory is a kind of topological quantum field theory (TQFT), assigning graded groups to closed, connected, oriented 3-manifolds and group homomorphisms to smooth, oriented four-dimensional cobordisms. Bordered Heegaard Floer homology is an extension of Heegaard Floer homology to 3-manifolds with boundary, with extended-TQFT-type gluing properties. In this survey, we explain the formal structure and construction of bordered Floer homology and sketch how it can be used to compute some aspects of Heegaard Floer theory. PMID- 21521789 TI - Switching processes in financial markets. AB - For an intriguing variety of switching processes in nature, the underlying complex system abruptly changes from one state to another in a highly discontinuous fashion. Financial market fluctuations are characterized by many abrupt switchings creating upward trends and downward trends, on time scales ranging from macroscopic trends persisting for hundreds of days to microscopic trends persisting for a few minutes. The question arises whether these ubiquitous switching processes have quantifiable features independent of the time horizon studied. We find striking scale-free behavior of the transaction volume after each switching. Our findings can be interpreted as being consistent with time dependent collective behavior of financial market participants. We test the possible universality of our result by performing a parallel analysis of fluctuations in time intervals between transactions. We suggest that the well known catastrophic bubbles that occur on large time scales--such as the most recent financial crisis--may not be outliers but single dramatic representatives caused by the formation of increasing and decreasing trends on time scales varying over nine orders of magnitude from very large down to very small. PMID- 21521790 TI - Direct reprogramming of mouse fibroblasts to neural progenitors. AB - The simple yet powerful technique of induced pluripotency may eventually supply a wide range of differentiated cells for cell therapy and drug development. However, making the appropriate cells via induced pluripotent stem cells (iPSCs) requires reprogramming of somatic cells and subsequent redifferentiation. Given how arduous and lengthy this process can be, we sought to determine whether it might be possible to convert somatic cells into lineage-specific stem/progenitor cells of another germ layer in one step, bypassing the intermediate pluripotent stage. Here we show that transient induction of the four reprogramming factors (Oct4, Sox2, Klf4, and c-Myc) can efficiently transdifferentiate fibroblasts into functional neural stem/progenitor cells (NPCs) with appropriate signaling inputs. Compared with induced neurons (or iN cells, which are directly converted from fibroblasts), transdifferentiated NPCs have the distinct advantage of being expandable in vitro and retaining the ability to give rise to multiple neuronal subtypes and glial cells. Our results provide a unique paradigm for iPSC-factor based reprogramming by demonstrating that it can be readily modified to serve as a general platform for transdifferentiation. PMID- 21521791 TI - Dynamic programming procedure for searching optimal models to estimate substitution rates based on the maximum-likelihood method. AB - The substitution rate in a gene can provide valuable information for understanding its functionality and evolution. A widely used method to estimate substitution rates is the maximum-likelihood method implemented in the CODEML program in the PAML package. A limited number of branch models, chosen based on a priori information or an interest in a particular lineage(s), are tested, whereas a large number of potential models are neglected. A complementary approach is also needed to test all or a large number of possible models to search for the globally optional model(s) of maximum likelihood. However, the computational time for this search even in a small number of sequences becomes impractically long. Thus, it is desirable to explore the most probable spaces to search for the optimal models. Using dynamic programming techniques, we developed a simple computational method for searching the most probable optimal branch-specific models in a practically feasible computational time. We propose three search methods to find the optimal models, which explored O(n) (method 1) to O(n(2)) (method 2 and method 3) models when the given phylogeny has n branches. In addition, we derived a formula to calculate the number of all possible models, revealing the complexity of finding the optimal branch-specific model. We show that in a reanalysis of over 50 previously published studies, the vast majority obtained better models with significantly higher likelihoods than the conventional hypothesis model methods. PMID- 21521792 TI - Redox potentials of primary electron acceptor quinone molecule (QA)- and conserved energetics of photosystem II in cyanobacteria with chlorophyll a and chlorophyll d. AB - In a previous study, we measured the redox potential of the primary electron acceptor pheophytin (Phe) a of photosystem (PS) II in the chlorophyll d-dominated cyanobacterium Acaryochloris marina and a chlorophyll a-containing cyanobacterium, Synechocystis. We obtained the midpoint redox potential (E(m)) values of -478 mV for A. marina and -536 mV for Synechocystis. In this study, we measured the redox potentials of the primary electron acceptor quinone molecule (Q(A)), i.e., E(m)(Q(A)/Q(A)(-)), of PS II and the energy difference between [P680.Phe a(-).Q(A)] and [P680.Phe a.Q(A)(-)], i.e., DeltaG(PhQ). The E(m)(Q(A)/Q(A)(-)) of A. marina was determined to be +64 mV without the Mn cluster and was estimated to be -66 to -86 mV with a Mn-depletion shift (130-150 mV), as observed with other organisms. The E(m)(Phe a/Phe a(-)) in Synechocystis was measured to be -525 mV with the Mn cluster, which is consistent with our previous report. The Mn-depleted downshift of the potential was measured to be approximately -77 mV in Synechocystis, and this value was applied to A. marina ( 478 mV); the E(m)(Phe a/Phe a(-)) was estimated to be approximately -401 mV. These values gave rise to a DeltaG(PhQ) of -325 mV for A. marina and -383 mV for Synechocystis. In the two cyanobacteria, the energetics in PS II were conserved, even though the potentials of Q(A)(-) and Phe a(-) were relatively shifted depending on the special pair, indicating a common strategy for electron transfer in oxygenic photosynthetic organisms. PMID- 21521793 TI - Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein. AB - It is well known that the endoplasmic reticulum (ER) is capable of expanding its surface area in response both to cargo load and to increased expression of resident membrane proteins. Although the response to increased cargo load, known as the unfolded protein response (UPR), is well characterized, the mechanism of the response to membrane protein load has been unclear. As a model system to investigate this phenomenon, we have used a HeLa-TetOff cell line inducibly expressing a tail-anchored construct consisting of an N-terminal cytosolic GFP moiety anchored to the ER membrane by the tail of cytochrome b5 [GFP-b(5)tail]. After removal of doxycycline, GFP-b(5)tail is expressed at moderate levels (1-2% of total ER protein) that, nevertheless, induce ER proliferation, as assessed both by EM and by a three- to fourfold increase in phosphatidylcholine synthesis. We investigated possible participation of each of the three arms of the UPR and found that only the activating transcription factor 6 (ATF6) arm was selectively activated after induction of GFP-b(5)tail expression; peak ATF6alpha activation preceded the increase in phosphatidylcholine synthesis. Surprisingly, up regulation of known ATF6 target genes was not observed under these conditions. Silencing of ATF6alpha abolished the ER proliferation response, whereas knockdown of Ire1 was without effect. Because GFP-b(5)tail lacks a luminal domain, the response we observe is unlikely to originate from the ER lumen. Instead, we propose that a sensing mechanism operates within the lipid bilayer to trigger the selective activation of ATF6. PMID- 21521794 TI - Repurposing lipoic acid changes electron flow in two important metabolic pathways of Escherichia coli. AB - In bacteria, cysteines of cytoplasmic proteins, including the essential enzyme ribonucleotide reductase (RNR), are maintained in the reduced state by the thioredoxin and glutathione/glutaredoxin pathways. An Escherichia coli mutant lacking both glutathione reductase and thioredoxin reductase cannot grow because RNR is disulfide bonded and nonfunctional. Here we report that suppressor mutations in the lpdA gene, which encodes the oxidative enzyme lipoamide dehydrogenase required for tricarboxylic acid (TCA) cycle functioning, restore growth to this redox-defective mutant. The suppressor mutations reduce LpdA activity, causing the accumulation of dihydrolipoamide, the reduced protein-bound form of lipoic acid. Dihydrolipoamide can then provide electrons for the reactivation of RNR through reduction of glutaredoxins. Dihydrolipoamide is oxidized in the process, restoring function to the TCA cycle. Thus, two electron transfer pathways are rewired to meet both oxidative and reductive needs of the cell: dihydrolipoamide functionally replaces glutathione, and the glutaredoxins replace LpdA. Both lipoic acid and glutaredoxins act in the reverse manner from their normal cellular functions. Bioinformatic analysis suggests that such activities may also function in other bacteria. PMID- 21521795 TI - In vitro age-dependent enzymatic metabolism of chlorpyrifos and chlorpyrifos-oxon in human hepatic microsomes and chlorpyrifos-oxon in plasma. AB - Age-dependent chlorpyrifos (CPF) metabolism was quantified by in vitro product formation in human hepatic microsomes (ages 13 days to 75 years) and plasma (ages 3 days to 43 years) with gas chromatography-mass spectrometry. Hepatic CPF cytochrome P450 desulfuration [CPF to chlorpyrifos-oxon (CPF-oxon)] and dearylation (CPF to 3,5,6-trichloro-2-pyridinol) V(max) values were 0.35 +/- 0.21 and 0.73 +/- 0.38 nmol . min(-1) . mg microsomal protein (-1) (mean +/- S.D.), respectively. The mean (+/-S.D.) hepatic CPF-oxon hydrolysis (chlorpyrifos oxonase [CPFOase]) V(max) was 78 +/- 44 nmol . min(-1) . mg microsomal protein ( 1). None of these hepatic measures demonstrated age-dependent relationships on a per microsomal protein basis using linear regression models. Ratios of CPF bioactivation to detoxification (CPF desulfuration to dearylation) V(max) values were consistent across ages. CPFOase in plasma demonstrated age-dependent increases on a volume of plasma basis, as did total plasma protein levels. Mean (+/-S.D.) CPF-oxon hydrolysis V(max) values for children <6 months of age and adults (>=16 years) were 1900 +/- 660 and 6800 +/- 1600 nmol . min(-1) . ml(-1), respectively, and at environmental exposure levels, this high- capacity enzyme is likely to be sufficient even in infants. Plasma samples were phenotyped for paraoxonase status, and frequencies were 0.5, 0.4, and 0.1 for QQ, QR, and RR phenotypes, respectively. These results will be integrated into a physiologically based pharmacokinetic and pharmacodynamic model for CPF and, once integrated, will be useful for assessing biological response to CPF exposures across life stages. PMID- 21521796 TI - Human paraoxonase 1 is the enzyme responsible for pilocarpine hydrolysis. AB - Pilocarpine has been widely used in ophthalmic preparations for the treatment of glaucoma and in oral preparations for the treatment of radiation-induced xerostomia and Sjogren syndrome. The major metabolic pathways of pilocarpine in human are hydrolysis and hydroxylation. It was found that CYP2A6 is responsible for the 3-hydroxylation, but the enzymes responsible for the hydrolysis have not been characterized. In this study, we attempted to identify esterases responsible for pilocarpine hydrolysis. Pilocarpine hydrolase activities in human liver microsomes and plasma were stimulated by the addition of CaCl(2), suggesting that the calcium-dependent esterase, paraoxonase (PON), was responsible for pilocarpine hydrolysis. To confirm this hypothesis, the pilocarpine hydrolase activity was measured using the recombinant human PONs (PON1, PON2, and PON3) established in this study, and the result was that only PON1 showed pilocarpine hydrolase activity. The effect of PON1 polymorphism (Q192R) on pilocarpine hydrolase activity was analyzed using recombinant human PON1 192Q and 192R and human plasma from 50 volunteers. The results showed that recombinant PON1 192R revealed significantly higher catalytic efficiency than PON1 192Q. In human plasma, the activity of the R/R genotype (117.0 +/- 25.2 pmol . min(-1) . MUl( 1), n = 23) was significantly higher than those of the Q/R and Q/Q genotypes (97.3 +/- 21.0 pmol . min(-1) . MUl(-1), n = 20 and 90.4 +/- 26.2 pmol . min(-1) . MUl(-1), n = 7, respectively). It is suggested that this polymorphism affects pilocarpine hydrolase activity. In this study, we found that human PON1 is the major enzyme for the catalytic efficiency of pilocarpine hydrolysis. PMID- 21521797 TI - Measuring risk perceptions: what does the excessive use of 50% mean? AB - OBJECTIVES: Risk perceptions are central to good health decisions. People can judge valid probabilities but use 50% disproportionately. The authors hypothesized that 50% is more likely than other responses to reflect not knowing the probability, especially among individuals with low education and numeracy, and evaluated the usefulness of eliciting "don't know" explanations. METHODS: Respondents (n = 1020) judged probabilities for living or dying in the next 10 years, indicating whether they gave a good estimate or did not know the chances. They completed demographics, medical history, and numeracy questions. RESULTS: Overall, 50% was more likely than other probabilities to be explained as "don't know" (v. "a good estimate"). Correlations of using 50% with low education and numeracy were mediated by expressing "don't know." Judged probabilities for survival and mortality explained as "don't know" had lower correlations with age, diseases, and specialist visits. CONCLUSIONS: When judging risks, 50% may reflect not knowing the probability, especially among individuals with low numeracy and education. Probabilities expressed as "don't know" are less valid. Eliciting uncertainty could benefit theoretical models and educational efforts. PMID- 21521798 TI - Spermatogonial morphology and kinetics during testis development in mice: a high resolution light microscopy approach. AB - Despite the knowledge of spermatogonial biology in adult mice, spermatogonial development in immature animals has not been fully characterized. Thus, the aim of this study was to evaluate the ontogeny of the morphological development of the spermatogonial lineage in C57BL/6 mouse testis, using high-resolution light microscopy. Spermatogonial morphology, chronology, and absolute number were determined for different ages postpartum (pp). The morphology of spermatogonia in immature mice was similar to that of adult spermatogonia, although their nuclear diameter was slightly smaller. The A(1) spermatogonia were first observed on day 2 pp, and only 24 h later, differentiating type A(3) and A(4) spermatogonia were observed in the seminiferous cords. This result indicated a shortening of the spermatogonial phase for immature mice of about ~2.5 days when compared with adult mice and suggests that gonocytes and/or A(1) spermatogonia could directly become A(4) spermatogonia, skipping the developmental sequence of type A spermatogonia. These A(4) spermatogonia are functional as they develop into type B spermatogonia by day 5 pp. At day 8 pp, while differentiation to spermatocytes begins, the A(und) spermatogonia reach their maximal numbers, which are maintained through adulthood. The various details of the spermatogonial behavior in immature normal mice described in this study can be used as a baseline for further studies under experimental or pathological conditions. PMID- 21521799 TI - Characterization of vancomycin pharmacokinetics in the adult acute myeloid leukemia population. AB - Current vancomycin dosing guidelines in our acute myeloid leukemia population too often achieve suboptimal initial drug concentrations. Our aim was to assess vancomycin pharmacokinetic parameters in acute myeloid leukemia patients and develop an improved dosing equation to attain more accurate initial therapeutic trough levels. Acute myeloid leukemia patients receiving vancomycin for a presumed or documented gram positive infection were eligible. Patients hospitalized in the intensive care unit, those with creatinine clearance <30 mL/min or with limb amputation were excluded. Three samples were collected at the following post-infusion time ranges: 1 h, 3-8 h, and 8-24 h post-infusion, contingent on the dosing interval. Pharmacokinetic data were then fit using a Bayesian-based population pharmacokinetic model. A total of 25 acute myeloid leukemia patients were studied with a mean volume in the central compartment (Vc; L/65 kg), volume of distribution at steady state (Vss; L/65 kg) and distributional clearance (CLd; L/h/65 kg) of 15, 38.9, and 9.32, respectively. CLslope was 0.59 (mg of vancomycin clearance per unit of creatinine clearance in mL/min); this value is 21.4% lower than the established literature value (0.75). The derived equation, based upon these values, was reasonably precise at achieving the desired trough concentration using a priori dosing. The mean (CV%) of the achieved trough was 94% (29%) with a range of 66-188%; 3/25 at <75% and >125%]. We have established that the derived dosing equation can place ~ 75% of adult acute myeloid leukemia patients at vancomycin trough levels within 75-125% of the target trough level. PMID- 21521800 TI - Screening and identification of a novel class of TGF-beta type 1 receptor kinase inhibitor. AB - Transforming growth factor beta (TGF-beta) type I receptor (activin receptor-like kinase 5, ALK5) has been identified as a promising target for fibrotic diseases. To find a novel inhibitor of ALK5, the authors performed a high-throughput screen of a library of 420,000 compounds using dephosphorylated ALK5. From primary hits of 1521 compounds, 555 compounds were confirmed. In total, 124 compounds were then selected for follow-up based on their unique structures and other properties. Repeated concentration-response testing and final interference assays of the above compounds resulted in the discovery of a structurally novel ALK5 inhibitor (compound 8) (N-(thiophen 2-ylmethyl)-3-(3,4,5 trimethoxyphenyl)imidazo[1,2beta]pyridazin 6-amine) with a low IC(50) value of 0.7 uM. Compound 8 also inhibited the TGF-beta-induced nuclear translocation of SMAD with an EC(50) value of 0.8 uM. Kinetic analysis revealed that compound 8 inhibited ALK5 via mixed-type inhibition, suggesting that it may bind to ALK5 differently than other published adenosine triphosphate site inhibitors. PMID- 21521801 TI - Open innovation for phenotypic drug discovery: The PD2 assay panel. AB - Phenotypic lead generation strategies seek to identify compounds that modulate complex, physiologically relevant systems, an approach that is complementary to traditional, target-directed strategies. Unlike gene-specific assays, phenotypic assays interrogate multiple molecular targets and signaling pathways in a target "agnostic" fashion, which may reveal novel functions for well-studied proteins and discover new pathways of therapeutic value. Significantly, existing compound libraries may not have sufficient chemical diversity to fully leverage a phenotypic strategy. To address this issue, Eli Lilly and Company launched the Phenotypic Drug Discovery Initiative (PD(2)), a model of open innovation whereby external research groups can submit compounds for testing in a panel of Lilly phenotypic assays. This communication describes the statistical validation, operations, and initial screening results from the first PD(2) assay panel. Analysis of PD(2) submissions indicates that chemical diversity from open source collaborations complements internal sources. Screening results for the first 4691 compounds submitted to PD(2) have confirmed hit rates from 1.6% to 10%, with the majority of active compounds exhibiting acceptable potency and selectivity. Phenotypic lead generation strategies, in conjunction with novel chemical diversity obtained via open-source initiatives such as PD(2), may provide a means to identify compounds that modulate biology by novel mechanisms and expand the innovation potential of drug discovery. PMID- 21521802 TI - Aurora A is a repressed effector target of the chromatin remodeling protein INI1/hSNF5 required for rhabdoid tumor cell survival. AB - Rhabdoid tumors (RT) are aggressive pediatric malignancies with poor prognosis. INI1/hSNF5 is a component of the chromatin remodeling SWI/SNF complex and a tumor suppressor deleted in RT. Previous microarray studies indicated that reintroduction of INI1/hSNF5 into RT cells leads to repression of a high degree of mitotic genes including Aurora Kinase A (Aurora A, STK6). Here, we found that INI1/SNF5 represses Aurora A transcription in a cell-type-specific manner. INI1 mediated repression was observed in RT and normal cells but not in non-RT cell lines. Chromatin immunoprecipitation (ChIP) assay indicated that INI1/hSNF5 associates with Aurora A promoter in RT and normal cells but not in non-RT cells. Real-time PCR and immunohistochemical analyses of primary human and mouse RTs harboring mutations in INI1/hSNF5 gene indicated that Aurora A was overexpressed/derepressed in these tumor cells, confirming that INI1/hSNF5 represses Aurora A in vivo. Knockdown of Aurora A impaired cell growth, induced mitotic arrest and aberrant nuclear division leading to decreased survival, and increased cell death and caspase 3/7-mediated apoptosis in RT cells (but not in normal cells). These results indicated that Aurora A is a direct downstream target of INI1/hSNF5-mediated repression in RT cells and that loss of INI1/hSNF5 leads to aberrant overexpression of Aurora A in these tumors, which is required for their survival. We propose that a high degree of Aurora A expression may play a role in aggressive behavior of RTs and that targeting expression or activity of this gene is a novel therapeutic strategy for these tumors. PMID- 21521803 TI - STAT3 inhibition is a therapeutic strategy for ABC-like diffuse large B-cell lymphoma. AB - Persistent STAT3 signaling contributes to malignant progression in many diverse types of human cancer. STAT3 is constitutively active in activated B-cell (ABC) like diffuse large B-cell lymphomas (DLBCL), a class of nongerminal center derived DLBCL cells for which existing therapy is weakly effective. In this report, we provide a preclinical proof of concept that STAT3 is an effective molecular target for ABC-like DLBCL therapy. Direct inhibition of STAT3 with short hairpin RNA suppressed the growth of human ABC-like DLBCL in mouse models in a manner associated with apoptosis, repression of STAT3 target genes, and inhibition of a tumor-promoting microenvironment. Together, these results suggest that STAT3 is essential to maintain the pathophysiology of ABC-like DLBCL and therefore that STAT3 inhibition may offer a promising approach in its therapy. PMID- 21521804 TI - The immune reconstitution inflammatory syndrome with tuberculosis: a common problem in Ethiopian HIV-infected patients beginning antiretroviral therapy. AB - The Immune Reconstitution Inflammatory Syndrome (IRIS) in Ethiopian HIV-infected patients coinfected with tuberculosis (TB) was studied. HIV-infected outpatients initiating antiretroviral therapy (ART) at an HIV clinic in northern Ethiopia from January 2007 through September 2008 were identified (n = 1977). Patients with TB-IRIS occurring within 6 months of starting ART (n = 143) were compared with a control group of patients with HIV who began ART but did not develop TB IRIS (n = 277). ART was not interrupted in any patient. Eleven (8%) patients with TB-IRIS died. New or "unmasked" TB with accompanying IRIS occurred in 132 or 92% of the cases. Worsening or "paradoxical" TB (ie, already known to be present and treated) was accompanied by IRIS in 11 (8%) patients. There was no significant difference between "unmasked" and "paradoxical" cases with respect to presentation of disease and outcome. Only a low baseline CD4 count (mean: 102 cells/MUL) and a past history of World Health Organization (WHO) Clinical Stage 3 or 4 were associated with TB-IRIS (P < .05). The clinical manifestations of TB IRIS were diverse, requiring a high index of suspicion. For example, pleural disease occurred in 13 patients, TB lymphadenitis in 17, intracranial TB in 9 patients, and disseminated TB in 15 patients. The majority of patients (88%) responded to continuation of ART and TB therapy. Thus, TB-IRIS is common in Ethiopian patients beginning ART, occurring in 7% of patients initiating antiretroviral therapy. PMID- 21521805 TI - A Comparison of Sonographic Assessments and Clinical Questionnaire in the Diagnosis of HIV-Associated Lipodystrophy. AB - The study evaluated the use of sonographic measurements as an alternative to assessments based on clinical or other imaging techniques for the diagnosis of body-fat abnormalities. The study enrolled 179 HIV-infected patients, 81 (45.3%) of them diagnosed as lipodystrophy (LD)-positive based on a clinical standard questionnaire. Association between clinical LD and sonographic measurements of face, right upper limb, subcutaneous abdomen, and visceral compartments was evaluated by multiple logistic regression. The predicted probability of the logistic model was 0.64, corresponding to a maximum sensitivity of 69.1% (58% 79%), a specificity of 94.9% (88%-98%), and to positive and negative predictive values of 92% (82%-97%) and 79% (70%-86%), respectively. Kappa measure of concordance was 65% (54%-77%). Low sensitivity poses a problem for the use of sonography to detect LD in the clinical routine as a single exam, speaking in favor of the combined use of clinical and sonographic measurements over time. PMID- 21521806 TI - Stigma and access to HIV care among HIV-infected women in Kolkata, West Bengal. AB - OBJECTIVES: Stigma is an important issue for marginalized HIV-infected populations. We describe stigma among HIV-infected women on antiretroviral therapy and associations with access to clinical care, demographic factors, and structural elements of support. METHODS: HIV-infected women attending a government-supported clinic in Kolkata, India, were asked about experiences with stigma. Clinical information was abstracted from medical records. We described factors associated with stigma using ordinal logistic regression. RESULTS: Among 198 women, higher levels of stigma were associated with lower CD4 count upon entry into care (aOR = 0.78; 95% confidence interval [CI]: [0.65, 0.94]), district of residence (aOR = 1.9; CI: [1.0, 3.4]), presence of extended family in the household (aOR = 0.57; CI: [0.32, 1.0]), and employment at the time of the interview (aOR = 0.48; CI: [0.26, 0.90]). Stigma was not associated with having missed scheduled HIV care appointments. CONCLUSION: Stigma is prevalent among Indian women with HIV, should be further explored, and may be important in considering public health interventions for better access to care. PMID- 21521807 TI - Assessment of stigma and discrimination experienced by people living with HIV and AIDS receiving care/treatment in University of Ilorin Teaching Hospital (UITH), Ilorin, Nigeria. AB - The research was designed to assess the stigma and discrimination faced by People living with HIV and AIDS (PLWHA) that are receiving treatment in UITH, Ilorin. The study was a descriptive cross-sectional survey conducted on three hundred (300) people living with HIV and AIDS receiving care at the antiretroviral therapy (ART) clinics within University of Ilorin Teaching Hospital (which was the only ART site in Kwara State as at then). A quantitative method through the use of interviewer administered questionnaire was used for data collection. This study was a cross-sectional descriptive study design. All the patients who came to the clinic and met the selection criteria were recruited until the desired sample size was reached. Data were analyzed by EPI-INFO 2005 software package. The mean age of the respondents was 39 years (SD = 9.32), and their age ranged between 19 and 65 years. About two thirds (64.7%) of the respondents were females, 62.7% were married, and 62.9% were from monogamous family settings. Slightly less than half (47.3%) of the respondents were not informed before they were tested for HIV, majority (63.3%) were not counseled before the test, but only 11% did not receive posttest counseling. One quarter of the respondents had experienced stigmatization/discrimination. Various forms of stigmatization/discrimination experienced by the respondents include blame for being responsible for their HIV status, various name callings, telling them that they are no more useful to anybody, violation of confidentiality, social isolation, restriction of their participation in family/religious activities, rejection by their spouses/families, dismissal from place of work, isolating them from other patients, and denying them care at health centers. It is therefore recommended that government at all levels should develop and implement programs to educate health care providers about HIV and AIDS, ethics, and treatment and care; educate the general population on HIV and AIDS, put in place policies that will reduce/stop HIV-related stigma and discrimination at all levels of the society, educate PLWHA on their right to live and work without discrimination, and also ensure full community participation in HIV control programs. PMID- 21521808 TI - Reducing waiting time at a Nigerian HIV treatment clinic: opinions from and the satisfaction of people living with HIV/AIDS. AB - We assessed the waiting time and perceived satisfaction with care among people living with HIV/AIDS (PLHIV) at an antiretroviral clinic in Nigeria. A structured questionnaire was administered during interviews. Four hundred patients completed the questionnaire. The mean age of the respondents was 36.4 years (SD 9.7 years), and 61% of them were females. A majority, 72.9%, reported that the time elapsed between entry into the clinic and access to medical care services (waiting time) was more than an hour. However, a majority (77%) expressed satisfaction with the medical care they received. Although the majority of PLHIV were satisfied with their medical care, more needs to be done to reduce patient waiting time before access to medical services. PMID- 21521809 TI - Vitamin D Deficiency in HIV-Infected Women on Antiretroviral Therapy Living in the Tropics. AB - The effects of HIV/AIDS and antiretroviral drugs on vitamin D metabolism are still mostly unknown. This was a cross-sectional study to estimate the prevalence of vitamin D deficiency and identify its association with the clinical and metabolic parameters among 214 HIV-positive female patients on antiretroviral therapy (ART) in Brazil. The prevalence of vitamin D deficiency (< 30 ng/ml) was 40.65% (87/214). Hypercholesterolemia, high LDL-c, duration of use of current antiretroviral regimen, hypertriglyceridemia, body mass index, age, hypertension, time with AIDS >= 10 years and hyperglycemia were selected for multivariate analysis (p < 0.20). After this analysis, hypercholesterolemia and use of current antiretroviral regimen >= 3 years remained independently associated with vitamin D deficiency. There was an inverse statistically significant correlation between total cholesterol and serum 25(OH)D levels. High prevalence of vitamin D deficiency was found among HIV-positive women on ART and was independently associated with its prolonged use and with hypercholesterolemia. PMID- 21521810 TI - Genetic analysis of longitudinal measurements of performance traits in selection lines for residual feed intake in Yorkshire swine. AB - A 5-generation selection experiment in Yorkshire pigs for feed efficiency consists of a line selected for low residual feed intake (LRFI) and a random control line (CTRL). The objectives of this study were to use random regression models to estimate genetic parameters for daily feed intake (DFI), BW, backfat (BF), and loin muscle area (LMA) along the growth trajectory and to evaluate the effect of LRFI selection on genetic curves for DFI and BW. An additional objective was to compare random regression models using polynomials (RRP) and spline functions (RRS). Data from approximately 3 to 8 mo of age on 586 boars and 495 gilts across 5 generations were used. The average number of measurements was 85, 14, 5, and 5 for DFI, BW, BF, and LMA. The RRP models for these 4 traits were fitted with pen * on-test group as a fixed effect, second-order Legendre polynomials of age as fixed curves for each generation, and random curves for additive genetic and permanent environmental effects. Different residual variances were used for the first and second halves of the test period. The RRS models were fitted with the same fixed effects and residual variance structure as the RRP models and included genetic and permanent environmental random effects for both splines and linear Legendre polynomials of age. The RRP model was used for further analysis because the RRS model had erratic estimates of phenotypic variance and heritability, despite having a smaller Bayesian information criterion than the RRP model. From 91 to 210 d of age, estimates of heritability from the RRP model ranged from 0.10 to 0.37 for boars and 0.14 to 0.26 for gilts for DFI, from 0.39 to 0.58 for boars and 0.55 to 0.61 for gilts for BW, from 0.48 to 0.61 for boars and 0.61 to 0.79 for gilts for BF, and from 0.46 to 0.55 for boars and 0.63 to 0.81 for gilts for LMA. In generation 5, LRFI pigs had lower average genetic curves than CTRL pigs for DFI and BW, especially toward the end of the test period; estimated line differences (CTRL-LRFI) for DFI were 0.04 kg/d for boars and 0.12 kg/d for gilts at 105 d and 0.20 kg/d for boars and 0.24 kg/d for gilts at 195 d. Line differences for BW were 0.17 kg for boars and 0.69 kg for gilts at 105 d and 3.49 kg for boars and 8.96 kg for gilts at 195 d. In conclusion, selection for LRFI has resulted in a lower feed intake curve and a lower BW curve toward maturity. PMID- 21521811 TI - Somatic cell score genetic parameter estimates of dairy cattle in Portugal using fractional polynomials. AB - Milk somatic cell count is an indicator trait for mastitis resistance. Genetic parameters for somatic cell score in the Portuguese Holstein-Friesian population were estimated by modeling the pattern of genetic correlation over the first 3 lactations (days in milk) with a random regression model. Data records from the first 3 lactations were from the national database of the Portuguese Holstein Association herds. Heritability estimates ranged from 0.05 at the beginning of the lactation for the 3 lactations, to 0.07 at the end of the lactation period for the first and third lactations, to 0.09 for the second lactation. This increase in the heritability values was due to an increase in the genetic variance and a decrease in the residual variances. Genetic correlations evaluated for monthly time points were high (0.65 to 0.99) for all 3 lactations, whereas phenotypic correlations were much less than the genetic correlations (0.13 to 0.62). PMID- 21521812 TI - Different ways to model biological relationships between fertility and pH of the semen in rabbits. AB - This work aimed to study the relationship between pH of the semen and fertility (Fert, defined as the success or failure of conception), which is of special interest because pH of the semen can be considered a global marker of the expression of some seminal quality traits. Different methods used to model the relationship between Fert and pH are presented here: 1) ignoring genetic and environmental correlations and including pH either as a covariate or as a cross classified effect on fertility, 2) a bivariate mixed model, and 3) recursive bivariate mixed models. A total of 653 pH records and 6,365 Fert records after AI were used. Crossbreed does from 2 maternal lines were artificially inseminated with buck semen from a paternal line in a commercial environment. A negative, and almost linear, effect of pH on Fert was detected. The posterior median of pH and Fert heritabilities, and the highest posterior density interval at 95% (in parentheses) were approximately 0.18 (0.05, 0.29) and approximately 0.10 (0.02, 0.20) across all the models, respectively. Genetic correlations between traits were negative, but the highest posterior density interval at 95% included zero [i.e., -0.31 (-0.91, 0.33) in the bivariate mixed model and -0.17 (-0.99, 0.48) and -0.44 (-0.99, 0.10) in the recursive bivariate mixed models including pH as a covariate or as a cross-classified effect, respectively]. All models predicted Fert data reasonably well (i.e., 76 and 62% correct predictions for success and failure, respectively). No differences in the prediction of the EBV for male fertility were encountered between models, showing a good concordance in the animals ranked by their EBV (the correlation between EBV in all models was close to 1). Thus, no differences in results were obtained considering, or not considering, genetic and environmental correlations between pH and Fert and assuming, or not assuming, recursiveness between each trait. This is because the magnitude of the effect of pH on Fert was not large enough; therefore, the same results were obtained even though the models were of different complexity. PMID- 21521813 TI - Monitoring of genetic diversity in the endangered Martina Franca donkey population. AB - The Martina Franca (MF) donkey, an ancient native breed of Apulia, was mostly famous for mule production. The breed was at serious risk of extinction in the 1980s following the decrease in demand for draft animals because they were increasingly replaced by agricultural machinery. Much has been done in the last few decades to safeguard the existing donkey breeds, but the situation remains critical. Successful implementation of conservation measures includes an evaluation of the present degree of breed endangerment, so the aim of this work was to analyze the demographic and genetic parameters of this breed to suggest effective conservation strategies. With a current breed register counting less than 500 recorded animals, the pedigree data set included 1,658 MF donkeys born between 1929 and 2006. Analyses were carried out on the whole data set as well as on a smaller one consisting of 422 living animals. Demographic and genetic variability parameters were evaluated using the ENDOG (v4.6) software. The pedigree completeness level was evaluated as well as the generation length, which was calculated for each of the 4 gametic pathways. This information was obtained from animal birth date records together with those of their fathers and mothers. The effective number of founders (f(e)), the effective number of ancestors (f(a)), the founder genome (f(g)), individual inbreeding (F), average relatedness (AR), and the rate of inbreeding per generation were analyzed to describe the genetic variability of the population. Because pedigree depth and completeness were appropriate, especially regarding the current population, the parameters defining genetic variability, namely, f(e), f(a), f(g), F, and AR, could be reliably estimated. Analysis of these parameters highlighted the endangerment status of the MF donkey. Our special concern was with the increased percentage of males and females exhibiting increased AR values. Moreover, the effective size of the current population, 48.08, is slightly less than the range of the minimum effective size, and the rates of inbreeding per generation found in the current MF population exceed the maximum recommended level of 1%. Such a scenario heightens concerns over the endangered status of the MF breed and calls for proper conservation measures and breeding strategies, such as selecting individuals for mating when relationships are below 12.5%. PMID- 21521814 TI - Bovine luteal prolactin receptor expression: potential involvement in regulation of progesterone during the estrous cycle and pregnancy. AB - In the present study, we performed quantitative reverse-transcription PCR (qPCR) to examine changes in gene expression of prolactin receptor (long form: l-PRLR; short form: s-PRLR) and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD; EC 1.1.1.149) in the bovine corpus luteum (CL) throughout the estrous cycle and pregnancy. Western blotting was used to determine protein abundance. Bovine CL were collected and luteal stages (n = 6/stage) were classified by macroscopic observation as early (d 1 to 4 after ovulation), mid (d 5 to 10), late (d 11 to 17), and regressing (d 18 to 20). A CL of pregnancy (n = 6) was determined by the presence of conceptus (d 28 to term). The mRNA for both forms of PRLR were expressed at all the luteal stages. Expression of s-PRLR and l-PRLR mRNA was less (P < 0.01) during early and regressing luteal stages compared with mid and late stages. Expression of s-PRLR mRNA in CL of pregnancy was greater (P < 0.01) than early, mid, and regressing CL and did not differ from late luteal stage expression. A greater (P < 0.01) expression of l-PRLR mRNA was observed in pregnant vs. early and regressing CL. In addition, qPCR showed the presence of 20alpha-HSD mRNA during all luteal stages of the estrous cycle, with the greatest (P < 0.01) expression observed in the regressing luteal stage. Western blotting revealed protein abundance of both PRLR isoforms during all luteal stages and pregnancy, with a predominance of the s-PRLR protein. Densitometry analysis indicated that protein abundances of s-PRLR were greater (P < 0.05) than l-PRLR during early, mid, and late luteal stages and did not differ during the regressing luteal stage. Protein abundances of 20alpha-HSD were least (P < 0.05) during the early luteal stage. In conclusion, results of the current study suggest a possible involvement of PRLR, especially s-PRLR, in the regulation of progesterone secretion and metabolism during the bovine estrous cycle and pregnancy. PMID- 21521815 TI - Modification of selected bacteria and markers of protein fermentation in the distal gastrointestinal tract of pigs upon consumption of chitosan is accompanied by heightened manure odor emissions. AB - Previous studies have indicated that reducing dietary CP may improve N utilization and effectively diminish manure ammonia emissions; however, the response of manure odor emissions to such dietary modifications has been inconsistent. The objective of the current experiment was to induce decreased lactobacilli (DL) numbers in the distal gastrointestinal tract (dGIT; cecum + colon) of finishing pigs offered both high- and low-CP diets through consumption of chitosan, and examine the influence of this model on manure ammonia and odor emissions when compared with a positive control diet. It was hypothesized that an DL population would be accompanied by an increase in markers of protein fermentation. When compared with normal lactobacilli populations in the dGIT, generation of an DL population would result in increased manure odor emissions from pigs offered both dietary CP concentrations. A 2 * 2 factorial arrangement of treatments was conducted to investigate the effect of including chitosan [0 (positive control) vs. 20 g/kg of feed] and high or low dietary CP concentration (200 vs. 150 g/kg of feed) on nutrient digestibility, N utilization, selected bacterial populations, and metabolite composition of the dGIT and manure emissions from finisher pigs (60.3 kg). Consumption of chitosan had no influence (P > 0.05) on nutrient digestibility or N utilization. In both high- and low-CP diets, consumption of chitosan decreased the lactobacilli-to-Enterobacteriaceae ratio (P < 0.01), generating an DL population, and increased pH (P < 0.01) in the dGIT and ammonia (P = 0.02) in the cecum compared with diets that supported normal lactobacilli populations. Consumption of chitosan decreased molar proportions of butyric acid (P < 0.01) and increased valeric acid (P < 0.01) in the dGIT compared with unsupplemented diets. Furthermore, consumption of chitosan increased manure odor emissions (P = 0.05) compared with unsupplemented diets. There was no effect (P > 0.05) of chitosan consumption on manure ammonia emissions from 0 to 240 h. The current study demonstrates that dietary chitosan suppressed populations of lactobacilli in the dGIT. In response, a considerable increase in Enterobacteriaceae, markers of protein fermentation, and manure odor emissions was observed compared with the positive control diet. These effects were observed in pigs offered both high-and low-CP diets. The current study indicates a possible role for lactic-acid bacteria in modulating manure odor emissions relatively independent of the proportions of dietary CP available for fermentation in the dGIT. PMID- 21521816 TI - Effects of dietary iodine value product on growth performance and carcass fat quality of finishing pigs. AB - A total of 120 barrows (initial BW = 47.9 +/- 3.6 kg; PIC 1050) were used in an 83-d study to determine the effects of dietary iodine value (IV) product (IVP) on growth performance and fat quality. Pigs were blocked by BW and randomly allotted to 1 of 6 treatments with 2 pigs per pen and 10 pens per treatment. Dietary treatments were fed in 3 phases and formulated to 3 IVP concentrations (low, medium, and high) in each phase. Treatments were 1) corn-soybean meal control diet with no added fat (low IVP), 2) corn-extruded expelled soybean meal (EESM) diet with no added fat (medium IVP), 3) corn-soybean meal diet with 15% distillers dried grains with solubles and choice white grease (DDGS + CWG; medium IVP), 4) corn-soybean meal diet with low CWG (medium IVP), 5) corn-EESM diet with 15% DDGS (high IVP), and 6) corn-soybean meal diet with high CWG (high IVP). On d 83, pigs were slaughtered and backfat and jowl fat samples were collected and analyzed. The calculated and analyzed dietary IVP values were highly correlated (r(2) = 0.86, P < 0.01). Pigs fed the control diet, EESM, or high CWG had greater (P < 0.05) ADG than pigs fed EESM + DDGS. Pigs fed the control diet had greater (P < 0.05) ADFI than pigs fed all other diets. Pigs fed EESM + DDGS and high CWG had improved (P < 0.05) G:F compared with pigs fed the control diet or DDGS + CWG. Pigs fed diets with DDGS had greater (P < 0.05) backfat and jowl fat IV, C18:2n-6, and PUFA and less SFA than pigs fed all other treatments. Pigs fed EESM had greater (P < 0.05) backfat and jowl fat IV, C18:2n-6, and PUFA than pigs fed the control diet, low CWG, or high CWG. Pigs fed low CWG or high CWG had greater (P < 0.05) jowl fat IV than control pigs. Feeding ingredients high in unsaturated fatty acids, such as DDGS and EESM, had a greater impact on fat IV than CWG, even when diet IVP was similar. Therefore, IVP was a poor predictor of carcass fat IV in pigs fed diets with different fat sources and amounts of unsaturated fats formulated with similar IVP. Dietary C18:2n-6 content was a better predictor of carcass fat IV than diet IVP. PMID- 21521817 TI - Companion animals symposium: microbes and health. PMID- 21521818 TI - Effect of feed withdrawal and dietary energy source on muscle glycolytic potential and blood acid-base responses to handling in slaughter-weight pigs. AB - The effects of dietary energy source and feed withdrawal on muscle glycolytic potential (GP) and blood acid-base responses to handling were investigated in slaughter-weight pigs (initial BW 94.7 +/- 1.01 kg). Crossbred pigs (n = 96; 48 barrows, 48 gilts) were used in a randomized complete block design with a 4 * 2 * 2 factorial arrangement of treatments: l) diet [control, high fat (10% supplemental fat), low-digestible carbohydrate (20% total starch), and high fat/low-digestible carbohydrate (10% supplemental fat and 20% total starch)]; 2) feed withdrawal (0 and 36 h); and 3) sex (barrow and gilt). Diets were fed for 28 d before the feed withdrawal treatment was applied, at the end of which all pigs were individually moved through a 12.20-m-long * 0.91-m-wide passageway for 16 laps (195 m total distance), with the assistance of an electric goad (2 times per lap). Longissimus muscle biopsies were collected at the beginning of the feeding and feed withdrawal periods and immediately after and 4 h after the handling procedure. Venous blood was collected 2 h before and immediately after the handling procedure to measure acid-base responses. At the end of the feeding period, pigs fed the control and high-fat diets were heavier (P < 0.001) than those on the low-digestible carbohydrate and the high-fat/low-digestible carbohydrate diets (129.8, 130.9, 114.0, and 122.1 kg, respectively; SEM 1.91). Diet, feed withdrawal, and sex did not affect (P > 0.05) blood acid-base responses to handling. Muscle GP at the end of the feeding period and 4 h posthandling was least (P < 0.05) for pigs fed the high-fat diet and similar for the other 3 diet treatments. Pigs subjected to 36 h compared with 0 h of feed withdrawal had less GP (P < 0.05) immediately after and 4 h after the handling procedure. There was an interaction between diet and feed withdrawal treatments for changes in GP from the start of feed withdrawal to 4 h posthandling. The reduction in GP was greater (P < 0.05) for fasted than for fed pigs receiving the control and high-fat diets, but was similar (P > 0.05) for fasted and fed pigs receiving the 2 low-digestible carbohydrate diets. In conclusion, neither dietary energy source nor fasting affected blood acid-base responses to handling; however, fasting-induced changes in LM GP were diet dependent. PMID- 21521819 TI - Immune response and blood chemistry of pigs fed conjugated linoleic acid. AB - Immune function (response to concanavalin A, cytokine production, and lymphocyte profiles) and blood chemistry variables were measured in growing-finishing pigs (Yorkshire/Landrace/Duroc dam * Hampshire sire) fed varying percentages of CLA (0, 0.12, 0.25, 0.50, and 1.0%). Blood was collected at 0, 14, 28, 42, and 56 d on feed (DOF). Total white blood cell (WBC) count increased (P < 0.01) linearly to 42 DOF. No differences (P = 0.53) were observed for WBC across CLA treatment. Nitric oxide was greater (P < 0.01) for the 1.0% CLA treatment compared with all other treatments. Flow cytometry using fluorescent labeled monoclonal antibodies to the CD4, CD8, double-positive CD4/CD8, and CD2 surface markers was used to determine lymphocyte subpopulations. Supplementation of CLA had no effect (P = 0.61) on lymphocyte subpopulation cell distribution. Most blood chemistry variables were within the normal metabolic range for pigs. A decrease was observed over DOF for P (P < 0.01) and K (P < 0.05). Additionally, Na and Cl concentrations increased (P < 0.05) from 14 to 28 DOF and decreased over the remainder of the trial. Electrolyte balance was not different (P = 0.38) across CLA treatments and was likely explained by no differences in feed intake among the CLA treatment groups. Blood lipid variables indicated that total cholesterol (P < 0.001), triglycerides (P < 0.001), high-density lipoproteins (P < 0.001), and low-density lipoproteins (P < 0.01) increased as the amount of CLA in the diet increased, but none of the results from these treatments exceeded the normal range of acceptability. These results suggested that CLA was safe when fed to growing-finishing pigs and had little effect on their immune function and blood chemistry variables. PMID- 21521820 TI - Heifer development systems: dry-lot feeding compared with grazing dormant winter forage. AB - Two hundred ninety-nine Angus-based, nulliparous heifers (253 +/- 2 kg initial BW) from 3 production years were utilized to compare traditional postweaning dry lot (DL) development with a more extensive winter grazing system utilizing a combination of corn residue and winter range (EXT). Heifers developed in the DL were offered a common diet after the weaning period for 208 d in yr 1, 194 d in yr 2, and 150 d in yr 3 until breeding. Heifers developed in EXT grazed corn residue for 135 d in yr 1, 106 d in yr 2, and 91 d in yr 3, and then fed in the DL until breeding (yr 1) or grazed dormant winter grass for approximately 60 d before being fed in the DL (yr 2 and 3). All 3 years, heifers were estrus synchronized, with timed AI performed in yr 1. In yr 2 and 3, estrus was detected and those detected in estrus were artificially inseminated approximately 12 h later. Heifers were exposed to bulls 10 d after the last AI for 60 d while grazing summer pasture. During the winter grazing period, EXT heifers gained less (P = 0.01) BW than DL heifers and EXT heifers had lighter (P = 0.02) BW at breeding. Fewer (P < 0.01) EXT heifers reached puberty before breeding. Conception to AI was not different (P = 0.23); however, AI pregnancy rate tended (P = 0.08) to be less in EXT heifers. Final pregnancy rates were not different (P = 0.38) between treatment groups. Although EXT heifers had lighter (P = 0.02) BW at pregnancy diagnosis; however, they did compensate with greater (P = 0.05) ADG after breeding, resulting in similar (P = 0.22) precalving BW. Winter development system did not influence (P > 0.10) percentage of calving in the first 21 d, calf birth date, and calf birth BW, or dystocia score. Pregnancy rate after the second breeding season was not different (P = 0.56) between treatments. Heifer development using extended winter grazing reduced (P < 0.01) the cost of producing a pregnant heifer by $45 compared with DL. PMID- 21521821 TI - Board-invited review: St. Anthony's Fire in livestock: causes, mechanisms, and potential solutions. AB - After a brief history of ergot alkaloids and ergotism, this review focuses on the metabolism and mechanisms of action of the ergot alkaloids. The authors provide models of how these alkaloids afflict grazing livestock under complex animal plant/endophyte-environmental interactions. Alkaloid chemistry is presented to orient the reader to the structure-function relationships that are known to exist. Where appropriate, the medical literature is used to aid interpretation of livestock research and to provide insight into potential modes of action and alkaloid metabolism where these are not known for livestock. In closing the paper, we discuss management of ergot alkaloid intoxication in livestock and future research needs for this field of study. PMID- 21521822 TI - Nutritional plane and selenium supply during gestation affect yield and nutrient composition of colostrum and milk in primiparous ewes. AB - The objectives were to investigate effects of nutritional plane and Se supply during gestation on yield and nutrient composition of colostrum and milk in first parity ewes. Rambouillet ewe lambs (n = 84, age = 240 +/- 17 d, BW = 52.1 +/- 6.2 kg) were allocated to 6 treatments in a 2 * 3 factorial array. Factors included Se [adequate Se (ASe, 11.5 ug/kg of BW) or high Se (HSe, 77.0 ug/kg of BW)] initiated at breeding, and nutritional plane [60 (RES), 100 (CON), or 140% (HIH) of requirements] initiated at d 40 of gestation. Ewes were fed individually from d 40, and lambs were removed at parturition. Colostrum was milked from all ewes at 3 h postpartum, and one-half of the ewes (n = 42) were transitioned to a common diet meeting lactation requirements and mechanically milked for 20 d. Colostrum yield was greater (P = 0.02) for HSe ewes than ASe, whereas CON had greater (P < 0.05) colostrum yield than RES and HIH. Colostrum Se (%) was greater (P < 0.01) for HSe than ASe. Colostrum from ewes fed HSe had less (P = 0.03) butterfat (%), but greater (P <= 0.05) total butterfat, solids-not-fat, lactose, protein, milk urea N, and Se than ASe. Colostrum from HIH ewes had greater (P <= 0.02) solids-not-fat (%) than RES, whereas RES had greater (P <= 0.04) butterfat (%) than CON and HIH. Colostrum from ewes fed the CON diet had greater (P = 0.01) total butterfat than HIH. Total solids-not-fat, lactose, and protein were greater (P < 0.05) in colostrum from CON than RES and HIH. Ewes fed HSe had greater (P < 0.01) milk yield (g/d and mL/d) than ASe, and CON and HIH had greater (P < 0.01) yield than RES. Milk protein (%) was greater (P <= 0.01) in RES compared with CON or HIH. Ewes fed HSe had greater (P < 0.01) milk Se (ug/g and mg/d) than ASe on each sampling day. Milk from CON and HIH ewes had greater (P < 0.01) total solids not-fat, lactose, protein, and milk urea N than RES. Total Se was greater (P = 0.02) in milk from ewes fed the CON diet compared with RES. Somatic cell count and total somatic cells were greater (P <= 0.05) in milk from CON than RES. A cubic effect of day (P >= 0.01) was observed for milk yield (g and mL). Butterfat, solids-not-fat, lactose, milk urea N, and Se concentration responded quadratically (P <= 0.01) to day. Protein (%), total butterfat, and total Se, and somatic cells (cells/mL and cells/d) decreased linearly (P < 0.01) with day. Results indicate that gestational nutrition affects colostrum and milk yield and nutrient content, even when lactational nutrient requirements are met. PMID- 21521823 TI - The acute toxicity of the death camas (Zigadenus species) alkaloid zygacine in mice, including the effect of methyllycaconitine coadministration on zygacine toxicity. AB - Death camas (Zigadenus spp.) is a common poisonous plant on foothill rangelands in western North America. The steroidal alkaloid zygacine is believed to be the primary toxic component in death camas. Poisonings on rangelands generally occur in the spring when death camas is abundant, whereas other more desirable forage species are limited in availability. In most cases where livestock are poisoned by plants in a range setting, there is more than one potential poisonous plant in that area. One common poisonous plant that is often found growing simultaneously in the same area as death camas is low larkspur (Delphinium nuttallianum). Consequently, the objectives of this study were to conduct acute toxicity studies in mice and to determine if coadministration of low larkspur will exacerbate the toxicity of death camas. We first characterized the acute toxicity of zygacine in mice. The LD(50) of zygacine administered intravenously (i.v.) and orally was 2.0 +/- 0.2 and 132 +/- 21 mg/kg, respectively. The rate of elimination of zygacine from whole blood was determined to be 0.06 +/- 0.01/min, which corresponds to an elimination half-life of 13.0 +/- 2.7 min. The i.v. LD(50) of total alkaloid extracts from a Utah and a Nevada collection were 2.8 +/- 0.8 and 2.2 +/- 0.3 mg/kg, respectively. The i.v. LD(50) of methyllycaconitine (MLA), a major toxic alkaloid in low larkspur, was 4.6 +/- 0.5 mg/kg, whereas the i.v. LD(50) of a 1:1 mixture of MLA and zygacine was 2.9 +/- 0.7 mg/kg. The clinical signs in mice treated with this mixture were very similar to those of mice treated with zygacine alone, including the time of onset and death. These results suggest that there is an additive effect of coadministering these 2 alkaloids i.v. in mice. The results from this study increase knowledge and understanding regarding the acute toxicity of death camas. As combined intoxications are most likely common, this information will be useful in further developing management recommendations for ranchers and in designing additional experiments to study the toxicity of death camas to livestock. PMID- 21521825 TI - Uncertainty and decision making for residents with dementia. AB - Uncertainty is a significant barrier confronting surrogate decision makers(SDMs) who make treatment decisions for nursing home (NH) residents with dementia. The study purpose is to describe uncertainty among SDMs of NH residents with dementia and to identify factors associated with greater Uncertainty. We employed a nonexperimental, cross-sectional design using mailed survey and recruited 155 SDM participants from eight NHs in New England. The survey contained the Mishel Uncertainty in Illness Scale For Family Members. Independent variables included resident and SDM sociodemographic characteristics, Advance Directives, Credible Authority, Social Support, and Perceived Self-Efficacy for Surrogate Decision Making. Results of a simultaneous multiple regression analysis identified Perceived Self-Efficacy,Social Support, and Close Relative explained 22% of the Uncertainty variance.These findings suggest that close family relatives who serve as SDMs for NH residents with dementia may benefit from increasing social support and enhancing SDMs' self-efficacy for decision making. PMID- 21521824 TI - TNF-alpha promotes LPA1- and LPA3-mediated recruitment of leukocytes in vivo through CXCR2 ligand chemokines. AB - Lysophosphatidic acid (LPA) is a bioactive lysophospholipid present in low concentrations in serum and biological fluids but in high concentrations at sites of inflammation. LPA evokes a variety of cellular responses via binding to and activation of its specific G protein-coupled receptors (GPCR), namely LPA(1-6). Even though LPA is a chemoattractant for inflammatory cells in vitro, such a role for LPA in vivo remains largely unexplored. In the present study, we used the murine air pouch model to study LPA-mediated leukocyte recruitment in vivo using selective LPA receptor agonist/antagonist and LPA(3)-deficient mice. We report that 1) LPA injection into the air pouch induced leukocyte recruitment and that both LPA(1) and LPA(3) were involved in this process; 2) LPA stimulated the release of the pro-inflammatory chemokines keratinocyte-derived chemokine (KC) and interferon-inducible protein-10 (IP-10) in the air pouch; 3) tumor necrosis factor-alpha (TNF-alpha) injected into the air pouch prior to LPA strongly potentiated LPA-mediated secretion of cytokines/chemokines, including KC, IL-6, and IP-10, which preceded the enhanced leukocyte influx; and 4) blocking CXCR2 significantly reduced leukocyte infiltration. We suggest that LPA, via LPA(1) and LPA(3) receptors, may play a significant role in inducing and/or sustaining the massive infiltration of leukocytes during inflammation. PMID- 21521826 TI - Overweight, obesity, and metabolic syndrome in adults and children in South Korea: a review of the literature. AB - Overweight, obesity, and metabolic syndrome are increasing in South Korea dramatically. This review of the literature summarizes published studies on the prevalence of overweight, obesity, and metabolic syndrome in South Korean adults and children; summarizes studies related to obesity management and prevention in South Korean adults and children; and identifies gaps in the literature for further research. A PubMed, CINAHL, and Google Scholar search identified articles published between January 1, 2000, and June 30, 2010, using the following key search terms: overweight, obesity, adult, children, adolescent, metabolic syndrome, prevention, and South Korea. Inclusion criteria included articles published in English or Korean, and primary or secondary research that measured the prevalence and characteristics of overweight and obesity or described a management or prevention program. Twelve articles met the inclusion criteria and were categorized into either adult or child studies. In adults, the prevalence of overweight and obesity has increased as South Korea has moved from an agricultural to a modern society. In children, there were associations between infant feeding patterns, familial relationships, and dietary and physical activity patterns. There were few programs to manage or prevent overweight. Further research is needed to develop effective strategies to prevent and manage overweight and obesity in adults and children, using family-based interventions that include multigenerational family members. PMID- 21521827 TI - Evaluation of night-time pain characteristics and quality of sleep in postoperative Turkish orthopedic patients. AB - This descriptive, correlational study was conducted to determine orthopedic patients' night-time pain characteristics, their quality of sleep and the contributing factors to poor sleep experiences, and the relationship between pain and sleep. Data were collected by using the McGill Pain Questionnaire-SF (MPQ-SF) and Pittsburgh Sleep Quality Index (PSQI) on the second postoperative day. Data were analyzed using the SPSS version 10.0 for Windows. Mean age of the 75 patients was 49.55 +/- 21.10 years and were hospitalized in the orthopedic wards for 10.56 +/- 14.74 days. Of the sample, 65.3% were female and 36% had hip/knee arthroplasty surgery. Pain (45%) and noise (23%) were found to be the most cited factors affecting the sleep of patients in postoperative periods. They experienced "external" pain at the surgical site and verbalized their pain as "stabbing" and "tiring-exhausting." Patients' night-time pain was determined to be severe (6.59 +/- 1.62); their quality of sleep was also poor (9.24 +/- 3.53). A statistically significant correlation was found between patients' pain intensity and quality of sleep (p<=.05). PMID- 21521828 TI - Fully differentiable coarse-grained and all-atom knowledge-based potentials for RNA structure evaluation. AB - RNA molecules play integral roles in gene regulation, and understanding their structures gives us important insights into their biological functions. Despite recent developments in template-based and parameterized energy functions, the structure of RNA--in particular the nonhelical regions--is still difficult to predict. Knowledge-based potentials have proven efficient in protein structure prediction. In this work, we describe two differentiable knowledge-based potentials derived from a curated data set of RNA structures, with all-atom or coarse-grained representation, respectively. We focus on one aspect of the prediction problem: the identification of native-like RNA conformations from a set of near-native models. Using a variety of near-native RNA models generated from three independent methods, we show that our potential is able to distinguish the native structure and identify native-like conformations, even at the coarse grained level. The all-atom version of our knowledge-based potential performs better and appears to be more effective at discriminating near-native RNA conformations than one of the most highly regarded parameterized potential. The fully differentiable form of our potentials will additionally likely be useful for structure refinement and/or molecular dynamics simulations. PMID- 21521829 TI - The greatest asset: addressing maternal-child health disparities in the United States. PMID- 21521830 TI - Recent progress in the diagnosis and treatment of ovarian cancer. AB - Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Screening strategies using ultrasound and the cancer antigen (CA) 125 tumor marker are currently under study and may lower stage at diagnosis but have not yet been shown to improve survival. Women who have inherited a deleterious mutation in the BRCA1 or BRCA2 gene and those with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have the highest risk of developing ovarian cancer but account for only approximately 10% of those with the disease. Other less common and less well-defined genetic syndromes may increase the risk of ovarian cancer, but their contribution to genetic risk is small. A clear etiology for sporadic ovarian cancer has not been identified, but risk is affected by reproductive and hormonal factors. Surgery has a unique role in ovarian cancer, as it is used not only for diagnosis and staging but also therapeutically, even in patients with widely disseminated, advanced disease. Ovarian cancer is highly sensitive to chemotherapy drugs, particularly the platinum agents, and most patients will attain a remission with initial treatment. Recent advances in the delivery of chemotherapy using the intraperitoneal route have further improved survival after initial therapy. Although the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately develop disease recurrence. Chemotherapy for recurrent disease includes platinum-based, multiagent regimens for women whose disease recurs more than 6 to 12 months after the completion of initial therapy and sequential single agents for those whose disease recurs earlier. New targeted biologic agents, particularly those involved with the vascular endothelial growth factor pathway and those targeting the poly (ADP ribose) polymerase (PARP) enzyme, hold great promise for improving the outcome of ovarian cancer. PMID- 21521831 TI - Current status of SRC inhibitors in solid tumor malignancies. AB - SUMMARY: Src is believed to play an important role in cancer, and several agents targeting Src are in clinical development. DESIGN: We reviewed Src structure and function and preclinical data supporting its role in the development of cancer via a PubMed search. We conducted an extensive review of Src inhibitors by searching abstracts from major oncology meeting databases in the last 3 years and by comprehensively reviewing ongoing clinical trials on ClinicalTrials.gov. RESULTS: In this manuscript, we briefly review Src structure and function, mechanisms involving Src that lead to the development of cancer, and Src inhibitors and key preclinical data establishing a rationale for clinical application. We then focus on clinical data supporting their use in solid tumor malignancies, a newer arena than their more well-established hematologic applications. Particularly highlighted are clinical trials investigating new biomarkers as well as ongoing studies assessing Src inhibitor activity in biomarker-selected patient populations. We also review newer investigational Src targeting agents. CONCLUSIONS: Src inhibitors have shown little activity in monotherapy trials in unselected solid tumor patient populations. Combination studies and biomarker-driven clinical trials are under way. PMID- 21521833 TI - One-year clinical outcome of interventionalist- versus patient-transfer strategies for primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction: results from the REVERSE-STEMI study. AB - BACKGROUND: Traditional reperfusion options for patients with acute ST-segment elevation myocardial infarction (STEMI) presenting to non-primary percutaneous coronary intervention (PPCI)-capable hospitals generally include onsite fibrinolytics or emergency transfer for PPCI. A third option, involving interventionalist transfer, was examined in the REVERSE-STEMI study. METHODS AND RESULTS: A total of 334 patients with acute STEMI who presented to 5 referral hospitals with angiographic facilities but without interventionalists qualified for PPCI were randomized to receive PPCI with either an interventionalist- (n=165) or a patient-transfer (n=169) strategy. The primary end point of door-to balloon (D2B) time and secondary end points of left ventricular ejection fraction and major adverse cardiac events (MACE) at 1-year clinical follow-up were compared between the 2 groups. Compared with the patient-transfer strategy, the interventionalist-transfer strategy resulted in a significantly shortened D2B time (median, 92 minutes versus 141 minutes; P<0.0001), with more patients having first balloon angioplasty within 90 minutes (21.2% versus 7.7%, P<0.001). This treatment strategy also was associated with higher left ventricular ejection fraction (0.60+/-0.07 versus 0.57+/-0.09, P<0.001) and improved 1-year MACE-free survival (84.8% versus 74.6%, P=0.019). Multivariate Cox proportional hazards modeling revealed that the interventionalist-transfer strategy was an independent factor for reduced risk of composite MACE (hazard ratio, 0.63; 95% CI, 0.45 to 0.88; P=0.003). CONCLUSIONS: The interventionalist-transfer strategy for PPCI may be effective in improving the care of patients with STEMI presenting to a non PPCI-capable hospital, particularly in a congested cosmopolitan region where patient transfers could be prolonged. PMID- 21521832 TI - Inter-area correlations in the ventral visual pathway reflect feature integration. AB - During object perception, the brain integrates simple features into representations of complex objects. A perceptual phenomenon known as visual crowding selectively interferes with this process. Here, we use crowding to characterize a neural correlate of feature integration. Cortical activity was measured with functional magnetic resonance imaging, simultaneously in multiple areas of the ventral visual pathway (V1-V4 and the visual word form area, VWFA, which responds preferentially to familiar letters), while human subjects viewed crowded and uncrowded letters. Temporal correlations between cortical areas were lower for crowded letters than for uncrowded letters, especially between V1 and VWFA. These differences in correlation were retinotopically specific, and persisted when attention was diverted from the letters. But correlation differences were not evident when we substituted the letters with grating patches that were not crowded under our stimulus conditions. We conclude that inter-area correlations reflect feature integration and are disrupted by crowding. We propose that crowding may perturb the transformations between neural representations along the ventral pathway that underlie the integration of features into objects. PMID- 21521834 TI - Pharmacodynamic evaluation of pantoprazole therapy on clopidogrel effects: results of a prospective, randomized, crossover study. AB - BACKGROUND: Safety concerns have recently emerged based on a drug interaction between clopidogrel and proton pump inhibitors leading to reduced pharmacodynamic effects. However, whether such drug interaction is a class effect or a drug effect and if this can be modulated by timing of drug administration remains a matter of debate. The aim of this study was to assess the impact of high-dose pantoprazole therapy, a proton pump inhibitor with low potential to interfere with clopidogrel metabolism, administered concomitantly or staggered, on clopidogrel-mediated pharmacodynamic effects. METHODS AND RESULTS: This was a prospective, randomized, crossover study conducted in 20 healthy volunteers. Subjects were randomly assigned to receive pantoprazole (80 mg daily) administered concomitantly (CONC) or staggered by 8 to 12 hours (STAG) for 1 week on a background of clopidogrel therapy (600-mg loading dose followed by a 75-mg maintenance dose during all phases) in a crossover fashion with a 2- to 4-week washout period between treatments. All subjects had a 1-week treatment phase with a clopidogrel-only regimen with a 2- to 4-week washout period from randomization sequence. Platelet function was assessed by flow cytometric analysis of the status of phosphorylation of the vasodilator-stimulated phosphoprotein, light transmittance aggregometry after adenosine diphosphate stimuli, and VerifyNow P2Y(12) system at 3 time points: baseline, 24 hours after loading dose, and 1 week after maintenance dose. The primary end point was the comparison of P2Y(12) reactivity index assessed by vasodilator-stimulated phosphoprotein at 1 week. After 1 week, there were no significant difference in P2Y(12) reactivity index between the CONC and STAG regimens (least-squares mean+/-SEM, 56.0+/-3.9% versus 56.1+/-3.9%; P=0.974), as well as when compared with the clopidogrel-only regimen (61.0+/-3.9%; P=0.100 versus CONC and P=0.107 versus STAG). Further, no differences were observed at baseline and 24 hours between regimens. Concordant results were obtained by light transmittance aggregometry and VerifyNow P2Y(12) assays. CONCLUSIONS: Pantoprazole therapy used at high doses is not associated with modulation of the pharmacodynamic effects of clopidogrel, irrespective of timing of drug administration. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01170533. PMID- 21521835 TI - Validity of estimated glomerular filtration rates for assessment of baseline and serial renal function in patients with atherosclerotic renal artery stenosis: implications for clinical trials of renal revascularization. AB - BACKGROUND: Despite routine use of estimated glomerular filtration rates (GFRs) as major renal end points in clinical trials of renal revascularization, serial GFR estimates have never been validated in patients with renal artery stenosis (RAS). The purpose of this study was to evaluate the validity of GFR estimates in patients with atherosclerotic RAS. METHODS AND RESULTS: Serum creatinine (SCr) and (125)I-iothalamate GFR (I-GFR) were measured in patients with RAS. GFR estimates were calculated from Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Cockroft-Gault (CG) formulas. Using I-GFR as the reference standard, the sensitivity, specificity, and receiver operating characteristic area under the curve (AUC) were determined for MDRD, CKD-EPI, CG, and reciprocal SCr for identifying I-GFR <60 mL/min per 1.73 m(2) and a 20% change in I-GFR over time. Between 1998 and 2007, 541 I-GFR measurements were performed in 254 consecutive patients with RAS. MDRD, CKD-EPI, and CG GFR estimates demonstrated good sensitivity (86% to 95%), modest specificity (67% to 71%), and good reliability (AUC, 0.86 to 0.94) for identifying I-GFR <60 mL/min per 1.73 m(2). GFR estimates had good specificity (87% to 95%), poor sensitivity (0% to 45%), and poor reliability (AUC, 0.61 to 0.65) for detecting 20% changes in I-GFR over follow-up. CONCLUSIONS: In patients with RAS, GFR estimates demonstrate good sensitivity and modest specificity for identifying I-GFR <60 mL/min per 1.73 m(2) but poor sensitivity and reliability for detecting 20% changes in I-GFR. GFR estimates should not be used in clinical trials as major end points to assess serial GFR after renal revascularization. PMID- 21521836 TI - Balloon angioplasty and stenting of branch pulmonary arteries: adverse events and procedural characteristics: results of a multi-institutional registry. AB - BACKGROUND: Pulmonary artery (PA) balloon angioplasty and/or stenting (PA rehabilitation) is one of the most common procedures performed in the cardiac catheterization laboratory, but comprehensive and consistently reported data on procedure-related adverse events (AE) are scarce. METHODS AND RESULTS: Data were prospectively collected using a multicenter registry (Congenital Cardiac Catheterization Project on Outcomes). All cases that included balloon angioplasty and/or stent implantation in a proximal or lobar PA position were included. Multivariate analysis was used to evaluate for independent predictors of AE and need for early reintervention. Between February 2007 and December 2009, 8 institutions submitted details on 1315 procedures with a PA intervention. An AE was documented in 22% with a high severity (level 3 to 5) AE in 10% of cases. Types of AE included vascular/cardiac trauma (19%), technical AE (15%), arrhythmias (15%), hemodynamic AE (14%), bleeding via endotracheal tube/reperfusion injury (12%), and other AE (24%). AE were classified as not preventable in 50%, possibly preventable in 41%, and preventable in 9%. By multivariate analysis, independent risk factors for level 3 to 5 AE were presence of >=2 indicators of hemodynamic vulnerability, age below 1 month, use of cutting balloons, and operator experience of <10 years. Reintervention during the study period occurred in 22% of patients undergoing PA rehabilitation. CONCLUSIONS: PA rehabilitation is associated with a 10% incidence of high-level severity AE. Hemodynamic vulnerability, young age, use of cutting balloons, and lower operator experience were significant independent risk factors for procedure-related AE. PMID- 21521837 TI - The cover. The puff of smoke. PMID- 21521838 TI - A piece of my mind. Paracentesis by moonlight. PMID- 21521839 TI - New high-risk criteria for CVD in women. PMID- 21521840 TI - Global partners take two steps closer to eradication of Guinea worm disease. PMID- 21521841 TI - Patients go online seeking support, practical advice on health conditions. PMID- 21521842 TI - Plasma beta-amyloid level, cognitive reserve, and cognitive decline. PMID- 21521843 TI - Plasma beta-amyloid level, cognitive reserve, and cognitive decline. PMID- 21521844 TI - Ultrasound and physical examinations for obese patients. PMID- 21521845 TI - Stroke center designation and mortality. PMID- 21521846 TI - Prevalence of levamisole in urine toxicology screens positive for cocaine in an inner-city hospital. PMID- 21521848 TI - Patterns of nonadherence to antiepileptic drug therapy in children with newly diagnosed epilepsy. AB - CONTEXT: Because of epilepsy's common occurrence, the narrow therapeutic and safety margins of antiepileptic medications, and the recognized complications of medication nonadherence in adults with epilepsy, identifying the rates, patterns, and predictors of nonadherence in children with epilepsy is imperative. The onset and evolution of antiepileptic drug nonadherence in children with newly diagnosed epilepsy remains unknown. OBJECTIVES: To identify and characterize trajectories of adherence in children with newly diagnosed epilepsy over the first 6 months of therapy and to determine sociodemographic and epilepsy-specific predictors of adherence trajectories. DESIGN, SETTING, AND PATIENTS: Prospective, longitudinal observational study of antiepileptic drug adherence in a consecutive cohort of 124 children (2-12 years old) with newly diagnosed epilepsy at Cincinnati Children's Hospital Medical Center. Patients were recruited from April 2006 through March 2009, and final data collection occurred in September 2009. MAIN OUTCOME MEASURE: Objective adherence measured using electronic monitors. RESULTS: Fifty-eight percent of children with newly diagnosed epilepsy demonstrated persistent nonadherence during the first 6 months of therapy. Group-based trajectory models identified 5 differential adherence patterns (Bayesian information criterion = -23611.8): severe early nonadherence (13%; 95% confidence interval [CI], 8%-20%), severe delayed nonadherence (7%; 95% CI, 3%-12%), moderate nonadherence (13%; 95% CI, 8%-20%), mild nonadherence (26%; 95% CI, 19% 34%), and near-perfect adherence (42%; 95% CI, 33%-50%). The adherence pattern of most patients was established by the first month of therapy. Socioeconomic status was the sole predictor of adherence trajectory group status (chi(4)(2) = 19.3 [n = 115]; P < .001; partial r(2) = 0.25), with lower socioeconomic status associated with higher nonadherence. CONCLUSION: Five trajectory patterns were identified that captured the spectrum of nonadherence to antiepileptic drugs among children with newly diagnosed epilepsy; the patterns were significantly associated with socioeconomic status. PMID- 21521847 TI - Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. AB - CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established. OBJECTIVE: To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks. MAIN OUTCOME MEASURES: The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures. RESULTS: Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was -35.2 U/L (95% CI, -56.9 to -13.5) with placebo vs -48.3 U/L (95% CI, -66.8 to -29.8) with vitamin E (P = .07) and -41.7 U/L (95% CI, -62.9 to -20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, -0.2 to 0.3) vs -0.5 with vitamin E (95% CI, -0.8 to -0.3; P = .006) and -0.3 with metformin (95% CI, -0.6 to -0.0; P = .04); and in NAFLD activity score, -0.7 with placebo (95% CI, -1.3 to -0.2) vs -1.8 with vitamin E (95% CI, -2.4 to -1.2; P = .02) and -1.1 with metformin (95% CI, -1.7 to -0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features. CONCLUSION: Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00063635. PMID- 21521849 TI - Association between adoption of evidence-based treatment and survival for patients with ST-elevation myocardial infarction. AB - CONTEXT: Only limited information is available on the speed of implementation of new evidence-based and guideline-recommended treatments and its association with survival in real life health care of patients with ST-elevation myocardial infarction (STEMI). OBJECTIVE: To describe the adoption of new treatments and the related chances of short- and long-term survival in consecutive patients with STEMI in a single country over a 12-year period. DESIGN, SETTING, AND PARTICIPANTS: The Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA) records baseline characteristics, treatments, and outcome of consecutive patients with acute coronary syndrome admitted to almost all hospitals in Sweden. This study includes 61,238 patients with a first time diagnosis of STEMI between 1996 and 2007. MAIN OUTCOME MEASURES: Estimated and crude proportions of patients treated with different medications and invasive procedures and mortality over time. RESULTS: Of evidence-based treatments, reperfusion increased from 66% (95%, confidence interval [CI], 52%-79%) to 79% (95% CI, 69%-89%; P < .001), primary percutaneous coronary intervention from 12% (95% CI, 11%-14%) to 61% (95% CI, 45%-77%; P < .001), and revascularization from 10% (96% CI, 6%-14%) to 84% (95% CI, 73%-95%; P < .001). The use of aspirin, clopidogrel, beta-blockers, statins, and angiotensin-converting enzyme (ACE) inhibitors all increased: clopidogrel from 0% to 82% (95% CI, 69%-95%; P < .001), statins from 23% (95% CI, 12%-33%) to 83% (95% CI, 75%-91%; P < .001), and ACE inhibitor or angiotensin II receptor blockers from 39% (95% CI, 26%-52%) to 69% (95% CI, 58%-70%; P < .001). The estimated in-hospital, 30-day and 1-year mortality decreased from 12.5% (95% CI, 4.3%-20.6%) to 7.2% (95% CI, 1.7%-12.6%; P < .001); from 15.0% (95% CI, 6.2%-23.7%) to 8.6% (95% CI, 2.7%-14.5%; P < .001); and from 21.0% (95% CI, 11.0%-30.9%) to 13.3% (95% CI, 6.0%-20.4%; P < .001), respectively. After adjustment, there was still a consistent trend with lower standardized mortality over the years. The 12-year survival analyses showed that the decrease of mortality was sustained over time. CONCLUSION: In a Swedish registry of patients with STEMI, between 1996 and 2007, there was an increase in the prevalence of evidence-based treatments. During this same time, there was a decrease in 30-day and 1-year mortality that was sustained during long-term follow-up. PMID- 21521850 TI - Association of CTNNB1 (beta-catenin) alterations, body mass index, and physical activity with survival in patients with colorectal cancer. AB - CONTEXT: Alterations of the WNT signaling pathway and cadherin-associated protein beta 1 (CTNNB1 or beta-catenin) have been implicated in colorectal carcinogenesis and metabolic diseases. OBJECTIVE: To test the hypothesis that CTNNB1 activation in colorectal cancer modifies prognostic associations of body mass index (BMI) and level of postdiagnosis physical activity. DESIGN, SETTING, AND PATIENTS: Two US prospective cohort studies (Nurses' Health Study and the Health Professionals Follow-up Study) were used to evaluate CTNNB1 localization by immunohistochemistry in 955 patients with stage I, II, III, or IV colon and rectal cancer from 1980 through 2004. A Cox proportional hazards model was used to compute the hazard ratio (HR) for mortality, adjusting for clinical and tumor features, including microsatellite instability, CpG island methylator phenotype, level of long interspersed nucleotide element 1 methylation, mutations in KRAS, BRAF, or PIK3CA, and tumor protein p53. MAIN OUTCOME MEASURES: Colorectal cancer specific mortality and overall mortality through June 30, 2009. RESULTS: In obese patients (BMI >=30), positive status for nuclear CTNNB1 was associated with significantly better colorectal cancer-specific survival (adjusted HR, 0.24 [95% confidence interval {CI}, 0.12-0.49], P <.001 for interaction; 5-year survival: 0.85 for patients with positive nuclear CTNNB1 status vs 0.78 for those with negative status) and overall survival (adjusted HR, 0.56 [95% CI, 0.35-0.90], P = .03 for interaction; 5-year survival: 0.77 for patients with positive nuclear CTNNB1 status vs 0.74 for those with negative status), while CTNNB1 status was not associated with prognosis among nonobese patients (BMI <30). Among patients with negative status for nuclear CTNNB1 and cancer in stages I, II, or III, postdiagnosis physical activity was associated with better colorectal cancer specific survival (adjusted HR, 0.33 [95% CI, 0.13-0.81], P = .05 for interaction; 5-year survival: 0.97 for >=18 vs 0.89 for <18 metabolic equivalent task hours/week), while postdiagnosis physical activity was not associated with colorectal cancer-specific survival among patients with positive status for nuclear CTNNB1 (adjusted HR, 1.07 [95% CI, 0.50-2.30]). CONCLUSIONS: Among obese patients only, activation of CTNNB1 was associated with better colorectal cancer specific survival and overall survival. Postdiagnosis physical activity was associated with better colorectal cancer-specific survival only among patients with negative status for nuclear CTNNB1. These molecular pathological epidemiology findings suggest that the effects of alterations in the WNT-CTNNB1 pathway on outcome are modified by BMI and physical activity. PMID- 21521851 TI - Health literacy and outcomes among patients with heart failure. AB - CONTEXT: Little is known about the effects of low health literacy among patients with heart failure, a condition that requires self-management and frequent interactions with the health care system. OBJECTIVE: To evaluate the association between low health literacy and all-cause mortality and hospitalization among outpatients with heart failure. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study conducted at Kaiser Permanente Colorado, an integrated managed care organization. Outpatients with heart failure were identified between January 2001 and May 2008, were surveyed by mail, and underwent follow-up for a median of 1.2 years. Health literacy was assessed using 3 established screening questions and categorized as adequate or low. Responders were excluded if they did not complete at least 1 health literacy question or if they did not have at least 1 year of enrollment prior to the survey date. MAIN OUTCOME MEASURES: All-cause mortality and all-cause hospitalization. RESULTS: Of the 2156 patients surveyed, 1547 responded (72% response rate). Of 1494 included responders, 262 (17.5%) had low health literacy. Patients with low health literacy were older, of lower socioeconomic status, less likely to have at least a high school education, and had higher rates of coexisting illnesses. In multivariable Cox regression, low health literacy was independently associated with higher mortality (unadjusted rate, 17.6% vs 6.3%; adjusted hazard ratio, 1.97 [95% confidence interval, 1.3 2.97]; P = .001) but not hospitalization (unadjusted rate, 30.5% vs 23.2%; adjusted hazard ratio, 1.05 [95% confidence interval, 0.8-1.37]; P = .73). CONCLUSION: Among patients with heart failure in an integrated managed care organization, low health literacy was significantly associated with higher all cause mortality. PMID- 21521852 TI - A proposed model for initial assessment and management of acute heart failure syndromes. PMID- 21521853 TI - Accountable care organizations and health care disparities. PMID- 21521854 TI - Studying health disparities by including incarcerated and formerly incarcerated individuals. PMID- 21521855 TI - Implementation of evidence-based therapies for myocardial infarction and survival. PMID- 21521856 TI - JAMA patient page. Epilepsy. PMID- 21521857 TI - Outcomes associated with AUC24/MIC nomogram dosing of vancomycin. PMID- 21521858 TI - Efficacy of agents to prevent and treat enteral feeding tube clogs. AB - OBJECTIVE: To review the efficacy and safety of agents used to prevent and treat clog formation in enteral feeding tubes. DATA SOURCES: A literature search was conducted through MEDLINE (1948-February 2011) and International Pharmaceutical Abstracts (1970-February 2011) using the search terms enteral feeding tube and occlusion. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language publications were reviewed for applicability. DATA SYNTHESIS: Occlusion is a common complication of enteral tube feeding. With Food and Drug Administration regulations, pancreatic enzymes have recently been reformulated and previously published reports can no longer be applied to currently available agents. This has led to concern over what available products have been shown to be efficacious. Three in vitro studies, 1 randomized in vivo trial, and 1 descriptive report were reviewed. In the prevention of tube clogging, it was concluded that water was comparable in efficacy, while being more readily available and cost effective, when compared to Coca-Cola, and both were superior to cranberry juice. For resolution of an existing clog, evidence of the efficacy of any individual agents is limited and has not been reproducible. New formulations of pancreatic enzymes, a new delivery system for enzymes, and products to mechanically dismantle clogs have become commercially available, but no studies have been completed to evaluate safety and efficacy. Comparative in vivo studies of currently available products are needed to evaluate possible methods for resolving an occlusion. CONCLUSIONS: Water flushes have shown to be the most effective method in preventing enteral feeding tube clogging. Well designed trials are needed to establish the proper place in therapy of new commercially available agents marketed for resolving clogs. In addition, well designed in vivo trials are needed to establish the role, dosage, and extemporaneous formulation of extended-release pancreatic enzymes in treating such clogs. PMID- 21521859 TI - Vitamin D status and response to daily 400 IU vitamin D3 and weekly alendronate 70 mg in men and women with osteoporosis. AB - BACKGROUND: Suboptimal vitamin D status is common in elderly individuals. However, the extent of vitamin D inadequacy in men and women being treated for osteoporosis in a family practice setting has not been well characterized. OBJECTIVE: To describe the distribution of serum 25-hydroxyvitamin D (25-[OH] D) in Canadian men and postmenopausal women with osteoporosis taking 400 IU or less of vitamin D daily and to evaluate the safety, tolerability, and impact of vitamin D(3) supplementation 400 IU daily taken concurrently with alendronate sodium 70 mg weekly. METHODS: This was a prospective, single-cohort, open-label, multicenter study. Community-dwelling men and postmenopausal women with osteoporosis were recruited at 197 sites across Canada. Patients received vitamin D(3) 400 IU/day supplementation coadministered with alendronate 70 mg/wk for 16 weeks. The primary outcome was the distribution of serum 25-(OH) D at baseline. Secondary outcome measures included changes from baseline in serum 25-(OH) D levels, adherence to study treatments, and incidence of treatment-related adverse events (AEs). RESULTS: Of the 681 patients included in the analysis, 485 (71.2%) completed the study. Patients were predominantly female (83.1%) with a mean (SD) age of 67.6 (10.7) years. At baseline, mean (SD) serum 25-(OH) D concentration was 25.4 (9.9) ng/mL and 68.0% of the patients had inadequate (less than 30 ng/mL) vitamin D status. At week 16, concentrations increased by 35.1% to 31.2 (9.2) ng/mL (p < 0.001) and the proportion of patients with inadequate 25-(OH) D levels was reduced to 47.0%. Adherence to the treatment regimen was high (greater than 95%). Gastrointestinal disorders were the most frequently reported (6.9%) treatment-related AEs. CONCLUSIONS: About two thirds of patients previously diagnosed with osteoporosis have inadequate vitamin D status. A treatment regimen consisting of alendronate 70 mg/wk administered with daily vitamin D(3) 400 IU supplementation significantly increased patients' serum 25-(OH) D levels, but 47% did not achieve optimal levels. These results support both the National Osteoporosis Foundation and Osteoporosis Canada recommendations for higher vitamin D supplement doses (at least 800 IU daily) in osteoporotic patients receiving pharmacologic therapy for osteoporosis and for monitoring their serum 25-(OH) D response. PMID- 21521860 TI - Generic substitution of levetiracetam resulting in increased incidence of breakthrough seizures. AB - OBJECTIVE: We report on 4 patients having an increased incidence of seizures when treatment was switched from brand name levetiracetam (Keppra) to generic levetiracetam formulations. CASE SUMMARY: Patients reported an increase in seizure activity to their neurologists after treatment was switched from Keppra to generic levetiracetam formulations. To confirm the timeline of increased seizure activity with use of the generic drug and report these adverse events to MedWatch, we made a telephone call to each patient's pharmacy to collect information on dispensing dates and the generic formulations' manufacturers. Subsequent to the increase in seizure frequency with generic levetiracetam, treatment in all 4 patients was switched back to Keppra. Seizure frequency in all patients returned to baseline when Keppra was reinstituted. DISCUSSION: The Food and Drug Administration (FDA) considers generic medications to be therapeutically equivalent to their corresponding brand name formulation when the generic meets bioequivalence criteria. Considering the linear pharmacokinetic profile of levetiracetam, loss of seizure control or fluctuations of serum concentrations are unexpected if the patient remains on a consistent dose. However, there is growing evidence to support the concept that brand name antiepileptic drugs (AEDs) are not clinically equivalent to their generic counterparts. Because the FDA relies on voluntary reporting of adverse events from health-care professionals and consumers to their MedWatch program, underreporting makes it difficult to quantify the significance of brand to generic switches, and, equally important, generic to generic switches. CONCLUSIONS: Until the use of generic AEDs can be evaluated in a large randomized blinded controlled study, clinicians must be vigilant in their efforts to report to MedWatch adverse events resulting from the switch from an AED brand to generic formulation of an AED. PMID- 21521861 TI - Symptom reporting compared with audiometry for the detection of cochleotoxicity in patients on long-term aminoglycoside therapy. AB - BACKGROUND: Aminoglycoside-associated auditory toxicity (cochleotoxicity) is a major concern in patients receiving prolonged aminoglycoside therapy. There are no published data comparing symptom monitoring to audiometry testing for the detection of aminoglycoside-induced cochleotoxicity; thus, agreement regarding the optimal monitoring of these patients for early detection of this effect is lacking. OBJECTIVE: To compare the sensitivity of symptom monitoring to that of audiometry in identifying cochleotoxicity in patients on prolonged aminoglycoside therapy. METHODS: A retrospective chart review of adult inpatients at Sunnybrook Health Sciences Centre prescribed prolonged aminoglycoside therapy (>=21 days) who completed at least 1 audiometry test between January 1, 1999, and December 31, 2009, was conducted. Data pertaining to results of audiometry testing and development of symptoms of auditory toxicity were collected. Symptom monitoring was compared with audiology testing for the detection of cochleotoxicity. RESULTS: Forty eligible patients were included for analysis. Audiometry was significantly better than symptom monitoring to identify early cochleotoxicity (absolute risk reduction = 17.5% and number needed to treat = 6; p = 0.023). Compared to audiometry, symptom monitoring has a sensitivity, negative predictive value, and accuracy for the detection of early cochleotoxicity of 61%, 75%, and 82%, respectively. CONCLUSIONS: Audiometry testing is significantly better than monitoring symptoms to identify early aminoglycoside-induced auditory toxicity in patients prescribed prolonged aminoglycoside therapy (>=21 days). Subclinical cochleotoxicity identified with audiometry may allow early termination of aminoglycoside therapy to prevent progression of cochlear damage to the audible frequency range. PMID- 21521862 TI - Defining the minimal detectable change in scores on the eight-item Morisky Medication Adherence Scale. AB - BACKGROUND: Self-report scales are used to assess medication adherence. Data on how to discriminate change in self-reported adherence over time from random variability are limited. OBJECTIVE: To determine the minimal detectable change for scores on the 8-item Morisky Medication Adherence Scale (MMAS-8). METHODS: The MMAS-8 was administered twice, using a standard telephone script, with administration separated by 14-22 days, to 210 participants taking antihypertensive medication in the CoSMO (Cohort Study of Medication Adherence among Older Adults). MMAS-8 scores were calculated and participants were grouped into previously defined categories (<6, 6 to <8, and 8 for low, medium, and high adherence). RESULTS: The mean (SD) age of participants was 78.1 (5.8) years, 43.8% were black, and 68.1% were women. Overall, 8.1% (17/210), 16.2% (34/210), and 51.0% (107/210) of participants had low, medium, and high MMAS-8 scores, respectively, at both survey administrations (overall agreement 75.2%; 158/210). The weighted kappa statistic was 0.63 (95% CI 0.53 to 0.72). The intraclass correlation coefficient was 0.78. The within-person standard error of the mean for change in MMAS-8 scores was 0.81, which equated to a minimal detectable change of 1.98 points. Only 4.3% (9/210) of the participants had a change in MMAS 8 of 2 or more points between survey administrations. CONCLUSIONS: Within-person changes in MMAS-8 scores of 2 or more points over time may represent a real change in antihypertensive medication adherence. PMID- 21521863 TI - Estimates of statin discontinuation rates are influenced by exposure and outcome definitions. AB - BACKGROUND: Estimates of statin discontinuation rates are generally high but show large variations. Discontinuation rates are possibly influenced by unrecognized supplies from previous prescriptions and the operational definitions of statin discontinuation. OBJECTIVE: To investigate whether the outcome (discontinuation) was affected by (1) the operational definition used to calculate statin exposure and (2) the operational definition and different cutoff values used to calculate discontinuation. METHODS: Data for this study were obtained from the PHARMO medical record linkage system in the Netherlands. Participants were patients with a new statin and no statin prescription in the preceding year. The outcome, discontinuation, was defined based on a variable number of days without medication after exposure (gaps) or based on the availability of supplies 12 months after the inclusion date (at 1 year). Exposure to statins was assessed by 2 methods. The method termed No Overlap accounted for only the supplies of the last prescription to calculate exposure, and the method termed Overlap accounted for all supplies from previous prescriptions. We investigated the effect of 4 exposure outcome combinations on statin discontinuation estimates. RESULTS: The exposure outcome combinations, including overlap, resulted in a 7% unit lower discontinuation rate. At gap lengths of 90 days and longer, no significant differences between No Overlap and Overlap were observed. Shorter minimum gap lengths gave higher discontinuation rates compared to longer minimum gap lengths and ranged from as high as 86% to 21%. CONCLUSIONS: If previous supplies are accounted for in the calculation of exposure to statins, lower discontinuation rates are observed. The influence of previous supplies on discontinuation rates is less pronounced than the influence of gap lengths. The calculation of exposure does not influence discontinuation if gaps longer than 90 days are used to assess discontinuation. PMID- 21521864 TI - Treatment of Alternaria keratitis with intrastromal and topical caspofungin in combination with intrastromal, topical, and oral voriconazole. AB - OBJECTIVE: To report a case of refractory atypical Alternaria keratitis that was treated with intrastromal and topical caspofungin 0.5% in combination with topical, oral, and intrastromal voriconazole. CASE SUMMARY: A 67-year-old female with a history of bilateral intraocular lens exchange and left pseudophakic bullous keratopathy was referred to the emergency department of the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. Visual acuity of her left eye was limited to counting fingers. A fine branching pattern was noted throughout the anterior stroma of her left corneal graft. The anterior chamber was deep and quiet. Hourly topical voriconazole 1% was initiated, with limited response. One week later, Alternaria spp. was cultured from the corneal scraping. Subsequently, topical caspofungin 0.5% was added, with concomitant use of topical, oral, and intrastromal voriconazole. Despite gradual symptomatic improvement, topical voriconazole was increased to 2% and intrastromal caspofungin was added. The patient was discharged after almost 5 weeks of treatment. Topical voriconazole 2% and topical caspofungin 0.5% were continued for an additional 3 weeks and 1 week, respectively, in the outpatient setting. The patient underwent left penetrating keratoplasty 3 weeks postdischarge. Visual acuity was stable at 20/150, with no reported adverse event 15 months postoperative. DISCUSSION: Treatment for Alternaria keratitis remains challenging, as it is refractory to existing antifungal agents. To our knowledge, this is the first reported instance of the use of intrastromal caspofungin to treat Alternaria keratitis in a case in which clinical resolution was not fully achieved despite the use of topical caspofungin in addition to extensive use of topical, intrastromal, and oral voriconazole. This case highlights the importance of intensive pharmacologic management and therapeutic penetrating keratoplasty in preventing evisceration of the patient's eye, especially when Alternaria keratitis is involved. CONCLUSIONS: Intrastromal and topical caspofungin were employed in combination with voriconazole for the management of refractory Alternaria keratitis, with no observed adverse effects. PMID- 21521865 TI - Assessment of vancomycin dosing and subsequent serum concentrations in pediatric patients. AB - BACKGROUND: Because of concerns regarding increasing microbial resistance to vancomycin, adult treatment guidelines recommend higher trough concentrations based on the type of infectious process. Although these recommendations are not specific to pediatrics, the principles can be extrapolated. Desired higher trough serum concentrations will require escalated dosages of vancomycin in children. OBJECTIVE: To evaluate current dosing regimens and subsequent trough serum concentrations of vancomycin in children, compare these to reference recommended dosages and guidelines, and predict a dosing equation to achieve desired serum concentrations. METHODS: Pharmacokinetic parameters of children in a community teaching hospital who were prescribed vancomycin from January 2005 to May 2010 were evaluated in this retrospective chart review. Vancomycin dosing and subsequent serum concentrations were analyzed. Therapeutic serum concentrations were evaluated and compared to vancomycin prescribing and monitoring guidelines by year. RESULTS: Four hundred thirty-five trough serum concentrations determined in 295 patients were analyzed. The average dosages, when evaluated by year, were 48 mg/kg/day (2005-2008) and 59 mg/kg/day (2009-2010). Using trough concentration recommendations of 5-15 mg/L, vancomycin regimens provided therapeutic trough concentrations 78% of the time from 2005 to 2008. Using 10-20 mg/L as the trough recommendations in 2009-2010, only 49% of serum concentrations reached a therapeutic level. Based on our predictive equation for children aged 1 month-18 years with normal renal function, a vancomycin dosage of 70 mg/kg/day is required to provide trough serum concentrations of 10 mg/L; a dosage of 85 mg/kg/day is required to provide trough serum concentrations of 15 mg/L. CONCLUSIONS: Our institution was primarily using vancomycin dosing regimens that were recommended in pediatric references (40-60 mg/kg/day), which resulted in subtherapeutic serum concentrations in our population based on new monitoring recommendations. Considering that the currently desired therapeutic trough concentrations of vancomycin are 10-20 mg/L, the total daily dosage should be increased. PMID- 21521866 TI - Vancomycin-induced neutropenia: is it dose- or duration-related? AB - OBJECTIVE: To systematically evaluate the literature to determine whether vancomycin-induced neutropenia is dose- or duration-related and provide clinicians with feasible treatment alternatives. DATA SOURCES: A literature search of PubMed (1949-November 2010), MEDLINE (1950-November 2010), EMBASE (1980 November 2010), and International Pharmaceutical Abstracts (1970-November 2010) was performed using the terms vancomycin, neutropenia, and leukopenia. Citations from publications were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: Studies and case reports were included if they reported neutropenia with vancomycin administration and excluded if they did not describe vancomycin dosages and/or concentrations, or if neutropenia resolved while the patient was still receiving vancomycin. Cases with significant confounders and those in which authors provided minimal information about patients were also excluded. DATA SYNTHESIS: Seven retrospective chart reviews (ie, case series) and 33 case reports were identified. Of these, 3 retrospective reviews and 26 case reports met inclusion criteria. To our knowledge, no prospective studies have assessed this clinical complication. Data suggest that vancomycin-induced neutropenia may not be completely related to daily dosages, total cumulative dosage, or supratherapeutic vancomycin concentrations. Furthermore, evidence suggests that neutropenia is more likely associated with therapy longer than 7 days, with the majority of episodes occurring beyond 20 days of therapy. Given these findings, a practical approach is to monitor white blood cell (WBC) count with a differential (including absolute neutrophil count) once a week in patients who are receiving vancomycin for more than 7 days. CONCLUSIONS: Vancomycin induced neutropenia is most likely associated with prolonged vancomycin exposure. Patients receiving vancomycin for longer than 7 days should have WBC count, differential, monitored weekly. Vancomycin should be discontinued if there is a high clinical suspicion of it causing neutropenia, and an alternative agent should be initiated. Prospective case-controlled studies are needed to better characterize this adverse event. PMID- 21521867 TI - Role of alpha2-agonists in the treatment of acute alcohol withdrawal. AB - OBJECTIVE: To evaluate literature reporting on the role of norepinephrine in alcohol withdrawal and to determine the safety and efficacy of alpha(2)-agonists in reducing symptoms of this severe condition. DATA SOURCES: Articles evaluating the efficacy and safety of the alpha(2)-agonists clonidine and dexmedetomidine were identified from an English-language MEDLINE search (1966-December 2010). Key words included alcohol withdrawal, delirium tremens, clonidine, dexmedetomidine, alpha(2)-agonist, norepinephrine, and sympathetic overdrive. STUDY SELECTION AND DATA EXTRACTION: Studies that focused on the safety and efficacy of clonidine and dexmedetomidine in both animals and humans were selected. DATA SYNTHESIS: The noradrenergic system, specifically sympathetic overdrive during alcohol withdrawal, may play an important role in withdrawal symptom development. Symptoms of sympathetic overdrive include anxiety, agitation, elevated blood pressure, tachycardia, and tremor. Therefore, alpha(2)-agonists, which decrease norepinephine release, may have a role in reducing alcohol withdrawal symptoms. The majority of controlled animal and human studies evaluated clonidine, but the most recent literature is from case reports on dexmedetomidine. The literature reviewed here demonstrate that these 2 alpha(2)-agonists safely and effectively reduce symptoms of sympathetic overdrive and concomitant medication use. Dexmedetomidine may offer an advantage over current sedative medications used in the intensive care unit, such as not requiring intubation with its use, and therefore further study is needed to fully elicit its benefit in alcohol withdrawal. CONCLUSION: Clonidine and dexmedetomidine may provide additional benefit in managing alcohol withdrawal by offering a different mechanism of action for targeting withdrawal symptoms. Based on literature reviewed here, the primary role for clonidine and dexmedetomidine is as adjunctive treatment to benzodiazepines, the standard of care in alcohol withdrawal. PMID- 21521868 TI - A synthesis of read-aloud interventions on early reading outcomes among preschool through third graders at risk for reading difficulties. AB - A synthesis and meta-analysis of the extant research on the effects of storybook read-aloud interventions for children at risk for reading difficulties ages 3 to 8 is provided. A total of 29 studies met criteria for the synthesis, with 18 studies providing sufficient data for inclusion in the meta-analysis. Read-aloud instruction has been examined using dialogic reading; repeated reading of stories; story reading with limited questioning before, during, and/or after reading; computer-assisted story reading; and story reading with extended vocabulary activities. Significant, positive effects on children's language, phonological awareness, print concepts, comprehension, and vocabulary outcomes were found. Despite the positive effects for read-aloud interventions, only a small amount of outcome variance was accounted for by intervention type. PMID- 21521869 TI - Associations between academic and motor performance in a heterogeneous sample of children with learning disabilities. AB - A heterogeneous sample of 137 school-aged children with learning disabilities (IQ > 80) attending special needs schools was examined on the Movement Assessment Battery for Children (MABC). The results show that compared to the available norm scores, 52.6% of the children tested performed below the 15th percentile on manual dexterity, 40.9% on ball skills, and 33.7% on balance skills. Furthermore, after controlling for IQ, significant small to moderate partial correlations were found between spelling and mathematics and the MABC total score, as well as small to moderate correlations between mathematics and balance, between reading and ball skills, and between spelling and manual dexterity. The present findings are compared with previously reported results obtained in more homogenous groups, and based on the resultant relationships between academic performance and motor development, recommendations for future motor intervention studies are made. PMID- 21521870 TI - A meta-analysis of the RTI literature for children at risk for reading disabilities. AB - This article synthesizes the literature comparing at-risk children designated as responders and low responders to interventions in reading. The central question addressed in this review is whether individual differences in reading-related skills at pretest predict responders at posttest across a variety of interventions and sets of criteria for determining responding and low responding. A total of 13 studies met criteria for the meta-analysis, yielding 107 weighted effect sizes (ESs) at posttest (M = .76, SE = .03, 95% confidence interval [CI] =.71, .81) and 108 weighted ESs at pretest (M = 1.02, SE = .03, CI = 1.02, 1.13). The results showed that the magnitude of ES between responders and low responders increased from pretest to posttest on measures of reading (e.g., real word identification = 1.06 vs. 1.53, word attack = 1.10 vs. 1.28, and passage comprehension, 0.45 vs. 1.43). Hierarchical linear modeling indicated that overall posttest ESs were significantly moderated by pretest scores as well as the type of measure administered, whereas no significant moderating effects were found for number of weeks of intervention, length of sessions, number of sessions, type of intervention (one-to-one vs. small group instruction), and criteria for defining responders (cutoff, scores, discrepancy, benchmark). Overall, the synthesis suggested that regardless of type of treatment and identification criteria, response-to-intervention (RTI) conditions were not effective in mitigating learner characteristics related to pretest conditions. PMID- 21521871 TI - Dedifferentiation of immortalized human podocytes in response to transforming growth factor-beta: a model for diabetic podocytopathy. AB - OBJECTIVE: Diabetic nephropathy is associated with dedifferentiation of podocytes, losing the specialized features required for efficient glomerular function and acquiring a number of profibrotic, proinflammatory, and proliferative features. These result from tight junction and cytoskeletal rearrangement, augmented proliferation, and apoptosis. RESEARCH DESIGN AND METHODS: Experiments were performed in conditionally immortalized human podocytes developed by transfection with the temperature-sensitive SV40-T gene. Cells were then cultured in the presence of transforming growth factor (TGF)-beta1 or angiotensin II in the presence or absence of a selective inhibitor of the TGF beta type I receptor kinase, SB-431542. Gene and protein expression were then examined by real-time RT-PCR and immunofluorescence, and correlated with changes observed in vivo in experimental diabetes. RESULTS: Treatment of cells with TGF beta1 resulted in dynamic changes in their morphology, starting with retraction and shortening of foot processes and finishing with the formation of broad and complex tight junctions between adjacent podocytes. This dedifferentiation was also associated with dose- and time-dependent reduction in the expression of glomerular epithelial markers (nephrin, p-cadherin, zonnula occludens-1) and increased expression of mesenchymal markers (alpha-smooth muscle actin, vimentin, nestin), matrix components (fibronectin, collagen I, and collagen IV alpha3), cellular proliferation, and apoptosis. The induction of diabetes in mice was also associated with similar changes in morphology, protein expression, and proliferation in glomerular podocytes. CONCLUSIONS: In response to TGF-beta and other TGF-dependent stimuli, mature podocytes undergo dedifferentiation that leads to effacement of foot processes, morphologic flattening, and increased formation of intercellular tight junctions. This simplification of their phenotype to a more embryonic form is also associated with reentry of mature podocytes into the cell cycle, which results in enhanced proliferation and apoptosis. These "pathoadaptive" changes are seen early in the diabetic glomerulus and ultimately contribute to albuminuria, glomerulosclerosis, and podocytopenia. PMID- 21521872 TI - In vivo conditional Pax4 overexpression in mature islet beta-cells prevents stress-induced hyperglycemia in mice. AB - OBJECTIVE: To establish the role of the transcription factor Pax4 in pancreatic islet expansion and survival in response to physiological stress and its impact on glucose metabolism, we generated transgenic mice conditionally and selectively overexpressing Pax4 or a diabetes-linked mutant variant (Pax4R129W) in beta cells. RESEARCH DESIGN AND METHODS: Glucose homeostasis and beta-cell death and proliferation were assessed in Pax4- or Pax4R129W-overexpressing transgenic animals challenged with or without streptozotocin. Isolated transgenic islets were also exposed to cytokines, and apoptosis was evaluated by DNA fragmentation or cytochrome C release. The expression profiles of proliferation and apoptotic genes and beta-cell markers were studied by immunohistochemistry and quantitative RT-PCR. RESULTS: Pax4 but not Pax4R129W protected animals against streptozotocin induced hyperglycemia and isolated islets from cytokine-mediated beta-cell apoptosis. Cytochrome C release was abrogated in Pax4 islets treated with cytokines. Interleukin-1beta transcript levels were suppressed in Pax4 islets, whereas they were increased along with NOS2 in Pax4R129W islets. Bcl-2, Cdk4, and c-myc expression levels were increased in Pax4 islets while MafA, insulin, and GLUT2 transcript levels were suppressed in both animal models. Long-term Pax4 expression promoted proliferation of a Pdx1-positive cell subpopulation while impeding insulin secretion. Suppression of Pax4 rescued this defect with a concomitant increase in pancreatic insulin content. CONCLUSIONS: Pax4 protects adult islets from stress-induced apoptosis by suppressing selective nuclear factor-kappaB target genes while increasing Bcl-2 levels. Furthermore, it promotes dedifferentiation and proliferation of beta-cells through MafA repression, with a concomitant increase in Cdk4 and c-myc expression. PMID- 21521873 TI - HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/gammac(null)/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells. AB - OBJECTIVE: Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing beta-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS: We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/gammac(null)/HLA-A*0201 (NOD-scid/gammac(null)/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/gammac(null)/A2 mice after transfer. RESULTS: Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/gammac(null)/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD scid/gammac(null)/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8(+) T cells among the islet infiltrates. CONCLUSIONS: We show that insulitis is transferred to NOD-scid/gammac(null)/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8(+) T cells are epitope-specific and produce interferon-gamma after in vitro peptide stimulation. This indicates that NOD-scid/gammac(null)/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes. PMID- 21521875 TI - Focus issue: moving in the right direction. AB - Cells interpret environmental cues to extend processes in the appropriate direction, descend upon sources of inflammation or necrosis, or determine the best path to the correct position in a developing organism. This Focus Issue of Science Signaling highlights the signaling pathways and mechanisms that enable cells to sense external signals and direct their movement accordingly. PMID- 21521876 TI - Analyzing the anatomy of integrin adhesions. AB - Cell adhesion to the extracellular matrix (ECM) is necessary for fundamental cellular processes such as survival, migration, and differentiation. Adhesion is mediated by integrin receptors, which recruit multiprotein adhesion complexes to sites of attachment to the ECM. Adhesion complexes provide a structural connection between the ECM and cytoskeleton, transmit mechanical force, and act as signaling hubs to control cell behavior. Recent high-resolution imaging studies of adhesion sites reveal some aspects of their spatial organization and provide insights into their function at the molecular level. PMID- 21521877 TI - PI3K and chemotaxis: a priming issue? AB - Although the spatiotemporal activation of phosphoinositide 3-kinases (PI3Ks) at the leading edge of chemotaxing cells represents a key marker of polarity, both Dictyostelium discoideum and neutrophils lacking measurable PI3K activity can still migrate directionally under certain conditions. Evidence from various papers suggests that the differentiation state of cells or their priming status can consolidate otherwise contradictory findings. PMID- 21521874 TI - Liver enzymes are associated with hepatic insulin resistance, insulin secretion, and glucagon concentration in healthy men and women. AB - OBJECTIVE: The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of gamma-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration. RESEARCH DESIGN AND METHODS: We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals. RESULTS: In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 +/- 5.1 vs. 9.3 +/- 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 +/- 4.3 vs. 7.6 +/- 3.1, P = 0.001). CONCLUSIONS: In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes. PMID- 21521878 TI - Sorting the signals from the signals in the noisy environment of inflammation. AB - Necrotic cells release dozens, possibly hundreds, of molecules that stimulate the inflammatory response. Healthy cells in the environment react to these by secreting other inflammatory mediators to amplify the response. In response to acute necrotic injury in the liver, neutrophils follow a restricted set of molecular cues to move along the sinusoids through the inflamed tissue and into the zone of necrosis, as demonstrated by intravital microscopy to view leukocyte migration live and in real time. Necrosis initiates an intricate interplay between damage-associated molecular pattern molecules, stromal inflammatory cells, and neutrophils. This results in a series of clear molecular signals, enabling neutrophils to follow an intravascular chemokine gradient along the sinusoid in the region where blood still circulates and a formyl peptide gradient through the nonperfused region to the necrotic focus. PMID- 21521879 TI - Thioredoxin mediates oxidation-dependent phosphorylation of CRMP2 and growth cone collapse. AB - Semaphorin3A (Sema3A) is a repulsive guidance molecule for axons, which acts by inducing growth cone collapse through phosphorylation of CRMP2 (collapsin response mediator protein 2). Here, we show a role for CRMP2 oxidation and thioredoxin (TRX) in the regulation of CRMP2 phosphorylation and growth cone collapse. Sema3A stimulation generated hydrogen peroxide (H2O2) through MICAL (molecule interacting with CasL) and oxidized CRMP2, enabling it to form a disulfide-linked homodimer through cysteine-504. Oxidized CRMP2 then formed a transient disulfide-linked complex with TRX, which stimulated CRMP2 phosphorylation by glycogen synthase kinase-3, leading to growth cone collapse. We also reconstituted oxidation-dependent phosphorylation of CRMP2 in vitro, using a limited set of purified proteins. Our results not only clarify the importance of H2O2 and CRMP2 oxidation in Sema3A-induced growth cone collapse but also indicate an unappreciated role for TRX in linking CRMP2 oxidation to phosphorylation. PMID- 21521881 TI - Lack of B and T lymphocyte attenuator exacerbates autoimmune disorders and induces Fas-independent liver injury in MRL-lpr/lpr mice. AB - MRL/Mp-Fas (lpr) (MRL-lpr) mice develop a systemic autoimmune disease and are considered to be a good model for systemic lupus erythematosus in humans. We have recently shown that mice lacking B and T lymphocyte attenuator (BTLA), an inhibitory co-receptor expressed mainly on lymphocytes, on a 129SvEv background spontaneously develop lymphocytic infiltration in multiple organs and an autoimmune hepatitis (AIH)-like disease. In this study, we investigated the role of BTLA in the pathogenesis of autoimmune diseases in MRL-lpr mice. We found that BTLA-deficient (BTLA(-/-)) MRL-lpr/lpr mice developed severe lymphocytic infiltration in salivary glands, lungs, pancreas, kidneys and joints as compared with BTLA-sufficient (BTLA(+/+)) MRL-lpr/lpr mice. In addition, although AIH-like disease was not found in BTLA(+/+) MRL-lpr/lpr mice, AIH-like disease was exacerbated in BTLA(-/-) MRL-lpr/lpr mice as compared with that in BTLA(-/-) 129SvEv mice. These results suggest that BTLA plays a protective role in autoimmune diseases in MRL-lpr mice and that AIH-like disease develops in BTLA(-/ ) mice even in the absence of Fas-dependent signaling. PMID- 21521882 TI - Affinity maturation of B cells involves not only a few but a whole spectrum of relevant mutations. AB - Affinity maturation of B lymphocytes within germinal centers involves both diversification of their B-cell receptors (BCRs) by somatic hypermutation (SHM) and a crucial receptor-mediated selection step. However, in contrast to recent advances in revealing the molecular mechanism of SHM, the fundamentals of the selection process are still poorly understood, i.e. it is often not clear how and how many mutations contribute to improving a BCR during the response against a given antigen. A general drawback in assessing the mutations relevant to the selection process is the difficult task of rating the relative contributions of selection and intrinsic biases to the experimentally observed mutation patterns of BCRs. The approach proposed here is premised on statistical comparison of the frequency distributions of nucleotide substitutions as observed in datasets of hypermutated BCRs against their frequency distribution expected under the null hypothesis of no selection. Thereby, we show that the spectrum of mutations relevant to maturation of canonical anti-(4-hydroxy-3-nitrophenyl)acetyl BCRs is much broader than previously acknowledged, going beyond the scope of single key mutations. Moreover, our results suggest that maturation not only involves selection by means of affinity but likewise expression and stabilization of BCRs. PMID- 21521883 TI - Clinical equipoise in sleep surgery: investigating clinical trial targets. AB - OBJECTIVE: Surgical approaches for alleviating snoring and/or obstructive sleep apnea (OSA) have been questioned because of a lack of evidence from high-quality randomized controlled trials (RCTs). An ethical requirement for RCTs is that they must test questions where community equipoise (ie, uncertainty) exists as to the correct treatment. We aimed to measure perceived importance, community equipoise, and willingness to enroll patients in 5 potential trial targets among members of the Australian Society for Otolaryngology Head and Neck Surgery (ASOHNS). STUDY DESIGN, SETTING, AND SUBJECTS: All ASOHNS members were surveyed using a multistage mail, email, Internet, and phone-based questionnaire. METHODS: Equipoise was measured for each of the scenarios using a bidirectional linear scale comparing 2 treatments. Responses were categorized into 1 of 3 groups: (A) preferred treatment 1, (B) completely undecided, and (C) preferred treatment 2. The resulting proportions are called equipoise ratios: A:B:C. Using tick boxes, the authors queried the general clinical importance and willingness to enroll patients for all scenarios. RESULTS: A total of 167 of 313 surgeons responded (53.4%). Three of the 5 trial scenarios exhibited evidence of community equipoise, but 2 scenarios, radiofrequency ablation plus uvulopalatopharyngoplasty (UPPP) versus UPPP alone and upper-airway reconstruction versus mandibular advancement splint (MAS), did not have strong support for enrolling patients. Informal feedback indicates one of these may be feasible in a smaller number of specifically trained surgeons. CONCLUSION: We suggest 2 potential RCT targets: septoplasty and turbinate reduction versus conservative measures for snoring and airway reconstruction versus MAS for OSA, where importance, clinical equipoise, and willingness all exist. PMID- 21521884 TI - Is a single miniplate at the inferior border adequate in the management of an angle fracture of the mandible? AB - OBJECTIVE: This prospective study evaluates the efficacy of using a single miniplate at the inferior border in the management of a displaced angle fracture. STUDY DESIGN: Case series with chart review. SETTING: Pt. B.D. Sharma University of Health Sciences. SUBJECTS AND METHODS: Fifty-two patients with angle fracture of the mandible were evaluated. All fractures were displaced. The displacement of fracture was assessed on panoramic radiography by measuring the displacement of the inferior alveolar canal. Fractures with displacement greater than 2 mm were included in the study. Fixation with a 4-hole noncompression miniplate along the inferior border and 2 bicortical screws on each side of the fracture was done. RESULTS: Among these 52 patients, 20 sustained isolated angle fracture, 2 sustained bilateral angle fracture, and 30 sustained angle fracture associated with contralateral parasymphysis or body fracture. Five patients (9.5%) experienced complications. All were considered minor and did not require hospitalization. Two had a slight occlusal discrepancy requiring selective occlusal grinding, and 2 minor infections were managed by incision and drainage. One patient suffered from paresis of the facial nerve that resolved itself after 3 months. CONCLUSION: Based on this single study, at a single institution, we can conclude that outcomes are acceptable in our patients, but there is very limited ability to generalize the results to different practice settings. Because of these limitations, a multicenter study with an appropriate comparison group is required to substantiate a more generalizable conclusion of efficacy of this single miniplate at inferior border. PMID- 21521885 TI - Painful traumatic neuroma of the tongue treated with serial alcohol injections. PMID- 21521886 TI - Resident physicians' perspectives on health care reform. AB - OBJECTIVE: To investigate the perspectives of resident physicians, in otolaryngology and other specialties, with respect to various health care reform proposals. Also, to determine if these opinions vary between residents training to become general medical doctors versus surgeons and specialists and between those with various levels of educational debt. STUDY DESIGN AND PARTICIPANTS: Survey of resident physicians across the United States. METHODS: Opinions of participants were measured on a 5-point Likert scale. RESULTS: Of the 1576 respondents, the majority agreed that tort reform and electronic medical records would improve quality of care and help contain health care costs. However, few residents agreed that bundling of services (BOS), hospital-acquired conditions penalties (HACP), and quality-based reimbursement (QBR) would improve the quality of care. Specialists and surgeons, in comparison to generalists, were (1) less likely to agree that BOS, HACP, or QBR would improve the quality of care; (2) more likely to agree that tort reform would help contain health care costs; and (3) more likely to believe that BOS, HACP, or QBR would decrease physician compensation. Higher educational debt burden was also an independent predictor of increased skepticism about health care reforms effects on physician compensation. CONCLUSIONS: Residents in general medicine and surgery/specialty training programs agreed that tort reform and electronic medical records would help improve the quality of health care and help contain costs. However, both groups expressed strong concern that certain elements of the Patient Protection and Affordable Care Act would not achieve these goals. PMID- 21521887 TI - A multilayer cartilaginous tip-grafting technique for improved nasal tip refinement in Asian rhinoplasty. AB - OBJECTIVE: Tip surgery remains the most difficult part of rhinoplasty in Asian patients because of the lower lateral cartilage characteristics and thick skin. The objective of this study was to evaluate the multilayer cartilaginous tip grafting technique used for tip refinement in Korean patients undergoing rhinoplasty. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary care medical center. SUBJECTS AND METHODS: A retrospective study of 99 Korean patients who underwent open rhinoplasty involving multilayer cartilaginous tip-grafting for tip refinement was performed. Autologous septal, conchal, costal, or homologous costal cartilage, or a combination of these materials was used as grafting materials. Preoperative and postoperative photographs were reviewed for objective and subjective assessment of aesthetic outcomes. RESULTS: Among patients, 7 had undergone previous rhinoplasty (7.1%), and removal of the previously placed silicone graft was required in 5 patients (5.1%). Two (6.7%), 3 (61.5%), 4 (28.8%), and 5 (3.0%) layers of cartilaginous graft were used. Postoperative aesthetic outcomes were graded as excellent in 63.6%, fair in 28.3%, and no change/worse in 8.1% of cases. Preoperative and postoperative objective measurements showed that the procedure resulted in increased nasal tip projection (0.52 +/- 0.06 vs 0.57 +/- 0.05; P < .05) and improved nasolabial angle (92.98 degrees +/- 9.95 degrees vs 95.34 degrees +/- 8.20 degrees ; P < .05). The overall complication rate was 12.1%, and 8 patients required revision surgery (8.1%). Complications included infection (5.1%), visible graft contour (1.0%), nostril deformity (1.0%), overprojection (2.0%), and visible hypertrophic scar at the marginal incision site (3.0%). CONCLUSIONS: The multilayer cartilaginous tip-grafting technique was found to be effective for aesthetic refinement of the nasal tip when used in rhinoplasty for Korean patients. PMID- 21521888 TI - Intratympanic dexamethasone to prevent cisplatin ototoxicity: a guinea pig model. AB - OBJECTIVE: To determine whether intratympanic administration of dexamethasone reduces ototoxicity from systemic cisplatin. STUDY DESIGN: Prospective animal study. Setting. Cisplatin chemotherapy induces ototoxicity manifesting as irreversible, sensorineural hearing loss. This is due to damage to the inner ear structures by free radicals. Steroidal anti-inflammatories have been shown to reduce the formation of free radicals and protect hearing in animal models. SUBJECTS AND METHODS: Pure tone auditory brainstem responses were obtained in 58 female albino guinea pigs before and 3 days after intraperitoneal (IP) cisplatin chemotherapy. Auditory brainstem responses were also taken up to 1 month after a low dose of cisplatin. Part I consisted of a dosing study to determine the optimal ototoxic dose of cisplatin. In part II, auditory brainstem response thresholds were compared after bilateral intratympanic dexamethasone doses to act as controls. For part III, the otoprotection of dexamethasone against cisplatin was tested in separate bilateral and unilateral studies. RESULTS: IP injection of 12 mg/kg of cisplatin induced significant hearing loss (57.2 +/- 4.4 dB, P < .01) with 0% mortality. Ears treated with intratympanic dexamethasone alone showed no significant threshold changes. Ears that received IP cisplatin and intratympanic dexamethasone showed reduced threshold shifts at 8 kHz when the greatest concentration of dexamethasone was administered. CONCLUSION: Modest intratympanic dexamethasone otoprotection of the guinea pig ear was greatest at the highest concentration tested and occurred in a frequency-dependent manner. Intratympanic dexamethasone presents as a safe, simple, and effective treatment modality to minimize cisplatin ototoxicity without interfering with the chemotherapeutic effects of cisplatin. PMID- 21521889 TI - Transcervical drainage for descending necrotizing mediastinitis may be sufficient. AB - OBJECTIVE: Descending necrotizing mediastinitis (DNM) is a serious form of mediastinitis with a high mortality rate. It is caused by the downward spread of an oropharyngeal or cervicofascial infection. The optimal surgical approach for this often fatal disease is controversial. This article describes the authors' experience and characterizes the surgical strategies and treatment outcomes of patients with DNM. STUDY DESIGN: Case series with chart review. SETTING: A tertiary referral medical center. SUBJECTS AND METHODS: This study conducted a retrospective chart review of patients with deep neck infections treated at a medical center from 1994 to 2007 and identified 29 patients with DNM. The clinical characteristics and outcomes were compared between patients treated with transcervical drainage alone (group I) and those with both cervical and thoracic drainage (group II). RESULTS: There were 20 patients in group I and 9 patients in group II. The overall mortality rate was 10.3%. The mean duration of the hospital stay was 29.3 +/- 15.5 days. There was no statistically significant difference in age, sex distribution, or duration from the appearance of symptoms to hospital admission between the 2 groups. The duration of hospital stay, tracheotomy rate, and mortality rate also did not differ significantly between the 2 groups. However, the numbers of surgeries were significantly higher in group II than in group I. CONCLUSION: Transthoracic mediastinal drainage is not a compulsory therapy, but timely, aggressive, transcervical mediastinal drainage with extensive debridement is very important for a good outcome when treating DNM patients. PMID- 21521890 TI - Migrating foreign body in the bronchus. PMID- 21521891 TI - Computed tomography is useful for preoperative identification of nonrecurrent laryngeal nerve in thyroid cancer patients. AB - OBJECTIVE: Nonrecurrent laryngeal nerve (NRLN) is a risk factor for nerve injury during thyroid or parathyroid surgery and is usually associated with vascular anomalies. This study investigated the usefulness of computed tomography (CT) scans for preoperative identification of NRLN in thyroid cancer patients. STUDY DESIGN: Case series with chart review. SETTING: Academic university hospital. SUBJECTS AND METHODS: Of the 6546 patients, 20 (0.3%) were intraoperatively identified with NRLN, and the medical records of 20 patients were reviewed retrospectively, with particular focus on preoperative CT findings. RESULTS: All 20 cases were right-sided NRLN, and no clinical symptoms were observed preoperatively in any patient. Two patients had type I NRLN and 18 had type II NRLN. NRLN injury occurred in 1 patient at a point where the nerve was close to the superior thyroid artery. Prior to surgery, surgeons identified only 5 suspected NRLN cases based on identification of vascular anomalies on CT scans. However, this review of CT scans revealed that vascular anomalies could be identified on the scans of all patients. CONCLUSIONS: Neck CT scanning appears to be an excellent method for predicting NRLN cases. However, thorough examination of the scans, with particular attention to the neck and mediastinum vascular structures, is required. PMID- 21521892 TI - Improved airway visualization during direct laryngoscopy using self-retaining laryngeal retractors: a quantitative study. AB - OBJECTIVE: To measure the degree to which the Lindholm laryngeal distending forceps improve visualization during direct laryngoscopy in selected pediatric patients. STUDY DESIGN: Case series with chart review. SETTING: Pediatric hospital. SUBJECTS AND METHODS: Subjects included children undergoing direct laryngoscopy using the Lindholm laryngeal distending forceps. Intraoperative endoscopic photos with and without false cord retraction via the Lindholm laryngeal distending forceps were obtained from the Seattle Children's Hospital airway endoscopy photo library. Analysis was performed using imaging software. Comparisons of visible vocal cord and glottic opening areas as well as anterior commissure angles with and without the Lindholm laryngeal distending forceps were performed with a paired and unpaired Student t test. RESULTS: The use of the Lindholm laryngeal distending forceps increased the glottic opening by a mean of 359% (95% confidence interval [CI], 255%-463%) and increased visualized true vocal cord area by 337% (197%-477%). Angle at the anterior commissure increased from a mean of 24.9 degrees to a mean of 71.5 degrees , resulting in a net mean angle increase of 46.6 degrees (95% CI, 40.2 degrees -52.9 degrees ). All measured changes were statistically significant with P values <.01. CONCLUSIONS: When placed at the level of the false vocal folds, Lindholm laryngeal distending forceps will, at least in certain cases, greatly increase the visible area of the superior surface of the vocal folds, the anterior commissure, and, by increasing the glottic opening, the subglottic region. This improved visualization may enhance the surgeon's ability to diagnose and treat pathologies in these anatomic regions during direct laryngoscopy. PMID- 21521893 TI - Complementary and alternative medicine use in the thyroid patients of a head and neck practice. AB - OBJECTIVE: To investigate the prevalence of complementary and alternative medicine (CAM) use among patients being investigated for thyroid nodules in a head and neck oncology practice. Subsequently, to determine whether the common therapies used were likely to interfere with the planned patient's care and whether the predominance was significant to warrant inclusion in routine history assessments. STUDY DESIGN: Cross-sectional survey. SETTING: Dalhousie University, Halifax, Nova Scotia, Canada. SUBJECTS AND METHODS: A survey regarding CAM use was completed by 100 patients being investigated for thyroid nodules upon their initial presentation to a head and neck oncology practice. RESULTS: Preliminary results showed that 79% of participants have a history of CAM use and 51% of participants were actively using oral supplements. Thirty-one percent of participants reported using supplements known to have hemostasis-affecting properties. CONCLUSION: Medical professionals should incorporate CAM questioning in any thyroid patient assessment to reduce patient risk and optimize medical and surgical outcomes. PMID- 21521894 TI - Management of a laryngeal injection needle impacted in the paraglottic space. PMID- 21521895 TI - Effects of chemesthetic stimuli, age, and genetic taste groups on swallowing apnea duration. AB - OBJECTIVE: This study tested the hypotheses that swallowing apnea duration (SAD) will increase given chemesthetic stimuli (ie, water < ethanol, acid, and carbonation), age (older > young), and genetic taste differences (supertasters > nontasters). STUDY DESIGN: Prospective group design. SETTING: University medical center. SUBJECTS AND METHODS: Eighty healthy adult women were identified as nontasters and supertasters, equally comprising 2 age groups: 18 to 35 years (n = 40) and 60+ years (n = 40). The KayPentax Swallowing Signals Lab was used to acquire SAD via nasal cannula during individually randomized swallows of 5 mL deionized water, 2.7% w/v citric acid, seltzer water, and 50:50 diluted ethanol/water. Data were analyzed using path analysis, with the mediator of chemesthetic perception, adjusted for repeated measures. RESULTS: Significant main effects of chemesthetic stimuli (P = .002), age (P < .001), and genetic taste differences (P = .04) on SAD were found. Older women and supertasters had longer SADs than young women and nontasters. Post hoc analyses revealed ethanol and acid boluses elicited significantly longer SADs than water boluses did. There was no significant effect of chemesthetic perception (P > .05). CONCLUSION: SAD in healthy women increased with changes in chemesthetic stimuli, older age, and in supertasters versus nontasters. It is unclear at this stage if increased SAD is a helpful mechanistic change (potentially protective against aspiration) or a maladaptive change (associated with aspiration). Future research should use these chemesthetic changes in bolus properties to assess if increased SAD decreases aspiration in patients with dysphagia while accounting for genetic taste differences. PMID- 21521896 TI - Bacterial pattern in chronic sinusitis and cystic fibrosis. AB - OBJECTIVE: To assess the association between pathogenic bacteria found in bronchoalveolar lavages and paranasal cavity cultures in patients with cystic fibrosis (CF) who underwent endonasal endoscopic sinus surgery. The authors hypothesized that the pathogenic bacterial pattern of the upper airway would be associated with that of the lower airway. STUDY DESIGN: Prospective case series with planned data collection. SETTING: Tertiary referral center. SUBJECTS AND METHODS: A group of 16 patients with diagnosis of CF who underwent endonasal endoscopic sinus surgery from July 2001 to August 2009 participated in the study. Culture samples were obtained from bronchoalveolar lavages and paranasal cavities. A Fisher exact test was performed to examine the significance of the association between upper airway and lower airway cultures. RESULTS: The most frequent microorganisms in cultures of para-nasal cavities and bronchoalveolar lavages were Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus viridans. Statistical analysis revealed a significant association between upper airway cultures (paranasal cavities) and lower airway cavities (bronchoalveolar lavages) for the 2 most frequent microorganisms, P. aeruginosa and S. aureus (P = .007 and P = .030, respectively). CONCLUSION: The authors confirmed their initial hypothesis that a significant association between bronchoalveolar lavages and sinus cultures was established, once more confirming the idea of a unified airway. They found chronic rhinosinusitis with polyps to be a common clinical presentation in patients with CF. Further studies are required to indicate the role of antibiotics and the pathogenesis of the microorganisms as a manifestation of clinical severity. PMID- 21521897 TI - Challenges and opportunities in the management of the aging voice. AB - Presbyphonia, or age-related dysphonia, is a diagnosis of exclusion, and other comorbidities must be considered in a complete evaluation of elderly patients with dysphonia. The aging voice can have a significant effect on the quality of life of the patient. In addition to the molecular effects of aging on the laryngeal tissues, the etiology of presbyphonia is often multifactorial because of comorbidities in the other organ systems involved in phonation. After a comprehensive evaluation, presbyphonia may be treated conservatively with voice therapy or with a range of interventions. Research into tissue engineering and electrical reanimation offers future options for treatment of presbyphonia. Currently, a multidisciplinary approach offers the most complete improvement in the vocal quality of life in this patient population. PMID- 21521898 TI - Tobacco use among rural African American young adult males. AB - OBJECTIVE: Tobacco-related disease is a primary source of mortality for African American men. Recent studies suggest that alternative tobacco products may have supplanted cigarettes as the most common products used by young African Americans. Effective cessation strategies require community-specific prevalence data. This project measures the prevalence of 9 tobacco products among young African American men in rural Alabama. STUDY DESIGN: Principles of community based participatory research were used to design a verbally administered tobacco product survey to measure the prevalence and behavioral factors influencing use. SETTING: Black Belt counties of rural Alabama. SUBJECTS AND METHODS: African American men aged 19 to 30 years were recruited from the target counties. Participants were stratified by income and education level. Prevalence rates for 9 products were determined, and logistic regression analysis was performed. RESULTS: A total of 415 participants completed surveys. Cigarettes were the most common product ever (54%) and currently (39.9%) used. Participants who attended school for more than 12 years or attended religious services were less likely to use cigarettes. Marijuana and blunts were used next most commonly. Only 35 respondents (8.9%) currently used mini-cigars. Other products, bidis/kreteks, smokeless tobacco, and pipes were used uncommonly in this sample. CONCLUSIONS: Cigarettes remain the dominant tobacco product used by young African American men in rural Alabama. Cigarette prevalence far exceeds that measured statewide for African American men of the same age. Alternative products were not commonly used in this study population. Effective community-based intervention must target cigarette initiation and cessation in this vulnerable population. PMID- 21521899 TI - Can otolaryngology compete with larger fields regarding impact factor?: is percentile-based impact factor a solution? AB - Impact factor (IF) consists of reporting the number of references an average article in a given journal receives over a 2-year period. Despite several valid criticisms, IF has become an important component of academic advancement. The authors sought to investigate the possible relationship between size of specialty field and IF. The top 10 journals of 13 specialty fields were selected based on IF as reported by Journal Citations Reports on the Web of Science. Specialty field population was obtained from the American Board of Medical Specialties. A highly positive correlation (r = 0.9) was noted with smaller fields (eg, otolaryngology) having lower IFs. To overcome this population bias, a percentile based impact factor (PIF) may be used where the top journal within a field is given 100%, the worst 0%, and all other journals' IFs are proportionately scaled in between the 2 extremes. PIF acts to "level the playing field," allowing between-specialty field comparisons. PMID- 21521900 TI - Topical mithramycin-A modulates submucosal collagen deposition after esophageal burn injury in rats. AB - OBJECTIVE: To evaluate efficacy of a drug-eluting, dissolvable esophageal (DEDE) stent for the prevention of submucosal collagen deposition in a rat model of acute esophageal injury. SETTING: University laboratory. STUDY DESIGN: Interventional randomized controlled trial. SUBJECTS AND METHODS: Forty two adult, male, age-matched Sprague Dawley rats were randomized to undergo either sham esophageal surgery, esophageal burn injury, or esophageal burn injury and placement of a DEDE stent. All animals underwent open gastrotomy under anesthesia. In group 1, a cautery device was inserted through the gastrotomy into the distal esophagus and removed without creating an injury. In group 2, the cautery was placed in the distal esophagus and a circumferential thermal burn injury was created. In group 3, an identical burn injury was created and a DEDE stent was placed at the site of injury and secured. On postoperative day 28, animals were sacrificed, and the distal esophagi were harvested and processed for histology. Submucosal collagen area was quantified histologically and compared across the 3 experimental groups. RESULTS: After the investigators controlled for luminal circumference and multiple measurements, submucosal collagen area was increased in group 2 (burn) compared with group 1 (sham) (P = .012). Submucosal collagen area was decreased in group 3 (DEDE stent) compared with group 2 (P = .042). No statistically significant difference in submucosal collagen area was observed between animals in group 1 and group 3 (P = .800). CONCLUSIONS;Topical application of mithramycin-A via a DEDE stent modulates collagen deposition after acute thermal injury in the rat esophagus. PMID- 21521901 TI - Curvature inversion technique: a novel tuboplastic technique for patulous Eustachian tube--a preliminary report. AB - OBJECTIVE: To assess the laser-assisted curvature inversion technique for the treatment of patients with patulous Eustachian tube (PET). STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary care medical center. SUBJECTS AND METHODS: Eleven patients with Eustachian tube dysfunction underwent laser-assisted curvature inversion technique (CIT) of the medial and lateral lamina of the Eustachian tube. A KTP laser is used to cross-hatch the medial and lateral lamina of the tube to modify the curvature and to alter the spring of the posterior cushion. A change in the direction of the cartilaginous structure curvature is created to promote full closure of the patulous gap without interfering with the tube's muscular activity. None of the patients had any concurrent disease or additional surgical procedure. RESULTS: There were no surgical complications. Following CIT, subjective symptoms of autophony on nasal breathing improved in 9 of 11 patients (81.8%), while voice autophony improved in 8 patients (72.7%); posterior cushion curvature became inverted and less wide, and the valve was seen more closed postoperatively on simple endoscopy and slow motion video-endoscopic analysis. On otoscopy, abnormal tympanic membrane excursions disappeared in 10 of 11 patients (90.9%). Mean immittance changes in tympanometric measurements for the forced respiration conditions improved postoperatively at least 0.05 mmhos in 9 of 11 patients (81.1%; P = .015). The follow-up period was 24 months. CONCLUSION: CIT appears to be a promising and relatively feasible technique for the treatment of PET. PMID- 21521902 TI - Pleural endometriosis in an aged rhesus macaque (Macaca mulatta): a histopathologic and immunohistochemical study. AB - Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity and is one of the most common reproductive abnormalities encountered in women as well as Old World primates. The majority of endometriosis cases in Old World primates occur within the abdominal cavity, with spread to extraabdominal sites considered to be a rare event. A 19-year-old multiparous female rhesus macaque (Macaca mulatta) presented to necropsy for difficulty breathing and weight loss. Grossly, the animal had marked abdominal endometriosis and severe hemoabdomen and hemothorax, the latter of which was accompanied by marked pleural fibrosis. Histologic examination confirmed the abdominal endometriosis and also revealed numerous uterine glands and stroma embedded within the pleural fibrosis. Rafts of endometrial tissue were present within pulmonary lymphatics and the tracheobronchial lymph nodes. Immunohistochemically, all ectopic endometrial tissue had varying degrees of positive immunoreactivity to cytokeratin, vimentin, progesterone and estrogen receptors, and calretinin but was negative for desmin and carcinoembryonic antigen. Pleural endometriosis is an extremely rare manifestation of endometriosis in nonhuman primates. This case report emphasizes lymphatic spread as a likely mechanism for extrauterine endometriosis. PMID- 21521903 TI - Addition of B-type natriuretic peptide to the GRACE score to predict outcome in acute coronary syndrome: a retrospective (development) and prospective (validation) cohort-based study. AB - AIMS: The present study was designed to build and validate a composite score based on the Global Registry of Acute Coronary Events (GRACE) score and B-type natriuretic peptide (BNP) concentrations to predict outcome in patients with acute coronary syndromes (ACS). METHODS: The GRACE risk score and BNP concentrations were obtained in a retrospective and a prospective cohort. A composite score including the GRACE score and BNP concentrations was first developed in a retrospective cohort of 248 patients with ACS and then validated in a prospective cohort of 575 patients. The primary outcome was 6-month death or myocardial infarction. RESULTS: End points were reached in 34 patients in the retrospective cohort and in 68 patients in the prospective cohort. Both higher BNP concentration and GRACE score were independently associated with outcome in the retrospective cohort (p=0.003 and p<0.0001). The composite score could be obtained as follows: GRACE+BNP/60. The use of the composite score increased the accuracy of the GRACE score, with an increase in the C statistic from 0.810 (0.727 to 0.892) to 0.822 (0.745 to 0.902) in the retrospective cohort and from 0.724 (0.657 to 0.791) to 0.750 (0.686 to 0.813) in the prospective cohort. Finally, 7% of patients in the prospective study population were reclassified from low to high risk or from high to low risk using this composite score. CONCLUSIONS: Plasma BNP levels refine the accuracy of the GRACE score. A comprehensive risk score, which includes BNP concentration and the GRACE risk score, might improve ACS risk stratification in clinical practice. PMID- 21521904 TI - The "infectious" nature of human prostate cancer: a cautionary note. PMID- 21521905 TI - GoQBot: a caterpillar-inspired soft-bodied rolling robot. AB - Rolling locomotion using an external force such as gravity has evolved many times. However, some caterpillars can curl into a wheel and generate their own rolling momentum as part of an escape repertoire. This change in body conformation occurs well within 100 ms and generates a linear velocity over 0.2 m s(-1), making it one of the fastest self-propelled wheeling behaviors in nature. Inspired by this behavior, we construct a soft-bodied robot to explore the dynamics and control issues of ballistic rolling. This robot, called GoQBot, closely mimics caterpillar rolling. Analyzing the whole body kinematics and 2D ground reaction forces at the robot ground anchor reveals about 1G of acceleration and more than 200 rpm of angular velocity. As a novel rolling robot, GoQBot demonstrates how morphing can produce new modes of locomotion. Furthermore, mechanical coupling of the actuators improves body coordination without sensory feedback. Such coupling is intrinsic to soft-bodied animals because there are no joints to isolate muscle-generated movements. Finally, GoQBot provides an estimate of the mechanical power for caterpillar rolling that is comparable to that of a locust jump. How caterpillar musculature produces such power in such a short time is yet to be discovered. PMID- 21521906 TI - A polygon-surface reference Korean male phantom (PSRK-Man) and its direct implementation in Geant4 Monte Carlo simulation. AB - Even though the hybrid phantom embodies both the anatomic reality of voxel phantoms and the deformability of stylized phantoms, it must be voxelized to be used in a Monte Carlo code for dose calculation or some imaging simulation, which incurs the inherent limitations of voxel phantoms. In the present study, a voxel phantom named VKH-Man (Visible Korean Human-Man), was converted to a polygon surface phantom (PSRK-Man, Polygon-Surface Reference Korean-Man), which was then adjusted to the Reference Korean data. Subsequently, the PSRK-Man polygon phantom was directly, without any voxelization process, implemented in the Geant4 Monte Carlo code for dose calculations. The calculated dose values and computation time were then compared with those of HDRK-Man (High Definition Reference Korean-Man), a corresponding voxel phantom adjusted to the same Reference Korean data from the same VKH-Man voxel phantom. Our results showed that the calculated dose values of the PSRK-Man surface phantom agreed well with those of the HDRK-Man voxel phantom. The calculation speed for the PSRK-Man polygon phantom though was 70-150 times slower than that of the HDRK-Man voxel phantom; that speed, however, could be acceptable in some applications, in that direct use of the surface phantom PSRK-Man in Geant4 does not require a separate voxelization process. Computing speed can be enhanced, in future, either by optimizing the Monte Carlo transport kernel for the polygon surfaces or by using modern computing technologies such as grid computing and general-purpose computing on graphics processing units programming. PMID- 21521908 TI - Linear energy transfer of proton clusters. AB - In conventional particle accelerators, protons are produced in long pulses, in which the average inter-proton distance is in the order of tens of centimeters or more. Therefore, the radiobiology of conventionally accelerated protons is primarily governed by the interaction of a single proton with the cell. In a laser-plasma interaction scheme, the accelerated protons come as a single bunch of particles (less than 1 ps in duration) with inter particle distances that are many orders of magnitude shorter than those in conventional particle accelerators. As laser-accelerated protons traverse the medium, they not only interact with each other, but also with the host medium. It is shown that when the average distance between protons in a cluster is less than or equal to their velocity divided by the characteristic frequency of the collective excitations supported by the medium, the cluster's linear stopping power increases and can reach several times that of sparsely distributed protons. As a result, the elevated radio biological effectiveness of the proton cluster may take place and conditions for its experimental observation are presented. PMID- 21521907 TI - Measurement of lung airways in three dimensions using hyperpolarized helium-3 MRI. AB - Large airway measurement is clinically important in cases of airway disease and trauma. The gold standard is computed tomography (CT), which allows for airway measurement. However, the ionizing radiation dose associated with CT is a major limitation in longitudinal studies and trauma. To avoid ionizing radiation from CT, we present a method for measuring the large airway diameter in humans using hyperpolarized helium-3 (HPHe) MRI in conjunction with a dynamic 3D radial acquisition. An algorithm is introduced which utilizes the significant airway contrast for semi-automated segmentation and skeletonization which is used to derive the airway lumen diameter. The HPHe MRI method was validated with quantitative CT in an excised and desiccated porcine lung (linear regression R(2) = 0.974 and slope = 0.966 over 32 airway segments). The airway lumen diameters were then compared in 24 human subjects (22 asthmatics and 2 normals; linear regression R(2) value of 0.799 and slope = 0.768 over 309 airway segments). The feasibility for airway path analysis to areas of ventilation defect is also demonstrated. PMID- 21521909 TI - Greetings from Davangere, Karnataka, India: searching versus researching. PMID- 21521910 TI - K-file vs ProFiles in cleaning capacity and instrumentation time in primary molar root canals: an in vitro study. AB - OBJECTIVES: This study compares the efficiency of manual K-files and rotary ProFiles in cleaning capacity and instrumentation time in primary molar root canals. MATERIALS AND METHODS: Seventy-five maxillary and mandibular primary molar root canals were instrumented with ProFiles and K-files in the step-back manner from size #10 to #40. The teeth were decalcified, dehydrated and cleared, and analyzed for the presence of dye remaining on the root canal walls, which served as an evidence of cleaning capacity of both the techniques. RESULTS: The results showed a significant difference in the cleaning capacity of the root canals with ProFiles and K-files, in apical and coronal thirds of the root canal. ProFiles have been found to be more efficient in cleaning the coronal thirds and K-files in cleaning apical thirds of the root canals. Both the techniques were almost equally effective in cleaning the middle thirds of the canals. The time taken during the cleaning of the root canals appeared to be statistically shorter with K-files than profiles. PMID- 21521911 TI - Comparative evaluation of shear bond strength of various esthetic restorative materials to dentin: an in vitro study. AB - AIM: To comparatively evaluate the shear bond strength of recent tooth-colored restorative materials to dentin. MATERIALS AND METHODS: Flat dentinal surface were prepared from 60 caries free, extracted human permanent molars and were mounted in acrylic rings. These were randomly divided into four groups - Group A to Group D, according to the restorative material used i.e. Glass ionomer cement (Fuji IX), Giomer (Beautifil), an Ormocer-based composite (Admira) and Nano Ceramic restorative material (Ceram X). These restorative materials were applied on dentinal surface of all the specimens using nylon cylinders. The mounted samples were stored in distilled water for 24 hours and thermocycled. They were then subjected to shear bond strength test using universal testing machine. Data was analyzed using a one-way analysis of variance (ANOVA) and student's 't'-test. RESULTS: Ceram X (16.63 +/- 0.94 MPa) and Admira (17.31 +/- 0.95 MPa) were comparable in their bond strength values, but depicted significantly higher bond strength when compared to Beautifil (12.39 +/- 1.05 MPa) and Fuji IX (7.76 +/- 1.07 MPa). CONCLUSION: Nano-ceramic and ormocer-based restorative materials showed better bonding potential to dentin as compared to GIC and Giomer. PMID- 21521912 TI - Progressive changes in arch width from primary to early mixed dentition period: a longitudinal study. AB - OBJECTIVE: The present study was conducted to evaluate, on a longitudinal basis, the changes in intercanine and intermolar widths form the primary to the early mixed dentition periods. MATERIALS AND METHODS: A total of 38 children aged 4-5 years, with normal occlusion without any proximal caries or any dental anomalies, were selected. The impressions were recorded and casts were prepared. Intercanine and intermolar widths were measured on these dental casts with the help of a digital vernier calliper. After 3 years follow-up, the impressions were recorded again and dental casts were prepared. Intercanine and intermolar widths were measured again at this stage and were compared with the baseline data using the paired t-test and the chi square test. RESULTS: There is a significant increase in the intercanine (3.93 + 1.70 mm) and intermolar width (1.49 + 1.77 mm) during the transition period from primary to early mixed dentition in both the arches and both the sexes. The gender-wise comparison showed a greater increase in males than in females, but this was not statistically significant. CONCLUSION: A thorough knowledge of growth changes during various stages of the mixed dentition period are important for a pediatric dentist to make an accurate diagnosis and treatment planning during preventive and interceptive orthodontics. PMID- 21521913 TI - Nanoionomer: evaluation of microleakage. AB - BACKGROUND: Glass ionomer cements are widely used in pediatric practice due to their advantage of fluoride release and chemical bond to tooth structure. Adherence of the restorative material to the cavity walls is one of the most important characteristic for it to be proven as an ideal material as it prevents microleakage. AIMS AND OBJECTIVES: This study was aimed at evaluating the microleakage of nanofilled resin-modified glass ionomer cement compared with the conventional and resin-modified glass ionomer cements. MATERIALS AND METHODS: Standard class V cavities of size 3 mm x 2 mm x 2 mm were made on a total of 30 extracted teeth and restored with the conventional glass ionomer, resin-modified glass ionomer or nanoionomer. After thermocycling, teeth were immersed in 0.5% methylene blue dye for 24 h. They were then sectioned buccolingually. Microleakage was assessed for the occlusal and gingival walls using a compound microscope by two examiners independently. RESULTS: Nanoionomer demonstrated the least microleakage, with a mean score of 1.3, compared with the resin-modified glass ionomer (score of 3.2) and conventional glass ionomer cement (score 2.6). CONCLUSION: Nanoionomer exhibited adequate resistance to microleakage and thus may prove better than conventional or resin-modified glass ionomers. PMID- 21521914 TI - Prevalence of oral health status in visually impaired children. AB - INTRODUCTION: The epidemiological investigation was carried out among 228 children selected from two schools of similar socioeconomic strata in and around Chennai city. MATERIALS AND METHODS: The study population consisted of 128 visually impaired and 100 normal school going children in the age group of 6-15 years. The examination procedure and criteria were those recommended by W.H.O. in 1997. RESULTS: The mean DMFT/deft was 1.1 and 0.17,0.87 and 0.47 in visually impaired and normal children, respectively. Oral hygiene levels in both groups were: mean value in good category was 0.19 and 0.67, in fair category was 0.22 and 0.1, and in poor category 0.40 and 0.23 in visually impaired children and normal children, respectively. Trauma experienced children were 0.29 and 0.13 in visually impaired children and normal children, respectively. CONCLUSION: The conclusions drawn from this study were that there was a greater prevalence of dental caries, poorer oral hygiene, and higher incidence of trauma in visually impaired children. PMID- 21521915 TI - Comparison of antimicrobial substantivity of root canal irrigants in instrumented root canals up to 72 h: an in vitro study. AB - Disinfection of the root canal system is one of the primary aims of root canal treatment. This can be achieved through the use of various antimicrobial agents in the form of irrigants and medicaments. The antimicrobial substantivity of 2% chlorhexidine gluconate, 1% povidone iodine, 2.5% hydrogen peroxide followed by 2% sodium hypochlorite, and 2% sodium hypochlorite alone as irrigants was assessed in instrumented root canals. 2% chlorhexidine showed antimicrobial substantivity lasting up to 72 h, followed by 1% povidone iodine, and 2% sodium hypochlorite. Thus 2% chlorhexidine should be used as a final rinse irrigant in endodontic treatment protocols. PMID- 21521916 TI - Mesiodens: a clinical and radiographic study in children. AB - BACKGROUND: A mesiodens is a supernumerary tooth located in the palatal midline between the two maxillary central incisors. The overall prevalence varies between 0.15 and 1.9%. The present study aimed to evaluate the epidemiological characteristics of mesiodens in the pediatric population. MATERIALS AND METHODS: A longitudinal prospective study was carried out in 7932 children to determine the prevalence of mesiodens. The following data were also recorded: age, sex, shape, sagittal position, orientation, eruption status, number and complications caused by mesiodens. RESULTS: The prevalence of mesiodens in the present study was 0.8%. The sex ratio was 1.78:1, favoring boys. The majority of mesiodens (67.9%) were conical in shape, followed by the supplemental (17.9) and tuberculate (14.1%) types. 71.8% of the mesiodens were palatally placed, 25.6% erupted on the arch and 2.6% were labially positioned. A majority of the mesiodens (62.8%) were vertically aligned. Inverted and horizontal positions were observed in 30.8% and 6.4% of the cases. Most of the mesiodens (53.8%) were impacted, and 14 children had two mesiodens. Most of the mesiodens were associated with complications, and only 26.9% were asymptomatic. CONCLUSIONS: The prevalence of mesiodens was 0.8% .Conical shape, palatal position and vertical orientation were common characteristic observations in the study. PMID- 21521917 TI - Effect of low-concentration daily topical fluoride application on fluoride release of giomer and compomer: an in vitro study. AB - AIMS AND OBJECTIVE: To determine the effect of low-concentration daily topical fluoride application on fluoride release of Giomer and Compomer and to compare the amount of fluoride release from Giomer to that of Compomer. MATERIALS AND METHODS: Forty-eight specimens of each Giomer and Compomer were divided into four treatment groups, namely, control group, fluoridated dentifrice (500 ppm) once daily group, fluoridated dentifrice (500 ppm) twice-daily group and fluoridated dentifrice (500 ppm) once-daily + fluoridated mouthwash (225 ppm) group. Each specimen was suspended in demineralising solution for 6 h and remineralising solution for 18 h. Fluoride release was measured in both the demineralising solution and the remineralising solution daily for 21 days. Total daily fluoride release for each specimen was calculated by adding the amount released in the demineralising solution to that released in the remineralising solution. RESULTS AND CONCLUSION: The fluoride release (ppm) was found to be higher in Giomer when compared with Compomer. The fluoride released from Giomer and Compomer was significantly higher in the acidic demineralising solution than in the neutral remineralising solution. It was found that increasing fluoride exposure significantly increased fluoride release from Giomer and Compomer. It was found that the fluoride release from the subgroups of Giomer and Compomer was in the following order: fluoridated dentifrice twice-daily > fluoridated dentifrice once daily + fluoridated mouthwash > fluoridated dentifrice once-daily > control group. It was found that Giomer showed a greater fluoride uptake Compomer. PMID- 21521918 TI - Cellulitis on face in a patient with congenital afibrinogenemia. AB - Congenital afibrinogenemia is a rare coagulation disorder, with an estimated prevalence of 1 : 1,000,000, characterized by a complete absence to reduced level of circulating fibrinogen. This article presents a case of congenital afibrinogenemia, which presented as cellulitis on the face. PMID- 21521919 TI - Bilateral fusion in primary mandibular teeth: a report of two cases. AB - The rare anomaly of fusion in primary dentition has very little documentation in Indian population. Two rare cases of bilateral fusion between primary mandibular lateral incisors and canines and primary mandibular central incisors and lateral incisors have been presented in this report. A minimal intervention approach, preventive procedures, and a long-term follow-up have been discussed. PMID- 21521920 TI - Dental rehabilitation of amelogenesis imperfecta using thermoformed templates. AB - Amelogenesis imperfecta represents a group of dental developmental conditions that are genomic in origin. Hypoplastic AI, hypomineralised AI or both in combination were the most common types seen clinically. This paper describes oral rehabilitation of a 9-year-old Malay girl with inherited hypoplastic AI using transparent thermoforming templates. The defective surface areas were reconstructed to their original dimensions on stone cast models of the upper and lower arches using composite, and transparent thermoform templates were fabricated on the models. The templates were used as crown formers to reconstruct the defective teeth clinically using esthetically matching composite. The usage of the templates allowed direct light curing of the composite, accurate reproducibility of the anatomic contours of the defective teeth, reduced chair side time and easy contouring and placement of homogenous thickness of composite in otherwise inaccessible sites of the affected teeth. PMID- 21521921 TI - Treatment of pseudo Class III malocclusion by modified Hawleys appliance with inverted labial bow. AB - Pseudo Class III malocclusion is characterized by an anterior crossbite with functional forward mandibular displacement. Various appliances have been devised for early treatment of a pseudo Class III. The aim of this article is to highlight the method of construction and use a simple removable appliance termed as "Modified Hawleys appliance with inverted labial bow" to treat psuedo class III malocclusion in the mixed dentition period. It also emphasizes the importance of differentiating between true Class III and pseudo Class III. This appliance in this type of malocclusion enabled the correction of a dental malocclusion in a few months and therapeutic stability of a mesially positioned mandible encouraging favorable skeletal growth. PMID- 21521922 TI - Oral findings in a child with lipoid proteinosis: a case report and review. AB - Lipoid proteinosis, a very rare autosomal recessive genodermatosis, results in hyaline material deposition in the skin and mucous membrane of various organs leading to multisystem involvement. A case report of a 12-year-old female child is presented here who showed classic features of the disease with generalized thickening, hardening, and scarring of the skin and vocal cord infiltration causing voice changes. The patient also had numerous oral mucosal and dental findings. The knowledge of the clinical features of the disease may help the oral health professional in rendering the appropriate treatment in order to improve the quality of life deteriorated by the disease. PMID- 21521923 TI - Posterior neonatal teeth. AB - Teeth which are present in the oral cavity of newborn infant at the time of birth are called "natal teeth" and which erupts in first month of postnatal life are called as "neonatal teeth." The incidence of these teeth is 1 in 2000 to 1 in 3500 live birth. The most common natal teeth reported are mandibular central incisors followed by maxillary incisors and mandibular canine. The natal or neonatal tooth in maxillary molar region is a rare occurrence. This article represents a rare case of bilateral neonatal maxillary molar teeth. PMID- 21521924 TI - Feeding obturator appliance for an infant with cleft lip and palate. AB - Clefts of the palate, alveolus and lip are some of the most frequently encountered anomalies of the face. This article presents a case report of a neonate with cleft lip and palate in whom a feeding obturator was delivered. This article demonstrates the indications, construction, and benefits of a palatal obturator in an 11-day-old infant with a bilateral cleft lip and palate. PMID- 21521925 TI - Dental management of hemophiliac child under general anesthesia. AB - Hemophilia is the most common inherited bleeding disorder. Hemophilic patients should be cosidered as special patients. There is no contraindication to general dental treatment for hemophiliacs, as they generally do not involve bleeding. But caution must be used with any surgical procedures that involve the local and general anesthesia. Such patients should always be managed in the setting of specialized units with appropriate clinical expertise and laboratory support. Recent advances in the management of hemophilia have enabled many hemophiliac patients to receive surgical dental procedures in an outpatient dental care on a routine basis. The purpose of this case report is to provide a few management strategies when providing full mouth rehabilitation under anesthesia and replacement therapies that are available. In addition, overviews of possible complication that may be encountered when providing such treatment are discussed here. PMID- 21521926 TI - Clinicopathological features of primary aldosteronism associated with subclinical Cushing's syndrome. AB - Primary aldosteronism (PA), an autonomous aldosterone hypersecretion from adrenal adenoma and/or hyperplasia, and subclinical Cushing syndrome (SCS), a mild but autonomous cortisol hypersecretion from adrenal adenoma without signs or symptoms of Cuhing's syndrome, are now well-recognized clinical entities of adrenal incidentaloma. However, the clinicopathological features of PA associated with SCS (PA/SCS) remain unknown. The present study was undertaken to study the prevalence of PA/SCS among PA patients diagnosed at our institute, and characterize their clinicopathlogical features. The prevalence of PA/SCS was 8 of 38 PA patients (21%) studied. These 8 PA/SCS patients were significantly older and had larger tumor, higher serum potassium levels, lower basal plasma levels of aldosterone, ACTH and DHEA-S as well as lower response of aldosterone after ACTH stimulation than those in 12 patients with aldosterone-producing adenoma without hypercortisolism. All 8 PA/SCS patients showed unilateral uptake by adrenal scintigraphy at the ipsilateral side, whereas the laterality of aldosterone hypersecretion as determined by adrenal venous sampling varied from ipsilateral (3), contralateral (2), and bilateral side (2). 6 PA/SCS patinets who underwent adrenalectomy required hydrocortisone replacement postoperatively. Histopathological analysis of the resected adrenal tumors from 5 PA/SCS patients revealed a single adenoma in 3, and double adenomas in 2, with varying degrees of positive immunoreactivities for steroidgenic enzymes (3beta-HSD, P450(C17)) by immunohistochemical study as well as CYP11B2 mRNA expression as measured by real time RT-PCR. In conclusion, PA/SCS consists of a variety of adrenal pathologies so that therapeutic approach differs depending on the disease subtype. PMID- 21521927 TI - Clinicopathological features, biochemical and molecular markers in 5 patients with adrenocortical carcinoma. AB - Adrenocortical carcinoma (ACC) is a very rare malignant tumor with poor prognosis. To gain insight into the pathogenic significance of ACC, we studied clinicopathological features and gene expression profile in ACC. We analyzed five ACC cases (two men and three women) with the median age of 45-year-old who underwent adrenalectomy at our institute. Endocrine studies revealed that two cases had subclinical Cushing's syndrome (SCS) and one with concomitant estrogen secreting tumor, while the rest of three cases had non-functioning tumors. Analysis of urinary steroids profile by gas chromatography/mass spectrometry showed increased metabolites of corticosteroid precursors, such as 17-OH pregnenolone, 17-OH progesterone, dehydroepiandorosterone (DHEA), and 11 deoxycortisol in all five cases. The pathological diagnosis of ACC was based on Weiss's criteria with its score >= 3. The mean size of the resected tumors was 87 mm and Ki67/MIB1 labeling index, a proliferative marker, was 3-27%. Immunohistochemical analysis revealed a disorganized expression of several steroidogenic enzymes, such as 3beta-hydroxysteroid dehydrogenase, 17alpha hydroxylase, and DHEA-sulfotransferase. Among several genes determined by RT-PCR, insulin-like growth factor (IGF)-II mRNA was consistently and abundantly expressed in all 5 tumor tissues. Postoperatively, two cases with SCS developed local recurrence and liver metastasis. The present study suggests that the disorganized expression of steroidogenic enzymes and the overexpression of IGF-II by the tumor are hallmarks of ACC, which could be used as biochemical and molecular markers for ACC. PMID- 21521928 TI - The prevalence of testicular adrenal rest tumors and associated factors in postpubertal patients with congenital adrenal hyperplasia caused by 21 hydroxylase deficiency. AB - Development of a testicular adrenal rest tumor (TART) is common in males with congenital adrenal hyperplasia, and it can be an important cause of infertility. In the present study, we observed the prevalence of TARTs, and analyzed its associated factors in patients with 21-hydroxylase deficiency. Testicular ultrasonography was performed in 48 postpubertal male patients aged 10.6 to 27.1 years. To determine whether patients were undertreated, we analyzed the serum 17 hydroxyprogesterone (17-OHP) levels to the time of ultrasonographic measurement and calculated the percentage of measurements when serum 17-OHP level was >10 ng/mL relative to the total number of measurements during the follow-up period. We divided the 6-year period before ultrasonographic measurement (time 0) into three 2-year intervals and calculated the average concentration of serum 17-OHP in each interval to give a -2(nd) to 0 year-average concentration (-2-0YAC), -4 2YAC and -6-4YAC. A TART was detected by ultrasonography in 31 of 48 patients (64.6%) and the median maximal cross-sectional area of the TARTs was 0.71 (0.03, 4.95) cm(2). The corrected final adult height was lower, and -4-2YAC and body mass index were higher in patients with TART than in those without. After controlling for the type of 21-hydroxylase deficiency, hydrocortisone-equivalent dose, age, and -6-4YAC, the size of TART was associated with a high undertreatment percentage with a marginal statistical significance. These results suggest that strict disease control is mandatory and regular examination with testicular ultrasonography is recommended in male patients, regardless of the type of 21-hydroxylase deficiency. PMID- 21521929 TI - Prevalence of and risk factors for lipodystrophy among HIV-infected patients receiving combined antiretroviral treatment in the Asia-Pacific region: results from the TREAT Asia HIV Observational Database (TAHOD). AB - The prevalence of and risk factors for lipodystrophy (LD) among patients receiving combined antiretroviral treatment (cART) in the Asia-Pacific region are largely unknown. LD diagnosis was based on the adverse event definition from the US NIH Division of AIDS (2004 version), and only cases with a severity grade of >= 3 were included. TAHOD patients who had recently commenced cART with >= 3 drugs after 1996 from sites which had ever reported LD were included in the analysis. Covariates for the forward multivariate logistic regression model included demographic variables, CDC disease classification, baseline CD4 and viral load, hepatitis B/C virus co-infection, and regimen and duration of cART. LD was diagnosed in 217 (10.5%) of 2072 patients. The median duration of cART was 3.8 (interquartile range, 2.2-5.3) years [stavudine, 2.0 (1.0-3.5) years; zidovudine, 1.8 (0.6-3.9) years; and protease inhibitors (PI), 2.6 (1.3-4.5) years]. In the multivariate model, factors independently associated with LD included use of stavudine (<= 2 years vs. no experience: OR 25.46, p<0.001, > 2 years vs. no experience: OR 14.92, p<0.001), use of PI (> 2.6 years vs. no experience: OR 0.26, p<0.001), and total duration of cART (> vs. <= 3.8 years: OR 4.84, p<0.001). The use of stavudine was strongly associated with LD in our cohort. Stavudine-sparing cART strategies are warranted to prevent the occurrence of LD in the Asia-Pacific region. PMID- 21521930 TI - Effects of mosapride citrate, a 5-HT4-receptor agonist, on gastric distension induced visceromotor response in conscious rats. AB - Mosapride citrate (mosapride), a prokinetic agent with 5-HT(4)-receptor agonistic activity, is known to enhance gastric emptying and alleviate symptoms in patients with functional dyspepsia (FD). As hyperalgesia and delayed gastric emptying play an important role in the pathogenesis of FD, we used in this study balloon gastric distension to enable abdominal muscle contractions and characterized the visceromotor response (VMR) to such distension in conscious rats. We also investigated the effects of mosapride on gastric distension-induced VMR in the same model. Mosapride (3-10 mg/kg, p.o.) dose-dependently inhibited gastric distension-induced VMR in rats. However, itopride even at 100 mg/kg failed to inhibit gastric distension-induced VMR in rats. Additionally, a major metabolite M1 of mosapride, which possesses 5-HT(3)-receptor antagonistic activity, inhibited gastric distension-induced VMR. The inhibitory effect of mosapride on gastric distension-induced visceral pain was partially, but significantly inhibited by SB-207266, a selective 5-HT(4)-receptor antagonist. This study shows that mosapride inhibits gastric distension-induced VMR in conscious rats. The inhibitory effect of mosapride is mediated via activation of 5-HT(4) receptors and blockage of 5-HT(3) receptors by a mosapride metabolite. This finding indicates that mosapride may be useful in alleviating FD-associated gastrointestinal symptoms via increase in pain threshold. PMID- 21521931 TI - Na+/Ca2+ exchanger inhibitors inhibit neurite outgrowth in PC12 cells. AB - To elucidate the role of Na(+)/Ca(2+) exchanger (NCX) in neurite outgrowth, we investigated the effects of NCX inhibitors on neurite outgrowth in PC12 cells. KB R7943 and 3',4'-dichlorobenzamil, NCX inhibitors, inhibited the neurite outgrowth caused by nerve growth factor (NGF). NCX inhibitors inhibited the neurite outgrowth caused by dibutylyl cAMP, which rapidly reorganizes the cytoskeleton. KB-R7943 inhibited the neurite outgrowth caused by Y-27632, an inhibitor of Rho kinase (ROCK) that regulates actin. However, NCX inhibitors did not inhibit NGF induced phosphorylation of extracellular signal-regulated kinase. These results suggest that NCX inhibitor affects downstream of the Rho-ROCK signal transduction pathways in neurite outgrowth. PMID- 21521932 TI - Pitavastatin increases ABCA1 expression by dual mechanisms: SREBP2-driven transcriptional activation and PPARalpha-dependent protein stabilization but without activating LXR in rat hepatoma McARH7777 cells. AB - Hepatic ATP-binding cassette transporter A1 (ABCA1) plays a key role in high density lipoprotein (HDL) production by apolipoprotein A-I (ApoA-I) lipidation. 3 Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, increase ABCA1 mRNA levels in hepatoma cell lines, but their mechanism of action is not yet clear. We investigated how statins increase ABCA1 in rat hepatoma McARH7777 cells. Pitavastatin, atorvastatin, and simvastatin increased total ABCA1 mRNA levels, whereas pravastatin had no effect. Pitavastatin also increased ABCA1 protein. Hepatic ABCA1 expression in rats is regulated by both liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP2) pathways. Pitavastatin repressed peripheral type ABCA1 mRNA levels and its LXR-driven promoter, but activated the liver-type SREBP-driven promoter, and eventually increased total ABCA1 mRNA expression. Furthermore, pitavastatin increased peroxisome proliferator-activated receptor alpha (PPARalpha) and its downstream gene expression. Knockdown of PPARalpha attenuated the increase in ABCA1 protein, indicating that pitavastatin increased ABCA1 protein via PPARalpha activation, although it repressed LXR activation. Furthermore, the degradation of ABCA1 protein was retarded in pitavastatin-treated cells. These data suggest that pitavastatin increases ABCA1 protein expression by dual mechanisms: SREBP2 mediated mRNA transcription and PPARalpha-mediated ABCA1 protein stabilization, but not by the PPAR-LXR-ABCA1 pathway. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10241FP]. PMID- 21521933 TI - Development of a high-expression system for staphylococcal exfoliative toxin genes. AB - We constructed a new expression system for staphylococcal exfoliative toxin (ET). The expression vector, pETA-exp2, was constructed based on Bacillus-Escherichia shuttle vector pHY300PLK. The pETA-exp2 vector includes the regulator of the ETA gene (eta), the promoter and Shine-Dalgarno (SD) sequences of eta, a SalI sequence at the end of the signal sequence of eta, a nucleotide sequence encoding mature ETA, an XhoI site, a 6x His sequence just before the stop codon and the end of the transcription sequence of eta. The nucleotide sequences coding for the mature proteins of ETB, ExhA, ExhB, ExhC, ExhD and SHETB were amplified by polymerase chain reaction (PCR) and inserted into pETA-exp2. These recombinant plasmids were transformed into Bacillus megaterium. The major protein in the culture supernatant of the transformant was recombinant ET (rET). The yields of all rETs were high, and all of them showed exfoliative activity in susceptible animals. The antigenicities of rETs and ETs were not distinguishable from each other. PMID- 21521934 TI - Relative associations of polycystic ovarian syndrome vs metabolic syndrome with thyroid function, volume, nodularity and autoimmunity. AB - BACKGROUND: The relative associations of polycystic ovarian syndrome (PCOS) and metabolic syndrome (MS) with the risk for thyroid disease (thyroid function, volume, nodularity and autoimmunity) are unknown.We compared thyroid features and function in patients with PCOS and control subjects by the presence of MS. METHODS: We recruited 84 women with PCOS and 81 age-matched healthy controls. PCOS was defined according to the Rotterdam criteria. Thyroid ultrasound and function tests were performed in all. RESULTS: Although thyroid disease was more prevalent in women with PCOS, ovarian disease was not significantly associated with the risk for thyroid disease. Thyroid volume did not differ between women with PCOS and control subjects (13.7+/-8.6 vs 12.4+/-4.4 ml, respectively; p=0.2); however, it differed significantly between subjects with and without MS (regardless of PCOS status): 19.1+/-14.8 vs 12.4+/-4.9 ml, respectively; p=0.001). Antithyroglobulin and antithyroid peroxidase antibody levels also were significantly higher in subjects with MS, but not in participants with PCOS vs control subjects. Overall, TSH level correlated significantly with body mass index (BMI), weight, waist circumference, diastolic blood pressure, and levels of LDL cholesterol, triglycerides, and HDL cholesterol. Thyroid volume correlated significantly with age, weight, BMI, waist circumference, systolic blood pressure, 120-min postprandial glucose and HDL level. CONCLUSIONS: PCOS alone was not associated with thyroid disease in our population. However, MS and some of its components appear to be related to thyroid volume, function, and antithyroid antibody levels. PMID- 21521935 TI - Oxidative status and its relation with insulin resistance in young non-obese women with polycystic ovary syndrome. AB - BACKGROUND: Oxidative stress may play a role in the pathophysiology of polycystic ovary syndrome (PCOS). Insulin resistance (IR) also can be found in young non obese women with PCOS. Hyperglycemia may increase reactive oxygen species production and decrease antioxidant levels. AIM: To investigate oxidative status and its relation with IR in young non-obese patients with PCOS. MATERIAL/SUBJECTS AND METHODS: Thirty-one patients with hyperinsulinemic (no.=13) and normoinsulinemic (no.=18) PCOS and 29 healthy controls were included in this study. Serum levels of glucose, insulin, gonadotropins, total testosterone, DHEAS, SHBG, 2-h plasma glucose on oral glucose tolerance test, malondialdehyde (MDA), protein carbonyl (PC), reduced glutathione (GSH), beta carotene, vitamin A, C, E and the enzyme activities of catalase and glutathione S-transferase (GST), IR [by homeostasis model assessment (HOMA)-IR], and beta cell function [by HOMA-B] were assessed. RESULTS: Serum glucose, insulin, total testosterone, DHEAS, HOMA-IR levels, and LH/FSH ratios were higher in young non-obese women with PCOS. Serum MDA and PC levels were also higher but GSH, vitamin C and E levels, and GST enzyme activity were lower in these women than in healthy controls, independently of the status of IR (p<0.05). CONCLUSIONS: Oxidative stress characterized by increased oxidants and decreased antioxidant levels which are independent of IR may be involved in the pathogenesis of PCOS in young non obese women. PMID- 21521936 TI - A sequence variation in 3'UTR of CYP21A2 gene correlates with a mild form of congenital adrenal hyperplasia. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) is mainly caused by the deficiency of the 21-hydroxylase enzyme coded by the CYP21A2 gene. However, some alleles in the non-classical form (NC-CAH) remain without identified mutations, suggesting the involvement of regulatory regions. AIM: Our objective was to study an allele carrying the variant *13 G>A in the 3'UTR of the CYP21A2 gene identified in some patients with a mild form of NC-CAH in order to verify the possible implication of this variation with the phenotype observed. SUBJECTS AND METHODS: Among all the subjects in whom the CYP21A2 gene was analyzed, 14 patients and 7 relatives heterozygous or homozygous for the *13 G>A substitution in 3'UTR were selected. Sequencing of DNA, genotyping, multiplex ligation dependent probe amplification (MLPA), in vitro studies and bioinformatic analysis were performed. RESULTS: The haplotype of the *13 G>A allele was identical in all the subjects with a monomodular structure composed by one C4A gene and one CYP21A2 gene without a second module with the CYP21A1P pseudogene. No other concomitant mutations were found in the region extending from 3 kb in the promoter and encompassing the polyadenylation signal. Both bioinformatic analysis and in vitro studies predicted an alteration of the RNA folding and expression, but no miRNA target sequences were found in this region. CONCLUSIONS: The identification of a substitution in the 3'UTR of the gene associated with a mild form of NC-CAH suggests the importance of analyzing the CYP21A2 untranslated regions to better characterize and treat this subgroup of patients. PMID- 21521937 TI - Exendin-4 regulates the expression of the ATP-binding cassette transporter A1 via transcriptional factor PREB in the pancreatic beta cell line. AB - BACKGROUND: PRL regulatory element-binding (PREB) protein is a transcription factor that regulates insulin promoter activity in the rat anterior pituitary. The PREB protein is expressed not only in the anterior pituitary but also in pancreatic beta cells. Previously, we have reported that PREB plays an important role in glucose-mediated insulin gene expression in pancreatic beta cells. The ATP-binding cassette transporter A1 (ABCA1) in pancreatic beta cells influences insulin secretion and glucose homeostasis. Exendin-4 (Ex-4), a longacting agonist of the glucagon-like peptide 1, stimulates ABCA1 expression in pancreatic beta cells. AIMS: In this study, we examined the role played by PREB in Ex-4-induced ABCA1 expression in pancreatic beta cells. MATERIAL/SUBJECTS AND METHODS: PREB mRNA and protein expression were evaluated in pancreatic beta cell line (INS-1 cells) treated with Ex-4 (10 nM). RESULTS: Ex-4 stimulated PREB protein and mRNA expression in INS-1 cells. PREB stimulated the activity of the luciferase reporter protein that was under the control of the ABCA1 promoter. Chromatin immunoprecipitation assay showed that PREB mediates its transcriptional activity by directly binding to the ABCA1 promoter region. Finally, we used small interfering RNA to inhibit PREB expression in the cells and demonstrated that the knockdown of PREB expression attenuated the effects of Ex-4 on ABCA1 expression. CONCLUSION: PREB mediates Ex-4-stimulated transcription of the ABCA1 gene in pancreatic beta cells. PMID- 21521938 TI - Inability of recombinant human thyrotropin to predict the evolution from subclinical hypothyroidism to overt disease. A pilot study. AB - BACKGROUND: The use of recombinant human TSH (rhTSH) is indicated to evaluate thyroid carcinoma patients. In recent years, some authors have reported that rhTSH could serve as a dynamic test of thyroid reserve. The aim of the present study was to determine whether or not rhTSH can predict the evolution from subclinical hypothyroidism (SH) to overt hypothyroidism. MATERIALS AND METHODS: Twenty-one women who met the diagnostic criteria of SH were enrolled. All patients received a single dose of rhTSH (0.1 mg). Basal blood samples for TSH, free T4 (fT4), thyroglobulin (Tg), and anti-thyoperoxidase and anti-Tg antibodies were obtained before and 1 day after rhTSH administration. All patients were followed for 2 yr, and blood samples were obtained every 6 months. RESULTS: Twenty-four hours after rhTSH administration, the TSH level increased to >20 mU/l in 14 patients; the serum peak TSH levels remained <10 mU/l in only 5 patients. On follow-up, 7 women (33%) required L-T4 replacement therapy for overt hypothyroidism or a persistent TSH level >10 mlU/l. None of the parameters analyzed differed significantly between patients who developed overt hypothyroidism from those who had persistent SH. CONCLUSIONS: The response of thyroid function tests to a single low dose of rhTSH is not useful in identifying those patients with SH who will develop overt hypothyroidism over a 2-yr period. PMID- 21521939 TI - Paramutation of tobacco transgenes by small RNA-mediated transcriptional gene silencing. AB - It has been well established that trans-acting small RNAs guide promoter methylation leading to its inactivation and gene silencing at the transcriptional level (TGS). Here we addressed the question of the influence of the locus structure and epigenetic modifications of the target locus on its susceptibility for being paramutated by trans-acting small RNA molecules. Silencing was induced by crossing a 35S promoter silencer locus 271 with two different 35S-driven transgene loci, locus 2 containing a highly expressed single copy gene and locus 1 containing an inverted posttranscriptionally silenced (PTGS) repeat of this gene. Three generations of exposure to RNA signals from the 271 locus were required to complete silencing and methylation of the 35S promoter within locus 2. Segregating methylated locus 2 epialleles were obtained only from the third generation of hybrids, and this methylation was not correlated with silencing. Strikingly, only one generation was required for the PTGS locus 1 to acquire complete TGS and 35S promoter methylation. In this case, paramutated locus 1 epialleles bearing methylated and inactive 35S promoters segregated already from the first generation of hybrids. The results support the hypothesis that PTGS loci containing a palindrome structure and methylation in the coding region are more sensitive to paramutation by small RNAs and exhibit a strong tendency to formation of meiotically transmissible TGS epialleles. These features contrast with a non-methylated single copy transgenic locus that required several generations of contact with RNA silencing molecules to become imprinted in a stable epiallele. PMID- 21521940 TI - Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta. AB - Birthweight has been associated with a number of health outcomes throughout life. Crucial to proper infant growth and development is the placenta, and alterations to placental gene function may reflect differences in the intrauterine environment which functionally contribute to infant growth and may ultimately affect the child's health. To examine if epigenetic alteration to the glucocorticoid receptor (GR) gene was linked to infant growth, we analyzed 480 human placentas for differential methylation of the GR gene exon 1F and examined how this variation in methylation extent was associated with fetal growth. Multivariable linear regression revealed a significant association (p < 0.0001) between differential methylation of the GR gene and large for gestational age (LGA) status. Our work is one of the first to link infant growth as a measure of the intrauterine environment and epigenetic alterations to the GR and suggests that DNA methylation may be a critical determinant of placental function. PMID- 21521941 TI - Regulation of autophagy by lysosomal positioning. AB - The mammalian target of rapamycin (mTOR) is a well-conserved negative regulator of autophagy. Here we review our recent data describing how lysosomal positioning influences and coordinates mTOR activity, autophagosome biogenesis and autophagosome-lysosome fusion. In this way, lysosomal positioning regulates many diverse cellular responses to starvation and subsequent nutrient replenishment. PMID- 21521942 TI - The purpose of the HIF-1/PHD feedback loop: to limit mTOR-induced HIF-1alpha. AB - Prolyl hydroxylases (PHDs) target hypoxia-inducible factor-1alpha (HIF-1alpha) for degradation. Hypoxia inactivates PHDs, causing accumulation of HIF-1alpha. In turn, HIF-1 further transactivates PHDs. It is thought that the purpose of this feedback loop is to limit HIF-1alpha accumulation caused by hypoxia. Here, we suggest that the feedback is intended to limit the induction of HIF-1alpha by insulin, growth factors, hormones, cytokines and nutrients. These stimuli induce HIF-1alpha by increasing its translation, not by inhibiting PHDs. As exemplified herein, in a mTOR-dependent manner, insulin transiently induced HIF-1alpha in retinal pigment epithelial (RPE) cells. Induction of HIF-1alpha was followed by activation of HIF-dependent transcription. Furthermore, DFX, which inactivates PHDs, potentiated the induction of HIF-1alpha by insulin. We propose that the most relevant function of the PHD-HIF feedback loop is to limit the induction of HIF-1alpha by mTOR. The failure to limit mTOR-dependent induction of HIF-1 may contribute to age-related macular degeneration and diabetic retinopathy, suggesting rapamycin for prevention of these age-related diseases. PMID- 21521943 TI - The dual-specificity phosphatase hYVH1 (DUSP12) is a novel modulator of cellular DNA content. AB - The dual-specificity phosphatase hYVH1 (DUSP12) is an evolutionary conserved phosphatase that also contains a unique zinc-binding domain. Recent evidence suggests that this enzyme plays a role in cell survival and ribosome biogenesis. Here, we report that hYVH1 expression also affects cell cycle progression. Overexpression of hYVH1 caused a significant increase in polyploidy and in the G 2/M cell population, with a subsequent decrease in the G 0/G 1 population. Phosphatase activity is dispensable, while the zinc-binding domain is necessary and sufficient for hYVH1-mediated cell cycle changes. In agreement with this, siRNA-mediated silencing of hYVH1 expression resulted in a dramatic increase in the G 0/G 1 population and susceptibility to cellular senescence. Additionally, mass spectrometry-based methods identified novel hYVH1 phosphorylation sites, including a C-terminal modification at position Ser ( 335) in the zinc-binding domain. Interestingly, phosphorylation at Ser335 regulates subcellular targeting of hYVH1 and augments the hYVH1 G 2/M phenotype. Collectively we demonstrate that hYVH1 is a novel modulator of cell cycle progression; a function mainly mediated by its C-terminal zinc-binding domain. PMID- 21521944 TI - The role of multipotent marrow stromal cells (MSCs) in tissue regeneration. AB - An extensive body of preclinical and clinical data has shown that administration of adult multipotent marrow stromal cells (MSCs) effectively ameliorates experimental and clinical conditions of many different organ systems. Differentiation into organ parenchymal cells, however, is very rare, and the main mechanism for organ protection and regeneration from different types of injury is the exertion of paracrine effects and stimulation of tissue repair. A large number of clinical trials have been conducted and are ongoing to investigate the safety and efficacy of MSCs in different organs after various types of organ injury. This article intends to give a brief overview about current applications of MSCs and mechanisms involved in organ protection and regeneration. PMID- 21521945 TI - AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation. AB - Ulk1 is a serine/threonine kinase and the mammalian functional homolog of yeast Atg1. It acts at the initiation step of autophagy and forms a complex with mAtg13, FIP200 and Atg101. Assembly of this complex is independent of mTOR signaling, indicating the regulation of autophagy initiation in mammals is different from that in yeast. In a recent study, we reported that Ulk1 can be phosphorylated by mTOR and AMPK kinases. AMPK associates with Ulk1 in nutrient dependent manner. Rapid dissociation between Ulk1 and AMPK primes cells for fast autophagy induction upon nutrient withdrawal. These studies show that both mTOR and AMPK directly regulate Ulk1 and coordinate the mammalian autophagy initiation. PMID- 21521946 TI - Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. AB - Breast cancer progression and metastasis are driven by complex and reciprocal interactions, between epithelial cancer cells and their surrounding stromal microenvironment. We have previously shown that a loss of stromal Cav-1 expression is associated with an increased risk of early tumor recurrence, metastasis and decreased overall survival. To identify and characterize the signaling pathways that are activated in Cav-1 negative tumor stroma, we performed gene expression profiling using laser microdissected breast cancer associated stroma. Tumor stroma was laser capture microdissected from 4 cases showing high stromal Cav-1 expression and 7 cases with loss of stromal Cav-1. Briefly, we identified 238 gene transcripts that were upregulated and 232 gene transcripts that were downregulated in the stroma of tumors showing a loss of Cav 1 expression (p <= 0.01 and fold-change >= 1.5). Gene set enrichment analysis (GSEA) revealed "stemness," inflammation, DNA damage, aging, oxidative stress, hypoxia, autophagy and mitochondrial dysfunction in the tumor stroma of patients lacking stromal Cav-1. Our findings are consistent with the recently proposed "Reverse Warburg Effect" and the "Autophagic Tumor Stroma Model of Cancer Metabolism." In these two complementary models, cancer cells induce oxidative stress in adjacent stromal cells, which then forces these stromal fibroblasts to undergo autophagy/mitophagy and aerobic glycolysis. This, in turn, produces recycled nutrients (lactate, ketones and glutamine) to feed anabolic cancer cells, which are undergoing oxidative mitochondrial metabolism. Our results are also consistent with previous biomarker studies showing that the increased expression of known autophagy markers (such as ATG16L and the cathepsins) in the tumor stroma is specifically associated with metastatic tumor progression and/or poor clinical outcome. PMID- 21521947 TI - Effectiveness of rotavirus vaccination in Spain. AB - With the aim of determining rotavirus vaccine effectiveness (RVVE) in Spain, from Oct-2008/Jun-2009, 467 consecutive children below 2 years old with acute gastroenteritis (AGE) were recruited using a pediatric research network (ReGALIP www.regalip.org) that includes primary, emergency and hospital care settings. Of 467 enrolled children, 32.3% were rotavirus positive and 35.0% had received at least one dose of any rotavirus vaccine. RRVE to prevent any episode of rotavirus AGE was 91.5% (95% CI: 83.7%-95.6%). RVVE to prevent hospitalization by rotavirus AGE was 95.6% (85.6-98.6%). No differences in RVVE were found regarding the vaccine used. Rotavirus vaccines have showed an outstanding effectiveness in Spain. PMID- 21521949 TI - Common interactions with herbal supplements and prescription drugs. PMID- 21521948 TI - Deep sequencing-based identification of small non-coding RNAs in Streptomyces coelicolor. AB - Streptomyces coelicolor is considered the model organism among Gram positive, GC rich bacteria. Its genome has been sequenced but little is known about the occurrence and distribution of small non-coding RNAs in this biotechnologically relevant organism. Using deep sequencing we analyzed the transcriptome at the end of exponential growth, which corresponds to the onset of secondary metabolism. We mapped 193 transcriptional start sites of mRNA genes and identified putative new and alternative open reading frames. We identified 63 non-coding RNAs including 29 cis encoded antisense RNAs, and confirmed expression for 11, most of them being growth-phase dependent. A comparison between the sequencing results and bioinformatic sRNA predictions using Dynalign and RNAz revealed only a small overlap between the different approaches. PMID- 21521951 TI - Helping children say goodbye to loved ones in adult and pediatric intensive care units: certified child life specialist--critical care nurse partnership. PMID- 21521952 TI - Non-ST-segment elevation acute coronary syndrome: impact of nursing care on optimal outcomes. AB - Of the nearly 1.4 million hospitalizations for acute coronary syndromes in 2006, approximately two-thirds were for unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI). Given the high risk for in-hospital ischemic events and late mortality in patients with UA/NSTEMI, it is critical to accurately and rapidly diagnose these patients, stratify their level of risk, and provide appropriate pharmacologic and nonpharmacologic treatment that maximizes anti-ischemic benefit and minimizes risk of bleeding. Appropriate in-hospital care following intervention is critical for optimizing both short- and long-term outcomes. However, evidence suggests that up to 26% of opportunities to provide guidelines-recommended care are missed. Nurses can play a critical role in ensuring that patients receive guidelines-based care. This review examines the most recent recommendations for the diagnosis and pharmacologic management of patients with UA/NSTEMI and discusses ways in which nursing staff can contribute to minimizing patient risk and optimizing patient benefit. PMID- 21521953 TI - "Higher pressurization to provide this lower cabin altitude increases the aircraft's structural weight, which increases fuel consumption". PMID- 21521954 TI - Life-threatening injuries in older adults. AB - Unintentional injuries are among the leading causes of death and disability in older adults. Although older adults account for approximately 12% of the US population, in 2008, they accounted for 15% of all traffic fatalities, 14% of all vehicle occupant fatalities, and 18% of all pedestrian fatalities. Severely injured older adults have far worse outcomes than younger adults. Despite this difference, many survive with aggressive resuscitation and goal-directed therapy. This article describes the impact of life-threatening injuries in the older adult population, specifically injuries sustained in motor vehicle collisions, and how these injuries relate to anatomic and physiologic changes of aging, the metabolic response to injury, the role of preexisting diseases and medications taken to treat these diseases, and complications. PMID- 21521956 TI - A system-level approach to improving the care of the older critical care patient. AB - As the population continues to age, the specialized needs of older adult patients warrant the close attention of the critical care nurse. The combination of critical illness, age-related changes, multiple comorbidities, and the hospital environment can make the diagnosis and management of the older adult's critical illness challenging. The NICHE (Nurses Improving Care for Healthsystem Elders) program provides a framework to create an aging-sensitive care environment in the critical care setting. The Geriatric Resource Nurse model is the foundation of the program. The goals of NICHE are to support nursing departments to (1) bring evidence-based geriatric practice to the bedside; (2) build patient- and family centered environments; (3) cultivate healthy and productive practice environments aligned with meeting the specialized needs of older adults and their families ("geriatric nursing practice environments"); and (4) conduct comprehensive measurement of geriatric initiatives. PMID- 21521957 TI - Use of protocols in older intensive care unit patients: is standardization appropriate? AB - Increasing numbers of older adults are cared for in intensive care units (ICUs) across the country. These patients are disproportionately impacted by illnesses such as sepsis, ventilator-associated pneumonia, and infections. Their care and course of recovery are complicated by myriad factors, including their often indistinct presentation of illness and issues related to pharmacotherapy. Increasingly, clinical practice guidelines are being used to facilitate the care of patients with select illnesses and presentations. However, these guidelines, protocols, or bundles, as they are known, generally have not been studied in an older population. This article describes the ventilator-associated pneumonia and sepsis bundles relative to the older critical care patient. Although an exhaustive discussion of every intervention within each bundle as it relates to older ICU patients is beyond the scope of this article, selected bundle parameters are presented, with examples of special considerations for the older ICU patient. PMID- 21521958 TI - Falls resulting in traumatic injury among older adults: nursing care issues. AB - Falls among community-dwelling older adults are common and dangerous, often leading to traumatic brain injury, cervical fractures, and spinal cord injury. Physical and physiologic changes with aging, preexisting diseases, and treatments result in increased morbidity and mortality for this population. Trauma critical care nurses can expect to see increasing numbers of older adults in intensive care units as the US population of those older than 65 years increases to 53 million by 2020. Older adults pose additional dilemmas in care. This article reviews falls, mechanism of injury, and nursing care issues of particular significance to this vulnerable population in the critical care setting. PMID- 21521960 TI - ECG alert: Wellens syndrome. PMID- 21521963 TI - Using recruitment maneuvers to decrease tidal volumes during one-lung ventilation. PMID- 21521965 TI - Hemoglobin-based oxygen carriers for reversing hypotension and shock: "NO" way, "NO" how? PMID- 21521967 TI - Exhaled breath condensate in mechanically ventilated brain-injured patients with no lung injury or sepsis. AB - BACKGROUND: The inflammatory influence of prolonged mechanical ventilation in uninjured lungs remains a matter of controversy and largely unexplored in humans. The authors investigated pulmonary inflammation by using exhaled breath condensate (EBC) in mechanically ventilated, brain-injured patients in the absence of acute lung injury or sepsis and explored the potential influence of positive end-expiratory pressure (PEEP). METHODS: Inflammatory EBC markers were assessed in 27 mechanically ventilated, brain-injured patients with neither acute lung injury nor sepsis and in 12 healthy and 8 brain-injured control subjects. Patients were ventilated with 8 ml/kg during zero end-expiratory pressure (ZEEP group, n = 12) or 8 cm H(2)O PEEP (PEEP group, n = 15). EBC was collected on days 1, 3, and 5 of mechanical ventilation to measure pH; interleukins (IL)-10, 1beta, 6, 8, and 12p70; and tumor necrosis factor-alpha. RESULTS: EBC pH was lower, whereas IL-1beta and tumor necrosis factor-alpha were greater in both patient groups compared with either control group; IL-6 was higher, whereas IL-10 and IL 12p70 were sporadically higher than in healthy control subjects; no differences were noted between the two patient groups, except for IL-10, which decreased by day 5 during PEEP. Leukocytes, soluble IL-6, and soluble triggering receptor expressed on myeloid cells-1 in blood were constantly higher during zero end expiratory pressure; EBC cytokines appeared mostly related to soluble IL-8 and inversely related to soluble triggering receptor expressed on myeloid cells-1. CONCLUSIONS: In brain-injured, mechanically ventilated patients with neither acute lung injury nor sepsis, EBC markers appear to indicate the presence of subtle pulmonary inflammation that is mostly unaffected by PEEP. There is evidence for a systemic inflammatory response, especially in patients during zero end-expiratory pressure. PMID- 21521969 TI - Fatal intraoperative cardiac thrombosis in a patient with renal cell carcinoma. PMID- 21521970 TI - A high significance level after analysis of covariance in a small-group study? PMID- 21521971 TI - Oxygen consumption: another key component in predicting ventilator weaning success. PMID- 21521974 TI - Bias and precision statistics: should we still adhere to the 30% benchmark for cardiac output monitor validation studies? PMID- 21521975 TI - Reduction of postoperative mortality: pattern of use of beta-blockade, bias, or both? PMID- 21521976 TI - Perioperative beta-blockade protocol unproven. PMID- 21521979 TI - Relevance of the postoperative quality recovery score to discharge readiness. PMID- 21521981 TI - Intraoperative ketamine and chronic opioid use: less pain, more morphine? PMID- 21521982 TI - Simple math or aberrant physiology: the complex question of modified metabolic syndrome. PMID- 21521983 TI - Intraoperative use of an automated chest compression device. PMID- 21521986 TI - Current world literature. PMID- 21521988 TI - On the road to a meaningful, cost-effective orientation program. PMID- 21521989 TI - Changing practice, one clinical question at a time. PMID- 21521990 TI - Making FMEA work for you. PMID- 21521991 TI - Compelled by demand, driven by experience. PMID- 21521993 TI - Leadership at all levels. PMID- 21521994 TI - At the crossroads: reconciling patient and staffing needs. PMID- 21521995 TI - From here to there: moving a hospital. PMID- 21521996 TI - Balancing quality and costs during economic downturns. PMID- 21521997 TI - Computerized I.V. documentation: identifying the barriers. PMID- 21522000 TI - Glycemic control and cardiovascular mortality. AB - PURPOSE OF REVIEW: Diabetes mellitus is associated with several-fold increased risk of cardiovascular events, including death, yet whether treatment of hyperglycemia can reduce this risk remains controversial. RECENT FINDINGS: Epidemiologic associations between hyperglycemia and cardiovascular risk have been confirmed and extended to levels below those diagnostic of diabetes. Long term follow-up of treatment early in diabetes suggests benefits may lag 10 years or more after initiation of treatment. Intensive glycemic treatment of high-risk persons with current methods may increase short-term mortality. SUMMARY: Further analyses of existing data to define high-risk and lower-risk subgroups of patients may allow revision of treatment guidelines. Future studies may begin early in diabetes, require long-term follow-up, and use improved methods of treatment. PMID- 21522001 TI - Remission of type 2 diabetes mellitus following bariatric surgery: review of mechanisms and presentation of the concept of 'reversibility'. AB - PURPOSE OF REVIEW: Roux-en-Y gastric bypass (RYGB) leads to remission of type 2 diabetes mellitus (T2DM) in a majority of patients. This is prompting investigation of RYGB, and other bariatric operations as interventional therapies for T2DM. RECENT FINDINGS: The impact of RYGB is due to an increase in the release of gastrointestinal hormones in response to a meal [glucagon-like peptide, peptide YY, oxyntomodulin]. This effect involves the parasympathetic nervous system. These same hormones are responsible for an early increase in beta cell secretion of insulin, leading to early remission of T2DM following RYGB. Progressive weight loss leads to a later improvement in peripheral insulin sensitivity, which is required for later remissions, and is responsible for re emergence of T2DM in individuals who regain weight in long-term follow-up. As the success of bariatric surgery has prompted the emergence of the concept that T2DM is reversible, we offer a theory to predict reversibility of diabetes after bariatric surgery that is based on baseline beta cell function. SUMMARY: This review will improve the understanding of the physiology of bariatric surgery and its impact on T2DM, stimulate investigations into new avenues to treat T2DM, and allow better selection of nonobese individuals for interventional therapy of T2DM. PMID- 21522002 TI - Management of diabetes mellitus in the elderly. AB - PURPOSE OF REVIEW: Description of management of diabetes in elderly. RECENT FINDINGS: Population of older adults is growing and so is the prevalence of diabetes in elderly individuals. Older adults are a heterogeneous group of individuals with varying physical capabilities, cognitive functioning and co morbidities and life expectancies. Also, older adults with diabetes are at increased risk for some geriatric conditions. Thus, clinicians taking care of elderly with diabetes must take this into consideration and prioritize treatment accordingly. SUMMARY: Goals of diabetes care in elderly and younger adults are alike, though managing diabetes in elderly requires individualized approach. Fit elderly with life expectancy over 10 years should have HbA1c target similar to younger adults, whereas in frail elderly with multiple co-morbidities, the goal should somewhat be higher. Pharmacological treatment options are similar to younger adults and avoidance of hypoglycemia is an important consideration in choosing therapeutic agents in elderly. Evaluation and treatment of microvascular and macrovascular complications of diabetes in elderly must also be individualized. PMID- 21522003 TI - Bibliography. Current world literature. Adrenal cortex. PMID- 21522004 TI - Clinical efficacy of raltegravir against B and non-B subtype HIV-1 in phase III clinical studies. AB - OBJECTIVE: We evaluated the long-term efficacy of raltegravir according to HIV-1 subtype (B and non-B) using data from three phase III studies in treatment experienced (BENCHMRK-1 and 2) and treatment-naive (STARTMRK) HIV-infected patients. METHODS: HIV-1 subtypes were identified from baseline plasma specimens using genotypic data of the PhenoSense GT test (Monogram Biosciences, South San Francisco, California, USA). Non-B subtypes were combined for the current analyses due to small numbers of each specific subtype. An observed failure approach was used (only discontinuations due to lack of efficacy were treated as failures). Resistance evaluation was performed in patients with documented virologic failure. RESULTS: Seven hundred and forty-three patients received raltegravir and 519 received comparator (efavirenz in STARTMRK; optimized background therapy in BENCHMRK). Non-B subtype virus (A, A/C, A/D, A/G, A1, AE, AG, B/G, BF, C, D, D/F, F, F1, G, and complex) was isolated at baseline in 98 (13%) raltegravir recipients and 62 (12%) comparator recipients. Subtypes AE and C were most common, isolated in 41 and 43 patients, respectively. The proportion of raltegravir recipients achieving HIV RNA less than 50 copies/ml was similar between non-B and B subtypes (STARTMRK: 94.5 vs. 88.7%; BENCHMRK-1 and 2: 66.7 vs. 60.7%); change in CD4 cell count also was similar between non-B and B subtypes (STARTMRK: 243 vs. 221 cells/MUl; BENCHMRK-1 and 2: 121 vs. 144 cells/MUl). Phenotypic resistance to raltegravir in non-B virus was associated with integrase mutations observed previously in subtype B virus. CONCLUSION: In phase III studies in treatment-naive and treatment-experienced patients, raltegravir showed comparable and potent clinical efficacy against B and non-B HIV-1 subtypes. PMID- 21522005 TI - Sexual behavior and HIV transmission risk of Ugandan adults taking antiretroviral therapy: 3 year follow-up. AB - BACKGROUND: Long-term impact of antiretroviral therapy (ART) on sexual HIV transmission risk in Africa is unknown. We assessed sexual behavior changes and estimated HIV transmission from HIV-infected adults on ART in Uganda. METHODS: Between 2003 and 2007, we enrolled and followed ART-naive HIV-infected adults in a home-based AIDS program with annual counseling and testing for cohabitating partners, participant transmission risk-reduction plans, condom distribution and prevention support for cohabitating discordant couples. We assessed participants' HIV plasma viral load and partner-specific sexual behaviors. We defined risky sex as intercourse with inconsistent/no condom use with HIV-negative or unknown serostatus partners in previous 3 months. We compared rates using Poisson regression models, estimated transmission risk using established viral load specific transmission estimates, and documented sero-conversion rates among HIV discordant couples. RESULTS: Of 928 participants, 755 (81%) had 36 months data: 94 (10%) died and 79 (9%) missing data. Sexual activity increased from 28% (baseline) to 41% [36 months (P < 0.001)]. Of sexually active participants, 22% reported risky sex at baseline, 8% at 6 months (P < 0.001), and 14% at 36 months (P = 0.018). Median viral load among those reporting risky sex was 122,500 [interquartile range (IQR) 45 100-353 000] copies/ml pre-ART at baseline and undetectable at follow-up. One sero-conversion occurred among 62 cohabitating sero-discordant partners (0.5 sero-conversions/100 person-years). At 36 months, consistent condom use was 74% with discordant partners, 55% with unknown and 46% with concordant partners. Estimated HIV transmission risk reduced 91%, from 47.3 to 4.2/1000 person-years. CONCLUSIONS: Despite increased sexual activity among HIV-infected Ugandans over 3 years on ART, risky sex and estimated risk of HIV transmission remained lower than baseline levels. Integrated prevention programs could reduce HIV transmission in Africa. PMID- 21522007 TI - Circulation of multiple patterns of unique recombinant forms B/CRF02_AG in France: precursor signs of the emergence of an upcoming CRF B/02. AB - BACKGROUND: HIV-1 group M is characterized by substantial genetic diversity, and includes nine subtypes, more than 45 circulating recombinant forms (CRFs), and numerous unique recombinant forms (URFs). In France, the epidemic is characterized by predominance of subtype B strains, increasing prevalence of non B subtypes (CRF02_AG being the most prevalent) and increasing at-risk behaviour in the MSM population. The high prevalence and co-circulation of B and CRF02_AG strains in this population raise the possibility that recombinant forms might emerge and spread. METHODS: Samples from seven patients (five being MSM) were selected on the basis of subtyping discordances in different regions. The pattern of each near full-length genome of the viruses was characterized. The relationships between the newly and previously described B/CRF02_AG URFs were analysed using phylogenetic networks. Single genome amplification was used to search for the parental strains and confirmation of the breakpoints. RESULTS: Seven unique recombination patterns were identified, breakpoints being found throughout the genomes, with hotspots in pol and accessory genes. No link was observed with the previous forms, but the CRF02 regions of two new viruses indicated that they are phylogenetically associated, suggesting a common ancestral strain. No evidence of circulating parental strains was found. CONCLUSION: This description of seven URFs involving subtype B and CRF02_AG highlights the growing complexity of HIV molecular epidemiology in France. These multiple patterns, found mostly in MSM, and the hypothesis of a better fitness of some recombinant strains, argue for a context that could lead to the genesis of CRFB/02_AG strains in France. PMID- 21522008 TI - Ipsilateral breast tumor recurrence after breast-conserving surgery for ductal carcinoma in situ. PMID- 21522010 TI - Robot-assisted endoscopic thyroidectomy: has the time come to abandon neck incisions? PMID- 21522006 TI - Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study. AB - BACKGROUND: We examined the association between vitamin D [25(OH)D] level and disease progression in HIV infection. METHODS: Within the EuroSIDA study, 2000 persons were randomly selected for 25(OH)D measurement in stored plasma samples closest to study entry. 25(OH)D results were stratified into tertiles. Factors associated with 25(OH)D levels and associations of 25(OH) levels with subsequent risk of all-cause mortality, AIDS and non-AIDS events were analyzed. RESULTS: Of 1985 persons with 25(OH)D levels available, 23.7% had 25(OH)D below 10, 65.3% between 10 and 30, and 11% above 30 ng/ml. At the time of 25(OH)D measurement, older persons, persons of black ethnic origin, living outside Southern Europe/Argentina, sampled during winter, and infected with HIV through nonhomosexual exposure were at higher odds of having low 25(OH)D levels, whereas persons receiving protease inhibitors were at lower odds. Compared to those in the lowest 25(OH)D tertile (<12 ng/ml), those in the middle (12-20) and higher (>20) tertiles had a significantly lower risk of clinical progression during subsequent follow-up. Adjusted incidence rate ratios for all-cause mortality were 0.68 (95% CI 0.47-0.99, P = 0.045) and 0.56 (95% CI 0.37-0.83, P = 0.0039), and for AIDS events were 0.58 (95% CI 0.39-0.87, P = 0.0086) and 0.61 (95% CI 0.40 0.93, P = 0.020), for the middle and higher tertiles, respectively. There was a similar, nonsignificant reduced incidence of non-AIDS events in the middle and higher tertiles. CONCLUSION: 25(OH)D deficiency was frequent in HIV-infected persons (83% on combined antiretroviral therapy), and was independently associated with a higher risk of mortality and AIDS events. Causality relationships should be examined, because of potential public health consequences. PMID- 21522011 TI - George Ryerson Fowler: Brooklyn's surgical pioneer: a biographical sketch based on historical documents. AB - The Fowler position, widely used in surgery and obstetrics for patient placement, marks a fraction of 19th-century Brooklyn surgeon George Ryerson Fowler's prodigious accomplishments. Fowler was a pioneer who refined the appendectomy, performed the first lung decortication, advocated for sterile techniques, introduced first aid in the US Army, and helped start a precursor to Annals of Surgery. His publications include the first US textbook on appendicitis- ironically, the disease that killed him. PMID- 21522012 TI - Assessment of different bariatric surgeries in the treatment of obesity and insulin resistance in mice. AB - OBJECTIVE: To assess the effects of different bariatric surgical procedures on the treatment of obesity and insulin resistance in high fat diet-induced obese (DIO) mice. BACKGROUND: Bariatric surgery is currently considered the most effective treatment for morbid obesity and its comorbidities; however, a systematic study of their mechanisms is still lacking. METHODS: We developed bariatric surgery models, including gastric banding, sleeve gastrectomy, Roux-en Y gastric bypass (RYGB), modified RYGB (mRYGB) and biliopancreatic diversion (BPD), in DIO mice. Body weight, body fat and lean mass, liver steatosis, glucose tolerance and pancreatic beta cell function were examined. RESULTS: All bariatric surgeries resulted in significant weight loss, reduced body fat and improved glucose tolerance in the short term (4 weeks), compared with mice with sham surgery. Of the bariatric surgery models, sleeve gastrectomy and mRYGB had higher success rates and lower mortalities and represent reliable restrictive and gastrointestinal (GI) bypass mouse bariatric surgery models, respectively. In the long term, the GI bypass procedure produced more profound weight loss, significant improvement of glucose tolerance and liver steatosis than the restrictive procedure. DIO mice had increased insulin promoter activity, suggesting overactivation of pancreatic beta cells, which was regulated by the mRYGB procedure. Compared with the restrictive procedure, the GI bypass procedure showed more severe symptoms of malnutrition following bariatric surgery. DISCUSSIONS: Both restrictive and GI bypass procedures provide positive effects on weight loss, fat composition, liver steatosis and glucose tolerance; however, in the long term, the GI bypass shows better results than restrictive procedures. PMID- 21522014 TI - Low CD4 count is associated with an increased risk of fragility fracture in HIV infected patients. AB - BACKGROUND: Low bone mineral density in HIV-infected patients is an increasingly recognized clinical problem. The aim of this study was to determine the incidence, prevalence, and risk factors for development of low trauma or fragility fractures in an HIV-infected population. METHODS: A 1:2 matched case control study was performed of HIV-infected patients attending the Alfred Hospital between 1998 and 2009. Controls were matched on gender, age, and duration of HIV infection. RESULTS: The overall fracture incidence rate was 0.53 per 100 person-years [95% confidence interval (CI): 0.43 to 0.65] and period prevalence of 3.34 per 100 patients (95% CI: 2.66 to 4.13). There were 73 low trauma fractures in 61 patients. Patients were predominantly male (89%) with a mean age of 49.8 years. Independent risk factors for fragility fracture were a CD4 cell count <200 cells per microliter odds ratio (OR): 4.91 (95% CI: 1.78 to 13.57, P = 0.002), corticosteroids OR: 8.96 (95% CI: 1.55 to 51.88, P = 0.014) and anti-epileptic medications OR: 8.88 (95% CI: 1.75 to 44.97, P = 0.008). There were no significant associations between HIV viremia (P = 0.18), use of or class of antiretroviral medication, and risk of fracture. Eighty-eight percent of patients with fracture had established osteopenia or osteoporosis. CONCLUSION: This is the largest clinical study to date of fragility fractures occurring in an HIV-infected population. The study found that risk of fracture was strongly associated with a low CD4 cell count, use of corticosteroids, and anti-epileptic medications. There were no associations between fracture risk and viral load, use of class, or duration of antiretroviral agent. PMID- 21522013 TI - The Coding Causes of Death in HIV (CoDe) Project: initial results and evaluation of methodology. AB - BACKGROUND: The Coding Causes of Death in HIV (CoDe) Project aims to deliver a standardized method for coding the underlying cause of death in HIV-positive persons, suitable for clinical trials and epidemiologic studies. METHODS: The project incorporates detailed data collection, a classification system, and a centralized adjudication process performed by 2 independent reviewers. The methodology was tested in the Data Collection on Adverse events of Anti-HIV Drugs Study , and independent reviews of causes of death were compared. Logistic regression models identified factors associated with initial agreement by reviewers on underlying cause of death. RESULTS: A total of 491 reported fatal cases were adjudicated; in only 5% of cases the cause of death remained undetermined after adjudication. Reviewers initially agreed on the underlying cause for 339 (69%) deaths. As compared with deaths due to AIDS-related causes, the odds of agreement were more than 80% lower when deaths were ultimately deemed to be due to non-AIDS-related causes (odds ratio = 0.17 [95% confidence interval = 0.08-0.37]) or undetermined causes (0.11 [0.04-0.36]). The odds of initial agreement were also lower for deaths occurring in subjects with hypertension (0.43 [0.22-0.85]) and depression (0.43 [0.23-0.80]). CONCLUSIONS: The extent and format of data collected in the CoDe Project appear to be sufficient for an informed review, and the proposed coding scheme is adequate for obtaining an underlying cause of death. PMID- 21522015 TI - HIV risk after release from prison: a qualitative study of former inmates. AB - BACKGROUND: Former prison inmates are at risk for HIV and hepatitis C (HCV) infection. This study was designed to understand how former inmates perceived their risk for HIV and HCV infection after release from prison, the behaviors and environmental factors that put patients at risk for new infection, and the barriers to accessing health care. METHODS: This was a qualitative study using individual, face-to-face, semistructured interviews exploring participants' perceptions and behaviors putting them at risk for HIV and HCV infection and barriers to engaging in regular medical care after release. Interview transcripts were coded and analyzed using a team-based general inductive approach. RESULTS: Participants were racially and ethnically diverse and consisted of 20 men and 9 women with an age range of 22-57 years who were interviewed within the first 2 months after their release from prison to the Denver, Colorado community. Four major themes emerged: (1) risk factors including unprotected sex, transactional sex, and drug use were prevalent in the postrelease period; (2) engagement in risky behavior occurred disproportionately in the first few days after release; (3) former inmates had educational needs about HIV and HCV infection; and (4) former inmates faced major challenges in accessing health care and medications. CONCLUSIONS: Risk factors for HIV and HCV infection were prevalent among former inmates immediately after release. Prevention efforts should focus on education, promotion of safe sex and needle practices, substance abuse treatment, and drug free transitional housing. Improved coordination between correctional staff, parole officers, and community health care providers may improve continuity of care. PMID- 21522016 TI - A twin response to twin epidemics: integrated HIV/syphilis testing at STI clinics in South China. AB - BACKGROUND: HIV testing is still stigmatized among many high-risk groups in China, whereas routine syphilis testing has been widely accepted at sexually transmitted infection (STI) clinics. This project used the platform of a rapid syphilis screening test to expand HIV test uptake. The objective of this study was to use multilevel modeling to analyze determinants of syphilis and HIV testing uptake at STI clinics in China. METHODS: 2061 STI patients at 6 clinics in Guangdong Province were offered free rapid syphilis and free rapid HIV testing. Test uptake was defined by patient receipt of results and a multilevel model was used to analyze predictors of uptake. RESULTS: This was the first syphilis or HIV test for the large majority (1388, 77.7%) of participants. Syphilis test uptake and HIV test uptake were high (1681, 81.6%, syphilis test uptake; 1673, 81.2% HIV test uptake). HIV test uptake was significantly concordant with syphilis test uptake (taub = 0.89, P < 0.001). The most parsimonious model of refusing HIV test uptake included the following variables: being married, having a previous HIV test, being unaccompanied, and participating in the last 2 months of the study. CONCLUSIONS: STI clinic-based screening for syphilis and HIV represents an excellent opportunity for scaling up integrated services, especially in South China where syphilis and sexually transmitted HIV cases are both rapidly increasing. Effective integration of HIV testing into routine clinical practice requires an understanding not only of individual test uptake but also of the broader social context of HIV testing. PMID- 21522017 TI - Comorbidity acquired before HIV diagnosis and mortality in persons infected and uninfected with HIV: a Danish population-based cohort study. AB - BACKGROUND: We aimed to estimate the impact of comorbidity acquired before HIV diagnosis on mortality in individuals infected with HIV. METHODS: This cohort study compared 2 different cohorts. The prospective population-based nationwide observational Danish HIV Cohort Study was used to compare all adults diagnosed with HIV in Denmark from 1997 with a matched general population cohort. Comorbidity history was ascertained from the Danish National Patient Registry and vital statistics obtained from the Danish Civil Registration System. Cox regression was used to estimate the impact of Charlson comorbidity index (CCI) and hepatitis C virus coinfection on mortality, and population attributable risk was used to assess the proportional impact of comorbidity on mortality. RESULTS: CCI comorbidity was present before HIV diagnosis in 11.3% of 1638 persons with HIV, and in 8.0% of 156,506 persons in the general population. The risk for death in patients with HIV with at least 1 CCI point was 1.84 times higher than in those with no CCI points (adjusted mortality rate ratio, 95% confidence interval: 1.32 to 2.57). The annual risk of dying for patients with HIV vs general population with 0, 1, 2, and 3+ CCI points was 1.70% (1.44 to 2.00) vs 0.27% (0.26 to 0.28), 4.37% (3.01 to 6.32) vs 1.36% (1.26 to 1.47), 8.06% (4.94 to 13.16) vs 2.44% (2.22 to 2.68), and 10.15% (5.08 to 20.30) vs 5.84% (5.19 to 6.58), respectively. Comorbidity acquired before HIV, hepatitis C virus coinfection, and background mortality accounted for 45% of total mortality in the population infected with HIV. CONCLUSIONS: Almost half of deaths in persons diagnosed with HIV in a health care setting with free access to highly active antiretroviral therapy stemmed from factors unrelated to HIV disease. PMID- 21522018 TI - Survival in XDR TB: shifting the curve and shifting the paradigm. PMID- 21522020 TI - Memory profiles of Down, Williams, and fragile X syndromes: implications for reading development. AB - The purpose of this review was to understand the types of memory impairments that are associated with intellectual disability (ID, formerly called mental retardation) and the implications of these impairments for reading development. Specifically, studies on working memory, delayed memory and learning, and semantic/conceptual memory in Down syndrome, Williams syndrome, and fragile X syndrome were examined. A distinct memory profile emerged for each of the 3 etiologies of ID. Memory profiles are discussed in relation to strengths and weaknesses in reading skills in these three etiologies. We suggest that reading instruction be designed to capitalize on relatively stronger memory skills while providing extra support for especially challenging aspects of reading. PMID- 21522019 TI - Applying surveillance and screening to family psychosocial issues: implications for the medical home. AB - Within the medical home, understanding the family and community context in which children live is critical to optimally promoting children's health and development. How to best identify psychosocial issues likely to have an impact on children's development is uncertain. Professional guidelines encourage pediatricians to incorporate family psychosocial screening within the context of primary care, yet few providers routinely screen for these issues. The authors propose applying the core principles of surveillance and screening, as applied to children's development and behavior, to also address family psychosocial issues during health supervision services. Integrating psychosocial surveillance and screening into the medical home requires changes in professional training, provider practice, and public policy. The potential of family psychosocial surveillance and screening to promote children's optimal development justifies such changes. PMID- 21522021 TI - Angle assessment by EyeCam, goniophotography, and gonioscopy. AB - PURPOSE: To compare EyeCam (Clarity Medical Systems, Pleasanton, CA) and goniophotography in detecting angle closure, using gonioscopy as the reference standard. METHODS: In this hospital-based, prospective, cross-sectional study, participants underwent gonioscopy by a single observer, and EyeCam imaging and goniophotography by different operators. The anterior chamber angle in a quadrant was classified as closed if the posterior trabecular meshwork could not be seen. A masked observer categorized the eyes as per the number of closed quadrants, and an eye was classified as having angle closure if there were 2 or more quadrants of closure. Agreement between the methods was analyzed by kappa statistic and comparison of area under receiver operating characteristic curves (AUC). RESULTS: Eighty-five participants (85 eyes) were included, the majority of whom were Chinese. Angle closure was detected in 38 eyes (45%) with gonioscopy, 40 eyes (47%) using EyeCam, and 40 eyes (47%) with goniophotography (P=0.69 in both comparisons, McNemar test). The agreement for angle closure diagnosis (by eye) between gonioscopy and the 2 imaging modalities was high (kappa=0.86; 95% Confidence Interval (CI), 0.75-0.97), whereas the agreement between EyeCam and goniophotography was not as good (kappa=0.72; 95% CI, 0.57-0.87); largely due to lack of agreement in the nasal and temporal quadrants (kappa=0.55 to 0.67). The AUC for detecting eyes with gonioscopic angle closure was similar for goniophotography and EyeCam (AUC 0.93, sensitivity=94.7%, specificity=91.5%; P>0.95). CONCLUSIONS: EyeCam and goniophotography have similarly high sensitivity and specificity for the detection of gonioscopic angle closure. PMID- 21522022 TI - Resident-performed Ex-PRESS shunt implantation versus trabeculectomy. AB - PURPOSE: To compare outcomes between resident-performed trabeculectomy and Ex PRESS shunt implantation. METHODS: A consecutive cohort of 36 Ex-PRESS shunt implantations and 57 trabeculectomies (1 eye/patient) performed by resident surgeons in their third year of ophthalmic training at the University of California, San Francisco and at the San Francisco Veterans Administration Hospital, under the supervision of a single glaucoma fellowship-trained surgeon were included in this study. Eyes with < 6 months of follow-up or previous glaucoma surgery were excluded. Preoperative and postoperative intraocular pressure (IOP), preoperative and postoperative number of ocular antihypertensive medications and complication rates were compared between the 2 procedures retrospectively. RESULTS: No difference was found in postoperative IOP (all, P>=0.099) or proportional decrease in IOP (all, P>=0.092) between the trabeculectomy and Ex-PRESS shunt groups at all follow-up points. On average, the Ex-PRESS shunt group required significantly less ocular antihypertensive medication to control IOP at 3 months postoperative (P=0.01), but no difference was found at 6 months or 1 year (all, P>=0.28). A larger proportion of Ex-PRESS shunt patients had good IOP control without medication at 3 (P=0.057) and 6 months (P=0.076) postoperatively. No difference was found in the rates of sight threatening complications between groups (all, P>=0.22). CONCLUSIONS: In the hands of ophthalmology residents in their third year of training, the trabeculectomy and Ex-PRESS shunt implantation procedures perform comparably in terms of postoperative IOP control, reduction in patient dependence on ocular antihypertensive medications, and risk of complication in our population. PMID- 21522023 TI - Effect of optic disc size and disease severity on the diagnostic capability of glaucoma imaging technologies in an Indian population. AB - PURPOSE: To evaluate the influence of optic disc size and disease severity on the diagnostic validity of optical coherence tomography (Stratus OCT), scanning laser polarimetry [GDx variable corneal compensator (VCC)], and confocal scanning laser ophthalmoscopy [Heidelberg retina tomograph II (HRT II)] in Indian eyes with glaucoma. METHODS: Ninety-five normal and 125 glaucoma patients underwent imaging with Stratus OCT, GDx VCC, and HRT II. One eye of each person was randomly selected for analysis. Using disc area determined on HRT II, discs were classified as small (<2 mm), moderate (2 to 3 mm), and large (>3 mm). The parameter with the best sensitivity for each device, at a fixed specificity, was compared for different disc sizes. Logistic marginal regression was used to study the effect of disc size and disease severity (mean deviation on standard automated perimetry) on the diagnostic performance of these imaging devices. RESULTS: At a fixed specificity of 84.2%, the sensitivity of HRT II was significantly different for varying disc sizes (P=0.0004). The sensitivities for dissimilar disc sizes were not significantly different for the GDx VCC (P=0.928) or Stratus OCT (P=0.381). Logistic marginal regression also showed that sensitivity of HRT II increased with increasing disc size, whereas sensitivity of OCT and GDx were independent of the disc size. The sensitivity of all 3 technologies increased with increasing disease severity (decreasing mean deviation). CONCLUSIONS: Optic disc size affects the diagnostic capability of HRT II but not that of GDx VCC or Stratus OCT. The sensitivity of all 3 imaging technologies increased with increasing disease severity. PMID- 21522024 TI - Optic disc parameters from optovue optical coherence tomography: comparison of manual versus automated disc rim determination. AB - PURPOSE: To compare optic disc parameters when using manual disc detection versus automated software on RTVue-100 Fourier-domain optical coherence tomography. METHODS: Nonrandomized comparative study using images obtained from a tertiary care Glaucoma Clinic from August, 2008 to May, 2009. Four hundred thirty-four patients with mean age of 67.1 years (+/-13.4) underwent OCT imaging with RTVue 100. Optic disc margins were manually defined by a single, trained operator and redefined with automated software that estimates the position of the retinal pigment epithelium edges. Bland-Altman plots and intraclass correlations measured agreement between the 2 detection methods for various optic disc parameters. RESULTS: Bland-Altman plots/intraclass correlations showed good agreement in the following optic disc parameters: optic disc area, cup area, rim area, cup-to-disc area ratio, cup-to-disc ratio, and retinal nerve fiber layer thickness. There was no significant difference in measurements when comparing hand versus automated disc contour determination (P>0.05). CONCLUSIONS: Automated determination of the disc margin was in high agreement with subjective, manual assessment and should be used in clinical practice as it can make optical coherence tomography scanning more efficient and standardized, as disc detection would only be done by the software and not biased by multiple operators. PMID- 21522025 TI - Constraint-induced movement therapy for children with hemiplegia after traumatic brain injury: a quantitative study. AB - OBJECTIVE: The aims of this study are to quantify the movement limitation of upper limbs in hemiplegic children with traumatic brain injury (TBI) by using a clinical-functional scale and upper limb kinematics and to evaluate the effectiveness of constraint-induced movement therapy (CIMT) on upper limbs. DESIGN: Pre-post study. SETTING: Clinical rehabilitation research laboratory. PARTICIPANTS: Ten children with TBI. MAIN OUTCOME MEASURES: The participants were evaluated by clinical examinations (Gross Motor Function Measure, Besta scale, Quality of Upper Extremities Skills Test, and Manual Ability Classification System) and 3D kinematic movement analysis of the upper limb before the CIMT program (pretest: 0.7 years after the injury) and at the end of the program (posttest: 10 weeks later). RESULTS: After the CIMT, most of the clinical measures improved significantly. Some significant improvements were present in terms of kinematics, in particular, in the movement duration and the velocity of movement execution of both tasks; the index of curvature and the average jerk improved, respectively, during reaching and hand-to-mouth task, while the adjusting sway parameter decreased during the 2 movements. Significant improvements were found in upper limb joint excursion after the rehabilitative programme too. CONCLUSIONS: Our results suggest that the CIMT program can improve movement efficiency and upper limb function in children after TBI. The integration of the clinical outcomes and upper limb kinematics revealed to be crucial in detecting the effects of the CIMT programme. PMID- 21522026 TI - Neuronal loss in the medial cholinergic pathway from the nucleus basalis of Meynert in patients with traumatic axonal injury: a preliminary diffusion tensor imaging study. AB - OBJECTIVE: The recent development of diffusion tensor imaging (DTI) allows visualization and estimation of the medial cholinergic pathway (MCP), which originates from the nucleus basalis of Meynert and provides cortical cholinergic innervation to the cerebral cortex. We investigated the injury to the MCP in patients with traumatic axonal injury (TAI), using DTI. DESIGN: Retrospective survey. PARTICIPANTS: Fourteen patients with chronic TAI and 14 age- and sex matched normal control subjects. MAIN OUTCOME MEASURES: Using the Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FMRIB analysis group, Oxford University, United Kingdom), diffusion tensor images were acquired by using a sensitivity-encoding head coil at 1.5 T DTIs. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume of the MCP were measured. RESULTS: The FA value and tract volume were significantly decreased in the group with TAI compared with those of the control group (P < .05); in contrast, there was no difference in the MD value between the 2 groups (P > .05). CONCLUSIONS: Changes in DTI parameters of the TAI group appear to be due to neuronal loss of the MCP. We believe that DTI would be useful for the evaluation of the MCP in patients with TAI. PMID- 21522027 TI - Identifying factors associated with perceived success in the transition from hospital to home after brain injury. AB - OBJECTIVE: : To identify the factors associated with perceived success of the transition from hospital to home after traumatic brain injury (TBI). DESIGN: : Prospective longitudinal cohort design with data collection at discharge and 1, 3, and 6 months postdischarge. PARTICIPANTS: : A total of 127 individuals with TBI discharged to the community and 83 significant others. MAIN MEASURES: : An analog scale (0-100) of perceived success of the transition from hospital to home rated by individuals and significant others; Sentinel Events Questionnaire; EuroQol Group Quality-of-Life measure visual analog scale; Sydney Psychosocial Reintegration Scale; Mayo-Portland Adaptability Inventory-4; short form of the Depression, Anxiety, Stress Scales; Craig Hospital Inventory of Environmental Factors; and Caregiver Strain Index. RESULTS: : Greater perceived success of transition for individuals with a TBI was associated with higher levels of health related quality of life, level of community integration, and more severe injury. Among survivors, sentinel events such as returning to work and independent community access and changing living situation were associated with greater perceived success; financial strain and difficulty accessing therapy services were associated with less success. Among significant others, lower ratings of transition success were associated with higher significant other stress levels as well as lower levels of community integration and changes in the living situation of the individual with TBI. CONCLUSION: : A combination of sentinel events and personal and environmental factors influences the perceptions of individuals and their families regarding the success of the transition from hospital to home. PMID- 21522028 TI - Health-related and sociodemographic risk factors for disability pension due to low back disorders: a 30-year prospective Finnish Twin Cohort Study. AB - OBJECTIVES: To investigate health-related and sociodemographic risk factors for disability pensions (DP) due to low back disorders (LBD). METHODS: Questionnaire data in 1975 of the Finnish Twin Cohort Study with record linkage to information on DP due to LBD from the official pension registers during follow-up 1975 to 2004 was analyzed with Cox proportional hazard models. RESULTS: Musculoskeletal pain (Hazards Ratio [HR] = 2.36 to 2.39; 95% CI 1.97 to 2.88), smoking (HR = 1.82; 1.49 to 2.22), frequent analgesics use (HR = 1.67; 1.38 to 2.02), and presence of other chronic disease (HR = 1.44; 1.22 to 1.70) increased the risk for DP due to LBD. Years of education decreased the risk (HR = 0.81; 0.77 to 0.85). Associations remained significant when adjusted for familial background. CONCLUSIONS: Health-related and sociodemographic risk factors for DP due to LBD can be identified early in life, and they seem independent from familial effects. PMID- 21522029 TI - Cell surface receptors in malignant glioma. AB - Despite advances in surgery, radiation, and chemotherapy, malignant gliomas are still highly lethal tumors. Traditional treatments that rely on nonspecific, cytotoxic approaches have a marginal impact on patient survival. However, recent advances in the molecular cancer biology underlying glioma pathogenesis have revealed that abnormalities in common cell surface receptors, including receptor tyrosine kinase and other cytokines, mediate the abnormal cellular signal pathways and aggressive biological behavior among the majority of these tumors. Some cell surface receptors have been targeted by novel agents in preclinical and clinical development. Such cancer-specific targeted agents might offer the promise of improved cancer control without substantial toxicity. Here, we review these common cell surface receptors with clinical significance for malignant glioma and discuss the molecular characteristics, pathological significance, and potential therapeutic application of these cell surface receptors. We also summarize the clinical trials of drugs targeting these cell surface receptors in malignant glioma patients. PMID- 21522030 TI - Substance abuse, violence, HIV, and depression: an underlying syndemic factor among Latinas. AB - BACKGROUND: Evidence from the literature suggests that substance abuse, violence, HIV risk, depressive symptoms, and underlying socioeconomic conditions are tied intrinsically to health disparities among Latinas. Although these health and social conditions appear to comprise a syndemic, an underlying phenomenon disproportionately accounting for the burden of disease among marginalized groups, these hypothesized relationships have not been formally tested. OBJECTIVES: The aim of this study was to assess (a) if substance abuse, violence, HIV risk, and depressive symptoms comprised a syndemic and (b) if this syndemic was related to socioeconomic disadvantage among Latinas. METHODS: Baseline assessment data from a randomized controlled community trial testing the efficacy of an HIV risk reduction program for adult Latinas (n = 548) were used to measure demographic variables, substance abuse, violence, risk for HIV, and depressive symptoms. Structural equation modeling was used to test a single underlying syndemic factor model and any relation to socioeconomic disadvantage. RESULTS: The results of this study support the idea that HIV risk, substance abuse, violence, and depressive symptoms comprise a syndemic, chi(27) = 53.26, p < .01 (relative chi = 1.97, comparative fit index = .91, root mean square error of approximation = .04). In addition, in limited accord with theory, this factor was related to 2 measures of socioeconomic disadvantage, percentage of years in the United States (b = 7.55, SE = 1.53, p < .001) and education (b = -1.98, SE = .87, p < .05). DISCUSSION: The results of this study could be used to guide public health programs and policies targeting behavioral health disparity conditions among Latinos and other vulnerable populations. Further study of the influence of gender-role expectations and community-level socioeconomic indicators may provide additional insight into this syndemic. PMID- 21522031 TI - Family strategies for achieving medication adherence in pediatric kidney transplantation. AB - BACKGROUND: Although nonadherence is well documented and strategies for adherence have been shown to be critical to overcoming barriers and improving overall adherence rates, it is unknown how family strategy use is related to adherence in the pediatric renal transplant population. OBJECTIVES: The aims of this study were to assess (a) the strategies used by adolescents with kidney transplants and their caregivers to adhere to the posttransplant oral medication regimen and (b) the relationship of these strategies to objective adherence rates. METHODS: Semistructured interviews to assess self-management were administered to 17 adolescents (14-18 years) and 17 caregivers. Adherence to oral immunosuppressant medication, measured via electronic monitors, was determined also for a subset of 13 dyads. RESULTS: Common strategies endorsed by families included the following: making it part of the routine (88.2%), verbal reminders by caregiver (82.4%), caregiver verifying medication was taken (76.5%), placing medication in a convenient location (76.5%), and using a pillbox (70.6%). A greater number of family-endorsed strategies were correlated with higher levels of adherence. Of those strategies spontaneously endorsed, only caregiver reminders to take medication and caregiver verification that medications were taken were related significantly to higher adherence rates. DISCUSSION: The findings highlight the importance of identification and use of specific strategies to improve adherence rates of pediatric renal transplant recipients and emphasize the need for continued caregiver involvement in the promotion of adherence to the treatment regimen. PMID- 21522032 TI - Development and validation of an instrument to assess women's toileting behavior related to urinary elimination: preliminary results. AB - BACKGROUND: Toileting behaviors have been implicated in women's bladder health; however, the lack of a standardized instrument to explore variations in women's toileting behaviors has contributed to an incomplete understanding about the effects of these behaviors on bladder health. OBJECTIVES: The aims of this study were to develop and initially validate an instrument, the Web-based Toileting Behavior (TB-WEB) scale, to assess behaviors women use when emptying their bladders. METHODS: An initial 41-item instrument was developed after a comprehensive literature review and a concept analysis of women's toileting behavior related to urinary elimination. Seven experts with clinical or research experience in women's bladder health were selected to evaluate the content validity of each item and of the entire instrument. The psychometric properties of the TB-WEB scale were assessed using a Web-based survey with community dwelling middle-aged women from June to August 2009. Construct validity and internal consistency were measured. RESULTS: An 18-item scale was developed. Principal component analysis with varimax rotation revealed 5 underlying factors that explained 67% of the variance. Internal consistency reliabilities of the 5 subscales ranged from .70 to .88. The 5 subscales were premature voiding (5 items), straining voiding (4 items), place preference for voiding (4 items), delayed voiding (3 items), and position preference for voiding (2 items). DISCUSSION: The TB-WEB scale shows reliability and initial validity to assess women's toileting behavior related to urinary elimination in community-dwelling middle-aged women. However, further testing is needed in other community-dwelling populations, as well as with hospitalized women, to strengthen its generalizability and to address areas for improvement. PMID- 21522033 TI - Race and ethnic differences in health beliefs about lower urinary tract symptoms. AB - BACKGROUND: Health beliefs are an important mediator between the experience of symptoms and health behaviors, and these beliefs can vary by race or ethnicity. OBJECTIVES: The aim of this study was to better understand the gap between experiencing symptoms and not seeking medical care by examining health beliefs about lower urinary tract symptoms across race and ethnic groups. METHOD: Qualitative, semistructured interviews were conducted with 35 Black, Hispanic, and White people who reported at least one urinary symptom but had not spoken with a healthcare provider about the symptom(s). Drawing on Shaw's framework of health behavior and outcomes, a range of beliefs was examined: cause, consequence, continuation, and treatability. Interviews were transcribed, coded, and analyzed for themes according to race or ethnic background. RESULTS: The belief that lower urinary tract symptoms are a typical part of aging and not amenable to medical treatment was most common among White respondents. Black respondents more commonly attributed their symptoms to personal behaviors over which they had control and therefore did not require medical care. Hispanic respondents appeared more often to live with uncertainty about the cause of their symptoms and an accompanying concern about a future health consequence. DISCUSSION: The combination of a range of health beliefs to form a cognitive representation made sense of the behavior of not seeking medical care. The finding that sociocultural differences shaped these cognitive representations underscores the need for cultural competency in patient assessment and education. Results have implications for theories of health behavior and indicate further research with larger samples, additional psychosocial influences, and other symptoms. PMID- 21522034 TI - Coping skills training for parents of children with type 1 diabetes: 12-month outcomes. AB - BACKGROUND: Although it is recognized that caring for a child with Type 1 diabetes (T1D) is stressful for parents, few interventions have been developed and tested for this population. OBJECTIVES: The aim of this study was to compare a group educational intervention for parents of children with T1D to a coping skills training intervention. METHODS: Parents of children with T1D were randomized to the group educational (n = 106) or coping skills training (n = 75) conditions. Parents completed measures of family conflict, responsibility for treatment, coping, and quality of life at baseline and at 3, 6, and 12 months postintervention. Clinical data (i.e., HbA1c) were collected from children's medical records preintervention and postintervention. RESULTS: There were no significant treatment effects 12 months postintervention, but parents in both groups reported improved coping (p < .001), less responsibility for treatment management (p < .001), and improved quality of life (p = .005). While children's metabolic control worsened over time, mean values at 12 months were still within the recommended levels in this well-controlled sample (HbA1c <8%). DISCUSSION: Group-based interventions for parents of children with T1D may lessen the impact of treatment management, improving coping and quality of life. PMID- 21522035 TI - Cerebral oxygenation in very low birth weight infants supported with sustained lung inflations after birth. AB - Sustained lung inflations (SIs) immediately after birth might decrease the need for subsequent mechanical ventilation in preterm infants. However, effects of SIs on oxygenation and hemodynamics are undetermined. Our aim was to study immediate effects of SIs on heart rate, arterial oxygen saturation, and cerebral tissue oxygen saturation in preterm infants supported with SIs after birth for lung recruitment. Heart rate, arterial oxygen saturation, and cerebral tissue oxygen saturation using near infrared spectroscopy was measured in 24 preterm infants of 28.0 (26.6-29.3) wk GA [median (interquartile range)] during resuscitation using up to three SIs of 20, 25, and 30 cm H2O of 15 s duration each followed by nasal continuous positive airway pressure (CPAP) as first line approach for respiratory support. During positioning and suctioning immediately after delivery infants became progressively hypoxemic and bradycardic before respiratory support was initiated. In 18 infants (75%), more than one SI were applied. During the last SIs, there was a rapid increase in the infants' heart rate and an increase in cerebral tissue oxygen saturation. Arterial saturation increased with slight delay. In conclusion, effective last sustained inflations increase heart rate and cerebral tissue oxygen saturation to be followed by an increase in arterial saturation. PMID- 21522036 TI - Biochemical amniotic fluid pattern for prenatal diagnosis of esophageal atresia. AB - Prenatal diagnosis of esophageal atresia (EA) may improve the outcome of affected neonates by allowing optimization of both prenatal and postnatal care. Prenatal sonographic detection is based on polyhydramnios and/or nonvisualization of the fetal stomach bubble, two signs with a large number of etiologies. We evaluated a biochemical approach to improving diagnostic efficiency. We compared amniotic fluid biochemical markers in 44 EA cases with 88 polyhydramnios and 88 nonpolyhydramnios controls. Both matched for GA with cases. Total proteins, alpha fetoprotein (AFP), and digestive enzyme activities were assayed, including gamma glutamyl transpeptidase (GGTP). We defined an EA index (AFP multiplied by GGTP). A significant difference (p < 0.0001) was observed for total protein, AFP, GGTP, and EA index between the EA group and each of the two control groups. No statistical difference was observed for any marker between the two most frequent EA subgroups (type I and type III) or between the two control groups. Using a cutoff of 3 for the EA index, 98% sensitivity and 100% specificity were observed for amniotic fluid prenatal diagnosis of EA, whatever the anatomical type. A large prospective series is required to confirm these results. PMID- 21522038 TI - Persistent subfoveal fluid and increased preoperative foveal thickness impair visual outcome after macula-off retinal detachment repair. AB - PURPOSE: To investigate the influence of subfoveal fluid and foveal thickness on visual outcome in patients who underwent reattachment surgery for rhegmatogenous retinal detachment (RRD). METHODS: This prospective study included 53 patients who were undergoing successful scleral buckling surgery for primary RRD. A thorough ophthalmologic examination including best-corrected visual acuity, slit lamp biomicroscopy, binocular indirect ophthalmoscopy, and optical coherence tomography scanning was performed preoperatively and during all subsequent follow up visits at 1, 3, 6, 9, 12, and 24 months postoperatively. RESULTS: Preoperative foveal thickness was significantly higher in the macula-off group (n = 38) compared with the macula-on group (n = 15) (P < 0.0001), whereas postoperative measurements were normal in both the groups. Linear mixed-model analysis revealed that persistent subfoveal fluid (P = 0.0004) was an independent predictor of a worse visual outcome after scleral buckling surgery for primary macula-off RRD, although the effect on visual outcome was small (0.1 logarithm of the minimal angle of resolution units). Moreover, increased preoperative foveal thickness was associated with a worse visual prognosis in macula-off RRD (P = 0.010). CONCLUSION: Persistent subfoveal fluid and increased preoperative foveal thickness were associated with a worse visual prognosis in macula-off RRD patients, albeit the effect of persistent subfoveal fluid was small and temporary. PMID- 21522039 TI - Mosaics versus Early Treatment Diabetic Retinopathy seven standard fields for evaluation of diabetic retinopathy severity. AB - PURPOSE: To compare agreement between mosaicked and seven field photographs for classification of the diabetic retinopathy (DR) severity. METHODS: Mosaic digital (MosD) images were compared with seven field stereo film (7FF) and stereo digital (7FD) photographs from a 152-eye cohort with full-spectrum Early Treatment of Diabetic Retinopathy severity levels for agreement on severity level, DR presence with ascending severity thresholds, DR index lesion presence, and classification repeatability. RESULTS: There was a substantial agreement classifying the Early Treatment Diabetic Retinopathy Study DR severity level between MosD and 7FF (kunweighted = 0.59, klinear weighted = 0.83), MosD and 7FD (kappa = 0.62, kappa weighted = 0.86), and 7FD and 7FF (kappa = 0.62, kappa weighted = 0.86) images. Marginal homogeneity analyses found no significant difference between MosD and 7FF (P = 0.44, Bhapkar's test). Kappa between MosD and 7FF ranged from 0.75 to 0.91 for the presence or absence of DR at 8 ascending severity thresholds. Repeatability among readers using MosD images was similar to repeatability among those using 7FF or 7FD. Repeatability among readers using MosD and 7FF images at various severity thresholds was similar. Kappa between MosD and 7FF grading for identifying DR lesions ranged from 0.61 to 1.00. CONCLUSION: Mosaic images are generally comparable with standard seven-field photographs for classifying DR severity. PMID- 21522037 TI - A randomized controlled trial of motavizumab versus palivizumab for the prophylaxis of serious respiratory syncytial virus disease in children with hemodynamically significant congenital heart disease. AB - Children with hemodynamically significant congenital heart disease (CHD) are at risk for serious respiratory syncytial virus (RSV) disease. This study was designed to assess the safety and tolerability of motavizumab versus palivizumab in children with CHD and was not powered for efficacy. Patients (n = 1236) aged <=24 mo were randomized to receive five monthly doses (15 mg/kg) of motavizumab or palivizumab during the RSV season. Adverse events (AEs) and serious AEs (SAEs) were recorded through 30 d after the last dose. RSV hospitalizations and RSV outpatient medically attended lower respiratory tract infections (MALRI; season 2) were summarized. Approximately 93 and 50% of patients reported an AE or SAE, respectively. Skin events occurred in 19.3% of motavizumab recipients and 16.2% of palivizumab recipients. Rates of hospitalizations and RSV MALRI were similar between treatment groups [relative risk (RR): 0.75; 95% CI, 0.34-1.59 and RR: 0.49; 95% CI, 0.10-1.99, respectively; both p > 0.05]. Motavizumab and palivizumab had similar safety profiles in children with hemodynamically significantly CHD; with the exception of skin events which were increased in motavizumab recipients. Safety and efficacy were consistent with another study comparing motavizumab with palivizumab in premature infants without CHD. PMID- 21522041 TI - Vascular dysfunction in sepsis: effects of the peroxynitrite decomposition catalyst MnTMPyP. AB - The mechanisms contributing to sepsis vascular dysfunction are not well known. We tested the hypothesis that peroxynitrite scavenging ameliorates sepsis-induced macrovascular and microvascular dysfunction. Male Sprague-Dawley rats were killed 48 h after cecal ligation (n = 15) and puncture or sham procedure (n = 15). Their aortas and mesenteric vessels were mounted in organ baths for isometric tension recording. We studied contraction in resting vessels (norepinephrine 1 nM-10 MUM and 10 nM-10 MUM) and endothelium-dependent relaxation (acetylcholine, 10 nM-10 MUM and 1 nM-10 MUM) for aortas and microvessels, respectively. Vascular rings were preincubated for 30 min with the superoxide scavenger Cu-Zn-superoxide dismutase (SOD) (100 U/mL), the SOD mimetic and peroxynitrite scavenger tempol (10 M), the NO synthase inhibitor N-nitro-l-arginine methyl ester (10 M), or the peroxynitrite decomposition catalyst manganese tetrakis(4-N methylpyridyl)porphyrin (MnTMPyP) (10 M). Fluorescence to 3-nitrotyrosine, oxidized dihydroethidium, and NOS2 was assessed in vascular tissue. Vascular NOS2, endothelial nitric oxide synthase (NOS1), NADPH-oxidase-1 (NOX-1), and SOD expression was analyzed by reverse transcription-polymerase chain reaction. Sepsis induced (i) in macrovessels, impairment of norepinephrine-induced contractions; (ii) in microvessels, impairment in norepinephrine-induced contractions and acetylcholine-induced relaxations; (iii) aortic and microvascular tissue increased reactivity to 3-nitrotyrosine, oxidized dihydroethidium, NOS2, and increased expression of NOS2, as well as increased expression of NOX-1 in microvascular tissue. Contractile responses in aortic and microvascular rings improved by ex vivo treatment with MnTMPyP and tempol, whereas vascular relaxation in microvessels improved only with MnTMPyP. Peroxynitrite scavenging protects from vascular dysfunction in sepsis. PMID- 21522040 TI - Intravitreal daptomycin: a safety and efficacy study. AB - PURPOSE: To determine the ocular toxicity of intravitreally injected daptomycin, a novel antibiotic for treatment of vancomycin-resistant organisms, and its efficacy in treating intraocular infection with coagulase-negative Staphylococcus epidermidis. METHODS: Four doses of intravitreal daptomycin were injected (75, 188, 375, and 750 MUg) into 1 eye of Dutch belted rabbits (n = 3 per dose). Clinical examination, electroretinography, and histologic analysis were performed preinjection and 2 weeks after injection and compared with the fellow eye that received only intravitreal balanced salt solution. Experimental S epidermidis endophthalmitis was induced in Dutch belted rabbits (n = 24), and the ability of 200 MUg of intravitreal daptomycin to result in culture-negative vitreous samples was measured at 24 hours and 48 hours. RESULTS: Seventy-five micrograms and 188 MUg of daptomycin demonstrated acceptable safety profiles when injected intravitreally in Dutch belted rabbits. There was a dose-dependent increase in cataract formation, electroretinogram suppression, and photoreceptor damage with higher doses. Two hundred micrograms of intravitreal daptomycin resulted in near complete vitreous sterilization 24 hours after treatment. Vitreous sterilization was complete by 48 hours. CONCLUSION: A dose of 200 MUg of intravitreal daptomycin appears to be safe and efficacious in a rabbit model of bacterial endophthalmitis. Future investigations should focus on daptomycin as a therapeutic option for treating intraocular infection caused by vancomycin resistant organisms. PMID- 21522042 TI - Fish oil-supplemented parenteral nutrition prolongs survival while beneficially altering phospholipids' Fatty Acid composition and modulating immune function in rat sepsis. AB - We investigated the therapeutic effects of parenteral fish oil (FO) on survival and fatty acid profile in plasma and erythrocyte membranes, T-lymphocyte subsets, and plasma cytokines in a rat model of sepsis. Adult male Sprague-Dawley rats were subjected to cecal ligation and puncture-induced sepsis. For recovery, central venous catheterization was performed 2 days before sepsis was induced. Rats were randomly assigned to receive normal saline (n = 20) or total parenteral nutrition (PN) containing a standard soybean oil emulsion (n = 20) or FO supplemented TPN (n = 20) at the onset of sepsis for 5 days. In the control group, rats were challenged by sham operation and underwent appropriate control treatment (n = 10). Sepsis led to a high mortality and body weight loss compared with sham operation. Total PN supplemented with FO, but not without FO, improved the survival compared with normal saline. Furthermore, parenteral infusion of FO increased the concentrations of eicosapentaenoic acid and docosahexaenoic acid, as well as the ratio of (eicosapentaenoic acid + docosahexaenoic acid) to arachidonic acid both in plasma and erythrocyte membrane. In addition, FO supplemented TPN improved the percentages of CD3 and CD3CD4 T cells, as well as the CD4/CD8 ratio in spleen. Meanwhile, the percentage of regulatory T cells (CD4CD25Foxp3) among CD4 T cells was reduced by FO-supplemented TPN. Fish oil supplemented TPN attenuated the production of high-mobility group box 1 and IL-10 in plasma. Moreover, parenteral FO decreased the bacterial loads in peritoneal lavage, blood, lung, and spleen. The present study suggests that FO-supplemented TPN initiated at the onset of sepsis improves survival, beneficially alters the lipids profile in plasma and erythrocyte membrane, modulates immune function, and regulates inflammatory response in a rat model. PMID- 21522044 TI - Systematic review of anterior interbody fusion techniques for single- and double level cervical degenerative disc disease. AB - STUDY DESIGN: A systematic review of randomized controlled trials. OBJECTIVE: To determine which technique of anterior cervical interbody fusion (ACIF) gives the best outcome in patients with cervical degenerative disc disease. SUMMARY OF BACKGROUND DATA: The number of surgical techniques for decompression and ACIF as treatment for cervical degenerative disc disease has increased rapidly, but the rationale for the choice between different techniques remains unclear. METHODS: From a comprehensive search, we selected randomized studies that compared anterior cervical decompression and ACIF techniques, in patients with chronic single- or double-level degenerative disc disease or disc herniation. Risk of bias was assessed using the criteria of the Cochrane back review group. RESULTS: Thirty-three studies with 2267 patients were included. The major treatments were discectomy alone and addition of an ACIF procedure (graft, cement, cage, and plates). At best, there was very low-quality evidence of little or no difference in pain relief between the techniques. We found moderate quality evidence for few secondary outcomes. Odom's criteria were not different between iliac crest autograft and a metal cage (risk ratio [RR]: 1.11; 95% confidence interval [CI]: 0.99-1.24). Bone graft produced more fusion than discectomy (RR: 0.22; 95% CI: 0.17-0.48). Complication rates were not different between discectomy and iliac crest autograft (RR: 1.56; 95% CI: 0.71-3.43). Low-quality evidence was found that iliac crest autograft results in better fusion than a cage (RR: 1.87; 95% CI: 1.10-3.17); but more complications (RR: 0.33; 95% CI: 0.12-0.92). CONCLUSION: When fusion of the motion segment is considered to be the working mechanism for pain relief and functional improvement, iliac crest autograft appears to be the golden standard. When ignoring fusion rates and looking at complication rates, a cage as a golden standard has a weak evidence base over iliac crest autograft, but not over discectomy. PMID- 21522043 TI - Endothelial cell activation in emergency department patients with sepsis-related and non-sepsis-related hypotension. AB - Previous studies found increased circulating levels of biomarkers related to endothelial cell activation in patients with sepsis, particularly in the most severe sepsis stages of sepsis shock. It remains unclear, however, whether this activation is mainly driven by sepsis-specific mechanisms or occurs as a generalized inflammatory response. The objective of this analysis was to compare patterns of biomarkers of endothelial cell activation in patients with hypotension due to sepsis and nonsepsis etiologies. This is a secondary analysis of a prospective, observational cohort study including emergency department patients older than17 years with an episode of hypotension defined as any systolic blood pressure measurement less than 100 mmHg. Etiology of hypotension episodes was classified as sepsis or nonsepsis (eg, cardiac or hemorrhagic). Endothelial activation biomarkers of cell adhesion (E-selectin, vascular cell adhesion molecule 1 [VCAM-1], and intercellular adhesion molecule 1 [ICAM-1]), coagulation (plasminogen activator inhibitor 1 [PAI-1]), and vascular endothelial growth factor (VEGF) signaling (VEGF, soluble fms-like tyrosine kinase 1 [sFLT 1]) were assayed. A total of 161 patients were analyzed. Hypotension was classified as sepsis (n = 69), nonsepsis (cardiac [n = 35], hemorrhagic [n = 12]), or indeterminate (n = 45). With the exception of PAI-1, median plasma levels of all endothelial markers were significantly higher in patients with sepsis compared with nonsepsis etiology (P < 0.05 for all comparisons). Logistic regression analysis, adjusted for age, sex, mean blood pressure level, and mortality, confirmed a significant association of E-selectin (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.7-7.8, P < 0.001) and sFLT-1 (OR, 2.0; CI, 1.1-3.8; P < 0.03) with sepsis etiology. Biomarkers VCAM-1 (OR, 2.0; CI, 0.88 4.4; P = 0.1), VEGF (OR, 1.5; CI, 0.98-2.2; P = 0.06), ICAM-1 (OR, 1.5; CI, 0.9 2.6; P = 0.2), and PAI-1 (OR, 1.4; CI, 0.8-2.3; P = 0.2) did not reach statistical significance. This study found a sepsis-specific activation of endothelium activation markers, particularly E-selectin and sFLT-1, in emergency department patients with hypotension. PMID- 21522045 TI - Heart rate variability in menopausal hot flashes during sleep. AB - OBJECTIVE: The aim of this study was to determine if heart rate variability changes during hot flashes recorded during sleep. METHODS: This study was performed in a university medical center laboratory with 16 postmenopausal women demonstrating at least four hot flashes per night. Polysomnography, heart rate, and sternal skin conductance to indicate hot flashes were recorded in controlled, laboratory conditions. RESULTS: For the frequency bin of 0 to 0.15 Hz, spectral power was greater during waking compared with non-rapid eye movement sleep and less during stages 3 and 4 compared with stages 1 and 2. Power was greater during hot flashes compared with subsequent periods for all hot flashes. Power was greater during hot flashes compared with preceding and subsequent periods for those recorded during stage 1 sleep. For waking hot flashes, power in this band was higher before hot flashes than during or after them. CONCLUSIONS: These data are consistent with our theory of elevated sympathetic activation as a trigger for menopausal hot flashes and with previous work on heart rate variability during the stages of sleep. PMID- 21522046 TI - Differentiated (simplex) vulvar intraepithelial neoplasia: a case report and review of the literature. AB - Differentiated (simplex) vulvar intraepithelial neoplasia (VIN) is an uncommon variant of VIN characterized by highly differentiated morphology, making it a potential diagnostic pitfall. It may arise in the background of lichen sclerosus, and unlike most VIN, is not causally associated with human papilloma virus infection. It occurs in an older demographic and is thought to be the precursor of aggressive, invasive vulvar squamous cell carcinoma. For this reason, the timely and accurate diagnosis of this unusual lesion is crucial. The clinical and histologic features of a case of a 70-year-old woman with newly diagnosed differentiated (simplex) VIN arising in a background of long-standing lichen sclerosus is reported, and the historic aspects, current terminology, and diagnostic criteria of differentiated (simplex) VIN are reviewed. PMID- 21522047 TI - Lesions of the lacrimal caruncle with an emphasis on oncocytoma. AB - Lesions of the lacrimal caruncle vary widely due to its unique composition. Rarely, dermatologists and dermatopathologists encounter biopsies taken from this location. The aims of this study were to (1) retrospectively review caruncular lesions of the eye examined at Duke University Medical Center and (2) review the literature associated with caruncle pathology with emphasis on oncocytoma. A retrospective search of all lesions of the caruncle examined at Duke University Medical Center from 1991 to 2009 was performed. Fifty-nine lesions of the caruncle were identified. Nevi (40.7%) were the most common lesions observed, although squamous papillomas were the second most common entity (8.5%). Three oncocytomas were identified (5.1%), and were the next most common lesion present at this body site. These 3 entities represented 54.3% of the lesions found in the caruncle. Fifteen percent of the caruncular biopsies contained malignant or borderline malignant lesions, whereas the remaining 85% were benign entities. Most lesions present in the caruncle are benign. Although relatively rare, oncocytomas may be encountered by the dermatopathologist and may be confused for other neoplasms. Oncocytomas should be considered in the differential diagnosis based on this location in addition to histopathologic features. PMID- 21522048 TI - Pseudolymphomatous folliculitis with marked lymphocytic folliculo- and focal epidermotropism--expanding the morphologic spectrum. PMID- 21522049 TI - Recommended measures for the assessment of behavioral disturbances associated with dementia. AB - OBJECTIVE: The study reviewed all the published instruments used for the assessment, diagnosis, screening, and outcomes monitoring/evaluation of behavioral disturbances associated with dementia (BDAD) to recommend a set of psychometrically valid measures for clinicians and researchers to use, across a range of different practice settings. METHODS: The study involved a broad scoping search, followed by a series of in-depth literature reviews on 29 instruments using scientific literature databases (MEDLINE, PsycINFO, CINAHL, and the Cochrane Library) and various national, international government, and government agency websites and professional organization websites. External consultations from measurement, clinical and research experts in dementia care, consumer representatives, and policy/decision makers, were sought in selecting the best instruments and in making the final recommendations. FINDINGS: Key attributes and psychometric properties of a short list of five instruments were measured against prespecified criteria. The Neuropsychiatry Inventory (NPI) and the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) were rated as the best measures for assessment of behavioral disturbances, followed by the Consortium to Establish a Registry for Alzheimer's Disease-Behavior Rating Scale for Dementia (CERAD-BRSD), the Dementia Behavior Disturbance Scale, and the Neurobehavioral Rating Scale. CONCLUSION: The use of valid and standardized outcome measures for the assessment of BDAD is critical for epidemiological studies, prevention, early intervention and treatment of dementia conditions, and funding for relevant healthcare services. The review recommends the NPI and BEHAVE-AD as the most appropriate measures for both clinical and research, whereas the CERAD-BRSD is suited better for research. The review was designed for the Australian context; however, the findings are applicable in other developed countries. PMID- 21522050 TI - Associations between self-rated mental health and psychiatric disorders among older adults: do racial/ethnic differences exist? AB - OBJECTIVE: [corrected] This study examined racial/ethnic differences in the association between self-rated mental health (SRMH) and psychiatric disorders among community-dwelling older adults in the United States. DESIGN: Cross sectional analyses of nationally representative data from the Collaborative Psychiatric Epidemiology Surveys (2001-2003). SETTING: In-person household interviews. PARTICIPANTS: Older adults aged 60 and older (N = 1,840), including non-Hispanic Whites (N = 351), Blacks (N = 826), Hispanics (N = 406), and Asians (N = 257). MEASUREMENTS: SRMH was measured with a single item, "How would you rate your own mental health?" Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnoses for mood and anxiety disorders were measured with the World Health Organization's World Mental Health version of the Composite International Diagnostic Interview. RESULTS: Results from logistic regression analyses showed significant main effects of both SRMH and race/ethnicity on the presence of mood and anxiety disorders: people who have poor SRMH and are non-Hispanic Whites were more likely to have mood and anxiety disorders. There were also significant interaction effects between SRMH and race/ethnicity, such that the relation of SRMH with diagnoses of psychiatric disorders was strongest in non-Hispanic Whites. CONCLUSIONS: Racial/ethnic variations were found in the relationship between self-perception of mental health and DSM-IV psychiatric disorders. The findings suggest the need to develop race/ethnicity-specific strategies to screen psychiatric disorders in diverse elderly populations. Future studies are needed to investigate possible reasons for the racial/ethnic group differences. PMID- 21522051 TI - Ethnoracial differences in the clinical characteristics of Alzheimer's disease at initial presentation at an urban Alzheimer's disease center. AB - OBJECTIVE: To compare presentation of Alzheimer disease (AD) at the time of initial evaluation at a university specialty clinic across three ethnoracial groups in order to understand similarities and differences in the demographic, clinical, cognitive, psychiatric, and biologic features. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 1,341 self-identified African American, Latino (primarily of Caribbean origin), and white non-Hispanic ("WNH") subjects were recruited from primary care sites or by referral by primary care physicians. MEASUREMENTS: Demographic variables and age of onset of AD, as well as cognitive, functional, and mood impairments at the time of initial presentation and frequencies of apolipoprotein E genotypes, were compared across groups. RESULTS: Differences among ethnoracial groups were found for nearly all variables of interest. In particular, the largely immigrant Puerto Rican Latino group had an earlier age of onset of AD, more cognitive impairment, and greater severity of cognitive impairment at the time of initial evaluation in the setting of low average education and socioeconomic status. There was more depression in the Latinos compared with African Americans and WNHs. Greater severity of symptoms was not accounted for by a difference in lag time between onset of symptoms and initial evaluation. The apolipoprotein E-4 genotype was not associated with AD in the Latino cohort. CONCLUSIONS: Minority groups in Philadelphia, especially Latinos, exhibit a more severe profile of AD at the time of presentation than WNHs. Important potential confounds need to be considered and future research comparing immigrant and nonimmigrant Latino groups will be necessary to elucidate the highly significant differences reported. PMID- 21522052 TI - Prognostically important molecular markers in cytogenetically normal acute myeloid leukemia. AB - Cytogenetically normal acute myeloid leukemia (CN-AML) is a heterogeneous disease with variable clinical outcomes. Emerging data has identified molecular markers that provide additional prognostic information to better classify these patients into those with a more favorable prognosis and those with an unfavorable prognosis who may require more aggressive or investigational therapies. Markers such as mutations in nucleophosmin 1 gene and CCAAT/enhancer binding protein alpha gene have been associated with a more favorable prognosis in CN-AML. In contrast, FMS-related tyrosine kinase 3 mutations, partial tandem duplication of mixed-lineage leukemia gene and overexpression of brain and acute leukemia, cytoplasmic gene are associated with inferior clinical outcomes. In this article, the authors discuss the classical clinical features of AML and the importance of cytogenetics that predict prognosis in AML. They review the best-described molecular markers in CN-AML and their significance to clinical decision making in CN-AML. PMID- 21522053 TI - Acamprosate attenuates cue-induced reinstatement of nicotine-seeking behavior in rats. AB - Acamprosate is used in the treatment of alcoholism; however, there is little information on its effects on nicotine addiction. The objective of this study was to determine whether acamprosate inhibits cue-induced relapse to nicotine self administration in the rat. Rats were trained to press a lever to obtain intravenous infusions of nicotine (0.03 mg/kg/infusion) that were associated with the illumination of a cue light. After 29 days of nicotine self-administration sessions, extinction sessions were run during which responses on the active lever did not result in the infusion of nicotine or the illumination of the cue light. After 14 days of extinction sessions the rats received twice-daily injections of saline or acamprosate (50, 100, or 200 mg/kg/intraperitoneally). Seven days later the response to the previously conditioned cue was tested, but only saline infusions were delivered. Pretreatment with all doses of acamprosate reduced responding to a cue previously associated with nicotine. The lowest dose of acamprosate (50 mg/kg) reduced responding for the cue previously associated with nicotine infusions, but had no effect on food-rewarded behavior. These results show that acamprosate reduced cue-induced nicotine-seeking behavior and suggest that acamprosate might be efficacious in treating nicotine addiction in humans. PMID- 21522054 TI - False positive in the intravenous drug self-administration test in C57BL/6J mice. AB - The objective of this study was to examine C57BL/6J (B6) mice during extinction conditions, after food training, and for rates and patterns of operant behavior that seems similar to behavior maintained by intravenous cocaine injections. The rationale was to evaluate the potential for false positives in the intravenous self-administration test using protocols common in studies of knockout mice backcrossed to B6. An additional aim was to assess the influence of food associated and drug-associated cues and mouse strain. Mice were allowed to acquire lever pressing reinforced by sweetened condensed milk under a fixed ratio 1 then fixed ratio 2 schedule of reinforcement accompanied by a flashing light. A catheter base was then implanted for simulation of intravenous self administration conditions. Mice were allowed to lever press with cues remaining the same as during food training but without further scheduled consequences (i.e. no drug or food reinforcers delivered). All mice sustained lever pressing for several weeks, and over half met commonly used criteria for 'self-administration behavior.' Thus, B6 mice showed perseveration of a previously reinforced behavior that closely resembled rates and patterns of drug self-administration. This effect in B6 mice was greater than with A/J mice, and the lack of extinction was even more robust in the presence of cocaine-associated cues than with food associated cues. We suggest that a necessary criterion for positive results in the intravenous drug self-administration test include an increase in responding when cocaine is made available after extinction with saline self-administration. PMID- 21522055 TI - Phencyclidine disturbs relational memory in the transitive inference task. AB - Transitive inference, that is, the ability to infer relationships among stimuli that are only indirectly associated, is impaired in schizophrenic patients and in rats with lesions of the prefrontal cortex. Symptoms of schizophrenia can be pharmacologically modeled by administration of the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP). Here, a subchronic administration of PCP (2.5 mg/kg for 5 days) to well-trained rats impaired the subsequent transitive inference judgment; the effect was observed 3 days, but not 10 days after the last dose. These results support the findings showing that PCP administration impairs cognitive domains specifically affected in schizophrenia in addition to mimicking the 'positive' and 'negative' symptoms of the disorder. PMID- 21522056 TI - A major metabolite of bupropion reverses motor deficits in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine-treated common marmosets. AB - The atypical antidepressant, bupropion, causes a partial reversal of motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. However, its monoamine uptake blocking actions are believed to be mediated by the major metabolites, racemic (-)-(2R,3R)-2-(3-chlorophenyl-3,5,5-trimethyl-2 morphinol) (R,R-hydroxybupropion) and (+)-(2S,3S)-2-(3-chlorophenyl-3,5,5 trimethyl-2-morphinol) (S,S-hydroxybupropion). Therefore, we have evaluated the ability of enantiomers to improve locomotor activity and motor disability in 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. Bupropion produced a little increase in locomotor activity and a more pronounced improvement in motor disability. The S,S-hydroxybupropion, but not the R,R hydroxybupropion, enantiomer dose-dependently increased both locomotor activity and reversed motor disability. Combined administration of S,S-hydroxybupropion and R,R-hydroxybupropion at the same dose (analogous to the racemate) again improved motor function and to the same extent as produced by S,S hydroxybupropion alone. The data suggest that the S,S-enantiomer of hydroxybupropion may possess potential antiparkinsonian activity. PMID- 21522057 TI - Behavioral effects of MDMA ('ecstasy') on adult zebrafish. AB - 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') is a potent psychedelic drug inducing euphoria and hypersociability in humans, as well as hyperactivity and anxiety in rodents. Adult zebrafish (Danio rerio) have become a widely used species in neurobehavioral research. Here, we explore the effects of a wide range (0.25-120 mg/l) of acute MDMA doses on zebrafish behavior in the novel tank test. Although MDMA was inactive at lower doses (0.25-10 mg/l), higher doses reduced bottom swimming and immobility (40-120 mg/l) and impaired intrasession habituation (10-120 mg/l). MDMA also elevated brain c-fos expression, collectively confirming the usage of zebrafish models for screening of hallucinogenic compounds. PMID- 21522059 TI - Breast cancer in a wife: how husbands cope and how well it works. AB - BACKGROUND: Husbands of patients with breast cancer (HBCs) experience as much as or even more distress than patients. Husbands' coping strategies may predict their level of distress. OBJECTIVE: The present study examined the coping strategies of HBCs compared with husbands of women without cancer (HWCs) and the relationship between coping and various psychosocial variables. METHODS: Psychosocial and physical health correlates of coping in both groups were assessed. Husbands of women with breast cancer (n=83) and without breast cancer (n=79) completed self-report questionnaires including the Ways of Coping Questionnaire, the Center for Epidemiological Studies Depression Scale, the Subjective Stress Scale, the Satisfaction With Life Scale, and the Locke-Wallace Marital Adjustment Test, in addition to measures of burden. RESULTS: The HBC and HWC groups were significantly different for 6 of the 8 coping styles assessed, with HBC using these strategies less than HWCs. Among HBCs, higher use of distancing, accepting responsibility, and escape-avoidance was associated with higher stress and symptoms of depression, and distancing and accepting responsibility were associated with lower marital satisfaction. CONCLUSIONS: Results suggest that coping strategies may be different when dealing with cancer in a wife than at other times and that coping relates to well-being and is therefore worthy of focus. IMPLICATIONS FOR PRACTICE: Simple assessments of primary coping strategies may help clinicians identify HBCs in need of interventions. Husbands of women with breast cancer can be given problems to solve that will help them cope and help the patient and clinic staff as well. Interventions aimed at the couple, and not exclusively the HBC, may be particularly helpful. PMID- 21522058 TI - Characteristics of the nighttime hospital bedside care environment (sound, light, and temperature) for children with cancer. AB - BACKGROUND: Children with cancer must cope not only with their disease and its treatment but also with the environment in which treatment is given. The intensities of sound and light levels required to perform necessary patient care may result in a disruptive nighttime care environment. OBJECTIVE: The purpose of this study was to describe nighttime patterns of environmental factors, sound, light, and temperature levels, at the bedside of children with cancer receiving inpatient chemotherapy. METHODS: Participants were 15 school-aged children receiving chemotherapy on an inpatient pediatric oncology unit. Sound, light, and temperature in the child's room were measured continuously using a digital-sound pressure-level meter and an external channel data logger. RESULTS: Mean nighttime sound levels were 49.5 (SD, 3.1) dB (range, 34.6-84.8 dB). Sound and light intensities were greatest early in the shift and decreased through the night. A basic mixed linear model identified significant main effects of time of night for both sound (F=50.42, P<.01) and light (F=12.43, P<.01). CONCLUSIONS: Study findings identified a bedside care environment with persistently elevated sound levels and abrupt increases in sound intensity throughout the night. Such a disruptive nighttime environment is not conducive to restful nighttime sleep and may serve as an additional source of physiological and psychological stress for hospitalized children with cancer. IMPLICATIONS FOR PRACTICE: Efforts are needed to identify modifiable sources of nighttime sound and develop interventions to reduce nighttime sound. Collaborative efforts to organize clinical care to minimize nighttime disruptions may lead to reduced bedside sound levels. PMID- 21522060 TI - Determinants of altered life perspectives among older-adult long-term cancer survivors. AB - BACKGROUND: In the recent literature on cancer survivorship, positive changes are emphasized in the aftermath of trauma. However, there is insufficient research on older-adult survivors and more complex transformations. OBJECTIVE: Consistent with nursing researchers' views about the duality of cancer survivor experiences, this research examined both positive and negative posttraumatic transformations (PTTs) among long-term survivors. Demographic, stress, and appraisal-related predictors of transformations were considered. METHODS: Using cross-sectional survey design, interviews were conducted with 288 survivors of breast, colorectal, and prostate cancer. The sample, obtained from a hospital tumor registry, was 58% female, 33% African American, and 67% white (mean age, 72.5 [SD, 7.6] years). Demographic characteristics, cumulative stress exposure, appraisals of stress, and self-reported PTTs were measured. RESULTS: Most respondents reported diverse transformations attributed to their illness experience. Demographic characteristics and stress appraisals were more strongly associated with PTT outcomes than was cumulative stress exposure. Appraisals of the cancer experience as stressful, as generating worry, and as stigmatizing were significantly associated with diverse PTT outcomes. CONCLUSION: Many long-term older cancer survivors report PTT reflecting altered perspectives on life. Posttraumatic transformations are related to the view that cancer is a continuing worrisome and stigmatizing experience. IMPLICATIONS FOR PRACTICE: Nurses have a unique opportunity to discuss with patients the potentially life-changing nature of the cancer experience in a manner that allows for understanding and acceptance of complex changes, incorporating benefit finding along with acknowledgement of loss and suffering. This type of discussion can enhance cancer survivors' mental health. PMID- 21522062 TI - Monitoring asthma status. AB - PURPOSE: Asthma is a chronic disorder of the airways involving inflammation and airway hyper-reactivity. Clinical diagnosis and monitoring of asthma must incorporate the immunological, biochemical, and histological changes of a chronic disorder, while recognizing acute phenotypic changes in order to optimally tailor therapeutics to each individual. RECENT FINDINGS: Articles published within the previous 18 months are summarized in this article in order to present an up to date review of the latest findings regarding the monitoring of asthma. The articles encompass a wide array of specialties from basic research and histology to clinical medicine as well as community medicine and nursing. SUMMARY: Exciting new advancements in the monitoring of asthma continue to unfold. Potentially new diagnostic and monitoring tools are highlighted in this study. Continued investigations may enable a select few methodologies to reach clinical utility in the ongoing monitoring and treatment of patients with asthma. PMID- 21522061 TI - Fatigue, sleep, pain, mood, and performance status in patients with multiple myeloma. AB - BACKGROUND: Cancer-related fatigue and insomnia are common distressing symptoms and may affect mood and performance status. OBJECTIVE: The objective of this study was to describe fatigue, sleep, pain, mood, and performance status and the relationships among these variables in 187 patients with newly diagnosed multiple myeloma (MM) and conduct an analysis using the correlates of fatigue. METHODS: Data were from baseline measures from the study, using the Profile of Mood States and the Functional Assessment of Cancer Therapy-Fatigue to assess fatigue, the actigraph to measure sleep, the Wong/Baker Faces Pain Rating Scale to assess pain, the Profile of Mood States to assess mood, and the 6-minute walk test along with a back/leg/chest dynamometer to test muscle strength to assess performance status. Data analysis consisted of descriptive statistics, Pearson and Spearman rho correlations, and multiple regression analysis using fatigue as the dependent variable. All P values were 2-sided, and P<.05 was considered significant. RESULTS: Patients with newly diagnosed MM presented with fatigue, pain, sleep and mood disturbances, and diminished functional performance. The regression model, which included all of these variables along with age, sex, and stage of disease, was statistically significant with a large measure of effect. Mood was a significant individual contributor to the model. CONCLUSIONS: Among patients with MM, fatigue, pain, sleep, mood, and functional performance are interrelated. IMPLICATIONS FOR PRACTICE: Interventions are needed to decrease fatigue and pain and to improve sleep, mood, and functional performance. PMID- 21522063 TI - Microarray of allergenic component-based diagnosis in food allergy. AB - PURPOSE OF REVIEW: The determination of specific IgE (sIgE) against allergenic components fixed in a solid support that is provided as a microarray of high capacity and allows a more precise evaluation in the food allergy diagnosis. In this review, we will analyze the results obtained to date with this technology applied to the component-based diagnosis of food allergy. RECENT FINDINGS: Microarrays of proteins or glycoproteins allow us to know the profile of sensitization of a patient with food allergy. At present, a commercially available technique exists which allows sIgE to be detected against 103 allergenic molecules. Several laboratories worldwide have explored and optimized this technique for few allergen extracts and the results have been promising with high reliabilities and sensitivities and above all, good correlations with previous existing conventional assays. SUMMARY: In recent years, as a result of advances in molecular biology, together with the development of new technologies of producing high-capacity solid-phase matrices such as microarrays, the diagnosis of food allergy has improved and the basic situation of analyzing sIgE against an allergenic source has now become real the possibility of analyzing sIgE against an allergenic protein or glycoprotein. This change has not only led to a more precise diagnosis of sensitization, but can also be used to explain the different hazards of certain molecular sensitizations, crossreactivity phenomena in many cases and can even change the clinical management according to the information provided. Further studies are clearly needed to evaluate more precisely the scope of this new technique. PMID- 21522064 TI - Cow's milk allergy as a global challenge. AB - PURPOSE OF REVIEW: Cow's milk is a leading cause of food allergy especially in infants and children. 'Diagnosis and Rationale for Action against Cow's Milk Allergy' published by the World Allergy Organization has underlined that there is not enough information concerning geographical trends in cow's milk allergy (CMA) in children or adults. Experts from Australia, Asia, North America, Latin America, the Middle East and Europe have gathered together in a 2-day meeting in order to present various regional approaches to CMA. This report is a summary of the information that was presented at this meeting. RECENT FINDINGS: Even though there seems to be uniformity concerning the diagnosis and treatment of CMA, the diagnostic approach to CMA shows variations among different regions. Common concerns were inadequate applications of challenge tests for the diagnosis and inadequate supply of the cow's milk substitute formulas. SUMMARY: CMA is a global challenge and collaboration of the national and international scientific communities is essential to produce and update practical guidelines for CMA. PMID- 21522065 TI - What is the best way to use conjugate vaccines? AB - PURPOSE OF REVIEW: The present review discusses recent advances, challenges and opportunities for the best use of conjugate vaccines now and in the future. RECENT FINDINGS: Direct protection in young children may be short-lived and programme effectiveness may depend heavily on indirect protection (herd immunity). Pneumococcal carriage serotype replacement has been widely reported following vaccine implementation. Use of pneumococcal conjugate vaccines is being trialled in the elderly. Vaccination in west Africa against Neisseria meningitidis serogroup A (Men A), a new monovalent conjugate vaccine, was commenced in December 2010. New conjugate vaccines against, for example, Salmonella typhi and Streptococcus agalactiae, are being developed and tested in clinical trials. SUMMARY: Conjugate vaccines have been extensively used to immunize children, resulting in significant decreases in childhood morbidity and mortality. Since their introduction, evidence has grown that protection against disease is due to both direct and indirect protection (herd immunity). The optimization of priming and booster dose regimens in existing paediatric vaccination programmes, aiming for maximal and sustained direct and indirect protection using as few doses per child as possible, may broaden conjugate vaccine impact and augment cost-effectiveness in the future. This may be particularly important in strategies for wider global use of conjugate vaccines in children, as well as use in adults and the elderly. Challenges such as pneumococcal serotype replacement make ongoing surveillance of carriage and invasive disease crucial and will have implications for conjugate reformulation and the development of alternative vaccines. New conjugate vaccines for other pathogens currently in clinical trials have the potential to reduce invasive bacterial disease further, particularly in resource-poor settings. PMID- 21522066 TI - Factors affecting the development of systemic inflammatory response syndrome in pneumococcal infections. AB - PURPOSE OF REVIEW: Streptococcus pneumoniae continues to be responsible for significant mortality and morbidity worldwide. A better understanding of the inflammatory response generated by the interaction of this microorganism with the host and antimicrobial therapy will improve the management of patients with pneumococcal infection. RECENT FINDINGS: On the side of the microorganism, recent studies have identified virulence factors such as capsular polysaccharides, surface protein, pili and pneumolysin, among others, that are able to trigger a complex inflammatory network. A misbalance in this network will precipitate a specific response that generates the systemic inflammatory response syndrome. Some of these virulence factors could be used as antigens for the production of vaccines with a broader spectrum than the currently used ones. On the host side, many single-nucleotide polymorphisms in genes controlling the immune response have been associated with specific clinical presentations. Finally, some antimicrobials or adjunctive therapies have recently been evaluated as inmunomodulatory agents. SUMMARY: Systemic inflammatory response syndrome is the result of an anomalous activation of the inflammatory network triggered by S. pneumoniae. Pneumococcal virulence factors, host comorbidities, the genetic background and the concomitant activity of antimicrobials and adjuvant therapies modulate the magnitude of this response. PMID- 21522067 TI - Evidence-based approach for making cochlear implant recommendations for infants with residual hearing. AB - OBJECTIVES: The aim of this study was to develop guidelines, based on the unaided pure-tone audiogram, for recommending a cochlear implant (CI) for infants and young children with residual hearing. As awareness of the benefits of early implantation increases and age at diagnosis decreases, an increasing number of infants are presenting for consideration of implantation with significant residual hearing in one or both ears. Determining the likelihood that these infants will have an improved speech and language outcome if they receive a CI is a challenge. DESIGN: Subjects were 142 hearing impaired children (ages 4.6 to 16.2 yrs) with unaided three-frequency pure-tone average (PTA; at 500, 1000, and 2000 Hz) ranging from 28 to 125 dB HL: 62 used conventional amplification (analog or digital hearing aids [HAs]) and the remaining 80 used a Nucleus 24 (N24) or Freedom CI. Open-set monosyllabic word (Phonetically Balanced Kindergarten or Consonant-Nucleus-Consonant words) and sentence (Bamford-Kowal-Bench sentences) testing was administered audition alone to both groups of children. RESULTS: Comparison of means for sentence testing showed that the children using CIs performed significantly better than their peers with profound hearing loss (PTA >90 dB HL) using HAs and not significantly differently to those with severe (PTA 66 to 90 dB HL) or moderate (PTA <66 dB HL) hearing loss. Comparison of means for monosyllabic word testing showed that the children using CIs performed significantly better than their peers with severe and profound hearing loss and not significantly differently to those with moderate hearing loss. Regression analysis was used to determine the equivalent unaided PTA values that corresponded to the median and first quartile scores for the children using CIs on speech perception testing. For open-set words, scored for phonemes correct, the equivalent unaided PTAs were 46 and 56 dB HL, respectively. For sentence testing, the equivalent unaided PTAs were 63 and 72 dB HL, respectively. CONCLUSIONS: Results suggest that recommendation for implantation can be made confidently for children presenting with bilateral profound hearing loss. For children with unaided PTA hearing levels in the range of 75 to 90 dB HL, a recommendation for implantation can also be made, provided that a 75% chance of improvement in hearing outcome is an acceptable level of benefit to the family and clinician. Children presenting with PTA hearing levels better than 75 dB HL should be encouraged to continue with binaural HA use. PMID- 21522068 TI - Cochlear dead regions in typical hearing aid candidates: prevalence and implications for use of high-frequency speech cues. AB - OBJECTIVES: This study had two purposes. The first was to assess the prevalence of cochlear dead regions (DRs) among listeners with moderate to severe hearing loss that is typical of a large proportion of adult hearing aid wearers. The second was to determine whether subjects who tested positive for DRs differed from those without DRs in their ability to utilize high-frequency speech cues in a laboratory test. DESIGN: One hundred and seventy adults (307 ears) were tested for DRs at frequencies from 0.5 to 4 kHz using the threshold equalizing noise (HL) test. Speech recognition ability was measured for high-frequency emphasis (HFE) stimuli and for low-pass filtered HFE (HFE-LP) stimuli using the Quick Speech In Noise test. Results obtained from the HFE and HFE-LP conditions were compared to examine changes in word recognition when more speech cues were provided above 2.5 kHz. Possible effects of audiogram differences between DR-no and DR-yes groups were examined by estimating the change in audibility for the two Quick Speech In Noise conditions using calculated differences in Speech Intelligibility Index for each condition for every subject. RESULTS: Thirty-one percent of subjects (23% of ears) were found to have a DR at one or more test frequencies. Sixty-eight percent of subjects who tested positive for DR had DRs in one ear only. DRs were most prevalent at frequencies above 1.5 kHz. Comparison of word recognition scores obtained with the HFE and HFE-LP conditions revealed that, on average, both groups scored significantly better when more high frequency cues were provided. The magnitude of the benefit was small for both groups, but the computed effect size was larger for listeners without DRs than for those with DRs. Further, subjects with contiguous DRs at 2 to 3 frequencies obtained less benefit than subjects with DRs at isolated frequencies. It was determined that the improved audibility of high-frequency cues in the HFE condition was significantly less for listeners with DRs, and this accounted for some, but not all, of the difference in effect sizes. CONCLUSIONS: Although about one-third of listeners with flat or sloping moderate to severe hearing losses tested positive for at least one DR, there was no evidence to support a proposal for reducing high-frequency gain in hearing aid fittings for these types of listeners. Making high frequencies more audible was helpful, on average, regardless of DR status. It is recommended that field trials be undertaken in which subjects with and without DRs wear hearing aids in daily life. This type of study would produce higher level evidence about best practice in hearing aid fitting for patients with flat or sloping moderate to severe hearing loss who test positive for DRs. PMID- 21522069 TI - Postexercise carbohydrate-protein supplementation improves subsequent exercise performance and intracellular signaling for protein synthesis. AB - Postexercise carbohydrate-protein (CHO + PRO) supplementation has been proposed to improve recovery and subsequent endurance performance compared to CHO supplementation. This study compared the effects of a CHO + PRO supplement in the form of chocolate milk (CM), isocaloric CHO, and placebo (PLA) on recovery and subsequent exercise performance. Ten cyclists performed 3 trials, cycling 1.5 hours at 70% VO2max plus 10 minutes of intervals. They ingested supplements immediately postexercise and 2 hours into a 4-hour recovery. Biopsies were performed at recovery minutes 0, 45, and 240 (R0, R45, REnd). Postrecovery, subjects performed a 40-km time trial (TT). The TT time was faster in CM than in CHO and in PLA (79.43 +/- 2.11 vs. 85.74 +/- 3.44 and 86.92 +/- 3.28 minutes, p <= 0.05). Muscle glycogen resynthesis was higher in CM and in CHO than in PLA (23.58 and 30.58 vs. 7.05 MUmol.g-1 wet weight, p <= 0.05). The mammalian target of rapamycin phosphorylation was greater at R45 in CM than in CHO or in PLA (174.4 +/- 36.3 vs. 131.3 +/- 28.1 and 73.7 +/- 7.8% standard, p <= 0.05) and at REnd in CM than in PLA (94.5 +/- 9.9 vs. 69.1 +/- 3.8%, p <= 0.05). rpS6 phosphorylation was greater in CM than in PLA at R45 (41.0 +/- 8.3 vs. 15.3 +/- 2.9%, p <= 0.05) and REnd (16.8 +/- 2.8 vs. 8.4 +/- 1.9%, p <= 0.05). FOXO3A phosphorylation was greater at R45 in CM and in CHO than in PLA (84.7 +/- 6.7 and 85.4 +/- 4.7 vs. 69.2 +/- 5.5%, p <= 0.05). These results indicate that postexercise CM supplementation can improve subsequent exercise performance and provide a greater intracellular signaling stimulus for PRO synthesis compared to CHO and placebo. PMID- 21522070 TI - The effects of low-dose caffeine on perceived pain during a grip to exhaustion task. AB - This double-blind, placebo-controlled, within-subject experiment examined the effects of low-dose caffeine on pain reported during an exhaustive grip task. The grip task consisted of holding a metal block attached to standard Olympic weight plates with the arm at the side until the participants could no longer maintain their grip. Apparently healthy recreationally trained college-aged adults (men, n = 5; women, n = 5) were given either a piece of Stay AlertTM gum that delivered 85% of the effective dose of 100 mg of caffeine in 5 minutes or an identical placebo gum that contained no caffeine. Subsequently, pain perception and ratings of perceived exertion were recorded during an exhaustive grip task every 15 seconds and the overall time to exhaustion. No significant difference was found in time to exhaustion between treatments. A significant main effect of treatment for reported pain (p < 0.001, Phi = 0.377) was observed. Thus, in a population of recreationally trained college-aged adults, low-dose caffeine may attenuate the individual's perception of pain during a grip to exhaustion task. PMID- 21522071 TI - Comparisons of peak ground reaction force and rate of force development during variations of the power clean. AB - The aim of this investigation was to determine the differences in vertical ground reaction forces and rate of force development (RFD) during variations of the power clean. Elite rugby league players (n = 11; age 21 +/- 1.63 years; height 181.56 +/- 2.61 cm; body mass 93.65 +/- 6.84 kg) performed 1 set of 3 repetitions of the power clean, hang-power clean, midthigh power clean, or midthigh clean pull, using 60% of 1-repetition maximum power clean, in a randomized order, while standing on a force platform. Differences in peak vertical ground reaction forces (F(z)) and instantaneous RFD between lifts were analyzed via 1-way analysis of variance and Bonferroni post hoc analysis. Statistical analysis revealed a significantly (p < 0.001) greater peak F(z) during the midthigh power clean (2,801.7 +/- 195.4 N) and the midthigh clean pull (2,880.2 +/- 236.2 N) compared to both the power clean (2,306.24 +/- 240.47 N) and the hang-power clean (2,442.9 +/- 293.2 N). The midthigh power clean (14,655.8 +/- 4,535.1 N.s-1) and the midthigh clean pull (15,320.6 +/- 3,533.3 N.s-1) also demonstrated significantly (p < 0.001) greater instantaneous RFD when compared to both the power clean (8,839.7 +/- 2,940.4 N.s-1) and the hang-power clean (9,768.9 +/- 4,012.4 N.s-1). From the findings of this study, when training to maximize peak F(z) and RFD the midthigh power clean and midthigh clean pull appear to be the most advantageous variations of the power clean to perform. PMID- 21522072 TI - Physiological responses during interval training with different intensities and duration of exercise. AB - The purpose of this study was to compare 4 interval training (IT) sessions with different intensities and durations of exercise to determine the effect on mean VO2, total VO2, and duration of exertion >=95% maximum power output (MPO), and the effects on biomarkers of fatigue such as blood-lactate concentration (BLC) and rating of perceived exertion. The subjects were 12 recreationally competitive male (n = 7, mean +/- SD age = 26.2 +/- 3.9 years) and female (n = 5, mean +/- SD age = 27.6 +/- 4.3 years) triathletes. These subjects performed 4 IT sessions on a cycle ergometer varying in intensity (90 and 100% MPO) and duration of exercise (30 seconds and 3 minutes). This study revealed that IT using 30-second duration intervals (30-30 seconds) allows the athlete to perform a longer session, with a higher total and mean VO2 HR and lower BLC than 3-minute durations. Similarly, submaximal exertion at 90% of MPO also allows performing longer sessions with a higher total VO2 than 100% intensity. Thus, the results of the present study suggested that to increase the total time at high intensity of exercise and total VO2 of a single exercise session performed by the athlete, IT protocols of short durations (i.e., 30 seconds) and submaximal intensities (i.e., 90% MPO) should be selected. Furthermore, performing short-duration intervals may allow the athlete to complete a longer IT session with greater metabolic demands (VO2) and lower BLC than longer (i.e., 3 minutes) intervals. PMID- 21522073 TI - Effects of speed, agility, quickness training method on power performance in elite soccer players. AB - The purpose of this study was to evaluate the effects of the speed, agility, quickness (SAQ) training method on power performance in soccer players. Soccer players were assigned randomly to 2 groups: experimental group (EG; n = 50) and control group (n = 50). Power performance was assessed by a test of quickness- the 5-m sprint, a test of acceleration--the 10-m sprint, tests of maximal speed- the 20- and the 30-m sprint along with Bosco jump tests--squat jump, countermovement jump (CMJ), maximal CMJ, and continuous jumps performed with legs extended. The initial testing procedure took place at the beginning of the in season period. The 8-week specific SAQ training program was implemented after which final testing took place. The results of the 2-way analysis of variance indicated that the EG improved significantly (p < 0.05) in 5-m (1.43 vs. 1.39 seconds) and in 10-m (2.15 vs. 2.07 seconds) sprints, and they also improved their jumping performance in countermovement (44.04 vs. 4.48 cm) and continuous jumps (41.08 vs. 41.39 cm) performed with legs extended (p < 0.05). The SAQ training program appears to be an effective way of improving some segments of power performance in young soccer players during the in-season period. Soccer coaches could use this information in the process of planning in-season training. Without proper planning of the SAQ training, soccer players will most likely be confronted with decrease in power performance during in-season period. PMID- 21522074 TI - Personal best time and training volume, not anthropometry, is related to race performance in the 'Swiss Bike Masters' mountain bike ultramarathon. AB - We investigated in 73 male ultraendurance mountain bikers, with (mean and SD) age 39.1 (8.6) years, weight 74.4 (8.3) kg, height 1.78 (0.07) m, and a body mass index of 23.3 (1.9) kg.m-2, whether variables of anthropometry, training, or prerace experience were associated with race time using bi and multivariate analysis. Our investigation was conducted at the "Swiss Bike Masters," which covers a distance of 120 km and an altitude of 5,000 m. In the bivariate analysis, body mass index (r = 0.29), circumference of upper arm (r = 0.28), sum of upper body skinfolds (r = 0.38), sum of lower body skinfolds (r = 0.25), sum of 8 skinfolds (r = 0.36), percent body fat (r = 0.41), total cycling kilometers per year (r = -0.47), yearly volume in both mountain bike (r = -0.33) and road cycling (r = -0.52), number of training units per week (r = -0.48), distance per unit in road cycling (r = -0.33), average speed during training in road cycling (r = -0.33), and personal best time in the "Swiss Bike Masters"(r = 0.67) were related to race time. In the multiple linear regression analysis, personal best time in the "Swiss Bike Masters" (p = 0.000), total yearly cycling kilometers (p = 0.004), and yearly training kilometers in road cycling (p = 0.017) were related to race time. When the personal best time was the dependent variable in a separate regression model, total yearly cycling kilometers (p = 0.002) remained the single predictor variable. We concluded that finishing a particular mountain bike ultramarathon does not seem to require a special anthropometry but rather a specific skill and experience for this selective kind of race coupled with a high training volume. For practical use, we concluded that successful athletes in a mountain bike ultramarathon, in a special environment and using sophisticated equipment, need prerace experience coupled with high training volume, rather than any special anthropometry. PMID- 21522075 TI - Lactate minimum is valid to estimate maximal lactate steady state in moderately and highly trained subjects. AB - Some evidence exists that the determination of maximal lactate steady state (MLSS) with lactate minimum (LM) in highly trained athletes is not as accurate as in less trained athletes. Therefore, we compared power output at LM with power output MLSS in moderately up to highly trained subjects. 63 subjects performed a test on a cycle ergometer to determine power output at LM and 3 or more constant load tests of 30 minutes to determine power output at MLSS. Mean power output at LM (245 +/- 29 W; mean +/- SD) was slightly lower than power output at MLSS (255 +/- 32 W). The correlation between power output at MLSS and LM was high, and the regression line runs parallel to the line of identity showing that the results of highly trained subjects agree with the results of less trained subjects (LM and MLSS r = 0.867, p < 0.001). The modified blood-lactate kinetic in highly trained athletes compared with less trained persons does not impair accuracy at LM. Therefore, we suggest LM as a valid and meaningful concept to estimate power output at MLSS in 1 single test in moderately up to highly trained athletes. PMID- 21522076 TI - Influence of previous experience on resistance training on reliability of one repetition maximum test. AB - The 1-repetition maximum test (1RM) has been widely used to assess maximal strength. However, to improve accuracy in assessing maximal strength, several sessions of the 1RM test are recommended. The aim of this study was to analyze the influence of previous resistance training experience on the reliability of 1RM test. Thirty men were assigned to the following 2 groups according to their previous resistance training experience: no previous resistance training experience (NOEXP) and more than 24 months of resistance training experience (EXP). All subjects performed the 1RM tests in bench press and squat in 4 sessions on distinct days. There was a significant session * group effect in bench press (F = 3.09; p < 0.03) and squat (F = 2.76; p < 0.05) showing that only the NOEXP increased maximal strength between the sessions. Significant increases (p < 0.05) in maximal strength occurred in the NOEXP between session 1 and the other sessions in bench press (session 1 vs. 2 = +3.8%; session 1 vs. 3 = +7.4%; session 1 vs. 4 = +10.1%), and squat (session 1 vs. 2 = +7.6%; session 1 vs. 3 = +10.1%; session 1 vs. 4 = +11.2%). Moreover, in bench press, maximal strength in sessions 3 and 4 were significantly higher than in session 2. The results of the present study suggest that the reliability of the 1RM test is influenced by the subject's previous experience in resistance training. Subjects without experience in resistance training require more practice and familiarization and show greater increases in maximal strength between sessions than subjects with previous experience in resistance training. PMID- 21522077 TI - Reliability, usefulness, and validity of the 30-15 Intermittent Ice Test in young elite ice hockey players. AB - The purpose of this study was to examine the reliability, usefulness, and validity of the 30-15 Intermittent Ice Test (30-15(IIT)) in 17 young elite ice hockey players. For the reliability and usefulness study, players performed the 30-15(IIT) 7 days apart. For the validity study, data derived from the first 30 15(IIT) were compared with those obtained from the 30-15 Intermittent Fitness Test (30-15(IFT), the running version of this test used as a reference marker for its ability to assess cardiovascular fitness in the field, that is, VO2peak). Maximal speed, heart rate at exhaustion (HR(peak)) and postexercise blood-lactate levels ([La](b)) were collected for all tests, whereas submaximal HR was taken at stages 4 and 8 (HR(stage4) and HR(stage8)) during the 30-15(IIT). All intra-class correlation coefficients were >0.94. Coefficients of variation were 1.6% (90% CI, 1.3-2.3), 1.7% (1.3-2.8), 1.4% (1.0-2.2), and 0.7% (0.5-1.1) for maximal skating speed, HR(stage4), HR(stage8), and HR(peak), respectively. Correlations between maximal velocities and HR(peak) obtained for the 30-15(IIT) vs. 30-15(IFT) were very large (r = 0.72) and large (r = 0.61), respectively. Maximal skating speed was also largely correlated to estimated VO2peak (r = 0.71). There was however no correlation for [La](b) values between both tests (r = 0.42). These results highlight the specificity of the on-ice 30-15(IIT) and show it to be a reliable and valid test for assessing cardiorespiratory fitness in young elite players. Coaches could interpret a change in performance of at least 2 stages, or a change in submaximal HR of more than 8% (~8 b.min-1) during the eighth stage to be a meaningful change in skating fitness. PMID- 21522078 TI - Test retest reliability and minimal detectable change of a novel submaximal graded exercise test in the measurement of graded exercise test duration. AB - Measurement of graded exercise test duration is clinically important and can be assessed by maximal graded exercise testing. Yet, limitations of maximal graded exercise testing exist. An alternative to maximal graded exercise testing is submaximal graded exercise testing. However, no studies have investigated the reliability of a submaximal graded exercise test in the measurement of graded exercise test duration. The purpose of this study was to determine the test retest reliability and minimal detectable change (MDC) of a novel submaximal graded exercise test in the measurement of graded exercise test duration. Fifteen people (4 men, 11 women) with a mean age of 26.20 years (SD = 9.04) participated in this study. A novel submaximal graded exercise test was used to measure graded exercise test duration for each participant. Endpoints of the test were either 85% of age-predicted maximum heart rate or voluntarily stopping the test, whichever endpoint occurred first. Heart rate and graded exercise test duration were constantly measured throughout the test. Graded exercise test duration was defined as the total duration (minutes) of the test. For all participants, the submaximal graded exercise test was conducted at baseline and 48-72 hours thereafter. The intraclass correlation coefficient for the test-retest reliability of the test in determining graded exercise test duration was 0.94 (95% CI = 0.83-0.98). The MDC of the test in the measurement of graded exercise test duration was 0.86 minutes. The results suggest that clinicians can use this novel submaximal graded exercise test to reliably measure graded exercise test duration with a measurement error, as expressed by the MDC, of 0.86 minutes. PMID- 21522079 TI - Reassignment of the structures of products produced by reactions of the product believed to be 2-(1-phenyl-2-thiocyanatoethylidene)-malononitrile with electrophiles. AB - The reactivity of the product believed to be 2-(1-phenyl-2-thiocyanato ethylidene)malononitrile toward a variety of electrophilic and nucleophilic reagents is reported. PMID- 21522080 TI - Thiophene derivatives with antileishmanial activity isolated from aerial parts of Porophyllum ruderale (Jacq.) Cass. AB - Porophyllum ruderale (Jacq.) Cass. is a plant native to Brazil and in the northwest region of the state of Parana, Brazil, aerial parts of P. ruderale have been used popularly in the treatment of lesions caused by Leishmania sp.. In this study the antileishmanial and cytotoxic activities of the crude extract, fractions, and isolated compounds from aerial parts of P. ruderale was evaluated. The dichloromethane extract was submitted to chromatography to yield compounds active against Leishmania amazonensis. Their structures were established by comparison of their spectroscopic data with literature values. The activities of crude extract against promastigote and axenic amastigote forms of L. amazonensis (IC(50)) were 60.3 and 77.7 MUg/mL, respectively. Its cytotoxic activity against macrophage cells (CC(50)) was 500 MUg/mL. The thiophene derivatives isolated were: 5-methyl-2,2':5',2"-terthiophene (compound A) and 5'-methyl-[5-(4-acetoxy-1 butynyl)]-2,2'-bithiophene (compound B). The activity of compound A against promastigote and axenic amastigote forms were 7.7 and 19.0 MUg/mL and of compound B were 21.3 and 28.7 MUg/mL, respectively. The activity of the isolated compounds against promastigote and axenic amastigote forms was better than that of the crude extract and more selective against protozoa than for macrophage cells. PMID- 21522081 TI - Study of the biological activity of novel synthetic compounds with antiviral properties against human rhinoviruses. AB - Picornaviridae represent a very large family of small RNA viruses, some of which are the cause of important human and animal diseases. Since no specific therapy against any of these viruses currently exists, palliative symptomatic treatments are employed. The early steps of the picornavirus replicative cycle seem to be privileged targets for some antiviral compounds like disoxaril and pirodavir. Pirodavir's main weakness is its cytotoxicity on cell cultures at relatively low doses. In this work some original synthetic compounds were tested, in order to find less toxic compounds with an improved protection index (PI) on infected cells. Using an amino group to substitute the oxygen atom in the central chain, such as that in the control molecule pirodavir, resulted in decreased activity against Rhinoviruses and Polioviruses. The presence of an -ethoxy-propoxy- group in the central chain (as in compound I-6602) resulted in decreased cell toxicity and in improved anti-Rhinovirus activity. This compound actually showed a PI >700 on HRV14, while pirodavir had a PI of 250. These results demonstrate that modification of pirodavir's central hydrocarbon chain can lead to the production of novel derivatives with low cytotoxicity and improved PI against some strains of Rhinoviruses. PMID- 21522082 TI - Synthesis, singlet oxygen photogeneration and DNA photocleavage of porphyrins with nitrogen heterocycle tails. AB - Eight novel compounds were prepared by reaction of 5-(bromo- propoxyphenyl) 10,15,20-triphenylporphyrin with oxazole thiols, 1,3,4-oxadiazole thiols and 1,3,4-thiadiazole thiols, and their structures confirmed by UV-vis, IR, 1H-NMR, MS and elemental analysis. The assessment of indirectly measured 1O(2) production rates against 5,10,15,20-tetraphenyl porphyrin (H(2)TPP) were described and the relative singlet oxygen production yields were:porphyrin 5 > porphyrins 1, 3, 4, 6-8, H(2)TPP > porphyrin 2. Porphyrin 4 and porphyrin 7 showed substantial photocleavage activities toward DNA, with over 75% cleavage observed at 40 uM. It suggested that these those porphyrins with nitrogen heterocycle tails are potential photosensitive agents. PMID- 21522083 TI - Phage display of combinatorial peptide libraries: application to antiviral research. AB - Given the growing number of diseases caused by emerging or endemic viruses, original strategies are urgently required: (1) for the identification of new drugs active against new viruses and (2) to deal with viral mutants in which resistance to existing antiviral molecules has been selected. In this context, antiviral peptides constitute a promising area for disease prevention and treatment. The identification and development of these inhibitory peptides require the high-throughput screening of combinatorial libraries. Phage-display is a powerful technique for selecting unique molecules with selective affinity for a specific target from highly diverse combinatorial libraries. In the last 15 years, the use of this technique for antiviral purposes and for the isolation of candidate inhibitory peptides in drug discovery has been explored. We present here a review of the use of phage display in antiviral research and drug discovery, with a discussion of optimized strategies combining the strong screening potential of this technique with complementary rational approaches for identification of the best target. By combining such approaches, it should be possible to maximize the selection of molecules with strong antiviral potential. PMID- 21522084 TI - Prevalence of hepatitis B and hepatitis C virus infection in human of Mymensingh, Bangladesh. AB - Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are among the most frequent viral infections in humans, and represent a major global public health problem, especially in Asia. HBV- and HCV-related chronic hepatitis is the main causes of cirrhosis and hepatocellular carcinoma (HCC) of liver that are responsible for a high rate of morbidity and mortality. The study was done to analyze the prevalence of HBV and HCV among the people of Mymensingh City, Bangladesh. This cross sectional data was collected from the blood transfusion department of Mymensingh Medical College Hospital and descriptive analysis was performed. Out of 2015 participants, 126 were HBsAg positive and 45% were found HCV positive cases. Based on the results, it concludes that similar prevalence of HBV and HCV infections were seen in Bangladesh as other Asian countries. PMID- 21522085 TI - Seroprevalence of genital Chlamydia trachomatis infection in women of reproductive age. AB - The genital chlamydial infection is the most common sexually transmitted diseases (STD) and major cause of infertility and ectopic pregnancy for millions of women in the world particularly in developing countries. This study was performed to find out the seroprevalence of Chlamydia trachomatis (CT) genital infection in women of reproductive age attending the Department of Obstetrics and Gynaecology, Mymensingh Medical College Hospital (MMCH) during the period from January 2009 to December 2009 through a cross sectional study. A total of 108 serum samples from symptomatic and asymptomatic pregnant and non-pregnant women were tested for CT specific IgG antibody by Enzyme Linked Immunosorbent Assay (ELISA). A total of 31(28.7%) patients were found to have antibody of which 44% (26/59) were from pregnant group and 10.2% (5/49) from non-pregnant group. The seropositivity was 21.6% (16/74) in symptomatic cases and 44.1% (15/34) in asymptomatic cases. The study shows high prevalence of Chlamydial antibody which is common in pregnant and non-pregnant, symptomatic and asymptomatic adult women in Bangladesh. So, screening for chlamydial infection should be done routinely by suitable tests in sexually active symptomatic and asymptomatic women including pregnant women to prevent serious complications. PMID- 21522086 TI - Ultrasonographic evaluation of contralateral exploration of patent processus vaginalis in unilateral inguinal hernia. AB - To see accuracy of ultrasound scan to detect patent processus vaginalis in padiatric patient. We investigated the presence of contralateral patent processus vaginalis (CPPV) by Ultrasound scan (US) in children with clinically diagnosed unilateral inguinal hernia. Thirty patents (17 boys and 13 Girls) with unilateral inguinal hernia underwent US examination using a 7.5 MHZ transducer. If a CPPV was visible as a hydrocele (inflow of peritoneal fluid) in to a processus vaginalis on straining, then US scanning was performed while the patient was at rest and while inducing straining by standing, coughing and or crying. A groin with hydrocele in the inguinal canal on straining was diagnosed as a CPPV and was explored bilaterally through surgery. The US findings were compared with surgical results. In 30 patients, 12 cases were diagnosed by US as patients with a CPPV, these patients underwent bilateral surgery. Eleven of 12 Cases were confirmed surgically as CPPV. From the findings of the present study it could be concluded that a PPV could be correctly detected by US in pediatric patients with the accuracy of 91.67%. US is a non invasive and accurate method for evaluating the presence of a PPV. Preoperative diagnosis of CPPV is important to remove the need for a second operation with patients presenting with unilateral inguinal hernia. PMID- 21522087 TI - Drop-out and admission cancel rate among the students in a selected medical college. AB - A record based descriptive type of study was carried out among the under-graduate students of Mymensingh Medical College from the session 1966-67 to 2006-07. The academic years were divided into four decades and admission was followed into three categories such as retained, cancellation and drop-out. Total number of the students was 5892. Among them 3848(65.30%) were male and 2044(34.69%) were female. Out of 5892 students drop-out was 282(4.78%) and admission cancel was 304(5.15%). It was also found that drop-out in male was 232(6.02%) and in female was 50(2.44%) and admission cancel in male was 266(5.87%) and in female was 78(3.81%). The difference was found statistically significant (p<0.001). It was observed that gradually the drop-out and admission cancel rate is decreasing from the very beginning to till now. It was also observed that all drop-out and admission cancellation were in first & second year students. There was no continuation of their class roll numbers in third year registration. PMID- 21522088 TI - Comparison between tramadol hydrochloride & nalbuphine hydrochloride in the treatment of per-operative shivering after spinal anaesthesia. AB - Per-operative shivering following spinal anaesthesia is a common problem in the operation theatre. Adequate management of shivering during operation is one of the goals of anesthesiologists for the benefit of the patient. Because there are many unpleasant and harmful effects caused by shivering in many patients especially respiratory and cardiac disease patients. For this reason aggressive and optimal treatment of per-operative shivering is essential to reduce the morbidity of the patients. Our observations were that occurrence of shivering was more in younger patients than older patients, thin patients than obese patients, anxious patients than non-anxious patients and more frequent in patients who received vasoconstrictor drugs, administration of fluid at running rate just before or during operation, administration of cold local anaesthetic agents (by taking drug from the freeze) into subarachnoid space. And shivering was better managed by administration of nalbuphine HCl and surface skin warming (wrapping of the skin). There are many studies regarding the incidence, prevention & treatment of post-operative shivering but there is no study regarding the incidence & treatment of per-operative shivering by nalbuphine following spinal anaesthesia. This study was designed to compare the anti-shivering efficacy and side effects (Nausea, Vomiting, and Somnolence) of tramadol hydrochloride with that of nalbuphine hydrochloride in the treatment of per-operative shivering following spinal anaesthesia. This study was also done to observe the incidence of shivering during operation following spinal anesthesia. PMID- 21522089 TI - Mineral homeostasis in children with acute lymphoblastic leukemia before and after chemotherapy. AB - A prospective study was carried out in the Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh to evaluate the pattern of mineral changes in children treated for acute lymphoblastic leukemia (ALL) before and after induction chemotherapy. A total number of 32 children aged 1-14 years of both sexes were evaluated. Serum calcium, phosphate, alkaline phosphatase, albumin and creatinine and urinary creatinine and calcium were estimated in cases and control. The mean calcium level at presentation and post induction was 9.50+/ 1.48 mg/dl and 9.08+/-1.30 mg/dl. Serum phosphate was higher in preinduction mean of 4.83+/-2.71 mg/dl than post induction value of 4.75+/-1.38 mg/dl and it was statistically significant. Serum alkaline phosphatase was higher in the post induction period. It was 324.8+/-128.17 U/L in pre induction and 331.59+/-93.97 u/l in post induction period. It was not statistically significant. No statistically significant difference was found in pre and post induction urinary calcium and creatinine. PMID- 21522090 TI - Maternal over weight and obesity: its effect on pregnancy outcome. AB - Obesity in pregnancy remains a significant health problem that result in physiological, emotional, social and economic consequences on woman, their families and society. Obesity is considered one of the nutritional problems complicating pregnancy in our country. This study was conducted in antenatal clinic at out patient department of Obstetrics & Gynecology, BIRDEM Hospital, one of the countries largest tertiary level hospitals, during January 2007 to December 2008. During the study period of two years, a total no. of 100 cases were enrolled in two groups. Out of this 50 were control and 50 were over weight and obese. In this study, Mean of height, weight and BMI of the over weight and obese group were 5.21+/-0.21, 79.35+/-13.66, 32.36+/-4.76 respectively. The Mean of birth weight, APGAR score after 1 min and after 5 min of the over weight and obese group were 3.07+/-0.75, 7.10+/-1.11, 9.92+/-0.98 respectively and in normal weight group were 2.74+/-0.55, 7.40+/-1.56, 9.92+/-1.83 respectively. There was significant difference in birth weight, APGAR score after 1 min between the groups (p<0.05) but there was no significant difference in APGAR score after 5 min between groups (p>0.05). Regarding the fetal outcome in this study, 20% of the over weight and obese group delivered macrosomic baby in comparison to only 4% in the normal weight group. On the other hand 46% of the case group had to refer their babies to the neonatal unit in comparison to only 12% in the control group. Gestational Diabetes Mellitus (GDM) (46%) and Preeclampsia (44%) developed more in obese group. Eighty eight (88%) of obese and overweight mother experienced in caesarean delivery. Asphyxia, Respiratory Distress Syndrome (RDS), congenital anomaly and prenatal death were more in the over weight and obese group than normal weight group. Thus, overweight and obesity has got significant deleterious effect on maternal and perinatal outcomes of pregnancy. PMID- 21522091 TI - Phytoestrogen intake and cardiovascular risk markers in Bangladeshi postmenopausal women. AB - Menopause is the transitional event of female life creating a considerable degree of clinical and psychological as well as social problem and it is known to affect the risk markers of cardiovascular diseases. Hormone replacement therapy (HRT) was though to be a cornerstone in the management of menopause, but evidences accumulated in the recent past have raised serious questions regarding its safety and usability. In this context, phytoestrogens are getting increasingly more attention for therapeutic (as an alternate of HRT) and dietary interventions. Menopause is a special problem for women in developing countries and intake of phytoestrogens can be highly useful also from the economic point of views. The nutraceuticals of specific vitamins, minerals and especially phytoestrogens supplementations are a vital component of the strategy to reduce health problem. The present study was aimed to assess the association of phytoestrogens and risk markers of cardiovascular diseases in postmenopausal women. A total of 111 postmenopausal subjects [age, (years, M+/-SD) 52+/-5.35] were studied. The dietary intake of phytoestrogens by study subjects was calculated by a specific food frequency questionnaire (FFQ). Serum fasting homocysteine was measured by AxSYM system. Serum glucose was estimated by glucose-oxidase method. Serum total cholesterol, triglyceride and HDL-C were estimated by enzymatic-colorimetric method LDL-C was estimated by the Friedewald's formula. The intake of total phytoestrogens, isoflavones and lignans (mean+/-SD, mg/day) were 7.65+/-3.33, 0.32+/-0.16, 7.32+/-3.28 respectively in postmenopausal women. The intake of diadzein, genistein, formononetin, biochanin A (mean+/-SD, mg/day) were 0.085+/ 0.035, 0.168+/-0.101, 0.074+/-0.052 and 0.001+/-0.0008 respectively. The intake of matairesinol and secoisolaiciresinol (SILR) (mean+/-SD, mg/day) were 0.022+/ 0.006 and 7.30+/-3.28 respectively. The total phytoestrogens (r=-0.19, p=0.03) and SILR, one specific type of lignans (r=-0.19, p=0.04) consumption in this study were inversely significantly associated with serum glucose level. The dietary formononetin, one specific type of isoflavones was negatively significantly associated with LDL-cholesterol (r=-0.18, p=0.04). There was no significant relationship found between phytoestrogen intake and serum homocysteine level (r=-0.11, p=0.23). Phytoestrogens containing food intake should be encouraged for reducing risk markers of cardiovascular disease in postmenopausal women. PMID- 21522092 TI - Evaluation of existing curriculum (2002) of undergraduate medical education in Bangladesh. AB - This study was conducted for evaluation of existing MBBS curriculum (2002) of undergraduate medical education in Bangladesh. The specific objectives of this study were: i) to assess the subject wise course content coverage in the new MBBS curriculum, ii) to assess different examination system for evaluation of MBBS students, iii) to evaluate the effectiveness of teaching and learning activities under the curriculum, iv) to explore students opinions regarding improvement of new curriculum. This was a descriptive cross-sectional study. The study was conducted among the students of Dhaka medical colleges of Bangladesh in 2008. Data was collected by self administered structured questioner adopting convenient sampling method. About ninety percent students opined that the coverage of course content of subjects in the curriculum in Phase I was enough. In case of the subjects in phase II except community medicine more than four fifth of the students expressed their opinion about coverage of course content in the curriculum as enough. In case of phase III it was mentioned by most of the students that coverage of course content was enough. Study revealed that teaching methods were perceived suitable by about three fourth of the respondents, to achieve learning objectives. Most of the students expressed their positive views regarding practice of block posting teaching. More than three fourth of the students perceived that formative assessment was encouraging for students to become time bound learner and Structured Oral Examination (SOE) was fair on an average. Only 31(8.6%) of the respondents had opinion that Objective Structured Practical Examination (OSPE)/Objective Structured Clinical Examination (OSCE) was not well organized. About half of the students opined that 20% marks in written test should be allocated for Multiple Choice Question (MCQ). Students' suggestions regarding teaching were: there should be smaller group sessions; more interactive sessions; more clinical and practical sessions; more problem oriented sessions; more sessions with senior and experienced teachers; teachers should follow the curriculum properly; and should be well prepared for class. Regarding assessment suggestions were: written script of the formative examination should be returned to students with feedback; teachers should not be biased. Study recommended that training of the teachers on teaching methodology and assessment system is needed; teachers should provide feedback to the students according to the performance of the formative assessment at the individual level; to maintain the standards of assessment proper planning, designing, conduction and evaluation of assessment should be taken into consideration; subject wise review and updating is essential to make the curriculum more need based, user friendly and applicable considering context of Bangladesh. PMID- 21522093 TI - Tubercular lymphadenitis - diagnostic evaluation. AB - Tuberculosis is one the commonest disease affecting peripheral lymph node and cervical tubercular lymphadenitis are frequently encountered in Otolaryngological practice. Three hundred fifty six (356) cases of Fine Needle Aspiration for Cytology (FNAC) positive tubercular lymphadenitis were studied from January 2006 to December 2008. FNAC positive but histopathologically negative cases were excluded from the study. Among 356 cases of FNAC positive cervical lymphadenopathy 300 cases (84.27%) were confirmed tuberculosis on histopathological examination. Remaining 50 cases (15.73%) were diagnosed as nontubercular lymphadenitis where nonspecific lymphadenitis was the commonest finding 34(9.55%) followed by metastatic carcinoma 7(1.97%), lymphoma 6(1.08%), Kikuchiz's disease 6(1.08%), Kala-Azar 2(0.56%) & Leukemia 1(0.28%). Most of the patients presented with only multiple lymph node swelling with other symptoms, such as fever 18(5.06%), pain (15.7%), tenderness 53(14.88%), weight loss 29(8.14%), anorexia 33(9.26%). Following observations are evident from this study: i) Disease is comparatively common between 12-35 years ii) Multiple matted/discrete lymph nodes are the earliest presentation iii) Multiple lymph node is the most consistent finding for clinical diagnosis. iv) Very few patients have constitutional symptoms v) Suppuration with or without abscess formation although confirms the diagnosis even then certainty is very essential. Though the evidence of cervical tuberculosis was thought to be decreasing in developing countries the real picture seems to be different. Random survey among the whole population was not done in any country rather hospital based laboratory research was made. PMID- 21522094 TI - Analysis of post operative complications following total thyroidectomy. AB - This prospective study was carried out to find out the incidence and nature of post operative complications following total thyroidectomy in the management of carcinoma thyroid and multinodular goiter and to analyze the factors which are related with the development of complications. Study was done in the Department of ENT & Head-Neck Surgery, Surgery, Bangabandhu Sheikh Mujib Medical University and Department of ENT & Head-Neck Surgery, Dhaka Medical College Hospital, Dhaka, Bangladesh from April 2006 to September 2006. Fifty patients (50) were included prospectively for this work. The patients were between 12-63 years of age with a maximum incidence in 4th decade. Female was the predominant sex with a ratio of 4.55:1. Twenty eight patients were suffering from papillary carcinoma. Nine patients were suffering from follicular carcinoma, four patients from medullary carcinoma and nine patients from multinodular goiter. Out of 50 patients, 14(28%) developed complications. The complications were haematoma (4%), recurrent laryngeal nerve palsy (6%), hypoparathyroidism (16%) and wound infection (2%). All of them suffered from temporary complications except one patient, who suffered from persistent hypoparathyroidism. Recurrent laryngeal nerve paralysis in all three cases was unilateral. Complications were relatively more common in male. In carcinoma patients the rate of complications was more than twice than the multinodular goiter cases. Among the carcinoma cases, 7.31% cases developed recurrent laryngeal nerve paralysis and 19.51% cases developed hypoparathyroidism. From this study it is observed that a good number of patients still suffer from complications following total thyroidectomy. PMID- 21522095 TI - Human rabies among the paediatric population in Bangladesh. AB - This cross sectional study in the Infectious Disease Hospital (IDH), Mohakhali, Dhaka on rabies affected paediatric population was carried out to see the patterns of presentation, age group at risk, state of vaccination following animal exposure and the interval between animal exposure and the development of the disease. This one year study included the patients aged less than 15 years with clinically diagnosed rabies referred to the IDH between July 2008 and June 2009. Data was collected from the case sheets of rabies patients given by the relatives and attendants of the victims. A total of 70 cases were included in the study. In the present study most common age group were 5 to 10 years of age with 31(44.3%) patients followed by less than 5 years 23(32.9%) and the rest 16(22.9%) were more than 10 years of age. The male female ratio was 3:1. Among the 70 patients 59(84.3%) were from rural areas and only 11(15.7%) were from urban areas. Sixty six (94.3%) patients presented with bleeding from the site of injury and 4(5.7%) were without bleeding. Among the patients 53(75.7%) presented with bite on the limbs followed by bite on the face 8(11.4%), body 5(7.1%) and head 4(5.7%) cases. Thirty nine of the cases (55.7%) presented with multiple bites and 31(44.3%) had single bite. More than half that is 37(52.9%) patients presented with severe bite, 31(44.3%) had moderate bite and only 2(2.9 %) patients presented with mild bite. Fifty nine (84.3%) patients were unvaccinated whereas 11(15.7%) had history of vaccination after bite. Fifty two (74.3%) gave the history of bite by stray animal, 10(14.3%) by known rabid animal whereas 8(11.4%) had the history of bite by pet animal. Sixty eight patients (97.1%) had the history of bite by dog whereas 2(2.9%) reported cat bite. The mean+/-SD incubation period 45.38+/-26.91 days and range was 11-150 days. In the present study it is concluded that the 5-10 years group children were affected most, bites were mostly by stray animal, most of the children did not get post exposure prophylaxis and incubation period was between 11 to 150 days. PMID- 21522096 TI - Role of magnesium sulphate in the treatment of hypomagnesaemia in eclamptic patients. AB - Hypomagnasaemia has been identified as one of the main causes of eclampsia and preeclampsia which causes maternal and fetal/neonatal morbidity and mortality. In spite of wide difference of opinion about the best anticonvulsant, magnesium sulphate, diazepam and phenytoin are currently the mostly widely used anticonvulsants. The present study tried to find out the role of MgSO4 in correcting hypomagnasaemia in eclamptic women in Bangladesh. The study included 60 healthy (non eclamptic) 60 eclamptic women and was carried out in two hospitals of Dhaka city, during January 1999 to June 2000. Required tests were done in the Department of Biochemistry, BSMMU. Comparison of pretreatment clinical parameters between the two study groups showed highly significant (p<0.001) differences, MgSO4 level, pulse rate, systolic and diastolic blood pressure, and respiratory rate. After the case group of women was treated with MgSO4, the clinical parameters, pulse rate, systolic and diastolic blood pressure, and respiratory rate, between control and case groups showed no significant differences. However, serum magnesium level in case group increased to 3.41+/-0.21 mg/dl from pretreatment level of 1.02+/-0.26 mg/dl, and when compared to control (2.25+/-0.26 mg/dl), the increase was highly significant (p<0.001). It may be concluded that correction of hypomagnesemia may help to improve eclamptic situation. PMID- 21522097 TI - Role of oral clonidine on intraopereative haemodynamic stability for craniotomies of intracranial space occupying lesion. AB - This was an analytical comparative study. Aim of this study was to observe the effect of oral clonidine on intra operative haemodynamic stability in intracranial space occupying lesion (ICSOL) patients who underwent craniotomy. Total 60 patients were distributed into case and control group. Number of cases was 30 in each study group of this study. Mean age of experimental and control were significantly close to each other. Baseline weight, pulse, systolic blood pressure, diastolic blood pressure and mean pressure also showed a significant similarity between each group. Variable of each group was collected during different events of craniotomy. All variable of pulse, systolic blood pressure, diastolic blood pressure and mean pressure were tabulated by line chart and fluctuation of variable was measured by significance test. The fluctuation of mean pressure was respectively 11.6%, 11.2%, 12.4%, 11.4%, 14.2%, 15.6%, 10% and 9.4% in different events of craniotomy in hemodynamically unstable group and it was respectively 11.1%, 10.9%, 10.4%, 9.9%, 9.2%, 9.4%, 8.6% and 8.7% in hemodynamically stable group. 'P' value was less than 0.05. It was observed that fluctuation of haemodynamic parameters were significantly less in experimental group where oral clonidine was used as premedication. PMID- 21522098 TI - Effect of hydration with or without n-acetylcysteine on contrast induced nephropathy in patients undergoing coronary angiography and percutaneous coronary intervention. AB - Contrast induced nephropathy (CIN), an acute decline in renal function after the administration of intravenous contrast in the absence of other causes, is the third leading cause of acute renal failure in hospitalized patients. Antioxidant N-acetylcysteine prevents acute contrast nephrotoxicity in patients with impaired renal function who underwent coronary angiography (CAG) and percutaneous coronary intervention (PCI). Hydration is the cornerstone in preventing CIN. N acetylcysteine has additive preventive affect. We compared N-acetylcysteine plus hydration with hydration alone in preventing CIN. Patients were assigned to receive either premedication with hydration with normal saline (1ml/kg/hour-12 hour before and 12 hour after CAG and intravenous PCI) alone or to receive both hydration and oral N acetylcysteine (600mg bid for 2 days, starting day before CAG and PCI). Main out come was occurrence of >=25% or >=0.5mg/dl increase in serum creatinine level within 24 to 48 hours after contrast administration; change in creatinine clearance and serum creatinine level. Six patients (12%) of hydration group i.e. Group A and none of the patients of N-acetylcysteine All group i.e. Group B develop CIN (p=0.012). Baseline serum creatinine level was slightly higher in N-acetylcysteine group than hydration group (1.52+/-0.32 and 1.44+/-0.22). After 24 hours of CAG and PCI serum creatinine level lower than base line in N-acetylcysteine group but slightly higher than base line in hydration group (1.42+/-0.39 and 1.51+/-0.38). Difference in serum creatinine in both the groups were statistically significant (p=0.006 in N-acetylcysteine group and p=0.029 in hydration group). Creatinine clearance rate significantly improved in N-acetylcysteine group after coronary intervention. In conclusion, N acetylcysteine and hydration prevent CIN better than hydration alone in high risk patients. PMID- 21522099 TI - Contrast induced nephropathy in patients with pre-existing renal impairment undergoing coronary angiogram and percutaneous transluminal coronary angioplasty. AB - Contrast induced nephropathy is the third leading cause of acute renal failure in hospitalized patients. However, its incidence and risk factors in Bangladeshi population undergoing coronary angiogram and percutaneous coronary intervention is not clear. This study was to assess the incidence of contrast induced nephropathy in patients, with or without pre existing renal impairment, undergoing coronary angiogram and percutaneous transluminal coronary angioplasty in Bangladeshi population. Two hundred patients undergoing coronary angiogram and percutaneous were included in the study .Patients having history of contrast allergy and patients on renal dialysis were excluded from the study. Serum creatinine level was estimated before the undergoing procedure. Creatinine clearance rate was calculated by applying Cockcroft Gault formula to the preprocedure serum creatinine level. Patients were assigned to one of the two groups, that is with or without chronic renal insufficiency. Serum creatinine levels were again estimated at the end of 24 hours of contrast exposure. The rise of serum creatinine by >=0.5mg/dl or >=25% occurring within 24 hours of contrast administration was defined as contrast induced nephropathy. The incidences of Contrast induced nephropathy (CIN) in these groups were compared. We tried to analyze whether there is relation between the incidence of CIN with contrast volume, chronic renal insufficiency, diabetes mellitus, and coronary procedures undergone. We enrolled 120 pre existing chronic renal insufficiency patients and 80 patients without pre existing chronic renal insufficiency. In this study 21.7% of pre existing chronic renal insufficiency group and 6.3% of no pre existing chronic renal insufficiency group developed contrast induced nephropathy (p=0.003). Contrast induced nephropathy is an iatrogenic disorder and pre existing renal impairment is one of the risk factors for developing contrast induced nephropathy. PMID- 21522100 TI - Association of cardiac ischemic score and coronary collateral circulation. AB - Coronary collateral circulation maintains myocardial perfusion in coronary atherosclerotic disease. The indicators of cardiac ischemia, (Angina pectoris on exertion, during emotion, previous myocardial infarction and prior coronary intervention) are associated with presence of coronary collateral circulation. In this prospective observational cross sectional study, 128 patients with history of angina pectoris on exertion and or during emotion and or myocardial infarction and or previous coronary intervention were enrolled. The cardiac ischemic score (range 1-4) was calculated by adding 1 point for each of the above four clinical factors, which can be easily assessed. Presence of coronary collaterals in coronary angiogram was defined as Rentrop grade >=1. Patients were divided into two groups. Group A patients having Rentrop grade 0 and Group B patients are with collateral circulation, having Rentrop grade 1-3. Patients having cardiac ischemic score (range 1-4) are compared in these groups. Maximum (83.3%) patients of Group B with coronary collateral circulation had cardiac ischemic score 2-4, but majority (86.4%) of Group A patients without collaterals showed the score only 1. Thus the cardiac ischemic score is strongly associated with the presence of coronary collaterals. PMID- 21522101 TI - Quantitative macroscopic study on preterm placenta in gestational diabetes mellitus and pregnancy induced hypertension. AB - Preterm birth is the major cause of perinatal mortality and morbidity. During the last decade, it has become an important issue in public health policies of developing countries. Gestational diabetes mellitus and Pregnancy induced hypertension are two important high-risk factors for preterm birth. The proposed study aimed to make a macroscopic analysis on the functional tissues (Parenchymal tissues) in preterm placenta in respect of Gestational diabetes mellitus (GDM) and pregnancy induced hypertension (PIH). The study was observational and cross sectional. The patients under this study were selected from the Obstetric ward of BSMMU and BIRDEM hospital, from June 2005 to October 2005. Sixty-six samples were collected from women during 28 weeks to 36 weeks of gestation. Among them, twenty two samples were from gestational diabetic mothers, twenty-two were from pregnancy induced hypertensive mothers and twenty-two were from mothers who were non-diabetic and non-hypertensive in current pregnancy. Placentas were fixed and preserved in 10% formal saline solution. The volume proportions of parenchymal and non-parenchymal components were measured by using a point counting technique on formalin fixed placentas. In this study, the GDM group had significantly more absolute volume and mean proportional volume of the parenchyma but less mean proportional volume of the non-parenchyma when compared with Control and PIH group. However, the PIH group had significantly less absolute volume of the parenchyma than the control group and the mean value of the absolute volume of non parenchyma was also less than control value but did not reach a significant level. The results obtained from diseased and control groups demonstrated a significant change in some events, and some trends were also observed among these groups. However, it could be suggest that, in these two pregnancy-induced disorders, there is placental insufficiency where the placenta tries to exert its reserve capacity by changing its functional structures and consequently overcomes the possible damage to the fetus. PMID- 21522102 TI - Awareness about organ donation among school girls. AB - Prevalence of organ failure is high through out the world. Organ transplantation, the definitive treatment option of organ failure keeps very low due to scarcity of organ. Most of the people are not aware about organ donation. Adolescent girls will be the mother of future nation and they can motivate family members for organ donation. This study was carried out to see attitudes towards organ donation and determine the negative factors of organ donation prevailing among school girls. One hundred sixty eight girls from class VIII to class X of a higher secondary school were participated. A structured questionnaire was filled up by the girls. The data were processed from questionnaire and analyzed. Among study population, most of them (64%) had no idea about on going organ donation and transplantation. The positive attitude of the girls towards organ donation was low when they are live (16%) and their attitudes also kept low even after their death (14%). The girls who did not agree to donate organ were further asked to mention the reasons. The reasons of negative attitude were religious belief, fear of illness and social and familial reservation. The result of this study suggests that among girls, awareness and attitudes about organ donation is poor. There were several reasons identified for low consent rates. Multidisciplinary actions should be taken to improve the awareness of the people about organ donation and motivate them for donation. PMID- 21522103 TI - Study on primary cesarean section. AB - Cesarean delivery has become a commonly used measure for delivery of the fetus. In the recent years incidence of Cesarean section (CS) has increased dramatically with massive pubic interest. It is called Primary Cesarean section when it is performed for the first time on a pregnant woman. This is a cross sectional study conducted on primary cesarean section from January to December 2004 in Bangabandhu Sheikh Mujib Medical University (BSMMU) Hospital, Dhaka. A total of 100 cases were selected for the study. The major findings of the study were as follows: Overall cesarean section rate was 57.87 percent and among them 74.34 percent were primary cesarean section. The median age group of patients being operated was 20 to 25 years. Most of the operations were carried out on primigravid patient due to various indications. The main indications were fetal distress (35%), pre-eclampsia (14%) and cervical dystocia (12%). The rate of emergency Cesarean section rate was 70% while elective Cesarean section was 30%. Most of the Cesarean section was performed under spinal anesthesia (96%). Maternal morbidity was 20%. Among those, post-operative infections (45%) and UTI (25%) were the most common. The less common complications were Post Partum Haemorrhage (PPH), puerperal-pyrexia, urinary bladder injury and spinal headache. 88% of the babies were born with good APGAR score (Appearance, Pulse, Grimace, Activity, and Respiration). Perinatal mortality was found to be 4%. The death cases were severe perinatal asphyxia, very LBW (Low Birth Weight) and stillborn. Most of the patients (69%) were discharged from hospital within 8 days of operation. PMID- 21522104 TI - The length of main pancreatic duct in Bangladeshi cadaver at different age groups. AB - The anatomy of the pancreatic ductal system has received attention because of its importance in pancreaticobiliary diseases. Any blockage in pancreatic ductal system needs emergency maneuver. A full understanding of the variations in pancreatic ductal pattern is essential in the diagnosis and treatment of pancreatic diseases. In an attempt to gather data on the length of main pancreatic duct the present study was carried out on the pancreas of Bangladeshi male cadaver. The descriptive cross-sectional study was carried out in the department of anatomy Dhaka Medical College from October 2008 to September 2009. Total 50 human pancreatic duct were studied. The samples were divided into 7 different age groups ranged from 10-70 years and above 70 years. Length of the main pancreatic duct was measured in fresh samples by x-ray. Length of the main pancreatic duct of formol saline fixed pancreas was measured in situ and after removal from pancreatic tissue. The results of the present study show that the length of the main pancreatic duct increases with age. In all groups length of the main pancreatic duct was more after total removal from pancreas than in situ and x-ray. The mean+/-SD length of main pancreatic duct was 14.34+/-3.10 cm, 16.13+/-3.26 cm, 12.88+/-3.28 cm in situ, after total removal and in X-ray respectively. Further studies with large sample in both sexes are recommended. Measurement of bendings of ductal course, number of pancreatic ducts and corrosion casts of pancreatic ducts are recommended. The comparison between endoscopic retrograde cholangio pancreatography (ERCP) findings and the cadaveric dissected specimen findings should also be done. PMID- 21522106 TI - Testicular tumour - a diagnostic dilemma. AB - A 45 year-old man presented to us with upper abdominal lumps of different sizes with heaviness and mild pain. He underwent two surgeries previously one was right sided orchidectomy through scrolal incision and another one laparatomy which was done four months later of 1st one. But in both situations - no biopsy were taken & failed to establish a diagnosis. On the basis of clinical, bio-chemical and radiological examinations - it was a diagnostic dilemma. Then we performed laparotomy followed by debulking and biopsy was taken for histopathological examination. It revealed metastatic teratoma of testis. PMID- 21522105 TI - Outcome of pregnancies after inadvertent exposure to GnRH agonist in early pregnancy. AB - Four pregnancies were exposed to gonadotrophin-releasing hormone agonist (GnRHa) during early pregnancy and the patients were followed up to find out the outcome of their pregnancies. In three patients long-acting GnRHa (triptorelin acetate 3.75 mg) once monthly was used for severe pelvic endometriosis as part of preparation for undergoing assisted reproductive technology (ART) cycle, and in one patient daily injections of short-acting GnRHa (buserelin 0.05 mg) was given for down-regulation for ART cycle. The age of the patients ranged from 29 to 38 years and duration of infertility was 3 to 13 years. In patients prescribed long acting GnRHa, diagnosis of pregnancy was done late at around 5-8 weeks by ultrasonography, whereas in patients using short-acting GnRHa diagnosis of pregnancy was made with blood beta human chorionic gonadotropin (HCG) level after the 26th day of injections. Three pregnancies were delivered around term and the babies had no apparent complication or any congenital anomaly. One of the pregnancies ended up into spontaneous abortion at 14 weeks of pregnancy. The children were regularly examined by pediatricians regarding physical and mental development and for any abnormal behavioral problems. All of them are normal till now. PMID- 21522107 TI - Melanotic neuroectodermal tumour of infancy. AB - Melanotic neuroectodermal tumour in infancy is rare, mainly benign with little tendency to recur after excision or effective curettage. This pigmented neoplasm of neural crest origin occurring in infants before 1 year of age. The most common site of occurrence is the anterior maxillary alveolar ridge (70%), following by the skull, brain and mandible. The genital organ is the most frequent extra cranial site. We report a 6 months old male baby with a similar tumour arising from right half of cheek involving the maxilla. We diagnosed the case after histological report. We remove the tumour through a sub-labial incision. The mass was blackish in colour, and was mobilized from all side including from the maxillary sinuses. The author thought that this should be reported for improving the clinical awareness and treatment of pigmented soft tissue mass in children. Almost one year follow up of the patients showed no recurrence. PMID- 21522108 TI - Recurrent synovial chondromatosis of the foot. AB - Synovial chondromatosis rarely occurs in the foot. We have diagnosed such a case in National Institute of Cancer Research and Hospital, Mohakhali, Dhaka. The patient came to us with a swelling in the dorsum of left foot. He had a history of operation but one year later swelling reappeared in the same place. Fine Needle Aspiration Cytology (FNAC) of the swelling revealed few atypical cells and diagnosed as a case of malignant neoplasm. Later on surgical intervention was done in the form of wide excision and final histopathology report came as Synovial chondromatosis. No special treatment was given other than periodical follow up. The patient has been responding well. There was no clinical or radiographic evidence of recurrence. PMID- 21522109 TI - Primary tuberculosis of breast. AB - Primary tuberculosis of breast is not uncommon in developing countries. Initial presentations may be confused with benign or malignant lesions of breast. Diagnosis in endemic areas is suggested on clinical consideration. FNAC and/or biopsy confirm the diagnosis. The adequate anti-tubercular chemotherapy is essential for sustained resolution of mammary tuberculosis. We have a case of primary tuberculosis of breast in a young female with complete follow up to be reported. We treated a 22-year-old married female patient who was admitted with an ulcerated lump over the right breast. Initially ultrasonographic scanning and FNAC from the lump suggested a breast abscess. She was treated surgically as breast abscess which failed to resolve in due course. Provisional diagnosis was breast abscess. Breast malignancy or granulomatous inflammation could not be excluded. On elective lumpectomy and subsequent histopathological examination of the lump could confirm the diagnosis of tuberculosis of breast. We failed to discover any tuberculous lesion over other sites of the body. The patient was treated postoperatively with anti-tubercular chemotherapy. On follow up after six months, she was reasonably healthy. Chemotherapy is continued for another two months. Follow up is being continued for next two years. PMID- 21522110 TI - Successful outcome of gestation in a young woman with severe oesophageal varices throughout the pregnancy. AB - During normal pregnancy there is an increase in the maternal blood volume leading to portal hypertension with some changes in liver functions. However, in an apparently healthy woman without known liver cirrhosis or other advanced liver disease, severe oesophageal varices with along with repeated variceal bleeding during pregnancy is rare. In this paper we described a case of severe oesophageal variceal bleeding in a young woman without having any pre-existing liver pathology. Due to repeated pregnancy with short intervel bleeding the patient developed severe anaemia. Packed cell transfusion was done repeatedly and oesophageal variceal ligation (EVL) was done three times. In spite of these measures variceal bleeding continued and patient's condition was deteriorating progressively; so caesarean section was at 33rd week of gestation and a preterm but healthy baby was delivered. The puerperium was uneventful with no haematemesis and there was gradual improvement of the condition. A brief review of the literature on pregnancy with oesophageal varices is also presented. PMID- 21522111 TI - Methicillin resistant Staphylococcus epidermidis. AB - Staphylococcus epidermidis is an emerging nosocomial pathogen. Due to its increasing incidence in many countries of the world it is a burning issue now a day. There is marked geographic variation in prevalence of methicillin resistant Staphylococcus epidermidis. Though it as is an endogenous human skin flora, it is therefore easily transmissible in the hospital environment well as in a community. Skin of patients and health care workers, medical equipment, clothing of personnel and environment surfaces can be sources of antibiotic-resistant S. epidermidis strains. This opportunistic pathogen causing different types of infections linked to implanted medical devices especially in immunocompromised patients. Early and specific diagnosis is important to ensure a favourable outcome. So Staphylococcus epidermidis found in culture should not always be ignored as contaminant and proper medical treatment and preventive guidelines should be applied against this alarming pathogen. PMID- 21522112 TI - 18F-fluorodeoxyglucose uptake in tumor. AB - The 18fluorine-fluorodeoxyglucose (18F-FDG), a glucose analog, has been widely used in tumor imaging. The tumoral uptake of 18F-FDG is based upon enhanced glycolysis. Following administration, 18F-FDG is phosphorylated and trapped intracellularly that forms the basis of PET imaging. An important mechanism to transport 18F-FDG into the tumor cell is based upon the action of glucose transporter proteins; furthermore, highly active hexokinase bound to tumor mitochondria helps to trap 18F-FDG into the cell. In addition, enhanced 18F-FDG uptake may be due to relative hypoxia in tumor masses, which activates the anaerobic glycolytic pathway. In spite of these processes, 18F-FDG uptake is relatively nonspecific since all living cells need glucose. Clinical application of 18F-FDG imaging is therefore recommended in carefully selected patients. PMID- 21522114 TI - Hepatitis C: Impact of ethnicity on hepatitis C treatment outcomes. PMID- 21522113 TI - Tuberculous otitis media. AB - Tuberculosis is one of the most common infectious diseases of developing countries including Bangladesh. It rarely affects the middle ear. The objective is to review the literature on tuberculous otitis media and know the facts, incidence, etiology, clinical presentation, investigations and treatment of tuberculous otitis media. It is characterized by painless otorrhoea which fails to respond to the usual antimicrobial treatment, in a patient with evidence of tubercle infection elsewhere followed by multiple tympanic membrane perforations, abundant granulation tissue, and bone necrosis, preauricular lymph node enlargement. Loss of hearing is also found in patients with development of the diseases seen by the otoscopy. Combination chemotherapy is prescribed. Surgery may be required in some cases to remove sequestra and improve drainage. A high level of clinical suspicion is needed for early diagnosis and antitubercular therapy should be started as soon as possible to prevent the possible complication. PMID- 21522115 TI - Cancer: HDL cholesterol and cancer risk. PMID- 21522117 TI - Biopsy: Desmopressin reduces risk of bleeding after percutaneous kidney biopsy. PMID- 21522116 TI - Treatment and surveillance strategies in achalasia: an update. AB - Controversy exists with regard to the optimal treatment for achalasia and whether surveillance for early recognition of late complications is indicated. Currently, surgical myotomy and pneumatic dilation are the most effective treatments for patients with idiopathic achalasia, and a multicenter, randomized, international trial has confirmed similar efficacy of these treatments, at least in the short term. Clinical predictors of outcome, patient preferences and local expertise should be considered when making a decision on the most appropriate treatment option. Owing to a lack of long-term benefit, endoscopic botulinum toxin injection and medical therapies are reserved for patients of advanced age and those with clinically significant comorbidites. The value of new endoscopic, radiologic or surgical treatments, such as peroral endoscopic myotomy, esophageal stenting and robotic-assisted myotomy has not been fully established. Finally, long-term follow-up data in patients with achalasia support the notion that surveillance strategies might be beneficial after a disease duration of more than 10-15 years. PMID- 21522120 TI - Surgery: colonic stenting no better than emergency surgery? PMID- 21522119 TI - Transplantation: 5-year benefits of rituximab for ABO-mismatched renal grafts. PMID- 21522121 TI - Clinical implications of cancer self-seeding. AB - Most metastatic cancers are incurable--a fact that underscores the limitations of our existing paradigms for understanding metastasis. In this Review, we use breast cancer to explore many of the enigmas revealed by these existing paradigms. Traditionally, metastatic models describe metastasis as a unidirectional process, whereby cancer cells leave a primary tumor and unidirectionally seed metastasis in regional lymph nodes or distant sites. By contrast, recent data indicate that metastasis is a multidirectional process whereby cancer cells can seed distant sites as well as the primary tumor itself. This later process, known as 'self-seeding,' has been validated in diverse experimental models. Here, we show that the self-seeding model may answer many of the mysteries inherent to cancer metastasis. Indeed, reframing our understanding of metastasis within the self-seeding model offers new opportunities for prevention and cure of metastatic cancer. PMID- 21522122 TI - Opportunities and pitfalls of cancer imaging in clinical trials. AB - Cancer treatment strategies have changed considerably over the past two decades, with increasing emphasis on cancer-specific biological therapies. This situation has led to the incorporation of biomarkers, including those obtained by medical imaging, into trial designs to better understand mechanisms of action and, hopefully, to provide early evidence of treatment efficacy at a molecular or physiological level. Unlike blood tests and tissue samples, an imaging biomarker allows assessment of treatment in the whole tumor, in all tumors in the body, and at multiple time points. This situation has increased the complexity of clinical trials, as each imaging modality has issues related to cost, ease of use, patient compatibility, data analysis, and interpretation. This article reviews strengths and limitations of the current imaging methods available in clinical cancer trials, including MRI, CT, PET, and ultrasonography. The information gained by each test, and the difficulties in acquiring the data and interpreting it are also discussed in order to help researchers plan imaging in clinical trials and interpret data from such studies. PMID- 21522124 TI - Treatment of multiple myeloma. AB - The treatment of multiple myeloma has changed dramatically in the past decade. The increase in the number of active agents has generated numerous possible drug combinations that can be used in the first-line and relapsed settings. As a result, there is considerable confusion about the choice of regimens for initial therapy, role of transplantation in the era of new drugs, end points for therapy, and the role of maintenance therapy. A hotly debated area is whether treatment approaches should achieve cure or disease control, which impacts greatly on the treatment strategy employed. This article provides an update on the treatment of multiple myeloma, with a focus on recent advances, newly diagnosed disease, role of transplantation and maintenance therapy. A synthesized approach to the treatment of myeloma is presented, along with a discussion of key paradigms that need to be challenged. PMID- 21522125 TI - Associations of maternal employment and three-generation families with pre-school children's overweight and obesity in Japan. AB - BACKGROUNDS: Maternal employment has been shown to be associated with childhood overweight and obesity (Ow/Ob), but the presence of family members who care for children in place of the mothers might influence children's Ow/Ob and lifestyles. The influence of maternal employment on children's Ow/Ob should be examined together with the presence of caregivers such as grandparents. OBJECTIVES: The effects of maternal employment and the presence of grandparents on lifestyles and Ow/Ob in Japanese pre-school children were investigated. DESIGN/SUBJECTS: Cross sectional study on 2114 children aged 3-6 years who attended all childcare facilities in a city and primary caregivers was conducted. MEASUREMENTS: Children's weight and height, family environments (family members, maternal employment, single parent, number of siblings and parental Ow/Ob) and lifestyles (dietary, physical activity and sleeping habits) were surveyed using a self administered questionnaire. Ow/Ob was defined by the International Obesity Task Force cut-offs. RESULTS: The eligible participants were 1765 children. The prevalence of Ow/Ob was 8.4% in boys and 9.9% in girls. Maternal employment was associated positively with irregular mealtimes, unfixed snacking times, bedtime after 10 p.m. and nighttime sleep duration of less than 10 h, whereas three generation families were associated negatively with irregular mealtimes after adjustment for children's characteristics and family environments. Irregular mealtimes (OR (95% CI); 2.03 (1.36, 3.06)) and nighttime sleep duration of less than 10 h (1.96 (1.28, 3.01)) were associated with increased risks of being Ow/Ob. Both maternal employment and three-generation families were significantly associated with children's Ow/Ob. However, three-generation families maintained a significant association (1.59 (1.08, 2.35)) after adjustment for maternal employment. CONCLUSIONS: These study results suggest that the grandparents who care for pre-school children in place of mothers are more likely to contribute to childhood Ow/Ob than maternal employment. The family-focused lifestyle strategies to prevent childhood Ow/Ob must include grandparents who care for children. PMID- 21522123 TI - Metastasis-suppressor genes in clinical practice: lost in translation? AB - Over the past 25 years, an expanding set of metastasis-suppressor genes (MSGs) has been identified that specifically regulate metastasis formation without affecting primary growth. MSGs are involved in diverse molecular processes in multiple tumor types. Given the wealth of metastasis biology that underlies their functions, treatment strategies based on MSGs have an unparalleled potential to improve patient care. Using NM23 as a prime example, we discuss how specific MSGs have been used as prognostic markers, tools for predicting response to treatment, and targets for the development of novel therapies. Barriers specific to the translation of MSG biology into clinical practice are reviewed and future research directions necessary for clinical advances are delineated. Although to date the impact of MSGs on patient care is limited, it is an expanding field with vast potential to help develop new treatments and identify patients who will most benefit from them. PMID- 21522126 TI - Brown adipocyte progenitor population is modified in obese and diabetic skeletal muscle. AB - Brown adipose tissue mitochondria express the unique thermogenic uncoupling protein-1. Recently, brown adipocyte progenitors have been identified in the CD34+ cell population of human skeletal muscle. The aims of this study were firstly to determine if obesity and diabetes have altered amounts of muscle brown adipocyte progenitors and, secondly, to establish if the latter are correlated with clinical parameters of obesity and diabetes. Body mass index (BMI), plasma glucose, insulin, cholesterol and triglycerides as well as homeostasis model assessment were measured in lean (n=10), obese (n=18) and obese-diabetic (n=15) subjects and muscle biopsies were taken from the rectus abdominus. CD34 being also expressed on endothelial cells, we measured CD31, another endothelial marker, and expressed the brown adipocyte progenitors, as the CD34/CD31 mRNA ratio. The latter was significantly reduced in the obese vs lean subjects suggesting a smaller pool of brown adipocyte progenitors. More strikingly, for lean and obese subjects negative correlations were observed between the CD34/CD31 mRNA ratios and BMI, fasting insulin levels and homeostasis model assessment. These correlations highlight the potential physiological relevance of the muscle CD34/CD31 mRNA ratio. PMID- 21522127 TI - USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. AB - Tumour suppressor p53 levels in the cell are tightly regulated by controlled degradation through ubiquitin ligases including Mdm2, COP1, Pirh2, and ARF-BP1. The ubiquitination process is reversible via deubiquitinating enzymes, such as ubiquitin-specific peptidases (USPs). In this study, we identified ubiquitin specific peptidase 4 (USP4) as an important regulator of p53. USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF BP1 and subsequent reduction of p53 levels. Usp4 knockout mice are viable and developmentally normal, but showed enhanced apoptosis in thymus and spleen in response to ionizing radiation. Compared with wild-type mouse embryonic fibroblasts (MEFs), Usp4-/- MEFs exhibited retarded growth, premature cellular senescence, resistance to oncogenic transformation, and hyperactive DNA damage checkpoints, consistent with upregulated levels and activity of p53 in the absence of USP4. Finally, we showed that USP4 is overexpressed in several types of human cancer, suggesting that USP4 is a potential oncogene. PMID- 21522128 TI - Differential control of Eg5-dependent centrosome separation by Plk1 and Cdk1. AB - Cyclin-dependent kinase 1 (Cdk1) is thought to trigger centrosome separation in late G2 phase by phosphorylating the motor protein Eg5 at Thr927. However, the precise control mechanism of centrosome separation remains to be understood. Here, we report that in G2 phase polo-like kinase 1 (Plk1) can trigger centrosome separation independently of Cdk1. We find that Plk1 is required for both C-Nap1 displacement and for Eg5 localization on the centrosome. Moreover, Cdk2 compensates for Cdk1, and phosphorylates Eg5 at Thr927. Nevertheless, Plk1-driven centrosome separation is slow and staggering, while Cdk1 triggers fast movement of the centrosomes. We find that actin-dependent Eg5-opposing forces slow down separation in G2 phase. Strikingly, actin depolymerization, as well as destabilization of interphase microtubules (MTs), is sufficient to remove this obstruction and to speed up Plk1-dependent separation. Conversely, MT stabilization in mitosis slows down Cdk1-dependent centrosome movement. Our findings implicate the modulation of MT stability in G2 and M phase as a regulatory element in the control of centrosome separation. PMID- 21522129 TI - An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity. AB - The p53 tumour suppressor gene, the most frequently mutated gene in human cancer, encodes a transcription factor that contains sequence-specific DNA binding and homo-tetramerization domains. Interestingly, the affinities of p53 for specific and non-specific DNA sites differ by only one order of magnitude, making it hard to understand how this protein recognizes its specific DNA targets in vivo. We describe here the structure of a p53 polypeptide containing both the DNA binding and oligomerization domains in complex with DNA. The structure reveals that sequence-specific DNA binding proceeds via an induced fit mechanism that involves a conformational switch in loop L1 of the p53 DNA binding domain. Analysis of loop L1 mutants demonstrated that the conformational switch allows DNA binding off-rates to be regulated independently of affinities. These results may explain the universal prevalence of conformational switching in sequence-specific DNA binding proteins and suggest that proteins like p53 rely more on differences in binding off-rates, than on differences in affinities, to recognize their specific DNA sites. PMID- 21522130 TI - The CW domain, a new histone recognition module in chromatin proteins. AB - Post-translational modifications of the N-terminal histone tails, including lysine methylation, have key roles in regulation of chromatin and gene expression. A number of protein modules have been identified that recognize differentially modified histone tails and provide their proteins with the capacity to sense such modifications. Here, we identify the CW domain of plant and animal chromatin-related proteins as a novel module that recognizes different methylated states of lysine 4 on histone H3 (H3K4me). The solution structure of the CW domain of the Arabidopsis ASH1 HOMOLOG2 (ASHH2) histone methyltransferase provides insight into how different CW domains can distinguish different methylated histone tails. We provide evidence that ASHH2 is acting on H3K4me marked genes, allowing for ASHH2-dependent H3K36 tri-methylation, which contributes to sustained expression of tissue-specific and developmentally regulated genes. This suggests that ASHH2 is a combined 'reader' and 'writer' of the histone code. We propose that different CW domains, dependent on their specificity for different H3K4 methylations, are important for epigenetic memory or participate in switching between permissive and repressive chromatin states. PMID- 21522131 TI - APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. AB - Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and its proteolytic fragments are still poorly understood. Previously, we generated APPsalpha knock-in (KI) mice expressing solely the secreted ectodomain APPsalpha. Here, we generated double mutants (APPsalpha-DM) by crossing APPsalpha-KI mice onto an APLP2-deficient background and show that APPsalpha rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPsalpha-DM mice exhibited impaired neuromuscular transmission, with reductions in quantal content, readily releasable pool, and ability to sustain vesicle release that resulted in muscular weakness. We show that these defects may be due to loss of an APP/Mint2/Munc18 complex. Moreover, APPsalpha-DM muscle showed fragmented post-synaptic specializations, suggesting impaired postnatal synaptic maturation and/or maintenance. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPsalpha-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP that could be rescued by GABA(A) receptor inhibition. Collectively, our data show that APLP2 and APP are synergistically required to mediate neuromuscular transmission, spatial learning and synaptic plasticity. PMID- 21522132 TI - CRM1 controls the composition of nucleoplasmic pre-snoRNA complexes to licence them for nucleolar transport. AB - Transport of C/D snoRNPs to nucleoli involves nuclear export factors. In particular, CRM1 binds nascent snoRNPs, but its precise role remains unknown. We show here that both CRM1 and nucleocytoplasmic trafficking are required to transport snoRNPs to nucleoli, but the snoRNPs do not transit through the cytoplasm. Instead, CRM1 controls the composition of nucleoplasmic pre-snoRNP complexes. We observed that Tgs1 long form (Tgs1 LF), the long isoform of the cap hypermethylase, contains a leucine-rich nuclear export signal, shuttles in a CRM1 dependent manner, and binds to the nucleolar localization signal (NoLS) of the core snoRNP protein Nop58. In vitro data indicate that CRM1 binds Tgs1 LF and promotes its dissociation from Nop58 NoLS, and immunoprecipitation experiments from cells indicate that the association of Tgs1 LF with snoRNPs increases upon CRM1 inhibition. Thus, CRM1 appears to promote nucleolar transport of snoRNPs by removing Tgs1 LF from the Nop58 NoLS. Microarray/IP data show that this occurs on most snoRNPs, from both C/D and H/ACA families, and on the telomerase RNA. Hence, CRM1 provides a general molecular link between nuclear events and nucleocytoplasmic trafficking. PMID- 21522133 TI - Aging and chronic DNA damage response activate a regulatory pathway involving miR 29 and p53. AB - Aging is a multifactorial process that affects most of the biological functions of the organism and increases susceptibility to disease and death. Recent studies with animal models of accelerated aging have unveiled some mechanisms that also operate in physiological aging. However, little is known about the role of microRNAs (miRNAs) in this process. To address this question, we have analysed miRNA levels in Zmpste24-deficient mice, a model of Hutchinson-Gilford progeria syndrome. We have found that expression of the miR-29 family of miRNAs is markedly upregulated in Zmpste24(-/-) progeroid mice as well as during normal aging in mouse. Functional analysis revealed that this transcriptional activation of miR-29 is triggered in response to DNA damage and occurs in a p53-dependent manner since p53(-/-) murine fibroblasts do not increase miR-29 expression upon doxorubicin treatment. We have also found that miR-29 represses Ppm1d phosphatase, which in turn enhances p53 activity. Based on these results, we propose the existence of a novel regulatory circuitry involving miR-29, Ppm1d and p53, which is activated in aging and in response to DNA damage. PMID- 21522134 TI - AAV mediated GDNF secretion from retinal glia slows down retinal degeneration in a rat model of retinitis pigmentosa. AB - Mutations in over 80 identified genes can induce apoptosis in photoreceptors, resulting in blindness with a prevalence of 1 in 3,000 individuals. This broad genetic heterogeneity of disease impacting a wide range of photoreceptor functions renders the design of gene-specific therapies for photoreceptor degeneration impractical and necessitates the development of mutation-independent treatments to slow photoreceptor cell death. One promising strategy for photoreceptor neuroprotection is neurotrophin secretion from Muller cells, the primary retinal glia. Muller glia are excellent targets for secreting neurotrophins as they span the entire tissue, ensheath all neuronal populations, are numerous, and persist through retinal degeneration. We previously engineered an adeno-associated virus (AAV) variant (ShH10) capable of efficient and selective glial cell transduction through intravitreal injection. ShH10-mediated glial-derived neurotrophic factor (GDNF) secretion from glia, generates high GDNF levels in treated retinas, leading to sustained functional rescue for over 5 months. This GDNF secretion from glia following intravitreal vector administration is a safe and effective means to slow the progression of retinal degeneration in a rat model of retinitis pigmentosa (RP) and shows significant promise as a gene therapy to treat human retinal degenerations. These findings also demonstrate for the first time that glia-mediated secretion of neurotrophins is a promising treatment that may be applicable to other neurodegenerative conditions. PMID- 21522136 TI - Synthesis of hexagonal close-packed gold nanostructures. AB - Solid gold is usually most stable as a face-centred cubic (fcc) structure. To date, no one has synthesized a colloidal form of Au that is exclusively hexagonal close-packed (hcp) and stable under ambient conditions. Here we report the first in situ synthesis of dispersible hcp Au square sheets on graphene oxide sheets, which exhibit an edge length of 200-500 nm and a thickness of ~ 2.4 nm (~ 16 Au atomic layers). Interestingly, the Au square sheet transforms from hcp to a fcc structure on exposure to an electron beam during transmission electron microscopy analysis. In addition, as the square sheet grows thicker (from ~ 2.4 to 6 nm), fcc segments begin to appear. A detailed experimental analysis of these structures shows that for structures with ultrasmall dimensions (for example, <~ 6 nm thickness for the square sheets), the previously unobserved pure hcp structure becomes stable and isolable. PMID- 21522135 TI - Nitric oxide synthase gene transfer restores activity of circulating angiogenic cells from patients with coronary artery disease. AB - Circulating angiogenic cells (CACs), represent a potential new therapeutic tool for the treatment of cardiovascular diseases, but their regenerative function is impaired in patients with coronary artery disease (CAD) and cardiac risk factors. The objective of this study is to assess the effect of lentiviral overexpression of endothelial nitric oxide synthase (eNOS) on the activity of CACs from patients with CAD and cardiac risk factors. In vitro and in vivo assays were employed to evaluate the regenerative capacity of the cells compared to CACs derived from healthy volunteers. Lentiviral eNOS transduction of cells from CAD patients significantly improved chemotactic migration compared with sham transduction, and increased the ability of CACs to induce angiogenic tube formation when cocultured with human umbilical vein endothelial cells (HUVECs) on Matrigel. In addition, eNOS transduction restored the ability of patient-derived CACs to enhance neovascularization and improve ischemic hind limb perfusion, approaching the efficacy of cells from healthy donors. These data indicate that CAC dysfunction seen in high-risk patients can be partially reversed by eNOS overexpression, suggesting that ex vivo gene delivery may improve the efficacy of autologous cell therapy for cardiovascular disease. PMID- 21522137 TI - South China Sea hydrological changes and Pacific Walker Circulation variations over the last millennium. AB - The relative importance of north-south migrations of the intertropical convergence zone (ITCZ) versus El Nino-Southern Oscillation and its associated Pacific Walker Circulation (PWC) variability for past hydrological change in the western tropical Pacific is unclear. Here we show that north-south ITCZ migration was not the only mechanism of tropical Pacific hydrologic variability during the last millennium, and that PWC variability profoundly influenced tropical Pacific hydrology. We present hydrological reconstructions from Cattle Pond, Dongdao Island of the South China Sea, where multi-decadal rainfall and downcore grain size variations are correlated to the Southern Oscillation Index during the instrumental era. Our downcore grain size reconstructions indicate that this site received less precipitation during relatively warm periods, AD 1000-1400 and AD 1850-2000, compared with the cool period (AD 1400-1850). Including our new reconstructions in a synthesis of tropical Pacific records results in a spatial pattern of hydrologic variability that implicates the PWC. PMID- 21522139 TI - Growth and development. PMID- 21522140 TI - Integrating addiction research. PMID- 21522138 TI - Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors. AB - N-methyl-D-aspartate (NMDA) receptors belong to the family of ionotropic glutamate receptors that mediate a majority of excitatory synaptic transmission. One unique property of GluN1/GluN2D NMDA receptors is an unusually prolonged deactivation time course following the removal of L-glutamate. Here we show, using x-ray crystallography and electrophysiology, that the deactivation time course of GluN1/GluN2D receptors is influenced by the conformational variability of the ligand-binding domain (LBD) as well as the structure of the activating ligand. L-glutamate and L-CCG-IV induce significantly slower deactivation time courses compared with other agonists. Crystal structures of the isolated GluN2D LBD in complex with various ligands reveal that the binding of L-glutamate induces a unique conformation at the backside of the ligand-binding site in proximity to the region at which the transmembrane domain would be located in the intact receptors. These data suggest that the activity of the GluN1/GluN2D NMDA receptor is controlled distinctively by the endogenous neurotransmitter L glutamate. PMID- 21522141 TI - The ups and downs of seizure activity. PMID- 21522142 TI - Calcium channels put synapses in their place. PMID- 21522143 TI - Hanging by the tail: progenitor populations proliferate. PMID- 21522144 TI - Scratching the surface: a role of pain-sensing TRPA1 in itch. PMID- 21522145 TI - The visual attention network untangled. PMID- 21522146 TI - Hyperthyroidism and human chorionic gonadotrophin production in gestational trophoblastic disease. AB - BACKGROUND: Gestational trophoblastic disease (GTD) is a rare complication of pregnancy, ranging from molar pregnancy to choriocarcinoma. Patients with persistent disease require treatment with chemotherapy. For the vast majority, prognosis is excellent. Occasionally, GTD is complicated by hyperthyroidism, which may require treatment. This is thought to occur due to molecular mimicry between human chorionic gonadotrophin (HCG) and thyroid-stimulating hormone (TSH), and hence cross-reactivity with the TSH receptor. Hyperthyroidism usually resolves as the GTD is successfully treated and correspondingly HCG levels normalise. METHODS: This paper reviews cases of GTD treated over a 5-year period at one of the three UK centres and identifies the prevalence of hyperthyroidism in this population. Four cases with clinical hyperthyroidism are discussed. RESULTS: On review of the 196 patients with gestational trophoblastic neoplasia treated with chemotherapy in Sheffield since 2005, 14 (7%) had biochemical hyperthyroidism. Of these, four had evidence of clinical hyperthyroidism. CONCLUSION: Concomitant biochemical thyroid disease in patients with GTD is relatively common, and measurement of thyroid function in patients with persistent GTD is, therefore, important. The development of hyperthyroidism is largely influenced by the level of HCG and disease burden, and usually settles with treatment of the persistent GTD. However, rarely the thyroid stimulation can have potentially life-threatening consequences. PMID- 21522147 TI - Trastuzumab beyond progression in HER2-positive advanced breast cancer: the Royal Marsden experience. AB - BACKGROUND: Recent UK clinical guidance advises against continuing trastuzumab (T) beyond disease progression (PD) in the absence of brain metastases in patients with HER-2 positive (+ve) advanced breast cancer .We have retrospectively evaluated the outcome of patients with HER-2+ve locally advanced (LA) or metastatic breast cancer (MBC) who continued T beyond PD, treated in our unit. METHODS: All HER-2+ve patients on our prospectively maintained database with LA or MBC who received T beyond PD after adjuvant or one line of T for advanced disease were assessed for response and outcome. From the timepoint of T continuation beyond PD, we calculated the overall disease control rate, time to progression (TTP), and overall survival (OS). RESULTS: One hundred and fourteen patients with HER-2+ve LA or MBC treated with T beyond PD were identified. The main site of disease was visceral in 84 (74%) patients. Seventy-six (66%) had one line of chemotherapy before continuation of T beyond PD and 21 (19%) had two or more. Post-progression, 66 (58%) received T combined with chemotherapy. Of the 93 (82%) patients with documented clinical or radiological response evaluation, 67 (59%) were considered as having stable disease or better. The median TTP was 24 weeks (95% CI: 21-28) and the median OS was 19 months (95% CI: 12-24). CONCLUSION: Our results from an unselected group of patients provide additional evidence that continuation of T beyond PD is of clinical benefit. PMID- 21522148 TI - Use of tamoxifen and aromatase inhibitors in a large population-based cohort of women with breast cancer. AB - BACKGROUND: Non-compliance with oral treatment in oncology is an emerging health issue. For breast cancer (BC) patients, few data are available on compliance and persistence to tamoxifen in younger women and to aromatase inhibitors (AIs) as compared with tamoxifen in older women. METHODS: We constituted a cohort of 13,479 women with BC who received at least one prescription of tamoxifen or AI between 1998 and 2008, in the United Kingdom General Practice Research Database. Days covered by medication and treatment discontinuation were studied. Time to treatment discontinuation was calculated using Kaplan-Meier estimates. RESULTS: Overall, 18.9% (95% CI: 15.1-23.0) of women on AIs as compared with 31.0% (95% CI: 29.6-32.2) of women on tamoxifen had discontinued their treatments within the first 5 years (P<0.001). This rate raised to 50.7% (95% CI: 43.0-57.9) among the 416 women under 40 years receiving tamoxifen as initial hormonal therapy. Among older women, treatment discontinuation was less frequent for AIs as compared with tamoxifen (P<0.001). Among women on AI therapy, 14% of them (n=374) had switched treatments. CONCLUSION: Among older women, the real-life patterns of use of AI show high rates of compliance. In younger women, tamoxifen is prematurely discontinued for half of patients. PMID- 21522149 TI - Co-overexpression of Bag-1 and heat shock protein 70 in human epidermal squamous cell carcinoma: Bag-1-mediated resistance to 5-fluorouracil-induced apoptosis. AB - BACKGROUND: The aim was to determine whether Bcl-2-associated athanogene-1 (Bag 1) and/or its binding protein heat shock protein-70 (Hsp70) exhibit deregulated expression in epidermal squamous cell carcinoma (SCC) and whether Bag-1 confers apoptosis resistance. METHOD: Immunohistochemistry for Bag-1 and Hsp70 was performed on 60 epidermal SCC and 10 normal skin samples. The epidermal SCC cell line SCC-13 was treated with 5-fluorouracil (5-FU) after Bag-1 knockdown to determine whether high Bag-1 levels contribute to growth and/or apoptosis resistance. RESULTS: Normal epithelium expressed primarily nuclear Bag-1. Most tumours showed reduced nuclear Bag-1 staining, but a subset exhibited strong Bag 1 staining, with cytoplasmic Bag-1 staining intensity correlating with cytoplasmic Hsp70 staining intensity (r(s)=0.462; P<0.001) and less differentiation (P<0.001). Bag-1 knockdown resulted in markedly reduced SCC-13 cell yield, increased spontaneous apoptosis and enhanced sensitivity to 5-FU induced apoptosis. Apoptosis induced by 5-FU in the Bag-1-knockdown cells was significantly greater than the additive apoptotic effect of 5-FU or Bag-1 knockdown alone. CONCLUSIONS: Overexpression of Bag-1 and Hsp70 in poorly differentiated SCC may confer both enhanced tumour cell growth and apoptosis resistance. Bag-1 may contribute to the resistance of more advanced epidermal SCC to chemotherapy. PMID- 21522150 TI - Diagnostic radiography and adult acute myeloid leukaemia: an interview and medical chart review study. AB - BACKGROUND: Aetiology of acute myeloid leukaemia (AML) is not well understood, perhaps because of its distinct subtypes. High-dose ionising radiation is a known risk factor, but less is known about risk from low-dose exposure such as from diagnostic radiography. METHODS: Subjects were 412 matched case-control pairs. Ten-year subject histories of diagnostic radiography were based on interview and medical records. RESULTS: There was no convincing association between AML risk and ionising radiation exposure from diagnostic imaging procedures, either for AML overall or for any AML subtype. CONCLUSION: The association between diagnostic radiography and AML risk remains uncertain. PMID- 21522151 TI - Differential trends in the rising incidence of endometrial cancer by type: data from a UK population-based registry from 1994 to 2006. AB - BACKGROUND: Endometrial cancer is the most common gynaecological cancer in the western world, the incidence increasing in the United Kingdom by over 40% since 1993. Two types of endometrial cancer exist - oestrogen-dependent type 1 with good prognosis and non-oestrogen-dependent type 2 with poor prognosis. The histopathological distribution of the increase in endometrial cancer is unknown. This study investigates the observed incidence trends of the two types, the age, stage, and socioeconomic distribution of this increase and survival outcome. METHODS: Data were analysed from 6867 women with endometrial cancer registered between 1994 and 2006, at a UK population-based cancer registry. RESULTS: Increased endometrial cancer incidence is confined to type 1 cancers with a significant increase in age standardised incidence rate (ASR) from 12.0 per 100,000 (confidence interval (CI) 10.7-13.2) in 1994 to 16.3 per 100,000 (CI 14.9 17.7), P<0.001 in 2006, while ASR of type 2 cancer changed from 2.5 per 100,000 (CI 2.0-3.1) in 1994 to 2.2 per 100,000 (CI 1.7-2.7) in 2006, which was not statistically significant P>0.05. Increase in type 1 cancer is most marked in age groups 60-69 years (P<0.001) and 70-79 years (P<0.001) and distributed equally among socioeconomic quintiles. While outcome for type 1 cancer has improved, 1 year survival in type 2 cancer is unchanged from 73.1% in 1994 to 74.3%, P=0.089 and 5-year survival decreased from 55.1% to 40.9%, P=0.001. CONCLUSION: Increased incidence in endometrial cancer is confined to type 1 cancers, seen most in the 60-79 age groups and across all socioeconomic quintiles. Survival in type 2 cancer has decreased significantly. Urgent research is needed to investigate prevention strategies in type 1 and improve therapy in type 2 cancers. PMID- 21522152 TI - Allelic imbalance of the TGFbetaR1 is not a major contributor to the genetic predisposition to colorectal cancer. PMID- 21522156 TI - A preparative method for the purification of isopenicillin N from genetically blocked Acremonium chrysogenum strain TD189: studies on the degradation kinetics and storage conditions. AB - A protocol for preparative isopenicillin N (IPN) purification, a highly interesting and hitherto unavailable intermediate of the penicillin and cephalosporin biosynthetic pathway due to its high unstability, is described. Culture broths of Acremonium chrysogenum TD189, a strain blocked in cephalosporin biosynthesis that accumulates this metabolite, were treated with acetone and filtered though charcoal and a hydrophobic resin in a single step as tandem columns. The cleared broth was then lyophilized and passed though a Sephadex G-25 column. The last step was the purification to homogeneity of IPN in a semipreparative HPLC equipment and, optionally, a desalting step by Sephadex G-10 column. Once purified, a complete analysis of the stability of the compound and the conditions for its long-term storage was carried out. Our results suggest a first-order model for IPN decomposition for all the pH and temperature analyzed. IPN is more stable at neutral pH, and once lyophilized, can be stored under vacuum and -75 degrees C with a half-life of 770 days. PMID- 21522157 TI - Enhancement effect of N-methyl-N"-dodecylguanidine on the vacuole-targeting fungicidal activity of amphotericin B against the pathogenic fungus Candida albicans. AB - The alkylguanidium chain attached to the polyol lactone ring of niphimycin (NM) is considered a requisite for the fungicidal activity of NM characterized by vacuole membrane fragmentation and oxidative stress induction. The addition of N methyl-N"-dodecylguanidine to the medium can enhance the vacuole-targeting fungicidal activity of amphotericin B (AmB), in which the lactone ring has no such alkylguanidium chain, on Saccharomyces cerevisiae cells. In this study, the enhancement effect of N-methyl-N"-dodecylguanidine on the vacuole-targeting fungicidal activity of AmB was examined against Candida albicans in RPMI 1640 medium at 37 degrees C. N-methyl-N"-dodecylguanidine was lethal to C. albicans cells and additionally enhanced the vacuole disruptive activity of AmB against this pathogenic fungus. N-methyl-N"-dodecylguanidine elevated the generation of cellular reactive oxygen species when added alone in a dose-dependent manner, but its enhancement effect on AmB lethality did not accompany amplification of oxidative stress induction. The fungal vacuoles were protected against the disruptive damage even if cells were treated with H(2)O(2) alone at a lethal concentration or treated with H(2)O(2) at a sublethal concentration in combination with AmB. N-methyl-N"-dodecylguanidine was ineffective in enhancing AmB lethality or AmB-induced vacuole disruption when cells had been pretreated with ergosterol. Ergosterol-dependent mechanism is thus considered to be a possible target of N-methyl-N"-dodecylguanidine in enhancing the vacuole targeting fungicidal activity of AmB in C. albicans cells. PMID- 21522158 TI - beta-Lactone natural products and derivatives inactivate homoserine transacetylase, a target for antimicrobial agents. AB - Homoserine transacetylase (HTA) catalyzes the transfer of an acetyl group from acetyl-CoA to the hydroxyl group of homoserine. This is the first committed step in the biosynthesis of methionine (Met) from aspartic acid in many fungi, Gram positive and some Gram-negative bacteria. The enzyme is absent in higher eukaryotes and is important for microorganism growth in Met-poor environments, such as blood serum, making HTA an attractive target for new antimicrobial agents. HTA catalyzes acetyl transfer via a double displacement mechanism facilitated by a classic Ser-His-Asp catalytic triad located at the bottom of a narrow actives site tunnel. We explored the inhibitory activity of several beta lactones to block the activity of HTA. In particular, the natural product ebelactone A, a beta-lactone with a hydrophobic tail was found to be a potent inactivator of HTA from Haemophilus influenzae. Synthetic analogs of ebelactone A demonstrated improved inactivation characteristics. Covalent modification of HTA was confirmed by mass spectrometry, and peptide mapping identified Ser143 as the modified residue, consistent with the known structure and mechanism of the enzyme. These results demonstrate that beta-lactone inhibitors are excellent biochemical probes of HTA and potential leads for new antimicrobial agents. PMID- 21522159 TI - Verticillin A is likely not produced by Verticillium sp. PMID- 21522160 TI - Toxicity of betulin derivatives and in vitro effect on promastigotes and amastigotes of Leishmania infantum and L. donovani. AB - The toxicity and antileishmanial activity of 20 betulin derivatives were studied. The toxicity of betulin and synthesized compounds was determined using a bacterial test (Microtox) and two mammalian cell lines (CHO-K1 and J774). The antileishmanial activity of compounds (50 MUM) was examined in both the promastigote and intracellular amastigote stages of Leishmania infantum and L. donovani. No correlation was found among the toxicity tests. All the compounds showed significant antipromastigote activity. The antiproliferative capacity of derivatives was dependent on the parasite stage studied, and no substantial differences were found between Leishmania species. Betulin, 3,28-di-O acetylbetulin and L-aspartyl amide of betulonic acid showed moderate activity against amastigotes. The highest inhibition of intracellular amastigote multiplication was achieved with a low micromolar concentration (IC(50) ca 9 MUM) of heterocyclic betulin derivative 3,28-di-O-acetyllup-13(18)-ene with N ethyltriazolo moiety 16, without significant toxicity for mammalian cells. These results point to the interest of this lead compound for further in vitro and in vivo tests. PMID- 21522161 TI - Reduced astrocytic contribution to the turnover of glutamate, glutamine, and GABA characterizes the latent phase in the kainate model of temporal lobe epilepsy. AB - The occurrence of spontaneous seizures in mesial temporal lobe epilepsy (MTLE) is preceded by a latent phase that provides a time window for identifying and treating patients at risk. However, a reliable biomarker of epileptogenesis has not been established and the underlying processes remain unclear. Growing evidence suggests that astrocytes contribute to an imbalance between excitation and inhibition in epilepsy. Here, astrocytic and neuronal neurotransmitter metabolism was analyzed in the latent phase of the kainate model of MTLE in an attempt to identify epileptogenic processes and potential biomarkers. Fourteen days after status epilepticus, [1-(13)C]glucose and [1,2-(13)C]acetate were injected and the hippocampal formation, entorhinal/piriform cortex, and neocortex were analyzed by (1)H and (13)C magnetic resonance spectroscopy. The (13)C enrichment in glutamate, glutamine, and gamma-aminobutyric acid (GABA) from [1 (13)C]glucose was decreased in all areas. Decreased GABA content was specific for the hippocampal formation, together with a pronounced decrease in astrocyte derived [1,2-(13)C]GABA and a decreased transfer of glutamine for the synthesis of GABA. Accumulation of branched-chain amino acids combined with decreased [4,5 (13)C]glutamate in hippocampal formation could signify decreased transamination via branched-chain aminotransferase in astrocytes. The results point to astrocytes as major players in the epileptogenic process, and (13)C enrichment of glutamate and GABA as potential biomarkers. PMID- 21522162 TI - Calculating occupancy when one does not have baseline: a comparison of different options. AB - Dopamine D(2) receptor occupancy of antipsychotic drugs is calculated relative to the subject's D(2) receptor binding potential (BP) in the drug-free state (baseline BP). Because baseline BP is seldom known in patients with schizophrenia, population means from unrelated control samples are often used to estimate it. However, this is likely to introduce bias and error into the occupancy measure. There is thus a need for a method to reliably estimate baseline BP for patient populations in whom it may be impractical or unethical to get baseline measurements. It has been previously found that the relationship between plasma concentration and dopamine receptor occupancy by antipsychotic drugs follows a sigmoid E(max) model. Based on this, we developed a method for calculating dopamine D(2) receptor occupancy by antipsychotic drugs using an inhibitory E(max) model (I(max) method) that estimates individual baseline BPs. To validate this, we compared the result from the I(max) method with actual occupancy and estimated occupancy calculated from the average baseline BP (substitution method). The data for validation were obtained from two different receptor occupancy studies with the antipsychotic medications YKP1358 and aripiprazole. We estimated the reliability between the true measured occupancy and the predicted occupancy using the intraclass correlation coefficient (ICC), and the variability of occupancy was also compared between the I(max) and substitution methods. In YKP1358 study, all the ICCs of the I(max) method were above 0.8, but those of the substitution method showed values lower than 0.8. In aripiprazole study, the ICCs of the I(max) method were higher than those of the substitution method, but all the ICCs showed higher values than 0.8. The variability of I(max) method was significantly smaller than that of substitution method in both studies. The I(max) method shows better reliability and less variability than the substitution method. The I(max) method can be applied for receptor occupancy study, and bring more reliability and accuracy to the occupancy study in patients with schizophrenia. PMID- 21522163 TI - Quantitation of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography. AB - This article describes the kinetic modeling of [(18)F]-FEPPA binding to translocator protein 18 kDa in the human brain using high-resolution research tomograph (HRRT) positron emission tomography. Positron emission tomography scans were performed in 12 healthy volunteers for 180 minutes. A two-tissue compartment model (2-CM) provided, with no exception, better fits to the data than a one tissue model. Estimates of total distribution volume (V(T)), specific distribution volume (V(S)), and binding potential (BP(ND)) demonstrated very good identifiability (based on coefficient of variation (COV)) for all the regions of interest (ROIs) in the gray matter (COV V(T)<7%, COV V(S)<8%, COV BP(ND)<11%). Reduction of the length of the scan to 2 hours is feasible as V(S) and V(T) showed only a small bias (6% and 7.5%, respectively). Monte Carlo simulations showed that, even under conditions of a 500% increase in specific binding, the identifiability of V(T) and V(S) was still very good with COV<10%, across high uptake ROIs. The excellent identifiability of V(T) values obtained from an unconstrained 2-CM with data from a 2-hour scan support the use of V(T) as an appropriate and feasible outcome measure for [(18)F]-FEPPA. PMID- 21522164 TI - Distribution of vesicular monoamine transporter 2 protein in human brain: implications for brain imaging studies. AB - The choice of reference region in positron emission tomography (PET) human brain imaging of the vesicular monoamine transporter 2 (VMAT2), a marker of striatal dopamine innervation, has been arbitrary, with cerebellar, whole cerebral, frontal, or occipital cortices used. To establish whether levels of VMAT2 are in fact low in these cortical areas, we measured VMAT2 protein distribution by quantitative immunoblotting in autopsied normal human brain (n=6). Four or five species of VMAT2 immunoreactivity (75, 55, 52, 45, 35 kDa) were detected, which were all markedly reduced in intensity in nigrostriatal regions of patients with parkinsonian conditions versus matched controls (n=9 to 10 each). Using the intact VMAT2 immunoreactivity, cerebellar and cerebral neocortices had levels of the transporter >100-fold lower than the VMAT2-rich striatum and with no significant differences among the cortical regions. We conclude that human cerebellar and cerebral cortices contain negligible VMAT2 protein versus the striatum and, in this respect, all satisfy a criterion for a useful reference region for VMAT2 imaging. The slightly lower PET signal for VMAT2 binding in occipital (the currently preferred reference region) versus cerebellar cortex might not therefore be explained by differences in VMAT2 protein itself but possibly by other imaging variables, for example, partial volume effects. PMID- 21522165 TI - Metabolic and perfusion responses to recurrent peri-infarct depolarization during focal ischemia in the Spontaneously Hypertensive Rat: dominant contribution of sporadic CBF decrements to infarct expansion. AB - Peri-infarct depolarizations (PIDs) contribute to the evolution of focal ischemic lesions. Proposed mechanisms include both increased metabolic demand under conditions of attenuated perfusion and overt vasoconstrictive responses to depolarization. The present studies investigated the relative contributions of metabolic and perfusion effects to PID-associated infarct expansion during middle cerebral artery (MCA) occlusion in the Spontaneously Hypertensive Rat. The initial distribution of ischemic depolarization (ID) was established within minutes after MCA occlusion at a cerebral blood flow threshold of ~40 mL/100 g per minute, with expansion of the depolarized territory during 3 hours detected in half of the animals. Peri-infarct depolarizations were associated with transient metabolic responses, comparable to those observed after spreading depression, with no evidence of cumulative energy failure after multiple transient depolarizations during 1 hour. Speckle contrast imaging of PID associated flow transients documented prominent distal hyperemic flow responses that became progressively attenuated in regions of already impaired perfusion, with modest propagated flow decreases more proximal to the ischemic core. However, sporadic PIDs were associated with persistent decrements in perfusion, increasing tissue volume below the threshold for energy failure, ID and infarction. These latter, comparatively rare, events can account for the pattern of stepwise infarct expansion in this model. PMID- 21522166 TI - MRI of bilateral sensorimotor network activation in response to direct intracortical stimulation in rats after unilateral stroke. AB - Reinstatement of perilesional activation and connectivity may underlie functional recovery after stroke. To measure activation responsiveness in perilesional cortex in relation to white matter integrity, we performed functional functional magnetic resonance imaging during stimulation of the contralesional cortex, together with diffusion tensor imaging, 3 and 28 days after stroke in rats. Despite disturbed sensorimotor function and abnormal callosal appearance at day 3, activation amplitudes were preserved in the perilesional sensorimotor cortex, although time-to-peak was significantly delayed. This indicates that in spite of dysfunction, perilesional cortical tissue can be activated subacutely after stroke, while delay of the hemodynamic activation response suggests impaired neurovascular coupling. PMID- 21522167 TI - Demographic and genetic factors shaping contemporary metapopulation effective size and its empirical estimation in salmonid fish. AB - The preservation of biodiversity requires an understanding of the maintenance of its components, including genetic diversity. Effective population size determines the amount of genetic variance maintained in populations, but its estimation can be complex, especially when populations are interconnected in a metapopulation. Theory predicts that the effective size of a metapopulation (meta-N(e)) can be decreased or increased by population subdivision, but little empirical work has evaluated these predictions. Here, we use neutral genetic markers and simulations to estimate the effective size of a putative metapopulation in Atlantic salmon (Salmo salar). For a weakly structured set of rivers, we find that meta-N(e) is similar to the sum of local deme sizes, whereas higher genetic differentiation among demes dramatically reduces meta-N(e) estimates. Interdemic demographic processes, such as asymmetrical gene flow, may explain this pattern. However, simulations also suggest that unrecognized population subdivision can also introduce downward bias into empirical estimation, emphasizing the importance of identifying the proper scale of distinct demographic and genetic processes. Under natural patterns of connectivity, evolutionary potential may generally be maintained at higher levels than the local population, with implications for conservation given ongoing species declines and habitat fragmentation. PMID- 21522168 TI - A new likelihood estimator and its comparison with moment estimators of individual genome-wide diversity. AB - The inbreeding coefficient of an individual, F, is one of the central parameters in population genetics theory. It has found important applications in evolutionary biology, conservation and ecology, such as the study of inbreeding depression. In the absence of detailed and reliable pedigree records, researchers have developed quite a few estimators to estimate F or the genome-wide homozygosity from genetic marker data. The statistical properties and comparative performances of these metrics are rarely known, however, which impedes an informed choice of the most appropriate one in practical applications. In this investigation, I propose a new likelihood F estimator that makes efficient use of marker information and takes into account of allelic dropouts, null alleles and prior knowledge of inbreeding. I compare the likelihood estimator with three moment estimators of F and three metrics of genomic homozygosity (or heterozygosity) by analysing both simulated and empirical datasets. It is shown that the likelihood estimator invariably outperforms the other estimators and metrics across all datasets analysed. For a typical dataset in heterozygosity fitness correlation studies involving 10-20 microsatellites and 50 individuals, the correlation between the likelihood estimator and F (the simulated true inbreeding coefficient) is about 8 ~ 35% higher than that between the moment estimators and F. A frequently applied metric, multilocus heterozygosity (MLH), and an F estimator based on the consideration of the proportion of alleles in homozygous conditions, [F R'), are shown to have particularly poor performances. The low correlation between MLH and fitness traits, which is widely observed in numerous empirical studies, might be partially caused by the adoption of this inefficient estimator of genomic inbreeding. PMID- 21522169 TI - Isolation and characterization of a female-specific DNA marker in the giant freshwater prawn Macrobrachium rosenbergii. AB - In this study, a female-specific DNA marker in the freshwater prawn Macrobrachium rosenbergii was identified through amplified fragment length polymorphism (AFLP). The AFLP-derived sequence-characterized amplified region (SCAR) marker was tested in over 200 individuals, giving reproducible sex identification. Further molecular characterization of the sex-marker's genomic region (~ 3 kb long) revealed the presence of tandem and inverted repeats. The ~ 3-kb sequence was identified both in male and female prawns, but with subtle differences: a deletion of 3 bp (present in female prawn but absent in male prawn) identified upstream of the SCAR marker sequence and two female-specific single-nucleotide polymorphisms, both indicating that male prawns are homozygous, whereas female prawns are heterozygous in this locus. Fluorescent in situ hybridization showed the ~ 3-kb sequence to be unique: to the best of our knowledge, this is the first report of a unique sex-specific sequence observed in situ in crustaceans. The sex specific marker identified in M. rosenbergii may have considerable applied merit for crustacean culture in that it will enable the determination of genetic sex at early developmental stages when phenotypic differences are not identifiable. PMID- 21522170 TI - Metabolism: Sex differences in fatty liver disease. PMID- 21522171 TI - No second thoughts about data access. PMID- 21522172 TI - Defining rare variants by their frequencies in controls may increase type I error. PMID- 21522173 TI - Bias due to selection of rare variants using frequency in controls. PMID- 21522175 TI - Cattle gain stature. PMID- 21522176 TI - High-throughput identification of genetic interactions in HIV-1. PMID- 21522177 TI - Estimating the mutation rate of Mycobacterium tuberculosis during infection. PMID- 21522182 TI - Muscular dystrophy with marked Dysferlin deficiency is consistently caused by primary dysferlin gene mutations. AB - Dysferlin is a 237-kDa transmembrane protein involved in calcium-mediated sarcolemma resealing. Dysferlin gene mutations cause limb-girdle muscular dystrophy (LGMD) 2B, Miyoshi myopathy (MM) and distal myopathy of the anterior tibialis. Considering that a secondary Dysferlin reduction has also been described in other myopathies, our original goal was to identify cases with a Dysferlin deficiency without dysferlin gene mutations. The dysferlin gene is huge, composed of 55 exons that span 233 140 bp of genomic DNA. We performed a thorough mutation analysis in 65 LGMD/MM patients with <=20% Dysferlin. The screening was exhaustive, as we sequenced both genomic DNA and cDNA. When required, we used other methods, including real-time PCR, long PCR and array CGH. In all patients, we were able to recognize the primary involvement of the dysferlin gene. We identified 38 novel mutation types. Some of these, such as a dysferlin gene duplication, could have been missed by conventional screening strategies. Nonsense-mediated mRNA decay was evident in six cases, in three of which both alleles were only detectable in the genomic DNA but not in the mRNA. Among a wide spectrum of novel gene defects, we found the first example of a 'nonstop' mutation causing a dysferlinopathy. This study presents the first direct and conclusive evidence that an amount of Dysferlin <=20% is pathogenic and always caused by primary dysferlin gene mutations. This demonstrates the high specificity of a marked reduction of Dysferlin on western blot and the value of a comprehensive molecular approach for LGMD2B/MM diagnosis. PMID- 21522183 TI - Clinical utility gene card for: Loeys-Dietz syndrome (TGFBR1/2) and related phenotypes. PMID- 21522181 TI - Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders. AB - Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings. PMID- 21522184 TI - Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11. AB - With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay. PMID- 21522185 TI - The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein. AB - DFNA5 was first identified as a gene causing autosomal dominant hearing loss (HL). Different mutations have been found, all exerting a highly specific gain-of function effect, in which skipping of exon 8 causes the HL. Later reports revealed the involvement of the gene in different types of cancer. Epigenetic silencing of DFNA5 in a large percentage of gastric, colorectal and breast tumors and p53-dependent transcriptional activity have been reported, concluding that DFNA5 acts as a tumor suppressor gene in different frequent types of cancer. Despite these data, the molecular function of DFNA5 has not been investigated properly. Previous transfection studies with mutant DFNA5 in yeast and in mammalian cells showed a toxic effect of the mutant protein, which was not seen after transfection of the wild-type protein. Here, we demonstrate that DFNA5 is composed of two domains, separated by a hinge region. The first region induces apoptosis when transfected in HEK293T cells, the second region masks and probably regulates this apoptosis inducing capability. Moreover, the involvement of DFNA5 in apoptosis-related pathways in a physiological setting was demonstrated through gene expression microarray analysis using Dfna5 knockout mice. In view of its important role in carcinogenesis, this finding is expected to lead to new insights on the role of apoptosis in many types of cancer. In addition, it provides a new line of evidence supporting an important role for apoptosis in monogenic and complex forms of HL. PMID- 21522186 TI - Clinical utility gene card for: Alstrom syndrome. PMID- 21522188 TI - Estimating exposures to indoor contaminants using residential dust. AB - Residential dust has been used as a medium for assessing human exposures to a constellation of indoor contaminants including radionuclides, persistent organic pollutants, metals, allergens, and tobacco smoke. Here, we review and comment on investigations of household dust levels of particular analytes of health significance, namely polybrominated diphenyl ethers, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons. In doing so, we not only describe methods for collecting and analyzing residential dust, but also describe global patterns in dust levels. Aside from geographic location, we discuss several potential determinants for dust levels of these contaminants. We also review previous estimates of the contribution of dust to overall intake of these three chemical classes and show how residential-dust measurements could be useful in either augmenting or replacing questionnaire-based assessment of human exposures in epidemiological studies. We conclude our review with a discussion of the current gaps in knowledge of worldwide dust levels and suggestions for how residential dust measurements could be used to describe human exposures to chemicals in developing countries. PMID- 21522187 TI - Spatial and seasonal distribution of aerosol chemical components in New York City: (2) road dust and other tracers of traffic-generated air pollution. AB - We describe spatial and temporal patterns of seven chemical elements commonly observed in fine particulate matter (PM) and thought to be linked to roadway emissions that were measured at residential locations in New York City (NYC). These elements, that is, Si, Al, Ti, Fe, Ba, Br, and black carbon (BC), were found to have significant spatial and temporal variability at our 10 residential PM(2.5) sampling locations. We also describe pilot study data of near-roadway samples of both PM(10-2.5) and PM(2.5) chemical elements of roadway emissions. PM(2.5) element concentrations collected on the George Washington Bridge (GWB) connecting NYC and New Jersey were higher that similar elemental concentration measured at residential locations. Coarse-particle elements (within PM(10-2.5)) on the GWB were 10-100 times higher in concentration than their PM(2.5) counterparts. Roadway elements were well correlated with one another in both the PM(2.5) and PM(10-2.5) fractions, suggesting common sources. The same elements in the PM(2.5) collected at residential locations were less correlated, suggesting either different sources or different processing mechanisms for each element. Despite the fact that these elements are only a fraction of total PM(2.5) or PM(10-2.5) mass, the results have important implications for near-roadway exposures where elements with known causal links to health effects are shown to be at elevated concentrations in both the PM(2.5) and PM(10-2.5) size ranges. PMID- 21522189 TI - Estimation of age-specific per capita home-produced food intake among populations that garden, farm, or raise animals. AB - Intake of home-produced foods may be a concern in areas where chemical contamination exists. Estimating exposure to contaminants in home-produced foods requires knowledge of the amount of these foods consumed. The US Environmental Protection Agency's (US EPA's) Exposure Factors Handbook provides data on consumption of home-produced foods based on the US Department of Agriculture's (USDA's) 1987-1988 Nationwide Food Consumption Survey (NFCS), the most recent national food survey that contains the information necessary to estimate home produced consumption. These data represent "consumer-only" intake rate distributions for various age and demographic categories. "Consumers-only" information is also provided for households who garden, farm, and raise animals for all age groups combined. However, these "consumer-only" values may not always be appropriate when assessing chronic exposures. Furthermore, data for all ages combined may not be useful for estimating exposure among age groups that may be of particular concern. This paper provides age-specific "per capita" intake rate distributions of home-produced foods specifically for the populations that garden, farm, and raise animals, using data from EPA's Exposure Factors Handbook. PMID- 21522190 TI - Acute effect of ambient ozone on heart rate variability in healthy elderly subjects. AB - Acute ambient ozone (O(3)) exposure is associated with the increased mortality and morbidity of cardiovascular diseases. The dysfunction of cardiac autonomic nervous system (ANS), indicated by the disturbed heart rate variability (HRV), may be the most important underlying mechanism. Previous studies reported the heterogeneous associations between O(3) within several hours' exposure and HRV on general elderly subjects, in which poor surrogate of exposure evaluation and different health status of the subjects may be responsible for the heterogeneous associations. No studies were found focusing on the O(3)-mediated HRV effects within several minutes' exposure on healthy older subjects until recently. We measured the real-time 5-min ambient O(3) concentration and HRV frequency indices in 20 healthy elderly subjects in two surveys, with the 1st and 2nd survey in summer and winter, respectively. Mixed-linear model was used to evaluate the associations between the ambient 5-min average O(3) and concurrent 5-min HRV frequency indices measured during the outdoor period. After adjusting the co pollutants (ambient PM(2.5) and nitrogen oxides concentrations) and subject characteristics, high frequency (HF) changed -4.87% (95% CI -8.62 to -0.97%) per 10 ppb increment of O(3), whereas decreased low frequency (LF) and increased LFHFR were found to be marginally associated with the elevated O(3) (P values were 0.092 and 0.069). We concluded that the ambient O(3) exert transient decrease effects on HRV, which may induce acute cardiac events. PMID- 21522192 TI - Transplantation: Donor risk scores: can they predict renal transplant outcomes? PMID- 21522193 TI - Transplantation: Transplant tourism--an update regarding the realities. PMID- 21522194 TI - Chronic kidney disease: Medial or intimal calcification in CKD-does it matter? PMID- 21522191 TI - Subversion of the actin cytoskeleton during viral infection. AB - Viral infection converts the normal functions of a cell to optimize viral replication and virion production. One striking observation of this conversion is the reconfiguration and reorganization of cellular actin, affecting every stage of the viral life cycle, from entry through assembly to egress. The extent and degree of cytoskeletal reorganization varies among different viral infections, suggesting the evolution of myriad viral strategies. In this Review, we describe how the interaction of viral proteins with the cell modulates the structure and function of the actin cytoskeleton to initiate, sustain and spread infections. The molecular biology of such interactions continues to engage virologists in their quest to understand viral replication and informs cell biologists about the role of the cytoskeleton in the uninfected cell. PMID- 21522195 TI - Dialysis: Dietary phosphorus restriction: changing the paradigm? PMID- 21522196 TI - Analysis of physicians' referrals: is further diagnosis needed? AB - BACKGROUND: As physical therapy gradually evolves into a more autonomous profession, physicians continue to play a major role in the clinical practice of physical therapists, particularly as a source of patient referral. The analysis of physicians' referrals to physical therapy may be a practical and effective way to study the relationship between physicians and physical therapists. OBJECTIVES: The objective of this study was to identify the primary reasons for physicians' referrals to an outpatient physical therapy clinic and to determine whether further diagnosis by the physical therapist is necessitated prior to treatment. METHODS: Between January 1, 2001 and March 31, 2003, 544 consecutive physicians' referrals were received in a rural physical therapy outpatient clinic. Physicians' specialties, diagnosis on referral (or reason for referral, if diagnosis not provided), and prescribed orders on referral were all reviewed by the authors. RESULTS: One-third (33%) of the referrals were sent to physical therapy with no medical diagnosis (non-specified referrals - NSRs), and the most common reason for the referral in this NSR category was "pain" (88%). Commonly recommended treatments accompanying the NSRs included: evaluation & treatment (60%) and routine rehabilitation protocol (24%) for the relevant joints. CONCLUSION: One-third (33%) of the referrals sent to physical therapy included no medical diagnosis, with the most common reason for the referral listed as "pain." Evaluation and treatment was the most recommended treatment accompanying these non-specific referrals (almost 2/3). Physical therapists cannot properly manage patients based on a physician referred diagnosis of "pain," therefore, it is necessary for physical therapists to make further diagnoses. PMID- 21522197 TI - Non-operative rehabilitation for traumatic and atraumatic glenohumeral instability. AB - Glenohumeral joint instability is a common pathology encountered in the orthopaedic and sports medicine setting. A wide range of symptomatic shoulder instabilities exist ranging from subtle subluxations due to contributing congenital factors to dislocations as a result of a traumatic episode. Non operative rehabilitation is utilized in patients diagnosed with shoulder instability to regain their previous functional activities through specific strengthening exercises, dynamic stabilization drills, neuromuscular training, proprioception drills, scapular muscle strengthening program and a gradual return to their desired activities. The specific rehabilitation program should be varied based on the type and degree of shoulder instability present and desired level of function. The purpose of this paper is to outline the specific principles associated with non-operative rehabilitation for each of the various types of shoulder instability and to discuss the specific rehabilitation program for each pathology type. PMID- 21522198 TI - Returning to sports after periacetabular osteotomy for developmental dysplasia of the hip. AB - BACKGROUND: A periacetabular osteotomy,indicated for adults or adolescents requiring correction of congruency and containment of the femoral head, is a common surgical procedure to address developmental dysplasia of the hip. OBJECTIVES: To describe developmental hip dysplasia, a surgical procedure performed to address the condition, as well as therapeutic exercise and functional progression principles utilized to return a patient to tennis following periacetabular osteotomy. CASE DESCRIPTION: The patient was a 14 year old female who underwent a Ganz periacetabular osteotomy of the right pelvis due to developmental dysplasia of the hip. Post-operative outpatient physical therapy consisted of strengthening of the hip, thigh, and core musculature, as well as activities to increase muscular and cardiovascular endurance, anaerobic conditioning, lower extremity proprioception, and soft tissue length. A functional progression program to return to tennis was also provided. OUTCOMES: The patient was seen in outpatient physical therapy for a total of 34 visits over the course of 42 weeks. Results of a Lower Extremity Functional Scale (LEFS) indicated that heavy activities of daily living, as well as recreational and sporting activities, were improved following the post-operative rehabilitation program. DISCUSSION: The role of the physical therapist is vital in prescribing and progressing activity levels to facilitate return of function following this periacetabular osteotomy. Surgery that is technically well performed followed by a comprehensive rehabilitation program can allow for resumption of pre-morbid activities, enhancement of the quality of life, and return to sports activities. PMID- 21522199 TI - The effect of pilates exercise on trunk and postural stability and throwing velocity in college baseball pitchers: single subject design. AB - BACKGROUND: Baseball pitchers need trunk strength to maximize performance. The Pilates method of exercise is gaining popularity throughout the country as a fitness and rehabilitation method of exercise. However, very few studies exist that examine the effects of the Pilates method of exercise on trunk strength or performance. OBJECTIVES: Using a single subject, multiple baseline across subjects design, this study examines the effects of the Pilates method of exercise on performance of double leg lowering, star excursion balance test, and throwing velocity in college-aged baseball pitchers. METHODS: A convenience sample of three college baseball pitchers served as the subjects for this single subject design study. For each subject, double leg lowering, star excursion balance test, and throwing speed were measured prior to the introduction of the intervention. When baseline test values showed consistent performance, the intervention was introduced to one subject at a time. Intervention was introduced to the other subjects over a period of 4 weeks as they also demonstrated consistent performance on the baseline tests. Intervention was continued with periodic tests for the remainder of the 10 week trial. RESULTS: Each subject improved in performance on double leg lowering (increased 24.43-32.7%) and star excursion balance test (increased 4.63-17.84%) after introduction of the intervention. Throwing speed improved in two of the three subjects (up to 5.61%). DISCUSSION AND CONCLUSIONS: The Pilates method of exercise may contribute to improved performance in double leg lowering, star excursion balance tests, and throwing speed in college baseball pitchers. PMID- 21522200 TI - Pectoralis major tendon repair post surgical rehabilitation. AB - Pectoralis major tendon rupture is a rare shoulder injury, most commonly seen in weight lifters. This injury is being seen more regularly due to the increased emphasis on healthy lifestyles. Surgical repair of the pectoralis major tendon rupture has been shown to provide superior outcomes regarding strength return. Thus it appears that surgical repair is the treatment of choice for those wishing to return to competitive or recreational athletic activity. This article describes the history and physical examination process for the athlete with pectoralis tendon major rupture. Surgical vs conservative treatment will be discussed. This manuscript provides post surgical treatment guidelines that can be followed after surgical repair of the pectoralis tendon rupture. PMID- 21522201 TI - Surface electromygraphic analysis of the lower trapezius muscle during exercises performed below ninety degrees of shoulder elevation in healthy subjects. AB - BACKGROUND: The lower trapezius is an important muscle for normal arthrokinematics of the scapula. In the early stages of rehabilitation, it is generally accepted to perform exercises with the shoulder kept below 90 degrees of elevation in order to minimize risk for shoulder impingement. Few exercises for the lower trapezius have been studied which maintain the shoulder below 90 degrees of humeral elevation. OBJECTIVE: To identify therapeutic exercises performed below 90 degrees of humeral elevation that activate marked levels of lower trapezius electromyographic (EMG) activity. METHODS: SURFACE EMG ACTIVITY OF THE LOWER, MIDDLE, UPPER TRAPEZIUS, AND SERRATUS ANTERIOR WAS COLLECTED BILATERALLY ON FIFTEEN HEALTHY SUBJECTS DURING FOUR EXERCISES: the press-up, unilateral scapular retraction with the shoulder positioned at 80 degrees of shoulder flexion, bilateral shoulder external rotation, and unilateral scapular depression. RESULTS: The press-up exercise elicited marked lower trapezius EMG activity, moderate upper trapezius EMG activity, and a high ratio of lower trapezius to upper trapezius EMG activity. Scapular retraction produced marked EMG activity of both the lower and upper trapezius and moderate activity of the middle trapezius. Bilateral shoulder external rotation generated moderate lower trapezius EMG activity, minimal upper trapezius activity, and the highest ratio of lower trapezius to upper trapezius EMG activity. Scapular depression produced moderate lower trapezius EMG activity, mimimal upper trapezius EMG activity, and a moderately high ratio of lower trapezius to upper trapezius EMG activity. DISCUSSION AND CONCLUSIONS: This study identified two exercises performed below 90 degrees of humeral elevation that markedly activated the lower trapezius: the press-up and scapular retraction. PMID- 21522202 TI - Differences in static scapular position between rock climbers and a non-rock climber population. AB - BACKGROUND: The increasingly popular sport of rock climbing is an activity which predisposes participants to overuse injuries. The unique physical demands associated with climbing, as well as a reported 33%-51% incidence of shoulder injuries in these athletes is suggestive of abnormalities in scapulohumeral biomechanics. OBJECTIVE: To examine the glenohumeral to scapulothoracic (GH:ST) ratio, as represented by end range static positions (ERSP) of the scapula and humerus, in a group of rock climbers and compare it to a group of non-climbers. METHODS: The GH:ST ratio of twenty-one experienced rock climbers was compared with 40 non-climbers using a bubble inclinometer to measure scapular upward rotation at the subjects' maximum glenohumeral elevation. RESULTS: As represented by ERSP, rock climbers had a significantly greater GH:ST ratio than non-climbers. The mean ratio of climbers was 3.7:1 compared with non-climbers at 2.8:1. Scapulothoracic motion appeared to be the source of this difference. DISCUSSION AND CONCLUSION: A possible explanation for this difference could be related to the extreme and prolonged positioning associated with rock climbing maneuvers that result in shoulder musculature imbalances in strength and flexibility. PMID- 21522203 TI - Unique positioning for using elastic resistance band in providing strengthening exercise to the muscles surrounding the ankle. AB - Ankle sprains are among the most common injuries incurred by participants in athletics. Conservative management of the patient after an ankle sprain includes a comprehensive rehabilitation program of which the resistance exercises are a part and are frequently advised by the clinician, many times as part of a home exercise program. The purpose of this Clinical Suggestion is to present a unique method of using elastic resistance band to provide strengthening activities to the inverters, ever-tors, plantarflexors, and dorsiflexors of the ankle. The method is unique, as well as convenient and efficient, as it allows the subject to perform all four exercises with a minimum of change in position, while staying seated in a chair. PMID- 21522204 TI - The effects of repetitive overhead throwing on shoulder rotator isokinetic work fatigue. AB - BACKGROUND: Muscle strength and endurance of the shoulder rotators is important for overhead throwing performance and dynamic glenohumeral stability. Baseball pitching is distinguished as an intermittent activity with explosive, high intensity muscle contractions separated by periods of rest. Rotator cuff muscle performance could acutely decrease due to fatigue associated with bouts of throwing. OBJECTIVE: This study examined the effects of repeated overhead throwing upon isokinetic muscle performance of the shoulder rotators. METHODS: Repeated-measures analyses of vari-ance were used to compare peak torque, total work, and work-fatigue by muscle group, time, and contraction type. Ten collegiate baseball pitchers underwent isokinetic testing of the internal (IR) and external shoulder (ER) rotators one week before and immediately after a throwing protocol of 60 maximal-effort pitches arranged into four innings of 15 pitches per inning. Isokinetic testing consisted of 12 concentric and eccentric repetitions at 300 deg/sec for internal and external rotation of the throwing extremity. RESULTS: The main effect of time and the interaction of muscle group and contraction type were significant for work-fatigue. Post-hoc analysis revealed that subjects had significantly greater eccentric IR work-fatigue (13.3 + 1%) compared to the pre-test (7.3 + 2%). DISCUSSION AND CONCLUSIONS: Throwing related fatigue affected both muscle groups, especially the IR, which has implications for dynamic glenohumeral stability. Rehabilitation and conditioning programs for competitive baseball pitchers should emphasize eccentric muscle endurance training of the shoulder rotators. PMID- 21522205 TI - Deconditioned Knee: The Effectiveness of a Rehabilitation Program that Restores Normal Knee Motion to Improve Symptoms and Function. AB - BACKGROUND: Knee pain can cause a deconditioned knee. Deconditioned is defined as causing one to lose physical fitness. Therefore, a deconditioned knee is defined as a painful syndrome caused by anatomical or functional abnormalities that result in a knee flexion contracture (functional loss of knee extension), decreased strength, and decreased function. To date, no published studies exist examining treatment for a deconditioned knee. OBJECTIVE: To determine the effectiveness of a rehabilitation program focused on increasing range of motion for patients with a deconditioned knee. METHODS: Fifty patients (mean age 53.2 years) enrolled in the study. Objective evaluation included radiographs, knee range of motion, and isokinetic strength testing. The International Knee Documentation Committee (IKDC) subjective questionnaire was used to measure symptoms and function. Patients were given a rehabilitation program to increase knee extension (including hyperextension) and flexion equal to the normal knee, after which patients were instructed in leg strengthening exercises. RESULTS: Knee extension significantly improved from a mean deficit of 10 degrees to 3 degrees and knee flexion significantly improved from a mean deficit of 19 degrees to 9 degrees . The IKDC survey scores significantly improved from a mean of 34.5 points to 70.5 points 1 year after beginning treatment. The IKDC subjective pain frequency and severity scores were significantly improved. CONCLUSIONS: A rehabilitation program that improves knee range of motion can relieve pain and improve function for patients with a deconditioned knee. PMID- 21522206 TI - Shoulder musculature activity and stabilization during upper extremity weight bearing activities. AB - BACKGROUND: Upper extremity weight-bearing exercises are routinely used in physical therapy for patients with shoulder pathology. However, little evidence exists regarding the demand on the shoulder musculature. OBJECTIVE: To examine changes in shoulder muscle activity and center of pressure during upper extremity weight-bearing exercises of increasing difficulty. METHODS: Electromyographic (EMG) and kinetic data were recorded from both shoulders of 15 healthy subjects (10 male and 5 female). Participants were tested in a modified tripod position under three conditions of increasing difficulty: (1) hand directly on the force plate, (2) on a green Stability Trainer(TM) and (3) on a blue Stability Trainer(TM). Ground reaction forces were recorded for each trial. Surface EMG was recorded from the serratus anterior, pectoralis major, upper trapezius, lower trapezius, infraspinatus, anterior deltoid, posterior deltoid, and the lateral head of the triceps muscles. RESULTS: Mean deviation from center of pressure significantly increased when using the Stability Trainer(TM) pads. The activities of the triceps, serratus anterior, and anterior deltoid muscles significantly increased as each trial progressed, irrespective of stability condition. Additionally, activity in the anterior deltoid, lower trapezius, and serratus anterior muscles significantly decreased with increasing difficulty, whereas activity in the triceps muscles significantly increased. DISCUSSION AND CONCLUSION: Balancing on a foam pad made it more difficult to maintain the upper extremity in a stable position. However, this activity did not alter the proprioceptive stimulus enough to elicit an increase in shoulder muscle activation. While the results on this study support the use of different level Stability Trainers(TM) to facilitate neuromuscular re-education, a less compliant unstable surface may produce larger training effects. PMID- 21522207 TI - Reactive Neuromuscular Training: A Multi-level Approach to Rehabilitation of the Unstable Shoulder. AB - In this clinical commentary, the use of reactive neuromuscular training (RNT) will be discussed as part of an overall functional rehabilitation program in the treatment of the unstable glenohumeral joint. The RNT program is designed to restore the synchrony and synergy of muscle firing patterns about the shoulder, which are required for dynamic joint stability and fine motor control. Reactive neuromuscular training allows the clinician to bridge the gap between the achievement of clinical based goals and a return to athletic competition. The possible effects of RNT on central nervous system (CNS) programming to establish appropriate reflex responses and functional stability at the glenohumeral joint will be explored. The issues reviewed in this article will highlight the need for future research in this area. PMID- 21522208 TI - Kinematic and kinetic reliability of two jumping and landing physical performance tasks in young adult women. AB - BACKGROUND: Jumping and landing tasks are commonly used functional measurement tools to assess lower extremity performance in female athletes. However, few studies have established the number of trials needed to achieve reliability of measurement for evaluating landing mechanics. OBJECTIVE: To determine the reliability of peak hip and knee joint angles and peak ground reaction forces during two anterior-posterior unilateral functional tasks performed by young women. METHODS: Sixteen young women (28.5 +/- 4.2 years; 162.2 +/- 4.8 cm; 59.5 +/- 8.1 kg) participated in this investigation. Each participant performed five trials of a 40-cm single leg drop jump and two trials of a ten-repetition, 20-cm, single leg up-down hop task during the same session. Peak hip and knee joint angles, peak vertical ground reaction forces, and ground contact time were measured. Intraclass correlation coefficients (ICC), standard errors of measurement, and 95% confidence intervals were calculated for all variables measured during multiple trials for both tasks. RESULTS: The five-trial mean ICC values of the drop jump were >= 0.75 for all variables. The single and two to four-trial average ICC values yielded good reliability for only some variables. Single-trial and two-trial mean ICC values for the up down test were >= .77. DISCUSSION AND CONCLUSION: The use of five-trial averages for the 40-cm drop jump and a single trial for the 20-cm, up-down hop task showed that for these functional tasks performed by young adult women, reliable measurement of lower extremity landing mechanics can be achieved. PMID- 21522209 TI - Community-associated methicillin-resistant Staphylococcus aureus. AB - Methicillin resistant Staphylococcus aureus (MRSA), is a problematic infection which is becoming more common in a variety of athletic related environments. Early recognition, diagnosis, and timely management of infection can help minimize the severity of infection and decrease the rate of transmission. Since most sports physical therapists typically lack adequate knowledge and ability to identify cases of MRSA infection, the pur-pose of this review is to provide a background for associated risk factors, recognition, treatment, and prevention of community associated-MRSA in athletic environments. PMID- 21522210 TI - Can Serious Injury in Professional Football be Predicted by a Preseason Functional Movement Screen? AB - BACKGROUND: Little data exists regarding injury risk factors for professional football players. Athletes with poor dynamic balance or asymmetrical strength and flexibility (i.e. poor fundamental movement patterns) are more likely to be injured. The patterns of the Functional Movement Screen(TM) (FMS) place the athlete in positions where range of motion, stabilization, and balance deficits may be exposed. OBJECTIVES: To determine the relationship between professional football players' score on the FMS(TM) and the likelihood of serious injury. METHODS: FMS(TM) scores obtained prior to the start of the season and serious injury (membership on the injured reserve for at least 3 weeks) data were complied for one team (n = 46). Utilizing a receiver-operator characteristic curve the FMS(TM) score was used to predict injury. RESULTS: A score of 14 or less on the FMS(TM) was positive to predict serious injury with specificity of 0.91 and sensitivity of 0.54. The odds ratio was 11.67, positive likelihood ratio was 5.92, and negative likelihood ratio 0.51. DISCUSSION AND CONSCLUSION: The results of this study suggest fundamental movement (as measured by the FMS(TM)) is an identifiable risk factor for injury in professional football players. The findings of this study suggest professional football players with dysfunctional fundamental movement patterns as measured by the FMS(TM) are more likely to suffer an injury than those scoring higher on the FMS(TM). PMID- 21522211 TI - Reference Values for the Closed Kinetic Chain Upper Extremity Stability Test (CKCUEST) for Collegiate Baseball Players. AB - BACKGROUND: The Closed Kinetic Chain Upper Extremity Stability Test (CKCUEST) is a tool developed and used in the clinic to evaluate progress during upper extremity rehabilitation. A need exists for reference values of CKCUEST for use in a clinical setting. OBJECTIVES: To calculate reference values for the CKCUEST that may assist clinicians in developing goals and objectives for male collegiate baseball players who are recovering from injuries to the upper extremity. To determine if differences exist in scores according to playing position. METHODS: The sample consisted of 77 collegiate, male baseball players between the ages of 18 and 22 who reported no recent history of injuries to the shoulder, elbow, or the hand-wrist complex. The CKCUEST was administered three times to the athletes and the number of touches when performing the CKCUEST during the 15-second test was measured and recorded. An average of the three tests was used for data analysis. RESULTS: No significant differences existed according to playing position. The data did not differ from the normal distribution; therefore, reference values were calculated and reported for use by clinicians in development of goals and objectives for this population. DISCUSSION AND CONCLUSION: The CKCUEST appears to be a clinically useful test for upper extremity function. PMID- 21522212 TI - Hip strength and knee pain in females. AB - BACKGROUND: Poor alignment between the patella, tibia, and femur has been identified as a primary cause of anterior knee pain. More recently, impaired hip strength has been discussed as a possible reason for the onset of knee pain. OBJECTIVES: The purpose of this study was to determine if individuals with knee pain had weakness in the hip muscles. METHODS: Nineteen females between the ages of 18 and 40, experiencing unilateral knee pain for no greater than four weeks, were examined. Bilateral gluteus maximus and medius strength were measured with a MicroFET hand-held dynamometer. RESULTS: Strength of the gluteus medius and maximus muscles were significantly less in the extremities of patients experiencing knee pain than the extremity without knee pain. DISCUSSION AND CONCLUSION: Given biomechanical relationships between the hip and knee, examining the entire lower kinetic chain should occur when evaluating patients with knee pain. Using impairment-based interventions, such as addressing hip strength in addition to knee pain, may enhance intervention effectiveness. Results of this study provide data that suggest that individuals with knee pain had weak hip muscles. PMID- 21522213 TI - Exercise Related Leg Pain (ERLP): a Review of The Literature. AB - Exercise related leg pain (ERLP) is a regional pain syndrome described as pain between the knee and ankle which occurs with exercise. Indiscriminant use of terminology such as "shin splints" has resulted in ongoing confusion regarding the pathoanatomic entities associated with this pain syndrome. Each of the pathoanatomic entities - medial tibial stress syndrome, chronic exertional compartment syndrome, tibial and fibular stress fractures, tendinopathy, nerve entrapment, and vascular pathology - which manifest as ERLP are each described in terms of relevant anatomy, epidemiology, clinical presentation, associated pathomechanics, and intervention strategies. Evidence regarding risk factors for ERLP general and specific pathoanatomic entities are presented in the context of models of sports injury prevention. PMID- 21522214 TI - Use of pool noodles for the shoulder and ankle. AB - The purpose of this manuscript is to provide two clinical suggestions that are inexpensive, easy to fabricate, and very user-friendly activities that can be used for most patients and athletes. The first clinical suggestion is a method of restoring stability of the scapular muscles around the shoulder complex. Following a period of disuse, whether from a surgery or an injury, weakness may be present in the shoulder. This suggestion is an easy and inexpensive tool which can be used in restoring stability of the scapula in all planes of movement as well as combinations of these planes. The method can also be used as a progression from gravity assisted to gravity resisted active range of motion. The purpose of the second clinical suggestion is to provide an inexpensive and easy to use method of improving proprioception in the ankle. Ankle sprains are among the most common injuries seen in sports. Proprioceptive activities are used not only in the rehabilitation process following an injury but as a training tool to help prevent ankle injuries. This method can be used in the clinic, in a training facility, or as part of a home exercise program. PMID- 21522215 TI - A Comparison of the Immediate Effects of Eccentric Training vs Static Stretch on Hamstring Flexibility in High School and College Athletes. AB - BACKGROUND: A pre-event static stretching program is often used to prepare an athlete for competition. Recent studies have suggested that static stretching may not be an effective method for stretching the muscle prior to competition. OBJECTIVE: The intent of this study was to compare the immediate effect of static stretching, eccentric training, and no stretching/training on hamstring flexibility in high school and college athletes. METHODS: Seventy-five athletes, with a mean age of 17.22 (+/- 1.30) were randomly assigned to one of three groups - thirty- second static stretch one time, an eccentric training protocol through a full range of motion, and a control group. All athletes had limited hamstring flexibility, defined as a 20 degrees loss of knee extension measured with the femur held at 90 degrees of hip flexion. RESULTS: A significant difference was indicated by follow up analysis between the control group (gain = -1.08 degrees ) and both the static stretch (gain = 5.05 degrees ) and the eccentric training group (gain = 9.48 degrees ). In addition, the gains in the eccentric training group were significantly greater than the static stretch group. DISCUSSION AND CONCLUSION: The findings of this study reveal that one session of eccentrically training through a full range of motion improved hamstring flexibility better than the gains made by a static stretch group or a control group. PMID- 21522216 TI - Pre-participation screening: the use of fundamental movements as an assessment of function - part 1. AB - To prepare an athlete for the wide variety of activities needed to participate in their sport, the analysis of fundamental movements should be incorporated into pre-participation screening in order to determine who possesses, or lacks, the ability to perform certain essential movements. In a series of two articles, the background and rationale for the analysis of fundamental movement will be provided. In addition, one such evaluation tool that attempts to assess the fundamental movement patterns performed by an individual, the Functional Movement Screen (FMS(TM)), will be described. Three of the seven fundamental movement patterns that comprise the FMS(TM) are described in detail in Part I: deep squat, hurdle step, and in-line lunge. Part II of this series, which will be published in the August issue of NAJSPT, will provide a brief review of the analysis of fundamental movements, as well a detailed description of the four additional patterns that complement those presented in Part I (to complete the total of seven fundamental movement patterns which comprise the FMS(TM)): shoulder mobility, active straight leg raise, trunk stability push-up, and rotary stability.The intent of this two part series is to introduce the concept of the evaluation of fundamental movements, whether it is the FMS(TM) system or a different system devised by another clinician. Such a functional assessment should be incorporated into pre-participation screening in order to determine whether the athlete has the essential movements needed to participate in sports activities with a decreased risk of injury. PMID- 21522217 TI - Electromyography of Selected Shoulder Musculature During Un-weighted and Weighted Pendulum Exercises. AB - BACKGROUND: Codman's pendulum exercises are commonly prescribed after shoulder surgery and injury to provide grade I and II distraction and oscillation resulting in decreased pain, increased flow of nutrients into the joint space, and early joint mobilization. Many shoulder protocols suggest that weight may be added to these pendulum exercises as rehabilitation progresses, however, very few guidelines exist to stipulate how much weight should be added. OBJECTIVES: To determine if added weight affected the subject's ability to relax the shoulder musculature during pendulum exercises. METHODS: Twenty-six participants, ages 20 to 56 years old (mean 32.26, +/- 8.51 years) were divided into two groups, nine pathological and 17 non-pathological. The muscle activity (EMG) of four variations of Codman's pendulum exercises 1) wrist suspended 1.5 kg weighted ball, 2) hand-held 1.5 kg dumbbell, 3) hand-held 1.5 kg weighted-ball, and 4) no weight were recorded in each muscle. RESULTS: When grouped across all patients and all other factors included in the ANOVA, the type of pendulum exercise did not have a significant effect on shoulder EMG activity regardless of patient population or muscle tested. Generally, the supraspinatus/upper trapezius muscle activity was significantly higher than the deltoid and infraspinatus activity - especially in the patients with pathological shoulders CONCLUSION: Performing the exercises with added weight did not result in significant increased shoulder EMG activity for the deltoid and infraspinatus muscles in subjects with and without shoulder pathology. However, patients with shoulder pathology had greater difficulty relaxing their supaspinatus/upper trapezius muscle group during Codman's pendulum exercises than healthy subjects. PMID- 21522218 TI - Trunk rotation strength and endurance in healthy normals and elite male golfers with and without low back pain. AB - BACKGROUND: The relative importance and asymmetric loading of the trunk muscles in golf (slow rotation backswing followed by high velocity downswing) may cause side-to-side imbalances in axial rotation strength and endurance characteristics amongst elite players who frequently play and practice. Such imbalances may further be compounded by the presence of low back pain. OBJECTIVE: To establish and compare trunk rotation strength and endurance of healthy individuals who do not play golf and those that are highly skilled at the sport. Additionally, a smaller group of elite golfers with non-debilitating low back pain (LBP) were also evaluated and compared to their healthy counterparts. METHODS: Forty healthy non-golfing control subjects, 32 healthy elite golfers, and 7 golfers with LBP participated in this study. Bilateral trunk rotation strength and endurance was assessed using the Biodex System III Isokinetic Dynamometer with torso rotation attachment. Strength and endurance data was analyzed using 2-way ANOVA. RESULTS: No significant differences in peak torque were found within or between groups. However, golfers with LBP demonstrated significantly less endurance in the non dominant direction (the follow-through of the golf swing) than either healthy group. No significant difference in endurance was found between the non-golfing controls and the healthy elite golfers. CONCLUSIONS: Trunk rotation endurance in golfers with LBP might be more important than strength alone in the prevention and treatment of LBP. The results from this study provide useful information on possible risk factors associated with low back pain in golfers (decreased endurance) and allow for sport-specific clinical intervention strategies to be developed. PMID- 21522219 TI - Prevention and Treatment of Swimmer's Shoulder. AB - Swimmer's shoulder is a musculoskeletal condition that results in symptoms in the area of the anterior lateral aspect of the shoulder, sometimes confined to the subacromial region. The onset of symptoms may be associated with impaired posture, glenohumeral joint mobility, neuromuscular control, or muscle performance. Additionally, training errors such as overuse, misuse, or abuse may also contribute to this condition. In extreme cases, patients with swimmer's shoulder may have soft tissue pathology of the rotator cuff, long head of the biceps, or glenoid labrum. Physical therapists involved in the treatment of competitive swimmers should focus on prevention and early treatment, addressing the impairments associated with this condition, and analyzing training methods and stroke mechanics. The purpose of this clinical commentary is to provide an overview of the biomechanics of swimming, the etiology of the clinical entity referred to as swimmer's shoulder, and strategies for injury prevention and treatment. PMID- 21522220 TI - Physiotherapist delivered preparticipation examination: rationale and evidence. AB - Preparticipation examinations are often performed based on the assumption that the exam contributes to the identification of risk factors for injury and, therefore, lead to the implementation of appropriate injury prevention strategies for athletes. Research evidence supporting the components, benefits, and limitations of the preparticipation examination performed by a physiotherapist is the focus of this paper. Evidence exists that some specific preparticipation examination components will identify known risk factors which may be addressed in the context of injury prevention strategies for that athlete. Examinations should use existing evidence-based practice to identify valid and appropriate tests examining known risk factors. Physiotherapists are encouraged to continue development, implementation, and evaluation of appropriate training techniques for the athletes to minimize their risk of injury. Physiotherapists need to be aware of athlete confidentiality issues as well as the importance of cost effectiveness of preparticipation examinations. The future of physiotherapist delivered preparticipation examinations may lie in the utilization of an evidence based approach to risk factor identification, development and evaluation of prevention strategies, and development and evaluation of performance enhancement strategies for the athlete. PMID- 21522221 TI - Cardiovascular prevention in a high risk sport, ice hockey: applications in wider sports physical therapy practice. AB - Although acute myocardial infarction and sudden cardiac death are relatively rare occurrences in athletics, cardiovascular accidents do occur. This manuscript presents information on the cardiovascular risks in athletics. In addition, information is provided on screening for cardiovascular risk - including history taking, chart review, physical examination - and the appropriate guidelines on the treatment of athletes found to be at risk. For the purpose of this article, the sport of ice hockey is used to illustrate the subject matter and highlight the behaviors in sport that carry cardiovascular risk. Physical therapists have ethical and legal responsibility to undertake the necessary screening procedures to recognize and respond to any signs of cardiovascular risk in their clients. PMID- 21522222 TI - Current knowledge, perceptions, and interventions used by collegiate coaches in the u.s. Regarding the prevention and treatment of the female athlete triad. AB - BACKGROUND: Coaches play an important role in the prevention of female athlete triad, but their current knowledge level, perceptions, and practice behaviors are not known. OBJECTIVES: The purpose of this study was to describe the knowledge, perceptions, and behaviors college coaches have about the female athlete triad. This study's purpose was to describe the relationships between these variables, and to compare coaches having high levels of general knowledge about the triad with coaches having low levels of general knowledge with their perceptions, behaviors, and more specific knowledge about the triad. METHODS: A questionnaire was sent to 300 Division I collegiate coaches in the United States. Descriptive statistics, the Pearson product-moment correlation, and independent t-tests were used to describe the participants, relationships between variables, and compare groups of coaches with high and low levels of knowledge about the triad. RESULTS: Forty-three percent of the 91 college coaches responding to the survey (30% return rate) were able to correctly list the specific components of the disorder. Coaches with high levels of general knowledge about the triad had statistically significant differences in their perceptions, behaviors, and more specific knowledge of the triad than coaches with low levels of general knowledge about the triad. CONCLUSION: The best intervention for the female athlete triad is prevention. Future education about the triad should focus on treatment and prevention as well as specific factors related to the syndrome, such as nutritional requirements, methods of assessing menstrual irregularities, and screening techniques. PMID- 21522223 TI - Rehabilitation of Patients Following Autogenic Bone-Patellar Tendon-Bone ACL Reconstruction: A 20-Year Perspective. AB - Rehabilitation of patients following anterior cruciate ligament (ACL) reconstruction has undergone remarkable improvements over the past two decades. During this time, ACL research has been at the forefront of many orthopaedic and sports physical therapy clinics. With over 20 years of ACL rehabilitation experience (senior author) and prior collaboration with accelerated ACL rehabilitation pioneer K. Donald Shelbourne, the authors wish to present a unique perspective on the evolution of ACL rehabilitation.Prior to the classic article by Paulos et al in 1981,(1) literature on ACL rehabilitation was quite sparse. The basis for ACL rehabilitation at this time was founded in basic science studies conducted with animal models. In an effort to protect the graft, emphasis was placed on immobilization, extension limitation, restricted weight bearing, and delayed return to activity. Despite achieving good ligamentous stability, patients often experienced a spectrum of complications.In 1990, Shelbourne and Nitz(2) proposed an accelerated rehabilitation protocol following ACL reconstruction based on clinical experience. Their program emphasized delayed surgery, earlier range of motion and weight bearing, and full extension. As a result, patients experienced better clinical outcomes while maintaining knee stability.The rehabilitation program presented in this paper is still largely based on the principles of the accelerated protocol. As evidence-based practice and the call for prospective, randomized clinical research continues, the continued progress in treating patients with this injury will be enhanced. Furthermore, clinicians are urged not to lose sight of the clinical reasoning that helped evolve the ACL rehabilitation process where it is today. PMID- 21522224 TI - Use of Knee Extension Device During Rehabilitation of a Patient with Type 3 Arthrofibrosis after ACL Reconstruction. AB - BACKGROUND: Arthrofibrosis is a frequent complication following rehabilitation of a patient with anterior cruciate ligament (ACL) reconstruction. Although prevention is the best treatment, little information exists within the literature regarding the management and rehabilitation intervention for arthrofibrosis. In this case report a rehabilitation program in the treatment of a patient with arthrofibrosis is described. OBJECTIVES: To identify the importance of discrete measures of knee range of motion in the knee of a patient following ACL reconstruction in order to help prevent postoperative complications. CASE DESCRIPTION: The patient was an 18-year-old female who sustained an ACL and medial collateral ligament (MCL) injury in a basketball game and underwent an ACL reconstruction with an ipsilateral patellar tendon graft. The patient developed arthrofibrosis and, despite traditional physical therapy of therapeutic exercise and manual therapy, the patient continued to complain of pain, stiffness, limited activities of daily living, and the inability to participate in competitive sports. This patient used a knee extension device as part of her rehabilitation program. OUTCOMES: The patient was able to obtain knee extension and flexion equal to her opposite normal knee. Upon completion of the rehabilitation program, the patient returned to full activities of daily living and competitive sports. DISCUSSION: Increasing and maintaining knee extension that is equal to the opposite normal knee is an important component in the successful outcome for the patient after ACL reconstruction. The use of a knee extension device may provide an effective rehabilitation intervention in the treatment of arthrofibrosis. PMID- 21522225 TI - Pre-participation screening: the use of fundamental movements as an assessment of function - part 2. AB - Part I of this two-part series (presented in the May issue of NAJSPT) provided the background, rationale, and a complete reference list for the use of fundamental movements as an assessment of function during pre-participation screening. In addition, Part I introduced one such evaluation tool that attempts to assess the fundamental movement patterns of an individual, the Functional Movement Screen (FMS)(TM), and described three of the seven fundamental movement patterns that comprise the FMS(TM).Part II of this series provides a brief review of the analysis of fundamental movement as an assessment of function. In addition, four additional fundamental tests of the FMS(TM), which complement those described in Part I, will be presented (to complete the total of seven fundamental tests): shoulder mobility, active straight leg raise, trunk stability push-up, and rotary stability. These four patterns are described in detail, a grading system from 0-III is defined for each pattern, and the clinical implications for receiving a grade less than a perfect III are proposed.By reading Part I and Part II, it is hoped that the clinician will recognize the need for the assessment of fundamental movements, critique current and develop new methods of functional assessment, and begin to provide evidence related to the assessment of fundamental movements and the ability to predict and reduce injury. By using such a screening system, the void between pre-participation screening and performance tests will begin to close. PMID- 21522226 TI - The Lateral Scapular Slide Test: A Reliability Study of Males with and without Shoulder Pathology. AB - BACKGROUND: Abnormal scapular movement or malposition is related to shoulder pathology. The lateral scapular slide test (LSST) is used to determine scapular position with the arm abducted in three positions. OBJECTIVE: The purpose of this study was to test the reliability of the LSST using a scoliometer. METHODS: Thirty-three male subjects (18 to 34 years) participated in this study. Group one (n=15) had shoulder pathology; Group two (n=18) did not have pathology. A test retest, repeated measures design, with three experienced raters and the three positions of the LSST, was used to test the reliability of the LSST. All measurements in each position were taken bilaterally. RESULTS: Pearson Correlations for Position 1 and 2 ranged from .78 to .92 whereas position 3 ranged from .62 to .81. The ICC (2,2) ranged from .87 to .95 for positions 1 and 2. ICC (2,2) ranged from .70 to.82 for positions 3. Overall ICC (2,3) ranged from .83 to .96. The coefficients of determination ranged from .38 to .89. The SEM ranged from 3.00 to 8.26 mm, with the largest error found in position 3. DISCUSSION AND CONCLUSION: The LSST can be reliable in screening scapular position. Although a large range of error exists in measurements as indicated by the standard error of the measurement, the LSST provides more objective measures than pure observation. PMID- 21522228 TI - Erratum: [Bis(2-pyrid-yl)amine-N,N'](nitrato-O,O')cobalt(II) nitrate. Corrigendum. AB - The chemical name and formula in the paper by Castillo, Luque, De la Pinta & Roman [Acta Cryst. (2001), E57, m384-m386] is corrected.[This corrects the article DOI: 10.1107/S1600536801012909.]. PMID- 21522227 TI - Retraction of articles. AB - This article reports the retraction of 11 articles published in Acta Crystallographica Section E between 2005 and 2009. PMID- 21522229 TI - Vanadium(V) oxide arsenate(V), VOAsO(4). AB - The vanadyl arsenate, VOAsO(4), has been isolated by a solid-state reaction. The structure consists of distorted VO(6) octa-hedra and AsO(4) tetra-hedra sharing corners to build up VAsO(7) layers parallel to ac linked by edge-sharing of VO(6) octa-hedra, forming a three-dimensional framework. PMID- 21522230 TI - Redetermination of AgPO(3). AB - Single crystals of silver(I) polyphosphate(V), AgPO(3), were prepared via a phospho-ric acid melt method using a solution of Ag(3)PO(4) in H(3)PO(4). In comparison with the previous study based on single-crystal Weissenberg photographs [Jost (1961 ?). Acta Cryst. 14, 779-784], the results were mainly confirmed, but with much higher precision and with all displacement parameters refined anisotropically. The structure is built up from two types of distorted edge- and corner-sharing [AgO(5)] polyhedra, giving rise to multidirectional ribbons, and from two types of PO(4) tetra-hedra linked into meandering chains (PO(3))(n) spreading parallel to the b axis with a repeat unit of four tetra hedra. The calculated bond-valence sum value of one of the two Ag(I) ions indicates a significant strain of the structure. PMID- 21522231 TI - Al(0.5)Nb(1.5)(PO(4))(3). AB - Single crystals of the title compound, aluminium niobium triphosphate, Al(0.5)Nb(1.5)(PO(4))(3), have been synthesized by a high-temperature reaction in a platinium crucible. The Al(III) and Nb(V) atoms occupy the same site on the axis, with disorder in the ratio of 1:3. The fundamental building units of the title structure are isolated Al/NbO(6) octa-hedra and PO(4) tetra-hedra (. 2 symmetry), which are further inter-locked by corner-sharing O atoms, leading to a three-dimensional framework structure with infinite channels along the a axis. PMID- 21522232 TI - KNb(1.75)V(0.25)PS(10). AB - The title compound, potassium diniobium vanadium phospho-rus deca-sulfide, KNb(1.75)V(0.25)PS(10), was obtained by reaction of the elements with a eutectic mixture of KCl/LiCl. It is isostructural with the quaternary KNb(2)PS(10), but the Nb sites are occupied by statistically disordered Nb (87.5%) and V (12.5%) atoms. The structure is composed of anionic (infinity) (1)[M(2)PS(10)](-) chains (M = Nb/V) separated from each other by K(+) ions. The chain is composed of [MS(8)] distorted bicapped trigonal prisms and [PS(4)] tetra-hedra. There are no inter-chain bonding inter-actions. The crystal used for the X-ray analysis was a racemic twin. PMID- 21522233 TI - Poly[[piperazine-1,4-dium [diaqua-tetra-kis-(MU-sulfanediyldiacetato) dicerate(III)]] trihydrate]. AB - The title compound, (C(4)H(12)N(2))[Ce(2)(C(4)H(4)O(4)S)(4)(H(2)O)(2)].3H(2)O, features a polymeric anion with a centrosymmetric Ce(2)O(2) core and a Ce?Ce distance of 4.3625 (4) A. The anions form ribbons {[Ce(2)(C(4)H(4)O(4)S)(4)(H(2)O)(2)](2-)}(n) extending along [100]. The doubly protonated piperazinium cations reside on centers of inversion and link the polymeric ribbons via N-H?O hydrogen bonding. Each Ce(III) cation is ten coordinated by an O(2)S donor set from two tridentate sulfanediyldiacetate (tda) ligands, one water mol-ecule and three other tda O donors from adjacent {Ce(tda)(2)(H(2)O)} units in a distorted bicapped cubic environment. Additional O H?O hydrogen bonding involving the coordinated and solvent water mol-ecules is also present. H atoms of the crystal water molecules could not be located and were not included in the refinement. PMID- 21522234 TI - Chloridobis[N'-(2-meth-oxy-benzyl-idene)-4-nitro-benzohydrazidato-kappaO,N'](4 methyl-pyridine-kappaN)cobalt(III). AB - In the title complex, [Co(C(15)H(12)N(3)O(4))(2)Cl(C(6)H(7)N)], the Co(III) ion is coordinated by two N atoms and two O atoms from two deprotonated Schiff base ligands, one N atom from a 4-methyl-pyridine ligand and one Cl atom, forming a distorted octa-hedral geometry. The Co(III) ion is displaced by 0.038 (2) A from the equatorial plane towards the axial Cl atom. PMID- 21522235 TI - Bis(2-amino-6-methyl-pyridinium) tris-(pyridine-2,6-dicarboxyl-ato)zirconate(IV) dihydrate. AB - In the title compound, (C(6)H(9)N(2))(2)[Zr(C(7)H(3)NO(4))(3)].2H(2)O, the Zr(IV) atom is nine-coordinated by three pyridine-2,6-dicarboxyl-ate ligands in a distorted tricapped trigonal-prismatic ZrN(3)O(6) environment. The crystal packing is stabilized by inter-molecular N-H?O and O-H?O hydrogen bonds. PMID- 21522236 TI - Poly[[[diaqua-sodium]-MU(3)-5-carb-oxy-2-ethyl-1H-imidazole-4-carboxyl-ato kappaN,O:O:O] monohydrate]. AB - In the title complex, {[Na(C(7)H(7)N(2)O(4))(H(2)O)(2)].H(2)O}(n), the Na(I) atom exhibits a distorted octa-hedral geometry and is six-coordinated in an NO(5) environment. The equatorial plane is defined by three O atoms and one N atom from two distinct 5-carb-oxy-2-ethyl-1H-imidazole-4-carboxyl-ate (H(2)EIDC) ligands and one coordinated water mol-ecule, and the apical sites are occupied by one carboxyl O atom from one H(2)EIDC ligand and one O atom from the other coordinated water mol-ecule. The Na(I) atoms are linked by H(2)EIDC ligands, generating an infinite double chain along the a axis. These chains are further connected via O-H?O and N-H?O hydrogen bonds into a three-dimensional supra molecular network. PMID- 21522237 TI - Tetra-kis[(4-meth-oxy-carbon-yl)anilinium] hexa-chloridostannate(IV) dichloride. AB - The asymmetric unit of the title compound, (C(8)H(10)NO(2))(4)[SnCl(6)]Cl(2), contains two (4-meth-oxy-carbon-yl)anilinium cations, one chloride anion and one half of a hexa-chlorido-stannate(IV) dianion situated on a twofold rotation axis. All aminium H atoms are involved in N-H?Cl hydrogen bonding, which consolidate the crystal packing along with weak C-H?O inter-actions. PMID- 21522238 TI - Dichloridobis[2-(morpholin-4-yl)ethanamine-kappaN,N']cadmium. AB - In the title compound, [CdCl(2)(C(6)H(14)N(2)O)(2)], the Cl and Cd(II) atoms are located on a twofold rotation axis and the Cd(II) atom is octa-hedrally coordinated by two N,N'-bidentate 2-(morpholin-4-yl)ethanamine ligands and two trans-located Cl atoms. In the crystal, adjacent mol-ecules are linked by N-H?Cl and C-H?O hydrogen bonds into a three-dimensional structure. An intra-molecular C H?Cl hydrogen bond is also observed. PMID- 21522239 TI - Bis[2,6-bis-(2-meth-oxy-phen-yl)pyridinium] di-MU-bromido-bis [dibromidocuprate(II)]. AB - The title salt, (C(19)H(18)NO(2))(2)[Cu(2)Br(6)], was obtained from an attempt to synthesize the copper(II) complex of 2,6-bis-(2-meth-oxy-phen-yl)pyridine (L) from a reaction between CuBr(2) and one equivalent of L in CH(2)Cl(2) at room temperature. The resulting compound is the salt of the 2,6-bis-(2-meth-oxy-phen yl)pyridinium cation and 0.5 equivalents of a hexa-bromido-dicuprate(II) dianion. Both meth-oxy groups of the cationic pyridinium moiety are directed towards the N atom of the pyridine ring as a result of intra-molecular N-H?O hydrogen bonds. The centrosymmetric hexabromidodicuprate dianion possesses a distorted tetra hedral geometry at the copper ion. The Cu-Br bond lengths are 2.3385 (7) and 2.3304 (7) A for the terminal bromides, whereas the bond length between the Cu atom and two bridging bromides is slightly longer [2.4451 (6) A]. PMID- 21522240 TI - Tris{4-[(2H-tetra-zol-5-yl)meth-yl]morpholinium} dodeca-tungstophosphate hexa hydrate. AB - The title heteropolyoxidotungstate-based inorganic-organic hybrid material, (C(6)H(12)N(5)O)(3)[W(12)(PO(4))O(36)].6H(2)O, consists of one alpha-Keggin-type [W(12)(PO(4))O(36)](3-) polyoxidometalate anion (POM), three crystallographically independent 4-[(2H-tetra-zol-5-yl)meth-yl]morpholinium cations and six water mol ecules of crystallization. The morpholine ring of the cation adopts a chair conformation. The anion shows characteristic features with respect to bond lengths and angles. An extensive network of N-H?O, N-H?N, O-H?O and O-H?N hydrogen-bonding inter-actions between the organic cations, inorganic anion and the crystal water mol-ecules lead to a three-dimensional structure. Moreover, six uncoordinated water mol-ecules increase the number of hydrogen bonds in the network and lead to the formation of (H(2)O)(infinity) clusters. PMID- 21522241 TI - Di-MU(2)-acetato-diacetato-bis-{MU(2)-3,3',5,5'-tetra-meth-oxy-2,2-[ethane-1,2 diylbis(nitrilo-methyl-idyne)]diphenolato}tricobalt(II,III) dichloro-methane disolvate. AB - The trinuclear title compound, [Co(3)(CH(3)COO)(4)(C(20)H(22)N(2)O(6))(2)].2CH(2)Cl(2), contains mixed-valence cobalt ions in the following order Co(III)-Co(II)-Co(III) where all the three cobalt ions are hexa-coordinated. The central cobalt ion is situated on an inversion centre and is in an all-oxygen environment, coordinated by four phenolate O atoms and two O atoms from bridging acetate groups, while the terminal cobalt ion is hexa-coordinated by two phenolate O atoms, two acetate O atoms and two imine N atoms. This complex contains a high-spin central Co(II) and two terminal low-spin Co(III)i.e. Co(III)(S = 0)-Co(II)(S = 3/2)-Co(III)(S = 0). There are weak inter-molecular C-H?O inter-actions involving the meth-oxy groups, as well as inter-molecular C-H?O inter-actions involving the acetate anions. In addition, the dichoromethane solvate mol-ecules are held in place by weak C-H?Cl inter-actions. PMID- 21522242 TI - (6,6'-Dimethyl-2,2'-bipyridine-kappaN,N')diiodidomercury(II). AB - In the title complex, [HgI(2)(C(12)H(12)N(2))], the Hg(II) atom has a distorted tetra-hedral coordination formed by two N atoms of the 6,6'-dimethyl-2,2' bipyridine ligand and two terminal I atoms [N-Hg-N = 70.1 (2) and I-Hg-I = 130.59 (3) degrees ]. The crystal packing features pi-pi contacts between the pyridine rings of adjacent mol-ecules [centroid-centroid distance = 3.773 (5) A] and also between a pyridine ring of one mol-ecule and the five-membered chelate ring of an adjacent mol-ecule [centroid-centroid distance = 3.668 (4) A]. PMID- 21522243 TI - Bis(2,2'-bipyridine-kappaN,N')(nitrato-kappaO)copper(II) perchlorate. AB - In the title compound, [Cu(NO(3))(C(10)H(8)N(2))(2)]ClO(4), the five-coordinated Cu(II) atom has a distorted square-pyramidal CuN(4)O environment; the O atom is in the axial position whereas the N atoms from two bipyridine (bipy) ligands are in the equatorial plane. In the crystal, mol-ecules are assembled by C-H?O hydrogen bonding and pi-pi inter-actions between bipy groups [centroid-centroid distances = 3.7686 (16) and 3.7002 (16) A] into a three-dimensional network. The nitrite anion is equally disordered over two sets of sites. PMID- 21522244 TI - Poly[[tetra-kis-(MU-2-anilinobenzoato-kappaO:O')tetra-MU(1,1,1)-azido-tetra MU(1,1)-azido-octa-methano-lhexa-nickel(II)] methanol hexa-solvate]. AB - The crystal structure of the title compound, [Ni(6)(C(13)H(10)NO(2))(4)(N(3))(8)(CH(3)OH)(8)].6CH(3)OH, consists of a centrosymmetric hexa-nuclear [Ni(II) (6)(C(13)H(10)NO(2))(4)(N(3))(8)(CH(3)OH)(8)] mol-ecule and six methanol solvent mol-ecules. In the hexa-nuclear unit, the six octa-hedrally coordinated Ni(II) atoms are linked by four MU(1,1,1)-azide and four MU(1,1)-azide bridges, forming a face-sharing Ni(6)N(8) tetra-cubane-like unit with four missing corners. The Ni(II) atoms are further bridged by four MU(1,2)-carboxalate groups. Neighbouring hexa-nuclear units are connected via N-H?O hydrogen-bonding inter-actions into a three-dimensional structure. Although the H atoms of the methanol OH groups could not be located, O?N/O contacts between 2.65 and 2.86 A suggest that these mol ecules participate in hydrogen bonding. PMID- 21522245 TI - Poly[bis-(acetonitrile-kappaN)di-MU-thio-cyanato-kappaN,S;kappaS,N-nickel(II)]. AB - In the title compound, [Ni(NCS)(2)(CH(3)CN)(2)](n), the Ni(II) cation is coordinated by two N-bonded and two S-bonded thio-cyanate anions, as well as two acetonitrile mol-ecules in an octa-hedral NiN(4)S(2) coordination mode. The asymmetric unit comprises one nickel cation, two thio-cyanate anions and two actonitrile mol-ecules. In the crystal, the Ni(II) cations are connected by bridging thio-cyanate anions into a three-dimensional coordination network. PMID- 21522246 TI - Poly[diaqua-tris-(MU(4)-1,3-phenyl-ene-diacetato)-dicerium(III)]. AB - In the title coordination polymer, [Ce(2)(C(10)H(8)O(4))(3)(H(2)O)(2)](n), each Ce(III) atom is nine-coordinated by eight O atoms from six different 1,3-phenyl enediacetate (pda) bivalent anions and one O atom from a coordinated water mol ecule, forming a distorted tricapped trigonal-prismatic coordination geometry. Eight Ce(III) ions and twelve pda ligands form a large [Ce(8)(pda)(12)] ring, and four Ce(III) ions and six pda ligands form a small [Ce(4)(pda)(6)] ring. The rings are further connected by the coordination inter-actions of pda ligands and Ce(III), generating a three-dimensional supra-molecular framework. PMID- 21522247 TI - Tris(4,4'-bi-1,3-thia-zole-kappaN,N')iron(II) tetra-bromidoferrate(III) bromide. AB - In the [Fe(4,4'-bit)(3)](2+) (4,4'-bit is 4,4'-bi-1,3-thia-zole) cation of the title compound, [Fe(C(6)H(4)N(2)S(2))(3)][FeBr(4)]Br, the Fe(II) atom (3 symmetry) is six-coordinated in a distorted octa-hedral geometry by six N atoms from three 4,4'-bit ligands. In the [FeBr(4)](-) anion, the Fe(III) atom (3 symmetry) is four-coordinated in a distorted tetra-hedral geometry. In the crystal, inter-molecular C-H?Br hydrogen bonds and Br?pi inter-actions [Br?centroid distances = 3.562 (3) and 3.765 (2) A] link the cations and anions, stabilizing the structure. PMID- 21522249 TI - (Dimethyl sulfoxide-kappaO){4,4',6,6'-tetra-tert-butyl-2,2'-[1,2-dicyano-ethene 1,2-diylbis(nitrilo-methyl-idyne)]diphenolato-kappaO,N,N',O'}zinc(II) acetonitrile monosolvate. AB - The Zn atom in the title acetonitrile solvate, [Zn(C(34)H(42)N(4)O(2))(C(2)H(6)OS)].CH(3)CN, exists in a distorted square pyramidal geometry with the basal plane defined by the N(2)O(2) atoms of the tetra-dentate Schiff base and with the dimethyl sulfoxide O atom in the apical position. The tetra-dentate mode of coordination of the Schiff base ligand leads to a five-membered ZnN(2)C(2) chelate ring which adopts an envelope conformation with the Zn atom at the flap, and two six-membered ZnOC(4)N chelate rings, one of which is approximately planar (r.m.s. deviation = 0.054 A) but the other has significant puckering (r.m.s. deviation = 0.203 A). PMID- 21522248 TI - (4-Chloro-2-{[(pyridin-2-ylmeth-yl)imino]-meth yl}phenolato)iodido(methanol)zinc(II). AB - The title Schiff base zinc(II) complex, [Zn(C(13)H(10)ClN(2)O)I(CH(3)OH)], was synthesized by the reaction of 5-chloro-salicyl-aldehyde, 2-amino-methyl-pyridine and zinc iodide in methanol. The Zn(II) atom is five-coordinated by one phenolate O atom, one imine and one pyridine N atom of the Schiff base ligand, one methanol O atom and one I atom, forming a distorted square-pyramidal geometry, with the I atom at the apical site. The dihedral angle between the benzene and pyridine rings is 22.9 (2) degrees . In the crystal, centrosymmetrically related mol ecules are linked through inter-molecular O-H?O hydrogen bonds, forming dimers. PMID- 21522250 TI - trans-Tetra-aqua-bis-(pyridazine-4-car-box-yl-ato-kappaO)magnesium(II) dihydrate. AB - The crystal structure of the title compound, [Mg(C(5)H(3)N(2)O(2))(2)(H(2)O)(4)].2H(2)O, is composed of centrosymmetric monomers in which an Mg(II) ion is coordinated by two carboxyl-ate O atoms from the two pyridazine-4-carboxylate ligands. The monomers linked by O-H?O and O-H?N hydrogen bonds into layers which are held together by hydrogen bonds in which solvent water O atoms act as donors and acceptors, resulting in a three dimensional network. PMID- 21522251 TI - Bis(cytosinium) aqua-penta-chlorido-indate(III). AB - The asymmetric unit of the title compound, (C(4)H(6)N(3)O)(2)[InCl(5)(H(2)O)], comprises two independent cytosinium cations and an aquapentachloridoindate anion. The In(III) ion is in a slightly distorted octa-hedral coordination geometry. In the crystal, alternating layers of cations and anions are arranged along [010] and are linked via inter-molecular N-H?O, O-H?Cl and N-H?Cl hydrogen bonds, forming sheets parallel to (001). Additional stabilization within these sheeets is provided by weak inter-molecular C-H?O inter-actions. PMID- 21522252 TI - Dichlorido(dimethyl sulfoxide-kappaS)(eta-mesitylene)ruthenium(II). AB - The title compound, [RuCl(2)(C(9)H(12))(C(2)H(6)OS)], features a planar [maximum deviation = 0.0075 (17) A] eta(6)-bound mesitylene ligand and a dimethyl sulfoxide ligand coordinated via the S atom. The overall complex geometry about the Ru(II) atom is best described as a piano-stool configuration. PMID- 21522253 TI - Bis[N-(2-hy-droxy-eth-yl)-N-propyl-dithio-carbamato-kappaS,S']bis-(4-{[(pyridin-4 yl-methyl-idene)hydrazinyl-idene]meth-yl}pyridine-kappaN)cadmium. AB - The complete mol-ecule of the title compound, [Cd(C(6)H(12)NOS(2))(2)(C(12)H(10)N(4))(2)], is generated by crystallographic inversion symmetry. The distorted octa-hedral trans-N(2)S(4) donor set for the Cd(2+) ion is defined by two symmetrically S,S'-chelating dithio-carbamate anions and two pyridine N atoms derived from two monodentate 4-pyridine-aldazine (or 4 {[(pyridin-4-yl-methyl-idene)hydrazinyl-idene}meth-yl]pyridine) mol-ecules [dihedral angle between the aromatic rings = 17.33 (8) degrees ]. In the crystal, mol-ecules are connected into a supra-molecular chain via O-H?N hydrogen bonds involving the 4-pyridine-aldazine N atoms not involved in coordination to cadmium. Weak C-H?O and C-H?N links consolidate the packing. PMID- 21522254 TI - Azido{4,4'-dibromo-2,2'-[ethane-1,2-diyl-bis(nitrilo-methanylylidene)]diphenol ato-kappaO,N,N',O'}manganese(III). AB - In the title compound, [Mn(C(16)H(12)Br(2)N(2)O(2))(N(3))], the Mn(III) ion is chelated by a tetra-dentate Schiff base ligand and coordinated by the N atom of an azide ligand in a distorted square-pyramidal arrangement. It forms phenolate bridged out-of-plane dimers with Mn?O(phenolate) distances of 2.667 (2) A between pairs of inversion-related mol-ecules. In the crystal, there are offset inter complex face-to-face pi-pi inter-actions [centroid-centroid distances = 3.598 (2) A] involving one of the benzene rings of the ligands. PMID- 21522255 TI - Dichlorido(3,5,5'-trimethyl-1,3'-bi-1H-pyrazole-kappaN,N)copper(II). AB - In the title complex, [CuCl(2)(C(9)H(12)N(4))], the Cu(II) atom exhibits a distorted square-planar coordination geometry involving two chloride ions and two N-atom donors from the bipyrazole ligand. The chelate ring including the Cu(II) atom is essentially planar, with a maximum deviation of 0.0181 (17) A for one of the coordinated N atoms. This plane forms a dihedral angle of 30.75 (6) degrees with the CuCl(2) plane. In the crystal, each pair of adjacent mol-ecules is linked into a centrosymmetric dimer by N-H?Cl hydrogen bonds. The crystal structure is stabilized by inter-molecular C-H?N and C-H?Cl hydrogen bonds and weak slipped pi-pi stacking inter-actions between symmetry-related mol-ecules, with an inter-planar separation of 3.439 (19) A and a centroid-centroid distance of 3.581 (19) A. PMID- 21522256 TI - Bis(MU-cyclo-hexane-1,4-dicarboxyl-ato)bis-{aqua-[1-(1H-imidazo[4,5 f][1,10]phenanthrolin-2-yl)naphthalen-2-ol]cadmium} monohydrate. AB - The asymmetric unit of the title compound, [Cd(2)(C(8)H(10)O(4))(2)(C(23)H(14)N(4)O)(2)(H(2)O)(2)].H(2)O, consists of one half of the dimeric complex, which lies about an inversion centre, and a half occupancy solvent water mol-ecule on a general position. Each Cd(II) cation is six-coordinated by the two N atoms from one 1-(1H-imidazo[4,5 f][1,10]phenanthrolin-2-yl)naphthalen-2-ol (L) ligand and three O atoms from two different 1,4-chdc(2-) ligands (1,4-H(2)chdc = cyclo-hexane-1,4-dicarb-oxy-lic acid), two coordinating in a bidentate fashion and the other in a monodentate fashion. The distorted octa-hedral coordination sphere is completed by a coordinated water mol-ecule. The Cd(II) atoms are each bridged by two 1,4-chdc(2 ) ligands, forming an inversion dimer with the L ligands located on the outside of the dimeric unit. An intra-molecular N-H?O hydrogen bond occurs. In the crystal, O-H?O and N-H?O hydrogen-bonding inter-actions stabilize the packing. PMID- 21522257 TI - Bis(3-carb-oxy-5-nitro-benzoato)bis-[2-(pyridin-4-yl)-1H-imidazo[4,5 f][1,10]phenanthroline]manganese(II). AB - In the title compound, [Mn(C(8)H(4)NO(6))(2)(C(18)H(11)N(5))(2)], the Mn(II) atom is six-coordinated by two N,N'-bidentate 6-(pyridin-4-yl)-5H-cyclo-penta [f][1,10]phenanthroline (pcp) ligands and two carboxyl-ate O atoms from two monodentate 3-carb-oxy-5-nitro-benzoate anions in a distorted cis-MnO(2)N(4) octa hedral arrangement. Within the pcp ligands, the dihedral angles between the polycyclic skeletons and pendant pyridine rings are 6.2 (2) and 8.3 (2) degrees . In the crystal, mol-ecules are linked by O-H?N and N-H?O hydrogen bonds. Several aromatic pi-pi stacking inter-actions [shortest centroid-centroid separation = 3.516 (3) A] are also observed. PMID- 21522258 TI - Di-MU-chlorido-bis-{chlorido[4-nitro-N-(pyridin-2-yl-methyl-idene-kappaN)aniline kappaN]mercury(II)}. AB - In the centrosymmetric dinuclear title complex, [Hg(2)Cl(4)(C(12)H(9)N(3)O(2))(2)], the Hg(II) ion is in a distorted square pyramidal coordination environment formed by the N atoms of the diimine ligand, two bridging Cl atoms and one terminal Cl atom. One of the bridging Hg-Cl bonds is significantly longer than the other. PMID- 21522259 TI - {6,6'-Dimeth-oxy-2,2'-[ethane-1,2-diylbis(nitrilo-methanylyl idene)]diphenolato}nickel(II) dimethyl-formamide monosolvate. AB - In the title compound, [Ni(C(18)H(18)N(2)O(4))].C(3)H(7)NO, the central Ni(II) atom is in a square-planar O(2)N(2) coordination environment. The planar Ni-salen moieties (r.m.s. deviation for the plane through the conjugated part of the Ni salen group = 0.07 A) form parallel stacks in the a-axis direction, with alternating Ni?Ni separations of 3.5339 (7) and 3.6165 (7) A. In the crystal, there are weak inter-molecular C-H?O inter-actions involving the dimethyl formamide O and phenolate O atoms. PMID- 21522260 TI - [N'-(3-Meth-oxy-2-oxidobenzyl-idene-kappaO)benzohydrazidato-kappaN',O]tris (pyridine-kappaN)cobalt(III) perchlorate. AB - In the mononuclear title compound, [Co(III)(C(15)H(12)N(2)O(3))(C(5)H(5)N)(3)]ClO(4), the Co(III) ion is coordinated by three pyridine mol-ecules and one N'-(3-meth-oxy-2-oxidobenzyl idene)benzohydrazidate Schiff base ligand in an O,N,O'-tridentate manner. The Co(III) ion adopts a distorted CoN(4)O(2) octa-hedral coordination environment. PMID- 21522261 TI - [2,9-Bis(3,5-dimethyl-1H-pyrazol-1-yl-kappaN)-1,10-phenanthroline kappaN,N'](methanol-kappaO)(nitrito-kappaO,O')cadmium(II) perchlorate. AB - In the title complex, [Cd(NO(2))(C(22)H(20)N(6))(CH(3)OH)]ClO(4), the Cd(II) ion is in a distorted penta-gonal-bipyramidal CdN(4)O(3) coordination geometry. The dihedral angles formed between the mean planes of the pyrazole rings and the phenanthroline ring system are 4.37 (19) and 5.84 (21) degrees . In the crystal, the anions and cations are connected by inter-molecular O-H?O hydrogen bonding, while pairs of weak inter-molecular C-H?O hydrogen bonds connect the cations into centrosymmetric dimers. In addition, there is a pi-pi stacking inter-action involving two symmetry-related benzene rings, with a centroid-centroid distance of 3.437 (3) A. PMID- 21522262 TI - Dinitro-sylbis[tris-(4-methyl-phen-yl)phosphane]iron. AB - The title compound, [Fe(NO)(2)(C(21)H(21)P)(2)], belongs to the family of metal dinitrosyl compounds with the general formula Fe(NO)(2)(L)(x), referred to collectively as 'dinitrosyl iron compounds' (DNICs). Herein we report the structure of a dinitrosyl iron diphosphane complex, [Fe(NO)(2)L(2)], with L = P(C(6)H(4)-p-CH(3))(3). There are two crystallographically independent but chemically equal mol-ecules per asymmetric unit. The iron atom in each mol-ecule is tetra-hedrally coordinated by two phosphane ligands and two NO groups, with Fe N-O angles in the range 173.84 (15)-179.31 (16) degrees . PMID- 21522263 TI - Dinitro-sylbis[tris-(4-fluoro-phen-yl)phosphane]iron chloro-form monosolvate. AB - The title compound, [Fe(NO)(2)(C(18)H(12)F(3)P)(2)].CHCl(3), belongs to the family of metal dinitrosyl compounds with the general formula Fe(NO)(2)(L)(x), referred to collectively as 'dinitrosyl iron compounds' (DNICs). Herein we report the structure of a dinitrosyl iron diphosphane complex, (Fe(NO)(2)L(2), with L = P(C(6)H(4)-p-F)(3). The structure includes one metal complex mol-ecule and one chloro-form solvent mol-ecule. The iron atom is tetra-hedrally coordinated with two phosphane ligands and with two NO groups with Fe-N-O angles of 178.1 (2) and 177.0 (2) degrees . PMID- 21522264 TI - (eta-s-cis-1,3-Butadiene)tetra-carbonyl-chromium(0). AB - In the title complex, [Cr(C(4)H(6))(CO)(4)], the Cr(0) atom shows a distorted octa-hedral environment from four C atoms of the carbonyl ligands and the two pi bonds of the s-cis-1,3-butadiene ligand. The complex has an approximate non crystallographic mirror symmetry m passing through the chromium atom, two carbonyl ligands and the mid-point of the central C-C bond of the s-cis-1,3 butadiene ligand. The C-C bond lengths in the s-cis-1,3-butadiene ligand alternate, the terminal distances being shorter than the central distance. PMID- 21522265 TI - Dichlorido{2-(morpholin-4-yl)-N-[1-(pyridin-2-yl)ethyl-idene]ethanamine kappaN,N',N''}copper(II) monohydrate. AB - In the title compound, [CuCl(2)(C(13)H(19)N(3)O)].H(2)O, the tridentate Schiff base ligand and the two Cl atoms complete a distorted square-pyramidal coordination geometry around the Cu(II) ion in which the three N atoms and one Cl atom are located in the basal plane and the other Cl atom is at the apical position. In the crystal, O-H?Cl hydrogen bonds link the complex mol-ecules and the uncoordinated water mol-ecules into infinite chains along the a axis. The chains are further connected into a three-dimensional network via C-H?O and C H?Cl inter-actions. PMID- 21522266 TI - catena-Poly[4,4'-bipyridinium [[tetra-aqua-(pyridine-2,6-dicarboxyl-ato kappaO,N,O)cerate(III)]-MU-pyridine-2,6-dicarboxyl-ato-kappaO:O,N,O-[(pyridine 2,6-dicarboxyl-ato-kappaO,N,O)cerate(III)]-MU-pyridine-2,6-dicarboxyl-ato kappaO,N,O:O] penta-hydrate]. AB - The title compound, {(C(10)H(10)N(2))[Ce(2)(C(7)H(3)NO(4))(4)(H(2)O)(4)].5H(2)O}(n), is composed of a one-dimensional anionic complex, a doubly protonated 4,4'-bipyridine mol-ecule as a counter-ion and five uncoordinated water mol-ecules. The anion bears two nine coordinate Ce(III) ions, each with a distorted tricapped trigonal-prismatic geometry. In the crystal, inter-molecular C-H?O, N-H?O and O-H?O hydrogen bonds, as well as pi-pi inter-actions with centroid-centroid distances of 3.514 (3) A connect the various components into a supra-molecular structure. PMID- 21522267 TI - [(1R*,2S*)-N-Benzyl-2-phenyl-1-(pyridin-2-yl)-N-(pyridin-2-ylmeth-yl)ethane-1,2 diamine]-dichloridozinc(II). AB - In the mononuclear zinc title complex, [ZnCl(2)(C(26)H(26)N(4))], the Zn(II) ion is surrounded by three N atoms from a (1R*,2S*)-N(1)-benzyl-2-phenyl-1-(pyridin-2 yl)-N(2)-(pyridin-2-ylmeth-yl)ethane-1,2-diamine (BPPPEN) ligand and two terminal chloride ligands, resulting in a highly distorted environment around the metal atom. The calculated tau parameter of 0.42 indicates that the coordination geometry is approximately square-pyramidal. Hydrogen bonds involving centrosymmetric N-H?Cl inter-actions form dimeric structures. The mol-ecules are stacked along the a and b axes. PMID- 21522268 TI - 1-(4-Cyano-benz-yl)-3,5-dimethyl-pyridinium bis-(benzene-1,2-dithiol ato)nickelate(III). AB - The asymmetric unit of the title compound, (C(15)H(15)N(2))[Ni(C(6)H(4)S(2))(2)], contains half each of two independent centrosymmetric anions and a single cation in a general position. The Ni(III) ions are coordinated by four S atoms in a square-planar geometry. The anions exhibit two packing modes, viz. stacked along the a axis in a face-to-face fashion with an alternate arrangement of anions and cations, and stacked in a side-by-side fashion, forming ribbons parallel to (011). PMID- 21522269 TI - Piperazinediium tetra-chloridocadmate monohydrate. AB - In the title compound, (C(4)H(12)N(2))[CdCl(4)].H(2)O, the [CdCl(4)](2-) anions adopt a slightly distorted tetra-hedral configuration. In the crystal, O-H?Cl hydrogen bonds link the anions and water mol-ecules into corrugated inorganic chains along the b axis which are inter-connected via piperazinediiumN-H?O and N H?Cl inter-actions into a three-dimensional framework structure. PMID- 21522270 TI - Pyridinium tetra-kis-(1,1,1-trifluoro-pentane-2,4-dionato)dysprosate. AB - In the anion of the title compound, (C(5)H(6)N)[Dy(C(5)H(4)F(3)O(2))(4)], the central metal ion, Dy(3+), is coordinated by four bidentate 1,1,1-trifluoro pentane-2,4-dionate (TAA) ligands, forming an approximate square-anti-prismatic configuration. The pyridin-ium cation is connected to the complex ion by an N-H?O hydrogen bond and electrostatic inter-actions in the crystal. There are two kinds of disorder in the structure, one involving rotational disorder of a CF(3) group [occupancy ratio 0.560 (15):0.440 (15)] and the other involving an exchange between a CF(3) group and CH(3) group within a given bidentate ligand (occupancy ratio 0.64:0.36). PMID- 21522271 TI - catena-Poly[[[diaqua-cadmium]-MU-2,2'-(1,2-phenyl-enedi-oxy)diacetato] mono hydrate]. AB - In the title coordination complex, {[Cd(C(10)H(8)O(6))(H(2)O)(2)].H(2)O}(n) the Cd(II) atom is seven-coordinated in a distorted penta-gonal-bipyramidal geometry, the penta-gonal plane comprising four O-atom donors from the 2,2'-(1,2-phenyl enedi-oxy)diacetate chelate ligand together with a bridging carboxyl-ate O-atom donor, with the axial sites occupied by two water mol-ecules. The resulting helical chains extend along the b axis and are inter-connected by extensive O-H?O hydrogen-bonding inter-actions, which also involve the water mol-ecule of solvation, giving a three-dimensional structure. PMID- 21522272 TI - Bis[4-(dimethyl-amino)-pyridinium] tetra-chloridozincate. AB - In the title compound, (C(7)H(11)N(2))(2)[ZnCl(4)], [ZnCl(4)](2-) anions and 4 (dimethyl-amino)-pyridinium cations are held together by various inter-molecular inter-actions including Coulombic attraction, hydrogen bonding and pi-pi stacking inter-actions. Three Cl atoms of the [ZnCl(4)](2-) tetra-hedron act as acceptors in N-H?Cl hydrogen bonds. The hydrogen bonds, both of which are bifurcated, lead to the formation of a three-dimensional network. Within the network, inter molecular pi-pi stacking inter-actions with a centroid-centroid distance of 3.5911 (7) A arrange the 4-(dimethyl-amino)-pyridinium cations into anti-parallel dimers. PMID- 21522273 TI - 1,4-Diazo-niabicyclo-[2.2.2]octane hexa-aqua-magnesium bis-(sulfate). AB - In the title compound, (C(6)H(14)N(2))[Mg(H(2)O)(6)](SO(4))(2), the Mg(II) ion, lying on an inversion center, is coordinated by six water mol-ecules in a slightly distorted octa-hedral geometry. The 1,4-diazo-niabicyclo-[2.2.2]octane cation is located about a twofold rotation axis. Inter-molecular N-H?O and O-H?O hydrogen bonds link the cations and the anions into a three-dimensional network. PMID- 21522274 TI - Bis(cyanato-kappaN)bis-(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-kappaN)zinc. AB - In the title complex, [Zn(NCO)(2)(C(7)H(8)N(4))(2)], the Zn(II) ion exhibits a distorted tetra-hedral coordination geometry. The coordination environment is formed by two 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) ligands, coordinated through the N atom in position 3, and two cyanate anions inter-acting by their N atoms. Supra-molecular dimers are generated by stacking inter-actions between the pyrimidine rings of two ligands related by an inversion center [centroid-centroid distance = 3.5444 (18) A]. PMID- 21522275 TI - Aqua-[4'-(4-chloro-phen-yl)-2,2':6',2''-terpyridine]-nitratocopper(II) nitrate [4'-(4-chloro-phen-yl)-2,2':6',2''-terpyridine]-dinitratocopper(II) monohydrate. AB - The crystal structure of the title compound, [Cu(NO(3))(C(21)H(14)ClN(3))(H(2)O)]NO(3).[Cu(NO(3))(2)(C(21)H(14)ClN(3))].H(2)O, con-sists of two crystallographically independent Cu(II) complexes, in which each copper cation is penta-coordinated by three N atoms of the chelating ligand and two O atoms of nitrate anions or water mol-ecules. One of the coordinated nitrate anions is disordered over two set of sites in a 0.85:0.15 ratio. PMID- 21522276 TI - Dibromido{2-(morpholin-4-yl)-N-[1-(2-pyrid-yl)ethyl-idene]ethanamine kappaN,N',N''}cadmium. AB - The Cd(II) ion in the title compound, [CdBr(2)(C(13)H(19)N(3)O)], is five coordinated by the N,N',N''-tridentate Schiff base ligand and two Br atoms in a distorted square-pyramidal geometry. In the crystal, inter-molecular C-H?O and C H?Br hydrogen bonds link adjacent mol-ecules into layers parallel to the ab plane. An intra-molecular C-H?Br inter-action is also observed. PMID- 21522277 TI - Dichlorido{N,N-dimethyl-N'-[1-(pyridin-2-yl)ethyl-idene]ethane-1,2-diamine kappaN,N',N''}cadmium. AB - In the title compound, [CdCl(2)(C(11)H(17)N(3))], the Schiff base acts as an N,N',N''-tridentate ligand towards the Cd(II) ion. Two Cl atoms complete a distorted square-pyramidal geometry around the metal atom. In the crystal, a C H?Cl inter-action connects pairs of mol-ecules into centrosymetric dimers. PMID- 21522278 TI - Dichlorido(3,5-dimethyl-1H-pyrazole-kappaN)[hydro-tris-(3,5-dimethyl-1H-pyrazol-1 yl-kappaN)borato]chromium(III) tetra-hydro-furan mono-solvate. AB - In the title compound, [Cr(C(15)H(22)BN(6))Cl(2)(C(5)H(8)N(2))].C(4)H(8)O, the Cr(III) atom is coordinated by three N atoms from the hydro-tris-(3,5-dimethyl pyrazol-1-yl)borate (Tp*) ligand, one 3,5-dimethyl-pyrazole (Dmpy) N atom and two Cl atoms in a distorted octa-hedral coordination geometry. Two N atoms occupy the axial sites, and the two Cl atoms and other two N atoms from Tp* lie in the equatorial plane. In the crystal, the complex mol-ecules and tetra-hydro-furan solvent mol-ecules are connected via inter-molecular N-H?O and C-H?O inter actions. PMID- 21522279 TI - catena-Poly[[dimethyl-bis-(thio-cyanato-kappaN)tin(IV)]-MU-(4,4'-bipyridine kappaN:N')]. AB - The title dimethyl-tin diisothio-cyanate adduct of 4,4'-bipyridine, [Sn(CH(3))(2)(NCS)(2)(C(10)H(8)N(2))](n), adopts a chain motif in which the N heterocycle functions as a bridge to adjacent all-trans octa-hedrally coordinated tin atoms. The Sn(IV) atom lies on a special position of 2/m site symmetry, the methyl C atom on a special position of 2 site symmetry, and the thio-cyanate and 4,4'-bipyridine on a special position of m site symmetry. PMID- 21522280 TI - Triethyl-ammonium tetra-chlorido(pyridine-2-carboxyl-ato-kappaN,O)stannate(IV). AB - The cation and the anion in the title salt, (C(6)H(16)N)[SnCl(4)(C(6)H(4)NO(2))], are linked by an N-H?O hydrogen bond. The Sn(IV) atom in the stannate anion is chelated by the pyridine-2-carboxyl-ate group and exists in a cis-SnCl(4)NO octa hedral geometry. The cation is disordered over two positions in a 0.564 (1):0.436 (1) ratio. PMID- 21522281 TI - (2,2'-Bipyridine-kappaN,N')bis-(3-meth-oxy-benzoato-kappaO,O)copper(II) mono hydrate. AB - The title compound, [Cu(C(8)H(7)O(3))(2)(C(10)H(8)N(2))].H(2)O, is comprised of a Cu(II) ion, two 3-meth-oxy-benzoate ligands, a 2,2'-bipyridine (bipy) ligand and one uncoordinated water mol-ecule. The Cu(II) ion and the water O atom lie on a twofold axis. The Cu(II) ion exhibits a six-coordinate distorted octa-hedral geometry, with two N atoms from the bipy ligand [Cu-N = 1.9996 (16) A] and four O atoms from two 3-meth-oxy-benzoate ligands [Cu-O = 1.9551 (15) and 2.6016 (16) A]. The mol-ecules are linked by O-H?O and C-H?O hydrogen bonds, forming a three dimensional network. PMID- 21522282 TI - catena-Poly[[[(2,2'-bipyridine-kappaN,N')(dimethyl sulfoxide-kappaO)(nitrato kappaO,O')bis-muth(III)]-MU-5-carb-oxy-benzene-1,3-dicarboxyl-ato-kappaO,O:O,O] dimethyl sulfoxide monosolvate]. AB - The polymeric title compound, {[Bi(C(9)H(4)O(6))(NO(3))(C(10)H(8)N(2))(C(2)H(6)OS)].C(2)H(6)OS}(n), was obtained by the reaction of bis-muth(III) nitrate, bipyridine (bpy) and 1,3,5 benzene-tricarb-oxy-lic acid (H(3)BTC). The Bi(III) ion is coordinated in a distorted tricapped trigonal-prismatic geometry, defined by two N atoms of the bipy ligand, four O atoms of two HBTC(2-) anions, two O atoms of a nitrate anion and one O atom of a dimethyl sulfoxide ligand. The crystal packing is stabilized by O-H?O and C-H?O hydrogen bonds. The S atom of the non-coordinating dimethyl sulfoxide mol-ecule is disordered over two sets of sites with refined site occupancies of 0.430 (19) and 0.570 (19). PMID- 21522283 TI - Bis(2-amino-5-chloro-pyridinium) tetra-chloridozincate. AB - The asymmetric unit of the title compound, (C(5)H(6)ClN(2))(2)[ZnCl(4)], contains two 2-amino-5-chloro-pyridinium cations and one [ZnCl(4)](2-) dianion which are held together by N-H?Cl and C-H?Cl hydrogen bonds. The [ZnCl(4)](2-) anions have a distorted tetra-hedral geometry. Weak inter-molecular pi-pi stacking inter actions exist between neighbouring aromatic rings of the cations with a centroid centroid distance of 3.712 (7) A. PMID- 21522284 TI - Poly[[triaqua-(MU(3)-4-oxidopyridine-2,6-dicarboxyl-ato)terbium(III)] monohydrate]. AB - In the title coordination polymer, {[Tb(C(7)H(2)NO(5))(H(2)O)(3)].H(2)O}(n), the Tb(III) atom is eight-coordinated by a tridentate 4-oxidopyridine-2,6-dicarboxyl ate trianion, two adjacent monodentate anions and three water mol-ecules, forming a distorted bicapped trigonal-prismatic TbNO(7) coordination environment. The anions bridge adjacent Tb(III) ions into double chains. Adjacent chains are further connected into sheets parallel to (10). O-H?O hydrogen bonds involving both coordinated and uncoordinated water mol-ecules generate a three-dimensional network. PMID- 21522285 TI - Diiodidobis[4-(4-nitro-benz-yl)pyridine-kappaN]zinc. AB - The asymmetric unit of the title compound, [ZnI(2)(C(12)H(10)N(2)O(2))(2)], obtained from the reaction of 4-(4-nitro-benz-yl)pyridine with zinc(II) iodide, contains two independent discrete distorted tetra-hedral complex units [Zn-I = 2.5472 (8)-2.5666 (7) A and Zn-N = 2.044 (4)-2.052 (4) A], which are essentially identical conformationally. The crystal used for measurement was a racemic twin. PMID- 21522286 TI - Bis(2,3-diamino-pyridinium) bis-(MU-pyridine-2,6-dicarboxyl-ato) kappaO,N,O:O;kappaO:O,N,O-bis-[aqua-(pyridine-2,6-dicarboxyl-ato-kappaO,N,O)bis muthate(III)] tetra-hydrate. AB - In the centrosymmetric dinuclear complex anion of the title compound, (C(5)H(8)N(3))(2)[Bi(2)(C(7)H(3)NO(4))(4)(H(2)O)(2)].4H(2)O, the Bi(III) atom is eight-coordinated in an N(2)O(6) environment and has a distorted bicapped trigonal-prismatic coordination environment. Extensive inter-molecular O-H?O, N H?O and weak C-H?O hydrogen bonds lead to the stability of the crystal structure. Inter-actions between one C-H group of the 2,3-diamino-pyridinium [(2,3 dapyH)(+)] cation and the aromatic ring of the pyridine-2,6-dicarboxyl-ate (pydc) ligand (C-H?centroid distance = 2.78 A) and pi-pi inter-actions between the (2,3 dapyH)(+) cations and between the (2,3-dapyH)(+) cation and the pydc ligand [centroid-centroid distances = 3.489 (5) and 3.694 (5) A] are observed. PMID- 21522287 TI - Poly[bis-[MU(2)-(dimethyl-aza-nium-yl)methyl-enediphospho-nato]magnesium]. AB - The title compound, [Mg(C(3)H(10)NO(6)P(2))(2)](n), synthesized by a hydro thermal method, adopts a one-dimensional polymeric chain structure and is isotypic with the previously reported Cd complex based on the ligand N,N-dimethyl amino-methane-1,1-diphospho-nic acid (H(4)L). The asymmetric unit contains one half Mg(2+) ion and one H(3)L(-) anion. The unique Mg(2+) ion lies on an inversion center and is octa-hedrally coordinated by O atoms from six phospho nate groups of four different H(3)L(-) anions. Each H(3)L(-) anion, with one protonated N atom and two phospho-nate OH groups, serves as a tridentate ligand. Two of its six phospho-nate O atoms chelate to a Mg(2+) cation in a bidentate fashion, while a third O atom bridges to a neighbouring Mg(2+) ion. The inter connection of Mg(2+) ions by the H(3)L(-)anions leads to the formation of a polymer chain along the a axis in which the adjacent Mg(2+) ions are doubly bridged by two equivalent H(3)L(-) anions. These discrete chains are further assembled into a three-dimensional supra-molecular network via O-H?O and N-H?O hydrogen bonds involving the non-coordin-ated phospho-nate O atoms and the protonated N atoms. PMID- 21522288 TI - [N-((E)-2-{[2-(Dimethyl-amino)-eth-yl]imino-meth-yl}phen-yl)-N-(2,6-dimethyl-phen yl)anilinido-kappaN,N',N'']ethyl-zinc. AB - The title eth-yl-zinc complex, [Zn(C(2)H(5))(C(19)H(24)N(3))], bears a tridentate anilinide-aldimine ligand and features one long Zn-N(amine) bond length, attributable to the crowded environment of the coordinated metal, arising from the dimethyl-phenyl group. The Zn(II) ion adopts a distorted tetra-hedral geometry, the dihedral angle between the two benzene rings being 86.05 (16) degrees . PMID- 21522289 TI - Acetonitrile-[2-(1-{bis-[2,4,6-tris-(trifluoro-meth-yl)phen-yl]phosphan-yloxy}-1 methyl-eth-yl)pyridine]-methyl-palladium(II) hexa-fluoridoanti-monate dichloro methane hemisolvate. AB - In the title compound, [Pd(CH(3))(C(26)H(14)F(18)NOP)(C(2)H(3)N)][SbF(6)].0.5CH(2)Cl(2), the Pd(2+) cation has a distorted square-planar environment, being coordinated by the acetonitrile [Pd-N = 2.078 (8) A] and methyl [Pd-C = 2.052 (9) A] groups and the bidentate ligand 2-(1-{bis-[2,4,6-tris-(trifluoro-meth-yl)phen-yl]phosphan-yloxy} 1-methyl-eth-yl)pyridine (L). In L, one -CF(3) group is rotationally disordered between two orientations in a 1:1 ratio. The solvent mol-ecule was treated as disordered between two positions related by an inversion center with occupancies fixed at 0.5. The crystal packing exhibits weak inter-molecular C-H?F contacts. PMID- 21522290 TI - Acetonitrile-[2-({bis[2,4,6-tris-(trifluorido-meth-yl)phen-yl]phosphan-yloxy}meth yl)pyridine]-meth-ylpalladium(II) hexa-fluoro-anti-monate dichloro-methane hemisolvate. AB - In the title compound, [Pd(CH(3))(C(24)H(10)F(18)NOP)(CH(3)CN)][SbF(6)].0.5CH(2)Cl(2), the Pd(II) atom has a distorted square-planar environment being coordinated by an acetonitrile N atom [Pd-N = 2.079 (3) A], a methyl C atom [Pd-C = 2.047 (4) A] and the bidentate ligand 2-({[2,4,6-tris-(trifluoro-meth-yl)phen-yl]phosphan-yloxy}meth-yl)pyridine (L). In L, the short distance of 3.621 (3) A between the centroids of pyridine and benzene rings indicates the presence of a pi-pi inter-action. The crystal packing exhibits weak inter-molecular C-H?F contacts. The solvent mol-ecule has been treated as disordered between two positions of equal occupancy related by an inversion center. PMID- 21522291 TI - {MU-6,6'-Dimeth-oxy-2,2-[propane-1,3-diylbis(nitrilo-methanylyl idene)]diphenolato}trinitratocopper(II)dysprosium(III) methanol monosolvate. AB - In the title heterodinuclear salen-type complex, [CuDy(C(19)H(20)N(2)O(4))(NO(3))(3)].CH(3)OH, the copper(II) ion is tetra coordinated by two imino N atoms [Cu-N = 1.961 (4) and 1.968 (4) A] and two phenolate O atoms [Cu-O = 1.931 (3) and 1.938 (3) A] in a planar geometry. The ten-coordin-ate Dy(III) ion is ligated by six O atoms of three nitrate groups and four O atoms from the ligand [Dy-O = 2.368 (3)-2.601 (3) A]. In the crystal, complex mol-ecules and solvent mol-ecules are linked by inter-molecular O-H?O hydrogen bonds. PMID- 21522292 TI - Di-MU(2)-methoxo-bis-{[MU-3,10,18,25-tetra-aza-penta-cyclo-[17.4.4.3.1.1]triconta 1(31),2,4(9),5,7,10,12,14,16(32),17,19(24),20,22,25,27,29-hexa-deca-ene-31,32 diolato]dizinc(II)} bis-(perchlorate) N,N-dimethyl-formamide disolvate. AB - The title compound, [Zn(4)(C(28)H(18)N(4)O(2))(2)(CH(3)O)(2)](ClO(4))(2).2C(3)H(7)NO, is a C2 symmetric tetra-nuclear zinc(II) complex comprised of two [Zn(2)L](2+) units bridged by a pair of MU(2)-OMe ligands (where L is the doubly-deprotonated form of the macrocyclic dinucleating ligand derived from the [2 + 2] Schiff base condensation between 2-hy-droxy-benzene-1,3-dicarbaldehyde and 1,2-diamino benzene). Each Zn(II) atom has a distorted square-pyramidal coordination geometry and the Zn(4)(MU-OMe)(2) unit lies in the cleft formed by two distinctly bent Schiff base ligands. The observed mol-ecular shape is supported by an intra molecular pi-pi inter-action between one of the phenolate rings on each of the two ligands [centroid-centroid distance = 3.491 (5) A]. The methyl groups of the solvent molecule are disordered over two sets of sites in a 0.6:0.4 ratio. PMID- 21522293 TI - cis-Diaqua-bis-[dimethyl (phenyl-sulfonyl-imino)-phospho-nato]cobalt(II). AB - In the title diaqua-cobalt complex, [Co(C(8)H(11)NO(5)PS)(2)(H(2)O)(2)], the Co(II) atom is surrounded by six O atoms belonging to the phosphoryl and sulfonyl groups of two deprotonated chelate ligands and two additional O atoms from water mol-ecules which are in cis positions with respect to one another. The coordination environment of cobalt can be described as a distorted octa-hedron. O H?O hydrogen bonds between the water and sulfonyl O atoms of neighboring mol ecules form chains running parallel to [010]. Two methoxy groups attached to one phosphorus are disordered over two sets of sites in a 0.6:0.4 ratio. PMID- 21522294 TI - 1,4-Diazo-niabicyclo-[2.2.2]octane tetra-bromidocuprate(II) monohydrate. AB - In the title monohydrated salt, (C(6)H(14)N(2))[CuBr(4)].H(2)O, the copper(II) ion is coordinated by the four bromide ions in a flattened tetra-hedral geometry. In the crystal, the cations, anions and water mol-ecules inter-act via N-H?O, O H?Br and N-H?Br hydrogen bonds, forming chains parallel to the b axis. The chains are further linked by O-H?Br hydrogen bonds into layers parallel to the bc plane. PMID- 21522295 TI - (N-Benzyl-N-ethyl-dithio-carbamato)di-tert-butyl-chloridotin(IV). AB - The Sn(IV) atom in the title diorganotin dithio-carbamate, [Sn(C(4)H(9))(2)Cl(C(10)H(12)NS(2))], is penta-coordinated by an asymmetrically coordinating dithio-carbamate ligand, a Cl and two C atoms of the Sn-bound tert butyl groups. The resulting C(2)ClS(2) donor set defines a coordination geometry inter-mediate between square pyramidal and trigonal bipyramidal with a slight tendency towards the former. In the crystal structure, C-H?pi contacts link centrosymmetrically related mol-ecules into dimeric aggregates. PMID- 21522296 TI - Tetra-aqua-(2-hy-droxy-acetato-kappaO,O)magnesium nitrate. AB - In the title complex, [Mg(C(2)H(3)O(3))(H(2)O)(4)]NO(3), the Mg(II) cation is hexa-coordinated by four O atoms from water mol-ecules and two O atoms from a 2 hy-droxy-acetate ligand in a distorted octa-hedral coordination geometry. The structure exhibits a three-dimensional supra-molecular network, which is stabilized by nine different O-H?O hydrogen bonds. PMID- 21522298 TI - Bis(MU-N-nitroso-N-phenyl-hydroxy-laminato)-kappaO,O':O';kappaO':O,O'-bis-[(N nitroso-N-phenyl-hydroxy-laminato-kappaO,O')lead(II)]. AB - The four cupferronate ions in the dinuclear title compound, [Pb(2)(C(6)H(5)N(2)O(2))(4)], O,O'-chelate to the two Pb(II) atoms; two of the four nitroso O atoms are also involved in bridging. The geometry of both five coordinate Pb(II)atoms is distorted Psi-octa-hedral; if another two longer inter molecular Pb?O inter-actions [at 2.955 (1) and 3.099 (1) A] are considered, the geometry is a distorted Psi-square anti-prism. PMID- 21522297 TI - catena-Poly[[[tetra-kis-(4-methyl-pyridine-kappaN)copper(II)]-MU-sulfato kappaO:O'] 4.393-hydrate]. AB - The structure of the title compound, {[Cu(SO(4))(C(6)H(7)N)(4)].4.393H(2)O}(n), consists of Cu(2+) ions surrounded in a square-planar fashion by 4-methyl pyridine ligands, forming two crystallographically independent Cu{H(3)C(C(5)H(4)N)}(4) units that are both located on crystallographic inversion centers. The Cu(4-methyl-pyridine)(4) units are, in turn, connected with each other via bridging sulfate anions, leading to the formation of infinite [Cu{H(3)C(C(5)H(4)N)}(4)SO(4)](n) zigzag chains along [001]. The completed coordination spheres of the Cu(2+) ions are slightly distorted octa-hedral. The axial Cu-O bonds are elongated [average length = 2.42 (4) A] compared to the equatorial Cu-N bonds [average length = 2.043 (2) A]. The inter-stitial space between the chains is filled with uncoordinated water mol-ecules that consolidate the structure through O-H?O hydrogen bonding. One of the five crystallographically independent solvent water mol-ecules is partially occupied with an occupancy factor of 0.396 (4). Due to hydrogen bonding between symmetry equivalent water mol-ecules across inversion centers, several of the water H atoms are disordered in 1:1 ratios over mutually exclusive positions. The crystal under investigation was found to be non-merohedrally twinned in a 0.789 (1):0.211 (1) ratio by a 180 degrees rotation around the reciprocal b axis. PMID- 21522299 TI - Bis(N-nitroso-N-phenyl-hydroxy-laminato-kappaO,O')(1,10-phenanthroline kappaN,N')lead(II). AB - The two cupferronate ions and the N-heterocycle in the mononuclear title compound, [Pb(C(6)H(5)N(2)O(2))(2)(C(12)H(8)N(2))], O,O'- and N,N'-chelate to the Pb(II) atom, the geometry of which is a distorted Psi-penta-gonal bipyramid. PMID- 21522300 TI - Bis(8-hy-droxy-2-methyl-quinolinium) bis-(pyridine-2,6-dicarboxyl-ato)cuprate(II) methanol monosolvate monohydrate. AB - The title compound, (C(10)H(10)NO)(2)[Cu(C(7)H(3)NO(4))(2)].CH(3)OH.H(2)O was prepared by the reaction of copper(II) nitrate hexa-hydrate, 8-hy-droxy-2-methyl quinoline, and pyridine-2,6-dicarb-oxy-lic acid in a 1:2:2 molar ratio in an aqueous solution. The geometry of the resulting CuN(2)O(4) coordination can be described as distorted octa-hedral. In the crystal, there are several inter molecular O-H?O, N-H?O and C-H?O hydrogen bonds. An intra-molecular N-H?O hydrogen bond occurs in one of the cations. Considerable pi-pi stacking inter actions are also observed between the aromatic rings of the cations, with centroid-centroid distances of 3.4567 (13), 3.5342 (14), 3.6941 (14) and 3.4568 (13) A. These non-covalent inter-actions connect the components, forming a three dimensional supra-molecular structure. PMID- 21522301 TI - trans-Dichloridobis(propane-1,3-diamine-kappaN,N')chromium(III) perchlorate. AB - In the title compound, [CrCl(2)(C(3)H(10)N(2))(2)]ClO(4), the Cr(III) atom is coordinated equatorially by four N atoms of two propane-1,3-diamine (tn) ligands and axially by two mutually trans Cl atoms, thus displaying a slightly distorted octa-hedral geometry with no crystallographically imposed symmetry. The two six membered chair chelate rings in the complex cation are in an anti conformation with respect to each other. The Cr-N bond lengths range from 2.0831 (18) to 2.0917 (19) A, and the Cr-Cl bond lengths are 2.3148 (6) and 2.3135 (6) A. The perchlorate anions have slightly distorted tetra-hedral geometries. Weak inter molecular hydrogen bonds involving the tn ligand NH groups as donors, and chloride ligands and anion O atoms as acceptors are observed. PMID- 21522302 TI - Bis(4-ethyl-benzoato-kappaO)bis-(nicotin-amide-kappaN)zinc(II). AB - The title Zn(II) complex, [Zn(C(9)H(9)O(2))(2)(C(6)H(6)N(2)O)(2)], contains two 4 ethyl-benzoate and two nicotinamide monodentate ligands, leading to a distorted tetrahedral coordination of the Zn(II) ion. The dihedral angles between the carboxyl-ate groups and the adjacent benzene rings are 10.33 (13) and 2.38 (11) degrees , while opposite pyridine and benzene rings are oriented at dihedral angles of 68.46 (5) and 81.09 (6) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules, forming a three-dimensional network. C-H?O inter-actions also occur as well as two weak C-H?pi inter-actions involving the benzene rings. PMID- 21522303 TI - (2,2'-Bipyridyl-kappaN,N')bis-(N-butyl-N-methyl-dithio-carbamato kappaS,S')cadmium(II). AB - The Cd(II) atom in the title compound, [Cd(C(6)H(12)NS(2))(2)(C(10)H(8)N(2))], is hexa-coordinated by two dithio-carbamate ligands and the N atoms from a bidentate 2,2'-bipyridyl mol-ecule. The coordination geometry is based on a distorted trigonal-prismatic arrangement of the N(2)S(4) donor set. Supra-molecular chains, aligned along the a-axis direction, are mediated by C-H?S inter-actions and these are connected into layers that stack along the c axis via pi-pi inter-actions [Cg(pyrid-yl)?Cg(pyrid-yl) = 3.6587 (13) A]. PMID- 21522304 TI - Di-tert-butyl-chlorido(N,N-dibenzyl-dithio-carbamato)tin(IV). AB - The Sn(IV) atom in the title diorganotin dithio-carbamate, [Sn(C(4)H(9))(2)(C(15)H(14)NS(2))Cl], is penta-coordinated by an asymmetrically coordinating dithio-carbamate ligand, a Cl atom and two C atoms of the Sn-bound tert-butyl groups. The resulting C(2)ClS(2) donor set defines a coordination geometry inter-mediate between square pyramidal and trigonal bipyramidal with a slight tendency towards the former. PMID- 21522305 TI - Poly[diaqua-tris-(MU(4)-1,3-phenyl-enediacetato)-dineodymium(III)]. AB - In the title coordination polymer, [Nd(2)(C(10)H(8)O(4))(3)(H(2)O)(2)](n), each of the two Nd(III) ions is nine-coordinated by eight O atoms from six different 2,2'-(m-phenyl-ene)diacetate (pda) bivalent anions and by one O atom from a water mol-ecule, forming a distorted tricapped trigonal-prismatic coordination geometry. Eight Nd(III) ions and 12 pda ligands form a large [Nd(8)(pda)(12)] ring, and four Nd(III) ions and six pda ligands form a small [Nd(4)(pda)(6)] ring. These rings are further connected by the coordination inter-actions of pda ligands and Nd(III), generating a three-dimensional supra-molecular framework. PMID- 21522306 TI - Diaqua-bis-[8-ethyl-5-oxo-2-(piperazin-4-ium-1-yl)-5,8-dihydro-pyrido[2,3 d]pyrimidine-6-carboxyl-ato]copper(II) bis[4-(4-carboxyphenoxy)benzoate]. AB - In the title compound, [Cu(C(14)H(17)N(5)O(3))(2)(H(2)O)(2)](C(14)H(9)O(5))(2), the Cu(2+) atom, located on an inversion centre, exhibits a distorted octa-hedral geometry, coordinated by four O atoms from two pipemidic acid ligands in equatorial positions and two water mol-ecules in axial positions. The pipemidic acid ligand acts a bidentate ligand and the single deprotonated 4,4'-oxydibenzoic acid acts as an anion. Classical N-H?O and O-H?O hydrogen bonds are present in the crystal structure. PMID- 21522307 TI - Two-dimensional polymeric [Hg(4)(MU(2)-I)(6)I(2)(MU(2)-C(4)S(6))](n). AB - The title compound, poly[(MU(2)-2H,5H-1,3-dithiolo[4,5-d][1,3]di-thiole-2,5 dithione)hexa-MU(2)-iodido-diiodidotetra-mercury(II)], [Hg(4)I(8)(C(4)S(6))](n), represents the first example of a coordination polymer assembled by the alpha,alpha-C(4)S(6) dithione ligand. The Hg(II) ions are four-coordinated in a distorted tetra-hedral geometry, the coordination demand being satisfied either by four bridging iodide ligands or by three iodide ligands (one terminal and two bridging) and a thio-carbonyl S atom. Due to the bridging nature of the dithione ligand, the coordination polymer has a two-dimensional structure, built up of undulated layers parallel to (001). There is an inversion center at the mid-point of the central C=C double bond. PMID- 21522309 TI - Ethyl 4-[2-(3,5-dimethyl-4-oxo-2,6-diphenyl-piperidin-1-yl)-2-oxoeth yl]piperazine-1-carboxyl-ate. AB - In the title compound, C(28)H(35)N(3)O(4), the piperidine ring adopts a boat conformation while the piperazine ring adopts a chair conformation with an equatorial orientation of the phenyl groups. The dihedral angle between the mean planes of the benzene rings is 74.14 (8) degrees . The mol-ecular conformation is stabilized by a weak intra-molecular C-H?N inter-action and the crystal packing is stabilized by weak inter-molecular C-H?O inter-actions. PMID- 21522308 TI - Ethyl 1-benzoyl-4-hy-droxy-2,6-diphenyl-1,2,5,6-tetra-hydro-pyridine-3-carboxyl ate. AB - In the title compound, C(27)H(25)NO(4), the tetra-hydro-pyridine ring adopts a half-chair conformation. The three phenyl rings form dihedral angles of 66.33 (7), 87.36 (8) and 36.90 (7) degrees with the least-squares plane through the tetra-hydro-pyridine ring. The mol-ecular conformation is stabilized by an intra molecular O-H?O hydrogen bond, generating an S(6) motif. PMID- 21522310 TI - 5-Bromo-3-cyclo-hexyl-sulfonyl-2-methyl-1-benzofuran. AB - In the title compound, C(15)H(17)BrO(3)S, the cyclo-hexyl ring adopts a practically undistorted chair conformation [endocyclic torsion angles are within a 54.5-56.4 (3) degrees range] and the aryl-sulfonyl unit is positioned equatorial relative to the cyclo-hexyl group. In the crystal, mol-ecules are linked through C-H?O hydrogen bonds and donor-acceptor Br?O contacts [3.250 (2) A]. The crystal structure also exhibits aromatic pi-pi overlap between the benzene and furan rings of neighbouring mol-ecules [centroid-centroid distance = 3.635 (2) A]. PMID- 21522311 TI - Adamantan-1-aminium p-toluene-sulfonate. AB - There are two unique cations and anions in the asymmetric unit of the title mol ecular salt, C(10)H(15)NH(3) (+).C(7)H(7)O(3)S(-). In the crystal, all three hydrogen-bond donors of the protonated amine group make hydrogen-bond inter actions with sulfonate O-atom acceptors, linking the cations and anions into chains parallel to the a axis. C-H?pi inter-actions are also present. PMID- 21522312 TI - Dimethyl 8-acetyl-2-methyl-1,2-dihydro-quinoline-2,4-dicarboxyl-ate. AB - In the title compound, C(16)H(17)NO(5), the six-membered N-containing ring has a half-boat form; the spiro C atom deviates by 0.34 (2) A from the plane (r.m.s. deviation = 0.051 A) defined by the N and four aromatic C atoms. Intra-molecular N-H?O hydrogen bonding generates an S(6) ring motif and the dihedral angle between the mean plane though the S(6) ring and that through the five-atom half boat plane is 3.39 (2) degrees . In the crystal, weak inter-molecular C-H?O hydrogen bonds link mol-ecules into zigzag chains along [001] due to c-glide symmetry, and C-H?pi inter-actions extend along [010]. PMID- 21522313 TI - 2,3-Dibromo-3-(5-nitro-2-fur-yl)-1-phenyl-propan-1-one. AB - In the title compound, C(13)H(9)Br(2)NO(4), the phenyl and 2-nitro-furan rings are linked by a 2,3-dibromo-propanal group, six atoms of which, including a furyl C atom, are disordered over two positions with a site-occupancy ratio of 0.733 (11):0.267 (11). The dihedral angle between the furan [maximum deviation = 0.028 (4) A] and phenyl rings in the major component is 16.9 (3) degrees . In the minor component, the corresponding values are 0.87 (4) A and 23.3 (5) degrees . In the crystal, inter-molecular C-H?O hydrogen bonds link the mol-ecules into two dimensional arrays parallel to the ab plane. PMID- 21522314 TI - (1S,2S,3R,4S,5R,7S,8S,10R,13S)-2-Debenzoyl-10-deacetyl-2-(3-fluoro-benzo-yl)-7,10 bis-(2,2,2-trichloro-eth-oxy-carbon-yl)baccatin III ethyl acetate monosolvate monohydrate. AB - In the title compound, C(35)H(37)Cl(6)FO(14).C(4)H(8)O(2).H(2)O, the absolute configurations (1S,2S,3R,4S,5R,7S,8S,10R,13S) for the nine chiral centres of the mol-ecule has been determined. In the crystal, mol-ecules are linked by O-H?O and O-H?Cl hydrogen bonds. PMID- 21522315 TI - 4-Bromo-1-nitro-benzene. AB - The non-H atoms of the title mol-ecule, C(6)H(4)BrNO(2), are essentially coplanar with an r.m.s. deviation of 0.040 A. In the crystal, pi-pi stacking occurs between parallel benzene rings of adjacent mol-ecules with centroid-centroid distances of 3.643 (3) and 3.741 (3) A. Weak inter-molecular C-H?O hydrogen bonding and short Br?O contacts [3.227 (4) 3.401 (4) A] are also observed in the crystal structure. The crystal studied was a non-morohedral twin with a 26.1 (6)% minor component. PMID- 21522316 TI - 2-Chloro-N-[(2-methyl-phen-yl)sulfon-yl]acetamide. AB - In the title compound, C(9)H(10)ClNO(3)S, the amide H atom is syn with respect to the ortho-methyl group in the benzene ring and the C-S-N-C torsion angle is -66.9 (2) degrees . An intra-molecular N-H?Cl hydrogen bond occurs. The crystal structure features inversion-related dimers linked by pairs of N-H?O hydrogen bonds. PMID- 21522317 TI - Nitro-furan-toin methanol monosolvate. AB - The anti-biotic nitro-furan-toin {systematic name: (E)-1-[(5-nitro-2-fur yl)methyl-idene-amino]-imidazolidine-2,4-dione} crys-tallizes as a methanol monosolvate, C(8)H(6)N(4)O(5).CH(4)O. The nitro-furan-toin mol-ecule adopts a nearly planar conformation (r.m.s. deviation = 0.0344 A). Hydrogen bonds involve the co-operative N-H?O-H?O heterosynthons between the cyclic imide of nitro-furan toin and methanol O-H groups. There are also C-H?O hydrogen bonds involving the nitro-furan-toin mol-ecules which support the key hydrogen-bonding synthon. The overall crystal packing is further assisted by weak C-H?O inter-actions, giving a herringbone pattern. PMID- 21522318 TI - Pyrimidin-2-amine-1-phenyl-cyclo-pentane-1-carb-oxy-lic acid (1/1). AB - In the crystal structure of the title co-crystal, C(4)H(5)N(3).C(12)H(14)O(2), the components are linked by N-H?O and O-H?N hydrogen bonds. Self-assembly of these dimeric units results in a four-component supra-molecular unit featuring a homosynthon between two mol-ecules of the pyrimidin-2-amine involving two N-H?O hydrogen bonds, and two heterosynthons between each one mol-ecule of pyrimidin-2 amine and 1-phenyl-cyclo-pentane-1-carb-oxy-lic acid involving N-H?O and O-H?N hydrogen bonds. PMID- 21522319 TI - 5,5'-Bis[(1H-imidazol-1-yl)meth-yl]-2,2'-bipyridine methanol disolvate. AB - The title compound, C(18)H(16)N(6).2CH(3)OH, was prepared by the reaction of 5,5' bis-(bromo-meth-yl)-2,2'-bipyridine with imidazole. The main mol-ecule lies on an inversion center located at the mid-point of the C-C bond joining the two pyridine rings. The asymmetric unit therefore contains one half-mol-ecule and one methanol solvent mol-ecule. The dihedral angle between the pyridine and imidazole rings is 72.32 (5) degrees . In the crystal, weak inter-molecular O-H?N, C-H?N and C-H?O hydrogen bonds contribute to the stabilization of the packing. PMID- 21522320 TI - 3-(2,4-Difluoro-anilino)-9-nitro-dibenzo[b,e]oxepin-11(6H)-one. AB - In the title compound, C(20)H(12)F(2)N(2)O(4), the two benzene rings of the tricyclic unit are oriented at a dihedral angle of 30.6 (1) degrees . The 2,4 difluoro-anilino residue is oriented at a dihedral angle of 68.2 (1) degrees with respect to the phen-oxy ring. In the crystal, N-H?O hydrogen bonds between the amino group and the carbonyl O atom of the oxepinone ring link the mol-ecules into infinte chains along the c axis. PMID- 21522321 TI - 1-Benzoyl-3,5-diphenyl-4,5-dihydro-1H-pyrazole. AB - In the title compound, C(22)H(18)N(2)O, the pyrazole ring is almost planar (r.m.s. deviation = 0.0098 A) and its mean plane makes dihedral angles of 62.2 (2), 87.2 (2) and 8.0 (2) degrees with the phenyl and benzoyl rings, respectively. The crystal packing is stabilized by pi-pi stacking inter-actions [centroid-centroid distance = 3.658 (2) A] and weak inter-molecular C-H?O hydrogen bonds. PMID- 21522322 TI - N,4-Dimethyl-benzamide. AB - In the crystal of the title compound, C(9)H(11)NO, mol-ecules are connected via inter-molecular N-H?O hydrogen bonds, forming a one-dimensional network in the b axis direction. The dihedral angle between the amide group and the benzyl ring is 13.8 (2) degrees . PMID- 21522323 TI - 5-Nitro-1-n-octyl-1H-benzimidazol-2(3H)-one. AB - The benzimidazolone part of the mol-ecule of the title compound, C(15)H(21)N(3)O(3), is almost planar (r.m.s. deviation = 0.007 A) with its mean plane aligned at a dihedral angle of 10.4 (3) degrees with respect to the mean plane of the nitro substituent. In the crystal, two mol-ecules are disposed about a center of inversion, generating an N-H?O hydrogen-bonded cyclic dimer with R(2) (2)(8) graph-set motif. PMID- 21522324 TI - N-[2-(Acetamido)-eth-yl]-2-hy-droxy-benzamide. AB - In the title mol-ecule, C(11)H(14)N(2)O(3), an intra-molecular O-H?O hydrogen bond closes an almost planar [maximum deviation = 0.022 (13) A] six-membered ring and enforces the cis conformation of the keto group with respect to the hy-droxy substituent. In the crystal, inter-molecular N-H?O hydrogen bonds link the moleclues into ribbons extended along [10]. Weak inter-molecular C-H?O inter actions further consolidate the crystal packing. PMID- 21522325 TI - 9-[(2-Hy-droxy-benzyl-idene)amino]-11-(2-hy-droxy-phen-yl)-10,13-diphenyl-8-oxa 12-azoniatricyclo-[7.3.1.0]trideca-2(7),3,5-triene acetate ethanol disolvate. AB - The title compound, C(36)H(31)N(2)O(3) (+),C(2)H(3)O(2) (-).2C(2)H(5)OH, the product of a domino condensation of dibenzyl ketone with salicylic aldehyde and ammonium acetate, crystallized as the ethanol disolvate. The cation of the salt comprises a fused tricyclic system containing three six-membered rings (piperidine, dihydro-2H-pyran and benzene). The piperidine ring has the usual chair conformation, while the dihydro-pyran ring adopts a slightly distorted sofa conformation. In the crystal, there are six (one intra- and five inter-molecular) independent hydrogen-bonding inter-actions: the inter-molecular hydrogen bonds link the cations and anions and ethanol solvent mol-ecules into ribbons along [001]. The ribbons are stacked along the a axis. PMID- 21522326 TI - 2,4-Bis[(3-butyl-imidazol-3-ium-1-yl)meth-yl]-1,3,5-trimethyl-benzene bis-(hexa fluoro-phosphate). AB - In the title molecular salt, C(25)H(38)N(4) (2+).2PF(6) (-), one of the butyl groups and four F atoms in the basal plane of one of the PF(6) (-) octa-hedra are disordered over two sets of sites, with occupancy ratios of 0.704 (5):0.296 (5) and 0.71 (3):0.29 (3), respectively. The central benzene ring makes dihedral angles of 85.17 (12) and 81.97 (12) degrees with the terminal imidazole rings. In the crystal, cations and anions are linked together via inter-molecular C-H?F hydrogen bonds forming a three-dimensional network. PMID- 21522327 TI - 6-Chloro-2-cyclo-propyl-4-(trifluoro-meth-yl)quinoline. AB - In the title compound, C(13)H(9)ClF(3)N, the quinoline ring system makes a dihedral angle of 88.8 (2) degrees with the cyclo-propyl ring. PMID- 21522328 TI - 9-Amino-acridinium nitrate monohydrate. AB - The pyridine N atom of the cation in the title hydrated salt, C(13)H(11)N(2) (+).NO(3) (-).H(2)O, is protonated; the N atom of the NH(2) group shows a planar conformation. The former N atom is hydrogen bonded to a water mol-ecule. The amino group is involved in three N-H?O hydrogen bonds with two neighboring nitrate anions. The water mol-ecule is hydrogen bonded to two adjacent nitrate anions. In the crystal, this results in a layered network. PMID- 21522329 TI - 4-Carbamoylpiperidinium 2-carb-oxy-benzoate-benzene-1,2-dicarb-oxy-lic acid (1/1). AB - The asymmetric unit of the title salt adduct, C(6)H(13)N(2)O(+).C(8)H(5)O(4) ( ).C(8)H(6)O(4), comprises one isonipecotamide cation, a hydrogen phthalate anion and a phthalic acid adduct mol-ecule. These form a two-dimensional hydrogen bonded network through head-to-tail cation-anion-adduct mol-ecule inter-actions which include a cyclic heteromolecular amide-carboxyl-ate motif [graph set R(2) (2)(8)], conjoint cyclic R(2) (2)(6) and R(3) (3)(10) piperidinium N-H?O(carbox yl) associations, as well as strong carboxyl O-H?O(carbox-yl) hydrogen bonds. PMID- 21522330 TI - 1,4-Bis{4-[bis-(prop-2-yn-1-yl)amino]-phen-oxy}benzene. AB - The asymmetric unit of the title compound, C(30)H(24)N(2)O(2), contains two independent mol-ecules, which both lie on centers of inversion. The central phenyl-ene ring is inclined at 61.4 (2) degrees with respect to the flanking aromatic ring [dihedral angle = 70.7 (3) degrees in the second mol-ecule]. PMID- 21522331 TI - 4,4'-Bis[(E)-(2,3-diiodo-prop-2-en-1-yl)-oxy]biphen-yl. AB - Iodine adds across both triple bonds of 4,4'-bis-(prop-2-yn--yl-oxy)biphenyl, yielding the 4,4'-bis-(2,3-diiodo-all-yloxy)biphenyl title compound, C(18)H(14)I(4)O(2); the 2,3-diiodo-ally-oxy substituents have the I atoms in an E configuration. In the biphenyl portion of the mol-ecule, the aromatic rings are inclined by 37.8 (2) degrees . PMID- 21522332 TI - Redetermination of 3-methyl-benzoic acid. AB - The asymmetric unit of the title compound, C(8)H(8)O(2), contains two crystallographically independent mol-ecules, which form dimers linked by O?H-O hydrogen bonds. The benzene rings in the dimers are inclined at a dihedral angle of 7.30 (8) degrees and both methyl groups display rotational disorder. This redetermination results in a crystal structure with significantly higher precision than the original determination [Ellas & Garcia-Blanco (1963 ?). Acta Cryst. 16, 434], in which the authors reported only the unit-cell parameters and space group, without any detailed information on the atomic arrangement. In the crystal, dimers are connected by weak C-H?O inter-actions, forming R(2) (2)(10) and R(4) (4)(18) rings along [110] and an infinite zigzag chain of dimers along the [001] direction also occurs. PMID- 21522333 TI - 1-Benzyl-3,5-bis-[(E)-3-thienyl-methyl-idene]piperidin-4-one. AB - In the title mol-ecule, C(22)H(19)NOS(2), the piperidine ring adopts an envelope conformation with the benzyl substituent in an equatorial position. Each of the olefinic double bonds has an E configuration. The dihedral angle between the two thio-phene rings is 1.55 (18) degrees . The thio-phene rings form angles of 72.21 (14) and 73.43 (14) degrees with the phenyl ring. Both thio-phene rings are disordered over two orientations [occupancy ratios of 0.799 (1):0.201 (1)] at 180 degrees from one another. In the crystal, weak inter-molecular C-H?O hydrogen bonds and C-H?pi inter-actions help to stabilize the packing. PMID- 21522334 TI - 2-Phenyl-2,3-dihydro-phenanthro[9,10-b][1,4]dioxine. AB - In the title compound, C(22)H(16)O(2), the phenanthrene ring system is essentially planar [maximum deviation = 0.058 (1) A] and is inclined at an angle of 58.39 (6) degrees to the phenyl ring. The 1,4-dioxane ring is in a chair conformation. In the crystal, mol-ecules are stacked along the b axis, but no significant hydrogen bonds are observed. PMID- 21522335 TI - 2-Methyl-6-(trifluoro-meth-yl)imidazo[1,2-a]pyridine-3-carbonitrile. AB - In the title compound, C(10)H(6)F(3)N(3), the imidazo[1,2-a]pyridine group is essentially planar with a maximum deviation of 0.021 (1) A. The F atoms in the trifluoro-methyl group and the methyl H atoms are each disordered over two sets of sites with refined site occupancies of 0.68 (1):0.32 (1). In the crystal, mol ecules are linked into infinite chains through two C-H?N inter-actions forming R(2) (2)(12) and R(2) (2)(8) hydrogen-bond ring motifs. These chains are stacked along the a axis. PMID- 21522336 TI - 2-[4-(Methyl-sulfon-yl)phen-yl]acetonitrile. AB - In the title compound, C(9)H(9)NO(2)S, the benzene ring and the acetonitrile group are approximately coplanar, with a C-C-C-C torsion angle of 1.1 (3) degrees between them. In the crystal, mol-ecules are linked via inter-molecular C-H?O hydrogen bonds into layers parallel to (001). PMID- 21522337 TI - 2-[(Meth-oxy-carbonothio-yl)sulfan-yl]acetic acid. AB - The title compound, C(4)H(6)O(3)S(2), features a characteristic xanthate group; the C=S double bond is shorter than the C-S single bond, and the methyl group is coplanar with the xanthate group. In the crystal pairs of mol-ecules form dimers through inter-molecular O-H?O hydrogen bonding. PMID- 21522338 TI - Dimethyl 5,6,7-trimeth-oxy-2-methyl-1,2-dihydro-quinoline-2,4-dicarboxyl-ate. AB - In the title compound, C(17)H(21)NO(7), the dihydro-pyridine ring assumes a screw boat conformation. In the crystal, inter-molecular C-H?O hydrogen bonds link the mol-ecules, forming supra-molecular chains running along the b axis. PMID- 21522339 TI - 5-Benzyl-7-methyl-hexa-hydro-3a,7-methano-1H-furo[3,4-c]azocine-3,10(4H)-dione. AB - The title compound, C(18)H(21)NO(3), was obtained via a double Mannich condensation reaction of 6-methyl-tetra-hydro-isobenzofuran-1,7(3H,7aH)-dione with formaldehyde and benzyl-amine. The mol-ecule contains three fused rings of which the cyclo-hexa-none and piperidine rings adopt chair conformations and the furan-one ring assumes an envelope conformation. An inter-molecular C-H?pi inter action is present in the crystal structure. PMID- 21522340 TI - 2-Amino-6-methyl-pyridinium 4-nitro-benzoate. AB - In the crystal structure of the title salt, C(6)H(9)N(2) (+).C(7)H(4)NO(4) (-), the cations and anions are linked by N-H?O hydrogen bonds, forming chains running parallel to the b axis. PMID- 21522341 TI - 4-Bromo-3-methyl-anilinium perchlorate 18-crown-6 clathrate. AB - The reaction of 4-bromo-3-methyl-anilinium perchlorate and 18-crown-6 in methanol solution yielded the title compound, C(7)H(9)BrN(+).ClO(4) (-).C(12)H(24)O(6). The protonated 4-bromo-3-methyl-amine unit contains one -NH(3) (+) substituent, resulting in a 1:1 supra-molecular rotator-stator structure, (C(7)H(9)Br-NH(3) (+))(18-crown-6), through three bifurcated N-H?(O,O) hydrogen bonds between the ammonium group of the cation and the O atoms of the crown ether mol-ecule. PMID- 21522342 TI - 2-Amino-1-(3-sulfonato-prop-yl)pyridinium monohydrate. AB - In the title compound, C(8)H(12)N(2)O(3)S.H(2)O, inter-molecular O-H?O and N-H?O hydrogen bonds and weak C-H?O inter-actions, which form R(1) (2)(6) and R(2) (2)(12) ring motifs, link the components into a three-dimensional network. PMID- 21522343 TI - tert-Butyl N-{(1S)-1-[(2,4-dihy-droxy-benzyl-idene)hydrazinecarbon-yl]-2-hy-droxy eth-yl}carbamate ethanol monosolvate. AB - The mol-ecule of the title ethanol solvate, C(15)H(21)N(3)O(6).C(2)H(6)O, adopts a curved shape; the conformation about the imine bond [N=N = 1.287 (3) A] is E. The amide residues occupy positions almost orthogonal to each other [dihedral angle = 85.7 (2) degrees ]. In the crystal, a network of O-H?O, O-H?N and N-H?O hydrogen bonds leads to the formation of supra-molecular arrays in the ab plane with the ethanol mol-ecules lying to the periphery on either side. Disorder in the solvent ethanol mol-ecule was evident with two positions being resolved for the C atoms [site occupancy of the major component = 0.612 (10)]. PMID- 21522344 TI - (E)-4-(1,3-Benzodioxol-5-yl)but-3-en-2-one. AB - In the title compound, C(11)H(10)O(3), the benzodioxole ring adopts a flattened [puckering parameters: q(2) = 0.107 (2) A, phi(2) = 160 (1) degrees ] envelope conformation with the methylene C atom as the flap. The crystal packing features chains, parallel to the c axis, composed of dimers connected by weak C-H-O hydrogen bonds and extending in layers in the bc plane. PMID- 21522345 TI - Monocrotophos: dimethyl (E)-1-methyl-2-(methyl-carbamo-yl)ethenyl phosphate. AB - In the title compound, C(7)H(14)NO(5)P, the phosphate group displays rotational disorder of three O atoms with an occupancy ratio of 0.832 (6):0.167 (6). The dihedral angle between the acryl-amide group and PO(2) plane of the phosphate group is 75.69 (7) degrees . In the crystal, inter-molecular N-H?O and C-H?O hydrogen bonds link the molecules. PMID- 21522346 TI - 1-{5-[2-Chloro-5-(trifluoro-meth-yl)phen-yl]thio-phen-2-yl}ethanone. AB - In the title molecule, C(13)H(8)ClF(3)OS, the dihedral angle between the mean planes of 2-chloro-5-(trifluoro-meth-yl)phenyl and tiophene rings is 54.37 (5) degrees . The acethyl group is twisted by 8.1 (2) degrees with respect to the thio-phene ring. The CF(3) group is disordered over two sets of sites with occupations of 0.49 (3) and 0.51 (3). The crystal packing features C-H?F and C H?O hydrogen bonds, forming dimers which are connected into chains along the c axis by C-H?O hydrogen bonds and C-Cl?pi [Cl?pi = 3.415 (1) A and C-Cl?pi = 151.56 (5) degrees ] inter-actions. The chains are further connected into layers perpendicular to the a axis by C-H?O inter-actions. PMID- 21522348 TI - Butane-1,4-diaminium 2-(meth-oxy-carbon-yl)benzoate dihydrate. AB - In the title compound, C(4)H(14)N(2) (+).2C(9)H(7)O(4) (-).2H(2)O, the butane-1,4 diaminium cation lies on an inversion center. In the crystal, inter-molecular N H?O and O-H?O hydrogen bonds link the components into layers parallel to (100). Addtional stabilization within these layers is provided by weak inter-molecular C H?O hydrogen bonds. PMID- 21522347 TI - l-Alanine methyl ester hydro-chloride monohydrate. AB - The enanti-opure title compound, C(4)H(10)NO(2) (+).Cl(-).H(2)O, forms a two dimensional network by inter-molecular hydrogen bonding parallel to (010). Non merohedral twinning with a twofold rotation about the reciprocal c* axis as twin operation was taken into account during intensity integration and structure refinement. This twinning leads to alternative orientations of the stacked hydrogen-bonded layers. PMID- 21522349 TI - 4-(2-Amino-phen-yl)-10-oxa-4-aza-tricyclo-[5.2.1.0]dec-8-ene-3,5-dione. AB - In the title compound, C(14)H(12)N(2)O(3), the essentially planar pyrrole ring [maximum deviation = 0.037 (4) A] and the benzene ring form a dihedral angle of 69.5 (2) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds connect mol-ecules into chains along [001]. Additional stabilization is provided by weak inter-molecular C-H?O hydrogen bonds. PMID- 21522350 TI - 4,4'-Bipyridine-5-fluoro-isophthalic acid (1/1). AB - Co-crystallization of 5-fluoro-isophthalic acid (H(2)fip) with 4,4'-bipyridine (bipy) leads to the formation of the title compound [(H(2)fip)(bipy)], C(8)H(5)FO(4).C(10)H(8)N(2), with an acid-base molar ratio of 1:1. The acid and base subunits are arrange alternately in the crystal structure, displaying a wave like tape motif via inter-molecular O-H?N and C-H?O hydrogen bonds [carbox-yl pyridine synthon of R(2) (2)(7) hydrogen-bond notation], which are further combined into a two-dimensional architecture through C-H?F inter-actions involving the bipy and H(2)fip mol-ecules. PMID- 21522351 TI - 5-Fluoro-isophthalic acid. AB - In the crystal structure of the title compound, C(8)H(5)FO(4), the complete molecule is generated by crystallographic twofold symmetry with two C atoms and the F atom lying on the axis. The mol-ecule is almost planar with the carboxyl group twisted with respect to the mean plane of the benzene ring by a dihedral angle of 2.01 (1) degrees . In the crystal, inter-molecular O-H?O hydrogen bonds and C-H?F inter-actions connect the mol-ecules into a two-dimensional supra molecular array. PMID- 21522352 TI - Bis(2,6-diamino-pyridinium) bis-(hydrogen oxalate) monohydrate. AB - The asymmetric unit of the title compound, 2C(5)H(8)N(3) (+).2C(2)HO(4) ( ).H(2)O, contains two crystallographically independent 2,6-diamino-pyridinium cations, a pair of hydrogen oxalate anions and a water mol-ecule. Both 2,6 diamino-pyridinium cations are planar, with maximum deviations of 0.011 (2) and 0.015 (1) A, and are protonated at the pyridine N atoms. The hydrogen oxalate anions adopt twisted conformations and the dihedral angles between the planes of their carboxyl groups are 31.01 (11) and 63.48 (11) degrees . In the crystal, the cations, anions and water mol-ecules are linked via O-H?O and N-H?O hydrogen bonds, forming a three-dimensional network. PMID- 21522353 TI - (E)-2-[4-(Diethyl-amino)-styr-yl]-1-methyl-pyridinium benzene-sulfonate mono hydrate. AB - The asymmetric unit of the title compound, C(18)H(23)N(2) (+).C(6)H(5)O(3)S( ).H(2)O, comprises a 2-[4-(diethyl-amino)-styr-yl]-1-methyl-pyridinium cation, a benzene-sulfonate anion and a solvent water mol-ecule. One ethyl substituent of the diethyl-amino group of the cation is disordered over two positions in a 0.73789 (9):0.26211 (9) ratio. The cation exists in the E configuration with respect to the C=C bond and the pi-conjugated system is essentially planar with a dihedral angle of 0.82 (10) degrees between the pyridinium and benzene rings. The cation and anion are almost orthogonal with a dihedral angle of 86.71 (10) degrees between the pi-conjugated system of the cation and benzene ring of the anion. In the crystal, mol-ecules are arranged into chains along [001] and adjacent chains are linked by weak C-H?O inter-actions. The crystal is further stablilized by O-H?O hydrogen bonds and weak C-H?pi inter-actions. PMID- 21522355 TI - 4-Iodo-anilinium perchlorate 18-crown-6 clathrate. AB - In the title compound, C(6)H(7)IN(+).ClO(4) (-).C(12)H(24)O(6), the proton-ated 4 iodo-anilinium cation inter-acts with the 18-crown-6 through three N-H?O hydrogen bonds, forming a rotator-stator-like structure. The cation, anion and 18-crown-6 mol-ecule all have crystallographically imposed mirror symmetry. PMID- 21522354 TI - N-(2-Chloro-phenyl-sulfon-yl)-2-methyl-propanamide. AB - In the title compound, C(10)H(12)ClNO(3)S, the amide H atom is syn with respect to the ortho-chloro group in the benzene ring and the C-S-N-C torsion angle is 64.35 (16) degrees . The benzene ring and the SO(2)-NH-CO-C segment form a dihedral angle of 87.4 (1) degrees . The crystal structure features inversion related dimers linked by pairs of N-H?O hydrogen bonds. PMID- 21522356 TI - 4-Bromo-2-[(E)-(4-chloro-phen-yl)imino-meth-yl]phenol. AB - In the title compound, C(13)H(9)BrClNO, the dihedral angle between the substituted benzene rings is 43.90 (11) degrees . Strong intra-molecular O-H?N hydrogen bonds generate S(6) ring motifs. The crystal structure features short intemolecular Br?Br [3.554 (2) A] and Cl?Cl [3.412 (2) A] contacts. The crystal packing is further stabilized by inter-molecular C-H?O and C-H?pi inter-actions. PMID- 21522357 TI - 4-Bromo-2-[(E)-(4-fluoro-phen-yl)imino-meth-yl]phenol. AB - In the title compound, C(13)H(9)BrFNO, the dihedral angle between the substituted benzene rings is 9.00 (11) degrees . Strong intra-molecular O-H?N hydrogen bonds generate S(6) ring motifs. PMID- 21522358 TI - 5-Diethyl-amino-2-[(E)-(4-eth-oxy-phen-yl)imino-meth-yl]phenol. AB - The title compound, C(19)H(24)N(2)O(2), adopts the phenol-imine tautomeric form. An intra-molecular O-H?N hydrogen bond results in the formation of a six-membered ring. The aromatic rings are oriented at a dihedral angle of 17.33 (16) degrees . Inter-molecular C-H?pi inter-actions occur in the crystal. PMID- 21522359 TI - 1-[(2R,4aR,8R,8aR)-8-Hy-droxy-4a,8-di-methyl-perhydronaphthalen-2-yl]ethan-1-one. AB - The title compound, C(14)H(24)O(2), was synthesized from ilicic acid, which was isolated from the aerial part of Inula Viscosa- (L) Aiton [or Dittrichia Viscosa- (L) Greuter]. The mol-ecule contains two fused six-membered rings, which both display a chair conformation. In the crystal, mol-ecules are linked into chains propagating along the b axis by inter-molecular O-H?O hydrogen bonds. PMID- 21522360 TI - 1-Benzoyl-3,3-bis-(2-methyl-prop-yl)thio-urea. AB - The title compound, C(16)H(24)N(2)OS, is twisted about the central N(H)-C bond with the C-N-C-S torsion angle being 119.6 (3) degrees . The carbonyl O and thione S atoms are directed to opposite sides of the mol-ecule, a conformation that allows for the formation of a linear supra-molecular chain comprising alternating eight-membered {?HNCS}(2) and 14-membered {?HCNCNCO}(2) synthons. PMID- 21522361 TI - 2,5-Dimethyl-3-[4-(trifluoro-meth-oxy)anilino]-cyclo-hex-2-enone. AB - In the title compound, C(15)H(16)F(3)NO(2), the dihedral angle between the benzene ring and the conjugated part of the cyclo-hexene ring is 60.00 (8) degrees . The non-conjugated part of the cyclohexene ring and the trifluoro methyl group are both disordered over two sets of sites with occupancies of 0.835 (2) and 0.165 (2). In the crystal, mol-ecules are linked into chains along [010] by inter-molecular N-H?O hydrogen bonds. Weak inter-molecular C-H?O inter-actions also occur. PMID- 21522362 TI - Methanaminium 3,4,5,6-tetra-chloro-2-(meth-oxy-carbon-yl)benzoate. AB - In the crystal structure of the title compound, CH(6)N(+).C(9)H(3)Cl(4)O(4) (-), the N atom of the methyl-amine mol-ecule is protonated and hydrogen bonded to the carboxyl group of the 3,4,5,6-tetra-chloro-2-(meth-oxy-carbon-yl)benzoate anion. The anions are linked by the cations via inter-molecular N-H?O inter-actions into chains extending along the c axis. PMID- 21522363 TI - Zwitterionic form of tris-({[5-(4-meth-oxy-phenyl-azo)salicyl-idene]amino}-eth yl)amine. AB - THE TITLE COMPOUND (SYSTEMATIC NAME: 2-{[2-(bis-{2-[({2-hy-droxy-5-[(4-meth-oxy phen-yl)diazen-yl]phen-yl}methyl-idene)amino]-eth-yl}amino)-eth-yl]aza niumylidenemeth-yl}-4-[(4-meth-oxy-phen-yl)diazen-yl]phenolate), C(48)H(48)N(10)O(6), exists as a zwitterion in the solid state. The three arms of the tripodal mol-ecule are located close to each other and an intra-molecular hydrogen bond occurs in each arm (O-H?N in two arms and N-H?O in the zwitterionic arm). The dihedral angles between the aromatic rings in the three arms are 16.36 (14), 23.94 (14) and, for the zwitterionic arm, 37.14 (14) degrees . In the crystal, a weak inter-moleclar N-H?O hydrogen bond occurs. PMID- 21522364 TI - N,N'-Bis(2-methyl-phen-yl)succinamide. AB - In the title compound, C(18)H(20)N(2)O(2), the conformations of the N-H and C=O bonds in the C-NH-C(O)-C segments are anti to each other and the amide O atom is anti to the H atoms attached to the adjacent C atoms. Further, the conformations of the N-H bonds in the amide fragments are anti to the ortho-methyl groups in the adjacent benzene rings. The complete molecule is generated by inversion symmetry. The dihedral angle between the benzene ring and the NH-C(O)-CH(2) segment in the two halves of the mol-ecule is 62.1 (2) degrees . In the crystal, N-H?O inter-molecular hydrogen bonds link the mol-ecules into sheet-like infinite chains along the a axis. PMID- 21522365 TI - 1-Chloro-2-methyl-3-nitro-benzene. AB - In the title compound, C(7)H(6)ClNO(2), the chloro, methyl and nitro substituents are situated next to each other in this order on the benzene ring, with the mean plane of the nitro group twisted away from the mean plane of the benzene ring by 38.81 (5) degrees . PMID- 21522366 TI - 1,8-Bis(3-chloro-anilino)-N,N'-bis-(3-chloro-phen-yl)octane-1,8-diimine. AB - There are two half-mol-ecules in the asymmetric unit of the title compound, C(32)H(30)Cl(4)N(4), in both of which the N-H bonds are syn to the meta-chloro substituents in the adjacent benzene ring. The other two Cl atoms of these two mol-ecules are disordered with occunpancy ratios of 0.79 (2):0.21 (2) and 0.68 (1):0.32 (1). Adjacent chloro-phenyl rings make dihedral angles of 74.3 (2) and 63.0 (2) degrees in the two mol-ecules. In the crystal, inter-molecular N-H?N hydrogen bonds link the mol-ecules into infinite chains. PMID- 21522367 TI - Propane-1,3-diaminium pyridine-2,5-di-carboxyl-ate dimethyl sulfoxide mono solvate. AB - In the crystal structure of the title solvated molecular salt, C(3)H(12)N(2) (2+).C(7)H(3)NO(4) (2-).C(2)H(6)OS, two amine groups of propane-1,3-diamine (pda) are protonated and two carb-oxy-lic acid groups of pyridine-2,5-dicarb-oxy-lic acid (2,5-pydcH(2)) are deprotonated. The crystal packing features N-H?O hydrogen bonds and weak C-H?O inter-molecular inter-actions. PMID- 21522368 TI - 1-Benzoyl-3-ethyl-3-phenyl-thio-urea. AB - In the title compound, C(16)H(16)N(2)OS, the conformation at the two partially double C-N bonds of the thio-urea unit is E. The amide group is twisted relative to the thio-urea fragment, forming a dihedral angle of 62.44 (16) degrees , and the two phenyl rings form a dihedral angle 75.93 (18) degrees . In the crystal, mol-ecules are linked by N-H?S hydrogen bonds, forming centrosymmetric dimers. PMID- 21522369 TI - 4-Hexyl-oxybenzamide. AB - In the title compound, C(13)H(19)NO(2), the dihedral angle between the benzene ring and the plane throught the non-H atoms of the amide group is 29.3 (1) degrees . The benzene ring and the alkane carbon skeleton plane are twisted slightly with respect to each other [5.40 (5) degrees ]. In the crystal, mol ecules are oriented with the amide groups head-to-head, forming N-H?O hydrogen bonded dimers. The dimers are connected by further N-H?O hydrogen bonds into a ladder-like motif along the b axis. PMID- 21522370 TI - 1-n-Decyl-5-nitro-1H-benzimidazol-2(3H)-one. AB - The benzimidazolone part of the title mol-ecule, C(17)H(25)N(3)O(3), is almost planar (r.m.s. deviation = 0.016 A) and its mean plane is aligned at 7.9 (4) degrees with respect to the mean plane of the nitro substituent. In the crystal, two mol-ecules are disposed about a center of inversion, generating a N-H?O hydrogen-bonded cyclic dimer with a R(2) (2)(8) graph-set motif. PMID- 21522371 TI - 4,4'-Dimeth-oxy-2,2'-[2,2-dimethyl-propane-1,3-diylbis(nitrilo-methanylyl idene)]diphenol. AB - In the title compound, C(21)H(26)N(2)O(4), the dihedral angle between the substituted benzene rings is 30.47 (15) degrees . Two strong intra-molecular O H?N hydrogen bonds generate two S(6) ring motifs. PMID- 21522372 TI - (1S,3R,8R,11S)-2,2-Dichloro-3,7,7,10-tetra-methyl-tricyclo-[6.4.0.0]dodec-9-en-11 ol. AB - The title compound, C(16)H(24)Cl(2)O, was synthesized from beta-himachalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzocyclo-heptene), which was isolated from essential oil of the Atlas cedar (Cedrus atlantica). The two fused rings exhibit different conformations: the six-membered ring has a screw-boat conformation, while the seven-membered ring displays a boat conformation. The dihedral angle between the two rings is 56.56 (18) degrees . In the crystal, mol ecules aggregate into supra-molecular chains along the c axis mediated by O-H?O hydrogen bonds. PMID- 21522373 TI - 4,4,4-Trifluoro-3-hy-droxy-3-(trifluoro-meth-yl)butanoic acid. AB - The asymmetric unit of the title compound, C(5)H(4)F(6)O(3), a polyfluorinated derivative of beta-hy-droxy-butyric acid, comprises two mol-ecules. Intra molecular O-H?O hydrogen bonds occur. In the crystal, inter-molecular O-H?O hydrogen bonds give rise to the formation of carb-oxy-lic acid dimers. Along with these hydrogen bonds, C-H?O contacts connect the mol-ecules into infinite strands along the a axis. PMID- 21522374 TI - 3-{[6-(4-Chloro-phen-yl)imidazo[2,1-b][1,3,4]thia-diazol-2-yl]meth-yl}-1,2 benzoxazole. AB - In the title compound, C(18)H(11)ClN(4)OS, the benzisoxazole and imidazothia diazole rings are inclined at an angle of 23.81 (7) degrees with respect to each other. The imidazothia-diazole and chloro-phenyl rings make a dihedral angle of 27.34 (3) degrees . In the crystal, inter-molecular C-H?N inter-actions generate a chain along the c axis and C-H?O inter-actions form centrosymmetric dimers resulting in an R(2) (2)(26) graph-set motif. Moreover, the C-H?N and S?N [3.206 (4) A] inter-actions links the mol-ecules into R(7) ring motifs. The packing is further stabilized by pi-pi stacking inter-actions between the thia-diazole rings with a shortest centroid-centroid distance of 3.497 (3) A. In addition, C-H?pi inter-actions are observed in the crystal structure. PMID- 21522375 TI - endo-11-(Dibenzyl-amino)-tetra-cyclo-[5.4.0.0.0]undecane-8-one. AB - The structure of the title compound, C(25)H(27)NO, is a mono-ketone penta-cyclo undecane (PCU) mol-ecule bearing a tertiary amine group. One of the methyl-ene groups in the PCU is disordered over two orientations with site-occupancy factors of 0.621 (7) and 0.379 (7). PMID- 21522376 TI - 6-Iodo-2-methyl-1,3-benzothia-zole. AB - The title compound, C(8)H(6)INS, is essentially planar, the largest deviation from the mean plane being for the I atom [0.075 (3) A]. The crystal structure is mainly stabilized by inter-molecular C-I?N halogen bonds, forming zigzag supra molecular chains in [10]. Relatively short off-set pi-pi contacts [centroid centroid distance = 3.758 (2) A] between the thia-zole rings of inversion-related mol-ecules link neighbouring chains and provide the secondary inter-actions for building the crystal structure. PMID- 21522377 TI - 3-(4-Chloro-phen-yl)-1-(2-methyl-4-phenyl-quinolin-3-yl)prop-2-en-1-one. AB - The crystal structure of the title compound, C(25)H(18)ClNO, shows that the mol ecules are isolated and not involved in inter-molecular C-H?O or C-H?Cl inter actions. However, the phenyl and quinoline rings are involved in pi-pi inter actions [centroid-centroid distance = 3.8829 (9) A]. PMID- 21522378 TI - 2,2'-(Sulfanediyldimethyl-ene)bis-(1,3-benzothia-zole). AB - In the title compound, C(16)H(12)N(2)S(3), the two benzothia-zole groups are oriented differently with respect to the -CH(2)- groups, one being approximately staggered and one nearly eclipsed. A sulfur-pi inter-action of 3.3627 (11) A is observed between the bridging thio-ether S atom and a thia-zole ring. The crystal packing is further stabilized by inter-molecular C-H?N and C-H?pi inter-actions. PMID- 21522379 TI - 2-Acetyl-anilinium chloride. AB - The cation of the title salt, C(8)H(10)NO(+).Cl(-), is essentially planar [C-C-C C torsion angle = 4.6 (2) degrees ], the conformation being stabilized by an intra-molecular N-H?O hydrogen bond. In the crystal, centrosymmetric aggregates are formed via N-H?Cl hydrogen bonds. These dimeric aggregates are sustained in the crystal packing by a combination of C-H?Cl, C-H?O and C-O?pi [O?ring centroid(benzene ring) = 3.1871 (13) and 3.3787 (13) A] inter-actions. PMID- 21522380 TI - (2E)-1-(6-Chloro-2-methyl-4-phenyl-quinolin-3-yl)-3-(4-chloro-phen-yl)prop-2-en-1 one. AB - Two independent mol-ecules comprise the asymmetric unit of the title chalcone, C(25)H(17)Cl(2)NO, and while each has an E configuration about the ethyl-ene double bond, they differ in the relative orientations of the carbonyl and ethyl ene double bonds within the prop-2-en-1-one residues, i.e. anti and syn. For each mol-ecule, the benzene [dihedral angles = 71.04 (9) and 73.34 (12) degrees ] and prop-2-en-1-one [C-C-C-O = 91.2 (2) and -119.1 (3) degrees ] substituents are twisted out of the plane of the quinoline moiety to which they are attached. The crystal structure is stabilized by C-H?pi and pi-pi [Cg(quinoline)?Cg(quinoline) = 3.7809 (12) and 3.8446 (11) A] inter-actions. PMID- 21522381 TI - 2,2',2''-(Nitrilo-trimethyl-ene)tris-(1H-benzimidazol-3-ium) trinitrate. AB - In the title compound, C(24)H(24)N(7) (3+).3NO(3) (-), the cation exhibits a distorted propeller-like conformation in which the benzimid-azolium fragments form dihedral angles of 9.4 (1), 10.7 (1) and 19.1 (1) degrees with each other. In the crystal, inter-molecular N-H?O hydrogen bonds link cations and anions into double ribbons propagated in [100]. Weak inter-molecular C-H?O inter-actions further consolidate the packing. PMID- 21522382 TI - 4-[(1,3-Dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl)meth-yl]-N'-[(E)-4-nitro benzyl-idene]benzene-sulfono-hydrazide dimethyl sulfoxide monosolvate. AB - The mol-ecular structure of the title compound, C(26)H(18)N(4)O(6)S.C(2)H(6)OS, shows an E conformation of the hydrazone double bond. The presence of a methyl ene group between the benzo[de]isoquinoline and benzene-sulfonyl moieties allows the 4-nitro-phenyl ring and the benzo[de]isoquinoline system to be parallel with respect to each other, so that the mol-ecule adopts a U-shaped spatial conformation. The dihedral angle between mean planes of these aromatic groups is 4.4 (1) degrees . This special arrangement enables neighboring mol-ecules to be inter-calated, forming slipped pi-pi inter-actions [centroid-centroid distance = 3.535 (2) A] between the 4-nitro-phenyl and benzo[de]isoquinoline groups and point-to-face C-H?pi inter-actions between the benzo[de]isoquinoline and benzene sulfonyl aromatic systems. In addition, the crystal packing also features an inter-molecular N-H?O inter-action involving the amine group and the dimethyl sulfoxide solvent mol-ecule. PMID- 21522383 TI - 1'-Methyl-4'-(1-naphth-yl)-1'',2'',3'',4''-tetra-hydro-indane-2-spiro-2' pyrrolidine-3'-spiro-2''-naphthalene-1,3,1''-trione. AB - In the title compound, C(32)H(25)NO(3), the pyrrolidine ring adopts an envelope conformation, whereas the cyclo-hexa-none ring in the tetra-hydro-naphthalene fused-ring system adopts a half-chair conformation. The indanedione unit is oriented at an angle of 58.9 (1) degrees with respect to the naphthyl ring system. Three intra-molecular C-H?O close contacts and an intra-molecular C-H?pi inter-action are observed. In the crystal, mol-ecules associate via C-H?O hydrogen bonds, forming a helical chain with a C(10) motif along the b axis. PMID- 21522384 TI - Propan-1-aminium 3,4,5,6-tetra-chloro-2-(meth-oxy-carbon-yl)benzoate. AB - In the anion of the title salt, C(3)H(10)N(+).C(9)H(3)Cl(4)O(4) (-), the meth-oxy carbonyl and carboxyl groups are aligned at dihedral angles of 57.8 (3) and 62.5 (3) degrees , respectively, with the aromatic ring. In the crystal, the cations and anions are linked by N-H?O hydrogen bonds, generating chains running aong the c axis. PMID- 21522385 TI - Morpholinium 4-amino-5-meth-oxy-2-methyl-benzensulfonate. AB - In the crystal structure of the title compound, C(4)H(10)NO(+).C(8)H(10)NO(4)S( ), the components are linked by N-H?O hydrogen bonds, forming a centrosymmetric 2:2 aggregate. The aggregates are further connected by N-H?O hydrogen bonds between the anions, forming a double-tape structure along the a axis. PMID- 21522386 TI - 3-Iodo-2-methyl-1-phenyl-sulfonyl-1H-indole. AB - In the title compound, C(15)H(12)INO(2)S, the sulfonyl-bound phenyl ring forms a dihedral angle 82.84 (9) degrees with the indole ring system. The mol-ecular structure is stabilized by a weak intra-molecular C-H?O hydrogen bond. The crystal structure exhibits weak inter-molecular C-H?pi inter-actions and pi-pi inter-actions between the indole groups [centroid-centroid distance between the five-membered and six-membered rings of the indole group = 3.7617 (18) A]. PMID- 21522387 TI - 1,3-Dimethyl-4-phenyl-sulfanyl-1H-pyrazol-5-ol. AB - In the title compound, C(11)H(12)N(2)OS, the pyrazole ring makes a dihedral angle of 85.40 (8) degrees with the phenyl ring. In the crystal, inter-molecular N-H?O and C-H?O hydrogen bonds link mol-ecules into a two-dimensional network parallel to the bc plane. PMID- 21522388 TI - (4-Meth-oxy-phen-yl)methanaminium chloride. AB - In the crystal structure of the title salt, C(8)H(12)NO(+).Cl(-), the methoxy group of the cation is co-planar with the phenylene moiety with an r.m.s. deviation from the mean plane of only 0.005 A. The ammonium N atom deviates from this plane by 1.403 (1) A. In the crystal, the (4-meth-oxy-phen-yl)methan-aminium cations and chloride anions are linked by N-H?Cl and C-H?O hydrogen bonds, resulting in an open framework architecture with hydrogen-bonded ammonium groups and chloride anions located in layers parallel to (011), separated by more hydrophobic layers with interdigitating anisole groups. PMID- 21522389 TI - 2,4-Bis(4-but-oxy-phen-yl)-3-aza-bicyclo-[3.3.1]nonan-9-one. AB - In the title compound, C(28)H(37)NO(3), a crystallographic mirror plane bis-ects the mol-ecule (one half-mol-ecule in the asymmetric unit). The title compound exists in a twin-chair conformation with an equatorial orientation of the 4-but oxy-phenyl groups. Both sides of the secondary amino group carry the 4-but-oxy phenyl groups at an angle of 38.54 (3) degrees with respect to one another. PMID- 21522390 TI - 3,3'-Dimeth-oxy-2,2'-[(4,5-dimethyl-o-phenyl-ene)bis-(nitrilo-methanylyl idene)]diphenol. AB - The asymmetric unit of the title compound, C(24)H(24)N(2)O(4), comprises two crystallographically independent mol-ecules A and B. The dihedral angles between the central dimethyl-substituted benzene ring and the two outer benzene rings are 49.5 (1) and 5.06 (11) degrees in mol-ecule A, and 42.55 (8) and 5.77 (9) degrees in mol-ecule B. In each mol-ecule, two strong intra-molecular O-H?N hydrogen bonds generate two S(6) ring motifs. The crystal structure is further stabilized by inter-molecular pi-pi [centroid-centroid distances of 3.591 (1) 3.876 (1) A] inter-actions. PMID- 21522391 TI - Ethane-1,2-diaminium dipicrate dihydrate. AB - The title compound, C(2)H(10)N(2) (2+).2C(6)H(2)N(3)O(7) (-).2H(2)O, crystallizes with a complete picrate anion and half an ethyl-enediammonium dication on a mirror plane, and two half-water mol-ecules (both on a mirror plane) in the asymmetric unit. The N atoms from separate half ethyl-enediammonium dications are in near proximity to a phenolate O atom and two o-NO(2) groups from the picrate anion, which, along with the water mol-ecule form N-H?O, O-H?O and weak intermolecular C-H?O hydrogen bonds that create cyclic patterns with graph-set descriptors R(2) (4)(8), R(4) (4)(12), and R(4) (4)(16). The crystal packing is strongly influenced by these inter-molecular inter-actions between symmetry related water mol-ecules, the half ethyl-enediammonium dication and the picrate anion, forming a three-dimensional supermolecular structure. PMID- 21522392 TI - 1-{5-[(E)-(2-Fluoro-phen-yl)diazen-yl]-2-hy-droxy-phen-yl}ethanone. AB - Theere are two independent mol-ecules in the asymmetric unit of the title compound, C(14)H(11)FN(2)O(2), each with a trans configuration with respect to the azo double bond. The dihedral angle between the aromatic rings is 17.21 (2) degrees in one mol-ecule and 19.06 (2) degrees in the other. Each of the independent mol-ecules has an intra-molecular O-H?O hydrogen bond. In the crystal, mol-ecules are stacked along [100]. PMID- 21522393 TI - 1-{5-[(E)-(4-Propyl-phen-yl)diazen-yl]-2-hy-droxy-phen-yl}ethanone. AB - The mol-ecular geometry of the title compound, C(17)H(18)N(2)O(2), displays an E configuration with respect to the azo group. The dihedral angle between the aromatic rings is 10.39 (4) degrees . In the mol-ecule, an intra-molecular O-H?O hydrogen bond generates an S(6) ring motif. PMID- 21522394 TI - (2-Hy-droxy-eth-yl)triphenyl-phospho-nium chloride. AB - In the crystal structure of the title compound, C(20)H(20)OP(+).Cl(-), the cations and anions are linked by inter-molecular C-H?Cl and O-H?Cl hydrogen bonds into chains running parallel to the b axis. In the cation, the hy-droxy-ethyl group is disordered over two orientations with site-occupancy factors of 0.554 (4) and 0.446 (4). PMID- 21522395 TI - 5-(3,6-Dibromo-9H-carbazol-9-yl)penta-nenitrile. AB - In the title compound, C(17)H(14)Br(2)N(2), the carbazole skeleton is nearly planar [maximum deviation = 0.055 (2) A]. In the crystal, aromatic pi-pi stacking is observed between parallel carbazole ring systems of adjacent mol-ecules, the shortest centroid-centroid distance between benzene rings being 3.4769 (11) A. PMID- 21522397 TI - 2,2'-[4,10-Bis(carb-oxy-meth-yl)-4,10-diaza-1,7-diazo-niacyclo-dodecane-1,7-di yl]diacetate dihydrate. AB - In the title compound, C(16)H(28)N(4)O(8).2H(2)O, the 12-membered macrocycle has twofold crystallographic symmetry and the asymmetric unit comprises one half-mol ecule. The four carbox-yl/carboxyl-ate groups reside on the same side of the macrocycle. The mol-ecule is a double zwitterion with two of the carb-oxy-lic acid H atoms transferred to the two N atoms on the opposite sides of the macrocycle, resulting in both N atoms having positive charges and leaving the two resulting carboxyl-ate groups with negative charges. The two remaining carb-oxy lic acid groups and the carboxyl-ate groups form O-H?O hydrogen bonds with the crystal water mol-ecules. The H atoms bound to the N atoms within the macrocyle are engaged in two equivalent hydrogen bonds with the adjacent N atoms. PMID- 21522396 TI - 3,3'-Dibenzyl-1,1'-(2,4,6-trimethyl-m-phenyl-enedimethyl-ene)diimidazol-3-ium dibromide. AB - In the title molecular salt, C(31)H(34)N(4) (2+).2Br(-), the central benzene ring makes dihedral angles of 80.47 (12) and 82.78 (12) degrees with the adjacent imidazole rings. The dihedral angle between the two terminal phenyl rings is 79.16 (13) degrees . In the crystal, the cations and anions are linked via C-H?Br hydrogen bonds, forming supra-molecular chains along the c axis. PMID- 21522398 TI - (1S,3R,8R)-9-(1-Amino-ethyl-idene)-2,2-dichloro-3,7,7-trimethyl-tricyclo [6.4.0.0]undecan-10-one. AB - The title compound, C(16)H(23)Cl(2)NO, was synthesised from beta-himachalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzocyclo-heptene), which was isolated from the essential oil of the Atlas cedar (Cedrus Atlantica). The mol ecule contains a seven membered ring, which is fused to a five- and a three membered ring. The five-membered ring has a twisted conformation, whereas the seven-membered ring displays a chair conformation. The dihedral angle between the five- and seven-membered rings is 45.26 (9) degrees . The absolute structure was established unambiguously from anomalous dispersion effects. In the crystal, mol ecules are linked into chains propagating along the b axis by inter-molecular N H?O hydrogen bonds; an intramolecular N-H?O link also occurs. PMID- 21522399 TI - N-Benzoyl-N',N'-dimethyl-thio-urea. AB - In the title compound, C(10)H(12)N(2)OS, the amide NCO group is twisted relative to the thio-ureido SCN(2) group, forming a dihedral angle of 55.3 (2) degrees . The crystal packing shows inter-molecular N-H?S and weak C-H?O inter-actions, the former giving rise to the formation of centrosymmetric R(2) (2)(8) dimers. PMID- 21522400 TI - tert-Butyl 2-hy-droxy-3-(4-methyl-benzene-sulfonamido)-butano-ate. AB - In the crystal of the title compound, C(15)H(23)NO(5)S, mol-ecules are linked through N-H?O and O-H?O hydrogen-bond inter-actions, resulting in centrosymmetric dimers in which the N-H?O inter-actions generate R(2) (2)(12) rings and the O-H?O inter-actions generate R(2) (2)(14) rings. Weak inter-molecular C-H?O inter actions are also observed. PMID- 21522401 TI - (E)-1-(4-Chloro-benzyl-idene)thio-semi-carbazide. AB - In the crystal of the title compound, C(8)H(8)ClN(3)S, mol-ecules are connected by N-H?S hydrogen bonds into strips parallel to the (112) planes and running along [10]. One of the amino H atoms is not involved in a classical hydrogen bond. In addition, there is a rather short inter-molecular Cl?S distance of 3.3814 (5) A. PMID- 21522402 TI - 5-Bromo-3-(indan-1-yl-oxy)pyridin-2-amine. AB - The title compound, C(14)H(13)BrN(2)O, was obtained by reaction of indan-1-yl methane-sulfonate with 2-amino-5-bromo-pyridin-3-ol in the presence of caesium carbonate. The indane ring system is approximately planar [all but one of the C atoms are coplanar within 0.03 A, the latter atom being displaced by 0.206 (2) A from the mean plane through the remaining atoms] and forms a dihedral angle of 58.41 (4) degrees with the pyridine ring. In the crystal, centrosymmetrically related mol-ecules are linked into dimers by N-H?N hydrogen bonds. PMID- 21522403 TI - N-{2-[(4S)-4-tert-Butyl-4,5-dihydro-1,3-oxazol-2-yl]phen-yl}-5,6-diphenyl-1,2,4 triazin-3-amine. AB - The title compound, C(28)H(27)N(5)O, was synthesized using palladium cross coupling amination of 3-bromo-5,6-diphenyl-1,2,4-triazine with 2-[(4S)-4-tert butyl-4,5-dihydro-1,3-oxazol-2-yl]aniline. The oxazoline ring is almost planar, with a maximum atomic deviation of 0.023 (5) A. The phenyl rings make dihedral angles of 29.0 (1) and 54.6 (1) degrees with the triazine ring while the benzene ring makes a dihedral angle of 0.6 (1) degrees with the oxazoline ring. The conformation of the mol-ecule is influenced by strong intra-molecular N-H?N and weak C-H?N hydrogen bonds. In the crystal, screw-axis related mol-ecules are linked into supra-molecular chains by inter-molecular C-H?O hydrogen bonds. pi-pi stacking is observed between the oxazoline and triazine rings of adjacent mol ecules, with a centroid-centroid distance of 3.749 (2) A. PMID- 21522404 TI - 4-Amino-3-methyl-benzoic acid-1,2-bis-(4-pyrid-yl)ethane (1/1). AB - In the crystal structure of the title 1:1 adduct, C(12)H(12)N(2).C(8)H(9)NO(2), the 4-amino-3-methyl-benzoic acid mol-ecules and 1,2-bis-(4-pyrid-yl)ethane mol ecules are linked by inter-molecular O-H?N, N-H?O and N-H?N hydrogen bonds, forming a two-dimensional supra-molecular network parallel to (001). In the 1,2 bis-(4-pyrid-yl)ethane mol-ecule, the two pyridine rings are twisted to each other by a dihedral angle of 12.12 (8) degrees . The non-H atoms of the 4-amino-3 methyl-benzoic acid mol-ecule are almost coplanar, the maximum atomic deviation being 0.029 (1) A. Weak C-H?pi inter-actions are present in the crystal structure. PMID- 21522405 TI - Methidathion: S-(5-meth-oxy-2-oxo-2,3-dihydro-1,3,4-thia-diazol-3-yl)methyl O,O dimethyl phospho-rodithio-ate. AB - The title compound, C(6)H(11)N(2)O(4)PS(3), crystallizes with two independent mol ecules in the asymmetric unit. The dihedral angles between the thia-diazole ring planes and the PS(2) planes of the phospho-rodithio-ate group are 86.51 (5) and 56.33 (5) degrees in the two mol-ecules. In the crystal, weak inter-molecular S?S [3.570 (8) A] inter-actions and C-H?O and C-H?N hydrogen bonds contribute to the stabilization of the packing. PMID- 21522406 TI - 3-Hy-droxy-1-methyl-2-[4-(piperidin-1-yl)phen-yl]quinolin-4(1H)-one. AB - There are two structurally similar but crystallographically independent mol ecules (A and B) in the asymmetric unit of the title compound, C(21)H(22)N(2)O(2), which are linked via two O-H?O hydrogen bonds. An intramolecular O-H?O hydrogen bond also occurs in each molecule. In the crystal, the A and B mol-ecules are further linked through C-H?O inter-actions. The benzene ring is twisted at an angle of 69.9 (1) and 83.4 (1) degrees relative to the 1,4-dihydro-quinoline skeleton in mol-ecules A and B, respectively. Adjacent 1,4-dihydro-quinoline units of mol-ecules A are parallel, while mol-ecules A and B are oriented at an angle of 32.8 (1) degrees . PMID- 21522407 TI - Decyl-ammonium octa-noate. AB - The title compound, C(10)H(24)N(+).C(8)H(15)O(2) (-), forms a layered structure in which inter-molecular N(+)-H?O hydrogen bonds connect anions and cations, forming a two-dimensional network parallel to (010). The n-alkyl chains of the decyl-ammonium cations pack according to an ortho-rhom-bic 'subcell' with approximate dimensions 5.1 * 7.3 A, and they are significantly distorted from planarity. PMID- 21522408 TI - (5S)-3-Chloro-5-[(1R,2S,5R)-2-isopropyl-5-methyl-cyclo-hex-yloxy]-4-(4-methyl piperidin-1-yl)furan-2(5H)-one. AB - The title compound, C(20)H(32)ClNO(3), was obtained via a tandem asymmetric Michael addition-elimination reaction of (5S)-3,4-dichloro-5-(l-menth-yloxy)furan 2(5H)-one and 4-methyl-piperidine in the presence of potassium fluoride. The furan-one ring is approximately planar [maximum atomic deviation = 0.022 (2) A] while the cyclo-hexane ring adopts a chair conformation. Weak inter-molecular C H?O hydrogen bonding is present in the crystal structure. PMID- 21522409 TI - 2-[1-(3-{2-[(2-Hy-droxy-benzyl-idene)amino]-phen-oxy}prop-yl)-1H-1,3-benzodiazol 2-yl]phenol. AB - In the title compound, C(29)H(25)N(3)O(3), the imine double bond has an E configuration. The dihedral angle between the hy-droxy-phenyl and benzene rings in the imine moiety is 26.95 (9) degrees , and the dihedral angle between the hy droxy-phenyl and benzimidazole rings in the other moiety is 14.83 (9) degrees . These angles are probably limited to small values as a consequence of two strong intra-molecular O-H?N hydrogen bonds formed between the hy-droxy groups and the imine and imidazole N atoms. The aliphatic chain linking the two ring systems has a gauche conformation, as reflected in C-C-C-O torsion angle of 70.9 (2) degrees . PMID- 21522410 TI - 2-Bromo-2-methyl-N-(4-nitro-phen-yl)propanamide. AB - The title compound, C(10)H(11)BrN(2)O(3), exhibits a small twist between the amide residue and benzene ring [the C-N-C-C torsion angle = 12.7 (4) degrees ]. The crystal structure is stabilized by weak N-H?O, C-H?Br and C-H?O inter actions. These lead to supra-molecular layers in the bc plane. PMID- 21522411 TI - 3,5-Dinitro-N-(1,3-thia-zol-2-yl)benzamide monohydrate. AB - In the title compound, C(10)H(6)N(4)O(5)S.H(2)O, the thia-zole ring is twisted at a dihedral angle of 25.87 (7) degrees with respect to the benzene ring. The water mol-ecule is linked with the benzamide mol-ecules via N-H?O, O-H?N and O H?O hydrogen bonds. In the crystal, pi-pi stacking is observed between nearly parallel [dihedral angle = 7.02 (7) degrees ] thia-zole and benzene rings of adjacent mol-ecules, the centroid-centroid distances being 3.7107 (9) and 3.7158 (9) A, respectively. PMID- 21522412 TI - 3,5,3'-Trihy-droxy-4'-meth-oxy-7-(3-methyl-but-2-en-yloxy)flavone. AB - The title compound pteleifolosin C, C(21)H(20)O(7), was isolated from the petroleum ether-soluble fraction of an indigenous Chinese tree Melicope pteleifolia (Rutaceae). The dihedral angle between the benzene rings is 2.7 (2) degrees . Intra-molecular O-H?O hydrogen bonds occur. In the crystal, mol-ecules are linked by inter-molecular O-H-O hydrogen bonds. PMID- 21522413 TI - 4-[(2-Chloro-4-nitro-phen-yl)diazen-yl]-N,N-diethyl-aniline. AB - In the title compound, C(16)H(17)ClN(4)O(2), the aromatic ring is twisted slightly with respect to the plane of the diazene group [N-N-C-C torsion angle = 3.9 (4) degrees ]. The NO(2) group is twisted by 16.2 (4) degrees relative to the aromatic ring. The two ethyl chains are positioned such that one ethyl chain lies above and the other below the ring. PMID- 21522414 TI - N,N'-Dibenzyl-N''-(2-chloro-2,2-difluoro-acet-yl)-N,N'-dimethyl-phospho-ric triamide. AB - In the title mol-ecule, C(18)H(21)ClF(2)N(3)O(2)P, the P=O and N-H groups are syn to each other. The P atom adopts a slightly distorted tetra-hedral environment and the N atoms of the tertiary amine groups are bonded in an essentially planar geometry. In the crystal, pairs of inter-molecular N-H?O(P) hydrogen bonds form centrosymmetric dimers. PMID- 21522415 TI - N-(2-Chloro-2,2-difluoro-acet-yl)-N',N''-diisopropyl-phospho-ric triamide. AB - In the title compound, C(8)H(17)ClF(2)N(3)O(2)P, the phosphoryl group and the NH unit of the C(O)NHP(O) moiety adopt a syn conformation with respect to each other. The P atom is in a tetra-hedral coordination environment and the environment of the N atom of the C(O)NHP(O) moiety is essentially planar. In the crystal, adjacent mol-ecules are linked via N-H?O =P and N-H?O =C hydrogen bonds, building R(2) (2)(8) and R(2) (2)(12) rings in a linear arrangement parallel to [110]. PMID- 21522416 TI - 2-{2-[4-(4-Fluoro-phen-yl)piperazin-1-yl]-2-oxoeth-yl}-6-(morpholin-4-yl)-4 phenyl-pyridazin-3(2H)-one. AB - In the title compound, C(26)H(28)FN(5)O(3), the morpholine ring adopts a chair conformation. The piperazine ring is puckered [Q(T) = 0.5437 (15) A, theta = 8.89 (15) and phi = 357.2 (11) degrees ]. The 1,6-dihydro-pyridazine ring makes dihedral angles of 28.03 (7) and 77.46 (7) degrees with the phenyl and benzene rings, respectively. In the crystal, mol-ecules are linked along the c axis by C H?O inter-actions and are flattened parallel to the ac plane. C-H?pi inter actions also contribute to the stability of the structure. PMID- 21522417 TI - (3,6-Dimeth-oxy-naphthalen-2-yl)(phen-yl)methanone. AB - In the title compound, C(19)H(16)O(3), the dihedral angle between the naphthalene ring system and the phenyl ring is 68.32 (5) degrees . The bridging carbonyl C C(=O)-C plane makes a dihedral angle of 54.32 (5) degrees with the naphthalene ring system and 21.45 (6) degrees with the phenyl ring. An inter-molecular C-H?O hydrogen bond exists between the H atom of one meth-oxy group and the O atom of the second meth-oxy group in an adjacent mol-ecule. The crystal packing is additionally stabilized by a weak C-H?O inter-molecular inter-action between an H atom of the naphthalene ring and the O atom of the carbonyl group. PMID- 21522418 TI - 5-Nitro-1-nonyl-1H-benzimidazol-2(3H)-one. AB - In the title mol-ecule, C(16)H(23)N(3)O(3), the dihedral angle between the benzimidazole and nitro group planes is 5.34 (9) degrees and the dihedral angle between the benzimidazole and aliphatic chain mean planes is 73.23 (5) degrees . The C-C-C-C torsion angles (about 176 degrees ) of the nonyl group indicate an all-anti-periplanar conformation. In the crystal, adjacent mol-ecules are linked by pairs of N-H?O hydrogen bonds into inversion dimers. These mol-ecules are further connected through C-H?O inter-actions, building tapes parallel to (22). PMID- 21522419 TI - 2-(2-Methyl-6-phenyl-1-propyl-1,4-dihydro-pyridin-4-yl-idene)propane-dinitrile. AB - In the title compound, C(18)H(17)N(3), the dihedral angle between the dihydropyridine and phenyl rings is 72.57 (5) degrees and that between the dihydropyridine ring and malononitrile plane is 5.19 (20) degrees . The C-C bond lengths in the pyridine ring are considerably shorter than those of normal single bonds, indicating that electrons on the dihydropyridine ring, including the non bonding electrons of the N atom, are delocalized on the ring. PMID- 21522420 TI - (E)-7-(4-Chloro-phen-yl)-5,7-dihydro-4H-pyrano[3,4-c]isoxazole-3-carbaldehyde oxime. AB - In the title compound, C(13)H(11)ClN(2)O(3), the nine-membered bicycle includes an oxime group having the C=N group in an E configuration. The isoxazole ring is almost planar [r.m.s. deviation = 0.0056 A]; the dihedral angle between the isoxazole and 4-chloro-phenyl ring is 75.60 (5) degrees . In the crystal, inter molecular O-H?N(isoxazole) hydrogen bonds give rise to chains running along the b axis. PMID- 21522421 TI - Dimethyl 2-methyl-1,2-dihydro-quinoline-2,4-dicarboxyl-ate. AB - In the crystal of the title compound, C(14)H(15)NO(4), pairs of inter-molecular N H?O hydrogen bonds link the mol-ecules into centrosymmetric R(2) (2)(10) dimers. These dimers are further connected via inter-molecular C-H?O hydrogen bonds, forming a three-dimensional network. The heterocyclic ring adopts a twisted conformation. PMID- 21522422 TI - 1,3-Dimethyl-3-tetra-decyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione. AB - The seven-membered ring of the title compound, C(25)H(40)N(2)O(2), adopts a boat shaped conformation (with the C atoms of the fused-ring as the stern and the methine C atom as the prow). The tetra-decyl substituent occupies an equatorial position, with the tetra-dodecyl chain exhibibiting an an all-trans conformation. PMID- 21522423 TI - 1-(2-Benzoyl-1-phenyl-eth-yl)-4-[(2-hy-droxy-1-naphth-yl)methyl-idene-amino]-3 phenyl-1H-1,2,4-triazole-5(4H)-thione. AB - In the title mol-ecule, C(34)H(26)N(4)O(2)S, the hy-droxy group is involved in an intra-molecular O-H?N hydrogen bond. The naphthyl ring system and the central triazole ring form a dihedral angle of 37.8 (1) degrees . The crystal packing exhibits weak inter-molecular C-H?O and C-H?pi inter-actions. PMID- 21522424 TI - (1R,2R)-2-(Pyridin-4-yl-methyl-amino)-cyclo-hexa-naminium chloride. AB - In the crystal structure of the title compound, C(12)H(20)N(3) (+).Cl(-), the protonated (1R,2R)-(pyridin-4-ylmeth-yl)cyclo-hexane-1,2-diamine cations and chloride anions are linked via N-H?N and N-H?Cl hydrogen bonds into a three dimensional network. PMID- 21522425 TI - Bis(2-amino-3-carb-oxy-pyrazin-1-ium) sulfate dihydrate. AB - The crystal structure of the title compound, 2C(5)H(6)N(3)O(2) (+).SO(4) (2 ).2H(2)O, displays a variety of N-H?O and O-H?O hydrogen bonds in which all potential donors and acceptors are involved. In the crystal, cations and anions are inter-connected, forming R(3) (3)(10) and R(2) (2)(8) ring motifs whereas the anions and water mol-ecules form R(2) (3)(10) rings, which develop in chains running along [100]. The resulting three-dimensional network exhibits undulating sheets parallel to (011), marked by the presence of R(6) (6)(26) rings in which six cations are involved. PMID- 21522426 TI - 3beta-Acet-oxy-12alpha-chloro-d-friedooleanan-28,14beta-olide. AB - The title compound, C(32)H(49)ClO(4), was obtained along with nitrile and lactam products in the POCl(3)-catalysed Beckmann rearrangement from 3beta-acet-oxy-12 hydroxyiminoolean-28-olic acid methyl ester. The mechanism of the transformation leading to the title compound remains unclear and requires further investigation. Rings A, B and E are in chair conformations, ring C has a twisted-boat conformation, ring D a conformation halfway between boat and twisted-boat and rings D and E are cis-fused. In the crystal, mol-ecules are connected by weak inter-molecular C-H?O hydrogen bonds into layers extending parallel to the bc plane. PMID- 21522427 TI - 10-Hydr-oxy-2-aza-penta-cyclo-[10.8.0.0.0.0]icosa-1(12),4(9),5,7,13,15(20),16,18 octa-ene-3,11-dione. AB - In the title compound, C(19)H(11)NO(3), the isoindolinone ring system is approximately planar with a maximum atomic deviation of 0.071 (1) A and the five membered ring of the dihydro-benzo[g]indol-3-one unit assumes an envelope conformation. The naphthalene ring system makes a dihedral angle of 39.47 (4) degrees with the mean plane of the isoindolinone system. Inter-molecular O-H?O and C-H?O hydrogen bonding helps to stabilize the crystal structure. PMID- 21522428 TI - 1,4-Bis[(5-phenyl-1,3,4-thia-diazol-2-yl)sulfan-yl]butane. AB - The asymmetric unit of the title compound, C(20)H(18)N(4)S(4), contains one half mol-ecule situated on a twofold rotation axis, in which the thia-diazole and phenyl rings are twisted by 7.2 (3) degrees . In the crystal, weak inter molecular C-H?pi inter-actions link the mol-ecules into layers parallel to (103). PMID- 21522429 TI - 5,7,7,12,14,14-Hexamethyl-4,8-diaza-1,11-diazo-niocyclotetra-deca-4,11-diene diiodide dihydrate. AB - The asymmetric unit of the title compound, C(16)H(34)N(4) (2+).2I(-).2H(2)O, contains one half-cation, one iodide anion and one water mol-ecule. The cation has crystallographically imposed centrosymmetric symmetry. Despite some differences in the unit-cell dimensions, packing analysis on a cluster of 15 cations and a comparison of the hydrogen bonding suggests that this compound is isostructural with its bromide analogue. Inter-molecular hydrogen bonding forms eight-membered [H-O-H?I](2) and [H-N-H?I](2) rings and creates a sheet structure. PMID- 21522430 TI - Racemic 9,10-dimeth-oxy-3-methyl-6-phenyl-7,7a-dihydro-benzo[b]benzo[4,5]isothia zolo[2,3-d][1,4]diazepine 12,12-dioxide. AB - There are two molecules in the asymmetric unit of the title compound, C(24)H(22)N(2)O(4)S. The conformation of the seven-membered ring is twisted boat for both molecules. The molecule is chiral, but crystal symmetry generates a recemate. The crystal packing is stabilized by weak intermolecular C-H?O hydrogen bonds. PMID- 21522431 TI - 2-Meth-oxy-anilinium 3-hy-droxy-2,4,6-trinitro-phenolate. AB - The cation and anion of the title mol-ecular salt, C(7)H(10)NO(+).C(6)H(2)N(3)O(8) (-), are linked via an N-H?O hydrogen bond. An intra-molecular O-H?O hydrogen bond is also found in the anion. In the crystal, the anions self-assemble via O-H?O hydrogen bonds, forming a C(9) supra-molecular chain the b axis. Further inter-molecular N-H?O inter-actions also occur. PMID- 21522432 TI - 6-Chloro-9-(2-nitro-phenyl-sulfon-yl)-9H-purine. AB - The title compound, C(11)H(6)ClN(5)O(4)S, crystallized with two independent mol ecules in the asymmetric unit. The benzene ring makes dihedral angles of 66.46 (8) and 85.77 (9) degrees with the mean plane of the purine ring in the two mol ecules. In the crystal, inter-molecular pi-pi stacking inter-actions [centroid centroid distance = 3.8968 (12) A], C-Cl?pi inter-actions [Cl?centroid = 3.2505 (10) A, C-Cl?centroid = 161.56 (18) degrees ] and non-classical C-H?O and C-H?N hydrogen bonds link the molecules. PMID- 21522433 TI - N-[(4-Carbamoylphen-yl)carbamothio-yl]-2,3,4,5-tetra-fluoro-benzamide. AB - In the title compound, C(15)H(9)F(4)N(3)O(2)S, the N,N'-disubstituted thio-urea fragment adopts a cis,trans geometry, stabilized by an intra-molecular N-H?O hydrogen bond to the carbonyl O atom of the tetra-fluoro-benzoyl group. The central thio-urea group makes dihedral angles of 47.79 (7) and 35.54 (8) degrees with the two aromatic rings. In the crystal, mol-ecules are linked via N-H?O and N-H?S hydrogen bonds into two-dimensional polymeric structures parallel to (100). In turn, pi-pi stacking inter-actions between tetra-fluoro-benzene and benzene units [centroid-centroid distance = 3.996 (10) A; dihedral angle = 13.60 (8) degrees ] organize these two-dimensional assemblies into a three-dimensional framework. PMID- 21522434 TI - (Z)-3-(Benzyl-carbamo-yl)prop-2-enoic acid. AB - The title compound, C(11)H(11)NO(3), was synthesized by the reaction of maleic andydride and phenyl-methanamine. The mol-ecular conformation is stabilized by by an intra-molecular O-H?O hydrogen bond. In the crystal, mol-ecules are linked by inter-molecular N-H?O and C-H?O hydrogen bonds, forming a chain along the b axis. PMID- 21522435 TI - Ethyl 2-{[4-(pyridin-4-yl)pyrimidin-2-yl]sulfan-yl}acetate. AB - In the title mol-ecule, C(13)H(13)N(3)O(2)S, the pyridine and pyrimidine rings form a dihedral angle of 3.8 (1) degrees . The crystal packing exhibits weak inter-molecular C-H?O hydrogen bonds. PMID- 21522436 TI - Bis(2-iodo-thio-phen-3-yl)methanone. AB - In the title mol-ecule, C(9)H(4)I(2)OS(2), the two five-membered rings form a dihedral angle of 64.2 (2) degrees . In the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into layers parallel to the ab plane. The crystal packing exhibits short C?I contacts of 3.442 (5) A between the mol-ecules of adjacent layers. PMID- 21522437 TI - 6-(1H-Tetra-zol-5-yl)-1H-indole monohydrate. AB - In the title compound, C(9)H(7)N(5).H(2)O, the tetra-zole ring forms a dihedral angle of 1.82 (1) degrees with the mean plane of the indole fragment. In the crystal, mol-ecules are linked by inter-molecular O-H?N, N-H?O and N-H?N hydrogen bonds into a two-dimensional network parallel to (100). Addtional stabilization is provide by weak pi-pi inter-actions with a centroid-centroid distance of 3.698 (2) A. PMID- 21522438 TI - 4-(3,4-Diacetyl-5-methyl-1H-pyrazol-1-yl)benzene-sulfonamide. AB - In the title mol-ecule, C(14)H(15)N(3)O(4)S, the pyrazole ring is aligned at a dihedral angle of 55.5 (1) degrees with respect to the benzene ring; the mean planes of the acetyl substituents are twisted by 13.4 (3) and 30.1 (3) degrees with respect to the pyrazole ring. Inter-molecular classical N-H?O and weak C-H?O hydrogen bonding links the mol-ecules, forming a three-dimensional network architecture in the crystal structure. PMID- 21522439 TI - 3-[(E)-3-(4-Meth-oxy-phen-yl)prop-2-eno-yl]-1-(4-methyl-phen-yl)-5-phenyl-1H pyrazole-4-carbonitrile. AB - In the title compound, C(27)H(21)N(3)O(2), the non-H atoms of the meth-oxy-phenyl acryloyl substitutent of the pyrazolyl ring are almost co-planar (r.m.s. deviation = 0.070 A), and the mean plane is twisted by 18.7 (1) degrees with respect to the pyrazolyl ring. The phenyl and tolyl substituents are aligned at 48.9 (1) and 44.5 (1) degrees with respect to the pyrazolyl ring. Weak inter molecular C-H?O and C-H?N hydrogen bonding is present in the crystal structure. PMID- 21522440 TI - 3-(5-Phenyl-4-phenyl-sulfonyl-1-p-tolyl-1H-pyrazol-3-yl)-1,2-dihydro-quinoxaline. AB - In the crystal structure of the title compound, C(30)H(24)N(4)O(2)S, the dihydro quinoxaline fused-ring system is disordered over three orientations in a 0.358 (2):0.318 (3):0.324 (3) ratio; the mean planes of the non-H atoms of the disorder components are aligned at 4.0 (3), 11.8 (4) and 41.7 (2) degrees with respect to the pyrazole ring. The rings of the phenyl and tolyl substituents are aligned at 64.0 (1) and 43.7 (1) degrees with respect to the pyrazole ring. Weak intermolecular C-H?O hydrogen bonding links the mol-ecules, forming supra molecular chains running along the a axis. PMID- 21522441 TI - Ethyl 5-bromo-1-benzofuran-2-carboxyl-ate. AB - In the title compound, C(11)H(9)BrO(3), the benzofuran fused-ring system is almost planar, with a maximum atomic deviation of 0.024 (5) A; the carboxyl CO(2) fragment is aligned at 4.8 (7) degrees with respect to the fused-ring plane. Weak inter-molecular C-H?O hydrogen bonding is present in the crystal structure. pi-pi stacking is also observed between parallel mol-ecules, the centroid-centroid distance between benzene and furan rings of adjacent mol-ecules being 3.662 (3) A. PMID- 21522442 TI - (E)-1-{4-[Bis(4-meth-oxy-phen-yl)meth-yl]piperazin-1-yl}-3-(4-fluoro-phen-yl)prop 2-en-1-one. AB - In the title compound, C(28)H(29)FN(2)O(3), the conformation about the ethene bond is E. The piperazine ring adopts a chair conformation. In the crystal, mol ecules are linked by inter-molecular C-H?O hydrogen bonds. PMID- 21522443 TI - 4-Nitro-phenyl 2-bromo-2-methyl-propano-ate. AB - In the title compound, C(10)H(10)BrNO(4), the planes of the carboxyl-ate and nitro groups are rotated by 60.53 (13) and 6.4 (3) degrees , respectively, to the benzene ring. In the crystal, inter-molecular C-H?O hydrogen bonds link the mol ecules into zigzag chains parallel to the c axis. PMID- 21522444 TI - 2-Amino-6-methyl-4,5,6,7-tetra-hydro-1-benzothio-phene-3-carbonitrile. AB - In the title compound, C(10)H(12)N(2)S, one of the C atoms of the cyclo-hexene ring (at position 6) and the methyl group attached to it are disordered over two sets of sites in a 0.650 (3):0.350 (3) ratio. The cyclo-hexene ring in both the major and minor occupancy conformers adopts a half-chair conformation. The thio phene ring is essentially planar (r.m.s. deviation = 0.05 A). In the crystal, N H?N hydrogen bonds involving the amino groups result in inversion dimers with R(2) (2)(12) graph-set motif. Further N-H?N hydrogen bonds involving the amino and carbonitrile groups generate zigzag chains along the a axis. PMID- 21522445 TI - [(1R,3S)-6,7-Dimeth-oxy-1-phenyl-1,2,3,4-tetra-hydro-isoquinolin-3-yl]methanol 2.33-hydrate. AB - The title compound, C(18)H(21)NO(3).2.33H(2)O, is the fourth reported member in a series of (1R,3S)-6,7-dimeth-oxy-1-phenyl-1,2,3,4-tetra-hydro-isoquinoline derivatives used in catalysis as ligands (or their precursors). The N-heterocycle in the structure adopts a half-chair conformation. The dihedral angle between the benzene rings is 77.29 (13) degrees . There are three ill-resolved water molecules of crystallization in the structure (one of them rotationally disordered about a threefold axis) involved in short contacts probably due to hydrogen bonding. PMID- 21522446 TI - 3-(4-Bromo-phen-yl)-5-[4-(dimethyl-amino)-phen-yl]-4,5-dihydro-1H-pyrazole-1 carbothio-amide. AB - The mol-ecule of the title pyrazole derivative, C(18)H(19)BrN(4)S, is twisted. The central pyrazole ring, which adopts a flattened envelope conformation, is almost coplanar with the 4-bromo-phenyl ring, whereas it is inclined to the 4 (dimethyl-amino)-phenyl ring making dihedral angles of 1.68 (6) and 85.12 (6) degrees , respectively. The dihedral angle between the two benzene rings is 86.56 (6) degrees . The dimethyl-amino group is slightly twisted from the attached benzene ring [C-C-N-C torsion angles = 8.4 (2) and 8.9 (2) degrees ]. In the crystal, mol-ecules are linked by inter-molecular N-H?S hydrogen bonds into chains along [20]. The crystal is further stabilized by C-H?pi inter-actions. PMID- 21522447 TI - 3-Benzyl-5,7-dimeth-oxy-chroman-4-ol. AB - In the crystal structure of the title compound, C(18)H(20)O(4), O-H?O hydrogen bonds connect the mol-ecules in parallel layers along the b axis. PMID- 21522448 TI - 2-Aza-niumylcarba-closo-dodeca-borate ethanol monosolvate. AB - Two formula units of the title compound, 2-H(3)N-closo-1-CB(11)H(11).CH(3)CH(2)OH or CH(14)B(11)N.C(2)H(5)OH, form a ring motif of R(4) (2)(8) type in the solid state that surrounds a crystallographic center of symmetry. The ring motif is a result of N-H?O hydrogen bonds. In contrast to many structures of {closo-1 CB(11)} clusters, the assignment of the position of the cluster C atom in the structure of the title compound is unambigious. The relatively long B-N bond length [1.5396 (10) A] documents the absence of any B-N pi-inter-action in the title compound although this was observed for a related 2-amino-carba-closo dodeca-borate. PMID- 21522449 TI - 4,5-Bis(2,4-di-tert-butyl-phen-oxy)phthalonitrile. AB - In the title compound, C(36)H(44)N(2)O(2), the dihedral angles between the phthalonitrile ring and the two di-tert-butyl-benzene rings are 68.134 (8) and 70.637 (11) degrees . The two nitrile groups are almost coplanar with the phthalonitrile ring except for one of the N atoms which deviates from the plane by 0.125 (4) A. One of the tert-butyl groups is disordered over two orientations, with refined occupancies of 0.814 (6) and 0.186 (6). Intra-molecular C-H?O inter actions stabilize the molecular structure. The crystal packing is stabilized by inter-molecular C-H?N inter-actions. PMID- 21522450 TI - (E)-Ethyl 2-cyano-3-[4-(4,5-diphenyl-1H-imidazol-2-yl)phen-yl]acrylate dihydrate. AB - In the title compound, C(27)H(21)N(3)O(2).2H(2)O, the three benzene rings attached to the heterocyclic imidazole ring are not coplanar with the latter, making dihedral angles of 14.8 (2), 31.4 (2), and 37.5 (2) degrees , respectively, for the benzene ring planes in the 2-, 4- and 5-positions. In the crystal, there are two water mol-ecules which serve as connectors between the acrylate mol-ecules and stabilize the structure via N-H?O, O-H?N, C-H?O and O-H?O hydrogen bonding. PMID- 21522451 TI - 2-Chloro-1-[4-(2-fluoro-benz-yl)piperazin-1-yl]ethanone. AB - In the title compound, C(13)H(16)ClFN(2)O, the piperazine ring is flanked by 1-(2 fluoro-benz-yl)piperazine and adopts a chair conformation. The dihedral angle between the fluoro-phenyl ring and the four planar C atoms (r.m.s. = 0.0055 A) of the piperazine chair is 78.27 (7) degrees , whereas the dihedral angle between the four planar C atoms of the piperazine chair and the ethanone plane is 55.21 (9) A; the Cl atom displaced by1.589 (2) A out of the plane. PMID- 21522452 TI - 1-[(4-tert-Butyl-phen-yl)sulfon-yl]-1H-benzimidazole. AB - The title compound, C(17)H(18)N(2)O(2)S, was synthesized by aryl-sulfonyl-ation of 1-hy-droxy-methyl-1H-benzimidazole in the presence of triethyl-amine. The benzimidazole and benzene rings form a dihedral angle of 84.1 (1) degrees . The tert-butyl group was treated as rotationally disordered over two orientations in a 0.51 (2):0.49 (2) ratio. In the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into chains propagating in [010]. PMID- 21522453 TI - 2-(4-Chloro-anilino)-1-phenyl-ethanone. AB - In the title compound, C(14)H(12)ClNO, the planes of the two aromatic rings form a dihedral angle of 4.16 (1) degrees . The mol-ecule is essentially planar with an r.m.s. deviation for all non-H atoms of 0.0372 A. PMID- 21522454 TI - 2-Methyl-6-(4,4,10,13,14-penta-methyl-3-oxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17 tetra-deca-hydro-1H-cyclo-penta-[a]phenanthren-17-yl)hept-2-enoic acid. AB - In the title compound, C(30)H(46)O(3), an isolation product of Pistacia integerima Stewart, the five-membered ring is nearly in the envelope form. A 6 carb-oxy-hept-5-en-2-yl group is attached to the five-membered ring. An S(6) ring motif is formed due to intra-molecular C-H?O hydrogen bonding. In the crystal, inter-molecular O-H?O hydrogen bonds form carboxyl-ate dimers with R(2) (2)(8) ring motifs. PMID- 21522455 TI - 4,6-Dibromo-2,3-dimethyl-phenol. AB - The mol-ecule of the title compound, C(8)H(8)Br(2)O, is approximately planar with a maximum deviation of 0.063 (1) A for one of the Br atoms. In the crystal, adjacent mol-ecules are joined inter-molecular O-H?O hydrogen bonds, forming chains parallel to [010]. The structure also features a short Br?Br inter-action of 3.362 (1) A. PMID- 21522456 TI - (E)-N'-[(2-Hy-droxy-naphthalen-1-yl)methyl-idene]-4-methyl-benzene-sulfono hydrazide. AB - In the title compound, C(18)H(16)N(2)O(3)S, the dihedral angle between the planes of the benzene ring and the naphthyl ring system is 83.37 (10) degrees . An intra molecular O-H?N hydrogen bond occurs. Inter-molecular N-H?O hydrogen bonds stabilize the crystal structure. There is a pi-pi inter-action between the naphthyl ring systems [centroid-centroid distance = 3.7556 (15) A]. In addition, naphth-yl-tolyl and naphth-yl-naphthyl C-H?pi inter-actions are observed. PMID- 21522457 TI - 2-(2-{2-[2-(Dibromo-meth-yl)phen-oxy]eth-oxy}benz-yloxy)benzaldehyde. AB - The mol-ecule of the title compound, C(23)H(20)Br(2)O(4), adopts a Z conformation as a result of inter-molecular C-H?Br bonding. One benzene ring, with the structure R-CHBr(2), makes a dihedral angle of 63.0 (2) degrees with the other benzene ring attached to the aldehyde group. Inter-molecular pi-pi stacking inter actions [centroid-centroid distance = 3.698 (4) A] and a weak C-H?Br contact is present in the crystal structure. PMID- 21522458 TI - 2-(2-Hy-droxy-3-meth-oxy-phen-yl)-6H-perimidin-6-one. AB - The mol-ecule of the title perimidine derivative, C(18)H(12)N(2)O(3), is essentially planar, the dihedral angle between the benzene and perimidine rings being 3.25 (5) degrees . The hy-droxy and meth-oxy groups lie in the plane of the benzene ring to which they are bound [O-C-C-C = 179.96 (11) degrees and C-O-C-C = -177.96 (12) degrees ]. An intra-molecular O-H?N inter-action generates an S(6) ring motif. In the crystal, mol-ecules are linked by pairs of C-H?O inter-actions into dimers, which generate S(16) ring motifs. These dimers are arranged into sheets parallel to the ac plane and further stacked down the b axis by pi-pi inter-actions, with centroid-centroid distances in the range 3.5066 (8)-3.7241 (7) A. PMID- 21522459 TI - n-Tridecyl-amine chloride monohydrate. AB - In the title compound, C(13)H(30)N(+).Cl(-).H(2)O, the C(13)H(27) alkyl chain is in an all-trans conformation. In the crystal, inter-molecular N-H?Cl, N-H?O and O H?Cl hydrogen bonds connect the components into layers parallel to (010), with the alkyl chains oriented approximately perpendicular to these layers. PMID- 21522460 TI - 2,2,5,7,8-Penta-methyl-chroman-6-yl 2,3,4,6-tetra-O-acetyl-alpha-d-glucopyran oside from synchrotron data. AB - The crystal structure of the title compound, C(28)H(38)O(11), solved and refined against synchrotron diffraction data, contains two formula units in the asymmetric unit. In both mol-ecules, the dihydro-pyran ring along with its methyl substituents is disordered and adopts two alternative half-chair conformations. The occupancy of the major conformers of the two mol-ecules refined to 0.858 (5) and 0.523 (5). PMID- 21522461 TI - N-(4,6-Dimethyl-pyrimidin-2-yl)-1H-benzimidazol-2-amine. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(13)H(13)N(5). In each mol-ecule, an amino N atom is connected to a benzimidazole fused-ring system and a pyrimidine ring [these are aligned at 1.3 (1) degrees in one independent mol-ecule and at 5.4 (1) degrees in the other]. The amino N atom of the fused ring forms an intra-molecular N-H?O hydrogen bond to a pyrimidine N atom in each mol-ecule. The amino N atom connecting the two ring systems inter-acts with the other N atom of the pyrimidine ring of an adjacent mol-ecule, generating centrosymmetric hydrogen-bonded dimers. PMID- 21522462 TI - 3-{[3-(4-Chloro-phen-yl)-4,5-dihydro-1,2-oxazol-5-yl]meth-yl}-1,5-dimethyl-1H-1,5 benzodiazepine-2,4(3H,5H)-dione. AB - The seven-membered ring of the title mol-ecule, C(21)H(20)ClN(3)O(3), adopts a boat-shaped conformation (with the C atoms of the fused-ring as the stern and the methine C atom as the prow). The substituent at the 3-position occupies an equatorial position; its five-membered ring is approximately planar (r.m.s. deviation = 0.081 A), and is aligned at 14.5 (1) degrees with respect to the chloro-phenyl ring to which it is connected. PMID- 21522463 TI - 4-(2,4,6-Trimethyl-benz-yl)-1,3-thia-zol-2-amine. AB - The methyl-ene C atom in the title compound, C(13)H(16)N(2)S, is connected to a five-membered thia-zole ring and a mesityl substituent. The rings are aligned at 75.4 (1) degrees . The amino substitutent inter-acts with the ring N atom of an adjacent mol-ecule by an inter-molecular N-H?N hydrogen bond, generating a helical chain running along the b axis. PMID- 21522464 TI - Dimethyl 2,2'-({2,2'-methyl-enebis[6-(2H-benzotriazol-2-yl)-4-(2,4,4-trimethyl pentan-2-yl)-2,1-phenyl-ene]}di-oxy)diacetate. AB - The asymmetric unit of the title compound, C(47)H(58)N(6)O(6), comprises three independent mol-ecules, in one of which one tert-butyl group is disordered in a 1:1 ratio. The mol-ecule is a di(ar-yl)methane having two aliphatic and one N heterocyclic substituent in each aryl ring. For the mol-ecule having the disordered tert-butyl group, the aryl rings make an angle of 115.3 (2) degrees at the methyl-ene carbon; one aryl ring is aligned at 42.0 (1) degrees with respect to the N-heterocyclic substituent and the other at 48.7 (1) degrees with respect to its substituent. The two ordered mol-ecules are disposed about a pseudo center of inversion. The pairs of twist angles in these two mol-ecules differ [52.7 (1) and 61.7 (1) degrees , and 29.1 (1) and 58.5 (1) degrees ]. PMID- 21522465 TI - 1-Dimethyl-amino-9,10-anthraquinone. AB - In the crystal structure of the title compound, C(16)H(13)NO(2), adjacent mol ecules are linked through C-H?pi and pi-pi [centroid-centroid distances = 3.844 (2) A] contacts. The anthracene ring system and dimethyl-amino group are oriented at a dihedral angle of 38.4 (1) degrees . In the crystal, the mean planes of adjacent anthracene units are inclined at angles of 59.3 (1), 75.7 (1) and 76.0 (1) degrees . PMID- 21522466 TI - Methyl 2-(3-oxo-3,4-dihydro-2H-1,4-benzothia-zin-4-yl)acetate. AB - In the crystal structure of the title compound, C(11)H(11)NO(3)S, the mol-ecules are linked by inter-molecular C-H?O hydrogen-bond inter-actions. The heterocyclic thia-zine ring adopts a conformation inter-mediate between twist and boat. PMID- 21522467 TI - 1-(1H-Imidazo[4,5-f][1,10]phenan-throlin-2-yl)naphthalen-2-ol. AB - In the title mol-ecule, C(23)H(14)N(4)O, the dihedral angle between the pyridine rings of the phenanthroline unit is 4.43 (8) degrees and the dihedral angle formed by the nine essentially planar [maximum deviation 0.0389 (16)A] non-H atoms of the benzimidazole unit and the naphthalene ring system is 74.22 (5) degrees . In the crystal, mol-ecules are linked by inter-molecular N-H?N and O H?N hydrogen bonds, forming a three-dimensional network. PMID- 21522468 TI - (E)-1-Methyl-5-(3-methyl-4-chloro-phen-oxy)-3-trifluoro-meth-yl-1H-pyrazole-4 carbaldehyde O-acetyl-oxime. AB - In the title mol-ecule, C(15)H(13)ClF(3)N(3)O(3), the pyrazole and benzene rings form a dihedral angle of 77.6 (3) degrees . In the crystal, mol-ecules related by translation along the a axis are linked into chains via C-H?O hydrogen bonds. The crystal packing is stabilized further by weak pi-pi [centroid-centroid distance = 3.734 (6) A] and dipole-dipole inter-actions [C?O = 3.174 (2) A]. PMID- 21522469 TI - (E)-3-Methyl-5-(4-methyl-phen-oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde O-[(2 chloro-1,3-thia-zol-5-yl)meth-yl]oxime. AB - In the title compound, C(22)H(19)ClN(4)O(2)S, the planes of the benzene ring, the substituted phenyl ring and the thia-zole ring make dihedral angles of 18.4 (3), 88.9 (2) and 63.0 (3) degrees , respectively, with the pyrazole ring. PMID- 21522470 TI - 5,11,17,23-Tetra-kis(chloro-meth-yl)-25,26,27,28-tetra-propoxycalix[4]arene. AB - The title calix[4]arene, C(44)H(52)Cl(4)O(4), displays the 1,3-alternate conformation with crystallographically imposed twofold symmetry. Four phenolic rings of the calixarene backbone are tilted into the calix cavity, making dihedral angles of 77.42 (2) and 77.71 (2) degrees with the plane of the four bridging methyl-ene C atoms. Pairs of opposite aromatic rings make dihedral angles of 25.16 (3) and 24.58 (4) degrees with each other. In the crystal, the calixarene mol-ecules pack with the formation of infinite columns along the b axis. The crystal packing shows a network of C-H?Cl contacts, which can be considered as non-classical hydrogen bonds. PMID- 21522471 TI - 9a-Hy-droxy-3,8a-dimethyl-5-methyl-ene-4,4a,5,6,9,9a-hexa-hydro-naphtho-[2,3 b]furan-2(8aH)-one. AB - The title compound, C(15)H(18)O(3), was isolated from Lacta-rius piperatus (Fr.) S. F. Gary collected from the Kunming area in Yunnan province, China. The central cyclo-hexyl ring adopts a chair conformation, while the furan-one ring is close to planar (r.m.s. deviation = 0.0174 A). The remaining methyl-ene cyclo-hexene ring has a flattened chair conformation. In the crystal, mol-ecules are linked via inter-molecular O-H?O and C-H?O hydrogen bonds into zigzag chains along the a axis. PMID- 21522472 TI - (E)-1-(2,4-Dihy-droxy-phen-yl)-3-(4-hydroxy-phen-yl)prop-2-en-1-one monohydrate. AB - In the title compound, C(15)H(12)O(4).H(2)O, the two benzene rings are not coplanar, making a dihedral angle of 7.24 (16) degrees . An intra-molecular hy droxy-carbonyl O-H?O hydrogen bond occurs. In the crystal, four inter-molecular O H?O hydrogen bonds involving the hy-droxy residues, the carbonyl group and the water mol-ecule lead to the formation of a three-dimensional network. The supra molecular structure is further stabilized by weak C-H?O inter-actions. PMID- 21522473 TI - [(2R,5R,6S,9R)-6-Isopropyl-9-methyl-1,4-dioxaspiro-[4.5]decan-2-yl]methyl 4-bromo benzoate. AB - The title compound, C(20)H(27)BrO(4), a 4-bromo-benzoyl derivative of a stereoisomer of glycerol menthonide, synthesized as part of a study of 3-carbon stereochemical moieties, crystallizes with two crystallographically independent mol-ecules in the asymmetric unit, the two mol-ecules differing only in one of the C-O-C-C torsion angles around the ester O atom [-106.5 (7) and 146.1 (6) degrees ]. The two mol-ecules are crystallographically related by a pseudotranslation along the (011) diagonal of the unit cell, emulating a primitive monoclinic cell of half the volume. The translational symmetry is broken by the 4-bromo-benzoate groups. The crystallographic assignment of the absolute stereochemistry is consistent with having started with (-)-menthone, the acetal C atom is R and the secondary alcohol is R. This brings the bromo-benzoate into approximately the same plane as the menthyl ring and cis to the isopropyl group. The glycerol menthonide sections of the molecules interact with each other via C-H?O interactions, leading to the formation of chains either A or B molecules that stretch parallel to [010], forming column-shaped double chains. Interactions between neighboring columns are limited to van der Waals contacts. PMID- 21522474 TI - (2Z,3E)-2-{[1-(4-Chloro-benz-yl)-1H-indol-3-yl]methyl-idene}quinuclidin-3-one oxime. AB - In the title compound, C(23)H(22)ClN(3)O, the benzene ring of the 4-chorobenzyl group makes a dihedral angle of 78.56 (6) degrees with the best plane of the indole ring. The double bond connecting the aza-bicyclic and indole groups adopts a Z geometry. The geometry adopted by the C=N bond with respect to the N-OH bond is trans. The absolute configuration of the compound was determined from refinement of the Flack parameter. PMID- 21522475 TI - (S)-1-(2-Chloro-phen-yl)-2-oxocyclo-hexan-1-aminium d-tartrate. AB - In the title compound, C(12)H(15)ClNO(+).C(4)H(5)O(6) (-), the cyclo-hexa-none ring adopts a chair conformation. The benzene ring is significantly twisted so that it is in an almost perpendicular position to the C-N bond with a C(Ar)-C(Ar) C-N torsion angle of -96.5 (5) degrees . Intermolecular N-H?O and O-H?O hydrogen bonds are observed in the crystal structure. PMID- 21522476 TI - cis-2,5-Bis(2-fluoro-5-meth-oxy-pheneth-yl)pyrrolidinium formate. AB - In the title compound, C(22)H(28)F(2)NO(2) (+).CHO(2) (-), there are three independent pyrrolidinium formate salt mol-ecules. In each cation, the central pyrrolidinium ring is not planar and the 2,5-disubstituted phenyl-ethyl groups are in equatorial positions. In the crystal, the ions are linked into a pair of chains parallel to the c axis by N-H?O hydrogen bonds between the NH group of the pyrrolidinium ring and the formate O atoms. PMID- 21522477 TI - Bis[3-(2H-benzotriazol-2-yl)-2-(prop-2-yn-yloxy)-5-(2,4,4-trimethyl-pentan-2 yl)phen-yl]methane. AB - In the title compound, C(47)H(54)N(6)O(2), the C-C-C bond angle between the rings is 108.40 (13) degrees . One aryl ring aligned at 38.5 (1) degrees with respect to the N-heterocyclic substituent and the other at 56.0 (1) degrees with respect to its substituent. In the crystal, adjacent mol-ecules are linked by C-H?N hydrogen bonds, forming a chain extending along the a axis. PMID- 21522478 TI - 1-(Piperidin-1-yl)-3-(2,4,6-trimethyl-phen-yl)propan-2-ol. AB - The title compound, C(17)H(27)NO, features a bufferfly-shaped substituted 2 propanol having an aromatic ring on the 1-carbon and a piperidine ring on the 3 carbon. The piperidine ring adopts a chair conformation and its N atom shows a trigonal coordination. In the crystal, the hy-droxy group inter-acts with the N atom of an inversion-related mol-ecule, generating an O-H?N hydrogen-bonded dimer. PMID- 21522479 TI - 1,4-Bis{[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]sulfan-yl}butane. AB - In the centrosymmetric title compound, C(18)H(16)N(6)O(2)S(2), the 1,3,4 oxadiazole and the attached pyridinyl ring are twisted by 5.3 (3) degrees . PMID- 21522480 TI - (1-Phenyl-sulfonyl-1H-indol-2-yl)(thio-phen-2-yl)methanone. AB - The crystal studied of the title compound, C(19)H(13)NO(3)S(2), was found to be a non-merohedral twin with a domain ratio of 0.877 (3):0.123 (3). There are two independent mol-ecules in the asymmetric unit. The dihedral angles between the mean plane of the indole ring system and the phenyl-sulfonyl ring are 71.67 (13) and 71.95 (13) degrees in the two mol-ecules while the indole unit and the thiophene ring make dihedral angles of 54.91 (12) and 56.92 (13) degrees in the two molecules. The crystal packing is stabilized by weak C-H?pi inter-actions. PMID- 21522481 TI - Methyl 2-(1H-indole-3-carboxamido)-acetate. AB - The title compound, C(12)H(12)N(2)O(3), was synthesized by condensation of methyl amino-acetate with 3-trichloro-acetyl-indole. In the crystal, inter-molecular N H?O hydrogen bonds link the mol-ecules into chains parallel to the b axis. The chains are further connected into a three-dimensional network by N-H?O hydrogen bonds involving the indole N atom. In the molecule, the indole skeleton is nearly planar [maximum deviation = 0.012 (1) A] and the mean plane of the amido group is twisted from the mean plane of indole ring by 17.2 (1) degrees . PMID- 21522482 TI - 2-(9,9-Diethyl-9H-fluoren-2-yl)-1-benzofuran. AB - In the title compound, C(25)H(22)O, the dihedral angle between the benzofuran and fluorene ring systems is 9.06 (6) degrees , and that between the two benzene rings of the fluorene system is 1.78 (12) degrees . Weak inter-molecular C-H?pi inter-actions help to stabilize the crystal structure. PMID- 21522483 TI - 10-(2-Hy-droxy-eth-yl)-9-(2-hy-droxy-phen-yl)-3,3,6,6-tetra-methyl 1,2,3,4,5,6,7,8,9,10-deca-hydro-acridine-1,8-dione. AB - The dihydro-pyridine ring in the title compound, C(25)H(31)NO(4), adopts an envelope conformation with the methine C atom representing the flap. The cyclo hexenone rings also adopt envelope conformations with the C atoms bearing the methyl C atoms representing the flaps. The phenolic hy-droxy group forms an intra molecular hydrogen bond to one of the two keto O atoms. The hy-droxy group of the N-bonded alkyl chain forms an inter-molecular hydrogen bond to the other keto O atom of an adjacent mol-ecule. The latter hydrogen bond leads to the formation of a helical chain running along the b axis. PMID- 21522484 TI - The wisdom of the body; a contemporary view. PMID- 21522485 TI - Over-, under- and misuse of pain treatment in Germany. AB - BACKGROUND: The HTA-report (Health Technology Assessment) deals with over- and undertreatment of pain therapy. Especially in Germany chronic pain is a common reason for the loss of working hours and early retirement. In addition to a reduction in quality of life for the affected persons, chronic pain is therefore also an enormous economic burden for society. OBJECTIVES: Which diseases are in particular relevant regarding pain therapy?What is the social-medical care situation regarding pain facilities in Germany?What is the social-medical care situation in pain therapy when comparing on international level?Which effects, costs or cost-effects can be seen on the micro-, meso- and macro level with regard to pain therapy?Among which social-medical services in pain therapy is there is an over- or undertreatment with regard to the micro-, meso- and macro level?Which medical and organisational aspects that have an effect on the costs and/or cost-effectiveness have to be particularly taken into account with regard to pain treatment/chronic pain?What is the influence of the individual patient's needs (micro level) in different situations of pain (e. g. palliative situation) on the meso- and macro level?Which social-medical and ethical aspects for an adequate treatment of chronic pain on each level have to be specially taken into account?Is the consideration of these aspects appropriate to avoid over- or undertreatment?Are juridical questions included in every day care of chronic pain patients, mainly in palliative care?On which level can appropriate interventions prevent over- or undertreatment? METHODS: A systematic literature research is done in 35 databases. In the HTA, reviews, epidemiological and clinical studies and economic evaluations are included which report about pain therapy and in particular palliative care in the years 2005 till 2010. RESULTS: 47 studies meet the inclusion criteria. An undertreatment of acupuncture, over- and misuse with regard to opiate prescription and an overuse regarding unspecific chest pain and chronic low back pain (LBP) can be observed. The results show the benefit and the cost-effectiveness of interdisciplinary as well as multi-professional approaches, multimodal pain therapy and cross-sectoral integrated medical care. Only rough values can be determined about the care situation regarding the supply of pain therapeutic and palliative medical facilities as the data are completely insufficient. DISCUSSION: Due to the broad research question the HTA-report contains inevitably different outcomes and study designs which partially differ qualitatively very strong from each other. In the field of palliative care hospices for in-patients and palliative wards as well as hospices for out patients are becoming more and more important. Palliative care is a basic right of all terminally ill persons. CONCLUSION: Despite the relatively high number of studies in Germany the HTA-report shows a massive lack in health care research. Based on the studies a further expansion of out-patient pain and palliative care is recommended. Further training for all involved professional groups must be improved. An independent empirical analysis is necessary to determine over or undertreatment in pain care. PMID- 21522486 TI - Neural correlates of the perception of dynamic versus static facial expressions of emotion. AB - AIM: This study investigated brain areas involved in the perception of dynamic facial expressions of emotion. METHODS: A group of 30 healthy subjects was measured with fMRI when passively viewing prototypical facial expressions of fear, disgust, sadness and happiness. Using morphing techniques, all faces were displayed as still images and also dynamically as a film clip with the expressions evolving from neutral to emotional. RESULTS: Irrespective of a specific emotion, dynamic stimuli selectively activated bilateral superior temporal sulcus, visual area V5, fusiform gyrus, thalamus and other frontal and parietal areas. Interaction effects of emotion and mode of presentation (static/dynamic) were only found for the expression of happiness, where static faces evoked greater activity in the medial prefrontal cortex. CONCLUSIONS: Our results confirm previous findings on neural correlates of the perception of dynamic facial expressions and are in line with studies showing the importance of the superior temporal sulcus and V5 in the perception of biological motion. Differential activation in the fusiform gyrus for dynamic stimuli stands in contrast to classical models of face perception but is coherent with new findings arguing for a more general role of the fusiform gyrus in the processing of socially relevant stimuli. PMID- 21522487 TI - Instrumented posterolateral fusion - clinical and functional outcome in elderly patients. AB - BACKGROUND: Data on the clinical outcome after spinal fusion in the elderly patient are rare. Limitation of most studies were small population, evaluation of the perioperative complication rate and the radiographic assessment. Therefore the aim of the current study was to evaluate the clinical outcome of patients older than 75 years who underwent a spinal fusion procedure (instrumentation and posterolateral fusion) for degenerative spinal stenosis with instability. METHODS: Elderly patients who underwent instrumented, posterolateral fusion were evaluated with regard to functional outcome, fusion rates and complications after a mean follow-up of 3.8 years. Questionnaires were completed by the patients before surgery and at final follow-up. Changes in mean visual analogue scale (VAS) and Owestry Disability Index (ODI) scores (decrease from the baseline VAS and ODI scores) were evaluated. RESULTS: The mean final follow-up for all subjects was 3.8 years. Of the 58 patients, 1 patient was deceased at the time of the follow-up, 1 patient did not want to participate and 56 patients completed the questionnaires. This resulted in an overall follow-up rate of 96%.At final follow-up, the patients demonstrated significant improvement in the VAS and ODI scores compared with the preoperative scores. CONCLUSIONS: The results of this study shows that elderly patients aged over 75 benefit from instrumented, posterolateral fusion. The study suggests that there is no need to force an intervertebral fusion because elderly patients do not seem to benefit from this procedure. PMID- 21522488 TI - De novo spine surgery as a predictor of additional spine surgery at the same or distant spine regions. AB - INTRODUCTION: Degenerative spine disorders are steadily increasing parallel to the aging of the population with considerable impact on cost and productivity. In this paper we study the prevalence and risk factors for multiple spine surgery and its impact on cost. METHODS: Data on 1,153 spine surgery inpatients operated between October 2005 and September 2008 (index spine surgery) in regard to the number of previous spine surgeries and location of surgeries (cervical or lumbar) were retrospectively collected. Additionally, prospective follow-up over a period of 2-5 years was conducted. RESULTS: Retrospectively, 365 (31.7%) patients were recurrent spine surgery patients while 788 (68.3%) were de novo spine surgery patients.Nearly half of those with previous spine surgery (51.5%) were on different regions of the spine. There were no significant differences in length of stay or hospital charges except in lumbar decompression and fusion (LDF) patients with multiple interventions on the same region of the spine. Significant differences (P<.05) in length of stay (5.4 days vs. 7.4 days) and hospital charges ($55,477 vs. $74,878) between LDF patients with one previous spine versus those with >=3 previous spine surgeries on the same region were noted.Prospectively, the overall reoperation rate was 10.4%. The risk of additional spine surgery increased from 8.0% in patients with one previous spine surgery (index surgery) to 25.6% in patients with >=4 previous spine surgeries on different regions of the spine (including index surgery).After excluding patients with previous spine surgeries on different regions of the spine, 17.2% of reoperated patients had additional spine surgery on a different spine region. The percentage of additional spine surgery on a distant spine region increased from 14.0% in patients with one spine surgery to 33.0% in patients with two spine surgeries on the same region. However, in patients with three or more spine surgeries on the same spine region there were no interventions on a distant spine region during the follow-up period. CONCLUSION: De novo spine surgery is associated with an increased incidence of additional spine surgery at the same or distant spine regions. Large prospective studies with extended follow-up periods and multifaceted cost-outcome analysis are needed to refine the appropriateness of spine surgery. PMID- 21522489 TI - A microfluidic platform for on-demand formation and merging of microdroplets using electric control. AB - We discuss a microfluidic system in which (programmable) local electric fields originating from embedded and protected electrodes are used to control the formation and merging of droplets in a microchannel. The creation of droplets-on demand (DOD) is implemented using the principle of electrowetting. Combined with hydrodynamic control, the droplet size and formation frequency can be varied independently. Using two synchronized DOD injectors, merging-on-demand (MOD) is achieved via electrocoalescence. The efficiency of MOD is 98% based on hundreds of observations. These two functionalities can be activated independently. PMID- 21522490 TI - Preface to Special Topic: Biological microfluidics in tissue engineering and regenerative medicine. AB - In this special issue of Biomicrofluidics, many manifestations of biological microfluidics have been highlighted that have significance to regenerative biology and medicine. The collated articles demonstrate the applicability of these biological microfluidics for studying a wide range of biomedical problems most useful for understanding and shining light on basic biology to those applications relevant to clinical medicine. PMID- 21522492 TI - Cell-enclosing gelatin-based microcapsule production for tissue engineering using a microfluidic flow-focusing system. AB - Gelatin-based microcapsule production using a microfluidic system and the feasibility of the resultant microcapsules for constructing spherical tissues surrounded by heterogeneous cells were studied. The first cell-encapsulation and subsequent cell-enclosing microparticle encapsulation were achieved using a microfluidic flow-focusing droplet production system. A hollow-core structure of about 150 MUm in diameter was developed by incubating the resultant microparticles at 37 degrees C, which induced thermal melting of the enclosed unmodified gelatin microparticles. Mammalian cells filled the hollow-cores after 4 days of incubation. A cell layer on the cell-enclosing microcapsules was developed by simply suspending the microcapsules in medium containing adherent fibroblast cells. This method may prove useful for the generation of gelatin microcapsules using a microfluidic system for formation of artificial tissue constructs. PMID- 21522491 TI - Stem cells in microfluidics. AB - Microfluidic techniques have been recently developed for cell-based assays. In microfluidic systems, the objective is for these microenvironments to mimic in vivo surroundings. With advantageous characteristics such as optical transparency and the capability for automating protocols, different types of cells can be cultured, screened, and monitored in real time to systematically investigate their morphology and functions under well-controlled microenvironments in response to various stimuli. Recently, the study of stem cells using microfluidic platforms has attracted considerable interest. Even though stem cells have been studied extensively using bench-top systems, an understanding of their behavior in in vivo-like microenvironments which stimulate cell proliferation and differentiation is still lacking. In this paper, recent cell studies using microfluidic systems are first introduced. The various miniature systems for cell culture, sorting and isolation, and stimulation are then systematically reviewed. The main focus of this review is on papers published in recent years studying stem cells by using microfluidic technology. This review aims to provide experts in microfluidics an overview of various microfluidic systems for stem cell research. PMID- 21522493 TI - Electrospinning jets and nanofibrous structures. AB - Electrospinning is a process that creates nanofibers through an electrically charged jet of polymer solution or melt. This technique is applicable to virtually every soluble or fusible polymer and is capable of spinning fibers in a variety of shapes and sizes with a wide range of properties to be used in a broad range of biomedical and industrial applications. Electrospinning requires a very simple and economical setup but is an intricate process that depends on several molecular, processing, and technical parameters. This article reviews information on the three stages of the electrospinning process (i.e., jet initiation, elongation, and solidification). Some of the unique properties of the electrospun structures have also been highlighted. This article also illustrates some recent innovations to modify the electrospinning process. The use of electrospun scaffolds in the field of tissue engineering and regenerative medicine has also been described. PMID- 21522494 TI - Aqueous biphasic microprinting approach to tissue engineering. AB - We summarize a recently developed microtechnology for printing biomaterials on biological surfaces. The technique is based on the use of immiscible aqueous solutions of two biopolymers and allows spatially defined placement of cells and biomolecules suspended in the denser aqueous phase on existing cell layers and extracellular matrix hydrogel surfaces maintained in the second phase. Printing takes place due to an extremely small interfacial tension and density difference between the two aqueous phases. The contact-free printing process ensures that both printed cells and the underlying cell monolayer maintain full viability and functionality. The technique accommodates both arbitrarily shaped patterns and microarrays of cells and bioreagents. The capability to print cells and small molecules on existing cell layers enables unique interrogations of the effects of cell-cell and cell-material interaction on cell fate and function. Furthermore, the very gentle conditions and the ability to directly pattern nongel embedded cells over cells make this technology appealing to tissue engineering applications where patterned multicellar organization with minimal scaffolding materials is needed, such as in dense tissues of the skeletal muscle and liver. PMID- 21522495 TI - Microfluidic formulation of pectin microbeads for encapsulation and controlled release of nanoparticles. AB - We report a method for formulation of pectin microbeads using microfluidics. The technique uses biocompatible ingredients and allows for controlled external gelation with hydrogen and calcium ions delivered from an organic phase of rapeseed oil. This method allows for encapsulation of nanoparticles into the microparticles of gel and for control of the rate of their release. PMID- 21522497 TI - Transport of particles and microorganisms in microfluidic channels using rectified ac electro-osmotic flow. AB - A new method is demonstrated to transport particles, cells, and other microorganisms using rectified ac electro-osmotic flows in open microchannels. The rectified flow is obtained by synchronous zeta potential modulation with the driving potential in the microchannel. Experiments were conducted to transport both neutral, charged particles, and microorganisms of various sizes. A maximum speed of 50 MUm/s was obtained for 8 MUm polystyrene beads, without any electrolysis, using a symmetrical square waveform driving electric field of 5 V/mm at 10 Hz and a 360 V gate potential with its polarity synchronized with the driving potential (phase lag=0 degrees ). PMID- 21522496 TI - Microfluidic devices for studying heterotypic cell-cell interactions and tissue specimen cultures under controlled microenvironments. AB - Microfluidic devices allow for precise control of the cellular and noncellular microenvironment at physiologically relevant length- and time-scales. These devices have been shown to mimic the complex in vivo microenvironment better than conventional in vitro assays, and allow real-time monitoring of homotypic or heterotypic cellular interactions. Microfluidic culture platforms enable new assay designs for culturing multiple different cell populations and/or tissue specimens under controlled user-defined conditions. Applications include fundamental studies of cell population behaviors, high-throughput drug screening, and tissue engineering. In this review, we summarize recent developments in this field along with studies of heterotypic cell-cell interactions and tissue specimen culture in microfluidic devices from our own laboratory. PMID- 21522499 TI - A microfluidic membrane device to mimic critical components of the vascular microenvironment. AB - Vascular function, homeostasis, and pathological development are regulated by the endothelial cells that line blood vessels. Endothelial function is influenced by the integrated effects of multiple factors, including hemodynamic conditions, soluble and insoluble biochemical signals, and interactions with other cell types. Here, we present a membrane microfluidic device that recapitulates key components of the vascular microenvironment, including hemodynamic shear stress, circulating cytokines, extracellular matrix proteins, and multiple interacting cells. The utility of the device was demonstrated by measuring monocyte adhesion to and transmigration through a porcine aortic endothelial cell monolayer. Endothelial cells grown in the membrane microchannels and subjected to 20 dynes/cm(2) shear stress remained viable, attached, and confluent for several days. Consistent with the data from macroscale systems, 25 ng/ml tumor necrosis factor (TNF)-alpha significantly increased RAW264.7 monocyte adhesion. Preconditioning endothelial cells for 24 h under static or 20 dynes/cm(2) shear stress conditions did not influence TNF-alpha-induced monocyte attachment. In contrast, simultaneous application of TNF-alpha and 20 dynes/cm(2) shear stress caused increased monocyte adhesion compared with endothelial cells treated with TNF-alpha under static conditions. THP-1 monocytic cells migrated across an activated endothelium, with increased diapedesis in response to monocyte chemoattractant protein (MCP)-1 in the lower channel of the device. This microfluidic platform can be used to study complex cell-matrix and cell-cell interactions in environments that mimic those in native and tissue engineered blood vessels, and offers the potential for parallelization and increased throughput over conventional macroscale systems. PMID- 21522498 TI - Biochip/laser cell deposition system to assess polarized axonal growth from single neurons and neuron/glia pairs in microchannels with novel asymmetrical geometries. AB - Axon path-finding plays an important role in normal and pathogenic brain development as well as in neurological regenerative medicine. In both scenarios, axonal growth is influenced by the microenvironment including the soluble molecules and contact-mediated signaling from guiding cells and cellular matrix. Microfluidic devices are a powerful tool for creating a microenvironment at the single cell level. In this paper, an asymmetrical-channel-based biochip, which can be later incorporated into microfluidic devices for neuronal network study, was developed to investigate geometric as well as supporting cell control of polarized axonal growth in forming a defined neuronal circuitry. A laser cell deposition system was used to place single cells, including neuron-glia pairs, into specific microwells of the device, enabling axonal growth without the influence of cytophilic/phobic surface patterns. Phase microscopy showed that a novel "snag" channel structure influenced axonal growth in the intended direction 4:1 over the opposite direction. In heterotypic experiments, glial cell influence over the axonal growth path was observed with time-lapse microscopy. Thus, it is shown that single cell and heterotypic neuronal path-finding models can be developed in laser patterned biochips. PMID- 21522500 TI - Microfluidic enrichment of small proteins from complex biological mixture on nanoporous silica chip. AB - The growing field of miniaturized diagnostics is hindered by a lack of pre analysis treatments that are capable of processing small sample volumes for the detection of low concentration analytes in a high-throughput manner. This letter presents a novel, highly efficient method for the extraction of low-molecular weight (LMW) proteins from biological fluids, represented by a mixture of standard proteins, using integrated microfluidic systems. We bound a polydimethylsiloxane layer patterned with a microfluidic channel onto a well defined nanoporous silica substrate. Using rapid, pressure-driven fractionation steps, this system utilizes the size-exclusion properties of the silica nanopores to remove high molecular weight proteins while simultaneously isolating and enriching LMW proteins present in the biological sample. The introduction of the microfluidic component offers important advantages such as high reproducibility, a simple user interface, controlled environment, the ability to process small sample volumes, and precise quantification. This solution streamlines high throughput proteomics research on many fronts and may find broad acceptance and application in clinical diagnostics and point of care detection. PMID- 21522501 TI - Biomimetic micro/nanostructured functional surfaces for microfluidic and tissue engineering applications. AB - This paper reviews our work on the application of ultrafast pulsed laser micro/nanoprocessing for the three-dimensional (3D) biomimetic modification of materials surfaces. It is shown that the artificial surfaces obtained by femtosecond-laser processing of Si in reactive gas atmosphere exhibit roughness at both micro- and nanoscales that mimics the hierarchical morphology of natural surfaces. Along with the spatial control of the topology, defining surface chemistry provides materials exhibiting notable wetting characteristics which are potentially useful for open microfluidic applications. Depending on the functional coating deposited on the laser patterned 3D structures, we can achieve artificial surfaces that are (a) of extremely low surface energy, thus water repellent and self-cleaned, and (b) responsive, i.e., showing the ability to change their surface energy in response to different external stimuli such as light, electric field, and pH. Moreover, the behavior of different kinds of cells cultured on laser engineered substrates of various wettabilities was investigated. Experiments showed that it is possible to preferentially tune cell adhesion and growth through choosing proper combinations of surface topography and chemistry. It is concluded that the laser textured 3D micro/nano-Si surfaces with controllability of roughness ratio and surface chemistry can advantageously serve as a novel means to elucidate the 3D cell-scaffold interactions for tissue engineering applications. PMID- 21522503 TI - Supernatant decanting on a centrifugal platform. AB - This study presents a novel approach to decant supernatant on a centrifugal platform. By manipulating the centrifugally induced pressure and the elastic deformation of the plastic lids in the decanting chamber, fixed amounts of the supernatant can be decanted into the detection chamber at lower rotational speeds. The experimental results showed that decanted volume is affected by the volume of deformation and the operating parameters. Factors that influence the decanting ratio are also discussed. This approach has the advantages of simple design and low manufacturing cost; further, it has no need of surface modification. It has been applied to on-disk separation of plasma from whole blood, and the results showed good stability and repeatability. PMID- 21522502 TI - Microfluidics-based devices: New tools for studying cancer and cancer stem cell migration. AB - Cell movement is highly sensitive to stimuli from the extracellular matrix and media. Receptors on the plasma membrane in cells can activate signal transduction pathways that change the mechanical behavior of a cell by reorganizing motion related organelles. Cancer cells change their migration mechanisms in response to different environments more robustly than noncancer cells. Therefore, therapeutic approaches to immobilize cancer cells via inhibition of the related signal transduction pathways rely on a better understanding of cell migration mechanisms. In recent years, engineers have been working with biologists to apply microfluidics technology to study cell migration. As opposed to conventional cultures on dishes, microfluidics deals with the manipulation of fluids that are geometrically constrained to a submillimeter scale. Such small scales offer a number of advantages including cost effectiveness, low consumption of reagents, high sensitivity, high spatiotemporal resolution, and laminar flow. Therefore, microfluidics has a potential as a new platform to study cell migration. In this review, we summarized recent progress on the application of microfluidics in cancer and other cell migration researches. These studies have enhanced our understanding of cell migration and cancer invasion as well as their responses to subtle variations in their microenvironment. We hope that this review will serve as an interdisciplinary guidance for both biologists and engineers as they further develop the microfluidic toolbox toward applications in cancer research. PMID- 21522504 TI - Integrated carbon fiber electrodes within hollow polymer microneedles for transdermal electrochemical sensing. AB - In this study, carbon fiber electrodes were incorporated within a hollow microneedle array, which was fabricated using a digital micromirror device-based stereolithography instrument. Cell proliferation on the acrylate-based polymer used in microneedle fabrication was examined with human dermal fibroblasts and neonatal human epidermal keratinocytes. Studies involving full-thickness cadaveric porcine skin and trypan blue dye demonstrated that the hollow microneedles remained intact after puncturing the outermost layer of cadaveric porcine skin. The carbon fibers underwent chemical modification in order to enable detection of hydrogen peroxide and ascorbic acid; electrochemical measurements were demonstrated using integrated electrode-hollow microneedle devices. PMID- 21522509 TI - K(0.53)Mn(2.37)Fe(1.24)(PO(4))(3). AB - During an attempt to crystallize potassium manganese diiron phosphate KMnFe(2)(PO(4))(3) by the flux method, a new phase, potassium dimanganese iron triphosphate, K(0.53)Mn(2.37)Fe(1.24)(PO(4))(3), was isolated. This phase, whose composition was confirmed by ICP analysis, is isotypic with the alluaudite-like phosphates, thus it exhibits the (A2)(A'2)(A1)(A'1)(A''1)(M1)(M2)(2)(PO(4))(3) general formula. The site occupancies led to the following cation distribution: 0.53 K on A'2 (site symmetry 2), 0.31 Mn on A''1, 1.0 Mn on M1 (site symmetry 2) and (0.62 Fe + 0.38 Mn) on M2. The structure is built up from infinite chains of edge-sharing M1O(6) and M2O(6) octa-hedra. These chains run along [10] and are connected by two different PO(4) tetrahedra, one of which exhibits 2 symmetry. The resulting three-dimensional framework delimits large tunnels parallel to [001], which are partially occupied by the K(+) and Mn(2+) cations. PMID- 21522510 TI - Silver indium diphosphate, AgInP(2)O(7). AB - Polycrystalline material of the title compound, AgInP(2)O(7), was synthesized by traditional high-temperature solid-state methods and single crystals were grown from the melt of a mixture of AgInP(2)O(7) and B(2)O(3) as flux in a platinium crucible. The structure consists of InO(6) octa-hedra, which are corner-shared to PO(4) tetra-hedra into a three-dimensional network with hexa-gonal channels running parallel to the c axis. The silver cation, located in the channel, is bonded to seven O atoms of the [InP(2)O(7)] framework with Ag-O distances ranging from 2.370 (2) to 3.015 (2) A. The P(2)O(7) diphosphate anion is characterized by a P-O-P angle of 137.27 (9) and a nearly eclipsed conformation. AgInP(2)O(7) is isotypic with the M(I)FeP(2)O(7) (M(I) = Na, K, Rb, Cs and Ag) diphosphate family. PMID- 21522511 TI - The beta-modification of trizinc borate phosphate, Zn(3)(BO(3))(PO(4)). AB - Crystals of beta-Zn(3)(BO(3))(PO(4)) have been grown by the Kyropoulos method. The asymmetric unit contains three Zn sites, three B-atom sites (all with symmetry 3), two P sites (both with m symmetry) and nine O-atom sites (four with m symmetry). The fundamental building units of the title structure are isolated BO(3) triangles and PO(4) tetra-hedra, which are bridged by ZnO(4) tetra-hedra or ZnO(5) trigonal bipyramids through common O atoms, leading to a three-dimensional framework structure. Some significant structural differences between the beta polymorph and the alpha-polymorph are discussed. PMID- 21522512 TI - Cs(0.49)NbPS(6). AB - The quaternary thio-phosphate, Cs(0.49)NbPS(6), caesium hexa-thio niobiophosphate(V), has been synthesized by the reactive halide flux method. The title compound is isotypic with Rb(0.46)TaPS(6) and is made up of a bicapped trigonal-biprismatic [Nb(2)S(12)] unit and a tetra-hedral [PS(4)] group. The [Nb(2)S(12)] units linked by the [PS(4)] tetra-hedra form infinite chains, yielding a three-dimensional network with rather large van der Waals gaps along the c axis in which the disordered Cs(+) ions reside. The electrons released by the Cs atoms are transferred to the pairwise niobium metal site and there are substantial inter-metallic Nb-Nb bonding inter-actions. This leads to a significant decrease of the inter-metallic distance in the title compound compared to that in TaPS(6). The classical charge balance of the title compound may be represented as [Cs(+)](0.49)[Nb(4.51+)][P(5+)][S(2-)](4)[S(2) (2-)]. PMID- 21522513 TI - Silver trimagnesium phosphate bis-(hydrogenphosphate), AgMg(3)(PO(4))(HPO(4))(2), with an alluaudite-like structure. AB - The title compound, AgMg(3)(PO(4))(HPO(4))(2), which has been synthesized by the hydro-thermal method, has an alluaudite-like structure which is formed by edge sharing MgO(6) octa-hedra (one of which has symmetry 2), resulting in chains linked together by phosphate groups and hydrogen bonds. The three-dimensional framework leads to two different channels along the c axis, one of which is occupied by Ag(+) ions with a square-planar coordination. The Ag(+) ions are disordered over two sites in a 0.89 (3):0.11 (3) ratio. The OH groups, which point into the other type of channel, are involved in strong O-H?O hydrogen bonds. The title compound is isotypic with the compounds AM(3)H(2)(XO(4))(HXO(4))(2) (A = Na or Ag, M = Mn, Co or Ni, and X = P or As) of the alluaudite structure type. PMID- 21522514 TI - Dipotassium hexa-aqua-nickel(II) bis-[hexa-fluoridozirconate(IV)]. AB - Single crystals of the title compound, K(2)[Ni(H(2)O)(6)][ZrF(6)](2), were grown by slow evaporation of a 40% aqueous HF solution in which a stoichiometric mixture of NiCl(2).6H(2)O, ZrF(4) and KCl was dissolved. The monoclinic structure is isotypic with its K(2)Cu, K(2)Zn, Cs(2)Zn and Cs(2)Cu analogues. The structure is built up from isolated, slightly elongated octa-hedral [Ni(H(2)O)(6)](2+) complex cations (symmetry ) and dimeric [Zr(2)F(12)](4-) complex anions (symmetry ) that are also isolated from each other. The [Zr(2)F(12)](4-) anion results from the association of two distorted penta-gonal-bipyramidal [ZrF(7)] coordination polyhedra by sharing an equatorial edge passing through an inversion center of the unit cell. Both isolated [Ni(H(2)O)(6)](2+) and [Zr(2)F(12)](4-) complex ions are situated in planes parallel to (010). They are connected by the eight coordinated K(+) ions into a three-dimensional structure. An intricate O-H?F hydrogen-bonding network consolidates the structure. PMID- 21522515 TI - N,N,N',N'-Tetra-methyl-ethylene-diammonium tetra-chloridocobaltate(II). AB - The asymmetric unit of the title compound, [(CH(3))(2)NH(CH(2))(2)NH(CH(3))(2)][CoCl(4)], contains a tetra-chlorido-cobalt ate(II) dianion and two halves of two centrosymmetric, crystallographically independent, dications. One independent dication is disordered between two conformations in a 0.784 (13):0.216 (13) ratio. In the crystal, inter-molecular N H?Cl hydrogen bonds link cations and anions into chains propagated in [01]. These hydrogen bonds contribute to the distorted tetra-hedral geometry at the Co(II) atom. PMID- 21522516 TI - Dibromidobis(pyridine-3-carbonitrile-kappaN)zinc(II). AB - In the title compound, [ZnBr(2)(C(6)H(4)N(2))(2)], the Zn(II) atom is four coordinated in a slightly distorted tetra-hedral fashion by two pyridine N atoms and two Br(-) anions. pi-pi inter-actions between adjacent pyridine rings [centroid-centroid distance = 3.6229 (19) A] are the main factor controlling the packing and are effective in the stabilization of the crystal structure. PMID- 21522517 TI - Bis(MU-3,5-dinitro-benzoato-kappaO:O)bis-(MU-3,5-dinitro-benzoato) kappaO,O:O;kappaO:O,O-bis-[(3,5-dinitro-benzoato-kappaO,O)(1,10-phenanthroline kappaN,N)dysprosium(III)]. AB - In the binuclear title complex, [Dy(2)(C(7)H(3)N(2)O(6))(6)(C(12)H(8)N(2))(2)], the Dy(III) ions exhibit a distorted monocapped square-anti-prismatic geometry and are coordinated by seven O atoms of four 3,5-dinitrobenzoate (DNBA) anions and two N atoms of a phenanthroline ligand. The carboxylate groups of the DNBA anions exhibit three coordination modes: bidentate chelating, bidentate chelating bridging and tridentate chelating-bridging. The center of the mol-ecule is located on a crystallographic center of inversion. PMID- 21522518 TI - Dibromidobis(1-ethyl-2,6-dimethyl-pyridinium-4-olate-kappaO)zinc(II). AB - In the bioactive title compound, [ZnBr(2)(C(9)H(13)NO)(2)], the Zn(II) atom is coordinated in a distorted tetra-hedral arrangement by two Br(-) anions and the O atoms of two zwitterionic organic ligands. The pyridinium rings are almost planar [maximum deviations = 0.004 (4) and 0.003 (4) A]. The ethyl groups are approximately perpendicular to the corresponding pyridinium ring planes [N-C-C-C = 88.8 (4) degrees in each ligand]. The packing of the mol-ecules is controlled by pi-pi inter-actions, with centroid-centroid distances of 3.625 (3) and 3.711 (2) A, forming chains approximately parallel to (102). The crystal studied was non-merohedrally twinned (twin relationship between the domains 1 0 0, 0 1 0, 0.4672 -0.1864 -1 and batch scale factor of 7.39%). PMID- 21522519 TI - Aqua-(4-nitro-phthalato)bis-[2-(1H-pyrazol-3-yl)pyridine]-zinc(II) hemihydrate. AB - In the title compound, [Zn(C(8)H(3)NO(6))(C(8)H(7)N(3))(2)(H(2)O)].0.5H(2)O, the Zn(II) atom shows a distorted octa-hedral ZnN(4)O(2) coordination environment and is bonded to two 3-(2-pyrid-yl)-1H-pyrazole ligands via the N atoms, one monodentate 4-nitro-phthalate ligand and one associated water mol-ecule. Additionally, one water of crystallization, with a site-occupation factor of 0.5, is present. The two 3-(2-pyrid-yl)-1H-pyrazole ligands are planar [r.m.s. deviations = 0.03 (1) and 0.35 (1) A] and the dihedral angle between the two planar 3-(2-pyrid-yl)-1H-pyrazole ligands is 67.31 (4) degrees . Inter-molecular pi-pi stacking inter-actions between 3-(2-pyrid-yl)-1H-pyrazole ligands with a face-to-face separation of 3.64 (1) A are observed. Moreover, the crystal structure is stabilized by O-H?O and N-H?O hydrogen bonds between the water of crystallization, the associated water mol-ecule and the 3-(2-pyrid-yl)-1H pyrazole ligands. PMID- 21522520 TI - Diaqua-bis-(5-carb-oxy-2-propyl-1H-imidazole-4-carboxyl-ato-kappaN,O)cobalt(II) 3.5-hydrate. AB - In the title complex, [Co(C(8)H(9)N(2)O(4))(2)(H(2)O)(2)].3.5H(2)O, the Co(II) cation is six-coordinated by two H(2)pimda(-) ligands (H(3)pimda is 2-propyl-1H imidazole-4,5-carboxylic acid) and two water mol-ecules in a distorted octa hedral environment. The crystal structures features a three-dimensional network stabilized by extensive O-H?O and N-H?O hydrogen bonds. The propyl groups of the ligands are disordered over two sets of sites with refined occupancies of 0.673 (8):0.327 (8) and 0.621 (17):0.379 (17). One of the water mol-ecules is located on a site with half-occupancy. PMID- 21522521 TI - Aqua-{2-morpholino-N-[1-(2-pyrid-yl)ethyl-idene]ethanamine-kappaN,N',N''}bis (thio-cyanato-kappaN)nickel(II). AB - In the title compound, [Ni(NCS)(2)(C(13)H(19)N(3)O)(H(2)O)], the Ni(II) ion is six-coordinated by the N,N',N''-tridentate Schiff base, the N atoms of two thio cyanate ligands and one water O atom in a distorted octa-hedral geometry. Intra molecular C-H?N and C-H?O hydrogen bonds occur. In the crystal, O-H?S, O-H?O and C-H?S hydrogen bonds link adjacent mol-ecules into layers parallel to the ac plane. PMID- 21522522 TI - Chloridobis(1,10-phenanthroline)zinc(II) tetra-chlorido(1,10-phenan-throline)bis muthate(III) monohydrate. AB - In the crystal structure of the title monohydrate salt, [ZnCl(C(12)H(8)N(2))(2)][BiCl(4)(C(12)H(8)N(2))].H(2)O, the ionic components are linked into three-dimensional supra-molecular channels by five pairs of C-H?Cl hydrogen bonds and pi-pi stacking inter-actions with an inter-planar distance of 3.643 (2) A. The solvent water mol-ecules are lodged in the channels. PMID- 21522523 TI - Poly[[MU(2)-(1Z,N'E)-2-(1,3-benzothia-zol-2-ylsulfan-yl)-N'-(2-oxidobenzyl-idene kappaO:O)acetohydrazidato-kappaO,N'](pyridine-kappaN)copper(II)]. AB - In the title compound, [Cu(C(16)H(11)N(3)O(2)S(2))(C(5)H(5)N)](n), the Cu(II) atom displays a square-pyramidal CuN(2)O(3) coordination geometry with strong elongation in the vertex direction. The hydrazone mol-ecule is coordinated to the Cu(II) atom in a tridentate manner in the enolic form, creating five- and six membered chelate metallarings. The pyridine mol-ecule completes the square-planar base of the copper coordination environment. The crystal structure displays zigzag polymeric Cu-O-Cu chains along [001]. Several weak pi-pi inter-actions between benzothia-zole rings were found in the same direction [centroid-centroid distances = 3.7484 (16), 3.7483 (16), 3.6731 (17) and 3.7649 (17) A]. PMID- 21522524 TI - Di-MU-aqua-bis-{triaqua-[5-(1-oxopyridin-4-yl)tetra-zol-1-ido]sodium}. AB - In the title compound, [Na(2)(C(6)H(4)N(5)O)(2)(H(2)O)(8)], the Na(I) atom is in a distorted octahedral environment defined by six O atoms, one from the 5-(1 oxopyridin-4-yl)tetra-zolide anion and five from water mol-ecules. Two water mol ecules act as bridging ligands, resulting in the formation of dimeric units organized around inversion centers. In the organic anion, the pyridine and tetra zole rings are nearly coplanar, forming a dihedral angle of 4.62 (1) degrees . The dimeric units and organic anions are connected by O-H?O and O-H?N hydrogen bonds, leading to the formation of a three-dimensional network. PMID- 21522525 TI - Bis(2-ethyl-1H-imidazol-3-ium) tetra-chloridocuprate(II). AB - In the crystal structure of the title salt, (C(5)H(9)N(2))(2)[CuCl(4)], the organic cations and the tetrahedral [CuCl(4)] anions are linked into a three dimensional network by N-H?Cl hydrogen bonds. The two 2-ethyl imidazolium cations in the asymmetric unit differ in the orientation of the ethyl group, with N-C-C-C torsion angles of -170.0 (4) and -87.6 (5) degrees . PMID- 21522526 TI - Hexaaqua-magnesium dibromide 5-(pyridinium-3-yl)tetra-zol-1-ide. AB - In the title compound, [Mg(H(2)O)(6)]Br(2).2C(6)H(5)N(5), the Mg(II) atom, lying on an inversion center, is coordinated by six water mol-ecules in a distorted octa-hedral geometry. The pyridine and tetra-zole rings in the 5-(pyridinium-3 yl)tetra-zol-1-ide zwitterion are nearly coplanar, twisted from each other by a dihedral angle of 5.70 (1) degrees . The zwitterions, Br anions and complex cations are connected by O-H?Br, O-H?N and N-H?Br hydrogen bonds, leading to the formation of a three-dimensional network. PMID- 21522527 TI - Diiodidobis(triphenyl-phosphine oxide)cadmium. AB - In the title compound, [CdI(2){(C(6)H(5))(3)PO}(2)], the Cd(II) atom is ligated by two I atoms and two O atoms from two triphenyl-phosphine oxide ligands in a disorted tetra-hedral arrangement. While the O-Cd-I angles vary from 106.67 (7) to 111.23 (7) degrees , the O-Cd-O angle is 88.60 (10) degrees and the I-Cd-I angle angle is 125.47 (2) degrees . The crystal structure is stabilized by van der Waals forces only. PMID- 21522528 TI - Tetra-kis(MU-3-aza-niumylbenzoato)-kappaO:O,O';kappaO,O':O;kappaO:O'-bis-[triaqua chloridolanthanum(III)] tetra-chloride dihydrate. AB - The tiltle complex, [La(2)(C(7)H(7)NO(2))(4)Cl(2)(H(2)O)(6)]Cl(4).2H(2)O, is a centrosymmetric dimer formed by edge-sharing LaO(5)(H(2)O)(3)Cl polyhedra linked together by a carboxyl-ate ligand. The two La(III) metal ions are linked by two bidentate bridging carboxyl-ate groups with a kappa(2)O:O' coordination mode and two bidentate chelating bridging carboxyl-ate groups with a kappa(3)O:O,O' coordination mode. The coordination sphere of lanthanum, completed by a terminal chloride and three water mol-ecules, adopts a distorted tricapped trigonal prismatic arrangement. N-H?Cl, N-H?O and O-H(water)?Cl hydrogen bonds, and slipped pi-pi inter-actions between parallel benzene rings [centroid-centroid distance of 3.647 (3) A] are observed in the structure. These combine to stabilize a three-dimensional network. PMID- 21522529 TI - Dicarbonyl-chlorido(phen-oxy-thio-carbonyl-kappaC,S)bis-(triphenyl-phosphane kappaP)molybdenum(II). AB - In the title complex, [Mo(C(7)H(5)OS)Cl(C(18)H(15)P)(2)(CO)(2)], the geometry around the metal atom is a capped octa-hedron. The phen-oxy-thio-carbonyl ligand coordinates the Mo(II) atom through the C and S atoms. A one-dimensional structure is formed by pi-pi inter-molecular inter-actions and a supra-molecular aggregation is determined by inter-molecular C-H?O, C-H?Cl, C-H?pi(arene) hydrogen bonds and CO?pi(arene) inter-actions [O?centroid distances = 3.485 (4) and 3.722 (3) A]. PMID- 21522530 TI - catena-Poly[[[diaqua-cobalt(II)]-MU-(3,5-dinitro-2-oxidobenzoato)-kappaO,O:O [tetra-aqua-cobalt(II)]-MU-(3,5-dinitro-2-oxidobenzoato)-kappaO:O,O] dihydrate]. AB - In polymeric title compound, {[Co(2)(C(7)H(2)N(2)O(7))(2)(H(2)O)(6)].2H(2)O}(n), obtained from the reaction of 3,5-dinitro-salicylic acid with cobalt(II) acetate, both Co(II) atoms are located on inversion centres and exhibit a distorted octahedral coordination geometry. The coordin-ation sphere about one Co(II) atom comprises four O-atom donors from two bidentate chelate (O(phenolate) and O(carbox-yl)) and bridging dianionic ligands and two water mol-ecules [Co-O range = 2.0249 (11)-2.1386 (14) A], while that about the second Co(II) atom has four water mol-ecules and two bridging carboxyl-ate O-donor atoms [Co-O range = 2.0690 (14)-2.1364 (11) A]. The coordinated water mol-ecules as well as the water mol ecules of solvation give O-H?O water-water and water-carboxyl hydrogen-bonding inter-actions in the three-dimensional framework structure. PMID- 21522531 TI - Bis(tetra-butyl-ammonium) bis-(3,4,5-trioxocyclo-pent-1-ene-1,2-dithiol-ato kappaS,S')cadmate(II) 0.25-hydrate. AB - The title compound, (C(16)H(36)N)(2)[Cd(C(5)O(3)S(2))(2)].0.25H(2)O, contains two disordered tetra-butyl-ammonium cations, a complex [Cd(C(5)O(3)S(2))(2)](2-) anion and a 0.25-hydrate water. The anion is composed of a bidentate coordinated 3,4,5-trioxocyclo-pent-1-ene-1,2-dithiol-ate (dtcroc) group forming a distorted tetra-hedral configuration around the Cd(II) ion. The dihedral angle between the least-squares planes of the ten-atom sulfur-substituted croconate groups in the anion is 84.10 (8) degrees . The crystal packing is stabilized by weak C-H?O and C-H?S cation-anion hydrogen-bond inter-actions. In each of the two cations one butyl group is disordered over two positions in the ratios 0.589 (11):0.411 (11) and 0.796 (12):0.204 (12). PMID- 21522532 TI - [MU-1,2-Bis(diphenyl-phosphan-yl)benzene-kappaP:P']bis-[chloridogold(I)]. AB - In the crystal structure of the non-solvate form of the title compound, [Au(2)Cl(2)(C(30)H(24)P(2))], two almost linear P-Au(I)-Cl units [175.87 (3) and 171.48 (3) degrees ] are in a skewed arrangement with a Cl-Au?Au-Cl torsion angle of -65.29 (3) degrees so as to form an intra-molecular Au?Au inter-action [3.0563 (2) A]. The complex mol-ecules are connected each other through inter molecular C-H?pi inter-actions, giving a sheet structure parallel to the bc plane. PMID- 21522533 TI - catena-Poly[triethyl-ammonium [[triphenyl-tin(IV)]-MU-3,3'-dihydroxy-4,4'-methyl ene-di-2-naphtho-ato]]. AB - The title compound, {(C(6)H(16)N)[Sn(C(6)H(5))(3)(C(23)H(14)O(6))]}(n), has an infinite chain structure, formed through monodentate carboxyl-ate groups of the pamoic acid anion. The anion bridges two symmetry-related Sn(IV) ions and the resulting polymeric chains are parallel to [201] in the crystal. Et(3)NH(+) cations are inserted between the chains. The coordination of the Sn(IV) atom is completed by three phenyl ligands, giving a distorted trigonal-bipyramidal geometry. PMID- 21522534 TI - Dichlorido{N'-[1-(2-pyridin-2-yl)ethyl-idene]acetohydrazide-kappaN',O}copper(II). AB - In the title compound, [CuCl(2)(C(9)H(11)N(3)O)], the Cu(II) atom is in a distorted square-pyramidal CuCl(2)N(2)O coordination geometry. The tridentate acetohydrazide ligand chelates in a meridional fashion. The chloride ligand in the axial position forms a long Cu-Cl distance of 2.4892 (9) A. In contrast, the Cu-Cl distance from the equatorial chloride ligand is much shorter [2.2110 (7) A]. Inter-molecular N-H?Cl and C-H?Cl hydrogen bonds link the complexes into a three-dimensional network. PMID- 21522535 TI - Azido-[1,2-bis-(diphenyl-phosphan-yl)ethane-kappaP,P'](eta-inden yl)ruthenium(II). AB - Facile ligand substitution is observed when the ruthenium chloride complex [Ru(eta(5)-C(9)H(7))Cl(dppe)] (dppe is diphenylphosphanyl ethane) is treated with NaN(3) in refluxing ethanol, yielding the title compound, [Ru(eta(5) C(9)H(7))(N(3))(dppe)] or [Ru(C(9)H(7))(N(3))(C(26)H(24)P(2))]. The Ru(II) atom has a typical piano-stool coordination. The Ru-P bond lengths are 2.284 (2) and 2.235 (2) A. NMR and MS analyses are in agreement with the structure of the title compound. PMID- 21522536 TI - Dichlorido(N,N'-diisopropyl-piperidine-1-carboximidamidato kappaN,N')titanium(IV). AB - In the mononuclear title complex, [Ti(C(12)H(24)N(3))(2)Cl(2)], the Ti(IV) ion, located on a crystallographic inversion center, is six-coordinated by four N atoms from two N',N''-diisopropyl-N-carboxamidine anions and two chloride atoms in a distorted octahedral geometry. The dihedral angles between the piperidine groups and the NCN chelate rings are 51.5 (1) and 52.3 (1) degrees . PMID- 21522537 TI - Diaqua-bis-(2-oxo-2H-chromene-3-carboxyl-ato-kappaO,O)cadmium. AB - In the title mononuclear cadmium complex, [Cd(C(10)H(5)O(4))(2)(H(2)O)(2)], the Cd(II) atom, located on a crystallographic inversion center, exhibits a slightly distorted octa-hedral geometry and is six-coordinated by two O atoms from water mol-ecules in the axial positions and four O atoms from two deprotonated coumarin 3-carb-oxy-lic acid ligands in the equatorial plane. Angles around the Cd(II) atom vary between 81.00 (5) and 99.00 (0) degrees . The Cd-O bond lengths vary between 2.1961 (13) and 2.3360 (13) A. O-H?O hydrogen bonds between the H atoms of coordinated water mol-ecules and the O atoms of carboxyl-ate groups link the complex mol-ecules into layers parallel to the ab plane. PMID- 21522538 TI - trans-Bis(dimethyl sulfoxide-kappaO)bis-(thio-semicarbazide-kappaN,S)cadmium dipicrate dihydrate. AB - In the cation of the title compound, [Cd(CH(5)N(3)S)(2)(C(2)H(6)OS)(2)](C(6)H(2)N(3)O(7))(2).2H(2)O, the Cd(II) atom is located on an inversion center. It is hexa-coordinated in an octahedral fashion by two thio-semicarbazide mol-ecules, which coordinate in a bidentate manner via the S and N atoms, and to the O atom of two dimethyl sufoxide (DMSO) mol-ecules. The charges are equilibrated by two picrate anions and the complex crystallizes as a dihydrate. In the crystal, these units are linked by a number of O-H?O and N-H?S hydrogen bonds and weak C-H?O inter-actions, forming a three dimensional network. PMID- 21522539 TI - {1,1'-[Butane-1,4-diylbis(nitrilo-methyl-idyne)]di-2-naphtho-lato}copper(II) ethanol monosolvate. AB - The asymmetric unit of the title compound, [Cu(C(26)H(22)N(2)O(2))].C(2)H(5)OH, comprises a Schiff base complex and an ethanol mol-ecule of crystallization. The Cu(II) atom shows a distorted square-planar geometry. The dihedral angle between the two aromatic rings is 48.16 (13) degrees . The crystal structure is stabilized by inter-molecular O-H?O and C-H?O hydrogen bonds and inter-molecular pi-pi inter-actions with centroid-centroid distances in the range 3.485 (2)-3.845 (3) A. PMID- 21522540 TI - Bis(2,3,5,6-tetra-2-pyridyl-pyrazine-kappaN,N,N)nickel(II) dithio-cyanate dihydrate. AB - In the title compound, [Ni(C(24)H(16)N(6))(2)](NCS)(2).2H(2)O, the central Ni(II) ion is octahedrally coordinated by six N atoms of two tridentate 2,3,5,6-tetra-2 pyridyl-pyrazine ligands (tppz). Two thio-cyanate anions act as counter-ions and two water mol-ecules act as solvation agents. O-H?N hydrogen bonds are observed in the crystral structure. PMID- 21522541 TI - cis-Dichloridotetra-kis-(trimethyl-phosphane-kappaP)ruthenium(II) benzene disolvate. AB - The title compound, cis-[RuCl(2)(C(3)H(9)P)(4)].2C(6)H(6), contains a complex mol ecule with a crystallographic mirror plane passing through the Ru(II) atom, the two cis-disposed Cl ligands and two P atoms of the two cis-disposed P(CH(3))(3) ligands. The Ru(II) atom adopts a distorted octa-hedral RuCl(2)P(4) coordination geometry with the two trans-disposed P atoms occupying the axial positions. The packing of the structure is accomplished through non-classical C-H?Cl hydrogen bonds between the benzene solvent mol-ecule and one of the Cl ligands. PMID- 21522542 TI - Poly[MU(3)-hydroxido-MU-(pyridine-2,4,6-tricarboxyl-ato)-dilead(II)]. AB - The asymmetric unit of the title coordination polymer, [Pb(2)(C(8)H(2)NO(6))(OH)](n), contains two crystallographically independent Pb(II) ions, one pyridine-2,4,6-tricarboxyl-ate (ptc) trianion and one hydroxide anion. One of the Pb(II) atoms is coordinated by one pyridine N and four carboxyl ate O atoms from the ptc trianion and a hydroxide O atom in a distorted octa hedral geometry. The other Pb(II) atom is five-coordinated by three carboxyl-ate O atoms and two hydroxide O atoms in a distorted tetra-gonal-pyramidal geometry. Four neighbouring Pb(II) atoms are bridged through two MU(3)-hydroxide ligands, forming the centrosymmetric Pb(4)(OH)(2) core. The three-dimensional structure is further achieved through bridging carboxyl-ate groups. There are also O-H?O hydrogen bonds between the hydroxide ligand and the carboxyl-ate group. PMID- 21522543 TI - (5,7,7,12,14,14-Hexamethyl-1,4,8,11-tetra-aza-cyclo-tetra-deca-4,11 diene)nickel(II) bis-[O,O'-bis-(4-tert-butyl-phen-yl) dithio-phosphate]. AB - The title salt, [Ni(C(16)H(32)N(4))](C(20)H(26)O(2)PS(2))(2), comprises a centrosymmetric [Ni(Me(6)[14]dieneN(4))](2+) dication (Me(6)[14]dieneN(4) is 5,7,7,12,14,14-hexa-methyl-1,4,8,11-tetra-aza-cyclo-tetra-deca-4,11-diene) and two O,O'-bis-(4-tert-butyl-phen-yl) dithio-phosphate anions. The Ni(II) ion lies on an inversion centre and displays a slightly distorted NiN(4) square-planar chelation arrangement with four N atoms from the Me(6)[14]dieneN(4) macrocycle. Two S atoms from symmetry-related anions are located in pseudo-axial positions with respect to the Ni(II) ion, with Ni?S distances of 3.2991 (7) A. Inter molecular N-H?S and C-H?S hydrogen bonds link the complex cation and pair of anions into a 1:2 type salt. PMID- 21522544 TI - Bis(1,3-dimethyl-1,3-diazinan-2-one)dinitratodioxidouranium(VI). AB - The title compound, [U(NO(3))(2)O(2)(C(6)H(12)N(2)O)(2)], exhibits a hexa-gonal bipyramidal geometry around the U(VI) ion, which is situated on an inversion centre and coordinated by two oxide ligands in the axial positions, and four O atoms from two bidentate NO(3) (-) and two O atoms from two 1,3-dimethyl-1,3 diazinan-2-one (DMPU) ligands in the equatorial plane. These ligands are located in trans positions. The -(CH(2))(3)- moiety in the DMPU ligand is disordered over two positions in a 0.786 (11):0.214 (11) ratio. PMID- 21522545 TI - Poly[[MU(2)-aqua-tetraaquadi-MU(3)-malonato-nickel(II)strontium(II)] dihydrate]. AB - The unit-cell parameters for the title mixed-metal coordination polymer, {[NiSr(C(3)H(2)O(4))(2)(H(2)O)(5)].2H(2)O}(n), which is isostructural with its Co containing analogue, were reported previously [Gil de Muro et al. (1999 ?). Eur. J. Inorg. Chem. pp. 935-943]; the full crystal structure including a description of the hydrogen bonding is reported here. The Sr(2+) ion is bonded to five O atoms from three different malonate dianions and four water mol-ecules, displaying a distorted tricapped trigonal-prismatic coordination geometry. Two malonate dianions, two water mol-ecules and one Ni(2+) ion build up a dianionic [Ni(C(3)H(2)O(4))(2)(H(2)O)(2)](2-) unit incorporating a slightly distorted NiO(6) octa-hedron, which coordinates to three nearby Sr(2+) ions. This arrangement creates a metal-organic framework having a 20-membered ring with four Ni and six Sr atoms lying in the bc plane. The coordinated and uncoordinated water mol-ecules are responsible for the formation of two D5 hydrogen-bonded water chains within the 20-membered ring and they are linked into an R4 water cluster via two bifurcated O-H?(O,O) links. PMID- 21522546 TI - Di-MU-thio-cyanato-bis-{[1,2-bis-(diiso-propyl-phosphan-yl)-1,2-dicarba-closo dodeca-borane]silver(I)}. AB - The title compound, [Ag(2)(NCS)(2)(C(14)H(38)B(10)P(2))(2)], was synthesized by the reaction of 1,2-bis-(diiso-propyl-phos-phan-yl)-1,2-dicarba-closo-dodeca borane with AgSCN. The diisopropyl-phosphanyl-closo-carborane ligand is coordinated in a bidentate manner to the Ag(I) atom through the two P atoms. The coordination of the Ag(I) atom is distorted tetra-hedral, in which two vertices are formed by the P atoms of the chelating diphosphine ligand, and the other two are occupied by the S and N atoms of the two bridging thio-cyanate anions, leading to a centrosymmetric binuclear complex. The distance between the two C atoms in the carborane skeleton is 1.851 (6) A. PMID- 21522547 TI - Poly[diaqua-MU(3)-4-nitro-phthalato-copper(II)]. AB - In the title complex, [Cu(C(8)H(3)NO(6))(H(2)O)(2)](n), the two carboxyl-ate groups of the 4-nitro-phthalate dianion ligands have monodentate and 1,3-bridging bonding modes, respectively. The Cu atom shows an approximate square-pyramidal coordination as it is bonded to O atoms from the carboxyl-ate groups of three 4 nitro-phthalate ligands and two O atoms of the non-equivalent coordinated water mol-ecules. Other Cu atoms in the coordination polymer are connected into a two dimensional layer in the ab plane. The layers are aggregated to a three dimensional structure through inter-layer hydrogen bonding involving an O atom of a nitro group. The whole three-dimensional structure is further maintained and stabilized by intra-layer hydrogen bonds between the O atoms of the carboxyl-ate groups and the coordinated water mol-ecules. PMID- 21522548 TI - Poly[tetra-aqua-di-MU(4)-malonato-barium(II)cadmium(II)]. AB - In the title complex, [BaCd(C(3)H(2)O(4))(2)(H(2)O)(4)](n), the Ba(II) atoms, located on crystallographic twofold axes, adopt slightly distorted square-anti prismatic coordination geometries, while the Cd(II) atoms, which lie on crystallographic centres of symmetry, have a distorted octa-hedral coordination. Each malonate dianion binds two different Cd(II) atoms and two different Ba(II) atoms. This connectivity generates alternating layers along [100] in the structure, with one type containing Cd(II) cations and malonate dianions, while the other is primarily composed of Ba(II) ions and coordinated water mol-ecules. The water mol-ecules also participate in extensive O-H?O hydrogen bonding. PMID- 21522549 TI - {2-[(Dimethyl-amino)-meth-yl]phen-yl}bis-(4-methyl-phen-yl)bis-muthane. AB - The title compound, [Bi(C(7)H(7))(2)(C(9)H(12)N)], was obtained by treating chlorodi(p-tol-yl)bis-muthane with o-lithio-N,N-dimethyl-benzyl-amine. An intra molecular Bi?N nonbonding inter-action is observed in the distorted trigonal triaryl-bis-muth coordination of the title compound. PMID- 21522550 TI - Bis(MU-4-amino-3,5-dimethyl-4H-1,2,4-triazole)bis-[diiodidozinc(II)]. AB - In the title compound, [Zn(2)I(4)(C(4)H(8)N(4))(2)], the Zn(II) atom is coordinated in a distorted tetra-hedral geometry by two N atoms from the triazole rings of two 4-amino-3,5-dimethyl-4H-1,2,4-triazole (admt) ligands and two iodide ligands. Doubly bridging admt ligands connect two Zn(II) atoms, forming a centrosymmetric dimer. Weak N-H?I and C-H?I hydrogen bonds play an important role in the inter-molecular packing. PMID- 21522551 TI - The azide-bridged mixed-valent cobalt(II,III) compound [(CH(3))(3)NH](2)[CoCo(2)(N(3))(10)]. AB - The crystal structure of the title compound, poly[bis-(tri-methyl-ammonium) hexa MU(1,1)-azido-tetra-azido-tricobalt-ate(II,III)], [(CH(3))(3)NH](2)[Co(II)Co(III) (2)(N(3))(10)], consists of anionic chains [Co(II)Co(III) (2)(N(3))(10)](2-) extending parallel to the c axis and [(CH(3))(3)NH](+) counter-cations situated between the chains. In the anionic chain, one tetra-hedrally coordinated Co(II) atom (site symmetry 2) and two octa-hedrally coordinated Co(III) atoms are arranged alternately and are linked by MU(1,1)-azide bridges. The anionic chains and cations are connected via N-H?N hydrogen bonding into a three-dimensional structure. PMID- 21522552 TI - Tetra-kis[MU-4-(diethyl-amino)-benzoato-kappaO:O']bis-[(N,N-diethyl-nicotinamide kappaN)cobalt(II)]. AB - In the centrosymmetric binuclear title complex, [Co(2)(C(11)H(14)NO(2))(4)(C(10)H(14)N(2)O)(2)], the two Co(II) cations [Co?Co = 2.6199 (5) A] are bridged by four 4-(diethyl-amino)-benzoate (DEAB) anions. The four nearest O atoms around each Co(II) ion form a distorted square-planar arrangement, the distorted square-pyramidal coordination geometry being completed by the pyridine N atom of an N,N-diethyl-nicotinamide (DENA) ligand. The dihedral angle between the benzene ring and the carboxyl-ate group is 7.06 (11) degrees in one of the independent DEAB ligands and 4.42 (9) degrees in the other. The benzene rings of the two independent DEAB ligands are oriented at a dihedral angle of 86.35 (8) degrees . The pyridine ring is oriented at dihedral angles of 31.43 (6) and 57.92 (7) degrees with respect to the two benzene rings. In the crystal, weak inter-molecular C-H?O inter-actions link the mol-ecules into a three-dimensional network. Weak C-H?pi inter-actions are also present in the crystal structure. PMID- 21522553 TI - Poly[[bis-[MU-1,2-bis-(4-pyrid-yl)ethene]bis-(trichloro-acetato)-cadmium(II)] monohydrate]. AB - In the crystal structure of the title compound, {[Cd(C(2)Cl(3)O(2))(2)(C(12)H(10)N(2))(2)].H(2)O}(n), the Cd(II) ion lies on a twofold rotation axis and 1,2-bis-(4-pyrid-yl)ethene ligands bridge symmetry related Cd(II) ions, forming a two-dimensional structure. Two trichloro-acetate ligands complete the coordination around the Cd(II )ion, forming a distorted octa hedral environment. In the crystal, solvent water mol-ecules, which also lie on twofold rotation axes, form inter-molecular O-H?O hydrogen bonds, which connect the two-dimensional structure into a three-dimensional network. The crystal studied was an inversion twin, the refined ratio of twin components being 0.75 (4):0.25 (4). PMID- 21522554 TI - Aqua-bis-(benzoato-kappaO)(1,10-phenanthroline-kappaN,N')zinc(II). AB - The Zn atom in the title compound, [Zn(C(7)H(5)O(2))(2)(C(12)H(8)N(2))(H(2)O)], is five-coordinate in a distorted trigonal-bipyramidal coordination environment involving two O atoms of two monodentate benzoates, two N atoms of a 1,10 phenanthroline mol-ecule and one O atom of a water mol-ecule. The axial positions are occupied by a carboxyl-ate O atom from the benzoate ligand and an N atom from the 1,10-phenanthroline ligand [N-Zn-O = 146.90 (7) degrees ]. The water mol ecule forms an intra-molecular O-H?O hydrogen bond; an inter-molecular O-H?O hydrogen bond gives rise to a dimer. PMID- 21522555 TI - Bis[1,3-bis-(2,4,6-trimethyl-phen-yl)-2,3-dihydro-1H-imidazol-2-yl idene]dichloridodinitro-syltungsten(II) tetra-hydro-furan-d(8) monosolvate. AB - The mol-ecular structure of the title compound, [WCl(2)(NO)(2)(C(21)H(24)N(2))(2)].C(4)D(8)O, displays a distorted octa-hedral arrangement around the W atom with two trans 1,3-bis-(2,4,6-trimethyl-phen yl)imidazol-2-yl-idene (IMes) carbene ligands in axial positions. The four equatorial positions are occupied by nitrosyl and chloride ligands, which are trans to each other. The C(carbene)-W-C(carbene) bond angle of 173.44 (18) degrees and the Cl-W-N(nitros-yl) bond angles of 171.34 (11) and 171.32 (13) degrees deviate only slightly from linearity. The distortion comes from the nitrosyl and chloride ligands which are not fully coplanar since the two N atoms deviate from the WCl(2) plane by -0.279 (4) and 0.272 (4) A, respectively. An inter-molecular C-H?O inter-action connects the organometallic mol-ecule and the tetra-hydro-furan-d(8) solvent mol-ecule. PMID- 21522556 TI - Tetra-ethyl-ammonium dibromido-tricarbon-yl(o-toluidine)rhenate(I). AB - In the title compound, (C(8)H(20)N)[ReBr(2)(C(7)H(9)N)(CO)(3)], the Re(I) atom is octa-hedrally surrounded by three carbonyl ligands orientated in a facial arrangement, two bromide ligands and an o-toluidine ligand. The amine lies trans to the carbonyl ligand and is substitutionally disordered over two positions in a 0.66 (1):0.34 (1) ratio. An array of C-H?O, C-H?Br and N-H?Br hydrogen-bonding inter-actions between the cations and the surrounding rhenate anions stabilize the crystal structure. PMID- 21522557 TI - Tetra-ethyl-ammonium (acetyl-acetonato)bromidotricarbonyl-rhenate(I). AB - In the title compound, (C(8)H(20)N)[ReBr(C(5)H(7)O(2))(CO)(3)], the Re(I) atom in the rhenate anion is surrounded by three carbonyl ligands orientated in a facial arrangement, a bromide ligand and an acetyl-acetonate ligand, leading to a distorted octa-hedral ReC(3)BrO(2) coordination with a O-Re-O bite angle of 85.66 (7) degrees . An array of C-H?O and C-H?Br hydrogen-bonding inter-actions between the cations and the surrounding rhenate anions stabilize the crystal structure. PMID- 21522558 TI - [N-Benzyl-N-(diphenyl-phosphanylmeth-yl)pyridin-2-amine]-chloridomethyl platinum(II). AB - In the mononuclear title complex, [Pt(CH(3))Cl(C(25)H(23)N(2)P)], the N-benzyl-N (diphenyl-phosphanylmeth-yl)pyridin-2-amine functions as a bidentate ligand with the pyridyl N atom and the phosphine P atom chelating the Pt(II) ion, forming a six-membered metallocycle. The Pt(II) atom adopts a square-planar coordination geometry with one methyl group and one chloride ligand bonding to the metal center in a cis relationship. C-H?pi and C-H?Cl inter-actions help to consolidate the packing. PMID- 21522559 TI - [(1,2,5,6-eta)-Cyclo-octa-1,5-diene]bis-(4-methyl-phen-yl)platinum(II). AB - In the mononuclear title complex, [Pt(C(7)H(7))(2)(C(8)H(12))], the Pt(II) ion exhibits a square-planar coordination geometry defined by two methyl-phenyl ligands and the mid-points of the two pi-coordinated double bonds of cyclo-octa 1,5-diene. The two methyl-phenyl groups have a cis relationship with a C-Pt-C bond angle of 88.54 (18) degrees and a dihedral angle between the mean planes of the benzene rings of 83.87 (1) degrees . Each complex mol-ecule links to four symmetry-related ones through inter-molecular C-H?pi inter-actions, forming a layer almost parallel to the bc plane. PMID- 21522560 TI - (2-{[2-(2-Amino-ethyl-amino)-eth-yl]imino-meth-yl}phenolato)nickel(II) chloride dihydrate. AB - In the title complex, [Ni(C(11)H(16)N(3)O)]Cl.2H(2)O, the Ni(II) ion is coordinated within a distorted square-planar environment. In the crystal, inter molecular N-H?Cl, N-H?O, O-H?O, O-H?Cl and weak C-H?O hydrogen bonds link the components into a two-dimensional network parallel to (001). PMID- 21522561 TI - Aqua-(2,9-dimethyl-1,10-phenanthroline-kappaN,N')(formato-kappaO,O')(formato kappaO)cobalt(II) monohydrate. AB - The asymmetric unit of the title compound, [Co(HCO(2))(2)(C(14)H(12)N(2))(H(2)O)].H(2)O, contains a mononuclear complex mol ecule hydrogen bonded to a lattice water mol-ecule. The Co(II) cation is in a distorted octa-hedral coordination environment defined by the two N atoms of the 2,9-dimethyl-1,10-phenanthroline ligand and four O atoms. Two of these are from a chelating formate anion, one from a monodentate formate and the last from an aqua ligand. In the crystal, mol-ecules are connected by O-H?O hydrogen bonds, forming double chains along [100] with the 2,9-dimethyl-1,10-phenanthroline ligands pointing outwards from each chain. These chains are further linked into layers parallel to (011) by inter-chain pi-pi stacking inter-actions with centroid centroid distances of 3.61 (1) A. PMID- 21522562 TI - Dichlorido{2-morpholino-N-[1-(2-pyrid-yl)ethyl-idene]ethanamine kappaN,N',N''}manganese(II). AB - In the title compound, [MnCl(2)(C(13)H(19)N(3)O)], the Mn(II) ion is penta coordinated in a distorted square-pyramidal geometry. The coordination environment is defined by the N,N',N''-tridentate Schiff base ligand and one Cl atom in the basal positions and one Cl atom in the apical position. In the crystal, inter-molecular C-H?Cl hydrogen bonds link the mol-ecules into a three dimensional network. An intra-molecular C-H?Cl hydrogen bond is also observed. PMID- 21522563 TI - [MU-1,2-Bis(diphenyl-phosphan-yl)-1,2-dimethyl-hydrazine-kappaP:P']bis-[chlorido gold(I)]. AB - The title compound, [Au(2)Cl(2)(C(26)H(26)N(2)P(2))], is formed from a bidentate phosphine ligand complexed to two linearly coordinated gold(I) atoms. The gold(I) atoms are 3.4873 (7) A apart. The mol-ecule exhibits a crystallographic twofold rotation axis. PMID- 21522564 TI - Bis(2,2'-bipyridyl-kappaN,N')(sulfato-kappaO,O')cobalt(II) ethane-1,2-diol monosolvate. AB - The title compound, [Co(SO(4))(C(10)H(8)N(2))(2)].C(2)H(6)O(2), has the Co(2+) ion in a distorted octa-hedral CoN(4)O(2) coordination geometry. A twofold rotation axis passes through the Co and S atoms, and through the mid-point of the C-C bond of the ethane-diol mol-ecule. In the crystal, the [CoSO(4)(C(10)H(8)N(2))(2)] and C(2)H(6)O(2) units are held together by a pair of O-H?O hydrogen bonds. PMID- 21522566 TI - cis-(Pyridin-2-ylcarbonimidodithio-ato-kappaS,S')bis-(triphenyl-phosphane kappaP)palladium(II). AB - The title compound, [Pd(C(6)H(4)N(2)S(2))(C(18)H(15)P)(2)], was obtained as a minor product from the reaction of trans-PdCl(2)(PPh(3))(2) with piperazine-1,4 dicarbothioic acid bis-(pyridin-2-yl)amide. The Pd(II) atom displays a slightly distorted square-planar PdP(2)S(2) geometry with a bidentately coordinated pyridin-2-ylcarbonimidodithio-ate ligand and two triphenyl-phosphine mol-ecules, coordinated in cis positions. The crystal structure features weak pi-pi [centroid centroid distance =3.7327(15) A] and C-H?pi inter-actions and contains an almost spherically shaped void of 50.4 A(3) per unit cell. PMID- 21522565 TI - Poly[tris-(MU-2-amino-benzene-1,4-dicarboxyl-ato)tetra-kis-(N,N-dimethyl formamide)-diyttrium(III)]. AB - The asymmetric unit of the title coordination polymer, [Y(2)(C(8)H(5)NO(4))(3)(C(3)H(7)NO)(4)](n), contains one Y(3+) ion, three half mol-ecules of the 2-amino-benzene-1,4-dicarboxyl-ate (abz) dianion and two O bonded N,N-dimethyl-formamide (DMF) mol-ecules. Each abz half-mol-ecule is completed by crystallographic inversion symmetry and its -NH(2) group is disordered in each case [relative occupancies within the asymmetric unit = 0.462 (18):0.538 (18), 0.93 (2):0.07 (2) and 0.828 (16):0.172 (16)]. The combination of disorder and crystal symmetry means that each of the four C-H atoms of the benzene ring of each of the dianions bears a statistical fraction of an -NH(2) group. The coordination geometry of the yttrium ion is a fairly regular YO(8) square anti-prism arising from its coordination by two DMF mol-ecules, four monodentate abz dianions and one O,O-bidentate abz dianion. The polymeric building unit is a dimeric paddle-wheel with two metal ions linked by four bridging abz dianions. Further bridging linkages connect the dimers into a three dimensional framework containing voids in which highly disordered DMF mol-ecules are presumed to reside. PMID- 21522567 TI - catena-Poly[[[aqua-(pyridine-4-carboxyl-ato-kappaN)silver(I)]-MU-hexa-methyl-ene tetra-amine-kappaN:N'] dihydrate]. AB - In the title compound, {[Ag(C(6)H(4)NO(2))(C(6)H(12)N(4))(H(2)O)].2H(2)O}(n), the Ag(I) atom shows a distorted triangular pyramidal geometry,, formed by two N atoms from two hexa-methyl-ene-tetra-amine (hmt) ligands and one N atom from a pyridine-4-carboxyl-ate (4-pdc) ligand and one water mol-ecule. The hmt ligands bridge the Ag atoms, forming a chain along [001]. The carboxyl-ate group of the 4 pdc ligand is uncoordinated. O-H?O hydrogen bonds between the water mol-ecules and carboxyl-ate groups stabilize the structure. PMID- 21522568 TI - trans-Bis(N,N-diethyl-ethylenediamine)-nickel(II) dibromide. AB - The structure of the title compound, [Ni(C(6)H(16)N(2))(2)]Br(2) or [Ni(Et(2)en)(2)]Br(2) (Et(2)en is asymmetric N,N-diethyl-ethylene-diamine), containing an Ni(II) atom (site symmetry ) in square-planar NiN(4) coordination, is described and contrasted with related structures containing Ni(II) in octa hedral coordination with axial X(-) ligands (X(-) = variable anions). The dialkyl ated N atom has an appreciably longer bond length to the Ni(II) atom [1.9666 (13) A] than does the unsubstituted N atom [1.9202 (14) A]. The Ni-N bond lengths in [Ni(Et(2)en)(2)]Br(2) are significantly shorter than corresponding values in tetra-gonally distorted [Ni(Et(2)en)(2)X(2)] compounds (X = (-)O(2)CCF(3), OH(2), or (-)NCS), which have a triplet ground state. The electronic configuration in these axially ligated [Ni(Et(2)en)(2)X(2)] compounds populates the metal-based d(x) (2) (-y) (2) orbital, which is Ni-N anti-bonding in character. Each Et(2)en ligand in each [Ni(Et(2)en)(2)](2+) cation forms a pair of N-H?Br hydrogen bonds to the Br(-) anions, one above and below the NiN(4) square plane. Thus, a ribbon of alternating Br(-) pairs and [Ni(Et(2)en)(2)](2+) cations that are canted at 65 degrees relative to one another is formed by hydrogen bonds. PMID- 21522569 TI - Bis(2,6-dihy-droxy-benzoato-kappaO,O)(nitrato-kappaO,O')bis-(1,10-phenanthroline kappaN,N')praseodymium(III). AB - The mononuclear title complex, [Pr(C(7)H(5)O(3))(2)(NO(3))(C(12)H(8)N(2))(2)], is isostructural with related complexes of other lanthanides. The Pr(III) atom is in a pseudo-bicapped square-anti-prismatic geometry, formed by four N atoms from two chelating 1,10-phenanthroline (phen) ligands and six O atoms, four from two 2,6 dihy-droxy-benzoate (DHB) ligands and the other two from nitrate anions. pi-pi stacking inter-actions between the phen and DHB ligands [centroid-centroid distances = 3.518 (2) and 3.778 (2) A] and the phen and phen ligands [face-to face separation = 3.427 (6) A] of adjacent complexes stabilize the crystal structure. Intra-molecular O-H?O hydrogen bonds are observed in the DHB ligands. PMID- 21522570 TI - Poly[di-MU-aqua-MU(4)-(pyrazine-2,5-dicarboxyl-ato)-dilithium(I)]. AB - In the title coordination polymer, [Li(2)(C(6)H(2)N(2)O(2))(H(2)O)(2)](n) the pyrazine-2,5-dicarboxyl-ate dianionic ligand bridges two symmetry-independent Li(+) ions using both its N,O-chelating sites. The carboxyl-ate O atom of one of them also bridges to another Li(+) ion, while the second O atom of this group is bonded to another Li(+) ion. Two symmetry-independent water O atoms participate also in the bridging system, which gives rise to a polymeric three-dimensional framework. Both Li(+) ions show distorted trigonal-bipyramidal LiNO(4) coordination geometries, with the N atom in an axial site in both cases. The packing is consolidated by O-H?O hydrogen bonds, which occur between water mol ecules as donors and carboxyl-ate O atoms as acceptors. PMID- 21522571 TI - Di-MU-chlorido-bis-{[2-(benzyl-imino-meth-yl)pyridine kappaN,N']chloridomercury(II)} dichloridomercury(II). AB - The Hg(II) ion in the title centrosymmetric dinuclear complex, [Hg(2)Cl(4)(C(13)H(12)N(2))(2)].[HgCl(2)], adopts a distorted square-pyramidal geometry, being coordinated by the bis-chelating N-heterocyclic ligand, two bridging Cl atoms and one terminal Cl atom. One of the bridging Hg-Cl bonds [2.8428 (11) A] is significantly longer than the other [2.5327 (10) A]. In the crystal, there are weak pi-pi inter-actions [centroid-centroid distance = 3.630 (3) A] between the aromatic rings of the discrete units. The HgCl(2) adduct molecule is located on an inversion centre and has an Hg-Cl bond length of 2.2875 (11) A. PMID- 21522572 TI - Chlorido(eta-cyclo-penta-dien-yl)[(4a,4b,8a,9,9a-eta)-fluoren-yl](fluorenyl kappaC)zirconium(IV) toluene solvate. AB - In the title compound, [Zr(C(5)H(5))(C(13)H(9))(2)Cl].C(7)H(8), the Zr(IV) atom is coordinated by a Cl atom, a cyclo-penta-dienyl (Cp) ligand [Zr-centroid (Cp) = 2.199 (3) A] and two fluorenyl ligands (Fl) [Zr-centroid (Fl) = 2.273 (2) A and Zr-CH from fluorenyl = 2.355 (2) A] in a distorted tetra-gonal geometry. The dihedral angles between the mean planes of the fluorenyl ring systems and the Cp ring are 36.62 (6) degrees for the eta(1)-coordinated fluorenyl and 52.85 (6) degrees for the eta(5)-coordinated fluorenyl, while the dihedral angle between the mean planes of the two fluorenyl ring systems is 76.18 (7) degrees . PMID- 21522573 TI - Dichlorido{2-morpholino-N-[1-(2-pyrid-yl)ethyl-idene]ethanamine kappaN,N',N''}zinc(II). AB - In the title compound, [ZnCl(2)(C(13)H(19)N(3)O)], the Schiff base ligand acts as an N,N',N''-tridentate chelating agent, making two five-membered rings with the Zn(II) ion. The metal atom is five-coordinated by the Schiff base ligand and two Cl atoms in a distorted square-pyramidal geometry. An intra-molecular C-H?Cl inter-action occurs. In the crystal, adjacent mol-ecules are linked together via C-H?Cl hydrogen-bonding and long range C-H?O and C-H?Cl inter-actions into a three-dimensional network. PMID- 21522574 TI - Butyl-trichlorido{2-[(diisopropyl-ammonio)-meth-yl]phen-yl}tin(IV) dichloro methane monosolvate. AB - The title compound, [Sn(C(4)H(9))(C(13)H(21)N)Cl(3)].CH(2)Cl(2), was obtained by recrystallization of [2-(diisopropyl-amino-meth-yl)phen-yl]tin(IV) butyl dichloride from a CH(2)Cl(2)/n-hexane mixture (1:4 v/v) in the presence of ambient moisture. Partial hydrolysis led to the title compound, the hydro-chloric acid adduct of the dichloride, having a penta-coordinated Sn atom with a trigonal bipyramidal C(2)SnCl(3) core. The N atom of the 2-[(diisopropyl-ammonio)-meth yl]phenyl ligand forms a strong intra-molecular N-H?Cl hydrogen bond, resulting in a zwitterionic species, [2-((i)Pr(2)HN(+)CH(2))C(6)H(4)]SnBuCl(3) ( ).CH(2)Cl(2). Disorder was found in the n-butyl group, which was refined as disordered over three positions, with site occupancies of 0.22 (1), 0.51 (1) and 0.27 (2). PMID- 21522575 TI - Chlorido(2-{1-[(2-morpholino-eth-yl)imino]-eth-yl}phenolato kappaN,N',O)copper(II). AB - In the title compound, [CuCl(C(14)H(19)N(2)O(2))], the Cu(II) ion is four coordinated by one deprotonated N,N',O-tridentate Schiff base and one chloride ion in a distorted square-planar geometry. In the crystal, adjacent mol-ecules are linked via C-H?Cl and C-H?O inter-actions, forming infinite layers parallel to the (100) plane. The structure was determined from a non-merohedrally twined crystal [twin ratio 0.777 (3):0.223 (3)]. PMID- 21522576 TI - {2-Morpholino-N-[1-(2-pyrid-yl)ethyl-idene]ethanamine-kappaN,N',N''}bis-(thio cyanato-kappaN)copper(II). AB - In the title compound, [Cu(NCS)(2)(C(13)H(19)N(3)O)], the Cu(II) ion is five coordinated by the N,N',N''-tridentate Schiff base and the N atoms of two isothio cyanate ligands in a square-pyramidal geometry. In the crystal, C-H?N, C-H?O and C-H?S inter-actions link adjacent mol-ecules into layers parallel to the ac plane. A weak inter-molecular pi-pi inter-action occurs between the aromatic rings with a centroid-centroid distance of 3.9412 (9) A. PMID- 21522577 TI - (meso-5,5,7,12,12,14-Hexamethyl-1,4,8,11-tetra-aza-cyclo-tetra-deca-ne)nickel(II) bis-[O,O'-bis-(4-methyl-phen-yl) thio-phosphate]. AB - In the centrosymmetric title complex, [Ni(C(16)H(36)N(4))](C(14)H(14)O(3)PS)(2), the Ni(II) ion is coordinated by four N atoms and two O atoms within a slightly distorted NiN(4)O(2) octa-hedral geometry. The asymmetric unit consits of one Ni(II) ion that is located on a center of inversion, half of the macrocylic ligand and one anion occupying general positions. Intra-molecular N-H?O and N-H?S hydrogen bonding is found between the macrocyclic ligand and the monothio phosphate anion. PMID- 21522578 TI - Bis(2,6-dihy-droxy-benzoato-kappaO,O)(nitrato-kappaO,O')bis-(1,10-phenanthroline kappaN,N')cerium(III). AB - The mononuclear title complex, [Ce(C(7)H(5)O(3))(2)(NO(3))(C(12)H(8)N(2))(2)], is isostructural to other related lanthanide structures. The Ce atom is in a pseudo bicapped square-anti-prismatic geometry formed by four N atoms from two chelating 1,10-phenanthroline (phen) ligands and by six O atoms, four from two 2,6-dihy droxy-benzoate (DHB) ligands and the other two from a nitrate anion. pi-pi stacking inter-actions between phen and DHB ligands [centroid-centroid distances = 3.513 (3) and 3.762 (2) A] and phen and phen ligands [face-to-face separation = 3.423 (7) A] of adjacent complexes stabilize the crystal structure. Intra molecular O-H?O hydrogen bonds are observed in the DHB ligands. PMID- 21522579 TI - Bis[MU-4-(4-carb-oxy-phen-oxy)phthalato]bis-[triaqua-nickel(II)]. AB - In the centrosymmetric binuclear title compound, [Ni(2)(C(15)H(8)O(7))(2)(H(2)O)(6)], the Ni(II) ion is in a distorted octa-hedral coordination geometry with O(6) donors, three from three water mol-ecules, the others from three carboxylate groups of two ligands. Extensive O-H?O hydrogen bonding connects the mol-ecules into a three-dimensional supra-molecular structure. PMID- 21522580 TI - {2-[6-(1H-Benzimidazol-2-yl-kappaN)-2-pyridyl-kappaN]benzimidazolato kappaN}(dicyanamido-kappaN)(methanol-kappaO)copper(II). AB - In the title compound, [Cu(C(19)H(12)N(5))(C(2)N(3))(CH(3)OH)], the Cu(II) atom is coordinated by three N atoms from an anionic 2,6-bis-(1H-benzimidazol-2 yl)pyridine (bbp) ligand, an O atom from a methanol mol-ecule and one N atom from a dicyanamide anion. The crystal structure is stabilized by O-H?N and N-H?N hydrogen bonds, forming a three-dimensional network. PMID- 21522581 TI - Dibromidobis[1-(2,4,6-trimethyl-phen-yl)-1,4,5,6-tetra-hydro-pyrimidine kappaN]palladium(II). AB - In the title complex, [PdBr(2)(C(13)H(18)N(2))(2)], the Pd(II) atom is situated on an inversion center. The tetra-hydro-pyrimidine group of the N-(2,4,6 trimethyl-phen-yl)-1,4,5,6-tetra-hydro-pyrimidine ligand is twisted from the square (PdN(2)Br(2)) coordination plane with a C-N-Pd-Br torsion angle of 81.8 (4) degrees ; this is different from the angle of 43.47 (14) degrees , reported in a closely related structure, dichloridobis(1-methyl-1,4,5,6-tetra-hydro pyrimidine)-palladium(II). PMID- 21522582 TI - (eta-Benzene){2-[2-(tert-butyl-sulfan-yl)phenyl]pyridine-kappaN,S}chlorido ruthenium(II) hexa-fluorido-phosphate. AB - In the title compound, [RuCl(C(6)H(6))(C(15)H(17)NS)]PF(6), the cation adopts a three-legged piano-stool structure around the Ru(II) atom with an eta(6)-benzene ligand, a chloride ligand and a 2-[2-(tert-butyl-sulfan-yl)phen-yl]pyridine (btppy) ligand. The btppy ligand acts as a N,S-bidentate ligand, forming a six membered ring, which has an envelope conformation. The S-Ru-N bite angle is 86.76 (9) degrees , and the dihedral angle between the pyridine and benzene rings in btppy is 39.8 (2) degrees . The unit cell contains two pairs of racemic diastereomers with (S(Ru),S(S)) and (R(Ru),R(S)) configurations, in which the tert-butyl group on the coordin-ated S atom is distant from the eta(6)-benzene ligand. PMID- 21522583 TI - [MU-Bis(diphenyl-phosphan-yl)acetonitrile-kappaP:P]bis-[chloridogold(I)]. AB - The title complex, [Au(2)Cl(2)(C(26)H(21)NP(2))], has an intra-molecular Au?Au inter-action of 3.1669 (4) A, but no inter-molecular Au?Au inter-actions in the solid state. The Cl-Au-P bond angle of 176.84 (7) degrees is slightly distorted from linearity. The P-C bond length to the phenyl group is shorter [1.810 (7) A] than the P-C bond length [1.876 (7) A] to the bridging carbon, indicative of the flexibility of the bidentate bite of the ligand. The C-C N fragment is essentially linear at 179.5 (9) degrees and the C N bond length of 1.125 (11) A indicates predominantly triple-bond character. In the crystal packing, there are no hydrogen-bonding or aurophilic inter-actions between the mol-ecules. PMID- 21522584 TI - Poly[bis-(MU(2)-4,4'-bipyridine)-bis-(3-nitro-benzoato)nickel(II)]. AB - The crystal structure of the title complex, [Ni(C(7)H(4)NO(4))(2)(C(10)H(8)N(2))(2)](n), exhibits a two-dimensional network, which is built up from slightly distorted NiN(4)O(2) polyhedra (2 symmetry), bipyridine ligands, and carboxyl-ate anions. The Ni(II) atoms are six-coordinated by two O atoms of two monodentate carboxyl-ate anions and four N atoms from bipyridine ligands and are connected into layers by the 4,4'-bipyridine ligands. PMID- 21522585 TI - [Malonato(2-)-kappaO,O']bis-(1,10-phenanthroline-kappaN,N')zinc(II) penta hydrate. AB - In the title complex, [Zn(C(3)H(2)O(4))(C(12)H(8)N(2))(2)].5H(2)O, the Zn(II) cation displays a distorted octa-hedral geometry, being coordinated by four N atoms from two 1,10-phenanthroline ligands and two O atoms from different carboxyl-ate groups of the chelating malonate dianion. In the crystal, the complexes are linked into a three-dimensional supra-molecular network by both O H?O hydrogen-bonding inter-actions between water mol-ecules and the uncoordinated carboxyl-ate O atoms of neighboring mol-ecules, and aromatic pi-pi stacking inter actions between neighboring phenanthroline rings with centroid-centroid distances of 3.4654 (17) and 3.697 (2) A. PMID- 21522586 TI - [2,9-Bis(3,5-dimethyl-1H-pyrazol-1-yl-kappaN)-1,10-phenanthroline-kappaN,N']bis (thio-cyanato-kappaN)cadmium(II). AB - In the title complex, [Cd(NCS)(2)(C(22)H(20)N(6))], the Cd(II) ion is in a CdN(6) coordination geometry which is inter-mediate between octa-hedral and trigonal prismatic. The dihedral angles formed between the mean planes of the pyrazole rings and the phenanthroline system are 15.74 (15) and 16.30 (13) degrees . In the crystal, there is a pi-pi stacking inter-action involving two symmetry related pyrazole rings, with a centroid-centroid distance of 3.664 (3) A. In addition, there is a relatively short inter-molecular contact between C atoms [C?C = 3.399 (6) A] involving symmetry-related pyridine rings along the a axis. PMID- 21522587 TI - Diaqua-bis-(2-oxo-2H-chromene-3-carboxyl-ato)zinc(II). AB - In the title compound, [Zn(C(10)H(5)O(4))(2)(H(2)O)(2)], the Zn(II) atom lies on a crystallographic inversion center and is six-coordinated by two O atoms from water mol-ecules in the axial positions and four O atoms from two deprotonated coumarin-3-carb-oxy-late ligands in the equatorial plane, forming a slightly distorted octa-hedral coordination geometry. O-H?O hydrogen-bonding inter-actions involving the water mol-ecules form infinite chains parallel to [010]. PMID- 21522588 TI - Bis[1-(3-cyano-benz-yl)pyridinium] bis-(1,2-dicyano-ethene-1,2-dithiol ato)nickelate(II). AB - In the ionic title complex, (C(13)H(11)N(2))(2)[Ni(C(4)N(2)S(2))(2)], the Ni(II) ion is located on an inversion centre so the asymmetric unit contains one-half [Ni(mnt)(2)](2-) dianion (mnt(2-) is maleonitrile-dithiolate) and one 1-(3-cyano benz-yl)pyridinium cation ([CNBzPy](+)). The Ni(II) ion in the [Ni(mnt)(2)](2-) anion is coordinated by four S atoms of two mnt(2-) ligands, and exhibits square planar coordination geometry. In the [CNBzPy](+) cation, the benzene and pyridine rings are twisted with respect to the C/C/N plane incorporating the methyl-ene C atom that links them. The crystal structure is stabilized by Coulombic inter actions. PMID- 21522589 TI - catena-Poly[[bis-(dimethyl-ammonium) [cadmate(II)-bis-(MU-1,1':4',1''-terphenyl 3,3''-dicarboxyl-ato)]] dimethyl-formamide disolvate]. AB - In the title compound, {(C(2)H(8)N)(2)[Cd(C(20)H(12)O(4))(2)].2C(3)H(7)NO}(n), the Cd(II) ion lies on a twofold rotation axis and is in a distorted octa-hedral CdO(6) environment, defined by four O atoms of two MU(2)-coordinated 1,1':4',1'' terphenyl-3,3''-dicarboxyl-ate (DCT) ligands and two O atoms of two MU(1) coordinated DCT ligands. Both types of DCT ligands act as bridging, forming a one dimensional polymeric structure propagating parallel to [10]. PMID- 21522590 TI - Chlorido(eta-1,5-cyclo-octa-diene)[(penta-fluoro-eth-yl)diphenyl phosphane]iridium(I). AB - The title structure,[IrCl(C(8)H(12))(C(14)H(10)F(5)P)], reveals that (C(2)F(5))PPh(2) (penta-fluoro-ethyl-diphenyl-phosphane or pfepp) disrupts the iridium dimer [(cod)IrCl](2) (cod = cyclo-octa-1,5-diene) by rupturing the bridging chloride ligands and binding in the open coordination site to form (cod)Ir(pfepp)Cl with the Ir(I) atom in a distorted square-planar coordination environment. The structure deviates very little from the Ir(I)-triphenyl phosphine analog, although a significantly (~20sigma) shorter Ir-P bond is noted for the title compound. PMID- 21522591 TI - Poly[tetra-aqua-bis-(MU(3)-benzene-1,3-di-carboxyl-ato-kappaO:O':O'')bis-(MU(2) benzene-1,3-dicarboxyl-ato-kappaO,O':O'')[MU(2)-1,4-bis-(1,2,4-triazol-1 yl)butane-kappaN:N']tetra-zinc(II)]. AB - In the crystal structure of the title compound, [Zn(4)(C(8)H(4)O(4))(4)(C(8)H(12)N(6))(H(2)O)(4)](n), one Zn(II) atom is four coordinated in a slightly distorted tetra-hedral geometry by two O atoms from benzene-1,3-dicarboxyl-ate (BDC) ligands, one N atom from a 1,4-bis-(1,2,4 triazol-1-yl)butane (BTB) ligand and one water mol-ecule, while a second Zn(II) atom is five-coordinated in a distorted square-pyramidal geometry bridged by four O atoms from BDC ligands and one water mol-ecule. The Zn(II) atoms are connected by the benzene-1,3-dicarboxyl-ate anions and the nitro-gen ligand into layers parallel to the ac plane. The asymmetric unit consits of two crystallographically independent Zn(II) cations, two BDC anions and two water mol-ecules in general positions, as well as one-half of the BTB ligand that is completed by inversion symmetry. PMID- 21522592 TI - (4-Chloro-benzoato)tris-(2-methyl-2-phenyl-prop-yl)tin(IV). AB - The title compound, [Sn(C(10)H(13))(3)(C(7)H(4)ClO(2))], crystallized with two independent mol-ecules per asymmetric unit. In each mol-ecule, the Sn(IV) atom is four-coordinate and possesses a distorted tetra-hedral geometry. One of the phenyl rings of one molecule is equally disordered over two positions. PMID- 21522593 TI - catena-Poly[tris-(MU(2)-1H-benzimidazole-5-carboxyl-ato)europium(III)]. AB - In the title one-dimensional coordination polymer, [Eu(C(8)H(5)N(2)O(2))(3)](n), the Eu(III) ion is eight-coordinated by the carboxyl-ate O atoms of six ligands in a distorted monocapped penta-gonal-bipyramidal geometry. The ligands link Eu(III) ions, forming helical chains parallel to the c axis, with Eu?Eu separations of 4.0678 (11) A. The chains are further inter-connected by N-H?N hydrogen bonds into a three-dimensional supra-molecular network. The crystal studied was a racemic twin, as suggested by the Flack parameter of 0.367 (14). PMID- 21522594 TI - Dibromido(2,2'-dimethyl-4,4'-bi-1,3-thia-zole-kappaN,N')mercury(II). AB - The asymmetric unit of the title compound, [HgBr(2)(C(8)H(8)N(2)S(2))], contains two crystallographically independent mol-ecules. The Hg(II) atoms are four coordinated in a distorted tetra-hedral geometry by two N atoms from a 2,2' dimethyl-4,4'-bi-1,3-thia-zole ligand and two Br atoms. In the crystal structure, inter-molecular C-H?Br hydrogen bonds and pi-pi contacts between the thia-zole rings [centroid-centroid distances = 3.670 (3) and 3.614 (2) A] stabilize the structure. PMID- 21522595 TI - Bis(tri-2-pyridyl-amine)-nickel(II) bis-(perchlorate). AB - In the title compound, [Ni(C(15)H(12)N(4))(2)](ClO(4))(2), the Ni(II) atom lies on an inversion center and is octa-hedrally coordinated by the N atoms of two tridentate tri-2-pyridyl-amine ligands. The two perchlorate anions are disordered over two sites with a refined occupancy ratio of 0.528 (19):0.472 (19). PMID- 21522596 TI - Chlorido[1-(4,5-dihydro-1,3-thia-zol-2-yl-kappaN)ethanone thio-semicarbazonato kappaN,S]nickel(II). AB - In the title compound, [Ni(C(6)H(9)N(4)S(2))Cl], the Ni atom is in a slightly distorted square-planar environment coordinated by a Cl atom and a deprotonated thio-semicarbazone ligand via its thia-zoline N, azomethine N and thiol-ate S atoms. Short inter-molecular N-H?Cl and C-H?S contacts are present in the crystal structure. PMID- 21522597 TI - Bis(MU-2-phenyl-quinoline-4-carboxyl-ato)-kappaO,O':O;kappaO:O,O'-bis-[(2,2' bipyridine-kappaN,N')(2-phenyl-quinoline-4-carboxyl-ato-kappaO,O')cadmium(II)]. AB - The neutral binuclear title complex, [Cd(2)(C(16)H(10)NO(2))(4)(C(10)H(8)N(2))(2)], is centrosymmetric, with the inversion center generating the central (MU-O)(2)Cd(2) bridge. The Cd(II) ion is in a strongly distorted CdN(2)O(5) penta-gonal-bipyramidal geometry, defined by two N atoms from one 2,2'-bipyridine ligand and five O atoms from three 2-phenyl quinoline-4-carboxyl-ate ligands, one monodentate, two bidentate. Weak inter molecular pi-pi inter-actions [centroid-centroid distance = 3.712 (3) A] help to establish the packing of the structure. PMID- 21522598 TI - MU-Decane-dioato-bis-[aqua-bis-(1,10-phenanthroline-kappaN,N')manganese(II)] dinitrate-sebacic acid-water (1/1/2). AB - In the title complex, [Mn(2)(C(10)H(16)O(4))(C(12)H(8)N(2))(4)(H(2)O)(2)](NO(3))(2).C(10)H(18)O(4).2H(2 O, the asymmetric unit contains one-half of the centrosymmetric dinuclear complex cation, one uncoordinated water molecule, one-half of a free sebaic acid (decanedioic acid) molecule that is also completed by inversion symmetry, and one disordered nitrate anion [occupancy ratio 0.454 (4):0.544 (6)]. The Mn(II) atoms are each octa-hedrally surrounded by four N atoms from two 1,10-phenanthroline (phen) ligands, one O atom from one carbonyl group of the bridging sebacate ligand and one O atom of a water mol-ecule. The crystal structure is stabilized by intermolecular O-H?O hydrogen bonds. PMID- 21522599 TI - {5,5'-Dimeth-oxy-2,2'-[4,5-dimethyl-o-phenyl-enebis(nitrilo-methyl idyne)]diphenolato}nickel(II). AB - In the title Schiff base complex, [Ni(C(24)H(22)N(2)O(4))], the Ni(II) atom shows a square-planar geometry. The dihedral angles between the central benzene ring and the two outer rings are 4.79 (15) and 7.54 (15) degrees . In the crystal, mol ecules are connected through inter-molecular C-H?O hydrogen bond, resulting in chains extending along the c axis. The crystal structure is further stabilized by inter-molecular pi-pi inter-actions, with centroid-centroid distances in the range 3.3760 (15)-3.7196 (17) A. PMID- 21522601 TI - {3-[Bis(2-pyridyl-methyl-kappaN)amino-kappaN]propanol}bis-(nitrato kappaO)copper(II). AB - In the title compound, [Cu(NO(3))(2)(C(15)H(19)N(3)O)], the Cu(II) ion is coordinated by the N atoms of the tetra-dentate 3-[bis-(2-pyridyl-meth-yl)amino] propanol ligand and two O atoms from two monodentate nitrate anions, resulting in a distorted square-pyramidal environment. An inter-molecular O-H?O hydrogen bonding inter-action between the free hy-droxy group of the ligand and a nitrate O atom of an adjacent complex unit, gives a chain structure which extends across the (101) planes. PMID- 21522600 TI - Bis{benzyl 3-[(1H-indol-3-yl)methyl-idene]dithio-carbazato-kappaN,S}palladium(II) N,N-dimethyl-formamide disolvate. AB - In the title compound, [Pd(C(17)H(14)N(3)S(2))(2)].2C(3)H(7)NO, the deprotonated Schiff base ligand acts as an N,S-bidentate chelate, forming a five-membered ring with the metal atom. The Pd(II) ion, located on an inversion center, is four coordinated by two of the Schiff base ligands in a square-planar geometry. In the crystal, the indolic NH groups are bonded to the dimethyl-formamide (DMF) solvent mol-ecules via an N-H?O inter-action. In addition, C-H?S inter-actions are observed. PMID- 21522602 TI - 1,10-Phenanthrolin-1-ium nitrate-aqua-bis-(4-hydroxy-benzoato-kappaO,O')(nitrato kappaO,O')(1,10-phenanthroline-kappaN,N')erbium(III)-1,10-phenanthroline-water (1/1/0.5/2). AB - In the title compound, C(12)H(9)N(2) (+).NO(3) ( ).[Er(C(7)H(5)O(3))(2)(NO(3))(C(12)H(8)N(2))(H(2)O)].0.5C(12)H(8)N(2).2H(2)O, the water-mol-ecule-coordinated Er(III) ion is chelated by one 1,10-phenanthroline (phen) ligand, two 4-hy-droxy-benzoate anions and one nitrate anion in a monocapped square-anti-prismatic coordination geometry. The uncoordinating phen mol-ecule is approximately parallel to the 1,10-phenanthrolin-1-ium (Hphen) anion [dihedral angle = 3.3 (4) degrees ]. The centroid-centroid distance of 3.801 (5) A between pyridine rings suggests the existence of pi-pi stacking. The crystal structure contains an extensive network of classical O-H?O and N-H?O and weak C H?O hydrogen bonds. C-H?pi inter-actions between phen and 4-hy-droxy-benzoate is also present in the crystal structure. In the crystal, the uncoordinating phen is equally disordered over two sites about an inversion center. PMID- 21522603 TI - Bromidotricarbon-yl[2-phenyl-5-(pyridin-2-yl-kappaN)-1,3,4-oxadiazole kappaN]rhenium(I) dichloro-methane monosolvate. AB - In the title rhenium(I) complex, [ReBr(C(13)H(9)N(3)O)(CO)(3)].CH(2)Cl(2), the dichloro-methane solvent mol-ecule is disordered over two positions with an occupancy ratio of 0.81 (15):0.19 (15). The Re(I) atom is coordinated by two N atoms from a 2-phenyl-5-(pyridin-2-yl-kappaN)-1,3,4-oxadiazole (L) ligand, three C atoms from three carbonyl groups and a Br atom in a distorted octa-hedral geometry. The three rings in L are almost coplanar (a mean plane fitted through all non-H atoms of this ligand has an r.m.s. deviation of 0.063 A), and the carbonyl ligands are coordinated in a fac arrangement. PMID- 21522604 TI - Bromidotricarbon-yl[2-(pyridin-2-yl-kappaN)-5-p-tolyl-1,3,4-oxadiazole kappaN]rhenium(I) dichloro-methane monosolvate. AB - In the title compound, [ReBr(C(14)H(11)N(3)O)(CO)(3)].CH(2)Cl(2), the coordination geometry of the Re(I) atom is a distorted ReC(3)N(2)Br octa-hedron with the carbonyl C atoms in a fac arrangement. Within the 2-(pyridin-2-yl)-5-p tolyl-1,3,4-oxadiazole ligand, the dihedral angles between the oxadiazole ring and the pyridine (py) and benzene (bz) rings are 1.7 (2) and 7.1 (2) degrees , respectively, and the dihedral angle between the py and bz rings is 5.5 (2) degrees . In the crystal, aromatic pi-pi stacking between the oxadiazole rings of adjacent mol-ecules [centroid-centroid separation = 3.465 (3) A] is seen. PMID- 21522605 TI - Bis{2-[3-(dimethyl-amino)-propyl-imino-meth-yl]-6-meth-oxy-phenolato} kappaN,N',O;kappaN,O-zinc(II) dihydrate. AB - In the title mononuclear Zn(II) complex, [Zn(C(13)H(19)N(2)O(2))(2)].2H(2)O, the Zn(II) atom is coordinated by two O atoms and three N atoms from two crystallographically different Schiff base ligands in a distorted trigonal bipyramidal environment. One O and two N atoms constitute the base of the pyramid, and one O and one N atoms occupy the apical positions. Inter-molecular O H?O and O-H?N hydrogen bonds between the lattice water mol-ecules and N/O atoms of the Schiff base ligands stabilize the conformation, whereas inter-molecular O H?O hydrogen bonds between the two lattice water mol-ecules lead to a chain structure in [001]. PMID- 21522606 TI - Bis{(E)-2-[(2-chloro-3-pyrid-yl)imino-meth-yl]-6-meth-oxy-phenolato kappaN,O}copper(II). AB - In the title mononuclear copper(II) complex, [Cu(C(13)H(10)ClN(2)O(2))(2)], the Cu(II) ion, lying on an inversion center, is four-coordinated in a trans CuN(2)O(2) square-planar geometry by two phenolate O and two imino N atoms from two symmetry-related N,O-bidentate Schiff base ligands. The shortest Cu?Cu distance is 7.5743 (9) A. However, there are weak intra-molecular electrostatic inter-actions between the Cu atom and the Cl atom of the ligand, with a Cu?Cl distance of 3.3845 (9) A. PMID- 21522607 TI - fac-{2-[Bis(2-amino-eth-yl)amino]-ethanaminium}trichloridorhodium(III) chloride hemihydrate. AB - The crystal structure of the title compound, [Rh(C(6)H(19)N(4))Cl(3)]Cl.0.5H(2)O, is isotypic with the previously reported Ru analogue. The structure contains two crystallographically independent [Rh(Htren)Cl(3)](+) cations with a facial tridentate coordination of the monoprotonated tren ligand [tren = tris-(2-amino eth-yl)amine], leading to an overall distorted octahedral coordination environment around the Rh(III) atom. In one of the two cations, the ethyl-ene groups of the two chelate rings as well as the non-coordinating ethyl-ammonium group are disordered over two sets of sites [0.579 (3):0.421 (3) occupancy ratio]. A series of N-H?Cl and O-H?Cl hydrogen bonds stabilizes the structure. PMID- 21522608 TI - Bis[1,3-bis-(2,4,6-trimethyl-phen-yl)-2,3-dihydro-1H-imidazol-2-yl-idene]dinitros yl(tetra-hydro-borato-kappaH,H')tungsten(0). AB - In the title paramagnetic 19-electron neutral complex, [W(BH(4))(C(21)H(24)N(2))(2)(NO)(2)], the W(0) atom is coordinated by two 1,3-bis (2,4,6-trimethyl-phen-yl)imidazol-2-yl-idene (IMes) carbene ligands, two NO groups and two H atoms of an eta(2)-tetra-hydro-borate ligand. Depending on the number of coordination sites (n) assigned to the BH(4) (-) ligand, the coordination geometry of the W atom may either be described as approximately trigonal-bipyramidal (n = 1) or as very distorted octa-hedral with the bridging H atoms filling two coordination positions (n = 2). In the latter case, the coplanar NO groups and bridging H atoms (r.m.s. deviation = 0.032 A) form one octa-hedral plane, with mutually trans-oriented carbene ligands. In the crystal, mol-ecules are connected via C-H?O inter-actions. PMID- 21522609 TI - Bis{N,N-bis-[(diphenyl-phosphan-yl)meth-yl]aniline-kappaP,P'}copper(I) tetra fluoridoborate. AB - In the cation of the title compound, [Cu(C(32)H(29)NP(2))(2)]BF(4), the Cu(I) atom is four-coordinated in a distorted tetra-hedral geometry by four P atoms from two N,N-bis-[(diphenyl-phosphan-yl)meth-yl]aniline ligands. In the crystal, the cations are linked by C-H?pi inter-actions, forming chains along the a axis. Intra-molecular C-H?N and inter-molecular C-H?F hydrogen bonds are also observed. PMID- 21522610 TI - Potassium bis-[bis-(1-benzyl-3-methyl-imidazolium)silver(I)] tris-(hexa fluoridophosphate). AB - In the title compound, K[Ag(C(11)H(12)N(2))(2)](2)(PF(6))(3), the 12-coordinate potassium cation lies on a crystallographic twofold axis and one of the hexa fluoro-phosphate anions is generated by symmetry. In the complex cation, the Ag(I) ion is coordinated by two C atoms; the two imidazolium rings are orientated at a dihedral angle of 8.14 (14) degrees . In the 1-benzyl-3-methyl-imidazolium units, the dihedral angles between imidazolium and phenyl rings are 80.47 (15) and 76.53 (14) degrees . The F atoms of the general-position hexa-fluoro phosphate anion are disordered over two sets of sites in a 0.767 (17):0.233 (17) ratio. In the crystal, the hexa-fluoro-phosphate anions link the cations into three-dimensional networks via inter-molecular C-H?F hydrogen bonds and are further consolidated by pi-pi stacking [centroid-centroid distances = 3.5518 (15) A] inter-actions. PMID- 21522611 TI - Dichlorido(eta-p-cymene)(4-fluoro-aniline-kappaN)ruthenium(II). AB - The title compound, [RuCl(2)(C(10)H(14))(C(6)H(6)FN)], a pseudo-octa-hedral d(6) complex, has the expected piano-stool geometry around the Ru(II) atom. The fluoro aniline ring forms a dihedral angle of 19.3 (2) degrees with the p-cymene ring. In the crystal, two mol-ecules form an inversion dimer via a pair of N-H?Cl hydrogen bonds. Weak inter-molecular C-H?Cl inter-actions involving the p-cymene ring consolidate the crystal packing. PMID- 21522612 TI - (5SR,10SR,15SR)-Trimethyl 5H,10H,15H-diindeno-[1,2-a:1',2'-c]fluorene-5,10,15 tricarboxyl-ate 0.167-hydrate. AB - The title compound, C(33)H(24)O(6).0.17H(2)O, which is commonly known as (SR,SR,SR)-trimethyl 1,10,19-truxentricarboxyl-ate, crystallizes as a hydrate with the water mol-ecule encapsulated between three ester groups by O-H?O hydrogen bonding to two of them. The water mol-ecule site is not fully occupied in the crystal studied, with a refined site occupancy of 0.167 (5). The 27-atom ring system is approximately planar, with a maximum deviation of 0.148 (1) A, and the three ester substituents are all on the same side of this plane. PMID- 21522613 TI - 2-Imi-niumyl-1,3-diazepane-4-carboxyl-ate. AB - The title compound, C(6)H(11)N(3)O(2), is a cyclized derivative of l-arginine and the mol-ecule is a zwitterion with the positive and negative charge residing in the guanidinium and carboxyl-ate groups, respectively. The conformation of 1,3 diazepane ring is close to a twisted chair. One intra-molecular and three inter molecular N-H?O hydrogen bonds stabilize the mol-ecular conformation and the crystal structure, respectively. PMID- 21522614 TI - 2-Meth-oxy-4-[(4-methyl-piperazin-1-yl)imino-meth-yl]phenol. AB - The title compound, C(13)H(19)N(3)O(2), was obtained by the direct solvent-free reaction of 4-hy-droxy-3-meth-oxy-benzaldehyde with 1-amino-4-methyl-piperazine. The piperazine ring adopts a chair conformation. In the crystal, strong inter molecular O-H?N and weak inter-molecular C-H?O and C-H?N hydrogen bonds help to establish the packing. PMID- 21522615 TI - 2,6-Diethyl-anilinium dihydrogen phosphate-phospho-ric acid (1/1). AB - In the crystal structure of the title salt, C(10)H(16)N(+).H(2)PO(4) ( ).H(3)PO(4), the H(2)PO(4) (-) and H(3)PO(4) components are connected into infinite chains extending along the b-axis direction by way of O-H?O links. These chains are also linked through O-H?O hydrogen bonds thus building up a supra molecular two-dimensional framework extending parallel to (001). The organic cations cross-link the anionic layers by way of multiple N-H?O inter-actions, leading to a cohesive network. PMID- 21522617 TI - N-(3,4-Dichloro-phen-yl)-4-methyl-benzene-sulfonamide. AB - In the title compound, C(13)H(11)Cl(2)NO(2)S, the conformation of the N-C bond in the C-SO(2)-NH-C segment has gauche torsions with respect to the S=O bonds. The mol-ecule is bent at the S atom with a C-SO(2)-NH-C torsion angle of 64.3 (4) degrees . Furthermore, the conformation of the N-H bond and the meta-chloro group in the adjacent benzene ring are anti to each other. The two benzene rings are tilted relative to each other by 82.5 (1) degrees . In the crystal, mol-ecules are linked by pairs of N-H?O(S) hydrogen bonds, forming inversion dimers. PMID- 21522616 TI - 2,9-Dimethyl-7-phenyl-N-(4-methyl-phen-yl)dibenzo[b,h][1,6]naphthyridin-6-amine. AB - The title compound, C(31)H(25)N(3), was synthesized from 6,4',4''-trimethyl-2,4 bis-(N-phenyl-amino)-quinoline and is the first structural example containing a phenyl and phenyl-amino fragment attached to a fused dibenzo[1,6]naphthyridine moiety. The fused tetra-cyclic ring system is essentially planar [r.m.s. deviation = 0.08 (3) A]. The phenyl ring and the phenyl-amino group are inclined by 82.68 (6) and 35.31 (5) degrees , respectively, to the mean plane of the fused tetra-cyclic ring system. A weak intra-molecular N-H?pi(arene) inter-action may in part influence the conformation of the mol-ecule. In the crystal, mol-ecules are linked by weak inter-molecular C-H?N hydrogen bonds into centrosymmetric dimers. Additional stabilization is provided by weak C-H?pi and pi-pi stacking inter-actions [centroid-centroid distances = 3.834 (2) and 3.898 (1) A]. PMID- 21522618 TI - (E)-4-[2-(4-Eth-oxy-phen-yl)ethen-yl]-1-methyl-pyridinium 4-bromo-benzene sulfonate methanol hemisolvate. AB - In the title compound, C(16)H(18)NO(+).C(6)H(4)BrO(3)S(-).0.5CH(3)OH, the cation exists in the E configuration and the whole mol-ecule of the cation, except for the O atom of the eth-oxy group, is disordered with a site-occupancy ratio of 0.695 (5):0.305 (5). The cation is disordered in such a way that the ethenyl units of the major and minor components are related by 180 degrees around the long mol-ecular axis. In the major component, the cation is almost planar, the dihedral angle between the pyridinium and benzene rings being 0.8 (3) degrees , whereas in the minor component, the dihedral angle between the two aromatic rings is 4.2 (6) degrees . In the crystal, the cations are stacked in an anti-parallel manner along the a axis, while the anions and methanol mol-ecules are linked through O-H?O hydrogen bonds and Br?O short contacts [3.0248 (13) A] into a tape along the same direction. The three components are further linked by weak C-H?O, C-H?Br and C-H?pi inter-actions. PMID- 21522619 TI - Etoricoxibium picrate. AB - IN THE CATION OF THE TITLE SALT (SYSTEMATIC NAME: 5-{5-chloro-3-[4-(methyl-sulfon yl)phen-yl]-2-pyrid-yl}-2-methyl-pyridinium 2,4,6-trinitro-phenolate), C(18)H(16)ClN(2)O(2)S(+).C(6)H(2)N(3)O(7) (-), the mean planes of the two pyridine rings in the bipyridine unit are twisted by 33.9 (2) degrees with respect to each other. The dihedral angles between the mean planes of the sulfonyl-benzene ring and the chloro-pyridine and methyl-pyridine rings are 51.2 (0) and 49.3 (9) degrees , respectively. The picrate anion inter-acts with the protonated N atom through a bifurcated N-H?(O,O) hydrogen bond, forming an R(1) (2)(6) ring motif with the N atom from the methyl-pyridine group of an adjacent cation. N-H?O hydrogen bonds, weak C-H?O and pi-pi stacking inter-actions [centroid-centroid distances = 3.8192 (9)and 3.6749 (9)] occur in the crystal packing, creating a two-dimensional network structure along [110]. PMID- 21522620 TI - [4-(1-Benzofuran-2-yl)phen-yl]diphenyl-amine. AB - The asymmetric unit of the title compound, C(26)H(19)NO, contains two mol-ecules. The dihedral angles between the benzofuran and benzene rings are 5.09 (8), 59.02 (8) and 67.74 (8) degrees in one mol-ecule and 18.70 (8), 52.78 (8) and 41.74 (8) degrees in the other. Weak inter-molecular C-H?pi inter-actions help to stabilize the molecular structure . PMID- 21522621 TI - 4-Hy-droxy-pyridinium-3-sulfonate. AB - The reaction of 4-hy-droxy-pyridine and oleum produces 4-hy-droxy-pyridinium-3 sulfonate, C(5)H(5)NO(4)S, which shows delocalized bonds in the six-membered ring. In the crystal, adjacent zwitterions are linked by N-H?O and O-H?O hydrogen bonds into a layer motif. The crystal studied was a racemic twin. PMID- 21522622 TI - (Z)-2-[(2,4-Dimethyl-phen-yl)imino]-1,3-thia-zinan-4-one. AB - In the title compound, C(12)H(14)N(2)OS, the 1,3-thia-zinane ring displays a screw-boat conformation. In the crystal, pairs of centrosymmetrically related mol ecules are linked by pairs of N-H?O hydrogen bonds into dimers. C-H?pi inter actions occur between adjacent dimers. PMID- 21522623 TI - 1-(2-Bromo-2-de-oxy-beta-d-xylofuranos-yl)uracil. AB - In the title compound, C(9)H(11)BrN(2)O(5), the ribofuran-ose ring has a C2-exo, C3-endo twist configuration and is attached to the uracil unit via a beta-N(1) glycosidic bond. The crystal structure is stabilized by two inter-molecular O-H?O inter-actions and one inter-molecular N-H?O inter-action. PMID- 21522624 TI - 1-(2-Bromobenzoyl)-6,7-(methylene-dioxy)isoquinoline. AB - In the title mol-ecule, C(17)H(10)BrNO(3), the mean planes of tricycle and bromo phenyl fragments form a dihedral angle of 75.5 (1) degrees . In the crystal, pi pi inter-actions [centroid-centroid distances = 3.556 (2) and 3.898 (8) A] between the isoquinoline systems link mol-ecules into stacks parallel to the a axis. The crystal packing also exibits weak inter-molecular C-H?O hydrogen bonds. PMID- 21522625 TI - N-(9,11-Dimeth-oxy-4-oxo-2,3,4,6,7,11b-hexa-hydro-1H-pyrido[2,1-a]isoquinolin-3 yl)benzamide. AB - The title schulzeine derivative, C(22)H(24)N(2)O(4), crystallizes with two crystallographically independent mol-ecules of almost identical conformation in the asymmetric unit. The tricyclic core of schulzeine has a fused-three-ring system comprising the tetra-hydro-isoquinoline and delta-lactam moieties. In both mol-ecules, the pyridine ring adopts a twisted-boat conformation, whereas the lactam ring is in a boat conformation. The two meth-oxy groups are slightly twisted from the attached benzene ring [C-O-C-C torsion angles = -21.3 (2) and 20.5 (2) degrees in mol-ecule A, and -6.3 (2) and -16.2 (2) degrees in mol ecule B] and the benzamide moiety is in a (-)-synclinal conformation with respect to the lactam ring. In the crystal, mol-ecules are linked into V-shaped dimers by inter-molecular N-H?O hydrogen bonds and weak C-H?O inter-actions. These dimers are stacked into V-shaped columns along the a axis. Adjacent columns are further linked in an anti-parallel manner. C-H?pi inter-actions are also observed. PMID- 21522626 TI - Methyl 4-bromo-3-hy-droxy-benzoate. AB - In the title compound, C(8)H(7)BrO(3), the meth-oxy-carbonyl group is twisted at a dihedral angle of 8.06 (4) degrees with respect to the benzene ring. In the crystal, mol-ecules are connected by O-H?O hydrogen bonds into helical chains running along the b axis. PMID- 21522627 TI - (3E,5E)-3,5-Bis(4-hy-droxy-benzyl-idene)oxan-4-one. AB - In the title compound, C(19)H(16)O(4), there are two 4-hy-droxy-benzyl substituents on the oxan-4-one (tetra-hydro-pyran-4-one) ring, which exhibits an envelope conformation. The dihedral angles between pyran-one ring and the two benzene rings are 26.69 (9) and 36.01 (9) degrees while the benzene rings make a dihedral angle of 20.88 (10) degrees . In the crystal, mol-ecules are linked by inter-molecular O-H?O hydrogen bonds into a supra-molecular three-dimensional twofold inter-penetrating hydrogen-bonded network. PMID- 21522628 TI - N,N'-Diphenyl-but-2-enediamide. AB - In the title compound, C(16)H(14)N(2)O(2), the conformations of the N-H and C=O bonds in the C-NH-CO-CH =CH-CO-NH-C segment are anti to each other. The two C=O bonds are also anti to each other. The two phenyl rings make an inter-planar angle of 41.2 (1) degrees . An intra-molecular N-H?O hydrogen bond occurs. In the crystal, inter-molecular N-H?O hydrogen bonding links the mol-ecules into infinite chains along the a axis. PMID- 21522629 TI - Bis(2-phenyl-biguanidium) adipate tetra-hydrate. AB - In the title salt, 2C(8)H(12)N(5) (+).C(6)H(8)O(4) (2-).4H(2)O, the anion is located on a centre of symmetry. The observed supra-molecular network of the crystal structure is produced by ten different hydrogen bonds of the N-H?N, N-H?O and O-H?O types. One additional O-H group is not connected to an acceptor site. PMID- 21522630 TI - (Z)-3-Chloro-methyl-idene-5,6-dimeth-oxy-2-methyl-2,3-dihydro-1,2-benzothia-zole 1,1-dioxide. AB - The title compound, C(11)H(12)ClNO(4)S, adopts a Z configuration about the C=C double bond. The benzisothia-zole system is essentially planar [maximum deviation of 0.235 (2) A for the S atom]. In the crystal, the mol-ecules stack parallel to each other in the b-axis direction, with inter-planar spacings for the benzene and thia-zole rings ranging from 3.402 (2) to 3.702 (2) A. PMID- 21522631 TI - N-(2,4,6-Trimethyl-phen-yl)formamide. AB - The title compound, C(10)H(13)NO, was obtained as the unexpected, almost exclusive, product in the attempted synthesis of a manganese(I)-N-heterocyclic carbene (NHC) complex. The dihedral angle between the planes of the formamide moiety and the aryl ring is 68.06 (10) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, forming infinite chains along the c axis. PMID- 21522632 TI - 3-(2-Fluoro-phen-oxy)propanoic acid. AB - In the title compound, C(9)H(9)FO(3), the dihedral angle between the carboxyl group and the benzene ring is 79.4 (3) degrees . In the crystal, mol-ecules form centrosymmetric dimers through pairs of classical O-H?O hydrogen bonds. These are further linked by weaker C-H?O inter-actions, forming a three-dimensional network. PMID- 21522633 TI - 4-Carbamoylpiperidinium 5-nitro-salicylate. AB - In the crystal structure of the title compound, C(6)H(13)N(2)O(+).C(7)H(4)NO(5) ( ), the isonipecotamide cations and the 5-nitro-salicylate anions form hydrogen bonded chain substructures through head-to-tail piperidinium-carboxyl-ate N-H?O hydrogen bonds and through centrosymmetric cyclic head-to-head amide-amide hydrogen-bonding associations [graph set R(2) (2)(8)]. These chains are cross linked by amide-carboxyl-ate N-H?O and piperidinium-nitro N-H?O associations, giving a sheet structure. PMID- 21522634 TI - Diethyl indolizine-1,3-dicarboxyl-ate. AB - The title compound, C(14)H(15)NO(4), was prepared by a 1,3-dipolar cyclo-addition from N-(eth-oxy-carbonyl-methy)pyridinium bromide and ethyl acrylate. The -CO(2) side chains form dihedral angles of 0.2 (3) and 2.4 (3) degrees with respect to the ring system. In the crystal, two neighbouring mol-ecules form a dimer through weak C-H?O interactions. The dimers form a three-dimensional structure via further weak C-H?O inter-actions. PMID- 21522635 TI - 2-[3-((Z)-2-{4-[Bis(2-chloro-eth-yl)amino]-phen-yl}ethen-yl)-5,5-dimethyl-cyclo hex-2-en-1-yl-idene]propane-dinitrile. AB - The highly conjugated title compound, C(23)H(25)Cl(2)N(3), is nearly planar (the mean deviation from the plane being 0.049 A), except for the -C(CH(3))(2) group on the cyclo-hexene ring and the two CH(2)Cl groups. The cyclo-hexene ring has an envelope configuration. In the crystal, the packing is stabilized by C-H?Cl inter actions and C-H?pi inter-actions involving the benzene ring. PMID- 21522636 TI - N-(4-{4-[2-(Trifluoro-meth-oxy)phen-yl]piperazin-1-yl}but-yl)thio-phene-2 carboxamide dihydrate. AB - In the title compound, C(20)H(24)F(3)N(3)O(2)S.2H(2)O, a dopamine D3 ligand, the piperazine ring adopts a chair conformation while the piperazine and benzene rings form a dihedral angle of 47.71 (6) degrees . In the crystal, mol-ecules are linked by inter-molecular N-H?O and O-H?O hydrogen bonds. In the mol-ecular structure, the F atoms of the trifluoro-methyl group are disordered over two sites with occupancies of 0.69 (11) and 0.31 (11). PMID- 21522637 TI - Acridine-benzene-1,3,5-tricarb-oxy-lic acid (3/1). AB - In the title adduct, 3C(13)H(9)N.C(9)H(6)O(6) or (acr)(3)(btc), associ-ations of one btc and three acr molecules linked by O-H?N hydrogen bonds occur. C-H?O interactions also occur, resulting in a cyclic hydrogen-bonded synthon R(2) (1)(6). The acr mol-ecules and the btc mol-ecules also form slipped or offset pi pi stacking inter-actions [centroid-centroid distances of 3.5212 (17) A for btc rings and 3.703 (2) and 3.731 (2) A for acr rings]. Together these inter-actions lead to a three-dimensional network. PMID- 21522638 TI - Ethyl 1-(2,6-difluoro-benz-yl)-1H-1,2,3-triazole-4-carboxyl-ate. AB - In the title compound, C(12)H(11)F(2)N(3)O(2), the dihedral angle between the triazole and phenyl rings is 73.74 (9) degrees . In the crystal, mol-ecules are linked into chains along [010] via weak C-H?O and C-H?N hydrogen bonds. PMID- 21522639 TI - 4-[(3-Benzamido-methyl-6-phenyl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thia diazin-7-yl)carbon-yl]-3-phenyl-1,2,3-oxadiazol-3-ium-5-olate 0.06-hydrate. AB - The asymmetric unit of the title compound, C(27)H(21)N(7)O(4)S.0.06H(2)O, contains four syndone mol-ecules and a water mol-ecule with a site occupancy of 0.25. In two of the syndone mol-ecules, three atoms in a terminal phenyl ring are disordered over two sets of sites, with occupancy ratios of 0.500 (18):0.500 (18) and 0.512 (17):0.488 (17). The dihedral angles between terminal phenyl rings for the syndone mol-ecules are 23.3 (4), 45.57 (16), 68.46 (16) and 56.5 (3) degrees . In the crystal, mol-ecules are connected via N-H?N, N-H?O, O-H?O, O-H?N and C H?O hydrogen bonds, forming a three-dimensional network. PMID- 21522640 TI - (S)-Methyl 2-{(S)-2-[bis-(4-meth-oxy-phen-yl)methyl-idene-amino]-3-hy-droxy propanamido}-3-methyl-butano-ate. AB - The title compound, C(24)H(30)N(2)O(6), a Schiff base, adopts an extended conformation in which the meth-oxy groups are essentially coplanar with the aromatic ring to which they are bonded (mean planes fitted through the non-H atoms of each methoxyphenyl group have r.m.s. deviations of 0.078 and 0.044 A) and the angle between mean planes fitted through the aromatic rings is 87.57 (10) degrees . An intra-molecular N-H?N hydrogen bond keeps the imine and amide groups essentially coplanar. A mean plane fitted through these groups has an r.m.s. deviation of 0.0545 A. Additional O-H?O hydrogen bonding parallel with the a axis links the mol-ecules into a hydrogen-bonded chain in the crystal. C-H?O and C H?pi inter-actions are found within the crystal packing. The compound has been assigned the S,S configuration on the basis of the chemical synthesis, which used pure homotopic l-amino acids, and we have no reason to believe that the compound has epimerized. PMID- 21522641 TI - 2-((Z)-{3-[(Z)-(2-Hy-droxy-5-methyl-benzyl-idene)amino]-2,2-dimethyl-prop yl}imino-meth-yl)-4-methyl-phenol. AB - In the title compound, C(21)H(26)N(2)O(2), the dihedral angle between the two benzene rings is 73.47 (16) degrees . Strong intra-molecular O-H?N hydrogen bonds generate S(6) ring motifs. The substituted benzene rings are twisted around the central quaternary C atom in opposite directions, making a vault geometry. PMID- 21522642 TI - 2-Chloro-N'-[4-(dimethyl-amino)-benzyl-idene]-N-[4-(3-methyl-3-phenyl-cyclo-but yl)-1,3-thia-zol-2-yl]acetohydrazide. AB - The mol-ecular conformation of the title compound, C(25)H(27)ClN(4)OS, is stabilized by an intra-molecular benzyl-idine C-H?N(thia-zole) hydrogen bond. The thiazole ring makes dihedral angles of 12.0 (3) and 20.4 (2) degrees , respectively, with the phenyl and benzene rings, while the phenyl and benzene rings make a dihedral angle of 22.6 (2) degrees . The crystal packing involves weak inter-molecular thia-zole C-H?O(carbon-yl) and methyl C-H?pi hydrogen bonding associations. PMID- 21522643 TI - 3-Benzyl-2-sulfanyl-idene-1,3-thia-zolidin-4-one. AB - In the title compound, C(10)H(9)NOS(2), the five-membered heterocyclic ring and the benzyl moiety are oriented at a dihedral angle of 77.25 (4) degrees . In the crystal, infinite polymeric C(6) chains extending along [001] are formed due to C H?O hydrogen bonds. C-H?pi inter-actions link the chains, building up a three dimensional network. PMID- 21522645 TI - 3,8-Dimethyl-4,7-diaza-deca-3,7-diene-2,9-dione dioxime. AB - The complete mol-ecule of the title compound, C(10)H(18)N(4)O(2), is generated by a crystallographic inversion centre at the mid-point of the central C-C bond. The two oxime groups have an E configuration. In the crystal, mol-ecules are linked through inter-molecular O-H?N hydrogen bonds. PMID- 21522644 TI - 19-Benzo-yloxy-13,16-seco-ent-beyeran 13,16-lactone. AB - The title compound, C(27)H(34)O(5), a beyerane-type diterpenoid prepared by peroxidation and benzoyl-ation of isosteviol, contains a fused six-membered ring system. The O atoms of the benzoic ester and the lactone are disordered with occupancy ratios of 0.6 (4):0.4 (4) and 0.6 (2):0.4 (2), respectively. Three cyclo-hexane rings have chair conformations, whereas the remaining lactone ring adopts a half-chair conformation. PMID- 21522646 TI - 6-Meth-oxy-4-methyl-2H-chromen-2-one. AB - The whole mol-ecule of the title coumarin derivative, C(11)H(10)O(3), is approximately planar, with a maximum deviation of 0.116 (3) A from the least squares plane defined by all non-H atoms. In the crystal, adjacent mol-ecules are linked into chains along [011] via inter-molecular C-H?O hydrogen bonds. PMID- 21522647 TI - 16-[(E)-4-Bromo-benzyl-idene]-13-(4-bromo-phen-yl)-2-hy-droxy-11-methyl-1,11 diaza-penta-cyclo-[12.3.1.0.0.0]octa-deca-3(8),4,6-triene-9,15-dione. AB - In the title pyrrolidine compound, C(30)H(24)Br(2)N(2)O(3), the two fused pyrrolidine rings adopt envelope and twisted conformations, whereas the piperidine ring adopts an envelope conformation. The essentially planar 2,3 dihydro-indanone unit [maximum deviation = -0.0163 (19) A] is inclined at inter planar angles of 14.29 (9) and 61.07 (9) degrees to the two benzene rings. In the crystal, adjacent mol-ecules are linked into dimers by inter-molecular O-H?N and C-H?O hydrogen bonds. Short inter-molecular Br?Br inter-actions [3.5140 (6) A] further inter-connect these dimers into double dimeric columns along the b axis. PMID- 21522648 TI - Imidazole-imidazolium picrate monohydrate. AB - The asymmetric unit of the title compound, C(3)H(5)N(2) (+).C(6)H(2)N(3)O(7) ( ).C(3)H(4)N(2).H(2)O or H(C(3)H(4)N(2))(2) (+).C(6)H(2)N(3)O(7) (-).H(2)O, contains a diimidazolium cationic unit, one picrate anion and one mol-ecule of water. In the crystal, the components are connected by N-H?O, N-H?N and O-H?O hydrogen bonds, forming a two-dimensional network parallel to (001). In addition, weak inter-molecular C-H?O hydrogen bonds lead to the formation of a three dimensional network featuring R(5) (5)(19) rings. PMID- 21522649 TI - Ethyl 2-(1H-1,2,3-benzotriazol-1-yl)acetate. AB - The title compound, C(10)H(11)N(3)O(2), was synthesized by the reaction of 1H benzotriazole with ethyl 2-chloro-acetate in ethanol. The non-H atoms, excluding the benzotriazol-1-yl group, are almost coplanar (r.m.s. deviation of the non-H atoms = 0.0409 A). The dihedral angle formed between this plane and the benzotriazole ring is 79.12 (5) degrees In the crystal, weak inter-molecular C H?N and C-H?O inter-actions help to consolidate the three-dimensional network. PMID- 21522650 TI - (E)-2-{2-tert-Butyl-6-[2-(4-hy-droxy-phen-yl)ethen-yl]-1-propyl-1,4-dihydro pyridin-4-yl-idene}indane-1,3-dione. AB - The title compound, C(29)H(29)NO(3), the nearly planar nine-membered indanedione ring [maximum deviation = 0.027 (2) A] is located approximately parallel to its carrier pyridine ring [maximum deviation = 0.021 (2) A] with a dihedral angle of 1.8 (1) degrees between the planes. However, because of steric hindrance, the benzene ring [maximum deviation = 0.006 (2) A] is not parallel to the pyridine ring [dihedral angle = 37.29 (8) degrees ]. The mol-ecules display numerous inter molecular pi-pi inter-actions between the five- and six-membered rings, the shortest centroid-centroid distance being 3.796 (2) A. There are inter- and intra molecular O-H?O and C-H?O hydrogen bonds. PMID- 21522651 TI - N-(2,6-Dichloro-phen-yl)-4-methyl-benzene-sulfonamide. AB - In the title compound, C(13)H(11)Cl(2)NO(2)S, the mol-ecule is bent at the S atom with a C-SO(2)-NH-C torsion angle of -90.4 (2) degrees . The sulfonyl benzene and the aniline benzene rings are tilted relative to each other by 51.7 (1) degrees . In the crystal, mol-ecules are linked by N- H?O inter-actions into chains with graph-set notation C(4) along [100]. PMID- 21522652 TI - 3-{(E)-[(4-Formyl-phen-yl)iminium-yl]meth-yl}naphthalen-2-olate. AB - The title Schiff base compound, C(18)H(13)NO(2), is a zwitterion, with the naphthol hy-droxy group deprotonated and the imine N atom protonated. It adopts an E configuration about the central C=N double bond. The dihedral angle between the naphthyl ring system and the benzene ring is 1.73 (11) degrees . An intra molecular N-H?O hydrogen bond generates an S(6) ring motif. In the crystal, adjacent mol-ecules are connected by inter-molecular C-H?O hydrogen bonds, forming a supra-molecular ribbon along the b axis. PMID- 21522653 TI - 5-[(E)-(2-Hy-droxy-benzyl-idene)amino]-1H-1,3-benzimidazole-2(3H)-thione. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(14)H(11)N(3)OS. In each, the benzimidazole ring system is essentially planar, with maximum deviations of 0.010 (2) and 0.006 (2) A, and makes dihedral angles of 8.70 (9) and 13.75 (8) degrees , respectively, with the hy-droxy-substituted benzene rings. Each mol-ecule adopts an E configuration about the central C=N double bond. In the crystal, the two independent mol-ecules are connected via inter-molecular N-H?S hydrogen bonds, forming dimers. Furthermore, the dimers are connected by N-H?O hydrogen bonds into mol-ecular ribbons along the c axis. There is an intra-molecular O-H?N hydrogen bond in each mol-ecule, which generates an S(6) ring motif. PMID- 21522654 TI - 2-Chloro-N-(4-chloro-benzo-yl)benzene-sulfonamide toluene hemisolvate. AB - The unit cell of the title compound, C(13)H(9)Cl(2)NO(3)S.0.5C(7)H(8), contains two mol-ecules of 2-chloro-N-(4-chloro-benzo-yl)benzene-sulfonamide and one toluene mol-ecule, which is disordered about a centre of inversion. The dihedral angle between the two aromatic rings is 85.7 (1) degrees . In the crystal, mol ecules are linked by pairs of N-H?O(S) hydrogen bonds, forming centrosymmetric dimers. PMID- 21522655 TI - 2-[(E)-(4-Methyl-phen-yl)imino-meth-yl]-6-(morpholin-4-ylmeth-yl)phenol. AB - In the title compound, C(19)H(22)N(2)O(2), the morpholine ring adopts an almost perfect normal chair conformation with puckering parameters Q(T), theta and phi of 0.5642 (18) A, 177.32 (17) and phi = 10 (4) degrees , respectively. The two benzene rings make a dihedral angle of 42.67 (8) degrees with each other. An intra-molecular O-H?N hydrogen bond helps to stabilize the mol-ecular conformation. Aromatic C-H?pi inter-actions and pi-pi stacking inter-actions [centroid-centroid distance = 3.6155 (15) A] between the benzene rings contribute to the stabilization of the crystal structure. PMID- 21522656 TI - 2,4,6-Trimethyl-pyridinium dihydrogen phosphate. AB - The asymmetric unit of the title compound, C(8)H(12)N(+).H(2)PO(4) (-), contains two H(2)PO(4) (-) anions and two 2,4,6-trimethyl-pyridinium cations. In the crystal, the anions are linked by O-H?O hydrogen bonds, forming supra-molecular chains running along the a axis; the cations are connected to the anion chains by N-H?O hydrogen bonds. Weak inter-molecular C-H?O hydrogen bonding is also present in the crystal structure. PMID- 21522657 TI - 3-Nitro-1H-1,2,4-triazole. AB - The asymmetric unit of the title compound, C(2)H(2)N(4)O(2), contains two crystallographically independent mol-ecules in which the triazole rings are essentially planar, with maximum deviations of 0.003 (1) A in both molecules. The dihedral angle between the two 1H-1,2,4-triazole rings is 56.58 (5) degrees . In the crystal, mol-ecules are linked via inter-molecular N-H?N and C-H?O hydrogen bonds, forming a supra-molecular chain along the b axis. PMID- 21522658 TI - 1-[3-Meth-oxy-4-(prop-2-yn-1-yl-oxy)phen-yl]ethanone. AB - In the title compound, C(12)H(12)O(3), the meth-oxy and prop-2-yn-yloxy groups are nearly coplanar with the attached benzene ring [C-O-C-C torsion angles = 1.2 (3) and 2.2 (3) degrees , respectively]. In the crystal, inversion dimers linked by pairs of C-H?O inter-actions occur. PMID- 21522659 TI - 4-Methyl-5-phenyl-1H-pyrazol-3(2H)-one. AB - The asymmetric unit of the title compound, C(10)H(10)N(2)O, contains two crystallographically independent mol-ecules with similar geometries, which exist in the keto form. The C=O bond lengths are 1.2878 (12) A in mol-ecule A and 1.2890 (12) A in mol-ecule B, indicating that the compound undergoes enol-to-keto tautomerism during the crystallization process. In mol-ecule A, the pyrazole ring is approximately planar [maximum deviation = 0.007 (1) A] and forms a dihedral angle of 36.67 (6) degrees with the attached phenyl ring. In mol-ecule B, the dihedral angle formed between the pyrazole ring [maximum deviation = 0.017 (1) A] and the phenyl ring is 41.19 (6) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds link neighbouring mol-ecules into dimers generating R(2) (2)(8) ring motifs. These dimers are linked into ribbons along [101] via inter-molecular N-H?O hydrogen bonds, forming R(4) (2)(10) ring motifs. PMID- 21522660 TI - rac-(1R*,2S*,3S*)-Diethyl 4-methyl-2-phenyl-6-(2-phenyl-hydrazinyl-idene)cyclo hex-4-ene-1,3-dicarboxyl-ate. AB - In the title compound, C(25)H(28)N(2)O(4), the cyclohexene ring adopts a half chair conformation and the dihedral angle between the aromatic rings is 59.44 (11) degrees . In the crystal, a weak intermolecular N-H?O hydrogen bond occurs. PMID- 21522661 TI - 3-{[5-(4-Bromo-phen-yl)imidazo[2,1-b][1,3,4]thia-diazol-2-yl]meth-yl}-1,2 benzoxazole. AB - In the title compound, C(18)H(11)BrN(4)OS, the imidazothia-diazole and benzisoxazole rings are individually planar with maximum deviations of 0.025 (3) 0.015 (4) A, respectively, and are inclined at an angle of 23.51 (7) degrees with respect to each other. The planes of the imidazothia-diazole and bromo phenyl rings are inclined at an angle of 27.34 (3) degrees . In the crystal, inter-molecular C-H?N inter-actions result in chains of mol-ecules along the b and c axes. Moreover, C-H?O inter-actions result in centrosymmetric head-to-head dimers with R(2) (2)(24) graph-set motifs. The mol-ecular packing is further stabilized by pi-pi stacking inter-actions between the imidazole rings with a shortest centroid-centroid distance of 3.492 (3) A. In addition, C-H?pi inter actions are observed in the crystal structure. PMID- 21522662 TI - (4-Chloro-phen-yl)(2,7-dimeth-oxy-8-nitro-naphthalen-1-yl)methanone. AB - In the title compound, C(19)H(14)ClNO(5), the aroyl group is attached to the naphthalene ring system with a non-coplanar configuration. The dihedral angle between naphthalene ring system and benzene ring is 70.62 (6) degrees . The nitro group is oriented in parallel with the adjacent carbonyl plane. The torsion angle of the carbonyl group and naphthalene ring is 54.68 (19) degrees (C-C-C-O), and that of nitro group and naphthalene ring is 54.26 (18) degrees (O-N-C-C). In the crystal, pi-pi inter-actions between naphthalene systems [centroid-centroid distances = 3.5633 (9), 3,5634 (9), and 3.9758(9) A], C-H?O hydrogen bonds, inter molecular N-O?Cl inter-actions [2.9937 (12) A] and C-H?pi contacts are observed. PMID- 21522663 TI - 5-Pentyl-1H-tetra-zole. AB - The title compound C(6)H(12)N(4), is one of a few known tetra-zoles with an alkyl chain in the 5-position. The asymmetric unit contains two independent mol-ecules. The mol-ecules are linked by N-H?N inter-actions into chains with graph-set notation D(2) and C(2) (2)(8) along [010]. The two independent mol-ecules form a layered structure, the layers being composed of inter-digitating strands of alternatingly oriented and nearly identical mol-ecules. PMID- 21522664 TI - 3-[(E)-(2,4-Dichloro-pbenzyl-idene)amino]-benzoic acid. AB - In the crystal of the title compound, C(14)H(9)Cl(2)NO(2), inversion-related dimers with R(2) (2)(8) ring motifs are formed by inter-molecular O-H?O hydrogen bonding. The 3-amino-benzoic acid group and the 2,4-dichlobenzaldehyde moiety subtend a dihedral angle of 55.10 (2) degrees . The H atom of the carboxyl group is disordered over two sites with equal occupancies. PMID- 21522666 TI - 5-(4-Hy-droxy-3-meth-oxy-benz-yl)-1,3-thia-zolidine-2,4-dione monohydrate. AB - In the title compound, C(11)H(11)NO(4)S.H(2)O, the five-membered thia-zolidine ring is nearly planar, with a maximum deviation of 0.010 (2) A. The dihedral angle between the thia-zolidine and benzene rings is 49.16 (9) degrees . Inter molecular O-H?O and N-H?O hydrogen bonding is present in the crystal structure. PMID- 21522665 TI - 7-Deacetyl-gedunin. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: (1S,3aS,4aR,4bS,5R,6aR,10aR,10bR,12aS)-1 (furan-3-yl)-5-hy-droxy-4b,7,7,10a,12a-penta-methyl-4b,5,6,6a,7,10a,10b,11,12,12a deca-hydro-naphtho-[2,1-f]oxireno[2,3-d]isochromene-3,8(1H,3aH)-dione], C(26)H(32)O(6), which is a limonoid-type triterpene isolated from the seeds of X. moluccensis, crystallizes with three independent mol-ecules with very similar geometries in the asymmetric unit. In each mol-ecule, the four fused six-membered rings of the genudin core adopt distorted half-chair, chair, twist-boat and twisted half-chair conformations. In the crystal, inter-molecular O-H?O hydrogen bonds link the mol-ecules into helical chains propagated in [100]. Weak non classical C-H?O contacts further consolidate the crystal packing. PMID- 21522667 TI - (E)-2-Fluoro-N'-(4-nitro-benzyl-idene)benzo-hydrazide. AB - In the title hydrazone compound, C(14)H(10)FN(3)O(3), the dihedral angle between the two substituted benzene rings is 13.7 (3) degrees . The mol-ecule exists in a trans configuration with respect to the central methyl-idene unit. In the crystal, mol-ecules are linked through inter-molecular N-H?O hydrogen bonds, forming chains along the a axis. PMID- 21522668 TI - 4-[4,5-Bis(pyridin-2-yl)-1H-imidazol-2-yl]phenol monohydrate. AB - In the title hydrate, C(19)H(14)N(4)O.H(2)O, the dihedral angle between the two pyridine rings is 38.0 (2) degrees . The dihedral angle between the imidazole and benzene rings is 25.3 (2) degrees . The crystal structure is stabilized by inter molecular O-H?O, O-H?N and N-H?O hydrogen bonds. PMID- 21522669 TI - 3-Chloro-N'-(2,4-dichloro-benzyl-idene)benzohydrazide. AB - The title compound, C(14)H(9)Cl(3)N(2)O, adopts an E configuration about the methyl-idene unit and the two aromatic rings form a dihedral angle of 6.6 (2) degrees . In the crystal, mol-ecules are linked via N-H?O hydrogen bonds, forming C(4) chains propagating in [001]. C-H?O inter-actions reinforce the chains. PMID- 21522670 TI - 5-[(4-Meth-oxy-benz-yl)sulfan-yl]-2-methyl-1,3,4-thia-diazole. AB - The title mol-ecule, C(11)H(12)N(2)OS(2), is twisted with a dihedral angle of 83.63 (12) degrees between the 1,3,4-thia-diazole and benzene rings. The meth oxy group deviates slightly from the attached benzene ring, with a C-C-O-C torsion angle of 4.2 (4) degrees . In the crystal, mol-ecules are linked by weak C-H?N inter-actions and stacked along the c axis. PMID- 21522671 TI - 4-(1,2,4-Triazol-1-yl)aniline. AB - In the title compound, C(8)H(8)N(4), the dihedral angle between the triazole ring [maximum deviation = 0.003 (1) A] and the benzene ring is 34.57 (7) degrees . In the crystal, mol-ecules are linked into sheets lying parallel to the ac plane via inter-molecular N-H?N and C-H?N hydrogen bonds. Aromatic pi-pi [centroid-centroid distance = 3.6750 (8) A] stacking and N-H?pi inter-actions are also observed. PMID- 21522672 TI - 2-(4-Methyl-phen-oxy)acetohydrazide. AB - In the title compound, C(9)H(12)N(2)O(2), the acetohydrazide group is approximately planar [maximum deviation = 0.034 (2) A]. In the crystal, mol ecules are linked via inter-molecular N-H?O, N-H?N and C-H?O hydrogen bonds into infinite two-dimensional networks parallel to (001). PMID- 21522673 TI - N'-(2-Hy-droxy-3,5-diiodo-benzyl-idene)-2-methyl-benzohydrazide. AB - The asymmetric unit of the title compound, C(15)H(12)I(2)N(2)O(2), contains two independent mol-ecules in which the dihedral angles between the two benzene rings are 62.4 (7) and 41.1 (7) degrees . Intra-molecular O-H?N hydrogen bonds generate S(6) ring motifs in each mol-ecule. In the crystal, mol-ecules are linked through inter-molecular N-H?O hydrogen bonds, forming chains along the a axis. PMID- 21522674 TI - 2-[4-(Carb-oxy-meth-yl)phen-oxy]acetic acid. AB - The title compound, C(10)H(10)O(5), was obtained by the reaction of 4-hy-droxy phenyl-acetic acid with chloro-acetic acid. In the crystal, the mol-ecules form a three-dimensional network by way of inter-molecular O-H?O hydrogen bonding. PMID- 21522675 TI - 2-(Furan-2-yl)-5-(2-nitro-benz-yl)-2,3-dihydro-1,5-benzothia-zepin-4(5H)-one. AB - The title compound, C(20)H(16)N(2)O(4)S, was prepared by introduction of a 2 nitro-benzyl group to 2-(furan-2-yl)-2,3-dihydro-1,5-benzothia-zepin-4(5H)-one via an alkaline-catalysed reaction. The thia-zepine ring adopts a twist-boat conformation. The furan ring is oriented at dihedral angles of 56.75 (14) and 10.82 (14) degrees with respect to the two benzene rings, while the two benzene rings make a dihedral angle of 62.96 (10) degrees . Weak inter-molecular C-H?O hydrogen bonds occur in the crystal structure. PMID- 21522676 TI - (E)-1-[4-(Hex-yloxy)phen-yl]-3-(4-hy-droxy-phen-yl)prop-2-en-1-one. AB - In the title compound, C(21)H(24)O(3), inter-molecular O-H?O and C-H?O inter actions form bifurcated acceptor bonds, generating R(2) (1)(6) ring motifs. These ring motifs link the mol-ecules into extended chains along [010]. The crystal structure is further stabilized by C-H?pi inter-actions. PMID- 21522677 TI - (E)-Isopropyl 3-(3,4-dihy-droxy-phen-yl)acrylate. AB - In the title compound, C(12)H(14)O(4), a derivative of caffeic acid [(E)-3-(3,4 dihy-droxy-phen-yl)-2-propenoic acid], an intra-molecular O-H?O hydrogen bond forms an S(5) ring. In the crystal, inter-molecular O-H?O hydrogen bonds link mol ecules into chains propagating in [110]. PMID- 21522678 TI - N'-(3,4-Dimeth-oxy-benzyl-idene)benzo-hydrazide. AB - The crystal structure of the title Schiff base compound, C(16)H(16)N(2)O(3), is characterized by chains of mol-ecules linked by inter-molecular N-H?O hydrogen bonds running along the c axis. Further stabilization is provided by weak C-H?O contacts. The dihedral angle between the aromatic rings is 38.31 (7) degrees . PMID- 21522679 TI - {2-[(Benzo-yloxy)meth-yl]-1-oxo-3H-pyrrolizin-2-yl}methyl benzoate. AB - The title compound, C(23)H(19)NO(5), was prepared by esterification of 2,2-bis (hy-droxy-meth-yl)-2,3-dihydro-1H-pyrrolizin-1-one with benzoyl chloride in pyridine.The pyrrolizine ring system is approximately planar with a maximum deviation of 0.008 (2) A from the least-squares plane; the two phenyl rings are oriented at dihedral angles of 64.26 (11) and 70.75 (10) degrees with respect to the pyrrolizine ring system. Weak inter-molecular C-H?O hydrogen bonding occurs in the crystal structure. PMID- 21522680 TI - rac-Ammonium cis-2-carb-oxy-cyclo-hexane-1-carboxyl-ate. AB - In the structure of the title compound, NH(4) (+).C(8)H(11)O(4) (-), the carboxyl and carboxyl-ate groups of the cation adopt C-C-C-O torsion angles of 174.9 (2) and -145.4 (2) degrees , respectively, with the alicyclic ring. The ammonium H atoms of the cations give a total of five hydrogen-bonding associations with carboxyl-ate O-atom acceptors of the anion which, together with a carboxyl O H?O(carboxyl-ate) inter-action give sheet structures which lie in the (101) planes. PMID- 21522681 TI - 1-[2-(4-Nitro-phen-yl)-5-(5-phenyl-1,2-oxazol-3-yl)-1,2,3,4-tetra-hydro-quinolin 4-yl]pyrrolidin-2-one monohydrate. AB - The title compound, C(28)H(24)N(4)O(4).H(2)O, crystallizes with two organic mol ecules and two solvent water mol-ecules in the asymmetric unit. The most obvious difference between the mol-ecules is the torsion angles between the isoxazole ring and the benzene and phenyl rings [47.0 (2)/56.4 (2) and 33.3 (2)/11.0 (2) degrees , respectively]. Another important difference is observed in the rotation of the nitro group with respect to the phenyl groups [3.5 (6) and 31.1 (6) degrees ]. The pyrrolidinone fragment is cis oriented with respect to the 4-nitro phenyl fragment. In the crystal, mol-ecules are linked into centrosymmetric R(4) (2)(8) and R(4) (4)(20) motifs by O-H?O and N-H?O inter-actions. PMID- 21522682 TI - Dibenzyl sulfoxide. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(14)H(14)OS, which have asymmetric S-C bonds [1.791 (5) and 1.804 (5) A in one mol-ecule and 1.798 (5) and 1.804 (5) A in the other]. The long axes of the mol-ecules are directed along the crystallographic b axis. PMID- 21522683 TI - (Z)-2-[2-(4-Methyl-benzyl-idene)hydrazin-yl]pyridine. AB - Mol-ecules of the title compound, C(13)H(13)N(3), are essentially planar (r.m.s. deviation for all non-H atoms = 0.054 A). The dihedral angle between the two aromatic rings is 6.33 (5) degrees . In the crystal, pairs of centrosymmetrically related mol-ecules are linked through N-H?N hydrogen bonds, forming N-H?N dimers with graph-set motif R(2) (2)(8). PMID- 21522684 TI - 2-[4-(4,5-Dihydro-1H-imidazol-2-yl)phen-yl]-4,5-dihydro-1H-imidazol-3-ium 4-amino benzoate. AB - In the cation of the title compound, C(12)H(15)N(4) (+).C(7)H(6)NO(2) (-), the benzene ring makes dihedral angles of 30.51 (9) and 25.64 (9) degrees with the imidazole and imidazolinium rings, respectively. In the crystal, inter-molecular N-H?O and N-H?N hydrogen-bonding inter-actions link the mol-ecules into a three dimensional network. PMID- 21522685 TI - 4-Amino-1H-1,2,4-triazol-1-ium nitrate. AB - The non-centrosymmetric crystal structure of the novel semi-organic title compound, C(2)H(5)N(4) (+).NO(3) (-), is based on alternating layers of 4-amino 1H-1,2,4-triazolinium cations (formed by parallel chains of cations mediated by weak C-H?N hydrogen bonds) and nitrate anions inter-connected via linear and bifurcated N-H?O hydrogen bonds and weak C-H?O hydrogen bonds. N-H?N hydrogen bonds link the anions and cations. PMID- 21522686 TI - 3-(9H-Carbazol-9-yl)propan-1-ol. AB - In the title compound, C(15)H(15)NO, the dihedral angle between the benzene rings is 2.25 (2) degrees . The C-C-C-O atoms of the propanol side chain are in a gauche conformation [torsion angle = -60.5 (2) degrees ]. In the crystal, O-H?O hydrogen bonds link the mol-ecules into C(2) chains propagating in [100]. The O bonded H atom is disordered over two sites of equal occupancy. PMID- 21522687 TI - The absolute structure of ptilosarcenone 2.5-hydrate, a diterpenoid briarane from the orange sea pen Ptilosarcus gurneyi (Gray). AB - In the title compound, C(24)H(29)ClO(8).2.5H(2)O, which contains two organic mol ecules (A and B) and five heavily disordered water mol-ecules in the asymmetric unit, the gamma-lactone ring and the cyclo-hexenone ring are both trans-fused to the central cyclo-decene ring. The cyclehexenone ring features an alpha,beta unsaturated ketone with torsion angles between the conjugated carbonyl and alkene bonds of 0.6 (3) and 7.4 (4) degrees for mol-ecules A and B, respectively. The ptilosarcenone torsion angles between conjugated alkene bonds are 56.2 (5) and 55.4 (6) degrees for A and B, respectively. In the crystal, the components are linked by O-H?O hydrogen bonds. The absolute configuration of ptilosarcenone was determined unambiguously and exhibits similar absolute stereochemistry to that found in the crystal structures of other octocoralline briaranes. PMID- 21522688 TI - 3-(2,4-Dichloro-phen-oxy)-1-(4-meth-oxy-phen-yl)-4-(3-nitro-phen-yl)azetidin-2 one. AB - In the title compound, C(22)H(16)Cl(2)N(2)O(5), the nearly planar four-membered beta-lactam ring [maximum deviations of 0.011 (2) for the N atom] makes dihedral angles of 68.34 (13), 83.04 (13) and 3.37 (13) degrees with the dichloro-, nitro and meth-oxy-phenyl rings, respectively. The crystal structure is stabilized by C-H?O hydrogen-bond inter-actions. In addition, a pi-pi stacking inter-action [centroid-centroid distance = 3.6622 (12) A] is observed between the beta-lactam and nitro-phenyl rings. PMID- 21522689 TI - 2-[6-(4-Chloro-phen-yl)imidazo[2,1-b][1,3]thia-zol-2-yl]-N'-[(E)-4-meth-oxy benzyl-idene]acetohydrazide. AB - In the imidazo[2,1-b][1,3]thia-zole group of the title compound, C(21)H(17)ClN(4)O(2)S, the dihedral angle between the thia-zole and imidazole rings is 1.9 (2) degrees . The mean plane of this group makes dihedral angles of 5.5 (2) and 39.9 (2) degrees with the benzene rings of the chloro-phenyl and meth-oxy-phenyl groups, respectively. The dihedral angle between these two benzene rings is 34.4 (2) degrees . In the crystal, mol-ecules are connected to each other by inter-molecular N-H?O hydrogen bonds along the b axis, generating a C(4) chain. Weak C-H?pi inter-actions also occur. PMID- 21522690 TI - N-(4-Meth-oxy-phen-yl)-4-methyl-benzene-sulfonamide. AB - In the title compound, C(14)H(15)NO(3)S, the dihedral angle between the aromatic rings is 59.39 (14) degrees and the C-S-N-C torsion angle is -71.4 (2) degrees . In the crystal, a supra-molecular chain running along the b axis with a C(4) graph set is formed via N-H?O hydrogen bonds. PMID- 21522691 TI - rac-Diethyl 6-hy-droxy-4-[(2-hy-droxy-eth-yl)amino]-6-methyl-2-phenyl-cyclo-hex-3 ene-1,3-dicarboxyl-ate. AB - The title compound, C(21)H(29)NO(6), is chiral with three stereogenic centres. The crystal is a racemate and consists of enanti-omeric pairs with the relative configuration rac-(2R*,3S*,4R*). The ethyl fragment of the eth-oxy-carbonyl group at position 1 is disordered in a 0.60:0.40 ratio. The crystal packing displays inter-molecular O-H?O hydrogen bonding. An intra-molecular N-H?O hydrogen bond also occurs. PMID- 21522692 TI - (E)-3-(1-Naphthyl-amino)-methyl-ene-(+)-camphor. AB - In the crystal structure of the title ketoamine {systematic name: (E)-1,7,7 trimethyl-3-[(1-naphthyl-amino)-methyl-idene]bicyclo-[2.2.1]heptan-2-one}, C(21)H(23)NO, there are two independent mol-ecules in the asymmetric unit. Both mol-ecules have an E configuration about the alkene function. The main conformational difference between the mol-ecules is in the orientation of the plane of the naphthyl rings with respect to the camphor fragment. The torsion angle about the enamine C-N bond is 21.3 (7) degrees for mol-ecule A, but -24.4 (8) degrees for mol-ecule B. Inter-molecular N-H?O hydrogen bonds between the amino and ketone groups of adjacent independent mol-ecules sustain the crystal, and the resulting extended chains, containing an alternating sequence of the two independent mol-ecules, run parallel to the [001] direction and can be described by a graph-set motif of C(2) (2)(12). PMID- 21522693 TI - Orphenadrinium picrate. AB - In the title molecular salt {systematic name: N,N-dimethyl-2-[(2-methyl-phen yl)(phen-yl)meth-oxy]ethanaminium 2,4,6-tri-nitro-phenolate}, C(18)H(24)NO(+).C(6)H(2)N(3)O(7) (-), the phenyl rings of the orphenadrinum cation are disordered [occupancies = 0.662 (4) and 0.338 (4)]. The N atom in the orphenadrinum cation is protonated. The picrate anion inter-acts with the protonated N atom through a bifurcated N-H?O hydrogen bond, forming an R(1) (2)(6) ring motif with an adjacent cation. The mean planes of the two o-NO(2) and single p-NO(2) groups in the picrate anion are twisted by 23.0 (6), 31.3 (3) and 6.3 (2) degrees with respect to the mean planes of the six-membered ring. Weak inter-molecular C-H?O hydrogen bonds, C-H?pi inter-molecular inter-actions and weak pi-pi stacking inter-actions [centroid-centroid distances = 3.677 (2) and 3.515 (3) A} stabilize the crystal packing, creating a three-dimensional network. PMID- 21522694 TI - [2-(2-Chloro-phen-yl)-2-hy-droxy-eth-yl](isoprop-yl)ammonium 4-hy-droxy-benzoate. AB - The title molecular salt, C(11)H(17)ClNO(+).C(7)H(5)O(3) (-), was obtained by the reaction of racemic clorprenaline and 4-hy-droxy-benzoic acid. In the crystal, the components are connected by O-H?O and N-H?O hydrogen bonds, resulting in a two-dimensional hydrogen-bonded network. PMID- 21522695 TI - 3-[3-(Pyridin-3-yl)-1,2,4-oxadiazol-5-yl]propanoic acid. AB - In the title compound, C(10)H(9)N(3)O(3), the benzene ring is almost coplanar with the heterocyclic ring, making a dihedral angle of 11.3 (1) degrees . The plane of the carboxyl group is rotated by 8.4 (2) degrees with respect to the 1,2,4-oxadiazole ring plane. The aliphatic chain exhibits an extended conformation. In the crystal, mol-ecules are liked through inter-molecular O-H?N bonds, forming a chain structure along the c axis. PMID- 21522696 TI - Disopropyl {[(2S,3S)-2-amino-3-methyl-penta-namido](phen-yl)meth-yl}phosphinate. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(19)H(33)N(2)O(4)P. In the crystal, the two independent mol-ecules are linked via N-H?O=P hydrogen bonds, forming dimers. PMID- 21522697 TI - (1S,2R,4S)-1-[(Benzyl-amino)-meth-yl]-4-(prop-1-en-2-yl)cyclo-hexane-1,2-diol. AB - The title compound, C(17)H(25)NO(2), was synthesized by epoxidation of the double bond of (S)-perillyl alcohol [(S)-4-isopropenyl-1-cyclo-hexenyl-methanol], followed by the oxirane ring-opening by benzyl-amine using [Ca(CF(3)CO(2))(2)] as catalyst under solvent-free condition at 313 K. The mol-ecular conformation is stabilized by an intra-molecular O-H?N hydrogen bond. In the crystal, mol-ecules are linked by inter-molecular N-H?O hydrogen bonds, forming chains parallel to the a axis, which are further connected by O-H?O hydrogen bonds into sheets parallel to (010). The absolute configuration of the mol-ecule is known from the synthetic procedure. PMID- 21522698 TI - N-(2-Oxo-2-phenyl-acet-yl)benzamide. AB - In the title compound, C(15)H(11)NO(3), the two essentially planar benzaldehyde groups [maximum deviations = 0.0487 (12) and 0.0205 (10) A] are inclined at a dihedral angle of 72.64 (6) degrees with respect to each other. The bridging C-C N-C torsion angle is 22.58 (18) degrees . In the crystal, inter-molecular bifurcated acceptor N-H?O and C-H?O hydrogen bonds link inversion-related mol ecules into dimers incorporating R(1) (2)(7) and R(2) (2)(8) ring motifs. The crystal structure is further stabilized by weak inter-molecular C-H?pi inter actions. PMID- 21522699 TI - N-[4-Cyano-3-(trifluoro-meth-yl)phen-yl]-2-meth-oxy-benzamide. AB - In the title compound, C(16)H(11)F(3)N(2)O(2), the carboxamide group connecting the two aromatic rings is in a syn-periplanar configuration; the mol-ecule is non planar; the dihedral angle between the two aromatic rings is 13.95 (18) degrees . Intra-molecular N-H?O and C-H?O hydrogen bonds occur. In the crystal, mol-ecules are linked by inter-molecular C-H?O hydrogen bonds. PMID- 21522700 TI - Benzothia-zol-2-amine-3-meth-oxy-carbonyl-7-oxabicyclo-[2.2.1]hept-5-ene-2-carb oxy-lic acid (1/1). AB - In the title 1:1 adduct, C(7)H(6)N(2)S.C(9)H(10)O(5), all non-H atoms of the benzothia-zol-2-amine mol-ecule are essentially coplanar, with a maximum deviation of 0.0286 (9) A for the S atom. In the crystal, inter-molecular N-H?O and O-H?N hydrogen bonds connect two mol-ecules of each type into centrosymmetric four-component clusters. PMID- 21522701 TI - 2,4-Dichloro-benzaldehyde 4-methyl-thio-semicarbazone. AB - The mol-ecule of the title compound, C(9)H(9)Cl(2)N(3)S, has an E configuration about the C=N bond. In the crystal, mol-ecules are linked through inter-molecular N-H?S hydrogen bonds, forming zigzag chains along the a axis. PMID- 21522702 TI - Ethanaminium 3,4,5,6-tetra-bromo-2-(meth-oxy-carbon-yl)benzoate methanol monosolvate. AB - In the crystal structure of the title compound, C(2)H(8)N(+).C(9)H(3)Br(4)O(4) ( ).CH(4)O, inter-molecular N-H?O and O-H?O hydrogen bonds link the components into chains along [001]. Additional stabilization is supplied by weak C-H?O and C-H?Br inter-actions. PMID- 21522703 TI - 7,7'-Dihy-droxy-4,4'-dimethyl-3,4-dihydro-2H,2'H-4,6'-bichromene-2,2'-dione. AB - The title compound, C(20)H(16)O(6), which contains one chiral centre, crystallizes as a racemate. The mean planes of the two coumarin units make a dihedral angle of 88.07 (2) degrees . The pyrone ring containing the chiral centre adopts a sofa conformation. In the crystal, four mol-ecules are linked by O-H?O hydrogen bonds, forming a tetrameric ring with graph-set motif R(4) (4)(32). These tetramers are further linked by O-H?O hydrogen bonds into a three dimensional network. PMID- 21522704 TI - 5-(4-Pyrid-yl)-1,3,4-thia-diazole-2(3H)-thione. AB - The title compound C(7)H(5)N(3)S(2), occurs as the thione tautomer in the solid state; the dihedral angle between the pyridine and thia-diazole ring planes is 2.08 (6) degrees . In the crystal, mol-ecules are linked by N-H?N hydrogen bonds, generating C(8) chains propagating in [010]. PMID- 21522705 TI - Bis(2-{2-[2-(benzyl-carbamo-yl)phen-oxy]acetamido}-eth-yl)ammonium nitrate ethanol disolvate. AB - In the title compound, C(36)H(40)N(5)O(6) (+).NO(3) (-).2C(2)H(5)OH, the nitrate anion is disordered over the two orientations of equal occupancy while the solvent mol-ecule reveals large displacement parameters. The cation is formed by protonation of the N atom of a secondary amine in the middle of the flexible chain and the whole compound has crystallographically imposed C-2 symmetry with the crystallographic b axis. An O atom of the nitrate anion links the acidic H atoms of the cation via N-H?O hydrogen bonding. In addition, neighbouring cations are connected by inter-molecular N-H?O hydrogen bonds and pi-pi inter-actions between the benzamide groups of the cations [centroid-centroid distance = 4.000 (3) A], forming a chain along [001]. The ethanol solvent mol-ecules are arranged on the side of the chain through O-H?O hydrogen bonds. PMID- 21522706 TI - 2-Methyl-5-[(3-methyl-4-nitro-benz-yl)sulfan-yl]-1,3,4-thia-diazole. AB - The mol-ecule of the title thia-diazole derivative, C(11)H(11)N(3)O(2)S(2), has a butterfly-like structure and the whole mol-ecule is disordered with a site occupancy ratio of 0.629 (4):0.371 (4). The mol-ecule is disordered in such a way that the 3-methyl-4-nitro-phenyl units of the major and minor components are approximately related by 180 degrees rotation around the C-N bond axis. The dihedral angle between the 1,3,4-thia-diazole and benzene rings is 70.8 (4) degrees in the major component and 74.9 (6) degrees in the minor component. In the crystal, mol-ecules are arranged into screw chains along the c axis. These chains are stacked along the b axis. Weak inter-molecular C-H?O and C-H?pi inter actions and a short C?O contact [3.005 (7) A] are present. PMID- 21522707 TI - 6-(4-Chloro-phen-yl)-2-isobutyl-imidazo[2,1-b][1,3,4]thia-diazole. AB - In the title compound, C(14)H(14)ClN(3)S, the imidazo[2,1-b][1,3,4]thia-diazole system is essentially planar, with a maximum deviation of 0.006 (2) A. The dihedral angle between the imidazo[2,1-b][1,3,4]thia-diazole and chloro-phenyl rings is 5.07 (8) degrees . In the crystal, there are no classical hydrogen bonds but stabilization is provided by weak pi-pi [centroid-centroid distance = 3.5697 (11) A] and C-H?pi inter-actions. PMID- 21522708 TI - Naphthalene-2,6-dicarb-oxy-lic acid-1-methyl-pyrrolidin-2-one (1/2). AB - The asymmetric unit of the title compound, C(12)H(8)O(4).2C(5)H(9)NO, contains one half-mol-ecule of naphthalene-2,6-dicarb-oxy-lic acid (NDA) and one mol-ecule of 1-methyl-pyrrolidin-2-one (NMP): the NDA molecules lie on the crystallographic twofold rotation axes. In the crystal, the components are linked by strong O-H?O hydrogen bonds and C-H?O inter-actions. PMID- 21522709 TI - (5-Hy-droxy-3-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanone monohydrate. AB - In the title compound, C(16)H(15)N(3)O(2).H(2)O, the mean plane of the approximately planar pyrazole ring [maximum deviation = 0.0474 (18) A] makes dihedral angles of 86.32 (11) and 45.04 (10) degrees with the phenyl and pyridine rings, respectively. The dihedral angle between the phenyl and pyridine rings is 69.62 (11) degrees . In the crystal, inter-molecular O-H?O and O-H?N hydrogen bonds connect the components into chains along [010]. The crystal structure is further stabilized by pi-pi stacking inter-actions with centroid centroid distances of 3.7730 (12) A. PMID- 21522710 TI - 4-Bromo-2-[1-(4-eth-oxy-phen-yl)-1-methyl-eth-yl]-1-methyl-benzene. AB - In title compound, C(18)H(21)BrO, the dihedral angle between two rings is 85.72 degrees . No classical hydrogen bonds are found and only van der Waals forces stabilize the crystal packing. PMID- 21522711 TI - 4-[(1-Adamant-yl)carbamo-yl]pyridinium chloride. AB - In the title compound, C(16)H(21)N(2)O(+).Cl(-), the amide group makes a dihedral angle of 25.9 (1) degrees with respect to the pyridine ring. In the crystal, inter-molecular N-H?Cl bonds and weak C-H?Cl and C-H?O contacts link the cations and the anions into layers parallel to the ac plane. The layers are packed along [010] by hydro-phobic inter-actions between adamantane units. PMID- 21522712 TI - 5-[(E)-2-Fluoro-benzyl-idene]-8-(2-fluoro-phen-yl)-2-hy-droxy-10-methyl-3,10-di aza-hexa-cyclo-[10.7.1.1.0.0.0]henicosa-1(20),12,14,16,18-pentaen-6-one. AB - In the title compound, C(33)H(26)F(2)N(2)O(2), the piperidone ring adopts a half chair conformation and the pyrrolidine rings adopt half-chair and envelope conformations. The two benzene rings make dihedral angles of 29.58 (5) and 76.33 (5) degrees with the mean plane of the 1,2-dihydro-acenaphthyl-ene unit. An intra-molecular O-H?N hydrogen bond helps to stabilize the mol-ecular structure. In the crystal, inter-molecular C-H?F hydrogen bonds link the mol-ecules into [010] chains. Weak C-H?pi inter-actions are also observed. PMID- 21522713 TI - 2'-Iodo-2,2'',3,3'',4,4'',5,5'',6,6''-deca-methyl-1,1':3',1''-terphenyl chloro form monosolvate. AB - The title compound, C(28)H(33)I.CHCl(3), forms dimers through C-I?pi inter actions. The crystal structure is consolidated by the presence of C-H?pi inter actions between the chloro-form solvent and the main mol-ecule. PMID- 21522714 TI - Redetermination of the salt hexa-methyl-ene-tetra-minium fumarate. AB - THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND [SYSTEMATIC NAME: 3,5,7-triaza-1 azoniatricyclo-[3.3.1.1(3,7)]decane (E)-3-carb-oxy-prop-2-enoate], C(6)H(13)N(4) (+).C(4)H(3)O(4) (-), had been determined previously by Bowes et al. [Acta Cryst. (2003), B59, 100-117]. Their structure contained an approximately 3:1 ratio of fumarate and succinate monoanions disordered over the same position. The succinate anion component forms a similar structural role to the fumarate anion and came about due to an impurity in the starting material, fumaric acid. In this work, the crystal structure of the pure salt is presented, which is identical, apart from the lack of disorder of the anions, to the previous structure. In the crystal, the ions assemble in the solid state, forming chains via N(+)-H?O(-) and O-H?O(-) hydrogen bonds, which are linked into a three-dimensional network by C H?O inter-actions. PMID- 21522715 TI - 3-(Pyridin-3-yl)propionic acid. AB - In the crystal of the title compound, C(8)H(9)NO(2), mol-ecules assemble to form C(8) chains along the b axis by N-H?O hydrogen bonds, supported by weaker C-H?O hydrogen bonded-inter-actions between adjacent chains. PMID- 21522716 TI - 2-(3,4-Dimethyl-5,5-dioxo-2H,4H-pyrazolo-[4,3-c][1,2]benzothia-zin-2-yl)-N'-(3 meth-oxy-benzyl-idene)aceto-hydrazide dimethyl-formamide hemisolvate. AB - In the title compound, C(21)H(21)N(5)O(4)S.0.5C(3)H(7)NO, the heterocyclic thia zine ring adopts a half-chair conformation, with the S and N atoms displaced by 0.451 (5) and 0.233 (5) A, respectively, from the plane formed by the remaining ring atoms. The asymmetric unit contains a disordered half-mol-ecule of solvent lying close to inversion centers. The crystal structure is stabilized by weak inter-molecular N-H?O and C-H?O inter-actions. PMID- 21522717 TI - N'-(2-Chloro-benzyl-idene)-2-(3,4-dimethyl-5,5-dioxo-2H,4H-pyrazolo-[4,3 c][1,2]benzothia-zin-2-yl)acetohydrazide. AB - The asymmetric unit of the title compound, C(20)H(18)ClN(5)O(3)S, contains two independent mol-ecules with significantly different conformations of the heterocyclic thia-zine rings. In both mol-ecules, the thia-zine rings adopt half chair conformations, with the S atoms displaced by 0.382 (3) and 0.533 (3) A and N atoms -0.351 and -0.275 A, respectively, from the planes formed by the remaining ring atoms. The crystal structure is stabilized by weak inter-molecular N-H?O and C-H?O inter-actions. PMID- 21522718 TI - 4-Chloro-N-(2-methyl-benzo-yl)benzene-sulfonamide. AB - In the title compound, C(14)H(12)ClNO(3)S, the conformation of the N-H bond in the C-SO(2)-NH-C(O) segment is anti to the C=O bond. The two aromatic rings are tilted relative to each other by 57.7 (1) degrees . In the crystal, mol-ecules are linked by pairs of N-H?O(S) hydrogen bonds, forming centrosymmetric dimers. PMID- 21522719 TI - 4,4'-Bis(2,2-diphenyl-vin-yl)-1,1'-biphen-yl. AB - The title mol-ecule, C(40)H(30), lies on an inversion center. The two unique phenyl rings form dihedral angles of 51.98 (8) and 67.58 (8) degrees with the essentially planar biphenyl unit [maximum deviation = 0.0360 (14) A]. PMID- 21522720 TI - 3-Bromo-propyl 2-(2-chloro-phen-yl)-2-(4,5,6,7-tetra-hydro-thieno[3,2-c]pyridin-5 yl)acetate. AB - In the crystal structure of the title compound, C(18)H(19)BrClNO(2)S, weak C-H?O inter-actions help to establish the packing. PMID- 21522721 TI - 2,2'-Bis(meth-oxy-meth-oxy)-3,3'-diphenyl-1,1'-binaphthalene. AB - The asymmetric unit of the title compound, C(36)H(30)O(4), contains two crystallographically independent mol-ecules of similar geometry. In both mol ecules, the meth-oxy-meth-oxy groups are disordered over two positions with refined site occupancies of 0.613 (3):0.387 (3) and 0.589 (4):0.411 (4). The dihedral angles between the naphthalene planes within the same mol-ecule are 71.72 (7) and 71.73 (8) degrees . In the crystal, neighbouring mol-ecules are linked by inter-molecular C-H?O hydrogen bonds, forming double chains parallel to the c axis. PMID- 21522722 TI - 2-[4-(2-Meth-oxy-phen-yl)piperazin-1-yl]-N-(pyridin-2-yl)acetamide. AB - In the title compound, C(18)H(22)N(4)O(2), the piperizine ring adopts a chair conformation and the dihedral angle between the pyridine and benzene rings is 67.6 (9) degrees . The conformations of the attachment of the anisole and N-ethyl pyridin-2-amine groups to the piperazine ring are (+)anti-periplanar. Intra molecular C-H?O and N-H?N inter-actions occur. In the crystal, inter-molecular C H?N hydrogen bonds are present. There are two crystallographically independent but identical mol-ecules per asymmetric unit. PMID- 21522723 TI - tert-Butyl 4-(4-chloro-anilino)-6-methyl-2-oxocyclo-hex-3-ene-carboxyl-ate. AB - In the title compound, C(18)H(22)ClNO(3), the dihedral angle between the benzene ring and the conjugated part of the enaminone ring is 55.19 (9) degrees . The ester substituent makes a dihedral angle of 81.0 (2) degrees with this latter moiety. The crystal structure features N-H?O and weak C-H?O inter-molecular inter actions. PMID- 21522724 TI - N-Phenyl-morpholine-4-carboxamide. AB - In the title compound, C(11)H(14)N(2)O(2), the urea-type NC=ON moiety [planar to within 0.0002 (13) A] is inclined to the phenyl ring by 42.88 (8) A, and the morpholine ring has a chair conformation. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into infinite chains in [001]. PMID- 21522725 TI - Ethyl 2-amino-6-benzyl-4,5,6,7-tetra-hydro-thieno[2,3-c]pyridine-3-carboxyl-ate. AB - In the title compound, C(17)H(20)N(2)O(2)S, the tetra-hydro-pyridine ring adopts an envelope conformation with the N atom at the flap position; the phenyl ring makes a dihedral angle of 81.06 (10) degrees with the thio-phene ring. The amino group links with the carbonyl O atom via intra-molecular N-H?O hydrogen bonding, forming a six-membered ring. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into infinite chains running along the b axis. PMID- 21522726 TI - N-(4-Methyl-phen-yl)succinamic acid. AB - In the title compound, C(11)H(13)NO(3), the conformations of the N-H and C=O bonds in the amide segment are anti to each other. Further, the conformations of the amide and carbonyl O atoms of the acid segment are also anti to the adjacent CH(2) groups. The C=O and O-H bonds of the acid group are syn to each other. In the crystal, mol-ecules are packed into infinite chains along the b axis through inter-molecular N-H?O and O-H?O hydrogen bonds. PMID- 21522727 TI - (3S)-2-Benzyl-3-carb-oxy-1,2,3,4-tetra-hydro-isoquinolinium chloride monohydrate. AB - In the title compound, C(17)H(18)NO(2) (+).Cl(-).H(2)O, a precursor to novel asymmetric catalysts, the N-containing six-membered ring of the tetra-hydro quinolinium unit assumes a half-boat conformation. In the crystal, inter molecular O-H?O, O-H?Cl, N-H?Cl and C-H?O hydrogen bonds and C-H?pi inter-actions link the mol-ecules into a three-dimensional network. PMID- 21522728 TI - 4-[(7-Fluoro-quinazolin-4-yl)-oxy]aniline. AB - In the mol-ecule of the title compound, C(14)H(10)FN(3)O, the bicyclic quinazoline system is effectively planar, with a mean deviation from planarity of 0.0140 (3) A. The quinazoline heterocyclic system and the adjacent benzene ring make a dihedral angle of 85.73 (9) degrees . Two inter-molecular N-H?N hydrogen bonds contribute to the stability of the crystal structure. In addition, a weak pi-pi stacking inter-action [centroid-centroid distance = 3.902 (2) A] is observed. PMID- 21522729 TI - 4-(Piperidin-1-yl)-4H-benzo[b]tetra-zolo[1,5-d][1,4]diazepin-5(6H)-one. AB - There are two crystallographically unique mol-ecules present in the asymmetric unit of the title compound, C(14)H(16)N(6)O; in both mol-ecules, the seven membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each mol-ecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between mol-ecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related N-H?O inter-actions and the second formed by C-H?O and C-H?N inter-actions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. Hydrogen bonding between mol-ecule B and symmetry equivalents forms one ring motif by inversion-related N-H?O inter-actions and a second ring motif by C-H?O inter-actions, which propagate as a single tape parallel with the c axis. PMID- 21522730 TI - Methyl 6-dimethyl-amino-4-hy-droxy-2-naphtho-ate. AB - In the title compound, C(14)H(15)NO(3), the ester group is oriented so that the carbonyl group points in the opposite direction to the hy-droxy group. The mol ecule as a whole is almost planar (the r.m.s. deviation of the non-H atoms is 0.0268 A). In the crystal, mol-ecules are linked by inter-molecular O-H?O hydrogen bonds into infinite chains that propagate parallel to the c axis. PMID- 21522731 TI - 4-({4-[Bis(2-cyano-eth-yl)amino]-phen-yl}diazen-yl)benzene-sulfonamide. AB - In the title compound, C(18)H(16)N(6)O(2)S, which belongs to the family of azo dyes, the dihedral angle between the benzene rings is 26.16 (7) degrees . In the crystal, mol-ecules are joined by N-H?N and C-H?N hydrogen bonds into double chains parallel to the a axis. PMID- 21522732 TI - 4-Chloro-N-(2,3-dichloro-phen-yl)benzene-sulfonamide. AB - In the title compound, C(12)H(8)Cl(3)NO(2)S, the two aromatic rings are tilted relative to each other by 56.5 (1) degrees . The crystal structure features centrosymmetric dimers in which mol-ecules are linked by N-H?O hydrogen bonds. PMID- 21522733 TI - N'-(2-Chloro-benzyl-idene)-2-fluoro-benzohydrazide. AB - The title hydrazone compound, C(14)H(10)ClFN(2)O, adopts an E configuration about the C=N double bond. The dihedral angle between the two substituted benzene rings is 11.6 (2) degrees . The F atom is disordered over two sites with occupancies of 0.488 (2) and 0.512 (2). In the crystal, mol-ecules are linked through inter molecular N-H?O hydrogen bonds, forming chains along the a axis. C-H?F and C-H?O inter-actions also occur. PMID- 21522734 TI - N-(3,5-Dimethyl-phen-yl)succinamic acid. AB - In the title compound, C(12)H(15)NO(3), the N-H and C=O bonds are anti to each other. The C=O and O-H bonds of the acid group display an anti-periplanar orientation relative to each other. The crystal packing features a three dimensional network of molecules held together by O-H?O and N-H?O hydrogen bonds. PMID- 21522735 TI - 2-Methyl-imidazolium picrate. AB - In both ionic components of the title salt, C(4)H(7)N(2) (+).C(6)H(2)N(3)O(7) ( ), the rings are approximately planar; the maximum deviation from the mean plane is an order of magnitude larger in the picrate ring [0.0289 (10) A] than in the imidazolium ring [0.0028 (10) A. The nitro groups are twisted with respect to the six-atom ring plane; the NO(2) groups next to the oxide O atom, at the 2- and 6 positions, are twisted more [by 53.59 (9) and 18.46 (12) degrees ] than the NO(2) group at the 4-postition, for which the twist angle is 7.28 (16) degrees . In the crystal, N-H?O hydrogen bonds, in which the hydroxyl O atom acts as a double acceptor and one of the O atoms from a nitro group acts as an additional acceptor, connect mol-ecules into chains along the c-axis direction. Relatively short C-H?O contacts and pi-pi inter-actions between symmetry-related six membered rings [centroid-centroid distances = 3.5938 (10) and 3.6223 (10) A] also occur. PMID- 21522736 TI - N-(2,3-Dimethyl-phen-yl)succinamic acid. AB - In the title compound, C(12)H(15)NO(3), the conformations of N-H and C=O bonds in the amide segment are anti to each other and that of the amide H atom is syn to the ortho- and meta-methyl groups in the benzene ring. In the crystal, the mol ecules are linked into infinite chains through inter-molecular O-H?O and N-H?O hydrogen bonds. PMID- 21522737 TI - 3-[4-(Dimethyl-amino)-phen-yl]-1-(4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octa-hydro naphthalen-2-yl)prop-2-en-1-one. AB - The title compound, C(23)H(31)NO, was semisynthesized from isocostic acid, isolated from the aerial part of Inula Viscosa- (L) Aiton [or Dittrichia Viscosa- (L) Greuter]. The cyclo-hexene ring has a half-chair conformation, whereas the cyclo-hexane ring displays a chair conformation. The dihedral angle between the latter ring and its substituent is 83.6 (7) degrees . PMID- 21522738 TI - Methyl 6'-amino-5'-cyano-2'-methyl-2-oxospiro-[indoline-3,4'-pyran]-3'-carboxyl ate. AB - In the mol-ecule of the title compound, C(16)H(13)N(3)O(4), the atoms of the spiro pyran ring are nearly planar with a maximum deviation of 0.095 (2) A. The indole and pyran rings are oriented at a dihedral angle of 87.3 (9) degrees . In the crystal, mol-ecules are linked by inter-molecular N-H?N and N-H?O hydrogen bonds. PMID- 21522739 TI - 3-[4-(Acetamido)-benzene-sulfonamido]-benzoic acid. AB - In the title compound, C(15)H(14)N(2)O(5)S, the dihedral angle between the aromatic rings is 63.20 (11) A. The crystal structure displays classical inter molecular O-H?O hydrogen bonding typical for carb-oxy-lic acids, forming centrosymmetric dimers. These dimers are further connected by N-H?O and C-H?O hydrogen bonds to form an extended network. PMID- 21522740 TI - (S)-(Z)-Methyl 2-[2,3-bis-(benzyl-oxy-carbon-yl)guanidino]-4-methyl-penta-no-ate. AB - The title mol-ecule, C(24)H(29)N(3)O(6), has a nearly planar ten-atom C(3)N(3)O(4) core, on account of both N-H groups forming six-membered-ring intra molecular hydrogen bonds to carbamate carbonyl O atoms. The absolute configuration was determined from resonant scattering of light atoms in Mo Kalpha radiation, agreeing with the configuration of starting materials. PMID- 21522741 TI - 2-Bromo-1-(3-nitro-phen-yl)ethanone. AB - In the title compound, C(8)H(6)BrNO(3), there are two mol-ecules, A and B, in the asymmetric unit. The nitro and ethanone groups lie close to the plane of the benzene ring and the bromine atom is twisted slightly: the dihedral angles between the mean planes of the nitro and ethanone groups and the benzene ring are 4.6 (4) (A) and 2.8 (3) (B), and 0.8 (8) (A) and 5.5 (8) degrees (B), respectively. An extensive array of weak C-H?O hydrogen bonds, pi-pi ring stacking [centroid-centroid distances = 3.710 (5) and 3.677 (5) A] and short non hydrogen Br?O and O?Br inter-molecular inter-actions [3.16 (6)and 3.06 (8) A] contribute to the crystal stability, forming a supermolecular three-dimensional network structure along 110. These inter-actions give rise to a variety of cyclic graph-set motifs and form inter-connected sheets in the three-dimensional structure. PMID- 21522742 TI - 3'-O-Acetyl-2'-de-oxy-uridine. AB - In the two independent but very similar mol-ecules of the title compound, C(11)H(14)N(2)O(6), both nucleobase fragments are nearly planar (both within 0.01 A) while the furan-ose rings exhibit (2)E-endo envelope conformations. In the crystal, the two 3'-O-acetyl-2'-de-oxy-uridine mol-ecules form a pseudosymmetric dimer of two bases connected via two nearly identical resonance-assisted N-H?O hydrogen bonds. The resulting pair is further connected with neighboring pairs via two similar O-H?O bonds involving the only hydroxyl group of the 2'-de-oxy furan-ose fragment and the remaining carbonyl oxygen of the nucleobase. These inter-actions result in the formation of an infinite 'double band' along the b axis that can be considered as a self-assembled analogue of a polynucleotide mol ecule with non-canonical Watson-Crick base pairs. The infinite chains of 3'-O acetyl-2'-de-oxy-uridine pairs are additionally held together by C-H?O inter actions involving C atoms of the uracyl base and O atoms of carbonyl groups. Only weak C-H?O contacts exist between neighboring chains. PMID- 21522743 TI - Piperazine-1,4-diium bis-(hydrogen 2-propyl-1H-imidazole-4,5-dicarbox-ylate) monohydrate. AB - The title compound, C(4)H(12)N(2) (2+).2C(8)H(9)N(2)O(4) (-).H(2)O, is a hydrated proton-transfer compound obtained from 2-propyl-1H-imidazole-4,5-dicarb-oxy-lic acid and piperazine. The asymmetric unit contains one half-cation, one anion and half a water mol-ecule. There is a centre of inversion at the centre of the cation ring and the water molecule O atom lies on a twofold rotation axis. In the crystal, inter-molecular N-H?O and N-H?N hydrogen bonds help to construct a three dimensional framework. Almost symmetrical, intramolecular O-H?O inter-actions are also observed. PMID- 21522744 TI - N'-[1-(2-Hy-droxy-phen-yl)ethyl-idene]thio-phene-2-carbohydrazide. AB - The title compound, C(13)H(12)N(2)O(2)S, was prepared by the reaction of 1-(2-hy droxy-phen-yl)ethanone and thio-phene-2-carbohydrazide. The dihedral angle between the benzene and thio-phene rings is 10.07 (17) degrees . An intra molecular O-H?N hydrogen bond may influence the mol-ecular conformation. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds into chains along [010]. PMID- 21522746 TI - 4a-Hy-droxy-9-(2-meth-oxy-phen-yl)-4,4a,5,6,7,8,9,9a-octa-hydro-3H-xanthene 1,8(2H)-dione. AB - In the title compound, C(20)H(22)O(5), an S(6) ring motif is formed by an intra molecular C-H?O hydrogen bond, which contributes to the stabilization of the mol ecule. In the xanthene system, the cyclo-hexane ring adopts a chair conformation, the cyclo-hexene ring adopts a half-boat conformation and the tetra-hydro-pyran ring adopts a half-chair conformation. The mean plane of the four essentially planar atoms of the tetra-hydro-pyran ring [r.m.s deviation = 0.092 (1) A] forms a dihedral angle of 64.13 (6) degrees with the mean plane of the meth-oxy-phenyl group. In the crystal, inter-molecular O-H?O and weak C-H?O hydrogen bonds link mol-ecules into chains along the a axis, which are further stabilized by C-H?pi inter-actions. PMID- 21522745 TI - (1E,4E)-1,5-Bis(2,4,6-trimeth-oxy-phen-yl)penta-1,4-dien-3-one. AB - There are two crystallographically independent mol-ecules in the asymmetric unit of the title bis-chalcone derivative, C(23)H(26)O(7). The mol-ecules are unsymmetrical and almost planar: the dihedral angle between two benzene rings is 1.04 (7) degrees in one mol-ecule and 2.31 (7) degrees in the other. The central penta-1,4-dien-3-one fragment makes dihedral angles of 7.61 (7) and 6.82 (7) degrees with the two adjacent benzene rings in one mol-ecule, while the corresponding values are 7.85 (7) and 9.42 (6) degrees in the other. In both mol ecules, the three meth-oxy groups of the two 2,4,6-trimeth-oxy-phenyl units are coplanar with the attached benzene rings [C-O-C-C- torsion angles of -1.5 (2), 7.2 (2) and 4.1 (2) degrees in one mol-ecule and -0.7 (2), -5.5 (2) and -0.6 (2) degrees in the other]. The mol-ecular conformations are stabilized by weak intra molecular C-H?O inter-actions generating two S(6) ring motifs. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O inter-actions into zigzag chains parallel to the c axis. The crystal structure is further stabilized by C H?pi inter-actions and pi-pi inter-actions with centroid-centroid distances of 3.6433 (8) A. PMID- 21522747 TI - 2-Amino-4-chloro-benzoic acid. AB - The title compound, C(7)H(6)ClNO(2), is almost planar, with an r.m.s. deviation of 0.040 A. An intra-molecular N-H?O hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are linked into centrosymmetric dimers by pairs of O H?O hydrogen bonds. These dimers are stacked along [010]. PMID- 21522749 TI - N-(2,5-Dichloro-phen-yl)-4-methyl-benzene-sulfonamide. AB - In the title compound, C(13)H(11)Cl(2)NO(2)S, the N-C bond in the C-SO(2)-NH-C segment has gauche torsion angles with respect to the S=O bonds. The mol-ecule is bent at the S atom with an C-SO(2)-NH-C torsion angle of 62.1 (2) degrees . Furthermore, the conformation of the N-H bond is syn to the ortho-chloro group in the adjacent benzene ring. The benzene rings are tilted by 67.8 (1) degrees relative to each other. The crystal structure features dimers linked by N-H?O hydrogen bonds. An intra-molecular N-H?Cl hydrogen bond is also observed. PMID- 21522748 TI - 6-Azido-3-O-benzyl-6-de-oxy-N,N-diethyl-1,2-O-isopropyl-idene-d-glycero-alpha-d gluco-heptofuran-uronamide. AB - Reaction of 3-O-benzyl-1,2-O-isopropyl-idene-alpha-xylo-pentodialdo-1,4-furan-ose with N,N-diethyl-2-(dimethyl-sulfuranil-idene)acetamide gave stereoselectively an ep-oxy-amide, which was regioselectively opened by NaN(3) in dimethyl formamide to give the title compound, C(21)H(30)N(4)O(6). X-ray crystallography confirmed the relative stereochemistry of the title compound and the absolute configuration was determined by the use of d-glucose as the starting material. There are two mol-ecules in the asymmetric unit (Z' = 2). The crystal structure consists of two types of chains of O-H?O hydrogen-bonded mol-ecules running parallel to the b axis, with each mol-ecule acting as a donor and acceptor of one hydrogen bond. PMID- 21522750 TI - 2,6-Bis(2-methyl-1,3-diazinan-2-yl)pyridine. AB - The title compound, C(15)H(25)N(5), is an aminalization product between 2,6 diacetyl-pyridine and 1,3-diamino-propane. It crystallizes with two independent mol-ecules in the asymmetric unit with different conformations. In the first mol ecule, the methyl groups are cis oriented with respect to the pyridine ring [N-C C-C torsion angles = 72.5 (1) and 80.3 (1) degrees ], while they are trans oriented in the second mol-ecule [N-C-C-C torsion angles = 82.6 (1) and -90.8 (1) degrees ]. Each of the two mol-ecules forms centrosymmetric dimers held together by N-H?N hydrogen bonds, thus forming R(2) (2)(16) rings. The two dimers are inter-linked by additional N-H?N bonds into R(4) (4)(14) rings, building chains along the a axis. These patterns influence the orientation (either equatorial or axial) of the N-H bonds. PMID- 21522751 TI - 1,4-Bis(3-chloro-prop-oxy)benzene. AB - The mol-ecule of the title compound, C(12)H(16)Cl(2)O(2), has a center of inversion at the centroid of the benzene ring and the asymmetric unit contains one half-mol-ecule. Inter-molecular C-H?pi inter-actions stabilize the crystal structure. PMID- 21522752 TI - 5-(Pyridinium-4-yl)-1H-1,2,3,4-tetra-zol-1-ide. AB - In the title zwitterionic mol-ecule, C(6)H(5)N(5), the tetra-zole and pyridine rings are nearly coplanar, making a dihedral angle of 2.08 (1) degrees . In the crystal, mol-ecules are connected by classical N-H?N and weak C-H?N hydrogen bonds. PMID- 21522753 TI - Tris(methylammonium thiocyanurate) monohydrate. AB - In the title compound, 3[(CH(3))(3)HN(+)].3C(3)H(2)N(3)S(3) (-).H(2)O, two independent trithio-cyanurate anions construct a planar hydrogen-bonded ribbon with two N-H?S hydrogen bonds linking each pair of adjacent anions in the chain. The third independent anion and the water mol-ecule form a chain by way of N-H?S and O-H?S contacts, which propagates parallel to the ribbon. The chains and ribbons are cross-linked by O-H?S hydrogen bonds, generating sheets. The three independent trimethyl-ammonium cations are contained between the sheets by way of various N-H?S and N-H?N contacts. PMID- 21522754 TI - Tris(4-methyl-phen-yl)phosphine selenide. AB - In the title mol-ecule, C(21)H(21)PSe or PSe(C(7)H(7))(3), the P atom has a distorted PSeC(3) tetra-hedral environment, formed by the Se atom [P=Se = 2.1119 (5) A] and three aryl rings. Two short intra-molecular C-H?Se contacts occur. In the crystal, weak inter-molecular C-H?Se inter-actions link the mol-ecules into zigzag double chains propagating in [100]. The previous report of this structure [Zhdanov et al. (1953 ?). Dokl. Akad. Nauk SSSR (Russ.) (Proc. Nat. Acad. Sci. USSR), 92, 983-985] contained no geometrical data. PMID- 21522755 TI - 1-(4-Bromo-phen-yl)-3-butano-ylthio-urea. AB - In the title compound, C(11)H(13)BrN(2)OS, there are two independent mol-ecules (A and B) in the asymmetric unit. The dihedral angle between the mean planes of the benzene ring and the carbamothioyl group is 63.66 (mol-ecule A) and 80.3 (0) degrees (mol-ecule B). The butanamide group in mol-ecule A is disordered [0.532 (6) and 0.468 (6) occupancy]. The carbamothioyl group is twisted by 63.6 (6) (mol ecule A) and 80.3 (0) degrees (mol-ecule B) from the respective benzene ring. A strong intra-molecular N-H?O hydrogen bond occurs in each mol-ecule. The crystal packing is stabilized by weak inter-molecular N-H?O and N-H?S hydrogen-bond inter actions, the latter forming an infinite co-operative hydrogen-bonded two dimensional network along [110]. PMID- 21522756 TI - 3-(5-Methyl-3-phenyl-1H-pyrazol-1-yl)propanamide monohydrate. AB - In the title compound, C(13)H(15)N(3)O.H(2)O, the dihedral angle between the pyrazole and benzene rings is 26.6 (2) degrees and the N-C-C-C torsion angle is 153.6 (3) degrees . In the crystal, adjacent mol-ecules are linked by N-H?N, N H?O and O-H?O hydrogen bonds into a network structure running along the a axis. PMID- 21522757 TI - 2-(1H-1,2,3-Benzotriazol-1-yl)-N'-(2-chloro-benzyl-idene)acetohydrazide. AB - In the title compound, C(15)H(12)ClN(5)O, the mean planes of the benzotriazole and chloro-phenyl fragments form a dihedral angle of 70.8 (1) degrees . In the crystal, mol-ecules are linked into infinite chains along the a axis by N-H?O hydrogen bonds. Weak inter-molecular C-H?N hydrogen bonds further link these chains into layers parallel to the ab plane. The crystal studied was a racemic twin. PMID- 21522758 TI - (2Z)-N-(4-Meth-oxy-phen-yl)-2-(4-meth-oxy-phenyl-imino)-2H-1,4-benzoxazin-3 amine. AB - In the crystal structure of the title compound, C(22)H(19)N(3)O(3), inter molecular C-H?O hydrogen bonds link the mol-ecules into a zigzag chain parallel to the face diagonal of the ac plane. The meth-oxy phenyl rings make a dihdral angle of 32.38 (7) degrees and form dihedral angles of 0.66 (8) and 24.17 (7) degrees with the fused benzooxazine ring system. PMID- 21522759 TI - Diphenyl (2-chloro-benzyl-amido)-phosphate. AB - In the title compound, C(19)H(17)ClNO(3)P, the P atom exhibits a distorted tetra hedral configuration. In the crystal, pairs of inter-molecular N-H?O(P) hydrogen bonds form centrosymmetric dimers. PMID- 21522760 TI - N'-Benzyl-idene-thio-phene-2-carbohydrazide. AB - In the title compound, C(12)H(10)N(2)OS, the dihedral angle between the phenyl and thio-phene rings is 10.2 (3) degrees . In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. PMID- 21522761 TI - (RS)-1-[5-(2-Chloro-prop-yl)indolin-1-yl]ethanone. AB - In the title compound, C(13)H(16)ClNO, the acetyl-indoline moiety is roughly planar (r.m.s. deviation = 0.0048 A). The chloro-propyl group is out of the plane and is statistically disordered over two positions. Indeed, the Cl and CH(3) groups located on the stereogenic carbon exchange with each other. The whole crystal is a racemate. Non-classical C-H?O hydrogen bonds between symmetry related benzene rings stabilize the crystal structure. PMID- 21522762 TI - (E)-1,1'-Dibutyl-3,3'-biindolinyl-idene-2,2'-dione. AB - In the title mol-ecule, C(24)H(26)N(2)O(2), the two indol-2-one units, which are connected by a C=C double bond, are almost coplanar with an inter-planar angle of 6.8 (1) degrees . On cooling from 293 to 120 K, the space group changes from P2(1)/n to P2(1). Two intra-molecular C-H?O hydrogen bonds occur. PMID- 21522763 TI - 4-(1H-Tetra-zol-5-yl)pyridinium bromide. AB - In the cation of the title compound, C(6)H(6)N(5) (+).Br(-), the pyridine and tetra-zole rings are nearly coplanar, forming a dihedral angle of 6.41 (2) degrees . The organic cations inter-act with the Br(-) anions by N-H?Br hydrogen bonds, leading to the formation of chains parallel to the b axis. PMID- 21522764 TI - 2-Amino-4-methyl-pyridinium 6-carb-oxy-pyridine-2-carboxyl-ate methanol monosolvate. AB - In the title solvated molecular salt, C(6)H(9)N(2) (+).C(7)H(4)NO(4) (-).CH(4)O, the pyridine N atom of 2-amino-4-methyl-pyridine is protonated and one carboxyl group of pyridine-2,6-dicarb-oxy-lic acid is deprotonated. The dihedral angles between the -CO(2) and -COH groups and the pyridine ring are 0.65 (13) and 7.4 degrees . The crystal packing is stabilized by inter-molecular N-H?O, O-H?O and weak C-H?O hydrogen bonds. PMID- 21522765 TI - N,N'-Diphenyl-thio-urea acetone monosolvate. AB - In the title compound, C(13)H(12)N(2)S.C(3)H(6)O, the phenyl rings of the thio urea mol-ecule are in syn and anti positions in relation to the C=S bond. Two mol ecules are connected by N-H?S=C hydrogen bonds into a centrosymmetric dimer. An additional N-H?O=C hydrogen bond to the acetone solvent mol-ecule and some weak C H?pi inter-actions reinforce the crystal structure. PMID- 21522766 TI - 2-Amino-4-(4-fluoro-phen-yl)-6-(naphthalen-1-yl)pyridine-3-carbonitrile. AB - The title compound, C(22)H(14)FN(3), was prepared by a one-pot condensation using malononitrile, an aromatic aldehyde, a methyl ketone and ammonium acetate as reacta-nts under microwave irradiation. The pyridine ring is twisted with respect to the benzene ring and the naphthalene ring system, making dihedral angles of 41.9 (1) and 45.2 (1) degrees , respectively. In the crystal, mol-ecules are connected via inter-molecular N-H?N and C-H?F hydrogen bonds, forming a three dimensional network. PMID- 21522767 TI - (4-Nitro-phenolato)(subphthalo-cyaninato)boron(III). AB - The main feature of the structure of the title compound, C(30)H(16)BN(7)O(3) or NO(2)PhO-BsubPc, are pairs of mol-ecules linked through pi-inter-actions between the concave faces of the BsubPc fragments at a distance of 3.5430 (11) A across an inversion centre. However, the angle between the planes of the five- and six menbered rings involved in this inter-action is 1.44 (10) degrees , causing the inter-acting BsubPcs units to be slightly askew rather than parallel as is typical for pi-stacking inter-actions. PMID- 21522768 TI - 2-Acetyl-3,5,5,9-tetra-methyl-6,7,8,9-tetra-hydro-5H-benzocyclo-hepten-7-one. AB - The title compound, C(17)H(22)O(2), was semi-synthesized from a mixture of alpha atlantone (Z) and alpha-atlantone (E), which were isolated from the essential oil of the Atlas cedar (cedrus atlantica). The mol-ecule consists of fused six- and seven-membered rings. The seven-membered ring is in a screw-boat conformation. PMID- 21522769 TI - (3R,6R,12R,20S,24S)-3,6,12-Triacetyl-20,24-ep-oxy-dammarane-3,6,12,25-tetra-ol. AB - The title compound, C(36)H(58)O(8), was prepared from 20(S)-protopanaxatriol, which was degraded from Panax quinquefolium saponin with sodium in glycerine, extracted and seperated by flash chromatography. Three six-membered rings are in chair conformations, the five-membered ring is in an envelope form and the tetra hydro-furan ring has a conformation inter-mediate between half-chair and envelope. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, and C H?O contacts also occur. The absolute structure was assigned on the basis of the synthesis. PMID- 21522771 TI - 3-[(E)-2-Chloro-3,3,3-trifluoro-prop-1-en-1-yl]-N-(2-fluoro-phen-yl)-2,2-dimethyl cyclo-propane-1-carboxamide. AB - The phenyl ring in the title compound, C(15)H(14)ClF(4)NO, makes a dihedral angle of 80.3 (3) degrees with the cyclo-propane ring. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds into chains running along the a axis. PMID- 21522770 TI - 2,4-Dimethyl-N-(4-methyl-phen-yl)benzene-sulfonamide. AB - The asymmetric unit of the crystal of the title compound, C(15)H(17)NO(2)S, contains two independent mol-ecules, which are twisted at the S-N bonds with C SO(2)-NH-C torsion angles of 48.3 (2) (mol-ecule 1) and -75.7 (3) degrees (mol ecule 2). The dihedral angles between the benzene rings are 72.0 (1) (mol-ecule 1) and 78.3 (1) degrees (mol-ecule 2). The crystal structure features inversion dimers linked by pairs of N-H?O hydrogen bonds. PMID- 21522772 TI - 3-[(E)-2-Chloro-3,3,3-trifluoro-prop-1-en-1-yl]-N-(2-chloro-phen-yl)-2,2-dimethyl cyclo-propane-1-carboxamide. AB - In the title compound, C(15)H(14)Cl(2)F(3)NO, synthesized by the reaction of 3 [(E)-2-chloro-3,3,3-trifluoro-prop-1-en-yl]-2,2-dimethyl-cyclo-propane-carb-oxy lic acid and 2-chloro-aniline, the aromatic ring makes a dihedral angle of 76.7 (3) degrees with the plane of the cyclo-propane ring. In the crystal, inter molecular N-H?O hydrogen bonds link the mol-ecules into chains running along the b axis. PMID- 21522773 TI - 2-[3-(2-Chloro-phen-yl)-5-oxo-1,5-diphenyl-pentyl-idene]malononitrile. AB - In the title compound, C(26)H(19)ClN(2)O, the 2-chloro-phenyl group forms dihedral angles of 59.6 (1) and 31.9 (1) degrees with the phenyl rings. The two phenyl rings are inclined at a dihedral angle of 32.9 (1) degrees with respect to each other. In the crystal, an inter-molecular C-H?N hydrogen bond links the mol-ecules into a polymeric chain running along the c axis. PMID- 21522774 TI - N,N'-Bis(pyridin-2-yl)benzene-1,4-dicarboxamide. AB - Mol-ecules of the title compound, C(18)H(14)N(4)O(2), are located around an inversion center and connected into chains in the crystal via inter-molecular N H?N hydrogen bonds generating an R(2) (2)(8) motif. PMID- 21522775 TI - Methyl 3-(2-furyl-methyl-idene)carbazate. AB - The asymmetric unit of the title compound, C(7)H(8)N(2)O(3), contains two approximately planar mol-ecules (r.m.s. deviations = 0.058 and 0.070 A). In the crystal, mol-ecules are linked into [010] chains by way of alternating N-H?O and N-H?(N,O) hydrogen-bond linkages. PMID- 21522776 TI - 2-(4-Chloro-phen-yl)-3-ethyl-sulfinyl-5-iodo-7-methyl-1-benzofuran. AB - In the title compound, C(17)H(14)ClIO(2)S, the 4-chloro-phenyl ring makes a dihedral angle of 12.13 (5) degrees with the mean plane of the benzofuran ring. In the crystal, pairs of inter-molecular I?O contacts [3.145 (1) A] link the mol ecules into inversion dimers. PMID- 21522777 TI - 4,4'-(1,8-Naphthalene-1,8-di-yl)dibenzonitrile. AB - In the title mol-ecule, C(24)H(14)N(2), the exterior C-C-C angle of the naphthalene ring system involving the two phenyl-substituted C atoms is 126.06 (11) degrees and the dihedral angles between the mean plane of the naphthalene ring system and those of the benzene rings are 66.63 (5) and 67.89 (5) degrees . In the crystal, mol-ecules are linked into a ladders by four weak C-H?pi inter actions. PMID- 21522778 TI - (S)-N-Benzyl-2-methyl-1,2,3,4-tetra-hydro-isoquinoline-3-carboxamide. AB - The structure of the title compound, C(18)H(20)N(2)O, at 173 K has hexa-gonal (P6(1)) symmetry. The N-containing six-membered ring assumes a half-chair conformation. In the crystal, inter-molecular N-H?O hydrogen bonding via the amide groups cross-link the mol-ecules along the a axis. The absolute configuration was confirmed by 2D NMR studies. PMID- 21522779 TI - 2-Chloro-N-methyl-N-phenyl-acetamide. AB - In the title compound, C(9)H(10)ClNO, the non-H atoms, excluding the phenyl group, are almost coplanar (r.m.s. deviation of the non-H atoms = 0.1015 A). The dihedral angle formed between this plane and the benzene ring is 87.07 (5) degrees . Weak inter-molecular C-H?O inter-actions help to stabilize the packing. PMID- 21522780 TI - 2-Fluoro-N'-(2-hy-droxy-benzyl-idene)benzohydrazide. AB - In the title compound, C(14)H(11)FN(2)O(2), an intra-molecular O-H?N hydrogen bond influences the mol-ecular conformation; the two benzene rings form a dihedral angle of 18.4 (3) degrees . The F atom is disordered over two positions in a 0.717 (5):0.283 (5) ratio. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into chains extending along the c axis. PMID- 21522781 TI - (E)-N'-(3-Hy-droxy-benzyl-idene)-3-nitro-benzohydrazide. AB - The title compound, C(14)H(11)N(3)O(4), was prepared by the reaction of 3-nitro benzohydrazide with 3-hy-droxy-benzalde-hyde. The mol-ecule adopts an E configuration about the C=N bond. The dihedral angle between the two benzene rings is 32.3 (2) degrees . In the crystal, the mol-ecules are linked through inter-molecular N-H?O, O-H?N, and O-H?O hydrogen bonds, forming chains in the a axis direction. PMID- 21522782 TI - 2-Fluoro-N'-(2-meth-oxy-benzyl-idene)benzohydrazide. AB - The mol-ecule of the title compound, C(15)H(13)FN(2)O(2), exists in a trans configuration with respect to the methyl-idene unit. The two benzene rings form a dihedral angle of of 64.7 (2) degrees . In the crystal, mol-ecules are linked through N-H?O hydrogen bonds into chains propagating along the c axis. PMID- 21522783 TI - 2-Amino-4-(2,4-dichloro-phen-yl)-6-(naphthalen-1-yl)nicotinonitrile. AB - In the crystal structure of the title compound, C(22)H(13)Cl(2)N(3), the mol ecules are connected via inter-molecular C-H?N and N-H?N hydrogen bonds, forming a three-dimensional network. The dihedral angles between naphthyl ring system and the pyridyl and benzene rings are 55.04 (7) and 75.87 (7) degrees , respectively, whereas the pyridyl and benzene rings are oriented at a dihedral angle of 59.56 (8) degrees . PMID- 21522784 TI - 2,4,6-Trimethyl-pyridinium dihydrogen phosphate. AB - In the title compound, C(8)H(9)N(+).H(2)PO(4) (-), both the cation and anion have crystallographically imposed mirror symmetry (all atoms apart from one O atom lie on the mirror plane). In the crystal, anions and cations are linked by O-H?O and pi-pi stacking inter-actions [centroid-centroid distance = 3.4574 (6) A], forming chains parallel to the b axis. Adjacent chains are further connected by N-H?O hydrogen bonds into a two-dimensional network. PMID- 21522785 TI - (5S)-3-Chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-5-[(1R,2S,5R)-2-isopropyl-5-methyl cyclo-hex-yloxy]furan-2(5H)-one. AB - The title compound, C(18)H(26)ClNO(3), was obtained via a tandem asymmetric Michael addition-elimination reaction of 3,4-dichloro-5-(S)-(l-menth-yloxy)furan 2(5H)-one and 2,5-di-hydro-1H-pyrrole in the presence of potassium fluoride. In the mol-ecule, the nearly planar dihydro-pyrrole ring [maximum atomic deviation = 0.019 (3) A] is oriented at a dihedral angle of 10.73 (8) degrees to the the nearly planar furan-one ring [maximum atomic deviation = 0.011 (2) A]; the cyclo hexane ring adopts a chair conformation. In the crystal, mol-ecules are linked via weak inter-molecular C-H?O hydrogen bonds, forming supra-molecular chains running along the b axis. PMID- 21522786 TI - Bis[3alpha,7alpha,12alpha-tris-(4-nitro-benzo-yloxy)-5beta-cholan-24-yl] disulfide-ethyl acetate-n-hexane (4/4/1). AB - The crystal structure of the title compound, C(90)H(100)N(6)O(24)S(2).C(4)H(8)O(2).0.25C(6)H(14), solved and refined against synchrotron diffraction data, contains two formula units in the asymmetric unit with the all-trans n-hexane mol-ecule having half-occupancy and one of the ethyl acetate mol-ecules disordered over two positions. The two symmetry-independent disulfide mol-ecules are assembled by approximate face-to-face and face-to-edge inter-actions between their 4-nitro-benzo-yloxy groups into an inter-twined dimer having a double-helix-type structure. The centrally placed disulfide bridges in the two symmetry-independent mol-ecules exhibit different helicity as shown by the C-S-S-C torsion angles of 71.0 (1) and -92.5 (1) degrees . PMID- 21522787 TI - (E)-2-[1-(3-Chloro-4-fluoro-phen-yl)ethyl-idene]hydrazinecarbothio-amide. AB - In the crystal of the title compound, C(9)H(9)ClFN(3)S, the molecules are inter connected by N-H?S and N-H?F hydrogen bonds. There are two different N-H?S hydrogen bond: the stronger one links mol-ecules into infinite chains along the b axis with graph-set motif C(4), while the weaker N-H?S hydrogen bond combines with the previous one into an R(2) (2)(8) network. Moreover, the chains are linked into layers parallel to (102) by weak N-H?F hydrogen bonds, which form an R(2) (2)(22) ring motif. In addition, there are also weak pi-pi inter-actions between the benzene rings of adjacent mol-ecules [centroid-centroid distance = 3.8997 (15) A]. PMID- 21522788 TI - Methyl (2Z)-3-[(4-nitro-phen-yl)carbamo-yl]prop-2-enoate. AB - In the title compound, C(11)H(10)N(2)O(5), the amide group is nearly coplanar and the ester group approximately perpendicular to the vinyl C-HC=CH-C group [dihedral angles of 5.0 (2) and 88.89 (5) degrees , respectively]. This results in a short intra-molecular O =C?O=C contact of 2.7201 (17) A between the amide O atom and the ester carbonyl C atom. The prop-2-enamide fragment and the nitro group make dihedral angles of 20.42 (6) and 13.54 (17) degrees , respectively, with the benzene ring. An intra-molecular C-H?O inter-action between the benzene ring and the amide group generates an S(6) ring motif. Inter-molecular C-H?O and N-H?O hydrogen bonds complete R(2) (2)(11) ring motifs and join mol-ecules into [100] chains. PMID- 21522789 TI - Dimethyl (E)-2-(N-phenyl-acetamido)-but-2-enedioate. AB - The title compound, C(14)H(15)NO(5), was obtained from the reaction of acetanilide with dimethyl acetyl-enedicarboxyl-ate in the presence of potassium carbonate. The C=C double bond adopts an E configuration and the geometry around the amide N atom is almost planar rather than pyramidal (mean deviation of 0.0032 A from the C(3)N plane). The packing of the mol-ecules in the crystal structure is stabilized by inter-molecular C-H?O hydrogen bonds. PMID- 21522790 TI - 2,3-Dibromo-1-(4-methyl-phen-yl)-3-(5-nitro-furan-2-yl)propan-1-one. AB - In the title compound, C(14)H(11)Br(2)NO(4), the whole mol-ecule is disordered over two positions with a refined occupancy ratio of 0.539 (9):0.461 (9). The 2 nitro-furan and toluene groups are approximately planar, with maximum deviations of 0.176 (11) and 0.121 (14) A, respectively, in the major component and 0.208 (11) and 0.30 (17) A in the minor component. The dihedral angles between the 2 nitro-furan and toluene groups are 8.7 (5) and 8.0 (9) degrees for the major and minor components, respectively. In the crystal, weak inter-molecular C-H?O inter actions connect mol-ecules into a three-dimensional network, generating R(2) (1)(6) ring motifs. PMID- 21522791 TI - (E)-N-Benzyl-2-cyano-3-phenyl-acryl-amide. AB - In the title compound, C(17)H(14)N(2)O, the N-benzyl-formamide and phenyl groups are located on the opposite sides of the C=C bond, showing an E configuration; the terminal phenyl rings are twisted to each other at a dihedral angle of 63.61 (7) degrees . Inter-molecular classical N-H?N and weak C-H?O hydrogen bonds occur in the crystal structure. PMID- 21522792 TI - 1,3-Bis[(3-allyl-imidazol-3-ium-1-yl)meth-yl]benzene bis-(hexa fluoridophosphate). AB - In the title compound, C(20)H(24)N(4) (2+).2PF(6) (-), the ethene and 3-allyl imidazolium moieties of the cation are disordered over two positions with refined site occupancies of 0.664 (19):0.336 (19) and 0.784 (7):0.216 (7), respectively, whereas four F atoms of one hexa-fluoridophosphate anion and all atoms in the other hexa-fluoridophosphate anion are disordered over two positions with refined site occupancies of 0.764 (5):0.2365) and 0.847 (9):0.153 (9), respectively. The benzene ring is inclined at angles of 78.2 (3), 81.3 (4) and 73.9 (12) degrees with the 1H-imidazol-3-ium ring and the major and minor components of the disordered 1H-imidazol-3-ium ring, respectively. In the crystal, the hexa fluoridophosphate anions link the cations into two-dimensional networks parallel to (001) via inter-molecular C-H?F hydrogen bonds. The crystal structure is further consolidated by pi-pi [centroid-centroid distance = 3.672 (3) A] and C H?pi inter-actions. PMID- 21522793 TI - 2-Aza-niumyl-4-(ethyl-carbamo-yl)butano-ate: the zwitterionic form of the amino acid theanine. AB - In the title zwitterion, C(7)H(14)N(2)O(3), the ethyl-amino and the 5-oxo groups are positionally disordered with occupancy ratios of 0.50:0.50 and 0.70:0.30, respectively. The terminal ethyl -CH(3) group undergoes considerable thermal motion. In the crystal, mol-ecules are linked via N-H?O hydrogen bonds, forming a two-dimensional arrangement propagating in the bc plane. PMID- 21522794 TI - 4,4-Dimethyl-3,4-dihydro-pyrido[2',3':3,4]pyrazolo-[1,5-a][1,3,5]triazin-2-amine ethanol monosolvate. AB - In the title compound, C(10)H(12)N(6).C(2)H(5)OH, the planarity of the heterocyclic system is slightly distorted at the triazine ring (r.m.s. deviation = 0.1191 A), which adopts a conformation best described as inter-mediate between a flattened twisted boat and a half-boat with the tertiary Csp(3) atom at the bow. In the crystal, mol-ecules form centrosymmetric dimers connected by N?H-O and O?H-N hydrogen bonds between the amino group H atom, the ethanol solvent mol ecule and the triazine N atom, making an R(4) (4)(12) graph-set motif. The other H atom of the amino group and the H atom on the endocyclic N atom form N?H-N hydrogen bonds with the N atoms of the pyrazole and pyridine rings, respectively, linking the mol-ecules into C(7)C(7) chains with the R(2) (2)(8) binary graph-set motif running along [010]. PMID- 21522795 TI - 2-Phenyl-7-(4-pyridyl-methyl-amino)-1,2,4-triazolo[1,5-a][1,3,5]triazin-5(4H) one. AB - In the title compound, C(16)H(13)N(7)O, the 1,2,4-triazolo[1,5-a][1,3,5]triazine heterocyclic system is essentially planar (r.m.s. deviation = 0.0375 A). The attached benzene ring lies almost in the mean plane of 1,2,4-triazolo[1,5 a][1,3,5]triazine [dihedral angle = 1.36 (23) degrees ], while the pyridine ring is turned out of this plane by the amino-methyl bridge [dihedral angle = 69.22 (9) degrees ]. The amino group H atom is involved in intra-molecular hydrogen bonding with a triazole N atom. In the crystal, mol-ecules are connected via C(=O)NH?N hydrogen bonds into C(11) chains parallel to [100]. The amino group H atom acts as a hydrogen-bond donor, forming an NH?O=C hydrogen bond with the carbonyl O atom, which links the mol-ecules into C(6) chains running along [011] and [01]. PMID- 21522796 TI - Bis(2,9-dimethyl-1,10-phenanthrolin-1-ium) hydrogen (S,S)-tartrate nona-hydrate. AB - The asymmetric unit of the title compound, 2C(14)H(13)N(2) (+).2C(4)H(5)O(6) ( ).9H(2)O, contains two cations and two anions in addition to nine mol-ecules of water. Each of the hydrogen tartrate anions is hydrogen bonded to itself by translation along [100] in a head-to-tail fashion via a short hydrogen bond with donor-acceptor distances of 2.473 (4) and 2.496 (4) A. A large number of inter molecular O-H?O, N-H?O and C-H?O hydrogen-bonding inter-actions, as well as pi-pi stacking [centroid-centroid distances in the range 3.642 (3) to 3.866 (3) A], play an important role in the crystal structure. PMID- 21522797 TI - Bis(2-meth-oxy-phen-yl)(phen-yl)phosphine selenide. AB - The title compound, C(20)H(19)O(2)PSe or SePPh(2-OMe-C(6)H(3))(2), crystallizes with two distinct orientations for the meth-oxy groups. The Se=P bond is 2.1170 (7) A and the cone angle is 176.0 degrees . Intra-molecular C-H?Se inter-actions occur. In the crystal, mol-ecules are linked by inter-molecular C-H?Se inter actions. PMID- 21522798 TI - Spiro-[indene-1,1'-benzo[e]indolin]-2'-one. AB - In the title compound, C(20)H(13)NO, the indene ring is disordered over two sites with an occupancy ratio of 0.557 (2):0.443 (2). Both disordered components of indene are nearly perpendicular to the naphthalene ring system, making dihedral angles of 90.9 (2) and 85.0 (5) degrees . The five-membered ring of the 1H-pyrrol 2(3H)-one adopts an envelope conformation with the spiro C atom at the flap position. Inter-molecular classical N-H?O and weak C-H?O hydrogen bonding is present in the crystal structure. PMID- 21522799 TI - 1,4-Bis(1H-benzimidazol-2-yl)benzene methanol monosolvate. AB - The asymmetric unit of the title compound, C(20)H(14)N(4).CH(4)O, contains two independent half-mol-ecules, each located on an inversion centre, and a methanol solvent mol-ecule. The benzimidazolyl groups form different dihedral angles [24.0 (1) and 11.6 (1) degrees ] with the plane of the central benzene ring in the two mol-ecules. In the crystal, a two-dimensional network is formed through N-H? N, N H?O and O-H?N hydrogen-bonding inter-actions between the benzimidazole units and methanol solvent mol-ecules. pi-pi stacking inter-actions also occur between the benzimidazole rings of adjacent mol-ecules, with centroid-centroid distances of 3.720 (14) A and inter-planar distances of 3.53 (1) A . PMID- 21522800 TI - 3-[4-(2-Amino-2-oxoeth-yl)phen-oxy]-2-hy-droxy-N-isopropyl-propanaminium 1,1' binaphthyl-2,2'-diyl phosphate. AB - In the title salt, C(14)H(23)N(2)O(3) (+).C(20)H(12)O(4)P(-), the dihedral angle between the two naphthyl ring systems in the anion is 57.77 (6) degrees . In the crystal, an O-H?O hydrogen bond links the components. The ammonium group engages in N-H?O hydrogen bonds, generating a layer structure. PMID- 21522801 TI - Methyl 5'-(2-hy-droxy-phen-yl)-4',5',6',7'-tetra-hydro-spiro-[2H-1-benzopyran 2,7'-1,2,4-triazolo[1,5-a]pyrimidine]-3-carboxyl-ate. AB - There are two crystallographically independent mol-ecules in the asymmetric unit of the title compound, C(21)H(18)N(4)O(4). The substituted benzopyran portion of one of the independent mol-ecules exhibits disorder [occupancy 0.5248 (18):0.4752 (18)], which was modelled by using two sets of atomic positions and restraints on the chemically equivalent bond lengths and angles. The central, partially saturated pyrimidine rings of both independent mol-ecules were found to assume unsymmetrical half-chair conformations. The hy-droxy-phenyl substituent occupies an equatorial position in both mol-ecules, and is rotated by 55.6 (1) degrees from the mean plane of the pyrimidine ring in one independent mol-ecule, and by 53.4 (1) degrees in the other. In the crystal, there are two types of inter molecular hydrogen bond present: reciprocal N-H?N inter-actions join the two crystallographically independent mol-ecules into a dimer and O-H?N inter-actions link the dimers into sheets in the ab plane. PMID- 21522802 TI - N-(Trimethyl-sil-yl)methane-sulfonamide. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(4)H(13)NO(2)SSi. In the crystal, mol-ecules are linked via inter-molecular N H?O hydrogen bonds, forming chains along [001]. The crystal studied was an inversion twin, the refined ratio of twin domains being 0.61 (9):0.39 (9). PMID- 21522803 TI - 1-[5-(Anthracen-9-yl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]ethanone. AB - In the title compound, C(25)H(20)N(2)O, the pyrazoline ring is nearly planar [maximum atomic deviation = 0.0254 (17) A]; but the anthracene ring system is distorted from a coplanar structure [maximum atomic deviation = 0.181 (3) A], the dihedral angle between the outer benzene rings being 10.68 (13) degrees . The pyrazoline ring is almost perpendicular to the mean plane of the anthracene ring system [dihedral angle = 76.94 (8) degrees ], but nearly coplanar with the phenyl ring [dihedral angle = 1.63 (7) degrees ]. pi-pi stacking is observed between parallel benzene rings of adjacent anthracene units, the face-to-face distance being 3.27 (3) A. Weak intra-molecular C-H?N hydrogen bonding also occurs. PMID- 21522804 TI - 2-[(E)-2-Hy-droxy-5-(trifluoro-meth-oxy)benzyl-idene-amino]-4-methyl-phenol. AB - The title compound, C(15)H(12)F(3)NO(3), is a Schiff base which adopts the cis quinoid form in the solid state. The dihedral angle between the least-squares planes of the benzene rings being 3.6 (1) degrees . The F atoms of the -CF(3) group are disordered over two sets of sites with refined occupancies of 0.61 (5) and 0.39 (5). An intra-molecular N-H?O hydrogen bond occurs. The crystal structure is stabilized by inter-molecular O-H?O hydrogen bonds. PMID- 21522805 TI - 2-Amino-4-(2-fluoro-phen-yl)-5,6-dihydro-benzo[h]quinoline-3-carbonitrile. AB - In the title compound, C(20)H(14)FN(3), the F atom of the fluoro-substituted benzene ring in the 4-position of the 5,6-dihydro-benzo[h]quinoline system is disordered over two positions (0.80 and 0.20 occupancy). The dihedral angle between the pyridine and fluorobenzene rings is 73.2 (2) A. The crystal structure is established by inter-molecular N-H?N hydrogen bonds, forming a three dimensional network. PMID- 21522806 TI - Bis(2,4-dimeth-oxy-phen-yl)(phen-yl)phosphine selenide. AB - In the title mol-ecule, C(22)H(23)O(4)PSe, the P atom has a distorted tetra hedral environment formed by the selenide atom [P=Se = 2.1219 (5) A] and three aryl rings. The orientations of the meth-oxy groups in the two 2,4-dimeth-oxy phenyl ligands are distinct, as seen from the torsion angles: C-C-O-C = 14.7 (3) and 175.97 (17) degrees in one ligand, and -9.1 (2) and 5.1 (3) degrees in the other. In the crystal, weak inter-molecular C-H?Se inter-actions link the mol ecules into zigzag chains propagated in [010]. PMID- 21522807 TI - Ethyl 4-(1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl)benzoate. AB - The title compound, C(21)H(15)NO(4), was synthesized by reducing the Schiff base obtained from acenaphthenequinone and ethyl-4-aminobenzoate. The dihedral angle between the essentially planar 1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoline ring system [maximum deviation = 0.061 (2) A] and the benzene ring is 75.08 (10) degrees . In the crystal, mol-ecules are connected via weak inter-molecular C-H?O hydrogen bonds, forming a two-dimensional network. The ethyl group is disordered over two sets of sites with a refined occupancy ratio of 0.502 (12):0.498 (12). PMID- 21522808 TI - K(0.12)Na(0.54)Ag(0.34)Nb(4)O(9)AsO(4). AB - Potassium sodium silver tetra-niobium nona-oxide arsenate, K(0.12)Na(0.54)Ag(0.34)Nb(4)AsO(13), synthesized by solid-state reaction at 1123 K, adopts a three-dimensional framework delimiting tunnels running along [001] in which occupationally disordered sodium, silver, and potassium ions are located. Of the 11 atoms in the asymmetric unit (two Nb, one As, one Ag, one K, one Na and fiveO), nine are located on special positions: one Nb and the K, Ag, Na and two O atoms are situated on mirror planes, the other Nb is on a twofold rotation axis, and the As atom and one O atom are on sites of m2m symmetry. PMID- 21522809 TI - Penta-europium dicadmium penta-anti-monide oxide, Eu(5)Cd(2)Sb(5)O. AB - The title compound, Eu(5)Cd(2)Sb(5)O adopts the Ba(5)Cd(2)Sb(5)F-type structure (Pearson symbol oC52), which contains nine crystallographically unique sites in the asymmetric unit, all on special positions. One Eu, two Sb, and the Cd atom have site symmetry m..; two other Eu, the third Sb and the O atom have site symmetry m2m; the remaining Eu atom has 2/m.. symmetry. Eu atoms fill penta-gonal channels built from corner-sharing CdSb(4) tetra-hedra. The isolated O atom, i.e., an oxide ion O(2-), is located in a distorted tetra-hedral cavity formed by four Eu cations. PMID- 21522810 TI - Praseodymium(III) sulfate hydroxide, Pr(SO(4))(OH). AB - The title compound, Pr(SO(4))(OH), obtained under hydro-thermal conditions, consists of Pr(III) ions coordinated by nine O atoms from six sulfate groups and three hydroxide anions. The bridging mode of the O atoms results in the formation of a three-dimensional framework, stabilized by two O-H?O hydrogen-bonding inter actions. PMID- 21522811 TI - Disodium calcium dinickel(II) bis-[diphosphate(V)] deca-hydrate. AB - In the title compound, Na(2)CaNi(2)(P(2)O(7))(2)(H(2)O)(10), there are two distinct P-atom sites, each tetra-hedrally coordinated by four O atoms. The resulting phosphate tetra-hedra link through a common O atom, forming a [P(2)O(7)](4-) diphosphate unit. The Ni-O coordination is square pyramidal with four O atoms from two diphosphate groups in equatorial positions and the vertex occupied by a water O atom. The (P(2)O(7))(H(2)O) units link the Ni atoms, forming a chain of pyramids and tetra-hedra. As a result of the d-glide and twofold-axis symmetry of space group Fdd2, the chains propagate along [101] and [10], and chains in adjacent layers are mutually orthogonal. The Ca cation, located on a rotation axis, and the Na cation are each octa-hedrally coordinated by four O atoms and two waters. The Ni-chain arrangement is stabilized by Ca and Na coordination and a network of O-H?O hydrogen bonds. PMID- 21522812 TI - Penta-potassium MU-arsenato-bis-(hy-droxy-tetra-molybdate) dihydrate. AB - The title arsenatomolybdate, K(5)[Mo(8)O(24)(OH)(2)(AsO(4))].2H(2)O, which was obtained hydro-thermally, features an [AsMo(8)O(28)(OH)(2)](5-) anion, which is formed by two Mo(4)O(14)(OH) units that are linked by As in a sandwich-like fashion. The overall symmetry of the anion is m2m. The {Mo(4)O(14)(OH)} core is composed of two pairs of confacial biocta-hedral {Mo(2)O(9)} units with two MU(4) O atoms which have been characterized as hydroxyl groups. The anions are further inter-connected by potassium cations, forming a three-dimensional network structure with the uncoordinated water mol-ecules occupying the channels. The structure is further stabilized by O-H?O hydrogen bonding. PMID- 21522813 TI - Tetra-yttrium(III) tris-ulfide disilicate. AB - Tetra-yttrium(III) tris-ulfide disilicate, Y(4)S(3)(Si(2)O(7)), crystallizes in the Sm(4)S(3)(Si(2)O(7)) structure type. The structure consists of isolated (Si(2)O(7))(6-) units (2mm. symmetry) and two crystallo-graphically independent Y(3+) cations bridged by one S and one O atom. The first Y atom (site symmetry .m.) is coordinated by three O atoms and three S atoms in a trigonal-prismatic arrangement whereas the second Y atom (site symmetry ..2) is coordinated by six O atoms and three S atoms in a tricapped trigonal-prismatic arrangement. PMID- 21522814 TI - Nickel bis-muth boride, Ni(23-x)Bi(x)B(6) [x = 2.44 (1)]. AB - The tau-boride Ni(23-x)Bi(x)B(6) [x = 2.44 (1)] adopts a ternary variant of the cubic Cr(23)C(6)-type structure, with Ni(8) cubes and Ni(12) cubocta-hedra arranged in a NaCl-type pattern. Two of the four independent metal sites (8c, 3m symmetry; 4a, mm symmetry) are occupied by a mixture of Ni and Bi atoms in a 0.106 (6):0.894 (6) and a 0.350 (7):0.650 (7) ratio, respectively. PMID- 21522815 TI - Redetermination of synthetic warwickite, Mg(3)TiO(2)(BO(3))(2). AB - Single crystals of warwickite, trimagnesium titanium(IV) dioxide bis-(borate), Mg(3)TiO(2)(BO(3))(2), were prepared by slow cooling of the melt. The title compound is isotypic with Co(3)TiO(2)(BO(3))(2). In contrast to the previous refinement of warwickite [Moore & Araki (1974 ?). Am. Mineral.59, 985-1004], that reported only isotropic atomic displacement parameters for all atoms, anisotropic displacement parameters of all atoms were refined during the current redetermination. All atoms are situated on special positions (site symmetry .m.). One of the two Mg sites is statistically disordered with Ti atoms (ratio 1:1), while the other is fully occupied by Mg atoms. The occupancy ratio of the Mg and Ti atoms is similar to that reported in the previous study. Metal atoms (M) at the Ti/Mg and Mg sites are coordinated by six O atoms in form of distorted octa hedra. Four edge-sharing MO(6) octa-hedra form M(4)O(18) units, which are connected by common corners into layers parallel to (010). Adjacent layers are linked along [010] into a framework structure by sharing common edges. The B atoms are located in the triangular prismatic tunnels of the framework. PMID- 21522816 TI - Redetermination of MoPt(3)Si(4) from single-crystal data. AB - The crystal structure of molybdenum triplatinum tetrasilicide, MoPt(3)Si(4), determined previously from powder diffraction data [Joubert et al. (2010 ?). J. Solid State Chem.183, 173-179], has been redetermined using a single crystal synthesized from the elements by high-frequency melting. The redetermination provides more precise geometrical data and also anisotropic displacement parameters. The crystal structure can be considered to be derived from the PtSi structure type with an ordered substitution of Pt by Mo atoms, but leading to a very distorted Si network compared to the parent structure. Mo and Pt exhibit different coordination polyhedra. These are based on bicapped-square anti-prisms, but with two additional vertices in cis positions for Mo, whereas they are in trans positions for Pt (as in PtSi). The coordination polyhedra for three of the Si atoms can be considered as highly deformed square anti-prisms (as in PtSi), while the fourth Si atom has a bicapped trigonal-prismatic coordination geometry. PMID- 21522817 TI - [Al(H(2)O)(6)][Cr(OH)(6)Mo(6)O(18)].10H(2)O. AB - The title compound, [Al(H(2)O)(6)][Cr(OH)(6)Mo(6)O(18)].10H(2)O, hexa-aqua aluminium hexa-hydroxidoocta-deca-oxido-molybdo-chromate(III) deca-hydrate, crystallizes isotypically with its gallium analogue [Ga(H(2)O)(6)][Cr(OH)(6)Mo(6)O(18)].10H(2)O. In the structure of the title compound, both the [Al(H(2)O)(6)](3+) cation and the Anderson-type [Cr(OH)(6)Mo(6)O(18)](3-) anion lie on centres of inversion. The anion is composed of seven edge-sharing octa-hedra, six of which are MoO(6) octa-hedra that are arranged hexa-gonally around the central Cr(OH)(6) octa-hedron. The anions are linked to each other by O-H?O hydrogen bonds into infinite chains along [100]. These chains are further connected with the [Al(H(2)O)(6)](3+) cations through O-H?O hydrogen bonds into sheets parallel to (01). O-H?O hydrogen bonds involving all the lattice water mol-ecules finally link the sheets into a three-dimensional network. PMID- 21522818 TI - Cs(2)UPd(3)Se(6). AB - Dicaesium uranium(IV) tripalladium(II) hexa-selenide, Cs(2)UPd(3)Se(6), crystallizes in the space group Fmmm in the Ba(2)NaCu(3)O(6) structure type. The asymmetric unit comprises the following atoms with site symmetries as shown: U1 (mm2), Cs1 (222), Cs2 (m2m), Pd1 (.m.), Pd2 (2mm), Se1 (m..), and Se2 (1). This layered structure contains six edge-sharing square-planar [PdSe(4)] units that form a hexa-gon. These, in turn, edge-share with [USe(6)] trigonal-prismatic units, forming an extended layer parallel to (010). The layers are stacked along [010]. They are staggered, and are separated by the Cs atoms. The Cs atoms are either coordinated in a square anti-prism of Se atoms or are ten-coordinate, with one square face and the opposite face hexa-gonal. PMID- 21522819 TI - {2-Morpholino-N-[1-(2-pyrid-yl)ethyl-idene]ethanamine-kappaN,N',N''}bis-(thio cyanato-kappaN)zinc(II). AB - The asymmetric unit of the title compound, [Zn(NCS)(2)(C(13)H(19)N(3)O)], contains two crystallographically independent mol-ecules. In each mol-ecule, the Zn(II) ion is five-coordinated by the N,N',N"-tridentate Schiff base and the N atoms of two thio-cyanate ligands in a distorted square-pyramidal geometry. The two mol-ecules differ mainly in the deviations from the ideal geometry, with tau values of 0.14 and 0.33. In the crystal, inter-molecular C-H?S hydrogen bonds are observed. An intra-molecular C-H?N hydrogen bond occurs in one of the independent mol-ecules. PMID- 21522820 TI - Hexaaqua-magnesium bis-{4-[(5-bromo-2-hy-droxy-benzyl-idene)amino]-benzene sulfonate} dihydrate. AB - In the title hydrated mol-ecular salt, [Mg(H(2)O)(6)](C(13)H(9)BrNO(4)S)(2).2H(2)O, the Mg(2+) ion (site symmetry ) adopts a near regular MgO(6) octa-hedral coordination geometry. In the anion, the dihedral angle between the aromatic rings is 2.5 (2) degrees and an intra molecular O-H?N hydrogen bond generates an S(6) ring. In the crystal, the components are linked by O-H?O and O-H?Br hydrogen bonds. PMID- 21522821 TI - (Dimethyl sulfoxide-kappaO)bis-(thio-semicarbazide-kappaN,S)zinc dipicrate dimethyl sulfoxide solvate monohydrate. AB - The title complex, [Zn(CH(5)N(3)S)(2)(C(2)H(6)OS)](C(6)H(2)N(3)O(7))(2).C(2)H(6)OS.H(2)O, is composed of a [Zn(thio-semi-carbazide)(2)(DMSO)](2+) cation (where DMSO is dimethyl sulfoxide), and two picrate anions. In the asymmetric unit, there is also a solvent mol-ecule of DMSO and a water mol-ecule of crystallization. In the cation, the Zn(II) atom is five-coordinated in a distorted square-pyramidal geometry. It coordinates to the O atom of a DMSO mol-ecule and to the S and one N atom of two thio-semicarbazide mol-ecules, which behave as bidentate ligands coordinating in a trans arrangement. In the crystal, a number of N-H?O, O-H?O and N-H?S hydrogen bonds link the mol-ecules into two-dimensional networks. These networks are further linked via weak C-H?O inter-actions, forming a three dimensional arrangement. Positional disorder in one methyl group of the coordinated DMSO molecule and in the two picrate anions was observed. PMID- 21522822 TI - Bis(2-amino-1,3-thia-zole-kappaN)diazido-zinc. AB - In the title complex, [Zn(N(3))(2)(C(3)H(4)N(2)S)(2)], the Zn(II) atom is tetra hedrally coordinated by two terminal azide ligands and by the ring N atoms of two different 2-amino-thia-zole ligands. Intra-molecular N-H?N hydrogen bonds between the amino groups of both 2-amino-thia-zole ligands and the N atom of one of the azide ligands ensure that the heterocyclic rings are oriented in the same direction. Inter-molecular N-H?N hydrogen bonds link the mol-ecules into zigzag sheets in the ac plane. PMID- 21522823 TI - Diaqua-[3,5-bis-(4-pyrid-yl)-1H-1,2,4-triazole-kappaN](pyridine-2,6-dicarboxyl ato-kappaO,N,O)nickel(II). AB - In the title compound, [Ni(C(7)H(3)NO(4))(C(12)H(9)N(5))(H(2)O)(2)], the Ni(II) atom is coordinated in a distorted octa-hedral geometry by one N and two O atoms from a pyridine-2,6-dicarboxyl-ate ligand, one N atom from a 3,5-bis-(4-pyrid-yl) 1H-1,2,4-triazole ligand in equatorial positions and two water mol-ecules in axial positions. The crystal packing is consolidated by inter-molecular O-H?O, O H?N and N-H?O hydrogen bonds. PMID- 21522824 TI - catena-Poly[[diaqua-cobalt(II)]-MU-4,4'-[1,4-phenyl-enebis(-oxy)]dibutano-ato kappaO,O':O'',O''']. AB - In the title coordination polymer, [Co(C(14)H(16)O(6))(H(2)O)(2)](n), the Co(II) ion, situated on a twofold rotation axis, is coordinated by four O atoms from two 4,4'-[1,4-phenyl-enebis(-oxy)]dibutano-ate (L) ligands and two water mol-ecules in a highly distorted octa-hedral geometry. Each L ligand is situated on an inversion center and bridges two Co(II) atoms, forming a zigzag polymeric chain propagating in [10]. Inter-molecular O-H?O hydrogen bonds further consolidate the crystal packing. PMID- 21522825 TI - cis-Dichloridobis(1,10-phenanthroline)chromium(III) chloride. AB - In the title complex, [CrCl(2)(C(12)H(8)N(2))(2)]Cl, the Cr(III) ion is situated on a twofold rotation axis and displays a slightly distorted octa-hedral CrCl(2)N(4) coordination geometry. The Cr environment is composed of a cis arrangement of two 1,10-phenanthroline and two chloride ligands. The chloride counter-anion exhibits half-occupation and is equally disordered over two positions. PMID- 21522826 TI - Hexa-MU(2)-chlorido-MU(4)-oxido-tetra-kis-[(3-methyl-5-phenyl-1H-pyrazole kappaN)copper(II)]. AB - The title compound, [Cu(4)Cl(6)O(C(10)H(10)N(2))(4)], contains four Cu(II) atoms which are bridged by six chloride anions. The central O atom is located on a crystallographic fourfold roto-inversion axis. Each Cu(II) atom is coordinated by an N atom of a neutral monodentate 3-methyl-5-phenyl-pyrazole ligand, three Cl(-) anions, and one O(2-) anion. The geometry at each Cu(II) atom is distorted trigonal-bipyramidal, with the three Cl(-) ions in the equatorial plane and the N and O atoms in the axial positions. PMID- 21522827 TI - Poly[MU-(1,3-dihy-droxy-propan-2-olato)-potassium]. AB - The asymmetric unit of the title compound, [K(C(3)H(7)O(3))](n) or K[H(2)gl](n), common name potassium glycerolate, contains half the K(+) cation and half of the glycerolate anion. The other half of the anion is generated through a mirror plane passing through the K atom, and a C, an H and an O atom of the glycerolate ligand. The K(+) ion is coordinated by the O atoms of the OH groups, leading to a six-membered chelate ring that adopts a very distorted boat conformation. The negatively charged O atom of the glycerolate anion, [H(2)gl(-)], is found in the flagpole position and forms an ionic bond with the K(+) ion. The O atoms of the hydroxo groups are coordinated to two K(+) ions, whereas the negatively charged O atom is bonded to one K(+) ion. The K(+) ion is coordinated by three other symmetry-related monodentate H(2)gl(-) ligands, so that each H(2)gl(-) ligand is bonded to two K(+) ions, and the potassium has a seven-coordinate environment. The H(2)gl(-) ligands are connected via a strong O-H?O hydrogen bond and, together with the K?O inter-connections, form polymeric sheets which propagate in the directions of the a and b axes. PMID- 21522828 TI - Acetonitrile-{3-[bis-(2-pyridyl-methyl-kappaN)amino-kappaN]propanol kappaO}(perchlorato-kappaO)copper(II) perchlorate. AB - In the title compound, [Cu(ClO(4))(C(2)H(3)N)(C(15)H(19)N(3)O)]ClO(4), the Cu(II) ion is coordinated by three N atoms and a hydroxyl-O atom of the tetra-dentate ligand, an O atom of a perchlorate ion and an N atom of an acetonitrile ligand giving a tetra-gonally distorted octa-hedral environment around the copper(II) atom. There is an offset inter-complex face-to-face pi-pi inter-action [centroid centroid distance = 3.718 (2) A] involving one of the pyridine rings of the ligand as well as an intra-complex O-H?O hydrogen-bonding inter-action between the coordinated hydroxyl group of the ligand and the perchlorate counter-ion. PMID- 21522829 TI - {1-[(2-Oxidonaphthalen-1-yl)methylidene]thiosemicarbazidato-kappaN,O,S}diphenyl tin(IV). AB - The asymmetric unit of the title compound, [Sn(C(6)H(5))(2)(C(12)H(9)N(3)OS)], contains two independent mol-ecules with almost identical configurations. In each mol-ecule, the Sn(IV) atom is coordinated by O, N and S atoms from a (2-oxido-1 naph-thaldehyde)-thio-semicarbazonato ligand and two C atoms from phenyl rings in a distorted trigonal-bipyramidal geometry. Weak inter-molecular N-H?O and N-H?S hydrogen bonds link four mol-ecules into a centrosymmetric tetra-mer. The crystal packing exhibits short inter-molecular S?S contacts of 3.335 (3) A. PMID- 21522830 TI - Di-MU-methanolato-kappaO:O-bis[tri-chlorido(dimethyl-formamide-kappaO)tin(IV)]. AB - The title compound, [Sn(2)(CH(3)O)(2)Cl(6)(C(3)H(7)NO)(2)], contains two hexa coordinated Sn(IV) atoms symmetrically bridged by two deprotonated methanol ligands, with an inversion center in the middle of the planar Sn(2)O(2) ring. The other sites of the distorted octa-hedral coordination geometry of the Sn(IV) atom are occupied by three Cl atoms and one O atom from a dimethyl-formamide mol ecule. The complex mol-ecules are connected by weak C-H?Cl hydrogen bonds into a two-dimensional supra-molecular network parallel to (10). PMID- 21522831 TI - Bis(MU-chloroacetato-kappaO:O')bis(chloro-acetato-kappaO)di-MU(3)-oxido tetrakis[dibenzyl-tin(IV)]. AB - The title tetra-nuclear complex mol-ecule, [Sn(4)(C(7)H(7))(8)(C(2)H(2)ClO(2))(4)O(2)], has crystallographically imposed inversion symmetry. Each Sn atom has a distorted trigonal-bipyramidal geometry, with the equatorial plane formed by an oxido O atom and two C atoms of two benzyl anions. The configuration of the complex is stabilized by a pair of C-H?O hydrogen bonds. In the crystal, complex mol-ecules are linked into zigzag chains along [110] by C-H?O hydrogen bonds. PMID- 21522832 TI - Bis(MU-3,5-difluorobenzoato)bis[(3,5-di-fluorobenzoato)dimethyltin(IV)]. AB - In the dinuclear title complex, [Sn(2)(CH(3))(4)(C(7)H(3)F(2)O(2))(4)], the Sn(IV) atom is chelated by two 3,5-difluoro-benzoate (dfb) anions and coordinated by two methyl groups while an O atom from the adjacent dfb anion bridges the Sb atom with a longer Sb-O bond distance of 2.793 (4) A. The complex mol-ecule has 2 symmetry and the Sn(IV) atom is in a distorted penta-gonal-bipyramidal coordination geometry. In the crystal, mol-ecules are connected by C-H?O and C H?F hydrogen bonds. PMID- 21522833 TI - Bis{tris[2-(2-oxidobenzylideneazaniumyl)ethyl]amine-kappaO,O',O''}calcium bis(perchlorate) acetonitrile disolvate. AB - The title complex, [Ca(C(27)H(30)N(4)O(3))(2)](ClO(4))(2).2CH(3)CN, is composed of centrosymmetric (CaL(2))(2+) cations [L = tris-(2-hy-droxy-benzoyl-amino-eth yl)amine = H(3)saltren], uncoordin-ated perchlorate anions and acetonitrile solvent mol-ecules. The calcium ion is six-coordinated and is bonded to all phen oxy O atoms from both zwitterionic saltren mol-ecules. There are strong intra molecular N-H?O hydrogen bonds. The cations are linked into chains via weak inter molecular C-H?O hydrogen bonds and C-H?pi and pi-pi stacking inter-actions [centroid-centroid distances = 3.306 (3) and 3.415 (3) A]. PMID- 21522834 TI - [MU(2)-Bis(diphenyl-phosphanyl)methane][MU(3)-bis-(diphenyl-phosphanyl)meth yl]trichlorido-tetra-gold(I) tetra-hydro-furan disolvate. AB - The title tetra-nuclear complex, [Au(4)(C(25)H(21)P(2))Cl(3)(C(25)H(22)P(2))].2C(4)H(8)O, features two non equivalent Ph(2)PCPPh(2) fragments, one of which represents the 'complete' mol ecule (with two H atoms at the central C atom); each of the two P atoms of this mol-ecule is coordinated by an Au atom [Au-P = 2.2256 (13) and 2.2710 (13) A], and these two Au atoms form an Au-Au bond [3.2945 (3) A], thus closing the five membered Au(2)P(2)C ring. The first of these Au atoms has a terminal chlorido ligand [Au-Cl = 2.2806 (12) A], whereas the second Au atom forms a covalent bond with the central C atom of the bis-(diphenyl-phosphino)methyl group [Au-C = 2.114 (5) A]; the latter group in turn coordinates with its P atoms the gold atoms of the Cl-Au-Au-Cl group [Au-P = 2.2356 (13) and 2.2338 (13), Au-Au = 3.3177 (3), Au Cl = 2.3091 (12) and 2.2950 (13) A], thus closing the second Au(2)P(2)C ring. The two such rings have different chemical functions, but both exhibit envelope conformations. However, the first (with different substituents at the Au atoms) is non-symmetrical with one of the P atoms in the flap position of the envelope; the other one has a conformation with mirror symmetry, and the gold-substituted C atom is displaced by 0.740 (5) A from the almost exactly planar (r.m.s. deviation = 0.0038 A) Au(2)P(2) group. PMID- 21522835 TI - catena-Poly[[trimethyl-tin(IV)]-MU-phenyl-seleninato-kappaO:O']. AB - In the title polymeric coordination compound, [Sn(CH(3))(3)(C(6)H(5)O(2)Se)](n), the Sn(IV) atom has a distorted trigonal-bipyramidal geometry, with two O atoms of two symmetry-related bridging phenyl-seleninate anions in axial positions and three methyl groups in equatorial positions. In the crystal, the complex exhibits a chain structure parallel to the b axis. PMID- 21522836 TI - MU-Carbonato-bis-(bis-{2-[(diethyl-amino)-meth-yl]phen-yl}bis-muth(III)). AB - The mol-ecular structure of the title compound, [Bi(2)(C(11)H(16)N)(4)(CO(3))], consists of a symmetrically bridging carbonato group which binds two [2 Et(2)NCH(2)C(6)H(4)](2)Bi units that are crystallographically related via a twofold rotation axis bis-ecting the carbonate group. The two Bi atoms and two of the C atoms directly bonded to bis-muth are quasi-planar [deviations of 0.323 (1) and 0.330 (9)A for the Bi and C atoms, respectively] with the carbonate group. The remaining two ligands are in a trans arrangement relative to the quasi-planar (CBi)(2)CO(3) system. The metal atom is strongly coordinated by the N atom of one pendant arm [Bi-N = 2.739 (6) A], almost trans to the O atom, while the N atom of the other pendant arm exhibits a weaker intra-molecular inter-action [Bi?N = 3.659 (7) A] almost trans to a C atom. If both these intra-molecular N->Bi inter actions per metal atom are considered, the overall coordination geometry at bis muth becomes distorted square-pyramidal [(C,N)(2)BiO cores] and the compound can be described as a hypervalent 12-Bi-5 species. Additional quite short intra molecular Bi?O inter-actions are also present [3.796 (8)-4.020 (9) A]. Inter molecular associations through weak eta(6)?Bi inter-actions [Bi?centroid of benzene ring = 3.659 (1) A] lead to a ribbon-like supra-molecular association. PMID- 21522837 TI - [MU-1,2-Bis(diphenyl-phosphan-yl)-1,2-diethyl-hydrazine-kappaP:P']bis-[chlorido gold(I)] tetra-hydro-furan disolvate. AB - The title compound, [Au(2)Cl(2)(C(28)H(30)N(2)P(2))].2C(4)H(8)O, was synthesized from a bidentate phosphine ligand complexed to two linear gold(I) chloride moieties. The Au(I) atom is in an almost linear coordination with a P-Au-Cl angle of 179.22 (4) degrees . The complex molecules reside on a twofold rotation axis. PMID- 21522838 TI - Methyl-(phenyl)-bis-(quinoline-2-carbox-ylato-kappaN,O)tin(IV) monohydrate. AB - The Sn(IV) atom in each of the two independent mol-ecules in the asymmetric unit of the title compound, [Sn(CH(3))(C(6)H(5))(C(10)H(6)NO(2))(2)].H(2)O, is N,O chelated by two quinoline-2-carboxyl-ate ions; the dative Sn-N bonds are significantly longer than the covalent Sn-O bonds. The two O and two N atoms comprise a trapezoid, and the diorganotin skeleton is bent over the longer N-N edge [C-Sn-C = 144.2 (1) and 144.5 (1) degrees in the two independent mol ecules]. The uncoordinated water mol-ecules serve to connect the skew-trapezoidal bipyramidal tin-bearing mol-ecules, generating a linear chain motif running along the ac diagonal. The crystal studied was a non-merohedral twin having a minor component of 33.2 (1)%. PMID- 21522839 TI - 1,1'-Di-n-butyl-4,4'-bipyridinium 2.375-bromido-1.625-chloridocadmate. AB - The title salt, (C(18)H(26)N(2))[CdBr(2.375)Cl(1.625)], consists of non-inter acting cations and tetra-hedral cadmate(II) anions. The halogen atoms are all disordered, the bromine components being in 0.9035 (17):0.0965 (17), 0.6581 (18):0.3419 (18), 0.5019 (19):0.4981 (19) and 0.6847 (19):0.3153 (18) ratios. The aromatic rings of the cation are twisted by 25.0 (1) degrees . PMID- 21522840 TI - Bis(2-{5-[(2-carb-oxy-phen-yl)sulfanylmeth-yl]-2,4-dimethyl-benzyl-sulfan yl}benzoato-kappaO,O')bis-(pyridine-kappaN)iron(II). AB - The title compound, [Fe(C(24)H(21)O(4)S(2))(2)(C(5)H(5)N)(2)], has 2 symmetry. The Fe(II) cation is located on a twofold rotation axis and is O,O'-chelated by two 2-{5-[(2-carb-oxy-phen-yl)sulfanylmeth-yl]-2,4-dimethyl-benzyl-sulfan yl}benzoate anions and further coordinated by two pyridine ligands in a distorted octa-hedral geometry. In the anion, the terminal benzene rings are oriented at dihedral angles of 63.81 (14) and 84.50 (14) degrees with respect to the central benzene ring. Inter-molecular O-H?O and C-H?O hydrogen bonding is present in the crystal structure. PMID- 21522841 TI - Diaqua-(6-bromo-picolinato-kappaN,O)(nitrato-kappaO,O)copper(II). AB - In the monomeric title complex, [Cu(C(6)H(3)BrNO(2))(NO(3))(H(2)O)(2)], the Cu(II) ion is coordinated by a bidentate 6-bromo-picolinate ion, one nitrate ion and two water mol-ecules in a geometry inter-mediate between five- and six coordinate. Conventional O-H?O hydrogen bonds link the complex mol-ecules, forming layers parallel to the ab plane. PMID- 21522842 TI - Poly[triaqua-tris-(MU(4)-pyridine-3,5-dicarboxyl-ato)dicerium(III)]. AB - The asymmetric unit of the title compound, [Ce(2)(C(7)H(3)NO(4))(3)(H(2)O)(3)](n), contains two Ce(III) cations, three pyridine-3,5-dicarboxyl-ate (pyd) anions and three coordinated water mol-ecules. One Ce(III) cation is coordinated by seven carboxyl-ate O atoms from six pyd anions and two water mol-ecules in a square-face-capped square-anti-prismatic geometry. Another Ce(III) cation is coordinated by seven O atoms from six pdy anions and one water mol-ecule in a bicapped trigonal-prismatic geometry. The pdy anions bridge the Ce(III) cations, forming the three-dimensional polymeric structure. The crystal structure contains extensive O-H?O, O-H?N and weak C-H?O hydrogen bonds. pi-pi stacking is present in the crystal structure, the shortest centroid-centroid distance between parallel pyridine rings being 3.509 (4) A. PMID- 21522843 TI - Poly[(MU(4)-pyridine-2,3-dicarboxyl-ato)lead(II)]. AB - In the title coordination polymer, [Pb(C(7)H(3)NO(4))](n), the Pb(II) ion is eight-coordinated in a distorted square-anti-prismatic geometry formed by one pyridine N atom and seven carboxyl-ate O atoms from four pyridine-2,3-dicarboxyl ate (pda) anions. In the pda anion, the dihedral angles between the pyridine ring and carboxyl-ate groups are 19.5 (6) and 73.3 (6) degrees . The carboxyl-ate groups of the pda anions bridge the Pb ions, forming a two-dimensional coordination polymer parallel to (100). Weak inter-molecular C-H?O hydrogen boning is present in the crystal structure. PMID- 21522844 TI - Bis[1-benzyl-3-(quinolin-8-ylmeth-yl)-2,3-dihydro-1H-imidazol-2-yl]dibromido palladium(II) acetonitrile disolvate. AB - In the title compound, [PdBr(2)(C(20)H(17)N(3))(2)].2CH(3)CN, the Pd atom, which lies on an inversion center, is four-coordinated in a square-planar geometry. The two imidazole rings are coplanar and nearly perpendicular to the plane formed by Pd, the coordinated imidazole C atom and one of the Br atoms, making a dihedral angle of 75.1 (2) degrees . PMID- 21522845 TI - catena-Poly[[[aqua-chlorido-manganese(II)]-bis-[MU-1,1'-(oxydi-p-phenyl-ene)di-1H imidazole-kappaN:N]] chloride dimethyl-formamide mono-solvate monohydrate]. AB - The title coordination polymer, {[MnCl(C(18)H(14)N(4)O)(2)(H(2)O)]Cl.C(3)H(7)NO.H(2)O}(n), obtained by the solvothermal reaction of BIDPE and manganese(II) salt in H(2)O/DMF (DMF is dimethyl-formamide), is composed of a chain of [Mn(2)(BIDPE)(2)] [BIDPE is 1,1' (oxydi-p-phenyl-ene)di-1H-imidazole] metallocyclic rings that exhibit inversion symmetry. The coordination about the Mn(II) ions is distorted octahedral with a MnClN(4)O coordination set. In the crystal, the polymeric chains are linked by O H?Cl hydrogen bonds, forming a two-dimensional network parallel to (100). A number of C-H?Cl and C-H?O inter-actions are also present. PMID- 21522846 TI - Tetra-kis(MU(2)-2-methyl-3,5-dinitro-benzoato-kappaO:O)bis-[aqua-copper(II)] tetra-hydrate. AB - The title compound, [Cu(2)(C(8)H(5)N(2)O(6))(4)(H(2)O)(2)].4H(2)O, forms a centrosymmetric paddle-wheel-type dimer with an intra-molecular Cu?Cu distance of 2.6540 (4) A. The Cu(II) atom is in a square-pyramidal coordination environment formed by four O atoms of four carboxyl-ate groups and one water mol-ecule, which is located in the apical position. The carboxyl-ate groups are twisted relative to the benzene rings by 11.09 (16) and 45.55 (19) degrees . The nitro groups are not coplanar with the parent aromatic rings [dihedral angles = 16.2 (3)-51.45 (14) degrees ]. O-H?O hydrogen bonds between the coordinated water mol-ecules and one of the nitro groups, as well as pi-pi stacking inter-actions [centroid centroid distance = 3.5764 (12) A] between the benzene rings, assemble the complex mol-ecules into a one-dimensional polymeric structure which is further extended into a three-dimensional polymeric network via O-H?O hydrogen bonds involving the water molecules of crystallization. PMID- 21522847 TI - Bis(N,N-diisopropyl-butanaminium) bis-[di-MU-chlorido-bis-[dichlorido cuprate(II)]]. AB - In the title compound, (C(10)H(24)N)(2)[Cu(2)Cl(6)], N,N-diisopropyl-butanamine is protonated on the N atom. The Cu(II) atom in the centrosymmetric [Cu(2)Cl(6)](2-) anion has a distorted tetra-hedral geometry. In the crystal, the cations and anions are connected by N-H?Cl and C-H?Cl hydrogen bonds into layers parallel to (100). PMID- 21522848 TI - 5-(Pyridinium-3-yl)tetra-zol-1-ide hexa-aqua-magnesium dichloride. AB - In the title compound, (C(6)H(5)N(5))(2)[Mg(H(2)O)(6)]Cl(2), the asymmetric unit contains one zwitterionic 5-(pyridinium-3-yl)tetra-zol-1-ide mol-ecule, one half of an [Mg(H(2)O)(6)](2+) cation ( symmetry) and one chloride ion. The Mg(II) ion is surrounded by six water mol-ecules, with their O atoms located at the apices, exhibiting a slightly distorted octa-hedral coordination. Mg-O bond lengths range from 2.0526 (14) to 2.0965 (16) A [mean value = 2.068 A]. The pyridine and tetra zole rings are nearly coplanar and only twisted from each other by a dihedral angle of 5.68 (1) degrees . The zwitterionic organic mol-ecules, anions and cations are connected by O-H?Cl, O-H?N and N-H?Cl hydrogen bonds, leading to the formation of a three-dimensional network. PMID- 21522849 TI - Aqua-[bis-(2-ethyl-5-methyl-1H-imidazol-4-yl-kappaN)methane]-oxalatocopper(II) dihydrate. AB - In the title compound, [Cu(C(2)O(4))(C(13)H(20)N(4))(H(2)O)].2H(2)O, the Cu(II) atom exhibits a distorted square-pyramidal geometry with the two N atoms of the imidazole ligand and the two O atoms of the oxalate ligand forming the basal plane, while the O atom of the coordinated water mol-ecule is in an apical position. The Cu(II) atom is shifted 0.232 (2) A out of the basal plane toward the water mol-ecule. The asymmetric unit is completed by two solvent water mol ecules. These water mol-ecules participate in the formation of an intricate three dimensionnal network of hydrogen bonds involving the coordinated water mol-ecule and the NH groups. PMID- 21522850 TI - catena-Poly[[[(3,5-dimethyl-1H-pyrazole)-copper(II)]-MU-{N-[1-(2-oxidophen yl)ethyl-idene]-l-valinato}] methanol monosolvate]. AB - The asymmetric unit of the title compound, {[Cu(C(13)H(15)NO(3))(C(5)H(8)N(2))].CH(3)OH}(n), contains two complex mol-ecules and two solvent mol-ecules. Each Cu(II) ion is in a distorted square-pyramidal coordination with one N and two O atoms from the Schiff base ligand and one N atom from the heterocycle in the basal positions and one carboxyl-ate O atom from a neighbouring ligand in the apical position. The apical Cu-O bonds are much longer than the basal Cu-O and Cu-N bonds. The carboxyl-ate groups of the Schiff base ligands bridge the Cu(II) ions, forming helical chains along [100]. The crystal packing is stabilized by inter-molecular O-H?O and N-H?O hydrogen bonds. PMID- 21522851 TI - [MU-Bis(diphenyl-phosphan-yl)ethane-1:2kappaP:P']nona-carbonyl 1kappaC,2kappaC,3kappaC-[tris-(4-(meth-oxy-phen-yl)arsane-3kappaAs]-triangulo triruthenium(0) chloro-form monosolvate. AB - The asymmetric unit of the title triangulo-triruthenium compound, [Ru(3)(C(21)H(21)AsO(3))(C(26)H(24)P(2))(CO)(9)].CHCl(3), consists of one mol ecule of the triangulo-triruthenium complex and one chloro-form solvent mol ecule. The bis(diphenyl-phosphan-yl)ethane ligand bridges an Ru-Ru bond and the monodentate arsane ligand bonds to the third Ru atom. Both the arsane and phosphine ligands are equatorial with respect to the Ru(3) triangle. Additionally, each Ru atom carries one equatorial and two axial terminal carbonyl ligands. The three arsane-substituted benzene rings make dihedral angles of 52.72 (19), 63.03 (19) and 88.19 (19) degrees with each other. The dihedral angles between the two benzene rings are 85.8 (2) and 89.2 (2) degrees for the two diphenyl-phosphanyl groups. In the crystal, mol-ecules are linked together into a three-dimensional network via inter-molecular C-H?O hydrogen bonds. Weak inter molecular C-H?pi inter-actions further stabilize the crystal structure. PMID- 21522852 TI - [MU-Bis(diphenyl-phosphan-yl)ethane-1:2kappaP:P']nona-carbonyl 1kappaC,2kappaC,3kappaC-(triphenyl-stibine-3kappaSb)-triangulo-triruthenium(0). AB - The asymmetric unit of the title triangulo-triruthenium compound, [Ru(3)(C(26)H(24)P(2))(C(18)H(15)Sb)(CO)(9)], consists of two crystallographically independent mol-ecules, A and B. The bis-(diphenyl-phosphan yl)ethane ligand bridges an Ru-Ru bond and the monodentate stibine ligand bonds to the third Ru atom. Both the stibine and phosphine ligands are equatorial with respect to the Ru(3) triangle. Additionally, each Ru atom carries one equatorial and two axial terminal carbonyl ligands. The three stibine-substituted benzene rings make dihedral angles of 38.7 (3), 71.5 (3) and 70.0 (3) degrees with each other in mol-ecule A whereas these angles are 83.9 (3), 88.2 (3) and 56.8 (3) degrees in mol-ecule B. Similarly, the dihedral angles between the two benzene rings are 80.7 (3) and 87.6 (3) degrees for the two diphenyl-phosphanyl groups in mol-ecule A and 84.0 (3) and 72.6 (4) degrees in mol-ecule B. In the crystal, mol-ecules are linked into tetra-mers via inter-molecular C-H?O hydrogen bonds. Weak inter-molecular C-H?pi inter-actions further stabilize the crystal structure. PMID- 21522853 TI - [MU-Bis(diphenyl-arsanyl)methane-1:2kappaAs:As']nona-carbonyl 1kappaC,2kappaC,3kappaC-[(4-methyl-sulfanylphen-yl)diphenyl-phosphane-3kappaP] triangulo-triruthenium(0). AB - In the title triangulo-triruthenium compound, [Ru(3)(C(25)H(22)As(2))(C(19)H(17)PS)(CO)(9)], the bis-(diphenyl-arsanyl)methane ligand bridges an Ru-Ru bond and the monodentate phosphane ligand bonds to the third Ru atom. Both arsine and phosphane ligands are equatorial with respect to the Ru(3) triangle. In addition, each Ru atom carries one equatorial and two axial terminal carbonyl ligands. The three phosphane-substituted benzene rings make dihedral angles of 57.91 (19), 84.31 (15) and 59.37 (18) degrees with each other. The dihedral angles between the two benzene rings are 60.9 (2) and 85.40 (18) degrees for the two diphenyl-arsanyl groups. In the crystal, mol-ecules are linked into a three-dimensional framework by inter-molecular C-H?O hydrogen bonds. Weak inter-molecular C-H?pi inter-actions stabilize the crystal structure. PMID- 21522854 TI - Bis(2,1,3-benzoselenadiazole-kappaN)dibromidocopper(II). AB - In the title complex, [CuBr(2)(C(6)H(4)N(2)Se)(2)], the Cu(II) ion is tetra coordinated by two bromide anions and two N atoms in a distorted square-planar geometry. The two essentially planar 2,1,3-benzoselenadiazole ligands [maximum deviations = 0.012 (2) and 0.030 (2) A] are approximately coplanar [dihedral angle = 6.14 (6) degrees ]. In the crystal, short inter-molecular Se?Br, Se?N and N?N inter-actions are observed. These short inter-actions and inter-molecular C H?Br hydrogen bonds link the complex mol-ecules into two-dimensional arrays parallel to the ac plane. PMID- 21522855 TI - (S)-1-Ferrocenyl-3-hy-droxy-3-phenyl-propan-1-one. AB - In the title compound, [Fe(C(5)H(5))(C(14)H(13)O(2))], the dihedral angle between the phenyl ring and the unsubstituted cyclo-petadienyl ring is 85.0 (2) degrees while that between the phenyl ring and the substituted cyclo-petadienyl ring is 83.6 (2) degrees . The dihedral angle between the two cyclo-penta-1,3-diene rings of the ferrocene unit is 2.2 (2) degrees . The mol-ecules are stabilized by inter molecular O-H?O hydrogen-bonding inter-action within the crystal lattice. PMID- 21522856 TI - Bis{2-meth-oxy-6-[(4-methyl-phen-yl)iminiometh-yl]phenolato-kappaO,O}tris (nitrato-kappaO,O')methano-lsamarium(III). AB - The asymmetric unit of the title compound, [Sm(NO(3))(3)(C(15)H(15)NO(2))(2)(CH(3)OH)], contains two Schiff base 2-meth-oxy 6-[(4-methyl-phen-yl)iminiometh-yl]phenolate (HL) ligands, three nitrate ions and one methanol mol-ecule that binds to the nine-coordinate samarium(III) ion via its O atoms. The HL ligands chelate with a strong Sm-O(deprotonated phenolic) bond and a weak Sm-O(meth-oxy) contact. The latter can be inter-preted as the apices of the bicapped square-anti-prismatic Sm(III)O(9) polyhedron. The Schiff base ligands are in a zwitterionic state with the phenolic H atom transferred to the imine N atom. O-H?O, O-H?N and N-H?O hydrogen bonds lend stability to the structure. One O atom of one nitrate group is equally disordered over two positions. PMID- 21522857 TI - Tris(1,10-phenanthroline-kappaN,N')zinc(II) chloride 2-phenyl-4-selenazole-5-car box-yl-ate decahydrate. AB - The asymmetric unit of the title salt, [Zn(C(12)H(8)N(2))(3)](C(10)H(6)NO(2)Se)Cl.10H(2)O, contains a [Zn(phen)(3)](2+) cation (phen is 1,10-phenanthroline), uncoordinated chloride and 2-phenyl-4 selenazole-5-carboxyl-ate anions and ten uncoord-in-ated water mol-ecules. The central Zn(II) ion is six-coordinated by six N atoms from three phen ligands in a distorted octa-hedral geometry. An extensive O-H?O, O-H?N and O-H?Cl hydrogen bonding network stabilizes the crystal structure. PMID- 21522858 TI - Bis[3-(meth-oxy-carbon-yl)anilinium] hexa-chloridostannate(IV). AB - In the title compound, (NH(3)C(6)H(4)CO(2)CH(3))(2)[SnCl(6)], the anions are situated on inversion centers so the asymmetric unit contains one cation and one half-anion. In the crystal, inter-molecular N-H?Cl and N-H?O hydrogen bonds link the cations and anions into layers parallel to the ac plane. The crystal packing exhibits voids of 37 A(3). PMID- 21522859 TI - Bis(2-amino-4-methyl-pyridinium) bis-(pyridine-2,6-dicarboxyl-ato)cuprate(II). AB - The asymmetric unit of the title compound, (C(6)H(9)N(2))(2)[Cu(C(7)H(3)NO(4))(2)], contains half of a [Cu(pydc)(2)](2-) (pydcH(2) is pyridine-2,6-dicarb-oxy-lic acid) anion and one protonated 2-amino-4 methyl-pyridine (2a4mpH)(+) counter-ion. The anion is a six-coordinated complex with a distorted CuN(2)O(4) octa-hedral geometry around the Cu(II) ion. N-H?O and C-H?O hydrogen bonds along with pi-pi contacts between the pyridine rings of the (2a4mpH)(+) cations [centroid-centroid distance = 3.573 (2) A] stabilize the crystal structure. PMID- 21522860 TI - Poly[dibromidobis[MU-1-(pyridin-4-ylmeth-yl)-1H-1,2,4-triazole kappaN:N']cadmium]. AB - The title coordination polymer, [CdBr(2)(C(8)H(8)N(4))(2)](n), arose from a layer separated diffusion synthesis at room temperature. The title compound is isotypic with the I and Cl analogues. The Cd atom, located on an inversion center, is coordinated by two bromide ions and four N atoms (two from triazole rings and two from pyridyl rings) in a distorted trans-CdBr(2)N(4) octa-hedral arrangement. The bridging 1-(4-pyridyl-meth-yl)-1H-1,2,4-triazole ligands are twisted [dihedral angle between the triazole and pyridine rings = 72.56 (13) degrees ], affording a two-dimensional 4(4) sheet structure in the crystal. PMID- 21522861 TI - [MU-2-(4-Hy-droxy-phen-yl)acetato]-kappaO:O,O';kappaO,O':O'-bis-{aqua-(4,4'-bi pyridine-kappaN)bis-[2-(4-hy-droxy-phen-yl)acetato-kappaO,O']holmium(III)} mono hydrate. AB - In the title dinuclear complex, [Ho(2)(C(8)H(7)O(3))(6)(C(10)H(8)N(2))(2)(H(2)O)(2)].H(2)O, each of the two independent Ho(III) ions is coordinated by eight O atoms from four 4-hy-droxy phenyl-acetate (HPAA) ligands and a water mol-ecule, and one N atom from a 4,4' bipyridine (bipy) ligand in a distorted tricapped trigonal-prismatic geometry. The HPAA ligands are coordinated in bis-chelate, bridging and bridging tridentate modes. In the crystal, O-H?O and O-H?N hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21522862 TI - Benzene-1,3-diammonium bis-(pyridine-2,6-dicarboxyl-ato)nickelate(II) penta hydrate. AB - In the title compound, (C(6)H(10)N(2))[Ni(C(7)H(3)NO(4))(2)].5H(2)O, the Ni(II) ion is six-coordinated by two N and four O atoms from two pyridine-2,6-dicarboxyl ate ligands in a distorted octa-hedral fashion. The crystal packing is stabilized by inter-molecular O-H?O and N-H?O and weak C-H?O hydrogen bonds and pi-pi inter actions [centroid-centroid distances = 3.4669 (19) and 3.764 (2) A]. PMID- 21522863 TI - [MU-Bis(di-o-tolyl-phosphan-yl)methane-1:2kappaP:P']nona-carbonyl 1kappaC,2kappaC,3kappaC-[diphen-yl(phenyl-sulfanylmeth-yl)phosphane-3kappaP] triangulo-triruthenium(0) dichloro-methane 0.25-solvate. AB - In the title compound, [Ru(3)(C(29)H(30)P(2))(C(19)H(17)PS)(CO)(9)].0.25CH(2)Cl(2), the atoms of the dichloro-methane solvent mol-ecule have a fractional site occupancy of 0.25; the dichloro-methane mol-ecule is disordered about an inversion centre. The bis-(di-o tolyl-phosphan-yl)methane ligand bridges an Ru-Ru bond and the monodentate phosphane ligand bonds to the third Ru atom; its S-bonded phenyl ring is disordered over two orientations in a 0.53 (4):0.47 (4) ratio. All the P atoms are equatorial with respect to the Ru(3) triangle: each Ru atom also bears one equatorial and two axial terminal carbonyl ligands. The dihedral angles between the two benzene rings attached to each P atom of the diphenyl-phosphanyl ligand are 68.4 (2) and 71.5 (2) degrees . In the crystal, mol-ecules are linked into [001] chains via inter-molecular C-H?O hydrogen bonds. Weak inter-molecular C H?pi inter-actions also occur. PMID- 21522864 TI - [MU-Bis(di-o-tolyl-phosphan-yl)methane-1:2kappaP:P']deca-carbonyl 1kappaC,2kappaC,3kappaC-triangulo-triruthenium(0)-methanol (8/1). AB - The asymmetric unit of the title compound, [Ru(3)(C(29)H(30)P(2))(CO)(10)].1/8CH(3)OH, contains two triangulo-triruthenium mol-ecules with similar configurations and a methanol solvent mol-ecule (fractional site occupancy for the latter = 0.25). The bis-(di-o-tolyl-phosphan yl)methane ligand bridges an Ru-Ru bond and its P atoms are equatorial with respect to the Ru(3) triangle. The phosphine-substituted Ru atoms each bear one equatorial and two axial terminal carbonyl ligands whereas the unsubstituted Ru atom carries two equatorial and two axial terminal carbonyl ligands. The dihedral angles between the two benzene rings attached to each P atom are 76.26 (13) and 74.76 (15) degrees for the first mol-ecule and 77.21 (13) and 75.68 (14) degrees for the second. In the crystal, mol-ecules are linked into [001] chains via inter-molecular C-H?O hydrogen bonds. Weak inter-molecular C-H?pi inter-actions also occur. PMID- 21522865 TI - catena-Poly[[(2,2'-bipyridine-kappaN,N')cadmium]-MU(3)-4-nitro-phthalato kappaO:O',O'':O''']. AB - In the title polymeric compound, [Cd(C(8)H(3)NO(6))(C(10)H(8)N(2))](n), two O atoms from both carboxyl-ate groups of a nitro-phthalate anion coordinate to the Cd(II) cation, forming a seven-membered chelate ring and two carboxyl-ate O atoms from another two nitro-phthalate anions and a 2,2'-bipyridine ligand coordinate to the Cd cation to complete the distorted octa-hedral coordination geometry. The carboxyl-ate groups of the nitro-phthalate anion adopt a syn-anti bridging mode, linking adjacent Cd(II) cations and forming a polymeric chain running along the a axis. Weak intra- and inter-molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 21522866 TI - Bis(2-{[2-(isopropyl-aza-nium-yl)eth-yl]imino-meth-yl}-6-meth-oxy phenolato)copper(II) bis-(thio-cyanate). AB - The asymmetric unit of the title compound, [Cu(C(13)H(20)N(2)O(2))(2)](NCS)(2), contains one half-dication, located on an inversion center, and one thio-cyanate anion. Each Cu(II) atom is four-coordinated by two phenolate O and two imine N atoms from two symmetry-related Schiff base 2-{[2-(isopropyl-aza-nium-yl)eth yl]imino-meth-yl}-6-meth-oxy-phenolate (L) ligands in a distorted square-planar geometry. The ammonium groups are involved in the formation of N-H?O and N-H?N hydrogen bonds, which link one dication and two anions into an electroneutral cluster. When very weak Cu-N interactions with a distance of 2.910 (5) A between the metal and the thiocyanate anions in apical positions are considered, the secondary coordination polyhedron is a very elongated CuN(4)O(2) octahedron. PMID- 21522867 TI - trans-Diaqua-(pyridazine-3-carboxyl-ato-kappaN,O)lithium. AB - The structure of the title complex, [Li(C(5)H(3)N(2)O(2))(H(2)O)(2)], is built of monomeric mol-ecules. In each, an Li(+) ion is N,O-chelated by the pyridazine-3 carboxyl-ate ligand and two water O atoms. The coordination geometry of the metal ion is distorted tetra-hedral. The monomers are linked by a system of hydrogen bonds in which water mol-ecules act as donors and carboxyl-ate O atoms act as acceptors. O-H?N hydrogen bonding is also present. PMID- 21522868 TI - Bis(trimethyl-ammonium) tetra-chlorido-diphenyl-stannate(IV). AB - The title compound, [(CH(3))(3)NH](2)[Sn(C(6)H(5))(2)Cl(4)], consists of [(CH(3))(3)NH](+) cations and [SnPh(2)Cl(4)](2-) anions in which the Sn atom, located on a centre of inversion, is bonded to four Cl atoms and two phenyl rings, giving an octa-hedral geometry with the phenyl rings in trans positions. In the crystal, the cations and the anions are connected by N-H?Cl hydrogen bonds and C-H?Cl inter-actions. PMID- 21522869 TI - Aqua-{2-morpholino-N-[1-(2-pyrid-yl)ethyl-idene]ethanamine-kappaN,N',N''}bis (thio-cyanato-kappaN)cobalt(II). AB - In the title complex, [Co(NCS)(2)(C(13)H(19)N(3)O)(H(2)O)], the Co(II) ion is six coordinated by the N,N',N''-tridentate Schiff base, the N atoms of two thio cyanate ligands and one water mol-ecule in a distorted octa-hedral geometry. Intra-molecular C-H?N and C-H?O hydrogen bonds occur. In the crystal, inter molecular O-H?O, O-H?S, C-H?S and S?S [3.5546 (18) A] inter-actions result in an infinite three-dimensional network. PMID- 21522870 TI - Tetra-kis-(MU-benzoato-kappaO:O')bis{[4-(di-methyl-amino)-pyridine kappaN]zinc(II)}. AB - In the centrosymmetric binuclear title complex, [Zn(2)(C(7)H(5)O(2))(4)(C(7)H(10)N(2))(2)], the Zn atoms [Zn?Zn = 3.0037 (6) A] are bridged by four benzoate ligands. Each of the Zn atoms assumes an approximately square-pyramidal environment, with four O atoms in a plane and the pyridine N atom at the apical site. PMID- 21522871 TI - Bis[2-(benzyl-amino)-pyridine-kappaN]bis-(2-formyl-phenolato kappaO,O')nickel(II). AB - In the title complex, [Ni(C(7)H(5)O(2))(2)(C(12)H(12)N(2))(2)], the Ni(II) atom lies on a center of inversion and is coordinated in an octa-hedral geometry by two 2-(benzyl-amino)-pyridine (2-BAP) and two 2-formyl-phenolate ligands with the O-atom donors in the equatorial plane and the pyridine N atoms in axial positions. There are hydrogen-bonding inter-actions between the secondary amine H atom and the phenolate O atom, as well as C-H?O inter-actions, which result in the dihedral angle between the aromatic phenyl ring of the 2-formyl-phenolate moiety and the pyridine ring being 80.23 (4) degrees . In the packing, there are both C-H?pi inter-actions, which link the mol-ecules into chains along the b axis, and offset pi-pi inter-actions involving both the pyridine and phenyl rings of the 2-BAP ligands [centroid-centroid distances = 4.0100 (8) A for the pyridine rings and 3.6601 (8) and 4.8561 (8) A for the phenyl rings]. PMID- 21522872 TI - catena-Poly[[aqua-bis-[2-(3-benzoyl-phen-yl)propano-ato-kappaO,O]cadmium(II)]-MU 4,4'-bipyridine-kappaN:N']. AB - The 4,4'-bipyridine heterocycle in the polymeric title compound, [Cd(C(16)H(13)O(3))(2)(C(10)H(8)N(2))(H(2)O)](n), links adjacent Cd(II) ions into a chain running along the c axis. The Cd atom, which lies on a twofold rotation axis, is chelated by the carboxyl-ate unit and exists in a seven-coordinate penta gonal-bipyramidal geometry. The apical sites are occupied by N atoms. The water mol-ecule also lies on the twofold rotation axis. The methyl substituent of the propano-ate group is disordered over two positions in a 1:1 ratio. O-H?O hydrogen bonding between water molecules and adjacent carboxylate O atoms is observed. PMID- 21522873 TI - Di-n-butyl-bis-(thio-cyanato-kappaN)(1,10-phenanthroline-kappaN,N')tin(IV). AB - In the asymmetric unit of the title compound, [Sn(C(4)H(9))(2)(NCS)(2)(C(12)H(8)N(2))], there are two independent mol-ecules, both lying on a twofold rotation axis. The axis passes through the mid-point of the 1,10 and 5,6 bonds of the N-heterocycle and through the Sn atom. The Sn atoms show a slightly distorted SnC(2)N(4) octa-hedral coordination. PMID- 21522874 TI - Dimeth-yl(4'-pyridyl-2,2':6',2''-terpyridine-kappaN,N,N)bis(thio-cyanato kappaN)tin(IV). AB - The Sn atom in the title compound, [Sn(CH(3))(2)(NCS)(2)(C(20)H(14)N(4))], is N,N',N''-chelated by the terpyridine part of the N-heterocycle. The Sn atom exists in a trans-C(2)SnN(5) penta-gonal-bipyramidal geometry [C-Sn-C = 173.66 (8) degrees ] with the methyl groups in axial and the N atoms in equatorial positions. PMID- 21522875 TI - Bis[bis-(2-ethyl-5-methyl-1H-imidazol-4-yl-kappaN)methane](nitrato kappaO,O')nickel(II) nitrate. AB - In the title compound, [Ni(NO(3))(C(13)H(20)N(4))(2)]NO(3), the Ni(II) ion shows a distorted octa-hedral geometry formed by four N atoms from two bis-(2-ethyl-5 methyl-1H-imidazol-4-yl)methane ligands and two O atoms from a chelating nitrate anion. Three ethyl groups in the complex cation and the O atoms of the uncoordinated nitrate anion are disordered over two sets of positions [occupancy ratios of 0.52 (3):0.48 (3) and 0.63 (3):0.37 (3), respectively]. In the crystal, inter-molecular N-H?O hydrogen bonds connect the complex cations into a zigzag chain along [010] and further N-H?O hydrogen bonds between the chains and the uncoordinated nitrate anions lead to layers parallel to (100). PMID- 21522876 TI - Diaqua-bis-[5-(1-oxidopyridin-1-ium-2-yl)-1,2,3,4-tetrazolido]manganese(II) di hydrate. AB - In the title compound, [Mn(C(6)H(4)N(5)O)(2)(H(2)O)(2)].2H(2)O, the Mn(II) ion is situated on an inversion centre and is coordinated by the O and N atoms of two bis-chelating 5-(2-pyridyl-1-oxide)tetra-zolate ligands and two O atoms of two water mol-ecules in a distorted octa-hedral geometry. All the water H atoms are involved in O-H?N and O-H?O hydrogen bonds with uncoordinated water O atoms and tetra-zole N atoms, which link the mol-ecules into a three-dimensional network. PMID- 21522877 TI - [MU-Bis(diphenyl-arsan-yl)methane-1:2kappaAs:As']nona-carbonyl 1kappaC,2kappaC,3kappaC-[tris-(biphenyl-4-yl)arsane-3kappaAs]-triangulo triruthenium(0). AB - In the title triangulo-triruthenium compound, [Ru(3)(C(25)H(22)As(2))(C(36)H(27)As)(CO)(9)], the bis-(diphenyl-arsan-yl)methane ligand bridges an Ru-Ru bond and the monodentate arsine ligand bonds to the third Ru atom. Both arsine ligands are equatorial with respect to the Ru(3) triangle. In addition, each Ru atom carries one equatorial and two axial terminal carbonyl ligands. The phenyl rings of biphenyl are twisted from each other by dihedral angles of 50.5 (2), 44.5 (2) and 27.8 (2) degrees . The arsine-substituted phenyl rings make dihedral angles of 61.56 (18), 89.36 (18) and 83.27 (18) degrees with each other. The dihedral angles between the two benzene rings are 87.5 (2) and 81.95 (19) degrees for the two diphenyl-arsanyl groups. In the crystal, mol ecules are linked into dimers by inter-molecular C-H?O hydrogen bonds. Weak inter molecular C-H?pi and pi-pi [centroid-centroid distance = 3.601 (3) A] inter actions stabilize the crystal structure. PMID- 21522878 TI - [MU-Bis(diphenyl-phosphan-yl)methane-1:2kappaP:P']nona-carbonyl 1kappaC,2kappaC,3kappaC-[tris-(biphenyl-4-yl)arsane-3kappaAs]-triangulo triruthenium(0). AB - In the title triangulo-triruthenium compound, [Ru(3)(C(36)H(27)As)(C(25)H(22)P(2))(CO)(9)], the bis-(diphenyl-phosphan yl)methane ligand bridges an Ru-Ru bond and the monodentate arsine ligand bonds to the third Ru atom. Both the arsine and phosphine ligands are equatorial with respect to the Ru(3) triangle. In addition, each Ru atom carries one equatorial and two axial terminal carbonyl ligands. In each biphenyl unit, the phenyl rings are twisted from each other, making dihedral angles of 51.22 (18), 42.94 (16) and 26.95 (16) degrees . The arsine-substituted phenyl rings make dihedral angles of 61.22 (15), 87.17 (15) and 83.32 (15) degrees with each other. The dihedral angles between the two benzene rings are 85.52 (18) and 81.77 (15) degrees for the two diphenyl-phosphanyl groups, respectively. In the crystal, mol-ecules are linked into dimers by inter-molecular C-H?O hydrogen bonds. Weak inter-molecular C-H?pi and pi-pi [centroid-centroid distance = 3.6981 (18) A] inter-actions stabilize the crystal structure. PMID- 21522879 TI - Bis{[MU-bis-(diphenyl-phosphan-yl)methane-1:2kappaP:P']nona-carbonyl 1kappaC,2kappaC,3kappaC-[(4-methyl-sulfanylphen-yl)diphenyl-phosphane-3kappaP] triangulo-triruthen-ium(0)} dichloro-methane monosolvate. AB - The asymmetric unit of the title triangulo-triruthenium compound, 2[Ru(3)(C(25)H(22)P(2))(C(19)H(17)PS)(CO)(9)].CH(2)Cl(2), contains one triangulo triruthenium complex mol-ecule and one half-mol-ecule of the dichloro-methane solvent. The dichloro-methane solvent mol-ecule lies across a crystallographic inversion center leading to the mol-ecule being disordered over two positions of equal occupancy. The bis-(diphenyl-phosphan-yl)methane ligand bridges an Ru-Ru bond and the monodentate phosphane ligand bonds to the third Ru atom. All phosphane ligands are equatorial with respect to the Ru(3) triangle. In addition, each Ru atom carries one equatorial and two axial terminal carbonyl ligands. The three phosphane-substituted benzene rings make dihedral angles of 87.18 (11), 59.59 (10) and 89.28 (11) degrees with each other. The dihedral angles between the two benzene rings are 78.48 (11) and 87.58 (11) degrees for the two diphenyl phosphanyl groups. In the crystal, the mol-ecules are stacked along the a axis. Weak inter-molecular C-H?pi inter-actions stabilize the crystal structure. PMID- 21522880 TI - Undeca-carbonyl-1kappaC,2kappaC,3kappaC-(triethyl phosphite-1kappaP)-triangulo triruthenium(0). AB - In the title triangulo-triruthenium compound, [Ru(3)(C(6)H(15)O(3)P)(CO)(11)], each Ru atom has distorted octa-hedral coord-ination geometry. The monodentate phosphine ligand is equatorially coordinated to one Ru atom, leaving one equatorial and two axial carbonyl substituents on the Ru atom. Each of the remaining two Ru atoms carries two equatorial and two axial carbonyl groups. In the crystal, mol-ecules are linked into an inversion dimer by a pair of inter molecular C-H?O hydrogen bonds and the dimers are stacked along the b axis. PMID- 21522881 TI - Poly[aqua-(dimethyl sulfoxide)(MU(4)-pyridine-2,5-dicarboxyl-ato)calcium(II)]. AB - In the polymeric title compound, [Ca(C(7)H(3)NO(4))(H(2)O)(C(2)H(6)OS)](n), the Ca(II) ion is coordinated in a distorted penta-gonal-bipyramidal CdNO(6) geometry. The crystal packing is stabilized by O-H?O hydrogen bonds and pi-pi stacking inter-actions between the aromatic rings of pyridine-2,5-dicarb-oxy-late with centroid-centroid distances of 3.6166 (13) A. PMID- 21522882 TI - Bis[2-(hy-droxy-imino-meth-yl)phenolato]nickel(II): a second monoclinic polymorph. AB - The title compound, [Ni(C(7)H(6)NO(2))(2)], (I), is a second monoclinic polymorph of the compound, (II), reported by Srivastava et al. [Acta Cryst. (1967), 22, 922] and Mereiter [Private communication (2002) CCDC refcode NISALO01]. The bond lengths and angles are similar in both structures. The mol-ecule in both structures lies on a crystallographic inversion center and both have an inter-nal hydrogen bond. The title compound crystallizes in the space group P2(1)/c (Z = 2), whereas compound (II) is in the space group P2(1)/n (Z = 2) with a similar cell volume but different cell parameters. In both polymorphs, mol-ecules are arranged in the layers but in contrast to the previously published compound (II) where the dihedral angle between the layers is 86.3 degrees , in the title polymorph the same dihedral angle is 29.4 degrees . The structure of (I) is stabilized by strong intra-molecular O-H?O hydrogen bonding between the O-H group and the phenolate O atom. PMID- 21522883 TI - Chloridonitros-yl[meso-5,10,15,20-tetra-kis-(p-tol-yl)porphyrinato kappaN,N',N'',N''']osmium(II) tetra-hydro-furan tetra-solvate. AB - The title compound, [OsCl(NO)(C(48)H(36)N(4))].4C(4)H(8)O, is a six-coordinate osmium(II) porphyrin complex with nitrosyl (NO) and chloride (Cl) ligands trans to each other in an octa-hedral geometry. The metal complex lies on a fourfold rotation axis that passes through the Os, N, O and Cl atoms. The NO and Cl ligands are disordered in an 0.511 (12):0.486 (12) ratio. PMID- 21522884 TI - catena-Poly[[aqua-bromidocopper(II)]-MU(3)-(picolinato N-oxide)]. AB - The title complex, [CuBr(C(6)H(4)NO(3))(H(2)O)](n), exhibits a layered structure which is stabilized by inter-molecular O-H?O and O-H?Br(-) hydrogen bonds, van der Waals forces and pi-pi inter-actions [centroid-centroid distance = 3.747(4) A] between the parallel pyridine rings from two neighboring layers. PMID- 21522885 TI - Chloridobis(1,10-phenanthroline-kappaN,N')copper(I) dichloridocopper(II). AB - The asymmetric unit of the title compound, [CuCl(C(12)H(8)N(2))(2)].[CuCl(2)], contains two complex Cu(II) cations and two cuprate(I) anions. The Cu(II) atom is coordinated by two phenanthroline (phen) mol-ecules and one chloride anion in a distorted trigonal-bipyramidal geometry. The Cu(II) complex cations form layers through pi-pi stacking [interplanar distance = 3.481 (2) A]. The dichloridocuprate(I) anions are located between the layers, forming a sandwich like structure. PMID- 21522886 TI - Bis(tetraphenylphosphonium) tetra-cyanido-nitridochromate(V) dihydrate. AB - In the title compound, (C(24)H(20)P)(2)[Cr(CN)(4)(N)].2H(2)O, the complex anion exhibits a square-based pyramidal geometry around the central Cr(V) atom, which is coordinated by a nitride ligand in the apical position and by four cyanide ligands in the equatorial plane. The chromium atom is located 0.4493 (13) A out of the plane formed by the ligating C atoms of the cyanide ligands. The water mol ecules of crystallization form inter-molecular O-H?N hydrogen bonds to the N atoms of two cyanide ligands of neighbouring complex anions, forming an infinite hydrogen-bonded chain parallel to [011] of water mol-ecules and [Cr(N)(CN)(4)](2 ) anions. The terminal nitride ligands are not engaged in inter-molecular inter actions. PMID- 21522887 TI - Dichlorido{N,N-dimethyl-N'-[1-(2-pyrid-yl)ethyl-idene]ethane-1,2-diamine kappaN,N',N''}manganese(II). AB - The asymmetric unit of the title compound, [MnCl(2)(C(11)H(17)N(3))], contains two crystallographically independent mol-ecules with slightly different geometries. In each mol-ecule, the Mn(II) ion is five coordinated by the N,N',N'' tridentate Schiff base and two Cl atoms in a distorted square-pyramidal geometry. In the crystal, C-H?Cl hydrogen bonds link adjacent mol-ecules into a three dimensional network. PMID- 21522888 TI - Bis{benzyl 3-[(1H-indol-3-yl)methyl-idene]dithio-carbazato-kappaN,S}palladium(II) pyridine disolvate. AB - The Pd(II) ion in the title compound, [Pd(C(17)H(14)N(3)S(2))(2)].2C(5)H(5)N, is located on an inversion center and is four-coordinated by two of the deprotonated N,S-bidentate Schiff base ligands in a square-planar geometry. The dihedral angle between the aromatic ring planes within the ligand is 71.12 (9) degrees . The indole NH groups are bonded to the pyridine solvent mol-ecules via an N-H?N inter action. The crystal structure is consolidated by inter-molecular C-H?S inter actions. PMID- 21522889 TI - (1-Ferrocenyl-4,4,4-trifluoro-butane-1,3-dionato-kappaO,O)bis-(triphenyl phosphane)copper(I). AB - In the title mononuclear coordination complex, [CuFe(C(5)H(5))(C(9)H(5)F(3)O(2))(C(18)H(15)P)(2)], the Cu(I) ion is coordinated by the chelating beta-diketonate 1-ferrocenyl-4,4,4-trifluoro-butane-1,3-dione ligand through two O atoms and the two datively bonded triphenyl-phosphane ligands resulting in a distorted tetra-hedral coordination sphere. The Cu(I) ion, together with its chelating butane-1,3-dione group, is mutually coplanar [greatest displacement of an atom from this plane = 0.037 (1) A], and the Cu(I) ion lies slightly above [0.013 (1) A] the plane. The overall geometry, including the bond distances and angles within the complex, corresponds to those of other reported copper(I) beta-diketon-ates featuring organic groups at the beta diketonate ligand. PMID- 21522890 TI - (1,4,7,10,13,16-Hexaoxacyclo-octa-deca-ne)dimethyl-indium(III) trifluoro-methane sulfonate. AB - In the title compound, [In(CH(3))(2)(C(12)H(24)O(6))](CF(3)O(3)S), two of the In O distances within the cation are significantly shorter than the other four. The In(III) atom is in a distorted hexa-gonal-bipyramidal coordination geometry in which the C-In-C angle is 175.44 (12) degrees . The crystal structure is stabilized by weak inter-molecular C-H?O hydrogen bonds. PMID- 21522891 TI - Bis(acetato-kappaO,O')bis-[4-(dimethyl-amino)-pyridine-kappaN]copper(II). AB - In the mononuclear title complex, [Cu(CH(3)COO)(2)(C(7)H(10)N(2))(2)], the Cu(II) ion, located on a crystallographic inversion centre, is six coordinated by two N atoms of two 4-(dimethyl-amino)-pyridine (DMAP) ligands in apical positions and four O atoms from two symmetry-related opposite acetate anions, which are asymmetrically bonded in the equatorial plane. The complex and the crystal packing of the complex are stabilized by intra- and inter-molecular C-H?O hydrogen bonds, giving R(4) (2)(10) rings and generating a layer-like structure. PMID- 21522892 TI - Redetermination of cyclo-tetra-kis-(MU-5,10,15,20-tetra-4-pyridyl porphyrinato)tetra-zinc(II) dimethyl-formamide octa-solvate trihydrate at 100 K. AB - The structure of the title compound, [Zn(4)(C(40)H(24)N(8))(4)].8C(3)H(7)NO.3H(2)O, has been redetermined at 100 K. The redetermination is of significantly higher precision and gives further insight into the disorder of pyridyl groups and solvent mol-ecules. The mol ecules of (5,10,15,20-tetra-4-pyridyl-porphyrinato)zinc(II) (ZnTPyP) form homomolecular cyclic tetra-mers by coordination of a peripheral pyridyl group to the central Zn atom of an adjacent symmetry-related mol-ecule. The tetra-mer so formed exhibits mol-ecular S(4) symmetry and is located about a crystallographic fourfold rotoinversion axis. Severely disordered dimethyl-formamide and water mol ecules are present in the crystal, the contributions of which were omitted from refinement. Inter-molecular C-H?N hydrogen bonding is observed. PMID- 21522893 TI - 3-Meth-oxy-carbonyl-1-methyl-pyrazinium tetra-chlorido(pyrazine-2-carboxyl-ato kappaN,O)stannate(IV). AB - In the reaction of pyrazine-2-carb-oxy-lic acid and stannic chloride in methanol, one equivalent of the carb-oxy-lic acid is methyl-ated at the 4-amino site and is also esterified, yielding the title salt, (C(7)H(9)N(2)O(2))[SnCl(4)(C(5)H(3)N(2)O(2))]. The Sn(IV) atom in the anion is N,O-chelated by a pyrazine-2-carboxyl-ate in a cis-SnNOCl(4) octa-hedral geometry. PMID- 21522894 TI - 2-Meth-oxy-carbonyl-pyridinium tetra-chlorido(pyridine-2-carboxyl-ato kappaN,O)stannate(IV). AB - In the reaction of pyridine-2-carb-oxy-lic acid and stannic chloride in methanol, one equivalent of the carb-oxy-lic acid is protonated at the amino site and is also esterified, yielding the title salt, (C(7)H(8)NO(2))[SnCl(4)(C(6)H(4)NO(2))]. The Sn(IV) atom in the anion is N,O chelated by a pyridine-2-carboxyl-ate in a cis-SnNOCl(4) octa-hedral geometry. The cation is linked to the anion by an N-H?O hydrogen bond. PMID- 21522895 TI - 8-Hy-droxy-2-methyl-quinolinium tetra-chlorido(pyridine-2-carboxyl-ato kappaN,O)stannate(IV). AB - In the reaction of pyridine-2-carb-oxy-lic acid and stannic chloride in the presence of 2-methyl-8-hy-droxy-quinoline, the 2-methyl-8-hy-droxy-quinoline is protonated, yielding the title salt, (C(10)H(10)NO)[SnCl(4)(C(6)H(4)NO(2))]. The Sn(IV) atom in the anion is N,O-chelated by a pyridine-2-carboxyl-ate in a cis SnNOCl(4) octa-hedral geometry. The cation is linked to the anion by an O-H?O hydrogen bond. PMID- 21522896 TI - 8-Hy-droxy-2-methyl-quinolinium tetra-chlorido(quinolin-2-olato kappaN,O)stannate(IV) methanol disolvate. AB - In the reaction of 8-hy-droxy-quinoline, 2-methyl-8-hy-droxy-quinoline and stannic chloride, the 2-methyl-8-hy-droxy-quinoline is protonated, yielding the disolvated title salt, (C(10)H(10)NO)[SnCl(4)(C(9)H(6)NO)].2CH(3)OH. The Sn(IV) atom in the anion is N,O-chelated by the hy-droxy-quinolinate in a cis-SnNOCl(4) octa-hedral geometry. In the crystal, the cation, anion and solvent mol-ecules are linked by N-H?O, O-H?O and O-H?Cl hydrogen bonds, generating a three dimensional network. PMID- 21522897 TI - Di-MU(2)-methano-lato-bis-(MU-4-methyl-5-sulfanyl-idene-4,5-dihydro-1H-1,2,4 triazolido-kappaN:N)di-MU(3)-oxido-tetra-kis-[dimethyl-tin(IV)]. AB - The title distannoxane, [Sn(4)(CH(3))(8)(C(3)H(4)N(3)S)(2)(CH(3)O)(2)O(2)], lies about a center of inversion; the tetra-nuclear mol-ecule features a three-rung staircase Sn(4)O(4) core in which the two crystallographically independent Sn(IV) atoms are bridged by the triazolide group. The negatively charged N atom of the triazolide group binds to the terminal Sn atom at a shorter distance [Sn-N = 2.239 (2) A] compared with the neutral N atom that binds to the central Sn atom [Sn<- N = 2.757 (3) A]. The oxide O atom is three-coordinate whereas the methano late O atom is two-coordinate. The terminal Sn atom is five-coordinate in a cis C(3)SnNO trigonal-bipyramidal environment, whereas the central Sn atom is six coordinate in a C(2)SnNO(3) skew-trapezoidal-bipyramidal geometry. PMID- 21522898 TI - Di-MU(2)-methano-lato-bis-(MU-4-methyl-5-sulfanyl-idene-4,5-dihydro-1H-1,2,4 triazolido-kappaN:N)di-MU(3)-oxido-tetra-kis-[dibutyltin(IV)]. AB - The asymmetric unit of the title distannoxane, [Sn(4)(C(4)H(9))(8)(C(3)H(4)N(3)S)(2)(CH(3)O)(2)O(2)], contains two mol-ecules, each of which lies about an individual center of inversion. The tetra-nuclear mol ecule features a three-rung-staircase Sn(4)O(4) core in which two independent Sn(IV) atoms are bridged by the triazolide group. The negatively charged N atom of the triazolide group binds to the terminal Sn atom at a shorter distance [Sn-N = 2.262 (3), 2.254 (3) A] compared with the neutral N atom that binds to the central Sn atom[SnN = 2.617 (4); 2.830 (3) A]. The oxide O atom is three coordinate whereas the methano-late O atom is two-coordinate. The terminal Sn atom is five-coordinate in a cis-C(3)SnNO trigonal-bipyramidal environment, whereas the central Sn atom is six-coordinate in a C(2)SnNO(3) skew-trapezoidal bipyramidal geometry. PMID- 21522899 TI - (4,7-Diphenyl-1,10-phenanthroline-kappaN,N')dimethyl-bis-(thio-cyanato kappaN)tin(IV). AB - In the title compound, [Sn(CH(3))(2)(NSC)(2)(C(24)H(16)N(2))], a 1:1 adduct of dimethyl-tin diisothio-cyanate with 4,7-diphenyl-1,10-phenanthroline, the Sn(IV) atom shows a slightly distorted octa-hedral SnC(2)N(4) coordination. The methyl groups are trans to each other in the octa-hedron surrounding the metal atom [C Sn-C = 176.61 (12) degrees ]. PMID- 21522900 TI - Bis[2-(cyclo-pentyl-imino-meth-yl)-4-nitro-phenolato-kappaN,O]cobalt(II). AB - In the title compound, [Co(C(12)H(13)N(2)O(3))(2)], the Co(II) ion is situated on a twofold rotation axis and is coordinated by two N and two O atoms from two symmetry-related Schiff base 2-(cyclo-pentyl-imino-meth-yl)-4-nitro-phenolate ligands (L) in a distorted tetra-hedral geometry. The cyclo-pentyl ring in L is disordered over two conformations in a 0.640 (19):0.360 (19) ratio. PMID- 21522901 TI - Bis[2-(4-hy-droxy-phen-yl)acetato-kappaO]bis-(1,10-phenanthroline kappaN,N')cadmium penta-hydrate. AB - In the title compound, [Cd(C(8)H(7)O(3))(2)(C(12)H(8)N(2))(2)].5H(2)O, the Cd(II) ion is six-coordinated by two carboxylate O atoms of monodentate 2-(4-hy-droxy phen-yl)acetate ligands and by four N atoms from two chelating 1,10-phenantroline ligands in a distorted trigonal-prismatic geometry. O-H?O hydrogen bonds between water mol-ecules and the complex mol-ecules result in the formation of a three dimensional network. Four water mol-ecules act as single acceptors and double donors while the fifth water mol-ecule is involved as a single acceptor and single donor in an O-H?O inter-action and as a donor in an O-H?pi inter-action. PMID- 21522902 TI - Dinitro-sylbis[tris-(4-chloro-phen-yl)phosphane]iron. AB - The title dinitrosyl iron diphosphane complex, [Fe(NO)(2)(C(18)H(12)Cl(3)P)(2)] or Fe(NO)(2)L(2) [L = P(C(6)H(4)-p-Cl)(3)] belongs to the family of metal dinitrosyl compounds with the general formula Fe(NO)(2)(L)(x), referred to collectively as dinitrosyl iron compounds (DNICs). The iron atom is tetra hedrally coordinated by two phosphane ligands and two NO groups with Fe-N-O bond angles of 178.76 (15) and 177.67 (14) degrees . PMID- 21522903 TI - (2,2'-Bipyridine)(pyridine-2,6-dicarboxyl-ato)oxidovanadium(IV) ethanol monosolvate. AB - In the title compound, [V(C(7)H(3)NO(4))O(C(10)H(8)N(2))].C(2)H(5)OH, the V(IV) atom exhibits a distorted octa-hedral coordination environment formed by two pyridyl N atoms of 2,2'-bipyridine (bpy), the vanadyl O atom, and two carboxyl ate O atoms and one pyridyl N atom of the tridentate pyridine-2,6-dicarboxyl-ate (pydc(2-)) ligand. The pyridyl N atom of the pydc(2-) anion and one pyridyl N atom of bpy occupy the axial positions. O-H?O hydrogen bonds involving the ethanol solvent mol-ecule as donor and a carboxyl-ate O atom as acceptor atoms, as well as C-H?O hydrogen bonds, together with pi-pi stacking inter-actions between adjacent aromatic rings (average centroid-centroid distance = 3.577 A), seem to be effective in the stabilization of the crystal packing, resulting in the formation of a three-dimensional structure. PMID- 21522904 TI - [(Nitrato-kappaO,O')(nitrito-kappaO,O')(0.25/1.75)]bis-(1,10-phenanthroline kappaN,N')cadmium(II). AB - The reaction of cadmium nitrate and sodium nitrite in the presence of 1,10 phenanthroline yields the mixed nitrate-nitrite title complex, [Cd(NO(2))(1.75)(NO(3))(0.25)(C(12)H(8)N(2))(2)]. The metal ion is bis-chelated by two N-heterocycles as well as by the nitrate/nitrite ions in a distorted dodeca-hedral CdN(4)O(4) coordination environment. One nitrite group is ordered; the other is disordered with respect to a nitrate group (ratio 0.75:0.25) concerning the O atom that is not involved in bonding to the metal ion. PMID- 21522905 TI - Di-MU-thio-cyanato-kappaN:S;kappaS:N-bis-({2-morpholino-N-[1-(2-pyrid-yl)ethyl idene]ethanamine-kappaN,N',N''}(thio-cyanato-kappaN)cadmium). AB - In the title complex, [Cd(2)(NCS)(4)(C(13)H(19)N(3)O)(2)], the two Cd(II) ions are bridged by a pair of thio-cyanate N:S-bridging ligands around an inversion center. One terminal thio-cyanate N atom and one N,N',N''-tridentate Schiff base ligand complete a distorted CdN(5)S octa-hedral geometry about each Cd(II) atom. In the crystal, the Schiff base aromatic rings of adjacent mol-ecules are arranged above each other into infinite chains along the a axis with alternate centroid-centroid separations of 3.5299 (13) and 3.7857 (13) A. PMID- 21522906 TI - 6-Cyclo-hexyl-6,7-dihydro-dibenzo[c,f][1,5]aza-bis-mocin-12(5H)-yl(N->Bi) trifluoro-methane-sulfonate. AB - In the title compound, [Bi(C(20)H(23)N)(CF(3)SO(3))], the Bi(III) ion shows a distorted pseudo-trigonal-bipyramidal geometry, with two C atoms and a lone electron pair of the Bi atom in equatorial positions and the N and O atoms at the apical positions. The cyclo-hexyl group is disordered over two orientations with site-occupancy factors of 0.600 (14) and 0.400 (14). PMID- 21522907 TI - Bis[MU-4-(1H-imidazol-3-ium-1-yl)benzoato-kappaO:O']bis-[(methanol)tris-(nitrato kappaO,O')terbium(III)]. AB - In the centrosymmetric dinuclear title complex, [Tb(2)(NO(3))(6)(C(10)H(8)N(2)O(2))(2)(CH(3)OH)(2)], the Tb atoms are bridged by the carboxyl-ate groups of the two 4-(1H-imidazol-3-ium-1-yl)benzoate (iba) ligands. The iba ligand adopts a zwitterionic form with a protonated imidazole group. The Tb atom adopts a distorted tricapped trigonal-prismatic coordination geometry and is coordinated by six O atoms of three chelating nitrate ions, one O atom of the methanol mol-ecule and two O atoms of two iba ligands. The intra molecular Tb?Tb separation is 5.1419 (3) A. O-H?O and N-H?O hydrogen bonds connect complex mol-ecules into a two-dimensional network. PMID- 21522908 TI - Trisilver(I) citrate. AB - Trisilver(I) citrate, 3Ag(+).C(6)H(5)O(7) (3-), was obtained by evaporation of a saturated aqueous solution of the raw material that had been obtained from sodium dihydrogen citrate and silver nitrate. It features one formula unit in the asymmetric unit. There is an intra-molecular O-H?O hydrogen bond between the OH group and one of the terminal carboxyl-ate groups. Different citrate groups are linked via the three Ag(+) ions, yielding a three-dimensional network with rather irregular [AgO(4)] polyhedra. PMID- 21522909 TI - (MU-Benzoato-kappaO:O')tris-[MU-N,N'-bis-(4-meth-oxy-phen-yl)formamidinato kappaN:N']dimolybdenum(II) dichloro-methane monosolvate. AB - The title compound, [Mo(2)(C(15)H(15)N(2)O(2))(3)(C(7)H(5)O(2))].CH(2)Cl(2), has a quadruply bonded Mo(2) (4+) unit equatorially coordinated by three N,N'-bis-(4 MU-meth-oxy-phen-yl)formamidinate (DAniF) ligands and one benzoate anion. The Mo Mo bond length of 2.0881 (8) A is typical for quadruply bonded species. The phenyl ring and the connected dimetal chelating ring (Mo(2)O(2)C) are nearly co planar, making a dihedral angle of 3.24 (13) degrees . The dichloromethane solvent molecule is disordered over four sets of sites with occupancies of 0.3:0.3:0.2:0.2. PMID- 21522910 TI - Tris(ethane-1,2-diamine-kappaN,N')nickel(II) 5-hy-droxy-isophthalate monohydrate. AB - The asymmetric unit of the title compound, [Ni(C(2)H(8)N(2))(3)](C(8)H(4)O(5)).H(2)O, contains one [Ni(en)(3)](2+) cation (en is ethane-1,2-diamine), one 5-hy-droxy-isophthalate dianion and one water mol ecule. In the cation, the Ni(2+) ion is coordinated by six N atoms from three ethyl-enediamine ligands in a distorted octa-hedral geometry. The complex ions and water mol-ecules are linked by weak N-H?N/O and O-H?N/O hydrogen bonds into a three-demensional structure. PMID- 21522911 TI - Poly[[bis-(2,2-bipyridine)-bis-[MU(6)-5-(carboxyl-atometh-oxy)benzene-1,3 dicarboxyl-ato]trimanganese(II)] monohydrate]. AB - The title compound, {[Mn(3)(C(10)H(5)O(7))(2)(C(10)H(8)N(2))(2)].H(2)O}(n), was synthesized under hydro-thermal conditions. Six carboxyl-ate groups of six 5 (carboxyl-atometh-oxy)benzene-1,3-dicarboxyl-ate anions (OABDC(3-)) join three Mn(II) ions into a trinuclear centrosymmetric [Mn(3)(MU(2)-COO)(6)] unit with one Mn site situated on a centre of inversion. The latter Mn(II) ion exhibits a distorted MnO(6) coordination, whereas the other Mn(II) ion has a trigonal bipyramidal MnN(2)O(3) coordination environment resulting from three carboxylate O atoms and the two N atoms of the bipyridine ligand. Adjacent units are linked to each other by OABDC(3-) ligands into a layer parallel to (010). Within the layer, O-H?O hydrogen-bonding inter-actions involving the uncoordinated and half occupied water mol-ecule and the free carboxyl-ate O atoms are observed. The layers stack along [010], constructing a three-dimensional structure through pi pi inter-actions between adjacent pyridine rings, with a centroid-centroid distance of 3.473 (5) A. PMID- 21522912 TI - Dibromido{2-morpholino-N-[1-(2-pyrid-yl)ethyl-idene]ethanamine kappaN,N',N''}zinc(II). AB - In the title complex, [ZnBr(2)(C(13)H(19)N(3)O)], the Zn(II) atom is five coordinated by the three N-donor atoms of the Schiff base ligand and by two Br atoms in a distorted square-pyramidal geometry. The morpholine ring adopts a chair conformation. PMID- 21522913 TI - (2,2'-Bipyridyl-kappaN,N')chlorido(dl-threoninato-kappaN,O)copper(II) monohydrate. AB - In the title compound, [Cu(C(4)H(8)NO(3))Cl(C(10)H(8)N(2))].H(2)O, the Cu(II) atom is in a slightly distorted square-pyramidal coordination geometry with the basal plane defined by the two N atoms of the bipyridine ligand and the N and O atoms from the threoninate ion and the apical site occupied by the Cl atom. In the crystal, inter-molecular O-H?O, N-H?O, O-H?Cl, C-H?O and C-H?Cl inter-actions link the mol-ecules into a three-dimensional network. A pi-pi inter-action with a centroid-centroid distance of 3.461 (1) A is also present. PMID- 21522914 TI - (2,2'-Bipyridine-kappaN,N')bromido(1,4,7-trithia-cyclo-nonane kappaS,S',S'')ruthenium(II) hexa-fluoridophosphate. AB - The title compound, [RuBr(C(10)H(8)N(2))(C(6)H(12)S(3))]PF(6) or [RuBr(bpy)([9]aneS(3))]PF(6) ([9]aneS(3) is 1,4,7-trithia-cyclo-nonane and bpy is 2,2'-bipyridine), exhibits a very similar octahedral coordination geometry for the Ru(2+) atom to that of its [RuCl(bpy)([9]aneS(3))](+) analogue, with only the chloride ligand being substituted by a bromide ligand. The presence of a PF(6) ( ) anion (alongside with the coordinated bromide ligand) promotes the existence of an extensive network of weak C-H?X (X = F, Br) inter-actions. PMID- 21522915 TI - Bis(MU(2)-quinoline-2-carboxyl-ato)-kappaN,O:O;kappaO:N,O-bis-[(acetato kappaO)(ethanol-kappaO)lead(II)]. AB - In the centrosymmetric dinuclear title compound, [Pb(2)(C(10)H(6)NO(2))(2)(CH(3)COO)(2)(C(2)H(5)OH)(2)], one O atom of the carboxyl-ate group of the quinoline-2-carboxyl-ate anion connects the two Pb(II) atoms. The Pb(II) atom is surrounded by four O atoms and one N atom in a Psi-octa hedral PbO(4)NE geometry (E is the electron lone pair). Two longer Pb?O inter actions distort the geometry towards a Psi-square-anti-prism. Inter-molecular O H?O hydrogen bonds link the mol-ecules. PMID- 21522916 TI - {rac-5-[Meth-oxy(phen-yl)meth-yl]-10,20-diphenyl-porphyrinato}nickel(II). AB - The title compound, [Ni(C(40)H(28)N(4)O)], was obtained from a Grignard reaction of the respective formyl-porphyrin to yield {5-[hy-droxy(phen-yl)meth-yl]-10,20 diphenyl-porphyrinato}nickel(II), followed by crystallization from methyl-ene chloride/methanol. The mol-ecule exhibits a ruffled macrocycle with an average deviation of the 24 macrocycle atoms from their least-squares plane (Delta24) of 0.26 A and an average Ni-N bond length of 1.931 (2) A. In line with the asymmetrical substituent pattern, the degree of distortion is slightly larger at point of attachment of the meth-oxy(phen-yl)methyl residue than at the unsubstituted meso position. The meth-oxy group attached to the chiral C atom is disordered in a 0.534 (4):0.466 (4) ratio. PMID- 21522917 TI - Bis(2-amino-6-methyl-pyridinium) trans-diaqua-bis-(pyrazine-2,3-dicarboxyl ato)cobaltate(II) octa-hydrate. AB - The title compound, (C(6)H(9)N(2))(2)[Co(C(6)H(2)N(2)O(4))(2)(H(2)O)(2)].8H(2)O, was obtained by the reaction of CoCl(2).6H(2)O with 1,4-pyrazine-2,3-dicarb-oxy lic acid and 2-amino-6-methyl-pyridine in aqueous solution (molar ratio 1:2:2). The Co(II) ion is situated on an inversion centre and is coordinated by two O and two N atoms of two symmetry-related 1,4-pyrazine-2,3-dicarboxyl-ate ligands and two water mol-ecules and has a disorted octa-hedral coordination environment. The asymmetric unit also contains four water mol-ecules. In the crystal, extensive inter-molecular classical N-H?O, O-H?O and O-H?N hydrogen bonds and pi-pi stacking inter-actions [centroid-centroid distance = 3.490 (1) A] connect the various components, forming a three-dimensional network. PMID- 21522918 TI - [5,10,15,20-Tetra-kis(4-meth-oxy-phen-yl)porphyrinato kappaN,N',N'',N'''](trifluoro-methane-sulfonato-kappaO)-iron(III). AB - The title compound, [Fe(CF(3)O(3)S)(C(48)H(36)N(4)O(4))], is a five-coordinate iron(III) porphyrin complex with a trifluoro-methane-sulfonate anion as an axial ligand. The Fe(III) atom is displaced by 0.40 (1) A towards the trifluoro-methane sulfonate anion from the 24-atom mean plane of the porphyrin. The average Fe-N(p) distance is 2.044 (2) A and the Fe-O distance is 2.001 (2) A. PMID- 21522919 TI - catena-Poly[[bis-[2-(2-pyrid-yl)-1-H-imidazole-kappaN,N]cadmium]-MU-benzene-1,3 dicarboxyl-ato-kappaO:O]. AB - In the title coordinaltion polymer, [Cd(C(8)H(4)O(4))(C(8)H(7)N(3))(2)](n), the Cd(II) atom, lying on a twofold rotation axis, is six-coordinated by two carboxyl ate O atoms from two benzene-1,3-dicarboxyl-ate (m-BDC) ligands and four N atoms from two chelating 2-(2-pyrid-yl)imidazole mol-ecules, forming a slightly distorted octa-hedral geometry. The m-BDC ligand is located over a twofold rotation axis. The Cd(II) atoms are bridged by the m-BDC ligands, leading to a wave-shaped chain structure along [010]. N-H?O hydrogen bonds connect the chains. PMID- 21522920 TI - Tetra-kis{4-[(2H-tetra-zol-5-yl)meth-yl]morpholin-4-ium} dodeca-tungstosilicate hexa-hydrate. AB - The crystal structure of the title compound, (C(6)H(12)N(5)O)(4)[W(12)(SiO(4))O(36)].6H(2)O, consists of an alpha-Keggin-type [W(12)(SiO(4))O(36)](4-) polyoxidoanion, four [(2H-tetra-zol-5-yl)meth yl]morpholinium cations and six uncoordinated water mol-ecules. In the cations, the morpholine rings display chair conformations. Extensive N-H?O, N-H?N, O-H?O and O-H?N hydrogen bonds are present in the crystal structure. PMID- 21522921 TI - Chlorido{N-[(diethyl-amino)-dimethyl-sil-yl]anilido-kappaN}(N,N,N',N'-tetra methyl-ethane-1,2-diamine-kappaN,N')cobalt(II). AB - In the title cobalt(II) compound, [Co(C(12)H(21)N(2)Si)Cl(C(6)H(16)N(2))], the ethane-1,2-diamine donor mol-ecule coordin-ates the metal atom in an N,N' chelating mode, with Co-N distances of 2.136 (2) and 2.140 (3) A. An anilide ligand connects to the Co(II) atom with a sigma-bond, the Co-N(anilide) distance being 1.931 (2) A. The four-coordinate Co(II) atom demonstrates a slightly distorted tetra-hedral geometry. PMID- 21522922 TI - (Methanol-kappaO)(methano-lato-kappaO)oxido[N-(2-oxidobenzyl-idene)phenyl alaninato-kappaO,N,O']vanadium(V). AB - In the title complex, [V(C(16)H(13)NO(3))(CH(3)O)O(CH(3)OH)], the V(V) atom is six-coordinated by a tridentate ligand derived from the condensation of salicyl aldehyde and l-phenyl-alanine, a vanadyl O atom, a methano-late O atom and a methanol O atom, forming a distorted octa-hedral coordination geometry. In the crystal, inter-molecular O-H?O and C-H?O hydrogen bonds result in a two dimensional structure parallel to (001). PMID- 21522923 TI - catena-Poly[[{bis-[tetra-aqua-(2-hy-droxy-3,4-dioxocyclo-but-1-en-1-olato kappaO)bariumstrontium(0.35/0.65)]di-MU-aqua}-bis-(MU-2-hy-droxy-4-oxocyclo-but-1 ene-1,3-diolato-kappaO:O)] monohydrate]. AB - The title structure, {[Ba(0.71)Sr(1.29)(C(4)HO(4))(4)(H(2)O)(10)].H(2)O}(n), is built from dimers of edge-sharing monocapped square anti-prisms [(Ba/Sr)O(3)(H(2)O)(6)], in which barium and strontium are statistically disordered [ratio 0.353 (8):0.647 (8)] on the same crystallographic site. Such dimers are connected via bidentate hydrogen squarate groups [HC(4)O(4)](-), leading to chains that propagate along the b axis. Inter- and intra-molecular O H?O hydrogen bonds maintain the crystal packing through a three-dimensional network. PMID- 21522924 TI - Monoclinic modification of bis-(MU(2)-pyridine-2,6-dicarboxyl-ato) kappaO,N,O:O;kappaO:O,N,O-bis-[aqua-dibutyl-tin(IV)]. AB - The Sn(IV) atom in the centrosymmetric dinuclear title compound, [Sn(2)(C(4)H(9))(4)(C(7)H(3)NO(4))(2)(H(2)O)(2)], exists in a trans-C(2)SnNO(4) penta-gonal-bipyramidal geometry. There are two half-mol-ecules in the asymmetric unit that are completed by inversion symmetry. The crystal studied was a non merohedral twin with a ratio of 47.3 (1)% for the minor twin component. Bond dimensions are similar to those found in the tetra-gonal polymorph [Huber et al. (1989 ?). Acta Cryst. C45, 51-54]. O-H?O hydrogen-bonding interactions stabilize the crystal packing. PMID- 21522925 TI - Bis(MU-pyridine-2,5-dicarboxyl-ato)-kappaN,O:O;kappaO:N,O-bis-[aqua-(2,2' bipyridine-kappaN,N')cobalt(II)] dihydrate. AB - In the centrosymmetric title compound, [Co(2)(C(7)H(3)NO(4))(2)(C(10)H(8)N(2))(2)(H(2)O)(2)].2H(2)O, the two Co(II) cations are bridged by pairs of pyridine-2,5-dicarboxyl-ate anions across an inversion center. Besides two pyridine-2,5-dicarboxyl-ate anions, one bidentate 2,2'-bipyridine and one water mol-ecule coordinate to the Co cation, completing a distorted octa-hedral coordination geometry. Within the dinuclear mol-ecule, pi pi stacking occurs between parallel pyridine rings with centroid-centroid distances of 3.802 (2) A. The crystal structure contains extensive O-H?O and weak C-H?O hydrogen bonds and C-H?pi inter-actions. PMID- 21522926 TI - Triaqua-(1,10-phenanthroline-kappaN,N')(sulfato-kappaO)zinc(II). AB - The Zn(II) atom in the title compound, [Zn(SO(4))(C(12)H(8)N(2))(H(2)O)(3)], is coordinated by one O atom from a sulfate dianion, two N atoms from a 1,10 phenanthroline mol-ecule and three water O atoms in an octa-hedral geometry. An intra-molecular O-H?O hydrogen bond occurs. Inter-molecular O-H?O hydrogen bonds generate a layer structure parallel to (001). There are weak C-H?O inter-actions within the layers. PMID- 21522927 TI - Poly[MU-aqua-MU(4)-terephthalato-strontium]. AB - In the title compound, [Sr(C(8)H(4)O(4))(H(2)O)](n), the Sr(II) atom exhibits coordination number eight, with six O atoms from four carboxylate groups (two bidentate and two monodentate) of terephthalate ligands and two water O atoms. The SrO(8) polyhedra are linked into inorganic chains by sharing three coplanar O atoms. These inorganic chains are extended along the b axis to form layers in the ab plane by O-C-O linking. Parallel layers are connected by terephthalic groups, forming a three-dimensional framework. O-H?O hydrogen-bonding inter-actions are observed. PMID- 21522928 TI - Poly[[hepta-MU(2)-aqua-bis-(MU(2)-pyrazine-2-carboxyl-ato)dibarium] bis-(pyrazine 2-carboxyl-ate)]. AB - In the layered title coordination polymer, {[Ba(2)(C(5)H(3)N(2)O(2))(2)(H(2)O)(7)](C(5)H(3)N(2)O(2))(2)}(n), the coordination geometries around the two independent Ba(II) ions can be described as bicapped square-anti-prismatic [BaNO(9)] arrangements. A two-dimensional polymeric framework with (6,3) topology can be observed in the ac plane, the nodes being provided by Ba(II) ions and the connectors being N and O atoms belonging to pyrazine-2-carboxyl-ate ligands and O atoms of bridging water mol ecules. Non-coordinating pyrazine-2-carboxyl-ate ions are located between the polymeric layers in the crystal and are interconnected through extensive O-H?N,O hydrogen bonding. PMID- 21522929 TI - catena-Poly[[[2-(pyridin-2-yldisulfan-yl)pyridine-kappaN,S]copper(I)]-MU(1,5) dicyanamido]. AB - In the title compound, [Cu(C(2)N(3))(C(10)H(8)N(2)S(2))](n), the Cu(I) atoms are connected by bridging dicyanamide ligands, forming chains parallel to [100]. Each Cu(I) atom displays a tetra-hedral coordination environment, formed by one S atom and three N atoms from one 2-(pyridin-2-yldisulfan-yl)pyridine and two dicyanamide ligands. The crystal structure is stabilized by C-H?N hydrogen bonds, forming a three-dimensional network. PMID- 21522930 TI - {2,6-Bis[(2,6-diphenyl-phosphan-yl)-oxy]-4-fluoro-phenyl-kappaP,C,P'}(6-methyl 2,2,4-trioxo-3,4-dihydro-1,2,3-oxathia-zin-3-ido-kappaN)palladium(II). AB - The title acesulfamate complex, [Pd(C(30)H(22)FO(2)P(2))(C(4)H(4)NO(4)S)], contains a four-coordinate Pd(II) ion with the expected, although relatively distorted, square-planar geometry where the four L-Pd-L angles range from 79.58 (8) to 102.47 (7) degrees . The acesulfamate ligand is N-bound to Pd [Pd-N = 2.127 (2) A] with a dihedral angle of 76.35 (6) degrees relative to the square plane. Relatively long phen-yl-acesulfamate C-H?O and phen-yl-fluorine C-H?F inter-actions consolidate the crystal packing. PMID- 21522931 TI - cis-Di-MU-oxido-bis-[(N,N-diethyl-dithio-carbamato kappaS,S')oxidomolybdenum(V)](Mo-Mo) tetra-hydro-furan monosolvate. AB - The title compound, [Mo(2)(C(5)H(10)NS(2))(2)O(4)].C(4)H(8)O, can be readily prepared in tetra-hydro-furan (THF) by an oxidation reaction between the Mo(IV) precursor [MoO(S(2)CNEt(2))(2)] with [ReMeO(3)]. The compound is an axially symmetric Mo(V) dimer (2 symmetry), in which the metal atoms exhibit a distorted square-pyramidal coordination environment. A THF mol-ecule was found to be equally disordered over two symmetry-related sites (around a twofold rotation axis), trans-coordinated to the apical oxido group and weakly inter-acting with the Mo(V) atoms [Mo-O = 2.6213 (19) A]. In the crystal, some weak C-H?O inter actions occur between the terminal oxido and neighbouring -CH(3) groups of an adjacent [Mo(MU-O)O(S(2)CNEt(2))](2) unit. PMID- 21522932 TI - Bis(4-carb-oxy-pyridine-2-carboxyl-ato-kappaN,O)copper(II) dimethyl sulfoxide disolvate. AB - In the title complex, [Cu(C(7)H(4)NO(4))(2)].2C(2)H(6)OS, the Cu(II) atom is situated on an inversion centre and is N,O-chelated by two monoanionic 4-carb-oxy pyridine-2-carboxyl-ate ligands in a slightly distorted square-planar coordination geometry. The dimethyl sulfoxide solvent mol-ecules and Cu(II) complex mol-ecules are linked by O-H?O hydrogen bonding. In addition, C-H?O contacts and pi-pi inter-actions [centroid-centroid distance = 3.590 (1) A] occur. PMID- 21522933 TI - (R)-(+)-Dimeth-yl[4-oxido-2-oxo-1-(1-phenyl-eth-yl)-1,2,5,6-tetra-hydro-pyridin-3 yl]sulfonium. AB - In the title zwitterionic compound, C(15)H(19)NO(2)S, the six-membered heterocycle adopts a sofa conformation. The negative charge is delocalized along the carbonyl and enolate system on the ring and the positive charge is localized on the S atom. Two inter-molecular C-H?O inter-actions help to establish the packing. PMID- 21522934 TI - (E)-N'-(2-Fluoro-benzyl-idene)furan-2-carbohydrazide. AB - The title compound, C(12)H(9)FN(2)O(2), was prepared by the reaction of 2-fluoro benzaldehyde and furan-2-carbohydrazide. The furan ring is disordered over two sets of sites with refined occupancies of 0.60 (3):0.40 (3). The major and minor components of the furan ring make dihedral angles of 51.9 (6) and 38.0 (10) degrees , respectively, with the benzene ring. In the crystal, mol-ecules are linked via bifurcated N-H?O(N) hydrogen bonds into chains along [001]. PMID- 21522935 TI - (E)-3-(4-Chloro-phen-yl)-1-(2,3,4-trichloro-phen-yl)prop-2-en-1-one. AB - In the title chalcone derivative, C(15)H(8)Cl(4)O, the C=C double bond exists in an E configuration and the dihedral angle between the two benzene rings is 48.13 (11) degrees . In the crystal, mol-ecules are arranged into columns and stacked down the a axis featuring possible weak aromatic pi-pi stacking inter-actions [centroid-centroid separation = 3.888 (2) A]. PMID- 21522937 TI - 3-(2-Methyl-benzyl-idene)-2,3-dihydro-1,5-benzothia-zepin-4(5H)-one. AB - In the crystal structure of the title compound, C(17)H(15)NOS, the mol-ecules form centrosymmetric dimers through pairs of N-H?O hydrogen bonds. The seven membered ring adopts a distorted half-chair conformation. PMID- 21522936 TI - (E)-2-(4-Methylbenzylidene)hydrazinecarboxamide. AB - The title compound, C(9)H(11)N(3)O, was synthesized by the reaction of 4-methyl benzaldehyde with semicarbazide. The mol-ecule adopts an E configuration about the central C=N double bond and the dihedral angle between the mean planes of the benzene ring and the carboxamide groups is 17.05 (9) degrees . The hydrazine N atoms are twisted slightly out of the plane of the carboxamide group [C-C-N-N torsion angle = 178.39 (14) degrees ] and an intra-molecular N-H?N bond generates an S(5) ring. In the crystal, adjacent mol-ecules are connected via a pair of N H?O hydrogen bonds, generating R(2) (2)(8) loops, resulting in supra-molecular [001] ribbons. PMID- 21522938 TI - (22E,24R)-3alpha,5-Cyclo-5alpha-ergosta-22-en-6-one. AB - In the title mol-ecule, C(28)H(44)O, the two six-membered rings have a chair conformation and the two five-membered rings haveenvelope conformations. The crystal packing exhibits no short inter-molecular contacts. The absolute configuration was assigned to correspond with that of the known chiral centres in a precursor molecule, which remained unchanged during the synthesis of the title compound. PMID- 21522939 TI - (S,Z)-1-Chloro-3-[(3,4,5-trimeth-oxy-benzyl-idene)amino]-propan-2-ol. AB - In the title compound, C(13)H(18)ClNO(4), the two meth-oxy groups at the meta positions of the attached benzene ring are close to being coplanar with the ring [the meth-oxy C atoms deviate by 0.267 (7) and 0.059 (7) A], whereas the third meth-oxy group at the para position is not coplanar with the benzene ring [methoxy C atom deviates by 1.100 (6) A]. In the crystal, mol-ecules are linked into a chain along the a axis by O-H?N hydrogen bonds. PMID- 21522940 TI - 5-Chloro-1-(4-meth-oxy-benz-yl)indoline-2,3-dione. AB - In the title compound, C(16)H(12)ClNO(3), an arm-like 4-meth-oxy-benzene links to 5-chloro-indoline-2,3-dione through a methyl-ene group, with a dihedral angle between the mean planes of the benzene ring and the indole moiety of 88.44 (8) degrees . In the crystal, weak inter-molecular C-H?O and pi-pi stacking inter actions [centroid-centroid distance = 3.383 (3) A] link the mol-ecules together to form a three-dimensional framework. PMID- 21522941 TI - meso-5,5'-Bis[(4-fluoro-phen-yl)diazen-yl]-2,2'-(pentane-3,3-di-yl)di-1H-pyrrole. AB - There are two independent molecules in the asymmetric unit of the title compound, C(25)H(24)F(2)N(6), in which the N=N bonds adopt a trans configuration with distances in the range 1.262 (2)-1.269 (3) A. The dihedral angles between heterocycles are 86.7 (2) and 85.6 (2) degrees in the two molecules while the dihedral angles between the heterocylic rings and the adjacent benzene rings are 13.4 (2) and 13.4 (2) degrees in one molecule and 5.3 (2) and 6.5 (2) degrees in the other. In the crystal, pairs of independent mol-ecules are held together by four N-H?N hydrogen bonds, forming inter-locked dimers. PMID- 21522942 TI - e,e-trans-Cyclo-hexane-1,4-carb-oxy-lic acid-hexa-methyl-ene-tetra-mine (1/2). AB - The asymmetric unit of the title compound, 2C(6)H(12)N(4).C(8)H(12)O(4), contains one half-mol-ecule of e,e-trans-cyclo-hexane-1,4-dicarb-oxy-lic acid (the complete molecule being generated by inversion symmetry) and one mol-ecule of hexa-methyl-ene-tetra-mine (HMTA), which are connected by O-H?N hydrogen bonds. This forms isolated trimers that pack in a herringbone fashion. PMID- 21522943 TI - N-Phenyl-succinamic acid. AB - In the crystal structure of the title compound, C(10)H(11)NO(3), the conformations of N-H and C=O bonds in the amide segment are anti to each other. Further, the conformations of the amide O atom and the carbonyl O atom of the acid segment are anti to each other and to the adjacent -CH(2) groups. The C=O and O-H bonds of the acid group are in syn positions with respect to each other. In the crystal, the mol-ecules are packed into infinite chains along the a axis through inter-molecular N-H?O and O-H?O hydrogen bonds. PMID- 21522944 TI - Bis(1,10-phenanthrolin-1-ium) 9,10-di-oxo-9,10-dihydroanthracene-1,5-disul-fonate hexa-hydrate. AB - The title hydrated molecular salt, 2C(12)H(9)N(2) (+).C(14)H(6)O(8)S(2) (2 ).6H(2)O, consists of 1,10-phenanthrolinium (phen-H(+)) cations, anthraquinone 1,5-disulfonate (AQDS(2-)) anions, which occupy a centre of inversion, and water molecules of crystal-lization. In the crystal, a supra-molecular network structure is formed via N-H?O and O-H?O hydrogen bonds and weak C-H?O and pi-pi stacking inter-actions [centroid-centroid distances = 3.651 (6) and 3.545 (8) A]. PMID- 21522945 TI - {4-[5-(4-tert-Butyl-phen-yl)-1,3,4-oxa-diazol-2-yl]phen-yl}methanol. AB - In the title compound, C(19)H(20)N(2)O(2), the 1,3,4-oxadiazole ring is almost coplanar with the two neighboring benzene rings [dihedral angles = 3.76 (4) and 5.49 (4) degrees ]. In the crystal, mol-ecules are connected by strong inter molecular O-H?N hydrogen bonds, forming chains parallel to the c axis. PMID- 21522946 TI - N'-(2,4-Dichloro-benzyl-idene)-2-fluoro-benzohydrazide. AB - The mol-ecule of the title compound, C(14)H(9)Cl(2)FN(2)O, exists in a trans configuration with respect to the methyl-idene unit and the benzene rings form a dihedral angle of 8.1 (2) degrees . In the crystal, mol-ecules are linked through N-H?O hydrogen bonds into C(4) chains propagating in [100]. PMID- 21522947 TI - 2,2-Dimethyl-5-[(pyridin-2-yl-amino)-methyl-idene]-1,3-dioxane-4,6-dione. AB - In the title compound, C(12)H(12)N(2)O(4), the dihedral angle between the pyridine and enamine planes is 3.5 (3) degrees , while the angle between the dioxanedione (seven atoms) and enamine planes is 4.6 (3) degrees . The dioxane ring approximates an envelope conformation. PMID- 21522948 TI - 2-Isobutyl-6-phenyl-imidazo[2,1-b][1,3,4]thia-diazole. AB - In the title compound, C(14)H(15)N(3)S, the imidazo[2,1-b][1,3,4]thia-diazole fused-ring system is close to planar, with a maximum deviation of 0.042 (1) A, and the dihedral angle between it and the phenyl ring is 24.21 (6) degrees . The isobutyl group is disordered over two sets of sites in a 0.899 (9):0.101 (9) ratio. In the crystal, weak aromatic pi-pi stacking inter-actions involving the imidazole and thia-diazole rings with a centroid-centroid distance of 3.8067 (7) A occur. PMID- 21522949 TI - 2-Isobutyl-6-(4-meth-oxy-phen-yl)imidazo[2,1-b][1,3,4]thia-diazole. AB - In the title compound, C(15)H(17)N(3)OS, the dihedral angle between the statistically planar imidazo[2,1-b][1,3,4]thia-dia-zole fused-ring system (r.m.s. deviation = 0.002 A) and the methyoxbenzene ring is 4.52 (6) degrees . In the crystal, mol-ecules are arranged into columns and stacked down the a axis. The crystal structure is stabilized by weak C-H?pi and pi-pi inter-actions [centroid centroid separations = 3.6053 (8) and 3.7088 (7) A]. PMID- 21522950 TI - 11,12-Dihy-droxy-10,6,8,11,13-icetexapentan-1-one. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: 14,15-dihy-droxy-7,7-dimethyl-13-(propan-2 yl)tricyclo-[9.4.0.0(3,8)]penta-deca-1(11),3(8),9,12,14-pentaen-4-one], C(20)H(24)O(3), is a new icetexane diterpenoid which was isolated from the roots of Premna obtusifolia (Verbenaceae). The mol-ecule has three fused rings: a cyclo hexenone, a central cyclo-heptene and a benzene ring. The cyclo-hexenone ring is in an envelope conformation, whereas the cyclo-heptene ring is in a twisted boat conformation. Intra-molecular O-H?O hydrogen bonds generate S(5) and S(8) ring motifs. In the crystal, mol-ecules are linked into dimers through O-H?O hydrogen bonds. These dimers are arranged in to sheets parallel to the ac plane. C-H?O and weak C-H?pi inter-actions are also present. PMID- 21522951 TI - rac-Ethyl 2-amino-3-hy-droxy-3-[4-(methyl-sulfon-yl)phen-yl]propano-ate. AB - In the title compound, C(12)H(17)NO(5)S, the orientations of the 2-ethyl-2-amino 3-hy-droxy-propano-ate group and the 4-methyl-sulfonyl moiety towards the aromatic ring are periplanar and (-)-anti-clinal, respectively. In the crystal packing, the dominant inter-action is O-H?N hydrogen bonding, which generates a chain running along [100]. N-H?O and C-H?O interactions are also observed. PMID- 21522952 TI - 4-{4-Methyl-2-[(meth-yl)(2-methyl-phen-yl)amino]-1,3-thia-zol-5-yl}-N-(3-methyl phen-yl)pyrimidin-2-amine. AB - In the title compound, C(23)H(23)N(5)S, the thia-zole ring and pyrimidine ring are almost coplanar, making a dihedral angle of 4.02 (9) degrees . in the crystal, weak inter-molecular N-H?N inter-actions link pairs of molecules into centrosymmetric dimers. PMID- 21522953 TI - 4-{2-[(3,4-Dichloro-phen-yl)(meth-yl)amino]-4-methyl-1,3-thia-zol-5-yl}-N-(3 methyl-phen-yl)pyrimidin-2-amine. AB - In the title compound, C(22)H(19)Cl(2)N(5)S, the thia-zole and pyrimidine rings are almost co-planar, making a dihedral angle of 6.48 (7) degrees . In the crystal, intermolecular N-H?N hydrogen bonds link pairs of molecules into centrosymmetric dimers.. PMID- 21522954 TI - N-(3-Meth-oxy-phen-yl)-4-{4-methyl-2-[(meth-yl)(4-methyl-phen-yl)amino]-1,3-thia zol-5-yl}pyrimidin-2-amine. AB - The asymmetric unit of the title compound, C(23)H(23)N(5)OS, contains two independent mol-ecules. In one mol-ecule, the thia-zole and pyrimidine rings are almost co-planar, making a dihedral angle of 2.48 (8) degrees . In the other mol ecule, the corresponding dihedral angle is 12.82 (8) degrees . The crystal structure is stabilized by weak inter-molecular N-H?N and C-H?O inter-actions that extend along the b axis. PMID- 21522955 TI - N-[4-(2-Morpholino-eth-oxy)phen-yl]acetamide monohydrate. AB - In the title compound, C(14)H(20)N(2)O(3).H(2)O, the geometry about the morpholine N atom implies sp(3) hybridization. In the crystal, symmetry-related mol-ecules are linked by inter-molecular N-H?O, O-H?O and O-H?N hydrogen bonds, forming infinite chains along the b axis. The chain structure is further stabilized by intra-molecular C-H?O inter-actions. PMID- 21522956 TI - 2,2'-(p-Phenyl-ene)bis-(4,5-dihydro-1H-imidazol-3-ium) bis-(3-nitro-benzoate). AB - In the title compound, C(12)H(16)N(4) (+).2C(7)H(4)NO(4) (-), the complete 2,2' (p-phenyl-ene)bis-(4,5-dihydro-1H-imidazol-3-ium) (bib) dication is generated by crystallographic inversion symmetry. The bib cations reside on crystallographic inversion centers, which coincide with the centroids of the respective benzene rings. In the cation, the imidazole ring adopts an envelop conformation with the flap atom displaced by 0.082 (3) A from the plane through the other ring atoms. In the crystal, the cations and anions are linked through inter-molecular N-H?O hydrogen bonds, forming chains running along the a axis. C-H?O inter-actions also occur. Weak pi-pi contacts between the imidazole rings of bib and between the benzene rings of NB [centroid-centroid distances = 3.501 (1) and 3.281 (2) A, respectively] may further stabilize the structure. PMID- 21522957 TI - 3-Hy-droxy-2-(4-hy-droxy-phen-yl)-4H-chromen-4-one. AB - In the title compound, C(15)H(10)O(4), the benzene ring is twisted at an angle of 20.7 (1) degrees relative to the 4H-chromene skeleton. In the crystal, adjacent mol-ecules are linked via a network of O-H?O and C-H?O hydrogen bonds. The mean planes of adjacent 4H-chromene moieties are parallel or oriented at an angle of 20.9 (1) degrees in the crystal structure. PMID- 21522958 TI - 2-(Furan-2-yl)-3-hy-droxy-4H-chromen-4-one. AB - In the crystal structure of the title compound, C(13)H(8)O(4), the inversely oriented mol-ecules form inversion dimers through pairs of O-H?O hydrogen-bonding inter-actions. An intramolecular O-H?O hydrogen bond occurs. In the packing of the mol-ecules, the nearly planar 2-(furan-2-yl)-4H-chromene units [dihedral angle between the chromene and furan rings = 3.8 (1) degrees ] are either parallel or inclined at an angle of 80.7 (1) degrees . PMID- 21522959 TI - 1'-Methyl-3'-(4-methyl-benzo-yl)-4'-[5-(2-thien-yl)-2-thien-yl]spiro-[acenaphthyl ene-1,2'-pyrrolidin]-2(1H)-one. AB - In the title compound, C(32)H(25)NO(2)S(2), the mean plane through the five membered pyrrolidine ring, which exhibits an envelope conformation, makes dihedral angles of 82.3 (1) and 83.9 (9) degrees with the benzene ring and the acenaphthyl-ene ring system, respectively. The dihedral angle between the thiophene rings is 19.0(3) degrees . The crystal structure shows C-H?pi and pi-pi inter-actions [centroid-centroid distance = 3.869 (2) A]. PMID- 21522960 TI - 3'-(4-Chloro-benzo-yl)-1'-methyl-4'-[5-(2-thien-yl)-2-thien-yl]spiro-[acenaphthyl ene-1,2'-pyrrolidin]-2(1H)-one. AB - In the title compound, C(31)H(22)ClNO(2)S(2), the five-membered pyrrolidine ring, which exhibits an envelope conformation, makes a dihedral angle of 87.4 (2) degrees with the acenaphthyl-ene ring system. The crystal structure is stabilized by pi-pi inter-actions [centroid-centroid distance = 3.869 (2) A]. A C atom and the S atom of the thiophene ring are disordered over two positions with refined occupancies of 0.629 (7) and 0.372 (7). PMID- 21522961 TI - 1-(2-Benzoyl-1-phenyl-eth-yl)-4-[(2-hy-droxy-1-naphth-yl)methyl-idene-amino]-3 methyl-1H-1,2,4-triazole-5(4H)-thione. AB - In the title compound, C(29)H(24)N(4)O(2)S, intra-molecular O-H?N hydrogen bonding influences the mol-ecular conform-ation; the naphthol system and triazole ring form a dihedral angle of 3.88 (7) degrees . In the crystal, pi-pi inter actions between the five- and six-membered rings of neighbouring mol-ecules [centroid-centroid distances = 3.541 (3) and 3.711 (3) A] consolidate the crystal packing. PMID- 21522962 TI - 2-{[3-Methyl-4-(2,2,2-trifluoro-eth-oxy)pyridin-2-yl]methyl-sulfan-yl}-1H benzimidazole monohydrate. AB - The asymmetric unit of the title compound, C(16)H(14)F(3)N(3)OS.H(2)O, contains two independent mol-ecules (A and B) and two water mol-ecules, one of which is disordered over two positions in a 0.790 (8):0.210 (8) ratio. The mol-ecular conformations are close, the benzimidazole mean plane and pyridine ring forming dihedral angles of 1.8 (3) and 0.1 (2) degrees in mol-ecules A and B, respectively. The water mol-ecules are involved in formation of two independent hydrogen-bonded chains via N-H?O and O-H?N hydrogen bonds. Chains propagating along the a axis are formed by mol-ecule A and one independent water mol-ecule, while chains propagating along the b axis are formed by mol-ecule B and the other independent water mol-ecule. The crystal packing exhibits pi-pi inter-actions, as indicated by short distances of 3.607 (3) and 3.701 (3) A between the centroids of the imidazole and pyridine rings of neighbouring mol-ecules. PMID- 21522963 TI - 2-Methyl-N'-[1-(2-pyrid-yl)ethyl-idene]benzohydrazide. AB - In the title compound, C(15)H(15)N(3)O, the dihedral angle between the pyridine and benzene rings is 36.3 (2) degrees . In the crystal, mol-ecules are linked through inter-molecular N-H?O hydrogen bonds, forming chains along the b axis. PMID- 21522964 TI - (1S,4S)-2-(2,4-Difluoro-phen-yl)-5-[(4-methyl-phen-yl)sulfon-yl]-2,5-diaza bicyclo-[2.2.1]hepta-ne. AB - In the title mol-ecule, C(18)H(18)F(2)N(2)O(2)S, the two benzene rings, which are oriented in opposite directions with respect to the rigid 2,5-diaza-bicyclo [2.2.1]heptane core, form a dihedral angle of 17.2 (1) degrees . Weak inter molecular C-H?O, C-H?F and C-H?N contacts consolidate the crystal packing. PMID- 21522965 TI - 2-{2-[(2,6-Dichloro-phen-yl)amino]-phen-yl}ethanol. AB - In the title compound, C(14)H(13)Cl(2)NO, the 2,6-dichloro-anilino unit is roughly planar (r.m.s. deviation = 0.0298 A) and makes a dihedral angle of 67.71 (4) degrees with the benzene ring containing the ethanol group. The C-C-O fragment is oriented at a dihedral angle of 64.94 (9) degrees with respect to its parent benzene ring. The molecular conformation is stabilised by a bifurcated N-H?(O,Cl) hydrogen bond. C-H?pi, O-H?pi and pi-pi inter-actions [centroid centroid distance = 3.5706 (11) A] stabilize the crystal structure. PMID- 21522966 TI - Methyl 2-[2-(benzyl-oxycarbonyl-amino)-propan-2-yl]-5-hy-droxy-6-meth-oxy pyrimidine-4-carboxyl-ate. AB - In the title compound, C(18)H(21)N(3)O(6), a pyrimidine derivative, the dihedral angle between the benzene and pyrimidine rings is 52.26 (12) degrees . The carboxyl-ate unit is twisted with respect to the pyrimidine ring, making a dihedral angle of 12.33 (7) degrees . In the crystal, mol-ecules are linked by a pair of O-H?O hydrogen bonds, forming an inversion dimer. The dimers are stacked into columns along the b axis through weak C-H?O inter-actions. PMID- 21522967 TI - 3-[(Furan-2-yl-methyl-idene)amino]-1-(4-methyl-phen-yl)thio-urea. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(13)H(13)N(3)OS, which was obtained from a condensation reaction of N (p-tol-yl)hydrazinecarbothio-amide and furfural. The dihedral angles between the mean planes of the tolyl ring and the (furan-2-yl-methyl-ene)hydrazine unit are 39.83 (8) and 48.95 (7) degrees in the two mol-ecules. The mol-ecules both exhibit an E configuration. In the crystal, inter-molecular N-H?N and N-H?S hydrogen bonds connect the two independent mol-ecules. PMID- 21522968 TI - 3-(4-Fluoro-benzyl-idene)-1,5-dioxa-spiro-[5.5]undecane-2,4-dione. AB - In the title mol-ecule, C(16)H(15)FO(4), the fused 1,3-dioxane and cyclo-hexane rings exhibit a bath and a chair conformation, respectively. In the crystal, weak inter-molecular C-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers. PMID- 21522969 TI - 3-Hy-droxy-N'-[(E)-2-thienyl-methyl-idene]-2-naphtho-hydrazide. AB - The asymmetric unit of the title compound, C(16)H(12)N(2)O(2)S, contains three independent mol-ecules. Intra-molecular N-H?O hydrogen bonds in the three mol ecules lead to very similar conformations: the thio-pene ring and naphthalene ring system in the three mol-ecules form dihedral angles of 10.3 (2), 9.1 (2) and 9.3 (3) degrees . In the crystal structure, inter-molecular O-H?O hydrogen bonds link the mol-ecules into chains propagating in [031]. PMID- 21522970 TI - A monoclinic modification of propane-1,3-diyl bis-(pyridine-3-carboxyl-ate). AB - In the title compound, C(15)H(14)N(2)O(4), (I), the mol-ecule lies on a twofold rotation axis which passes through the central C atom of the aliphatic chain, giving one half-mol-ecule per asymmetric unit. The structure is a monoclinic polymorph of the triclinic structure previously reported [Brito, Vallejos, Bolte & Lopez-Rodriguez (2010). Acta Cryst. E66, o792], (II). The most obvious difference between them is the O/C/C/C-O/C/C/C torsion angle [58.2 (7) degrees in (I) and 173.4 (3)/70.2 (3) degrees in (II) for GG and TG conformations, respectively]. Another important difference is observed in the dihedral angle between the planes of the aromatic rings [86.49 (7) degrees for (I) and 76.4 (3) degrees for (II)]. The crystal structure features a weak pi-pi inter-action [centroid-centroid distance = 4.1397 (10)A]; this latter kind of inter-action is not evident in the triclinic polymorph. PMID- 21522971 TI - N-(4-Bromo-phen-yl)-4-nitro-benzamide. AB - In the title compound, C(13)H(9)BrN(2)O(3), the dihedral angle between the mean planes of the two benzene rings is 3.6 (7) degrees . The amide group is twisted by 28.1 (6) and 31.8 (3) degrees from the mean planes of the 4-bromo-phenyl and 4-nitro-benzene rings, respectively. The crystal packing features weak inter molecular N-H?O and C-H?O hydrogen bonds resulting in a three-dimensional network. PMID- 21522972 TI - 7-Bromo-1-(4-fluoro-phenyl-sulfon-yl)-2-methyl-naphtho-[2,1-b]furan. AB - In the title compound, C(19)H(12)BrFO(3)S, the 4-fluoro-phenyl ring makes a dihedral angle of 80.32 (5) degrees with the mean plane of the naphtho-furan fragment. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O and C-H?pi inter-actions. The crystal structure also exhibits aromatic pi-pi inter actions between the central benzene rings of neighbouring mol-ecules [centroid centroid distance = 3.564 (3) A]. PMID- 21522973 TI - 5-Cyclo-hexyl-3-methyl-sulfinyl-2-phenyl-1-benzofuran. AB - In the title compound, C(21)H(22)O(2)S, the cyclo-hexyl ring adopts a chair conformation while the phenyl ring makes a dihedral angle of 33.38 (5) degrees with the mean plane of the benzofuran fragment. In the crystal, mol-ecules are linked through weak inter-molecular C-H?O and C-H?pi inter-actions. PMID- 21522974 TI - 1-(3-Chloro-phen-yl)-4,4,6-trimethyl-3,4-dihydro-pyrimidine-2(1H)-thione. AB - In the title compound, C(13)H(15)ClN(2)S, the dihydro-pyrimidine ring is essentially planar, with a maximum deviation from the least-squares plane of 0.122 (3) A for the unsubstitued olefinic C atom. The dihedral angle between the dihydro-pyrimidine and benzene rings is 86.62 (13) degrees . The crystal structure is stabilized by inter-molecular N-H?S hydrogen bonds, which form centrosymmetric dimers arranged along the c axis. PMID- 21522975 TI - 1-Nonyl-1H-benzimidazol-2(3H)-one. AB - The crystal structure of the title compound, C(16)H(24)N(2)O, is built up from two fused six- and five-membered rings linked to C(9)H(19) chains. The fused-ring system is essentially planar, the largest deviation from the mean plane being 0.009 (2) A. The chain is nearly perpendicular to this plane [dihedral angle = 80.27 (17) degrees ]. In the crystal, inter-molecular N-H?O hydrogen bonds form dimers with an R(2) (2)(8) graph-set motif. These dimers are further connected through C-H?O hydrogen bonds, building sheets parallel to (100). PMID- 21522976 TI - rac-4-[4-Cyano-2-(hy-droxy-meth-yl)phen-yl]-4-(4-fluoro-phen-yl)-4-hy-droxy-N,N dimethyl-butanaminium hemifumarate. AB - In the title salt, C(20)H(24)FN(2)O(2) (+).0.5C(4)H(2)O(4) (2-), the fumarate anion is located on an inversion centre. In the cation, the two benzene rings are nearly perpendicular to each other, making a dihedral angle of 87.41 (10) degrees . The cation is linked to the anion by a bifurcated N-H?O hydrogen bond. Classical O-H?O and weak C-H?F hydrogen bonding is also present in the crystal structure. Three C atoms of the N,N-dimethyl-butanaminium moiety are disordered over two sites with refined site occupancies of 0.466 (14) and 0.534 (14). PMID- 21522977 TI - N-(2,3-Dimeth-oxy-benzyl-idene)naphthalen-1-amine. AB - The title compound, C(19)H(17)NO(2), represents a trans isomer with respect to the C=N bond. The dihedral angle between the planes of the naphthyl ring system and the benzene ring is 71.70 (3) degrees . In the crystal, weak C-H?O hydrogen bonding is present. PMID- 21522978 TI - 1,3,5,7-Tetra-bromo-adamantane. AB - In the pyramidal-shaped mol-ecule of the title compound, C(10)H(12)Br(4), the four terminal Br-C bond distances are nearly identical, ranging from 1.964 (4) to 1.974 (4) A. The Br?Br distance of 3.6553 (7) A indicates van der Waals contacts between mol-ecules in the crystal structure. PMID- 21522979 TI - 3-Cyano-N-(2-hy-droxy-benz-yl)anilinium nitrate. AB - In the crystal structure of the title compound, C(14)H(13)N(2)O(+).NO(3) (-), N H?O and O-H?O hydrogen bonds link cations and anions into a two-dimensional network parallel to (100). The dihedral angle between the rings is 9.48 (2) degrees . PMID- 21522980 TI - N-Cyclo-hexyl-2-(5-meth-oxy-1H-indol-3-yl)-2-oxoacetamide. AB - In the title compound, C(17)H(20)N(2)O(3), the cyclo-hexane ring adopts a chair conformation. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol ecules into layers parallel to the ac plane. PMID- 21522981 TI - Bis[bis-(2-methyl-phen-yl)phosphan-yl]methane. AB - In the title compound, C(29)H(30)P(2), the dihedral angles between the two substituted benzene rings to the same P atom are 88.39 (7) and 83.88 (9) degrees . In the crystal, mol-ecules are arranged into columns and stacked down the b axis. Weak inter-molecular C-H?pi inter-actions stabilize the crystal structure. PMID- 21522982 TI - (Z)-1,2-Dichloro-1,2-bis-(3-chloro-quinoxalin-2-yl)ethene. AB - The title compound, C(18)H(8)Cl(4)N(4), exists in a cis configuration with respect to the bridging C=C bond. The two essentially planar quinoxaline ring systems [maximum deviations = 0.012 (1) and 0.022 (1) A] are inclined at an angle of 59.84 (3). In the crystal, adjacent mol-ecules are linked into chains propagating along [001] via inter-molecular C-H?N hydrogen bonds. Weak inter molecular pi-pi [centroid-centroid distance = 3.6029 (7) degrees ] and C-H?pi inter-actions are also observed. PMID- 21522983 TI - rac-Diethyl 9-hy-droxy-9-methyl-7-phenyl-1,4-diaza-spiro-[4.5]decane-6,8 dicarboxyl-ate. AB - The title mol-ecule, C(21)H(30)N(2)O(5), is chiral with four stereogenic centres. The crystal is a racemate and consists of enanti-omeric pairs with the relative configuration rac-(6S*,7R*,8R*,9S*). The ethyl fragment of the eth-oxy-carbonyl group at position 6 is disordered in a 0.46 (3):0.54 (3) ratio. The crystal structure features inter-molecular N-H?O. Intra-molecular O-H?N and N-H?O hydrogen bonds also occur. PMID- 21522984 TI - 2,2'-Azanediyl-diethanaminium pyridine-2,5-dicarboxyl-ate. AB - The crystal structure of the title compound, C(4)H(15)N(3) (2+).C(7)H(3)NO(4) (2 ), consists of diethyl-enetriaminium (2,2'-azanediyl-diethanaminium) cations and pyridine-2,5-dicarboxyl-ate anions, which are linked by N-H?O, N-H?N and C-H?O hydrogen bonds. C-H?pi inter-actions are also observed. In the anion, the carboxyl-ate groups are oriented at dihedral angles of 11.04 (15) and 6.31 (14) degrees with respect to the pyridine ring. PMID- 21522985 TI - N-[5-Methyl-2-(2-nitro-phen-yl)-4-oxo-1,3-thia-zolidin-3-yl]pyridine-3 carboxamide monohydrate. AB - In the title compound, C(16)H(14)N(4)O(4)S.H(2)O, the benzene and pyridine rings make a dihedral angle of 85.8 (1) degrees . Both enanti-omers of the chiral title compound are statistically disordered over the same position in the unit cell. The methyl and carbonyl group attached to the stereogenic center (C(5) of the thia-zolidine ring) were therefore refined with common site-occupation factors of 0.531 (9) and 0.469 (9), respectively, for each stereoisomer. In the crystal, inter-molecular N-H?O, O-H?O and O-H?N hydrogen bonds link the mol-ecules, forming a three-dimensional supra-molecular network. The crystal structure further shows pi-pi stacking inter-actions [centroid-centroid distance = 3.5063 (13) A] between the pyridine rings. PMID- 21522986 TI - N-(2-Hy-droxy-1,1-dimethyl-eth-yl)-4-methyl-benzene-sulfonamide. AB - In the title mol-ecule, C(11)H(17)NO(3)S, the S atom has a distorted tetra-hedral geometry [maximum deviation: O-S-O = 119.08 (9) degrees ]. In the crystal, mol ecules are connected by inter-molecular N-H?O, O-H?O and C-H?O hydrogen bonds, forming layers of mol-ecules aligned parallel to (110). The 2-methyl-propan-1-ol group of the mol-ecule is disordered over two positions with an 0.592 (4):0.408 (4) occupancy ratio. PMID- 21522987 TI - 5,11,17,23,29-Penta-tert-butyl-31,32,33,34,35-penta-propoxycalix[5]arene dichloro methane hemisolvate. AB - The title compound, tert-butyl-propoxycalix[5]arene, C(70)H(100)O(5).0.5CH(2)Cl(2), crystallizes as a solvate with two mol-ecules of calix[5]arene in 1,2-alternate conformations and one mol-ecule of dichloro methane in the asymmetric unit. One tert-butyl group in one of the mol-ecules and two in the other are disordered over two positions with occupancy factors fixed at 0.5917:0.4083, 0.5901:0.4099 and 0.8535:0.1465, respectively, in the final refinement. The C atoms of a prop-oxy group in each of the mol-ecules are also disordered over two positions with occupancies of 0.7372:0.2628 and 0.5027:0.4973. The mol-ecules form intra-molecular hydrogen bonds between prop oxy O atoms and an adjacent CH(2) group in a neighbouring prop-oxy chain. In the crystal, inter-molecular C-H?O and C-H?Cl inter-actions occur involving the dichloro-methane mol-ecule. PMID- 21522988 TI - N-(4-Meth-oxy-phen-yl)benzene-sulfonamide. AB - In the title compound, C(13)H(13)NO(3)S, the benzene ring of the benzene sulfonamide moiety is disordered with an occupancy ratio of 0.56 (3):0.44 (3), the disorder components being twisted at and angle of 21 (1) degrees to each other. The meth-oxy-benzene group is roughly planar (r.m.s. deviation = 0.0144 A) and the amide N atom is displaced from this plane by 0.090 (6) A. The dihedral angles between the meth-oxy-benzene group and the major and minor occupancy components of the disordered benzene ring are 54.6 (4) and 62.9 (5) degrees , respectively. In the crystal, infinite polymeric chains are formed along [100] due to inter-molecular N-H?O hydrogen bonding. Weak C-H?pi inter-actions are also present in the crystal. PMID- 21522989 TI - 5-Carb-oxy-2,4-dihy-droxy-anilinium chloride dihydrate. AB - In the title compound, C(7)H(8)NO(4) (+).Cl(-).2H(2)O, the organic mol-ecule is almost planar with an r.m.s. deviation of 0.0164 A for all non-H atoms. An S(6) ring motif is formed due to an intra-molecular O-H?O hydrogen bond. In the crystal, the mol-ecules are linked into a three-dimensional network by N-H?Cl, N H?O, O-H?Cl and O-H?O hydrogen bonds. PMID- 21522990 TI - 4-Hy-droxy-N'-(4-hy-droxy-3-nitro-benzyl-idene)benzohydrazide. AB - The mol-ecule of the title compound, C(14)H(11)N(3)O(5), assumes an E configuration with respect to the methyl-idene unit. An intra-molecular O-H?O hydrogen bond is present in the mol-ecule. The dihedral angle between the mean planes of the two benzene rings is 5.46 (15) degrees . The crystal structure is stabilized by inter-molecular O-H?O, O-H?N, and N-H?O hydrogen bonds. PMID- 21522991 TI - 2-Hy-droxy-N'-(4-hy-droxy-3-nitro-benzyl-idene)benzohydrazide. AB - The title compound, C(14)H(11)N(3)O(5), crystallized with two independent mol ecules per asymmetric unit. Each mol-ecule assumes an E configuration with respect to the methyl-idene unit. Intra-molecular O-H?O and N-H?O hydrogen bonds are present in each mol-ecule and they are linked by an O-H?O hydrogen bond. The dihedral angles between the mean planes of the two benzene rings are 4.45 (16) and 1.7 (2) degrees in the two mol-ecules. The crystal structure is stabilized by inter-molecular O-H?O and N-H?O hydrogen bonds. PMID- 21522992 TI - 2,6-Bis(tosyl-oxymeth-yl)pyridine. AB - The title compound, C(21)H(21)NO(6)S(2), is organized around a twofold axis parallel to the crystallographic c axis and containing the N atom and a C atom of the pyridine ring. The tosyl moiety and the pyridine ring are both essentially planar [maximum deviations 0.028 (2) and 0.020 (3) A, respectively]; their mean planes form a dihedral angle of 33.0 (2) degrees . PMID- 21522993 TI - N-{4-[(2-Meth-oxy-phen-yl)sulfamo-yl]phen-yl}acetamide. AB - In the title compound, C(15)H(16)N(2)O(4)S, the S atom has a distorted tetra hedral geometry [maximum deviation: O-S-O = 118.25 (7) degrees ]. The two aromatic rings make a dihedral angle of 62.67 (10) degrees with each other. An intra-molecular N-H?O hydrogen bond forms an S(6) ring motif. In the crystal, mol ecules form centrosymmetric dimers via pairwise N-H?O inter-actions, forming an R(2) (2)(8) ring motif, and these dimers are connected by N-H?O hydrogen bonds, generating a three-dimensional network. Furthermore, a weak C-H?pi inter-action helps to reinforce the crystal structure. The O atom in the acetamide group is disordered over two positions with major and minor occupancies of 0.52 (5) and 0.48 (5), respectively. PMID- 21522994 TI - Diethyl 1,1-dioxo-3,5-bis-(pyridin-2-yl)-1lambda,4-thio-morpholine-2,6-dicarbox ylate. AB - The title compound, C(20)H(23)N(3)O(6)S, crystallizes with two crystallographically independent mol-ecules in the asymmetric unit. The thio morpholine ring in both mol-ecules adopts a chair conformation. The crystal structure is stabilized by C-H?O inter-actions. The amino groups are shielded and, as a result, these groups are not involved in hydrogen bonding. PMID- 21522995 TI - 1,2-Bis(2-meth-oxy-6-formyl-phen-oxy)ethane. AB - IN THE TITLE COMPOUND [SYSTEMATIC NAME: 3,3'-dimethoxy-2,2'-(ethane-1,2 diyldioxy)dibenzaldehyde], C(18)H(18)O(6), prepared from 1,2-dibromo-ethane and ortho-vanillin in the presence of sodium carbonate, the two vanillin units are linked via a CH(2)-CH(2) bridge. The two benzene rings are inclined at a dihedral angle of 41.6 (5) degrees . PMID- 21522996 TI - 4-Bromo-3-hy-droxy-3-(4-hy-droxy-2-oxo-2H-chromen-3-yl)indolin-2-one. AB - In the mol-ecule of the title compound, C(17)H(10)BrNO(5), the indoline system and the attached coumarin ring are each essentially planar with maximum deviations of 0.074 (2) and 0.062 (2) A, respectively. The dihedral angle between them is 85.09 (3) degrees . In the crystal, all heteroatoms (except for the coumarin oxo O atoms) are involved in intra- and inter-molecular hydrogen bonds. An intra-molecular O-H?O hydrogen bond occurs. In the crystal, mol-ecules are linked through O-H?O, N-H?O and C-H?O contacts, forming a complex three dimensional structure. PMID- 21522997 TI - 1-[2-(4-Nitrophenyl)-5-(5-phenyl-1,2-oxazol-3-yl)-1,2,3,4-tetrahydroquinolin-4 yl]pyrrolidin-2-one. AB - The title compound, (I) C(28)H(24)N(4)O(4), is the trans diastereo-isomer of the compound 1-[2-(4-nitro-phen-yl)-6-(5-phenyl-3-isoxazol-yl)-1,2,3,4-tetra-hydro-4 quinolin-yl]-2-pyrrolidinone monohydrate, (II) [Gutierrez et al. (2011 ?). Acta Cryst. E67, o175-o176]. The most obvious differences between the diastereo isomers are the dihedral angles between the isoxazole ring and the benzene and phenyl rings [47.0 (2); 56.4 (2) and 33.3 (2); 11.0 (2) degrees , respectively, for (II) 75.4 (2) and 5.8 (3), respectively, for (I)]. In the crystal of (I), the mol-ecules are linked by N-H?O inter-actions into a chain along [001] with graph set notation C(8). PMID- 21522998 TI - 2-Chloro-N-[4-(3-methyl-3-phenyl-cyclo-but-yl)-1,3-thia-zol-2-yl]-N'-(naphthalen 1-yl-methyl-idene)acetohydrazide. AB - In the mol-ecular structure of the title hydrazide derivative, C(27)H(24)ClN(3)OS, the acetohydrazide group is approximately planar, with a maximum deviation of 0.017 (3) A. The dihedral angle between the naphthyl-ene system and the phenyl ring is 78.91 (18) degrees . The crystal structure is stabilized by one weak inter-molecular C-H?O hydrogen bond and two aliphatic C H?pi hydrogen-bonding associations. PMID- 21522999 TI - Tetra-kis(benzyl-amino)-phospho-nium chloride. AB - The title salt, [P(NHCH(2)C(6)H(5))(4)](+).Cl(-), crystallizes with the P atom and Cl(-) anion lying on a twofold rotation axis. The P atom has a slightly distorted tetra-hedral geometry with two classes of N-P-N angles [101.15 (10) and 100.55 (11) degrees and 113.07 (9) and 114.83 (8) degrees ] and the environments of sp(2)-hybridized N atoms are essentially planar (sum of angles = 359.9 and 360.1 degrees ). In the crystal, the phospho-nium ion inter-acts with each neighboring chloride ion via two approximately equal N-H?Cl inter-actions, forming parallel chains along the c axis. PMID- 21523000 TI - 2-Chloro-4,6-bis-(piperidin-1-yl)-1,3,5-triazine. AB - The title compound, C(13)H(20)ClN(5), crystallizes with two mol-ecules in the asymmetric unit. The piperidine rings in both mol-ecules adopt chair conformations. Weak pi-pi inter-actions [centroid-centroid distance = 3.9815 (8) A] are observed in the crystal structure. PMID- 21523001 TI - (2E)-3-[4-(Dimethyl-amino)-phen-yl]-1-(4-fluoro-phen-yl)prop-2-en-1-one. AB - The mean planes of the two benzene rings in the title compound, C(17)H(16)FNO, are twisted slightly, making a dihedral angle of 7.8 (1) degrees . The prop-2-en 1-one group is also twisted slightly with a C-C-C-O torsion angle of -11.6 (3) degrees . In the crystal, weak inter-molecular C-H?O inter-actions link pairs of mol-ecules, forming centrosymmetric dimers. PMID- 21523002 TI - 1-(4-Chloro-phen-yl)-3-(2-meth-oxy-anilino)propan-1-one. AB - In the title compound, C(16)H(16)ClNO(2), the mol-ecule adopts a bowed conformation, with a dihedral angle of 39.9 (2) degrees between the aromatic rings. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, generating C(6) chains propagating in [010]. Very weak aromatic pi-pi stacking is also observed [centroid-centroid distance = 4.040 (2) A]. PMID- 21523003 TI - Gallic Acid. AB - Anhydrous 3,4,5-trihy-droxy-benzoic acid, C(7)H(6)O(5), is essentially planar, with its non-H atoms exhibiting mean and maximum deviations from coplanarity of 0.014 and 0.0377 (5) A, respectively. The C-C-C-OH torsion angle about the bond linking the carboxyl group to the benzene ring is -0.33 (10) degrees . In the crystal, the -COOH groups form centrosymmetric hydrogen-bonded cyclic dimers [graph set R(2) (2)(8)] and the phenolic -OH groups participate in both intra- and inter-molecular hydrogen bonds, forming a three-dimensional network structure. PMID- 21523005 TI - Bis(cyclohexylammonium) 2,2'-disulfanediyldibenzoate. AB - In the title molecular salt, 2C(6)H(14)N(+).C(14)H(8)O(4)S(2) (2-), the complete dianion is generated by crystallographic twofold symmetry and a twisted conformation is found [the C-S-S-C torsion angle is 87.13 (2) degrees and the dihedral angle between the rings is 83.4 (2) degrees ]. In the crystal, inter molecular N-H?O hydrogen bonds link the cations and anions. PMID- 21523006 TI - 1-[4-(3-{[5-(4-Chloro-phen-yl)furan-2-yl]methyl-idene-amino}-2,5-dioxoimidazol idin-1-yl)but-yl]-4-methyl-piperazine-1,4-diium dichloride hemihydrate. AB - The title compound, C(23)H(30)ClN(5)O(3) (2+).2Cl(-).0.5H(2)O, was synthesized by N-alkyl-ation of 1-({[5-(4-chloro-phen-yl)-2-furan-yl]methyl-ene}amino)-2,4 imidazolidinedione with 1-bromo-4-chloro-butane, and N-methyl-piperazine. In the crystal, the cations, anions and water mol-ecules are linked by O-H?Cl and N-H?Cl hydrogen bonds. PMID- 21523004 TI - 6,9-Dimeth-oxy-3,4-dihydro-1H-1,4-oxazino[4,3-a]indol-1-one. AB - The title compound, C(13)H(13)NO(4), is one cyclization product of the reaction of ethyl 1-(2-bromo-eth-yl)-4,7-dimeth-oxy-1H-indole-2-carboxyl-ate with sodium azide in refluxing dioxane and was synthesized with the aim of finding new compounds with biological properties. Bond lengths and angles are within the expected values and confirm the bond orders giving in the scheme. The shortest contacts between mol-ecules are set along the a axis, where stacked mol-ecules related by an inversion center form an ABAB array through pi-pi stacking inter actions with centroid-centroid distances ranging from 3.922 (2) to 4.396 (2) A. Weak C-H?O hydrogen bonds further stabilize the structure. PMID- 21523007 TI - Methyl 2-{[2,8-bis-(trifluoro-meth-yl)quinolin-4-yl]-oxy}acetate. AB - In the crystal structure of the title compound, C(14)H(9)F(6)NO(3), mol-ecules are connected by inter-molecular C-H?O hydrogen bonds. The best planes through the benzene and pyridyl rings make a dihedral angle of 1.59 (12) degrees . PMID- 21523008 TI - 1-[(Butyl-amino)(phen-yl)meth-yl]naphthalen-2-ol. AB - In the title compound, C(21)H(23)NO, obtained via a one-pot synthesis, an intra molecular O-H?N hydrogen bond stabilizes the mol-ecular conformation. The dihedral angle between the fused ring system and the phenyl ring is 78.27 (5) degrees . The crystal packing is characterized by helical chains of mol-ecules linked by C-H?O hydrogen bonds. PMID- 21523009 TI - 8-[(Hydrazinyl-idene)meth-yl]-4-methyl-2-oxo-2H-chromen-7-yl 4-methyl-benzene sulfonate. AB - In the title compound, C(18)H(16)N(2)O(5)S, the coumarin ring system is nearly planar, with a maximum out-of-plane deviation of 0.078 (1) A (r.m.s. deviation = 0.046 A). The dihedral angle between the coumarin ring system and the toluene ring (r.m.s. deviation = 0.004 A) is 2.77 (1) degrees . The crystal packing is stabilized by C-H?O and N-H?O inter-molecular hydrogen bonds generating C(8), C(9) and C(11) chains and R(2) (2)(14), R(2) (2)(23) and R(4) (3)(13) ring graph sets. PMID- 21523010 TI - (4Z)-4-[(2,6-Diisopropyl-anilino)(phen-yl)methyl-idene]-3-methyl-1-phenyl-1H pyrazol-5(4H)-one. AB - In the title compound, C(29)H(31)N(3)O, the three terminal benzene rings are oriented at dihedral angles of 20.7 (3), 65.8 (3) and 72.6 (3) degrees with respect to the central pyrazolone ring. Intra-molecular N-H?O hydrogen bonding occurs between the imine and carbonyl groups. Inter-molecular C-H?pi inter actions are present in the crystal structure. PMID- 21523011 TI - (3R*,4R*)-1-(4-Chloro-phen-yl)-4-[2-hy-droxy-3-(morpholinomethyl)-phen-yl]-3-phen oxy-azetidin-2-one. AB - The beta-lactam ring of the title compound, C(26)H(25)ClN(2)O(4), is nearly planar (r.m.s. deviation = 0.025 A) and the morpholine ring adopts a chair conformation. The mean plane of the beta-lactam ring makes dihedral angles of 21.6 (4), 84.4 (4) and 33.7 (4) degrees with the two benzene rings and the phenyl ring, respectively. The conformation of the title compound is stabilized by intra-molecular C-H?O and O-H?N inter-actions. The crystal structure features C-H?pi and aromatic pi-pi stacking inter-actions [centroid-centroid distances = 3.684 (4) and 3.883 (4) A]. PMID- 21523012 TI - 1-(4-Meth-oxy-phen-yl)-4-(4-methyl-phen-yl)-3-phen-oxy-azetidin-2-one. AB - The central beta-lactam ring of the title compound, C(23)H(21)NO(3), is almost planar (r.m.s. deviation = 0.032A). The meth-oxy-benzene ring is almost coplanar with the beta-lactam ring [dihedral angle = 1.87 (11) degrees ], whereas the tolyl ring is almost normal to it [75.73 (12) degrees ]. The dihedral angle between the beta-lactam ring and the O-bonded phenyl ring is 51.95 (12) degrees . An intra-molecular C-H?O inter-action generates an S(6) ring. The crystal structure features inter-molecular C-H?O hydrogen bonds, forming layers parallel to (011), and weak C-H?pi inter-actions. Two aromatic pi-pi stacking inter actions [centroid-centroid distances = 3.6744 (12) and 3.6799 (11) A] are also observed. PMID- 21523013 TI - 3,5-Bis(4-meth-oxy-phen-yl)-1-phenyl-4,5-dihydro-1H-pyrazole. AB - In the title compound, C(23)H(22)N(2)O(2), the central pyrazole ring is nearly planar (r.m.s. deviation = 0.046 A) and it makes a dihedral angle of 18.5 (2) degrees with the phenyl ring. The dihedral angles between the phenyl and the two meth-oxy-substituted phenyl rings are 26.2 (2) and 80.6 (2) degrees . The crystal structure is stabilized by C-H?pi stacking inter-actions and weak pi-pi inter actions [centriod-centroid distance = 3.891 (2) A]. PMID- 21523014 TI - 3-Chloro-N'-(3,5-dibromo-2-hy-droxy-benzyl-idene)benzohydrazide methanol monosolvate. AB - The title Schiff base compound, C(14)H(9)Br(2)ClN(2)O(2).CH(3)OH, features an intra-molecular O-H?N hydrogen bond, which contributes to the planarity of the mol-ecule: the dihedral angle between the two benzene rings is 4.6 (2) degrees . In the crystal, pairs of adjacent mol-ecules are linked through inter-molecular N H?O and O-H?O hydrogen bonds, forming dimers. The methanol solvent mol-ecule is linked by inter-molecular O-H?O hydrogen bonds. PMID- 21523015 TI - 3-Chloro-N'-(4-hy-droxy-benzyl-idene)benzohydrazide. AB - The title compound, C(14)H(11)ClN(2)O(2), was prepared by the reaction of 4-hy droxy-benzaldehyde with 3-chloro-benzo-hydrazide in methanol. The dihedral angle between the two benzene rings is 38.2 (2) degrees . In the crystal, mol-ecules are linked through inter-molecular N-H?O, O-H?N and O-H?O hydrogen bonds, forming layers lying parallel to the bc plane. PMID- 21523016 TI - N-Cyclo-hexyl-cyclo-hexa-naminium chloride. AB - In the title salt, C(12)H(24)N(+).Cl(-), both cyclo-hexyl rings adopt chair conformations and the NH(2) unit is situated in the equatorial position with respect to the rings in the cation. The large C-N-C bond angle [117.99 (14) degrees ] in the cation is a result of linking two bulky cyclo-hexyl rings to the N atom. The aminium H atoms are involved in inter-molecular N-H?Cl hydrogen bonds, forming an infinite zigzag chain parallel to the c axis. The crystal studied was a racemic twin with a twin fraction of 0.28 (18). PMID- 21523017 TI - N,N'-Bis(2-chloro-benz-yl)-N''-(dichloro-acet-yl)phospho-ric triamide. AB - In the title compound, C(16)H(16)Cl(4)N(3)O(2)P, the phosphoryl and carbonyl groups are anti to each other. The dihedral angle between the benzene rings is 33.59 (16) degrees . In the crystal, adjacent mol-ecules are linked via N-H?O=P and N-H?O=C hydrogen bonds, into an extended chain running parallel to the a axis. PMID- 21523018 TI - (1RS,6SR)-Ethyl 4-(4-chloro-phen-yl)-6-(4-fluoro-phen-yl)-2-oxocyclo-hex-3-ene-1 carboxyl-ate toluene hemisolvate. AB - In the crystal structure of the title compound, C(21)H(18)ClFO(3).0.5C(7)H(8), the toluene solvent mol-ecules occupy special positions on centres of symmetry, and consequently are disordered across this site. The cyclo-hexene ring has a slightly distorted sofa conformation; the two benzene rings are inclined by 72.90 (7) degrees and their planes make dihedral angles of 30.09 (10) (chloro-phen-yl) and 88.13 (6) degrees (fluoro-phen-yl) with the approximately planar part of the cyclo-hexenone ring [maximum deviation from plane through five atoms is 0.030 (2) A, the sixth atom is 0.672 (3)A out of this plane]. Weak inter-molecular C-H?O and C-H?X (X = F, Cl) inter-actions join mol-ecules into a three-dimensional structure. Also, a relatively short and directional C-Cl?F-C contact is observed [Cl?F = 3.119 (2) A, C-Cl?F = 157.5 (2) degrees and C-F?Cl 108.3 (2) degrees ]. The solvent mol-ecules fill the voids in the crystal structure and are kept there by relatively short and directional C-H?pi inter-actions. PMID- 21523019 TI - (1RS,6SR)-Ethyl 4,6-bis-(4-fluoro-phen-yl)-2-oxocyclo-hex-3-ene-1-carboxyl-ate. AB - In the crystal structure of the title compound, C(21)H(18)F(2)O(3), the cyclo hexene ring has a slightly distorted sofa conformation; the two benzene rings are inclined by 76.27 (8) degrees and their planes make dihedral angles of 16.65 (10) and 67.53 (7) degrees with the approximately planar part of the cyclo hexenone ring [maximum deviation 0.044 (2) A, while the sixth atom is displaced by 0.648 (3) A from this plane]. In the crystal, weak inter-molecular C-H?O, C H?F and C-H?pi inter-actions join mol-ecules into a three-dimensional structure. PMID- 21523020 TI - 2,2-Dichloro-1-(4-methyl-phen-yl)ethanone. AB - The mol-ecule of the title compound, C(9)H(8)Cl(2)O, is almost planar: the dihedral angle between the benzene ring and the plane defined by the carbonyl O and ethane C atoms is 15.5 (2) degrees . The crystal packing is stabilized by inter-molecular C-H?O hydrogen bonds. PMID- 21523021 TI - Bis(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl) carbonate. AB - The title compound, C(21)H(22)O(5), crystallizes with three mol-ecules in the asymmetric unit. In one mol-ecule, two methyl groups are disordered over two positions with a site occupation factor of 0.72 (2) for the major occupancy site. The benzene rings make dihedral angles of 35.3 (6), 29.7 (6) and 40.6 (7) degrees in the three molecules. PMID- 21523022 TI - 2-Methyl-1,3-benzoxazol-4-yl diphenyl-phosphinate. AB - The title compound, C(20)H(16)NO(3)P, was synthesized by the addition of diphenyl phosphine chloride to a tetra-hydro-furan solution of Et(3)N and 2-methyl-1,3 benzoxazol-4-ol at 233 K. In the mol-ecule, the almost planar (r.m.s. deviation = 0.010 A) benzoxazole moiety is attached to the slightly distorted tetra-hedral P atom [C-P-C-C torsion angle = 132.20 (18) degrees ]. The crystal structure does not exhibit any significant inter-molecular inter-actions. PMID- 21523023 TI - Monoclinic polymorph of 2-(pyrimidin-2-ylsulfan-yl)acetic acid. AB - The title compound, C(6)H(6)N(2)O(2)S, is a new polymorphic form of 2-(pyrimidin 2-ylsulfan-yl)acetic acid. Unlike the previous orthorhombic polymorph [Pan & Chen (2009 ?) Acta Cryst. E65, o652], the mol-ecules are not planar: the aromatic ring makes an angle of 80.67 (17) degrees with the carboxyl plane. In the crystal, mol-ecules are linked by O-H?N hydrogen bonds into chains along [02]. PMID- 21523024 TI - 2-(4-Methyl-sulfanylphen-yl)-1H-benzimidazol-3-ium bromide. AB - In the cation of the title compound, C(14)H(13)N(2)S(+).Br(-), the essentially planar benzimidazole system (r.m.s. deviation = 0.0082 A) is substituted with a 4 methyl-sulfanylphenyl ring. The dihedral angle between the benzimidazole system and the 4-methyl-sulfanylphenyl ring is 2.133 (2) degrees . The crystal structure is characterized by strong and highly directional inter-molecular N-H?Br hydrogen bonds involving the bromide ion. Moreover, C-H?S inter-actions result in chains of mol-ecules along the c axis. The supra-molecular assembly is further stabilized by pi-pi stacking inter-actions between the benzimidazole system and 4 methyl-sulfanylphenyl rings [centroid-centroid distance = 3.477 (4) A]. PMID- 21523025 TI - 3-Meth-oxy-2-[(E)-(4-meth-oxy-phen-yl)imino-meth-yl]phenol. AB - The title compound, C(15)H(15)NO(3), adopts the enol-imine tautomeric form. The two rings are twisted with respect to each other, making a dihedral angle of 44.08 (5) degrees . The 3-methoxy-2-[(E)-(4-methoxyphenyl)-iminomethyl]phenol unit is almost planar, the largest deviation from the mean plane being 0.047 (2) A. Such a planar conformation might be related to the occurrence of an intra molecular O-H?N hydrogen bond. In the crystal, inter-molecular C-H?O hydrogen bonds link the mol-ecules into sheets parallel to (010). These sheets are inter connected by weak C-H?pi inter-actions. PMID- 21523027 TI - 1-Chloro-methyl-1,4-diazo-niabicyclo-[2.2.2]octane bis-(hexa-fluoro-phosphate). AB - In the crystal structure of the title compound, C(7)H(15)ClN(2) (2+).2PF(6) (-), the cations and anions are linked by inter-molecular N-H?F hydrogen bonds. PMID- 21523026 TI - [(E)-(1-Phenyl-ethyl-idene)amino]-urea methanol monosolvate. AB - In the title compound, C(9)H(11)N(3)O.CH(4)O, the semicarbazone moiety is nearly planar [maximum deviation = 0.017 (2) A] and is twisted by a dihedral angle of 29.40 (13) degrees with respect to the phenyl ring. The semicarbazone moiety and phenyl ring are located on opposite sides of the C=N bond, showing the E configuration. An inter-molecular O-H?O and N-H?O hydrogen-bonding network occurs in the crystal structure. PMID- 21523028 TI - 4-Amino-1-(2-benzoyl-1-phenyl-eth-yl)-3-phenyl-1H-1,2,4-triazol-5(4H)-thione. AB - In the title compound, C(23)H(20)N(4)OS, the two phenyl rings of the diphenyl propanone fragment form a dihedral angle of 86.8 (1) degrees , and the third phenyl ring attached to the triazole ring is twisted from the latter at 40.1 (1) degrees . In the crystal, mol-ecules are paired into centrosymmetric dimers via pairs of inter-molecular N-H?O and N-H?S hydrogen bonds. PMID- 21523029 TI - rac-4-Amino-1-(2-benzoyl-1-phenyl-eth-yl)-3-methyl-1H-1,2,4-triazole-5(4H) thione. AB - The title compound, C(18)H(18)N(4)OS, has an almost planar 1,2,4-triazole ring [r.m.s. deviation = 0.0036 (2) A], which makes dihedral angles of 78.5 (2) and 77.6 (11) degrees with the two phenyl rings. An intra-molecular N-H?S inter action occurs. In the crystal, mol-ecules are linked by an inter-molecular three centre N-H?(O,S) cyclic hydrogen-bonding inter-action. PMID- 21523030 TI - Methyl 3-(4-fluoro-phen-yl)-1-methyl-1,2,3,3a,4,9b-hexa-hydro-chromeno[4,3 b]pyrrole-3a-carboxyl-ate. AB - In the title compound, C(20)H(20)FNO(3), the pyrrolidine and benzopyran rings adopt half chair and twisted half chair conformations, respectively. The carboxyl ate group is almost perpendicular to the pyran ring [89.4 (1) degrees ]. PMID- 21523031 TI - (Z)-N-[5-Bromo-2-(4-methyl-anilino)-3H-indol-3-yl-idene]-4-methyl-aniline oxide. AB - The crystal structure of the title compound, C(22)H(18)BrN(3)O, is stabilized by pi-pi contacts [centroid-centroid distance = 3.476 (2) A] between five-membered rings as well as inter-molecular C-H?O and C-H?N hydrogen bonds. An intra molecular N-H?O hydrogen bond occurs. The benzene rings make a dihedral angle of 59.89 (8) degrees . The dihedral angles between the fused ring systemand the two benzene rings are 3.46 (7) and 61.97 (7) degrees . PMID- 21523032 TI - 5-Bromo-3-(4-fluoro-phenyl-sulfin-yl)-2,7-dimethyl-1-benzofuran. AB - In the title compound, C(16)H(12)BrFO(2)S, the 4-fluoro-phenyl ring makes a dihedral angle of 83.29 (5) degrees with the mean plane of the benzofuran fragment. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O hydrogen bonds. PMID- 21523033 TI - (2E)-3-(3-Bromo-4-meth-oxy-phen-yl)-1-(pyridin-2-yl)prop-2-en-1-one. AB - The mean planes of the benzene and pyridine rings in the title compound, C(15)H(12)BrNO(2), are nearly coplanar, subtending an angle of 2.8 (8) degrees . The prop-2-en-1-one group is also in the plane of these rings with an N-C-C-O torsion angle of 179.6 (3) degrees . A weak C-H?Br inter-molecular inter-action contributes to the crystal packing, creating a chain-like structure along the a axis. PMID- 21523034 TI - (E)-Methyl 3-(3,4-dihy-droxy-phen-yl)acrylate. AB - The benzene ring in the title compound, C(10)H(10)O(4), makes an angle of 4.4 (1) degrees with the C-C-C-O linker. The hy-droxy groups are involved in both intra- and inter-molecular O-H?O hydrogen bonds. The crystal packing is stabilized by O H?O hydrogen-bonding inter-actions. The mol-ecules of the caffeic acid ester form a dimeric structure in a head-to-head manner along the a axis through O-H?O hydrogen bonds. The dimers inter-act with one another through O-H?O hydrogen bonds, forming supermolecular chains. These chains are further extended through C H?O hydrogen bonds as well as van der Waals inter-actions into the final three dimensional architecture. PMID- 21523035 TI - 5,5'-Bis[(2,2,2-trifluoro-eth-oxy)meth-yl]-2,2'-bipyridine. AB - The complete molecule of the title compound, C(16)H(14)F(6)N(2)O(2), is generated by crystallographic inversion symmetry, which results in two short intramolecular C-H?N hydrogen-bond contacts per molecule. In the crystal, aromatic pi-pi stacking [centroid-centroid distance = 3.457 (2) A] and weak C-H?pi inter-actions occur. A short H?H [2.32 (3) A] contact is present. PMID- 21523036 TI - 1,3-Bis(2-nitro-phen-oxy)propan-2-ol. AB - In the title compound, C(15)H(14)N(2)O(7), the planes of the two benzene rings form a dihedral angle of 33.16 (17) degrees . In the crystal, inter-molecular hydrogen bonds involveing the OH group and nitro O atoms link the mol-ecules into chains propagating along the a axis. PMID- 21523037 TI - 2-(1-Ethyl-5-meth-oxy-1H-indol-3-yl)-N-(4-meth-oxy-phen-yl)-2-oxoacetamide. AB - The title compound, C(20)H(20)N(2)O(4), crystallizes with four independent mol ecules in the asymmetric unit. In the mol-ecules, the dihedral angles between the benzene rings and indole mean planes are 24.5 (1), 22.5 (1), 8.8 (1) and 13.9 (1) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds are present between the imino groups and the adjacent carbonyl groups. pi-pi stacking is also observed with a centroid-centroid distance between nearly parallel pyrrole rings of 3.745 (3) A. PMID- 21523038 TI - 16-Isopropyl-5,9-dimethyl-tetra-cyclo-[10.2.2.0.0]hexa-dec-15-ene-5,14 dimethanol. AB - The title compound, C(23)H(38)O(2), a tetra-cyclo-[10.2.2.0(1,10).0(4,9)] hexa decane structure, crystallized with four independent mol-ecules in the asymmetric unit. In the crystal, these independent mol-ecules are linked by O-H?O hydrogen bonds, forming a polymeric chain propagating in [100]. PMID- 21523039 TI - Triamcinolone acetonide acetate. AB - IN THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND [SYSTEMATIC NAME: 2-(4b-fluoro-5 hy-droxy-4a,6a,8,8-tetra-methyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodeca hydro-7,9-dioxa-penta-leno[2,1-a]phenanthren-6b-yl)-2-oxoethyl acetate], C(26)H(33)FO(7), the mol-ecules are connected by inter-molecular O-H?O hydrogen bonds into an infinite supra-molecular chain along the b axis. The mol-ecular framework consists of five condensed rings, including three six-membered rings and two five-membered rings. The cyclo-hexa-2,5-dienone ring is nearly planar [maximum deviation = 0.013 (3) A], while the cyclo-hexane rings adopt chair conformations. The two five-membered rings, viz. cyclo-pentane and 1,3-dioxolane, display envelope conformations. PMID- 21523040 TI - 2-(4-Fluoro-phen-yl)-4-(4-meth-oxy-phen-yl)-5-(piperidin-1-ylmeth-yl)thia-zole. AB - In the title compound, C(22)H(23)FN(2)OS, the piperidine ring shows chair confirmation and the two benzene rings make a dihedral angle of 17.0 (6) degrees . The thia-zole fragment is essentially planar with an r.m.s. deviation of 0.004 (2) A and a maximum deviation of 0.006 (2) A.. In the crystal, inter-molecular C H?pi inter-actions lead to the formation of a layer structure. PMID- 21523041 TI - 1,3-Bis[2-(2-oxo-1,3-oxazolidin-3-yl)eth-yl]-1H-benzimidazol-2(3H)-one. AB - The mol-ecular structure of the title compound, C(17)H(20)N(4)O(5), contains a central fused-ring system, comprised of six- and five-membered rings. This unit is linked by C(2) chains to two 2-oxo-1,3-oxazolidine five-membered rings. The central fused-ring system is essentially planar, with a maximum deviation of 0.008 (1) A from the mean plane. Both oxazolidine five-membered rings are also nearly planar, with maximum deviations of 0.090 (1) and 0.141 (1) A. PMID- 21523042 TI - (Z)-5-Benzene-carbothioyl-1,11-dimethyl-6-phenyl-5H-dibenzo[d,f][1,3]diazepine. AB - The seven-membered ring in the title compound, C(28)H(22)N(2)S, has a two coordinate N atom as well as a three-coordinate N atom. The ring adopts a boat shaped conformation with two C atoms of one methyl-phenyl ring as the stern and the three-coordinate N atom as the prow. The N,N-dimethyl-ethane-thio-amide fragment is nearly planar (r.m.s. deviation = 0.049 A); the phenyl ring of the benzene-carbothioyl unit connected to the three-coordinate N atom is aligned at 83.72 (4) degrees with respect to the mean plane of this fragment. Weak inter molecular C-H?S hydrogen bonding is present in the crystal structure. PMID- 21523043 TI - Ethyl (Z)-2-(4-chloro-benzyl-idene)-3-oxobutano-ate. AB - The C=C double-bond in the title compound, C(13)H(13)ClO(3), has a Z configuration. The aliphatic substituents at one end of the double bond, i.e. the CH(3)CO- and C(2)H(5)O(2)C- groups, are aligned at 82.1 (3) degrees with respect to each other. PMID- 21523044 TI - 2-Chloro-5-(chloro-meth-yl)pyridine. AB - The title compound, C(6)H(5)Cl(2)N, is almost planar, with an r.m.s. deviation of 0.0146 A for all atoms except for the 5-choloromethyl Cl atom. The offset Cl atom lies above this plane with a Cl-C-C angle of 111.11 (17) degrees . In the crystal, mol-ecules are connected via inter-molecular C-H?N hydrogen bonds, forming dimers. PMID- 21523045 TI - (Furan-2-yl)(5-hy-droxy-3-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone. AB - In the title compound, C(15)H(14)N(2)O(3), the furan ring is disordered over two positions with a refined site-occupancy ratio of 0.587 (11):0.413 (11). The mean plane of the approximately planar pyrazole ring [maximum deviation = 0.0469 (11) A] makes dihedral angles of 86.13 (11) and 4.5 (5) degrees with the phenyl and furan rings, respectively. The dihedral angle between the phenyl ring and the major component of the disordered furan ring is 81.8 (5) degrees . The mol-ecule shows chirality in one of the carbon atoms but the centrosymmetric space group means the compound is a racemic mixture. In the crystal, inter-molecular O-H?O and C-H?O hydrogen bonds connect the mol-ecules. The crystal structure is further stabilized by pi-pi stacking inter-actions with a centroid-centroid distance of 3.8646 (12) A. PMID- 21523046 TI - Bis[4-(2-isopropyl-2H-tetra-zol-5-yl)phen-yl]dimethyl-silane. AB - The title compound, C(22)H(28)N(8)Si, has crystallographic 2 symmetry with the Si atom located on a twofold rotation axis. The tetra-zole ring is oriented at a dihedral angle of 5.32 (18) degrees with respect to the benzene ring. A C-H?pi inter-action occurs between adjacent mol-ecules in the crystal structure. PMID- 21523047 TI - 2,5-Dichloro-N-(4-meth-oxy-phen-yl)benzensulfonamide. AB - In the title compound, C(13)H(11)Cl(2)NO(3)S, the dihedral angle between the benzene rings is 74.37 (3) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into chains along the b axis. PMID- 21523048 TI - N,N-Bis(diphenyl-phosphan-yl)benzyl-amine. AB - In the title compound, C(31)H(27)NP(2), the diphenyl-phosphanyl groups are staggered relative to the PNP backbone. The N atom is displaced by 0.219 (2) A from the plane formed by the two P atoms and the methylene C atom. The angles around the N atom are 120.84 (16), 113.29 (16) and 120.57 (12) degrees , indicating that it exhibits a distorted trigonal-pyramidal geometry. There are no classical inter-molecular inter-actions. PMID- 21523049 TI - Disordered structure of propane-1,2-diaminium dichloride. AB - In the title compound, C(3)H(12)N(2) (2+).2Cl(-), the cations are disordered over two well resolved positions in a 0.525 (13):0.475 (13) ratio. The disorder involves two C atoms which assume positions that make an almost mirror-sym metrical system. Similar disorder is observed both at room temperature and at 120 (1) K. The conformation of the NCCN chain in both components is close to trans (the torsion angles ca +/-170 degrees ), while that of CCCN chain is close to gauche (+/-50 degrees ). In the crystal, a network of relatively strong N-H?Cl hydrogen bonds connects the cations and anions into one-cation-deep layers parallel to (001); there are R(2) (4)(8) and R(2) (4)(11) ring motifs within the plane. The planes are only loosely connected by van der Waals contacts and electrostatic inter-actions between cations and anions. PMID- 21523050 TI - 3-Chloro-N'-[(2-hy-droxy-naphthalen-1-yl)methyl-idene]benzohydrazide. AB - The title compound, C(18)H(13)ClN(2)O(2), was prepared by the reaction of 2-hy droxy-1-naphthaldehyde with 3-chloro-benzohydrazide in methanol. An intra molecular O-H?N hydrogen bond influences the mol-ecular conformation; the benzene ring and naphthyl ring system form a dihedral angle of 17.1 (3) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into chains propagated in [101]. PMID- 21523051 TI - 3-Chloro-N'-[(2-meth-oxy-naphthalen-1-yl)methyl-idene]benzohydrazide. AB - The title compound, C(19)H(15)ClN(2)O(2), was prepared by the reaction of 2-meth oxy-1-naphthaldehyde with 3-chloro-benzohydrazide in methanol. The dihedral angle between the benzene ring and the naphthyl ring system is 69.0 (3) degrees . In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into chains along the c axis. The crystal packing exhibits pi-pi inter-actions, as indicated by distances of 3.768 (3) A between the centroids of the naphthyl rings of neighbouring mol-ecules. PMID- 21523052 TI - 7-(tert-Butyl-diphenyl-sil-yloxy)-2,2-dimethyl-1-benzofuran-3(2H)-one. AB - The title compound, C(26)H(28)O(3)Si, is an allylic oxidation product of the tert but-yl(2,2-dimethyl-2,3-dihydro-benzo-furan-7-yl-oxy)diphenyl-silane with N-bromo succinimide and 2,2'-azobis-isobutyronitrile. The nine-atom bicyclic system is almost planar, with an r.m.s deviation of 0.0123 (2) A and a maximum deviation of 0.031 (2) A for the O atom. In the crystal, the mol-ecules pile up along the b axis but the strongest inter-molecular contacts are the pi-pi stacking inter actions between the benzene rings along the c axis [centroid-centroid distance = 3.655 (3) A]. PMID- 21523053 TI - N-(3-Chloro-4-eth-oxy-benzo-yl)-N'-(2-meth-oxy-phen-yl)thio-urea. AB - In the title compound, C(17)H(17)ClN(2)O(3)S, the central carbonyl-thio-urea unit is nearly planar [maximum atomic deviation = 0.019 (3) A] and makes dihedral angles of 2.47 (7) and 17.76 (6) degrees with the terminal benzene rings. An intra-molecular N-H?O hydrogen bond occurs. Weak inter-molecular C-H?S and C-H?Cl hydrogen bonding is observed in the crystal structure. PMID- 21523054 TI - 3-Chloro-N'-(3-eth-oxy-2-hy-droxy-benzyl-idene)benzohydrazide monohydrate. AB - In the title compound, C(16)H(15)ClN(2)O(3).H(2)O, the water mol-ecule is linked to the Schiff base mol-ecule via an O-H?O hydrogen bond. In the Schiff base mol ecule, an intramolecular O-H?N hydrogen bond occurs and the dihedral angle between the two benzene rings is 20.5 (5) degrees . In the crystal, the Schiff base and water mol-ecules are linked by inter-molecular N-H?O and O-H?O hydrogen bonds, forming layers in the ab plane. PMID- 21523055 TI - 1-Chloro-4-(3,4-dichloro-phen-yl)-3,4-dihydro-naphthalene-2-carbaldehyde. AB - The title compound, C(17)H(11)Cl(3)O, was synthesized via the Vilsmeier-Haack reaction. The dihydro-naphthalene ring system is non-planar, the dihedral angle between the two fused rings being 10.87 (13) degrees ; it forms a dihedral angle of 81.45 (10) degrees with the dichloro-phenyl ring. The crystal structure features inter-molecular C-H?O hydrogen bonds. PMID- 21523056 TI - 2-(4-Bromo-phen-yl)-1-ethyl-1H-1,3-benzodiazole. AB - In the title compound, C(15)H(13)BrN(2), the benzimidazole group is almost planar, as indicated by the dihedral angle of 2.6 (3) degrees between the best planes through the benzene and imidazole rings. The best plane through the attached benzene makes an angle of 44.5 (2) degrees with the best plane through the benzimidazole system. C-H?pi inter-actions are observed in the crystal structure. PMID- 21523057 TI - 1,1'-[4-(2,4-Dichloro-phen-yl)-2,6-di-methyl-1,4-di-hydro-pyridine-3,5-di yl]diethanone. AB - In the title compound, C(17)H(17)Cl(2)NO(2), the central 1,4-dihydro-pyridine ring adopts a flattened-boat conformation. The ethanone substituents of the dihydro-pyridine ring at positions 3 and 5 have synperiplanar (cis) or anti periplanar (trans) conformations with respect to the adjacent C=C bonds in the dihydro-pyridine ring. The 2,4-dichloro-phenyl ring is almost planar [r.m.s. deviation = 0.0045 (1) A] and almost perpendicular [89.27 (3) degrees ] to the mean plane of the dihydro-pyridine ring. In the crystal, an N-H?O hydrogen bond links mol-ecules into a zigzag chain along the ac diagonal. C-H?Cl contacts form centrosymmetric dimers and additional weak C-H?O contacts further consolidate the packing. PMID- 21523058 TI - 6-Oxo-5-[(trifluoro-meth-yl)sulfon-yl]-1,2,4a,5,6,11b-hexa-hydro-1,3-dioxolo[4,5 j]phenanthridin-2-yl benzoate. AB - In the title compound, C(22)H(16)F(3)NO(7)S, the two benzene rings are almost perpendicular, the dihedral angle between their mean planes being 87.1 (1) degrees . The terminal O atom of the benzoate moiety is disordered over two positions with site occupancies of 0.244 (15) and 0.756 (15). The crystal structure is stablized by two types of weak inter-molecular C-H?O hydrogen bonds. PMID- 21523059 TI - 3-Chloro-N'-(4-diethyl-amino-2-hy-droxy-benzyl-idene)benzohydrazide. AB - The asymmetric unit of the title Schiff base compound, C(18)H(20)ClN(3)O(2), contains two independent mol-ecules. An O-H?N hydrogen bond contributes to the planarity of each mol-ecule: the dihedral angles between the two benzene rings are 12.8 (3) and 27.2 (3) degrees in the two mol-ecules. In the crystal, mol ecules are linked through inter-molecular N-H?O hydrogen bonds, forming chains along the a axis. PMID- 21523060 TI - (R)-2,2'-Bis[N'-(3,5-dichloro-phen-yl)ureido]-1,1'-binaphthalene chloro-form disolvate. AB - The title compound, C(34)H(22)Cl(4)N(4)O(2).2CHCl(3), is a new urea based on the 1,1'-binaphthalene skeleton, which crystallizes with two mol-ecules of binaphthalene and four mol-ecules of chloro-form in the unit cell. The chloro form solvent mol-ecules do not participate in non-covalent inter-actions and therefore, can be found in several positions. The binaphthalene mol-ecules are connected via a system of N-H?O hydrogen bonds between the ureido units. C-H?O inter-actions also occur. In contrast to unsubstituted urea, where mol-ecules form squares in crystals, the bulky substituents disturb this arrangement and three ureido groups form infinite chains, while the fourth inter-acts with a neighbouring binaphthalene ring via an N-H?pi inter-action. The solvent molecules are disordered with occupancy ratios of 0.60:0.40, 0.58:0.42, 0.50:0.50 and 0.77:0.23. PMID- 21523061 TI - 1-[5-(Anthracen-9-yl)-3-(4-nitro-phen-yl)-4,5-dihydro-1H-pyrazol-1-yl]ethan-1 one. AB - In the title compound, C(25)H(19)N(3)O(3), steric repulsion between the methine H atom and one of the anthryl H atoms seems to be concomitant with the considerable distortion of the anthryl fragment from planarity. The side rings of the anthryl subtend an angle of 9.57 (8) degrees , which is an extreme value among the known reliably determined structures. This angle correlates with the length of the bond by which the anthryl is attached to the rest of the mol-ecule. In the anthryl fragment, the maximum deviation of one of the C atoms from the mean plane is 0.126 (3) A and regards the carrier C atom involved in the repulsion between the anthryl and the methine H atoms. The inter-planar angle between the pyrazoline ring and the anthryl fragment is 88.36 (5) degrees and that between the pyrazoline and 4-nitro-phenyl rings is 8.80 (15) degrees . Weak inter-molecular C H?N, C-H?pi and pi-pi inter-actions [centroid-centroid distances of 3.7659 (17), 3.9477 (15) and 3.8972 (15) A] are pesent in the structure. PMID- 21523062 TI - 1-Dibenzylamino-1-de-oxy-4,5-O-isopropyl-idene-beta-d-fructopyran-ose. AB - The title compound C(23)H(29)NO(5), synthesized by the Amadori rearrangement of alpha-d-glucose with dibenzyl-amine and the ketalization, is shown to be a beta anomer. The fructopyran-ose ring adopts a chair conformation. The two benzene rings form a dihedral angle of 68.9 (1) degrees . In the crystal, non-classical inter-molecular C-H?O hydrogen bonds link the mol-ecules into a three-dimensional network. PMID- 21523063 TI - 2-(4-Meth-oxy-phen-yl)-4H-1,3,2-benzoxathia-phosphinine 2-sulfide. AB - The asymmetric unit of the title compound, C(14)H(13)O(2)PS(2), contains two crystallographically independent mol-ecules, which differ in the conformation of the 1,3,2-benzoxathia-phosphinine moieties (screw boat in the first mol-ecule and envelope in the second mol-ecule). In the crystal, neither classical nor non classical hydrogen bonds are found. Weak inter-actions (about 2.9-3.0 A) between the lone pair of the terminal S atoms with H atoms occur. This compound was further characterized by (1)H NMR and IR spectroscopy. PMID- 21523064 TI - 1-Methyl-piperazine-1,4-diium dipicrate. AB - IN THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND [SYSTEMATIC NAME: 1-methyl piperazine-1,4-diium bis-(2,4,6-trinitro-phen-ol-ate)], C(5)H(14)N(2) (2+).2C(6)H(2)N(3)O(7) (-), the ionic components are connected by relatively strong N-H?O hydrogen bonds into centrosymmetric six-membered conglomerates, which comprise two dications and four anions. Besides Coulombic inter-actions, only weak C-H?O inter-actions and some stacking between picrates (separation between the planes of ca. 3.4 A but only a small overlapping) can be identified between these 'building blocks' of the crystal structure. The piperazine ring adopts a chair conformation with the methyl substituent in the equatorial position. In the picrate anions, the twist angles of the nitro groups depend on their positions relative to the phenolate O atom: it is much smaller for the NO(2) groups para to the C-O(-) group [15.23 (9)and 3.92 (14) degrees ] than for the groups in the ortho positions [28.76 (13)-39.84 (11) degrees ]. PMID- 21523065 TI - 5-[(2-Chloro-4-nitro-anilino)methyl-idene]-2,2-dimethyl-1,3-dioxane-4,6-dione. AB - In the title compound, C(13)H(11)ClN(2)O(6), the dihedral angles between the benzene ring and the amino-methyl-ene unit and between the amino-methyl-ene group and the dioxane ring are 8.19 (14) and 1.39 (17) degrees , respectively. The dioxane ring has a half-boat conformation, in which the C atom between the dioxane O atoms is 0.662 (4)A out of the plane through the remaining ring atoms. Intra-molecular N-H?O and N-H?Cl inter-actions occur. PMID- 21523066 TI - (Z)-3-[(2-Fluoro-anilino)carbon-yl]prop-2-enoic acid. AB - In the title mol-ecule, C(10)H(8)FNO(3), the dihedral angle between the fluoro phenyl group and the essentially planar [within 0.064 (3) A] COC=CCOOH unit, which has a Z configuration, is 19.99 (14) degrees . There is an intra-molecular O-H?O bond in the mol-ecule involving the acid -OH group and the adjacent carbonyl O atom. In the crystal, inter-molecular N-H?O bonds lead to the formation of polymer chains propagating along [011]. PMID- 21523067 TI - rac-(rel-1R,2R,4S)-Spiro-[bicyclo-[2.2.1]heptane-2,3'-indol]-2'-amine. AB - In the racemic title compound, C(14)H(16)N(2), the aromatic ring component of the amino-indoline system occupies the endo cavity of the norbornane component. The aromatic ring lies at an angle of 74.12 (5) degrees to the plane defined by the four C atoms that comprises the rigid part of the boat-shaped six-membered ring of the norbornane unit. Pairs of mol-ecules assemble in the crystal structure, forming centrosymmetric hydrogen-bonded dimers via pairs of N-H?N hydrogen bonds through the syn H atom of the amine group. PMID- 21523068 TI - Anthriscifolcine A, a C18-diterpenoid alkaloid. AB - The title compound, C(26)H(39)NO(7), which was isolated from Delphinium anthriscifolium var. majus, has a lycoctonine carbon skeleton containing four six membered rings (A, B, D and E) and three five-membered rings (C, F and G). Rings A, B and E adopt chair conformation, while ring D adopts a boat conformation. Rings C and F adopt envelope conformations. PMID- 21523069 TI - 2-[2-(1H-Imidazol-1-yl)-2-adamant-yl]phenol. AB - In the title mol-ecule, C(19)H(22)N(2)O, the imidazole and benzene rings form a dihedral angle of 84.53 (5) degrees . In the crystal, classical inter-molecular O H?N hydrogen bonds pair the mol-ecules into centrosymmetric dimers, and C-H?pi inter-actions further link these dimers into columns propagated in [100]. PMID- 21523070 TI - Bis(piperidin-1-yl)methanone. AB - The title compound, C(11)H(20)N(2)O, is a urea derivative bearing two piperidine moieties in place of the amino groups. The mol-ecule shows approximate non crystallographic C(2) symmetry. The six-membered rings adopt (1)C(4) and (4)C(1) conformations and their mean planes make a dihedral angle of 35.87 (5) degrees . In the crystal, inter-molecular C-H?O contacts connect the mol-ecules into infinite strands along the a axis. PMID- 21523071 TI - N,N'-Bis(4-amino-benz-yl)oxalamide. AB - In the title compound, C(16)H(18)N(4)O(2), the two carbonyl groups are in an anti periplanar conformation with an O=C-C=O torsion angle of 173.86 (17) degrees . In the crystal, a pair of inter-molecular N-H?O hydrogen bonds, forming an R(2) (2)(10) ring motif, connect the mol-ecules into an inversion dimer. The dimers are further linked by N-H?N and C-H?pi inter-actions, forming a zigzag chain along the b axis. PMID- 21523072 TI - trans-2,3-Bis(2,4,5-trimethyl-3-thien-yl)but-2-enedinitrile. AB - In title compound, C(18)H(18)N(2)S(2), the dihedral angle between two thio-phene rings is 61.83 (8) degrees . PMID- 21523073 TI - (3,6-Dibromo-o-phenyl-ene)dimethanol. AB - The title compound, C(8)H(8)Br(2)O(2), was synthesized from the hydrolysis of 1,4 dibromo-2,3-bis-(bromo-meth-yl)benzene. One intra-molecular O-H?O and two intra molecular C-H?Br inter-actions occur. In the crystal, mol-ecules are linked into a chain running parallel to [010]. Adjacent chains are linked into a two dimensional layer by a combination of inter-molecular O-H?O hydrogen bonds and C H?pi inter-actions. PMID- 21523074 TI - Ethyl 1-formamido-4-oxo-2,6-diphenyl-cyclo-hexa-necarboxyl-ate. AB - In the title compound, C(22)H(23)NO(4), the central six-membered ring is in a twist-boat conformation, the two aryl groups are in equatorial positions and the dihedral angle between the two aromatic rings is 75.98 (12) degrees . PMID- 21523075 TI - (-)-crebanine. AB - THE ASYMMETRIC UNIT OF THE TITLE COMPOUND [SYSTEMATIC NAME: 9,10-dimeth-oxy-7 methyl-6,7,7a,8-tetra-hydro-5H-benzo[g][1,3]benzodioxolo[6,5,4-de]quinoline], C(20)H(21)NO(4), contains two independent mol-ecules with very similar bond lengths and angles. The crystal packing exhibits voids of 131 A(3). PMID- 21523076 TI - 5-Ethyl-4-phenyl-1H-pyrazol-3(2H)-one. AB - The asymmetric unit of the title compound, C(11)H(12)N(2)O, consists of two crystallographically independent mol-ecules (A and B) with similar geometries. Both mol-ecules exist in a keto form, the C=O bond length being 1.286 (2) A in A and 1.283 (2) A in B. The dihedral angles between the pyrazole ring and the attached phenyl ring are 43.28 (12) and 46.88 (11) degrees , respectively, for A and B. The ethyl unit in mol-ecule B is disordered over two positions with a site occupancy ratio of 0.508 (5):0.492 (5). In the crystal, each of the independent mol-ecules forms a centrosymmetric dimer with an R(2) (2)(8) ring motif through a pair of N-H?O hydrogen bonds. These dimers are further connected into a three dimensional network by inter-molecular N-H?O and C-H?O hydrogen bonds. Inter molecular C-H?pi inter-actions are also present. PMID- 21523077 TI - 1-Isobutyl-N,N-dimethyl-1H-imidazo[4,5-c]quinolin-4-amine. AB - In the title compound, C(16)H(20)N(4), the 1H-imidazo[4,5-c]quinoline ring system is approximately planar, with a maximum deviation of 0.0719 (15) A. An intra molecular C-H?N hydrogen bond contributes to the stabilization of the mol-ecule, forming an S(6) ring motif. In the crystal, the mol-ecules are stacked along the b axis through weak aromatic pi-pi inter-actions between benzene and imidazole and benzene and pyridine rings [centroid-centroid distances = 3.6055 (10) and 3.5342 (10) A, respectively]. PMID- 21523078 TI - 4-Hydrazinyl-1-isobutyl-1H-imidazo[4,5-c]quinoline. AB - In the title compound, C(14)H(17)N(5), the 1H-imidazo[4,5-c]quinoline ring system is essentially planar, with a maximum deviation of 0.0325 (7) A. In the crystal, a pair of inter-molecular N-H?N hydrogen bonds link neighbouring mol-ecules, forming an inversion dimer and generate an R(2) (2)(10) ring motif. These dimers are further connected into a chain along the b axis via inter-molecular C-H?N hydrogen bonds, resulting in an R(2) (2)(14) ring motif. PMID- 21523079 TI - 4-Chloro-benzaldehyde (1-isobutyl-1H-imidazo[4,5-c]quinolin-4-yl)hydrazone monohydrate. AB - In the title compound, C(21)H(20)ClN(5).H(2)O, the 1H-imidazo[4,5-c]quinoline ring is approximately planar, with a maximum deviation of 0.0795 (7) A, and it forms a dihedral angle of 7.65 (3) degrees with the chloro-phenyl ring. In the crystal, the components are linked into chains along the a axis via inter molecular N-H?O, O-H?N and C-H?O hydrogen bonds. One of the H atoms of the water mol-ecule is disordered over two positions with a site-occupancy ratio of 0.80 (4):0.20 (4). PMID- 21523080 TI - 2-(1H-Benzimidazol-2-yl)-4-nitro-phenol. AB - The title compound, C(13)H(9)N(3)O(3), was prepared by the reaction of 5-nitro salicyl-aldehyde with 1,2-diamino-benzene in methanol. The whole mol-ecule is approximately planar, with a mean deviation from the plane defined by the non-H atoms of 0.0311 (4) A, and with a dihedral angle between the benzene ring and the benzimidazole ring system of 1.1 (3) degrees . An intra-molecular O-H?N hydrogen bond occurs. In the crystal, adjacent mol-ecules are linked through inter molecular N-H?O hydrogen bonds, forming centrosymmetric dimers. PMID- 21523081 TI - 3-Chloro-N'-(2-chloro-benzyl-idene)benzohydrazide. AB - The title compound, C(14)H(10)Cl(2)N(2)O, was prepared from the reaction of 2 chloro-benzaldehyde with 3-chloro-benzo-hydrazide in methanol. The mol-ecule adopts an E configuration about the methyl-idene unit and the two aromatic rings form a dihedral angle of 13.8 (2) degrees . In the crystal, mol-ecules are linked via inter-molecular N-H?O and C-H?O hydrogen bonds, forming chains along the c axis. PMID- 21523082 TI - A new ortho-rhom-bic polymorph of 1,1'-seleno-bis-(N,N-diethyl-sulfanecarbothio amide). AB - THE TITLE COMPOUND [SYSTEMATIC NAME: N,N-dieth-yl({[(diethyl-carbamothio yl)sulfan-yl]selan-yl}sulfan-yl)carbothio-amide], C(10)H(20)N(2)S(4)Se, crystallizes in a new form in the space group Pca2(1): the previously reported polymorph crystallizes in the space group P2(1)2(1)2(1). The new phase contains two independent mol-ecules in the asymmetric unit. The Se atoms are tetra coordinated, with a distorted square-planar geometry. The ligands coordinate asymmetrically to the Se atoms, with one strong Se-S bond [range 2.2833 (13) 2.3041 (15) A] and one weaker bond [range 2.7318 (14)-2.7873 (12) A]. PMID- 21523083 TI - 2,2-Dimethyl-5-{[(4-nitro-phen-yl)amino]-methyl-idene}-1,3-dioxane-4,6-dione. AB - In the title compound, C(13)H(12)N(2)O(6), the dihedral angle between the benzene ring and the amino-methyl-ene unit is 5.42 (16) degrees , while the angle between the amino-methyl-ene unit and the dioxane ring is 3.06 (43) degrees . The dioxane ring shows a half-boat conformation, in which the C atom between the dioxane ring O atoms is 0.464 (10) A out of the plane. An intra-molecular N-H?O hydrogen bond stabilizes the mol-ecular conformation. In the crystal, a three-dimensional framework is built up via inter-molecular N-H?O hydrogen bonds. PMID- 21523084 TI - 1,3-Bis{[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]sulfan-yl}propan-2-one. AB - In the distorted W-shaped mol-ecule of the title compound, C(17)H(12)N(6)O(3)S(2), a twofold axis passes through the carbonyl group. The mol ecules stack in the crystal through pi-pi inter-actions [centroid-centroid distance = 3.883 A] and weak C-H?N hydrogen-bonding inter-actions, forming a three-dimensional architecture. PMID- 21523085 TI - 5-Fluoro-1,3-dihydro-2,1-benzoxaborol-1-ol. AB - In the crystal structure of the title compound, C(7)H(6)BFO(2), a broad-spectrum anti-fungal drug (AN2690), the planar [maximum deviation 0.035 (1) A] mol-ecules form centrosymmetric R(2) (2)(8) dimers via strong O-H?O hydrogen bonds. The dimers are arranged into layers by weak inter-molecular C-H?O and C-H?F hydrogen bonds. The symmetry of this two-dimensional supra-molecular assembly can be described by the layer group p and topologically classified as a simple uninodal four-connected two-dimensional network of a (4.4.4.4.6.6) topology. Further weak C-H?O inter-actions build up the three-dimensional structure. PMID- 21523086 TI - Acridinium 6-carb-oxy-pyridine-2-carboxyl-ate monohydrate. AB - The title compound, C(13)H(10)N(+).C(7)H(4)NO(4) (-).H(2)O or (acrH)(+)(pydcH)( ).H(2)O, is a monohydrate of acridinium cations and a mono-deprotonated pyridine 2,6-dicarb-oxy-lic acid. The structure contains a range of non-covalent inter actions, such as O-H?O, O-H?N and N-H?O hydrogen bonds, as well as pi-pi stacking [range of centroid-centroid distances = 3.4783 (5)-3.8059 (5) A]. The N-H?O hydrogen bond between the donor acridinium cation and the carboxyl-ate acceptor is particularly strong. The average separation between the pi-stacked acridinium planes is 3.42 (3) A. PMID- 21523087 TI - 4-(1-Ethyl-1H-1,3-benzimidazol-2-yl)-N,N-diphenyl-aniline monohydrate. AB - In the title compound, C(27)H(23)N(3)O.H(2)O, the benzimidazole ring system has an r.m.s. deviation of 0.0071 A and makes dihedral angles of 34.51 (2), 55.22 (3) and 41.05 (5) degrees with the central and N-bonded phenyl rings, respectively. In the crystal, the water mol-ecular is connected to the organic mol-ecule by inter-molecular O-H?N hydrogen bonds. Weak inter-molecular C-H?O hydrogen bonds also occur. PMID- 21523088 TI - 1-[2-(Pyrazin-2-ylsulfan-yl)eth-yl]pyrazine-2(1H)-thione. AB - The title multifunctional twisted organic ligand, C(10)H(10)N(4)S(2), contains a short C=S bond [1.671 (2) A]. The dihedral angle between the two pyrazine rings is 39.83 (6) degrees . In the crystal, inter-molecular C-H?N and C-H?S hydrogen bonds result in the formation of a supra-molecular network. PMID- 21523089 TI - N-(4-Chloro-butano-yl)-N'-phenyl-thio-urea. AB - The asymmetric unit of the title compound, C(11)H(13)ClN(2)OS, contains two independent mol-ecules. Both mol-ecules maintain a trans-cis configuration with respect to the position of the carbonyl group and the benzene ring against the thione group across the C-N bonds. The mol-ecules are stabilized by intra molecular N-H?O hydrogen bonds. In the crystal, the mol-ecules are linked by inter-molecular N-H?S, N-H?O and C-H?S hydrogen bonds into chains along the c axis. C-H?pi inter-actions further stabilize the crystal structure. PMID- 21523090 TI - Benzyl N-{2-[5-(4-chloro-phen-yl)-1,2,4-oxadiazol-3-yl]propan-2-yl}carbamate. AB - In the title 1,2,4-oxadiazole derivative, C(19)H(18)ClN(3)O(3), the 1,2,4 oxadiazole ring makes dihedral angles of 12.83 (8) and 4.89 (8) degrees , respectively, with the benzyl and 4-chloro-phenyl rings, while the dihedral angle between the benzyl and 4-chloro-phenyl rings is 11.53 (7) degrees . In the crystal, mol-ecules are linked by N-H?N hydrogen bonds into helical chains along the b axis. A weak C-H?pi inter-action is also present. PMID- 21523091 TI - 5-Hy-droxy-8,8-dimethyl-10-(2-methyl-but-3-en-2-yl)-2H,6H-7,8-dihydro-pyrano[3,2 g]chromene-2,6-dione. AB - In the title compound, C(19)H(20)O(5), the pyran ring is in an envelope conformation, whereas the benzene and dihydro-pyran ring system is planar with an r.m.s. deviation of 0.0190 (1) A. The hy-droxy group is coplanar with the attached benzene ring [r.m.s. deviation = 0.0106 (1) A]. An intra-molecular O-H?O hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are linked into chains along the b axis by weak C-H?O inter-actions. These chains are stacked along the a axis. C-H?pi and weak pi-pi inter-actions [centroid-centroid distance = 3.7698 (7) A] are also observed. PMID- 21523092 TI - 3-(4-Hy-droxy-3-meth-oxy-phen-yl)acrylic acid-2,3,5,6-tetra-methyl-pyrazine (2/1). AB - The asymmetric unit of the title compound, C(8)H(12)N(2).2C(10)H(10)O(4), contains a tetra-methyl-pyrazine mol-ecule, situated about an inversion center, and two substituted acrylic acid derivatives. The dihedral angle between the phenyl and pyrazine rings is 69.45 (9) degrees . In the crystal, inter-molecular O-H?O, O-H?N hydrogen bonds and weak C-H?O inter-actions lead to the formation of a supra-molecular network. The acrylic acid side chain is positionally disordered [occupancy ratio 0.852 (7):0.148 (7)]. PMID- 21523093 TI - 2-[1-(4-Chloro-benzo-yl)pyrrolidin-2-yl]-4,4,5,5-tetra-methyl-4,5-dihydro imidazole-1-oxyl-3-oxide. AB - In the title compound, C(18)H(23)ClN(3)O(3), the imidazole ring system has an envelope conformation, whereas the nitronyl nitroxide unit displays a half-chair or twisted conformation. In the crystal, C-H?O hydrogen bonds build up a three dimensional network. PMID- 21523094 TI - 3-(4-Bromo-benzyl-idene)-1,5-dioxaspiro-[5.5]undecane-2,4-dione. AB - The title mol-ecule, C(16)H(15)BrO(4), was prepared by the reaction of (R)-2,4 dioxo-1,5-dioxaspiro-[5.5]undecane and 4-bromo-benzaldehyde with ethanol. The 1,3 dioxane ring exhibits a distorted boat and the fused cyclo-hexane ring exhibits a chair conformation. PMID- 21523095 TI - Adeninium perchlorate. AB - IN THE TITLE SALT (SYSTEMATIC NAME: 6-amino-9H-purin-1-ium perchlorate), C(5)H(6)N(5) (+).ClO(4) (-), the adeninium cation is essentially planar, with a maximum deviation of 0.038 (1) A. The whole of the perchlorate anion is disordered over two sets of sites with an occupancy ratio of 0.589 (13):0.411 (13). In the crystal, the adeninium cations are linked by pairs of N-H?N hydrogen bond into inversion dimers. The dimers and the anions are further inter-connected into a three-dimensional supra-molecular structure via inter-molecular N-H?O, C H?O and C-H?N hydrogen bonds. PMID- 21523096 TI - Carb-oxy-methyl ursolate monohydrate. AB - In the title compound, C(28)H(50)O(5).H(2)O, all of the six-membered rings of the penta-cyclic triterpene skeleton adopt chair conformations. In the crystal, mol ecules are linked by O-H?O and C-H?O hydrogen bonds. PMID- 21523097 TI - (E)-1-{2-Hy-droxy-5-[(4-methyl-phen-yl)diazen-yl]phen-yl}ethanone. AB - The structure of the title compound, C(15)H(14)N(2)O(2), an azo dye, displays a trans configuration with respect to the N=N bridge. The dihedral angle between the aromatic rings is 5.06 (8) degrees . The mol-ecular conformation is stabilized by a strong intra-molecular O-H?O hydrogen bond. In the crystal, inter molecular C-H?O hydrogen bonds occur. PMID- 21523098 TI - 1-(10H-Phenothia-zin-2-yl)ethanone. AB - In the title compound, C(14)H(11)NOS, the thia-zine ring adopts a slightly distorted boat conformation. The dihedral angle between the mean planes of the two benzene rings is 20.2 (9) degrees . An inter-molecular N-H?O hydrogen bond and a weak C-H?pi inter-action occur in the crystal, creating a two-dimensional network parallel to the bc plane. PMID- 21523099 TI - Enrofloxacinium picrate. AB - There is one cation-anion pair in the asymmetric unit of the title compound [systematic name: 4-(3-carb-oxy-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-1-ethyl piperazin-1-ium 2,4,6-tri-nitro-phenolate], C(19)H(23)FN(3)O(3) (+).C(6)H(2)N(3)O(7) (-). The six-membered piperazine group in the cation adopts a slightly distorted chair conformation and contains a protonated N atom. The dihedral angles between the mean planes of the cyclo-propyl and piperazine rings in the cation with the 10-atom ring system of the quinolone group are 48.1 (1) and 69.9 (5) degrees , respectively. The picrate anion inter-acts with the protonated N atom of an adjacent cation through a bifurcated N-H?O three-center hydrogen bond, forming an R(1) (2)(6) ring motif. Furthermore, there is an intra molecular O-H?O hydrogen bond. The dihedral angle between the mean planes of the anion benzene and cation piperizine, quinoline and cyclo-propyl rings are 61.3 (6), 31.1 (4) and 70.4 (9) degrees , respectively. The mean planes of the two o NO(2) and single p-NO(2) groups in the picrate anion are twisted by 6.7 (6), 38.3 (9) and 12.8 (7) degrees with respect to the mean plane of the benzene ring. Strong N-H?O and weak inter-molecular C-H?O hydrogen bonds in concert with weak pi-pi stacking inter-actions [centroid-centroid distances = 3.5785 (13), 3.7451 (12) and 3.6587 (13) A] dominate the crystal packing. PMID- 21523100 TI - 4-tert-Butyl-pyridinium triiodide-4-tert-butyl-pyridine (1/1). AB - The title compound, C(9)H(14)N(+).I(3) (-).C(9)H(13)N, consists of monoprotonated 4-tert-butyl-pyridinium cations and triiodide anions. The triiodide ion has near symmetric linear geometry, with bond lengths of 2.9105 (4) A (I-I) and a bond angle of 177.55 (3) degrees (I-I-I). For this room-temperature structure, the butyl group on the pyridine ring is disordered and has been treated as a rigid rotator, modeled in three separate positions with 1/3, 1/3, 1/3 occupancies. The cations assemble into dimeric forms by way of N-H?N hydrogen bonds. PMID- 21523101 TI - 4-Meth-oxy-quinolinium-2-carboxyl-ate dihydrate. AB - The title hydrated quinoline derivative, C(11)H(9)NO(3).2H(2)O, crystallizes as a zwitterion in which the quinoline N atom is protonated. The quinoline ring is essentially planar, with a maximum deviation of 0.017 (2) A. An intra-molecular N H?O hydrogen bond between the protonated N atom and the O atom of the carboxyl ate group in the zwitterion forms an S(5) ring motif. In the crystal, the zwitterions are connected into inversion dimers via pairs of N-H?O and C-H?O hydrogen bonds with R(2) (2)(4) and R(1) (2)(6) motifs. The water mol-ecules are connected via O-H?O hydrogen bonds, forming supra-molecular chains along the c axis. Furthermore, the chains and the dimers are connected via O-H?O hydrogen bonds, forming ladder-like supra-molecular ribbons along the c axis. PMID- 21523102 TI - 3-[5-(2,4-Dichloro-phen-yl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]-4-hy-droxy-2H chromen-2-one. AB - In the title compound, C(24)H(16)Cl(2)N(2)O(3), the chromene ring system is almost planar, with a maximum deviation of 0.042 (1) A. It makes dihedral angles of 3.72 (6), 73.37 (5) and 12.00 (5) degrees with the dihydro-pyrazole, benzene and phenyl rings, respectively. An intra-molecular O-H?N hydrogen bond forms an S(6) ring motif. In the crystal, mol-ecules are linked via C-H?O inter-actions, forming an infinite chain along the a axis. The crystal packing is further stabilized by a pi-pi stacking inter-action [centroid-centroid distance = 3.5471 (7) A] and a Cl?Cl short contact [Cl?Cl = 3.214 (1) A]. PMID- 21523103 TI - Deltaline from Delphinium delavayi Franch. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: 6beta,10-dihy-droxy-1alpha,14alpha,16beta trimeth-oxy-4-methyl-7beta,8-(methyl-enedi-oxy)-20-ethyl-aconitan-6-yl acetate], C(27)H(41)NO(8), is a C(19)-diterpenoid alkaloid and a major diterpenoid alkaloid component of the roots of Delphinium delavayi Franch. var. pogonanthum (Hand. Mazz.) W. T. Wang. The mol-ecule has a lycoctonine carbon-atom skeleton with four six-membered rings and three five-membered rings among; three of the six-membered rings adopt chair conformations with the fourth adopting a boat conformation while all of the five-membered rings exhibit envelope conformations. Inter molecular O-H?O hydrogen bonding is present in the crystal structure. PMID- 21523104 TI - 3-Hy-droxy-2-(4-meth-oxy-phen-yl)-4H-chromen-4-one. AB - In the title compound, C(16)H(12)O(4), the benzene ring is twisted at an angle of 12.3 (1) degrees relative to the 4H-chromene skeleton, and an intramolecular O H?O hydrogen bond occurs. The meth-oxy group is almost coplanar with the benzene ring [1.5 (1) degrees ]. In the crystal, inversely oriented mol-ecules are arranged in double (A, A') columns, along the b axis, and are linked by a network of inter-molecular O-H?O hydrogen bonds (between A and A') and C-H?pi contacts (within A or A'). The 4H-chromene cores are parallel within A or A', but make a dihedral angle of 88.6 (1) degrees between A and A'. PMID- 21523105 TI - N-(4-Butanoyl-3-hy-droxy-phen-yl)butanamide. AB - The title compound, C(14)H(19)NO(3), was prepared via the intra-molecular rearrangement of 3-(butanoyl-amino)-phenyl butano-ate in the presence of anhydrous aluminium chloride. The near coplanarity of the aromatic ring, the amide group and the carbonyl group of the butanoyl fragment [N-C-C-C = -179.65 (17) and O-C-C-C = -178.34 (17) degrees ] results from the intra-molecular O-H?O and C-H?O hydrogen bonds. In the crystal, the mol-ecules form a one-dimensional polymeric structure via N-H?O inter-actions between their amide groups. PMID- 21523106 TI - 2-Hy-droxy-ethyl 4-hy-droxy-benzoate. AB - In the title compound, C(9)H(10)O(4), the dihedral angle between the benzene ring and the -CO(2) unit is 11.93 (8) degrees and the conformation of the 2-hy-droxy ethyl side chain is gauche [O-C-C-O = -71.91 (17) degrees ]. In the crystal, mol ecules are linked by O-H?O and C-H?O hydrogen bonds. PMID- 21523107 TI - N-{4-[(E)-(4-Methyl-phen-yl)imino-meth-yl]phen-yl}acetamide. AB - There are two symmetry-independent mol-ecules in the asymmetric unit of the title compound, C(16)H(16)N(2)O, that differ in conformation. The dihedral angles between the benzene rings in the two mol-ecules are 44.35 (19) and 48.14 (17) degrees , but the rings twist in opposite directions. The acetamide groups make nearly equal dihedral angles of 25.4 (3) and 25.7 (3) degrees with the parent benzene rings. An S(6) ring motif is formed in each mol-ecule by intra-molecular C-H?O close contacts. In the crystal, strong N-H?O hydrogen bonds between acetamide groups generate a C(4) chain motif arranging the mol-ecules into two symmetry-independent polymeric structures extending along [010]. PMID- 21523108 TI - (Z)-4-{1-[(2-Hy-droxy-ethyl)-amino]-ethyl-idene}-3-methyl-1-phenyl-1H-pyrazol 5(4H)-one. AB - In the title compound C(14)H(17)N(3)O(2), the dihedral angle between the rings is 16.68 (13) degrees . Although the compound crystallizes in the keto form, the possibility of keto-enamine-enol-imine tautomerism is explained by a strong intra molecular N-H?O hydrogen bond. PMID- 21523109 TI - (1RS,6SR)-Ethyl 4-(2,4-dichloro-phen-yl)-6-(4-fluoro-phen-yl)-2-oxocyclo-hex-3 ene-1-carboxyl-ate. AB - There are two symmetry-independent mol-ecules in the asymmetric unit of the title compound, C(21)H(17)Cl(2)FO(3). Both these mol-ecules are very similar: the normal probability plots for bond lengths, angles and even for torsion angles show that the differences are of a statistical nature. A pseudocentre of symmetry is located between the symmetry-independent mol-ecules at [0.245 (1), 0.535 (19), 0.909 (1)]. The cyclo-hexene rings have slightly distorted sofa conformations in both mol-ecules and the two benzene rings are inclined by dihedral angles of 61.33 (14) and 62.85 (14) degrees . In the crystal, relatively short inter molecular C-H?O inter-actions join mol-ecules into homomolecular (i.e. ?AAA? and ?BBB?) chains along the b axis. These chains are inter-connected by further heteromolecular C-H?O inter-actions. PMID- 21523110 TI - 4-[5-(Pyridin-4-yl)-1,3,4-oxadiazol-2-yl]pyridinium benzoate. AB - In the title compound, C(12)H(9)N(4)O(+).C(7)H(5)O(2) (-), pi-pi stacking inter actions [centroid-centroid distance = 3.6275 (14) A] stabilize the crystal structure. The dihedral angles between the central ring and the terminal rings are 3.27 (12) and 10.30 (13) degrees . PMID- 21523111 TI - Ethyl 1-benzene-sulfonyl-2-[(E)-2-(2-methyl-phen-yl)ethen-yl]indole-3-carboxyl ate. AB - In the title compound, C(26)H(23)NO(4)S, the phenyl, tolyl and ester groups make dihedral angles of 82.28 (5), 77.67 (6) and 8.52 (6) degrees , respectively, with the indole ring system. The S atom of the sulfonyl group is displaced by 0.1968 (4) A from the indole mean plane. The mol-ecular structure is stabilized by weak intra-molecular C-H?O inter-actions. The crystal structure structure features short intramolecular C-H?O contacts and pi-pi stacking inter-actions between the phenyl and tolyl groups [centroid-centroid distance = 3.9448 (11) A]. PMID- 21523112 TI - 1-Benzyl-idene-amino-3-(4-methyl-phen-yl)thio-urea. AB - In the title compound, C(15)H(15)N(3)S, the almost planar 2-benzyl idenehydrazinecarbothio-amide unit (r.m.s. deviation = 0.0351 A) is aligned at a dihedral angle of 64.42 (6) degrees with respect to the plane of the tolyl ring. The mol-ecule exhibits an E configuration for the azomethine linkage. In the crystal, inter-molecular N-H?S hydrogen bonds about centers of inversion lead to the formation of dimers. PMID- 21523113 TI - N,N',N'',N'''-Tetrakis(2-methylphenyl)-oxybis(phospho-nic diamide): a redetermination at 150 K with Mo Kalpha radiation. AB - The structure of the title compound, C(28)H(32)N(4)O(3)P(2), has been redetermined at 150 K, with much improved precision. The structure and mol-ecular packing of the title compound was previously determined using Cu Kalpha radiation, with an R value of 0.0933 [Cameron et al. (1978 ?). Z. Naturforsch. Teil B, 33, 728-730]. The c-axis length in this structure [13.8401 (8) A] is almost half that reported in the original study. In the title compound, two (C(6)H(4)(2-CH(3))NH)(2)P(O) units are bridged via an O atom [P-O-P = 133.31 (11) degrees ]. The P atoms adopt a slightly distorted tetra-hedral coordination geometry. In the crystal, mol-ecules are linked via N-H?OP hydrogen bonds into extended chains parallel to the c axis. An intra-molecular N-H?O=P hydrogen bond is also found in the mol-ecule. PMID- 21523114 TI - 1-(4-Carb-oxy-phen-yl)-1H-imidazol-3-ium chloride dihydrate. AB - In the crystal structure of the title compound, C(10)H(9)N(2)O(2) (+).Cl( ).2H(2)O, the components are linked by O-H?O, N-H?O, O-H?Cl and N-H?Cl hydrogen bonds. In the cation, the imidazole ring is oriented at a dihedral angle of 13.67 (17) degrees with respect to the benzene ring. In the crystal, pi-pi stacking occurs between nearly parallel benzene rings, which are oriented at a dihedral angle of 3.4 (1) degrees , the centroid-centroid distance being 3.798 (3) A. PMID- 21523115 TI - 2-{5,5-Dimethyl-3-[2-(pyridin-2-yl)ethen-yl]cyclo-hex-2-enyl-idene}propane dinitrile. AB - The mol-ecule of the title compound, C(18)H(17)N(3), with the exception of the C(CH(3))(2) group, is nearly planar [maximum deviation: 0.208 (4), r.m.s. deviation 0.099 (6) A] and the disubstituted C atom is displaced by 0.679 (2) A from the mean plane through the remaining non-H atoms. In the crystal, the packing is stabilized by weak C-H?pi inter-actions. PMID- 21523116 TI - 2,3,4-Tri-O-acetyl-beta-l-arabinopyranosyl trichloro-acetimidate. AB - In the title compound, C(13)H(16)Cl(3)NO(8), the trichloro-acetimidate group is located in an axial postion on the anomeric carbon of the sugar ring. PMID- 21523117 TI - N,N'-Dibenzyl-2,2'-(3,6-dioxaoctane-1,8-diyldi-oxy)dibenzamide. AB - The title compound, C(34)H(36)N(2)O(6), located on a center of inversion, crystallizes with one half-mol-ecule in the asymmetric unit. The dihedral angle between the benzene rings is 86.19 (2) degrees . An intra-molecular N-H?O hydrogen bond forms a six-membered ring; it affects the conformation of the mol ecule which adopts a folded rather than open conformation. The crystal packing is stabilized by inter-molecular C-H?O inter-actions. PMID- 21523118 TI - 4-Amino-pyridinium-3-sulfonate monohydrate. AB - The reaction of 4-amino-pyridine and oleum yielded the title hydrated zwitterion, C(5)H(6)N(2)O(3)S.H(2)O. There are two formula units in the asymmetric unit. The H and non-H atoms of both zwitterions lie on a mirror plane except for one sulfonate O atom. The water mol-ecules are also situated on a mirror plane. In the crystal, the zwitterions and water mol-ecules are linked by O-H?O and N-H?O hydrogen bonds, generating a three-dimensional network. PMID- 21523119 TI - Tris(biphenyl-4-yl)arsane. AB - The asymmetric unit of title compound, C(36)H(27)As, contains two crystallographically independent mol-ecules, A and B, with similar conformations. The two phenyl rings of each biphenyl unit are twisted slightly away from each other with dihedral angles of 6.0 (2), 27.7 (3) and 33.4 (2) degrees in mol ecule A and 5.7 (3), 27.5 (2) and 33.0 (2) degrees in mol-ecule B. The As-bonded phenyl rings make dihedral angles of 54.9 (2), 76.0 (2) and 88.2 (2), degrees with each other in mol-ecule A, and 60.3 (2), 78.1 (2) and 79.5 (2) degrees in mol-ecule B. In the crystal, the mol-ecules are stacked down the b axis. Weak inter-molecular C-H?pi inter-actions stabilize the crystal structure. The crystal studied was a racemic twin, the refined ratio of twin components being 0.461 (7):0.539 (7). PMID- 21523120 TI - (E)-N'-(2,4-Dihy-droxy-benzyl-idene)-4-nitro-benzohydrazide. AB - The title compound, C(14)H(11)N(3)O(5), is essentially planar, with an r.m.s. deviation for the non-H atoms of 0.0832 (3) A. In the crystal, O-H?O and N-H?O hydrogen bonds link adjacent mol-ecules into layers parallel to (101). These layers are further connected into a three-dimensional network via C-H?O inter actions. In addition, a pi-pi inter-action occurs between the aromatic rings [centroid-centroid distance = 3.5425 (8) A]. An intra-molecular O-H?N hydrogen bond is also observed. PMID- 21523121 TI - Ethyl 3-oxo-2-(2-phenyl-hydrazinyl-idene)butano-ate: a re-determination. AB - The previous crystallographic studies [Wang et al. (2005 ?). Huaxue Yanjiu16, 29 32; Wang et al. (2007 ?). Youji Huaxue, 27, 524] of the title compound, C(12)H(14)N(2)O(3), gave only the unit-cell dimensions and an R factor with no other details available: the full structure is presented here. The eth-oxy group is disordered over two orientations with refined occupancies of 0.642 (15):0.358 (15). The nine C atoms and two N atoms of the 1-phenyl-2-(propan-2-yl idene)hydrazine segment of the mol-ecule are close to being coplanar, with a maximum deviation of 0.0779 (14) A for the phenyl-amino N atom and an intra molecular N-H?O hydrogen bond generates an S(6) ring. In the crystal, pairs of C H?O hydrogen bonds link mol-ecules into inverson dimers, generating R(2) (2)(16) loops. PMID- 21523122 TI - 1-[4-(2-Chloro-eth-oxy)-2-hy-droxy-phen-yl]ethanone. AB - In the title compound, C(10)H(11)ClO(3), obtained by the reaction of 2,4-dihy droxy-acetophenone, potassium carbonate and 1-bromo-2-chloro-ethane, an intra molecular O-H?O hydrogen bond occurs. PMID- 21523123 TI - 1-[4-(4-Chloro-but-oxy)-2-hy-droxy-phen-yl]ethanone. AB - In the title compound, C(12)H(15)ClO(3), the eth-oxy group is nearly coplanar with the benzene ring, making a dihedral angle of 9.03 (4) degrees , and is involved in an intra-molecular O-H?O hydrogen bond to the neighbouring hy-droxy group. PMID- 21523124 TI - 3-Isobutyl-4-phenyl-sulfan-yl-1H-pyrazol-5-ol. AB - The asymmetric unit of the title compound, C(13)H(16)N(2)OS, contains two independent mol-ecules (A and B). The pyrazole ring [maximum deviations = 0.0049 (17) A in mol-ecule A and 0.0112 (19) A in mol-ecule B] makes a dihedral angle of 70.23 (11) and 73.18 (12) degrees with the phenyl ring in mol-ecules A and B, respectively. The isobutyl group in mol-ecule B is disordered over two sets of sites with a ratio of refined occupancies of 0.858 (5):0.142 (5). In the crystal, mol-ecules A and B are linked via a pair of inter-molecular N-H?O hydrogen bonds, generating an R(2) (2)(8) ring motif. These ring motifs are further linked into two-dimensional arrays parallel to the bc plane by inter-molecular N-H?O and weak C-H?S hydrogen bonds. The crystal is further stablized by weak pi-pi inter actions [centroid-centroid distances = 3.5698 (13) and 3.5287 (12) A]. PMID- 21523125 TI - Ethyl 2-(4-nitro-benzamido)-benzoate, a non-merohedral twin. AB - In the title compound, C(16)H(14)N(2)O(5), a non-merohedral twin, the dihedral angle between the mean planes of the two benzene rings is 4.0 (9) degrees . The ethyl group is disordered [0.643 (14) and 0.357 (14) occupancy]. The nitro group is twisted by 16.4 (4) degrees from the mean plane of the benzene ring and the mean plane of the carbonyl group is twisted from the mean planes of the two benzene rings by 4.5 (0) and 4.7 (9) degrees . An intra-molecular N-H?O hydrogen bond occurs. The crystal packing is stabilized by weak inter-molecular C-H?O hydrogen-bond inter-actions. PMID- 21523126 TI - 4-(5-Amino-1H-1,2,4-triazol-3-yl)pyridinium chloride monohydrate. AB - In the cation of the title compound, C(7)H(8)N(5) (+).Cl(-).H(2)O, the mean planes of the pyridine and 1,2,4-triazole rings form a dihedral angle of 2.3 (1) degrees . The N atom of the amino group adopts a trigonal-pyramidal configuration. The N atom of the pyridine ring is protonated, forming a chloride salt. In the crystal, inter-molecular N-H?O, N-H?N, N-H?Cl and O-H?Cl hydrogen bonds link the cations, anions and water mol-ecules into layers parallel to the (1, 0, ) plane. PMID- 21523127 TI - Ethyl 1-benzyl-3-(4-methyl-phen-yl)-1H-pyrazole-5-carboxyl-ate. AB - In the title compound, C(20)H(20)N(2)O(2), the pyrazole ring makes dihedral angles of 15.68 (4) and 83.40 (4) degrees , respectively, with the tolyl and benzyl rings, respectively. PMID- 21523128 TI - 4,9-Dioxa-1,3(1,2)-dibenzena-2(4,5)-1,3-oxazolidinacyclononaphane. AB - The oxazole ring in the title compound, C(20)H(23)NO(3), adopts an envelope conformation while the 12-membered ring is in a chair conformation. The dihedral angle between the benzene rings is 37.8 (1) degrees . The crystal structure displays inter-molecular C-H?O hydrogen bonding. PMID- 21523129 TI - 5-Cyclo-hexyl-2-(4-fluoro-phen-yl)-3-methyl-sulfinyl-1-benzofuran. AB - In the title compound, C(21)H(21)FO(2)S, the cyclo-hexyl ring adopts a classic chair conformation. The 4-fluoro-phenyl ring makes a dihedral angle of 31.05 (6) degrees with the mean plane of the benzofuran fragment. In the crystal, mol ecules are linked through weak inter-molecular C-H?O and C-H?pi inter-actions. PMID- 21523130 TI - 5-Bromo-3-(4-fluoro-phenyl-sulfin-yl)-2,4,6-trimethyl-1-benzofuran. AB - In the title mol-ecule, C(17)H(14)BrFO(2)S, the 4-fluoro-phenyl ring makes a dihedral angle of 75.92 (5) degrees with the mean plane of the benzofuran fragment. In the crystal, mol-ecules are linked by weak inter-molecular C-H?O hydrogen bonds and aromatic pi-pi inter-actions between the benzene and the furan rings of neighbouring mol-ecules [centroid-centroid distance = 3.556 (1) A]. PMID- 21523131 TI - 2-Meth-oxy-ethanaminium periodate 18-crown-6 clathrate. AB - In the crystal structure of the title organic salt, C(3)H(10)NO(+).IO(4) ( ).C(12)H(24)O(6), the protonated 2-meth-oxy-ethanaminium (CH(3)OC(2)H(4)-NH(3) (+)) cation forms a 1:1 supra-molecular rotator-stator complex with the 18-crown 6 mol-ecule via N-H?O hydrogen bonds. The (CH(3)OC(2)H(4)-NH(3) (+)) group is attached from the convex side of the bowl-shaped crown, in contrast to similar ammonium cations that nest in the curvature of the bowl. The cations are associated via N-H?O inter-actions, while the cations and anions are linked by weak C-H?O hydrogen bonds, forming cation-crown-anion chains parallel to [010]. PMID- 21523132 TI - 4,5-Dicarb-oxy-naphthalene-1,8-dicarb-oxy-lic anhydride-1,10-phenanthroline (1/1). AB - In the crystal structure of the title 1:1 adduct, C(12)H(8)N(2).C(14)H(6)O(7), the carboxyl groups are involved in inter-molecular O-H?O hydrogen bonds, which link the mol-ecules into centrosymmetric dimers. These dimers are further linked by inter-molecular O-H?N hydrogen bonds. C-H?O inter-actions also occur between the 1,10-phenanthroline (phen) and 4,5-dicarb-oxy-naphthalene-1,8-dicarb-oxy-lic anhydride (H(2)NTC) mol-ecules. In addition, the crystal structure exhibits pi-pi inter-actions of the phen?phen and H(2)NTC?H(2)NTC types with centroid-centroid distances of 3.579 (3) and 3.774 (3) A, respectively. PMID- 21523133 TI - 5-Ethyl-2-(4-fluoro-phen-yl)-4-phen-oxy-1H-pyrazol-3(2H)-one. AB - In the title compound, C(17)H(15)FN(2)O(2), the essentially planar pyrazole ring [maximum deviation = 0.026 (1) A] makes dihedral angles of 72.06 (7) and 33.05 (7) degrees , with the phenyl and fluoro-benzene rings, respectively. The dihedral angle between the two six-membered rings is 87.88 (7) degrees . In the crystal, inter-molecular N-H?O and C-H?F hydrogen bonds link the mol-ecules into layers lying parallel to the bc plane. PMID- 21523134 TI - 1,5-Dimethyl-4-{[(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl-idene)(thio phen-2-yl)meth-yl]amino}-2-phenyl-1H-pyrazol-3(2H)-one. AB - In the title compound, C(26)H(23)N(5)O(2)S, an intra-molecular N-H?O inter-action generates an S(6) ring. The essentially planar S(6) and pyrazole rings [maximum deviations = -0.0270 (14) and 0.0195 (15) A, respectively] are nearly coplanar, making a dihedral angle of 3.94 (6) degrees . The S(6) ring makes dihedral angles of 23.79 (6), 78.53 (6) and 67.91 (6) degrees with the pyrazolone ring, the pyrazole ring and the benzene ring of anti-pyrine, respectively. The structure exhibits a thienyl-ring flip disorder with occupancy factors in the ratio 0.82:0.18. PMID- 21523135 TI - 2,2-Dimethyl-5-[(5-methyl-furan-2-yl)methyl-idene]-1,3-dioxane-4,6-dione. AB - The asymmetric unit of the title compound, C(12)H(12)O(5), contains two independent mol-ecules. In each, the 1,3-dioxane ring adopts an envelope conformation with the dimethyl-substituted C atom forming the flap. The crystal structure is stabilized by weak inter-molecular C-H?O hydrogen bonds. PMID- 21523136 TI - N-Nitro-1H-pyrrole-2-carboxamide. AB - In the title compound, C(5)H(5)N(3)O(3), the nitro group is twisted with respect to the amide group, with C-N-N-O torsion angles of 29.0 (2) and -153.66 (14) degrees . In the crystal, mol-ecules are linked through inter-molecular N-H?O and C-H?O hydrogen bonds, forming supra-molecular chains along the a axis. These chains stack in parallel and form distinct layer motifs in the (001) plane. PMID- 21523137 TI - Ethyl 3,6-dihy-droxy-6-methyl-4-phenyl-4,5,6,7-tetra-hydro-1H-indazole-5-carboxyl ate monohydrate. AB - In the title compound, C(17)H(20)N(2)O(4).H(2)O, the cyclo-hexene ring adopts a half-chair conformation while the indazole ring is essentially planar [maximum deviation = 0.0192 (12) A]. In the crystal, pairs of inter-molecular O-H?N hydrogen bonds link the mol-ecules into dimers lying about inversion centers and intra-molecular O-H?O hydrogen bonds result in six-membered rings. The dimers are further connected by N-H?O and O-H?O hydrogen bonds. PMID- 21523138 TI - 2-(2,2-Dibromo-ethen-yl)thio-phene. AB - The title compound, C(6)H(4)Br(2)S, represents a versatile building block for the preparation of pi-conjugated redox-active thienyl oligomers and metal-mediated cross-coupling reactions. This is due to the presence of an electrochemically active thienyl heterocycle and a reactive dibromo-vinyl substituent, which easily undergoes dehydro-bromination in the presence of n-butyl-lithium to afford 2 ethynyl-thio-phene. In the molecule, the alkenyl unit and the thio-phene ring are almost coplanar with an angle of 3.5 (2) degrees between the normals of the best planes of the thio-phene ring and the vinyl moiety. PMID- 21523139 TI - Dimethyl 2-(1-benzyl-2-oxoindolin-3-yl-idene)-1,3-dithiole-4,5-dicarboxyl-ate. AB - In the title compound, C(22)H(17)NO(5)S(2), the dithiole and oxindole rings are almost coplanar [dihedral angle = 2.71 (8) degrees ] and the phenyl ring makes a dihedral angle of 73.65 (5) degrees with the oxindole ring. Inter-molecular pi pi contacts between adjacent oxindole and dithiole rings [centroid-centroid distance = 3.7273 (11) A] stabilize the crystal packing. PMID- 21523140 TI - Lomefloxacinium picrate. AB - IN THE CATION OF THE TITLE COMPOUND [SYSTEMATIC NAME: (RS)-4-(3-carb-oxy-1-ethyl 6,8-difluoro-4-oxo-1,4-dihydro-quinolin-7-yl)-2-methyl-piperazin-1-ium 2,4,6 trinitro-phenolate], C(17)H(20)F(2)N(3)O(3) (+).C(6)H(2)N(3)O(7) (-), the piper azine ring adopts a slightly distorted chair conformation and contains a protonated N atom. An intra-molecular O-H?O hydrogen bond occurs in the cation. The dihedral angles between the mean planes of the six-atom piperazine ring and the 10-atom fused ring system is 43.3 (5) degrees . The picrate anion inter-acts with the protonated N atom of an adjacent cation through a bifurcated N-H?(O,O) three-center hydrogen bond. Strong N-H?O hydrogen bonds in concert with weak pi pi stacking inter-actions [centroid-centroid distance = 3.6460 (14) A] dominate the crystal packing, creating a two-dimensional network structure along [011]. PMID- 21523141 TI - Methyl 3,5,5,6,8,8-hexa-methyl-5,6,7,8-tetra-hydro-naphthalene-2-carboxyl-ate (AHTN-COOMe). AB - Crystals of the title compound, C(18)H(26)O(2), were grown from ethyl acetate. Due to the racemic precursor, the title compound is also obtained as a racemate. Disorder was observed during structure refinement, originating from two possible half-chair conformations of the non-aromatic ring. The disorder was refined by introducing split positions in the cyclo-hexane ring regarding the two possible R and S-enantiomers at the chiral CH group [ratio 0.744 (3):0.256 (3)]. The crystal structure features pairs of inversion-related molecules connected by pairs of non classical C-H?O hydrogen bonds. PMID- 21523142 TI - 1,2,3,3',4',6'-Hexaacetyl-4,6-O-benzyl-idenesucrose. AB - In the title compound, C(31)H(38)O(17), the 1,3-dioxane and pyran-oside rings both show (4)C(1) chair conformations while for the d-fructofuran-oside moiety an envelop 3E conformation is observed. The phenyl ring is oriented almost perpendicular to the 1,3-dioxane ring [dihedral angle = 79.3 (2) degrees ], and the acetate groups are equatorial for the pyran-oside ring and axial for the furan-oside ring. The analysis of potential hydrogen bonds shows both intra- and inter-molecular C-H?O contacts to be present. PMID- 21523143 TI - 3-(2,4-Dimeth-oxy-anilino)-8-meth-oxy-dibenz[b,e]oxepin-11(6H)-one. AB - In the title compound, C(23)H(21)NO(5), the two benzene rings of the tricyclic unit are oriented at a dihedral angle of 37.5 (8) degrees . The 2,4-dimeth-oxy anilino residue is oriented at a dihedral angle of 60.2 (8) degrees towards the phen-oxy ring. In the crystal, the central carbonyl O atom accepts two hydrogen bonds from the N-H and C-H groups. A further inter-molecular C-H?O inter-action involving one of the meth-oxy O atoms is also observed. PMID- 21523144 TI - 3-(4-Carb-oxy-5-carboxyl-ato-1H-imidazol-2-yl)pyridin-1-ium monohydrate. AB - In the zwitterionic mol-ecule of the title compound, C(10)H(7)N(3)O(4).H(2)O, one carboxyl group is deprotonated and the pyridine N atom is protonated. The pyridinium and imidazole rings form a dihedral angle of 5.23 (1) degrees . An intramolecular O-H?O hydrogen bond occurs. In the crystal, inter-molecular N-H?O, O-H?N and O-H?O hydrogen bonds link the zwitterions and water mol-ecules into sheets parallel to (102). PMID- 21523145 TI - 2-[(4-Methyl-phen-yl)sulfan-yl]aniline. AB - The least-squares planes defined by the aromatic moieties in the title aniline derivative, C(13)H(13)NS, are nearly perpendicular to each other, forming a dihedral angle of 87.80 (7) degrees . Apart from a weak intramolecular N-H?S hydrogen bond, a co-operative set of N-H?N hydrogen bonds present in the crystal structure leads to the formation of tetra-meric units. PMID- 21523146 TI - 4-Chloro-6-methyl-N-(4-methyl-phen-yl)quinolin-2-amine. AB - In the title compound C(17)H(15)ClN(2), the dihedral angle between the quinoline ring system and the phenyl ring is 50.18 (6) degrees . In the crystal, mol-ecules are linked into chains running along the c axis by N-H?N hydrogen bonds. PMID- 21523147 TI - 2-Chloro-N-[(4-chloro-phen-yl)(phen-yl)meth-yl]-N-[2-(4-nitro-1H-imidazol-1 yl)eth-yl]ethanamine. AB - In the title compound, C(20)H(20)Cl(2)N(4)O(2), the nitro-imidazole ring makes dihedral angles of 17.00 (1) and 60.45 (11) degrees with the phenyl and chloro phenyl rings, respectively. The three-coordinate N atom connected to two methyl ene and one methine C atoms shows pyramidal coordination. PMID- 21523148 TI - 3-Hy-droxy-2-[(4-hy-droxy-3,5-dimeth-oxy-phen-yl)(2-hy-droxy-4,4-dimethyl-6-oxo cyclo-hex-1-en-1-yl)meth-yl]-5,5-dimethyl-cyclo-hex-2-en-1-one. AB - In the title compound, C(25)H(32)O(7), the 3-hy-droxy-5,5-dimethyl-cyclo-hex-2 enone rings adopt slightly distorted envelope conformations with the two planes at the base of the envelope forming dihedral angles of 57.6 (4) and 53.9 (9) degrees with the benzene ring. There is an intra-molecular hy-droxy-ketone O-H?O inter-action between the two substituted cyclo-hexane rings as well as a short intra-molecular phenol-meth-oxy O-H?O inter-action. PMID- 21523149 TI - 1H-Pyrrole-2-carbohydrazide. AB - The title compound, C(5)H(7)N(3)O, was obtained by the reaction of ethyl 1H pyrrol-2-carboxyl-ate and hydrazide hydrate. In the crystal, mol-ecules are linked via inter-molecular N-H?N and N-H?O hydrogen bonds, forming a supra molecular grid. PMID- 21523150 TI - 4-Hy-droxy-3-[(4-hy-droxy-6-methyl-2-oxo-3,6-dihydro-2H-pyran-3-yl)(3-thien yl)meth-yl]-6-methyl-3,6-dihydro-2H-pyran-2-one. AB - The asymmetric unit of the title compound, C(17)H(14)O(6)S, contains four crystallographically independent mol-ecules in which the pyran-one units are essentially planar, with maximum deviations of 0.016 (2), 0.019 (2), 0.025 (2), 0.014 (2), 0.020 (2), 0.010 (2), 0.003 (2) and 0.012 (2) A. One of the thio-phene rings is disordered over two positions, with an occupancy ratio of 0.739 (4):0.261 (4). The dihedral angles between the two pyran-one rings in the independent mol-ecules are 59.42 (8), 48.67 (8), 60.62 (9) and 51.60 (8) degrees . In the crystal, mol-ecules are linked through inter-molecular O-H?O and C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 21523151 TI - 1-{4-Chloro-2-[2-(2-fluoro-phen-yl)-1,3-dithio-lan-2-yl]phen-yl}-2-methyl-1H imidazole-5-carbaldehyde. AB - There are two mol-ecules in the asymmetric unit of the title imidazole derivative, C(20)H(16)ClFN(2)OS(2). In one mol-ecule, the dithiol-ane ring is disordered over two positions in a 0.849 (9):0.151 (10) ratio. The imidazole ring makes dihedral angles of 79.56 (9) and 18.45 (9) degrees with the 4-chloro phenyl and 2-fluoro-phenyl rings, respectively, in one mol-ecule; in the other mol-ecule, the corresponding angles are 82.72 (9) and 17.39 (10) degrees . In the crystal, mol-ecules are linked by weak C-H?O inter-actions and these linked mol ecules are stacked along the b axis by pi-pi inter-actions with a centroid centroid distance of 3.4922 (11) A. In addition, pi-pi inter-actions between the imidazole and 2-fluoro-phenyl rings are also observed, with centroid-centroid distances of 3.4867 (11) and 3.4326 (10) A. The crystal is further consolidated by weak C-H?pi inter-actions. Cl?S [3.5185 (8) A], C?O [3.192 (3) A] and C?C [3.326 (2)-3.393 (3) A] short contacts are also observed. PMID- 21523152 TI - 5-Chloro-2-(4-fluoro-phen-yl)-3-phenyl-sulfinyl-1-benzofuran. AB - In the title compound, C(20)H(12)ClFO(2)S, the O atom and the phenyl ring of the phenyl-sulfinyl substituent lie on opposite sides of the plane of the benzofuran fragment; the phenyl ring is almost perpendicular to this plane [82.44 (5) degrees ]. The 4-fluoro-phenyl ring is rotated out of the benzofuran plane, making a dihedral angle of 20.83 (6) degrees . PMID- 21523153 TI - 3-[Bis(p-tolyl-sulfon-yl)amino]-N-(4-chloro-benz-yl)-6-(3,4-dichloro-phen yl)thieno[2,3-b]pyridine-2-carboxamide. AB - In the title compound, C(35)H(26)Cl(3)N(3)O(5)S(3), the dihedral angle between the mean plane through the thieno[2,3-b]pyridine ring system and the attached benzene ring is 3.89 (6) degrees . The mol-ecular conformation is stabilized by an intra-molecular N-H?O hydrogen bond. In the crystal, mol-ecules are linked by inter-molecular C-H?O hydrogen bonds, forming chains parallel to [100]. PMID- 21523154 TI - Cinnarizinium dipicrate. AB - In the cinnarizinium dication of the title compound {systematic name: 1-diphenyl methyl-4-[(2E)-3-phenyl-prop-2-en-1-yl]piperazine-1,4-diium bis-(2,4,6-trinitro phenolate)}, C(26)H(30)N(2) (2+).2C(6)H(2)N(3)O(7) (-), the piperazine group is protonated at both N atoms and adopts a slightly distorted chair conformation. Strong N-H?O(hy-droxy) cation-anion hydrogen bonds link the dication and two anions. In the cation, the (2E)-3-phenyl-prop-2-en-1-yl fragment is disordered over two positions in a ratio of 0.586 (4): 0.414 (4). Two nitro groups in one anion and three in the other one demonstrate rotational disorder. The crystal packing is stabilized by weak inter-molecular pi-pi [centroid-centroid distances = 3.844 (7), 3.677 (9), 3.825 (5), 3.634 (2) and 3.729 (7) A], C-H?pi and C-H?O inter-actions. PMID- 21523155 TI - N,N'-Dicyclo-hexyl-N'',N''-dimethyl-phospho-ric triamide. AB - In the title compound, C(14)H(30)N(3)OP, both cyclo-hexyl groups adopt chair conformations with the NH unit in an equatorial position. The P atom adopts a slightly distorted tetra-hedral environment. In the (CH(3))(2)NP(O) unit, the O-P N-C torsion angles, showing the orientations of the methyl groups with respect to the phosphoryl group, are -166.6 (3) and 34.6 (4) degrees . The O atom of the P=O group acts as a double hydrogen-bond acceptor and is involved in two different inter-molecular N-H?OP hydrogen bonds, building R(2) (2)(8) rings that are further linked into chains running parallel to the b axis. PMID- 21523156 TI - rac-6-Hy-droxy-2,5,7,8-tetra-methyl-chroman-2-carboxamide from synchrotron data. AB - The crystal structure of the title water-soluble analogue of vitamin E, trolox amide, C(14)H(19)NO(3), solved and refined against synchrotron diffraction data, contains two mol-ecules in the asymmetric unit. In both molecules, the heterocyclic ring is in a half-chair conformation. The crystal packing features a herring-bone pattern generated by N-H?O hydrogen bonds between the hy-droxy and amide groups. O-H?O hydrogen bonds also occur. PMID- 21523157 TI - (4-Cyano-phenolato)(subphthalocyaninato)boron. AB - The crystal structure of the title compound, C(31)H(16)BN(7)O, (CNPhO-BsubPc) is characterized by pairs of pi-pi stacking inter-actions between the concave faces of inversion-related BsubPc fragments with a centroid-centroid distance of 3.600 (1) A. In addition, these pairs of mol-ecules are linked into chains along [101] through further weak pi-pi stacking inter-actions with a centroid-centroid distance of 3.8587 (9) A. There are also weak C-H?pi(arene) inter-actions within the chains. PMID- 21523158 TI - (22E,24R)-5alpha-Ergosta-2,22-dien-6-one. AB - In the title mol-ecule, C(28)H(44)O, two six-membered rings have regular chair conformations, while the six-membered ring containing the C=C double bond exhibits a distorted chair conformation. The five-membered ring adopts an envelope conformation. In the crystal, weak inter-molecular C-H?O inter-actions link mol-ecules into chains along the b axis. The absolute configuration was assigned to correspond with that of the known chiral centres in a precursor mol ecule. PMID- 21523159 TI - 2,7-Dimethyl-2,7-diazo-niapyrene bis-(hexa-fluoro-phosphate). AB - In the title compound, C(16)H(14)N(2) (2+).2PF(6) (-), the 2,7-dimethyl-2,7-diaza pyrenium (DM-diaz) cation lies on a crystallographic twofold rotation axes. The diaz groups are nearly coplanar, with a maximum deviation of 0.008 (3) A. In the crystal, mol-ecules are linked into a two-dimensional lamellar framework parallel to (104) through weak C-H?F inter-actions. PMID- 21523160 TI - Ethyl 2-(2-hy-droxy-5-nitro-phen-yl)acetate. AB - In the crystal structure of the title compound, C(10)H(11)NO(5), inter-molecular O-H?O hydrogen bonds link the mol-ecules into chains along the b-axis direction. Weak C-H..O hydrogen bonds also occur. PMID- 21523161 TI - 1-(4-Chloro-phen-yl)-3-{5-[(E)-2-phenyl-ethen-yl]-1,3,4-thia-diazol-2-yl}urea. AB - In the title compound, C(17)H(13)ClN(4)OS, the 1,3,4-thia-diazole ring makes dihedral angles of 9.70 (15) and 7.22 (10) degrees with the benzene and phenyl rings, respectively; the dihedral angle between these two rings is 6.37 (19) degrees . In the crystal, pairs of N-H?N and C-H?O hydrogen bonds between inversion-related mol-ecules result in supra-molecular ribbons displaying alternate R(2) (2)(8) and R(2) (2)(14) graph-set ring motifs. PMID- 21523162 TI - Ethyl 1-benzyl-3-(4-fluoro-phen-yl)-1H-pyrazole-5-carboxyl-ate. AB - In the title compound, C(19)H(17)FN(2)O(2), the pyrazole ring makes dihedral angles of 4.57 (16) and 81.19 (18) degrees with the fluoro-phenyl and benzene rings, respectively. PMID- 21523163 TI - (1SR,2RS,3SR,5SR,6RS)-6-[(Z)-1-Acet-oxy-2-phenyl-ethen-yl]-3-eth-oxy-2-phenyl bicyclo-[3.1.0]hexan-1-yl acetate. AB - The mol-ecule of the title compound, C(26)H(28)O(5), is chiral with five stereogenic centres; however, the centrosymmetric triclinic group gives a racemic crystal. The fused ring system adopta boat conformation in which the cyclo propane ring plane is roughly perpendicular to the styryl group plane, forming a dihedral angle of 74.78 (19) degrees . The dihedral angle between the two benzene rings is 77.24 (6) degrees . PMID- 21523164 TI - [1-(Carb-oxy-meth-yl)cyclo-hex-yl]methanaminium nitrate. AB - The title compound, C(9)H(18)NO(2) (+).NO(3) (-), is an anhydrous nitrate salt of gabapentin, which is formed serendipitously in the presence of selected non coordinating metals. The crystal structure involves extensive hydrogen bonding between the -NH(3) (+) and -COOH groups and the nitrate anion. PMID- 21523165 TI - 3-[1-(4-Chloro-phen-yl)eth-yl]-1,3-thia-zinane-2-thione. AB - In the title compound, C(12)H(14)ClNS(2), the thia-zole ring adopts an envelope conformation; the basal plane is nearly perpendicular to the benzene ring at a dihedral angle of 85.72 (5) degrees . Weak inter-molecular C-H?S hydrogen bonding is present in the crystal structure. PMID- 21523166 TI - 2-[(E)-2-(4-Eth-oxy-phen-yl)ethen-yl]-1-methyl-pyridinium 4-chloro-benzene sulfonate monohydrate. AB - In the title compound, C(16)H(18)NO(+).C(6)H(4)ClO(3)S(-).H(2)O, the cation exists in an E configuration with respect to the ethenyl bond and is slightly twisted with a dihedral angle of 9.85 (5) degrees between the pyridinium and the benzene rings. The anion is inclined to the cation with the dihedral angles between the benzene ring of the anion and the pyridinium and benzene rings of the cation of 78.33 (6) and 68.73 (6) degrees , respectively. In the crystal, the cations and anions are arranged alternately into head-to-head ribbons along the c axis, with the cationic ribbons stacked along the b axis. The crystal is consolidated by O-H?O hydrogen bonds, weak C-H?O and C-H?pi inter-actions. pi-pi inter-actions with centroid-centroid distances of 3.6111 (7) and 3.6466 (7) A are also observed. PMID- 21523167 TI - cis-6-Bromo-4-(1-methyl-1H-indol-3-yl)-10,10a-dihydro-1H,4H-2,9-dioxa-3-aza benz[f]azulene. AB - In the title compound, C(20)H(17)BrN(2)O(2), the seven-membered oxepine ring adopts a chair conformation. The indole moiety is essentially planar with a maximum deviation of 0.031 (3)A. The indole ring system forms a dihedral angle of 21.87 (8) degrees with the mean plane of the 10-membered heterobicycle. The crystal packing is stabilized by inter-molecular C-H?O and C-H?pi inter-actions. PMID- 21523168 TI - 4-Bromo-2-{[(pyridin-3-ylmeth-yl)imino]-meth-yl}phenol. AB - The title compound, C(13)H(11)BrN(2)O, is a polydentate Schiff base and reveals intra-molecular O-H?N hydrogen bonding between the hy-droxy O atom and the imino N atom. The dihedral angle between the aromatic ring and the pyridyl ring is 71.7 (1) degrees . In the crystal, the mol-ecules are stacked in columns along the c axis and several inter-molecular pi-pi inter-actions are present between the six membered rings, with a shortest centroid-centroid distance of 3.707 (2) A. PMID- 21523169 TI - [(Dibenzo[b,d]thio-phen-4-yl)tellan-yl]methane-thiol. AB - In the title compound, C(13)H(10)S(2)Te, the dibenzothio-phene moiety is almost planar, the maximum atomic deviation being 0.055 (5) A. The two Te-C bonds are nearly perpen-dicular to each other with a C-Te-C bond angle of 93.0 (2) degrees . An inter-molecular C-H?pi inter-action is present between the methyl-ene group and thio-phene ring. PMID- 21523170 TI - 1,3-Diallyl-5-chloro-1H-benzimidazol-2(3H)-one. AB - The benzimidazolone part of the title mol-ecule, C(13)H(13)ClN(2)O, is almost planar (r.m.s. deviation = 0.006 A) and its mean plane is aligned at dihedral angles of 62.5 (1) and 78.0 (1) degrees with respect to the mean planes of the allyl substituents. PMID- 21523171 TI - 2-(Biphenyl-4-yl-oxy)acetic acid. AB - In the title compound, C(14)H(12)O(3), the phenyl and benzene rings make a dihedral angle of 47.51 (4) degrees . In the crystal, mol-ecules are dimerized by double O-H?O hydrogen bonds, forming centrosymmetric R(2) (2)(8) ring motifs. The dimers are inter-linked by C-H?pi inter-actions into zigzag layers. PMID- 21523172 TI - N,N'-Bis(3beta-acet-oxy-5alpha-cholest-6-yl-idene)hydrazine. AB - The asymmetric unit of the title compound, C(58)H(96)N(2)O(4), contains two crystallographically independent mol-ecules. All cyclohexane rings are in chair conformations, while the furan ring is in an envelope conformation in one mol ecule and a twist conformation in the other. Two acetaldehyde and one isobutane groups are disordered over two orientations with refined site occupancies of 0.940 (4):0.060 (4) and 0.791 (7):0.209 (7), respectively. In the crystal, mol ecules are stacked along the a axis through van der Waals inter-actions. PMID- 21523173 TI - 4-(Imidazol-1-yl)benzoic acid. AB - In the title mol-ecule, C(10)H(8)N(2)O(2), the imidazole and benzene rings form a dihedral angle of 14.5 (1) degrees . In the crystal, inter-molecular O-H?N hydrogen bonds link the mol-ecules into chains extending in [01], which are further linked into sheets parallel to (102) through weak C-H?O inter-actions. PMID- 21523174 TI - 2-Amino-3-carb-oxy-pyrazin-1-ium nitrate monohydrate. AB - In crystal structure of the title compound, C(5)H(6)N(3)O(2) (+).NO(3) (-).H(2)O, inter-molecular N-H?O, O-H?N and O-H?O hydrogen bonds link the cations, anions and water mol-ecules into ribbons extending in [10]. Weak inter-molecular C-H?O hydrogen bonds further link these ribbons into sheets parallel to (3). PMID- 21523175 TI - 5-Bromo-3-cyclo-hexyl-sulfinyl-2-methyl-1-benzofuran. AB - In the asymmetric unit of the title compound, C(15)H(17)BrO(3)S, there are two independent mol-ecules. The cyclo-hexane rings in each adopt classic chair conformations. In the crystal, mol-ecules are linked by weak inter-molecular C H?O hydrogen bonds and aromatic pi-pi inter-actions between the furan rings of symmetry-related mol-ecules [centroid-centroid distance = 3.555 (2) A]. PMID- 21523176 TI - (E)-Benzaldehyde (2,4,6-trichloro-phen-yl)hydrazone. AB - The title compound, C(13)H(9)Cl(3)N(2), was obtained from a condensation reaction of benzaldehyde and 2,4,6-trichloro-phenyl-hydrazine. The mol-ecule assumes an E configuration with the phenyl ring and trichloro-phenyl ring located on opposite sides of the C=N bond. The phenyl ring is oriented at a dihedral angle of 42.58 (12) degrees with respect to the tricholorophenyl ring. In the crystal, the mol ecules are linked via N-H?N hydrogen bonds, forming supra-molecular chains running along the c axis. pi-pi stacking is present between parallel trichloro phenyl rings of adjacent mol-ecules, the face-to-face and centroid-centroid distances being 3.369 (14) and 3.724 (2) A, respectively. PMID- 21523177 TI - 4-Oxo-1,4-dihydro-benzo[h][1,3]thia-zeto[3,2-a]quinoline-1,3-dicarb-oxy-lic acid. AB - In the title mol-ecule, C(16)H(9)NO(5)S, there is an intra-molecular O-H?O hydrogen bond involving the quinolone carbonyl O atom and a carboxyl OH group. In the crystal, inter-molecular O-H?O hydrogen bonds between the carbonyl group of the quinolone carboxyl group, and a second carboxyl group on the thia-zeto moiety lead to the formation of chains propagating along [201] and perpendicular to the pi-stacks of mol-ecules. PMID- 21523178 TI - Bis[5-chloro-2-(prop-2-yn-1-yl-oxy)phen-yl]methane. AB - The mol-ecule of the title compound, C(19)H(14)Cl(2)O(2), has two benzene rings connected to a methyl-ene C atom, and the rings are aligned at 66.3 (1) degrees . Inter-molecular C-H?pi and pi-pi stacking inter-actions are observed in the crystal structure, the centroid-centroid distances between parallel benzene rings being 3.7529 (12) and 3.6201 (12) A, respectively. PMID- 21523179 TI - 2,3-Dimeth-oxy-benzaldehyde azine. AB - There are one-and-a-half independent mol-ecules in the asymmetric unit of the title compound, C(18)H(20)N(2)O(4). One mol-ecule is centrosymmetric with the mid point of the N-N bond located on a center of inversion. In the other, which lies on a general position, the benzene rings are aligned at 21.6 (1) degrees . Weak inter-molecular C-H?O hydrogen bonding is present in the crystal strcture. PMID- 21523180 TI - tert-Butyl 2-(4-nitro-phen-oxy)acetate. AB - In the title mol-ecule, C(12)H(15)NO(5), the nitro-phen-oxy portion is approximately planar (r.m.s. deviation = 0.034 A) and makes an angle of 84.8 (1) degrees with respect to the -CH(2)-C(=O)-O-C fragment. In the crystal, pi-pi stacking is observed between nearly parallel benzene rings of adjacent mol ecules, the centroid-centroid distance being 3.6806 (10) A. Weak inter-molecular C-H?O hydrogen bonding is present in the crystal structure. PMID- 21523181 TI - Di-tert-Butyl 2,2'-[2,2'-methyl-enebis(naphthalene-2,1-diyldi-oxy)]diacetate. AB - In the title compound, C(33)H(36)O(6), two naphthalene ring systems are connected through a methyl-ene linkage [C-C-C = 114.9 (2) degrees ]; the ring systems are aligned at an angle of 76.5 (1) degrees . Of the two -O-CH(2)-C(=O)-C(CH(3))(3) substituents, one adopts an extended conformation whereas the other is U-shaped. In the crystal, mol-ecules are linked via weak C-H?O hydrogen bonding, forming supra-molecular chains running along the c axis. PMID- 21523182 TI - 6-Cyclo-hexyl-meth-yl-5-ethyl-2-[(2-oxo-2-phenyl-eth-yl)sulfan-yl]pyrimidin-4(3H) one. AB - In the title compound, C(21)H(26)N(2)O(2)S, the cyclo-hexane ring adopts a chair conformation. The angle at the methyl-ene bridge linking the pyrimidine and cyclo hexane rings is 113.41 (13) degrees . This is in the range considered optimal for maximum activity of non-nucleoside reverse transcriptase inhibitors. In the crystal, mol-ecules are connected into centrosymmetric dimers via pairs of N-H?O hydrogen bonds. PMID- 21523183 TI - Methyl 2-{2-[(E)-(2-hy-droxy-3-meth-oxy-benzyl-idene)amino]-ethyl-amino}-cyclo pentene-1-carbodithio-ate. AB - In the title Schiff base compound, C(17)H(22)N(2)O(2)S(2), which adopts an E configuration with respect to the imine C=N double bond, the C=N and N-C bond distances are 1.2789 (16) and 1.4546 (16) A, respectively. In the mol-ecule there are intra-molecular O-H?N and N-H?S hydrogen bonds, and the CH=N-C substituent is almost coplanar with the benzene ring [C-N-C-C torsion angle = -178.80 (11) degrees ]. The crystal packing is stabilized by inter-molecular C-H?O and C-H?pi inter-actions involving the aromatic ring. PMID- 21523184 TI - 2,2-Dimethyl-N-(2-methyl-phenyl-sulfon-yl)propanamide. AB - In the title compound, C(12)H(17)NO(3)S, the amide H atom is syn to the ortho methyl group of the benzene ring and the C-S-N-C torsion angle is -65.39 (17) degrees . The crystal structure features inversion-related dimers linked by pairs of N-H?O hydrogen bonds in which the acceptor O atom is bound to the S atom. PMID- 21523185 TI - 1-(4-Meth-oxy-phen-yl)-4-(3-nitro-phen-yl)-3-phen-oxy-azetidin-2-one. AB - In the title compound, C(22)H(18)N(2)O(5), the four-membered beta-lactam ring is nearly planar, with a maximum deviation of 0.023 (2) A for the N atom, and has long C-C distances of 1.525 (5) and 1.571 (5) A. The mean plane of this group makes dihedral angles of 11.61 (19), 74.5 (2) and 72.3 (2) degrees with three aromatic rings. An intra-molecular C-H?O hydrogen bond occurs. The packing of the mol-ecules in the crystal structure is governed mainly by inter-molecular C-H?O hydrogen-bonding and C-H?pi stacking inter-actions. Furthermore, a pi-pi inter action [centroid-centroid distance = 3.6129 (19) A] helps to stabilize the crystal structure. PMID- 21523186 TI - 2,4,6-Trifluoro-benzoic acid. AB - In the title compound, C(7)H(3)F(3)O(2), the C-C-C angles in the ring are greater than 120 degrees for F-bonded C atoms [123.69 (13), 123.88 (12) and 123.66 (12) degrees ]. In the crystal, inter-molecular O-H?O hydrogen bonds between carboxyl groups give rise to the formation of a centrosymmetric dimer, while dispersive F?O contacts [2.8849 (16) A] connect the dimers into infinite strands along the a axis. PMID- 21523187 TI - Tropical species of Cladobotryum and Hypomyces producing red pigments. AB - Twelve species of Hypomyces/Cladobotryum producing red pigments are reported growing in various tropical areas of the world. Ten of these are described as new, including teleomorphs for two previously known anamorphic species. In two species the teleomorph has been found in nature and in three others it was obtained in culture; only anamorphs are known for the rest. None of the studied tropical collections belongs to the common temperate species H. rosellus and H. odoratus to which the tropical teleomorphic collections had previously been assigned. Instead, taxa encountered in the tropics are genetically and morphologically distinct from the nine species of Hypomyces/Cladobotryum producing red pigments known from temperate regions. Besides observed host preferences, anamorphs of several species can spread fast on soft ephemeral agaricoid basidiomata but the slower developing teleomorphs are mostly found on polyporoid basidiomata or bark. While a majority of previous records from the tropics involve collections from Central America, this paper also reports the diversity of these fungi in the Paleotropics. Africa appears to hold a variety of taxa as five of the new species include material collected in scattered localities of this mostly unexplored continent. In examining distribution patterns, most of the taxa do not appear to be pantropical. Some species are known only from the Western Hemisphere, while others have a geographic range from southeastern Asia to Africa or Australia. The use of various morphological characters of anamorphs and teleomorphs as well as culture characteristics in species delimitation is evaluated. For detecting genetic segregation, partial sequences of the two largest subunits of the ribosomal polymerase perform the best in terms of providing informative sites and the number of well-supported groups recognised in the phylogenies. These are followed by the sequence data of the translation-elongation factor 1-alpha, while the ribosomal DNA ITS regions are of only limited use in distinguishing species and their phylogenetic relationships. PMID- 21523188 TI - A morphological and phylogenetic revision of the Nectria cinnabarina species complex. AB - The genus Nectria is typified by N. cinnabarina, a wood-inhabiting fungus common in temperate regions of the Northern Hemisphere. To determine the diversity within N. cinnabarina, specimens and cultures from Asia, Europe, and North America were obtained and examined. Their phylogeny was determined using sequences of multiple loci, specifically act, ITS, LSU, rpb1, tef1, and tub. Based on these observations, four species are recognised within the N. cinnabarina complex. Each species is delimited based on DNA sequence analyses and described and illustrated from specimens and cultures. The basionym for N. cinnabarina, Sphaeria cinnabarina, is lectotypified based on an illustration that is part of the protologue, and an epitype specimen is designated. Nectria cinnabarinas. str. is recircumscribed as having 2-septate ascospores and long stipitate sporodochia. Nectria dematiosa, previously considered a synonym of N. cinnabarina, has up to 2-septate ascospores and sessile sporodochia or no anamorph on the natural substrate. A third species, Nectria nigrescens, has up to 3-septate ascospores and short to long stipitate sporodochia. One newly described species, Nectria asiatica with a distribution restricted to Asia, has (0-)1 septate ascospores and short stipitate sporodochia. Young and mature conidia developing on SNA were observed for each species. Mature conidia of N. asiatica, N. cinnabarina, and N. nigrescens but not N. dematiosa bud when the mature conidia are crowded. On PDA the optimal temperature for growth for N. dematiosa is 20 degrees C, while for the other three species it is 25 degrees C. Based on our phylogenetic analyses, three subclades are evident within N. dematiosa. Although subtle culture and geographical differences exist, these subclades are not recognised as distinct species because the number of samples is small and the few specimens are insufficient to determine if morphological differences exist in the natural environment. PMID- 21523189 TI - Delimitation of Neonectria and Cylindrocarpon (Nectriaceae, Hypocreales, Ascomycota) and related genera with Cylindrocarpon-like anamorphs. AB - Neonectria is a cosmopolitan genus and it is, in part, defined by its link to the anamorph genus Cylindrocarpon. Neonectria has been divided into informal groups on the basis of combined morphology of anamorph and teleomorph. Previously, Cylindrocarpon was divided into four groups defined by presence or absence of microconidia and chlamydospores. Molecular phylogenetic analyses have indicated that Neonectriasensu stricto and Cylindrocarponsensu stricto are phylogenetically congeneric. In addition, morphological and molecular data accumulated over several years have indicated that Neonectria sensu lato and Cylindrocarponsensu lato do not form a monophyletic group and that the respective informal groups may represent distinct genera. In the present work, a multilocus analysis (act, ITS, LSU, rpb1, tef1, tub) was applied to representatives of the informal groups to determine their level of phylogenetic support as a first step towards taxonomic revision of Neonectriasensu lato. Results show five distinct highly supported clades that correspond to some extent with the informal Neonectria and Cylindrocarpon groups that are here recognised as genera: (1) N. coccinea-group and Cylindrocarpon groups 1 & 4 (Neonectria/Cylindrocarponsensu stricto); (2) N.rugulosa-group (Rugonectria gen. nov.); (3) N. mammoidea/N. veuillotiana-groups and Cylindrocarpon group 2 (Thelonectria gen. nov.); (4) N. radicicola-group and Cylindrocarpon group 3 (Ilyonectria gen. nov.); and (5) anamorph genus Campylocarpon. Characteristics of the anamorphs and teleomorphs correlate with the five genera, three of which are newly described. New combinations are made for species where their classification is confirmed by phylogenetic data. PMID- 21523190 TI - An overview of the taxonomy, phylogeny, and typification of nectriaceous fungi in Cosmospora, Acremonium, Fusarium, Stilbella, and Volutella. AB - A comprehensive phylogenetic reassessment of the ascomycete genus Cosmospora (Hypocreales, Nectriaceae) is undertaken using fresh isolates and historical strains, sequences of two protein encoding genes, the second largest subunit of RNA polymerase II (rpb2), and a new phylogenetic marker, the larger subunit of ATP citrate lyase (acl1). The result is an extensive revision of taxonomic concepts, typification, and nomenclatural details of many anamorph- and teleomorph-typified genera of the Nectriaceae, most notably Cosmospora and Fusarium. The combined phylogenetic analysis shows that the present concept of Fusarium is not monophyletic and that the genus divides into two large groups, one basal in the family, the other terminal, separated by a large group of species classified in genera such as Calonectria, Neonectria, and Volutella. All accepted genera received high statistical support in the phylogenetic analyses. Preliminary polythetic morphological descriptions are presented for each genus, providing details of perithecia, micro- and/or macro-conidial synanamorphs, cultural characters, and ecological traits. Eight species are included in our restricted concept of Cosmospora, two of which have previously documented teleomorphs and all of which have Acremonium-like microconidial anamorphs. A key is provided to the three anamorphic species recognised in Atractium, which is removed from synonymy with Fusarium and epitypified for two macroconidial synnematous species and one sporodochial species associated with waterlogged wood. Dialonectria is recognised as distinct from Cosmospora and two species with teleomorph, macroconidia and microconidia are accepted, including the new species D. ullevolea. Seven species, one with a known teleomorph, are classified in Fusicolla, formerly considered a synonym of Fusarium including members of the F. aquaeductuum and F. merismoides species complex, with several former varieties raised to species rank. Originally a section of Nectria, Macroconia is raised to generic rank for five species, all producing a teleomorph and macroconidial anamorph. A new species of the Verticillium-like anamorphic genus Mariannaea is described as M. samuelsii. Microcera is recognised as distinct from Fusarium and a key is included for four macroconidial species, that are usually parasites of scale insects, two of them with teleomorphs. The four accepted species of Stylonectria each produce a teleomorph and micro- and macroconidial synanamorphs. The Volutella species sampled fall into three clades. Pseudonectria is accepted for a perithecial and sporodochial species that occurs on Buxus. Volutella s. str. also includes perithecial and/or sporodochial species and is revised to include a synnematous species formerly included in Stilbella. The third Volutella like clade remains unnamed. All fungi in this paper are named using a single name system that gives priority to the oldest generic names and species epithets, irrespective of whether they are originally based on anamorph or teleomorph structures. The rationale behind this is discussed. PMID- 21523191 TI - A revision of Cyanonectria and Geejayessia gen. nov., and related species with Fusarium-like anamorphs. AB - A revision of Fusarium-like species associated with the plant genus Buxus led to a reconsideration of generic concepts in the Fusarium clade of the Nectriaceae. Phylogenetic analyses of the partial second largest subunit of the RNA polymerase II (rpb2) and the larger subunit of the ATP citrate lyase (acl1) gene exons confirm the existence of a clade, here called the terminal Fusarium clade, that includes genera such as Fusariumsensu stricto (including its Gibberella teleomorphs), Albonectria, Cyanonectria, "Haematonectria", the newly described genus Geejayessia, and "Nectria" albida. Geejayessia accommodates five species. Four were previously classified in Nectria sensu lato, namely the black perithecial, KOH-species G. atrofusca and the orange or reddish, KOH+ G. cicatricum, G. desmazieri and G. zealandica.Geejayessia celtidicola is newly described. Following our phylogenetic analyses showing its close relationship with Cyanonectria cyanostoma, the former Gibbera buxi is recombined as the second species of Cyanonectria. A three gene phylogenetic analysis of multiple strains of each morphological species using translation elongation factor 1 alpha (tef 1), rpb2 and acl1 gene exons and introns confirms their status as distinct phylogenetic species. Internal transcribed spacer of the ribosomal RNA gene cluster and nuclear large ribosomal subunit sequences were generated as additional DNA barcodes for selected strains. The connection of Fusarium buxicola, often erroneously reported as the anamorph of G. desmazieri, with the bluish black and KOH+ perithecial species C. buxi is reinstated. Most Cyanonectria and Geejayessia species exhibit restricted host ranges on branches or twigs of Buxus species, Celtisoccidentalis, or Staphyleatrifolia. Their perithecia form caespitose clusters on well-developed, mostly erumpent stromata on the bark or outer cortex of the host and are relatively thin-walled, mostly smooth, and therefore reminiscent of the more or less astromatous, singly occurring perithecia of Cosmospora, Dialonectria, and Microcera. The cell walls in outer- and inner layers of the perithecial walls of Cyanonectria and Geejayessia have inconspicuous pore-like structures, as do representative species of Albonectria, Fusarium sensu stricto, "Haematonectria", and "Nectria" albida. The taxonomic significance of these structures, which we call Samuels' pores, is discussed. PMID- 21523192 TI - Acremonium phylogenetic overview and revision of Gliomastix, Sarocladium, and Trichothecium. AB - Over 200 new sequences are generated for members of the genus Acremonium and related taxa including ribosomal small subunit sequences (SSU) for phylogenetic analysis and large subunit (LSU) sequences for phylogeny and DNA-based identification. Phylogenetic analysis reveals that within the Hypocreales, there are two major clusters containing multiple Acremonium species. One clade contains Acremonium sclerotigenum, the genus Emericellopsis, and the genus Geosmithia as prominent elements. The second clade contains the genera Gliomastixsensu stricto and Bionectria. In addition, there are numerous smaller clades plus two multi species clades, one containing Acremonium strictum and the type species of the genus Sarocladium, and, as seen in the combined SSU/LSU analysis, one associated subclade containing Acremonium breve and related species plus Acremonium curvulum and related species. This sequence information allows the revision of three genera. Gliomastix is revived for five species, G. murorum, G. polychroma, G. tumulicola, G. roseogrisea, and G. masseei. Sarocladium is extended to include all members of the phylogenetically distinct A. strictum clade including the medically important A. kiliense and the protective maize endophyte A. zeae. Also included in Sarocladium are members of the phylogenetically delimited Acremonium bacillisporum clade, closely linked to the A. strictum clade. The genus Trichothecium is revised following the principles of unitary nomenclature based on the oldest valid anamorph or teleomorph name, and new combinations are made in Trichothecium for the tightly interrelated Acremonium crotocinigenum, Spicellum roseum, and teleomorph Leucosphaerinaindica. Outside the Hypocreales, numerous Acremonium-like species fall into the Plectosphaerellaceae, and A. atrogriseum falls into the Cephalothecaceae. PMID- 21523193 TI - Monilochaetes and allied genera of the Glomerellales, and a reconsideration of families in the Microascales. AB - We examined the phylogenetic relationships of two species that mimic Chaetosphaeria in teleomorph and anamorph morphologies, Chaetosphaeriatulasneorum with a Cylindrotrichum anamorph and Australiasca queenslandica with a Dischloridium anamorph. Four data sets were analysed: a) the internal transcribed spacer region including ITS1, 5.8S rDNA and ITS2 (ITS), b) nc28S (ncLSU) rDNA, c) nc18S (ncSSU) rDNA, and d) a combined data set of ncLSU-ncSSU-RPB2 (ribosomal polymerase B2). The traditional placement of Ch. tulasneorum in the Microascales based on ncLSU sequences is unsupported and Australiasca does not belong to the Chaetosphaeriaceae. Both holomorph species are nested within the Glomerellales. A new genus, Reticulascus, is introduced for Ch. tulasneorum with associated Cylindrotrichum anamorph; another species of Reticulascus and its anamorph in Cylindrotrichum are described as new. The taxonomic structure of the Glomerellales is clarified and the name is validly published. As delimited here, it includes three families, the Glomerellaceae and the newly described Australiascaceae and Reticulascaceae. Based on ITS and ncLSU rDNA sequence analyses, we confirm the synonymy of the anamorph genera Dischloridium with Monilochaetes. Consequently Dischloridium laeense, type species of the genus, and three related species are transferred to the older genus Monilochaetes. The teleomorph of D. laeense is described in Australiasca as a new species. The Plectosphaerellaceae, to which the anamorph genus Stachylidium is added, is basal to the Glomerellales in the three-gene phylogeny. Stilbella annulata also belongs to this family and is newly combined in Acrostalagmus. Phylogenetic analyses based on ncLSU, ncSSU, and combined ncLSU-ncSSU-RPB2 sequences clarify family relationships within the Microascales. The family Ceratocystidaceae is validated as a strongly supported monophyletic group consisting of Ceratocystis, Cornuvesica, Thielaviopsis, and the type species of Ambrosiella. The new family Gondwanamycetaceae, a strongly supported sister clade to the Ceratocystidaceae, is introduced for the teleomorph genus Gondwanamyces and its Custingophora anamorphs. Four families are accepted in the Microascales, namely the Ceratocystidaceae, Gondwanamycetaceae, Halosphaeriaceae, and Microascaceae. Because of a suggested affinity of a Faurelina indica isolate to the Microascales, the phylogenetic position of the Chadefaudiellaceae is reevaluated. Based on the results from a separate ncLSU analysis of the Dothideomycetes, Faurelina is excluded from the Microascales and placed in the Pleosporales. PMID- 21523194 TI - Discovery of the teleomorph of the hyphomycete, Sterigmatobotrys macrocarpa, and epitypification of the genus to holomorphic status. AB - Sterigmatobotrys macrocarpa is a conspicuous, lignicolous, dematiaceous hyphomycete with macronematous, penicillate conidiophores with branches or metulae arising from the apex of the stipe, terminating with cylindrical, elongated conidiogenous cells producing conidia in a holoblastic manner. The discovery of its teleomorph is documented here based on perithecial ascomata associated with fertile conidiophores of S. macrocarpa on a specimen collected in the Czech Republic; an identical anamorph developed from ascospores isolated in axenic culture. The teleomorph is morphologically similar to species of the genera Carpoligna and Chaetosphaeria, especially in its nonstromatic perithecia, hyaline, cylindrical to fusiform ascospores, unitunicate asci with a distinct apical annulus, and tapering paraphyses. Identical perithecia were later observed on a herbarium specimen of S. macrocarpa originating in New Zealand. Sterigmatobotrys includes two species, S. macrocarpa, a taxonomic synonym of the type species, S. elata, and S. uniseptata. Because no teleomorph was described in the protologue of Sterigmatobotrys, we apply Article 59.7 of the International Code of Botanical Nomenclature. We epitypify (teleotypify) both Sterigmatobotrys elata and S. macrocarpa to give the genus holomorphic status, and the name S. macrocarpa is adopted for the holomorph. To evaluate the ordinal and familial affinities of Sterigmatobotrys and its relationships with the morphologically similar genera Carpoligna and Chaetosphaeria, phylogenetic relationships were inferred based on aligned sequences of the large subunit nuclear ribosomal DNA (ncLSU rDNA). PMID- 21523195 TI - A molecular re-appraisal of taxa in the Sordariomycetidae and a new species of Rimaconus from New Zealand. AB - Several taxa that share similar ascomatal and ascospore characters occur in monotypic or small genera throughout the Sordariomycetidae with uncertain relationships based on their morphology. Taxa in the genera Duradens, Leptosporella, Linocarpon, and Rimaconus share similar morphologies of conical ascomata, carbonised peridia and elongate ascospores, while taxa in the genera Caudatispora, Erythromada and Lasiosphaeriella possess clusters of superficial, obovoid ascomata with variable ascospores. Phylogenetic analyses of 28S large subunit nrDNA sequences were used to test the monophyly of these genera and provide estimates of their relationships within the Sordariomycetidae. Rimaconus coronatus is described as a new species from New Zealand; it clusters with the type species, R. jamaicensis. Leptosporella gregaria is illustrated and a description is provided for this previously published taxon that is the type species and only sequenced representative of the genus. Both of these genera occur in separate, well-supported clades among taxa that form unsupported groups near the Chaetosphaeriales and Helminthosphaeriaceae. Lasiosphaeriella and Linocarpon appear to be polyphyletic with species occurring in several clades throughout the subclass. Caudatispora and Erythromada represented by single specimens and two putative Duradens spp. have unclear affinities in the Sordariomycetidae. PMID- 21523196 TI - A systematic account of the genus Plagiostoma (Gnomoniaceae, Diaporthales) based on morphology, host-associations, and a four-gene phylogeny. AB - Members of the genus Plagiostoma inhabit leaves, stems, twigs, and branches of woody and herbaceous plants predominantly in the temperate Northern Hemisphere. An account of all known species of Plagiostoma including Cryptodiaporthe is presented based on analyses of morphological, cultural, and DNA sequence data. Multigene phylogenetic analyses of DNA sequences from four genes (beta-tubulin, ITS, rpb2, and tef1-alpha) revealed eight previously undescribed phylogenetic species and an association between a clade composed of 11 species of Plagiostoma and the host family Salicaceae. In this paper these eight new species of Plagiostoma are described, four species are redescribed, and four new combinations are proposed. A key to the 25 accepted species of Plagiostoma based on host, shape, and size of perithecia, perithecial arrangement in the host, and microscopic characteristics of the asci and ascospores is provided. Disposition of additional names in Cryptodiaporthe and Plagiostoma is also discussed. PMID- 21523197 TI - Two new pathogenic ascomycetes in Guignardia and Rosenscheldiella on New Zealand's pygmy mistletoes (Korthalsella: Viscaceae). AB - Two new pathogens, Guignardia korthalsellae and Rosenscheldiella korthalsellae, are described from New Zealand's pygmy mistletoes (Korthalsella, Viscaceae). Both form ascomata on living phylloclades with minimal disruption of the tissue. Fungal hyphae within the phylloclade are primarily intercellular. Guignardia korthalsellae disrupts a limited number of epidermal cells immediately around the erumpent ascoma, while the ascomata of Rosenscheldiellakorthalsellae develop externally on small patches of stromatic tissue that form above stomatal cavities. Rosenscheldiella is applied in a purely morphological sense. LSU sequences show that R. korthalsellae as well as another New Zealand species, Rosenscheldiella brachyglottidis, are members of the Mycosphaerellaceaesensu stricto. Genetically, Rosenscheldiella, in the sense we are using it, is polyphyletic; LSU and ITS sequences place the two New Zealand species in different clades within the Mycosphaerellaceae. Rosenscheldiella is retained for these fungi until generic relationships within the family are resolved. Whether or not the type species of Rosenscheldiella, R. styracis, is also a member of the Mycosphaerellaceae is not known, but it has a similar morphology and relationship to its host as the two New Zealand species. PMID- 21523198 TI - Compression syndrome as a complication of percutaneous coronary intervention. AB - Coronary artery perforation is a rare complication of percutaneous coronary intervention with potentially fatal consequences. A case of perforation occurring during percutaneous coronary intervention to a saphenous vein graft, complicated by the subsequent development of a compressive right atrial hematoma, is reported. The management of the case is described, and similar case reports in the literature are reviewed. The role of imaging in making the initial diagnosis and formulating an appropriate management strategy is emphasized. PMID- 21523199 TI - Experimental & Clinical Cardiology: A rebirth. PMID- 21523200 TI - Efficacy of Pt-modified TiO(2) nanoparticles in cardiac cells. AB - BACKGROUND: The application of TiO(2) nanoparticles promises to revolutionize cardiac imaging and targeted medical treatment. METHODS: A novel type of platinum modified TiO(2) (Pt-TiO(2)) nanoparticle was synthesized and characterized. Commercially available P25 TiO(2) nanoparticles were used for comparison. Cellular toxicity and its mechanisms were evaluated by analyzing nanoparticle uptake, oxidative stress and mitochondrial membrane potential in rat cardiac (H9c2) cells. RESULTS: There was greater cellular uptake of Pt-TiO(2). Furthermore, Pt-TiO(2) caused a greater increase in oxidative stress and greater decrease in mitochondrial membrane potential. These data suggest that Pt modification of TiO(2) nanoparticles rendered them more cytotoxic than their commercial counterparts at lower, more physiologically relevant concentrations. CONCLUSION: Despite the functional advantages of Pt modification, which results in increased uptake at a lower concentration, the corresponding increase in cardiotoxic effect indicates that a thoughtful, cautious approach to cardiac nanotechnologies is required. PMID- 21523201 TI - Abdominal aortic aneurysm: A comprehensive review. AB - An arterial aneurysm is defined as a focal dilation of a blood vessel with respect to the original artery. The risk of abdominal aortic aneurysms (AAAs) increases dramatically in the presence of the following factors: age older than 60 years, smoking, hypertension and Caucasian ethnicity. The likelihood that an aneurysm will rupture is influenced by the aneurysm size, expansion rate, continued smoking and persistent hypertension. The majority of AAAs are asymptomatic and are detected as an incidental finding on ultrasonography, abdominal computed tomography or magnetic resonance imaging performed for other purposes. It can also present with abdominal pain or complications such as thrombosis, embolization and rupture. Approximately 30% of asymptomatic AAAs are discovered as a pulsatile abdominal mass on routine physical examination. Abdominal ultrasonography is considered the screening modality of choice for detecting AAAs because of its high sensitivity and specificity, as well as its safety and relatively lower cost. The decision to screen for AAAs is challenging. The United States Preventive Services Task Force recommended that men between the age of 65 to 75 years who have ever smoked should be screened at least once for AAAs by abdominal ultrasonography. Management options for patients with an asymptomatic AAA include reduction of risk factors such as smoking, hypertension and dyslipidemia; medical therapy with beta-blockers; watchful waiting; endovascular stenting; and surgical repair depending on the size and expansion rate of the aneurysm and underlying comorbidities. PMID- 21523203 TI - New generation of transvenous left ventricular leads - first experience with implantation of multipolar left ventricular leads. AB - BACKGROUND: Aside from unfavourable anatomy, inacceptable pacing thresholds and phrenic nerve stimulation represent major obstacles for successful left ventricular (LV) lead placement for cardiac resynchronization therapy (CRT). OBJECTIVE: To implant, for the first time, a new generation of transvenous multipolar LV leads (a quad-electrode lead) in combination with a CRT cardioverter defibrillator, and to demonstrate that this combination allows for 10 different pacing vectors to combat the problems cited above. METHODS: Thirty patients were selected for CRT-cardioverter defibrillator implantation. At implantation, standard lead parameters were recorded. The reason for choosing a vector other than the standard bipolar vector for LV pacing, the LV lead implantation time, x-ray exposure time required for lead placement, and the reason for and number of repositions were documented. Before hospital discharge, a system inspection was performed. RESULTS: The implantation lead parameters were satisfactory. In 17 patients, a vector other than the standard bipolar vector was chosen to avoid phrenic nerve stimulation or to establish a better pacing threshold. In seven cases, the LV lead was repositioned (three phrenic nerve stimulations, two inacceptable pacing captures and two nonstable lead positions). Phrenic nerve stimulation was noted in eight cases; however, in five, this was eliminated by changing the stimulation vector. At hospital discharge, two-thirds of patients retained the implantation stimulation vector and in one-third, the vector was modified to further optimize the system. CONCLUSIONS: The quad electrode lead provides good handling and may reduce the risk of inacceptable pacing thresholds and phrenic nerve stimulation. Consequently, implantation time, x-ray exposure and contrast agent load may be decreased, leading to lower kidney stress. Furthermore, the option for vector change after implantation may reduce the number of necessary reinterventions resulting from the pacing threshold and impedance increase. PMID- 21523204 TI - A patient with multiple vascular atherosclerotic distributions. AB - The present report describes a patient who experienced unstable angina late after coronary artery bypass surgery, in which the left internal mammary artery was grafted to the left anterior descending artery. Catheterization revealed the culprit, which was left main stem obstructive disease, a significant proximal left subclavian artery (SCA) lesion and a large abdominal aortic aneurysm. The latter lesions were not suspected or revealed before catheterization. Combined surgical management was recommended; however, the patient died following recurrent angina that was complicated with pulmonary edema and cardiac arrest. Patients with severe coronary artery disease are at high risk of having multiple vascular atherosclerotic distributions including SCA stenosis and abdominal aortic aneurysm. Recurrent angina after left internal mammary artery grafting should always raise the suspicion of a left SCA stenosis causing coronary subclavian steal. Such patients should undergo a comprehensive cardiovascular evaluation to reveal the extent of atherosclerotic disease. Such an approach affects decision making in the catheterization laboratory and aids in choosing the safest and most effective treatment for the individual patient. PMID- 21523202 TI - Coronary revascularization in diabetic patients: Current state of evidence. AB - Although diabetic patients constitute an increasing number of individuals undergoing percutaneous coronary intervention (PCI) and surgical revascularization, they experience worse outcomes than nondiabetic patients. The optimal coronary revascularization strategy in the diabetic population remains unclear in view of advancements in pharmacotherapy and technology of both PCI and surgical revascularization. Data to guide decision making are limited regarding the current choice between coronary artery bypass graft surgery and PCI using drug-eluting stents and newer antiplatelet agents in diabetic patients with multivessel coronary artery disease. The present article summarizes the current state of evidence for coronary revascularization in the diabetic population. PMID- 21523205 TI - Stress-induced cardiomyopathy associated with a transfusion reaction: A case of potential crosstalk between the histaminic and adrenergic systems. AB - The adrenergic and histaminergic systems have been reported to have analogous effects on the heart. A case of transient ventricular dysfunction with echocardiographic findings characteristic of stress-induced cardiomyopathy (also known as takotsubo cardiomyopathy) in a patient who had an urticarial transfusion reaction is described. The effect of histamine on ventricular function and its interaction with the adrenergic system are discussed. PMID- 21523206 TI - A member of the peptidase M48 superfamily of Porphyromonas gingivalis is associated with virulence in vitro and in vivo. AB - BACKGROUND: In vivo-induced antigen technology was previously used to identify 115 genes induced in Porphyromonas gingivalis W83 during human infection. One of these, PG2197, a conserved hypothetical protein which has homology to a Zn dependent protease, was examined with respect to a role in disease. DESIGN: The expression of PG2197 in human periodontitis patients was investigated, but as there is increasing evidence of a direct relationship between P. gingivalis and cardiovascular disease, a mutation was constructed in this gene to also determine its role in adherence, invasion, and persistence within human coronary artery endothelial cells (HCAEC) and neutrophil killing susceptibility. RESULTS: Plaque samples from 20 periodontitis patients were analyzed by real-time PCR, revealing that PG2197 was expressed in 60.0% of diseased sites compared to 15.8% of healthy sites, even though P. gingivalis was detected in equal numbers from both sites. The expression of this gene was also found to be up-regulated in microarrays at 5 and 30 min of invasion of HCAEC. Interestingly, a PG2197 mutant displayed increased adherence, invasion, and persistence within HCAEC when compared to the wild-type strain. CONCLUSION: This gene appears to be important for the virulence of P. gingivalis, both in vivo and in vitro. PMID- 21523207 TI - Phylogenetic analyses and detection of viridans streptococci based on sequences and denaturing gradient gel electrophoresis of the rod shape-determining protein gene. AB - BACKGROUND: Population analysis of viridans streptococci is important because these species are associated with dental caries, bacteremia, and subacute endocarditis, in addition to being important members of the human oral commensal microbiota. DESIGN: In this study, we phylogenetically analyzed the rod shape determining protein gene (rodA), which is associated with cellular morphology, cell division, and sensitivity for antibiotics, and demonstrated that the diversity of the rodA gene is sufficient to identify viridans streptococci at the species level. Moreover, we developed a more convenient denaturing gradient gel electrophoresis (DGGE) method based on the diversity of the rodA gene (rodA-DGGE) for detecting nine dominant streptococcal species in human saliva, namely, Streptococcus sanguinis, Streptococcus oralis, Streptococcus mitis, Streptococcus parasanguinis, Streptococcus gordonii, Streptococcus vestibularis, Streptococcus salivarius, Streptococcus mutans, and Streptococcus sobrinus. RESULTS: This rodA DGGE method proved useful in detecting viridans streptococci without cultivation, isolation, and phenotypic characterization. CONCLUSION: Analysis of the oral microbiota by rodA-DGGE offers a higher resolution than the conventional DGGE using 16S rDNA and may be an alternative in the microbial diagnosis of streptococcal infection. PMID- 21523209 TI - Genetic relatedness of subgingival and buccal Candida dubliniensis isolates in immunocompetent subjects assessed by RAPD-PCR. AB - BACKGROUND: It is recognized that Candida dubliniensis commonly colonizes oral and subgingival sites in immunocompetent subjects with periodontal disease. OBJECTIVE: Since there are few data available on genetic characterization of C. dubliniensis in periodontal pockets and other oral sites, the aim of this study was to characterize subgingival and mucosal C. dubliniensis isolates recovered from immunocompetent subjects and to assay the genetic similarity of such isolates from both niches in the same patient by random amplified polymorphic DNA (RAPD). DESIGN: C. dubliniensis recovered from subgingival plaque and from buccal cavity samples were studied in 240 immunocompetent non-smoking individuals. Arbitrary amplification was carried out by RAPD-polymerase chain reaction (PCR). RESULTS: RAPD analysis showed identical genotypes of C. dubliniensis in different sampling sites (buccal cavity and subgingival areas) in eight of 10 patients except for those derived from two participants who presented presumably unrelated isolates. CONCLUSIONS: On the basis of the findings presented, the origin of the colonization of C. dubliniensis in subgingival biofilm seems to be the buccal cavity in a single patient. Consequently, it may be assumed that most of C. dubliniensis in these sites arise from the endogenous commensal strains. PMID- 21523208 TI - Distinctive features of the microbiota associated with different forms of apical periodontitis. AB - Microorganisms infecting the dental root canal system play an unequivocal role as causative agents of apical periodontitis. Although fungi, archaea, and viruses have been found in association with some forms of apical periodontitis, bacteria are the main microbial etiologic agents of this disease. Bacteria colonizing the root canal are usually organized in communities similar to biofilm structures. Culture and molecular biology technologies have demonstrated that the endodontic bacterial communities vary in species richness and abundance depending on the different types of infection and different forms of apical periodontitis. This review paper highlights the distinctive features of the endodontic microbiota associated with diverse clinical conditions. PMID- 21523210 TI - The thrombotic potential of oral pathogens. AB - In recent times the concept of infectious agents playing a role in cardiovascular disease has attracted much attention. Chronic oral disease such as periodontitis, provides a plausible route for entry of bacteria to the circulation. Upon entry to the circulation, the oral bacteria interact with platelets. It has been proposed that their ability to induce platelet aggregation and support platelet adhesion is a critical step in the pathogenesis of the infection process. Many published studies have demonstrated multiple mechanisms through which oral bacteria are able to bind to and activate platelets. This paper will review the various mechanisms oral bacteria use to interact with platelets. PMID- 21523211 TI - Tracking of plasma antibodies against Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis during 15 years. AB - BACKGROUND: Plasma antibody measurements of antibody levels to periodontal pathogens may be used to support diagnosis, disease activity, classification, and prognosis of periodontitis. OBJECTIVE: The aim of this study was to investigate the long-term stability of plasma antibody levels against Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. DESIGN: Plasma immunoglobulin G (IgG) antibody levels against the pathogens were analyzed annually during 15 years from 21 voluntary subjects, whose periodontal status was not known at the point of selection. The total number of plasma samples was 315. In connection of the last sampling, the clinical and radiographic periodontal status was examined. Pooled bacterial samples from periodontal pockets, as well as salivary samples were collected for A. actinomycetemcomitans and P. gingivalis detection, and antibody determinations, respectively. According to the clinical status, six subjects had periodontitis, whereas 15 did not. RESULTS: Plasma IgG-class antibody levels to periodontal pathogens remained extremely stable during the 15 year period and no significant (p>0.05) intra-individual variations were observed. Retrospectively, the average plasma IgG antibody levels against A. actinomycetemcomitans and P. gingivalis were 1.6-2.3 (p<0.05) and 1.4-1.7 (p<0.05) fold higher in the subjects with periodontitis than those without, respectively, during the whole 15-year tracking. As expected, at the time of the periodontal examination the plasma and salivary IgG antibody levels were associated both with periodontitis and bacterium-positivity. CONCLUSIONS: Plasma IgG levels against A. actinomycetemcomitans and P. gingivalis are extremely stable during 15 years both in subjects with and without periodontitis. PMID- 21523214 TI - Open access to oral microbiology. PMID- 21523213 TI - Bacterial diversity in persistent periapical lesions on root-filled teeth. AB - BACKGROUND: The purpose of this study was to analyze the bacterial diversity in persistent apical lesions on root-filled teeth by using culture-independent molecular methods. DESIGN: Twenty surgically removed apical lesions from therapy resistant teeth were examined for the presence of bacterial DNA using PCR targeting the 16s ribosomal RNA gene, followed by cloning and sequencing. RESULTS: Bacterial DNA was detected in 17 of the 20 samples (85%). A total of 236 clones were analyzed. Seven different bacterial phyla were represented and a total of 75 different bacterial taxa were identified; 36% of the species have not yet been cultivated. Commonly detected bacterial species included Fusobacterium spp., Prevotella spp., Tannerella forsythia, Porphyromonas endodontalis, Treponema denticola, Bacteroidetes spp., Peptostreptococcus spp., and Streptococcus spp. CONCLUSIONS: A wide range of bacteria was identified in periapical lesions on therapy-resistant teeth. These bacteria may contribute in the etiology of periapical infection and impede healing of these lesions. PMID- 21523212 TI - Prospects for the development of probiotics and prebiotics for oral applications. AB - There has been a paradigm shift towards an ecological and microbial community based approach to understanding oral diseases. This has significant implications for approaches to therapy and has raised the possibility of developing novel strategies through manipulation of the resident oral microbiota and modulation of host immune responses. The increased popularity of using probiotic bacteria and/or prebiotic supplements to improve gastrointestinal health has prompted interest in the utility of this approach for oral applications. Evidence now suggests that probiotics may function not only by direct inhibition of, or enhanced competition with, pathogenic micro-organisms, but also by more subtle mechanisms including modulation of the mucosal immune system. Similarly, prebiotics could promote the growth of beneficial micro-organisms that comprise part of the resident microbiota. The evidence for the use of pro or prebiotics for the prevention of caries or periodontal diseases is reviewed, and issues that could arise from their use, as well as questions that still need to be answered, are raised. A complete understanding of the broad ecological changes induced in the mouth by probiotics or prebiotics will be essential to assess their long-term consequences for oral health and disease. PMID- 21523215 TI - Diabetes, periodontitis, and the subgingival microbiota. AB - Both type 1 and type 2 diabetes have been associated with increased severity of periodontal disease for many years. More recently, the impact of periodontal disease on glycaemic control has been investigated. The role of the oral microbiota in this two-way relationship is at this stage unknown. Further studies, of a longitudinal nature and investigating a wider array of bacterial species, are required in order to conclusively determine if there is a difference in the oral microbiota of diabetics and non-diabetics and whether this difference accounts, on the one hand, for the increased severity of periodontal disease and on the other for the poorer glycaemic control seen in diabetics. PMID- 21523216 TI - Respiratory disease and the role of oral bacteria. AB - The relationship between oral health and systemic conditions, including the association between poor oral hygiene, periodontal disease, and respiratory disease, has been increasingly debated over recent decades. A considerable number of hypotheses have sought to explain the possible role of oral bacteria in the pathogenesis of respiratory diseases, and some clinical and epidemiological studies have found results favoring such an association. This review discusses the effect of oral bacteria on respiratory disease, briefly introduces the putative biological mechanisms involved, and the main factors that could contribute to this relationship. It also describes the role of oral care for individuals who are vulnerable to respiratory infections. PMID- 21523217 TI - Rheumatoid arthritis and the role of oral bacteria. AB - Rheumatoid arthritis (RA) and periodontal disease (PD) have shown similar physiopathologic mechanisms such as chronic inflammation with adjacent bone resorption in an immunogenetically susceptible host; however, PD has a well recognized bacterial etiology while the cause of RA is unclear. Some reports have indicated that an infectious agent in a susceptible host could be one possible trigger factor for RA, and it has been suggested that oral microorganisms, specialty periodontal bacteria could be the infectious agent (mainly Porphyromonas gingivalis). It has been reported that PD is more frequent and more severe in patients with RA, suggesting a positive association between both diseases. There have been reports regarding the detection of antibodies against periodontal bacteria while other studies have identified periodontal bacterial DNA in serum and synovial fluid of RA patients and have explored the possible pathways of transport of periodontal bacterial DNA. In conclusion, there is no question that RA and PD have pathologic features in common and there is strong evidence of an association between both diseases, but further studies, including experimental models, are needed to demonstrate the arthritogenicity of oral microorganisms. PMID- 21523218 TI - General health screening as part of a periodontal examination. AB - Cardiovascular disease (CVD) and type 2 diabetes are common systemic illnesses with reliable, predictive risk factors. CVD is the number one killer worldwide accounting for nearly 30% of deaths and type 2 diabetes has reached epidemic proportions in many western industrialized countries. Both of these illnesses can go undiagnosed in an alarming number of people for significant periods of time. The relationship between oral health and systemic health has become the focus of much discussion and research in recent times. It is now widely accepted that periodontal disease is associated with systemic illnesses such as CVD and type 2 diabetes. Cigarette smoking and obesity are major risk factors accounting for a large portion of the global disease burden. Many periodontal patients may be at risk of systemic conditions but be asymptomatic and undiagnosed. With an aging population who are mostly retaining their natural dentition, the need for periodontal management will continue to rise in the future. Dental professionals are well placed to perform general health screening for their patients. Therefore, risk assessment during the periodontal examination may facilitate the early identification of the large proportion of people who are unaware of their risk status. As identification and intervention of patients with increased risk factors is key to lowering the systemic disease burden, general health screening during periodontal examinations may present an important opportunity for many patients. PMID- 21523219 TI - Porphyromonas gingivalis-dendritic cell interactions: consequences for coronary artery disease. AB - An estimated 80 million US adults have one or more types of cardiovascular diseases. Atherosclerosis is the single most important contributor to cardiovascular diseases; however, only 50% of atherosclerosis patients have currently identified risk factors. Chronic periodontitis, a common inflammatory disease, is linked to an increased cardiovascular risk. Dendritic cells (DCs) are potent antigen presenting cells that infiltrate arterial walls and may destabilize atherosclerotic plaques in cardiovascular disease. While the source of these DCs in atherosclerotic plaques is presently unclear, we propose that dermal DCs from peripheral inflamed sites such as CP tissues are a potential source. This review will examine the role of the opportunistic oral pathogen Porphyromonas gingivalis in invading DCs and stimulating their mobilization and misdirection through the bloodstream. Based on our published observations, combined with some new data, as well as a focused review of the literature we will propose a model for how P. gingivalis may exploit DCs to gain access to systemic circulation and contribute to coronary artery disease. Our published evidence supports a significant role for P. gingivalis in subverting normal DC function, promoting a semimature, highly migratory, and immunosuppressive DC phenotype that contributes to the inflammatory development of atherosclerosis and, eventually, plaque rupture. PMID- 21523221 TI - Revisiting the association between candidal infection and carcinoma, particularly oral squamous cell carcinoma. AB - BACKGROUND: Tobacco and alcohol are risk factors associated with cancer of the upper aerodigestive tract, but increasingly the role of infection and chronic inflammation is recognized as being significant in cancer development. Bacteria, particularly Helicobacter pylori, and viruses such as members of the human papilloma virus family and hepatitis B and C are strongly implicated as etiological factors in certain cancers. There is less evidence for an association between fungi and cancer, although it has been recognized for many years that white patches on the oral mucosa, which are infected with Candida, have a greater likelihood of undergoing malignant transformation than those that are not infected. OBJECTIVE: This article reviews the association between the development of oral squamous cell carcinoma in potentially malignant oral lesions with chronic candidal infection and describes mechanisms that may be involved in Candida-associated malignant transformation. PMID- 21523220 TI - Cardiovascular disease and the role of oral bacteria. AB - In terms of the pathogenesis of cardiovascular disease (CVD) the focus has traditionally been on dyslipidemia. Over the decades our understanding of the pathogenesis of CVD has increased, and infections, including those caused by oral bacteria, are more likely involved in CVD progression than previously thought. While many studies have now shown an association between periodontal disease and CVD, the mechanisms underpinning this relationship remain unclear. This review gives a brief overview of the host-bacterial interactions in periodontal disease and virulence factors of oral bacteria before discussing the proposed mechanisms by which oral bacterial may facilitate the progression of CVD. PMID- 21523223 TI - Note from the Editor-in-Chief. PMID- 21523222 TI - Preterm low birthweight and the role of oral bacteria. AB - Preterm and low birthweight (PTLBW) continues to be a major cause of mortality and morbidity across the world. In recent years, maternal periodontal disease has been implicated as a risk factor for adverse pregnancy outcomes. There is conflicting evidence to support such an outcome as illustrated by descriptive, case control and randomised controlled trials involving pregnant women from across the world, using different measurement tools to determine the level of periodontal disease. Whilst considering the literature, there is evidence for both arguments, based on the effect of periodontal inflammatory by products. Bacteria associated with periodontal disease are not dissimilar to those known to be associated with genito-urinary bacterial infections and adverse pregnancy outcomes. Several groups have demonstrated the apparent translocation of Fusobacterium nucleatum, Prevotella nigrescens, Prevotella intermedia, Porphyromonus gingivalis, Treponema denticola to the foetal placental unit whereby a maternal or foetal response has been detected resulting in premature birth or low birthweight. The normal process of parturition involves a cascade of events including a build-up of inflammatory mediators as linked to inflammation, whereby the maternal environment becomes hostile and threatens the well-being of the infant, and the foetus expelled. The question remains therefore, is there a greater risk of delivering a PTLBW infant when the mother has detectable periodontal disease, or is the release of inflammatory mediators and their translocation via the haematogenous route sufficient to induce a poor pregnancy outcome? The data investigated would suggest that there is a positive outcome when certain oral gram-negative bacteria create a cumulative effect sufficient to trigger early delivery, which represents the final straw to result in preterm or low birthweight delivery. There is equally sufficient epidemiological evidence that does not support this outcome, but it is agreed that maintaining oral health during pregnancy is beneficial to the mother and her infant. PMID- 21523225 TI - Effect of the probiotic Lactobacilli reuteri (Prodentis) in the management of periodontal disease: a preliminary randomized clinical trial. AB - OBJECTIVES: The aim of this study was to evaluate the effects of Lactobacilli reuteri (Prodentis) alone and in combination with scaling and root planing (SRP) in a double blind, randomized, placebo-controlled clinical trial of volunteers with chronic periodontitis. METHODS: Thirty, otherwise systemically healthy, chronic periodontitis patients (19 males and 11 females, aged between 34 and 50 years) were included. The study period was 42 days. 'Split-mouth' design was used for the SRP, which was performed on day 0; two quadrants (either right or left) were treated with SRP whereas the remaining two quadrants were left untreated. The participants received a toothbrush, toothpaste, and brushing instructions. L. reuteri Prodentis lozenges (1*10(8) CFU DSM17938+1*10(8) CFU ATCC PTA 5289) or the corresponding placebo lozenges were taken twice daily from day 21 to day 42. Statistical analysis was done for comparisons of clinical parameters (Plaque Index (PI), Gingival Index (GI), Gingival Bleeding Index (GBI), probing pocket depth (PPD), clinical attachment level (CAL)) and microbiological levels of the pathogens Aggregibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), and Prevotella intermedia (Pi). All p-values less than 0.05 were considered significant. Assessments were made on day 0 before SRP treatment, on day 21 before administration of the lozenges, and on day 42. RESULTS: At day 42, the PI, GI, and GBI were significantly reduced by all treatment modalities. When ranked, the amount of PI, GI and GBI reduction by the different treatments was SRP + Prodentis Prodentis SRP + placebo placebo; all differences were statistically significant. For PPD and CAL, the best result was obtained with the SRP+Prodentis treatment. PPD was reduced from 5.08+/-0.75 to 3.78+/-0.61 mm (p<0.001) and CAL from 3.93+/-0.93 to 2.85+/-0.74 mm (p<0.001). Prodentis, either alone or following SRP, reduced Aa, Pi, and Pg by 1 log(10) unit (p<0.01). The SRP+placebo combination did not significantly affect the levels of the pathogens. CONCLUSION: The present randomized controlled trial confirms the plaque inhibition, anti inflammatory, and antimicrobial effects of L. reuteri Prodentis. L. reuteri Prodentis probiotic can be recommended during non-surgical therapy and the maintenance phase of periodontal treatment. Considering the beneficial effects of probiotics, this therapy could serve as a useful adjunct or alternative to periodontal treatment when SRP might be contraindicated. Further studies are required in this direction. PMID- 21523224 TI - Role of periodontal pathogenic bacteria in RANKL-mediated bone destruction in periodontal disease. AB - Accumulated lines of evidence suggest that hyperimmune responses to periodontal bacteria result in the destruction of periodontal connective tissue and alveolar bone. The etiological roles of periodontal bacteria in the onset and progression of periodontal disease (PD) are well documented. However, the mechanism underlying the engagement of periodontal bacteria in RANKL-mediated alveolar bone resorption remains unclear. Therefore, this review article addresses three critical subjects. First, we discuss earlier studies of immune intervention, ultimately leading to the identification of bacteria-reactive lymphocytes as the cellular source of osteoclast-induction factor lymphokine (now called RANKL) in the context of periodontal bone resorption. Next, we consider (1) the effects of periodontal bacteria on RANKL production from a variety of adaptive immune effector cells, as well as fibroblasts, in inflamed periodontal tissue and (2) the bifunctional roles (upregulation vs. downregulation) of LPS produced from periodontal bacteria in a RANKL-induced osteoclast-signal pathway. Future studies in these two areas could lead to new therapeutic approaches for the management of PD by down-modulating RANKL production and/or RANKL-mediated osteoclastogenesis in the context of host immune responses against periodontal pathogenic bacteria. PMID- 21523226 TI - Should patients with hip joint prosthesis receive antibiotic prophylaxis before dental treatment? AB - The safety committee of the American Academy of Orthopedic Surgeons (AAOS) recommended in 2009 that clinicians should consider antibiotic prophylaxis for all patients with total joint replacement before any invasive procedure that may cause bacteremia. This has aroused confusion and anger among dentists asking for the evidence. The present review deals with different aspects of the rationale for this recommendation giving attention to views both in favor of and against it. PMID- 21523228 TI - Contaminated mouth swabs caused a multi-hospital outbreak of Pseudomonas aeruginosa infection. PMID- 21523227 TI - Oral microbiota and cancer. AB - Inflammation caused by infections may be the most important preventable cause of cancer in general. However, in the oral cavity the role of microbiota in carcinogenesis is not known. Microbial populations on mouth mucosa differ between healthy and malignant sites and certain oral bacterial species have been linked with malignancies but the evidence is still weak in this respect. Nevertheless, oral microorganisms inevitably up-regulate cytokines and other inflammatory mediators that affect the complex metabolic pathways and may thus be involved in carcinogenesis. Poor oral health associates statistically with prevalence of many types of cancer, such as pancreatic and gastrointestinal cancer. Furthermore, several oral micro-organisms are capable of converting alcohol to carcinogenic acetaldehyde which also may partly explain the known association between heavy drinking, smoking, poor oral health and the prevalence of oral and upper gastrointestinal cancer. A different problem is the cancer treatment-caused alterations in oral microbiota which may lead to the emergence of potential pathogens and subsequent other systemic health problems to the patients. Hence clinical guidelines and recommendations have been presented to control oral microbiota in patients with malignant disease, but also in this area the scientific evidence is weak. More controlled studies are needed for further conclusion. PMID- 21523229 TI - Analysis of microbiota associated with peri-implantitis using 16S rRNA gene clone library. AB - BACKGROUND: Peri-implantitis (PI) is an inflammatory disease which leads to the destruction of soft and hard tissues around osseointegrated implants. The subgingival microbiota appears to be responsible for peri-implant lesions and although the complexity of the microbiota has been reported in PI, the microbiota responsible for PI has not been identified. OBJECTIVE: The purpose of this study was to identify the microbiota in subjects who have PI, clinically healthy implants, and periodontitis-affected teeth using 16S rRNA gene clone library analysis to clarify the microbial differences. DESIGN: Three subjects participated in this study. The conditions around the teeth and implants were evaluated based on clinical and radiographic examinations and diseased implants, clinically healthy implants, and periodontally diseased teeth were selected. Subgingival plaque samples were taken from the deepest pockets using sterile paper points. Prevalence and identity of bacteria was analyzed using a 16S rRNA gene clone library technique. RESULTS: A total of 112 different species were identified from 335 clones sequenced. Among the 112 species, 51 (46%) were uncultivated phylotypes, of which 22 were novel phylotypes. The numbers of bacterial species identified at the sites of PI, periodontitis, and periodontally healthy implants were 77, 57, and 12, respectively. Microbiota in PI mainly included Gram-negative species and the composition was more diverse when compared to that of the healthy implant and periodontitis. The phyla Chloroflexi, Tenericutes, and Synergistetes were only detected at PI sites, as were Parvimonas micra, Peptostreptococcus stomatis, Pseudoramibacter alactolyticus, and Solobacterium moorei. Low levels of periodontopathic bacteria, such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were seen in peri-implant lesions. CONCLUSIONS: The biofilm in PI showed a more complex microbiota when compared to periodontitis and periodontally healthy teeth, and it was mainly composed of Gram-negative anaerobic bacteria. Common periodontopathic bacteria showed low prevalence, and several bacteria were identified as candidate pathogens in PI. PMID- 21523230 TI - Osteoradionecrosis contains a wide variety of cultivable and non-cultivable bacteria. AB - BACKGROUND: Direct microscopy, anaerobic culture and DNA-DNA hybridization have previously demonstrated an association between microorganisms and osteoradionecrosis (ORN). The purpose of our study was to use culture independent molecular techniques to detect bacteria in necrotic bone lesions of the mandible after radiation therapy. DESIGN: Bacterial DNA was extracted from eight deep medullar specimens from resected mandibles (six cases), including one patient with relapse. 16S rRNA genes were PCR amplified, cloned, transformed into Escherichia coli and sequenced to determine species identity and closest relatives. RESULTS: From the analysis of 438 clones, 59 predominant species were detected, 27% of which have not been cultivated. The predominant species detected from radionecrotic mandibles were Campylobacter gracilis, Streptococcus intermedius, Peptostreptococcus sp. oral clone FG014, uncultured bacterium clone RL178, Fusobacterium nucleatum, and Prevotella spp. The study demonstrated intersubject variability of the bacteria present in ORN. In contrast to the diverse bacterial profile detected in primary infection, only a few members of the oral indigenous flora were identified from the relapse case. CONCLUSIONS: Diverse bacterial profiles in specimens of ORN in marrow spaces of the mandible were detected by culture independent molecular techniques. To better understand the pathogenesis and to improve the therapy of the infection, detection of all members of the complex bacterial flora associated with ORN is necessary. PMID- 21523231 TI - Differential effects of periopathogens on host protease inhibitors SLPI, elafin, SCCA1, and SCCA2. AB - OBJECTIVE: Secretory leukocyte peptidase inhibitors (SLPI), elafin, squamous cell carcinoma antigen 1 and 2 (SCCA1 and SCCA2) are specific endogenous serine protease inhibitors expressed by epithelial cells that prevent tissue damage from excessive proteolytic enzyme activity due to inflammation. To determine the effects of various periopathogens on these protease inhibitors, we utilized human gingival epithelial cells (GECs) challenged with cell-free bacteria supernatants of various periopathogens Porphyromonas gingivalis, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum. DESIGN: The gene expression and secretion of SLPI, elafin, SCCA1, and SCCA2 were determined using real-time PCR and ELISA, respectively. The direct effects of periopathogens and P. gingivalis gingipain mutants on these inhibitors were examined in vitro by Western Blot. The effect on the innate immune response of GECs was measured by expression of antimicrobial peptides: human beta-defenisin-2 (hBD2) and chemokine (C-C motif) ligand 20 (CCL20). RESULTS: We found that SLPI, SCCA2, elafin, hBD2, and CCL20 gene expression levels were significantly induced (p<0.001) in response to P. gingivalis, whose virulence factors include cysteine proteases, but not in response to stimulation by other bacteria. P. gingivalis reduced the secretion of SLPI and elafin significantly in GECs, and degraded recombinant SLPI, elafin, SCCA1, and SCCA2. Differential degradation patterns of SLPI, elafin, SCCA1, and SCCA2 were observed with different bacteria as well as P. gingivalis mutants associated with the loss of specific gingipains secreted by P. gingivalis. In addition, pretreatment of GECs with SLPI, SCCA1, or SCCA2 partially blocked hBD2 and CCL20 mRNA expression in response to P. gingivalis, suggesting a protective effect. CONCLUSION: Our results suggest that different periopathogens affect the host protease inhibitors in a different manner, suggesting host susceptibility may differ in the presence of these pathogens. The balance between cellular protease inhibitors and their degradation may be an important factor in susceptibility to periodontal infection. PMID- 21523233 TI - Retraction. PMID- 21523232 TI - The role of viruses in oral disease. AB - The focus has traditionally been on bacteria and fungi when discussing microbiological aspects of oral disease. Viruses are probably more involved in diseases associated with the oral cavity than has been previously thought. The role of several viruses in ulceration is well known, but viruses of the herpes family may play a role in periodontitis, and papillomaviruses are probably involved in oral cancer. This review offers a brief introduction to virology before discussing the role of the more relevant viruses in oral disease. As to clinical application, it is concluded that the anti-herpes medication may, in some cases, be relevant in treating periodontitis, while papillomavirus vaccine would be expected to decrease the prevalence of oral cancer. PMID- 21523234 TI - Effect of bariatric surgery on future general surgical procedures. AB - Bariatric surgery is now accepted as a safe and effective procedure for morbid obesity. The frequency of bariatric procedures is increasing with the adoption of the laparoscopic approach. The general surgeons will be facing many more of such patients presenting with common general surgical problems. Many of the general surgeons, faced with such situations, may not be aware of the changes in the gastrointestinal anatomy following bariatric procedures and management of these clinical situations will therefore present diagnostic and therapeutic challenges. We hereby present a review of management of few common general surgical problems in patients with a history of bariatric surgery. PMID- 21523235 TI - Endoscopic treatment of vesicoureteral reflux in a paediatric surgery ambulatory unit. AB - BACKGROUND: Vesicoureteral reflux (VUR) is a major urological problem in children. Its incidence ranges from 1 to 3% in healthy children. MATERIALS AND METHODS: We treated 38 children and analysed their data on age, sex, reflux grade, laterality, and results of endoscopic treatment (ET), at the different grades of reflux. All children were operated on an Ambulatory Surgery basis, studying the complications and post-operative course. RESULTS: Thirty-eight patients were operated during a period of six years, of age between one and twelve years. VUR was bilateral in 24 (63%) patients, unilateral in 14 (34%), with a collection of a total of 62 renal units or ureters. In 29 children (76%), 46 refluxing ureters (70%) completely disappeared after just 1 ET. Nine patients (24%) with 16 ureteral units (30%) received a second ET, with the reflux disappearing successfully in seven children (12 ureteral units), changing the success rate in the disappearance of VUR, after two injections of Deflux, to 90% of the total group of ureters (58 of 62). CONCLUSION: The endoscopic treatment of VUR has become the first choice of treatment to control the primary reflux, not just because of the good results, but because of the low post-operative morbidity and the direct relationship with the Ambulatory Surgery Unit. PMID- 21523236 TI - Laparoscopic management of appendicular mass. AB - BACKGROUND: Laparoscopic appendectomy is becoming the preferred technique for treating acute appendicitis. However, its role in the treatment of complicated appendicitis is controversial. This study was undertaken to assess the feasibility of laparoscopic appendectomy for appendicular mass. MATERIALS AND METHODS: A retrospective review was performed of all the patients who were treated laparoscopically for appendicular mass from March 2007 to October 2009. SETTING: Tertiary care hospital. RESULTS: A total of 120 patients were treated for appendicitis. A retrospective review of the patients' records demonstrated that 19 patients (15.8%) had appendicular mass at the time of admission. The average operative time was 95 minutes (range 45-140 minutes). Pathological evidence of appendicitis was present in all the patients. The average length of hospital stay was six days (rang 6-9 days). Three patients (15.7%) had post- operative complications. Two patients developed wound infections and one patient was re-admitted with pain and a lump below the umbilical port. CONCLUSION: The findings suggest that laparoscopic appendectomy is feasible in patients with appendicular mass. The authors propose a prospective, randomized trial to verify this finding. PMID- 21523237 TI - Laparoscopic adrenal surgery in children: Lessons from a single centre experience. AB - PURPOSE: Although commonly performed in adults, laparoscopic adrenalectomy in children is performed only in centres with advanced laparoscopic expertise. MATERIALS AND METHODS: This is a retrospective analysis of laparoscopic adrenalectomies performed at a single centre between January 2003 and May 2010. After preoperative evaluation with biochemical assays and radiologic imaging, surgery was performed by using the lateral transabdominal approach in all patients. RESULTS: Ten laparoscopic adrenalectomies (including three bilateral) were performed in seven children, with a mean age of 9.6 years. The tumours ranged from 2 - 7 cms in size. The operative durations were 75 - 130 minutes (unilateral) and 250 - 270 minutes (bilateral). Operative blood loss was minimal. There were no open conversions, but terminal hand assistance was required in one large right pheochromocytoma. The postoperative hospital stay ranged from 3 - 10 days. The final pathological diagnoses included pheochromocytoma, hyperplasia and neuroblastoma. Follow-up at 24 - 87 months was uneventful. CONCLUSION: With adequate experience in laparoscopy, it is possible to perform adrenalectomy in selected children. PMID- 21523238 TI - A very unusual anatomical variation and complication of common iliac artery and ureter in retroperitonoscopic ureterolithotomy. AB - Anatomical localization of theureter comes along psoas major muscle and crosses over common iliac artery bifurcation. Common iliac artery aneurysm and impacted atherosclerosis are a rare condition that should be differed from the impacted ureter stone to avoid from undesirable complication. In this case, we present a very unusual anatomical variation and complication of common iliac artery and ureter in retroperitonoscopic ureterolithotomy. PMID- 21523239 TI - Thoracoscopic removal of oesophageal duplication cyst. AB - A 4-year-old boy presented with vomiting and recurrent cough. He was investigated and found to have thoracic oesophageal duplication cyst. He was taken up for thoracoscopic removal of the cyst. The cyst was attached to the oesophagus and shared a common wall. The boy tolerated the procedure well and follow-up showed no recurrence of the cyst with total resolution of the symptoms. We share our experience with the management of this boy. PMID- 21523240 TI - Leiomyoma mimicking an incarcerated inguinal hernia: A rare complication of laparoscopic hysterectomy. AB - A 52-year-old, obese, female patient was referred for a right inguinal mass, which appeared seven months after a laparoscopic hysterectomy, which was performed because of myomatosis. Despite several examinations, including ultrasound, computed tomography (CT)-Scan, positron emission tomography (PET)-CT, and ultrasound-guided biopsy, the diagnosis remained unclear until surgical exploration, which disclosed a well-encapsulated solid tumour corresponding to a fibrotic leiomyoma. Spilling of leiomyoma cells is a rare and unusual complication of laparoscopic surgery. Tumour development in the inguinal canal after laparoscopic gynaecological surgery should be kept in mind in the differential diagnosis of inguinal hernia and other uncommon pathologies. PMID- 21523241 TI - Retained portion of the appendix following laparosocpic appendicectomy causing peritonitis and ileus. AB - We describe a patient who developed peritonitis and paralytic ileus due to a retained portion of the inflammed appendix following laparoscopic appendicectomy (LA). The details of the presentation and management are discussed along with a brief review of the unusual complications LA. PMID- 21523242 TI - Single port access sleeve gastrectomy: Is it reasonable? AB - This short letter is in response to the article published in your publication about single-incision laparoscopic bariatric surgery, by Chih-Kun Huang. We want to focus on the technical aspects. PMID- 21523243 TI - Combined laparoscopy and transabdominal endoscopy: Case report of dislodged oesophageal stent retrieval. AB - The patient is a 39-year-old male with a five-month history of progressive dysphagia and a 70 lb weight loss. On upper gastrointestinal (GI) endoscopy he was found to have a near-obstructing mass in the lower oesophagus that was proven by biopsy to be oesophageal adenocarcinoma. Stricture caused by the adenocarcinoma mass was stented with a Cook Evolution 12.5 cm / 24 Fr stent, which dislodged subsequently. We report the first case of a dislodged Cook Evolution 12.5 cm / 24 Fr oesophageal stent that was retrieved using combined laparoscopic and transabdominal endoscopy. PMID- 21523244 TI - Authors' reply. PMID- 21523245 TI - Is oesophageal manometry a must before laparoscopic fundoplication? PMID- 21523246 TI - Laparoscopic bladder injury and ascites. PMID- 21523248 TI - Critical self-organized self-sustained oscillations in large regulatory networks: towards understanding the gene expression initiation. AB - In this paper, a new model of self-organized criticality is introduced. This model, called the gene expression paradigm, is motivated by the problem of gene expression initiation in the newly-born daughter cells after mitosis. The model is fundamentally different in dynamics and properties from the well known sand pile paradigm. Simulation experiments demonstrate that a critical total number of proteins exists below which transcription is impossible. Above this critical threshold, the system enters the regime of self-sustained oscillations with standard deviations and periods proportional to the genes' complexities with probability one. The borderline between these two regimes is very sharp. Importantly, such a self-organization emerges without any deterministic feedback loops or external supervision, and is a result of completely random redistribution of proteins between inactive genes. Given the size of the genome, the domain of self-organized oscillatory motion is also limited by the genes' maximal complexities. Below the critical complexity, all the regimes of self organized oscillations are self-similar and largely independent of the genes' complexities. Above the level of critical complexity, the whole-genome transcription is impossible. Again, the borderline between the domains of oscillations and quiescence is very sharp. The gene expression paradigm is an example of cellular automata with the domain of application potentially far beyond its biological context. The model seems to be simple enough for staging an experiment for verification of its remarkable properties. PMID- 21523249 TI - Numerical modeling of motion trajectory and deformation behavior of a cell in a nonuniform electric field. AB - The motion trajectory and deformation behavior of a neutral red blood cell (RBC) in a microchannel subjected to an externally applied nonuniform electric field are numerically investigated, where both the membrane mechanical force and the dielectrophoresis (DEP) force are considered. The simulation results demonstrate that the DEP force is significantly influenced by several factors, namely, the RBC size, electrode potential, electric frequency, RBC permittivity, and conductivity, which finally results in the different behaviors of the cell motion and deformation in the nonuniform electric field. PMID- 21523250 TI - The dynamics of the impact and coalescence of droplets on a solid surface. AB - A simple experimental setup to study the impact and coalescence of deposited droplets is described. Droplet impact and coalescence have been investigated by high-speed particle image velocimetry. Velocity fields near the liquid-substrate interface have been observed for the impact and coalescence of 2.4 mm diameter droplets of glycerol/water striking a flat transparent substrate in air. The experimental arrangement images the internal flow in the droplets from below the substrate with a high-speed camera and continuous laser illumination. Experimental results are in the form of digital images that are processed by particle image velocimetry and image processing algorithms to obtain velocity fields, droplet geometries, and contact line positions. Experimental results are compared with numerical simulations by the lattice Boltzmann method. PMID- 21523247 TI - Biology of the Mi-2/NuRD Complex in SLAC (Stemness, Longevity/Ageing, and Cancer). AB - The dynamic chromatin activities of Mi-2/Nucleosome Remodeling and Histone deacetylation (Mi-2/NuRD) complexes in mammals are at the basis of current research on stemness, longevity/ageing, and cancer (4-2-1/SLAC), and have been widely studied over the past decade in mammals and the elegant model organism, Caenorhabditis elegans. Interestingly, a common emergent theme from these studies is that of distinct coregulator-recruited Mi-2/NuRD complexes largely orchestrating the 4-2-1/SLAC within a unique paradigm by maintaining genome stability via DNA repair and controlling three types of transcriptional programs in concert in a number of cellular, tissue, and organism contexts. Thus, the core Mi-2/NuRD complex plays a central role in 4-2-1/SLAC. The plasticity and robustness of 4-2-1/SLAC can be interpreted as modulation of specific coregulator(s) within cell-specific, tissue-specific, stage-specific, or organism specific niches during stress induction, ie, a functional module and its networking, thereby conferring differential responses to different environmental cues. According to "Occam's razor", a simple theory is preferable to a complex one, so this simplified notion might be useful for exploring 4-2-1/SLAC with a holistic view. This thought could also be valuable in forming strategies for future research, and could open up avenues for cancer prevention and antiageing strategies. PMID- 21523252 TI - High-throughput single-cell manipulation system for a large number of target cells. AB - A sequential and high-throughput single-cell manipulation system for a large volume of cells was developed and the successive manipulation for single cell involving single-cell isolation, individual labeling, and individual rupture was realized in a microhydrodynamic flow channel fabricated by using two-dimensional simple flow channels. This microfluidic system consisted of the successive single cell handlings of single-cell isolation from a large number of cells in cell suspension, labeling each isolated single cell and the lysate extraction from each labeled single cell. This microfluidic system was composed of main channels, cell-trapping pockets, drain channels, and single-cell content collection channels which were fabricated by polydimethylsiloxane. We demonstrated two kinds of prototypes for sequential single-cell manipulations, one was equipped with 16 single-cell isolation pockets in microchannel and the other was constructed of 512 single-cell isolation pockets. In this study, we demonstrated high-throughput and high-volume single-cell isolation with 512 pocket type device. The total number of isolated single cells in each isolation pocket from the cell suspension at a time was 426 for the cell line of African green monkey kidney, COS-1, and 360 for the rat primary brown preadipocytes, BAT. All isolated cells were stained with fluorescence dye injected into the same microchannel successfully. In addition, the extraction and collection of the cell contents was demonstrated using isolated stained COS-1 cells. The cell contents extracted from each captured cell were individually collected within each collection channel by local hydrodynamic flow. The sequential trapping, labeling, and content extraction with 512 pocket type devices realized high-throughput single-cell manipulations for innovative single-cell handling, feasible staining, and accurate cell rupture. PMID- 21523251 TI - A microfluidic device for simultaneous electrical and mechanical measurements on single cells. AB - This paper presents a microfluidic device for simultaneous mechanical and electrical characterization of single cells. The device performs two types of cellular characterization (impedance spectroscopy and micropipette aspiration) on a single chip to enable cell electrical and mechanical characterization. To investigate the performance of the device design, electrical and mechanical properties of MC-3T3 osteoblast cells were measured. Based on electrical models, membrane capacitance of MC-3T3 cells was determined to be 3.39+/-1.23 and 2.99+/ 0.82 pF at the aspiration pressure of 50 and 100 Pa, respectively. Cytoplasm resistance values were 110.1+/-37.7 kOmega (50 Pa) and 145.2+/-44.3 kOmega (100 Pa). Aspiration length of cells was found to be 0.813+/-0.351 MUm at 50 Pa and 1.771+/-0.623 MUm at 100 Pa. Quantified Young's modulus values were 377+/-189 Pa at 50 Pa and 344+/-156 Pa at 100 Pa. Experimental results demonstrate the device's capability for characterizing both electrical and mechanical properties of single cells. PMID- 21523253 TI - Monodispersed magnetite nanoparticles optimized for magnetic fluid hyperthermia: Implications in biological systems. AB - Magnetite (Fe(3)O(4)) nanoparticles (MNPs) are suitable materials for Magnetic Fluid Hyperthermia (MFH), provided their size is carefully tailored to the applied alternating magnetic field (AMF) frequency. Since aqueous synthesis routes produce polydisperse MNPs that are not tailored for any specific AMF frequency, we have developed a comprehensive protocol for synthesizing highly monodispersed MNPs in organic solvents, specifically tailored for our field conditions (f = 376 kHz, H(0) = 13.4 kA/m) and subsequently transferred them to water using a biocompatible amphiphilic polymer. These MNPs (sigma(avg.) = 0.175) show truly size-dependent heating rates, indicated by a sharp peak in the specific loss power (SLP, W/g Fe(3)O(4)) for 16 nm (diameter) particles. For broader size distributions (sigma(avg.) = 0.266), we observe a 30% drop in overall SLP. Furthermore, heating measurements in biological medium [Dulbecco's modified Eagle medium (DMEM) + 10% fetal bovine serum] show a significant drop for SLP (~30% reduction in 16 nm MNPs). Dynamic Light Scattering (DLS) measurements show particle hydrodynamic size increases over time once dispersed in DMEM, indicating particle agglomeration. Since the effective magnetic relaxation time of MNPs is determined by fractional contribution of the Neel (independent of hydrodynamic size) and Brownian (dependent on hydrodynamic size) components, we conclude that agglomeration in biological medium modifies the Brownian contribution and thus the net heating capacity of MNPs. PMID- 21523254 TI - Effect of the TiN content in the Pd-TiN seed layer on the microstructure and magnetic properties of Co/Pd multilayered media. AB - [Co(0.2 nm)/Pd(0.8 nm)](20) multilayered films on 15 nm Pd-TiN seed layers were fabricated by dc magnetron sputtering without heating the substrate. The effects of TiN content on microstructure and magnetic properties of the [Co/Pd] multilayered media were studied. By increasing the TiN content in the Pd-TiN seed layer to an optimum level, coercivity of the [Co/Pd] multilayered media increased to 6.7 kOe. However, further increase of TiN content beyond 22 vol % reduced coercivity (Hc), implying that there exists a critical TiN concentration to enhance the magnetic property of the [Co/Pd] multilayered media. Transmission electron microscopic observations revealed that well-isolated [Co/Pd] multilayered grains with apparent grain boundaries were achieved by controlling the TiN content in the Pd-TiN seed layer. The average grain diameter was 8 nm with a dispersion of 11.2%, grown on the Pd-TiN seed layer with TiN content of 22 vol %. PMID- 21523255 TI - Looking forward: the Canadian Association of Gastroenterology strategic plan. PMID- 21523256 TI - Advances in our understanding of the pathogenesis of celiac disease. PMID- 21523257 TI - Carpet-like polypoid lesion in collagenous colitis with mucosal giant cells. PMID- 21523258 TI - Collagenous sprue. AB - Collagenous sprue is a small bowel mucosal lesion that has been historically associated with persistent diarrhea, progressive weight loss and severe malabsorption causing multiple nutrient deficiencies. A severe to variably severe mucosal lesion with distinct subepithelial collagen deposits occurs. Celiac disease has been intimately linked to collagenous sprue and, similar to celiac disease, small bowel ulceration, perforation and lymphoma may complicate the clinical course of collagenous sprue. In collagenous sprue, concomitant collagen deposits may also occur in gastric or colonic mucosal sites (or both), indicating that this unusual mucosal process may be very heterogeneous and far more extensive in the intestinal tract than previously appreciated. Moreover, reports of diagnosis during infancy suggest that the natural history of the disorder could be more prolonged than is currently appreciated. Finally, the collagen deposits, per se, may be due to different causes and, in some, even represent a novel paraneoplastic histopathological marker. Future studies are needed to more precisely define molecular and genetic biomarkers that identify homogeneous groups and permit the development of improved treatment strategies for this increasingly recognized disorder. PMID- 21523260 TI - Evaluation of colonoscopy skills - how well are we doing? AB - Colonoscopy is a complex task that requires the interplay of motor and cognitive skill sets. Traditional teaching of colonoscopy involves observation in an apprenticeship model. Individual trainees vary in their rate of their skill acquisition, and this trial-and-error method often results in frustration and anxiety for both the educator and the learner. Currently, there are no guidelines to determine the competence or proficiency of an individual for colonoscopy. Furthermore, there is a paucity of information regarding formal training curricula for colonoscopy skills acquisition. The present study investigated a formal and validated educational framework for colonoscopy teaching and compared it with the traditional apprenticeship model in first-year trainees. PMID- 21523259 TI - Testing for gluten-related disorders in clinical practice: the role of serology in managing the spectrum of gluten sensitivity. AB - Immunoglobulin A tissue transglutaminase is the single most efficient serological test for the diagnosis of celiac disease. It is well known that immunoglobulin A tissue transglutaminase levels correlate with the degree of intestinal damage, and that values can fluctuate in patients over time. Serological testing can be used to identify symptomatic individuals that need a confirmatory biopsy, to screen at-risk populations or to monitor diet compliance in patients previously diagnosed with celiac disease. Thus, interpretation of serological testing requires consideration of the full clinical scenario. Antigliadin tests are no longer recommended for the diagnosis of classical celiac disease. However, our understanding of the pathogenesis and spectrum of gluten sensitivity has improved, and gluten-sensitive irritable bowel syndrome patients are increasingly being recognized. Studies are needed to determine the clinical utility of antigliadin serology in the diagnosis of gluten sensitivity. PMID- 21523261 TI - Risk factors and complications following percutaneous endoscopic gastrostomy: a case series of 1041 patients. AB - BACKGROUND: Most studies exclude patients with severe coagulation disorders or those taking anticoagulants when evaluating the outcomes of percutaneous endoscopic gastrostomy (PEG). OBJECTIVE: To investigate complications and risk factors of PEG in a large clinical series including patients undergoing antiplatelet and anticoagulant therapy. METHODS: During a six-year period, 1057 patients referred for PEG placement were prospectively audited for clinical outcome. Exclusion criteria and follow-up care were defined. Complications were defined as minor or severe. Uni- and multivariate analyses were used to evaluate 14 risk factors. No standardized antibiotic prophylaxis was given. RESULTS: A total of 1041 patients (66% male, 34% female) with the following conditions underwent PEG: neurogenic dysphagia (n=450), cancer (n=385) and others (n=206). No anticoagulants were administered to 351 patients, thrombosis prophylaxis was given to 348 while full therapeutic anticoagulation was received by 313. No increased bleeding risk was associated with patients who had above-normal international normalized ratio values (OR 0.79 [95% CI 0.08 to 7.64]; P=1.00). The total infection rate was 20.5% in patients with malignant disease, and 5.5% in those with nonmalignant disease. Severe complications occurred in 19 patients (bleeding 0.5%, peritonitis 1.3%). Cirrhosis (OR 2.91 [95% CI 1.31 to 6.54]; P=0.008), cancer (OR 2.34 [95% CI 1.33 to 4.12]; P=0.003) and radiation therapy (OR 2.34 [95% CI 1.35 to 4.05]; P=0.002) were significant predictors of post-PEG infection. The 30-day mortality rate was 5.8%. There were no procedure-related deaths. CONCLUSIONS: Cancer, cirrhosis and radiation therapy were predictors of infection. Post-PEG bleeding and other complications were rare events. Collectively, the data suggested that patients taking concurrent anticoagulants had no elevated risk of post-PEG bleeding. PMID- 21523262 TI - Bovine antibody-based oral immunotherapy for reduction of intragastric Helicobacter pylori colonization: a randomized clinical trial. AB - BACKGROUND: Antibiotic-based regimens are frequently used for the treatment of Helicobacter pylori infection. These regimens fail to eradicate H pylori in 15% to 40% of patients, primarily due to antimicrobial resistance and insufficient patient compliance. Effective prevention and eradication of H pylori by passive immunization with orally administered bovine antibodies has been demonstrated in animal studies, and may serve as an alternative therapy in humans. OBJECTIVE: To study the efficacy and safety of orally administered bovine anti-H pylori antibodies for the reduction of intragastric bacterial load and eradication of H pylori in humans. METHODS: Dairy cows were immunized against H pylori. After confirmation of the presence of anti-H pylori antibodies in the milk, the milk was subsequently processed into a whey protein concentrate (WPC). In a prospective, double-blind, placebo-controlled randomized clinical trial, H pylori infected subjects were randomly assigned to treatment with the WPC preparation or placebo. Study medication was continued for 28 days; subjects were followed-up for 56 days. RESULTS: Of the 30 subjects included, 27 completed the protocol. Of these 27 evaluable subjects, 14 were treated with WPC and 13 with placebo. There was no significant difference in urea breath test decrease between the WPC- and placebo-treated group (P=0.75). H pylori-associated gastritis and density were not significantly reduced in either group after treatment (P>0.05 for all). CONCLUSION: Bovine antibody-based oral immunotherapy appears to be safe, but does not significantly reduce intragastric density in humans. Further studies are needed to determine whether WPC treatment has additional value to conventional antibiotic treatment for H pylori. PMID- 21523263 TI - Moderate and severe postendoscopic retrograde cholangiopancreatography pancreatitis despite prophylactic pancreatic stent placement: the effect of early prophylactic pancreatic stent dislodgement. AB - BACKGROUND: Placement of prophylactic pancreatic stents (PPS) is a method proven to reduce the rate and severity of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk patients; however, PPS do not eliminate the risk completely. Early PPS dislodgement may occur prematurely and contribute to more frequent or severe PEP. OBJECTIVE: To determine the effect of early dislodgement of PPS in patients with moderate or severe PEP. METHODS: A total of 27,176 ERCP procedures from January 1994 to September 2007 for PPS placement in high-risk patients were analyzed. Patient and procedure data were analyzed to assess risk factors for PEP, and to evaluate the severity of pancreatitis, length of hospitalization and subsequent complications. Timing of stent dislodgment was assessed radiographically. RESULTS: PPS were placed in 7661 patients. Of these, 580 patients (7.5%) developed PEP, which was graded as mild in 460 (6.0%), moderate in 87 (1.1%) and severe in 33 (0.4%). Risk factors for developing PEP were not different in patients who developed moderate PEP compared with those with severe PEP. PPS dislodged before 72 h in seven of 59 (11.9%) patients with moderate PEP and five of 27 (18.5%) patients with severe PEP (P=0.505). The mean (+/- SD) length of hospitalization in patients with moderate PEP with stent dislodgement before and after 72 h were 7.43 +/- 1.46 days and 8.37 +/- 1.16 days, respectively (P=0.20). The mean length of hospitalization in patients with severe PEP whose stent dislodged before and after 72 h were 21.6 +/- 6.11 and 22.23 +/- 3.13 days, respectively (P=0.96). CONCLUSION: Early PPS dislodgement was associated with moderate and severe PEP in less than 20% of cases and was not associated with a more severe course. Factors other than ductal obstruction contribute to PEP in high-risk patients undergoing ERCP and PPS placement. PMID- 21523264 TI - Combining carbohydrate substitutions at bioinspired positions with multivalent presentation towards optimising lectin inhibitors: case study with calixarenes. AB - Carbohydrate derivatisation and glycocluster formation are both known to enhance avidity for lectin binding. Using a plant toxin and human adhesion/growth regulatory lectins (inter- and intrafamily comparisons) the effect of their combination is examined. In detail, aromatic substituents were introduced at the 2-N or 3'-positions of N-acetyllactosamine and the products conjugated to two types of calix[n]arenes (n = 4, 6) via thiourea-linker chemistry. PMID- 21523265 TI - Exchange between sub-surface and surface oxygen vacancies on CeO2(111): a new surface diffusion mechanism. AB - Using first principles calculations for O vacancy diffusion on CeO(2)(111), we locate a surface diffusion mechanism, the two-step O vacancy exchange one, which is more favored than the most common hopping mechanism. By analyzing the results, we identify quantitatively the physical origin of why the two-step exchange mechanism is preferred. PMID- 21523266 TI - NiO nanosheets grown on graphene nanosheets as superior anode materials for Li ion batteries. AB - This paper reports a hydrothermal preparation of NiO-graphene sheet-on-sheet and nanoparticle-on-sheet nanostructures. The sheet-on-sheet nanocomposite showed highly reversible large capacities at a common current of 0.1 C and good rate capabilities. A large initial charge capacity of 1056 mAh/g was observed for the sheet-on-sheet composite at 0.1 C, which decreased by only 2.4% to 1031 mAh/g after 40 cycles of discharge and charge. This cycling performance is better than that of NiO nanosheets, graphene nanosheets, NiO-graphene nanoparticle-on-sheet, and previous carbon/carbon nanotube supported NiO composites. It is believed that the mechanical stability and electrical conductivity of NiO nanosheets are increased by graphene nanosheets (GNS), the aggregation or restacking of which to graphite platelets are, on the other hand, effectively prevented by NiO nanosheets. PMID- 21523268 TI - Effect of ionic strength and type of ions on the structure of water swollen polyelectrolyte multilayers. AB - This study addresses the effect of ionic strength and type of ions on the structure and water content of polyelectrolyte multilayers. Polyelectrolyte multilayers of poly(sodium-4-styrene sulfonate) (PSS) and poly(diallyl dimethyl ammonium chloride) (PDADMAC) prepared at different NaF, NaCl and NaBr concentrations have been investigated by neutron reflectometry against vacuum, H(2)O and D(2)O. Both thickness and water content of the multilayers increase with increasing ionic strength and increasing ion size. Two types of water were identified, "void water" which fills the voids of the multilayers and does not contribute to swelling but to a change in scattering length density and "swelling water" which directly contributes to swelling of the multilayers. The amount of void water decreases with increasing salt concentration and anion radius while the amount of swelling water increases with salt concentration and anion radius. This is interpreted as a denser structure in the dry state and larger ability to swell in water (sponge) for multilayers prepared from high ionic strengths and/or salt solution of large anions. No exchange of hydration water or replacement of H by D was detected even after eight hours incubation time in water of opposing isotopic composition. PMID- 21523267 TI - Entropy and Mg2+ control ligand affinity and specificity in the malachite green binding RNA aptamer. AB - The binding of small molecule targets by RNA aptamers provides an excellent model to study the versatility of RNA function. The malachite green aptamer binds and recognizes its ligand via stacking and electrostatic interactions. The binding of the aptamer to its original selection target and three related molecules was determined by isothermal titration calorimetry, equilibrium dialysis, and fluorescence titration. The results reveal that the entropy of complex formation plays a large role in determining binding affinity and ligand specificity. These data combined with previous structural studies show that metal ions are required to stabilize the complexes with non-native ligands whereas the complex with the original selection target is stable at low salt and in the absence of divalent metal ions. PMID- 21523269 TI - Pipette-friendly laminar flow patterning for cell-based assays. AB - Laminar flow patterning (LFP) is a characteristic method of microfluidic systems that allows two (or more) different solutions to flow side-by-side in a channel without convective mixing. This fluid behavior can be used to pattern cell suspensions, particles, and treatments as well as to create chemical gradients. LFP is typically implemented using syringe pumps and, for this reason, is most effective in constant flow scenarios such as long-term gradient generation. However, the complexity of using syringe pumps for patterning cell suspensions typically makes it a less attractive option than other standard patterning methods. We present a passive microfluidic method that enables short-term LFP of multiple fluids using a single pipette and allows each sample to be loaded in any sequence, at any point in time relative to one another. The proposed method is well-suited for cell-based assays, reduces the complexity of LFP to be on a similar level as other cell patterning methods, can be scaled to include more than two streams of fluid, and enables arrays of individually addressable devices for LFP on a single chip. PMID- 21523270 TI - Microwave discharge electrodeless lamps (MDEL). Part VII. Photo-isomerization of trans-urocanic acid in aqueous media driven by UV light from a novel Hg-free Dewar-like microwave discharge thermally-insulated electrodeless lamp (MDTIEL). Performance evaluation. AB - A novel mercury-free Dewar-like (double-walled structure) microwave discharge thermally-insulated electrodeless lamp (MDTIEL) was fabricated and its performance evaluated using the photo-isomerization of trans-urocanic acid (trans UA) in aqueous media as a test process driven by the emitted UV light when ignited with microwave radiation. The photo-isomerization processes trans-UA -> cis-UA and cis-UA -> trans-UA were re-visited using light emitted from a conventional high-pressure Hg light source and examined for the influence of UV light irradiance and solution temperature; the temperature dependence of the trans -> cis process displayed a negative activation energy, E(a) = -1.3 cal mol( 1). To control the photo-isomerization of urocanic acid from the heat usually dissipated by a microwave discharge electrodeless lamp (single-walled MDEL), it was necessary to suppress the microwave-initiated heat. For comparison, the gas fill in the MDEL lamp, which typically consists of a mixture of Hg and Ar, was changed to the more eco-friendly N(2) gas in the novel MDTIEL device. The dynamics of the photo-isomerization of urocanic acid driven by the UV wavelengths of the N(2)-MDTIEL light source were compared to those from the more conventional single-walled N(2)-MDEL and Hg/Ar-MDEL light sources, and with those from the Hg lamp used to irradiate, via a fiber optic, the photoreactor located in the wave guide of the microwave apparatus. The heating efficiency of a solution with the double-walled N(2)-MDTIEL was compared to the efficiency from the single-walled N(2)-MDEL device. Advantages of N(2)-MDTIEL are described from a comparison of the dynamics of the trans-UA -> cis-UA process on the basis of unit surface area of the lamp and unit power consumption. The considerably lower temperature on the external surface of the N(2)-MDTIEL light source should make it attractive in carrying out photochemical reactions that may be heat-sensitive such as the photothermochromic urocanic acid system. PMID- 21523271 TI - Electronic structure and reactivity of a biradical cluster: Sc3O6(-). AB - The Sc(3)O(6)(-) cluster anions were produced by laser ablation and studied by reaction with n-butane in a fast flow reactor and by photoelectron spectroscopy. The reactivity experiments indicated that one Sc(3)O(6)(-) cluster can activate two n-butane molecules consecutively with rate constants on the order of 10(-10) cm(3) molecule(-1) s(-1) under near room-temperature conditions, suggesting that the even-electron system Sc(3)O(6)(-) has a highly reactive electronic structure. The photoelectron spectroscopy determined a high vertical detachment energy (VDE) of 5.63 +/- 0.08 eV for the Sc(3)O(6)(-) cluster. Density functional computations indicated that the lowest energy isomer of Sc(3)O(6)(-) is an oxygen-centered biradical with a high VDE and is highly reactive toward n-butane, which is in good agreement with the experiments. The Sc(3)O(6)(-) cluster may serve as an ideal model system to provide insight into the real-life chemistry involved with the coupled O(-)...O(-) dimers over the surfaces of metal oxide catalysts. PMID- 21523272 TI - Luminescent nanomaterials. PMID- 21523273 TI - A new micropatterning method of soft substrates reveals that different tumorigenic signals can promote or reduce cell contraction levels. AB - In tissues, cell microenvironment geometry and mechanics strongly impact on cell physiology. Surface micropatterning allows the control of geometry while deformable substrates of tunable stiffness are well suited for the control of the mechanics. We developed a new method to micropattern extracellular matrix proteins on poly-acrylamide gels in order to simultaneously control cell geometry and mechanics. Microenvironment geometry and mechanics impinge on cell functions by regulating the development of intra-cellular forces. We measured these forces in micropatterned cells. Micropattern geometry was streamlined to orient forces and place cells in comparable conditions. Thereby force measurement method could be simplified and applied to large-scale experiment on chip. We applied this method to mammary epithelial cells with traction force measurements in various conditions to mimic tumoral transformation. We found that, contrary to the current view, all transformation phenotypes were not always associated to an increased level of cell contractility. PMID- 21523274 TI - Dual fluorescence in 9-amino-2,7,12,17-tetraphenylporphycene. AB - The absorption spectrum of the asymmetric 9-amino-2,7,12,17-tetraphenylporphycene shows new, strongly red-shifted bands compared to the symmetric parental 2,7,12,17-tetraphenylporphycene and to the also asymmetric 9-acetoxy-2,7,12,17 tetraphenylporphycene. Dual emission is also observed with relative contributions that depend strongly on the excitation wavelength and temperature. The gap between the two fluorescence bands is 84 nm. Tautomerization in both the ground and excited states is shown to account for these observations, the 9-amino group being particularly able to selectively lower the energy of the first excited singlet state of just one of the trans tautomers. Introduction of amino groups in porphycenes may be a convenient way to gain a deeper insight into the tautomerization mechanisms in this macrocyclic core. PMID- 21523275 TI - Colorimetric sensing of polyhydroxy compounds by an inclusion complex of boronic acid-modified amylose. AB - A novel sensing method for polyhydroxy compounds has been established based on the stimuli-responsive inclusion complex of boronic acid-modified amylose with iodine. An aqueous solution containing the boronic acid-modified amylose and iodine was coloured bluish purple due to encapsulation of iodine within the helical cavity of amylose. When polyhydroxy compounds were added, the solution gradually lost its colour with increasing concentration of polyhydroxy compounds. This colour change was attributed to the dissociation of iodine from the amylose cavity in response to the polyhydroxy compounds. According to detailed examinations, it was concluded that the origin of the responsiveness is derived from an electrostatic repulsion between anionic boronate groups and iodine. PMID- 21523291 TI - Synthesis of electron deficient acene derivatives via a bidirectional iterative elongation reaction. AB - Previously, we developed an iterative elongation methodology to synthesize acene esters, nitriles, and imides. The strategy uses the concept of bidirectional synthesis, and we can now make a series of electron deficient anthracene, tetracene, and pentacene derivatives via the bidirectional iterative elongation protocol. Central units, used to initiate the bidirectional elongation, were synthesized by employing a double anionic Fries rearrangement as the key step. The photophysical and electrochemical properties of these novel electron acceptors are investigated and interpreted based on the electron withdrawing power of the substitutions. An excited state charge transfer was proposed for one compound to account for its peculiar fluorescent behavior. PMID- 21523276 TI - Copper(II) complexes incorporating poly/perfluorinated alkoxyaluminate-type weakly coordinating anions: syntheses, characterization and catalytic application in stereoselective olefin aziridination. AB - The synthesis and characterization of a series of cationic copper(II) complexes of the type [Cu(NCR)(6)][Al(OC(CF(3))(2)R')(4)](2) (R = CH(3), Ph; R' = CF(3), Ph, PhCH(3)), incorporating poly/perfluoronated alkoxyaluminates as weakly coordinating anions (WCAs) is presented. Aziridination of various olefins, such as the unreactive olefins e.g. ethylhex-2-enoate and 1-decene, with N tosyliminophenyliodinane catalyzed by [Cu(NCR)(6)][Al(OC(CF(3))(2)R')(4)](2) affords very good yields (up to 96%) and high TOFs (up to 5000 h(-1)) under mild conditions. Using disubstituted olefins as substrates, high stereoselectivities are obtained at room temperature. The to date highest cis : trans ratio (98 : 2) of the obtained aziridines is achieved for cis-stilbene in good yield (85%) as well as promising TOF (> 2000 h(-1)). The investigation of the solvent effect on yield and selectivity reveals that for certain oleophilic substrates (1-decene), less polar solvents, such as dichloromethane are a better choice than acetonitrile, which is commonly considered as the best solvent for olefin aziridination. Accordingly, a mechanism involving a paramagnetic copper nitrene intermediate with both concerted and stepwise pathways is proposed. PMID- 21523292 TI - Studies on [3]pseudorotaxane formation from a bis-azacrown derivative as host and imidazolium ion-derivatives as guest. AB - A new host molecule, having two azacrown derivatives bridged by luminescent naphthalene diimide functionality, is found to form a [3]pseudorotaxane derivative with imidazolim ion-based guest molecules in non-polar solvents through hydrogen-bonded adduct formation. Depending upon the length of the covalent linker that links the imidazolium ion and the luminescent naphthalene fragment in the guests, the [3]pseudorotaxane adducts adopt different conformation or orientation with varying pi-pi/donor-acceptor interaction. The mechanism for the naphthalene-based luminescence quenching by NDI fragment on adduct formation was found to be a combination of static, as well as dynamic with static quenching as the dominant one. PMID- 21523293 TI - New multicomponent cyclization: domino synthesis of pentasubstituted pyridines under solvent-free conditions. AB - An efficient methodology for the synthesis of highly functionalized pyridine derivatives starting from readily available common reactants has been developed under microwave irradiation and solvent-free conditions. The new domino reaction enables successful assembly of five new sigma bonds including two C-N bonds in a one-pot operation. A new mechanism has been proposed, which involves a novel reaction and sequence consisting of deprotonation-imine formation-anionic carbonyl addition. PMID- 21523294 TI - Improved surface-enhanced Raman scattering on micro-scale Au hollow spheres: synthesis and application in detecting tetracycline. AB - Au nanoparticles (NPs) forming a Au shell are coated on the surfaces of Ni microparticles (MPs) through a simple redox-transmetalation reaction, forming Ni/Au core-shell MPs. Then Au hollow spheres (HSs) are prepared by etching the Ni core in 1 mol L(-1) HCl solution. Surface-enhanced Raman scattering (SERS) spectroscopy signals of typical analytes such as rhodamine 6G (R6G) are observed on micro-scale Au HSs, even though the concentration of the analyte is as low as 10(-15) mol L(-1) (R6G). The Au HSs are also applied to detect tetracycline (TC), and a strong SERS signal is observed with the TC concentration of 0.1 MUg L(-1). The quantitative analysis can be performed at 1595 and 1320 cm(-1), and a good linear response is also obtained. This work provides a potential and unique technique to detect broad-spectrum polyketide antibiotics in the future, and the detection of TC in foods and milk can also be performed using this SERS-based Au HSs substrate, which will benefit human health. PMID- 21523295 TI - CSC-pincer versus pseudo-pincer complexes of palladium(II): a comparative study on complexation and catalytic activities of NHC complexes. AB - Three thioether bridged diimidazolium dibromides with different steric and electronic properties have been synthesized as precursors to carbene-based CSC pincer ligands. Palladation afforded CSC Pd(II) pincer complexes for bulky and electron rich ligand systems, whereas the least donating ligand led to the formation of a pseudo-pincer complex. All complexes have been fully characterized by multinuclei NMR spectroscopies, ESI mass spectrometry and X-ray diffraction analysis. The catalytic activities of pincer versus pseudo-pincer complexes have been compared in the intermolecular hydroamination of alkynes with anilines as well. PMID- 21523296 TI - The devil is in the details (or the surface): impact of surface structure and surface energetics on understanding the behavior of nanomaterials in the environment. AB - Metal and metal oxide nanomaterials are found in many consumer products for use in a wide range of applications including catalysis, sensors and contaminant remediation. Because of the extensive use of metal-based nanomaterials, there are concerns that these materials have the potential to get into the environment sometime during production, distribution, use and/or disposal. In particular, there exists the potential that they will make their way into water systems, e.g. drinking water systems, ground water systems, estuaries and lakes. In this review, some of the uncertainties in understanding nanoparticle behavior, which is often due to a lack of fundamental knowledge of the surface structure and surface energetics for very small particles, are discussed. Although classical models may provide guidance for understanding dissolution and aggregation of nanoparticles in water, it is the detailed surface structure and surface chemistry that are needed to accurately describe the surface free energy, a large component of the total free energy, in order to fully understand these processes. Without this information, it is difficult to develop a conceptual framework for understanding the fate, transport and potential toxicity of nanomaterials. Needed research areas to fill this void are discussed. PMID- 21523297 TI - Supramolecular self-assembly of biopolymers with carbon nanotubes for biomimetic and bio-inspired sensing and actuation. AB - Biopolymers are important natural multifunctional macromolecules for biomimetic and bio-inspired advanced functional material design. They are not only simple dispersants for carbon nanotube stabilization as they have been found to have specific interactions with carbon nanotubes. Their molecular activity, orientation and crystallization are influenced by the CNTs, which endow their composites with a variety of novel sensing and actuation performances. This review focuses on the progress in supramolecular self-assembly of biopolymers with carbon nanotubes, and their advances in sensing and actuation. To promote the development of advanced biopolymer/CNT functional materials, new electromechanical characteristics of biopolymer/CNT composites are discussed in detail based on the relationship between the microscopic biopolymer structures and the macroscopic composite properties. PMID- 21523298 TI - Cationic modified nucleic acids for use in DNA hairpins and parallel triplexes. AB - Non-nucleosidic DNA monomers comprising partially protonated amines at low pH have been designed and synthesized. The modifications were incorporated into DNA oligonucleotides via standard DNA phosphoramidite synthesis. The ability of cationic modifications to stabilize palindromic DNA hairpins and parallel triplexes were evaluated using gel electrophoresis, circular dichroism and thermal denaturation measurements. The non-nucleosidic modifications were found to increase the thermal stability of palindromic hairpins at pH 8.0 as compared with a nucleosidic tetraloop (TCTC). Incorporation of modifications at the 5'-end of a triplex forming oligonucleotide resulted in a significant increase in thermal stability at low pH when the modifications were placed as the 5'-dangling end. PMID- 21523299 TI - N-aryl pyrazoles: DFT calculations of CH acidity and deprotonative metallation using a combination of lithium and zinc amides. AB - A series of N-aryl and N-heteroaryl pyrazoles have been deproto-metallated using a 2,2,6,6-tetramethylpiperidino-based mixed lithium-zinc combination. Mono-, di-, and tri-iodides have been obtained after subsequent trapping with iodine, depending on the substrate and on the quantity of base used. The results have been discussed in the light of the CH acidities of the substrates, determined both in the gas phase and in THF solution using the DFT B3LYP method. PMID- 21523300 TI - Modification of the deoxy-myoglobin/carbonmonoxy-myoglobin UV-vis assay for reliable determination of CO-release rates from organometallic carbonyl complexes. AB - The deoxy-myoglobin (deoxy-Mb)/carbonmonoxy-myoglobin (Mb-CO) UV-vis assay is the principal method used for quantifying the rates of CO release from CO-releasing molecules (CO-RMs) that might possess therapeutic benefits. Some issues emerge when the Mb-CO assay is utilized for testing CO-RMs with novel structures, which are comprehensively discussed here for the first time. Two methods for processing raw UV-vis spectroscopic data generated from the assay are presented in this paper. PMID- 21523301 TI - Interaction of Triapine and related thiosemicarbazones with iron(III)/(II) and gallium(III): a comparative solution equilibrium study. AB - Stoichiometry and stability of Ga(III), Fe(III), Fe(II) complexes of Triapine and five related alpha-N heterocyclic thiosemicarbazones with potential antitumor activity have been determined by pH-potentiometry, UV-vis spectrophotometry, (1)H NMR spectroscopy, and spectrofluorimetry in aqueous solution (with 30% DMSO), together with the characterization of the proton dissociation processes. Additionally, the redox properties of the iron complexes were studied by cyclic voltammetry at various pH values. Formation of high stability bis-ligand complexes was found in all cases, which are predominant at physiological pH with Fe(III)/Fe(II), whilst only at the acidic pH range with Ga(III). The results show that among the thiosemicarbazones with various substituents the N-terminal dimethylation does not exert a measurable effect on the redox potential, but has the highest impact on the stability of the complexes as well as the cytotoxicity, especially in the absence of a pyridine-NH(2) group in the molecule. In addition the fluorescence properties of the ligands in aqueous solution and their changes caused by Ga(III) were studied. PMID- 21523302 TI - Enrichment and sequencing of phosphopeptides on indium tin oxide coated glass slides. AB - Unambiguous identification of phosphorylation sites is of premier importance to biologists, who seek to understand the role of phosphorylation from the perspective of site-specific control of biological phenomena. Despite this widely asked and highly specific information, many methods developed are aimed at analysis of complete proteomes, indeed even phospho-proteomes, surpassing the basic requests of many biologists. We have therefore further developed a simple method that specifically deals with the analysis of multiple phosphorylation sites on singular proteins or small collections of proteins. With this method, the whole purification process, from sample application to MALDI-MS analysis, can be performed on commercially available indium tin oxide (ITO) coated glass slides. We show that fifteen (15) samples can be purified within one hour, and that low femtomole sensitivity can be achieved. This limit of identification is demonstrated by the successful MS/MS-based identification of 6 fmol of monophosphopeptide from beta-casein. We demonstrate that the method can be applied for identifying phosphorylation sites from recombinant and cell-derived biological protein samples. Since ITO-coated glass slides are inexpensive and available from several suppliers the method is readily and inexpensively available to other researchers. Taken together, the presented protocols and materials render this method as an extremely fast and sensitive phosphopeptide identification protocol that should aid biologists in discovery and validation of phosphorylation sites. PMID- 21523303 TI - Synthesis and reactivity of cationic niobium and tantalum methyl complexes supported by imido and beta-diketiminato ligands. AB - The synthesis and reactivity of the cationic niobium and tantalum monomethyl complexes [(BDI)MeM(N(t)Bu)][X] (BDI = [Ar]NC(CH(3))CHC(CH(3))N[Ar], Ar = 2,6 (i)Pr(2)C(6)H(3); M = Nb, Ta; X = MeB(C(6)F(5))(3), B(C(6)F(5))(4)] was investigated. The cationic alkyl complexes failed to irreversibly bind CO but formed phosphine-trapped acyl complexes [(BDI)(R(3)PC(O)Me)M(N(t)Bu)][B(C(6)F(5))(4)] (R = Et, Cy) in the presence of a combination of trialkylphosphines and CO. Treatment of the monoalkyl cationic Nb complex with XylNC (Xyl = 2,6-Me(2)-C(6)H(3)) resulted in irreversible formation of the iminoacyl complex [(BDI)(XylN[double bond, length as m dash]C(Me))Nb(N(t)Bu)][B(C(6)F(5))(4)], which did not bind phosphines but would add a methide group to the iminoacyl carbon to provide the known ketimine complex (BDI)(XylNCMe(2))Nb(N(t)Bu). Further stoichiometric chemistry explored i) migratory insertion reactions to form new alkoxide, amidinate, and ketimide complexes; ii) protonolysis reactions with Ph(3)SiOH to form thermally robust cationic siloxide complexes; and iii) catalytic high-density polyethylene formation mediated by the cationic Nb methyl complex. PMID- 21523304 TI - Incorporation of graphene in quantum dot sensitized solar cells based on ZnO nanorods. AB - We demonstrate a novel architecture of solar cell by incorporating graphene thin film in a quantum dot sensitized solar cell. Quantum dot sensitized nanorods with a graphene layer exhibited a 54.7% improvement comparing a quantum dot sensitized ZnO nanorods without graphene layer. A fill factor as high as ~62% was also obtained. PMID- 21523305 TI - Monomeric, trimeric, and tetrameric transition metal complexes (Mn, Fe, Co) containing N,N-bis(2-pyridylmethyl)-2-aminoethanol/-ate: preparation, crystal structure, molecular magnetism and oxidation catalysis. AB - The reaction of N,N-bis(2-pyridylmethyl)-2-aminoethanol (bpaeOH), NaSCN/NaN(3), and metal (M) ions [M = Mn(II), Fe(II/III), Co(II)] in MeOH, leads to the isolation of a series of monomeric, trimeric, and tetrameric metal complexes, namely [Mn(bpaeOH)(NCS)(2)] (1), [Mn(bpaeO)(N(3))(2)] (2), [Fe(bpaeOH)(NCS)(2)] (3), [Fe(4)(bpaeO)(2)(CH(3)O)(2)(N(3))(8)] (4), [Co(bpaeOH)(NCS)(2)] (5), and [Co(3)(bpaeO)(2)(NO(3))(N(3))(4)](NO(3)) (6). These compounds have been investigated by single crystal X-ray diffractometry and magnetochemistry. In complex 1 the Mn(II) is bonded to one bpaeOH and two thiocyanate ions, while in complex 2 it is coordinated to a deprotonated bpaeO(-) and two azide ions. The oxidation states of manganese ions are 2+ for 1 and 3+ for 2, respectively, indicating that the different oxidation states depend on the type of binding anions. The structures of monomeric iron(II) and cobalt(II) complexes 3 and 5 with two thiocyanate ions are isomorphous to that of 1. Compounds 1, 2, 3, and 5 exhibit high-spin states in the temperature range 5 to 300 K. 4 contains two different iron(III) ions in an asymmetric unit, one is coordinated to a deprotonated bpaeO(-), an azide ion, and a methoxy group, and the other is bonded to three azide ions and two oxygens from bpaeO(-) and a methoxy group. Two independent iron(III) ions in 4 form a tetranuclear complex by symmetry. 4 displays both ferromagnetic and antiferromagnetic couplings (J = 9.8 and -14.3 cm(-1)) between the iron(III) ions. 6 is a mixed-valence trinuclear cobalt complex, which is formulated as Co(III)(S = 0)-Co(II)(S = 3/2)-Co(III)(S = 0). The effective magnetic moment at room temperature corresponds to the high-spin cobalt(II) ion (~4.27 MU(B)). Interestingly, 6 showed efficient catalytic activities toward various olefins and alcohols with modest to excellent yields, and it has been proposed that a high-valent Co(V)-oxo species might be responsible for oxygen atom transfer in the olefin epoxidation and alcohol oxidation reactions. PMID- 21523306 TI - Characterization of non-8-17 sequences uncovers structurally diverse RNA-cleaving deoxyribozymes. AB - RNA-cleaving deoxyribozymes (DNAzymes) can be isolated from random-sequence DNA pools via the process of in vitro selection. However, small and simple catalytic motifs, such as the 8-17 DNAzyme, are commonly observed in sequence space, presenting a challenge in discovering large and complex DNAzymes. In an effort to investigate underrepresented molecular species derived from in vitro selection, in this study we sought to characterize non-8-17 sequences obtained from a previous in vitro selection experiment wherein the 8-17 deoxyribozyme was the dominant motif. We examined 9 sequence families from 21 motifs by characterizing their structural and functional features. We discovered 9 novel deoxyribozyme classes with large catalytic domains (>40 nucleotides) utilizing three-way or four-way junction structural frameworks. Kinetic studies revealed that these deoxyribozymes exhibit moderate to excellent catalytic rates (k(obs) from 0.003 to 1 min(-1)), compared to other known RNA-cleaving DNAzymes. Although chemical probing experiments, site-directed mutational analyses, and metal cofactor dependency tests suggest unique catalytic cores for each deoxyribozyme, common dinucleotide junction selectivity was observed between DNAzymes with similar secondary structural features. Together, our findings indicate that larger, structurally more complex, and diverse catalytic motifs are able to survive the process of in vitro selection despite a sequence space dominated by smaller and structurally simpler catalysts. PMID- 21523307 TI - Universal relation for size dependent thermodynamic properties of metallic nanoparticles. AB - The previous model on surface free energy has been extended to calculate size dependent thermodynamic properties (i.e., melting temperature, melting enthalpy, melting entropy, evaporation temperature, Curie temperature, Debye temperature and specific heat capacity) of nanoparticles. According to the quantitative calculation of size effects on the calculated thermodynamic properties, it is found that most thermodynamic properties of nanoparticles vary linearly with 1/D as a first approximation. In other words, the size dependent thermodynamic properties P(n) have the form of P(n) = P(b)(1 -K/D), in which P(b) is the corresponding bulk value and K is the material constant. This may be regarded as a scaling law for most of the size dependent thermodynamic properties for different materials. The present predictions are consistent literature values. PMID- 21523308 TI - Two levels of conformational pre-organization consolidate strong CH hydrogen bonds in chloride-triazolophane complexes. AB - Structural rigidity is verified as a pre-organizational factor that acts together with the macrocyclic effect such that synthesis helps in paying the cost of bringing together electropositive CH donors ready for H-bonding with chloride. PMID- 21523309 TI - Stereochemical effects of chiral monolayers on enhancing the resistance to mammalian cell adhesion. AB - This work describes the different durations of surface confinement of adhered mammalian cells by monolayers comprised of enantiomers of bio-inert polyol terminated alkanethiols. Enhanced resistance to protein adsorption and cell adhesion is obtained on monolayers formed by a racemic mixture of the enantiomeric alkanethiols. PMID- 21523310 TI - Morphological families of self-assembled porphyrin structures and their photosensitization of hydrogen generation. AB - Varying the solution growth conditions of cooperative binary ionic solids composed of anionic and cationic metalloporphyrins produces a series of families of self-assembled structures that efficiently and durably photosensitize the evolution of hydrogen. PMID- 21523311 TI - Highly chemoselective hydrogenation of crotonaldehyde over Ag-In/SBA-15 fabricated by a modified "two solvents" strategy. AB - In the challenging crotonaldehyde hydrogenation to crotyl alcohol, an Ag-In/SBA 15 catalyst fabricated by a modified "two solvents" strategy shows an unprecedentedly high yield of 86% at a selectivity of 87%, which exceeds the best results on Pt-, Au- and other Ag-based heterogeneous catalysts reported so far. PMID- 21523312 TI - Efficient and facile formation of two-component nanoparticles via aromatic moiety directed self-assembly. AB - Here we present a two-component self-assembling system employing the interaction of aromatic groups (Fmoc) to construct nanoparticles. Spherical particles of around 70 nm were formed spontaneously by a simple trigonal Fmoc-conjugate, which were then stabilized by Fmoc-dipeptides at physiological pH in aqueous solution. These novel particles, being well-tolerated by cells, capable of encapsulating hydrophobic compounds, and readily decorated by short peptides, are promising carriers for drug delivery. PMID- 21523313 TI - Singlet and triplet energy transfer rate acceleration by additions of clusters in supramolecular pigment-organometallic cluster assemblies. AB - Both S(1) and T(1) energy transfer rates (porphyrin -> cluster) increase from mono- to di- to tetracarboxylate[tetraphenyl-(zinc)porphyrin] adducts with [Pd(3)(dppm)(3)(CO)](2+) clusters. PMID- 21523314 TI - Superhydrophobic nanostructured silicon surfaces with controllable broadband reflectance. AB - Nanostructured superhydrophobic silicon surfaces with tunable reflectance are fabricated via a simple maskless deep reactive-ion etching process. By controlling the scale of the high-aspect-ratio nanostructures on a wafer-scale surface, surface reflectance is maximized or minimized over the UV-vis-IR range while maintaining superhydrophobic properties. PMID- 21523315 TI - Role of free space and weak interactions on geometric isomerization of stilbenes held in a molecular container. AB - Photochemical geometric isomerization of olefins is long known to depend on the medium in which it occurs. Highest selectivity occurs in flexible biological systems as well as in inflexible crystals. We present results in this report that suggest the isomerization is selective even in an isotropic flexible aqueous medium provided it occurs within an isolated water-soluble inflexible reaction cavity. By examining the photochemistry of twelve stilbenes (trans and corresponding cis isomers) included in an organic cavitand octa acid we have been able to probe the role of 'free volume', 'weak interactions' and 'supramolecular steric effects' on the geometric isomerization process. Geometric isomerization becomes selective when the olefin's mobility is restricted by the medium through weak interactions, supramolecular steric effects and controlled free space (free volume). PMID- 21523316 TI - Functional status measurement in COPD: a review of available methods and their feasibility in primary care. AB - AIM: Guidelines advocate that improvement in functional status should be a major goal in COPD treatment. Many tools are available to assess aspects of functional status. This review aims to categorize systematically the available tools based on their construct (i.e. what the tool intends to measure) and to rate the tools for use in the primary care setting. METHODS: PubMed was searched with the keywords 'functional status' or 'physical capacity' or 'functional capacity' and 'COPD'. All tools were categorised and rated on their measurement properties, feasibility, and usage in primary care COPD patients. The tools were divided into four constructs - functional capacity, functional performance, functional reserve, and capacity utilisation - and used the following modes of measurement: laboratory tests; semi-laboratory tests; field tests; and patient-reported outcomes. RESULTS: The PubMed search resulted in 364 articles. Thirty-two tools were identified and rated. CONCLUSIONS: In primary care, the 6-minute walking distance test is the most reliable semi-laboratory functional capacity test, but is not very practical. The pedometer is the best functional performance field test. The Medical Research Council (MRC) dyspnoea questionnaire and the functional status domain of the Clinical COPD Questionnaire (CCQ) are the best patient-reported outcome tools to assess functional performance. PMID- 21523317 TI - Integrating evidence in disability evaluation by social insurance physicians. AB - OBJECTIVE: The aim of this study was to explore applying the method of evidence based medicine (EBM) to resolve common questions in the field of disability evaluation. METHODS: We used three clinical questions corresponding to problems encountered by insurance physicians in daily practice to explore opportunities for and barriers to the application of EBM. The questions fell under two topics: the prognosis of work ability and the effectiveness of interventions to enhance work participation. We used the four-step EBM strategy: (i) formulation of a clinical question, (ii) searching the literature, (iii) appraisal of the evidence, and (iv) implementation of the findings into clinical practice. We restricted the searches to PubMed (Medline). RESULTS: For rheumatoid arthritis, we found evidence on the prognosis of work disability over a long-term period. For remaining sciatica after lumbar discectomy, we found evidence for the stability of the limitations at this stage. For depression with co-morbid alcoholism, we found evidence that treatment of both conditions would enhance work participation. The searches were effective and efficient. The interpretation of the findings was hampered by a lack of consensus in the literature about outcomes such as the concept of a poor prognosis of work ability. CONCLUSIONS: The EBM strategy and methods can be used by social insurance physicians to find and apply evidence for common questions in disability evaluation. The World Health Organization's International Classification of Functioning, Disability, and Health (ICF) model is instrumental in this, although more consensus on central outcome measures is needed. Further research is needed on the translation of evidence into practice. Development of valid specific search strategies for physicians in disability evaluation would improve the implementation of EBM. PMID- 21523318 TI - Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. AB - The MAPK pathway is one of the most important pathways for novel anticancer drug development. We performed high-throughput screening for compounds that induce expression of p15INK4b, and identified JTP-74057 (GSK1120212), which is being evaluated in ongoing phase I, II and III clinical trials. We characterized its antitumor activities in vitro and in vivo. JTP-74057 strongly inhibited MEK1/2 kinase activities, but did not inhibit another 98 kinase activities. Treatment by JTP-74057 resulted in growth inhibition accompanied with upregulation of p15INK4b and/or p27KIP1 in most of the colorectal cancer cell lines tested. Daily oral administration of JTP-74057 for 14 days suppressed tumor growth of HT-29 and COLO205 xenografts in nude mice. Notably, tumor regression was observed only in COLO205 xenografts, and COLO205 was much more sensitive to JTP-74057-induced apoptosis than HT-29 in vitro. Treatment with an Akt inhibitor enhanced the JTP 74057-induced apoptosis in HT-29 cells. Finally, JTP-74057 exhibited an additive or a synergistic effect in combination with the standard-of-care agents, 5 fluorouracil, oxaliplatin or SN-38. JTP-74057, a highly specific and potent MEK1/2 inhibitor, exerts favorable antitumor activities in vitro and in vivo. Sensitivity to JTP-74057-induced apoptosis may be an important factor for the estimation of in vivo efficacy, and sensitivity was enhanced by an Akt inhibitor. These results suggest the usefulness of JTP-74057 in therapeutic applications for colorectal cancer patients. PMID- 21523319 TI - Molecular characteristics of three hemoglobin variants observed in a Chinese population: Hb Ube-1 [beta98 (FG5) Val->Met], Hb Ube-2 [alpha68 (E17) Asn->Asp] and Hb Ube-4 [alpha116 (GH4) Glu->Ala]. AB - In this study we report three cases of Hb Ube-1, one case of Hb Ube-2 and one case of Hb Ube-4 in mainland China. One case of Hb Ube-1 had the clinical manifestation of hemolytic anemia. Hb Ube-2 and Hb Ube-4 did not appear to be associated with clinical or hematological abnormalities. The variants were detected by Hb electrophoresis during a thalassemia screening. Genomic DNA was extracted from the peripheral blood leukocytes of Hb specimens. alpha1, alpha2 and beta-globin genes were amplified by polymerase chain reaction (PCR). All variants were confirmed by DNA sequence analysis and the PCR-restriction fragment length polymorphism assay. PMID- 21523320 TI - Immunohistochemical analysis of in vivo UVB-induced secretion of IL-1alpha and IL 6 in keratinocytes. AB - Keratinocytes play an important role in the inflammatory response of the skin. UVB stimulates keratinocytes to secrete several cytokines. To our knowledge, there are no reports that have examined which layer or cell type is responsible for producing these cytokines. Thus, in this study we performed immunohistochemical experiments to determine the potential cells or layers that express interleukin (IL)-1 and IL-6. The results show that the expression of IL 1alpha and IL-6 was induced 3 and 6 h after irradiation, respectively. Furthermore, IL-1alpha was maximally expressed earlier than IL-6, suggesting that IL-1alpha exists in the cytokine cascade of the UVB response upstream of IL-6. In addition, IL-1alpha expression began in the upper layers of the epidermis, whereas all layers expressed IL-6. This study provides further insight into the roles of cytokines in UVB-induced skin inflammation. PMID- 21523321 TI - Homer expression in the hippocampus of an animal model of attention deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a pervasive neurobehavioral disorder. We previously demonstrated differential expression of some isoforms of Homer, a family of scaffolding proteins localized to the postsynaptic density of glutamatergic excitatory synapses, in the spontaneous hypertensive rat (SHR), which is the most frequently used animal model of ADHD. Since these changes were observed in the prefrontal cortex (PFC), a critical structure in ADHD, it was hypothesized that these Homer isoforms may play a role in ADHD. The present study aimed to extend these findings to the hippocampus, which has direct connections to the PFC and subserves attention and cognition, two functions that are disturbed in ADHD. Hippocampal mRNA and protein expression of several Homer isoforms were investigated in both SHR and control Wistar-Kyoto (WKY) rats using reverse transcription-polymerase chain reaction and Western blotting, respectively. Both mRNA and protein for Homer 1a and Homer 2a/b, but not Homer 1b/c, were expressed at significantly lower levels in the hippocampus of SHR compared to WKY rats. The effects of methylphenidate (MPH) on spatial learning and memory in SHRs were also examined using the Morris water maze and on hippocampal expression of Homer isoforms. MPH improved spatial learning and memory and up-regulated hippocampal expression of Homer 1a and Homer 2a/b, but not Homer 1b/c, in SHRs. The animal model of ADHD may have altered expression of Homer 1a and Homer 2a/b in the hippocampus, in addition to the PFC. Future studies will focus on elucidating the specific mechanisms of Homer 1a and Homer 2a/b in ADHD. PMID- 21523322 TI - Osteosarcoma amplified 9 is highly expressed in mouse adipocytes and controls lipid storage. AB - Adipocytes are among the most important cells for energy storage, metabolism and balance in mammals. Dysfunctional adipocytes are closely associated with type 2 diabetes and obesity, and thus with insulin resistance and inflammation. Recent studies show that endoplasmic reticulum (ER) stress may be responsible for obesity-induced insulin resistance. In this study, we investigated an ER associated degradation-related protein in adipocytes, namely osteosarcoma amplified 9 (OS-9), a protein that is reported to have lectin activity and to be involved in ER quality control. We found that OS-9 is expressed at high levels in both types of fat tissues - brown and white adipose tissues - and we examined the subcellular localization of OS-9 in 3T3-L1 adipocytes. Furthermore, we observed that the expression levels of the OS-9 protein gradually increased as 3T3-L1 adipocytes differentiated. Most notably, we found that the depletion of this protein influences adipocyte differentiation and lipid storage, although the mechanism behind this is unclear. PMID- 21523323 TI - Analysis of the role of the BMP7-Smad4-Id2 signaling pathway in SW480 colorectal carcinoma cells. AB - The bone morphogenetic proteins (BMPs) Smad4 and Id2 exert their effect on colorectal carcinoma via several uncharacterized mechanisms. In this study, we investigated whether the transcription factor Id2, which has been implicated in colorectal carcinoma proliferation and metastasis, is involved in BMP-7/Smad4 signaling, or whether it is regulated by BMP-7 via another mechanism in this cell type. A Smad4-cDNA vector was constructed and stably transfected into SW480 cells. Protein levels of Smad4 and Id2 were examined by Western blotting. Inhibitory effects on cellular proliferation activity were determined by the methyl thiazolyl tetrazolium (MTT) assay, and invasion and migration potential was detected using the in vitro Matrigel-coated invasion and migration assay. Levels of Smad4 protein were significantly increased in SW480 cells transfected with Smad4-cDNA, compared to those transfected with empty vector. Growth curve analysis revealed that live cell numbers were lower in the Smad4-expressing group than in the control group after 36 h, and that BMP7 treatment caused an increase in live cell numbers in Smad4-expressing cells. Transwell chamber analysis revealed that migration/invasion activity was significantly suppressed when Smad4 was expressed. Finally, Smad4-expressing cells treated with BMP7 expressed a higher level of Id2 protein than the controls. The results indicate that Smad4 expression may inhibit the growth and invasion of SW480 cells, and that BMP7 affects Id2 levels through Smad4. Therefore, BMP7-Smad4-Id2 signaling may play a significant role in the development of colorectal carcinoma. PMID- 21523324 TI - Identification of genes related to carcinogenesis of oral leukoplakia by oligo cancer microarray analysis. AB - The aim of this study was to identify genes that are predictive of carcinogenic change in patients of oral leukoplakia (OLK) using a cancer-related microarray. Candidate biomarkers were discovered using the Oligo GEArray OHS-802 and validated on independent samples by semi-quantitative reverse transcription-PCR (RT-PCR) and real-time RT-PCR. Both the discovery and the validation cohorts of samples included normal oral tissues, OLK tissues and oral squamous cell carcinoma (OSCC) tissues. Based on the microarray results, we found that there were nine genes successively up-regulated or down-regulated more than 2-fold between the normal group and OLK group and then again between the OLK group and OSCC group. The expression levels of the nine signature genes had statistically significant differences (p<0.05) between the OLK and normal groups and between the OSCC and OLK groups. In summary, the expression of the 9 signature genes might be representative of OLK carcinogenesis. A cancer-related microarray was used to identify a panel of candidate biomarkers for determining carcinogenesis of OLK lesions, in combination with semi-quantitative and real-time RT-PCR to validate the results. Our data indicated that alterations in gene expression that result in carcinogenesis can be identified in precancerous oral tissues. PMID- 21523325 TI - Impact of newer unidirectional and bidirectional barbed suture on vesicourethral anastomosis during robot-assisted radical prostatectomy and its comparison with polyglecaprone-25 suture: an initial experience. AB - OBJECTIVE: To evaluate impact of unidirectional barbed suture on vesicourethral anastomosis (VUA) during robot-assisted radical prostatectomy (RARP) and its comparison with Polyglecaprone-25 suture. PATIENTS AND METHODS: The study was initiated as pilot study; the participants were grouped into three based on the suture material used for VUA, i.e., monofilament Polyglecaprone-25 (group 1), unidirectional barbed Glycolic acid-trimethylene carbonate (group 2), and bidirectional barbed Polyglycolic acid-polycaprolactone (group 3), respectively. Group 1 was included retrospectively and the latter two prospectively. All cases were operated upon by the same surgeon, proficient in RARP. Patient-demographics, intraoperative and peri-operative data were collected. Our technique of mucosa-to mucosa VUA is carried out in a choreographed manner using unibarbed suture. RESULTS: Fifty-five patients were included; 25 each in group 1 and 2. The group 3 was prematurely closed after 5 cases due to perceived inappropriateness of needle characteristics of the suture material. Therefore, the statistical analysis was performed between group 1 and 2 only. Preoperative characteristics including age, PSA, clinical stage, and biopsy grade were similar between the groups. The anastomosis time was significantly less in group 2 (8.4 +/- 1.7 min vs. 14.3 +/- 4.8 min; P = 0.0001; t test). Postoperative hospital stay was less in group 2 (2.7 +/- 1.1 days vs. 1.9 +/- 0.8 days; P = 0.023; Mann-Whitney U). None of the patient had presented with urinary leaks, urinary retention, or anastomotic strictures at follow-up of 6 months. CONCLUSION: VUA with unidirectional barbed suture is safe and takes less time compared to monofilament suture as repeated cinching; help of assistance and knot tying are not required by virtue of its self-retaining characteristics. PMID- 21523326 TI - Long-term functional outcome in geriatric hip fracture patients. AB - BACKGROUND: Fragility fractures are a major health care problem worldwide. The proportion of the geriatric population and the overall life expectancy will increase. Hip fractures are the most common fragility fractures needing surgery and nowadays treatment concepts are changing. We studied the long-term functional outcome and their influencing factors in patients treated without any interdisciplinary aspects. DESIGN AND SETTING: A retrospective cohort study with functional long-term follow-up examination was carried out in a level one trauma centre on hip fracture patients 80 years old and above treated without any formalized interdisciplinary aspects ("usual care"). PATIENTS: Of 281 consecutive patients who were treated 2005 and 2006 with usual care, 246 patients with a mean age of 86.8 years met our inclusion criteria. 69.1% died within the study period of 4.9 years. On the remaining patients, the residential status, the Barthel Index and the Parker Score were assessed. RESULTS: The mean Barthel Index was 49.6 and the mean Parker Score was 2.7. More than one-fourth of the survivors were found to be bedridden and 45% were not able to walk outside. 88% are bound to one floor and only 8% are able to walk unaided. Patients with more comorbidities and patients with subsequent fractures had significant higher mortality rates. Patients with trochanteric fractures had significant better functional outcome scores compared to patients with femoral neck fractures. Nursing home residents showed significant higher mortality rates and lower functional outcome scores. Patients who were transferred to a nearby acute geriatric hospital for further treatment had significantly higher functional outcome scores. CONCLUSION: This paper shows the frustrating long-term outcome of geriatric hip fracture patients but it also suggests that an early geriatric intervention may lead to better function. PMID- 21523327 TI - Prospective analysis of health-related quality of life and clinical evaluations in patients with anterior cruciate ligament injury undergoing reconstruction. AB - INTRODUCTION: This study aimed to evaluate the treatment outcome of patients with anterior cruciate ligament (ACL) injury using the patient-based quality of life (QOL) survey SF-36, and investigate the correlation with conventional objective assessment methods. Our hypothesis that SF-36 is a useful assessment method for QOL in patients with ACL injury, and this assessment clarifies the concord and the discord between doctor-based objective assessment. PATIENTS AND METHODS: A prospective study was conducted on patients who underwent ligament reconstruction. Eighty-one patients with a mean age of 27.4 years were analyzed. Clinical evaluations comprising SF-36 survey, Lysholm scoring, and anterior tibial translation measurement were conducted before as well as after surgery. The changes over time and the correlation between these evaluation methods were analyzed. RESULTS: All SF-36 subscales were significantly improved after surgery. Regarding QOL of patients with ACL injury, the preoperative scores of all the subscales except vitality and mental health were lower than the national standard values, while the postoperative scores of all subclasses were not different from the national standards. A correlation was found between Lysholm score and all SF 36 subscale scores except general health before surgery, but a correlation was observed only with physical functioning, bodily pain and role emotional at 6 months after surgery, and with physical functioning, role physical, bodily pain and vitality at 12 months. No correlation between SF-36 scores and distance of anterior tibial translation was observed both before and after surgery. DISCUSSION: The QOL of patients with ACL injury as assessed by SF-36 improved significantly after reconstruction surgery. The mental health subscales of SF-36 correlate with Lysholm score before surgery suggesting that apart from the physical impairment, lowered mental health is also an important clinical issue in patients with ACL injury. PMID- 21523328 TI - Antibody characterization and immunoassays for palytoxin using an SPR biosensor. AB - Palytoxin (PLTX), a polyether marine toxin originally isolated from the zoanthid Palythoa toxica, is one of the most toxic non-protein substances known. Fatal poisonings have been linked to ingestion of PLTX-contaminated seafood, and effects in humans have been associated with dermal and inhalational exposure to PLTX containing organisms and waters. Additionally, PLTX co-occurrence with other well-characterized seafood toxins (e.g., ciguatoxins, saxitoxins, tetrodotoxin) has hindered direct associations of PLTX to seafood-borne illnesses. There are currently no validated methods for the quantitative detection of PLTX(s). As such, a well-characterized, robust, specific analytical technique is needed for the detection of PLTX(s) in source organisms, surrounding waters, and clinical samples. Surface plasmon resonance (SPR) biosensors are ideally suited for antibody characterization and quantitative immunoassay detection. Herein, we describe a newly developed SPR assay for PLTX. An anti-mouse substrate was used to characterize the kinetic values for a previously developed monoclonal anti PLTX. The characterized antibody was then incorporated into a sensitive, rapid, and selective PLTX assay. Buffer type, flow rate, analyte-binding time, and regeneration conditions were optimized for the antibody-PLTX system. Cross reactivity to potentially co-occurring seafood toxins was also evaluated. We show that this optimized assay is capable of measuring low- to sub-ng/mL PLTX levels in buffer and two seafood matrices (grouper and clam). Preliminary results indicate that this SPR biosensor assay allows for (1) rapid characterization of antibodies and (2) rapid, sensitive PLTX concentration determination in seafood matrices. Method development information contained herein may be broadly applied to future PLTX detection and/or antibody characterization efforts. PMID- 21523329 TI - Cholesterol effects on vesicle pools in chromaffin cells revealed by carbon-fiber microelectrode amperometry. AB - Cell-cell communication is often achieved via granular exocytosis, as in neurons during synaptic transmission or neuroendocrine cells during blood hormone control. Owing to its critical role in membrane properties and SNARE function, cholesterol is expected to play an important role in the highly conserved process of exocytosis. In this work, membrane cholesterol concentration is systematically varied in primary culture mouse chromaffin cells, and the change in secretion behavior of distinct vesicle pools as well as pool recovery following stimulation is measured using carbon-fiber microelectrode amperometry. Amperometric traces obtained from activation of the younger readily releasable and slowly releasable pool (RRP/SRP) vesicles at depleted cholesterol levels showed fewer sustained fusion pore features (6.1 +/- 1.1% of spikes compared with 11.2 +/- 1.0% for control), revealing that cholesterol content influences fusion pore formation and stability during exocytosis. Moreover, subsequent stimulation of RRP/SRP vesicles showed that cellular cholesterol level influences both the quantal recovery and kinetics of the later release events. Finally, diverging effects of cholesterol on RRP and the older reserve pool vesicle release suggest two different mechanisms for the release of these two vesicular pools. PMID- 21523330 TI - Quantitative determination of element concentrations in industrial oxide materials by laser-induced breakdown spectroscopy. AB - Calibration-free laser-induced breakdown spectroscopy (CF-LIBS) method is employed for quantitative determination of oxide concentrations in multi component materials. Industrial oxide materials from steel industry are laser ablated in air, and the optical plasma emission is collected by spectrometers and gated detectors. The temperature and electron number density of laser-induced plasma are determined from measured LIBS spectra. Emission lines of aluminium (Al), calcium (Ca), iron (Fe), manganese (Mn), magnesium (Mg), silicon (Si), titanium (Ti), and chromium (Cr) of low self-absorption are selected, and the concentration of oxides CaO, Al(2)O(3), MgO, SiO(2), FeO, MnO, TiO(2), and Cr(2)O(3) is calculated by CF-LIBS analysis. For all sample materials investigated, we find good match of calculated concentration values (C(CF)) with nominal concentration values (C(N)). The relative error in oxide concentration, e(r) = |C(CF) - C(N)|/C(N), decreases with increasing concentration and it is e(r) <= 100% for concentration C(N) >= 1 wt.%. The CF-LIBS results are stable against fluctuations of experimental parameters. The variation of laser pulse energy over a large range changes the error by less than 10% for major oxides (C(N) >= 10 wt.%). The results indicate that CF-LIBS method can be employed for fast and stable quantitative compositional analysis of multi-component materials. PMID- 21523331 TI - Droplet microfluidics for the study of artificial cells. AB - In this review, we describe recent advances in droplet-based microfluidics technology that can be applied in studies of artificial cells. Artificial cells are simplified models of living cells and provide valuable model platforms designed to reveal the functions of biological systems. The study of artificial cells is promoted by microfluidics technologies, which provide control over tiny volumes of solutions during quantitative chemical experiments and other manipulations. Here, we focus on current and future trends in droplet microfluidics and their applications in studies of artificial cells. PMID- 21523332 TI - Dopamine-loaded chitosan nanoparticles: formulation and analytical characterization. AB - The formulation and characterization of dopamine (DA)-loaded chitosan nanoparticles (CSNPs) are described as preliminary steps for the development of potential DA carrier systems intended for Parkinson's disease treatment. For this purpose, CSNPs were firstly produced and, afterwards, they were incubated in a DA aqueous solution to promote neurotransmitter loading. The characterization of the resulting nanoparticles started with Fourier transform infrared spectroscopy analysis to ascertain the presence of DA in the nanocarrier, whereas X-ray photoelectron spectroscopy analysis provided evidence of the localization of DA on the nanoparticle surface. A quartz crystal microbalance with dissipation monitoring (QCM-D) was then exploited to investigate both swelling of CSNPs and interaction of DA with CSNPs. In particular, the QCM-D revealed that this interaction is fast and so this allows a stable nanostructured system to be obtained. PMID- 21523333 TI - Relative temporal leading or following position of the contralateral limb generates different aftereffects in muscle phasing following adaptation training post-stroke. AB - Locomotor coordination depends on precise and appropriate adjustments of intra- and interlimb muscle activity phasing. Muscle coordination deficits, in the form of inappropriately phased muscle activity patterns, are well recognized in both the paretic and non-paretic limbs of stroke survivors. Our recent work demonstrated that muscle phasing can be systematically influenced by changing the relative angular positions of limbs in both neurologically intact individuals and people post-stroke. However, it is still unknown whether the observed transient changes in adjusted muscle phasing can be adapted following a short-bout of training on the split-crank ergometer. To explore the extent to which the non paretic and paretic limbs of people with stroke can adapt to new muscle activity phasing changes, we examined the adaptation of muscle phasing following a short bout of pedaling training at two specific relative spatial angular positions of limbs that had caused the greatest phasing changes in our previous studies. Twelve individuals with post-cerebral stroke and twelve age- and gender-matched control subjects participated in this study. We demonstrated that both intact and cerebrally impaired nervous systems are capable of adapting new muscle phasing patterns and producing aftereffects that persisted for at least 10 min. However, we observed a completely different trend of aftereffects in post-stroke subjects compared with controls. Specifically, in controls, the aftereffects were observed only in the leg that was in the following position during the adaptation training whereas in post-stroke subjects, aftereffects were observed only in the leg that acted as the leading leg during adaptation, regardless of the limb being paretic or non-paretic. These findings suggest that adapting a new muscle activity pattern during a bilateral locomotor task depends mainly on the relative temporal position of contralateral limb. PMID- 21523334 TI - Emerging therapeutic targets for soft tissue sarcoma. AB - Soft tissue sarcomas (STS) are malignancies of mesenchymal origin that represent approximately 1% of cancers in adults. Systematic research into the treatment of STS is challenging given its rarity and disease heterogeneity. Despite the ability to histologically subtype STS, only recently has our approach to therapy begun to differentiate along these lines. The purpose of this review is to highlight emerging therapeutic targets and therapies that hold the potential to add to the current state of systemic treatment for STS. PMID- 21523335 TI - Polycomb group proteins in hematopoietic stem cell aging and malignancies. AB - Protection of the transcriptional "stemness" network is important to maintain a healthy hematopoietic stem cells (HSCs) compartment during the lifetime of the organism. Recent evidence shows that fundamental changes in the epigenetic status of HSCs might be one of the driving forces behind many age-related HSC changes and might pave the way for HSC malignant transformation and subsequent leukemia development, the incidence of which increases exponentially with age. Polycomb group (PcG) proteins are key epigenetic regulators of HSC cellular fate decisions and are often found to be misregulated in human hematopoietic malignancies. In this review, we speculate that PcG proteins balance HSC aging against the risk of developing cancer, since a disturbance in PcG genes and proteins affects several important cellular processes such as cell fate decisions, senescence, apoptosis, and DNA damage repair. PMID- 21523336 TI - Hematopoietic stem cell development, aging and functional failure. AB - Hematopoietic stem cells (HSCs) are found in yolk sac, fetal liver, umbilical cord blood, placenta, and amniotic fluid during mammalian embryonic development. In adults, HSCs reside in marrow cavity of long bones where they self-renew and differentiate to replenish short-lived mature blood cells. HSCs exist in very low frequencies within specific "niches" where they interact with the surrounding environment through molecular associations. Overall HSC function can last much longer than a normal lifetime, but HSCs do show functional senescence with characteristic features of decreased self-renewal, reduced clonal stability, reduced homing and engraftment, and biased lineage commitment. The progressive shortening of telomeres with increasing age, especially under conditions with specific mutations in the telomerase gene complex, could predispose patients to HSC dysfunction and bone marrow failure diseases. Continuous investigation into HSC biology should facilitate the utilization of HSCs as a therapeutic modality and helps to prevent HSC malfunction. PMID- 21523337 TI - Coexistence of inversion 16 and the Philadelphia chromosome comprising P190 BCR/ABL in chronic myeloid leukemia blast crisis. AB - A 63-year-old woman presented with leukocytosis (278 * 10(9)/L) with 72% blasts. Bone marrow blast cells showed cytogenetic abnormality with 46,XX, t(9;22), inv(16). Despite achievement of hematological remission by induction chemotherapy, Philadelphia chromosome did not disappear; chronic myeloid leukemia (CML) in blast crisis (BC) was thus diagnosed. The P190 BCR/ABL fusion transcript was detected. Imatinib mesylate introduced a hematological remission of short duration; however, infiltration into the central nervous system occurred, and the patient died 7 months after presentation. Coexistence of inv(16) and t(9:22) has been described in CML-BC and de novo AML, and CML-BC patients always carry P210 BCR/ABL, while de novo AML patients usually have P190 BCR/ABL. To the best of our knowledge, this is the first report of CML-BC with inv(16) and P190 BCR/ABL. We discuss this case with reference to the literature. PMID- 21523338 TI - Nilotinib as frontline therapy for patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: results from the Japanese subgroup of ENESTnd. AB - Recent results from the phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) study have demonstrated superiority of nilotinib over imatinib for the treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (CML-CP). Here, we report results from the Japanese subset of patients in ENESTnd, and assess whether results in this subpopulation are consistent with the overall study population. Seventy-nine Japanese patients with CML-CP were randomized to receive nilotinib 300 mg twice daily (BID) (n = 30), nilotinib 400 mg BID (n = 24) or imatinib 400 mg once daily (QD) (n = 25). Major molecular response rates at 12 months, the primary endpoint, were at least twice as high for nilotinib 300 mg BID (57%) and nilotinib 400 mg BID (50%) compared with imatinib 400 mg QD (24%). No patient on nilotinib progressed, while one patient progressed on imatinib. Both drugs were generally well tolerated and discontinuations due to adverse events were comparable among treatment arms. The results in the subpopulation of Japanese patients from ENESTnd closely mirror the results of the overall population, and support the use of nilotinib at 300 mg BID in Japanese patients with newly diagnosed CML-CP. PMID- 21523340 TI - Analysis of the pediatric surgery match: factors predicting outcome. AB - INTRODUCTION: Applicants in the NRMP for pediatric surgery have little objective data available regarding factors predicting successful matching. We analyzed data from applicants at our institution to attempt to identify parameters correlated with three outcomes: successfully matching, or attaining either a top ten or top three ranking in our final submitted match list. METHODS: After IRB approval, we reviewed ERAS documents for all applicants (n = 146) over 3 years (candidates for the 2007, 2008, and 2009 fellowship years). An interview was offered to 75% of the applicants (Table 1). We analyzed over 20 factors; including demographics, number of publications and first author publications, number of book chapters, national presentations, prior match attempts, advanced degrees, quality of recommendation letters, and ABSITE scores. Significant variables were evaluated with multiple logistic regression analysis to identify independent predictors. RESULTS: Variables correlated with successful outcome for each of the three endpoints are shown in Table 2. The number of peer-reviewed publications and first author publications, and AOA membership were highly correlated with a favorable outcome for all three endpoints. High ABSITE scores were significantly correlated with top ten rank. Research experience and outstanding letters of recommendation were significantly associated with a top ten ranking and overall match success. Variables associated only with overall match success included number of book chapters, graduation from a US medical school, quality of recommendation letters, and being granted an interview at our institution. Logistic regression analysis demonstrated no independent factors for overall match success; number of publications was significant for both top ten and top three ranking (P = 0.006 for each); number of first author publications (P = 0.002) and AOA membership (P = 0.03) were independent predictors for top three ranking. CONCLUSIONS: Applicant variables associated with success in the match included quality of letters, number and type of publications, research experience, graduation from a US medical school, and AOA membership. Factors not correlated with outcome included advanced degrees (PhD, Masters), other fellowship training, and community-based versus university-based residency training. Logistic regression analysis demonstrated no independent factors for overall match success. PMID- 21523339 TI - Adherence to the standard dose of imatinib, rather than dose adjustment based on its plasma concentration, is critical to achieve a deep molecular response in patients with chronic myeloid leukemia. AB - The correlation between imatinib (IM) trough plasma concentration (Cmin) and clinical response was assessed in patients with chronic-phase chronic myeloid leukemia. The Cmin correlated with neither the achievement of complete cytogenetic response (977 vs. 993 ng/ml, P = 0.48) nor a major molecular response (1,044 vs. 818 ng/ml, P = 0.17). Although this was significantly higher in patients with complete molecular response (CMR) than in those without (1,430 vs. 859 ng/ml, P = 0.04), the difference was not significant in the sub-population treated with a standard dose of IM (400 mg/day). Finally, multivariate analysis showed that the IM standard dose, but not Cmin, was predictive of the achievement of CMR. We thus suggest that, in practical clinics at least, adherence to the standard dose is the most important factor for the achievement of CMR. PMID- 21523341 TI - Accuracy of ultrasound-guided suprascapular nerve block measured with neurostimulation. AB - Although the use of ultrasound (US) to perform suprascapular nerve block (SsNB) is rapidly gaining popularity, information about its accuracy is still lacking. The aim of this study was to investigate the proximity of the needle to suprascapular nerve under US guidance by means of neurostimulation current intensity in SsNB. The patients who were referred for SSnB due to shoulder pain were included in the study. The patients were placed in sitting position, and when the operator decided that the needle was in the correct place under US guidance, the time duration until that time and the current amplitude in that location were recorded. Current intensity was obtained by gradually increasing the amplitude until patient feels parestesia over the shoulder area or contractions of the supraspinatus or infraspinatus muscles. Out of 27 patients, in five patients current intensity was between 0.1 and 0.8 mA (successful) and time duration was 2.52 +/- 1.67 min in this group; in 19 patients, current intensity was between 0.9 and 1.4 mA (semi-successful) and time duration was 1.86 +/- 1.02 min in this group; in three patients, current intensity was >= 1.5 mA (unsuccessful) and time duration was 2.41 +/- 1.02 min in this group. Our results show that the needle could not reach sufficient proximity to the suprascapular nerve with only US guidance by means of NS current intensity. PMID- 21523342 TI - Association of Rsa polymorphism of the estrogen receptor-beta gene with rheumatoid arthritis. AB - To investigate the possible influence of the single nucleotide polymorphism (SNP) of the estrogen receptor-beta gene, rs1256049 (Rsa) in exon 5, on the frequency of rheumatoid arthritis (RA), 263 RA patients and 174 control subjects with osteoarthritis (OA) were recruited. Rsa polymorphism was detected using a PCR RFLP, Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method. The occurrence of both mutant allele (G) and genotype (GG) were significantly higher in RA than in OA patients (allele P = 0.008, OR: 1.501, 95%CI: 1.12-2.02). In RA patients, GG genotype frequency was higher in severe RA patients than mild RA patients. Moreover, there was significant difference between severe RA patients and OA patients (P = 0.009), also the allele distribution was significant different between severe RA, mild RA, and OA patients (P = 0.025, 95%CI = 0.61-0.93). With respect to gender, GG genotype was statistically more frequent in female RA patients than that of OA, while such an association was not observed in men. Above all, the presence of the GG genotype could be a risk factor for RA and such trend might be different in gender, although additional larger scale study is needed. PMID- 21523343 TI - IL1B -511(G>A) and IL1RN (VNTR) allelic polymorphisms and susceptibility to knee osteoarthritis in Croatian population. AB - Osteoarthritis (OA) is a frequent, destructive joint disease, with debilitating impact on a society regarding medical, social, and economic issues. Although causes of primary OA were still not fully elucidated, evidence points to complex genetic risk that varies among different population groups, including the interleukin-1 (IL-1) gene cluster. Here, we sought to determine allelic and genotypic frequencies of the IL-1beta (IL1B) and the IL-1 receptor antagonist (IL1RN) genes using single nucleotide polymorphism (SNP) at -511(G>A; rs16944) and the variable number tandem repeat (VNTR) in a case-control study with 238 patients that have undergone total or partial knee replacement and 495 healthy blood donors as controls in Croatia. The alleles of the IL1B gene at -511G>A were detected by Taqman real-time polymerase chain reaction (PCR) method and IL1RN VNTR by amplifying its DNA by PCR. The genotypes 1-2/1-2 and 2-1/2-2 at IL1B G 511A-IL1RN (VNTR) showed trends for association with the occurrence of the knee OA in this population (P = 0.09; P = 0.07, respectively). Furthermore, neither the alleles nor the haplotypes were found associated with the predisposition to knee OA. Our findings suggest that knee OA might have a different genetic risk in this Caucasian population. We did not found significant association of the IL1 gene cluster (IL1B-IL1RN) with severe knee OA. However, we found that two genotypes (1-2/1-2 and 2-1/2-2) show a trend toward association with susceptibility to disease. PMID- 21523344 TI - Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate therapy. AB - To determine the efficacy of oral vitamin D [25(OH)D] in patients with active rheumatoid arthritis (RA) who are in methotrexate (MTX) therapy, patients receiving stable doses of MTX were randomized to one of two dose groups and received 12 weeks of double-blind vitamin D[25(OH)D] (50,000 IU per week) or matching placebo. The moderate and major efficacy measure was the proportion of patients with >0.6 and >1.2 improvement in RA based on the Disease Activity Score 28(DAS 28) at 12 weeks. Safety measures included adverse events and laboratory assessments. On a background of MTX, the percentage of patients with a moderate/major DAS 28 response at week 12 in the vitamin D groups (76/44%) was not significantly different from placebo (64.6/33.4%). Adverse events were typically mild and included small hepatic enzyme elevation; we did not have any undesirable events resulting in discontinuation of study drug. In patients with active RA receiving stable doses of MTX, vitamin D showed non-significant improvement in efficacy outcomes compared to placebo. PMID- 21523346 TI - Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period. AB - RATIONALE: Netrin-1 guidance cues contribute to amphetamine-induced plasticity of the adult mesocorticolimbic dopamine system in rodents. The netrin-1 receptor, deleted in colorectal cancer (DCC), is upregulated by repeated amphetamine treatment selectively in the ventral tegmental area (VTA) of adult rats and wild type mice. Furthermore, adult dcc heterozygous mice fail to show amphetamine induced increases in VTA DCC expression and do not develop sensitization to this drug. OBJECTIVES: The effects of netrin-1 receptor signaling on mesocorticolimbic dopamine system function change across development. However, the effects of AMPH on DCC receptor regulation and behavioral sensitization before puberty have not been determined. Here we examined whether (1) repeated amphetamine treatment would also alter DCC expression in juvenile rats and wild-type mice, and (2) dcc heterozygotes treated with amphetamine during the juvenile period (PND 22-32) would develop behavioral sensitization to this drug. RESULTS: Repeated amphetamine downregulates DCC expression selectively in the VTA of juvenile rodents. Moreover, the behavioral phenotype of adult dcc heterozygous mice is not present before puberty and is abolished by amphetamine treatment during the juvenile period. Remarkably, adult dcc heterozygotes pretreated with amphetamine as juveniles no longer exhibit reduced DCC expression in the VTA compared to wild type controls. CONCLUSIONS: Our results indicate that netrin-1 receptor signaling may be a key factor in determining individual differences in vulnerability to the behaviorally sensitizing effects of amphetamine at different ages. Moreover, they suggest that the juvenile period marks a window of vulnerability during which exposure to stimulant drugs can reverse the behavioral phenotype of adult dcc heterozygous mice. PMID- 21523347 TI - Biphasic dopamine regulation in mesoaccumbens pathway in response to non contingent binge and escalating methamphetamine regimens in the Wistar rat. AB - RATIONALE: Methamphetamine (MA) increases extracellular dopamine (DA) and at chronic high doses induces toxicity as indicated by decreased expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Notably, rats will self administer MA in escalating quantities producing such toxicity. However, the impact of MA at sub-toxic doses on DA regulation is not well established. OBJECTIVE: The temporal dynamics of DA regulation following cessation of sub toxic escalating and binge doses of non-contingent MA were investigated as changes therein may be associated with escalation of MA intake. MATERIALS AND METHODS: MA was administered 3*/day using an established 14-day escalating-dose regimen (0.1-4.0 mg/kg) or a single-day binge-style administration (3 * 4 mg/kg). DA tissue content, DA turnover, TH protein, TH phosphorylation, DAT, and vesicular monoamine transporter 2 were measured in nigrostriatal and mesoaccumbens pathways 48 h and 2 weeks after MA cessation. RESULTS: Changes in striatal DA regulation were limited to increased DA turnover. However, in the mesoaccumbens pathway, escalating MA had biphasic effects. DA was increased in ventral tegmental area (VTA) and decreased in nucleus accumbens at 48 h post-MA while the reverse was seen at 2 weeks. These changes were matched by similar changes in TH protein and, in the VTA, by changes in DAT. CONCLUSION: Escalation of MA intake produces both transient and long-lasting effects upon DA, TH, and DAT in the mesoaccumbens pathway. The eventual decrease of DA in the VTA is speculated to contribute to craving for MA and, thus, may be associated with MA escalation and resulting dopaminergic toxicity. PMID- 21523348 TI - Neuroprotection of paliperidone on SH-SY5Y cells against beta-amyloid peptide(25 35), N-methyl-4-phenylpyridinium ion, and hydrogen peroxide-induced cell death. AB - RATIONALE: Antipsychotic drugs (APDs) were widely used in treating schizophrenia. Some APDs were reported to have neuroprotective effects against neurotoxicants in the cell level. OBJECTIVES: Thus, one typical APD (haloperidol) and three atypical APDs (paliperidone, olanzapine, and risperidone) were tested whether they provide neuroprotection against stressor-induced cell death of SH-SY5Y. METHODS: Hydrogen peroxide, N-methyl-4-phenylpyridinium ion, and beta-amyloid peptide were used to treat cells with or without preconditioning by APDs; cell survival and indicators of oxidative stress were measured, respectively. RESULTS: Paliperidone has the lowest baseline cytotoxicity compared with other APDs at 24 h; in addition, the paliperidone group showed a better survival than the other APD groups (P < 0.05). In stressor challenging, with a fixed concentration of stressors, olanzapine provided the best neuroprotection at 100 MUM against Abeta(25-35) and MPP(+) (P < 0.05). In contrast, paliperidone works finely at low concentrations (10 and 50 MUM) against Abeta(25-35) and MPP(+) and solely protected SH-SY5Y from hydrogen peroxide. At 100 MUM, paliperidone completely diminished cell reduction induced by different stressors, regardless of their dosages. Paliperidone was demonstrated with a higher oxidative stress-scavenging properties than other APDs in several aspects, such as generated bulk glutathione, low HNE, and protein carbonyl productions. Contradictorily, olanzapine, at 24 h, also enhanced HNE and protein carbonyl productions, which may underlie its induced cytotoxicity. CONCLUSIONS: Different APDs exhibit variations against different stressors. Paliperidone might be useful not only in alleviating oxidative stress induced by Abeta(25-35) and MPP(+) but also in providing neuroprotection against hydrogen peroxide. PMID- 21523349 TI - The exercise programming preferences and activity levels of cancer patients undergoing radiotherapy treatment. AB - INTRODUCTION: Research has shown that patients who undergo regular physical activity during cancer treatment have significantly better physical functioning, cardiorespiratory fitness, psychological well-being and quality of life than those who do not. Despite the apparent value of exercise, few patients undertake regular physical activity during treatment and usually find it difficult to return to pre-treatment levels of activity following treatment completion. The purpose of this study was to compare pre-treatment versus on-treatment activity levels of outpatients receiving radiotherapy at a cancer centre in Australia and to identify patients' preferences and barriers to exercise during this time. METHODS: One hundred and twenty consecutive patients undergoing radical radiotherapy were approached. Ninety-two patients (77%) answered questions on medical and demographic variables, past and current activity levels and exercise counselling and programming preferences. RESULTS: Patients reported a decrease in the time spent exercising once radiotherapy treatment started and were less likely to engage in strenuous activities. Seventy-nine percent of patients reported that cancer and its treatments had affected their ability to exercise. Seventy-one percent wanted information about exercise during treatment and preferred to receive this information from an exercise specialist who is affiliated with the hospital. A home-based independent exercise program was preferred by 53% of patients but there was less consistency around when to begin an exercise program. CONCLUSIONS: The study indicates that a significant proportion of cancer patients undergoing radiotherapy want information, counselling and support regarding exercise and exercise programming. PMID- 21523350 TI - Nasal prosthesis rehabilitation using CAD-CAM technology after total rhinectomy: a pilot study. AB - PURPOSE: This study describes a nose prosthetic rehabilitation using computer aided design and manufacturing (CAD-CAM) technology after facial disfigurement because of a total rhinectomy. METHODS: A patient with a total rhinectomy was scheduled for a nasal prosthesis. Based on the 3-D model of the patient's face reconstructed with the CT data, a four-piece mould for the nasal prosthesis was prototyped using a CAD-CAM procedure. Conventional silicone was processed with this physical mould to fabricate the definitive nasal prosthesis. RESULTS: A silicone nasal prosthesis was manufactured. The size, shape, and cosmetic look of the prosthesis were satisfactory and matched the nasal defect area well. CONCLUSIONS: The protocol presented herein illustrates favorable clinical treatment outcomes in the prosthetic rehabilitation after a total rhinectomy by means of CAD-CAM technology. PMID- 21523351 TI - Predictors of the community pharmacy white-coat effect in treated hypertensive patients. The MEPAFAR study. AB - OBJECTIVE: To determine whether age, gender, body mass index (BMI), community pharmacy blood pressure (CPBP), daytime ambulatory BP (ABP) variability, treatment compliance, number of anti-hypertensive drugs and smoking status are factors associated with the community pharmacy white-coat effect (CPWCE) in treated hypertensive patients. SETTING: Eight community pharmacies in Gran Canaria, Spain. METHOD: A cross-sectional study was carried out from June 2008 to June 2009. The study included treated hypertensive patients older than 18 years. Patients were excluded if: systolic BP (SBP)/diastolic BP (DBP) >= 200/110 mmHg, not-recommended or unable to perform home BP measurements, changes in anti hypertensive treatment <4 weeks, history of cardiovascular disease <6 months or pregnancy. Blood pressure (BP) was measured by a community pharmacist at 4 visits to the community pharmacy and using ABP monitoring (24 h). MAIN OUTCOME MEASURE: The CPWCE was calculated as the difference between the mean BP in the community pharmacy and daytime ABP. Independent predictors of the CPWCE were identified using multivariate linear regression analysis. RESULTS: Two hundred thirteen patients agreed to participate in the study. After exclusion and withdrawal, 169 patients were included in the analysis. Multiple linear regression analysis for systolic CPWCE revealed only community pharmacy SBP as an independent factor (beta = 0.35; P < 0.001). The regression analysis for diastolic CPWCE revealed female gender (beta = 4.88; P < 0.001), BMI (beta = 0.48; P < 0.001) and community pharmacy DBP (beta = 0.24; P < 0.001) as independent determinants. CONCLUSION: In this sample of treated hypertensive patients, factors such as gender, community pharmacy DBP and BMI were positively associated and may exert an important influence on the magnitude of the diastolic CPWCE. On the other hand, the CPWCE on SBP increased as the community pharmacy SBP increased. PMID- 21523352 TI - Properties and regulation of organic cation transport in freshly isolated mouse proximal tubules analyzed with a fluorescence reader-based method. AB - The main elimination site of organic cations (OCs) is the renal proximal tubule (PT). OC transporters (OCT) accept endogenous and exogenous substances and xenobiotics. As transgenic mouse models are increasingly used in translational medicine, functional properties with special focus on regulation of OCT of isolated mouse PTs were studied with a new fluorescence reader-based method, which allows studying larger numbers of tubules per kidney. OC transport across the basolateral membrane of PTs from male mice was measured as initial uptake of the fluorescent dye 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP). A microtiter plate fluorescence reader was used to semi-automatically analyze OC transport in freshly isolated tubules. Relative mRNA expression of OCT1/OCT2/OCT3 in PTs was 1/0.3/0.01 and did not vary from S1 to S3 segments. ASP was transported by PTs with a K (m) of 6 MUM. It was inhibited by TEA, TPA, or cimetidine (IC(50)=5, 19, or 53 MUM, respectively). Angiotensin II stimulated ASP uptake (+63%), while stimulation of PKC reduced (-37%) OC transport. Inhibition of p56(lck) tyrosine kinase (-60%), of PI3K (-36%), of Ca(2+)/calmodulin (-25%), or of PKA (-33%) reduced OC transport. In PTs from OCT1/2(-/-) mice ASP uptake was reduced to ~20%. Using this fluorescence reader-based method, we report substrate specificities and a complex pattern of acute regulation of OC transport in isolated mouse PTs. Compared to isolated human PTs or rat and human OCT isoforms expressed in HEK293-cells, OC transport across the basolateral membrane of freshly isolated mouse PTs shows similarities but also specific differences. PMID- 21523353 TI - A quest in neurosciences: neuroportraits. PMID- 21523354 TI - Oral metastasis of lung cancer. A challenge for the clinician. AB - BACKGROUND: Bone metastases are a major cause of morbidity in cancer patients. Jawbone metastasis from lung cancer is a rare condition that may occur in the late state of the disease. CASE REPORT: We report the case of a 74-year-old male presenting with an oral asymptomatic swelling that had grown substantially over the last 2 months. Biopsy and histological examination revealed the presence of a metastatic lung cell adenocarcinoma. DISCUSSION: Although metastases to the oral cavity are uncommon, clinicians may play a crucial role also in the diagnosis of primary tumors. PMID- 21523355 TI - Insights to sequence information of polyphenol oxidase enzyme from different source organisms. AB - Polyphenol oxidases (PPOs) are widely distributed enzymes among animals, plants, bacteria, and fungi. PPOs often have significant role in many biologically essential functions including pigmentation, sclerotization, primary immune response, and host defense mechanisms. In the present study, forty-seven full length amino acid sequences of PPO from bacteria, fungi, and plants were collected and subjected to multiple sequence alignment (MSA), domain identification, and phylogenetic tree construction. MSA revealed that six histidine, two phenylalanine, two arginine, and two aspartic acid residues were highly conserved in all the analyzed species, while a single cysteine residue was conserved in all the plant and fungal PPOs. Two major sequence clusters were constructed by phylogenetic analysis. One cluster was of the plant origin, whereas the other one was of the fungal and bacterial origin. Motif GGGMMGDVPTANDPIFWLHHCNVDRLWAVWQ was found in all the species of bacterial and fungus sources. In addition, seven new motifs which were unique for their group were also identified. PMID- 21523356 TI - Identification and quantitation of reaction intermediates and residuals in lipase catalyzed transesterified oils by HPLC. AB - A high-performance liquid chromatography (HPLC) unit equipped with size exclusion column and a refractive index detector was used for simultaneous monitoring, identification, and quantitation of the reaction components from lipase-catalyzed transesterification of three oils. The procedure simultaneously separated and detected the unreacted triacylglycerols (TAG), diacyl-, and monoacyl-glycerol (DAG and MAG) co-products, residual alcohol as well as free fatty acid (FFA) based on retention times. The chromatograms showed well separated and resolved peaks. The elution of the components from the transesterification reaction in increasing order was: TAG < DAG < FFA < MAG. Generally, higher alcohol ratios decreased the conversion of TAG in all the oils studied with between 14% and 94% of TAG remaining at all the treatment combinations. Higher amount of salmon skin oil (SSO) TAG was generally converted to DAG than Rothsay composite (RC) and olive oil (OO) TAG. Relatively higher amount of OO DAG was converted to MAG than SSO and RC with only 5-14% DAG remaining in OO. RC and OO generally accumulated less MAG, and this was reflected as lower MAG levels in RC (<6%) and OO (<14%) compared with SSO (<27%). For the various treatment combinations and the three oils used in this study, the least amount of FFA was recorded in transesterified OO with a maximum of approximately 4%. This HPLC method can be used as a simple and fast technique to analyze the reaction components and products of transesterification reactions without the need for additional derivatization steps. PMID- 21523357 TI - Spontaneous disruption of dura mater and fascicular continuity of the L5 nerve root by a calcified disc herniation. PMID- 21523358 TI - Terminal ventriculostomy as an adjuvant treatment of complex syringomyelia: a case report and review of the literature. AB - Complex syringomyelia is multifactorial, and treatment strategies are highly individualized. In refractory cases, sectioning of the filum terminale, also known as terminal ventriculostomy, has been described as a potential adjuvant treatment to alleviate syrinx progression. A 10-year-old boy with a history of arachnoiditis presented with complex syringomyelia, progressive lower extremity motor weakness, and spasticity. Previously, he had failed spinal cord detethering and direct syrinx shunting. Imaging studies demonstrated a holocord syrinx extending to the level of his conus medullaris and into the filum terminale. The patient underwent an uncomplicated lumbar laminectomy and transection of the filum terminale. Operative pathologic specimens demonstrated a dilated central canal within the filum. Postoperative imaging demonstrated significant reduction in the diameter of the syrinx. At follow-up, the patient's motor symptoms had improved. Terminal ventriculostomy may be a useful adjuvant in treating caudally placed syringes refractory to other treatments. This procedure carries low neurological risk and involves no hardware implantation. In select cases, terminal ventriculostomy may help preserve neurological function in the face of otherwise progressive syringomyelia. PMID- 21523359 TI - How I do it: epidural anterior petrosectomy. AB - BACKGROUND: Among the potential approaches to access the petroclival area, epidural anterior petrosectomy (EAP) appears to be the most direct and conservative transpetrous route. In this article, we aim to detail the relevant surgical steps necessary to perform EAP in a reproducible and safe manner. METHOD: The temporo-pterional bone flap is tailored to access the floor of the middle fossa and expose the foramen ovale and foramen spinosum. Elevation of the dura covering the upper surface of the petrous apex is conducted medially toward the level of the petrous ridge. Identification of the landmarks of the rhomboid fossa delineates the limits of the drilling zone (necessary for removal of the petrous apex)-beneath Meckel's cave and just anterior to the anterior margin of the internal auditory meatus. The tentorium is divided at its free edge and is followed by opening of the posterior fossa dura. CONCLUSION: Epidural anterior petrosectomy is a conservative trans-petrous approach that offers an excellent direct surgical corridor for exposure of disease processes involving Meckel's cave, the petroclival area and the ventrolateral pons. PMID- 21523360 TI - The value of intra-operative MRI in trans-sphenoidal pituitary surgery. PMID- 21523361 TI - Intra-operative MRI facilitates tumour resection during trans-sphenoidal surgery for pituitary adenomas. AB - BACKGROUND: During trans-sphenoidal microsurgical resection of pituitary adenomas, the extent of resection may be difficult to assess, especially when extensive suprasellar and parasellar growth has occurred. In this prospective study, we investigated whether intra-operative magnetic resonance imaging (iMRI) can facilitate tumour resection. METHODS: Twenty patients with macroadenomas, (16 non-functioning, three growth-hormone secreting and one pharmaco-resistant prolactinoma) were selected for surgery in the iMRI. The mean tumour diameter was 27 mm (range 11-41). The mean parasellar grade, according to the Knosp classification, was 2.3. Pre-operative coronal and sagittal T1-weighted and T2 weighted images were obtained. The trans-sphenoidal tumour resection was performed at the edge of the tunnel of a Signa SP 0.5-Tesla MRI. The surgeon aimed at a radical tumour resection that was followed by a peri-operative MRI scan. When a residual tumour was visualised and deemed resectable, an extended resection was performed, followed by another MRI scan. This procedure was repeated until the imaging results were satisfactory. In all patients, we were able to obtain images to assess the extent of resection and to classify the resection as either total or subtotal. RESULTS: After primary resection, eight out of 20 cases were classified as total resections. A second resection was performed in 11 of 12 cases classified as subtotal resections, and in four of these, total resection was achieved. A third resection was performed in three of the remaining seven cases with subtotal resections, but we did not achieve total resection in any of these cases. Therefore, the use of iMRI increased the number of patients with total resection from 8/20 (40%) to 12/20 (60%). The only observed complication was a transient spinal fluid leakage. CONCLUSION: Intra operative MRI during trans-sphenoidal microsurgery is useful in selected patients for a safe and more complete resection. PMID- 21523362 TI - Long-term follow-up of different refractory systemic vasculitides treated with rituximab. AB - There is increasing interest in rituximab (RTX) as an alternative to cyclophosphamide (CYC) for remission induction in systemic vasculitis. Recent studies have reported high remission rates, but it is not clear how long the initial remission lasts [1, 2]. A retrospective study was undertaken of 15 cases of refractory systemic vasculitis (11 Wegener's granulomatosis, 1 Churg-Strauss syndrome, 1 cutaneous polyarteritis nodosa and 2 cryoglobulinaemic vasculitis) treated with RTX, with a mean follow-up of 34 months. All had previously received CYC, and 14, at least one other immunosuppressive drug. All had active disease when treated (median Birmingham Vasculitis Activity Score (BVAS) 2003, 13). All cases achieved remission (BVAS 2003, 0). Thirteen required re-treatment, nine due to relapse (mean, 9 months after initial treatment) and four because of repopulation or rising ANCA in the context of CYC intolerance or previous CYC refractory disease. Relapsing cases have been successfully re-treated up to five further cycles, either at B cell repopulation or at six monthly intervals. Infections were rare. Mean IgG levels fell significantly, and IgM levels became subnormal in six cases. There were three cases of neutropenia, one severe at 10 months post-treatment. These results provide further evidence that RTX is an effective induction agent in systemic vasculitis. The optimal and long-term outcome of re-treatment remains to be defined. PMID- 21523363 TI - Lipid profile in Tunisian patients with rheumatoid arthritis. AB - This study aims to assess the prevalence of dyslipidaemia in Tunisian patients with active RA and to investigate the clinical and biological associated factors. A cross-sectional study was conducted on 92 unselected patients with active RA (77 females and 15 males, aged 49.1 +/- 12.5 years) and 82 healthy subjects (68 females and 14 males, aged 50.8 +/- 13.3 years). We recorded the patients' characteristics and the results of a lipid profile test (total cholesterol, TC; high-density lipoprotein cholesterol, HDL-c; low-density lipoprotein cholesterol, LDL-c; triglyceride, TG; lipoprotein (a), Lp (a); apolipoprotein A-1, apo A-1 and apolipoprotein B, apo B). In comparison to the control group, RA patients showed a higher prevalence of associated dyslipidaemia (95.7% versus 65.9% of cases, p < 0.001). Sera of patients showed higher TC (4.86 +/- 1.07 versus 3.98 +/- 0.73 mmol/L, p < 0.001), LDL-c (3.49 +/- 0.98 versus 1.99 +/- 0.62 mmol/L, p < 0.001), Lp (a) (288.04 +/- 254.59 versus 187.94 +/- 181.37 mmol/L, p = 0.004) and lower HDL-c (0.66 +/- 0.24 versus 1.12 +/- 0.3 mmol/L, p < 0.001). TC/HDL-c, LDL-c/HDL c and non-HDL-c/HDL-c were also higher in RA patients; they were 8.24 +/- 3.20 versus 3.76 +/- 1.26 (p < 0.001), 5.91 +/- 2.48 versus 1.92 +/- 0.99 (p < 0.001) and 7.24 +/- 3.20 versus 2.76 +/- 1.26 (p < 0.001), respectively. Apo A-1 was correlated to Lp (a) (r = 0.291, p = 0.005). Corticoid dose was not associated to dyslipidaemia, but in multiple regression models, corticoid dose may be negatively related to some atherogenic markers, in particular non-HDL-c. Tunisian patients with markedly active RA experience substantially reduced serum HDL-c and increased TC, LDL-c and Lp (a) concentrations as well as increased TC/HDL-c, LDL c/HDL-c and non-HDL-c/HDL-c ratios. PMID- 21523364 TI - Moderate incidence of prior rheumatoid arthritis in patients with polymyositis and dermatomyositis. PMID- 21523365 TI - Gender and ethnicity differences in the prevalence of scleroderma-related autoantibodies. AB - Autoantibodies to topoisomerase I (topo I), RNA polymerase III (RNAPIII), centromere, U3RNP/fibrillarin, Th, PM-Scl, and U1RNP found in scleroderma (SSc) are associated with unique clinical subsets. The effects of race and gender on autoantibody prevalence and clinical manifestations were examined. Autoantibodies in sera from 105 SSc (include 75 Caucasian, 24 African-American, 6 others; 89 females and 16 males) were analyzed by immunofluorescence and immunoprecipitation. Clinical information was from database. SSc-related autoantibodies seldom coexist except for anti-topo I and anti-U1RNP. Anti-topo I (35% vs 15%), anti-U3RNP (30% vs 3%, p = 0.0005), and anti-U1RNP (30% vs 13%) were more common in African-Americans vs Caucasians. Anti-centromere (17%) and anti-PM-Scl (only in 8% of female) were found only in Caucasians. In race/gender combination, all three African-American males had anti-topo I (p = 0.04). Anti U3RNP (35% vs 3%, p = 0.0005) and anti-U1RNP were common in African-American females. In African-American, all nucleolar dominant staining sera had anti U3RNP; nuclear pattern was topo I (50%), U1RNP (19%), and RNAPIII (13%). In Caucasian, nucleolar was anti-Th (43%) and PM-Scl (29%); nuclear pattern was RNAPIII (29%), topo I (24%), and U1RNP (18%). Anti-topo I, anti-RNAPIII, and anti U3RNP were associated with diffuse SSc while anti-centromere, anti-Th, and anti U1 with limited disease. Proximal scleroderma was less common in African-American with anti-topo I (38% vs 91% in Caucasian, p = 0.04). The production of SSc related autoantibodies is gender and race dependent, and this can be highly relevant in understanding their clinical significance. PMID- 21523367 TI - Letter to the editor: asymptomatic carotid stenosis--more misunderstandings in the expectation of a surgical benefit. PMID- 21523368 TI - [Nanotechnology: New Social Dynamics at the Interface between Science and the Public]. PMID- 21523369 TI - Lubiprostone for the treatment of adults with constipation and irritable bowel syndrome. AB - Chronic constipation and IBS-C are two of the most common functional bowel disorders encountered by primary care providers and gastroenterologists, affecting up to 27% of the population in Western countries [1-4]. The treatment of these disorders is often empiric and most current therapies are indicated for episodic constipation. Over time, most patients become refractory to one or more laxatives. Lubiprostone (Amitiza) has been approved by the US Food and Drug Administration (FDA) for the treatment of chronic-idiopathic constipation [6]. It is an oral bicyclic fatty acid that selectively activates type 2 chloride channels in the apical membrane of the intestinal epithelial cells, hence stimulating chloride secretion, along with passive secretion of sodium and water, inducing peristalsis and laxation, without stimulating gastrointestinal smooth muscle. Several trials have shown it to be effective in the treatment of chronic idiopathic constipation, and recently also IBS-C. It has little systemic absorption and almost free of any serious adverse effects, however, occasionally can cause nausea. Based on the available evidence, it is reasonable to conclude that lubiprostone should be added to the short list of evidence-based pharmacotherapies for chronic constipation and IBS-C. Given the overlap between chronic constipation and IBS-C, clinicians can consider two strategies when deciding on the initial dose of lubiprostone. Based on current product labeling, it is recommended that 8 MUg bid be started in patients with IBS-C whereas 24 MUg bid be used in those with chronic constipation. Thus far, lubiprostone offers a novel approach to our therapeutic armamentarium, however, there is a need for more drugs with different mechanisms of action, in order to treat constipation that is often multifunctional. PMID- 21523370 TI - Methylation of the promoter A of estrogen receptor alpha gene in hBMSC and osteoblasts and its correlation with homocysteine. AB - Recent studies have shown that adult osteoporosis could be induced by ageing and estrogen deficiency and homocysteine (Hcy) is an independent risk factor of fracture in osteoporosis patients. In this study, we found hypermethylation of the promoter A region in the estrogen receptor alpha (ERalpha) gene, and methylation in 70.59% of 68 post-menopausal women, whose methylation degree was significantly higher than the pre-menopausal women (P < 0.05). Their methylation frequency was detected only 26.67% in 30 subjects. An obvious correlation between the degree of methylation in ERalpha gene and the level of Hcy (r = 0.809, P < 0.05) was explored. The cultured human bone marrow strom cells (hBMSC) and osteoblasts treated by Hcy resulted in de novo methylation of the promoter A region in the ERalpha gene and suppressed proliferation and differentiation with time and dose dependence. Meanwhile, ERalpha gene mRNA in osteoblast-like cells treated by Hcy was much lower than the control group (P < 0.05). Thus, both in vivo and in vitro data showed that Hcy could promote hypermethylation of the promoter A region and reduce ERalpha mRNA transcription, which may be an important mechanism for the pathogenesis of postmenopausal osteoporosis. PMID- 21523371 TI - Internalization of exogenous ADP-ribosylation factor 6 (Arf6) proteins into cells. AB - Endogenous Arf6 is a myristoylated protein mainly involved in endosomal membrane traffic and structural organization at the plasma membrane. It has been shown that Arf6 mediates cancer cell invasion and shedding of plasma membrane microvesicles derived from tumor cells. In this article, we determined that Arf6 proteins both in the GDP and GTPgammaS bound forms can enter cells when simply added in the cell culture medium without requiring the myristoyl group. The GTPgammaS bound can enter cells at a faster rate than the GDP-bound Arf6. Despite the role of the endogenous Arf6 in endocytosis and membrane trafficking, the internalization of exogenous Arf6 may involve non-endocytic processes. As protein therapeutics is becoming important in medicine, we examined the effect of the uptake of Arf6 proteins on cellular functions and determined that exogenous Arf6 inhibits proliferation, invasion, and migration of cells. Future studies of the internalization of Arf6 mutants will reveal key residues that play a role in the internalization of Arf6 and its interaction and possible structural conformations bound to the plasma membrane. PMID- 21523372 TI - Update on diagnosis and treatment of mastocytosis. AB - Mastocytosis is a disorder characterized by increased numbers of mast cells in tissues. Recent clinical observations highlight the association of mastocytosis with an increased risk of anaphylaxis and underline the diversity of this disease. At the molecular level, recent studies have attempted to unravel specific gene expression profiles for activating c-kit mutations in the etiology of mastocytosis. The diagnosis may be facilitated by surrogate markers and detection of aberrant immunophenotypic surface markers. New therapeutic strategies are in development based on intracellular signal pathways, or on application of topical treatments, as are novel forms of cytoreductive therapy, including tyrosine kinase inhibitors. PMID- 21523374 TI - Overall and KRAS-specific results of combined cetuximab treatment and chemotherapy for metastatic colorectal cancer: a meta-analysis. AB - PURPOSE: This study compared the efficacy and toxicities of cetuximab combined with chemotherapy versus chemotherapy for patients with metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on the outcomes was also investigated. METHODS: Literature retrieval, trials selection and assessment, data collection, and statistical analysis were performed according to the Cochrane Handbook 5.0.2. The outcome measures were tumor response rate, progression-free survival, overall survival, and adverse effects. RESULTS: Four randomized controlled trials, comprising totally 2,912 patients, were included. Meta-analysis showed higher response rate (RR 1.93; 95% CI, 1.14-3.26) and significant improvement in progression-free survival (PFS; HR 0.80; 95% CI, 0.67 0.95) in cetuximab-chemotherapy groups versus chemotherapy groups. There was no significant difference between the two treatment groups regarding overall survival (OS; HR 0.95; 95% CI, 0.87-1.05). In wild-type KRAS patients, treatment with cetuximab plus chemotherapy significantly increased response rate (RR 1.44; 95% CI, 1.20-1.73) and improved PFS (HR 0.64; 95% CI, 0.50-0.84), as compared with chemotherapy groups, but not for OS (HR 0.84; 95% CI, 0.64-1.11). In mutant KRAS patients, there was no significant difference between those treated with cetuximab plus chemotherapy and those with chemotherapy alone regarding response rate (RR 0.81; 95% CI, 0.61-1.08), PFS (HR 1.37; 95% CI, 0.81-2.31), and OS (HR 1.03; 95% CI, 0.74-1.44). The risk of grade 3/4 rash, diarrhea, neutropenia, and fatigue was significantly increased in cetuximab combination groups as compared with chemotherapy groups. CONCLUSIONS: The use of cetuximab in addition to chemotherapy was a valid alternative for patients with mCRC. Benefit of cetuximab was only limited to patients with wild-type KRAS tumors. PMID- 21523376 TI - Quality of life and cost-utility assessment after strabismus surgery in adults. AB - PURPOSE: To understand the functional and psychosocial aspects of strabismus surgery, an evaluation based on the patient's perspective is essential. In this study, we assessed quality of life and utility in adult patients who had undergone strabismus surgery, and we modeled the cost of providing this intervention in order to calculate the cost-utility of strabismus surgery in adults. METHODS: The study population comprised 226 patients with strabismus aged 18 years or older who were scheduled for ocular alignment surgery at 12 facilities of the Strabismus Surgery Study Group in Japan. Survey questionnaires consisting of the Japanese versions of the Visual Function Questionnaire-25 (VFQ 25) and 8-Item Short-Form Health Survey (SF-8) and utility assessment by a time trade-off method were administrated preoperatively and 3 months postoperatively. On the basis of the cost model and measured utility data, the gains in quality adjusted life years (QALYs) and $/QALY were estimated. RESULTS: Postoperatively, the subscale scores of the VFQ-25 and the physical and mental component summary scores of the SF-8 showed a statistically significant improvement. A significant improvement of utility was also noted: 0.82 +/- 0.28 postoperatively versus 0.76 +/- 0.31 preoperatively. On the basis of the life expectancy of these patients and the cost model, the surgery resulted in a mean value gain of 0.99 QALYs and a cost-utility for strabismus surgery of 1,303 $/QALY. CONCLUSIONS: By using standard tools to assess vision-associated and general health status, we confirmed the psychosocial benefits of corrective surgery for adults with strabismus. Our study concurrently demonstrated that strabismus surgery in adults is very cost-effective. PMID- 21523378 TI - Indirect imaging of branch retinal vein occlusion using a scanning laser ophthalmoscope. PMID- 21523377 TI - Regulation of soluble interleukin-6 (IL-6) receptor release from corneal epithelial cells and its role in the ocular surface. AB - PURPOSE: Interleukin (IL)-6 signaling through its soluble receptor (sIL-6R) (IL-6 trans-signaling) plays an important role in various inflammatory states. We investigated production of sIL-6R in the corneal epithelium and examined the role of IL-6 trans-signaling in the cornea. METHODS: In-vitro experiments were performed using SV40-transformed human corneal epithelial cells (HCEC) and primary human corneal fibroblasts (HCF, keratocytes). Ectodomain shedding in HCEC was stimulated by adding phorbol myristate acetate (PMA, 3 MUM: ) both with and without ectodomain shedding inhibition using TNF-alpha processing inhibitor-1 (TAPI-1, 250 ng/mL), and the concentration of sIL-6R in the culture medium was determined by enzyme-linked immunosorbent assay (ELISA). Expression of differential sIL-6R mRNA splicing (DS-sIL-6R) in HCEC was examined by using reverse transcription (RT)-PCR. The recombinant IL-6 or combination of recombinant IL-6/sIL-6R was added to HCF culture medium and phosphorylation of STAT3 was analyzed by Luminex assay. Tear fluid from patients with Sjogren syndrome was collected and analyzed by ELISA for sIL-6R concentration. RESULTS: In HCEC culture medium, sIL-6R release was increased significantly (P < 0.01) by adding PMA and this increased release of sIL-6R was inhibited significantly by adding TAPI-1, indicating the participation of ectodomain shedding in sIL-6R production. In RT-PCR, DS-sIL-6R expression was noted in HCEC. IL-6/sIL-6R induced STAT3 phosphorylation was recognized in cultured HCF, suggesting IL-6 trans-signaling induced inflammatory cellular signaling in HCF. In the tear fluid of the patients with Sjogren syndrome, sIL-6R expression was up-regulated (Sjogren syndrome; 2.38 +/- 0.98 ng/mL, normal control; 0.16 +/- 0.34 ng/mL). CONCLUSIONS: Production of sIL-6R was induced by both ectodomain shedding and mRNA splicing in the corneal epithelium. IL-6 trans-signaling can induce an inflammatory response in corneal fibroblasts. The up-regulation of sIL-6R in inflamed ocular surfaces suggests a pivotal role of sIL-6R at the ocular surface. PMID- 21523379 TI - Screening for hereditary spherocytosis in routine practice: evaluation of a diagnostic algorithm with focus on non-splenectomised patients. PMID- 21523380 TI - Possible prediction of underlying lymphoma by high sIL-2R/ferritin ratio in hemophagocytic syndrome. AB - In some instances, because of the lack of mass formation and the absence of prominent lymph node enlargement, diagnosis of lymphoma-associated hemophagocytic syndrome (LAHS) is difficult, which results in the development of progressive disease with unfavorable prognosis. Therefore, in the diagnosis of secondary hemophagocytic syndrome (HPS), markers for underlying malignant lymphoma are required. We reviewed 110 Japanese patients, including 57 LAHS cases and 53 benign disease-associated HPS cases, and demonstrated that the values of the serum sIL-2R level and sIL-2R/ferritin ratio in LAHS patients were both statistically higher than those of patients with benign disease-associated HPS. Most LAHS patients showed high values of both indices. The positive predictive value of patients showing high values of both indices for LAHS was 95.6%. On the other hand, the predictive value of patients showing low values of both indices for benign disease-associated HPS was 92.1%. We propose serum sIL-2R/ferritin ratio as a novel useful marker for predicting underlying malignant lymphoma in HPS patients. PMID- 21523381 TI - Biomanipulation of hypereutrophic ponds: when it works and why it fails. AB - Phytoplankton, zooplankton, submerged vegetation and main nutrients have been monitored in 48 eutrophic ponds from the Brussels Capital Region (Belgium) between 2005 and 2008. Nine ponds have been biomanipulated in order to improve their ecological quality and prevent the occurrence of noxious cyanobacterial blooms. The 4-year study of a large number of ponds allowed identification of the factors having the strongest influence on phytoplankton growth. Continuous monitoring of the biomanipulated ponds allowed the significance of changes caused by biomanipulation to be tested as well as the main reasons of biomanipulation successes and failures to be elucidated. The main factors controlling phytoplankton in the ponds studied appeared to be grazing by large cladocerans and inhibition of phytoplankton growth by submerged vegetation. Biomanipulation resulted in a significant decrease in phytoplankton biomass in general and biomass of bloom-forming cyanobacteria in particular that were associated with a significant increase in large Cladocera density and size. In six out of nine ponds biomanipulation resulted in the restoration of submerged vegetation. The maintenance of the restored clearwater state in the biomanipulated ponds was strongly dependent on fish recolonisation and nutrient level. In the absence of fish, the clearwater state could be maintained by submerged vegetation or large zooplankton grazing alone. In case of fish recolonisation, restoration of extensive submerged vegetation could buffer, to a considerable degree, the effect of fish except for ponds with high nutrient levels. PMID- 21523382 TI - Dynamics and quantification of dissolved heavy metals in the Mahanadi River estuarine system, India. AB - Dynamics of heavy metals such as Fe, Mn, Zn, Cr, Cu, Co, Ni, Pb, and Cd in surface water of Mahanadi River estuarine systems were studied taking 31 different stations and three different seasons. This study demonstrates that the elemental concentrations are extremely variable and most of them are higher than the World river average. Among the heavy metals, iron is present at highest concentration while cadmium is at the least. The spatial pattern of heavy metals suggests that their anthropogenic sources are possibly from two major fertilizer plants and municipal sewage from three major towns as well as agricultural runoff. The temporal variations for metals like Fe, Cu, and Pb exhibit higher values during the monsoon season, which are related to agricultural runoff. Concentrations of Ni, Pb, and Cd exceed the maximum permissible limits of surface water quality in some polluted stations and pose health risks. Dissolved heavy metals like Fe, Mn, Cr, Ni, and Pb exhibit a non-conservative behavior during estuarine mixing, while Zn, Cu, and Co distribution is conservative. Distribution of cadmium in the estuarine region indicates some mobilization which may be due to desorption. The enrichment ratio data suggest that various industrial wastes and municipal wastes contribute most of the dissolved metals in the Mahanadi River. The Mahanadi River transports 18.216 * 10(3) t of total heavy metals into the Bay of Bengal and the calculated rate of erosion in the basin is 128.645 kg km(-2) year(-1). PMID- 21523383 TI - The paradox of low BNP levels in obesity. AB - The aim of this review is to analyze in detail some possible pathophysiological mechanisms linking obesity and cardiac endocrine function, in order to try to explain the negative association previously observed between BMI and BNP values in both healthy subjects and patients with cardiovascular diseases. In particular, we discuss the hypothesis that the response of the cardiac endocrine system is the integrated resultant of several and contrasting physiological and pathological interactions, including the effects of peptide and steroid hormones, cytokines, cardiovascular hemodynamics, clinical conditions, and pharmacological treatment. Several studies suggested that gonadal function regulates both body fat distribution and cardiac endocrine function. Visceral fat expansion can increase the clearance of active natriuretic peptides by means of an increased expression of clearance receptors on adipocytes, and in this way, it may contribute to decrease the activity of the cardiac endocrine system. Moreover, obesity is associated with ectopic lipid deposition even in the heart, which may directly exert a lipotoxic effect on the myocardium by secreting in loco several cytokines and adipokines. Obese subjects are frequently treated for hypertension and coronary artery disease. Pharmacological treatment reduces plasma level of cardiac natriuretic peptides, and this effect may explain almost in part the lower BNP levels of some asymptomatic subjects with increased BMI values. At present time, it is not possible to give a unique and definitive answer to the crucial question concerning the inverse relationship between the amount of visceral fat distribution and BNP levels. Our explanation for these unsatisfactory results is that the cardiac endocrine response is always the integrated resultant of several pathophysiological interactions. However, only few variables can be studied together; as a result, it is not possible to perform a complete evaluation of pathophysiological mechanisms under study. We are still not able to well integrate these multiple information together; therefore, we should learn to do it. PMID- 21523384 TI - Acceptance of two liquid vitamin D3 formulations among mothers with newborn infants: a randomized, single-blind trial. AB - In Switzerland, children are prescribed 7.5-12.5 MUg per day of vitamin D(3) dissolved in alcohol, but many families do not adhere to the recommendation. The aim of the trial was to compare the acceptance of vitamin D(3) dissolved in alcohol or in medium-chain triglycerides among mothers of Swiss newborn infants. The acceptance was tested in 42 healthy newborn infants (20 girls and 22 boys) aged between 2 and 7 days. Their neonatal body weight ranged between 2.225 and 4.150 kg, and the gestational age between 36 1/7 and 41 3/7 weeks. The blinded mothers rated the facial reaction of their children by pointing on a facial hedonic scale. Thirty eight of the 41 mothers, who brought the comparison to completion, assigned a better score to the oily preparation with no difference in the remaining three cases (P < 0.0001). The acceptance for the oily preparation was significantly better both among mothers whose babies were initially presented the alcoholic preparation and among mothers whose babies were initially presented the oily preparation. Furthermore, the acceptance for the oily preparation was better irrespective of gender of the infant or parity of the mother. In conclusion, from the perspective of mothers, Swiss newborn infants prefer the taste of the oily vitamin D(3) preparation over the alcoholic preparation. PMID- 21523385 TI - Evaluation and treatment of intracardiac thrombus in ten neonates. PMID- 21523386 TI - Comparative studies on tolerance of Medicago truncatula and Medicago falcata to freezing. AB - Medicago falcata is a legume species that exhibits great capacity of tolerance to abiotic stresses. To elucidate the mechanism underlying tolerance of M. falcata to freezing, we compared the characteristics of M. falcata in response to cold acclimation and freezing with those of the legume model plant Medicago truncatula. M. falcata seedlings were more tolerant to freezing than M. truncatula, as evidenced by a lower value of EL(50) (temperature at which 50% electrolyte leakage after freezing) and greater survival rate for M. falcata than M. truncatula. Cold acclimation led to greater reduction in EL(50) for M. falcata than M. truncatula. Sucrose was the most abundant sugar in both M. falcta and M. truncatula, and a greater accumulation of sucrose and Pro in M. falcata than in M. truncatula during cold acclimation was observed. Cold acclimation induced small amounts of raffinose and stachyose in M. falcata, but not in M. truncatula. The activities of sucrose phosphate synthase and sucrose synthase were greater in M. falcata than in M. truncatula. In contrast, the activity of acid invertase was higher in M. truncatula than in M. falcata. There was an increase in transcript of CRT binding factor (CBF) upon exposure to low temperature in the two species. The low temperature-induced increase in transcript of CBF2 was much higher in M. truncatula than in M. falcata, while transcript of CBF3 in M. falcata was greater than that in M. truncatula. There were sustained increases in transcripts of cold acclimation specific (CAS), a downstream target of CBF, during cold acclimation and the increases were greater in M. falcata than in M. truncatula. These results demonstrate that accumulation of greater amounts of soluble sugars coupled with higher CBF3 and CAS transcript levels in M. falcata may play a role in conferring greater tolerance of M. falcata to freezing than that of M. truncatula. PMID- 21523387 TI - Metagenomic analysis of the 1-aminocyclopropane-1-carboxylate deaminase gene (acdS) operon of an uncultured bacterial endophyte colonizing Solanum tuberosum L. AB - Deamination of the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) is a key plant-beneficial trait found in many plant growth-promoting bacteria. In this study, we analysed ACC deaminase genes (acdS) of bacterial endophytes colonizing field-grown potato plants. PCR analysis revealed the presence of two types of acdS genes, the dominant one showing high homology to an acdS gene derived from Pseudomonas fluorescens. Construction, functional screening and sequence analysis of metagenomic libraries revealed clones containing the acdS gene identified in the PCR library. Sequence analysis of one metagenomic clone identified the entire acdS operon of an uncultivated endophyte and revealed that the acdS gene is coupled upstream with an acdR transcriptional regulator gene as previously found in P. putida strain UW4 (Grichko and Glick 2000). However, in silico analysis of 195 fully sequenced, acdS-containing bacterial genomes revealed that the majority of strains, including numerous strains belonging to the genus Pseudomonas, do not contain an acdR regulatory gene in the vicinity of the acdS gene or elsewhere in the genome. The acdR (+)-acdS (+) operon was exclusively found in several Alpha- and Betaproteobacteria most prominently in the genus Burkholderia. PMID- 21523388 TI - Mathematical modeling to distinguish cell cycle arrest and cell killing in chemotherapeutic concentration response curves. AB - Concentration response experiments are utilized widely to characterize the response of tumor cell lines to chemotherapeutic drugs, but the assay methods are non-standardized and their analysis based on phenomenological equations. To provide a framework for better interpretation of these experiments, we have developed a mathematical model in which progression through the tumor cell cycle is inhibited by drug treatment via either cell cycle arrest or entrance into cell death pathways. By fitting concentration response data, preferably over a dynamic range, the contributions of these mechanisms can be delineated. The model was shown to fit well experimental data for three glioma cell lines treated with either carmustine or etoposide. In each cell line, the major mechanism of tumor cell inhibition was cell death for carmustine in contrast to cell cycle arrest for etoposide. The model also provides a possible interpretation for the acquired in vitro resistance of U87 cells to carmustine as an accelerated desensitization to cell killing effects. This approach will aid in understanding better the action of chemotherapeutic agents on tumor cells. PMID- 21523389 TI - School disengagement as a predictor of dropout, delinquency, and problem substance use during adolescence and early adulthood. AB - Over the past 5 years, a great deal of attention has been paid to the development of early warning systems for dropout prevention. These warning systems use a set of indicators based on official school records to identify youth at risk for dropout and then appropriately target intervention. The current study builds on this work by assessing the extent to which a school disengagement warning index predicts not only dropout but also other problem behaviors during middle adolescence, late adolescence, and early adulthood. Data from the Rochester Youth Development Study (N = 911, 73% male, 68% African American, and 17% Latino) were used to examine the effects of a school disengagement warning index based on official 8th and 9th grade school records on subsequent dropout, as well as serious delinquency, official offending, and problem substance use during middle adolescence, late adolescence, and early adulthood. Results indicate that the school disengagement warning index is robustly related to dropout as well as serious problem behaviors across the three developmental stages, even after controlling for important potential confounders. High school dropout mediates the effect of the warning index on serious problem behaviors in early adulthood. PMID- 21523390 TI - Keystone design perforator island flap for closure of myelomeningocele. AB - OBJECT: We present a series of three infants who underwent keystone design perforator island flap (KDPIF) closure for myelomeningocele in a paediatric neurosurgical centre in Australia. This is the first recorded utilization of this flap for primary closure of myelomeningocele (MMC). METHODS: The prospective data from the Monash Neurosurgical Database were used to select all cases of MMC between December 2008 and September 2010. Retrospective analysis of these cases revealed three patients who underwent KDPIF at Monash Medical Centre for MMC repair at birth. RESULTS: Wound healing was prompt and satisfactory in all three cases. No minor or major complications were noted. In particular, there was no associated skin flap separation, skin flap dehiscence, skin flap necrosis, infection, cerebrospinal fluid leak, or need for return to theatre for further intervention to the wound. This keystone design perforator island flap is based on random perforating musculo/fasciocutaneous perforators. In our experience, this robust flap provides better tissue bulk, more reliable vascularity and a wider geometrical versatility than traditional random 1:1 cutaneous flaps. CONCLUSION: Whilst primary closure remains an option for myelomeningocele closure, primary repair of larger defects can lead to closure site tension, stretching of inelastic scar tissue and inadequate soft tissue cover. In this small series, we have demonstrated the use of keystone design perforator island flap closure as an alternative for larger and more complex lesions. PMID- 21523391 TI - Comparison of the binding and internalization properties of 12 DOTA-coupled and 111In-labelled CCK2/gastrin receptor binding peptides: a collaborative project under COST Action BM0607. AB - PURPOSE: Specific overexpression of cholecystokinin 2 (CCK2)/gastrin receptors has been demonstrated in several tumours of neuroendocrine origin. In some of these cancer types, such as medullary thyroid cancer (MTC), a sensitive diagnostic modality is still unavailable and therapeutic options for inoperable lesions are needed. Peptide receptor radionuclide therapy (PRRT) may be a viable therapeutic strategy in the management of these patients. Several CCK2R-targeted radiopharmaceuticals have been described in recent years. As part of the European Union COST Action BM0607 we studied the in vitro and in vivo characteristics of 12 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CCK2R binding peptides. In the present study, we analysed binding and internalization characteristics. Stability, biodistribution and imaging studies have been performed in parallel by other centres involved in the project. METHODS: Determination of IC(50) values was performed using autoradiography, with DOTA-peptides displacing (125)I-CCK from receptors on tissue sections from human tumours. Saturation binding and internalization experiments were performed using (111)In-labelled peptides. The rat AR42J cell line and the human A431-CCK2R transfected cell line were utilized for in vitro experiments; dissociation constants (K(d)) and apparent number of binding sites (B(max)) were determined. Internalization was determined in receptor-expressing cells by incubating with tracer amounts of peptide at 37 and 4 degrees C for different times up to 120 min. Surface-bound peptide was then stripped either by acid wash or subsequent incubation with 1 MUM unlabelled peptide at 4 degrees C. RESULTS: All peptides showed high receptor affinity with IC(50) values ranging from 0.2 to 3.4 nM. Saturation experiments also showed high affinity with K(d) values in the 10(-9) 10(-8) M range. B(max) values estimated in A431-CCK2R cells ranged from 0.6 to 2.2 * 10(6) per cell. All peptides showed high levels of internalization when incubated at 37 degrees C. CONCLUSION: All DOTA-conjugated peptides showed high receptor binding and internalization properties and appear suitable for further characterization, as described in other articles of this issue. PMID- 21523392 TI - Relationships between serum vitamin D levels, neuromuscular and neuropsychological function and falls in older men and women. AB - Among 463 community dwellers aged 70-90 years, those with vitamin D insufficiency showed reduced neuromuscular function, balance control and stepping ability and performed worse in tests of cognitive function. In men, vitamin D insufficiency was associated with an increased risk of falling. INTRODUCTION: The purpose of this study was to investigate the relationship between serum 25-hydroxy vitamin D (serum 25OHD) levels, physiological and neuropsychological function in older people, and to examine the relationship between serum 25OHD and prospective falls. METHODS: Four hundred sixty-three community-dwelling people aged 70-90 years underwent an assessment of physiological and neuropsychological performance and structured interviews relating to comorbidity and disability. Fall frequency during the 12 months follow-up was monitored with monthly falls diaries. RESULTS: Twenty-one percent of the men and 44% of the women were vitamin D insufficient (serum 25OHD <= 50 nmol/L). Participants with vitamin D insufficiency had weaker upper and lower limb strength, slower simple finger press and choice stepping reaction time, poorer leaning balance and slower gait speed, after controlling for age and body mass index, and, poorer executive function and visuospatial ability, after controlling for age and education. Vitamin D insufficiency significantly increased the rate of falls in men (IRR = 1.94, 95% CI = 1.19-3.15, p = 0.008) but not in women. CONCLUSIONS: These findings highlight the associations between vitamin D insufficiency and impairments in physiological and neuropsychological function that predispose older people to fall. The significant relationship between vitamin D insufficiency and falls found in the men may relate to the stronger association found between serum 25OHD levels and dynamic balance measures evident in this male population. PMID- 21523393 TI - Biomaterials and interface with bone. AB - In this paper, some examples from the literature or from my own experience will be given to illustrate the influence of surface topography and surface chemistry at the nano- and micro-scale on the cell and tissue response. PMID- 21523394 TI - Bone regeneration and limb lengthening. AB - Regeneration of bone in the presence of stable fixation and the maintenance of the osteogenic tissue (marrow, endosteum, nutrient artery, and periosteum) required another factor to stimulation of bone regeneration: incremental distraction produces bone of both endosteal and periosteal origin. The soft tissues undergo to same growth phenomenon. The mechanism of ossification occurs without intermediate fibrocartilage. PMID- 21523395 TI - Biomechanics and tissue engineering. AB - Development of artificial scaffold for musculo-skeletal applications, especially in load-bearing situations, requires the consideration of biomechanical aspects for its integrity and its function. However, the biomechanical loading could also be used to favour tissue formation through mechano-transduction phenomena. Design of scaffold could take advantages of this intrinsic mechanical loading. PMID- 21523396 TI - Cell and gene therapy for bone repair. AB - Improving bone repair remains an important and challenging issue. Therapeutic approaches to amplify osteogenic cell pool or function include cell and gene therapies. We identified genes that promote human mesenchymal cell differentiation and bone formation. Targeting these or other genes may improve the efficacy of cell therapy for bone repair. PMID- 21523397 TI - Strategies for improving the efficacy of bioengineered bone constructs: a perspective. AB - Bioengineered bone scaffolds are intended for use in large bone defects. Successful bone constructs should stimulate and support both the onset and the continuance of bone ingrowth. In an attempt to improve their performance and to compete with the one of autologous bone grafts, a growing symbiosis at the biological and material level is required. Recent advances have been made to further exploit the osteogenic potential of MSCs in scaffold development. Current research encompasses new strategies for reducing cell death after implantation and the manufacturing of tailored, instructive scaffolds. PMID- 21523398 TI - Bone lengthening (distraction osteogenesis): a literature review. AB - Distraction osteogenesis (DO) is a surgical technique widely used in orthopedic surgery for the treatment of various pathological conditions such as leg length discrepancy, bone deformity or bone defects. The basic principle of the callotasis technique includes performing a transverse bone section before gradually distracting the two bone segments. New bone tissue is generated in the gap between the two segments. Bone regeneration during DO is believed to occur in response to the longitudinal mechanical strain applied to the callus during healing. One of the limitations of this technique is the long period of time required for the newly formed bone tissue to mineralize and consolidate. Various studies have reported that among growth factors, bone morphogenetic proteins (BMPs) may play a central role in the molecular signaling cascade leading to bone renegeration and remodeling in a DO procedure. Ongoing research is aimed at developing methods to accelerate bone consolidation in order to reduce the time required to obtain consolidation. One of these methods is to test the ability of exogenous BMPs to increase bone regeneration and accelerate bone consolidation. PMID- 21523399 TI - Bone repair in osteoporotic bone: postmenopausal and cortisone-induced osteoporosis. AB - Although osteoporosis has been the subject of a considerable number of publications in recent years, very few studies have investigated the effects of osteoporosis on the process of tissue repair. Most of the studies are based on animal data, using the ovariectomized rat model, and in most cases, fractures were obtained by femoral osteotomy. This model is imperfect in several aspects to fit with postmenopausal osteoporosis which is a complex, multifactorial disorder. Furthermore, a surgically induced fracture is not exactly the same as a fracture which occurs as a result of bone fragility. However, and despite contradictory results in some of the studies, in ovariectomized rats a delay in bone consolidation has been reported in the model, associated locally with a decrease in bone mineral density and mechanical resistance. Very few human data are available, which confirm the existence of a delay in consolidation subsequent to femoral fractures in aged patients compared to young patients. PMID- 21523400 TI - Bone fracture and bone fracture repair. AB - Fracture healing is a multistage repair process that involves complex, well orchestrated steps initiated in response to tissue injury. The early upregulation of IL-6, osteoprotegerin (OPG), VEGF, and BMPs indicates a central role for these factors in the initiation of cartilage and periosteal woven bone formation. In both callus fracture repair and stress fracture repair, the RANKL/OPG ratio is initially reduced, but peaks earlier in stress fracture healing than callus fracture healing. Though the understanding of the biological processes and molecular signals that coordinate fracture repair has advanced, the cause of variability observed in fracture repair is poorly understood. PMID- 21523401 TI - Macroscopic and microscopic process of long bone fracture healing. AB - The growth of each type of callus (cortical, medullary and periosteal) depends on the mechanical condition of fracture fixation (elastic fixation and instability or rigid immobilization), the type of treatment (non-operative, close or open surgical procedure, intra-medullary nailing, external fixation, plate...) and the high or poor quality of soft tissue and the specific characteristics of the local vascularisation. PMID- 21523402 TI - Evaluation of bone scaffolds by micro-CT. AB - This paper reviews the possibilities offered by X-ray micro-CT in bone tissue engineering. This technique provides a fast, nondestructive, and 3D quantification of bone scaffolds, bone ingrowth, and microvascularization. Synchrotron radiation absorption and phase micro-CT offer additional advantages to image newly formed bone in bioceramic scaffolds and pre-bone matrix. PMID- 21523403 TI - Lipopolysaccharide binding protein, interleukin-6 and C-reactive protein in acute gastrointestinal infections: value as biomarkers to reduce unnecessary antibiotic therapy. AB - AIM: Several new biomarkers, such as lipopolysaccharide binding protein (LBP) and interleukin-6 (IL-6), have the potential to determine the severity and outcome of infectious diseases. LBP and IL-6 serum levels have not been reported in patients with gastrointestinal infections. The aim of this study was to compare established markers of infection with new markers, such as LBP and IL-6, in patients with acute gastrointestinal infections METHOD: LBP, C-reactive protein (CRP), white blood cell count (WBC) and IL-6 serum levels were determined in patients with acute viral or bacterial (positive stool cultures) gastroenteritis. The final diagnosis and empiric antibiotic use were recorded. In total, medical data on 88 patients with acute gastroenteritis (22 bacterial, 66 viral or nonspecific) were analyzed. RESULTS: LBP and CRP levels were significantly increased in patients with acute bacterial gastroenteritis [28.5 +/- 16.5 vs. 15.2 +/- 11.5 MUg/mL (p < 0.05) and 10.4 +/- 9.6 vs. 3.8 +/- 5.5 mg/dL (p < 0.001), respectively]. LBP at a cut-off value of 14.6 MUg/mL and CRP at a cut-off value of 1.7 mg/dL distinguished between bacterial and non-bacterial gastrointestinal infection (receiver operator characteristic analysis). Empiric antibiotic therapy was initiated in 82% of patients with bacterial gastroenteritis and in 27% of patients with viral gastroenteritis. CONCLUSION: The use of the cut-off values for LBP and CRP determined here would have avoided unnecessary antibiotic therapy in 14 and 11%, of patients respectively. CRP and LBP appear to be superior to IL-6 and WBC as diagnostic markers of bacterial gastrointestinal infection. Cut-off values may be a useful tool to support clinical decision-making on whether or not to initiate empiric antibiotic therapy. PMID- 21523404 TI - Diagnostic relevance of simultaneous testing for Chlamydia trachomatis and Neisseria gonorrhoeae. AB - BACKGROUND: The prevalence of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infection in a Swiss cohort among individuals consulting for screening or symptomatic reasons is not very well known. METHODS: Between January 2009 and January 2010, diagnostic samples referred to us to test for either CT or NG or both were simultaneously analysed for both infections. Testing was performed using the commercial m2000sp and m2000rt devices from Abbott Diagnostics involving automated DNA extraction and semi-quantitative real-time polymerase chain reaction (PCR), respectively. RESULTS: A total of 9,245 individuals (8,009 female, 1,236 male) were tested. CT alone was found in 318 (3.97%) samples from female patients and NG infections were found in 5 (0.06%) of the female samples. Six (0.08%) women had both CT and NG infections. The numbers for males were 72 (5.83%) for CT alone, 18 (1.14%) for NG alone and 8 (0.65%) for coincident infections. Among women, a selective testing approach in which only the presence of CT was investigated missed six NG cases (0.07% prevalence, 54.55% of all NG-positive women) and the request to test only for NG missed two CT cases (0.02% prevalence, 0.62% of all CT-positive women). For the male samples, one NG case (0.08% prevalence, 3.85% of all NG-positive men) was missed when only CT was requested and three CT cases (0.24% prevalence, 3.75% of all CT-positive men) were overlooked when only NG testing was requested. CONCLUSION: A sizeable number (12) of CT and NG cases is missed by physician-referred testing for only one of the two pathogens. PMID- 21523405 TI - Oral antibiotic treatment and long-term outcomes of Lyme facial nerve palsy. AB - PURPOSE: To study the long-term functional outcomes of patients with Lyme facial nerve palsy treated with oral antibiotics. METHODS: We conducted a retrospective double-cohort study involving patients with Lyme facial nerve palsy treated with oral antibiotics matched to three controls with early localized Lyme disease. Chart review was completed and an SF-36 health questionnaire and standardized symptom questionnaire administered. RESULTS: Lyme facial nerve palsy patients were treated with oral antibiotics for a median duration of 21 days (range 7-30 days). Only three patients underwent lumbar puncture and each demonstrated lymphocytic pleocytosis. Fourteen of 15 patients with Lyme facial nerve palsy completely regained nerve function. The long-term outcomes were similar between patients with Lyme facial nerve palsy and controls after a median follow-up duration of 4.6 years. Patients with Lyme facial nerve palsy had significantly higher reported rates of fatigue (60%) than controls (27%) (p = 0.019), but similar energy and vitality scores on the SF-36 questionnaire (55.0 vs. 58.4, p = 0.621). SF-36 social functioning domain scores were significantly lower in patients with Lyme facial nerve palsy (77.5) than in controls (88.6) (p = 0.044). There were no other significant differences noted between the two cohorts. CONCLUSIONS: For patients with Lyme facial nerve palsy in North America, treatment with oral doxycycline appears to be an effective therapeutic strategy. PMID- 21523406 TI - Action potentials in primary osteoblasts and in the MG-63 osteoblast-like cell line. AB - Whole-cell patch-clamp analysis revealed a resting membrane potential of -60 mV in primary osteoblasts and in the MG-63 osteoblast-like cells. Depolarization induced action potentials were characterized by duration of 60 ms, a minimal peak to-peak distance of 180 ms, a threshold value of -20 mV and a repolarization between the spikes to -45 mV. Expressed channels were characterized by application of voltage pulses between -150 mV and 90 mV in 10 mV steps, from a holding potential of -40 mV. Voltages below -60 mV induced an inward current. Depolarizing voltages above -30 mV evoked two currents: (a) a fast activated and inactivated inward current at voltages between -30 and 30 mV, and (b) a delayed activated outward current that was induced by voltages above -30 mV. Electrophysiological and pharmacological parameters indicated that hyperpolarization activated strongly rectifying K(+) (K(ir)) channels, whereas depolarization activated tetrodotoxin sensitive voltage gated Na(+) (Na(v)) channels as well as delayed, slowly activated, non-inactivating, and tetraethylammonium sensitive voltage gated K(+) (K(v)) channels. In addition, RT PCR showed expression of Na(v)1.3, Na(v)1.4, Na(v)1.5, Na(v)1.6, Na(v)1.7, and K(ir)2.1, K(ir)2.3, and K(ir)2.4 as well as K(v)2.1. We conclude that osteoblasts express channels that allow firing of action potentials. PMID- 21523407 TI - Impact of oxidative stress on Acanthamoeba castellanii mitochondrial bioenergetics depends on cell growth stage. AB - Addition of a moderate (1.4 mM) concentration of H(2)O(2) to protozoon Acanthamoeba castellanii cell cultures at different growth phases caused a different response to oxidative stress. H(2)O(2) treatment of exponentially growing cells significantly delayed their growth; however, in mitochondria isolated from these cells, no damage to their bioenergetic function was observed. In contrast, addition of H(2)O(2) to A. castellanii cells approaching the stationary phase did not influence their growth and viability while seriously affecting mitochondrial bioenergetic function. Although mitochondrial integrity was maintained, oxidative damage was revealed in the reduction of cytochrome pathway activity, uncoupling protein activity, and the efficiency of oxidative phosphorylation as well as the membrane potential and the endogenous ubiquinone reduction level of the resting state. An increase in the alternative oxidase protein level and activity as well as an increase in the membranous ubiquinone content were observed in mitochondria isolated from late H(2)O(2)-treated cells. For the first time, the regulation of ubiquinone content in the inner mitochondrial membrane is shown to play a role in the response to oxidative stress. A physiological role for the higher activity of the alternative oxidase in response to oxidative stress in unicellular organisms, such as amoeba A. castellanii, is discussed. PMID- 21523408 TI - Involvement of thermoplasmaquinone-7 in transplasma membrane electron transport of Entamoeba histolytica trophozoites: a key molecule for future rational chemotherapeutic drug designing. AB - The quinone composition of the transplasma membrane electron transport chain of parasitic protozoa Entamoeba histolytica was investigated. Purification of quinone from the plasma membrane of E. histolytica and its subsequent structural elucidation revealed the structure of the quinone as a methylmenaquinone-7 (thermoplasmaquinone-7), a napthoquinone. Membrane bound thermoplasmaquinone-7 can be destroyed by UV irradiation with a concomitant loss of plasma membrane electron transport activity. The abilities of different quinones to restore transplasma membrane electron transport activity in UV irradiated trophozoites were compared. The lost activity was recovered completely by the addition of thermoplasmaquinone-7, but ubiquinones are unable to restore the same. These findings clearly indicate that thermoplasmaquinone-7 acts as a lipid shuttle in the plasma membrane of the parasite to mediate electron transfer between cytosolic reductant and non permeable electron acceptors. This thermoplasmaquinone-7 differs from that of the mammalian host and can provide a novel target for future rational chemotherapeutic drug designing. PMID- 21523409 TI - Traits and stress: keys to identify community effects of low levels of toxicants in test systems. AB - Community effects of low toxicant concentrations are obscured by a multitude of confounding factors. To resolve this issue for community test systems, we propose a trait-based approach to detect toxic effects. An experiment with outdoor stream mesocosms was established 2-years before contamination to allow the development of biotic interactions within the community. Following pulse contamination with the insecticide thiacloprid, communities were monitored for additional 2 years to observe long-term effects. Applying a priori ecotoxicological knowledge species were aggregated into trait-based groups that reflected stressor-specific vulnerability of populations to toxicant exposure. This reduces inter-replicate variation that is not related to toxicant effects and enables to better link exposure and effect. Species with low intrinsic sensitivity showed only transient effects at the highest thiacloprid concentration of 100 MUg/l. Sensitive multivoltine species showed transient effects at 3.3 MUg/l. Sensitive univoltine species were affected at 0.1 MUg/l and did not recover during the year after contamination. Based on these results the new indicator SPEAR (mesocosm) was calculated as the relative abundance of sensitive univoltine taxa. Long-term community effects of thiacloprid were detected at concentrations 1,000 times below those detected by the PRC (Principal Response Curve) approach. We also found that those species, characterised by the most vulnerable trait combination, that were stressed were affected more strongly by thiacloprid than non-stressed species. We conclude that the grouping of species according to toxicant-related traits enables identification and prediction of community response to low levels of toxicants and that additionally the environmental context determines species sensitivity to toxicants. PMID- 21523410 TI - Efficacy and safety of antifungal prophylaxis with oral itraconazole solution among patients receiving corticosteroids: who should be given prophylaxis? AB - The incidence of systemic fungal infections has risen, as shown by increases in the numbers of immunosuppressed or immunocompromised patients. The consequences of these fungal infections are occasionally serious. However, the efficacy of antifungal prophylaxis in patients receiving corticosteroid treatment has not been well investigated, even though they are susceptible to severe fungal infections. Therefore, we retrospectively evaluated the prophylactic efficacy of an antifungal agent-oral itraconazole solution (ITCZ-OS)-for immunosuppressed patients receiving corticosteroids in a single institution. Of 39 patients, 18 received prophylaxis with ITCZ-OS at a dose of 200 mg/day, and 21 did not. As a result, no fungal infections developed in the prophylactic group, but 7 of the 21 patients (33%) in the non-prophylactic group suffered from fungal infections consisting of 3 non-invasive candidiases, 2 invasive candidiases, and 2 invasive pulmonary aspergilloses. Among the non-prophylactic group, aging and hypoalbuminemia were statistically significantly associated with incidence of invasive fungal infections. Of the four patients with invasive fungal infections, three had concomitant chronic illness such as diabetes. Toxicity among the prophylactic group was not statistically significantly different from that of the non-prophylactic group. In addition, none needed discontinuation of the drug. These results indicate the potential antifungal prophylactic effect of ITCZ-OS for a subset of patients treated with moderate or high doses of corticosteroids. PMID- 21523411 TI - Comparative study of lipophilic and hydrophilic antioxidants from in vivo and in vitro grown Coriandrum sativum. AB - Coriander is commonly used for medicinal purposes, food applications, cosmetics and perfumes. Herein, the production of antioxidants in vegetative parts (leaves and stems) of in vivo and in vitro grown samples was compared. In vitro samples were clone A- with notorious purple pigmentation in stems and leaves and clone B- green. Seeds were also studied as they are used to obtain in vivo and in vitro vegetative parts. Lipophilic (tocopherols, carotenoids and chlorophylls) and hydrophilic (sugars, ascorbic acid, phenolics, flavonols and anthocyanins) compounds were quantified. The antioxidant activity was evaluated by radical scavenging activity, reducing power and lipid peroxidation inhibition. The in vivo sample showed the highest antioxidant activity mainly due to its highest levels of hydrophilic compounds. Otherwise, in vitro samples, mainly clone A, gave the highest concentration in lipophilic compounds but a different profile when compared to the in vivo sample. Clones A and B revealed a lack of beta carotene, beta- and delta-tocopherols, a decrease in alpha-tocopherol, and an increase in gamma-tocopherol and clorophylls in comparison to the in vivo sample. In vitro culture might be useful to explore the plants potentialities for industrial applications, controlling environmental conditions to produce higher amounts of some bioactive products. PMID- 21523412 TI - In vitro and in vivo antioxidant properties of extracts from Coptis chinensis inflorescence. AB - The inflorescence of cultivated Coptis chinensis has been valued for tea production for many years in China. The antioxidant activities of C. chinensis inflorescence extracts prepared by various solvents were investigated by using several established in vitro systems: 2,2'-azinobis(3-ethylbenzthiazoline-6 sulphonic acid (ABTS), alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) and superoxide radical scavenging assays, reducing power assay, and ferrothiocyanate (FTC) and thiobarbituric acid (TBA) assays. The results showed that the 70% ethanol extract (EE) had the strongest antioxidant activity in vitro among the various extracts. Based on the in vitro results, EE was used to evaluate the antioxidant activity of C. chinensis inflorescence in vivo. The liver and kidney of intoxicated animals showed a significant decrease in superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels, while the malondialdehyde (MDA) level showed a significant increase. These changes were significantly reversed after treatment with EE and the standard vitamin E. Thus, the C. chinensis inflorescence may be a valuable natural source that can be applicable to food industries. PMID- 21523413 TI - Effect of girdling at various positions of 'Huang Zhi Xiang' tea tree (Camellia sinensis) on the contents of catechins and starch in fresh leaf. AB - The contents of starch and catechins in the fresh leaf of 'Huang Zhi Xiang' Oolong tea trees girdled at the bottom, middle (on the big branches) and top (on the small branches) were determined. The study demonstrated that the starch contents from girdled trees were significantly higher (p<0.05) than that from non girdled ones. Furthermore, the contents of (-)-epicatechin (EC), (-) epigallocatechin (EGC), total catechins (TC) and simple catechins (SC) from girdled trees were significantly higher (p<0.05) than those from non-girdled ones. Especially, the contents of (-)-epigallocatechin gallate (EGCG), (-) epicatechin gallate (ECG) and catechin gallate (CG) from girdled at the middle were also significantly higher (p<0.05) than those from the non-girdled. The starch contents were negatively correlated with the contents of (-)-gallocatechin (GC), EC, SC, TC and EGC, while positively correlated with the contents of EGCG and CG in fresh shoots. PMID- 21523414 TI - Organic and conventional Coffea arabica L.: a comparative study of the chemical composition and physiological, biochemical and toxicological effects in Wistar rats. AB - Differentiation between organic and conventional coffee has increased due to the growing demand and high consumption of healthy foods that contain compounds with antioxidant potential, which have been associated with the reduction of chronic diseases. We used organic and conventional coffee in powder 4% (w/w) and infusions 5%, 10% and 20% (w/v) incorporated in a commercial diet to test in vivo. The levels of chlorogenic acid, caffeine and trigonelline were determined by high performance liquid chromatography. The body weight, weight gain, food consumption, aberrant foci crypt, mucin depleted foci, stress biomarkers protein carbonyl and malondialdehyde, biochemical parameters and behavior of the rats were compared between the experimental and control groups within a framework of colon carcinogenesis. The organic coffee showed higher levels of chlorogenic acid, caffeine and trigonelline than conventional, however, this difference did not significantly affect behavior. The infusions had an antioxidant effect, reducing the levels of malondialdehyde; however, the biochemical parameters of the serum were not altered, and there was neither induction nor prevention of preneoplasic lesions. PMID- 21523415 TI - Liver functional volumetry for portal vein embolization using a newly developed 99mTc-galactosyl human serum albumin scintigraphy SPECT-computed tomography fusion system. AB - BACKGROUND: We developed a new combined (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy single-photon emission computed tomography (SPECT)/CT system to evaluate the changes in functional liver volume with portal vein embolization (PVE). METHODS: We performed a prospective analysis of 25 patients treated with right PVE, and evaluated their functional liver volume perioperatively with a (99m)Tc-GSA scintigraphy SPECT-CT fusion system. The percentage of the non tumorous remnant liver volume (%LV) and the percentage of functional remnant liver volume (%FLV) were estimated by using the following calculations: (future remnant volume - tumor volume)/(total liver volume - tumor volume) and functional future remnant liver volume/functional total liver volume, respectively. RESULTS: Before PVE, the correlation was strongly significant between %LV and %FLV of the non-embolized liver, and the data were nearly equal (the regression coefficient was 1.005, P < 0.0001). In contrast, after PVE, there was a significant correlation between %LV and %FLV (P < 0.0001), but the regression coefficient was 1.192. The % LV increased significantly, from 38.1 to 52.0%, and the increment was 13.9% (P < 0.0005). The %FLV was also increased significantly, from 36.6 to 58.0%, and the increment was 21.4% (P < 0.0001). The increment was 7.5% greater for the %FLV compared to that of the %LV (P < 0.001). CONCLUSIONS: The (99m)Tc GSA scintigraphy SPECT-CT fusion system can estimate the correct functional liver volume and is useful in comparison with conventional CT volumetry. PMID- 21523416 TI - Analytical expressions for the transfer matrix to standardize scalp potentials to infinity reference. AB - A procedure based on the multiple expansion of the brain electrical generator is used here to derive analytical expressions for the transfer matrix necessary to obtain potentials referenced to infinity. Its features include: avoidance of computations that involve a large number of discrete dipole sources; faster evaluation compared to the use of the dipole layer; and a transparency showing the parameters that constitute the transfer matrix. The paper also proposes the construction of the standardization matrix without the use of the general inverse of a non-symmetrical matrix. PMID- 21523417 TI - Mechanism of conduction block in amphibian myelinated axon induced by biphasic electrical current at ultra-high frequency. AB - The mechanism of axonal conduction block induced by ultra-high frequency (>= 20 kHz) biphasic electrical current was investigated using a lumped circuit model of the amphibian myelinated axon based on Frankenhaeuser-Huxley (FH) equations. The ultra-high frequency stimulation produces constant activation of both sodium and potassium channels at the axonal node under the block electrode causing the axonal conduction block. This blocking mechanism is different from the mechanism when the stimulation frequency is between 4 kHz and 10 kHz, where only the potassium channel is constantly activated. The minimal stimulation intensity required to induce a conduction block increases as the stimulation frequency increases. The results from this simulation study are useful to guide future animal experiments to reveal the different mechanisms underlying nerve conduction block induced by high-frequency biphasic electrical current. PMID- 21523418 TI - Second invited commentary to the letter by Jan Lambrecht. PMID- 21523419 TI - Invited commentary to letter by Jan Lambrecht. PMID- 21523420 TI - [Orthopedic aspects in interdisciplinary multimodal therapy of chronic back pain]. AB - The effect of interdisciplinary multimodal therapy of chronic back pain is well documented. With elapsing time changing diagnostic focuses, therapeutic strategies and objectives have to be considered. The chronicity leads to a modification of the relevance of structure-related diagnosis and therapy and changes the significance of the classic orthopedic instruments. The requirement of a rational causal therapy in chronic back pain still remains but the focal points shift to the consideration of somatic, psychological and social disposing and supporting factors.The aim of this paper is to reflect the necessary orthopedic expertise in the context of the pathomechanics of chronic back pain and the interdisciplinary teamwork. PMID- 21523421 TI - [Not Available]. PMID- 21523422 TI - Insecticidal properties of phenols on Culex quinquefasciatus Say and Musca domestica L. AB - Thirteen simple phenols and 8 phenolic acids were tested for toxicity to Culex quinquefasciatus larvae and Musca domestica adults. It was found that while the phenolic acids (except salicylic acid) showed little or no effect on acute toxicity, all the tested simple phenols caused mortality within 24 h after application. Lethal doses for acute toxicity of C. quinquefasciatus were successfully estimated for 12 substances using probit analysis. Thymol, carvacrol, 2-ethylphenol, and salicylaldehyde showed significantly the highest efficiency, for which the lethal doses LD(50) were estimated as 30, 36, 38, and 43 MUg/ml, respectively. Lethal doses for acute toxicity of M. domestica adults were successfully estimated for ten substances. Thymol, carvacrol, and 2,6 dimethoxyphenol showed significantly the highest efficiency, for which the lethal doses LD(50) were estimated 53, 69, and 87 MUg/fly, respectively. PMID- 21523423 TI - Amoebicidal activity and chemical composition of Pterocaulon polystachyum (Asteraceae) essential oil. AB - Acanthamoeba species are free-living amoebae that constitute an etiological agent of Acanthamoeba keratitis, an illness that may cause severe ocular inflammation and blindness and has a very difficult treatment. These molecules that are found in plants may be an alternative for the development of new drugs. Plants of the genus Pterocaulon (Asteraceae) are used in folk medicine as an antiseptic and antifungal agent. In this work, we analyzed Pterocaulon polystachyum essential oil and assessed its amoebicidal activity against Acanthamoeba polyphaga. The leaves of the fresh plant submitted to hydrodistillation yielded 0.15% (w/v) of essential oil that was analyzed by gas chromatography-mass spectrometry being E sesquilavandulyl acetate as the major component, representing 43.8% of the oil. For the assessment of the amoebicidal activity, concentrations of 20, 10, 5, 2.5, and 1.25 mg/mL of essential oil were tested, being lethal to 100% of the A. polyphaga trophozoites at the concentrations of 10 and 20 mg/mL in 24 and 48 h. The cytotoxic effect of essential oil was also tested in mammalian cells using MTT assay. Amoebicidal activity results are in accordance with previous work in which the lipophilic compounds from this plant were active against Acanthamoeba castellanii. However, further studies with the major component of the essential oil will be carried out. PMID- 21523424 TI - Gedunin and photogedunin of Xylocarpus granatum possess antifilarial activity against human lymphatic filarial parasite Brugia malayi in experimental rodent host. AB - The present study is aimed to evaluate antifilarial activity of Xylocarpus granatum (fruit from Andaman) against human lymphatic filarial parasite Brugia malayi in vivo. The in vitro antifilarial activity has already been reported earlier for this mangrove plant which has traditionally been used against several ailments. Aqueous ethanolic crude extract, four fractions (ethyl acetate fraction, n-butanol fraction, water-soluble fraction and water-insoluble fraction) and pure molecule/s of X. granatum (fruit) were tested in vitro on adult worms and microfilariae (mf) of B. malayi and the active samples were further evaluated in vivo in B. malayi (intraperitoneally) i.p. transplanted in the jird model (Meriones unguiculatus) and Mastomys coucha subcutaneously infected with infective larvae (L3). The crude aqueous ethanolic extract was active in vitro (IC50: adult = 15.46 MUg/ml; mf = 13.17 MUg/ml) and demonstrated 52.8% and 62.7% adulticidal and embryostatic effect on B. malayi, respectively, in Mastomys at a dose of 5 * 50 mg/kg by oral route. The antifilarial activity was primarily localized in the ethyl acetate-soluble fraction which revealed IC50 of 8.5 and 6.9 MUg/ml in adult and mf, respectively. This fraction possessed moderate adulticidal and embryostatic action in vivo in Mastomys. Out of eight pure molecules isolated from the active fraction, two compounds gedunin (IC50 = 0.239 MUg/ml, CC50 = 212.5 MUg/ml, SI = 889.1) and photogedunin (IC50 = 0.213 MUg/ml, CC50 = 262.3 MUg/ml, SI = 1231.4) at 5 * 100 mg/kg by subcutaneous route revealed excellent adulticidal efficacy resulting in to the death of 80% and 70% transplanted adult B. malayi in the peritoneal cavity of jirds respectively in addition to noticeable microfilaricidalo action on the day of autopsy. The findings reveal that the extract from the fruit X. granatum contains promising in vitro and in vivo antifilarial activity against human lymphatic filarial parasite B. malayi which could be attributed to the presence of two pure compounds gedunin and photogedunin. PMID- 21523425 TI - Phlebotomus (Transphlebotomus) mascittii Grassi, 1908, in Carinthia: first record of the occurrence of sandflies in Austria (Diptera: Psychodidae: Phlebotominae). AB - During an entomology survey in July 2009 and July 2010, 4 males and 22 females of Phlebotomus (Transphlebotomus) mascittii were caught in southeastern Carinthia. These are the first documented records of the occurrence of Phlebotominae in Austria. PMID- 21523426 TI - Computer-based identification of type 2 diabetic subjects with and without neuropathy using dynamic planter pressure and principal component analysis. AB - Diabetes is a chronic disease that is characterized by an increased blood glucose level due to insulin resistance. Type 2 diabetes is common in middle aged and old people. In this work, we present a technique to analyze dynamic foot pressures images and classify them into normal, diabetes type 2 with and without neuropathy classes. Plantar pressure images were obtained using the F-Scan (Tekscan, USA) in shoe measurement system. We used Principal Component Analysis (PCA) and extracted the eigenvalues from different regions of the foot image. The features extracted from region 1 of the foot pressure image, which were found to be clinically significant, were fed into the Fuzzy classifier (Sugeno model) for automatic classification. Our results show that the proposed method is able to identify the unknown class with an accuracy of 93.7%, sensitivity of 100%, and specificity of 83.3%. Moreover, in this work, we have proposed an integrated index using the eigenvalues to differentiate the normal subjects from diabetes with and without neuropathy subjects using just one number. This index will help the clinicians in easy and objective daily screening, and it can also be used as an adjunct tool to cross check their diagnosis. PMID- 21523427 TI - Comparison of several texture features for tumor detection in CE images. AB - Capsule endoscopy (CE) has been widely used as a new technology to diagnose gastrointestinal tract diseases, especially for small intestine. However, the large number of images in each test is a great burden for physicians. As such, computer aided detection (CAD) scheme is needed to relieve the workload of clinicians. In this paper, automatic differentiation of tumor CE image and normal CE image is investigated through comparative textural feature analysis. Four different color textures are studied in this work, i.e., texture spectrum histogram, color wavelet covariance, rotation invariant uniform local binary pattern and curvelet based local binary pattern. With support vector machine being the classifier, the discrimination ability of these four different color textures for tumor detection in CE images is extensively compared in RGB, Lab and HSI color space through ten-fold cross-validation experiments on our CE image data. It is found that HSI color space is the most suitable color space for all these texture based CAD systems. Moreover, the best performance achieved is 83.50% in terms of average accuracy, which is obtained by the scheme based on rotation invariant uniform local binary pattern. PMID- 21523428 TI - Factors associated with health information exchange system usage in a safety-net ambulatory care clinic setting. AB - The Meaningful Use criteria promises to make health information exchange (HIE) much more widespread. However, the usage of the information systems made available by existing HIE efforts tends to be very low. This study sought to examine the factors associated with usage of an operational HIE system during ambulatory care visits to safety-net clinics. Overall the HIE system was accessed for 21% of encounters. However, system access took on two distinct forms. In general, usage was more likely for patients with recent emergency department visits and chronic conditions. This study indicates the organizational commitment to engage in HIE does not necessarily mean that the information systems will be always used. In addition, system usage will take on various forms for different reasons. These results reveal considerations for the development, operation and evaluation of HIE efforts. PMID- 21523429 TI - Mapping of main and epistatic effect QTLs associated to grain protein and gluten strength using a RIL population of durum wheat. AB - Quality, specifically protein content and gluten strength are among the main objectives of a durum wheat breeding program. The aim of this work was to validate quantitative trait loci (QTLs) associated with grain protein content (GPC) and gluten strength measured by SDS sedimentation volume (SV) and to find additional QTLs expressed in Argentinean environments. Also, epistatic QTL and QTL x environmental interactions were analyzed. A mapping population of 93 RILs derived from the cross UC1113 x Kofa showing extreme values in gluten quality was used. Phenotypic data were collected along six environments (three locations, two years). Main effect QTLs associated with GPC were found in equivalent positions in two environments on chromosomes 3BS (R(2)=21.0-21.6%) and 7BL (R(2)=12.1-13%), and in one environment on chromosomes 1BS, 2AL, 2BS, 3BL, 4AL, 5AS, 5BL and 7AS. The most important and stable QTL affecting SV was located on chromosome 1BL (Glu B1) consistently detected over the six environments (R(2)=20.9- 54.2%). Additional QTLs were found in three environments on chromosomes 6AL (R(2)=6.4 12.5%), and in two environments on chromosomes 6BL (R(2)=11.5-12.1%), 7AS (R(2)=8.2-10.2%) and 4BS (R(2)=11-16.4%). In addition, pleiotropic effects were found affecting grain yield, test weight, thousand-kernel-weight and days to heading in some of these QTLs. Epistatic QTLs and QTL x environment interactions were found for both quality traits, mostly for GPC. The flanking markers of the QTLs detected in this work could be efficient tools to select superior genotypes for the mentioned traits. PMID- 21523430 TI - Host plant invests in growth rather than chemical defense when attacked by a specialist herbivore. AB - Plant defensive compounds may be a cost rather than a benefit when plants are attacked by specialist insects that may overcome chemical barriers by strategies such as sequestering plant compounds. Plants may respond to specialist herbivores by compensatory growth rather than chemical defense. To explore the use of defensive chemistry vs. compensatory growth we studied Brugmansia suaveolens (Solanaceae) and the specialist larvae of the ithomiine butterfly Placidina euryanassa, which sequester defensive tropane alkaloids (TAs) from this host plant. We investigated whether the concentration of TAs in B. suaveolens was changed by P. euryanassa damage, and whether plants invest in growth, when damaged by the specialist. Larvae feeding during 24 hr significantly decreased TAs in damaged plants, but they returned to control levels after 15 days without damage. Damaged and undamaged plants did not differ significantly in leaf area after 15 days, indicating compensatory growth. Our results suggest that B. suaveolens responds to herbivory by the specialist P. euryanassa by investing in growth rather than chemical defense. PMID- 21523431 TI - In honor of the 80th birthday of Kurt Jellinger: a living legend in neuropathology. PMID- 21523432 TI - [Study to castrate-resistant prostate cancer: AUO study AP 60/10]. PMID- 21523433 TI - [Non-neurogenic bladder dysfunction and vesicoureteral reflux in children]. AB - Various types of bladder dysfunction are associated with urinary tract infection, renal damage and vesicoureteral reflux (VUR). In this article the influence of functional bladder disturbances such as detrusor instability (overactive bladder, OAB) and bladder sphincter dyssynergia (dysfunctional voiding), on the resolution of vesicoureteral reflux are reviewed. In summary, it is important to distinguish between children with dysfunctional voiding (increased activity of the pelvic floor during voiding) and those with OAB (detrusor overactivity during filling) because the latter has less effects on VUR. PMID- 21523434 TI - [Hydronephrosis: urgency of interventions and recommended times for surgical correction]. AB - The prevalence of malformations of the kidneys is quite high compared to other congenital malformations. In a study of the Association for Neonatology of Mecklenburg-West Pomerania examining 37,634 births, a hydronephrotic kidney was diagnosed in 16.7 of 10,000 children. Depending on the type and severity of the congenital malformation it might be difficult to find out when there is a risk for loss of renal function. Unfortunately, in 2010 health politicians (the Gemeinsame Bundesausschuss) voted against routine ultrasound screening for renal abnormalities in newborns despite an increasing number of pre- or postnatally diagnosed dilated kidneys in recent years. Will this lead to a decrease in the diagnosis of hydronephrosis with possible loss of renal function later on? According to Roth et al. the incidence of in utero dilatations of the urinary tract is about 1:100, but only 1:500 children have a clinically relevant problem. This raises the question of which of these young patients need an intervention and which might be monitored expectantly. PMID- 21523435 TI - The mechanism for heme to prevent Abeta(1-40) aggregation and its cytotoxicity. AB - The beta-amyloid peptide (Abeta) aggregation in the brain, known as amyloid plaques, is a hallmark of Alzheimer's disease (AD). The aberrant interaction of Cu(2+) ion with Abeta potentiates AD by inducing Abeta aggregation and generating neurotoxic reactive oxygen species (ROS). In this study, the biosynthesized recombinant Abeta(1-40) was, for the first time, used to investigate the mechanism for heme to prevent Abeta(1-40) aggregation and its cytotoxicity. Cell viability studies of SH-SY5Y cells and rat primary hippocampal neurons showed that exogenous heme can protect the cells by reducing cytotoxicity in the presence of Cu(2+) and/or Abeta(1-40). UV-vis spectroscopy, circular dichroism spectroscopy, and differential pulse voltammetry were applied to examine the interaction between heme and Abeta(1-40). It was proven that a heme-Abeta(1-40) complex is formed and can stabilize the alpha-helix structure of Abeta(1-40) to inhibit Abeta(1-40) aggregation. The heme-Abeta(1-40) complex possesses peroxidase activity and it may catalyze the decomposition of H(2)O(2), reduce the generation of ROS downstream, and ultimately protect the cells. These results indicated that exogenous heme is able to alleviate the cytotoxicity induced by Abeta(1-40) and Cu(2+). This information may be a foundation to develop a potential strategy to treat AD. PMID- 21523437 TI - 1H, 13C and 15N resonance assignments for a putative ADF/Cofilin from Trypanosoma brucei. AB - Actin-depolymerizing factor (ADF)/cofilin proteins are a family of actin-binding proteins expressed in almost all eukaryotic cells, and play a significant role in regulating actin-filament dynamics. Here we report the resonance assignments of a putative ADF/cofilin from Trypanosoma brucei for further understanding of the relationship between its structure and function. PMID- 21523436 TI - Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress. AB - Cancer cells produce galectin-1 as a tumor promoting protein. Thiodigalactoside (TDG) as a non-metabolised small drug, is shown to suppress tumor growth by inhibiting multiple cancer enhancing activities of galectin-1, including immune cell dysregulation, angiogenesis and protection against oxidative stress. Thus, using B16F10 melanoma and 4T1 orthotopic breast cancer models, intratumoral injection of TDG significantly raised the levels of tumor-infiltrating CD8(+) lymphocytes and reduced CD31(+) endothelial cell content, reducing tumor growth. TDG treatment of tumors in Balb/c nude mice (defective in T cell immunity) reduced angiogenesis and slowed tumor growth by a third less than in immunocompetent mice. Knocking down galectin-1 expression (G1KD) in both cancer cell types significantly impeded tumor growth and the sensitivity of the G1KD tumors to TDG was severely reduced, highlighting a specific role for galectin-1. Endothelial cells were protected by galectin-1 from oxidative stress-induced apoptosis induced by H(2)O(2), but TDG inhibited this antioxidant protective effect of galectin-1 and reduced tube forming activity in angiogenic assays. We show for the first time that the single agent, TDG, concurrently prevents many tumor promoting effects of galectin-1 on angiogenesis, immune dysregulation and protection against oxidative stress, providing a potent and novel small molecule as an anti-cancer drug. PMID- 21523438 TI - NMR assignments of ubiquitin fold domain (UFD) in SUMO-activating enzyme subunit 2 from rice. AB - The small ubiquitin-related modifier (SUMO) is a ubiquitin-like post translational modifier that alters the localization, activity, or stability of many proteins. In the sumoylation process, an activated SUMO is transferred from SUMO-activating enzyme E1 complex (SAE1/SAE2) to SUMO-conjugating enzyme E2 (Ubc9). Among the multiple domains in E1, a C-terminal ubiquitin fold domain (UFD) of SAE2 shows high affinity for Ubc9, implying that UFD will be functionally important. We report NMR chemical shift assignments of UFD in SAE2 from rice. Almost all the resonances of UFD were assigned uniquely, representing a single conformation of UFD in solution. This is a contrast to the previous report for the corresponding UFD of human SAE2 which shows two conformational states. The secondary structure prediction of UFD in rice SAE2 shows the similar overall structure to the crystal structures of UFD in other E1 proteins such as SAE2 of human and yeast, ubiquitin-activating enzyme of yeast, and NEDD8 activating enzyme E1 catalytic subunit of human. Concomitantly, differences in the length of helices, strands, and loops are observed, particularly in the binding region to E2, supposing the variation in the UFD-E2 binding mode which may play a critical role in determining E1-E2 specificity. PMID- 21523439 TI - 1H, 13C, and 15N resonance assignment of the central domain of hRSV transcription antitermination factor M2-1. AB - M2-1 is an essential co-factor of the respiratory syncytial virus, an important respiratory pathogen in infants and calves. It acts as a transcription antitermination factor which enhances the processivity of the polymerase. Within the polymerase complex, M2-1 interacts with a second co-factor, the phosphoprotein P. It has been shown previously that P and RNA bind to M2-1 in a competitive manner in vitro and that these properties are related to a central domain located between residues Glu59 and Lys177. Here we report the almost complete (1)H, (13)C and (15)N assignment of a fragment of M2-1 corresponding to this region, for further structure determination and interaction studies. PMID- 21523440 TI - Backbone assignment of the tyrosine kinase Src catalytic domain in complex with imatinib. AB - The Src tyrosine kinase is the paradigm of an oncogenic kinase, and of regulation by intramolecular inhibitory interactions, as well as an important anticancer target due to its roles in cell proliferation and metastasis. The assignment of backbone (1)H(N), (13)C(alpha), (13)CO, and (15)N, and sidechain (13)C(beta) resonances of the catalytic domain of Src (283 residues) in complex with the anticancer drug Imatinib is reported here. Consistent with previous X-ray studies of the same complex, most signals from the activation loop are not detected, indicating that, even in the presence of the drug, it probably adopts highly heterogeneous conformations in intermediate exchange. For the rest of the polypeptide backbone, assignments have been completed for ~88% of residues, with only a few solvent-exposed amides remaining unassigned. PMID- 21523441 TI - [Bernhard von Gudden on the occasion of the 125th anniversary of his death]. AB - Bernhard von Gudden died 125 years ago together with King Ludwig II of Bavaria, his royal patient. The prominence of the "Fairy Tale King", the circumstances surrounding the deprivation of his power and his psychiatric internment as well as the establishment of Luitpold's reign and above all the catastrophic ending of the Bavarian royal drama still outshine Gudden's importance for the scientific development of the new subject of Nervenheilkunde (psychiatry and neurology), particularly Bernhard von Gudden's importance and integrity as a physician. Not only was he a much sought-after academic teacher, but he was also a patient focused advocate of the principle of no restraint. As director of mental institutions, Gudden gave vital impulses for the improvement of mental health treatment. For 14 years he treated Prince Otto, the mentally ill brother of Ludwig II. Gudden rendered an expert opinion together with three other Bavarian psychiatrists resulting in Ludwig's legal incapacitation. Concerning the justification for the King's ousting there have been very different and controversial arguments from the constitutional and psychiatric point of view even in recent times. There is, however, a growing conviction that Ludwig II was incapable of reigning, the deprivation of his power followed the path prescribed by the constitution, and Gudden and his colleagues carried out a reviewing procedure considered valid by today's standards and appropriate under the circumstances. The royal disaster ending with the patient's and reviewer's death, however, has to be attributed to a misjudgement by Gudden that is based on the role diffusion between reviewer and treating physician. PMID- 21523442 TI - [Psychobiosocial interventions for autism]. AB - A multitude of interventions is offered for the treatment of autism spectrum disorders (ASD). However, only few have demonstrated scientific evidence, and even the evaluated methods need further examination of their mechanisms and scope. This article provides a brief summary of the premises and principles of successful psychobiosocial ASD intervention. ABA, TEACCH, PECS, social skills and cognitive training are described as examples for established approaches to ASD. Training of MU-suppression using neurofeedback and reanimation of the fusiform gyrus and amygdala using computer-aided facial affect recognition training are introduced as neurobiologically based ASD interventions. PMID- 21523443 TI - [Dementia and depression determine care dependency in Parkinson's disease: analysis of 1,449 outpatients receiving nursing care in Germany]. AB - BACKGROUND: Parkinson's disease (PD) is frequently accompanied by dementia or depression which can aggravate the clinical picture of the disease and increase the risk of care dependency (CD). Little is known about the associations between PD, these neuropsychiatric comorbidities and CD in outpatients. PATIENTS AND METHODS: A nationwide sample of outpatients (n=1,449) was examined by office based neurologists (n=315) comprising the documentation of the general, neurological status and the degree of CD. The dementia status was clinically rated according to the established DSM-IV criteria. Depression was screened with the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Overall, 18.3% of all patients were care dependent. Even after adjustment for PD severity, patients with depression (OR=2.8; 95% CI 1.8-4.3), dementia (OR=2.7; 95% CI 1.8-4.1) or both (OR=3.9; 95% CI 2.5-60,0) were at higher risk for CD than patients without dementia or depression. Patients aged >=76 years were fourfold more likely to be care dependent than patients aged <=65 years (OR=3.5; 95% CI 2.3-5.5). Across all age groups, patients with depression featured the highest increments (from 11.9 to 42.0%). CONCLUSION: The risk for CD is substantially elevated in outpatients with PD when further neuropsychiatric symptoms are present. The data suggest that depression contributes equally to disability as does dementia. PMID- 21523444 TI - A potential diagnostic blood test for attention deficit hyperactivity disorder. AB - Diagnosis of attention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults remains controversial. Dramatic growth in the diagnosis of this disorder in both young people and adults has focused criticism on the subjective nature of the diagnostic procedure. A new blood test that measures blood cell membrane potential (expressed as membrane potential ratio [MPR(TM)]) has been recently developed. The current study was performed to explore the potential utility of this blood test in diagnosis of ADHD. Consecutive outpatient children (n = 89), adolescents (n = 18), and adults (n = 89) diagnosed with ADHD, or not (n = 60, 17, and 92, respectively), provided sample in which the blood test was performed. ADHD subjects were relatively depolarized with an MPR(TM) of 0.804 +/- 0.0381, compared to non-ADHD subjects, 0.684 +/- 0.0260 (P < 0.05). The sensitivity is between 0.75 and 0.9, depending on the definition used, and the specificity is 0.75. MPR(TM) appears to be a viable potential diagnostic tool for ADHD. Larger studies utilizing standardized diagnostic procedures, taking into account medications and comorbidity, and exploring variables such as age and gender are warranted. PMID- 21523445 TI - Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer. AB - The potential anti-senescence gene Klotho (KL) has been recently found to participate in the progression of several different human cancers including breast, lung, and cervical cancer. In this current study, we identified KL as a candidate tumor suppressor gene silenced through promoter hypermethylation in colorectal cancer (CRC). KL gene expression is found to be absent or reduced in colon cancer cell lines (5/6, 83.3%), which can be reversed by treatment with demethylation agent 5-aza-2'-deoxycytidine (Aza), but not HDAC inhibitor trichostatin A. In addition, KL expression is markedly downregulated in colorectal carcinoma tissues when compared to the adjacent nontumor tissues (n=25, p<0.001). The methylation of the KL gene promoter was frequently detected in primary tumor tissues (34/40, 85%) when compared with adjacent nontumor colon tissues. Furthermore, ectopic expression of KL led to the cell proliferation inhibition of colon cancer cell lines via the induction of cell apoptosis and S phase cell cycle arrest. Taken together, our results suggest that KL is inactivated through promoter hypermethylation and potentially functions as a tumor suppressor gene in CRC. PMID- 21523446 TI - Toward cognitivist ontologies : on the role of selective attention for upper ontologies. AB - Ontologies play a key role in modern information society although there are still many fundamental questions regarding their structure to be answered. In this paper, some of these are presented, and it is argued that they require a shift from realist to cognitivist ontologies, with ontology design crucially depending on taking both cognitive and linguistic aspects into consideration. A detailed discussion of central parts of a proposed cognitivist upper ontology based on qualitative representations of selective attention is presented. PMID- 21523448 TI - Bioethanol production from tension and opposite wood of Eucalyptus globulus using organosolv pretreatment and simultaneous saccharification and fermentation. AB - During tree growth, hardwoods can initiate the formation of tension wood, which is a strongly stressed wood on the upper side of the stem and branches. In Eucalyptus globulus, tension wood presents wider and thicker cell walls with low lignin, similar glucan and high xylan content, as compared to opposite wood. In this work, tension and opposite wood of E. globulus trees were separated and evaluated for the production of bioethanol using ethanol/water delignification as pretreatment followed by simultaneous saccharification and fermentation (SSF). Low residual lignin and high glucan retention was obtained in organosolv pulps of tension wood as compared to pulps from opposite wood at the same H-factor of reaction. The faster delignification was associated with the low lignin content in tension wood, which was 15% lower than in opposite wood. Organosolv pulps obtained at low and high H-factor (3,900 and 12,500, respectively) were saccharified by cellulases resulting in glucan-to-glucose yields up to 69 and 77%, respectively. SSF of the pulps resulted in bioethanol yields up to 35 g/l that corresponded to 85-95% of the maximum theoretical yield on wood basis, considering 51% the yield of glucose to ethanol conversion in fermentation, which could be considered a very satisfactory result compared to previous studies on the conversion of organosolv pulps from hardwoods to bioethanol. Both tension and opposite wood of E. globulus were suitable raw materials for organosolv pretreatment and bioethanol production with high conversion yields. PMID- 21523447 TI - The archaic distinction between functioning and nonfunctioning neuroendocrine neoplasms is no longer clinically relevant. AB - BACKGROUND: Neuroendocrine neoplasms (NENs) are increasing in incidence and prevalence. This reflects greater clinical awareness, effective imaging, and increasing pathological diagnostic recognition. Although the identification and treatment of clinical neuroendocrine syndromes are established, there is confusion when a NEN has no discernible clinical symptoms. DISCUSSION: Nonfunctional tumors are usually diagnosed incidentally and at a later stage largely because either they do not secrete a bioactive product or do so, but in a form that is either inactive or in quantities that have no discernible effect. Nevertheless, the histopathology is indistinguishable from functional NENs, and tumors exhibit somatostatin receptor expression, and positive immunohistochemistry for neuroendocrine cell markers (CgA, NSE/synaptophysin). Similarly, their rates of growth and metastatic behavior are, like other NENs, predictably based on staging and grading (mitotic rate and Ki67 expression). Both types are diagnosed biochemically (CgA) and by imaging in an identical fashion with computed tomography, magnetic resonance imaging, somatostatin receptor scintigraphy, and endoscopic ultrasound. NENs, irrespective of function or bioactive secretory profile, respond with equal efficacy to the same regimen of surgery or antitumor drugs (e.g., somatostatin analogs with or without tyrosine kinase inhibitors/antiangiogenics or cytotoxics) depending on grade. Given the efficacy of somatostatin analogs in increasing progression free survival, nonfunctional NENs should be managed identically to symptomatic NENs. The consideration of NENs as functional or nonfunctional is an archaic clinical concept that should be discarded since the tumors are indistinguishable at a cellular, biological, and morphological level. All current evidences indicate that their diagnosis and treatment should follow the same common principles. PMID- 21523449 TI - The role of calcium channel blockers and resveratrol in the prevention of paraquat-induced parkinsonism in Drosophila melanogaster: a locomotor analysis. AB - Studies have suggested that neuronal loss in Parkinson's disease (PD) could be related to the pacemaker activity of the substantia nigra pars compacta generated by L-type Ca(v) 1.3 calcium channels, which progressively substitute voltage dependent sodium channels in this region during aging. Besides this mechanism, which leads to increases in intracellular calcium, other factors are also known to play a role in dopaminergic cell death due to overproduction of reactive oxygen species. Thus, dihydropyridines, a class of calcium channel blockers, and resveratrol, a polyphenol that presents antioxidant properties, may represent therapeutic alternatives for the prevention of PD. In the present study, we tested the effects of the dihydropyridines, isradipine, nifedipine, and nimodipine and of resveratrol upon locomotor behavior in Drosophila melanogaster. As previously described, paraquat induced parkinsonian-like motor deficits. Moreover, none of the drugs tested were able to prevent the motor deficits produced by paraquat. Additionally, isradipine, nifedipine, resveratrol, and ethanol (vehicle), when used in isolation, induced motor deficits in flies. This study is the first demonstration that dyhidropyridines and resveratrol are unable to reverse the locomotor impairments induced by paraquat in Drosophila melanogaster. PMID- 21523450 TI - [Complications of venous port systems : Radiological diagnostics and minimally invasive therapy]. AB - INTRODUCTION: Documentation of a correct port placement is a routine investigation in radiology. This article describes typical complications of port catheters and minimally invasive treatment options which can guarantee further use without complications. MATERIAL AND METHODS: From January 2009 to May 2010 a surgical port placement was carried out on 174 patients at the University Clinic in Mannheim and of these, 52 patients were admitted to our institute for radiological imaging of the port. Minimally invasive treatment options are presented based on the observed port complications. RESULTS: Of the 52 patients 7 (13.5%) received a port catheter lysis. A successful port position correction was carried out in 3 (5.8%) patients with a malpositioned port catheter and port removal was recommended in 2 patients (3.8%) due to extensive arm venous thrombosis. A minimally invasive port catheter treatment allowed further use of the port system without operative revision in the corresponding patients. The measures were tolerated very well by the patients without postinterventional complications. PMID- 21523451 TI - Axillary lymph node dissection in early-stage invasive breast cancer: is it still standard today? AB - Evaluation of axillary lymph node status by sentinel lymph node biopsy (SLNB) and complete axillary lymph node dissection (ALND) are an inherent part of breast cancer treatment. Increased understanding of tumor biology has changed the prognostic and therapeutic impact of lymph node status. Non-invasive imaging techniques like axillary ultrasound, FDG-PET, or MRI revealed moderate sensitivity and high specificity in evaluation of lymph node status. Therefore, they are not sufficient for lymph node staging. Otherwise, the impact of remaining micrometastases and even macrometastases for prognosis and treatment decisions is overestimated. Considering tumor biology, the distinction of axillary metastases in isolated tumor cells (ITC, pN0(i+)); micrometastases (pN1mi), and macrometastases (pN1a) is not comprehensible. Increasing data support the thesis that remaining axillary metastases neither increase the axillary recurrence rate nor decrease overall survival. It is doubtful that axillary tumor cells are capable to complete the complex multistep metastatic process. If applied, axillary metastases are sensitive to systemic treatment and are targeted by postoperative tangential breast irradiation. Therefore, the controversy about the clinical relevance of tumor cell clusters or micrometastases in SLN is a sophisticated but not contemporary discussion. Currently, there is no indication for axillary surgery in elderly patients with favorable tumors and clinically tumor-free lymph nodes. Nonetheless, a rational and evidence-based approach to the management of clinically and sonographically N0 patients with planned breast-conserving surgery and limited tumor size is needed now. PMID- 21523452 TI - Genetic variation in proinflammatory cytokines IL6, IL6R, TNF-region, and TNFRSF1A and risk of breast cancer. AB - Proinflammatory cytokines are associated with age-related diseases including arthritis and heart disease. IL6 and TNF also play key roles in estrogen modulation in older women. We explored whether variation in IL6 and TNF genes influenced the risk of breast cancer in samples that differed by age group: <44 years (228 cases and 271 controls), 45-64 years (426 cases and 396 controls), and 65+ years (228 cases and 239 controls). Samples were drawn from population-based case-control studies conducted in Seattle. Age-adjusted odds ratios (ORs) were calculated to evaluate the risk associated with variants in IL6, IL6R, TNF, and TNFRSF1A. There was a significantly increased risk of breast cancer associated with one or more C>T alleles at IL6 rs2069861 among subjects in the oldest age group (OR 1.8, 95% CI 1.1-2.9), but no overall increased risk of breast cancer associated with any IL6 or IL6R variants in the combined data. There were significantly elevated risks of breast cancer among women 45-64 years old associated with a UTR 5' flanking SNP LTA rs2009658 C>G allele (OR 1.5, 95% CI 1.1-1.9) and a nonsynonomous coding SNP TNFRSF1A rs767455 T>C allele (OR 1.3, 95% CI 1.1-1.6); these two variants were also elevated in the combined data (OR 1.3, 95% CI 1.1-1.5 and OR 1.2, 95% CI 1.1-1.4, respectively). This study supports a modest association between a variant in IL6 and breast cancer among older women and TNF-related variants and breast cancer among middle-aged women. Further evaluation of these genes in other studies is warranted. PMID- 21523453 TI - [Therapeutic strategies in erosive digital polyarthrosis]. AB - One of the most common forms of osteoarthritis is hand osteoarthritis. A subgroup, termed erosive hand osteoarthritis (EHOA), shows a highly destructive disease course with involvement of multiple joints, swelling as well as cartilage and bone destruction leading to progressive loss of hand function. EHOA is characterized by subchondral erosions of the finger joints as well as ankylosis. No disease modifying therapy is currently available for the treatment of EHOA and treatment options are confined to the control of symptoms. Acetaminophen and non steroidal anti-inflammatory drugs are used to treat the signs and symptoms. So far cytokine blocking agents have not shown a convincing therapeutic effect and the effect size of chondroitin sulfate and bisphosphonates in EOHA is small. PMID- 21523454 TI - Assessment of the involvement of oxidative stress and Mitogen-Activated Protein Kinase signaling pathways in the cytotoxic effects of arsenic trioxide and its combination with sulindac or its metabolites: sulindac sulfide and sulindac sulfone on human leukemic cell lines. AB - The purpose of the study was to characterize the involvement of reactive oxygen species (ROS) in mediating the cytotoxic effects of arsenic trioxide (ATO) in combination with sulindac or its metabolites: sulfide (SS) and sulfone (SF) on human leukemic cell lines. Jurkat, HL-60, K562, and HPB-ALL cells were exposed to the drugs alone or in combinations. Cell viability was measured using WST-1 or XTT reduction tests and ROS production by dichlorodihydrofluorescein diacetate staining (flow cytometry). Modulation of (a) intracellular glutathione (GSH) level was done by using L: -buthionine sulfoximine (BSO) or diethylmaleate (DEM), (b) NADPH oxidase by using diphenyleneiodonium (DPI), and (c) MAP kinases by using SB202190 (p38), SP600125 (JNK), and U0126 (ERK) inhibitors. ATO cytotoxicity (0.5 or 1 MUM) was enhanced by sulindacs, with higher activity showed by the metabolites. Strong cytotoxic effects appeared at SS and SF concentrations starting from 50 MUM. The induction of ROS production seemed not to be the major mechanism responsible for the cytotoxicity of the combinations. A strong potentiating effect of BSO on ATO cytotoxicity was demonstrated; DEM (10 300 MUM) and DPI (0.0025-0.1 MUM; 72 h) did not influence the effects of ATO. Some significant decreases in the viability of the cells exposed to ATO in the presence of MAPK inhibitors comparing with the cells exposed to ATO alone were observed; however, the effects likely resulted from a simple additive cytotoxicity of the drugs. The combinations of ATO with sulindacs offer potential therapeutic usefulness. PMID- 21523455 TI - [What is new in the 2009 ESC guidelines?]. AB - The 2009 ESC guideline emphasizes active risk stratification and the diagnostic strategy of prolonged ECG monitoring using an implantable loop recorder. The initial evaluation aims at establishing a prima vista diagnosis or at least a diagnostic hypothesis and risk stratification according to ECG criteria and clinical findings. Carotid sinus massage as a diagnostic procedure remains controversial. Electrophysiological study for evaluation of suspected arrhythmogenic syncope is of decreasing relevance. The loop recorder enables documentation of the rhythm during a subsequent syncope. Neurological work-up is not routinely recommended. A standardized evaluation minimizes the rate of unexplained syncopes. Therapeutic decisions include ICD or pacemaker, as indicated in cases of arrhythmogenic syncope or carotid sinus syncope, and mostly general measures in case of other reflex syncopes. PMID- 21523456 TI - Effect of the cord pretension of the Dynesys dynamic stabilisation system on the biomechanics of the lumbar spine: a finite element analysis. AB - The Dynesys dynamics stabilisation system was developed to maintain the mobility of motion segment of the lumbar spine in order to reduce the incidence of negative effects at the adjacent segments. However, the magnitude of cord pretension may change the stiffness of the Dynesys system and result in a diverse clinical outcome, and the effects of Dynesys cord pretension remain unclear. Displacement-controlled finite element analysis was used to evaluate the biomechanical behaviour of the lumbar spine after insertion of Dynesys with three different cord pretensions. For the implanted level, increasing the cord pretension from 100 to 300 N resulted in an increase in flexion stiffness from 19.0 to 64.5 Nm/deg, a marked increase in facet contact force (FCF) of 35% in extension and 32% in torsion, a 40% increase of the annulus stress in torsion, and an increase in the high-stress region of the pedicle screw in flexion and lateral bending. For the adjacent levels, varying the cord pretension from 100 to 300 N only had a minor influence on range of motion (ROM), FCF, and annulus stress, with changes of 6, 12, and 9%, respectively. This study found that alteration of cord pretension affects the ROM and FCF, and annulus stress within the construct but not the adjacent segment. In addition, use of a 300 N cord pretension causes a much higher stiffness at the implanted level when compared with the intact lumbar spine. PMID- 21523457 TI - The use of BoneWelding(r) technology in spinal surgery: an experimental study in sheep. AB - The innovative BoneWelding((r)) technology, where ultrasound energy bonds bioresorbable implants to bone, was tested for its feasibility in spine surgery and its local thermal effects. The three tested concepts consisted of implementation of a resorbable plating system, two converging polymer pins and suture anchors to the cervical vertebral bodies. Bioresorbable polylactide implants (PLDLLA 70/30) were inserted ventrally into the third and fourth vertebral body of seven sheep, of which six were sacrificed at 2 months and one sheep immediately after temperature measurements during implant insertion. Polymer screws were used as controls. Qualitative, semi-quantitative histological, and quantitative histomorphometrical evaluation showed excellent anchorage of the implants, new mineralized bone at the implant-bone interface, no inflammatory cell reaction or thermal damage to the adjacent bone in response to the novel insertion technology. The application of two converging pins, parallel inserted polymer pins, or fusion of the implant to the polymer plates did not affect the overall excellent tissue tolerance of the technology. Temperature increase during insertion was noticed but never exceeded 47 degrees C for less than 1 s. The BoneWelding((r)) technology was proven to be safe and easy to apply. PMID- 21523458 TI - Hyperbaric oxygen in the treatment of postoperative infections in paediatric patients with neuromuscular spine deformity. AB - The aim of this study is to evaluate possible benefits of hyperbaric oxygen (HBO) therapy in the treatment of deep postoperative infections in six high risk paediatric patients with neuromuscular spine deformity. The study involved review of medical records including radiology, office visits, and telephone contacts for six patients, referred for postoperative HBO therapy in 2003-2005. Infection control and healing without removal of implants or major revision surgery with a minimum of 2-year follow-up after index surgery were considered to represent success. All infections were resolved. Median time for wound healing, normalisation of blood tests and antibiotic weaning were 3 months. Radiological bony fusion, intact implants without any signs of radiolucent zones were seen in all cases at a mean follow-up of 54 months (37-72). Side effects of HBO treatment were minor. HBO is a safe and potentially useful adjuvance in the treatment of early deep postoperative infections in complex situations with spinal implants in high risk paediatric patients. PMID- 21523459 TI - Postoperative rehabilitation does not improve functional outcome in lumbar spinal stenosis: a prospective study with 2-year postoperative follow-up. AB - The aim was to study if postoperative rehabilitation improves functional outcome in lumbar spinal stenosis (LSS). Surgically treated LSS patients (n = 102) were randomized to rehabilitation-group (A) and "standard postoperative treatment"- group (B). Intervention for A-group started 3 months postoperatively, consisting of once a week outpatient visits for 12 weeks (1.5 h per visit; 1-6 patients per one physiotherapist). Physiotherapist guided stretching and strengthening exercises. A-group performed individually estimated exercises at those visits with guiding and at home up to 24-month postoperative follow-up. Physiotherapeutic guidance (12 times) was repeated after 12 months, in order to update exercises and motivate patients to keep training. For B-group, the "standard treatment" thus included normal postoperative treatment, or no treatment/self-management. Outcome measures were measured at the start and the end of the first physiotherapeutic intervention (3 and 6 months postoperatively), and at 12- and 24-month postoperative follow-ups. Oswestry Disability Index (ODI, 0-100%) was the main outcome measure. The other outcome measures were back- and leg pain separately (NRS-11); satisfaction (7-point scale) and treadmill test (0 1,000 m; not at 6 month). The intervention consisting of 12 + 12 physiotherapeutic sessions with further home exercises did not influence the course ODI in the 24-month postoperative follow-up (p = 0.95 for ODI; "as rehabilitated" analysis). No influence on any other outcome measures was observed. After LSS surgery, routinely performed outpatient rehabilitation did not improve functional outcome compared to standard treatment. In addition, it had no impact on the back and leg pain, satisfaction and walking ability. PMID- 21523461 TI - Sonographic assessment of the optic nerve sheath in idiopathic intracranial hypertension. AB - The aim of this work was to investigate the potential of ultrasound-based optic nerve sheath diameter (ONSD) measurements in detecting raised intracranial pressure in patients with idiopathic intracranial hypertension (IIH) and to describe ONSD response to lumbar puncture. In ten patients with newly diagnosed IIH, transorbital sonography was carried out to assess ONSD, OND (optic nerve diameter), and optic disc elevation before and after lumbar puncture. Twenty-five patients with other neurological disorders served as controls. Subjects with IIH showed a significantly enlarged ONSD on both sides (6.4 +/- 0.6 mm vs. 5.4 +/- 0.5 mm in controls; p < 0.001). The best cut-off value of ONSD for detecting raised ICP was 5.8 mm with a sensitivity of 90% and a specificity of 84%. After lumbar puncture, ONSD decreased bilaterally (right 5.8 +/- 0.7 mm, p < 0.004; left 5.9 +/- 0.7 mm, p < 0.043). No post-puncture changes could be observed with regard to OND and optic disc elevation. Sonographic ONSD evaluation may be useful as an additional tool to identify patients with raised intracranial pressure, as in IIH. Furthermore, our data suggest a potential usefulness of this method for monitoring of treatment effects. The degree of ONSD response to lumbar puncture differs in subjects with IIH, which may possibly be related to findings of a defective CSF circulation in the optic nerve sheath in this disorder, a state that is referred to as optic nerve compartment syndrome. PMID- 21523460 TI - A survey of metabolic databases emphasizing the MetaCyc family. AB - Thanks to the confluence of genome sequencing and bioinformatics, the number of metabolic databases has expanded from a handful in the mid-1990s to several thousand today. These databases lie within distinct families that have common ancestry and common attributes. The main families are the MetaCyc, KEGG, Reactome, Model SEED, and BiGG families. We survey these database families, as well as important individual metabolic databases, including multiple human metabolic databases. The MetaCyc family is described in particular detail. It contains well over 1,000 databases, including highly curated databases for Escherichia coli, Saccharomyces cerevisiae, Mus musculus, and Arabidopsis thaliana. These databases are available through a number of web sites that offer a range of software tools for querying and visualizing metabolic networks. These web sites also provide multiple tools for analysis of gene expression and metabolomics data, including visualization of those datasets on metabolic network diagrams and over-representation analysis of gene sets and metabolite sets. PMID- 21523462 TI - Life-threatening bradycardia after bilateral paramedian thalamic and midbrain infarction. PMID- 21523463 TI - Does the cortical bone resorption rate change due to 90Sr-radiation exposure? Analysis of data from Techa Riverside residents. AB - The Mayak Production Association released large amounts of (90)Sr into the Techa River (Southern Urals, Russia) with peak amounts in 1950-1951. Techa Riverside residents ingested an average of about 3,000 kBq of (90)Sr. The (90)Sr-body burden of approximately 15,000 individuals has been measured in the Urals Research Center for Radiation Medicine in 1974-1997 with use of a special whole body counter (WBC). Strontium-90 had mainly deposited in the cortical part of the skeleton by 25 years following intake, and (90)Sr elimination occurs as a result of cortical bone resorption. The effect of (90)Sr-radiation exposure on the rate of cortical bone resorption was studied. Data on 2,022 WBC measurements were selected for 207 adult persons, who were measured three or more times before they were 50-55 years old. The individual-resorption rates were calculated with the rate of strontium recirculation evaluated as 0.0018 year(-1). Individual absorbed doses in red bone marrow (RBM) and bone surface (BS) were also calculated. Statistically significant negative relationships of cortical bone resorption rate were discovered related to (90)Sr-body burden and dose absorbed in the RBM or the BS. The response appears to have a threshold of about 1.5-Gy RBM dose. The radiation-induced decrease in bone resorption rate may not be significant in terms of health. However, a decrease in bone remodeling rate can be among several causes of an increased level of degenerative dystrophic bone pathology in exposed persons. PMID- 21523464 TI - Characterization of quorum sensing signals in coral-associated bacteria. AB - Marine environment habitats, such as the coral mucus layer, are abundant in nutrients and rich with diverse populations of microorganisms. Since interactions among microorganisms found in coral mucus can be either mutualistic or competitive, understanding quorum sensing-based acyl homoserine lactone (AHL) language may shed light on the interaction between coral-associated microbial communities in the native host. More than 100 bacterial isolates obtained from different coral species were screened for their ability to produce AHL. When screening the isolated coral bacteria for AHL induction activity using the reporter strains Escherichia coli K802NR-pSB1075 and Agrobacterium tumefaciens KYC55, we found that approximately 30% of the isolates tested positive. Thin layer chromatography separation of supernatant extracts revealed different AHL profiles, with detection of at least one active compound in the supernatant of those bacterial extracts being able to induce AHL activity in the two different bioreporter strains. The active extract of bacterial isolate 3AT 1-10-4 was subjected to further analysis by preparative thin layer chromatography and liquid chromatography tandem mass spectrometry. One of the compounds was found to correspond with N-(3-hydroxydecanoyl)-L-homoserine lactone. 16S rRNA gene sequencing of the isolates with positive AHL activity affiliated them with the Vibrio genus. Understanding the ecological role of AHL in the coral environment and its regulatory circuits in the coral holobiont-associated microbial community will further expand our knowledge of such interactions. PMID- 21523465 TI - Prenatal and postnatal psychological symptoms of parents and family functioning: the impact on child emotional and behavioural problems. AB - Although relations of various parental psychological problems and family functioning with child development are well documented, it remains unclear whether specific prenatal or specific postnatal risk factors are independently associated with child emotional and behavioural problems, or whether observed associations can be explained by general parental psychopathology. Using a stepwise approach, we examined the effects of prenatal and postnatal parental depressive symptoms, prenatal and postnatal hostility of the parents, as well as prenatal family functioning on the risk of child emotional and behavioural problems. This study was embedded in Generation R: a population-based cohort from foetal life onwards. Mothers and fathers of 2,698 children provided information about depressive symptoms, symptoms of hostility and family functioning during pregnancy and 3 years after birth. Mother and father each reported on child behaviour when the child was 3 years old. Parental depressive symptoms increased the risk of child emotional and behavioural problems, but this increase was explained by postnatal parental hostile behaviour. Postnatal symptoms of hostility of mothers (OR = 1.34, p value <0.001) and postnatal symptoms of hostility of fathers (OR = 1.30, p value <0.001) each contributed independently to the risk of child emotional and behavioural problems. Postnatal parental hostility is associated with an increased risk of child emotional and behavioural problems, independent of parental depressive symptoms. These findings suggest that prevention and intervention strategies should focus on psychological symptoms of both mothers and fathers, in particular on hostile behaviour, in families with young children. PMID- 21523466 TI - The genetic dynamics of the rapid and recent colonization of Denmark by Arion lusitanicus (Mollusca, Pulmonata, Arionidae). AB - We describe the genetic dynamics of the recent establishment of the 'Iberian slug', Arion lusitanicus J. Mabille 1868, in Denmark and compare its population structure to two other members of the 'large Arion complex', Arion ater ater, native to Denmark, and Arion ater rufus, introduced into Denmark in the early 1900s. Assaying allozyme polymorphism at seven enzyme loci, we found that: (1) None of the three taxa reproduce primarily by self-fertilization. Differences among loci and colonies in the pattern of deviation from Hardy-Weinberg equilibrium are most consistent with isolate mixing and perhaps with low amounts of selfing. (2) For both A. lusitanicus and A. a. rufus, gene diversity is lower in Danish colonies than in southern German colonies, implying population bottlenecks in the establishment of Danish colonies. (3) Significant linkage disequilibrium values usually involve the same three loci, viz. PGI, MDH-1 and MDH-2, suggesting physical linkage among these loci. (4) For both A. a. rufus and A. lusitanicus, the overall gene frequencies from Denmark and southern Germany are homogeneous, while variation among colonies within these regions ranges from around 15 to 28% for the three taxa. This indicates strong, local population genetic subdivision but with little restriction to gene flow from possible source areas. The heterogeneity in measures of diversity and differentiation indicates that population structure for all three taxa is dominated by ongoing founder effects, local extinction/colonisation dynamics, and genetic drift processes. PMID- 21523467 TI - Effect of cavtratin, a caveolin-1 scaffolding domain peptide, on oligodendroglial signaling cascades. AB - Caveolin and caveolin containing rafts are involved in the signaling of growth factors in various cell types. Previous reports of our lab indicated a co localization of caveolin and the high affinity nerve growth factor (NGF) receptor tyrosine kinase A (TrkA). Mutual effects have been observed among which a caveolin-1 knock-down resulted in an impairment of the NGF signaling cascade rather than in an increase of activity as expected from other growth factor reports. On the other hand, an over-expression of caveolin-1 impaired the NGF stimulated activity of p42/44 mitogen activated protein kinases (MAPK). In this study, we used a caveolin-1 scaffolding domain (CSD) peptide (cavtratin) of which an inhibitory effect on growth factor receptors was reported. Our data showed that cavtratin suppresses the NGF-induced phosphorylation of TrkA as well as the activation of MAPK in porcine oligodendrocytes significantly. PMID- 21523468 TI - Targeting the target of rapamycin (TOR): looking to mother nature. PMID- 21523469 TI - Detection of ventricular shunt malfunction in the ED: relative utility of radiography, CT, and nuclear imaging. AB - The study objective was to determine the relative diagnostic utility of the radiographic shunt series (SS), head computed tomography (CT), and nuclear imaging performed in our Emergency Department (ED) for evaluating ventricular shunt malfunction. We retrospectively reviewed medical records, head CT (if performed), and nuclear imaging (if performed) for all ED patients with suspected shunt malfunction from 2002 to 2007 who underwent plain film shunt evaluation (296 cases/186 individuals) to determine if surgical shunt revision was performed. Logistic regression analysis was applied. Four percent (12/296) of radiographic SS were abnormal. Only 0.3% (1/296) underwent surgical revision in the absence of an abnormal head CT or nuclear imaging. Eighteen percent (51/282) of head CT exams were positive and 19% (24/128) of nuclear imaging exams were positive for shunt malfunction. Twenty-three percent (67/296) underwent surgical shunt revisions. Statistical analysis demonstrated that SS evaluation was not significantly associated with surgical shunt revision (OR 0.92; 95% CI, 0.7-1.2; p=0.47). Head CT demonstrated a significant association with surgical revision (OR 1.4; 95% CI, 1.2-1.5; p<0.001), as did nuclear imaging (OR 1.4; 95% CI, 1.2 1.6; p<0.001). Patients with suspected ventricular shunt malfunction frequently require surgical revision. Abnormal radiographic SS was not associated with progression to surgical shunt revision, whereas abnormal head CT and abnormal nuclear imaging were significantly associated with surgical revision. We conclude that radiographic SS in the ED is of low diagnostic utility and that patients with suspected shunt malfunction should instead initially undergo CT and/or nuclear imaging. PMID- 21523470 TI - Bladder trauma: multidetector computed tomography cystography. AB - Multidetector computed tomography (MDCT) cystography is rapidly becoming the most recommended study for evaluation of the bladder for suspected trauma. This article reviews the bladder trauma with emphasis on the application of MDCT cystography to traumatic bladder injuries using a pictorial essay based on images collected in our level I trauma center. PMID- 21523471 TI - Device-guided paced respiration as an adjunctive therapy for hypertension in obstructive sleep apnea: a pilot feasibility study. AB - Data suggest that device-guided paced respiration (<10 breaths/min) may reduce blood pressure in hypertensive patients. We hypothesized that daily device-guided slow breathing may lower blood pressure in patients with hypertension and obstructive sleep apnea (OSA). In this one-arm pilot study, we enrolled 25 subjects with hypertension and OSA. Subjects were asked to perform device-guided paced respiration 30 min a day for 8 weeks. Our primary outcome was change in office systolic and diastolic blood pressures from baseline to 8 weeks. Twenty four subjects completed the study. Mean baseline blood pressure was 140.0 +/- 10.2 mmHg systolic and 82.7 +/- 8.9 mmHg diastolic. Complete device data were available for 17 subjects. Mean device adherence was 81 +/- 24% and 51% achieved a mean breath rate <=10 breaths/min over 8 weeks. Three subjects had changes in their anti-hypertensive medications during the study. Among the remaining 21 subjects, mean difference in office blood pressure from baseline to 8 weeks was 9.6 +/- 11.8 mmHg systolic (p <= 0.01) and -2.52 +/- 8.9 mmHg diastolic (p = 0.21). Device-guided paced respiration may lower systolic blood pressure in patients with hypertension and OSA; however, our findings need to be confirmed with larger randomized controlled trials. PMID- 21523472 TI - The subcutaneous defibrillator will replace the transvenous defibrillator. PMID- 21523473 TI - An endo-beta-1,6-glucanase involved in Lentinula edodes fruiting body autolysis. AB - A beta-1,6-glucanase, LePus30A, was purified and cloned from fruiting bodies of the basidiomycete Lentinula edodes. beta-1,6-glucanases degrade beta-1,6-glucan polysaccharides, a unique and essential component of fungal cell walls. The complementary DNA of LePus30A includes an open reading frame of 1,575 bp encoding an 18 amino acid signal peptide and the 506 amino acid mature protein. Sequence analysis indicated that LePus30A is a member of glycoside hydrolase family 30, and highly similar genes are broadly conserved among basidiomycetes. The purified LePus30A catalyzed depolymerization of beta-1,6-glucan endolytically and was highly specific toward beta-1,6-glucan polysaccharide. It is known that the cell walls of fruiting bodies of basidiomycetes are autodegraded after harvesting by means of enzymatic hydrolysis. The transcript level of LePus30A gene (lepus30a) was significantly increased in fruiting bodies after harvesting. Moreover, LePus30A showed hydrolyzing activity against the cell wall components of L. edodes fruiting bodies. These results suggest that LePus30A is responsible for the degradation of the cell wall components during fruiting body autolysis after harvest. PMID- 21523474 TI - Improving the decolorization for textile dyes of a metagenome-derived alkaline laccase by directed evolution. AB - To obtain better performing laccases for textile dyes decolorization, random mutagenesis of Lac591, a metagenome-derived alkaline laccase, was carried out. After three rounds of error-prone PCR and high-throughput screening by assaying enzymatic activity toward the phenolic substrate 2,6-dimethoxyphenol (2,6-DMP), a mutant (Lac3T93) with remarkably improved enzymatic activity was obtained. Sequence analysis revealed that four amino acid substitutions (N40S, V55A, F62L, and E316V) were accumulated in the Lac3T93. Compared to the wild-type enzyme, the specific activity of Lac3T93 toward 2,6-DMP was increased to 4.8-fold (61.22 U/mg), and its optimal temperature and pH were changed to 60 degrees C and 8.0 from 55 degrees C and 7.5 of the wild-type enzyme, respectively. Furthermore, the degradation ability of Lac3T93 for textile dyes was investigated, and the new variant represented improved decolorization percentage for four industrial dyes with complex phenyl structure (Basic Blue 3, Methylene Blue, Bromophenol Blue, and Crystal Violet) and higher decolorization efficiency for Indigo Carmine than that of the parent enzyme. Furthermore, the decolorization percentage of Lac3T93 for five dyes in the absence of hydroxybenzotrizole (HBT) is clearly higher than those of the wild-type enzyme with 1 mM HBT, and HBT can further improve its decolorization ability. PMID- 21523475 TI - Functionalization of biomolecules on nanoparticles: specialized for antibacterial applications. AB - Biological efficiency of existing antimicrobial agents is still inadequate to ensure optimal therapeutic index. Developing biocompatible advanced functional materials with antimicrobial properties could be promising for environmentally benign applications. Nanoparticles and other nanoscale materials are of great interest due to their multiple potential applications in material science, medicine, and industry. Nanomaterials possess well renowned antimicrobial activity against several microorganisms; however, it has some non-specific toxicity. Biofunctionalization of nanomaterials is one such topic to address this issue. Rational selection of therapeutically active biomolecules for design of nanoparticles will certainly increase the biological applicability. The present paper describes the current status of different types of biofunctionalized nanoparticles and their antibacterial applications. Key principles such as strategies involved at bio-/nanointerface, the structural activity relationship, and mechanism of action involved in the antibacterial activity of functionalized nanoparticles are briefly discussed. This knowledge is important from the objective of generation of advanced functional nanomaterials with antimicrobial properties. PMID- 21523476 TI - Roles of Hfq in the stress adaptation and virulence in fish pathogen Vibrio alginolyticus and its potential application as a target for live attenuated vaccine. AB - Vibrio alginolyticus has brought about severe economic damage to the mariculture industry by causing vibriosis in various fish species in South China. The virulent determinants of this bacterium have not been well characterized except the exotoxin alkaline serine protease, Asp. In addition, the mechanism of virulence regulation in V. alginolyticus remains largely unknown apart from a Vibrio harveyi-like quorum sensing (QS) system which is established to manipulate the expression of various virulence-related genes. Hfq, an sRNA chaperone, is an important post-transcriptional regulator in a variety of bacteria. Here, the roles of Hfq were characterized in regulating the stress resistance and pathogenesis in V. alginolyticus. We demonstrated that the hfq deletion mutant became more sensitive to several environmental stresses, including osmotic stress, ethanol, temperature shift, and iron starvation. The deletion of hfq abrogated the motility and biofilm formation in this bacterium. Hfq negatively regulated the expression of main virulence factor, Asp, through QS system. The results also indicated that Hfq modulated the survival and multiplication of V. alginolyticus in fish. Hfq thus appears to be a new pleiotropic regulator of pathogenesis in V. alginolyticus. Moreover, high immunoprotective rate was achieved with a single dose of injection or immersion vaccination with live hfq mutant, suggesting the mutant's merits as a valuable vaccine candidate against V. alginolyticus. PMID- 21523477 TI - Microbial enzymes for aromatic compound hydroxylation. AB - Redox enzymes are ubiquitous in all living organisms. In fact, oxidation and reduction reactions are fundamental for the transformation of cellular and external compounds both for cell reproduction and for energy production. Redox enzymes share a common characteristic that is the capacity of transferring electrons to and from molecules. In addition, microorganisms contain many oxidative enzymes, and because they are relatively easier to cultivate and study, they have been investigated in details, in particular for potential use in biotechnological field. One important reaction that oxidative enzymes perform is the introduction of one or two oxygen atoms on aromatic compounds. The most representative classes of enzymes that perform this reaction are oxygenases/hydroxylases, peroxidases, and laccases; they differ in many aspects: the metal present in the active site, the used reductive cofactor, the final oxidant, and the number of electrons transferred in each step. Their essential features and mechanisms of action have been the subject of several studies, together with some structural analyses. This review reports recent developments and summarizes some of the most interesting results concerning both structural requirements and mechanisms implicated in aromatic hydroxylation. PMID- 21523478 TI - High yield secretion of heterologous proteins in Corynebacterium glutamicum using its own Tat-type signal sequence. AB - Efficient protein secretion, the basis of large-scale production of many compounds central to the biotechnology industry, is achieved by signal peptide and propeptide optimization in addition to optimizing host factors affecting heterologous protein production. Here, we fused green fluorescent protein (GFP) to the recently identified Tat-type secretory signal peptide of CgR0949 to demonstrate a high-yield protein secretion system of Corynebacterium glutamicum. The resultant secretion vector facilitated effective secretion of active-form GFP (20 mg l(-1)) into C. glutamicum culture medium. The expression of GFP was enhanced 2.9-fold using the Shine-Dalgarno sequence of triosephosphate isomerase in the secretion vector. Moreover, GFP drastically accumulated in the culture supernatant upon addition of calcium chloride even though Ca(2+) addition did neither enhanced the transcription of gfp nor resulted in the accumulation of cytosolic GFP. Active-form GFP concentration reached 1.8 g l(-1) after 48-h incubation in a jar fermentor. Likewise, alpha-amylase accumulation in C. glutamicum cultures was also enhanced by Ca(2+) addition, suggesting that Ca(2+) may affect general protein secretion in C. glutamicum. PMID- 21523479 TI - Fungal endophytes: unique plant inhabitants with great promises. AB - Fungal endophytes residing in the internal tissues of living plants occur in almost every plant on earth from the arctic to the tropics. The endophyte-host relationship is described as a balanced symbiotic continuum ranging from mutualism through commensalism to parasitism. This overview will highlight selected aspects of endophyte diversity, host specificity, endophyte-host interaction and communication as well as regulation of secondary metabolite production with emphasis on advanced genomic methods and their role in improving our current knowledge of endophytic associations. Furthermore, the chemical potential of endophytic fungi for drug discovery will be discussed with focus on the detection of pharmaceutically valuable plant constituents as products of fungal biosynthesis. In addition, selected examples of bioactive metabolites reported in recent years (2008-2010) from fungal endophytes residing in terrestrial plants are presented grouped according to their reported biological activities. PMID- 21523480 TI - Photocatalytic disinfection using titanium dioxide: spectrum and mechanism of antimicrobial activity. AB - The photocatalytic properties of titanium dioxide are well known and have many applications including the removal of organic contaminants and production of self cleaning glass. There is an increasing interest in the application of the photocatalytic properties of TiO(2) for disinfection of surfaces, air and water. Reviews of the applications of photocatalysis in disinfection (Gamage and Zhang 2010; Chong et al., Wat Res 44(10):2997-3027, 2010) and of modelling of TiO(2) action have recently been published (Dalrymple et al. , Appl Catal B 98(1-2):27 38, 2010). In this review, we give an overview of the effects of photoactivated TiO(2) on microorganisms. The activity has been shown to be capable of killing a wide range of Gram-negative and Gram-positive bacteria, filamentous and unicellular fungi, algae, protozoa, mammalian viruses and bacteriophage. Resting stages, particularly bacterial endospores, fungal spores and protozoan cysts, are generally more resistant than the vegetative forms, possibly due to the increased cell wall thickness. The killing mechanism involves degradation of the cell wall and cytoplasmic membrane due to the production of reactive oxygen species such as hydroxyl radicals and hydrogen peroxide. This initially leads to leakage of cellular contents then cell lysis and may be followed by complete mineralisation of the organism. Killing is most efficient when there is close contact between the organisms and the TiO(2) catalyst. The killing activity is enhanced by the presence of other antimicrobial agents such as Cu and Ag. PMID- 21523484 TI - Bone morphogenetic protein 4 is an efficient inducer for mouse embryonic stem cell differentiation into primordial germ cell. AB - Presence of specific growth factors and feeder layers are thought to be important for in vitro embryonic stem cell (ESCs) differentiation. In this study, the effect of bone morphogenetic protein 4 (BMP4) and mouse embryonic fibroblasts (MEFs) co-culture system on germ cell differentiation from mouse ESCs was evaluated. One-day-old embryoid body was cultured for 4 d in simple culture systems or on top of the MEFs, both in the presence or absence of BMP4. Data showed significant higher viability percent and proliferation rate in simple culture media compared to co-culture systems. Analysis of gene expression indicated that the germ cell-specific genes (VASA and Stra8) were expressed in a significant higher ratio in BMP4-treated cells in simple culture system. Also, the results of immunocytochemistry in simple culture systems showed that the mean percentage of immunostaining cells of VASA, the primordial germ cell (PGC) marker, was increased significantly in BMP4-treated cells compared with BMP4-free group. Meanwhile, CDH1, the late premiotic germ cell marker, showed no significant difference between these two groups. The results suggest that BMP4 is an efficient inducer in PGC derivation from mouse ESC. However, the employment of MEFs as feeder has no apparent effect on PGC derivation. PMID- 21523485 TI - Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis. AB - Epigenetic silencing of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is associated with improved survival in patients with high-grade gliomas (HGG), with varying estimates of magnitude. The objective of this meta-analysis is to determine the prognostic value of MGMT silencing, and assess its predictive value by treatment type. MEDLINE and EMBASE databases were searched for studies relating to gliomas and MGMT. Studies reporting overall survival (OS) by MGMT status in patients with HGG were considered potentially eligible. We excluded studies that did not control for potential confounding variables. A meta-analysis of studies was performed via random-effects modelling. Subgroup meta-analyses by treatment were performed according to a priori hypotheses. Twenty studies were ultimately eligible, including 2,018 patients. In the pooled analysis, MGMT silencing was associated with improved OS (HR = 0.436; 95% CI: 0.333-0.571; P < 0.001). The prognostic utility of MGMT status varies significantly by treatment type (P = 0.001): the HR for OS for MGMT silenced tumors is 0.190 (0.047-0.770), 0.403 (0.282-0.576), 0.743 (0.579-0.954), and 1.070 (0.722-1.585) for studies using surgery plus the addition of either: chemotherapy (CT), chemoradiotherapy (CRT), radiotherapy (RT), and nothing (surgery alone), respectively. Epigenetic silencing of MGMT is associated with markedly improved survival in patients with HGG who receive adjuvant therapy. MGMT silencing serves as a predictive marker, with the largest benefit seen in patients receiving CT as a component of adjuvant treatment, an intermediate benefit in patients receiving adjuvant RT, and no evidence to support benefit in those receiving surgery alone. PMID- 21523486 TI - Safety and feasibility of motexafin gadolinium administration with whole brain radiation therapy and stereotactic radiosurgery boost in the treatment of <= 6 brain metastases: a multi-institutional phase II trial. AB - To determine the safety, tolerability, and report on secondary efficacy endpoints of motexafin gadolinium (MGd) in combination with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) for patients with <= 6 brain metastases. We conducted an international study of WBRT (37.5 Gy in 15 fractions) and SRS (15-21 Gy) with the addition of MGd (5 mg/kg preceding each fraction beginning week 2). The primary endpoint was to evaluate the rate of irreversible grade 3 or any grade >= 4 neurotoxicity and establish feasibility in preparation for a phase III trial. Sixty-five patients were enrolled from 14 institutions, of which 45 (69%) received SRS with MGd as intended and were available for evaluation. Grade >= 3 neurotoxicity attributable to radiation therapy within 3 months of SRS was seen in 2 patients (4.4%), including generalized weakness and radionecrosis requiring surgical management. Immediately following the course of MGd plus WBRT, new brain metastases were detected in 11 patients (24.4%) at the time of the SRS treatment planning MRI. The actuarial incidence of neurologic progression at 6 months and 1 year was 17 and 20%, respectively. The median investigator-determined neurologic progression free survival and overall survival times were 8 (95% CI: 5-14) and 9 months (95% CI: 6-not reached), respectively. We observed a low rate of neurotoxicity, demonstrating that the addition of MGd does not increase the incidence or severity of neurologic complications from WBRT with SRS boost. PMID- 21523488 TI - State estimation bias induced by optimization under uncertainty and error cost asymmetry is likely reflected in perception. AB - It is well known from numerous studies that perception can be significantly affected by intended action in many everyday situations, indicating that perception and related decision-making is not a simple, one-way sequence, but a complex iterative cognitive process. However, the underlying functional mechanisms are yet unclear. Based on an optimality approach, a quantitative computational model of one such mechanism has been developed in this study. It is assumed in the model that significant uncertainty about task-related parameters of the environment results in parameter estimation errors and an optimal control system should minimize the cost of such errors in terms of the optimality criterion. It is demonstrated that, if the cost of a parameter estimation error is significantly asymmetrical with respect to error direction, the tendency to minimize error cost creates a systematic deviation of the optimal parameter estimate from its maximum likelihood value. Consequently, optimization of parameter estimate and optimization of control action cannot be performed separately from each other under parameter uncertainty combined with asymmetry of estimation error cost, thus making the certainty equivalence principle non applicable under those conditions. A hypothesis that not only the action, but also perception itself is biased by the above deviation of parameter estimate is supported by ample experimental evidence. The results provide important insights into the cognitive mechanisms of interaction between sensory perception and planning an action under realistic conditions. Implications for understanding related functional mechanisms of optimal control in the CNS are discussed. PMID- 21523487 TI - Magnetic resonance imaging targeting of intracranial glioma xenografts by Resovist-labeled endothelial progenitor cells. AB - Accumulating evidence suggests that endothelial progenitor cells (EPCs) play a key role in the development and infiltration of gliomas. Thus, it has been considered that EPCs may be good vehicles for delivering anti-angiogenesis genes for tumor therapy. However, limited means of tracking these cells in vivo has restricted the effective evaluation of the curative effects of genetically modified EPCs in gliomas at different stages. The aim of this study was to develop a non-invasive method to monitor the migration of EPCs to gliomas using 1.5-T MR scanning. We successfully labeled EPCs isolated from cord blood with Resovist-PLL without any influence on the biological properties of these cells. After intravenous administration into glioma-bearing nude mice, the labeled EPCs specifically homed to gliomas and could be reliably tracked by 1.5-T MR as early as 1 day after transplantation, causing a signal loss on T2-weighted images. The dark area was detected throughout the entire tumor zone on day 5, and did not develop a ring as previously described. Histological analysis showed the labeled cells were mainly located at the periphery of the tumor where abundant neo vessels were identified using CD34 staining; this finding indicates that the transplanted cells may be able to differentiate into ECs and become incorporated into glioma neovasculature. These results suggested that Resovist labeling of EPCs is feasible, efficient and safe for MRI tracking, and 1.5-T MR could be a powerful method for in vivo monitoring of EPCs as an anti-angiogenic drug therapy vector targets against glioma. PMID- 21523489 TI - Biologically inspired kinematic synergies enable linear balance control of a humanoid robot. AB - Despite many efforts, balance control of humanoid robots in the presence of unforeseen external or internal forces has remained an unsolved problem. The difficulty of this problem is a consequence of the high dimensionality of the action space of a humanoid robot, due to its large number of degrees of freedom (joints), and of non-linearities in its kinematic chains. Biped biological organisms face similar difficulties, but have nevertheless solved this problem. Experimental data reveal that many biological organisms reduce the high dimensionality of their action space by generating movements through linear superposition of a rather small number of stereotypical combinations of simultaneous movements of many joints, to which we refer as kinematic synergies in this paper. We show that by constructing two suitable non-linear kinematic synergies for the lower part of the body of a humanoid robot, balance control can in fact be reduced to a linear control problem, at least in the case of relatively slow movements. We demonstrate for a variety of tasks that the humanoid robot HOAP-2 acquires through this approach the capability to balance dynamically against unforeseen disturbances that may arise from external forces or from manipulating unknown loads. PMID- 21523490 TI - Combined effects of virus, pesticide, and predator cue on the larval tiger salamander (Ambystoma tigrinum). AB - Emerging diseases and environmental contamination are two of the leading hypotheses for global amphibian declines. Yet few studies have examined the influence of contaminants on disease susceptibility, and even fewer have incorporated the role of natural stressors such as predation. We performed a factorial study investigating the interaction of the insecticide carbaryl, dragonfly predator cue, and the emerging pathogen Ambystoma tigrinum virus (ATV) on fitness correlates and disease susceptibility in tiger salamander larvae. Four week old larvae were exposed for 22 days in a 2 (0, 500 MUg/l carbaryl) * 2 (control, predator cue water) * 2 (0, 1 * 10(4) pfu ATV) factorial designed laboratory study. Results show significant impacts to survival of larvae for both virus and predator cue treatments, as well as an interactive effect between the two, in which predator cue strongly exacerbated disease-driven mortality. There was a clear pattern of reduced survival with the addition of stressors, with those where all three stressors were present exhibiting the worst effects (a decrease in survival from 93 to 60%). On those that survived, we also detected several sub-lethal impacts in mass, SVL, and development. Predator cue and pesticide treatments significantly reduced both SVL and mass. Virus and predator treatments significantly slowed development. Stressors also exhibited opposing effects on activity. Predator cue caused a significant reduction in activity, whereas virus caused a significant increase in activity over time. These results highlight the importance of examining combined natural and introduced stressors to understand potential impacts on amphibian species. Such stressors may contribute to the emergence of ATV in particular regions, raising concerns about the influence of pesticides on disease emergence in general. PMID- 21523491 TI - Molecular dynamics simulations of pro-apoptotic BH3 peptide helices in aqueous medium: relationship between helix stability and their binding affinities to the anti-apoptotic protein Bcl-X(L). AB - The B-cell lymphoma 2 (Bcl-2) family of proteins regulates the intrinsic pathway of apoptosis. Interactions between specific anti- and pro-apoptotic Bcl-2 proteins determine the fate of a cell. Anti-apoptotic Bcl-2 proteins have been shown to be over-expressed in certain cancers and they are attractive targets for developing anti-cancer drugs. Peptides from the BH3 region of pro-apoptotic proteins have been shown to interact with anti-apoptotic Bcl-2 proteins and induce biological activity similar to that observed in parent proteins. However, the specificity of BH3 peptides derived from different pro-apoptotic proteins differ for different anti-apoptotic Bcl-2 proteins. In this study, we have investigated the relationship between the stable helical nature of BH3 peptides and their affinities to Bcl-X(L), an anti-apoptotic Bcl-2 protein. We have carried out molecular dynamics simulations of six BH3 peptides derived from Bak, Bad and Bim pro-apoptotic proteins for a period of 50 ns each in aqueous medium. Due to the amphipathic nature of BH3 peptides, the hydrophobic residues on the hydrophobic face tend to cluster together in all BH3 peptides. While this process resulted in a complete loss of helical structure in 16-mer Bak and 16-mer Bad wild type peptides, stabilizing interactions in the hydrophilic face of the BH3 peptides and capping interactions helped to maintain partial helical character in 16-mer Bad mutant and 16-mer Bim peptides. The latter two 16-mer peptides exhibit higher affinity for Bcl-X(L). Similarly the longer BH3 peptides, 25-mer Bad and 33-mer Bim, also resulted in smaller and stable helical fragments and their helical conformation is stabilized by interactions between residues in the solvent-exposed hydrophilic half of the peptide. The stable nature of helical segment in a BH3 peptide can be directly correlated to its binding affinity and the helical region encompassed the highly conserved Leu residue. We propose that upon approaching the hydrophobic groove of anti-apoptotic proteins, a longer helix will be induced in high affinity BH3 peptides by extending the smaller stable helical segments around the conserved Leu residue in both N- and C terminal regions. The results reported in this study will have implications in developing peptide-based inhibitors for anti-apoptotic Bcl-2 proteins. PMID- 21523492 TI - Education in sleep disorders in US dental schools DDS programs. AB - INTRODUCTION: Medical school surveys of pre-doctoral curriculum hours in the somnology, the study of sleep, and its application in sleep medicine/sleep disorders (SM) show slow progress. Limited information is available regarding dentist training. This study assessed current pre-doctoral dental education in the field of somnology with the hypothesis that increased curriculum hours are being devoted to SM but that competencies are still lacking. MATERIALS AND METHODS: The 58 US dental schools were surveyed for curriculum offered in SM in the 2008/2009 academic year using an eight-topic, 52-item questionnaire mailed to the deans. Two new dental schools with interim accreditation had not graduated a class and were not included. Responses were received from 49 of 56 (87.5%) of the remaining schools. RESULTS AND CONCLUSIONS: Results showed 75.5% of responding US dental schools reported some teaching time in SM in their pre-doctoral dental program with curriculum hours ranging from 0 to 15 h: 12 schools spent 0 h (24.5%), 26 schools 1-3 h, 5 schools 4-6 h, 3 schools 7-10 h, and 3 schools >10 h. The average number of educational hours was 3.92 h for the schools with curriculum time in SM, (2.96 across all 49 responding schools). The most frequently covered topics included sleep-related breathing disorders (32 schools) and sleep bruxism (31 schools). Although 3.92 h is an improvement from the mean 2.5 h last reported, the absolute number of curriculum hours given the epidemic scope of sleep problems still appears insufficient in most schools to achieve any competency in screening for SRBD, or sufficient foundation for future involvement in treatment. PMID- 21523493 TI - Breeding practices, growth, and carcass potential of fat-tailed Washera sheep breed in Ethiopia. AB - On-farm survey of farmers' breeding practices, breeding objectives, and selection criteria and on-station feedlot performance evaluation of Washera sheep were undertaken in Ethiopia. The survey revealed that most (79.8%) of the farmers had no breeding ram. The mating system was predominantly uncontrolled. A majority (75.5%) of the sheep owners reported that they herded their sheep flock by mixing with other livestock species mainly with cattle. During grazing, 44.6% of the farmers mix their sheep flock with neighboring sheep flocks. The major sheep production objective was to generate income from the sale of live sheep. Fast growth, appearance, coat color, and pedigree performance were important ram selection criteria, respectively. Ability to breed at early age, pedigree information, mothering ability, and lambing interval were important selection criteria for ewe, respectively. The on-station performance study involved evaluation of feedlot gains and carcass production under five levels of feeding regimes (300, 400, 500, 600, and 700 g day(-1) of concentrate feed) for a period of 93 days. The results indicated that the feedlot growth and carcass performance of Washera sheep were very high, with average daily weight gains of up to 126 g and carcass weight of 16 kg, with the optimal level of supplementation for Washera sheep being at 500 g of concentrate per day for a period of 93 days. PMID- 21523494 TI - Fat-tailed sheep in Indonesia; an essential resource for smallholders. AB - This paper discusses the historical development of fat-tailed sheep in Indonesia, the dynamics of production systems, production and reproduction performances under farmers' conditions, and roles of sheep in livelihoods. In the eighteenth and nineteenth century, fat-tailed sheep from southwest Asia and Africander sheep from South Africa were introduced. Crossing of fat-tailed sheep with the local thin-tailed sheep produced the Javanese fat-tailed sheep. Main motives for the gradual change-over to fat-tailed sheep have been their potential larger body size and the preference of consumers for their meat. Management systems are changing in response to the intensification of land use. The reproductive performances of fat-tailed sheep are good. Households keep four to six animals, housed close to the family quarters. This results in very high levels of faecal bacteria contamination of drinking water sources. Sheep provide a small income, manure, security and help to accumulate capital. Sheep also play a key role in religious festivities. Farmers hardly profit from the increased demand for the feast of sacrifice; animals are sold mainly when the owners have urgent cash needs. Systematic sheep fattening can contribute to higher economic results, if sufficient family labour and crop residues are available. PMID- 21523495 TI - How the Affordable Care Act will strengthen the nation's primary care foundation. AB - As the country turns toward implementation of the Patient Protection and Affordable Care Act, realizing the potential of reform will require significant transformation of the American system of health care delivery. To that end, the new law seeks to strengthen the nation's primary care foundation through enhanced reimbursement rates for providers and the use of innovative delivery models such as patient-centered medical homes. Evidence suggests that these strategies can return substantial benefits to both patients and providers by increasing access to primary care services, reducing administrative hassles and burdens, and facilitating coordination across the continuum of care. If successfully implemented, the Affordable Care Act has the potential to realign incentives within the health system and create opportunities for providers to be rewarded for delivering high value, patient-centered primary care. Such a transformation could lead to better outcomes for patients, increase job satisfaction among physicians and encourage more sustainable levels of health spending for the nation. PMID- 21523496 TI - Patient, resident physician, and visit factors associated with documentation of sexual history in the outpatient setting. AB - BACKGROUND: Providers need an accurate sexual history for appropriate screening and counseling, but data on the patient, visit, and physician factors associated with sexual history-taking are limited. OBJECTIVES: To assess patient, resident physician, and visit factors associated with documentation of a sexual history at health care maintenance (HCM) visits. DESIGN: Retrospective cross-sectional chart review. PARTICIPANTS: Review of all HCM clinic notes (n = 360) by 26 internal medicine residents from February to August of 2007 at two university-based outpatient clinics. MEASUREMENTS: Documentation of sexual history and patient, resident, and visit factors were abstracted using structured tools. We employed a generalized estimating equations method to control for correlation between patients within residents. We performed multivariate analysis of the factors significantly associated with the outcome of documentation of at least one component of a sexual history. KEY RESULTS: Among 360 charts reviewed, 25% documented at least one component of a sexual history with a mean percent by resident of 23% (SD = 18%). Factors positively associated with documentation were: concern about sexually transmitted infection (referent: no concern; OR = 4.2 [95% CI = 1.3-13.2]); genitourinary or abdominal complaint (referent: no complaint; OR = 4.3 [2.2-8.5]); performance of other HCM (referent: no HCM performed; OR = 3.2 [1.5-7.0]), and birth control use (referent: no birth control; OR = 3.0 [1.1, 7.8]). Factors negatively associated with documentation were: age groups 46-55, 56-65, and >65 (referent: 18-25; ORs = 0.1, 0.1, and 0.2 [0.0-0.6, 0.0-0.4, and 0.1-0.6]), and no specified marital status (referent: married; OR = 0.5 [0.3-0.8]). CONCLUSIONS: Our findings highlight the need for an emphasis on documentation of a sexual history by internal medicine residents during routine HCM visits, especially in older and asymptomatic patients, to ensure adequate screening and counseling. PMID- 21523497 TI - Thyroid tuberculosis in southeastern Turkey: is this the resurgence of a stubborn disease? AB - BACKGROUND: While tuberculosis (TB) has been found in many parts of the body, involvement of the thyroid gland is rare. In this study we describe the clinicopathological characteristics of seven patients with primary thyroid tuberculosis (TTB). METHODS: This report is a retrospective case study of seven patients with thyroid tuberculosis who were treated surgically in our clinic between 2004 and 2010. Data collected from the cases included age, sex, clinical presentation, concurrent medical illness, initial diagnosis, and history of pulmonary tuberculosis. Testing used to establish the diagnosis of TTB included thyroid function tests, histopathological examination, a tuberculin skin test, and FNAC (fine needle aspiration cytology). Surgical procedures, antitubercular therapy, and follow-up data were also analyzed. RESULTS: All seven cases were females between the age of 30 and 60 years (mean = 44.1 +/- 9.5 years). Four cases had neck swelling and three had additional complaints of dysphagia and dyspnea. While total thyroidectomy was performed in six patients with multinodular goiter, a lobectomy was performed in one patient in whom a solitary thyroid nodule was detected. Histopathologic changes consistent with thyroid tuberculosis were detected in all patients. Thoracic X-ray, erythrocyte sedimentation rate (ESR) test, and tuberculin skin test (PPD) were performed and all patients were screened for other possible foci of infection. In conclusion, all seven cases were diagnosed with primary tuberculosis. While the lobectomy patient was administered a 6-month antitubercular treatment, the total thyroidectomy patients did not receive any medical treatment postoperatively. During the postoperative follow-up period, which lasted between 6 and 53 months (mean = 37.3 +/- 18.6 months), none of the patients had a recurrence of disease. CONCLUSION: Tuberculosis should be considered in the list of differential diagnoses for thyroid abscesses and nodular lesions in people living in geographic regions with a high tuberculosis prevalence. PMID- 21523498 TI - Minilaparoscopic varicocelectomy with preservation of testicular artery and lymphatic vessels by using intracorporeal knot-tying technique: five-year experience. AB - BACKGROUND: In this study we present our experience using minilaparoscopic intracorporeal knot tying to ligate internal spermatic veins (ISV) while sparing the spermatic artery and lymphatics. METHODS: Minilaparoscopic varicocelectomies were performed in 87 patients between January 2004 and January 2009. All varicoceles were detected clinically according to the World Health Organization (WHO) classification and confirmed by scrotal color Doppler ultrasonography. The surgical indications were scrotal symptoms in 71, infertility in 16, and both conditions in 2. Three 3.5 mm minilaparoscopic ports were used for the operation. The ISVs were dissected and then ligated with intracorporeal knot-tying. The testicular artery and lymphatic vessels were carefully preserved to minimize procedure-related complications. RESULTS: Unilateral laparoscopic varicocelectomy was performed in 21 (24.2%) patients and bilateral in 66 (75.8%). Mean operative time was 71.1 +/- 29.2 and 46.8 +/- 12.6 min for bilateral and unilateral varicocelectomies, respectively. All patients were discharged within 24 h after surgery. Neither immediate major nor late procedure-related complications were noted. Of the 71 patients with scrotal symptoms, the symptoms completely subsided in 55 (77.5%) and partially subsided in 10 (14.1%). Only one (1.2%) recurrent varicocele was detected within a mean follow-up of 21 months (range = 3-42). Neither hydrocele formation nor testicular atrophy was found during the follow-up period. CONCLUSION: Our 5-year experience revealed that minilaparoscopic varicocelectomy with sparing of artery and lymphatic vessels could safely and effectively ligate all spermatic veins and preserve spermatic arteries and lymphatic channels without leading to a high varicocele persistence or recurrence. PMID- 21523499 TI - NeoGemTax: gemcitabine and docetaxel as neoadjuvant treatment for locally advanced nonmetastasized pancreatic cancer. AB - BACKGROUND: About 30% of patients with pancreatic cancer suffer from locally advanced nonmetastatic carcinoma at the time of diagnosis. We conducted a prospective phase II clinical trial using neoadjuvant chemotherapy, consisting of gemcitabine and docetaxel, to assess the rate of complete radical resection and overall survival. METHODS: Gemcitabine (900 mg/m2) and docetaxel (35 mg/m2) were given on days 1, 8, and 15 of a 28-day cycle. Two cycles were administered for a preoperative treatment duration of 8 weeks. Patients experiencing tumor regression or stable disease and improved performance status subsequently underwent surgical exploration and pancreatic resection, if feasible. All patients were followed postoperatively to assess long-term survival. RESULTS: A total of 25 patients were eligible and included in the intent-to-treat and evaluable population. Thirteen patients had unresectable disease at inclusion and 12 patients had borderline resectable pancreatic cancer. Finally, 8 of 25 (32%) patients underwent resection after neoadjuvant chemotherapy; 7 (87%) of these patients had R0 resection. The median overall survival of patients who underwent resection was 16 months (95% confidence interval [CI], 8-24 months) compared to 12 months (95% CI, 8-16 months) for those without resection (p=0.276). The median recurrence-free survival rate after resection was 12 months (95% CI, 2-21 months). CONCLUSIONS: NeoGemTax was safe and resection was feasible in a number of patients after systemic neoadjuvant treatment. Further randomized clinical trials are needed to identify novel multimodal regimens that would be able to increase the percentage of patients undergoing curative pancreatic cancer surgery despite advanced tumor stage at the time of diagnosis. PMID- 21523500 TI - A collaborative transdisciplinary "geriatric surgery service" ensures consistent successful outcomes in elderly colorectal surgery patients. AB - BACKGROUND: We hypothesized that a dedicated collaborative transdisciplinary Geriatric Surgery Service (GSS) will improve care for elderly colorectal surgery patients. METHODS: Patients older than 75 years of age who underwent major colorectal surgery were included in this study. The Geriatric Surgery Service employed a transdisciplinary, collaborative model of care. There were frequent quality reviews and a patient-centered culture was ensured. Treatment protocols and checklists were instituted. Perioperative outcome data were collected prospectively between 2007 and 2009. These data were compared to those from similar patients not managed by the service. Success and failure of surgical treatment of the two groups were analyzed using CUSUM methodology. Failure was defined as mortality, prolonged hospital stay for any reason, including morbidity, and failure to regain preoperative function by 6 weeks. RESULTS: Twenty-nine patients managed by the GSS were compared to 52 patients who underwent standard treatment. The median age of the patients managed by the GSS was higher but there was no difference in the ASA score and predicted morbidity scores based on the POSSUM model. The GSS achieved lower mortality and major complication rates. A large majority (84.6%) of the patients managed by the GSS returned to preoperative functional status by 6 weeks. The GSS was able to produce a trend of successively desired outcomes consistently leading to the CUSUM curve exhibiting a sustained downward slope. This was in contrast to patients not managed by the GSS. CONCLUSION: The Geriatric Surgery Service, through its transdisciplinary, collaborative care processes, was able to achieve sustained superior outcomes compared to standard management. PMID- 21523501 TI - Outcome after open repair of ruptured abdominal aortic aneurysm in patients>80 years old: a systematic review and meta-analysis. AB - BACKGROUND: The role of open repair in the management of ruptured abdominal aortic aneurysm (RAAA) in patients>80 years old is questioned by the perceived high operative risk of these patients. This issue has been investigated in the present meta-analysis of observational studies. METHODS: Studies on open repair of RAAA in patients>80 years old were identified in July 2010. The immediate and intermediate results were expressed as pooled proportions with 95% confidence interval (95% CI). Linear regression and meta-regression were performed to evaluate the impact of variables on the immediate postoperative mortality. RESULTS: Pooled analysis of 29 studies showed that the risk of immediate postoperative mortality in patients>80 years old was significantly higher than in younger patients (risk ratio 1.440, 95%CI 1.365-1.519, I2 36.8%, P=0.002; risk difference 19.4%, 95% CI 16.4-22.4%, I2 38.8%, P=0.019). Pooled analysis of 36 studies showed an immediate postoperative mortality rate of 59.2% (95% CI 55.7 62.5, I2 35.62). Immediate postoperative mortality in patients<80 years old positively correlated with that of patients>80 years old (rho: 0.686, P<0.0001). Intermediate survival data of 111 operative survivors were available from six studies, and their pooled survival rates at 1-, 2-, and 3-year were 82.4, 75.6, and 68.7%, respectively. CONCLUSIONS: Immediate and intermediate survival rates of patients>80 years old after open repair of RAAA are acceptable. These findings suggest a more confident approach toward emergency repair of RAAA in the very elderly. PMID- 21523502 TI - The road to reduced port surgery: from single big incisions to single small incisions, and beyond. AB - Single-port surgery has seen almost as rapid an application as multiport laparoscopy during the early 1990s. Hopefully, we will learn from our predecessors to apply the dictums of safety and science as we move forward with this new technique to ensure adequate adoption and successful outcomes with limited errors and concerns along the way. PMID- 21523503 TI - Selenium deficiency a factor in endemic goiter persistence in sub-Saharan Africa. AB - BACKGROUND: Goiter is still common in Uganda, despite the present iodized salt coverage of at least 95%. Where there is endemic goiter after adequate iodine supplementation, selenium deficiency could be a factor for the continued occurrence of goiter. The objectives of the present study, therefore, were to determine the serum selenium levels among goitrous patients and nongoitrous controls and to determine the association between goiter and selenium levels among these patients. METHODS: The investigation was designed as a case control study in which 92 subjects were enrolled, 46 cases and 46 controls of similar age and sex distribution. Subjects were interviewed and examined. Blood samples were taken and selenium concentrations were determined by electrothermal atomic absorption spectrometry. RESULTS: The overall mean serum selenium levels were 77.25 MUg/l (SD 16.78) for the goiter patients and 95.50 MUg/l (24.47) for the nongoiter controls. The difference between goitrous and nongoitrous populations was statistically significant (p=0.0001). Selenium levels above 102.8 MUg/l had a statistically significant protective effect against goiter with adjusted odds ratio 0.3 (0.13-0.69); p=0.005. Other factors, such as age, main food constituent, and use of iodized salt, had no association with goiter. CONCLUSIONS: There were significant differences between selenium levels among goitrous patients and nongoitrous controls. High selenium levels seem to have a protective effect against goiter. Selenium supplementation as a preventive strategy is worth further exploration. PMID- 21523504 TI - Carrying the pain: the journey from suffering to transformation-perspectives from Shakespearean tragedy and pastoral care. AB - This paper proposes an admittedly difficult thesis that emotional pain and suffering can be good news. Rather than denying and running from emotional pain and suffering, we suggest embracing and carrying the pain. Through academic and spiritual writings, an observation of Hamlet's tragic suffering, an examination of pastoral care case study data, and a B.L.E.S.S. acronym, this paper proposes that within the experience of suffering lies the transformative potential for meaning and fullness. PMID- 21523505 TI - The Evil Eye--an ancient superstition. AB - This paper describes and discusses the ancient superstition of the Evil Eye. The author describes his own personal childhood introduction to the subject of the Evil Eye which years later instigated his scholarly inquiry. The history of this very geographically widespread folk belief is elaborated upon, along with common manifestations as they appear in a number of different countries and cultures. Some of the methods used to thwart the negative effects of the Evil Eye are enumerated. Relevant psychodynamics and common expressions of the Evil Eye superstition are elucidated upon. PMID- 21523507 TI - Effect of two herbicides on Xenylla welchi (Hexapoda:Collembola) under laboratory conditions. AB - Xenylla welchi was used to evaluate toxicity of two herbicide formulations, pretilachlor (50 EC) and pendimethalin (30 EC) under laboratory conditions. Twenty four hours LC50 value of pretilachlor and pendimethalin formulations on Xenylla welchi were 72.7 and 190.0 g a.i/ha respectively which were less than their corresponding recommended agricultural doses. Again pretilachlor attained fastest LT50 (110 min) followed by pendimethalin (140 min). Significant reductions in hatching success were noted with the application of both the herbicide formulations at all doses excepting 1/8 and 1/10th of LC50 (9.1, 7.3 and 23.8, 19.0 g a.i/ha for pretilachlor and pendimethalin, respectively). Hatching success of the test specimens recorded 44.1 and 63.3% reduction from control for the highest applied dose (1/2 of LC50) of pretilachlor and pendimethalin, respectively. Juveniles of Xenylla welchi exposed to 1/6, 1/8 and 1/10th LC50 for pretilachlor (12.1, 9.1, 7.3 g a.i/ha) and 1/8 and 1/10th LC50 for pendimethalin (23.8, 19.0 g ai/ha) survived and exhibited increased moulting frequency (7 moultings in 28 days in both the herbicide treatments) in comparison to control (8 moulting in 42 days). Test specimens required 26.0 +/- 1.2 and 28.1 +/- 2.1 days to attain sexual maturity exposed to pretilachlor and pendamethalin respectively which was significantly less than control (42 +/- 2.6 days). PMID- 21523506 TI - Screening of plant species for phytoremediation of uranium, thorium, barium, nickel, strontium and lead contaminated soils from a uranium mill tailings repository in South China. AB - The concentrations of uranium, thorium, barium, nickel, strontium and lead in the samples of the tailings and plant species collected from a uranium mill tailings repository in South China were analyzed. Then, the removal capability of a plant for a target element was assessed. It was found that Phragmites australis had the greatest removal capabilities for uranium (820 MUg), thorium (103 MUg) and lead (1,870 MUg). Miscanthus floridulus had the greatest removal capabilities for barium (3,730 MUg) and nickel (667 MUg), and Parthenocissus quinquefolia had the greatest removal capability for strontium (3,920 MUg). In this study, a novel coefficient, termed as phytoremediation factor (PF), was proposed, for the first time, to assess the potential of a plant to be used in phytoremediation of a target element contaminated soil. Phragmites australis has the highest PFs for uranium (16.6), thorium (8.68), barium (10.0) and lead (10.5). Miscanthus floridulus has the highest PF for Ni (25.0). Broussonetia papyrifera and Parthenocissus quinquefolia have the relatively high PFs for strontium (28.1 and 25.4, respectively). On the basis of the definition for a hyperaccumulator, only Cyperus iria and Parthenocissus quinquefolia satisfied the criteria for hyperaccumulator of uranium (36.4 MUg/g) and strontium (190 MUg/g), and could be the candidates for phytoremediation of uranium and strontium contaminated soils. The results show that the PF has advantage over the hyperaccumulator in reflecting the removal capabilities of a plant for a target element, and is more adequate for assessing the potential of a plant to be used in phytoremediation than conventional method. PMID- 21523508 TI - GC/MS-based profiling of amino acids and TCA cycle-related molecules in ulcerative colitis. AB - OBJECTIVE: The roles that amino acids play in immunity and inflammation are well defined, and the relationship between inflammatory bowel disease (IBD) and certain amino acids has recently attracted attention. In this study, the levels of amino acids and trichloroacetic acid (TCA) cycle-related molecules in the colonic tissues and sera of patients with ulcerative colitis (UC) were profiled by gas chromatography/mass spectrometry (GC/MS), with the aim of evaluating whether the clinical state induced by UC leads to variations in the amino acid profile. MATERIALS AND METHODS: Colonic biopsy samples from 22 UC patients were used, as well as serum samples from UC patients (n = 13), Crohn's disease (CD) patients (n = 21), and healthy volunteers (n = 17). RESULTS: In the GC/MS-based profiling of amino acids and TCA cycle-related molecules, lower levels of 16 amino acids and 5 TCA cycle-related molecules were observed in the colonic lesion tissues of the UC patients, and the serum profiles of amino acids and TCA cycle related molecules of the UC patients were different from those of the CD patients and healthy volunteers. CONCLUSIONS: Our study raises the possibility that GC/MS based profiling of amino acids and TCA cycle-related molecules is a useful early diagnostic tool for UC. PMID- 21523509 TI - G1 cell cycle arrest signaling in hepatic injury after intraperitoneal sepsis in rats. AB - OBJECTIVE AND DESIGN: Hepatocytes emerge from a quiescent state into a proliferative state to recover from septic injury. We hypothesize that hepatocyte cell cycle regulation after sepsis potentially contributes to the recovery of liver function. METHODS: An animal model of sepsis was induced by cecal ligation and puncture (CLP) in rats. At serial time points after CLP, hepatocyte expression of p21, P53, cyclin D1, cyclin E, CDK2, CDK4 and PCNA was determined by immunoblot analysis, and the DNA content of isolated hepatocytes was analyzed using flow cytometry. RESULTS: Sepsis-induced liver injury of rats was associated with G1 cell cycle arrest. Recovery of liver function was related to cell cycle progression 48 h after CLP. The upregulation of p53 and p21 correlated with G1 cell arrest 48 h after CLP. The upregulation of cyclin D1/CDK4 and cyclin E/CDK2 also correlated with the G1/S transition 48 h after CLP, resulting in PCNA expression. CONCLUSIONS: The data suggests that G1 cell cycle arrest and p53, p21, CDKs, cyclins and PCNA expression may be involved in the injury/recovery of liver function after intraperitoneal sepsis. PMID- 21523510 TI - An algebraic approach to signaling cascades with N layers. AB - Posttranslational modification of proteins is key in transmission of signals in cells. Many signaling pathways contain several layers of modification cycles that mediate and change the signal through the pathway. Here, we study a simple signaling cascade consisting of n layers of modification cycles such that the modified protein of one layer acts as modifier in the next layer. Assuming mass action kinetics and taking the formation of intermediate complexes into account, we show that the steady states are solutions to a polynomial in one variable and in fact that there is exactly one steady state for any given total amounts of substrates and enzymes.We demonstrate that many steady-state concentrations are related through rational functions that can be found recursively. For example, stimulus-response curves arise as inverse functions to explicit rational functions. We show that the stimulus-response curves of the modified substrates are shifted to the left as we move down the cascade. Further, our approach allows us to study enzyme competition, sequestration, and how the steady state changes in response to changes in the total amount of substrates.Our approach is essentially algebraic and follows recent trends in the study of posttranslational modification systems. PMID- 21523511 TI - Fatty acid binding proteins: potential chaperones of cytosolic drug transport in the enterocyte? AB - PURPOSE: Several poorly water-soluble drugs have previously been shown to bind to intestinal (I-FABP) and liver fatty acid binding protein (L-FABP) in vitro. The purpose of this study was to examine the potential role of drug binding to FABPs on intestinal permeability and gut wall metabolism in vivo. METHODS: The intestinal permeability of ibuprofen, progesterone and midazolam (which bind FABPs) and propranolol (which does not) was examined using an autoperfused recirculating permeability model in control rats and rats where FABP levels were upregulated via pre-feeding a fat-rich diet. RESULTS: The intestinal permeability of drugs which bind FABPs in vitro was increased in animals where FABP levels were upregulated by prefeeding a high fat diet. The gut wall metabolism of midazolam was also reduced in animals with elevated FABP levels. CONCLUSIONS: Consistent with their role in the cellular transport of endogenous lipophilic substrates, FABPs appear to facilitate the intracellular disposition of drug molecules that bind FABPs in vitro. Drug binding to FABPs in the enterocyte may also attenuate gut wall metabolism in a manner analogous to the reduction in hepatic extraction mediated by drug binding to plasma proteins in the systemic circulation. PMID- 21523512 TI - Modelling dermal drug distribution after topical application in human. AB - PURPOSE: To model and interpret drug distribution in the dermis and underlying tissues after topical application which is relevant to the treatment of local conditions. METHODS: We created a new physiological pharmacokinetic model to describe the effect of blood flow, blood protein binding and dermal binding on the rate and depth of penetration of topical drugs into the underlying skin. We used this model to interpret literature in vivo human biopsy data on dermal drug concentration at various depths in the dermis after topical application of six substances. This interpretation was facilitated by our in vitro human dermal penetration studies in which dermal diffusion coefficient and binding were estimated. RESULTS: The model shows that dermal diffusion alone cannot explain the in vivo data, and blood and/or lymphatic transport to deep tissues must be present for almost all of the drugs tested. CONCLUSION: Topical drug delivery systems for deeper tissue delivery should recognise that blood/lymphatic transport may dominate over dermal diffusion for certain compounds. PMID- 21523513 TI - How stealthy are PEG-PLA nanoparticles? An NIR in vivo study combined with detailed size measurements. AB - PURPOSE: Detailed in vivo and ex vivo analysis of nanoparticle distribution, accumulation and elimination processes were combined with comprehensive particle size characterizations. METHODS: The in vivo fate of near infrared (NIR) nanoparticles in nude mice was carried out using the MaestroTM in vivo fluorescence imaging system. Asymmetrical field flow field fractionation (AF4) coupled with multi-angle laser light scattering (MALLS), photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM) were employed for detailed in vitro characterization. RESULTS: PEG-PLA block polymers were synthesized and used for the production of defined, stable, nontoxic nanoparticles. Nanoparticle analysis revealed narrow size distribution; AF4/MALLS permitted further accurate size evaluation. Multispectral fluorescence imaging made it possible to follow the in vivo fate non-invasively even in deep tissues over several days. Detailed fluorescence ex vivo imaging studies were performed and allowed to establish a calculation method to compare nanoparticle batches with varying fluorescence intensities. CONCLUSION: We combined narrow-size distributed nanoparticle batches with detailed in vitro characterization and the understanding of their in vivo fate using fluorescence imaging, confirming the wide possibilities of the non-invasive technique and presenting the basis to evaluate future size-dependent passive tumor accumulation studies. PMID- 21523514 TI - Help-seeking behaviors in a community sample of young adults with substance use disorders. AB - Despite the high prevalence of substance use disorders (SUDs) in the U.S., many with a SUD go untreated and/or report lengthy delays to help-seeking initiation. From a public health standpoint, because SUDs often emerge in early adulthood, information on help-seeking behaviors among young adults is important. Using data from young adults ages 18-23 years with a history of a SUD (n = 672) in Miami Dade County, Florida, this study estimates the prevalence of lifetime help seeking initiation and examines factors related to help seeking and delays to help-seeking initiation. The majority (68%) of young adults with a history of a SUD reported never having sought help, and those who reported help seeking experienced relatively lengthy delays (1-7 years) to help-seeking initiation. These findings underscore the need for both timely substance abuse treatment and for accelerated research on successful outreach strategies for young adults with SUDs. PMID- 21523515 TI - Introduction to Special Section on the System of Care Implementation Survey (SOCIS). PMID- 21523516 TI - Dissolution testing of sublingual tablets: a novel in vitro method. AB - In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40 mg SL tablet formulations under development and two commercial SL tablets, isosorbide dinitrate 5 mg and nitroglycerin 0.6 mg, were studied. The dissolution medium was 2 mL of distilled water at 25 degrees C. Dissolution was measured at 60 and 120 s. The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and was compared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different (p < 0.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method. PMID- 21523517 TI - Depletion of serum carotenoid and other fat-soluble vitamin concentrations following obesity surgery. AB - BACKGROUND: Obesity constitutes a growing health problem, and surgical treatment of severe obesity is increasingly used. Nutrient deficiencies are common following bariatric surgery and the evidence indicates a progressive increase in the incidence and severity of the deficiency of certain vitamins and related clinical conditions. Because of the potential role of carotenoids in disease prevention, our aim was to assess the carotenoid status in candidates for obesity surgery and the time-course changes following two bariatric procedures. METHODS: Seventy-five candidates for bariatric surgery (17 men, 58 women; age 43 +/- 10 years) and a total of 362 serum samples after obesity surgery (i.e., Roux-en-Y gastric bypass (n = 187) and biliopancreatic diversion (n = 175)) were consecutively collected and assessed. Retinol, alpha- and gamma-tocopherol, 25-OH vitamin D3, lutein, zeaxanthin, alpha- and beta-cryptoxanthin, lycopene (trans and cis), alpha- and beta-carotene (trans and cis) were analyzed by high performance liquid chromatography. RESULTS: Mean serum levels of carotenoids in candidates for obesity surgery were within the reference values reported in controls and seasonal variations were present in several analytes. After surgery, and regardless of the type of intervention, all serum carotenoids dropped following first-order kinetics. Cis/trans ratio of lycopene and beta-carotene did not change after surgery, over the time or between surgical procedures. On a long term, serum carotenoids were at or below fifth percentile of reference groups. CONCLUSIONS: The chronic low levels of carotenoids in these patients compromise their availability to tissues, constituting an additional risk factor for other clinical conditions. Dietary advice on carotenoid-rich, fortified foods or supplements should be also evaluated in these patients. PMID- 21523518 TI - Transition to parenthood: the role of social interaction and endogenous networks. AB - Empirical studies indicate that the transition to parenthood is influenced by an individual's peer group. To study the mechanisms creating interdependencies across individuals' transition to parenthood and its timing, we apply an agent based simulation model. We build a one-sex model and provide agents with three different characteristics: age, intended education, and parity. Agents endogenously form their network based on social closeness. Network members may then influence the agents' transition to higher parity levels. Our numerical simulations indicate that accounting for social interactions can explain the shift of first-birth probabilities in Austria during the period 1984 to 2004. Moreover, we apply our model to forecast age-specific fertility rates up to 2016. PMID- 21523519 TI - [Treatment of granulomatous cheilitis with fumaric acid esters in a young woman]. AB - Granulomatous cheilitis is a rare granulomatous inflammation of the lips of unknown origin; mainly young adults are affected. So far, there is no generally effectual treatment available for this disfiguring dermatosis. We show the efficacy of a treatment with fumaric acid esters reporting the case of a 14-year old girl with granulomatous cheilitis resistant to previous therapy. Our successful therapy consisted of fumaric acid esters according to the therapeutic schedule for psoriasis and showed a good tolerance subjectively and objectively. PMID- 21523520 TI - [Therapy of venous leg ulcers. New and established approaches]. AB - Venous leg ulcers are the most severe complication of chronic venous insufficiency. Based on the pathogenesis and the clinical evidence, the first step in treating a venous leg ulcer should be the treatment of the venous insufficiency. According to the guidelines of the German Society of Phlebology, several methods are available: the surgical or interventional therapy of varicosities, the stenting of stenotic pelvic veins in a post-thrombotic syndrome, direct surgical intervention at the ulcer as excision, debridement or fasciotomy. In the case of an arthrogenic venous stasis syndrome, physical therapy can be helpful. Additionally wound dressings, medicinal therapy and reduction of pain are relevant.There is a good level of evidence only for sufficient compression therapy and elimination of varicosities by surgery or sclerotherapy. PMID- 21523521 TI - Elevated serum gamma-glutamyltransferase predicts the development of impaired glucose metabolism in middle-aged and elderly Chinese. AB - The aim of this article is to prospectively investigate the association of the liver enzyme gamma-glutamyltransferase (GGT) with the development of diabetes and impaired glucose regulation (IGR) in a Chinese population. Seven hundred and sixty normoglycaemic subjects aged 40 years or older randomly selected from an urban community of Shanghai received a baseline investigation in May 2005. The participants were invited to receive a standard 75-g oral glucose tolerance test (OGTT) in November 2008. Incident diabetes and IGR were determined according to the 1999 WHO criteria. Serum GGT levels were significantly associated with incident diabetes or combined diabetes and IGR prospectively. After extensive adjustment, the diabetes risk was significantly increased with incrementing serum GGT quartiles (P value for trend = 0.0027). As compared with the lowest quartile of GGT, the highest quartile had an adjusted hazard ratio of 1.30 (95% CI 1.03 1.65) for developing combined diabetes and IGR. Furthermore, a high serum GGT level at baseline was independently associated with an increase in the index of homeostasis model assessment of insulin resistance (HOMA-IR) at follow-up. Serum GGT concentration, even within its normal range, is a risk marker for developing impaired glucose metabolism in middle-aged and elderly Chinese. PMID- 21523522 TI - Absence of CD71 transferrin receptor characterizes human gastric adenosquamous carcinoma stem cells. AB - BACKGROUND: Although the importance of cancer stem cells (CSCs) in overcoming resistance to therapy and metastasis has recently been reported, the role of CSCs in gastric cancer remains to be elucidated. METHODS: MKN-1 cells were used to study markers of CSCs in gastric adenosquamous carcinoma, as these cells are suitable for determining multidifferentiation ability. Changes in expression of CD44, CD49f, CD133, and CD71 following 5-fluorouracil (5-FU) treatment were assessed. RESULTS: After 5-FU treatment, only the CD71- fraction was significantly increased. Investigation of CD71 indicated that the CD71- cell fraction was present in the G1/G0 cell cycle phase and showed high resistance to the anticancer agent 5-FU. Limiting dilution and serial transplantation assays revealed the CD71- cell fraction to have higher tumorigenicity than the CD71+ cell fraction. The CD71- cell fraction showed multipotency to adenocarcinoma and squamous cell carcinoma. A three-dimensional (3D) invasion assay and immunohistochemical analysis showed CD71- cells to be highly invasive and to exist in the invasive fronts of cancer foci. CONCLUSION: The present study suggests that use of CD71- as a marker for adenosquamous carcinoma may provide a useful model for studying CSCs. PMID- 21523523 TI - The ketogenic diet for medically and surgically refractory status epilepticus in the neurocritical care unit. AB - BACKGROUND: Refractory status epilepticus carries a high risk of morbidity and mortality despite, and at times as a result of, aggressive pharmacologic interventions. Dietary therapies have been used for almost a century in children for controlling medically refractory seizures and status epilepticus and recent studies suggest efficacy and safety in adults as well. METHODS: Case report and literature review. RESULTS: We describe a case of medically and surgically refractory status epilepticus that was controlled after initiation of the ketogenic diet and maintenance with the modified Atkins diet in an adult in the neurocritical care unit. CONCLUSIONS: Dietary therapy should be considered as a treatment option in adult patients with refractory status epilepticus. PMID- 21523524 TI - The genesis of low pressure hydrocephalus. AB - BACKGROUND: Low pressure hydrocephalus (LPH) is an uncommon entity. Recognition of this treatable condition is important when clinicians are faced with the paradox of symptomatic hydrocephalus despite low intracranial pressures (ICP). Its etiology remains enigmatic. METHODS: We identified patients with LPH from the prospective, inpatient neuro-intensive care database over a 4-year period (2006 2010). RESULTS: Nine patients with LPH were identified over a 4-year period. The time from diagnosis of the initial neurosurgical condition to development of LPH varied from 7 days to 5 years. The sub-zero drainage method of Pang and Altschuler was successful in all cases. LPH was accompanied by transependymal edema in five patients despite low ICP. Four patients developed LPH during their initial admission for intracranial bleeding. As patients entered the LPH state, the ICP remained in a normal range yet daily CSF output from the external ventricular drain was reduced. When LPH patients were drained at sub-zero levels, daily CSF output exceeded baseline values for several days and then receded to baseline. Long-term management was achieved with low pressure shunt systems: six programmable shunts; one valveless ventriculoperitoneal shunt; two ventriculopleural shunts. Conditions most commonly associated with LPH are: subarachnoid hemorrhage, chronic hydrocephalus, brain tumors, and chronic CNS infections. CONCLUSIONS: Low pressure hydrocephalus is a challenging diagnosis. The genesis of LPH was associated with a drop in EVD output, symptomatic ventriculomegaly, and a remarkable absence of intracranial hypertension. When LPH was treated with the sub-zero method, a 'diuresis' of CSF ensued. These observations support a Darcy's flux of brain interstitial fluid due to altered brain poroelastance; in simpler terms, a boggy brain state. PMID- 21523525 TI - Limitations of threshold-based brain oxygen monitoring for seizure detection. AB - BACKGROUND: Brain tissue oxygen (PbtO(2)) monitors are utilized in a threshold based fashion, triggering actions based on the presumption of tissue compromise when PbtO(2) is less than 20 mmHg. Some early published practice guidelines suggest that seizure is a potential culprit when PbtO(2) crosses this threshold; evidence for this is not well defined. METHODS: Data were collected manually as part of a prospective observational database. PbtO(2) monitors and continuous electroencephalogram (cEEG) were placed by clinical protocol in aneurysmal subarachnoid hemorrhage (aSAH) or traumatic brain injury (TBI) patients with a Glasgow Coma Scale (GCS) <= 8. Eight patients with discrete seizures during an overlapping monitored period were identified. Probability of seizure when PbtO(2) value was <20 mmHg (and the inverse) were calculated. RESULTS: There were 343 distinct seizure episodes and 1797 PbtO(2) measurements. 8.9% of seizures were followed by a PbtO(2) value below 20 mmHg. Of all observed low PbtO(2) values, 3.8% were associated with seizure. Seizure length did not influence PbtO(2). Two patients with the highest number of seizures developed low PbtO(2) values post seizure. CONCLUSIONS: Seizures were neither associated with a PbtO(2) value of <20 mmHg nor associated with a drop in PbtO(2) value across a clinically significant threshold. However, we cannot rule out the existence of any relationship between PbtO(2) and seizure with this limited data set. Prospective research using electronically recorded data is required to more effectively examine the relationship between PbtO(2) and seizure. PMID- 21523528 TI - A broader discussion of authorship. AB - While it may be useful to consider the development of new topics in teaching the responsible conduct of research (RCR), it is perhaps equally important to reconsider the traditionally taught core topic areas in both more nuanced and broader ways. This paper takes the topic of authorship as an example. Through the description of two specific cases from sociocultural anthropology, ideas about credit and responsibility are examined. It is suggested that placing more focus on the array of meanings found in the act of authoring might help students see themselves as part of a wider community both of scientists and beyond science. PMID- 21523529 TI - A density functional theory approach toward substituent effect in Meerwein Eschenmoser-Claisen rearrangement. AB - B3LYP/6-31 G(d) level of theory has been used for the examination of substituent effect in the concerted step of the Meerwein-Eschenmoser-Claisen rearrangement. In this regard, the effect of NO(2) and NH(2) groups in different positions has been investigated. The obtained results show that substituent effect is very sensitive to its position and configuration. Electron withdrawing and electron donating groups in different positions and various configurations show different and sometimes opposite results. PMID- 21523530 TI - Ab initio and DFT conformational study on N-nitrosodiethylamine, (C2H5)2N-N=O. AB - Ab initio (MP2) and DFT (B3LYP) calculations, using the cc-pVTZ and aug-cc-pVTZ basis sets, have been performed to characterize some stationary points on the ground state potential energy surface of the title molecules. Several properties as, for instance, relative energies, the barriers for NO rotation around the NN bond, NBO charges on O and amino N atoms, as well as the dipole moments, have been calculated and analyzed in the light of the structures found. Both computational levels here employed yield three minima, in which the C(2)NNO frame is 'planar' or 'quasi-planar'. Important correlations between NBO charges and geometric parameters, as well as between some structural features and dipole moments are also discussed. A total of 17 structures have been found for the (C(2)H(5))(2)N-N=O molecule. Two ranges of values have been obtained for the dipole moment, with the largest values occurring for the structures in which the nitrogen lone pair is parallel to the NO group pi system. For instance, these two ranges are from ~4.1 to 4.5 D, and from ~1.6 to 2.1 D, at the MP2/cc-pVTZ level. These ranges are consistent with a larger and a smaller contribution of a dipolar resonance structure, respectively. As the method or basis set changes the values of the dipole moments change by at most ~0.23 D. PMID- 21523531 TI - Electron-topological, energetic and pi-electron delocalization analysis of ketoenamine-enolimine tautomeric equilibrium. AB - The ketoenamine-enolimine tautometic equilibrium has been studied by the analysis of aromaticity and electron-topological parameters. The influence of substituents on the energy of the transition state and of the tautomeric forms has been investigated for different positions of chelate chain. The quantum theory of atoms in molecules method (QTAIM) has been applied to study changes in the electron-topological parameters of the molecule with respect to the tautomeric equilibrium in intramolecular hydrogen bond. Dependencies of the HOMA aromaticity index and electron density at the critical points defining aromaticity and electronic state of the chelate chain on the transition state (TS), OH and HN tautomeric forms have been obtained. PMID- 21523532 TI - A DFT study on equilibrium geometries, stabilities, and electronic properties of small bimetallic Na-doped Au(n) (n = 1-9) clusters: comparison with pure gold clusters. AB - A systematic study on the geometric structures, relative stabilities, and electronic properties of small bimetallic Au(n)Na (n = 1-9) clusters has been performed by means of first-principle density functional theory calculations at the PW91PW91 level. The results show that the optimized ground-state isomers adopt planar structures up to n = 5, and the Na-capped geometries are dominant growth patterns for n = 6-9. Dramatic odd-even alternative behaviors are obtained in the second-order difference of energies, fragmentation energies, highest occupied-lowest unoccupied molecular orbital energy gaps, and chemical hardness for both Au(n)Na and Au(n+1) clusters. It is found that Au(5)Na and Au(6) have the most enhanced stability. Here, the size evolutions of the theoretical ionization potentials are in agreement with available experimental data, suggesting a good prediction of the lowest energy structures in the present study. In addition, the charge transfer has been analyzed on the basis of natural population analysis. PMID- 21523533 TI - Simulated Q-annealing: conformational search with an effective potential. AB - We have tested a version of the generalized simulated annealing algorithm based on molecular dynamics simulations with effective potential suggested by Tsallis statistics. The generalized annealing method, termed "simulated Q-annealing (SQ)," is applied to the simulations of a synthetic 11-residue peptide segment (1AQG). In SQ, the energy barriers between local minima change as the parameter q is varied and specific degrees of freedom can be selectively heated up and annealed. Conformational dynamics obtained by ordinary simulated annealing (SA) and SQ simulations are compared in order to illustrate the effectiveness of the SQ approach in conformational searching. We show that SQ can navigate the potential energy surface efficiently with a simple annealing protocol and demonstrate that conformations sampled by SQ can represent the funnel-like free energy surface. PMID- 21523534 TI - Receptor recognition mechanism of human influenza A H1N1 (1918), avian influenza A H5N1 (2004), and pandemic H1N1 (2009) neuraminidase. AB - Influenza A neuraminidase (NA) is a target for anti-influenza drugs. The function of this enzyme is to cleave a glycosidic linkage of a host cell receptor that links sialic acid (Sia) to galactose (Gal), to allow the virus to leave an infected cell and propagate. The receptor is an oligosaccharide on the host cell surface. There are two types of oligosaccharide receptor; the first, which is found mainly on avian epithelial cell surfaces, links Sia with Gal by an alpha2,3 glycosidic linkage; in the second, found mainly on human epithelial cell surfaces, linkage is via an alpha2,6 linkage. Some researchers believe that NAs from different viruses show selectivity for each type of linkage, but there is limited information available to confirm this hypothesis. To see if the linkage type is more specific to any particular NA, a number of NA-receptor complexes of human influenza A H1N1 (1918), avian influenza A H5N1 (2004), and a pandemic strain of H1N1 (2009) were constructed using homology modeling and molecular dynamics simulation. The results show that the two types of receptor analogues bound to NAs use different mechanisms. Moreover, it was found that a residue unique to avian virus NA is responsible for the recognition of the Siaalpha2,3Gal receptor, and a residue unique to human virus NA is responsible for the recognition of Siaalpha2,6Gal. We believe that this finding could explain how NAs of different virus origins always possess some unique residues. PMID- 21523535 TI - Microsolvation effect and hydrogen-bonding pattern of taurine-water TA-(H2O)n (n = 1-3) complexes. AB - The microsolvation of taurine (TA) with one, two or three water molecules was investigated by a density functional theory (DFT) approach. Quantum theory of atoms in molecules (QTAIM) analyses were employed to elucidate the hydrogen bond (H-bond) interaction characteristics in TA-(H(2)O)(n) (n = 1-3) complexes. The results showed that the intramolecular H-bond formed between the hydroxyl and the N atom of TA are retained in most TA-(H(2)O)(n) (n = 1-3) complexes, and are strengthened via cooperative effects among multiple H-bonds from n = 1-3. A trend of proton transformation exists from the hydroxyl to the N atom, which finally results in the cleavage of the origin intramolecular H-bond and the formation of a new intramolecular H-bond between the amino and the O atom of TA. Therefore, the most stable TA-(H(2)O)(3) complex becomes a zwitterionic complex rather than a neutral type. A many-body interaction analysis showed that the major contributors to the binding energies for complexes are the two-body energies, while three-body energies and relaxation energies make significant contributions to the binding energies for some complexes, whereas the four-body energies are too small to be significant. PMID- 21523536 TI - Elucidation of specific aspects of dielectric constants of conjugated organic compounds: a QSPR approach. AB - The characteristic aspects of dielectric constants of pi-conjugated compounds are elucidated by a quantitative structure property relationship (QSPR) study. To develop a QSPR model, among 141 collected pi-conjugated compounds, a subset of 116 compounds was used as the training set for the model building and the rest was used as the test set for the model validation. Statistical regression models using 396 molecular descriptors were generated based on the genetic function approximation algorithm. The predicted dielectric constants obtained by the best model are highly correlated with the experimental values (squared correlation coefficient R(2) of 0.93 and 0.97 for the training and test sets, respectively), while a previous prediction model for general organic molecules (Sild S, Karelson M (2002) J Chem Inf Comput Sci 42:360-367) is not valid for our collected pi conjugated organic compounds. It has been known that the dielectric constants of organic materials are largely influenced by orientational correlations of the constituent molecules. In general, hydrogen bonding is one of the most important intermolecular interactions affecting orientational correlation. In the case of pi-conjugated compounds, however, pi-pi interaction could be another comparable interaction with the hydrogen bonding. PMID- 21523537 TI - Computer-aided de novo ligand design and docking/molecular dynamics study of vitamin D receptor agonists. AB - 1alpha,25(OH)(2)D(3), which is directly mediated by the vitamin D receptor (VDR), exerts a wide variety of biological actions. However, the treatment with 1alpha,25(OH)(2)D(3) is limited because of its side effects. Many analogs and several nonsteroidal mimics with potent biological activity have been reported so far, and our rationale for designing the VDR agonists was on the basis of computer-aided drug design method by de novo design of A-ring and C/D-ring position of 1alpha,25(OH)(2)D(3). Pyrimidine-2,4-diamine was selected as A-ring, and naphthalene and benzene were chosen as C/D-ring. By linking different components, a virtue compound library was obtained. To evaluate the contribution to activity of each component, we performed a series of automated molecular docking operations. Results revealed that the 19-dimethyl derivatives (the C-19 position correspond to C-20 in 1alpha,25(OH)(2)D(3)) show the favorable docking affinity to VDR. Moreover, the docking results are quite robust when further validated by molecular dynamics simulations. In addition, by free energy analysis using molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method, the driving force of the binding between VDR and the ligands is proved to be hydrophobic interactions. Thus, a possible strategy to design new series of VDR agonists is proposed. The strategy can be successfully applied to explain the high potential activities of the 19-dimethyl derivatives. It is anticipated that the findings reported here may provide useful information for designing effective VDR agonists as well as the therapeutic treatment of VDR-related diseases. PMID- 21523538 TI - Bronsted-Evans-Polanyi relationships for C-C bond forming and C-C bond breaking reactions in thiamine-catalyzed decarboxylation of 2-keto acids using density functional theory. AB - The concept of generalized enzyme reactions suggests that a wide variety of substrates can undergo enzymatic transformations, including those whose biotransformation has not yet been realized. The use of quantum chemistry to evaluate kinetic feasibility is an attractive approach to identify enzymes for the proposed transformation. However, the sheer number of novel transformations that can be generated makes this impractical as a screening approach. Therefore, it is essential to develop structure/activity relationships based on quantities that are more efficient to calculate. In this work, we propose a structure/activity relationship based on the free energy of binding or reaction of non-native substrates to evaluate the catalysis relative to that of native substrates. While Bronsted-Evans-Polanyi (BEP) relationships such as that proposed here have found broad application in heterogeneous catalysis, their extension to enzymatic catalysis is limited. We report here on density functional theory (DFT) studies for C-C bond formation and C-C bond cleavage associated with the decarboxylation of six 2-keto acids by a thiamine-containing enzyme (EC 1.2.7.1) and demonstrate a linear relationship between the free energy of reaction and the activation barrier. We then applied this relationship to predict the activation barriers of 17 chemically similar novel reactions. These calculations reveal that there is a clear correlation between the free energy of formation of the transition state and the free energy of the reaction, suggesting that this method can be further extended to predict the kinetics of novel reactions through our computational framework for discovery of novel biochemical transformations. PMID- 21523539 TI - Tetrahydroisoquinolines acting as dopaminergic ligands. A molecular modeling study using MD simulations and QM calculations. AB - A molecular modeling study on 16 1-benzyl tetrahydroisoquinolines (BTHIQs) acting as dopaminergic ligands was carried out. By combining molecular dynamics simulations with ab initio and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of BTHIQs interacting with the human dopamine D2 receptor (D2 DR) is reported here, providing a clear picture of the binding interactions of BTHIQs from both structural and energetic viewpoints. Molecular aspects of the binding interactions between BTHIQs and the D2 DR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental pKi values was obtained, predicting the potential dopaminergic effect of non-synthesized BTHIQs. PMID- 21523540 TI - Hydrogen sequential dissociative chemisorption on Ni n(n = 2~9,13) clusters: comparison with Pt and Pd. AB - Hydrogen dissociative chemisorption and desorption on small lowest energy Ni(n) clusters up to n=13 as a function of H coverage was studied using density functional theory. H adsorption on the clusters was found to be preferentially at edge sites followed by 3-fold hollow sites and on-top sites. The minimum energy path calculations suggest that H(2) dissociative chemisorption is both thermodynamically and kinetically favorable and the H atoms on the clusters are mobile. Calculations on the sequential H(2) dissociative chemisorption on the clusters indicate that the edge sites are populated first and subsequently several on-top sites and hollow sites are also occupied upon full cluster saturation. In all cases, the average hydrogen capacity on Ni(n) clusters is similar to that of Pd(n) clusters but considerably smaller than that of Pt(n) clusters. Comparison of hydrogen dissociative chemisorption energies and H desorption energies at full H-coverage among the Ni family clusters was made. PMID- 21523541 TI - Theoretical study of the surface properties of poly(dimethylsiloxane) and poly(tetrafluoroethylene). AB - Molecular dynamics (MD) simulations of poly(dimethylsiloxane) (PDMS) and poly(tetrafluoroethylene) (PTFE) were carried out to determine their surface properties and energies. This study helps to gain better insight into the molecular modeling of PDMS and PTFE, in particular how different approaches affect calculations of surface energy. Current experimental and theoretical data were used to further understand the surface properties of PDMS and PTFE as well as to validate and verify results obtained from the combination of density functional theory (DFT) calculations (including periodic boundary conditions) and MD simulations. Detailed analysis of the structure and electronic properties (by calculation of the projected density of states) of the bulk and surface models of PDMS and PTFE was performed. The sensitivity of the surface energy calculation of these two polymers to the chemistry and model preparation was indicated. The balance between the molecular density, weight (which also reflects bond orientation in the surface region), bond flexibility, and intramolecular interactions including bond stretching was revealed to govern the results obtained. In modeling, the structural organization of polymer near a given surface (types and number of end groups and broken bonds due to application of different cut offs of the periodic structure) also significantly affects the final results. Besides the structural differences, certain simulation parameters, such the DFT functionals and simulation boxes utilized, play an important role in determining surface energy. The models used here were shown to be sufficient due to their good agreement with experimental and other theoretical data related to surface properties and surface energies. PMID- 21523542 TI - Noscapinoids with anti-cancer activity against human acute lymphoblastic leukemia cells (CEM): a three dimensional chemical space pharmacophore modeling and electronic feature analysis. AB - We have identified a new class of microtubule-binding compounds-noscapinoids-that alter microtubule dynamics at stoichiometric concentrations without affecting tubulin polymer mass. Noscapinoids show great promise as chemotherapeutic agents for the treatment of human cancers. To investigate the structural determinants of noscapinoids responsible for anti-cancer activity, we tested 36 structurally diverse noscapinoids in human acute lymphoblastic leukemia cells (CEM). The IC(50) values of these noscapinoids vary from 1.2 to 56.0 MUM. Pharmacophore models of anti-cancer activity were generated that identify two hydrogen bond acceptors, two aromatic rings, two hydrophobic groups, and one positively charged group as essential structural features. Additionally, an atom-based quantitative structure-activity relationship (QSAR) model was developed that gave a statistically satisfying result (R(2) = 0.912, Q(2) = 0.908, Pearson R = 0.951) and effectively predicts the anti-cancer activity of training and test set compounds. The pharmacophore model presented here is well supported by electronic property analysis using density functional theory at B3LYP/3-21*G level. Molecular electrostatic potential, particularly localization of negative potential near oxygen atoms of the dimethoxy isobenzofuranone ring of active compounds, matched the hydrogen bond acceptor feature of the generated pharmacophore. Our results further reveal that all active compounds have smaller lowest unoccupied molecular orbital (LUMO) energies concentrated over the dimethoxy isobenzofuranone ring, azido group, and nitro group, which is indicative of the electron acceptor capacity of the compounds. Results obtained from this study will be useful in the efficient design and development of more active noscapinoids. PMID- 21523543 TI - Theoretical investigations of a high density cage compound 10-(1-nitro-1, 2, 3, 4 tetraazol-5-yl)) methyl-2, 4, 6, 8, 12-hexanitrohexaazaisowurtzitane. AB - A new polynitro cage compound with the framework of HNIW and a tetrazole unit, i.e., 10-(1-nitro-1, 2, 3, 4-tetraazol-5-yl)) methyl-2, 4, 6, 8, 12 hexanitrohexaazaisowurtzitane (NTz-HNIW) has been proposed and studied by density functional theory (DFT) and molecular mechanics methods. Properties such as IR spectrum, heat of formation, thermodynamic properties, and crystal structure were predicted. The compound belongs to the Pbca space group, with the lattice parameters a = 15.07 A, b = 12.56 A, c = 18.34 A, Z = 8, and rho = 1.990 g.cm( 3). The stability of the compound was evaluated by the bond dissociation energies and results showed that the first step of pyrolysis is the rupture of the N-NO(2) bond in the side chain. The detonation properties were estimated by the Kamlet Jacobs equations based on the calculated crystal density and heat of formation, and the results were 9.240 km.s(-1) for detonation velocity and 40.136 GPa for detonation pressure. The designed compound has high thermal stability and good detonation properties and is probably a promising high energy density compound (HEDC). PMID- 21523544 TI - Ab initio calculation of the geometries, stabilities, and electronic properties for the bimetallic Be2Au(n) (n = 1-9) clusters: comparison with pure gold clusters. AB - Ab initio methods based on density functional theory at BP86 level were applied to the study of the geometrical structures, relative stabilities, and electronic properties of small bimetallic Be(2)Au(n) (n = 1-9) clusters. The optimized geometries reveal that the most stable isomers have 3D structures at n = 3, 5, 7, 8, and 9. Here, the relative stabilities were investigated in terms of the averaged atomic binding energies, fragmentation energies and second-order difference of energies. The results show that the planar Be(2)Au(4) structure is the most stable structure for Be(2)Au(n) clusters. The HOMO-LUMO gap, vertical ionization potential, vertical electron affinity and chemical hardness exhibit a pronounced even-odd alternating phenomenon. In addition, charge transfer and natural electron configuration were analyzed and compared. PMID- 21523545 TI - Gas adsorption on the Zn-, Pd- and Os-doped armchair (5,5) single-walled carbon nanotubes. AB - The adsorption of NO(2), NH(3), H(2)O, CO(2) and H(2) gases on the undoped, Zn-, Pd- and Os-doped armchair (5,5) single-walled carbon nanotubes (SWCNTs) were studied using density functional method. The adsorptions of these five gases on the Zn-, Pd- and Os-doped SWCNTs are obviously stronger than on the undoped SWCNT and their adsorption abilities are in the same order: NO(2) > NH(3) > H(2)O > CO(2) > H(2). Adsorption energies for all the studied gases on the undoped, Zn-, Pd- and Os-doped SWCNTs computed at the B3LYP/LanL2DZ level are reported. PMID- 21523546 TI - DFT studies of the phenol adsorption on boron nitride sheets. AB - We perform first principles total energy calculations to investigate the atomic structures of the adsorption of phenol (C(6)H(5)OH) on hexagonal boron nitride (BN) sheets. Calculations are done within the density functional theory as implemented in the DMOL code. Electron-ion interactions are modeled according to the local-spin-density-approximation (LSDA) method with the Perdew-Wang parametrization. Our studies take into account the hexagonal h-BN sheets and the modified by defects d-BN sheets. The d-BN sheets are composed of one hexagon, three pentagons and three heptagons. Five different atomic structures are investigated: parallel to the sheet, perpendicular to the sheet at the B site, perpendicular to the sheet at the N site, perpendicular to the central hexagon and perpendicular to the B-N bond (bridge site). To determine the structural stability we apply the criteria of minimum energy and vibration frequency. After the structural relaxation phenol molecules adsorb on both h-BN and d-BN sheets. Results of the binding energies indicate that phenol is chemisorbed. The polarity of the system increases as a consequence of the defects presence which induces transformation from an ionic to covalent bonding. The elastic properties on the BN structure present similar behavior to those reported in the literature for graphene. PMID- 21523547 TI - Interference of H-bonding and substituent effects in nitro- and hydroxy substituted salicylaldehydes. AB - Two intramolecular interactions, i.e., (1) hydrogen bond and (2) substituent effect, were analyzed and compared. For this purpose, the geometry of 4- and 5-X substituted salicylaldehyde derivatives (X = NO(2), H or OH) was optimized by means of B3LYP/6-311 + G(d,p) and MP2/aug-cc-pVDZ methods. The results obtained allowed us to show that substituents (NO(2) or OH) in the para or meta position with respect to either OH or CHO in H-bonded systems interact more strongly than in the case of di-substituted species: 4- and 3-nitrophenol or 4- and 3 hydroxybenzaldehyde by ~31%. The substituent effect due to the intramolecular charge transfer from the para-counter substituent (NO(2)) to the proton-donating group (OH) is ~35% greater than for the interaction of para-OH with the proton accepting group (CHO). The total energy of H-bonding for salicylaldehyde, and its derivatives, is composed of two contributions: ~80% from the energy of H-bond formation and ~20% from the energy associated with reorganization of the electron structure of the systems in question. PMID- 21523548 TI - Structural determinants of benzodiazepinedione/peptide-based p53-HDM2 inhibitors using 3D-QSAR, docking and molecular dynamics. AB - As a tumor suppressor, p53 protein regulates the cell cycle and is involved in preventing tumorgenesis. The protein level of p53 is under the tight control of its negative regulator human double minute 2 (HDM(2)) via ubiquitination. Therefore, the design of inhibitors of HDM(2) has attracted much interest of research on developing novel anticancer drugs. Presently, two classes of molecules, i.e., the 1,4-benzodiazepine-2,5-diones (BDPs) and N-Acylpolyamine (NAPA) derivatives were studied by three-dimensional quantitative structure activity relationship (3D-QSAR) modeling approaches including the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) as promising p53-HDM(2) inhibitors. Based on both the ligand based and receptor-guided (docking) alignments, two optimal 3D-QSAR models were obtained with good predictive power of q(2) = 0.41, r(2)(pred) = 0.60 for BDPs, and q(2) = 0.414, r(2)(pred) = 0.69 for NAPA analogs, respectively. By analysis of the model and its related contour maps, it is revealed that the electrostatic interactions contributed much larger to the compound binding affinity than the steric effects. And the contour maps intuitively suggested where to modify the molecular structures in order to improve the binding affinity. In addition, molecular dynamics simulation (MD) study was also carried out on the dataset with purpose of exploring the detailed binding modes of ligand in the HDM(2) binding pocket. Based on the CoMFA contour maps and MD-based docking analyses, some key structural aspects responsible for inhibitory activity of these two classes of compounds were concluded as follows: For BDPs, the R(1) and R(3) regions should have small electronegativity groups; substituents R(2) and R(4) should be larger, and R(3) substituent mainly involves in H-bonds forming. For NAPA derivatives, bulky and electropositive groups in ring B and ring A, small substituent at region P is favorable for the inhibitory activity. The models and related information, we hope, may provide important insight into the inhibitor-p53-HDM(2) interactions and be helpful for facilitating the design of novel potent inhibitors. PMID- 21523549 TI - Theoretical evaluation of isotopic fractionation factors in oxidation reactions of benzene, phenol and chlorophenols. AB - We have studied theoretically the rate determining steps of reactions of benzene with permanganate, perchlorate, ozone and dioxygen in the gas phase and aqueous solution as well as phenol and dichlorophenol in protonated and unprotonated forms in aqueous solution. Kinetic isotope effects were then calculated for all carbon atoms and based on their values isotopic fractionation factors corresponding to compound specific isotopic analysis have been evaluated. The influence of the oxidant, substituents, environment and protonation on the isotopic fractionation factors has been analyzed. PMID- 21523550 TI - Identification of novel, less toxic PTP-LAR inhibitors using in silico strategies: pharmacophore modeling, SADMET-based virtual screening and docking. AB - Human leukocyte antigen-related (PTP-LAR) is a receptor-like transmembrane phosphatase and a potential target for diabetes, obesity and cancer. In the present study, a sequence of in silico strategies (pharmacophore mapping, a 3D database searching, SADMET screening, and docking and toxicity studies) was performed to identify eight novel nontoxic PTP-LAR inhibitors. Twenty different pharmacophore hypotheses were generated using two methods; the best (hypothesis 2) consisted of three hydrogen-bond acceptor (A), one ring aromatic (R), and one hydrophobic aliphatic (Z) features. This hypothesis was used to screen molecules from several databases, such as Specs, IBS, MiniMaybridge, NCI, and an in-house PTP inhibitor database. In order to overcome the general bioavailability problem associated with phosphatases, the hits obtained were filtered by Lipinski's rule of five and SADMET properties and validated by molecular docking studies using the available crystal structure 1LAR. These docking studies suggested the ligand binding pattern and interactions required for LAR inhibition. The docking analysis also revealed that sulfonylurea derivatives with an isoquinoline or naphthalene scaffold represent potential LAR drugs. The screening protocol was further validated using ligand pharmacophore mapping studies, which showed that the abovementioned interactions are indeed crucial and that the screened molecules can be presumed to possess potent inhibitory activities. PMID- 21523551 TI - A model for the shuttle motions of puerarin and daidzin inside the cavity of beta cyclodextrin in aqueous acetic acid: insights from molecular dynamics simulations. AB - Acetic acid acts as one component of the mobile phase to influence separation of puerarin from daidzin when using beta-cyclodextrin-substituted media. In this work considering an explicit acetic acid solution, host-guest complexes of beta cyclodextrin (beta-CD) with puerarin and daidzin were investigated by molecular dynamics simulations. Computational results indicate different shuttle motions of puerarin and daidzin inside the cavity of beta-CD. A model detailing the shuttle motion was constructed, and the relationships between shuttle depth and guest rotation angles, hydrogen bonds, and host-guest interaction energies were analyzed. The results can be used to explain the chromatographic retention mechanisms of puerarin and daidzin with beta-CD, and to explore the complexity of host-guest interactions involving beta-CD. PMID- 21523552 TI - Virtual screening and in vitro assay of potential drug like inhibitors from spices against glutathione-S-transferase of filarial nematodes. AB - Glutathione-S-transferase(s) (GST) enzyme from Brugia malayi has been exploited as a target in lymphatic filariasis therapeutics. An active GST is a homodimer of a 208 residue long monomer consisting of two domains, a smaller alpha/beta domain and a larger alpha domain. The components of the glutathione (GSH) system, mainly GST enzymes, are critical antioxidant and detoxification system responsible for the long-term existence of filarial worms in mammalian host; hence they are major chemotherapeutic targets in filarial species. In the present study, 58 phytochemicals from 10 plants, predicted and reported to have potential nematicidal activity and ADMET satisfaction, have been docked to GST enzyme of B. malayi to assess their binding affinity and consequently their inhibitory activity. A comparative study has been made with commonly employed chemotherapeutic GST inhibitors such as cibacron-blue, butylated hydroxyanisole, hexyl glutathione and ethacrynic acid. In vitro effects of potential drug like compound from in silico results have been done for validation of docking studies. In vitro assay revealed efficacy in GST inhibition in the following compounds: linalool (97.50%), alpha-pinene (90.00%), strychnine (87.49%), vanillin (84.99%), piperine (79.99%), isoeugenol (62.49%), curcumin (57.49%), beta-caryophyllene (39.50%), cinnamic acid (27.49%), capsaicin (19.99%), citronellol (19.99%) and geraniol (17.49%). An online database ( www.spicebioinfo.res.in/gstleadbase ) has been developed, which will serve as a useful repository of information on GST inhibitors for future development of drugs against filarial nematodes. These findings thus suggest that the above phytochemicals could be potentially developed as lead molecules for targeting GST of lymphatic filarial parasites. PMID- 21523553 TI - A selectivity study on mTOR/PI3Kalpha inhibitors by homology modeling and 3D QSAR. AB - The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival and proliferation. mTOR and PI3K have attracted particular attention as cancer targets. These kinases belong to the phosphatidylinositol-3-kinase-related kinase (PIKK) family and therefore have considerable homology in their active sites. To accelerate the discovery of inhibitors with selective activity against mTOR and PI3K as cancer targets, in this work, a homology model of mTOR was developed to identify the structural divergence in the active sites between mTOR and PI3Kalpha. Furthermore, two highly predictive comparative molecular similarity index analyses (CoMSIA) models were built based on 304 selective inhibitors docked into mTOR and PI3Kalpha, respectively (mTOR: q(2) = 0.658, r(pre)(2) = 0.839; PI3Kalpha: q(2) = 0.540, r(pre)(2) = 0.719). The results showed that steric and electrostatic fields have an important influence on selectivity towards mTOR and PI3Kalpha-a finding consistent with the structural divergence between the active sites. The findings may be helpful in investigating selective mTOR/PI3Kalpha inhibitors. PMID- 21523554 TI - Fuzzy oil drop model to interpret the structure of antifreeze proteins and their mutants. AB - Mutations in proteins introduce structural changes and influence biological activity: the specific effects depend on the location of the mutation. The simple method proposed in the present paper is based on a two-step model of in silico protein folding. The structure of the first intermediate is assumed to be determined solely by backbone conformation. The structure of the second one is assumed to be determined by the presence of a hydrophobic center. The comparable structural analysis of the set of mutants is performed to identify the mutant induced structural changes. The changes of the hydrophobic core organization measured by the divergence entropy allows quantitative comparison estimating the relative structural changes upon mutation. The set of antifreeze proteins, which appeared to represent the hydrophobic core structure accordant with "fuzzy oil drop" model was selected for analysis. PMID- 21523555 TI - Modeling of the mass spectrum of dodecacarbonylo-triangulo-triosmium. AB - The present work attempts to predict the mass spectra of structures containing many clusters of doubly charged ions as well as singly charged ions. The method is applied to dodecacarbonylo-triangulo-triosmium, Os(3)(CO)(12), a particularly difficult example for modeling. The starting spectrum (25 points) can be reconstructed satisfactorily with 2% precision into a full form containing more than 400 peaks, which is consistent with the experimental form. PMID- 21523556 TI - Activation of the cisplatin and transplatin complexes in solution with constant pH and concentration of chloride anions; quantum chemical study. AB - The thermodynamics of cisplatin and transplatin hydration is studied within the model of constant pH solution. Several implicit solvation models were chosen for the determination of pK(a) and pK constants of the hydration reactions. The polarizable dielectric model (DPCM), integral equation formalism polarizable model (IEFPCM), and polarizable conductor model (CPCM) were combined with the 'united atom model for Hartree-Fock' (UAHF) method for cavity construction and the B3LYP/6-31++G(2dp,2pd) level of calculations for the determination of electronic energies. The results were compared with the COSMO-RS and SM8 model developed by Truhlar (with M06 and MPWX functionals and the charge model CM4). The RMS difference between experimental and calculated pK(a) values of cis/transplatin, water, HCl, and NH (4) (+) was used to evaluate accuracy of calculations. The DPCM model was confirmed to perform the best. The predicted pK(a) constants were used in Legendre transformation for the estimation of the DeltaG' energies in the constant-pH model. The dependence of the pK constant on pH is plotted and compared with experimental value at pH=7.4. The influence of various chloride concentrations on the molar fractions of dissolved forms of cisplatin is examined for the DPCM model. The increased ratio of cisplatin active aqua-forms is clearly visible for 4 mM chloride solution in comparison with 104 mM Cl(-) concentration. PMID- 21523557 TI - Capsaicin-induced vasodilatation in human nasal vasculature is mediated by modulation of cyclooxygenase-2 activity and abrogated by sulprostone. AB - Extensively based on evidence gained from experimental animal models, the transient receptor potential vanilloid receptor type 1 (TRPV1)-activator capsaicin is regarded as a valuable tool in the research on neurogenic inflammation. Although capsaicin-related drugs gained renewed interest as a therapeutic tool, there is also controversy as whether neurogenic inflammation actually takes place in humans. In this study, we verified the involvement of capsaicin in vascular responses that are regarded to be implicated in the cascade of neurogenic inflammatory mechanisms. By means of ex vivo functional experiments on human nasal mucosal vascular beds, the effect and mechanism of action of capsaicin was assessed in the absence and presence of various agents that interfere with potentially related transduction pathways. Ten micromolars of capsaicin induced vasodilatations that were reduced by the selective EP(1) prostanoid receptor antagonist SC19220 (10 MUM) and almost abolished by the selective COX-2 inhibitor NS398 (1 MUM) and the EP(1/3) receptor agonist sulprostone (0.1-10 nM), but not affected by the TRPV1-antagonists capsazepine (5 MUM), the neurokinin NK(1) receptor antagonist GR20517A (1 MUM), and the calcitonin-gene-related peptide (CGRP) receptor antagonist CGRP8-37 (100 nM). Spontaneously released PGE(2) and PGD(2) levels were significantly reduced in the presence of capsaicin. In conclusion, capsaicin-at concentrations clinically applied or under investigation for diverse disease backgrounds-induces a vasodilatory response in human nasal mucosa via a mechanism involving TRPV1 independent reduction of PGE(2) production by modulation of COX-2 enzymatic activity. These vasodilatations can be suppressed by the EP(1/3) receptor agonist sulprostone at subnanomolar concentrations. PMID- 21523558 TI - Effective kinetics of schisandrin B on serum/hepatic triglyceride and total cholesterol levels in mice with and without the influence of fenofibrate. AB - Schisandrin B, an active ingredient isolated from the fruit of Schisandra chinensis, increased serum and hepatic triglyceride levels in mice. In the present study, the effective kinetics of schisandrin B on serum/hepatic triglyceride and total cholesterol levels in mice without and with the influence of fenofibrate were investigated. Parameters on hepatic index (the ratio of liver weight to body weight * 100) were also analyzed. Mice were intragastrically treated with schisandrin B at a single dose of 0.2, 0.4, 0.8, or 1.6 g/kg, without or with fenofibrate pretreatment (0.1 g/kg/day for 4 days, p.o.). Twenty four hours after schisandrin B treatment, serum/hepatic triglyceride and total cholesterol levels were measured. Schisandrin B treatment dose-dependently increased serum and hepatic triglyceride levels as well as hepatic index in mice. In contrast, hepatic total cholesterol levels were decreased in a dose-dependent manner in schisandrin B-treated mice. Data obtained from effective kinetics analysis indicated that the action of schisandrin B on serum triglyceride had a higher specificity than those on hepatic total cholesterol and hepatic index. While fenofibrate pretreatment inhibited the schisandrin B-induced elevation in serum triglyceride levels, it completely abrogated the elevation of hepatic triglyceride levels in schisandrin B-treated mice. The combined treatment with schisandrin B and fenofibrate decreased hepatic total cholesterol level and increased the hepatic index in an additive or semi-additive manner, respectively. In conclusion, the results of effective kinetics analysis indicated that the schisandrin B-induced hypertriglyceridemia was competitively inhibited by fenofibrate. Schisandrin B may offer the prospect of setting up a mouse model of hypertriglyceridemia and fatty liver for screening triglyceride-lowering drug candidates. PMID- 21523559 TI - Hypoxia effects on proangiogenic factors in human umbilical vein endothelial cells: functional role of the peptide somatostatin. AB - The aim of this study was to investigate hypoxia effects on vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 in human umbilical vein endothelial cells (HUVEC) and to determine their modulation by the peptide somatostatin (SRIF) and its analogues. The involvement of signal transducer and activator of transcription (STAT) 3 and hypoxia inducible factor (HIF)-1 was also investigated. Quantitative real-time PCR, Western blot and ELISA were used. Hypoxia upregulated VEGF expression and release, whereas it downregulated VEGFR-1 and VEGFR-2. In contrast, neither the expression nor the phosphorylation of the platelet-derived growth factor receptor (PDGFR) beta was affected by hypoxia. SU1498 at 1 MUM did not affect pVEGFR-2 and pPDGFRbeta, whereas at 20 MUM it inhibited pVEGFR-2, but not pPDGFRbeta. Upregulated VEGF expression and release were prevented by SU1498, which also inhibited the hypoxia-induced pSTAT3 and HIF 1alpha. Blocking pSTAT3 with S3I-201 inhibited HIF-1alpha and VEGF upregulation, suggesting the existence of an autocrine loop involving STAT3, HIF-1, VEGF and VEGFR-2. Endothelial cells express somatostatin (SRIF) receptors (sst(1-5)) although less is known in HUVEC. We found that sst(1) and sst(4) were expressed by HUVEC with sst(1) more expressed than sst(4) mRNA. Hypoxia downregulated sst(1), whereas it upregulated sst(4). The sst(1) downregulation, but not the sst(4) upregulation, was prevented by SU1498, S3I-201 or YC-1, an inhibitor of HIF-1alpha. SRIF and the sst(1) agonist CH-275, but not the sst(4) agonist L803,087 and the sst(2)/sst(3)/sst(5) agonist octreotide, prevented hypoxia effects on VEGF and its receptors. In addition, SRIF and CH-275 inhibited the hypoxia-induced pSTAT3 and HIF-1alpha accumulation. Our results suggest that SRIF acting at sst(1) limits upregulated VEGF expression and release through a control on the activity of STAT3 and HIF-1, supporting the possible use of sst(1) agonists in antiangiogenic therapies. PMID- 21523561 TI - The role of lymph node dissection in renal cell carcinoma. AB - Due to the relatively heterogeneous metastatic spread of renal cell carcinoma (RCC) through both hematogenous and lymphatogenous routes, the surgical extirpation of regional lymph nodes in the treatment of RCC has long been a controversial topic. Individual risk is dependent on multiple variables including tumor stage, grade, and histologic sub-type, in addition to many others. Controversy exists over whether lymph node dissection (LND) simply provides improved staging or whether removal of pathologic nodes offers a therapeutic advantage. Herein, we evaluate the available data regarding the use of LND in the treatment of RCC. While we believe that LND may provide an opportunity for cure in a select group of patients, there are many variables to consider when determining its applicability to an individual patient. PMID- 21523560 TI - HLA antigen and NK cell activating ligand expression in malignant cells: a story of loss or acquisition. AB - Malignant transformation of cells is often associated with changes in classical and non-classical HLA class I antigen, HLA class II antigen as well as NK cell activating ligand (NKCAL) expression. These changes are believed to play a role in the clinical course of the disease since these molecules are critical to the interactions between tumor cells and components of both innate and adaptive immune system. For some time, it has been assumed that alterations in the expression profile of HLA antigens and NKCAL on malignant cells represented loss of classical HLA class I antigen and induction of HLA class II antigen, non classical HLA class I antigen and/or NKCAL expression. In contrast to these assumptions, experimental evidence suggests that in some cases dysplastic and malignant cells can acquire classical HLA class I antigen expression and/or lose the ability to express HLA class II antigens. In light of the latter findings as well as of the revival of the cancer immune surveillance theory, a reevaluation of the interpretation of changes in HLA antigen and NKCAL expression in malignant lesions is warranted. In this article, we first briefly describe the conventional types of changes in HLA antigen and NKCAL expression that have been identified in malignant cells to date. Second, we discuss the evidence indicating that, in at least some cell types, classical HLA class I antigen expression can be acquired and/or the ability to express HLA class II antigens is lost. Third, we review the available evidence for the role of immune selective pressure in the generation of malignant lesions with changes in HLA antigen expression. This information contributes to our understanding of the role of the immune system in the control of tumor development and to the optimization of the design of immunotherapeutic strategies for the treatment of cancer. PMID- 21523563 TI - Body weight and the reward system: the volume of the right amygdala may be associated with body mass index in young overweight men. AB - We aimed to investigate the relationship between BMI (body mass index) and the volumes of the structures of the reward system (hippocampus, amygdala, accumbens, caudatum, putamen, and orbitofrontal cortex). The right and left structures were examined separately. Their volumes were assessed using a 3-T MRI scanner and Freesurfer software. Ninety-two healthy subjects were involved (mean BMI: 22.3 +/ 3.4 kg/m(2), mean age: 23.2 +/- 2.7). We found that the volume of the right amygdala positively correlated with the BMI in men but not in women. Moreover, we could demonstrate this association only in the overweight male sub-population. We suggest that an association between body weight and the morphological variability of the reward system can be demonstrated by MRI. This may be further evidence for a different body-weight regulation in the two sexes. The potential relationship between the volume of the right amygdala and the BMI in heavier individuals requires further studies with larger samples. PMID- 21523562 TI - Bending tau into shape: the emerging role of peptidyl-prolyl isomerases in tauopathies. AB - The Hsp90-associated cis-trans peptidyl-prolyl isomerase--FK506 binding protein 51 (FKBP51)--was recently found to co-localize with the microtubule (MT) associated protein tau in neurons and physically interact with tau in brain tissues from humans who died from Alzheimer's disease (AD). Tau pathologically aggregates in neurons, a process that is closely linked with cognitive deficits in AD. Tau typically functions to stabilize and bundle MTs. Cellular events like calcium influx destabilize MTs, disengaging tau. This excess tau should be degraded, but sometimes it is stabilized and forms higher-order aggregates, a pathogenic hallmark of tauopathies. FKBP51 was also found to increase in forebrain neurons with age, further supporting a novel role for FKBP51 in tau processing. This, combined with compelling evidence that the prolyl isomerase Pin1 regulates tau stability and phosphorylation dynamics, suggests an emerging role for isomerization in tau pathogenesis. PMID- 21523564 TI - Growth temperature and salinity impact fatty acid composition and degree of unsaturation in peanut-nodulating rhizobia. AB - Growth and survival of bacteria depend on homeostasis of membrane lipids, and the capacity to adjust lipid composition to adapt to various environmental stresses. Membrane fluidity is regulated in part by the ratio of unsaturated to saturated fatty acids present in membrane lipids. Here, we studied the effects of high growth temperature and salinity (NaCl) stress, separately or in combination, on fatty acids composition and de novo synthesis in two peanut-nodulating Bradyrhizobium strains (fast-growing TAL1000 and slow-growing SEMIA6144). Both strains contained the fatty acids palmitic, stearic, and cis-vaccenic + oleic. TAL1000 also contained eicosatrienoic acid and cyclopropane fatty acid. The most striking change, in both strains, was a decreased percentage of cis-vaccenic + oleic (>= 80% for TAL1000), and an associated increase in saturated fatty acids, under high growth temperature or combined conditions. Cyclopropane fatty acid was significantly increased in TAL1000 under the above conditions. De novo synthesis of fatty acids was shifted to the synthesis of a higher proportion of saturated fatty acids under all tested conditions, but to a lesser degree for SEMIA6144 compared to TAL1000. The major adaptive response of these rhizobial strains to increased temperature and salinity was an altered degree of fatty acid unsaturation, to maintain the normal physical state of membrane lipids. PMID- 21523578 TI - Infection in pediatric interventional radiology. AB - Interventional radiology in children involves nearly every aspect of infectious disease. Diagnosis, treatment, prophylaxis and disease transmission in infectious disease are a daily part of pediatric interventional radiology practice. This article will discuss each of these aspects of infection with respect to interventional radiology. PMID- 21523569 TI - Pulmonary infections. AB - This paper reviews the most common imaging findings of pulmonary infection in children. Pneumonia is a leading cause of mortality in children in developing and industrialized countries. While the imaging findings usually are nonspecific, correlation with the patient's age, immune status and pertinent history can limit the differential diagnoses. The paper will review the common and unique features of pneumonia caused by specific organisms and in specific patient populations. PMID- 21523581 TI - Paediatric musculoskeletal US beyond the hip joint. AB - US is a technique particularly suited to the investigation of musculoskeletal disorders in children and adolescents. This review paper describes a range of clinical settings beyond the hip joint where US has a significant role to play, including sports injuries, infectious diseases, inflammatory and degenerative conditions, congenital and developmental disorders, acute trauma of bone and joints, and peripheral nerve injuries. In some circumstances, US can be regarded as the most effective means of diagnostic imaging, whereas in other instances, it is an alternative or supplement to other more comprehensive imaging modalities, like MRI and CT. Although MRI offers superior soft-tissue contrast resolution, US is low-cost, non-invasive and has higher spatial resolution and real-time capability for the assessment of musculoskeletal structures during joint movement and stress manoeuvres. PMID- 21523583 TI - Infection: musculoskeletal. AB - The imaging approach to osteomyelitis has evolved in the past two decades. Advances in MRI allow for whole body imaging, decreasing the need for scintigraphy when symptoms are not localized or the disease may be multifocal. There is an increasing clinical need for depiction of abscesses in the soft tissues and subperiosteal space, particularly because methicillin-resistant Staphylococcus aureus infections constitute more than one-third of all the infections. The increasing emphasis on radiation dose reduction has also led away from scintigraphy and computed tomography. MR imaging has become the advanced imaging modality of choice in osteomyelitis. There is an increasing understanding of the appropriate role for gadolinium enhancement, which is not indicated when the pre-gadolinium images are normal. Other related infections, including pyomyositis, are best imaged with MRI. PMID- 21523589 TI - Neonatal brain infections. AB - Infections of the brain in the neonatal period differ considerably from infections in the older child, due to a variety of age-specific factors that are related not only to the child, but also to the mother, and to specific pathogenic organisms. It has been recognized that clinical and neurological signs are often non-specific, sometimes scarce, and seldom correlate with the extent of neuroimaging findings, thus warranting early imaging to ensure timely therapy and improved outcome. PMID- 21523592 TI - Transcranial Doppler in children. AB - Transcranial Doppler US, a non-invasive tool for evaluating the cerebral arteries, has evolved significantly during the last two decades. This review describes the practical procedure, and summarises and illustrates its established and "work-in-progress" indications in children. Indications for a transcranial Doppler US examination include, but are not limited to: (1) evaluation of cerebral blood flow velocities in the circle of Willis in patients with sickle cell anaemia to guide transfusion therapy; (2) diagnosis and follow-up of vasculopathy, such as moyamoya disease; (3) diagnosis and monitoring of acute cerebrovascular disorders in intensive care patients, in particular following traumatic brain injury, and during cardiovascular surgery; and (4) confirmation of a clinical diagnosis of brain death by documentation of cerebral circulatory arrest. PMID- 21523594 TI - Pediatric oncology and the future of oncological imaging. AB - The future of pediatric oncology will be influenced by changes in drug design and treatment strategy, with genomic medicine and molecular-based diagnostics and therapeutics playing increasingly important roles. The role of imaging as a means of measuring response to therapy has also evolved, with the development of new technologies and higher sensitivity means of detecting tumors. Conventional anatomical imaging techniques are being increasingly supplemented with functional techniques, including FDG-PET imaging and diffusion-weighted MR imaging. The risk adapted treatment regimens of the past, which led to improved event-free and overall survival in many pediatric cancers, have paved the way for new response based treatment paradigms. Response-based approaches seek to identify patients with a high likelihood of cure, treating them less aggressively, while those not responding to therapy are identified early and redirected into more aggressive therapeutic regimens. These advances will require concurrent development of imaging biomarkers as surrogates of early response to therapy. Incorporating these techniques into new response-directed treatment algorithms will be crucial as personalized medicine and molecular-targeted, tumor-specific therapies gain acceptance for the treatment of children with cancer. PMID- 21523595 TI - Regional and whole-body imaging in pediatric oncology. AB - The goals of tumor imaging include tumor detection, tumor characterization and differential diagnosis, imaging-guided biopsy, evaluation of tumor extent and staging, assessment of treatment responses, and surveillance for residual tumor or tumor recurrence. In clinical practice, various combinations of imaging modalities are used to achieve these goals. Recently introduced tumor imaging methods, such as diffusion MRI, perfusion MRI, whole-body MRI, and positron emission tomography (PET-CT), have shown promising results. Depending on tumor type and management plan, imaging protocols for children should be individually optimized to achieve the shortest examination time, the highest image quality, the lowest risk, and maximum clinical benefits. In this article, the roles of regional and whole-body tumor imaging will be reviewed, and several important issues related to recent technical developments will be discussed. PMID- 21523599 TI - Interventional oncology: the future. AB - Interventional radiology techniques to treat oncological disease have already shown value in adults. The adoption and development of interventional oncology (IO) in children have been more limited and challenging. This relates to the approval process for new devices and agents, oncology group protocol limitations and the inherent hesitation of trying new treatments in children. This paper will discuss how new procedures are developed and approved, and the new therapies that will become available to better treat pediatric malignancies. Bringing the benefits of IO to children will require initiative on the part of pediatric diagnostic and interventional radiologists as well as the cooperation of our clinical colleagues. PMID- 21523605 TI - The future of pediatric US. AB - Despite advances in other modalities, US remains an essential technology in pediatric imaging. Improvements in technology provide increasingly detailed anatomical images, and new techniques show promise in providing novel anatomical as well as physiological and structural information. Other specialties are recognizing the value of US to their patients and are increasingly performing their own examinations. Economic and social factors are also influencing the development and use of US. This review will evaluate many of these issues and demonstrate that the future of pediatric US is bright and that pediatric radiologists can and should continue to be leaders in its use and development. PMID- 21523606 TI - Potential role of 3DUS in infants and children. AB - The objective of this review is to discuss basic technical aspects as well as potential pediatric applications of three-dimensional ultrasound (3DUS). Different 3DUS-techniques are already commercially available. Most commonly, a transducer-integrated motor drives a scan-head to acquire a volumetric dataset, which is then reconstructed and viewed using various post-processing techniques. It has been proved feasible to apply 3DUS with pediatric transducers in typical pediatric investigations. Based on our own experiences and on review of the literature, 3DUS can be successfully used in infants and children for brain, spine, cardiac, urinary tract (particularly assessment of hydronephrosis, and virtual cystoscopy), and female genital (e.g., for assessment of uterine malformations) US, and for various other applications, particularly in small parts. Power Doppler data can be integrated, allowing 3DUS-angiography. Thus, 3DUS promises to become a useful adjunct for imaging children, particularly as it enhances ultrasound by offering additional, previously inaccessible planes, rendering options and surface assessments. 3DUS should be increasingly exploited, thus hopefully helping reduce the need for more invasive or burdening (e.g., ionizing radiation) investigations in children. PMID- 21523607 TI - Contrast-enhanced sonography in pediatrics. AB - Microbubble US contrast agents are composed of an outer shell of protein, phospholipid or polymer that encase air or perfluorocarbon gas. These contrast agents have been widely used in adult cardiology patients to improve endocardial border delineation and have been proved safe and well tolerated in this patient population. There is also a growing body of literature elucidating the value of contrast-enhanced sonography to distinguish benign from malignant liver lesions in adults and to characterize non-hepatic adult malignancies. Because these agents have not been approved for pediatric use in many countries, less is known of the value of contrast-enhanced sonography in children. In this review I will discuss several proven and potential pediatric applications of contrast-enhanced sonography. PMID- 21523614 TI - Are tutor behaviors in problem-based learning stable?: a generalizability study of social congruence, expertise and cognitive congruence. AB - The purpose of this study was to investigate the stability of three distinct tutor behaviors (1) use of subject-matter expertise, (2) social congruence and (3) cognitive congruence, in a problem-based learning (PBL) environment. The data comprised the input from 16,047 different students to a survey of 762 tutors administered in three consecutive semesters. Over the three semesters each tutor taught two of the same course and one different course. A generalizability study was conducted to determine whether the tutor behaviors were generalizable across the three measurement occasions. The results indicate that three semesters are sufficient to make generalizations about all three tutor behaviors. In addition the results show that individual differences between tutors account for the greatest differences in levels of expertise, social congruence and cognitive congruence. The study concludes that tutor behaviors are fairly consistent in PBL and somewhat impervious to change. Implications of these findings for tutor training are discussed. PMID- 21523615 TI - The association of depressive symptoms and ischemic heart disease in older adults is not moderated by gender, marital status or education. AB - OBJECTIVES: To investigate whether the association of depression and ischemic heart disease (IHD) is moderated by gender, marital status or education. METHODS: Data from the 1998 Medicare Health Outcome Survey (HOS) with a 2 year follow-up were re-analyzed. 63,965 older adults who had not reported IHD at baseline were included. Logistic regression analysis modelled the effects of depression, somatic risk factors, and demographic variables on IHD after 2 years. RESULTS: Two year reported incidence of IHD was 6.2%. Depression was associated with a 1.53-fold risk of developing IHD after controlling for somatic risk factors and demographic variables. Male gender, lower than high-school education, and being married were associated with IHD. Neither of these variables yielded significant interactions with depression, nor did any of the higher-order interaction terms. CONCLUSIONS: The association of depression and IHD seems independent from pivotal demographic variables. Possibly the impact of psychosocial factors in this sample of older people is weak compared to medical conditions and age. Also the possibility exists that a common factor such as a shared genetic vulnerability contributes to both depressive symptoms and IHD. PMID- 21523616 TI - Early substance use initiation and suicide ideation and attempts among students in France and the United States. AB - OBJECTIVE: In response to recent research documenting a link between early substance use and suicidal behaviors among youth, the current study sought to examine the associations between ages of substance use initiation and suicidal behavior among students in France and the USA. METHODS: Cross-sectional logistic regression analyses based on the 2003 European School Survey Project on Alcohol and Other Drugs (ESPAD) survey (France; n = 13,187) and the 2003 Youth Risk Behavior Survey (YRBS) (United States; n = 15,136) assessed associations between early substance use initiation (i.e., alcohol, cigarette and cannabis/marijuana) and suicide ideation and attempts while controlling for potential confounders. RESULTS: Early alcohol use initiation (OR(adj) = 1.52; 95% CI 1.17-1.97) and early cannabis/marijuana use initiation (OR(adj) = 2.90; 95% CI 2.20-3.83) were associated with suicide attempt in France. Early smoking was associated with suicide attempt in both France (OR(adj) = 1.92; 95% CI 1.55-2.37) and the USA (OR(adj) = 1.53; 95% CI 1.02-2.28). Sex differences were also noted. CONCLUSIONS: The associations between substance use initiation and suicidal behaviors differed in the United States and France. These findings, placed into context, can assist the development and implementation of prevention strategies that seek to reduce the harmful consequences of early substance use among youth. PMID- 21523618 TI - From shake flasks to bioreactors: survival of E. coli cells harboring pGST-hPTH through auto-induction by controlling initial content of yeast extract. AB - A high content of yeast extract in complex media can cause auto-induction of phage T7 RNA polymerase and the consequent expression of recombinant protein in Escherichia coli BL21(DE3) during long-term cultivation. Our study demonstrated that the auto-induction of recombinant protein varied in different vectors harboring heterologous genes. Trx, GST, and their fusion proteins such as GST human parathyroid hormone (hPTH), expressed by pET32a (+), were easily auto induced by media containing a high content of yeast extract; however, rtPA was not easily auto-induced when using pET22b (+), although both pET systems were under the control of T7lac promoter. Furthermore, the auto-induction of GST-hPTH may start within 1-2 h after inoculation in bioreactors, which is a deficiency in the scale-up from shake flasks to bioreactors. Our results indicated that too much yeast extract in bioreactor cultivations may be responsible for the early auto-induction of target proteins and consequent loss of cell viability and plasmid instability. To achieve a satisfactory yield, host cells with both high cell viability and plasmid stability were necessary for the starter cultures in shake flasks and pre-induction cultures in bioreactors. This could be achieved simply by controlling the initial content of yeast extract and its subsequent supplementation. PMID- 21523617 TI - A comparison of depression prevalence estimates measured by the Patient Health Questionnaire with two administration modes: computer-assisted telephone interviewing versus computer-assisted personal interviewing. AB - OBJECTIVE: To compare depression prevalence estimates measured by the 8-item Patient Health Questionnaire (PHQ-8) with two administration modes in two national surveys. METHODS: Data on adults aged 18 years and older who participated in the 2006 Behavioral Risk Factor Surveillance System (BRFSS) (n = 198,678) and those who participated in the 2005-2006 National Health and Nutrition Examination Survey (NHANES) (n = 4,800) were analyzed. RESULTS: The crude PHQ-8 depression prevalence estimate using the diagnostic algorithm was higher in BRFSS with computer-assisted telephone interviewing (CATI) (9.16%, SE 0.15) than in NHANES with computer-assisted personal interviewing (CAPI) (6.28%, SE 0.59) (P < 0.001). After adjustment for demographic characteristics, the difference in the prevalence estimates remained (9.68% in BRFSS vs. 6.13% in NHANES, P < 0.001). Similar differences in the depression prevalence estimates using the PHQ-8 cutoff score >=10 were detected (9.22% in BRFSS vs. 5.15% in NHANES, P < 0.001). Significant differences in the depression prevalence persisted in subgroups stratified by demographic characteristics and major health risk factors and outcomes. CONCLUSIONS: The PHQ-8 administered by CATI yielded about 3.5% higher depression prevalence estimate than that by CAPI. PMID- 21523620 TI - Olfactory test performance and its relationship with the perceived location of odors. AB - Odors are generally perceived as arising via the nose when sniffed and as part of an orally located flavor during ingestion. The perceived location of an odor may in part be an attentional phenomenon, with concurrent oral stimulation occurring at the expense of access to the olfactory channel. Two predictions were derived from this account: (a) tasks dependent on a capacity to attend to the olfactory channel--odor discrimination and naming--should be adversely affected by oral localization; and (b) tasks not dependent upon a capacity to attend--incidental learning/recognition memory--should not. Using a procedure to generate oral localization, in which odors were presented via the nose with concurrent oral stimulation (sucrose, a viscous fluid or water), greater reported oral localization was associated with poorer odor discrimination and naming, but not with recognition memory performance. These results support the notion that attentional processes contribute to oral localization of odors by reducing the capacity to attend to the olfactory channel. PMID- 21523622 TI - [Surgical manipulators in ear surgery: a future vision?]. AB - INTRODUCTION: Middle ear surgery bears a high risk for injury of difficult to differentiate risk structures. Thus, a precise preparation in this area must be the surgical task. LIMITATIONS: However, there are human (tremor) and systematic limitations (OR setup, narrow access). Assistance systems in terms of manipulators are so far not part of the clinical routine. Although, they could compensate for the above mentioned limitations. MANIPULATORS: This work reviews existing surgical manipulator systems. The expected value is an elevated patient safety through improving surgical accuracy and the reduction of ergonomic deficits. CLINICAL APPLICATION AND DEVELOPMENT: In clinical application there are simply modified industrial robots, highly complex master slave systems and small miniature master slave systems which are directly located at the patient. CONCLUSION: A disadvantage of most systems is the limited number of applicable instruments. Often, only especially designed instruments can be used. The goal in development should be to create a compact, short distance operated master slave system. The usability of standard (already available) instruments with an easy integration into the surgical and sterilisation procedure would lower the threshold for acceptance of such systems.The surgeon will remain the key player. He can only work efficiently in an ergonomic environment and will always have the responsibility for the intervention. From the authors perspective, highly automated systems should not be the research goal. PMID- 21523621 TI - The influence of prognostic factors and adjuvant chemoradiation on survival after pancreaticoduodenectomy for ampullary carcinoma. AB - INTRODUCTION: The prognosis after pancreaticoduodenectomy (PD) for ampullary carcinoma (AC) is superior to that of pancreatic cancer. Decisions regarding adjuvant therapy are influenced by factors such as nodal status, stage, and grade, but the influence of these individual variables on survival is unclear. METHODS: A prospective tumor registry database was queried to identify patients who underwent PD for AC at Thomas Jefferson University between Jan 1997 and Apr 2009. The study was conducted with the approval of the institutional review board. Data were collected through review of hospital and departmental charts. Overall survival (OS) was analyzed using univariate and multivariate Cox proportional hazard models. The proportional hazard assumption was verified for the overall model and individual covariates. RESULTS: A total of 61 patients underwent PD for AC at our institution. There were five perioperative deaths (8.2%). Mean age was 70 years (62% male). Median survival time (MST) was 50 months for all patients. Only primary tumor stage, T1/T2 versus T3/T4 (American Joint Committee on Cancer Staging, version 6), was associated with OS in univariate analyses (p = 0.003). The association of nodal status with OS was borderline-significant (p = 0.08), with the MST being 84 months for node-negative and 17 months for node-positive patients. The remaining covariates were not predictors of OS. In the multivariate analysis, only primary tumor stage (HR, 5.1; p < 0.001) and age (HR, 1.04; p = 0.06), but not nodal status or adjuvant therapy, were associated with overall survival. CONCLUSIONS: Advanced primary tumor stage and age were associated with inferior OS after PD for AC. Adjuvant therapy did not impact survival. Patients with advanced tumor stage should be considered for clinical trials of adjuvant therapy after PD with novel compounds and optimized radiation therapy strategies. PMID- 21523624 TI - [Adenoidectomy also inpatient: comments on the Dessai-Robetalau decision of 24 February 2010]. PMID- 21523625 TI - [Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) as an example of a rare disease relevant for oto-rhino-laryngology]. AB - Diagnosis and treatment of rare diseases are difficult. Hereditary hemorrhagic telangiectasia (HHT, Rendu-Osler-Weber disorder) is a relatively common rare disease. Because epistaxis is the most frequent manifestation of this disease, affected individuals often approach otorhinolaryngologists first. The latter ones often have a key position for early diagnosis and screening for visceral involvement which can prevent life-threatening complications. Treatment of epistaxis can improve quality of life of affected persons. Diagnosis and treatment of rare diseases can be complex and it can be very helpful to use information resources to ensure a correct management. Various possibilities to access these resources are presented in general and in relation to HHT. PMID- 21523626 TI - [Comment on J. Helms and L. Maser: Quality of hearing and communication with various cochlear implants]. PMID- 21523628 TI - [The transnasal approach to the skull base. From sinus surgery to skull base surgery]. AB - The indications for endonasal endoscopic approaches to diseases of the skull base and its adjacent structures have expanded considerably during the last decades. This is not only due to improved technical possibilities such as intraoperative navigation, the development of specialized instruments, and the compilation of anatomical studies from the endoscopic perspective but also related to the accumulating experience with endoscopic procedures of the skull base by multidisciplinary centers. Endoscopic endonasal operations permit new approaches to deeply seated lesions and are characterized by a reduced manipulation of neurovascular structures and brain parenchyma while at the same time providing improved visualization. They reduce the trauma caused by the approach, avoid skin incisions and minimize the surgical morbidity. Transnasal endoscopic procedures for the closure of small and large skull base defects have proven to be reliable and more successful than operations with craniotomies. The development of new local and regional vascularized flaps like the Hadad-flap have contributed to this. These reconstructive techniques are furthermore effectively utilized in tumor surgery in this region. This review delineates the classification of expanded endonasal approaches in detail. They provide access to lesions of the anterior, middle and partly also to the posterior cranial fossa. Successful management of these complex procedures requires a close interdisciplinary collaboration as well as continuous education and training of all team members. PMID- 21523629 TI - [Implication of stem cells in the biology and therapy of head and neck cancer]. AB - Stem cells play a central role in re- and generation of tissues. Special importance has been attributed to them in cancer biology. 2 entities can be discriminated: cancer infiltrating stem cells and cancer initiating stem cells. Infiltrating stem cells will be attracted to the tumor in order to be remodelled for tumor expansion, e. g. endothelial cells or other cancerous tissue components, yet these cells are per se benign. Malignant cancer stem cells are capable to generate a new tumor, histologically identical with the cancer they originate from. Many steps in cancer stem cell biology are not understood to date. It is still believed that CSC are only a minor cell fraction in tumor but capable to differentiate in hierarchical manner into any other tissue type. These stem cells are undergoing many steps of differentiation and dedifferentiation in a steady state. The factors of the micromilieu contributing to this are largely not understood. Still these steps are regarded as the key to tumor initiation, metastases and resistance to therapy. The biological functions and associated signal transduction pathways, e. g. self renewal pathways will be the key to future therapeutical strategies. PMID- 21523630 TI - [Imaging in cochlear implant patients]. AB - Imaging procedures are a mainstream tool in the daily ENT workflow. Cochlear Implant patients are representing a special population with specific demands for imaging. There are different imaging techniques available for pre-operative evaluation, surgery and postoperative controls with different indications and consequences. High-resolution computed tomography and magnetic resonance imaging are mainly used in the evaluation process. New procedures, as digital volume tomography, are increasingly used intra- and postoperatively. Especially the intracochlear positioning in malformations of the inner ear, eventually added with radiological assisted navigation, can be considered a standard of modern cochlear implant surgery. In addition, digital volume tomography may serve as a quality control tool focusing on the evaluation of the intracochlear electrode position. The range of applications, indications and current results are illustrated. PMID- 21523631 TI - [Molecular biology of hearing]. AB - The inner ear is our most sensitive sensory organ and can be subdivided into 3 functional units: organ of Corti, stria vascularis and spiral ganglion. The appropriate stimulus for the organ of hearing is sound which travels through the external auditory canal to the middle ear where it is transmitted to the inner ear. The inner ear habors the hair cells, the sensory cells of hearing. The inner hair cells are capable of mechanotransduction, the transformation of mechanical force into an electrical signal, which is the basic principle of hearing. The stria vascularis generates the endocochlear potential and maintains the ionic homeostasis of the endolymph. The dendrites of the spiral ganglion form synaptic contacts with the hair cells. The spiral ganglion is composed of neurons that transmit the electrical signals from the cochlea to the central nervous system. In the past years there was significant progress in research on the molecular basis of hearing. More and more genes and proteins which are related to hearing can be identified and characterized. The increasing knowledge on these genes contributes not only to a better understanding of the mechanism of hearing but also to a deeper understanding of the molecular basis of hereditary hearing loss. This basic research is a prerequisite for the development of molecular diagnostics and novel therapies for hearing loss. PMID- 21523632 TI - [Perspectives in neurotology]. AB - Vestibular diagnostics and therapy is the mirror of technological, scientific and socio-economics trends as are other fields of clinical medicine. These trends have led to a substantial diversification of the field of neurotology. The improvements in diagnostics have been characterized by the introduction of new receptor testing tools (e. g., VEMPs), progress in imaging (e. g., the endolymphatic hydrops) and in the description of central-vestibular neuroplasticity. The etiopathology of vestibular disorders has been updated by geneticists (e. g., the description of the COCH gene mutations), the detection of structural abnormalities (e. g., dehiscence syndromes) and related disorders (e. g. migraine-associated vertigo). The therapeutic options were extended by re evaluation of techniques known a long time ago (e. g., saccus exposure), the development of new approaches (e. g., dehiscence repair) and the introduction of new drug therapy concepts (e. g., local drug delivery). Implantable, neuroprosthetic solutions have not yet reached experimental safety and validity and are still far away. However, externally worn neuroprosthetic solution were introduced in the rehab of vestibular disorders (e. g., VertiGuard system). These and related trends point into a medical future which is characterized by presbyvertigo as classical sign of the demographic changes ahead, by shortage of financial resources and a medico-legally over-regulated, even hostile environment for physicians in clinical medicine. PMID- 21523633 TI - [Dysfunction of the chemical senses smell and taste]. AB - Dysfunction of the senses of taste and smell may strongly affect our lives. During the last years reliable techniques for the standardized investigation of the 2 senses have been introduced to clinical routine. These techniques are highly standardized and can be easily used, for example, for quality control before and after surgery. Although there are proven therapeutic approaches to taste or smell loss, by far not all patients can be helped. New ideas need to tested within rigorous double-blind studies. The regenerative capacity within the chemical senses provides a major basis for hopes on therapeutic success. PMID- 21523634 TI - [Paragangliomas and paraganglioma syndromes]. AB - Paragangliomas are rare tumors of neural crest origin. They are benign in the majority of cases and are characterized by a strong vascularisation. In the head and neck region they most commonly occur as carotid body tumors. Jugulotympanic and especially vagal paragangliomas are seen less frequently. Complete surgical resection represents the only curative treatment option even though resection of locally advanced tumors regularly results in lesions of the lower cranial nerves and major vessels. Approximately 30% of all head and neck paragangliomas (HNPs) are hereditary and associated with different tumor syndromes. The paraganglioma syndromes 1, 3 and 4 (PGL 1, 3 and 4) make up the majority of those familial cases. PGL 1 is associated with mutations of the succinate dehydrogenase subunit D (SDHD) gene, PGL 3 is caused by SDHC and PGL 4 by SDHB gene mutations. Multiple HNPs and the occurrence of HNPs together with pheochromocytomas are seen in SDHD as well as SDHB mutation carriers. In patients with SDHB mutations the risk for the development of malignant paraganglial tumors is significantly higher compared to SDHC and SDHD patients as well as patients with sporadic tumors. SDHC mutation carriers almost exclusively present with benign HNPs that are unifocal in the majority of cases. The role of transmission is autosomal dominant for all 3 symptoms. Interestingly, there is a "parent-of-origin-dependent-inheritance" in subjects with SDHD gene mutations. This means that the disease phenotype may only become present if the mutation is inherited through the paternal line. We recommend screening for mutations of the genes SDHB, SDHC and SDHD in all patients with HNPs. Certain clinical parameters can help to set up the order in which the 3 genes should be tested. PMID- 21523635 TI - [Functional organ preservation in laryngeal and hypopharyngeal cancer]. AB - The principles of open vs. laser microsurgical approaches for partial resections of the larynx are described, oncological as well as functional results discussed and corresponding outcomes following primary radiotherapy are opposed. Over the last decade, the endoscopic partial resection of the larynx has developed to an accepted approach in the treatment of early glottic and supraglottic carcinomas thus leading to a remarkable decline in the use of open surgery. Comparing the various surgical approaches of laryngeal partial resections, the oncological outcome of the patients, as far as survival and organ preservation are concerned, are comparable, whereas functional results of the endoscopic procedures are superior with less morbidity. The surgical procedures put together, are all superior to radiotherapy concerning organ preservation. Transoral laser microsurgery has been used successfully for vocal cord carcinomas with impaired mobility or fixation of the vocal cord, supraglottic carcinomas with infiltration of the pre- and/or paraglottic space as well as for selected hypopharyngeal carcinomas. It has been well documented that laser microsurgery achieves good oncological as well as functional results with reasonable morbidity. However, patients with those tumours have been successfully treated by open partial resections of the larynx at medical centres with appropriate expertise. The initially enthusiastic assessment of study results concerning the efficacy of various protocols of chemoradiation with the intent of organ preservation for laryngeal and hypopharyngeal carcinomas are judged more cautious, today, due to recent reports of rather high rates of late toxicity complications. PMID- 21523636 TI - [The future of academic endocrinology]. PMID- 21523637 TI - [The motivation to become a medical doctor - doctoral students in a formal academic study program compared with those pursuing their doctorate independently]. AB - BACKGROUND AND OBJECTIVE: Weight and quality of medical doctoral theses have been discussed in Germany for years. Doctoral study programs in various graduate schools offer opportunities to improve quality of medical doctoral theses. The purpose of this study was to demonstrate distinctions and differences concerning motivation, choice of subject and the dissertation process between doctoral candidates completing the doctoral seminar for doctoral students in the Ludwig Maximilians-University (LMU) Munich and doctoral candidates doing their doctorate individually. METHODS: All 4000 medical students of the LMU obtained an online questionnaire which was completed by 767 students (19 % response rate). The theoretical framework of this study was based upon the Self-Determination-Theory by Deci and Ryan. RESULTS: Doctoral candidates completing the doctoral study program were more intrinsically motivated than doctoral candidates doing their doctorate individually; no difference was found in their extrinsic motivation. In regard to choice of subject and dissertation process the doctoral students in the seminar were distinguished from the individual group by having chosen a more challenging project. They anticipated a demanding dissertation process including conference participation, publishing of papers, etc. Intrinsic motivation correlates positively with choosing a challenging project and a demanding dissertation process. CONCLUSION: High intrinsic motivation seems to be very important for autonomous scholarly practice. Our results suggest that doctoral study programs have a positive impact on intrinsic motivation and interest in research. PMID- 21523638 TI - [Hypertension and hypokalemia - a reninoma as the cause of suspected liquorice induced arterial hypertension]. AB - HISTORY AND CLINICAL FINDINGS: A 28-year-old woman presented with dizziness and arterial hypertension. She reported a daily intake of 300 mg liquorice. INVESTIGATIONS: Laboratory analysis revealed hypokalaemia of 2.5 mmol/l and an elevated serum renin activity of 18.6 ug/l/h. Abdominal ultrasound and magnetic resonance imaging showed a circumscribed non-homogenuous round lesion (18 * 22 mm) in the upper third of the right kidney. Selective catheterization of the renal veins revealed increased renin activity in blood from the right renal vein, suggestive of a renin-producing tumor. TREATMENT AND COURSE: Initially antihypertensive therapy with the direct renin receptor antagonist aliskiren was started and followed by a partial nephrectomy, which brought about adequate blood pressure and potassium levels. CONCLUSION: The constellation of hypokalaemia and hypertension often leads to important causes of secondary hypertension such as primary hyperaldosteronism or renal artery stenosis. But less frequent causes should also be considered in the differential diagnoses, such as liquorice overindulgence or reninoma. PMID- 21523639 TI - [80-year-old woman with hypodense lesion in the right hepatic duct]. PMID- 21523640 TI - [The treatment of differentiated thyroid cancer]. PMID- 21523641 TI - [Resection of metastases in neuroendocrine tumors: pro]. PMID- 21523642 TI - [Resection of metastases in neuroendocrine tumors: contra]. PMID- 21523643 TI - [New targets for treatment of osteoporosis]. PMID- 21523644 TI - [Treatment of hyponatremia: new developments and controversies]. AB - This article summarizes improvements in diagnosis and therapy in patients with symptomatic hyponatremia. The available treatment options for hyponatremia have been limited, and consisted mainly of isotonic or hypertonic saline, urea, and fluid restriction. Vasopressin receptor antagonists, also known as vaptans or aquaretics are a new class of drugs that now offer an additional treatment option for hyponatremic patients with euvolemic hyponatremia due to SIADH in Europe. In short and long term studies, tolvaptane has been shown to be effective in raising serum sodium levels in a predictable fashion in patients with SIADH with only few side effects, when serum sodium was frequently monitored and dosage of tolvaptans was properly adjusted. Further studies are needed to find out which patients benefit from treatment with respect to morbidity and mortality. Until now, therapy is limited to the treatment of moderate symptomatic hyponatremia in SIADH due to the high cost of therapy. PMID- 21523645 TI - [Do oral proton pump inhibitors lose effect after splitting?]. PMID- 21523646 TI - Fatal complication after thrombin injection for post-catheterization femoral pseudoaneurysm. AB - Femoral artery pseudoaneurysm (FAP) is one of the most common vascular complications after cardiac and peripheral angiographic procedures. Ultrasound guided thrombin injection is the standard procedure for the treatment of FAP. Complications such as thrombotic events with leg ischemia after thrombin leakage into the femoral artery or immunogenic consequences are rare. Our experience indicates the need for caution when treating FAP, as severe complications can occur after thrombin injection in a femoral pseudoaneurysm, leading to a fatal event. PMID- 21523648 TI - [Hospices - a place to die with dignity]. PMID- 21523647 TI - Surgical removal of a ruptured, detached angioplasty balloon after popliteal stenting. AB - Balloon catheter entrapment after stent implantation is a potential interventional complication. However, angioplasty balloon disconnection from the catheter shaft and in-stent entrapment is a very uncommon event that could have serious thrombotic or embolic consequences. The management of this event may be interventional or surgical, depending on the patient's status and the position of the balloon inside the vessel. We describe a case of acute lower limb ischemia after popliteal self-expandable stenting, due to loss of the balloon along with a portion of its shaft. Surgical retrieval was accomplished without any further complications. PMID- 21523649 TI - Neurosurgical strategies and operative results in the treatment of tumors of or extending to the petrous apex. AB - BACKGROUND: Tumors originating from or involving the petrous apex are considered to be an operative challenge due to their deep location and close relationship to critical neural and vascular structures. Extensive skull base approaches have been developed to deal with these lesions. The purpose of this study is to review an institutional series of 57 petrous apex tumors, to report our operative experiences and to address the usefulness and limits of standard approaches. MATERIAL AND METHODS: 57 patients (22 men, 35 women) with petrous apex tumors were treated microsurgically. We analyzed the type of surgical approach, histological diagnoses, pre- and postoperative clinical findings, diagnostic imaging and surgery-associated complications. RESULTS: According to the location and its predominant extension, a retromastoid approach (n=27), subtemporal approach (n=18), subtemporal/anterosigmoid approach (n=5), transnasal transsphenoidal approach (n=2), pterional approach (n=2) or a subtemporal/retrosigmoid approach, biphasic approach (subtemporal and pterional), transmastoidal approach (n=1 each) was chosen. In the majority of cases, histological analysis revealed a meningeoma (n=31) or neurinoma (n=7). A total tumor resection was accomplished in 37 patients (64.9%). New permanent neurological deficits, mainly cranial nerve palsies, were found in 18 (31.6%), transient deficits in 5 patients (9.6%). Postoperative improvements of neurological deficits were observed in 17 patients (29.8%), and the neurological status remained unchanged in 17 patients (32.7%). CONCLUSION: Complete resection of petrous apex tumors using standard neurosurgical approaches without permanent surgery-associated neurological deficits is achievable in the majority of cases. PMID- 21523650 TI - Isolation and characterization of novel microsatellite markers in commercial selected golden Malaysian arowana fish, Scleropages formosus (Osteoglossidae). AB - Malaysian arowana (dragonfish; Scleropages formosus) is an ancient osteoglossid fish from southeast Asia. Due to the high demand of the ornamental fish trade and because of habitat loss, the species is close to extinction. We isolated and characterized 10 polymorphic microsatellites of this species, using 5'-anchored PCR. The number of alleles at the 10 microsatellite loci ranged from 2 to 28, with a mean of 7.8/locus. The observed heterozygosity ranged from 0.03 to 0.93 (mean: 0.39), whereas the expected heterozygosity ranged from 0.03 to 0.94 (mean: 0.46). Seven microsatellites deviated from Hardy-Weinberg equilibrium, and three conformed to Hardy-Weinberg equilibrium and were in linkage equilibrium. These 10 novel microsatellites should facilitate studies of genetic diversity and population structure of arowana to help plan actions for the conservation of the indigenous Malaysian arowana. PMID- 21523651 TI - Structural analysis of a 4414-bp element in Drosophila melanogaster. AB - We cloned a 4414-bp element from a mutant of Drosophila melanogaster. Its insertion site was 18,929,626 bp. Analysis of the nucleotide and amino acid sequences demonstrated that the element is homologous to Pifo_I, first obtained from D. yabuka, which belongs to the gypsy/Ty3 subfamily. We also obtained a 3754 bp length element from a wild-type fly by PCR, with a pair of primers designed from the conserved region of the 4414-bp length element. The two elements included a pair of long terminal repeats and part of the GAG and ENV proteins, but the POL protein was completely lost. This element is found in the subgenus of D. melanogaster, but it is a degenerate type of Pifo_I and is not infective. Also, a 714-bp region structured in 5.0 tandem repeats of 143 bp each was found in the 5'UTR of the degenerate element; these could interact with transcription factor CF2. Phylogenetic analysis and alignment of amino acids indicated that the Pifo_I element was closer to the ZAM retrotransposon, which gave us some clues to their functional similarity. Based on these data, we propose that there is a relationship between the degenerate element and the mutant phenotype, which would provide a foundation for further research. PMID- 21523652 TI - Polymorphisms of the cocaine-amphetamine-regulated transcript (CART) gene and their association with reproductive traits in Chinese goats. AB - Polymorphisms of the CART gene were investigated by PCR-single-strand conformation polymorphism analysis in 540 samples from 10 goat breeds. Ten novel single-nucleotide polymorphisms as well as three microsatellites were detected; a mutation, 77T -> C, led to an amino acid change (Leu -> Ser). Associations between polymorphic loci and reproductive traits were analyzed in Chuandong White, Guizhou White and Gulin Ma breeds. Mutation at position 524 had no significant effect on litter size in these three goat breeds. The polymorphism 539C -> A differed significantly among the three breeds (P < 0.05); C(7)T(8)/C(9)T(8) at 939 was associated with larger litter size (P < 0.05) than genotypes C(7)T(8)/C(7)T(8) and C(7)T(8)/C(8)T(8). No significant association of birth weight was found with gene variation (524C -> T, 539C -> A and 939 CnTn). These findings could be valuable for marker-assisted selection for goat breeding. PMID- 21523653 TI - Genetic data for 15 STR loci in a Kadazan-Dusun population from East Malaysia. AB - Allele frequencies of 15 short tandem repeat (STR) loci, namely D5S818, D7S820, D13S317, D16S539, TH01, TPOX, Penta D, Penta E, D3S1358, D8S1179, D18S51, D21S11, CSF1PO, vWA, and FGA, were determined for 154 individuals from the Kadazan-Dusun tribe, an indigenous population of East Malaysia. All loci were amplified by polymerase chain reaction, using the Powerplex 16 system. Alleles were typed using a gene analyzer and the Genemapper ID software. Various statistical parameters were calculated and the combined power of discrimination for the 15 loci in the population was calculated as 0.999999999999999. These loci are thus, informative and can be used effectively in forensic and genetic studies of this indigenous population. PMID- 21523654 TI - Polymorphisms of three new microsatellite sites of the dystrophin gene. AB - To look for novel microsatellites in the dystrophin gene for the diagnosis of Duchenne muscular dystrophy, candidate microsatellite sites in the dystrophin gene were analyzed with the SSRHunter software and were also genotyped. Among the 15 candidate microsatellite sites, three novel microsatellite sites in the 60th, 30th, and 2nd intron were found to have a high degree of polymorphism. We submitted these three new loci to the European Molecular Biology Laboratory, under accession Nos. FN547040, FN547041 and FN557526, which were called DXSDMD in60, DXSDMD-in30 and DXSDMD-in2, respectively. In these three loci, we found 9, 6 and 11 alleles, respectively, in the 205 individuals. In addition, we also detected 20, 19 and 20 genotypes for the three loci in female samples, with a polymorphism information content of more than 0.600. In conclusion, the three microsatellite sites in the intron region of the dystrophin gene have a high degree of polymorphism, and they can be used in population genetics, as well as to provide a theoretical basis for genetic diagnosis and elucidation of molecular mechanisms in Duchenne muscular dystrophy. PMID- 21523655 TI - Cloning and molecular modeling of Litopenaeus vannamei (Penaeidae) C-type lectin homologs with mutated mannose binding domain-2. AB - C-type lectins are animal proteins that contain at least one carbohydrate recognition domain (CRD) capable of mediating sugar and calcium binding. Carbohydrate recognition is directly required for some biological functions, including the innate immune response. We cloned two novel C-type lectin (CTL) precursors from the commercial marine shrimp Litopenaeus vannamei. The cloned cDNAs encompass ORFs of 1044 nucleotides and encode highly similar two-domain polypeptides of 347 residues. The predicted proteins, LvCTL-br1 and -br2, contain the consensus triad that recognizes galactose (-GlnProAsp-) in CRD1 but also contain a mutated mannose-binding site (-GluProAsn-) in the second domain (CRD2). Phylogenetic analysis of LvCTL-br1 and -br2 and hundreds of CTL-like domain containing proteins have allowed grouping of penaeid shrimp CTLs into three functional clusters. Reverse transcription coupled to PCR indicated that LvCTL br1 expression is induced in shrimp gills upon IHHNV infection. Computational molecular modeling of LvCTL-br1 and -br2 revealed that three amino acid substitutions in CRD1 occur near the sugar binding site. Also, the 3-D models show a long loop of LvCTL-br1 CRD2 that might accommodate complex sugars. The structural data, evolutionary history and functional analysis support the hypothesis that gene duplication and accelerated evolution have caused functional diversification of penaeid shrimp C-type lectins. PMID- 21523656 TI - Genetic structure based on nuclear and chloroplast microsatellite loci of Solanum lycocarpum A. St. Hil. (Solanaceae) in Central Brazil. AB - Solanum lycocarpum (Solanaceae) is a woody species found in the Brazilian Cerrado. The flowers are pollinated by Xylocopa spp bees, and seeds are dispersed by mammals with distinct home range sizes. As a consequence, relative contributions of pollen and seeds to overall gene flow can vary according to different spatial scales. We studied the genetic structure of four natural populations of S. lycocarpum separated by 19 to 128 km, including individuals located along dirt roads that interlink three of the populations. A total of 294 individuals were genotyped with five nuclear and six chloroplast microsatellite markers. Significant spatial genetic structure was found in the total set of individuals; the Sp statistic was 0.0086. Population differentiation based on the six chloroplast microsatellite markers (theta(pC) = 0.042) was small and similar to that based on the five nuclear microsatellite markers (theta(p) = 0.054). For this set of populations, pollen and seed flow did not differ significantly from one another (pollen-to-seed flow ratio = 1.22). Capability for long distance seed dispersion and colonization of anthropogenic sites contributes to the ability of S. lycocarpum to maintain genetic diversity. Seed dispersion along dirt roads may be critical in preserving S. lycocarpum genetic diversity in fragmented landscapes. PMID- 21523657 TI - Differential gene expression and functional analysis of pit cells from regenerating rat liver. AB - Hepatic pit cells are a population of large granular lymphocytes that substantially contribute to hepatic immunity. Studies have proven that pit cells have a role in liver regeneration, but the details of the relationship between pit cells and liver regeneration is not clear at present. We subjected rats to a two-third hepatectomy; pit cells with high purity were obtained with Percoll density centrifugation and immunomagnetic bead methods, and the changes in mRNA levels in pit cells from the regenerating liver were monitored up to 168 h using a Rat Genome 230 2.0 Array composed of 25,020 distinct rat liver cDNA clones. Of the 25,020 genes analyzed, 612 known and 358 unknown genes were identified to be associated with liver regeneration. The 612 known genes are classified into up regulation and down-regulation patterns based on the expression levels; they primarily participate in at least 23 biological activities based on gene ontology analysis. Together with gene function enrichment analysis, cytokines and a growth factor-mediated pathway in pit cells were activated at an early phase of liver regeneration; pit cell proliferation occurred from 24-72 h after liver hepatectomy; the machinery of pit cell differentiation commenced early and came into play late; an immune/inflammatory response was enhanced late. Expression pattern analysis of functionally classified genes in pit cells can give insights into the relationship between pit cells and liver regeneration. PMID- 21523658 TI - Molecular cloning and characterization of a tocopherol cyclase gene from Lactuca sativa (Asteraceae). AB - Tocopherol cyclase is a rate-limiting enzyme involved in tocopherol biosynthesis. The full-length cDNA encoding tocopherol cyclase (designated as LsTC) was cloned from lettuce (Lactuca sativa) for the first time by rapid amplification of cDNA ends (RACE) and characterized by means of quantitative RT-PCR. The full-length cDNA of LsTC was 1675 bp, with an open reading frame of 1521 bp, encoding a tocopherol cyclase protein of 506 amino acids, with a calculated molecular mass of 56.76 kD and an isoelectric point of 6.49. Comparative analysis revealed that LsTC has a close similarity with tocopherol cyclases from other plant species. Bioinformatic analysis indicated that LsTC shares a common evolutionary origin based on sequence and has the closest relationship to tocopherol cyclase from Helianthus annuus. Quantitative RT-PCR analysis suggested that expression of LsTC is induced and strengthened by oxidative stresses, such as strong light and drought. This cloning and characterization of LsTC will be helpful for further understanding of its role in the tocopherol biosynthesis pathway and provide a candidate gene for metabolic engineering of vitamin E. PMID- 21523659 TI - Polymorphism of somatostatin gene and its association with growth traits in Chinese cattle. AB - Somatostatins play a crucial role in the regulation of growth and development in vertebrates, especially muscle growth. We assessed the association of somatostatin gene polymorphisms with growth traits by PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) and DNA sequencing methods in 694 individuals from six Chinese cattle breeds. A novel single nucleotide polymorphism, G126A, was detected, and significant associations were found with body length, body height, hip width, heart girth, and hucklebone width index. Polymorphism of the somatostatin gene was found to be highly associated with growth traits in the Qinchuan breed at various ages. Gene frequency analysis showed significant differences among the breeds. Individuals with genotype AA had significantly lower body height, body length, hip width, and hucklebone width values compared to AG at 1.5 years old, and had significantly lower hip width, body length and hucklebone width compared to AG at 2 years old. At 2.5 years old, populations with genotype AA had significantly lower body length, hip width and hucklebone width than AG individuals, with the exception of the Luxi breed, in which two genotypes were found. The Luxi and Ximentaer crossbreed had the lowest frequency of the G allele, while the highest G allele frequencies were found in the Luxi breed. PMID- 21523660 TI - The effects of cardiac rehabilitation on haemodynamic parameters measured by impedance cardiography in patients with heart failure. AB - BACKGROUND: Cardiac rehabilitation (CR) is an important element of heart failure (HF) treatment although the mechanisms of its beneficial effects remain debatable. AIM: To evaluate the haemodynamic effects of CR measured by impedance cardiography in patients with HF. METHODS: Study group included 50 HF patients (aged 56.2 +/- 8.8 years, NYHA class II and III, left ventricular ejection fraction <= 40%) who underwent 8-week CR. Clinical and haemodynamic assessment was performed before and after CR. RESULTS: As a result of CR, exercise tolerance improved significantly as measured by peak VO(2) (18.7 +/- 4.4 vs 20.8 +/- 4.7 mL/kg/min; p = 0.025), six-minute walking test distance (6-MWT; 417.8 +/- 103.6 vs 467.7 +/- 98.4 m, p = 0.016) and NYHA class (change to the lower NYHA class in 30% of subjects). A significant reduction of the left atrial diameter was observed in echocardiography (4.55 +/- 0.63 vs 4.43 +/- 0.59 cm, p = 0.017). Impedance cardiography revealed a significant change in diastolic to systolic wave ratio (O/C ratio; 54.8 +/- 24.0 vs 47.9 +/- 20.8%, p = 0.021). A significant change in the haemodynamic profile of the left ventricular blood ejection was also observed. Before CR, transthoracic fluid content (TFC) correlated with stroke index (SI; R = 0.37, p < 0.01), compared to no correlation after CR (R = 0.00, NS). Reduction in TFC correlated with prolongation of the 6-MWT (R = -0.32, p = 0.06), and increase in systolic time ratio (STR) correlated with increase in peak VO(2)(R = 0.40, p = 0.006). Subjects who benefited from CR tended to have lower heart rate (61.4 +/- 9.0 vs 67.7 +/- 10.7 1/min, p = 0.07), longer pre ejection period (PEP; 12.2 +/- 11.6 ms vs -2.6 +/- 23.1 ms, p = 0.018) and non significantly higher STR (0.423 +/- 0.123 vs 0.377 +/- 0.102, p = 0.37). CONCLUSIONS: Impedance cardiography revealed beneficial effects of CR, manifested by reduced fluid retention and a reduced effect of preload on left ventricular relaxation and ejection. PMID- 21523661 TI - [Evaluation of cardiac rehabilitation]. PMID- 21523662 TI - Uric acid as a link between renal dysfunction and both pro-inflammatory and prothrombotic state in patients with metabolic syndrome and coronary artery disease. AB - BACKGROUND: Hyperuricaemia has long been known to be associated with cardiovascular disease, and it is particularly common in patients with kidney disease, metabolic syndrome and diabetes mellitus. Metabolic syndrome is associated with pro-inflammatory and prothrombotic state. AIM: To examine the association between renal function, serum uric acid and markers of both pro inflammatory and prothrombotic state in patients with diabetes mellitus (DM), metabolic syndrome and coronary artery disease. METHODS: The study population consisted of 91 patients (58 men, 33 women) aged 57.6 +/- 10.3 years with metabolic syndrome and type 2 DM. Patients were selected from a large group of patients scheduled for routine coronary angiography between 2006 and 2009. The patients were evaluated for the common risk factors for atherosclerosis: smoking, hypertension, DM, family history and hyperlipidaemia. Laboratory tests included complete blood counts, serum urea and creatinine, aminotransferases, C-reactive protein (CRP), fibrinogen, uric acid, total cholesterol, LDL-cholesterol, HDL cholesterol, triglycerides, fasting glucose, glycated haemoglobin (HbA1c), glomerular filtration rate (GFR) and urinary protein. We also measured body mass, height, waist circumference, hip circumference and calculated body mass index (BMI) and waist-to-hip ratio (WHR). RESULTS: The following significant correlations were observed: body mass vs serum creatinine (r = 0.291; p = 0.009), WHR vs serum creatinine (r = 0.672; p < 0.001), WHR vs GFR (r = -0.706; p < 0.001), WHR vs uric acid (r = -0.341; p = 0.001), WHR vs uric acid (r = 0.295; p = 0.05), BMI vs CRP (r = 0.231; p = 0.031), WHR vs CRP (r = 0.236; p = 0.024), serum creatinine vs uric acid (r = 0.362; p < 0.001), GFR vs uric acid (r = 0.341; p = 0.001), uric acid vs CRP (r = 0.251; p = 0.016), CRP vs fibrinogen (r = 0.470; p < 0.001), CRP vs platelet count (r = 0.282; p = 0.04) and HbA(1c) vs platelet count (r = 0.263; p = 0.0112). Multiple stepwise regression analysis showed that uric acid level was independently associated with WHR, GFR and CRP. CONCLUSIONS: In patients with ischaemic heart disease, DM and metabolic syndrome, obesity, particularly visceral obesity, is associated with renal dysfunction and elevated markers of pro-inflammatory state. Renal dysfunction co-exists with elevated serum uric acid. Elevated serum uric acid is associated with markers of pro-inflammatory state. Markers of pro-inflammatory state correlate with prothrombotic markers such as serum fibrinogen and platelet count. Uric acid should be taken into consideration as a link between renal dysfunction and both pro-inflammatory and prothrombotic state in patients with metabolic syndrome and coronary artery disease. PMID- 21523663 TI - [Restriction of fructose intake can prevent hyperuricemia, glomerular filtration and cardiovascular diseases]. PMID- 21523664 TI - Cardiac myxoma - clinical presentation and long-term post-operative follow-up. AB - BACKGROUND: Myxoma is the commonest cardiac neoplasm. Due to varying symptomatology, its diagnosis can prove difficult. It is agreed to have an excellent prognosis. AIM: Assessing the clinical course in patients operated on due to cardiac myxoma in two departments of cardiac surgery over the course of a decade. METHODS: The medical records of patients operated on due to cardiac myxoma between 1999 and 2009 were analysed. The patients were then invited for an ambulatory visit, during which transthoracic and transoesophageal echocardiographic examinations were performed. RESULTS: There were 61 patients (47 females) with histologically confirmed myxoma operated upon. The commonest symptoms leading to diagnosis were heart failure (16 patients, 26%) and syncope (12 patients, 20%). There were five (8%) in-hospital deaths and two (3%) non fatal strokes. Follow-up duration ranged between one and ten years (6.1 +/- 3.2 years). Nine (15%) deaths occurred during follow-up. In four (7%) patients, myxoma recurred in the original location. Echocardiography performed at follow-up visit revealed one recurrence of myxoma, and minor pathologies in 20 patients. Patients who died perioperatively were significantly older compared to those who survived (69 +/- 9.7 years vs 56 +/- 13, p = 0.02). Patients who died during the follow-up were also significantly older than those who were alive at the time of the contact visit (65 +/- 15 years vs 56 +/- 12, p = 0.02). Death during follow up occurred four times more often in males than females (36% vs 8.5%, p = 0.02). There were more deaths during the follow-up in patients whose initial presenting symptom was dyspnea: five deaths (31%) vs four deaths (9%, p = 0.04). The recurrence of myxoma was significantly more frequent in patients with a shorter duration of symptoms before the operation: 8.6 +/- 15 weeks with relapse vs 33.9 +/- 40 weeks without relapse (p = 0.04). CONCLUSIONS: Both, serious and benign events following myxoma excision are common. Clinical and echocardiographic surveillance should be implemented in all patients who undergo a myxoma operation. PMID- 21523665 TI - [Left atrium cardiac myxoma]. PMID- 21523666 TI - Impact of multivessel coronary disease on one-year clinical outcomes and five year mortality in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention. AB - BACKGROUND: Multivessel coronary disease (MVD) occurs in approximately 40-65% of patients with ST-segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI), and is associated with significantly increased morbidity and mortality rates. AIM: To evaluate the impact of MVD on in hospital and long-term clinical outcomes in patients with STEMI and PCI, and to compare these results with those from a group of patients with a single coronary vessel disease (SVD). METHODS: Consecutive patients with STEMI treated with PCI were included in the analysis. Patients were divided into two groups: patients with SVD (n = 828, 46.6%) and patients with MVD (n = 948, 53.4%). Clinical follow up was performed at 12 months, and five-year mortality was assessed. Major adverse cardiac events (MACE) at 12-month follow-up were defined as death (from any cause), stroke, need for percutaneous or any surgical coronary artery revascularisation, and non-fatal myocardial infarction. RESULTS: The in-hospital mortality was 2.9% vs 9.5% (p < 0.0001) and the five-year mortality was 11.9% vs 23.8% (p < 0.0001), for SVD vs MVD patients, respectively. The cumulative incidence of MACE during 12-month follow-up was significantly higher in patients with MVD (32.5% vs 14.5%, p < 0.0001). Moreover, multivariate analysis revealed that after a correction for baseline differences, the presence of MVD was a strong and independent predictor for five-year mortality in patients treated with PCI (hazard ratio 1.45, 95% confidence interval 1.13-1.88, p = 0.004). CONCLUSIONS: The presence of MVD in patients with STEMI is a strong and independent risk factor for higher long-term mortality. PMID- 21523667 TI - [Are results of multivessel coronary disease undergoing percutaneous coronary intervention satisfied?]. PMID- 21523668 TI - Successful primary coronary angioplasty improves early and long-term outcomes in ST segment elevation acute coronary syndromes in patients above 80 years of age. AB - BACKGROUND: ST segment elevation myocardial infarction (STEMI) in patients above 80 years of age continues to be a therapeutic challenge. Patients in this age group are rarely included in randomised clinical trials. AIM: Comparison of the effectiveness and safety of STEMI management in octogenarians in hospitals with a 24-hour percutaneous coronary intervention (PCI) capability and hospitals without PCI access. METHODS: A retrospective analysis of medical records of 50 octogenarians who were treated with PCI (group 1) in one center and 50 patients treated noninvasively in the other 3 hospitals (group 2). We evaluated mortality and major adverse cardiac events after 10 days, 30 days and 1 year. RESULTS: There were no significant differences in the demographic characteristics of the study groups. The duration of coronary pain was similar in both groups: 318 min in group 1 vs 383 min in group 2 (NS). Mortality in group 2 was significantly higher than in group 1: 40% vs 14%, respectively, after 10 days (p = 0.0034); 48 vs 18% after 30 days (p = 0.0014); and 54% vs 24% after 1 year (p = 0.0021). Thrombolytic treatment was used in only 40% of the patients in group 2. In group 2, acute heart failure (HF) (Killip class III and IV) was diagnosed more frequently than in group 1 (28% vs 12%, p = 0.034). In patients with Killip class I/II HF, mortality in patients in group 2 and group 1 was 22% vs 9%, at 10 days; 31% vs 14% at 30 days; and 39% vs 20% at 1 year. In patients with Killip class III/IV HF, mortality was 86% vs 50%, at 10 days; 93% vs 50% at 30 days; and 93% vs 50% at 1 year, respectively (all differences NS). In multivariate analysis adjusted for the differences between groups, HF (a negative effect) and a successful PCI (a positive effect) were independent predictors of 1-year survival. CONCLUSIONS: Successful primary PCI in STEMI patients above 80 years of age resulted in a reduction of early and long-term mortality compared to the medically treated patients. The benefits of PCI treatment accrued during the follow-up. In patients treated in the tertiary reference centre in whom PCI was not successful or was not deemed feasible, prognosis was similar to that in the medically treated patients. The latter patients rarely received thrombolytic treatment. PMID- 21523669 TI - [Prolong life...]. PMID- 21523670 TI - Two-dimensional longitudinal strain for the assessment of the left ventricular systolic function as compared with conventional echocardiographic methods in patients with acute coronary syndromes. AB - BACKGROUND: The evaluation of the left ventricular (LV) function is one of the most important elements of diagnosis in patients with cardiovascular (CV) diseases. A low LV ejection fraction (LVEF) is a strong and independent predictor of CV events. Traditionally, echocardiography characterises the LV systolic function by the estimation of LVEF with use of the Simpson method, supported by the wall motion score index (WMSI). Speckle tracking imaging is a new method of LV function imaging based on the estimation of longitudinal peak systolic strain (LPSS), by tracing of the automatically detected myocardial speckles. AIM: To evaluate the usefulness of global longitudinal peak systolic strain (GLPSS) and regional longitudinal peak systolic strain (r-LPSS) in LV systolic function assessment and to compare LPSS with conventional parameters such as LVEF, WMSI and regional wall motion score index (r-WMSI). METHODS: The study was performed in a group of 44 patients with a clinical diagnosis of acute coronary syndrome (mean age 63.6 +/- 12.2 years). The LVEF, WMSI, r-WMSI were estimated by echocardiography (VIVID 7 Dimension, GE Healthcare, USA). Moreover, LPSS (GLPSS and r-LPSS) with use of automated function imaging (AFI) were also estimated. RESULTS: In the study group mean LVEF was 43.1 +/- 12.7%, mean WMSI: 1.68 +/- 0.52, and GLPSS: -13.8 +/- 5.6%. A very strong linear correlation between the conventional and new parameters was observed - for GLPSS and LVEF: r = -0.86 (p < 0.00001), for GLPSS and WMSI: r = 0.88 (p < 0.00001). The results of the regional myocardial contractility assessment (r-LPSS and r-WMSI) were also in agreement, especially for LV anterior wall (r = 0.87, p < 0.00001). CONCLUSIONS: These results suggest a considerable usefulness of LPSS - a new method of echocardiographical imaging - in the estimation of global and regional LV function in patients with acute coronary syndrome and its agreement with conventional parameters such as LVEF and WMSI. PMID- 21523671 TI - [Mark Twain and echocardiography]. PMID- 21523672 TI - [Cardiac involvement in Fabry's disease - typical disease course and diagnostic problems]. AB - Fabry disease is a rare X-linked recessive lysosomal storage disease, which can cause a wide range of systemic symptoms. A deficiency of the enzyme alpha galactosidase A due to mutation causes a glycolipid to accumulate within the blood vessels, other tissues, and organs. This accumulation leads to an impairment of proper heart function. Wide range of symptoms makes diagnosis difficult. We present a case of a 43 year-old male with typical Fabry disease. PMID- 21523673 TI - [Coarctation of aorta in a 40 year-old female with bicuspid aortic valve - a case report]. AB - Patients with bicuspid aortic valve quite often have another abnormalities of cardiovascular system. In the paper we present diagnostic difficulties in 40 year old woman with bicuspid aortic valve and coarctation of aorta. PMID- 21523674 TI - [Patient with left ventricular aneurysm and thrombus after myocardial infarction long-term observation]. AB - A 14-year follow-up of a 69 year-old male with left ventricular aneurysm and thrombus after antero-septal myocardial infarction is presented. We describe problems with thromboembolic and bleeding complications in the context of changes in the guidelines over the period of treatment. PMID- 21523675 TI - ["eThrombosis" - venous thromboembolism provoked by prolonged sitting position by a computer. A case series report of six patients]. AB - Immobility due to sitting position during traveling is a well-known risk factor for venous thromboembolism (VTE). Beasley et al. (2003) first proposed the name "eThrombosis" for a case in which VTE was related to prolonged seated immobility at computer. We present clinical and laboratory data of six patients with "eThrombosis". As this kind of immobility probably plays an underestimated role in VTE development, other risk factors can also be usually found. "eThrombosis" affects mainly young people, but it may occur at any age. Limited time of seated immobility, intervals for physical exercise and graduated compression stockings use are forms of "eThrombosis" prophylaxis. PMID- 21523677 TI - [Spinal cord stimulation for the treatment of refractory angina pectoris]. AB - Spinal cord stimulation (SCS) is a well known method of treatment used worldwide since the 80's of the last century. High efficiency of SCS was observed in the treatment of various types of pain. Promising clinical results were observed in the treatment of patients with refractory angina (RA). Reduction of angina attacks reduces doses of medications and improves quality of life. SCS efficacy in RA is comparable to that observed among patients treated with cardiac surgery (CABG) and percutaneous coronary intervention (PCI), with lower risk of complications and rehospitalisation. SCS is more cost effective compared to CABG and PCI. SCS might be considered for patients who did not respond to reperfusion therapy. The mechanism of action in RA is not well understood. It is known that SCS reduces the activity of the sympathetic nervous system, by which improves the coronary perfusion and oxygenation of the heart muscle. It is important that SCS does not mask the pain related to the infarct. PMID- 21523678 TI - [Chronic inflammation in patients with acute coronary syndrome and chronic kidney disease]. AB - Chronic kidney disease is a worldwide growing problem in public health. It is a risk factor for complications in patients with acute coronary syndrome (ACS). Diabetes, hypertension (hypertrophy and left ventricular failure), impaired fibrinolysis and coagulation processes, as well as the rapid development of atherosclerosis (partly associated with chronic inflammation) are responsible for higher prevalence of cardiovascular diseases in patients with chronic kidney disease. Inflammatory process of unknown aetiology belongs to the so-called non traditional risk factors in development of cardiovascular system diseases. It is thought that this process is responsible for adverse remodelling of atherosclerosis plaque and its instability which causes plaque rupture and as a result a coronary syndrome occurrence. Important inflammatory mediators, which take part in pathogenesis of ACS, are acute phase proteins such as: C-reactive protein, adhesion molecules VCAM-1, ICAM-1, selectins, plasma amyloid A, metalloproteinases, interleukins-1 and -6, tumour necrosis factor-a and vascular endothelial growth factor. PMID- 21523679 TI - [T wave pseudo-normalisation during exercise test as a marker of significant ischaemia]. AB - A case of a 50 year-old woman with unstable angina is presented. During the exercise test performed at 5th day of hospitalisation T wave normalisation in leads III, aVF, V4-V6 was observed. The subsequent angiography revealed critical stenosis of the right coronary artery and percutaneous coronary intervention was performed. Following intervention there were no T wave changes during exercise. PMID- 21523681 TI - An unusual echocardiographic image of a hiatal hernia. AB - Diagnosis of a hiatal hernia (HH) is typically made using an upper gastro intestinal barium X-ray. A complementary test is gastroscopy or upper-intestinal endoscopy. There are reports in which HH has been diagnosed by echocardiography. We here describe a case of a HH visible on an echocardiogram in a female with palpitations. PMID- 21523682 TI - Thrombus aspiration for treating distal coronary macroemboli during primary percutaneous coronary intervention. AB - Percutaneous coronary interventions (PCI) of thrombus-containing lesions are associated with increased risk of complications such as distal coronary embolisation and impaired coronary circulation. Although the use of thrombectomy devices to aspirate thrombus during primary PCI is currently not routinely recommended, there is growing evidence suggesting the use of thrombus aspiration catheters during PCI. Here, we report the case of a 70 year-old patient undergoing thrombus aspiration therapy because of the development of coronary bifurcation macroemboli during initial phase of primary PCI. After successful thrombus aspiration therapy, dramatic improvements in both coronary flow and ST segment resolution were achieved. PMID- 21523684 TI - [Complex embolic protection during primary percutaneous coronary intervention]. AB - We describe a case of 61 year-old man with acute myocardial infarction (AMI) and with large thrombus in right coronary artery. The patient underwent primary angioplasty with complex embolic protection: pharmacological, thromboaspiration and filter protection device. This triple embolic protection was necessary to evacuate thrombi and successfully restore normal flow in coronary artery. Despite distal protection has no evidence to be beneficial in AMI, the use of filter protection might be considered in selected patients. PMID- 21523686 TI - [Cryoablation of ventricular arrhythmias originating from septal aspects of mitral and tricuspid annulus]. AB - Two cases of frequent ventricular ectopy are described. Case one: a 49 year-old woman with post myocarditis extrasytoles (34 000/24 h). The ectopic focus was located on the tricuspid annulus - directly in the area of largest and sharpest His bundle potential and where direct His bundle capture was observed during all pace mapping attempts. Case two: a 15 year- -old men with idiopathic, very frequent premature ventricular beats from septal aspect of the mitral annulus. The area of earliest activation during the spontaneous ectopy with 12/12 pace map match showed obvious His bundle potential, moreover, the radiofrequency ablation catheter was unstable in that position (inferoseptal from retrograde aortic approach). In both cases treatment with cryoablation was successfully and uneventful. In conclusion, cryoablation instead of radiofrequency current ablation should be used for ventricular ectopy from septal part of the tricuspid or mitral annuli especially in cases of parahisian localisation and/or catheter instability. PMID- 21523687 TI - [Summary of the article: Goldman S, Sethi G, Holman W et al. Radial artery grafts vs saphenous vein grafts in coronary artery bypass surgery. JAMA, 2011; 305: 167 174]. PMID- 21523688 TI - [Be careful of material used for coronary artery bypass surgery]. PMID- 21523689 TI - [The use of extracorporeal membrane oxygenation (ECMO) in the treatment of acute respiratory distress syndrome due to pandemic influenza]. AB - Pandemic influenza particularly often is associated with symptoms of acute respiratory failure, and in case of refractory hypoxemia patients may have indications for the extracorporeal membrane oxygenation (ECMO). The paper presents a case of a pandemic influenza virus infection, where classical indications for veno-venous ECMO occured. Practical aspects of this kind of treatment in the intensive care unit are discussed. PMID- 21523690 TI - [ECMO-reactivation, new challenge for cardiologists, anesthesiologists and intensive care units]. PMID- 21523694 TI - Use of antibiotics in uncomplicated diverticulitis. AB - BACKGROUND: The value of antibiotics in the treatment of acute uncomplicated left sided diverticulitis is not well established. The aim of this review was to assess whether or not antibiotics contribute to the (uneventful) recovery from acute uncomplicated left-sided diverticulitis, and which types of antibiotic and route of administration are most effective. METHODS: Medline, the Cochrane Library and Embase databases were searched. Randomized controlled trials (RCTs), prospective or retrospective cohort studies addressing conservative treatment of mild uncomplicated left-sided diverticulitis and use of antibiotics were included. RESULTS: No randomized or prospective studies were found on the topic of effect on outcome. One retrospective cohort study was retrieved that compared a group treated with antibiotics with observation alone. This study showed no difference in success rate between groups. Only one RCT of moderate quality compared intravenous and oral administration of antibiotics, and found no differences. One other RCT of very poor quality compared two different kinds of intravenous antibiotic and also found no difference. A small retrospective cohort study comparing antibiotics with and without anaerobe coverage showed no difference in group outcomes. CONCLUSION: Evidence on the use of antibiotics in mild or uncomplicated diverticulitis is sparse and of low quality. There is no evidence mandating the routine use of antibiotics in uncomplicated diverticulitis, although several guidelines recommend this. Copyright (c) 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. PMID- 21523697 TI - Impact of endoscopic assessment and treatment on operative and non-operative management of acute oesophageal perforation. AB - BACKGROUND: Surgeons have not typically utilized an endoscopic approach for diagnosis and management of acute oesophageal perforation, mainly due to fears of increased mediastinal contamination. This study assessed the evolution of endoscopic approaches and their effect on outcomes over time in acute oesophageal perforation. METHODS: All patients with documented acute oesophageal perforation between 1990 and 2009 were enrolled prospectively in an Institutional Review Board-approved database. RESULTS: Of 81 patients who presented during the study period, 52 had upper gastrointestinal endoscopy for diagnosis alone (12 patients; 23 per cent) or as a component of acute management (40 patients; 77 per cent). Use of endoscopy increased from four of 13 patients in the first 5 years of the study to 20 of 24 patients in the final 5 years. Endoscopy was used in conjunction with surgery in 28 patients, of whom 21 underwent primary repair, three had resection, and one a diversion; 12 patients in this group had hybrid operations (combination of surgical and endoscopic management). Primary endoscopic treatment was used in 15 patients (29 per cent), most commonly involving stent placement (7). Of those having endoscopy, complication rates improved (from 3 of 4 to 8 of 20 patients), as did mean length of stay (from 21.8 to 13.4 days) between the initial and final 5 years of the study. There were two deaths (4 per cent). Of 21 patients who had both endoscopic assessment and management in the operating room, endoscopy identified additional pathology in ten, leading to a change in management plan in five patients. CONCLUSION: Endoscopy is a safe and important component of the management of acute oesophageal perforation. It provides additional information that modifies treatment, and its wider use should result in improved outcomes. PMID- 21523699 TI - High intra-abdominal pressure during experimental laparoscopic liver resection reduces bleeding but increases the risk of gas embolism. AB - BACKGROUND: Various recommendations exist regarding intra-abdominal pressure (IAP) during laparoscopic liver resection. A high IAP may reduce bleeding but at the same time increase the risk of gas embolism. This study investigated the effects of two different IAPs during laparoscopic left liver lobe resection in piglets. METHODS: Sixteen piglets underwent laparoscopic left liver lobe resection using carbon dioxide pneumoperitoneum of either 8 or 16 mmHg (8 per group). A combination of CUSA System 200TM and LigaSureTM instruments was used for parenchymal division. During resection, a standard injury to the left liver vein was also created to increase the risk of bleeding and/or gas embolism during the operation. Heart rate, cardiac output, and arterial, pulmonary arterial, pulmonary capillary wedge and central venous pressures were measured. Arterial blood gases were monitored continuously. Transoesophageal echocardiography was video recorded to detect and quantify gas embolism within the right cardiac ventricle. The duration of operation and bleeding were noted. RESULTS: High IAP resulted in reduced bleeding (P = 0.016), but gas embolism occurred more frequently (P = 0.001) than with low IAP. Gas embolism disturbed gas exchange, with an increase in arterial pressure of carbon dioxide, and a decrease in arterial partial pressure of oxygen and pH. These effects were sustained for at least 30 min after surgery. CONCLUSION: High IAP reduces the amount of bleeding but increases the risk of gas embolism. Monitoring for gas embolism is therefore indicated if a high IAP is used during laparoscopic liver resection. PMID- 21523701 TI - Letter 1: Randomized clinical trial of routine on-table cholangiography during laparoscopic cholecystectomy (Br J Surg 2011; 98: 362-367). PMID- 21523702 TI - Comparison of three separate antiadhesive barriers for intraperitoneal onlay mesh hernia repair in an experimental model (Br J Surg 2011; 98: 442-449). PMID- 21523704 TI - Randomized controlled trial of ultrasonic dissection versus standard surgical technique in open left hemicolectomy or total gastrectomy (Br J Surg 2011; 98: 220-227). PMID- 21523706 TI - Letter 2: Randomized clinical trial of routine on-table cholangiography during laparoscopic cholecystectomy (Br J Surg 2011; 98: 362-367). PMID- 21523709 TI - NCI, Cooperative Groups gear up for changes in clinical trials system: new policies initiated in response to institute of medicine report. PMID- 21523712 TI - Metabolic risk factors in prostate cancer. PMID- 21523714 TI - Clinicopathologic factors of the recurrent tumor predict outcome in patients with ipsilateral breast tumor recurrence. AB - BACKGROUND: The role of clinicopathologic characteristics of the recurrent tumor in determining survival in a cohort of patients with ipsilateral breast tumor recurrence (IBTR) was investigated. METHODS: Among 6020 women with pT1-T2, pN0-1, M0 treated with breast-conserving surgery from 1989 to 1999, 269 developed isolated IBTR. Ten-year Kaplan-Meier breast cancer-specific survival (BCSS) and overall survival (OS), calculated from date of IBTR, were analyzed according to clinicopathologic characteristics. RESULTS: Factors that were associated with diminished OS and BCSS on univariate analysis were: time to IBTR <=48 months, lymphovascular invasion positive status, estrogen receptor (ER) negative status, high grade, clinical IBTR detection, biopsy alone, and close/positive margins (all P < .05). On multivariate analysis, time to IBTR <=48 months (hazard ratio [HR], 1.87, P = .012), lymphovascular invasion positive status (HR, 2.46; P < .001), ER negative status (HR, 2.08; P = .013), high-grade recurrent disease (HR, 1.88; P = .013), and close/positive margins after surgery for IBTR (HR, 1.94; P = .013) retained significance for prediction of diminished OS. When stratified according to number of adverse prognostic features, 10-year OS was 70.4% in patients with 1 factor, 35.8% with 2 factors, and 19.9% with 3 or more factors (P < .001). CONCLUSIONS: Time to recurrence <=48 months, lymphovascular invasion positive status, ER negative status, high-grade histology, and close/positive margins in association with the recurrent tumor are independent prognostic factors for survival after IBTR. The presence of 2 or more of these features at recurrence is significantly associated with poor OS. These criteria can be used to prognosticate and guide clinical decisions after recurrence. PMID- 21523713 TI - Genomic differences between estrogen receptor (ER)-positive and ER-negative human breast carcinoma identified by single nucleotide polymorphism array comparative genome hybridization analysis. AB - BACKGROUND: Estrogen receptor (ER) remains one of the most important biomarkers for breast cancer subtyping and prognosis, and comparative genome hybridization has greatly contributed to the understanding of global genetic imbalance. The authors used single-nucleotide polymorphism (SNP) arrays to compare overall copy number aberrations (CNAs) as well as loss of heterozygosity (LOH) of the entire human genome in ER-positive and ER-negative breast carcinomas. METHODS: DNA was extracted from frozen tumor sections of 21 breast carcinoma specimens and analyzed with a proprietary 50K XbaI SNP array. Copy number and LOH probability values were derived for each sample. Data were analyzed using bioinformatics and computational software, and permutation tests were used to estimate the significance of these values. RESULTS: There was a global increase in CNAs and LOH in ER-negative relative to ER-positive cancers. Gain of the long arm of chromosome 1 (1q) and 8q were the most obvious changes common in both subtypes: An increase in the chromosome 1 short arm (1p)/1q ratio was observed in ER negative samples, and an increased 16p/16q ratio was observed in ER-positive samples. Significant CNAs (adjusted P<.05) in ER-negative relative to ER-positive tumors included 5q deletion, loss of 15q, and gain of 2p and 21q. Copy-neutral LOH (cnLOH) common to both ER-positive and ER-negative samples included 9p21, the p16 tumor suppressor locus, and 4q13, the RCHY1 (ring finger and CHY zinc finger domain-containing 1) oncogene locus. Of particular interest was an enrichment of 17q LOH among the ER-negative tumors, potentially suggesting breast cancer 1 gene (BRCA1) mutations. CONCLUSIONS: SNP array detected both genetic imbalances and cnLOH and was capable of discriminating ER-negative breast cancer from ER positive breast cancer. PMID- 21523715 TI - Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma. AB - BACKGROUND: Neoadjuvant therapy has been used to improve survival in operable pancreatic cancer. The authors' objective was to compare long-term outcomes in patients receiving neoadjuvant versus adjuvant therapy for resectable pancreatic adenocarcinoma. METHODS: The California Cancer Surveillance Program for Los Angeles County retrospectively identified 458 patients with nonmetastatic pancreatic adenocarcinoma who underwent definitive pancreatic resection and received systemic chemotherapy between 1987 and 2006. The cohort was grouped by timing of systemic therapy-neoadjuvant or adjuvant. Clinicopathologic characteristics and overall survival were compared. Multivariate Cox regression analysis was used to determine the benefit of neoadjuvant therapy, independent of other significant factors. RESULTS: Of the 458 patients, 39 (8.5%) received neoadjuvant therapy, and 419 (91.5%) received adjuvant therapy. There was a significantly lower rate of lymph node positivity in the neoadjuvant group (45% vs 65%; P = .011) despite a higher rate of extrapancreatic tumor extension. On Kaplan-Meier analysis, the neoadjuvant group had significantly better overall survival compared with the adjuvant group (median survival, 34 vs 19 months; P = .003). Overall survival was also improved in the neoadjuvant therapy patients with extrapancreatic disease (median survival, 31 vs 19 months; P = .018). On multivariate Cox regression analysis, neoadjuvant therapy was an independent predictor of improved survival (hazard ratio, 0.57; 95% confidence interval, 0.37 0.89; P = .013). CONCLUSIONS: This is the first population-based study to compare neoadjuvant versus adjuvant treatment strategies in resectable pancreatic cancer. Neoadjuvant therapy is associated with a lower rate of lymph node positivity and improved overall survival and should be considered an acceptable alternative to the surgery-first paradigm in operable pancreatic cancer. PMID- 21523716 TI - A randomized phase 2 study of docetaxel and S-1 versus docetaxel and cisplatin in advanced gastric cancer with an evaluation of SPARC expression for personalized therapy. AB - BACKGROUND: The purpose of this study was to compare 2 weekly docetaxel-based regimens as first-line treatments for advanced gastric cancer and to investigate the expression of secreted protein acidic and rich in cysteine (SPARC) and its abilities to predict treatment-related clinical outcomes. METHODS: Patients were randomly selected to receive 3 weekly cycles of docetaxel (35 mg/m(2) on days 1 and 8) plus S-1 (35 mg/m(2) each twice daily on days 1-14) (DS), or docetaxel plus cisplatin (35 mg/m(2) each on days 1 and 8) (DC). Endpoints included overall response rate (primary), survival, toxicity, and quality of life (secondary). SPARC expression in prechemotherapy specimens of primary gastric tumors was evaluated via immunohistochemical analysis. RESULTS: Eighty patients were enrolled in the study. Confirmed overall response rates were 46% (95% confidence interval, 30%-62%) for DS and 24% (95% confidence interval, 11%-38%) for DC via intent-to-treat analysis. Median progression-free survival was 7.3 and 4.9 months and overall survival was 16.0 and 8.3 months for DS and DC, respectively. The most common grade >= 3 toxicity was neutropenia. Grade >= 3 mucositis (18%) and hand-foot syndrome (8%) were the toxicities most associated with DS, whereas anorexia (20%) and lethargy (20%) were more common with DC. High SPARC expression was related to early progression (hazard ratio, 3.67; P = .042) and poor overall survival (hazard ratio, 2.01; P = .010) in docetaxel chemotherapy on multivariate analysis. CONCLUSIONS: The outcomes in this study favored DS over DC for further phase 3 study. The findings suggest that split-dose weekly docetaxel alleviates hematological toxicity without compromising efficacy, and that SPARC expression may help individualize therapy in advanced gastric cancer. PMID- 21523717 TI - Overtreatment of men with low-risk prostate cancer and significant comorbidity. AB - BACKGROUND: Men with low-risk prostate cancer and significant comorbidity are susceptible to overtreatment. The authors sought to compare the impact of comorbidity and age on treatment choice in men with low-risk disease. METHODS: The authors sampled 509 men with low-risk prostate cancer diagnosed at the Greater Los Angeles and Long Beach Veterans Affairs Medical Centers between 1997 and 2004. Rates of aggressive treatment (radical prostatectomy, radiation therapy, brachytherapy) were determined among men of different ages and with different Charlson comorbidity scores. Multivariate modeling was used to determine the influence of both variables in predicting nonaggressive treatment, and Cox proportional hazards analysis was used to compare the risk of other-cause mortality among groups according to Charlson score and age. RESULTS: Men with Charlson scores >= 3 were treated aggressively in 54% of cases (30 of 56 men), while men aged >75 years at diagnosis were treated aggressively in 16% of cases (7 of 44 men). In multivariate analysis, age >75 years was a much stronger predictor of nonaggressive treatment (relative risk, 12.0; 95% confidence interval [CI], 5.4-28.3) than a Charlson score >= 3 (relative risk, 2.0; 95% CI, 1.3-2.9). In survival analysis, men with Charlson scores >= 3 had an 8-fold increased risk (hazard ratio, 8.4; 95% CI, 4.2-16.6) and 70% probability of other cause mortality at 10 years, whereas age >75 years was associated with a 5-fold increased risk (hazard ratio, 4.9; 95%CI, 1.7-13.8) and a 24% probability of other-cause mortality. CONCLUSIONS: Men with significant comorbidity often were overtreated for low-risk prostate cancer. Like advanced age, significant comorbidity should be a strong relative contraindication to aggressive treatment in men with low-risk disease. PMID- 21523718 TI - Etiologic role of human papillomavirus infection in bladder carcinoma. AB - BACKGROUND: The authors elucidated an etiologic role of human papillomavirus (HPV) infection in carcinoma of the bladder. METHODS: One hundred seventeen of 224 patients with bladder carcinoma who were treated between 1997 and 2009 were enrolled in this study. The presence of HPV DNA was tested on frozen carcinoma tissues that were obtained by transurethral resection using a polymerases chain reaction-based method. Localization of HPV was observed on archival tissue specimens by in situ hybridization (ISH) for high-risk HPV DNA. Cyclin-dependent kinase (CDK) inhibitor 2A (inhibits CDK4) (p16-INK4a) and minichromosome maintenance protein-7 (mcm-7)-surrogate markers for high-risk HPV-E7 oncoprotein and HPV-L1 (capsid) protein expression were evaluated by immunohistochemistry. RESULTS: HPV types 16, 18, 31, 33, 52, and 58, and an unknown HPV type were detected in 18 of 117 samples (15%) from patients with bladder carcinoma. HPV16 was identified in 6 samples, HPV18 was identified in 4 samples, and HPV33 was identified in 3 samples. All were single HPV type infections. HPV was detected in 38% (12 of 28) of histologic grade 1 bladder carcinomas, 8.5% (6 of 71) of grade 2 bladder carcinomas, and in 0% (0 of 18) of grade 3 bladder carcinomas. Multivariate analysis indicated that younger age (<60 years; odds ratio [OR], 10.9; 95% confidence interval [CI], 2.6-45.3) and grade 1 tumors (OR, 4.5; 95% CI, 1.2-17.0) were associated with HPV infection. ISH analysis indicated that high-risk HPV DNA was localized in the nuclei of tumor cells of all HPV-positive samples. p16-INK4a and mcm-7 were expressed in 94% and 89% of HPV-positive carcinoma cells, respectively. HPV-L1 protein expression, which suggested reproductive HPV infection, was not observed in any carcinoma. CONCLUSIONS: The current results indicated that high-risk HPV is likely to be a causative agent of some low-grade bladder carcinomas that develop in younger patients. PMID- 21523719 TI - Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. AB - BACKGROUND: The natural history of castration-resistant nonmetastatic prostate cancer is poorly defined. METHODS: The authors used data from 331 subjects in the placebo group of a randomized controlled trial to evaluate the relations of disease and host characteristics with time to first bone metastases in men with prostate cancer, rising prostate-specific antigen (PSA) despite androgen deprivation therapy, and no radiographic evidence of metastases. Relations between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were age, body mass index, prior prostatectomy, prior orchiectomy, Gleason score, performance status, PSA, urinary N-telopeptide, bone alkaline phosphatase, albumin, lactate dehydrogenase, and hemoglobin. RESULTS: At 2 years, 46% of subjects had developed bone metastases, and 20% had died. Median bone metastasis-free survival was 25 months. In multivariate analyses, baseline PSA >= 13.1 ng/mL was associated with shorter overall survival (relative risk [RR], 2.34; 95% confidence interval [CI], 1.71 3.21; P < .0001), time to first bone metastasis (RR, 1.98; 95% CI, 1.43-2.74; P < .0001), and bone metastasis-free survival (RR, 1.98; 95% CI, 1.45-2.70; P < .0001). PSA velocity was significantly associated with overall and bone metastasis-free survival. Other covariates were not consistently associated with clinical outcomes. CONCLUSIONS: In men with progressive castration-resistant prostate cancer and no detectable metastases, baseline PSA was significantly associated with time to first bone metastasis, bone metastasis-free survival, and overall survival. Other disease and host characteristics, including body mass index and bone turnover markers, were not consistently associated with clinical outcomes. PMID- 21523720 TI - Prostate cancer risk in the Swedish AMORIS study: the interplay among triglycerides, total cholesterol, and glucose. AB - BACKGROUND: In a cohort including 5112 prostate cancer (pCa) patients, the authors investigated associations among triglycerides (TG), total cholesterol (TC), and pCa while taking into account glucose. METHODS: A cohort (n = 200,660) based on 4 groups of men, according to age at cohort entry, with TG, TC, and glucose measurements was selected from the Apolipoprotein MOrtality RISk (AMORIS) database. Of these, 5112 men developed pCa. Multivariate Cox proportional hazard models were used to analyze associations among TG, TC, and pCa. Competing risks were assessed graphically. RESULTS: Age-stratified analyses for quartiles of TG, TC, and glucose showed a negative association between glucose and pCa risk (HR, 0.93; 95% CI, 0.86-1.01), 0.93 (0.86-1.01), 0.87 (0.81-0.94) for the second, third, and fourth quartiles compared with the first (P(trend) = .001). Stratified analysis by glucose levels (<6.11 or >= 6.11 mmol/L) showed a positive association between hypertriglyceridemia (TG >= 1.71 mmol/L) and pCa risk, when there were high glucose levels (HR, 1.23; 95% CI, 1.01-1.48). No association was found for hypercholesterolemia (TC >= 6.50 mmol/L). Competing risk analysis showed that protective effects of glucose were overestimated in conventional Cox proportional hazard models and strengthened positive findings between TG and pCa risk. CONCLUSIONS: The authors'; findings supported the hypothesis that factors of the glucose and lipid metabolism influence pCa risk. Competing risk assessment showed that it is important to take into account the long natural history and age distribution of pCa when interpreting results. The authors'; findings indicate another reason to fight the increasing prevalence of obesity and dyslipidemia. PMID- 21523721 TI - KIT gene mutation and amplification in dysgerminoma of the ovary. AB - BACKGROUND: Dysgerminoma, the ovarian counterpart of seminoma, is the most common type of malignant ovarian germ cell tumor. The role of KIT mutation and amplification in the development of dysgerminoma is not currently established. The purpose of this study was to analyze alterations of the KIT gene in a large series of dysgerminomas and correlate the findings with clinicopathological parameters. METHODS: Dysgerminoma cells from 22 patients were analyzed for KIT mutations at exon 17 codon 816. KIT amplification and chromosome 12p anomalies were investigated by way of dual color fluorescence in situ hybridization. KIT protein expression was also examined by way of immunohistochemistry. RESULTS: KIT exon 17 codon 816 mutations and KIT amplification were each detected in 6 cases of dysgerminoma (27%); however, there was no correlation between these 2 factors. KIT expression was detected in 87% of dysgerminomas. The KIT mutation was associated with advanced pathological stage (P < .05), and KIT amplification was associated with elevated KIT protein expression (P < .05). Chromosome 12p anomalies were found in 82% of the dysgerminomas and did not correlate with KIT abnormalities. CONCLUSIONS: KIT mutations occur in approximately one-third of cases of dysgerminomas and are associated with advanced stage at presentation. KIT is a potential therapeutic target for those dysgerminomas that have the mutation. PMID- 21523722 TI - Phase II study of belotecan, a camptothecin analogue, in combination with carboplatin for the treatment of recurrent ovarian cancer. AB - BACKGROUND: Belotecan (CKD602; Camtobell, Chong Keun Dang Corp., Seoul, Korea) is a recently developed camptothecin derivative with antitumor properties. This phase II study was designed to evaluate the toxicity and efficacy of belotecan combined with carboplatin in patients with recurrent epithelial ovarian cancer (EOC). METHODS: Thirty-eight patients with recurrent EOC were treated with belotecan 0.3 mg/m(2) /day (days 1-5) and carboplatin AUC 5 (day 5) every 3 weeks for 6 cycles. The primary objective was to determine the response rate as defined by Response Evaluation Criteria in Solid Tumors and CA-125 response. Other end points included toxicities and progression-free survival (PFS). RESULTS: All 38 patients were assessed for toxicity, and 35 patients were assessed for response. The overall response rate was 57.1%; there were 7 complete responses (20.0%), 13 partial responses (37.1%), 6 patients with stable disease (17.1%), and 9 patients with progressive disease (25.7%). Grades 3 and 4 hematologic toxicities included neutropenia (28.8%), thrombocytopenia (19.8%), and anemia (14.4%), and there were 2 episodes of febrile neutropenia. Median PFS was 7 months, with a median follow up of 12 months. CONCLUSIONS: The newly developed topoisomerase I inhibitor belotecan (CKD-602) combined with carboplatin is a well-tolerated regimen with activity in recurrent EOC. Further testing of this regimen is warranted to further characterize efficacy and indications for use. PMID- 21523723 TI - Phase 2 study of dasatinib in the treatment of head and neck squamous cell carcinoma. AB - BACKGROUND: Treatment options for patients with advanced head and neck squamous cell carcinoma (HNSCC) are scarce. This phase 2 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and efficacy of dasatinib in this setting. METHODS: Patients with recurrent and/or metastatic HNSCC after platinum based therapy were treated with dasatinib either orally or via percutaneous feeding gastrostomy (PFG). Primary endpoints were 12-week progression-free survival (PFS) and objective response rate with a 2-stage design and early withdrawal if the 12-week PFS rate was <=20% and no patients had an objective response (OR). Forty-nine serum cytokines and angiogenic factors (CAFs) were analyzed from treated patients. RESULTS: Of the 15 patients enrolled, 12 were evaluable for response, and all patients were evaluable for toxicity. No OR was observed and 2 patients (16.7%) had stable disease (SD) at 8 weeks. The median treatment duration was 59 days, the median time to disease progression was 3.9 weeks, and the median survival was 26 weeks. One patient required a dose reduction, 3 patients required dose interruptions, and 4 patients were hospitalized for toxicity. Dasatinib inhibited c-Src both when administered orally and via PFG. Greater mean drug exposure, decreased half-life, and greater maximum concentration were observed in patients receiving dasatinib via PFG. Eleven baseline CAFs were associated with treatment outcome and 1 CAF, macrophage migration inhibitory factor, was found to be differentially modulated in correlation with SD versus disease progression. CONCLUSIONS: Single-agent dasatinib failed to demonstrate significant activity in patients with advanced HNSCC, despite c-Src inhibition. The toxicity profile was consistent with that reported in other solid tumors, and the drug can be given via PFG tube. PMID- 21523724 TI - Radiation-induced osteosarcomas of the calvarium and skull base. AB - BACKGROUND: Although a rare complication of ionizing radiation, radiation-induced osteosarcoma is now more frequently recognized as radiation therapy has become common and cancer survival has increased. To date, publications on radiation induced osteosarcoma of the cranium are limited to a few small series and case reports. METHODS: Data from 175 patients with a history of sarcoma of the head at The University of Texas M. D. Anderson Cancer Center from 1975 to 2007 were reviewed to identify patients with radiation-induced osteosarcoma. The diagnostic criteria were: 1) osteosarcoma arose within the previously irradiated field; 2) new sarcoma was histologically distinct from the original neoplasm; 3) no evidence of new sarcoma at the time of radiation; and 4) distinct latency period could be recognized. Frequencies and descriptive statistics were obtained for the various characteristics under study. RESULTS: The authors identified 16 patients with radiation-induced osteosarcoma of the cranium at their institution. The average age at diagnosis was 35 years. The median latency period was 12.5 years. Nine patients had skull base tumors, and 7 had calvarial tumors. Of the 14 patients treated surgically, 86% developed local recurrence. The median survival time was 29 months, and the 5-year survival rate was 29.6%. CONCLUSIONS: The authors report the largest series of cranial radiation-induced osteosarcoma. Although radiation-induced osteosarcoma is an uncommon but dire complication of radiotherapy, its incidence will probably increase in the future as the frequency of radiation treatment and cancer survival increase. These tumors are locally aggressive, and despite aggressive surgical and medical management, they have a high rate of local recurrence and mortality. PMID- 21523725 TI - Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. AB - BACKGROUND: In patients with chronic lymphocytic leukemia (CLL), treatment with lenalidomide induces a unique, previously uncharacterized, immune response called tumor flare reaction (TFR). The clinical significance of this reaction remains unknown. METHODS: Forty-five patients with CLL who were treated with lenalidomide in a phase 2 clinical trial were evaluated for the clinical features, intensity, and duration of TFR. Correlation was made with tumor response and the immune cellular microenvironment. Steroids for the prophylaxis of TFR was not given to patients in Group A (n = 29) whereas patients in Group B (n = 16) received low dose prednisone as well as a slow dose escalation of lenalidomide for the prevention of TFR. RESULTS: Thirty (67%) patients experienced a TFR, with a grade 2 or 3 reaction (according to National Cancer Institute Common Toxicity Criteria [version 3.0]) observed in 33% of patients (47% in Group A and 9% in Group B; P = .05). The median time to onset of the TFR was 6 days, and was longer in the patients receiving prophylaxis (4 days vs 9 days, respectively; P = .01). A complete response was observed in 7 of 30 (23%) patients with TFR and 1 of 15 (7%) patients without TFR. The median progression-free survival was 19.9 months and 19.4 months, respectively, for patients with versus those without TFR (P = .92). CONCLUSIONS: TFR is a unique immune-mediated phenomenon noted with lenalidomide treatment only in patients with CLL that correlates with clinical response. It can be effectively managed with anti-inflammatory agents. PMID- 21523726 TI - Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone. AB - BACKGROUND: In the era of novel agents such as lenalidomide and bortezomib, risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches in patients with multiple myeloma (MM). METHODS: The authors analyzed the prognostic value of deletion del(13q14), del(17p13), +1q21, translocation t(4;14), t(11;14), and t(14;16) by fluorescence in situ hybridization (FISH) in a series of 92 patients with recurrent MM who were treated with lenalidomide and dexamethasone (len/dex) at the study center. RESULTS: Patients carrying del(13q14) or t(14;16) were found to have a shorter median time to disease progression (TTP) of 5.1 months (vs 14.4 months; P = .009) and 2.0 months (vs 10.5 months; P <.001), respectively. However, no effect on TTP was observed in patients harboring del(13q14) as an exclusive chromosomal aberration without the concomitant presence of t(4;14) or del(17p13). The median overall survival (OS) for patients with del(17p13) or +1q21 was 6.7 months (P = .002) and 8.3 months (P < .001), respectively, whereas the median OS for patients carrying none of these abnormalities was not reached. Multivariate analysis revealed that the effects of del(17p13) and +1q21 on OS were independent of patient age as well as the type and number of regimens administered before len/dex. CONCLUSIONS: The results of the current study suggest that the prognostic significance of t(4;14) may be ameliorated or eliminated in patients treated with len/dex, whereas the presence of del(17p13) or +1q21 is still associated with a dismal OS. The presence of t(11;14) and del(13q14) as exclusive chromosomal aberrations indicates no impact on outcome. Because of its rarity in MM, a confirmation of the prognostic role of the t(14;16) aberration is still pending. PMID- 21523727 TI - Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia. AB - BACKGROUND: The impact of FMS-like tyrosine kinase 3 (FLT3) mutations and mutation burden among cytogenetic subgroups of patients with acute myeloid leukemia (AML) other than normal karyotype (NK) AML is unclear. METHODS: Patients with newly diagnosed AML were divided among 3 cytogenetic subgroups: core binding factor (CBF) AML, NK-AML, and poor-risk AML. RESULTS: In total, 481 patients were included: 13% had, CBF-AML, 57% had NK-AML, and 30% had poor risk AML, and the frequency of any FLT3 mutations was 20%, 32%, and 7.6% in the respective cytogenetic subgroups. FLT3 mutation did not have an impact on event-free survival (EFS) in patients with CBF-AML (P = .84) and poor-risk AML (P = .37). In patients with NK-AML, EFS was worse in the FLT3-internal tandem duplication (ITD) group (20 weeks vs 41 weeks; P < .00,001) but not in the FLT3-tyrosine kinase domain (TKD) point mutation group (61 weeks vs 41 weeks; P = .15). Worse EFS and overall survival (OS) were observed among patients with NK-AML and higher FLT3 ITD burden but not among patients with FLT3-TKD mutation. In multivariate analysis, FLT3-ITD mutation was prognostic of EFS in patients with NK-AML (hazard ratio, 3.1; P = .03). CONCLUSIONS: FLT3 mutations did not have a prognostic impact in patients with AML who had good-risk and poor-risk karyotypes. In patients with NK-AML, FLT3-ITD mutations led to worse survival, which was even worse among patients who had high mutation burden. PMID- 21523728 TI - Concomitant ABCG2 overexpression and FLT3-ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse. AB - BACKGROUND: ABCG2 protein overexpression and FLT3 internal tandem duplication (ITD) correlate with higher relapse rate and shorter disease-free survival (DFS) in acute myeloid leukemia (AML), but no data are available on the possible effect of concomitant presence of these 2 factors. METHODS: The authors analyzed the outcome of 166 cases of adult AML patients who were homogeneously treated with a fludarabine-based induction therapy. RESULTS: ABCG2 overexpression and FLT3-ITD were detected in 83 (50%) and 47 (28%) patients, respectively. A significant correlation was found between ABCG2 positivity and FLT3 mutation, with 33 (40%) ITD in 83 ABCG2-positive patients compared with 14 (17%) ITD in 83 ABCG2-negative patients (P = .002). Complete remission (CR) after induction therapy was achieved in 95 (57%) patients. Neither ABCG2 overexpression nor FLT3-ITD had any impact on achievement of CR. Relapse occurred in 42 of 95 (44%) patients at a median time of 28 months. Time to relapse was shortened in patients overexpressing ABCG2 (P = .0004). DFS was not affected by FLT3-ITD alone, but FLT3 mutation significantly worsened long-term outcome of ABCG2-positive patients. DFS at 1 and 3 years in patients with overexpression of both ABCG2 and FLT3-ITD was only 36% and 28%, respectively; in ABCG2-positive/FLT3-negative patients, DFS at 1 and 3 years was 65% and 48%, respectively; and in ABCG2-negative cases (regardless of FLT3 status), DFS at 1 and 3 years was greater than 85% and 75%. CONCLUSIONS: Concomitant overexpression of ABCG2 and FLT3-ITD is relatively frequent and identifies a subgroup of AML patients with a significantly worse prognosis. The possible interactions between these 2 prognostic factors need to be defined. PMID- 21523729 TI - Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia. AB - BACKGROUND: Early stage chronic lymphocytic leukemia is characterized by a highly variable course of disease. Because it is believed that regulatory T cells (T(regs) ) are potent suppressors of antitumor immunity, the authors hypothesized that increased T(regs) may favor disease progression. METHODS: T(reg) levels (cluster of differentiation 3 [CD3]-positive, [CD4]-positive, CD25-positive, and CD127-negative) in peripheral blood from 102 patients were analyzed by flow cytometry. Statistical analysis was used to evaluate correlations with clinical data. RESULTS: The relative T(reg) numbers in CD4-positive T cells were significantly greater in patients with chronic lymphocytic leukemia compared with the numbers in a control group of 170 healthy individuals (P = .001). Patients were divided into 2 groups using a median T(reg) value of 9.7% (the percentage of CD4-positive T cells). Patients with higher T(reg) levels had a significantly shorter time to initial treatment (median, 5.9 years) compared with patients who had lower T(reg) levels (median, 11.7 years; log-rank P = .019). Furthermore, T(reg) levels (the percentage of CD4-positive T cells) had significant prognostic power to predict the time to initial treatment in univariate analysis (P = .023) and in multivariate Cox regression analysis that included the variables Rai stage, immunoglobulin heavy-chain variable region gene mutational status, chromosomal aberrations, and CD38 expression (P = .028). CONCLUSIONS: Higher T(reg) levels had significant and independent prognostic power for predicting the time to initial treatment in patients with low to intermediate stage chronic lymphocytic leukemia. PMID- 21523730 TI - AJCC 7th edition of TNM staging accurately discriminates outcomes of patients with resectable intrahepatic cholangiocarcinoma: By the AFC-IHCC-2009 study group. AB - BACKGROUND: This year, the 7th edition of the AJCC staging manual has for the first time attributed a unique pTNM staging to intrahepatic cholangiocarcinoma (IHCC) that is intended to replace the 2 Western and ideally also the 2 Eastern systems currently in use. This proposal, which has not yet been validated, was tested in the current study. METHODS: Among 522 patients operated on with curative intent for an IHCC between 1994 and 2008 in tertiary hepatobiliary centers, those with mass-forming-type IHCCs, an R0 resection, and accurate pathological node staging were retained for evaluation. The distribution of these patients and their actuarial survival in the new TNM stages (as well as in the 4 previous ones) were compared. RESULTS: Only 163 patients fulfilled the inclusion criteria, mainly because of the lack of routine lymphadenectomy, but patients and tumors characteristics of this population were representative. These patients were evenly distributed between AJCC 7th edition stages (stage I, 28%; stage II, 32%; stage III, 35%), which was not the case for the other systems. With an average follow-up of 34 months in survivors, the AJCC 7th edition was more discriminating than the others in predicting survival (median for stage I not reached; for stage II, 53 months, P = .01; for stage III, 16 months, P < .0001). Survival of these patients according to the 2 Japanese classifications was identical to that anticipated. CONCLUSIONS: The 7th edition is clinically relevant and may be applicable worldwide, provided routine lymphadenectomy at the time of surgery for IHCC becomes the standard of care. PMID- 21523731 TI - A phase 2 study of irinotecan, cisplatin, and simvastatin for untreated extensive disease small cell lung cancer. AB - BACKGROUND: The objective of this study was to investigate the efficacy of simvastatin in combination with irinotecan and cisplatin in chemotherapy-naive patients with extensive-disease small-cell lung cancer (ED-SCLC). METHODS: In this phase 2 study, 61 patients received treatment with irinotecan (65 mg/m(2) ) and cisplatin (30 mg/m(2) ) on Days 1 and 8 every 3 weeks until either death or disease progression occurred. Patients also received oral simvastatin (40 mg daily) during the course of chemotherapy. The primary endpoint was 1-year survival. Secondary endpoints included the response rate (RR), progression-free survival (PFS), and toxicity. RESULTS: The 1-year survival rate was 39.3%. The median overall survival (OS) was 11 months, and the median PFS was 6.1 months. Overall, the RR was 75%. The most common grade 3/4 toxicity was neutropenia (67%). Efficacy of the treatment was associated significantly with smoking status. Compared with never-smokers, ever-smokers had a better RR (40% vs 78%; P = .01), a longer PFS (2.5 months vs 6.4 months; P = .018), and had a trend toward an improved OS (9.0 months vs 11.2 months; P = .095). The effect of smoking on survival was apparent when ever-smokers were subdivided according to pack-years (PY) of smoking. Ever-smokers who had smoked >65 PY had a significantly longer OS compared with ever-smokers who had smoked <=65 PY or never-smokers (20.6 months vs 10.6 months vs 9.0 months, respectively; log-rank P = 0.032). In multivariate analysis, PY >65 was predictive of longer survival (hazard ratio, 0.280; 95% confidence interval, 0.113-0.694). CONCLUSIONS: The current results indicated that simvastatin in combination with irinotecan and cisplatin did not improve the survival of patients with ED-SCLC. Although the subgroup analysis by smoking status was exploratory, the addition of simvastatin to irinotecan and cisplatin may improve the outcome of heavy smokers with ED-SCLC. PMID- 21523732 TI - Lysyl oxidase: a lung adenocarcinoma biomarker of invasion and survival. AB - BACKGROUND: Lung adenocarcinoma invasion and metastasis arises from autocrine and paracrine signaling events between tumor epithelial cells and the stromal microenvironment that is mediated in part by transforming growth factor-beta (TGF beta) signaling. The copper-dependent amine oxidase lysyl oxidase (LOX) plays a role in extracellular matrix structure and is up-regulated in invasive type II TGF-beta receptor-deficient cells. The authors hypothesized that LOX expression is associated with extent of invasion and survival in patients with lung adenocarcinoma. METHODS: LOX immunohistochemical staining was examined in 166 surgically resected lung adenocarcinomas and results were correlated with clinicopathological features and survival. RESULTS: High-intensity LOX staining was found to be associated with the linear extent of invasion (Spearman correlation coefficient = 0.2; P = .01). There was an association between high LOX staining and decreased 5-year survival observed within the entire cohort (log rank P < .001) and among the patients with stage I disease (n = 119; P < .001). Cox proportional hazards regression analysis confirmed that LOX was a significant prognostic indicator of increased risk of 5-year mortality for all patients (hazard ratio [HR], 2.55; 95% confidence interval [95% CI], 1.51-4.30 [P < .001]) and for patients with Stage I disease (HR, 3.51; 95% CI, 1.77-6.99 [P < .001]). LOX expression was found to be independently associated with risk of death after adjustment for relevant covariates (HR, 2.29; 95% CI, 1.33-3.94 [P = .003]). CONCLUSIONS: Higher expression of LOX is associated with invasion and is an independent predictor of poor prognosis in patients with early stage lung adenocarcinoma. PMID- 21523733 TI - Overall survival and PD-L1 expression in metastasized malignant melanoma. AB - BACKGROUND: Cancers are known to elude the immune system, for example, by MHC loss, FAS up-regulation, or increased secretion of TGF-beta. Recently, ligands of coinhibitory receptors like programmed cell death ligand-1 (PD-L1, B7-H1) have come to attention for their role in tumor immune escape. Various tumors have been tested for PD-L1 expression, and conflicting results were obtained regarding its correlative impact on patient survival. This study aimed to determine the prognostic relevance of PD-L1 expression for the survival of melanoma patients. METHODS: Paraffin-embedded nevi, primary melanoma, and in-transit, lymph node, and distant organ metastases from a set of 63 stages III-IV melanoma patients referred to the Netherlands Cancer Institute between 2000 and 2004 for a sentinel node procedure or systemic therapy were studied. A large effort was invested in validating specific PD-L1 staining. In addition to immunological factors such as T-cell infiltration (CD8, CD4, and regulatory T cells), TGF-beta and MHC-I expression were assessed. RESULTS: Longitudinal analysis revealed no relevant PD L1 expression on primary melanoma compared with metastatic disease. No significant correlations with prognosis were found regarding immunological factors, whereas known prognostic markers such as Breslow thickness and sex could be confirmed. Analyses of the overall survival of our patient cohort did not reveal a negative association with PD-L1 expression. CONCLUSIONS: Correlation of overall survival with PD-L1 expression by melanoma cells remains controversial, and future clinical studies should focus on antibody validation and time of analysis in respect to disease progression. PMID- 21523734 TI - A phase 2 trial of dasatinib in advanced melanoma. AB - BACKGROUND: Inhibiting src kinases (non-receptor tyrosine kinase signaling intermediates) reduces melanoma cell proliferation and invasion. Dasatinib inhibits c-kit, PDGFbetaR, and EPHA2 and src kinases c-src, c-Yes, Lck, and Fyn. A phase 2 trial of dasatinib in melanoma was conducted to assess response rate (RR), progression-free survival (PFS), and toxicity. METHODS: Adults with stage 3/4 chemotherapy-naive unresectable melanoma were eligible. Dasatinib was initially administered at 100 mg twice daily continuously to 17 patients. Due to toxicity, the starting dosage was decreased to 70 mg twice daily. Tumor assessments occurred every 8 weeks. RESULTS: Thirty-nine patients were enrolled, 36 of whom were evaluable for activity and toxicity. Five, 4, and 3 patients had acral-lentiginous, ocular, or mucosal primaries, respectively. Two patients had confirmed partial responses lasting 64 and 24 weeks (RR 5%). Three patients had minor responses lasting 136, 64, and 28 weeks, and 1 patient who was responding discontinued due to noncompliance. The median PFS was 8 weeks; the 6-month PFS rate was 13%. One patient with an exon-13 c-kit mutation had a partial response, whereas disease in another patient with an exon-11 c-kit mutation progressed. Common toxicities were fatigue, dyspnea, and pleural effusion. CONCLUSIONS: Daily dasatinib has minimal activity in unselected melanoma patients, excluding those with c-kit mutations. The study did not meet the prespecified endpoints of 30% response rate or 6-month PFS. Dasatinib was poorly tolerated overall, often requiring dose reduction or interruption. Because activity was observed in a small subset without c-kit mutations, identifying predictive biomarkers is important for future development of dasatinib in melanoma alone or in combination trials. PMID- 21523735 TI - Update on mammography trends: comparisons of rates in 2000, 2005, and 2008. AB - BACKGROUND: Mammography screening allows for the early detection of breast cancer, which helps reduce mortality from breast cancer, especially in women aged 50 to 69 years. For this report, the authors updated a previous analysis of trends in mammography using newly available data from the National Health Interview Survey (NHIS). METHODS: NHIS data from 2008 were used to update trends in rates of US women who had a mammogram within the 2 years before their interview, and 2 methods of calculating rates were compared. The authors focused particularly on the 2000, 2005, and 2008 mammography rates for women aged >= 40 years, 40 to 49 years, 50 to 64 years, and >= 65 years according to selected sociodemographic and healthcare access characteristics. RESULTS: For women aged 50 to 64 years and >= 65 years, the patterns were similar: Rates rose rapidly from 1987 to 2000, declined, or were stable and then declined, from 2000 to 2005, and increased from 2005 to 2008. Rates for women aged 40 to 49 years rose rapidly from 1987 to 1992 and were relatively stable through 2008. There were large increases in mammography rates among immigrants who had been in the United States for <10 years, non-Hispanic Asian women, and women aged >= 65 years who were without ambulatory care insurance. CONCLUSIONS: Overall, mammography rates did not continue to decline between 2005 and 2008. Even so, in 2008, the percentage of women aged >= 40 years who had a recent mammogram fell below the Healthy People 2010 objective of 70%, which was met in 2000. However, women aged 50 to 64 years exceeded the Healthy People objective in 2000, 2005, and 2008; and some groups with very low mammography rates currently are catching up. These are important public health achievements. PMID- 21523736 TI - Association of cyclophosphamide use with dental developmental defects and salivary gland dysfunction in recipients of childhood antineoplastic therapy. AB - BACKGROUND: The aim of this study was to examine the effect of antineoplastic therapy on dental development and saliva function in recipients of childhood antineoplastic therapy. METHODS: Patients attending the long-term follow-up clinic at Children's Hospital at Westmead, NSW, Australia, were included if they had received treatment prior to 16 years of age and were in remission for more than 5 years. A dental examination and saliva test were performed for each participant. Holtta's Defect Index (HDI) was used to assess tooth aplasia, microdontia, and root-crown ratio on an orthopantomogram (OPG). Multivariable adjusted regression analyses were used to estimate the association of patient characteristics and treatment modalities with dental outcomes. RESULTS: One hundred six participants (61% male) were recruited (response rate = 88%). The mean HDI score was 24.7 +/- 17.8. A cumulative dose of cyclophosphamide >7500 mg/m(2) increased the HDI score by 13.06 (P = .01). Recipients of cyclophosphamide also had significantly increased odds of exhibiting very low saliva flow (<0.7 mL/min) (odds ratio = 12.43; 95% confidence interval, 2.08 74.35; P = .006). CONCLUSIONS: Children and adolescents who received high doses of cyclophosphamide were at increased risk of dental disturbances. Cyclophosphamide recipients were also at greater risk of exhibiting very low saliva flow. This study applied the HDI to patients receiving all forms of antineoplastic treatment and highlights the dose-dependent relation between cumulative dose of cyclophosphamide and dental disturbances. PMID- 21523737 TI - Induction therapy and outcome in acute myeloid leukemia. PMID- 21523739 TI - Adolescents and young adults with cancer: towards better outcomes in Canada. Preamble. PMID- 21523740 TI - A review of Canadian health care and cancer care systems. AB - Canada is a westernized, market-economy nation with a publicly funded health care and cancer control system and has health indices reflective of a high-resource economy. Provision of health services is in accord with the Canada Health Act and is implemented through federal, provincial, and territorial relations wherein federal funding partly provides support for the provincial/territorial delivery of health services. Cancer services are provided within the acute health care system with dedicated entities existing in parallel in most provinces to provide services specific to the diagnosis, treatment, and support of cancer patients. Interprovincial and territorial collaboration to enhance and facilitate optimal cancer system performance is enabled through the Canadian Partnership Against Cancer (the Canadian national cancer control initiative). Adolescent and young adult (AYA) cancer patients use both the pediatric and adult cancer systems. There is recognition, however, that although AYA patients are numerically a small portion of all cancer patients, the negative personal, societal, and socioeconomic impacts of potential years of life lost are substantial and can be lessened through attention to awareness, education, redesign of care and care pathways, quality of life, developmental aspects related to adolescent-teen-adult transitions, continuity of care, and surveillance across pediatric and adult settings. Appropriate solutions need to be established within the framework of the Canadian Health Service by innovative rethinking and realignment of system capacity and performance to the special needs of AYA cancer patients. PMID- 21523741 TI - Adolescents, young adults, and cancer--the international challenge. AB - Cancer in adolescents and young adults is an important public health issue, because there are approximately 1 million new cases annually. The distribution of diseases in this age group varies geographically, contributing to differences in survival rates. Although an overall survival rate exceeding 80 % has been reported in optimal circumstances, emerging knowledge about distinctions in tumor biology and enhanced clinical accrual to clinical trials should lead to further gains. The challenges of cancer survivorship demand further attention with a particular focus on the quality of life of survivors and amelioration of the long term complications of treatment. Programs in cancer screening and prevention provide potential for considerable benefits in this age group. A renewed perspective on the adolescent and young adult cohort is required; and, in all of these opportunities for change, there are important roles to be played by advocacy groups internationally. PMID- 21523742 TI - The cancer is over, now what?: Understanding risk, changing outcomes. AB - About 26,000 adolescents and young adults ages 15 to 29 years are diagnosed with invasive cancer each year. Although >80% will survive beyond 5 years from their cancer diagnosis, many will develop serious morbidity or die prematurely secondary to health problems in part related to their cancer therapy. This article provides a brief overview of mortality, morbidity, and health status among long-term survivors of adolescent and young adult (AYA) cancer. Four examples were used to illustrate the potential of risk-reducing strategies: breast cancer after chest irradiation, coronary artery disease after chest irradiation, cardiovascular disease in testicular cancer survivors, and the multitude of health problems faced by survivors receiving an allogeneic hematopoietic stem cell transplant. A conceptual model for risk-based health care was presented and future directions of the delivery of care for AYA cancer survivors discussed. PMID- 21523743 TI - Treatment of cancer in adolescents and young adults: is affordability a concern? AB - Progress in the treatment of cancers in young people has resulted in an increasing success rate in curing the different forms of malignant diseases. The mission of the CPAC/C(17) Task Force on Adolescents and Young Adults (AYA) with cancer is to ensure prompt, equitable access to the best care; establish research priorities to optimize health outcomes and health-related quality of life; and mitigate current disparities of care through advances in treatment, education, and research. Although these goals are important, the mission statement seems to ignore an important factor: "affordability," or the ability to achieve these goals due to scarcity of resources. In this article, the role of economics in helping decision makers decide on resource allocation is discussed. Also described is the economic basis for the healthcare problem; the inability of the current methodology of cost-effectiveness to provide information that can help improve resource allocation in health; and how economics should be used to promote efficient use of healthcare resources. The author argued that "affordability" should be recognized in the mission statement. Recognizing "affordability" means recognizing the need to justify the transfer (or allocation) of additional resources to AYA cancer, which requires demonstration that the value of what is gained from the use of these resources in AYA cancer exceeds the value of what is forgone by using them elsewhere. This will also require making explicit the values or equity criteria to which society subscribes. PMID- 21523744 TI - Cancer genome variation in children, adolescents, and young adults. AB - This mini-review describes the rapid changes in genome technologies that are leading to comprehensive views of genetic alterations in cancer, and presents high-level thoughts on ways to accelerate translation into clinical medicine. Issues that are more relevant to children, adolescents, and young adult patients with cancer are highlighted. PMID- 21523745 TI - Targeted therapy in pediatric and adolescent oncology. AB - Cancers in children and adolescents are fortunately infrequent. Overall, cure rates are good, approximately 80%, although this varies by histology and stage. Targeted therapies aim to improve efficacy and decrease toxicity by more specifically affecting malignant cells or their supporting stroma. Cancers of early life are often of different histology than those seen in adults. Sometimes, the same pathway is affected, even if the histology is different. Toxicities may also be different, particularly in younger children. These factors render drug development in young people challenging. This article reviews some successes and challenges to that development, including brief discussions of imatinib, lestaurtinib, antiangiogenesis, and anti-GD2 therapies. PMID- 21523746 TI - Screening for cancer in children, adolescents, and young adults: questions--and more questions. AB - Cancer screening interventions offer the potential for both risk and benefit. Research related to screening and cancer in children or adolescents/young adults (AYA) can approach any of several questions. One question to be addressed is whether population-based screening tests can be developed that would reduce incidence or mortality from cancer in children or AYA without causing undue risk to the healthy population and with reasonable cost-effectiveness. This has not yet proven to be possible, and some of the relevant considerations are discussed in this article. The second question concerns the use of screening tests commonly applied to the general population and the special considerations when applied in the context of children/AYA with cancer or of adult survivors. Finally, a third general area of research concerns the inclusion of specialized screening in the follow-up of survivors of cancer in children and AYA to address the potential for recurrences, new primaries, and long-term sequelae of treatment. Although current guidelines for screening in follow-up are derived from a blend of evidence and expert clinical opinion, it is likely that future guidelines will evolve as a result of clinically intense research that takes into consideration the needs of this very unique group. PMID- 21523747 TI - Youth Excel: towards a pan-Canadian platform linking evidence and action for prevention. AB - Population-level intervention is required to prevent cancer and other chronic diseases. It also promotes health for those living with established risk factors and illness. In this article, the authors describe a vision and approach for continuously improving population-level programs and policies within and beyond the health sector. The vision and approach are anchored in contemporary thinking about what is required to link evidence and action in the field of population and public health. The authors believe that, as a cancer prevention and control community, organizations and practitioners must be able to use the best available evidence to inform action and continually generate evidence that improves prevention policies and programs on an ongoing basis. These imperatives require leaders in policy, practice, and research fields to work together to jointly plan, conduct, and act on relevant evidence. The Propel Center and colleagues are implementing this approach in Youth Excel-a pan-Canadian initiative that brings together national and provincial organizations from health and education sectors and capitalizes on a history of collaboration. The objective of Youth Excel is to build sustainable capacity for knowledge development and exchange that can guide and redirect prevention efforts in a rapidly evolving social environment. This goal is to contribute to creating health-promoting environments and to accelerate progress in preventing cancer and other diseases among youth and young adults and in the wider population. Although prevention is the aim, health-promoting environments also can support health gains for individuals of all ages and with established illness. In addition, the approach Youth Excel is taking to link evidence and action may be applicable to early intervention and treatment components of cancer control. PMID- 21523748 TI - Psychological, social, and behavioral issues for young adults with cancer. AB - Theories of human development suggest that, although all cancer patients experience a common set of life disruptions, they experience them differently, focus on different issues, and attach different levels of importance to different aspects of the experience depending on the time in life at which they were diagnosed. During the critical developmental transition from childhood to adulthood, older adolescents and young adults in particular have typical concerns with establishing identity, developing a positive body image and sexual identity, separating from parents, increasing involvement with peers and dating, and beginning to make decisions about careers or employment, higher education, and/or family. Accordingly, cancer-related issues such as premature confrontation with mortality, changes in physical appearance, increased dependence on parents, disruptions in social life and school/employment because of treatment, loss of reproductive capacity, and health-related concerns about the future may be particularly distressing for adolescents and young adults. Psychosocial and behavioral interventions for young adult cancer patients and survivors often involve assisting these individuals in retaining or returning to function in significant social roles, such as spouse, parent, student, worker, or friend. Successful interventions will enable these young people to overcome the detrimental impact of a health crisis and strengthen the internal and external coping resources available to them. PMID- 21523749 TI - Research challenges in adolescent and young adult cancer survivor research. AB - Every year in Canada and the United States, about 26,000 adolescent and young adults (AYA) between ages 15 and 29 years are diagnosed with cancer. Although the majority of AYA cancer patients will survive their primary cancer, many will develop serious health problems or die prematurely secondary to their curative cancer therapy. Much is known about the long-term health outcomes after adolescent cancer. In contrast, there remain substantial gaps in our understanding of the long-term outcomes after most young adult cancers. To optimize the health and quality of life of AYA cancer survivors and improve upon curative cancer therapy, it is essential to further investigate the long-term outcomes of this population. Before embarking upon this endeavor, it is important for the investigator and the funding agency to be cognizant about some of the unique challenges in research of AYA cancer survivors. To this end, the authors present a brief overview of some of the key research challenges, discuss the strengths and limitations of using available AYA cohorts and databases, and highlight potential future directions. PMID- 21523750 TI - Oncofertility and preservation of reproductive capacity in children and young adults. AB - With increasing numbers of survivors from cancer at a young age, the issue of fertility preservation has assumed greater importance. This review describes normal ovarian and testicular function and summarizes what is known about the effect of chemotherapy and radiotherapy on the gonads and uterus. All young patients with cancer or leukemia should have their fertility prognosis discussed before the initiation of treatment. Sperm and embryo cryopreservation should be considered standard practice and be widely available for those at significant risk of infertility. For prepubertal girls, ovarian tissue cryopreservation should be considered if the risk of premature menopause is high, but for the prepubertal boy there are no established techniques in current practice. PMID- 21523751 TI - Awareness and advocacy for adolescents and young adults with cancer. AB - Increasing the awareness of the clinical and psychosocial needs that are particular to adolescents and young adults (AYA) was a top priority, as was strengthening advocacy efforts to empower and support this group. To date, AYA advocates had some success in generating public awareness and building a solid clinical justification for increased focus on this population. It had been established that the economic burden of their mortality was significant, their cancers were unusual, their medical care was often inadequate, and their outcomes for many cancers had not improved in the past 3 decades. As the awareness and advocacy campaign continued to grow and evolve across the globe, it was an important goal to integrate the efforts of all stakeholders to ensure that it progressed with a single, consensual, focused message identifying a common priority for action. By coordinating the efforts of the scientific, medical, and advocacy communities, it was possible to amplify their separate efforts and activities and more efficiently achieve large-scale change in the world of AYA oncology. PMID- 21523752 TI - Active therapy and models of care for adolescents and young adults with cancer. AB - The reduction in the cancer mortality rate in adolescents and young adults (AYA) with cancer has lagged behind the reduction noted in children and older adults. Studies investigating reasons for this are limited but causes appear to be multifactorial. Host factors such as developmental stage, compliance, and tolerance to therapy; provider factors such as lack of awareness of cancer in AYA and referral patterns; differences in disease biology and treatment strategies; low accrual onto clinical trials; and lack of psychosocial support and education programs for AYA all likely play a role. Recommendations for change from a recent international workshop include education of physicians and patients concerning AYA cancer, improved cooperation between pediatric and adult centers, age appropriate psychosocial support services, programs to help AYA with issues relevant to them, dedicated AYA hospital space, improved accrual to clinical trials, the use of technology to educate patients and enhance communication between patients and the health care team, and ensuring that resident and fellowship training programs provide adequate education in AYA oncology. The longer term goal is to develop AYA oncology into a distinct subspecialist discipline within oncology. The ideal model of care would incorporate medical care, psychosocial support services, and a physical environment that are age appropriate. When this is not feasible, the development of "virtual units" connecting patients to the health care team or a combination of physical and virtual models are alternative options. The assessment of outcome measures is necessary to determine whether the interventions implemented result in improved survival and better quality of life, and are cost-effective. PMID- 21523754 TI - Providing developmentally appropriate psychosocial care to adolescent and young adult cancer survivors. AB - To deliver developmentally appropriate psychosocial care, the key developmental tasks facing adolescents and young adults (AYA) need to be taken into consideration. These include establishing autonomy from parents; a personal set of values and identity; strong peer relationships, including intimate and sexual relationships; and obtaining adequate preparation to join the workforce. To minimize the amount of disruption caused by the cancer experience and to maximize the health-related quality of life of AYA patients, young individuals with cancer need opportunities to participate as much as possible in typical AYA activities and to master the developmental tasks of this life stage. Promoting a sense of normalcy is essential. To achieve this, the health care environment must be flexible and recognize the important role of peers. Informational and practical supports also are necessary for AYA to stay on track developmentally in the context of coping with cancer. Critical elements of effective AYA psychosocial services should include access to AYA-specific information and support resources, fertility and sexuality counseling, programs to maximize academic and vocational functioning, and financial support. PMID- 21523753 TI - Palliative care in adolescents and young adults with cancer. AB - Adolescents and young adults (AYA) with advanced or terminal cancer have distinctive medical and psychosocial needs that may not have been adequately provided by either pediatric or adult palliative care services. A discussion group, as part of a larger workshop on AYA with cancer, was held in Toronto on March 11-13, 2010;117:-. Recommendations were as follows: Develop a specific AYA screening tool designed to detect increased anxiety or new symptoms and to initiate discussion about palliative or symptom care; Set Canadian standards for palliative care in AYA patients. These standards should be included in hospital accreditation; Involve the palliative/symptom care team early in the disease trajectory to help manage clinically important symptoms that may not be associated with imminent death; Establish specific AYA multidisciplinary palliative care teams throughout Canada that are flexible and can work in both pediatric and adult facilities, and are able to work in a "virtual" environment to support patients being cared for at home; Improve physical facilities in hospices and hospitals to meet the distinctive needs of terminally ill AYA patients; Enhance support for palliative care at home by: changing legislation to improve Compassionate Care Benefits and developing "virtual palliative care support teams". Adequate provision of AYA palliative care and symptom management services will likely confer notable benefits to AYA patients and their families, and is likely to be cost saving to the tax payer by avoiding prolonged hospitalization and promoting easier return to work for the families and caregivers. PMID- 21523755 TI - Critical issues in transition and survivorship for adolescents and young adults with cancers. AB - The majority of children, adolescents, and young adults diagnosed with cancer will become long-term survivors with many potential years of life ahead of them. Their journey from health through diagnosis and treatment to survivorship involves multiple transitions. Transitional services that should be available throughout this journey include health-related education, health surveillance and screening, management of cancer-related complications, and psychosocial support relevant to their developmental needs. Survivors require lifelong care that focuses not only on the medical risks arising from their cancer therapy, but also the psychosocial, educational, and vocational implications of surviving cancer. Because many community health care providers lack familiarity with the health risks associated with childhood or adolescent/young adult cancer, survivors must have sufficient health knowledge to advocate for risk-based cancer-related follow up; the provision of a treatment summary and care plan at the conclusion of their cancer therapy is an important tool for facilitating this process. The availability of resources for survivors varies by geography, health care system, and survivor characteristics. Adolescents and young adults who receive their care outside of a pediatric cancer center have particularly limited access. The limitations in cancer center resources (along with survivor preference) strongly suggest that the long-term care of survivors will need to be shared between the cancer centers and primary care providers in survivors' communities. PMID- 21523756 TI - Outcomes and metrics: measuring the impact of a comprehensive adolescent and young adult cancer program. AB - Against a background of poorly coordinated provision of holistic care to the adolescent and young adult (AYA) cancer population, the Canadian National Task Force on Adolescent and Young Adult Oncology, which is supported by the Canadian Partnership Against Cancer and the C17 network, convened a workshop to formulate the components of a systematic approach to care for this age group. Because such a program will deflect scarce resources, it must be validated and justified by reproducible metrics. A subgroup of experts was convened, comprising attendees at the AYA workshop, including AYA cancer survivors. A substantial number of key, feasible, and consistent metrics were identified and are systematized, justified, and presented in this article. Prioritization from within this range will be necessary. PMID- 21523757 TI - Opportunities and challenges of establishing a nationwide strategy for adolescents and young adults in Canada with cancer: impressions from the Toronto workshop. AB - Currently, there is priority to address the complex needs of the adolescent and young adult (AYA) cancer population. At a workshop in Toronto, the Canadian healthcare community brought together a broad range of stakeholders to discuss the opportunities and challenges of developing a nationwide strategy for AYA cancer patients. Summarized here is an overview of the workshop objectives and considerations coming from the conference participants relative to opportunities, challenges, and future directions. It is concluded that the Canadian healthcare and advocacy communities are well-positioned to have a major impact and assume a leadership role in AYA cancer care. PMID- 21523760 TI - CT-guided percutaneous microwave ablation of adrenal malignant carcinoma: preliminary results. AB - BACKGROUND: Microwave ablation has recently been developed as a safe and effective treatment for a variety of tumors. The authors evaluated the safety and efficacy of computed tomography (CT)-guided percutaneous microwave ablation of adrenal malignant tumors. METHODS: Nine patients between 41 and 83 years of age (average age, 54 years) with adrenal carcinoma (a total of 10 lesions) received CT-guided percutaneous water-cooled microwave ablation. The 9 cases included 1 primary adrenocortical carcinoma and 8 metastatic carcinomas (4 from lung cancer, 2 from hepatocellular carcinoma, 1 from intrahepatic cholangiocarcinoma, and 1 from left tibial osteosarcoma). Of the 8 metastatic cases, 7 were unilateral, and 1 was bilateral. All cases were pathologically confirmed by aspiration biopsy or postsurgical biopsy. The tumor diameters ranged from 2.1 cm to 6.1 cm (average, 3.8 cm). The average number of ablation sites was 1.5 sites (1-3 sites), and the average accumulated ablation time was 7.7 minutes (4-15 minutes). The procedures were performed using a cooled-shaft antenna. RESULTS: The patients were followed for 3-37 months, with an average of 11.3 months. Nine of 10 lesions were completely necrotized after first treatment. The other lesion was completely necrotized after 2 treatments. One of the patients experienced hypertensive crisis during treatment. No patient experienced recurrent tumor at the treated site, and this lack of recurrence indicated effective local control. All patients had progression of metastatic disease at extra-adrenal sites. CONCLUSIONS: CT guided percutaneous water-cooled microwave ablation is a minimally invasive and effective method for the treatment of adrenal carcinoma. PMID- 21523759 TI - Racial variation in willingness to trade financial resources for life-prolonging cancer treatment. AB - BACKGROUND: Minority patients receive more aggressive care at the end of life, but it is unclear whether this trend is consistent with their preferences. We compared the willingness to use personal financial resources to extend life among white, black, Hispanic, and Asian cancer patients. METHODS: Patients with newly diagnosed lung or colorectal cancer participating in the Cancer Care Outcomes Research and Surveillance observational study were interviewed about myriad aspects of their care, including their willingness to expend personal financial resources to prolong life. We evaluated the association of race/ethnicity with preference for life-extending treatment controlling for clinical, sociodemographic, and psychosocial factors using logistic regression. RESULTS: Among patients (N = 4214), 80% of blacks reported a willingness to spend all resources to extend life, versus 54% of whites, 69% of Hispanics, and 72% of Asians (P<.001). In multivariate analyses, blacks were more likely to opt for expending all financial resources to extend life than whites (odds ratio, 2.41; 95% confidence interval, 1.84-3.17; P < .001). CONCLUSIONS: Black cancer patients are more willing to exhaust personal financial resources to extend life. Delivering quality cancer care requires an understanding of how these preferences impact cancer care and outcomes. PMID- 21523761 TI - Patterns of extralaryngeal spread of laryngeal cancer: thyroid cartilage penetration occurs in a minority of patients with extralaryngeal spread of laryngeal squamous cell cancers. AB - BACKGROUND: Laryngeal preservation programs for patients with advanced laryngeal squamous cell carcinomas (SCC) have generally excluded patients with T4 disease. The accuracy of preoperative imaging in evaluating thyroid cartilage penetration and extralaryngeal spread (ELS) has previously been questioned. Clinically, SCC spread into noncartilaginous structures may have less of a functional impact when compared with thyroid cartilage penetration. The current study was designed to characterize and quantify the routes and frequency of ELS. METHODS: A total of 103 laryngectomy specimens with preoperative contrast-enhanced neck computed tomography scans were coded according to the observed extent of disease by pathological and radiological data. Previously irradiated tumors or those of pyriform sinus origin were omitted. Routes of spread were categorized as anterior (thyroid cartilage penetration), posterior (arytenoid cartilage destruction and thyroarytenoid space widening), inferior (conus elasticus penetration), and superior (base of tongue, thyrohyoid membrane or thyroid notch penetration involvement). RESULTS: Sixty-three cases of ELS were identified. Anterior spread by thyroid cartilage penetration occurred in 44% of all instances of ELS, followed by both inferior and posterior spread each representing 33% of ELS cases. Superior spread occurred with a frequency of 24%. CONCLUSIONS: Although thyroid cartilage penetration is a common route of ELS of glottic and supraglottic SCC, ELS into surrounding structures with thyroid cartilage penetration was found to occur in only 44% of the cases of ELS in the current study. As illustrated, advanced SCC spreads in a variety of pathways. Once these patterns are better understood and identified at the time of initial evaluation, subgroups of patients with ELS who may still be candidates for laryngeal preservation may be identified. PMID- 21523763 TI - Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) tumor cells produce copious amounts of myeloid cell-stimulating factors. The current study examined the prognostic significance of circulating monocytes and tumor-infiltrating macrophages on overall survival in patients with MPM. METHODS: The authors retrospectively reviewed 667 patients with MPM who underwent cytoreductive surgery at the Brigham and Women's Hospital in Boston, Massachusetts between 1989 and 2009. Kaplan-Meier and Cox proportional hazards models were used to determine the impact of preoperative circulating monocytes on overall survival. Immunohistochemical staining for CD68 was performed on a tissue microarray of MPM tumors from 52 patients undergoing cytoreductive surgery. The phenotype of circulating monocytes and tumor-infiltrating macrophages in 7 additional patients was determined by flow cytometry. RESULTS: The median survival for all patients was 13.4 months, and 35% of patients had tumors of nonepithelial histology. For patients with nonepithelial compared with epithelial tumors, survival was significantly worse (9.3 months vs 16.6 months; P < .0001), the number of monocytes was significantly higher (580 +/- 20 cells/MUL vs 520 +/- 10 cells/MUL; P = .002), and higher monocyte counts were associated with higher tumor stage. Increasing monocyte counts were correlated with poor survival for all patients with MPM. Within MPM tumors, macrophages comprised 27% +/- 9% of the tumor area and demonstrated an immunosuppressive phenotype with high expression of CD163, CD206, and interleukin-4 receptor alpha. The degree of macrophage infiltration was found to be negatively correlated with survival in patients with nonepithelial (P = .008) but not those with epithelial (P = .7) MPM, independent of disease stage. CONCLUSIONS: Higher numbers of circulating monocytes are associated with poor survival in all patients with MPM and higher densities of tumor-infiltrating macrophages are associated with poor survival in patients with nonepithelial MPM. Both may enable a novel target for immunotherapy. PMID- 21523762 TI - Colonoscopy screening rates among patients of colonoscopy-trained African American primary care physicians. AB - BACKGROUND: When performed competently, colonoscopy screening can reduce colorectal cancer rates, especially in high-risk groups such as African Americans. Training primary care physicians (PCPs) to perform colonoscopy may improve screening rates among underserved high-risk populations. METHODS: The authors compared colonoscopy screening rates and computed adjusted odds ratios for colonoscopy-eligible patients of trained African American PCPs (study group) versus untrained PCPs (comparison group), before and after initiating colonoscopy training. All colonoscopies were performed at a licensed ambulatory surgery center with specialist standby support. Retrospective chart review was conducted on 200 consecutive, established outpatients aged >=50 years at each of 12 PCP offices (7 trained African American PCPs and 5 untrained PCPs, practicing in the same geographic region). There were a total of 1244 study group and 923 comparison group patients. RESULTS: Post-training colonoscopy rates in both groups were higher than pretraining rates: 48.3% versus 9.3% in the study group, 29.6% versus 9.8% in the comparison group (both P < .001). African American patients in the study group showed a >5-fold increase (8.9% pretraining vs 52.8% post-training), with no change among whites (18.2% vs 25.0%). Corresponding pretraining and post-training rates among comparison patients were 10.4%% and 38.7%, respectively, among African Americans (P < .001), and 13.3% versus 13.2%, respectively, among whites. After adjusting for demographics, duration since becoming the PCP's patient, and health insurance, the study group had a 66% higher likelihood of colonoscopy in the post-training period (odds ratio, 1.66; 95% confidence interval, 1.30-2.13), and African Americans had a 5-fold increased likelihood of colonoscopy relative to whites. CONCLUSIONS: Colonoscopy-trained PCPs may help reduce colorectal cancer disparities. PMID- 21523764 TI - Retinoic acid induces REST degradation and neuronal differentiation by modulating the expression of SCF(beta-TRCP) in neuroblastoma cells. AB - BACKGROUND: The repressor element-1 silencing transcription factor (REST) is a repressor of neuronal genes. Its expression is associated with poor neuronal differentiation in many neuroblastoma patient samples and cell lines. Because retinoic acid promotes neuronal differentiation, the authors postulated that it involves modulation of REST expression. METHODS: The expression of REST and of an S-phase kinase-associated protein 1/cullin 1/F-box (SCF) protein complex that contains the F-box protein beta-transducin repeat-containing protein (beta-TRCP) (SCF(beta-TRCP) ) in neuroblastoma tumor samples and cell lines was analyzed by immunofluorescence and Western blot analysis. SK-N-SH and SK-N-AS cells were treated with retinoic acid and MG-132 to measure proteasomal degradation of REST by Western blot and quantitative real-time polymerase chain reaction analyses. Immunoprecipitation and coimmunoprecipitation assays were done in SK-N-AS cells that were transfected either with a control plasmid or with an enhanced green fluorescent protein-SCF(beta-TRCP) -expressing plasmid. RESULTS: Several neuroblastoma patient samples and cell lines displayed elevated REST expression. Although, REST transcription increased upon retinoic acid treatment in SK-N-SH and SK-N-AS cells, REST protein levels declined, concomitant with the induction of neuronal differentiation, in SK-N-SH cells but not in SK-N-AS cells. MG-132 treatment countered the retinoic acid-mediated decline in REST protein. SCF(beta TRCP) , a known REST-specific E3-ligase, was poorly expressed in many neuroblastoma samples, and its expression increased upon retinoic acid treatment in SK-N-SH cells but declined in SK-N-AS cells. Ectopic expression of SCF(beta TRCP) in SK-N-AS cells promoted REST ubiquitination and degradation and neuronal differentiation. CONCLUSIONS: The current results indicated that elevated transcription of REST compounded by its impaired degradation by SCF(beta-TRCP) may contribute to the failure of these tumors to differentiate in response to retinoic acid. PMID- 21523766 TI - Do multidisciplinary team meetings make a difference in the management of lung cancer? AB - BACKGROUND: There is limited evidence regarding the effectiveness of multidisciplinary team (MDT) meetings in lung cancer. The objective of this study was to compare the patterns of care for patients with newly diagnosed lung cancer who were presented at a lung cancer MDT meeting with the patterns of care for patients who were not presented. METHODS: All patients who had lung cancer newly diagnosed in South West Sydney (SWS) between December 1, 2005, and December 31, 2008, were identified from the local Clinical Cancer Registry. Patient and tumor characteristics and treatment receipt were compared between patients who were and were not presented at MDT meetings. A logistic regression model was constructed to determine predictors for receiving treatment and survival. RESULTS: In total, there were 988 patients, including 504 patients who were presented at MDT meetings and 484 who were not presented at MDT meetings. The median patient age was 69 years and 73 years in the MDT group and the non-MDT group, respectively (P < .01). There was no pathologic diagnosis for 13% of non-MDT patients compared with 4% of MDT patients (P < .01). Treatment receipt for MDT patients versus non MDT patients was 12% versus 13%, respectively, for surgery (P value nonsignificant); 66% versus 33%, respectively, for radiotherapy (P < .001); 46% versus 29%, respectively, for chemotherapy (P < .001); and 66% versus 53%, respectively, for palliative care (P < .001). In patients with good performance status, the MDT group had significantly better receipt of radiotherapy among patients with stage I through IV nonsmall cell lung cancer (NSCLC) and had significantly better receipt of chemotherapy among patients with stage IV NSCLC. MDT discussion was an independent predictor of receiving radiotherapy, chemotherapy, and referral to palliative care but did not influence survival. CONCLUSIONS: MDT discussion was associated with better treatment receipt, which potentially may improve quality of life for patients with lung cancer. However, it did not improve survival. PMID- 21523765 TI - Prognostic impact of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia treated with nilotinib or dasatinib. AB - BACKGROUND: Deletions of derivative chromosome 9 are a poor prognostic factor in patients with chronic myeloid leukemia (CML) treated with hydroxyurea, interferon, or stem cell transplantation. Imatinib may overcome the adverse prognostic impact of deletions of derivative chromosome 9. METHODS: A study was undertaken to investigate the prognostic impact of deletions of derivative chromosome 9 in 353 patients with CML receiving the second generation tyrosine kinase inhibitors (TKIs) nilotinib (n = 161) or dasatinib (n = 192). RESULTS: Deletion of derivative chromosome 9 status was determined in 245 (69%). Twenty eight (11%) patients, 22 in chronic phase, 4 in accelerated phase, and 2 in blast phase, carried deletions of derivative chromosome 9, including 17 receiving nilotinib and 11 receiving dasatinib (P = .47). Overall survival (OS) at 24 months was similar between patients with or without deletions of derivative chromosome 9 (70% vs 71%, P = .76). For patients in chronic phase, no significant differences in overall major cytogenetic response (77% vs 82%, P = .57) or complete cytogenetic response (77% vs 81%, P = .71) rates were observed between patients with or without deletions of derivative chromosome 9. At 24 months, patients with CML in chronic phase without deletions of derivative chromosome 9 had improved event-free survival (EFS) (88% vs 66%, P = .07) and OS (96% vs 82%; P = .08) compared with those carrying deletions of derivative chromosome 9. However, multivariate analysis established second-line versus frontline second generation TKI therapy as the only adverse prognostic factor for EFS and increased bone marrow blast burden and older age as independent adverse prognostic factors for OS. CONCLUSIONS: Deletions of derivative chromosome 9 do not appear to be an independent risk factor for survival among patients with CML in chronic phase receiving second generation TKIs. PMID- 21523767 TI - Expression and function role of DNA methyltransferase 1 in human bladder cancer. AB - BACKGROUND: The identification of potential tumor markers will help improve therapeutic planning and patient management. Therefore, the aim of this study was to highlight the role of DNA methyltransferase 1 (DNMT1) in bladder cancer. METHODS: A total of 50 samples of nonmalignant urothelium, 65 of muscle-invasive bladder cancers, 15 of distant metastasis, and 50 of nonmuscle-invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments investigating changes in tumor behavior, treatment response, and related signaling in bladder cancer. RESULTS: The incidence of nuclear DNMT1 immunoreactivity in the bladder cancer specimens (45%) was significantly higher than in nonmalignant urothelium (15%, P = .0005), and the incidence in cancer was positively linked to clinical stage (24% in <=T1 vs 55% in T2-T4, P = .0007). The staining of DNMT1 was also significantly linked to lower complete response rates (P = .0014) and reduced survival rates (P = .000). By in vitro and in vivo experiments, DNMT1 silencing vector reduced tumor growth and attenuated treatment resistance in bladder cancer cells. Less epithelial-mesenchymal transition, less invasion, and slower tumor growth were noted in cancer cells with inhibited DNMT1. Furthermore, the epidermal growth factor receptor-mediated phosphatidylinositol 3'-kinase-protein kinase B pathway might be the mechanism underlying the effects of DNMT1 on bladder cancer. CONCLUSIONS: DNMT1 could be a significant clinical predictor for stage and treatment response of bladder cancer. Moreover, targeting this enzyme could be a promising strategy for treating bladder cancer, as evidenced by inhibited tumor growth and enhanced radiosensitivity. PMID- 21523768 TI - Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. AB - BACKGROUND: It has been reported that antidiabetic drugs affect the risk of cancer and the prognosis of patients with diabetes, but few studies have demonstrated the influence of different antidiabetic agents on outcomes after anticancer therapy among patients with cancer. The objective of this study was to evaluate the influence of the antidiabetic drugs metformin and insulin on the prognosis of patients with advanced nonsmall cell lung cancer (NSCLC) plus type 2 diabetes who received first-line chemotherapy. METHODS: Data on patients with NSCLC who had diabetes from 5 hospitals in China during January 2004 to March 2009 were reviewed retrospectively. Ninety-nine patients were included in the final analysis. The influence of metformin and insulin on chemotherapy response rates and survival in these patients was evaluated. RESULTS: Chemotherapy with metformin (Group A) produced superior results compared with insulin (Group B) and compared with drugs other than metformin and insulin (Group C) in terms of both progression-free survival (PFS) (8.4 months vs 4.7 months vs 6.4 months, respectively; P = .002) and overall survival (OS) (20.0 months vs 13.1 months vs 13.0 months, respectively; P = .007). Although no significant differences in the response rate (RR) were observed between these 3 groups, when groups B and C (ie, the nonmetformin group) were combined, there was a tendency for better disease control in Group A than that in nonmetformin group. No significant difference in survival was observed between chemotherapy with insulin (Group B) versus other drugs (Group C). CONCLUSIONS: The current data suggested that metformin may improve chemotherapy outcomes and survival for patients who have NSCLC with diabetes. PMID- 21523769 TI - A functional polymorphism (-1607 1G->2G) in the matrix metalloproteinase-1 promoter is associated with development and progression of lung cancer. AB - BACKGROUND: Matrix metalloproteinase-1 (MMP-1), an interstitial collagenase, plays an important role in the breakdown of extracellular matrix and mediates pathways of apoptosis, angiogenesis, and immunity. It has been demonstrated that the overexpression of this enzyme is associated with tumor initiation, invasion, and metastasis. The -1607 single guanine (1G)-to-2G polymorphism (reference single nucleotide polymorphism 1799750) in the MMP-1 promoter region creates an E26 (Ets) binding site and results in transcriptional up-regulation. The authors hypothesized that this MMP-1 polymorphism may affect susceptibility to the development and progression of cancer. METHODS: The authors investigated their hypothesis in a lung cancer case-control study. Genotypes were analyzed in 825 patients with lung cancer and in 825 controls. Odds ratios were estimated by multivariate logistic regression, and a meta-analysis also was conducted to verify the findings. RESULTS: Patients who had the MMP-1 2G/2G genotype had a 1.71-fold increased risk of lung cancer (95% confidence interval, 1.22-fold to 2.41-fold increased risk) compared with patients who had the 1G/1G genotype. Moreover, when patients with stage I disease were considered as a reference group, patients who carried the 2G/2G genotype had a significantly increased risk of invasive disease (stage III-IV: odds ratio, 2.02; 95% confidence interval, 1.09-3.74) compared with patients who had the 1G/1G genotype. Pooled results from the meta-analysis confirmed that those who had the 2G/2G genotype had a significantly increased risk of lung cancer compared with those who had the 1G/1G genotype, consistent with the case-control findings. CONCLUSIONS: The current study demonstrated that the MMP-1 -1607 1G-to-2G polymorphism is associated with susceptibility to both development and progression of lung cancer. PMID- 21523770 TI - Increased genetic susceptibility to intestinal-type gastric cancer is associated with increased activity of the RUNX3 distal promoter. AB - BACKGROUND: The runt-related transcription factor RUNX3 plays essential roles in various types of tumors, including gastric cancer. Epigenetic changes in the methylation of the RUNX3 proximal promoter, but not common genetic changes in RUNX3, have been associated with both changes in the gene expression and development of the cancer. METHODS: A case-control association study was conducted by genotyping 865 unrelated Korean subjects. Subsequent functional studies were performed to reveal functional implication of genetic association. RESULTS: Several single-nucleotide polymorphisms (SNPs) in RUNX3 were significantly associated with susceptibility to intestinal-type gastric cancer (.0028 <= P <= .022) but not diffuse-type gastric cancer (.70 <= P <= .96). The risk-associated, minor variant of an intestinal-type gastric cancer-associated SNP in the RUNX3 distal promoter (rs7528484) significantly increased promoter activity in a CREB1-dependent manner. The distal promoter-derived, 33 kDa isoform of RUNX3 increased the activity of transcription factor nuclear factor kappa B (NF-kappaB), which had been activated by Helicobacter pylori infection, a risk factor for intestinal-type gastric cancer, and the expression of the interleukin 1beta gene (IL1B), an NF-kappaB target genetically and functionally associated with gastric cancer. In contrast, the proximal promoter-derived, 44 kDa isoform of RUNX3 decreased both NF-kappaB activity and IL1B expression. CONCLUSIONS: In addition to epigenetic changes in the RUNX3 proximal promoter, genetic changes in the distal promoter may be associated with susceptibility to intestinal-type gastric cancer by increasing promoter activity. Functionally, 2 RUNX3 isoforms may contribute differentially to intestinal-type gastric cancer susceptibility, at least in part through regulating NF-kappaB activity and IL1B expression. PMID- 21523771 TI - Failure patterns and clinical implications in early stage nasal natural killer/T cell lymphoma treated with primary radiotherapy. AB - BACKGROUND: This study aimed to evaluate the failure patterns and clinical implications in patients with early stage nasal natural killer (NK)/T-cell lymphoma treated with primary radiotherapy. METHODS: Two-hundred fourteen patients were included. There were 182 cases of stage I and 32 cases of stage II disease. Patients received radiotherapy alone (n = 96) or radiotherapy and chemotherapy (n = 118). The median dose was 50 grays, and most patients received doxorubicin-based chemotherapy. RESULTS: The 5-year overall survival (OS) and progression-free survival rates for all patients were 72% and 65%, respectively. Sixty-three patients experienced treatment failure. The 5-year cumulative incidences of locoregional, systemic, and overall failures were 12.0%, 25.5%, and 32.9%, respectively. Stage and paranasal extension were significant predictors for systemic failure. The 5-year cumulative incidence of systemic failure was 22.6% for stage I disease versus 42.7% for stage II disease (P < .001), and 16.9% for limited disease versus 30.4% for paranasal extension (P < .001), respectively. Adding chemotherapy to extended involved-field radiotherapy did not significantly decrease the systemic failure rate nor improve survival. The cumulative incidence of systemic failure and OS rate at 5 years were 24.1% and 74.4% for combined modality therapy compared with 28.5% (P = 0.758) and 69.8% (P = 0.529) for radiotherapy alone. A very low incidence of cervical lymph node or central nervous system relapse was observed. CONCLUSIONS: Patients with early stage nasal NK/T-cell lymphoma have excellent locoregional control and favorable prognosis with radiotherapy, but patients with stage II disease or paranasal extension are at high risk of systemic failure, emphasizing the importance of integration of optimal radiotherapy with innovative systemic therapy. PMID- 21523772 TI - Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer. AB - BACKGROUND: Prostacyclin synthase (PGIS) metabolizes prostaglandin H(2), into prostacyclin. This study aimed to determine the expression profile of PGIS in nonsmall cell lung cancer (NSCLC) and examine potential mechanisms involved in PGIS regulation. METHODS: PGIS expression was examined in human NSCLC and matched controls by reverse transcriptase polymerase chain reaction (RT-PCR), Western analysis, and immunohistochemistry. A 204-patient NSCLC tissue microarray was stained for PGIS and cyclooxygenase 2 (COX2) expression. Staining intensity was correlated with clinical parameters. Epigenetic mechanisms underpinning PGIS promoter expression were examined using RT-PCR, methylation-specific PCR, and chromatin immunoprecipitation analysis. RESULTS: PGIS expression was reduced/absent in human NSCLC protein samples (P < .0001), but not mRNA relative to matched controls. PGIS tissue expression was higher in squamous cell carcinoma (P = .004) and in male patients (P < .05). No significant correlation of PGIS or COX2 expression with overall patient survival was observed, although COX2 was prognostic for short-term (2-year) survival (P < .001). PGIS mRNA expression was regulated by DNA CpG methylation and histone acetylation in NSCLC cell lines, with chromatin remodeling taking place directly at the PGIS gene. PGIS mRNA expression was increased by both demethylation agents and histone deacetylase inhibitors. Protein levels were unaffected by demethylation agents, whereas PGIS protein stability was negatively affected by histone deacetylase inhibitors. CONCLUSIONS: PGIS protein expression is reduced in NSCLC, and does not correlate with overall patient survival. PGIS expression is regulated through epigenetic mechanisms. Differences in expression patterns between mRNA and protein levels suggest that PGIS expression and protein stability are regulated post translationally. PGIS protein stability may have an important therapeutic role in NSCLC. PMID- 21523776 TI - Medical societies unite to support research in Europe. PMID- 21523778 TI - Professor Jurg Tschopp (1951-2011). PMID- 21523780 TI - A clinical perspective of IL-1beta as the gatekeeper of inflammation. AB - An expanding spectrum of acute and chronic non-infectious inflammatory diseases is uniquely responsive to IL-1beta neutralization. IL-1beta-mediated diseases are often called "auto-inflammatory" and the dominant finding is the release of the active form of IL-1beta driven by endogenous molecules acting on the monocyte/macrophage. IL-1beta activity is tightly controlled and requires the conversion of the primary transcript, the inactive IL-1beta precursor, to the active cytokine by limited proteolysis. Limited proteolysis can take place extracellularly by serine proteases, released in particular by infiltrating neutrophils or intracellularly by the cysteine protease caspase-1. Therefore, blocking IL-1beta resolves inflammation regardless of how the cytokine is released from the cell or how the precursor is cleaved. Endogenous stimulants such as oxidized fatty acids and lipoproteins, high glucose concentrations, uric acid crystals, activated complement, contents of necrotic cells, and cytokines, particularly IL-1 itself, induce the synthesis of the inactive IL-1beta precursor, which awaits processing to the active form. Although bursts of IL 1beta precipitate acute attacks of systemic or local inflammation, IL-1beta also contributes to several chronic diseases. For example, ischemic injury, such as myocardial infarction or stroke, causes acute and extensive damage, and slowly progressive inflammatory processes take place in atherosclerosis, type 2 diabetes, osteoarthritis and smoldering myeloma. Evidence for the involvement of IL-1beta and the clinical results of reducing IL-1beta activity in this broad spectrum of inflammatory diseases are the focus of this review. PMID- 21523782 TI - PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 1: goals, properties of the PhRMA dataset, and comparison with literature datasets. AB - This study is part of the Pharmaceutical Research and Manufacturers of America (PhRMA) initiative on predictive models of efficacy, safety, and compound properties. The overall goal of this part was to assess the predictability of human pharmacokinetics (PK) from preclinical data and to provide comparisons of available prediction methods from the literature, as appropriate, using a representative blinded dataset of drug candidates. The key objectives were to (i) appropriately assemble and blind a diverse dataset of in vitro, preclinical in vivo, and clinical data for multiple drug candidates, (ii) evaluate the dataset with empirical and physiological methodologies from the literature used to predict human PK properties and plasma concentration-time profiles, (iii) compare the predicted properties with the observed clinical data to assess the prediction accuracy using routine statistical techniques and to evaluate prediction method(s) based on the degree of accuracy of each prediction method, and (iv) compile and summarize results for publication. Another objective was to provide a mechanistic understanding as to why one methodology provided better predictions than another, after analyzing the poor predictions. A total of 108 clinical lead compounds were collected from 12 PhRMA member companies. This dataset contains intravenous (n = 19) and oral pharmacokinetic data (n = 107) in humans as well as the corresponding preclinical in vitro, in vivo, and physicochemical data. All data were blinded to protect the anonymity of both the data and the company submitting the data. This manuscript, which is the first of a series of manuscripts, summarizes the PhRMA initiative and the 108 compound dataset. More details on the predictability of each method are reported in companion manuscripts. PMID- 21523781 TI - Cytoarchitecture and ultrastructure of neural stem cell niches and neurogenic complexes maintaining adult neurogenesis in the olfactory midbrain of spiny lobsters, Panulirus argus. AB - New interneurons are continuously generated in small proliferation zones within neuronal somata clusters in the olfactory deutocerebrum of adult decapod crustaceans. Each proliferation zone is connected to a clump of cells containing one neural stem cell (i.e., adult neuroblast), thus forming a "neurogenic complex." Here we provide a detailed analysis of the cytoarchitecture of neurogenic complexes in adult spiny lobsters, Panulirus argus, based on transmission electron microscopy and labeling with cell-type-selective markers. The clump of cells is composed of unique bipolar clump-forming cells that collectively completely envelop the adult neuroblast and are themselves ensheathed by a layer of processes of multipolar cell body glia. An arteriole is attached to the clump of cells, but dye perfusion experiments show that hemolymph has no access to the interior of the clump of cells. Thus, the clump of cells fulfills morphological criteria of a protective stem cell niche, with clump forming cells constituting the adult neuroblast's microenvironment together with the cell body glia processes separating it from other tissue components. Bromodeoxyuridine pulse-chase experiments with short survival times suggest that adult neuroblasts are not quiescent but rather cycle actively during daytime. We propose a cell lineage model in which an asymmetrically dividing adult neuroblast repopulates the pool of neuronal progenitor cells in the associated proliferation zone. In conclusion, as in mammalian brains, adult neurogenesis in crustacean brains is fueled by neural stem cells that are maintained by stem cell niches that preserve elements of the embryonic microenvironment and contain glial and vascular elements. PMID- 21523784 TI - Diclofenac salts, part 6: release from lipid microspheres. AB - The release of diclofenac (20%, w/w) was studied from lipidic solid dispersions using three different chemical forms (acid, sodium salt, and pyrrolidine ethanol salt) and two different lipid carriers (Compritol 888 ATO or Carnauba wax) either free or together with varying amounts (10%-30%, w/w) of stearic acid. Microspheres were prepared by ultrasound-assisted atomization of the molten dispersions and analyzed by scanning electron microscopy, differential scanning calorimetry, and hot stage microscopy. The effects of different formulations on the resulting drug release profiles as a function of pH were studied and the results were discussed. The formulation of the 18 systems and the chemical form of the drug were found to strongly affect the mode of the drug release. The solubility of the chemical forms in the lipid mixture is in the following order: pyrrolidine ethanol salt ? acid > sodium salt (according to the solubility parameters), and the nature of the systems thus obtained ranges from a matrix, for mutually soluble drug/carrier pairs, to a microcapsule, for pairs wherein mutual solubility is poor. Drug release from microspheres prepared by pure lipids was primarily controlled by diffusion, whereas the release from microspheres containing stearic acid was diffusion/erosion controlled at pH 7.4. PMID- 21523783 TI - Evaluation of pharmacokinetic, biodistribution, pharmacodynamic, and toxicity profile of free juglone and its sterically stabilized liposomes. AB - The present study was aimed to formulate and compare the pharmacokinetic, biodistribution, pharmacodynamic, and toxicity profiles of free 5-hydroxy-1,4 naphthoquinone (juglone) with sterically stabilized liposomal form. The liposomes were optimized for size, zeta potential, entrapment efficiency (EE), and in vitro release properties. The optimized formulation had a mean size, zeta potential, and EE value of 137.1 nm, -43.1 mV, and 67.2%, respectively. In vitro release studies showed biphasic pattern with initial burst followed by sustained release over the study period, releasing about 61% after 24 h. In vitro cytotoxicity studies against melanoma cells indicated that liposomal juglone was more toxic than free juglone. Free juglone had short plasma half-life of about 2 h, whereas liposomal juglone exhibited significantly improved pharmacokinetics with a 12 fold increase in plasma half-life. Further, biodistribution studies indicated rapid renal elimination of free juglone, evidenced by its significant localization in kidneys. Conversely, the accumulation of liposomal juglone in kidneys reduced significantly with enhanced tumor localization, thereby resulting in enhanced antitumor activity. The histological studies revealed lower levels of nephrotoxicity for liposomal juglone compared with that of free juglone. To conclude, sterically stabilized liposomes could be a promising approach for the intravenous delivery of hydrophobic compounds such as juglone. PMID- 21523785 TI - DNA hydrodynamic degradation controlled by Kolomogorov length scales in pipe flow. AB - Strict US Food and Drug Administration regulations on contamination levels for DNA therapeutics acceptable for human use complicate the manufacturing process. This study aims to improve therapeutic production through the investigation of the molecular effects of hydrodynamic forces encountered during processing. Results suggest that the strain rate and residence time were not solely responsible for degradation within the system. Instead, turbulent flows at the entrance or developing flow regions dominate especially when the Kolmogorov length scale approaches the stretched molecular length scale. We specifically suggest this for linear genomic DNA and supercoiled plasmid DNA when the ratio of the molecular length to the Kolmogorov length scale must remain smaller than unity to minimize loss of the desired structure. These findings suggest that bioprocessing systems should design expansions and contractions to minimize recirculation and turbulent mixing zones, although, not always possible, careful attention should be paid to pipe surface roughness to ensure that turbulent eddies are not generated in low Reynolds number flows. PMID- 21523786 TI - Interindividual differences in placental expression of the SLC22A2 (OCT2) gene: relationship to epigenetic variations in the 5'-upstream regulatory region. AB - Organic cation transporters (OCTs) mediate the transport of organic cations and some drugs (e.g., metformin and cimetidine). OCT1, OCT2, and OCT3 are located in the imprinting cluster of the insulin-like growth factor 2 receptor. It has been reported that OCT1 and OCT3 show a biallelic expression, whereas OCT2 undergoes maternal imprinting in the human placenta; however, a loss of the imprinting of OCT2 has recently been reported in some placental samples. This study investigated whether epigenetic mechanisms are involved in interindividual differences in the placental expression of OCT2. Because OCT2 mRNA levels were higher in biallelic samples than that in monoallelic samples, we compared the DNA methylation and chromatin modifications in the promoter regions. There was no remarkable difference in DNA methylation between the mono allelic samples and biallelic samples. In contrast, histone H3 acetylation (H3Ac) was increased in the biallelic samples. A significant negative correlation was observed between the trimethylation of lysine-9 on histone H3 (H3K9me3) and the OCT2 mRNA levels. Our results suggest that H3Ac plays a role in the allelic expression of OCT2. In addition, H3K9me3 in the OCT2 promoter may explain the interindividual differences in placental OCT2 mRNA levels. PMID- 21523787 TI - Effects of surfaces and leachables on the stability of biopharmaceuticals. AB - Therapeutic proteins are exposed to various potential contact surfaces, particles, and leachables during manufacturing, shipping, storage, and delivery. In this review, we present published examples of interfacial- or leachable induced aggregation or particle formation, and discuss the mitigation strategies that were successfully utilized. Adsorption to interfaces or interactions with leachables and/or particles in some cases has been reported to cause protein aggregation or particle formation. Identification of the cause(s) of particle formation involving minute amounts of protein over extended periods of time can be challenging. Various formulation strategies such as addition of a nonionic surfactant (e.g., polysorbate) have been demonstrated to effectively mitigate adsorption-induced protein aggregation. However, not all stability problems associated with interfaces or leachables are best resolved by formulation optimization. Detectable leachables do not necessarily have any adverse impact on the protein but control of the leachable source is preferred when there is a concern. In other cases, preventing protein aggregation and particle formation may require manufacturing process and/or equipment changes, use of compatible materials at contact interfaces, and so on. This review summarizes approaches that have been used to minimize protein aggregation and particle formation during manufacturing and fill-finish operations, product storage and transportation, and delivery of protein therapeutics. PMID- 21523789 TI - Maternal concern, social support, and health-related quality of life across childhood. AB - Mothers play a critical role in child and family health yet little is known about the concerns and health-related quality of life (HRQOL) of mothers beyond early childhood. The purpose of this study of 234 mothers of children up to 18 years of age was to examine relationships among maternal concern, social support, and HRQOL. Mothers reported a low level of concern, but concern was a significant predictor of HRQOL. The health burden for mothers was demonstrated primarily in the mental health components of HRQOL. The effect of social support was minimal and limited to the mental health domain of HRQOL. Results suggest regular assessment of maternal concerns and mental health coupled with education regarding coping strategies to support HRQOL for all mothers. PMID- 21523790 TI - Parameterization of Org27569: an allosteric modulator of the cannabinoid CB1 G protein-coupled receptor. AB - The cannabinoid CB1 receptor is a class A G protein-coupled receptor (GPCR) that is the most widely expressed GPCR in the brain. Many GPCRs contain allosteric binding sites for endogenous and/or synthetic ligands, which are topographically distinct from the agonist-binding site that is known as the orthosteric site. While both endogenous and synthetic ligands that act at the CB1 orthosteric site have been known for some time, compounds that act at a CB1 allosteric site have only recently been discovered. The most studied of these is 5-chloro-3-ethyl-1H indole-2-carboxylic acid [2-(4-piperidin-1-ylphenyl)ethyl]amide (Org27569). Because allosteric ligands are thought to act through conformational changes in the receptor that are transmitted from the allosteric to the orthosteric site, computational studies of the structural and dynamic interactions of Org27569 with the CB1 receptor are crucial to achieve a molecular level understanding of the basis of action of this important new class of compounds. To date, such computational studies have not been possible due to the lack of a complete set of molecular mechanics force field parameters for Org27569. Here, we present the development of missing CHARMM force field parameters for Org27569 using previously published methods and the validation and application of these new parameters using normal mode analysis and molecular dynamics simulations combined with experimental infrared measurements. PMID- 21523791 TI - Empirical prediction of protein pKa values with residue mutation. AB - A fast, empirical method, Mut-pKa, is presented for predicting the pKa values of ionizable residues in proteins based on mutation. The method compares the effect of mutating each residue that may act as a hydrogen bond donor or acceptor for the ionizable residue. The energetic effect of each type of mutation, along with a desolvation measure and the overall background charge, is fit against pKa data for histidine and carboxyl residues. A total of 214 residues from 35 different proteins were used in the dataset. Using 11 parameters for each type of ionizable residue, a root mean squared error (RMSE) of 0.78 and 1.12 pH units were obtained for carboxyl and histidines residues, respectively, using leave one out cross validation (LOOCV). The results were particularly promising for buried residues, which had RMSE values of 0.99 and 1.13 for carboxyl and histidine residues, respectively. A number of desolvation measures were tested. The simplest measure, the number of atoms surrounding the residue, was found to work best. The effect of using dynamics was also studied using short molecular dynamics runs, followed by minimization of the structures. Mut-pKa has significantly fewer parameters than, but similar performance to, other empirical methods. Because of this and the LOOCV results, we believe the model is robust and that overfitting is not a problem. PMID- 21523792 TI - HIV-1 NNRTIs: structural diversity, pharmacophore similarity, and implications for drug design. AB - Nonnucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent very potent and most promising anti-AIDS agents that specifically target the HIV-1 reverse transcriptase (RT). However, the effectiveness of NNRTI drugs can be hampered by rapid emergence of drug-resistant viruses and severe side effects upon long-term use. Therefore, there is an urgent need to develop novel, highly potent NNRTIs with broad spectrum antiviral activity and improved pharmacokinetic properties, and more efficient strategies that facilitate and shorten the drug discovery process would be extremely beneficial. Fortunately, the structural diversity of NNRTIs provided a wide space for novel lead discovery, and the pharmacophore similarity of NNRTIs gave valuable hints for lead discovery and optimization. More importantly, with the continued efforts in the development of computational tools and increased crystallographic information on RT/NNRTI complexes, structure-based approaches using a combination of traditional medicinal chemistry, structural biology, and computational chemistry are being used increasingly in the design of NNRTIs. First, this review covers two decades of research and development for various NNRTI families based on their chemical scaffolds, and then describes the structural similarity of NNRTIs. We have attempted to assemble a comprehensive overview of the general approaches in NNRTI lead discovery and optimization reported in the literature during the last decade. The successful applications of medicinal chemistry strategies, crystallography, and computational tools for designing novel NNRTIs are highlighted. Future directions for research are also outlined. PMID- 21523793 TI - Recent attempts at RNAi-mediated P-glycoprotein downregulation for reversal of multidrug resistance in cancer. AB - Multidrug resistance (MDR) is among the major mechanisms leading to failure in chemotherapy of cancer patients. The ATP-binding cassette proteins are major contributors to MDR, involved in the active efflux of xenobiotics out of cancer cells. Among them, P-glycoprotein (P-gp) is the most dominant protein involved in the efflux of drugs. For more than 30 years, scientists have searched for the ideal P-gp inhibitor to modulate drug resistance activity of P-gp. This inhibitor should be tissue and cell specific with side effects on other tissues, must not provoke immune responses from the host, should provide sustained inhibition, and must be synthesized readily with low cost. Chemical P-gp inhibitors tested to date, have shown nonspecific toxic effects limiting their clinical applications. Sequence-specific P-gp gene silencing by RNA interference (RNAi) may provide a more effective approach for downregulation of specific protein targets due to high specificity, limited toxicity and immunogenicity, and relative ease in synthesis. RNAi can be implemented by delivery of synthetic small interfering RNAs (siRNAs) or by gene expression of short hairpin RNAs using gene expressing vectors. Specific delivery systems and expression vectors have been designed for this purpose and many researchers have explored their effectiveness for P-gp downregulation. In this report, we review the efficiency of various methods for siRNA delivery and transfection for P-gp downregulation in cancer cells for MDR reversal. Novel ideas and observations by different research groups were discussed for future improvement in this essential field. PMID- 21523794 TI - Broken barriers: human-induced changes to gene flow and introgression in animals: an examination of the ways in which humans increase genetic exchange among populations and species and the consequences for biodiversity. AB - We identify two processes by which humans increase genetic exchange among groups of individuals: by affecting the distribution of groups and dispersal patterns across a landscape, and by affecting interbreeding among sympatric or parapatric groups. Each of these processes might then have two different effects on biodiversity: changes in the number of taxa through merging or splitting of groups, and the extinction/extirpation of taxa through effects on fitness. We review the various ways in which humans are affecting genetic exchange, and highlight the difficulties in predicting the impacts on biodiversity. Gene flow and hybridization are crucially important evolutionary forces influencing biodiversity. Humans alter natural patterns of genetic exchange in myriad ways, and these anthropogenic effects are likely to influence the genetic integrity of populations and species. We argue that taking a gene-centric view towards conservation will help resolve issues pertaining to conservation and management. Editor's suggested further reading in BioEssays A systemic view of biodiversity and its conservation: Processes, interrelationships, and human culture Abstract. PMID- 21523796 TI - Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis. AB - Tumor necrosis factor (TNF) has been implicated in the progression of many chronic liver diseases leading to fibrosis; however, the role of TNF in fibrogenesis is controversial and the specific contribution of TNF receptors to hepatic stellate cell (HSC) activation remains to be established. Using HSCs from wild-type, TNF-receptor-1 (TNFR1) knockout, TNF-receptor-2 (TNFR2) knockout, or TNFR1/R2 double-knockout (TNFR-DKO) mice, we show that loss of both TNF receptors reduced procollagen-alpha1(I) expression, slowed down HSC proliferation, and impaired platelet-derived growth factor (PDGF)-induced promitogenic signaling in HSCs. TNFR-DKO HSCs exhibited decreased AKT phosphorylation and in vitro proliferation in response to PDGF. These effects were reproduced in TNFR1 knockout, but not TNFR2 knockout, HSCs. In addition, matrix metalloproteinase 9 (MMP-9) expression was dependent on TNF binding to TNFR1 in primary mouse HSCs. These results were validated in the human HSC cell line, LX2, using neutralizing antibodies against TNFR1 and TNFR2. Moreover, in vivo liver damage and fibrogenesis after bile-duct ligation were reduced in TNFR-DKO and TNFR1 knockout mice, compared to wild-type or TNFR2 knockout mice. CONCLUSION: TNF regulates HSC biology through its binding to TNFR1, which is required for HSC proliferation and MMP-9 expression. These data indicate a regulatory role for TNF in extracellular matrix remodeling and liver fibrosis, suggesting that targeting TNFR1 may be of benefit to attenuate liver fibrogenesis. PMID- 21523797 TI - Isolated del(5q) in myeloid malignancies: clinicopathologic and molecular features in 143 consecutive patients. AB - World Health Organization (WHO) criteria were used to identify 143 consecutive patients (median age 73 years; 90 females) with myeloid neoplasms and isolated del(5q) seen between 1989 and 2009. We have previously reported on 88 (61%) of these patients who met criteria for WHO defined "myelodysplastic syndromes (MDS) with isolated del(5q)." The remaining 55 patients were classified as having "other" MDS variants (n = 29; 20%), acute myeloid leukemia (AML; n = 14; 10%), or myeloproliferative neoplasms (MPN; n = 12; 8%). DNA was available in 138 patients and mutation screening revealed 20 cases with JAK2, 6 with IDH, and 3 with MPL mutations; JAK2 and MPL mutations were seen mostly in MPN or "MDS with isolated del(5q)" whereas IDH mutations were frequent in other MDS variants. Overall median survival for the 143 patient cohort was 35 months and leukemic transformation (LT) was documented in 19 (~13%) cases. "MDS with isolated del(5q)" had the best prognosis with median survival of 66 months and LT rate of ~6%. Survival was poor among the other myeloid neoplasm subgroups regardless of specific morphologic diagnosis. Multivariable analysis identified higher leukocyte count and percentage of bone marrow and circulating blasts as independent predictors of shortened survival. The first two parameters and the presence of IDH mutations predicted inferior leukemia-free survival. The current study validates the prognostic relevance of considering "MDS with isolated del(5q)" as a separate WHO subcategory and identifies leukocytosis, higher blast count, and IDH mutations as being prognostically detrimental, in myeloid neoplasms associated with isolated del(5q). PMID- 21523798 TI - Clinical effect of reduced-intensity conditioning regimen containing antithymocyte globulin for hematopoietic cell transplantation from unrelated donors. AB - The impact of reduced-intensity conditioning (RIC) on the outcomes of hematopoietic cell transplantation (HCT) from unrelated -donors (UD) remains to be determined. We therefore assessed 128 patients, aged 16 to 66 years, with acute leukemia (n = 105) or myelodysplastic syndrome (n = 23) in a UD-HCT trial using RIC with busulfan, fludarabine, and antithymocyte globulin. Patients were transplanted with unmanipulated bone marrow (BM, n = 41) or mobilized peripheral blood mononuclear cells (M-PB, n = 87) and received cyclosporine and methotrexate for graft-versus-host disease (GVHD) prophylaxis. After a median follow-up of 26.7 months (range, 5.9-70.7 months) in surviving patients, 19 patients had died without progression/recurrence of underlying disease, giving a cumulative incidence of transplantation-related mortality (TRM) of 17% (95% confidence interval, 11%-27%; 1-year TRM, 14%). Graft failure (n = 7) and infections (n = 5) were the most common causes of TRM. Only three patients died due to GVHD (acute, one; chronic, two). Graft failure, which occurred in eight patients, showed a significant correlation with graft source (BM, 6/41 vs. M-PB, 2/87; P = 0.009). Donor-patient HLA-disparity did not correlate with GVHD, 1-year TRM, and graft failure. RIC containing antithymocyte globulin led to decreased GVHD-associated, as well as overall, TRM after UD-HCT. PMID- 21523799 TI - Predicted costs of iron-chelators in myelodysplastic syndromes: a 10-year analysis based on actual prevalence and red cell transfusion rates. AB - Consideration of iron-chelation (IC) in transfusion-dependent patients is recommended in most clinical-practice guidelines on myelodysplastic syndromes (MDS). The financial impact of IC on health-care systems is predicted through economic modeling, but an analysis based on actual prevalence is lacking. Here, we have investigated the potential drug-costs and need for IC in a cohort of 189 United Kingdom-based MDS patients diagnosed from 2000 to 2010. Patients with low or intermediate-1 IPSS scores were identified as eligible for IC if >=24 red cell units (RCU) had been transfused over 12 consecutive months or the transfusion intensity averaged >=2 RCU per month. Drug-costs were calculated from the time patients qualified for IC until death or last follow-up. In 159 patients with low/intermediate-1 MDS, survival was superior with a low IPSS score (P = 0.014), age <70 years (P = 0.043), transfusion-independence at diagnosis (P = 0.0056) and transfusion-intensity of <2 RCU per month (P = 0.009). Reflecting the time elapsed since diagnosis, longer survival was observed with a cumulative red cell load of >=75 U (P = 0.046). By logistic-regression analysis, transfusion intensity independently predicted survival (P = 0.0035) in low and intermediate-1 risk MDS patients. Forty-one patients fulfilled criteria for consideration of IC. Of these, 6 patients died within 1 month; 35 patients survived for a median of 16 months (range 1-61). Had patients commenced IC, the anticipated drug-costs alone would have been ~$526,880-$2,064,800 over 10 years. The lack of association between cumulative transfusion-load and survival calls for a prospective evaluation of the cost-utility of IC in patients surviving long-term, to enable evidence-based recommendations in MDS management. PMID- 21523800 TI - Waldenstrom macroglobulinemia: 2011 update on diagnosis, risk stratification, and management. AB - DISEASE OVERVIEW: Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. DIAGNOSIS: Presence of IgM monoclonal protein associated with 10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. RISK STRATIFICATION: Age, hemoglobin level, platelet count, b2-microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. RISK ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analogue, or both. The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem cell transplantation should be considered in induction therapy selection. MANAGEMENT OF REFRACTORY DISEASE: Bortezomib, thalidomide, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials. PMID- 21523801 TI - Neutropenia and anemia with reduced serum vitamin B12. PMID- 21523802 TI - Protein S abnormalities: a diagnostic nightmare. AB - Heterozygous deficiency of Protein S (PS) increases the risk for developing thrombosis. Many acquired conditions alter plasma PS levels. These complex interactions of PS in plasma make it imperative that clinical PS assay limitations are understood so that the assays are reliable, reproducible and specific to diagnose true genetic abnormalities based on plasma phenotype alone. Unfortunately, the diagnosis of PS deficiency is difficult and complicated. Three basic assays can be utilized for assessing PS in plasma: PS activity assay, Free PS antigen assay, and Total PS antigen assay. This article will review these clinical assays and their associated problems. We also discuss the confounding and interfering factors that make it difficult to obtain an accurate diagnosis of PS deficiency. PMID- 21523803 TI - EBV-associated hemophagocytic syndrome. PMID- 21523804 TI - Hairy cell leukemia presenting as a cranial mass. PMID- 21523805 TI - Bone marrow trephine biopsy findings in a case of myeloma with large immunoblast like cells. PMID- 21523806 TI - Plasma glial fibrillary acidic protein levels in children with sickle cell disease. AB - To determine if glial fibrillary acidic protein (GFAP) is associated with brain injury in children with sickle cell disease (SCD), we measured plasma GFAP among cross-sectional groups of unselected children with SCD, subsets of children with SCD and normal brain MRI or MRI evidence of cerebral infarct, healthy pediatric controls, and adults with brain injury. Children with SCD had higher plasma GFAP than healthy pediatric controls (mean concentrations 0.14 +/- 0.37 vs. 0.07 +/- 0.08 ng/mL; P 5 0.003); also, 16.0% (16/100) of children with SCD and cerebral infarct had GFAP elevations above the 95th percentile of healthy pediatric controls (P 5 0.04). Although not statistically significant, children with SCD and cerebral infarct had more elevated GFAP levels than with SCD and no infarct (16/100, 16.0% vs. 14/168, 8.3%; P 5 0.07). Children with SCD and acute brain ischemia had a higher proportion of elevated GFAP than SCD children with normal MRI (3/6, 50% vs.8.3%; P 5 0.01). GFAP was associated with elevated systolic blood pressure in the preceding year and correlated positively with white blood cell count and negatively with age and performance IQ. Plasma GFAP is elevated among children with SCD and may be associated with subclinical brain injury. PMID- 21523807 TI - Protective role of hemoglobin and fetal hemoglobin in early kidney disease for children with sickle cell anemia. AB - Patients with sickle cell anemia are at risk for organ damage including kidney disease. Microalbuminuria may be an early marker of disease progression. This retrospective review analyzed laboratory and clinical findings in children with sickle cell anemia according to the presence or absence of MA during well clinic sickle cell visits. Results were analyzed in sum as well as by therapeutic intervention (not on therapy,hydroxyurea therapy, or chronic transfusion therapy). Thirty two of 144(22%) children had MA, including 20 of 82 (24%) children not on a therapeutic intervention (chronic transfusion or hydroxyurea). In children not on therapy, low hemoglobin, low fetal hemoglobin and high lactate dehydrogenase were associated with MA. Frequency of positive screens for MA for the different treatment groups were: Hydroxyurea 13%; chronic transfusion 26% and children on no treatment 24%. However,the difference between the hydroxyurea group and the chronic transfusion or no treatment groups did not reach statistical significance.Increased hemoglobin and fetal hemoglobin may provide protection against kidney disease in sickle cell anemia and should be evaluated in a randomized, prospective clinical trial. PMID- 21523808 TI - Iron chelation adherence to deferoxamine and deferasirox in thalassemia. AB - The Thalassemia Clinical Research Network collected adherence information from 79 patients on deferoxamine and 186 on deferasirox from 2007 to 2009. Chelation adherence was defined as percent of doses administered in the last 4 weeks (patient report) out of those prescribed(chart review). Chelation history since 2002 was available for 97 patients currently on deferoxamine and 217 on deferasirox, with crude estimates of adherence from chart review. Self-reported adherence to both deferoxamine and deferasirox were quite high, with slightly higher adherence to the oral chelator (97 vs. 92%). Ninety percent of patients on deferasirox reported at least 90% adherence, compared with 75% of patients on deferoxamine. Adherence to both chelators was highest in children, followed by adolescents and older adults.Predictors of lower deferoxamine adherence were smoking in the past year, problems sticking themselves (adults only), problems wearing their pump, and fewer transfusions in the past year. Predictors of lower deferasirox adherence were bodily pain and depression. Switching chelators resulted in increased adherence, regardless of the direction of the switch, although switching from deferoxamine to deferasirox was far more common. As adherence to deferoxamine is higher than previously reported, it appears beneficial for patients to have a choice in chelators. PMID- 21523816 TI - Spatial trends of polybrominated diphenyl ethers in Canadian fish and implications for long-term monitoring. AB - A nationwide study was conducted to examine concentrations of polybrominated diphenyl ethers (PBDEs) in top predatory fish, with a focus on lake trout (Salvelinus namaycush), across Canada, and to explore possible influences of food web processes. Concentrations of the three most abundant PBDE homolog groups (tetra-, penta-, and hexa-PBDEs) were, for the most part, higher in Great Lakes and Lake Champlain fish compared with fish from other systems. The Canadian Federal Environmental Quality Guideline for the penta-homolog was exceeded in 70% of the fish examined. However, virtually no guideline exceedances were found for other congeners. In general, PBDE-47 (a representative lower brominated congener) was significantly and positively correlated with fish length, weight, age, lipid content, and stable isotopes of nitrogen and carbon. Significant differences in the slopes of the PBDE-47/covariate relationships between sites prevented concentrations from being adjusted using an analysis of covariance (ANCOVA). However, plots showed that elevated concentrations of PBDE-47 in Great Lakes and Lake Champlain fish remained after accounting for the influence of covariates. In contrast, for PBDE-183 (a representative higher brominated congener), the relationships between fish concentrations and covariates were not consistent, which could be a result of biotransformation being more important in controlling its bioaccumulation. The data from the current study show an overall disconnect between fish PBDE concentrations and likely loadings, which may be caused by differences in food web processes between systems. Continued long-term fish contaminant monitoring is needed to evaluate potential risk to fish and their consumers. However, we also recommend sediment sampling and focused food web studies to provide information on PBDE inputs to the systems and mechanisms of biomagnification, respectively. PMID- 21523817 TI - Nerve sparing-distally based sural flap. AB - The management of soft-tissue defects in the ankle and foot area is a challenging task. Distally based sural flap is widely used, however it leaves donor area paresthesia. For this purpose, the sural nerve was dissected and preserved in the distally based sural flap in five cases of ankle and foot soft tissue reconstruction. This modification did not cause any compromise in flap circulation. All flaps survived with one partial distal necrosis. We suggest that, the distally based nerve sparing sural flap can be securely elevated with only a 3-4 cm wide subcutaneous pedicle without any compromise in flap circulation. PMID- 21523818 TI - Combined use of T2-weighted MRI and T1-weighted dynamic contrast-enhanced MRI in the automated analysis of breast lesions. AB - A multiparametric computer-aided diagnosis scheme that combines information from T1-weighted dynamic contrast-enhanced (DCE)-MRI and T2-weighted MRI was investigated using a database of 110 malignant and 86 benign breast lesions. Automatic lesion segmentation was performed, and three categories of lesion features (geometric, T1-weighted DCE, and T2-weighted) were automatically extracted. Stepwise feature selection was performed considering only geometric features, only T1-weighted DCE features, only T2-weighted features, and all features. Features were merged with Bayesian artificial neural networks, and diagnostic performance was evaluated by ROC analysis. With leave-one-lesion-out cross-validation, an area under the ROC curve value of 0.77+/-0.03 was achieved with T2-weighted-only features, indicating high diagnostic value of information in T2-weighted images. Area under the ROC curve values of 0.79+/-0.03 and 0.80 +/ 0.03 were obtained for geometric-only features and T1-weighted DCE-only features, respectively. When all features were considered, an area under the ROC curve value of 0.85+/-0.03 was achieved. We observed P values of 0.006, 0.023, and 0.0014 between the geometric-only, T1-weighted DCE-only, and T2-weighted-only features and all features conditions, respectively. When ranked, the P values satisfied the Holm-Bonferroni multiple-comparison test; thus, the improvement of multiparametric computer-aided diagnosis was statistically significant. A computer-aided diagnosis scheme that combines information from T1-weighted DCE and T2-weighted MRI may be advantageous over conventional T1-weighted DCE-MRI computer-aided diagnosis. PMID- 21523819 TI - Radiofrequency pulse designs for three-dimensional MRI providing uniform tipping in inhomogeneous B1 fields. AB - Although high-field MRI offers increased signal-to-noise, the nonuniform tipping produced by conventional radiofrequency (RF) pulses leads to spatially dependent contrast and suboptimal signal-to-noise, thus complicating the interpretation of the MR images. For structural imaging, three-dimensional sequences that do not make use of frequency-selective RF pulses have become popular. Therefore, the aim of this research was to develop non-slice-selective (NSS) RF pulses with immunity to both amplitude of (excitation) RF field (B(1) ) inhomogeneity and resonance offset. To accomplish this, an optimization routine based on optimal control theory was used to design new NSS pulses with desired ranges of immunity to B(1) inhomogeneity and resonance offset. The design allows the phase of transverse magnetization produced by the pulses to vary. Although the emphasis is on shallow tip designs, new designs for 30 degrees , 60 degrees , 90 degrees , and 180 degrees NSS RF pulses are also provided. These larger tip angle pulses are compared with recently published NSS pulses. Evidence is presented that the pulses presented in this article have equivalent performance but are shorter than the recently published pulses. Although the NSS pulses generate higher specific absorption rates and larger magnetization transfer effects than the rectangular pulses they replace, they nevertheless show promise for three-dimensional MRI experiments at high field. PMID- 21523820 TI - In vivo and ex vivo MR imaging of slowly cycling melanoma cells. AB - Slowly cycling cells are believed to play a critical role in tumor progression and metastatic dissemination. The goal of this study was to develop a method for in vivo detection of slowly cycling cells. To distinguish these cells from more rapidly proliferating cells that constitute the vast majority of cells in tumors, we used the well-known effect of label dilution due to division of cells with normal cycle and retention of contrast agent in slowly dividing cells. To detect slowly cycling cells, melanoma cells were labeled with iron oxide particles. After labeling, we observed dilution of contrast agent in parallel with cell proliferation in the vast majority of normally cycling cells. A small and distinct subpopulation of iron-retaining cells was detected by flow cytometry after 20 days of in vitro proliferation. These iron-retaining cells exhibited high expression of a biological marker of slowly cycling cells, JARID1B. After implantation of labeled cells as xenografts into immunocompromised mice, iron retaining cells were detected in vivo and ex vivo by magnetic resonance imaging that was confirmed by Prussian Blue staining. Magnetic resonance imaging detects not only iron retaining melanoma cells but also iron positive macrophages. Proposed method opens up opportunities to image subpopulation of melanoma cells, which is critical for continuous tumor growth. PMID- 21523821 TI - Signal-to-noise ratio for hyperpolarized 3He MR imaging of human lungs: a 1.5 T and 3 T comparison. AB - The signal-to-noise ratio in hyperpolarized noble gas MR imaging is expected to be independent of field strength at frequencies typical of clinical systems (e.g., 1.5 T), where body noise dominates over coil noise. Furthermore, at higher fields (e.g., 3 T), the SNR of lung images may decline due to decreases in T(2) originating from increases in susceptibility-induced field gradients at the air tissue interface. In this work, the SNR of hyperpolarized (3) He lung imaging at two commonly used clinical field strengths (1.5 T and 3 T) were compared in the same volunteers. Thermally polarized and hyperpolarized (3) He phantoms were used to account for differences in MR imaging system and (3) He polarizer performance, respectively, at the two field strengths. After correcting for T(2) values measured at 1.5 T (16 +/- 2 ms) and 3 T (7 +/- 1 ms), no significant difference in image SNR between the two field strengths was observed, consistent with theory. PMID- 21523822 TI - Use of respiratory biofeedback and CLAWS for increased navigator efficiency for imaging the thoracic aorta. AB - A novel technique to guide a subjects' breathing pattern using a respiratory biofeedback (rBF) "game" to improve respiratory efficiency is presented. The continuously adaptive windowing strategy, a fully automatic and highly efficient free-breathing navigator gated technique, is used to acquire the data as it ensures that all potential navigator acceptance windows are possible. This enables the rBF to be fully adaptable to a subject's respiratory pattern. Images of the thoracic aorta acquired using balanced steady-state free precession with continuously adaptive windowing strategy respiratory motion control, with and without rBF, were compared in 10 healthy subjects. Total scan time was reduced by using rBF. The mean scan time was reduced from 7 min 44 s (463 cardiac cycles, +/ 127 cc) without rBF to 5 min 43 s (380 cardiac cycles, +/- 118 cc) with the use of rBF (P < 0.05). Respiratory efficiency was increased from 45% without rBF to 56% with rBF (P < 0.01). Image quality was the same for both techniques (P = ns). In conclusion, rBF significantly improved respiratory efficiency and reduced acquisition duration without affecting image quality. PMID- 21523823 TI - Improved temporal resolution in cardiac imaging using through-time spiral GRAPPA. AB - Previous work has shown that the use of radial GRAPPA for the reconstruction of undersampled real-time free-breathing cardiac data allows for frame rates of up to 30 images/s. It is well known that the spiral trajectory offers a higher scan efficiency compared to radial trajectories. For this reason, we have developed a novel through-time spiral GRAPPA method and demonstrate its application to real time cardiac imaging. By moving from the radial trajectory to the spiral trajectory, the temporal resolution can be further improved at lower acceleration factors compared to radial GRAPPA. In addition, the image quality is improved compared to those generated using the radial trajectory due to the lower acceleration factor. Here, we show that 2D frame rates of up to 56 images/s can be achieved using this parallel imaging method with the spiral trajectory. PMID- 21523824 TI - Sensitivity calibration with a uniform magnetization image to improve arterial spin labeling perfusion quantification. AB - Quantification of perfusion with arterial spin labeling MRI requires a calibration of the imaging sensitivity to water throughout the imaged volume. Since this sensitivity is affected by coil loading and other interactions between the subject and the scanner, the sensitivity must be calibrated in the subject at the time of scan. Conventional arterial spin labeling perfusion quantification assumes a uniform proton density and acquires a proton density reference image to serve as the calibration. This assumption, in the form of an assumed constant brain-blood partition coefficient, incorrectly adds inverse proton density weighting to the perfusion image. Here, a sensitivity calibration is proposed by generating a uniform magnetization image whose intensity is highly independent of brain tissue type. It is shown that such a uniform magnetization image can be achieved, and brain tissue perfusion values quantified with the sensitivity calibration agree with those quantified with a proton density image when segmentation of brain tissues is performed and appropriate partition coefficients are assumed. Quantification of brain tissue water density is also demonstrated using this sensitivity calibration. This approach can improve and simplify quantification of arterial spin labeling perfusion and may have broader applications to measurement of edema and sensitivity calibration for parallel imaging. PMID- 21523825 TI - Study on metabonomic characteristics of human lung cancer using high resolution magic-angle spinning 1H NMR spectroscopy and multivariate data analysis. AB - Lung cancer causes serious health problems. Clinical diagnosis of lung cancer relies on histopathological evalution of tissue specimen. However, extensive knowledge of the metabolic biochemistry of tumors can potentially provide important information for accurate diagnosis of lung cancer. High resolution magic-angle spinning NMR spectroscopy has emerged and be widely acknowledged as an excellent tool in investigating tissue metabolism. Moreover, the combination of high resolution magic-angle spinning NMR technique and multivariate data analysis has become an important metabonomics platform for studying the intact biological tissues. This study reported the metabonomic characteristics of 51 lung tissues from 17 patients with lung cancer using the high resolution magic angle spinning 1H NMR spectroscopy and the multivariate data analysis methods including principal component analysis and orthogonal partial least squares discriminant analysis. Clear differences among the metabonomic characteristics of lung cancer tissues at various sites were disclosed. Compared with the adjacent noninvolved tissues, the lung cancer tissues had significantly high levels of aspartate, phosphocholine, glycerophosphocholine and lactate but significantly low levels of glucose and valine. Furthermore, significantly positive (or negative) correlations were observed between the levels of some metabolites such as lactate, fatty acids, valine, phosphocholine, and glycerophosphocholine. PMID- 21523826 TI - Statistical assessment of non-Gaussian diffusion models. AB - In human brain diffusion measurements, there are deviations from monoexponential signal decay at high values of the diffusion-weighting factor b. This is known as non-Gaussian diffusion and can provide novel kinds of image contrast. We evaluated quantitatively the goodness-of-fit of five popular diffusion models. Because of the Rician signal distribution and physiological noise, the measurement errors are unknown. This precludes standard chi(2) testing. By repeating the measurement 25 times, the errors were estimated. Hypothesis testing based on the residual after least squares curve fitting was then carried out. Systematic errors originating from the Rician signal bias were eliminated in the fitting procedure. We performed diffusion measurements on four healthy volunteers with b-values ranging from 0 to 5000 s/mm(2) . The data were analyzed voxelwise. The null hypothesis of a given model being adequate was rejected, if the residual after fitting exceeded a limit that corresponds to a significance level of 1%. The fraction of rejected voxels depended strongly on the number of free model parameters. The rejected fraction was: monoexponential model with two parameters, 94%; statistical model with three parameters, 29%; stretched exponential model with three parameters, 35%; cumulant model with three parameters, 48%; cumulant model with four parameters, 11%; biexponential model with four parameters, 2.9%. PMID- 21523827 TI - Osteoinductive signals and heterotopic ossification. PMID- 21523828 TI - Exclusion of the GNAS locus in PHP-Ib patients with broad GNAS methylation changes: evidence for an autosomal recessive form of PHP-Ib? AB - Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. PMID- 21523829 TI - The relationship between posttraumatic stress disorder and smoking outcome expectancies among U.S. military veterans who served since September 11, 2001. AB - Posttraumatic stress disorder (PTSD) is associated with increased rates of smoking although little is known regarding the mechanisms underlying this relationship. The current study examined expectations about smoking outcomes among smokers with and without PTSD. The sample included 96 veterans (mean age of 34 years) and included 17% women and 50% racial minorities. Smoking expectancies were measured with the Smoking Consequences Questionnaire-Adult (Copeland, Brandon, & Quinn, 1995). Consistent with previous work suggesting that smokers with PTSD smoke in an effort to reduce negative affect, unadjusted analyses indicated that smokers with PTSD (n = 38) had higher expectations that smoking reduces negative affect than smokers without PTSD (d = 0.61). Smokers with PTSD also had increased expectancies associated with boredom reduction (d = 0.48), stimulation (d = 0.61), taste/sensorimotor manipulation aspects of smoking (d = 0.73), and social facilitation (d = 0.61). Results of hierarchical linear regression analyses indicated that PTSD symptom severity was uniquely associated with these expectancies beyond the effects of gender and nicotine dependence. More positive beliefs about the consequences of smoking may increase risk of continued smoking among those with PTSD who smoke. Further understanding of smoking expectancies in this group may help in developing interventions tailored for this vulnerable population. PMID- 21523830 TI - Traumatic stress is linked to a deficit in associative episodic memory. AB - Individuals with posttraumatic stress disorder (PTSD) are haunted by persistent memories of the trauma, but ironically are impaired in memories of daily life. The current set of 4 experiments compared new learning and memory of emotionally neutral content in 2 groups of patients and aged- and education-matched controls: 20 patients diagnosed with chronic posttraumatic stress disorder (C-PTSD) and 20 patients diagnosed with acute stress disorder (ASD). In all experiments, participants studied a list of stimuli pairs (words or pictures) and were then tested for their memory of the items, or for the association between items in each pair. Results indicated that both types of patients showed associative memory impairment compared to a control group, although their item memory performance was relatively intact. Potential mechanisms underlying such associative memory deficits in posttraumatic patients are discussed. PMID- 21523831 TI - Unexpected efficiency of non-C(2) -symmetric bis(hydroxyamide)-based zinc-chelate catalysts. AB - Asymmetric bis(hydroxyamide)-based zinc-chelate catalysts are able to promote the enantioselective addition of diethylzinc to benzaldehyde in the absence of titanium with yields and ees comparable, or inclusively superior, to their C(2) symmetric analogues. This unexpected fact demonstrates that the previously established assumption on the necessity of using C(2) -symmetric bis(hydrdoxyamides) to generate C(2) -symmetric zinc-chelate catalysts can be discarded, which expand the possibilities for designing new ligands based on the interesting hydroxyl-amide functional grouping. PMID- 21523833 TI - Three-dimensional writing of conducting polymer nanowire arrays by meniscus guided polymerization. PMID- 21523834 TI - High-strength carbon nanotube fibers fabricated by infiltration and curing of mussel-inspired catecholamine polymer. PMID- 21523836 TI - Dearomatisation of o-xylene by P450BM3 (CYP102A1). AB - The oxidation of o-xylene by P450(BM3) from Bacillus megaterium yields, in addition to the products formed by microsomal P450s, two metabolites containing an NIH-shifted methyl group, one of which lacks the aromatic character of the substrate. The failure of the epoxide precursor of these two products to rearrange to the more stable 2,7-dimethyloxepin suggests that ring opening is P450-mediated. With m-xylene, the principal metabolite is 2,4-dimethylphenol. The partition between aromatic and benzylic hydroxylation is primarily governed by the steric prescriptions of the active site rather than by C-H bond reactivity. It is also substrate-dependent, o- and m-xylene appearing to bind to the enzyme in different orientations. The product distributions given by variants containing the F87A mutation, which creates additional space in the active site, resemble those reported for microsomal systems. PMID- 21523837 TI - Combining glycomimetic and multivalent strategies toward designing potent bacterial lectin inhibitors. AB - As part of ongoing activities toward the design of potent and selective ligands against galactoside-binding proteins from animal, bacterial, and plant lectins, a systematic investigation involving the synthesis and binding evaluations of a series of original beta-C-galactopyranoside mimetics is described. The multivalent presentation of partly optimized candidates on various dendritic scaffolds through Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAc) has also been achieved. Biophysical investigations based on isothermal titration calorimetry (ITC) have indicated a dissociation constant in the low micromolar range for the best optimized monovalent conjugate (K(d)=37 MUM). The results thus confirmed that stable C-galactosides could represent efficient synthetic glycomimetics of natural alpha-linked oligosaccharidic inhibitors of PA-IL lectin (Lec A) from the pathogenic Pseudomonas aeruginosa. Striking enhancements in the avidity of the glycoconjugates were also observed for tri-, hexa-, and nonavalent derivatives, among which the most potent exhibited dissociation constants below 500 nM, corresponding to a 400-fold increase in affinity compared with the beta-D Gal-O-Me used as reference. To deepen our understanding of the binding mode of the best glycomimetics involved in the recognition process, molecular modeling studies, docking calculations, and NMR diffusion measurements have been performed. Although favorable complementary interactions induced by the addition of the hydrophobic aglycon might explain the affinity enhancement, experimental determination of the size and the topology of the multivalent conjugates further supported the formation of aggregative complexes as a major multivalent binding mode. This work represents a systematic and comprehensive study towards a thorough understanding of the protein-carbohydrate interactions involved in Pseudomonas aeruginosa infection, and as such should prove useful for the development of stable and optimized anti-adhesive agents. PMID- 21523838 TI - A temperature-guided diastereoselectivity switch during the desymmetrization of meso-7-azabicyclo[2.2.1]heptadiene: new strategy towards the synthesis of aminocyclitols. PMID- 21523839 TI - B-N Chemistry@ZIF-8: dehydrocoupling of dimethylamine borane at room temperature by size-confinement effects. PMID- 21523840 TI - BODIPY-fused porphyrins as soluble and stable near-IR dyes. PMID- 21523841 TI - Rapid separation and identification of anthocyanins from flowers of Viola yedoensis and V. prionantha by high-performance liquid chromatography-photodiode array detection-electrospray ionisation mass spectrometry. AB - INTRODUCTION: Anthocyanins are important plant secondary metabolites. They show strong antioxidant activities and have potential as anti-cancer agents. Viola yedoensis and V. prionantha are traditional Chinese medicines and ornamental plants. However, the anthocyanin compositions of these two species are still unresolved. OBJECTIVE: To develop a rapid and reliable high-performance liquid chromatography (HPLC) method for the separation and identification of anthocyanins from V. yedoensis and V. prionantha. METHODOLOGY: Samples were extracted in methanol-water-formic acid-TFA (70:27:2:1, v/v). HPLC analysis was done on a C(18) column (TSK-GEL ODS-80Ts: 150 * 4.6 mm i.d.). Four solvent systems were tested to optimise the separation of anthocyanins using different gradient separation systems. HPLC-photodiode array detection (DAD) coupled to electrospray ionisation mass spectrometry (ESI-MS) was used to carry out the comprehensive characterisation of anthocyanins. RESULTS: Fourteen anthocyanins were characterised within 40 min with satisfactory peak resolution by a gradient composed of 10% aqueous formic acid and formic acid-acetonitrile-water (10:40:50, v/v). The calibration curve showed an excellent linear regression (r(2) = 0.9995) and low intra- and inter-day variations (RSD < 3.67%). The detected anthocyanins derived from Dp, Cy, Pt, Mv and Pn, could be divided into three groups: non-acylated glycosides, acetylglycosides and coumaroylglycosides. Anthocyanins distribution exhibited remarkable differences in aglycone levels and acylation patterns. CONCLUSION: The optimised method was successfully applied for the analysis of 14 anthocyanins from V. yedoensis and V. prionantha. The identification of anthocyanin constitutions is valuable for breeding and will open up new prospects for their medicinal application. PMID- 21523842 TI - Intrapartum sonographic imaging of fetal head asynclitism. AB - Anterior asynclitism was suspected on digital examination of a laboring woman with late arrest of dilatation and no evidence of fetal head progression. Clinical examination revealed a fixed non-engaged fetal head (station -1), with a transverse posterior sagittal suture. A static three-dimensional volume was obtained by translabial ultrasound, offline analysis of which confirmed the clinical diagnosis of anterior asynclitism. Owing to the posterior twisting of the head towards the sacrum, the midline echo could only be obtained by cutting the volume with an oblique line, the direction of which was not perpendicular to the pubis as expected in cases of synclitic head. The sonographic appearance of the midline echo approaching the sacrum in a non-engaged transverse fetal head strongly supports the clinical suspicion of anterior asynclitism. PMID- 21523843 TI - Osteonecrosis of the jaws associated with the use of yearly zoledronic acid: report of 2 cases. AB - BACKGROUND: Once-yearly zoledronic acid has been proven effective in the management of osteoporosis. Osteonecrosis of the jaws (ONJ) related to its use has not been reported since its approval in 2007. METHODS: Two women with osteoporosis/osteopenia developed ONJ after the second infusion of yearly zoledronic acid. They had no other systemic diseases and ONJ occurred after oral surgeries, which were performed about 2 months following drug administration. RESULTS: In 1 case osteonecrosis of the maxilla resolved after conservative therapy and sequestrectomy. In the other case bone necrosis developed on both sides of mandible, and the symptoms/signs of ONJ were partially responsive to conservative treatment. CONCLUSIONS: ONJ related to yearly zoledronic acid is a severe complication that should not be ignored. To minimize the risk, we recommend preventive oral care before the start of therapy and avoiding dental invasive procedures within 3 months after drug administration. PMID- 21523845 TI - Topographic anatomy of the internal laryngeal nerve: surgical considerations. AB - BACKGROUND: This study is focused on the topographic features of the internal branch of the superior laryngeal nerve (ibSLN) at the thyrohyoid membrane area using as anatomic landmarks the posterior border of the thyrohyoid muscle and the superior border of the thyroid cartilage. METHODS: Thirty-six fresh adult cadavers were dissected to determine the topography and branching pattern of the ibSLN and the superior laryngeal artery. RESULTS: The ibSLN prior to thyrohyoid membrane's penetration was divided into 3 or 2 branches, in 72.22% and 27.78% of cases. The trifurcated ibSLN was more common than the bifurcated in both sexes and in both sides of the neck. In over 80% of cases the ibSLN penetrated the thyrohyoid membrane 0.1 to 0.9 cm far from the posterior border of the thyrohyoid muscle and 0.1 to 1.2 cm far from the superior border of the thyroid cartilage. CONCLUSIONS: We provide a schematic overview of the ibSLN penetration zone at the thyrohyoid membrane, the so-called danger zone, to avoid ibSLN damage. PMID- 21523844 TI - Prediction of surgical outcome using plasma Epstein-Barr virus dna and (18)F-FDG PET-CT scan in recurrent nasopharyngeal carcinoma. AB - BACKGROUND: This study was carried out to determine the role of plasma Epstein Barr virus (pEBV)-DNA and positron-emission tomography (PET)-CT scan in predicting the outcome of nasopharyngectomy and cervical lymphadenectomy for recurrent nasopharyngeal carcinoma (NPC). METHODS: Between 2007 and 2009, we recruited patients who had local or regional recurrent NPC after radiotherapy. The relationship between preoperative pEBV-DNA level, maximal standard uptake value (SUVmax), and surgical outcome was analyzed. RESULTS: Forty-two patients had local tumor recurrence. Their median pEBV-DNA level and SUVmax were 348 copies and 4.7, respectively. Both values were significantly lower than those with palliative nasopharyngectomy. Twenty-two patients had regional failure. Their mean pEBV-DNA level and tumor SUVmax were 626 copies and 7.6, respectively. The metastatic lymph nodes with extracapsular spread had a significantly higher mean SUVmax. CONCLUSIONS: Preoperative pEBV-DNA and PET-CT predict the surgical outcome of nasopharyngectomy for recurrent NPC. Similarly, PET-CT scan predicts the presence of extracapsular spread of metastatic lymph nodes. These patients may warrant further postoperative adjuvant therapy. PMID- 21523846 TI - Evidence for treatment strategies in sinonasal adenocarcinoma. AB - Adenocarcinomas of various types account for 10% to 20% of all primary malignant neoplasms of the nasal cavity and paranasal sinuses. There is a general consensus that the optimal treatment of adenocarcinoma is surgery and postoperative radiotherapy. The purpose of this report was to review the results of this combined treatment as well as other treatment strategies and their outcome. Most series present outcome data from a heterogeneous group of patients, with a wide variety of tumor subtypes presenting at differing stages, who received a variety of treatment strategies. Surgical excision remains the treatment of choice. The choice of approach is determined by what will best allow complete excision of the disease. Endoscopic techniques, if feasible for complete removal of the tumor, offer results comparable to those of external approaches with lower morbidity. Although clear evidence to support the use of radiotherapy in sinonasal adenocarcinoma is difficult to obtain, local control rates of combined treatment strategies for advanced cases are comparable to less advanced cases with surgery alone, suggesting a positive role for postoperative radiotherapy. However, the importance of thorough surgical resection should be stressed. PMID- 21523847 TI - Patient characteristics and process factors associated with antipsychotic polypharmacy in a nationwide sample of psychiatric inpatients in Italy. AB - PURPOSE: The present study investigated: (i) the rate of prescription of antipsychotic (AP) polypharmacy (APP) in a large, representative sample of psychiatric inpatients; and (ii) the relationship between APP prescription and the characteristics of patients and facilities. METHODS: The sample included 1022 psychiatric patients scheduled to be discharged from acute inpatient facilities with drug therapies including AP. Demographic and clinical data were obtained from the treating physician or retrieved from patients' records through a standardized Patient Form. Patients were administered the 24-item Brief Psychiatric Rating Scale. Three indicators were used to describe the process of care in the facilities: a Restrictiveness score, a Standardization score, and a Treatment score. A multilevel mixed-effect logistic regression was used to predict APP using patient and facility as the variables. RESULTS: APP was prescribed to 333 (32.5%) patients, the most common patterns being a first generation and a second-generation AP (n = 178, 17.6%) or of two first-generation APs (n = 80, 7.8%). Patients with a diagnosis of schizophrenia and poorer insight into illness at admission were significantly more likely to receive APP. The availability of more complex therapeutic interventions in the facility was also associated with APP. CONCLUSIONS: In our nationwide sample of psychiatric inpatients, APP was frequently prescribed to treat the more severe patients. However, it was also associated with process of care characteristics such as delivery of more complex therapeutic interventions, and was therefore not used only to control patient behavior. PMID- 21523848 TI - Prevalence, incidence and persistence of etanercept and adalimumab in Norway 2005 2009. AB - PURPOSE: Examining the prevalence, incidence and persistence of use of etanercept and adalimumab in Norway during 2005-2009. METHODS: We retrieved data from the nationwide Norwegian Prescription Database (NorPD) for all individuals who were dispensed etanercept or adalimumab from pharmacies during 2005-2009. The NorPD covers the total Norwegian population in ambulatory care. Key measurements were one-year prevalence, incidence rate and persistence (minimum refill). RESULTS: The one-year prevalence for etanercept and adalimumab was 1.590/00 (n = 3840) for men and 1.850/00 (n = 4483) for women in 2009, an increase from 0.760/00 (n = 1752) for men and 1.210/00 (n = 2830) for women from 2005. The prevalence increased during the entire study time in all ages, with the highest prevalence for both genders among those aged 50-69. A total of 7786 individuals started therapy with etanercept or adalimumab during 2005-2009. Annual incidence of new users increased with 23.6% from 2005 to 2009. Sixty one percent of new users redeemed etanercept as the first drug, and 39% redeemed adalimumab. Sixty seven percent of all individuals who received etanercept or adalimumab in 2005 refilled their prescription at least once each of the following 4 years. CONCLUSIONS: Both prevalence and incidence of use of etanercept and adalimumab increased in Norway during 2005-2009. A high proportion of the individuals redeemed prescriptions regularly over 5 years. PMID- 21523850 TI - General practitioners' prescribing patterns for the elderly in a province of Iran. AB - PURPOSE: To determine prescribing patterns by general physicians working in primary care (GPs) in Iran for the elderly and the prevalence of inappropriate prescribing. METHODS: We collected information about prescribed medicines for 10% of patients in primary care aged 65 years or above in six cities in one province during two separate months 1 year apart. Inappropriate prescribing was determined using Beers criteria, excluding diagnosis-related medications. The WHO indicators for appropriateness of prescribing in general practice and drug-drug interactions (DDIs) were also assessed. RESULTS: A total of 2041 patients were studied (mean age 73 years, 56% were women). Drugs for the alimentary system (20%), nervous system (15%), cardiovascular system (14%), and anti-infectives (12%) were most frequently prescribed. Almost all drugs (96%) were prescribed by generic names. Thirty percent of patients received at least one inappropriate drug (27% for men; 33% for women), whereof 94% were categorized as high risk for adverse effects. Indomethacin, diphenhydramine, and methocarbamol were the most common inappropriate medications. The average number of drugs per patient was 4.4 (4.2 for men; 4.5 for women). Forty-four percent of patients received five or more drugs. Antibiotics and injections were prescribed in 39 and 55% of all patients, respectively. Clinically relevant DDIs were observed for 14% of the patients. CONCLUSION: Our findings call for further interventions aiming at educating GPs to reduce potential errors. National drug policies and prescribing guidelines should be implemented to address the problem of inappropriate drug usage among the elderly. PMID- 21523849 TI - Management of cannabis use during pregnancy: an assessment of healthcare professionals' practices. AB - PURPOSE: Because of the increase of cannabis use, healthcare professionals are more and more confronted with pregnancies which have been exposed to this drug. There may be health consequences during the course of pregnancy and also for the babies throughout their development. We have made a study in order to evaluate practices of detection and care for pregnant women who use cannabis. METHODS: A questionnaire was sent to all gynaecologists (GYNs), obstetricians (OBs) and midwives (MWs) in the district of Loire-Atlantique and to a 20% randomized sample of general practitioners (GPs). RESULTS: The participation rate was 60.1%. Only 51.4% of healthcare professionals asked their patients about drugs use and 68.1% didn't feel informed enough about the risks of cannabis use during pregnancy. There was a significant difference between the healthcare professionals who deliver babies (OBs and MWs) and those who only do prenatal consultations (GYNs and GPs). The first group question their patients about the use of cannabis more often (69.1% versus 39.8%; p = 0.01), and also feel more informed about the risks of cannabis use during pregnancy (42.0% versus 24.4%; p = 0.025). CONCLUSIONS: Healthcare professionals who supervise childbirth have a more accurate perception of the risk related to the consumption of cannabis during pregnancy. But preventive action must be taken early on because the lack of early identification at the beginning of pregnancy represents a public health problem. After observing the results we feel there is a strong need for training for all practitioners. PMID- 21523851 TI - Clinical characteristics of patients with drug hypersensitivity in Norway: a single-centre study. AB - BACKGROUND: Drug hypersensitivity reactions (DHRs) represent an important public health problem. Knowledge of their clinical characteristics will provide improved diagnostic approaches to this topic. OBJECTIVES: The aim of the present study was to describe the clinical characteristics of patients with suspected DHRs. METHODS: The medical records of 206 outpatients with suspected DHRs, who consulted a Norwegian allergy centre from January 2005 to December 2009, were investigated in a retrospective study. RESULTS: Mean age (range) was 44.3 (11-84) years, and 72% of the patients were women. The most common underlying diseases justifying the use of drugs were infections (49%) and pain-related diseases (23%). Antibiotics (53%), non-steroidal anti-inflammatory drugs (NSAIDs) (32%), paracetamol (15%) and other drugs (46%), used as monotherapy or combinations, were the most often suspected drugs. Cutaneous symptoms were the most frequently reported symptoms (83%). Hospitalisation or prolonged hospitalisation was needed in 38% of the cases, and anaphylaxis was reported in 28% of all the patients. Skin prick tests were performed in 185 patients, of which 14 patients had positive test results. Drug provocation tests (DPTs) were performed in only 86 patients, six of which had positive reactions. DHRs were confirmed in 24 and rejected in 81 patients. Unsettled cases (39%) were mainly due to not performing DPTs. CONCLUSIONS: Suspected DHRs occur predominantly in women. The most common manifestations are cutaneous symptoms, but life-threatening reactions justifying hospitalisation may occur. Antibiotics and NSAIDs are the two drug families most frequently suspected. DPTs need to be included in diagnostic protocols in order to evaluate suspected DHRs. PMID- 21523852 TI - Drug prescriptions of adults with adolescent depression in a community sample. AB - PURPOSE: The prescription drugs have, to our knowledge, not been much studied in epidemiological samples with long-term follow-up. Accordingly, our purpose was to analyze the use of prescription drugs in adults with adolescent depression. METHODS: A population-based cohort of adolescents (n = 2465) was screened for the presence of depressive symptoms and diagnosed according to a structured interview. Totally, 362 individuals were identified as depressed and compared with 250 non-depressed controls. The prescription drugs were evaluated at the age of 29-31 years from a register kept by the National Health and Welfare Board. RESULTS: The formerly depressed females received significantly more prescription drugs, such as antidepressants, antiepileptics, antibacterials, antimycotics, and antihistamines for systemic use as well as other drugs, compared with controls (15.6 +/- 27.4 vs 8.2 +/- 7.4 recipes, p < 0.001). Formerly depressed males did not differ from controls regarding prescription drugs. CONCLUSIONS: The females but not males with adolescent depression subsequently received more prescription drugs than non-depressed peers. Depressed female adolescents received more psychotropic and non-psychotropic drugs later in life compared to the non depressed. This might be as a result of physical illnesses, different treatment seeking behaviors, or somatizing reactions. PMID- 21523854 TI - Lgr4-deficient mice showed premature differentiation of ureteric bud with reduced expression of Wnt effector Lef1 and Gata3. AB - We previously reported that Lgr4 has a critical role in the morphogenesis of kidney, but the detailed functions of Lgr4 in kidney development have not been elucidated. In contrast to Lgr4 null mice with 129Ola * C57BL/6J mixed background, C57BL/6J-backcrossed Lgr4 null mice (Lgr4(-/-)) showed the severe phenotype of embryonic lethality and also had dilated tubules in kidneys at E16.5. Based on quantitative RT-PCR and in situ hybridization, branching morphogenesis at E15.5 in the Lgr4(-/-) was arrested earlier, and both DBA-lectin staining and immunohistochemical analysis using Aqp3 antibodies showed that the ureteric bud (UB) of Lgr4(-/-) kidneys underwent premature differentiation. Furthermore, quantitative RT-PCR and histological analysis suggested that the impaired UB differentiation was caused by down-regulation of the Wnt pathway and Gata3 in the Lgr4(-/-) kidneys. We demonstrate here that Lgr4 has a novel function for maintaining the UB in an undifferentiated state. PMID- 21523853 TI - Tumor suppressor Lzap regulates cell cycle progression, doming, and zebrafish epiboly. AB - Initial stages of embryonic development rely on rapid, synchronized cell divisions of the fertilized egg followed by a set of morphogenetic movements collectively called epiboly and gastrulation. Lzap is a putative tumor suppressor whose expression is lost in 30% of head and neck squamous cell carcinomas. Lzap activities include regulation of cell cycle progression and response to therapeutic agents. Here, we explore developmental roles of the lzap gene during zebrafish morphogenesis. Lzap is highly conserved among vertebrates and is maternally deposited. Expression is initially ubiquitous during gastrulation, and later becomes more prominent in the pharyngeal arches, digestive tract, and brain. Antisense morpholino-mediated depletion of Lzap resulted in delayed cell divisions and apoptosis during blastomere formation, resulting in fewer, larger cells. Cell cycle analysis suggested that Lzap loss in early embryonic cells resulted in a G2/M arrest. Furthermore, the Lzap-deficient embryos failed to initiate epiboly--the earliest morphogenetic movement in animal development- which has been shown to be dependent on cell adhesion and migration of epithelial sheets. Our results strongly implicate Lzap in regulation of cell cycle progression, adhesion and migratory activity of epithelial cell sheets during early development. These functions provide further insight into Lzap activity that may contribute not only to development, but also to tumor formation. PMID- 21523855 TI - Comprehensive prediction of mRNA splicing effects of BRCA1 and BRCA2 variants. AB - Variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes potentially affecting coding sequence as well as normal splicing activity have confounded predisposition testing in breast cancer. Here, we apply information theory to analyze BRCA1/2 mRNA splicing mutations categorized as VUS. The method was validated for 31 of 36 mutations known to cause missplicing in BRCA1/2 and all 26 that do not alter splicing. All single-nucleotide variants in the Breast Cancer Information Resource (BIC; Breast Cancer Information Core Database; http://research.nhgri.nih.gov/bic; last access June 1, 2010) were then analyzed. Information analysis is similar in sensitivity to other predictive methods; however, the thermodynamic basis of the theory also enables splice-site affinity to be determined accurately, which is important for assessing mutations that render natural splice sites partially functional and competition between cryptic and natural splice sites. We report 299 of 2,071 single-nucleotide BIC mutations that are predicted to significantly weaken natural sites and/or strengthen cryptic splice sites, 171 of which are not designated as splicing mutations in the database. Splicing alterations are predicted for 68 of 690 BRCA1 and 60 of 958 BRCA2 mutations designated as VUS. These analyses should be useful in prioritizing suspected mutations for downstream expression studies and for predicting aberrantly spliced isoforms generated by these mutations. PMID- 21523856 TI - Reading skill is related to individual differences in brain structure in college students. AB - We compared cortical anatomy, using 3D brain MRI scans, between three groups of university students: proficient readers (skilled at phonological decoding and text comprehension), poor readers (impaired at phonological decoding and text comprehension), and resilient readers (impaired at phonological decoding but skilled in text comprehension). This latter group provides a unique opportunity to investigate associations between cortical morphology and phonological decoding deficits in individuals without attendant reading comprehension deficits. We predicted widespread reductions in gray matter thickness and brain size in temporal and frontal regions in poor readers, and more focal differences in brain morphology in resilient readers. Typical asymmetry of gray matter thickness in the temporo-parietal region was reduced in both poor and resilient readers. Poor readers also exhibited smaller brain sizes in the right inferior frontal region than both proficient and resilient readers. Altered asymmetry in the temporo parietal region may therefore be associated with poor phonological decoding and impaired text comprehension may be associated with altered frontal morphology. Resilient readers show relatively focal behavioral differences from typical readers, so it is interesting that they show reliable differences in brain morphology. PMID- 21523857 TI - Normal sexual dimorphism in the human basal ganglia. AB - Male and female brains differ in both structure and function. Investigating this sexual dimorphism in healthy subjects is an important first step to ultimately gain insight into sex-specific differences in behavior and risk for neuropsychiatric disorders. The basal ganglia are among the main regions containing sex steroid receptors in the brain and play a central role in cognitive (dys)functioning. However, little is known about sexual dimorphism of different basal ganglia nuclei. The aim of the present study was to investigate sex-specific differences in basal ganglia morphology using MRI. We applied automatic volumetry on anatomical MRI data of two large cohorts of healthy young adults (n = 463 and n = 541) and assessed the volume of four major nuclei of the basal ganglia: caudate nucleus, globus pallidus, nucleus accumbens, and putamen, while controlling for total gray matter volume, total white matter volume, and age of the participant. No significant sex differences were found for caudate nucleus and nucleus accumbens, but males showed significantly larger volumes for globus pallidus and putamen, as confirmed in both cohorts. These results show that sexual dimorphism is neither a general effect in the basal ganglia nor confined to just one specific nucleus, and will aid the interpretation of differences in basal ganglia (dys)function between males and females. PMID- 21523858 TI - Influence of fetal bovine serum on cytotoxic and genotoxic effects of lectins in MCF-7 cells. AB - Canavalia ensiformis (ConA), Canavalia brasiliensis (Conbr), and Cratylia floribunda (CFL) lectins have exhibited glucose-mannose binding specificity. We investigated the effect of fetal bovine serum (FBS) concentrations (1, 5, 10, and 20%) on the cytotoxic effect of these lectins against breast tumor cell line MCF 7. Cell viability was examined using the MTT reduction assay. When cells were grown in a medium supplemented with a higher serum concentration (10 or 20%), all lectins were much less toxic. When we used 1% FBS, it was possible to achieve a concentration-dependent activity by all examined lectins, with an IC(50) of 3.5, 25, and 60 ug/mL for ConA, Conbr, and CFL, respectively. All lectins incubated with 1% FBS induced apoptosis and DNA damage in MCF-7 cells. We conclude that ConA, Conbr, and CFL lectins' cytotoxic and genotoxic effects were observed only at low concentrations of serum. PMID- 21523859 TI - Neither nitrite nor nitric oxide mediate toxic effects of nitroglycerin on mitochondria. AB - It is commonly accepted that the major effect of nitroglycerin (NG) is realized through the release of nitric oxide (NO) catalyzed by aldehyde dehydrogenase-2 (ALDH2). In addition, it has been shown that NG inhibits mitochondrial respiration. The aim of this study was to clarify whether NG-mediated inhibition of mitochondrial respiration is mediated by NO. In rat liver mitochondria, NG inhibited complex-I-dependent respiration and induced reactive oxygen species (ROS) production, preferentially at complex I. Both effects were insensitive to chloral hydrate, an ALDH2 inhibitor. Nitrite, an NG intermediate, had no influence on either mitochondrial respiration or the production of ROS. NO inhibited preferentially complex I but did not elevate ROS production. Hemoglobin, an NO scavenger, and blue light had contrary effects on mitochondria inhibited by NO or NG. In summary, our data suggest that although NG induces vasodilatation via NO release, it causes mitochondrial dysfunction via an NO independent pathway. PMID- 21523860 TI - Gene expression profiling to examine the thyroid hormone-disrupting activity of hydroxylated polychlorinated biphenyls in metamorphosing amphibian tadpole. AB - Hydroxylated polychlorinated biphenyls are the metabolites produced from parent compounds by the drug-metabolizing enzyme cytochrome P450. These compounds are suspected to disrupt postembryonic neural development in the brains of mammals including humans. We studied the effects of these compounds on thyroid hormone function in the brain by using metamorphosing tadpoles of the African clawed toad (Xenopus laevis) as a model for mammalian postembryonic development. The metamorphosis assay revealed that these compounds inhibit thyroid hormone-induced metamorphosis. Genome-wide gene expression analysis in the brain following short term exposure demonstrated that delayed metamorphosis could partially be caused by disruption of thyroid hormone-induced gene expression. Furthermore, we associated the terms of functional ontology with the genes, whose expression was disrupted by these compounds. We suggest that the use of a genome-wide analysis coupled with bioinformatics might provide an overview of the molecular mechanism underlying thyroid-disrupting activities in vivo. PMID- 21523861 TI - Ornithine decarboxylase prevents dibenzoylmethane-induced apoptosis through repressing reactive oxygen species generation. AB - Dibenzoylmethane (DBM) belongs to the flavonoid family and is a minor constituent of the root extract of licorice and the beta-diketone analogue of curcumin. It exhibits antimutagenic, anticancer, and chemopreventive effects. Ornithine decarboxylase (ODC), the rate-limiting enzyme of the polyamine biosynthetic pathway, plays an important role in growth, proliferation, and transformation. Our previous studies showed ODC overexpression prevented etoposide-, paclitaxel-, and cisplatin-induced apoptosis. Here, we investigated one mechanism of DBM induced apoptosis and the antiapoptotic effects of ODC during DBM treatment. We found that DBM induced apoptosis, promoted reactive oxygen species (ROS) generation, and disrupted the mitochondrial membrane potential (Deltapsi(m). N acetylcysteine, a ROS scavenger, reduced DBM-induced apoptosis, which led to the loss of Deltapsi(m) due to reduced ROS. Overexpression of ODC in parental cells had the same effects as the ROS scavenger. The results demonstrated that DBM induced apoptosis was a ROS-dependent pathway and ODC overexpression blocked DBM induced apoptosis by inhibiting intracellular ROS production. PMID- 21523864 TI - Chiral metal-DNA four-arm junctions and metalated nanotubular structures. PMID- 21523865 TI - General and selective palladium-catalyzed oxidative esterification of alcohols. PMID- 21523866 TI - Glycan structure of a high-mannose glycoprotein from Raman optical activity. PMID- 21523867 TI - Nickel-catalyzed cross-coupling of aryltrimethylammonium iodides with organozinc reagents. PMID- 21523868 TI - Coupling amperometry and total internal reflection fluorescence microscopy at ITO surfaces for monitoring exocytosis of single vesicles. PMID- 21523869 TI - [n]Cyclo-2,7-naphthylenes: synthesis and isolation of macrocyclic aromatic hydrocarbons having bipolar carrier transport ability. PMID- 21523870 TI - An expedient synthesis of a functionalized core structure of bielschowskysin. PMID- 21523871 TI - Organocatalysis and C-H activation meet radical- and electron-transfer reactions. PMID- 21523876 TI - Theoretical and experimental studies on the mechanism of coloration of polyimides. AB - The mechanism of coloration of polyimides is investigated theoretically and experimentally. Since light is considered to be absorbed by polyimides via charge transfer excitation, we used the long-range-corrected time-dependent density functional theory recently developed by Tawada et al. [Y. Tawada, T. Tsuneda, S. Yanagisawa, T. Yanai, K. Hirao J. Chem. Phys.2004, 120, 8425] for the calculation of excitation energies and oscillator strengths. Classical molecular dynamic simulations for packed chain models of polyimides were also performed to analyze the structural information of polyimides in condensed phase. In order to predict the transparency of polyimide film, we developed a theoretical method by combining the results of electronic structure calculations and those of molecular dynamics simulations. We compare our theoretical results with experimental ones and discuss the difference between them. As a result, we clarify the new mechanism of coloration and obtain results for the theoretical UV/Visible spectra. PMID- 21523877 TI - Recognition and ordering at surfaces: the importance of handedness and footedness. AB - The expression of chirality at surfaces, arising from the adsorption of chiral molecules, is usually discussed in terms of the molecular handedness. However, the adsorption process often leads to a new manifestation of chirality in the form of the adsorption footprint. Therefore, in order to fully define the chirality of the interface we propose that both the handedness and the footedness of the system must be considered. To illustrate this point, we describe the ordering behavior of the molecules tartaric acid, succinic acid, proline, and 3 pyrroline-2-carboxylic (PCA) on a Cu(110) surface using deconvolution maps separating the arrangement of enantiomers, conformers, adsorption footprints and rotamers within an organized assembly. Tartaric and succinic acid mimic the behavior of a conventional 3D conglomerate and racemic compound in terms of both the handedness and footedness, respectively. However, racemic PCA and proline, while expressing a random solid solution of enantiomers and conformers, both display unexpected degrees of order when adsorbate footprint and orientation are considered. PMID- 21523878 TI - Inelastic neutron scattering study of Pt(II) complexes displaying anticancer properties. AB - The well-known platinum(II) chemotherapeutic drugs cisplatin [cis (NH(3))(2)PtCl(2)] and carboplatin [Pt(NH(3))(2)C(6)O(4)H(6)], as well as the analogous transplatin [trans-(NH(3))(2)PtCl(2)], were studied by inelastic neutron scattering (INS) spectroscopy, coupled to quantum mechanical methods, and some ancillary work with X-ray diffraction on powders. An assignment of the experimental spectra was carried out based on the calculated INS transition frequencies and intensities (at the DFT level), thereby achieving a good correspondence between the calculated and observed data. Unusually good-quality INS spectra were obtained from about 250 mg, which is the smallest sample of a hydrogenous compound for which a successful INS interpretation has been reported. The knowledge of the local configuration of this kind of complexes is essential for an accurate understanding of their activity, which will pave the way for the rational design of novel third-generation drugs comprising cisplatin- and carboplatin-like moieties. PMID- 21523879 TI - Multi-field effect on the electronic properties of silicon nanowires. AB - The quantum confinement and electronic properties of silicon nanowires (SiNWs) under an external strain field epsilon and an electric field E-as well as both (epsilon plus E)-are systematically investigated using density functional theory. These two fields exist in working environments of integrated circuits. It is found that both epsilon and E lead to a drop of the band gap E(g)(epsilon,E) of the SiNWs. If both fields coexist, the interaction between epsilon and E causes that E(g)(epsilon,E) becomes orientation-dependent, which results from variations of both the conduction-band minimum and the valence-band maximum. The interaction is further illustrated by the density of states near the Fermi level and the eigenvalue of the highest occupied molecular orbital. PMID- 21523880 TI - The rate-determining step is dead. Long live the rate-determining state! AB - The concept of a rate-determining step (RD-Step) is central to the kinetics community, and it is basic knowledge even for the undergraduate chemical student. In spite of this, too many different definitions of the RD-Step appear in the literature, all of them with drawbacks. This dilemma has been thoroughly studied by several authors in the attempt to "patch" the drawbacks and bring the RD-Step to a correct physical meaning. Herein we review with simple models the most notable definitions and some challengers of the RD-Step concept, to conclude with the deduction that there are no rate-determining steps, only rate-determining states. PMID- 21523881 TI - High-fat diet protects BB/OK rats from developing type 1 diabetes. AB - BACKGROUND: It is well known that lipid metabolism plays an important role in the early stages of type 1 diabetes (T1D). For that reason, we examined factors that influence lipid metabolism of BioBreeding/Ottawa Kalsburg (BB/OK) rats that spontaneously develop an insulin-dependent T1D. METHODS: BB/OK female rats were fed a high-fat diet during pregnancy (Ssniff R-Z + 10% tallow) and their progeny were also given this diet up to an age of 30 weeks (n = 55) or 4 weeks (n = 14) to study gene expression of Pparg, Fasn, Lep, Adipoq, Repin1, Rarres 2, and Glut4 in adipose tissue. Forty-two BB/OK rats fed the normal diet (Ssniff R-Z) during pregnancy and the observation period served as controls. RESULTS: The high-fat diet significantly decreased diabetes frequency in BB/OK rats when compared with control rats (71 versus 95%, p = 0.002). Although this difference was also reflected in the male rats (68 versus 100%, p = 0.003), no significant variation was observed in female rats (73 versus 90%, p = 0.23). The high-fat diet resulted in significantly reduced mRNA expression of examined genes in subcutaneous adipose tissue, but not in visceral adipose tissue, except for Fasn and Repin1 expression. CONCLUSIONS: A high-fat diet seems to protect BB/OK rats from T1D in a sex-specific manner. The data suggest that a high-fat diet might influence fat accumulation and/or fat metabolism and prevent T1D development in male rats, which is supported by changes in adipose tissue gene expression. PMID- 21523882 TI - Is balloon aortic valvuloplasty safe in patients with significant aortic valve regurgitation? AB - OBJECTIVES: To assess safety and effectiveness of balloon aortic valvuloplasty (BAV) in patients with symptomatic severe aortic stenosis (AS) and significant aortic regurgitation. BACKGROUND: BAV is a palliative procedure that has possibly been underused in patients with symptomatic AS not suitable for surgical aortic valve replacement or transcatheter aortic valve implantation. Significant aortic regurgitation is commonly perceived as a contraindication to BAV. METHODS: Among 416 consecutive patients undergoing BAV at our Institution, 73 patients showed moderate or severe AR before the procedure. Demographics and baseline characteristics, as well as in-hospital clinical outcome, have been prospectively collected in a dedicated database. Transthoracic echocardiography was regularly performed in all patients undergoing BAV before the procedure and at hospital discharge. RESULTS: Patients had a high-risk profile, confirmed by advanced age (77.2 +/- 11.8 years) and important comorbidity (logistic Euroscore 26.5 +/- 16.3%). Advanced heart failure was present in 73.9%. Indication to BAV was cardiogenic shock in 9.6%, palliation in 31.5%, bridge in 58.9% of the patients. BAV was performed with standard retrograde approach. Aortic valve area increased from 0.62 +/- 0.15 cm(2) at baseline to 0.83 +/- 0.17 cm(2) before discharge (P < 0.001). The degree of AR was improved or unchanged in 65 patients (89%). In hospital mortality was 6.9%, mainly limited to terminal patients. Symptomatic status at discharge was improved in all surviving patients. Acute AR occurred in seven patients; in five of them it was successfully resolved in the catheterization laboratory. CONCLUSIONS: When clinically indicated, BAV can be safely performed in patients with combined aortic stenosis and significant aortic regurgitation. PMID- 21523883 TI - Endovascular treatment of abdominal aortic aneurysms combined with bilateral common and internal iliac aneurysms. AB - INTRODUCTION: Combined aneurysms of aortic and iliac arteries are rare with a prevalence of less than 0.1%. However, these combined aneurysms are associated with a high incidence of thrombosis, distal embolism, or rupture. Endovascular repair is a therapeutic option and includes embolization of the internal iliac artery in numerous cases. Embolization of the internal iliac artery may cause severe ischemia with hip and buttock complications in 2-5%. Therefore, preservation of internal iliac arteries is essential to reduce complications. PATIENT AND METHOD: We describe in detail an endovascular procedure for combined abdominal aortic (diameter of 8.6 cm) and bilateral common and internal iliac aneurysm (diameter of the left side: 6.4 cm; diameter of the right side: 4.3 cm) in a 44-year-old patient caused by media necrosis Erdheim-Gsell. The blood flow of both internal arteries was preserved in this patient. RESULT: Operation was done without any complications. Conversion to an open procedure was not necessary. During follow up (3, 6, and 12 months after operation) the patient did not develop any signs of severe hip and buttock complications. Furthermore, sonography and CT angiography revealed a good blood flow via the internal and external iliac arteries. CONCLUSION: Endovascular repair of abdominal aortic aneurysms combined with bilateral common and internal iliac aneurysms offers a promising minimal invasive procedure. Most importantly, this technique is less invasive than open operations and reduces complications by preserving the pelvic perfusion. PMID- 21523884 TI - Embolization of an Amplatzer mVSD occluder device used for percutaneous closure of an ascending aortic pseudoaneurysm: case report and literature review. AB - Pseudoaneurysm of the ascending aorta is a rare, but potentially dangerous condition. The high morbidity and mortality rate associated with its surgical management has led to the development of transcatheter approaches. We report a case of percutaneous closure of an ascending aortic pseudoaneurysm using an Amplatzer mVSD occluder device complicated by device embolization at day 27 and we review the literature of Amplatzer devices in this off-label use. PMID- 21523885 TI - Percutaneous pulmonary valve implantation in the native right ventricular outflow tract. AB - Percutaneous pulmonary valve implantation into dysfunctional right ventricular (RV) to pulmonary artery conduits is being increasingly performed in many European and North American centers with satisfactory results and low complication rates. We report the first application of this elaborate technique in the native RV outflow tract of a young patient who developed severe supravalvular pulmonary stenosis following an arterial switch operation for transposition of the great arteries. The procedure may be used as an alternative to surgical repair for the treatment of selected patients with supravalvular pulmonary stenosis complicating congenital heart surgery. PMID- 21523886 TI - Endovascular treatment of mesenteric ischemia. AB - OBJECTIVES: Our goal was to describe a single-center's experience in managing acute and chronic mesenteric ischemia with endovascular therapies. BACKGROUND: Open surgical revascularization has been considered the historical gold standard treatment for mesenteric ischemia though it poses considerable morbidity and mortality risk. An aging population with increased comorbidities makes endovascular treatment a more attractive treatment option. METHODS: Consecutive subjects receiving percutaneous mesenteric interventions for acute and chronic mesenteric ischemia from 2004 to 2010 were identified retrospectively. Information on comorbidities, symptoms, screening tests, procedural outcomes, and follow up was obtained. RESULTS: Thirty-one patients received percutaneous mesenteric interventions during this period. The mean age of the population was 65.0 years with roughly equal proportions of males (48.4%) and females (51.6%). Traditional cardiovascular risk factors were highly prevalent (hypertension 45.2%, diabetes 25.8%, dyslipidemia 38.7%, nicotine use 45.2%). Procedural success was 93.5%; no periprocedural complications were reported. During a mean follow up of 13 months, 16.1% required repeat revascularization and 22.6% died. Endovascular treatment of acute mesenteric ischemia was successful (n = 8) and no patient required open surgical revascularization acutely or during follow-up. CONCLUSIONS: Endovascular treatment of mesenteric ischemia is a safe and effective therapy with acceptable long-term results. Our experience with acute mesenteric ischemia suggests that percutaneous treatment may be an effective alternative to surgical revascularization in appropriately selected patients. PMID- 21523887 TI - Very late stent thrombosis due to DES fracture: description of a case and review of potential causes. AB - Stent fracture and subsequent stent thrombosis are known complications after stent implantation, especially in stents with closed cell design like the first generation sirolimus drug eluting stents (DES). Late stent thrombosis is very rarely encountered in our patient population, majority Chinese. We report a case of non-ST elevation myocardial infarction as a result of very late stent thrombosis (three years after implantation) due to stent fracture at the site of overlap of two first generation sirolimus DES. There were initial difficulties in restoring coronary flow by conventional reperfusion therapies but a successful outcome after implantation of an endothelial progenitor cell capture stent, with no further recurrence of ischemic event after 12 months. An attempt was made to analyze all existing factors present and contributing to the stent fracture and stent thrombosis in this case, as reported in the literature. PMID- 21523888 TI - Angina pectoris in a patient with protein C deficiency and deep vein thrombosis: thrombus versus myxoma? AB - A 55-year-old Caucasian man with history of hypertension, diabetes mellitus, protein C deficiency, and deep vein thrombosis presented with typical angina. Both computed tomography and transesophageal echocardiography identified a mobile mass in left atrium but could not differentiate between thrombus and myxoma. A cardiac catheterization with coronary angiography demonstrated tumor neovascularization, suggestive of myxoma. Pathology examination after mass resection confirmed the diagnosis. Patients with myxoma could present with obstructive, embolic, or constitutional symptoms. However, typical angina has never been reported as the primary manifestation. Although being helpful, various noninvasive imaging modalities, including magnetic resonance image, often have limitations to help making a definitive diagnosis, before surgery decision, especially under hypercoagulable condition. In contrast, cardiac catheterization can help not only in differentiation diagnosis but also in detecting possible intracoronary embolization from myxoma. In patients with myxoma complicated with hypercoagulable disorders, anticoagulation will play essential role in long-term care. PMID- 21523889 TI - Impella assisted transradial coronary intervention in patients with acute coronary syndromes and cardiogenic shock: case series. AB - Operators may feel apprehension when considering the transradial approach in patients with cardiogenic shock due to concerns of the need for femoral access for mechanical support. There is however potential benefit of transradial approach in this setting by reducing bleeding complications in patients on potent anticoagulant and antiplatelet agents. We report three cases of patients with cardiogenic shock with successful transradial intervention (TRI) whilst using unilateral femoral access for Impella (ABIOMED, Danvers, MA) mechanical support. In two cases, the need for mechanical support was not clear at the beginning of the procedure, and in the third there was a clear need to combine femoral and radial access due to pre-existing anatomic issues. Two patients required transfusion of red blood cells but otherwise there were no vascular access complications. PMID- 21523890 TI - A novel way to reduce thrombus build-up in vena cava filters. AB - OBJECTIVES AND BACKGROUND: The build-up of thromboses in vena cava filters after deployment presents serious problem to the patients. We proposed a novel way to overcome this problem in a belief that intentionally induced swirling flow can optimize blood flow patterns in vena cava filters, enhance the stirring motion of flow, in turn accelerate the dissolution of blood clots captured in the filter and facilitate blood to flow pass through the filters. METHODS: In this study, we experimentally compared the work efficiency of a vena cava filter under swirling flow condition with that of the same filter under normal flow condition. RESULTS: The results show that when compared to the normal flow, the swirling flow indeed has a significantly beneficial effect on a VCF which can decrease its flow-out time nearly 40% and reduce clot build-up in the filter more than 50%. CONCLUSIONS: We therefore believe that the design of an ideal VCF should take how to create swirling flow in the filter into the consideration. PMID- 21523891 TI - Agreement and reproducibility of gray-scale intravascular ultrasound and optical coherence tomography for the analysis of the bioresorbable vascular scaffold. AB - OBJECTIVE: To report the agreement between gray-scale intravascular ultrasound (GS-IVUS) and optical coherence tomography (OCT) in assessing the bioresorbable vascular scaffolds (BVS) structures and their respective reproducibility. BACKGROUND: BVS are composed of an erodible polymer. Ultrasound and light signals backscattered from polymeric material differs from metallic stents using GS-IVUS and OCT. METHODS: Forty-five patients included in the ABSORB trial were treated with a 3.0 * 18 mm BVS and imaged with GS-IVUS 20 MHz and OCT post-implantation. Qualitative (ISA, side-branch struts, protrusion, and dissections) and quantitative (number of struts, lumen, and scaffold area) measurements were assessed by two investigators. The agreement and the inter- and intraobserver reproducibility were investigated using the kappa (kappa) and the interclass correlation coefficient (ICC). RESULTS: GS-IVUS and OCT agreement was predominantly poor at a lesion, frame, and strut level analysis (kappa and ICC <0.4) for qualitative measurements. GS-IVUS demonstrated a reduced ability to detect cross-sections with ISA (4.5% vs. 20.6%), side-branch (SB) struts (6.3% vs. 7.8%), protrusions (3.2% vs. 9.6%), and dissections (0.2% vs. 9.0%) compared with OCT. GS-IVUS reproducibility was poor-moderate (kappa and ICC <0.6) except for ISA and SB-struts (kappa and ICC between 0.2 and 0.75). OCT showed an excellent reproducibility (kappa and ICC > 0.75) except for the assessment of tissue protrusion (kappa and ICC between 0.47 and 0.94). GS-IVUS reproducibility was poor-moderate (ICC <= 0.5) in assessing the number of struts but excellent with OCT (ICC > 0.85). The reproducibility to assess lumen and scaffold areas was excellent using both techniques (ICC > 0.85). CONCLUSIONS: GS-IVUS has a poor capacity to detect qualitative findings post-BVS implantation and its reproducibility is low compared with OCT. The use of GS-IVUS should be limited when assessing lumen and scaffold areas. PMID- 21523892 TI - Intracoronary bolus-only compared with intravenous bolus plus infusion of tirofiban application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - OBJECTIVES: The aim of this pilot study was to compare intracoronary bolus-only with standard intravenous bolus plus maintenance infusion of tirofiban with respect to improvement in myocardial reperfusion after primary percutaneous coronary intervention (p-PCI). BACKGROUND: Changes in clinical practice may obviate the need for a maintenance infusion of small molecule glycoprotein IIb/IIIa inhibitors in current practice. METHODS: Forty-nine patients undergoing p-PCI were randomized to either intracoronary bolus-only (n = 25) or intravenous bolus plus infusion (n = 24) of tirofiban. The primary end point was coronary hemodynamic indices of microvascular perfusion measured 4-5 days after p-PCI. The secondary end points were ST segment resolution at 90 min, the corrected TIMI frame count and myocardial blush grade. At 6 months, echocardiography and technetium-99m single-photon-emission computed tomography were performed. RESULTS: Microvascular perfusion did not differ significantly between the two treatment groups: index of microvascular resistance (27 +/- 13 vs. 35 +/- 15 U, P = 0.08) and coronary flow reserve (2.2 +/- 0.7 vs. 1.9 +/- 0.6, P = 0.25). The corrected TIMI frame counts assessed in the first (P = 0.13) and the second (P = 0.09) catheterization or the myocardial blush grades evaluated immediately (P = 0.23) and 4-5 days after MI (P = 1.00) were not significantly different between the two groups. At 6 months, there was no difference between the two groups in infarct size, left ventricular volumes, or ejection fraction. CONCLUSIONS: The standard intravenous bolus plus maintenance infusion of tirofiban in p-PCI is not superior to intracoronary bolus-only administration with respect to microvascular perfusion. Further, adequately powered randomized trials are warranted to evaluate the clinical outcomes associated with this strategy. PMID- 21523893 TI - Sustained clinical safety and efficacy of a biodegradable-polymer coated sirolimus-eluting stent in "real-world" practice: three-year outcomes of the CREATE (Multi-Center Registry of EXCEL Biodegradable Polymer Drug Eluting Stents) study. AB - BACKGROUND: The CREATE is a post-marketing surveillance multicenter registry that demonstrated satisfactory angiographic and clinical (at 18 months) outcomes of a biodegradable polymer based sirolimus-eluting stent (EXCEL, JW Medical System, Weihai, China) for the treatment of patients in routine clinical practice. OBJECTIVES: To evaluate the three-year clinical safety and efficacy outcomes in patients enrolled in the CREATE study. METHODS: A total of 2077 all comers have been enrolled in the CREATE study at 59 centers from four countries. Recommended antiplatelet regimen was clopidogrel and aspirin for six months followed by chronic aspirin therapy. The prespecified primary outcome was the rate of major adverse cardiac events (MACE) at 12, 18, and 36 months. RESULTS: Clinical follow up was completed in 2025 (97.5%) patients at three years. The average duration of clopidogrel treatment was 199.8 +/- 52.7 days and 80.5% of discharged patients discontinued clopidogrel at six months. The cumulative rate of MACE was 4.5% and the rate of stent thrombosis was 1.53% at three years. At six months to three years, prolonged clopidogrel therapy (>6 months) was not beneficial in reducing cumulative hazards of MACE (3.4% vs. 3.1%, log rank P = 0.725) or stent thrombosis (1.5% vs. 0.6%, log rank P = 0.053). CONCLUSIONS: This study demonstrates sustained three-year clinical safety and efficacy of biodegradable polymer-based sirolimus-eluting stents when used with six months of dual antiplatelet therapy in a "real-world" setting. PMID- 21523894 TI - Successful implantation of the Edwards Sapien THV via direct aortic access in a patient with previous pneumonectomy and no other access. AB - The Edwards Sapien transcatheter heart valve (THV) is available for treatment of severe symptomatic aortic stenosis via transfemoral access or trans-apical access when ilio-femoral vessels are considered unsuitable. Some patients, however, may be unsuitable for access via either of these routes. We describe successful implantation of an Edwards Sapien THV via direct access of the ascending aorta in a patient with previous right pneumonectomy and pulmonary disease who was considered unsuitable for implantation via femoral vessels or via trans-apical approach. The potential advantages of this novel access route over trans-apical approach are discussed. PMID- 21523895 TI - Occupational radiation dose during transcatheter aortic valve implantation. AB - OBJECTIVES: To examine the occupational radiation dose during transcatheter aortic valve implantation (TAVI) in both transfemoral and transapical approach. BACKGROUND: Interventional fluoroscopic guided cardiac procedures lead inevitably to radiation exposure of workers, which over time may be associated with an increased incidence of cancer and cataract. METHODS: Using thermoluminescence dosimeters, the radiation dose of the cardiothoracic surgeon, cardiologist, and two assistants was measured on the apron at chest height and on both feet. In addition, dose measurements were performed on the hands of the two operators and on the eyes of the cardiothoracic surgeon. This study involved 11 transapical and 11 transfemoral TAVIs. The effective dose was estimated from the dose measured on the apron. RESULTS: In the transapical TAVI the cardiothoracic surgeon received a significantly higher equivalent hand dose (average +/- SD), 1.9 +/- 0.6 mSv, equivalent foot dose, 0.57 +/- 0.31 mSv, equivalent eye dose, 0.11 +/- 0.06 mSv, and effective dose, 0.03 +/- 0.02 mSv, than any staff member in the transfemoral TAVI, with highest average doses of 0.03 +/- 0.02 mSv, 0.22 +/- 0.19 mSv, 0.03 +/ 0.01 mSv, and 0.003 +/- 0.005 mSv, respectively. CONCLUSIONS: This study provides hitherto unavailable data on the radiation exposure of staff during transfemoral and transapical TAVIs. Relatively high doses were observed in the transapical approach. The dose of the right hand of the cardiothoracic surgeon will reach the annual limit within about 250 procedures per year, implying that hand dose measurements should become standard and that the number of procedures performed by the cardiothoracic surgeon involving X-rays may have to be limited. PMID- 21523896 TI - Perforation of the sinus of Valsalva by guiding catheter during the percutaneous coronary intervention via the right transradial approach: a very unusual complication. AB - Iatrogenic dissection of the sinus of Valsalva or of the ascending aorta is a rare but potentially fatal event, during the percuteneous coronary intervention (PCI). We reported a case of perforation of the sinus of Valsalva by guiding catheter during PCI via the right transradial approach (TRA) successfully managed and sealed without any sequelae. The choice of guiding catheter into the right TRA should be done carefully and its manipulation should be performed with caution in the coronary artery and in the sinus of Valsalva. PMID- 21523897 TI - Characterization of radiation exposure and effect of a radiation monitoring policy in a large volume pediatric cardiac catheterization lab. AB - OBJECTIVES: This study aimed to characterize radiation dose during cardiac catheterization in congenital heart disease and to assess changes in dose after the introduction of a radiation monitoring policy. BACKGROUND: Minimizing radiation exposure is an important patient safety initiative and relatively few data are available characterizing radiation dose for the broad spectrum of congenital cardiac catheter-based interventions. METHODS: Radiation dose data were reviewed on all cases since 7/1/05 at a single large center. Procedures were classified according to 20 common case types then subdivided into five age categories. Groups with <20 cases were excluded. Radiation dose was estimated by cumulative air KERMA (mGy) and DAP (dose area product, MUGym(2)) which were reported as median and interquartile range (IQR). We also examined differences in radiation dose before and after the implementation of a radiation policy. RESULTS: Between 7/1/05 and 12/10/08, 3,365 cases were identified for inclusion. Radiation dose increased with age and procedural complexity. Patients were characterized into low, medium, and high dose categories relative to each other. "Low" dose cases included isolated pulmonary or aortic valvotomy, pre-Fontan assessment, and ASD closure. "High" dose cases involved multiple procedures in pulmonary arteries or veins. After introduction of a radiation policy, there was a significant decrease in radiation dose across a variety of case types, particularly among infants and young children. CONCLUSIONS: Radiation dose in congenital cardiac catheterization varies by age and procedure type. A radiation monitoring and notification policy may have contributed to reduced radiation dose. PMID- 21523898 TI - Percutaneous transcatheter closure of interatrial septal defect in adults: procedural outcome and long-term results. AB - BACKGROUND: Percutaneous transcatheter closure of patent foramen ovale (PFO) and atrial septal defect (ASD) has been shown to be feasible. AIM: The aim of this study was to evaluate the safety and efficacy of transcatheter interatrial septal shunt closure with prosthesis implantation in adults patients during long-term follow-up. In addition, the impact of thrombophilia and pulmonary hypertension on the outcome were investigated. METHODS: Between June 1999 and November 2009, 287 patients (112 males, 43 +/- 14 years) were treated in our institution by transcatheter closure of PFO (N = 175) or ASD (N = 112). Clinical and echocardiographic follow-up were prospectively performed at 1, 6 and 12 months followed by a 1 once a year evaluation. RESULTS: All procedures were successful with eight procedural complications (2.7%): one stroke, two femoral pseudoaneurysms, three transient atrial fibrillation, two minors pericardial effusions. Among patients with presumed paradoxical embolism, thrombophilia was observed in 29 patients (17%); only one of them experienced a recurrent stroke. Among patients with ASD, pulmonary hypertension was observed in 32 cases (28%) and significantly reduced 6 months after shunt closure (from 47 +/- 7 to 31 +/- 11 mm Hg, P < 0.0001). 99% of patients achieved a complete follow-up. Clinical improvement was observed in 93%. Freedom from death, cardiac surgery or recurrent embolism was 98 +/- 1% at 5 years. CONCLUSION: Percutaneous transcatheter interatrial septal defect closure is a safe and effective treatment in adults patients, even in case of thrombophilia or pulmonary hypertension, during a long term follow-up, up to 11 years. PMID- 21523899 TI - Rapid cycle change to predominantly radial access coronary angiography and percutaneous coronary intervention: effect on vascular access site complications. AB - OBJECTIVES: This study sought to evaluate the safety and feasibility of all operators at a single center changing from predominantly femoral to radial access for coronary percutaneous procedures. BACKGROUND: The radial artery is currently regarded as a useful vascular access site for coronary angiography and percutaneous coronary intervention (PCI). The reduction in local vascular access complications is thought to be a major advantage of the radial route. Despite this, the technique is used less frequently possibly reflecting concerns by cardiologists about the feasibility of using radial access as a preferred option. METHODS: A retrospective study of 1004 consecutive patients who underwent coronary angiography with or without PCI was analyzed. Procedure details and clinical outcomes were assessed according to the radial or femoral approaches. RESULTS: The success rate for cardiac catheterization via the radial approach was 97.4% (815/837) and the femoral approach was 98.8% (165/167). The procedural failure rate for radial access was not different from the femoral route [2.6% vs. 1.2%; odds ratio (OR), 2.26; 95% confidence interval (CI), 0.53-9.71; P = 0.41]. Major access site complications occurred in 0.25% patients in the radial group compared with 4.8% patients in the femoral group [OR, 0.05 (95% CI, 0.01-0.23); P < 0.0001]. CONCLUSIONS: The radial approach has a high rate of success and is associated with fewer major local vascular access site complications than the femoral route. These results can be achieved early in the operator learning curve of low to medium volume operators. PMID- 21523900 TI - Thrombus formation after left atrial appendage exclusion using an Amplatzer cardiac plug device. AB - The feasibility and safety of left atrial appendage closure with the Amplatzer cardiac plug (AGA Medical Corp., Minneapolis, MN) have been recently published; no thrombus formation on the device surface has been reported previously. We describe a case of a 66-year-old man with permanent atrial fibrillation, previous stroke, and contraindication for long-term oral anticoagulant therapy. A 22-mm ACP device was deployed successfully without complications. The patient was discharged on acetyl salicylic acid 100 mg and clopidogrel 75 mg daily. After 4 weeks, the patient was admitted for a lower gastrointestinal bleeding and clopidogrel was stopped. A 3-month follow-up echocardiogram confirmed the exclusion of the LAA but it demonstrated the presence of a thrombus on the atrial surface of the device. It was decided to keep the patient on acetyl salicylic acid 100 mg with the addition of enoxaparin 60 mg bid. Transesophageal echocardiogram demonstrated total resolution of the thrombus after 2 months. PMID- 21523901 TI - Neuroblastoma: a 20-year experience in a UK regional centre. AB - PURPOSE: The role of surgery in the management of neuroblastoma yields conflicting reports. We report a 20-year experience from a UK centre in the context of evolving cancer therapies for neuroblastoma. METHODS: Hospital records of 91 neuroblastoma patients from 1985 to 2005 were studied. Patient demographics, data from operating notes and tumour biology (MYCN status) where available were analysed. RESULTS: Surgery consisted of primary resection or delayed operation following tumour biopsy/chemotherapy. Overall survival was 100% for stage 1(n = 3), 90% for stage 2 (n = 10), 46% for stage 3 (n = 13), 13% for stage 4 (n = 55) and 56% for stage 4S disease (n = 9). During the eras 1985-1994 versus 1995-2005, survival for stage 3 lesions was 25% and 80% (P = 0.04) with marginal increase in survival observed in stage 4 disease (12% vs. 22%, P = 0.083). Delayed tumour resection was not performed in 20 (36%) stage 4 patients due to progressive disease. Complete tumour resection was achieved in 62% of stage 3-4 patients during 1995-2005 compared to 38% in 1985-1994. The extent of surgical resection (complete vs. partial) showed no significant differences in overall survival or relapse rates. Postoperative morbidity occurred in 15.7% of cases emphasising technical challenges in resection of neuroblastoma. No child with MYCN amplification survived versus 59% survival in non-amplified cases (P = 0.012). CONCLUSIONS: While complete tumour resection may be desirable in advanced neuroblastoma (stage 3-4) these findings suggest that the radicality of operation is not significantly associated with better overall survival/relapse. Improving outcomes in the 1995-2005 era for patients with stage 3-4 tumours complements the introduction of new high dose-intensive chemotherapy regimens and other adjuvant therapies for this enigmatic disease. PMID- 21523902 TI - Superabsorbent polysaccharide hydrogels based on pullulan derivate as antibacterial release wound dressing. AB - To accomplish ideal wound dressing, hydrogels based on a natural polysaccharide, pullulan were synthesized by chemical cross-linking. The tensile strengths of the hydrogel films (1 mm thick) were determined to range from 0.663 to 1.097 MPa in proportion to cross-linking degrees and water contents. The swelling study of the hydrogels in water showed remarkable water absorption property with swelling ratio up to 4000%, which provided the hydrogel with quick hemostatic ability and prevent the wound bed from accumulation of exudates. The water vapor transmission rate and water retention of the hydrogels were found to be in the range of 2213 3498 g/m2/day and 34.74-45.81% (after 6 days), indicating that the hydrogel can maintain a moist environment over wound bed, which could prevent the dehydration of the wound bed and prevent the scab formation. Biocompatibility test revealed that the hydrogels were not cytotoxic. The hydrogel could load antimicrobial agents and effectively suppress bacterial proliferation to protect the wound from bacterial invasion. These results suggest that the pullulan hydrogels prepared in this study may have high potential as new ideal wound-dressing materials. PMID- 21523903 TI - Factors influencing alginate gel biocompatibility. AB - Alginate remains the most popular polymer used for cell encapsulation, yet its biocompatibility is inconsistent. Two commercially available alginates were compared, one with 71% guluronate (HiG), and the other with 44% (IntG). Both alginates were purified, and their purities were verified. After 2 days in the peritoneal cavity of C57BL/6J mice, barium (Ba)-gel and calcium (Ca)-gel beads of IntG alginate were clean, while host cells were adhered to beads of HiG alginate. IntG gel beads, however, showed fragmentation in vivo while HiG gel beads stayed firm. The physicochemical properties of the sodium alginates and their gels were thoroughly characterized. The intrinsic viscosity of IntG alginate was 2.5-fold higher than that of HiG alginate, suggesting a greater molecular mass. X-ray photoelectron spectroscopy indicated that both alginates were similar in elemental composition, including low levels of counterions in all gels. The wettabilities of the alginates and gels were also identical, as measured by contact angles of water on dry films. Ba-gel beads of HiG alginate resisted swelling and degradation when immersed in water, much more than the other gel beads. These results suggest that the main factors contributing to the biocompatibility of gels of purified alginate are the mannuronate/guluronate content and/or intrinsic viscosity. PMID- 21523904 TI - Cathepsin K-sensitive poly(ethylene glycol) hydrogels for degradation in response to bone resorption. AB - We propose a new strategy of biomaterial design to achieve selective cellular degradation by the incorporation of cathepsin K-degradable peptide sequences into a scaffold structure so that scaffold biodegradation can be induced at the end of the bone formation process. Poly(ethylene glycol) diacrylate (PEGDA) hydrogels were used as a model biomaterial system in this study. A cathepsin K-sensitive peptide, GGGMGPSGPWGGK (GPSG), was synthesized and modified with acryloyl-PEG succinimidyl carbonate to produce a cross-linkable cathepsin K-sensitive polymer that can be used to form a hydrogel. Specificity of degradation of the GPSG hydrogels was tested with cathepsin K and proteinase K as a positive control, with both resulting in significant degradation compared to incubation with nonspecific collagenases over a 24-h time period. No degradation was observed when the hydrogels were incubated with plasmin or control buffers. Cell-induced degradation was evaluated by seeding differentiated MC3T3-E1 osteoblasts and RAW264.7 osteoclasts on GPSG hydrogels that were also modified with the cell adhesion peptide RGDS. Resulting surface features and resorption pits were analyzed by differential interference contrast (DIC) and fluorescent images obtained with confocal microscopy. Results from both analyses demonstrated that GPSG hydrogels can be degraded specifically in response to osteoclast attachment but not in response to osteoblasts. In summary, we have demonstrated that by incorporating a cathepsin K-sensitive peptide into a synthetic polymer structure, we can generate biomaterials that specifically respond to cues from the natural process of bone remodeling. PMID- 21523905 TI - Understanding osteoblast responses to stiff nanotopographies through experiments and computational simulations. AB - An increasing number of studies have demonstrated the positive role nanotopographies can have toward promoting various cell functions. However, the relevant mechanism(s) behind this improvement in biological interactions at the cell-material interface is not well understood. For this reason, here, osteoblast (bone forming cell) functions (including adhesion, proliferation, and differentiation) on two carefully-fabricated diamond films with dramatically different topographies were tested and modeled. The results over all the time periods tested revealed greater cell responses on nanocrystalline diamond (NCD, grain sizes <100 nm) compared to submicron crystalline diamond (SMCD, grain sizes 200-1000 nm). To understand this positive impact of cell responses per stiff nanotopographies, cell filopodia extension and cell spreading were studied through computational simulations and the results suggested that increasing the lateral dimensions or height of nanometer surface features could inhibit cell filopodia extension and, ultimately, decrease cell spreading. The computational simulation results were further verified by live cell imaging (LCI) experiments. This study, thus, describes a possible new approach to investigate (through experiments and computational simulation) the mechanisms behind nanotopography enhanced cell functions. PMID- 21523906 TI - Laser-modified nanostructures of PET films and cell behavior. AB - The surface of polyethylene terephthalate (PET) films was irradiated using KrF excimer laser (lambda = 248 nm) with different number of pulses at constant repetition rate. The adhesion behavior of L-929 fibroblast cells on the irradiated surface was investigated. The changes in films' morphology were characterized by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The hydrophilicity and both polar and dispersion components of the surface tension of the treated films were evaluated by contact angle and surface tension measurement techniques. The films roughness was evaluated by atomic force microscopy. AFM and SEM observations showed that a specific nanostructure was created on the laser-treated polyethylene terephthalate surface. Contact angle and surface energy measurements have indicated an increase in wettability of the laser treated samples up to 5 pulses as optimum result; while, by increasing the laser pulses beyond 5 pulses the hydrophilicity of laser treated samples dropped and the surface energy of the treated films was leveled off. Data from in vitro assays showed significant cell attachment and cell growth onto laser treated samples in comparison with the untreated films. Moreover, a number of fibroblast cells attached and proliferated onto treated PET films were achieved under optimum condition of 5 pulses which was significantly higher than the other treated samples. PMID- 21523908 TI - Cerebroretinal microangiopathy with calcifications and cysts: characterization of the skeletal phenotype. AB - Cerebral cysts and calcifications with leukoencephalopathy and retinal vascular abnormalities are diagnostic hallmarks of cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Previous studies have suggested that skeletal involvement is also common, but its characteristics remain unknown. This study aimed to assess the skeletal phenotype in CRMCC. All Finnish patients with features consistent with CRMCC and for whom radiographs were available were included. Clinical information pertinent to the skeletal phenotype was collected from hospital records, and all plain radiographs were reviewed for skeletal features. Bone mineral density (BMD) was measured by DXA. In one patient, bone biopsies were obtained for bone histology and histomorphometric analyses. The LRP5 gene was analyzed for mutations by direct sequencing. Our results show that the skeletal phenotype in CRMCC includes (1) compromised longitudinal growth pre- and postnatally, (2) generalized osteopenia or early onset low turnover osteoporosis with fragility fractures, and (3) metaphyseal abnormalities that may lead to limb deformities such as short femoral neck or genua valga. DXA measurements in three patients showed low BMD, and bone biopsies in the fourth patient with pathological fractures and impaired fracture healing showed low turnover osteoporosis, with reduced osteoclast and osteoblast activity. Direct sequencing of all LRP5 coding exons and exon-intron boundaries in six patients with CRMCC revealed no putative mutations. We conclude that the CRMCC-associated bone disease is characterized by low BMD and pathological fractures with delayed healing, metaphyseal changes, and short stature pre- and postnatally. LRP5 is not a disease-causing gene in CRMCC. PMID- 21523909 TI - A new way APP mismetabolism can lead to Alzheimer's disease. PMID- 21523910 TI - Synthesis of triazenoazaindoles: a new class of triazenes with antitumor activity. AB - Despite improvements in the treatment and prevention of cancer, the number of new diagnoses continues to rise; this has fuelled substantial interest in the development of new and effective chemotherapeutic agents. Compounds of the triazene class, such as dacarbazine, have been used in the clinical management of many cancer types including brain, leukemia, and melanoma. A new compound class bearing a triazenoazaindole scaffold was synthesized with the aim of identifying new antiproliferative agents. Compounds 5a-g and 6a-c were screened against a panel of human tumor cell lines, and two of them, 5e and 5f, showed cytotoxicity (GI(50) range: 2.2-8.2 MUM) in all cell lines. These two compounds even maintained their cytotoxicity in some multidrug-resistant cell lines. Flow cytometry analysis demonstrated their ability to induce cell death by apoptosis with involvement of lysosomes. PMID- 21523911 TI - beta N-O turns and helices induced by beta2-aminoxy peptides: synthesis and conformational studies. AB - Herein, we report an efficient route for the asymmetric synthesis of beta(2) aminoxy acids as well as experimental and theoretical studies of conformations of peptides composed of beta(2)-aminoxy acids. The nine-membered-ring intramolecular hydrogen bonds, namely, beta N-O turns, are generated between adjacent residues in those peptides, in accordance with our computational results. The presence of two consecutive homochiral beta N-O turns leads to the formation of beta N-O helical structures in solution, although both helical (composed of two beta N-O turns of the same handedness) and reverse-turn (composed of two beta N-O turns with opposite handedness) structures are of similar stability, as suggested by theoretical studies. Nevertheless, two slightly different conformations, with the same handedness, of beta(2)-aminoxy monomers have been observed in the solid state and in solution according to our X-ray and 2D NOESY studies. PMID- 21523912 TI - Synthesis and antitumor activity of 3-(2-phenyl-1,3-thiazol-4-yl)-1H-indoles and 3-(2-phenyl-1,3-thiazol-4-yl)-1H-7-azaindoles. AB - Given the potent antimicrobial, antiviral, and antitumor activities of many natural products, there is an increasing interest in the synthesis of new molecules based on natural compound scaffolds. Based on a 2,4-bis(3' indolyl)imidazole skeleton, two new series of phenylthiazolylindoles and phenylthiazolyl-7-azaindoles were obtained by Hantzsch reaction between substituted phenylthioamides and the alpha-bromoacetyl derivatives. Some azaindole derivatives, tested at the National Cancer Institute against a panel of ~60 tumor cell lines derived from nine human cancer cell types, showed inhibitory effects against all cell lines investigated at micromolar to nanomolar concentrations. Two of them exhibited a high affinity for CDK1, with IC(50) values of 0.41 and 0.85 MUM. These promising results will set the foundation for future investigations into the development of anticancer therapies. PMID- 21523913 TI - An efficient copper(I)-catalyst system for the asymmetric hydroboration of beta substituted vinylarenes with pinacolborane. PMID- 21523914 TI - Silver-mediated exo-selective tandem desilylative bromination/oxycyclization of silyl-protected alkynes: synthesis of 2-bromomethylene-tetrahydrofuran. PMID- 21523915 TI - A roadmap for successful applications of clinical proteomics. AB - Despite over 30,000 publications on proteomics in the last decade, and the accumulation of extensive interesting information on the human proteome in diverse observations, the clinical translation of proteomics to-date has had major setbacks. I review here a roadmap for improving the success rate of clinical proteomics. The roadmap includes steps for improvements that need to be made in analytical tools, discovery, validation, clinical application, and post clinical application appraisal. It is likely that most if not all of the components that are necessary for clinical success are either readily available, or should be possible to put in place with more rigorous research standards and concerted efforts of the research community, clinicians, and health agencies. Enthusiasm for the clinical impact of proteomics may need to be tempered currently until robust evidence can be obtained, but some clinical successes should eventually be feasible. PMID- 21523916 TI - Urinary proteomics in cardiovascular disease: Achievements, limits and hopes. AB - Cardiovascular disease (CVD) is the major cause of mortality and morbidity worldwide. Diagnosis of CVD and risk stratification of patients with CVD remains challenging despite the availability of a wealth of non-invasive and invasive tests. Clinical proteomics analyses a large number of peptides and proteins in biofluids. For clinical applications, the urinary proteome appears particularly attractive due to the relative low complexity compared with the plasma proteome and the noninvasive collection of urine. In this article, we review the results from pilot studies into urinary proteomics of coronary artery disease and discuss the potential of urinary proteomics in the context of pathogenesis of CVD. PMID- 21523917 TI - The mediastinal waltz - a representation of asymmetrical mediastinal anatomy. AB - This article describes a representation formed by a waltzing couple of two students that can be used to teach the asymmetrical anatomical relationships among the trachea, bronchi, pulmonary trunk, and the pulmonary arteries in the mediastinum. PMID- 21523918 TI - Who hears the voice of the deceased? PMID- 21523919 TI - Integration of cardiovascular regulation by the blood/endothelium cell-free layer. AB - The cell-free layer (CFL) width separating red blood cells in flowing blood from the endothelial cell membrane is shown to be a regulator of the balance between nitric oxide (NO) production by the endothelium and NO scavenging by blood hemoglobin. The CFL width is determined by hematocrit (Hct) and the vessel wall flow velocity gradient. These factors and blood and plasma viscosity determine vessel wall shear stress which regulates the production of NO in the vascular wall. Mathematical modeling and experimental findings show that vessel wall NO concentration is a strong nonlinear function of Hct and that small Hct variations have comparatively large effects on blood pressure regulation. Furthermore, NO concentration is a regulator of inflammation and oxygen metabolism. Therefore, small, sustained perturbations of Hct may have long-term effects that can promote pro-hypertensive and pro-inflammatory conditions. In this context, Hct and its variability are directly related to vascular tone, peripheral vascular resistance, oxygen transport and delivery, and inflammation. These effects are relevant to the analysis and understanding of blood pressure regulation, as NO bioavailability regulates the contractile state of blood vessels. Furthermore, regulation of the CFL is a direct function of blood composition therefore understanding of its physiology relates to the design and management of fluid resuscitation fluids. From a medical perspective, these studies propose that it should be of clinical interest to note small variations in patient's Hct levels given their importance in modulating the CFL width and therefore NO bioavailability. WIREs Syst Biol Med 2011 3 458-470 DOI: 10.1002/wsbm.150 PMID- 21523921 TI - Cutaneous vasculopathy associated with cocaine use. AB - OBJECTIVE: Cocaine is known to cause thrombotic complications. Its use has also been associated with a variety of rheumatologic manifestations, most notably cutaneous vasculopathy. We report clinical features and laboratory findings of cocaine-related cutaneous vasculopathy. METHODS: Here we describe 8 patients with cocaine-related cutaneous vasculopathy. RESULTS: Our patients most commonly presented with purpuric lesions and ulcers with areas of skin necrosis. Extracutaneous features included fatigue and arthritis in most patients, as well as weight loss in 3 patients, pneumonia in 3, diffuse reactive lymphadenopathy in 1, and acute upper airway obstruction in 2. Laboratory abnormalities included elevated inflammatory markers and positive perinuclear antineutrophil cytoplasmic antibodies (ANCAs) in all patients, and antimyeloperoxidase antibodies in 7 of 8 patients. Cytoplasmic ANCA was positive in 5 of 8, equivocal in 2 of 8, and negative in 1 of 8 patients. Anti-proteinase 3 antibodies were found in 6 of 8 patients. Six of 8 patients had positive antinuclear antibodies and 5 of 8 had positive anti-double-stranded DNA antibodies (4 of 5 were at low titers). Two patients previously thought to have systemic lupus erythematosus had low complement levels. Lupus anticoagulant was positive in 3 of 8 and equivocal in 5 of 8. Anticardiolipin IgG was positive in 1 of 8 and IgM was positive in 6 of 8; beta(2) -glycoprotein I IgM was positive in 2 of 8. Cold agglutinins were strongly positive in 6 of 6 patients in whom they were measured. Skin disease improved in 3 patients who appeared to have stopped using cocaine. It was chronic and progressive in 4 patients who continued to use cocaine, 2 of whom died presumably due to multidrug overdose. CONCLUSION: This report outlines clinical features and distinctive laboratory findings that, when present in the right clinical setting, should prompt consideration of cocaine-related cutaneous vasculopathy. PMID- 21523920 TI - Polymer-based therapeutics: nanoassemblies and nanoparticles for management of atherosclerosis. AB - Coronary arterial disease, one of the leading causes of adult mortality, is triggered by atherosclerosis. A disease with complex etiology, atherosclerosis results from the progressive long-term combination of atherogenesis, the accumulation of modified lipoproteins within blood vessel walls, along with vascular and systemic inflammatory processes. The management of atherosclerosis is challenged by the localized flare-up of several multipronged signaling interactions between activated monocytes, atherogenic macrophages and inflamed or dysfunctional endothelial cells. A new generation of approaches is now emerging founded on multifocal, targeted therapies that seek to reverse or ameliorate the atheroinflammatory cascade within the vascular intima. This article reviews the various classes and primary examples of bioactive configurations of nanoscale assemblies. Of specific interest are polymer-based or polymer-lipid micellar assemblies designed as multimodal receptor-targeted blockers or drug carriers whose activity can be tuned by variations in polymer hydrophobicity, charge, and architecture. Also reviewed are emerging reports on multifunctional nanoassemblies and nanoparticles for improved circulation and enhanced targeting to atheroinflammatory lesions and atherosclerotic plaques. PMID- 21523922 TI - Thrombotic thrombocytopenic purpura in IgG4-related disease with severe deficiency of ADAMTS-13 activity and IgG4 autoantibody against ADAMTS-13. PMID- 21523923 TI - Central serous retinopathy. PMID- 21523924 TI - Neuromyelitis optica spectrum disorder in patients with connective tissue disease and myelitis. PMID- 21523925 TI - Manual lymph drainage improving upper extremity edema and hand function in patients with systemic sclerosis in edematous phase. AB - OBJECTIVE: In systemic sclerosis (SSc; scleroderma) patients in edematous phase, hand edema is often present. Manual lymph drainage (MLD) stimulates the lymphatic system and reduces edema. Our aim was to evaluate the efficacy of MLD in reducing edema and in improving functionality of the hands and perceived quality of life (QOL) in SSc patients in edematous phase. METHODS: Of 35 SSc patients with edematous hands, 20 were treated with MLD according to the Vodder technique once a week for 5 weeks (intervention group), and 15 served as the observation group. Patients were evaluated at enrollment, at the end of treatment (T1), and after 9 weeks of followup (T2) by volumetric test (assessing hand volume), the Hand Mobility in Scleroderma (HAMIS) test, and 4 visual analog scales (VAS; scored 0 10) evaluating the perception of hand edema and pain and their interference on daily activities. QOL and disability were assessed by the physical synthetic index (PSI) and mental synthetic index (MSI) of the Short Form 36 (SF-36) and by the Health Assessment Questionnaire (HAQ). RESULTS: In the intervention group, hand volume, the HAMIS test, and the 4 VAS were improved significantly at the end of treatment (P < 0.001). The results were maintained at T2 (P < 0.001). The HAQ and the PSI and MSI of the SF-36 also improved significantly at T1 (P < 0.001), but only PSI improvement was maintained at T2 (P < 0.001). In the observation group, no improvement at T1 and at T2 was observed. CONCLUSION: In SSc, MLD significantly reduces hand edema and improves hand function and perceived QOL. PMID- 21523926 TI - Cardiometabolic comorbidities and rheumatic diseases: focus on the role of fat mass and adipokines. PMID- 21523927 TI - A new microfluidic concept for parallel operated milliliter-scale stirred tank bioreactors. AB - Parallel miniaturized stirred tank bioreactors are an efficient tool for "high throughput bioprocess design." As most industrial bioprocesses are pH-controlled and/or are operated in a fed-batch mode, an exact scale-down of these reactions with continuous dosing of fluids into the miniaturized bioreactors is highly desirable. Here, we present the development, characterization, and application of a novel concept for a highly integrated microfluidic device for a bioreaction block with 48 parallel milliliter-scale stirred tank reactors (V = 12 mL). The device consists of an autoclavable fluidic section to dispense up to three liquids individually per reactor. The fluidic section contains 144 membrane pumps, which are magnetically driven by a clamped-on actuator section. The micropumps are designed to dose 1.6 MUL per pump lift. Each micropump enables a continuous addition of liquid with a flow rate of up to 3 mL h(-1) . Viscous liquids up to a viscosity of 8.2 mPa s (corresponds to a 60% v/v glycerine solution) can be pumped without changes in the flow rates. Thus, nearly all feeding solutions can be delivered, which are commonly used in bioprocesses. The functionality of the first prototype of this microfluidic device was demonstrated by double-sided pH-controlled cultivations of Saccharomyces cerevisiae based on signals of fluorimetric sensors embedded at the bottom of the bioreactors. Furthermore, fed-batch cultivations with constant and exponential feeding profiles were successfully performed. Thus, the presented novel microfluidic device will be a useful tool for parallel and, thus, efficient optimization of controlled fed-batch bioprocesses in small-scale stirred tank bioreactors. This can help to reduce bioprocess development times drastically. PMID- 21523928 TI - Integrating a 250 mL-spinner flask with other stirred bench-scale cell culture devices: a mass transfer perspective. AB - The bioprocess development cycle is a complex task that requires a complete understanding of the engineering of the process (e.g., mass transfer, mixing, CO(2) removal, process monitoring, and control) and its affect on cell biology and product quality. Despite their widespread use in bioprocess development, spinner flasks generally lack engineering characterization of critical physical parameters such as k(L)a, P/V, or mixing time. In this study, mass transfer characterization of a 250-mL spinner flask using optical patch-based sensors is presented. The results quantitatively show the effect of the impeller type, liquid filling volume, and agitation speed on the volumetric mass transfer coefficient (k(L)a) in a 250-mL spinner flask, and how they can be manipulated to match mass transfer capability at large culture devices. Thus, process understanding in spinner flasks can be improved, and these devices can be seamlessly integrated in a rational scale-up strategy from cell thawing to bench scale bioreactors (and beyond) in biomanufacturing. PMID- 21523929 TI - Optimization of therapeutic proteins to delete T-cell epitopes while maintaining beneficial residue interactions. AB - Exogenous enzymes, signaling peptides, and other classes of nonhuman proteins represent a potentially massive but largely untapped pool of biotherapeutic agents. Adapting a foreign protein for therapeutic use poses numerous design challenges. We focus here on one significant problem: modifying the protein to mitigate the immune response mounted against "non-self" proteins, while not adversely affecting the protein's stability or therapeutic activity. In order to propose such variants suitable for experimental evaluation, this paper develops a computational method to select sets of mutations predicted to delete immunogenic T-cell epitopes, as evaluated by a 9-mer potential, while simultaneously maintaining important residues and residue interactions, as evaluated by one- and two-body potentials. While this design problem is NP-hard, we develop an integer programming approach that works very well in practice. We demonstrate the effectiveness of our approach by developing plans for biotherapeutic proteins that, in previous studies, have been partially deimmunized via extensive experimental characterization and modification of limited segments. In contrast, our global optimization technique considers an entire protein and accounts for all residues, residue interactions, and epitopes in proposing candidates worth subjecting to experimental evaluation. PMID- 21523930 TI - Temporal graphical models for cross-species gene regulatory network discovery. AB - Many genes and biological processes function in similar ways across different species. Cross-species gene expression analysis, as a powerful tool to characterize the dynamical properties of the cell, has found a number of applications, such as identifying a conserved core set of cell cycle genes. However, to the best of our knowledge, there is limited effort on developing appropriate techniques to capture the causality relations between genes from time series microarray data across species. In this paper, we present hidden Markov random field regression with L(1) penalty to uncover the regulatory network structure for different species. The algorithm provides a framework for sharing information across species via hidden component graphs and is able to incorporate domain knowledge across species easily. We demonstrate our method on two synthetic datasets and apply it to discover causal graphs from innate immune response data. PMID- 21523931 TI - Classification of large microarray datasets using fast random forest construction. AB - Random forest is an ensemble classification algorithm. It performs well when most predictive variables are noisy and can be used when the number of variables is much larger than the number of observations. The use of bootstrap samples and restricted subsets of attributes makes it more powerful than simple ensembles of trees. The main advantage of a random forest classifier is its explanatory power: it measures variable importance or impact of each factor on a predicted class label. These characteristics make the algorithm ideal for microarray data. It was shown to build models with high accuracy when tested on high-dimensional microarray datasets. Current implementations of random forest in the machine learning and statistics community, however, limit its usability for mining over large datasets, as they require that the entire dataset remains permanently in memory. We propose a new framework, an optimized implementation of a random forest classifier, which addresses specific properties of microarray data, takes computational complexity of a decision tree algorithm into consideration, and shows excellent computing performance while preserving predictive accuracy. The implementation is based on reducing overlapping computations and eliminating dependency on the size of main memory. The implementation's excellent computational performance makes the algorithm useful for interactive data analyses and data mining. PMID- 21523932 TI - Comparing multiple ChIP-sequencing experiments. AB - New high-throughput sequencing technologies can generate millions of short sequences in a single experiment. As the size of the data increases, comparison of multiple experiments on different cell lines under different experimental conditions becomes a big challenge. In this paper, we investigate ways to compare multiple ChIP-sequencing experiments. We specifically studied epigenetic regulation of breast cancer and the effect of estrogen using 50 ChIP-sequencing data from Illumina Genome Analyzer II. First, we evaluate the correlation among different experiments focusing on the total number of reads in transcribed and promoter regions of the genome. Then, we adopt the method that is used to identify the most stable genes in RT-PCR experiments to understand background signal across all of the experiments and to identify the most variable transcribed and promoter regions of the genome. We observed that the most variable genes for transcribed regions and promoter regions are very distinct. Gene ontology and function enrichment analysis on these most variable genes demonstrate the biological relevance of the results. In this study, we present a method that can effectively select differential regions of the genome based on protein-binding profiles over multiple experiments using real data points without any normalization among the samples. PMID- 21523933 TI - Analyzing modular RNA structure reveals low global structural entropy in microRNA sequence. AB - Secondary structure remains the most exploitable feature for noncoding RNA (ncRNA) gene finding in genomes. However, methods based on secondary structure prediction may generate superfluous amount of candidates for validation and have yet to deliver the desired performance that can complement experimental efforts in ncRNA gene finding. This paper investigates a novel method, unpaired structural entropy (USE) as a measurement for the structure fold stability of ncRNAs. USE proves to be effective in identifying from the genome background a class of ncRNAs, such as precursor microRNAs (pre-miRNAs) that contains a long stem hairpin loop. USE correlates well and performs better than other measures on pre-miRNAs, including the previously formulated structural entropy. As an SVM classifier, USE outperforms existing pre-miRNA classifiers. A long stem hairpin loop is common for a number of other functional RNAs including introns splicing hairpins loops and intrinsic termination hairpin loops. We believe USE can be further applied in developing ab initio prediction programs for a larger class of ncRNAs. PMID- 21523934 TI - Lex-SVM: exploring the potential of exon expression profiling for disease classification. AB - Exon expression profiling technologies, including exon arrays and RNA-Seq, measure the abundance of every exon in a gene. Compared with gene expression profiling technologies like 3' array, exon expression profiling technologies could detect alterations in both transcription and alternative splicing, therefore they are expected to be more sensitive in diagnosis. However, exon expression profiling also brings higher dimension, more redundancy, and significant correlation among features. Ignoring the correlation structure among exons of a gene, a popular classification method like L1-SVM selects exons individually from each gene and thus is vulnerable to noise. To overcome this limitation, we present in this paper a new variant of SVM named Lex-SVM to incorporate correlation structure among exons and known splicing patterns to promote classification performance. Specifically, we construct a new norm, ex norm, including our prior knowledge on exon correlation structure to regularize the coefficients of a linear SVM. Lex-SVM can be solved efficiently using standard linear programming techniques. The advantage of Lex-SVM is that it can select features group-wisely, force features in a subgroup to take equal weihts and exclude the features that contradict the majority in the subgroup. Experimental results suggest that on exon expression profile, Lex-SVM is more accurate than existing methods. Lex-SVM also generates a more compact model and selects genes more consistently in cross-validation. Unlike L1-SVM selecting only one exon in a gene, Lex-SVM assigns equal weights to as many exons in a gene as possible, lending itself easier for further interpretation. PMID- 21523935 TI - ncRNA consensus secondary structure derivation using grammar strings. AB - Many noncoding RNAs (ncRNAs) function through both their sequences and secondary structures. Thus, secondary structure derivation is an important issue in today's RNA research. The state-of-the-art structure annotation tools are based on comparative analysis, which derives consensus structure of homologous ncRNAs. Despite promising results from existing ncRNA aligning and consensus structure derivation tools, there is a need for more efficient and accurate ncRNA secondary structure modeling and alignment methods. In this work, we introduce a consensus structure derivation approach based on grammar string, a novel ncRNA secondary structure representation that encodes an ncRNA's sequence and secondary structure in the parameter space of a context-free grammar (CFG) and a full RNA grammar including pseudoknots. Being a string defined on a special alphabet constructed from a grammar, grammar string converts ncRNA alignment into sequence alignment. We derive consensus secondary structures from hundreds of ncRNA families from BraliBase 2.1 and 25 families containing pseudoknots using grammar string alignment. Our experiments have shown that grammar string-based structure derivation competes favorably in consensus structure quality with Murlet and RNASampler. Source code and experimental data are available at http://www.cse.msu.edu/~yannisun/grammar-string. PMID- 21523937 TI - If I were you. By Caveman. PMID- 21523936 TI - Inferring haplotypes from genotypes on a pedigree with mutations, genotyping errors and missing alleles. AB - Inferring the haplotypes of the members of a pedigree from their genotypes has been extensively studied. However, most studies do not consider genotyping errors and de novo mutations. In this paper, we study how to infer haplotypes from genotype data that may contain genotyping errors, de novo mutations, and missing alleles. We assume that there are no recombinants in the genotype data, which is usually true for tightly linked markers. We introduce a combinatorial optimization problem, called haplotype configuration with mutations and errors (HCME), which calls for haplotype configurations consistent with the given genotypes that incur no recombinants and require the minimum number of mutations and errors. HCME is NP-hard. To solve the problem, we propose a heuristic algorithm, the core of which is an integer linear program (ILP) using the system of linear equations over Galois field GF(2). Our algorithm can detect and locate genotyping errors that cannot be detected by simply checking the Mendelian law of inheritance. The algorithm also offers error correction in genotypes/haplotypes rather than just detecting inconsistencies and deleting the involved loci. Our experimental results show that the algorithm can infer haplotypes with a very high accuracy and recover 65%-94% of genotyping errors depending on the pedigree topology. PMID- 21523938 TI - [50th anniversary of the Journal of the Japanese respiratory society]. PMID- 21523939 TI - The chest pain patient dilemma and discussion for chest pain units. PMID- 21523940 TI - The challenge of chest pain in the emergency room: now and the future. PMID- 21523941 TI - The development of chest pain units in Germany. PMID- 21523942 TI - William (Vilem) Ganz, 1919-2009, cardiologist and co-inventor of the Swan-Ganz catheter which revolutionized cardiovascular investigations. PMID- 21523944 TI - Crossing borders. PMID- 21523945 TI - Race, racial resentment, attentiveness to the news media, and public opinion toward the Jena Six. AB - Objective. We outline the role of race, racial resentment, and attentiveness to news in structuring public opinion toward the prosecution of the Jena Six, the name given to six African-American high school students who beat a white student, five of whom were subsequently charged with attempted second-degree murder.Method. We rely on a telephone survey of 428 registered voters collected in the aftermath of the protests in Jena, Louisiana.Results. Public reactions were heavily filtered by race and associated with measures of racial resentment. African Americans followed news about the protests more closely, believed race was the most important consideration in the decision to prosecute, and believed the decision to prosecute was the wrong decision. Racially conservative white respondents were less likely to believe race was the most important consideration in the decision to prosecute and were more likely to believe that the decision to prosecute was the right decision. Consistent with theories of agenda setting and framing, attentiveness to the news influenced perceptions regarding the importance of race in the decision to prosecute but not whether the decision was the right decision.Conclusions. At least within the context of the Deep South, race and racial attitudes continue to be an important predictor of public reactions to racially charged events. Attentiveness to the news influenced the lens through which events were interpreted, but not perceptions of whether the outcome was the right decision. PMID- 21523946 TI - Religion and attitudes toward same-sex marriage among U.S. Latinos. AB - Objectives. This study examines links between multiple aspects of religious involvement and attitudes toward same-sex marriage among U.S. Latinos. The primary focus is on variations by affiliation and participation, but the possible mediating roles of biblical beliefs, clergy cues, and the role of religion in shaping political views are also considered.Methods. We use binary logistic regression models to analyze data from a large nationwide sample of U.S. Latinos conducted by the Pew Hispanic Forum in late 2006.Results. Findings highlight the strong opposition to same-sex marriage among Latino evangelical (or conservative) Protestants and members of sectarian groups (e.g., LDS), even compared with devout Catholics. Although each of the hypothesized mediators is significantly linked with attitudes toward same-sex marriage, for the most part controlling for them does not alter the massive affiliation/attendance differences in attitudes toward same-sex marriage.Conclusions. This study illustrates the importance of religious cleavages in public opinion on social issues within the diverse U.S. Latino population. The significance of religious variations in Hispanic civic life is likely to increase with the growth of the Latino population and the rising numbers of Protestants and sectarians among Latinos. PMID- 21523947 TI - Parental job loss and children's educational attainment in black and white middle class families. AB - Objectives. We aim to understand why blacks are significantly less likely than whites to perpetuate their middle-class status across generations. To do so, we focus on the potentially different associations between parental job loss and youth's educational attainment in black and white middle-class families.Methods. We use data from the Panel Study of Income Dynamics (PSID), following those children "born" into the survey between 1968 and 1979 and followed through age 21. We conduct multivariate regression analyses to test the association between parental job loss during childhood and youth's educational attainment by age 21.Results. We find that parental job loss is associated with a lesser likelihood of obtaining any postsecondary education for all offspring, but that the association for blacks is almost three times as strong. A substantial share of the differential impact of job loss on black and white middle-class youth is explained by race differences in household wealth, long-run measures of family income, and, especially, parental experience of long-term unemployment.Conclusions. These findings highlight the fragile economic foundation of the black middle class and suggest that intergenerational persistence of class status in this population may be highly dependent on the avoidance of common economic shocks. PMID- 21523948 TI - A better blood thinner: news for those with heart rhythm problems. PMID- 21523949 TI - Weighing gastric band surgery for the less obese. PMID- 21523950 TI - Why aren't you being screened for lung cancer? Research suggests CT scans may help pinpoint problems early enough to make a difference. PMID- 21523951 TI - Get rhinitis relief and breathe easier. PMID- 21523952 TI - How much vitamin D do you need? PMID- 21523953 TI - Is sudden cardiac arrest the same as a heart attack? PMID- 21523954 TI - Meta-analysis for linkage to asthma and atopy in the chromosome 5q31-33 candidate region. AB - Asthma is a common, complex human disease. Gene discovery in asthma has been complicated by substantial etiological heterogeneity, the possibility of genes of small effect and the concomitant requirement for large sample sizes. Linkage to asthma phenotypes has been investigated most intensively in the 5q chromosomal region, although results have been inconsistent across studies and all studies have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis by pooling either summary statistics or raw data. The International Consortium on Asthma Genetics combined data from 11 data sets (n = 6277 subjects) to investigate evidence for linkage of 35 markers spanning the cytokine cluster on chromosome 5q31-33 to 'asthma' dichotomy and total serum immunoglobulin E (IgE) levels. Chromosome 5q markers typed in different centers were integrated into a consensus map to facilitate effective data pooling. Multipoint linkage analyses using a new Haseman-Elston method were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by meta-analytic methods. Our results did not provide any evidence significant at the 5% level that loci conferring susceptibility to asthma or atopy are present in the 5q31-33 region; however, there was some weak evidence (empirical P = 0.077) of linkage to asthma affection. This study suggests that loci in 5q31-33 have at most a modest effect on susceptibility to asthma or total serum IgE levels, may not be detectable or present in all human populations and are difficult to detect even using combined linkage evidence from 2400-2600 full sibling pairs. PMID- 21523955 TI - [Current problems in surgical oncology: 1. Theoretical models in oncology and their implications in surgical therapy]. AB - Cancer biology has proven to be far more complex than imagined twenty years ago. While current treatment strategies (i.e., surgery, chemotherapy, and radiation) are successful in many cancers, they all have limitations. In some types of solid tumors some survival progress has been recorded, such in the case of breast and colorectal cancer, but these improvements are probably mainly due to screening programmes and earlier detection than to more-effective treatment. In other tumor types the mortality certainly increased: the death rate from lung cancer rose from 43 to 53 per 100,000 people from 1975 to 2005, the death rate from melanoma has risen nearly 30 percent, and death rate from liver and bile-duct cancer almost doubled, from 2.8 to 5.3 per 100,000. Cancer is commonly viewed as minimally controlled by modern medicine, especially when compared with other major diseases (Sharon Begley, 2008). Either directly from the phenomenological observation or through the biological model, mathematicians and biologists can generate mathematical models aimed at describing the biological phenomenon. The analysis of the solution properties by mathematical methods will give a description of the dynamics resulting in a deeper insight into the problem. The models can be implemented numerically to give rise to in silico models. The quality of the modeling process can be tested, validating the results of the simulations with experiments and clinical data. The theoretical predictions generated from the models may optimize the experimental protocol by identifying the most promising candidates for further clinical investigation. The speed with which large numbers of simulations can be performed may reduce the number of animal experiments and identify new experimental programmes and optimal cancer therapy schedules. However, it is clear that surgical decisions in cancer therapy are strongly driven by the theoretical hypotheses of local tumor evolution and malignant cells dissemination. For 60 years cancer was seen as a disease that arose in one location and spread through the lymphatic system first to nearby lymph nodes and subsequently to other organs. This theory of "contiguous" development of metastases has become known as the Virchow-Halsted theory. After 1954 an alternative theory was formulated by B. Fisher stating "that breast cancer is a systemic disease". Following the therapeutic implications of this "systemic theory," the disease has been attacked in recent years by chemotherapy and hormone therapy to the whole body. In 1994 S. Hellman stated the case for what he calls the "spectrum theory." He observed that there are intermediate tumor states between purely localized lesions and widely metastatic. Such clinical circumstances are not accounted for by either the contiguous (Halsted theory) or the systemic (systemic theory) hypotheses and supports the idea that loco-regional therapies (surgery and radiotherapy) may be useful in some cases. So, it is obvious that the extent and the role of cancer surgery are direct consequences of our theoretical understanding of cancer natural history. The genetical, pathological and clinical heterogeneity of cancers suggest new theoretical approaches based on chaos and fractal theory. PMID- 21523956 TI - [Retroperitoneal hematoma in pelvic fractures]. AB - Retroperitoneal trauma implies a wide variety of organs in multiple systems (digestive, urinary, circulatory, musculoskeletal); although their common result is the retroperitoneal hematoma, their management is completely different, an intervention indicated for a particular lesion being able to completely decompensate other lesions in case of insufficient diagnostic. The present material highlights the recent diagnostic and therapeutic particularities in retroperitoneal hematoma from pelvic fractures. We noted a recent trend in diminishing the role of the fracture pattern on standard pelvis X-ray in assessing the risk of hemodinamic instability, new markers being indicated as more predictive. CT scan with contrast substance, when applies, remains the gold standard in identifying the source of the vascular bleeding and in guiding the subsequent therapeutic maneuvers. The angiographic embolisation in arterial lesions remains the main therapeutic procedure in hemodinamical unstable patients, with the possibility of repeating it when needed; the C-clamp external fixator application is associated. The pre-peritoneal packing constantly gains support as an emergency hemostasis maneuver. The treatment should be adapted in each case, the hemodinamic instability being the trigger in initiation and repetition of the emergency therapeutic interventions mentioned above. PMID- 21523957 TI - [Therapeutic approach for patients with positive resection line (R1) after gastrectomy for gastric cancer]. AB - INTRODUCTION: The radical treatment of the gastric cancer consist in large gastric resections and lymphadenectomy. Resection line involvement at microscopic histopathological examination (R1) could change prognostic unfavorable. MATERIAL AND METHODS: They were 135 patients with gastric cancer operated between 2006 2007, with radical gastric resections and lymphadenectomy. In 3 patients with early gastric cancer and 23 patients with different stages of cancers, histopathological examination showed resection line involvement. From this study were eliminated the patients with stage IV cancers in whom resections were palliative. RESULTS: Incidence of positive resection line involvement was 19,25%. 88,46% of the tumors were staged pT2 and pT3 and the majority was poorly differentiated or undifferentiated (G3 and G4). Lymphatic involvement (pN1 or pN2) was demonstrated in 18 (69,23%0 patients with R1. Perioperative complications were encountered in 15,38% of this patients, with 7,69% mortality. CONCLUSIONS: Presence of tumoral tissue at resection line level could decrease survival in this patients. Therapeutic protocol in patients with resection line involvement (re-laparotomy with re-resection or surveillance) must be establish in accordance with several factors: T and N category, risks of another surgical interventions, patients acceptance. PMID- 21523958 TI - [Surgical treatment of esophageal diverticula]. AB - The aim of this paper is to evaluate the methods and therapeutic principles of esophageal diverticula pathology. We analyze the main pathological mechanisms which establish the therapeutic attitude linked with a complex pretherapeutic evaluation. In our study we enrolled 12 patients operated between 2001-2009 for esophageal diverticula with different topography. In this period of time there were much more patients diagnosed with this pathology, but the need for surgery was establish very tight regarding the actual practical guide which impose the identification and interception of physiological mechanisms by the surgical procedure. We highlight the particular technical details, as well as the important differences of postoperatory complications according to the topography of the diverticula pouch. PMID- 21523959 TI - [Surgical management of Meckel's diverticulum in adults--retrospective analyses of 62 cases]. AB - Meckel's diverticulum (MD) is the most common congenital anomaly of the small intestine. We searched and analyzed the records of 62 cases with MD admitted in University Emergency Hospital Bucharest between 2001-2009. Sex ratio was M:F 3:1, with 74% male and 26% female. 51.6% (n = 32) of this where symptomatic and 48.4% (n = 30) asymptomatic, discovered during laparotomy for other reasons. The analysis highlights an increased frequency of symptomatic diverticulum at early ages, with a medium age of about 39.2 years comparing to asymptomatic group with a medium age of about 54.2 years. The diverticulum complication generated: occlusion--43.7% (n = 15), inflammation--37.5% (n = 12), bleeding, two cases of diverticulum tumor, an intussusception case and a perforation case with unknown object. 25% of the diverticulectomies were followed by postsurgery complications, the parietal suppuration being the most frequent (50%). Three patients died independent of the diverticulum or its resection, all three having an asymptomatic diverticulum. The difficult diagnosis and the seriousness of diverticulum complications force us to take into consideration DM in all cases of severe or chronic abdominal pain. The diverticulum has to be surgically removed to all patients under 50 years, especially men. PMID- 21523960 TI - [Quantitative microscopic modifications of the diaphragm and the paraesophageal structures in hiatal hernia. Clinical aspects]. AB - In the last decade has seen an increase in hiatal hernia diagnosis. These issues led us to study and deepen the anatomic substrate of the changes that occur in the diaphragm muscle and periesophageal structures for optimum management of the disorder. The studied material was represented by fragments of the thoraco abdominal diaphragm and tissues around the esophagus, biopsy sampling by classic open approach or celioscopic in patients with hiatal hernia, compared with a control group. Histological processing was carried out by current or special methods. After qualitative examining of the selected structures, quantification was performed using an interactive digital program. In the adult diaphragm with hiatal hernia was found in percentage volume reduction pillar of the diaphragm muscle fibers, increased the percentage of vascular lumina in the muscle portion of the crura, while the percentage volume of interstitial spaces increase. The changes of the percentage volume of connective tissue are significant, both crura suffering a fibrous transformation of muscle portions. Microanatomic changes are their quantitative objectivity suggest loss of elasticity and reduced functional capacity of diaphragm muscle in hiatal hernias. PMID- 21523961 TI - [Acute-on-chronic renal disease caused by pancreatitis--impact of renal replacement therapy]. AB - Acute pancreatitis is often complicated by acute renal failure, either isolated or part of multiple organ failure. Preexisting chronic kidney disease worsens the prognosis, especially when the pancreatitis is severe and/or other major comorbidities are present. In case of acute-on-chronic renal failure secondary to acute pancreatitis, an early application of renal replacement therapy has improved the prognosis of patients included in the present clinical study. PMID- 21523962 TI - [Laparoscopic gastric plication at the greater curvature (for treatment of morbid obesity)]. PMID- 21523963 TI - [Solid tumor of the abdominal wall, 1937]. PMID- 21523964 TI - [Bleomycin therapy for lymphangioma]. AB - Lymphangiomas are uncommun congenital malformations of the lymphatic system, that involve the skin and subcutaneous tissues. Of the several types of treatment, surgical excision has been the preferred. There is a high recurrence rate because lymphangiomas tend to infiltrate the surrounding tissues. The bleomycin is a cytotoxic antitumoral antibiotic, that causes modifications of DNA. It has been also successfully used in intralesional injection treatment of cystic hygromas and haemangiomas, based specifically on a high sclerosing effect on vascular endothelium. We report the cases of five patients, with congenital lymphangioma, localized on the leg, in cervical and latero-thoracal region, treated with repeated intralesional bleomycin injections. The treatment indication was given by the location of this lesions and the infiltration of the surrounding vital tissues, that made the complete surgical excision impossible. Intralesional injection of bleomycin into the lymphangiomas was given at a dose, not exceeding 0,5 mg/kg of body weight, at intervals of 4 weeks. Complete resolution (n = 4) or significant improvement (n = 1) occurred in all patients treated. No other treatment was needed. We didn't notice local or general adverse effects. With this method we set the purpose to treat effectively this congenital malformations, obviating the need for invasive primary surgery or systemic treatment regimens. Toward other methods, intralesional bleomycin injections have a minimal risk of side effects (ulceration, pulmonary fibrosis). PMID- 21523965 TI - [Gastric necrosis, rare complication after laparoscopic gastric banding--case report]. AB - In the last years, laparoscopic gastric banding has become a popular surgical option for morbidly obese patients, because of the minimally invasive and easy surgical technique, its reversibility, and the possibility to calibrate the stoma. Gastric necrosis, as a complication of laparoscopic gastric banding, has been rarely reported. We present the case of a 34 -year-old pregnant patient (18 week pregnancy) with 5 days history of abdominal pain. She had undergone laparoscopic adjustable gastric banding 24 months earlier with a body mass index (BMI) of 43 kg/m2. Diagnostic workup was very difficult because the patient was pregnant and we can use only ultrasonography and clinically signs. After initial conservative management, the patient underwent urgent surgery and we found an anterior gastric prolapse through the band with necrosis of the herniated stomach. A longitudinal (sleeve) gastrectomy was performed. The postoperative evolution was god and the patient left our clinic after 9 day. Emergency sleeve gastrectomy could represent a good option to treat, in a safe way. PMID- 21523966 TI - [Giant parathyroid adenoma with hypersecretion and severe clinical course- clinical case]. AB - Primary hyperparathyroidism is an uncommon disease, with late diagnosis due to insidious and various symptoms. Parathyroid adenoma is the most frequent cause of primary hyperparathyroidism. This paper presents the clinic of disease, the necessary exams to perform in order to obtain a positive diagnosis also the case of young man with long evolution period prior to diagnosis and with severe complications at bones. Surgery represents the only valid option resulting complete healing. PMID- 21523967 TI - [Intussusception in adult--a rare case]. AB - Authors present a case of adult intussusception, an extremely rare entity in this age group, which manifested in a particular context and with an unusual symptomatology. PMID- 21523968 TI - [Synchronous gastrointestinal stromal tumor (GIST) and multiple digestive neoplasms, benign and malignant]. AB - Gastrointestinal stromal tumors (GIST) are a broad category of mesenchymal, non epithelial primary tumors of the digestive tract, located in the wall of hollow viscera, from the esophagus to the anus and often in adjacent mesentery and omentum. They are clinically unpredictable (may be discovered incidentally during an imagistic investigation or during surgery for other pathological entity, or at necropsy) and also have an unpredictable behavior (GISTs with very low risk, with low or moderate malignancy, which have benign histopathologic features but can recurr or can metastasize). The case we present here represents a rare association between a synchronous gastrointestinal stromal tumor (GIST) and multiple gastric benign and malignant tumors. PMID- 21523969 TI - [Intestinal intussusception due to ileal gastrointestinal stromal tumor--a case report]. AB - Intestinal occlusion due to intussusception produced by intestinal tumors is a very rare condition. Gastrointestinal stromal tumors are also rare digestive neopasias, with an impredictable malignant behavior, which are usually growing outside the intestinal wall, being rarely the initiators of an intestinal intussusception. We present the case of a 59 years old female, admitted in our hospital to elucidate the etiology of her iron deficient anaemia, which developed an intestinal occlusion at the intestinal preparation for colonoscopy. The abdominal CT scan performed in emergency conditions highlighted occlusive intestinal tumor complicated with intestinal intussusception. We performed an emergency laparotomy that revealed intestinal occlusion due to ileo-ileal intussusception produced by an ileal tumor. The surgical intervention consisted in segmental ileal enterectomy including the tumor with latero-lateral entero enteral anastomosis. The patient recovered without complications. The histopathological and immunohisto-chemical examinations established the diagnose of gastro-intestinal stromal tumor with high risk malignant behavior, therefore the patient was guided in the oncological department for specific treatment and oncological surveillance. PMID- 21523971 TI - [Hypotheses on physiopathology of OCD and its therapeutic theory]. PMID- 21523970 TI - Occurrence of Anopheles (Anopheles) neomaculipalpus Curry in north-western Argentina. PMID- 21523972 TI - [Suicide prevention and the role of mental health service]. PMID- 21523973 TI - [Disease concept and psychiatric care and welfare--with special reference to vulnerability for disease onset]. PMID- 21523974 TI - [Drug therapy of schizophrenia with cognitive function and QOL taken into consideration]. PMID- 21523975 TI - Our decade of change. PMID- 21523976 TI - Marion's message. Placenta accreta. PMID- 21523977 TI - Culture within culture. PMID- 21523978 TI - Cord burning. PMID- 21523979 TI - Breastfeeding in public. PMID- 21523980 TI - The cultural aspect of birth: my midwest experience. PMID- 21523981 TI - Hey, Miz Pinkie. PMID- 21523982 TI - Opening the pelvic brim with Walcher's position. PMID- 21523983 TI - Ethics and lessons learned in transport. PMID- 21523984 TI - Treating infertility: differences between Western reproductive medicine and traditional Chinese medicine. PMID- 21523985 TI - Lavender and letting go: a miscarriage-birth story. PMID- 21523986 TI - Release, rejuvenation and rejoicing: the blossoming of a woman. PMID- 21523987 TI - Friedman's curve vs. the pure heart approach to labor. PMID- 21523988 TI - Birth stories from a mountain midwife. PMID- 21523989 TI - Birthing with Orthodox Jewish women. PMID- 21523990 TI - The soul's knowing: connecting with our babies in the womb. PMID- 21523991 TI - Cultural diversity in childbirth education. PMID- 21523992 TI - An open letter. PMID- 21523993 TI - Time in a bottle. PMID- 21523994 TI - Celebrity births: the good, the bad, the influence. PMID- 21523995 TI - Birth with the Amish: a unique experience. PMID- 21523996 TI - Goals for China. PMID- 21523997 TI - Delivery room: the heart of nurses and midwives. PMID- 21523998 TI - Homebirth in Peru's Sacred Valley. PMID- 21523999 TI - Midwifery and women's health in Peru: visions and dreams. PMID- 21524000 TI - Blood: a private issue? PMID- 21524001 TI - Birth the Filipino way. PMID- 21524002 TI - Cross cultural birth: it's a human rights issue. PMID- 21524003 TI - Evaluation of a prevention programme efficiency for patients with fixed orthodontic appliances. AB - BACKGROUND/AIM: Orthodontic treatment enables the establishment of functional occlusion and improvement of oral health, however, it increases the risk of periodontal disease development. The aim of this paper was to examine the efficiency of the applied programme for the prevention of gingivitis in children undergoing the fixed orthodontic appliance therapy and to determine the most efficient devices and techniques for maintaining oral hygiene during orthodontic treatment. METHODS: The study included 80 patients of both genders--60 patients comprised the experimental group and 20 patients comprised the control group. All of them were patients of the Clinic for Orthodontics at the School of Dentistry in Belgrade, aged between 13 and 18. The Silness-Loe Plaque Index (PI) was utilised for the assessment of oral hygiene quality and Silness-Loe Gingival Index (GI) and Muhlemann Papilla Bleeding Index (PBI) were utilised for the assessment of gingival state. Checkups were conducted as a single-blind study at the beginning and after the first, the third and the sixth month of the preventive and prophylactic programme. RESULTS: During the observed period, a statistically significant change in PI, GI and PBI values was noticed (p < 0.005), as well as the difference in the dynamics of value changes during the periods between the observed groups. CONCLUSION: The preventive programme, applied to children undergoing the fixed orthodontic appliance therapy, had a positive effect both on oral hygiene quality and gingival state. The values of the examined parameters of the patients from the experimental group were significantly lower in comparison with those of the patients from the control group. The most efficient combination of devices for oral hygiene during orthodontic treatment was: a Curaprox CP5460 toothbrush, CD Ortho 60 orthodontic toothbrush and Curaprox CPS 14 interdental brush. PMID- 21524004 TI - Clinical characteristics of respiratory syncytial virus infection in neonates and young infants. AB - INTRODUCTION/AIM: Infection with respiratory syncytial virus (RSV) occurs during the first year of life in 50% of children and 20%-40% of them have signs of lower respiratory tract infection (bronchiolitis or pneumonia). There is an increased risk for complicated course and death from RSV infection in premature infants, especially those with bronchopulmonary dysplasia (BPD) or congenital heart disease. The aim of our study was to analyze clinical characteristics of laboratory confirmed RSV infection in order to evaluate the need for preventive measures in neonates and young infants. METHODS: The prospective study included children under age of 12 months admitted to our hospital in the period November 2008-March 2009 who were positive for RSV by enzyme immunoassay membrane test. The course of disease was assessed by clinical score and radiographic findings. RESULTS: Infection with RSV was confirmed in 91 patients: 21 (23.0%) were under the age of 30 days, 37 (40.7%) were between 31-60 days, and 33 patients (36.3%) were older than 60 days (p > 0.05). The highest hospitalization rate was in January--33 patients (36.3%; p < 0.01). Disease severity score in these age groups (AG) were: 8.4 +/- 0.4 (AG 0-30 days); 9.0 +/- 0.3 (AG 31-60 days) and 8.3 +/- 0.3 (AG > 60 days), without statistically significant difference among the groups (p > 0.05). Clinical scores in patients with and without risk factors were 10.5 +/- 0.5 and 8.3 +/- 0.2, respectively (p < 0.01). Pathological radiographic findings were observed in 72 (79.1%) and complications (apnea, significant atelectasis, encephalopathy) occured in 15 (16.5%) patients. The average length of hospital stay in complicated and uncomplicated course of the disease was 9 days and 6 days, respectively (p < 0.01). Therapy in 85 (93.4%) patients included bronchodilators, while systemic glucocorticoids and oxygen therapy were used in 51 (56.0%) and 44 (48.4%) patients, respectively. Death occured in 2 (2.2%) patients, both from a high risk group (the patient with BPD and the other one with congenital heart disease and Down syndrome). CONCLUSION: Infection with RSV in our settings showed marked seasonal characteristics with highest hospitalization rate in January. Although the course and outcome of the disease were favorable in the majority of our patients, the need for hospitalization and administration of therapy with possible side effects warrants that general measures for prevention of respiratory infections are followed especially in the first year of life. Severe disease and death are more probable in neonates and infants with risk factors. In these children passive immunisation with specific monoclonal antibody (e.g. palivizumab) during RSV season should be considered. PMID- 21524005 TI - [Evaluation of body mass index and lipid fractions levels in patients with retinal artery occlusion]. AB - BACKGROUND/AIM: There are studies stressing out that atherosclerosis is most common associated systemic condition in patients with retinal artery occlusion. The aim of this study was to analyze values of body mass index and lipid fractions in healthy individuals and patients with retinal artery occlusion. METHODS: This study included 90 participants during a 6-year period. The population was divided into 2 groups: the group with the diagnosed retinal artery occlusion and the group without retinal artery occlusion. The observed parameters were as follows: body mass index, low and high density lipoproteins and triglycerides. RESULTS: The study revealed no significant difference regarding body mass index and triglycerides values between the two evaluated groups, while low and high density lipoproteins values were significantly higher in the group of patients with retinal artery occlusion. CONCLUSIONS: The study demonstrated that body mass index and triglycerides have less important role in atherogenic pathogenesis of retinal artery occlusion, while low density lipoprotein is the fraction that is shown to be most potent in such etiological processes. PMID- 21524006 TI - Clinical manifestations, therapy and outcome of pandemic influenza A (H1N1) 2009 in hospitalized patients. AB - BACKGROUND/AIM: Increasing number of epidemiological and clinical studies to date showed that the pandemic influenza A (H1N1) 2009, by its characteristics, significantly differs from infection caused by seasonal influenza. Therefore, the information about clinical spectrum of manifestations, risk factors for severe form of the disease, treatment and outcome in patients with novel flu are still collected. METHODS; A total of 98 patients (mean age 32 +/- 15 years, range 14-88 years) with the signs and symptoms of novel influenza were treated in the Clinic for Infectious and Tropical Diseases, Military Medical Academy. There were 74 (75.5%) patients with suspected influenza A (H1N1) 2009, 10 (10.2%) with the likelihood and 14 (14.3%) with the confirmed influenza. In all the patients we registered the basic demographic data, risk factors for severe disease, symptoms and signs of influenza, laboratory tests and chest radiography. We analyzed antiviral therapy use and disease outcome (survived, died). RESULTS: The average time from the beginning of influenza A (H1N1) to the admission in hospital was 3 days (0-16 days) and from the moment of hospitalization to the Intensive Care Unit (ICU) admission was 2 days (0-5 days). There were 49 (50.0) patients, 20-29 years of age and 5 (5.1) patients older than 65. A total of 21 (21.4%) patients were with underlying disease, 18 (18.4%) were obese, 19 (19.4) were cigarette smokers. All of the patients had fever, 81 (82.6%) cough, while dyspnea and diarrhea were registered in 4 of the patients. In more than 75% of the patients laboratory tests were within normal limits. The real-time polymerase chain reaction (PCR) test for identification of influenza A (H1N1) 2009 was positive in 14 (77.8%), while pneumonia was verified in 30 (30.7%) of the patients. Six (6.1%) patients, mean age of 45 +/- 14 years (31-59 years) were admitted to the ICU, of whom five (5.1%) had Adult Respiratory Distress Syndrome (ARDS). Risk factors were registered more frequently in the patients with acute respiratory failure (14.2% vs 4.9%, p < 0.05). A total of 67 (68.4%) patients received oseltamivir, 89 (90.1%) was applied to antibiotics and 64 (65.3%) were treated with a combined therapy. Antiviral therapy was applied to 43 (43.3%) patients in the first 48 hours from the onset of the disease, of whom only one (3.4) developed ARDS. Fatal outcome was noted in 2.0% of the patients (2 of 98 patients) and in 33.3% of the patients treated in the ICU. CONCLUSION: Novel influenza A (H1N1) is most commonly manifested as a mild acute respiratory disease, which usually affects young healthy adults. A small number of the patients develop severe illness with acute respiratory failure and death. Patients seem to have benefit from antiviral therapy especially in first 48 hours. PMID- 21524007 TI - Health claims made on food. PMID- 21524008 TI - [Reconstruction of the columella and the tip of the nose with an island-shaped forehead flap]. AB - BACKGROUND: Posttraumatic and postoperative defects of columella and the tip of the nose are difficult to reconstruct. There are several operative methods described in the literature, and many of them are step-by-step procedures with long duration. The aim of this study was to present one-step procedure for reconstruction of the columella and the tip of the nose with island-shaped arterial forehead flap. CASE REPORT: A 45-year old man was submitted to surgical excision of basocellular skin cancer. After the excision, a defect of the columella and tip of the nose the remained, 3 x 2.5 cm in dimensions, with exposed alar cartilages. During the same operation, the defect was covered with an island-shaped arterial forehead flap. Postoperative one-year course was uneventful, without signs of tumor recurrence after one year, and further surgical corrections were unnecessary. CONCLUSION: Considering the results of our operative technique, we believe that middle island-shaped forehead flap is suitable for reconstruction of the columella and the tip of the nose, due to the following reasons: safe vascularization of flap, similarity of the transferred tissue with the excised one, the procedure is completed in one step, simple surgical technique and uncomplicated healing of a flap-harvesting site. PMID- 21524009 TI - [Medical Corps Colonel Doctor Sava Petkovic "Flora of the town of Nis region"- inheritance for the future]. PMID- 21524010 TI - Durational patterning at syntactic and discourse boundaries in Mandarin spontaneous speech. AB - This study focused on durational cues (i.e., syllable duration, pause duration, and syllable onset intervals (SOIs)) at discourse boundaries in two dialects of Mandarin,Taiwan and Mainland varieties. Speech was elicited by having 18 participants describe events in The Pear Story film. Recorded data were transcribed, labeled, and segmented into clauses. Discourse boundary indices were used to label discourse disjuncture levels. Results showed that the scope of lengthening included both the final and the penultimate syllables. Pause was a robust but optional indicator for discourse boundaries, and Taiwan Mandarin preferred unfilled over filled ones, while the Mainland variety did not show such strong preferences. Discourse hierarchy corresponded consistently with occurrences of pauses and duration of SOIs, within which pause was the main contributor. Higher discourse levels were more likely to be accompanied by pauses, and were indicated by longer pauses and SOIs. Syllable duration only played a secondary role in indicating discourse disjuncture size when pause was absent.When there was an accompanying pause, Mainland Mandarin relied solely on it to indicate discourse hierarchy, while Taiwan Mandarin used both syllable and pause duration, a dialectal difference that seemed to be rhythm-related. By shortening the degree of lengthening in the boundary syllable and lengthening the following pause at the same time,Taiwan Mandarin increased the absolute and relative duration of pause and maximized its role in indicating discourse hierarchy.The results of this study implied that the use of pause in discourse disjuncture demarcation was more of a language-specific choice while its role in discourse hierarchy encoding is more language-universal. PMID- 21524011 TI - Are women more influenced than men by top-down semantic information when listening to disrupted speech? AB - Perception is a product of the interaction between bottom-up sensory processing and top-down higher order cognitive activity. For example, when the initial phoneme of a word is obliterated and replaced with noise, listeners hear it as intact provided there is semantic context. We modified this phonemic restoration paradigm by masking (not obliterating) the initial phoneme of a target word and presenting it within a carrier phrase which was informative (I), uninformative (U), or misinformative (M). Bias in favor of top-down context was measured as the extent to which M trials mislead listeners into reporting a target word other than that which was presented (relative to U trials that have irrelevant top-down semantic context). Forty-one participants (20 men) completed 600 test trials (300 delayed report of the phrase, 300 forced choice). Relative to the U condition, women were more affected by both the I and M cues than men, at certain levels of audibility during the forced choice condition. Moreover, the semantic strength of the I carrier phrases was correlated with the rate of correct reports of the target words in women but not in men.This suggests that women can be more affected by top-down semantic context than men. PMID- 21524012 TI - Sensitivity to visual prosodic cues in signers and nonsigners. AB - Three studies are presented in this paper that address how nonsigners perceive the visual prosodic cues in a sign language. In Study 1, adult American nonsigners and users of American Sign Language (ASL) were compared on their sensitivity to the visual cues in ASL Intonational Phrases. In Study 2, hearing, nonsigning American infants were tested using the same stimuli used in Study I to see whether maturity, exposure to gesture, or exposure to sign language is necessary to demonstrate this type of sensitivity. Study 3 addresses nonsigners' and signers' strategies for segmenting Prosodic Words in a sign language. Adult participants from six language groups (3 spoken languages and 3 sign languages) were tested.The results of these three studies indicate that nonsigners have a high degree of sensitivity to sign language prosodic cues at the Intonational Phrase level and the Prosodic Word level; these are attributed to modality or'channel' effects of the visual signal.There are also some differences between signers' and nonsigners' sensitivity; these differences are attributed to language experience or language-particular constraints.This work is useful in understanding the gestural competence of nonsigners and the ways in which this type of competence may contribute to the grammaticalization of these properties in a sign language. PMID- 21524013 TI - Acoustic correlates of stress in central Catalan and Castilian Spanish. AB - The general literature on the phonetic correlates of stress agrees that duration, and in stress accent languages, F0 are consistent correlates of stress. However, the role of amplitude changes in the speech signal is more controversial. In particular, the conflicting results of spectral tilt as a correlate of stress have been attributed to the effects of vowel reduction. We examined the stress correlates of duration, overall intensity and spectral tilt in Catalan and Spanish in both accented and unaccented contexts while controlling for formant frequency differences between morphologically corresponding vowels in stressed and unstressed environments by comparing vowels that maintain the same quality across stress contexts with those that do not. Duration was a consistent stress correlate in all vowels in both languages, regardless of their formant frequency differences across stress contexts and of the absence of pitch accents. In fact, stress-related formant frequency differences between corresponding vowels amplify the duration cues to the stress contrast. On the other hand, the use speakers made of intensity was not as pervasive as that of duration. Specifically, changes in spectral tilt were significant only in Catalan and in those vowels that alternate a more open and peripheral realization in stressed syllables with a mid central realization in unstressed syllables, indicating that spectral tilt is related to the formant frequency differences linked to the centralization processes rather than to the stress contrast. PMID- 21524014 TI - Speaker age and vowel perception. AB - Recent research provides evidence that individuals shift in their perception of variants depending on social characteristics attributed to the speaker.This paper reports on a speech perception experiment designed to test the degree to which the age attributed to a speaker influences the perception of vowels undergoing a chain shift. As a result of the shift, speakers from different generations produce different variants from one another. Results from the experiment indicate that a speaker's perceived age can influence vowel categorization in the expected direction. However, only older participants are influenced by perceived speaker age.This suggests that social characteristics attributed to a speaker affect speech perception differently depending on the salience of the relationship between the variant and the characteristic.The results also provide evidence of an unexpected interaction between the sex of the participant and the sex of the stimulus.The interaction is interpreted as an effect of the participants' previous exposure with male and female speakers.The results are analyzed under an exemplar model of speech production and perception where social information is indexed to acoustic information and the weight of the connection varies depending on the perceived salience of sociophonetic trends. PMID- 21524015 TI - Acoustic markers of prominence influence infants' and adults' segmentation of speech sequences. AB - Two experiments investigated the way acoustic markers of prominence influence the grouping of speech sequences by adults and 7-month-old infants. In the first experiment, adults were familiarized with and asked to memorize sequences of adjacent syllables that alternated in either pitch or duration. During the test phase, participants heard pairs of syllables with constant pitch and duration and were asked whether the syllables had appeared adjacently during familiarization. Adults were better at remembering pairs of syllables that during familiarization had short syllables preceding long syllables, or high-pitched syllables preceding low-pitched syllables. In the second experiment, infants were familiarized and tested with similar stimuli as in the first experiment, and their preference for pairs of syllables was accessed using the head-turn preference paradigm.When familiarized with syllables alternating in pitch, infants showed a preference to listen to pairs of syllables that had high pitch in the first syllable. However, no preference was found when the familiarization stream alternated in duration. It is proposed that these perceptual biases help infants and adults find linguistic units in the continuous speech stream.While the bias for grouping based on pitch appears early in development, biases for durational grouping might rely on more extensive linguistic experience. PMID- 21524016 TI - Effect of a geriatric nurse education program on the knowledge, attitudes, and certification of hospital nurses. AB - Although nurses are the primary care providers for hospitalized and vulnerable older adults living in the community, they are generally not prepared in geriatric care. This study examined the effect of a 21-hour nursing education program on nurses' knowledge and attitudes regarding care of older adults and the geriatric nursing certification of the participants. The program was offered to 92 nurses in three cohorts over a 1-year period. Participants completed pre- and posttest measures of geriatric knowledge and attitudes. Significant differences were found between pretest and posttest knowledge and attitudes. Program evaluation and success in achieving certification in gerontological nursing also indicated a positive effect of the program. PMID- 21524017 TI - Effects of concept map teaching on students' critical thinking and approach to learning and studying. AB - The purpose of this study was to explore the effects of concept mapping in developing critical thinking ability and approach to learning and studying. A quasi-experimental study design with a purposive sample was drawn from a group of nursing students enrolled in a medical-surgical nursing course in central Taiwan. Students in the experimental group were taught to use concept mapping in their learning. Students in the control group were taught by means of traditional lectures. After the intervention, the experimental group had better overall critical thinking scores than did the control group, although the difference was not statistically significant. After controlling for the effects of age and the pretest score on critical thinking using analysis of covariance, the experimental group had significantly higher adjusted mean scores on inference and overall critical thinking compared with the control group. Concept mapping is an effective tool for improving students' ability to think critically. PMID- 21524018 TI - Bridging the gap between clinical experience and client access: community engagement. AB - Service-learning involvement can be a useful adjunct to a traditional educational experience and can provide clinical exposure in mental health practice settings for undergraduate nursing students. Education and practice collaboratives in community settings benefit community partners through the service provided by students to the respective community organizations. Benefits to students are obvious through greater exposure to community agencies, avenues to meet academic clinical course objectives, and incentives for their critical and independent thinking. An overview of the process of engaging students in community engagement opportunities that provide clinical hours in an undergraduate mental health course is presented. PMID- 21524019 TI - Using distance technology to learn across borders: a virtual travel course in nursing. AB - A 6-week online course was developed and delivered to nursing students and instructors at universities in two countries. The course exposed students and faculty to nursing and health concerns in both countries. All course communications were conducted in both English and Spanish, with support from online translation software as needed. Course content covered professional nursing, global health issues, and nursing interventions used with clinical problems. Although students were initially intimidated by the course language requirements, students valued the opportunity to learn about cultural and health issues. Faculty experienced a learning curve as well and enjoyed this international experience. PMID- 21524020 TI - Transforming attitudes of nursing students: evaluating a service-learning experience. AB - Homelessness is a compelling social and public health issue. Nurse educators are challenged to better prepare graduates to serve this growing segment of the population. Clinical experiences with those experiencing homelessness allow students a better understanding of this population and may foster more compassionate care. This pretest-posttest intervention study examined nursing students' attitudes toward homelessness before and after participation in a service-learning clinical rotation with families experiencing homelessness. Twenty-three students enrolled in a public health nursing course at a small midwestern university participated in the research. The Attitudes Toward Homelessness Inventory was used to measure students' attitudes at the beginning and end of the course. Data analysis using descriptive statistics revealed significant differences in both global and specific attitudes toward people experiencing homelessness. These results suggest the clinical experiences positively influenced students' attitudes and support the value of integrating service-learning clinical opportunities with homeless individuals into nursing curricula. PMID- 21524021 TI - Innovations in bereavement education. AB - Advanced practice nursing students provide care for clients and families in numerous settings where they will encounter end-of-life issues. Thus, graduate nursing education should include information on current trends in thanatology, such as the debate over the proposed complicated grief criteria and the paradigmatic shift toward evidence-based grief theory. In this article, an innovative approach to teaching bereavement content to graduate nursing students during a 3-hour class is presented. The assignments were developed specifically for adult learners with clinical experience. Students' responses to the learning activities and recommendations for modifications of the teaching methods are presented. PMID- 21524022 TI - Effects of formal and informal support structures on the motivation of Native American students in nursing. AB - Native Americans have traditionally been underrepresented in nursing. The authors surveyed 19 undergraduate nursing students participating in a university sponsored Native American nursing student support program and examined which social support factors influenced the students' success. Using validated quantitative measures from social psychology, the authors found that overall perceived social support, as well as support from the university sponsored program, positively influenced Native American students' identification with nursing, their interest in nursing, their perception of the value of nursing, and their motivation to continue pursuing nursing as a career. Conversely, perceptions of unfairness due to racial bias within the major negatively affected students' perception of the value of nursing, as well as their motivation to pursue a nursing career. PMID- 21524023 TI - Wavefront-optimized surface ablation with the Allegretto Wave Eye-Q excimer laser platform: 12-month visual and refractive results. AB - PURPOSE: To evaluate the wavefront-optimized algorithm of the Allegretto Wave Eye Q (Wavelight AG) 400-Hz excimer laser platform. METHODS: Three hundred three eyes of 303 patients treated with advanced surface ablation were evaluated prospectively. Topical mitomycin C (MMC) was used when ablation was >=80 MUm. Efficacy, safety, and predictability at 12 months were quantified with subjective refraction, visual acuity (logMAR), and slit-lamp examination. RESULTS: Mean postoperative uncorrected distance visual acuity (UDVA) was 20/20.5 (0.01+/-0.05 logMAR). Postoperative UDVA was equal or better than preoperative corrected distance visual acuity (CDVA) in 94.7% of eyes. Efficacy index was 1.05. Corrected distance visual acuity was maintained (93.7%) or improved (5.9%) in 99.6% of treated eyes. No patient lost >=2 lines. Safety index was 1.05. Haze at 12 months was grade <=0.5 in 98% of treated eyes and grade <=1 in 100% of treated eyes. Mean postoperative manifest refraction spherical equivalent (MRSE) was 0.03+/-0.15 diopters (D). Postoperative MRSE was within +/-0.50 D in 99% of eyes. Overcorrection was documented in 0.66% and undercorrection in 0.33% of eyes. CONCLUSIONS: The wavefront-optimized algorithm of the Allegretto Wave Eye-Q excimer laser platform showed good efficacy, safety, and predictability in advanced surface ablation, with or without MMC intraoperative use. PMID- 21524024 TI - Thank you, CMS, for your leadership! PMID- 21524027 TI - Should carotid artery stenosis be examined as a cause of dizziness? PMID- 21524028 TI - Appropriate use of MRI for evaluating common musculoskeletal conditions. PMID- 21524030 TI - Constipation in adults. PMID- 21524031 TI - Neonatal resuscitation: an update. AB - Appropriate resuscitation must be available for each of the more than 4 million infants born annually in the United States. Ninety percent of infants transition safely, and it is up to the physician to assess risk factors, identify the nearly 10 percent of infants who need resuscitation, and respond appropriately. A team or persons trained in neonatal resuscitation should be promptly available to provide resuscitation. The Neonatal Resuscitation Program, which was initiated in 1987 to identify infants at risk of needing resuscitation and provide high quality resuscitation, underwent major updates in 2006 and 2010. Among the most important changes are to not intervene with endotracheal suctioning in vigorous infants born through meconium-stained amniotic fluid (although endotracheal suctioning may be appropriate in nonvigorous infants); to provide positive pressure ventilation with one of three devices when necessary; to begin resuscitation of term infants using room air or blended oxygen; and to have a pulse oximeter readily available in the delivery room. The updated guidelines also provide indications for chest compressions and for the use of intravenous epinephrine, which is the preferred route of administration, and recommend not to use sodium bicarbonate or naloxone during resuscitation. Other recommendations include confirming endotracheal tube placement using an exhaled carbon dioxide detector; using less than 100 percent oxygen and adequate thermal support to resuscitate preterm infants; and using therapeutic hypothermia for infants born at 36 weeks' gestation or later with moderate to severe hypoxic-ischemic encephalopathy. PMID- 21524032 TI - House calls. AB - House calls provide a unique perspective on patients' environment and health problems. The demand for house calls is expected to increase considerably in future decades as the U.S. population ages. Although study results have been inconsistent, house calls involving multidisciplinary teams may reduce hospital readmissions and long-term care facility stays. Common indications for house calls are management of acute or chronic illnesses, and palliative care. Medicare beneficiaries must meet specific criteria to be eligible for home health services. The INHOMESSS mnemonic provides a checklist for components of a comprehensive house call. In addition to performing a clinical assessment, house calls may involve observing the patient performing daily activities, reconciling medication discrepancies, and evaluating home safety. House calls can be integrated into practice with careful planning, including clustering house calls by geographic location and coordinating visits with other health care professionals and agencies. PMID- 21524033 TI - Update on subclinical hyperthyroidism. AB - Subclinical hyperthyroidism is defined by low or undetectable serum thyroid stimulating hormone levels, with normal free thyroxine and total or free triiodothyronine levels. It can be caused by increased endogenous production of thyroid hormone (as in Graves disease or toxic nodular goiter), administration of thyroid hormone for treatment of malignant thyroid disease, or unintentional excessive thyroid hormone therapy. The rate of progression to overt hyperthyroidism is higher in persons who have suppressed thyroid-stimulating hormone levels compared with those who have low but detectable levels. Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation in older adults, and with decreased bone mineral density in postmenopausal women; however, the effectiveness of treatment in preventing these conditions is unknown. There is lesser-quality evidence suggesting an association between subclinical hyperthyroidism and other cardiovascular effects, including increased heart rate and left ventricular mass, and increased bone turnover markers. Possible associations between subclinical hyperthyroidism and quality of life parameters, cognition, and increased mortality rates are controversial. Prospective randomized controlled trials are needed to address the effects of early treatment on potential morbidities to help determine whether screening should be recommended in the asymptomatic general population. PMID- 21524034 TI - Information from your family doctor. Subclinical hyperthyroidism: what it means to you. PMID- 21524035 TI - Carpal tunnel syndrome. AB - Carpal tunnel syndrome is the most common entrapment neuropathy, affecting approximately 3 to 6 percent of adults in the general population. Although the cause is not usually determined, it can include trauma, repetitive maneuvers, certain diseases, and pregnancy. Symptoms are related to compression of the median nerve, which results in pain, numbness, and tingling. Physical examination findings, such as hypalgesia, square wrist sign, and a classic or probable pattern on hand symptom diagram, are useful in making the diagnosis. Nerve conduction studies and electromyography can resolve diagnostic uncertainty and can be used to quantify and stratify disease severity. Treatment options are based on disease severity. Six weeks to three months of conservative treatment can be considered in patients with mild disease. Lifestyle modifications, including decreasing repetitive activity and using ergonomic devices, have been traditionally advocated, but have inconsistent evidence to support their effectiveness. Cock-up and neutral wrist splints and oral corticosteroids are considered first-line therapies, with local corticosteroid injections used for refractory symptoms. Nonsteroidal anti-inflammatory drugs, diuretics, and pyridoxine (vitamin B6) have been shown to be no more effective than placebo. Most conservative treatments provide short-term symptom relief, with little evidence supporting long-term benefits. Patients with moderate to severe disease should be considered for surgical evaluation. Open and endoscopic surgical approaches have similar five-year outcomes. PMID- 21524036 TI - Information from your family doctor. Carpal tunnel syndrome. PMID- 21524037 TI - Keratotic lesions on the nipples and areolae of a 62-year-old man. PMID- 21524038 TI - FPIN's clinical inquiries. Secondary causes of obesity. PMID- 21524041 TI - Case report: colonoscopy-associated splenic injury in a 56-year-old woman. PMID- 21524044 TI - A medical alert tattoo. PMID- 21524045 TI - Screening for prostate cancer: prostate-specific antigen testing is not effective. PMID- 21524046 TI - Vaginitis. AB - Bacterial vaginosis, trichomoniasis, and vulvovaginal candidiasis are the most common infectious causes of vaginitis. Bacterial vaginosis occurs when the normal lactobacilli of the vagina are replaced by mostly anaerobic bacteria. Diagnosis is commonly made using the Amsel criteria, which include vaginal pH greater than 4.5, positive whiff test, milky discharge, and the presence of clue cells on microscopic examination of vaginal fluid. Oral and topical clindamycin and metronidazole are equally effective at eradicating bacterial vaginosis. Symptoms and signs of trichomoniasis are not specific; diagnosis by microscopy is more reliable. Features of trichomoniasis are trichomonads seen microscopically in saline, more leukocytes than epithelial cells, positive whiff test, and vaginal pH greater than 5.4. Any nitroimidazole drug (e.g., metronidazole) given orally as a single dose or over a longer period resolves 90 percent of trichomoniasis cases. Sex partners should be treated simultaneously. Most patients with vulvovaginal candidiasis are diagnosed by the presence of vulvar inflammation plus vaginal discharge or with microscopic examination of vaginal secretions in 10 percent potassium hydroxide solution. Vaginal pH is usually normal (4.0 to 4.5). Vulvovaginal candidiasis should be treated with one of many topical or oral antifungals, which appear to be equally effective. Rapid point-of-care tests are available to aid in accurate diagnosis of infectious vaginitis. Atrophic vaginitis, a form of vaginitis caused by estrogen deficiency, produces symptoms of vaginal dryness, itching, irritation, discharge, and dyspareunia. Both systemic and topical estrogen treatments are effective. Allergic and irritant contact forms of vaginitis can also occur. PMID- 21524047 TI - Information from your family doctor. Vaginitis. PMID- 21524048 TI - Medical management of stable coronary artery disease. AB - All patients with stable coronary artery disease require medical therapy to prevent disease progression and recurrent cardiovascular events. Three classes of medication are essential to therapy: lipid-lowering, antihypertensive, and antiplatelet agents. Lipid-lowering therapy is necessary to decrease low-density lipoprotein cholesterol to a target level of less than 100 mg per dL, and physicians should consider a goal of less than 70 mg per dL for very high-risk patients. Statins have demonstrated clear benefits in morbidity and mortality in the secondary prevention of coronary artery disease; other medications that can be used in addition to statins to lower cholesterol include ezetimibe, fibrates, and nicotinic acid. Blood pressure therapy for patients with coronary artery disease should start with beta blockers and angiotensin-converting enzyme inhibitors. If these medications are not tolerated, calcium channel blockers or angiotensin receptor blockers are acceptable alternatives. Aspirin is the first line antiplatelet agent except in patients who have recently had a myocardial infarction or undergone stent placement, in which case clopidogrel is recommended. Anginal symptoms of coronary artery disease can be treated with beta blockers, calcium channel blockers, nitrates, or any combination of these. Familiarity with these medications and with the evidence supporting their use is essential to reducing morbidity and mortality in patients with coronary artery disease. PMID- 21524049 TI - Failure to thrive: an update. AB - Failure to thrive in childhood is a state of undernutrition due to inadequate caloric intake, inadequate caloric absorption, or excessive caloric expenditure. In the United States, it is seen in 5 to 10 percent of children in primary care settings. Although failure to thrive is often defined as a weight for age that falls below the 5th percentile on multiple occasions or weight deceleration that crosses two major percentile lines on a growth chart, use of any single indicator has a low positive predictive value. Most cases of failure to thrive involve inadequate caloric intake caused by behavioral or psychosocial issues. The most important part of the outpatient evaluation is obtaining an accurate account of a child's eating habits and caloric intake. Routine laboratory testing rarely identifies a cause and is not generally recommended. Reasons to hospitalize a child for further evaluation include failure of outpatient management, suspicion of abuse or neglect, or severe psychosocial impairment of the caregiver. A multidisciplinary approach to treatment, including home nursing visits and nutritional counseling, has been shown to improve weight gain, parent-child relationships, and cognitive development. The long-term effects of failure to thrive on cognitive development and future academic performance are unclear. PMID- 21524050 TI - Failure to thrive: what this means for your child. PMID- 21524051 TI - Tongue lesion with sensation of fullness in the mouth. PMID- 21524053 TI - Noncovalent interactions in the gas phase: the anisole-phenol complex. AB - The present paper reports on an integrated spectroscopic study of the anisole phenol complex in a molecular beam environment. Combining REMPI and HR-LIF spectroscopy experimental data with density functional computations (TD-M05 2X/M05-2X//N07D) and first principle spectra simulations, it was possible to locate the band origin of the S(1) <- S(0) electronic transition and determine the equilibrium structure of the complex, both in the S(0) and S(1) electronic states. Experimental and computational evidence indicates that the observed band origin is due to an electronic transition localized on the phenol frame, while it was not possible to localize experimentally another band origin due to the electronic transition localized on the anisole molecule. The observed structure of the complex is stabilized by a hydrogen bond between the phenol, acting as a proton donor, and the anisole molecule, acting as an acceptor through the lone pairs of the oxygen atom. A secondary interaction involving the hydrogen atoms of the anisole methyl group and the pi electron system of the phenol molecule stabilizes the complex in a nonplanar configuration. Additional insights about the landscapes of the potential energy surfaces governing the ground and first excited electronic states of the anisole-phenol complex, with the issuing implications on the system photodynamic, can be extracted from the combined experimental and computational studies. PMID- 21524054 TI - Ginsenoside Rb1 inhibits proliferation and inflammatory responses in rat aortic smooth muscle cells. AB - Ginsenoside Rb1, a known phytoestrogen, is a major pharmacologically active component in ginseng. The present study was designed to investigate the effect of ginsenoside Rb1 on fetal bovine serum (FBS)-induced proliferation and tumor necrosis factor-alpha (TNF-alpha)-evoked inflammatory responses in cultured rat aortic vascular smooth muscle cells (VSMCs). The data showed that Rb1 potently inhibited VSMC proliferation and cell growth induced by 5% FBS. These inhibitory effects were associated with G(1) cell cycle arrest and down-regulation of cell cycle proteins. Treatment with Rb1 reduced FBS-induced extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Furthermore, TNF-alpha-evoked inflammatory responses were inhibited by Rb1. Reporter gene assay indicated that Rb1 could transactivate ERbeta especially. Moreover, Rb1-mediated inhibition of VSMCs proliferation was greatly blocked by transfection of ERbeta siRNA. These results suggest that Rb1 inhibits FBS-induced proliferation and TNF-alpha-evoked inflammatory responses in VSMCs. The findings presented here highlight the possible therapeutic use of Rb1 in cardiovascular disease. PMID- 21524055 TI - Regioselective esterification and etherification of cellulose: a review. AB - Deep understanding of the structure-property relationships of polysaccharide derivatives depends on the ability to control the position of the substituents around the monosaccharide ring and along the chain. Equally important is the ability to analyze position of substitution. Historically, both synthetic control and analysis of regiochemistry have been very difficult for cellulose derivatives, as for most other polysaccharide derivatives. With the advent of cellulose solvents that are suitable for chemical transformations, it has become possible to carry out cellulose derivatization under conditions sufficiently mild to permit increasingly complete regiochemical control, particularly with regard to the position of the substituents around the anhydroglucose ring. In addition, new techniques for forming cellulose and its derivatives from monomers, either by enzyme-catalyzed processes or chemical polymerization, permit us to address new frontiers in regiochemical control. We review these exciting developments in regiocontrolled synthesis of cellulose derivatives and their implications for in depth structure-property studies. PMID- 21524056 TI - Study of single-stranded DNA binding protein-nucleic acids interactions using unmodified gold nanoparticles and its application for detection of single nucleotide polymorphisms. AB - We have developed a label-free homogeneous phase bioassay to characterize the DNA binding properties of single-stranded DNA binding (SSB) protein, a key protein involved in various DNA processes such as DNA replication and repair. This assay uses gold nanoparticles (AuNPs) as sensing probe and is based on the phenomenon that preformed SSB-single-stranded DNA (ssDNA) complexes can protect AuNPs against salt-induced aggregation better than SSB or ssDNA alone. With the controlled particle aggregation/dispersion as measure, this assay can be used to detect the formation of SSB complexes with ssDNA of different length and nucleotide composition and to assess their binding properties without tedious and complicated assay procedures. On the basis of the inverse relationship between DNA hybridization efficiency and the tendency of SSB to form protection complex with unhybridized ssDNA to AuNPs, this assay is further developed to detect DNA hybridization with single nucleotide polymorphism selectivity. Owing to the high affinity between SSB and dissociated ssDNA, single-base mismatch discrimination in a long sequence of 30-mer DNA was achieved for both the end- and center-base mismatch. Unlike the conventional techniques for DNA and protein analysis, current AuNPs-based sensing strategy is simple in design, fast in detection, and economical for operation without the need of sophisticated equipment. PMID- 21524058 TI - Thin wire shortening of plasmonic nanoparticle dimers: the reason for red shifts. AB - We studied experimentally and theoretically resonance characteristics of plasmonic nanoparticle dimers connected by a narrow metal wire. The "conductive" coupling between the particles results in complete redistribution of the surface charge yielding abrupt red shift of the plasmon resonance: detuning >900 nm and order of magnitude improvement in intensity enhancement. The resonance in the conductive coupling regime is determined completely by the characteristics of the unified particle and significantly different from that of capacitive coupling. PMID- 21524057 TI - Interaction of nitric oxide with catalase: structural and kinetic analysis. AB - We present the structures of bovine catalase in its native form and complexed with ammonia and nitric oxide, obtained by X-ray crystallography. Using the NO generator 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate, we were able to generate sufficiently high NO concentrations within the catalase crystals that substantial occupation was observed despite a high dissociation rate. Nitric oxide seems to be slightly bent from the heme normal that may indicate some iron(II) character in the formally ferric catalase. Microspectrophotometric investigations inline with the synchrotron X-ray beam reveal photoreduction of the central heme iron. In the cases of the native and ammonia-complexed catalase, reduction is accompanied by a relaxation phase. This is likely not the case for the catalase NO complex. The kinetics of binding of NO to catalase were investigated using NO photolyzed from N,N'-bis(carboxymethyl)-N,N'-dinitroso-p-phenylenediamine using an assay that combines catalase with myoglobin binding kinetics. The off rate is 1.5 s(-1). Implications for catalase function are discussed. PMID- 21524059 TI - Proton-coupled electron transfer reactions at a heme-propionate in an iron protoporphyrin-IX model compound. AB - A heme model system has been developed in which the heme-propionate is the only proton donating/accepting site, using protoporphyrin IX-monomethyl esters (PPIX(MME)) and N-methylimidazole (MeIm). Proton-coupled electron transfer (PCET) reactions of these model compounds have been examined in acetonitrile solvent. (PPIX(MME))Fe(III)(MeIm)(2)-propionate (Fe(III)~CO(2)) is readily reduced by the ascorbate derivative 5,6-isopropylidine ascorbate to give (PPIX(MME))Fe(II)(MeIm)(2)-propionic acid (Fe(II)~CO(2)H). An excess of the hydroxylamine TEMPOH or of hydroquinone similarly reduces Fe(III)~CO(2), and TEMPO and benzoquinone oxidize Fe(II)~CO(2)H to return to Fe(III)~CO(2). The measured equilibrium constants, and the determined pK(a) and E(1/2) values, indicate that Fe(II)~CO(2)H has an effective bond dissociation free energy (BDFE) of 67.8 +/- 0.6 kcal mol(-1). In these PPIX models, electron transfer occurs at the iron center and proton transfer occurs at the remote heme propionate. According to thermochemical and other arguments, the TEMPOH reaction occurs by concerted proton-electron transfer (CPET), and a similar pathway is indicated for the ascorbate derivative. Based on these results, heme propionates should be considered as potential key components of PCET/CPET active sites in heme proteins. PMID- 21524060 TI - Ultrasensitive microarray detection of short RNA sequences with enzymatically modified nanoparticles and surface plasmon resonance imaging measurements. AB - A novel multiplexed method for short RNA detection that employs an enzymatic capture reaction onto DNA-modified silica nanoparticles (SiNPs) followed by nanoparticle-enhanced surface plasmon resonance imaging (SPRI) is demonstrated. SiNPs functionalized with 5'-phosphorylated single stranded DNA (ssDNA) are used with T4 RNA ligase to capture various short 20-24 base single-stranded RNA (ssRNA) oligonucleotides from a target solution. The ssRNA-modified SiNPs are collected from the target solution, specifically adsorbed onto a cDNA microarray and then detected with SPRI. The use of DNA-modified SiNPs to capture ssRNA for profiling has several advantages as compared to a planar SPRI surface bioaffinity adsorption format: (i) the target solution is exposed to a larger total surface area for the RNA ligation reaction; (ii) the SiNPs enhance the diffusion rate of the ssRNA to the surface; (iii) the SiNPs can be collected, washed, and preconcentrated prior to detection; and (iv) the ssRNA-modified SiNPs give an enhanced SPRI signal upon hybridization adsorption to the microarray. Our initial measurements demonstrate that this detection method can be used to detect multiple ssRNA sequences at concentrations as low as 100 fM in 500 MUL. PMID- 21524061 TI - Cyanine dyes as optical contrast agents for ophthalmological surgery. AB - Cyanine dyes were prepared as optical contrast media for supporting the surgery of the lamina limitans interna (LLI) of the retina and other structures of the human eye. Their absorption spectra were adapted both to the spectral sensitivity of the human eye and to standard illumination. The contrast could be further amplified by the application of the strong fluorescence of the dyes used. The binding of the dyes to various surfaces was studied. No toxic effects could be detected for the applied dyes. PMID- 21524063 TI - Structure and surface chemistry of gold-based model catalysts. PMID- 21524062 TI - Use of size and a copolymer design feature to improve the biodistribution and the enhanced permeability and retention effect of doxorubicin-loaded mesoporous silica nanoparticles in a murine xenograft tumor model. AB - A key challenge for improving the efficacy of passive drug delivery to tumor sites by a nanocarrier is to limit reticuloendothelial system uptake and to maximize the enhanced permeability and retention effect. We demonstrate that size reduction and surface functionalization of mesoporous silica nanoparticles (MSNP) with a polyethyleneimine-polyethylene glycol copolymer reduces particle opsonization while enhancing the passive delivery of monodispersed, 50 nm doxorubicin-laden MSNP to a human squamous carcinoma xenograft in nude mice after intravenous injection. Using near-infrared fluorescence imaging and elemental Si analysis, we demonstrate passive accumulation of ~12% of the tail vein-injected particle load at the tumor site, where there is effective cellular uptake and the delivery of doxorubicin to KB-31 cells. This was accompanied by the induction of apoptosis and an enhanced rate of tumor shrinking compared to free doxorubicin. The improved drug delivery was accompanied by a significant reduction in systemic side effects such as animal weight loss as well as reduced liver and renal injury. These results demonstrate that it is possible to achieve effective passive tumor targeting by MSNP size reduction as well as by introducing steric hindrance and electrostatic repulsion through coating with a copolymer. Further endowment of this multifunctional drug delivery platform with targeting ligands and nanovalves may further enhance cell-specific targeting and on-demand release. PMID- 21524064 TI - Iron(II)-catalyzed amidation of aldehydes with iminoiodinanes at room temperature and under microwave-assisted conditions. AB - A method for the amidation of aldehydes with PhI=NTs/PhI=NNs as the nitrogen source and an inexpensive iron(II) chloride + pyridine as the in situ formed precatalyst under mild conditions at room temperature or microwave assisted conditions is described. The reaction was operationally straightforward and accomplished in moderate to excellent product yields (20-99%) and with complete chemoselectivity with the new C-N bond forming only at the formylic C-H bond in substrates containing other reactive functional groups. By utilizing microwave irradiation, comparable product yields and short reaction times of 1 h could be accomplished. The mechanism is suggested to involve insertion of a putative iron nitrene/imido group to the formylic C-H bond of the substrate via a H-atom abstraction/radical rebound pathway mediated by the precatalyst [Fe(py)(4)Cl(2)] generated in situ from reaction of FeCl(2) with pyridine. PMID- 21524065 TI - Coupling multi-criteria decision analysis, life-cycle assessment, and risk assessment for emerging threats. AB - Emerging environmental threats such as novel chemical compounds, biological agents, and nanomaterials present serious challenges to traditional models of risk analysis and regulatory risk management processes. Even a massive expansion of risk and life-cycle assessment research efforts is unlikely to keep pace with rapid technological change resulting in new and modified materials with changing properties. Therefore, it is essential to have a framework for interpreting available information in the context of high uncertainty and a strategy for prioritizing research efforts to reduce those uncertainties that are most critical. We discuss how integrating the three analytic approaches of risk assessment, life-cycle assessment, and multicriteria decision analysis into a framework permits understanding uncertainty and prioritizes needs for scientific research. Our approach is illustrated with two separate cases: nanomaterials and contaminated sediment remediation. PMID- 21524066 TI - Neomycin-neomycin dimer: an all-carbohydrate scaffold with high affinity for AT rich DNA duplexes. AB - A dimeric neomycin-neomycin conjugate 3 with a flexible linker, 2,2' (ethylenedioxy)bis(ethylamine), has been synthesized and characterized. Dimer 3 can selectively bind to AT-rich DNA duplexes with high affinity. Biophysical studies have been performed between 3 and different nucleic acids with varying base composition and conformation by using ITC (isothermal calorimetry), CD (circular dichroism), FID (fluorescent intercalator displacement), and UV (ultraviolet) thermal denaturation experiments. A few conclusions can be drawn from this study: (1) FID assay with 3 and polynucleotides demonstrates the preference of 3 toward AT-rich sequences over GC-rich sequences. (2) FID assay and UV thermal denaturation experiments show that 3 has a higher affinity for the poly(dA).poly(dT) DNA duplex than for the poly(dA).2poly(dT) DNA triplex. Contrary to neomycin, 3 destabilizes poly(dA).2poly(dT) triplex but stabilizes poly(dA).poly(dT) duplex, suggesting the major groove as the binding site. (3) UV thermal denaturation studies and ITC experiments show that 3 stabilizes continuous AT-tract DNA better than DNA duplexes with alternating AT bases. (4) CD and FID titration studies show a DNA binding site size of 10-12 base pairs/drug, depending upon the structure/sequence of the duplex for AT-rich DNA duplexes. (5) FID and ITC titration between 3 and an intramolecular DNA duplex [d(5'-A(12)-x-T(12)-3'), x = hexaethylene glycol linker] results in a binding stoichiometry of 1:1 with a binding constant ~10(8) M(-1) at 100 mM KCl. (6) FID assay using 3 and 512 hairpin DNA sequences that vary in their AT base content and placement also show a higher binding selectivity of 3 toward continuous AT rich than toward DNA duplexes with alternate AT base pairs. (7) Salt-dependent studies indicate the formation of three ion pairs during binding of the DNA duplex d[5'-A(12)-x-T(12)-3'] and 3. (8) ITC-derived binding constants between 3 and DNA duplexes have the following order: AT continuous, d[5'-G(3)A(5)T(5)C(3) 3'] > AT alternate, d[5'-G(3)(AT)(5)C(3)-3'] > GC-rich d[5'-A(3)G(5)C(5)T(3)-3']. (9) 3 binds to the AT-tract-containing DNA duplex (B* DNA, d[5'-G(3)A(5)T(5)C(3) 3']) with 1 order of magnitude higher affinity than to a DNA duplex with alternating AT base pairs (B DNA, d[5'-G(3)(AT)(5)C(3)-3']) and with almost 3 orders of magnitude higher affinity than a GC-rich DNA (A-form, d[5' A(3)G(5)C(5)T(3)-3']). PMID- 21524067 TI - Modeling stochastic dynamics in biochemical systems with feedback using maximum caliber. AB - Complex feedback systems are ubiquitous in biology. Modeling such systems with mass action laws or master equations requires information rarely measured directly. Thus rates and reaction topologies are often treated as adjustable parameters. Here we present a general stochastic modeling method for small chemical and biochemical systems with emphasis on feedback systems. The method, Maximum Caliber (MaxCal), is more parsimonious than others in constructing dynamical models requiring fewer model assumptions and parameters to capture the effects of feedback. MaxCal is the dynamical analogue of Maximum Entropy. It uses average rate quantities and correlations obtained from short experimental trajectories to construct dynamical models. We illustrate the method on the bistable genetic toggle switch. To test our method, we generate synthetic data from an underlying stochastic model. MaxCal reliably infers the statistics of the stochastic bistability and other full dynamical distributions of the simulated data, without having to invoke complex reaction schemes. The method should be broadly applicable to other systems. PMID- 21524068 TI - Transparent conductors from carbon nanotubes LBL-assembled with polymer dopant with pi-pi electron transfer. AB - Single-walled carbon nanotube (SWNT) and other carbon-based coatings are being considered as replacements for indium tin oxide (ITO). The problems of transparent conductors (TCs) coatings from SWNT and similar materials include poor mechanical properties, high roughness, low temperature resilience, and fast loss of conductivity. The simultaneous realization of these desirable characteristics can be achieved using high structural control of layer-by-layer (LBL) deposition, which is demonstrated by the assembly of hydroethyl cellulose (HOCS) and sulfonated polyetheretherketone (SPEEK)-SWNTs. A new type of SWNT doping based on electron transfer from valence bands of nanotubes to unoccupied levels of SPEEK through pi-pi interactions was identified for this system. It leads to a conductivity of 1.1 * 10(5) S/m at 66 wt % loadings of SWNT. This is better than other polymer/SWNT composites and translates into surface conductivity of 920 Omega/? and transmittance of 86.7% at 550 nm. The prepared LBL films also revealed unusually high temperature resilience up to 500 degrees C, and low roughness of 3.5 nm (ITO glass -2.4 nm). Tensile modulus, ultimate strength, and toughness of such coatings are 13 +/- 2 GPa, 366 +/- 35 MPa, and 8 +/- 3 kJ/m(3), respectively, and exceed corresponding parameters of all similar TCs. The cumulative figure of merit, ?(TC), which included the critical failure strain relevant for flexible electronics, was ?(TC) = 0.022 and should be compared to ?(TC) = 0.006 for commercial ITO. Further optimization is possible using stratified nanoscale coatings and improved doping from the macromolecular LBL components. PMID- 21524069 TI - Photocatalytic water oxidation with nonsensitized IrO2 nanocrystals under visible and UV light. AB - Rutile IrO(2) is known as being among the best electrocatalysts for water oxidation. Here we report on the unexpected photocatalytic water oxidation activity of 1.98 nm +/- 0.11 nm succinic acid-stabilized IrO(2) nanocrystals. From aqueous persulfate and silver nitrate solution the nonsensitized particles evolve oxygen with initial rates up to 0.96 MUmol min(-1), and with a quantum efficiency of at least 0.19% (measured at 530 nm). The catalytic process is driven by visible excitations from the Ir-d(t(2g)) to the Ir-d(e(g)) band (1.5 2.75 eV) and by ultraviolet excitations from the O-p band to the Ir-d(e(g)) (>3.0 eV) band. The formation of the photogenerated charge carriers can be directly observed with surface photovoltage spectroscopy. The results shed new light on the role of IrO(2) in dye- and semiconductor-sensitized water splitting systems. PMID- 21524070 TI - Adenosine-1,3-diazaphenoxazine derivative for selective base pair formation with 8-oxo-2'-deoxyguanosine in DNA. AB - The selective detection of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in DNA without chemical or enzymatic treatment is an attractive tool for genomic research. We designed and synthesized the non-natural nucleoside analogue, the adenosine-1,3 diazaphenoxazine (Adap) derivative, for selective recognition of 8-oxo-dG in DNA. This study clearly showed that Adap has a highly selective stabilizing effect on the duplex containing the Adap-8-oxo-dG base pair. Furthermore, the fluorescent property of Adap was shown to be useful for the selective detection of 8-oxo-dG in the duplex DNA. To the best of our knowledge, this is the first successful demonstration of a non-natural nucleoside with a high selectivity for 8-oxo-dG in DNA. PMID- 21524071 TI - Imaging secondary structure of individual amyloid fibrils of a beta2 microglobulin fragment using near-field infrared spectroscopy. AB - Amyloid fibril diseases are characterized by the abnormal production of aggregated proteins and are associated with many types of neuro- and physically degenerative diseases. X-ray diffraction techniques, solid-state magic-angle spinning NMR spectroscopy, circular dichroism (CD) spectroscopy, and transmission electron microscopy studies have been utilized to detect and examine the chemical, electronic, material, and structural properties of amyloid fibrils at up to angstrom spatial resolution. However, X-ray diffraction studies require crystals of the fibril to be analyzed, while other techniques can only probe the bulk solution or solid samples. In the work reported here, apertureless near field scanning infrared microscopy (ANSIM) was used to probe the secondary structure of individual amyloid fibrils made from an in vitro solution. Simultaneous topographic and infrared images of individual amyloid fibrils synthesized from the #21-31 peptide fragment of beta(2)-microglobulin were acquired. Using this technique, IR spectra of the amyloid fibrils were obtained with a spatial resolution of less than 30 nm. It is observed that the experimental scattered field spectrum correlates strongly with that calculated using the far-field absorption spectrum. The near-field images of the amyloid fibrils exhibit much lower scattering of the IR radiation at approximately 1630 cm(-1). In addition, the near-field images also indicate that composition and/or structural variations among individual amyloid fibrils were present. PMID- 21524072 TI - Solvent-driven association and dissociation of the hydrogen-bonded protonated decavanadates. AB - Hydrogen-bond-assisted molecular aggregation of decavanadate anions, [H(n)V(10)O(28)]((6-n)-), in non-aqueous solutions was probed by systematic small angle X-ray scattering and (1)H and (51)V NMR spectroscopic measurements in mixtures of acetone and 1,4-dioxane. Under acetone-rich conditions, the decavanadate anion prefers a self-associated hydrogen-bonded dimer of {[H(3)V(10)O(28)](2)}(6-), which dissociates into monomeric species as the proportion of 1,4-dioxane increases. The association/dissociation behaviors of the decavanadate anions were proven to be reversible and driven by the protophobic/protophilic nature of the solvent. PMID- 21524074 TI - Anisochronous dynamics in a crystalline array of steroidal molecular rotors: evidence of correlated motion within 1D helical domains. AB - We describe the solid-state dynamics of a molecular rotator (2) consisting of a p phenylene rotor flanked by two ethynyl steroidal moieties that act as a stator. Single-crystal X-ray diffraction analysis of polymorph I revealed a packing motif containing 1D columns of nested rotors arranged in helical arrays (space group P3(2)) with the central phenylenes disordered over two sites related by an 85 degrees rotation about their 1,4-axes. Unexpected line shapes in quadrupolar echo (2)H NMR measurements between 155 and 296 K for the same polymorph with a deuterated phenylene isotopologue (2-d(4)) were simulated by trajectories involving fast (>10(8) s(-1)) 180 degrees rotation (twofold flips) in each of the two rotationally disordered sites and slower exchange (2 * 10(4) to 1.5 * 10(6) s(-1)) between them. A negative activation entropy and a low enthalpic barrier for the slower 85 degrees exchange are interpreted in terms of highly correlated processes within the 1D helical domains. PMID- 21524073 TI - Free energy of nascent-chain folding in the translocon. AB - During their synthesis, many water-soluble proteins and nearly all membrane proteins transit through a protein-conducting channel in the membrane, the Sec translocon, from where they are inserted into the lipid bilayer. Increasing evidence indicates that folding of the nascent protein begins already within the ribosomal exit tunnel in a sequence- and environment-dependent fashion. To examine the effects of the translocon on the nascent-chain folding, we have calculated the potential of mean force for alpha-helix formation of a 10-alanine oligopeptide as a function of its position within the translocon channel. We find that the predominant conformational states, alpha-helical and extended, reflect those found for the peptide in water. However, the translocon, via its surface properties and its variable diameter, shifts the equilibrium in favor of the alpha-helical state. Thus, we suggest that the translocon facilitates not only the insertion of membrane proteins into the bilayer but also their folding. PMID- 21524075 TI - Synthesis and biological evaluation of 1alpha,25-dihydroxyvitamin D(3) analogues hydroxymethylated at C-26. AB - We designed by docking and synthesized two novel analogues of 1alpha,25 dihydroxyvitamin D(3) hydroxymethylated at C-26 (2 and 3). The syntheses were carried out by the convergent Wittig-Horner approach via epoxide 12a as a common key intermediate. The antiproliferative and transactivation potency of the compounds was evaluated in colon and breast cancer cell lines. The analogues showed a similar but reduced activity compared to 1,25(OH)(2)D(3). Analogue 3 was more potent than analogue 2, and in some assays it exhibited potency similar to that of the natural ligand. PMID- 21524076 TI - An atom-economic synthesis of bicyclo[3.1.0]hexanes by rhodium N-heterocyclic carbene-catalyzed diastereoselective tandem hetero-[5+2] cycloaddition/Claisen rearrangement reaction of vinylic oxiranes with alkynes. AB - The first synthetic application of a vinylic oxirane as a heteroatom-containing five-atom component in transition-metal-catalyzed cycloaddition reactions is reported. A new, efficient, diastereoselective tandem intramolecular hetero-[5+2] cycloaddition/Claisen rearrangement of vinylic oxirane-alkyne substrates that uses a rhodium NHC complex and provides strategically novel, atom-economic, regiospecific, and diastereoselective access to [3.1.0] bicyclic products has been developed. PMID- 21524077 TI - Catalytic asymmetric hydrogenation of N-Boc-imidazoles and oxazoles. AB - Substituted imidazoles and oxazoles were respectively hydrogenated into the corresponding chiral imidazolines and oxazolines (up to 99% ee). The highly enantioselective hydrogenation was achieved by using the chiral ruthenium catalyst, which is generated from Ru(eta(3)-methallyl)(2)(cod) and a trans chelating chiral bisphosphine ligand, PhTRAP. This is the first successful catalytic asymmetric reduction of 5-membered aromatic rings containing two or more heteroatoms. PMID- 21524078 TI - Toward more "ideal" polyketide natural product synthesis: a step-economical synthesis of zincophorin methyl ester. AB - A highly efficient and step-economical synthesis of zincophorin methyl ester has been achieved. The unprecedented step economy of this zincophorin synthesis is principally due to an application of the tandem silylformylation crotylsilylation/Tamao oxidation-diastereoselective tautomerization reaction, which achieves in a single step what would typically require a significant multistep sequence. PMID- 21524080 TI - Rapid identification of bacteria with a disposable colorimetric sensing array. AB - Rapid identification of both species and even specific strains of human pathogenic bacteria grown on standard agar has been achieved from the volatiles they produce using a disposable colorimetric sensor array in a Petri dish imaged with an inexpensive scanner. All 10 strains of bacteria tested, including Enterococcus faecalis and Staphylococcus aureus and their antibiotic-resistant forms, were identified with 98.8% accuracy within 10 h, a clinically important time frame. Furthermore, the colorimetric sensor arrays also proved useful as a simple research tool for the study of bacterial metabolism and as an easy method for the optimization of bacterial production of fine chemicals or other fermentation processes. PMID- 21524083 TI - Topological variations of the PDP ligand and its prospects in molybdenum(0) dearomatization agents. AB - The compounds fac-(kappa(3)-PDP)Mo(CO)(3) {1; PDP = 2-[[2-(1-(pyridin-2 ylmethyl)pyrrolidin-2-yl)pyrrolidin-1-yl]methyl]pyridine}, [(cis-beta PDP)Mo(NO)(CO)]PF(6) ([cis-beta-3]PF(6)), [(cis-alpha-PDP)Mo(NO)(CO)]PF(6) ([cis alpha-3]PF(6)), [(cis-alpha-PDP)Mo(NO)Br]PF(6) ([4]PF(6)), [(trans PDP)Cu](BF(4))(2).CH(3)CN ([5](BF(4))(2).CH(3)CN), and [(trans PDP)Cu](OSO(2)CF(3))(2) ([5](OSO(2)CF(3))(2)) have been synthesized and structurally characterized by single-crystal X-ray diffraction. These are the first reported complexes of PDP on metal centers other than iron(II). The observed configurations indicate a broader range of accessible PDP topologies than has been reported. The {(cis-alpha-PDP)Mo(NO)}(+) fragment is found to be less pi-basic than the dearomatizing {Tp(MeIm)Mo(NO)} fragment [Tp = hydridotris(1-pyrazolyl)borato; MeIm = 1-methylimidazole]. PMID- 21524082 TI - A concise approach for the total synthesis of pseudolaric acid A. AB - A new strategy for the stereoselective total synthesis of natural product pseudolaric acid A (1) was accomplished in 16 steps from commercially available starting material, featuring a samarium diiodide (SmI(2))-mediated intramolecular alkene-ketyl radical cyclization and a ring-closing metathesis (RCM) reaction to stereoselectively cast the unusual trans-fused [5-7]-bicyclic core of pseudolaric acid A (1). PMID- 21524084 TI - Ytterbium-catalyzed conjugate allylation of alkylidene malonates. AB - Alkylidene malonates undergo efficient conjugate allylation upon treatment with allylstannanes or allylsilanes under the action of ytterbium catalysis. PMID- 21524085 TI - Loops, chains, sheets, and networks from variable coordination of Cu(hfac)2 with a flexibly hinged aminoxyl radical ligand. AB - One pair of reactants, Cu(hfac)(2) = M and the hinge-flexible radical ligand 5-(3 N-tert-butyl-N-aminoxylphenyl)pyrimidine (3PPN = L), yields a diverse set of five coordination complexes: a cyclic loop M(2)L(2) dimer; a 1:1 cocrystal between an M(2)L(2) loop and an ML(2) fragment; a 1D chain of M(2)L(2) loops linked by M; two 2D M(3)L(2) networks of (M-L)(n) chains cross-linked by M with different repeat length pitches; a 3D M(3)L(2) network of M(2)L(2) loops cross-linking (M L)(n)-type chains with connectivity different from those in the 2D networks. Most of the higher dimensional complexes exhibit reversible, temperature-dependent spin-state conversion of high-temperature paramagnetic states to lower magnetic moment states having antiferromagnetic exchange within Cu-ON bonds upon cooling, with accompanying bond contraction. The 3D complex also exhibited antiferromagnetic exchange between Cu(II) ions linked in chains through pyrimidine rings. PMID- 21524086 TI - Anion binding to hydrophobic concavity is central to the salting-in effects of Hofmeister chaotropes. AB - For over 120 years it has been appreciated that certain salts (kosmotropes) cause the precipitation of proteins, while others (chaotropes) increase their solubility. The cause of this "Hofmeister effect" is still unclear, especially with the original concept that kosmotropic anions "make" water structure and chaotropes "break" it being countered by recent studies suggesting otherwise. Here, we present the first direct evidence that chaotropic anions have an affinity for hydrophobic concavity and that it is competition between a convex hydrophobe and the anion for a binding site that leads to the apparent weakening of the hydrophobic effect by chaotropes. In combination, these results suggest that chaotropes primarily induce protein solubilization by direct binding to concavity in the molten globule state of a protein. PMID- 21524087 TI - Evaluation of the potential of fungal and plant laccases for active-packaging applications. AB - Laccases from Trametes versicolor (TvL), Myceliophthora thermophila (MtL), and Rhus vernicifera (RvL) were investigated with regard to their potential utilization as oxygen scavengers in active packages containing food susceptible to oxidation reactions. The substrate selectivity of the laccases was investigated with a set of 17 reducing substrates, mainly phenolic compounds. The temperature dependence of reactions performed at low temperatures (4-31 degrees C) was studied. Furthermore, the laccases were subjected to immobilization in a latex/clay matrix and drying procedures performed at temperatures up to 105 degrees C. The results show that it is possible to immobilize the laccases with retained activity after dispersion coating, drying at 75-105 degrees C, and subsequent storage of the enzyme-containing films at 4 degrees C. TvL and, to some extent, MtL were promiscuous with regard to their reducing substrate, in the sense that the difference in activity with the 17 substrates tested was relatively small. RvL, on the other hand, showed high selectivity, primarily toward substrates resembling its natural substrate urushiol. When tested at 7 degrees C, all three laccases retained >20% of the activity they had at 25 degrees C, which suggests that it would be possible to utilize the laccases also in refrigerated food packages. Coating and drying resulted in a remaining enzymatic activity ranging from 18 to 53%, depending on the drying conditions used. The results indicate that laccases are useful for active-packaging applications and that the selectivity for reducing substrates is an important characteristic of laccases from different sources. PMID- 21524088 TI - Probing the dioxygen route in Melanocarpus albomyces laccase with pressurized xenon gas. AB - Laccases catalyze the oxidation of phenolic substrates and the concominant reduction of dioxygen to water. We used xenon as an oxygen probe in search of routes for the entry of dioxygen into the catalytic center. Two xenon-pressurized crystal structures of recombinant Melanocarpus albomyces laccase were determined, showing three hydrophobic Xe-binding sites located in domain C. The analysis of hydrophobic cavities in other laccase structures further suggested the preference of domain C for binding of hydrophobic species such as dioxygen, thus suggesting that the hydrophobic core of domain C could function as a channel through which dioxygen can enter the trinuclear copper center. PMID- 21524090 TI - One-pot metal-free syntheses of acetophenones from styrenes through aerobic photo oxidation and deiodination with iodine. AB - A one-pot synthetic protocol of acetophenones from styrenes with molecular oxygen, visible light, and molecular iodine is reported. This procedure involves aerobic photo-oxidation and deiodination in one pot and provides the first report of metal-free direct syntheses of acetophenones from styrenes. PMID- 21524089 TI - Nobilamides A-H, long-acting transient receptor potential vanilloid-1 (TRPV1) antagonists from mollusk-associated bacteria. AB - New compounds nobilamides A-H and related known compounds A-3302-A and A-3302-B were isolated based upon their suppression of capsaicin-induced calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, nobilamide B and A-3302-A, were shown to be long-acting antagonists of mouse and human TRPV1 channels, abolishing activity for >1 h after removal of drug presumably via a covalent attachment. Other derivatives also inhibited the TRPV1 channel, albeit with low potency, affording a structure-activity profile to support the proposed mechanism of action. While the activities were modest, we propose a new mechanism of action and a new site of binding for these inhibitors that may spur development of related analogues for treatment of pain. PMID- 21524091 TI - Bifunctional dendronized cellulose surfaces as biosensors. AB - Well-defined dendronized cellulose substrates displaying multiple representations of dual-functionality were constructed by taking advantage of the efficiency of the click reaction combined with traditional anhydride chemistry. First, activated cellulose surfaces were decorated with several generations of dendrons, and their peripheral reactive groups were subsequently reacted with a trifunctional orthogonal monomer. The generated substrate tool box was successfully explored by accurately tuning the surface function using a versatile orthogonal dual postfunctionalization approach. In general, the reactions were monitored by using a click-dye reagent or a quartz crystal microbalance (QCM) technique, and the resulting surfaces were well-characterized using XPS, FT-IR, and contact angle measurements. Utilizing this approach two different surfaces have been obtained; that is, triethylenglycol oligomers and amoxicillin molecules were efficiently introduced to the dendritic surface. As a second example, mannose-decorated hydroxyl functional surfaces illustrated their potential as biosensors by multivalent detection of lectin protein at concentration as low as 5 nM. PMID- 21524092 TI - Heat shock protein B1 and its regulator genes are negatively correlated with intramuscular fat content in the longissimus thoracis muscle of Hanwoo (Korean cattle) steers. AB - In previous proteomic studies, heat shock protein beta 1 (HSPB1) was detected as a candidate protein related to meat quality in cattle. This study sought to determine if its gene expression was associated with intramuscular fat content in the longissimus thoracis muscle of Korean cattle (Hanwoo). Tissue from two groups of 10 steers each, low-marbling (mean intramuscular fat content, 7.4 +/- 1.5%) and high-marbling (23.5 +/- 2.8%), were used for immunoblotting, real-time PCR, and statistical analyses. HSPB1 expression in both mRNA and protein was shown to be negatively related to intramuscular fat content (P < 0.05). Pathway analysis found two genes, TNF receptor superfamily member 6 (FAS) and angiotensinogen (AGT), that were regulators of the HSPB1 gene. The expression of the two genes showed a negative correlation with intramuscular fat content (P < 0.05). These results suggest that HSPB1, FAS, and AGT may be good candidate genes associated with intramuscular fat content in the longissimus muscle of Korean cattle. PMID- 21524093 TI - Coarse-grained molecular dynamics simulations of the sphere to rod transition in surfactant micelles. AB - Surfactant molecules self-assemble in aqueous solutions to form various micellar structures such as spheres, rods, or lamellae. Although phase transitions in surfactant solutions have been studied experimentally, their molecular mechanisms are still not well understood. In this work, we show that molecular dynamics (MD) simulations using the coarse-grained (CG) MARTINI force field and explicit CG solvent, validated against atomistic MD studies, can accurately represent micellar assemblies of cetyltrimethylammonium chloride (CTAC). The effect of salt on micellar structures is studied for aromatic anionic salts, e.g., sodium salicylate, and simple inorganic salts, e.g., sodium chloride. Above a threshold concentration, sodium salicylate induces a sphere to rod transition in the micelle. CG MD simulations are shown to capture the dynamics of this shape transition and support a mechanism based on the reduction in the micelle-water interfacial tension induced by the adsorption of the amphiphilic salicylate ions. At the threshold salt concentration, the interface is nearly saturated with adsorbed salicylate ions. Predictions of the effect of salt on the micelle structure in different CG solvent models, namely, single-site standard water and three-site polarizable water, show qualitative agreement. This suggests that phase transitions in aqueous micelle solutions could be investigated by using standard CG water models which allow for 3 orders of magnitude reduction in the computational time as compared to that required for atomistic MD simulations. PMID- 21524094 TI - Facile syntheses of O(2)-[4-(3-pyridyl-4-oxobut-1-yl]thymidine, the major adduct formed by tobacco specific nitrosamine 4-methylnitrosamino-1-(3-pyridyl)-1 butanone (NNK) in vivo, and its site-specifically adducted oligodeoxynucleotides. AB - O(2)-[4-(3-Pyridyl)-4-oxobut-1-yl]thymidine (O(2)-POB-dThd) is the most persistent adduct detected in the lung and liver of rats treated with tobacco specific nitrosamines: N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK), and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl) 1-butanol (NNAL). It is an important biomarker to assess the human exposure to these carcinogens. The only synthetic method reported for O(2)-POB-dThd requires repeated HPLC purifications and could only be used to prepare an analytical standard due to very low yield (0.4%). We have developed for the first time a regioselective and efficient method for the total synthesis of O(2)-POB-dThd and its site-specifically adducted oligonucleotides. The main step in the synthesis of O(2)-POB-dThd was achieved by a novel method. The treatment of O(2)-5' anhydrothymidine with the sodium salt of 4-(1,3-dithian-2-yl)-4-(3-pyridyl)butan 1-ol gave exclusively the O(2)-alkylated adduct, which was deprotected in one step to furnish the desired O(2)-POB-dThd in excellent yield. The product was characterized by NMR ((1)H and (13)C), high-resolution MS, and HPLC analysis. This work provided for the first time a reliable method for large scale total synthesis of O(2)-POB-dThd that allowed for solid state site-specifically adducted oligomer synthesis. The O(2)-POB-dThd was converted to its phosphoramidite and subsequently used for the synthesis of oligodeoxynucleotides by standard methods. The oligomers were characterized by MS and HPLC analysis. These oligomers will facilitate the elucidation of the mutagenic potential of the O(2)-POB-dThd adduct, which will provide further insight into the role of tobacco specific nitrosamines in inducing cancers in smokers. PMID- 21524095 TI - A tale of two subunits: how the neomorphic R132H IDH1 mutation enhances production of alphaHG. AB - Heterozygously expressed single-point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2, respectively) render these dimeric enzymes capable of producing the novel metabolite alpha-hydroxyglutarate (alphaHG). Accumulation of alphaHG is used as a biomarker for a number of cancer types, helping to identify tumors with similar IDH mutations. With IDH1, it has been shown that one role of the mutation is to increase the rate of conversion from alphaKG to alphaHG. To improve our understanding of the function of this mutation, we have detailed the kinetics of the normal (isocitrate to alphaKG) and neomorphic (alphaKG to alphaHG) reactions, as well as the coupled conversion of isocitrate to alphaHG. We find that the mutant IDH1 is very efficient in this coupled reaction, with the ability to form alphaHG from isocitrate and NADP(+). The wild type/wild type IDH1 is also able to catalyze this conversion, though it is much more sensitive to concentrations of isocitrate. This difference in behavior can be attributed to the competitive binding between isocitrate and alphaKG, which is made more favorable for alphaKG by the neomorphic mutation at arginine 132. Thus, each partial reaction in the heterodimer is functionally isolated from the other. To test whether there is a cooperative effect resulting from the two subunits being in a dimer, we selectively inactivated each subunit with a secondary mutation in the NADP/H binding site. We observed that the remaining, active subunit was unaffected in its associated activity, reinforcing the notion of each subunit being functionally independent. This was further demonstrated using a monomeric form of IDH from Azotobacter vinelandii, which can be shown to gain the same neomorphic reaction when a homologous mutation is introduced into that protein. PMID- 21524096 TI - A digital microfluidic method for in situ formation of porous polymer monoliths with application to solid-phase extraction. AB - We introduce the marriage of two technologies: digital microfluidics (DMF), a technique in which droplets are manipulated by application of electrostatic forces on an array of electrodes coated by an insulator, and porous polymer monoliths (PPMs), a class of materials that is popular for use for solid-phase extraction and chromatography. In this work, circular PPM discs were formed in situ by dispensing and manipulating droplets of monomer solutions to designated spots on a DMF device followed by UV-initiated polymerization. We used PPM discs formed in this manner to develop a digital microfluidic solid-phase extraction (DMF-SPE) method, in which PPM discs are activated and equilibrated, samples are loaded, PPM discs are washed, and the samples are eluted, all using microliter droplets of samples and reagents. The new method has extraction efficiency (93%) comparable to that of pipet-based ZipTips and is compatible with preparative sample extraction and recovery for on-chip desalting, removal of surfactants, and preconcentration. We anticipate that DMF-SPE may be useful for a wide range of applications requiring preparative sample cleanup and concentration. PMID- 21524097 TI - Evidence for multisite ligand binding and stretching of filamin by integrin and migfilin. AB - Filamin, a large cytoskeletal adaptor, connects plasma membrane to cytoskeleton by binding to transmembrane receptor integrin and actin. Seven of 24 filamin immunoglobulin repeats have conserved integrin binding sites, of which repeats 19 and 21 were shown to be autoinhibited by their adjacent repeats 18 and 20, respectively. Here we show using nuclear magnetic resonance spectroscopy that the autoinhibition can be relieved by integrin or integrin regulator migfilin. We further demonstrate that repeats 19 and 21 can simultaneously engage ligands. The data suggest that filamin is mechanically stretched by integrin or migfilin via a multisite binding mechanism for regulating cytoskeleton and integrin-mediated cell adhesion. PMID- 21524098 TI - Exploring the mechanism of fluorescence quenching in proteins induced by tetracycline. AB - The binding of the antibiotic tetracycline hydrochloride (TC) to three proteins was investigated by steady-state, time-resolved, and circular dichroism spectroscopy. The tryptophan (Trp) amino acid residues were used as an intrinsic fluorophore to decipher the structure-function relationship. As monitored by CD spectroscopy, the addition of TC causes the protein to alter some of its helical content although such changes are only marginal. The gradual decrease in fluorescence intensity of Trp can be ascribed to static quenching which takes place by the interaction of the drug with the protein. Besides Trp quenching, there is evidence of fluorescence resonance energy transfer (FRET) in all three proteins with different values of efficiency of energy transfer. Various quenching/binding and thermodynamic parameters associated with such drug-protein interactions have been estimated. The results thus obtained can provide guidelines to synthetic chemists to design and synthesize target-oriented drugs. PMID- 21524099 TI - Sulfonated diiron complexes as water-soluble models of the [Fe-Fe]-hydrogenase enzyme active site. AB - A series of diiron complexes developed as fundamental models of the two-iron subsite in the [FeFe]-hydrogenase enzyme active site show water-solubility by virtue of a sulfonate group incorporated into the -SCH(2)NRCH(2)S- dithiolate unit that bridges two Fe(I)(CO)(2)L moieties. The sulfanilic acid group imparts even greater water solubility in the presence of beta-cyclodextrin, beta-CyD, for which NMR studies suggest aryl-sulfonate inclusion into the cyclodextrin cavity as earlier demonstrated in the X-ray crystal structure of 1Na.2 beta-CyD clathrate, where 1Na = Na(+)(MU-SCH(2)N(C(6)H(4)SO(3)(-))CH(2)S-)[Fe(CO)(3)](2), (Singleton et al., J. Am. Chem. Soc.2010, 132, 8870). Electrochemical analysis of the complexes for potential as electrocatalysts for proton reduction to H(2) finds the presence of beta-CyD to diminish response, possibly reflecting inhibition of structural rearrangements required of the diiron unit for a facile catalytic cycle. Advantages of the aryl sulfonate approach include entry into a variety of water-soluble derivatives from the well-known (MU-SRS)[Fe(CO)(3)](2) parent biomimetic, that are stable in O(2)-free aqueous solutions. PMID- 21524100 TI - Tunable control over the ionization state of single Mn acceptors in GaAs with defect-induced band bending. AB - A scanning tunneling microscope was used to study the ionization of single Mn acceptors in GaAs(110). The ionization state switches when the GaAs valence band is bent across a Mn acceptor level. This produces a ringlike feature in STM images, whose diameter depends on the tunneling conditions and distance to charged arsenic vacancies. By varying the latter, we could tune the ionization switching, as well as quantify the contributions from tip- and vacancy-induced band bending. PMID- 21524101 TI - Dimeric prenylated C6-C3 compounds from the stem bark of Illicium oligandrum. AB - Three new dimeric prenylated C6-C3 compounds, namely, illicidiones A (1), B (2), and C (3), were isolated from the stem bark of Illicium oligandrum. The structure and absolute configuration of these compounds were determined by extensive spectroscopic and chemical analyses, including NMR, modified Mosher method, and single-crystal X-ray study. Compounds 1-3 exhibited weak anti-inflammatory activities. PMID- 21524102 TI - Geobacter sulfurreducens cytochrome c peroxidases: electrochemical classification of catalytic mechanisms. AB - Bacterial cytochrome c peroxidase (CcP) enzymes are diheme redox proteins that reduce hydrogen peroxide to water. They are canonically characterized by a peroxidatic (called L, for "low reduction potential") active site heme and a secondary heme (H, for "high reduction potential") associated with electron transfer, and an enzymatic activity that exists only when the H-heme is prereduced to the Fe(II) oxidation state. The prereduction step results in a conformational change at the active site itself, where a histidine-bearing loop will adopt an "open" conformation allowing hydrogen peroxide to bind to the Fe(III) of the L-heme. Notably, the enzyme from Nitrosomonas europaea does not require prereduction. Previously, we have shown that protein film voltammetry (PFV) is a highly useful tool for distinguishing the electrocatalytic mechanisms of the Nitromonas type of enzyme from other CcPs. Here, we apply PFV to the recently described enzyme from Geobacter sulfurreducens and the Geobacter S134P/V135K double mutant, which have been shown to be similar to members of the canonical subclass of peroxidases and the Nitrosomonas subclass of enzymes, respectively. Here we find that the wild-type Geobacter CcP is indeed similar electrochemically to the bacterial CcPs that require reductive activation, yet the S134P/V135K mutant shows two phases of electrocatalysis: one that is low in potential, like that of the wild-type enzyme, and a second, higher-potential phase that has a potential dependent upon substrate binding and pH yet is at a potential that is very similar to that of the H-heme. These findings are interpreted in terms of a model in which rate-limiting intraprotein electron transfer governs the catalytic performance of the S134P/V135K enzyme. PMID- 21524103 TI - Mechanically interlocked mechanophores by living-radical polymerization from rotaxane initiators. AB - Two [2]rotaxane initiators for single-electron-transfer living-radical polymerization were synthesized and used for the controlled polymerization of methyl acrylate. The mechanically interlocked polymers exhibited distinct responses to mechanical activation by ultrasound. Monitoring the fate of the rotaxanes' charge transfer absorption bands provides evidence for preferential mechanical degradation of a midsection rotaxane unit as compared to a terminal rotaxane entity as a consequence of mechanical forces accumulating in the central region of the polymer chain. PMID- 21524104 TI - Theoretical analysis of proton relays in electrochemical proton-coupled electron transfer. AB - The coupling of long-range electron transfer to proton transport over multiple sites plays a vital role in many biological and chemical processes. Recently the concerted proton-coupled electron transfer (PCET) reaction in a molecule with a hydrogen-bond relay inserted between the proton donor and acceptor sites was studied electrochemically. The standard rate constants and kinetic isotope effects (KIEs) were measured experimentally for this double proton transfer system and a related single proton transfer system. In the present paper, these systems are studied theoretically using vibronically nonadiabatic rate constant expressions for electrochemical PCET. Application of this approach to proton relays requires the calculation of multidimensional proton vibrational wave functions and the incorporation of multiple proton donor-acceptor motions. The decrease in proton donor-acceptor distances due to thermal fluctuations and the contributions from excited electron-proton vibronic states play important roles in these systems. The calculated KIEs and the ratio of the standard rate constants for the single and double proton transfer systems are in agreement with the experimental data. The calculations indicate that the standard PCET rate constant is lower for the double proton transfer system because of the smaller overlap integral between the ground state reduced and oxidized proton vibrational wave functions, resulting in greater contributions from excited electron-proton vibronic states with higher free energy barriers. The theory predicts that this rate constant may be increased by modifying the molecule in a manner that decreases the equilibrium proton donor-acceptor distances or alters the molecular thermal motions to facilitate the concurrent decrease of these distances. These insights may guide the design of more efficient catalysts for energy conversion devices. PMID- 21524105 TI - C60 fullerene nanocolumns--polythiophene heterojunctions for inverted organic photovoltaic cells. AB - Inverted organic photovoltaic cells have been fabricated based on vertical C(60) nanocolumns filled with spin-coated poly[3-(4-carboxybutyl)thiophene-2,5-diyl] (P3CBT). These C(60) nanocolumns were prepared via glancing angle deposition (GLAD), an efficient synthetic approach that controls the morphology of the resulting film, including intercolumn spacing, nanostructure shapes, and overall film thickness, among others. Intercolumn spacing was tuned to better match the expected P3CBT exciton diffusion length while simultaneously increasing heterointerface area. Due to observed in situ dissolution of the C(60) nanocolumns in solvents typically used to spin-coat polythiophene-based polymers (i.e., chloroform and chlorobenzene), the carboxylic acid-substituted polythiophene, P3CBT, was used as it is soluble in dimethyl sulfoxide (DMSO), a solvent that did not affect the structure of the GLAD-produced C(60) nanostructures. Preservation of the C(60) nanocolumnar structure in the presence of DMSO, with and without P3CBT, was verified by absorbance spectroscopy and SEM imaging. Incorporating these nanostructured C(60)/P3CBT films into photovoltaic devices on indium tin oxide (ITO) showed that the engineered nanomorphology yielded a 5-fold increase in short-circuit current and a power conversion efficiency (PCE) increase from (0.2 +/- 0.03)% to (0.8 +/- 0.2)% when compared to a planar device. When compared to a standard bulk heterojunction (BHJ) device based upon the same materials, the C(60)-GLAD device outperformed fully solution processed bulk heterojunctions, which were observed to have PCEs of (0.49 +/- 0.03)%. PMID- 21524106 TI - Folding of a salivary intrinsically disordered protein upon binding to tannins. AB - We used ion mobility spectrometry to explore conformational adaptability of intrinsically disordered proteins bound to their targets in complex mixtures. We investigated the interactions between a human salivary proline-rich protein IB5 and a model of wine and tea tannin: epigallocatechin gallate (EgCG). Collisional cross sections of naked IB5 and IB5 complexed with N = 1-15 tannins were recorded. The data demonstrate that IB5 undergoes an unfolded to folded structural transition upon binding with EgCG. PMID- 21524107 TI - Iron-catalyzed stereospecific activation of olefinic C-H bonds with Grignard reagent for synthesis of substituted olefins. AB - The reaction of an aryl Grignard reagent with a cyclic or acyclic olefin possessing a directing group such as pyridine or imine results in the stereospecific substitution of the olefinic C-H bond syn to the directing group. The reaction takes place smoothly and without isomerization of the product olefin in the presence of a mild oxidant (1,2-dichloro-2-methylpropane) and an aromatic cosolvent. Several lines of evidence suggest that the reaction proceeds via iron catalyzed olefinic C-H bond activation rather than an oxidative Mizoroki-Heck type reaction. PMID- 21524108 TI - Substituent effect on the acid-promoted hydrolysis of 2-aryloxazolin-5-one: normal vs reverse. AB - Computational investigations on the acid-promoted hydrolysis of 2-aryl-4,4 dimethyloxazolin-5-one (AMO) and its seven para- and meta-substituted derivatives (with electron-donating groups R = OH, OCH(3), CH(3) and electron-withdrawing groups R = Cl, m-Cl, CF(3), NO(2)) were presented by the density functional theory (B3LYP) method. Two types of reaction mechanism, N-path and O-path, are taken into account, in which the attacks by water molecules at the C2 and C5 are accelerated after the protonation on N3 and carbonyl oxygen atoms, respectively. Our computational results clearly manifest that the hydrolysis of AMOs has an obvious substituent effect at the para and meta positions of the benzene ring by correlating the barrier heights with the Hammett constants of substituents. Furthermore, the N-path shows a normal substituent effect, while the favorable O path shows a reverse substituent effect. The observed reverse substituent effect in experiment actually springs from the reverse substituent effect of the O-path, not the N-path. The substituent effect of the N-path and O-path can be explained by the electrostatic potential at nuclei (EPN) values and Fukui function, respectively. Our theoretical data provided will allow for a better understanding of the acid-promoted hydrolysis mechanism and the observed reverse substituent effect of the AMOs, in nice agreement with the available experimental conclusion. PMID- 21524109 TI - IR spectroscopy on jet-cooled isolated two-station rotaxanes. AB - High-resolution IR spectroscopy has been employed to study isolated, switchable [2]rotaxanes. IR absorption spectra of two-station rotaxanes, their separate thread, and macrocycle components, as well as those of the individual stations incorporated into the thread, have been measured in the 1800-1000 cm(-1) region. These spectra have been fully analyzed, aided by quantum chemical predictions of the IR spectra. From these analyses, a comprehensive picture emerges of the conformational structure and binding interactions between the mechanically interlocked components of the rotaxane. PMID- 21524110 TI - Determining the magnitude and direction of photoinduced ligand field switching in photochromic metal-organic complexes: molybdenum-tetracarbonyl spirooxazine complexes. AB - The ability to optically switch or tune the intrinsic properties of transition metals (e.g., redox potentials, emission/absorption energies, and spin states) with photochromic metal-ligand complexes is an important strategy for developing "smart" materials. We have described a methodology for using metal-carbonyl complexes as spectroscopic probes of ligand field changes associated with light induced isomerization of photochromic ligands. Changes in ligand field between the ring-closed spirooxazine (SO) and ring-opened photomerocyanine (PMC) forms of photochromic azahomoadamantyl and indolyl phenanthroline-spirooxazine ligands are demonstrated through FT-IR, (13)C NMR, and computational studies of their molybdenum-tetracarbonyl complexes. The frontier molecular orbitals (MOs) of the SO and PMC forms differ considerably in both electron density distributions and energies. Of the multiple pi* MOs in the SO and PMC forms of the ligands, the LUMO+1, a pseudo-b(1)-symmetry phenanthroline-based MO, mixes primarily with the Mo(CO)(4) fragment and provides the major pathway for Mo(d)->phen(pi*) backbonding. The LUMO+1 is found to be 0.2-0.3 eV lower in energy in the SO form relative to the PMC form, suggesting that the SO form is a better pi-acceptor. Light-induced isomerization of the photochromic ligands was therefore found to lead to changes in the energies of their frontier MOs, which in turn leads to changes in pi-acceptor ability and ligand field strength. Ligand field changes associated with photoisomerizable ligands allow tuning of excited-state and ground-state energies that dictate energy/electron transfer, optical/electrical properties, and spin states of a metal center upon photoisomerization, positioning photochromic ligand-metal complexes as promising targets for smart materials. PMID- 21524111 TI - Determination of soluble immunoglobulin G in bovine colostrum products by Protein G affinity chromatography-turbidity correction and method validation. AB - Immunoglobulin-containing food products and nutraceuticals such as bovine colostrum are of interest to consumers as they may provide health benefits. Commercial scale colostrum products are valued for their immunoglobulin G (IgG) content and therefore require accurate analysis. One of the most commonly used methods for determining total soluble IgG in colostrum products is based on affinity chromatography using a Protein G column and UV detection. This paper documents improvements to the accuracy of the Protein G analysis of IgG in colostrum products, especially those containing aggregated forms of IgG. Capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) analysis confirmed that aggregated IgG measured by Protein G does not contain significant amounts of casein or other milk proteins. Size exclusion chromatography identified the content of soluble IgG as mainly monomeric IgG and aggregated material MW > 450 kDa with small amounts of dimer and trimer. The turbidity of the eluting IgG, mainly associated with aggregated IgG, had a significant effect on the quantitative results. Practical techniques were developed to correct affinity LC data for turbidity on an accurate, consistent, and efficient basis. The method was validated in two laboratories using a variety of colostrum powders. Precision for IgG was 2-3% (RSD(r)) and 3-12% (RSD(R)). Recovery was 100.2 +/- 2.4% (mean +/- RSD, n = 10). Greater amounts of aggregated IgG were solubilized by a higher solution:sample ratio and extended times of mixing or sonication, especially for freeze-dried material. It is concluded that the method without acid precipitation and with turbidity correction provides accurate, precise, and robust data for total soluble IgG and is suitable for product specification and quality control of colostrum products. PMID- 21524112 TI - Reactions in the rechargeable lithium-O2 battery with alkyl carbonate electrolytes. AB - The nonaqueous rechargeable lithium-O(2) battery containing an alkyl carbonate electrolyte discharges by formation of C(3)H(6)(OCO(2)Li)(2), Li(2)CO(3), HCO(2)Li, CH(3)CO(2)Li, CO(2), and H(2)O at the cathode, due to electrolyte decomposition. Charging involves oxidation of C(3)H(6)(OCO(2)Li)(2), Li(2)CO(3), HCO(2)Li, CH(3)CO(2)Li accompanied by CO(2) and H(2)O evolution. Mechanisms are proposed for the reactions on discharge and charge. The different pathways for discharge and charge are consistent with the widely observed voltage gap in Li O(2) cells. Oxidation of C(3)H(6)(OCO(2)Li)(2) involves terminal carbonate groups leaving behind the OC(3)H(6)O moiety that reacts to form a thick gel on the Li anode. Li(2)CO(3), HCO(2)Li, CH(3)CO(2)Li, and C(3)H(6)(OCO(2)Li)(2) accumulate in the cathode on cycling correlating with capacity fading and cell failure. The latter is compounded by continuous consumption of the electrolyte on each discharge. PMID- 21524113 TI - Antifungal activity and fungal metabolism of steroidal glycosides of Easter lily (Lilium longiflorum Thunb.) by the plant pathogenic fungus, Botrytis cinerea. AB - Botrytis cinerea Pers. Fr. is a plant pathogenic fungus and the causal organism of blossom blight of Easter lily (Lilium longiflorum Thunb.). Easter lily is a rich source of steroidal glycosides, compounds which may play a role in the plant pathogen interaction of Easter lily. Five steroidal glycosides, including two steroidal glycoalkaloids and three furostanol saponins, were isolated from L. longiflorum and evaluated for fungal growth inhibition activity against B. cinerea, using an in vitro plate assay. All of the compounds showed fungal growth inhibition activity; however, the natural acetylation of C-6''' of the terminal glucose in the steroidal glycoalkaloid, (22R,25R)-spirosol-5-en-3beta-yl O-alpha L-rhamnopyranosyl-(1->2)-[6-O-acetyl-beta-D-glucopyranosyl-(1->4)]-beta-D glucopyranoside (2), increased antifungal activity by inhibiting the rate of metabolism of the compound by B. cinerea. Acetylation of the glycoalkaloid may be a plant defense response to the evolution of detoxifying mechanisms by the pathogen. The biotransformation of the steroidal glycoalkaloids by B. cinerea led to the isolation and characterization of several fungal metabolites. The fungal metabolites that were generated in the model system were also identified in Easter lily tissues infected with the fungus by LC-MS. In addition, a steroidal glycoalkaloid, (22R,25R)-spirosol-5-en-3beta-yl O-alpha-L-rhamnopyranosyl-(1->2) beta-D-glucopyranoside (6), was identified as both a fungal metabolite of the steroidal glycoalkaloids and as a natural product in L. longiflorum for the first time. PMID- 21524114 TI - High-resolution 2D J-resolved spectroscopy in inhomogeneous fields with two scans. AB - A scheme via spatially encoded intermolecular zero-quantum coherences was proposed for high-resolution 2D J-resolved spectra in inhomogeneous fields with high acquisition efficiency. Compared to a recent paper (Pelupessy et al. Science, 2009, 324, 1693-1697), the novel method can obtain chemical shifts and J multiplicity patterns directly. PMID- 21524116 TI - Fully biodegradable self-rolled polymer tubes: a candidate for tissue engineering scaffolds. AB - We report an approach for the fabrication of fully biodegradable self-rolled tubes based on patterned polysuccinimide/polycaprolactone bilayers. These polymers are biocompatible, biodegradable, produced industrially, and are already approved for biomedical purposes. Both polycaprolactone and polysuccinimide are hydrophobic and intrinsically water-insoluble. Polysuccinimide, however, hydrolyzes in physiological buffer environment yielding water-swellable polyaspartic acid that causes the rolling of the polymer bilayer and formation of tubes. We demonstrate the possibility to encapsulate yeast cells using self rolled tubes. PMID- 21524117 TI - Benzene under high pressure: a story of molecular crystals transforming to saturated networks, with a possible intermediate metallic phase. AB - In a theoretical study, benzene is compressed up to 300 GPa. The transformations found between molecular phases generally match the experimental findings in the moderate pressure regime (<20 GPa): phase I (Pbca) is found to be stable up to 4 GPa, while phase II (P4(3)2(1)2) is preferred in a narrow pressure range of 4-7 GPa. Phase III (P2(1)/c) is at lowest enthalpy at higher pressures. Above 50 GPa, phase V (P2(1) at 0 GPa; P2(1)/c at high pressure) comes into play, slightly more stable than phase III in the range of 50-80 GP, but unstable to rearrangement to a saturated, four-coordinate (at C), one-dimensional polymer. Actually, throughout the entire pressure range, crystals of graphane possess lower enthalpy than molecular benzene structures; a simple thermochemical argument is given for why this is so. In several of the benzene phases there nevertheless are substantial barriers to rearranging the molecules to a saturated polymer, especially at low temperatures. Even at room temperature these barriers should allow one to study the effect of pressure on the metastable molecular phases. Molecular phase III (P2(1)/c) is one such; it remains metastable to higher pressures up to ~200 GPa, at which point it too rearranges spontaneously to a saturated, tetracoordinate CH polymer. At 300 K the isomerization transition occurs at a lower pressure. Nevertheless, there may be a narrow region of pressure, between P = 180 and 200 GPa, where one could find a metallic, molecular benzene state. We explore several lower dimensional models for such a metallic benzene. We also probe the possible first steps in a localized, nucleated benzene polymerization by studying the dimerization of benzene molecules. Several new (C(6)H(6))(2) dimers are predicted. PMID- 21524115 TI - Controlling in vivo stability and biodistribution in electrostatically assembled nanoparticles for systemic delivery. AB - This paper demonstrates the generation of systemically deliverable layer-by-layer (LbL) nanoparticles for cancer applications. LbL-based nanoparticles designed to navigate the body and deliver therapeutics in a programmable fashion are promising new and alternative systems for drug delivery, but there have been very few demonstrations of their systemic delivery in vivo due to a lack of knowledge in building LbL nanofilms that mimic traditional nanoparticle design to optimize delivery. The key to the successful application of these nanocarriers in vivo requires a systematic analysis of the influence of film architecture and adsorbed polyelectrolyte outer layer on their pharmacokinetics, which has thus far not been examined for this new approach to nanoparticle delivery. Herein, we have taken the first steps in stabilizing and controlling the systemic distribution of multilayer nanoparticles. Our findings highlight the unique character of LbL systems; the electrostatically assembled nanoparticles gain increased stability in vivo with larger numbers of deposited layers, and the final layer adsorbed generates a critical surface cascade, which dictates the surface chemistry and biological properties of the nanoparticle. This outer polyelectrolyte layer dramatically affects not only the degree of nonspecific particle uptake, but also the nanoparticle biodistribution. For hyaluronic acid (HA) outer layers, a long blood elimination half-life (~9 h) and low accumulation (~10-15% recovered fluorescence/g) in the liver were observed, illustrating that these systems can be designed to be highly appropriate for clinical translation. PMID- 21524118 TI - Large amplitude oscillatory shear of block copolymer spheres on a body-centered cubic lattice: are micelles like metals? AB - Small-angle X-ray diffraction experiments have uncovered a remarkable mechanism of grain alignment during plastic deformation of ordered sphere-forming diblock copolymer micelles when subjected to large amplitude dynamic shearing. A nearly monodisperse poly(styrene-b-ethylene-alt-propylene) (SEP) diblock copolymer with block molecular weights of 42,000 and 60,000 was mixed with squalane (C(30)H(62)), an EP selective solvent, at a concentration of 10 wt%. After high temperature annealing, the sample formed an ordered polydomain morphology containing glassy S cores at room temperature. SAXS powder patterns confirm body centered cubic (BCC) symmetry and reveal the development of a complex array of two-dimensionally resolved Bragg reflections following the application, and cessation, of oscillatory shearing. These diffraction results are interpreted on the basis of the classic mechanism of crystalline slip, which accounts for plastic deformation of ductile materials such as metals. Four distinct slip systems are shown to be active in this work, suggesting a robust basis for deforming and mixing of soft ordered solids. PMID- 21524119 TI - Transparent, flexible, all-reduced graphene oxide thin film transistors. AB - Owing to their unique thickness-dependent electronic properties, together with perfect flexibility and transparency, graphene and its relatives make fantastic material for use in both active channel and electrodes in various electronic devices. On the other hand, the electronic sensors based on graphene show high potential in detection of both chemical and biological species with high sensitivity. In this contribution, we report the fabrication of all-reduced graphene oxide (rGO) thin film transistors by a combination of solution-processed rGO electrodes with a micropatterned rGO channel, and then study their applications in biosensing. Our all-rGO devices are cost-effective, highly reproducible, and reliable. The fabricated electronic sensor is perfectly flexible with high transparency, showing good sensitivity in detecting proteins in the physiological buffer. As a proof of concept, fibronectin as low as 0.5 nM was successfully detected, which is comparable with the previously reported protein sensors based on single-layer pristine graphene obtained from mechanical cleavage. The specific detection of avidin by using biotinylated all-rGO sensor is also successfully demonstrated. PMID- 21524120 TI - Artificial amino acids in nickel(II) and nickel(II)/lanthanide(III) chemistry. AB - The synthesis and magnetic properties of five new homo- and heterometallic nickel(II) complexes containing artificial amino acids are reported: [Ni(4)(aib)(3)(aibH)(3)(NO(3))](NO(3))(4).3.05MeOH (1.3.05MeOH), [Ni(6)La(aib)(12)](NO(3))(3).5.5H(2)O (2.5.5H(2)O), [Ni(6)Pr(aib)(12)](NO(3))(3).5.5H(2)O (3.5.5H(2)O), [Ni(5)(OH)(2)(l aba)(4)(OAc)(4)].0.4EtOH.0.3H(2)O 6(4.0.4EtOH.0.3H(2)O), and [Ni(6)La(l aba)(12)][La(2)(NO(3))(9)] (5; aibH = 2-aminoisobutyric acid; l-abaH = l-2 aminobutyric acid). Complexes 1 and 4 describe trigonal-pyramidal and square based pyramidal metallic clusters, respectively, while complexes 2, 3, and 5 can be considered to be metallocryptand-encapsulated lanthanides. Complexes 4 and 5 are chiral and crystallize in the space groups I222 and P2(1)3, respectively. Direct-current magnetic susceptibility studies in the 2-300 K range for all complexes reveal the presence of dominant antiferromagnetic exchange interactions, leading to small or diamagnetic ground states. PMID- 21524121 TI - A general copper powder-catalyzed Ullmann-type reaction of 3-halo-4(1H) quinolones with various nitrogen-containing nucleophiles. AB - 3-(N-Substituted) 4(1H)-quinolinones were synthesized using the copper-catalyzed Ullmann C-N bond forming strategy in moderate to quantitative yields. Starting from 3-halo-4(1H)-quinolones, various nucleophiles including amides, lactams, sulfonamides and NH-containing azoles have been used successfully. In all cases, the reactions take place rapidly in toluene and proceed by using copper powder as a catalyst, DMEDA as a ligand and K(2)CO(3) as a base. In addition, other related heterocycles such as 3-bromoquinolin-2(1H)-ones, 3-bromocoumarin, and 3,5-dibromo 2-pyridone show good to very high reactivity with various nucleophiles under our Cu/DMEDA catalyst system. PMID- 21524122 TI - Definition of drug-likeness for compound affinity. AB - We proposed a new definition of drug-likeness based on protein-compound docking simulation. Active and decoy compounds of 40 target proteins were investigated. These compounds were docked to protein sets consisting of 53-160 proteins. The protein sets did not include the target proteins. The average value and deviation of docking scores against the multiple proteins were calculated for each compound. Our study revealed that the docking scores of active compounds are more widely distributed than those of decoy compounds. Thus, the deviation of docking scores with multiple proteins should be a measure of drug-likeness for compound affinity. PMID- 21524123 TI - Computationally designed and experimentally confirmed diastereoselective rhodium catalyzed Pauson-Khand reaction at room temperature. AB - The computational analysis of the rhodium-catalyzed Pauson-Khand reaction indicates that the key transition state is highly charge-polarized, wherein different diastereoisomers have distinctively different charge polarization patterns. Experimental studies demonstrate that chloro-enynes provide the optimal sigma-electron-withdrawing group to promote polarization and thereby reduce the activation barrier to provide a highly diastereoselective reaction at room temperature. PMID- 21524124 TI - Coherent nuclear dynamics in ultrafast photoinduced structural change of bis(diimine)copper(I) complex. AB - The photoinduced structural change of a prototype metal complex, [Cu(dmphen)(2)](+) (dmphen = 2,9-dimethyl-1,10-phenanthroline), was studied by ultrafast spectroscopy with time resolution as high as 30 fs. Time-resolved absorption measured with direct S(1) excitation clearly showed spectral changes attributable to the D(2d) (perpendicular) -> D(2) (flattened) structural change occurring in the metal-to-ligand charge transfer singlet excited state ((1)MLCT) and the subsequent S(1) -> T(1) intersystem crossing. It was confirmed that the two processes occur with time constants of ~0.8 ps (structural change) and ~10 ps (intersystem crossing), and their time scales are clearly well-separated. A distinct oscillation of the transient absorption signal was observed in the femtosecond region, which arises from the coherent nuclear motion of the perpendicular S(1) state that was directly generated by photoexcitation. This demonstrated that the perpendicular S(1) state has a well-defined vibrational structure and can vibrate within its subpicosecond lifetime. In other words, the S(1) state stays undistorted in a short period, and the coherent nuclear motion is maintained in this state. Time-dependent density functional theory (TDDFT) calculations gave consistent results, indicating a very flat feature and even a local minimum at the perpendicular structure on the S(1) potential energy surface. The vibrational assignments of the S(1) nuclear wavepacket motion were made on the basis of the TDDFT calculation. It was concluded that photoexcitation induces a(1) vibrations containing the Cu-ligand bond length change and a b(1) vibration attributed to the ligand-twisting motion that has the same symmetry as the flattening distortion. Ultrafast spectroscopy and complementary quantum chemical calculation provided an overall picture and new understanding of the photoinduced structural change of the prototypical metal complex. PMID- 21524125 TI - Multiple-filled skutterudites: high thermoelectric figure of merit through separately optimizing electrical and thermal transports. AB - Skutterudites CoSb(3) with multiple cofillers Ba, La, and Yb were synthesized and very high thermoelectric figure of merit ZT = 1.7 at 850 K was realized. X-ray diffraction of the densified multiple-filled bulk samples reveals all samples are phase pure. High-resolution scanning transmission electron microscopy (STEM) and energy dispersive X-ray spectroscopy (EDS) analysis confirm that multiple guest fillers occupy the nanoscale-cages in the skutterudites. The fillers are further shown to be uniformly distributed and the Co-Sb skutterudite framework is virtually unperturbed from atomic scale to a few micrometers. Our results firmly show that high power factors can be realized by adjusting the total filling fraction of fillers with different charge states to reach the optimum carrier density, at the same time, lattice thermal conductivity can also be significantly reduced, to values near the glass limit of these materials, through combining filler species of different rattling frequencies to achieve broad-frequency phonon scattering. Therefore, partially filled skutterudites with multiple fillers of different chemical nature render unique structural characteristics for optimizing electrical and thermal transports in a relatively independent way, leading to continually enhanced ZT values from single- to double-, and finally to multiple-filled skutterudites. The idea of combining multiple fillers with different charge states and rattling frequencies for performance optimization is also expected to be valid for other caged TE compounds. PMID- 21524126 TI - Metal-free catalytic C-Si bond formation in an aqueous medium. Enantioselective NHC-catalyzed silyl conjugate additions to cyclic and acyclic alpha,beta unsaturated carbonyls. AB - A metal-free method for enantioselective conjugate addition of a dimethylphenylsilyl group to alpha,beta-unsaturated carbonyls is reported. Transformations are catalyzed by a chiral N-heterocyclic carbene (NHC), performed in an aqueous solution (3:1 mixture of water and tetrahydrofuran) and are operationally simpler to perform than the NHC-Cu-catalyzed variant. The chiral catalyst is generated from an enantiomerically pure imidazolinium salt (prepared in three steps) and a common organic amine base (dbu). NHC-catalyzed processes proceed with 5.0-12.5 mol % catalyst loading at 22 degrees C within 1-12 h, affording the desired beta-silyl carbonyls in 85:15 to >98:2 enantiomeric ratio and in 50% to >98% yield. Cyclic enones or lactones and acyclic alpha,beta unsaturated ketones, esters, and aldehydes can be used as substrates. PMID- 21524127 TI - Semiconducting organic assemblies prepared from tetraphenylethylene tetracarboxylic acid and bis(pyridine)s via charge-assisted hydrogen bonding. AB - Principles of crystal engineering have been applied toward the construction of supramolecular assemblies between an acid-functionalized tetraphenylethylene derivative and three different bis(pyridine)s [4,4'-bis(pyridyl)ethylene, 4,4' bis(pyridyl)ethane, and 4,4'-bipyridine]. Each assembly was structurally characterized, and charge transfer interactions within each sample were visually apparent. Quantum chemical calculations were used to determine crystal band structure and band gap magnitude, and electrical properties of the materials were measured using conducting probe atomic force microscopy (CP-AFM). The crystals displayed charge-carrier capability, and the magnitude of semiconductivity varied systematically as a function of conjugation in the bis(pyridine) component. Crystals incorporating 4,4'-bis(pyridyl)ethylene and 4,4'-bipyridine displayed conductivities comparable to those of established organic semiconductors (MU(eff) = 0.38 and 1.7 * 10(-2) cm(2)/V.s, respectively). PMID- 21524129 TI - Structure of CO2 adsorbed on the KCl(100) surface. AB - The structure and dynamics of the adsorbate CO(2)/KCl(100) from a diluted phase to a saturated monolayer have been investigated with He atom scattering (HAS), low-energy electron diffraction (LEED), and polarization dependent infrared spectroscopy (PIRS). Two adsorbate phases with different CO(2) coverage have been found. The low-coverage phase is disordered at temperatures near 80 K and becomes at least partially ordered at lower temperatures, characterized by a (2?2*?2)R45 degrees diffraction pattern. The saturated 2D phase has a high long-range order and exhibits (6?2*?2)R45 degrees symmetry. Its isosteric heat of adsorption is 26 +/- 4 kJ mol(-1). According to PIRS, the molecules are oriented nearly parallel to the surface, the average tilt angle in the saturated monolayer phase is 10 degrees with respect to the surface plane. For both phases, structure models are proposed by means of potential calculations. For the saturated monolayer phase, a striped herringbone structure with 12 inequivalent molecules is deduced. The simulation of infrared spectra based on the proposed structures and the vibrational exciton approach gives reasonable agreement between experimental and simulated infrared spectra. PMID- 21524130 TI - Synthesis of vinyl-substituted polypyridyl ligands through Suzuki-Miyaura cross coupling of potassium vinyltrifluoroborate with bromopolypyridines. AB - Suzuki-Miyauru cross-coupling of bromopolypyridines with potassium vinyltrifluoroborate affords vinyl-substituted polypyridyl ligands in moderate to good yields. This reaction allows simple and practical syntheses of numerous vinyl-substituted polypyridines, such as 4'-vinyl-2,2':6',2''-terpyridine, 5,5' divinyl-2,2'-bipyridine, and 4,4'-divinyl-2,2'-bipyridine. In addition, a new ruthenium complex, [Ru(5,5'-divinyl-2,2'-bipyridine)(3)](2+), was synthesized and found to undergo reductive electropolymerization smoothly. PMID- 21524128 TI - Aptamer in bioanalytical applications. PMID- 21524131 TI - Detection of trace proteins in multicomponent mixtures using displacement chromatography. AB - Model protein feed mixtures containing three abundant and seven trace proteins at various concentrations were identified and employed in a series of displacement experiments. Reversed-phase liquid chromatography (RPLC) and matrix assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry were used to evaluate the compositions of both the feed mixtures and effluent fractions from the displacement experiments. The results demonstrated that trace proteins were focused at the boundaries between the abundant solutes where they were enriched and concentrated. For many of the multicomponent feed mixtures, mass spectrometry analyses of the displacement column effluent fractions resulted in the identification of trace proteins that were not detectable in the feed. In addition, the use of minimal or no salt in the carrier solutions enabled the analysis of displacement fractions by direct infusion mass spectrometry. These results are significant in that they indicate that while the presence of abundant proteins can often be problematic for the detection of trace components, displacement chromatography may be able to employ these abundant proteins to focus trace proteins in the displacement train, thus facilitating detection. PMID- 21524132 TI - Graphene oxide enwrapped Ag/AgX (X = Br, Cl) nanocomposite as a highly efficient visible-light plasmonic photocatalyst. AB - In this paper, we have reported that well-defined graphene oxide (GO) enwrapped Ag/AgX (X = Br, Cl) nanocomposites, which are composed of Ag/AgX nanoparticles and gauze-like GO nanosheets, could be facilely fabricated via a water/oil system. We have shown that thus-synthesized GO-based hybrid nanocomposites could be used as a stable plasmonic photocatalyst for the photodegradation of methyl orange (MO) pollutant under visible-light irradiation. Compared with the corresponding bare Ag/AgX nanospecies, the GO-involved nanocomposites (Ag/AgX/GO) display distinctly enhanced photocatalytic activities. The hybridization of Ag/AgX with GO nanosheets causes the nice adsorptive capacity of Ag/AgX/GO to MO molecules, the smaller size of the Ag/AgX nanoparticles in Ag/AgX/GO, the facilitated charge transfer, and the suppressed recombination of electron-hole pairs in Ag/AgX/GO. It is suggested that these multifactors, resulting from the hybridization of GO, contribute to the enhanced photocatalytic performance observed from Ag/AgX/GO. The investigation likely opens up new possibilities for the development of original yet highly efficient and stable GO-based plasmonic photocatalysts that utilize visible light as an energy source. PMID- 21524133 TI - Effect of the dielectric properties of substrates on the scattering patterns of gold nanorods. AB - Understanding the electromagnetic interactions between plasmonic noble metal nanocrystals and different substrates is very important because a number of plasmon-based devices and applications, such as chemical and biological sensing, metamaterials, subwavelength waveguides, plasmon-enhanced photovoltaic cells, plasmon-enhanced spectroscopy, and photoswitches, require the attachment of metal nanocrystals onto various substrates. In this study, we focused on the effect of the dielectric properties of substrates on the far-field scattering patterns of supported Au nanorods. Seven types of substrates, including metals, semiconductors, and insulators, were examined. The far-field scattering patterns from individual Au nanorods were found to exhibit a doughnut shape when the modulus of the dielectric constant of the substrate is above ~7, while they appear as solid bright spots when the modulus is below ~7. This finding was validated by numerical electrodynamic calculations. Moreover, the doughnut-shaped scattering patterns are very sensitive to the spacing between the nanorod and substrate. For the nanorods supported on silicon wafers, when the spacing is increased above ~14 nm, the scattering patterns change from the doughnut shape to the solid bright spot. These results will be useful for the understanding of the plasmonic properties of noble metal nanocrystals supported on substrates and the development of a number of plasmon-based optical and optoelectronic devices at different size scales. PMID- 21524134 TI - Morphology control of hairy nanopores. AB - The properties of polymer layers end-grafted to the inner surface of nanopores connected to solvent reservoirs are studied theoretically as a function of solvent quality and pore geometry. Our systematic study reveals that nanoconfinement is affected by both pore radius and length and that the conformations of the polymer chains strongly depend on their grafting position along the nanopore and on the quality of the solvent. In poor solvent, polymer chains can collapse to the walls, form a compact plug in the pore, or self assemble into domains of different shape due to microphase separation. The morphology of these domains (aggregates on pore walls or stacked micelles along the pore axis) is mainly determined by the relationship between chain length and pore radius. In other cases the number of aggregates depends on pore length. The presence of reservoirs decreases confinement at pore edges due to the changes in available volume and introduces new organization strategies not available for infinite nanochannels. In good solvent conditions, chains grafted at the pore entrances stretch out of the pore, relieving the internal osmotic pressure and increasing the entropy of the polymers. Our study also addresses the experimentally relevant case of end-grafted chains on the outer walls of the membrane surrounding the nanopore. The effect of these polymer chains on the organization within the nanopore depends on solvent quality. For good solvents the outer chains increase the confinement of the chains at the entrance of the pore; however, the effect does not result in new structures. For poor solvents the presence of the outer polymer layer may lead to changes in the morphology of the microphase-separated domains. Our results show the complex interplay between the different interactions in a confined environment and the need to develop theoretical and experimental tools for their study. PMID- 21524136 TI - An environment for management. PMID- 21524135 TI - Salt-mediated self-assembly of thioctic acid on gold nanoparticles. AB - Self-assembled monolayer (SAM) modification is a widely used method to improve the functionality and stability of bulk and nanoscale materials. For instance, the chemical compatibility and utility of solution-phase nanoparticles are often improved using covalently bound SAMs. Herein, solution-phase gold nanoparticles are modified with thioctic acid SAMs in the presence and absence of salt. Molecular packing density on the nanoparticle surfaces is estimated using X-ray photoelectron spectroscopy and increases by ~20% when molecular self-assembly occurs in the presence versus the absence of salt. We hypothesize that as the ionic strength of the solution increases, pinhole and collapsed-site defects in the SAM are more easily accessible as the electrostatic interaction energy between adjacent molecules decreases, thereby facilitating the subsequent assembly of additional thioctic acid molecules. Significantly, increased SAM packing densities increase the stability of functionalized gold nanoparticles by a factor of 2 relative to nanoparticles functionalized in the absence of salt. These results are expected to improve the reproducible functionalization of solution-phase nanomaterials for various applications. PMID- 21524137 TI - From dishwasher to tap? Xenobiotic substances benzotriazole and tolyltriazole in the environment. AB - There is increasing evidence that the use of chemicals frequently results in widespread environmental contamination with little understanding of the toxicological implications. Benzotriazoles are used in, among other applications, dishwashing formulations for home use, and are a class of chemicals recently reported to be present in European waters. This study demonstrates their presence in UK wastewaters, rivers, and drinking water. It also estimates that their use as silver polishing agents in dishwasher tablets and powders may account for a significant proportion of inputs to wastewaters. The lack of a complete set of good quality (eco)toxicological data on possible chronic effects of these high use chemicals should caution against using them in a manner which may have contributed to such widespread environmental contamination. PMID- 21524139 TI - Imaging time-resolved electrothermal atomization laser-excited atomic fluorescence spectrometry for determination of mercury in seawater. AB - In this study, direct determination of mercury at the nanogram per liter level in the complex seawater matrix by imaging time-resolved electrothermal atomization laser-excited atomic fluorescence spectrometry (ITR-ETA-LEAFS) is described. In the case of mercury, the use of a nonresonant line for fluorescence detection with only one laser excitation is not possible. For measurements at the 253.652 nm resonant line, scattering phenomena have been minimized by eliminating the simultaneous vaporization of salts and by using temporal resolution and the imaging mode of the camera. Electrothermal conditions (0.1 M oxalic acid as matrix modifier, low atomization temperature) have been optimized in order to suppress chemical interferences and to obtain a good separation of specific signal and seawater background signal. For ETA-LEAFS, a specific response has been obtained for Hg with the use of time resolution. Moreover, an important improvement of the detection limit has been obtained by selecting, from the furnace image, pixels collecting the lowest number of scattered photons. Using optimal experimental conditions, a detection limit of 10 ng L(-1) for 10 MUL of sample, close to the lowest concentration level of total Hg in the open ocean, has been obtained. PMID- 21524140 TI - Tocopherol concentration in almond oil: genetic variation and environmental effects under warm conditions. AB - The concentration of the different tocopherol homologues in almond kernel oil was determined in 17 almond cultivars grown in two different experimental orchards, in Spain and Morocco. The three main homologues showed a large variability, ranging from 210.9 to 553.4 mg/kg of oil for alpha-tocopherol, from 4.64 to 14.92 mg/kg for gamma-tocopherol, and from 0.2 to 1.02 mg/kg for delta-tocopherol. The year effect was significant, independent of the experimental site, for all homologues and total tocopherol, the values of alpha-tocopherol, gamma tocopherol, and total tocopherol being higher in 2009 than in 2008, whereas the value of delta-tocopherol was higher in 2008. The location effect was also significant, the values of gamma- and delta-tocopherol being higher in Spain than in Morocco, whereas for alpha-tocopherol the location effect was dependent on the genotype. These effects could not be explained by the temperature differences between sites, but probably other undetermined environmental factors might explain the effect of the location, such as rainfall and irrigation supplementation during fruit growing and ripening. PMID- 21524141 TI - Paper bioassay based on ceria nanoparticles as colorimetric probes. AB - We report the first use of redox nanoparticles of cerium oxide as colorimetric probes in bioanalysis. The method is based on changes in the physicochemical properties of ceria nanoparticles, used here as chromogenic indicators, in response to the analyte. We show that these particles can be fully integrated in a paper-based bioassay. To construct the sensor, ceria nanoparticles and glucose oxidase were coimmobilized onto filter paper using a silanization procedure. In the presence of glucose, the enzymatically generated hydrogen peroxide induces a visual color change of the ceria nanoparticles immobilized onto the bioactive sensing paper, from white-yellowish to dark orange, in a concentration-dependent manner. A detection limit of 0.5 mM glucose with a linear range up to 100 mM and a reproducibility of 4.3% for n = 11 ceria paper strips were obtained. The assay is fully reversible and can be reused for at least 10 consecutive measurement cycles, without significant loss of activity. Another unique feature is that it does not require external reagents, as all the sensing components are fixed onto the paper platform. The bioassay can be stored for at least 79 days at room temperature while maintaining the same analytical performance. An example of analytical application was demonstrated for the detection of glucose in human serum. The results demonstrate the potential of this type of nanoparticles as novel components in the development of robust colorimetric bioassays. PMID- 21524143 TI - Identification of organic materials in historic oil paintings using correlated extractionless surface-enhanced Raman scattering and fluorescence microscopy. AB - A novel spectroscopic approach, correlated surface-enhanced Raman scattering (SERS) and fluorescence microscopy, is used to identify organic materials in two 18th century oil paintings. The vibrational fingerprint of analyte molecules is revealed using SERS, and corresponding fluorescence measurements provide a probe of local environment as well as an inherent capability to verify material identification. Correlated SERS and fluorescence measurements are performed directly on single pigment particles obtained from historic oil paintings with Ag colloids as the enhancing substrate. We demonstrate the first extractionless nonhydrolysis SERS study of oil paint as well as the potential of correlated SERS and fluorescence microscopy studies for the simultaneous identification of organic colorants and binding media in historic oil paintings. PMID- 21524142 TI - Use of a HEHEHE purification tag instead of a hexahistidine tag improves biodistribution of affibody molecules site-specifically labeled with (99m)Tc, (111)In, and (125)I. AB - Affibody molecules are a class of small (~7 kDa) robust scaffold proteins suitable for radionuclide molecular imaging in vivo. The attachment of a hexahistidine (His(6))-tag to the Affibody molecule allows facile purification by immobilized metal ion affinity chromatography (IMAC) but leads to high accumulation of radioactivity in the liver. Earlier, we have demonstrated that replacement of the His(6)-tag with the negatively charged histidine-glutamate histidine-glutamate-histidine-glutamate (HEHEHE)-tag permits purification of Affibody molecules by IMAC, enables labeling with [(99m)Tc(CO)(3)](+), and provides low hepatic accumulation of radioactivity. In this study, we compared the biodistribution of cysteine-containing Affibody molecules site-specifically labeled with (111)In, (99m)Tc, and (125)I at the C-terminus, having a His(6)-tag at the N- or C-terminus or a HEHEHE-tag at the N-terminus. We show that the use of a HEHEHE-tag provides appreciable reduction of hepatic radioactivity, especially for radiometal labels. We hope that this information can also be useful for development of other scaffold protein-based imaging agents. PMID- 21524144 TI - Nondestructive identification of natural and synthetic organic colorants in works of art by surface enhanced Raman scattering. AB - We present a new method based on surface-enhanced Raman scattering (SERS) for the nondestructive identification of organic colorants in objects whose value or function precludes sampling, such as drawings, prints, historic and archeological textiles, handwritten or printed documents, and forensic evidence. A bead of a polymer hydrogel loaded with a solution containing water, an organic solvent, and a chelating agent is used to extract minimal amounts of the colorants from the work of art for SERS analysis. Using a gel as a medium for the solvent mixture confines its action only to the areas of the work of art covered by the gel bead. The gel bead is then removed from the work of art, covered with a drop of Ag colloid, and examined with a Raman microscope. Transfer of the dye from the substrate to the gel does not require removing a sample from the work of art, therefore preserving the physical integrity of the object. Spectrophotometric color measurements confirm that color change is below the limit perceivable by a human observer. Finally, the size of the polymer bead can be reduced to a fraction of a millimeter in order to further minimize any impact on the work of art, without detriment to the effectiveness of the method. The technique has been successfully used for the analysis of a mordant dye on the 15th century Netherlandish tapestry, "The Hunt for the Unicorn", and of a synthetic lake pigment on a Meiji period Japanese woodblock print. PMID- 21524145 TI - Characterization of triacetone triperoxide by ion mobility spectrometry and mass spectrometry following atmospheric pressure chemical ionization. AB - The atmospheric pressure chemical ionization of triacetone triperoxide (TATP) with subsequent separation and detection by ion mobility spectrometry has been studied. Positive ionization with hydronium reactant ions produced only fragments of the TATP molecule, with m/z 91 ion being the most predominant species. Ionization with ammonium reactant ions produced a molecular adduct at m/z 240. The reduced mobility value of this ion was constant at 1.36 cm(2)V(-1)s(-1) across the temperature range from 60 to 140 degrees C. The stability of this ion was temperature dependent and did not exist at temperatures above 140 degrees C, where only fragment ions were observed. The introduction of ammonia vapors with TATP resulted in the formation of m/z 58 ion. As the concentration of ammonia increased, this smaller ion appeared to dominate the spectra and the TATP ammonium adduct decreased in intensity. The ion at m/z 58 has been noted by several research groups upon using ammonia reagents in chemical ionization, but the identity was unknown. Evidence presented here supports the formation of protonated 2-propanimine. A proposed mechanism involves the addition of ammonia to the TATP-ammonium adduct followed by an elimination reaction. A similar mechanism involving the chemical ionization of acetone with excess ammonia also showed the formation of m/z 58 ion. TATP vapors from a solid sample were detected with a hand-held ion mobility spectrometer operated at room temperature. The TATP ammonium molecular adduct was observed in the presence of ammonia and TATP vapors with this spectrometer. PMID- 21524147 TI - Determining the extent and stage of disease in patients with newly diagnosed non Hodgkin's lymphoma using 18F-FDG-PET/CT. AB - Positron emission tomography (PET) using 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (18F-FDG) combined with computed tomography (CT) represents a three-dimensional imaging method suitable for staging in patients with non-Hodgkin's lymphomas (NHLs). The aim of our prospective multicenter study was to assess the value of initial PET/CT as compared with CT and PET alone for determining the stage and extent of the disease. A total of 122 patients with newly diagnosed NHL were examined using PET/CT. Four patients with resected lymphoma lesion and negative PET/CT were therefore excluded from the study. Of the remaining 118 cases, a total of 117 (99%) were described as 18F-FDG-avid. When compared with PET/CT, CT and PET showed very good sensitivity of lymph node imaging (97% and 100%, respectively); the specificity, however, was significantly lower (66.7% and 94.4%, respectively; p=0.0001). When detecting organ lesions, the sensitivity of CT and PET was lower than that of PET/CT (92.5% and 96.3%, respectively; p=0.0001); specificity was significantly decreased in CT and a little lower in PET (59.5% and 91.9%; p=0.0001). When compared with CT alone, PET/CT changed staging of the disease in 11 patients (9%) and was able to detect a total of 82 discrepancies in 67 of the 117 patients (57%). In conclusion, PET/CT is a new standard in imaging the involvement of lymph nodes and extranodal organs in NHL patients regardless of their histopathological types. Both sensitivity and specificity of the examination are higher than those of CT as well as PET alone. PMID- 21524146 TI - Discovery of neuropeptides in the nematode Ascaris suum by database mining and tandem mass spectrometry. AB - Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to discover peptides in extracts of the large parasitic nematode Ascaris suum. This required the assembly of a new database of known and predicted peptides. In addition to those already sequenced, peptides were either previously predicted to be processed from precursor proteins identified in an A. suum library of expressed sequence tags (ESTs) or newly predicted from a library of A. suum genome survey sequences (GSSs). The predicted MS/MS fragmentation patterns of this collection of real and putative peptides were compared with the actual fragmentation patterns found in the MS/MS spectra of peptides fractionated by MS; this enabled individual peptides to be sequenced. Many previously identified peptides were found, and 21 novel peptides were discovered. Thus, this approach is very useful, despite the fact that the available GSS database is still preliminary, having only 1* coverage. PMID- 21524148 TI - Enzyme Inhibition and more--a tribute to John Smith. PMID- 21524149 TI - Design, synthesis and pharmacological evaluation of conformationally restricted N arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands. AB - A series of novel conformationally restricted N(1)-arylsulfonyl-3-aminoalkoxy indoles were designed and synthesized as 5-HT(6) receptor (5-HT(6)R) ligands. Many of the synthesized compounds have moderate in vitro-binding affinities at 5 HT(6)R. The lead compound 8b (% inhibition = 97.2 at 1 MUM) from this series has good pharmacokinetic profile in male Wister rats and is active in animal model of cognition like Morris water maze. The details of chemistry, SAR, pharmacokinetics and pharmacological data constitute the subject matter of this report. PMID- 21524150 TI - Chemical composition and protective effect of oregano (Origanum heracleoticum L.) ethanolic extract on oxidative damage and on inhibition of NO in LPS-stimulated RAW 264.7 macrophages. AB - The present study shows the chemical profile and the in vitro properties (antioxidant and inhibition of nitric oxide production) of the Origanum heracleoticum L. (Lamiaceae). The ethanolic extract of the aerial parts is characterized by terpenes and fatty acids. The extract, with high total phenol and flavonoid content, showed a significant radical-scavenging activity (IC(50) value of 12.8 MUg/mL) using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test and an interesting antioxidant activity with the beta-carotene bleaching test (IC(50) values of 12.9 and 14.1 MUg/mL at 30 and 60 min of incubation, respectively). The test for the inhibition of NO production, performed using the murine monocytic macrophage RAW 264.7 cell line, showed that the extract had significant activity with an IC(50) value of 108.5 MUg/mL. The cytotoxic effect of O. heracleoticum extract in presence of lipopolysaccharide (LPS) (1 MUg/mL) was evaluated but found to be negligible. PMID- 21524152 TI - Development of multiple-unit colon-targeted drug delivery system by using alginate: in vitro and in vivo evaluation. AB - Drug delivery systems to the colon are being actively investigated. However, it is difficult to ensure that an oral preparation disintegrates specifically in the human colon. In this study, a pH- and enzyme-controlled, colon-targeted tablets (PECCTT) was established by using outer pH-coated layer and inner alginate-coated compression layer. The influence of the amount of alginate and enteric coat thickness on drug release had been investigated and the formulation that contained 30% alginate in compression layer and 13% weight gain in pH-coated layer was proved to protect the drug release from stomach and small intestine, the lag time was 7.04 +/- 0.17 h, and 84.45 +/- 1.3% of prednisone was released at 12 h. The results of drug release behaviors and SEM study indicated that drug release mechanism of PECCTT was corrosion. Hybrid scanner combining SPECT and CT was employed to monitor (99m)Tc-contained tablets in the human gastrointestinal tract (GIT) and to obtain the images of the disintegration process. The results showed that the tablet remained intact during its transit through the upper GIT, the anatomical site of disintegration was found to be the sigmoidal colon, and the disintegration of the tablet started at 8 h post-dose in the volunteer. PMID- 21524151 TI - Understanding the limitations of radiation-induced cell cycle checkpoints. AB - The DNA damage response pathways involve processes of double-strand break (DSB) repair and cell cycle checkpoint control to prevent or limit entry into S phase or mitosis in the presence of unrepaired damage. Checkpoints can function to permanently remove damaged cells from the actively proliferating population but can also halt the cell cycle temporarily to provide time for the repair of DSBs. Although efficient in their ability to limit genomic instability, checkpoints are not foolproof but carry inherent limitations. Recent work has demonstrated that the G1/S checkpoint is slowly activated and allows cells to enter S phase in the presence of unrepaired DSBs for about 4-6 h post irradiation. During this time, only a slowing but not abolition of S-phase entry is observed. The G2/M checkpoint, in contrast, is quickly activated but only responds to a level of 10 20 DSBs such that cells with a low number of DSBs do not initiate the checkpoint or terminate arrest before repair is complete. Here, we discuss the limitations of these checkpoints in the context of the current knowledge of the factors involved. We suggest that the time needed to fully activate G1/S arrest reflects the existence of a restriction point in G1-phase progression. This point has previously been defined as the point when mitogen starvation fails to prevent cells from entering S phase. However, cells that passed the restriction point can respond to DSBs, albeit with reduced efficiency. PMID- 21524153 TI - Enhanced cellular uptake of folic acid-conjugated PLGA-PEG nanoparticles loaded with vincristine sulfate in human breast cancer. AB - The aim of this paper is to evaluate the cellular uptake of vincristine sulfate loaded poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles with the folic acid modification (PLGA-PEG-folate NPs). PLGA-PEG-folate NPs were prepared using a water-oil-water emulsion solvent evaporation method. The particle size, surface morphology, drug encapsulation efficiency, and the drug release behavior were investigated. The NPs exhibited a biphasic drug release with a moderate initial burst followed by a sustained release profile. Internalization of the NPs labeled with coumarin- 6 by MCF-7 (Michigan Cancer Foundation-7) human breast cancer cells was quantitatively measured by microplate reader, and qualitatively analyzed by fluorescent microscopy and confocal laser scanning microscopy. The results showed PLGA-PEG-folate NPs achieved significantly higher cellular uptake in the folic acid receptor overexpressed MCF 7 cells, compared to PLGA-mPEG NPs without the folic acid modification. Due to the enhanced cellular uptake, PLGA-PEG-folate NPs displayed the highest cytotoxicity. Judged by IC(50) after 24 h culture, the therapeutic effects of the drug formulated in the NPs with surface modification could be 1.52 times, 3.91 times higher than that of PLGA-mPEG NPs and free vincristine sulfate, respectively. PMID- 21524154 TI - Association of RSV lower respiratory tract infection and subsequent healthcare use and costs: a Medicaid claims analysis in early-preterm, late-preterm, and full-term infants. AB - OBJECTIVE: Healthcare use and costs within 1 year of a respiratory syncytial virus lower respiratory tract infection (RSV-LRI) among Medicaid early-preterm and late-preterm infants compared with full-term infants were evaluated. METHODS: Infants born during 2003-2005 were identified from the Thomson Reuters MarketScan Multi-State Medicaid Database. Infants <1 year of age were grouped based on RSV LRI and unspecified bronchiolitis/pneumonia (UBP) diagnosis codes and stratified by inpatient or outpatient setting. Infants without RSV-LRI/UBP were selected for comparison. Economic and clinical outcomes were analyzed descriptively; the relationship between RSV-LRI/UBP and costs incurred within 1 year of infection were analyzed using logged ordinary least squares models. Results were stratified by gestational age. RESULTS: Most infants were diagnosed with RSV-LRI/UBP after 90 days of chronologic age. Early-preterm infants had the greatest mean number of inpatient, outpatient, and emergency department visits after an RSV-LRI/UBP episode. The marginal costs among infants with RSV-LRI compared with controls were $34,132 (p < 0.001) and $3869 (p = 0.115) among inpatients and outpatients, respectively. Among late-preterm infants, the marginal costs were $17,465 (p < 0.001) and $2158 (p < 0.001) among inpatients and outpatients, respectively. Full term infants had the lowest marginal costs (inpatients, $9151 [p < 0.001]; outpatients, $1428 [p < 0.001]). Overall, inpatient infants with RSV-LRI/UBP had higher costs than outpatients, suggesting that increased downstream costs are associated with severity of RSV-LRI/UBP disease. LIMITATIONS: Infants with unknown etiology for bronchiolitis were assigned to the UBP group, which may underestimate the costs of the comparison group. CONCLUSIONS: The burden of RSV LRI was substantial among early-preterm Medicaid infants. Costs were also higher among late-preterm relative to full-term infants. PMID- 21524155 TI - Pediatric acute myeloid leukemia--is there a scope for change in the developing world? PMID- 21524156 TI - Piperacillin/tazobactam monotherapy versus piperacillin/tazobactam plus amikacin as initial empirical therapy for febrile neutropenia in children with acute leukemia. AB - The purpose of this study is to compare the efficacy and safety of piperacillin/tazobactam (PIP/TAZO) versus PIP/TAZO plus amikacin in febrile neutropenic children with acute leukemia (AL). Children with AL who had febrile neutropenic episodes were randomized to treatment with PIP/TAZO versus PIP/TAZO plus amikacin. Modification was defined as addition of other antimicrobials and/or antifungal agents to the empirical therapy. Protocol failure was defined as withdrawal of the empirical regimen and introduction of other antimicrobials due to failure in controlling infection. Seventy-two febrile episodes of 42 patients with a median age of 4.5 years (3.5 months to 19 years) were evaluated. There were 37 and 35 episodes in PIP/TAZO and combination arms, respectively. Success without modification, with modification, protocol failure, duration of treatment were 45.9%, 35.1%, 18.9%, and 10 days in PIP/TAZO arm and 42.9%, 37.1%, 20%, and 12 days in combination arm, respectively (P > .05). There was no significant difference between the empirical therapy arms regarding median duration of neutropenia and defervescence of fever. Empirical therapy was substituted by other drugs in 6 and 5 episodes in PIP/TAZO and combination arms, respectively. There was no infection-related death. There was reversible increase in serum creatinine in 1 episode on the combination arm. Monotherapy with PIP/TAZO was effective and safe for initial empirical treatment of febrile neutropenic episodes in children with AL. However, local bacterial resistance patterns should be considered in daily practice. Combination of amikacin with PIP/TAZO did not improve treatment success, but it may increase nephrotoxicity. PMID- 21524157 TI - Yin Yang of immunoregulation in organ transplantation and cancer. AB - The 'Yin Yang of Immunoregulation: Cancer and Organ Transplantation' meeting took place in Nantes, France on 2-3 December 2010 and was dedicated to the biology of myeloid and lymphoid immune cells in the context of cancer and transplantation. This meeting was organized by the Immunotherapy Research group of the Western France Cancer Network Canceropole Grand-Ouest and the Immunomonitorage et Biotherapies network (IMBIO) research program, which is supported by the Region Pays de la Loire. PMID- 21524159 TI - Modulation of the dendritic cell-T-cell synapse to promote pathogen immunity and prevent autoimmunity. AB - The molecular interactions occurring at the interface between dendritic cells (DCs) and T cells play an important role in the immune surveillance against infectious agents, as well as in autoimmune pathogenesis. Therefore, regulation of this interaction arises as an important tool for the prevention and treatment of immune disorders and to improve the protection against pathogens without causing detrimental inflammation. Some of the molecular interactions defining the outcome of the DC-T cell interaction are: T-cell receptor (TCR) binding to the pMHC on the DC surface, which is responsible for the antigenic specificity; and the ratio of activating/inhibitory receptor pairs on the surface of DCs and T cells, which modulate DC immunogenicity and T-cell function, respectively. An alteration in the proper function of these molecules could lead to unbalanced DC T-cell synapses that either cause a failure to control infections or exacerbated inflammation. Furthermore, some pathogens have developed molecular strategies to impair the function of the synapse to evade adaptive immunity. In this article, we will discuss recent work relative to the molecular mechanisms controlling DC-T cell synapse and their implications on immunoregulation to control autoimmunity and potentiate pathogen immunity. PMID- 21524160 TI - What is the role of antigen-processing mechanisms in autologous tolerogenic dendritic cell therapy in organ transplantation? AB - Injection of autologous tolerogenic dendritic cells is a promising strategy to diminish the burden of harmful immunosuppression in clinical transplantation. We discuss the immunoregulatory mechanisms triggered by this approach. Tolerogenic dendritic cells have long been associated with decreased antigen-processing capacities. However, different lines of evidence led us to propose that injected autologous dendritic cells may need to process donor antigens from graft passenger leukocytes. It is known that drugs such as calcineurin inhibitors can interfere with antigen processing. Indeed, this issue is of the most importance to rationalize the translation of autologous tolerogenic dendritic cell therapy to the clinic. PMID- 21524161 TI - Heme oxygenase and carbon monoxide as an immunotherapeutic approach in transplantation and cancer. AB - Heme oxygenases (HOs) are the rate-limiting intracellular enzymes that degrade heme into carbon monoxide (CO), biliverdin and free divalent iron. Among HOs, HO 1 is the only isoform that is highly inducible in response to numerous stress factors and proinflammatory cytokines. This enzyme has shown cytoprotective, antioxidant and anti-inflammatory properties. Moreover, HO-1 and, in particular, CO also have tolerogenic actions in adaptive immune responses. HO-1 can provide immunosuppression through its expression by regulatory T cells or antigen presenting cells. The physiological importance of HO-1 has been demonstrated in both mice and humans, and modulation of HO-1 expression has therapeutic effects in a variety of disorders involving inflammation and immune responses, including organ transplantation and cancer. Consistently, upregulation of the HO-1 pathway has a significant protective effect against spontaneous or induced autoimmune diseases, allergy and can be beneficial to graft survival. However, HO-1 may also play a role in tumorigenesis by lowering antitumor innate immune responses that control tumor growth or reduce tumor expansion. Thus, controlling HO-1 expression may be of great interest in immune intervention protocols where tolerance is desirable, such as in transplantation, or where enhanced immunogenicity is needed in the case of cancer. PMID- 21524162 TI - Regulatory B cells control dendritic cell functions. AB - IL-10-producing B cells are a new family of regulatory cells that control the immune responses at the innate and adaptive levels. In the neonatal context, we described that such regulatory B cells (Bregs) dampened immune responses to adjuvants and vaccines. For a long time, it has been postulated that immune system immaturity was responsible for this phenomenon; however, increasing evidence indicates that immune regulation rather than immaturity is at work. We demonstrated that innate CD5(+) Bregs negatively control innate inflammation and dendritic cell functions in neonatal mice by producing high amounts of IL-10 following Toll-like receptor triggering. These immune regulatory mechanisms can protect from lethal inflammation, control the development of autoimmune diseases, such as experimental autoimmune encephalomyelitis, and could be evoked in chronic inflammatory states, such as in cancer. PMID- 21524164 TI - IL-6 and leukemia-inhibitory factor are involved in the generation of tumor associated macrophage: regulation by IFN-gamma. AB - Tumor-associated macrophages (TAMs), the most abundant immunosuppressive myeloid cells in the tumor microenvironment, exhibit an IL-10(high)IL-12(low) profile called M2, opposite to the immunostimulatory M1. We reported that ovarian cancer ascites switched monocyte differentiation into TAM-like cells that exhibit most phenotypic and functional characteristics of TAMs, suggesting that soluble mediators are involved in the differentiation of monocytes into TAM-like cells. We observed that leukemia-inhibitory factor and IL-6, present at high concentrations in ovarian cancer ascites, skew monocyte differentiation into TAM like cells by increasing macrophage colony-stimulating factor consumption. Moreover, we observed that IFN-gamma switches established TAMs into immunostimulatory M1 cells and skews monocyte differentiation from TAM-like cells to M1s. In addition to revealing a new tumor-escape mechanism associated with TAM generation via leukemia-inhibitory factor and IL-6, these findings offer novel therapeutic perspectives to subvert TAM-induced immunosuppression and to improve antitumor immunotherapy efficacy. PMID- 21524166 TI - Cell therapy to promote transplantation tolerance: a winning strategy? AB - Organ transplantation is currently the only effective treatment for end-stage organ failure. However, success is limited by the immune response of the recipient to allogeneic tissues (recognized by the direct and indirect alloresponses) and by the morbidity and mortality associated with the immunosuppressive drugs that are used to control alloimmunity. One solution to these problems is the induction of immunological tolerance. In our laboratory, we have selected two strategies to achieve this goal. The first is to expand and/or generate Tregs directly in vivo using infusions of 'tolerogenic' DCs into patients; the second is to purify Tregs from the blood of patients on the waiting list for a transplant, enrich and expand these cells in vitro and then inject back in vivo after transplantation. Here, we have summarized our results both in the murine and human systems on the use of Treg-based strategies to induce tolerance to the transplanted organs. PMID- 21524167 TI - Immunotherapy of hepatocellular carcinoma: is there a place for regulatory T lymphocyte depletion? AB - Immunotherapy represents a potential therapeutic option for patients with hepatocellular carcinoma (HCC), especially as secondary treatment to prevent recurrence. It has been shown that a patient's survival is directly correlated to the type and number of tumor-infiltrating immune cells, indicating that immune responses have a direct effect on the clinical course of the disease. We have assessed the potential of immunotherapy against HCC in preclinical models of low tumor burden. An antigen-specific strategy targeting alpha-fetoprotein, and consisting of immunization with a DNA-based synthetic vector (DNAmAFP/704), was tested on an autochthonous model of chemical hepatocarcinogenesis and led to an important (65%) reduction of the tumor burden. A nonspecific approach of CD25(+) T-cell depletion by injection of PC61 antibody was also tested on an orthotopic HCC model and led to a significant protection against tumor development. Antigen specific immunotherapy and Treg depletion are promising strategies in physiologically relevant HCC preclinical models. Future clinical trials will demonstrate if a combination of Treg depletion with an antigen-specific immunotherapy will also translate into clinical responses in HCC patients. PMID- 21524168 TI - T-cell receptor specificity of CD8(+) Tregs in allotransplantation. AB - Recent studies in the field of CD8(+) Tregs have allowed a better identification and characterization of this subset of regulatory cells. Their key role in the regulation of allogeneic responses is now well established. To take full advantage of CD8(+) Treg cells in future therapeutic applications, a better knowledge is required, particularly concerning the contribution of the T-cell receptor (TCR) in cell function as well as the role and importance of its antigenic specificity. Here, we focused on the CD8(+)CD45RC(low) Tregs, which in rats induce an indefinite long-term allograft acceptance. We summarized recent findings on their interaction properties with antigen-presenting cells. Identification of the antigenic targets and TCR repertoire of CD8(+) Tregs will allow a better understanding of their recognition properties and will highlight the potential of such of specific population in cell-based treatment. PMID- 21524169 TI - Immunoregulatory properties of neural stem cells. AB - Transplantation of neural cells provides an interesting form of therapy for certain CNS disorders. Although the brain has a special immune status, xenografts of fetal porcine neuroblasts are ultimately rejected after a lag of several weeks. Various strategies have been proposed to prevent this process. These include the design of transgenic pigs whose neurons have an increased immunosuppressive potential. An interesting alternative is provided by the use of neural stem/progenitor cells, which are multipotent cells found in the fetal or adult CNS. These cells are known to be poorly immunogenic. However, pig or rat neural stem/progenitor cells are highly immunosuppressive, as shown by their ability to block the proliferation of activated T lymphocytes. This effect is mediated by cell secreted factor(s), whose nature is discussed. PMID- 21524170 TI - Mechanisms of immunomodulation in human glioblastoma. AB - Glioblastoma multiforme (GBM), WHO grade IV astrocytoma, is the most dramatic primary brain cancer with a very poor prognosis due to inevitable disease recurrence. Less than 10% of GBM patients are still alive 5 years after diagnosis despite a multimodal treatment with surgical resection of the tumor, radiation therapy and chemotherapy. Cellular immunotherapy in gliomas, one of the promising new therapies, has shown convincing results in some patients with induction of antitumor immune responses and prolonged survival. In particular, several patients treated with dendritic cell vaccinations have demonstrated systemic antigen-specific cytotoxicity and intratumor infiltration of cytotoxic T cells. However, this is not always correlated with clinical improvement because GBM cells have multiple mechanisms that lead to suppression of the patient's antitumor immune responses. This article will focus on some aspects of the systemic immunosuppression observed in GBM patients as well as the multiple mechanisms of local immunoresistance developed by GBM. PMID- 21524173 TI - Interest in surgical research. AB - Interest in surgical research is a decisive factor in the surgical advances seen in the 20th century since interest in research represents the first key to the progress of the surgical sciences. How do you stimulate interest in research by non-believers or those not attracted to the research enterprise? This is the critical question that needs to be answered in order to achieve the best participation possible. We believe that intermixing the interest in research and research results observed today demonstrates the benefit of research in the clinical sciences and patient care. Furthermore, bringing the importance of research interest into medical and surgical staff meetings represents the best way to position its prominence among all attendees. Knowing that research is the basis for evidence-based medicine makes it obvious that having interest in research would facilitate the understanding and application of evidence-based principles. In this regard, then, interest in research becomes of paramount importance. PMID- 21524174 TI - Developing the research idea. AB - After the interest in surgical research, developing the research idea is of fundamental importance because without it we can not have research. Where do the research ideas come from then? Is there any better way to improve our ability to generate research ideas? Where do they come from? What are the factors that stimulate the research idea? Anything we do in and out of medicine or surgery should be the force that will maintain our mind occupied on our future research ideas. From events in the clinical arena to discussions in formal rounds or informal meetings should be the origin of our thinking in research. So, the generation of research ideas come from any place and we should be aware of it. We could be successful in research if we could produce and accumulate the ideas as they frequently present to us in our professional or daily life. The research environment could help us in securing the presence and evolution of the idea. Be aware of changes and future developments and be ready to admit and grow the research idea that could be presented to you during the practice of medicine. PMID- 21524172 TI - Dental anxiety in 6-7-year-old children treated in accordance with conventional restorative treatment, ART and ultra-conservative treatment protocols. AB - OBJECTIVE: To test the hypothesis that dental anxiety levels of children treated in accordance with the conventional restorative treatment (CRT) are higher than in children treated with the atraumatic restorative treatment (ART) or ultra conservative treatment (UCT) protocols. MATERIALS AND METHODS: In total, 302 children aged 6-7-years old, with at least two dentine carious lesions, constituted the sample. A parallel group study design was used with ART and UCT as test groups and CRT as the control. The treatment was divided into two sessions. In the first session, one carious tooth (class II in a primary molar) was randomly selected and treated according to one of the treatments. All other treatments were performed in the second session. Before the first (FIS Tx-1) and before the second session (FIS Tx-2) the level of dental anxiety was assessed using the Facial Image Scale (FIS). The GLM test and Spearman's Rank Correlation Coefficient were used to analyse the data. RESULTS: No treatment group effect was observed on the FIS Tx-2 score (p = 0.64). A FIS Tx-1 score (p < 0.0001) effect on the FIS Tx-2 score was observed. The correlation coefficient between FIS Tx-1 and FIS Tx-2 scores was r = 0.30 (p < 0.0001). CONCLUSION: At the beginning of the second session there was no difference in dental anxiety levels of the children treated in the first session according to the three treatment protocols. A high dental anxiety score before the first session was a predictor of a high dental anxiety score at the second treatment session. PMID- 21524175 TI - Limited efficacy of early enteral nutrition in patients after total gastrectomy. AB - BACKGROUND: Evaluable data documenting the efficacy of early enteral nutrition (EEN) in patients after total gastrectomy are still limited. AIMS: This study aimed to evaluate the clinical efficacy of EEN through a nasojejunal tube on the recovery of patients after total gastrectomy compared with that of patients receiving only total parenteral nutrition (TPN). MATERIALS AND METHODS: One hundred and sixteen patients who underwent total gastrectomy were divided into the EEN and TPN groups. The clinical recovery and postoperative complications of these two groups were compared. RESULTS: There were 62 patients in the EEN group and 54 in the TPN group. The postoperative length of hospital stay, time of flatus passage, and time to start a semisolid diet were similar in the two groups. In the TPN group, however, patients started a liquid diet earlier. No difference in any postoperative complications or perioperative death were found between the EEN and TPN groups. CONCLUSION: Since there was no significant difference regarding either the postoperative recovery course or complications, the routine placement of a nasojejunal tube for EEN is unnecessary in elective total gastrectomy. PMID- 21524176 TI - Metabolism and gastric remnant changes after Roux-en-Y gastric bypass in rats. AB - BACKGROUND: The Roux-en-Y gastric bypass (RYGB) may affect metabolism, microbiology, and histology of gastric remnant. Therefore, this study aimed to investigate these issues in rats. METHODS: Twelve rats were randomly allocated to a RYGB group (n = 6) and nonoperated normal rats group (n = 6). After 30 postoperative days, all rats were injected with 0.1 ml of Na(99m)Tc(-) i.v. (radioactivity 0.66 MBq). After 30 min, liver, stomach, thyroid, heart, lung, kidney, and femur samples were harvested and weighed. Percentage radioactivity per gram of organ (%ATI/g) was determined using a Perkin-Elmer gamma counter. Serum albumin, calcium, aminotransferases (ALT, AST), T3, T4, and PTH were determined. Samples of the excluded stomach mucosa were harvested for bacterial and fungal count such as colony-forming units/g and histology. RESULTS: A significant reduction (t test) in %ATI/g was observed in the liver, stomach, and femur in the RYGB rats, compared with normal rats (p < .05). A significant reduction in serum albumin and calcium in RYGB rats was detected, compared with normal rats (p < .05). ALT and AST were significantly different between the two groups. T3 and T4 levels were significantly lower in RYGB rats than in normal rats (p < .05); PTH levels were higher in RYGB rats than in controls (p = .009). The gastric remnant mucosa of RYGB rats showed higher bacterial and fungal count, atrophy, intestinal metaplasia, and neutrophilic polymorphonuclear inflammation than in normal rats. CONCLUSIONS: This investigation demonstrated that a model of murine RYGB significantly modified metabolic parameters and the microbiology/histology of the remnant stomach. PMID- 21524177 TI - Chemical adhesion barriers: do they affect the intraperitoneal behavior of a composite mesh? AB - INTRODUCTION: The intraperitoneal behavior of a prosthetic material used to repair a hernia is key to the success of the postimplant repair process. This study was designed to laparoscopically examine the real-time behavior of three composite meshes incorporating a chemical adhesion barrier when placed in contact with the visceral peritoneum. MATERIAL AND METHODS: The defects of 7 * 5 cm were created in the ventral abdominal wall of 18 New Zealand White rabbits and repaired using Parietex Composite(r) (n = 6), Sepramesh(r) (n = 6), or Proceed(r) (n = 6). At 24 hr, 3, 7, and 14 days postimplant, adhesion formation was quantified by subjecting photographs obtained during laparoscopy to image analysis. At 14 days, specimens of the implants and surrounding host tissue were obtained for histologic, morphometric, and immunohistochemical analyses. RESULTS: There were no cases of infection and/or rejection of the implant. Adhesion formation followed by laparoscopy 3, 7, and 14 days after implant was significantly lower for Parietex(r) than the other biomaterials. Degradation of the chemical barrier occurred earliest in Sepramesh(r), this barrier being most stable at 14 days for the Parietex(r) implants. Macrophage counts were significantly greater for Sepramesh(r). The thickness of the neoformed peritoneum formed on the three implants varied significantly (p < .05): 276.89 +/- 38.87 MUm, 84.49 +/- 19.05 MUm, and 161.97 +/- 47.05 MUm, respectively for Paritex(r), Sepramesh(r), and Proceed(r). CONCLUSIONS: (a) The most stable barrier against biodegradation was that of Parietex(r); (b) the first postimplant week was the most critical period for adhesion formation; and (c) all three biomaterials showed good intraperitoneal behavior. PMID- 21524178 TI - A novel experimental animal model of arterial stenosis based on endovascular radiofrequency energy application. AB - PURPOSE: To develop a new rabbit model of arterial stenosis using endovascular radiofrequency (RF) energy. MATERIALS AND METHODS: Ten rabbits were used for multiple endovascular RF applications to the aorta and left common carotid artery through the HabibTM VesCoagTM catheter. Angiography and color Doppler ultrasound were used to assess vessel patency immediately following the procedure and six weeks later. One rabbit was sacrificed following the procedure for histopathologic analysis of the vessel wall. Two rabbits died of aortic and carotid rupture, respectively, immediately after the procedure. The remaining seven rabbits were sacrificed after six-week follow-up for histopathological analysis. RESULTS: Optimal RF generator settings to induce significant arterial stenosis (>50%) without complications were standardized at 24-26 watts (W) for 1.5 min for the aorta and 6 W for 1 min for the common carotid artery. The six week follow-up showed permanent results in all surviving rabbits. Histopathology revealed intima and medial smooth muscle layer necrosis. CONCLUSION: We have developed a novel rabbit model of arterial stenosis using endovascular RF energy. Our model is fast, safe, inexpensive, and reproducible. It would be useful for experimental investigations and new therapeutic devices. PMID- 21524179 TI - Effects of intraperitoneal albumin on systemic and cerebral hemodynamics in a swine model of acute liver failure. AB - BACKGROUND: Currently, albumin dialysis is the most widely used nonbiological liver support system. We hypothesized that direct peritoneal albumin exposure in the peritoneal cavity would stabilize blood flow and prevent liver and brain injury, in the same way that had previously been seen with extracorporeal albumin dialysis systems. MATERIALS AND METHODS: Fourteen Landrace pigs (weight 25-30 kg) underwent 70% right hepatectomy and were randomly assigned into a control (C, n = 7) and an intraperitoneal albumin treated group (A, n = 7). The systemic, cerebral, and pulmonary hemodynamic parameters of the animals were recorded at 0, 6, 9, and 12 hr following reperfusion of the liver remnant. RESULTS: Mean arterial blood pressure, cardiac output, and stroke volume were significantly higher in group A at the end of the experiment. Significantly higher mean intracranial pressure (ICP) values were observed in group C compared to group A, both at 9 hr (21.3 +/- 5.2 versus 14.1 +/- 3.5 mmHg, p < .0005) and 12 hr (23 +/- 4.3 versus 11 +/- 3.5 mmHg, p < .0005). On the contrary, cerebral perfusion pressure (CPP) remained stable in albumin-treated groups after the sixth postreperfusion hour. Mean pulmonary artery pressure and pulmonary vascular resistance (PVR) were significantly lower in group A compared to group C at 12 hr, while pulmonary capillary wedge pressure (PCWP) stabilized in albumin-treated animals. CONCLUSIONS: This study provides the first evidence that intraperitoneal albumin may be able to attenuate systemic, pulmonary, and cerebral hemodynamic disturbances associated with acute liver failure. PMID- 21524180 TI - The rabbit as an animal model for proctology research: anatomical and histological description. AB - PURPOSE: This study was designed to describe the surgical anatomy and histology of the rabbit anorectum comparing it to that of humans, in order to decide whether it can be a good experimental model for research in proctology. MATERIAL AND METHODS: This study of the anorectal region was performed on six female New Zealand white rabbits, weighting between 2.5-2.9 kg. An autopsy was performed immediately after sacrificing the animal and an anatomical and histological description was performed. RESULTS: The mean rectum and anal canal lengths were of 7.2 cm and 0.9 cm, respectively. The macroscopic study showed that the musculature of the anal canal is formed by the coccygeus muscle, which serves as puborectalis in humans. It also defined an external anal sphincter with a deep and superficial portion. The histological evaluation showed similarity to that of humans, with mucosa of simple columnar type, muscularis mucosae, a small submucosa, with a muscular wall divided into internal and external layers, separated by the myenteric plexus. CONCLUSION: The great similarity to both the anatomy and the histology of humans, appropriate size and easy-handling and care, make the rabbit an attractive animal for the use as experimental and research model in proctology. PMID- 21524183 TI - Changes of aquaporins in the lacrimal glands of a rabbit model of Sjogren's syndrome. AB - AIMS: To test the hypothesis that the expression of aquaporins (AQPs) 4 and 5 is altered in the lacrimal glands (LG) of rabbits with induced autoimmune dacryoadenitis (IAD). MATERIALS AND METHODS: LGs were obtained from adult female rabbits with IAD, and age-matched female control rabbits. LGs were processed for laser capture microdissection (LCM), real time RT-PCR, Western blot, and immunofluorescence for the detection and quantification of protein and mRNAs of AQP4 and AQP5 in whole LGs, and purified acinar cells and duct cells from specific duct segments. RESULTS: In rabbits with IAD, abundances of mRNAs for AQP4 and AQP5 from whole LGs were significantly lower than controls. Levels of mRNA for AQP4 were lower in most duct segments from rabbits with IAD. However, the mRNA abundance for AQP5 was significantly lower in acini from rabbits with IAD, while its abundance was higher in each duct segment. Western blot showed that the expression of AQP4 in LGs from rabbits with IAD was 36% more abundant than normal controls, whereas AQP5 was 72% less abundant. Immunofluorescence indicated that AQP4 immunoreactivity (AQP4-IR) was present on the basolateral membranes of acinar and ductal cells in control and diseased LGs, with ductal cells showing stronger AQP4-IR than acinar cells. AQP5-IR was found on apical and basolateral membranes of acinar cells, and showed a "mosaic" pattern, i.e., with some acini and/or acinar cells showing stronger AQP5-IR than others. Minimal AQP5 IR was detected in ductal cells from control animals, while its intensity was significantly increased in rabbits with IAD. CONCLUSIONS: These data strongly support our hypothesis that expressions of AQPs are altered in rabbits with IAD, and that specific ductal segment play important roles in lacrimal secretion. PMID- 21524184 TI - Use of diversity arrays technology markers for integration into a cotton reference map and anchoring to a recombinant inbred line map. AB - A diversity array technology (DArT) marker platform was developed for the cotton genome, to evaluate the use of DArT markers compared with AFLP markers in mapping and transferability across the mapping populations. We used a reference genetic map of tetraploid Gossypium L. that already contained ~5000 loci, which coalesced into 26 chromosomes, to anchor newly developed DArT and AFLP markers with the aim of further improving utility and map resolution. Our results indicated that the percentage of polymorphic DArT markers that could be genetically mapped (78.15%) was much higher than that of AFLP markers (22.28%). Sequence analysis of DArT markers indicated that a majority matched known expressed sequence tag (EST) sequences from tetraploid and diploid Gossypium species. A total of 794 Arabidopsis genes were homologous with various DArT marker sequences. Chromosomes 5(A), 7(A), 19(D), 23(D), and 24(D) had more Arabidopsis syntenic DArT markers than the other chromosomes. Anchoring DArT markers from the reference map to a recombinant inbred line (RIL) map indicated that DArT markers will speed the building of maps in de novo RIL populations. PMID- 21524185 TI - Reducing the risk of being a victim of crime in South Africa: you can tell and be heard! AB - People who use Augmentative and Alternative Communication (AAC) know that silence is not always golden. Persons with disabilities and in particular those with complex communication needs, have a heightened risk of becoming victims of crime, abuse, and neglect. This study looked at the vocabulary needed to disclose or report crime or abuse in South Africa, and also focussed on the development of communication boards for this purpose, in four of the 11 official South African languages (Afrikaans, English, Sepedi, and isiZulu). Thirty-six participants in four language-based focus groups (English, Afrikaans, Sepedi, and isiZulu) were asked to generate a list of possible words they deemed important when wanting to disclose a crime, abuse or neglect. Participants then prioritized the top 55 words. A total of 56 words appeared on two or more of the lists from the four language groups. The board was developed using Picture Communication Symbols (PCS), the most frequently used symbol set in South Africa, according to an electronic mail survey. A discrepancy analysis revealed that these 56 words could be represented by 219 symbols. Symbols were developed for two words (swear, threaten) for which no PCS symbols existed. The process of developing the communication boards described in this paper may be useful to AAC communities in other countries, and the boards can serve as templates for other languages. PMID- 21524186 TI - A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. AB - OBJECTIVE: To develop an evidence-based monitoring protocol for clozapine-induced myocarditis. METHODS: Potential cases of clozapine-related myocarditis occurring between January 1994 and January 2009 and a comparative group of patients taking clozapine for at least 45 days without cardiac disease were documented from the patients' medical records. RESULTS: A total of 75 cases and 94 controls were included. Nine cases died. The time to onset was 10-33 days with 83% of cases developing between days 14 and 21 inclusive. At least twice the upper limit of normal troponin was found in 90% of cases, but 5 cases had C-reactive protein more than 100 mg/L and left ventricular impairment by echocardiography without a clinically significant rise in troponin. The proposed monitoring protocol recommends obtaining baseline troponin I/T, C-reactive protein and echocardiography, and monitoring troponin and C-reactive protein on days 7, 14, 21 and 28. Mild elevation in troponin or C-reactive protein, persistent abnormally high heart rate or signs or symptoms consistent with infective illness should be followed by daily troponin and C-reactive protein investigation until features resolve. Cessation of clozapine is advised if troponin is more than twice the upper limit of normal or C-reactive protein is over 100 mg/L. Combining these two parameters has an estimated sensitivity for symptomatic clozapine induced myocarditis of 100%. The sensitivity for asymptomatic disease is unknown. CONCLUSION: This protocol recommends active monitoring for 4 weeks, relying predominantly on troponin and C-reactive protein results. It encourages continuation of clozapine in the presence of mild illness, but defines a threshold for cessation. PMID- 21524187 TI - Responsiveness and sensitivity of the Stroke Specific Quality of Life Scale Danish version. AB - PURPOSE: To test responsiveness and sensitivity to change of the Stroke Specific Quality of Life Scale Danish version (SSQOL-DK) scores in patients following stroke. METHODS: A follow-up study of 150 patients with first-ever stroke was used. Questionnaires on quality of life, fatigue, depression, and functional level were completed. Direction of change was categorised as deterioration, no change or improvement. Proportion of concordant classification with external criteria was assessed. Associations between differences in SSQOL-DK domains and the other instruments were estimated using Spearman's rank order correlation coefficients. Paired t-test was used to assess change in the SSQOL-DK domains in patients affected in that domain. Effect size and standardised response mean (SRM) were used to express domain responsiveness. RESULTS: SSQOL-DK classified concordantly in 42.2 to 58.1%, and misclassified from zero to 31.3%. Changes in SSQOL-DK and in the corresponding measures correlated from (r(s)) 0.08 to -0.58. Fatigue and domain energy in SSQOL-DK were negatively correlated. Effect size ranged from -0.03 to -0.53, SRM from -0.02 to -0.56 reflecting mild-to-moderate responsiveness in eight out of 12 domains. CONCLUSION: SSQOL-DK is mildly to moderately responsive and sensitive and can be used for descriptive purposes over time in groups of patients with mild stroke. PMID- 21524188 TI - Spirituality and the International Classification of Functioning, Disability and Health: content comparison of questionnaires measuring mindfulness based on the International Classification of Functioning. AB - PURPOSE: To identify and compare the concepts contained in questionnaires measuring mindfulness using the International Classification of Functioning (ICF) as external reference. METHOD: Questionnaires which are published in peer reviewed journals and listed in Pubmed or PsycInfo were included. The questionnaires were analysed and, using a content-analytical approach, the respective items were categorised and linked to the ICF. RESULTS: Ten questionnaires were included. Ninety-four per cent (N = 341) of the concepts could be linked to 37 different ICF categories. One hundred and seventy-one (50.1%) concepts were linked to ICF categories of the component Body Function, 74 (21.7%) to categories of the component Activity and Participation and none to categories of the component Environmental Factors. In total, 28.2% of the linked concepts belonged to Personal factors, which are not yet classified in the ICF. The questionnaires exhibited considerable differences regarding content density (i.e. the average number of concepts per item) and content diversity (i.e. the number of ICF categories per concept). CONCLUSIONS: The ICF provides an useful external reference to identify and compare the concepts contained in mindfulness questionnaires. Also, mindfulness questionnaire concepts suggest potentially useful factors for classification within the ICF. PMID- 21524189 TI - Evidence for differences in regioselective and stereoselective glucuronidation of silybin diastereomers from milk thistle (Silybum marianum) by human UDP glucuronosyltransferases. AB - The flavonolignan silybin, the main component of silymarin, extract from the seeds of Silybum marianum, is used mostly as a hepatoprotectant. Silybin is almost 1:1 mixture of two diastereomers A and B. The individual UDP glucuronosyltransferases (UGTs) contributing to the metabolism of silybin diastereomers have not been identified yet. In this study, the contribution of UGTs to silybin metabolism was examined. The potential silybin metabolites were formed in vitro by incubating silybin (i) with the human liver microsomal fraction, (ii) with human hepatocytes and finally (iii) with 12 recombinant UGTs (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17). High performance liquid chromatographic (HPLC) techniques with UV detection and additionally MS detection were used for metabolite identification. Hepatocytes and microsomes formed silybin A-7-O-beta-D-glucuronides, B-7-O-beta-D glucuronides, A-20-O-beta-D-glucuronides and B-20-O-beta-D-glucuronides. With recombinant UGTs, the major role of the UGT1A1, 1A3, 1A8 and 1A10 enzymes but also of the UGT1A6, 1A7, 1A9, 2B7 and 2B15 in the stereoselective reactions leading to the respective silybin glucuronides was confirmed. UGT1A4, UGT2B4 and UGT2B17 did not participate in silybin glucuronidation. The predominant formation of 7-O-beta-D-glucuronides and the preferential glucuronidation of silybin B diastereomer in vitro by human UGTs were confirmed. PMID- 21524190 TI - Assessment of UDP-glucuronosyltransferase catalyzed formation of Picroside II glucuronide in microsomes of different species and recombinant UGTs. AB - This study compared the hepatic glucuronidation of Picroside II in different species and characterized the glucuronidation activities of human intestinal microsomes (HIMs) and recombinant human UDP-glucuronosyltransferases (UGTs) for Picroside II. The rank order of hepatic microsomal glucuronidation activity of Picroside II was rat > mouse > human > dog. The intrinsic clearance of Picroside II hepatic glucuronidation in rat, mouse and dog was about 10.6-, 6.0- and 2.3 fold of that in human, respectively. Among the 12 recombinant human UGTs, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 catalyzed the glucuronidation. UGT1A10, which are expressed in extrahepatic tissues, showed the highest activity of Picroside II glucuronidation (K(m) = 45.1 MUM, V(max) = 831.9 pmol/min/mg protein). UGT1A9 played a primary role in glucuronidation in human liver microsomes (HLM; K(m) = 81.3 MUM, V(max) = 242.2 pmol/min/mg protein). In addition, both mycophenolic acid (substrate of UGT1A9) and emodin (substrate of UGT1A8 and UGT1A10) could inhibit the glucuronidation of Picroside II with the half maximal inhibitory concentration (IC(50)) values of 173.6 and 76.2 MUM, respectively. Enzyme kinetics was also performed in HIMs. The K(m) value of Picroside II glucuronidation was close to that in recombinant human UGT1A10 (K(m) = 58.6 MUM, V(max) = 721.4 pmol/min/mg protein). The intrinsic clearance was 5.4-fold of HLMs. Intestinal UGT enzymes play an important role in Picroside II glucuronidation in human. PMID- 21524191 TI - Interaction of sirolimus and everolimus with hepatic and intestinal organic anion transporting polypeptide transporters. AB - The goal of this study was to assess the interaction of the mTOR inhibitors (ImTORs) sirolimus and everolimus with the human organic anion-transporting polypeptides (OATPs) expressed in hepatocytes and enterocytes by conducting uptake experiments using (i) transfected HEK293T cells, (ii) the hepatocyte-like HepaRG cell line and (iii) the enterocyte-like Caco-2 cell line. Sirolimus and everolimus inhibited in a dose-dependent manner the uptake of [3H]-estrone sulphate by OATP1A2 and OATP1B1 and that of mycophenolic acid 7-O-glucuronide (MPAG) by OATP1B3. ImTOR apparent 50% inhibitory concentrations (IC50) for OATPs were 11.9 uM (OATP1A2), 9.8 uM (OATP1B1) and 1.3 uM (OATP1B3) for sirolimus and 4.2 uM (OATP1A2), 4.1 uM (OATP1B1) and 4.3 uM (OATP1B3) for everolimus. No transport of sirolimus or everolimus by OATP1A2, OATP1B1 or OATP1B3 was observed in HEK-transfected cells and the OAT/OATP/MRP chemical inhibitor probenecid did not significantly decrease the uptake of sirolimus and everolimus in HepaRG and Caco-2 cells, but tended to increase their intracellular accumulation presumably through efflux inhibition. In conclusion, our data suggest that the major OATP transporters expressed in the liver and the intestine do not contribute to the pharmacokinetics of sirolimus and everolimus. However, ImTORs are inhibitors of these transporters. PMID- 21524192 TI - A method to enhance student teams in palliative care: piloting the McMaster Ottawa Team Observed Structured Clinical Encounter. AB - BACKGROUND: The need for palliative and end-of-life care (PEOLC) education in prelicensure education has been identified. PEOLC requires effective collaborative teamwork. The competencies required for effective collaborative teamwork are only now emerging and methods to evaluate them must be developed. OBJECTIVE: The adaptation of the traditional Objective Structured Clinical Examination (OSCE) for assessment of a student team addressing palliative care issues was undertaken. The McMaster-Ottawa Team Observed Structured Clinical Encounter (TOSCE) is intended as a formative evaluation tool for both competencies in interprofessional collaboration for patient-centered practice and PEOLC. METHODS: Three stations based on palliative care scenarios were developed. From January 2007 to January 2008, a total of 141 students and 38 observers participated in the evaluation of three stations, with 6-7 students per group and two observers per station. Observers completed checklists for both PEOLC and interprofessional collaborative competencies and, after completing the TOSCEs, students and observers completed questionnaires on their feasibility and acceptability. RESULTS: Eighty-nine percent of the students and 44% of the observers were from medicine. Students and observers found the TOSCE to be an acceptable and feasible assessment tool for both sets of competencies. Reliability and validity data show that the items in both the clinical and interprofessional checklists fit well together, and interrater reliability is readily achieved. CONCLUSIONS: The new formative evaluation TOSCE tool, adapted from the traditional OSCE, was acceptable and feasible to students and observers. PMID- 21524193 TI - Timing of stage II lactogenesis is predicted by antenatal metabolic health in a cohort of primiparas. AB - BACKGROUND: Time to onset of stage II lactogenesis varies widely, and delayed onset of lactogenesis (OL) is common among first-time mothers in the United States. Higher body mass index, older age, and larger infant birth weight are identified risk factors for delayed OL; all are known correlates with glucose metabolism. Our objective was to prenatally assess maternal biomarkers related to metabolic health and determine the extent to which these biomarkers predict timing of OL. METHODS: We enrolled a population-based sample of expectant primiparas attending a single prenatal clinic. We obtained a blood sample 1-hour post-glucose load from an antenatal oral glucose challenge test and assayed for the following biomarkers: serum insulin, glucose, adiponectin, leptin, C-reactive protein, interleukin-6, resistin, and tumor necrosis factor-alpha. Our outcome measure was timing of OL, based on maternal report at 3-5 days postpartum. We used linear regression to model OL hour. RESULTS: Twenty-six of 29 (90%) agreed to screening, 18 delivered at term and initiated breastfeeding, and 16 have complete data. Median (minimum-maximum) postpartum body mass index was 27.4 (21.8 34.7) kg/m(2), and median time to OL was 64 (10-121) hours. The model, OL = 232 - 34.9(ln[ratio insulin/glucose]) - 1.4(adiponectin), explained 56% of the variation in OL hour (p = 0.005) and was not weakened by potential confounders. CONCLUSIONS: Higher serum insulin secretion relative to serum glucose after a glucose challenge and higher serum adiponectin are associated with earlier onset of OL. These findings suggest that factors associated with better glucose tolerance predict earlier OL. PMID- 21524195 TI - Differentiation of Campylobacter species by surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry. AB - The genus Campylobacter contains several, widespread pathogens causing food-borne diseases of zoonotic nature in humans. In case of outbreaks, the differentiation of closely related Campylobacter is essential for epidemiological studies, which investigate the routes of geographical spread and ways of transmission. Recent advances in mass spectrometry (MS) have shown that matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) MS is a valuable tool for speciation of bacteria such as Campylobacter. Surface-enhanced laser desorption/ionization (SELDI)-TOF-MS is a specific MALDI-TOF application that combines a chip-based chromatographic enrichment of proteins with TOF-MS. This pilot study aims at investigating for the first time whether SELDI-TOF-MS can be applied for discrimination of Campylobacter at the level of species and even strains. Campylobacter type-strains and isolates from different regions were cultured and subsequently subjected to physicochemical lysis. Protein lysates were then applied on CM10 and IMAC30 ProteinChip Array surfaces and analyzed using a PCS 4000 SELDI Protein Chip System (Bio-Rad Laboratories). By comparison of the spectra from Campylobacter jejuni, Campylobacter coli, Campylobacter upsaliensis, and Campylobacter lari, 166 and 160 different protein peaks were observed (p<0.05) using CM10 and IMAC30 chips, respectively. Development of classification trees, comprising 2-4 of these peaks, allows for discrimination of different Campylobacter species and even strains. Moreover, species and strains can be sufficiently separated from each other by hierarchical cluster analysis. Thus, SELDI-TOF-MS is a promising tool to differentiate Campylobacter species and even strains. Species/strain-specific ions observed in addition to well established markers identified by MALDI-TOF might be of value for future Campylobacter-identifying algorithms. To further clarify the potential advantages of this method, our results have to be validated against several independent test datasets of, preferably, a multitude of prospectively collected different isolates and compared with other typing techniques. PMID- 21524194 TI - Besnoitiosis in a southern plains woodrat (Neotoma micropus) from Uvalde, Texas. AB - Recently, Besnoitia neotomofelis was described from a southern plains woodrat (Neotoma micropus) from southern Texas. During May 2010, 1 of 55 southern plains woodrats trapped in Uvalde County, Texas, was diagnosed with besnoitiosis. Grossly, the woodrat had bilateral swellings of the cheeks, and numerous Besnoitia sp.-like cysts were observed in the tongue, facial region, musculature of the limbs, and subcutis of the dorsum and flanks. Little to no inflammation was noted around cysts. The cysts were morphologically similar to B. neotomofelis based on light and transmission electron microcopy. The sequence of the internal transcribed spacer region-1 was identical to the type isolate of B. neotomofelis. Attempts to isolate Besnoitia sp. in laboratory mice failed; however, Toxoplasma gondii was isolated in a Swiss Webster mouse. This represents the first report of besnoitiosis caused by B. neotomofelis in a southern plains woodrat and the first concurrent Besnoitia sp. and T. gondii infection in any host species. PMID- 21524196 TI - In vitro potentiation of ampicillin, oxacillin, norfloxacin, ciprofloxacin, and vancomycin by sanguinarine against methicillin-resistant Staphylococcus aureus. AB - Few new drugs are available against methicillin-resistant Staphylococcus aureus (MRSA), because MRSA has the ability to acquire resistance to most antibiotics, which consequently increases the cost of medication. The objective of this study is to evaluate the potentiation of sanguinarine (SN) with selected antibiotics (ampicillin [AC], oxacillin [OX], norfloxacin [NR], ciprofloxacin [CP], and vancomycin [VC]) against MRSA. Minimum inhibitory concentration was determined by using the broth microdilution method and the synergistic effect of AC, OX, NR, CP, and VC in combination with SN was examined by the checkerboard dilution test. The results of the checkerboard test suggested that all combinations exhibited some synergy, partial synergy, or additivity. None of the combinations showed an antagonism effect. The combination of SN plus CP exhibited maximum synergistic effect in 11/13 strains, followed by SN plus NR in 9/13 strains, and AC and OX in 7/13 strains each. The combination of SN with VC, however, mostly showed partial synergy in 11/13 strains. The time-kill assay showed that SN in combination with other antibiotics reduced the bacterial count by 10(2)-10(3) colony forming units after 4 h and to less than the lowest detectable limit after 24 h. Although in vivo synergy and clinical efficacy of SN cannot be predicted, it can be concluded that SN has the potential to restore the effectiveness of the selected antibiotics, and it can be considered in an alternative MRSA treatment. PMID- 21524197 TI - Evaluation of commercial grated cheese in the central region of Brazil for microbiological quality and safety. AB - This study aims to further the scientific understanding of the microbial quality and safety of grated cheese. Samples of grated cheese product (n = 20) were obtained from markets in the central region of Brazil and submitted to microbiological analysis using conventional and alternative (PetrifilmTM and RIDA((r)) plates) methodologies. Based only on the criteria from the Brazilian Health Ministry, all samples were considered adequate for consumption. However, most samples presented foreign substances and high levels of contamination by other hygiene indicator microorganisms, indicating failures in processing and possible risks to consumers. Despite the hygienic quality of the samples, the obtained results showed good correlation indexes and similarities between the conventional and the alternative methodologies, indicating their viability for the quality control of grated cheese. PMID- 21524198 TI - Reviews on trichinellosis (IV): hepatic involvement. AB - Trichinella sp. larvae are released from the intestine and usually migrate through the liver into the general circulation. Nevertheless, hepatic involvement does not represent a leading feature of human trichinellosis. This narrative systematic review focuses exclusively on hepatic complications of trichinellosis and includes a brief overview and analysis of selected cases reported in the literature. Our major goals were to gather important data to understand the substrate of trichinous liver injury and to provide helpful clinical hints for practitioners. To our knowledge, this is the first international review dedicated to this topic. Thirty two cases were detailed enough to allow pooled analysis. The mean age of the analyzed group was 30.5+/-17 years old with most cases aged 19 to 29 years (29%). Hepatomegaly was noticed in 34.4% of cases, hypoalbuminemia in 40.6%, and hypoproteinemia in 34.4%. Our systematic analyses demonstrated that hepatic complications were mainly evidenced in fatal cases of trichinellosis (65.6%). The most frequent necroptic findings were parenchymatous and/or fatty degeneration of the liver (59.4%). Although less discussed in the literature than other complications, hepatic involvement should be considered more carefully because of its significant consequences on protein metabolism and liver function. Difficult to be revealed intra vitam, hepatic involvement may represent an additional concern to the classical clinical picture of trichinellosis and other life-threatening complications, especially in severe cases of infection. Consequently, physicians should be aware of any possible liver involvement to ensure adequate management of their patients. PMID- 21524199 TI - Laparoendoscopic single-site nephrectomy for single-system ectopic ureters with dysplastic kidneys in children: early experience. AB - BACKGROUND AND AIM: Single-system ectopic ureter with dysplastic kidney is a rare urologic anomaly. We report our early experience in 4 children who underwent laparoendoscopic single-site (LESS) nephrectomy for single-system ectopic ureters with dysplastic kidney. PATIENTS AND METHODS: We diagnosed 4 consecutive children (aged 18-59 months; mean: 3.2 years) with single-system ectopic ureter with dysplastic kidney. A single, experienced surgeon performed LESS nephrectomy using a homemade single-port device in all patients. RESULTS: LESS nephrectomy was completed successfully in all 4 patients without complications, insertion of an additional port, or open conversion. Blood loss was minimal. Mean operation time was 83.3 minutes (range: 55-125 minutes), and patients began oral intake on the first postoperative day. Mean postoperative hospital stay was 1.3 days (range: 1 2 days). Urine dribbling and wetting resolved immediately after surgery, and no patient has developed a urinary tract infection to date. CONCLUSIONS: LESS nephrectomy for an ectopic ureter with dysplastic kidney is a safe and feasible method with better cosmesis, compared with classic nephrectomy. LESS nephrectomy is a promising method in pediatrics. PMID- 21524200 TI - Preliminary experience and development of an algorithm for the optimal use of the laparoscopic component separation technique for myofascial advancement during ventral incisional hernia repair. AB - BACKGROUND: Component separation technique (CST) enables rectus abdominus medialization, but may cause wound complications. Few published outcomes exist involving laparoscopic CST. Our aim was to examine feasibility and outcomes involving open and laparoscopic (lap) CST during ventral incisional hernia repair (VIHR) and present an algorithm for ventral herniorrhaphy. STUDY DESIGN: Our design was a retrospective cohort study. Over 22 months, 28 patients underwent one of the following: (i) unilateral (U-) lap CST with open VIHR [n = 5], (ii) bilateral (B-) lap CST with open VIHR [n = 7], (iii) B-lap CST with lap VIHR [n = 8], or (iv) B-open CST with open VIHR [n = 8]. Indications for open VIHR included mesh removal, concomitant visceral procedure, wound revision, thin/ulcerated skin, abdominal wall tumor, frozen abdomen, and/or off-midline hernia. During open VIHR, CST was performed in the Ramirez fashion. Lap CST was performed before intraperitoneal access in lap VIHR and after retrorectus dissection in open VIHR. Patient surveillance consisted of clinical encounters and telephone interviews. RESULTS: Groups were similar regarding age, body mass index, American Society of Anesthesiologists classification, hernia width, operative time, and hospital stay. Six of the 20 patients who underwent open VIHR developed wound complications, and two required early reoperation. Four of the six with concomitant visceral procedures had wound complications. No laparoscopic VIHR patients had a wound complication. Based on 11 months' follow-up, one open VIHR patient has concern for recurrence. CONCLUSIONS: Laparoscopic CST is feasible during open and laparoscopic VIHR, but it appears most beneficial for wound healing after laparoscopic VIHR. During open VIHR, laparoscopic CST may not substantially reduce wound complications. PMID- 21524201 TI - Rural adults' use of health-related information online: data from a 2006 National Online Health Survey. AB - OBJECTIVE: The objective of this study was to examine access and use of health related information online in rural versus nonrural Internet users, using national data from the 2006 Pew Internet and American Life Project. MATERIALS AND METHODS: A national telephone survey of 2,928 adults in August 2006 yielded a sample of 1,992 adults who use the Internet regularly. A structured interview was administered to assess frequency of Internet use and access and use of health related information online. RESULTS: Most Internet-using rural adults search for health-related information online; two-thirds seek information about specific medical problems and over half seek information about treatment. Three-fifths of rural adults surveyed stated that online health-related information affected the decisions they made in health maintenance and managing treatment of an illness. More than one-third reported being significantly helped by information they found, whereas one-fourth reported being confused. Comparisons between rural and nonrural Internet users suggested that rural users were more likely to seek information about smoking cessation (chi(2)[1, N=1,990]=7.91, p<0.01) and mental health issues (chi(2)[1, N=1,988]=3.71, p=0.05), less likely to seek information about a particular doctor or hospital (chi(2)[1, N=1,983]=15.49, p<0.001), and more likely to report being helped (chi(2)[1, N=1,534]=5.24, p<0.05)-but also confused (chi(2)[1, N=1,592]=9.83, p<0.01)-by information they found. CONCLUSIONS: Rural Americans are increasingly using the Internet to acquire information about chronic disease, mental health, doctors, and treatment options. Priorities should include further development and rigorous evaluation of online resources to ensure high-quality, more direct tailoring of resources to rural families and development of tools to assist consumers in assessing the credibility of online information. PMID- 21524202 TI - Religiosity and sexual risk behaviors among Latina adolescents: trends from 1995 to 2008. AB - PURPOSE: The purpose of this study was to determine trends in the influence of religiosity on sexual activity of Latina adolescents in the United States from 1995 to 2008 and to determine if differences existed between the Mexican American and other Latina groups. METHODS: The sample comprised the subset of unmarried, 15-21-year-old (mean 17 years) Latina female respondents in the 1995 (n=267), 2002 (n=306), and 2006-2008 (n=400) National Survey of Family Growth (NSFG) datasets. Associations between religiosity (importance of religion and service attendance) and history of ever having sex, number of sex partners, and age of sexual debut were investigated. RESULTS: Less than one half of Latinas in 1995 (44%) and in 2006-2008 (44%) reported that religion was very important to them, whereas in 2002, 50% reported it was important. Only in 1995 did Latinas who viewed religion as very important have a significantly lower level of sexual initiation. In 1995 and in 2006-2008, Latinas who held religion as very important had significantly fewer partners. In all three cohorts, the higher religious importance group had higher virgin survival rates. Across cohorts, approximately one third of respondents reported frequent religious attendance. In all cohorts, frequent attenders were less likely to have had sex, had fewer partners, and had older age at sexual debut. The survival rate as virgins for Mexican origin Latinas was higher in 1995 and 2002 compared to non-Mexican Latinas but was almost the same in 2006-2008. CONCLUSIONS: Religiosity had a protective association with sexual activity among Latina adolescents. The association of importance of religion with sexual activity has diminished from 1995 to 2008, however, whereas the importance of service attendance has remained stable. The influence of religion was more apparent among the Latinas of Mexican origin, but this greater influence also diminished by 2006-2008. PMID- 21524203 TI - Granulicatella adiacens bacteremia in an elderly trauma patient. AB - BACKGROUND: Granulicatella adiacens is a normal commensal of human mucosal surfaces, inhabiting the oral cavity and urogenital and gastrointestinal tracts and only rarely causing disease. These gram-positive cocci can be difficult to identify. CASE REPORT: We report a first case of bacteremia caused by Granulicatella adiacens in an elderly female trauma victim. The infection was diagnosed accurately, and the patient was treated successfully. CONCLUSION: Granulicatella adiacens may be a more important pathogen than thus far recognized because of a lack of adequate diagnostic resources. Standards for sensitivity testing are needed urgently. PMID- 21524204 TI - Prediction of serious infection during prehospital emergency care. AB - BACKGROUND: Regionalization of emergency care for patients with serious infections has the potential to improve outcomes, but is not feasible without accurate identification of patients in the prehospital environment. OBJECTIVE: To determine the incremental predictive value of provider judgment in addition to prehospital physiologic variables for identifying patients who have serious infections. METHODS: We conducted a prospective study at a single teaching tertiary-care emergency department (ED) where a convenience sample of emergency medical services (EMS) providers and ED clinicians completed a questionnaire about the same patients. Prehospital providers provided limited demographics and work history about themselves. They also reported the presence of abnormal prehospital physiology for each patient (heart rate >90 beats/min, systolic blood pressure <100 mmHg, respiratory rate >20 breaths/min, pulse oximetry <95%, history of fever, altered mental status) and their judgment about whether the patient had an infection. At the end of formal evaluation in the ED, the physician was asked to complete a survey describing the same patient factors in addition to patient disposition. The primary outcome of serious infection was defined as the presence of both 1) ED report of acute infection and 2) patient admission. We included prehospital factors associated with serious infection in the prediction models. Operating characteristics for various cutoffs and the area under the curve (AUC) were calculated and reported with 95% confidence intervals (95% CIs). RESULTS: Serious infection occurred in 32 (16%) of 199 patients transported by EMS, 50% of whom were septic, and 16% of whom were admitted to the intensive care unit. Prehospital systolic blood pressure <100 mmHg, EMS-elicited history or suspicion of fever, and prehospital judgment of infection were associated with primary outcome. Presence of any one of these resulted in a sensitivity of 0.59 (95% CI 0.40-0.76) and a specificity of 0.81 (95% CI 0.74 0.86). The AUC for the model was 0.71. CONCLUSIONS: Including prehospital provider impression to objective physiologic factors identified three more patients with infection at the cost of overtriaging five. Future research should determine the effect of training or diagnostic aids for improving the sensitivity of prehospital identification of patients with serious infection. PMID- 21524205 TI - Reduced mortality in injured adults transported by helicopter emergency medical services. AB - BACKGROUND: Some studies have shown improved outcomes with helicopter emergency medical services (HEMS) transport, while others have not. Safety concerns and cost have prompted reevaluation of the widespread use of HEMS. OBJECTIVE: To determine whether the mode of transport of trauma patients affects mortality. METHODS: Data for 56,744 injured adults aged >= 18 years transported to 62 U.S. trauma centers by helicopter or ground ambulance were obtained from the National Sample Program of the 2007 National Trauma Data Bank. In-hospital mortality was calculated for different demographic and injury severity groups. Adjusted odds ratios (AOR) were produced by utilizing a logistic regression model measuring the association of mortality and type of transport, controlling for age, gender, and injury severity (Injury Severity Score [ISS] and Revised Trauma Score [RTS]). RESULTS: The odds of death were 39% lower in those transported by HEMS compared with those transported by ground ambulance (AOR = 0.61, 95% confidence interval [CI] = 0.54-0.69). Among those aged >= 55 years, the odds of death were not significantly different (AOR = 0.92, 95% CI = 0.74-1.13). Among all transports, male patients had a higher odds of death (AOR = 1.23, 95% CI = 1.10-1.38) than female patients. The odds of death increased with each year of age (AOR = 1.040, 95% CI = 1.037-1.043) and each unit of ISS (AOR = 1.080, 95% CI = 1.075-1.084), and decreased with each unit of RTS (AOR = 0.46, 95% CI = 0.45-0.48). CONCLUSION: The use of HEMS for the transport of adult trauma patients was associated with reduced mortality for patients aged 18-54 years. In this study, HEMS did not improve mortality in adults aged >= 55 years. Identification of additional variables in the selection of those patients who will benefit from HEMS transport is expected to enhance this reduction in mortality. PMID- 21524206 TI - Multidrug-resistant pathogens and pneumonia: comparing the trauma and surgical intensive care units. AB - BACKGROUND: As acute care surgery evolves, more trauma surgeons are caring for critically ill general surgery as well as trauma patients. However, these two populations are unique, and infectious complications may need to be addressed differently, as the causative organisms may not be the same in the two groups. To study this, we evaluated ventilator-associated (VAP) and hospital-acquired (HAP) pneumonia in the trauma (TICU) and general surgical (SICU) intensive care units to investigate differences in the causative pathogens. Our hypothesis was that SICU patients would have a higher incidence of multi-drug-resistant (MDR) organisms causing VAP/HAP, possibly contributing to inadequate empiric antibiotic (IEA) coverage. METHODS: Retrospective review of 116 patients admitted with VAP or HAP over a one-year period to the TICU (n = 72) or SICU (n = 44) at a tertiary medical center. Culture was followed by initiation of empiric antibiotics on the basis of an antibiotic algorithm derived from trauma patients. Demographics, illness, and pneumonia characteristics were assessed; MDR organisms were identified. RESULTS: Multi-drug-resistant organisms caused 30.6% of first pneumonias in the TICU vs. 65.9% in the SICU (p = 0.0002). Subsequent pneumonias were seen in 31.8% of SICU patients and 16.7% of TICU patients (p = 0.0576). Inadequate empiric antibiotic coverage was documented in 38.6% of SICU pneumonias vs. 26.4% in the TICU (p = 0.12). CONCLUSIONS: Multiply-resistant pathogens cause a significantly greater number of VAP/HAPs in the SICU than in the TICU. Associated with this, when using an antibiotic algorithm based on TICU bacterial pathogens, there is a trend toward a greater likelihood of subsequent pneumonias and toward more IEA coverage in the SICU population compared with TICU patients. Our results indicate that these distinct patient populations have different pathogens causing VAP/HAP and affirm the necessity for population-specific algorithms to tailor empiric coverage for presumed VAP/HAP. PMID- 21524207 TI - Reforming Medicare--toward a modified Ryan plan. PMID- 21524208 TI - Prescriptions, privacy, and the First Amendment. PMID- 21524209 TI - Consensus and conflict in health system reform--the Republican budget plan and the ACA. PMID- 21524211 TI - Images in clinical medicine. Diversion stones. PMID- 21524210 TI - IRF8 mutations and human dendritic-cell immunodeficiency. AB - BACKGROUND: The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette Guerin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. METHODS: We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. RESULTS: We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. CONCLUSIONS: These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.). PMID- 21524212 TI - Our bulging medicine cabinets--the other side of medication nonadherence. PMID- 21524213 TI - Probable zoonotic leprosy in the southern United States. AB - BACKGROUND: In the southern region of the United States, such as in Louisiana and Texas, there are autochthonous cases of leprosy among native-born Americans with no history of foreign exposure. In the same region, as well as in Mexico, wild armadillos are infected with Mycobacterium leprae. METHODS: Whole-genome resequencing of M. leprae from one wild armadillo and three U.S. patients with leprosy revealed that the infective strains were essentially identical. Comparative genomic analysis of these strains and M. leprae strains from Asia and Brazil identified 51 single-nucleotide polymorphisms and an 11-bp insertion deletion. We genotyped these polymorphic sites, in combination with 10 variable number tandem repeats, in M. leprae strains obtained from 33 wild armadillos from five southern states, 50 U.S. outpatients seen at a clinic in Louisiana, and 64 Venezuelan patients, as well as in four foreign reference strains. RESULTS: The M. leprae genotype of patients with foreign exposure generally reflected their country of origin or travel history. However, a unique M. leprae genotype (3I-2 v1) was found in 28 of the 33 wild armadillos and 25 of the 39 U.S. patients who resided in areas where exposure to armadillo-borne M. leprae was possible. This genotype has not been reported elsewhere in the world. CONCLUSIONS: Wild armadillos and many patients with leprosy in the southern United States are infected with the same strain of M. leprae. Armadillos are a large natural reservoir for M. leprae, and leprosy may be a zoonosis in the region. (Funded by the National Institute of Allergy and Infectious Diseases and others.). PMID- 21524214 TI - Clinical practice. Vertebral fractures. PMID- 21524215 TI - Inherited cardiomyopathies. PMID- 21524216 TI - Images in clinical medicine. Tuberculoid leprosy. PMID- 21524217 TI - Case records of the Massachusetts General Hospital. Case 13-2011. A 49-year-old man with adenocarcinoma of the rectum. PMID- 21524218 TI - Cardiac arrest in public versus at home. PMID- 21524219 TI - Cardiac arrest in public versus at home. PMID- 21524220 TI - Cardiac arrest in public versus at home. PMID- 21524222 TI - Chronic thromboembolic pulmonary hypertension. PMID- 21524223 TI - Chronic thromboembolic pulmonary hypertension. PMID- 21524224 TI - Chronic thromboembolic pulmonary hypertension. PMID- 21524226 TI - Calcitonin administration in X-linked hypophosphatemia. PMID- 21524227 TI - Increased 36-week survival with high oxygen saturation target in extremely preterm infants. PMID- 21524232 TI - High-risk pools--merely a stopgap reform. PMID- 21524233 TI - Anesthesiologist assistance in endoscopic retrograde cholangiopancreatography procedures in the elderly: is it worthwhile? AB - BACKGROUND: Anesthesiologists provide sedation of the patients for mini-invasive procedures such as endoscopic retrograde cholangiopancreatography (ERCP) at many institutions at present, particularly for the elderly. The purpose of the present study was to define the safety of sedation and the tolerance of ERCP procedures in the extremely elderly patients at our institution, in which sedation is provided and controlled by endo team only. METHODS: Forty-one ERCP procedures were performed in patients aged 90 years or older. All patients had chronic concomitant diseases, and 88% of the patients belonged to American Society of Anesthesiologists group IV. The patients were sedated with midazolam, and 7 out of 41 patients received fentanyl. RESULTS: All ERCP procedures except one could be successfully completed, indicating good tolerance in 98% of the patients. There were neither sedation-related complications nor procedural mortality. In none of the cases, anesthesiologist assistance was needed. CONCLUSIONS: Routine anesthesiological assistance in ERCP procedures in the elderly seems unnecessary. PMID- 21524234 TI - Analysis of the alternative splicing of an FGFR2 transcript due to a novel 5' splice site mutation (1084+1G>A): case report. AB - Craniosynostosis is characterized by premature fusion of one or more cranial sutures and is associated with mutations in fibroblast growth factor receptor (FGFR) genes. Here we describe a novel mutation (1084+1G>A) in the FGFR2 gene of a patient with isolated bicoronal synostosis. We detected two isoforms that result from the mutation and are characterized, respectively, by exon skipping and the use of a cryptic splice site. Interestingly, the alternatively spliced forms of FGFR2 appear to induce fusion of the cranial sutures suggesting that the mutation acts via a gain-of-function mechanism rather than a loss of protein functionality. PMID- 21524235 TI - Significant genetic heterogeneity of the SIVmac251 viral swarm derived from different sources. AB - Infecting rhesus macaques (Macaca mulatta) with the simian immunodeficiency virus (SIV) is an established animal model of human immunodeficiency virus (HIV) pathogenesis. Many studies have used various derivatives of the SIVmac251 viral swarm to investigate several aspects of the disease, including transmission, progression, response to vaccination, and SIV/HIV-associated neurological disorders. However, the lack of standardization of the infecting inoculum complicates comparative analyses. We investigated the genetic diversity and phylogenetic relationships of the 1991 animal-titered SIVmac251 swarm, the peripheral blood mononuclear cell (PBMC) passaged SIVmac251, and additional SIVmac251 sequences derived over the past 20 years. Significant sequence divergence and diversity were evident among the different viral sources. This finding highlights the importance of characterizing the exact source and genetic makeup of the infecting inoculum to achieve controlled experimental conditions and enable meaningful comparisons across studies. PMID- 21524236 TI - Cough pharmacotherapy: current and future status. AB - INTRODUCTION: Chronic cough is responsible for a significant illness burden in the community. Refractory cough causes substantial quality-of-life impairment in people with this problem. Neuromodulators for sensory neuropathic cough and new compounds to block transient receptor potential (TRP) receptors hold promise for chronic cough and upper airway hypersensitivity. AREAS COVERED: The authors examine current evidence on the new concepts of chronic cough that relate to the study of idiopathic/refractory cough, the role of central nervous system control of cough and the role of laryngeal irritability and sensory neuropathy in cough. Compounds in development to block TRP receptors, treatment for a neuropathic disorder with neuromodulators and cough suppression with opioids, especially codeine and morphine, are investigated. Relevant randomized control trials and case reports were identified through a PubMed search of English-language literature referring to these concepts. EXPERT OPINION: The concept that sensory neuropathic disorder may underlie some cases of chronic cough is useful in characterizing cough, understanding its mechanisms and guiding drug development. PMID- 21524237 TI - Vinflunine: drug safety evaluation of this novel synthetic vinca alkaloid. AB - INTRODUCTION: Vinca alkaloid agents have been widely used in several different types of malignancies. However, cancer cells, ultimately, develop resistance to these agents. Therefore, the development of new agents with improved efficacy is warranted. Recently, a new synthetic vinca alkaloid, vinflunine, was developed through the addition of two fluor molecules by superacidic chemistry. AREAS COVERED: The authors describe the development of the new vinca alkaloid vinflunine from preclinical studies to the late-stage clinical trials, highlighting the most important clinical and safety data of vinflunine. In vitro and in vivo studies have shown a superior efficacy of vinflunine over other vinca alkaloids and with an improved safety profile. Early clinical trials have demonstrated a significant activity of vinflunine against different malignancies. Phase III trials showed that vinflunine increases survival in patients with advanced transitional cell carcinoma of the urothelium (TCCU) tract treated in the second-line and is as effective as docetaxel in second-line NSCLC. EXPERT OPINION: Vinflunine is currently approved in Europe for the treatment of second line TCCU and is currently being developed in other malignancies. It has been shown to have predictable and manageable adverse effects, such as neutropenia, anemia, constipation and fatigue. PMID- 21524238 TI - Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials. AB - OBJECTIVE: To demonstrate that a fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg has comparable efficacy to celecoxib for knee osteoarthritis. RESEARCH DESIGN AND METHODS: Two randomized, double-blind, parallel-group, placebo-controlled, multicenter phase III studies (PN400-307 and PN400-309) enrolled patients aged >=50 years with symptomatic knee osteoarthritis. Following an osteoarthritis flare, patients received naproxen/esomeprazole magnesium twice daily, celecoxib 200 mg once daily, or placebo for 12 weeks. CLINICAL TRIAL REGISTRATION: NCT00664560 and NCT00665431. MAIN OUTCOME MEASURES: Three co-primary efficacy endpoints were mean change from baseline to week 12 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain and function subscales, and Patient Global Assessment of osteoarthritis using a visual analog scale (PGA-VAS). RESULTS: In Study 307, 619 patients were randomized and 614 treated. In Study 309, 615 patients were randomized and 610 treated. Both naproxen/esomeprazole magnesium and celecoxib were associated with improvements (least squares mean change from baseline to week 12) in WOMAC pain (Study 307: -42.0 and -41.8, respectively; Study 309: 44.2 and -42.9, respectively), WOMAC function (Study 307: -36.4 and -36.3, respectively; Study 309: -38.9 and -36.8, respectively), and PGA-VAS (Study 307: 21.2 and 21.6, respectively; Study 309: 29.0 and 25.6, respectively). A prespecified non-inferiority margin of 10 mm between naproxen/esomeprazole magnesium and celecoxib was satisfied for each co-primary endpoint at week 12 in both studies. Significant improvements were observed with naproxen/esomeprazole magnesium versus placebo in both studies (p < 0.05). Celecoxib was significantly different from placebo in Study 307 (p < 0.05); however, the improvements were not significant in Study 309. Acetaminophen use and patient expectation of receiving active treatment (80% probability) may have contributed to a high placebo response observed. CONCLUSIONS: Naproxen/esomeprazole magnesium has comparable efficacy to celecoxib for the management of pain associated with osteoarthritis of the knee over 12 weeks. PMID- 21524239 TI - Comparative efficacy of nilotinib and dasatinib in newly diagnosed chronic myeloid leukemia: a matching-adjusted indirect comparison of randomized trials. AB - OBJECTIVE: Nilotinib and dasatinib have not been directly compared in a randomized trial for the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP). The purpose of this study was to indirectly compare rates of major molecular response (MMR), progression-free survival (PFS) and overall survival by month 12 with nilotinib and dasatinib treatment of newly diagnosed CML-CP. METHODS: Individual patient data from a randomized trial of nilotinib vs. imatinib (ENESTnd) and published summary data from a separate randomized trial of dasatinib vs. imatinib (DASISION) were utilized. A matching adjusted indirect comparison was conducted by weighting individual patients treated with nilotinib to match baseline characteristics reported for dasatinib treated patients, including age, gender, ECOG performance status and hematology lab values. After matching, efficacy outcomes were compared for patients treated with nilotinib 300 mg twice daily vs. dasatinib 100 mg once daily. Patients randomized to imatinib 400 mg once daily in each trial were used to assess the adequacy of the matching. RESULTS: Before matching, patients randomized to nilotinib in ENESTnd (n = 273) were older, with a lower median platelet count and more favorable performance status compared to patients randomized to dasatinib in DASISION (n = 259). After matching, all baseline characteristics were balanced across treatment groups. Matched patients treated with nilotinib vs. dasatinib experienced significantly higher rates of MMR (56.8 vs. 45.9%, p = 0.014) and overall survival (99.5 vs. 97.3%, p = 0.046) and numerically higher rates of PFS (98.8 vs. 96.5%). Matched imatinib arms showed no statistically significant or clinically meaningful differences in these outcomes. LIMITATIONS: Baseline measures unavailable in one or both trials could not be matched. Adverse event rates were not formally compared across trials due to differences in reporting. CONCLUSION: Nilotinib was associated with significantly higher rates of MMR and overall survival compared with dasatinib by month 12 in the treatment of newly diagnosed CML-CP. PMID- 21524240 TI - Ultrasound enhanced antitumor activity of liposomal doxorubicin in mice. AB - Liposomal encapsulation of doxorubicin (DXR) improves tumor accumulation and reduces adverse effects. One possible strategy for further optimization of this delivery technology would be to design the liposome carrier to release its content within the tumor tissue in response to specific stimuli such as ultrasound (US). In this study, the tumor uptake properties and therapeutic efficacy of 1,2 distearoyl-sn-glycero-3-phosphatidylethanolamine-based liposomes containing DXR were investigated in nude mice bearing tumor xenografts. The liposomal DXR formulation alone showed no inhibitory effect on tumor growth. However, upon exposure to low frequency US in situ inhibition of tumor growth was demonstrated. PMID- 21524241 TI - A comparison of traditional and computer-aided bracket placement methods. AB - OBJECTIVE: To test the hypothesis that there is no difference in the accuracy of bracket placement produced by OrthoCAD iQ indirect bonding (IDB) and that of an in-house fabricated IDB system by measuring the quality of intra-arch dental alignment at the end of simulated orthodontic treatment. MATERIALS AND METHODS: Twenty-eight artificial teeth were arranged to resemble a typical preorthodontic malocclusion. Forty-six sets of models were duplicated from the original malocclusion and randomly divided into two sample groups. Half of the models had their bracket positions selected by OrthoCAD, while the others were completed by a combination of faculty and residents in a university orthodontic department. Indirect bonding trays were fabricated for each sample and the brackets were transferred back to the original malocclusion following typical bonding protocol. The individual teeth were ligated on a .021 * .025-inch stainless steel archwire to simulate their posttreatment positions. The two sample groups were compared using the objective grading system (OGS) originally designed by the American Board of Orthodontics. RESULTS: The mean total OGS score for the OrthoCAD sample group was 39.25 points, while the traditional IDB technique scored 41.00 points. No statistical difference was found between total scores or any of the four components evaluated. Similar ranges of scores were observed, with the OrthoCAD group scoring from 30 to 52 points and the traditional IDB group scoring from 33 to 53 points. CONCLUSIONS: The hypothesis is not accepted. OrthoCAD iQ does not currently offer a system that can position orthodontic brackets better or more reliably than traditional indirect bonding techniques. PMID- 21524242 TI - Three-dimensional analysis of pharyngeal airway form in children with anteroposterior facial patterns. AB - OBJECTIVE: To test the null hypothesis that the form and size of the pharyngeal airways in preadolescents do not differ among various skeletal patterns. MATERIALS AND METHODS: Sixty healthy children (mean age, 11.79 +/- 1.11 years) were divided into three groups by anteroposterior jaw relationships. Using cone beam computed tomography, the inclination and the volume of the pharyngeal airway were measured and compared with craniocervical angles and cephalometric variables. RESULTS: Children with Class II malocclusion have a larger angle between the FH plane and midplane of the oropharyngeal airway (ang-OA) compared with children with Class I and III malocclusion (P < .01). Ang-OA was significantly correlated with craniocervical angle (ang-cc) and anteroposterior variables, mainly ANB angle, Pog-N perpendicular (P < .01). Airway volume had a positive correlation with facial depth (P < .01). CONCLUSION: Children with Class II malocclusion have more backward orientation and smaller volume of the pharyngeal airway than do children with Class I and III malocclusion. Inclination of the oropharyngeal airway might be a key factor in determining the form of the entire pharyngeal airway and is related to head posture. PMID- 21524243 TI - Resveratrol and its analogues: promising antitumor agents. AB - Resveratrol, a well-known natural product and a major component in grape, has attracted considerable attention as one of the most promising cancer during the past decade. Many studies have established that resveratrol can exert a broad range of biological activities including ceramide-mediated proapoptotic, antineoplastic, apoptosis-inducing, etc. Most important, resveratrol has been identified as an effective candidate for cancer chemoprevention based on its striking inhibitory effects on cellular events associated with cancer initiation, promotion, and progression. This review describes the general properties of resveratrol and its potential effect against cancer including its evidences as an antitumor agent in vitro, in vivo and clinically. In addition, we also summarized the structure-activity relationship of resveratrol and its analogues regarding the antitumor effects. PMID- 21524244 TI - Medical treatment of primary, secondary, and tertiary hyperparathyroidism. AB - Hyperparathyroidism is a condition with elevated parathyroid hormone (PTH). The increase may be due to a) primary hyperparathyroidism which is caused by adenoma of one or more parathyroid glands or hyperplasia of all four glands, b) secondary hyperparathyroidism, which may be caused by deficiency in vitamin D or uremia, and 3) tertiary hyperparathyroidism, which most often is the result of a long standing, severe secondary hyperparathyroidism, which has turned autonomous once the cause of the secondary hyperparathyroidism has been removed. Many new treatment options have been introduced in recent years. Cinacalcet is calcium sensing receptor agonist, which by stimulating the receptor decreases PTH and calcium levels. It may be used in primary hyperparathyroidism, secondary hyperparathyroidism caused by uremia, which may not be controlled with calcium and activated vitamin D. It may also be used in tertiary hyperparathyroidism. Newer analogues of vitamin D such as paricalcitol have also been introduced, which may have an advantage over traditional compounds such as alphacalcidol and calcitriol. PMID- 21524245 TI - Vitamin D treatment in primary hyperparathyroidism. AB - BACKGROUND: Primary hyperparathyroidism (PHPT) and vitamin D insufficiency are two very frequent conditions. In cases where the combination of both vitamin D insufficiency and PHPT is diagnosed, vitamin D repletion is an option. However, only limited evidence exists for this treatment. OBJECTIVE: The aim of this review is to describe different aspects of concomitant vitamin D insufficiency and PHPT and in this setting to evaluate existing evidence on safety and possible outcome of vitamin D treatment. METHODS: Background literature was found based on a search in pubmed.com and scirus.com. RESULTS: Multiple association studies support the hypothesis that the clinical presentation of PHPT is more severe in patients with vitamin D insufficiency. Treatment with vitamin D in PHPT may decrease PTH levels and bone turnover and potentially increase bone mass in various compartments. However, some patients experience increasing plasma or urine levels of calcium, triggering either vitamin D withdrawal or surgery. CONCLUSION: Measurement of vitamin D in PHPT is important to fully assess the disorder. The causality of the frequent coexistence of vitamin D insufficiency and PHPT is not fully understood. Vitamin D treatment is recommended and may decrease PTH levels in PHPT. However, there is no randomized controlled trial to prove any beneficial effect. For safety reasons, it is recommended to monitor plasma and urinary calcium during treatment. Furthermore, the effect of vitamin D repletion on other outcomes like quality of life, muscle function and CNS symptoms should be assessed. PMID- 21524246 TI - PTH treatment in hypoparathyroidism. AB - Hypoparathyroidism (HypoPT) is one of the few major hormone deficiency diseases that are not usually treated with the missing hormone. Bovine parathyroid hormone (PTH) has been purified and used as experimental treatment, as long back as in 1928 by Fuller Albright. Treatment, however, was abolished mainly because of antibody formation and costs. The recent approval of fully humanized truncated parathyroid hormone (Teriparatide, PTH (1-34)) and intact parathyroid hormone (Preotact, PTH(1-84)) for treatment of osteoporosis, has made the PTH drugs more accessible and thereby made clinical trials with PTH treatment of HypoPT feasible. Resent clinical trials have shown that treatment with PTH (1-34) and PTH (1-84) can stabilize plasma calcium, normalize plasma phosphate and reduce urine excretion of calcium. Furthermore, it seems that some patients with hypoPT experience an improved quality of life when treated with PTH compared with conventional treatment with 1alpha-hydroxylated vitamin D metabolites and calcium supplements. PMID- 21524247 TI - New and emerging antiresorptive treatments in osteoporosis. AB - Bisphosphonates has for many years been the mainstay of antiresorptive treatment, acting predominantly by inducing apoptosis of mature osteoclasts. During recent years, an advanced understanding of the genetic and biological mechanism involved in bone resorption has revealed new therapeutic targets for antiresorptive treatments. Several of these new drugs act by targeting specific pathways within the osteoclastic cells and may reduce bone resorption without a concomitant decrease in bone formation. Such an uncoupling may result in a net bone formation, thereby causing a bone "anabolic" effect through an antiresorptive mechanism. Moreover, in contrast to e.g., bisphosphonates several of the new drugs are not deposited within bone and therefore their duration of action is related to their presence in plasma. Accordingly, their antiresorptive effect is quickly reversible, which may be of advantages if reversal of a suppressed bone turnover is warranted under certain clinical conditions such as osteonecrosis of the jaw. In this paper, we will review the pharmacological properties and clinical effects of drugs that recently have been (denosumab, bazedoxifene, lasofoxifene), or currently are being tested in large phase III clinical trials (Catepsin K inhibitor), as well as drugs that have shown potential beneficial effects in phase I or II trials and may be tested in upcoming phase III trials (integrin antagonists, c-Src kinase inhibitor, inhibitors of the acidification process within the resorption lacuna, and glucagon-like peptide). PMID- 21524248 TI - Emerging anabolic treatments in osteoporosis. AB - Anabolic treatment that remodels bone tissue and restores bone biomechanical competence is essential in the treatment of osteoporosis. In addition, long term antiresorptive therapy may have limitations because of the reduced renewal of bone tissue. The only pure anabolic drugs available at present are intact PTH (1 84) (Preotact(r)) and the truncated PTH (1-34) (Teriparatide, Forteo(r)) while strontium ranelate may possess antiresorptive as well as anabolic properties. The marketed antiresorptive and anabolic antiosteoporotic drugs have limitations in their use due to adverse effects or to the occurrence of rare but severe late complications. Furthermore, indications may be restricted by co-existing diseases or treatment duration may be limited. However, new anabolic drugs are being developed mimicking the effect of PTH, or targeting the calcium sensing receptor (CaSR) or the Wnt/beta-catenin signalling pathway. The PTH mimetics are truncated or altered PTH fragments, parathyroid hormone related peptide (PTHrP) and calcilytics stimulating endogenous PTH secretion. Calcimimetics (e.g. strontium) and calcilytics (e.g. lithium) may also affect bone cells directly through the CaSR. The Wnt pathway that stimulates osteoblastic proliferation, differentiation and function may be activated by neutralizing antibodies to secreted inhibitors of Wnt signalling (e.g. Sclerostin or Dickkopf) or by small molecules (e.g. lithium) that inhibits the glycogen synthase kinase 3beta mediated degradation of beta-catenin. Finally, blocking of activin A by soluble receptor fusion proteins has been shown to increase bone mass by a dual anabolic-antiresorptive action. The present paper summarises the physiological background and the present evidence for these effects. PMID- 21524249 TI - VIP and PACAP: novel approaches to brain functions and neuroprotection. PMID- 21524250 TI - NAP (davunetide) provides functional and structural neuroprotection. AB - NAP (davunetide) is an eight amino acid peptide (NAPVSIPQ) that has been shown to provide potent neuroprotection, in vitro and in vivo. In human clinical trials, NAP has been shown to increase memory scores in patients suffering from amnestic mild cognitive impairment, a precursor to Alzheimer's disease and to enhance functional daily behaviors in schizophrenia patients. NAP is derived from activity-dependent neuroprotective protein (ADNP) a molecule that is essential for brain formation, interacting with chromatin associated protein alpha and the chromatin remodeling complex SWI/SNF and regulating >400 genes during embryonic development. Partial loss in ADNP results in cognitive deficits and pathology of the microtubule associated protein tau (tauopathy) that is ameliorated in part by NAP replacement therapy. Recent studies increased the scope of NAP neuroprotection and provided further insights into the NAP mechanisms of action. Thus, it has been hypothesized that the presence of tau on axonal microtubules renders them notably less sensitive to the microtubule-severing protein katanin, and NAP was shown to protect microtubules from katanin disruption in the face of reduced tau expression. Parallel studies showed that NAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate or both PI-3K/Akt and MAPK/MEK1 kinases in the white matter. The interaction of these disparate yet complementary pathways is the subject of future studies toward human brain neuroprotection in the clinical scenario. PMID- 21524251 TI - VIP-induced neuroprotection of the developing brain. AB - Excitotoxicity is a key molecular mechanism of perinatal brain damage and is associated with cerebral palsy and long term cognitive deficits. VIP induces a potent neuroprotection against perinatal excitotoxic white matter damage. VIP does not prevent the initial appearance of white matter lesion but promotes a secondary repair with axonal regrowth. This plasticity mechanism involves an atypical VPAC2 receptor and BDNF production. Stable VIP agonists mimic VIP effects when given systemically and exhibit a large therapeutic window. Unraveling cellular and molecular targets of VIP effects against perinatal white matter lesions could provide a more general rationale to understand the neuroprotection of the developing white matter against excitotoxic insults. PMID- 21524252 TI - Immunomodulatory roles of VIP and PACAP in models of multiple sclerosis. AB - Multiple sclerosis (MS) is a progressive neurodegenerative disease affecting myelin and axons, which is perpetuated by autoreactive lymphocytes and other inflammatory cell types. Because of the multifactorial nature of this disease, therapies targeting a single process may not be sufficient to halt its progression. VIP and PACAP are two neuropeptides shown to regulate multiple aspects of innate and adaptive immunity, and can also act independently on neural cells to promote their survival and regeneration. Animal studies have proven the efficacy of these peptides for the treatment of several models of neural inflammatory disorders, including those which, like MS, have major Th1/Th17 components. In this review, the immunomodulatory actions of VIP and PACAP will be discussed, with particular emphasis on their potential significance in MS. PMID- 21524253 TI - Strategies to convert PACAP from a hypophysiotropic neurohormone into a neuroprotective drug. AB - In neurological insults, such as cerebral ischemia and traumatic brain injury, complex molecular mechanisms involving inflammation and apoptosis are known to cause severe neuronal cell loss, emphasizing the necessity of developing therapeutic strategies targeting simultaneously these two processes. Over the last decade, numerous in vitro and in vivo studies have demonstrated the unique therapeutical potential of pituitary adenylate cyclase-activating polypeptide (PACAP) for the treatment of neuronal disorders involving apoptotic cell death and neuroinflammation. The neuroprotective activity of PACAP is based on its capacity to reduce the production of deleterious cytokines from activated microglia, to stimulate the release of neuroprotective agents from astrocytes and to inhibit pro-apoptotic intracellular pathways. However, the use of PACAP as a clinically applicable drug is hindered by its peptidic nature. As most natural peptides, native PACAP shows poor metabolic stability, low bioavailability, inadequate distribution and rapid blood clearance. Moreover, injection of PACAP to human can induce peripheral adverse side effects. Therefore, targeted chemical modifications and/or conjugation of PACAP to different macromolecules are required to improve the pharmacokinetic and pharmacological properties of PACAP. This review presents the chemical, biochemical and pharmacological strategies that are currently under development to convert PACAP from a hypophysiotropic neurohormone into a clinically relevant neuroprotective drug. PMID- 21524254 TI - The role of the PACAP signaling system in depression. AB - Major Depressive Disorder (MDD) is a psychiatric condition that represents an important public health concern in modern society. Current pharmacological antidepressant treatments improve depressive symptoms through complex mechanisms that are incompletely understood. There is a consensus that in the clinic they act through the modulation of monoaminergic neurotransmission, primarily involving the serotonin and norepinephrine systems. Recent studies have suggested that action of antidepressants on synaptic plasticity is mediated by their regulatory influence not only upon small-molecule neurotransmitters, but also via neuropeptides which may act both as neurotransmitters and as neuromodulators. Prominent among these neuropeptides is PACAP, whose signaling system is intensively studied for its pleiotropic involvement in various physiological and pathological conditions. This review outlines the current knowledge concerning the PACAP signaling system's involvement in depressive disorders. PMID- 21524256 TI - Role of PACAP in neural stem/progenitor cell and astrocyte--from neural development to neural repair. AB - After central nervous system (CNS) injury, reactive astrocytes display opposing functions, inducing neural repair and axonal regeneration via the release of growth factors, or forming a glial scar which acts as a barrier to axonal regeneration. Endogenous neural stem/progenitor cells have also recently been identified at the site of CNS injury, where they have been shown to differentiate into mature neurons in an animal model of ischemia. However, the pathophysiological mechanisms underpinning the contribution of reactive astrocytes and neural stem/progenitor cells to neural repair are still to be fully elucidated. Pituitary adenylate cyclase activating polypeptide (PACAP) is widely expressed in the CNS, where it has been shown to exert numerous biological effects. This review will summarize the current state of knowledge regarding the expression of PACAP and its receptors during neural development, as well as the involvement of PACAP in astrocytes and neural stem/progenitor cell biology. In addition, we will also discuss emerging evidence that implicates PACAP in neurogenesis and neural repair in response to brain pathophysiology. PMID- 21524255 TI - PACAP is implicated in the stress axes. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide that functions as a neurotransmitter, neuromodulator and neurotrophic factor. Accumulating evidence implicates PACAP as an important regulator of both central and/or peripheral components of the stress axes, particularly exposure to prolonged or traumatic stress. Indeed, PACAP and its cognate receptors are widely expressed in the brain regions and peripheral tissues that mediate stress-related responses. In the sympathoadrenomedullary system, PACAP is required for sustained epinephrine secretion during metabolic stress. It is likely that PACAP regulates autonomic function and contributes to peripheral homeostasis by maintaining a balance between sympathetic and parasympathetic activity, favoring stimulation of the sympathetic system. Furthermore, PACAP is thought to act centrally on the paraventricular nucleus of the hypothalamus to regulate both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Intriguingly, PACAP is also active in brain structures that mediate anxiety- and fear-related behaviors, and the expression of PACAP and its receptors are dynamically altered under pathologic conditions. Thus PACAP may influence both hard-wired (genetically determined) stress responses and gene-environment interactions in stress-related psychopathology. This article aims to overview the molecular mechanisms and psychiatric implications of PACAP-dependent stress responses. PMID- 21524257 TI - Review on the protective effects of PACAP in models of neurodegenerative diseases in vitro and in vivo. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic and multifunctional peptide exerting its effects via 3 main receptors (PAC1, VPAC1 and VPAC2). PACAP is now considered to be a potent neurotrophic and neuroprotective peptide. It plays an important role during the embryonic development of the nervous system. PACAP also protects neurons against various toxic insults in neuronal cultures of diverse origins. In vivo, PACAP shows neuroprotection in models of ischemic and traumatic brain injuries, and those of neurodegenerative diseases. The present review summarizes the findings on the neuroprotective potential of PACAP in models of neurodegenerative diseases, with special focus on in vitro and in vivo models of Parkinson's disease, Huntington chorea and Alzheimer's disease. Based on these observations, both endogenous and exogenously administered PACAP or its novel analogs, fragments offer a novel therapeutic approach in treatment of neurodegenerative diseases. PMID- 21524258 TI - Pharmacological treatments of alcohol and drug addiction: what's new? PMID- 21524259 TI - Pharmacological treatments for cocaine dependence: is there something new? AB - INTRODUCTION: There is no specific and approved treatment, by regulatory authorities, for cocaine dependence. Therefore, developing new medications for the treatment of this disease continues to be a research priority. Recent advances in neurobiology and brain imaging studies have suggested several promising pharmacological approaches. MATERIALS AND METHODS: Literature searches were conducted for the period from January 1990 to February 2011 using PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov, which are the main electronic sources of ongoing trials. RESULTS: Recent controlled clinical studies have highlighted some very promising medications, especially glutamatergic (N-Acetylcysteine, modafinil, topiramate) and GABAergic (vigabatrin) agents, agonist replacement therapy (sustained-release methylphenidate, d-amphetamine) and dopamine agents (disulfiram). Additionally, immunotherapy is a new and promising pharmacological approach. CONCLUSION: Promising pharmacological approaches have emerged for the treatment of cocaine dependence, but larger, randomized, placebo-controlled studies are needed for some medications. Preclinical studies suggest new targets of interest in cocaine dependence. The optimal therapeutic platform is the combination of pharmacotherapies with behavioral therapies. PMID- 21524260 TI - The potential interest of topiramate in addiction. AB - Topiramate is one of the currently most promising compounds in the field of addiction medicine. This paper discusses its potential utility related to a phase model of addiction development, focusing on the assumption that addiction is a continuous process involving different neurobiological pathways, depending on the stage of addiction. A specific emphasis will be made on the development of dysfunctional automatic behaviors in late stage of addiction and the central role of glutamate and AMPA receptors. The aim is to propose that if a too broad effect of anti-addiction medication is expected (such as anti-craving, anti-relapse and preventive effects), the results might be disappointing. The speculative specific efficacy of topiramate in addiction is described. PMID- 21524261 TI - Aripiprazole and ropinirole treatment for cocaine dependence: evidence from a pilot study. AB - BACKGROUND: Currently, there is no specific pharmacological therapy with established efficacy for the treatment of cocaine dependence. The aim of this study was to determine the safety, tolerability and the effects of aripiprazole and ropinirole in patients with cocaine dependence. METHODS: This randomized clinical trial of 12-week duration was carried out on 28 consecutive patients with cocaine dependence presenting for treatment. The diagnostic assessment was performed using ICD-9-CM criteria and Mini International Neuropsychiatric Interview. The Clinical Global Impression Scale, a Visual Analogue Scale to assess craving and a self-report questionnaire on the use of cocaine were administered at baseline and then weekly throughout the study. Urinalyses were carried out three times per weeks to search for benzoylecgonine. RESULTS: Of the 28 study participants, 14 completed the protocol. Treatment discontinuation was unrelated with side effects. One patient required a dosage reduction of ropinirole because of sleepiness and one patient assigned to aripiprazole who reported moderate akathysia had the dosage reduced to 5 mg/day. Routine blood works did not show significant changes from baseline and the overall proportion of positive urinalyses for benzoylecgnonine did not differ significantly between treatments. Using linear mixed-effect models a significant decrease in craving was found in the overall sample (p<0.001). The mean number of cocaine administrations exhibited a faster decrease with aripiprazole compared with ropinirole (p=0.009). CONCLUSIONS: Our pilot study indicates that cocaine craving decreases with both aripiprazole and ropinirole treatment but aripiprazole is more efficacious in reducing cocaine use. PMID- 21524262 TI - Pharmaceutical approaches of binge drinking. AB - Binge Drinking (BD) is often considered to be recurrent alcohol abuse amongst adolescents and young adults. However, the close link between adolescence and impulsivity has led many authors to define BD as intoxication-seeking behaviour. Medications may sometimes be justified because of the major short-term and long term risks that underlie the most severe BD-related behaviours. The most common consequences in the long run are the occurrence of alcohol dependence, psycho- and neurodevelopmental disruptions and alcohol liver disease. To understand the specificities of BD among other forms of alcohol addiction, this article is based on a two-headed conception of alcohol dependence: on one hand, psychological dependence, which refers to the behavioural habituation of alcohol intake, clinically results in craving and is neurobiologically supported by the reward system, particularly the dopaminergic mesolimbic pathway (MLP); on the other hand, physical dependence, which refers to the pharmacological tolerance induced by chronic alcohol intake, results in Alcohol Withdrawal Syndrome (AWS) and is neurobiologically supported by the imbalance between GABA and Glutamate-NMDA neurotransmission. Medications for psychological dependence include anticraving drugs, which all act by regulating MLP. Medications for physical dependence on alcohol include GABA-A and perhaps GABA-B agonists and some NMDA antagonists. In practice, many alcohol-dependence treatments seem to have a dual action. This article proposes an attempt to classify current and forthcoming medications for alcohol addiction based on this two-headed approach to treating alcohol dependence. Drawing from this classification, specific therapeutic schemes for treating BD are proposed, with currently approved alcohol medications and possible future treatments. These schemes are justified by recent literature on the subject and propose to prioritize pure anticraving medications, taking into account the clinical specificities of BD. Furthermore, these schemes also mention harm-reductive neuroprotective and hepatoprotective strategies, which could be included in the arsenal of possible medications for BD in the near future. PMID- 21524263 TI - Current and promising pharmacotherapies, and novel research target areas in the treatment of alcohol dependence: a review. AB - Harmful alcohol use is a risk factor in more than 60 diseases and injuries resulting in approximately 2.5 million deaths per year worldwide. In the United States (US) and Europe, there are only a few medications approved for alcohol dependence (AD) however, these medications have only been moderately effective and there is a crucial need for more effective treatments. This review briefly summarizes research on currently approved medications for AD, as well as promising medications like topiramate, baclofen and ondansetron. Topiramate is likely the most promising new treatment for AD, however, further research is needed to determine the optimal dose and appropriate length of treatment. Baclofen, a GABA(B) agonist, is a promising medication as a treatment for AD, especially for patients with AD and severe liver disease. Ondansetron has shown promising results as a potential medication for AD, but only within a certain subtype of individuals. This review also discusses more recent findings on other potential pharmacotherapies for AD, such as serotonin-specific reuptake inhibitors (SSRIs; i.e. sertraline), aripiprazole and prazosin, as well as on some examples of other potentially interesting new neuropharmacological targets (i.e. cannabinoid receptors, CRF, NPY, ghrelin). Finally, the present review also discusses the attempts to personalize medication for AD treatment by alcohol typology and pharmacogenetics. PMID- 21524264 TI - Psychopharmacological treatment in pathological gambling: a critical review. AB - Given the rates of pathological gambling and its impact on affected individuals and their relatives, effective treatments are needed. There are, however, no approved pharmacological treatments for pathological gambling. This paper describes the development of pharmacological treatments for pathological gambling and is based on a review of the literature published in the past 10 years. Important studies were carried-out on antidepressants, mood stabilizers, and antipsychotic agents. In the absence of comorbid psychiatric disorder, these studies did not conclude to the efficacy of these psychotropic drugs. A possible efficacy of opiate antagonist treatment for pathological gambling has been replicated in a number of placebo-controlled studies. Preliminary results on N acetyl cysteine, Memantine and Topiramate produced significant improvement for pathological gamblers and may open new avenues for treatment. PMID- 21524265 TI - GABAergic and glutamatergic modulation in binge eating: therapeutic approach. AB - Lifetime prevalence estimates for binge eating disorder (BED) and bulimia nervosa (BN) are 3.5% and 1.5% among women and 2.0% and 0.5% among men, respectively. Night eating syndromes (NES) affect 1.1%-1.5% of the general population. All of these disorders induce an impaired quality of life and significant disability. Symptom overlaps are reported between substance use disorders and eating disorders such as BED, BN and NES. A growing body of evidence suggests that gamma amino-butyric acid (GABA) and glutamate modulation pathways might be useful targets in the treatment of alcohol and substance use disorders. Their involvement in the reward process and in the regulation of food intake could be the source of new pharmacological strategies for the treatment of eating disorders. We review published data on the efficacy and safety of drugs targeting the GABA and glutamate modulation pathways for the treatment of BED, BN and NES. Preliminary results indicate that baclofen and topiramate are effective in reducing binge eating, craving and weight gain. However, the potential clinical drug-placebo difference is not detected for acamprosate and lamotrigine. Limitations of these studies are discussed. In view of these data, first- and second-line pharmacological interventions are proposed. PMID- 21524267 TI - Pharmacological treatments of opiate dependence. AB - Opiate substitution therapies have largely contributed to improving outcomes in opiate dependent patients. Their impact has significantly diminished HIV transmission rates, decreased incidence of overdose and reduced delinquency due to heroin trafficking. Since then, some advances have been made in the formulations and dosing regimen of these treatments. They have also largely facilitated opiate withdrawal. However, concerning the maintenance of opiate abstinence, very few new treatments have been proposed. Despite considerable advances in our knowledge of the neurobiological mechanisms of opiate dependence, few clinical trials have been proposed to test new molecules both in accompanying opiate substitution and in maintaining abstinence from illicit opiate use. The objective of this article is to examine the evidence concerning the treatment of opiate dependent patients, especially new treatments and to examine the eventual gaps between currently knowledge, available treatment and demands. PMID- 21524266 TI - Pharmacological treatment of cannabis dependence. AB - Cannabis is the most frequently used illegal psychoactive substance in the world. There is a significant increase in the number of treatment admissions for cannabis use disorders in the past few years, and the majority of cannabis dependent individuals who enter treatment have difficulty in achieving and maintaining abstinence. Thus, there is increased need for medications that can be used to treat this population. So far, no medication has been shown broadly and consistently effective; none has been approved by any national regulatory authority. Medications studied have included those that alleviate symptoms of cannabis withdrawal (e.g., dysphoric mood, irritability),those that directly affect endogenous cannabinoid receptor function, and those that have shown efficacy in treatment of other drugs of abuse or psychiatric conditions. Buspirone is the only medication to date that has shown efficacy for cannabis dependence in a controlled clinical trial. Results from controlled human laboratory studies and small open-label clinical trials suggest that dronabinol, the COMT inhibitor entacapone, and lithium may warrant further study. Recent pre clinical studies suggest the potential of fatty acid amide hydrolase (FAAH) inhibitors such as URB597, endocannabinoid-metabolizing enzymes, and nicotinic alpha 7 receptor antagonists such as methyllycaconitine (MLA).Controlled clinical trials are needed to evaluate the clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications. PMID- 21524268 TI - Pharmacotherapy for smoking cessation: present and future. AB - Tobacco dependence is a chronic disease that often requires repeated interventions and multiple attempts to quit. To date, three medications are FDA approved for smoking cessation: nicotine replacement therapy, sustained-release bupropion, and varenicline. These treatments are effective across a broad range of populations, and are recommended for all smokers, including those with psychiatric or addictive comorbidity. Less is known however concerning the benefit-risk profile of these medications in pregnant women and adolescents. With these limitations in mind, clinicians should encourage and offer counseling and a prescription of pharmacotherapy to every patient willing to make a quit attempt. Despite the relative efficacy of first-line medications, many smokers relapse after one given quit attempt, and alternative pharmacotherapies are needed. Clonidine and nortriptyline have been proposed as second-line medications. In addition, this review indentifies a series of promising drugs that hopefully will be available to complete our current armory. PMID- 21524269 TI - From substance dependence to addiction: impact of a conceptual shift on therapeutic approaches? AB - Switching from the concept of substance or alcohol dependence to that of addiction has profoundly modified our ways of approaching, treating and organizing the care of this disease. This more complex and subtle approach gives less importance to the substance and its effects and focuses more on the initiation of pathological behavior. It is important to keep in mind that the addictive process associates a substance (more or less addictive), an individual (more or less vulnerable) and an environment (more or less condoning). Today, it is no longer possible to consider that a drug acts on only one receptor or one system. Current understanding of inner regulation mechanisms integrates the interactions between the various stimulated brain pathways. Addiction treatments which should benefit from advances in genetics, neuropsychology and neuroimaging could be increasingly individualized in the years to come. The "addictology" approach has triggered thinking about other therapeutic approaches such as modification of therapeutic objectives toward "risk reductions" or applying this model to behavioral addictions (food, sex, sport, gaming...). This conceptual shift seems to enrich clinical analysis, the therapeutic possibilities and the avenues for research. PMID- 21524271 TI - The overlapping syndromes of the pick complex. AB - A significant expansion of knowledge in the last few years, especially in the molecular biology of frontotemporal dementia (FTD) is summarized. This condition, formerly known as Pick's disease and considered rare, is estimated to be 12-15% of all dementias and 30-50% early onset ones. The clinical picture is protean, mainly a behavioural and language impairment, but the extrapyramidal syndromes of CBD and PSP are often seen and conversely FTD and progressive aphasia often has motor symptoms, including ALS. These seemingly different presentations converge, as one or other areas in the brain are affected. Our experience with FTD in a clinical cohort, with high rate of autopsy confirmation is presented. Less than half of the cases are tauopathies, the majority has been discovered to have a TDP 43 and most recently a FUS proteinopathy, shared with ALS, opening potential opportunities for pharmacological approaches to treatment. Tau and progranulin mutations on Ch-17 and some others, point to molecular mechanisms. A glossary is provided to navigate the complex terminology. PMID- 21524270 TI - Changes in the expression of the Alzheimer's disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction. AB - Mutations in the presenilin genes cause the majority of early-onset familial Alzheimer's disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis. PMID- 21524272 TI - Recent breakthroughs in the understanding of frontotemporal lobar degeneration and its related disorders. PMID- 21524273 TI - Agrin triggers the clustering of raft-associated acetylcholine receptors through actin cytoskeleton reorganization. AB - BACKGROUND INFORMATION: Cholesterol/sphingolipid-rich membrane microdomains or membrane rafts have been implicated in various aspects of receptor function such as activation, trafficking and synapse localization. More specifically in muscle, membrane rafts are involved in AChR (acetylcholine receptor) clustering triggered by the neural factor agrin, a mechanism considered integral to NMJ (neuromuscular junction) formation. In addition, actin polymerization is required for the formation and stabilization of AChR clusters in muscle fibres. Since membrane rafts are platforms sustaining actin nucleation, we hypothesize that these microdomains provide the suitable microenvironment favouring agrin/MuSK (muscle specific kinase) signalling, eliciting in turn actin cytoskeleton reorganization and AChR clustering. However, the identity of the signalling pathways operating through these microdomains still remains unclear. RESULTS: In this work, we attempted to identify the interactions between membrane raft components and cortical skeleton that regulate, upon signalling by agrin, the assembly and stabilization of synaptic proteins of the postsynaptic membrane domain at the NMJ. We provide evidence that in C2C12 myotubes, agrin triggers the association of a subset of membrane rafts enriched in AChR, the -MuSK and Cdc42 (cell division cycle 42) to the actin cytoskeleton. Disruption of the liquid-ordered phase by methyl-beta-cyclodextrin abolished this association. We further show that actin and the actin-nucleation factors, N-WASP (neuronal Wiscott-Aldrich syndrome protein) and Arp2/3 (actin-related protein 2/3) are transiently associated with rafts on agrin engagement. Consistent with these observations, pharmacological inhibition of N-WASP activity perturbed agrin-elicited AChR clustering. Finally, immunoelectron microscopic analyses of myotube membrane uncovered that AChRs were constitutively associated with raft nanodomains at steady state that progressively coalesced on agrin activation. These rearrangements of membrane domains correlated with the reorganization of cortical actin cytoskeleton through concomitant and transient recruitment of the Arp2/3 complex to AChR-enriched rafts. CONCLUSIONS: The present observations support the notion that membrane rafts are involved in AChR clustering by promoting local actin cytoskeleton reorganization through the recruitment of effectors of the agrin/MuSK signalling cascade. These mechanisms are believed to play an important role in vivo in the formation of the NMJ. PMID- 21524274 TI - Alternative affinity tools: more attractive than antibodies? AB - Antibodies are the most successful affinity tools used today, in both fundamental and applied research (diagnostics, purification and therapeutics). Nonetheless, antibodies do have their limitations, including high production costs and low stability. Alternative affinity tools based on nucleic acids (aptamers), polypeptides (engineered binding proteins) and inorganic matrices (molecular imprinted polymers) have received considerable attention. A major advantage of these alternatives concerns the efficient (microbial) production and in vitro selection procedures. The latter approach allows for the high-throughput optimization of aptamers and engineered binding proteins, e.g. aiming at enhanced chemical and physical stability. This has resulted in a rapid development of the fields of nucleic acid- and protein-based affinity tools and, although they are certainly not as widely used as antibodies, the number of their applications has steadily increased in recent years. In the present review, we compare the properties of the more conventional antibodies with these innovative affinity tools. Recent advances of affinity tool developments are described, both in a medical setting (e.g. diagnostics, therapeutics and drug delivery) and in several niche areas for which antibodies appear to be less attractive. Furthermore, an outlook is provided on anticipated future developments. PMID- 21524275 TI - The remarkable diversity of plant PEPC (phosphoenolpyruvate carboxylase): recent insights into the physiological functions and post-translational controls of non photosynthetic PEPCs. AB - PEPC [PEP (phosphoenolpyruvate) carboxylase] is a tightly controlled enzyme located at the core of plant C-metabolism that catalyses the irreversible beta carboxylation of PEP to form oxaloacetate and Pi. The critical role of PEPC in assimilating atmospheric CO(2) during C(4) and Crassulacean acid metabolism photosynthesis has been studied extensively. PEPC also fulfils a broad spectrum of non-photosynthetic functions, particularly the anaplerotic replenishment of tricarboxylic acid cycle intermediates consumed during biosynthesis and nitrogen assimilation. An impressive array of strategies has evolved to co-ordinate in vivo PEPC activity with cellular demands for C(4)-C(6) carboxylic acids. To achieve its diverse roles and complex regulation, PEPC belongs to a small multigene family encoding several closely related PTPCs (plant-type PEPCs), along with a distantly related BTPC (bacterial-type PEPC). PTPC genes encode ~110-kDa polypeptides containing conserved serine-phosphorylation and lysine-mono ubiquitination sites, and typically exist as homotetrameric Class-1 PEPCs. In contrast, BTPC genes encode larger ~117-kDa polypeptides owing to a unique intrinsically disordered domain that mediates BTPC's tight interaction with co expressed PTPC subunits. This association results in the formation of unusual ~900-kDa Class-2 PEPC hetero-octameric complexes that are desensitized to allosteric effectors. BTPC is a catalytic and regulatory subunit of Class-2 PEPC that is subject to multi-site regulatory phosphorylation in vivo. The interaction between divergent PEPC polypeptides within Class-2 PEPCs adds another layer of complexity to the evolution, physiological functions and metabolic control of this essential CO(2)-fixing plant enzyme. The present review summarizes exciting developments concerning the functions, post-translational controls and subcellular location of plant PTPC and BTPC isoenzymes. PMID- 21524276 TI - Lentivirus-mediated overexpression of TGF-beta inducible early gene 1 inhibits SW1990 pancreatic cancer cell growth. AB - TIEG1 (TGF-beta inducible early gene 1) plays a significant role in regulating cell proliferation and apoptosis in various cell types. Previous studies have shown a close relationship between the expression level of TIEG1 and various cancers, including breast, prostate, colorectal and pancreatic cancer. In this study, we up-regulated the gene expression of TIEG1 in SW1990 pancreatic cancer cell line by a lentivirus transfection system and investigated its potential as a therapeutic target for pancreatic cancer. The results showed that lentivirus mediated overexpression of TIEG1 gene inhibited human pancreatic cancer SW1990 cell proliferation and caused the cell cycle arrest at the G1-phase in vitro. SW1990 cells transduced with lenti-TIEG1 showed significant inhibition of colony formation and cancer cell growth in 3-D culture model. Moreover, overexpression of TIEG1 gene significantly slowed the growth of SW1990 xenografts in nude mice. Taken together, these data provided evidence that overexpression of TIEG1 gene by a lentivirus transfection system led to suppressed human pancreatic cancer cell growth and might therefore be a feasible approach in the clinical management of pancreatic cancer. PMID- 21524277 TI - Dispensable role of PTEN in mouse spermatogenesis. AB - PTEN (phosphatase and tensin homologue deleted on chromosome ten) plays critical roles in multiple cellular processes, including cell proliferation, survival, migration and transformation. A role of PTEN in mammalian spermatogenesis, however, has not been explored. To address this question, we generated a mouse model with PTEN conditional knockout in postnatal male germ cells. We found that spermatogenesis was normal in PTEN-deleted male germ cells. PTEN conditional mutant males produced sperm and sired offspring as competently as wild-type littermates. Moreover, our biochemical analysis also indicated that the Akt (acutely transforming retrovirus AKT8 in rodent T cell lymphoma) signalling pathway was not affected in mutant testis. Taken together, these findings demonstrate that PTEN is dispensable in mouse spermatogenesis. PMID- 21524278 TI - ECM remodelling components regulated during jaw periosteal cell osteogenesis. AB - Human JPCs (jaw periosteal cells) are a promising source for the engineering of cell-based osteoinductive grafts in oral surgery. For this purpose, cell characteristics of this stem cell source should be elucidated in detail. Analysis of gene expression profiles may help us to evaluate key factors and cellular targets of JPC osteogenesis. Because little is known about the interplay of osteogenic-related components, we analysed the expression of different collagen types reflecting important players for extracellular matrix assembly and of TIMPs (tissue inhibitors of metalloproteinases) responsible for the inhibition of matrix degradation. Gene expression analyses using microarrays and quantitative RT-PCR (reverse transcription-PCR) during JPC osteogenesis revealed the induction of several collagen types' expression (VII, VIII, XI and XII), and some of them (types I, VIII and XI) seemed to be susceptible to BMP-2 (bone morphogenetic protein-2) that is known to be a potent osteogenic inducer of periosteal cells. Among the TIMPs, only TIMP-4 and RECK (reversion-inducing cysteine-rich protein with Kazal motifs) expressions were strongly up-regulated during JPC osteogenesis. Proteome profiler analysis of supernatants from untreated and differentiated JPCs confirmed the gene expression data in terms of TIMP expression. In summary, we identified new collagen types and TIMPs that seem to play important roles during the osteogenesis of jaw periosteal progenitor cells. PMID- 21524279 TI - Bazooka mediates secondary axon morphology in Drosophila brain lineages. AB - In the Drosophila brain, neural lineages project bundled axon tracts into a central neuropile. Each lineage exhibits a stereotypical branching pattern and trajectory, which distinguish it from other lineages. In this study, we used a multilineage approach to explore the neural function of the Par-complex member Par3/Bazooka in vivo. Drosophila bazooka is expressed in post-mitotic neurons of the larval brain and localizes within neurons in a lineage-dependent manner. The fact that multiple GAL4 drivers have been mapped to several lineages of the Drosophila brain enables investigation of the role of Bazooka from larval to adult stages Bazooka loss-of-function (LOF) clones had abnormal morphologies, including aberrant pathway choice of ventral projection neurons in the BAla1 lineage, ectopic branching in the DALv2 and BAmv1 lineages, and excess BLD5 lineage axon projections in the optic medulla. Exogenous expression of Bazooka protein in BAla1 neurons rescued defective guidance, supporting an intrinsic requirement for Bazooka in the post-mitotic neuron. Elimination of the Par complex member Par6 recapitulated Bazooka phenotypes in some but not all lineages, suggesting that the Par complex functions in a lineage-dependent manner, and that Bazooka may act independently in some lineages. Importantly, this study highlights the potential of using a multilineage approach when studying gene function during neural development in Drosophila. PMID- 21524280 TI - Improving the prediction of yeast protein function using weighted protein-protein interactions. AB - BACKGROUND: Bioinformatics can be used to predict protein function, leading to an understanding of cellular activities, and equally-weighted protein-protein interactions (PPI) are normally used to predict such protein functions. The present study provides a weighting strategy for PPI to improve the prediction of protein functions. The weights are dependent on the local and global network topologies and the number of experimental verification methods. The proposed methods were applied to the yeast proteome and integrated with the neighbour counting method to predict the functions of unknown proteins. RESULTS: A new technique to weight interactions in the yeast proteome is presented. The weights are related to the network topology (local and global) and the number of identified methods, and the results revealed improvement in the sensitivity and specificity of prediction in terms of cellular role and cellular locations. This method (new weights) was compared with a method that utilises interactions with the same weight and it was shown to be superior. CONCLUSIONS: A new method for weighting the interactions in protein-protein interaction networks is presented. Experimental results concerning yeast proteins demonstrated that weighting interactions integrated with the neighbor counting method improved the sensitivity and specificity of prediction in terms of two functional categories: cellular role and cell locations. PMID- 21524281 TI - Simvastatin suppresses dexamethasone-induced secretion of plasminogen activator inhibitor-1 in human bone marrow adipocytes. AB - BACKGROUND: Osteonecrosis of the femoral head is a common complication of high dose glucocorticoid treatment. Intravascular thrombosis is thought to be associated with the ischemic state of the femoral head. Plasminogen activator inhibitor-1 (PAI-1) is an adipokine, which are physiologically active substances secreted from visceral and subcutaneous adipocytes. PAI-1 suppresses fibrinolysis by binding tissue-type plasminogen activator. Several reports have described the relationship between PAI-1 and steroid-induced osteonecrosis of the femoral head, and the preventive effects of lipid-lowering agents (statins) against steroid induced osteonecrosis of the femoral head. We previously reported that adipokines and dexamethasone induced PAI-1 secretion from bone marrow adipocytes. The purpose of the present study is to examine the effects of simvastatin on PAI-1 secretion from human bone marrow adipocytes in vitro. METHODS: Primary bone marrow adipocytes were extracted from collagenase-treated bone marrow fluid obtained from the femoral necks of 40 patients (6 men, 34 women; age range, 52-81 years) undergoing hip joint replacement surgery. After suspended culture with or without dexamethasone or simvastatin, PAI-1 mRNA expression was assessed by real time RT-PCR. Total PAI-1 protein secretion in culture medium was assessed by enzyme-linked immunosorbent assay. RESULTS: PAI-1 mRNA expression was up regulated by 388% (P=0.002) with dexamethasone, and down-regulated by 45% (P=0.002) with simvastatin, as compared to control levels. Dexamethasone increased total PAI-1 secretion by 166% (P=0.001) and simvastatin decreased total PAI-1 secretion by 64% (P=0.002). No significant changes were observed in adiponectin mRNA expression and secretion by dexamethasone and simvastatin, while pre-treatment with simvastatin reversed dexamethasone induced PAI-1 secretion by 89%, as compared to control levels. CONCLUSION: The present study confirmed the suppressive effects of simvastatin on PAI-1 expression and secretion from bone marrow adipocytes. Furthermore, pre-treatment with simvastatin reversed dexamethasone induced PAI-1 secretion. Simvastatin may thus exhibit preventive effects against steroid-induced osteonecrosis of the femoral head by suppressing PAI-1 secretion. PMID- 21524283 TI - The primary therapy chosen for patients with localized prostate cancer between the university hospital and its affiliated hospitals in Nara Uro-Oncological Research Group registration. AB - BACKGROUND: We investigated the differences between the preferential primary therapy conceived by the primary doctors and the primary therapy actually conducted for prostate cancer patients in Nara, Japan. METHODS: The distribution of primary therapy and clinical characteristics of 2303 prostate cancer patients diagnosed between 2004 and 2006 at Nara Medical University and its 23 affiliated hospitals - were assessed. Moreover, the preferential primary therapy for the patients at each clinical stage (cT1-T3bN0M0) conceived by the primary doctors was investigated and compared to the actual therapy. RESULTS: Of all patients, 51% received primary androgen deprivation therapy (PADT), 30% underwent radical prostatectomy (RP), and 14% received radiation therapy (RT). The preferential primary therapy for cT1-2N0M0 was RP (92%) while 38% of the patients actually received PADT (RP: 40%). For cT3aN0M0, the preferential primary therapy was both RP and external beam radiation therapy (EBRT) while 58% of the patients actually received PADT (RP: 16%, EBRT: 24%). For cT3bN0M0, the most preferential primary therapy was EBRT (46%) while 67% of the patients actually received PADT (EBRT: 21%). This trend was more notable in the affiliated hospitals than in the University hospital. The hospitals with lower volume of RP per year significantly conducted PADT compared with those with higher volume of RP. CONCLUSIONS: PADT was commonly used to treat localized prostate cancer as well as locally advanced prostate cancer in Japan. There was a definite discrepancy between the preferential primary therapy conceived by the primary doctors and the actual therapy provided to the patients. PMID- 21524282 TI - Genetic variation in TIMP1 but not MMPs predict excess FEV1 decline in two general population-based cohorts. AB - BACKGROUND: An imbalance in matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs) contributes to chronic obstructive pulmonary disease (COPD) development. Longitudinal studies investigating Single Nucleotide Polymorphisms (SNPs) in MMPs and TIMPs with respect to COPD development and lung function decline in the general population are lacking. METHODS: We genotyped SNPs in MMP1 (G-1607GG), MMP2 (-1306 C/T), MMP9 (3 tagging SNPs), MMP12 (A-82G and Asn357Ser) and TIMP1 (Phe124Phe and Ile158Ile) in 1390 Caucasians with multiple FEV1 measurements from a prospective cohort study in the general population. FEV1 decline was analyzed using linear mixed effect models adjusted for confounders. Analyses of the X-chromosomal TIMP1 gene were stratified according to sex. All significant associations were repeated in an independent general population cohort (n=1152). RESULTS: MMP2 -1306 TT genotype carriers had excess FEV1 decline (-4.0 ml/yr, p=0.03) compared to wild type carriers. TIMP1 Ile158Ile predicted significant excess FEV1 decline in both males and females. TIMP1 Phe124Phe predicted significant excess FEV1 decline in males only, which was replicated (p=0.10) in the second cohort. The MMP2 and TIMP1 Ile158Ile associations were not replicated. Although power was limited, we did not find associations with COPD development. CONCLUSIONS: We for the first time show that TIMP1 Phe124Phe contributes to excess FEV1 decline in two independent prospective cohorts, albeit not quite reaching conventional statistical significance in the replication cohort. SNPs in MMPs evidently do not contribute to FEV1 decline in the general population. PMID- 21524284 TI - Evolving dimensions in medical case reporting. AB - Medical case reports (MCRs) have been undervalued in the literature to date. It seems that while case series emphasize what is probable, case reports describe what is possible and what can go wrong. MCRs transfer medical knowledge and act as educational tools. We outline evolving aspects of the MCR in current practice. PMID- 21524286 TI - Fish bone foreign body presenting with an acute fulminating retropharyngeal abscess in a resource-challenged center: a case report. AB - INTRODUCTION: A retropharyngeal abscess is a potentially life-threatening infection in the deep space of the neck, which can compromise the airway. Its management requires highly specialized care, including surgery and intensive care, to reduce mortality. This is the first case of a gas-forming abscess reported from this region, but not the first such report in the literature. CASE PRESENTATION: We present a case of a 16-month-old Yoruba baby girl with a gas forming retropharyngeal abscess secondary to fish bone foreign body with laryngeal spasm that was managed in the recovery room. We highlight specific problems encountered in the management of this case in a resource-challenged center such as ours. CONCLUSION: We describe an unusual presentation of a gas forming organism causing a retropharyngeal abscess in a child. The patient's condition was treated despite the challenges of inadequate resources for its management. We recommend early recognition through adequate evaluation of any oropharyngeal injuries or infection and early referral to the specialist with prompt surgical intervention. PMID- 21524285 TI - Detection of small RNAs in Bordetella pertussis and identification of a novel repeated genetic element. AB - BACKGROUND: Small bacterial RNAs (sRNAs) have been shown to participate in the regulation of gene expression and have been identified in numerous prokaryotic species. Some of them are involved in the regulation of virulence in pathogenic bacteria. So far, little is known about sRNAs in Bordetella, and only very few sRNAs have been identified in the genome of Bordetella pertussis, the causative agent of whooping cough. RESULTS: An in silico approach was used to predict sRNAs genes in intergenic regions of the B. pertussis genome. The genome sequences of B. pertussis, Bordetella parapertussis, Bordetella bronchiseptica and Bordetella avium were compared using a Blast, and significant hits were analyzed using RNAz. Twenty-three candidate regions were obtained, including regions encoding the already documented 6S RNA, and the GCVT and FMN riboswitches. The existence of sRNAs was verified by Northern blot analyses, and transcripts were detected for 13 out of the 20 additional candidates. These new sRNAs were named Bordetella pertussis RNAs, bpr. The expression of 4 of them differed between the early, exponential and late growth phases, and one of them, bprJ2, was found to be under the control of BvgA/BvgS two-component regulatory system of Bordetella virulence. A phylogenetic study of the bprJ sequence revealed a novel, so far undocumented repeat of ~90 bp, found in numerous copies in the Bordetella genomes and in that of other Betaproteobacteria. This repeat exhibits certain features of mobile elements. CONCLUSION: We shown here that B. pertussis, like other pathogens, expresses sRNAs, and that the expression of one of them is controlled by the BvgA/BvgS system, similarly to most virulence genes, suggesting that it is involved in virulence of B. pertussis. PMID- 21524287 TI - Increase in intracellular PGE2 induces apoptosis in Bax-expressing colon cancer cell. AB - BACKGROUND: NSAIDs exhibit protective properties towards some cancers, especially colon cancer. Yet, it is not clear how they play their protective role. PGE2 is generally shown as the only target of the NSAIDs anticancerous activity. However, PGE2 known targets become more and more manifold, considering both the molecular pathways involved and the target cells in the tumour. The role of PGE2 in tumour progression thus appears complex and multipurpose. METHODS: To gain understanding into the role of PGE2 in colon cancer, we focused on the activity of PGE2 in apoptosis in colon cancer cell lines. RESULTS: We observed that an increase in intracellular PGE2 induced an apoptotic cell death, which was dependent on the expression of the proapoptotic protein Bax. This increase was induced by increasing PGE2 intracellular concentration, either by PGE2 microinjection or by the pharmacological inhibition of PGE2 exportation and enzymatic degradation. CONCLUSIONS: We present here a new sight onto PGE2 in colon cancer cells opening the way to a new prospective therapeutic strategy in cancer, alternative to NSAIDs. PMID- 21524288 TI - Magnetic resonance imaging findings within the posterior and lateral columns of the spinal cord extended from the medulla oblongata to the thoracic spine in a woman with subacute combined degeneration without hematologic disorders: a case report and review of the literature. AB - INTRODUCTION: Subacute combined degeneration of the spinal cord is a rare cause of demyelination of the dorsal and lateral columns of the spinal cord and is a neurological complication of vitamin B12 deficiency. Subacute combined degeneration without anemia or macrocytosis is rare. CASE PRESENTATION: We present a case of cobalamin deficiency in a 29-year-old Moroccan woman who presented with subacute combined degeneration without evidence of anemia or macrocytosis. Magnetic resonance imaging of the spinal cord demonstrated abnormal hyperintense signal changes on T2-weighted imaging of the posterior and lateral columns from the medulla oblongata to the thoracic spine. A diagnosis of subacute combined degeneration of the spinal cord was considered and confirmed by low serum cobalamin. The patient was treated with vitamin B12 supplements and showed improvement in her clinical symptoms. CONCLUSION: Physicians should diagnose subacute combined degeneration in patients early by having a high index of suspicion and using diagnostic tools such as magnetic resonance imaging. PMID- 21524289 TI - Gastrointestinal stromal tumours treated before and after the advent of c-kit immunostaining. AB - BACKGROUND: Recently developed immunohistochemical markers have revolutionised the classification of gastrointestinal stromal tumours (GISTs) whilst tyrosine kinase inhibitors (imatinib) have had a significant impact on the treatment of advanced tumours. We review the clinicopathological features of previously resected mesenchymal tumours of the gastrointestinal tract in our institution to 1) reclassify the histological diagnosis of those stained prior to c-kit availability; 2) perform survival analysis to identify prognostic factors, and 3) to consider the implications for patients. METHODS: Clinicopathological records of patients with a diagnosis of mesenchymal tumours treated between May 1992 and April 2007 were reviewed. RESULTS: 82 patients were reviewed. 26 (32%) were reclassified as GISTs following c-kit immunostaining and a further 14 patients were treated for GIST up to April 2007 (Total: 40 patients; 21 males and 19 females, mean age 67, range 30-92 years). 36 (90%) underwent complete resection. 5-year survival of patients with GIST alone was 80%. Females had a better median survival (M: F 43 months: 73 months). CONCLUSIONS: The availability of c-kit staining allowed 32% of previously diagnosed mesenchymal tumours to be reclassified as GISTs. This may have implications for the follow-up of patients diagnosed prior to the availability of this method. PMID- 21524290 TI - Sequence characteristics of T4-like bacteriophage IME08 benome termini revealed by high throughput sequencing. AB - BACKGROUND: T4 phage is a model species that has contributed broadly to our understanding of molecular biology. T4 DNA replication and packaging share various mechanisms with human double-stranded DNA viruses such as herpes virus. The literature indicates that T4-like phage genomes have permuted terminal sequences, and are generated by a DNA terminase in a sequence-independent manner; METHODS: genomic DNA of T4-like bacteriophage IME08 was subjected to high throughput sequencing, and the read sequences with extraordinarily high occurrences were analyzed; RESULTS: we demonstrate that both the 5' and 3' termini of the IME08 genome starts with base G or A. The presence of a consensus sequence TTGGA|G around the breakpoint of the high frequency read sequences suggests that the terminase cuts the branched pre-genome in a sequence-preferred manner. Our analysis also shows that terminal cleavage is asymmetric, with one end cut at a consensus sequence, and the other end generated randomly. The sequence-preferred cleavage may produce sticky-ends, but with each end being packaged with different efficiencies; CONCLUSIONS: this study illustrates how high throughput sequencing can be used to probe replication and packaging mechanisms in bacteriophages and/or viruses. PMID- 21524291 TI - Combining best evidence: a novel method to calculate the alcohol-attributable fraction and its variance for injury mortality. AB - BACKGROUND: The alcohol-attributable fraction for injury mortality is defined as the proportion of fatal injury that would disappear if consumption went to zero. Estimating this fraction has previously been based on a simplistic view of drinking and associated risk. This paper develops a new way to calculate the alcohol-attributable fraction for injury based on different dimensions of drinking, mortality data, experimental data, survey research, new risk scenarios, and by incorporating different distributions of consumption within populations. For this analysis, the Canadian population in 2005 was used as the reference population. METHODS: Binge drinking and average daily consumption were modeled separately with respect to the calculation of the AAF. The acute consumption risk was calculated with a probability-based method that accounted for both the number of binge drinking occasions and the amount of alcohol consumed per occasion. The average daily consumption was computed based on the prevalence of daily drinking at various levels. These were both combined to get an overall estimate. 3 sensitivity analyses were performed using different alcohol consumption parameters to test the robustness of the model. Calculation of the variance to generate confidence limits around the point estimates was accomplished via Monte Carlo resampling methods on randomly generated AAFs that were based on the distribution and prevalence of drinking in the Canadian population. RESULTS: Overall, the AAFs decrease with age and are significantly lower for women than men across all ages. As binge drinking increases, the injury mortality AAF also increases. Motor vehicle collisions show the largest relative increases in AAF as alcohol consumption is increased, with over a 100% increase in AAF from the lowest to highest consumption category. Among non-motor vehicle collisions, the largest change in total AAF occurred both for homicide and other intentional injuries at about a 15% increase in the AAF from the lowest to the highest binge consumption scenarios. CONCLUSIONS: This method combines the best available evidence to generate new alcohol-attributable fractions for alcohol-attributable injury mortality. Future research is needed to refine the risk function for non motor vehicle injury types and to investigate potential interactions between binge drinking and average volume of alcohol consumption. PMID- 21524292 TI - Interventions encouraging the use of systematic reviews by health policymakers and managers: a systematic review. AB - BACKGROUND: Systematic reviews have the potential to inform decisions made by health policymakers and managers, yet little is known about the impact of interventions to increase the use of systematic reviews by these groups in decision making. METHODS: We systematically reviewed the evidence on the impact of interventions for seeking, appraising, and applying evidence from systematic reviews in decision making by health policymakers or managers. Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment Database, and LISA were searched from the earliest date available until April 2010. Two independent reviewers selected studies for inclusion if the intervention intended to increase seeking, appraising, or applying evidence from systematic reviews by a health policymaker or manager. Minimum inclusion criteria were a description of the study population and availability of extractable data. RESULTS: 11,297 titles and abstracts were reviewed, leading to retrieval of 37 full-text articles for assessment; four of these articles met all inclusion criteria. Three articles described one study where five systematic reviews were mailed to public health officials and followed up with surveys at three months and two years. The articles reported from 23% to 63% of respondents declaring they had used systematic reviews in policymaking decisions. One randomised trial indicated that tailored messages combined with access to a registry of systematic reviews had a significant effect on policies made in the area of healthy body weight promotion in health departments. CONCLUSIONS: The limited empirical data renders the strength of evidence weak for the effectiveness and the types of interventions that encourage health policymakers and managers to use systematic reviews in decision making. PMID- 21524293 TI - Reversal to air-driven sound production revealed by a molecular phylogeny of tongueless frogs, family Pipidae. AB - BACKGROUND: Evolutionary novelties often appear by conferring completely new functions to pre-existing structures or by innovating the mechanism through which a particular function is performed. Sound production plays a central role in the behavior of frogs, which use their calls to delimit territories and attract mates. Therefore, frogs have evolved complex vocal structures capable of producing a wide variety of advertising sounds. It is generally acknowledged that most frogs call by moving an air column from the lungs through the glottis with the remarkable exception of the family Pipidae, whose members share a highly specialized sound production mechanism independent of air movement. RESULTS: Here, we performed behavioral observations in the poorly known African pipid genus Pseudhymenochirus and document that the sound production in this aquatic frog is almost certainly air-driven. However, morphological comparisons revealed an indisputable pipid nature of Pseudhymenochirus larynx. To place this paradoxical pattern into an evolutionary framework, we reconstructed robust molecular phylogenies of pipids based on complete mitochondrial genomes and nine nuclear protein-coding genes that coincided in placing Pseudhymenochirus nested among other pipids. CONCLUSIONS: We conclude that although Pseudhymenochirus probably has evolved a reversal to the ancestral non-pipid condition of air driven sound production, the mechanism through which it occurs is an evolutionary innovation based on the derived larynx of pipids. This strengthens the idea that evolutionary solutions to functional problems often emerge based on previous structures, and for this reason, innovations largely depend on possibilities and constraints predefined by the particular history of each lineage. PMID- 21524294 TI - Antiangiogenic properties of Koetjapic acid, a natural triterpene isolated from Sandoricum koetjaoe Merr. AB - BACKGROUND: Angiogenesis, the formation of new blood vessels, has become an important target in cancer therapy. Angiogenesis plays an important role in tumor growth and metastasis. Koetjapic acid (KA) is a seco-A-ring oleanene triterpene isolated from S. koetjape. The solvent extract of this plant species was shown previously to have strong antiangiogenic activity; however the active ingredient(s) that conferred the biological activity and the mode of action was not established. Given the high concentration of KA in S. koetjape, an attempt has been made in this study to investigate the antiangiogenic properties of KA. RESULTS: Treatment with 10-50 MUg/ml KA resulted in dose dependent inhibition of new blood vessels growth in ex vivo rat aortic ring assay. KA was found to be non cytotoxic against HUVECs with IC50 40.97 +/- 0.37 MUg/ml. KA inhibited major angiogenesis process steps, endothelial cell migration and differentiation as well as VEGF expression. CONCLUSIONS: The non-cytotoxic compound, KA, may be a potent antiangiogenic agent; its activity may be attributed to inhibition of endothelial cells migration and differentiation as well VEGF suppression. PMID- 21524295 TI - Heart rate monitoring on the stroke unit. What does heart beat tell about prognosis? An observational study. AB - BACKGROUND: Guidelines recommend maintaining the heart rate (HR) of acute stroke patients within physiological limits; data on the frequency and predictors of significant deviations from these limits are scarce. METHODS: Demographical data, stroke risk factors, NIH stroke scale score, lesion size and location, and ECG parameters were prospectively assessed in 256 patients with ischemic stroke. Patients were continuously monitored for at least 24 hours on a certified stroke unit. Tachycardia (HR >= 120 bpm) and bradycardia (HR <45 bpm) and cardiac rhythm (sinus rhythm or atrial fibrillation) were documented. We investigated the influence of risk factors on HR disturbances and their respective influence on dependence (modified Rankin Scale >= 3 after three months) and mortality. RESULTS: HR >= 120 bpm occurred in 39 patients (15%). Stroke severity (larger lesion size/higher NIHSS-score on admission), atrial fibrillation and HR on admission predicted its occurrence. HR <45 bpm occurred in 12 patients (5%) and was predicted by lower HR on admission. Neither HR >= 120 nor HR <45 bpm independently predicted poor outcome at three moths. Stroke location had no effect on the occurrence of HR violations. Clinical severity and age remained the only consistent predictors of poor outcome. CONCLUSIONS: Significant tachycardia and bradycardia are frequent phenomena in acute stroke; however they do not independently predict clinical course or outcome. Continuous monitoring allows detecting rhythm disturbances in stroke patients and allows deciding whether urgent medical treatment is necessary. PMID- 21524296 TI - Molecular detection of multiple viral targets in untreated urban sewage from Greece. AB - BACKGROUND: Urban sewage virological analysis may produce important information about the strains that cause clinical and subclinical infections in the population, thus supporting epidemiological studies. METHODS: In the present study, a twenty one-month survey (November 2007 to July 2009) was conducted in order to evaluate the presence of human adenoviruses (hAdV), hepatitis A viruses (HAV), hepatitis E viruses (HEV), Noroviruses (NoV), and human Polyomaviruses (hPyV) in untreated sewage samples collected from the inlet of Patras' municipal biological wastewater treatment plant, located in southwestern Greece. Nucleic acid amplification techniques were applied for viral nucleic acid detection. Positive samples were confirmed by sequencing and comparative phylogenetic analysis was performed on the isolated viral strains. RESULTS: In total, viruses were detected in 87.5% (42/48) of sewage samples. AdVs, PyVs, HAV, and NoVs were detected in 45.8% (22/48), 68.8% (33/48), 8.3% (4/48), and 6.3% (3/48) of the samples collected from the plant's inlet, while HEV was not detected at all. Adenovirus types 8 (Ad8), 40 (Ad40) and 41 (Ad41) were recognized, while JC and BK polyomaviruses were recorded. Noroviruses were identified as GII.4. HAV was typed as genotype IA. CONCLUSIONS: Our study demonstrates the advantages of environmental surveillance as a tool to elucidate the molecular epidemiology of community circulating viruses. We underline the need of environmental surveillance programs in countries such as Greece with inadequate and problematic epidemiological surveillance system and no environmental surveillance system currently in action. PMID- 21524297 TI - Improving hand sensibility in vibration induced neuropathy: A case-series. AB - OBJECTIVES: We report a long-term series of nine workers suffering from vibration induced neuropathy, after many years of exposure to hand-held vibrating tools at high or low frequency. They were treated with temporary selective cutaneous anaesthesia (EMLA(r) cream) of the forearm repeatedly for a period up to one year (in two cases four years). The aim was to improve their capacity to perceive touch and thereby improve hand function and diminish disability. The treatment principle is based on current concepts of brain plasticity, where a deafferentation of a skin area results in improved sensory function in adjacent skin areas. METHODS: All participants had sensory hand problems in terms of numbness (median touch thresholds > 70 mg) and impaired hand function influencing ADL (mean DASH score 22).After an initial identical self-administered treatment period of 8 weeks (12-15 treatments with increasing intervals) they did one treatment every 2-3 month. RESULTS: After one year sensibility (touch thresholds and tactile discrimination) as well as hand function (mean DASH score 13) were improved in a majority of the cases. Seven of the participants choose to continue the treatment after the first year and two of them have continued at a regular basis for up to four years. A surprising, secondary finding was diminishing nocturnal numbness of the hand and arm in eight of the nine subjects from "frequently" to "hardly ever or never". CONCLUSIONS: Our observations open new perspectives for treatment of impaired sensibility and hand function in a group of patients with vibration induced hand problems where we have no treatment to offer today. PMID- 21524298 TI - Longitudinal evaluation the pulmonary function of the pre and postoperative periods in the coronary artery bypass graft surgery of patients treated with a physiotherapy protocol. AB - BACKGROUND: The treatment of coronary artery disease (CAD) seeks to reduce or prevent its complications and decrease morbidity and mortality. For certain subgroups of patients, coronary artery bypass graft surgery (CABG) may accomplish these goals. The objective of this study was to assess the pulmonary function in the CABG postoperative period of patients treated with a physiotherapy protocol. METHODS: Forty-two volunteers with an average age of 63 +/- 2 years were included and separated into three groups: healthy volunteers (n = 09), patients with CAD (n = 9) and patients who underwent CABG (n = 20). Patients from the CABG group received preoperative and postoperative evaluations on days 3, 6, 15 and 30. Patients from the CAD group had evaluations on days 1 and 30 of the study, and the healthy volunteers were evaluated on day 1. Pulmonary function was evaluated by measuring forced vital capacity (FVC), maximum expiratory pressure (MEP) and Maximum inspiratory pressure (MIP). RESULTS: After CABG, there was a significant decrease in pulmonary function (p < 0.05), which was the worst on postoperative day 3 and returned to the preoperative baseline on postoperative day 30. CONCLUSION: Pulmonary function decreased after CABG. Pulmonary function was the worst on postoperative day 3 and began to improve on postoperative day 15. Pulmonary function returned to the preoperative baseline on postoperative day 30. PMID- 21524299 TI - Peripheral and central arterial pressure and its relationship to vascular target organ damage in carotid artery, retina and arterial stiffness. Development and validation of a tool. The Vaso risk study. AB - BACKGROUND: Ambulatory blood pressure monitoring (ABPM) shows a better correlation to target organ damage and cardiovascular morbidity-mortality than office blood pressure. A loss of arterial elasticity and an increase in carotid artery intima-media thickness (IMT) has been associated with increased cardiovascular morbidity-mortality. Tools have been developed that allow estimation of the retinal arteriovenous index but not all studies coincide and there are contradictory results in relation to the evolution of the arteriosclerotic lesions and the caliber of the retinal vessels. The purpose of this study is to analyze the relationship between peripheral and central arterial pressure (clinic and ambulatory) and vascular structure and function as evaluated by the carotid artery intima-media thickness, retina arteriovenous index, pulse wave velocity (PWV) and ankle-brachial index in patients with and without type 2 diabetes. In turn, software is developed and validated for measuring retinal vessel thickness and automatically estimating the arteriovenous index. METHODS/DESIGN: A cross-sectional study involving a control group will be made, with a posterior 4-year follow-up period in primary care. The study patients will be type 2 diabetics, with a control group of non-diabetic individuals. Consecutive sampling will be used to include 300 patients between 34-75 years of age and no previous cardiovascular disease, one-half being assigned to each group. MAIN MEASUREMENTS: age, gender, height, weight and abdominal circumference. Lipids, creatinine, microalbuminuria, blood glucose, HbA1c, blood insulin, high sensitivity C-reactive protein and endothelial dysfunction markers. Clinic and ambulatory blood pressure monitoring. Carotid ultrasound to evaluate IMT, and retinography to evaluate the arteriovenous index. ECG to assess left ventricle hypertrophy, ankle-brachial index, and pulse wave analysis (PWA) and pulse wave velocity (PWV) with the Sphigmocor System. DISCUSSION: We hope to obtain information on the correlation of different ABPM-derived parameters and PWA to organ target damage--particularly vascular structure and function evaluated from the IMT and PWV--and endothelial dysfunction in patients with and without type 2 diabetes. We also hope to demonstrate the usefulness of the instrument developed for the automated evaluation of retinal vascularization in the early detection of alterations in vascular structure and function and in the prognosis of middle-term cardiovascular morbidity. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01325064. PMID- 21524300 TI - Prevention of bronchial hyperreactivity in a rat model of precapillary pulmonary hypertension. AB - BACKGROUND: The development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones. METHODS: Five groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezosentan via an intraperitoneally implemented osmotic pump, or by orally administered sildenafil. An additional group underwent sham surgery. Four weeks later, the lung responsiveness to increasing doses of an intravenous infusion of methacholine (2, 4, 8 12 and 24 MUg/kg/min) was determined by using the forced oscillation technique to assess the airway resistance (Raw). RESULTS: BHR developed in the untreated rats, as reflected by a significant decrease in ED50, the equivalent dose of methacholine required to cause a 50% increase in Raw. All drugs tested prevented the development of BHR, iloprost being the most effective in reducing both the systolic pulmonary arterial pressure (Ppa; 28%, p = 0.035) and BHR (ED50 = 9.9 +/- 1.7 vs. 43 +/- 11 MUg/kg in ACS control and iloprost-treated rats, respectively, p = 0.008). Significant correlations were found between the levels of Ppa and ED50 (R = 0.59, p = 0.016), indicating that mechanical interdependence is primarily responsible for the development of BHR. CONCLUSIONS: The efficiency of such treatment demonstrates that re-establishment of the balance of constrictor/dilator mediators via various signalling pathways involved in PHT is of potential benefit for the avoidance of the development of BHR. PMID- 21524301 TI - Tolerability of the Oscar 2 ambulatory blood pressure monitor among research participants: a cross-sectional repeated measures study. AB - BACKGROUND: Ambulatory blood pressure monitoring (ABPM) is increasingly used to measure blood pressure (BP) in research studies. We examined ease of use, comfort, degree of disturbance, reported adverse effects, factors associated with poor tolerability, and association of poor tolerability with data acquisition of 24-hour ABPM using the Oscar 2 monitor in the research setting. METHODS: Sixty adults participating in a research study of people with a history of borderline clinic BP reported on their experience with ABPM on two occasions one week apart. Poor tolerability was operationalized as an overall score at or above the 75th percentile using responses to questions adapted from a previously developed questionnaire. In addition to descriptive statistics (means for responses to Likert-scaled "0 to 10" questions and proportions for Yes/No questions), we examined reproducibility of poor tolerability as well as associations with poor tolerability and whether poor tolerability was associated with removal of the monitor or inadequate number of BP measurements. RESULTS: The mean ambulatory BP of participants by an initial ABPM session was 148/87 mm Hg. After wearing the monitor the first time, the degree to which the monitor was felt to be cumbersome ranged from a mean of 3.0 to 3.8, depending on whether at work, home, driving, or other times. The most bother was interference with normal sleeping pattern (mean 4.2). Wearers found the monitor straightforward to use (mean 7.5). Nearly 67% reported that the monitor woke them after falling asleep, and 8.6% removed it at some point during the night. Reported adverse effects included pain (32%), skin irritation (37%), and bruising (7%). Those categorized as having poor tolerability (kappa = 0.5 between sessions, p = 0.0003) were more likely to report being in fair/poor health (75% vs 22%, p = 0.01) and have elevated 24-hour BP average (systolic: 28% vs 17%, p = 0.56; diastolic: 30% vs 17%, p = 0.37). They were also more likely to remove the monitor and have inadequate numbers of measurements. CONCLUSIONS: The Oscar 2 ABPM device is straightforward to use but can interfere with sleep. Commonly reported adverse effects include pain, skin irritation, and bruising. Those who tolerate the monitor poorly are more likely to report being in fair or poor health and to remove it, particularly at night. PMID- 21524302 TI - Simrank: Rapid and sensitive general-purpose k-mer search tool. AB - BACKGROUND: Terabyte-scale collections of string-encoded data are expected from consortia efforts such as the Human Microbiome Project http://nihroadmap.nih.gov/hmp. Intra- and inter-project data similarity searches are enabled by rapid k-mer matching strategies. Software applications for sequence database partitioning, guide tree estimation, molecular classification and alignment acceleration have benefited from embedded k-mer searches as sub routines. However, a rapid, general-purpose, open-source, flexible, stand-alone k mer tool has not been available. RESULTS: Here we present a stand-alone utility, Simrank, which allows users to rapidly identify database strings the most similar to query strings. Performance testing of Simrank and related tools against DNA, RNA, protein and human-languages found Simrank 10X to 928X faster depending on the dataset. CONCLUSIONS: Simrank provides molecular ecologists with a high throughput, open source choice for comparing large sequence sets to find similarity. PMID- 21524303 TI - Disseminating quality improvement: study protocol for a large cluster-randomized trial. AB - BACKGROUND: Dissemination is a critical facet of implementing quality improvement in organizations. As a field, addiction treatment has produced effective interventions but disseminated them slowly and reached only a fraction of people needing treatment. This study investigates four methods of disseminating quality improvement (QI) to addiction treatment programs in the U.S. It is, to our knowledge, the largest study of organizational change ever conducted in healthcare. The trial seeks to determine the most cost-effective method of disseminating quality improvement in addiction treatment. METHODS: The study is evaluating the costs and effectiveness of different QI approaches by randomizing 201 addiction-treatment programs to four interventions. Each intervention used a web-based learning kit plus monthly phone calls, coaching, face-to-face meetings, or the combination of all three. Effectiveness is defined as reducing waiting time (days between first contact and treatment), increasing program admissions, and increasing continuation in treatment. Opportunity costs will be estimated for the resources associated with providing the services. OUTCOMES: The study has three primary outcomes: waiting time, annual program admissions, and continuation in treatment. Secondary outcomes include: voluntary employee turnover, treatment completion, and operating margin. We are also seeking to understand the role of mediators, moderators, and other factors related to an organization's success in making changes. ANALYSIS: We are fitting a mixed-effect regression model to each program's average monthly waiting time and continuation rates (based on aggregated client records), including terms to isolate state and intervention effects. Admissions to treatment are aggregated to a yearly level to compensate for seasonality. We will order the interventions by cost to compare them pair wise to the lowest cost intervention (monthly phone calls). All randomized sites with outcome data will be included in the analysis, following the intent-to-treat principle. Organizational covariates in the analysis include program size, management score, and state. DISCUSSION: The study offers seven recommendations for conducting a large-scale cluster-randomized trial: provide valuable services, have aims that are clear and important, seek powerful allies, understand the recruiting challenge, cultivate commitment, address turnover, and encourage rigor and flexibility. TRIAL REGISTRATION: ClinicalTrials. govNCT00934141. PMID- 21524305 TI - Value of diffusion weighted MR imaging as an early surrogate parameter for evaluation of tumor response to high-dose-rate brachytherapy of colorectal liver metastases. AB - BACKGROUND: To assess the value of diffusion weighted imaging (DWI) as an early surrogate parameter for treatment response of colorectal liver metastases to image-guided single-fraction 192Ir-high-dose-rate brachytherapy (HDR-BT). METHODS: Thirty patients with a total of 43 metastases underwent CT- or MRI guided HDR-BT. In 13 of these patients a total of 15 additional lesions were identified, which were not treated at the initial session and served for comparison. Magnetic resonance imaging (MRI) including breathhold echoplanar DWI sequences was performed prior to therapy (baseline MRI), 2 days after HDR-BT (early MRI) as well as after 3 months (follow-up MRI). Tumor volume (TV) and intratumoral apparent diffusion coefficient (ADC) were measured independently by two radiologists. Statistical analysis was performed using univariate comparison, ANOVA and paired t test as well as Pearson's correlation. RESULTS: At early MRI no changes of TV and ADC were found for non-treated colorectal liver metastases. In contrast, mean TV of liver lesions treated with HDR-BT increased by 8.8% (p = 0.054) while mean tumor ADC decreased significantly by 11.4% (p < 0.001). At follow-up MRI mean TV of non-treated metastases increased by 50.8% (p = 0.027) without significant change of mean ADC values. In contrast, mean TV of treated lesions decreased by 47.0% (p = 0.026) while the mean ADC increased inversely by 28.6% compared to baseline values (p < 0.001; Pearson's correlation coefficient of r = -0.257; p < 0.001). CONCLUSIONS: DWI is a promising imaging biomarker for early prediction of tumor response in patients with colorectal liver metastases treated with HDR-BT, yet the optimal interval between therapy and early follow-up needs to be elucidated. PMID- 21524304 TI - Evidence of association with type 1 diabetes in the SLC11A1 gene region. AB - BACKGROUND: Linkage and congenic strain analyses using the nonobese diabetic (NOD) mouse as a model for human type 1 autoimmune diabetes (T1D) have identified several NOD mouse Idd (insulin dependent diabetes) loci, including Slc11a1 (formerly known as Nramp1). Genetic variants in the orthologous region encompassing SLC11A1 in human chromosome 2q35 have been reported to be associated with various immune-related diseases including T1D. Here, we have conducted association analysis of this candidate gene region, and then investigated potential correlations between the most T1D-associated variant and RNA expression of the SLC11A1 gene and its splice isoform. METHODS: Nine SNPs (rs2276631, rs2279015, rs1809231, rs1059823, rs17235409 (D543N), rs17235416 (3'UTR), rs3731865 (INT4), rs7573065 (-237 C -> T) and rs4674297) were genotyped using TaqMan genotyping assays and the polymorphic promoter microsatellite (GT)n was genotyped using PCR and fragment length analysis. A maximum of 8,863 T1D British cases and 10,841 British controls, all of white European descent, were used to test association using logistic regression. A maximum of 5,696 T1D families were also tested for association using the transmission/disequilibrium test (TDT). We considered P <= 0.005 as evidence of association given that we tested nine variants in total. Upon identification of the most T1D-associated variant, we investigated the correlation between its genotype and SLC11A1 expression overall or with splice isoform ratio using 42 PAXgene whole blood samples from healthy donors by quantitative PCR (qPCR). RESULTS: Using the case-control collection, rs3731865 (INT4) was identified to be the variant most associated with T1D (P = 1.55 * 10-6). There was also some evidence of association at rs4674297 (P = 1.57 * 10-4). No evidence of disease association was obtained at any of the loci using the family collections (PTDT >= 0.13). We also did not observe a correlation between rs3731865 genotypes and SLC11A1 expression overall or with splice isoform expression. CONCLUSION: We conclude that rs3731685 (INT4) in the SLC11A1 gene may be associated with T1D susceptibility in the European ancestry population studied. We did not observe a difference in SLC11A1 expression at the RNA level based on the genotypes of rs3731865 in whole blood samples. However, a potential correlation cannot be ruled out in purified cell subsets especially monocytes or macrophages. PMID- 21524306 TI - The natural triterpene maslinic acid induces apoptosis in HT29 colon cancer cells by a JNK-p53-dependent mechanism. AB - BACKGROUND: Maslinic acid, a pentacyclic triterpene found in the protective wax like coating of the leaves and fruit of Olea europaea L., is a promising agent for the prevention of colon cancer. We have shown elsewhere that maslinic acid inhibits cell proliferation to a significant extent and activates mitochondrial apoptosis in colon cancer cells. In our latest work we have investigated further this compound's apoptotic molecular mechanism. METHODS: We used HT29 adenocarcinoma cells. Changes genotoxicity were analyzed by single-cell gel electrophoresis (comet assay). The cell cycle was determined by flow cytometry. Finally, changes in protein expression were examined by western blotting. Student's t-test was used for statistical comparison. RESULTS: HT29 cells treated with maslinic acid showed significant increases in genotoxicity and cell-cycle arrest during the G0/G1 phase after 72 hours' treatment and an apoptotic sub G0/G1 peak after 96 hours. Nevertheless, the molecular mechanism for this cytotoxic effect of maslinic acid has never been properly explored. We show here that the anti-tumoral activity of maslinic acid might proceed via p53-mediated apoptosis by acting upon the main signaling components that lead to an increase in p53 activity and the induction of the rest of the factors that participate in the apoptotic pathway. We found that in HT29 cells maslinic acid activated the expression of c-Jun NH2-terminal kinase (JNK), thus inducing p53. Treatment of tumor cells with maslinic acid also resulted in an increase in the expression of Bid and Bax, repression of Bcl-2, release of cytochrome-c and an increase in the expression of caspases -9, -3, and -7. Moreover, maslinic acid produced belated caspase-8 activity, thus amplifying the initial mitochondrial apoptotic signaling. CONCLUSION: All these results suggest that maslinic acid induces apoptosis in human HT29 colon-cancer cells through the JNK-Bid-mediated mitochondrial apoptotic pathway via the activation of p53. Thus we propose a plausible sequential molecular mechanism for the expression of the different proteins responsible for the intrinsic mitochondrial apoptotic pathway. Further studies with other cell lines will be needed to confirm the general nature of these findings. PMID- 21524307 TI - Mutagenesis Objective Search and Selection Tool (MOSST): an algorithm to predict structure-function related mutations in proteins. AB - BACKGROUND: Functionally relevant artificial or natural mutations are difficult to assess or predict if no structure-function information is available for a protein. This is especially important to correctly identify functionally significant non-synonymous single nucleotide polymorphisms (nsSNPs) or to design a site-directed mutagenesis strategy for a target protein. A new and powerful methodology is proposed to guide these two decision strategies, based only on conservation rules of physicochemical properties of amino acids extracted from a multiple alignment of a protein family where the target protein belongs, with no need of explicit structure-function relationships. RESULTS: A statistical analysis is performed over each amino acid position in the multiple protein alignment, based on different amino acid physical or chemical characteristics, including hydrophobicity, side-chain volume, charge and protein conformational parameters. The variances of each of these properties at each position are combined to obtain a global statistical indicator of the conservation degree of each property. Different types of physicochemical conservation are defined to characterize relevant and irrelevant positions. The differences between statistical variances are taken together as the basis of hypothesis tests at each position to search for functionally significant mutable sites and to identify specific mutagenesis targets. The outcome is used to statistically predict physicochemical consensus sequences based on different properties and to calculate the amino acid propensities at each position in a given protein. Hence, amino acid positions are identified that are putatively responsible for function, specificity, stability or binding interactions in a family of proteins. Once these key functional positions are identified, position-specific statistical distributions are applied to divide the 20 common protein amino acids in each position of the protein's primary sequence into a group of functionally non disruptive amino acids and a second group of functionally deleterious amino acids. CONCLUSIONS: With this approach, not only conserved amino acid positions in a protein family can be labeled as functionally relevant, but also non conserved amino acid positions can be identified to have a physicochemically meaningful functional effect. These results become a discriminative tool in the selection and elaboration of rational mutagenesis strategies for the protein. They can also be used to predict if a given nsSNP, identified, for instance, in a genomic-scale analysis, can have a functional implication for a particular protein and which nsSNPs are most likely to be functionally silent for a protein. This analytical tool could be used to rapidly and automatically discard any irrelevant nsSNP and guide the research focus toward functionally significant mutations. Based on preliminary results and applications, this technique shows promising performance as a valuable bioinformatics tool to aid in the development of new protein variants and in the understanding of function-structure relationships in proteins. PMID- 21524308 TI - Discovering time-lagged rules from microarray data using gene profile classifiers. AB - BACKGROUND: Gene regulatory networks have an essential role in every process of life. In this regard, the amount of genome-wide time series data is becoming increasingly available, providing the opportunity to discover the time-delayed gene regulatory networks that govern the majority of these molecular processes. RESULTS: This paper aims at reconstructing gene regulatory networks from multiple genome-wide microarray time series datasets. In this sense, a new model-free algorithm called GRNCOP2 (Gene Regulatory Network inference by Combinatorial OPtimization 2), which is a significant evolution of the GRNCOP algorithm, was developed using combinatorial optimization of gene profile classifiers. The method is capable of inferring potential time-delay relationships with any span of time between genes from various time series datasets given as input. The proposed algorithm was applied to time series data composed of twenty yeast genes that are highly relevant for the cell-cycle study, and the results were compared against several related approaches. The outcomes have shown that GRNCOP2 outperforms the contrasted methods in terms of the proposed metrics, and that the results are consistent with previous biological knowledge. Additionally, a genome wide study on multiple publicly available time series data was performed. In this case, the experimentation has exhibited the soundness and scalability of the new method which inferred highly-related statistically-significant gene associations. CONCLUSIONS: A novel method for inferring time-delayed gene regulatory networks from genome-wide time series datasets is proposed in this paper. The method was carefully validated with several publicly available data sets. The results have demonstrated that the algorithm constitutes a usable model-free approach capable of predicting meaningful relationships between genes, revealing the time-trends of gene regulation. PMID- 21524309 TI - Oral bisphosphonate-related osteonecrosis of the jaws in rheumatoid arthritis patients: a critical discussion and two case reports. AB - BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition characterized by the presence of exposed bone in the maxillofacial region. Its pathogenesis is still undetermined, but may be associated with risk factors such as rheumatoid arthritis (RA). The aim of this paper is to report two unpublished cases of BRONJ in patients with RA and to conduct a literature review of similar clinical cases with a view to describe the main issues concerning these patients, including demographic characteristics and therapeutic approaches applied. METHODS: Two case reports of BRONJ involving RA patients were discussed RESULTS: Both patients were aging female taking alendronate for more than 3 years. Lesions were detected in stage II in posterior mandible with no clear trigger agent. The treatment applied consisted of antibiotics, oral rinses with chlorhexidine, drug discontinuation and surgical procedures. Complete healing of the lesions was achieved. CONCLUSIONS: This paper brings to light the necessity for rheumatologists to be aware of the potential risk to their patients of developing BRONJ and to work together with dentists for the prevention and early detection of the lesions. Although some features seem to link RA with oral BRONJ and act as synergistic effects, more studies should be developed to support the scientific bases for this hypothesis. PMID- 21524311 TI - Echium acanthocarpum hairy root cultures, a suitable system for polyunsaturated fatty acid studies and production. AB - BACKGROUND: The therapeutic and health promoting role of highly unsaturated fatty acids (HUFAs) from fish, i.e. eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) are well known. These same benefits may however be shared by some of their precursors, the polyunsaturated fatty acids (PUFAs), such as stearidonic acid (SDA, 18:4 n-3). In order to obtain alternative sources for the large-scale production of PUFAs, new searches are being conducted focusing on higher plants oils which can contain these n-3 and n-6 C18 precursors, i.e. SDA and GLA (18:3n-6, gamma-linolenic acid). RESULTS: The establishment of the novel Echium acanthocarpum hairy root cultures represents a powerful tool in order to research the accumulation and metabolism of fatty acids (FAs) in a plant particularly rich in GLA and SDA. Furthermore, this study constitutes the first example of a Boraginaceae species hairy root induction and establishment for FA studies and production. The dominant PUFAs, 18:2n-6 (LA, linoleic acid) and 18:3n-6 (GLA), accounted for about 50% of total FAs obtained, while the n-3 PUFAs, 18:3n-3 (ALA, alpha-linolenic acid) and 18:4n-3 (SDA), represented approximately 5% of the total. Production of FAs did not parallel hairy root growth, and the optimal productivity was always associated with the highest biomass density during the culture period. Assuming a compromise between FA production and hairy root biomass, it was determined that sampling times 4 and 5 gave the most useful FA yields. Total lipid amounts were in general comparable between the different hairy root lines (29.75 and 60.95 mg/g DW), with the major lipid classes being triacylglycerols. The FAs were chiefly stored in the hairy roots with very minute amounts being released into the liquid nutrient medium. CONCLUSIONS: The novel results presented here show the utility and high potential of E. acanthocarpum hairy roots. They are capable of biosynthesizing and accumulating a large range of polyunsaturated FAs, including the target GLA and SDA fatty acids in appreciable quantities. PMID- 21524312 TI - Analyzing generic and branded substitution patterns in the Netherlands using prescription data. AB - BACKGROUND: As in other societies, pharmaceutical expenditures in the Netherlands are rising every year. As a consequence, needs for cost control are often expressed. One possible solution for cost control could come through increasing generic substitution by pharmacists. We aim to analyse the extent and nature of substitution in recent years and estimate the likelihood of generic or branded substitution in Dutch pharmacies in relation to various characteristics. METHODS: We utilized a linked prescription dataset originating from a general practitioner (GP) and a pharmacy database, both from the northern Netherlands. We selected specific drugs of interest, containing about 55,000 prescriptions from 15 different classes. We used a crossed generalized linear mixed model to estimate the effects that certain patient and pharmacy characteristics as well as timing have on the likelihood that a prescription will eventually be substituted by the pharmacist. RESULTS: Generic substitution occurred at 25% of the branded prescriptions. Generic substitution was more likely to occur earlier in time after patent expiry and to patients that were older and more experienced in their drug use. Individually owned pharmacies had a lower probability of generic substitution compared to chain pharmacies. Oppositely, branded substitution occurred in 10% of generic prescriptions and was positively related to the patients' experience in branded use. Individually owned pharmacies were more likely to substitute a generic drug to a branded compared to other pharmacies. Antidepressant and PPI prescriptions were less prone to generic and more prone to branded substitution. CONCLUSION: Analysis of prescription substitution by the pharmacist revealed strong relations between substitution and patient experience on drug use, pharmacy status and timing. These findings can be utilised to design further strategies to enhance generic substitution. PMID- 21524310 TI - Update in the methodology of the chronic stress paradigm: internal control matters. AB - To date, the reliability of induction of a depressive-like state using chronic stress models is confronted by many methodological limitations. We believe that the modifications to the stress paradigm in mice proposed herein allow some of these limitations to be overcome. Here, we discuss a variant of the standard stress paradigm, which results in anhedonia. This anhedonic state was defined by a decrease in sucrose preference that was not exhibited by all animals. As such, we propose the use of non-anhedonic, stressed mice as an internal control in experimental mouse models of depression. The application of an internal control for the effects of stress, along with optimized behavioural testing, can enable the analysis of biological correlates of stress-induced anhedonia versus the consequences of stress alone in a chronic-stress depression model. This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and non-anhedonic groups subjected to stress. These results argue for the use of a subgroup of individuals who are negative for the induction of a depressive phenotype during experimental paradigms of depression as an internal control, for more refined modeling of this disorder in animals. PMID- 21524313 TI - Prostate transglutaminase (TGase-4) antagonizes the anti-tumour action of MDA 7/IL-24 in prostate cancer. AB - BACKGROUND: Transglutamiase-4 (TGase-4), also known as prostate transglutaminase, belongs to the TGase family and is uniquely expressed in the prostate gland. The functions of this interesting protein are not clearly defined. In the present study, we have investigated an unexpected link between TGase-4 and the melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24), a cytokine known to regulate the growth and apoptosis of certain cancer and immune cells. METHODS: Frozen sections of normal and malignant human prostate tissues and human prostate cancer (PCa) cell lines PC-3 and CA-HPV-10, cell lines expressing low and high levels of TGase-4, and recombinant MDA-7/IL-24 (rhMDA-7/IL-24) were used. Expression construct for human TGase-4 was generated using a mammalian expression vector with full length human TGase-4 isolated from normal human prostate tissues. PC-3 cells were transfected with expression construct or control plasmid. Stably transfected cells for control transfection and TGase-4 over expression were created. Similarly, expression of TGase-4 in CA-HPV-10 cells were knocked down by way of ribozyme transgenes. Single and double immunofluorescence microscopy was used for localization and co-localization of TGase-4 and MDA-7/IL 24 in PCa tissues and cells with antibodies to TGase-4; MDA-7/IL-24; IL-20alpha; IL-20beta and IL-22R. Cell-matrix adhesion, attachment and migration were by electric cell substrate impedance sensing and growth by in vitro cell growth assay. A panel of small molecule inhibitors, including Akt, was used to determine signal pathways involving TGase-4 and MDA-7/IL-24. RESULTS: We initially noted that MDA-7 resulted in inhibition of cell adhesion, growth and migration of human PCa PC-3 cells which did not express TGase-4. However, after the cells over expressed TGase-4 by way of transfection, the TGase-4 expressing cells lost their adhesion, growth and migratory inhibitory response to MDA-7. On the other hand, CA-HPV-10 cells, a cell type naturally expressing high levels of TGase-4, had a contrasting response to MDA-7 when compared with PC-3 cells. Inhibitor to Akt reversed the inhibitory effect of MDA-7, only in PC-3 control cells, but not the TGase-4 expressing PC-3 cells. In human prostate tissues, TGase-4 was found to have a good degree of co-localization with one of the MDA-7 receptor complexes, IL-20Ra. CONCLUSION: The presence of TGase-4 has a biological impact on a prostate cancer cell's response to MDA-7. TGase-4, via mechanism(s) yet to be identified, blocked the action of MDA-7 in prostate cancer cells. This has an important implication when considering the use of MDA-7 as a potential anticancer cytokine in prostate cancer therapies. PMID- 21524314 TI - Comparison of high protein and high fiber weight-loss diets in women with risk factors for the metabolic syndrome: a randomized trial. AB - BACKGROUND: Studies have suggested that moderately high protein diets may be more appropriate than conventional low-fat high carbohydrate diets for individuals at risk of developing the metabolic syndrome and type 2 diabetes. However in most such studies sources of dietary carbohydrate may not have been appropriate and protein intakes may have been excessively high. Thus, in a proof-of-concept study we compared two relatively low-fat weight loss diets - one high in protein and the other high in fiber-rich, minimally processed cereals and legumes - to determine whether a relatively high protein diet has the potential to confer greater benefits. METHODS: Eighty-three overweight or obese women, 18-65 years, were randomized to either a moderately high protein (30% protein, 40% carbohydrate) diet (HP) or to a high fiber, relatively high carbohydrate (50% carbohydrate, > 35 g total dietary fiber, 20% protein) diet (HFib) for 8 weeks. Energy intakes were reduced by 2000 - 4000 kJ per day in order to achieve weight loss of between 0.5 and 1 kg per week. RESULTS: Participants on both diets lost weight (HP: -4.5 kg [95% confidence interval (CI):-3.7, -5.4 kg] and HFib: -3.3 kg [95% CI: -4.2, -2.4 kg]), and reduced total body fat (HP: -4.0 kg [5% CI:-4.6, -3.4 kg] and HFib: -2.5 kg [95% CI: -3.5, -1.6 kg]), and waist circumference (HP: -5.4 cm [95% CI: -6.3, -4.5 cm] and HFib: -4.7 cm [95% CI: -5.8, -3.6 cm]), as well as total and LDL cholesterol, triglycerides, fasting plasma glucose and blood pressure. However participants on HP lost more body weight (-1.3 kg [95% CI: -2.5, -0.1 kg; p = 0.039]) and total body fat (-1.3 kg [95% CI: -2.4, -0.1; p = 0.029]). Diastolic blood pressure decreased more on HP (-3.7 mm Hg [95% CI: 6.2, -1.1; p = 0.005]). CONCLUSIONS: A realistic high protein weight-reducing diet was associated with greater fat loss and lower blood pressure when compared with a high carbohydrate, high fiber diet in high risk overweight and obese women. PMID- 21524315 TI - Comparison of user groups' perspectives of barriers and facilitators to implementing electronic health records: a systematic review. AB - BACKGROUND: Electronic health record (EHR) implementation is currently underway in Canada, as in many other countries. These ambitious projects involve many stakeholders with unique perceptions of the implementation process. EHR users have an important role to play as they must integrate the EHR system into their work environments and use it in their everyday activities. Users hold valuable, first-hand knowledge of what can limit or contribute to the success of EHR implementation projects. A comprehensive synthesis of EHR users' perceptions is key to successful future implementation. This systematic literature review was aimed to synthesize current knowledge of the barriers and facilitators influencing shared EHR implementation among its various users. METHODS: Covering a period from 1999 to 2009, a literature search was conducted on nine electronic databases. Studies were included if they reported on users' perceived barriers and facilitators to shared EHR implementation, in healthcare settings comparable to Canada. Studies in all languages with an empirical study design were included. Quality and relevance of the studies were assessed. Four EHR user groups were targeted: physicians, other health care professionals, managers, and patients/public. Content analysis was performed independently by two authors using a validated extraction grid with pre-established categorization of barriers and facilitators for each group of EHR users. RESULTS: Of a total of 5,695 potentially relevant publications identified, 117 full text publications were obtained after screening titles and abstracts. After review of the full articles, 60 publications, corresponding to 52 studies, met the inclusion criteria. The most frequent adoption factors common to all user groups were design and technical concerns, ease of use, interoperability, privacy and security, costs, productivity, familiarity and ability with EHR, motivation to use EHR, patient and health professional interaction, and lack of time and workload. Each user group also identified factors specific to their professional and individual priorities. CONCLUSIONS: This systematic review presents innovative research on the barriers and facilitators to EHR implementation. While important similarities between user groups are highlighted, differences between them demonstrate that each user group also has a unique perspective of the implementation process that should be taken into account. PMID- 21524317 TI - 6th German Conference on Chemoinformatics, GCC 2010 Goslar, Germany. 7-9 November 2010. Abstracts. PMID- 21524316 TI - Effectiveness of PRECEDE model for health education on changes and level of control of HbA1c, blood pressure, lipids, and body mass index in patients with type 2 diabetes mellitus. AB - BACKGROUND: Individual health education is considered to be essential in the overall care of patients with type 2 diabetes (DM2), although there is some uncertainty regarding its metabolic control benefits. There have been very few randomized studies on the effects of individual education on normal care in DM2 patients with a control group, and none of these have assessed the long-term results. Therefore, this study aims to use this design to assess the effectiveness of the PRECEDE (Predisposing, Reinforcing, Enabling, Causes in Educational Diagnosis, and Evaluation) education model in the metabolic control and the reduction of cardiovascular risk factors, in patients with type 2 diabetes. METHODS: An open community effectiveness study was carried out in 8 urban community health centers in the North-East Madrid Urban Area (Spain). Six hundred patients with DM2 were randomized in two groups: PRECEDE or conventional model for health promotion education. The main outcome measures were glycated hemoglobin A1c, body mass index (BMI), blood pressure, lipids and control criteria during the 2-year follow-up period. RESULTS: Glycated hemoglobin A1c and systolic blood pressure (SBP) levels decreased significantly in the PRECEDE group (multivariate analysis of covariance, with baseline glycated hemoglobin A1c, SBP, and variables showing statistically significant differences between groups at baseline visits). The decrease levels in diastolic blood pressure (DBP), triglycerides and LDL cholesterol were nonsignificant. PRECEDE increased compliance in all control criteria, except for LDL cholesterol. BMI did not change during the study in either of the two models analyzed. CONCLUSIONS: PRECEDE health education model is a useful method in the overall treatment in patients with type 2 diabetes, which contributes to decrease glycated hemoglobin A1c and SBP levels and increase the compliance in all the control criteria, except for LDL cholesterol. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01316367. PMID- 21524319 TI - Pressure ulcers. AB - INTRODUCTION: Unrelieved pressure or friction of the skin, particularly over bony prominences, can lead to pressure ulcers in up to one third of people in hospitals or community care, and one fifth of nursing home residents. Pressure ulcers are more likely in people with reduced mobility and poor skin condition, such as older people or those with vascular disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in people at risk of developing pressure ulcers? What are the effects of treatments in people with pressure ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 64 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: air-filled vinyl boots, air-fluidised supports, alternating-pressure surfaces (including mattresses), alternative foam mattresses, constant low-pressure supports, debridement, electric profiling beds, electrotherapy, hydrocellular heel supports, low-air-loss beds (including hydrotherapy beds), low-level laser therapy, low-tech constant-low-pressure supports, medical sheepskin overlays, nutritional supplements, orthopaedic wool padding, pressure-relieving overlays on operating tables, pressure-relieving surfaces, repositioning (regular "turning"), seat cushions, standard beds, standard care, standard foam mattresses, standard tables, surgery, therapeutic ultrasound, topical lotions and dressings, topical negative pressure, and topical phenytoin. PMID- 21524320 TI - Determinants of life-history traits in a fish ectoparasite: a hierarchical analysis. AB - OBJECTIVE: Unravelling the determinants of parasite life-history traits in natural settings is complex. Here, we deciphered the relationships between biotic, abiotic factors and the variation in 4 life-history traits (body size, egg presence, egg number and egg size) in the fish ectoparasite Tracheliastes polycolpus. We then determined the factors affecting the strength of the trade off between egg number and egg size. METHODS: To do so, we used 4-level (parasite, microhabitat, host and environment) hierarchical models coupled to a field database. RESULTS: Variation in life-history traits was mostly due to individual characteristics measured at the parasite level. At the microhabitat level (fins of fish hosts), parasite number was positively related to body size, egg presence and egg number. Higher parasite number on fins was positively associated with individual parasite fitness. At the host level, host body size was positively related to the individual fitness of the parasite; parasites were bigger and more fecund on bigger hosts. In contrast, factors measured at the environmental level had a weak influence on life-history traits. Finally, a site dependent trade-off between egg number and egg size existed in this population. CONCLUSION: Our study illustrates the importance of considering parasite life history traits in a hierarchical framework to decipher complex links between biotic, abiotic factors and parasite life-history traits. PMID- 21524318 TI - Crohn's disease. AB - INTRODUCTION: Crohn's disease is a chronic condition of the gastrointestinal tract. It is characterised by transmural, granulomatous inflammation that occurs in a discontinuous pattern, with a tendency to form fistulae. The cause is unknown but may depend on interactions between genetic predisposition, environmental triggers, and mucosal immunity. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments to induce remission in adults with Crohn's disease? What are the effects of surgical interventions to induce and maintain remission in adults with small-bowel Crohn's disease? What are the effects of surgical interventions to induce remission in adults with colonic Crohn's disease? What are the effects of medical interventions to maintain remission in adults with Crohn's disease; and to maintain remission following surgery? What are the effects of lifestyle interventions to maintain remission in adults with Crohn's disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 93 systematic reviews, RCTs, or observational studies that met our inclusion criteria. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: aminosalicylates, antibiotics, azathioprine/mercaptopurine, ciclosporin, corticosteroids (oral), enteral nutrition, fish oil, infliximab, methotrexate, probiotics, resection, segmental colectomy, smoking cessation, and strictureplasty. PMID- 21524321 TI - The potential impact of native Australian trypanosome infections on the health of koalas (Phascolarctos cinereus). AB - Whole blood collected from koalas admitted to the Australian Zoo Wildlife Hospital (AZWH), Beerwah, QLd, Australia, during late 2006-2009 was tested using trypanosome species-specific 18S rDNA PCRs designed to amplify DNA from Trypanosoma irwini, T. gilletti and T. copemani. Clinical records for each koala sampled were reviewed and age, sex, blood packed cell volume (PCV), body condition, signs of illness, blood loss, trauma, chlamydiosis, bone marrow disease, koala AIDS and hospital admission outcome ('survival'/ 'non-survival') were correlated with PCR results. Overall 73.8% (439/595) of the koalas were infected with at least 1 species of trypanosome. Trypanosoma irwini was detected in 423/595 (71.1%), T. gilletti in 128/595 (21.5%) and T. copemani in 26/595 (4.4%) of koalas. Mixed infections were detected in 125/595 (21%) with co infections of T. irwini and T. gilletti (101/595, 17%) being most common. There was a statistical association between infection with T. gilletti with lower PCV values and body condition scores in koalas with signs of chlamydiosis, bone marrow disease or koala AIDS. No association between T. gilletti infection and any indicator of health was observed in koalas without signs of concurrent disease. This raises the possibility that T. gilletti may be potentiating other disease syndromes affecting koalas. PMID- 21524322 TI - Mixed Theileria infections in free-ranging buffalo herds: implications for diagnosing Theileria parva infections in Cape buffalo (Syncerus caffer). AB - Buffalo-adapted Theileria parva causes Corridor disease in cattle. Strict control measures therefore apply to the movement of buffalo in South Africa and include mandatory testing of buffalo for the presence of T. parva. The official test is a real-time hybridization PCR assay that amplifies the V4 hypervariable region of the 18S rRNA gene of T. parva, T. sp. (buffalo) and T. sp. (bougasvlei). The effect that mixed T. parva and T. sp. (buffalo)-like infections have on accurate T. parva diagnosis was investigated in this study. In vitro mixed infection simulations indicated PCR signal suppression at 100 to 1000-fold T. sp. (buffalo) excess at low T. parva parasitaemia. Suppression of PCR signal was found in field buffalo with mixed infections. The T. parva-positive status of these cases was confirmed by selective suppression of T. sp. (buffalo) amplification using a locked nucleic acid clamp and independent assays based on the p67, p104 and Tpr genes. The incidence of mixed infections in the Corridor disease endemic region of South Africa is significant, while the prevalence in buffalo outside the endemic area is currently low. A predicted increase of T. sp. (buffalo)-like infections can affect future diagnoses where mixed infections occur, prompting the need for improvements in current diagnostics. PMID- 21524323 TI - Environmental constraints influencing survival of an African parasite in a north temperate habitat: effects of temperature on egg development. AB - Factors affecting survival of parasites introduced to new geographical regions include changes in environmental temperature. Protopolystoma xenopodis is a monogenean introduced with the amphibian Xenopus laevis from South Africa to Wales (probably in the 1960s) where low water temperatures impose major constraints on life-cycle processes. Effects were quantified by maintenance of eggs from infections in Wales under controlled conditions at 10, 12, 15, 18, 20 and 25 degrees C. The threshold for egg viability/ development was 15 degrees C. Mean times to hatching were 22 days at 25 degrees C, 32 days at 20 degrees C, extending to 66 days at 15 degrees C. Field temperature records provided calibration of transmission schedules. Although egg production continues year round, all eggs produced during >8 months/ year die without hatching. Output contributing significantly to transmission is restricted to 10 weeks (May-mid July). Host infection, beginning after a time lag of 8 weeks for egg development, is also restricted to 10 weeks (July-September). Habitat temperatures (mean 15.5 degrees C in summer 2008) allow only a narrow margin for life-cycle progress: even small temperature increases, predicted with 'global warming', enhance infection. This system provides empirical data on the metrics of transmission permitting long-term persistence of isolated parasite populations in limiting environments. PMID- 21524324 TI - A case-controlled study of Dientamoeba fragilis infections in children. AB - Dientamoeba fragilis is a pathogenic protozoan parasite that is implicated as a cause of human diarrhoea. A case-controlled study was conducted to determine the clinical signs associated with D. fragilis infection in children presenting to a Sydney Hospital. Treatment options are also discussed. Stool specimens were collected from children aged 15 years or younger and analysed for the presence of D. fragilis. In total, 41 children were included in the study along with a control group. Laboratory diagnosis was performed by microscopy of permanently stained, fixed faecal smears and by real-time PCR. Gastrointestinal symptoms were present in 40/41 (98%) of these children with dientamoebiasis, with diarrhoea (71%) and abdominal pain (29%) the most common clinical signs. Chronic gastrointestinal symptoms were present in 2% of cases. The most common anti microbial used for treatment was metronidazole (n=41), with complete resolution of symptoms and clearance of parasite occurring in 85% of cases. A treatment failure rate occurred in 15% of those treated with metronidazole. Follow-up treatment comprised of an additional course of metronidazole or iodoquinol was needed in order to achieve complete resolution of infection and symptoms in this group. This study demonstrates the pathogenic potential of D. fragilis in children and as such it is recommended that all laboratories must routinely test for this organism and treat if detected. PMID- 21524325 TI - Effects of inbreeding on potential and realized immune responses in Tenebrio molitor. AB - Although numerous studies on vertebrates suggest that inbreeding reduces their resistance against parasites and pathogens, studies in insects have found contradictory evidence. In this study we tested the effect of 1 generation of brother-sister mating (inbreeding) on potential and realized immune responses and other life-history traits in Tenebrio molitor. We found that inbreeding reduced adult mass, pre-adult survival and increased development time, suggesting that inbreeding reduced the condition of the adults and thus potentially made them more susceptible to physiological stress. However, we found no significant effect of inbreeding on the potential immune response (encapsulation response), but inbreeding reduced the realized immune response (resistance against the entomopathogenic fungi, Beauveria bassiana). There was a significant family effect on encapsulation response, but no family effect on the resistance against the entomopathogenic fungi. Given that this latter trait showed significant inbreeding depression and that the sample size for the family-effect analysis was small it is likely that the lack of a significant family effect is due to reduced statistical power, rather than the lack of a heritable basis to the trait. Our study highlights the importance of using pathogens and parasites in immunoecological studies. PMID- 21524326 TI - Analysis of elemental composition of the eggshell before and after incubation in the loggerhead turtle ( Caretta caretta) in Oman. AB - To date, there are limited studies on loggerhead turtle (Caretta caretta) eggshell ultrastructure and its elemental composition. Eggs were collected from turtle nests immediately after oviposition and post hatching. Three eggshell layers were recognized. The outer calcareous layer consists of loose nodular units of different shapes and sizes with loose attachment between the units, resulting in numerous spaces and openings. Each unit consists of CaCO3 crystals in aragonite (99%) and calcite (1%). The middle layer has several strata with numerous openings connecting the calcareous and the inner shell membrane. Crystallites of the middle layer are a mix of amorphous material with aragonite (62%) and calcite (38%). The inner shell membrane has numerous reticular fibers mixed predominantly with halite (NaCl) and small amounts of sylvite. Thermogravimetry analysis of the calcareous showed a low exothermic peak at 425 degrees C, which corresponds to a transitional phase from aragonite to calcite. A high endothermic peak at 814 degrees C corresponds to decomposition of calcite CaCO3 to CaO and CO2. Electron diffraction confirmed the presence of NaCl halite crystal. A significant difference was found in the percentage of elements and crystal configurations in the three layers. This study has value in assessing the emergence success in this endangered species. PMID- 21524327 TI - The relationship between coping and subclinical psychotic experiences in adolescents from the general population--a longitudinal study. AB - BACKGROUND: Subclinical psychotic experiences during adolescence may represent liability for developing psychotic disorder. Both coping style and the degree of persistence of psychotic experiences may play a role in the progression to clinical psychotic disorder, but little is known about the causal relationship between the two. METHOD: Path modelling was used to examine longitudinal relationships between subclinical positive psychotic experiences and three styles of coping (task-, emotion- and avoidance-oriented) in an adolescent general population sample (n=813) assessed three times in 3 years. Distinct developmental trajectories of psychotic experiences, identified with growth mixture modelling, were compared on the use of these coping styles. RESULTS: Over time, emotion oriented coping in general was bi-directionally related to psychotic experiences. No meaningful results were found for task- or avoidance-oriented coping. Females reported using a wider range of coping styles than males, but the paths between coping and psychotic experiences did not differ by gender. Persistence of psychotic experiences was associated with a greater use of emotion-oriented coping, whereas a decrease in experiences over time was associated with an increased use of task-orientated coping. CONCLUSIONS: Emotion-oriented coping is the most important coping style in relation to psychotic experiences, as it may contribute to a 'vicious cycle' and is associated with persistence of experiences. In addition, more task-oriented coping may result in a decrease in psychotic experiences. Results suggest that opportunities for intervention may already be present at the level of subclinical psychosis. PMID- 21524328 TI - Coblation of rhinophyma. AB - INTRODUCTION: Rhinophyma is a disfiguring hypertrophy of the skin of the tip of the nose. OBJECTIVE: To assess the new technique of coblation of rhinophyma. STUDY DESIGN: Case series of six patients. RESULTS: All patients had a good cosmetic result. Comparison with existing techniques showed advantages due to the lower tissue temperature involved. CONCLUSION: Coblation of rhinophyma is an effective treatment with few side effects. PMID- 21524329 TI - The point-touch technique for botulinum toxin injection in adductor spasmodic dysphonia: quality of life assessment. AB - BACKGROUND: Botulinum toxin injection under electromyographic guidance is the 'gold standard' for adductor spasmodic dysphonia treatment. The point-touch technique, an alternative injection method which relies on anatomical landmarks, is cheaper, quicker and more accessible, but has not yet gained widespread acceptance due to concerns about patient satisfaction. OBJECTIVE: To assess swallowing and voice-related quality of life following point-touch botulinum toxin injection in adductor spasmodic dysphonia patients. SETTING: Stanford University Voice and Swallowing Center. DESIGN: Prospective case series (evidence level four). METHODS: Consecutive adductor spasmodic dysphonia patients with a stable botulinum toxin dose-response relationship were recruited prospectively. The Eating Assessment Tool and Voice-Related Quality of Life questionnaires were completed pre-treatment and at 10 and 30 per cent completion of the injection cycle, respectively. RESULTS: Thirty-seven patients completed follow up. The mean total botulinum toxin dose was 0.88 units. Pre-treatment Voice-Related Quality of Life questionnaire results reflected the burden of disease. Post-treatment Eating Assessment Tool and Voice-Related Quality of Life questionnaire results were collected at 2.53 and 7.84 weeks, respectively; the former showed an increase in dysphagia, albeit statistically insignificant, while the latter showed significantly improved scores (both domain and total). CONCLUSION: The point touch technique is a viable alternative for botulinum toxin injection in the treatment of adductor spasmodic dysphonia. PMID- 21524330 TI - Contrecoup injury in patients with traumatic temporal bone fracture. AB - OBJECTIVE: To study the prevalence and patterns of contrecoup injury in traumatic temporal bone fracture cases. METHOD: A prospective, cohort study was undertaken of all patients with traumatic head injury admitted to a tertiary referral hospital in Malaysia within an 18-month period. High resolution computed tomography scans of the brain and skull base were performed in indicated cases, based on clinical findings and Glasgow coma score. Patients with a one-sided temporal bone fracture were selected and subsequent magnetic resonance imaging performed in all cases. Contrecoup injury incidence, type, severity and outcome were recorded. RESULTS: Of 1579 head injury cases, 81 (5.1 per cent) met the inclusion criteria and were enrolled in the study. Temporal bone fractures were significantly associated with intracranial injuries (p < 0.001). The incidence of a contrecoup injury in cases with temporal bone fracture was 13.6 per cent. Contrecoup injury was significantly associated with petrous temporal bone fracture (p < 0.01). The commonest contrecoup injury was cerebral contusion, followed by extradural haematoma and subdural haematoma. CONCLUSION: Contrecoup injury is not uncommon in cases of temporal bone fracture, and is significantly associated with petrous temporal bone fracture. PMID- 21524331 TI - The use of transient evoked otoacoustic emissions as a hearing screen following grommet insertion. AB - OBJECTIVE: This study aimed to evaluate the sensitivity of transient evoked otoacoustic emission testing as a screening tool for hearing loss in children, after grommet insertion. METHOD: A prospective study was conducted of 48 children (91 ears) aged three to 16 years who had undergone grommet insertion for glue ear. At post-operative review, pure tone audiometry was performed followed by transient evoked otoacoustic emission testing. Outcomes for both tests, in each ear, were compared. RESULTS: The pure tone audiometry threshold was <= 20 dB in 85 ears (93.4 per cent), 25 dB in two ears (2.2 per cent) and >= 30 dB in four ears (4.4 per cent). Transient evoked otoacoustic emissions were detected in 69 ears (75.8 per cent). The sensitivity of transient evoked otoacoustic emission testing for detecting hearing loss was 100 per cent for >= 30 dB loss but only 66.7 per cent for >= 25 dB loss. CONCLUSION: Transient evoked otoacoustic emission testing offers a sensitive means of detecting hearing loss of >= 30 dB following grommet insertion in children. However, the use of such testing as a screening tool may miss some cases of mild hearing loss. PMID- 21524332 TI - Increased mortality risk among offspring of mothers with postnatal depression: a nationwide population-based study in Taiwan. AB - BACKGROUND: There is compelling evidence that children of mothers with postnatal depression (PD) experience poor developmental outcomes. However, no studies have specifically ascertained the risk of mortality for offspring during preschool years, the most catastrophic outcome in the vulnerable period. This nationwide population-based study aimed to investigate whether maternal depression in the first year after giving birth was associated with increased mortality risk among their preschool children aged up to 5 years. METHOD: Three nationwide population based datasets [the National Health Insurance Research Database (NHIRD), birth certificate registry and death certificate registry] were linked in this study. A total of 10 236 offspring of mothers with PD were recruited, together with a comparison cohort of 81 888 births matched with the affected women in terms of maternal age and year of delivery. Each child was traced for 5 years from delivery between 2001 and 2003 until the end of 2008 to determine mortality during preschool years. RESULTS: During preschool years, 98 (0.96%) deaths were identified among the offspring of mothers with PD and 470 (0.57%) children in the comparison cohort died. For children up to 5 years old, exposure to maternal PD was independently associated with a 1.47-fold [95% confidence interval (CI) 1.16 1.87] increased mortality risk, after adjusting for family income, urbanization level and the characteristics of mother, father and infant. The risk of death by unnatural causes was even higher (about 2.23 times the risk, 95% CI 1.34-3.70) among exposed offspring. CONCLUSIONS: PD places preschool children at significantly increased risk of mortality, especially from unnatural causes of death. PMID- 21524333 TI - Sensitivity to stress among the offspring of parents with bipolar disorder: a study of daytime cortisol levels. AB - BACKGROUND: It is well known that the hypothalamic-pituitary-adrenal (HPA) axis is compromised in major depression and bipolar disorder. There is increasing evidence that subtle HPA abnormalities, such as elevated cortisol levels, precede the development of an affective disorder. Interpersonal stress is also associated with the development of affective disorders. The present study sought to determine whether interpersonal chronic and episodic stress moderated the relationship between cortisol levels in the natural environment and risk status, defined as having a parent with bipolar disorder. METHOD: Sixty-two offspring of parents with bipolar disorder (OBD) and 60 offspring with no family history of affective disorders (OFH-), aged 19.48 years (s.d.=3.38, range 14-28), completed interviews assessing mental disorders and chronic and episodic stress, and provided saliva samples over 3 days. RESULTS: Regression analyses revealed that the OBD who experienced high interpersonal chronic stress displayed a larger cortisol rise following awakening than the OBD reporting low interpersonal chronic stress. The same relationship was also found for levels of non interpersonal chronic stress. The OBD who reported experiencing severe interpersonal episodic stress exhibited higher levels of daytime cortisol than the OBD reporting interpersonal episodic stress of mild severity. Importantly, none of the above relationships were detected in the OFH-. Each of the interactions between family history of affective disorders and stress remained after controlling for age, gender and offspring lifetime affective disorders and current non-affective disorders. CONCLUSIONS: A biological sensitivity to stress may underlie the susceptibility to affective disorders among the OBD. PMID- 21524334 TI - Schizophrenia patients are impaired in empathic accuracy. AB - BACKGROUND: Empathy is crucial for successful social relationships. Despite its importance for social interactions, little is known about empathy in schizophrenia. This study investigated the degree to which schizophrenia patients can accurately infer the affective state of another person (i.e. empathic accuracy). METHOD: A group of 30 schizophrenia patients and 22 healthy controls performed an empathic accuracy task on which they continuously rated the affective state of another person shown in a video (referred to as the 'target'). These ratings were compared with the target's own continuous self-rating of affective state; empathic accuracy was defined as the correlation between participants' ratings and the targets' self-ratings. A separate line-tracking task was administered to measure motoric/attentional factors that could account for group differences in performance. Participants' self-rated empathy was measured using the Interpersonal Reactivity Index, and targets' self-rated emotional expressivity was measured using the Berkeley Expressivity Questionnaire. RESULTS: Compared with controls, schizophrenia patients showed lower empathic accuracy although they performed the motoric tracking task at high accuracy. There was a significant group*target expressivity interaction such that patients showed a smaller increase in empathic accuracy with higher levels of emotional expressivity by the target, compared with controls. Patients' empathic accuracy was uncorrelated with self-reported empathy or clinical symptoms. CONCLUSIONS: Schizophrenia patients showed lower empathic accuracy than controls, and their empathic accuracy was less influenced by the emotional expressivity of the target. These findings suggest that schizophrenia patients benefit less from social cues of another person when making an empathic judgement. PMID- 21524336 TI - Deep transcranial magnetic stimulation add-on for treatment of negative symptoms and cognitive deficits of schizophrenia: a feasibility study. AB - Treatment for negative symptoms and cognitive deficits, core elements of schizophrenia, remains inadequate. Stimulation of the prefrontal cortex via transcranial magnetic stimulation (TMS) yields only moderate results, possibly due to limited stimulation depth. Deep-TMS enables deeper and wider stimulation than before. This preliminary study is the first to examine deep-TMS as a possible add-on treatment for negative symptoms and cognitive deficits of schizophrenia. The effect of 20 daily deep-TMS sessions (20 Hz, 120% motor threshold) over the prefrontal cortex of 15 patients indicated improvement in cognition and negative symptoms that was maintained at 2-wk post-treatment follow up. PMID- 21524335 TI - Modulation of haloperidol-induced patterns of the transcription factor Nur77 and Nor-1 expression by serotonergic and adrenergic drugs in the mouse brain. AB - Different patterns of expression of the transcription factors of Nur77 and Nor-1 are induced following acute administration of typical and atypical antipsychotic drugs. The pharmacological profile of atypical antipsychotics suggests that serotonergic and/or adrenergic receptors might contribute to these reported differences. In order to test this possibility, we examined the abilities of serotonin 5-HT(1A) and 5-HT(2A/2C), and alpha1- and alpha2-adrenergic receptor drugs to modify the pattern of Nur77 (NR4A1) and Nor-1 (NR4A3) mRNA expression induced by haloperidol. Various groups of mice were treated with either saline, DOI, a 5-HT(2A/2C) agonist, MDL11939, a 5-HT(2A) antagonist, 8-OH-DPAT, a 5 HT(1A) agonist, prazosin, an alpha1-adrenergic antagonist and idazoxan, an alpha2 adrenergic antagonist, alone or in combination with haloperidol. The 5-HT(2A/2C) agonist DOI alone significantly increased Nur77 expression in the medial striatum and nucleus accumbens. DOI reduced Nor-1 expression, while MDL11939 increased the expression of this transcript in the cortex. Prazosin reduced Nur77 expression in the dorsal striatum and nucleus accumbens. Interestingly, 8-OH-DPAT and MDL11939 partially prevented haloperidol-induced Nur77 up-regulation, while MDL11939 completely abolished Nor-1 expression in the striatum. In addition, MDL11939 decreased haloperidol-induced Nur77 and Nor-1 mRNA levels in the ventral tegmental area. On the contrary, idazoxan (alpha2 antagonist) consistently potentiated haloperidol-induced Nur77, but not Nor-1 mRNA levels in the striatum, whereas prazosin (alpha1 antagonist) remained without effect. Taken together, these results show the ability of a 5-HT(1A) agonist or a 5-HT(2A) antagonist to reduce haloperidol-induced Nur77 and Nor-1 striatal expression, suggesting that these serotonin receptor subtypes participate in the differential pattern of gene expression induced by typical and atypical antipsychotic drugs. PMID- 21524337 TI - Electronic detectors for electron microscopy. AB - Electron microscopy (EM) is an important tool for high-resolution structure determination in applications ranging from condensed matter to biology. Electronic detectors are now used in most applications in EM as they offer convenience and immediate feedback that is not possible with film or image plates. The earliest forms of electronic detector used routinely in transmission electron microscopy (TEM) were charge coupled devices (CCDs) and for many applications these remain perfectly adequate. There are however applications, such as the study of radiation-sensitive biological samples, where film is still used and improved detectors would be of great value. The emphasis in this review is therefore on detectors for use in such applications. Two of the most promising candidates for improved detection are: monolithic active pixel sensors (MAPS) and hybrid pixel detectors (of which Medipix2 was chosen for this study). From the studies described in this review, a back-thinned MAPS detector appears well suited to replace film in for the study of radiation-sensitive samples at 300 keV, while Medipix2 is suited to use at lower energies and especially in situations with very low count rates. The performance of a detector depends on the energy of electrons to be recorded, which in turn is dependent on the application it is being used for; results are described for a wide range of electron energies ranging from 40 to 300 keV. The basic properties of detectors are discussed in terms of their modulation transfer function (MTF) and detective quantum efficiency (DQE) as a function of spatial frequency. PMID- 21524338 TI - What the bird's brain tells the bird's eye: the function of descending input to the avian retina. AB - As Cajal discovered in the late 19th century, the bird retina receives a substantial input from the brain. Approximately 10,000 fibers originating in a small midbrain nucleus, the isthmo-optic nucleus (ION), terminate in each retina. The input to the ION is chiefly from the optic tectum which, in the bird, is the primary recipient of retinal input. These neural elements constitute a closed loop, the centrifugal visual system (CVS), beginning and ending in the retina, that delivers positive feedback to active ganglion cells. Several features of the system are puzzling. All fibers from the ION terminate in the ventral retina and an unusual axon-bearing amacrine cell, the target cell, is the postsynaptic partner of these fibers. While the rest of the CVS is orderly and retinotopic, target cell axons project seemingly at random, mostly to distant parts of the retina. We review here the most significant features of the anatomy and physiology of the CVS with a view to understanding its function. We suggest that many of the facts about this system, including some that are otherwise difficult to explain, can be accommodated within the hypothesis that the images of shadows cast on the ground or on objects in the environment, initiate a rapid and parallel search of the sky for a possible aerial predator. If a predator is located, shadow and predator would be temporarily linked together and tracked by the CVS. PMID- 21524341 TI - Age factor and implication of human papillomavirus type-specific prevalence in women with normal cervical cytology. AB - The prevalence and genotype distribution of human papillomavirus (HPV) infection in women with normal cervical cytology varies widely according to the population studied. Two non-overlapping population-based cohort studies of women aged >=30 years for the periods 2008-2009 (n=5026) and 2004-2005 (n=10 014) were analysed. The prevalence rate of HPV was 11.0% (95% CI 10.5-11.6). HPV infection was significantly associated with age, menopausal status, and inversely associated with hormone replacement therapy. There was an increasing trend of alpha3/alpha15, alpha5/alpha6, and multiple HPV infections with increasing age. The five most common types were HPV52, 18, 53, 58 and 70, while HPV16, 31, 33 ranked 21st, 25th, and 16th, respectively, in the merged cohort with normal cytology (n=14 724). HPV16, 31, and 33 were significantly associated with abnormal cytology, which could have resulted in their rarity in the total merged cohort (n=15 040). PMID- 21524339 TI - Evidence for Nipah virus recrudescence and serological patterns of captive Pteropus vampyrus. AB - This study aimed to describe the transmission dynamics, the serological and virus excretion patterns of Nipah virus (NiV) in Pteropus vampyrus bats. Bats in captivity were sampled every 7-21 days over a 1-year period. The data revealed five NiV serological patterns categorized as high and low positives, waning, decreasing and increasing, and negative in these individuals. The findings strongly suggest that NiV circulates in wild bat populations and that antibody could be maintained for long periods. The study also found that pup and juvenile bats from seropositive dams tested seropositive, indicating that maternal antibodies against NiV are transmitted passively, and in this study population may last up to 14 months. NiV was isolated from the urine of one bat, and within a few weeks, two other seronegative bats seroconverted. Based on the temporal cluster of seroconversion, we strongly believe that the NiV isolated was recrudesced and then transmitted horizontally between bats during the study period. PMID- 21524340 TI - Clinical significance of methicillin-resistant Staphylococcus aureus colonization in residents in community long-term-care facilities in Spain. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent in Spanish hospitals and community long-term-care facilities (LTCFs). This longitudinal study was performed in community LTCFs to determine whether MRSA colonization is associated with MRSA infections and overall mortality. Nasal and decubitus ulcer cultures were performed every 6 months for an 18-month period on 178 MRSA colonized residents (86 490 patient-days) and 196 non-MRSA carriers (97 470 patient-days). Fourteen residents developed MRSA infections and 10 of these were skin and soft tissue infections. Two patients with respiratory infections required hospitalization. The incidence rate of MRSA infection was 0.12/1000 patient-days in MRSA carriers and 0.05/1000 patient-days in non-carriers (P=0.46). No difference in MRSA infection rate was found according to the duration of MRSA colonization (P=0.69). The mortality rate was 20.8% in colonized residents and 16.8% in non-carriers; four residents with MRSA infection died. Overall mortality was statistically similar in both cohorts. Our results suggest that despite a high prevalence of MRSA colonization in LTCFs, MRSA infections are neither frequent nor severe while colonized residents remain at the facility. The epidemiological impact of an MRSA reservoir is more relevant than the clinical impact of this colonization for an individual resident and supports current recommendations to control MRSA spread in community LTCFs. PMID- 21524342 TI - A meta-analysis of the effect of dose and age at exposure on shedding of Mycobacterium avium subspecies paratuberculosis (MAP) in experimentally infected calves and cows. AB - A meta-analysis was performed using all published and one unpublished long-term infection-challenge experiments to quantify the age- and dose-dependence of early and late shedding of Mycobacterium avium subsp. paratuberculosis (MAP) in cattle. There were 194 animals from 17 studies that fulfilled the inclusion criteria, of which 173 received a known dose of MAP and 21 were exposed naturally. Results from parametric time-to-event models indicated that challenging older calves or using multiple-exposure experimental systems resulted in a smaller proportion and shorter duration of early shedding as well as slower transition to late shedding from latent compartments. Calves exposed naturally showed variable infection progression rates, not dissimilar to other infection routes. The log-normal distribution was most appropriate for modelling infection-progression events. The infection pattern revealed by the modelling allowed better understanding of low grade endemicity of MAP in cattle, and the parameter estimates are the basis for future transmission dynamics modelling. PMID- 21524343 TI - Norovirus outbreak associated with undercooked oysters and secondary household transmission. AB - During December 2009, over 200 individuals reported gastrointestinal symptoms after dining at a North Carolina restaurant. An outbreak investigation included a case-control study of restaurant patrons, a secondary household transmission study, environmental assessment of the restaurant facilities and operations, and laboratory analysis of stool and food samples. Illness was primarily associated with consumption of steamed oysters (odds ratio 12, 95% confidence interval 4.8 28) and 20% (8/41 households) reported secondary cases, with a secondary attack rate of 14% among the 70 susceptible household contacts. Norovirus RNA was detected in 3/5 stool specimens from ill patrons; sequencing of RT-PCR products from two of these specimens identified identical genogroup II genotype 12 sequences. Final cooked temperatures of the steamed oysters were generally inadequate to inactivate norovirus, ranging from 21 degrees C to 74 degrees C. Undercooked contaminated oysters pose a similar risk for norovirus illness as raw oysters and household contacts are at risk for secondary infection. PMID- 21524344 TI - An outbreak of rubella in the Federation of Bosnia and Herzegovina between December 2009 and May 2010 indicates failure to vaccinate during wartime (1992 1995). AB - A rubella outbreak involving 1900 cases was recorded in the Federation of Bosnia and Herzegovina between mid-December 2009 and the end of May 2010. Sera from 389 suspected rubella cases were examined for the presence of rubella-specific IgM and IgG antibodies. A total of 32 throat swabs from suspected rubella cases were tested by RT-PCR and were used to attempt virus isolation. Most patients (945/1900, 49.73%) had never received rubella vaccination or had an unknown vaccination status (563/1900, 29.63%). About 45% (178/389) of suspected rubella patients were IgM positive. From 13 of the throat swabs a virus isolate and E1 gene sequences attributed to genotype 2B were obtained. The rubella outbreak was due to failure to vaccinate during the war period (1992-1995) and emphasizes the need for additional vaccination opportunities. PMID- 21524345 TI - Statistics: all together now, one step at a time. PMID- 21524346 TI - Mechanism of T cell exhaustion in a chronic environment. AB - T cell exhaustion develops under conditions of antigen-persistence caused by infection with various chronic pathogens, such as human immunodeficiency virus (HIV) and mycobacterium tuberculosis (TB), or by the development of cancer. T cell exhaustion is characterized by stepwise and progressive loss of T cell function, which is probably the main reason for the failed immunological control of chronic pathogens and cancers. Recent observations have detailed some of the intrinsic and extrinsic factors that influence the severity of T cell exhaustion. Duration and magnitude of antigenic activation of T cells might be associated with up-regulation of inhibitory receptors, which is a major intrinsic factor of T cell exhaustion. Extrinsic factors might include the production of suppressive cytokines, T cell priming by either non-professional antigen-presenting cells (APCs) or tolerogenic dendritic cells (DCs), and alteration of regulatory T (Treg) cells. Further investigation of the cellular and molecular processes behind the development of T cell exhaustion can reveal therapeutic targets and strategies for the treatment of chronic infections and cancers. Here, we report the properties and the mechanisms of T cell exhaustion in a chronic environment. PMID- 21524347 TI - Current progress on development of respiratory syncytial virus vaccine. AB - Human respiratory syncytial virus (HRSV) is a major cause of upper and lower respiratory tract illness in infants and young children worldwide. Despite its importance as a respiratory pathogen, there is currently no licensed vaccine for prophylaxis of HRSV infection. There are several hurdles complicating the development of a RSV vaccine: 1) incomplete immunity to natural RSV infection leading to frequent re-infection, 2) immature immune system and maternal antibodies of newborn infants who are the primary subject population, and 3) imbalanced Th2-biased immune responses to certain vaccine candidates leading to exacerbated pulmonary disease. After the failure of an initial trial featuring formalin-inactivated virus as a RSV vaccine, more careful and deliberate efforts have been made towards the development of safe and effective RSV vaccines without vaccine-enhanced disease. A wide array of RSV vaccine strategies is being developed, including live-attenuated viruses, protein subunit-based, and vector based candidates. Though licensed vaccines remain to be developed, our great efforts will lead us to reach the goal of attaining safe and effective RSV vaccines in the near future. PMID- 21524348 TI - Functional analysis of expressed sequence tags from the liver and brain of Korean Jindo dogs. AB - We generated 16,993 expressed sequence tags (ESTs) from two libraries containing full-length cDNAs from the brain and liver of the Korean Jindo dog. An additional 365,909 ESTs from other dog breeds were identified from the NCBI dbEST database, and all ESTs were clustered into 28,514 consensus sequences using StackPack. We selected the 7,305 consensus sequences that could be assembled from at least five ESTs and estimated that 12,533 high-quality single nucleotide polymorphisms (SNPs) were present in 97,835 putative SNPs from the 7,305 consensus sequences. We identified 58 Jindo dog-specific SNPs in comparison to other breeds and predicted seven synonymous SNPs and ten non-synonymous SNPs. Using PolyPhen, a program that predicts changes in protein structure and potential effects on protein function caused by amino acid substitutions, three of the non-synonymous SNPs were predicted to result in changes in protein function for proteins expressed by three different genes (TUSC3, ITIH2, and NAT2). PMID- 21524349 TI - Ex12 helper phage improves the quality of a phage-displayed antibody library by ameliorating the adverse effect of clonal variations. AB - The quality of a phage-displayed antibody library deteriorates with clonal variations, which are caused by differentially expressed Escherichia coli antibody genes. Using the human Fab SP114 against the pyruvate dehydrogenase complex-E2 (PDCE2), we created four E. coli TOP10F' clones with a pCMTG phagemid encoding Fab-pIII (pCMTG-Fab), Fd (V(H)+C(H1))-pIII (pCMTG-Fd), or light chain (L) (pCMTG-L), or the vector only (pCMTG-?Fab) to investigate the effect of clonal variations in a defined manner. Compared to the others, the E. coli clone with pCMTG-Fab was growth retarded in liquid culture, but efficiently produced phage progenies by Ex12 helper phage superinfection. Our results suggest that an antibody library must be cultured for a short duration before helper phage superinfection, and that the Ex12 helper phage helped to alleviate the detrimental effect of clonal variation, at least in part, by preferentially increasing functional phage antibodies during phage amplification. PMID- 21524350 TI - Predicting tissue-specific expressions based on sequence characteristics. AB - In multicellular organisms, including humans, understanding expression specificity at the tissue level is essential for interpreting protein function, such as tissue differentiation. We developed a prediction approach via generated sequence features from overrepresented patterns in housekeeping (HK) and tissue specific (TS) genes to classify TS expression in humans. Using TS domains and transcriptional factor binding sites (TFBSs), sequence characteristics were used as indices of expressed tissues in a Random Forest algorithm by scoring exclusive patterns considering the biological intuition; TFBSs regulate gene expression, and the domains reflect the functional specificity of a TS gene. Our proposed approach displayed better performance than previous attempts and was validated using computational and experimental methods. PMID- 21524351 TI - The protein truncation caused by fusion of PEP-1 peptide and protective roles of transduced PEP-1-MsrA in skin cells. AB - PEP-1 peptide has been used for transduction of native protein into mammalian cells. This work describes the findings that the fusion of PEP-1 to target proteins led to protein truncation likely in a non-protein-specific manner. Approximately 75% of PEP-1-MsrA fusion protein was truncated in the N-terminal region of MsrA between Lys-27 and Val-28 during expression in Escherichia coli and purification. This large protein truncation was also observed in another PEP 1 fused protein, PEP-1- MsrB2, in the N-terminal region of MsrB2. The full-length PEP-1-MsrA protein was rapidly transduced into keratinocyte cells within 15 min. The transduced PEP-1-MsrA was functionally active and could protect skin cells against oxidative stress-and ultraviolet radiation-induced cell death. Collectively, our data demonstrated the protective roles of MsrA in skin cells and, moreover, may raise a concern of protein truncation caused by fusion of PEP 1 about the general use of this peptide for protein transduction. PMID- 21524352 TI - Identification of strain harboring both aac(6')-Ib and aac(6')-Ib-cr variant simultaneously in Escherichia coli and Klebsiella pneumoniae. AB - The aac(6')-Ib gene is the most prevalent gene that encodes aminoglycoside modifying enzymes and confers resistance to tobramycin, kanamycin, and amikacin. The aac(6')-Ib-cr variant gene can induce resistance against aminoglycoside and fluoroquinolone simultaneously. Two main methods, sequence analysis and the restriction enzyme method, can detect the aac(6')-Ib-cr variant in clinical strains. We collected the 85 strains that were believed to be aac(6')-Ib positive from clinical isolates. Among them, 38 strains were the wild-type; the remaining 47 strains were the aac(6')-Ib-cr variant. Of these 47 strains, 19 simultaneously harbored aac(6')-Ib and aac(6')-Ib-cr. Our study aims to report the characteristics of the 19 strains that simultaneously harbored both genes. This study is the first investigation published in Korea of strains that included both aac(6')-Ib and aac(6')-Ib-cr variant. PMID- 21524353 TI - ZAS3 promotes TNFalpha-induced apoptosis by blocking NFkappaB-activated expression of the anti-apoptotic genes TRAF1 and TRAF2. AB - ZAS3 is a large zinc finger transcription repressor that binds the kappaB-motif via two signature domains of ZASN and ZASC. A loss-of-function study showed that lack of ZAS3 protein induced accelerated cell proliferation and tumorigenesis. Conversely, gain-of-function studies showed that ZAS3 repressed NFkappaB activated transcription by competing with NFkappaB for the kappaB-motif. Based on these observations, we hypothesize that ZAS3 promotes apoptosis by interrupting anti-apoptotic activity of NFkappaB. Here, we present evidence that upon TNFalpha stimulation, ZAS3 inhibits NFkappaB-mediated cell survival and promotes caspase mediated apoptosis. The inhibitory effect of ZAS3 on NFkappaB activity is mediated by neither direct association with NFkappaB nor disrupting nuclear localization of NFkappaB. Instead, ZAS3 repressed the expression of two key anti apoptotic genes of NFkappaB, TRAF1 and TRAF2, thereby sensitizing cells to TNFalpha-induced cell death. Taken together, our data suggest that ZAS3 is a tumor suppressor gene and therefore serves as a novel therapeutic target for developing anti-cancer drugs. PMID- 21524354 TI - Effects of lipopolysaccharide and CpG-DNA on burn-induced skin injury. AB - Destruction of the skin barrier by thermal injury induces microbial invasion, which can lead to the development of systemic infection and septic shock. Microbial pathogens possess pathogen-associated molecular patterns (PAMPs), which are recognized by conserved receptors. To understand the role of PAMPs in thermal injury-induced mice, LPS or CpG-DNA were topically applied to dorsal skin after thermal injury. We observed an increase in the number of inflammatory cell infiltrates as well as thickening in the dermis upon treatment with LPS or CpG DNA. We also found that expression of IL-1beta, MIP-2, and RANTES induced by thermal injury was enhanced by LPS or CpG-DNA. In addition, the proportions of CD4(+) and CD8(+) T cells in the spleen and lymph nodes were altered by LPS or CpG-DNA. These results provide important information concerning PAMPs-induced inflammation upon thermal injury and provide a basis for studying the role of PAMPs in thermal injury-induced complications. PMID- 21524355 TI - Improved recovery of active GST-fusion proteins from insoluble aggregates: solubilization and purification conditions using PKM2 and HtrA2 as model proteins. AB - The glutathione S-transferase (GST) system is useful for increasing protein solubility and purifying soluble GST fusion proteins. However, purifying half of the GST fusion proteins is still difficult, because they are virtually insoluble under non-denaturing conditions. To optimize a simple and rapid purification condition for GST-pyruvate kinase muscle 2 (GST-PKM2) protein, we used 1% sarkosyl for lysis and a 1:200 ratio of sarkosyl to Triton X-100 (S-T) for purification. We purified the GST-PKM2 protein with a high yield, approximately 5 mg/L culture, which was 33 times higher than that prepared using a conventional method. Notably, the GST-high-temperature requirement A2 (GST-HtrA2) protein, used as a model protein for functional activity, fully maintained its proteolytic activity, even when purified under our S-T condition. This method may be useful to apply to other biologically important proteins that become highly insoluble in the prokaryotic expression system. PMID- 21524356 TI - A potential role for fatty acid biosynthesis genes during molting and cuticle formation in Caenorhabditis elegans. AB - Caenorhabditis elegans undergoes a developmental molting process that involves a coordinated interplay among diverse intracellular pathways. Here, we investigated the functions of two fatty acid biosynthesis genes; pod-2, encoding acetyl-CoA carboxylase, and fasn-1, encoding fatty acid synthase, in the C. elegans molting process. Although both the pod-2 and fasn-1 genes were expressed at constant levels throughout C. elegans development, knockdown of the proteins encoded by these genes using RNA interference produced severe defects in triglyceride production, molting, and reproduction that were coupled to suppression of NAS-37, a metalloprotease. An assessment of the structure and integrity of the cuticle using a COL-19::GFP marker and Hoechst 33258 staining showed that downregulation of either pod-2 or fasn-1 impaired cuticle formation and disrupted the integrity of the cuticle and the hypodermal membrane. PMID- 21524357 TI - Housing conditions in 2 Canadian First Nations communities. AB - OBJECTIVES: Housing conditions were assessed in 2 Canadian First Nations communities. Possible associations with tuberculosis (TB) were explored. Study design. Participatory community-based survey. METHODS: Qualitative and quantitative data on housing and health were collected in the northern Dene community at Lac Brochet (LB), which has experienced endemic and epidemic TB, and the southern Ojibwa community at Valley River (VR), which has not. Results. 72 of 135 (53%) houses at LB and 57 of 95 (60%) houses at VR were enrolled. Houses in both communities were small (mean 882 and 970 sq. ft., respectively) compared to the Manitoba average (1,200 sq. ft.). Crowding was evident at LB (mean persons per room [ppr] 1.1) and VR (mean ppr 0.9). The provincial mean ppr is 0.5. However, only 49% of householders at LB and 19% at VR felt "crowded" in their homes. More than two-thirds of houses had absent or non-functional heat recovery ventilation systems. Mould was observed in 44% of LB houses and 19% of VR houses. At LB a significant association was found between the number of permanent residents in the house and the presence of selfreported latent or active TB, either currently or during residence in that house (p=0.001). CONCLUSIONS: Houses that were studied in these 2 First Nations communities were predominantly small, crowded and in poor repair. An association was found between the number of persons in a house and self-reported TB. Improved housing conditions in First Nations communities are indicated to promote and sustain health as well as human and Indigenous rights. PMID- 21524358 TI - Adherence to tuberculosis care in Canadian Aboriginal populations, Part 2: a comprehensive approach to fostering adherent behaviour. AB - OBJECTIVES: In a 2-part series, the current literature with respect to adherence to tuberculosis care among Canadian Aboriginal populations is reviewed. In the current paper, which comprises part 2 of this review, strategies to remove barriers to TB adherence and to sustain and improve adherence are explored. Study design. Literature review. METHODS: The biomedical and social science literature, including electronic databases (PubMed, PsychINFO, MEDLINE, Native Health Database. Scopus, Social Science Citation Index) were searched and reviewed with regard to relevant studies on adherence to health care, and to tuberculosis care specifically. RESULTS: The majority of published studies of interventions to remove barriers to TB adherence are focused on the health service system and on the individual. The former include enhanced programs of directly observed therapy and directly observed preventive therapy, as well as "permeable" health services that require minimal negotiation. At the personal level, effort must be made to develop a shared knowledge of and care plan for TB, which includes Indigenous and Western scientific health beliefs and practice. The quality of the relationship between health care provider and patient is critical to the outcome of educational efforts that support adherence. Few studies address interventions within the social context, and few have used participatory methodologies in partnership with families and communities. Social supports such as assistance with childcare, transportation and shelter have been shown to be associated with improved adherence to care for other conditions. TB programs may wish to use techniques used in other health programs, such as the identification of patient "sponsors" or mentors, or the use of verbal and/or written "contracts." CONCLUSIONS: Many of the interventional studies addressing health system barriers to TB adherence are grounded in the view that the problem rests with the patient. What is required is an approach that is responsive to the patient's needs while holding the patient to his or her personal and societal responsibilities. Adherence to therapy is unlikely to improve in a substantial way unless Indigenous beliefs about causation and care are incorporated into a program which has meaning for the patient. PMID- 21524359 TI - Adherence to tuberculosis care in Canadian Aboriginal populations, Part 1: definition, measurement, responsibility, barriers. AB - OBJECTIVES: In a 2-part series, the current literature with respect to adherence to tuberculosis care among Canadian Aboriginal populations is reviewed. In the current paper, which comprises part 1 of this review, adherence is defined, and methods of measurement, issues of responsibility and potential barriers to adherence are explored. Study design. Literature review. METHODS: A systematic search and analytic review of relevant studies was undertaken, including an online search of electronic databases (PubMed, PsychINFO, MEDLINE, Native Health Database, Scopus, Social Science Citation Index) and publications by governmental and non-governmental agencies. RESULTS: Poor adherence to therapy for TB disease is the most common cause of initial treatment failure and of disease relapse worldwide. Adherence to care for TB disease is necessary for the health of both the affected individual and society as a whole. Adherence is a task-specific behaviour that is not inherent to ethnic identity. The term applies only when common agreement over a care plan has been reached between patient and provider. The International Standards for Tuberculosis Care and the Patients Charter outline the responsibilities for adherence on the part of both patients and providers. For Canadian Aboriginals, barriers to adherence may derive from a complex interaction between the health system, personal factors and social factors, which may include dysfunctional acute and public health systems, dissonant (between health care provider and patient) belief systems, concurrent co-morbidities and life stressors, poverty and social stigma. CONCLUSIONS: Adherence is a task-specific behaviour, not a personality trait. It is influenced by the interaction of systemic, personal and societal factors. These factors must be understood within the historical experience of TB and the cultural meaning of health and illness among Indigenous Canadians. PMID- 21524360 TI - The association between parental images and satisfaction in intimate relationships in a Northern Finland sample. AB - OBJECTIVES: Experiences in one's family of origin, especially the relationship to one's parents, supposedly form the basis of relationships in adulthood. The connection between traumatic childhood events and later life has been studied intensively, whereas average childhood growth experiences have been given less attention. The aim of this study was to find out the association between images of the mother and father and the psychosocial well-being of young adults from the perspective of satisfaction in intimate relationships. STUDY DESIGN: Cross sectional study. METHODS: The research is a part of the Oulu University Hospital Mother-Child Follow-up Study 1971-1972. The follow-up data were collected from the young adults (n=337) in 2000 by way of mailed questionnaires, which included 17 questions about the participants' images of their parents and 18 questions about their intimate relationship satisfaction. In this study we used attachment theory as a theoretical frame of reference. RESULTS: Mental images of dominating parents were associated with quarrelsome intimate relationships, and the image of a dominating father, with repressive/submissive and less balanced relationships. Mental images of diligent and sociable parents were associated with a loving and balanced relationship, and the image of supportive parents, with a balanced relationship. Parental diligence was associated with a less quarrelsome relationship. CONCLUSION: The young adults' mental images of their parents were associated with their intimate relationship satisfaction. Positive mental images of the father, in particular, seemed to protect young adults from a quarrelsome and repressive/submissive intimate relationship. PMID- 21524361 TI - Prevalence of anemia among Inuit women in Nunavik, Canada. AB - OBJECTIVES: To assess the prevalence and main types of anemia present among non pregnant Inuit women of Nunavik using a representative sample. STUDY DESIGN: A cross-sectional population-based study. Methods. Iron status was assessed in 466 women aged 18-74 who participated in the 2004 Nunavik Inuit Health Survey. The presence of different types of anemia has been evaluated based on available biochemical indicators of vitamins and of iron status. The correlation between iron status indicators, vitamin status parameters, inflammation markers and heavy metal concentrations was also assessed. RESULTS: Anemia was present in 43% of the Inuit women in Nunavik and 21% suffered from iron deficiency anemia (IDA). The main type of anemia present among women 18-49 years old was IDA (61% of anemia cases) while anemic women 50 years and over suffered mainly from anemia related to chronic inflammation (ACI) (42%). Over 99% of women had normal values for vitamin A, vitamin B12 and folate. Of interest is that ferritin was positively correlated with blood mercury and lead levels. CONCLUSION: The prevalence of anemia in Nunavik women is similar to levels observed in non-industrialized countries and represents a severe public health problem that should be further investigated. The most prevalent type of anemia in these women shifted from IDA to ACI with age. Vitamin A, vitamin B12 and folate deficiencies do not constitute a widespread problem and their contribution to anemia is probably minimal. Sources of heavy metals are also major sources of iron in the diet of Nunavik women which could explain the positive association found between heavy metals and iron status. PMID- 21524362 TI - Obesity risks: towards an emerging Inuit pattern. AB - OBJECTIVES: The aim of this study was to provide analytical overviews of anthropometric measurements and their relationships with type 2 diabetes and cardiovascular disease (CVD) risk factors within the Inuit population, given that few studies have focused on this issue. Study design. Cross-sectional study. METHODS: Anthropometric and biological data were obtained from 867 Inuit participants from Nunavik (>=18 years). RESULTS: Obesity prevalence for men and women, respectively, was 25.1% and 31.3% according to body mass index (BMI: >30 kg/m2); 20.2% and 55.3% according to waist circumference (WC: >102 cm for men and >88 cm for women); 22.4% and 22.5% according to body fat percentage (%BF: >=30 in men and >=40 in women). There was substantial agreement between anthropometric obesity measurements, except for the waist-to-hip ratio (WHR) which showed the lowest agreement with the other measurements. All risk factors were significantly associated with anthropometry. The prevalence of abnormal values for risk factors increased across quartiles of BMI and WC. Among obese participants, as defined by the WC cutoff, 22% had metabolic syndrome based on the National Cholesterol Education Program in the Adult Treatment Panel III (NCEP-ATPIII) definition and 64.8% of them were also insulin resistant. CONCLUSION: Obesity rates among Inuit are high, especially among women. Inuit women display especially high rates of abdominal obesity. Further longitudinal work is needed to evaluate the effects of central and global obesity among Inuit. PMID- 21524363 TI - An economic evaluation of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence. AB - OBJECTIVES: To review the published economic studies that have evaluated positron emission tomography/computed tomography (PET/CT) in the treatment of recurrent breast cancer, and to develop and carry out a model-based economic evaluation to investigate the relative cost-effectiveness of PET/CT to detect breast cancer recurrence compared with conventional work-up. DATA SOURCES: A systematic review of economic and diagnostic evidence for PET/CT in diagnosis of breast cancer recurrence. The original databases searched include MEDLINE (Ovid) (1950 to week 5 May 2009), EMBASE (Ovid) (1980 to 2009 week 22) and the NHS Economic Evaluation Database. An updated search was conducted for each database from May 2009 to week 4 April 2010. METHODS: A decision tree was developed in TREEAGE software (TreeAge Software Inc., Williamstown, MA, USA). The relevant data on accuracy, sensitivity and specificity of each diagnostic test were linked in the model, to costs and the primary outcome measure, cost per quality-adjusted life-year (QALY). The model estimated the mean cost associated with each diagnostic procedure and assumed that patients entering the model were aged 50-75 years. The results of the cost-effectiveness analysis are presented in terms of the incremental cost effectiveness ratios (ICERs). RESULTS: The ICER for the strategy of PET compared with conventional work-up was estimated at L29,300 per QALY; the ICER for PET/CT compared with PET was L 31,000 per QALY; and the ICER for PET/CT combined with conventional work-up versus PET/CT was L 42,100. Clearly, for each additional diagnostic test that is added to PET, the more expensive the package becomes, but also the more effective it becomes in terms of QALYs gained. The probabilistic sensitivity analysis shows that at a willingness-to-pay threshold of L 20,000 per QALY, conventional work-up is the preferred option. LIMITATIONS: Only data from indirect comparisons are available from the accuracy review, and there is some uncertainty about whether the data defining the accuracy of PET/CT present its use as a replacement or as an adjunct to conventional work-up. CONCLUSIONS: Based on the current model and given the limitations that are apparent in terms of limited availability of data, the result of the current analysis suggests that the use of PET/CT in the diagnosis of recurrent breast cancer in every woman suspected of having a recurrence is unlikely to be cost-effective given the current willingness-to-pay thresholds that are accepted in the UK by decision making bodies such as the National Institute for Health and Clinical Excellence. Our modelling suggests that conventional work-up could be the most cost-effective diagnostic strategy given current data. Future studies need to secure robust cost data that can be verified from more than one source for the diagnostic tests involved in PET and PET/CT. Reliable and verifiable data on quality of life associated with this clinical condition are also crucial. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 21524364 TI - Book cover grows mould. PMID- 21524365 TI - The toothless smile. PMID- 21524368 TI - Uncharted. PMID- 21524369 TI - Practice variability in the management of complex febrile seizures by pediatric emergency physicians and fellows. AB - OBJECTIVE: Febrile seizures are the most common type of childhood seizure and are categorized as simple or complex. Complex febrile seizures (CFSs) are defined as events that are focal, prolonged (> 15 minutes), or recurrent. The management of CFS is poorly defined. The objective of this study was to determine the degree of variability in the emergency department evaluation of children with CFSs. METHODS: An online survey questionnaire was developed and sent to physicians identified via the listserv of the emergency medicine section of the American Academy of Pediatrics and the pediatric emergency medicine discussion list. The questionnaire consisted of five hypothetical case vignettes describing children under 5 years of age presenting with a CFS. Following review of the first four vignettes, participants were asked if they would (1) obtain blood and urine for evaluation; (2) perform a lumbar puncture; (3) perform neurologic imaging while the child was in the emergency department; (4) admit the child to the hospital; or (5) discharge with follow-up as an outpatient, with either the primary care provider or a neurologist. The final vignette determined if antiepileptic medication would be prescribed by the physician on discharge. RESULTS: Of the 353 physicians who participated, 293 (83%) were pediatric emergency medicine attending physicians and 60 (17%) were pediatric emergency medicine fellows. Overall, 54% of participants indicated that they would obtain blood for evaluation, 62% would obtain urine, 34% would perform a lumbar puncture, and 36% would perform neurologic imaging. The overall hypothetical admission rate for the case vignettes was 42%. CONCLUSIONS: This study indicates that extensive variability exists in the emergency department approach to patients with CFS. Our findings suggest that optimal management for CFS remains unclear and support the potential benefit of future prospective studies on this subject. PMID- 21524370 TI - Failed validation of the quebec shoulder dislocation rule for young adult patients in an Australian emergency department. AB - OBJECTIVE: The Quebec shoulder dislocation rule is a recently derived clinical decision rule to guide physicians on the selective use of radiography in patients with shoulder dislocation. The aim of this study was to validate the Quebec shoulder dislocation rule. METHODS: This was a secondary analysis of data collected in a retrospective cohort study. All patients presenting to the emergency department (ED) between January 1, 2003, and October 31, 2008, with a diagnosis of shoulder dislocation or fracture-dislocation were identified from ED management databases. Data collected included demographics, mechanism of injury, and presence of fracture. The outcome of interest was predictive performance of the Quebec shoulder dislocation rule for patients aged under 40 years on this cohort. Data analysis is descriptive. RESULTS: Of the 346 patients identified, 196 were aged under 40 years, and 174 (89%) were male; the median age was 25 years (interquartile range 21-29 years), and 58 were recurrent dislocations. One hundred sixteen patients (59%) met the Quebec high-risk criteria, and 80 (41%) were classified as low risk. In the 196 patients aged less than 40 years, 12 fractures as defined were identified (6%). When applied to this cohort, the Quebec clinical decision rule had a sensitivity of 0.42 (95% CI 0.16-0.71), a specificity of 0.40 (95% CI 0.33-0.47), and a negative predictive value of 0.91 (95% CI 0.82-0.96). CONCLUSION: The Quebec shoulder dislocation rule had poor sensitivity for clinically significant fractures associated with shoulder dislocations in young patients (aged 16-39 years) presenting to an Australian emergency department. Its use cannot be recommended. PMID- 21524371 TI - Dispatches from the front: emergency medicine teachers' perceptions of competency based education. AB - OBJECTIVES: Controversy exists regarding the applicability of competency-based education during clinical rotations in emergency medicine (EM). Little has been written about the perceptions of front-line teachers regarding one such competency-based education paradigm, the CanMEDS framework. We undertook to determine 1) what perceptions exist among front-line teachers at two academic health science emergency departments (EDs) regarding the use of the CanMEDS roles to frame what residents should learn on ED rotations and 2) how those same teachers envision practically incorporating the CanMEDS roles into feedback provided to residents. METHODS: Teachers at two sites volunteered for a semistructured focus group study. Focus groups were moderated by an experienced qualitative researcher, and verbatim transcriptions were coded by two independent reviewers. The codes were merged into final themes. The final focus group was used to further explore issues raised and test assumptions made in the preceding groups. RESULTS: In five focus groups involving 21 participants, the Medical Expert and Professional roles were seen as most relevant to an EM rotation, whereas the Health Advocate, Manager, Scholar, and Collaborator roles were least relevant. On further exploration, however, faculty identified highly relevant components of each role that they could envision teaching in an ED. Participants also felt that the framework helped highlight the breadth of physician competencies and provided structure for teaching and feedback. CONCLUSIONS: EM faculty find the CanMEDS framework helpful for structuring teaching and learning and that many elements of the roles, when defined, are feasible to integrate into a clinical rotation. PMID- 21524372 TI - The "guitar pick" sign: a novel sign of retrobulbar hemorrhage. AB - Retrobulbar hemorrhage is a rare complication of blunt ocular trauma. Without prompt intervention, permanent reduction in visual acuity can develop in as little as 90 minutes. We report a novel bedside ultrasound finding of conical deformation of the posterior ocular globe: the "guitar pick" sign. In our elderly patient, the ocular globe shape normalized post-lateral canthotomy and inferior cantholysis. Identifying this sonographic finding may add to the clinical examination when deciding whether to perform decompression. PMID- 21524373 TI - Massive levothyroxine ingestion in a pediatric patient: case report and discussion. AB - We describe the course of a toddler who ingested a massive amount of levothyroxine and review treatment options for such overdoses. A 21/2-year-old boy presented shortly after an ingestion of up to 7.6 mg of levothyroxine (potentially as much as 700 MUg/kg). He was initially asymptomatic, treated with oral charcoal 1 g/kg, and discharged home from the emergency department after a few hours. He returned approximately 24 hours later with a temperature of 38.5 degrees C, heart rate of 163 beats per minute, respiratory rate of 30 breaths per minute, and blood pressure of 136/70 mm Hg. He had a slightly decreased appetite and no signs or symptoms of infection. He was admitted to hospital and treated with oral acetaminophen. The initial free thyroxine (T4) was > 100 pmol/L and free triiodothyronine (T3) was 35.3 pmol/L. The patient had desquamation of the palms and soles, hair loss, and irritability during the month following the ingestion. Resolution of the elevated free T4 occurred by 12 days post-ingestion and normalization of the thyroid-stimulating hormone by 7 weeks post-ingestion. There were no long-term sequelae. Levothyroxine overdose can result in significant complications, including seizures and arrhythmias, both of which should be monitored for. However, as our case illustrates, massive ingestion of levothyroxine in children typically follows a benign course. PMID- 21524374 TI - How to give a consultation and how to get a consultation. PMID- 21524381 TI - Circadian clocks in mammalian reproductive physiology: effects of the "other" biological clock on fertility. AB - As a discipline, chronobiology has come of age in the last 25 years. There has been an exponential increase in our understanding of the molecular mechanism underlying circadian rhythms of gene expression, physiology, and behavior. While the mammalian clock mechanism has not yet been fully described, most of the primary gears have probably been identified; however, there remains a large submerged portion of this physiological iceberg. What is the extent of "clock controlled gene" expression in the myriad cell types in mammals? What are the cell specific physiological processes that depend either directly or indirectly on the clock? These questions remain largely unanswered, but recent advances suggest a substantial link between basic clock function and physiology in several systems. In the reproductive system, there has been a recent surge in research on molecular clock function in neuroendocrine and endocrine tissues. This makes sense a priori, given the established link between the circadian clock, behavior (including reproductive behavior), and endocrine physiology. By understanding the role of the clock in basic mammalian reproductive physiology, we can begin to explore its role in the onset and progression of diseases that negatively affect fertility. Advances in this area will certainly yield novel insights into the etiology of these disorders and may provide new and exciting avenues for clinical research in reproduction and fertility. PMID- 21524382 TI - Novel cytokine-directed therapies for asthma. AB - For the majority of asthmatic patients, inhaled corticosteroid anti-inflammatory therapy is effective at controlling disease symptoms. However, this requires life time therapy while a subset of patients remains symptomatic despite optimal treatment creating a clear unmet medical need. Biopharmaceutical approaches have been used to target key elements in the complex pro-inflammatory processes controlling pro-inflammatory cell accumulation and the secretory function of these and structural cells within the asthmatic lung. Asthma-relevant cytokines or chemokines have been targeted in a number of ways. These include the use of humanized blocking mAb to their receptors, removal of cytokines or chemokines via their binding to soluble receptors or small molecule receptor antagonists. Other approaches include the development of biologics that block specific bioactive agents such as IgE. This review will discuss the current status, therapeutic potential and potential problems of these novel drug biologics in asthma therapy. PMID- 21524383 TI - Autoantigen based vaccines for type 1 diabetes. AB - Type 1 diabetes is an organ-specific autoimmune disease caused by chronic inflammation (insulitis), which damages the insulin producing beta-cells of the pancreatic Islets of Langerhans. Dendritic cells (DCs) are generally the first cells of the immune system to process beta-cell autoantigens and, by promoting autoreactivity, play a major role in the onset of insulitis. Although no cure for diabetes presently exists, the onset of insulitis can be diminished in the non obese diabetic (NOD) mouse type 1 diabetes model by inoculation with endogenous beta-cell autoantigens. These include the single peptide vaccines insulin, GAD(65) (glutamic acid decarboxylase), and DiaPep277 (an immunogenic peptide from the 60-kDa heat shock protein). DiaPep277 is the only autoantigen so far to demonstrate positive results in human clinical trials. Diamyd (an alum adjuvant + recombinant GAD(65) protein formulation) has shown great promise for suppressing beta-cell autoreactivity in phase I and II clinical trials. While Diamyd preserved residual insulin secretion in early-onset type 1 diabetes patients, it did not reduce the amounts of insulin required to maintain euglycemia. Recently, multi-component vaccines composed of the anti-inflammatory cytokine (IL-10) and insulin or GAD(55) linked to an immunostimulatory molecule, the cholera toxin B subunit, were shown to safely and completely inhibit diabetes onset in NOD mice. This result suggests that multi-component vaccine strategies are promising for prevention and reversal of diabetes autoimmunity in humans. Here we focus on the development of autoantigen vaccines for type 1 diabetes and demonstrate that multi-component vaccines are promising candidates for type 1 diabetes clinical studies. PMID- 21524384 TI - The role of glycosphingolipids in HIV/AIDS. AB - Much remains unknown about basic aspects of HIV-1 infection and cell susceptibility. Glycosphingolipid (GSL) binding by the HIV-1 adhesin gp120 has long been implicated in the infection of non-lymphoid cells, as well as CD4(+) T cells and monocytes, the primary targets of HIV-1 infection. We have identified the P(k) blood group antigen (a GSL) globotriaosylceramide (Gb(3)) as a new resistance effector against HIV-1 infection. Significantly, the alpha galactosyltransferase (A4GALT, Gb(3) synthase) responsible for the synthesis of Gb(3) is included among markers genetically linked to HIV-1 resistance. Other GSLs, including GalCer and GM3, have been implicated as facilitators of HIV infection. This review will address the role of GSLs in HIV/AIDS but focus on the role of Gb(3) as a newly described natural resistance factor for the prevention of HIV infection and examine potential therapies that would utilize soluble analogues of this unique GSL. PMID- 21524385 TI - Prolactin in breast and prostate cancer: molecular and genetic perspectives. AB - Prostate and breast cancers affect millions of men and women, respectively. Advanced forms of the disease, which can no longer be controlled by hormonal disruption or chemotherapy, have very limited treatment options. Consequently, there is a major benefit to identify new targets for therapy in both types of cancer. The prolactin (PRL) signaling cascade, by virtue of its importance to the pathology of both diseases, has emerged as a potential treatment target. To date, several methods for antagonizing the PRL receptor (PRLR) and its signaling pathways have been developed which include protein-based and small molecule antagonists. However, a better understanding of the genetic and molecular characteristics of the PRL cascade is needed for the successful therapeutic application of antagonists. At the level of genetics, it is necessary to determine the functional significance of non-synonymous single nucleotide polymorphisms of the PRLR and their association with disease prevalence and severity. At the molecular level, a comprehensive knowledge of interactions of the PRL signaling pathway with other oncogenic molecules is warranted so as to identify beneficial combinatorial strategies. This review discusses multiple features of the PRL signaling cascade and how they can be exploited in the search for effective therapies for patients with breast and prostate cancers. PMID- 21524387 TI - Identification and functions of the plasma membrane receptor for thyroid hormone analogues. AB - Integrin alphavbeta3 is a heterodimeric structural protein of the plasma membrane that bears a cell surface receptor for thyroid hormone. The functions of this receptor are distinct from those of the classical nuclear receptor (TR) for thyroid hormone. The integrin is expressed primarily by cancer cells, dividing endothelial and vascular smooth muscle cells, and osteoclasts. The hormone receptor on alphavbeta3 enables L-thyroxine (T(4)) and 3, 5, 3'-triiodo-L thyronine (T(3)) to stimulate cancer cell proliferation and angiogenesis and to regulate the activity of certain membrane ion pumps. Bound to the receptor, the hormone ligand also stimulates protein trafficking within the cell. A deaminated derivative of T(4), tetraiodothyroacetic acid (tetrac), blocks binding and actions of T(4) and T(3) at the receptor on alphavbeta3; tetrac also has anti proliferative actions at the integrin thyroid hormone receptor beyond the effects of antagonizing actions of agonist thyroid hormone analogues at the receptor. The structure-activity relationships of hormone analogues at the receptor have been computer-modeled and indicate that the receptor includes a site that binds T(3) and a site that binds both T(4) and T(3). Mathematical modeling of the kinetics of hormone-binding also suggests the existence of two sites. Cell proliferation is modulated from the T(4)/T(3) site. Tetrac has been re-formulated as a nanoparticle (nanotetrac) that acts exclusively at the alphavbeta3 receptor and does not enter cells. Nanotetrac disrupts expression of genes in multiple cancer cell survival pathways. The tetrac formulations block human cancer cell proliferation in vitro and in tumor xenografts. Nanotetrac and tetrac inhibit the pro-angiogenic actions in vitro of vascular endothelial growth factor, basic fibroblast factor, and other growth factors. Thus, the receptor described on integrin alphavbeta3 for T(4) and T(3), the function of which is materially affected by tetrac and nanotetrac, provides insight into tumor cell biology and vascular biology. PMID- 21524388 TI - Gene expression regulation through 14-3-3 interactions with histones and HDACs. AB - 14-3-3s are phosphoserine- or phosphothreonine-binding proteins, which are involved in a variety of cellular processes, including gene regulation, differentiation, cell cycle progression, and metabolism. Their mechanism of regulation is typically to induce a conformational change on the target phosphoprotein, which can alter its catalytic activity, localization within the cell, or interactions with other proteins. In addition, 14-3-3s can act as a scaffolding protein, leading to multiprotein complex formation on the target phosphoprotein. As such, 14-3-3s are integrated into a number of important phosphorylation-dependent signaling pathways. In this review, we will examine the interaction of 14-3-3 with chromatin and chromatin modifying enzymes, specifically with phosphorylated histone H3 and histone deacetyltransferases, respectively. Through diverse mechanisms, these interactions directly affect the expression of target genes, many of which are known oncogenes and lead to tumorigenesis and metastasis. Various research studies have indicated that the mechanism of 14-3-3 interaction and its role in transcription is complex and diverse, and likely involving additional components as yet undefined. PMID- 21524386 TI - Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. AB - Vitamin D is involved in mineral and bone homeostasis, immune responses, anti inflammation, anti-infection, and cancer prevention. Vitamin D receptor (VDR) is a nuclear receptor that mediates most biological functions of 1,25(OH)(2)D(3) or vitamin D(3), the active form of vitamin D. Recently, vitamin D(3)-induced autophagy has been reported. Autophagy is a lysosome-mediated catabolic pathway classified into three different types: macroautophagy, microautophagy, and chaperone-mediated autophagy. Autophagy contributes to anti-aging, antimicrobial defense, and tumor suppression. The functions of autophagy overlap remarkably with those of vitamin D/VDR signaling. This review focuses on vitamin D(3), VDR, and macroautophagy in inflammation and infection. We place emphasis on the regulatory roles of vitamin D(3) on autophagy at different steps, including induction, nucleation, elongation to maturation, and degradation. We summarize the known molecular mechanisms of vitamin D/VDR signaling on autophagy homeostasis. The potential application of the insights gleaned from these research findings to anti-inflammation and anti-infection is also discussed. PMID- 21524390 TI - Regulatory considerations for developing drugs for rare diseases: orphan designations and early phase clinical trials. AB - The development of drug and biological products intended to treat rare diseases (Orphan diseases) is one of the fastest growing areas of clinical research, and also one of the most challenging. This article provides an introduction to two important regulatory considerations for Orphan drugs: Orphan status designations and general considerations for the administration of investigational agents in early phase clinical trials. Incentives available to orphan drug developers under the Orphan Drug Act (ODA) and requirements for obtaining an orphan status designation are discussed. An introductory overview of ethical and statutory considerations for investigational drugs, requirements for initiating investigational new drug applications (INDs), and sources of information and advice from the US Food and Drug Administration (FDA) are also described. PMID- 21524389 TI - Genome-wide approach to identify novel candidate genes for beta blocker response in heart failure using an experimental model. AB - BACKGROUND: We explored use of a canine model of heart failure (HF) for pharmacogenomic discovery, specifically analyzing response to beta blockers (BB). METHODS: Dogs with HF that received BB (n=39) underwent genome-wide genotyping to test the association with changes in left ventricular (LV) volume and ejection fraction after treatment. Resulting candidate genes underwent RNA quantification in cardiac tissue from normal (n=5), placebo-HF (n=5), and BB-HF (n=7) dogs. RESULTS: Three markers met whole-genome significance for association with improved LV end-systolic volume after BB therapy (each p<5 x 10(-7)). RNA quantification of three candidate genes near these markers -- GUCA1B, RRAGD, and MRPS10 -- revealed that gene expression levels in BB-HF dogs were between that of placebo-HF dogs and normal dogs. CONCLUSION: Genome-wide pharmacogenomic screening in a canine model of HF suggests 3 novel BB response candidate loci. This approach is adaptable to discovering mechanisms of action for other drug therapies, and may be a useful strategy for identifying candidate genes for drug response in the pre-clinical setting. PMID- 21524391 TI - [WHIM syndrome: on the track of an interplay between human papillomavirus and the CXCL12 chemokine]. PMID- 21524392 TI - [An original approach to enrich cDNA libraries with functional non-coding RNAs]. PMID- 21524393 TI - [Reappraisal of the role of pTalpha for pre-TCR signaling: lessons from non mammalian vertebrates]. PMID- 21524394 TI - [Transcytosis of IGF1 through the hematoencephalic barrier]. PMID- 21524395 TI - [Greatwall, a new guardian of mitosis]. PMID- 21524396 TI - [A bacterial attack on the ubiquitin-proteolytic system]. PMID- 21524398 TI - [Long non-coding RNAs with enhancer-like function in human cells]. PMID- 21524397 TI - [ZNF703: a novel oncogene involved in breast cancer]. PMID- 21524399 TI - [A breakthrough in the understanding of neonatal group B streptococcus meningitis]. PMID- 21524400 TI - [beta(2) adrenergic receptor and beta-arrestins: the meningococcal instruments to breach meninges]. PMID- 21524401 TI - [West Nile virus - I. conquest of the West]. PMID- 21524402 TI - [West Nile virus. II. Immunopathophysiology in humans]. AB - Since its emergence in 1999 in America, West Nile virus (WNV) has become the leading cause of arboviral encephalitis in the United States. The infection is often asymptomatic but, when clinical manifestations occur, a broad range of symptoms is observed from flu-like symptoms to more serious neurological disorders that can sometimes lead to death. No treatment or vaccine is available for humans. Ongoing studies are trying to understand the host-virus dynamics that lead to the development of severe neurological symptoms in a minority of infected subjects. The amount of knowledge that was gained from parallel studies in animals and humans, comparing asymptomatic and symptomatic individuals, and using what was known of other Flaviviruses, will eventually translate to the development of potential therapeutic and prophylactic solutions. This review presents a synthesis of the most relevant findings concerning the immune response to WNV and its impact on disease outcome and gives an overview of the most promising therapeutic and prophylactic solutions. PMID- 21524403 TI - [A new era in rat genetics]. AB - Rat and mice are privileged tools for scientists. However, despite obvious advantages, such as a larger size, more faithful reproduction of human diseases, and utility for physiological and cognitive studies, rats have suffered from limited genetic technologies such as targeted mutagenesis. However, the gap between rat and mouse for genetic approaches will soon disappear with the recent advances of zinc finger nucleases applicable to early-stage rat embryos and the successful derivation of germ line competent rat ES cells, almost thirty years after murine ES cells. This will lead to new opportunities and to increase our capacity to model human pathologies. PMID- 21524404 TI - [CXCR4, a therapeutic target in rare immunodeficiencies?]. AB - Currently, more than 200 primary immunodeficiency diseases have been discovered. In most cases, genetic defects affect the expression or the function of proteins involved in immune development and homeostasis. Some orphan immuno-hematological disorders are characterized by an abnormal leukocyte trafficking, a notion predictive of an anomaly of the chemokine/chemokine receptor system. In this review, we focus on recent advances in the characterization of dysfunctions of the CXCL12 (SDF-1)/CXCR4 signaling axis in two rare human immunodeficiencies, one associated with a loss of CXCR4 function, the Idiopathic CD4(+) T-cell Lymphocytopenia, and the other with a gain of CXCR4 function, the WHIM syndrome. PMID- 21524405 TI - [MicroRNAs in pathophysiology of renal disease: an increasing interest]. AB - MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs, evolutionarily conserved, that post-transcriptionnaly regulate gene expression by promoting degradation or repressing translation of the targetted messenger RNA. Recent data suggest the implication of miRNAs in renal development, and in renal diseases pathophysiology including fibrogenesis, regulation of innate and adaptive immunity, autoimmune diseases and acute rejection of the renal allograft. Herein, we review the implication of miRNAs in renal pathophysiology. PMID- 21524406 TI - [Reactive oxygen species and oxidative stress]. AB - Oxidative stress is defined as an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity of the cell. For long, ROS have been considered as harmful by-products of the normal aerobic metabolism process of the mitochondria, implicated in a large variety of diseases. But there are now growing evidences that controlled ROS production also play physiological roles especially in regulating cell redox homeostasis and cell signaling. Biological ROS effects are now well documented. Data show that living organisms have not only adapted themselves to coexist with free radicals but have also developed mechanisms to use them advantageously. However their main sources and mechanisms of action remain poorly described. This review focuses on the main properties of ROS and their paradoxical effects. PMID- 21524407 TI - [Functional brain plasticity associated with motor learning]. AB - This review presents the results of studies carried out in our laboratory that aim to investigate, through functional magnetic resonance imaging (fMRI), the brain plasticity associated with motor sequence learning, defined as our ability to integrate simple stereotyped movements into a single motor representation. Following a brief description of Doyon and colleagues' model (2002, 2005, 2009) of motor skill learning that has guided this work, we then describe the functional changes that occur at the different (rapid, slow, automatization) acquisition phases, and propose specific roles that the putamen, the cerebellum and their motor-related cortical areas, play in this form of motor behavior. Finally, we put forward evidence that post-training, non-REM sleep (and spindles in Stage 2 sleep, in particular) contributes to the consolidation of a motor sequence memory trace, and that increased activity within the striatum and/or the hippocampus mediates this mnemonic process. PMID- 21524408 TI - [Greatness and tribulations of two German optic companies - II. The Leitz company]. AB - A parallel is drawn between the histories of the two most famous German optic companies. Born in the middle of the 19th century, Zeiss and Leitz went through National Socialism. But their histories are very different. Leitz Archive documents abound, especially from one of the main actors, Oskar Barnack (father of the Leica). Ernst Leitz II and his daughter Elsie tried to help the Jewish workers, their families and, later, the Ukrainian women working in the factory. Leitz succeeded to establish what has become known among historians of the Holocaust as "the Leica Freedom Train". Their tribulations throw light on the German adventure during the last century. PMID- 21524409 TI - [Time shapes the cell]. AB - Dynamics is the essence of life, from the most macroscopic scale of evolution theories or ecology, down to the submicroscopic scale of the molecular mechanisms underlying for instance the activity of enzymes on their chemical target or their mechanical work in our muscles. Thanks to new methods, most phenomena in cell biology must now be reported not only in terms of their biochemistry, but also with a description of their geometric and temporal characteristics using quantitative imaging. This is leading to a dramatic accumulation of data, with little understanding of its deep physiological significance. Based on recent results, we raise here a few questions regarding the possible role of time as a key determinant of the metabolic energy budget, that impacts living cells from the organisation of macromolecular assemblies up to the morphogenesis and stabilisation of tissues. PMID- 21524410 TI - [The democratic side of science-fiction]. AB - Suspicion towards technological advances has progressively grown during the xx(th) century. However, in the XXI(st) century, reading the NBIC (nanotechnology, biotechnology, information technology and cognitive science) report of the National Science Foundation, we can note that science has caught up with science fiction. These changes in public mentality on one side and in scientific capacities on the other argue for an evolution of the debate on sciences. The recent example of the national debate on nanotechnology in France has clearly shown that the public is no longer waiting for additional sources of scientific knowledge but rather waiting for the recognition of its authority to participate in the definition of the national R&D priority and associated scientific strategies. This is all the more legitimate that these strategies will have profound impact on the future of our societies and therefore cannot be decided only by scientists. Hence, it is crucial to identify innovative tools promoting debate on sciences and their technological spin-off. Here, we contend that science fiction has major assets that could face this challenge and facilitate the dialogue between sciences and society. PMID- 21524411 TI - [Publishing impulsivity...]. PMID- 21524412 TI - [Human pluripotent stem cells: opening key for pathological modeling]. PMID- 21524413 TI - Thioglycosylation of 1,2-cis-glycosyl acetates: a long-standing overlooked issue in preparative carbohydrate chemistry. AB - 1,2-cis-Glycosyl acetates with the alpha-configuration were revealed to be very unreactive towards Lewis acid catalyzed thioglycosylations. Optimal and cost effective conditions for enabling this direct conversion is absent in the literature. Our studies have shown that elevating the reaction temperature with a catalytic amount of BF(3).OEt(2) was more effective than changing Lewis acids with higher acidities to accommodate the low reactivity of alpha-glycosyl acetates. The effect of impurities in stored BF(3).OEt(2) on the reaction is also discussed. PMID- 21524414 TI - Three-dimensional magnetic resonance imaging analysis of hip morphology in the assessment of femoral acetabular impingement. AB - AIM: To determine a possible association between femoral-acetabular impingement (FAI) volume and the development of labral tear using a three-dimensional (3D) model reconstruction of the acetabulum and the femoral head. MATERIALS AND METHODS: Magnetic resonance arthrography images of the hip in 42 patients with pain and suspected labral tear were acquired using a 1.5T MRI machine. Using 3D analysis software, outlines of the acetabular cup and femoral head were drawn and 3D reconstruction obtained. To control for differences in patient size, ratios of acetabulum : femoral head volume (AFV) and acetabulum : femoral head surface area (AFA) were used for analysis. The association between volume of acetabulum : femoral head and FAI was investigated using ANOVA analysis. RESULTS: There were 19 men and 23 women with a mean age of 39 years (range 18-78 years). The average AFV was 0.64 (range 0.37-1.05, SD 0.16) and AFA was 0.73 (range 0.36-1.26, SD 0.23). Herniation pit was significantly associated with a small AFV. CONCLUSION: Femoral neck herniation pits are associated with a low AFV. Gross volume and surface area ratios do not appear to correlate with labral tears or cartilage loss. This technique will enable more advanced analysis of morphological variations associated with FAI. PMID- 21524415 TI - Regional diagnosis of lymphoedema and selection of sites for lymphaticovenular anastomosis using elastography. AB - AIM: To evaluate the use of ultrasound elastography as a basis for determining the most appropriate sites for lymphaticovenular anastomosis (LVA) for treatment of lymphoedema. MATERIALS AND METHODS: Preoperative elastography and LVA were performed in 11 patients (11 legs) with leg lymphoedema, including two cases of primary oedema and nine of secondary oedema. RESULTS: The mean number of LVAs applied per leg was 4.4 (range 3-7). The mean reduction in the leg circumference was 91.7%, and 10 of the 11 cases (90.0%) were improved. Hardness was reduced from a mean of 1.6 before surgery to 0.9 after surgery, and improvement was also noted in 10 cases (90.9%). The severity of oedema was determined in five regions in each leg, and was classified as elastography stage (ES) 0 in 11 regions, ES1 in 23, ES2 in 15, and ES3 in six. CONCLUSIONS: These results demonstrate the value of ultrasound elastography for the diagnosis of early-stage lymphoedema and determination of LVA sites. This is the first report of diagnosis of lymphoedema using elastography and the findings suggest that this procedure followed by LVA could be used as a new therapeutic method for early-stage lymphoedema. PMID- 21524416 TI - Focal liver lesion detection and characterization with GD-EOB-DTPA. AB - Superior soft-tissue contrast affords magnetic resonance imaging (MRI) some advantages compared to computed tomography (CT) in both detection and characterization of focal liver lesions. Because of its relatively recently introduction into clinical practice, a growing number of articles in the literature have demonstrated the usefulness of the hepatobiliary-specific MRI contrast agent gadoxetic acid disodium (Gd-EOB-DTPA) in liver imaging. The purpose of this review is to demonstrate the typical enhancement patterns of the most common liver lesions using Gd-EOB-DTPA in daily clinical scenarios and briefly describe its mechanism of action. Radiologists interpreting liver MRI studies with this agent must be familiar with the appearance of focal lesions in the hepatocyte phase to avoid misinterpretation. PMID- 21524417 TI - Imaging of postoperative middle ear cholesteatoma. AB - Cholesteatoma is often treated surgically using canal wall-preserving techniques. Clinical and otoscopic diagnosis of residual or recurrent disease after this form of surgery is unreliable and thus radiological imaging is often used prior to mandatory "second-look" surgery. Imaging needs to be able to differentiate residual or recurrent disease from granulation tissue, inflammatory tissue or fluid within the middle ear cavity and mastoid cavity. High-resolution computed tomography (HRCT), conventional magnetic resonance imaging (MRI), and delayed contrast MRI have all been used in detecting postoperative cholesteatoma. Although delayed contrast MRI performs better than HRCT and conventional MRI, the sensitivities and specificities of these different imaging methods are relatively poor. Diffusion-weighted MRI (DWI and, in particular, non-echo planar DWI) has been shown to have a high sensitivity and specificity for detecting recurrent cholesteatoma. In this review we provide examples of postoperative imaging appearances following cholesteatoma surgery and we review the relevant literature with an emphasis on studies evaluating the diagnostic accuracy of DWI. PMID- 21524418 TI - Contrast-enhanced ultrasonography for the detection and characterization of prostate cancer: correlation with microvessel density and Gleason score. AB - AIM: To determine whether there is a correlation between the peak intensity of the lesion at contrast-enhanced ultrasonography and the microvessel density (MVD) and Gleason score in biopsy specimens of prostate cancer. MATERIALS AND METHODS: Contrast-enhanced ultrasonography using cadence-contrast pulse sequence (CPS) technology was performed in 147 patients with suspected prostate cancer before biopsy. An auto-tracking contrast quantification (ACQ) software was used to analyse the peak intensity (PI) of the lesion. The Gleason score and MVD immunoreactivity were determined in the prostate biopsy specimens. Ultrasound findings were correlated with biopsy findings. RESULTS: Prostate cancer was detected in 73 of 147 patients. The PI values of prostate cancer patients were significantly higher than those of non-malignant patients [9.81 (4.23) versus 5.69 (3.19) dB; p<0.01]. The mean (SD) PIs of prostate cancer lesions with a Gleason score of 6-9 were 7.08 (3.80), 8.65 (4.08), 9.76 (3.75), and 9.85 (4.13) dB, respectively. The PI value increased significantly with a higher Gleason score (p<0.01). The mean (SD) MVDs observed in prostate cancer lesions with a Gleason score of 6-9 were 52.50 (10.54), 56.85 (10.31), 59.91 (9.29), and 66.04 (11.82), respectively. There was a positive correlation between PI and MVD in prostate cancer, with a correlation coefficient of 0.617. No correlation was found between PI value and age, prostate specific antigen (PSA) or prostate specific antigen density (PSAD) level (p>0.05). CONCLUSION: The PI obtained by CPS harmonic ultrasonography appears to be of value as an indicator of MVD and increases with a higher Gleason score. CPS harmonic ultrasonography could be promising as a useful imaging technique in the detection and characterization of prostate cancer. PMID- 21524419 TI - Air-water interfacial behavior of linear-dendritic block copolymers containing PEG and azobenzene chromophores. AB - Fabrication of Langmuir films at the air-water interface of four linear-dendritic block copolymers (LDBCs) is described. The LDBCs are composed of a linear hydrophilic chain of poly(ethylene glycol) (PEG) and the first four generations of hydrophobic aliphatic polyester dendrons functionalized at the periphery with cyanoazobenzene chromophores. Langmuir films of the LDBCs, coded as PEG-AZOn (n indicates the number of cyanoazobenzene units at the periphery of the dendritic block), have been characterized by a combination of surface pressure versus area per molecule isotherms, UV-vis reflection spectroscopy and Brewster angle microscopy. The observed PEG-AZOn Langmuir film behavior depends strongly on the hydrophilic/hydrophobic ratio. A typical transition, related to PEG chains desorption from the air-water interface into the water subphase is observed for all the LDBCs, except for PEG-AZO16. In addition, PEG-AZO2 and PEG-AZO4 show a second transition whose nature has been studied in detail. Azobenzene chromophore interactions have been shown to be relevant in the organization of PEG-AZOn (n=4, 8 and 16) Langmuir films. Moreover, for PEG-AZO16 the orientation of the azobenzene units has been determined, revealing the formation of a well organized structure of azobenzene moieties at the air-water interface. PMID- 21524420 TI - A physico-chemical investigation of poly(ethylene oxide)-block-poly(L-lysine) copolymer adsorption onto silica nanoparticles. AB - The adsorption behavior of poly(ethylene oxide)-b-poly(L-lysine) (PEO(113)-b PLL(10)) copolymer onto silica nanoparticles was investigated in phosphate buffer at pH 7.4 by means of dynamic light scattering, zeta potential, adsorption isotherms and microcalorimetry measurements. Both blocks have an affinity for the silica surface through hydrogen bonding (PEO and PLL) or electrostatic interactions (PLL). Competitive adsorption experiments from a mixture of PEO and PLL homopolymers evidenced greater interactions of PLL with silica while displacement experiments even revealed that free PLL chains could desorb PEO chains from the particle surface. This allowed us to better understand the adsorption mechanism of PEO-b-PLL copolymer at the silica surface. At low surface coverage, both blocks adsorbed in flat conformation leading to the flocculation of the particles as neither steric nor electrostatic forces could take place at the silica surface. The addition of a large excess of copolymer favoured the dispersion of flocs according to a presumed mechanism where PLL blocks of incoming copolymer chains preferentially adsorbed to the surface by displacing already adsorbed PEO blocks. The gradual addition of silica particles to an excess of PEO-b-PLL copolymer solution was the preferred method for particle coating as it favoured equilibrium conditions where the copolymer formed an anchor-buoy (PLL-PEO) structure with stabilizing properties at the silica-water interface. PMID- 21524421 TI - Synthesis and characterization of polyhedral Pt nanoparticles: their catalytic property, surface attachment, self-aggregation and assembly. AB - In this paper, we presented the preparation procedure of Pt nanoparticles with the well-controlled polyhedral morphology and size by a modified polyol method using AgNO(3) in accordance with the reduction of H(2)PtCl(6) in EG at high temperature around 160 degrees C. The methods of UV-vis spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), and high resolution (HR) TEM measurements were used to characterize their surface morphology, size, and crystal structure. We have observed that the polyhedral Pt nanoparticles of sharp edges and corners were produced in the preferential homogenous growth as well as the formation of porous and large Pt particles by self-aggregation and assembly originating from as-prepared polyhedral Pt nanoparticles. It is most impressive to find that the arrangement of Pt nanoparticles was observed in their surface attachments, self-aggregation, random and directed surface self-assembly by the bottom-up approach. Their high electrocatalytic activity for methanol oxidation was predicted. The findings and results showed that the polyhedral Pt nanoparticle-based catalysts exhibited the high electrocatalytic activity for their potential applications in developing the efficient Pt-based catalysts for direct methanol fuel cells. PMID- 21524422 TI - Find the picture of eight turtles: a link between children's counting and their knowledge of number word semantics. AB - An essential part of understanding number words (e.g., eight) is understanding that all number words refer to the dimension of experience we call numerosity. Knowledge of this general principle may be separable from knowledge of individual number word meanings. That is, children may learn the meanings of at least a few individual number words before realizing that all number words refer to numerosity. Alternatively, knowledge of this general principle may form relatively early and proceed to guide and constrain the acquisition of individual number word meanings. The current article describes two experiments in which 116 children (21/2- to 4-year-olds) were given a Word Extension task as well as a standard Give-N task. Results show that only children who understood the cardinality principle of counting successfully extended number words from one set to another based on numerosity-with evidence that a developing understanding of this concept emerges as children approach the cardinality principle induction. These findings support the view that children do not use a broad understanding of number words to initially connect number words to numerosity but rather make this connection around the time that they figure out the cardinality principle of counting. PMID- 21524423 TI - Preschoolers' use of dynamic facial, bodily, and vocal cues to emotion. AB - In daily experience, children have access to a variety of cues to others' emotions, including face, voice, and body posture. Determining which cues they use at which ages will help to reveal how the ability to recognize emotions develops. For happiness, sadness, anger, and fear, preschoolers (3-5 years, N = 144) were asked to label the emotion conveyed by dynamic cues in four cue conditions. The Face-only, Body Posture-only, and Multi-cue (face, body, and voice) conditions all were well recognized (M > 70%). In the Voice-only condition, recognition of sadness was high (72%), but recognition of the three other emotions was significantly lower (34%). PMID- 21524424 TI - Life stress and first onset of psychiatric disorders in daughters of depressed mothers. AB - This study used a comprehensive, interview-based measure of life stress to assess the role of different types of stress in predicting first onset of psychiatric disorders among daughters of depressed (n = 22) mothers and healthy (n = 22) mothers. Several types of stress were assessed: Chronic interpersonal stress, chronic non-interpersonal stress, episodic dependent (i.e., self-generated) interpersonal stress, episodic dependent non-interpersonal stress, episodic independent interpersonal stress, and episodic independent non-interpersonal stress. Daughters (ages 9-14) were recruited to have no clinically significant symptoms upon entry (T1). By a 30-month follow-up assessment (T2), 45% of the daughters of depressed mothers, but none of the daughters of healthy mothers, had developed a psychiatric disorder. Overall, daughters of depressed mothers were exposed to more severe chronic interpersonal and non-interpersonal stress than were daughters of healthy mothers. Further, daughters of depressed mothers who developed a psychiatric disorder by T2 were exposed to more severe chronic non interpersonal stress and episodic dependent stress than were daughters of depressed mothers who remained healthy. We discuss the implications of these findings in the context of a stress-generation model for the intergenerational transmission of psychiatric risk among children of depressed mothers. PMID- 21524425 TI - Perioperative aminoglycoside treatment is associated with a higher incidence of postoperative dialysis in adult cardiac surgery patients. AB - BACKGROUND: Aminoglycoside treatment has been associated with nephrotoxic effects. However, the effect of perioperative aminoglycoside treatment on the risk of acute kidney injury requiring dialysis among patients undergoing cardiac surgery remains uncertain. METHODS: We performed a register study based on prospectively collected data from population-based health care databases of 3625 consecutive patients undergoing cardiac surgery at the Aarhus University Hospital, Skejby, Denmark. Patients requiring preoperative dialysis were excluded, leaving a total of 3587 patients (99% of original patient cohort), of whom 89 received perioperative aminoglycosides. RESULTS: The cumulative risk of in-hospital dialysis-dependent acute kidney injury was 3.2% (n = 115). Perioperative use of aminoglycosides was associated with an increased risk of postoperative dialysis (adjusted odds ratio [OR], 4.41; 95% confidence interval [CI], 1.83-10.59). Other predictors included reoperation because of bleeding (adjusted OR, 2.80; 95% CI, 1.63-4.80), use of inotropic support during anesthesia (adjusted OR, 2.10; 95% confidence interval, 1.49-2.95), and cardiopulmonary bypass lasting longer than 120 minutes (adjusted OR, 1.95; 95% CI, 1.19-3.20) along with EuroSCORE variables. Postoperative dialysis was associated with higher 30-day mortality (10.9% vs 2.5%, P < .0001, chi(2) test), but use of aminoglycosides was not independently associated with mortality. CONCLUSIONS: Perioperative use of aminoglycosides in adults undergoing cardiac surgery was associated with increased risk of postoperative dialysis. PMID- 21524426 TI - Prevalence of skin test reactivity to aeroallergens in the Pakistani population. AB - OBJECTIVES: The prevalence of allergies has increased in all parts of the world. The present study was conducted to determine the prevalence of sensitivity to common aeroallergens, pollen, thresher dust and cotton dust, in Pakistan. STUDY DESIGN: Retrospective cohort study. METHOD: Record of 65067 who attended the Allergy Centre, National Institute of Health, Islamabad, Pakistan from January 2007 to August 2008 was retrieved. Subjects that were skin prick test (SPT) negative and those that were SPT positive to aeroallergens were extracted and subcategorized on the basis of the 8 provinces of Pakistan, including, Islamabad Capital Territory, Punjab, Baluchistan, Sindh, Northern Areas, Kashmir, North Western Frontier Province (NWFP) and Federally Administered Tribal Areas (FATA). Monthly analysis of prevalence of allergies was also determined. RESULTS: Of the total, 68.6% were SPT positive. The highest number of affected individuals was from the Punjab region (41%). The highest number of cases of all aeroallergens was reported in the month of August (3532, 13.7%). Significant high correlations were observed between mixed pollen, thresher dust and raw cotton and allergic rhinitis, asthma, uriticaria and allergic conjunctivitis. There was no significant correlation between allergen sensitivity and atopic edema. CONCLUSION: A high prevalence of sensitivity to aeroallergens is observed in the Punjab Province of Pakistan. PMID- 21524427 TI - Characterization of a mannose-binding lectin from channel catfish (Ictalurus punctatus). AB - Mannose-binding lectin (MBL) is an important component of innate immunity capable of activating the lectin pathway of the complement system. A MBL gene was isolated from channel catfish (Ictalurus punctatus). The deduced protein contains a canonical collagen-like domain, a carbohydrate recognition domain (CRD), and a neck region similar to mammalian mannose-binding lectin. The catfish mannose binding lectin CRD contains the EPN motif shown previously to mediate mannose specificity. The catfish mannose-binding lectin showed 30-43% identity with MBL protein sequences of rainbow trout, zebrafish, common carp, and goldfish, and 33 35% identity with sequences of mammalian species. In this study, while liver was the predominant source of mannose-binding lectin gene expression in healthy tissues, mannose-binding lectin expression in spleen rose sharply following challenge with a Gram-negative bacterium. PMID- 21524428 TI - Comparison of bovine cysticercosis prevalence detected by antigen ELISA and visual inspection in the North East of Spain. AB - A cross-sectional serological study on cattle less than 2 years old, using an antigen ELISA for the detection of bovine cysticercosis was carried out between November 2009 and February 2010 in 10 slaughterhouses from the Catalonia region (North-Eastern Spain). Circulating antigen was detected in 23 of 2073 animals, i.e. a sero-prevalence of 1.11% (CI95%: 0.76-1.75%). The determined sero prevalence was about 50 times higher than the prevalence obtained by visual inspection within the same period: 19 positive animals of 90,891 slaughtered animals (0.02%) in the same slaughterhouses. None of the animals with positive result in the Ag-ELISA was detected by meat inspection. PMID- 21524429 TI - Effects of the organophosphate insecticide azinphos-methyl on the reproduction and cholinesterase activity of Biomphalaria glabrata. AB - Azinphos-methyl is an organophosphate insecticide used for pest control on a number of food crops in many parts of the world. The snail Biomphalaria glabrata is a freshwater gastropod widely distributed in South America, Central America and Africa. The aim of the present work was to investigate whether azinphos methyl causes alterations in the reproduction of B. glabrata. To this end, gastropod pigmented specimens were exposed to various concentrations of the insecticide (0.021, 0.5, 2.5, and 5 mg L(-1)) for either 2 or 14 d. Along 14 d, several reproduction parameters and cholinesterase (ChE) activity were evaluated. In each group, the number of egg masses, the number of eggs per mass, the number of hatchings, the time to hatching, and the survival of the offspring after one month of treatment was evaluated. The results showed that, depending on the concentration and time of exposure, azinphos-methyl induced alterations in the reproduction of B. glabrata. These alterations were mainly represented by a decrease in the number of egg masses, and, in some cases, by a lower number or even the total absence of hatchings. Thus, the gastropods exposed to 2.5 and 5 mg L(-1) of azinphos-methyl for 14 d showed ChE inhibitions higher than 35% along time and completely lost their ability to reproduce. On the other hand, exposure to high acute concentrations or exposure to low concentrations for 14 d resulted in ChE inhibition equal to or lower than 35% between 7 and 14 d of treatment and similar alterations in reproduction. These were represented by a decrease in the number of egg masses. At low pestice levels, the number of egg masses and the number of offspring resulted to be more sensitive biomarkers than ChE inhibition. It is concluded that the insecticide azinphos-methyl can cause a decline in the reproductive performance of B. glabrata. PMID- 21524430 TI - One-carbon metabolism and Alzheimer's disease: is it all a methylation matter? AB - The sporadic form of Alzheimer disease, late onset Alzheimer's disease (LOAD), is a multifactorial disease; a strong link between nutritional and genetic factors with normal aging and dementia is supported by studies on nutrition, metabolism, and neurodegeneration. Specifically, the involvement of homocysteine (HCY) and its dietary determinants (vitamins B6, B12, and folate, besides methionine) in dementia has been a topic of intense investigation. In this Commentary we would like to highlight the role of 1-carbon metabolism in epigenetics and Alzheimer's disease and evidence the co-involvement of this metabolism in amyloid and tau pathways. PMID- 21524432 TI - Local brain atrophy accounts for functional activity differences in normal aging. AB - Functional brain imaging studies of normal aging typically show age-related under and overactivations during episodic memory tasks. Older individuals also undergo nonuniform gray matter volume (GMv) loss. Thus, age differences in functional brain activity could at least in part result from local atrophy. We conducted a series of voxel-based blood oxygen level-dependent (BOLD)-GMv analyses to highlight whether age-related under- and overrecruitment was accounted for by GMv changes. Occipital GMv loss accounted for underrecruitment at encoding. Efficiency reduction of sensory-perceptual mechanisms underpinned by these areas may partly be due to local atrophy. At retrieval, local GMv loss accounted for age-related overactivation of left dorsolateral prefrontal cortex, but not of left dorsomedial prefrontal cortex. Local atrophy also accounted for age-related overactivation in left lateral parietal cortex. Activity in these frontoparietal regions correlated with performance in the older group. Atrophy in the overrecruited regions was modest in comparison with other regions as shown by a between-group voxel-based morphometry comparison. Collectively, these findings link age-related structural differences to age-related functional under- as well as overrecruitment. PMID- 21524431 TI - Dl-3-n-butylphthalide, a natural antioxidant, protects dopamine neurons in rotenone models for Parkinson's disease. AB - In the absence of a cure for Parkinson's disease, development of preventive medications for this devastating disease is particularly encouraged. Dl-3-n butylphthalide (NBP), an established natural antioxidant for clinical stroke treatment in China, can reportedly reduce beta-amyloid-induced neuronal toxicity in cultured neuronal cells, and attenuate neurodegenerative changes in aged rats. However, whether or not NBP confers neuroprotection in parkinsonian models is still unknown. In this study, we investigated the effects of NBP in rotenone models for Parkinson's diseases. In a cellular model, pretreatment with NBP enhanced cell viability by decreasing nuclear fragmentation, retaining mitochondrial membrane potential, and preventing reactive oxygen species (ROS) from generation. In a rodent model, 2-week treatment with NBP was able to ameliorate apomorphine-evoked rotations by 48% and rescue dopaminergic (DA) neurons by 30% and striatal DA terminal by 49%. Furthermore, NBP upregulated the vesicular monoamine transporter 2 gene expression in vitro and in vivo. Together, NBP protects DA neurons likely by reducing oxidative stress, offering an alternative neuroprotective medication for Parkinson's disease. PMID- 21524433 TI - Successful removal of a floating thrombus in ascending aorta. AB - Free-floating thrombus in ascending aorta is a rare cause of peripheral embolism with potentially fatal consequences. We report the case of a young patient with syncope and sudden lumbar pain. Computed tomographic scan revealed a large pedunculated floating mass attached to the posterior wall of the ascending aorta, probably responsible of renal embolic infarction; transthoracic echocardiography confirmed the diagnosis. Surgery was urgently performed. The thrombus was excised, and was not related to atherosclerotic disease of the aortic wall. We conclude that once diagnosis is clear, urgent surgery must be considered to avoid any further embolic complications. PMID- 21524434 TI - Transforming growth factor-beta receptor type II mutation in a patient with bicuspid aortic valve disease and intraoperative aortic dissection. AB - We report on a patient with familial bicuspid aortic valve disease operated on for proximal aortic aneurysm. The surgery was complicated by intraoperative aortic dissection. Multi-generational genetic analysis demonstrated a mutation in the transforming growth factor-beta receptor type II gene. This case confirms the clinical hypothesis that the proximal aortic disease has a genetic origin in some bicuspid aortic valve patients. PMID- 21524435 TI - Real-time three-dimensional transesophageal echocardiography is useful for the localization of a small mitral paravalvular leak. AB - The use of multiplane transesophageal echocardiography (TEE) to reconstruct 3 dimensional (3D) images is limited by time-consuming, multiplane image acquisition and the need for offline processing. To overcome these limitations, a 3D fully sampled matrix array transducer was recently developed to allow real time acquisition and online display of 3D images. In this case, real-time 3D transesophageal echocardiography produced clear image of a small paraprosthetic leak point. Although the surgical view from the left atrium was poor due to severe adhesions, we were able to perform optimal repair of the small leak after intraoperative confirmation of the location of the leak that was identified by preoperative real-time 3D transesophageal echocardiography. PMID- 21524436 TI - Transatrial stent-valve implantation in a stenotic tricuspid valve bioprosthesis. AB - A 69-year-old man presented with symptoms of right heart failure due to stenosis of a tricuspid valve bioprosthesis. Echocardiography revealed right atrial dilatation and an estimated tricuspid valve area of 0.4 cm2. Because of advanced poor general condition and comorbidities, he was found unfit for conventional reoperation. Instead, transcatheter transatrial stent-valve implantation through a right thoracotomy was scheduled. The procedure resulted in a markedly improved clinical condition and an increased valve area measured to 2.5 cm2. In conclusion, transcatheter transatrial stent-valve implantation in stenotic valves is technically feasible and may lead to substantial improvement of the clinical condition. PMID- 21524437 TI - Kergin pneumonectomy: a rare procedure. AB - We have evaluated our cases of "Kergin" pneumonectomy in which a bronchial flap of the medial part of the right main stem bronchus was created during right pneumonectomy and was turned upward to cover the lateral airway defect at the level of the carina. Five male patients with a mean age of 53.6 underwent "Kergin" pneumonectomy due to nonsmall cell carcinoma arising from right upper lobe entrance, which does not allow a classical pneumonectomy. Postoperative pathology stagings were stage IIB in 1 patient and stage IIIA in 4 patients. Any operative mortality or short-term complication was not observed. Two of the patients died in the second year of follow-up. "Kergin" pneumonectomy is a rarely performed procedure with acceptable morbidity and mortality and good lung cancer resection. Actually, our current report of five cases will be one of the largest series of "Kergin" pneumonectomy. PMID- 21524438 TI - How does an apico-aortic conduit look after death? PMID- 21524439 TI - Giant right atrial dilation and left atrial calcification. PMID- 21524440 TI - Monitoring cardiac output trends with end-tidal carbon dioxide pressures in off pump coronary bypass. AB - The optimum method of intraoperative monitoring in patients undergoing off-pump coronary bypass remains debatable. Using capnography and end-tidal carbon dioxide pressure may be a helpful method of monitoring cardiac output trends, especially when grafting posterior and lateral vessels. After repositioning the heart, End tidal carbon dioxide pressures that continue to trend down usually indicate decreased cardiac output and precede hemodynamic and electrical instability. The advantages of this method include simplicity, universal availability, and a short response time to changes in cardiac output. PMID- 21524441 TI - Invited commentary. PMID- 21524442 TI - Impact of renal function before mechanical circulatory support on posttransplant renal outcomes. AB - BACKGROUND: Renal dysfunction is common before mechanical circulatory support (MCS). Mechanical circulatory support frequently improves renal function, but the impact of pre-MCS renal dysfunction on renal function after cardiac transplantation (CTX) is unknown. METHODS: Patients with MCS from January 1995 until April 2008 at a single center were included if their MCS duration was at least 60 days and they underwent successful CTX. Patients were followed for 1 year after CTX. RESULTS: A total of 116 patients were included in the study. Mechanical circulatory support was biventricular assist device in 28% and left ventricular assist device in 72% (continuous flow left ventricular assist device, 14%). Mean duration of MCS was 124 days. Patients were grouped according to tertiles of pre-MCS creatinine clearance (CrCl): group 1, CrCl less than 45 mL/min; group 2, CrCl between 45 and 65 mL/min inclusive; and group 3, CrCl more than 65 mL/min. Group 3 had the best renal outcomes both after MCS and 1 year after CTX. Regardless of group, patients who had a CrCl of at least 60 mL/min before CTX had similar 1-year posttransplant CrCl (55 versus 53 versus 56 mL/min for groups 1 through 3, respectively; not significantly different). However, the ability to achieve this level of renal function after MCS was less likely in those with the worst renal function before the initiation of MCS (53% versus 74% versus 90% for groups 1 through 3, respectively; p=0.001). CONCLUSIONS: The use of MCS leads to improvements in renal function in patients after MCS. However, the renal outcomes after CTX seem to be more dependent on the level of renal function achieved during MCS than on the level of renal function before MCS. PMID- 21524443 TI - Invited commentary. PMID- 21524444 TI - One-year results after implantation of the CorCap for dilated cardiomyopathy and heart failure. AB - BACKGROUND: We conducted a prospective study of the clinical outcomes and health related quality of life after implantation of the CorCap support device (Acorn Cardiovascular Inc, St Paul, MN) for dilated cardiomyopathy. METHODS: The criteria adopted for CorCap implantation were dilated cardiomyopathy (left ventricular [LV] end-diastolic diameter>=60 mm, LV ejection fraction<=0.30 and >0.10), and New York Heart Association functional class II or III despite maximal medical therapy. Echocardiographic follow-up and evaluation with the Short Form 36 questionnaire were performed. RESULTS: Included were 39 patients: 5 in New York Heart Association class II and 32 in class III. At 13.3+/-2.5 months of follow-up, a statistically significant improvement was evident in mean LV volume (LV end-systolic volume from 202+/-94 to 138+/-72 ml. p=0.005) and systolic function (LV ejection fraction from 0.26+/-0.05 to 0.36+/-0.05, p<0.001). The mean LV sphericity index was significantly increased at the end of the follow-up (p=0.009). Ischemic etiology, diabetes, advanced age, and LV ejection fraction of less than 0.15 predicted lesser reversal of the LV alterations. Operative mortality was 5.1%. Cumulative follow-up mortality was 10.2%. The average Physical Health domain scores (Physical Functioning, Role Physical, General Health) were improved. Average Mental Health domain scores were also increased. CONCLUSIONS: The cardiac support device obtains reverse remodelling of the LV and is useful to improve the quality of life of patients with dilated cardiomyopathy and New York Heart Association class III symptoms of heart failure. The integration of different and complementary strategies (cardiac support device and resynchronization therapy) may represent the key to success for more complex patients, although further studies are required. PMID- 21524445 TI - Invited commentary. PMID- 21524446 TI - Invited commentary. PMID- 21524447 TI - Impact of the learning curve for endoscopic vein harvest on conduit quality and early graft patency. AB - BACKGROUND: Recent studies have suggested that endoscopic vein harvest (EVH) compromises graft patency. To test whether the learning curve for EVH alters conduit integrity owing to increased trauma compared with an open harvest, we analyzed the quality and early patency of conduits procured by technicians with varying EVH experience. METHODS: During coronary artery bypass grafting, veins were harvested open (n=10) or by EVH (n=85) performed by experienced (>900 cases, >30/month) versus novice<100 cases, <3/month) technicians. Harvested conduits were imaged intraoperatively using optical coherence tomography and on day 5 to assess graft patency using computed tomographic angiography. RESULTS: Conduits from experienced (n=55) versus novice (n=30) harvesters had similar lengths (33 versus 34 cm) and harvest times (32.4 versus 31.8 minutes). Conduit injury was noted in both EVH groups with similar distribution among disruption of the adventitia (62%), intimal tears at branch points (23%), and intimal or medial dissections (15%), but the incidence of these injuries was less with experienced harvesters and rare in veins procured with an open technique. Overall, the rate of graft attrition was similar between the two EVH groups (6.45% versus 4.34% of grafts; p=0.552). However, vein grafts with at least 4 intimal or medial dissections showed significantly worse patency (67% versus 96% patency; p=0.05). CONCLUSIONS: High-resolution imaging confirmed that technicians inexperienced with EVH are more likely to cause intimal and deep vessel injury to the saphenous vein graft, which increases graft failure risk. Endoscopic vein harvest remains the most common technique for conduit harvest, making efforts to better monitor the learning curve an important public health issue. PMID- 21524448 TI - Consumer comprehension of surgeon performance data for coronary bypass procedures. AB - BACKGROUND: Public and private organizations have called for increased transparency in reporting of outcomes data for hospitals and surgeons, including risk-adjusted coronary artery bypass graft surgery (CABG) mortality data. Limited information is available about how the public actually interprets these data. METHODS: Four different graphical and tabular displays of CABG outcomes for surgeons, three of which were modeled on current state public reports, were shown to 337 adults. Each display contained data for 3 to 5 hypothetical surgeons. For each format, respondents were asked to choose which surgeon they would be most and least likely to choose based on the data. Additionally, they were asked questions about public reporting. RESULTS: Accurate identification of best surgeon performance varied by display format, with a high of 66% on one display and a low of 16% on another. Only 6.4% identified the surgeon with the lowest risk mortality across all four displays. Respondents with at least some college education were significantly more likely to identify the surgeon with the lowest risk-adjusted mortality, compared with respondents having no college education (21% to 72% vs. 9% to 59%; p<0.01). In one display, the surgeon with the lowest risk-adjusted mortality was effectively penalized for taking on higher-risk patients; respondents tended to select the surgeon with the lowest-risk population but the highest risk-adjusted mortality. Overall, 82% of respondents said that access to these types of data would be "absolutely essential" or "very important" in choosing a surgeon. CONCLUSIONS: Comprehension by the public of risk-adjusted CABG outcomes is limited and varies by display format. Poorly constructed displays may have led to misinterpretation, with potential unintended adverse consequences such as risk aversion. Further work is needed to design displays that maximize accurate interpretation by the public and more clearly define the risk and benefit of public reporting of surgeon performance. PMID- 21524449 TI - Survival of surgically treated infective endocarditis: a comparison with the general Dutch population. AB - BACKGROUND: Infective endocarditis (IE) remains associated with high in-hospital and long-term mortality. The outcome of patients with IE who are operated on has never been put into perspective by comparing it to the age-matched and gender matched general population. The aim of the present study was to evaluate the long term mortality of patients with IE who undergo operation in relation to the age matched and gender-matched general population. METHODS: A retrospective observational cohort study of 138 patients with IE who underwent consecutive operations (1998-2007) was conducted. Cumulative survival was analyzed using the Kaplan-Meier method. Comparison of patient survival with the general population was done using the Dutch population life table. The standardized mortality ratio was used to assess the degree of late deaths. RESULTS: The observed in-hospital mortality risk was 10.9%. The observed long-term survival was 85% (95% confidence interval, 78% to 90%), 74% (95% confidence interval, 65% to 79%), 71% (95% confidence interval, 62% to 78%) after 1, 5, and 10 years, respectively. Age matched and gender-matched survival in the general population was 99%, 93%, and 80% after a follow-up period of 1, 5, and 10 years, respectively. The standardized mortality ratio was 0.99 (95% confidence interval, 0.67 to 1.31). CONCLUSIONS: Although mortality of IE patients who have undergone operation remains considerable during the immediate postoperative period, the mortality of hospital survivors is, with increasing follow-up time, comparable with the general population. PMID- 21524450 TI - Invited commentary. PMID- 21524451 TI - Midterm surgical outcomes of noncomplicated active native multivalve endocarditis: single-center experience. AB - BACKGROUND: Surgical treatment for endocarditis is still challenging and only a handful of studies have analyzed surgical outcomes in patients with active multivalvular endocarditis. METHODS: From June 1996 to October 2007, 152 patients underwent surgery for active native valve endocarditis; 117 patients with single valve endocarditis and 35 patients with multivalvular endocarditis. Preoperative and postoperative data were retrospectively reviewed to determine risk factors for early and late mortality. RESULTS: One-year and 5-year survival were 78.6%+/ 3.8% and 54.8%+/-5.3% in the single-valve group, and 74.3%+/-7.4% and 64.8%+/ 8.3% in the multivalve group, respectively (log-rank 0.64). The rates of valve replacement were significantly higher in the single-valve group than in the multivalve group in all sites except the pulmonary valve. Freedom from reoperation was 90.0%+/-3.6% in the single-valve group and 79.5%+/-8.5% in the multivalve group in 5 years (log-rank 0.30). No recurrence of endocarditis was noted in the multivalve group, while 4 patients (3.4%) had recurrence in the single-valve group during the follow-up period (p=0.57). There was no significant difference in postoperative complications between the two groups. Multivariate analysis of the multivalve group identified postoperative renal failure as a predictor of late mortality with no predictors identified for early mortality, reoperation, and recurrence. Statistical analysis of the overall cohorts showed multivalve endocarditis was not an independent predictor of early and late mortality. CONCLUSIONS: Surgical treatment for active, native, and noncomplicated multivalve endocarditis was associated with respectable early and late morbidity and mortality comparable with single-valve endocarditis, and was not an independent predictor of early and late mortality. PMID- 21524452 TI - Invited commentary. PMID- 21524453 TI - Center variation in patient age and weight at Fontan operation and impact on postoperative outcomes. AB - BACKGROUND: The impact of age and weight on outcomes after the Fontan operation is unclear. Previous analyses have suggested that lower weight-for-age z-score is an important predictor of poor outcome in patients undergoing bidirectional Glenn. We evaluated variation in age, weight, and weight-for-age z-score at Fontan across institutions, and the impact of these variables on postoperative morbidity and mortality. METHODS: Patients in The Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Fontan operation (2000 to 2009) were included. Center variation in age, weight, and weight-for-age z-score were described. Multivariable analysis was performed to evaluate the impact of age, weight, and weight-for-age z-score on in-hospital mortality, Fontan failure (combined in-hospital mortality and Fontan takedown/revision), postoperative length of stay, and complications, adjusting for other patient and center factors. RESULTS: A total of 2,747 patients (68 centers) were included: 61% male; 45% right dominant lesions (38% left dominant, 17% undifferentiated). An extracardiac conduit Fontan (versus lateral tunnel) was performed in 63%; 65% were fenestrated. Median age, median weight at Fontan operation, and proportion with weight-for-age z-score less than -2 varied across centers and ranged from 1.7 to 4.8 years, 10.5 to 16.1 kg, and 0% to 30%, respectively. In multivariable analysis, age and weight were not significantly associated with outcome. Weight for-age z-score less than -2 was associated with increased in-hospital mortality (odds ratio 2.73, 95% confidence interval: 1.09 to 6.86), Fontan failure (odds ratio 2.59, 95% confidence interval: 1.24 to 5.40), and longer length of stay (+1.2 days, 95% confidence interval: 0.1 to 2.4). CONCLUSIONS: Weight-for-age z score less than -2 is associated with significant morbidity and mortality after the Fontan operation independent of other patient and center characteristics. PMID- 21524454 TI - Early results of the "clamp and sew" Fontan procedure without the use of circulatory support. AB - BACKGROUND: A modification of the Fontan operation was recently applied, which includes anastomoses of the extracardiac conduit to the right pulmonary artery and inferior vena cava using simple clamping with no additional circulatory support, venous shunting, pulmonary artery preparation, or prior maintenance of azygos vein patency. The objective of this study is to assess the outcomes of this novel off-pump "clamp and sew" Fontan procedure. METHODS: This is a retrospective review of all patients having a Fontan procedure between January 2009 and October 2010 at a single institution. RESULTS: Twelve patients had a Fontan procedure with the use of cardiopulmonary bypass (CPB group), and 12 had an off-pump Fontan procedure (off-pump group). Preoperative demographic and hemodynamic data were similar except for higher mean pulmonary artery pressure in the CPB group (12.2+/-1.6 mm Hg versus 9.9+/-2.4 mm Hg; p=0.02). No patients in the off-pump group required conversion to CPB. The mean inferior vena cava clamp time in the off-pump group patients was 10+/-3 minutes. There were no early or midterm deaths. No patients exhibited postoperative hepatic or renal dysfunction. Postoperative maximal serum creatinine and aspartate transaminase were significantly lower in the off-pump group compared with the CPB group (0.59+/ 0.12 versus 0.77+/-0.22 mg/dL; p=0.03 and 35.5+/-8.3 versus 53.1+/-19.0 U/L; p=0.02, respectively). At median follow-up of 13 months (range, 1 to 20 months), all but 1 patient in the CPB group are in New York Heart Association class I with unobstructed Fontan circulation. CONCLUSIONS: The clamp and sew technique for completion of an extracardiac conduit Fontan procedure appears safe and feasible for selected patients. PMID- 21524455 TI - Hybrid therapy for pulmonary atresia with intact ventricular septum. AB - BACKGROUND: In patients with pulmonary atresia with intact ventricular septum without right ventricular-dependent coronary circulation, catheter techniques, including the use of a stiff wire, lasers, and radiofrequency, have been most widely used for initial therapy; however, percutaneous perforation and balloon valvuloplasty have been associated with higher rates of procedural failure and serious complications. We report our experience with a hybrid approach involving the combination of surgery and interventional catheterization techniques for right ventricular decompression. METHODS: Between March 2005 and April 2010, we performed a hybrid procedure in 30 newborns and infants (age, 1 day to 2 years; median age, 3 months) with favorable anatomy. The heart was exposed by performing midline sternotomy. A purse-string suture was placed in the right ventricular outflow tract 2 cm away from the pulmonary trunk. Then, a 16-gauge intravenous catheter was placed periventricular with the guidance of echocardiography to perforate the atretic pulmonary ventricle. Subsequently, a guide wire was inserted into the sheath and used to guide a balloon across the pulmonary ventricle. Sequential dilations were performed under the guidance of epicardial echocardiography until full opening of the pulmonary ventricle was obtained. In newborns, ductal ligation was performed, followed by modified Blalock-Taussig (mBT) shunt placement. Patients aged greater than 1 month were treated mostly with ductal ligation, and an mBT shunt was inserted if severe systemic oxygen desaturation occurred after ductal ligation; bidirectional Glenn shunt placement was performed if a patient showed severe hypoplasia. RESULTS: The hybrid procedure was successfully performed in all patients. Patent ductus arteriosus ligation was simultaneously performed in 27 cases. Six newborns were treated with mBT shunt placement after pulmonary valvuloplasty and patent ductus arteriosus ligation, and 2 patients aged greater than 1 month were treated with mBT shunt placement alone. Another 2 patients were selected for univentricular palliation with bidirectional Glenn procedure because of a diminutive monopartite right ventricle. No pericardial effusion or cardiac tamponade was observed. One patient in whom ductal ligation could not be performed was treated with mBT shunt placement because of hypoxemia 3 days after the hybrid procedure; the other patients were discharged without any further surgical intervention. During the follow-up period of 1.5 months to 5 years, 5 patients died; 25 (83.3%) survived and all were in New York Heart Association functional class 1. Saturation of peripheral oxygen in the survivors increased from 73.1+/-8.5% to 94+/-3.5% (p<001). Two-ventricle circulation was achieved in 24 patients, whereas 1 patient had a single-ventricle pathway. CONCLUSIONS: In conclusion, periventricular balloon pulmonary valvuloplasty using a hybrid approach was safe and feasible for patients with pulmonary atresia with intact ventricular septum. PMID- 21524456 TI - Invited commentary. PMID- 21524457 TI - Surgical repair of truncus arteriosus associated with interrupted aortic arch: long-term outcomes. AB - BACKGROUND: Truncus arteriosus (TA) with interrupted aortic arch (IAA) is a rare combination of complex anomalies. We report long-term follow-up after one-stage repair of TA associated with IAA. METHODS: From April 1985 to August 2007, 16 patients with TA associated with IAA underwent one-stage repair. RESULTS: There were 2 (12.5%) early deaths and no late deaths. Follow-up was 92.9% complete (13 of 14 patients), with 1 patient lost to follow-up. Median duration of follow-up was 18.2 years (range, 2.1 to 21.9 years). Functional status in all patients was good. Thirteen patients underwent 25 surgical reoperations and 5 interventional procedures (3 aortic arch balloon angioplasties and 2 pulmonary artery balloon angioplasties). Overall freedom from any reoperation was 69.2% at 1 month, 54.5% at 3 years, 30% at 5 years, 11.1% at 10 years, and 0% at 15 years after the initial operation. Freedom from aortic reoperation was 76.9% at 1 month, 72.7% at 3 years, 70% at 5 years, 66.7% at 10 years, and 57.1% at 15 years; while freedom from right ventricular-to-pulmonary artery conduit replacement was 84.6% at 1 month, 63.6% at 3 years, 40% at 5 years, 11.1% at 10 years, and 0% at 15 years. Finally, freedom from truncal valve reoperation was 100% at 5 years, 88.9% at 10 years, and 85.7% at 15 years. CONCLUSIONS: One-stage repair of TA-IAA can be undertaken with good long-term results. Despite a significant reoperation rate, patients' functional status remains good at the long-term follow-up. PMID- 21524458 TI - Invited commentary. PMID- 21524459 TI - A comparison of the modified Blalock-Taussig shunt with the right ventricle-to pulmonary artery conduit. AB - BACKGROUND: This study compared the modified Blalock-Taussig (MBT) shunt with the right ventricle-to-pulmonary artery (RVPA) conduit with respect to outcome and PA growth. METHODS: PA growth was assessed in 19 MBT patients and in 15 RVPA patients before stage 2 palliation for hypoplastic left heart syndrome. The RVPA was done with a ringed Gore-Tex tube (W. L. Gore and Assoc, Flagstaff, AZ) at each anastomosis. RESULTS: The two cohorts had similar pre-Glenn demographic and hemodynamic data. No patient required transcatheter or surgical intervention on the shunt or PAs after stage 1 palliation. The branch PA growth was better in RVPA (McGoon ratio: MBT, 1.5+/-0.2 vs RVPA, 2.0+/-0.6; p<0.003) and was significantly more balanced (right-to-left PA area ratio: MBT, 1.5+/-0.5 vs RVPA, 0.9+/-0.6; p=0.002). The Nakata index trended higher in RVPA (MBT, 242A+/-90 mm2/m2 vs RVPA, 267+/-95 mm2/m2, p=0.2). After stage 2 palliation, oxygen saturation trended higher in the RVPA (81%+/-5%) vs MBT cohort (77%+/-8%, p<0.08). CONCLUSIONS: The Norwood operation using a RVPA nonvalved conduit is associated with improved branch PA growth. PMID- 21524460 TI - Pathologic lymph node staging practice and stage-predicted survival after resection of lung cancer. AB - BACKGROUND: Lymph node status is the most important prognostic factor in resectable nonsmall-cell lung cancer (NSCLC). We examined the relationship between the pattern of lymph node examination (including the number and anatomic location of resected lymph nodes), pathologic nodal stage, and survival after NSCLC resection. METHODS: Retrospective review of all NSCLC resections in the Memphis Metropolitan Area from January 1, 2004, to December 31, 2007. RESULTS: In 656 resections, the number of lymph nodes examined differed significantly between patients grouped by pathologic nodal stage (p<0.0001) and extent of resection (p<0.001). Thirty-seven percent of "mediastinal node-negative" patients had no mediastinal lymph nodes examined. Patients with pN1 and no mediastinal lymph node examination had better [corrected] survival than patients with mediastinal lymph node examination (p < 0.02) . Approximately 10% of patients with pN0 and pN2 disease had no hilar/intrapulmonary lymph nodes examined. CONCLUSIONS: Suboptimal lymph node staging was prevalent in this cohort. Large proportions of pN1 and pN0 patients were probably understaged. In patients with pathologic positive pulmonary/hilar lymph nodes, mediastinal lymph node examination was associated with poorer survival [corrected]. Interventions are needed to improve lymph node staging of NSCLC. PMID- 21524461 TI - Invited commentary. PMID- 21524462 TI - Prediction of major pulmonary complications after esophagectomy. AB - BACKGROUND: Pulmonary complications are the most frequent morbid event after esophagectomy. Understanding factors that are associated with pulmonary complications may help in patient selection and postoperative management. METHODS: We performed a retrospective review of patients who underwent esophagectomy between 1980 and 2009. Univariate analysis was used to identify potential covariates for the development of major pulmonary complications. Multivariable logistic regression analysis was used to identify predictors of complications. A scoring system was developed, and its ability to predict complications was assessed. RESULTS: A total of 516 patients (382 men [74%]) with a mean age of 59.0+/-12.5 years underwent esophagectomy for cancer (398 [77%]) or benign disease. Major pulmonary complications occurred in 197 patients (38%) and were associated with a 10-fold increase in operative mortality (2.5% vs 28%; p<0.001). Independent predictors included patient age, forced expiratory volume in 1 second (% predicted), diffusion capacity of the lung for carbon monoxide (% predicted), performance status, serum creatinine, current cigarette use, and transthoracic resection. The scoring system (based on weighted scores for the first 4 covariates listed above) predicted pulmonary complications with an accuracy of 70.8% (p<0.001). Score groups identified an incremental risk of complications of 0 to 2, 12%; 3 to 4, 18%; 5 to 6, 46%; 7 to 8, 52%; and 9 to 13, 60% (p<0.001). CONCLUSIONS: Major pulmonary complications are frequent after esophagectomy and can be predicted using commonly available clinical information. A scoring system identifying the risk of such complications may assist in patient selection and in providing appropriate resources for postoperative management of higher-risk patients. PMID- 21524463 TI - High expression of p300 has an unfavorable impact on survival in resectable esophageal squamous cell carcinoma. AB - BACKGROUND: p300 is a transcriptional regulator that is involved in fundamental processes such as cell proliferation, cell differentiation, and tumor progression. However, its role and clinical significance in resectable esophageal squamous cell carcinoma (ESCC) has not been elucidated. The purpose of this study was to explore whether there was a correlation between the expression of p300 by immunohistochemistry and the clinical outcome of a group of patients with ESCC treated with surgical resection. METHODS: Tissue microarray that included 240 surgically resected ESCC specimens and 56 cases of paracancerous tissues was successfully generated for immunohistochemical evaluation. The clinical and prognostic significance of p300 expression was analyzed statistically. Kaplan Meier analysis was used to compare the postoperative survival between groups. RESULTS: The expression frequency and expression levels of p300 were significantly higher in ESCC specimens (62.5%, 150 of 240) than in normal esophageal mucosa (8.9%, 5 of 56; p<0.001). Increased p300 expression was associated with higher histologic grade (p=0.012), T category (p=0.032), and N category (p=0.013). Patients with low expression of p300 demonstrated higher overall survival compared with those with high expression of p300 (mean, 80.0 months versus 56.9 months; p<0.001). A similar result was observed for disease free survival (mean, 78.3 months versus 53.1 months; p<0.001). Furthermore, p300 expression could stratify the patient survival (disease-free survival and overall survival) in stage II (p=0.002, 0.003, respectively). Multivariate analysis showed that the level of p300 expression was an independent prognostic factor in ESCC (relative risk, 1.658; p=0.017). CONCLUSIONS: High expression of p300 suggests poor prognosis for patients with resectable ESCC. PMID- 21524464 TI - Invited commentary. PMID- 21524465 TI - Association between hormone receptor expression and epidermal growth factor receptor mutation in patients operated on for non-small cell lung cancer. AB - BACKGROUND: Estrogen receptor (ER) and progesterone receptor (PR) play important roles in breast cancer. Similarly, there have been several reports of ER and PR expression in lung cancers, but the results have not been consistent. The aim of this study was to investigate the association between hormone receptor expression and clinicopathologic factors and epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). METHODS: We evaluated 316 resected NSCLC specimens for ER-alpha, PR, human epidermal growth factor receptor 2, and aromatase (n=272) expression using immunohistochemical methods. EGFR mutations were evaluated with polymerase chain reaction (PCR). RESULTS: ER-alpha and PR were detected in 36.1% and 44.9% of all patients, respectively. The expression of ER-alpha was observed mostly in cytoplasm (94.7%) and the expression of PR was observed mostly in nucleus (95.8%). Aromatase was detected in the cytoplasm of 64.0% of patients. ER-alpha expression was significantly associated with female gender (p=0.004). The expression of PR was significantly associated with better clinicopathologic features. ER-alpha expression showed a positive correlation with PR (r=0.275; p<0.001) and aromatase (r=0.244; p<0.001) expression levels. EGFR mutation was independently associated with the female gender (p=0.001), negative expression of PR (p<0.001), and negative expression of aromatase (p=0.027). CONCLUSIONS: The expression of ER-alpha and PR distinguish a subset of NSCLC that has defined clinicopathologic features. Negative expression of PR and aromatase correlate with EGFR mutation. PMID- 21524466 TI - Invited commentary. PMID- 21524467 TI - Portable mechanical circulatory support: human experience with the LIFEBRIDGE system. AB - PURPOSE: This study was designed to demonstrate the safety and functional performance of the LIFEBRIDGE B2T system (Medizintechnik GmbH, Ampfing, Germany), a novel portable life support system, during human applications under controlled conditions. DESCRIPTION: The LIFEBRIDGE system was used as a modular closed circuit miniaturized cardiopulmonary bypass system for total support of circulation and gas exchange in a series of 8 elective coronary artery bypass grafting procedures using normothermic cardioplegic arrest. EVALUATION: Mean blood flow rates provided by the LIFEBRIDGE system were 4.82+/-0.47 L/min throughout the procedures (ie, 100% of calculated normal blood flow). Adequate gas exchange and arterial oxygenation were provided at all times. All patients survived the operations with no neurologic sequelae. CONCLUSIONS: The LIFEBRIDGE system provides sufficient circulatory support and gas exchange during cardiac arrest and apnea, which are the maximum stress conditions for a life support system. It is anticipated that the system will be widely used as a circulatory support system in future applications that require portability and rapid delivery of short-term mechanical circulatory support, such as with cardiogenic shock. PMID- 21524468 TI - Invited commentary. PMID- 21524469 TI - Patch repair of a giant left ventricular pseudoaneurysm after mitral valve replacement. AB - Left ventricular pseudoaneurysm (LVP) is a rare cardiac disorder. We describe the repair of a large LVP that was identified in a 73-year-old woman 10 months after she underwent mitral valve replacement for infective endocarditis at another hospital 10 months previously. Follow-up echocardiography showed an enlarged large mass beside the left ventricle, and computed tomography revealed a LVP and an orifice just beside the mitral annulus. We removed the implanted valve and closed the large orifice (35*4 mm) using a Xenomedica (Baxter Healthcare Corp, Horw, Switzerland) patch. Computed tomography 3 months later revealed a thrombosed LVP. PMID- 21524470 TI - Original aortic valve plasty with autologous pericardium for quadricuspid valve. AB - Quadricuspid aortic valves represent a very rare pathology. Most cases have been discovered incidentally during heart operations or at autopsy. Patients may become symptomatic with aortic regurgitation. We encountered a symptomatic patient with aortic regurgitation and a quadricuspid aortic valve. Successful aortic valve plasty was done with our original technique of tricuspid replacement by glutaraldehyde-treated autologous pericardium. PMID- 21524471 TI - Hybrid one-stage approach to extensive atherosclerotic aneurysm of thoracoabdominal aorta. AB - We report a 62-year-old man with an atherosclerotic Crawford type II aneurysm involving both common iliac arteries who underwent surgical revascularization of the visceral vessels and renal arteries from the ascending aorta and subsequent endovascular aneurysmal exclusion. Computed tomography imaging at 2 years showed complete exclusion of the aneurysm throughout the thoracoabdominal aorta, confirming the successful antegrade revascularization of visceral vessels and renal arteries. A hybrid approach to thoracoabdominal aneurysms using antegrade visceral and renal revascularization from the ascending aorta before endovascular repair is technically feasible and might constitute an attractive alternative to conventional surgical treatment. PMID- 21524472 TI - Mycotic aneurysm of the left anterior descending coronary artery after coronary artery bypass graft surgery. AB - Mycotic aneurysms of the coronary artery are extremely uncommon and can be very difficult to diagnose. We report a unique case of a mycotic aneurysm of the left anterior descending coronary artery with a history of two-vessel off-pump coronary artery bypass graft surgery 9 months previously. The aneurysmectomy was successful. PMID- 21524473 TI - Breast infarction due to calciphylaxis after coronary artery bypass grafting. AB - The use of the internal mammary artery for coronary artery bypass grafting is common. We describe a patient with chronic renal insufficiency who had no need for dialysis, and who suffered from breast necrosis after coronary artery bypass grafting with internal mammary artery harvesting due to calciphylaxis. The histology report of the breast tissue showed mural vascular calcification and intima proliferation of small-sized to medium-sized vessels. This causes ischemic necrosis of the skin and septal panniculitis. We believe that this is the first case report of breast necrosis after coronary artery bypass grafting, due to calciphylaxis in a patient with known chronic renal insufficiency, without renal replacement therapy. PMID- 21524474 TI - Hemophilia A in cardiac operations: a model of reduced thrombin generation. AB - Patients with hemophilia A have a congenital defect in thrombin generation. Only limited data are available on the substitution regimens in hemophilia A patients during and after cardiac operations. There are no data on heparinization of these patients during cardiopulmonary bypass. Whereas most case reports suggest factor VIII replacement in combination with standard heparinization to achieve near normal physiologic factor VIII activity, we describe the successful management of a hemophilic A patient using a low-level factor VIII replacement combined with a reduced heparin dosage during cardiopulmonary bypass. This approach facilitated adequate anticoagulation and minimized the amount of factor VIII treatment necessary without compromising bleeding control. PMID- 21524475 TI - Erosion of an Amplatzer septal occluder device into the aortic root. AB - Atrial septal defects can be closed surgically or percutaneously. We report a patient who underwent percutaneous closure of an atrial septal defect with an Amplatzer septal occluder device (AGA Medical Corp, Golden Valley, MN). The patient presented 4 months later with congestive heart failure secondary to an erosion of the Amplatzer septal occluder into the aortic root. The device was removed surgically, and the fistula was repaired. Amplatzer septal occluder indications, selection criteria, and complications are discussed. PMID- 21524476 TI - Coupling of central venous pressure and intracranial pressure in a 6-year-old patient with fontan circulation and intracranial hemorrhage. AB - A sharp rise in intracranial pressure (ICP) was noted in a 6-year-old girl with Fontan circulation after surgical removal of a hematoma associated with intracranial hemorrhage. Inhalation of nitric oxide resulted in reduction of central venous pressure (CVP) and precipitous fall in ICP, which was otherwise resistant to conventional therapy. Specifically, the rate of fall of ICP (9 mm Hg) exceeded that of the CVP (3 mm Hg), indicating disproportionate CVP-ICP coupling. The present case provides not only a novel insight into cardio-cerebral interaction in Fontan physiology but also useful information regarding the treatment of Fontan patients in the setting of increased ICP. PMID- 21524478 TI - Mediastinoscopy as a therapeutic tool. AB - Mediastinoscopy is a safe and effective diagnostic modality to obtain tissue specimens from the anterior mediastinum in most patient lymph node tissue. The technique can also be applied to remove other material from the mediastinum. We describe a case in which a bullet was retrieved from the mediastinum, lying very close to the innominate artery. Important differences in using the device for this purpose are highlighted. PMID- 21524477 TI - Transesophageal bronchoscopic ultrasound-guided fine-needle aspiration for diagnosis of peripheral lung cancer. AB - Peripheral lung cancer is still a diagnostic challenge. The transbronchial approach with bronchoscopy or the transthoracic approach with radiologic imaging has been used extensively for the pathologic diagnosis of peripheral lung cancer. However, the explorability or feasibility with these modalities depends on the lesion location or patient's respiratory function. Herein, we report a case with severe pulmonary emphysema and lung cancer located at a parenchymal region difficult to access through an airway with a bronchoscope. Successful diagnosis was obtained by a transesophageal ultrasound-guided needle aspiration using an endobronchial ultrasound bronchoscope. This technique is accurate and less invasive in the primary diagnosis of lung cancer adjoining the esophagus. PMID- 21524479 TI - Fast-growing large cell neuroendocrine carcinoma of mediastinum. AB - Neuroendocrine carcinomas combine a heterogeneous group of tumors occurring in lungs on a rare occasion, and in some cases, they appear to have extraordinary quick growth and extrapulmonary localization. In this case we present a 42-year old patient who underwent a right upper lobectomy for emphysema, and 6 months later, the tumor developed again into a giant neuroendocrine carcinoma of the mediastinum. PMID- 21524480 TI - Thymoma with pure red cell aplasia and Good's syndrome. AB - Thymoma patients with pure red cell aplasia (PRCA) or hypogammaglobulinemia (Good's syndrome) are rare, whereas those with both PRCA and Good's syndrome are even rarer. Here we present the case report of a 70-year-old woman with invasive thymoma and simultaneous PRCA and Good's syndrome, who achieved complete PRCA remission after thymectomy. PMID- 21524481 TI - Rapid enlargement of elastofibroma dorsi after physical therapy. AB - Elastofibroma dorsi is an uncommon, slow-growing, ill-defined soft tissue tumor. Its most prominent symptom is back and shoulder pain. Elastofibroma dorsi is usually located beneath the scapula and bilateral involvement occurs in only 10% of patients. We report herein a case of bilateral elastofibroma dorsi who underwent physical therapy for treatment of shoulder pain. Elastofibroma was misdiagnosed and rapidly progressed after physical therapy. We conclude that elastofibroma should be kept in mind for patients with shoulder or back pain, and the patient should be evaluated carefully before initiating physical therapy. PMID- 21524482 TI - Rapid progression of left main coronary disease causing acute coronary syndrome. PMID- 21524483 TI - Recurrent circumflex artery embolization due to a free-floating fibroelastoma at the aortic valve. PMID- 21524484 TI - Operation for a massive bilobed thoracoabdominal aortic aneurysm complicated with the occlusion of inferior vena cava. PMID- 21524485 TI - A novel method for repairing aortic regurgitation due to commissural detachment. AB - Currently, aortic valve replacement is the mainstay treatment for aortic regurgitation due to commissural detachment. Herein, we report a novel technique of aortic root and commissural repair and its intermediate clinical outcome in patients with significant aortic regurgitation caused by commissural detachment. The detached commissure and aortic root were treated concomitantly by en bloc reattachment of the detached commissure and aortic wall by using multiple pledgeted sutures, in addition to aortic root reimplantation. PMID- 21524486 TI - Double telescopic anastomosis with interrupted suture technique in acute aortic dissection. AB - We describe a new method for aortic anastomosis in the repair of acute aortic dissection. The anastomosis sites are prepared and sutured in an interrupted horizontal mattress manner with telescoping technique. By this kind of method, the interrupted sutures decrease damage to the fragile aortic wall and the antegrade blood flow promotes anastomotic sealing. This interrupted telescoping suturing technique will greatly help in managing aortic dissecting disease. PMID- 21524487 TI - Self-covered technique for a varix on a saphenous vein graft. AB - We describe a simple technique for eliminating a varix on a saphenous vein graft (SVG). The SVG with varix is passed through a short section of the saphenous vein, and the varix is covered by the short cylinder of the vein. Both parts are fixed by arterial pressure, which expands the SVG. This technique was used in two SVGs in 2 patients undergoing coronary artery bypass grafting. The grafts were investigated by angiography 1 year after the surgery, and the patency without varix was confirmed. This simple method is feasible to repair a varix of the SVG. PMID- 21524488 TI - A novel and simple atrial retractor. AB - Minimally invasive cardiac operations require specialized equipment. Atrial retractors are a frequently used tool to expose heart valves for minimally invasive and open procedures. The models currently available in the market are efficient; however, they may be complex, bulky, or expensive. We introduce a novel, very simple atrial retractor we designed using ubiquitously available materials. PMID- 21524489 TI - The Society of Thoracic Surgeons expert consensus for the surgical treatment of hyperhidrosis. AB - Significant controversies surround the optimal treatment of primary hyperhidrosis of the hands, axillae, feet, and face. The world's literature on hyperhidrosis from 1991 to 2009 was obtained through PubMed. There were 1,097 published articles, of which 102 were clinical trials. Twelve were randomized clinical trials and 90 were nonrandomized comparative studies. After review and discussion by task force members of The Society of Thoracic Surgeons' General Thoracic Workforce, expert consensus was reached from which specific treatment strategies are suggested. These studies suggest that primary hyperhidrosis of the extremities, axillae or face is best treated by endoscopic thoracic sympathectomy (ETS). Interruption of the sympathetic chain can be achieved either by electrocautery or clipping. An international nomenclature should be adopted that refers to the rib levels (R) instead of the vertebral level at which the nerve is interrupted, and how the chain is interrupted, along with systematic pre and postoperative assessments of sweating pattern, intensity and quality-of-life. The recent body of literature suggests that the highest success rates occur when interruption is performed at the top of R3 or the top of R4 for palmar-only hyperhidrosis. R4 may offer a lower incidence of compensatory hyperhidrosis but moister hands. For palmar and axillary, palmar, axillary and pedal and for axillary-only hyperhidrosis interruptions at R4 and R5 are recommended. The top of R3 is best for craniofacial hyperhidrosis. PMID- 21524490 TI - Spinal cord ischemia risk factors with thoracic endovascular aneurysm repair. PMID- 21524491 TI - Benefits and risks with using cannulation at the innominate artery with a side graft during arch surgery. PMID- 21524492 TI - Is regional high-flow perfusion safe for cerebral function in pediatric patients during deep hyperthermia? PMID- 21524494 TI - Video-assisted thoracoscopic patent ductus arteriosus closure without tube thoracostomy. PMID- 21524495 TI - Does presence of hematologic malignancy change our approach to non-small cell lung cancer? PMID- 21524496 TI - Postoperative radiotherapy after esophagectomy: ripe for a randomized trial. PMID- 21524497 TI - The true false-negative rates of EBUS and EUS. PMID- 21524499 TI - Endoscopic or conservative management of postintubation tracheal membrane laceration. PMID- 21524502 TI - Synthesis and inhibitory activity of sialic acid derivatives targeted at viral sialate-O-acetylesterases. AB - A series of sialosides modified at the 4- and 9-hydroxy group were synthesised and tested for inhibition of the viral haemagglutinin-esterase activity from various Orthomyxoviruses and Coronaviruses. While no inhibition of the sialate-4 O-acetylesterases from mouse hepatitis virus strain S or sialodacryoadenitis virus was found, a 9-O-methyl derivative displayed inhibitory activity against recombinant sialate-9-O-acetylesterase from influenza C virus. PMID- 21524503 TI - Dual IGF-1R/SRC inhibitors based on a N'-aroyl-2-(1H-indol-3-yl)-2 oxoacetohydrazide structure. AB - The N'-aroyl-2-(1H-indol-3-yl)-2-oxoacetohydrazide motif was identified as a novel scaffold for the development of kinase inhibitors. Derivatives with a biphenyl element attached to the hydrazide structure proved to be submicromolar dual inhibitors of the cancer-related kinases IGF-1R and SRC. One of the most potent kinase inhibitors of the series produced a selective growth inhibition in a panel of cultivated cancer cell lines. PMID- 21524504 TI - Rural/urban mortality differences in England and Wales and the effect of deprivation adjustment. AB - Perceptions that rural populations are inevitably healthier and live longer than urban populations are increasingly being challenged. But very few publications have investigated the extent to which these putative differences can be explained by variation in area composition. Existing publications have tended to use conventional deprivation measures, often thought to mask rural deprivation by favourable averages. Further, they have typically been based on large and variably-sized geographical units, or confined to studies of a single region or cause of death. This study examines differences in mortality between rural and urban areas in the entire population of England and Wales for 2002-2004. It uses the most up-to-date small geographical units of similar size and homogeneity of population together with the recently-introduced Rural and Urban Area Classification, and adjusts for five different deprivation measures (including modern composite indices). The causes of death investigated were all-cause mortality, cancer, lung cancer, respiratory disease, circulatory disease, suicide and accidents. Particular points of focus for the study were the potential for interaction between deprivation and rurality, and the importance of choice of deprivation measure in quantifying the relationships between mortality, rurality and deprivation. Choice of deprivation measure was not found to alter the substantive conclusions of any analysis, and little evidence for differential effects of deprivation in rural and urban areas was uncovered. Differences between rural and urban areas in all-cause, circulatory disease and cancer mortality could largely be accounted for by adjusting for deprivation. For these causes of death, therefore, rural populations were not found to be inherently healthier than their urban counterparts. However, substantial residual differences between rural and urban areas were found in comparisons of mortality from lung cancer and respiratory disease, mortality being lower in rural areas. Stronger relationships between rurality and mortality were found in 'village and dispersed' settlements. PMID- 21524505 TI - Invited review: Are adaptations present to support dairy cattle productivity in warm climates? AB - Environmental heat stress, present during warm seasons and warm episodes, severely impairs dairy cattle performance, particularly in warmer climates. It is widely viewed that warm climate breeds (Zebu and Sanga cattle) are adapted to the climate in which they evolved. Such adaptations might be exploited for increasing cattle productivity in warm climates and decrease the effect of warm periods in cooler climates. The literature was reviewed for presence of such adaptations. Evidence is clear for resistance to ticks and tick-transmitted diseases in Zebu and Sanga breeds as well as for a possible development of resistance to ticks in additional breeds. Development of resistance to ticks demands time; hence, it needs to be balanced with potential use of insecticides or vaccination. The presumption of higher sweating rates in Zebu-derived breeds, based upon morphological differences in sweat glands between breeds, has not been substantiated. Relatively few studies have examined hair coat characteristics and their responses to seasonal heat, particularly in temperate climate breeds. Recently, a gene for slick hair coat has been observed that improved heat tolerance when introduced into temperate climate breeds. No solid evidence exists that hair coat in these lines is lighter than in well-fed warm climate-adapted Holsteins. Warm climate breeds and their F1 crosses share as dominant characteristics lower maintenance requirements and milk yields, and limited response to improved feeding and management. These characteristics are not adaptations to a feed-limited environment but are constitutive and useful in serving survival when feed is scarce and seasonal and high temperatures prevail. The negative relationship between milk yield and fertility present in temperate climates breeds also prevails in Zebu cattle. Fertility impairment by warm conditions might be counteracted in advanced farming systems by extra corporeal early embryo culture. In general, adaptations found in warm climate cattle breeds did not increase heat dissipation capacity, but rather diminished climate-induced strain by decreasing milk production. The negative relationship between reproductive efficiency and milk yield, although relatively low, also appears in Zebu cattle. This association, coupled with limited feed intake, acting over millennia, probably created the selection pressure for a low milk production in these breeds. PMID- 21524506 TI - Preparation and comparison of cytotoxic complexes formed between oleic acid and either bovine or human alpha-lactalbumin. AB - alpha-Lactalbumin is a ubiquitous calcium-binding milk protein with a well characterized function in regulating the synthesis of lactose. An entirely different activity has been shown to occur when a complex is formed between calcium-free alpha-lactalbumin and oleic acid. This complex shows strong cytotoxic action against several cancer cells, and several mechanisms have been suggested to account for this cell-killing activity. Most studies have been performed using the human protein, but bovine alpha-lactalbumin shows similar activity. A new and simple 2-step method for purification of calcium-free alpha lactalbumin has been developed, and the resulting highly purified preparation was used to generate a complex with oleic acid. Using 3 different cell lines and 2 types of cell viability assays, the bovine and human alpha-lactalbumin showed comparable cytotoxic activity. The effect was apparent after 15 min of incubation and was inhibited by the presence of fetal bovine serum or bovine serum albumin. The bovine protein might be a useful alternative to the human protein, but also raises the question whether cytotoxic activity could be generated in different kinds of food containing alpha-lactalbumin. PMID- 21524507 TI - Assessment of an extraction protocol to detect the major mastitis-causing pathogens in bovine milk. AB - Despite all efforts to control its spread, mastitis remains the most costly disease for dairy farmers worldwide. One key component of better control of this disease is identification of the causative bacterial agent during udder infections in cows. Mastitis is complex, however, given the diversity of pathogens that must be identified. Development of a rapid and efficient bacterial species identification tool is thus necessary. This study was conducted to demonstrate the feasibility of bacterial DNA extraction for the automated molecular detection of major mastitis-causing pathogens directly in milk samples to complement traditional microbiological identification. Extraction and detection procedures were designed and optimized to achieve detection in a respectable time frame, at a reasonable cost, and with a high throughput capacity. The following species were identified: Staphylococcus aureus, Escherichia coli, Streptococcus uberis, Streptococcus agalactiae, Streptococcus dysgalactiae, and Klebsiella spp. (including Klebsiella oxytoca and Klebsiella pneumoniae). The detection procedure includes specific genomic DNA amplification by multiplex PCR for each species, separation by capillary electrophoresis, and laser-assisted automated detection. The specificity of the primers was assessed with a panel of bacteria representing mastitis-negative control species. The extraction protocol comprised multiple steps, starting with centrifugation for fat removal, followed by heating in the presence of a cation exchange resin to trap divalent ions. The analytical sensitivity was 100 cfu/mL for milk samples spiked with Staph. aureus, Strep. dysgalactiae, and E. coli, with a tendency for K. pneumoniae. The detection limit was 500 cfu/mL for Strep. uberis and Strep. agalactiae. The overall diagnostic sensitivity (95.4%) and specificity (97.3%) were determined in a double-blind randomized assay by processing 172 clinical milk samples with microbiological characterization as the gold standard. When the physical nature of the milk samples was too altered, DNA purification with a magnetic bead-based system was used. Of the apparent false-positive samples, 5 were identified by specific microbiological analysis as true-positive Staph. aureus co-infections, with further confirmation by ribosomal 16S sequencing. The proposed methodology could, therefore, become an interesting tool for automated PCR detection of major mastitis pathogens in dairy cattle. PMID- 21524508 TI - Use of gases to improve survival of Bifidobacterium bifidum by modifying redox potential in fermented milk. AB - The aim of this work was to study the effect of the oxidoreduction potential, modified using gas, on the growth and survival of a probiotic strain, Bifidobacterium bifidum, and 2 yogurt strains, Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus. Three fermented milks were manufactured with an initial oxidoreduction potential value adjusted to +440 mV (control milk), +350 mV (milk gassed with N(2)), and -300 mV [milk gassed with N(2) plus 4% (vol/vol) H(2) (N(2)-H(2))]. Acidification profiles, growth during milk fermentation and survival during storage at 4 degrees C for 28 d were determined. This study showed that fermented probiotic dairy products made from milk gassed with N(2) and, more particularly, those made from milk gassed with N(2)H(2) were characterized by a significant increase in B. bifidum survival during storage without affecting the fermentation kinetics and the survival of Strep. thermophilus and L. delbrueckii ssp. bulgaricus. PMID- 21524509 TI - Inulin blend as prebiotic and fat replacer in dairy desserts: optimization by response surface methodology. AB - The purpose of this work was to optimize the formulation of a prebiotic dairy dessert with low fat content (<0.1g/100g) using a mixture of short- and long chain inulin. Response surface methodology was applied to obtain the experimental design and data analysis. Nineteen formulations of dairy dessert were prepared, varying inulin concentration (3 to 9 g/100g), sucrose concentration (4 to 16 g/100g), and lemon flavor concentration (25 to 225 mg/kg). Sample acceptability evaluated by 100 consumers varied mainly in terms of inulin and sucrose concentrations and, to a lesser extent, of lemon flavor content. An interaction effect among inulin and sucrose concentration was also found. According to the model obtained, the formulation with 5.5 g/100g inulin, 10 g/100g sucrose and 60 mg/kg of lemon flavor was selected. Finally, this sample was compared sensorially with the regular fat content (2.8 g/100g) sample previously optimized in terms of lemon flavor (146 mg/kg) and sucrose (11.4 g/100g). No significant difference in acceptability was found between them but the low-fat sample with inulin possessed stronger lemon flavor and greater thickness and creaminess. PMID- 21524511 TI - Effect of storage temperature on quality of light and full-fat ice cream. AB - Ice cream quality is dependent on many factors including storage temperature. Currently, the industry standard for ice cream storage is -28.9 degrees C. Ice cream production costs may be decreased by increasing the temperature of the storage freezer, thus lowering energy costs. The first objective of this research was to evaluate the effect of 4 storage temperatures on the quality of commercial vanilla-flavored light and full-fat ice cream. Storage temperatures used were 45.6, -26.1, and -23.3 degrees C for the 3 treatments and -28.9 degrees C as the control or industry standard. Ice crystal sizes were analyzed by a cold-stage microscope and image analysis at 1, 19.5, and 39 wk of storage. Ice crystal size did not differ among the storage temperatures of light and full-fat ice creams at 19.5 or 39 wk. An increase in ice crystal size was observed between 19.5 and 39 wk for all storage temperatures except -45.6 degrees C. Coldness intensity, iciness, creaminess, and storage/stale off-flavor of the light and full-fat ice creams were evaluated at 39 wk of storage. Sensory evaluation indicated no difference among the different storage temperatures for light and full-fat ice creams. In a second study, light and full-fat ice creams were heat shocked by storing at -28.9 degrees C for 35 wk and then alternating between -23.3 and 12.2 degrees C every 24h for 4 wk. Heat-shocked ice creams were analyzed at 2 and 4 wk of storage for ice crystal size and were evaluated by the sensory panel. A difference in ice crystal size was observed for light and full-fat ice creams during heat-shock storage; however, sensory results indicated no differences. In summary, storage of light or full-fat vanilla-flavored ice creams at the temperatures used within this research did not affect quality of the ice creams. Therefore, ice cream manufacturers could conserve energy by increasing the temperature of freezers from -28.9 to -26.1 degrees C. Because freezers will typically fluctuate from the set temperature, usage of -26.1 degrees C allows for a safety factor, even though storage at -23.3 degrees C did not affect ice cream quality. PMID- 21524510 TI - Membrane-rich milk fat diet provides protection against gastrointestinal leakiness in mice treated with lipopolysaccharide. AB - Milk fat globule membrane is a protein-lipid complex that may strengthen the gut barrier. The main objective of this study was to assess the ability of a membrane rich milk fat diet to promote the integrity of the gut barrier and to decrease systemic inflammation in lipopolysaccharide (LPS)-challenged mice. Animals were randomly assigned to one of 2 American Institute of Nutrition (AIN)-76A formulations differing only in fat source: control diet (corn oil) and milk fat diet (anhydrous milk fat with 10% milk fat globule membrane). Each diet contained 12% calories from fat. Mice were fed diets for 5 wk, then injected with vehicle or LPS (10mg/kg of BW) and gavaged with dextran-fluorescein to assess gut barrier integrity. Serum was assayed for fluorescence 24h after gavage, and 16 serum cytokines were measured to assess the inflammatory response. Gut permeability was 1.8-fold higher in LPS-challenged mice fed the control diet compared with the milk fat diet. Furthermore, mice fed the milk fat diet and injected with LPS had lower serum levels of IL-6, IL-10, IL-17, monocyte chemotactic protein (MCP)-1, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and IL-3 compared with LPS-injected mice fed the control diet. The results indicate that the membrane rich milk fat diet decreases the inflammatory response to a systemic LPS challenge compared with corn oil, and the effect coincides with decreased gut permeability. PMID- 21524512 TI - Survival of probiotic adjunct cultures in cheese and challenges in their enumeration using selective media. AB - Various selective media for enumerating probiotic and cheese cultures were screened, with 6 media then used to study survival of probiotic bacteria in full fat and low-fat Cheddar cheese. Commercial strains of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus paracasei, or Bifidobacterium lactis were added as probiotic adjuncts. The selective media, designed to promote growth of certain lactic acid bacteria (LAB) over others or to differentiate between LAB, were used to detect individual LAB types during cheese storage. Commercial strains of Lactococcus, Lactobacillus, and Bifidobacterium spp. were initially screened on the 6 selective media along with nonstarter LAB (NSLAB) isolates. The microbial flora of the cheeses was analyzed during 9 mo of storage at 6 degrees C. Many NSLAB were able to grow on media presumed selective for Lactococcus, Bifidobacterium spp., or Lb. acidophilus, which became apparent after 90 d of cheese storage, Between 90 and 120 d of storage, bacterial counts changed on media selective for Bifidobacterium spp., suggesting growth of NSLAB. Appearance of NSLAB on Lb. casei selective media [de man, Rogosa, and Sharpe (MRS)+vancomycin] occurred sooner (30 d) in low-fat cheese than in full-fat control cheeses. Differentiation between NSLAB and Lactococcus was achieved by counting after 18 to 24h when the NSLAB colonies were only pinpoint in size. Growth of NSLAB on the various selective media during aging means that probiotic adjunct cultures added during cheesemaking can only be enumerated with confidence on selective media for up to 3 or 4 mo. After this time, growth of NSLAB obfuscates enumeration of probiotic adjuncts. When adjunct Lb. casei or Lb. paracasei cultures are added during cheesemaking, they appear to remain at high numbers for a long time (9 mo) when counted on MRS+vancomycin medium, but a reasonable probability exists that they have been overtaken by NSLAB, which also grow readily on this medium. Enumeration using multiple selective media can provide insight into whether it is the actual adjunct culture or a NSLAB strain that is being enumerated. PMID- 21524513 TI - Physical properties, molecular structures, and protein quality of texturized whey protein isolate: effect of extrusion moisture content. AB - To explore the complex relationship between processing conditions and functional and nutritional properties of food products containing whey protein isolate (WPI), we investigated the effect of extrusion texturization at various temperatures (50, 75, and 100 degrees C) and varying moisture levels of the feed (20, 30, 40, and 50%) on changes in the composition, molecular structure, and protein quality of the extrudates. Bradford assay methods were used to determine protein solubility of the extruded WPI as a function of changing level of moisture. Protein compositional changes as a function of extrusion conditions were quantitatively characterized and analyzed by sodium dodecyl sulfate-PAGE and reversed-phase-HPLC techniques. We showed that at a given temperature, increasing the extrusion moisture content resulted in a slight increase in the overall protein water solubility (at 50 and 75 degrees C), averaging approximately 5% per 10% increase in moisture content. A reduction in beta-lactoglobulin content was observed at 50 degrees C with increasing moisture content, indicative of the sensitive nature of beta-lactoglobulin to extrusion treatment, whereas the amount of alpha-lactalbumin remained unchanged at all moisture contents used at a set temperature. The protein quality of the extruded WPI, determined chemically by available sulfhydryl and primary and secondary amines, remained relatively unchanged as a function of moisture level. Circular dichroism and intrinsic tryptophan fluorescence spectroscopic studies revealed considerable structural changes, both at the secondary structural level and the tertiary contacts as a function of increasing temperature, and higher moisture levels can slightly preserve secondary structures but not the tertiary contacts of the protein molecules. Atomic force microscopy provided direct visualization of the fine difference of the protein particles caused by changing extrusion moisture contents, which is in close agreement with the results obtained using other techniques in this work. PMID- 21524514 TI - Fat replacers in low-fat carboxymethyl cellulose dairy beverages: Color, rheology, and consumer perception. AB - Low-fat foods are an interesting option for consumers interested in health related issues or in maintaining adequate body weight; however, fat reduction may influence consumer acceptance of the end product. This study aims to obtain information about the effectiveness of lambda-carrageenan and a blend (50:50) of short- and long-chain inulin as fat replacers in dairy beverages prepared with carboxymethyl cellulose (CMC) and to determine to what extent consumers perceive instrumental color and rheological differences among samples. Results showed that both lambda-carrageenan and the inulin blend could be used as fat replacers in CMC-based dairy beverages and that consumers could distinguish among samples that differed in color and rheological behavior. PMID- 21524515 TI - Purification, characterization, and milk coagulating properties of ginger proteases. AB - Ginger proteases are used as milk coagulants in making a Chinese traditional milk product (Jiangzhinai or Jiangzhuangnai), suggesting their potential as a source of rennet substitute that might be applicable in the modern dairy industry. In this study, ginger proteases were extracted from fresh ginger rhizome by using phosphate buffer and subsequently purified by ion exchange chromatography. Ginger proteases, all with a molecular weight around 31 kDa, were found to exist in 3 forms with isoelectric point values around 5.58, 5.40, and 5.22, respectively. These enzymes had very similar biochemical behavior, exhibiting optimal proteolytic activity from 40 to 60 degrees C and maximum milk clotting activity at 70 degrees C. They were capable of hydrolyzing isolated alpha(S1)-, beta-, and kappa-casein, of which alpha(S1)-casein was most susceptible to the enzyme; kappa-casein was hydrolyzed with a higher specificity than alpha(S1)- and beta casein. In addition, the ginger proteases exhibited a similar affinity for kappa casein and higher specificity with increasing temperature. Gel electrophoresis and mass spectra indicated that Ala90-Glu91 and His102-Leu103 of kappa-casein were the preferred target bonds of ginger proteases. The milk clotting activity, affinity, and specificity toward kappa-casein showed that ginger protease is a promising rennet-like protease that could be used in manufacturing cheese and oriental-style dairy foods. PMID- 21524516 TI - Purification and identification of lactoperoxidase in milk basic proteins as an inhibitor of osteoclastogenesis. AB - A milk protein fraction with alkaline isoelectric points (milk basic protein, MBP) inhibits both bone resorption and osteoclastogenesis for in vitro models. We previously identified bovine angiogenin as a component of MBP that inhibits bone resorption. However, purified angiogenin had no effect on osteoclastogenesis, suggesting that MBP contains unidentified component(s) that inhibit osteoclast formation. In this study, we purified lactoperoxidase (LPO) as the predominant inhibitor of osteoclastogenesis in MBP. The LPO treatment downregulated levels of reactive oxygen species in osteoclasts. Signaling by receptor activator of NF kappa-B ligand/receptor activator of NF-kappa-B (RANKL/RANK) was downregulated in LPO-treated cells, and, in particular, the ubiquitination of tumor necrosis factor receptor associate factor 6 (TRAF6) and activation of downstream signaling cascades (JNK, p38, ERK, and NFkappaB) were suppressed. Ultimately, LPO treatment led to decreased expression of c-Fos and NFAT2. These results suggest that MBP contains at least 2 components that independently suppress bone resorption through a unique mechanism: angiogenin inhibits bone resorption and LPO inhibits RANKL-induced osteoclast differentiation. These data explain many of the positive aspects of milk consumption on bone health. PMID- 21524517 TI - Short communication: Assessing antihypertensive activity in native and model Queso Fresco cheeses. AB - Hispanic-style cheeses are one of the fastest growing varieties in the United States, making up approximately 2% of the total cheese production in this country. Queso Fresco is one of most popular Hispanic-style cheeses. Protein extracts from several varieties of Mexican Queso Fresco and model Queso Fresco were analyzed for potential antihypertensive activity. Many Quesos Frescos obtained from Mexico are made from raw milk and therefore the native microflora is included in the cheese-making process. Model Queso Fresco samples were made from pasteurized milk and did not utilize starter cultures. Water-soluble protein extracts from 6 Mexican Quesos Frescos and 12 model cheeses were obtained and assayed for their ability to inhibit angiotensin-converting enzyme, implying potential as foods that can help to lower blood pressure. All model cheeses displayed antihypertensive activity, but mainly after 8 wk of aging when they were no longer consumable, whereas the Mexican samples did display some angiotensin-converting enzyme inhibitory action after minimal aging. PMID- 21524518 TI - Effects of differential supplementation of fatty acids during the peripartum and breeding periods of Holstein cows: II. Neutrophil fatty acids and function, and acute phase proteins. AB - The objectives were to evaluate the effects of differential supplementation of Ca salts (CS) of fatty acids (FA) on plasma acute phase proteins and both FA composition and function (i.e., activity and cytokine production) of neutrophils, during the peripartum and breeding periods. Holstein cows were assigned randomly to receive either CS of palm (PO) or safflower (SO) oils from 30 d prepartum until 35 d postpartum (dpp) and CS of PO or fish oil (FO) from 35 to 160 dpp. Supplementation of CS of FA was at 1.5% of dietary dry matter. Cows (n=32) were sampled three times weekly from parturition to 35 dpp for analyses of plasma concentrations of haptoglobin and fibrinogen. Cows (n=47) were sampled for neutrophil phagocytic and oxidative burst activities toward Escherichia coli and Staphylococcus aureus, and neutrophil abundances of L-selectin and beta(2) integrin assessed by flow cytometry at 32 d prepartum, within 7h after parturition, and 4 and 7 dpp. Profiles of FA in neutrophils and cytokine production (i.e., tumor necrosis factor alpha, TNF-alpha, and IL-1beta) were assessed prepartum (n=14), 35 (PO vs. SO; n=26) and 85 dpp (PO vs. FO; n=28). Plasma concentrations of haptoglobin and fibrinogen were greater for cows fed SO compared with PO. The percentage of neutrophils with phagocytic and oxidative burst activities was not affected by transition diets, but activities per neutrophil were greater in SO compared with PO diets at 4 (phagocytosis and oxidative burst) and 7 dpp (oxidative burst). Neutrophil abundance of L-selectin, but not beta(2)-integrin, was greater in SO compared with PO at 4 and 7 dpp. Neutrophil productions of TNF-alpha and IL-1beta were increased at 35 dpp in SO compared with PO diets, but production of TNF-alpha was attenuated in FO compared with PO at 85 dpp. Neutrophil ratios of n-6:n-3 FA were greater at 35 dpp in the SO diet and less at 85 dpp in FO compared with PO diets. In conclusion, cows supplemented with CS of SO had improved innate immunity (i.e., acute phase response and neutrophil function) to better cope with the bacterial challenges in the postpartum period. Conversely, CS of FO attenuated neutrophil cytokine production. PMID- 21524519 TI - Complete-lactation milk and component yields following a short (35-d) or a conventional (60-d) dry period management strategy in commercial Holstein herds. AB - A total of 850 cows distributed among 13 commercial Holstein herds were involved in this study to compare the effects of 2 different dry period (DP) management strategies on milk and component yields as well as body condition score (BCS) over complete lactations. Within each herd and every 2 mo, cows were assigned to a short (35 d dry; SDP) or conventional (60 d dry; CDP) DP management based on previous lactation 305-d milk yield, predicted calving interval, and parity: primiparous (n=414) and multiparous (n=436). Cows assigned to CDP were fed a far off dry cow ration from dry-off until 21 d prepartum, and were then switched to a precalving ration. Cows assigned to SDP were fed the precalving ration throughout their DP. Rations were different across herds, but the late-lactation, precalving, and early lactation rations were identical for both treatment groups within each herd. Additional milk was obtained at the end of lactation from cows assigned to SDP due to the extended lactation. Average daily milk yield in the following lactation was not different between treatments for third- or greater lactation cows, but was significantly decreased in second-lactation SDP cows. However, when expressed as energy-corrected milk, this difference was not significant. Although lower for primiparous than multiparous cows, body weight and BCS were not affected by DP management strategy. Milk production and BCS responses to treatments varied among herds. Results from the present study suggest that a short DP management strategy could be more appropriate for today's dairy cows, although not suitable for all cows or all herds. PMID- 21524520 TI - Short-term effects of regrouping on behavior of prepartum dairy cows. AB - The objectives were to determine the effect of regrouping during the dry period on feeding, social, rumination, and lying behavior for cows that were moved to a new pen and cows that remained in their home pen but had new cows introduced. Forty-eight prepartum Holstein dairy cows were housed in groups of 6 and regrouped in groups of 3 (16 triads) with 1 triad moving to another pen and 1 triad staying in the same pen; the triad was considered the experimental unit. For 7 d before and 8 d after regrouping, cows were continuously monitored for feeding, rumination, and lying behavior by means of an electronic feeding system, a rumination logger on each cow's neck, and a data logger attached to 1 of the hind legs, respectively. Video recording was used to monitor displacements at the feeder for 3h following the afternoon fresh feed delivery before regrouping and for the 2 subsequent afternoon feed deliveries after regrouping. Cows that were moved to a new pen after regrouping decreased DMI by approximately 9% on the day of regrouping compared with baseline values, but cows that remained in their home pen showed no significant decrease in intake after regrouping. Feeding rate decreased in both treatments by 10% after regrouping. Rumination times also decreased by approximately 9% in both treatments, reaching the lowest values on the day of regrouping for cows that stayed in the home pen and on the day after regrouping for the moved cows. Cows that were moved to a new pen displaced other cows at the feeder twice as frequently after regrouping, but no such effect of regrouping on cows that stayed in the home pen was observed. These results indicate that regrouping can affect behavior of prepartum dairy cows, especially those cows that are moved to a new pen. PMID- 21524522 TI - Some coagulase-negative Staphylococcus species affect udder health more than others. AB - A longitudinal study in 3 dairy herds was conducted to profile the distribution of coagulase-negative Staphylococcus (CNS) species causing bovine intramammary infection (IMI) using molecular identification and to gain more insight in the pathogenic potential of CNS as a group and of the most prevalent species causing IMI. Monthly milk samples from 25 cows in each herd as well as samples from clinical mastitis were collected over a 13-mo period. Coagulase-negative staphylococci were identified to the species level using transfer-RNA intergenic spacer PCR. The distribution of CNS causing IMI was highly herd-dependent, but overall, Staphylococcus chromogenes, Staphylococcus xylosus, Staphylococcus cohnii, and Staphylococcus simulans were the most prevalent. No CNS species were found to cause clinical mastitis. The effect of the most prevalent species on the quarter milk somatic cell count (SCC) was analyzed using a linear mixed model, showing that Staph. chromogenes, Staph. simulans, and Staph. xylosus induced an increase in the SCC that is comparable with that of Staphylococcus aureus. Almost all CNS species were able to cause persistent IMI, with Staph. chromogenes causing the most persistent infections. In conclusion, accurate species identification cannot be ignored when studying the effect of CNS on udder health, as the effect on SCC differs between species and species distribution is herd specific. Staphylococcus chromogenes, Staph. simulans, and Staph. xylosus seem to be the more important species and deserve special attention in further studies. Reasons for herd dependency and possible cow- and quarter-level risk factors should be examined in detail for the different species, eventually leading to cost-benefit analyses for management changes and, if needed, treatment recommendations. PMID- 21524521 TI - Bayesian analysis of longitudinal Johne's disease diagnostic data without a gold standard test. AB - A Bayesian methodology was developed based on a latent change-point model to evaluate the performance of milk ELISA and fecal culture tests for longitudinal Johne's disease diagnostic data. The situation of no perfect reference test was considered; that is, no "gold standard." A change-point process with a Weibull survival hazard function was used to model the progression of the hidden disease status. The model adjusted for the fixed effects of covariate variables and random effects of subject on the diagnostic testing procedure. Markov chain Monte Carlo methods were used to compute the posterior estimates of the model parameters that provide the basis for inference concerning the accuracy of the diagnostic procedure. Based on the Bayesian approach, the posterior probability distribution of the change-point onset time can be obtained and used as a criterion for infection diagnosis. An application is presented to an analysis of ELISA and fecal culture test outcomes in the diagnostic testing of paratuberculosis (Johne's disease) for a Danish longitudinal study from January 2000 to March 2003. The posterior probability criterion based on the Bayesian model with 4 repeated observations has an area under the receiver operating characteristic curve (AUC) of 0.984, and is superior to the raw ELISA (AUC=0.911) and fecal culture (sensitivity=0.358, specificity=0.980) tests for Johne's disease diagnosis. PMID- 21524523 TI - Changes in hoof health and animal hygiene in a dairy herd after covering concrete slatted floor with slatted rubber mats: a case study. AB - The objective was to investigate the effect of changing the flooring in the alleys of a barn from slatted concrete to slatted rubber mats on hoof disorders and animal hygiene in 44 loose-housed Brown Swiss dairy cows. Cows were examined for disorders of the hind hooves (hemorrhages, white line fissures, ulcers, heel horn erosion, and digital dermatitis) and for skin lesions. The dirtiness of the animals and of the floor was recorded. Climatic (temperature, humidity) and ammonia gas conditions were measured. Evaluations were carried out when the cows were housed on a concrete slatted floor and after 4 and 10 mo on soft flooring (slatted rubber mats, 29-mm thick). The anatomical portion of claw (medial, lateral), number of lactations (parity), and days in milk were included as covariates in the statistical model. Changing the flooring from slatted concrete to slatted rubber mats increased the score for white line fissures [1.0 +/- 0.3 (concrete) vs. 2.5 +/- 0.4 (10 mo rubber mats)] and influenced air humidity (i.e., the difference in the absolute humidity between the inside and outside of the barn increased from 1.5 +/- 0.1 to 1.7 +/- 0.2g/m(3)), whereas the other hoof disorders, skin lesions (score of 8.7 +/- 0.3), the dirtiness of the animals (score of 5.9 +/- 0.3), and the floor (score of 2.1 +/- 0.1), and ammonia gas concentration (2.6 +/- 0.3mg/kg) were not affected (overall scores or measures; mean +/- SE). Lateral claws were more affected (except for heel horn erosion) than medial claws (estimated effects between 1.3 +/- 0.2 and 3.0 +/- 0.6). Parity influenced hoof disorders (except for hemorrhages) and skin lesions (estimated effects between -0.6 +/- 0.3 and 0.5 +/- 0.2). Days in milk influenced hoof disorders, but had no effect on skin lesions and on the dirtiness of the animal. Irrespective of floor type, the slots (2.6 +/- 0.1) were dirtier than the slats (1.6 +/- 0.1). In conclusion, covering slatted concrete flooring with slatted rubber mats partially impaired hoof health but did not influence skin lesions or the dirtiness of the cows or the floor. Similar results were found for climatic conditions, as ammonia gas concentration was not affected, but absolute humidity increased in the barn when rubber mats were present. PMID- 21524524 TI - Effect of duration and level of supplementation of diets of lactating dairy cows with selenized yeast on selenium concentrations in milk and blood after the withdrawal of supplementation. AB - Cows' milk containing elevated concentrations of Se provides a rich nutritional source of this essential element for meeting daily nutritional requirements or providing health benefits in humans with low immune function or at risk of cancer. An experiment involving either 2 or 6 wk of dietary supplementation with Se yeast (with the yeast supplying about 30, 40, and 60 mg of Se/d for cows supplemented for 2 wk, and about 20, 30, 40, and 60 mg of Se/d for cows supplemented for 6 wk), and 21 wk of monitoring of Se status after the withdrawal of supplementation, was undertaken between September 2008 and April 2009 using 35 multiparous Holstein-Friesian cows. Using milk and blood Se concentrations as surrogates, the research examined the time taken for Se build-up in tissue due to supplementation of lactating dairy cows with Se yeast to dissipate back to normal levels. At the end of Se supplementation, a significant relationship was found between milk Se concentration and Se intake, whereby milk Se concentration had increased by 4.5 MUg of Se/kg of milk for each mg of Se eaten per day, but no effect of duration of supplementation on this relationship was observed. At the same time, both Se intake and duration of supplementation affected blood Se concentration; it increased by 3.6 MUg of Se/kg of blood for each mg of Se eaten per day, and was 86 MUg of Se/kg higher after 6 wk compared with 2 wk of supplementation. After the withdrawal of Se supplementation, milk Se concentrations responded quickly to the change in the quantity of Se consumed, and again, duration of supplementation had no effect on the response, but any effect that Se intake had on milk Se had completely dissipated by 4 wk. In contrast to milk, blood Se concentrations continued to be affected by both amount and duration of Se supplementation for at least 4 mo after the withdrawal of supplementation, although by 5 mo the effects of the previous supplementation treatments had virtually disappeared. The slow decline in blood Se concentrations after the withdrawal of supplementation would most likely be due to the protracted clearance of Se from the various tissues that had accumulated Se during supplementation and the rate of erythrocyte turnover. When undertaking an on-farm Se enhancement program to generate milk for the manufacture of Se enriched milk products, post-supplementation milk Se concentrations are unlikely to create any problems at the milk factory beyond 4 wk, but the high residual blood/tissue Se concentrations that take considerably more time to dissipate may provide the potential for possible unintended consequences at the food chain/farm environment level. PMID- 21524525 TI - Latent class evaluation of a milk test, a urine test, and the fat-to-protein percentage ratio in milk to diagnose ketosis in dairy cows. AB - In this study, 3 commonly used tests to diagnose ketosis were evaluated with a latent class model to avoid the assumption of an available perfect test. The 3 tests were the KetoLac BHB (Sanwa Kagaku Kenkyusho Co. Ltd., Nagoya, Japan) test strip that tests milk for beta-hydroxybutyrate, the KetoStix (Bayer Diagnostics Europe Ltd., Dublin, Ireland) test strip that tests urine for acetoacetate, and the fat-to-protein percentage ratio (FPR) in milk. A total of 8,902 cows were included in the analysis. The cows were considered to be a random sample from the population of Danish dairy cattle under intensive management, thus representing a natural spectrum of ketosis as a disease. All cows had a recorded FPR between 7 and 21 d postpartum. The KetoLac BHB recordings were available from 2,257 cows and 6,645 cows had a KetoStix recording. The recordings were analyzed with a modified Hui-Walter model, in a Bayesian framework. The specificity of the KetoLac BHB test and the KetoStix test were both high [0.99 (0.97-0.99)], whereas the specificity of FPR was somewhat lower [0.79 (0.77-0.81)]. The best sensitivity was for the KetoStix test [0.78 (0.55-0.98)], followed by the FPR [0.63 (0.58-0.71)] and KetoLac BHB test [0.58 (0.35-0.93)]. PMID- 21524526 TI - Body temperature around induced estrus in dairy cows. AB - The overall objective of this study was to study the influence of induced estrus on body temperature, comparing 5 distinct intervals around induced estrus and to determine the diurnal pattern from 4 +/- 1 d before to 4 +/- 1 d after induced estrus. Sixteen estrous cycles of 9 postpartum dairy cows were synchronized with 2 injections of PGF(2alpha), 10 d apart. After the second PGF(2alpha) injection on d 10, temperature loggers were inserted into the vaginal cavity for a 12 +/- 1 d period. Two days later, a third dose of PGF(2alpha) was injected to induce estrus. After confirmation of a corpus luteum, loggers were removed on d 5 +/- 1. Observation of estrus, rectal palpation, and ultrasound scanning to determine ovulation were carried out every 4 +/- 1h, beginning at 12h after the third PGF(2alpha) injection. Blood samples from the vena coccygea mediana were collected twice daily from d 11 to 12 and every 4 +/- 1h after the third PGF(2alpha) injection until ovulation. Vaginal temperature was recorded every 5 min and averaged to hourly means for the following 5 periods: 1) 48 h preceding the third PGF(2alpha) injection, 2) from the third PGF(2alpha) injection to first signs of estrus, 3) estrus to ovulation, 4) a 4-h interval in which ovulation occurred, and 5) a 96-h post-ovulation period. High body temperatures (39.0 +/- 0.5 degrees C) and low progesterone (P4) concentrations (<0.5 ng/mL) were observed during estrus, whereas low body temperatures were observed from PGF(2alpha) injection to estrus (38.6 +/- 0.3 degrees C) and around ovulation (38.5 +/- 0.2 degrees C), respectively. An association between body temperature and serum P4 concentrations did not exist. However, P4 concentrations on d 11 and 12 were high (5.0 +/- 1.5 ng/mL) and decreased (0.9 +/- 0.2 ng/mL) after ovulation. Diurnal temperature rhythms were similar before and after estrus. Vaginal temperature before estrus (d 11 and 12) was slightly (0.1 degrees C) higher compared with the post-ovulation period. PMID- 21524527 TI - Perturbations of plasma metabolites correlated with the rise of rumen endotoxin in dairy cows fed diets rich in easily degradable carbohydrates. AB - Feeding dairy cows diets high in easily degradable carbohydrates increases the incidence of rumen and systemic metabolic disorders; however, the triggering factor is not well understood. In this study, dairy cows were fed 4 different amounts of barley grain-based concentrate at 15, 30, 45, and 60% (dry matter basis) of a total mixed ration to determine whether alterations in the rumen environment would be associated with perturbations of the plasma profile of selected metabolites. In addition, associations among free rumen endotoxin and several plasma metabolites were determined. The study was a replicated 4 * 4 Latin square design with 8 rumen-cannulated lactating dairy cows (60 +/- 15 d in milk). Multiple rumen fluid and blood plasma samples were collected and analyzed for pH and rumen fluid endotoxin and for concentrations of glucose, insulin, cholesterol, beta-hydroxybutyrate (BHBA), nonesterified fatty acids (NEFA), and lactate in the plasma. Rumen pH decreased below 6.0, from 8 to 12h after the morning feeding, with the augmentation of the proportion of concentrate in the diet of >= 30%. Feeding diets with >30% concentrate resulted in a rise of free endotoxin in the rumen fluid (8.87 +/- 0.39 MUg/mL). Inclusion of 60% concentrate in the total mixed ration was associated with enhanced concentrations of glucose (64.5 +/- 1.0 mg/dL) and lactate (540.9 +/- 36.5 MUmol/L) and lowered cholesterol (265.5 +/- 13.7 mg/dL), BHBA (449.1 +/- 47.4 MUmol/L), and NEFA (138.8 +/- 19.1 MUEq/L) in the blood plasma. The regression analysis revealed that greater concentrations of plasma lactate and lower concentrations of cholesterol, BHBA, and NEFA were related to the rise of rumen endotoxin. Interestingly, 93% of the increase in the plasma lactate was explained by the rise of rumen endotoxin. Moreover, the analysis revealed inverse relationships of rumen endotoxin with plasma cholesterol (R(2)=0.47), BHBA (R(2)=0.37), and NEFA (R(2)=0.50) and a biphasic response of plasma insulin (R(2)=0.58). Taken together, feeding dairy cows diets rich in rumen-degradable carbohydrates and low in fiber led to lower rumen pH and a large accumulation of rumen endotoxin; the latter was correlated with perturbations of plasma metabolites allied to carbohydrate and lipid metabolism. PMID- 21524528 TI - The low fertility of repeat-breeder cows during summer heat stress is related to a low oocyte competence to develop into blastocysts. AB - It was hypothesized the lower fertility of repeat-breeder (RB) Holstein cows is associated with oocyte quality and this negative effect is enhanced during summer heat stress (HS). During the summer and the winter, heifers (H; n=36 and 34, respectively), peak-lactation (PL; n=37 and 32, respectively), and RB (n=36 and 31, respectively) Holstein cows were subjected to ovum retrieval to assess oocyte recovery, in vitro embryonic developmental rates, and blastocyst quality [terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells and total cell number]. The environmental temperature and humidity, respiration rate, and cutaneous and rectal temperatures were recorded in both seasons. The summer HS increased the respiration rate and the rectal temperature of PL and RB cows, and increased the cutaneous temperature and lowered the in vitro embryo production of Holstein cows and heifers. Although cleavage rate was similar among groups [H=51.7% +/- 4.5 (n=375), PL=37.9% +/- 5.1 (n=390), RB=41.9% +/- 4.5 (n=666)], blastocyst rate was compromised by HS, especially in RB cows [H=30.3% +/- 4.8 (n=244) vs. 23.3% +/- 6.4 (n=150), PL=22.0% +/- 4.7 (n=191) vs. 14.6% +/- 7.6 (n=103), RB=22.5% +/- 5.4 (n=413) vs. 7.9% +/- 4.3 (n=177)]. Moreover, the fragmentation rate of RB blastocysts was enhanced during the summer, compared with winter [4.9% +/- 0.7 (n=14) vs. 2.2% +/ 0.2 (n=78)] and other groups [H=2.5% +/- 0.7 (n=13), and PL=2.7% +/- 0.6 (n=14)] suggesting that the association of RB fertility problems and summer HS may potentially impair oocyte quality. Our findings provide evidence of a greater sensitivity of RB oocytes to summer HS. PMID- 21524529 TI - Induction of successive follicular waves by gonadotropin-releasing hormone and prostaglandin F(2alpha) to improve fertility of high-producing cows during the summer and autumn. AB - Reduced conception rate during the hot summer and subsequent autumn is a well documented phenomenon. Evaporative cooling systems greatly increase milk production but only slightly improve reproductive performance; hence, additional approaches to improving fertility during the hot season are required. The purpose of the present study was to examine whether the combination of an efficient cooling system and hormonal manipulation (GnRH+PGF(2alpha)) might improve fertility during the summer and autumn. The experiment was conducted from July to December in 2 commercial herds in Israel and included 382 healthy Holstein cows. Cows (50 to 60 d in milk) were hormonally treated to induce 3 consecutive 9-d follicular waves, with GnRH administration followed by PGF(2alpha) injection 7 d later. Both control (n=187) and treated (n=195) cows were inseminated following estrus, and pregnancy was determined by palpation 45 d post-insemination. Data revealed an interaction between treatment and primiparous cows, reflected by a 16% increase in conception rate [odds ratio (OR) 2.32, 95% confidence interval (CI): 0.96-5.61] and 14% increase in pregnancy rate at 120 d in milk (OR 3.16, 95% CI: 0.93-10.47). Interaction between treatment and high body condition score was reflected by a 14% increase in pregnancy rate at 90 d in milk (OR 3.02, 95% CI: 1.14-7.96). About 60% of the treated cows expressed estrus at the expected time (normal response within 5 d following the third PGF(2alpha) injection); the remaining 40% that manifested estrus later (late response) had higher milk yield and lower body condition score. Additional analyses indicated that treatment interacted with normal response to raise conception rates and pregnancy rates of primiparous cows and cows with high body condition score. On the other hand, treatment by late-response interaction lowered conception rate during the summer. Implementation of such hormonal treatment in combination with an efficient cooling system may improve reproductive performance of dairy cows during the summer and subsequent autumn. PMID- 21524530 TI - Short communication: Breed differences affecting dairy cattle welfare in traditional alpine tie-stall husbandry systems. AB - The aim of this investigation was to compare the prevalence of indicators of poor welfare among 5 Italian cattle breeds (Italian Holstein-Friesian, Italian Bruna, Pezzata Rossa Italiana, Grigia Alpina, and Pezzata Rossa d'Oropa) kept in tie stalls in the Italian Alps under similar housing and management conditions. We recorded the presence of integument alterations (hairless patch areas, lesion/swollen areas, or overgrown claws) and lameness in 612 cows. Additionally, we checked 834 cows for the presence of physical malformations ("open" shoulders). In general, the prevalence of welfare problems showed a decreasing trend from the more productive to the less productive breeds. Local breeds (Grigia Alpina and Pezzata Rossa d'Oropa) showed a significantly lower prevalence of welfare problems compared with the other 3 breeds, whereas Italian Holstein Friesian usually had the highest percentage of individuals with problems. No differences were found between Pezzata Rossa Italiana and Italian Bruna, both of which showed fewer problems than Italian Holstein-Friesian. The effect of the breed significantly affected the welfare of dairy cows in tie-stalls in alpine traditional husbandry systems. The prevalence of the negative welfare indicators studied was lower in local breeds, which are better adapted to local breeding conditions. Our results indicate an urgent need to promote changes in the criteria used for genetic selection in the dairy industry and underline the importance of maintaining the diversity of local breeds, which should be carefully chosen for each specific environmental condition. PMID- 21524531 TI - Short communication: Metritis affects milk production and cull rate of Holstein multiparous and primiparous dairy cows differently. AB - Metritis, a common transition disease in dairy cows, reduces milk production during the duration of the disease. To our knowledge, no work has investigated the short-term effects of metritis on feed intake and the long-term consequences on milk yield and risk of culling. The objectives were to determine the effect of metritis on 305-d lactation curves, dry matter intake (DMI), reproduction, and the probability of being culled. Identifying differences in response to metritis between primiparous and multiparous cows was of interest. Milk records were collected twice daily from Holstein cows diagnosed with puerperal metritis (11 primiparous and 16 multiparous) or classified as healthy (14 primiparous and 43 multiparous) during the first 3 wk after calving. Metritic cows were treated at the discretion of the herd veterinarian. Lactation curves of healthy and metritic cows were compared using a mixed model with a Wilmink function. Differences in DMI, days open, and the number of services per conception were assessed using mixed models. The probabilities that cows with and without metritis were not bred, were bred but never confirmed pregnant, or were culled were compared using Fisher's exact tests. Primiparous and multiparous animals were assessed separately. Multiparous cows with metritis produced less milk (35.1+/-1.5 vs. 39.2+/-1.0 kg/d), ate less during the 3 wk after calving (12.2+/-1.2 vs.14.0+/ 0.8 kg/d), and were more likely to be culled (50.0%) than healthy cows (20.9%). The decision to cull was likely influenced by the lower milk yield in early lactation as a result of metritis; the decision to cull was made early, as 7 of the 8 culled metritic cows were not bred. No differences were found in any measurement between primiparous cows with and without metritis. These results indicate that metritis in early lactation has long-term effects on multiparous cows but not primiparous cows. PMID- 21524532 TI - Short communication: Effect of a stable pen management strategy for precalving cows on dry matter intake, plasma nonesterified fatty acid levels, and milk production. AB - During the close-up transition period, dairy cows are at risk for negative energy balance due to increasing energy demands and decreasing feed intake. This can result in postparturient health problems and decreased milk production after calving. Cows are frequently regrouped during this period, which can negatively affect feeding and resting behavior. The hypothesis was that housing in a stable pen during the close-up transition period should result in a more settled environment resulting in fewer displacements from the feed bunk, which would result in improved feed intake, energy balance [lower nonesterified fatty acid (NEFA) concentrations], and lactation performance. This study addresses precalving pen grouping strategies, which have the potential to affect feed intake and energy balance. A randomized complete block design with pen as the experimental unit was used to compare a stable (S) housing strategy (cows with similar calving dates added to a precalving pen at once) to the more traditional dynamic (D) housing strategy (cows added up to 2 times per week to a precalving pen). Twice-weekly blood samples were collected for NEFA analysis and cow interactions within the pen were observed. Dry matter intake (DMI), milk production, and postparturient health problems were recorded. Mean DMI for the duration of the 28 d of the study was not different (S: 25.5 +/- 1.6 vs. D: 25.7 +/- 1.0 kg/d), and when examined over time relative to calving, no treatment by time interaction was observed. Concentrations of NEFA were not different when cows initially entered the pens (S: 0.21 +/- 0.10 vs. D: 0.18 +/- 0.04 mEq/L) and remained not different for the time intervals closer to calving (d -9 to -14: S: 0.28 +/- 0.09 vs. D: 0.21 +/- 0.04; d -3 to -6: S 0.36 +/- 0.10, D 0.32 +/- 0.05 mEq/L). Pen grouping strategy did not affect DMI, plasma NEFA concentrations, or milk production. PMID- 21524533 TI - Short communication: Mouse mammary tumor virus driven alpha-lactalbumin expression effects on lactation and fertility of transgenic mice. AB - alpha-Lactalbumin (Alac) is one of the major milk proteins. Its gene expression is restricted to epithelial cells of the lactating mammary gland. The Alac interaction with a uridine 5'-diphosphate-galactosyltransferase induces lactose synthesis, a major osmotic regulator of milk secretion. Other functions attributed to this protein include induction of apoptosis and anti-inflammatory activities. To assess if forced expression of this gene during early gestation or involution could affect mammary physiology, an Alac-encoding minigene was expressed in transgenic mice under the transcriptional regulation of the mouse mammary tumor virus promoter. The mammary expression did not interfere with gestation, resulted in a slight increase in milk yield as indirectly assessed by the 11% increased growth rate of the pups reared by transgenic females compared with that of those reared by control mice, and induced a slight delay in the early involution process, as demonstrated by histological analyses. The use of the mouse mammary tumor virus promoter resulted in Alac expression in several nonmammary tissues, such as the brain, the testis, the ovary, and the uterus. Although it did not affect male reproductive performances, it induced a female subfertile phenotype, characterized by embryonic implantation failure in the transgenic female reproductive tract. PMID- 21524534 TI - Technical note: Validation of candidate reference genes for normalization of quantitative PCR in bovine mammary epithelial cells responding to inflammatory stimuli. AB - Mammary epithelial cells (MEC) participate in the first line of defense of the mammary gland to invading pathogens. In vitro culture of MEC is widely used as a model to study the capacity of these cells to sense and respond to mastitis causing bacteria. Analysis of gene expression by quantitative PCR (qPCR) following exposure to bacteria or bacterial constituents is a powerful tool to assess responses of MEC to pathogens. Although internal standards such as reference genes are required for qPCR to yield valid data, the validation of proper genes to quantify mRNA transcripts in MEC exposed to pro-inflammatory stimuli has never been reported. In this study, 10 commonly used reference genes belonging to different functional classes (ACTB, ATP5B, EIF2B2, GAPDH, PPIA, SDHA, SUZ12, UXT, YWHAZ, and 18s rRNA) were analyzed by qPCR to determine the most stable in bovine MEC unstimulated and stimulated with mastitis pathogens (Staphylococcus aureus or Escherichia coli), microbial agonists of the innate immune system (lipoteichoic acid and muramyl dipeptide, or lipopolysaccharide), or proinflammatory cytokines (IL-17A and tumor necrosis factor-alpha). An M value was used as a measure of gene stability as determined using the geNorm application. This study demonstrated that the expression of the 10 reference genes was stable under the different experimental conditions. These data will be useful for bovine mastitis research in selecting reference genes and validating reverse transcription-qPCR data. PMID- 21524535 TI - Differing effects of 2 active dried yeast (Saccharomyces cerevisiae) strains on ruminal acidosis and methane production in nonlactating dairy cows. AB - Fifteen ruminally cannulated, nonlactating Holstein cows were used to measure the effects of 2 strains of Saccharomyces cerevisiae, fed as active dried yeasts, on ruminal pH and fermentation and enteric methane (CH(4)) emissions. Nonlactating cows were blocked by total duration (h) that their ruminal pH was below 5.8 during a 6-d pre-experimental period. Within each block, cows were randomly assigned to control (no yeast), yeast strain 1 (Levucell SC), or yeast strain 2 (a novel strain selected for enhanced in vitro fiber degradation), with both strains (Lallemand Animal Nutrition, Montreal, QC, Canada) providing 1 * 10(10) cfu/head per day. Cows were fed once daily a total mixed ration consisting of a 50:50 forage to concentrate ratio (dry matter basis). The yeast strains were dosed via the rumen cannula daily at the time of feeding. During the 35-d experiment, ruminal pH was measured continuously for 7 d (d 22 to 28) by using an indwelling system, and CH(4) gas was measured for 4 d (d 32 to 35) using the sulfur hexafluoride tracer gas technique (with halters and yokes). Rumen contents were sampled on 2 d (d 22 and 26) at 0, 3, and 6h after feeding. Dry matter intake, body weight, and apparent total-tract digestibility of nutrients were not affected by yeast feeding. Strain 2 decreased the average daily minimum (5.35 vs. 5.65 or 5.66), mean (5.98 vs. 6.24 or 6.34), and maximum ruminal pH (6.71 vs. 6.86 or 6.86), and prolonged the time that ruminal pH was below 5.8 (7.5 vs. 3.3 or 1.0 h/d) compared with the control or strain 1, respectively. The molar percentage of acetate was lower and that of propionate was greater in the ruminal fluid of cows receiving strain 2 compared with cows receiving no yeast or strain 1. Enteric CH(4) production adjusted for intake of dry matter or gross energy, however, did not differ between either yeast strain compared with the control but it tended to be reduced by 10% when strain 2 was compared with strain 1. The study shows that different strains of S. cerevisiae fed as active dried yeasts vary in their ability to modify the rumen fermentative pattern in nonlactating dairy cows. Because strain 2 tended (when compared with strain 1) to lower CH(4) emissions but increase the risk of acidosis, it may be prudent to further evaluate this strain in cattle fed high-forage diets, for which the risk of acidosis is low but CH(4) emissions are high. PMID- 21524536 TI - The effects of starch and rapidly degradable dry matter from concentrate on ruminal digestion in dairy cows fed corn silage-based diets with fixed forage proportion. AB - This study investigated the effects of the type (starch vs. nonstarch) and rate of ruminal degradation of carbohydrates from the concentrate on digestion in dairy cows fed corn silage-based diets. Six ruminally cannulated cows were assigned to 6 treatments in a 6 * 6 Latin square design. Treatments were arranged in a 3 * 2 factorial design. Two starch levels [25 and 41% dry matter (DM) for low starch (LS) and high starch (HS) diets, respectively] were obtained by replacing starch-rich feedstuffs by nonstarch feedstuffs. These starch levels were combined with slowly, moderately, and rapidly rumen-degradable feedstuffs to obtain 3 levels of rapidly degradable carbohydrates from concentrate (18, 23, and 28% DM). These levels were estimated from the DM disappearance of concentrate after 4h of in sacco incubation (CRDM). Wheat and corn grain were used as rapidly degradable and slowly degradable starch feedstuffs, respectively. Soybean hulls and citrus pulp were used as slowly degradable and rapidly degradable nonstarch feedstuffs, respectively. No interaction effect was found between dietary starch content and CRDM on pH range, volatile fatty acid (VFA) range, or VFA profile. Increasing CRDM led to a linear decrease in acetate-to-propionate ratio (from 2.7 to 2.1), and a linear increase in the pH and VFA ranges (from 0.86 to 1.12 pH units and from 34 to 56mM, respectively). Feeding HS diets decreased acetate-to propionate ratio (2.6 vs. 2.0) and increased pH range (0.89 vs. 1.04 pH units), but had no effect on VFA range. Increasing CRDM linearly decreased mean ruminal pH in LS diets but linearly increased mean ruminal pH in HS diets. Fibrolytic activity was unaffected in LS diets but decreased strongly in HS diets (from 62 to 50%). These findings suggest that pH regulation differs on a short-term and on a longer-term basis. In the short-term, increasing CRDM increased the rate of VFA production, which may have been partly buffered under LS diets due to the higher cation exchange capacity of nonstarch feedstuffs compared with starch-rich feedstuffs. In the longer term, feeding starch reduced fibrolytic activity, which may have led to lower total VFA production and higher mean pH. The results of this experiment clearly show that both fermentative characteristics of the concentrate and dietary starch content should be taken into account when formulating diets to prevent subacute ruminal acidosis and to predict VFA profile. PMID- 21524537 TI - Effects of essential oils on rumen fermentation, milk production, and feeding behavior in lactating dairy cows. AB - Seven ruminally cannulated lactating Holstein dairy cows were used in an incomplete Latin rectangle design to assess the effects of 2 commercial essential oil (EO) products on rumen fermentation, milk production, and feeding behavior. Cows were fed a total mixed ration with a 42:58 forage:concentrate ratio (DM basis). Treatments included addition of 0.5 g/d of CE Lo (85 mg of cinnamaldehyde and 140 mg of eugenol), 10 g/d of CE Hi (1,700 mg of cinnamaldehyde and 2,800 mg of eugenol), 0.25 g/d of CAP (50mg of capsicum), or no oil (CON). Cows were fed ad libitum twice daily for 21 d per period. Dry matter intake, number of meals/d, h eating/d, mean meal length, rumination events/d, h ruminating/d, and mean rumination length were not affected by EO. However, length of the first meal after feeding decreased with addition of CE Hi (47.2 min) and CAP (49.4 min) compared with CON (65.4 min). Total volatile fatty acids, individual volatile fatty acids, acetate:propionate ratio, and ammonia concentration were not affected by EO. Mean rumen pH as well as bouts, total h, mean bout length, total area, and mean bout area under pH 5.6 did not differ among treatments. Total tract digestibility of organic matter, dry matter, neutral detergent fiber, acid detergent fiber, crude protein, and starch were not affected by EO. Milk yield and composition did not change with EO. In situ dry matter disappearance of ground soybean hulls was not affected by EO. However, organic matter disappearance of soybean hulls with CE Hi tended to decrease compared with CON. Compared with CON, neutral detergent fiber disappearance (41.5 vs. 37.6%) and acid detergent fiber disappearance (44.5 vs. 38.8%) decreased with addition of CE Hi. The CE Lo had no effect on rumen fermentation, milk production, or feeding behavior but CAP shortened the length of the first meal without changing rumen fermentation or production, making it a possible additive for altering feeding behavior. The CE Hi negatively affected rumen fermentation and shortened the length of the first meal, suggesting that a dose of 10 g/d is not beneficial to lactating dairy cows. PMID- 21524538 TI - Influence of ensiling time and inoculation on alteration of the starch-protein matrix in high-moisture corn. AB - The fates of hydrophobic zein proteins, which encapsulate corn starch to create vitreous endosperm, have not been investigated in high-moisture corn (HMC). To assess influences of ensiling time and inoculation on zein proteins in HMC, quadruplicate samples of 2 random corn hybrids (A and B), containing 25.7 and 29.3% moisture, were ground, inoculated with (I) or without 600,000 cfu/g of Lactobacillus buchneri 40788 (Lallemand Animal Nutrition, Milwaukee, WI), and ensiled for 0, 15, 30, 60, 120, and 240 d. Nutrient composition [crude protein (CP), starch, acid detergent fiber, and neutral detergent fiber], fermentation (pH, lactate, and acetate), and protein degradation markers (buffer-soluble CP, isopropanol-soluble CP, and NH(3)-N) were evaluated. At 0 and 240 d, alpha, gamma, delta, and beta zein subunits were profiled using HPLC. Data were evaluated as a split-split plot using the PROC MIXED procedures of SAS. Ensiling time and inoculation decreased pH, and altered lactate and acetate contents of HMC. Lactate and acetate contents of A, AI, B, and BI at 240 d were 0.40, 0.32, 1.11, 0.73, and 0, 0.35, 0.30, and 0.87% of DM, respectively. Buffer-soluble CP in HMC increased from 1.5 to 2.0% of DM at 0 d to >4.0% of DM at 240 d. Inoculation had no effect on buffer-soluble CP but increased NH(3)-N content of HMC. Corn A contained more isopropanol-soluble CP than did corn B and peak areas for 6 alpha, and all gamma and delta zein regions were greater for corn A. Ensiling (0 vs. 240 d) decreased all zein subunits with the exception of 2 alpha and 1 delta subunit. Ensiling decreased (42.2-73.2%) gamma zeins, which are primarily responsible for cross-linking in the starch-protein matrix. Despite altering lactate and acetate contents, inoculation had no effect on degrading hydrophobic zein proteins in HMC. Data suggest that hydrophobic zein proteins in the starch-protein matrix of HMC are degraded by proteolytic activity over an extended ensiling time. PMID- 21524539 TI - Effect of drinking water temperature on water intake and performance of dairy calves. AB - Very limited information is available on the effects of drinking water temperature on dairy calves. Therefore, the present experiment was designed to study the effects on performance, health, and water consumption of dairy calves offered drinking water either warm (16 to 18 degrees C) or cold (6 to 8 degrees C). The calves (60 calves/treatment) were housed in an insulated barn in pens (3.0 * 3.5m; 5 calves in each) providing 2.1m(2)/calf. During the experimental period (20 to 195 d of age), the calves had free access to water from an open water bowl (depth 80 mm, diameter 220 mm, 2-L capacity, 1 bowl/pen). During the preweaning period (20 to 75 d of age), all calves received milk replacer (7.5L/calf daily) and had free access to commercial starter, grass silage, and hay. During the postweaning period (75 to 195 d), the weaned calves had free access to grass silage and hay and were given 3 kg/d (air-dry basis) of a commercial concentrate mixture. During the preweaning period, the water intake of the calves offered warm water was 47% higher than that of the calves offered cold water. Water intake in both treatments increased rapidly during weaning and for a few days following weaning. At 180 to 195 d of age, the calves consumed approximately 18 to 20 L of water daily. Calves offered warm water drank 7 and 8% more water during the postweaning period and overall during the experimental period, respectively, compared with those offered cold water. No treatment differences were observed in dry matter or energy intakes, body weight gains, or feed conversion rates. Furthermore, total serum IgG concentrations of the calves did not differ during the preweaning or postweaning periods. Dairy calves consumed more warm than cold water, but the increase in water intake did not influence feed intake, body weight gain, or health parameters. PMID- 21524540 TI - Effect of fatty acid profile in vegetable oils and antioxidant supplementation on dairy cattle performance and milk fat depression. AB - This study was conducted to evaluate the effect of dietary supplementation of unprotected vegetable oils differing in fatty acid profiles with or without a commercial antioxidant (Agrado Plus, Novus International, St. Charles, MO) on dairy cattle performance, milk fatty acid profiles, and milk fat depression. Twenty-four multiparous Holstein cows were blocked by production (high and low) and assigned to Agrado Plus or no Agrado Plus diets as the main plot in this experiment. The 6 cows in each of the fixed effect groups (high with and without Agrado, low with and without Agrado) were then assigned to a 6 * 6 Latin square as a split plot with 21-d periods. The 6 dietary treatments in the split-plot Latin square were no added oil (control), or 5% DM as oil from palm (PO), high oleic safflower (OSAF), high-linoleic safflower (LSAF), linseed (LNSD), or corn (CO). Added oil replaced corn starch in the total mixed ration. Diets were formulated to have similar crude protein and neutral detergent fiber, and consisted of 41.2% alfalfa silage, 18.3% corn silage, and 40.5% concentrate mix (dry matter basis). Feeding Agrado Plus did not affect milk, milk fat, or milk protein production or milk fatty acid composition in this study. No significant differences were found between oil feeding versus control for dry matter intake, milk yield, and milk protein yield, but oils other than PO significantly decreased milk fat concentration and proportion and yield of milk short- and medium-chain fatty acids (C(<16)). Feeding PO effectively maintained milk fat yield (1.18 kg/d) and concentration (3.44%), whereas the oils rich in linoleic acid (CO and LSAF) significantly decreased milk fat yield (0.98 and 0.86 vs. 1.14 kg/d) and concentration (3.05 and 2.83 vs. 3.41%) compared with control. Similar lactation performance between OSAF and LNSD suggests that oleic and linolenic acids are roughly equal in potency of milk fat depression. PMID- 21524541 TI - Milk production and nutrient digestibility by dairy cows when fed exogenous amylase with coarsely ground dry corn. AB - The digestibility of starch provided by coarsely ground corn is often low, which reduces the digestible energy (DE) concentration of the diet. We hypothesized that adding exogenous amylase to diets based on coarsely ground dent corn would increase dietary DE resulting in greater milk production. Total-tract nutrient digestibility was measured in a partially replicated Latin square experiment (6 cows and 4 periods) with a 2 * 2 factorial arrangement of treatments. Diets had 26 or 31% starch with or without exogenous amylase (amylase was added to the concentrate mixes at the feed mill). In the low and high starch diets, coarsely ground dry corn (mean particle size=1.42 mm) provided 43 and 62% of total dietary starch (corn silage provided most of the remaining starch). No treatment interactions were observed. High starch diets had greater dry matter (DM), organic matter, and energy digestibility than low starch diets, and diets with amylase had greater neutral detergent fiber digestibility than diets without amylase. Digestibility of starch averaged 88% and was not affected by treatment. A long-term (98-d) lactation study with 48 Holstein cows (74 d in milk) was conducted using 3 of the diets (low starch diets with and without amylase and the high starch diet without amylase). Addition of amylase to a diet with 26% starch did not affect intake, milk yield, milk composition, body weight, or body condition. Cows fed the diet with 31% starch had greater DM and DE intakes; yields of milk, fat, and protein; and feed efficiency than those fed diets with 26% starch. Milk composition was not affected by starch concentration. Adding exogenous amylase to a lower starch diet did not make the diet nutritionally equivalent to a higher starch diet. PMID- 21524542 TI - Forage conservation efficiency and lactation response to bahiagrass conserved as barn-stored hay, outdoor-stored hay, or baleage. AB - A study was conducted to determine the effect of conserving bahiagrass as outdoor stored hay (OSH), barn-stored hay (BSH), or baleage (BAL) on storage losses and lactation performance by Holstein cows. For baleage production, bahiagrass forage was cut and allowed to dry for 20 h in windrows, baled (1.2 * 1.4 m), and individually wrapped with white stretch film. Forage cut on the same day was dried to hay stage, baled (1.2 * 1.6 m round bales), and stored either outdoors (OSH) or in an enclosed hay barn (BSH). Bales were core sampled and weighed at harvest and again following a 6-mo storage period. At the end of the storage period, 30 multiparous mid-lactation Holstein cows [39.2 +/- 5.6 kg of 3.5% fat corrected milk and 142 +/- 27 d in milk (DIM)] were stratified according to milk yield and DIM and randomly assigned to 1 of the 3 forage conservation treatments. Cows were trained to Calan feeding gates and were offered a common partial mixed ration in a 10-d covariate period followed by a 42-d treatment feeding period. Forage dry matter losses were highest for OSH, but were similar between BSH and baleage. Conservation method had little effect on poststorage crude protein levels, but acid detergent fiber and neutral detergent fiber concentrations were higher in OSH than in either BSH or BAL, which resulted in a 12.8% depression in net energy for OSH compared with the other treatments. Dry matter intake (20.5 vs. 22.1 kg/d) and milk yield (28.2 vs. 30.2 kg/d) tended to be lower for OSH than for BSH. Lactation performance was similar between BSH and BAL: 29.6 versus 28.7 kg/d of fat-corrected milk, respectively. No differences in milk composition, feed efficiency, body weight, or body condition score change related to conservation system were observed. In this study, dry matter losses and lactation performance from bahiagrass conserved as baleage were similar to that of similar forage stored indoors as hay, whereas hay stored outside resulted in less satisfactory forage quality. PMID- 21524543 TI - Effects of supplementing condensed tannin extract on intake, digestion, ruminal fermentation, and milk production of lactating dairy cows. AB - A lactation experiment was conducted to determine the influence of quebracho condensed tannin extract (CTE) on ruminal fermentation and lactational performance of dairy cows. The cows were fed a high forage (HF) or a low forage (LF) diet with a forage-to-concentrate ratio of 59:41 or 41:59 on a dry matter (DM) basis, respectively. Eight multiparous lactating Holstein cows (62 +/- 8.8 d in milk) were used. The design of the experiment was a double 4 * 4 Latin square with a 2 * 2 factorial arrangement of treatments, and each period lasted 21 d (14 d of treatment adaptation and 7 d of data collection and sampling). Four dietary treatments were tested: HF without CTE, HF with CTE (HF+CTE), LF without CTE, and LF with CTE (LF+CTE). Commercial quebracho CTE was added to the HF+CTE and the LF+CTE at a rate of 3% of dietary DM. Intake of DM averaged 26.7 kg/d across treatments, and supplementing CTE decreased intakes of DM and nutrients regardless of forage level. Digestibilities of DM and nutrients were not affected by CTE supplementation. Milk yield averaged 35.3 kg/d across treatments, and yields of milk and milk component were not influenced by CTE supplementation. Negative effects of CTE supplementation on feed intake resulted in increased feed efficiency (milk yield/DM intake). Although concentration of milk urea N (MUN) decreased by supplementing CTE in the diets, efficiency of N use for milk N was not affected by CTE supplementation. Feeding the LF diet decreased ruminal pH (mean of 6.47 and 6.33 in HF and LF, respectively). However, supplementation of CTE in the diets did not influence ruminal pH. Supplementing CTE decreased total volatile fatty acid concentration regardless of level of forage. With CTE supplementation, molar proportions of acetate, propionate, and butyrate increased in the HF diet, but not in the LF diet, resulting in interactions between forage level and CTE supplementation. Concentration of ammonia-N tended to decrease with supplementation of CTE. The most remarkable finding in this study was that cows fed CTE-supplemented diets had decreased ruminal ammonia-N and MUN concentrations, indicating that less ruminal N was lost as ammonia because of decreased degradation of crude protein by rumen microorganisms in response to CTE supplementation. Therefore, supplementation of CTE in lactation dairy diets may change the route of N excretion, having less excretion into urine but more into feces, as it had no effect on N utilization efficiency for milk production. PMID- 21524544 TI - A Bayesian approach to analyze energy balance data from lactating dairy cows. AB - The objective of the present investigation was to develop a Bayesian framework for updating and integrating covariate information into key parameters of metabolizable energy (ME) systems for dairy cows. The study addressed specifically the effects of genetic improvements and feed quality on key parameters in current ME systems. These are net and metabolizable energy for maintenance (NE(M) and ME(M), respectively), efficiency of utilization of ME for milk production (k(L)) and growth (k(G)), and efficiency of utilization of body stores for milk production (k(T)). Data were collated from 38 studies, yielding 701 individual cow observations on milk energy, ME intake, and tissue gain and loss. A function based on a linear relationship between milk energy and ME intake and correcting for tissue energy loss or gain served as the basis of a full Bayesian hierarchical model. The within-study variability was modeled by a Student t-distribution and the between-study variability in the structural parameters was modeled by a multivariate normal distribution. A meaningful relationship between genetic improvements in milk production and the key parameters could not be established. The parameter k(L) was linearly related to feed metabolizability, and the slope predicted a 0.010 (-0.0004; 0.0210) change per 0.1-unit change in metabolizability. The effect of metabolizability on k(L) was smaller than assumed in present feed evaluation systems and its significance was dependent on collection of studies included in the analysis. Three sets of population estimates (with 95% credible interval in parentheses) were generated, reflecting different degrees of prior belief: (1) Noninformative priors yielded 0.28 (0.23; 0.33) MJ/(kg(0.75)d), 0.55 (0.51; 0.58), 0.86 (0.81; 0.93) and 0.66 (0.58; 0.75), for NE(M), k(L), k(G), and k(T), respectively; (2) Introducing an informative prior that was derived from a fasting metabolism study served to combine the most recent information on energy metabolism in modern dairy cows. The new estimates of NE(M), k(L), k(G) and k(T) were 0.34 (0.28; 0.39) MJ/(kg(0.75)d), 0.58 (0.54; 0.62), 0.89 (0.85; 0.95), and 0.69 (0.60; 0.79), respectively; (3) finally, all informative priors were used that were established from literature, yielding estimates for NE(M), k(L), k(G), and k(T) of 0.29 (0.11; 0.46) MJ/(kg(0.75)d), 0.60 (0.54; 0.70), 0.70 (0.50; 0.88), and 0.80 (0.67; 0.97), respectively. Bayesian methods are especially applicable in meta analytical studies as information can enter at various stages in the hierarchical model. PMID- 21524545 TI - Effects of nitrogen supply on inter-organ fluxes of urea-N and renal urea-N kinetics in lactating Holstein cows. AB - The effects of decreasing ruminal urea infusion in lactating dairy cows fed a basal diet deficient in rumen degradable protein on inter-organ urea-N fluxes, epithelial urea-N extraction, and renal urea-N kinetics were investigated. Eight Danish Holstein cows fitted with a ruminal cannula and permanent indwelling catheters in the major splanchnic blood vessels and the gastrosplenic vein were used. The cows were randomly allocated to a triplicate incomplete 3 * 3 Latin square design with 14-d periods. Treatments were continuous ventral ruminal infusion of water, 4.1g of feed urea/kg of dry matter intake, and 8.5 g of feed urea/kg of dry matter intake. Dry matter intake and milk yield decreased linearly with decreasing urea infusion. Arterial blood urea-N and ruminal ammonia concentrations decreased linearly with decreasing urea infusion. In absolute amounts, the urea-N recycling did not increase when urea infusion was decreased. Arterial urea-N extraction across the portal-drained viscera and rumen wall increased linearly with decreasing urea infusion (2.46, 3.65, and 4.32 +/- 0.31% and 7.5, 11.5, and 16.9 +/- 0.9%, respectively), indicating that cows responded to the changes in N supply. The relative urea-N extraction across the ruminal wall increased compared with the total portal-drained viscera extraction. We observed a postprandial decrease in ruminal extraction of arterial urea-N that might reflect that the activity of the protein, presumably facilitating urea-N transport, is regulated by ruminal ammonia. The urea-N clearance by the kidneys decreased (35, 30, and 25 +/- 2L/h) and the urea-N reabsorbed by the kidney increased (42, 51 and 56 +/- 3%) with decreasing urea infusion, indicating that the kidneys salvaged urea-N with low-N supply. The urea transporter B mRNA abundance in rumen papillae (papillae harvested at sampling days) was not affected by dietary N supply. The study showed, that rumen wall extraction of arterial urea-N is subjected to both long- and short-term regulation. Extraction increases with decreasing N supply long-term; however, a short-term postprandial decrease in extraction was observed. No association between long-term adaptation of urea-N extraction across the rumen wall and urea transporter B mRNA abundance could be demonstrated. PMID- 21524546 TI - The effects of early weaning on innate immune responses of Holstein calves. AB - The objectives of this study were to compare innate immune responses of calves weaned early (EW; n=23; weaned at 23.7 +/- 2.3 d of age) with those of conventionally weaned calves (CW; n=22; weaned at 44.7 +/- 2.3 d of age). All calves were fed 3.8L of colostrum within 12h of birth and were subsequently fed milk replacer twice daily. The weaning process began by withdrawal of the afternoon milk-replacer feeding. Milk was fully withdrawn, and the calf was considered completely weaned when it consumed 900 g of calf starter as-fed for 2 consecutive days. Blood samples were collected from all calves at 24, 27, 31, 45, 48, 52, and 66 +/- 2.3 d of age. Early weaned calves took a variable amount of time to completely wean from milk replacer; therefore, data were also analyzed by comparing calves grouped by latency to completely weaned (fast=1 to 5 d; intermediate=6 to 8 d; slow=15 to 17 d). Slow-EW calves weighed less than either the fast- or intermediate-EW calves before initiating weaning. At 27 d of age, circulating neutrophils were greater among EW calves than CW calves. Moreover, fast-EW calves had lower neutrophil:mononuclear cell ratios at 45 d of age than other EW calves. Slow-EW calves had lower TNF-alpha concentrations from whole blood stimulated with endotoxin at 27 and 31 d of age compared with fast- and intermediate-EW calves. All EW calves had decreased neutrophil L-selectin at d 27 and increased neutrophil L-selectin at 31 d of age. At 31 d of age, neutrophil beta(2)-integrin was the greatest among the fast-EW calves. All EW calves had decreased neutrophil oxidative burst at 27 and 31 d of age. Three days after CW calves were weaned they had higher neutrophils, hematocrit percentages, and circulating cortisol than EW calves. In addition, 3 d after CW calves were weaned they had decreased neutrophil oxidative burst responses to Escherichia coli. Weaning, irrespective of age, suppressed many innate immune responses. In addition, early weaning transiently suppressed L-selectin expression on neutrophils; however, the immunological significance in the context of the resistance to disease is unknown because EW calves likely had greater protection from passively derived immunoglobulins when they were weaned. Finally, calves with lower BW around 24 d of age may not be suitable for early weaning programs as evident in the suppressed secretion of TNF-alpha from whole blood cultures during the week following the initiation of weaning. PMID- 21524547 TI - Effects of changing milk replacer feedings from twice to once daily on Holstein calf innate immune responses before and after weaning. AB - The objectives of this study were to determine the effects of switching Holstein calves to once-daily feeding during the fourth week of life (24 +/- 2.3 d of age; once-fed n=22; twice-fed n=22) on innate immune responses, and to evaluate whether carry-over effects occurred when the calves were weaned during the seventh week of life. Peripheral blood samples were taken immediately before the change in feeding strategy (24 d of age) and at 27, 31, 45, 48, 52, and 66 d of age and were analyzed for circulating cortisol, haptoglobin, total leukocyte counts, neutrophil:mononuclear cells, and hematocrit percentage. Heparinized whole blood was also stimulated with lipopolysaccharide (LPS) for 24h and the concentration of tumor necrosis factor-alpha (TNF-alpha) in the supernatant was analyzed. Neutrophil L-selectin and beta(2)-integrin expression were analyzed by flow cytometry. Simultaneous neutrophil phagocytic and oxidative burst responses to a heat-killed Escherichia coli were quantified by dual-color flow-cytometry. Treatment (once-daily or twice daily feeding) had no effect on pre- or postweaning performance. Once-fed calves tended to have more circulating neutrophils at 27 d of age, greater expression of L-selectin on neutrophils at 31 and 45 d of age, and greater intensity of phagocytosis at 45 d of age. Once-fed calves secreted less TNF-alpha in LPS-stimulated whole blood cultures at 45 d of age compared with twice-fed calves and this tended to persist through the immediate postweaning period. None of the other immune parameters differed after weaning between the preweaning feeding strategies. Consolidating calf milk replacer into one feeding during the fourth week of life was likely a mild and acute stressor, as evidenced by transient neutrophilia in the absence of suppressed functional capacities of neutrophils. Future research should address the mechanism and immunological significance of the persistent decreased TNF alpha response in once-fed calves. PMID- 21524548 TI - Metabolic effects of feeding ethanol or propanol to postpartum transition Holstein cows. AB - Eight lactating Holstein cows implanted with a ruminal cannula and permanent indwelling catheters in major splanchnic blood vessels were used to investigate metabolism of propanol and ethanol in the postpartum transition period. Cows were randomly allocated to 1 of 4 treatments in a randomized design with a 2 by 2 factorial arrangement of treatments. Factor 1 was 2.6g of calcium carbonate/kg of dry matter (DM) versus 1.5 g of 2-hydroxy-4-(methylthio)-butanoic acid isopropyl ester/kg of DM. Factor 2 was supplementation with 14 g of propanol/kg of DM (propanol treatment; PT) versus 14 g of ethanol/kg of DM (ethanol treatment; ET). Only factor 2 data are presented in the present paper. Treatments were administered in silage-based total mixed rations and cows were fed the experimental total mixed ration from the day of parturition. Daily rations were fed in 3 equally sized portions at 8-h intervals. Eight hourly sets of ruminal fluid, arterial, and hepatic portal and hepatic vein samples were collected at day -15 +/- 5, 4, 15, and 29 relative to parturition. Dry matter intake and milk yield increased with days in milk (DIM), but were not affected by treatment. From prepartum to 4 DIM ruminal concentrations of propanol and ethanol increased with PT and ET, respectively. Postpartum, alcohol intake increased 49% in PT and 34% in ET from 4 to 29 d in milk, respectively. Ruminal concentrations of the alcohols remained unaffected by DIM. Treatments did not affect total ruminal volatile fatty acid concentrations, but the molar proportion of acetate increased in ET and the molar proportion of propionate increased in PT compared with the contrasting treatment. Propanol treatment decreased milk fat content at 15 to 29 DIM compared with ET. The net portal release of propanol and ethanol increased with increasing ruminal concentration of the respective alcohol. The portal release of alcohol accounted for 43 to 85% of ingested propanol and 36 to 57% of ingested ethanol. Hepatic uptake of propanol and ethanol equaled the net portal flux and no effect of treatment was detected for net splanchnic release of propanol and ethanol. In conclusion, ruminal metabolism is a major component of alcohol metabolism in dairy cows. The postpartum transition dairy cow has sufficient metabolic capacity to cope with high dietary concentrations of primary alcohols even when alcohol intake is abruptly increased at the day of calving. Alcohol intake affects milk fat content and alcohol composition of silage might be important to improve predictions of milk composition. PMID- 21524549 TI - Short communication: Effect of stocking rate on the economics of pasture-based dairy farms. AB - Data from a multiyear farm systems study evaluating the effect of stocking rate (SR) on pasture production and utilization, milk production per cow and per hectare, reproduction, and cow health were used to determine the economic implications of altering SR. The effect of SR was also evaluated relative to cow size and total feed available (comparative stocking rate; CSR), to account for differences in cow size and feed supplement availability. Milk production, gross revenue, operating expenses, and operating profit per cow all declined with increasing SR and CSR. In comparison, milk production, gross revenue, and operating expenses per hectare increased with increasing SR and CSR. These effects were irrespective of milk price. The effect of SR on operating profit and return on assets, however, was dependent on milk payment system. When payment was based on the economic value of milk fat and protein, operating profit and return on assets were quadratically associated with both SR and CSR, declining at an SR greater or less than 3.3 cows/ha and a CSR greater or less than 77 kg of body weight/t of feed dry matter available. In comparison, when milk payment was based on a fluid milk pricing system, profit per hectare increased linearly with increasing SR and CSR, but return on assets was not affected by SR or CSR. PMID- 21524550 TI - Short communication: Effects of dietary nitrogen concentration on messenger RNA expression and protein abundance of urea transporter-B and aquaporins in ruminal papillae from lactating Holstein cows. AB - To test the hypothesis that dietary N concentrations affect gut epithelial urea transport by modifying the expression of urea transporter B (UT-B) and aquaporins (AQP), the mRNA expression and protein abundance of UT-B and AQP3, AQP7, AQP8, and AQP10 were investigated in ruminal papillae from 9 lactating dairy cows. Ruminal papillae were harvested from cows fed low N (12.9% crude protein) and high N (17.1% crude protein) diets in a crossover design with 21-d periods. The mRNA expression was determined by real-time reverse transcription-PCR and protein abundance by immunoblotting. The mRNA expression of UT-B was not affected by dietary treatment, whereas mRNA expression of AQP3, 7, and 10 were greater in the high N compared with the low N fed cows. Using peptide-derived rabbit antibodies to cow AQP3, 7, and 8, immunoblotting revealed bands of approximately 27, 27, and 24 kDa in ruminal papillae, respectively. A peptide-derived chicken antibody to cow UT-B detected a band of approximately 30 to 32 kDa in ruminal papillae. The abundance of UT-B and AQP3 and 7 were not affected by dietary treatment. In contrast, the abundance of AQP8 was greater in high N compared with low N diets. In conclusion, AQP3, 7, and 8 were found to be expressed in bovine rumen papillae. None of the investigated transcripts or proteins correlated to the increased rumen epithelial urea permeability observed with low dietary N concentration. PMID- 21524551 TI - Selection of bull dams for production and functional traits in an open nucleus herd. AB - The aim of this study was to compare different scenarios for bull dam selection in a nucleus herd. A deterministic simulation study using selection index methodology was undertaken. In the scenarios studied, differing amounts of information on functional traits were available when bull dams were selected, and the resulting genetic responses in these traits were compared. Field-recorded fertility traits used in the scenarios were available as progeny test results of artificial insemination bulls: these included pregnant at first insemination (PFI), interval between calving and first insemination (CFI), and cases of reproductive disorders (RD). Similarly, field-recorded cases of clinical mastitis (CM), lactation somatic cell score (LSCS), and protein yield (PY) were included for pedigree selection. In the scenarios, heat intensity score and progesterone levels were treated as new indicator traits of fertility recorded in the nucleus herd. Traits CFI and LSCS were assumed to be better recorded with higher heritability in the nucleus herd than in ordinary herds. Economic weights currently used in Nordic Cattle Genetic Evaluation (NAV) were adapted and used in the scenarios. The results showed that these weights, if used in multiple trait genetic evaluation, would lead to undesirable genetic changes in functional traits for the bull dam selection path in a nucleus environment. More frequent recording of additional traits failed to improve selection for functional traits, as did more frequent recording of ordinary traits. Restriction index methodology was used to derive the bull dam total weights that gave no unfavorable response (i.e., zero genetic change) in traits PFI, CFI, and CM. When summarized over lactations, the new bull dam total weights, when additional records from nucleus were used, had to be 12 to 23 times higher for fertility, and 3 times higher for mastitis, than the presently used NAV weights, if these traits were to remain unchanged through the bull dam selection path. Thus, nucleus herd selection of bull dams is questionable for low heritability traits that are already recorded in the field. PMID- 21524552 TI - Assessment of the value of international genetic evaluations for yield in predicting domestic breeding values for foreign Holstein bulls. AB - International genetic evaluations are a valuable source of information for decisions about the importation of (the semen of) foreign bulls. This study analyzed data from 6 countries (Australia, Canada, Italy, France, the Netherlands, and the United States) and compared international evaluations for production traits of foreign bulls (i.e., when no national daughter information was available) to their national breeding values in August 2009, which were based only on domestic daughters' data. A total of 821 bulls with highly reliable estimated breeding values (EBV) for milk, fat, and protein yield were analyzed. No evidence of systematic over- or underestimation was found in most of the countries analyzed. Observed correlations between national and international evaluations were close to 0.9 and, for most countries, generally close to their expected values (calculated from national and international EBV reliabilities). In Italy, however, higher differences between observed and expected correlations and significant mean differences between EBV for more than one trait were observed in bulls progeny-tested in the United States and in other European countries (with differences up to 33.1% of the genetic standard deviation). These results were probably induced by a relatively recent change in the model for national evaluation. The findings in this study reflect a conservative estimate of the real value of international evaluations, as changes in methodologies in either the national or the international evaluations decreased the ability of past international evaluations to predict current national evaluations. Nevertheless, our results indicate that international evaluations based on foreign information for Holstein bulls were reasonably accurate predictors of the future national breeding values based only upon domestic daughters. PMID- 21524553 TI - Differences among methods to validate genomic evaluations for dairy cattle. AB - Two methods of testing predictions from genomic evaluations were investigated. Data used were from the August 2006 and April 2010 official USDA genetic evaluations of dairy cattle. The training data set consisted of both cows and bulls that were proven (had own or daughter information) as of August 2006 and included 8,022, 1,959, and 1,056 Holsteins, Jerseys, and Brown Swiss, respectively. The validation data set consisted of bulls that were unproven as of August 2006 and were proven by April 2010 with 2,653, 411, and 132 Holsteins, Jerseys, and Brown Swiss for the production traits. Method 1 used the training animal's predicted transmitting ability (PTA) from August of 2006. Method 2 used the training animal's April 2010 PTA to estimate single nucleotide polymorphism effects. Both methods were tested using several regressions with the same validation animals. In both cases, the validation animals were tested using the deregressed April 2010 PTA. All traits that had genomic evaluations from the official USDA April 2010 genetic evaluations were tested. Results included bias, differences from expected regressions (calculated using selection intensities), and the coefficients of determination. The genomic information increased the predictive ability for most of the traits in all of the breeds. The 2 methods of testing resulted in some differences that would affect interpretation of results. The coefficient of determination was higher for all traits using method 2. This was the expected result as the data were not independent because evaluations of the validation bulls contributed to their sires' evaluations. The regression coefficients from method 2 were often higher than the regression coefficients from method 1. Many traits had regression coefficients that were higher than 2 standard deviations from the expected regressions when using method 2. This was partially due to the lack of independence of the training and validation data sets. Most traits did have some level of bias in the prediction equations, regardless of breed. The use of method 1 made it possible to evaluate the increased accuracy in proven first-crop bull evaluations by using genomic information. Proven first-crop bulls had an increase in accuracy from the addition of genomic information. It is advised to use method 1 for validation of genomic evaluations. PMID- 21524554 TI - Multiple trait genomic evaluation of conception rate in Holsteins. AB - A national data set of artificial inseminations in US Holsteins was used to obtain genetic evaluations for conception rate (CR). The objective of this study was to investigate the feasibility and resulting accuracy from using all available phenotypic, pedigree, and genomic information. Evaluations were performed by regular BLUP or by BLUP with the traditional pedigree and genomic relationships combined in a unified single-step procedure (SSP). Genetic parameters of CR in the first 3 parities were estimated with data from New York State only. Heritability estimates were around 2% and genetic correlations between CR in different parities were >0.73. The R(2) obtained with the SSP were almost twice as large as those achieved with regular BLUP. Computing the SSP took 2h, and it was 33% slower than a regular BLUP. A multiple-trait evaluation of CR using the SSP is both possible and advantageous. PMID- 21524555 TI - Short communication: Genomic selection using a multi-breed, across-country reference population. AB - Three breeds (Fleckvieh, Holstein, and Jersey) were included in a reference population, separately and together, to assess the accuracy of prediction of genomic breeding values in single-breed validation populations. The accuracy of genomic selection was defined as the correlation between estimated breeding values, calculated using phenotypic data, and genomic breeding values. The Holstein and Jersey populations were from Australia, whereas the Fleckvieh population (dual-purpose Simmental) was from Austria and Germany. Both a BLUP with a multi-breed genomic relationship matrix (GBLUP) and a Bayesian method (BayesA) were used to derive the prediction equations. The hypothesis tested was that having a multi-breed reference population increased the accuracy of genomic selection. Minimal advantage existed of either GBLUP or BayesA multi-breed genomic evaluations over single-breed evaluations. However, when the goal was to predict genomic breeding values for a breed with no individuals in the reference population, using 2 other breeds in the reference was generally better than only 1 breed. PMID- 21524556 TI - Short communication: Quantifying bias in a single-trait international model ignoring covariances from multiple-trait national models. AB - The current method in use for international genetic evaluations, called single trait multiple across-country evaluation (ST-MACE), does not consider residual covariances among traits, making possible only the inclusion of one trait per country in an analysis. The aim of this study was to quantify the effect of bias resulting from treating traits from the same country as nationally independent in an international genetic evaluation. Data from the September 2007 Interbull test evaluation for Holstein female fertility traits were used. Data included were 1 trait from Belgium, Switzerland, Spain, and the United States of America, and 2 traits from Canada, Germany-Austria, and Denmark-Finland-Sweden. The biased results were obtained from a 10-variate ST-MACE analysis including all country traits. The unbiased results were obtained from 8 different 7-variate ST-MACE analyses, each including only 1 trait per country. Average absolute bias in the genetic correlations among 2-trait countries (0.11) was higher than for between 1 trait countries and 2-trait countries (0.07) and for among 1-trait countries (0.03). The results of the biased and the unbiased analyses were different, not only due to bias, but also because of different number of traits involved in the analyses. Differences were considerable (on average, 0.08 to 6.91) for reliabilities, which were higher for traits with lower heritability. Average differences were minor (-0.04 to 0.03 standard deviations) for predicted genetic merits. However, for the top 100 bulls in each country trait, these differences were important (on average, -0.26 to 0.11 standard deviation of predicted genetic merit), which caused considerable changes in bull rankings. The results of this study showed that the effect of bias, caused by ignoring covariances from multiple-trait national models in an ST-MACE analysis, is of such a magnitude that necessitates the use of another method such as multiple-trait multiple across-country evaluation. PMID- 21524557 TI - Producer assessment of dairy extension programming in Kentucky. AB - To assess the dairy production issues extension programming should be addressing, a survey was distributed to all licensed milk producers in Kentucky (n=1,074). A total of 236 surveys were returned; 7 were omitted due to incompletion, leaving 229 for subsequent analyses (21% response rate). Mean herd size was 83.0 +/- 101.8 cows with a projected increase to 102.1 +/- 114.4 cows by 2013. Mean producer age was 50.9 +/- 12.9 with a range of 22 to 82. Mean milk production (kg/cow per day) was 23.9 +/- 5.4 with a range of 6.8 to 38.6 kg. Mean somatic cell counts (SCC) were 304,824 +/- 123,580 with a range of 75,000 to 750,000 cells/mL. When asked about meeting attendance frequency, 25% of producers indicated they attended meetings annually, whereas 29% attended twice yearly, 13% quarterly, 3% monthly, 2% at least twice monthly, and 28% indicated they never attended meetings. Surveyed producers were asked to assess what level of importance should be placed on a predetermined list of management topics. Mean response to each topic was calculated after assigning the following numeric values to producer response categories: not important: 1, important: 3, and very important: 5. Producers indicated mastitis and milk quality was the most important management topic with a response of 4.35 +/- 1.05, followed by animal well-being (4.05 +/- 1.14), disease prevention and vaccinations (4.01 +/- 1.06), cow comfort (3.97+/-1.09), disease treatment (3.95 +/- 1.10), and lameness and hoof health (3.95 +/- 1.16). Producers were asked to identify their preferred information delivery method. The most effective delivery methods were printed farm magazines (81.0%), agricultural newspapers (77.4%), printed newsletters from county agricultural agents (75.7%), printed newsletters from university extension (65.0%), and local or regional meetings (55.8%). The least effective delivery methods were university website (11.9%), indirect access through allied industry consultants (11.5%), webinars (2.7%), podcasts (0.4%), and blogs (0.4%). These results provide invaluable insight for future dairy-related Cooperative Extension Service programming efforts. PMID- 21524558 TI - Dairy nutrition management: Assessing a comprehensive continuing education program for veterinary practitioners. AB - The purpose of this study was to assess the effectiveness of a team-based educational program designed to enhance the flow of applied, research-based, nutrition information to dairy veterinarians. A comprehensive dairy cattle nutrition curriculum was developed and participants from 11 veterinary practices located in 5 states (IN, NY, PA, NM, and OH), serving an estimated 186,150 dairy cattle in 469 herds, attended the 2 advanced nutrition modules (~2.5 d each and ~40 h of learning) held in 2009. Nutrients, feeding transition cows, calves, and heifers, dry matter intake, feed storage, metabolic diseases, evaluating cows (scoring body condition, manure, and lameness), metabolic blood profiles, and feeding behavior were discussed. Educational materials were delivered through in class lectures, followed by case-based learning and group discussions. A farm visit and out-of-class assignments were also implemented. Attendees were assessed using pre- and post-tests of knowledge to determine the level of knowledge gained in both nutrition modules. Participants evaluated the program and provided feedback at the conclusion of each module. Veterinarians (100%) reported that the overall program, presentations, and discussions were useful. Attendees found the presented information relevant for their work (agree=60% and strongly agree=40%) and of great immediate use to them (neutral=6.5%, agree=56%, and strongly agree=37.5%). The presented materials and the implemented educational delivery methods substantially increased the knowledge level of the attendees (16.9% points increase from pre-test to post-test scores). Importance of feed particle size, ration evaluation, interpreting feed analysis, balancing carbohydrate components, and metabolic profiling in fresh cows were listed as learned concepts that participants could apply in their practices. Results suggested that both nutrition modules were relevant and effective, offering new information with immediate field application. This program has important implications for dairy veterinarians because they serve as a vital source of information for dairy producers. PMID- 21524559 TI - Smoking reduces language lateralization: a dichotic listening study with control participants and schizophrenia patients. AB - Schizophrenia has been associated with deficits in functional brain lateralization. According to some authors, the reduction of asymmetry could even promote this psychosis. At the same time, schizophrenia is accompanied by a high prevalence of nicotine dependency compared to any other population. This association is very interesting, because sex-dependent effects of smoking in auditory language asymmetries have been reported recently, and the verbal domain is also one major focus in cognitive deficit studies of schizophrenia. Thus, the altered laterality pattern in schizophrenia could, at least in part, result from secondary artefacts due to smoking rather than being a pure cause of the disease itself. To test this hypothesis, the present study examined auditory language lateralization in 67 schizophrenia patients and in 72 healthy controls in a phonemic and an emotional dichotic listening task. Our findings replicate previous research, in that smoking reduces language lateralization in men in phonemic dichotic listening. In addition, we show that smoking also reduces laterality in women in the emotional dichotic listening task. Thus, smoking alters phonemic and emotional language asymmetries differentially for men and women, with a stronger effect for men in the left hemisphere phonemic task, and a stronger effect for women in the right hemisphere emotional task. Together, these findings point towards an effect of smoking which is possibly independent of sex and hemisphere. Importantly, by testing equal numbers of smoking and non-smoking patients and controls, we found no schizophrenia-associated asymmetry effect. Possible neurobiological mechanisms with which smoking may alter auditory microcircuits and thereby diminish left-right differences are discussed. PMID- 21524560 TI - Towards sustainable biotechnology. III. International Conference on Environmental, Industrial, and Applied Microbiology (BioMicroWorld 2009). PMID- 21524561 TI - A figure of merit for vocal attack time measurement. AB - OBJECTIVES: To develop and evaluate a figure of merit (FOM) for the measurement of vocal attack time (VAT) for sustained /a/. The FOM assesses a critical assumption of vocal startup on which the VAT measure is based and therefore represents integrity of the derived measure. METHODS: Pearson's correlation coefficient (0 <= |r| <= 1) was determined from amplitude features of sound pressure (SP) and electroglottographic (EGG) signals (n=1,033 tokens) to serve as a candidate FOM for the study. SP and EGG signals from 102 tokens were visually inspected to empirically derive a criterion level of FOM less than 0.75 to indicate when an assumption underlying a measurement had failed and the VAT measure should be disregarded. RESULTS: The median FOM value for all 1,033 tokens was 0.975. Thirty-two tokens (2.8%) were rejected on the basis of the FOM criterion. There was no correlation between VAT and FOM. CONCLUSIONS: A companion metric, Pearson's r, can be readily obtained to assess the quality of VAT measurement. Decisions to retain or disregard VAT measures may therefore be made on the basis of measurement quality rather than on the basis of group statistics. PMID- 21524562 TI - Measures of vocal attack time for healthy young adults. AB - OBJECTIVE: To determine the vocal attack time (VAT) in a healthy young adult population. STUDY DESIGN: Sound pressure (SP) and electroglottographic (EGG) recordings were obtained for 57 female and 55 male subjects while performing multiple tokens of three tasks (sustained /a/, "always," and "hallways") at comfortable pitch and loudness. METHODS: Generalized sinusoidal models were obtained for SP and EGG signals to compare rates of amplitude change. VAT was computed from the time lag of the cross-correlation function using a fully automated process accompanied by operator validation. RESULTS: Adjusted mean VAT values were significantly shorter for females than for males. There was no systematic effect of age on VAT. However, 25- to 29-year-old men showed longer VAT than did the other age and sex subgroups. CONCLUSIONS: Normative data are presented for a new measure of the duration of vocal initiation, VAT. Acquiring this measure requires very little intervention by the user and, thereby, eliminates the influence of subjective decision making. Although beyond the scope of this article, we suggest several factors that might underlie VAT as a function of speaker sex and age. PMID- 21524563 TI - Sir Felix Semon (1849-1921): pioneer in neurolaryngology. AB - This article will attempt to review the historical and scientific literature pertaining to the life and work of Felix Semon (1849-1921). Sir Felix Semon was one of the most distinguished figures in the early development of laryngology. He was an astute researcher of laryngeal pathophysiology and an active participant in laryngological scientific societies. Felix Semon was a talented doctor and was one of the most esteemed laryngologists in London for 35 years (1875-1910). Primarily, his scientific interests included complications after thyroid surgery, laryngeal cancer, tuberculosis and motor innervation of the larynx, and movement disorders of the larynx. Semon formulated the law regarding the sequence of occurrence of the laryngeal muscle paralysis-abduction before adduction. The 132 articles he had published over the years have had a significant impact on contemporary medical knowledge. At the 160th anniversary of Semon's birth, we attempt to summarize his invaluable contribution to laryngology. PMID- 21524564 TI - Coronary flow velocity reserve in the three main coronary arteries assessed with transthoracic Doppler: a comparative study with quantitative coronary angiography. AB - BACKGROUND: The purpose of this study was to evaluate the potential of combined use of transthoracic Doppler echocardiographic coronary flow velocity reserve (CFVR) measurements and findings of retrograde coronary flow in the three main coronary arteries for the assessment of borderline (angiographic diameter stenosis, 50%-75%) and high-grade (angiographic diameter stenosis, 76%-100%) coronary artery stenoses. METHODS: A total of 108 patients scheduled for coronary angiography because of chest pain or acute coronary syndromes were studied. CFVR was measured during adenosine-induced hyperemia in the mid to distal segments of the left anterior descending coronary artery, the marginal branches of the left circumflex coronary artery, and the posterior descending coronary artery, with peak CFVR (pCFVR) <2.0 implying hemodynamic significant stenosis. CFVR results were compared with results from quantitative coronary angiography, with stenosis severity in the left main and three major coronary arteries divided into three groups: (1) diameter stenosis 0% to 49%, (2) diameter stenosis 50% to 75%, and (3) diameter stenosis 76% to 100%. RESULTS: In patients with antegrade flow in the relevant coronary artery segment, CFVR was successfully measured in the mid to distal left anterior descending artery, the marginal branches of the left circumflex artery, and the posterior descending artery in 97%, 63%, and 75% of patients, respectively. CFVR was significantly different among the stenosis groups, with pCFVR of 2.79 +/- 0.77 in group 1, 2.01 +/- 0.72 in group 2, and 1.50 +/- 0.69 in group 3 (P < .001 among groups). Angiography confirmed retrograde flow in seven of the nine arteries found by transthoracic echocardiography. Findings of pCFVR <2.0 or retrograde coronary artery flow correctly identified 42 of 49 patients with stenoses in group 3, with sensitivity, specificity, and positive and negative predictive values of 86%, 70%, 70%, and 85%, respectively. In group 2, pCFVR values were widely distributed above or below the defined pCFVR cutoff value. CONCLUSIONS: CFVR measurement in the mid to distal left anterior descending artery was feasible in almost all patients, and in the marginal branches of the left circumflex artery and the posterior descending artery in two thirds and three quarters of patients, respectively. Use of the combined echocardiographic criteria had high precision for diagnosing severe coronary stenoses (diameter stenosis, 76%-100%). The functional significance of angiographically borderline stenoses (diameter stenosis, 50%-75%) may be further differentiated by the use of CFVR measurements. PMID- 21524565 TI - Zoster vaccine recommendations: the importance of using a clinically valid correlate of protection. PMID- 21524566 TI - Using different approaches to conducting postal questionnaires affected response rates and cost-efficiency. AB - OBJECTIVE: To compare three different approaches for consent in postal questionnaire in terms of response rate, time consumption, and cost-efficiency, and to collect a demographic questionnaire for dropout analyses. STUDY DESIGN AND SETTING: Population survey in Sweden. Mothers and fathers (n=600) of three hundred 3-year olds were divided into three groups. One group was asked to Actively Agree to participate in a cover letter and send consent back to receive the main questionnaire. The second group received the cover letter, the consent, and the main questionnaire in the initial mailings, Direct Delivery. The third group received the cover letter and consent form in which they were asked to Actively Decline participation within 7 days if they did not want to participate. Otherwise, they were sent the main questionnaire. All parents were asked to fill in a demographic questionnaire regardless of whether they wanted to complete the main questionnaire. RESULTS: The highest response rate was in the Actively Decline mode. The cost-efficiency for this approach was 1.52 compared with Direct Delivery and 1.29 compared with Actively Agree. CONCLUSION: Researchers can improve the response rate, time consumption, and cost-efficiency and obtain a demographic questionnaire for dropout analysis by using the Actively Decline approach for postal questionnaires. PMID- 21524567 TI - Incomplete reporting of recruitment information in breast cancer trials published between 2003 and 2008. AB - OBJECTIVES: To review the reporting of key items of recruitment information in trial reports and estimate the number needed to screen to recruit one additional participant. STUDY DESIGN AND SETTING: Review of breast cancer trials published in the years 2003-2005, 2007, and 2008. RESULTS: The search identified 1,570 potentially eligible studies. After a random selection of 20% from each year and checking against inclusion criteria, a total of 207 studies were included in the review. Some items of information were well reported, such as the number included in the analysis. Sample size calculations were often not presented, but reporting is slowly improving. Who recruits participants and how many individuals were screened are often not reported. The median number needed to screen to recruit one additional participant was two (range, 1-593). CONCLUSIONS: Without reporting the when, where, by whom, and how many of recruitment, trialists deny readers part of the contextual description they need to judge whether a trial's results are applicable to their own situation. Trialists and journal editors need to be more diligent in following the reporting recommendations of the Consolidated Standards of Reporting Trials statement. PMID- 21524569 TI - Metastatic triple-negative breast cancer. AB - The triple-negative class (oestrogen receptor-negative, progesterone receptor negative and human epidermal growth factor receptor 2 [HER2]-negative) comprises about 15% of breast cancer. It is associated with a poor prognosis compared with tumours that are positive for hormone receptors or HER2. Despite being sensitive to chemotherapy, many women with metastatic triple-negative breast cancer (TNBC) relapse quickly, and commonly develop visceral metastasis, including lung, liver and brain metastasis. TNBC has molecular features that overlap with breast cancer in BRCA1 germline mutation carriers and with those of the basal-like molecular class of tumours. Furthermore, tumours with the triple-negative phenotype have specific features and express markers that are potential therapeutic targets, for example an impaired DNA repair mechanism and increased expression of proliferation and basal-associated markers. The presence of these features has important implications for clinical practice and for the design of clinical trials looking at novel therapies. Targeted agents that are currently being investigated include poly (ADP-ribose) polymerase inhibitors, epidermal growth factor receptor inhibitors and anti-angiogenic compounds. Here we discuss the epidemiology, morphological and molecular spectrum of TNBC, the clinical significance of this important class of breast cancer and the current treatment options. PMID- 21524568 TI - Placebo effect studies are susceptible to response bias and to other types of biases. AB - OBJECTIVE: Investigations of the effect of placebo are often challenging to conduct and interpret. The history of placebo shows that assessment of its clinical significance has a real potential to be biased. We analyze and discuss typical types of bias in studies on placebo. STUDY DESIGN AND SETTING: A methodological analysis and discussion. RESULTS: The inherent nonblinded comparison between placebo and no-treatment is the best research design we have in estimating effects of placebo, both in a clinical and in an experimental setting, but the difference between placebo and no-treatment remains an approximate and fairly crude reflection of the true effect of placebo interventions. A main problem is response bias in trials with outcomes that are based on patients' reports. Other biases involve differential co-intervention and patient dropouts, publication bias, and outcome reporting bias. Furthermore, extrapolation of results to a clinical settings are challenging because of a lack of clear identification of the causal factors in many clinical trials, and the nonclinical setting and short duration of most laboratory experiments. CONCLUSIONS: Creative experimental efforts are needed to assess rigorously the clinical significance of placebo interventions and investigate the component elements that may contribute to the therapeutic benefit. PMID- 21524570 TI - Re-challenging patients with oxaliplatin allergy: the successful use of a standardised pre-medication protocol in a single institute. PMID- 21524571 TI - Increased lipid production of the marine oleaginous microalgae Isochrysis zhangjiangensis (Chrysophyta) by nitrogen supplement. AB - Effects of nitrate feeding on the cell growth and lipid accumulation of marine microalgae Isochrysis zhangjiangensis were investigated. When nitrate was supplied at interval of 24h, instead of 72 h, a high lipid content of 40.9% and a biomass density of 3.1 g L(-1) were obtained. To confirm whether I. zhangjiangensis accumulates lipid during nitrogen-repletion, a two-stage cultivation method was applied. This algal strain had a high lipid content during sustained nitrate addition and showed a high carbohydrate content under nitrate depletion conditions. These results revealed that this algal strain can accumulate lipids under nitrogen-repletion conditions and accumulate carbohydrate under nitrogen-depletion conditions. When cultured in an extremely high nitrate concentration, 9 g L(-1) at 24h intervals, the growth of algal cells was suppressed, but the highest lipid content of 53% was attained. This special characteristic of lipid accumulation makes I. zhangjiangensis an ideal candidate for producing biodiesel using N-rich wastewater. PMID- 21524572 TI - Two methionine aminopeptidases from Acinetobacter baumannii are functional enzymes. AB - Drug resistance in gram-negative bacteria, such as Acinetobacter baumannii, is emerging as a significant healthcare problem. New antibiotics with a novel mechanism of action are urgently needed to overcome the drug resistance. Methionine aminopeptidase (MetAP) carries out an essential cotranslational methionine excision in many bacteria and is a potential target to develop such novel antibiotics. Two putative MetAP genes were identified in A. baumannii genome, but whether they actually function as MetAP enzymes was not known. Therefore, we established an efficient E. coli expression system for their production as soluble and metal-free proteins for biochemical characterization. We demonstrated that both could carry out the metal-dependent catalysis and could be activated by divalent metal ions with the order Fe(II) ~ Ni(II) > Co(II) > Mn(II) for both. By using a set of metalloform-selective inhibitors discovered on other MetAP enzymes, potency and metalloform selectivity on the A. baumannii MetAP proteins were observed. The similarity of their catalysis and inhibition to other MetAP enzymes confirmed that both may function as competent MetAP enzymes in A. baumannii and either or both may serve as the potential drug target. PMID- 21524573 TI - New antiplasmodial indole alkaloids from Hunteria zeylanica. AB - Two new indole alkaloids, bisnicalaterine D (1), consisting of an eburnane and a corynanthe type of skeletons, and nicalaterine A (2) were isolated from the bark of Hunteria zeylanica. Their structures were elucidated by various spectroscopic data such as NMR and CD spectra. A series of bisnicalaterines and nicalaterine A showed potent antiplasmodial activity against Plasmodium falciparum 3D7. PMID- 21524574 TI - Synthesis and evaluation of indole-based new scaffolds for antimicrobial activities--identification of promising candidates. AB - Search for new antimicrobial agents led to the synthesis of series of N-1, C-3 and C-5 substituted bis-indoles. Their evaluation for antifungal and antibacterial activities resulted in the optimization of pyrrolidine/morpholine/N benzyl moiety at the C-3 end and propane/butane/xylidine groups as linkers between two indoles for significant inhibition of microbial growth. Preliminary investigations have identified three highly potent antimicrobial agents. Dockings of these molecules in the active sites of lanosterol demethylase, dihydrofolate reductase and topoisomerase II indicate their strong interactions with these enzymes. PMID- 21524575 TI - Synthesis of 5-thiodidehydropyranylcytosine derivatives as potential anti-HIV agents. AB - As a part of our ongoing efforts to identify new anti-HIV agents, a 5'-thiopyrano nucleoside derivative 4, designed based on 4'-thioD4C 1 and cyclohexenylnucleoside 3, was synthesized. The dihydrothiopyran skeleton of 4 was constructed by the ring closing metathesis of 21 which was synthesized from but-2 yne-1,4-diol. After converting the protecting group from MOM to TBS followed by oxidation, a Pummerer-type thioglycosylation reaction of 24 with persilylated uracil gave the desired 5-thiodihydrothiopyranyluracils 25 and 26 as a mixture of anomers. The conversion of 25 to a cytosine derivative and subsequent deprotection gave a 5-thiodidehydropyranosylcytosine derivative 4 in good yield. The anti-HIV activity of 4 was also evaluated. PMID- 21524576 TI - 2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity. AB - Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (s.c. 60 mg/kg). PMID- 21524577 TI - Synthesis and properties of triazole-linked RNA. AB - RNA oligonucleotides having triazole linkages between uridine and adenosine nucleosides have been prepared and studied using spectroscopic techniques. UV melting and CD showed that triazole strongly destabilized RNA duplex (7-14 degrees C per modification). NMR data suggested that, despite relative flexibility around the modified linkage, all base pairs were formed. PMID- 21524578 TI - Macrocyclic chelator assembled RGD multimers for tumor targeting. AB - Macrocyclic chelators have been extensively used for complexation of metal ions. A widely used chelator, DOTA, has been explored as a molecular platform to assemble multiple bioactive peptides in this paper. The multivalent DOTA-peptide bioconjugates demonstrate promising tumor targeting ability. PMID- 21524579 TI - Clusters of ligands on dendrimer surfaces. AB - The development of methodology that is designed to allow a significant increase in the patterning and in the functionalization of the dendrimer is the ultimate goal of the research described here. Glycoside clusters based on TRIS were formed using click chemistry and were attached to PAMAM dendrimers. A series of dendrimers bearing tris-mannoside and an ethoxyethanol group was synthesized, and the binding interactions of these dendrimers with Concanavalin A were evaluated using inhibition ELISAs. The results of the inhibition ELISAs suggest that tris mannoside clusters can replace individual sugars on the dendrimer without loss of function. Since tris-mannoside clustering allows for a redistribution of the dendrimers' surface functionalities, from this chemistry one can envision patterned dendrimers that incorporate multiple groups to increase the function and utility of the dendrimer. PMID- 21524580 TI - Novel 12-membered non-antibiotic macrolides from erythromycin A; EM900 series as novel leads for anti-inflammatory and/or immunomodulatory agents. AB - Herein, we report the design and synthesis of the novel 12-membered non antibiotic macrolide (8R,9S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900), which was found to be a potent anti-inflammatory and/or immunomodulatory agent, capable of promoting monocyte to macrophage differentiation. This molecule shows improved acid stability, does not exhibit any anti-bacterial activity and has relatively low cytotoxicity against THP-1 cells. In addition, one of its analogues, (8R,9S)-4",13-O-diacetyl-8,9-dihydro 6,9-epoxy-8,9-anhydropseudoerythromycin A (EM911), was found to be twice as effective as EM900. PMID- 21524581 TI - Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl carbamates as potent and long acting muscarinic antagonists. AB - Novel quaternary ammonium derivatives of N,N-disubstituted (3R)-quinuclidinyl carbamates have been identified as potent M(3) muscarinic antagonists with long duration of action in an in vivo model of bronchoconstriction. These compounds have also presented a high level of metabolic transformation (human liver microsomes). The synthesis, structure-activity relationships and biological evaluation of these compounds are reported. PMID- 21524582 TI - A new iridoid and effect on the rat aortic vascular smooth muscle cell proliferation of isolated compounds from Buddleja officinalis. AB - A new iridoid, named methylscutelloside (1) together with 19 known compounds belonging to the iridoids (2-4), monoterpenoids (5), flavonoids (6-8), triterpenoids (9-14), and phenylethanoids (15-20) were isolated from the flowers of Buddleja officinalis. Their chemical structures were elucidated on the basis of physicochemical properties, and by spectroscopic methods including 1D, 2D NMR, and MS. All isolated compounds were tested in vitro for their effects on the proliferation of rat aortic vascular smooth muscle cells (VSMCs). Among them, iridoids were the main active components and showed significant inhibitory effects on PDGF-BB-induced proliferation in rat aortic VSMCs. PMID- 21524583 TI - Thiazole-based chalcones as potent antimicrobial agents. Synthesis and biological evaluation. AB - As part of ongoing studies in developing new antimicrobials, we report the synthesis of a new class of structurally novel derivatives, that incorporate two known bioactive structures a thiazole and chalcone, to yield a class of compounds with interesting antimicrobial properties. Evaluation of antibacterial activity showed that almost all the compounds exhibited greater activity than reference drugs and thus could be promising novel drug candidates. PMID- 21524584 TI - Concise site-specific synthesis of DTPA-peptide conjugates: application to imaging probes for the chemokine receptor CXCR4. AB - Diethylenetriaminepentaacetic acid (DTPA) is a useful chelating agent for radionuclides such as (68)Ga, (99m)Tc and (111)In, which are applicable to nuclear medicine imaging. In this study, we established a facile synthetic protocol for the production of mono-DTPA-conjugated peptide probes. A novel monoreactive DTPA precursor reagent was synthesized in two steps using the chemistry of the o-nitrobenzenesulfonyl (Ns) protecting group, and under mild conditions this DTPA precursor was incorporated onto an N(epsilon) bromoacetylated Lys of a protected peptide resin. The site-specific DTPA conjugation was facilitated by using a highly acid-labile 4-methyltrityl (Mtt) protecting group for the target site of the bioactive peptide during the solid phase synthesis. A combination of both techniques yielded peptides with disulfide bonds, such as octreotide and polyphemusin II-derived CXCR4 antagonists. DTPA peptide conjugates were purified in a single step following cleavage from the resin and disulfide bond formation. This site-specific on-resin construction strategy was used for the design and synthesis of a novel In-DTPA-labeled CXCR4 antagonist, which exhibited highly potent inhibitory activity against SDF-1-CXCR4 binding. PMID- 21524585 TI - Synthesis and evaluation of new carbonic anhydrase inhibitors. AB - A series of new sulfamide derivatives have been synthesized, their structures were confirmed by (1)H NMR and ESI-MS. Some target compounds were assessed by the tool of Dock6, and inhibition effects of all the new compounds on carbonic anhydrase II have been investigated. In addition, some compounds have been investigated for their antihypoxic effects in mice. Results indicated that nine target compounds exhibit as effectively as acetazolamide and 10 compounds have more potent inhibition effects on carbonic anhydrase II than acetazolamide. Three of them (I-8, I-18 and I'-3) can prolong markedly the survival time of mice in hypoxia, which are worth carrying out further studies. PMID- 21524586 TI - Inhibitory potential of chemical substitutions at bioinspired sites of beta-D galactopyranose on neoglycoprotein/cell surface binding of two classes of medically relevant lectins. AB - Galactose is the key contact site for plant AB-toxins and the human adhesion/growth-regulatory galectins. Natural anomeric extensions and 3' substitutions enhance its reactivity, thus prompting us to test the potential of respective chemical substitutions of galactose in the quest to develop potent inhibitors. Biochemical screening of a respective glycoside library with 60 substances in a solid-phase assay was followed by examining the compounds' activity to protect cells from lectin binding. By testing 32 anomeric extensions, 18 compounds with additional 3'-substitution, three lactosides and two Lewis-type trisaccharides rather mild effects compared to the common haptenic inhibitor lactose were detected in both assays. When using trivalent glycoclusters marked enhancements with 6- to 8-fold increases were revealed for the toxin and three of four tested galectins. Since the most potent compound and also 3'-substituted thiogalactosides reduced cell growth of a human tumor line at millimolar concentrations, biocompatible substitutions and scaffolds will be required for further developments. The synthesis of suitable glycoclusters, presenting headgroups which exploit differences in ligand selection in interlectin comparison to reduce cross-reactivity, and the documented strategic combination of initial biochemical screening with cell assays are considered instrumental to advance inhibitor design. PMID- 21524587 TI - Synthesis and evaluation of carbaborane derivatives of indomethacin as cyclooxygenase inhibitors. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological activities by inhibiting cyclooxygenase (COX)-1 and COX-2. Previous studies have shown that esters and amides of non-selective inhibitors such as indomethacin are selective against COX-2, which is the therapeutically relevant isoform. Structure activity analysis indicates that substituted phenyl rings are tolerated as ester components. In the present study, the introduction of inorganic ortho- and meta carbaborane moieties was explored with the aim to create COX-2 inhibitors and more importantly to investigate the validity of using these boron clusters as drug entities. Interestingly, only the ortho-carbaborane ester was active whereas the meta isomer was not. A similar lack of inhibitory potency was observed when an adamantyl substituent or alkylene spacers at the carbaborane were introduced in the ester functionality. PMID- 21524588 TI - Tryptamine derivatives as novel non-nucleosidic inhibitors against hepatitis B virus. AB - A series of tryptamine derivatives were synthesized and evaluated for their anti hepatitis B virus (HBV) activity and cytotoxicity in the HepG2.2.15 cell line. The preliminary SAR was discussed. Compounds 2e and 4a showed potent antiviral activity (IC(50)=0.4 and <1 MUM, respectively) and low cytotoxicity (CC(50)=40.6 and >25 MUM, respectively). PMID- 21524589 TI - Avoidance of the Ames test liability for aryl-amines via computation. AB - Aryl-amines are commonly used synthons in modern drug discovery, however a minority of these chemical templates have the potential to cause toxicity through mutagenicity. The toxicity mostly arises through a series of metabolic steps leading to a reactive electrophilic nitrenium cation intermediate that reacts with DNA nucleotides causing mutation. Highly detailed in silico calculations of the energetics of chemical reactions involved in the metabolic formation of nitrenium cations have been performed. This allowed a critical assessment of the accuracy and reliability of using a theoretical formation energy of the DNA reactive nitrenium intermediate to correlate with the Ames test response. This study contains the largest data set reported to date, and presents the in silico calculations versus the in vitro Ames response data in the form of beanplots commonly used in statistical analysis. A comparison of this quantum mechanical approach to QSAR and knowledge-based methods is also reported, as well as the calculated formation energies of nitrenium ions for thousands of commercially available aryl-amines generated as a watch-list for medicinal chemists in their synthetic optimization strategies. PMID- 21524590 TI - Protective effect of epsilon-viniferin on beta-amyloid peptide aggregation investigated by electrospray ionization mass spectrometry. AB - Abnormal beta-amyloid peptide accumulation and aggregation is considered to be responsible for the formation and cerebral deposition of senile plaques in the brains of patients with Alzheimer's disease (AD). Inhibition of the formation of beta-amyloid (Abeta) fibrils would be an attractive therapeutic target for the treatment of AD. Resveratrol and its derivatives exhibit a broad range of pharmacological properties such as protection against cardiovascular diseases and cancers, as well as promoting antiaging effects. We reported previously that epsilon-viniferin glucoside (VG), a resveratrol-derived dimer, strongly inhibits Abeta (25-35) fibril formation in vitro. In this study, we investigated the effects of VG on the aggregation of the full-length peptides (Abeta (1-40) and Abeta (1-42)) and on the beta-amyloid-induced toxicity in PC12 cells. VG inhibited Abeta cytotoxicity and the non-covalent complex between VG and Abeta was observed by electrospray ionization mass spectrometry. PMID- 21524591 TI - The Wildbad Kreuth initiative: European current practices and recommendations for optimal use of blood components. AB - With the aging population in Europe it is anticipated that the growing demand for blood products will not be met by the estimated supply. Therefore up-to-date recommendations for optimal administration of blood products in hemotherapy are needed. Ten years after the first meeting on optimal use of blood products at Wildbad Kreuth, Germany, a second symposium was organized to convene leading experts from the clinical, regulatory and economic perspective. The aim was to re evaluate the existing state of hemotherapy, identify areas where further studies are needed, and to provide up-dated recommendations. A preparatory survey by questionnaire concerning guidelines, quality management in clinical use of blood products, provision of products in the individual countries and re-evaluation of the 1999 Wildbad Kreuth recommendations was completed in advance. The second Kreuth Meeting in April 2009 was attended by 110 experts in transfusion medicine, regulators and regulatory authorities from 38 countries. By consensus, 20 new recommendations were adopted. Most of the 1999 recommendations were found to still be valid 10 years later. But their realization and implementation on the levels of clinical practice, regulatory authorities and health policy decision makers is still lagging behind leaving an important task to accomplish. The Kreuth initiative toward optimal use of blood products should continue. PMID- 21524592 TI - Variation in rates of fatal coronary heart disease by neighborhood socioeconomic status: the atherosclerosis risk in communities surveillance (1992-2002). AB - PURPOSE: Racial and gender disparities in out-of-hospital deaths from coronary heart disease (CHD) have been well-documented, yet disparities by neighborhood socioeconomic status (nSES) have been less systematically studied in US population-based surveillance efforts. METHODS: We examined the association of nSES, classified into tertiles, with 3,743 out-of-hospital fatal CHD events, and a subset of 2,191 events classified as sudden, among persons aged 35 to 74 years in four US communities under surveillance by the Atherosclerosis Risk in Communities (ARIC). Poisson generalized linear mixed models generated age-, race- (white, black) and gender-specific standardized mortality rate ratios and 95% confidence intervals (RR, 95% CI). RESULTS: Regardless of nSES measure used, inverse associations of nSES with all out-of-hospital fatal CHD and sudden fatal CHD were seen in all race-gender groups. The magnitude of these associations was larger among women than men. Further, among blacks, associations of low nSES (vs. high nSES) were stronger for sudden cardiac deaths (SCD) than for all out-of hospital fatal CHD. CONCLUSIONS: Low nSES was associated with an increased risk of out-of-hospital CHD death and SCD. Measures of the neighborhood context are useful tools in population-based surveillance efforts for documenting and monitoring socioeconomic disparities in mortality over time. PMID- 21524593 TI - Reliability of self-reported information on skin cancer among elderly patients with squamous cell carcinoma. AB - PURPOSE: We aimed to evaluate reliability of self-reported information on skin cancer among individuals aged > 65 years with cutaneous squamous cell carcinoma (SCC). METHODS: A test-retest was performed with patients completing two questionnaires one month apart. RESULTS: Among 102 recruited patients the response rate was 97.1% (mean age 80.9 years, 74.8% men). The majority of items showed substantial agreement: history of skin cancer screening (k = 0.88), past skin cancer in general (k = 0.92), basal cell carcinoma (k = 0.75), patient delay (k = 0.64) and total delay (k = 0.86). Agreement was high also for ages > 80 years. Recall of past SCCs (k = 0.48) and sunscreen use (k = 0.38) was less accurate. CONCLUSIONS: Our study provided evidence on the reliability of patient reported skin cancer information among elderly individuals, who represent the majority of affected cases. PMID- 21524594 TI - HIV, nursing practice, and the law: what does HIV criminalization mean for practicing nurses. PMID- 21524596 TI - A public health service. PMID- 21524595 TI - Diffusion effects on longitudinal relaxation in poorly mixed compartments. AB - Diffusion of spins between physical or virtual, communicating compartments having different states of longitudinal magnetization leads to diffusion-driven longitudinal relaxation. Herein, in two model systems, the effects of diffusion driven longitudinal relaxation are explored experimentally and analyzed quantitatively. In the first case, longitudinal relaxation in a single slice of a water phantom is monitored spectroscopically as a function of slice thickness. In the second case, mimicking vascular flow/diffusion effects, longitudinal relaxation is monitored in a two-compartment, semi-permeable fiber phantom. In both cases, apparent longitudinal relaxation, though clearly multi-exponential, is well-modeled as bi-exponential. PMID- 21524597 TI - Relating vision status to academic achievement among year-2 school children in Malaysia. AB - BACKGROUND: Vision affects daily activities, but of particular importance is the impact upon the learning process. Many studies have been conducted to establish the relationship between vision problems and academic performance. The results are varied, however, and suggest additional research is needed with particular care given to study design. METHODS: This study included 1,103 year-2 school children enrolled in 7 public schools in the Klang Valley region of Malaysia. There were an equal proportion of males (50.6%) and females (49.4%). The testing battery was designed to assess visual acuity, ocular muscle balance, visual analysis skills, visual-spatial skills, and visual-motor integration skills. RESULTS: Children with average and above-average achievement showed a different visual performance profile from those children with low academic achievement. They had a statistically significant better pass rate in physical aspects (visual acuity), physiological aspects (ocular motor balance), and perceptual aspects (visual-motor integration/visual-spatial and visual-analysis skills). CONCLUSION: Children with low academic achievement are more likely to exhibit problems in visual acuity, ocular motor balance, visual-motor integration and most all components of visual analysis skills. This finding supports the concept that visual performance is key to learning and therefore of chief concern as to school achievement. PMID- 21524598 TI - Intercollegiate usage schedule and the impact resistance of used football helmet faceshields. AB - PURPOSE: Although new polycarbonate helmet faceshields can withstand impacts exceeding forces of 2,400 N, repeated impacts and ultraviolet radiation degrade the structural integrity. In this study, the impact resistances of unused, solar radiated, and of game-used faceshields were analyzed. Also, Division 1 National Collegiate Athletic Association football programs were surveyed concerning their faceshield practices. METHODS: Impact resistance was tested by impacting faceshields with baseballs at velocities exceeding 67.1 m/s. Twenty-four new faceshields were exposed to southern daylight, 3 hours per day for 3 months before testing. Subsequent testing was performed on 60 game-used faceshields. Additionally, a faceshield utilization survey was distributed to 117 college programs. RESULTS: Solar-irradiated shields did not fail at maximum test velocity. The survivability of nonimpacted shields was greater than game-worn shields (P = 0.0003). Fifty-nine surveys were returned with 58 programs reporting faceshield use. Approximately 21 players per program use a faceshield. The main reason reported for use was aesthetic. Only 21% of reporting programs require a faceshield for players with reduced visual acuity in 1 eye. CONCLUSION: Faceshields lose impact resistance with typical use. Programs should incorporate a policy for replacement and require that players with reduced vision in at least 1 eye wear a faceshield. PMID- 21524599 TI - Elevated coherent motion thresholds in mild traumatic brain injury. AB - PURPOSE: Individuals with mild traumatic brain injury (mTBI) frequently complain of increased sensitivity to visual motion. Thus, the purpose of this study was to assess the coherent motion threshold (CMT) in subjects with mTBI and reported visual motion sensitivity. METHODS: Fourteen adult subjects with mTBI and symptoms of motion sensitivity were tested. They were compared with 40 age matched asymptomatic visually normal individuals. CMT was assessed using a 2 alternative, forced choice paradigm. A symptom rating-scale questionnaire related to motion and light sensitivity, vertigo, and self-reported reading ability was also administered to the mTBI group. RESULTS: Mean CMTs were significantly elevated in the mTBI (8.81%) versus the normal subjects (6.53%). There was a trend for a progressive increase in mean CMT in mTBI with increased symptoms related to visual motion sensitivity and vertigo. However, there was no apparent relation to either light sensitivity or self-reported reading ability in mTBI. There was no significant age effect in either group. CONCLUSIONS: The elevated CMT in mTBI suggests damage to the magnocellular pathway, such as extrastriate visual cortical area V5, visual area medial temporal, and the medial superior temporal cortex, which is involved directly in various aspects of motion processing. These findings are consistent with the subjects' symptoms of motion sensitivity and vertigo in their natural environments. PMID- 21524600 TI - Idiopathic amblyopia: a diagnosis of exclusion. A report of 3 patients. AB - PURPOSE: The aim of this study was to report the clinical course for 3 young patients diagnosed with idiopathic amblyopia. CASE REPORTS: The clinical course for 3 young patients with unilateral visual loss initially attributed to idiopathic amblyopia is presented. Extensive evaluations over the years, including optical coherence tomography, were performed in addition to routine clinical testing. In 1 patient, transient anisometropic refractive error during infancy was likely causative for the unilateral visual loss. For the second patient, a subclinical microtropia with varying eccentric fixation was subsequently diagnosed, and for the third patient, a subtle retinal disorder was subsequently diagnosed. CONCLUSION: The diagnosis of idiopathic amblyopia is one of exclusion and should only be made after extensive testing to rule out subclinical binocular vision or pathological anomalies. PMID- 21524601 TI - Transient complete homonymous hemianopia associated with migraine. AB - INTRODUCTION: Because of the transient and rare nature, objective visual and neuroimaging evaluation during an acute, spontaneous attack of a migrainous aura causing a complete homonymous hemianopia has not been reported. CASE REPORT: A healthy 27-year-old white woman with a history of typical aura with migraine presented during an episode of no light perception in the right hemifield of both eyes. Ophthalmic testing and neuroimaging were unremarkable. The visual field defect started to resolve 1 hour after initial symptoms, and significant improvement was seen after 4 hours. One year later, the patient had no visual field defects and had not experienced another episode of homonymous hemianopia. DISCUSSION: More than one third of migrainous patients experience visual symptoms. Typical aura with migraine is diagnosed usually by history. Laboratory testing and neuroimaging are necessary if an alternative cause is suspected, i.e., the aura begins after age 40 years, negative features are predominant, or the aura is very short or prolonged. Correct diagnosis is critical, because conditions that mimic migrainous aura have potentially devastating consequences. Migraine with aura patients may have persistent visual field defects and are at an increased risk for stroke compared with nonmigraine patients. This case improves our knowledge of the nature of a transient homonymous hemianopia associated with migraine. PMID- 21524602 TI - Sturge-Weber syndrome and glaucoma. AB - BACKGROUND: Sturge-Weber syndrome (SWS) belongs to a group of disorders known as the phakomatoses. It is characterized by congenital hamartomatous malformations involving the eye, skin, and central nervous system. Several ocular complications are associated with SWS, including glaucoma. CASE: A 66-year-old black man presented with a history of SWS and previously diagnosed glaucoma. CONCLUSION: Clinicians need to be aware of cutaneous, neurologic, and ocular complications of this condition. However, glaucoma is the most common ocular complication of SWS. PMID- 21524604 TI - Adverse action reports against optometrists: perspectives from the National Practitioner Data Bank over 18 years. AB - PURPOSE: The aim of this analysis is to describe characteristics of National Provider Data Bank (NPDB) adverse action reports against optometrists. METHODS: NPDB public use files were analyzed for details of reported optometrist adverse actions from 1991 through 2008. Types of actions, basis for actions, and reporting source were identified, along with geographic and demographic data. RESULTS: Between 1991 and 2008, a total of 216 adverse actions against optometrists were recorded nationally. Exclusion from Medicare or another government program accounted for 92% of all reports; the remaining 8% were related to unfavorable privileging decisions. Most cases with identifiable explanations were the result of either defaults on student loans (55%) or charges of fraud and abuse (39%). Over two thirds of all reports originated in just 12 states, and 74% involved younger optometrists (age 30 to 49). Repeat offenses were reported for 38% of sanctioned optometrists. CONCLUSION: NPDB reported adverse actions against optometrists are infrequent but most commonly involve exclusion from Medicare or similar government programs. Student loan default, particularly by younger optometrists, is the single most common cause, followed by allegations of fraud and abuse. Because this national database is permanently archived and widely used by licensing and credentialing bodies, optometrists should endeavor to be ethically responsible and strive to avoid behaviors that mandate such action reports. PMID- 21524603 TI - Knowledge about the relationship between smoking and blindness in Canada, the United States, the United Kingdom, and Australia: results from the International Tobacco Control Four-Country Project. AB - PURPOSE: Smoking is causally associated with certain prevalent visually impairing eye diseases, including age-related macular degeneration and cataract. Studies have found that people are afraid of "going blind" and may be motivated to quit smoking if they know that vision loss is associated with smoking behavior. METHODS: A random-digit dialed telephone survey was used to measure health knowledge of adult smokers in Canada (n = 2,765), the United States (n = 3,178), the United Kingdom (n = 2,767), and Australia (n = 2,623) as part of the International Tobacco Control Four-Country Project. RESULTS: A low proportion of smokers from Canada (13.0%), the United States (9.5%), and the United Kingdom (9.7%) believed that smoking can cause blindness. In contrast, 47.2% of Australian smokers believed that smoking causes blindness. Australia was the only country during the sampling period to have national awareness campaigns about smoking and its effects on eye health. CONCLUSION: These findings point to the need across countries to educate the public on this important consequence of smoking. There is an opportunity for the public health and eye health communities to work to educate the public about the impacts smoking has on eye health to improve quit rates and help discourage people from starting to smoke. PMID- 21524607 TI - Temporal window of integration in the somatosensory modality: an MEG study. AB - OBJECTIVE: We sought to clarify the presence of a temporal window of integration (TWI) in the somatosensory modality by manipulating the inter-stimulus interval (ISI). METHODS: We recorded cortical activity following the last of a train of electric pulses (stimulus offset) applied to the left hand in nine healthy volunteers using magnetoencephalography (MEG). Somatosensory evoked magnetic fields (SEFs) were elicited by the offset of a train of pulses 3s in total duration with four ISIs (25, 50, 75, and 100 ms). RESULTS: Results show that (i) off-M100 was clearly elicited by the ISI-25 and 50 ms conditions but not ISI-75 and 100 ms conditions, and (ii) the generator for off-M100 was mainly located in the contralateral primary and secondary somatosensory cortex (SI and SII). CONCLUSION: The upper limit of the TWI in the somatosensory modality is between 50 and 75 ms, and the contralateral SI and SII play an important role in integrating temporal information. SIGNIFICANCE: The present study clarifies the presence of the TWI in the somatosensory modality. PMID- 21524608 TI - Emergence and spread of multi-drug resistant organisms: think globally and act locally. PMID- 21524606 TI - Spinal associative stimulation: a non-invasive stimulation paradigm to modulate spinal excitability. AB - OBJECTIVE: Repetitive, paired peripheral and transcranial stimulation targeting the cerebral cortex can increase cortical excitability, outlasting the stimulation period. It is unknown whether paired stimulation specifically targeting the spinal cord can modulate spinal excitability. We tested whether the H-reflex facilitation from a sub-threshold conditioning TMS pulse could modulate spinal excitability if delivered repetitively. METHOD: In 13 healthy subjects, we delivered single-pulse TMS (80% RMT) for the right soleus muscle, 20 ms prior to an electrical peripheral nerve stimulus delivered over the posterior tibial nerve on the same side at 0.1 Hz during 15 min. RESULTS: PNS alone evoked an H-reflex of 0.25 mV +/- 0.06 SEM, while pairing of TMS and PNS facilitated the H-reflex to 0.7 +/- 0.11 mV. TMS-PNS pairs delivered at 0.1 Hz for 15 min progressively increased in the evoked response to ~130% (r(2) = 0.97) of the starting amplitude (normalized to 1st min). Post-intervention, H-reflex threshold decreased (pre = 12.9 +/- 1.7 mA; post =11.6 +/- 1.6 mA; p = 0.04), as did the stimulus intensity at maximum H-reflex amplitude (pre = 23.5 +/- 02.8 mA; post = 21.6 +/- 2.6 mA; p = 0.03), and recruitment curve width (pre = 11.6 +/- 1.5 mA; post = 10.93 +/- 1.4 mA; p = 0.03). No such changes were observed with intervention of PNS or TMS alone. CONCLUSION: Paired stimulation targeting spinal facilitatory interactions, when applied repetitively, can increase spinal excitability during and after the intervention. SIGNIFICANCE: Spinal associative stimulation may have potential for neuromodulation in spinal cord injury patients. PMID- 21524609 TI - Molecular typing and in vitro fluconazole susceptibility of Candida species isolated from diabetic and nondiabetic women with vulvovaginal candidiasis in India. AB - BACKGROUND: Candida albicans and Candida glabrata are the major causes of vulvovaginal candidiasis (VVC) in Indian women with diabetes mellitus. Little information is available regarding the genotyping of Candida species isolated from Indian diabetic women with VVC. METHODS: In this study, a total of 57 Candida species, comprising Candida albicans and Candida glabrata, isolated from Indian women with VVC, were genotyped and tested for fluconazole susceptibility. Arbitrarily primed polymerase chain reaction (AP-PCR) was used to genotype C glabrata isolates, whereas Southern blot hybridization using a Candida albicans repetitive element-2 (CARE-2) probe was used to genotype C albicans. RESULTS: Genotyping showed that all the C albicans isolates were genetically heterogenous. The pattern of DNA bands obtained after AP-PCR for C glabrata strains were predominantly conformed to genotype A. In vitro fluconazole-susceptibility testing of the isolates using the Clinical and Laboratory Standards Institute M27A2 protocol showed that more than 93% of the Candida isolates were susceptible. CONCLUSIONS: Ninety-five percent of the C albicans isolates analyzed were different and genetically unrelated. The analysis of the AP-PCR DNA banding pattern of C glabrata isolates showed that it resembled genotype "A". The Candida isolates were found to be susceptible to fluconazole, with minimum inhibitory concentrations ranging from 0.5 MUg/mL to 8 MUg/mL. This correlates with the use of fluconazole as a first-choice antifungal for treating VVC in India. PMID- 21524610 TI - Oral Candida isolates among HIV-infected subjects in Nigeria. AB - BACKGROUND: Nigeria is a West African country of more than 150 million persons with the second highest case of HIV/AIDS infected patients in the world. The species spectrum of oral yeast colonization and the susceptibility to a wide range of antifungal agents is poorly understood in Nigeria especially in the south east, south south, and the northern axis. This study evaluates the species spectrum of oral colonization by Candida species in HIV-infected patients in Nigeria and the in vitro susceptibility pattern of the Candida isolates to a broad range of antifungal agents. METHODS: Two hundred oropharyngeal swabs from HIV-infected patients and 100 age-matched healthy controls were screened for yeast isolates using standard procedures and confirmed by the analytical profile index 20C along with other biochemical tests. In vitro susceptibility testing of the yeast isolates to antifungals were performed using the broth microdilution method protocol recommended by the Clinical Laboratory Scientific Institute. RESULTS: Of 200 patients screened, 120 (60%) were colonized by yeasts. C albicans was the dominating species in both groups with 54 (45%) isolated from HIV subjects. The non-albicans Candida species accounted for 55% with C tropicalis 22 (18.3%) showing the highest frequency. We observed that 11.7% of all yeasts isolates were resistant to fluconazole, 8.3% to flucytosine, 7.5% to itraconazole, and 1.7% to voriconazole. All isolates were susceptible to amphotericin B and most of them demonstrated very low voriconazole minimal inhibitory concentrations. Apart from C albicans, C tropicalis and C parapsilosis isolates were also recovered from apparently healthy control subjects. CONCLUSION: Although C albicans continues to be the dominant Candida species in oral Candida carriage of HIV-infected patients in Nigeria, the nonalbicans Candida species are increasing. Furthermore, the finding of resistant isolates in our study emphasizes the need for antifungal susceptibility testing whenever antifungal treatment is desired especially in HIV-infected subjects. PMID- 21524611 TI - Molecular diagnosis and clinical presentations of enteroviral infections in Taipei during the 2008 epidemic. AB - BACKGROUND: In 2008, an epidemic of enterovirus (EV) infection caused hand, foot, and mouth disease (HFMD) and herpangina in children in Taiwan, and some of them died. To establish an early detection and effective management for children with EV71 infection, sensitive molecular diagnostic methods were applied from May to July 2008. METHODS: We used virus isolation, EV71 real-time reverse-transcription polymerase chain reaction (RT-PCR), and viral protein 1 (VP1) RT-PCR followed by direct sequencing to detect EV71 and the other EVs in the infected outpatient or inpatient children. Clinical presentations of children infected with EV71 and other EVs were compared. RESULTS: From May 2008 to July 2008, 255 swabs were tested by both PCR diagnostic methods. Based on the viral isolation results, the sensitivities of EV71 real-time RT-PCR and VP1 RT-PCR followed by direct sequencing were 71% and 86%, respectively. Among the 221 children who were enrolled for clinical analysis, 73% (161 of 221) had herpangina, and 27% (60 of 221) had HFMD. Coxsackievirus A2 (CA2) was the most prevalent among the identifiable viruses (65%, 104 of 160), followed by EV71 (28%, 45 of 160). EV71 was the most commonly detected virus among the HFMD cases (63%, 38 of 60), whereas herpangina was mainly caused by CA2 (61%, 98 of 161). Of the CA2 cases, 94% (98 of 104) had herpangina, and the most common manifestation of EV71 infection was HFMD with or without complications (84%, 38 of 45). Phylogenetic study revealed that the genotype of EV71 cases during this epidemic was of B5 lineage. CONCLUSION: During the 2008 EV epidemic, most of the HFMD was caused by EV71, whereas herpangina was mainly caused by CA2. Real-time RT-PCR for EV71 is a time-saving and sensitive diagnostic tool. PMID- 21524612 TI - Viral etiology of acute lower respiratory tract infections in hospitalized young children in Northern Taiwan. AB - BACKGROUND: Lower respiratory tract infections (LRTIs) comprise a great proportion of diagnoses among hospitalized children. This study identifies the viral pathogens causing LRTIs in young children and compares their clinical features and disease severity. METHODS: Children younger than 36 months old, hospitalized at a medical center in Northern Taiwan with acute bronchiolitis or pneumonia from April to December 2007, were prospectively enrolled. Nasopharyngeal aspiration fluid samples were sent for virus culture, for direct immunofluorescence test of respiratory syncytial virus (RSV), for rapid influenza viral identification, and for polymerase chain reaction of human metapneumovirus (hMPV), human boca virus (hBoV), and human corona virus. The clinical features and laboratory findings were recorded and analyzed. RESULTS: A total of 48 children were enrolled. RSV was the most common pathogen (41.7%), followed by hMPV (27.1%), hBoV, and enterovirus (both 6.3%). There were no significant differences in clinical presentation and disease severity between the RSV and hMPV groups. However, the hMPV group had a higher mixed infection rate (p = 0.038). Fourteen children had no identifiable viruses. Children with single, dual, and triple pathogens numbered 26, 7, and 1, respectively. The mixed infection rate reached 23.5% among 34 children with identifiable viruses. Children with a higher severity score had greater chance to develop asthma in the next 2 years (p = 0.042). CONCLUSION: RSV is the most common pathogen causing LRTIs in young children, followed by hMPV. The hMPV group had higher mixed infection rate than RSV group. hBoV does circulate in northern Taiwan. PMID- 21524613 TI - Causes, clinical symptoms, and outcomes of infectious diseases associated with hemophagocytic lymphohistiocytosis in Taiwanese adults. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon but a potentially life-threatening condition. Few systematic reviews have been published on the clinical manifestations, causes, and indicators for prognosis of HLH caused by infections. METHODS: We retrospectively reviewed the medical records of patients diagnosed with HLH documented by bone marrow study at a teaching hospital between 2000 and 2007. HLH was defined according to the HLH 2004 diagnostic guidelines, which include fever; splenomegaly; cytopenia; hypertriglyceridemia; hypofibrinogenemia; and hemophagocytosis evident on pathological examination of bone marrow, spleen, or lymph node tissue; low or absent natural killer cell activity; hyperferritinemia; and high serum levels of soluble CD25. The demographic characteristics, clinical presentations, laboratory results, and final outcomes were recorded. The cause of HLH was diagnosed by microbiological, pathological, serological, and molecular biological methods. RESULTS: Among the studied patients, 66 had HLH because of noninfectious causes and 30 because of infections. Compared with patients with HLH related to noninfectious causes, those with HLH related to infections had lower mortality (70% vs. 47%, p=0.03). The most common causative pathogens causing HLH were virus (41%), mycobacteria (23%), bacteria (23%), and fungi (13%), in that order of frequency. Clinical presentations of HLH were variable and included fever (90%), tachypnea (83%), tachycardia (80%), hepatosplenomegaly (40%), lymphadenopathy (27%), and altered consciousness (23%). Laboratory findings revealed thrombocytopenia in 93%, hyperferritinemia in 90%, elevated serum lactate dehydrogenase levels in 80%, anemia in 67%, and leukopenia in 60% of the patients. Fourteen patients (47%) died. In multivariate analysis, age more than 50 years (p=0.05; odds ratio [OR], 3.46; 95% confidence interval [CI], 1.00 15.73), fever not subsiding within 3 days of diagnosing HLH (p=0.003; OR, 2.38; 95% CI, 1.21-11.25), and occurrence of disseminated intravascular coagulation as a complication (p=0.009; OR, 3.22; 95% CI, 1.68-10.01) were found to be statistically significant indicators of mortality in patients with HLH. CONCLUSIONS: The infectious diseases associated with HLH were diverse and resulted in a high mortality rate. Cases in which the patients were aged more than 50 years, developed DIC, and had persistent fever even after 3 days of being diagnosed with HLH showed poor prognosis. PMID- 21524614 TI - Clinical manifestations of treatment-naive patients with acquired immunodeficiency syndrome and responses to highly active antiretroviral therapy in the Taipei Veterans General Hospital: a 5-year prospective study. AB - BACKGROUND: Taipei Veterans General Hospital, one of the medical centers in Taiwan, has provided highly active antiretroviral therapy (HAART) to human immunodeficiency virus/AIDS patients for more than 10 years. Five years ago, we began a prospective follow-up of our patients' clinical manifestations and responses to HAART by collecting their clinical data. In this study, we analyzed the morbidity, mortality, and responses to HAART of treatment-naive AIDS patients. The purpose was to provide local data that may be valuable in Taiwan. METHODS: Study cases were enrolled from January 1, 2004, to February 28, 2009, with inclusion criteria of newly diagnosed AIDS during hospitalization and being naive to HAART. Antiretroviral therapy was initiated. To evaluate the clinical responses to HAART, we excluded patients who were pregnant, died within 1 month after confirmation of an AIDS diagnosis, failed to initiate HAART, or were lost to follow-up for more than 6 months. Plasma viral loads and CD4(+) counts were quantified by reverse-transcriptase polymerase chain reaction and flow cytometry, respectively. Statistical analysis was performed using SPSS statistical software. RESULTS: A total of 49 patients were enrolled and 45 patients fulfilled the inclusion criteria for evaluating the efficacy of HAART. At 3 months, 12 months, and 30 months after the initiation of HAART, 64.4% (29 of 45), 88.2% (30 of 34), and 93.8% (15 of 16) had undetectable plasma viral loads, respectively, and 37.8% (17 of 45), 73.5% (25 of 34), and 81.2% (13 of 16) had CD4(+) counts of more than 200 cells/MUL, respectively. Median CD4(+) counts increased from baseline at Month 3 by 171 cells/MUL and at Month 30 by 375 cells/MUL. The overall mortality was 22.4% (11 of 49). CONCLUSION: The virologic and immunologic responses after initiating HAART in this study demonstrated our achievements in providing care and treatment for AIDS patients during this 5-year period, which provides a strong evidence of the efficacy of HAART. PMID- 21524615 TI - Clinical and microbiological analysis of adult perianal abscess. AB - BACKGROUND: In Taiwan, Klebsiella pneumoniae is the predominant pathogen causing pyogenic liver abscess in patients with diabetes mellitus (DM). The purpose of our hospital-based study was to determine the predominant bacterial species causing perianal abscess in hospitalized patients with and without DM in Taiwan. METHODS: Data on patients admitted and then operated on for perianal abscess during the period of March 2001 to December 2008 were reviewed. Information extracted from medical records included clinical information and laboratory data as well as culture and antibiotic sensitivity results. RESULTS: A total of 183 patients underwent surgery for perianal abscess. The most common pathogen causing perianal abscess in non-DM patients was Escherichia coli (67.1%), and the most common pathogen isolated in DM patients was K pneumoniae (60%; p=0.009). Among the 25 patients with DM, incident DM was diagnosed in 24.0% (6 of 25). In addition, five patients had transient hyperglycemia. CONCLUSIONS: Escherichia coli was the predominant pathogen isolated from perianal abscesses in patients without DM. Klebsiella pneumoniae, however, was the predominant pathogen isolated in DM patients. In both DM and non-DM patients, more than 90% of K pneumoniae isolates showed in vitro sensitivity to first-generation cephalosporins. PMID- 21524616 TI - Predictors of mortality in surgical patients with Acinetobacter baumannii bacteremia. AB - BACKGROUND: Acinetobacter baumannii has emerged as an important pathogen of nosocomial infection. The aim of this study was to evaluate the predictors of poor outcome in surgical patients with A baumannii bacteremia. METHODS: We retrospectively recruited a total of 50 patients who developed A baumannii bacteremia within 2 weeks after surgery during a 113-month period. The primary outcome for this study was all-cause 14-day mortality. Clinical and laboratory data, antimicrobial susceptibility, treatment, and Sequential Organ Failure Assessment (SOFA) score were evaluated as possible predictors of outcome. RESULTS: The 14-day mortality was 20% and there was no association between type of surgery and mortality. The SOFA score was the only independent predictor of 14 day mortality after adjustment for other variables. The calibration was acceptable (Hosmer-Lemeshow chi(2) = 3.65, p = 0.72) and the discrimination was good (area under the receiver operating characteristic curve: 0.80 +/- 0.07, 95% confidence interval, 0.67-0.94). We found that a SOFA score >= 7 was a significant predictor of 14-day mortality in surgical patients with A baumannii bacteremia. CONCLUSIONS: The SOFA score assessed at the onset of bacteremia is a reliable tool for predicting 14-day mortality in surgical patients with A baumannii bacteremia. PMID- 21524617 TI - Isolated pathogens and clinical outcomes of adult bacteremia in the emergency department: a retrospective study in a tertiary Referral Center. AB - BACKGROUND: Approximately two-thirds of the patients with severe sepsis or septic shock are first encountered in the emergency departments (EDs) of western countries, in which bacteremia is present in about 50% of patients with severe sepsis. The situation of bacteremia presenting to the EDs in Taiwan is not well documented. The objective of this study was to examine the epidemiology and microbiology of bacteremia in adult patients who visited the ED of a medical center in southern Taiwan. METHODS: A retrospective observational study of the epidemiology and microbiology of bacteremia was conducted in the ED of a medical center involving 6,137 adult patients and 13,903 blood cultures. RESULTS: A total of 831 consecutive patients with 890 episodes of bacteremia were obtained from January 1 to December 31, 2004, indicating a positive culture rate of 13.5% (1,872/13,903). Among these episodes, 525 (59%) were defined as true community acquired infections followed by 263 (29.5%) as health care-associated infections and 102 (11.5%) as nosocomial infections. Of the 972 isolates, 289 (29.7%) were gram-positive species and 683 (70.3%) were gram-negative species. Urinary tract infections (32.2%, 287/890) were most common in these patients, with Escherichia coli (30.8%, 299/972) being the most common pathogen. Bacteremia caused by Staphylococcus aureus was more common in nosocomial than true community-acquired infections (31.3% vs. 12%) and had significantly higher possibility of resistance to methicillin in infections not purely acquired from community (odds ratio = 24.92; 95% confidence interval, 9.88-62.87). The overall crude mortality rate was 21% and nearly half of the mortalities occurred within 3 days of visiting the ED. All patients discharged inadvertently were uneventful (n = 65, two lost at follow up). CONCLUSIONS: Categories of bacteremia acquisition was associated with different distribution of pathogens, antimicrobial resistance, and clinical outcome. Traditional classification might overestimate the problem of drug resistance in community-acquired infections. The concept of health care associated infection should be introduced to avoid overemphasis of drug-resistant problem in true community-acquired infection. PMID- 21524618 TI - The initial manifestations and final diagnosis of patients with high and low titers of antinuclear antibodies after 6 months of follow-up. AB - BACKGROUND: The antinuclear antibody (ANA) test is the most commonly used test to screen for autoimmune diseases. However, only a limited numbers of studies have addressed the characteristics of patients positive for ANA. In this study, we aimed to clarify the relationship between initial presentations, ANA titer, and final diagnoses. METHODS: Patients who visited National Taiwan University Hospital and received a first ANA test were enrolled and then followed for a further 6 months. The symptoms and signs at the time of ANA testing, ANA titers, and the final diagnoses were recorded and analyzed. RESULTS: A total of 355 patients were positive for ANA. Joint pain was the most common initial presentation at the time of ANA testing. Compared with the patients with low ANA titers (<1:640), those with high ANA titers (>= 1:640) were more susceptible to autoimmune diseases. More importantly, of the patients with initial presentations of joint pain, fever, abnormal urinalysis, or skin rash/skin tightness, autoimmune diseases were more frequently diagnosed in those with high ANA titers than with low ANA titers (p<0.05). In addition, both anti-double strand DNA antibodies and anti-extractable nuclear antibodies were more commonly detected in patients with high ANA titers. CONCLUSIONS: A high ANA titer seems to be a useful biomarker for the diagnosis of autoimmune diseases, especially for patients presenting with joint pain, fever, abnormal urinalysis, or skin rash/skin tightness. PMID- 21524619 TI - Impact of delayed diagnosis in children with primary antibody deficiencies. AB - BACKGROUND: Primary antibody deficiencies (PADs) are heterogeneous group of disorders, characterized by hypogammaglobulinemia and increased susceptibility to recurrent infections. To evaluate the diagnostic delay in Iranian PADs in association with their infections, we scored such manifestations to find an association between such delay and the scoring system. METHODS: Forty-eight patients with PADs, who were referred to our center during a 25-year period, were enrolled in this study. Each episode of infection, before making the PADs diagnosis, got a score of 5 or 10 based on the severity of infections. RESULTS: The diagnosis was made with median delay of 34.5 months, when the patients had mean score of 94.48 +/- 52.89. There was a significant direct association between this scoring system and delay diagnosis. The score of 50 was considered as the cutoff point in our patient group. In this score, the suspicions to PADs in more than 90% of patients true positively lead to diagnosis of PADs. CONCLUSION: Although diagnosis delay significantly decreased over time, PADs still continue to be diagnosed late. Based on the results of this study, the assessment of immune system should be performed in the patients with 50 total score or about 25 score per year. PMID- 21524620 TI - Kawasaki disease and human bocavirus--potential association? AB - Kawasaki disease (KD) is an acute febrile multisystem vasculitic syndrome of unknown etiology, occurring mostly in infants and children younger than 5 years of age. We present a 13-month-old male with KD from whom was found human bocavirus DNA in nasopharyngeal secretions. Human bocavirus DNA in a patient with KD raised question about the coincidental or possible etiological association. PMID- 21524621 TI - Disseminated nocardiosis with thyroid involvement: a case report. AB - Nocardiosis is a life-threatening infection that affects the lungs, skin, and central nervous system, particularly in immune-compromised patients. We report a case of disseminated nocardiosis with pneumonia, brain abscesses, meningitis, and thyroiditis, for an individual with recent steroid therapy. Recovery was uneventful with a 4-month course of sulfamethoxazole-trimethoprim. PMID- 21524622 TI - Persistent hypocalcemia associated with therapeutic plasma exchange performed to reduce HLA antibody levels in cardiac transplant recipients. AB - BACKGROUND: Patients who receive heart transplants may undergo therapeutic plasma exchange to reduce high levels of HLA antibodies which may increase the risk of allograft rejection. Plasma exchange may predispose to hypocalcemia because of chelation of calcium by sodium citrate, used as an anticoagulant both during the procedure and in thawed fresh frozen plasma often used for replacement. METHODS: We report three adults with dilated cardiomyopathy who underwent cardiac transplantation and serial plasma exchange for high levels of HLA antibodies. We followed these patients' pre-exchange serum calcium levels and the quantity of calcium supplementation they received. Further, we examined myocardial tissue sections post-transplantation for calcium deposition. RESULTS: Our patients' serum calcium levels were initially normal, but, despite aggressive calcium repletion, remained low (nadirs for pre-exchange ionized calcium in two patients 4.48 and 3.8mg/dL, respectively, reference range 4.6-5.4mg/dL). For patient 3, pre-exchange total calcium on day 2 was 7.9mg/dL (reference range 8.4-10.2mg/dL). Two patients had intermittent symptoms of hypocalcemia. Studies of cardiac tissue sections (available only from these two patients) were consistent with the presence of calcium deposition post transplantation. In comparison, six patients who underwent lung transplantation and plasma exchange for high levels of HLA antibodies did not manifest significant hypocalcemia. CONCLUSIONS: We emphasize the need for prompt and sufficient calcium replacement, monitored by serum ionized calcium levels, in the early post-cardiac transplantation period when plasma exchange is performed with thawed fresh frozen plasma replacement. The persistently low serum calcium levels we observed post heart transplantation were possibly contributed to by increased myocardial calcium influx. PMID- 21524623 TI - Exclusive breastfeeding is recommended in the first 6 months of life for healthy term infants. PMID- 21524624 TI - Panton-Valentine leukocidin in the pathogenesis of community-associated methicillin-resistant Staphylococcus aureus infection. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen that causes serious infectious diseases and was endemic in hospitals by the late 1960s. Beginning with its first report in the late 1990s, the rapid emergence of community-associated MRSA (CA-MRSA) worldwide responsible for a wide spectrum of diseases ranging from minor skin infections to fatal necrotizing pneumonia has been found in previously healthy individuals without established risk factors for MRSA acquisition. Recently, various virulence determinants unique to CA-MRSA have been uncovered, which explain how the pathogen spreads easily and causes severe CA-MRSA infections among humans. However, the role of Panton-Valentine leukocidin (PVL) in the pathogenesis of CA-MRSA infection is currently a matter of much debate because of conflicting data from epidemiologic studies of CA-MRSA infections and various murine disease models. Identifying specialized pathogenic traits of CA-MRSA and the concerted regulation of these factors remains a challenge that will foster development of vaccines and therapies designed to control CA-MRSA infections. This review focuses on the current status of molecular epidemiology associated with CA-MRSA in Taiwan and progresses toward understanding the enhanced virulence properties of CA-MRSA, with an emphasis on the role of Panton-Valentine leukocidin. PMID- 21524625 TI - Reciprocal changes of renal neuronal nitric oxide synthase-alpha and -beta associated with renal progression in a neonatal 5/6 nephrectomized rat model. AB - BACKGROUND: Nitric oxide (NO) deficiency contributes to chronic kidney disease progression. NO deficiency could occur for many reasons, one of which is decreased NO synthase (NOS) abundance and/or activity. METHODS: In these experiments, we studied two groups of male Sprague Dawley rats given sham or surgical excision of both poles of the left kidney (at 2 days of age) followed by sham or surgical removal of the right kidney at 10 days. Rats were sacrificed at 9 weeks of age and the kidneys examined for abundance of neuronal NOS (nNOS) alpha and -beta, endothelial NOS, arginase II, argininosuccinate synthase and lysate, protein arginine methyltransferase 1, dimethylarginine dimethylamino hydrolase 1 and 2, as well as renal pathology. RESULTS: The 5/6 nephrectomy (NX) group showed renal dysfunction, severe rapidly progressing glomerulosclerosis, and hypertension. Renal cortical nNOSalpha abundance was significantly reduced, whereas nNOSbeta abundance was increased in the 5/6 NX group versus sham. Renal endothelial NOS was unchanged. Next, renal protein arginine methyltransferase 1 abundance was higher, whereas dimethylarginine dimethylamino-hydrolase 2 expression was lower in the 5/6 NX group versus sham. Renal arginase II, argininosuccinate synthase, and argininosuccinate lysate abundances were significantly decreased in 5/6 NX rats than those in sham. CONCLUSION: The neonatal kidney is very susceptible to 5/6 NX-induced injury, and, as in adults, reciprocal changes in the nNOSalpha and nNOSbeta in renal cortex occur during progression of chronic kidney disease and may contribute to the injury. PMID- 21524626 TI - Nonenteropathic hemolytic uremic syndrome: the experience of a medical center. AB - BACKGROUND: Hemolytic uremic syndrome (HUS) is an uncommon cause of acute renal failure in children. In contrast to Western countries, most HUSs in Taiwan are caused by Streptococcus pneumoniae. In this article, we demonstrate the clinical courses of children with HUS in Taiwan and try to explain the pathophysiology of complications. METHODS: We retrospectively reviewed the medical records of children with HUS who were admitted to the Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan, between January 1997 and February 2008. The clinical courses, laboratory data, complications, and prognosis were recorded. We divided the patients into dialysis group and non-dialysis group. The laboratory data for the two groups were expressed as mean, standard deviation, and range. RESULTS: Nine patients were enrolled in the study, and all were diagnosed with S pneumoniae-associated HUS. One patient had meningitis, and the others had pneumonia. The mean durations of anemia and thrombocytopenia were 19.2 days and 10.2 days, respectively. Five patients received renal replacement therapy because of oligouria. The average of the peak total bilirubin levels of patients in the dialysis and non-dialysis groups were 24.6 +/- 20.7mg/dL and 3.8 +/- 1.9mg/dL, respectively. In addition to one patient who had meningitis, four other patients experienced central nervous system (CNS) complications. The mean durations of hypertension in five patients with CNS manifestations and four patients without CNS manifestations were 16.8 +/- 7.8 days and 4.8 +/- 6.6 days, respectively. Two patients died in acute stage, and most of the others had regained normal renal function at discharge or during follow-up. CONCLUSION: (1) Streptococcus pneumoniae is the most common causative pathogen of HUS in Taiwan; (2) the mean duration of hypertension in patients with CNS manifestations was much longer than that in patients without CNS manifestations; and (3) the average of the peak total bilirubin levels of patients in the dialysis group was much higher than that in the patients of the non-dialysis group. PMID- 21524627 TI - The changing face of early-onset neonatal sepsis after the implementation of a maternal group B Streptococcus screening and intrapartum prophylaxis policy--a study in one medical center. AB - BACKGROUND: Early-onset sepsis (EOS) is the major cause of neonatal morbidity and mortality. Maternal group B Streptococcus (GBS) screening and intrapartum antibiotic prophylaxis (IAP) were implemented in our hospital in 2004. Our aim was to evaluate the effectiveness of the program and changes in pathogens and antibiotic susceptibility. METHODS: The medical charts of mothers and infants with EOS between January 2001 and November 2008 were retrospectively reviewed. EOS was defined as sepsis occurring within 72 hours of birth. Data were pooled and compared for January 2001 through September 2004 (Period 1, without GBS screening) and October 2004 through November 2008 (Period 2, with GBS screening and IAP). RESULTS: The GBS screening rate increased from 10.11% in 2004 to 65% in 2008 and the IAP rate increased from 40% in 2004 to 90% in 2008. The most common EOS pathogen in Period 1 was GBS (45.4%), which decreased to 20% in Period 2 (p=0.081; trend p=0.009). The percentage of EOS because of Escherichia coli in Period 1 was 40.9% but increased to 70% in Period 2 (p=0.059). E coli EOS increased in extremely low birth weight premature babies weighing 500-1000g from Period 1 to Period 2 (p=0.031). The incidence of ampicillin-resistant E coli EOS was relatively high, but no significant change (88.9% vs. 92.9%) after implementation of GBS screening and IAP was noted. CONCLUSION: GBS screening plus IAP is effective in decreasing the incidence of GBS EOS; however, an increase in EOS caused by E coli was noted. Monitoring of pathogens causing EOS is important for effective treatment. PMID- 21524628 TI - Influence of breast-feeding on weight loss, jaundice, and waste elimination in neonates. AB - BACKGROUND: The Baby-Friendly Hospital Initiative began promoting exclusive breast-feeding in 2001 in Taiwan; however, few studies have investigated its impact. This study evaluated the influence of breast-feeding on Taiwanese neonates with regard to the frequency of jaundice, body weight loss (BWL), and elimination of both urine and stool. METHODS: The medical records of 313 healthy mother-neonate pairs admitted at our hospital were reviewed retrospectively and divided into three groups: exclusively breast-feeding (n=161), mixed (breast/formula) feeding (n=80), and exclusively formula feeding (n=72). RESULTS: Compared with the exclusively formula feeding group, in the exclusively breast fed neonates, the average total serum bilirubin level at 3 days after birth (p < 0.001) and the rate of significant hyperbilirubinemia >= 15 mg/dL (p<0.05) were significantly higher; the average BWLs at 2 and 3 days after birth (p < 0.001, p < 0.001) and the rate of BWL >= 10% (p < 0.05) were significantly higher; the average frequency of stool passage at 2 and 3 days after birth (p < 0.001, p < 0.001) and urination at 1, 2, and 3 days after birth (p < 0.001, p < 0.001, p < 0.001) were significantly less. The factors associated with a mother's choice of infant feeding type include maternal age and delivery method. CONCLUSION: Breast feeding during the initial days of life has a significant influence on the degree of jaundice, amount of BWL, and the frequency of stool passage and urination. PMID- 21524629 TI - Profile of nucleotides and nucleosides in Taiwanese human milk. AB - BACKGROUND: Human milk-borne nucleotides and their related metabolic products have been reported to have important physiological roles in breast-fed infants. The purpose of this study was to measure the concentrations of free nucleotides and nucleosides in human milk from Taiwanese women. METHODS: A total of 24 individual milk specimens were collected from women in Taipei and Kaohsiung, at four stages of lactation. Vegetarian or non-vegetarian dietary patterns were recorded. The samples were analyzed for nucleotides and nucleosides by high performance liquid chromatography. RESULTS: The mean (+/-standard deviation) free nucleotide and nucleoside concentrations in Taiwanese human milk were 213.13 +/- 76.26 MUmol/L and 16.38 +/- 7.11 MUmol/L. The predominant nucleotide was cytidine diphosphate for almost all samples, regardless of the location, stage of lactation, or dietary status of the subjects. Overall, the mean concentrations of cytidine diphosphate, cytidine monophosphate, uridine monophosphate, guanosine monophosphate, adenosine monophosphate, and inosine monophosphate, in milk samples were 129.86 MUmol/L, 49.10 MUmol/L, 5.60 MUmol/L, 0.82 MUmol/L, 2.96 MUmol/L, and 25.25 MUmol/L, respectively (equivalent to 61.0%, 23.1%, 2.6%, 0.4%, 1.0%, and 11.9% of free nucleotide composition). In free nucleosides, cytidine and uridine were predominant during all stages of lactation. The average concentrations of cytidine, uridine, adenosine, guanosine, and inosine, in milk samples were 9.25 MUmol/L, 6.33 MUmol/L, 0.18 MUmol/L, 0.36 MUmol/L, and 0.23 MUmol/L, respectively (equivalent to 56.5%, 38.7%, 1.1%, 2.2%, and 1.4% of free nucleoside composition). Comparing vegetarian and non-vegetarian statuses, it was found that the total free nucleotide concentration was high in the vegetarian group (p=0.037). CONCLUSION: Our data showed a wide range of concentrations of individual nucleotides and nucleosides in Taiwanese human milk. Unique dietary status could affect the nucleotide and nucleoside levels in human milk, especially the nucleotides in our study. However, the mechanism of modulation of nucleotide and nucleoside levels in human milk is not clear. PMID- 21524630 TI - Parents' views about the vaccination program in Taiwan. AB - PURPOSE: To investigate parents' views about new vaccines, we surveyed the attitudes and awareness toward immunization program among parents of children younger than 14 years in Taiwan. METHODS: Parents of children were invited to complete a questionnaire in a tertiary referral medical center in Kaoshiung, southern Taiwan from 2006 to 2008. A total of 535 questionnaires were completed. We used descriptive data for the analysis of parents' views and attitudes toward the current vaccination program in Taiwan. RESULTS: Of the 535 respondents, most parents (93%) did not think the current vaccination program was satisfactory. Few (approximately 8%) preferred self-paid vaccines. About 63% of parents believed that the new (self-paid) vaccines provided more protection, whereas 48% deemed them too expensive. The most popular reason for preferring the new vaccines was greater protection (73%). One-half of parents considered the new vaccines to be expensive. Regarding parental awareness of side effect of vaccination, fever was the most well known and of greatest concern (91%). Most parents (68%) had good awareness of conjugated pneumococcal vaccines, and only few (13%) had heard of the human papilloma virus vaccine. Most parental information of vaccines came from pamphlets at the hospital (56%). CONCLUSION: We found the awareness of parents about new vaccines to be insufficient. They also considered the new vaccines to be expensive. PMID- 21524631 TI - Inguinal hernia containing uterus and uterine adnexa in female infants: report of two cases. AB - We herein report two female cases, aged 1 and 1.5 months, of inguinal sliding hernias containing the uterus, fallopian tube, and ovary. The diagnosis of inguinal hernia with uterus and uterine adnexa was highly suspected preoperatively by ultrasonography and was confirmed during surgical correction. Freeing the attachment of fallopian tube and uterus from the sac and with reduction of the uterus, ovary, and fallopian tube back to the peritoneal cavity, high ligation of the hernia sac was performed in these cases. In conclusion, the hernia sac containing fallopian tube, ovary, and uterus in the female is very rare. We present our experience of treatment with these rare cases and suggest that sonography be performed routinely in female infants with an inguinal hernia containing a palpable movable mass. PMID- 21524632 TI - Elimination of postoperative pyloric stricture by endoscopic electrocauterization and balloon dilatation in an infant with congenital antral web. AB - We, herein, report a male infant who presented with recurrent pyloric stricture after two surgeries (web excision and antropyloroplasty), which were done, respectively, at 5 days of age for congenital antral web and 6 months of age for the subsequent pyloric stricture. The patient suffered from anorexia, progressed vomiting, and weight loss gradually after the first and second surgeries, and then, endoscopy revealed severe pyloric deformity and stricture. Poor inflation was noted during endoscopic balloon dilatation because of tight pylorus; a subsequent electrocauterization and balloon dilatation were done, and the patient's clinical symptoms improved significantly 2 weeks later. A follow-up endoscopy was performed 1 month and 12 months after endoscopic therapy, showing steady regression of pyloric stricture. The patient had adequate diet intake and growth in the later 12 months. PMID- 21524633 TI - Rectal prolapse in a child: an unusual presentation of Clostridium difficile associated pseudomembranous colitis. AB - Pseudomembranous colitis after short-course antibiotics is rare in children. We report a 14-month-old girl who presented with rectal prolapse complicated with Clostridium difficile-associated pseudomembranous colitis after a 4-day course of oral cefuroxime for treatment of acute otitis media. Abdominal sonogram showed a pelvic mass, and computed tomography revealed thickened wall of the rectum. Sigmoidoscopy demonstrated discrete yellowish plaques adherent to an edematous mucosa. Stool cultures for C difficile were positive and C difficile toxins A and B were detected in her stool. Histological examination of colonic biopsy showed superficial erosion of the mucosa and the adherent pseudomembranes. She achieved a full recovery after discontinuing cefuroxime. Our case implied that C difficile infection should be considered in children presenting with rectal prolapse, especially when they are taking or have recently received antibiotic therapy. Supportive therapy and discontinuation of antibiotics are generally sufficient for patients with C difficile-associated pseudomembranous colitis who present with mild diarrheal illness. PMID- 21524634 TI - Acute onset of dizziness caused by a cavernous malformation lateral to the fourth ventricle: a case report. AB - Dizziness, diplopia, and nystagmus may be nonspecific symptoms and in part attributed to central causes. We report a case with brain stem lesion and discuss these nonspecific symptoms. A 13-year-old boy presented to our emergency department with a lasting dizziness for 1 week and diplopia for 5 days. New onset horizontal nystagmus was also noted during the physical examination. A cavernous malformation in the right middle cerebral peduncle lateral to the fourth ventricle was suspected by brain computed tomography and confirmed by magnetic resonance imaging. Without progression of the lesion, conservative treatment and regular follow-up were performed. This case report demonstrates the importance of primary physicians paying attention to children with dizziness, diplopia, and nystagmus for considering possible central nervous problems. PMID- 21524635 TI - Ectopic pelvic kidney with urinary tract infection presenting as lower abdominal pain in a child. AB - Ectopic pelvic kidney is a rare developmental anomaly. Ectopic pelvic kidney can present without the characteristic symptoms associated with the urinary tract pathology. Ectopic pelvic kidney is usually unknown, and nonspecific vague abdominal comfort maybe the only symptom. Early detection and recognition of an ectopic kidney can prevent long-term complications. We report a 3-year-5-month old girl with ectopic pelvic kidney who experienced intermittent episodes of lower abdominal pain for about 1 month. Abdominal ultrasound, computed tomography, and intravenous pyelography demonstrated a pelvic kidney. Thereafter, the urinalysis showed pyuria (white blood cell 20/high power field), and urine culture grew Escherichia coli. We emphasize that pelvic kidney should be considered in patients presenting unexplained vague abdominal pain, especially in pediatric patients who had intermittent recurrent episodes. PMID- 21524636 TI - A pilot study to gauge nutritional behavior regarding eye health in an urban community health center population. AB - PURPOSE: The purpose of this pilot study was to assess the knowledge base of an urban community health center population on the link between nutrition and eye health to determine current habits and then utilize this information for an educational intervention. METHODS: A survey was given to 150 patients of an ethnically mixed, lower socioeconomic cohort. The data served as a guide for a focus group. An exit survey and a 1-month follow-up call were used to assess the success of the group. RESULTS: Approximately 83% of respondents were aware of a link between healthy food and healthy eyes. Fewer knew of the ocular benefits of specific nutrients such as omega-3 (42.7%) or vitamin C, vitamin E, lutein, and zeaxanthin (32.7%). Only 60% knew smoking could negatively affect eyesight. The largest age group was older than 55 years (26%), and the largest racial group was black (31.3%). The majority (64.7%) ate fish 1 to 2 days a week, and 40% ate green leafy vegetables 3 to 4 days a week. In the cohort, 73.3% reported they would take supplements or change eating habits to improve ocular health. Only 8% who participated in the survey attended the focus group. At the 1-month follow up, 75% said they had changed their eating habits based on the information presented. CONCLUSIONS: Although educating a community health center population about nutrition and ocular health can have a positive effect on patient behaviors, it is difficult, even with incentives, to engage this cohort in participating in focus groups aimed at changing behavior. PMID- 21524637 TI - Management of corneal scarring secondary to explosion with excimer laser treatment. AB - BACKGROUND: Improper use of pyrotechnics can result in ocular injuries producing severe vision loss. CASE: A 20-year-old man had a pyrotechnics device explode in his face, hospitalizing him for 4 days. He was told he needed a corneal transplant and that his vision would be impaired permanently. As an alternative, phototherapeutic keratectomy was performed on each eye to remove as much scar tissue as possible. Photorefractive keratectomy was then used to treat the residual hyperopia and remove more of the scarring. CONCLUSIONS: The combination of phototherapeutic keratectomy/photorefractive keratectomy proved to be a safe and effective method to treat corneal scarring secondary to explosive trauma and to restore normal vision. PMID- 21524638 TI - Racial disparities in cardiovascular risk factors among diagnosed hypertensive subjects. AB - Racial disparities in cardiovascular disease (CVD) have become a matter of national concern. We investigated racial disparities and trends in glycosylated hemoglobin, high-density lipoprotein (HDL), C-reactive protein, plasma homocysteine, albuminuria, and other risk factors among 4758 diagnosed hypertensive subjects age 18 years or older from the National Health and Nutrition Examination Survey, 1999-2006. Compared with non-Hispanic whites, Hispanics, and non-Hispanic blacks were more likely to have uncontrolled blood pressure (BP) (Hispanics odds ratio [OR]: 1.58, 95% confidence interval [CI]: 1.21-2.07; blacks OR: 1.42, 95% CI: 0.21-1.67), elevated glycosylated hemoglobin (Hispanics OR: 2.70, 95% CI: 1.89-3.87; blacks OR: 2.17, 95% CI: 1.70-2.77), albuminuria (Hispanics OR: 2.36, 95% CI: 1.71-3.27; blacks OR: 1.80, 95% CI: 1.47 2.20), and less likely to have central obesity (Hispanics OR: 0.68, 95% CI: 0.51 0.91; blacks OR: 0.70, 95% CI: 0.58-0.84). Blacks had lower risks of elevated serum cholesterol (OR: 0.81, 95% CI: 0.67-0.98) and low HDL (OR: 0.76, 95% CI: 0.61-0.94) than whites. The risk of high serum homocysteine was lower in Hispanics and higher in blacks compared with whites (Hispanics OR: 0.64, 95% CI: 0.46-0.90; blacks OR: 1.36, 95% CI: 1.14-1.63). These results highlight the need for targeted interventions to aggressively treat uncontrolled BP, elevated glycosylated hemoglobin in Hispanic and black hypertensive subjects, and high serum homocysteine in blacks, to reduce disparities in CVD risk factors and CVD associated morbidity and mortality. PMID- 21524639 TI - Association of high-sensitivity C-reactive protein with carotid artery intima media thickness in hypertensive older adults. AB - Hypertension is a major traditional risk factor for atherosclerosis. Increased carotid artery intima-media thickness (IMT) is considered to be a noninvasive marker of global atherosclerotic disease. The aim of this study is to assess the association between C-reactive protein (CRP) and carotid artery IMT among hypertensive older adults. A case-control study was done on 90 adults age 60 years and older, of which 60 were hypertensive (30 males and 30 females) and 30 were matched healthy controls. Measurements included conventional cardiovascular risk factors including obesity parameters, blood pressure, lipid profiles, smoking habits, the serum concentrations of high-sensitivity CRP (hs-CRP), and the carotid artery IMT. Hypertensive patients had higher body mass index, Total cholesterol, low-density lipoprotein, and hs-CRP level (P < .001) than the control group. Carotid artery IMT was significantly higher among the hypertensive group (P < .001). hs-CRP and hypertension duration were positively correlated to carotid IMT among the hypertensive group. All of the other factors failed to show a significant relationship with the carotid IMT. These results suggest inflammation, as measured by hs-CRP level, is associated with carotid artery IMT among hypertensive adults rather than other traditional risk factors. PMID- 21524640 TI - Characterization of the metacaspase 1 gene in Plasmodium vivax field isolates from southern Iran and Italian imported cases. AB - Plasmodium vivax is still the more prevalent human Plasmodium outside Africa and despite this fact, there is still a deep lack of knowledge on its biology. Metacaspases are cysteine proteases related to metazoan caspases, involved in programmed cell death. Here, we have characterized the P. vivax metacaspase 1 gene in a total of 63 vivax isolates, 32 isolates collected in southern Iran and 31 Italian imported isolates originating from 12 different endemic countries. We have firstly identified DNA size polymorphism in P. vivax metacaspase 1 gene. A total of four different allelic sizes were found, resulting from the insertion of 1 to 4 tandem repeat units located within the intronic region of the P. vivax metacaspase 1. Similarly, we also have identified four distinct allelic types by using vivax merozoite surface protein-1 size polymorphism analysis. PMID- 21524641 TI - Phylogenetic reconstruction based on Cytochrome b (Cytb) gene sequences reveals distinct genotypes within Colombian Trypanosoma cruzi I populations. AB - Chagas disease caused by Trypanosoma cruzi comprises an important problem of public health in the Americas. This parasite has been recently divided into six Discrete Typing Units (DTUs) due to its high genetic diversity. We sequenced the Cytochorme b (Cytb) gene of 70 T. cruzi I Colombian clones finding four genotypes related to transmission cycles of Chagas disease in Colombia and also to specific hosts of T. cruzi. The genotypes herein described based on Cytb gene sequences are in accordance with those found using the mini-exon gene and reveals once again the enormous genetic diversity at sub-DTU level evidenced in T. cruzi I. PMID- 21524642 TI - A membrane filtering method for the purification of giant unilamellar vesicles. AB - The use of giant unilamellar vesicles (GUVs) for investigating the properties of biomembranes is advantageous compared to the use of small-sized vesicles such as large unilamellar vesicles (LUVs). Experimental methods using GUVs, such as the single GUV method, would benefit if there was a methodology for obtaining a large population of similar-sized GUVs composed of oil-free membranes. We here describe a new membrane filtering method for purifying GUVs prepared by the natural swelling method and demonstrate that, following purification of GUVs composed of dioleoylphosphatidylglycerol (DOPG)/dioleoylphosphatidylcholine (DOPC) membranes suspended in a buffer, similar-sized GUVs with diameters of 10-30 MUm are obtained. Moreover, this method enabled GUVs to be separated from water-soluble fluorescent probes and LUVs. These results suggest that the membrane filtering method can be applied to GUVs prepared by other methods to purify larger-sized GUVs from smaller GUVs, LUVs, and various water-soluble substances such as proteins and fluorescent probes. This method can also be used for concentration of dilute GUV suspensions. PMID- 21524643 TI - Ultraviolet-radiation induced skin inflammation: dissecting the role of bioactive lipids. AB - Acute exposure of human skin to the ultraviolet radiation (UVR) in sunlight results in the sunburn response. This is mediated in part by pro-inflammatory eicosanoids and other bioactive lipids, which are in turn produced via mechanisms including UVR-induction of oxidative stress, cell signalling and gene expression. Sunburn is a self-limiting inflammation offering a convenient and accessible system for the study of human cutaneous lipid metabolism. Recent lipidomic applications have revealed that a wider diversity of eicosanoids may be involved in the sunburn response than previously appreciated. This article reviews the effects of UVR on cutaneous lipids and examines the contribution of bioactive lipid mediators in the development of sunburn. Since human skin is an active site of polyunsaturated fatty acid (PUFA) metabolism, and these macronutrients can influence the production of eicosanoids/bioactive lipids, as well as modulate cell signalling, gene expression and oxidative stress, the application of PUFA as potential photoprotective agents is also considered. PMID- 21524644 TI - Revaluation of biological variation of glycated hemoglobin (HbA(1c)) using an accurately designed protocol and an assay traceable to the IFCC reference system. AB - BACKGROUND: Glycated hemoglobin (HbA(1c)) has a key role for diagnosing diabetes and monitoring glycemic state. As recently reviewed, available data on HbA(1c) biological variation show marked heterogeneity. Here we experimentally revaluated these data using a well designed protocol. METHODS: We took five EDTA whole blood specimens from 18 apparently healthy subjects on the same day, every two weeks for two months. Samples were stored at -80 degrees C until analysis and assayed in duplicate in a single run by Roche Tina-quant(r) Gen.2 immunoassay. Data were analyzed by the ANOVA. To assess the assay traceability to the IFCC reference method, we preliminarily carried out a correlation experiment. RESULTS: The bias (mean+/-SD) of the Roche immunoassay was 0.3%+/-0.7%, confirming the traceability of the employed assay. No difference was found in HbA(1c) values between men and women. Within- and between-subject CV were 2.5% and 7.1%, respectively. Derived desirable analytical goals for imprecision, bias, and total error resulted 1.3%, 1.9%, and 3.9%, respectively. HbA(1c) had marked individuality, limiting the use of population-based reference limits for test interpretation. The estimated critical difference was ~10%. CONCLUSIONS: For the first time we defined biological variation and derived indices for the clinical application of HbA(1c) measurements using an accurately designed protocol and an assay standardized according to the IFCC. PMID- 21524645 TI - PTH inhibition rate is useful in the detection of early-stage primary hyperparathyroidism. AB - OBJECTIVE: This study was to establish biochemical thresholds for the intravenous calcium suppression test in the early diagnosis of primary hyperparathyroidism (PHPT). DESIGN AND METHODS: One hundred and thirty-three patients were divided into three groups: Group 1: surgically proven hypercalcemic PHPT, Group 2 surgically proven mild PHPT, and Group 3: normocalcemia with elevated serum PTH levels. Intravenous calcium suppression tests were performed in Groups 2 and 3 as well as in 20 controls with normal serum calcium and PTH concentrations. RESULTS: The serum PTH inhibition rate (PTH-IR) was less pronounced in Group 2 compared with Group 3 (P<0.001) and the controls (P<0.001). Receiver operating characteristic curve analysis suggests that a serum calcium level higher than 2.43mmol/L and a PTH-IR less than 73% may differentiate Group 2 from normal controls. CONCLUSION: It is quite useful to combine serum calcium levels with the PTH-IR to identify patients at early stage of PHPT, even in the presence of vitamin D deficiency. PMID- 21524646 TI - Low cryoprotectant concentrations and fast cooling for nematode cryostorage. AB - Cryopreservation protocols based on slow freezing or vitrification often result in cell injury due to ice formation, cell dehydration and/or toxic concentrations of cryoprotectant (CPA). In this study, we present a cryopreservation technique based on low, non-toxic concentrations of cryoprotectants (~ 2-4M) combined with a rapid cooling rate in the liquid nitrogen phase (-196 degrees C). Protocols for successfully cryopreserving the plant parasitic nematodes Globodera tabacum tabacum, Heterodera schachtii and Meloidogyne incognita were developed, as demonstrated by the high survival rates and reproducibility of cyst and root-knot nematode species post-cryostorage. This approach for effective cryopreservation of viable plant-parasitic nematodes was developed by inducing an "apparent vitrification" by rapid cooling of the microscopic samples in less than 2M of cryoprotectant. The extremely thin structure (15-20 MUm width, 350-400 MUm length) of these nematodes, in combination with a direct and rapid exposure to LN(2), likely prevents the formation of damaging ice crystals. Moreover, this procedure results in viability of both short- and long-cryostorage samples. These techniques could potentially be used for the near-indefinite preservation of thousands of different nematode species. A cryo-nematode collection produced in our lab is available and presented here. PMID- 21524647 TI - Functional analysis of missense mutations G36A and G51A in PAX6, and PAX6(5a) causing ocular anomalies. AB - The PAX6 has been described a "master regulator of eye development". A specific ratio of PAX6, and its alternatively spliced isoform, PAX6(5a), has also been observed essential for optimal function. Mutations into PAX6 lead to a number of ocular, and neuronal defects of variable penetrance and expressivity but the mechanism is either poorly understood or underrepresented. This report describes analysis of functions of two missense mutations, G36A, and G51A, causing optic nerve hypoplasia and optic-disc coloboma in humans, respectively. Mutations were created by site-directed mutagenesis. Products were detected by in-vitro translation and transient transfection to the cultured NIH-3T3 cells. Their DNA binding, and transcriptional activation properties were analysed through electrophoretic mobility shift assay and luciferase reporter assay, respectively. Mutations induced changes in conformation and secondary structure of PAX6, and PAX6(5a) not only restrict to specific site of mutation in the paired-domain but extend to homeodomain, and transactivation domain. The PAX6-G36A showed reduced binding to PAX6-consensus binding sequence and PAX6(5a)-consensus binding sequence but its binding affinity to homeodomain binding sequence was unaffected. It showed significantly higher transactivation potential through PAX6-consensus binding sequence but reduced activity with PAX6(5a)-consensus binding sequence and homeodomain binding sequence containing luciferase reporters. The PAX6(5a) G36A showed enhanced transactivation potential with PAX6-consensus binding sequence, PAX6(5a)-consensus binding sequence, and homeodomain binding sequence containing luciferase reporters. The binding affinity of PAX6(5a)-G36A was significantly higher to PAX6-consensus binding sequence, and PAX6(5a)-consensus binding sequence as compared to PAX6(5a) but remains unaffected to homeodomain binding sequence. The enhanced binding affinity was observed by PAX6-G51A to PAX6 consensus binding sequence, PAX6(5a)-consensus binding sequence, and homeodomain binding sequence. The transactivation potential was observed higher with PAX6 consensus binding sequence but significant reduction was evident with PAX6(5a) consensus binding sequence, and homeodomain binding sequence containing luciferase reporters. The lower binding affinity to PAX6-consensus binding sequence and PAX6(5a)-consensus binding sequence was observed by PAX6(5a)-G51A but loss of binding affinity was detected to homeodomain binding sequence. However, PAX6(5a)-G51A showed significantly higher transactivation with PAX6 consensus binding sequence, PAX6(5a)-consensus binding sequence, and homeodomain binding sequence containing luciferase reporters. With the eye-specific alpha-A crystallin promoter, PAX6-G36A and PAX6-G51A mutants were found to have higher ability to transactivate whereas PAX6(5a)-G36A and PAX6(5a)-G51A have lower transactivation potential compared to their respective wild type forms. Thus, variable DNA-binding and transactivation properties of the mutants with different PAX6-binding sequences provide an insight towards their variable penetrance and expressivity. PMID- 21524648 TI - Chemical composition of melanosomes, lipofuscin and melanolipofuscin granules of human RPE tissues. AB - Energy-filtered analytical transmission electron microscopy was used to image the ultrastructure and determine quantitatively the chemical composition of pigment granules of the choroid and retinal pigment epithelium of two healthy human donors, aged 68 and 85 years. The electron microscopy preparation procedure did not affect the autofluorescence of melanolipofuscin and lipofuscin granules, since staining was omitted during sample preparation. Oval melanosomes, melanolipofuscin and lipofuscin granules were observed, having sizes of about 1.5 MUm*0.5 MUm, and were analyzed using energy-dispersive X-ray microanalysis and electron energy loss spectroscopy. Up to now, these pigments could only be identified by scattering contrast in bright field images, with melanosomes having dark contrast and lipofuscin being much brighter. High-precision energy dispersive X-ray microanalysis of pigment granules (>15,000 integrated counts in the oxygen K(alpha) peak) yielded minimum detectable mole fractions of about 0.02 at% for copper and zinc. For the first time, quantitative analytical electron microscopy yielded the chemical composition of the different pigments without prior isolation from the tissue. This is important to better understand physical and chemical properties of the pigments and their metabolism and turnover. The composition of melanosomes and lipofuscin can clearly be distinguished by the applied methods. Melanosomes were the pigments with largest oxygen (about 5 at%) and nitrogen (about 10 at%) mole fractions. The S/N ratio determination demonstrated a high pheomelanin content of the melanosomes. Lipofuscin had a significantly smaller oxygen mole fraction (about 4 at%) and nitrogen was found to be only slightly above the limit of detection (0.4 at%). For comparison, the cytoplasm contained oxygen and nitrogen mole fractions of 3 at% and 0.8 at%. Bright field images showed melanolipofuscin granules having a core-shell structure with a dark inner and a bright outer fraction. The dark fraction had a chemical composition close to the melanosomes and the composition of the bright fraction could be distinguished from that of lipofuscin due to a significantly increased nitrogen mole fraction in the melanolipofuscin granule. For all pigments observed the oxygen mole fraction yielded a positive correlation with the calcium mole fraction as previously established for melanosomes. Only lipofuscin contained measurable phosphorus mole fractions, which also correlated positively with oxygen. In lipofuscin, mole fractions of nitrogen were significantly smaller than in melanosomes and only indicated a small fraction of proteins. In contrast, the phosphorus mole fraction was significantly larger indicating the presence of significant amounts of phospholipids. Copper and zinc mole fractions were larger than 0.1at% in the melanosomes, but were below the detection limit in the lipofuscin granules. Compared to melanosomes of monkeys and rats analyzed beforehand, human retinal pigment epithelium melanosomes contained the highest amount of zinc, which even exceeded the calcium mole fraction. Trace elements like zinc are of great importance for metabolism and anti-oxidative mechanisms and also play a role in the progression of age related macular degeneration. They can now be investigated by quantitative analytical electron microscopy. PMID- 21524649 TI - Update on the role of alpha-agonists in glaucoma management. AB - Glaucoma is the second most common cause of world blindness (following cataract) with estimated cases reaching 79.6 million by 2020. Although the etiology of glaucoma is multi-factorial, intraocular pressure (IOP) is the only modifiable factor in glaucoma management proven to alter the natural course of the disease. Among various classes of IOP-lowering medications currently available, alpha adrenergic receptor agonists are used either as monotherapy, as second-line therapy, or in fixed combination with beta-blockers. Non-selective adrenergic agonists such as epinephrine and dipivefrin are infrequently used today for the treatment of glaucoma or ocular hypertension, and have been replaced by the alpha 2-selective agonists. The use of apraclonidine for IOP reduction in glaucoma or OHT is limited due to a high rate of follicular conjunctivitis. The alpha-2 selective agonist in use today is brimonidine. The brimonidine-purite formulations are preferred to brimonidine-benzalkonium chloride (BAC) formulations due better tolerability while maintaining similar efficacy. Brimonidine is also effective when used in combination with a beta-blocker. Using brimonidine-timolol fixed combination (BTFC) as first-line therapy has an added potential for neuroprotection. This would be a valuable strategy for glaucoma treatment, for patients who are intolerant of prostaglandin analogs, or for patients where prostaglandin analogues are contraindicated as first-line therapy, such as in patients with inflammatory glaucoma. PMID- 21524650 TI - Functional neuromuscular stimulation to improve severe hand dysfunction after stroke: does inhibitory rTMS enhance therapeutic efficiency? AB - BACKGROUND: Novel strategies to improve hand function after stroke are needed. Electromyography-triggered functional neuromuscular stimulation (EMG-FNMS) and repetitive transcranial magnetic stimulation (rTMS) are promising techniques to facilitate recovery of sensory-motor hand dysfunction after stroke. OBJECTIVE: To investigate if 1Hz rTMS over the contralesional primary motor cortex enhances the effectiveness of EMG-triggered FNMS of the hand and finger extensors to improve severe sensory-motor hand dysfunction after stroke. METHODS: 24 subjects with a first stroke received 10 daily sessions of 20 min EMG-triggered FNMS of the hand and finger extensors of the affected forearm preceded by 15 min of either 1Hz rTMS (rTMS group, n = 12) or sham rTMS (control group, n = 12) over the contralesional primary motor cortex. Prior to and after each intervention motor function and spasticity were rated at both hands, and cortical excitability of the contralesional primary motor cortex was assessed. RESULTS: Motor function and spasticity of the affected hand were significantly improved by either intervention, whereas behavioural measures of the unaffected hand did not change. There were no significant differences between both intervention groups. Improvement of motor function of the affected hand was positively correlated with cortical excitability of the contralesional primary motor cortex after EMG triggered FNMS preceded by 1Hz rTMS. CONCLUSIONS: 1Hz rTMS does not enhance the general effectiveness of EMG-FNMS to the wrist and finger extensors of the affected forearm after stroke. Motor recovery of the severely affected hand after stroke appears to depend on excitability of the contralesional primary motor cortex. PMID- 21524651 TI - Caspase-8 cleavage of the interleukin-21 (IL-21) receptor is a negative feedback regulator of IL-21 signaling. AB - We screened a library of human single-transmembrane proteins (sTMPs), produced by a cell-free system, using a luminescent assay to identify those that can be cleaved by caspase-8 (CASP8). Of the 407 sTMPs screened, only the interleukin-21 receptor (IL21R), vezatin (VEZT), and carbonic anhydrase XIV were cleaved at Asp344, Asp655 and Asp53, respectively. We confirmed that IL21R and VEZT were also cleaved in apoptotic HeLa cells with the cleavage sites. Interestingly, IL21R was cleaved within 30 min after apoptosis induction. Furthermore the CASP8 cleaved form of IL21R did not induce phosphorylation at Tyr705 of STAT3. Our results suggest that the interleukin-21 signaling cascade is negatively regulated by CASP8. PMID- 21524652 TI - Autoimmune hepatitis: the dilemma of rare diseases. PMID- 21524653 TI - Which way to die: the regulation of acinar cell death in pancreatitis by mitochondria, calcium, and reactive oxygen species. PMID- 21524654 TI - Failure to thrive: an unexpected finding after Whipple's resection. Image 1: Extensive hepatic infarction: an extremely rare complication of Whipple's resection. PMID- 21524655 TI - Species-specific patterns in fecal glucocorticoid and androgen levels in zoo living orangutans (Pongo spp.). AB - In contrast to most primate species, including the other great apes, orangutans maintain a fission-fusion social system in the wild without being part of a stable community. In zoos, however, they are kept in permanent groups, usually consisting of one adult male and several females. In zoo orangutans, we predict higher levels of glucocorticoids and androgens in the Bornean species compared to its congener from Sumatra, due to the much more solitary lifestyle of Bornean orangutans and the apparent higher frequency of male aggression directed towards females in this species in the wild. To compare hormone levels of the two orangutan species, we validated a fecal glucocorticoid and a fecal androgen assay. Subsequently, fecal samples from a total of 73 female and 38 male orangutans housed in 29 European zoos were analyzed to investigate the effect of species, social group size, age and (for female glucocorticoid levels) reproductive state and the presence of adult males on fecal hormone metabolite concentrations. The results of linear mixed effect models indicate that both male and female Bornean orangutans show a steeper increase in glucocorticoid levels with increasing group size than Sumatran orangutans. We therefore conclude that Sumatran zoo orangutans are better able to adjust to social housing conditions than their Bornean congeners. In addition, our analyses reveal higher glucocorticoid levels in lactating females of both species compared to non lactating and juvenile females. Concerning androgen levels in males, our analyses revealed significantly higher concentrations in Bornean than Sumatran orangutans. These differences in both glucocorticoid and androgen output between the two species of orangutan are presumably linked to ecological and behavioral differences and could possibly be attributed to phenotypic plasticity. However, given that we found interspecific differences in hormone excretion in captivity, where both species live under very similar conditions, we conclude that this variation has a genetic basis. PMID- 21524656 TI - Phorid fly, Pseudacteon tricuspis, response to alkylpyrazine analogs of a fire ant, Solenopsis invicta, alarm pheromone. AB - The phorid fly, Pseudacteon tricuspis Borgmeier, is a parasitoid of the red imported fire ant, Solenopsis invicta Buren. This fly has been reported to use fire ant chemicals, specifically venom alkaloids and possibly alarm pheromone to locate its host. A recent study identified 2-ethyl-3,6-dimethyl pyrazine as a component of the alarm pheromone of S. invicta. To determine the possible involvement of this fire ant alarm pheromone component in mediating fire ant phorid fly interactions, we tested electroantennogram (EAG) and behavioral responses of P. tricuspis females to the commercially available mixture of 2 ethyl-3,6-dimethyl pyrazine and its 3,5-dimethyl isomer, as well as six structurally related alkylpyrazine analogs at varying doses. Pseudacteon tricuspis females showed significant EAG response to 2-ethyl-3,6(or 5)-dimethyl pyrazine (herein referred to as pheromone-isomer) at all doses, 0.001-10 MUg. Among the tested alkylpyrazine analogs, 2,3-diethyl-5-methyl pyrazine showed significant EAG activity at 0.1 and 1 MUg. 2,3-dimethyl pyrazine also showed significant EAG activity at 0.1 MUg. Results of four-choice olfactometer bioassays demonstrated significant attraction of P. tricuspis females to the pheromone-isomer (2-ethyl-3,6(or 5)-dimethyl pyrazine) at all tested doses (0.01, 0.1, 1 and 10 MUg). The analogs, 2,3-diethyl-5-methyl pyrazine and 2,3-dimethyl pyrazine were significantly better than the control at the higher doses (0.1, 1 and 10 MUg). The pheromone-isomer was significantly better than both analogs at two doses, 0.1 and 1 MUg. These results confirm that the reported fire ant alarm pheromone component plays a role in mediating attraction of phorid flies to host workers. Venom alkaloids were previously shown to attract P. tricuspis; therefore, we propose that fire ant alarm pheromones may act in tandem or synergistically with venom alkaloids to attract phorid fly parasitoids to fire ant workers. PMID- 21524657 TI - The Aicardi-Goutieres syndrome. Molecular and clinical features of RNAse deficiency and microRNA overload. AB - Intracellular RNAses are involved in various functions, including microRNA maturation and turnover. Mutations occurring in genes encoding RNAses cause Aicardi-Goutieres syndrome (AGS). AGS mutations silence RNAse activity, thus inducing accumulation of endogenous RNAs, mainly consisting of short RNAs and microRNAs. Overload of intracellular RNA triggers Toll like receptor-dependent interferon-alpha production in the brain, which in turn activates neurotoxic lymphocytes and inhibits angiogenesis thus inducing the typical clinical phenotype of AGS. However, these pathogenic mechanisms are attenuated after three years of age by the endogenous production of DNAJP58IPK and Cystatin F, which arrest AGS progression. Because RNAses are involved in microRNA turnover, we evaluated the expression of 957 microRNAs in lymphocytes from AGS patients and control patients. Our results indicate that microRNA overload occurs in AGS patients. This upregulation inhibits microRNA turnover impeding the synthesis of the novel microRNAs required for the differentiation and myelination of the brain during the initial period of postnatal life. These pathogenic mechanisms result in AGS, a neurological syndrome characterized by irritability, mild hyperpyrexia, pyramidal and extrapyramidal signs, and spastic-dystonic tetraplegia. Typical cerebrospinal fluid alterations include lymphocytosis and elevated interferon alpha levels. Brain imaging demonstrates cerebral calcifications, white matter abnormalities, and progressive cerebral atrophy.Thus, evidence exists that mutations silencing intracellular RNases affect microRNA turnover resulting in the severe clinical consequences in the brain characterizing the clinical feature of AGS. PMID- 21524658 TI - Comment on "Preclinical assessment of the neutralizing capacity of antivenoms produced in six Latin American countries against medically-relevant Bothrops snake venoms". PMID- 21524659 TI - The rhodocetin alphabeta subunit targets GPIb and inhibits von Willebrand factor induced platelet activation. AB - Rhodocetin, a heterotetrameric snake C-type lectin from Calloselasma rhodostoma is a specific antagonist of alpha2beta1 integrin. Its gammadelta subunit is responsible for binding to alpha2beta1 integrin. In this study we show that the rhodocetin alphabeta subunit can bind to platelet glycoprotein GPIb. Binding of the rhodocetin alphabeta subunit does not depend on divalent cations. When added to washed human platelets the rhodocetin alphabeta subunit effectively inhibits platelet aggregation induced by von Willebrand factor plus ristocetin. In contrast, it does not affect collagen-induced platelet activation. By itself the rhodocetin alphabeta subunit does not induce any changes when added to washed platelets or platelet-rich plasma. However, rhodocetin alphabeta, after biotinylation and cross-linkage with avidin induces small platelet agglutination but not aggregation. These agglutinated platelets change their pattern of protein tyrosine phosphorylation slightly as kinase p72SYK but not p125FAK is phosphorylated. PMID- 21524660 TI - Efficient bubbles for visual categorization tasks. AB - Bubbles is a classification image technique that randomly samples visual information from input stimuli to derive the diagnostic features that observers use in visual categorization tasks. To reach statistical significance, Bubbles performs an exhaustive and repetitive search in the stimulus space. To reduce the search trials, we developed an adaptive method that uses reinforcement learning techniques to optimize sampling by exploiting the observer's history of categorization. We compared the performance of the original and the adaptive Bubbles algorithms in a model observer and eight human adults who all resolved the same visual categorization task (i.e., five facial expressions of emotion). We demonstrate the feasibility of a substantial reduction (by a factor of ~2) in the number of search trials required to locate the same diagnostic features with the adaptive method, but only when the observer reaches a performance threshold of 50% correct for each expression category. When this threshold is not reached, both the original and adaptive algorithms converge in the same number of trials. PMID- 21524661 TI - Risk communication and college students: the 2009 H1N1 pandemic influenza. PMID- 21524663 TI - A study of neurotoxic biomarkers, c-fos and GFAP after acute exposure to GSM radiation at 900 MHz in the picrotoxin model of rat brains. AB - The acute effects of microwave exposure from the Global System for Mobile Communication (GSM) were studied in rats, using 900MHz radiation at an intensity similar to mobile phone emissions. Acute subconvulsive doses of picrotoxin were then administered to the rats and an experimental model of seizure-proneness was created from the data. Seventy-two adult male Sprague-Dawley rats underwent immunochemical testing of relevant anatomical areas to measure induction of the c fos neuronal marker after 90min and 24h, and of the glial fibrillary acidic protein (GFAP) 72h after acute exposure to a 900MHz electromagnetic field (EMF). The experimental set-up facilitated measurement of absorbed power, from which the average specific absorption rate was calculated using the finite-difference time domain (FDTD) 2h after exposure to EMF radiation at 1.45W/kg in picrotoxin treated rats and 1.38W/kg in untreated rats. Ninety minutes after radiation high levels of c-fos expression were recorded in the neocortex and paleocortex along with low hippocampus activation in picrotoxin treated animals. Most brain areas, except the limbic cortical region, showed important increases in neuronal activation 24h after picrotoxin and radiation. Three days after picrotoxin treatment, radiation effects were still apparent in the neocortex, dentate gyrus and CA3, but a significant decrease in activity was noted in the piriform and entorhinal cortex. During this time, glial reactivity increased with every seizure in irradiated, picrotoxin-treated brain regions. Our results reveal that c-fos and glial markers were triggered by the combined stress of non-thermal irradiation and the toxic effect of picrotoxin on cerebral tissues. PMID- 21524662 TI - Temporal trends and correlates of passive commuting to and from school in children from 9 provinces in China. AB - OBJECTIVE: To examine trends and correlates of passive (inactive) commuting to school among Chinese children aged 6-18 years in nine provinces. METHODS: The trends analysis used school commuting data from the China Health and Nutrition Surveys in 1997 (n=2454), 2000 (n=1978), 2004 (n=1549) and 2006 (n=1236). Generalized estimating equations examined trends after adjusting for age, sex and region, and also explored the correlates of passive commuting to school in urban and rural areas (n=6935). RESULTS: An increase in passive commuting to school was noted (3.6% in 1997, 14.1% in 2006, P<0.0001). Children attending schools not located in their local community were more likely to passively commute. In urban areas, maternal education was associated with increased passive commuting (AOR=1.41, 95% CI: 1.03-1.92). In rural areas, family income (AOR(high/low)=2.12, 95% CI: 1.52-2.96), paternal education (AOR(high/low)=1.56, 95%CI: 1.17-2.07), and motorcycle ownership (AOR=1.57, 95%CI: 1.19-2.07) were associated with passive commuting. CONCLUSION: Passive commuting to school increased in China over a decade and was associated with family socioeconomic status, school location, and in rural children, with access to motorized vehicles. PMID- 21524664 TI - Measuring vigilance while assessing the functioning of the three attentional networks: the ANTI-Vigilance task. AB - Vigilance could be a crucial aspect of attention that may modulate the functioning of the attentional system. Some behavioural tests, such as the Attention Network Test (ANT), have been developed to obtain an individual index of the three attentional networks (alertness, orientation, and executive control). However, alerting network measures are usually inferred using a phasic alertness task, and some indirect indexes of tonic alertness or vigilance have been proposed but not properly evaluated. The general aim for the present study is to provide the ANT with a direct measure of vigilance and then to analyse the relationship between this measure and other alternative indirect indexes. The obtained results suggest that the proposed new test (ANTI-Vigilance or ANTI-V) is useful to achieve a direct measure of vigilance and could be considered as a new tool available in cognitive, clinical or behavioural neurosciences for analysing vigilance in addition to the usual ANT scores. Other alternative indexes (such as global reaction time and global accuracy averaged across conditions) are only moderately correlated to a direct vigilance measure. As a consequence, although they may be to some extent related to the participants' vigilance level, they could not be used isolatedly as appropriate indexes of vigilance. Also, the role played by these global measures in the ANT task, which have been previously associated with some performance measures in applied areas (such as driving performance), is discussed. PMID- 21524665 TI - Time-frequency spectral analysis of TMS-evoked EEG oscillations by means of Hilbert-Huang transform. AB - A single pulse of Transcranial Magnetic Stimulation (TMS) generates electroencephalogram (EEG) oscillations that are thought to reflect intrinsic properties of the stimulated cortical area and its fast interactions with other cortical areas. Thus, a tool to decompose TMS-evoked oscillations in the time frequency domain on a millisecond timescale and on a broadband frequency range may help to understand information transfer across cortical oscillators. Some recent studies have employed algorithms based on the Wavelet Transform (WT) to study TMS-evoked EEG oscillations in healthy and pathological conditions. However, these methods do not allow to describe TMS-evoked EEG oscillations with high resolution in time and frequency domains simultaneously. Here, we first develop an algorithm based on Hilbert-Huang Transform (HHT) to compute statistically significant time-frequency spectra of TMS-evoked EEG oscillations on a single trial basis. Then, we compared the performances of the HHT-based algorithm with the WT-based one by applying both of them to a set of simulated signals. Finally, we applied both algorithms to real TMS-evoked potentials recorded in healthy or schizophrenic subjects. We found that the HHT-based algorithm outperforms the WT-based one in detecting the time onset of TMS-evoked oscillations in the classical EEG bands. These results suggest that the HHT-based algorithm may be used to study the communication between different cortical oscillators on a fine time scale. PMID- 21524666 TI - An acidic polysaccharide of Panax ginseng ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells. AB - An acidic polysaccharide of Panax ginseng (APG), so called ginsan, is a purified polysaccharide. APG has multiple immunomodulatory effects of stimulating natural killer (NK) and T cells and producing a variety of cytokines that proved to diminish the proinflammatory response, and protect from septic lethality. To determine APG's role in the autoimmune demyelinating disease, we tested whether APG can regulate inflammatory and encephalitogenic response in experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS). Here, we demonstrate the therapeutic efficacy of the APG which induces the suppression of an encephalitogenic response during EAE. APG significantly ameliorates the progression of EAE by inhibiting the proliferation of autoreactive T cells and the production of inflammatory cytokines such as IFN gamma, IL-1beta and IL-17. More importantly, APG promotes the generation of immunosuppressive regulatory T cells (Tregs) through the activation of transcription factor, Foxp3. Furthermore, the depletion of CD25+ cells from APG treated EAE mice abrogates the beneficial effects of EAE. The capacity of APG to induce clinically beneficial effects furthers our understanding of the basis for its therapeutic immunosuppression of EAE and, possibly, MS. Thus, our results suggest that APG may serve as an effective therapy for MS and other autoimmune diseases. PMID- 21524667 TI - Respiratory and sniffing behaviors throughout adulthood and aging in mice. AB - Orienting responses are physiological and active behavioral reactions evoked by novel stimulus perception and are critical for survival. We explored whether odor orienting responses are impacted throughout both adulthood and normal and pathological aging in mice. Novel odor investigation (including duration and bout numbers) and its subsequent habituation as assayed in the odor habituation task were preserved in adult C57BL/6J mice up to 12 mo of age with <6% variability between age groups in investigation time. Separately, using whole-body plethysmography we found that both spontaneous respiration and odor-evoked sniffing behaviors were strikingly preserved in wildtype (WT) mice up to 26 mo of age. In contrast, mice accumulating amyloid-beta protein in the brain by means of overexpressing mutations in the human amyloid precursor protein gene (APP) showed preserved spontaneous respiration up to 12 mo, but starting at 14 mo showed significant differences from WT. Similar to WTs, odor-evoked sniffing was not impacted in APP mice up to 26 mo. These results show that odor-orienting responses are minimally impacted throughout aging in mice, and suggest that the olfactomotor network is mostly spared of insults due to aging. PMID- 21524668 TI - Enzymatic activity and immunolocalization of Schistosoma mansoni and Schistosoma haematobium neutral sphingomyelinase. AB - We predicted, and provided evidence for, the existence of a schistosome tegument associated Mg(2+)-dependent neutral sphingomyelinase (nSMase), which controls hydrolysis of surface membrane sphingomyelin molecules, thus allowing nutrients, but not host antibodies, to access proteins at the host-parasite interface. While a putative nSMase was identified in a recent Schistosoma mansoni genome sequencing and analysis study, our report is the first to measure nSMase enzymatic activity in Triton X-100-solubilized surface membrane (Sup 1) and whole worm soluble (SWAP) molecules of male and female S. mansoni and Schistosoma haematobium. Neutral, but no acidic, sphingomyelinase activity was readily detectable by the amplex red sphingomyelinase assay, and increased with incubation time and protein amount. Like nSMase family members, the schistosome nSMase activity was significantly (P<0.05 to <0.0001) enhanced by unsaturated fatty acids and phosphatidyl serine and significantly (P<0.01) decreased following exposure to the nSMase specific inhibitor GW4869. Peptides based on the published sequence of S. mansoni putative nSMase and used in a multiple antigen peptide form induced the generation of specific antibodies, which readily bound to the immunogen and to the cognate protein in Sup 1 and SWAP. Immunofluorescence studies suggested the parasite nSMase is located in the worm tegument and gut lining. Studies using RNA interference are in progress to define nSMase role in larval and adult worm surface membrane antigen exposure and unsaturated fatty acid-mediated attrition. PMID- 21524669 TI - Transcriptional profiling of stage specific gene expression in the parasitic ciliate Ichthyophthirius multifiliis. AB - The parasitic ciliate, Ichthyophthirius multifiliis (Ich), is among the most important protozoan pathogens of freshwater fish. Ichthyophthirius cannot be grown in cell culture, and the development of effective prophylactic and therapeutic treatments has been hampered by a lack of information regarding genes involved in virulence, differentiation and growth. To help address this issue, we have generated EST libraries from the two major stages of the parasite life cycle that infect and develop within host tissues. A total of 25,084 ESTs were generated from non-normalized libraries prepared from polyA+ RNA of infective theronts and host-associated trophonts, respectively. Cluster analysis identified 5311 unique transcripts (UniScripts), of which 2091 were contigs and 3220 singletons. Extrapolation of the data based on rates of EST discovery suggests that more than half the expected protein-coding genes of I. multifiliis are represented in this data. BLASTX comparisons against GenBank nr, UniProtKB (SwissProt and TrEMBL), as well as Tetrahymena thermophila, Plasmodium falciparum, and Paramecium tetraurelia protein databases produced 3694 significant (E-value <=1e(-10)) hits, of which 1178 were annotated using gene ontology (GO) analysis. A high proportion of UniScripts (63%) showed similarity to other ciliate proteins. When combined with expression profiling data, GO ontology analysis of Biological Process, Cellular Component, and Molecular Function revealed interesting differences in gene families expressed in the two stages. Indeed, the most abundant transcripts were highly stage-specific and coincided with the metabolic activities associated with each stage. This work provides an effective genomics resource to further our understanding of Ichthyophthirius biology, and lays the groundwork for the identification of potential drug targets and vaccines candidates for the control of this devastating fish pathogen. PMID- 21524670 TI - The Haemonchus contortus UNC-49B subunit possesses the residues required for GABA sensitivity in homomeric and heteromeric channels. AB - Hco-UNC-49 is a GABA receptor from the parasitic nematode Haemonchus contortus that has a relatively low overall sequence similarity to vertebrate GABA receptors but is very similar to the UNC-49 receptor found in the free living nematode Caenorhabditis elegans. While the nematode receptors do share >80% sequence similarity they exhibit different sensitivities to GABA. In addition, the UNC-49C subunit appears to be a positive modulator of GABA sensitivity in the H. contortus heteromeric channel, but is a negative modulator in the C. elegans heteromeric channel. The cause(s) of these differences is currently unknown since the structural elements essential for GABA sensitivity in nematode receptors have been largely unexplored. Thus, the overall aim of this study was to investigate the residues that are important for UNC-49 receptor sensitivity through the use of homology modeling, site-directed mutagenesis, and two-electrode voltage clamp. This study revealed that Met(170) in Loop B of the GABA binding-site may partially account for the observed differences in GABA receptor sensitivity between the nematode species. Residues in Loops A-D that have been reported to form the GABA binding pocket in mammalian receptors, including those forming the conserved 'aromatic box', also appear to play analogous roles in Hco-UNC-49. In addition, the two mutations that produced the most significant reduction in GABA sensitivity were R66S and Y166S. Homology modeling indicates that these two residues share a hydrogen bond and are positioned close to the carboxyl end of the GABA molecule. However, of residues examined in this study, only those on the Hco-UNC-49B subunit and not its subunit partner, Hco-UNC-49C, appear important for GABA sensitivity. Overall, results from this study suggest that the binding site of the UNC-49 heteromeric GABA receptor exhibits some differences compared to classical vertebrate GABA(A) receptors. PMID- 21524671 TI - HIV-1 clade C envelopes obtained from late stage symptomatic Indian patients varied in their ability towards relative CD4 usages and sensitivity to CCR5 antagonist TAK-779. AB - The mechanism by which strictly CCR5 using HIV-1 clade C variants exacerbate disease progression in absence of coreceptor switch is not clearly known. We previously reported HIV-1 clade C envelopes (Env) obtained from late stage Indian patients with expanded coreceptor tropism. Here we compared such Envs (having expanded coreceptor tropism) with strictly CCR5 using Envs also obtained from late stage in their capacity to utilize CD4 and CCR5 for productive entry. We found that while envelopes with low CD4 dependence tend to infect primary CD4(+) T cells better than those required optimum CD4 for entry, no significant association was found between low CD4 usage and infectivity of primary CD4(+) T cells by Env-pseudotyped viruses and their sensitivity to CCR5 antagonist TAK 779. Interestingly, Envs that readily infected HeLa cells expressing low CD4 showed relative resistance to T20 indicating that conformational intermediates of these envelopes remained for a shorter period of time than is required for efficient inhibition by T20. PMID- 21524672 TI - A novel conotoxin, qc16a, with a unique cysteine framework and folding. AB - A novel conotoxin, qc16a, was identified from the venom of vermivorous Conus quercinus. qc16a has only 11 amino acid residues, DCQPCGHNVCC, with a unique cysteine pattern. Its disulfide connectivity was determined to be I-IV, II-III. The NMR structure shows that qc16a adopts a ribbon conformation with a simple beta-turn motif formed by residues Gly6, His7 and Asn8. qc16a causes depression symptom in mice when injected intracranially. Point mutation results showed that Asp1, His7 and Asn8 are all essential for the activity of qc16a. Electrophysiologically, qc16a has no strong effect on the whole-cell currents of neurons and the currents of Drosophila Shaker channels, human BK channels and Na(V)1.7 channels. Its specific target still remains to be identified. PMID- 21524673 TI - Ghrelin-mediated appetite regulation in the central nervous system. AB - The gut hormone and neuropeptide ghrelin was initially identified in the periphery as a compound released in the bloodstream in response to a negative energetic status. In the central nervous system (CNS), ghrelin mainly acts on the hypothalamus and the limbic system, with its best-known biological role being the regulation of appetitive functions. Recent research has shown that ghrelin is not an indispensable factor in the regulation of food intake. However, it plays a key role in the metabolic changes of lipids, mainly those involving hypothalamic NOS, AMPK, CaMKK2, CPT1 and UCP2 proteins. Ghrelin participates in the regulation of memory processes and the feeling of pleasure resulting from eating, both of which are metabolism-dependent and may be essential for the successful achievement of adaptive appetitive behavior. Ghrelin exerts its biological effect through a complicated network of neuroendocrine links, including the melanocortin and endocannabinoid systems. The activity of ghrelin is connected with circadian and annual fluctuations, which depend on seasons and food availability. PMID- 21524674 TI - The effects of linear and cyclic analogs of Locmi-DH, Dippu-DH(46) and Dippu DH(31) on appetitive behavior in Locusta migratoria. AB - The effects of analogs of the diuretic peptides Locmi-DH, Dippu-DH(46) and Dippu DH(31) on two aspects of appetitive behavior are investigated in previously food deprived nymphs of Locusta migratoria. The analogs tested are the C-terminal 15 mer and nonapeptides and their corresponding cyclic analogs. At a nominal dose of 1pmol injected per nymph, the linear fragments and their cyclic analogs of Dippu DH(46) display no significant effects on the latency to feed or on the length of the first meal in nymphs. However, at the same dose, the linear fragments of Dippu-DH(31) and their cyclic analogs, and analogs of Locmi-DH modulate appetitive behavior: they are anorexigenic in reducing the duration of the first meal, and generally increasing the latency to feed. The cyclic analogs of Dippu DH(31) are at least as effective as their linear counterparts in influencing these aspects of appetitive behavior in locust nymphs. PMID- 21524675 TI - FMRFamide-related peptides: anti-opiate transmitters acting in apoptosis. AB - Members of the FMRFamide-related peptide (FaRP) family are neurotransmitters, hormone-like substances and tumor suppressor peptides. In mammals, FaRPs are considered as anti-opiate peptides due to their ability to inhibit opioid signaling. Some FaRPs are asserted to attenuate opiate tolerance. A recently developed chimeric FaRP (Met-enkephalin-FMRFa) mimics the analgesic effects of opiates without the development of opiate-dependence, displaying a future therapeutical potential in pain reduction. In this review we support the notion, that opiates and representative members of the FaRP family show overlapping effects on apoptosis. Binding of FaRPs to opioid receptors or to their own receptors (G-protein linked membrane receptors and acid-sensing ion channels) evokes or suppresses cell death, in a cell- and receptor-type manner. With the dramatically increasing incidence of opiate abuse and addiction, understanding of opioid-induced cell death, and in this context FaRPs will deserve growing attention. PMID- 21524676 TI - Genetic study of two single nucleotide polymorphisms within corresponding microRNAs and susceptibility to tuberculosis in a Chinese Tibetan and Han population. AB - MicroRNAs (miRNA) are thought to play important roles in the pathogenesis of diseases. Single nucleotide polymorphisms (SNPs) within miRNAs can change their characteristics via altering their target selection and/or expression, resulting in functional and/or phenotypic changes. We decided to investigate the genetic association with pulmonary tuberculosis with 2 nucleotide variations within corresponding microRNAs regulating the Toll-like receptor (TLR)-mediating signal pathway. MiRNAs potentially regulating the TLR-mediating signal pathway were predicted via bioinformatics. Finally, 2 SNPs, rs2910164 G>C and rs3746444 T>C within miR-146a and miR-499, were selected as candidates in accordance with some criteria. SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism and validated by sequencing to demonstrate their association with susceptibility to pulmonary tuberculosis (PTB) in 337 PTB cases and 738 healthy controls, including 318 Tibetan and 757 Han individuals. Bioinformatics databases were searched to support the association between miRNAs and PTB. There was no association between rs3746444 and PTB risk (p = 0.118) in the Han population, but subjects carrying the C allele exhibited decreased PTB risk (odds ratio [OR] = 0.403 [95% confidence interval (95% CI) 0.278-0.583]). However, there was an association between rs3746444 and PTB in the Tibetan population, and individuals carrying the C allele exhibited increased PTB risk (OR = 1.870 [95% CI 1.218-2.871]). A polymorphism (rs2910164 G>C) indicated an association with PTB risk in both Tibetan (p = 0.031) and Han (p = 0.000) populations. However, the role of the G allele of rs2910164, like the C allele in rs3746444, differed in the Tibetan (OR = 1.509, p < 0.05) and Han (OR = 0.575, p < 0.05) groups. This is the first report to suggest that a genetic association with pulmonary tuberculosis with SNPs within the corresponding miRNAs potentially regulates the TLR signal pathway. It is interesting that both the G allele (rs2910164) and the C allele (rs3746444) play different roles in 2 populations. Further functional analysis of the SNP and its impact on mRNA targets is required to confirm the relationship between genotype and phenotype. PMID- 21524677 TI - Asphalt fume dermal carcinogenicity potential: I. dermal carcinogenicity evaluation of asphalt (bitumen) fume condensates. AB - Asphalt (bitumen) fume condensates collected from the headspace above paving and Type III built up roofing asphalt (BURA) tanks were evaluated in two-year dermal carcinogenicity assays in male C3H/HeNCrl mice. A third sample was generated from the BURA using a NIOSH laboratory generation method. Similar to earlier NIOSH studies, the BURA fume condensates were applied dermally in mineral oil twice per week; the paving sample was applied 7 days/week for a total weekly dose of 50 mg/wk in both studies. A single benign papilloma was observed in a group of 80 mice exposed to paving fume condensate at the end of the two-year study and only mild skin irritation was observed. The lab generated BURA fume condensate resulted in statistically significant (P<0.0001) increases in squamous cell carcinomas (35 animals or 55% of animals at risk). The field-matched BURA condensate showed a weaker but significant (P=0.0063) increase (8 carcinomas or 13% of animals) and a longer average latency (90 weeks vs. 76 for the lab fume). Significant irritation was observed in both BURA condensates. It is concluded that the paving fume condensate was not carcinogenic under the test conditions and that the field-matched BURA fume condensate produced a weak tumor response compared to the lab generated sample. PMID- 21524678 TI - Comparative protective effects of HI-6 and MMB-4 against organophosphorous nerve agent poisoning. AB - The oximes pralidoxime (2-PAM), its dimethanesulphonate salt derivative P2S, and obidoxime (toxogonin) are currently licensed and fielded for the treatment of chemical warfare (CW) organophosphorous (OP) nerve agent poisoning. While they are effective against several of the identified threat CW OP agents, they have little efficacy against others such as soman (GD) and cyclosarin (CF). In addition, they are also significantly less effective than other investigational oximes against the nerve agent known as Russian VX (RVX). Among the oximes currently being investigated, two in particular, HI-6 (asoxime) and MMB-4 (ICD 039, methoxime) have been proposed as replacement therapies for the currently licensed oximes. HI-6 has been safely used in individuals to treat OP insecticide poisoning, as well as in human volunteers, although its efficacy against OP nerve agent poisoning in humans cannot be demonstrated due to ethical considerations. It is currently available for use in defined military settings in Canada, Sweden and the Czech Republic, and is also under development in a number of other countries. The oxime MMB-4 has not yet been studied clinically, but is fielded by the Czech Republic, and is being developed by the United States armed services as a replacement for the currently fielded 2-PAM. This review compares the effectiveness of HI-6 and MMB-4 against nerve agent threats where comparisons can be made. HI-6 has been demonstrated to be generally a superior reactivator of nerve agent inhibited enzyme, particularly with human and non-human primate derived enzyme, and has also shown better protective effects against the lethality of most OP agents in a variety of species. Both compounds appear to be clearly superior to the available oximes, obidoxime and 2-PAM. PMID- 21524679 TI - Involvement of putative glutamate receptors in plant defence signaling and NO production. AB - Ionotropic glutamate receptors (iGluRs) are non-selective cation channels permeable to calcium, present in animals and plants. In mammals, glutamate is a well-known neurotransmitter and recently has been recognized as an immunomodulator. As animals and plants share common mechanisms that govern innate immunity with calcium playing a key role in plant defence activation, we have checked the involvement of putative iGluRs in plant defence signaling. Using tobacco cells, we first provide evidence supporting the activity of iGluRs as calcium channels and their involvement in NO production as reported in animals. Thereafter, iGluRs were shown to be activated in response to cryptogein, a well studied elicitor of defence response, and partly responsible for cryptogein induced NO production. However, other cryptogein-induced calcium-dependent events including anion efflux, H(2)O(2) production, MAPK activation and hypersensitive response (HR) did not depend on iGluRs indicating that different calcium channels regulate different processes at the cell level. We have also demonstrated that cryptogein induces efflux of glutamate in the apoplast by exocytosis. Taken together, our results demonstrate for the first time, an involvement of a putative iGluR in plant defence signaling and NO production, by mechanisms that show homology with glutamate mode of action in mammals. PMID- 21524680 TI - Antagonistic RNA aptamer specific to a heterodimeric form of human interleukin 17A/F. AB - Interleukin-17 (IL-17) is a pro-inflammatory cytokine produced primarily by a subset of CD4(+)T cells, called Th17 cells, that is involved in host defense, inflammation and autoimmune disorders. The two most structurally related IL-17 family members, IL-17A and IL-17F, form homodimeric (IL-17A/A, IL-17F/F) and heterodimeric (IL-17A/F) complexes. Although the biological significance of IL 17A and IL-17F have been investigated using respective antibodies or gene knockout mice, the functional study of IL-17A/F heterodimeric form has been hampered by the lack of an inhibitory tool specific to IL-17A/F. In this study, we aimed to develop an RNA aptamer that specifically inhibits IL-17A/F. Aptamers are short single-stranded nucleic acid sequences that are selected in vitro based on their high affinity to a target molecule. One selected aptamer against human IL-17A/F, AptAF42, was isolated by repeated cycles of selection and counterselection against heterodimeric and homodimeric complexes, respectively. Thus, AptAF42 bound IL-17A/F but not IL-17A/A or IL-17F/F. The optimized derivative, AptAF42dope1, blocked the binding of IL-17A/F, but not of IL-17A/A or IL-17F/F, to the IL-17 receptor in the surface plasmon resonance assay in vitro. Consistently, AptAF42dope1 blocked cytokine GRO-alpha production induced by IL 17A/F, but not by IL-17A/A or IL-17F/F, in human cells. An RNA footprinting assay using ribonucleases against AptAF42dope1 in the presence or absence of IL-17A/F revealed that part of the predicted secondary structure fluctuates between alternate forms and that AptAF42dope1 is globally protected from ribonuclease cleavage by IL-17A/F. These results suggest that the selected aptamer recognizes a global conformation specified by the heterodimeric surface of IL-17A/F. PMID- 21524681 TI - Biomarker-based dissection of neurodegenerative diseases. AB - The diagnosis of neurodegenerative diseases within neurology and psychiatry are hampered by the difficulty in getting biopsies and thereby validating the diagnosis by pathological findings. Biomarkers for other types of disease have been readily adopted into the clinical practice where for instance troponins are standard tests when myocardial infarction is suspected. However, the use of biomarkers for neurodegeneration has not been fully incorporated into the clinical routine. With the development of cerebrospinal fluid (CSF) biomarkers that reflect pathological events within the central nervous system (CNS), important clinical diagnostic tools are becoming available. This review summarizes the most promising biomarker candidates that may be used to monitor different types of neurodegeneration and protein inclusions, as well as different types of metabolic changes, in living patients in relation to the clinical phenotype and disease progression over time. Our aim is to provide the reader with an updated lexicon on currently available biomarker candidates, how far they have come in development and how well they reflect pathogenic processes in different neurodegenerative diseases. Biomarkers for specific pathogenetic processes would also be valuable tools both to study disease pathogenesis directly in patients and to identify and monitor the effect of novel treatment strategies. PMID- 21524683 TI - Using network context as a filter for miRNA target prediction. PMID- 21524682 TI - Development of biomarkers for multiple sclerosis as a neurodegenerative disorder. AB - Multiple sclerosis (MS) is the most common neurological disorder leading to permanent disability in young adults in the developed world. While traditionally conceived as an autoimmune inflammatory disease it is becoming increasingly evident that axonal and neuronal degeneration occur, at least partly independent of inflammation, and already at the earliest stages of the disease. In addition, it is the progressive neurodegeneration which determines the amount of accumulating clinical disability. Therefore, MS should be considered as a neurodegenerative disorder. Development of disease-modifying drugs to treat MS is currently highly dynamic. Already, several drugs have shown short-term efficacy to delay progression of clinical disability, but the ultimate aim is to halt disease progression. In this context, the development of sensitive, reliable and valid biomarkers to measure neurodegeneration is an indispensible need to facilitate successful informative clinical trials. While no such biomarker is currently fully established, several promising candidate biomarkers obtained with multimodal techniques, including cerebrospinal fluid and serum analysis, neuroimaging and neurophysiology, are presently developed and evaluated. This paper compiles an up-to-date critical review of the available knowledge of candidate biomarkers of neurodegenerative processes in MS. PMID- 21524684 TI - Differential effects of IGF-I, IGF-II and insulin in human preadipocytes and adipocytes--role of insulin and IGF-I receptors. AB - We compared insulin and IGF effects in adipocytes expressing IR (insulin receptors), and preadipocytes expressing IR and IGF-IR (IGF-I receptors). Treatment of adipocytes with insulin, IGF-II or IGF-I resulted in phosphorylation of IR. Order of potency was insulin>IGF-II>IGF-I. In preadipocytes IR, IGF-IR and insulin/IGF-I hybrid receptors (HR) were detected. Treatment of preadipocytes with IGF-I and IGF-II 10(-8)M resulted in activation of IGF-IR and IR whereas insulin was more potent in activating IR, with no effect on IGF-IR. In adipocytes glucose transport was 100-fold more sensitive to insulin than to IGFs and the maximal effect was higher with insulin. In preadipocytes glucose accumulation and DNA synthesis was equally sensitive to insulin and IGFs but the maximal effect was higher with IGF-I. In conclusion, insulin and IGF-I activate their cognate receptors and IGF-I also HR. IGF-II activates IR, IGF-IR and HR. Insulin and IGF I are partial agonists to each other's receptors. PMID- 21524685 TI - Clonidine as adjuvant for oxybuprocaine, bupivacaine or dextrorphan has a significant peripheral action in intensifying and prolonging analgesia in response to local dorsal cutaneous noxious pinprick in rats. AB - The aim of the study was to evaluate co-administration of clonidine with oxybuprocaine (ester type), bupivacaine (amide type) or dextrorphan (non-ester or non-amide type) and to see whether it could have a peripheral action in enhancing local anesthesia on infiltrative cutaneous analgesia in rats. Cutaneous analgesia was evaluated by a block of the cutaneous trunci muscle reflex (CTMR) in response to local dorsal cutaneous noxious pinprick in rats. The analgesic effect of the addition of clonidine with oxybuprocaine, bupivacaine or dextrorphan by subcutaneous injection was evaluated. On an ED(50) basis, the rank of drug potency was oxybuprocaine>bupivacaine>dextrorphan (P<0.01). Mixtures of clonidine (0.12MUmol) with oxybuprocaine, bupivacaine or dextrorphan (ED(50) or ED(95)) extended the duration of action and increased the potency on infiltrative cutaneous analgesia. Among these drugs, the addition of clonidine to bupivacaine (amide type) elicits the most effective cutaneous analgesia. Clonidine at the dose of 0.12 and 0.24MUmol did not produce cutaneous analgesia. Oxybuprocaine showed more potent cutaneous analgesia than bupivacaine or dextrorphan in rats. Co-administration of oxybuprocaine, bupivacaine or dextrorphan with clonidine increased the potency and duration on infiltrative cutaneous analgesia. The addition of clonidine to bupivacaine (amide type) elicits more effective cutaneous analgesia than oxybuprocaine (ester type) or dextrorphan (non-ester or non-amide type). PMID- 21524686 TI - Protective effects of catalpol on oligodendrocyte death and myelin breakdown in a rat model of chronic cerebral hypoperfusion. AB - Chronic cerebral hypoperfusion is thought to induce white matter lesions (WMLs) with oligodendrocyte (OLG) death and myelin breakdown. Although apoptosis is believed to be involved in the pathologic process of WMLs, effective therapies for such remain lacking. In the present study, we investigated whether catalpol, an iridoid glycoside, could act on oligodendrocytes (OLGs) and myelin sheaths in a rat chronic hypoperfusion model, and whether transcription factor cAMP responsive element binding protein (CREB) phosphorylation is involved in the resulting neuroprotection. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. On the 30th day after hypoperfusion, OLG loss and myelin disruption in the ischemic white matter were more severe and evident than in the sham control. Spatial memory was also more seriously impaired in rats after hypoperfusion. Treatment with catalpol significantly suppressed diminished OLGs and myelin breakdown, and promoted the recovery of cognitive decline. The expression of Bcl-2 and phosphorylated CREB (p CREB) was also significantly increased by catalpol treatment. In conclusion, catalpol could protect against hypoperfusion-induced WMLs and cognitive impairment through the p-CREB signaling pathway leading to downstream upregulation of Bcl-2. Our results suggest that catalpol may be a useful approach for treating cerebrovascular WMLs. PMID- 21524687 TI - An enriched environment reverses the synaptic plasticity deficit induced by chronic cerebral hypoperfusion. AB - Chronic cerebral hypoperfusion (CCH) leads to a long-term, inadequate blood supply in the brain, which eventually causes cognitive impairment. An enriched environment (EE) improves learning and memory by improving synaptic plasticity. The impact of an EE on cognitive impairment induced by CCH is not, however, well known. To investigate this possible effect, we permanently occluded the bilateral common carotid arteries (2-vessel occlusion) in rats to induce CCH and studied EE effects on cognitive impairment and synaptic plasticity following CCH. We found that EE treatment reversed spatial memory deficits induced by CCH. An EE also reversed the deficit in long-term potentiation following CCH, but the input output curves and paired-pulse facilitation were not affected. CCH led to reduced expression of phosphorylated CREB in the rats, but EE reversed this reduction. In addition, CCH reduced the expression of synaptophysin and microtubule-associated protein 2, whereas EE reversed this reduced expression. Thus, EE reversed CCH induced spatial cognitive impairment without affecting basal synaptic transmission or the release probability of presynaptic neurotransmitters. The EE effect probably resulted from the regulation of postsynaptic potentiation. PMID- 21524688 TI - Increased adult neurogenesis in the subventricular zone in a rat model of sepsis. AB - Neurogenesis occurs in the adult brain throughout the lives of all mammals. The dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles have been established as the primary sites of adult neurogenesis, and recent studies have shown that inflammation has a modulating effect on adult neurogenesis. However, only limited studies have investigated how neurogenesis is affected during sepsis and sepsis-associated encephalopathy. Therefore, we investigated adult neurogenesis in the cecal ligation and puncture (CLP) model of sepsis using a cell proliferation marker, 5-bromo-2'-deoxyuridine (BrdU). Twenty-four rats were placed into the following three groups: an un operated control group, a sham-operated group that underwent exactly the same procedures except for CLP, and a CLP group that survived surgical procedures and developed signs of sepsis. Rats were monitored for twenty-four hours before they were euthanized and their brains were harvested. Significantly higher numbers of BrdU-immunoreactive cells were observed in the SVZ of the lateral ventricles in the CLP group as compared with both control groups, while no significant difference was found in the number of DG granule cells between the three groups. The majority of BrdU-positive cells in the SVZ co-expressed the neuronal marker doublecortin but not the astrocytic marker glial fibrillary acidic protein. Taken together, our results suggest that sepsis induced by CLP in rats increases region specific cellular regeneration, in a possible attempt to compensate for the devastating effect of sepsis and sepsis-associated encephalopathy on the brain. PMID- 21524689 TI - Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: a potential model of geriatric depression. AB - Numerous studies support the hypothesis that deficiency of insulin-like growth factor I (IGF-1) in adults contributes to depression, but direct evidence is limited. Many psychological and pro-cognitive effects have been attributed to IGF 1, but appropriate animal models of adult-onset IGF-1 deficiency are lacking. In this study, we use a viral-mediated Cre-loxP system to knockout the Igf1 gene in either the liver, neurons of the CA1 region of the hippocampus, or both. Knockout of liver Igf1 reduced serum IGF-1 levels by 40% and hippocampal IGF-1 levels by 26%. Knockout of Igf1 in CA1 reduced hippocampal IGF-1 levels by 13%. The most severe reduction in hippocampal IGF-1 occurred in the group with knockouts in both liver and CA1 (36% reduction), and was associated with a 3.5-fold increase in immobility in the forced swim test. Reduction of either circulating or hippocampal IGF-1 levels did not alter anxiety measured in an open field and elevated plus maze, nor locomotion in the open field. Furthermore, local compensation for deficiencies in circulating IGF-1 did not occur in the hippocampus, nor were serum levels of IGF-1 upregulated in response to the moderate decline of hippocampal IGF-1 caused by the knockouts in CA1. We conclude that adult-onset IGF-1 deficiency alone is sufficient to induce a depressive phenotype in mice. Furthermore, our results suggest that individuals with low brain levels of IGF-1 are at increased risk for depression and these behavioral effects are not ameliorated by increased local IGF-1 production or transport. Our study supports the hypothesis that the natural IGF-1 decline in aging humans may contribute to geriatric depression. PMID- 21524690 TI - Noradrenergic regulation of period1 expression in spinal astrocytes is involved in protein kinase A, c-Jun N-terminal kinase and extracellular signal-regulated kinase activation mediated by alpha1- and beta2-adrenoceptors. AB - Our recent data suggest that noradrenaline (NA) regulates expression of Per1 mRNA in rat C6 cells, as a model of brain astrocytes, by two distinct NA-mediating pathways. Although C6 cells possess potential astrocyte-type characteristics, we hypothesize that astrocytes located in a distinct tissue or organ play specific roles consistent with their own unique functions in response to the surrounding environment. We have herein found in primary rat spinal astrocytes using real time RT-PCR that NA induced robust transient increases in Per1, Cry1, Cry2 and Bmal1 mRNA expression. Cry1, Cry2 and Bmal1 expressions induced by NA were attenuated by transfection of Per1 small interference RNA (siRNA). The effect of NA on Per1 expression was partially blocked by either prazosin (a selective antagonist of alpha1-adrenoceptor) or ICI118551 (a selective antagonist of beta2 adrenoceptor), and completely blocked by the combination of both antagonists. Treatment with H89 (a protein kinase A [PKA] inhibitor), SP600125 (a c-Jun N terminal kinase [JNK] inhibitor), or PD98059 (an extracellular signal-regulated kinase [ERK] inhibitor), partially inhibited NA-induced Per1 mRNA expression, and the combination of these three inhibitors inhibited expression to nearly a non stimulated level. Furthermore, NA phosphorylated not only ERK but also JNK1, an effect that was detected by western blotting. These actions were inhibited only by prazosin, and not by ICI118551. In addition, we found that NA induced phosphorylation of transcription-related proteins such as cAMP response element binding protein (CREB) and c-Jun. These phosphorylation processes were regulated through distinct pathways: CREB phosphorylation was dependent on the PKA and JNK pathways but c-Jun phosphorylation was mediated by the ERK and JNK pathways. These results suggest that Per1 plays a key role in noradrenergic regulation on clock gene expression in spinal astrocytes and activation of alpha1 and beta2 adrenoceptors are of importance in regulation of Per1 mRNA expression via PKA/JNK CREB and ERK/JNK-c-Jun cascades. PMID- 21524691 TI - Neuroprotection of Scutellarin is mediated by inhibition of microglial inflammatory activation. AB - Inhibition of microglial over-reaction and the inflammatory processes may represent a therapeutic target to alleviate the progression of neurological diseases, such as neurodegenerative diseases and stroke. Scutellarin is the major active component of Erigeron breviscapus (Vant.) Hand-Mazz, a herbal medicine in treatment of cerebrovascular diseases for a long time in the Orient. In this study, we explored the mechanisms of neuroprotection by Scutellarin, particularly its anti-inflammatory effects in microglia. We observed that Scutellarin inhibited lipopolysaccharide (LPS)-induced production of proinflammatory mediators such as nitric oxide (NO), tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta) and reactive oxygen species (ROS), suppressed LPS stimulated inducible nitric oxide synthase (iNOS), TNFalpha, and IL-1beta mRNA expression in rat primary microglia or BV-2 mouse microglial cell line. Scutellarin inhibited LPS-induced nuclear translocation and DNA binding activity of nuclear factor kappaB (NF-kappaB). It repressed the LPS-induced c-Jun N terminal kinase (JNK) and p38 phosphorylation without affecting the activity of extracellular signal regulated kinase (ERK) mitogen-activated protein kinase. Moreover, Scutellarin also inhibited interferon-gamma (IFN-gamma)-induced NO production, iNOS mRNA expression and transcription factor signal transducer and activator of transcription 1alpha (STAT1alpha) activation. Concomitantly, conditioned media from Scutellarin pretreated BV-2 cells significantly reduced neurotoxicity compared with conditioned media from LPS treated alone. Together, the present study reported the anti-inflammatory activity of Scutellarin in microglial cells along with their underlying molecular mechanisms, and suggested Scutellarin might have therapeutic potential for various microglia mediated neuroinflammation. PMID- 21524692 TI - Forebrain specific heparin-binding epidermal growth factor-like growth factor knockout mice show exacerbated ischemia and reperfusion injury. AB - Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a hypoxia inducible neuroprotective protein that also stimulates proliferation of neuronal precursor cells. In this study, we investigated the possible role of HB-EGF in ischemia and reperfusion injury by measuring the changes in its mRNA expression following focal cerebral ischemia. We also examined neural damage after a middle cerebral artery occlusion (MCAO) and reperfusion in ventral forebrain specific HB EGF knockout (KO) mice. The levels of HB-EGF mRNA in the cerebral cortex of wild type (WT) mice were significantly increased 3-24 h after MCAO and reperfusion. Cerebral infraction in HB-EGF KO mice was aggravated at 1 day and 6 days after MCAO and reperfusion compared with WT mice. The number of terminal deoxynucleotidyl transferase (TdT)-mediated dNTP nick end labeling (TUNEL) and an oxidative stress marker, 8-hydroxy-2'-deoxyguanosine (8-OHdG) positive cells, were higher in HB-EGF KO mice than in WT mice. On the other hand, fewer bromodeoxyuridine (BrdU) positive cells were found in the subventricular zone in HB-EGF KO mice compared with WT mice. These results indicate that HB-EGF may play a pivotal role in ischemia and reperfusion injury and that endogenously synthesized HB-EGF is necessary for both the neuroprotective effect and for regulation of cell proliferation in the subventricular zone. PMID- 21524693 TI - Morphine-conditioned cue alters c-Fos protein expression in the brain of crayfish. AB - With a highly organized stereotypic behavior and a simplified neuronal system that is characterized by cellular modularity, crayfish (Orconectes rusticus) represents an excellent model that we used in this study to explore how a drug conditioned-cue alters c-Fos protein expression in the brain of an invertebrate species. The first set of experiments revealed that a single injection of different doses of morphine (3.0 MUg/g, 6.0 MUg/g and 12.0 MUg/g) into the circulatory system of crayfish significantly increased locomotor activity. Repeated injections of morphine increased locomotion at lower doses (3.0 MUg/g and 6.0 MUg/g), and decreased locomotion at a higher dose of 12.0 MUg/g. The second experiment revealed that a repeated or single injection of morphine serves as reward when paired with a distinct visual environment. In the third experiment, we found that the c-Fos profile of morphine treated crayfish in an unconditioned environment did not show a significant increase from the basal level comparable to saline treated crayfish. The brains of crayfish were more active during exposure to the cue-elicited drug conditioned environment than the unconditioned environment. These results indicate that chronic morphine treatment alone is not sufficient to induce changes in the expression of c-Fos; instead, morphine-environment pairing in a specific context contributes to the expression of alterations in c-Fos regulation. The enhancement of c-Fos expression in the brain of crayfish seems to reflect the sensory or anticipatory facets of conditioning that suggests that potential and even unanticipated hypotheses in drug addiction can emerge from studies of addiction in crayfish. PMID- 21524694 TI - Sulfur mustard induces differentiation in human primary keratinocytes: opposite roles of p38 and ERK1/2 MAPK. AB - The chemical warfare agent sulfur mustard (SM) severely affects the regeneration capacity of skin. The underlying molecular and cellular mechanisms, however, are far from clear. Here, we demonstrate that normal human epidermal keratinocytes (NHEK) after exposure to SM strongly upregulated expression of keratin-1, involucrin, and loricrin, thus indicating premature epidermal differentiation. Furthermore, proliferation was repressed after treatment with SM. Analysis of intracellular signaling in NHEK revealed that SM enhances phosphorylation, nuclear translocation, and activity of the mitogen-activated protein kinases (MAPK) p38 and ERK1/2. Inhibition of p38 activity downregulated expression of keratin-1 and loricrin, whereas blockage of ERK1/2 significantly stimulated biosynthesis of these markers, pointing to opposite roles of p38 and ERK1/2 in the differentiation process. Simultaneous interruption of p38 and ERK1/2 activity led to a decreased expression of keratin-1 and loricrin. This suggests that NHEK differentiation is essentially controlled by p38 activity which may be negatively influenced by ERK1/2 activity. Functional analysis demonstrated that SM affects NHEK in their ability to migrate through extracellular matrix which can be rescued upon application of an inhibitor of p38 activity. Thus, our findings indicate that SM triggers premature differentiation in keratinocytes via p38 activity which may contribute to impaired regeneration of SM-injured skin. PMID- 21524695 TI - Evolution of and perspectives on therapeutic approaches to nerve agent poisoning. AB - After more than 70 years of considerable efforts, research on medical defense against nerve agents has come to a standstill. Major progress in medical countermeasures was achieved between the 50s and 70s with the development of anticholinergic drugs and carbamate-based pretreatment, the introduction of pyridinium oximes as antidotes, and benzodiazepines in emergency treatments. These drugs ensure good protection of the peripheral nervous system and mitigate the acute effects of exposure to lethal doses of nerve agents. However, pyridostigmine and cholinesterase reactivators currently used in the armed forces do not protect/reactivate central acetylcholinesterases. Moreover, other drugs used are not sufficiently effective in protecting the central nervous system against seizures, irreversible brain damages and long-term sequelae of nerve agent poisoning.New developments of medical counter-measures focus on: (a) detoxification of organophosphorus molecules before they react with acetylcholinesterase and other physiological targets by administration of stoichiometric or catalytic scavengers; (b) protection and reactivation of central acetylcholinesterases, and (c) improvement of neuroprotection following delayed therapy.Future developments will aim at treatment of acute and long-term effects of low level exposure to nerve agents, research on alternative routes for optimizing drug delivery, and therapies. Though gene therapy for in situ generation of bioscavengers, and cell therapy based on neural progenitor engraftment for neuronal regeneration have been successfully explored, more studies are needed before practical medical applications can be made of these new approaches. PMID- 21524696 TI - Neurobehavioral and physiological effects of low doses of polybrominated diphenyl ether (PBDE)-99 in male adult rats. AB - Polybrominated diphenyl ethers (PBDEs) are flame retardants. Because of their high lipophilicity and persistence, PBDEs bioaccumulate in all abiotic and biological matrices. The aim of this study was to investigate the long-term neurobehavioral and physiological effects of exposure to environmental doses of PBDE-99 in adult rats. Rats received a daily administration of PBDE-99 for 90 days by oral gavage at 0.15, 1.5 and 15MUg/kg, doses which are relevant of human exposure. Before and after the 90 days of exposure, behavioral tests including the open-field and the elevated plus-maze tests for locomotor activity and anxiety, and the Morris water maze for spatial learning were conducted. Physiological measures such as body weight, food and water consumption, organs weight, hepatic enzymes levels and PBDE-99 concentration in adipose tissue were also evaluated at the end of exposure. There was no effect on body weight, food and water consumption, organs weight, hepatic enzymes levels despite rising PBDE 99 concentration in adipose tissue with the doses tested. Moreover, there was no effect on locomotor activity and exploration, and spatial learning. Deleterious effects of PBDE-99 at high doses have often been highlighted in many studies after an acute dose whereas exposure during 90 days at realistic doses would have no significant effect in adult rats. PMID- 21524697 TI - Evaluation of Lysimachia christinae Hance extracts as anticholecystitis and cholagogic agents in animals. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lysimachia christinae Hance is one of the herbs commonly used in traditional Chinese medicine for the treatment of cholecystitis and cholagogic efficiency. AIMS OF THE STUDY: The water extract of Lysimachia christinae Hance was investigated to see if it possesses cholecystitis and cholagogic effects through traditional pathways. MATERIALS AND METHODS: Lithocholic acid (LCA) and Escherichia coli were used to induce cholecystitis in adult guinea pigs. The present study evaluated the cholagogic effects of LCHE treatment on bile secretion and bile emptying in Sprague-Dawley rats and male Kunming mice. RESULTS: The results showed that LCHE not only produced excellent anticholecystitis effects but also improved lesion severity in gallbladders induced by LCA. Similarly, LCHE administered to animals in the high-dose group exhibited an antibacterial effect in acute cholecystitis, and treatment with a mid-range or a high dose of LCHE resulted in an antipyretic effect, however, three doses of LCHE treatment groups had no effect on pathological change induced by Escherichia coli in gallbladder. Treatment with a high dose of LCHE significantly promoted bile secretion (0-90min, P<0.01), and treatment with a mid range dose also significantly promoted bile secretion (30-60min P<0.05). Furthermore, treatment with a high dose of LCHE significantly promoted bile emptying (P<0.01). CONCLUSIONS: Our results demonstrate that LCHE exhibits a marked anticholecystitis and cholagogic activity in animals, which supports previous claims of its use in traditional Chinese medicine. PMID- 21524698 TI - Identification of novel pregnane X receptor activators from traditional Chinese medicines. AB - AIM OF THE STUDY: To investigate the ability of traditional Chinese medicines (TCMs) and their bioactive compounds to activate pregnane X receptor (PXR) signalling pathway. MATERIALS AND METHODS: We screened ethanol extracts of 28 commonly used TCMs for their capability to induce cytochrome P450 3A4 (CYP3A4) via PXR signalling pathway using a cell-based reporter gene assay combined with RT-PCR analysis. In addition, 34 bioactive components from these TCMs were examined for their potential to activate PXR. RESULTS: Our observations showed that 22 ethanol extracts and 8 compounds could activate human PXR and induce CYP3A4 reporter construct in HepG2 cells. Among them, Ginkgo biloba, Ligusticum chuanxiong, Chinese angelica, prepared Rehmannia root, Epimedium brevicornum, Atractylodes macrocephala, Schisandra chinensis, Paeonia lactiflora, Ophiopogon japonicus, Polygonum multiflorum, Coptis chinensis, Artemisia scoparia, Trichosanthes kirilowii, Silybum marianum, Gardenia fruit and Lycium chinense could strongly trans-activate PXR. Moreover, ligustilide, schisantherin A, berberine hydrochloride and trans-resveratrol were identified for the first time as efficacious PXR agonists. CONCLUSIONS: Twenty-two TCM ethanol extracts and eight bioactive compounds could activate PXR signalling pathway and induce CYP3A4 reporter gene. Therefore, caution should be taken when these PXR activators are used in combination with prescribed drugs metabolized by CYP3A4. PMID- 21524699 TI - Atractylenolide II induces G1 cell-cycle arrest and apoptosis in B16 melanoma cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Atractylenolide II (AT-II) is a sesquiterpene compound isolated from the dried rhizome of Atractylodes macrocephala (Baizhu in Chinese), which is traditionally prescribed for melanoma treatment by Chinese medicine practitioners. Our previous study showed that AT-II can inhibit B16 cells proliferation. Here we investigate the mechanistic basis for the anti proliferative activity of AT-II in B16 melanoma cells. MATERIALS AND METHODS: Cell viability was examined by MTT assay. Cell cycle distribution and apoptosis were determined by flow cytometry. Protein expression was determined by Western blotting. RESULTS: AT-II treatment for 48 h dose-dependently inhibited cell proliferation with an IC(50) of 82.3 MUM, and induced G1 phase cell cycle arrest. Moreover, treatment with 75 MUM AT-II induced apoptosis. These observations were associated with the decrease of the expression of Cdk2, phosphorylated-Akt, phosphorylated-ERK and Bcl-2, the increase of the expression of phosphorylated p38, phosphorylated-p53, p21, p27, and activation of caspases-8, -9 and -3. In addition, a chemical inhibitor of p53, PFTalpha, significantly decreased AT-II mediated growth inhibition and apoptosis. CONCLUSIONS: We demonstrated that the G1-arresting and apoptotic effects of AT-II in B16 cells involve p38 activation as well as ERK and Akt inactivation, and the cytotoxic/apoptotic effects of AT-II are potentially p53 dependent. These findings provided chemical and pharmacological basis for the traditional application of Baizhu in melanoma treatment. PMID- 21524700 TI - Labisia pumila var. alata reduces bacterial load by inducing uroepithelial cell apoptosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Labisia pumila var. alata (LPva) is a traditional medicinal herb used by Malaysian women to treat many ailments of the genitourinary tract. Its phytoestrogenic properties suggest potential to prevent recurrent urinary tract infection (UTI) in women post menopause. The aim of this study was therefore to investigate the mechanisms of action of LPva in an in vitro model of UTI. MATERIALS AND METHODS: Bladder epithelial cell lines T24 and 5637 and uropathogenic Escherichia coli (UPEC) strain CFT073 were used to model uroepithelial infection. The ability of LPva to induce programmed cell death was tested using the Annexin-V-FLUOS and TUNEL assays. Expression of caveolin-1, beta1 integrin and antimicrobial peptides HBD-2 and LL-37 in response to LPva treatment and/or infection, was assessed using RT real-time PCR. Effects on protein expression were confirmed by Western blot analysis. Sensitivity and yeast agglutination assays were employed to determine if LPva had antimicrobial activities and/or interacted with type 1 fimbriae, respectively. Finally, bacterial adherence and invasion to cells treated with LPva was examined. RESULTS: LPva induced uroepithelial apoptosis which was coupled with upregulated expression of caveolin-1 and downregulation of beta1 integrin. LPva did not exhibit direct antimicrobial properties and did not influence antimicrobial peptide levels in cells. Additionally, LPva did not interact with type 1 fimbriae and did not affect adherence in comparison to non-treated control cells. However, LPva significantly reduced the number of intracellular UPEC in bladder epithelial cells. CONCLUSIONS: Our findings suggest that LPva has beneficial applications against UPEC infection due to its ability to induce programmed cell death and reduce bacterial invasion of the uroepithelium. PMID- 21524701 TI - Targeted sequencing of the human X chromosome exome. AB - We used a RainDance Technologies (RDT) expanded content library to enrich the human X chromosome exome (2.5 Mb) from 26 male samples followed by Illumina sequencing. Our multiplex primer library covered 98.05% of the human X chromosome exome in a single tube with 11,845 different PCR amplicons. Illumina sequencing of 24 male samples showed coverage for 97% of the targeted sequences. Sequence from 2 HapMap samples confirmed missing data rates of 2-3% at sites successfully typed by the HapMap project, with an accuracy of at least ~99.5% as compared to reported HapMap genotypes. Our demonstration that a RDT expanded content library can efficiently enrich and enable the routine sequencing of the human X chromosome exome suggests a wide variety of potential research and clinical applications for this platform. PMID- 21524702 TI - Regional differences in the expression of laminin isoforms during mouse neural tube development. AB - Many significant human birth defects originate around the time of neural tube closure or early during post-closure nervous system development. For example, failure of the neural tube to close generates anencephaly and spina bifida, faulty cell cycle progression is implicated in primary microcephaly, while defective migration of neuroblasts can lead to neuronal migration disorders such as lissencephaly. At the stage of neural tube closure, basement membranes are becoming organised around the neuroepithelium, and beneath the adjacent non neural surface ectoderm. While there is circumstantial evidence to implicate basement membrane dynamics in neural tube and surface ectodermal development, we have an incomplete understanding of the molecular composition of basement membranes at this stage. In the present study, we examined the developing basement membranes of the mouse embryo at mid-gestation (embryonic day 9.5), with particular reference to laminin composition. We performed in situ hybridization to detect the mRNAs of all eleven individual laminin chains, and immunohistochemistry to identify which laminin chains are present in the basement membranes. From this information, we inferred the likely laminin variants and their tissues of origin: that is, whether a given basement membrane laminin is contributed by epithelium, mesenchyme, or both. Our findings reveal major differences in basement composition along the body axis, with the rostral neural tube (at mandibular arch and heart levels) exhibiting many distinct laminin variants, while the lumbar level where the neural tube is just closing shows a much simpler laminin profile. Moreover, there appears to be a marked difference in the extent to which the mesenchyme contributes laminin variants to the basement membrane, with potential contribution of several laminins rostrally, but no contribution caudally. This information paves the way towards a mechanistic analysis of basement membrane laminin function during early neural tube development in mammals. PMID- 21524703 TI - Effect of 17beta-estradiol on adhesion of Mytilus galloprovincialis hemocytes to selected substrates. Role of alpha2 integrin subunit. AB - The process of hemocyte adhesion to extracellular matrix (ECM) proteins plays a crucial role in cell immunity. In most of these interactions between ECM proteins and cells, integrins are involved. The results of the present study showed that incubation of Mytilus galloprovincialis hemocytes with 17beta-estradiol caused significant increased adhesion of hemocytes to ECM proteins and specifically to laminin-1, collagen IV and oxidized collagen IV, in relation to control cells. The adhesion of hemocytes to oxidized collagen was significantly higher than to either collagen IV or to laminin-1. In accordance with this, inhibition of either NADPH oxidase or nitric oxide (NO) synthase attenuated 17beta-estradiol effect on hemocyte adhesion, suggesting that the high levels of free radicals, produced after 17beta-estradiol effect, could contribute to the high adhesion of hemocytes to laminin-1 and collagen IV. The implication of ROS was further confirmed by the use of the oxidant rotenone, which caused elevation of cell adhesion in relation to control and by the antioxidant NAC which attenuated 17beta-estradiol effect. The mechanism of 17beta-estradiol induced adhesion to laminin-1, collagen IV and oxidized collagen IV involves a large number of intracellular components, as Na+/H+ exchanger (NHE), all isoforms of protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K) and c-jun N-terminal kinase (JNK) as well as alpha2 integrin subunit. Maintenance of high cyclic adenosine-3'-5'-monophosphate (cAMP) levels caused non significant higher adhesion of hemocytes to ECM proteins in relation to control cells. Our results showed that 17beta-estradiol caused a significant increase in alpha2 integrin subunit levels, which was reduced after inhibition of NHE, PI3K, PKC, NO synthase, NADPH oxidase and JNK. In addition, our results showed that apart from 17beta-estradiol, high cAMP and high ROS levels caused significantly higher induction of alpha2 integrin subunit levels in relation to control. Our results imply a potential involvement of cAMP in immune responses of Mytilus hemocytes, which needs further investigation. PMID- 21524704 TI - Brain functional integration decreases during propofol-induced loss of consciousness. AB - Consciousness has been related to the amount of integrated information that the brain is able to generate. In this paper, we tested the hypothesis that the loss of consciousness caused by propofol anesthesia is associated with a significant reduction in the capacity of the brain to integrate information. To assess the functional structure of the whole brain, functional integration and partial correlations were computed from fMRI data acquired from 18 healthy volunteers during resting wakefulness and propofol-induced deep sedation. Total integration was significantly reduced from wakefulness to deep sedation in the whole brain as well as within and between its constituent networks (or systems). Integration was systematically reduced within each system (i.e., brain or networks), as well as between networks. However, the ventral attentional network maintained interactions with most other networks during deep sedation. Partial correlations further suggested that functional connectivity was particularly affected between parietal areas and frontal or temporal regions during deep sedation. Our findings suggest that the breakdown in brain integration is the neural correlate of the loss of consciousness induced by propofol. They stress the important role played by parietal and frontal areas in the generation of consciousness. PMID- 21524705 TI - Mitochondrial phylogeny of the Chrysisignita (Hymenoptera: Chrysididae) species group based on simultaneous Bayesian alignment and phylogeny reconstruction. AB - The ignita species group within the genus Chrysis includes over 100 cuckoo wasp species, which all lead a parasitic lifestyle and exhibit very similar morphology. The lack of robust, diagnostic morphological characters has hindered phylogenetic reconstructions and contributed to frequent misidentification and inconsistent interpretations of species in this group. Therefore, molecular phylogenetic analysis is the most suitable approach for resolving the phylogeny and taxonomy of this group. We present a well-resolved phylogeny of the Chrysis ignita species group based on mitochondrial sequence data from 41 ingroup and six outgroup taxa. Although our emphasis was on European taxa, we included samples from most of the distribution range of the C. ignita species group to test for monophyly. We used a continuous mitochondrial DNA sequence consisting of 16S rRNA, tRNA(Val), 12S rRNA and ND4. The location of the ND4 gene at the 3' end of this continuous sequence, following 12S rRNA, represents a novel mitochondrial gene arrangement for insects. Due to difficulties in aligning rRNA genes, two different Bayesian approaches were employed to reconstruct phylogeny: (1) using a reduced data matrix including only those positions that could be aligned with confidence; or (2) using the full sequence dataset while estimating alignment and phylogeny simultaneously. In addition maximum-parsimony and maximum-likelihood analyses were performed to test the robustness of the Bayesian approaches. Although all approaches yielded trees with similar topology, considerably more nodes were resolved with analyses using the full data matrix. Phylogenetic analysis supported the monophyly of the C. ignita species group and divided its species into well-supported clades. The resultant phylogeny was only partly in accordance with published subgroupings based on morphology. Our results suggest that several taxa currently treated as subspecies or names treated as synonyms may in fact constitute separate species. Our study provides a solid basis for further systematic investigations of this enigmatic insect group. PMID- 21524706 TI - Fine-scale genetic structure, phylogeny and systematics of threatened crayfish species complex. AB - Systematic uncertainties in the crayfish Austropotamobius pallipes are well grounded by the number of species and subspecies described using different approaches, causing scientists to define this taxon as "complex". However, a key task that conservation programmes are facing regarding the recent and drastic decline of European populations, is the coherent systematic classification of this threatened species. Here we present results obtained by coupling mtDNA and genome analysis suggestive of a novel evolutionary framework to explain the relationships among phylogenetic lineages of A. pallipes. The direct sequencing of mtDNA COI gene fragment revealed a strong geographic structure with four distinct haplogroups separated by a range of 5-25 mutations. However, mitochondrial data were not supported by genomic fingerprinting based on 535 AFLP polymorphisms. Nuclear markers showed an unexpected moderate level of genetic differentiation and the absence of any geographic structure. Consequently, this study proposes that the taxonomic hypothesis of a single species of A. pallipes settling the Italian continental waters, is affected by complex evolutionary events. To solve the paradox, we hypothesized an evolutive scenario in which the separation of ancient mtDNA lineages likely occurred before the latest glacial periods. However, the speciation process remained incomplete due to secondary intensive postglacial contacts that forced the mingling of the genomes, and confounds the phylogeographic signature still detectable within mtDNA. Postglacial dispersion and the following demographic events, such as founder effects, drift and bottlenecks, abruptly depleted the local mtDNA variation, and shaped the current genetic population structure of white-clawed crayfish. PMID- 21524707 TI - Weight gain and the risk of total hip replacement a population-based prospective cohort study of 265,725 individuals. AB - OBJECTIVE: To study the association between change in the body mass index (BMI) at different ages and the risk of a later total hip replacement (THR) due to primary osteoarthritis (OA). DESIGN: A total of 265,725 individuals who had two repeated measurements of weight and height were included from national health screenings. These individuals were followed prospectively. The data were matched with the Norwegian Arthroplasty Register and 4,442 of these individuals were identified as having received a THR for primary OA. Cox proportional hazard regression was used to calculate sex-specific relative risks for having a THR according to age at screening and BMI change. RESULTS: Men and women aged 20 years or younger at the first screening in the quartile with the greatest BMI change per year had more than twice the risk of later having a THR compared with those in the quartile with the smallest BMI change per year. For men older than 30 years at the first screening, there was no relationship between BMI gain, or weight gain, and later risk of THR. For older women, BMI gain was associated with risk of THR, but to a lesser degree than in younger women. CONCLUSION: There was a clear relationship between change in BMI and the risk of later THR in young men and women, whereas the association was absent in older men and weaker in older women. It is important to focus on weight control to prevent future OA, and the preventive strategy should be focused on the young population. PMID- 21524708 TI - MicroRNA regulation of neural plasticity and memory. AB - MicroRNAs (miRNAs) are a class of endogenous, small non-coding RNAs that mediate post-transcriptional gene silencing by complementary binding to the 3'untranslated region of target mRNAs. The transient and localized expression of these small RNAs in dendrites, their capacity to respond in an activity-dependent manner, and the observation that a single miRNA can simultaneously regulate many genes, make brain-specific miRNAs ideal candidates for the fine-tuning of gene expression associated with neural plasticity and memory formation. Here we provide an overview of the current literature, which supports the proposal that non-coding RNA-mediated regulation of gene function represents an important, yet underappreciated, layer of epigenetic control that contributes to learning and memory in the adult brain. PMID- 21524709 TI - Intracellular calcium chelation and pharmacological SERCA inhibition of Ca2+ pump in the insular cortex differentially affect taste aversive memory formation and retrieval. AB - Variation in intracellular calcium concentration regulates the induction of long term synaptic plasticity and is associated with a variety of memory/retrieval and learning paradigms. Accordingly, impaired calcium mobilization from internal deposits affects synaptic plasticity and cognition in the aged brain. During taste memory formation several proteins are modulated directly or indirectly by calcium, and recent evidence suggests the importance of calcium buffering and the role of intracellular calcium deposits during cognitive processes. Thus, the main goal of this research was to study the consequence of hampering changes in cytoplasmic calcium and inhibiting SERCA activity by BAPTA-AM and thapsigargin treatments, respectively, in the insular cortex during different stages of taste memory formation. Using conditioned taste aversion (CTA), we found differential effects of BAPTA-AM and thapsigargin infusions before and after gustatory stimulation, as well as during taste aversive memory consolidation; BAPTA-AM, but not thapsigargin, attenuates acquisition and/or consolidation of CTA, but neither compound affects taste aversive memory retrieval. These results point to the importance of intracellular calcium dynamics in the insular cortex during different stages of taste aversive memory formation. PMID- 21524710 TI - Effect of banana consumption on faecal microbiota: a randomised, controlled trial. AB - Banana is a widely consumed fruit, which contains considerable amounts of potential prebiotic indigestible carbohydrates. In our randomised, controlled trial we aimed to evaluate the in vivo prebiotic effect of banana consumption on faecal microbiota. Thirty-four healthy women participated in the study, having Body Mass Index (BMI) 24-30 kg/m(2), age 19-45 years, without history of gastrointestinal disease and no antibiotic and other medication use two months prior the initiation and during the study. All women were asked to maintain their usual dietary habits for 60 days and they were randomly assigned to consume twice a day a pre-meal snack, either one medium banana, or one cup of banana-flavoured drink or one cup of water (control group). Stool samples were collected at baseline, on days 30 and 60 of intervention for enumeration of total anaerobes, bifidobacteria and lactobacilli by plate count techniques, as well as for pH and short chain fatty acids (SCFAs) measurement. Gastrointestinal symptoms were also recorded. Mean bifidobacterial levels were increased only in the banana group both at 30 and 60 days of intervention, but this change did not reach a statistical significance. No significant overall differences in the total concentrations and molar ratios of SCFAs were detected according to dietary intervention. Analysis of the gastrointestinal symptoms records revealed significantly lower bloating levels in the banana group, compared to controls, at 26-35 days (p = 0.009) and 51-60 days (p = 0.010). Banana consumption had also no adverse effects on evacuation patterns. We concluded that daily consumption of bananas is a well-tolerated eating behaviour, which may induce bifidogenesis in healthy women experiencing body weight problems. PMID- 21524711 TI - Antibacterial activity of different honeys against pathogenic bacteria. AB - To study the antimicrobial activity of honey, 60 samples of various botanical origin were evaluated for their antimicrobial activities against 16 clinical pathogens and their respective reference strains. The microbiological quality of honeys and the antibiotic susceptibility of the various isolates were also examined. The bioassay applied for determining the antimicrobial effect employs the well-agar diffusion method and the estimation of minimum active dilution which produces a 1mm diameter inhibition zone. All honey samples, despite their origin (coniferous, citrus, thyme or polyfloral), showed antibacterial activity against the pathogenic and their respective reference strains at variable levels. Coniferous and thyme honeys showed the highest activity with an average minimum dilution of 17.4 and 19.2% (w/v) followed by citrus and polyfloral honeys with 20.8 and 23.8% respectively. Clinical isolates of Staphylococcus aureus subsp. aureus, Escherichia coli, Salmonella enterica subsp. Enterica, Streptococcus pyogenes, Bacillus cereus and Bacillus subtilis were proven to be up to 60% more resistant than their equal reference strains thus emphasizing the variability in the antibacterial effect of honey and the need for further research. PMID- 21524712 TI - Spiramycin resistance in human periodontitis microbiota. AB - PURPOSE: The occurrence of in vitro resistance to therapeutic concentrations of spiramycin, amoxicillin, and metronidazole was determined for putative periodontal pathogens isolated in the United States. MATERIALS AND METHODS: Subgingival plaque specimens from 37 consecutive adults with untreated severe periodontitis were anaerobically cultured, and isolated putative periodontal pathogens were identified to a species level. In vitro resistance to spiramycin at 4 MUg/ml, amoxicillin at 8 MUg/ml, and/or metronidazole at 16 MUg/ml was noted when putative periodontal pathogen growth was noted on the respective antibiotic supplemented primary culture plates. RESULTS: A total of 18 (48.7%) subjects yielded antibiotic-resistant putative periodontal pathogens with spiramycin at 4 MUg/ml in drug-supplemented primary isolation plates, as compared to 23 (62.2%) subjects with amoxicillin at 8 MUg/ml, and 10 (27.0%) subjects with metronidazole at 16 MUg/ml. Spiramycin in vitro resistance occurred among species of Fusobacterium nucleatum (44.4% of organism-positive subjects), Prevotella intermedia/nigrescens (11.1%), Parvimonas micra (10.8%), Streptococcus constellatus (10%), Streptococcus intermedius (10%), Porphyromonas gingivalis (6.7%), and Tannerella forsythia (5.3%). Amoxicillin in vitro resistance was found in P. intermedia/nigrescens (55.5%), T. forsythia (15.8%), S. constellatus (10%), F. nucleatum (5.6%), and P. micra (2.7%). Only S. constellatus (70%) and S. intermedius (40%) exhibited in vitro resistance to metronidazole. When subject based resistance data for spiramycin and metronidazole were jointly considered, all isolated putative periodontal pathogens were inhibited in vitro by one or the other of the antibiotic concentrations, except for one strain each of S. constellatus and S. intermedius from one study subject. Similarly, either amoxicillin or metronidazole at the drug concentrations tested inhibited in vitro all recovered putative periodontal pathogens, except S. constellatus in one subject. CONCLUSIONS: In vitro spiramycin resistance among putative periodontal pathogens of United States origin occurred in approximately one-half of severe periodontitis patients evaluated, particularly among subgingival F. nucleatum species. In vitro resistance patterns also suggest that therapeutic concentrations of spiramycin plus metronidazole may have potential antimicrobial efficacy in non-Aggregatibacter actinomycetemcomitans-associated periodontitis similar to amoxicillin plus metronidazole, which may be beneficial, where spiramycin is clinically available, for patients hypersensitive to amoxicillin or other beta-lactam antibiotics. PMID- 21524713 TI - State of the art; microbiology in health and disease. Intestinal bacterial flora in autism. AB - Autism of the regressive variety is selected as an example of the importance of intestinal bacterial microflora in disease other than classical infection. Our studies have indicated that intestinal bacteria play a role in this disease since it responds to oral vancomycin, a drug that is not absorbed from the GI tract. Pyrosequencing studies document an abnormal gut microflora in regressive autism subjects as compared to controls. Finally, we present preliminary evidence suggesting that Desulfovibrio may play a key role in this disease. PMID- 21524714 TI - Interpreting the epidemiology and natural history of bacterial vaginosis: are we still confused? AB - Bacterial vaginosis (BV) is a common cause of vaginitis and increases women's risk of pelvic inflammatory disease, adverse pregnancy outcomes, and risk of STD/HIV acquisition. The etiology of BV is unclear, though it is believed to involve loss of vaginal hydrogen peroxide-producing lactobacilli and acquisition of complex bacterial communities that include many fastidious BV-associated bacteria (BVAB) that have recently been detected using PCR methods. Treatment failure (persistence) is common, and may be facilitated by unprotected sex. Potential contributions to BV and BV persistence include (1) sexual partners as a reservoir for BVAB; (2) specific sexual practices, including male partners' condom use; and (3) the composition of the vaginal microbiota involved in BV. Specific BVAB in the Clostridiales order may predict BV persistence when detected pre-treatment, and have been detected in men whose female partners have BV. BVAB may be associated with unprotected sexual behavior and failure of BV to resolve in women, supporting the hypothesis that BVAB colonization of male genitalia may serve as a reservoir for re-infection of female partners. Moreover, specific sexual practices may favor vaginal colonization with certain BVAB that have been associated with persistence. This review provides background on BV, and discusses the epidemiologic and microbiologic data to support a role for acquisition of BVAB and how this process might differ among subsets of women. PMID- 21524715 TI - Photomicronucleus assay of phototoxic and pseudophotoclastogenic chemicals in human keratinocyte NCTC2544 cells. AB - Photochemical genotoxicity was evaluated in human keratinocyte NCTC2544 cells. The cells were pre-treated with photogenotoxic or pseudophotoclastogenic chemicals and irradiated with a solar-simulator for 50min at a total UV dose of 5J/cm(2) or placed in the dark for the same period. After washing, the cells were cultured for 1.5-2 cell cycles with fresh culture medium. At the end of culturing, slide specimens were prepared and examined for micronucleus formation. 8-Methoxypsoralen, a photogenotoxic chemical, strongly induced micronucleated cells with UV irradiation but not under non-irradiation conditions. Therefore, NCTC2544 cells were subjected to further investigation to evaluate the possible photogenotoxicity of other chemicals. 6-Methylcoumarin, 3,3',4',5 tetrachlorosalicylanilide and protoporphyrin IX disodium salt, which are all known phototoxic substances, induced micronucleated cells with irradiation but not in the non-irradiation state. These phototoxic substances were confirmed to be photogenotoxic. Tetrabenzoporphine and 5-aminolevulinic acid, which are used for photodynamic therapy, showed phototoxicity. However, these chemicals did not induce micronucleated cells in the irradiated or non-irradiated state, suggesting a lack of photogenotoxicity. Among 3 pseudophotoclastogenic chemicals having no light absorbance at 290-700nm, neither cycloheximide nor disulfoton induced micronucleated cells with or without irradiation; zinc oxide induced micronucleated cells with irradiation and, to a lesser extent, without irradiation. Based on the results of the photogenotoxicity assays of these 9 chemicals, NCTC2544 cells are considered to be a suitable test system to evaluate the photogenotoxic potential of chemicals. PMID- 21524716 TI - Organic extracts of urban air pollution particulate matter (PM2.5)-induced genotoxicity and oxidative stress in human lung bronchial epithelial cells (BEAS 2B cells). AB - Traffic is a major source of particulate matter (PM), and ultrafine particulates and traffic intensity probably contribute significantly to PM-related health effects. As a strong relationship between air pollution and motor vehicle originated pollutants has been shown to exist, air pollution genotoxicity studies of urban cities are steadily increasing. In Korea, the death rate caused by lung cancer is the most rapidly increased cancer death rate in the past 10 years. In this study, genotoxicity of PM2.5 (<2.5MUm in aerodynamic diameter particles) collected from the traffic area in Suwon City, Korea, was studied using cultured human lung bronchial epithelial cells (BEAS-2B) as a model system for the potential inhalation health effects. Organic extract of PM2.5 (CE) generated significant DNA breakage and micronucleus formation in a dose-dependent manner (1MUg/cm(3)-50MUg/cm(3)). In the acid-base-neutral fractionation of PM2.5, neutral samples including the aliphatic (F3), aromatic (F4) and slightly polar (F5) fractions generated significant DNA breakage and micronucleus formation. These genotoxic effects were significantly blocked by scavenging agents [superoxide dismutase (SOD), sodium selenite (SS), mannitol (M), catalase (CAT)]. In addition, in the modified Comet assay using endonucleases (FPG and ENDOIII), CE and its fractions (F3, F4, and F5) increased DNA breakage compared with control groups, indicating that CE and fractions of PM2.5 induced oxidative DNA damage. These results clearly suggest that PM2.5 collected in the Suwon traffic area has genotoxic effects and that reactive oxygen species may play a distinct role in these effects. In addition, aliphatic/chlorinated hydrocarbons, PAH/alkylderivatives, and nitro-PAH/ketones/quinones may be important causative agents of the genotoxic effects. PMID- 21524717 TI - Herpes simplex virus type 2 and cancer: a medical geography approach. AB - Herpes simplex virus type-2 (HSV-2) has been identified as a possible aetiological agent of cancer in humans, especially prostate cancer, but results remain controversial. Here, we have addressed this question using a medical geography approach based on the national incidence of various cancers and seroprevalence of HSV-2 in 64 countries worldwide. We corrected reports of cancer incidence for national gross domestic product (GDP) because living in a wealthy nation likely increases the probability of having a cancer detected. Data were also corrected for latitude and diet. Our analysis not only confirms that prostate cancer and HSV-2 seroprevalence are positively associated, but it also reveals the existence of a positive relationship between HSV-2 and melanoma incidence in both men and women. These results, though correlational, suggest that HSV-2 should continue to be investigated as a possible oncogenic pathogen of humans. PMID- 21524719 TI - Sex differences in exertional dyspnea in patients with mild COPD: physiological mechanisms. AB - The purpose of this study was to evaluate the physiological basis for sex differences in exercise-induced dyspnea in patients with mild COPD. We compared operating lung volumes, breathing pattern and dyspnea during incremental cycling in 32 men (FEV(1)=86+/-10% predicted) and women (FEV(1)=86+/-12% predicted) with mild COPD and 32 age-matched controls. There were no sex differences in dyspnea in the control group at any work-rate or ventilation (V(E)). Women with COPD had significantly greater dyspnea than men at 60 and 80 W. At 80 W, dyspnea ratings were 5.7+/-2.3 and 3.3+/-2.5 Borg units (P<0.05) and the V(E) to maximal ventilatory capacity ratio was 72% and 55% in women and men, respectively (P<0.05). Comparable increases in dynamic hyperinflation were seen in both male and female COPD groups at symptom limitation but women reached tidal volume constraints at a lower work rate and V(E) than men. Superimposing mild COPD on the normal aging effects had greater sensory consequences in women because of their naturally reduced ventilatory reserve. PMID- 21524720 TI - Energetics and oxygen transport mechanisms in embryos. PMID- 21524721 TI - Rheumatologic and neurological events in an elderly patient with tricho-rhino phalangeal syndrome type I. AB - Sparse scalp hair, a peculiar shape of the nose, and cone-shaped epiphyses of the phalanges are the hallmarks of the tricho-rhino-phalangeal syndromes (TRPS). Short stature, hip dysplasia, and malformations of inner organs including mitral valve prolpase have also often been described for these conditions. Here, we described a 64-year-old woman with molecularly proved TRPS I and several atypical late-onset rheumatologic and neurological symptoms. PMID- 21524722 TI - Improved electrical wiring of microbes: anthraquinone-modified electrodes for biosensing of chlorinated hydrocarbons. AB - The present study reports the development of a novel bioelectrochemical sensor for trichloroethene (TCE), a common subsurface contaminant, based on the measurement of the electrical current resulting from the microbially catalysed reduction of TCE at anthraquinone (AQ)-modified electrodes. Firstly, we describe the development and electrochemical characterisation of AQ-modified electrodes, prepared via spontaneous or electrochemical reduction of AQ diazonium derivatives. Finally, the proof-of-principle of the bioelectrochemical sensor for TCE was evaluated, using a TCE-dechlorinating microbial culture as the biosensing element. The response of the bioelectrochemical sensor was measured either as the peak current in cyclic voltammetry or the steady-state current in chronoamperometry; in both cases, it was found to be proportional to TCE concentrations in the range 0-100 MUmol/L. On the other hand, the microorganisms in contact with the electrode surface caused severe fouling problems which drastically reduced the life-time of the sensor. PMID- 21524723 TI - Proteomics as an approach to the understanding of the molecular physiology of fruit development and ripening. AB - Fruit ripening is a developmental complex process which occurs in higher plants and involves a number of stages displayed from immature to mature fruits that depend on the plant species and the environmental conditions. Nowadays, the importance of fruit ripening comes mainly from the link between this physiological process in plants and the economic repercussions as a result of one of the human activities, the agricultural industry. In most cases, fruit ripening is accompanied by colour changes due to different pigment content and increases in sugar levels, among others. Major physiological modifications that affect colour, texture, flavour, and aroma are under the control of both external (light and temperature) and internal (developmental gene regulation and hormonal control) factors. Due to the huge amount of metabolic changes that take place during ripening in fruits from higher plants, the accomplishment of new throughput methods which can provide a global evaluation of this process would be desirable. Differential proteomics of immature and mature fruits would be a useful tool to gain information on the molecular changes which occur during ripening, but also the investigation of fruits at different ripening stages will provide a dynamic picture of the whole transformation of fruits. This subject is furthermore of great interest as many fruits are essential for human nutrition. Thus far different maturation profiles have been reported specific for each crop species. In this work, a thorough review of the proteomic database from fruit development and maturation of important crop species will be updated to understand the molecular physiology of fruits at ripening stages. PMID- 21524724 TI - Words of wisdom. Re: male reproductive tract abnormalities: more common after assisted reproduction? PMID- 21524725 TI - Words of wisdom. Re: management of disseminated nonseminomatous germ cell tumors with risk-based chemotherapy followed by response-guided postchemotherapy surgery. PMID- 21524726 TI - Words of wisdom. Re: efficacy and safety of an orodispersible vardenafil formulation for the treatment of erectile dysfunction in elderly men and those with underlying conditions: an integrated analysis of two pivotal trials. PMID- 21524727 TI - Words of wisdom. Re: the influence of family history on prostate cancer risk: implications for clinical management. PMID- 21524728 TI - Words of wisdom. Re: active surveillance compared with initial treatment in men with low-risk prostate cancer: a decision analysis. PMID- 21524729 TI - Words of wisdom. Re: active surveillance compared with initial treatment for men with low-risk prostate cancer: a decision analysis. PMID- 21524730 TI - Glycine-activated chloride currents of neurons freshly isolated from the prefrontal cortex of young rats. AB - Strychnine-sensitive glycine receptors (GlyR) play a major role in the excitability of CNS neurons and are also a major target of many drugs including some general anesthetics and ethanol. The prefrontal cortex (PFC) is an important substrate responsible for cognitive function and for sedation, as well as hypnosis (unconsciousness) which is induced by general anesthetics and ethanol. However, the functions and the physiological and pharmacological properties of GlyRs in mature PFC neurons have not been well studied. In this study, whole-cell currents induced by glycine (I(Gly)) were recorded from freshly isolated PFC neurons of Sprague-Dawley rats aged 5 to 39 postnatal days (neonatal, P5-12; weanling, P17-21 and peri-adolescent, P30-39). We found that most of the neurons examined were responsive to glycine and the response was concentration dependent. With the increase of age, the sensitivity to glycine was significantly decreased and the sensitivity to picrotoxin was significantly increased. Conversely, the changes in sensitivity to strychnine were not significant. Interestingly, I(Gly) of all age groups was suppressed (to different scope) by low concentrations of picrotoxin (<= 30 MUM), which selectively blocked alpha homomeric GlyRs. Conversely, about 20-65% of I(Gly) remained in the presence of 300 MUM picrotoxin, suggesting the picrotoxin-resistant subtype the alphabeta heteromeric GlyR, was also present. These data provide the first evidence that there are at least two subtypes of functional GlyRs in the PFC neurons of young rats, and their physiological and pharmacological properties change substantially during maturation. PMID- 21524731 TI - PITX3 gene polymorphism is associated with Parkinson's disease in Chinese population. AB - Genetic variants of PITX3 gene have been reported to be associated with Parkinson's disease (PD) in several populations. We conducted a case-control study and genotyped the three SNPs of PITX3 gene: rs2281983, rs4919621 and rs3758549 in 512 mainland Chinese PD patients and 506 healthy controls. Our findings show that the PITX3 gene rs3758549 polymorphism is associated with PD (p=0.02). Moreover, the difference between late onset PD patients and healthy controls is stronger (p=0.007). There is no statistical difference in genotype or allele frequencies of rs2281983 or rs4919621 variant in PITX3 gene between sporadic PD (SPD) group and healthy control group in our study. To assess the possible role of the PITX3 gene rs3758549 polymorphism in PD, we conducted a meta analysis on the topic. The results of meta-analysis further support that the PITX3 gene rs3758549 polymorphism is associated with PD: Z=3.09, p=0.002, OR=0.89. These findings suggest that the PITX3 gene rs3758549 polymorphism may increase the susceptibility of PD. PMID- 21524733 TI - Enantiomerically pure 3-hydroxypropyl diisopropylidene mannose derivatives. AB - Enantiomerically pure 3-hydroxypropyl diisopropylidene mannose derivatives were prepared and fully characterized. The procedure is generally applicable to monosaccharides and thus facilitates access to differently substituted glycosidic precursors. PMID- 21524732 TI - Four new phenolic diglycosides from the roots of Illicium oligandrum. AB - Four new phenolic diglycosides (1-4), named illoliganoside A-D, and three known glycosides (5-7), were isolated from the roots of Illicium oligandrum. The structures of the new diglycosides were determined on the basis of HRMS, NMR spectroscopic, and chemical methods. The anti-inflammatory and cytotoxic activities for 1-7 were evaluated. PMID- 21524734 TI - [Subxiphoid incisional hernia treatment: a technique using a double mesh adjusted to the defect]. AB - INTRODUCTION: Subxiphoid incisional hernia has characteristics that differentiate it from the rest and make it a distinctive entity. The fact that it has its sac very near the rib cage and sternum determines the pressure in the margins. The repair, by open or by laparoscopic approach, has not demonstrated good results despite the generalised use of a prosthesis. They are uncommon, and have a significant comorbidity in patients (severe heart diseases, transplants, immunosuppressed), after surgery of the hepato-bilio-pancreatic area with transverse incisions, or very high mid-laparotomies for gastro-oesophageal surgery. MATERIAL AND METHODS: A new technique has been developed in our Unit, based on a double mesh and adapted to the anatomical and physiological characteristics of the region. The series consisted of 35 consecutive patients operated on between 2004 and 2010, following an agreed surgical and management protocol. RESULTS: There were no significant complications -the most frequent (17.4%) was a seroma- except one case of a wound infection due to skin ischaemia in one patient who had had multiple operations and a transplant. During the post surgical follow up to the present (between 4 and 80 months), there has been no recurrence of the incisional hernia and no significant local discomfort has been reported. CONCLUSIONS: The "adjusted double mesh" technique achieved good results in our hands, from the surgical point of view (reproducibility, recurrence), and for the patient, with minimal discomfort and recovery of quality of life. PMID- 21524735 TI - [An unusual foreign body in the thoracic wall]. PMID- 21524736 TI - [Duodenal fistula after cholecystectomy]. PMID- 21524737 TI - Incidental detection of high-riding innominate artery and bilateral retropharyngeal carotid arteries: radiological findings and clinical relevance. PMID- 21524738 TI - Imaging Paget's disease of bone--from head to toe. AB - Paget's disease of the bone is a common, non-inflammatory, metabolic, skeletal disorder of unknown aetiology characterized by an increase in osteoclast-mediated bone resorption and compensatory excessive osteoblast activation. Prevalence increases with age, and a pronounced geographical variation is well documented. The disease is often an incidental finding on a radiological examination requested for an unrelated indication. The osteolytic, mixed osteolytic/osteoblastic, and osteosclerotic phases may occur in the same patient and same bone in a synchronous or metachronous fashion. Radiological features in each phase mirror the histopathological appearances, and are distinctive enough to establish a diagnosis with confidence. Using multi-technique imaging, this review illustrates the most common and the not so common radiological patterns of involvement in Paget's disease of bone observed at our centre during the past 20 years. PMID- 21524739 TI - A computational model of word segmentation from continuous speech using transitional probabilities of atomic acoustic events. AB - Word segmentation from continuous speech is a difficult task that is faced by human infants when they start to learn their native language. Several studies indicate that infants might use several different cues to solve this problem, including intonation, linguistic stress, and transitional probabilities between subsequent speech sounds. In this work, a computational model for word segmentation and learning of primitive lexical items from continuous speech is presented. The model does not utilize any a priori linguistic or phonemic knowledge such as phones, phonemes or articulatory gestures, but computes transitional probabilities between atomic acoustic events in order to detect recurring patterns in speech. Experiments with the model show that word segmentation is possible without any knowledge of linguistically relevant structures, and that the learned ungrounded word models show a relatively high selectivity towards specific words or frequently co-occurring combinations of short words. PMID- 21524740 TI - Design of a smart biomarker for bioremediation: a machine learning approach. AB - Many trace elements (TE) occur naturally in marine environments and accomplish decisive functions in humans to maintain good health. Mytilus galloprovincialis (MG) is a rich source of TE, but since it is grown near industrial outfalls, they become polluted with elevated levels of TE concentration and serve as biomarkers of pollution. As bioremediation is increasingly reliant on machine learning data processing techniques, we propose the information theoretic concept of using MG for bioremediation. The in situ bioremediation in MG is accomplished by reduction in concentration of TE by the technique of determinant inequalities and the maximization of Mutual Information (MI) without adding any chemical element externally. We bring out the superiority of our technique of MI over that of Principal Component Analysis (PCA) in predicting lower concentration for bioremediation of Cd and Pb in MG. PMID- 21524741 TI - [Early response to idursulfase in a 31-year old male patient with Hunter syndrome]. AB - The response to Enzyme Replacement Therapy (ERT) in Hunter syndrome (MPS II) occurs early in most of the patients after its initiation and continues during the first 12-18 months. However, almost all the patients with MPS II have severe forms of the disease and death occurs prematurely. More than 90% of subjects die before 25 years, and only a minority will survive after the age of 30. There is very limited information on early response to ERT among adult patients with Hunter's syndrome. We report the case of a 31 year-old male with MPS II, with a remarkably severe joint disability, but mild cognitive impairment, who was treated with idursulfase for six months. The pattern of response observed, was similar to what can be expected in younger patients. The amelioration in joint mobility observed in this case suggests that older patients with advanced articular involvement may benefit from idursulfase, even when therapy is started in later stages of the disease. PMID- 21524742 TI - [Mixed bacterial pneumonia: is it an unrecognized reality?]. PMID- 21524743 TI - [Calcific uremic arteriolopathy. a case report and review of the literature]. AB - BACKGROUND: Calcific uremic arteriolopathy is defined as a syndrome consisting of ischemic skin ulceration due to calcification of the wall of the arterioles of the subcutaneous tissue as a result of hyperparathyroidism in uremic patients. CASE REPORT: A 55-year old female patient, hypertense, with heart failure and kidney failure treated with hemodialysis, who presented lower limb pain and hypercalcemia. On physical examination, skin lesions with symmetrical peripheral pulses present in the limbs. Laboratory tests revealed hypercalcemia, hyperphosphatemia, and very high parathyroid hormone levels. Parathyroidectomy was performed and biopsy of skin lesions, the patient having a torpid course causing exitus. Autopsy was performed, with histologic features characteristic of calcific uremic arteriolopathy. CONCLUSIONS: Calcific calcium uremic arteriolopathy or calciphylaxis is a complex and variable disease that is difficult to diagnose and whose treatment is complicated. Despite the efforts of the investigators, there are still many questions regarding its pathogenesis. This acts as an incentive for further research to establish the most appropriate actions to take to maintain an adequate quality of life for the patients and avoid complications that trigger death in some cases. PMID- 21524744 TI - [Author's reply to considerations on the living will document]. PMID- 21524745 TI - Treatment of long bone non-unions with polytherapy: indications and clinical results. AB - The incidence of long bone non-unions has been estimated to range between 5 and 10%. Autologous bone graft usually harvested from the iliac crest continues to be the gold standard for biological enhancement of atrophic non-unions. However, its use has been hampered by minor and major donor site complications. Moreover despite possessing the properties of osteogenecity, osteoconductivity and some osteoinductivity the overall results of treatment have not been consistent with disappointing success rates at times. The concept of polytherapy for the treatment of non-unions, namely the simultaneous application of the three fundamental elements of the diamond concept, osteoprogenitor cells, growth factor and osteoconductive scaffold, appears to be an attractive alternative but more studies are desirable to validate this strategy. PMID- 21524746 TI - Medical abortion in women with impaired renal function. PMID- 21524748 TI - Glycaemic control and other cardiovascular risk factors should be targeted independently in patients with type 2 diabetes mellitus. PMID- 21524747 TI - High plasma cholesteryl ester transfer but not CETP mass predicts incident cardiovascular disease: a nested case-control study. AB - OBJECTIVE: The relationship of cardiovascular disease (CVD) with plasma cholesteryl ester transfer protein (CETP) levels is controversial. We determined whether plasma cholesteryl ester transfer (CET), reflecting CETP-mediated transfer of cholesteryl esters from endogenous HDL towards apolipoprotein B lipoproteins, predicts incident CVD. METHODS: A prospective nested case-control study was carried out in 114 men who developed CVD and 105 controls. Participants did not use lipid lowering drugs at baseline. Plasma CET was assayed using an isotope method. RESULTS: Plasma CET was 19% higher (P=0.030), whereas CETP mass was unaltered (P=0.30) in cases vs. controls. Plasma CET predicted CVD (age adjusted hazard ratio (HR): 1.20 (95% CI 1.02-1.46, P=0.028), but incident CVD was unrelated to CETP mass (HR: 0.88 (95% CI 0.73-1.07), P=0.20). Plasma CET still predicted CVD after additional adjustment for total cholesterol/HDL cholesterol, triglycerides and non-lipid risk markers (HR: 1.22 (95% CI 1.02 1.46, P=0.031). CONCLUSION: Plasma CET rather than CETP mass may be a determinant of cardiovascular risk. PMID- 21524750 TI - Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome. AB - OBJECTIVE: Th1 activation and regulatory T (Treg) cell suppression have been observed in acute coronary syndrome (ACS), including unstable angina (UA) and acute myocardial infarction (AMI). However, the role of Th17 cell or IL-17A remains controversial in ACS patients, and little is known about the role of recently discovered Th17/Th1 cells, a subset of Th17 cells, in coronary artery disease (CAD). The purpose of this study is to investigate functional changes of Th17/Th1, Th17, Th1, Th2 and Treg cells in ACS patients. METHODS: The contents of Th17/Th1, Th17, Th1, Th2 and Treg cells, related gene expression, and plasma cytokines from CAD and control patients with normal coronary arteries (NCA) were measured by flow cytometry, real-time quantitative PCR and ELISA. RESULTS: Th17/Th1 and Th1 cell contents and related gene expression (T-bet, IFN-gamma, STAT4, RORgammat, STAT3 and IL-17) were significantly increased in ACS patients, whereas plasma IFN-gamma only increased in CAD patients. In contrast, Treg cell population, Foxp3 levels, and plasma TGF-beta1 were decreased in ACS patients compared with stable angina (SA) and NCA patients. CONCLUSION: The study showed activation of Th17/Th1 and Th1 cell in ACS patients, which may provide insight into the mechanisms underlying culprit plaque relevant T-cell activation in ACS patients. PMID- 21524749 TI - Nox2-derived reactive oxygen species contribute to hypercholesterolemia-induced inhibition of neovascularization: effects on endothelial progenitor cells and mature endothelial cells. AB - BACKGROUND: Hypercholesterolemia has been associated with impaired angiogenesis and reduced blood flow recuperation after ischemia. However, the precise mechanisms involved are unknown. Here we investigated the role of Nox2-derived reactive oxygen species (ROS) in the modulation of neovascularization by hypercholesterolemia. METHODS AND RESULTS: Mice deficient for the Nox2-containing NADPH oxidase (Nox2(-/-)) and control mice (Nox2(+/+)) were put on a high cholesterol diet (HCD) for a total of 15 weeks. After three months, hindlimb ischemia was surgically induced by femoral artery removal. Nox2 expression and oxidative stress levels in ischemic tissues were significantly increased by HCD in control mice, but not in Nox2(-/-) mice. Nox2(-/-) mice were also protected against hypercholesterolemia-induced impairment of neovascularization, as demonstrated by faster blood flow recovery after ischemia and increased capillary density in ischemic muscles. Nox2 deficiency was associated with preserved activity of eNOS in ischemic tissues, and improved activity of endothelial progenitor cells (EPCs). In vitro, HUVECs treated with the NADPH oxidase inhibitor apocynin or endothelial cells isolated from the aorta of Nox2(-/-) mice exhibited reduced ROS formation following exposure to oxLDL. This was associated with improved nitric oxide (NO) bioavailability and protection against oxLDL induced inhibition of angiogenic activities. CONCLUSIONS: Nox2-containing NADPH oxidase deficiency protects against hypercholesterolemia-induced impairment of neovascularization. The potential mechanisms involved include reduced ROS formation, preserved activation of angiogenic signals, and improved functional activities of EPCs and mature endothelial cells. PMID- 21524751 TI - Impaired inhibition of P2Y(12) by clopidogrel is a major determinant of cardiac death in diabetes mellitus patients treated by percutaneous coronary intervention. AB - OBJECTIVES: We sought to determine whether low platelet response (LR) to the P2Y(12) receptor antagonist as assessed by vasodilator-stimulated phosphoprotein flow cytometry (VASP-FCT) differentially affects outcome in patients with or without diabetes mellitus undergoing percutaneous coronary intervention. BACKGROUND: While both DM and LR to clopidogrel are known to predict an unfavorable outcome after PCI, the deleterious effect of their association is less well established. The VASP-FCT is specific for the P2Y(12) ADP receptor pathway. In this test, platelet activation is expressed as the platelet reactivity index (PRI). METHODS: Patients were assigned to four different groups according to the presence or not of DM (DM, NDM) and LR to clopidogrel (LR, R). LR was defined as a PRI of >61%, a threshold previously identified as the optimal cut-off value to predict cardiac death following PCI. RESULTS: A total of 436 consecutive patients (163 DM, 273 NDM) were enrolled. The proportion of LR patients was higher in DM (47.9% vs. 35.2% p=0.011). At 9+/-2 months follow-up, the rates of total and cardiac mortality and possible and overall stent thrombosis were higher in DM-LR patients. Conversely, the cardiovascular outcome of DM-R patients was comparable to that of NDM (-LR or -R) patients. In DM, a multivariate analysis identified LR to clopidogrel (HR 6.09 [1.27-29.08], p=0.023) as the sole independent predictor of cardiac mortality. CONCLUSIONS: In DM patients undergoing PCI, LR to clopidogrel is an independent predictor of cardiac death. PMID- 21524752 TI - Au nanoparticles stabilised by PEGylated low generation PAMAM dendrimers: design, characterisation and properties. AB - The preparation and characterisation of a series of well-defined low generation (poly)amidoamine (PAMAM)-based dendrimers with end-grafted ethylene glycol ether moieties of type N(CH(2)CH(2)C(O)NHCH(2)CH(2)NR(2))(3) (3a, R=CH(2)CH(2)C(O)OCH(2)CH(2)OCH(3); 3b, R=CH(2)CH(2)C(O)O(CH(2)CH(2)O)(2)C(2)H(5); 3c, R=CH(2)CH(2)C(O)O(CH(2)CH(2)O)(9)CH(3)), [CH(2)N(CH(2)CH(2)C(O)NHCH(2)CH(2)NR(2))(2)](2) (4, R=CH(2)CH(2)C(O)O(CH(2)CH(2)O)(2)C(2)H(5)) and (R(2)NCH(2)CH(2)NHC(O)CH(2)CH(2))N[CH(2)CH(2)N(CH(2)CH(2)C(O)NHCH(2)CH(2)NR(2))(2 ](2) (5a, R=CH(2)CH(2)C(O)OCH(2)CH(2)OCH(3); 5b, R=CH(2)CH(2)C(O)O(CH(2)CH(2)O)(2)C(2)H(5); 5c, R=CH(2)CH(2)C(O)O(CH(2)CH(2)O)(9)CH(3)) and their application for the stabilisation of gold nanoparticles (Au NPs) is described. These dendrimers were prepared by a consecutive divergent synthesis methodology including Michael addition and amidation cycles. For comparison, amidoamine related model compounds N(C(3)H(7))R(2) (1, R=CH(2)CH(2)C(O)O(CH(2)CH(2)O)(2)C(2)H(5)) and [CH(2)NR(2)](2) (2, R=CH(2)CH(2)C(O)O(CH(2)CH(2)O)(2)C(2)H(5)) were also synthesised to estimate the minimum required donating capabilities of the stabiliser. Loading the appropriate dendritic templates with H[AuCl(4)] (12) and subsequent reduction of the respective metallodendrimers with Na[BH(4)] produced dendrimer encapsulated gold colloids. The dendrimeric scaffold, the length of the ethylene glycols, the adjusted stabilizer:gold ratio and the duration of reaction time affects the average Au particle diameter in a range of 4.0 (+/-0.9) to 58.5 (+/-14.5) nm. Furthermore, depending on the nature of the stabiliser, nanoparticles were formed having spherical or multiple morphologies. Characterisation by transmission electron microscopy (TEM), dynamic light scattering (DLS), UV/vis, and IR spectroscopy revealed that Au NPs are formed and protected inside the dendrimer scaffold. PMID- 21524753 TI - Synthesis and antibacterial property of hollow SiO2/Ag nanocomposite spheres. AB - This paper presents a novel and facile method to fabricate hollow silica/sliver (SiO(2)/Ag) nanocomposite spheres. In this approach, the monodisperse hollow SiO(2) colloids bearing quantenary ammonium groups were prepared by dispersion polymerization combined sol-gel process and used as templates. The Ag(+) ions were first adsorbed onto the surfaces of the hollow SiO(2) beads via electrostatic interaction and then in situ reduced by the deprotonated silanol groups of the hollow SiO(2) beads, no extra reducing agents or catalysts were added during the reduction process. TEM, SEM and EDX analyses indicated that Ag nanoparticles were successfully deposited onto the surfaces of hollow SiO(2) beads. Some influencing parameters, such as the amount of quantenary ammonium groups in the inner wall of hollow SiO(2) colloids, Ag(+) ions concentration and reaction temperature, on the deposition of Ag nanoparticles onto SiO(2) colloids were investigated. Preliminary antibacterial tests indicated that these hollow nanocomposite spheres showed excellent antibacterial ability. PMID- 21524754 TI - Evaluation of depolarization changes during acute myocardial ischemia by analysis of QRS slopes. AB - OBJECTIVE: This study evaluates depolarization changes in acute myocardial ischemia by analysis of QRS slopes. METHODS: In 38 patients undergoing elective percutaneous coronary intervention, changes in upward slope between Q and R waves and downward slope between R and S waves (DS) were analyzed. In leads V1 to V3, upward slope of the S wave was additionally analyzed. Ischemia was quantified by myocardial scintigraphy. Also, conventional QRS and ST measures were determined. RESULTS: QRS slope changes correlated significantly with ischemia (for DS: r = 0.71, P < .0001 for extent, and r = 0.73, P < .0001 for severity). Best corresponding correlation for conventional electrocardiogram parameters was the sum of R-wave amplitude change (r = 0.63, P < .0001; r = 0.60, P < .0001) and the sum of ST-segment elevation (r = 0.67, P < .0001; r = 0.73, P < .0001). Prediction of extent and severity of ischemia increased by 12.2% and 7.1% by adding DS to ST. CONCLUSIONS: The downward slope between R and S waves correlates with ischemia and could have potential value in risk stratification in acute ischemia in addition to ST-T analysis. PMID- 21524755 TI - T wave alternans patterns during sleep in various populations. PMID- 21524756 TI - Two cases of torsades de pointes associated with Takotsubo cardiomyopathy as the second insult. AB - Torsades de pointes (TdP) is a fatal polymorphic ventricular tachyarrhythmia that is related to QTc prolongation. Takotsubo cardiomyopathy (TCM) is characterized by acute transient left ventricular dysfunction without obstructive coronary artery disease. The QTc interval is always prolonged in TCM; however, TdP is rarely reported in patients with TCM. Despite that the electrocardiograms of patients with TCM unexceptionally demonstrate marked QTc interval prolongation, TdP is rarely associated with TCM, leading to the proposal that TCM is another cause of acquired long QT syndrome and another insult to the repolarization reserve. We identified 2 cases that reinforce this concept. PMID- 21524757 TI - Differentiating challenge reactivity from psychomotor activity in studies of children's psychophysiology: considerations for theory and measurement. AB - Current methods of assessing children's physiological "stress reactivity" may be confounded by psychomotor activity, biasing estimates of the relation between reactivity and health. We examined the joint and independent contributions of psychomotor activity and challenge reactivity during a protocol for 5- and 6-year old children (N = 338). Measures of parasympathetic reactivity (respiratory sinus arrhythmia [RSA]) and sympathetic reactivity (preejection period [PEP]) were calculated for social, cognitive, sensory, and emotional challenge tasks. Reactivity was calculated relative to both resting and a paired comparison task that accounted for psychomotor activity effects during each challenge. Results indicated that comparison tasks themselves elicited RSA and PEP responses, and reactivity adjusted for psychomotor activity was incongruent with reactivity calculated using rest. Findings demonstrate the importance of accounting for confounding psychomotor activity effects on physiological reactivity. PMID- 21524758 TI - The association of psoriasis and elevated blood lipids in overweight and obese children. AB - OBJECTIVE: To investigate whether obesity and cardiovascular risk factors are associated with psoriasis in children and adolescents. STUDY DESIGN: For this population-based, cross-sectional study, measured weight and height, laboratory data, and psoriasis diagnoses were extracted from electronic medical records of 710,949 patients age 2 to 19 years enrolled in an integrated health plan. Weight class was assigned on the basis of body mass index-for-age. RESULTS: The OR for psoriasis was 0.68, 1.00, 1.31, 1.39, and 1.78 (95% CI, 1.49 to 2.14) for underweight, normal-weight, overweight, moderately obese, and extremely obese children, respectively (P for trend < .001). The OR for psoriasis treated with systemic therapy or phototherapy as an indicator of severe or widespread psoriasis was 0.00, 1.00, 2.78, 2.93, and 4.19 (95% CI, 1.81 to 9.68) for underweight, normal-weight, overweight, moderately obese, and extremely obese children, respectively (P for trend < .003). In adolescents, mean total cholesterol, low-density lipoprotein cholesterol, triglycerides, and alanine aminotransferase were significantly higher in children with psoriasis compared with children without psoriasis after adjustment for body mass index. CONCLUSION: Overweight and obesity are associated with higher odds of psoriasis in youths. Independent of body weight, adolescent patients with psoriasis have higher blood lipids. These data suggest that pediatricians and dermatologists should screen youths with psoriasis for cardiovascular disease risk factors. PMID- 21524759 TI - Detecting, studying, and treating autism early: the one-year well-baby check-up approach. AB - OBJECTIVES: To determine the feasibility of implementing a broadband screen at the 1-year check-up to detect cases of autism spectrum disorders (ASD), language delay (LD), and developmental delay (DD). STUDY DESIGN: The Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist was distributed at every 1-year pediatric check-up; 137 pediatricians and 225 infants participated. Screens were scored immediately, and failures referred for further evaluation. RESULTS: Pediatricians screened 10 479 infants at the 1-year check up; 184 infants who failed the screen were evaluated and tracked. To date, 32 infants received a provisional or final diagnosis of ASD, 56 of LD, nine of DD, and 36 of "other." Five infants who initially tested positive for ASD no longer met criteria at follow-up. The remainder of the sample was false positive results. Positive predictive value was estimated to be .75. CONCLUSIONS: The 1 Year Well-Baby Check-Up Approach shows promise as a simple mechanism to detect cases of ASD, LD, and DD at 1 year. This procedure offers an alternative to the baby sibling design as a mechanism to study autism prospectively, the results of which will enrich our understanding of autism at an early age. PMID- 21524760 TI - [Susceptibility to varicella among health care workers. Acceptability and response to vaccination]. AB - BACKGROUND AND OBJECTIVE: To determine the prevalence of health care workers (HCW) susceptibility to varicella zoster virus (VZV). As a secondary objective, we describe the immunogenicity and reactogenicity of the vaccine. SUBJECTS AND METHODS: A multicenter analytic cross-sectional study was conducted in 5 hospitals in Catalonia, Spain, in a total of 1,111 HCW, aged between 18-60 years. We studied the prevalence of anti-VZV antibodies (IgG) and obtained demographic, occupational and health related variables that were expected to be associated with immunogenicity, as well as past history of varicella. All susceptible HCW were vaccinated and we studied the immunogenicity (antibody detection) and reactogenicity of the 1st and 2nd doses of the vaccine. Detection of antibodies against VZV was obtained by ELISA. All negative results were confirmed with FAMA. RESULTS: Forty two subjects (3.8%) were negative. Susceptibility to VZV was associated (p<0.05) with decreased age (29.6 years +/- 8.5 vs. 32,5 +/- 9,3 in non-susceptible individuals), having fewer siblings and having no previous clinical history of varicella. Postvaccination detection tests with ELISA showed a seroconversion rate of 52 and 86% after the 1st and 2nd doses of the vaccine respectively, and 100% when using FAMA. There were no significant adverse events. CONCLUSIONS: Susceptibility to varicella among HCW is low. Positive past history of varicella is a good predictor of previous exposure to VZV, since 99% (687/696) of the individuals that declared having experienced the disease were immune. This would avoid prevaccination screening in nearly two thirds of HCW. PMID- 21524762 TI - Non-detectable Chlamydophila pneumoniae DNA in peripheral leukocytes in type 2 diabetes mellitus patients with and without carotid atherosclerosis. AB - BACKGROUND AND OBJECTIVE: To study Chlamydophila pneumoniae DNA (CP-DNA) in leukocytes measured by real-time polymerase chain reaction (PCR) in patients with type 2 diabetes mellitus (DM2) with different degrees of atherosclerosis, a cross sectional protocol was performed. PATIENTS AND METHODS: We included 135 patients with DM2. Clinical, metabolic and inflammatory variables were measured. Previous clinical macrovascular disease was recorded and carotid ultrasound and real-time PCR for CP-DNA were performed. RESULTS: Mean age was 62 (7) years and mean diabetes duration 16 (9) years; 40.7% of patients presented clinical atherosclerosis, 32.5% subclinical atherosclerosis and 26.6% no evidence of atherosclerosis. Anthropometric data were homogeneous in the three groups. Patients with clinical atherosclerosis had greater carotid intima-media thickness compared to the other two groups. No CP-DNA was detected in any patient. CONCLUSIONS: The lack of detection of CP-DNA in blood leukocytes suggests that C. pneumoniae plays no active, systemic role in the pathogenesis of atherosclerosis in DM2 patients and is not a reliable marker of atherosclerosis in high-risk patients. PMID- 21524761 TI - [Comparative performance of QuantiFERON((r))-TB Gold IT versus tuberculin skin test among contact investigations for latent tuberculosis infection]. AB - BACKGROUND AND OBJECTIVE: Until recently, the only tool for detection of latent tuberculosis infection (LTI) was the tuberculin skin test (PPD). QuantiFERON((r)) TB Gold In-Tube (QF), as well as other Mycobacterium tuberculosis-specific interferon-gamma release assays (IGRAs), appears to be an alternative or adjunct to the PPD. The goal of the study was to compare QF with PPD to evaluate de accuracy of QF for routinely identifying LTI in contact investigations. PATIENTS AND METHOD: We performed a descriptive and prospective study with contacts of culture-confirmed tuberculosis source cases in Bizkaia and Araba from May 2007 through February 2008 who underwent QF and PPD. Concordance between both tests was analyzed using the kappa statistic (kappa). RESULTS: 376 contacts were found: 8 were high-risk children (age < 15), 30 low-medium risk children, 46 high-risk adults (age>14) and 270 low-medium risk adults. PPD was positive in 160 subjects (42.5%) at PPD >= 5mm, 141 (37.5%) at PPD >= 10mm and 95 (25.3%) at PPD >= 15 mm. In QF analysis 94 subjects were positive, 279 negative and 3 indeterminate. Overall agreement between QF and PPD was good at PPD >= 10mm (kappa=0.53; p<0.0001) but agreement was poor when the index case had positive baciloscopy at PPD >= 5mm (kappa=0.28; p<0.001) and high-risk contacts at PPD >= 15 mm (kappa=0.048; p=0.36). CONCLUSIONS: IGRAs are an accurate indicator of LTI, providing a more specific way of diagnostic and reducing the number of subjects to be treated. QF appears to be a valuable public health tool with potential advantages over the PPD and improving resources. PMID- 21524763 TI - [Added value of glomerular filtration estimation by MDRD-4 in the risk assessment of the digitalic overdose]. PMID- 21524764 TI - [Recommendations of good practices for molecular diagnosis of Huntington disease]. PMID- 21524765 TI - [Low doses of megestrol acetate increase weight and improve nutrition status in patients with severe chronic obstructive pulmonary disease and weight loss]. AB - BACKGROUND AND OBJECTIVE: Weight loss in patients with severe chronic obstructive pulmonary disease (COPD) is a prognostic bad factor. The objective of this study is to analyze the effectively of megestrol acetate (MA) to increase appetite of these patients. PATIENTS AND METHODS: Randomized double blind placebo controlled trial to study the effect of 160 mg/bid of MA, for 8 weeks, on nutritional, functional, analytical and quality of life parameters, in 38 patients with severe COPD and body mass index (BMI) < 21 kg/m(2), or between 21-25 with involuntary weight loss of 5% in the last 3 months. RESULTS: At 8 weeks, in the MA group the body weight increased (2.3 kg) with respect to the control group (0.1 kg) (p<0.04). MA improved significantly the triceps skin-fold thickness (p < 0.04), prealbumin (p<0.004), lymphocytes (p<0.0006), C3 (p<0.04), PCO(2) (p<0.007) and bicarbonate levels (p<0.008). MA did not increase the MRC and SGRQ scales, the distance of 6 MWT nor BODE index. The IL-6 and TNF alpha levels were not modified in the MA group, but leptin did increase (p<0.043). MA improved the sense of wellbeing (p<0.02) and the appetite (p<0.008), compared to the control group. Adverse effects were similar in both groups. CONCLUSIONS: MA safely increases the body weight and the appetite in severe COPD patients with weight loss. MA improves blood gases and nutritional parameters and the sense of wellbeing, but it does not improve the respiratory muscular function or exercise tolerance. PMID- 21524766 TI - [Multiple involvement of cranial nerves by an uncommon pathogen: human herpesvirus type 7]. PMID- 21524767 TI - [Efficacy of cognitive-behavior therapy for mental disorders]. PMID- 21524768 TI - [A case of Noonan Syndrome with coeliac disease due to SOS1 mutation]. PMID- 21524769 TI - [Hyperferritinemia, ferropenia and metabolic syndrome in a patient with a new mutation of gene TFR2 and another in gene FTL. A family study]. AB - BACKGROUND AND OBJECTIVES: Hyperferritinemia is a common finding in clinical practice. This condition can be congenital or acquired, although it is not always associated with iron overload. Genetic hyperferritinemia is associated with iron overload, hereditary hemochromatosis, or cataracts that progress without iron overload (hereditary hyperferritinemia-cataract syndrome). Metabolic syndrome is associated with hyperferritinemia and mild iron overload, with no increase in transferrin saturation. We report a family with hyperferritinemia. PATIENTS AND METHODS: We present the study of a family with dual hyperferritinemia (congenital and acquired) and an analysis of the genes involved in iron metabolism. RESULTS: Patients with hereditary hyperferritinemia-cataract syndrome have the mutation c. 167C>T in the FTL gene; patients with metabolic syndrome present a new mutation in the TFR2 gene (c.1259G>A, p.Arg420His). CONCLUSIONS: The phenotypic and genotypic diversity of hyperferritinemia makes it a diagnostic challenge for clinicians. Basic research and clinical research should be combined to ensure better patient care. PMID- 21524770 TI - [Cytomegalovirus infection in renal transplantation: from learned lessons to future challenges]. PMID- 21524771 TI - [Interferon-gamma-based assays: can we optimize the diagnosis of latent tuberculosis infection in contact tracing studies?]. PMID- 21524772 TI - Mortality rate for children under 5 years of age in China from 1996 to 2006. AB - OBJECTIVES: To study the change in mortality rate for children under 5 years of age in China over the past decade, and to evaluate China's progress in achieving Millennium Development Goal 4. STUDY DESIGN: Population-based descriptive study. METHODS: A population-based survey was conducted through a nationwide multi-level surveillance network. The mortality rate and the leading causes of death for children under 5 years of age were analysed. RESULTS: The mortality rate for children under 5 years of age in China dropped by 54.2% between 1996 and 2006 (from 45.0 per 1000 livebirths to 20.6). During this period, deaths due to pneumonia and diarrhoea dropped by 69.4% and 69.7%, respectively. The proportion of deaths due to pneumonia dropped from 23.4% in 1996 to 15.6% in 2006, and the proportion of deaths due to diarrhoea dropped from 5.6% in 1996 to 3.7% in 2006. CONCLUSION: The mortality rate for children under 5 years of age in China dropped remarkably from 1996 to 2006. This reduction was mainly due to a significant decrease in deaths due to pneumonia and diarrhoea. Based on the survey results, China should be able to achieve Millennium Development Goal 4. PMID- 21524773 TI - One year later: Mental health problems among survivors in hard-hit areas of the Wenchuan earthquake. AB - OBJECTIVES: To investigate the prevalence of probable post-traumatic stress disorder (PTSD), anxiety and depression, and to identify risk factors related to these mental disorders among hard-hit survivors 1 year after the earthquake in Wenchuan, China. STUDY DESIGN: : Cross-sectional survey. METHODS: A door-to-door survey covering the entire temporary community was undertaken to investigate 1195 adult earthquake survivors. The survey instruments included a questionnaire determining exposure to the earthquake, the PTSD Checklist-Civilian Version (PCL C), the Hopkins Symptoms Checklist-25 (HSCL-25), and the Perceived Social Support Scale (PSSS). Univariate and multivariate logistic regression analyses were undertaken to examine potential risk factors. RESULTS: The prevalence rates of probable PTSD, anxiety and depression were 26.3%, 49.8% and 49.6%, respectively. Risk factors varied between the disorders. Among middle-aged and elderly people, bodily injury, loss of livelihood and initial fear during the earthquake were independently and significantly associated with all three mental disorders, while female gender was independently and significantly associated with PTSD and depression. CONCLUSIONS: PTSD, anxiety and depression remained at an elevated level among survivors in hard-hit regions 1 year after the earthquake in Wenchuan. The groups at high risk of mental problems should be specifically attended. PMID- 21524774 TI - Challenges of global surveillance during an influenza pandemic. AB - Surveillance is an essential foundation for monitoring and evaluating any disease process, and is especially critical when new disease agents appear. The H1N1 influenza pandemic of 2009 tested the capacities of countries to detect, assess, notify and report events as required by the 2005 International Health Regulations (IHR). As detailed in the IHR, the World Health Organization drew on official reports from Member States as well as unofficial sources (e.g., media alerts) to quickly report and disseminate information about the appearance of the novel influenza virus. The pre-existing Global Influenza Surveillance Network for virological surveillance also provided crucial information for rapid development of a vaccine and for detection of changes in the virus. However, the pandemic also highlighted a number of shortcomings in global epidemiological surveillance for respiratory disease. These included the lack of standards for reporting illness, risk factor and mortality data, and a mechanism for systematic reporting of epidemiological data. Such measures would have facilitated direct comparison of data between countries and improved timely understanding of the characteristics and impact of the pandemic. This paper describes the surveillance strategies in place before the pandemic and the methods that were used at global level to monitor the pandemic. Enhancements of global surveillance are proposed to improve preparedness and response for similar events in the future. PMID- 21524775 TI - Design and in vitro evaluation of a real-time catheter localization system using time of flight measurements from seven 3.5 MHz single element ultrasound transducers towards abdominal aortic aneurysm procedures. AB - Interventional surgical instrument localization is a crucial component of minimally invasive surgery. Image guided surgery researchers are investigating devices broadly categorized as surgical localizers to provide real-time information on the instrument's 3D location and orientation only. This paper describes the implementation and in vitro evaluation of a prototype real-time nonimaging ultrasound-based catheter localizer system towards use in abdominal aortic aneurysm procedures. The catheter-tip is equipped with a single element ultrasound transducer which is tracked with an array of seven external single element transducers. The performance of the system was evaluated in a water tank and additionally in the presence of pork belly tissue and also a nitinol-dacron stent graft. The mean root mean square errors were respectively 1.94+/-0.06, 2.54+/-0.31 and 3.33+/-0.06 mm. In addition, this paper illustrates errors induced by transducer aperture size and suggests a method for aperture error compensation. Aperture compensation applied to the same experimental data yielded mean root mean square errors of 1.05+/-0.07, 2.42+/-0.33 and 3.23+/-0.07mm respectively for water; water and pork; and water, pork and stent experiments. Lastly, this paper presents a video showing free-hand movement of the catheter within the water tank with data capture at 25 frames per second. PMID- 21524776 TI - Subcellular location and topology of severe acute respiratory syndrome coronavirus envelope protein. AB - Severe acute respiratory syndrome (SARS) coronavirus (CoV) envelope (E) protein is a transmembrane protein. Several subcellular locations and topological conformations of E protein have been proposed. To identify the correct ones, polyclonal and monoclonal antibodies specific for the amino or the carboxy terminus of E protein, respectively, were generated. E protein was mainly found in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) of cells transfected with a plasmid encoding E protein or infected with SARS-CoV. No evidence of E protein presence in the plasma membrane was found by using immunofluorescence, immunoelectron microscopy and cell surface protein labeling. In addition, measurement of plasma membrane voltage gated ion channel activity by whole-cell patch clamp suggested that E protein was not present in the plasma membrane. A topological conformation in which SARS-CoV E protein amino terminus is oriented towards the lumen of intracellular membranes and carboxy terminus faces cell cytoplasm is proposed. PMID- 21524777 TI - Enhancing p-cresol extraction from soil. AB - Soil washing is a potential technology for rapid removal of organic hydrocarbons sorbed to soils. In this work, p-cresol desorption with different non-ionic surfactants (Tween 80, Brij 30 and Triton X-100) was compared to cyclodextrine and citrate as solubilizer. A series of batch extraction experiments were conducted at 20 degrees C using the field soil with different extracting solutions at various concentrations to investigate the removal efficiency and to optimize the concentration of the extractant. The use of the different extracting agents was very selective to p-cresol extraction, minimizing soil organic matter releasing and maintaining the natural pH of the soil. The highest asymptotic values of desorption percentages were obtained for Tween 80 and Brij 30 at 48 h. However, Brij 30 ecotoxicity (EC(50)=0.5 mgL(-1)) is in the same order of that obtained for p-cresol, being this surfactant clearly ruled out. Liquid to solid ratio of 2.5 mLg(-1) presented the best extraction results, while concentrations higher than 1 gL(-1) for Tween 80 and Citrate did not produce any significant effect on the desorption efficiency. p-Cresol extraction efficiencies higher than 70% and 60% for Tween 80 and Citrate, respectively. PMID- 21524778 TI - Emissions of PCDD and PCDF from combustion of forest fuels and sugarcane: a comparison between field measurements and simulations in a laboratory burn facility. AB - Release of PCDD and PCDF from biomass combustion such as forest and agricultural crop fires has been nominated as an important source for these chemicals despite minimal characterisation. Available emission factors that have been experimentally determined in laboratory and field experiments vary by several orders of magnitude from <0.5 MUg TEQ (t fuel consumed)(-1) to >100 MUg TEQ (t fuel consumed)(-1). The aim of this study was to evaluate the effect of experimental methods on the emission factor. A portable field sampler was used to measure PCDD/PCDF emissions from forest fires and the same fuel when burnt over a brick hearth to eliminate potential soil effects. A laboratory burn facility was used to sample emissions from the same fuels. There was very good agreement in emission factors to air (EF(Air)) for forest fuel (Duke Forest, NC) of 0.52 (range: 0.40-0.79), 0.59 (range: 0.18-1.2) and 0.75 (range: 0.27-1.2) MUg TEQ(WHO2005) (t fuel consumed)(-1) for the in-field, over a brick hearth, and burn facility experiments, respectively. Similarly, experiments with sugarcane showed very good agreement with EF(Air) of 1.1 (range: 0.40-2.2), 1.5 (range: 0.84-2.2) and 1.7 (range: 0.34-4.4) MUg TEQ (t fuel consumed)(-1) for in-field, over a brick hearth, open field and burn facility experiments respectively. Field sampling and laboratory simulations were in good agreement, and no significant changes in emissions of PCDD/PCDF could be attributed to fuel storage and transport to laboratory test facilities. PMID- 21524779 TI - Determination of lindane leachability in soil-biosolid systems and its bioavailability in wheat plants. AB - The leachability of lindane from different biosolid amended soils was determined and compared to its bioavailability. Sand, soil, and a mixture of soil-sand (1:1 w/w) were spiked with lindane, blended with different amounts of biosolids, and subjected to a leaching process with water that lasted for 1-28 d. This procedure is in accordance with ISO/TS 21268-1: 2007. After these batch tests, lindane was extracted from the leachates using three different solvent-free microextraction techniques, including solid phase microextraction (SPME), stir-bar sorptive extraction (SBSE), and silicone rod extraction (SRE). The amount of lindane was determined with thermal desorption and gas chromatography coupled to mass spectrometry (GC-MS). The efficiencies of the three microextraction techniques were statistically different, and the efficiency could be related to the amount of polydimethylsiloxane (PDMS) in each extraction device. However, all of the techniques provide data that shows that the leachability of lindane is dependent on the amount of organic matter contained in the matrix. The results of the lindane leachability assay were compared to the bioavailability of lindane, which was determined by measuring the amount of lindane that accumulated in the roots of wheat plants grown in similar soil-biosolid systems. It was confirmed that the amount of organic matter in the matrix is a determining factor for lindane immobilization. The presence of biosolids decreases the mobility of lindane in all of the systems under study. Similarly, increasing biosolid concentrations in the soil significantly decreased the bioavailability of lindane and, consequently, plant absorption. The good correlation (R(2)=0.997) between the leachability of lindane from the matrix and plant absorption of lindane indicates that the proposed biomimetic methodology can predict the bioavailability of lindane in a time period as short as 7d. The results of this work confirm that amending contaminated soils with biosolids is beneficial for immobilizing lindane and helps prevent the percolation of lindane through the soil profile and into groundwater. PMID- 21524780 TI - Effect of structural composition of humic acids on the sorption of a branched nonylphenol isomer. AB - By using dialysis equilibrium experiments, the sorption of a branched nonylphenol isomer [4-(1-ethyl-1,3-dimethylpentyl)-phenol] (NP111) on various humic acids (HAs) isolated from river sediments and two reference HAs was studied. The HAs were characterized by solid-state (13)C direct polarization/magic angle spinning nuclear magnetic resonance ((13)C DP/MAS NMR) spectroscopy. Sorption isotherms of NP111 on HAs were described by a linear model. The organic carbon-normalized sorption coefficient (K(OC)) ranged from 2.3*10(3) to 1.5*10(4)Lkg(-1). Interestingly, a clear correlation between K(OC) value and alkyl C content was observed, indicating that the aliphaticity of HAs markedly dominates the sorption of NP111. These new mechanistic insights about the NP111 sorption indicate that the fate of nonylphenols in soil or sediment depends not only on the content of HA, but also on its structural composition. PMID- 21524781 TI - Perfluorinated compounds in Haihe River and Dagu Drainage Canal in Tianjin, China. AB - In this study, nine perfluorinated compounds (PFCs) were investigated in water and sediment of Haihe River (HR) and Dagu Drainage Canal (DDC), Tianjin, China. The total PFCs in water samples from DDC (40-174 ngL(-1)) was much greater than those from HR (12-74 ngL(-1)). PFC contamination was severe at lower reaches of HR due to industry activities, while high PFCs were found in the middle of DDC due to the effluents from wastewater treatment plants. Perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) were the predominant PFCs in aqueous phase. The total PFCs in sediments from DDC (1.6 7.7 ngg(-1) dry weight) were lower as compared to HR (7.1-16 ngg(-1)), maybe due to the dredging of sediment in DDC conducted recently. PFOS was the major PFC in HR sediments followed by PFOA; while PFHxA was the major PFC in DDC sediments. Organic carbon calibrated sediment-water distribution coefficients (K(OC)) were calculated for HR. The Log K(OC) ranged from 3.3 to 4.4 for C7-C11 perfluorinated carboxylic acids, increasing by 0.1-0.6 log units with each additional CF(2) moiety. The log K(OC) for 8:2 fluorotelomer unsaturated acid was reported for the first time with a mean value of 4.0. The log Koc of PFOS was higher than perfluoronanoic acid by 0.8 log units. PMID- 21524782 TI - Efficient removal of pollutants from olive washing wastewater in bubble-column bioreactor by Trametes versicolor. AB - The white-rot fungi Panus tigrinus, Funalia trogii and Trametes versicolor have been tested in shake flasks for the reduction of olive washing wastewater (OWW) pollutants and production of oxidases on OWW-based media. P. tigrinus was rejected for its scarce performance. F. trogii showed best production of laccase (27 000 Ug(-1)), while T. versicolor appeared a good pollutant degrader reducing colour, COD and phenols by 60, 72 and 87%, respectively. Only T. versicolor grew well in bubble-column bioreactor: its OWW depollution, in continuous process, led to colour, COD and phenols reduction by 65%, 73% and 89%, respectively. Optimal dilution rate was 0.225d(-1) (0.225 m(3) of effluent treated daily per m(3) of bioreactor). Thus, a small bioreactor (10 m(3)) could treat daily the amount of OWW produced by a standard olive washing machine (2m(3)d(-1)). For these reasons, this process could be proposed as a simple, efficient and low-cost OWW treatment. PMID- 21524783 TI - Impact of different land uses on polycyclic aromatic hydrocarbon contamination in coastal stream sediments. AB - PAHs are ubiquitous environmental pollutants that can cause adverse health and ecological effects. In the present study, we examined the impact of land use on the concentration and composition of PAHs in 28 coastal stream sediments on the Island of Oahu, Hawaii. In densely populated urban areas, the concentration range of total PAHs in the stream sediments affected by mixed residential and industrial activities (RI) are 0.40-9.05 ppm, which is significantly higher than the 0.36-4.21 ppm detected in the stream sediments affected predominantly by urban residential land uses (UR). The stream sediments affected by agricultural activities (AG) reported a concentration range of 0.09-2.14 ppm, which is lower than those of the RI and UR stream sediments. The molecular weight of PAH is a factor, as only high molecular weight (HMW) PAHs were significantly affected by land uses (ANOVA P=0.009). Correlation analysis showed that only in the UR stream sediments were significant correlations observed between PAH concentration and two anthropogenic indicators: population density (r=0.57, P=0.027) and vehicle density (r=0.55, P=0.034). The fractional concentrations of PAHs were analyzed by using PCA analysis, which led to the separate clustering of the RI and AG stream sediments and suggest distinct PAH sources between the two land uses. Two PAH source indicators, including Ant/(Ant+Phe) and Fl/(Fl+Py), indicates that PAHs sources in the RI stream sediments are most likely of petroleum origin, while PAHs in the UR and AG stream sediments most likely came from combustion activities. In addition, the concentration and relative potency of carcinogenic PAHs in the coastal stream sediments exhibited similar patterns as the total PAH concentration with respect to land uses. PMID- 21524784 TI - Persistence of two neonicotinoid insecticides in wastewater, and in aqueous solutions of surfactants and dissolved organic matter. AB - Wastewater treatment plants receive organic contaminants, such as pesticides, which reach the sewage system from domestic, industrial or agricultural activities. In wastewater, which is a complex mixture of organic and inorganic compounds, biotic or abiotic degradation of contaminants can be affected by the presence of co-solutes. The photodecomposition in natural sunlight of two neonicotinoid insecticides, thiamethoxam and thiacloprid, was investigated in wastewater, aqueous extracts of sewage sludge and in aqueous surfactant solutions, which are abundant in wastewater. Dissipation in the dark was also studied in wastewater, due to reduction of transmitted sunlight in wastewater ponds. With regard to photolysis, thiamethoxam degraded rapidly in all the aqueous solutions. Among them sewage sludge extracts slightly modified (average half-life 17.6h), wastewater increased (13.7h) and non-ionic surfactants led, as a family, to the highest dissipation rates (average 6.2h), with respect to control water (18.7h). Additionally this pesticide also underwent a slower biodegradation process in wastewater in the dark under anaerobic conditions (around 25d). A metabolite of thiamethoxam from the biological decomposition in wastewater was identified by HPLC/MS. On the other hand thiacloprid was found to be resistant to photo- and biodecomposition and remained almost unchanged during the experimental periods in all the tested media. PMID- 21524785 TI - Determinants of exposure to mercury in hair from inhabitants of the largest mercury mine in the world. AB - Mercury exposure of the local population was assessed in two areas of the Almaden mercury mining district, Spain, which has been the world's largest producer of this element. Two groups, who are exposed to different sources of mercury, from a point source in Almaden and a diffuse source hundreds of kilometres away in the same region, were studied. Total mercury (THg) in human hair ranged from 0.20 to 9.35 mg kg(-1) and the mean value was 2.64 mg kg(-1). About 87% of subjects had THg levels in excess of the EPA reference dose (RfD=1.0 mg kg(-1)), while a high percentage (68%) of them live in Almaden. There was a clear increase in hair Hg with reported fish consumption and the highest mean hair mercury level was 4 times the RfD in a group who had reported the highest consumption of fish. For the whole group, there was a significant effect of age, gender and fish consumption in relation to Hg concentration in the hair. Nevertheless, when both groups were tested separately by means of a multivariate regression model, there was significant exposure in those living near the mine area. Several factors such as age, gender and fish consumption remained statistically significant and were associated with THg. The main conclusion is that people living close to the hot spot are more impacted by mercury than people living further away. The intake of Hg through consumption of fish is an important parameter for Hg exposure; however, in the case of people living close to the hot spot, their levels are related to the highly Hg-impacted living environment. PMID- 21524786 TI - The effects of active chlorine on photooxidation of 2-methyl-2-butene. AB - Active chlorine comprising hypochlorite (OCl-), hypochlorous acid (HOCl) and chlorine (Cl2) is the active constituent in bleach formulations for a variety of industrial and consumer applications. However, the strong oxidative reactivity of active chlorine can cause adverse effects on both human health and the environment. In this study, aerosolized Oxone(r) [2KHSO5, KHSO4, K2SO4] with saline solution has been utilized to produce active chlorine (HOCl and Cl2). To investigate the impact of active chlorine on volatile organic compound (VOC) oxidation, 2-methyl-2-butene (MB) was photoirradiated in the presence of active chlorine using a 2-m3 Teflon film indoor chamber. The resulting carbonyl products produced from photooxidation of MB were derivatized with O-(2,3,4,5,6 pentafluorobenzyl) hydroxyamine hydrochloride (PFBHA) and analyzed using gas chromatograph-ion trap mass spectrometer (GC/ITMS). The photooxidation of MB in the presence of active chlorine was simulated with an explicit kinetic model using a chemical solver (Morpho) which included both Master Chemical Mechanism (MCM) and Cl radical reactions. The reaction rate constants of a Cl radical with MB and its oxidized products were estimated using a Structure-Reactivity Relationship method. Under dark conditions no effect of active chlorine on MB oxidation was apparent, whereas under simulated daylight conditions (UV irradiation) rapid MB oxidation was observed due to photo-dissociation of active chlorine. The model simulation agrees with chamber data showing rapid production of oxygenated products that are characterized using GC/ITMS. Ozone formation was enhanced when MB was oxidized in the presence of irradiated active chlorine and NO(x). PMID- 21524787 TI - Demonstration of free fatty acids in the integument of semi-aquatic and aquatic mammals. AB - The sensitive red fluorescence dye BODIPY(r) 665/676, and embedding in the water soluble resin Technovit(r) 7100 were used to demonstrate free fatty acids in the epidermis of seven semi-aquatic and aquatic mammalian species with a sparse or dense hair coat. The staining generally marked lipid layers of varying thickness between the lamellae of the Stratum corneum, as found particularly in very densely haired species (otter), but also in rather sparsely haired animals (beaver, nutria), and especially in the seal. The very sparsely haired capybara contained no free fatty acids in the corneal layer system, but exhibited an accumulation of such substances in the vital epidermis. All haired species showed a strongly positive reaction staining of the sebaceous glands. In the hairless species, a distinct intracellular staining was restricted to cells of the thick vital epidermis in the hippopotamus, whereby in the Str. corneum positive intercellular reactions appeared. In the dolphin, on the contrary, positive intercellular reactions became visible in the vital epidermis, whereas in the Str. corneum the lipids concentrated in large longitudinal intracellular vesicles. PMID- 21524788 TI - Wear performance of substructure ceramics and veneering porcelains. AB - AIM: The aim of this in vitro study was to compare the two-body wear resistance of substructure zirconia and veneering porcelain versus steatite and human enamel antagonists, respectively. MATERIALS AND METHODS: Two-body wear tests were performed in a chewing simulator with steatite and enamel antagonists (enamel cusps). A pin-on-block design with a vertical load of 50 N for 1.2 * 10(5) cycles; (f=1.6 Hz; lateral movement: 1mm, mouth opening: 2mm) was used for the wear test. For quantification of the wear resistance, wear tests were performed with standardized steatite spheres. Human enamel was used as a reference. Five zirconia ceramics and four veneering porcelains were investigated. One zirconia ceramic was tested with superficial glaze, which was applied after polishing or sandblasting, respectively. Surface roughness R(a) (SP6, Perthen-Feinpruf, G) and wear depth were determined using a 3D-Profilometer (Laserscan 3D, Willytec, G). SEM (Quanta FEG 400, FEI, USA) pictures were used for evaluating wear performance of both, ceramics and antagonists. RESULTS: No wear was found for zirconia substructures. Veneering porcelain provided wear traces between 186.1+/-33.2 MUm and 232.9+/-66.9 MUm (steatite antagonist) and 90.6+/-3.5 MUm and 123.9+/-50.7 MUm (enamel). Wear of the steatite antagonists varied between 0.812+/-0.256 mm(2) and 1.360+/-0.321 mm(2) for zirconia and 1.708+/-0.275 mm(2) and 2.568+/-0.827 mm(2) for porcelain. Enamel generally showed wear, cracks or even fractures at the ridge, regardless whether opposed by zirconia or porcelain/glaze. Enamel was polished, when opposed to zirconia, or plowed, provoked and grinded, when opposed to porcelain/glaze. CONCLUSION: The results of the wear test with steatite or enamel antagonists indicated no measurable wear on zirconia surfaces. Porcelain showed higher wear than zirconia, but comparable or lower wear than an enamel reference. Antagonistic wear against zirconia was found to be lower than wear against porcelain. PMID- 21524789 TI - Influence of surface roughness on streptococcal adhesion forces to composite resins. AB - OBJECTIVE: To determine streptococcal adhesion forces with composite resins with different surface roughness. METHODS: Polishing and grinding were applied to obtain smooth (roughness 20 nm), moderately rough (150 nm) and rough (350 nm) surfaces of two orthodontic, light-cured composites. Adhesion forces between Streptococcus sanguinis and Streptococcus mutans and the composite surfaces were measured using atomic force microscopy in absence or presence of a salivary conditioning film. Initial adhesion forces were measured as well adhesion after 120 s of contact, as longer contact times are known to result in stronger adhesion forces ("bond-strengthening"). Surface roughness in absence and presence of salivary conditioning films were compared using ANOVA, while adhesion forces were subjected to a Weibull analysis. RESULTS: Initial adhesion forces in absence of a salivary conditioning film amounted between -0.7 and -0.9 nN for smooth composite resins and increased between -1.0 and -2.0 nN for the roughest surfaces. Streptococcal adhesion forces after bond-strengthening were significantly stronger than upon initial contact, irrespective of the composite type. Salivary conditioning films significantly decreased the surface roughness of the composites, as well as the streptococcal adhesion forces. Yet, also in the presence of a conditioning film, rougher composite surfaces exerted stronger adhesion forces, irrespective of composite type or bacterial strain. CONCLUSION: Streptococcal adhesion forces to orthodontic composite resins increase with increasing roughness of the composite surfaces. Composite surface roughness less affects adhesion forces with S. mutans than with S. sanguinis. PMID- 21524790 TI - Effect of fatigue on biaxial flexural strength of bilayered porcelain/zirconia (Y TZP) dental ceramics. AB - OBJECTIVES: The aim of this study was to evaluate the effect of fatigue on biaxial flexural strength of bilayered disks of two Y-TZP cores. METHODS: Twenty bilayered veneer/zirconia disks were fabricated from each material (Lava veneer+core, 3M/ESPE, and Cercon veneer+core, Densply). Ten specimens from each material were tested for biaxial flexural strength either with or without being subjected to fatigue (20,000 cycles, 2 Hz, 200 N load) in a universal testing machine (1mm/min). Stresses generated at the core and the veneer, at the top and the bottom surfaces, and the interface of bilayered disk were calculated using Huesh's solutions. Data were statistically analyzed using Weibull statistics. The fractured core was also examined via Raman spectroscopy and the monoclinic fraction was calculated at the top, the middle of thickness, and the bottom of the cross-section of fractured core. The results of monoclinic fraction were statistically analyzed by Three-Factor ANOVA with Repeated Measures on One Factor. RESULTS: Weibull modulus (m) of Cercon control (CC), Cercon fatigue (CF), Lava control (LC) and Lava fatigue (LF) were between 11.8 and 14.3, 7.1 and 13.1, 9.4 and 13, and 7.1 and 8.2, respectively. There were no significant differences between characteristic strength (sigma(0)) of CC (970.9 MPa) and CF (947.7 MPa) (p>0.05). For Lava, sigma(0) of LF (1444.8 MPa) was significantly higher than LC (1240.5 MPa) (p<0.05). At the interfaces, sigma(0) values of CC and CF groups were not significantly different while LF showed significantly higher sigma(0) than LC. The monoclinic zirconia was significantly lower for CF than CC and significantly higher for LF than LC. SIGNIFICANCE: Fatigue showed different effects on the strength of Cercon and Lava ceramic systems. Decreases in m values were observed at the interfaces of two materials after fatigue. PMID- 21524791 TI - Ethical aspects in placental perfusion studies: views of the researchers. AB - Within the EU-project NewGeneris human placental perfusion has been used for predicting fetal exposure to food carcinogens. Within the work package of ethical aspects of the research, we studied opinions of the researchers (n = 23) who carried out perfusions of human placenta. Data were collected by focus group interviews (n = 12) and an open-ended questionnaire (n =19 of which 8 were also attending the group session) from scientists representing 9 different nationalities. Both types of data were analysed together thematically and with data triangulation. Studied researchers considered communication between all stakeholders extremely important. Good communication was considered a prerequisite for the recruitment of mothers to donate the placenta, as well as for the process of getting the informed consent. Voluntariness, confidentiality and societal meaning were mentioned as important by all studied researchers. Educating the hospital personnel was regarded as essential in order to provide the best possible information to the mothers. The researchers also pointed out that cultural aspects should be respected, and that in Western thinking placenta is mostly considered as waste. Some researchers suggested that current guidelines and processes for obtaining informed consent should be reviewed also from a cultural perspective. With the development of biobanks, the use of human tissues, including placenta will most probably increase in the future, and the awareness of ethical considerations both in legislation and in practice need support. Thus, continuous effort for better research ethics is essential and requires research on research ethics. PMID- 21524792 TI - Overexpression of transient receptor potential canonical type 1 (TRPC1) alters both store operated calcium entry and depolarization-evoked calcium signals in C2C12 cells. AB - When the intracellular calcium stores are depleted, a Ca(2+) influx is activated to refill these stores. This store-operated Ca(2+) entry (SOCE) depends on the cooperation of several proteins as STIM1, Orai1, and, possibly, TRPC1. To elucidate this role of TRPC1 in skeletal muscle, TRPC1 was overexpressed in C2C12 cells and SOCE was studied by measuring the changes in intracellular Ca(2+) concentration ([Ca(2+)](i)). TRPC1 overexpression significantly increased both the amplitude and the maximal rate-of-rise of SOCE. When YM-58483, an inhibitor of TRPC1 was used, these differences were eliminated, moreover, SOCE was slightly suppressed. A decrease in the expression of STIM1 together with the downregulation of SERCA was confirmed by Western-blot. As a consequence, a reduction in maximal Ca(2+) uptake rate and a higher resting [Ca(2+)](i) following the Ca(2+) transients evoked by 120mM KCl were detected. Morphological changes also accompanied the overexpression of TRPC1. Differentiation of the myoblasts started later, and the myotubes were thinner in TRPC1-overexpressing cultures. For these changes the observed decrease in the nuclear expression of NFAT1 could be responsible. Our results suggest that enhanced expression of TRPC1 increases SOCE and has a negative effect on the STIM1-Orai1 system, indicating an interaction between these proteins. PMID- 21524793 TI - Ecofriendly degradation, decolorization and detoxification of textile effluent by a developed bacterial consortium. AB - Present study illustrates the effectual decolorization and degradation of the textile effluent using a developed bacterial consortium SDS, consisted of bacterial species Providencia sp. SDS and Pseudomonas aeuroginosa strain BCH, originally isolated from dye contaminated soil. The intensive metabolic activity of the consortium SDS led to complete decolorization of textile effluent within 20 h at pH 7 and temperature 30 degrees C. Significant induction in the activities of veratryl alcohol oxidase, laccase, azoreductase and DCIP reductase were observed during decolorization, which indicates their involvement in decolorization and degradation process. The decolorization and biodegradation was monitored using UV-vis spectroscopy, IR spectroscopy, HPLC and HPTLC analysis. Toxicological analysis of effluent before and after treatment was performed using classical Allium cepa test. Investigations of various toxicological parameters viz, oxidative stress response, cytotoxicity, genotoxicity and phytotoxicity, collectively concludes that, the toxicity of effluent reduces significantly after treatment with consortium SDS. PMID- 21524794 TI - Sexual offenders with serious mental illness: prevention, risk, and clinical concerns. AB - Individuals with serious and persistent mental illness who have also engaged in illegal sexual behavior present a unique challenge for our legal and clinical systems. Frequently, these individuals may engage in problematic sexual behaviors which result in hospitalization rather than incarceration, and an overburdened and resource-deficient public community mental health system is ill-equipped to address the seriousness of these sexual behaviors. We have a rather limited understanding of how prevention programs, intervention strategies, and risk assessment would work with this population. Here we evaluate data from a sample of 245 inpatient psychiatric sexual offenders in a forensic mental health setting and compare these with what information has already been presented in some of the literature. Through an examination of seriously mentally ill sexual offenders and their clinical presentation, legal history, and risk management concerns, we illustrate a variety of tertiary prevention needs. Future directions in the area of prevention and risk management for seriously mentally ill sexual offenders are also discussed. PMID- 21524795 TI - Evaluation of exposure reduction to indoor air pollution in stove intervention projects in Peru by urinary biomonitoring of polycyclic aromatic hydrocarbon metabolites. AB - Burning biomass fuels such as wood on indoor open-pit stoves is common in developing regions. In such settings, exposure to harmful combustion products such as fine particulate matter (PM(2.5)), carbon monoxide (CO) and polycyclic aromatic hydrocarbons (PAHs) is of concern. We aimed to investigate if the replacement of open pit stoves by improved stoves equipped with a chimney would significantly reduce exposure to PAHs, PM(2.5) and CO. Two stove projects were evaluated in Peru. Program A was part of the Juntos National Program in which households built their own stoves using materials provided. In Program B, Barrick Gold Corporation hired a company to produce and install the stoves locally. A total of 30 and 27 homes participated in Program A and B, respectively. We collected personal and kitchen air samples, as well as morning urine samples from women tasked with cooking in the households before and after the installation of the improved stoves. Median levels of PM(2.5) and CO were significantly reduced in kitchen and personal air samples by 47-74% after the installation of the new stoves, while the median reduction of 10 urinary hydroxylate PAH metabolites (OH PAHs) was 19%-52%. The observed OH-PAH concentration in this study was comparable or higher than the 95th percentile of the general U.S. population, even after the stove intervention, indicating a high overall exposure in this population. PMID- 21524796 TI - Guest editorial. Environmental fate and effects of nanoparticles. PMID- 21524798 TI - Smiling in newborns during communicative wake and active sleep. AB - Many studies have investigated infant smiling behaviour during wake and active sleep. In the majority of studies authors agreed that two month-old infants exhibit social smiles. However it is not clear if newborns exhibit different kinds of smiles during wake and active sleep to two month-old infants and if the communicative context can affect the quantity and quality of these smiles. The aim of this study was to test if different kinds of communication affects the amount and the quality of smiles during different behavioural states. Smiling behaviour was analyzed during interactive wake (IW) and active sleep (AS), in 40 newborns randomly assigned to 4 groups of 10 newborns each: continuous tactile communication group, discontinuous non periodic tactile communication group, discontinuous periodic tactile communication group, absent communication group. In the total sample the open/closed mouth (social/non social) smiles ratio was 38/5 during IW and 1/28 during AS (p < .001). Moreover these ratios were different between the four groups. Different kinds of tactile communication affect amount and quality of the smiles of newborns during IW and AS. Moreover the morphological difference of the smiles during IW and AS suggested that for newborns the smiling behaviour during IW could have a social meaning, as it does for two month-old infants. PMID- 21524797 TI - Phthalates exposure of Chinese reproductive age couples and its effect on male semen quality, a primary study. AB - Phthalates are suspected of having adverse effects on androgen-regulated reproductive development in animals and may be toxic for human sperm. The purposes of our study were to investigate the general exposure of a Chinese reproductive age cohort to these ubiquitous pollutants and to assess their potential effect on semen quality. Six phthalate metabolites, monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-2-ethylhexyl phthalate (MEHP), and mono-2-ethyl-5-oxohexyl phthalate (MEOHP) were measured in spot urines of 150 individuals recruited from a Chongqing, China, reproductive institute. The questionnaire and clinical data were evaluated, and the correlations of phthalate exposure and semen qualities like semen volume, sperm concentration, motility and sperm motion parameters, were determined by multiple logistic regression analysis. The creatinine adjusted average concentrations for MMP, MEP, MBP, MBzP, MEHP and MEOHP were 41.3, 300, 41.0, 0.78, 2.99 and 3.90 MUg/g, respectively. After adjustment for age, body mass index (BMI), abstinence, smoking, drinking, and education, there was a borderline-significant dose-response relationship between MBP and sperm concentration, with odd ratios (ORs) 1.0, 6.8 and 12.0 for increasing exposure tertiles (p=0.05). Although the dose-response relationships for MMP and MEP versus sperm concentration were not significant, a significant positive correlation between MEP and straight-line velocity of sperm motion was observed. The present data may imply some effects of phthalate exposure on semen. However, due to the small sample size, our finding needs to be confirmed on a larger population. PMID- 21524799 TI - Association study between plasma GDNF and cognitive function in late-onset depression. AB - OBJECTIVE: Improving evidence suggest that neurotrophic growth factor systems might be involved in the pathophysiology of major depressive disorder (MDD). The glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor from the transforming growth factor-beta-family, which plays a role in the development and function of hippocampal cells. This study was aimed to test whether GDNF in plasma was abnormal in late-onset depression (LOD), and whether it was associated with the cognitive impairment of LOD. METHODS: The plasma GDNF levels in LOD patients (n=27) before antidepressant treatment and normal control subjects (n=28) were measured with the ELISA method. All subjects were assessed by neuropsychological tests and Hamilton Depression Rating Scale (HDRS). RESULTS: The performance of neuropsychological tests of the LOD group except TMT-B was significantly poorer than those of the control group. The plasma GDNF levels in LOD patients were significantly increased compared to control subjects (P<0.05). Furthermore, the increase of plasma GDNF level was significantly positively correlated with Digit Span Test backward score in LOD patients, and negatively associated with TMT-B performance. CONCLUSIONS: The findings suggest that LOD patients in acute phase have extensive impairments of cognitive function, and higher plasma GDNF might be involved in the pathogenesis of LOD, which may be associated with the cognitive dysfunction in LOD. PMID- 21524800 TI - The association between trauma and delusional-like experiences. AB - Individuals exposed to childhood trauma are more likely to report delusional-like experiences (DLE). This study examined the association between trauma exposure and DLE in a large community sample, investigating different trauma types and age at-first-exposure to trauma. Subjects were from the Australian National Survey of Mental Health and Wellbeing 2007. Associations between DLE and (i) exposure to different trauma types and (ii) age-at-first-exposure were assessed using logistic regression with adjustments for potential confounding factors. 8.4% of 8773 subjects reported DLE and almost 75% reported at least one traumatic event. Exposure to a traumatic event was significantly associated with more than twice the odds of delusional-like experiences and exposure to more types of trauma increased the likelihood of DLE in a dose dependent fashion. The majority of the individual trauma items were independently associated with any endorsement of DLE. First exposure of trauma in childhood, adolescence and adulthood was all associated with DLE. Further understanding of biological and cognitive pathways is required to unravel the association between trauma exposure and delusional like experiences. PMID- 21524801 TI - Vaccine development for the prevention of staphylococcal mastitis in dairy cows. AB - Staphylococci are the most common and costly mammary disease of dairy cattle worldwide. Target of RNAIII Activating Protein (TRAP), a membrane associated 167AA protein, is highly conserved among staphylococci and was shown in Staphylococcus aureus to be involved in bacterial stress response. The aims of this study were to test the safety and efficacy of recombinant TRAP (rTRAP) vaccine in dairy animals. The vaccine was safe as 2-3 subcutaneous injections of rTRAP (54-100 MUg) with adjuvant ISA 206 to cows and goats did not lead to any abnormal symptoms of sensitivity to the vaccine. The rTRAP vaccine was immunogenic and caused the induction of a humoral immune response that remained high for at least 160 d post second immunization. The rTRAP vaccine was efficacious; at parturition only 13.5% (5/37) heifers in the immunized group were infected with Staphylococcus chromogenes as compared to 42.9% (18/42) in the non immunized group. Additionally, when cows were immunized in mid-lactation, the difference between somatic cell count (SCC) in immunized and control animals was profound (45 +/- 7 vs. 470 +/- 194, respectively). At the same time, the difference in milk yield was also evident (48.3 +/- 1.4 L d(-1)vs. 44.3 +/- 0.9 L d(-1), respectively). Put together, these studies indicate the value of the rTRAP vaccine in preventing new udder infections by staphylococci, which significantly lead to lowered SCC and some increase in milk yield. TRAP is conserved among all strains and species and is constitutively expressed in any strain of S. aureus or CNS tested so far, including those isolated from cows. TRAP may thus serve as a universal anti-staphylococcus vaccine. PMID- 21524802 TI - Transfer of humoral and cell-mediated immunity via colostrum in pigs. AB - The first aim of our study was to obtain information on the transmission of antigen-specific antibodies from colostrum to respiratory tract mucosa in piglets. The second aim was to confirm the biological relevance of the presence of lymphocytes in colostrum and the already described fact that these cells can penetrate the intestinal barrier and "colonize" peripheral blood and lymphatic tissues of piglets. Therefore, we performed an experiment in which sows were immunized with a model antigen Keyhole Limpet Hemocyanin and their piglets were euthanized at different intervals after birth and colostrum intake. Colostrum, bronchoalveolar lavage fluid and blood samples were collected for serological detection of antigen-specific antibodies. Lymphocytes isolated from peripheral blood and lymphatic tissues (mesenteric and tracheobronchial lymph nodes and spleen) of piglets were in vitro activated with the antigen. We found that colostrum-derived antibodies can cross into the respiratory tract mucosa. Furthermore, we found that antigen-specific lymphocytes were detectable in mesenteric lymph nodes and peripheral blood, but very rarely in spleen and tracheobronchial lymph nodes. PMID- 21524803 TI - Bilateral superior semicircular canal dehiscence in a child with sensorineural hearing loss and without vestibular symptoms. AB - To report a rare case of bilateral superior semicircular canal dehiscence (SCCD) in a child. Case report, 11-year-old female patient. Descriptive case report. Audiological findings of bilateral symmetrical low frequency sensorineural hearing loss with ascending curves and bilateral superior semicircular canal dehiscence on a high resolution computed tomography (CAT) scan. The young child presented with bilateral fluctuating hearing loss with no vestibular symptoms. She was found to have bilateral superior semicircular canal dehiscence. We hereby present a rare case of bilateral semicircular canal dehiscence found incidentally on high resolution CAT scan in a young child during work up for bilateral sensorineural hearing loss. PMID- 21524804 TI - Evaluation of cochlear involvement by transient evoked otoacoustic emission test in children with Crimean-Congo hemorrhagic fever. AB - OBJECTIVE: The aim of this study was to investigate cochlear involvement in child patients with Crimean-Congo hemorrhagic fever (CCHF) disease. METHODS: Twenty eight CCHF disease patients (56 ears) and 26 sex- and age-matched healthy control subjects (52 ears) were included in the study. Pure-tone audiometry at frequencies 0.25, 0.5, 1, 2, 4, and 6 kHz, immittance measures including tympanometry and acoustic reflex testing, and transient evoked otoacoustic emission (TEOAE) testing were performed in the patients and controls. RESULTS: The proportion with a result of 'fail' for the TEOAE test in the CCHF patients was not statistically significant from the control group (p>0.05). CONCLUSIONS: CCHF disease does not impair cochlear function in children. The clinical course of CCHF among children seems to be milder than in adults. PMID- 21524805 TI - Treatment of congenital nasal cavity stenosis by balloon dilatation in a newborn: a case report. AB - Neonates are obligate nasal breathers, and any form of neonatal nasal obstruction may have serious consequences. Prompt diagnosis and appropriate treatment are essential to avoid severe hypoxia. Congenital bony nasal stenosis (CBNS) is an extremely rare cause of neonatal nasal airway obstruction and can easily be confused with choanal atresia or stenosis. This is a paper to describe a balloon dilatation technique that can be an effective alternative to surgery for the treatment of congenital nasal cavity stenosis, with minimal stress to the patient. PMID- 21524806 TI - Epidemiology of foreign bodies injuries in Ecuador: a first look based on a single centre experience. AB - OBJECTIVE: The analysis of foreign bodies (FB) injuries in the upper aero digestive tract is not available for Ecuador and in this context, the present article represent the is the first presenting to the international community the basic epidemiological data on the Ecuador's experience on foreign bodies juries. METHODS: Data on 258 cases were gleaned using Susy Safe database, choosing the cases coming from Ecuador's institutions, namely Francisco De Icaza Bustamante Children Hospital, in Guayaquil (Ecuador) which collects data on children injuries due to foreign bodies with the aid of a standardized case report forms. RESULTS: Patients showed a female:male ratio of 1:1.2. Fifty-three percent of the children were younger than 2 years of age, with a mean age of 3.22 years. The most frequent location of retrieval was the oesophagus (37.98%) followed by the ears (34.88%). Coins were the most frequent cause of accident (37.21%). Seeds and grain were the most frequent food FBs and they were seen in 13.95% of cases. Adult presence was recorded in 113 cases. There was indeed a significant correlation between the presence of an adult and the activity that the children were doing when the incident occurred. CONCLUSIONS: This first breach into the analysis of injuries in Ecuador gives the confirmation that the results coming from country's data agreed with the general Susy Safe ones. Similar preventive strategies are therefore highly recommended, stressing that primary prevention has the main role in children's protection. PMID- 21524807 TI - Coordination dynamics of elliptic shape drawing: effects of orientation and eccentricity. AB - The aim of the present study was to show the effect of orientation on producing ellipses of various eccentricities. Ten right-handed adults were required to reproduce eight series of 84 ellipses on a graphic tablet at spontaneous speed. The ellipses displayed seven eccentricities, corresponding to the Lissajous plot produced by two orthogonal harmonic oscillators whose relative phase (RP) varied from 0 degrees (a line) to 90 degrees (a circle), and twelve orientations, the long axis of the ellipses aligned in a direction ranging from three to nine o'clock with respect to the body transverse plane. Results confirmed the participant's preference for two eccentricities, 0 degrees and 45 degrees , that is, a line and an ellipse of intermediate eccentricity, respectively. Except for the circle, insensitive to orientation by definition, orientation became a cogent constraint: In the 10:30 o'clock direction, line drawing (0 degrees RP) increased in variability and the intermediate ellipse (45 degrees RP) was attracted towards a circle (90 degrees RP). These findings suggest an interaction between orientation effects, putatively due to differences in the motion of the wrist and fingers, and eccentricity effects, which may pertain to preferences arising from the non-linear coupling between the effectors. PMID- 21524808 TI - Contextual interference and augmented feedback: is there an additive effect for motor learning? AB - Learning to perform a skilled behavior is affected by the context of the practice session and the frequency of augmented feedback. We studied the combined effect of these variables in the acquisition of a ballistic, bi-directional lever movement pattern involving four different target locations as measured by performance in practice, retention, and transfer tests. Augmented feedback was presented in either an every-trial or a faded schedule during random and blocked practice. Consistent with the contextual interference effect, the blocked practice group produced lower errors in acquisition, but the random practice group outperformed the blocked practice group in both retention and transfer. In contrast, faded feedback did not have a beneficial effect on learning and degraded learning when provided during blocked practice. While the results were consistent with previous findings of random and blocked practice, they were not consistent with previous findings of reduced feedback frequencies. PMID- 21524809 TI - Clinical implications of the early detection of urinary microalbumin in diabetic patients using a new high performance liquid chromatography (HPLC) method. AB - We assessed urine albumin in 180 diabetics by conventional immunonephelometry (IN) and HPLC methods. Those with HPLC but not IN detectable albuminuria had higher BP, worse glycaemic control and more vascular events (p<0.05 for all) but received fewer vascular risk reduction treatments. PMID- 21524810 TI - Utilization patterns and cost of complementary and alternative medicine compared to conventional medicine in patients with type 2 diabetes mellitus. AB - AIMS: We evaluated the use and annual cost of complementary and alternative medicine (CAM) compared to conventional medicine in type 2 diabetes mellitus (DM) in the Korean population. METHODS: We analyzed the database of 2752 DM patients obtained from the Korean National Diabetes Program (KNDP). The cost data of conventional medicine starting 1-year before enrolment of the KNDP were obtained from the hospital electronic database. The cost data of CAM over the same period were obtained from questionnaires. RESULTS: Among the 2752 subjects, 677 patients (24.6%) used CAM, with the most common type being red ginseng and herbal medicine. Patients with a higher income, neuropathy, and self-monitoring of blood glucose (SMBG) were more likely to use CAM. Men, those with a higher education level and income, no cerebrovascular accident (CVA) history, and SMBG showed a relatively higher cost of CAM of total medical cost. The independent predictors for CAM were a higher income, the existence of diabetic neuropathy, no CVA history, and SMBG. CONCLUSIONS: Use and cost of CAM varied depending on income, accompanying complications and SMBG. To evaluate the total medical costs in DM patients, a comprehensive approach considering not only conventional cost but also CAM is required. PMID- 21524811 TI - Three-year experience with alendronate treatment in postmenopausal osteoporotic Japanese women with or without type 2 diabetes. AB - AIMS: The increased risk of fractures in patients with type 2 diabetes can partly be explained by poor bone quality and extra-skeletal factors. A retrospective study was conducted to compare the outcome of alendronate (ALN) treatment for 3 years in postmenopausal osteoporotic Japanese women with or without type 2 diabetes. METHODS: One-hundred and fifty-one postmenopausal osteoporotic Japanese women (mean age at baseline: 67.8 years) who had been treated with ALN for more than 3 years in our outpatient clinic were analysed. The lumbar spine bone mineral density (BMD) was measured using dual energy X-ray absorptiometry, and the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) and the serum levels of alkaline phosphatase (ALP) were monitored during the 3-year treatment period. The incidence of osteoporotic fractures was also assessed. RESULTS: Sixteen women had type 2 diabetes and were receiving pharmacological treatment, and 135 were non-diabetic. The urinary NTX and serum ALP levels significantly decreased and the lumbar spine BMD significantly increased, compared with the baseline values, without causing any severe adverse events including osteonecrosis of the jaw, femoral diaphysis atypical fractures, and atrial fibrillation, in a manner that was similar among women with type 2 diabetes and non-diabetics. However, the incidence of non-vertebral fractures was significantly higher among women with type 2 diabetes than among the non diabetics. CONCLUSIONS: ALN treatment appeared to have the similar effect on surrogate markers in postmenopausal osteoporotic Japanese women with or without type 2 diabetes. Because of lacking in statistical power for fracture incidence due to the small sample size, further studies are warranted to confirm the results of the fracture incidence. PMID- 21524812 TI - Anti-diabetic effect of standardized herbal formula PM021 consisting of Mori Folium and Aurantii Fructus on type II diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. AB - PM021, which consists of two herbal components, Mori Folium and Aurantii Fructus, is routinely used to treat diabetes in Korea. In this study, the anti-diabetic effect of PM021 on an animal model of developing type 2 diabetes of Otsuka Long Evans Tokushima Fatty (OLETF) rats was investigated. Eight weeks of age male OLETF rats were treated daily with PM021 or vehicle for five months. Specifically, changes in body weight, blood glucose, urine volume, food intake and oral glucose tolerance were measured in rats for five months. The rats in this study were divided into four groups: a Long-Evans Tokushima Otsuka (LETO) rat group, which is a genetic control group for OLETF, that received no treatment; a PM021 treatment group of LETO rats; OLETF rats that received no treatment; and OLETF rats that received PM021 treatment. The results showed that PM021 significantly prevented increases in body weight, blood glucose, and urine and food intake that resulted from the induction of obesity and diabetes. PM021 also improved glucose tolerance in OLETO rats. However, PM021 had no effect on LETO rats, a control group of OLETF rats. Taken together, these findings indicate that PM021 has distinct anti-diabetic effects without any adverse effects or toxicities. PMID- 21524813 TI - A hybrid system based on information gain and principal component analysis for the classification of transcranial Doppler signals. AB - A transcranial Doppler (TCD) is a non-invasive, easy to apply and reliable technique which is used in the diagnosis of various brain diseases by measuring the blood flow velocities in brain arteries. This study aimed to classify the TCD signals, and feature ranking (information gain - IG) and dimension reduction methods (principal component analysis - PCA) were used as a hybrid to improve the classification efficiency and accuracy. In this context, each feature within the feature space was ranked depending on its importance for the classification using the IG method. Thus, the less important features were ignored and the highly important features were selected. Then, the PCA method was applied to the highly important features for dimension reduction. As a result, a hybrid feature reduction between the selection of the highly important features and the application of the PCA method on the reduced features were achieved. To evaluate the effectiveness of the proposed method, experiments were conducted using a support vector machine (SVM) classifier on the TCD signals recorded from the temporal region of the brain of 82 patients, as well as 24 healthy people. The experimental results showed that using the IG and PCA methods as a hybrid improves the classification efficiency and accuracy compared with individual usage. PMID- 21524814 TI - The role of positron emission tomography in management of small cell lung cancer. AB - Accurate radiological staging of small-cell lung cancer (SCLC) is of paramount importance in selection of individual patients with limited stage disease for potentially curative treatment while avoiding toxic treatment in those with distant metastatic disease. [(18)F] flurodeoxy-D-glucose (FDG) positron emission tomography (PET) is an attractive tool for this purpose but there is limited evidence to support its use in the routine staging of SCLC. Whether therapeutic decisions based on FDG-PET imaging should be made remains uncertain. There is only preliminary evidence for use of FDG-PET as a prognostic biomarker, in the assessment of response to treatment and delineation of disease in conformal radiation planning. PMID- 21524815 TI - Wound healing gene therapy: cartilage regeneration induced by vascular endothelial growth factor plasmid. AB - AIMS: The identification of growth factors and cytokines with angiogenic activity has enabled new therapeutic treatments for a variety of diseases; this concept is called therapeutic angiogenesis. The vascular endothelial growth factor (VEGF) is the most critical regulator of vascular formation. In the present study, we were interested in the therapeutic angiogenesis effect using plasmid transfer of human complementary DNA VEGF(165) (phVEGF(165)) in experimental skin and cartilage trauma. METHODS: Ten BALB/c mice were used for cartilage injury model. At 6 weeks of age, all mice were ear-punched, resulting in 2-mm-diameter puncture through the center of both pinnae. Each mouse got phVEGF(165) injection into the first ear and vector without insert or saline injection into the second one. The healing process was followed. The hollow diameter was measured on days 0, 14, and 42. Histological sections of experimental and control pinnae were taken from days 1, 3, 5, 7, 9, 11, 13, 15, 20, and 30 after experimental injury for hematoxylin and eosin and periodic acid Schiff staining and for human VEGF immunocytochemistry. The expression of human VEGF was also checked by real-time polymerase chain reaction in formalin-fixed, paraffin-embedded tissue sections. KEY FINDINGS: In BALB/c mouse strain, a significant angiogenesis promotion and cartilage repair were observed after phVEGF(165) injection into the punched ear area. SIGNIFICANCE: We suggest that administering phVEGF(165) leads to faster cartilage regeneration even if not only on the angiogenic basis. PMID- 21524816 TI - A retrospective study of induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiotherapy with cetuximab in locally advanced head and neck cancer. AB - BACKGROUND: The objective was to study the results of induction chemotherapy followed by external beam radiation therapy with concurrent cetuximab in the treatment of locally advanced head and neck cancer. METHODS: Seventeen patients with stage III or IV squamous cell carcinomas of the head and neck who received docetaxel, cisplatinum, and 5-fluorouracil followed by radiation therapy with concurrent cetuximab were retrospectively analyzed. All radiation was delivered with image-guided intensity-modulated radiation treatments. Primary end points analyzed were local control and overall survival. RESULTS: With a median follow up of 17 months, the approximate 2-year local control was 85%, with overall survival being 91%. At time of last follow-up, only 1 death was observed, with the cause of death unknown. Two local failures were observed, and the patients were under active management for their recurrences at time of last follow-up. No distant metastatic failures were noted among the patients. CONCLUSIONS: Induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiation with cetuximab provides for excellent locoregional control of disease. Future prospective studies can better establish the efficacy of this treatment regimen to current favored protocols. PMID- 21524817 TI - [Detection of therapeutic non-compliance and pharmaceutical intervention in institutionalised geriatric patients]. AB - OBJECTIVE: To detect and analyse therapeutic non-compliance in the institutionalised elderly patient who self-administer their own treatment in a geriatric residence. To assess the pharmaceutical intervention with a useful tool to detect non-compliance. MATERIAL AND METHODS: An observational study on a population of 386 residents. A clinical interview was conducted on those who treated themselves by the Pharmacy Department. An individual case report card was prepared to record demographic and clinical data, and incidents found). An interview was conducted on their treatment (drugs, dose, posology, indication and administration form), together with the compliance test validated by Morinsky Green. Non-compliance was calculated by comparing the responses with the pharmacotherapeutic information from the Pharmacy Department and from the medical prescription of the medical charts. RESULTS: Eleven per cent of patients administered their own treatment. Their mean age was 84 years and all attended the interview, which detected a non-compliance of 41%. The compliance test only detected 55% of the non-compliers. The main errors were non-compliance to the time, incorrect dosage and not taking treatment when feeling better. There was 39% involuntary non-compliance. The cardiovascular system drug group was the most involved in errors. The error could have a clinically significant repercussion in 44% of the patients. CONCLUSIONS: The interview helped to detect and analyse non compliance. The test, although specific, was not very sensitive. The main errors were easy to correct and there no problems of acceptance by the patients. With it being fundamental to preserve function and to prevent progression to dependence, and adding to this the administering of drugs, pharmaceutical intervention is a useful tool to detect and correct errors and increase adherence. PMID- 21524818 TI - [When and by how much should we lower the systolic blood pressure in the elderly? The debate continues]. PMID- 21524819 TI - [Inappropriate prescribing in the elderly: clinical tools beyond the simple assessment]. PMID- 21524820 TI - [Fat embolism after joint prosthesis in a geriatric patient]. PMID- 21524821 TI - [Crisis in family medicine? Perhaps someone in the profession has got it wrong?]. PMID- 21524822 TI - [Before and after glomerular filtration]. PMID- 21524823 TI - [Interobserver agreement in the visual and semi-quantitative analysis of the 123I FP-CIT SPECT images in the diagnosis of Parkinsonian syndrome]. AB - AIMS: Using (123)I-FP-CIT SPECT images makes it possible to identify presynaptic deterioration of the dopaminergic pathway by studying the dopamine transporter (DAT). A correct analysis of the SPECT images contributes to an adequate interpretation and diagnosis of movement disorders. Aims: 1. To compare visual and semiquantitative analysis of (123)I-FP-CIT SPECT images in patients with movement disorders. 2. To evaluate interobserver agreement in visual and semiquantitative analysis. 3. To obtain a cut-off in the semiquantitative analysis to discriminate primary Parkinsonism Syndrome (PS) from non-primary PS. METHODS: A (123)I-FP-CIT SPECT was performed in 32 patients with movement disorders suggestive of primary PS. Visual and semiquantitative images analyses were performed independently by two nuclear medicine physicians. Visual analysis was based on the visual interpretation. Semiquantitative analysis was calculated as specific uptake (caudate, putamen and striatum) versus non-specific uptake (occipital). Sensitivity, specificity, PPV, and NPV were calculated. Data were compared using ANOVA test followed by Bonferroni post-hoc test. Interobserver agreement of the visual and semiquantitative analysis was assessed by intraclass correlation coefficient and Kappa statistics, respectively. ROC curve was generated with semiquantitative data. RESULTS: Visual analysis showed 86% sensitivity and 100-88% specificity for the differential diagnosis of primary PS from non-primary PS. Semiquantitative analysis showed a gradual hypo-uptake proportional to the disease severity obtained in the visual analysis. Semiquantitative analysis did not provide any additional information to the visual analysis. Intraclass correlation coefficient and Kappa statistics showed 0.92 and 0.80 values, respectively. The Cut-off value to differentiate primary PS from non-primary PS was 1.9 on the putamen index. PMID- 21524824 TI - [Measurement of 75Se-SeHCAT abdominal retention in the initial diagnosis of Bile Acid Absorption (BAM)]. AB - AIM: To evaluate the usefulness of the (75)SeHCAT abdominal retention (AR) measurement in the early diagnosis of diarrhea syndrome (DS). METHODS: Thirty seven patients with diarrhea syndrome within the first month of evolution were prospectively evaluated. The (75)Se-SeHCAT abdominal retention was measured 4 and 7 days post-administration of 0.01 mCi of (75)SeHCAT. The test was performed prior to treatment and at 3 months when the baseline study was positive. The test was considered positive if the RA was <25% at 4(th) and <10% on the 7th day. The patients were visited at 3 months. Depending on the response, 3 groups were established: a) complete response: normalization of stool frequency, b) partial response, decrease of frequency or c) no response. RESULTS: Group A: The AR of (75)Se-SEHCAT was normal in 21 patients. Six were diagnosed of colonic diverticulosis, 8 of irritable bowel syndrome, 1 of lymphocytic colitis, 1 of post-gastroenteritis syndrome, 1 of celiac disease and 1 of stenosis of the cardia. Four are still under study. Group B: The AR of (75)Se-SEHCAT decreased in 16 patients. All showed abnormal AR at day 7 and all but 1 at day 4. Following administration of cholestyramine resin, 8 (50%) presented partial response and 8 (50%) complete response. At 3 months, AR had increased at day 4 and 9 at day 7. CONCLUSION: The measurement of (75)SEHCAT abdominal retention allows the early diagnosis of bile acid malabsorption in 43% of the patients with DS. Measurement at 7 days seems more accurate than that at 4 days. PMID- 21524825 TI - [Identification of the lymph node drainage and selective sentinel lymph node biopsy in a patient with amelanotic melanoma of the uvula]. PMID- 21524826 TI - [Adaptation of the (18)FDG module for the preparation of a sodium fluoride [(18)F] injection solution in agreement with the United States (USP 32) and European Pharmacopeia (PhEur 6)]. AB - OBJECTIVE: To establish an automated procedure for the preparation of sodium fluoride (18)F injection using the resources available in our laboratory for the preparation of (18)FDG and to analyze the repercussion of the conditioning column of the fluoride ion entrapment on the characteristics of the final product. MATERIAL AND METHOD: The sequence of an (18)FDG synthesis module prepared so that it traps the fluoride ion from the cyclotron in ion-exchange resin diluted with 0.9% sodium chloride. The final solution was dosified and sterilized in a final vial in an automatized dispensing module. Three different column conditioning protocols within the process were tested. Quality controls were run according to USP 32 and EurPh 6, adding control of ethanol levels of residual solvent and quality controls of the solution at 8 h post-preparation. RESULTS: Activation of the resin cartridges with ethanol and water was the chosen procedure, with fluoride ion trapping > 95% and pH around 7. Ethanol levels were < 5.000 ppm. Quality controls at 8 h indicated that the solution was in compliance with the USP 32 and EurPh 6 specifications. CONCLUSION: This is an easy, low-cost, reliable automated method for sodium fluoride preparation in PET facilities with existing equipment for (18)FDG synthesis and quality control. PMID- 21524827 TI - Synthesis and antibacterial activity of novel 4"-O-benzimidazolyl clarithromycin derivatives. AB - Novel 4"-O-benzimidazolyl clarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. These benzimidazolyl derivatives exhibited excellent activity against erythromycin-susceptible strains better than the references, and some of them showed greatly improved activity against erythromycin-resistant strains. Compounds 16 and 17, which have the terminal 2-(4-methylphenyl)benzimidazolyl and 2-(2-methoxyphenyl)benzimidazolyl groups on the C-4" bishydrazide side chains, were the most active against erythromycin-resistant Staphylococcus pneumoniae expressing the erm gene and the mef gene. In addition, compound 17 exhibited the highest activity against erythromycin-susceptible S. pneumoniae ATCC49619 and Staphylococcus aureus ATCC25923 as well. It is worth noting that the 4"-O-(2-aryl)benzimidazolyl derivatives show higher activity against erythromycin-susceptible and erythromycin-resistant strains than the 4"-O-(2-alkyl)benzimidazolyl derivatives. PMID- 21524828 TI - The new 5- or 6-azapyrimidine and cyanuric acid derivatives of l-ascorbic acid bearing the free C-5 hydroxy or C-4 amino group at the ethylenic spacer: CD spectral absolute configuration determination and biological activity evaluations. AB - We report on the synthesis of the novel types of cytosine and 5-azacytosine (1 9), uracil and 6-azauracil (13-18) and cyanuric acid (19-22) derivatives of l ascorbic acid, and on their cytostatic activity evaluation in human malignant tumour cell lines vs. their cytotoxic effects on human normal fibroblasts (WI38). The CD spectra analysis revealed that cytosine (5 and 6), uracil (14-16), 6 azauracil (17) and cyanuric acid (21) derivatives of l-ascorbic acid bearing free amino group at ethylenic spacer existed as a racemic mixture of enantiomers, whereas L-ascorbic derivatives containing the C-5 substituted hydroxy group at the ethylenic spacer were obtained in (4R, 5S) enantiomeric form. The stereochemistry of 6-azauracil derivative of l-ascorbic acid (13) was confirmed by X-ray crystal structure analysis. The molecules are self-assembled by one N H?O hydrogen bond, two C-H?O hydrogen bonds and two C-H?pi interactions into three-dimensional framework. Cytostatic activity evaluation indicated that compounds did not show distinctive antiproliferative effects on tested cell line panel. However, the cytosine derivative of l-ascorbic acid (1) containing the C4 C5 double bond conjugated with the lactone moiety produced rather marked growth inhibitory effect on hepatocellular carcinoma (HepG2), metastatic breast epithelial carcinoma (MCF-7) and cervical carcinoma (HeLa) cell lines at micromolar concentrations, but also exerted strong cytostatic effect on WI38. 5 Azacytosine derivative of l-ascorbic acid (2) with a double bond at the C4-C5 conjugated with the lactone moiety displayed potent antitumour activity against tested tumour cell lines with meanIC(50) values ranging from 0.92 to 5.91 MUM. However, this compound also exhibited pronounced cytotoxicity towards WI38. Flow cytometric analysis of the cell cycle revealed that compound 2 triggers S phase arrest, which clearly demonstrates its interference with DNA replication, a key event of cell proliferation. Marked anticancer efficacy of compound 2 supports further in vivo investigation into its possible clinical utility. PMID- 21524829 TI - Novel imidazo[4,5-b]pyridine and triaza-benzo[c]fluorene derivatives: synthesis, antiproliferative activity and DNA binding studies. AB - In the present paper, we have described the synthesis and biological activity of the novel derivatives of imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes (7 21, 24-26, 28-29). A preponderance of these compounds exerted strong cytostatic effects on the panel of seven human tumour cell lines in a dose-dependent manner. In particular, imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes including 2 imidazolinyl derivatives showed the most potent antitumour activity. Similarly, triaza-benzo[c]fluorenes 18 and 20 induced strong growth inhibition of tested tumour cell lines, and showed low cytotoxicity in normal human fibroblasts. DNA interaction studies of these compounds demonstrated that N-methylated 16 and 2 imidazolinyl 28 triaza-benzo[c]fluorenes bind to DNA in an intercalative mode. PMID- 21524830 TI - Second-generation sulfonamide inhibitors of D-glutamic acid-adding enzyme: activity optimisation with conformationally rigid analogues of D-glutamic acid. AB - D-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of d glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-l alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-d-Glu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of d-Glu. The compounds that contained either constrained d-Glu or related rigid d-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4 aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities. PMID- 21524831 TI - The first pharmacophore model for potent G protein-coupled receptor 119 agonist. AB - G protein-coupled receptor 119 (GPR119) has emerged as arguably one of the most exciting targets for the treatment of type 2 diabetes mellitus in the new millennium. Pharmacophore models were developed by using Discovery Studio V2.1 with a training set of 24 GPR119 agonists. The best hypothesis consisting of five features, namely, two hydrogen bond acceptors and three hydrophobic features, has a correlation coefficient of 0.969, cost difference of 62.68, RMS of 0.653, and configuration cost of 15.24, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model shows great success in predicting the activities of the 25 known GPR119 agonists in our test set with a correlation coefficient of 0.933. PMID- 21524832 TI - A novel class of trans-methylpyrazoline analogs of combretastatins: synthesis and in-vitro biological testing. AB - Thirteen methylpyrazoline analogs (1a-m) of combretastatin A-4 (CA-4, 2) were synthesized. The trans-geometry of the two substituted phenyl moieties was ascertained by a single crystal X-ray diffraction study of compound 1d. The cytotoxicities of the analogs against the growth of murine B16 melanoma and L1210 lymphoma cells in culture were measured using the MTT assay. One of the derivatives, 1j, which has the same substituents as CA-4 was the most active in the series with IC(50) values of 3.3 MUM and 6.8 MUM against the growth of L1210 and B16 cells, respectively. The activity of this analog against human cancer cell lines was confirmed in the NCI 60 panel. The other active analogs against L1210 were 1b and 1f, which gave IC(50) values in the 6-8 MUM range. Compound 1j caused microtubule depolymerization with an EC(50) value of 4.1 MUM. This compound has good water solubility of 372 MUM. Molecular modeling studies using DFT showed that compound 1j adopts a "twisted" conformation mimicking CA-4 that is optimal for binding to the colchicine site of tubulin. PMID- 21524833 TI - Body mass index and weight-for-length ratio references for infants born at 33-42 weeks gestation: a new tool for anthropometric assessment. AB - BACKGROUND & AIMS: The risk of childhood obesity, an increasingly prevalent problem worldwide, might be predictable by early body mass index measurements. This study sought to develop body mass index and weight-for-length ratio references for infants born at 33-42 weeks gestation and to validate these data against the growth curves of the World Health Organization Multicenter Growth Reference Study. METHODS: Data were collected from the Neonatal Registry of Rabin Medical Center for all healthy singleton babies born live at 33-42 weeks gestation. Crude and smoothed reference tables and graphs for body mass index and weight-for-length ratio by gestational age were created for males and females, separately. RESULTS: Birth weight, length, and body mass index percentiles for full-term neonates were similar to the World Health Organization study, reinforcing the generalizability of our reference charts for infants born at 33 42 weeks. Cutoff values for small for date (<5th, <10th percentile) and large for date (>85th, >95th percentile) infants differed across gestational ages in both pre-term and full-term infants. CONCLUSIONS: As body proportionality indexes provide an assessment of body mass and fatness relative to length, we suggest that BMI and Wt/L ratio percentiles be added to weight and length growth curves as a routine intrauterine growth assessment at birth. PMID- 21524834 TI - Radiological investigations at the "Taiga" nuclear explosion site: Site description and in situ measurements. AB - In the summer of 2009, we performed a field survey of the "Taiga" peaceful underground nuclear explosion site, the Perm region, Russia (61.30 degrees N, 56.60 degrees E). The explosion was carried out by the USSR in 1971. This paper provides an extended summary of the available published data on the "Taiga" experiment. A detailed description of the site is illustrated by original aerial and ground-level photos. A large artificial lake (700 m long and 350 m wide) currently occupies the central area of the experimental site. The ground lip surrounding the lake is covered by a newly grown mixed forest. In situ measurements, performed in August 2009, revealed elevated levels of the gamma-ray dose rate in air on the banks of the lake "Taiga". Two hot spots were detected on the eastern bank of the lake. The excess of the gamma-ray radiation is attributable to the man-made radionuclides (60)Co and (137)Cs. The current external gamma-ray dose rate to a human from the contaminations associated with the "Taiga" experiment was between 9 and 70 MUSv per week. Periodic monitoring the site is recommended. PMID- 21524835 TI - A methodology for building culture and gender norms into intervention: an example from Mumbai, India. AB - This paper responds to the call for culturally-relevant intervention research by introducing a methodology for identifying community norms and resources in order to more effectively implement sustainable interventions strategies. Results of an analysis of community norms, specifically attitudes toward gender equity, are presented from an HIV/STI research and intervention project in a low-income community in Mumbai, India (2008-2012). Community gender norms were explored because of their relevance to sexual risk in settings characterized by high levels of gender inequity. This paper recommends approaches that interventionists and social scientists can take to incorporate cultural insights into formative assessments and project implementation These approaches include how to (1) examine modal beliefs and norms and any patterned variation within the community; (2) identify and assess variation in cultural beliefs and norms among community members (including leaders, social workers, members of civil society and the religious sector); and (3) identify differential needs among sectors of the community and key types of individuals best suited to help formulate and disseminate culturally-relevant intervention messages. Using a multi-method approach that includes the progressive translation of qualitative interviews into a quantitative survey of cultural norms, along with an analysis of community consensus, we outline a means for measuring variation in cultural expectations and beliefs about gender relations in an urban community in Mumbai. Results illustrate how intervention strategies and implementation can benefit from an organic (versus a priori and/or stereotypical) approach to cultural characteristics and analysis of community resources and vulnerabilities. PMID- 21524836 TI - [Transesophageal endobronchial ultrasound-guided fine-needle aspiration]. PMID- 21524838 TI - Maternal cardiac arrest--rarely occurs, rarely researched. PMID- 21524837 TI - Association between Cerebral Performance Category, Modified Rankin Scale, and discharge disposition after cardiac arrest. AB - BACKGROUND: Cerebral Performance Category (CPC), Modified Rankin Scale (mRS) and discharge disposition are commonly used to determine outcomes following cardiac arrest. This study tested the association between these outcome measures. METHODS: Retrospective chart review of subjects who survived to hospital discharge between 1/1/2006 and 12/31/2009 was conducted. Charts were reviewed for outcomes (CPC, mRS, and discharge disposition). Discharge disposition was classified in 6 categories: home with no services, home with home healthcare, acute rehabilitation facility, skilled nursing facility, long term acute care facility, and hospice. Intra-and inter-rater reliabilities were calculated for outcome measures. Rates of "good outcome" (defined as a CPC of 1-2, mRS of 0-3, or discharge disposition to home or acute rehabilitation facility) were also determined. Kendall's tau correlation coefficients explored relationships among measures. RESULTS: A total of 211 charts were reviewed. Mean age was 60 years (SD 16), the majority (75%) were white males, in- and out-of hospital cardiac arrests were equally prevalent, and ventricular dysrhythmia was most common (N=109, 52%). Half of the subjects were comatose following resuscitation and 75 (35%) received therapeutic hypothermia. Inter-rater percentage agreement for CPC and mRS abstraction was 95.24% (kappa 0.89, p<0.001) and 95.24% (kappa 0.90, p<0.001) respectively. "Good outcomes" were found in 44 subjects (20%) using the CPC definition, 47 subjects (22%) using the mRS definition, and 129 subjects (61%) subjects using discharge disposition definition. There was fair relationship between the CPC and mRS (tau 0.43) and poor relationships between CPC and discharge disposition (tau 0.23) and between mRS and discharge disposition (tau 0.25). CONCLUSIONS: Determination of the CPC, mRS and discharge disposition at hospital discharge is reliable from chart review. These instruments provide widely differing estimates of "good outcome". Agreement between these measures ranges from poor to fair. A more nuanced outcome measure designed for the post cardiac arrest population is needed. PMID- 21524839 TI - Irrigation pricing policies and its impact on agricultural inputs demand in Tunisia: a DEA-based methodology. AB - This paper estimates farmers' individual irrigation water demand functions employing the information hidden in individual farmers' technical efficiency. This information is extracted through the development of a new deductive methodology based on inverse Data Envelopment Analysis (DEA) models. The empirical results for Tunisia show that farmers who are more technically efficient have less elastic irrigation water demand functions; these farmers would adjust demand only to a limited extent and they can afford the water price. In contrast, water pricing significantly affects those that are less efficient. These farmers shift towards a different cropping pattern using significantly less water and more land when the price of water increases. Thus, higher water prices would threaten this category's livelihood if their efficiency is not improved. However, if the technical efficiency of these farmers were to improve, then it would be more difficult to reach water saving objectives since their demand will also become highly inelastic. The findings have important implications in view of the objectives of Tunisia water policy which include:full cost recovery, continuity of the irrigation activity, and water saving at the national level. PMID- 21524840 TI - The effect of environmental regulation on firms' competitive performance: the case of the building & construction sector in some EU regions. AB - There is a considerable debate on the effects of environmental regulation on competitive performance. Based on survey data, this paper analyzes the two main research questions, derived from literature, on the links between environmental regulation and competitiveness, by focusing on firms operating in the building and construction sector, i.e.: 1) whether environmental policy stringency affects the competitive performance of firms in the building and construction sector 2) and how a specific form of environmental regulation (direct regulation, economic instruments and soft instruments) affects this performance? By applying a regression analysis, we find that a more stringent environmental regulation, measured by inspection frequency, provides a positive impulse for increasing investments in advanced technological equipment and innovative products and on business performance. Moreover, a well-designed "direct regulation" appears to be the most effective policy instrument for prompting the positive impact of environmental policies on innovation and intangible performance while economic instruments do negatively affect business performance. PMID- 21524841 TI - MicroRNA-519d targets MKi67 and suppresses cell growth in the hepatocellular carcinoma cell line QGY-7703. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate the translation of target mRNA transcripts. In this study, we demonstrated that miR-519d was downregulated in human HCC and could suppress growth of the human HCC cell line QGY-7703. Bioinformatics analysis indicated that MKi67 was a putative target of miR-519d. In an EGFP reporter system, we confirmed that MKi67 was a direct target gene of miR-519d. Furthermore, knockdown of MKi67 inhibited QGY-7703 cell growth. These findings indicate that miR-519d targets the MKi67 transcript and suppresses HCC cell growth, suggesting that miR-519d has a tumor suppressive role in human HCC pathogenesis. PMID- 21524842 TI - Decolorization of methylene blue in layered manganese oxide suspension with H2O2. AB - Layered birnessite-type manganese oxides (Na-OL-1) were prepared via a redox reaction involving MnO(4)(-) and Mn(2+) under markedly alkaline conditions. According to the XRD analysis, the resulting material exhibited a well crystallized octahedral layer (OL) structure with several different phases, including beta-MnOOH, alpha-MnOOH and gamma-Mn(3)O(4). The catalyst was highly effective for the decolorization and degradation of methylene blue (MB) in the presence of H(2)O(2) at neutral pH. The tested MB was completely decolorized in Na-OL-1 suspension by the fraction dosing of H(2)O(2) (556.5mM at the beginning and then 183.8mM at 40 min). Based on the studies of electron spin resonance and the effect of radical scavengers, the (1)O(2) and O(2)(-) were the main reactive oxygen species (ROS) in the reaction. It was found that both oxygen and ROS were generated from the decomposition of H(2)O(2) in Na-OL-1 suspension, wherein the decomposition pathways were proposed. The generation of H(2)O(2) in Na-OL-1 suspension at air atmosphere indicated that the existence of multivalent manganese oxides greatly enhanced the interfacial electron transfer, leading to the high activity of Na-OL-1. PMID- 21524843 TI - Adsorption of tetracycline on soil and sediment: effects of pH and the presence of Cu(II). AB - Tetracycline (TC) is frequently detected in the environment, however, knowledge on the environmental fate and transport of TC is still limited. Batch adsorption experiments of TC by soil and sediment samples were conducted. The distribution of charge and electrostatic potential of individual atoms of various TC species in the aqueous solution were determined using MOPAC version 0.034 W program in ChemBio3D Ultra software. Most of the adsorption isotherms on the soil, river and marine sediments were well fitted with the Freundlich and Polanyi-Manes (PMM) models. The single point organic carbon (OC)-normalized adsorption distribution coefficients (K(OC)) and PMM saturated adsorption capacity (Q(OC)(0)) values of TC were associated with the mesopore volume and clay content to a greater extent, indicating the mesopore volume of the soil and sediments and their clay content possibly influenced the fate and transport of TC in the natural environment. The adsorption of TC on soil and sediments strongly depended on the pH and presence of Cu(II). The presence of Cu(II) facilitated TC adsorption on soil and sediments at low pH (pH<5), possibly due to the metallic complexation and surface-bridging mechanism by Cu(II) adsorption on soil and sediments. The cation exchange interaction, metallic complexation and Coulombic interaction of mechanisms for adsorption of TC to soils and sediments were further supported by quantum chemical calculation of various TC species in different pH. PMID- 21524844 TI - Characterizations of strontium(II) and barium(II) adsorption from aqueous solutions using dolomite powder. AB - In this research, adsorption technique was applied for strontium and barium removal from aqueous solution using dolomite powder. The process has been investigated as a function of pH, contact time, temperature and adsorbate concentration. The experimental data was analyzed using equilibrium isotherm, kinetic and thermodynamic models. The isotherm data was well described by Langmuir isotherm model. The maximum adsorption capacity was found to be 1.172 and 3.958 mg/g for Sr(II) and Ba(II) from the Langmuir isotherm model at 293 K, respectively. The kinetic data was tested using first and pseudo-second order models. The results indicated that adsorption fitted well with the pseudo-second order kinetic model. The thermodynamic parameters (DeltaG degrees , DeltaH degrees , and DeltaS degrees ) were also determined using the equilibrium constant value obtained at different temperatures. The results showed that the adsorption for both ions was feasible and exothermic. PMID- 21524845 TI - Remediation of petroleum contaminated soils through composting and rhizosphere degradation. AB - Composting along with rhizodegradation was used to remediate petroleum contaminated soils in the Yellow River Delta, China. The average concentration of total petroleum hydrocarbons (TPH) in these soils was reduced from 7900-17,900 mg kg(-1) to 1400-3700 mg kg(-1) after field composting. The best volume ratio of amendment to contaminated soil was 2/1 and the best C/N ratio was 15/1. After composting, four local dominant plant species, Seepweed, Sealavander, Central Asia Saltbush and Reed, were selected and planted in composted soils for rhizodegradation in the field. After 90 days of cultivation, the highest net TPH degradation rate was over 40% for Seepweed, probably because of strong root system and active microbial community. In addition, Seepweed roots significantly reduced the surface and volume of soil micropores (which are able to sequestrate organic compounds inside), thus increasing the bioavailability of TPH. In sum, composting followed with planting Seepweed was most effective in remediating the contaminated soil in the Yellow River Delta. PMID- 21524846 TI - Ozonation of imidacloprid in aqueous solutions: reaction monitoring and identification of degradation products. AB - This paper presents the degradation of imidacloprid by ozonation. Solutions of 39.0 MUg/mL imidacloprid were prepared either by dissolution of standard or by dilution of Gaucho Ble((r)) seed loading solution and then ozonated under different conditions. The concentration of imidacloprid and oxidation products in both solutions was monitored by HPLC-UV as a function of the treatment time for a concentration of 100g/m(3) of ozone in the inlet gas. No significant difference was observed: in both cases, imidacloprid degradation was a pseudo-first order reaction with similar reaction rates (0.129-0.147 min(-1)), degradation by products with the same HPLC retention times were observed and their concentrations as a function of the treatment time followed a very similar trend. The study of ozone concentration in the inlet gas (from 25 to 100g/m(3)) showed that imidacloprid degradation is also a first-order reaction with respect to ozone. The ozonation by-products were then collected and identified by ESI(+)-MS. A degradation pathway of imidacloprid was finally proposed. PMID- 21524847 TI - Enhancement of cadmium bioremediation by endophytic bacterium Bacillus sp. L14 using industrially used metabolic inhibitors (DCC or DNP). AB - Bioremediations of cadmium by endophytic bacterium (EB) L14 (Bacillus sp.) in the presence of industrially used metabolic inhibitors (DCC or DNP) were investigated. In the presence of DCC or DNP, the biomass population of EB L14 was greatly inhibited. However, the cadmium removal of EB L14 increased from 73.6% (in the absence of DCC or DNP) to 93.7% and 80.8%, respectively. The analysis of total and intracellular cadmium concentrations during 24h of incubation indicated that this enhanced cadmium removal was the inhibition effect of DCC or DNP on the cations export resistance system of EB L14. This unique property strongly indicated the superiority of this endophyte for practical application in cadmium bioremediation in the presence of industrially used metabolic inhibitors. PMID- 21524848 TI - Impact of low molecular weight organic acids and dissolved organic matter on sorption and mobility of isoproturon in two soils. AB - Isoproturon is a selective herbicide belonging to the phenylurea family and widely used for pre- and post-emergence control of annual weeds. Soil amendments (e.g. organic compounds or dissolved organic matter) may affect environmental behavior and bioavailability of pesticides. However, whether the physiochemical process of isoproturon in soils is affected by organic amendments and how it is affected in different soil types are unknown. To evaluate the impact of low molecular weight organic acids (LMWOA) and dissolved organic matter (DOM) on sorption/desorption and mobility of isoproturon in soils, comprehensive analyses were performed using two distinct soil types (Eutric gleysols and Hap udic cambisols). Our analysis revealed that adsorption of isoproturon in Eutric gleysols was depressed, and desorption and mobility of isoproturon were promoted in the presence of DOM and LMWOA. However, the opposite result was observed with Hap udic cambisols, suggesting that the soil type affected predominantly the physiochemical process. We also characterized differential components of the soils using three-dimensional excitation-emission matrix (EEM) fluorescence spectroscopy and Fourier transform infrared (FT-IR) spectroscopy and show that the two soils displayed different intensity of absorption bands for several functional groups. PMID- 21524849 TI - Effects of chloride ions on bleaching of azo dyes by Co2+/oxone reagent: kinetic analysis. AB - Orange II (Org II), one of the most common used azo dyes, was taken as a model to investigate the effects of chloride ion on dye decoloration in cobalt/peroxymonosulfate (Co/PMS) system. A significant decrease in the rate of Org II decoloration was observed upon addition of Cl(-) (0.05-10mM), but further addition of Cl(-) (>50mM) apparently accelerated dyes degradation. This dual effect of chloride on dyes bleaching was also observed as other halide ions (e.g. Br(-), I(-)) or other azo dyes were present in Co/PMS system. In the Co-free PMS solutions, the observed first-order rate constant always exponentially increased with the chloride content. The reactive chlorine species generated from chloride oxidation by PMS should be responsible for this non-radical mechanism for dye decoloration, however, these rapid decoloration of Org II as chloride ion was present, did not readily lead to much mineralization. Therefore, this finding may have significant technical implications for utilizing Co/PMS regent to detoxify chloride-rich azo dyes wastewater. PMID- 21524850 TI - Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain. AB - Data on comparative safety of opioid analgesics are limited, but some reports suggest disproportionate mortality risk associated with methadone. Our objective was to compare mortality rates among patients who received prescribed methadone or long-acting morphine for pain. This is a retrospective observational cohort drawn from Department of Veterans Affairs (VA) health care databases, January 1, 2000, to December 31, 2007. We included 28,554 patients who received methadone and 79,938 who received long-acting morphine from VA pharmacies. Compared with those who received long-acting morphine, patients who received methadone were younger, less likely to have some medical comorbidities, and more likely to have psychiatric and substance use disorders. Patients were stratified into quintiles according to propensity score; the probability of receiving methadone was conditional on demographic, clinical, and VA service area variables. Overall propensity-adjusted mortality was lower for methadone than for morphine. Hazard ratios varied across propensity score quintiles; the magnitude of the between drug difference in mortality decreased as the propensity to receive methadone increased. Mortality was significantly lower for methadone in all but the last quintile, in which there was no between-drug difference in mortality (hazard ratio=0.92, 95% confidence interval=0.74, 1.16). Multiple sensitivity analyses found either no difference in mortality between methadone and long-acting morphine or lower mortality rates among patients who received methadone. In summary, we found no evidence of excess all-cause mortality among VA patients who received methadone compared with those who received long-acting morphine. Randomized trials and prospective observational research are needed to better understand the relative safety of long-acting opioids. PMID- 21524852 TI - Central hyperexcitability as measured with nociceptive flexor reflex threshold in chronic musculoskeletal pain: a systematic review. AB - Chronic musculoskeletal conditions are increasingly conceived as involving altered central nervous system processing, and impaired nociceptive flexor reflex (NFR) appears to reflect altered central nervous system processing. The primary objective was to synthesize the evidence for impaired NFR in these conditions. The secondary objective was to evaluate the NFR stimuli parameters employed by reviewed studies. Electronic databases: MEDLINE, CINAHL, Embase, PEDro, Google Scholar, and Cochrane library were searched from the mid-1960s to June 2010. Experimental reports were systematically reviewed and meta-analysis (where possible) was performed. NFR thresholds and parameters of NFR stimuli were extracted. Sixteen trials were identified, 11 of which were suitable for inclusion in the meta-analysis. Compared to healthy controls, standardized mean differences in NFR threshold were significantly lower in subjects with primary headache (-0.45; 95% confidence interval [CI] -0.77 to -0.13, P=0.005), fibromyalgia (-0.63; 95% CI -0.93 to -0.34, P<0.0001), knee pain (-1.51; 95% CI 2.10 to -0.93, P<0.00001) and whiplash (-0.73; 95% CI -1.11 to -0.35, P=0.0002). Employed stimuli parameters vary between studies, with inter-pulse duration (P=0.044) being identified by multiple regression analysis as independent predictors of the variability in NFR threshold in healthy controls. The results indicate that there is evidence of central hyperexcitability in people with chronic musculoskeletal pain. Our review also suggests that shorter inter-pulse duration tends to yield smaller variability in NFR threshold. However, further research investigating optimal stimulation parameters is still warranted. PMID- 21524851 TI - Dysmenorrhoea is associated with central changes in otherwise healthy women. AB - Patients with chronic pain conditions demonstrate altered central processing of experimental noxious stimuli, dysfunction of the hypothalamic-pituitary-adrenal axis, and reduced quality of life. Dysmenorrhoea is not considered a chronic pain condition, but is associated with enhanced behavioural responses to experimental noxious stimuli. We used behavioural measures, functional magnetic resonance imaging, and serum steroid hormone levels to investigate the response to experimental thermal stimuli in otherwise healthy women, with and without dysmenorrhoea. Women with dysmenorrhoea reported increased pain to noxious stimulation of the arm and abdomen throughout the menstrual cycle; no menstrual cycle effect was observed in either group. During menstruation, deactivation of brain regions in response to noxious stimulation was observed in control women but not in women with dysmenorrhoea. Without background pain (ie, in nonmenstrual phases), activity in the entorhinal cortex appeared to mediate the increased responses in women with dysmenorrhoea. Mean cortisol was significantly lower in women with dysmenorrhoea and was negatively correlated with the duration of the symptom. Additionally, women with dysmenorrhoea reported significantly lower physical but not mental quality of life. Thus, many features of chronic pain conditions are also seen in women with dysmenorrhoea: specifically a reduction in quality of life, suppression of the hypothalamic-pituitary-adrenal axis, and alterations in the central processing of experimental noxious stimuli. These alterations persist when there is no background pain and occur in response to stimuli at a site distant from that of the clinical pain. These findings indicate the potential importance of early and adequate treatment of dysmenorrhoea. PMID- 21524853 TI - Prevalence of specific IgG-antibodies against Toxoplasma gondii in domestic turkeys determined by kinetic ELISA based on recombinant GRA7 and GRA8. AB - The protozoan parasite Toxoplasma (T.) gondii is one of the most common zoonotic infectious agents worldwide. Besides its sexual reproduction in cats, T. gondii can also infect a wide spectrum of other warm-blooded animals. These include animals used for human consumption such as pigs or chickens. Nevertheless, the role of turkeys for the epidemiology of T. gondii infections has not been studied thoroughly. We have established a kinetic ELISA (KELA) for the detection of T. gondii-specific IgG antibodies in turkey serum samples. The test is based on the recombinant dense granule antigens GRA7 and GRA8. These proteins were used as an antigen mixture at a concentration of 0.13 MUg per well. The overall sensitivity of the assay was between 92.6% and 100% and the specificity ranged from 78.1% to 100%, depending on the method used to calculate these parameters. Using this KELA we examined 1913 turkey serum samples from 14 turkey farms from different areas of Germany. From these sera, 387 produced a signal in the KELA, corresponding to a true seroprevalence of up to 20.2%. The seropositivity rate in individual fattening cycles at individual farms ranged from 0.0% to 77.1%, whereas the rates were highly variable within the individual farms and individual fattening cycles. Consequently, conditions of animal husbandry could not be associated with particular seroprevalence rates. Although seropositivity cannot be linked directly to infectious tissue cysts in the muscle tissue of commercially produced turkey meat, we state that there is a potential risk of being infected by consuming turkey meat products that were not heat treated. PMID- 21524854 TI - Genetic diversity and relatedness of Fasciola spp. isolates from different hosts and geographic regions revealed by analysis of mitochondrial DNA sequences. AB - The present study examined sequence variability in a portion of the mitochondrial cytochrome c oxidase subunit 1 (pcox1) and NADH dehydrogenase subunits 4 and 5 (pnad4 and pnad5) among 39 isolates of Fasciola spp., from different hosts from China, Niger, France, the United States of America, and Spain; and their phylogenetic relationships were re-constructed. Intra-species sequence variations were 0.0-1.1% for pcox1, 0.0-2.7% for pnad4, and 0.0-3.3% for pnad5 for Fasciola hepatica; 0.0-1.8% for pcox1, 0.0-2.5% for pnad4, and 0.0-4.2% for pnad5 for Fasciola gigantica, and 0.0-0.9% for pcox1, 0.0-0.2% for pnad4, and 0.0-1.1% for pnad5 for the intermediate Fasciola form. Whereas, nucleotide differences were 2.1-2.7% for pcox1, 3.1-3.3% for pnad4, and 4.2-4.8% for pnad5 between F. hepatica and F. gigantica; were 1.3-1.5% for pcox1, 2.1-2.9% for pnad4, 3.1-3.4% for pnad5 between F. hepatica and the intermediate form; and were 0.9-1.1% for pcox1, 1.4-1.8% for pnad4, 2.2-2.4% for pnad5 between F. gigantica and the intermediate form. Phylogenetic analysis based on the combined sequences of pcox1, pnad4 and pnad5 revealed distinct groupings of isolates of F. hepatica, F. gigantica, or the intermediate Fasciola form irrespective of their origin, demonstrating the usefulness of the mtDNA sequences for the delineation of Fasciola species, and reinforcing the genetic evidence for the existence of the intermediate Fasciola form. PMID- 21524855 TI - Gastrointestinal parasites and their prevalence in the Arabian red fox (Vulpes vulpes arabica) from the Kingdom of Saudi Arabia. AB - The gastrointestinal parasites and prevalence of infestation in the Arabian red fox Vulpes vulpes arabica Thomas, were investigated at the King Khalid Wildlife Research Centre (KKWRC) in Thumamah, Riyadh Province, Saudi Arabia. Faecal samples were collected from 58 wild caught foxes while under anaesthesia and examined for gastrointestinal parasites stages. Male and female foxes were infected with three major groups of parasites; cestodes, nematodes, protozoa as well as an acanthocephalan. Faecal analyses revealed that 22 foxes (37.9%) were infected with two different Isospora spp. and three (5.2%) with an undescribed Eimeria sp., 12 (20.7%). Nine individuals (15.5%) harboured hookworms, (Trichosomoides sp.), two (3.5%) were infected with Trichuris sp. (probably Trichuris vulpes) and one individual (1.7%) with Taenia sp. (probably Taenia hydatigena). Carcasses of five male and three female foxes were necropsied. Four of the necropsied carcasses yielded Ancylostoma caninum, two each harboured Pterygodermatitis affinis, T. vulpes and Macracanthorhynchus catalinus, in six foxes Joyeuxiella echinorynchoides was found. Five and four foxes were infected with T. hydatigena and Diplopylidium nolleri, respectively. The possible role of the Arabian red fox as an intercalary host essential for the life cycle of Trichosomoides sp., common to the Libyan jird, Meriones libycus, in particular and the importance of this species as a vector for zoonotic infections and in the spread of other parasites to wild and domestic animals in general is discussed. PMID- 21524856 TI - The factors affecting the distribution of babesiosis in dogs in Poland. AB - The aim of this paper was to determine the factors affecting the development of canine babesiosis in Poland. The studies included 800 animals from 16 polish voivodeships-districts (50 from each voivodeship) with suspected piroplasmosis. Hematological and molecular tests confirmed infections in 158 animals. Analysis of the genetic material using the Real-Time Sybr Green HRM technique showed that 96 dogs were infected with Babesia canis 18S RNA-A and 62 with B. canis 18S RNA B. It was observed that the disease occurs more often in eastern Poland (OR: 8.91; CI: 5.7-13.8), in males (OR: 1.04; CI: 0.7-1.5) and especially in rural areas (OR: 1.7; CI: 1.2-2.4). More prone to infection were pure-bred dogs (OR: 2.24; CI: 1.6-3.2), young animals under 1 year old (OR: 0.73; CI: 0.4-1.5), animals that had suffered from babesiosis in the past (OR: 17.9; CI: 10.9-29.2) and those that had not received preventive measures against ectoparasites (OR: 0.32; CI: 0.2-0.5). Knowledge of the factors facilitating the development of canine babesiosis helps to understand the causal connection between the dogs' exposure to the pathogen and the development of the disease and to limit the occurrence of the infection in these animals, to diagnose it early and to start proper treatment before serious complications develop. PMID- 21524857 TI - Trypanocidal potentials of Azadirachta indica seeds against Trypanosoma evansi. AB - The trypanocidal potentials of Azadirachta indica seeds methanolic extract (NSME) against Trypanosoma evansi was examined. In vitro studies with the NSME 100mg/ml, 50mg/ml and 25mg/ml immobilized the parasites within 3 min, 8 min and 14 min respectively. In vivo experiments in infected rats at various dosage with NSME expressed transient ability of clearing the parasites in the infected blood. Thin layer chromatographic (TLC) separations of the NSME gave 4 fractions in toluene and ethyl acetate [1:0.25] solvent system on TLC of which only fraction 3 (F3) retained the trypanocidal properties which cleared the parasites in the infected rats for 14 days. The high performance liquid chromatography (HPLC) analysis of NSF F3 revealed the presence of Azadirachtins A and B as active components. The NSF F3 manifested prophylactic potency at a dose of 500 mg/kg/day * 3/7. The packed cell volume (PCV) of the group administered 500 mg/kg/day * 3/7 NSF F3 and normal control (NC) had no significant difference. The NSF F3 also inhibited Phospholipase A(2) enzyme in a dose-dependent pattern. PMID- 21524858 TI - The detection of snail host habitats in liver fluke infected farms by use of plant indicators. AB - Field investigations in 361 liver fluke infected cattle- or sheep-breeding farms on acid soil were carried out during thirty years in March and April to record indicator plants in relation to the category of site colonized by the intermediate host of liver fluke, the snail Galba truncatula. Seven types of snail zones and six species of indicator plants were recorded in the 7709 positive sites studied. The most frequent habitats were located at the peripheral extremities of open drainage furrows. Juncus acutiflorus, Juncus effusus, Glyceria fluitans, and Agrostis stolonifera were the indicator plants. Plant indicators were highly efficient (38-80% of variance explained) when used with the size of site area within a hydrographical zone. The identification of positive sites for G. truncatula is a key for controlling the intermediate host on pastures through biological control with predatory molluscs. The positive sites may be detected using a two-step method including first categorization of hydrographical zones and then, within a zone, use of one or several indicator plants (frequently J. acutiflorus). PMID- 21524860 TI - Cotransplantation of autologous bone marrow stromal cells and chondrocytes as a novel therapy for reconstruction of condylar cartilage. AB - Condylar cartilage is absolutely necessary for the normal function of temporomandibular joint (TMJ). Unfortunately, condylar cartilage defect or missing is also one of the common clinical problems. Repair or reconstruction of cartilage is always a hot topic. Cell based cartilage regeneration is suggested as novel therapies in cartilage tissue engineering, and autologous chondrocytes were initially regarded as the ideal cell source. However, there are some disadvantages such as its limited augmentation capability for culture in vitro and may differentiate to other types of cells. On the other hand, bone marrow stromal cells (BMSCs) have gained special interest in tissue engineering. Because they can be obtained easily, cause relatively minor trauma and show the potential of long-run ex vivo expansion capacity. What most important is their capacity of multi-directional differentiation. They can differentiate into a variety of other types of cells when there are supplement exogenous factors or genes, but their clinical use is limited by safety concerns such as toxicity, insertional teratogenic, uncontrollable gene expression. Fortunately, the chondrocytes microenvironment has been demonstrated that could induce BMSCs to structure cartilage when culture in vitro or reimplanted in nude mice subcutaneously area. So in this article, we hypothesize that cotransplantation of autologous BMSCs and chondrocytes, which coculture with extracellular scaffolds, is a novel therapy for reconstruction of TMJ condylar cartilage. In our strategy, advantages of two types of cells are utilized and shortcomings are avoided, which strongly improve the feasibility and clinical safety, finally bring great hope to the patients with TMJ disease. PMID- 21524861 TI - Typologies of recanting of lifetime cigarette, alcohol and marijuana use during a six-year longitudinal panel study. AB - AIM: To identify if there are different typologies for adolescent self-reporters and recanters for alcohol, cigarette and marijuana use. METHODS: This study is a secondary data analysis and utilized four waves of the National Longitudinal Survey of Youth child panel data. The study included adolescents aged ten and older who self-reported ever use of cigarettes (n=872), marijuana (n=854) or alcohol (n=837). Consistent responders were those who reported lifetime use of a specific substance and continued to report such use at each latter wave of data collection. Latent class analyses were utilized to investigate if there are different types of self-reporters for each substance class. RESULTS: Three unique groups for each substance was identified. The first group of users, who had a late age of onset, tended to be consistent self-reporters across waves. Those who were early onset users of cigarettes and marijuana tended to recant their use while early onset alcohol users were consistent reporters. Those with moderate ages of onset had no consistent recanting patterns. The highest degree of recanting was found among the early onset marijuana users. CONCLUSIONS: The results suggest that youth who begin their use at an earlier age may not be as reliable reporters as youth who initiate use at later ages. Our results suggest that the veracity of prevalence estimates for licit and illicit substances could be different depending on the age of the respondent. PMID- 21524862 TI - Glutamate transporter subtype 1 (GLT-1) activator ceftriaxone attenuates amphetamine-induced hyperactivity and behavioral sensitization in rats. AB - BACKGROUND: The beta-lactam antibiotic and glutamate transporter subtype 1 (GLT 1) activator ceftriaxone prevents relapse to cocaine-seeking and inhibits morphine-induced physical dependence and tolerance in rats, but its efficacy against amphetamine-induced behaviors is unknown. METHODS: Here, we tested the hypothesis that ceftriaxone (200mg/kg, i.p.) inhibits hyperactivity produced by acute amphetamine administration (2mg/kg, i.p.) and sensitization of hyperactivity induced by repeated amphetamine exposure (2mg/kg, i.p.). For acute experiments, rats treated with ceftriaxone for 5 days were injected with amphetamine or saline on day 6. RESULTS: Amphetamine elicited less ambulatory and stereotypical activity in ceftriaxone-treated rats than in ceftriaxone-naive rats. For chronic experiments, rats injected with ceftriaxone or saline for 8 days were also injected with amphetamine or saline on days 6-8 and then challenged with amphetamine 5 days later. Amphetamine produced greater ambulatory and stereotypical activity in amphetamine-pretreated rats than in rats previously naive to amphetamine. Amphetamine challenge produced less ambulatory and stereotypical activity in rats pretreated with a combination of ceftriaxone (200mg/kg) and amphetamine than in rats pretreated with only amphetamine. CONCLUSION: The present demonstration that ceftriaxone attenuates amphetamine induced hyperactivity and behavioral sensitization suggests its documented efficacy against adverse cocaine and morphine effects extends to amphetamine. PMID- 21524863 TI - Follicular fluid nitric oxide and ascorbic acid concentrations in relation to follicle size, functional status and stage of estrous cycle in buffalo. AB - The objective of this study was to evaluate the changes in follicular fluid nitric oxide (NO) and ascorbic acid (AA) concentrations with varying follicle size and functional status, and stage of estrous cycle in buffalo. The main effect of follicle size on NO concentration and size-by-status interaction were statistically significant (P<0.05). Small follicles had a higher (P<0.05) NO concentration compared to medium and large follicles. Further, estrogen-active (EA) small follicles showed increased (P<0.05) NO concentrations than the corresponding estrogen-inactive (EI) follicles. Within EA category, higher (P<0.01) concentrations were recorded in small compared to medium and large follicles. There was no significant main effect of stage (P>0.1) on NO concentration but the stage-by-size interaction was significant (P<0.05) with medium follicles showing a higher (P<0.05) concentration during late luteal stage compared to the mid luteal stage. During early and mid luteal stages, higher (P<0.05) NO concentrations were recorded in small than in medium follicles. A significant (P<0.01) main effect of size on AA concentration was observed with higher values in medium than in small and large follicles. Size-by-status interaction for AA approached statistical significance (P<0.06) with higher (P<0.05) concentrations recorded in medium than in large EA follicles. The main effect of stage on AA concentration was, however, non-significant (P>0.1) but the stage-by-size interaction approached statistical significance (P<0.06) with lower (P<0.05) levels recorded in large compared to medium size follicles during the follicular stage. In conclusion, the present study demonstrates that the concentrations of follicular fluid NO and AA vary according to the follicle size, functional status and stage of estrous cycle suggesting their possible role in process of follicular development during estrous cycle in buffalo. PMID- 21524864 TI - The proximal hamstring muscle-tendon-bone unit: a review of the normal anatomy, biomechanics, and pathophysiology. AB - Proximal hamstring injuries occur during eccentric contraction with the hip and the knee on extension; hence they are relatively frequent lesions in specific sports such as water skiing and hurdle jumping. Additionally, the trend toward increasing activity and fitness training in the general population has resulted in similar injuries. Myotendinous strains are more frequent than avulsion injuries. Discrimination between the two types of lesions is relevant for patient management, since the former is treated conservatively and the latter surgically. MRI and Ultrasonography are both well suited techniques for the diagnosis and evaluation of hamstring tendon injuries. Each one has its advantages and disadvantages. The purpose of this article is to provide a comprehensive review of the anatomy and biomechanics of the proximal hamstring muscle-tendon-bone unit and the varied imaging appearances of hamstring injury, which is vital for optimizing patient care. This will enable the musculoskeletal radiologist to contribute accurate and useful information in the treatment of athletes at all levels of participation. PMID- 21524865 TI - Clinical data and CT findings of pulmonary infection caused by different pathogens after kidney transplantation. AB - PURPOSE: The overall objective was to review clinical data and CT findings of pulmonary infection caused by different pathogens after kidney transplantation in an attempt to help early clinical qualitative diagnosis. MATERIALS AND METHODS: 446 cases of clinically confirmed pulmonary infection after kidney transplantation in recent 10 years were evaluated with respect to the time of occurrence and 89 cases with complete CT data and pathogenic diagnosis were further analyzed for pathogen types and CT manifestations. Statistical analysis was performed using Fisher's exact test. RESULTS: Pulmonary infection reached the peak in 3 months after transplantation. Bacterial infection and mixed infection were predominant between 1 and 6 months. And most tuberculosis occurred after one year. Bacterial (38.2%) and mixed infections (38.2%) were the common types. The next was fungal infection, tuberculosis and viral infection (10.1%, 7.9% and 5.6%, respectively). CT manifestations of pulmonary infections after kidney transplantation were diverse and complex, lacking characteristic signs. CONCLUSION: More than 3/4 of pulmonary infections after kidney transplantation can be attributed to bacteria and mixed pathogens. The combination of time course, clinical data and CT manifestations plays an important role in the early clinical qualitative diagnosis. PMID- 21524866 TI - Co-existence of bilateral fetal type posterior cerebral artery and the bilateral giant internal carotid artery aneurysms in an ataxic patient. PMID- 21524867 TI - Complete ten-year follow-up after endovascular abdominal aortic aneurysm repair: survival and causes of death. AB - PURPOSE: To analyze the hazard and causes of death after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms during a complete ten year follow-up. METHODS: This is a retrospective clinical study of 130 consecutive patients undergoing EVAR between 1995 and 1998. One-hundred twenty-one patients (93.1%) were treated with first-generation stentgrafts and nine patients (6.9%) received second-generation devices. All patients completed a follow-up of at least 10 years, unless death occurred before then. Time and causes of death were provided by the Austrian central register of deaths. RESULTS: The median follow-up was 7.6 years, and the 130 patients had 968.5 person-years of follow-up. The ten-year mortality rate was 62.3%. Cardiovascular events were the most frequent causes of death, with a 3.9 incidence rate per 100 person-years. Cancer death and death due to other causes occurred in 2.1 and 1.8 cases per 100 person-years, respectively. Lethal late aneurysm rupture happened in 4.6% (n=6), which corresponds to an annual incidence rate of 0.6 per 100 person-years. All of those patients had been treated with first-generation devices. CONCLUSIONS: Cardiovascular events were the most frequent cause of death after EVAR, followed by malignancy and other diseases. The risk of dying from secondary rupture was clearly lower than that of death due to other reasons during ten years after EVAR, even in patients with first-generation stentgrafts. PMID- 21524868 TI - Bone and soft tissue tumors of hip and pelvis. AB - Objective is to identify epidemiologic and radiologic criteria allowing specific diagnoses of tumors and tumor-like lesions in the hip region and pelvis, and to optimize pre-operative staging. Patients with pelvic tumors are usually older, and their tumors are larger relative to patients with tumors in extremities. The majority of tumors in the pelvis are malignant (metastases, myeloma, chondrosarcoma, Ewing-, osteo-, and MFH/fibrosarcoma), while those in the proximal femur are in majority benign (fibrous dysplasia, solitary bone cyst, and osteoid osteoma). Soft tissue masses in the thigh in the elderly are typically sarcomas without tumor specific signs. Common tumor-like lesions occurring in the hip and pelvis that can mimic neoplasm are: infections (including tuberculosis), insufficiency/avulsion fractures, cysts, fibrous dysplasia, aneurysmal bone cyst, Langerhans cell histiocytosis, and Paget's disease. Local MR staging is based on the compartmental anatomy. The psoas and gluteal muscles are easily invaded by sarcoma originating in the ileum. The pectineus muscle protects the neurovascular bundle at the level of the hip. The thigh is separated into three compartments, some structures (Sartorius muscle) cross borders between compartments. Immobile joints (SI-joints, osteoarthritic hip) are relatively easily crossed by sarcoma and giant cell tumor. PMID- 21524869 TI - Quantitative T(1)(rho) imaging using phase cycling for B0 and B1 field inhomogeneity compensation. AB - T(1)(rho) imaging is useful in a number of clinical applications. T(1)(rho) preparation methods, however, are sensitive to non-uniformities of the B0 magnetic field and the B1 RF field. These common system imperfections can result in image artifacts and quantification errors in T(1)(rho) imaging. We report on a phase-cycling method which can eliminate B1 RF inhomogeneity effects in T(1)(rho) imaging. This method does not only correct for image artifacts but also for T(2)(rho) contamination caused by B1 RF inhomogeneity. The presence of B0 magnetic field inhomogeneity can compromise the effectiveness of this method for B1 RF inhomogeneity correction. We demonstrate that, by combining the spin locking scheme reported by Dixon et al. (Myocardial suppression in vivo by spin locking with composite pulses. Magn Reson Med 1996; 36:90-94) with phase cycling, we can simultaneously correct B0 magnetic field inhomogeneity effects and B1 RF inhomogeneity effects in T(1)(rho) imaging. Phantom and in vivo data sets are used to demonstrate the proposed methods and to compare them with other existing T(1)(rho) preparation methods. PMID- 21524871 TI - Generalized equation for describing the magnetization in spoiled gradient-echo imaging. AB - The purpose of this study was to demonstrate a generalized equation for describing the magnetization in spoiled gradient-echo (SPGR) imaging in which the in-pulse relaxation and magnetization transfer (MT) effects are taken into account. First, the time-dependent Bloch equations for the two-pool exchange model with MT effect were reduced to an inhomogeneous linear differential equation, and then a simple equation was derived to solve it using a matrix operation. Second, the equations describing the magnetization before and after the radiofrequency (RF) pulse were derived based on the above solution for the RF pulse excitation and evolution phases. Finally, a generalized equation describing the steady-state magnetization was derived. The validity of this equation was investigated by comparing with the transverse magnetization obtained by the regular Ernst equation and analytical solution in which the in-pulse transverse relaxation is considered. When the same assumption was made in our method, there were good agreements between them, indicating the validity of our method. The in pulse transverse and longitudinal relaxations decreased the transverse magnetization compared to the case in which these effects were neglected, whereas MT increased it. In conclusion, we derived a generalized equation for describing the magnetization in SPGR imaging. This equation will provide a suitable basis for understanding the signal intensity in SPGR imaging and/or T1 measurement using an SPGR sequence in cases in which the effect of in-pulse relaxation and/or MT cannot be neglected. PMID- 21524872 TI - B(1)(+)/actual flip angle and reception sensitivity mapping methods: simulation and comparison. AB - Knowledge of the spatial distribution of transmission field B(1)(+) and reception sensitivity maps is important in high-field (>=3 T) human magnetic resonance (MR) imaging for several reasons: these include post-acquisition correction of intensity inhomogeneities, which may affect the quality of images; modeling and design of radiofrequency (RF) coils and pulses; validating theoretical models for electromagnetic field calculations; testing the compatibility with MR environment of biomedical implants. Moreover, inhomogeneities in the RF field are an essential source of error for quantitative MR spectroscopy. Recent studies have also shown that B(1)(+) and reception sensitivity maps can be used for direct calculation of tissue electrical parameters and for estimating the local specific absorption rate (SAR) in vivo. Several B(1)(+) mapping techniques have been introduced in the past few years based on actual flip angle (FA) mapping, but, to date, none has emerged as a standard. For reception sensitivity calculation, the signal intensity equation can be used where the nominal FA distribution must be replaced with the actual FA distribution calculated by one of the B(1)(+) mapping techniques. This study introduces a quantitative comparison between two known methods for B(1)(+)/actual FA and reception sensitivity mapping: the double-angle method (DAM) and the fitting (FIT) method. Experimental data obtained using DAM and FIT methods are also compared with numerical simulation results. PMID- 21524870 TI - Magnetic resonance in the era of molecular imaging of cancer. AB - Magnetic resonance imaging (MRI) has played an important role in the diagnosis and management of cancer since it was first developed, but other modalities also continue to advance and provide complementary information on the status of tumors. In the future, there will be a major continuing role for noninvasive imaging in order to obtain information on the location and extent of cancer, as well as assessments of tissue characteristics that can monitor and predict treatment response and guide patient management. Developments are currently being undertaken that aim to provide improved imaging methods for the detection and evaluation of tumors, for identifying important characteristics of tumors such as the expression levels of cell surface receptors that may dictate what types of therapy will be effective and for evaluating their response to treatments. Molecular imaging techniques based mainly on radionuclide imaging can depict numerous, specific, cellular and molecular markers of disease and have unique potential to address important clinical and research challenges. In this review, we consider what continuing and evolving roles will be played by MRI in this era of molecular imaging. We discuss some of the challenges for MRI of detecting imaging agents that report on molecular events, but highlight also the ability of MRI to assess other features such as cell density, blood flow and metabolism which are not specific hallmarks of cancer but which reflect molecular changes. We discuss the future role of MRI in cancer and describe the use of selected quantitative imaging techniques for characterizing tumors that can be translated to clinical applications, particularly in the context of evaluating novel treatments. PMID- 21524873 TI - Z intensity-weighted position self-respiratory gating method for free-breathing 3D cardiac CINE imaging. AB - A free-breathing 3D cine steady-state free precession (SSFP) technique was developed using the z intensity-weighted position (ZIP) which is the center of mass of a projection along the slice direction as a respiratory gating signal. The ZIP signal was continuously acquired using a slice encoded k-space center sampling in every TR. The performance of this gating method was compared with a method using the k-space center signal (KC) and with conventional 2D breath-hold cine SSFP in healthy subjects by measuring image quality and left ventricular function. The preliminary data obtained here demonstrated that the ZIP gating method provided superior respiratory motion artifact suppression when compared to the KC gating and provided left ventricular ejection fractions, and end-diastolic and end-systolic volumes similar to those obtained with the breath-hold 2D cine SSFP acquisition. PMID- 21524874 TI - Multiple focal nodular hyperplasia lesions of the liver associated with congenital absence of the portal vein. AB - Congenital absence of the portal vein (CAPV) is a rare anomaly in which the intestinal and splenic venous drainage bypass the liver and drain directly into the systemic veins through various porto-systemic shunts. In this article, we illustrate a case of multiple focal nodular hyperplasia (FNH) with congenital absence of the portal vein in a male, which, to our knowledge, is the third reported case in the literature since its first description in 1793. Furthermore, we discuss the embryology of the portal vein and the Morgan and Superina classification of portosystemic anomalies, the association between portal vein agenesis and multiple FNHs, and, lastly, the use of a hepatocellular-specific MRI contrast agent as an important diagnostic tool in the confirmation of FNH. PMID- 21524875 TI - ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. PMID- 21524876 TI - Cardiocerebral resuscitation vs cardiopulmonary resuscitation for cardiac arrest: a systematic review. AB - OBJECTIVE: The objective of this study is to evaluate the efficacy of cardiocerebral resuscitation (CCR) vs cardiopulmonary resuscitation (CPR) for patients with out-of-hospital cardiac arrest (OHCA). METHODS: We conducted a systematic review of controlled trials and observational studies. We searched Cochrane Central Register of Controlled Trials; MEDLINE; Embase; and Chinese databases such as VIP, CNKI, WANFANG, and CBM from their inception to September 2010. Data from original studies were extracted and assessed with predefined criteria. RESULTS: Thirteen studies comprising 3 randomized controlled trials and 10 observational studies were included. Pooled analysis of 4 observational studies suggested that neurologically intact survival of patients with OHCA was improved in CCR group (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.07 1.97). Survival to hospital discharge in the CCR group was superior or at least equal to that in CPR group (randomized controlled trial OR, 1.25; 95% CI, 1.01 1.55; cohort studies OR, 1.15; 95% CI, 0.72-1.82; case-control studies OR 0.85; 95% CI, 0.65-1.12). In the subgroup analysis of patients with a shockable rhythm as an initial rhythm, survival to hospital discharge was significantly improved in the CCR group (cohort studies OR, 2.03; 95% CI, 1.44-2.86). However, when only noncardiac origin cardiac arrest was taken into consideration, survival rate was better in the CPR group (cohort studies OR, 0.87; 95% CI, 0.77-0.98). CONCLUSION: Cardiocerebral resuscitation might be equivalent or superior to CPR in patients with OHCA in both survival rate and neurologic benefits. Further work is needed to assess the efficacy of CCR for victims who had OHCA of noncardiac causes. PMID- 21524877 TI - Validation of a 6-hour observation period for cocaine body stuffers. PMID- 21524878 TI - ED patients with vertigo: can we identify clinical factors associated with acute stroke? AB - BACKGROUND: Vertigo is a common emergency department (ED) complaint with benign and serious etiologies with overlapping features. Misdiagnosis of acute stroke may result in significant morbidity and mortality. Magnetic resonance imaging (MRI) is superior to computer tomography (CT) for diagnosis of acute stroke but is costly with limited availability. OBJECTIVE: The aim of this study was to identify clinical characteristics associated with a cerebrovascular cause for vertigo. METHODS: We performed a retrospective chart review on patients with an MRI for vertigo, with or without additional historical or physical examination findings, over 18 months. Study patients were seen in the ED for vertigo within 2 weeks of MRI. Data collected included medical history, physical findings, and imaging results. Fisher's exact test was used to identify factors associated with the primary outcome, an acute stroke. RESULTS: There were 325 eligible patients; 131 were ED patients. Patients were 57 (+/- 18) years, and 53% were women. There were 12 ED patients with a new stroke (9.2%). Two variables were associated with acute stroke: a presenting complaint of gait instability (odds ratio, 9.3; 95% confidence interval, 2.6-33.9) or a subtle neurologic finding (odds ratio, 8.7; 95% confidence interval, 2.3-33.1). One patient with a new stroke had a prior stroke, 3 were age >65 years, and none had coronary artery disease or dysrhythmia. Among patients with acute stroke, 5 also had head CT, and none detected the stroke. CONCLUSIONS: This study identified 2 variables associated with acute stroke that should be considered in the evaluation of ED patients with vertigo. Head CT was inadequate for diagnosing acute stroke in this patient population. PMID- 21524879 TI - Posterior vitreal detachment in decompression illness--case report and discussion. AB - We report a case of a healthy leisure diver presenting with simultaneous unilateral posterior vitreous detachment and decompression illness. The literature is reviewed for both conditions. There are no known publications associating these 2 entities and leads us to propose that nitrogen bubble formation could have contributed to the etiology of vitreal separation from the retina. PMID- 21524880 TI - Cerebral fat embolism after severe road traffic accident. PMID- 21524881 TI - Implications of 25% to 50% coronary stenosis with cardiac computed tomographic angiography in ED patients. AB - OBJECTIVE: The aim of this study was to determine if patients presenting with symptoms of acute coronary syndrome and found to have 25% to 50% diameter reduction with coronary computed tomographic angiography (CCTA) are likely to benefit from further diagnostic testing. METHODS: A registry study of 213 subjects (median age, 51 years; 53% women) with symptoms concerning for possible acute coronary syndrome with low-risk features found to have 25% to 50% maximal diameter stenosis on CCTA was performed at 2 academic medical centers. The analysis was approved by an institutional review board and was conducted with waiver of consent. The potential contribution of additional testing was determined by measuring the major adverse cardiac events (MACEs) from presentation through 30 days. The MACEs included myocardial infarction, coronary revascularization, unstable angina, and cardiovascular death. Sample size calculations were predicated on a 0% MACE rate leading to upper bounds of a 2 sided exact 95% confidence interval less than 2%. RESULTS: Thrombolysis in myocardial infarction risk score of less than 2 was present in 92% subjects, 70% (150 of 213) had 2 or more serial cardiac markers performed, and 40% (87 of 213) had stress testing or cardiac catheterization. The MACEs occurred in 1 (0.5%) of 213 subjects (95% confidence interval, 0%-2.6%) and was identified by an elevation of serial cardiac markers during the index hospitalization. No patients experienced cardiovascular death or required revascularization. CONCLUSIONS: In patients with emergent low-risk chest pain and 25% to 50% diameter coronary stenosis by CCTA, the rate of near-term MACE is very low. Serial cardiac markers may be beneficial in this subgroup. Routine provocative testing is unlikely to be beneficial during the index visit. PMID- 21524882 TI - Primary sternal osteomyelitis with bacteremia and distal seeding. AB - BACKGROUND: Primary sternal osteomyelitis is a rare disease, whereas secondary sternal osteomyelitis is relatively well known as a complication in post sternotomy patients. OBJECTIVE: Describe a case of primary Staphylococcus aureus sternal osteomyelitis in an immunocompetent man and its diagnostic challenges, treatment, and complications. CASE REPORT: A 46-year-old man presented with prolonged sternal pain and swelling, fatigue, and fever. He is diagnosed with primary sternal osteomyelitis with concurrent bacteremia and complicated by local and distant abscess formation. The diagnosis was aided by computed tomography, and treatment consisted of incision and drainage and long-term antibiotics. CONCLUSION: Primary sternal osteomyelitis is uncommon and often difficult to diagnose. Complications include abscess formation and distal seeding. Diagnosis can be aided by a detailed history and radiography, and treatment may consist of a prolonged course of antibiotics and incision and drainage. PMID- 21524883 TI - Massive hemothorax from a type-B aortic dissection. PMID- 21524884 TI - Diagnostic and therapeutic evaluation of community-acquired methicillin-resistant Staphylococcus Aureus (MRSA) skin and soft tissue infections in the emergency department. AB - BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus (CA MRSA) infections commonly present as skin and soft-tissue infections (SSTIs). Treatment often includes incision and drainage with or without adjunctive antibiotics. Emergency department (ED) pharmacists wished to provide specific data to emergency physicians to better inform antibiotic choices for patients with SSTIs. STUDY OBJECTIVES: The objectives of this study were to describe local susceptibility trends of CA-MRSA isolates obtained from patients with SSTIs and describe diagnostic and empiric therapeutic management of CA-MRSA SSTIs among ED health care providers at University of Utah Hospitals and Clinics. METHODS: Susceptibility of all unique CA-MRSA SSTI isolates for 2008 were identified and compiled into an antibiogram. ED providers evaluated their diagnostic and treatment habits using a self-assessment questionnaire, which was verified against charted information documented in the electronic medical records for patients presenting to the ED with a CA-MRSA SSTI. RESULTS: The ED antibiogram indicated that 57/58 (98%) CA-MRSA SSTI isolates were susceptible to sulfamethoxazole/trimethoprim (SMX/TMP); 50/58 (86%) isolates were susceptible to tetracycline, and 47/58 (81%) isolates were susceptible to clindamycin. Incision and drainage were performed in 23/25 (92%) patient cases, which was consistent with providers' perceived habits (100%). SMX/TMP monotherapy was preferred among 23/35 (66%) providers, however, SMX/TMP combined with cephalexin was the antibiotic regimen prescribed in 9/22 (41%) patient cases. CONCLUSIONS: Cephalexin was often added to cover for potential cellulitis due to Streptococcus spp., however, the surrounding erythema may simply be an extension of the CA-MRSA infection. Department-specific antibiograms are useful in guiding empiric antibiotic selection and may help providers judiciously prescribe antibiotics only when necessary. PMID- 21524885 TI - beta2-Glycoprotein-I based peptide regulate endothelial-cells tissue-factor expression via negative regulation of pGSK3beta expression and reduces experimental-antiphospholipid-syndrome. AB - Antiphospholipid syndrome (APS) is characterized by thromboembolic phenomena and recurrent fetal loss associated with elevated circulating anti phospholipid/beta2glycoprotein-I(beta2GPI)-binding-antibodies(Abs). Individual APS patients harbor diverse clusters of circulating anti-beta2GPI Abs, targeting different epitopes on the beta2GPI molecule. Our novel approach was to construct a peptide composed of beta2GPI-ECs-binding-site (phospholipids-membrane), named "EMBI". EMBI exert dual activities: a) At first EMBI prevented beta2GPI ECs binding, thus reduced by 89% the binding of beta2GPI/anti-beta2GPI to the cells in comparison with 9.3% inhibition by EMBI scrambled form (scEMBI). b) Longer exposure of ECs to EMBI resulted in intracellular EMBI penetration which did not prevent beta2GPI/anti-beta2GPI binding to HUVEC. Surprisingly, beta2GPI/anti beta2GPI did not activate ECs harboring EMBI, illustrated by prevention of E selectin and tissue factor (TF) expression. The inhibition of TF mRNA transcription was illustrated by quantitative RT-PCR. EMBI decreased the expression of phosphorylated JNK1/2, p38, HSP27 and enhanced phosphorylation of glycogen synthase kinase-3beta (pGSK3beta). Knocking down the GSK3beta expression by siRNA-GSK3beta, reduced the TF expression by beta2GPI/anti-beta2GPI-exposed HUVEC. In-vivo, EMBI significantly decreased the percentage of fetal loss in naive mice infused with anti-beta2GPI Abs, p<0.04. Thus, the dual activity of EMBI may introduce EMBI as a potential novel candidate peptide, to treat patients with APS. PMID- 21524886 TI - Detection of melanocyte autoantigens reacting with autoantibodies in vitiligo patients by proteomics. PMID- 21524887 TI - Semaphorin 7A on keratinocytes induces interleukin-8 production by monocytes. AB - BACKGROUND: Semaphorin 7A (Sema7A) expressed on activated T cells stimulates cytokine production in monocytes through its receptor, alpha1beta1 integrin. OBJECTIVE: To study the significance of Sema7A expressed on keratinocytes in skin inflammation where interaction between keratinocytes and beta1-integrin expressing inflammatory cells, such as monocytes, takes place. METHODS: The regulation of Sema7A expression on keratinocytes by various cytokines was studied by flow cytometry and immunoblot. beta1-integrin expressing human monocyte cell line, THP-1 cells, were co-cultured with paraformaldehyde-fixed normal human epidermal keratinocytes (NHK) and IL-8 production by THP-1 cells was studied. The significance of beta1-integrin or Sema7A within this cell interaction was examined by the experiments using beta1-integrin blocking antibody or Sema7A siRNA. RESULTS: IFN-gamma and TNF-alpha slightly increased Sema7A expression, while IL-4 decreased it. Among cytokines tested, TGF-beta1 most strikingly increased the Sema7A expression on NHK. When NHK was stimulated by TGF-beta1, paraformaldehyde-fixed, and co-cultured with THP-1 cells, IL-8 production by THP 1 cells was increased compared to THP-1 cells only. When THP-1 cells were pretreated with beta1-integrin blocking antibody, this increase in IL-8 production by THP-1 cells was inhibited. Likewise, when NHK were pretreated with Sema7A siRNA before fixation and co-cultured with THP-1 cells, increase in IL-8 production by THP-1 cells was inhibited. CONCLUSION: Our results suggest that Sema7A on keratinocytes and beta1-integrin on monocytes contribute to monocyte activation by keratinocytes within skin inflammation, such as psoriasis or wound. PMID- 21524888 TI - Differentiation-dependent expression of NADP(H):quinone oxidoreductase-1 via NF E2 related factor-2 activation in human epidermal keratinocytes. AB - BACKGROUND: NADP(H):quinone oxidoreductase-1 (NQO-1) is known for its protective role in skin carcinogenesis, but the expression of NQO-1 during keratinocyte (KC) differentiation has not been studied. OBJECTIVE: The purpose of the current study was to evaluate modulation of NQO-1 and NF-E2-related factor-2 (Nrf2) during KC differentiation. METHODS: Normal human epidermal keratinocytes (NHEKs) were induced to differentiation by prolonged culture after confluency (postconfluence). RESULTS: NQO-1 was induced at the late stage of differentiation of NHEKs (7th day of postconfluence). The expression of postconfluence-induced NQO-1 was stimulated by 0.1 mM H(2)O(2), but attenuated by 5 mM N-acetylcysteine, implying that reactive oxygen species (ROS) are implicated in the expression of NQO-1 in differentiated KCs. Nrf2 was up-regulated at the earlier than NQO-1 induction (3rd day of postconfluence). The Nrf2-dependent expression of NQO-1 was further supported by Nrf2-siRNA experiments. A confocal study confirmed the differentiation-dependent induction and activation of NOQ-1 and Nrf-2 in NHEKs. Immunohistochemistry showed that NQO-1 was accentuated in the upper epidermal layers, supporting the notion that differentiation-dependent NQO-1 expression is functional in human skin in vivo. CONCLUSION: These results demonstrate that NQO 1 is modulated during KC differentiation via Nrf2 pathway, suggesting the active role of NQO-1 in the differentiating epidermis. PMID- 21524889 TI - Minoxidil activates beta-catenin pathway in human dermal papilla cells: a possible explanation for its anagen prolongation effect. AB - BACKGROUND: It is believed that the length of the actively growing phase of the anagen hair cycle mainly contributes to hair length. Recent studies showed that maintenance of beta-catenin activity in the dermal papilla cells (DPCs) enables hair follicles to keep actively growing. Topical minoxidil treatment promotes hair growth in men with androgenetic alopecia, suggesting that minoxidil may prolong the actively growing phase of the anagen hair cycle. OBJECTIVE: To investigate whether minoxidil prolongs the anagen hair cycle in mice and, if so, to investigate whether minoxidil activates beta-catenin pathway in human DPCs. METHODS: Dorsal skins of C57BL/6 mice were depilated to synchronize the hair cycle. After 10 days, 3% minoxidil were topically applied daily for 10 days. Sections of back skins were stained with hematoxylin and eosin. Hair follicles were graded and hair cycle score (HCS) was calculated. Cultured human DPCs were transiently transfected with the beta-catenin responsive TCF reporter plasmid (pTopflash) and corresponding negative control reporter (pFopflash) to assess the activity of beta-catenin signaling by minoxidil. Immunofluorescence staining and immunoblot were performed to examine the expression and localization of beta catenin in the presence or absence of minoxidil. Phosphorylation of GSK3beta, PKA and PKB were also examined by immunoblot after minoxidil treatment. RT-PCR analysis and immunoblot were employed to investigate the expression of beta catenin pathway targets in DPCs, such as Axin2, Lef-1, and EP2. RESULTS: Modest extension of anagen phase thereby delay of catagen progression was observed by application of minoxidil in mice. Minoxidil stimulated the transcriptional activity of pTopflash but not pFopflash. Nuclear accumulation of beta-catenin was also observed after minoxidil treatment. Immunoblot further showed that minoxidil treatment increases the phosphorylation of GSK3beta, PKA and PKB. Moreover, minoxidil induced Axin2, Lef-1, and EP2 expression. CONCLUSION: Our results strongly suggest that minoxidil extends the anagen phase by activating beta catenin activity in the DPCs. PMID- 21524890 TI - Effect of human astrocytes on the characteristics of human brain-microvascular endothelial cells in the blood-brain barrier. AB - A blood-brain barrier (BBB) model in vitro was established by cultivating human brain-microvascular endothelial cells (HBMECs) with the regulation of human astrocytes (HAs) (HBMEC/HA). Astrocyte-conditioned medium (ACM) was employed to constitute a confluent monolayer of HBMECs without directly conjugated HAs. HBMECs exhibited an orientated multiplication on the supporting membrane; while HAs grew in an overlapping fashion. In addition, HBMECs could propagate over the membrane pore, and the end-feet of HAs extended into the membrane pore to improve the integral feature of the BBB. HBMEC/HA demonstrated a high transendothelial electrical resistance (TEER) about 230 Omega cm2 and low permeability of propidium iodide (PI) about 4 * 10-6 cm/s. The order in TEER was HBMEC/HA>HBMECs with 100% ACM>HBMECs with 50% ACM > HBMECs. The reverse order was valid for the permeability of PI and uptake of calcein-AM by HBMECs. The tranwell culture of HBMECs and HAs displays appropriate characteristics of the BBB and can be applied to estimate the delivery efficiency of therapeutic chemicals for the brain related disease. PMID- 21524891 TI - Penetration behaviour of alkylbetainate chlorides into lipid monolayers. AB - In this paper, the penetration behaviour of the alkylbetainate chloride surfactants (C(n)BC, n=10-16) into lipid monolayers of dipalmitoylphosphatidylserine (DPPS), dipalmitoylphosphatidic acid (DPPA), dipalmitoylphosphatidylethanolamine (DPPE), palmitoyoleoylphosphatidylcholine (POPC) and cholesterol (CHOL) is investigated using the Langmuir trough technique. The penetration of C(n)BC is followed by measurement of the surface pressure increase (Deltapi) at a constant surface area after the injection of C(n)BC into the aqueous phase, underneath the lipid monolayer previously spread at the air-water interface at 25 degrees C and at different initial surface pressures (pi(i)). The influence of both the lipid head group and the surfactant hydrocarbon chain length on the effectiveness of C(n)BC penetration into these monolayers is discussed. The results have shown that C(n)BC adsorb at the air water interface giving evidence of their surface-active properties. The adsorption kinetics of C16BC into different lipid monolayers are lipid head charge and lipid head volume-dependent. The magnitude of the surface pressure increase (Deltapi) arises in the following order: DPPA>DPPS?CHOL~DPPE>POPC. C(n)BC penetration into negatively-charged (DPPS and DPPA) monolayers does not seem to depend on surfactant alkyl-chain length compared to uncharged (CHOL) and zwitterionic (DPPE and POPC) monolayers for which Deltapi increases with a larger alkyl-chain length. Electrostatic interactions are mainly involved in the affinity of C(n)BC with monolayers but the hydrophobic effect plays also a role. PMID- 21524892 TI - Lipid nanoparticles as vitamin matrix carriers in liquid food systems: On the role of high-pressure homogenisation, droplet size and adsorbed materials. AB - Twelve oil-in-water nano-emulsions were prepared using a melt high-pressure homogenisation process (HPH) at 300, 800 or 1200 bar. The resulting emulsions containing 20 wt% palm oil in the absence or presence of alpha-tocopherol were stabilised by whey proteins alone or in mixture with lecithin. Lipid nanoparticles in these emulsions were characterized for their particle size, surface charge and protein surface concentration (PSC) in relation to their stability against aggregation and coalescence, and to their ability for encapsulation and protection of alpha-tocopherol against chemical degradation. Increasing HPH values were accompanied by the formation of lipid nanoparticles with decreasing size and PSC, but increasing long-term stability against aggregation and coalescence in parallel with an increase in alpha-tocopherol degradation (up to 15 wt% for 1200 bar). Presence of alpha-tocopherol, led to increasing (or decreasing) PSC values with increasing (or decreasing) HPH values for lipid nanoparticles stabilised by proteins alone (or in mixture with lecithins). In addition to these structural properties, the ability for alpha tocopherol long-term stability of nanoparticles in emulsions was shown to differ more depending on their adsorbed materials (protein alone, or in mixture with lecithin) than on their particle size values. After 2 months storage, alpha tocopherol in emulsions prepared at 300, 800 or 1200 bar was protected against chemical degradation at 79, 77, 67 wt%, respectively, when whey proteins were used alone, instead of 66, 63, 48 wt% when proteins were used in mixture with lecithins. These results indicated the dominant role of adsorbed proteins on the protection of vitamin models by nanoemulsions. They are of a great technological importance for production of lipid nanoparticles presenting a high volume-to diameter ratio values and consequently high exchange surfaces between the matrix carrier and water and oxygen environmental factors. PMID- 21524893 TI - Effect of bases with different solubility on the release behavior of risperidone loaded PLGA microspheres. AB - Poly (D, L-lactide-co-glycolide) (PLGA) microspheres are attractive delivery vehicles due to their excellent sustained release capabilities. One major problem with PLGA microspheres is that the hydrophobic properties of PLGA generally cause a lag period in the process of drug release, leading to fluctuation of drug concentration in the blood and various resulting adverse reactions. Herein, Mg(OH)2, an inorganic base, and arginine, an organic base, were separately co encapsulated into risperidone-loaded PLGA microspheres at varying concentration using the solvent evaporation method to improve release profiles from the microspheres. High encapsulation efficiencies were obtained in all formulations. The surface of base-free microspheres was smooth, whereas a few pores formed in base co-encapsulated microspheres. After 7-days degradation, many inter connecting pores were formed in the interior of the microspheres containing 10 mg Mg(OH)2. The final pH in the microspheres with Mg(OH)2 was higher than in those with arginine after 28-days degradation. The initial release of risperidone from microspheres containing Mg(OH)2 was higher than from those containing arginine, and the latter release exhibited a more uniform pattern. Microspheres with 5mg and 10mg arginine exhibited zero-order release kinetics. However, both bases eliminated the lag phase of release. These results indicate that the incorporation of bases has potential in addressing the problem of the lag period in drug release from PLGA microspheres, and improving release behavior toward an ideal model. PMID- 21524894 TI - Synthesis and immobilization of micro-scale drug particles in cellulosic films. AB - The anti-solvent synthesis of micron-scale particles, their stabilization, and subsequent self-assembly into polymer films suitable for drug delivery is presented. The colloidal particles were stabilized using low molecular weight hydroxypropyl methylcellulose (HPMC), while drug encapsulation was carried out with high molecular weight HPMC and polyvinylpyrrolidone (PVP). Griseofulvin (GF) was used as the model drug compound, and the polymer films were evaluated in terms of their surface morphology, mechanical properties and in vitro drug release. In general, the release rates were best described by first-order and Hixson-Crowell kinetic models, and in a typical film containing 57% HPMC, 100% of GF was released within 50 min. PMID- 21524895 TI - [Maternal group B streptococcal bacteriuria and neonatal infective endocarditis: a case report]. AB - Bacterial endocarditis is rare in children. We report the case of streptococcal B endocarditis in a newborn whose mother had asymptomatic bacteriuria during pregnancy. This report emphasizes the importance of maternal intrapartum antibiotic therapy when there is a major risk of neonatal infection and underlines the diagnostic value of echocardiography in case of prolonged fever. PMID- 21524896 TI - Penicillium chrysogenum var. halophenolicum, a new halotolerant strain with potential in the remediation of aromatic compounds in high salt environments. AB - A halotolerant phenylacetate-degrading fungus Penicillium CLONA2, previously isolated from a salt mine at Algarve (Portugal), was identified as a variant of P. chrysogenum using the ITS-5,8S rDNA and the D1/D2 domain of 28S rDNA sequences. The metabolic features and genetic characteristics suggest that this strain belongs to a subgroup of P. chrysogenum, named var. halophenolicum. The presence of the penicillin biosynthetic cluster was proven by Southern hybridizations using probes internal to the pcbAB and penDE genes and sequencing of the pcbAB-pcbC intergenic region. However the pcbAB-pcbC divergent promoter region contained 20 point modifications with respect to that of the wild type P. chrysogenum NRRL1951. The CLONA2 strain produced non-aromatic natural penicillins rather than benzylpenicillin in a medium containing potassium phenylacetate (the precursor of benzylpenicillin) and was able to grow well on phenylacetatic acid using it as sole carbon source. Due to the ability of P. chrysogenum CLONA2 to degrade aromatic compounds, this strain may be an interesting organism for aromatic compounds remediation in high salinity environments. PMID- 21524899 TI - Promising cutting-edge technologies and tools to accelerate the discovery and development of new vaccines. PMID- 21524898 TI - CD4+ memory T cell survival. AB - Memory CD4+ T cells specific for a given antigen are generated during the primary response from the effector lymphoblast progeny of naive precursors. How memory CD4+ T cells differentiate from the effector population is not understood but new tools to assess transcription factor and cytokine expression are allowing for a more careful assessment of this process. Here we review the factors that allow some effector CD4+ T cells to survive the contraction phase of the primary response and become memory cells, and consider whether parallels can be drawn between T and B cells. PMID- 21524897 TI - Role of immune mechanisms in induction of HIV-1 broadly neutralizing antibodies. AB - Although antibodies can be elicited by HIV-1 infection or immunization, those that are broadly neutralizing (bnAbs) are undetectable in most individuals, and when they do arise in HIV-1 infection, only do so years after transmission. Until recently, the reasons for difficulty in inducing such bnAbs have been obscure. Recent technological advances in isolating bnAbs from rare patients have increased our knowledge of their specificities and features, and along with gene targeting studies, have also begun uncovering evidence of immunoregulatory roadblocks preventing their induction. One crucial avenue towards developing an effective HIV-1 vaccine is to harness this emerging information into the rational design of immunogens and formulation of adjuvants, such that structural and immunological hurdles to routinely eliciting bnAbs can be overcome. PMID- 21524900 TI - Oral endotracheal tube exchange to the nasal route in a patient with facial trauma. PMID- 21524901 TI - Interaction of calf thymus dsDNA with anti-tumor drug tamoxifen studied by zero current potentiometry. AB - Since the electrochemical oxidation peaks of both DNA and anti-tumor drug tamoxifen (TAM) overlapped with each other, the known electrochemical methods were limited in the study of the interactions between DNA and TAM. In this paper, zero current potentiometry, a new electrochemical method, was used to study the interaction of calf thymus dsDNA with TAM. The dsDNA was immobilized on the surface of carbon paste (dsDNA/CP). The dsDNA/CP connected in series between the clips of working and counter electrodes of a potentiostat and a reference electrode were immersed in aqueous solution containing TAM, the interaction of dsDNA with TAM produced a change in interfacial potential at the dsDNA/CP/solution interface. When linear sweep potential was applied to the dsDNA/CP and the corresponding I-E curve was recorded, interfacial potential offset applied potential partially, making the I-E curve displace along potential axis. Zero current potential where circuit current I was equal to zero in the I-E curve was measured to check the displacement of the I-E curve. Based on the displacement, the thermodynamic constants of the interaction between dsDNA and TAM were determined. The binding ratio of dsDNA with TAM was found to be 1:1 and the apparent binding constant was (6.85+/-0.20)*10(6) M(-1). As zero current potentiometry was independent of the changes in redox potential or current of both dsDNA and TAM themselves, the interaction was studied in their natural forms without damage. Moreover, TAM can be determined. The detection limit was 1.1*10( 7) M. PMID- 21524902 TI - Electrochemical DNA biosensor for screening of chlorinated benzene pollutants. AB - In this work, an electrochemical DNA biosensor based on double-stranded DNA modified Au electrode (dsDNA/Au) was proposed for the rapid screening and detection of chlorinated benzenes pollutants, in which redox-active methylene blue (MB) was used to amplify the interaction between dsDNA and the target analyte. Using hexachlorobenzene (HCB) as a model analyte of chlorinated benzenes, the biosensor demonstrated a linear response with the logarithm of HCB concentrations from 100 pmol L(-1) to 100 nmol L(-1). The obtained detection limit was 30 pmol L(-1), which was remarkably superior to other biosensors. The interaction mechanism of the biosensor with HCB was proposed based on systematical characterization by cyclic voltammetry (CV), differential pulse voltammetry (DPV), UV-vis spectrometry and electrochemical quartz crystal microbalance (EQCM). Further studies revealed that the biosensor could screen chlorinated benzenes in the presence of 100 fold amount of other co-existing chemicals (ethyl acetate and sodium oxalate, etc.), and the response signal of the biosensors for different chlorinated benzenes was correlative to their respective toxicity. The proposed biosensor proved to be a promising "alarm" tool for rapid screening of chlorinated benzenes in real water samples. PMID- 21524903 TI - Silicon photonic crystal nanocavity-coupled waveguides for error-corrected optical biosensing. AB - A photonic crystal (PhC) waveguide based optical biosensor capable of label-free and error-corrected sensing was investigated in this study. The detection principle of the biosensor involved shifts in the resonant mode wavelength of nanocavities coupled to the silicon PhC waveguide due to changes in ambient refractive index. The optical characteristics of the nanocavity structure were predicted by FDTD theoretical methods. The device was fabricated using standard nanolithography and reactive-ion-etching techniques. Experimental results showed that the structure had a refractive index sensitivity of 10(-2) RIU. The biosensing capability of the nanocavity sensor was tested by detecting human IgG molecules. The device sensitivity was found to be 2.3+/-0.24*10(5) nm/M with an achievable lowest detection limit of 1.5 fg for human IgG molecules. Additionally, experimental results demonstrated that the PhC devices were specific in IgG detection and provided concentration-dependent responses consistent with Langmuir behavior. The PhC devices manifest outstanding potential as microscale label-free error-correcting sensors, and may have future utility as ultrasensitive multiplex devices. PMID- 21524904 TI - Bottom-up tissue engineering. AB - Recapitulating the elegant structures formed during development is an extreme synthetic and biological challenge. Great progress has been made in developing materials to support transplanted cells, yet the complexity of tissues is far beyond that found in even the most advanced scaffolds. Self-assembly is a motif used in development and a route for the production of complex materials. Self assembly of peptides, proteins and other molecules at the nanoscale is promising, but in addition, intriguing ideas are emerging for self-assembly of micron-scale structures. In this brief review, very recent advances in the assembly of micron scale cell aggregates and microgels will be described and discussed. PMID- 21524905 TI - Purification of waste gas containing high concentration trimethylamine in biotrickling filter inoculated with B350 mixed microorganisms. AB - A biotrickling filter packed with ceramic particles and seeded with B350 microorganisms was applied to remove trimethylamine (TMA) from gaseous waste. A 100% removal efficiency (RE) was obtained when the empty bed residence time (EBRT) was larger than 110 s at an inlet concentration of 0.30 m g/L. Maximum elimination capacity (EC) was 13.13 g m(-3)h(-1) (RE=64.7%) at 55 s of EBRT. TMA concentrations <0.20mg/L at 83 s of EBRT did not affect the REs (100%). Maximum EC was 13.95 g m(-3)h(-1) (RE=78.1%) at a TMA concentration of 0.42 mg/L. Approximately 53.1% of the carbon in TMA was completely mineralized. Bacterial community analysis in the bioreactor revealed more than 21 species in a stable state. Based on all these results, biotrickling filter inoculated with B350 microorganisms is deemed highly capable of ridding waste gas of TMA. PMID- 21524906 TI - Optimisation of a microwave pretreatment of wheat straw for methane production. AB - This study aims at the optimisation of a microwave pretreatment for wheat straw solubilisation and anaerobic biodegradability. The maximum yield of methane production was obtained at 150 degrees C with an improvement of 28% compared to an untreated sample. In addition, at this temperature, the time to reach 80% of the methane volume obtained from untreated straw was about 35%. The study of ramp time and holding time at targeted temperature showed that they had no improvement effect. Thus, the best conditions are the highest heating rate for a final temperature 150 degrees C without any holding time. The reading of energy consumed by pretreatment and energy overproduced by pretreated samples showed that increasing tVS amount and heating rate led to a saving of energy consumption. Nevertheless, to obtain a positive energy balance, a microwave device should consume less than 2.65 kJ/g(tVS). PMID- 21524907 TI - Aerobic granular sludge formation for high strength agro-based wastewater treatment. AB - The present study investigates the formation of aerobic granular sludge in sequencing batch reactor (SBR) fed with palm oil mill effluent (POME). Stable granules were observed in the reactor with diameters between 2.0 and 4.0mm at a chemical oxygen demand (COD) loading rate of 2.5 kg COD m(-3) d(-1). The biomass concentration was 7600 mg L(-1) while the sludge volume index (SVI) was 31.3 mL g SS(-1) indicating good biomass accumulation in the reactor and good settling properties of granular sludge, respectively. COD and ammonia removals were achieved at a maximum of 91.1% and 97.6%, respectively while color removal averaged at only 38%. This study provides insights on the development and the capabilities of aerobic granular sludge in POME treatment. PMID- 21524908 TI - Comparative material balances around pretreatment technologies for the conversion of switchgrass to soluble sugars. AB - For this project, six chemical pretreatments were compared for the Consortium for Applied Fundamentals and Innovation (CAFI): ammonia fiber expansion (AFEX), dilute sulfuric acid (DA), lime, liquid hot water (LHW), soaking in aqueous ammonia (SAA), and sulfur dioxide (SO(2)). For each pretreatment, a material balance was analyzed around the pretreatment, optional post-washing step, and enzymatic hydrolysis of Dacotah switchgrass. All pretreatments+enzymatic hydrolysis solubilized over two-thirds of the available glucan and xylan. Lime, post-washed LHW, and SO(2) achieved >83% total glucose yields. Lime, post-washed AFEX, and DA achieved >83% total xylose yields. Alkaline pretreatments, except AFEX, solubilized the most lignin and a portion of the xylan as xylo-oligomers. As pretreatment pH decreased, total solubilized xylan and released monomeric xylose increased. Low temperature-long time or high temperature-short time pretreatments are necessary for high glucose release from late-harvest Dacotah switchgrass but high temperatures may cause xylose degradation. PMID- 21524910 TI - Research on PEGylation of porcine prothrombin for improving biostability and reducing animal immunogenicity. AB - Prothrombin is a vitamin K-dependent serine protease and plays pivotal roles in both procoagulant and anticoagulant pathway of hemostasis. In this study, prothrombin purified from porcine plasma was modified through PEGylation at N terminal residue using 40 kDa PEG-phenyl-isothiocyanate (PIT-PEG40K). The monoPEGylated prothrombin enhanced biostability and remarkably prolonged circulating half-life in mice as compared with that of the nonmodified prothrombin. Moreover, the immunogenicity of PEGylated prothrombin in mice is significantly decreased compared to nonmodified prothrombin. These studies demonstrated the feasibility of PEGylating prothrombin as a promising way for the development of new prothrombin drugs. PMID- 21524909 TI - Detection of 5-hydroxymethylcytosine in a combined glycosylation restriction analysis (CGRA) using restriction enzyme Taq(alpha)I. AB - 5-Hydroxymethylcytosine (5-hmC) is a newly discovered DNA base in mammalian cells that is believed to be another important epigenetic modification. Here we report the use of a methylation-insensitive restriction enzyme Taq(alpha)I coupled with selective chemical labeling of 5-hmC in a combined glycosylation restriction analysis (CGRA) to detect 5-hmC in TCGA sequences. This method, differentiates fully versus hemi-hydroxymethylated cytosine in the CpG dinucleotide, adds a new tool to facilitate biological studies of 5-hmC. PMID- 21524911 TI - Synthesis and characterisation of a novel tubulin-directed DO3A-colchicine conjugate with potential theranostic features. AB - Colchicine is a known tubulin binding agent enabling necrosis in tumors. A novel tubulin-directed DO3A-colchicine conjugate and its Gd(III) complex were prepared from N-deacetylcolchicine, coupling alkaloid and polyaza-alicyclic functions via a peptide coupling methodology. The longitudinal proton relaxivity of the Gd(III) complex in water at 4.7 T is 2.86 mM(-1) s(-1) and a similar efficacy as colchicine towards ovarian carcinoma cells in vitro. PMID- 21524912 TI - Sampling duration effects on centre of pressure descriptive measures. AB - The different measures used to characterize postural sway are sensitive to variations in sampling duration, yet there remains marked variability and a lack of consistency in this temporal parameter when compared between studies. We investigated the effect of sampling duration on 22 commonly used frequency and time domain measures and stabilogram diffusion coefficients. Participants stood quietly on a forceplate during two 600s standing trials with eyes open and eyes closed. The results clearly show that the amplitudes of the descriptive measures are sensitive to sampling duration. Only measures related to the amount of sway were sensitive for eyes open versus eyes closed conditions. In addition to sample duration, the filter settings, sampling frequency and fitting windows should be standardized since they also affect the magnitude of the descriptive measures. Without such standards, the inability to accurately compare between studies will persist. PMID- 21524913 TI - Kinetic asymmetry in transfemoral amputees while performing sit to stand and stand to sit movements. AB - Transitional movements are a determinant of functional independence and have limited study in amputees. Microprocessor prosthetic knees' abilities to assist transfemoral amputees with sitting and standing have not been studied. Through cross-sectional study, 21 transfemoral amputees, divided into 3 groups of 7 by knee type (power knee, C-leg, Mauch SNS) and 7 non-amputee controls (n=28) performed sit to stand and stand to sit while kinematic and kinetic data were recorded. Transfemoral amputees can stand (1.6-2.0s) and sit (2.1-2.8s) at rates comparable to controls (1.6s). Controls' ground reaction force (GRF) and knee moment production was <7% asymmetric and superior to amputees' during both movements. For sit to stand, amputees' asymmetry for GRF ranged from 53 to 69% and 110 to 124% for knee moments. For stand to sit, amputees' asymmetry for GRF ranged from 32 to 60% and 84 to 114% for knee moments. Hip moment asymmetry for sit to stand was less for control (21%) and power knee (34%) groups than that produced by the Mauch SNS (59%) group. For stand to sit, hip moment production for the Mauch SNS (47%) and C-leg groups (71%) were more asymmetric than controls (19%). In the majority of cases transfemoral amputees do not load their prosthesis extensively for standing up or sitting down. Therefore, this transitional movement is currently a one-legged task, which increases stress on the sound limb. Generally, the prosthetic knees studied did not produce a significant knee moment in either task. Although most differences between knee groups were not statistically significant, differences may be clinically meaningful on an individual basis. PMID- 21524914 TI - Cellular zwitterionic metabolite analogs simultaneously enhance reaction rate, thermostability, salt tolerance, and substrate specificity of alpha-glucosidase. AB - We investigated the structural effects of metabolite analogs derived from a naturally-occurring zwitterionic metabolite, glycine betaine, on the activity of several hydrolases. The initial velocities of the hydrolases were enhanced by the addition of the solutes into the buffer solution. Based on a detailed study using alpha-glucosidases, the acceleration efficiency of the enzymatic activity was strongly induced by solutes possessing bulky and aliphatic ammonium cations, indicating that enhancement of activity by the solutes depended on their chemical structures. Kinetic analysis revealed that the acceleration of the hydrolysis reaction was related to both the decrement of K(m) and increment of V(max) values. Furthermore, the addition of the metabolite analogs enhanced not only the rate constant but also the thermostability, salt tolerance, and substrate specificity of alpha-glucosidase simultaneously through the reduction of conformational perturbation of the enzyme. PMID- 21524915 TI - Bioorthogonal proteomics of 15-hexadecynyloxyacetic acid chemical reporter reveals preferential targeting of fatty acid modified proteins and biosynthetic enzymes. AB - Chemical reporters are powerful tools for the detection and discovery of protein modifications following cellular labeling. The metabolism of alkyne- or azide functionalized chemical reporters in cells can influence the efficiency and specificity of protein targeting. To evaluate the effect of degradation of chemical reporters of protein fatty acylation, we synthesized 15 hexadecynyloxyacetic acid (HDYOA), a reporter that was designed to be resistant to beta-oxidation, and compared its ability to label palmitoylated proteins with an established reporter, 17-octadecynoic acid (ODYA). HDYOA was able to label known candidate S-palmitoylated proteins similarly to ODYA. Accordingly, bioorthogonal proteomic analysis demonstrated that 70% of proteins labeled with ODYA were also labeled with HDYOA. However, the proteins observed differentially in our proteomic studies suggested that a portion of ODYA protein labeling is a result of beta-oxidation. In contrast, downstream enzymes involved in beta oxidation of fatty acids were not targeted by HDYOA. Since HDYOA can label S palmitoylated proteins and is not utilized by downstream beta-oxidation pathways, this fatty acid chemical reporter may be particularly useful for bioorthogonal proteomic studies in cell types metabolically skewed toward fatty acid breakdown. PMID- 21524916 TI - In vitro isolation, elicitation of psoralen in callus cultures of Psoralea corylifolia and cloning of psoralen synthase gene. AB - Psoralen, an important furanocoumarin occurring abundantly in seeds of Psoralea corylifolia is used as an anticancerous compound against leukemia and other cancer cell lines. Evaluation and isolation of psoralen from the calluses derived from different plant parts, viz. cotyledons, nodes, leaves and roots have been done in the present case for the first time. Amongst all, a maximum of 1934.75 MUg/g f.w. of psoralen was recorded in callus derived from cotyledons, followed by 1875.50 and 1465.75 MUg/g f.w. of psoralen in node and leaf derived calluses, respectively. Amount of psoralen enhanced further when cotyledonary calluses were exposed to different concentrations of organic elicitors (yeast extract, proline, inositol, casein hydrolyzate (CH), glycine, glutamine and sucrose) and precursors of psoralen (umbelliferone, cinnamic acid and NADPH). Isolation of psoralen was done using methanol as solvent through column chromatography and TLC. FT-IR and NMR further characterized and confirmed the structure of psoralen. In addition, the putative gene, psoralen synthase involved in psoralen synthesis pathway has been isolated, cloned and sequenced which comprised 1237 bp length. BLAST analysis of the gene sequence of psoralen synthase revealed that its nucleotide sequence showed 93% homology with psoralen synthase isolated from Ammi majus. This is the first report of isolation, cloning and characterization of psoralen synthase from Psoralea corylifolia. PMID- 21524918 TI - The level of serum visfatin (PBEF) is associated with total number of B cells in patients with rheumatoid arthritis and decreases following B cell depletion therapy. AB - OBJECTIVE: Visfatin, also known as pre-B cell colony-enhancing factor, was recently characterized as a potent pro-inflammatory mediator in rheumatoid arthritis (RA). The aim of this study was to determine the effect of B cell depletion with rituximab on serum visfatin levels in patients with active RA. METHODS: We evaluated 31 patients with RA starting rituximab therapy at baseline and after 16 and 24 weeks using disease activity score (DAS28). The control group consisted of 33 gender and age-matched healthy individuals. CD19(+) B cells were assessed by flow cytometry and serum levels of visfatin and B cell-activating factor of the TNF family (BAFF) were measured by ELISA at baseline and week 16. RESULTS: Total number of B cells correlated positively with serum visfatin levels (rs=0.417, P=0.025) and negatively with serum BAFF levels (rs=-0.486, P=0.008) at baseline. Serum visfatin levels were significantly higher in patients with RA compared with healthy controls (P=0.026), and significantly decreased (P=0.010), while BAFF increased (P<0.001), and both proteins became negatively correlated following treatment with rituximab (rs=-0.438, P=0.017). Visfatin levels did not correlate with the disease activity, but lack of change in the serum visfatin levels between baseline and week 16 predicted worsening disease activity between weeks 16 and 24 (rs=0.452, P=0.014). CONCLUSION: In patients with active RA, serum visfatin levels are related to the number of B cells rather than to disease activity and decrease in response to treatment with rituximab. Further studies are necessary to show if visfatin is a marker with predictive value for deterioration of RA. PMID- 21524917 TI - Calcium in the oxygen-evolving complex: structural and mechanistic role determined by X-ray spectroscopy. AB - This review describes the results from X-ray Absorption Spectroscopy studies that have contributed to an understanding of the role of Ca in the photosynthetic water-oxidation reaction. The results include the first Mn, Ca and Sr X-ray spectroscopy studies using Ca or Sr-substituted PS II samples that established the presence of a MnCa heteronuclear structure and its orientation, and the most recent Sr X-ray spectroscopy study using biosynthetically prepared Sr-containing PS II in the various S-states that provide important insights into the requirement for Ca in the mechanism of the Mn(4)Ca catalytic center. PMID- 21524919 TI - DC electric stimulation upregulates angiogenic factors in endothelial cells through activation of VEGF receptors. AB - Small direct current (DC) electric fields direct some important angiogenic responses of vascular endothelial cells. Those responses indicate promising use of electric fields to modulate angiogenesis. We sought to determine the regulation of electric fields on transcription and expression of a serial of import angiogenic factors by endothelial cells themselves. Using semi quantitative PCR and ELISA we found that electric stimulation upregulates the levels of mRNAs and proteins of a number of angiogenic proteins, most importantly VEGF165, VEGF121 and IL-8 in human endothelial cells. The up-regulation of mRNA levels might be specific, as the mRNA encoding bFGF, TGF-beta and eNOS are not affected by DC electric stimulation at 24h time-point. Inhibition of VEGF receptor (VEGFR1 or VEGFR2) signaling significantly decreased VEGF production and completely abolished IL-8 production. DC electric stimulation selectively regulates production of some growth factors and cytokines important for angiogenesis through a feed-back loop mediated by VEGF receptors. PMID- 21524920 TI - H-Ras-specific upregulation of granulocyte colony-stimulating factor promotes human breast cell invasion via matrix metalloproteinase-2. AB - Ras expression has been suggested to be a marker for tumor aggressiveness of breast cancer. We previously showed that H-Ras, but not N-Ras, induced invasive/migratory phenotypes in MCF10A human breast epithelial cells. The present study aimed to determine the role of granulocyte colony-stimulating factor in H-Ras-induced malignant progression of human breast epithelial cells. Here, we show that G-CSF plays a crucial role in H-Ras-induced MCF10A cell invasion and migration. The siRNA-mediated knockdown of G-CSF significantly reduced H-Ras-induced matrix metalloproteinase (MMP)-2 expression, as well as invasion/migration, suggesting the functional significance of G-CSF in the invasive phenotype of human breast cells. Importantly, the induction of G-CSF expression conferred the invasive/migratory phenotypes to MCF10A cells with up regulation of MMP-2 and activation of Rac1, MKK3/6, p38 MAPK, Akt, and ERKs. Knockdown of Rac1 by siRNA significantly inhibited MMP-2 upregulation and invasiveness of G-CSF MCF10A cells, demonstrating that G-CSF-induced MMP-2 upregulation and invasive phenotype is mediated by Rac1. Using human breast tissues and sera from breast cancer patients, we further demonstrate that the expression level of G-CSF is strongly correlated with pathologically-diagnosed breast cancer. These data provide a molecular basis for the crucial role of G-CSF in promoting invasiveness of human breast epithelial cells. PMID- 21524921 TI - Patellofemoral pain syndrome alters neuromuscular control and kinetics during stair ambulation. AB - The aim of the study was to investigate differences in frontal plane knee kinetics, onset timing and duration of the gluteus medius (GMed), adductor longus (AL), and vastus medialis oblique (VMO) during stair ambulation between those with and without patellofemoral pain syndrome (PFPS). Twenty PFPS patients and twenty healthy participants completed stair ambulation while surface electromyography (EMG), video, and ground reaction forces were collected. PFPS patients had a higher peak internal knee abduction moment during stair ascent, and a higher internal knee abduction impulse for both ascent and descent. During stair ascent, PFPS patients displayed earlier onset of the AL and later onset of GMed, compared to the healthy individuals. Also, PFPS patients had longer activation duration of the AL and shorter activation durations of the VMO and GMed during stair ascent. During stair descent, PFPS patients displayed delayed GMed onset and shorter activation duration of GMed and VMO. The results of the study suggest that altered neuromuscular control of the medial thigh musculature may be an important contributor to PFPS. PMID- 21524922 TI - The impact of preoperative smoking habit on rotator cuff tear: cigarette smoking influences rotator cuff tear sizes. AB - HYPOTHESIS: Smoking is an important risk factor for the development of rotator cuff tears. We hypothesized that smoking may also influence rotator cuff tear size. MATERIALS AND METHODS: The study included 408 patients who underwent arthroscopic repair of cuff tear. Cuff tears were classified during surgery. We analyzed the percentage of smokers and the association of the amount and duration of smoking exposure with the type of tear. The average number of daily cigarettes and the total number of cigarettes in life were studied using age and gender as covariates. RESULTS: Smokers comprised 131 of 408 patients (32.1%). A type I tear affected 95 patients (23.3%), type II affected 214 (52.5%), type III affected 74 (18.1%), and type IV affected 25 (6.1%). Smokers comprised 23.2% (22 patients) of patients with type I tear, 33.6% (72 patients) of patients with type II tears, 36.5% (27 patients) of patients with type III tears and 40% (10 patients) of patients with IV tears. The frequency of smokers with at least a type II tear was 34.8% and differed significantly from the 23.2% of the type I tear patients (P = 0.033). Total number of cigarettes was significantly higher in patients with an at least a type II tear (F(1,127) = 4.694, P = .032). DISCUSSION: Rotator cuff has a relatively hypovascular insertion into the greater tuberosity. Cigarette smoking negatively affects vascularity of tendons. CONCLUSIONS: There is a correlation between cigarette smoking habit, rotator cuff tear, and tear size. There was an increasing daily average number of cigarettes and a total number of cigarettes smoked in life across patients with increasing severity of tears. PMID- 21524923 TI - Clinical success of biceps tenodesis with and without release of the transverse humeral ligament. AB - BACKGROUND: Multiple methods for biceps tenodesis exist, but long-term studies have demonstrated high failure rates. We hypothesized that tenodesis techniques that do not release the biceps sheath are associated with a higher surgical revision rate than those that do. METHODS: A retrospective study was conducted of 127 biceps surgeries over a 2-year period. The mean follow-up post surgery was 22 months (range, 6-59). Clinical failure was defined as ongoing pain localized in the biceps groove, severe enough to warrant revision surgery. RESULTS: When all techniques that released the biceps sheath (6.8%, 4/59) were compared to those that did not release the biceps sheath (20.6%, 14/68), a statistically significant difference was found, P = .026 (chi-square). Proximal arthroscopic techniques were revised at a significantly higher rate than distal tenodesis techniques (P = .005). CONCLUSION: Biceps tenodesis techniques which do not release the biceps sheath or remove the tendon from the sheath have increased revision rates, compared to techniques that do. This may be supportive evidence for the theory that residual pain generating elements in the biceps groove is a cause of failure of proximal tenodesis methods. PMID- 21524924 TI - Reconstruction with constrained prosthesis after total scapulectomy. AB - HYPOTHESIS: Scapular prosthetic replacement after total scapulectomy can result in oncologic salvage and good postoperative function with a low rate of complications. MATERIALS AND METHODS: Ten patients who underwent constrained scapular prosthetic replacement after total scapulectomy between 2003 and 2009 were reviewed retrospectively. RESULTS: At a mean follow-up of 36 months, 2 patients died of their disease. One patient showed recurrence and metastasis. Complications, including dislocation and superficial wound infection, occurred in 2 patients. The mean Musculoskeletal Tumor Society 93 score was 23.2 of 30 points. High scores were achieved for most items except hand position; only 5 patients can raise their hands above their waist. The ranges of active shoulder abduction and forward flexion motion were 20 degrees to 45 degrees and 40 degrees to 65 degrees , respectively. All patients retained normal hand and elbow functions. CONCLUSION: Although there are limitations in the shoulder's active motion, reconstruction with a scapular prosthesis can provide oncologic salvage and result in good postoperative function with a low rate of complications. PMID- 21524925 TI - Elastofibroma dorsi: diagnostic and therapeutic algorithm. AB - BACKGROUND: Elastofibroma typically occurs in the subscapular region of elderly individuals and has a high incidence in Kyushu and the surrounding islands in southern Japan. The treatment of this lesion is somewhat controversial. PATIENTS AND METHODS: Eleven patients with a diagnosis of elastofibroma dorsi were identified from the unit's database. The clinical presentation, diagnosis, and treatment options were evaluated. RESULTS: There were 6 men and 5 women, with a mean age of 66.7 years (range, 49-82 years). Bilateral lesions were found in 2 patients. The mean lesion size was 6.6 cm in greatest dimension (range, 5-9 cm). The mean follow-up of both surgically and conservatively managed patients was 16.4 months (range, 2-69 months). All were diagnosed by magnetic resonance imaging, and early in the series, 1 also underwent an open biopsy to confirm the diagnosis. Five patients underwent marginal excision of the lesion. No recurrence was observed at last follow-up. CONCLUSIONS: Magnetic resonance imaging can be used as a first-line investigation of the lesion, and biopsy is not necessary in most cases. We suggest that a conservative "wait-and-watch" attitude is reasonable and may be considered even when patients are symptomatic. PMID- 21524926 TI - Endovenous laser ablation: the role of intraluminal blood. AB - OBJECTIVE: In this histological study, the role of the intraluminal blood during endovenous laser ablation was assessed. METHODS: In 12 goats, 24 lateral saphenous veins were treated with a 1500-nm diode laser. Four goats were treated in an anti-Trendelenburg position (group 1). The next four goats were treated in a Trendelenburg position (group 2) and the remaining four goats in the Trendelenburg position with additional injection of tumescent liquid (group 3). Postoperatively, the veins were removed after 1 week and sent for histological examination. We measured the number of perforations. Vein wall necrosis and the perivenous tissue destruction were quantified using a graded scale. RESULTS: The 'calculated total vein wall destruction' was significantly higher in the third group (81.83%), as compared with groups one (61.25%) (p < 0.001) and two (65.92%) (p < 0.001). All three groups showed a significant difference in the perivenous tissue destruction scale (p < 0.001) with the lowest score occurring in the third group. Vein wall perforations were significantly more frequent in groups one and two as compared with the third group (T-test respectively p < 0.001, p = 0.02). CONCLUSION: A higher intraluminal blood volume results in reduced total vein wall destruction. Injection of tumescent liquid prevents the perivenous tissue destruction and minimises the number of perforations. PMID- 21524927 TI - Should I choose open surgery or EVAR for my aortic aneurysm repair? reflections on the PREFER study on patients' preferences. PMID- 21524928 TI - Pseudomembranous cystitis, an unusual condition associated with feline urine outflow obstruction: Four cases. AB - The clinical follow-up of four cats presumptively diagnosed with pseudomembranous cystitis is described. All presented with acute urine outflow obstruction and acute renal failure. Urethral catheterisation was performed without difficulty but ultrasonography and contrast radiography consistently revealed abnormal bladder wall and content. One cat was euthanased, the remaining three underwent an exploratory cystotomy. Abundant inflammatory and necrotic tissue covering an ulcerated bladder mucosa was removed. All cats recovered uneventfully. No definitive cause was identified but the clinical course of the disease was not typical of idiopathic cystitis. PMID- 21524929 TI - [Paediatric pharmacy: training and information]. PMID- 21524930 TI - [Preferences, satisfaction level of patient participation in making decisions in health centre nursing clinics]. AB - AIMS: To assess patient preferences their satisfaction level and their participation in decision making with nurses. METHODS: Cross-sectional and mixed quantitative-qualitative study carried out in people attending the nursing services of 9 Health Centres in Andalusia. Patients were interviewed immediately after receiving nursing treatment using two different questionnaires for assessing their opinions, satisfaction and perception of involvement in the decisional process. A descriptive analysis using the chi(2) test (P<.05) was performed to assess the differences among close-ended and open-ended questions. Qualitative analysis: Open-ended questions were grouped into categories by a process involving three researchers independently. RESULTS: A total of 235 patients took part, of whom 59% (138) preferred a collaborative role with the nurse when making decisions. In the closed questions, 96.2% (228) of the surveyed patients declared to be satisfied or very satisfied with the decision making process; nevertheless 17.4% (41) made specific suggestions for improving this process. For them the main improvement areas were related to: general communication skills or a more specific one such as: strategies for helping them make decisions, reaching common ground or giving advice. CONCLUSIONS: Nurses should be aware that most patients wish to be involved in decision making and in clinical practice this participation can be improved by obtaining specific communicational skills. Surveys that include open-ended questions are more useful to assess the quality of care. PMID- 21524931 TI - Urinary schistosomiasis in France. PMID- 21524932 TI - Epidemiology and burden of rotavirus disease in Central Asia. AB - BACKGROUND: Rotavirus infection is the most common cause of severe gastroenteritis in children worldwide. New rotavirus vaccines are not currently used in the five countries that make up the Central Asian region. Three of these countries, Kazakhstan, Uzbekistan, and Kyrgyzstan, have a combined total population of 48 million and an estimated 1 million annual births. METHODS: We conducted prospective hospital-based surveillance for rotavirus diarrhea in three Central Asian countries (Kazakhstan, Uzbekistan, and Kyrgyzstan) during 2005-2009 to estimate the burden of rotavirus. We calculated the proportion of rotavirus among children aged <5 years hospitalized with acute diarrhea and estimated numbers of rotavirus-associated deaths, hospitalizations, outpatient visits, and home care episodes. RESULTS: Of 20 780 children hospitalized with diarrhea and enrolled in the study, 26% (95% confidence interval (CI) 25-27) were positive for rotavirus antigen by ELISA. On an annual basis, 4007 (2.6 per 1000 child-years) rotavirus hospitalizations occur in Kazakhstan, 5491 (2.1 per 1000 child-years) in Uzbekistan, and 3883 (6.8 per 1000 child-years) in Kyrgyzstan. Rotavirus is also estimated to cause 68 (0.04 per 1000 child-years) deaths in children aged <5 years in Kazakhstan, 662 (0.25 per 1000 child-years) in Uzbekistan, and 156 (0.27 per 1000 child-years) in Kyrgyzstan. CONCLUSION: This study presents an epidemiological picture of rotavirus disease in Central Asia and illustrates a substantial rotavirus burden, which is preventable with rotavirus vaccination. PMID- 21524933 TI - Electronic structure, molecular electrostatic potential and hydrogen bonding in DMSO-X complexes (X = ethanol, methanol and water). AB - In the present work, we have studied the electronic structure, molecular electrostatic potential (MEP) and hydrogen bonding in DMSO-ethanol, DMSO-methanol and DMSO-water complexes by employing the MP2 method. Different conformers were simulated on the basis of possible binding sites guided by molecular electrostatic potential topology. The stronger hydrogen bonded interaction lowers the energy of the conformer. Molecular electron density topology and natural bond orbital analysis were used to explain the strength of interactions. Experimental vibrations are also compared with the calculated normal vibrations. Blue shift is predicted for SC vibration in experimental and theoretical spectra as well. Molecular electrostatic potential and topology are used to understand the interaction strength of the conformer. PMID- 21524934 TI - Density functional theory calculation and vibrational spectroscopy study of 2 amino-4,6-dimethyl pyrimidine (ADMP). AB - The solid phase FTIR and FT-Raman spectra of 2-amino-4,6-dimethyl pyrimidine (ADMP) have been recorded in the regions 4000-400 cm(-1) and 3500-50 cm(-1) respectively. The structure was investigated by utilizing density functional theory (DFT) calculations with the Becke 3-Lee-Yang-Parr (B3LYP) method employing the 6-31+G and 6-311++G basis sets. The optimized geometrical parameters obtained by B3LYP method show good agreement with experimental data. Complete vibrational assignments were made on the basis of normal coordinate analysis (NCA) for the molecule. The infrared and Raman spectra were also predicted from the calculated intensities. The observed and the calculated spectra were found to be in good agreement. The thermodynamic properties like entropies and their correlations with temperatures were also obtained from the harmonic frequencies of the optimized structures. PMID- 21524935 TI - Investigations of zero-field splitting (ZFS) and local distortion parameters of Fe3+ ions doped into three oxi-spinels (ZnAl2O4, MgAl2O4, and ZnGa2O4) by theoretical analysis. AB - The local environment around the paramagnetic centers formed by the Fe(3+) ions doped into three oxi-spinel crystals (ZnAl(2)O(4), MgAl(2)O(4), and ZnGa(2)O(4)) is investigated utilizing the fourth-order perturbation formula of the axial zero field splitting parameter D on the basis of the dominant spin-orbit coupling mechanism. In order to fix a plausible cubic space group for B-sites located by Al(3+)/Ga(3+) cations, several modeling approaches are used and the results are discussed in detail. PMID- 21524936 TI - EPR evidence for the restricted mobility of NO2 in gamma irradiated thorium nitrate pentahydrate Th(NO3)4.5H2O. AB - Electron paramagnetic resonance (EPR) studies were conducted on gamma irradiated polycrystalline sample of thorium nitrate pentahydrate, Th(NO(3))(4).5H(2)O, in the temperature range of 100-300 K. The most prominent species with triplet hyperfine structure in the EPR spectrum was identified as NO(2). The EPR spectrum gave evidence for the stabilization of NO(2) in at least three different sites slightly differing in spin Hamiltonian parameters (Site(1): g(x)=2.0042, g(y)=1.9911, g(z)=2.0020, A(x)=54.20 G, A(y)=48.50 G and A(z)=65.25 G; Site(2): g(x)=2.0042, g(y)=1.9911, g(z)=2.0020, A(x)=54.20 G, A(y)=48.50 G and A(z)=67.85 G; Site(3): g(x)=2.0045, g(y)=1.9911, g(z)=2.0015, A(x)=54.20 G, A(y)=49.05 G and A(z)=72.45 G). The EPR spectra for Site(1) revealed molecular dynamics of NO(2) from a slow motion region to fast motion region as the sample temperature was varied from 100 to 300 K. This led to a change in EPR spectrum from orthorhombic to axial, indicating preferred rotation of NO(2) molecule about the O-O bond direction. However, the NO(2) molecule at Site(2) was found to be rigid throughout the entire temperature range. The differences in the mobility of NO(2) molecules occupying the two sites could be attributed to the fact that in one case NO(2) was bonded to thorium or water and in the other case it was weakly bound. The NO(2) bound to thorium through two oxygen atoms or bound to thorium on one side through one oxygen atom and hydrogen bonded to water on the other side remains rigid throughout the entire temperature range, while NO(2) situated at interstitial sites or adsorbed on the surface exhibits mobility with increase in temperature above 100K. PMID- 21524937 TI - Chiral Salarg and its metal complex: unique extrinsic fluorophores. AB - We present a fluorescence spectroscopic study of a chiral amino acid Schiff base ligand Salarg and its metal complex Mn-Salarg. This study reveals that the Salarg ligand and its metal complex have the properties of a typical extrinsic fluorophore. A detailed comparison has been made with the fluorescence spectroscopic properties of various other extrinsic and intrinsic fluorophores. It is suggested that Salarg and Mn-Salarg, which are economic, efficient, easy to synthesize and environment-friendly extrinsic fluorophores, might be used to label DNA and lipids respectively. PMID- 21524938 TI - Equating accelerometer estimates of moderate-to-vigorous physical activity: in search of the Rosetta Stone. AB - No universally accepted ActiGraph accelerometer cutpoints for quantifying moderate-to-vigorous physical activity (MVPA) exist. Estimates of MVPA from one set of cutpoints cannot be directly compared to MVPA estimates using different cutpoints, even when the same outcome units are reported (MVPA mind(-1)). The purpose of this study was to illustrate the utility of an equating system that translates reported MVPA estimates from one set of cutpoints into another, to better inform public health policy. Secondary data analysis. ActiGraph data from a large preschool project (N=419, 3-6-yr-olds, CHAMPS) was used to conduct the analyses. Conversions were made among five different published MVPA cutpoints for children: Pate (PT), Sirard (SR), Puyau (PY), Van Cauwengerghe (VC), and Freedson Equation (FR). A 10-fold cross-validation procedure was used to develop prediction equations using MVPA estimated from each of the five sets of cutpoints as the dependent variable, with estimated MVPA from one of the other four sets of cutpoints (e.g., PT MVPA predicted from FR MVPA). The mean levels of MVPA for the total sample ranged from 22.5 (PY) to 269.0 (FR) mind(-1). Across the prediction models (5 total), the median proportion of variance explained (R(2)) was 0.76 (range 0.48-0.97). The median absolute percent error was 17.2% (range 6.3-38.4%). The prediction equations developed here allow for direct comparisons between studies employing different ActiGraph cutpoints in preschool-age children. These prediction equations give public health researchers and policy makers a more concise picture of physical activity levels of preschool-aged children. PMID- 21524939 TI - A comparison of muscle damage, soreness and performance following a simulated contact and non-contact team sport activity circuit. AB - The aim was to compare the effect of a simulated team sport activity circuit (reflective of the activity demands of Australian football) either with or without body 'contact' on muscle soreness, damage, and performance when the circuit was repeated 48 h later. Eleven male, team-sport athletes completed a 'non-contact' (NCON) and a 'contact' (CON) version of the team sport activity circuit in a crossover design with at least 1 week between trials. The effect of CON and NCON on repeated 15m sprint and vertical jump performance was assessed by completing the same version of the circuit 48 h after the initial trial. The effect on perceived soreness and blood markers of muscle damage and inflammation was also determined. Subsequent performance was affected to a greater extent by CON, with both best and mean sprint times significantly slower 48h following CON (p<0.05), while performance was maintained after NCON. Best and mean vertical jump performance was significantly impaired following CON (p<0.05), while only best vertical jump was affected by NCON (p<0.05). Perceived soreness and pressure sensitivity were elevated following both NCON and CON (p<0.001); however, the increase in soreness was greater with CON (p=0.012). Both CON and NCON resulted in elevated serum creatine kinase, myoglobin and lactate dehydrogenase, while c reactive protein increased following CON but not NCON. In conclusion, Greater perceived soreness and decrements in performance of the simulated team sport activity circuit when repeated 48 h later were observed following CON. PMID- 21524940 TI - Multicystic dysplastic kidney disease and hypertension: clinical and pathological correlation. AB - We report on a child with hypertension secondary to MCDK who underwent an elective retroperitoneoscopic nephrectomy and is normotensive on follow up. We looked at the pathological correlation with respect to the hypertension caused by a non-functioning kidney. PMID- 21524941 TI - Efficacy and safety of methylphenidate in treating ADHD symptoms in children and adolescents with uncontrolled seizures: a Brazilian sample study and literature review. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is observed in 30% of children and adolescents with epilepsy. Recent studies have demonstrated the safety of methylphenidate (MPH) in patients with controlled epilepsy. There are few studies of patients with uncontrolled epilepsy. The goal was to study the efficacy and safety of MPH use in children and adolescents diagnosed with ADHD and uncontrolled epilepsy. METHODS: We evaluated 24 patients ranging from 7 to 16 years of age who took MPH for 6 months. Inclusion criteria were at least two epileptic seizures in the previous 6 months and a diagnosis of ADHD based on DSM IV criteria. CONCLUSION: Patients were classified according to ADHD subtype as follows: 41.7% inattentive type, 37.5% combined, and 20.8% hyperactive/impulsive type; 58.3% had partial epilepsy and 41.7% generalized epilepsy. There was an overall improvement in ADHD symptoms in 70.8% of patients, and there was no increase in frequency of epileptic seizures in 22 patients (91.6%). PMID- 21524942 TI - Simultaneous determination of selenomethionine enantiomers in biological fluids by stable isotope dilution gas chromatography-mass spectrometry. AB - A method for the stereoselective determination of D- and L-enantiomers of selenomethionine in mouse plasma was developed using gas chromatography-mass spectrometry with selected-ion monitoring (GC-MS-SIM). DL [(2)H(3,)(82)Se]selenomethionine was used as analytical internal standard to account for losses associated with the extraction, derivatization and chromatography. Selenomethionine enantiomers in mouse plasma were purified by cation-exchange chromatography using BondElut SCX cartridge and derivatized with HCl in methanol to form methyl ester followed by subsequent N-acylation with optically active (+)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride to form diastereomeric amide. Quantification was performed by SIM of the molecular related ions of the diastereomers on the chemical ionization mode. The intra- and inter-day precision for D- and L-selenomethionine spiked to mouse plasma gave good reproducibility with relative standard deviation of 3% and 3% for D selenomethionine and 6% and 3% for L-selenomethionine, respectively. The estimated amounts were in good agreement with the actual amounts spiked, the intra- and inter-day relative error being 5% and 2% for D-selenomethionine and 2% and 1% for L-selenomethionine, respectively. The present method is sensitive enough to determine pharmacokinetics of selenomethionine enantiomers. PMID- 21524943 TI - Quantification of 4 antidepressants and a metabolite by LC-MS for therapeutic drug monitoring. AB - A liquid chromatography method coupled to mass spectrometry was developed for the quantification of bupropion, its metabolite hydroxy-bupropion, moclobemide, reboxetine and trazodone in human plasma. The validation of the analytical procedure was assessed according to Societe Francaise des Sciences et Techniques Pharmaceutiques and the latest Food and Drug Administration guidelines. The sample preparation was performed with 0.5 mL of plasma extracted on a cation exchange solid phase 96-well plate. The separation was achieved in 14 min on a C18 XBridge column (2.1 mm*100 mm, 3.5 MUm) using a 50 mM ammonium acetate pH 9/acetonitrile mobile phase in gradient mode. The compounds of interest were analysed in the single ion monitoring mode on a single quadrupole mass spectrometer working in positive electrospray ionisation mode. Two ions were selected per molecule to increase the number of identification points and to avoid as much as possible any false positives. Since selectivity is always a critical point for routine therapeutic drug monitoring, more than sixty common comedications for the psychiatric population were tested. For each analyte, the analytical procedure was validated to cover the common range of concentrations measured in plasma samples: 1-400 ng/mL for reboxetine and bupropion, 2-2000 ng/mL for hydroxy-bupropion, moclobemide, and trazodone. For all investigated compounds, reliable performance in terms of accuracy, precision, trueness, recovery, selectivity and stability was obtained. One year after its implementation in a routine process, this method demonstrated a high robustness with accurate values over the wide concentration range commonly observed among a psychiatric population. PMID- 21524944 TI - D-Aspartate--an important bioactive substance in mammals: a review from an analytical and biological point of view. AB - It was long believed that D-amino acids were either unnatural isomers or laboratorial artifacts and that the important functions of amino acids were exerted only by l-amino acids. However, recent investigations have shown that a variety of D-amino acids are present in mammals and that they play important roles in physiological functions in the body. Among the free d-amino acids that have been identified in mammals, D-aspartate (D-Asp) has been shown to play a crucial role in the neuroendocrine and endocrine systems as well as in the central nervous system. Here, we present an overview of recent studies of free D Asp, focusing on the analytical methods in real biological matrices, expression and localization in tissues and cells, biological and physiological activities, biosynthesis, degradation, cellular transport, and possible relevance to disease. In addition to frequently used techniques for the enantiomeric determination of amino acids, including high-performance liquid chromatography and enzymatic methods, the recent development of analytical methods is also described. PMID- 21524945 TI - Effect of D-aspartate uptake on uncoupling protein-3 and alpha-tubulin expressions in rat Harderian gland. AB - Although D-aspartate (D-Asp) has been recognized as having an important physiological role within different organs, high concentrations could elicit detrimental effects on those same organs. In this study, we evaluated the oxidative stress response to D-Asp treatment in rat Harderian gland (HG) by measuring total cellular hydroperoxide levels. Further, we examined the effect of D-Asp uptake on the expression of the mitochondrial uncoupling protein-3 (UCP3), beta-actin, and alpha-tubulin. In rat HG, elevated levels of D-Asp significantly increased hydroperoxide production. This phenomenon was probably due to D-Asp uptake as well as lipid and porphyrin increased levels. Higher UCP3 levels and lower alpha-tubulin expression were also observed after D-Asp treatment. On the contrary, beta-actin expression was unchanged. Given the possible role of UCP3 in lipid handling, the higher expression of mitochondria UCP3 protein in D-Asp treated HG may reflect a major need to export excessive amounts of hydroperoxides deriving from a greater fatty acid flux across these organelles and higher mitochondrial porphyrin levels. Moreover, abundance of hydroperoxides in D-Asp treated rat HG could determine the decrease of alpha-tubulin expression. Thus, our findings indicate that a high concentration of D-Asp is critical in initiating a cascade of events determined by oxidative stress. PMID- 21524946 TI - [An evaluation of glycosylated hemoglobin requesting patterns in a primary care setting: a pilot experience in the Valencian Community (Spain)]. AB - OBJECTIVE: To assess the pattern of glycosylated hemoglobin (HbA(1c)) requests by clinicians from eight health departments by calculating indicators of demand appropriateness. METHODS: A cross-sectional study of the number of HbA(1c) requests by primary care clinics in 2008 and 2009. The indicator of demand appropriateness was the proportion of HbA(1c) values lower than 6.5%. Variables were collected and indicators were automatically calculated. The number of HbA(1c) measurements that should theoretically have been requested according to known diabetes prevalence data was also calculated. RESULTS: A progressive increase was seen in demand for HbA(1c) measurements. Approximately 54% of HbA(1c) values obtained in seven of the eight departments studied were lower than 6.5%. The number of theoretical HbA(1c) requests that would have been expected based on the known prevalence of diabetes was higher than the number of HbA(1c) requests in all departments. CONCLUSION: The results appear to suggest that HbA(1c) requests by the health departments studied were not always appropriate. HbA(1c) measurements were probably overused in patients without diabetes and underused in patients with diabetes. PMID- 21524947 TI - [Bariatric surgery in duodenal switch procedure: weight changes and associated nutritional deficiencies]. AB - INTRODUCTION: Bariatric surgery using the technique of duodenal switch is considered as one of the most effective treatments to lose weight and decrease comorbidity in morbidly obese patients. However, we have to be familiar with and adequately manage the various nutritional deficiencies that may occur as a consequence of its practice. OBJECTIVES: To assess weight loss and development of nutritional deficiencies in morbidly obese patients undergoing bariatric surgery through the duodenal switch procedure. MATERIAL AND METHODS: One hundred and twenty-eight morbidly obese patients underwent a duodenal switch procedure at Hospital General Universitario in Albacete. Weight changes and the most important nutritional deficiencies occurring after surgery were recorded. RESULTS: Median follow-up time was 30 months (interquartile range, 18 months). Body weight markedly decreased, with mean body mass index (BMI) decreasing from a preoperative value of 52.9+/-7.7kg/m(2) to 30.8+/-5.2kg/m(2) 18 months after surgery. The percentage of excess weight lost (% EWL) was 81.4+/-16.4% in this period. Weight loss slowed down subsequently, reaching its lowest value 30 months after surgery (% EWL 82.1%+/-16.8, BMI 30.2+/-4.3kg/m(2)) and tended to stabilize in patients with longer follow-up times. Significant nutritional deficiencies requiring replacement therapy were detected in some micronutrients with iron (42.9%), zinc (38.3%), vitamin A (55.5%), and vitamin D (57.8%) deficiencies being most relevant. CONCLUSIONS: Duodenal switch is a very effective surgical procedure for treating morbidly obese patients because it allows for achieving a significant and sustained weight loss.Close lifetime monitoring is required in these patients because of the high prevalence of nutritional deficiencies during follow-up. PMID- 21524948 TI - A case report of nasopharyngeal teratoma with a cleft palate and an inguinal hernia. AB - Nasopharyngeal teratoma is a rare teratoma arising anywhere from the oronasal cavity, regarded as an expanding, cavity-filling lesion, with a high mortality rate due to severe airway obstruction, especially in the neonatal period. We report a patient with a single, firm, hairy swelling arising from vomer, protruding into the oral cavity associated with cleft palate and an inguinal hernia. Excision of the lesion and reconstruction of the cleft palate was successfully performed in a single stage. To the best of our knowledge, this is the first report of a child with a nasopharyngeal teratoma, cleft palate and an inguinal hernia. PMID- 21524949 TI - Small-incision orbicularis-levator fixation technique: a modified double-eyelid blepharoplasty for treating trichiasis in young Asian patients. AB - Upper-eyelid trichiasis often occurs with a single puffy eyelid or shallow eyelid crease in young Asian patients. This study presents a novel modified trichiasis correction method to simultaneously treat trichiasis and create a natural eyelid crease. It combines the modified small-incision debulking procedure and the orbicularis-levator fixation technique. The eyelash lift angle (LA), body curl angle (BCA) and end curl angle (ECA) were quantitatively analysed. A total of 90 patients (152 trichiasis eyelids) were followed up for approximately 22 months. The LA changed from 24.32 degrees +/- 9.21 degrees -54.12 degrees +/- 10.32 degrees in the nasal section of the eyelid (section 1), from 21.03 degrees +/- 11.34 degrees -52.03 degrees +/- 10.56 degrees in the middle section of the eyelid (section 2) and from 23.31 degrees +/- 8.12 degrees -63.15 degrees +/- 8.43 degrees in the temporal section of the eyelid (section 3). All patients were satisfied with the eyelid-fold appearance. In conclusion, for young Asian patients with upper-eyelid trichiasis, the small-incision orbicularis-levator fixation technique is able to acquire a stable up-curved position of the eyelashes and satisfactory aesthetic results. PMID- 21524950 TI - Cutaneous manifestation of silicone dissemination from a PIP implant--a case for prophylactic explantation? AB - The recent withdrawal of PIP (Poly Implant Prosthese, France) implants for breast augmentation enforced by the Medicines and Healthcare products Regulatory Agency (MHRA) on 31st March 2010 has ignited speculation into possible side effects relating to an unauthorized gel fill content. Local and migratory silicone granulomata and regional lymphadenopathy are well reported in the literature. Gel bleed from high cohesive gel implants with similar effect is also well known. However dissemination to sites distant from the breast manifest as cutaneous abnormalities in a patient implanted with a PIP product raises concern. We report such a case. PMID- 21524951 TI - Breast augmentation: Part III--preoperative considerations and planning. AB - The past four decades since the introduction of silicone mammary prostheses have seen significant improvements in their quality and durability. Advances in our understanding of the aetiopathology and prevention of adverse capsular contracture (ACC) have occurred such that surgical technique itself has now probably become the single most important determinant of both immediate and long term outcome. Considered a simple, and in some quarters mindless, procedure it has evolved such that high-quality short- and stable long-term results are now expected. Whilst the fundamentals of breast augmentation (BA) remain, evolutionary philosophies confront today's surgeon with a wealth of options. Of fundamental importance has been the paradigm shift from a purely, or predominantly, volumetric, through biodimensional to a tissue-based approach. With BA, more than any other aesthetic procedure, possessing more variables, choice and influential external factors a thorough understanding of the myriad options available is essential. This review seeks to cover the key elements in obtaining an optimal primary result. It provides a rational basis for the selection of an option tailored to both the patient and the individual tissue characteristics in addition to the pertinent medico-legal issues. PMID- 21524952 TI - [Renal involvement in patients with systemic sclerosis]. AB - Scleroderma renal crisis is characterized by malignant hypertension and oligo anuric acute renal failure. Scleroderma renal crisis occurs in 2 to 5% of patients with systemic sclerosis, particularly those with diffuse cutaneous systemic sclerosis in the first years of disease evolution. High-dose corticosteroid therapy (> 15 mg/d) is associated with an increased risk of scleroderma renal crisis. Patients present with prominent left heart failure and hypertensive encephalopathy. Renal failure can be associated with moderate proteinuria, without hematuria. Thrombotic microangiopathy is detected in 43% of the cases. Anti-RNA polymerase III antibodies are present in one third of patients with scleroderma renal crisis. In case of renal failure, iatrogenic or functional origin must be investigated, as well as crescentic glomerulonephritis associated with antineutrophil cytoplasm antibodies (ANCA) or thrombotic microangiopathy. Renal biopsy is not necessary to establish the diagnosis in typical forms of scleroderma renal crisis. However, it can help to evaluate the prognosis and it is recommended when clinical presentation of scleroderma renal crisis is unusual. The prognosis of scleroderma renal crisis dramatically improved with the use of angiotensin-converting enzyme (ACE) inhibitors. However, 5-year survival of patients who developed a scleroderma renal crisis is only 65%. The treatment relies on the early control of blood pressure with increasing doses of ACE inhibitors, in association with calcium channel blockers if necessary. In case of severe renal failure and/or hypertension, dialysis can help to quickly control the vascular overload and the blood pressure. Dialysis can be stopped in about half of cases. After 2 years on dialysis, eligible patients should be considered for renal transplantation. The prevention of scleroderma renal crisis lacks consensus. Corticosteroids and/or nephrotoxic drugs should be avoided in patients with diffuse cutaneous systemic sclerosis. PMID- 21524953 TI - Complementary and alternative medicine for induction of labour. AB - BACKGROUND: Induction of labour is a common obstetric procedure. Some women are likely to turn to complementary and alternative medicine in order to avoid medical intervention. AIM: The aim of this paper is to examine the scientific evidence for the use of complementary and alternative medicine to stimulate labour. METHOD: An initial search for relevant literature published from 2000 was undertaken using a range of databases. Articles were also identified by examining bibliographies. RESULTS: Most complementary and alternative medicines used for induction of labour are recommended on the basis of traditional knowledge, rather than scientific research. Currently, the clinical evidence is sparse and it is not possible to make firm conclusions regarding the effectiveness of these therapies. There is however some data to support the use of breast stimulation for induction of labour. Acupuncture and raspberry leaf may also be beneficial. Castor oil and evening primrose oil might not be effective and possibly increase the incidence of complications. There is no evidence from clinical trails to support homeopathy however, some women have found these remedies helpful. Blue cohosh may be harmful during pregnancy and should not be recommended for induction. Other complementary and alternative medicine (CAM) therapies may be useful but further investigation is needed. CONCLUSIONS: More research is needed to establish the safety and efficacy of CAM modalities. Midwives should develop a good understanding of these therapies, including both the benefits and risks, so they can assist women to make appropriate decisions. PMID- 21524954 TI - Epidemiologic and clinical features of non-polio enteroviral infections in northern Taiwan in 2008. AB - BACKGROUND: Non-polio enteroviruses may cause different diseases, including herpangina, hand-foot-mouth disease (HFMD), meningitis, and nonspecific febrile illness; and cause epidemic outbreak annually. This study delineates the diversity of clinical presentations based on different serotypes and different groups [human enterovirus (HEV)-A and HEV-B] of enteroviruses (EVs) during the 2008 epidemic in National Taiwan University Hospital (NTUH). METHODS: We retrospectively identified patients younger than 18 years who had positive isolates of non-polio EV in throat swabs, rectal swabs, or cerebrospinal fluid, in NTUH from January 1 to December 31, 2008. For serotyping, immunofluorescence assay and polymerase chain reaction followed by viral structure protein-1 sequencing were applied. We analyzed and compared their clinical features among different serotypes and different groups of EVs. RESULTS: Among 172 patients who were enrolled, 16 serotypes were identified. The major serotype in NTUH was EV71 (25.6%) followed by coxsackievirus A (CA)16 and coxsackievirus B (CB)4. EV71 manifested mostly as HFMD (89%) and was complicated with encephalomyelitis in three patients. Serotypes of HFMD included EV71 (70%), CA16 (27%), CA4, and CA6. Serotypes of herpangina were heterogeneous, and the major serotype was CA2 (35.7%) followed by CB4 (23.8%). Aseptic meningitis was entirely caused by HEV-B and mostly infected by echovirus 30 (50%). Among children with EV-related respiratory tract infection, CB4 (32%) was dominant in upper respiratory tract infection, whereas echovirus 4 (71%) was the major cause of lower respiratory tract infection. Cases of HEV-A were significantly younger than the cases of HEV B (p = 0.04). Multivariate analysis revealed that the most significant factor associated with hospitalization is HEV-B (odds ratio, 2.2; 95% confidence interval, 1.1-4.2; p = 0.02). CONCLUSIONS: At least 16 serotypes circulated in northern Taiwan in 2008. EV71 is the predominant strain in this outbreak. All patients with HFMD were infected by HEV-A, but HEV-B was associated with a higher rate of hospitalization and aseptic meningitis, which should be a cause of alert regarding public health. PMID- 21524955 TI - A case of acute respiratory distress syndrome associated with novel H1N1 treated with intravenous immunoglobulin G. AB - Influenza A "novel H1N1" with severe acute respiratory distress syndrome (ARDS) is a serious illness that poses a challenge to clinicians managing such cases. This case report reveals a patient with ARDS secondary to influenza A with deteriorating clinical status, who improved tremendously after intravenous immunoglobulin G (IV IgG). Patients with H1N1 associated with ARDS may be given a trial of IV IgG. More case reports and trials are required to ascertain the efficacy of IV IgG and the best dosage and timing of starting IV IgG in relation to antiviral therapy. PMID- 21524956 TI - The relationship between health care and nonhealth care norovirus outbreak settings and norovirus genotype in Victoria, Australia, 2002-2005. AB - BACKGROUND: There is evidence that norovirus genotype is an important factor in determining norovirus epidemiology, but detailed information is lacking. This report examined this question by studying whether the mix of norovirus genotypes associated with norovirus outbreaks in health care settings was different to that in nonhealth care settings. METHODS: Norovirus outbreaks tested in Victoria, Australia, 2002-2005 were classified as either health care or nonhealth care. Open reading frame 1 nucleotide sequencing analysis was then used to determine the mix of norovirus genotypes in health care and nonhealth care norovirus outbreaks. RESULTS: For the three most common genotypes detected (GI.2, GII.4, and GIIb), the differences between health care and nonhealth care settings were significant. GII.4 was significantly more common in health care settings than in nonhealth care settings, whereas the genotypes GI.2 and GIIb were significantly more common in nonhealth care settings than in health care settings. CONCLUSION: Norovirus genotype was found to be an important factor associated with norovirus outbreak setting. PMID- 21524957 TI - Coinfection with Mycobacterium tuberculosis and pandemic H1N1 influenza A virus in a patient with lung cancer. AB - Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus were responsible for bacterial coinfection during previous or 2009 influenza pandemic and were associated with a higher risk of influenza-related morbidity and mortality. Despite tuberculosis (TB) is still a growing problem worldwide, Mycobacterial tuberculosis is rarely a copathogen with influenza. We hereby report a cancer patient with TB and pandemic H1N1 influenza A virus coinfection. Physicians should be aware that TB may present as a coinfection in an immunocompromised patient with 2009 influenza A (H1N1) infection, especially in TB endemic area. PMID- 21524958 TI - Human herpesvirus-6 viral load and antibody titer in serum samples of patients with multiple sclerosis. AB - BACKGROUND: Despite the number of cases with definite diagnosis of multiple sclerosis (MS) being on increase, the role of human herpesvirus-6 (HHV-6) infection as a trigger for MS disease still is deliberated. Based on antibody detection and quantitative HHV-6 polymerase chain reaction assay, this study was achieved to find out the possible association between infection with HHV-6 and clinical progression of MS disease. METHODS: A total of 108 serum samples were obtained from 30 MS patients followed prospectively for a 6-month period. These samples were analyzed for the presence of HHV-6 DNA by nested polymerase chain reaction enzyme-linked immunosorbent assay and for anti-HHV-6 IgG titer. Activation of the disease was determined by either magnetic resonance imaging or by clinical status of the patients. Control groups were also included. RESULTS: The average antibody index for the MS patients in the first sample collection was higher than both control groups (p = 0.001). HHV-6 DNA was detected in the serum samples of 10 of 30 MS patients. The mean HHV-6 viral load in patients with relapsing-remitting multiple sclerosis (RRMS) with and without relapse was 973 and 714, respectively. Seven patients showed an exacerbation during the study period. Of those, four patients had HHV-6 DNA in their collected samples. The prevalence of HHV-6 DNA was significantly higher in patients with MS as compared with control groups (p = 0.001). CONCLUSIONS: The results indicate that HHV-6 is implicated somehow in MS disease. Over time, rising HHV-6 IgG antibody titers together with an exacerbation and detection of HHV-6 DNA in serum samples of some MS patients suggests possible association between the reactivation of the virus and disease progression. PMID- 21524959 TI - Infection in liver transplant recipients--analysis of 68 cases at teaching hospital in Taiwan. AB - BACKGROUND: In Taiwan, liver transplantation is a common treatment of end-stage liver diseases. Infection has a negative impact on the survival of these patients and their grafts. We evaluated the timing and frequency of infections, and the risk factors associated with infection and mortality in liver transplant recipients from Taiwan. METHODS: This retrospective study enrolled all adult patients who underwent orthotopic liver transplantation from January 2004 to November 2008 at a tertiary hospital in Taiwan. RESULTS: Sixty-eight patients were enrolled (male/female = 46/22) and average age was 51.3 years. Bacterial infection (26/68, 38.2%) was the most common infectious disease, with a rate of 0.3/1,000 person-days in the perioperative period, 0.27/1,000 person-days in the early operative period, and 0.38/1,000 person-days in the late-operative period. Operation-related complications increased the risk of bacterial infection. Biliary stricture was the most common operation-related complication, and this was associated with biliary tract infection (p < 0.001). The average time from first stent placement for biliary stricture by endoscopic retrograde cholangiography to biliary tract infection was 34.5 days. The overall mortality rate was 11.7%, and the mortality rate was 14% for patients with infections. CONCLUSIONS: Bacterial infection was the most common type of infection in liver transplant recipients. Surgery-related complication, especially biliary tract stricture was risk factor for infection. We suggest that the current recommendations about the timing of endoscopic retrograde cholangiography intervention be reevaluated. PMID- 21524960 TI - Clinical and epidemiologic features of Coxsackievirus A6 infection in children in northern Taiwan between 2004 and 2009. AB - BACKGROUND: Isolates of Coxsackievirus A6 (Cox A6) is increasing clinically in 2009 in Taiwan but detailed clinical features of Cox A6 infections in children have not been reported. This study is to define clinical manifestations and laboratory findings of Cox A6 infection in children. METHODS: From January 2004 to December 2009, a total of 4,664 children with enterovirus infections, based on throat virus culture, were treated in Chang Gung Children's hospital. Two hundred and ninety-six (6.3%) patients positive for Cox A6 infection were included in this study. One hundred and forty-one (47.6%) inpatients were further analyzed for clinical presentations, laboratory findings, and clinical diagnoses. RESULTS: There were two peaks of Cox A6 infection in 2007 and 2009 during the study period, especially during the warm season. The proportion of Cox A6 among total enterovirus isolates was 15.5% in 2007 and up to 22.2% in 2009. The mean age of inpatients was 2.42 +/- 0.14 years. The mean hospitalization duration was 4.21 +/ 0.11 days. The most common symptoms were fever (100%), oral ulcers (90.8%), and decreased oral intake (89.4%). The mean duration of fever was 2.78 +/- 1 days (range, 1-7 days). Seventy-seven (54.6%) patients had fever more than 3 days. The mean leukocyte count was 14,850/mm(3), and 63 (45%) patients had leukocytosis (>15,000/mm(3)). The mean serum C-reactive protein (CRP) level was 44.1 +/- 3.3 mg/L (normal, <10 mg/L) and 62 (44%) had a CRP level >40 mg/L. One hundred and eight (76.6%) inpatients were diagnosed as herpangina and 18 (12.8%) hand-foot mouth disease. Three patients had complications, including aseptic meningitis in one and encephalitis in two. All 141 inpatients recovered uneventfully. CONCLUSIONS: Cox A6 is among the major serotypes of enteroviruses in Taiwan and most cases presented as herpangina and hand-foot-mouth disease. Nearly half of the cases may have leukocytosis and elevated CRP levels. Outcomes are usually good. PMID- 21524961 TI - Outcomes of switch to atazanavir-containing combination antiretroviral therapy in HIV-1-infected patients with hyperlipidemia. AB - BACKGROUND: Prolonged exposure to combination antiretroviral therapy (CART) may result in hyperlipidemia and other metabolic complications. This study aimed to evaluate the clinical, virologic, and immunologic outcomes in HIV-infected patients with hyperlipidemia whose CART was switched to atazanavir-containing antiretroviral regimens. METHODS: In this 48-week prospective, observational study that was conducted at designated hospitals for HIV care in Taiwan, HIV infected patients aged 18 years or older who had developed hyperlipidemia after receiving CART that did not contain atazanavir were enrolled. Antiretroviral regimens were switched to regimens containing two nucleoside reverse transcriptase inhibitors plus atazanavir 400 mg once daily or atazanavir 300 mg boosted with ritonavir 100 mg once daily. The lipid profiles, including total triglycerides, total cholesterol, low-density lipoprotein-cholesterol, high density lipoprotein-cholesterol, CD4+ lymphocyte counts, and plasma HIV RNA load were determined every 3 months. RESULTS: Sixty-six patients with hyperlipidemia were enrolled. At the end of the study, triglyceride levels declined by 49.0% (p = 0.0002) and total cholesterol levels by 18.1% from baseline (p < 0.0001), whereas there were no significant changes observed for low-density lipoprotein- and high-density lipoprotein-cholesterol levels. Mean CD4 lymphocyte count increased from 465 cells/MUL at baseline to 498 cells/MUL at the end of the study, whereas the proportion of patients with undetectable plasma HIV RNA load increased from 73.1% to 81.7%. The regimens were well tolerated. CONCLUSIONS: Switch to atazanavir-containing regimens that were well tolerated resulted in significant improvement of hyperlipidemia and maintenance of clinical, immunologic, and virologic responses to CART. PMID- 21524962 TI - Clinical manifestations and prognostic factors in cancer patients with bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumoniae. AB - BACKGROUND: Clinical information about bacteremia due to extended-spectrum beta lactamase (ESBL)-producing pathogens in cancer patients was limited. The study was aimed to identify the clinical manifestations and risk factors for mortality in ESBL-producer bacteremia in cancer patients. METHODS: A retrospective study of bacteremia caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae in adults with cancer in National Cheng Kung University Hospital and National Taiwan University Hospital from July 2002 to August 2007 was conducted. Clinical characteristics, initial manifestations, and antimicrobial therapy were analyzed for their association with crude mortality at 14 days after bacteremia onset. RESULTS: A total 113 episodes of bacteremia caused by E coli (59.3%), K pneumoniae (39.8%) or both (0.9%) were included. Patients with hematological malignancy were younger (55 +/- 22 vs. 69 +/- 14 years, p < 0.003) and had less co-morbidity, but were more likely to have neutropenia (73.1% vs. 4.6%, p < 0.001) than those with solid tumor. By the univariate analysis in 113 episodes of ESBL-producer bacteremia, several risk factors, including pneumonia or soft tissue infection as the bacteremia source, initial manifestations with high Pitt bacteremia scores, shock, respiratory failure or severe sepsis, and inappropriate definitive therapy were associated with 14-day crude mortality. By multivariate analysis, only pneumonia [adjusted odds ratio (AOR), 5.2; 95% confident interval (CI), 1.3-21.0; p = 0.021], severe sepsis (AOR, 24.3; 95% CI, 5.6-105.0; p < 0.001), and inappropriate definitive therapy (AOR, 11.3; 95% CI, 1.7-72.8; p = 0.011) were independently associated with a fatal outcome. CONCLUSION: The presence of neutropenia or underlying hematological malignancy in cancer patients with ESBL-producer bacteremia was not associated with an increase in the mortality rate. Appropriate definitive antimicrobial therapy will be beneficial in improving clinical outcome. PMID- 21524963 TI - Clinical characteristics of hepatosplenic fungal infection in pediatric patients. AB - BACKGROUND: Hepatosplenic fungal infection (HSF) is a distinct form of invasive fungal infection with main involvement of the liver, spleen, and occasionally the kidney. In this study, we investigated the clinical characteristics and outcomes of patients with HSF in childhood. METHODS: We retrospectively reviewed pediatric patients with the diagnosis of HSF in a tertiary medical center in Taiwan between July 1999 and June 2009. The definition of HSF included imaging studies demonstrating multiple focal lesions in the liver and/or spleen with or without a microbiologic evidence for fungal infection. The clinical characteristics and outcomes were analyzed. RESULTS: We identified 15 pediatric patients with HSF. Eleven patients had diagnosis of hemato-oncologic malignancy, and two patients had severe aplastic anemia. All patients had fever, and most patients had abdominal pain, nausea, vomiting, and hepatosplenomegaly. The detection rate of computed tomography scan (15/15, 100%) was superior to abdominal sonography (10/15, 67%, p = 0.01). Ten (91%) of the 11 patients with microbiologic evidence were infected by Candida species. Neither recurrence nor breakthrough fungal infection was noted when the patients underwent further chemotherapy and stem cell transplantation. Six patients (40%) died before the end of the study, but no mortality was directly related to HSF. CONCLUSION: Candida species was the major pathogen for HSF, and computed tomography scan was a good diagnostic tool to detect the multiple focal lesions. Under adequate antifungal treatment, HSF could be cured without recurrence in spite of further chemotherapy and stem cell transplantation. PMID- 21524964 TI - Mortality predictors of Pneumocystis jirovecii pneumonia in human immunodeficiency virus-infected patients at presentation: Experience in a tertiary care hospital of northern Taiwan. AB - BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) remains the leading cause of opportunistic infections and deaths among human immunodeficiency virus (HIV) infected patients. We would like to identify the predictors of mortality of these patients at initial presentation, and assist clinicians to aware the patients in risk of mortality earlier. METHODS: From 1997 to 2009, adults with HIV infection and a discharge diagnosis of PJP at Mackay Memorial Hospital were included in this retrospective study. Patients' demographic data and laboratory data were analyzed by reviewing the medical records. RESULTS: Eighty-five patients were included in this study. The overall mortality rate was 37.7%. Univariate analysis revealed several host factors significantly related to mortality, including age, systolic blood pressure, diastolic blood pressure, partial pressure of oxygen in arterial blood (PaO(2)), percentage of lymphocyte, percentage of CD4 lymphocyte, CD4 counts, serum total protein, serum albumin, and blood urea nitrogen. Multivariate analysis identified three independent predictors associated with mortality, i.e. systolic blood pressure <=110 mmHg [adjusted odds ratio (AOR) 3.88; 95% confidence interval (CI) 1.17-12.83; p = 0.03], PaO(2) at room air <=60 mmHg (AOR 4.97; 95% CI 1.34-18.23; p = 0.01), and lymphocytes <=10% (AOR 8.19; 95% CI 1.48-45.36; p = 0.02). With these predictors, we can stratify patients into three groups with increasing risks for mortality, <=one predictor (mortality rate 14%), any two predictors (47%), and three predictors (75%). CONCLUSIONS: HIV infected patients with PJP can be clinically stratified by three prognostic variables identified by multivariate analysis. Early recognition of patients in higher risk can assist clinicians to prevent rapid deterioration and seek for better outcomes. PMID- 21524965 TI - Risk factors associated with Sphingomonas paucimobilis infection. AB - BACKGROUND: Sphingomonas paucimobilis is rarely isolated from clinical specimens and it is associated with a great variety of infections. The aim of this study is to investigate the microbiological and clinical features of S paucimobilis infection in southern Taiwan. METHODS: S paucimobilis isolates from the microbiology laboratory of Chi-Mei Medical Center and their relevant clinical data from October 2005 to October 2009 were retrospectively reviewed. RESULTS: A total of 55 patients with documented S paucimobilis infections were identified. Among them, 29 (52.7%) have community-acquired infections and 13 of them presented with primary bacteremia (44.8%). Multivariate logistic regression showed that community-acquired infection [adjusted odds ratio 13.473, 95% confidence interval (CI) 1.79-101.41, p = 0.01], diabetes mellitus (adjusted odds ratio 7.03, 95% CI 1.16-42.66, p = 0.03), and alcoholism (adjusted OR 10.87, 95% CI 1.00-117.69, p = 0.05) were significant risk factors for S paucimobilis primary bacteremia. Most of those who have health care-associated S paucimobilis infections presented with pneumonia (10 of 26, 38.5%) and only 7.7% presented with catheter-related infection. The overall mortality rate was 5.5%. CONCLUSION: Community-acquired S paucimobilis infections were not uncommon, mainly presenting with primary bacteremia. Multivariate analysis showed that community-acquired infection, diabetes mellitus, and alcoholism were significant risk factors for primary bacteremia. PMID- 21524966 TI - Evaluation of the BD GeneOhm StaphSR assay for detection of Staphylococcus aureus in patients in intensive care units. AB - BACKGROUND: Staphylococcus aureus is the major nosocomial pathogen and rapid detection of colonized patients with subsequent precaution is needed to prevent transmission. A new assay, the BD GeneOhmTM SaphSR assay (BD GeneOhmTM, San Diego, CA, USA), is a multiplex real-time polymerase chain reaction (PCR) for rapid detection of both methicillin-sensitive S aureus (MSSA) as well as methicillin-resistant S aureus (MRSA). METHODS: Anterior nasal swab specimens of 273 pediatric and adult patients hospitalized in intensive care units at Chang Gung Memorial Hospital were collected for this assay in parallel with conventional cultures as standard. RESULTS: Overall, 71 (26.0%) patients were colonized with S aureus by conventional culture and MRSA accounted for 67.6% of all isolates. For the detection of MRSA, 79 patients (28.9%) were positive by PCR and 48 (17.6%) were positive by conventional cultures. The sensitivity, specificity, and positive and negative predictive values were 95.9%, 85.3%, 58.5%, 99.0%, respectively. For the detection of MSSA, 48 patients (17.6%) were positive by PCR and 23 (8.4%) were positive by conventional culture. The sensitivity, specificity, and positive and negative predictive values were 91.3%, 89.2%, 43.8%, and 99.1%, respectively. CONCLUSION: As a screening method, the BD GeneOhmTM StaphSR assay could rapidly detect and differentiate between MRSA and MSSA colonization. A negative result of the assay could almost exclude S aureus colonization. PMID- 21524967 TI - Fatal subdural empyema caused by Streptococcus constellatus and Actinomyces viscosus in a child--case report. AB - Group milleri streptococci that colonize the mouth and the upper airways are generally considered to be commensal. In combination with anaerobics, they are rarely responsible for brain abscesses in patients with certain predisposing factors. Mortality in such cases is high and complications are frequent. We present a case of fatal subdural empyema caused by Streptococcus constellatus and Actinomyces viscosus in a previously healthy 7-year-old girl. PMID- 21524968 TI - Are empiric antibiotics for acute exudative tonsillitis needed in children? AB - BACKGROUND: Empiric antibiotics are frequently given for children with acute exudative tonsillitis. A few studies have investigated the causative agent of acute "exudative" tonsillitis in children to evaluate the necessity of antibiotic therapy. This study tried to explore the common causative agent of acute exudative tonsillitis among children. METHODS: From April 2009 to March 2010, throat swabs were obtained and cultured for viruses and bacteria from children who visited the pediatric emergency rooms of two medical centers in central Taiwan with acute exudative tonsillitis. Demographic data and microbiological results were analyzed. RESULTS: A total of 294 children with acute exudative tonsillitis were enrolled during the 1-year prospective study, and 173 (58.8%) of them were younger than 7 years. Group A streptococci were isolated from only three (1.0%) children, and they were all older than 6 years. A total of 143 viruses were isolated from 140 (47.6%) children. Adenovirus (18.7%) and enterovirus (16.3%) were the most common viral etiologies, followed by influenza virus (5.4%), parainfluenza virus (5.1%), herpes simplex virus Type 1 (2.7%), and respiratory syncytial virus (0.3%). Group A streptococcus only contributed to a minimal portion of acute exudative tonsillitis. CONCLUSION: Routine or immediate antibiotic therapy for acute exudative tonsillitis in children is not necessary. PMID- 21524969 TI - Nonpigmented Chromobacterium violaceum bacteremic cellulitis after fish bite. AB - A case of nonpigmented Chromobacterium violaceum bacteremic cellulitis after fish bite in Taiwan is reported. The patient was successfully treated with ciprofloxacin and doxycycline for an extended period. Chromobacterium violaceum should be listed in the differential diagnosis of patients with nonspecific cellulitis associated with marked leukocytosis and rapid progression to septicemia either with or without a distinct history of exposure to water or soil. A combination of prompt diagnosis, optimal antimicrobial therapy, and adequate therapeutic duration for C violaceum infection is the key for successful therapy. PMID- 21524970 TI - Diagnostic utility of enzyme-linked immunospot assay for interferon-gamma in a patient with tuberculous arthritis and pyomyositis. AB - The indolent and nonspecific presentations of tuberculous arthritis and pyomyositis render their diagnosis a great challenge for clinicians. We describe a 78-year-old man with swelling and pain of right knee for 6 months. The patient was empirically treated for tuberculosis because positive enzyme-linked immunospot assay for interferon-gamma of blood was reported at 2 days after aspiration of synovial fluid, which was negative for acid-fast stain but subsequently grew Mycobacterium tuberculosis 6 weeks later. He recovered uneventfully with 1-year antituberculous combination therapy. PMID- 21524971 TI - Candida albicans versus non-albicans bloodstream infections: the comparison of risk factors and outcome. AB - BACKGROUND: Candidemia caused by non-albicans Candida spp. is of special concern because of its high drug resistance and increase in prevalence. In clinical practice, early identification of non-albicans candidemia is crucial. We investigated the outcome in patients with candidemia caused by Candida albicans and Candida non-albicans. METHODS: We retrospectively evaluated candidemic patients from October 2007 to July 2009. Underlying diseases, predisposing factors, laboratory data, and outcome were analyzed. RESULTS: One hundred and eight patients of candidemia were enrolled. Candida albicans and non-albicans spp. were responsible for 56.5% (61 of 108) and 43.5% (47 of 108) of candidemia cases, respectively. Among patients with non-albicans candidemia, significantly more patients had neutropenia (p=0.001) and less patients had candiduria (p=0.001) and intensive care unit stay (p=0.002) in comparison with those with C albicans candidemia. All-cause Day 7 mortality was high in both C albicans and non-albicans spp. candidemia [44.3% (27 of 61) vs. 29.8% (14 of 47)]. Multivariate analysis revealed that poor renal function (odds ratio, 1.035; 95% confidence interval, 1.001-1.071; p=0.04) and shock (odds ratio, 19.4; 95% confidence interval, 2.53-149.5; p=0.004) are independent risk factors for fatal candidemia. CONCLUSIONS: The outcome of candidemia was poor. The identified risk factors may help us to differentiate fatal candidemia in early infection. PMID- 21524972 TI - Comparisons of clinical features and mortality of cryptococcal meningitis between patients with and without human immunodeficiency virus infection. AB - BACKGROUND: Cryptococcosis is a systemic infection caused by Cryptococcus neoformans, and cryptococcal meningitis can occur in patients with late-stage human immunodeficiency virus (HIV) infection and other forms of immunosuppressive status. This study was designed to compare clinical features and laboratory findings of cryptococcal meningitis in HIV-positive and HIV-negative patients. METHODS: From January 1, 2000 to December 31, 2009, all patients aged more than 18 years hospitalized at National Taiwan University Hospital with a diagnosis of cryptococcal meningitis were analyzed retrospectively. RESULTS: In total, 88 patients with cryptococcal meningitis were identified and 37 (42%) were HIV infected. Cryptococcal meningitis occurred in young (mean, 38 vs. 60; p < 0.001) and male (97% vs. 63%, p < 0.001) populations more frequently among HIV-positive group with higher Charlson comorbidity score (mean, 7 vs. 4; p < 0.001), higher initial complaint of cough (36% vs. 16%; p = 0.032), lower cerebrospinal fluid (CSF) white count (mean, 26 vs. 86; p = 0.024), lower total protein of the CSF (mean, 88 vs. 149; p = 0.012), higher percentage of serum latex agglutination cryptococcal antigen titer exceeding 1:512 (77% vs. 50%; p = 0.026), more extraneural involvement (70% vs. 49%; p = 0.046), more cryptococcemia (68% vs. 35%; p = 0.003), and higher proportion of normal brain images (44% vs. 13%; p = 0.003) than HIV-negative group. The all-cause mortality rates on Day 30 and Day 90 were 23.9% and 31.8%, respectively. The independent risk factors for Day 30 mortality were altered mental status, extraneural involvement, absence of lymphocyte predominance, and absence of leptomeningeal enhancement (odds ratio: 7.84, 9.71, 0.22, and 0.07, respectively; 95% confidence interval): 2.03-30.27, 2.01-46.94, 0.06-0.80, and 0.01-0.49, respectively). Those for Day 90 mortality were serum white count more than 11,000/MUL, higher Charlson comorbidity score, and absence of normal brain images (odds ratio: 5.39, 1.40, and 0.09, respectively; 95% confidence interval: 1.22-23.72, 1.11-1.76, and 0.01-0.78, respectively). CONCLUSIONS: The clinical features of cryptococcal meningitis between HIV and non-HIV patients have some divergences, including age, sex, underlying diseases, CSF parameters, extraneural site involvement, fungemia, and so on. We also identified risk factors for mortality of this disease. However, the mortality of cryptococcal meningitis was not different in HIV-positive and HIV-negative patients in terms of Day 30 and Day 90 mortality. PMID- 21524973 TI - Difference in imipenem, meropenem, sulbactam, and colistin nonsusceptibility trends among three phenotypically undifferentiated Acinetobacter baumannii complex in a medical center in Taiwan, 1997-2007. AB - BACKGROUND: To determine whether the susceptibilities and the trends of nonsusceptibility of imipenem, meropenem, sulbactam, and colistin differed among Acinetobacter baumannii, Acinetobacter genomic species 3 (AGS 3), and Acinetobacter genomic species 13TU (AGS 13TU) over 11 years. METHODS: A total of 1,039 nonduplicate blood isolates of A baumannii complex from bacteremic patients between 1997 and 2007 were collected at Taipei Veterans General Hospital and were identified to the species level using a multiplex polymerase chain reaction method and sequence analysis of 16S-23S intergenic spacer. The minimal inhibitory concentrations of antibiotics were determined by the agar dilution method. RESULTS: The nonsusceptibility rates of carbepenems and sulbactam were highest in A baumannii, which also showed a trend toward increasing rate of carbapenems nonsusceptibility over the 11-year period of the study. AGS 13TU had the highest nonsusceptible rate to colistin, comparably increasing trend of carbapenem nonsusceptiblity as that of A baumannii, and is the only species with increasing sulbactam nonsusceptibility. AGS 3 had the lowest rate of nonsusceptibility to all four antimicrobial agents. CONCLUSION: Although A baumannii had the highest nonsusceptibility rate to imipenem, meropenem, and sulbactam over the years, the higher rate of colistin nonsusceptibility and the emergence of nonsusceptibility of carbapenems and sulbactam in AGS 13TU suggested that this species might cause a great problem in the near future. PMID- 21524974 TI - Antimicrobial susceptibilities of urinary extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae to fosfomycin and nitrofurantoin in a teaching hospital in Taiwan. AB - BACKGROUND: Urinary tract infections (UTIs) caused by extended-spectrum beta lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae have become clinical problems because of limited therapeutic options. The role of fosfomycin in the era of growing bacteria resistance has been widely discussed recently. In this study, we aimed to know the local antimicrobial susceptibilities, fosfomycin susceptibility in particular, of urinary ESBL-producing E coli and K pneumoniae isolates in Taiwan. METHODS: We collected 200 urine isolates, including 134 ESBL producing E coli (ESBL-EC) and 66 ESBL-producing K pneumoniae (ESBL-KP) isolates from July 2008 to December 2009 in a university-affiliated teaching hospital in Taiwan. We used disk diffusion method to determine susceptibility to fosfomycin. Fosfomycin may have lower susceptibility when using disk diffusion method compared with agar dilution method. Broth microdilution test was also used to determine minimal inhibitory concentrations (MICs) and susceptibilities to other antimicrobial agents. RESULTS: Imipenem was active against ESBL-EC and ESBL-KP. Fosfomycin had good susceptibility to ESBL-EC (95.5%), including in hospital acquired isolates, but lower antimicrobial activity against ESBL-KP (57.6%). Trimethoprim-sulfamethoxazole had the highest resistance rate to ESBL-EC and ESBL KP. Comparing with non-hospital-acquired isolates, hospital-acquired ESBL-KP was associated with significantly lower susceptibility of gentamicin (13.3% vs. 66.7%), trimethoprim-sulfamethoxazole (8.9% vs. 38.1%), ciprofloxacin (26.7% vs. 61.9%), and amikacin (46.1% vs. 81.0%) (p<0.05). The resistance of some strains to ciprofloxacin was significantly associated with lower susceptibilities of gentamicin (32.6% in ESBL-EC), nitrofurantoin (2.4% in ESBL-KP) and trimethoprim sulfamethoxazole (9.8% in ESBL-KP) (p<0.05) but not accompanied with decreasing susceptibility of fosfomycin. CONCLUSION: Fosfomycin had the excellent activity against ESBL-EC but not ESBL-KP in this study. Based on the study findings, we suggest that fosfomycin can be a therapeutic option for UTIs with ESBL-EC. Nitrofuranoin was actively against ESBL-EC. Nitrofurantoin may be an alternative option for uncomplicated UTIs with ESBL-EC in Taiwan. PMID- 21524975 TI - Microbial isolation and emergence of antimicrobial resistance associated with tigecycline usage. AB - BACKGROUND: With the increasing experience of tigecycline usage, its ecological impact on microorganisms raises concerns but remains unknown. We aimed to analyze the difference in microorganisms isolated before, during, and after tigecycline usage and their susceptibility to antimicrobial agents. METHODS: Between July 2008 and August 2009, 66 patients who received tigecycline monotherapy for more than 2 days at a Taiwan medical center were enrolled. Antimicrobial susceptibility testing was performed by broth microdilution method with VITEK-2 system and was analyzed according to the Clinical and Laboratory Standards Institute guidelines, except for tigecycline. We followed USA Food and Drug Administration criteria for interpretation of susceptibility to tigecycline. RESULTS: The median duration of tigecycline monotherapy was 13.4 days. After tigecycline treatment, the isolation frequency of Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae decreased, but that of Pseudomonas aeruginosa, Proteus sp, and Stenotrophomonas maltophilia did not change. A baumannii and P aeruginosa were the two most common pathogens when tigecycline was administered. The tigecycline susceptibility rate of A baumannii isolates decreased after the administration of tigecycline. CONCLUSION: The most common pathogens isolated in patients receiving tigecycline were A baumannii and P aeruginosa. Tigecycline usage decreased the isolation frequency of A baumannii, methicillin-resistant S aureus, E coli, and K pneumoniae. Exposure to tigecycline may be associated with a decreased susceptibility rate of A baumannii for tigecycline. PMID- 21524976 TI - Clinical manifestations of eosinophilic meningitis caused by Angiostrongylus cantonensis: 18 years' experience in a medical center in southern Taiwan. AB - BACKGROUND: With the improvement of public health, eosinophilic meningitis associated with Angiostrongylus cantonensis infection is now seldom reported in Taiwan. Eosinophilic meningitis typically occurred sporadically in children. This study aims to analyze the clinical manifestations and change in the contemporary epidemiology of eosinophilic meningitis in Taiwan. METHODS: This is a retrospective study of patients diagnosed with eosinophilic meningitis at Kaohsiung Veterans General Hospital, from December 1991 to September 2009. The demographic characteristics, clinical presentations, laboratory data, radiographic imaging, and treatment and clinical outcome were analyzed. A PubMed search with the keywords of eosinophilic meningitis, A cantonensis, and Taiwan was performed to retrieve cases of eosinophilic meningitis caused by A cantonensis since 1960. RESULTS: Thirty-seven patients were diagnosed to have eosinophilic meningitis during a period of 18 years. The median age was 32 years (range, 2-80 years). Ninety five percent (35/37) of the patients were adults. The median incubation period was 10.5 days (range, 3-80 days). Most of the patients presented with headache (29, 78%), fever (25, 68%), and 11(30%) had hyperesthesia. Patients with hyperesthesia had longer incubation period (55 vs. 7 days, p=0.004), lower serum immunoglobulin E levels (127.5 vs. 1295 IU/mL, p<0.001), and longer duration between symptom onset and spinal taps (14 vs. 5 days, p=0.011). Three patients presented initially with lymphocytic meningitis, and eosinophilia only appeared on a second lumbar puncture. Magnetic resonance imaging of the brain disclosed leptomeningeal enhancement (17/26, 65%) and increased signal intensity (10/26, 38%) on T2-weighted and fluid-attenuated inversion recovery images. There were eight relapses and two patients died. No sequela was noted except in one 2-year-old toddler, who had weakness of both lower limbs. CONCLUSIONS: The epidemiology of eosinophilic meningitis has changed during the past two decades in Taiwan and occurs mainly in adults in the setting of outbreaks. Hyperesthesia; repeated lumbar puncture in cases with lymphocytic meningitis of uncertain cause; and a detailed history, including food consumption, are important to establish an accurate diagnosis. PMID- 21524977 TI - Antimicrobial susceptibility of bacteremic isolates from cancer patients with or without neutropenia at a medical center in southern Taiwan. AB - BACKGROUND: Few studies focus on comparison of antimicrobial susceptibility for bacteremic isolates in neutropenic and nonneutropenic cancer patients. The purpose of this study was to elucidate the antimicrobial susceptibility of bacteremic isolates from cancer patients. METHODS: We collected bacterial isolates causing bloodstream infections in cancer patients at a tertiary care hospital from 2003 to 2005 and performed in vitro antimicrobial susceptibility of these pathogens by the disc diffusion method. RESULTS: A total of 588 bacterial isolates were identified from 476 episodes of bloodstream infections in cancer patients. Major pathogens were Escherichia coli (22.4%), Klebsiella pneumoniae (17.6%), and Pseudomonas aeruginosa (14.1%) in neutropenic patients and E coli (13.3%), K pneumoniae (10.1%), and Staphylococcus aureus (9.7%) in nonneutropenic patients. Of S aureus, 55.8% were resistant to methicillin, and of coagulase negative Staphylococcus 87.0%. Cefepime, cefpirome, piperacillin/tazobactam, meropenem, or imipenem in combination with or without an aminoglycoside, were active against more than 85% of gram-negative bacilli (GNB). Ceftazidime, piperacillin, or ciprofloxacin plus an aminoglycoside were also active against more than 85% of GNB. The susceptibility rate of GNB or gram-positive cocci to any agent was not different between the isolates from neutropenic and nonneutropenic patients, but more GNB isolates from the former were susceptible to imipenem or meropenem plus an aminoglycoside. CONCLUSION: GNB remained dominant among bacteremic isolates in cancer patients. Antimicrobial agents, especially aminoglycoside-containing combination regimens, as recommended by Infectious Diseases Society of Taiwan for febrile neutropenia, were active against more than 85% of GNB isolates. PMID- 21524978 TI - Impact of age on neutrophil phagocytic reaction with different capsular serotypes of Klebsiella pneumoniae. AB - BACKGROUND: Although the prevalence of K pneumoniae liver abscess is higher in patients older than 55 years, the possible relationship of age with decreased phagocytic function of the patients with Klebsiella pneumoniae liver abscess has not been investigated. Our aim was to determine whether susceptibility to K pneumoniae infection depended on age-related impairment of phagocytic function. METHODS: The study enrolled 42 subjects in three age groups: younger than 40 years (n=10), 40-65 years (n=12), and older than 65 years (n=20). Seventy-five strains of K pneumoniae were investigated, including liver abscess isolates (n=25) and blood isolates from the patients without liver abscesses (n=50). The rate of phagocytosis of K1/K2 (n=36) and non-K1/K2 (n=39) K pneumoniae by neutrophils was determined using flow cytometry and compared among the three age groups. RESULTS: The rate of phagocytosis of serotype K1/K2 isolates was significantly lower in the middle-aged group than that in the younger group (p=0.015) and significantly lower in the older group than those in the middle aged and younger groups (p=0.025 and p<0.01). In contrast, the rate of phagocytosis of non-K1/K2 isolates was similar in all three age groups at 60 minutes (66.4+/-1.85%, 65.2+/-2.0%, and 62.3+/-1.81%; p=not significant). CONCLUSIONS: Thus, as age increases, the ability of neutrophils to phagocytose virulent K1/K2 K pneumoniae decreases. This finding may account for the higher prevalence of K pneumoniae liver abscesses in older patients. PMID- 21524979 TI - Human bocavirus as an important cause of respiratory tract infection in Taiwanese children. AB - BACKGROUND: Human bocavirus (HBoV), first described in September 2005, was considered a causative agent of previously unexplained respiratory tract diseases. However, only few reports provide the evidence for an association between HBoV and respiratory tract diseases. We conducted a prospective clinical and molecular study of HBoV in Taiwan. METHODS: We enrolled 705 children who visited our outpatient pediatric clinics in a medical center because of symptoms and signs of respiratory tract infections from November 2008 to October 2009. Throat swab was performed and HBoV polymerase chain reaction and viral culture were done simultaneously. RESULTS: Positive viral results were confirmed in 159 (22.6%) of the 705 children. HBoV was found in 35 samples and it was supposed to be as a single virus in 32 samples because viral isolation of these 32 samples did not identify other virus. The other three patients had coinfection with another virus. One child got HBoV reinfection 6 months after the first infection. Seventy-one percentage of these HBoV infections occurred between November and March. Of the 34 children with positive HBoV, 26 (76%) patients were younger than 5 years; their common symptoms were cough, rhinorrhea, and fever; the most common diagnoses were bronchitis (34%, 12/35) and sinusitis (31%, 11/35) followed by pharyngitis (29%, 10/35) and asthma exacerbation (26%, 9/35). Three of the 34 patients needed hospitalization. CONCLUSION: HBoV is an emerging human parvovirus that may cause respiratory tract infection in young children. Diseases associated with HBoV may range from pharyngitis, sinusitis, acute otitis media to bronchitis, asthma, and even pneumonia. PMID- 21524980 TI - In vitro activity of linezolid, tigecycline, and daptomycin on methicillin resistant Staphylococcus aureus blood isolates from adult patients, 2006-2008: stratified analysis by vancomycin MIC. AB - BACKGROUND: The recent molecular epidemiological studies concerning epidemiological studies concerning methicillin-resistant Staphylococcus aureus (MRSA) blood isolates from adult patients and susceptibilities of MRSA isolates with high vancomycin minimum inhibitory concentrations (MICs) (>=2 mg/L) to linezolid, tigecycline, and daptomycin in Taiwan remain limited. The objectives of the study were (1) to better understand the change of molecular epidemiology of MRSA blood isolates and (2) to evaluate the in vitro activity of new anti-Gram positive agents, including linezolid, tigecycline, and daptomycin. METHODS: A total of 470 nonduplicate MRSA blood isolates from adult patients (older than 18 years) were collected from January 2006 to December 2008. The MICs of these isolates to various antibiotics were determined. Multilocus sequence typing was also performed in all isolates. RESULTS: Three sequence types (STs) constitute most (92.1%) of these 470 MRSA isolates: ST239 (53.2%), ST59 (23.2%), and ST5 (15.7%). Throughout the 3-year study, the ST239 strain remained predominant but with a significant trend of declining annually (p=0.03). In contrast, the proportion of isolates of ST59 increased, although the increment was insignificant (p=0.14). The proportion of MRSA isolates with a vancomycin MIC of 2 mg/L was 17.2%. All of these isolates with a vancomycin MIC of 2 mg/L were susceptible to linezolid and tigecycline, whereas most of them (98.8%) were susceptible to daptomycin. CONCLUSIONS: ST239 remained predominant during the 3 year period but with a significant trend of declining. Moreover, linezolid, tigecycline, and daptomycin remained highly active against MRSA blood isolates, even with a vancomycin MIC of 2 mg/L. PMID- 21524981 TI - Case report: high prenatal bisphenol a exposure and infant neonatal neurobehavior. AB - CONTEXT: Most of the U.S. population is exposed to the high-production-volume chemical bisphenol A (BPA), but targetable sources of exposure remain to be determined. Animal studies and one human study suggest that BPA is a neurotoxicant. CASE PRESENTATION: A mother in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective birth cohort examining prenatal and postnatal environmental toxicants and childhood health outcomes, had a urinary BPA concentration of 583 ug/g creatinine at 27 weeks of pregnancy, which was the highest concentration observed in this cohort (median, 2.0 ug/g creatinine) and the general population. We used prenatal questionnaire data and a follow-up interview to identify potential sources of exposure that included daily plastic use and consumption of canned beverages and foods. Her male infant had a normal newborn neurobehavioral assessment but presented with abnormalities at the 1 month examination that prompted physician referral. Subsequently, the child had normal neurobehavioral testing results at annual evaluations from 1 to 5 years of age. DISCUSSION: Investigations into sources of high gestational urinary BPA concentrations provide an opportunity to identify potential targets for reduction of BPA exposure. This case highlights a potential link between gestational BPA exposure and transient neurobehavioral changes that is hypothesis generating and can serve to alert researchers to potential areas for examination in future studies. RELEVANCE TO CLINICAL PRACTICE: It is important to educate health care practitioners regarding potential sources of BPA exposure and anticipatory guidance on minimization of exposures during vulnerable periods of development. PMID- 21524983 TI - Localized scleroderma en coup de sabre exacerbated during pregnancy followed by postpartum development of rheumatoid arthritis. PMID- 21524982 TI - Engine-operating load influences diesel exhaust composition and cardiopulmonary and immune responses. AB - BACKGROUND: The composition of diesel engine exhaust (DEE) varies by engine type and condition, fuel, engine operation, and exhaust after treatment such as particle traps. DEE has been shown to increase inflammation, susceptibility to infection, and cardiovascular responses in experimentally exposed rodents and humans. Engines used in these studies have been operated at idle, at different steady-state loads, or on variable-load cycles, but exposures are often reported only as the mass concentration of particulate matter (PM), and the effects of different engine loads and the resulting differences in DEE composition are unknown. OBJECTIVES: We assessed the impacts of load-related differences in DEE composition on models of inflammation, susceptibility to infection, and cardiovascular toxicity. METHODS: We assessed inflammation and susceptibility to viral infection in C57BL/6 mice and cardiovascular toxicity in APOE-/- mice after being exposed to DEE generated from a single-cylinder diesel generator operated at partial or full load. RESULTS: At the same PM mass concentration, partial load resulted in higher proportions of particle organic carbon content and a smaller particle size than did high load. Vapor-phase hydrocarbon content was greater at partial load. Compared with high-load DEE, partial-load DEE caused greater responses in heart rate and T-wave morphology, in terms of both magnitude and rapidity of onset of effects, consistent with previous findings that systemic effects may be driven largely by the gas phase of the exposure atmospheres. However, high-load DEE caused more lung inflammation and greater susceptibility to viral infection than did partial load. CONCLUSIONS: Differences in engine load, as well as other operating variables, are important determinants of the type and magnitude of responses to inhaled DEE. PM mass concentration alone is not a sufficient basis for comparing or combining results from studies using DEE generated under different conditions. PMID- 21524984 TI - Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy (EPPER) mimicking bullous pemphigoid in a patient with anaplastic large cell lymphoma. PMID- 21524985 TI - Hair follicle stem cell marker nestin expression in regenerating hair follicles of patients with alopecia areata. AB - Cells that are nestin positive and keratin 15 (K15) negative are located in the hair follicle pluripotent stem cell (hfPS) area (hfPSA). The hfPSA is located within the root of the sebaceous glands, in a region just above the hair follicle bulge area. In the current study, we investigated the expression pattern of the stem cell marker nestin in the hair follicle cycling of patients with alopecia areata. In the normal human scalp, the majority of hair follicles are in the anagen phase of development. While it is often difficult to identify nestin expression in late anagen phases, nestin-expressing cells are easily identified in proliferating cells located in the hfPSA of the growing early and middle anagen phase hair follicles. In patients exhibiting alopecia areata, the middle anagen hair follicles with growing cells were found to be nestin positive and K15 negative. In contrast, the hair follicles undergoing degradation in alopecia areata patients demonstrated lymphocytic infiltration within the nestin- and K15 negative dermal papilla cells. Both the nestin-positive hfPSA and K15-positive hair follicle bulge areas were not damaged in all phases. In addition, the regenerating early anagen hair follicles demonstrated nestin-positive and K15 negative cells within the dermal papilla and in the area surrounding the hair bulb. These results suggest that the nestin-positive cells play an important role not only in the hfPSA, but also in the dermal papilla in the regenerating hair follicle. PMID- 21524986 TI - Sjogren-Larsson syndrome due to a novel mutation in the FALDH gene. PMID- 21524987 TI - Allergic contact dermatitis in a volleyball player due to protective adhesive taping. PMID- 21524988 TI - Corticosteroids should not be used in urticaria because of the potential risk of steroid dependence and development of severe anti-H1- resistant urticaria. PMID- 21524989 TI - Penile verrucous carcinoma arising in HPV-negative condylomatous papules. PMID- 21524990 TI - Lichen planus in a patient with long-term exposure to chrome. PMID- 21524991 TI - Mucocutaneous-type pemphigus vulgaris with anti-desmoplakin autoantibodies. PMID- 21524992 TI - Eosinophilic cellulitis (Wells' syndrome) and an insect bite-like reaction in a patient with non-Hodgkin B cell lymphoma. PMID- 21524993 TI - Systemic allergic contact dermatitis to black cumin essential oil expressing as generalized erythema multiforme. PMID- 21524994 TI - Rotation and structure of FoF1-ATP synthase. AB - F(o)F(1)-ATP synthase is one of the most ubiquitous enzymes; it is found widely in the biological world, including the plasma membrane of bacteria, inner membrane of mitochondria and thylakoid membrane of chloroplasts. However, this enzyme has a unique mechanism of action: it is composed of two mechanical rotary motors, each driven by ATP hydrolysis or proton flux down the membrane potential of protons. The two molecular motors interconvert the chemical energy of ATP hydrolysis and proton electrochemical potential via the mechanical rotation of the rotary shaft. This unique energy transmission mechanism is not found in other biological systems. Although there are other similar man-made systems like hydroelectric generators, F(o)F(1)-ATP synthase operates on the nanometre scale and works with extremely high efficiency. Therefore, this enzyme has attracted significant attention in a wide variety of fields from bioenergetics and biophysics to chemistry, physics and nanoscience. This review summarizes the latest findings about the two motors of F(o)F(1)-ATP synthase as well as a brief historical background. PMID- 21524995 TI - Cytosolic CD38 protein forms intact disulfides and is active in elevating intracellular cyclic ADP-ribose. AB - CD38 catalyzes the synthesis of cyclic ADP-ribose (cADPR), a Ca(2+) messenger responsible for regulating a wide range of physiological functions. It is generally regarded as an ectoenzyme, but its intracellular localization has also been well documented. It is not known if internal CD38 is enzymatically active and contributes to the Ca(2+) signaling function. In this study, we engineered a novel soluble form of CD38 that can be efficiently expressed in the cytosol and use cytosolic NAD as a substrate to produce cADPR intracellularly. The activity of the engineered CD38 could be decreased by mutating the catalytic residue Glu 226 and increased by the double mutation E146A/T221F, which increased its cADPR synthesis activity by >11-fold. Remarkably, the engineered CD38 exhibited the ability to form the critical disulfide linkages required for its enzymatic activity. This was verified by using a monoclonal antibody generated against a critical disulfide, Cys-254-Cys-275. The specificity of the antibody was established by x-ray crystallography and site-directed mutagenesis. The engineered CD38 is thus a novel example challenging the general belief that cytosolic proteins do not possess disulfides. As a further refinement of this approach, the engineered CD38 was placed under the control of tetracycline using an autoregulated construct. This study has set the stage for in vivo manipulation of cADPR metabolism. PMID- 21524996 TI - Biochemical, proteomic, structural, and thermodynamic characterizations of integrin-linked kinase (ILK): cross-validation of the pseudokinase. AB - Integrin-linked kinase (ILK) is one of the few evolutionarily conserved focal adhesion proteins involved in diverse cell adhesion-dependent physiological and pathological responses. Despite more than a decade of studies and extensive literature, the kinase function of ILK is controversial. ILK contains a highly degraded kinase active site but it has been argued that ILK may be an unusual manganese (Mn)-dependent serine-threonine kinase that targets specific substrates such as glycogen synthase kinase-3beta (GSK-3beta). In this study, we have tackled this issue by a systematic bottom-up biochemical, proteomic, structural, and thermodynamic analysis of ILK. We show that recombinant ILK from either bacteria or mammalian cells exhibits no kinase activity on GSK-3beta in the presence of either Mn(2+) or the conventional kinase co-factor Mg(2+). A comprehensive and unbiased whole cell-based kinase assay using entire mammalian CG-4 and C2C12 cell lysate did not identify any specific ILK substrates. High resolution crystallographic structure analysis further confirmed that the Mn bound ILK adopts the same pseudo active site conformation as that of the Mg-bound ILK. More importantly, thermodynamic analysis revealed that the K220M mutation, previously thought to inactivate ILK by disrupting ATP binding, significantly impairs the structural integrity and stability of ILK, which provides a new basis for understanding how this mutation caused renal agenesis, a failure of fetal kidney development. Collectively, our data provide strong evidence that ILK lacks intrinsic kinase function. It is a bona fide pseudokinase that likely evolved from an ancestral catalytic counterpart to act as a distinct scaffold to mediate protein-protein interactions during focal adhesion assembly and many other cellular events. PMID- 21524997 TI - The virulence factor PEB4 (Cj0596) and the periplasmic protein Cj1289 are two structurally related SurA-like chaperones in the human pathogen Campylobacter jejuni. AB - The PEB4 protein is an antigenic virulence factor implicated in host cell adhesion, invasion, and colonization in the food-borne pathogen Campylobacter jejuni. peb4 mutants have defects in outer membrane protein assembly and PEB4 is thought to act as a periplasmic chaperone. The crystallographic structure of PEB4 at 2.2-A resolution reveals a dimer with distinct SurA-like chaperone and peptidyl-prolyl cis/trans isomerase (PPIase) domains encasing a large central cavity. Unlike SurA, the chaperone domain is formed by interlocking helices from each monomer, creating a domain-swapped architecture. PEB4 stimulated the rate of proline isomerization limited refolding of denatured RNase T(1) in a juglone sensitive manner, consistent with parvulin-like PPIase domains. Refolding and aggregation of denatured rhodanese was significantly retarded in the presence of PEB4 or of an engineered variant specifically lacking the PPIase domain, suggesting the chaperone domain possesses a holdase activity. Using bioinformatics approaches, we identified two other SurA-like proteins (Cj1289 and Cj0694) in C. jejuni. The 2.3-A structure of Cj1289 does not have the domain swapped architecture of PEB4 and thus more resembles SurA. Purified Cj1289 also enhanced RNase T(1) refolding, although poorly compared with PEB4, but did not retard the refolding of denatured rhodanese. Structurally, Cj1289 is the most similar protein to SurA in C. jejuni, whereas PEB4 has most structural similarity to the Par27 protein of Bordetella pertussis. Our analysis predicts that Cj0694 is equivalent to the membrane-anchored chaperone PpiD. These results provide the first structural insights into the periplasmic assembly of outer membrane proteins in C. jejuni. PMID- 21524998 TI - Single channel characterization of the mitochondrial ryanodine receptor in heart mitoplasts. AB - Heart mitochondria utilize multiple Ca(2+) transport mechanisms. Among them, the mitochondrial ryanodine receptor provides a fast Ca(2+) uptake pathway across the inner membrane to control "excitation and metabolism coupling." In the present study, we identified a novel ryanodine-sensitive channel in the native inner membrane of heart mitochondria and characterized its pharmacological and biophysical properties by directly patch clamping mitoplasts. Four distinct channel conductances of ~100, ~225, ~700, and ~1,000 picosiemens (pS) in symmetrical 150 mm CsCl were observed. The 225 pS cation-selective channel exhibited multiple subconductance states and was blocked by high concentrations of ryanodine and ruthenium red, known inhibitors of ryanodine receptors. Ryanodine exhibited a concentration-dependent modulation of this channel, with low concentrations stabilizing a subconductance state and high concentrations abolishing activity. The 100, 700, and 1,000 pS conductances exhibited different channel characteristics and were not inhibited by ryanodine. Taken together, these findings identified a novel 225 pS channel as the native mitochondrial ryanodine receptor channel activity in heart mitoplasts with biophysical and pharmacological properties that distinguish it from previously identified mitochondrial ion channels. PMID- 21524999 TI - Alpha-synuclein populates both elongated and broken helix states on small unilamellar vesicles. AB - The misfolding of the protein alpha-synuclein (alphaS) has been implicated in the molecular chain of events leading to Parkinson disease. Physiologically, alphaS undergoes a transition from a random coil to helical conformation upon encountering synaptic vesicle membranes. On analogous small unilamellar vesicles (SUVs), the conformation of alphaS is dominated by a single elongated alphaS helix. However, alternative broken helix states have been postulated, mandating experimental clarification. Here, the upper limit for the free energy difference between elongated and broken helix conformations on SUVs resembling synaptic vesicles was determined to be 1.2 +/- 0.4 kcal/mol, which amounts to a population ratio of 7.6:1 between both states (12% broken helices). In response to helix breaks at different positions, alphaS rearranged in an opportunistic manner, thereby minimizing helix abrogations to as little as one to two turns. Enthalpy and entropy measurements of gel state SUV-alphaS interactions indicated that broken helix states retain the ability to relieve membrane-packing stress. Thus, broken helix states are a distinct physiological feature of the vesicle-bound alphaS state, making it a "checkered" protein of multiple parallel conformations. A continuous interconversion between structural states may contribute to pathological alphaS misfolding. PMID- 21525000 TI - Phospholipase D regulates myogenic differentiation through the activation of both mTORC1 and mTORC2 complexes. AB - How phospholipase D (PLD) is involved in myogenesis remains unclear. At the onset of myogenic differentiation of L6 cells induced by the PLD agonist vasopressin in the absence of serum, mTORC1 complex was rapidly activated, as reflected by phosphorylation of S6 kinase1 (S6K1). Both the long (p85) and short (p70) S6K1 isoforms were phosphorylated in a PLD1-dependent way. Short rapamycin treatment specifically inhibiting mTORC1 suppressed p70 but not p85 phosphorylation, suggesting that p85 might be directly activated by phosphatidic acid. Vasopressin stimulation also induced phosphorylation of Akt on Ser-473 through PLD1-dependent activation of mTORC2 complex. In this model of myogenesis, mTORC2 had a positive role mostly unrelated to Akt activation, whereas mTORC1 had a negative role, associated with S6K1-induced Rictor phosphorylation. The PLD requirement for differentiation can thus be attributed to its ability to trigger via mTORC2 activation the phosphorylation of an effector that could be PKCalpha. Moreover, PLD is involved in a counter-regulation loop expected to limit the response. This study thus brings new insights in the intricate way PLD and mTOR cooperate to control myogenesis. PMID- 21525002 TI - Cyclization of the intrinsically disordered alpha1S dihydropyridine receptor II III loop enhances secondary structure and in vitro function. AB - A key component of excitation contraction (EC) coupling in skeletal muscle is the cytoplasmic linker (II-III loop) between the second and third transmembrane repeats of the alpha(1S) subunit of the dihydropyridine receptor (DHPR). The II III loop has been previously examined in vitro using a linear II-III loop with unrestrained N- and C-terminal ends. To better reproduce the loop structure in its native environment (tethered to the DHPR transmembrane domains), we have joined the N and C termini using intein-mediated technology. Circular dichroism and NMR spectroscopy revealed a structural shift in the cyclized loop toward a protein with increased alpha-helical and beta-strand structure in a region of the loop implicated in its in vitro function and also in a critical region for EC coupling. The affinity of binding of the II-III loop binding to the SPRY2 domain of the skeletal ryanodine receptor (RyR1) increased 4-fold, and its ability to activate RyR1 channels in lipid bilayers was enhanced 3-fold by cyclization. These functional changes were predicted consequences of the structural enhancement. We suggest that tethering the N and C termini stabilized secondary structural elements in the DHPR II-III loop and may reflect structural and dynamic characteristics of the loop that are inherent in EC coupling. PMID- 21525001 TI - Induction of inflammasome-dependent pyroptosis by carbon black nanoparticles. AB - Inhalation of nanoparticles has been implicated in respiratory morbidity and mortality. In particular, carbon black nanoparticles are found in many different environmental exposures. Macrophages take up inhaled nanoparticles and respond via release of inflammatory mediators and in some cases cell death. Based on new data, we propose that exposure of macrophages (both a macrophage cell line and primary human alveolar macrophages) to carbon black nanoparticles induces pyroptosis, an inflammasome-dependent form of cell death. Exposure of macrophages to carbon black nanoparticles resulted in inflammasome activation as defined by cleavage of caspase 1 to its active form and downstream IL-1beta release. The cell death that occurred with carbon black nanoparticle exposure was identified as pyroptosis by the protective effect of a caspase 1 inhibitor and a pyroptosis inhibitor. These data demonstrate that carbon black nanoparticle exposure activates caspase 1, increases IL-1beta release after LPS priming, and induces the proinflammatory cell death, pyroptosis. The identification of pyroptosis as a cellular response to carbon nanoparticle exposure is novel and relates to environmental and health impacts of carbon-based particulates. PMID- 21525004 TI - Progesterone impairs human ether-a-go-go-related gene (HERG) trafficking by disruption of intracellular cholesterol homeostasis. AB - The prolongation of QT intervals in both mothers and fetuses during the later period of pregnancy implies that higher levels of progesterone may regulate the function of the human ether-a-go-go-related gene (HERG) potassium channel, a key ion channel responsible for controlling the length of QT intervals. Here, we studied the effect of progesterone on the expression, trafficking, and function of HERG channels and the underlying mechanism. Treatment with progesterone for 24 h decreased the abundance of the fully glycosylated form of the HERG channel in rat neonatal cardiac myocytes and HERG-HEK293 cells, a cell line stably expressing HERG channels. Progesterone also concentration-dependently decreased HERG current density, but had no effect on voltage-gated L-type Ca(2+) and K(+) channels. Immunofluorescence microscopy and Western blot analysis show that progesterone preferentially decreased HERG channel protein abundance in the plasma membrane, induced protein accumulation in the dilated endoplasmic reticulum (ER), and increased the protein expression of C/EBP homologous protein, a hallmark of ER stress. Application of 2-hydroxypropyl-beta-cyclodextrin (a sterol-binding agent) or overexpression of Rab9 rescued the progesterone-induced HERG trafficking defect and ER stress. Disruption of intracellular cholesterol homeostasis with simvastatin, imipramine, or exogenous application of cholesterol mimicked the effect of progesterone on HERG channel trafficking. Progesterone may impair HERG channel folding in the ER and/or block its trafficking to the Golgi complex by disrupting intracellular cholesterol homeostasis. Our findings may reveal a novel molecular mechanism to explain the QT prolongation and high risk of developing arrhythmias during late pregnancy. PMID- 21525003 TI - Defining structural and functional dimensions of the extracellular thyrotropin receptor region. AB - The extracellular region of the thyrotropin receptor (TSHR) can be subdivided into the leucine-rich repeat domain (LRRD) and the hinge region. Both the LRRD and the hinge region interact with thyrotropin (TSH) or autoantibodies. Structural data for the TSHR LRRD were previously determined by crystallization (amino acids Glu(30)-Thr(257), 10 repeats), but the structure of the hinge region is still undefined. Of note, the amino acid sequence (Trp(258)-Tyr(279)) following the crystallized LRRD comprises a pattern typical for leucine-rich repeats with conserved hydrophobic side chains stabilizing the repeat fold. Moreover, functional data for amino acids between the LRRD and the transmembrane domain were fragmentary. We therefore investigated systematically these TSHR regions by mutagenesis to reveal insights into their functional contribution and potential structural features. We found that mutations of conserved hydrophobic residues between Thr(257) and Tyr(279) cause TSHR misfold, which supports a structural fold of this peptide, probably as an additional leucine-rich repeat. Furthermore, we identified several new mutations of hydrophilic amino acids in the entire hinge region leading to partial TSHR inactivation, indicating that these positions are important for intramolecular signal transduction. In summary, we provide new information regarding the structural features and functionalities of extracellular TSHR regions. Based on these insights and in context with previous results, we suggest an extracellular activation mechanism that supports an intramolecular agonistic unit as a central switch for activating effects at the extracellular region toward the serpentine domain. PMID- 21525005 TI - Angiotensin II type 1 receptor signaling regulates feeding behavior through anorexigenic corticotropin-releasing hormone in hypothalamus. AB - The activation of renin-angiotensin system contributes to the development of metabolic syndrome and diabetes as well as hypertension. However, it remains undetermined how renin-angiotensin system is implicated in feeding behavior. Here, we show that angiotensin II type 1 (AT(1)) receptor signaling regulates the hypothalamic neurocircuit that is involved in the control of food intake. Compared with wild-type Agtr1a(+/+) mice, AT(1) receptor knock-out (Agtr1a(-/-)) mice were hyperphagic and obese with increased adiposity on an ad libitum diet, whereas Agtr1a(-/-) mice were lean with decreased adiposity on a pair-fed diet. In the hypothalamus, mRNA levels of anorexigenic neuropeptide corticotropin releasing hormone (Crh) were lower in Agtr1a(-/-) mice than in Agtr1a(+/+) mice both on an ad libitum and pair-fed diet. Furthermore, intracerebroventricular administration of CRH suppressed food intake both in Agtr1a(+/+) and Agtr1a(-/-) mice. In addition, the Crh gene promoter was significantly transactivated via the cAMP-responsive element by angiotensin II stimulation. These results thus demonstrate that central AT(1) receptor signaling plays a homeostatic role in the regulation of food intake by maintaining gene expression of Crh in hypothalamus and suggest a therapeutic potential of central AT(1) receptor blockade in feeding disorders. PMID- 21525006 TI - ATP and Mg2+ promote the reversible oligomerization and aggregation of chloroplast 2-Cys peroxiredoxin. AB - 2-Cys peroxiredoxins (2-Cys Prxs) are ubiquitous peroxidases with important roles in cellular antioxidant defense and hydrogen peroxide-mediated signaling. Post translational modifications of conserved cysteines cause the transition from low to high molecular weight oligomers, triggering the functional change from peroxidase to molecular chaperone. However, it remains unclear how non-covalent interactions of 2-Cys Prx with metabolites modulate the quaternary structure. Here, we disclose that ATP and Mg(2+) (ATP/Mg) promote the self-polymerization of chloroplast 2-Cys Prx (polypeptide 23.5 kDa) into soluble higher order assemblies (>2 MDa) that proceed to insoluble aggregates beyond 5 mM ATP. Remarkably, the withdrawal of ATP or Mg(2+) brings soluble oligomers and insoluble aggregates back to the native conformation without compromising the associated functions. As confirmed by transmission electron microscopy, ATP/Mg drive the toroid-like decamers (diameter 13 nm) to the formation of large sphere-like particles (diameter ~30 nm). Circular dichroism studies on ATP-labeled 2-Cys Prx reveal that ATP/Mg enhance the proportion of beta-sheets with the concurrent decrease in the content of alpha-helices. In line with this observation, the formation of insoluble aggregates is strongly prevented by 2,2,2-trifluoroethanol, a cosolvent employed to induce alpha-helical conformations. We further find that the response of self-polymerization to ATP/Mg departs abruptly from that of the associated peroxidase and chaperone activities when two highly conserved residues, Arg(129) and Arg(152), are mutated. Collectively, our data uncover that non-covalent interactions of ATP/Mg with 2-Cys Prx modulate dynamically the quaternary structure, thereby coupling the non-redox chemistry of cell energy with redox transformations at cysteine residues. PMID- 21525007 TI - Ras/mitogen-activated protein kinase (MAPK) signaling modulates protein stability and cell surface expression of scavenger receptor SR-BI. AB - The mitogen-activated protein kinase (MAPK) Erk1/2 has been implicated to modulate the activity of nuclear receptors, including peroxisome proliferator activator receptors (PPARs) and liver X receptor, to alter the ability of cells to export cholesterol. Here, we investigated if the Ras-Raf-Mek-Erk1/2 signaling cascade could affect reverse cholesterol transport via modulation of scavenger receptor class BI (SR-BI) levels. We demonstrate that in Chinese hamster ovary (CHO) and human embryonic kidney (HEK293) cells, Mek1/2 inhibition reduces PPARalpha-inducible SR-BI protein expression and activity, as judged by reduced efflux onto high density lipoprotein (HDL). Ectopic expression of constitutively active H-Ras and Mek1 increases SR-BI protein levels, which correlates with elevated PPARalpha Ser-21 phosphorylation and increased cholesterol efflux. In contrast, SR-BI levels are insensitive to Mek1/2 inhibitors in PPARalpha-depleted cells. Most strikingly, Mek1/2 inhibition promotes SR-BI degradation in SR-BI overexpressing CHO cells and human HuH7 hepatocytes, which is associated with reduced uptake of radiolabeled and 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyane-labeled HDL. Loss of Mek1/2 kinase activity reduces SR BI expression in the presence of bafilomycin, an inhibitor of lysosomal degradation, indicating down-regulation of SR-BI via proteasomal pathways. In conclusion, Mek1/2 inhibition enhances the PPARalpha-dependent degradation of SR BI in hepatocytes. PMID- 21525008 TI - ERp29 regulates DeltaF508 and wild-type cystic fibrosis transmembrane conductance regulator (CFTR) trafficking to the plasma membrane in cystic fibrosis (CF) and non-CF epithelial cells. AB - Sodium 4-phenylbutyrate (4PBA) improves the intracellular trafficking of DeltaF508-CFTR in cystic fibrosis (CF) epithelial cells. The underlying mechanism is uncertain, but 4PBA modulates the expression of some cytosolic molecular chaperones. To identify other 4PBA-regulated proteins that might regulate DeltaF508-CFTR trafficking, we performed a differential display RT-PCR screen on IB3-1 CF bronchiolar epithelial cells exposed to 4PBA. One transcript up regulated by 4PBA encoded ERp29, a luminal resident of the endoplasmic reticulum (ER) thought to be a novel molecular chaperone. We tested the hypothesis that ERp29 is a 4PBA-regulated ER chaperone that influences DeltaF508-CFTR trafficking. ERp29 mRNA and protein expression was significantly increased (~1.5 fold) in 4PBA-treated IB3-1 cells. In Xenopus oocytes, ERp29 overexpression increased the functional expression of both wild-type and DeltaF508-CFTR over 3 fold and increased wild-type cystic fibrosis transmembrane conductance regulator (CFTR) plasma membrane expression. In CFBE41o- WT-CFTR cells, expression of and short circuit currents mediated by CFTR decreased upon depletion of ERp29 as did maturation of newly synthesized CFTR. In IB3-1 cells, DeltaF508-CFTR co immunoprecipitated with endogenous ERp29, and overexpression of ERp29 led to increased DeltaF508-CFTR expression at the plasma membrane. These data suggest that ERp29 is a 4PBA-regulated ER chaperone that regulates WT-CFTR biogenesis and can promote DeltaF508-CFTR trafficking in CF epithelial cells. PMID- 21525009 TI - BUBR1 and closed MAD2 (C-MAD2) interact directly to assemble a functional mitotic checkpoint complex. AB - The mitotic checkpoint maintains genomic stability by ensuring that chromosomes are accurately segregated during mitosis. When the checkpoint is activated, the mitotic checkpoint complex (MCC), assembled from BUBR1, BUB3, CDC20, and MAD2, directly binds and inhibits the anaphase-promoting complex/cyclosome (APC/C) until all chromosomes are properly attached and aligned. The mechanisms underlying MCC assembly and MCC-APC/C interaction are not well characterized. Here, we show that a novel interaction between BUBR1 and closed MAD2 (C-MAD2) is essential for MCC-mediated inhibition of APC/C. Intriguingly, Arg(133) and Gln(134) in C-MAD2 are required for BUBR1 interaction. The same residues are also critical for MAD2 dimerization and MAD2 binding to p31(comet), a mitotic checkpoint silencing protein. Along with previously characterized BUBR1-CDC20 and C-MAD2-CDC20 interactions, our results underscore the integrity of the MCC for its activity and suggest the fundamental importance of the MAD2 alphaC helix in modulating mitotic checkpoint activation and silencing. PMID- 21525010 TI - Novel vinculin binding site of the IpaA invasin of Shigella. AB - Internalization of Shigella into host epithelial cells, where the bacteria replicates and spreads to neighboring cells, requires a type 3 secretion system (T3SS) effector coined IpaA. IpaA binds directly to and activates the cytoskeletal protein vinculin after injection in the host cell cytosol, and this was previously thought to be directed by two amphipathic alpha-helical vinculin binding sites (VBS) found in the C-terminal tail domain of IpaA. Here, we report a third VBS, IpaA-VBS3, that is located N-terminal to the other two VBSs of IpaA and show that one IpaA molecule can bind up to three vinculin molecules. Biochemical in vitro Shigella invasion assays and the 1.6 A crystal structure of the vinculin.IpaA-VBS3 complex showed that IpaA-VBS3 is functionally redundant with the other two IpaA-VBSs in cell invasion and in activating the latent F actin binding functions of vinculin. Multiple VBSs in IpaA are reminiscent of talin, which harbors 11 VBSs. However, most of the talin VBSs have low affinity and are buried in helix bundles, whereas all three of the VBSs of IpaA are high affinity, readily available, and in close proximity to each other in the IpaA structure. Although deletion of IpaA-VBS3 has no detectable effects on Shigella invasion of epithelial cells, deletion of all three VBSs impaired bacterial invasion to levels found in an ipaA null mutant strain. Thus, IpaA-directed mimicry of talin in activating vinculin occurs through three high affinity VBSs that are essential for Shigella pathogenesis. PMID- 21525011 TI - Involvement of Jun dimerization protein 2 (JDP2) in the maintenance of Epstein Barr virus latency. AB - Reactivation of the Epstein-Barr virus from latency is dependent on expression of the BZLF1 viral immediate-early protein. The BZLF1 promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical inducers such as 12-O-tetradecanoylphorbol-13-acetate and calcium ionophore. We found that Jun dimerization protein 2 (JDP2) plays a significant role in suppressing Zp activity. Reporter, EMSA, and ChIP assays of a Zp mutant virus revealed JDP2 association with Zp at the ZII cis-element, a binding site for CREB/ATF/AP-1. Suppression of Zp activity by JDP2 correlated with HDAC3 association and reduced levels of histone acetylation. Although introduction of point mutations into the ZII element of the viral genome did not increase the level of BZLF1 production, silencing of endogenous JDP2 gene expression by RNA interference increased the levels of viral early gene products and viral DNA replication. These results indicate that JDP2 plays a role as a repressor of Zp and that its replacement by CREB/ATF/AP-1 at ZII is crucial to triggering reactivation from latency to lytic replication. PMID- 21525012 TI - Epidermal growth factor receptor-mediated tissue transglutaminase overexpression couples acquired tumor necrosis factor-related apoptosis-inducing ligand resistance and migration through c-FLIP and MMP-9 proteins in lung cancer cells. AB - Acquired chemoresistance not only blunts anticancer therapy but may also promote cancer cell migration and metastasis. Our previous studies have revealed that acquired tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in lung cancer cells is associated with Akt-mediated stabilization of cellular caspase 8 and Fas-associated death domain (FADD)-like apoptosis regulator-like inhibitory protein (c-FLIP) and myeloid cell leukemia 1 (Mcl-1). In this report, we show that cells with acquired TRAIL resistance have significantly increased capacities in migration and invasion. By gene expression screening, tissue transglutaminase (TGM2) was identified as one of the genes with the highest expression increase in TRAIL-resistant cells. Suppressing TGM2 dramatically alleviated TRAIL resistance and cell migration, suggesting that TGM2 contributes to these two phenotypes in TRAIL-resistant cells. TGM2-mediated TRAIL resistance is likely through c-FLIP because TGM2 suppression significantly reduced c-FLIP but not Mcl-1 expression. The expression of matrix metalloproteinase 9 (MMP-9) was suppressed when TGM2 was inhibited, suggesting that TGM2 potentiates cell migration through up-regulating MMP-9 expression. We found that EGF receptor (EGFR) was highly active in the TRAIL-resistant cells, and suppression of EGFR dramatically reduced TGM2 expression. We further determined JNK and ERK, but not Akt and NF-kappaB, are responsible for EGFR mediated TGM2 expression. These results identify a novel pathway that involves EGFR, MAPK (JNK and ERK), and TGM2 for acquired TRAIL resistance and cell migration in lung cancer cells. Because TGM2 couples TRAIL resistance and cell migration, it could be a molecular target for circumventing acquired chemoresistance and metastasis in lung cancer. PMID- 21525014 TI - The impact of comprehensive services in substance abuse treatment for women with a history of intimate partner violence. AB - This study examines the impact of comprehensive services on posttreatment substance use among women with a history of intimate partner violence. The sample includes 1,123 women from 50 treatment facilities derived from the National Treatment Improvement Evaluation Study (NTIES). Generalized linear mixed modeling was used to determine whether a history of intimate partner violence moderates the association between service receipt and posttreatment substance use. Significant interactions were found between history of intimate partner violence and concrete ( p = .016) and family services (p = .023) in predicting substance use. PMID- 21525013 TI - TWEAK induces apoptosis through a death-signaling complex comprising receptor interacting protein 1 (RIP1), Fas-associated death domain (FADD), and caspase-8. AB - The tumor necrosis factor (TNF) superfamily member TNF-like weak inducer of apoptosis (TNFSF12, CD255) (TWEAK) can stimulate apoptosis in certain cancer cells. Previous studies suggest that TWEAK activates cell death indirectly, by inducing TNFalpha-mediated autocrine signals. However, the underlying death signaling mechanism has not been directly defined. Consistent with earlier work, TWEAK assembled a proximal signaling complex containing its cognate receptor FN14, the adaptor TRAF2, and cellular inhibitor of apoptosis protein 1 (cIAP1). Neither the death domain adaptor Fas-associated death domain nor the apoptosis initiating protease caspase-8 associated with this primary complex. Rather, TWEAK induced TNFalpha secretion and TNF receptor 1-dependent assembly of a death signaling complex containing receptor-interacting protein 1 (RIP1), FADD, and caspase-8. Knockdown of RIP1 by siRNA prevented TWEAK-induced association of FADD with caspase-8 but not formation of the FN14-TRAF2-cIAP1 complex and inhibited apoptosis activation. Depletion of the RIP1 E3 ubiquitin ligase cIAP1 enhanced assembly of the RIP1-FADD-caspase-8 complex and augmented cell death. Conversely, knockdown of the RIP1 deubiquitinase CYLD inhibited these functions. Depletion of FADD, caspase-8, BID, or BAX and BAK but not RIP3 attenuated TWEAK-induced cell death. Pharmacologic inhibition of the NF-kappaB pathway or siRNA knockdown of RelA attenuated TWEAK induction of TNFalpha and association of RIP1 with FADD and caspase-8. These results suggest that TWEAK triggers apoptosis by promoting assembly of a RIP1-FADD-caspse-8 complex via autocrine TNFalpha-TNFR1 signaling. The proapoptotic activity of TWEAK is modulated by cIAP1 and CYLD and engages both the extrinsic and intrinsic signaling pathways. PMID- 21525015 TI - Tumour biomarkers in heart failure: is there a role for CA-125? AB - Tumour markers are used for the screening, diagnosis, and stratification of cancer disease. Recently, the potential role of some tumour markers has also been explored in the context of heart failure. These include CA-125, CA 15-3, CA 19-9, carcinoembryonic antigen, alpha-feto protein, tissue polypeptide antigen, tissue polypeptide specific antigen, cytokeratin 19 fragment, and chromogranins. Of these markers, CA-125, a tumour antigen that is expressed on the surface of ovarian cancer cells and which is a well-established biomarker for monitoring ovarian cancer growth, has been investigated most extensively. Trials have consistently indicated that CA-125 could serve as both a diagnostic and prognostic biomarker of heart failure, although the pathophysiology remains to be established. In this review paper we discuss the potential role of tumour markers in heart failure with a special focus on CA-125 within the context of recent trials. PMID- 21525016 TI - Predicting fluid responsiveness in mechanically ventilated children under general anaesthesia using dynamic parameters and transthoracic echocardiography. AB - BACKGROUND: Dynamic variables are accurate predictors of fluid responsiveness in adults undergoing mechanical ventilation. They can be determined using respiratory variation in aortic flow peak velocity (?Vpeak), arterial pulse pressure [?PP and pulse pressure variation (PPV)], or plethysmographic waveform amplitude [?POP and pleth variability index (PVI)]. These indices have not been validated in children. We studied the ability of these variables to predict fluid responsiveness in mechanically ventilated children. METHODS: All results are expressed as median [median absolute deviation (MAD)]. Thirty mechanically ventilated children were studied after undergoing general anaesthesia. Mechanical ventilation was maintained with a tidal volume of 10 ml kg(-1) of body weight. ?PP, PPV, ?POP, PVI, ?Vpeak, and aortic velocity-time integral were recorded before and after volume expansion (VE). Patients were considered to be responders to VE when the aortic velocity-time integral increased more than 15% after VE. RESULTS: VE induced significant changes in ?PP [13 (MAD 4) to 9 (5)%], PPV [15 (5) to 9 (5)%], ?POP [15 (10) to 10 (6)%], PVI [13 (6) to 8 (5)%], and ?Vpeak [16 (9) to 8 (3)%] (P<0.05 for all). Differences in ?PP, ?POP, PPV, and PVI did not reach statistical significance. Only ?Vpeak was significantly different between responders (R) and non-responders (NR) to VE [22 (3) vs 7 (1)%, respectively; P<0.001]. The threshold ?Vpeak value of 10% allowed discrimination between R and NR. CONCLUSIONS: In this study, ?Vpeak was the most appropriate variable to predict fluid responsiveness. PMID- 21525017 TI - Autophagy process is associated with anti-neoplastic function. AB - Autophagy is a highly conserved process of cellular degradation, which is present in yeast, plants, and mammals. Under normal physiological conditions, autophagy acts to maintain cellular homeostasis and regulate the turnover of organelles. In response to cellular stresses, autophagy prevents the accumulation of impaired proteins and organelles, which serves to inhibit carcinogenesis. On this basis, it is widely accepted that most tumor suppressors, such as beclin 1 associated proteins, forkhead box class O (FoxO) family proteins, multiple mammalian target of Rapamycin (mTOR) inactivators, and nuclear p53 play a role in inducing autophagy. Here, we focus on how the process of autophagy is associated with anti neoplastic function. PMID- 21525018 TI - Counting the SNAREs needed for membrane fusion. AB - SNARE proteins mediate most membrane fusion reactions in eukaryotic cells, and are thereby vital for many functions, including synaptic transmission, cell growth, and cytokinesis. However, until recently it was still unclear how many of these proteins are required to catalyze membrane fusion in vivo. In a recent Science paper, Mohrmann et al. (2010) elegantly show that in chromaffin cells, three SNARE complexes are required for the synchronous release of granules, whereas only a single SNARE complex is sufficient for overall release. PMID- 21525019 TI - Determining best interests under the Mental Capacity Act 2005. In the matter of G (TJ) [2010] EWHC 3005 (COP). PMID- 21525021 TI - Characterization of a novel beta-lactamase-producing plasmid in Neisseria gonorrhoeae: sequence analysis and molecular typing of host gonococci. AB - OBJECTIVES: To determine the complete nucleotide sequence of the novel Johannesburg beta-lactamase-encoding gonococcal plasmid (pEM1) and to determine the strain relatedness of Johannesburg plasmid-containing penicillinase-producing Neisseria gonorrhoeae (PPNG) by molecular typing. METHODS: Eleven PPNG isolates containing the Johannesburg beta-lactamase-encoding plasmid were previously identified among gonococci isolated from men with urethral discharge attending a clinic in Alexandra (Johannesburg) using a PCR assay. DNA sequence-based characterization of one such plasmid was performed to determine its relatedness to the prototype Asia plasmid. The 11 PPNG isolates containing the Johannesburg plasmid and 105 other clinical gonococci isolates were typed using N. gonorrhoeae multi-antigen sequence typing (NG-MAST). RESULTS: Plasmid pEM1 was determined to comprise 4865 bp and to be a deletion derivative of the prototype Asia plasmid with a unique 2560 bp deletion in the non-TnA region. NG-MAST genotyping demonstrated a significant association between sequence type (ST) 502, or other closely related STs, and the Johannesburg plasmid-containing PPNG (P < 0.0001). CONCLUSIONS: Sequencing of a novel beta-lactamase-encoding plasmid (pEM1) found in PPNG isolates in Johannesburg shows it to be a deletion derivative of the prototype Asia plasmid, the deletion most likely arising as a result of DNA rearrangements. The majority of Johannesburg plasmid-containing PPNG isolates were, or were very closely related to, ST502. PMID- 21525020 TI - Cellular HIV-1 DNA quantification and short-term and long-term response to antiretroviral therapy. AB - BACKGROUND: The aim of our study was to determine whether HIV-1 DNA level before antiretroviral therapy (ART) was associated with short- and long-term virological and immunological responses. METHODS: Patients starting first-line protease inhibitor-containing regimens were enrolled in a prospective multicentre cohort in 1998-99. HIV-1 DNA was quantified using real-time PCR at baseline and after 1 year of ART. The association between HIV-1 DNA and virological and immunological responses after 1 and 7 years on ART was studied in multivariate regression models along with other biological and clinical variables. Virological failure (VF) at month 12 (M12) was defined as a plasma HIV-1 RNA >500 copies/mL. Time to death or two plasma HIV-1 RNA >500 copies/mL between M12 and M84 was studied for long-term VF. RESULTS: HIV-1 DNA levels were measured in 148 patients. The median baseline peripheral blood mononuclear cell (PBMC) HIV-1 DNA was 3.7 log(10) copies/10(6) PBMCs. At M12, the median PBMC HIV-1 DNA was 2.99 log(10) copies/10(6) PBMCs. The median decrease in PBMC HIV-1 DNA between M0 and M12 was 0.7 log(10) copies/10(6) PBMCs. Higher baseline PBMC HIV-1 DNA and plasma HIV-1 RNA were independently associated with a higher risk of VF at M12. Only the baseline plasma HIV-1 RNA was independently associated with long-term virological response. The baseline CD4 cell count was the only parameter associated with short- and long-term immunological responses. CONCLUSIONS: HIV-1 DNA impacted the virological response in our cohort. Further research is warranted to study the impact of HIV-1 DNA with currently recommended first-line cART. PMID- 21525023 TI - Antimicrobial activity data in support of nitrofurantoin three times per day. PMID- 21525022 TI - Influence of multidrug efflux systems on methylene blue-mediated photodynamic inactivation of Candida albicans. AB - OBJECTIVES: To investigate whether the major fungal multidrug efflux systems (MESs) affect the efficiency of methylene blue (MB)-mediated antimicrobial photodynamic inactivation (APDI) in pathogenic fungi and test specific inhibitors of these efflux systems to potentiate APDI. METHODS: Candida albicans wild-type and mutants that overexpressed two classes of MESs [ATP-binding cassette (ABC) and major facilitator superfamily (MFS)] were tested for APDI using MB as the photosensitizer with and without addition of MES inhibitors. The uptake and cytoplasm localization of photosensitizer were achieved using laser confocal microscopy. RESULTS: ABC MES overexpression reduced MB accumulation and APDI killing more than MFS MES overexpression. Furthermore, by combining MB APDI with the ABC inhibitor verapamil, fungal killing and MB uptake were potentiated, while by combining MB APDI with the MFS inhibitor INF(271), fungal killing and MB uptake were inhibited. This latter surprising finding may be explained by the hypothesis that the MFS channel can also serve as an uptake mechanism for MB. CONCLUSIONS: The ABC pumps are directly implicated in MB efflux from the cell cytoplasm. Both the influx and efflux of MB may be regulated by MFS systems, and blocking this gate before incubation with MB can decrease the uptake and APDI effects. An ABC inhibitor could be usefully combined with MB APDI for treating C. albicans infections. PMID- 21525024 TI - Relevance of vancomycin-intermediate susceptibility and heteroresistance in methicillin-resistant Staphylococcus aureus bacteraemia. AB - OBJECTIVES: To assess the relevance of vancomycin-intermediate susceptibility (VISA) and heteroresistance (hVISA) in methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. METHODS: We determined vancomycin MICs for 371 saved MRSA blood isolates (2002-03; 2005-06) by Etest and broth microdilution (BMD), screened for hVISA (Etest methods), determined the population analysis profile (PAP)/AUC for isolates with suspected reduced susceptibility (MICs >2 mg/L and/or hVISA-screen-positive versus Mu3 (hVISA control), and stratified patient characteristics and outcome according to susceptibility phenotype: VISA (PAP/AUC >1.3), hVISA (PAP/AUC 0.9-1.3), and susceptible (S-MRSA; PAP/AUC <0.9). RESULTS: PAP/AUC revealed 6 (1.6%) VISA and 30 (8.1%) hVISA phenotypes. The Etest MIC was above the susceptibility cut-off (2 mg/L) for all VISA isolates, whereas the BMD MIC was within the susceptibility range in two (33.3%) instances. Eight hVISA isolates (26.7%) with MICs of 2 mg/L were hVISA-screen negative. SCCmec typing revealed SCCmec II in 100% of VISA, 86.7% of hVISA and 75.5% of S-MRSA isolates (P = 0.04). Prior vancomycin use was documented in 100% of VISA, 73.3% of hVISA and 52.2% of S-MRSA cases (P = 0.002). Outcome (compared in 243 vancomycin treated patients with MICs of 2 mg/L) revealed longer time to clearance in VISA cases [12.1 +/- 13.1 days versus 3.3 +/- 3.9 (hVISA) and 3.7 +/- 5.1 (S-MRSA); P = 0.001], more frequent endocarditis [33.3% versus 9.1% (hVISA; P = 0.1) and 4.2% (S-MRSA; P = 0.001)] and attributable mortality [33.3% versus 9.1% (hVISA; P = 0.1) and 8.4% (S-MRSA); P = 0.08]. CONCLUSIONS: No adverse outcome was documented with hVISA phenotype, whereas VISA contributed to vancomycin treatment failure. VISA and hVISA appear to emerge in SCCmec II isolates among vancomycin-exposed patients and are better detected by Etest. PMID- 21525025 TI - Regulation of adverse remodelling by osteopontin in a genetic heart failure model. AB - AIMS: Desmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice. The hallmarks of desmin-deficient (des(-/-)) mice pathology include pronounced myocardial degeneration, extended fibrosis, and osteopontin (OPN) overexpression. We sought to identify the molecular and cellular events regulating adverse cardiac remodelling in des(-/-) mice and their potential link to OPN. METHODS AND RESULTS: In situ hybridization, histology, and immunostaining demonstrated that inflammatory cells and not cardiomyocytes were the source of OPN. RNA profile comparison revealed that activation of inflammatory pathways, sustained by innate immunity mechanisms, predominated among all changes occurring in degenerating des(-/-) myocardium. The expression of the most highly up-regulated genes (OPN: 226*, galectin-3: 26*, osteoactivin/Gpnmb/DC-HIL: 160* and metalloprotease-12: 98*) was associated with heart infiltrating macrophages. To evaluate the role of OPN, we generated des(-/-)OPN(-/-) mice and compared their cardiac function and remodelling indices with those of des(-/-). Osteopontin promoted cardiac dysfunction in this model since des(-/-)OPN(-/-) mice showed 53% improvement of left ventricular function, paralleled to an up to 44% reduction in fibrosis. The diminished fibrotic response in the absence of OPN could be partly mediated by a dramatic reduction in myocardial galectin-3 levels, associated with an impaired galectin-3 secretion by OPN-deficient infiltrating macrophages. CONCLUSION: Cardiomyocyte death due to desmin deficiency leads to inflammation and subsequent overexpression of a series of remodelling modulators. Among them, OPN seems to be a major regulator of des(-/-) adverse myocardial remodelling and it functions at least by potentiating galectin-3 up-regulation and secretion. PMID- 21525026 TI - A half ounce of prevention ... PMID- 21525027 TI - Effects of reclassification from the TNM-6 into the TNM-7 staging system in bronchoplastic resection for non-small cell lung cancer. AB - In 2007, the International Association for the Study of Lung Cancer proposed changes to the sixth edition of the lung cancer stage classification system, which were adopted by the Union Internationale Contre le Cancer in 2009 (TNM-7). Using historic patient data, the effects of reclassification from the TNM-6 to the TNM-7 system were researched within a single institution. We retrospectively reclassified the pathological records of 145 patients who underwent bronchoplastic resection for non-small cell lung cancer between 1991 and 2004, by applying the new TNM-7 classification for lung cancer. A comparison between the previous and the new system was conducted. Out of 145 patients, 49 (33.8%) were reclassified into a new stage, 42 (85.7% of reclassified cases) being allocated to a lower and seven (14.3%) being assigned to a higher stage. Most of the patients switched from stage IIB to IIA (n=31, 63.3%). The application of the new TNM-7 staging system resulted in a more accurate stratification of five-year survival curves. The newly revised TNM classification for lung cancer appears to be superior in defining different prognostic groups for this cohort and should lead to an improvement in stage specific tumor therapy. PMID- 21525028 TI - Proteomic analysis of resectable non-small cell lung cancer: post-resection serum samples may be useful in identifying potential markers. AB - Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS) can be used to analyse peptides and proteins in clinical samples. A prospective study was undertaken on patients undergoing curative resection for non-small cell lung cancer (NSCLC): we used SELDI-TOF-MS to compare the proteomic profiles of serum from these patients both before surgical resection and after resection (disease-free) to identify potential biomarkers. Student t-tests were used, and a P-value of <0.01 was considered significant. Twenty-five patients with NSCLC [76% male, mean age 69 (range 53-81) years] were analysed. There were 13 squamous cell carcinomas, 10 adenocarcinomas and 2 large cell carcinomas with a stage distribution of four stage IA, 11 stage IB, five stage IIB, three stage IIIA, one stage IIIB and one stage IV. SELDI spectra generated with immobilised metal affinity chromatography arrays produced 170 peaks. Of these, 35 showed significant differences in their intensities between the preoperative and post resection states (P<0.01). Postoperative samples in the disease-free state may represent good controls to identify biomarkers in NSCLC, avoiding the difficulties associated with cross-sectional studies. These pilot data need to be validated with larger numbers of patients. PMID- 21525029 TI - Retropharyngeal angiomyxoma presenting with transoral intussusception. AB - We report on a 66-year-old female who presented with a massive lesion protruding from her mouth and obstructing her airway, which was found to be an angiomyxoma arising from the retropharyngeal tissue. PMID- 21525030 TI - Emergency surgical intervention after unsuccessful percutaneous transluminal angioplasty and stenting of aortic coarctation. AB - Coarctation of thoracic aorta is an uncommon diagnosis in adults. Catheter-based intervention consisting of primary ballooning and stenting is becoming one of the methods of choice for the treatment of native coarctation. We describe the case of a young adult with coarctation of the aorta treated unsuccessfully with percutaneous transluminal angioplasty and stent implantation that resulted in stent migration into the aortic arch and led to an urgent operative intervention. In one step, we performed the evacuation of the foreign body from the aortic arch as well as the treatment of the aortic coarctation through an extra-anatomical vascular graft interposition between the ascending and descending thoracic aorta. In this article, we discuss the need for emergency surgical intervention in this case. PMID- 21525031 TI - Air leaks following pulmonary resection for malignancy: risk factors, qualitative and quantitative analysis. AB - Air leaks are a common complication of pulmonary resection. The aims of this study were to analyze risk factors for postoperative air leak and to evaluate the role of air leak measurement in identifying patients at increased risk for cardiorespiratory morbidity and prolonged air leak. From March to December 2009, 142 consecutive patients underwent pulmonary resection for malignancy and were prospectively followed up. Preoperative and intraoperative risk factors for air leak were evaluated. Air leaks were qualitatively and quantitatively labeled twice daily. There were 52 (36.6%) patients who had an air leak on day 1, and 32 (22.5%) who had an air leak on day 2. Air leak was >=180 ml/min in 12 (37.5%) of these patients. Independent predictors of air leak on day 2 included type of pulmonary resection, presence of adhesions, and incomplete fissures. Cardiorespiratory morbidity was significantly higher (34.4%) in patients who experienced air leak on day 2 than in those who did not (10.9%) (P=0.002). Nine (75%) out of 12 patients with air leak >=180 ml/min on day 2 had prolonged air leak (greater than five days) (P=0.0001). PMID- 21525032 TI - Does prophylactic therapy with antioxidant vitamins have an effect on atrial fibrillation following cardiac surgery? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether prophylactic therapy with antioxidant vitamins reduces the incidence of postoperative atrial fibrillation (AF). One hundred and fifty-four papers were found using the reported search, of which five were judged to represent the best evidence to answer the question. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results were tabulated. Four of the five studies found antioxidant vitamins to significantly reduce the incidence of postoperative AF. Two of the studies show that prophylactic treatment with adjuvant vitamin C and beta-blockers is more effective than beta-blocker therapy alone. The quality of these studies was assessed using a Jadad scoring system, which identified four of the studies to be of low and one to be of high methodological quality. We conclude that although preliminary evidence suggests that prophylactic antioxidant vitamins may be effective in reducing the incidence of postoperative AF, there is a lack of high-quality data. Additional large-scale, adequately powered clinical studies are warranted before antioxidant vitamins can be considered for routine use in this setting. PMID- 21525033 TI - Phagocytosis of dying tumor cells by human peritoneal mesothelial cells. AB - Peritoneal carcinomatosis is an advanced form of metastatic disease characterized by cancer cell dissemination onto the peritoneum. It is commonly observed in ovarian and colorectal cancers and is associated with poor patient survival. Novel therapies consist of cytoreductive surgery in combination with intraperitoneal chemotherapy, aiming at tumor cell death induction. The resulting dying tumor cells are considered to be eliminated by professional as well as semi professional phagocytes. In the present study, we have identified a hitherto unknown type of 'amateur' phagocyte in this environment: human peritoneal mesothelial cells (HMCs). We demonstrate that HMCs engulf corpses of dying ovarian and colorectal cancer cells, as well as other types of apoptotic cells. Flow cytometric, confocal and electron microscopical analyses revealed that HMCs ingest dying cell fragments in a dose- and time-dependent manner and the internalized material subsequently traffics into late phagolysosomes. Regarding the mechanisms of prey cell recognition, our results show that HMCs engulf apoptotic corpses in a serum-dependent and -independent fashion and quantitative real-time PCR (qRT-PCR) analyses revealed that diverse opsonin receptor systems orchestrating dying cell clearance are expressed in HMCs at high levels. Our data strongly suggest that HMCs contribute to dying cell removal in the peritoneum, and future studies will elucidate in what manner this influences tumor cell dissemination and the antitumor immune response. PMID- 21525034 TI - Emerin inhibits Lmo7 binding to the Pax3 and MyoD promoters and expression of myoblast proliferation genes. AB - X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is caused by mutations in the inner nuclear membrane protein emerin. Previous studies have shown that emerin binds to and inhibits the activity of LIM domain only 7 (Lmo7), a transcription factor that regulates the expression of genes implicated in X-EDMD. Here, we analyzed Lmo7 function in C2C12 myoblast differentiation and its regulation by emerin. We found that Lmo7 was required for proper myoblast differentiation. Lmo7 downregulated myoblasts exhibited reduced expression of Pax3, Pax7, Myf5 and MyoD, whereas overexpression of GFP-Lmo7 increased the expression of MyoD and Myf5. Upon myotube formation, Lmo7 shuttled from the nucleus to the cytoplasm, concomitant with reduced expression of MyoD, Pax3 and Myf5. Importantly, we show that Lmo7 bound the Pax3, MyoD and Myf5 promoters both in C2C12 myoblasts and in vitro. Because emerin inhibited Lmo7 activity, we tested whether emerin competed with the MyoD promoter for binding to Lmo7 or whether emerin sequestered promoter bound Lmo7 to the nuclear periphery. Supporting the competition model, emerin binding to Lmo7 inhibited Lmo7 binding to and activation of the MyoD and Pax3 promoters. These findings support the hypothesis that the functional interaction between emerin and Lmo7 is crucial for temporally regulating the expression of key myogenic differentiation genes. PMID- 21525035 TI - PEX14 is required for microtubule-based peroxisome motility in human cells. AB - We have established a procedure for isolating native peroxisomal membrane protein complexes from cultured human cells. Protein-A-tagged peroxin 14 (PEX14), a central component of the peroxisomal protein translocation machinery was genomically expressed in Flp-In-293 cells and purified from digitonin-solubilized membranes. Size-exclusion chromatography revealed the existence of distinct multimeric PEX14 assemblies at the peroxisomal membrane. Using mass spectrometric analysis, almost all known human peroxins involved in protein import were identified as constituents of the PEX14 complexes. Unexpectedly, tubulin was discovered to be the major PEX14-associated protein, and direct binding of the proteins was demonstrated. Accordingly, peroxisomal remnants in PEX14-deficient cells have lost their ability to move along microtubules. In vivo and in vitro analyses indicate that the physical binding to tubulin is mediated by the conserved N-terminal domain of PEX14. Thus, human PEX14 is a multi-tasking protein that not only facilitates peroxisomal protein import but is also required for peroxisome motility by serving as membrane anchor for microtubules. PMID- 21525036 TI - Cdc42-interacting protein 4 is a Src substrate that regulates invadopodia and invasiveness of breast tumors by promoting MT1-MMP endocytosis. AB - Invadopodia are actin-rich membrane protrusions that promote extracellular matrix degradation and invasiveness of tumor cells. Src protein-tyrosine kinase is a potent inducer of invadopodia and tumor metastases. Cdc42-interacting protein 4 (CIP4) adaptor protein interacts with actin regulatory proteins and regulates endocytosis. Here, we show that CIP4 is a Src substrate that localizes to invadopodia in MDA-MB-231 breast tumor cells expressing activated Src (MDA SrcYF). To probe the function of CIP4 in invadopodia, we established stable CIP4 knockdown in MDA-SrcYF cell lines by RNA interference. Compared with control cells, CIP4 knockdown cells degrade more extracellular matrix (ECM), have increased numbers of mature invadopodia and are more invasive through matrigel. Similar results are observed with knockdown of CIP4 in EGF-treated MDA-MB-231 cells. This inhibitory role of CIP4 is explained by our finding that CIP4 limits surface expression of transmembrane type I matrix metalloprotease (MT1-MMP), by promoting MT1-MMP internalization. Ectopic expression of CIP4 reduces ECM digestion by MDA-SrcYF cells, and this activity is enhanced by mutation of the major Src phosphorylation site in CIP4 (Y471). Overall, our results identify CIP4 as a suppressor of Src-induced invadopodia and invasion in breast tumor cells by promoting endocytosis of MT1-MMP. PMID- 21525037 TI - The guanine nucleotide exchange factor Arhgef5 plays crucial roles in Src-induced podosome formation. AB - Podosomes and invadopodia are actin-rich membrane protrusions that play a crucial role in cell adhesion and migration, and extracellular matrix remodeling in normal and cancer cells. The formation of podosomes and invadopodia is promoted by upregulation of some oncogenic molecules and is closely related to the invasive potential of cancer cells. However, the molecular mechanisms underlying the podosome and invadopodium formation still remain unclear. Here, we show that a guanine nucleotide exchange factor (GEF) for Rho family GTPases (Arhgef5) is crucial for Src-induced podosome formation. Using an inducible system for Src activation, we found that Src-induced podosome formation depends upon the Src SH3 domain, and identified Arhgef5 as a Src SH3-binding protein. RNA interference (RNAi)-mediated depletion of Arhgef5 caused robust inhibition of Src-dependent podosome formation. Overexpression of Arhgef5 promoted actin stress fiber remodeling through activating RhoA, and the activation of RhoA or Cdc42 was required for Src-induced podosome formation. Arhgef5 was tyrosine-phosphorylated by Src and bound to Src to positively regulate its activity. Furthermore, the pleckstrin homology (PH) domain of Arhgef5 was required for podosome formation, and Arhgef5 formed a ternary complex with Src and phosphoinositide 3-kinase when Src and/or Arhgef5 were upregulated. These findings provide novel insights into the molecular mechanisms of podosome and invadopodium formation induced by Src upregulation. PMID- 21525038 TI - Formation and stability of eisosomes in the filamentous fungus Ashbya gossypii. AB - One hallmark of the rapid expansion of the polar surface of fungal hyphae is the spatial separation of regions of exocytosis and endocytosis at hyphal tips, as recently shown for Ashbya gossypii and Aspergillus nidulans. To determine where cortex-associated eisosomes form with respect to these two regions, we monitored fluorescently marked eisosomes in A. gossypii. Each minute, 1.6 +/- 0.5 eisosomes form within the first 30 MUm of each hypha and are exclusively subapical of the endocytosis region. This spatial separation of the processes of eisosome formation and endocytosis, and the much lower frequency of eisosome formation compared with that of endocytic vesicle production do not support a recently proposed role for eisosomes in endocytosis. Levels of mRNA encoding eisosome components are tenfold higher in spores than in hyphae, explaining the observed higher eisosome density at the cortex of germ bubbles. As in Saccharomyces cerevisiae, eisosomes in A. gossypii are very stable. In contrast to S. cerevisiae, however, the A. gossypii homologue of Pil1, one of the main eisosome subunits, is very important for polar growth, whereas the homologue of Nce102, which colocalizes with eisosomes, is not needed for eisosome stability. By testing partial deletions of the A. gossypii homologue of Ymr086w, another component of the eisosome, we identified a novel protein domain essential for eisosome stability. We also compare our results with recent findings about eisosomes in A. nidulans. PMID- 21525040 TI - Current status of radiological protection at nuclear power stations in Japan. AB - The radiation dose to workers at nuclear power stations (NPSs) in Japan was drastically reduced between the late-1970s and the early-1990s by continuous dose reduction programmes. The total collective dose of radiation workers in FY 2008 was 84.04 person Sv, while the average collective dose was 1.5 person Sv per reactor. The average annual individual dose was 1.1 mSv and the maximum annual individual dose was 19.5 mSv. These values are sufficiently lower than the regulatory dose limits. Radioactive effluent released from NPSs is already so trivial that additional protective measures will not be necessary. Experience in radiation protection at NPSs has been accumulated over 40 y and will be very useful in establishing a rational radiation control system in the future. PMID- 21525041 TI - Comparison of operator radiation exposure between C-arm and O-arm fluoroscopy for orthopaedic surgery. AB - The O-arm system has recently been introduced and has the capability of combined two-dimensional (2-D) fluoroscopy imaging and three-dimensional computed tomography imaging. In this study, an orthopaedic surgical procedure using C-arm and O-arm systems in their 2-D fluoroscopy modes was simulated and the radiation doses to susceptible organs to which operators can be exposed were investigated. The experiments were performed in four configurations of the location of the X ray source and detector. Shielding effects on the thyroid surface and the direct exposure delivered to the surgeon's hands were also compared. The results obtained show that the O-arm delivered higher doses to the sensitive organs of the operator in all configurations. The thyroid shield cut-off 89 % of the dose in the posteroanterior configuration of both imaging systems. Thus, the operators need to pay more attention to managing radiation exposure, especially when using the O-arm system. PMID- 21525039 TI - CCN6 (WISP3) decreases ZEB1-mediated EMT and invasion by attenuation of IGF-1 receptor signaling in breast cancer. AB - During progression of breast cancer, CCN6 protein exerts tumor inhibitory functions. CCN6 is a secreted protein that modulates the insulin-like growth factor-1 (IGF-1) signaling pathway. Knockdown of CCN6 in benign mammary epithelial cells triggers an epithelial to mesenchymal transition (EMT), with upregulation of the transcription factor ZEB1/deltaEF1. How CCN6 regulates ZEB1 expression is unknown. We hypothesized that CCN6 might regulate ZEB1, EMT and breast cancer invasion by modulating IGF-1 signaling. Exogenously added human recombinant CCN6 protein was sufficient to downregulate ZEB1 mRNA and protein levels in CCN6-deficient (CCN6 KD) HME cells and MDA-MB-231 breast cancer cells. Recombinant CCN6 protein decreased invasion of CCN6 KD cells compared with controls. We discovered that knockdown of CCN6 induced IGF-1 secretion in HME cells cultivated in serum-free medium to higher concentrations than found in MDA MB-231 cells. Treatment with recombinant CCN6 protein was sufficient to decrease IGF-1 protein and mRNA to control levels, rescuing the effect of CCN6 knockdown. Specific inhibition of IGF-1 receptors using the pharmacological inhibitor NVP AE541 or short hairpin shRNAs revealed that ZEB1 upregulation due to knockdown of CCN6 requires activation of IGF-1 receptor signaling. Recombinant CCN6 blunted IGF-1-induced ZEB1 upregulation in MDA-MB-231 cells. Our data define a pathway in which CCN6 attenuates IGF-1 signaling to decrease ZEB1 expression and invasion in breast cancer. These results suggest that CCN6 could be a target to prevent or halt breast cancer invasion. PMID- 21525042 TI - New idea of a small-sized neutron detector with a plastic fibre. AB - A small-sized thermal neutron detector based on a (6)Li-glass scintillator and a plastic optical fibre has been developed for precise measurement of the spatial distribution of thermal neutron fluence rate. This detector was tested in experiments performed using thermal neutrons. The detector is useful in a thermal neutron field. However, the gamma-ray discrimination ability of the (6)Li-glass scintillator is not good in a low-intensity thermal neutron field. A new idea using a gamma-ray suppression method is proposed to reduce the uncertainty in the neutron counts due to the gamma-ray background. A novel small-sized thermal neutron detector consists of a (6)Li-glass scintillator, a hollow CsI(Tl) scintillator and plastic optical fibres. The evaluation of the gamma-ray suppression ability of the detector using the EGS4 code indicates that the gamma ray suppression is effective. PMID- 21525043 TI - Radioecological studies in Korea atomic energy research institute, KAERI. AB - Regarding the assessment of the terrestrial food chain dose to man, radioecology may be the field that is focused on the transfer of radionuclides from environmental media to food crops. In Korea, the environmental transfer of radionuclides to staple food crops have been investigated at Korea Atomic Energy Research Institute (KAERI) for the last 25 y mainly through radiotracer experiments in greenhouses. As a result, several hundreds of parameter values for the prediction of the radionuclide transfer have been produced. Many of them appear in two recent publications of International Atomic Energy Agency. This paper outlines the KAERI's past radioecological work and introduces the ongoing research and future plans. PMID- 21525044 TI - Monte Carlo simulation of the movement and detection efficiency of a whole-body counting system using a BOMAB phantom. AB - This study reports on the computational analysis and experimental calibration of the whole-body counting detection equipment at the Nuclear and Technological Institute (ITN) in Portugal. Two state-of-the-art Monte Carlo simulation programmes were used for this purpose: PENELOPE and MCNPX. This computational work was undertaken as part of a new set of experimental calibrations, which improved the quality standards of this study's WBC system. In these calibrations, a BOMAB phantom, one of the industry standards phantoms for WBC calibrations in internal dosimetry applications, was used. Both the BOMAB phantom and the detection system were accurately implemented in the Monte Carlo codes. The whole body counter at ITN possesses a moving detector system, which poses a challenge for Monte Carlo simulations, as most codes only accept static configurations. The continuous detector movement was approximately described in the simulations by averaging several discrete positions of the detector throughout the movement. The computational efficiency values obtained with the two Monte Carlos codes have deviations of less than 3.2 %, and the obtained deviations between experimental and computational efficiencies are less than 5 %. This work contributes to demonstrate the great effectiveness of using computational tools for understanding the calibration of radiation detection systems used for in vivo monitoring. PMID- 21525045 TI - Development of nuclear emergency exercise programme (NEEP) in Korea. AB - The nuclear emergency exercise programme (NEEP) is a PC-based application intended for design and planning emergency preparedness and response (EP&R) exercises for a potential nuclear emergency in Korea. The application programme allows EP&R staff to create and edit exercise scenarios based on information customised for a specific nuclear power plant's emergency plans. NEEP includes the following features: (1) step-by-step guide to developing new exercise scenario according to emergency alarm level and potential accident type, (2) database of specific plant's field exercise scenarios that can be easily modified by users, (3) generating master scenario events list and messages of exercise participants and (4) allowing the quantitative evaluation of exercise participants from the view of exercise objectives and evaluator guides. NEEP also features tools for queries, reports and visualisation that can be used to create documentation during the scenario planning and exercise evaluation processes. PMID- 21525046 TI - Do solitary foraging nocturnal mammals plan their routes? AB - Large-brained diurnal mammals with complex social systems are known to plan where and how to reach a resource, as shown by a systematic movement pattern analysis. We examined for the first time large-scale movement patterns of a solitary ranging and small-brained mammal, the mouse lemur (Microcebus murinus), by using the change-point test and a heuristic random travel model to get insight into foraging strategies and potential route-planning abilities. Mouse lemurs are small nocturnal primates inhabiting the seasonal dry deciduous forest in Madagascar. During the lean season with limited food availability, these lemurs rely on few stationary food resources. We radio-tracked seven lemurs and analysed their foraging patterns. First change-points coincided with out-of-sight keystone food resources. Travel paths were more efficient in detecting these resources than a heuristic random travel model within limits of estimated detection distance. Findings suggest that even nocturnal, solitary-ranging mammals with small brains plan their route to an out-of-sight target. Thus, similar ecological pressures may lead to comparable spatial cognitive skills irrespective of the degree of sociality or relative brain size. PMID- 21525047 TI - Chemical kin label in seabirds. AB - Chemical signals yield critical socio-ecological information in many animals, such as species, identity, social status or sex, but have been poorly investigated in birds. Recent results showed that chemical signals are used to recognize their nest and partner by some petrel seabirds whose olfactory anatomy is well developed and which possess a life-history propitious to olfactory mediated behaviours. Here, we investigate whether blue petrels (Halobaena caerulea) produce some chemical labels potentially involved in kin recognition and inbreeding avoidance. To overcome methodological constraints of chemical analysis and field behavioural experiments, we used an indirect behavioural approach, based on mice olfactory abilities in discriminating odours. We showed that mice (i) can detect odour differences between individual petrels, (ii) perceive a high odour similarity between a chick and its parents, and (iii) perceive this similarity only before fledging but not during the nestling developmental stage. Our results confirm the existence of an individual olfactory signature in blue petrels and show for the first time, to our knowledge, that birds may exhibit an olfactory kin label, which may have strong implications for inbreeding avoidance. PMID- 21525048 TI - Female but not male dogs respond to a size constancy violation. AB - Differences between sexes in cognitive processes are widespread in humans and permeate many, if not most, cognitive domains. In animal cognition research, however, possible sex differences are still often neglected. Here, we provide striking evidence for a sex-specific response in an object permanence task in domestic dogs (Canis familiaris). Female dogs responded with significantly increased looking times to a violation of expectancy--a ball 'magically' changing size while temporarily occluded. By contrast, male dogs, irrespective of their neuter status, did not respond to the size constancy violation. These results indicate that sex differences in basic cognitive processes may extend to mammals in general, and call for increased consideration of possible sex effects when analysing and interpreting data in animal cognition. PMID- 21525049 TI - Synthesizing and databasing fossil calibrations: divergence dating and beyond. AB - Divergence dating studies, which combine temporal data from the fossil record with branch length data from molecular phylogenetic trees, represent a rapidly expanding approach to understanding the history of life. National Evolutionary Synthesis Center hosted the first Fossil Calibrations Working Group (3-6 March, 2011, Durham, NC, USA), bringing together palaeontologists, molecular evolutionists and bioinformatics experts to present perspectives from disciplines that generate, model and use fossil calibration data. Presentations and discussions focused on channels for interdisciplinary collaboration, best practices for justifying, reporting and using fossil calibrations and roadblocks to synthesis of palaeontological and molecular data. Bioinformatics solutions were proposed, with the primary objective being a new database for vetted fossil calibrations with linkages to existing resources, targeted for a 2012 launch. PMID- 21525050 TI - Local perceptions of climate change validated by scientific evidence in the Himalayas. AB - The Himalayas are assumed to be undergoing rapid climate change, with serious environmental, social and economic consequences for more than two billion people. However, data on the extent of climate change or its impact on the region are meagre. Based on local knowledge, we report perceived changes in climate and consequences of such changes for biodiversity and agriculture. Our analyses are based on 250 household interviews administered in 18 villages, and focused group discussions conducted in 10 additional villages in Darjeeling Hills, West Bengal, India and Ilam district of Nepal. There is a widespread feeling that weather is getting warmer, the water sources are drying up, the onset of summer and monsoon has advanced during last 10 years and there is less snow on mountains than before. Local perceptions of the impact of climate change on biodiversity included early budburst and flowering, new agricultural pests and weeds and appearance of mosquitoes. People at high altitudes appear more sensitive to climate change than those at low altitudes. Most local perceptions conform to scientific data. Local knowledge can be rapidly and efficiently gathered using systematic tools. Such knowledge can allow scientists to test specific hypotheses, and policy makers to design mitigation and adaptation strategies for climate change, especially in an extraordinarily important part of our world that is experiencing considerable change. PMID- 21525051 TI - Long-distance migrating species of birds travel in larger groups. AB - How individuals migrate over long distances is an enduring mystery of animal migration. Strong selection pressure for travelling in groups has been suggested in long-distance migrating species. Travelling in groups can reduce the energetic demands of long migration, increase navigational accuracy and favour group foraging at migratory halts. Nevertheless, this hypothesis has received scant attention. I examined evolutionary transitions in migration distance in all North American breeding species of birds. I documented 72 evolutionary shifts in migration distance in the pool of 409 species. In contrasting clades, long distance migration, as opposed to short-distance migration, was associated with a larger travelling group size. No other transitions occurred alongside in other traits such as group size in the non-breeding season or body mass. The results suggest that larger group sizes have been beneficial in the evolution of long distance migration in a large clade of birds. PMID- 21525052 TI - Evidence that gastropod torsion is driven by asymmetric cell proliferation activated by TGF-beta signalling. AB - Gastropods are characterized by their asymmetric bodyplan, which develops through a unique ontogenetic process called 'torsion'. Despite several intensive studies, the driving force of torsion remains to be determined. Although torsion was traditionally believed to be driven by contraction of the retractor muscle connecting the foot and the shell, some recent reports cast doubt on that idea. Here, we report that torsion is accompanied by left-right asymmetric cell proliferation in the mantle epithelium in the limpet Nipponacmea fuscoviridis. Furthermore, we found that pharmacological inhibition of the transforming growth factor-beta (TGF-beta) signalling pathway, including that of Nodal, blocked torsion. We confirmed that the blocking was brought about through failure of the activation of cell proliferation in the right-hand side of the mantle epithelium, while the retractor muscle apparently developed normally. These results suggest that limpet torsion is driven by left-right asymmetric cell proliferation in the mantle epithelium, induced by the TGF-beta pathway. PMID- 21525053 TI - Brains and the city: big-brained passerine birds succeed in urban environments. AB - Urban regions are among the most human-altered environments on Earth and they are poised for rapid expansion following population growth and migration. Identifying the biological traits that determine which species are likely to succeed in urbanized habitats is important for predicting global trends in biodiversity. We provide the first evidence for the intuitive yet untested hypothesis that relative brain size is a key factor predisposing animals to successful establishment in cities. We apply phylogenetic mixed modelling in a Bayesian framework to show that passerine species that succeed in colonizing at least one of 12 European cities are more likely to belong to big-brained lineages than species avoiding these urban areas. These data support findings linking relative brain size with the ability to persist in novel and changing environments in vertebrate populations, and have important implications for our understanding of recent trends in biodiversity. PMID- 21525054 TI - Nemo through the looking-glass: a commentary on Desjardins & Fernald. PMID- 21525055 TI - Do interactions between plant and soil biota change with elevation? A study on Fagus sylvatica. AB - Theoretical models predict weakening of negative biotic interactions and strengthening of positive interactions with increasing abiotic stress. However, most empirical tests have been restricted to plant-plant interactions. No empirical study has examined theoretical predictions of interactions between plants and below-ground micro-organisms, although soil biota strongly regulates plant community composition and dynamics. We examined variability in soil biota effects on tree regeneration across an abiotic gradient. Our candidate tree species was European beech (Fagus sylvatica L.), whose regeneration is extremely responsive to soil biota activity. In a greenhouse experiment, we measured tree survival in sterilized and non-sterilized soils collected across an elevation gradient in the French Alps. Negative effects of soil biota on tree survival decreased with elevation, similar to shifts observed in plant-plant interactions. Hence, soil biota effects must be included in theoretical models of plant biotic interactions to accurately represent and predict the effects of abiotic gradient on plant communities. PMID- 21525056 TI - Using network properties to predict disease dynamics on human contact networks. AB - Recent studies have increasingly turned to graph theory to model more realistic contact structures that characterize disease spread. Because of the computational demands of these methods, many researchers have sought to use measures of network structure to modify analytically tractable differential equation models. Several of these studies have focused on the degree distribution of the contact network as the basis for their modifications. We show that although degree distribution is sufficient to predict disease behaviour on very sparse or very dense human contact networks, for intermediate density networks we must include information on clustering and path length to accurately predict disease behaviour. Using these three metrics, we were able to explain more than 98 per cent of the variation in endemic disease levels in our stochastic simulations. PMID- 21525057 TI - The high fidelity of the cetacean stranding record: insights into measuring diversity by integrating taphonomy and macroecology. AB - Stranded cetaceans have long intrigued naturalists because their causation has escaped singular explanations. Regardless of cause, strandings also represent a sample of the living community, although their fidelity has rarely been quantified. Using commensurate stranding and sighting records compiled from archived datasets representing nearly every major ocean basin, I demonstrated that the cetacean stranding record faithfully reflects patterns of richness and relative abundance in living communities, especially for coastlines greater than 2000 km and latitudinal gradients greater than 4 degrees . Live-dead fidelity metrics from seven different countries indicated that strandings were almost always richer than live surveys; richness also increased with coastline length. Most death assemblages recorded the same ranked relative abundance as living communities, although this correlation decreased in strength and significance at coastline lengths greater than 15,000 km, highlighting the importance of sampling diversity at regional scales. Rarefaction analyses indicated that sampling greater than 10 years generally enhanced the completeness of death assemblages, although protracted temporal sampling did not substitute for sampling over longer coastlines or broader latitudes. Overall, this global live-dead comparison demonstrated that strandings almost always provided better diversity information about extant cetacean communities than live surveys; such archives are therefore relevant for macroecological and palaeobiological studies of cetacean community change through time. PMID- 21525058 TI - Explaining rapid reinfections in multiple-wave influenza outbreaks: Tristan da Cunha 1971 epidemic as a case study. AB - Influenza usually spreads through the human population in multiple-wave outbreaks. Successive reinfection of individuals over a short time interval has been explicitly reported during past pandemics. However, the causes of rapid reinfection and the role of reinfection in driving multiple-wave outbreaks remain poorly understood. To investigate these issues, we focus on a two-wave influenza A/H3N2 epidemic that occurred on the remote island of Tristan da Cunha in 1971. Over 59 days, 273 (96%) of 284 islanders experienced at least one attack and 92 (32%) experienced two attacks. We formulate six mathematical models invoking a variety of antigenic and immunological reinfection mechanisms. Using a maximum likelihood analysis to confront model predictions with the reported incidence time series, we demonstrate that only two mechanisms can be retained: some hosts with either a delayed or deficient humoral immune response to the primary influenza infection were reinfected by the same strain, thus initiating the second epidemic wave. Both mechanisms are supported by previous empirical studies and may arise from a combination of genetic and ecological causes. We advocate that a better understanding and account of heterogeneity in the human immune response are essential to analysis of multiple-wave influenza outbreaks and pandemic planning. PMID- 21525059 TI - Vision, touch and object manipulation in Senegal parrots Poicephalus senegalus. AB - Parrots are exceptional among birds for their high levels of exploratory behaviour and manipulatory abilities. It has been argued that foraging method is the prime determinant of a bird's visual field configuration. However, here we argue that the topography of visual fields in parrots is related to their playful dexterity, unique anatomy and particularly the tactile information that is gained through their bill tip organ during object manipulation. We measured the visual fields of Senegal parrots Poicephalus senegalus using the ophthalmoscopic reflex technique and also report some preliminary observations on the bill tip organ in this species. We found that the visual fields of Senegal parrots are unlike those described hitherto in any other bird species, with both a relatively broad frontal binocular field and a near comprehensive field of view around the head. The behavioural implications are discussed and we consider how extractive foraging and object exploration, mediated in part by tactile cues from the bill, has led to the absence of visual coverage of the region below the bill in favour of more comprehensive visual coverage above the head. PMID- 21525060 TI - The Hadropithecus conundrum reconsidered, with implications for interpreting diet in fossil hominins. AB - The fossil 'monkey lemur' Hadropithecus stenognathus has long excited palaeontologists because its skull bears an astonishing resemblance to those of robust australopiths, an enigmatic side branch of the human family tree. Multiple lines of evidence point to the likelihood that these australopiths ate at least some 'hard', stress-limited food items, but conflicting data from H. stenognathus pose a conundrum. While its hominin-like craniofacial architecture is suggestive of an ability to generate high bite forces, details of its tooth structure suggest that it was not well equipped to withstand the forces imposed by cracking hard objects. Here, we use three-dimensional digital reconstructions and finite element analysis to test the hard-object processing hypothesis. We show that Archaeolemur sp. cf. A. edwardsi, a longer-faced close relative of H. stenognathus that lacked hominin convergences, was probably capable of breaking apart large, stress-limited food items, while Hadropithecus was better suited to processing small, displacement-limited (tougher but more compliant) foods. Our suggestion that H. stenognathus was not a hard-object feeder has bearing on the interpretation of hominin cranial architecture; the features shared by H. stenognathus and robust australopiths do not necessarily reflect adaptations for hard-object processing. PMID- 21525061 TI - A new Early Permian reptile and its significance in early diapsid evolution. AB - The initial stages of evolution of Diapsida (the large clade that includes not only snakes, lizards, crocodiles and birds, but also dinosaurs and numerous other extinct taxa) is clouded by an exceedingly poor Palaeozoic fossil record. Previous studies had indicated a 38 Myr gap between the first appearance of the oldest diapsid clade (Araeoscelidia), ca 304 million years ago (Ma), and that of its sister group in the Middle Permian (ca 266 Ma). Two new reptile skulls from the Richards Spur locality, Lower Permian of Oklahoma, represent a new diapsid reptile: Orovenator mayorum n. gen. et sp. A phylogenetic analysis identifies O. mayorum as the oldest and most basal member of the araeoscelidian sister group. As Richards Spur has recently been dated to 289 Ma, the new diapsid neatly spans the above gap by appearing 15 Myr after the origin of Diapsida. The presence of O. mayorum at Richards Spur, which records a diverse upland fauna, suggests that initial stages in the evolution of non-araeoscelidian diapsids may have been tied to upland environments. This hypothesis is consonant with the overall scant record for non-araeoscelidian diapsids during the Permian Period, when the well known terrestrial vertebrate communities are preserved almost exclusively in lowland deltaic, flood plain and lacustrine sedimentary rocks. PMID- 21525062 TI - Special issue on structural genomic alterations: ready for prime time. PMID- 21525064 TI - Limited value of annual tuberculosis symptom reminders for health care workers. AB - BACKGROUND: (UK) National Institute for Health and Clinical Excellence tuberculosis (TB) guidance (2006) recommends that occupational health services send annual TB symptom reminders to staff at increased risk of occupational TB exposure. AIMS: To evaluate the effectiveness of annual TB symptom reminders. METHODS: Retrospective analysis of returns from 4 years' annual TB symptom reminders compared with numbers of hospital staff diagnosed with active TB in the same time period. RESULTS: There were 405 responses to symptom reminders received during the period studied that represented a response rate of 16%. None of the respondents declared TB symptoms. Twelve staff were diagnosed with active TB over the same period. From their work location, only two of these would have received TB symptom reminders according to local TB policy. CONCLUSIONS: Annual TB symptom reminders as currently used result in little direct benefit. PMID- 21525066 TI - Managing Black when in the red, challenges for general practice. PMID- 21525067 TI - La maladie de porcelaine. PMID- 21525063 TI - Genomic alterations that contribute to the development of isolated and non isolated congenital diaphragmatic hernia. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is a life threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified. OBJECTIVE: To identify genomic alterations that contribute to the development of diaphragmatic defects. METHODS: A cohort of 45 unrelated patients with CDH or diaphragmatic eventrations was screened for genomic alterations by array comparative genomic hybridisation or single nucleotide polymorphism based copy number analysis. RESULTS: Genomic alterations that were likely to have contributed to the development of CDH were identified in 8 patients. Inherited deletions of ZFPM2 were identified in 2 patients with isolated diaphragmatic defects and a large de novo 8q deletion overlapping the same gene was found in a patient with non-isolated CDH. A de novo microdeletion of chromosome 1q41q42 and two de novo microdeletions on chromosome 16p11.2 were identified in patients with non-isolated CDH. Duplications of distal 11q and proximal 13q were found in a patient with non-isolated CDH and a de novo single gene deletion of FZD2 was identified in a patient with a partial pentalogy of Cantrell phenotype. CONCLUSIONS: Haploinsufficiency of ZFPM2 can cause dominantly inherited isolated diaphragmatic defects with incomplete penetrance. These data define a new minimal deleted region for CDH on 1q41q42, provide evidence for the existence of CDH related genes on chromosomes 16p11.2, 11q23-24 and 13q12, and suggest a possible role for FZD2 and Wnt signalling in pentalogy of Cantrell phenotypes. These results demonstrate the clinical utility of screening for genomic alterations in individuals with both isolated and non-isolated diaphragmatic defects. PMID- 21525068 TI - Why I became an occupational physician ... PMID- 21525069 TI - The RailCorp Lantern test. AB - BACKGROUND: The RailCorp Lantern (RL) is a simulation of light emitting diode railway signals developed as a practical and consistent test for colour vision deficient workers. AIMS: To analyse errors made on the RL and correlate with diagnosis and results on other colour vision tests. METHODS: Retrospective audit of RL tests conducted between February 2006 and December 2008 and comparison between results on the RL conducted at 3 and 6 m, the Standard Farnsworth-Munsell D15 (D15) and the Farnsworth Lantern (FL). RESULTS: Two-hundred and seven tests were available for analysis. There were significant differences between pass rates by test with 57% passing the D15, 14% the FL and 26% for the RL at 6 m (RL6) and 47% for the RL at 3 m (RL3) (P < 0.001). Both deutans and protans had most difficulty identifying the white light of the FL followed by the yellow of the RL. Seventy-nine percent of protans made red omissions at 6 m compared with 33% of deutans (P < 0.01), and 23% of protans made red omissions at 3 m compared with 3% of deutans (P < 0.001). CONCLUSIONS: The RL identifies individuals who can safely read railway signals and who would have been excluded from working had the FL been the sole test. It is proposed that the RL be considered for use by other rail operators. PMID- 21525070 TI - Differentiating occupational asthmatics from non-occupational asthmatics and irritant-exposed workers. AB - BACKGROUND: Serial peak expiratory flow (PEF) records have been recommended as a first-line investigation in workers suspected as having occupational asthma (OA). AIMS: To determine which PEF variability index best differentiates workers with OA from non-occupational asthmatics and unaffected irritant-exposed workers. METHODS: PEF was measured at least four times daily for at least 3 weeks in three groups of subjects: (i) forty healthy grain-exposed farmers and dockers, (ii) forty-two consecutive workers with independently confirmed OA and (iii) forty eight non-occupational asthmatics. Indices of PEF variability were compared between groups. RESULTS: The difference in mean PEF between rest and work periods best separated the occupational asthmatic workers from the others. The upper 95% confidence limit of this index for grain-exposed workers was 2.8% of predicted PEF (16 l/min) and 3.3% (15 l/min) for non-occupational asthmatics. Sensitivity for diagnosing OA using this index was 70%. An increase in diurnal variation on workdays of >7% had a sensitivity of only 27% for the diagnosis of OA. The difference between maximum PEF on workdays and minimum PEF on rest days had a sensitivity of <10% against non-occupational asthmatic controls. CONCLUSIONS: Difference in mean PEF between workdays and rest days is the best simple index for differentiating subjects with OA from those with non-OA or irritant-exposed healthy subjects. Differences >16 l/min are unlikely to be due to significant irritant exposure in healthy workers. PMID- 21525071 TI - Environmental discomfort and musculoskeletal disorders. AB - BACKGROUND: Musculoskeletal disorders (MSDs) are the most common occupational disease in Europe, with high prevalence among hospital workers. Both environmental and psychosocial work factors may impact significantly on the development and exacerbation of MSDs. AIMS: To evaluate whether environmental factors at work are associated with MSDs in hospital workers and to investigate potential interactions between environmental and psychosocial risk factors in the workplace that are associated with MSDs. METHODS: A cross-sectional investigation was performed using the Nordic questionnaire to assess MSDs, the IAQ/MM-040 indoor air questionnaire for environmental factors, the demand-control model for job strain and the Goldberg questionnaire for anxiety and depression. The association between environmental factors and MSDs was studied using logistic regression analysis. In addition, the interactions of environmental factors with strain, anxiety and depression for MSDs were examined. RESULTS: Environmental complaints were associated with MSDs. The strongest associations were found between temperature complaints (OR 2.73), noise and light complaints (OR 2.22), other environmental complaints (OR 3.12) and upper limb disorders. A significant interaction between temperature complaints and strain for upper limb disorders (F = 9.52, P < 0.05) was found. CONCLUSIONS: To prevent MSDs, a multi-level approach is needed, including environmental measures and interventions directed to both psychosocial and organizational factors. PMID- 21525072 TI - Occupational health referrals for advice on cancer-related sickness absence. AB - BACKGROUND: Work-related difficulties experienced by employees diagnosed with cancer are widely reported. However, there is limited reliable quantitative evidence that employers treat employees with such diagnoses differently from staff with other chronic disorders. AIMS: To assess delays to management referral for occupational health advice for employees on long-term sickness absence attributable to cancer, compared with other common causes of long-term health related absence. METHODS: An audit of management delays to occupational health referral for all employees with a cancer diagnosis who subsequently applied for ill-health early retirement in a large UK public sector employer. Similar data were collected for two control groups, with musculoskeletal or psychological complaints, matched by age, sex, job title and pension scheme membership. Data were collected for the period 2004-07. RESULTS: Twenty-three cases were identified. Referral to the occupational health services for cases with a cancer diagnosis was delayed on average by 187 days compared with cases with a psychological or musculoskeletal diagnosis (P < 0.001). CONCLUSIONS: There is evidence that employers differ in their referral practices for employees with a cancer diagnosis, compared with those with other common disorders leading to long term absence. This may represent a loss of opportunity for effective vocational rehabilitation or timely support for access to health-related benefits. PMID- 21525073 TI - Impacts on work performance; what matters 6 months on? AB - BACKGROUND: Presenteeism often precedes and follows a period of work absence. Cross-sectional analysis of a workforce survey highlighted health, psychosocial and work characteristics as being particularly important in understanding current work performance, but it is unclear whether these variables predict future work performance. AIMS: To establish whether self-reported health, perceptions of work and objective characteristics of work measured at baseline can predict performance at 6 months follow-up. METHODS: Self-completed questionnaires to assess health, objective characteristics of work and perceptions of work were completed at two public sector organizations. Follow-up questionnaires were completed at 6 months to assess workplace performance using a visual analogue scale for self-rated performance and the Stanford Presenteeism Scale 6 (SPS6). RESULTS: Five hundred and five employees completed questionnaires at baseline and 310 (61%) of these completed follow-up questionnaires. Psychological distress as measured with the General Health Questionnaire and perceptions of work predicted both self-rated performance and SPS6 score. Objective characteristics of work were relatively unimportant in the prediction of future performance. CONCLUSIONS: This study has provided an initial indication of the factors that may predict performance at follow-up in the population studied. These findings may be used to generate hypotheses for future studies and highlights the need to assess a range of factors in relation to an individual's performance at work including health and perceptions of work. PMID- 21525074 TI - Depression and work performance: an ecological study using web-based screening. AB - BACKGROUND: Depression is reported to be a major cause of illness-related sub optimal work performance (presenteeism). However, the majority of studies examining presenteeism have relied on self-report measures of work performance. Furthermore, employers currently face a number of practical challenges in attempting to facilitate early identification of depression. AIMS: To test whether a web-based screening tool for depression could be used successfully in the workplace and whether it was possible to detect an association between rates of depression and objective measures of impaired workgroup performance. METHODS: All permanent employees of a telecommunications company with UK-based call centres were encouraged to complete a web-based psychological assessment using the Patient Health Questionnaire depression scale (PHQ-9). In addition to confidential individual level results, the tool was able to provide anonymized summary statistics for each workgroup. Four objective measures of work performance were collected for each workgroup. RESULTS: During the study period, 1161 web-based PHQ-9 questionnaires were completed. There was a negative linear relationship between rates of depressive symptoms and the overall performance of a workgroup (P < 0.001). The linear relationship between depression and workgroup performance remained after controlling for gender balance, percent of temporary staff, employees' perceived level of engagement and satisfaction with their line manager (P < 0.01). CONCLUSIONS: Workgroups with high levels of depressive symptoms tend to perform poorly. Computer-aided web-based screening for symptoms of depression is feasible in a work setting. PMID- 21525075 TI - Actin-Capping Protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila. AB - The conserved Hippo tumor suppressor pathway is a key kinase cascade that controls tissue growth by regulating the nuclear import and activity of the transcription co-activator Yorkie. Here, we report that the actin-Capping Protein alphabeta heterodimer, which regulates actin polymerization, also functions to suppress inappropriate tissue growth by inhibiting Yorkie activity. Loss of Capping Protein activity results in abnormal accumulation of apical F-actin, reduced Hippo pathway activity and the ectopic expression of several Yorkie target genes that promote cell survival and proliferation. Reduction of two other actin-regulatory proteins, Cofilin and the cyclase-associated protein Capulet, cause abnormal F-actin accumulation, but only the loss of Capulet, like that of Capping Protein, induces ectopic Yorkie activity. Interestingly, F-actin also accumulates abnormally when Hippo pathway activity is reduced or abolished, independently of Yorkie activity, whereas overexpression of the Hippo pathway component expanded can partially reverse the abnormal accumulation of F-actin in cells depleted for Capping Protein. Taken together, these findings indicate a novel interplay between Hippo pathway activity and actin filament dynamics that is essential for normal growth control. PMID- 21525078 TI - Epidemiology of bowling-related injuries presenting to US emergency departments, 1990-2008. AB - Objective. To examine bowling-related injuries presenting to US emergency departments (EDs) from 1990 to 2008. Methods. Bowling-related injury data were analyzed from the US Consumer Product Safety Commission's National Electronic Injury Surveillance System. Results. From 1990 to 2008, 8754 bowling injuries presented to US EDs, correlating to an estimated 375 468 injuries nationwide. Common body parts injured were the finger (19.0%), trunk (15.8%), and ankle/foot/toe (14.9%). Common diagnoses were sprain/strain (42.7%) and soft tissue injury (20.3%). Children <7 years old had a higher proportion of finger injuries (49.2%) and injuries from dropping the ball (42.8%) than individuals >=7 years old (15.9%, injury proportion ratio [IPR] = 3.09, 95% confidence interval [CI] = 2.76-3.45, P < .001; and 15.9%, IPR = 2.69, 95% CI = 2.32-3.12, P < .001, respectively). Seniors >=65 years old sustained a greater proportion of injuries related to falling/slipping/tripping (72.4%) than individuals <65 years old (38.3%; IPR = 1.89, 95% CI = 1.74-2.05, P < .001). Conclusions. Bowling injuries vary by age and gender. Further research on such differences is needed to drive the development of targeted, evidence-based injury prevention strategies. PMID- 21525077 TI - Risk factors and clinical presentation of hepatitis C virus infection in Nigerians with chronic liver disease. AB - Chronic liver disease is becoming a major public health problem in Nigeria and hepatitis C virus is becoming a significant causative factor in its aetiology worldwide and in Nigeria. We determined the risk factors and clinical presentation of hepatitis C virus infection in Nigerians with chronic liver disease. A structured interviewer-administered questionnaire was administered in order to determine the risk factors for hepatitis C virus infection and a physical examination was carried out in order to determine the clinical presentation. Ninety patients with clinical, biochemical and sonographic evidence of chronic liver disease and 85 controls without liver disease were studied. Anti HCV antibodies were detected in 14.4% and 2.4% of patients and controls, respectively (P < 0.05). The main risk factors were scarification, traditional surgery and blood transfusion. Ascites, jaundice, pedal swelling, abdominal distension, hepatomegaly, abdominal pain and splenomegaly were the main presentations. PMID- 21525076 TI - The DEAD-box RNA helicase Vasa functions in embryonic mitotic progression in the sea urchin. AB - Vasa is a broadly conserved ATP-dependent RNA helicase that functions in the germ line of organisms from cnidarians to mammals. Curiously, Vasa is also present in the somatic cells of many animals and functions as a regulator of multipotent cells. Here, we report a mitotic function of Vasa revealed in the sea urchin embryo. We found that Vasa protein is present in all blastomeres of the early embryo and that its abundance oscillates with the cell cycle. Vasa associates with the spindle and the separating sister chromatids at metaphase, and then quickly disappears after telophase. Inhibition of Vasa protein synthesis interferes with proper chromosome segregation, arrests cells at M-phase, and delays overall cell cycle progression. Cdk activity is necessary for the proper localization of Vasa, implying that Vasa is involved in the cyclin-dependent cell cycle network, and Vasa is required for the efficient translation of cyclinB mRNA. Our results suggest an evolutionarily conserved role of Vasa that is independent of its function in germ line determination. PMID- 21525080 TI - The referral pattern and evaluation of children prior to the diagnosis of pauciarticular juvenile rheumatoid arthritis. PMID- 21525079 TI - Diagnostic yield of genetic testing in children diagnosed with autism spectrum disorders at a regional referral center. AB - The aim was to systematically review genetic testing guidelines in the evaluation of children with autism spectrum disorders (ASDs). The Clinical Report published by the American Academy of Pediatrics (AAP)(1) recommended individualizing the workup, including karyotype and specific DNA testing for fragile X syndrome. A recent publication reported higher rates of abnormalities on CGH microarray (CMA) testing on children with ASD.(2) The medical records of 507 children seen through the Kirch Developmental Services Center were abstracted for genetic testing and factors associated with this testing. Abnormalities were found on karyotype in 2.3% and in DNA for fragile X in 0.04%. The author concludes that the diagnostic yield of the genetic testing was low in this population. Furthermore, their findings support the theory that CMA can be considered as part of the initial genetic screening in children with ASD in most situations. Future studies will need to be done prospectively to evaluate children in a standard fashion. PMID- 21525082 TI - Girl with a cat eye. PMID- 21525081 TI - beta-blockers for infantile hemangiomas: a single-institution experience. AB - Propranolol has become first-line therapy for the treatment of infantile hemangiomas in many centers. Of 302 children with hemangiomas seen at the University of North Carolina from 2008 through 2010, 15.6% were treated with oral propranolol alone, 5.6% with topical timolol (a propranolol derivative) alone, and 2.3% with both. The use of these agents increased over time from 7% of patients seen in 2008 to 54% of patients first seen in 2010. Starting doses of propranolol ranged from 0.25 to 1 mg/kg/d, with target doses of 1 to 4 mg/kg/d. Serious side effects, noted in 6/54 (10.9%) patients, included somnolence, bradycardia, hypotension, hypoglycemia, and mottling of extremities.The authors confirm the variation in use of propranolol for vascular lesions and extend experience with timolol. They suggest daily home monitoring of patients for the first 2 weeks of initiating or increasing doses. Frequent feeding of infants and young children on this drug is recommended. PMID- 21525083 TI - Prevention and treatment of childhood obesity: care received by a state medicaid population. AB - Based on chart review for a representative cluster sample of North Carolina Medicaid enrollees aged 3 to 5 years (n = 1951) and 13 to 16 years (n = 1922) years, this study describes prevalence, practice patterns, and comorbidities related to overweight/obese immediately prior to 2007 Expert Recommendations. In total, 16% of children in both age groups were overweight, and 20% (ages 3-5 years) and 25% (ages 13-16 years) were obese. For 3- to 5-year-olds, body mass index percentile was infrequently recorded (22%) or plotted on growth charts (24%), and weight status category was rarely documented (10%). Results were similar for adolescents (21%, 20%, and 12%, respectively). In both groups, documentation of counseling in nutrition or physical activity was rare (16% for ages 3-5 years; 7% for ages 13-16 years). In adolescents, approximately 20% received recommended laboratory screening and overweight/ obesity was significantly associated with chart-documented asthma, back pain, prediabetes, gastroesophageal reflux disease, hypertension, and sleep apnea. Whether improvements in documentation of care followed these new guidelines deserves further research. PMID- 21525084 TI - Presentations and treatment of childhood scleroderma: localized scleroderma, eosinophilic fasciitis, systemic sclerosis, and graft-versus-host disease. AB - Juvenile scleroderma is a rare connective tissue disease that involves the skin and subcutaneous tissue. Among all presentations of juvenile scleroderma, localized scleroderma (JLSc) is the most frequent, followed by systemic disease (JSSc) and eosinophilic fasciitis (EF). In posttransplantation chronic graft versus-host disease (GvHD), scleroderma-like skin involvement can occur. Systemic forms of juvenile scleroderma and GvHD can affect the internal organs, such as the lungs, the gastrointestinal tract, the heart, and kidneys and cause disability and severe, sometimes lethal, complications. Here, the authors give an overview of different presentations of juvenile scleroderma. They report their experience with the different forms and presentations of scleroderma, diagnostic workups, treatment, and outcome of all forms of childhood scleroderma in the context of the existing literature. PMID- 21525085 TI - Communication practices for pediatric immunization information: physician perceptions of parent health literacy skills. PMID- 21525086 TI - A premature neonate with leukocytosis. PMID- 21525087 TI - A case of pyomyositis due to Escherichia coli in a 14-year-old with aplastic anemia. PMID- 21525088 TI - Interprofessional team training in pediatric resuscitation: a low-cost, in situ simulation program that enhances self-efficacy among participants. AB - INTRODUCTION: Simulation-based interprofessional team training is important to ensure high-quality, safe patient care, but several barriers exist, including diverging learning needs and schedules as well as limited available resources. METHODS: The authors developed an in situ, simulation-based interprofessional team training program around pediatric emergencies for physicians, nurses, respiratory therapists, and pharmacists at their institution and performed an analysis of the program's impact on self-efficacy in resuscitation skills among pediatric residents and nurses. RESULTS: The results showed that with a design based in best principles of team training and simulation education, interprofessional team training is feasible and sustainable. The program had a beneficial effect on self-efficacy in resuscitation skills among both residents and nurses at the authors' institution and received widespread acceptance. CONCLUSIONS: A collaborative approach to design and implementation of interprofessional team training can lead to a sustainable program that serves both patient safety and training requirements set forth by professional organizations. PMID- 21525089 TI - Epidemiology and profile of pediatric burns in a large referral center. AB - BACKGROUND: Burns are a preventable cause of pediatric injury with over 100 000 annual hospitalizations. The authors hypothesize that analysis of injury patterns can generate age-specific and injury-specific prevention strategies to reduce these injuries. METHODS: Data from the burn registry were collected over a 9-year period. Cross-tabulations were employed to examine associations. An analysis of variance model was used to examine differences in injury pattern. RESULTS: Burns in children less than 1 year accounted for 16% of all admissions. The most common mechanism of injury was scalds (48.4%). Electrical and chemical burns occurred more often in older children. Suspected abuse (N = 142) accounted for 6.7% of all admissions. House fire injuries (N = 94) had a higher mean total burn surface area (18.2%). Smoke detectors were present in two thirds of the cases. CONCLUSIONS: These predictors can form the basis for targeted public health initiatives with a potential reduction in the number of burn injuries. PMID- 21525090 TI - Obesity prevention, screening, and treatment: practices of pediatric providers since the 2007 expert committee recommendations. AB - This study surveyed pediatric primary care providers at a major academic center regarding their attitudes and practices of obesity screening, prevention, and treatment. The authors compared the care providers' reported practices to the 2007 American Medical Association and Centers for Disease Control and Prevention Expert Committee Recommendations to evaluate their adherence to the guidelines and differences based on level of training and specialty. Of 96 providers surveyed, less than half used the currently recommended criteria for identifying children who are overweight (24.7%) and obese (34.4%), with attendings more likely to use the correct criteria than residents (P < .05). Although most providers felt comfortable counseling patients and families about the prevention of overweight and obesity, the majority felt their counseling was not effective. There was considerable variability in reported practices of lab screening and referral patterns of overweight and obese children. More efforts are needed to standardize providers' approach to overweight and obese children. PMID- 21525091 TI - A rare cause of recurrent spontaneous pneumothorax. PMID- 21525093 TI - The lawyer's brief on ethics. PMID- 21525094 TI - Diagnosis and treatment of lung cancer: summary of updated NICE guidance. PMID- 21525095 TI - Metastatic spinal cord compression. PMID- 21525096 TI - We need leaders, not leadership fads. PMID- 21525100 TI - US doctors were complicit in Guantanamo Bay torture, report says. PMID- 21525101 TI - An unusual cause of stroke and hypoxia. PMID- 21525103 TI - Women with symptoms of ovarian cancer should have a CA125 test, says NICE. PMID- 21525105 TI - Detection of unruptured cerebral artery aneurysms by MRA at 3.0 tesla: comparison with multislice helical computed tomographic angiography. AB - BACKGROUND: Computed tomographic angiography (CTA) has become the primary non invasive method for detection of cerebral artery aneurysms in many neurovascular centers. PURPOSE: To compare MR-angiography at a 3.0 tesla (3T) scanner to CTA in the detection of unruptured intracranial aneurysms. MATERIAL AND METHODS: CTA and 3T MRA data from 60 patients were evaluated. CTA was obtained with a 4-16-row helical CT-scanner after administration of 120 cc intravenous contrast agent, MRA was performed by a 3T MR-scanner using time-of-flight pulse sequence. RESULTS: Fifty-five cerebral artery aneurysms were detected by MRA and 47 aneurysms by CTA. Most of the aneurysms detected by MRA but not by CTA were small internal carotid artery (ICA) aneurysms. Bone structures and venous enhancement deteriorated CTA accuracy, especially in skull base. In one patient a fairly large anterior communicating artery aneurysm was not visible in MRA due to spin saturation, although it was clearly visualized in CTA. After contrast injection the aneurysm was also seen in MRA. Although the overall image quality of MRA and CTA were comparable, MRA was more susceptible to artifacts and thus re-formatted surface-shaded volume rendered 3-dimensional images of aneurysms from MRA were inferior compared to those from CTA. CONCLUSION: MRA at 3T appears to be at least as sensitive as CTA in the detection of unruptured cerebral artery aneurysms, however image quality control is crucial and contrast agent enhances visualization of complex and large aneurysms. PMID- 21525106 TI - Influence of adenosine on ventricular function measurements as part of a comprehensive stress perfusion magnetic resonance imaging study. AB - BACKGROUND: Stress-rest perfusion magnetic resonance imaging (MRI) has become one of the major indications for cardiovascular MRI. Standard multibreath hold short axis image acquisition is the gold standard for LV function assessment and part of a comprehensive stress-rest perfusion MRI study, but takes up to 10 min. The total scan time could significantly be shortened when cine imaging would be performed between stress and rest perfusion. PURPOSE: To systematically study whether adenosine, albeit its short half-life time, influences LV function measurements in this setting. MATERIAL AND METHODS: Thirty-nine patients with suspected and/or known coronary artery disease underwent 3-Tesla adenosine (140 ug/min/kg) stress-rest perfusion MRI. A stack of short-axis slices covering the entire ventricles was acquired before and >=3 min after adenosine infusion using standard multibreath-hold 2D steady-state free precession imaging. LV volumes (EDV, ESV), EF, and mass were calculated by the slice summation method, and wall motion was assessed using a 4-point scoring scale. Reproducibility was assessed by Bland-Altman statistics. RESULTS: EDV, ESV, EF, and mass were not significantly different between the two imaging time points (before versus after adenosine administration) in all patients (P >= 0.346) and patients with impaired LV function (P >= 0.718). Wall motion scores did not differ either (P >= 0.124). Inter-observer variability before (P >= 0.468) and after (P >= 0.451) adenosine infusion was low. CONCLUSION: Short-axis cine imaging for LV function assessment can accurately be performed between stress and rest imaging. These data demonstrate that potential effects of adenosine on LV function are of short duration, and propose a new time-saving imaging protocol without compromising accuracy. PMID- 21525107 TI - Percutaneous radiofrequency ablation of renal cell carcinomas in patients with von Hippel Lindau disease previously undergoing a radical nephrectomy or repeated nephron-sparing surgery. AB - BACKGROUND: Radiofrequency ablation (RFA) is accepted as a minimally invasive treatment of renal cell carcinoma (RCC). However, RFA is not fully evaluated for treating RCC in patients with von Hippel Lindau (VHL) disease who cannot undergo surgery due to serious postoperative morbidity or mortality. PURPOSE: To evaluate the role of RFA of RCC in patients with VHL disease previously undergoing renal surgery. MATERIAL AND METHODS: Percutaneous RFA was performed for treating 14 RCCs in six patients who had undergone radical nephrectomy (n = 3) or repeated nephron-sparing surgery (n = 3). Treatment feasibility, complications, outcome, and the change of renal function were evaluated. RESULTS: To completely ablate 14 RCCs, 23 ablations during 12 sessions were necessary. Of 14 RCCs, nine were in proximity (<5 mm) to one or more following organs: bowel (n = 4), ureteropelvic junction or pelvis (n = 2), psoas muscle (n = 2), vascular pedicle (n = 1), and pancreas (n = 1). Of 12 sessions, one major complication (pneumothorax) developed in one session (8%). No residual or recurrent tumors were identified at the ablation areas. However, new three solid tumors less than 1 cm in diameter developed during the follow-up period but ablation was withheld until these tumors had grown to more than 1 cm in size. The mean level of serum creatinine increased with 6.4% and the mean estimated glomerular filtration rate decreased by 12.8% after the last ablation compared to those before the initial ablation (P < 0.05). CONCLUSION: Despite technical difficulties, percutaneous RFA is a promising treatment for VHL patients who cannot undergo surgery because of excellent treatment outcome and minimal change of renal function. PMID- 21525108 TI - Focal time-to-peak changes on perfusion MRI in children with Moyamoya disease: correlation with conventional angiography. AB - BACKGROUND: Moyamoya disease is a chronic progressive steno-occlusion of the distal internal carotid arteries with unknown etiology. As the classical presentation of childhood Moyamoya disease is ischemic stroke, cerebral hemodynamic evaluation is important for patient selection for surgery to prevent recurrent ischemic attacks. Perfusion MR imaging has been applied to evaluate cerebral hemodynamics. PURPOSE: To correlate the 'basal time-to-peak preservation sign', 'auto-synangiosis sign', and 'posterior involvement sign' on time-to-peak map of perfusion MRI with catheter angiography. MATERIAL AND METHODS: Thirty-four children (6.91 +/- 3.08 years) with Moyamoya disease who underwent both perfusion weighted MRI and catheter angiography were enrolled in this study. Given catheter angiography as a reference standard, basal time-to-peak preservation sign, auto synangiosis sign, and posterior involvement sign were evaluated on time-to-peak maps. RESULTS: The basal time-to-peak preservation sign was accurate for the diagnosis of childhood Moyamoya disease; both sensitivity and specificity were 100%. The auto-synangiosis sign showed lower sensitivity (65%), however, with an acceptable specificity (98%). The posterior involvement sign showed lower sensitivity (61%) but had an acceptable specificity (96%). CONCLUSION: The basal time-to-peak preservation sign may be a universal finding in childhood Moyamoya disease. The auto-synangiosis and posterior involvement sign may be useful in determining transdural collateral status and posterior circulation involvement in childhood Moyamoya disease. PMID- 21525109 TI - Estimation of organ-absorbed radiation doses during 64-detector CT coronary angiography using different acquisition techniques and heart rates: a phantom study. AB - BACKGROUND: Though appropriate image acquisition parameters allow an effective dose below 1 mSv for CT coronary angiography (CTCA) performed with the latest dual-source CT scanners, a single-source 64-detector CT procedure results in a significant radiation dose due to its technical limitations. Therefore, estimating the radiation doses absorbed by an organ during 64-detector CTCA is important. PURPOSE: To estimate the radiation doses absorbed by organs located in the chest region during 64-detector CTCA using different acquisition techniques and heart rates. MATERIAL AND METHODS: Absorbed doses for breast, heart, lung, red bone marrow, thymus, and skin were evaluated using an anthropomorphic phantom and radiophotoluminescence glass dosimeters (RPLDs). Electrocardiogram (ECG) gated helical and ECG-triggered non-helical acquisitions were performed by applying a simulated heart rate of 60 beats per minute (bpm) and ECG-gated helical acquisitions using ECG modulation (ECGM) of the tube current were performed by applying simulated heart rates of 40, 60, and 90 bpm after placing RPLDs on the anatomic location of each organ. The absorbed dose for each organ was calculated by multiplying the calibrated mean dose values of RPLDs with the mass energy coefficient ratio. RESULTS: For all acquisitions, the highest absorbed dose was observed for the heart. When the helical and non-helical acquisitions were performed by applying a simulated heart rate of 60 bpm, the absorbed doses for heart were 215.5, 202.2, and 66.8 mGy for helical, helical with ECGM, and non-helical acquisitions, respectively. When the helical acquisitions using ECGM were performed by applying simulated heart rates of 40, 60, and 90 bpm, the absorbed doses for heart were 178.6, 139.1, and 159.3 mGy, respectively. CONCLUSION: ECG-triggered non-helical acquisition is recommended to reduce the radiation dose. Also, controlling the patients' heart rate appropriately during ECG-gated helical acquisition with ECGM is crucial. PMID- 21525110 TI - Thrombosis and cancer: spectrum of multidetector CT findings in oncologic patients with thromboembolic disease. A pictorial review. AB - This article is a reasoned pictorial review illustrating the many faces of thrombotic and embolic disease developing in the cancer patient. From a clinical point of view, we particularly point out the importance of properly identifying this occurrence in its various presentations. From a radiological point of view, special emphasis is given to the wide spectrum of multidetector CT findings, to the clues of benign and malignant thrombus diagnosis, and to the potential interpretative pitfalls. PMID- 21525111 TI - Radiologic characteristics of sinonasal fungus ball: an analysis of 119 cases. AB - BACKGROUND: It is important to differentiate sinonasal fungus ball from non fungal sinusitis and other forms of fungal sinusitis in order to determine the optimal treatment. In particular, a sinonasal fungus ball, a non-invasive fungal sinusitis, can be characterized by radiologic findings before surgery. PURPOSE: To differentiate a sinonasal fungus ball from other types of sinusitis and determine optimal treatment on the basis of radiologic findings before surgery. MATERIAL AND METHODS: We studied 119 patients with clinically and pathologically proven sinonasal fungus balls. Their condition was evaluated radiologically with contrast-enhanced CT (99 patients), non-contrast CT (18 patients) and/or MRI (17 patients) prior to sinonasal surgery. RESULTS: Calcifications were found in 78 of 116 (67.2%) patients who underwent CT scans for fungus ball. As opposed to non contrast CT scans, contrast CT scans revealed hyperattenuating fungal ball in 82.8% and enhanced inflamed mucosa in 65.5% of the patients, respectively. On MRI, most sinonasal fungal balls showed iso- or hypointensity on T1-weighted images and marked hypointensity on T2-weighted images. Inflamed mucosal membranes were noted and appeared as hypointense on T1-weighted images (64.7%) and hyperintense on T2-weighted images (88.2%). CONCLUSION: When there are no calcifications visible on the CT scan, a hyperattenuating fungal ball located in the central area of the sinus with mucosal thickening on enhanced CT scans is an important feature of a non-invasive sinonasal fungus ball. On MRI, a sinonasal fungus ball has typical features of a marked hypointense fungus ball with a hyperintense mucosal membrane in T2-weighted images. A contrast-enhanced CT scan or MRI provides sufficient information for the preoperative differentiation of a sinonasal fungus ball from other forms of sinusitis. PMID- 21525112 TI - Understanding intra-abdominal hypertension: from the bench to the bedside. AB - Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are highly morbid conditions that are common and underrecognized in the intensive care unit. Intra-abdominal hypertension affects the critically ill patient population and is not solely limited to the trauma and surgical subgroups. The recognition of IAH and ACS as distinct clinical states has become more apparent. Extensive bench and clinical research has shed significant light into the definition, incidence, etiology, physiology, clinical manifestations, and treatment strategies. Although further research into this morbid condition is needed, improvement in recognition is a critical first step. This review aims to scrutinize the basic science and clinical literature available on this condition in a surgically focused, organ-system-based approach. PMID- 21525113 TI - Dexmedetomidine and clonidine: from second- to first-line sedative agents in the critical care setting? AB - In the critical care setting, alpha-2 agonists present a multifaceted profile: sedation combined with arousability, suppression of delirium, preservation of respiratory drive, reduced O(2) consumption, preserved renal function, and reduced protein metabolism. In addition, this review details the reduced arterial impedance, improved left ventricular performance, preserved vascular reactivity to exogenous amines, preserved cardiac baroreflex reactivity, preserved vasomotor baroreflex activity combined with a lowered pressure set point: these features may explain the good tolerance observed when alpha-2 agonists are used as continuous infusion without any loading dose. Reviewing the literature allows one to suggest that a new management appears possible with arousable sedation. However, it remains to be demonstrated whether this arousable sedation can be combined with the preservation of spontaneous ventilation, in the setting of severe respiratory distress, as opposed to conventional controlled mechanical ventilation combined with conventional sedation. Should such a speculative view be confirmed, then alpha-2 agonists will move from second-line sedative agents to first-line sedative agents. However, key studies are lacking to demonstrate the effect of alpha-2 agonists on physiological endpoints and outcome. Presently, the existing body of data suggests a niche for the use of alpha-2 agonists in the critical care setting. PMID- 21525114 TI - Editor's Letter. California Department of Corrections and Rehabilitation. PMID- 21525115 TI - The current state of quality of care measurement in the California Department of Corrections and Rehabilitation. AB - The quality of health care in prisons is lacking in many states. In particular, the California Department of Corrections and Rehabilitation (CDCR) is in the midst of an extreme legal remedy to address problems related to access to and quality of care; it now operates under the direction of a federally appointed receiver for medical care. To understand the current state of access and quality measurement and to assess strengths and weaknesses of current activities, the RAND Corporation conducted a series of interviews and site visits in the CDCR and related offices as well as document reviews (December 2008 to February 2009). Findings supported RAND's larger project goals to identify measures for use in a sustainable quality measurement system. PMID- 21525116 TI - A review of quality measures used by state and federal prisons. AB - In response to deficiencies in the delivery of health care in prisons, a number of state correctional systems and the Federal Bureau of Prisons (BOP) have established quality of care monitoring systems. In 2009, the California Department of Corrections and Rehabilitation and the federal receiver overseeing the system asked the RAND Corporation to identify existing indicators of quality performance and to recommend a set of indicators applicable to the prison population. An environmental scan of quality measures being used by other state correctional systems and the BOP found substantial variation in the number and type of measures being used and the underlying data systems used to construct measures. Explicit quality measures were being used, as were measures of disease prevalence and standards. PMID- 21525117 TI - Selecting performance indicators for prison health care. AB - Improving prison health care requires a robust measurement dashboard that addresses multiple domains of care. We sought to identify tested indicators of clinical quality and access that prison health managers could use to ascertain gaps in performance and guide quality improvement. We used the RAND/UCLA modified Delphi method to select the best indicators for correctional health. An expert panel rated 111 indicators on validity and feasibility. They voted to retain 79 indicators in areas such as access, cardiac conditions, geriatrics, infectious diseases, medication monitoring, metabolic diseases, obstetrics/gynecology, screening/prevention, psychiatric disorders/substance abuse, pulmonary conditions, and urgent conditions. Prison health institutions, like all other large health institutions, need robust measurement systems. The indicators presented here provide a basic library for prison health managers developing such systems. PMID- 21525118 TI - Initial dental needs and a projection of needed dental capacity in the Iowa Department of Corrections. AB - The dental health data for the Iowa Department of Corrections (IDOC) inmate population were analyzed to better understand dental health issues experienced by inmates and IDOC's system for responding to those dental needs. Each inmate is given a dental health assessment upon admission to Iowa's prison system. These data were analyzed for frequency of dental health needs and frequency of dental health services. In addition, emergency dental health services were analyzed. The findings show that each inmate has approximately 7.6 dental codes, including the initial exam, dental services provided, and dental needs not yet addressed. When reviewing only dental needs (and not the initial exam), 32% (5,110) identified dental needs were completed and 66% (10,572) were not. PMID- 21525119 TI - Trauma and life event stressors among young and older adult prisoners. AB - This study examined lifetime trauma and life event stressors among young and older prisoners. A stratified random sample of young (age 18 to 24 years) and older (age 55 and above) male prisoners was drawn from the New Jersey Department of Corrections. Fifty-eight participants completed a modified version of the Trauma and Stressful Life Experiences Screening Inventory during face-to-face interviews. Approximately 40% of young and older adult prisoners reported exposure to violent victimization. Young prisoners were significantly more likely to report witnessing physical assault, whereas older prisoners were significantly more likely to report experiencing a natural disaster, life-threatening illness, or the death of a loved one. Information about the frequency of lifetime trauma and life event stressors can be used to develop or improve trauma-informed services that target age-specific needs, especially for young and older prisoners. PMID- 21525120 TI - Chronic care model implementation in the California State Prison System. AB - The chronic care model (CCM) deployed through a learning collaborative strategy, such as the Institute for Healthcare Improvement's Breakthrough Series (BTS), is a widely adopted approach to improve care that has guided clinical quality initiatives nationally and internationally. The BTS collaborative approach has been used to improve chronic conditions at national and state levels and in single health care delivery systems but not in correctional health care. Combining the CCM with a learning collaborative strategy in prison health care is a new frontier. This article describes the adoption of the CCM using a learning collaborative approach in the California prison system under the mandate of a federal receivership and elucidates some barriers to implementation. Results from the first phase of a pilot study were positive in terms of benefit/ cost analysis and suggest financial and political viability to continue the program. PMID- 21525121 TI - From knowledge to action: establishing an international network for justice health. AB - A group of 38 researchers, policy makers, and practitioners from seven countries, speaking nine languages and representing diverse perspectives, gathered in May 2009 in Orlando, Florida, to establish the International Network for Justice Health. The Network can assist policy makers, researchers, and practitioners to improve the health of justice-involved populations; however, achieving progress will require individual and organizational commitment to working with colleagues across different disciplines and different countries. The Network aims to facilitate this collaboration and become a focal point for the sharing and dissemination of knowledge. Its priorities will continue to evolve and to be determined by members. As a collaborative venture, the Network is only as strong as its membership. Readers are encouraged to join (membership is free) and to contribute. PMID- 21525123 TI - Resting heart rate is associated with cardiovascular and all-cause mortality after adjusting for inflammatory markers: the Copenhagen City Heart Study. AB - AIMS: To investigate the association between resting heart rate (RHR) and markers of chronic low-grade inflammation. Also, to examine whether elevated resting heart rate is independently associated with cardiovascular and all-cause mortality in the general population, or whether elevated RHR is merely a marker of chronic low-grade inflammation. METHODS AND RESULTS: A group of 6518 healthy subjects from the the Danish general population were followed for 18 years during which 1924 deaths occurred. Subjects underwent assessment of baseline RHR, conventional cardiovascular risk factors, high-sensitivity C-reactive protein (hsCRP), and fibrinogen. RHR was associated with hsCRP and fibrinogen in uni- and multivariate models (p < 0.0001). A 10 beats per minute increase in RHR was associated with increased cardiovascular and all-cause mortality in univariate models - HR (95%CI) (1.21 (1.14-1.29) and 1.15 (1.11-1.19); multivariate models adjusted for conventional risk factors - 1.16 (1.09-1.24) and 1.10 (1.06-1.14); multivariate models including hsCRP - 1.14 (1.07-1.22) and 1.09 (1.05-1.14); fibrinogen - 1.15 (1.07-1.22) and 1.09 (1.05-1.14); and both hsCRP and fibrinogen - 1.14 (1.07-1.22) and 1.09 (1.05-1.14). CONCLUSION: RHR was associated with markers of chronic low-grade inflammation. However, RHR remained associated with both cardiovascular and all-cause mortality after adjusting for markers of chronic low-grade inflammation. This suggests that RHR is an independent risk factor for cardiovascular and all-cause mortality, and not merely a marker of chronic low-grade inflammation. PMID- 21525124 TI - Discrepancy between coronary artery calcium score and HeartScore in middle-aged Danes: the DanRisk study. AB - BACKGROUND: Coronary artery calcification (CAC) is an independent and incremental risk marker. This marker has previously not been compared to the HeartScore risk model. DESIGN: A random sample of 1825 citizens (men and women, 50 or 60 years of age) was invited for screening. METHODS: Using the HeartScore model, the 10-year risk of fatal cardiovascular events based on gender, age, smoking, systolic blood pressure, and total cholesterol was estimated. A low risk was defined as <5%. The CAC score was calculated from a non-contrast enhanced cardiac-CT scan and given in Agatston U. RESULTS: A total of 1257 (69%) of the invited subjects were interested in the screening. Due to previous cardiovascular disease or diabetes mellitus, 101 were excluded. Of the remaining 1156, 47% were men and 53% women; one half were 50 years old and the other half 60 years old. A low HeartScore was found in 901 of which 334 (37%) had CAC. A high HeartScore was recorded in 251 of which 80 (32%) did not have any CAC. High HeartScores and CAC were significantly more common in males than females. CONCLUSIONS: CAC is common in healthy middle aged Danes with a low HeartScore, and, on the contrary, high-risk subjects very frequently do not have CAC. The therapeutic and prognostic implications of these observations remain to be clarified. PMID- 21525125 TI - Molecular determinants of cardiac specification. AB - In this review, we report and analyse the molecular factors involved in cardiogenesis from the earliest stages of development, using mainly the chick embryo as a model. The first part of the review demonstrates the areas where cardiogenic cells are located from gastrula stages, analysing a brief summary of the fate map of cardiogenic cells, from the epiblast through to the primitive heart tube. The next part analyses the commitment of pre-cardiac cells in cardiogenesis before, during, and after ingression through the primitive streak. Throughout the different journeys of the pre-cardiac cells, from the origin on the epiblast level up to the constitution of the tubular heart in the mid-line, the genes involved in the different stages of the process of cardiogenesis are very numerous. These have a greater or lesser importance depending on their specificity and the order in which they appear, bearing in mind that they become more valuable as the developmental process advances and the precursor cells start acquiring the commitment of pre-cardiac cells. Next, we show some box-filled diagrams to illustrate the dynamic gene expression pattern throughout the early stages of heart development, grouping the genes by their chronological significance. Finally, we discuss the implications that this temporal genomic expression could have in the induction and specification of the different types of cells and regions of the heart. PMID- 21525126 TI - Principal component analysis-based filtering improves detection for Affymetrix gene expression arrays. AB - Gene expression array technology has reached the stage of being routinely used to study clinical samples in search of diagnostic and prognostic biomarkers. Due to the nature of array experiments, which examine the expression of tens of thousands of genes simultaneously, the number of null hypotheses is large. Hence, multiple testing correction is often necessary to control the number of false positives. However, multiple testing correction can lead to low statistical power in detecting genes that are truly differentially expressed. Filtering out non informative genes allows for reduction in the number of null hypotheses. While several filtering methods have been suggested, the appropriate way to perform filtering is still debatable. We propose a new filtering strategy for Affymetrix GeneChips(r), based on principal component analysis of probe-level gene expression data. Using a wholly defined spike-in data set and one from a diabetes study, we show that filtering by the proportion of variation accounted for by the first principal component (PVAC) provides increased sensitivity in detecting truly differentially expressed genes while controlling false discoveries. We demonstrate that PVAC exhibits equal or better performance than several widely used filtering methods. Furthermore, a data-driven approach that guides the selection of the filtering threshold value is also proposed. PMID- 21525127 TI - Stimulation of stop codon readthrough: frequent presence of an extended 3' RNA structural element. AB - In Sindbis, Venezuelan equine encephalitis and related alphaviruses, the polymerase is translated as a fusion with other non-structural proteins via readthrough of a UGA stop codon. Surprisingly, earlier work reported that the signal for efficient readthrough comprises a single cytidine residue 3'-adjacent to the UGA. However, analysis of variability at synonymous sites revealed strikingly enhanced conservation within the ~ 150 nt 3'-adjacent to the UGA, and RNA folding algorithms revealed the potential for a phylogenetically conserved stem-loop structure in the same region. Mutational analysis of the predicted structure demonstrated that the stem-loop increases readthrough by up to 10-fold. The same computational analysis indicated that similar RNA structures are likely to be relevant to readthrough in certain plant virus genera, notably Furovirus, Pomovirus, Tobravirus, Pecluvirus and Benyvirus, as well as the Drosophilia gene kelch. These results suggest that 3' RNA stimulatory structures feature in a much larger proportion of readthrough cases than previously anticipated, and provide a new criterion for assessing the large number of cellular readthrough candidates that are currently being revealed by comparative sequence analysis. PMID- 21525128 TI - Native homing endonucleases can target conserved genes in humans and in animal models. AB - In recent years, both homing endonucleases (HEases) and zinc-finger nucleases (ZFNs) have been engineered and selected for the targeting of desired human loci for gene therapy. However, enzyme engineering is lengthy and expensive and the off-target effect of the manufactured endonucleases is difficult to predict. Moreover, enzymes selected to cleave a human DNA locus may not cleave the homologous locus in the genome of animal models because of sequence divergence, thus hampering attempts to assess the in vivo efficacy and safety of any engineered enzyme prior to its application in human trials. Here, we show that naturally occurring HEases can be found, that cleave desirable human targets. Some of these enzymes are also shown to cleave the homologous sequence in the genome of animal models. In addition, the distribution of off-target effects may be more predictable for native HEases. Based on our experimental observations, we present the HomeBase algorithm, database and web server that allow a high throughput computational search and assignment of HEases for the targeting of specific loci in the human and other genomes. We validate experimentally the predicted target specificity of candidate fungal, bacterial and archaeal HEases using cell free, yeast and archaeal assays. PMID- 21525129 TI - Single-molecule analysis of genome rearrangements in cancer. AB - Rearrangements of the genome can be detected by microarray methods and massively parallel sequencing, which identify copy-number alterations and breakpoint junctions, but these techniques are poorly suited to reconstructing the long range organization of rearranged chromosomes, for example, to distinguish between translocations and insertions. The single-DNA-molecule technique HAPPY mapping is a method for mapping normal genomes that should be able to analyse genome rearrangements, i.e. deviations from a known genome map, to assemble rearrangements into a long-range map. We applied HAPPY mapping to cancer cell lines to show that it could identify rearrangement of genomic segments, even in the presence of normal copies of the genome. We could distinguish a simple interstitial deletion from a copy-number loss at an inversion junction, and detect a known translocation. We could determine whether junctions detected by sequencing were on the same chromosome, by measuring their linkage to each other, and hence map the rearrangement. Finally, we mapped an uncharacterized reciprocal translocation in the T-47D breast cancer cell line to about 2 kb and hence cloned the translocation junctions. We conclude that HAPPY mapping is a versatile tool for determining the structure of rearrangements in the human genome. PMID- 21525130 TI - Measurement of telomere DNA content by dot blot analysis. AB - Telomeres play a central role in human cancer, cardiovascular aging and possibly longevity. However, present methods to measure telomere length are fraught with shortcomings that limit their use. Here, we describe a novel method to measure the relative telomere DNA content by dot blot analysis. In each dot, the DNA content is measured by a DNA stain (Dx) and the telomeric DNA content is measured with a telomeric probe (T). The T normalized for Dx (T/Dx) of each dot is a measure of telomere content. The method requires ~20 ng of DNA per assay. Moreover, the T/Dx data are highly correlated linearly with mean telomere lengths derived from Southern blots of the terminal restriction fragments (r > 0.96, P < 0.0001). The method is also simple to use, has a relatively low interassay coefficient of variation (<6%), retains its precision in moderately degraded DNA and can be forged for high throughput analysis. The method might help researchers and clinicians alike in understanding risks for and extent of human diseases. PMID- 21525131 TI - Genetically tagged TRE5-A retrotransposons reveal high amplification rates and authentic target site preference in the Dictyostelium discoideum genome. AB - Retrotransposons contribute significantly to the evolution of eukaryotic genomes. They replicate by producing DNA copies of their own RNA, which are integrated at new locations in the host cell genome. In the gene-dense genome of the social amoeba Dictyostelium discoideum, retrotransposon TRE5-A avoids insertional mutagenesis by targeting the transcription factor (TF) IIIC/IIIB complex and integrating ~ 50 bp upstream of tRNA genes. We generated synthetic TRE5-A retrotransposons (TRE5-A(bsr)) that were tagged with a selection marker that conferred resistance to blasticidin after a complete retrotransposition cycle. We found that the TRE5-A(bsr) elements were efficiently mobilized in trans by proteins expressed from the endogenous TRE5-A population found in D. discoideum cells. ORF1 protein translated from TRE5-A(bsr) elements significantly enhanced retrotransposition. We observed that the 5' untranslated region of TRE5-A could be replaced by an unrelated promoter, whereas the 3' untranslated region of TRE5 A was essential for retrotransposition. A predicted secondary structure in the RNA of the 3' untranslated region of TRE5-A may be involved in the retrotransposition process. The TRE5-A(bsr) elements were capable of identifying authentic integration targets in vivo, including formerly unnoticed, putative binding sites for TFIIIC on the extrachromosomal DNA element that carries the ribosomal RNA genes. PMID- 21525132 TI - The ancestral role of ATP hydrolysis in type II topoisomerases: prevention of DNA double-strand breaks. AB - Type II DNA topoisomerases (topos) catalyse changes in DNA topology by passing one double-stranded DNA segment through another. This reaction is essential to processes such as replication and transcription, but carries with it the inherent danger of permanent double-strand break (DSB) formation. All type II topos hydrolyse ATP during their reactions; however, only DNA gyrase is able to harness the free energy of hydrolysis to drive DNA supercoiling, an energetically unfavourable process. A long-standing puzzle has been to understand why the majority of type II enzymes consume ATP to support reactions that do not require a net energy input. While certain type II topos are known to 'simplify' distributions of DNA topoisomers below thermodynamic equilibrium levels, the energy required for this process is very low, suggesting that this behaviour is not the principal reason for ATP hydrolysis. Instead, we propose that the energy of ATP hydrolysis is needed to control the separation of protein-protein interfaces and prevent the accidental formation of potentially mutagenic or cytotoxic DSBs. This interpretation has parallels with the actions of a variety of molecular machines that catalyse the conformational rearrangement of biological macromolecules. PMID- 21525133 TI - Genetic deficiency of Smad3 protects against murine ischemic acute kidney injury. AB - TGF-beta1 contributes to chronic kidney disease, at least in part, via Smad3. TGF beta1 is induced in the kidney following acute ischemia, and there is increasing evidence that TGF-beta1 may protect against acute kidney injury. As there is a paucity of information regarding the functional significance of Smad3 in acute kidney injury, the present study explored this issue in a murine model of ischemic acute kidney injury in Smad3(+/+) and Smad3(-/-) mice. We demonstrate that, at 24 h after ischemia, Smad3 is significantly induced in Smad3(+/+) mice, whereas Smad3(-/-) mice fail to express this protein in the kidney in either the sham or postischemic groups. Compared with Smad3(+/+) mice, and 24 h following ischemia, Smad3(-/-) mice exhibited greater preservation of renal function as measured by blood urea nitrogen (BUN) and serum creatinine; less histological injury assessed by both semiquantitative and qualitative analyses; markedly suppressed renal expression of IL-6 and endothelin-1 mRNA (but comparable expression of MCP-1, TNF-alpha, and heme oxygenase-1 mRNA); and no increase in plasma IL-6 levels, the latter increasing approximately sixfold in postischemic Smad3(+/+) mice. We conclude that genetic deficiency of Smad3 confers structural and functional protection against acute ischemic injury to the kidney. We speculate that these effects may be mediated through suppression of IL-6 production. Finally, we suggest that upregulation of Smad3 after an ischemic insult may contribute to the increased risk for chronic kidney disease that occurs after acute renal ischemia. PMID- 21525134 TI - Bilateral ureteral obstruction induces early downregulation and redistribution of AQP2 and phosphorylated AQP2. AB - Bilateral ureteral obstruction (BUO) is characterized by impairment of urine flow from the kidneys and altered expression of specific membrane proteins in the kidney involved in regulation of renal water and salt transport. Importantly, 24 h BUO reduces the abundance of the collecting duct water channel aquaporin-2 (AQP2) and AQP2 phosphorylated at serine 256 (AQP2pS256). To investigate the mechanism behind downregulation of AQP2 in BUO, rats were subjected to BUO and examined after 2, 6, 12, and 24 h. Q-PCR and immunoblotting showed significantly decreased AQP2 mRNA expression after 2-h BUO and decreased abundance of total AQP2 after 12 and 24 h. In parallel, immunohistochemistry showed weaker labeling of AQP2 at the apical surface of inner medullary collecting ducts (IMCD) compared with controls. The abundance of AQP2pS256 was significantly reduced from 6-h BUO and was confirmed by immunohistochemistry. Importantly, immunoblotting showed reduced abundance of AQP2pS261 after 12- and 24-h BUO mimicking total AQP2. Immunohistochemistry demonstrated early changed intracellular localization of AQP2pS261 in BUO, and colocalization studies showed redistribution from the apical membrane to early endosomes and lysosomes. In conclusion, BUO induces a very early regulation of AQP2 both at the level of abundance and on cellular localization. AQP2 and AQP2 phosphorylated at ser261 redistribute to more intracellular localizations and colocalize with the early endosomal marker EEA1 and the lysosomal marker cathepsin D, suggesting that early downregulation of AQP2 could in part be caused by degradation of AQP2 through a lysosomal degradation pathway. PMID- 21525136 TI - TNF receptor subtype 2 induction by viral dsRNA involves IP-10 and TNF-alpha in glomerular mesangial inflammation. PMID- 21525135 TI - Connections in chronic kidney disease: connexin 43 and connexin 37 interaction. PMID- 21525138 TI - Acute sarcoidosis as parotid fever in rheumatoid arthritis under anti-tumor necrosis factor-alpha therapy. PMID- 21525137 TI - The phosphatidylcholine-hydrolysing phospholipase C NPC4 plays a role in response of Arabidopsis roots to salt stress. AB - Phosphatidylcholine-hydrolysing phospholipase C, also known as non-specific phospholipase C (NPC), is a new member of the plant phospholipase family that reacts to environmental stresses such as phosphate deficiency and aluminium toxicity, and has a role in root development and brassinolide signalling. Expression of NPC4, one of the six NPC genes in Arabidopsis, was highly induced by NaCl. Maximum expression was observed from 3 h to 6 h after the salt treatment and was dependent on salt concentration. Results of histochemical analysis of P(NPC4):GUS plants showed the localization of salt-induced expression in root tips. On the biochemical level, increased NPC enzyme activity, indicated by accumulation of diacylglycerol, was observed as early as after 30 min of salt treatment of Arabidopsis seedlings. Phenotype analysis of NPC4 knockout plants showed increased sensitivity to salinity as compared with wild-type plants. Under salt stress npc4 plants had shorter roots, lower fresh weight, and reduced seed germination. Expression levels of abscisic acid-related genes ABI1, ABI2, RAB18, PP2CA, and SOT12 were substantially reduced in salt-treated npc4 plants. These observations demonstrate a role for NPC4 in the response of Arabidopsis to salt stress. PMID- 21525139 TI - Efficacy and tolerance of systemic steroids in sciatica: a systematic review and meta-analysis. AB - OBJECTIVES: The efficacy of pharmacological interventions in sciatica is limited and the use of systemic steroids is still controversial. We aimed at evaluating the efficacy and tolerance of systemic steroids in sciatica. METHODS: A systematic literature search was performed in the Medline, Embase and Cochrane databases until February 2010. Randomized placebo-controlled trials evaluating the efficacy and the tolerance of systemic steroids in sciatica were included. Efficacy and tolerance were assessed using the relative risk (RR) and 95% CI with the inverse variance method (RR > 1 means that the event is more likely to occur in the steroid group). We explored the heterogeneity between the studies using subgroup analysis. RESULTS: Seven studies (383 patients) were included. The difference in the rate of responders between both groups was not statistically significant (RR = 1.22, 95% CI 0.96, 1.56). The rate of adverse events was 13.3% for the patients in the steroid group and 6.6% for the placebo group (RR = 2.01, 95% CI 1.06, 3.80). The number needed to harm was 20 (95% CI 10, infinity). Twenty (15.3%) patients in the steroid group and seven (5.7%) patients in the placebo group underwent surgery. A trend towards a higher requirement for spinal surgery was observed in the steroid group (RR = 1.14, 95% CI 0.74, 1.75). The methodological quality slightly influenced the results. We did not find any publication bias. CONCLUSION: Steroid efficacy is not superior to the placebo in sciatica, but it has more side effects. The tolerance : efficacy ratio indicates against the use of systemic steroids in sciatica. PMID- 21525140 TI - A score for assessing the risk of first-time adolescent pregnancy. AB - BACKGROUND: Adolescent pregnancy is an important health issue. Prevention programs are usually aimed at the prevention of repeat pregnancy, ignoring the adolescents at risk of becoming pregnant for the first time. OBJECTIVES: To analyse if socio-economic status, family type and mother's age at first pregnancy are risk factors for adolescent pregnancy and to design a risk score of first time adolescent pregnancy. METHODS: A case-control study was performed: cases were primiparous adolescents and controls were primiparous adult women. Participants were asked about their socio-economic status and family structure during adolescence and the age at which their mothers' first pregnancy occurred. Odds ratio (OR) and 95% confidence intervals were calculated. A first-time adolescent pregnancy risk score was designed based on a multiple logistic regression model. RESULTS: Sixty-six adolescents and 140 adults were interviewed. Belonging to a family other than nuclear or extended types was an independent risk factor for adolescent pregnancy (OR 9.37, 95% CI 3.36-38.07). Low socio economic status and having a mother with history of adolescent pregnancy were not independent risk factors (OR 1.04, 95% CI 0.34-5.11 and OR 1.13, 95% CI 0.42 4.32, respectively), achieving significance only when simultaneously present (OR 6.01, 95% CI 2.36-20.79). The presence of all these factors determined the highest adolescent pregnancy probability (OR 10.49, 95% CI 3.43-51.00). A first time adolescent pregnancy risk assessment score was designed, with an estimated sensitivity of 75.8% and specificity of 75.0%. CONCLUSIONS: Adolescent pregnancy is associated with unfavorable precedents that can be used to identify adolescents at increased risk of early pregnancy. PMID- 21525141 TI - Efficacy of dioctahedral smectite in acute watery diarrhea in Indian children: a randomized clinical trial. AB - OBJECTIVE: To determine the effects and safety of dioctahedral smectite (DS) on the duration of acute watery diarrhea in children. METHODS: A Randomized, open labeled, clinical controlled trial in a tertiary care hospital outpatient department (OPD) and emergency department. Participants were one hundred and seventeen children without any chronic illness between 2 and 5 years presenting to OPD, having acute watery diarrhea for <48 h with mild to moderate dehydration, not on antibiotics and requiring oral rehydration therapy. Intervention done was DS with a dose of 1.5 g thrice daily. RESULTS: Freshly dissolved DS in a dose of 1.5 g thrice daily for 5 days significantly shortened the duration of acute watery diarrhea in children aged 2-5 years. There were no adverse effects on the use of DS. DS was acceptable to the children, and its administration was not accompanied with any side effects. CONCLUSION: DS reduces the duration of diarrhea in Indian children and prevents a prolonged course, and therefore, may consistently reduce the costs in treatment of acute watery diarrhea. PMID- 21525142 TI - Quadriplegia due to celiac crisis with hypokalemia as initial presentation of celiac disease: a case report. AB - Celiac crisis is a rare, life-threatening complication of celiac disease characterized by worsening of clinical symptoms, multiple metabolic derangements and shock. We report an 8-year-old girl with previously undiagnosed celiac disease who presented with flaccid quadriparesis secondary to severe hypokalemia associated with celiac crisis. Diagnosis was expedited by an elevated anti-tissue transglutaminase antibody titer. The patient improved with correction of hypokalemia, corticosteroids and gluten-free diet. In tropical countries such as India, where both acute flaccid paresis and diarrhea are usually of infective etiologies, this rare clinical condition should also be considered in the differential diagnosis of both. PMID- 21525143 TI - A large-scale benchmark study of existing algorithms for taxonomy-independent microbial community analysis. AB - Recent advances in massively parallel sequencing technology have created new opportunities to probe the hidden world of microbes. Taxonomy-independent clustering of the 16S rRNA gene is usually the first step in analyzing microbial communities. Dozens of algorithms have been developed in the last decade, but a comprehensive benchmark study is lacking. Here, we survey algorithms currently used by microbiologists, and compare seven representative methods in a large scale benchmark study that addresses several issues of concern. A new experimental protocol was developed that allows different algorithms to be compared using the same platform, and several criteria were introduced to facilitate a quantitative evaluation of the clustering performance of each algorithm. We found that existing methods vary widely in their outputs, and that inappropriate use of distance levels for taxonomic assignments likely resulted in substantial overestimates of biodiversity in many studies. The benchmark study identified our recently developed ESPRIT-Tree, a fast implementation of the average linkage-based hierarchical clustering algorithm, as one of the best algorithms available in terms of computational efficiency and clustering accuracy. PMID- 21525144 TI - The use of RNAi technologies for gene knockdown in zebrafish. AB - Despite being a popular and versatile model organism in which to study development and model disease, the use of zebrafish has been hampered by the lack of a reliable, stable and cost-effective method of gene knockdown. It is therefore not surprising that the discovery of RNAi as an exploitable method of post-transcriptional gene regulation has created a lot of excitement within the zebrafish research community. However, despite concerted efforts in the field, progress in the use of RNAi technologies in zebrafish has been extremely slow and a reliable means of RNAi-mediated gene knockdown remains elusive. The following reviews progress in the field to date, highlights the major pitfalls identified and suggests possible future directions. PMID- 21525145 TI - Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts. AB - The TREX (transcription/export) complex has been conserved throughout evolution from yeast to man and is required for coupled transcription elongation and nuclear export of mRNAs. The TREX complex in mammals and Drosophila is composed of the THO subcomplex (THOC1, THOC2, THOC5, THOC6, and THOC7), THOC3, UAP56, and Aly/THOC4. In human and Drosophila, various studies have shown that THO is required for the export of heat shock mRNAs, but nothing is known about other mRNAs. Our previous study using conditional THOC5 (or FMIP) knockout mice revealed that the presence of THOC5 is critical in hematopoietic cells but not for terminally differentiated cells. In this study, we describe the establishment of a mouse embryo fibroblast cell line (MEF), THOC5 flox/flox. Four days after infection of MEF THOC5 flox/flox with adenovirus carrying Cre-recombinase gene (Ad-GFP-Cre), THOC5 is down-regulated >95% at the protein level, and cell growth is strongly suppressed. Transcriptome analysis using cytoplasmic RNA isolated from cells lacking functional THOC5 reveals that only 2.9% of all genes were down regulated more than twofold. Although we examined these genes in fibroblasts, one fifth of all down-regulated genes (including HoxB3 and polycomb CBX2) are known to play a key role in hematopoietic development. We further identified 10 genes that are spliced but not exported to the cytoplasm in the absence of THOC5. These mRNAs were copurified with THOC5. Furthermore, Hsp70 mRNA was exported in the absence of THOC5 at 37 degrees C, but not under heat shock condition (42 degrees C), suggesting that THOC5 may be required for mRNA export under stress and/or upon signaling-induced conditions. PMID- 21525146 TI - Interaction between FLASH and Lsm11 is essential for histone pre-mRNA processing in vivo in Drosophila. AB - Metazoan replication-dependent histone mRNAs are the only nonpolyadenylated cellular mRNAs. Formation of the histone mRNA 3' end requires the U7 snRNP, which contains Lsm10 and Lsm11, and FLASH, a processing factor that binds Lsm11. Here, we identify sequences in Drosophila FLASH (dFLASH) that bind Drosophila Lsm11 (dLsm11), allow localization of dFLASH to the nucleus and histone locus body (HLB), and participate in histone pre-mRNA processing in vivo. Amino acids 105 154 of dFLASH bind to amino acids 1-78 of dLsm11. A two-amino acid mutation of dLsm11 that prevents dFLASH binding but does not affect localization of U7 snRNP to the HLB cannot rescue the lethality or histone pre-mRNA processing defects resulting from an Lsm11 null mutation. The last 45 amino acids of FLASH are required for efficient localization to the HLB in Drosophila cultured cells. Removing the first 64 amino acids of FLASH has no effect on processing in vivo. Removal of 13 additional amino acids of dFLASH results in a dominant negative protein that binds Lsm11 but inhibits processing of histone pre-mRNA in vivo. Inhibition requires the Lsm11 binding site, suggesting that the mutant dFLASH protein sequesters the U7 snRNP in an inactive complex and that residues between 64 and 77 of dFLASH interact with a factor required for processing. Together, these studies demonstrate that direct interaction between dFLASH and dLsm11 is essential for histone pre-mRNA processing in vivo and for proper development and viability in flies. PMID- 21525147 TI - Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with high-altitude pulmonary oedema: a meta-analysis. AB - BACKGROUND AND OBJECTIVE: High-altitude pulmonary oedema (HAPE) is a non cardiogenic hydrostatic oedema involving a genetic component. Considering the low incidence of HAPE, sample sizes in current reports are relatively limited. We aimed to assess the association between the angiotensin-converting enzyme (ACE) I/D polymorphism and HAPE via a meta-analysis of published and unpublished data. MATERIALS AND METHODS: We searched PubMed, CBM, CNKI, and Cochrane Library Database before 20 November 2010. A random-effects model was applied (STATA) and study quality was assessed in duplicate. RESULTS: A total of five studies including 305 cases and 662 controls were meta-analysed. The summary odds ratio (OR) indicated that no significant differences in risk of developing HAPE were found between carriers of ACE D and I alleles (OR = 1.20; 95% confidence interval (CI), 0.98-1.48; p = 0.084). Lack of association persisted for genotypes under the recessive mode. However, genotype association under the dominant mode showed D allele carriers significantly conferred a 1.55-fold increased HAPE risk compared with II genotype carriers (95% CI, 1.15-2.08; p = 0.004). Funnel plot and Egger's test suggested no evidence of publication bias. CONCLUSIONS: Our results supported the notion that ACE D allele carriers were at significant increased risk of developing HAPE. PMID- 21525148 TI - Novel use of biodegradable casein conduits for guided peripheral nerve regeneration. AB - Recent advances in nerve repair technology have focused on finding more biocompatible, non-toxic materials to imitate natural peripheral nerve components. In this study, casein protein cross-linked with naturally occurring genipin (genipin-cross-linked casein (GCC)) was used for the first time to make a biodegradable conduit for peripheral nerve repair. The GCC conduit was dark blue in appearance with a concentric and round lumen. Water uptake, contact angle and mechanical tests indicated that the conduit had a high stability in water and did not collapse and cramped with a sufficiently high level of mechanical properties. Cytotoxic testing and terminal deoxynucleotidyl transferase dUTP nick-end labelling assay showed that the GCC was non-toxic and non-apoptotic, which could maintain the survival and outgrowth of Schwann cells. Non-invasive real-time nuclear factor-kappaB bioluminescence imaging accompanied by histochemical assessment showed that the GCC was highly biocompatible after subcutaneous implantation in transgenic mice. Effectiveness of the GCC conduit as a guidance channel was examined as it was used to repair a 10 mm gap in the rat sciatic nerve. Electrophysiology, labelling of calcitonin gene-related peptide in the lumbar spinal cord, and histology analysis all showed a rapid morphological and functional recovery for the disrupted nerves. Therefore, we conclude that the GCC can offer great nerve regeneration characteristics and can be a promising material for the successful repair of peripheral nerve defects. PMID- 21525149 TI - Transient pseudohypoaldosteronism masquerading as congenital adrenal hyperplasia. AB - We report a six-week-old boy with genitourinary structural abnormalities who presented with profound hyponatraemia and hyperkalaemia due to transient type 1 pseudohypoaldosteronism (PHA) precipitated by a urinary tract infection (UTI), which responded rapidly to intravenous saline and antibiotics. In infants with structural abnormalities of the urinary tract, we wish to highlight the importance of recognizing type 1 PHA and its association with a UTI since prompt and appropriate treatment rapidly corrects the associated metabolic abnormalities. Conversely, the identification of type 1 PHA in an infant should precipitate a search for a UTI and structural abnormalities of the urinary tract. PMID- 21525150 TI - Food allergy: which tests are worth doing and which are not? AB - Adverse reactions to foods may arise by a variety of mechanisms, both immune (IgE and non-IgE) and non-immune mediated. This article considers those assays useful in the diagnosis of Type 1 hypersensitivity to foods (IgE-based) and, importantly, discusses those assays where evidence is lacking for their use. In all cases of suspected food allergy, a full clinical history is indispensable in facilitating diagnosis. Total serum IgE is not a suitable screen for food allergy. Suspect allergens may be confirmed by either skin prick testing or serological assays for specific IgE. Several studies suggest concentrations of food-specific IgE at which there is a high probability of reaction on food challenge. These cut-off levels are now being used by physicians to direct clinical advice. However, it is important to note that not all studies agree on these limits and the chosen cut-off is dependent on the population studied and the assay used. PMID- 21525151 TI - Zinc poisoning from excessive denture fixative use masquerading as myelopolyneuropathy and hypocupraemia. AB - A 50-year-old man presented with a four-year history of unsteadiness, with recent falls and tingling in his fingers. Neurological examination found an ataxic gait, with a positive Romberg's sign. There was distal wasting and weakness in all four limbs and impaired co-ordination, with pseudoathetosis in the arms. Initial investigations showed a normochromic, normocytic anaemia, leucopenia, neutropenia and a low vitamin B(12) (172 ng/L). Treatment with intramuscular cobalamin injections showed no clinical improvement. Further investigations showed an undetectable caeruloplasmin (<0.085 g/L), a very low serum copper (1.1 MUmol/L) and a markedly raised serum zinc concentration (36.2 MUmol/L). On detailed questioning it became apparent that he had ill-fitting dentures requiring excessive use of denture fixative with high zinc content. The patient was switched to a non-zinc containing denture fixative and commenced copper supplementation. Although within three months the bone marrow suppression had resolved, there was no clinical improvement in neurological presentation. Questioning a patient about their denture fixative usage and checking if zinc is an ingredient may be considered during an investigation for myelopolyneuropathy when vitamin B(12) deficiency is not a cause. PMID- 21525152 TI - Prostate-specific antigen: does the current evidence support its use in prostate cancer screening? AB - Although widely used, the value of prostate-specific antigen (PSA) in screening asymptomatic men for prostate cancer is controversial. Reasons for the controversy relate to PSA being less than an ideal marker in detecting early prostate cancer, the possibility that screening for prostate cancer may result in the overdetection and thus overtreatment of indolent disease and the lack of clarity as to the definitive or best treatment for men diagnosed with localized prostate cancer. Although the results from some randomized prospective trials suggest that screening with PSA reduces mortality from prostate cancer, the overall benefit was modest. It is thus currently unclear as to whether the modest benefit of reduced mortality outweighs the harms of overdetection and overtreatment. Thus, prior to undergoing screening for prostate cancer, men should be informed of the risks and benefits of early detection. Newly emerging markers that may complement PSA in the early detection of prostate cancer include specific isoforms of PSA and PCA3. PMID- 21525153 TI - Parental smoking, exposure to secondhand smoke at home, and smoking initiation among young children. AB - INTRODUCTION: To investigate the associations of parental smoking and secondhand smoke (SHS) exposure at home with smoking initiation among young children in Hong Kong. METHODS: A prospective school-based survey of Hong Kong primary 2-4 students was conducted at baseline in 2006 and followed up in 2008. Self administered anonymous questionnaires were used to collect information about smoking, SHS exposure at home, parental smoking, and sociodemographic characteristics. Cross-sectional and prospective associations of SHS exposure at home and parental smoking with student smoking were analyzed using logistic regression adjusting for potential confounders. RESULTS: Cross-sectional association between parental smoking and ever smoking was significant with adjustment of sociodemographic characteristics but became insignificant after adjusting for home SHS exposure. Home SHS exposure mediated the association between parental smoking and students smoking (p = .03). Prospectively, parental smoking was not associated with smoking initiation after adjusting for home SHS exposure. Each day increase in home SHS exposure significantly predicted 16% excess risk of smoking initiation after adjusting for parental smoking. The prospective effect of parental smoking on smoking initiation was significantly mediated by baseline home SHS exposure (p < .01). CONCLUSIONS: Higher exposure to SHS at home predicted smoking initiation of young Chinese children in Hong Kong independent of parental smoking status. On the other hand, the effect of parental smoking on smoking initiation was mediated through SHS exposure at home. To prevent children from smoking as well as the harm of SHS exposure, parents and other family members should quit smoking or at least reduce smoking at home. PMID- 21525154 TI - Antigen-independent development of Foxp3+ regulatory T cells suppressing autoantibody production in experimental pemphigus vulgaris. AB - The CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play suppressive roles in various types of autoimmunity. It has been reported that Tregs develop in the thymus after high-affinity interaction of their TCR with self-peptide/MHC ligands mostly utilizing TCR-transgenic system. In this study, we examined whether the specific antigen is involved in the development of polyclonal Tregs in pemphigus vulgaris (PV), an autoimmune blistering disease caused by anti-desmoglein 3 (Dsg3) IgG antibodies, as a model system. Adoptive transfer of splenocytes of Dsg3(-)(/-) mice immunized with recombinant mouse Dsg3 to Rag2(-)(/-) recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and the development of PV phenotypes. We show here that Tregs control anti-Dsg3 antibody production in PV model mice: the adoptive transfer of Tregs and the depletion of endogenous Tregs suppressed and augmented, respectively, the anti-Dsg3 antibody production. To examine whether the endogenous expression of Dsg3 is involved in the generation of these PV-relevant Tregs, we compared the potential of wild-type Tregs with that of Tregs from Dsg3(-)(/-) mice. Polyclonal Tregs from Dsg3(-)(/-) mice were more potent than that of wild-type mice, in both adoptive transfer and Treg-depletion experiments, while suppressive activities against IgG production against an irrelevant antigen were similar between Tregs from wild-type and Dsg3( )(/-) mice. Our observation implies that Tregs capable of suppressing T(h) cells that drive autoantibody production can develop in the absence of the target antigen. PMID- 21525155 TI - Radiation therapy in the management of pituitary adenomas. AB - CONTEXT: Optimal management of pituitary adenomas involves consideration of the roles of medical therapy, surgery, and radiation therapy. The different forms of radiation therapy and their results are reviewed here. EVIDENCE ACQUISITION: A literature search through the U.S. National Library of Medicine was used to identify and review clinical experiences of radiation therapy in the management of pituitary adenomas. Emphasis was placed on studies within the last 5-10 yr, with 5 or more years of follow-up data, and of reasonable quality of data. Older studies with larger numbers or particular significance are also highlighted. EVIDENCE SYNTHESIS: Success of radiation therapy in controlling tumor growth is high, 90-100% in most series, regardless of radiation technique and adenoma subtype. Success in achieving hormonal normalization in secretory tumors is more variable because of differences in patient population, radiation technique, and doses employed and variation of the definition of success. Complete biochemical remission is generally achieved in 50% of patients at 10 yr after treatment for most adenomas. Higher rates of normalization can be achieved with additional medical therapy. Hypopituitarism is an expectant result of radiation therapy. Overall rate of other treatment-related adverse effects is low. CONCLUSIONS: Radiation therapy should be considered in the management of patients with pituitary adenomas, particularly when medical and surgical options have been exhausted. Because response evolves slowly over many years and because hypopituitarism is likely to occur, patients should be counseled on the importance of continued endocrinological surveillance and medical management. PMID- 21525156 TI - Genetic ancestry affects the phenotype of normogonadotropic anovulatory (WHOII) subfertility. AB - INTRODUCTION: Normogonadotropic (World Health Organization category II) anovulation is the most frequent cause of reduced fertility. Anovulation is associated with endocrine changes, i.e. hyperandrogenism, obesity, and insulin resistance. However, the phenotype is notoriously heterogeneous, depending on population characteristics and diagnostic criteria. OBJECTIVE: Our objective was to study the phenotype of normogonadotropic anovulatory women among various ethnic subgroups that coexist in an urban community (The Netherlands). Moreover, we studied whether genetic ancestry testing can be used to identify bio geographic ancestry and predict the phenotype of individual patients. MATERIALS AND METHODS: A standardized clinical and endocrine examination was performed in 1517 normogonadotropic anovulatory women. Bio-geographic ancestry was ascertained by questionnaire and genetic testing (637 cases), using a set of 10 previously validated ancestry informative markers. RESULTS: Subgroups constituted individuals from northwestern European (n = 774), Mediterranean European (north of Sahara and Middle East, n = 220), African (n = 111), Southeast Asian (n = 53), and Hindustani (n = 83) origin. Phenotypic differences included fasting insulin levels, androgen levels, and the frequency of hyperandrogenism (ranging from 76% in Mediterranean-European women to 41% in northwestern European women). Genetic ancestry testing was able to identify population structure on a continental level, i.e. European, African and Southeast Asian descent. We did not observe improved informativeness when genotype data were added to the prediction model. CONCLUSION: Population differences add to the phenotype of normogonadotropic anovulation and need to be taken into account when evaluating the individual patient. Although effective on a continental level, the present set of ancestry markers was not sufficiently effective to describe all ethnic variation in the phenotype of anovulatory subfertility. PMID- 21525157 TI - Effects of risedronate and low-dose transdermal testosterone on bone mineral density in women with anorexia nervosa: a randomized, placebo-controlled study. AB - CONTEXT: Anorexia nervosa is complicated by severe bone loss and clinical fractures. Mechanisms underlying bone loss in adults with anorexia nervosa include increased bone resorption and decreased formation. Estrogen administration has not been shown to prevent bone loss in this population, and to date, there are no approved, effective therapies for this comorbidity. OBJECTIVE: To determine whether antiresorptive therapy with a bisphosphonate alone or in combination with low-dose transdermal testosterone replacement would increase bone mineral density (BMD) in women with anorexia nervosa. DESIGN AND SETTING: We conducted a12-month, randomized, placebo-controlled study at a clinical research center. STUDY PARTICIPANTS: Participants included 77 ambulatory women with anorexia nervosa. INTERVENTION: Subjects were randomized to risedronate 35 mg weekly, low-dose transdermal testosterone replacement therapy, combination therapy or double placebo. MAIN OUTCOME MEASURES: BMD at the spine (primary endpoint), hip, and radius and body composition were measured by dual-energy x ray absorptiometry. RESULTS: Risedronate increased posteroanterior spine BMD 3%, lateral spine BMD 4%, and hip BMD 2% in women with anorexia nervosa compared with placebo in a 12-month clinical trial. Testosterone administration did not improve BMD but increased lean body mass. There were few side effects associated with either therapy. CONCLUSIONS: Risedronate administration for 1 yr increased spinal BMD, the primary site of bone loss in women with anorexia nervosa. Low-dose testosterone did not change BMD but increased lean body mass. PMID- 21525158 TI - Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism. AB - CONTEXT: Glucokinase regulatory protein (GCKR) regulates the trafficking and enzymatic activity of hepatic glucokinase, the rate-limiting enzyme in glycogen synthesis and glycolysis. The intronic single-nucleotide polymorphism (SNP) rs780094 (intron 16) and the missense SNP rs1260326 (P446L) in the GCKR gene are strongly associated with increased circulating triglyceride and C-reactive protein levels and, paradoxically, reductions in diabetes incidence, fasting glucose levels, and insulin resistance. OBJECTIVE, SETTING, AND PATIENTS: We sought to replicate these associations and evaluate interactions with lifestyle and metformin interventions in the multiethnic Diabetes Prevention Program (DPP). INTERVENTIONS AND MAIN OUTCOME MEASURES: We genotyped the two GCKR SNP in 3346 DPP participants and evaluated association with progression to diabetes and both baseline levels and changes in triglycerides, homeostasis model assessment of insulin resistance (HOMA-IR), oral disposition index, and inflammatory markers along with their interactions with DPP interventions. RESULTS: GCKR variation did not predict development of type 2 diabetes. At baseline, the 446L allele was associated with higher triglyceride and C-reactive protein levels (both P < 0.0001) and lower fasting glucose (P = 0.001) and HOMA-IR (P = 0.06). The lifestyle intervention was associated with a decrease in magnitude of the effect of the 446L allele on triglyceride levels (interaction P = 0.04). Metformin was more effective in reducing HOMA-IR in carriers of the P446 allele (interaction P = 0.05). CONCLUSIONS: Intensive lifestyle intervention appears to partially mitigate the effect of the 446L allele on higher triglycerides, whereas the P446 allele appears to enhance responsiveness to the HOMA-IR-lowering effect of metformin. PMID- 21525159 TI - Increased risk for non-autoimmune hypothyroidism in young patients with congenital heart defects. AB - CONTEXT: Newborns with congenital hypothyroidism (CH) have an increased risk for congenital heart defects (CHD) due to a common embryonic developmental program between thyroid gland and heart and great vessels. OBJECTIVE: Our objective was to investigate the prevalence and origin of thyroid disorders in young patients with CHD. DESIGN AND SETTING: We conducted a prospective observational study between January 2007 and January 2009 in academic Pediatric Cardiosurgery and Endocrinology. PATIENTS: Patients included 324 children (164 males, 160 females, aged 0.2-15.4 yrs) with CHD. INTERVENTION: Subjects underwent hormonal and genetic screening. MAIN OUTCOME MEASURES: Serum TSH and thyroid hormone levels were assessed. RESULTS: Two CHD patients were diagnosed with CH at the neonatal screening (1:162). Mild hypothyroidism (serum TSH > 4.0 MUU/ml) was diagnosed and confirmed 6 months later [TSH = 5.4 +/- 1.5 MUU/ml; free T(4) = 1.3 +/- 0.2 ng/dl (normal values 0.8-1.9)] in 37 children (11.5%) who were negative at neonatal screening. Hypothyroidism was not related to type of CHD, whereas TSH levels positively correlated with serum N-terminal pro-type B natriuretic peptide levels. Biochemical and ultrasound findings consistent with thyroid autoimmunity were present in three of 37 hypothyroid children (8.1%). One patient had hemiagenesis (2.7%). Variations in candidate genes were screened in CHD patients. NKX2.5 coding sequence was normal in all samples. A 3-Mb microdeletion in 22q11.2 was detected in three patients (8.3%), whereas only known polymorphisms were identified in TBX1 coding sequence. CONCLUSIONS: CHD patients have an increased risk for both CH (10-fold higher) and acquired mild hypothyroidism (3-fold higher). Unrecognized mild hypothyroidism may negatively affect the outcome of CHD children, suggesting that thyroid function should be repeatedly checked. Thyroid autoimmunity and 22q11.2 microdeletions account for small percentages of these cases, and still unknown mechanisms underline such a strong association. PMID- 21525160 TI - Increased prevalence of carpal tunnel syndrome in albright hereditary osteodystrophy. AB - CONTEXT: Albright hereditary osteodystrophy (AHO) is a rare genetic disorder characterized by phenotypic abnormalities including brachydactyly/brachymetacarpia, short stature, and sc ossifications. Carpal tunnel syndrome (CTS) is a chief complaint in many patients with AHO. OBJECTIVE: The objective of the study was to investigate the prevalence of CTS in patients with AHO. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at the Clinical Research Center (Institute of Clinical and Translational Medicine), Johns Hopkins University School of Medicine and Albright Clinic, Kennedy Krieger Institute. PARTICIPANTS: Thirty-three subjects with a diagnosis of AHO participated in the study. MAIN OUTCOME MEASURES: We assessed for the presence and location of hand tingling, numbness, pain, weakness, flick sign, difficulty with fine motor skills, severe hand or nail biting, and nocturnal symptoms in the setting of normocalcemia and a euthyroid state. Patients were considered to have CTS if they were positive for three of these symptoms. All subjects were analyzed for mutations in the GNAS gene. RESULTS: Twenty-two subjects (67%) had a clinical diagnosis of CTS (95% confidence interval 0.48, 0.82). Twenty-eight of 33 subjects were confirmed to have mutations in GNAS, of whom 68% had CTS (95% confidence interval 0.48, 0.84). There were 14 children in this study; 36% had a clinical diagnosis of CTS. Body mass index, brachydactyly/brachymetacarpia, prior GH treatment, and specific GNAS mutations were not associated with CTS. CONCLUSIONS: We report a high prevalence of CTS in both adults and children with AHO. The diagnosis of CTS should be considered when evaluating a patient with AHO because the intervention for CTS could improve overall function and quality of life in these patients. PMID- 21525161 TI - Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition. AB - BACKGROUND: The antidepressant effect of estrogen in women undergoing the menopause transition is hypothesized to be mediated by central nervous system effects of increasing estradiol on mood or through a pathway involving suppression of hot flashes and associated sleep disturbance. Estrogen therapy (ET) and the hypnotic agent zolpidem were selected as interventions in a three arm, double-blind, placebo-controlled trial to distinguish the effects of estradiol, sleep, and hot flashes on depression. METHODS: Women with depressive disorders, hot flashes, and sleep disturbance were randomly assigned to transdermal 17beta-estradiol 0.05 mg/d, zolpidem 10 mg/d, or placebo for 8 wk. Changes in serum estradiol, perceived sleep quality, objectively measured sleep, and hot flashes were examined as predictors of depression improvement [Montgomery Asberg Depression Rating Scale (MADRS)] using multivariate linear regression. RESULTS: Seventy-two peri/postmenopausal women with depression disorders were randomized to 17beta-estradiol (n = 27), zolpidem (n = 31), or placebo (n = 14). There was no significant difference between groups in depression improvement (overall MADRS decrease 11.8 +/- 8.6). Increasing estradiol (P = 0.009) and improved sleep quality (P < 0.001) predicted improved mood in adjusted models but reduced hot flashes (P = 0.99) did not. Post hoc subgroup analyses revealed that the therapeutic effect of increasing estradiol levels on mood was seen in perimenopausal (P = 0.009), but not postmenopausal, women. CONCLUSIONS: For women with menopause-associated depression, improvement in depression is predicted by improved sleep, and among perimenopausal women, by increasing estradiol levels. These results suggest that changes in estradiol and sleep quality, rather than hot flashes, mediate depression during the menopause transition. Therapies targeting insomnia may be valuable in treating menopause-associated depression. PMID- 21525162 TI - Decreased circulating soluble Tie2 levels in preeclampsia may result from inhibition of vascular endothelial growth factor (VEGF) signaling. AB - OBJECTIVES: Recent studies have found dysregulation in circulating levels of a number of angiogenic factors and their soluble receptors in preeclampsia. In this study, we examined the mechanism of production of soluble Tie2 (sTie2) and its potential connection to the failure of vascular remodeling in preeclamptic pregnancies. DESIGN/SETTING/PATIENTS: Serum samples were collected prospectively from 41 pregnant subjects at five different time points throughout pregnancy. Five of these subjects developed preeclampsia. For a second study, serum and placental samples were collected at delivery from preeclamptic and gestational age-matched controls. We examined serum sTie2 levels, and angiopoietin 1, angiopoietin 2, and Tie2 mRNA expression and localization in placental samples from the central basal plate area. We also examined the effects of vascular endothelial growth factor (VEGF) and a matrix metalloproteinase (MMP) inhibitor on proteolytic shedding of Tie2 in uterine microvascular endothelial cells. RESULTS: Serum sTie2 levels were significantly lower in preeclamptic subjects starting at 24-28 wk of gestation and continued to be lower through the time of delivery. In culture experiments, VEGF treatment significantly increased sTie2 levels in conditioned media, whereas the MMP inhibitor completely blocked this increase, suggesting that VEGF-induced Tie2 release is MMP dependent. CONCLUSIONS: Our data suggest, for the first time, an interaction between VEGF and Tie2 in uterine endothelial cells and a potential mechanism for the decrease in circulating sTie2 levels in preeclampsia, likely through inhibition of VEGF signaling. Further studies on VEGF-Tie2 interactions during pregnancy should provide new insights into the mechanisms underlying the failure of vascular remodeling in preeclampsia and other pregnancy complications. PMID- 21525164 TI - Nonendocrine cancers associated with benign and malignant parathyroid tumors. AB - CONTEXT: There are limited reliable epidemiological data concerning whether individuals with benign/malignant parathyroid tumor are at an elevated risk of developing nonendocrine malignancies or vice versa. OBJECTIVE: The objective of the study was to quantify these risks, especially risk of parathyroid tumors after other cancers. DESIGN: This was a population-based retrospective cohort study. PARTICIPANTS: Participants included the Swedish Family-Cancer Database (1958-2008; 11,697,301 individuals; 1,128,735 survivors of first primary cancers including 12,037 patients with parathyroid adenoma and 83 parathyroid adenocarcinoma). MAIN OUTCOME MEASURE: Standardized incidence ratios (SIR) were adjusted for age; sex; period; residential area; socioeconomic status; and history of hospitalization for obesity, alcoholism, or chronic obstructive pulmonary disease. RESULTS: Nonendocrine cancer sites with significantly increased risk after parathyroid adenoma were small intestine (SIR 2.3), blood (polycythemia vera 2.0), kidney (1.8), nervous system (1.6), skin (melanoma 1.4), and breast (women 1.2). Risk of parathyroid adenoma significantly increased after polycythemia vera (3.9) and malignancy in small intestine (3.5), kidney (2.8), nervous system (2.0), prostate (1.5), skin (melanoma 1.5), bladder (1.4), and breast (women 1.2). Twelve cases of parathyroid adenocarcinoma showed significantly higher risk after other tumors (2.4), especially after thyroid cancer (46.6) and parathyroid adenoma (27.3) but not vice versa in 11 cancer survivors. CONCLUSIONS: Parathyroid adenoma can be a risk factor for parathyroid adenocarcinoma; polycythemia vera; melanoma; and small intestine, kidney, nervous system and breast cancers. Further studies are suggested to find underlying mechanisms for these elevated risks, especially for increased risk of parathyroid tumor in patients with melanoma polycythemia vera, or malignancy in small intestine, kidney, nervous system, bladder, prostate, or breast. PMID- 21525163 TI - Fatty acid binding protein 4 regulates intracellular lipid accumulation in human trophoblasts. AB - CONTEXT: Maternal obesity, gestational diabetes (GDM), or type 2 diabetes (T2DM) is associated with altered lipid metabolism and fetal overgrowth. OBJECTIVE: The objective of the study was to test the hypothesis that hyperlipidemia and hyperinsulinemia regulate lipid content and expression of lipid-trafficking proteins in human placental trophoblasts. STUDY DESIGN: Pregnant women were prospectively enrolled for clinical specimens collection, and cultured human trophoblasts were used for experiments. SETTING: This was a translational study conducted at an academic biomedical research center. PATIENTS OR OTHER PARTICIPANTS: Normal weight, obese, or obese with gestational diabetes or type 2 diabetes pregnant women (n = 10 in each group) undergoing scheduled cesarean delivery at term were enrolled. INTERVENTIONS: Cultured primary human trophoblasts, exposed to insulin (10 nM) and/or fatty acids mix (1200 MUM) in the absence or presence of an fatty acid binding protein 4 (FABP4) inhibitor or after small interfering RNA-mediated knockdown of FABP4. MAIN OUTCOME MEASURES: Serum lipid levels were analyzed in the maternal venous and fetal cord blood. Placental biopsies and cultured trophoblasts were analyzed for FABP expression and lipid accumulation. RESULTS: Obese diabetic women and their fetuses had elevated serum triglyceride levels. Nonesterified fatty acids were elevated and triglycerides were reduced in placental villi from obese diabetic women, and this was accompanied by a 2.6-fold increase in FABP4 expression (P < 0.05). In primary human trophoblasts, fatty acids markedly increased the expression of FABP4 (20- to 40-fold, P < 0.05) and cellular triglyceride content (4-fold, P < 0.05), and this effect was attenuated by small interfering RNA-mediated knockdown of FABP4 or the selective FABP4 inhibitor BMS309403. CONCLUSIONS: Hyperlipidemia alters lipid content and increases the expression of FABP4 in trophoblasts. The reduced triglyceride content after FABP4 inhibition suggests that FABP4 is essential for trophoblast lipid accumulation. PMID- 21525165 TI - Protective effects of L-type fatty acid-binding protein (L-FABP) in proximal tubular cells against glomerular injury in anti-GBM antibody-mediated glomerulonephritis. AB - BACKGROUND: In glomerulonephritis (GN), an overload of free fatty acids (FFA) bound to albumin in urinary protein may induce oxidative stress in the proximal tubules. Human liver-type fatty acid-binding protein (hL-FABP) expressed in human proximal tubules, but not rodents, participates in intracellular FFA metabolism and exerts anti-oxidative effects on the progression of tubulointerstitial damage. We examined whether tubular enhancement of this anti-oxidative action modulates the progression of glomerular damage in immune-mediated GN in hL-FABP chromosomal gene transgenic (Tg) mice. METHODS: Anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM GN) was induced in Tg and wild-type mice (WT). Proteinuria, histopathology, polymorphonuclear (PMN) influx, expression of tubulointerstitial markers for oxidative stress 4-hydroxy-2-Nonenal (HNE) and fibrosis (alpha-smooth muscle actin), proximal tubular damage (Kim-1), Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma) and inflammatory cytokines [Monocyte Chemotactic Protein-1, tumor necrosis factor-alpha (TNF alpha) and Transforming growth factor beta (TGF-beta)] were analyzed. The mice were also treated with an angiotensin type II receptor blocker (ARB). RESULTS: The urinary protein level in Tg mice decreased significantly during the acute phase (~Day 5). Tg mice survived for a significantly longer time than WT mice, with an attenuation of tubulointerstitial damage score and expression of each tubulointerstitial damage marker observed at Day 7. Expression of inflammatory cytokines on Day 7 was higher in WT mice than Tg mice and correlated strongly with PPARgamma expression in WT mice, but not in Tg mice. Interestingly, Tg mice showed insufficient PMN influx at 3 and 6 h, with simultaneous elevation of urinary L-FABP and reduction in HNE expression. The two strains of mice showed different types of glomerular damage, with mild mesangial proliferation in Tg mice and severe endothelial swelling with vascular thrombosis in WT mice. The glomerular damage in Tg mice was improved by administration of an ARB. CONCLUSIONS: The present experimental model suggests that tubular enhancement of L-FABP may protect mice with anti-GBM GN from progression of both tubulointerstitial and glomerular injury. PMID- 21525166 TI - Social cognitive training for schizophrenia: a meta-analytic investigation of controlled research. AB - A wealth of evidence has revealed that deficits in social cognitive skills (including facial affect recognition (FAR), social cue perception, Theory of Mind (ToM), and attributional style) are evident in schizophrenia and are linked to a variety of domains of functional outcome. In light of these associations, a growing number of studies have attempted to ameliorate these deficits as a means of improving outcome in the disorder through the use of structured behavioral training. This study used quantitative methods of meta-analysis to assess the efficacy of behavioral training programs designed to improve social cognitive function. A total of 19 studies consisting of 692 clients were aggregated from relevant databases. Outcome measures were organized according to whether they were social cognitive tests proximal to the intervention or whether they represented measures of treatment generalization (symptoms, observer-rated community, and institutional function). With respect to social cognitive measures, weighted effect-size analysis revealed that there were moderate-large effects of social cognitive training procedures on FAR (identification, d = 0.71 and discrimination, d = 1.01) and small-moderate effects of training on ToM (d = 0.46), while effects on social cue perception and attributional style were not significant. For measures of generalization, weighted effect-size analysis revealed that there were moderate-large effect on total symptoms (d = 0.68) and observer-rated community and institutional function (d = 0.78). Effects of social cognitive training programs on positive and negative symptoms of schizophrenia were nonsignificant. Moderating variables and implications for future research and treatment development are discussed. PMID- 21525167 TI - Testing the psychosis continuum: differential impact of genetic and nongenetic risk factors and comorbid psychopathology across the entire spectrum of psychosis. AB - A growing number of studies demonstrate high rates of subthreshold psychotic experiences, but there is considerable heterogeneity in rates due to study cohort and design factors, obscuring how prevalent psychotic experiences may or may not relate to rare psychotic disorders. In a representative general population sample (n = 4011) in Izmir, Turkey, the full spectrum of expression of psychosis was categorized across 5 groups representing (1) absence of psychosis, (2) subclinical psychotic experiences, (3) low-impact psychotic symptoms, (4) high impact psychotic symptoms, and (5) full-blown clinical psychotic disorder and analyzed for continuity and discontinuity in relation to (1) other symptom dimensions associated with psychotic disorder and (2) proxies of genetic and nongenetic etiology. Results were tested for linear and extralinear contrasts between clinical and nonclinical and between disorder and nondisorder expression of psychosis. Demographic variables, indexing premorbid social adjustment and socioeconomic status, impacted mostly linearly; proxy variables of genetic loading (more or more severely affected relatives) impacted in a positive extralinear fashion; environmental risk factors sometimes impacted linearly (urbanicity and childhood adversity) and sometimes extralinearly (cannabis), occasioning a disproportional shift in risk at the clinical disorder end of the spectrum. Affective symptoms were associated with a disproportionally higher risk below the disorder threshold, whereas a disproportionally higher risk above the threshold was associated with psychotic symptom load, negative symptoms, disorganization, and visible signs of mental illness. Liability associated with respectively affective and nonaffective symptom domains, in interaction with environmental risks, may operate by impacting differentially over a quasi continuous extended psychosis phenotype in the population. PMID- 21525169 TI - An evaluation of the dilution method for identifying metabolism-dependent inhibitors of cytochrome P450 enzymes. AB - Metabolism-dependent inhibition (MDI) of cytochrome P450 is usually assessed in vitro by examining whether the inhibitory potency of a drug candidate increases after a 30-min incubation with human liver microsomes (HLMs). To augment the IC(50) shift, many researchers incorporate a dilution step whereby the samples, after being preincubated for 30 min with a high concentration of HLMs (with and without NADPH), are diluted before measuring P450 activity. In the present study, we show that the greater IC(50) shift associated with the dilution method is a consequence of data processing. With the dilution method, IC(50) values for direct-acting inhibitors vary with the dilution factor unless they are based on the final (postdilution) inhibitor concentration, whereas the IC(50) values for MDIs vary with the dilution factor unless they are based on the initial (predilution) concentration. When the latter data are processed on the final inhibitor concentration, as is commonly done, the IC(50) values for MDI (shifted IC(50) values) decrease by the magnitude of the dilution factor. The lower shifted IC(50) values are a consequence of data processing, not enhanced P450 inactivation. In fact, for many MDIs, increasing the concentration of HLMs actually leads to considerably less P450 inactivation because of inhibitor depletion and/or binding of the inhibitor to microsomes. A true increase in P450 inactivation and IC(50) shift can be achieved by assessing MDI by a nondilution method and by decreasing the concentration of HLMs. These results have consequences for the conduct of MDI studies and the development of cut-off criteria. PMID- 21525168 TI - Identification of increased amounts of eppin protein complex components in sperm cells of diabetic and obese individuals by difference gel electrophoresis. AB - Metabolic disorders like diabetes mellitus and obesity may compromise the fertility of men and women. To unveil disease-associated proteomic changes potentially affecting male fertility, the proteomes of sperm cells from type-1 diabetic, type-2 diabetic, non-diabetic obese and clinically healthy individuals were comparatively analyzed by difference gel electrophoresis. The adaptation of a general protein extraction procedure to the solubilization of proteins from sperm cells allowed for the resolution of 3187 fluorescent spots in the difference gel electrophoresis image of the master gel, which contained the entirety of solubilized sperm proteins. Comparison of the pathological and reference proteomes by applying an average abundance ratio setting of 1.6 and a p <= 0.05 criterion resulted in the identification of 79 fluorescent spots containing proteins that were present at significantly changed levels in the sperm cells. Biometric evaluation of the fluorescence data followed by mass spectrometric protein identification revealed altered levels of 12, 71, and 13 protein species in the proteomes of the type-1 diabetic, type-2 diabetic, and non diabetic obese patients, respectively, with considerably enhanced amounts of the same set of one molecular form of semenogelin-1, one form of clusterin, and two forms of lactotransferrin in each group of pathologic samples. Remarkably, beta galactosidase-1-like protein was the only protein that was detected at decreased levels in all three pathologic situations. The former three proteins are part of the eppin (epididymal proteinase inhibitor) protein complex, which is thought to fulfill fertilization-related functions, such as ejaculate sperm protection, motility regulation and gain of competence for acrosome reaction, whereas the putative role of the latter protein to function as a glycosyl hydrolase during sperm maturation remains to be explored at the protein/enzyme level. The strikingly similar differences detected in the three groups of pathological sperm proteomes reflect a disease-associated enhanced formation of predominantly proteolytically modified forms of three eppin protein complex components, possibly as a response to enduring hyperglycemia and enhanced oxidative stress. PMID- 21525170 TI - Effects of chronic renal failure on kidney drug transporters and cytochrome P450 in rats. AB - Chronic renal failure (CRF) leads to decreased drug renal clearance due to a reduction in the glomerular filtration rate. However, little is known about how renal failure affects renal metabolism and elimination of drugs. Because both depend on the activity of uptake and efflux by renal transporters as well as enzymes in tubular cells, the purpose of this study was to investigate the effects of CRF on the expression and activity of select renal drug transporters and cytochrome P450. Two groups of rats were studied: control and CRF (induced by 5/6 nephrectomy). Compared with control rats, we observed reductions in the expression of both protein and mRNA of Cyp1a, sodium-dependent phosphate transport protein 1, organic anion transporter (Oat)1, 2, and 3, OatK1/K2, organic anion-transporting polypeptide (Oatp)1 and 4c1, P-glycoprotein, and urate transporter 1, whereas an induction in the protein and mRNA expression of Mrp2, 3, and 4 and Oatp2 and 3 was observed. Cyp3a expression remained unchanged. Similar results were obtained by incubating a human proximal tubule cell line (human kidney-2) with sera from CRF rats, suggesting the presence of uremic modulators. Finally, the renal elimination of [(3)H]digoxin and [(14)C]benzylpenicillin was decreased in CRF rats, compared with controls, as shown by a 4- and 9-fold accumulation, respectively, of these drugs in kidneys of rats in CRF. Our results demonstrate that CRF affects the expression and activity of several kidney drug transporters leading to the intrarenal accumulation of drugs and reduced renal clearance that could, at least partially, explain the tubular toxicity of many drugs. PMID- 21525171 TI - Bortezomib primes glioblastoma, including glioblastoma stem cells, for TRAIL by increasing tBid stability and mitochondrial apoptosis. AB - PURPOSE: Searching for novel approaches to sensitize glioblastoma for cell death, we investigated the proteasome inhibitor bortezomib. EXPERIMENTAL DESIGN: The effect of bortezomib on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis signaling pathways was analyzed in glioblastoma cell lines, primary glioblastoma cultures, and in an in vivo model. RESULTS: Bortezomib and TRAIL synergistically trigger cell death and reduce colony formation of glioblastoma cells (combination index < 0.1). Investigations into the underlying molecular mechanisms reveal that bortezomib and TRAIL act in concert to cause accumulation of tBid, the active cleavage product of Bid. Also, the stability of TRAIL-derived tBid markedly increases on proteasome inhibition. Notably, knockdown of Bid significantly decreases bortezomib- and TRAIL-mediated cell death. By comparison, silencing of Noxa, which is also upregulated by bortezomib, does not confer protection. Coinciding with tBid accumulation, the activation of Bax/Bak and loss of mitochondrial membrane potential are strongly increased in cotreated cells. Overexpression of Bcl-2 significantly reduces mitochondrial perturbations and cell death, underscoring the functional relevance of the mitochondrial pathway. In addition, bortezomib cooperates with TRAIL to reduce colony formation of glioblastoma cells, showing an effect on long-term survival. Of note, bortezomib profoundly enhances TRAIL-triggered cell death in primary cultured glioblastoma cells and in patient-derived glioblastoma stem cells, underlining the clinical relevance. Importantly, bortezomib cooperates with TRAIL to suppress tumor growth in an in vivo glioblastoma model. CONCLUSION: These findings provide compelling evidence that the combination of bortezomib and TRAIL presents a promising novel strategy to trigger cell death in glioblastoma, including glioblastoma stem cells, which warrants further investigation. PMID- 21525172 TI - Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. AB - PURPOSE: Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders. EXPERIMENTAL DESIGN: In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function. RESULTS: The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus. CONCLUSIONS: This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation. PMID- 21525173 TI - MicroRNAs are independent predictors of outcome in diffuse large B-cell lymphoma patients treated with R-CHOP. AB - PURPOSE: Diffuse large B-cell lymphoma (DLBCL) heterogeneity has prompted investigations for new biomarkers that can accurately predict survival. A previously reported 6-gene model combined with the International Prognostic Index (IPI) could predict patients' outcome. However, even these predictors are not capable of unambiguously identifying outcome, suggesting that additional biomarkers might improve their predictive power. EXPERIMENTAL DESIGN: We studied expression of 11 microRNAs (miRNA) that had previously been reported to have variable expression in DLBCL tumors. We measured the expression of each miRNA by quantitative real-time PCR analyses in 176 samples from uniformly treated DLBCL patients and correlated the results to survival. RESULTS: In a univariate analysis, the expression of miR-18a correlated with overall survival (OS), whereas the expression of miR-181a and miR-222 correlated with progression-free survival (PFS). A multivariate Cox regression analysis including the IPI, the 6 gene model-derived mortality predictor score and expression of the miR-18a, miR 181a, and miR-222, revealed that all variables were independent predictors of survival except the expression of miR-222 for OS and the expression of miR-18a for PFS. CONCLUSION: The expression of specific miRNAs may be useful for DLBCL survival prediction and their role in the pathogenesis of this disease should be examined further. PMID- 21525174 TI - Thyrotropin receptor stimulates internalization-independent persistent phosphoinositide signaling. AB - The thyrotropin [thyroid-stimulating hormone (TSH)] receptor (TSHR) is known to acutely and persistently stimulate cAMP signaling and at higher TSH concentrations to acutely stimulate phosphoinositide signaling. We measured persistent signaling by stimulating TSHR-expressing human embryonic kidney-EM293 cells with TSH and measuring cAMP or inositol monophosphate (IP1) production, a measure of phosphoinositide signaling, 60 min or longer after TSH removal. In contrast to persistent cAMP production, persistent IP1 production increased progressively when TSH exposure was increased from 1 to 30 min, whereas the rates of decay of persistent signaling were similar. A small-molecule agonist and a thyroid-stimulating antibody also caused persistent IP1 and cAMP signaling. A small-molecule inverse agonist and a neutral antagonist inhibited TSH-stimulated persistent IP1 production, whereas the inverse agonist but not the neutral antagonist inhibited persistent cAMP production. As with persistent cAMP production, persistent IP1 production was not affected when TSHR internalization was inhibited or enhanced. Moreover, Alexa546-TSH-activated TSHR internalization was not accompanied by Galpha(q) coupling protein internalization. Thus, transient exposure to high concentrations of TSH causes persistent phosphoinositide and cAMP signaling that is not dependent on internalization. To our knowledge, this is the first demonstration of persistent activation by any G protein-coupled receptor (GPCR) via the Galpha(q) pathway and of two G protein mediated pathways by any GPCR. PMID- 21525175 TI - Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias. AB - Calorie restriction (CR) has been demonstrated to alter cytokine levels; however, its potential to modify sickness behavior (fever, anorexia, cachexia) has not. The effect of CR on sickness behavior was examined in male C57BL/6J mice fed ad libitum or restricted 25% (CR25%) or restricted 50% (CR50%) in food intake for 28 days and injected with 50 MUg/kg of LPS on day 29. Changes in body temperature, locomotor activity, body weight, and food intake were determined. A separate cohort of mice were fed ad libitum or CR50% for 28 days, and hypothalamic mRNA expression of inhibitory factor kappaB-alpha (IkappaB-alpha), cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), suppressor of cytokine signaling 3 (SOCS3), IL-10, neuropeptide Y (NPY), leptin, proopiomelanocortin (POMC), and corticotrophin-releasing hormone (CRH) were determined at 0, 2, and 4 h post-LPS. CR50% mice did not develop fevers, whereas the CR25% mice displayed a fever shorter in duration but with the same peak as the controls. Both CR25% and CR50% mice showed no sign of anorexia and reduced cachexia after LPS administration. Hypothalamic mRNA expression of NPY and CRH were both increased by severalfold in CR50% animals preinjection compared with controls. The CR50% mice did not demonstrate the expected rise in hypothalamic mRNA expression of COX-2, microsomal prostaglandin E synthase-1, POMC, or CRH 2 h post-LPS, and leptin expression was decreased at this time point. Increases in SOCS3, IL-10, and IkappaB-alpha expression in CR50% animals were enhanced compared with ad libitum fed controls at 4 h post-LPS. CR results in a suppression of sickness behavior in a dose-dependent manner, which may be due to CR attenuating proinflammatory pathways and enhancing anti-inflammatory pathways. PMID- 21525176 TI - Recovered insulin response by 2 weeks of leptin administration in high-fat fed rats is associated with restored AS160 activation and decreased reactive lipid accumulation. AB - Leptin is an adipokine that increases fatty acid (FA) oxidation, decreases intramuscular lipid stores, and improves insulin response in skeletal muscle. In an attempt to elucidate the underlying mechanisms by which these metabolic changes occur, we administered leptin (Lep) or saline (Sal) by miniosmotic pumps to rats during the final 2 wk of a 6-wk low-fat (LF) or high-fat (HF) diet. Insulin-stimulated glucose transport was impaired by the HF diet (HF-Sal) but was restored with leptin administration (HF-Lep). This improvement was associated with restored phosphorylation of Akt and AS160 and decreased in reactive lipid species (ceramide, diacylglycerol), known inhibitors of the insulin-signaling cascade. Total muscle citrate synthase (CS) activity was increased by both leptin and HF diet, but was not additive. Leptin increased subsarcolemmal (SS) and intramyofibrillar (IMF) mitochondria CS activity. Total muscle, sarcolemmal, and mitochondrial (SS and IMF) FA transporter (FAT/CD36) protein content was significantly increased with the HF diet, but not altered by leptin. Therefore, the decrease in reactive lipid stores and subsequent improvement in insulin response, secondary to leptin administration in rats fed a HF diet was not due to a decrease in FA transport protein content or altered cellular distribution. PMID- 21525177 TI - The temporal structure of feeding behavior. AB - Meals have long been considered relevant units of feeding behavior. Large data sets of feeding behavior of cattle, pigs, chickens, ducks, turkeys, dolphins, and rats were analyzed with the aims of 1) describing the temporal structure of feeding behavior and 2) developing appropriate methods for estimating meal criteria. Longer (between-meal) intervals were never distributed as the negative exponential assumed by traditional methods, such as log-survivorship analysis, but as a skewed Gaussian, which can be (almost) normalized by log-transformation of interval lengths. Log-transformation can also normalize frequency distributions of within-meal intervals. Meal criteria, i.e., the longest interval considered to occur within meals, can be estimated after fitting models consisting of Gaussian functions alone or of one Weibull and one or more Gaussian functions to the distribution of log-transformed interval lengths. Nonuniform data sets may require disaggregation before this can be achieved. Observations from all species were in conflict with assumptions of random behavior that underlie traditional methods for criteria estimation. Instead, the observed structure of feeding behavior is consistent with 1) a decrease in satiety associated with an increase in the probability of animals starting a meal with time since the last meal and 2) an increase in satiation associated with an increase in the probability of animals ending a meal with the amount of food already consumed. The novel methodology proposed here will avoid biased conclusions from analyses of feeding behavior associated with previous methods and, as demonstrated, can be applied across a range of species to address questions relevant to the control of food intake. PMID- 21525178 TI - Genome-wide deficiency mapping of the regions responsible for temporal canalization of the developmental processes of Drosophila melanogaster. AB - Developmental processes of organisms are programmed to proceed in a finely regulated manner and finish within a certain period of time depending on the ambient environmental conditions. Therefore, variation in the developmental period under controlled genetic and environmental conditions indicates innate instability of the developmental process. In this study, we aimed to determine whether a molecular machinery exists that regulates the canalization of the developmental period and, if so, to test whether the same mechanism also stabilizes a morphological trait. To search for regions that influence the instability of the developmental period, we conducted genome-wide deficiency mapping with 441 isogenic deficiency strains covering 65.5% of the Drosophila melanogaster genome. We found that 11 independent deficiencies significantly increased the instability of the developmental period and 5 of these also significantly increased the fluctuating asymmetry of wing shape although there was no significant correlation between the instabilities of developmental period and wing shape in general. These results suggest that canalization processes of the developmental period and morphological traits are at least partially independent. Our findings emphasize the potential importance of temporal variation in development as an indicator of developmental stability and canalization and provide a novel perspective for understanding the regulation of phenotypic variability. PMID- 21525181 TI - Influence of brachial plexus blockade on oxygen balance during surgery. AB - The combined effects of anesthesia, motor blockade, and chemically induced sympathectomy after brachial plexus blockade can have a beneficial impact, when applied in selected, isolated diseased states of the upper limb. With the aim of using the prolonged effects of brachial plexus blockade for a future therapeutic application, we demonstrated a dependable methodology of venous blood gas monitoring and confirmed an improved oxygen balance of the blocked versus nonblocked upper extremity in a controlled, prospective study in healthy patients undergoing elective hand surgery. PMID- 21525180 TI - Efficient long-distance gene flow into an isolated relict oak stand. AB - Geographically isolated and small populations outside a species' central distribution range are likely to be of major importance to a species' ability to quickly adjust its distribution range to global change dynamics. Gene flow from the outside plays a pivotal role in the fate of these marginal populations. It has been proposed that spatial fragmentation and perceived geographic isolation do not necessarily reflect a loss of genetic connectivity in tree species. However, the spatial limits of long-distance gene flow, as well as its magnitude and impact, are still generally unknown. In the present study, we analyzed long distance pollen-mediated gene flow into an isolated relict stand consisting of 7 individuals of Quercus robur L. based on a total sample of 177 trees and 9 microsatellite loci. We show that pollen-mediated gene flow across more than 80 km in this wind-pollinated tree species contributed at least 35% of all successful pollinations in the investigated isolated and small oak stand at the eastern limit of the species' distribution. The observed pollen immigration shaped the genetic diversity of acorn progenies in the stand and might explain the comparably high genetic diversity in the persisting adult population. PMID- 21525179 TI - Genomics of environmentally induced phenotypes in 2 extremely plastic arthropods. AB - Understanding how genes and the environment interact to shape phenotypes is of fundamental importance for resolving important issues in adaptive evolution. Yet, for most model species with mature genetics and accessible genomic resources, we know little about the natural environmental factors that shape their evolution. By contrast, animal species with deeply understood ecologies and well characterized responses to environmental cues are rarely subjects of genomic investigations. Here, we preview advances in genomics in aphids and waterfleas that may help transform research on the regulatory mechanisms of phenotypic plasticity. This insect and crustacean duo has the capacity to produce extremely divergent phenotypes in response to environmental stimuli. Sexual fate and reproductive mode are condition-dependent in both groups, which are also capable of altering morphology, physiology and behavior in response to biotic and abiotic cues. Recently, the genome sequences for the pea aphid Acyrthosiphon pisum and the waterflea Daphnia pulex were described by their respective research communities. We propose that an integrative study of genome biology focused on the condition-dependent transcriptional basis of their shared plastic traits and specialized mode of reproduction will provide broad insight into adaptive plasticity and genome by environment interactions. We highlight recent advances in understanding the genome regulation of alternative phenotypes and environmental cue processing, and we propose future research avenues to discover gene networks and epigenetic mechanisms underlying phenotypic plasticity. PMID- 21525182 TI - Performance characteristics and validation of the Opioid-Related Symptom Distress Scale for evaluation of analgesic side effects after orthopedic surgery. AB - BACKGROUND: The Opioid-Related Symptom Distress Scale (ORSDS) is a 4-point scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness) for 12 symptoms. The symptom-specific ORSDS is the average of the 3 symptom distress dimensions. The composite ORSDS is the average of 12 symptom specific scores. The ORSDS was validated for outpatient laparoscopic cholecystectomy (under general anesthesia) by assessment of internal consistency, content validity, construct validity, principal components analysis, known group validity, responsiveness, and opioid dose dependency. Additional validation studies were suggested. We investigated performance characteristics and validity of the ORSDS for postoperative analgesia after 4 types of anesthetic and analgesic regimens. METHODS: The ORSDS and validation questions were administered to 4 groups of 50 orthopedic patients. Peripheral nerve blockade (Peripheral) was performed for distal upper extremity surgery; neuraxial anesthesia (Neuraxial) was performed for anterior cruciate ligament reconstruction; combined spinal epidural anesthesia/femoral nerve block/epidural analgesia (Regional) was performed for total knee arthroplasty; and general anesthesia/IV opioids (GA) was performed for posterior lumbar spine fusion. All patients also received oral opioid analgesics. RESULTS: Median composite ORSDS scores on postoperative day 1 were 0.19 (Peripheral), 0.52 (Neuraxial), 0.51 (Regional), and 0.94 (GA). The following symptoms had median symptom-specific ORSDS scores >0: Neuraxial = drowsiness, dry mouth; Regional = dizziness, dry mouth; GA = nausea, fatigue, dizziness, drowsiness, dry mouth. Problematic symptoms (symptoms for which at least 25%of patients reported symptom-specific ORSDS scores >1) were: all groups = drowsiness, dry mouth, fatigue; Neuraxial = nausea, dizziness, itchiness; Regional = nausea, dizziness, itchiness; GA = difficulty concentrating, headache, nausea, dizziness, itchiness. High symptom-specific ORSDS scores were associated with clinically meaningful adverse events. In some cases, relevant ORSDS scores were related to activity level, patient satisfaction, and nausea and vomiting measures. Many components occurred in correlated clusters. Responsiveness statistics (the ability of an instrument to detect changes once they have occurred) were high for nausea and vomiting. Linear regression analysis indicated that opioid use was associated with composite ORSDS scores for Peripheral, Regional, and GA. CONCLUSIONS: Validity of the ORSDS was supported by predetermined validation criteria, including measures of internal consistency, content validity, construct validity, principal components analysis, known group validity, responsiveness, and correlation with opioid intake. The ORSDS is a valid tool for assessment of opioid side effects after orthopedic surgery, and can be used in clinical trials involving a wide variety of anesthetic and analgesic regimens. PMID- 21525183 TI - The local anesthetic effect of memantine on infiltrative cutaneous analgesia in the rat. AB - BACKGROUND: Memantine blocks N-methyl-D-aspartate receptors and the Na(+) current, one principal mechanism of local anesthesia. Until now, no study mentioned that memantine had a local anesthetic effect, and therefore we investigated the local anesthetic effect of memantine. METHODS: After blockade of cutaneous trunci muscle reflex with subcutaneous injections, we evaluated the cutaneous analgesic effect of memantine, lidocaine, and dizocilpine (MK-801) in rats. The dose-dependent response of memantine on cutaneous analgesia was compared with lidocaine and MK-801 in rats. The duration of action for each drug was evaluated and compared on an equipotent basis (20% effective dose [ED(20)], ED(50), and ED(80)). Lidocaine, a frequently used local anesthetic, was used as control. RESULTS: We demonstrated that memantine, lidocaine, and MK-801 produced dose-dependent local anesthetic effects as infiltrative cutaneous analgesia. The relative potency was MK-801 (10.4 [9.7-11.1]) > memantine (17.6 [15.2-20.4]) > lidocaine (25.9 [23.8-28.1 ]) (P < 0.01). On an equipotent basis, memantine showed longer duration than lidocaine (P = 0.012) and MK-801 (P = 0.008). Coadministration of memantine (13.3 MUmol/kg) and MK-801 (1.3 MUmol/kg) produced greater blockade and duration than memantine (13.3 MUmol/kg) or MK-801 (1.3 MUmol/kg) alone. Neither local injection of saline nor intraperitoneal administration of a large dose of memantine, lidocaine, or MK-801 produced cutaneous analgesia (data not shown). CONCLUSIONS: This study indicated that memantine is less potent than MK-801, and that memantine elicits longer analgesic duration than both lidocaine and MK-801. When combined with MK-801, memantine demonstrates a synergetic effect of cutaneous analgesia. We conclude that memantine produces better local analgesia than lidocaine and that N-methyl-D aspartate receptors also contribute to the analgesic effect of memantine. PMID- 21525184 TI - Reactive oxygen species scavenger inhibits STAT3 activation after transient focal cerebral ischemia-reperfusion injury in rats. AB - BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) activation in ischemic brain has been verified. However, the mechanism and the role of STAT3 activation after cerebral ischemia-reperfusion are poorly elucidated. In the present study, we sought to test the hypothesis that STAT3 activation after cerebral ischemia-reperfusion was related to reactive oxygen species (ROS) production. METHODS: Adult male Sprague-Dawley rats were subjected to focal cerebral ischemia induced by middle cerebral artery occlusion. STAT3 activation was evaluated by immunohistochemistry and Western blotting. Rats were subjected to permanent ischemia or ischemia-reperfusion to clarify the temporal profile of STAT3 activation. The role of ROS in inducing STAT3 activation was assessed by administration of the ROS scavenger dimethylthiourea (DMTU). The effects of DMTU and the STAT3 activation inhibitor AG490 administration on brain ischemic injuries were evaluated by neurologic behavior scores and brain infarct volumes. RESULTS: The activation of STAT3 after middle cerebral artery occlusion was significantly increased within peri-ischemia neurons and astrocytes. STAT3 activation mainly occurred in the reperfusion phase rather than in the ischemia phase. In addition, DMTU suppressed STAT3 activation in a dose-dependent manner, indicating that STAT3 activation may be a subsequent event after ROS production. DMTU and AG490 significantly reduced infarct sizes and improved neurologic outcomes. CONCLUSION: In comparison with ischemia, reperfusion is a more powerful stimulus for STAT3 activation. ROS scavenging is closely correlated with an inhibition of STAT3 activation. Neuroprotective effects are achieved through ROS scavenging and down-regulation of STAT3 activation. PMID- 21525185 TI - Induction of in vitro and in vivo NK cell cytotoxicity using high-avidity immunoligands targeting prostate-specific membrane antigen in prostate carcinoma. AB - Cancer that might develop as host natural killer (NK) cells fail to detect ligands for their activating NK receptors. Immunoligands represent promising immunotherapeutic tools to overcome this deficit. These are fusion proteins containing a single-chain antibody fragment (scFv) to target an available tumor antigen and ULBP2 to activate host NK cells by targeting the activatory receptor NKG2D. Prostate-specific membrane antigen (PSMA) is an integral non-shed type 2 membrane protein that is highly and specifically expressed on prostate epithelial cells and strongly upregulated in prostate cancer. Here, we compare the impact of various anti-PSMA immunoligand formats on the therapeutic efficacy against prostate carcinoma cells by activating NK cells via NKG2D. Shortening of the linker separating the heavy and light chain antibody domain leads to the formation of dimers, trimers, and higher molecular mass oligomers. NK cells are most efficiently activated by multimeric immunoligands, thus showing an altered cytokine release pattern. The high avidity format is also superior in in vitro NK mediated tumor cell targeting as shown in cytotoxicity assays. Finally, the efficacy of a multimeric immunoligand is shown in a prostate carcinoma mouse xenograft model showing a strong activity against advanced established tumors. PMID- 21525186 TI - The open microcirculation in human spleens: a three-dimensional approach. AB - It has long been debated whether the red pulp of human spleens harbors an open or a closed microcirculation or both. To solve this issue, the authors differentially stained the endothelium in red pulp arterial microvessels and in venous sinuses using brightfield and fluorescence immunohistology with reagents against CD34 and CD141. Three-dimensional models of red pulp arterial microvessels and sinuses were derived from serial double-stained paraffin sections with the help of license-free open-access software. In each model, arterial microvascular ends were traced and verified by reference to the original serial sections. In total, 142 ends were analyzed in the specimens of three individuals. None of these ends was connected to a sinus, suggesting that the human splenic red pulp harbors an entirely open circulatory system. Thus, the spleen is the only human organ where blood passes through spaces not lined by endothelia or other barrier-forming cells. PMID- 21525187 TI - Different patterns of mast cells distinguish diffuse from encapsulated neurofibromas in patients with neurofibromatosis 1. AB - Multiple neurofibromas are cardinal features of neurofibromatosis 1 (NF1). Several different types of NF1-associated neurofibromas occur, each distinct in terms of pathological details, clinical presentation, and natural history. Mast cells are present in most neurofibromas and have been shown to be critical to the origin and progression of neurofibromas in both human NF1 and relevant mouse models. In this investigation, the authors determined whether mast cell involvement is the same for all types of NF1-associated neurofibromas. They examined the density and distribution of mast cells within 49 NF1-associated neurofibromas classified histopathologically as diffuse or encapsulated on the basis of the presence or absence of the perineurium or its constituent cells. They made two observations: (1) Diffuse neurofibromas had significantly higher densities of mast cells than did encapsulated neurofibromas, and (2) mast cells were evenly distributed throughout diffuse neurofibromas but were primarily restricted to the periphery of encapsulated neurofibromas. The differences in mast cell density and distribution differentiate the two basic types of NF1 associated neurofibromas, suggesting that the pathogenesis of diffuse and encapsulated neurofibromas may be significantly different. PMID- 21525188 TI - Specific in situ visualization of plasma cells producing antibodies against Porphyromonas gingivalis in gingival radicular cyst: application of the enzyme labeled antigen method. AB - The enzyme-labeled antigen method was applied to visualize plasma cells producing antibodies to Porphyromonas gingivalis, flora of the human oral cavity. Antibodies to P. gingivalis have reportedly been detected in sera of patients with periodontitis. Biotinylated bacterial antigens, Ag53, and four gingipain domains (Arg-pro, Arg-hgp, Lys-pro, and Lys-hgp) were prepared by the cell-free protein synthesis system using the wheat germ extract. In paraformaldehyde-fixed frozen sections of rat lymph nodes experimentally immunized with Ag53-positive and Ag53-negative P. gingivalis, plasma cells were labeled with biotinylated Arg hgp and Lys-hgp. Antibodies to Ag53 were detected only in the nodes immunized with Ag53-positive bacteria. In two of eight lesions of gingival radicular cyst with inflammatory infiltration, CD138-positive plasma cells in frozen sections were signalized for Arg-hgp and Lys-hgp. An absorption study using unlabeled antigens confirmed the specificity of staining. The AlphaScreen method identified the same-type antibodies in tissue extracts but not in sera. Antibodies to Ag53, Arg-pro, and Lys-pro were undetectable. In two cases, serum antibodies to Arg-hgp and Lys-hgp were AlphaScreen positive, whereas plasma cells were scarcely observed within the lesions. These findings indicate the validity of the enzyme labeled antigen method. This is the very first application of this novel histochemical technique to human clinical samples. PMID- 21525189 TI - A sensitive alternative for microRNA in situ hybridizations using probes of 2'-O methyl RNA + LNA. AB - The use of short, high-affinity probes consisting of a combination of DNA and locked nucleic acid (LNA) has enabled the specific detection of microRNAs (miRNAs) by in situ hybridization (ISH). However, detection of low-copy number miRNAs is still not always possible. Here the authors show that probes consisting of 2'-O-methyl RNAs (2OMe) and LNA at every third base (2:1 ratio), under optimized hybridization conditions, excluding yeast RNA from the hybridization buffer, can provide superior performance in detection of miRNA targets in terms of sensitivity and signal-to-noise ratio compared to DNA + LNA probes. Furthermore, they show that hybridizations can be performed in buffers of 4M urea instead of 50% formamide, thereby yielding an equally specific but nontoxic assay. The use of 2OMe + LNA-based probes and the optimized ISH assay enable simple and fast detection of low-copy number miRNA targets, such as miR-130a in mouse brain. PMID- 21525190 TI - Cytoplasmic HDPR1 is involved in regional lymph node metastasis and tumor development via beta-catenin accumulation in esophageal squamous cell carcinoma. AB - The aim of this study was to evaluate HDPR1 expression in esophageal squamous cell carcinoma (ESCC) and the relationship between HDPR1 and beta-catenin by immunohistochemical analysis. The clinical relevance of these proteins was also analyzed. Immunohistochemistry was performed on paraffin-embedded tissue specimens from 184 ESCC patients to detect the expression of HDPR1 and beta catenin. The correlation between the results of immunoexpression and the clinicopathologic features was processed statistically. Increased cytoplasmic and nuclear HDPR1 expression was noted in 100 (54.3%) and 131 (71.2%) of 184 specimens, respectively. Statistical analysis showed significant associations of cytoplasmic HDPR1 with regional lymph node metastasis (p = 0.021) and P-stage (p = 0.004). The increased nuclear staining was only correlated with P-stage (p = 0.047). Significant associations of coexpression of cytoplasmic and nuclear HDPR1 with regional lymph node metastasis (p = 0.015) or P-stage (p = 0.002) were observed. Enhanced cytoplasmic expression of HDPR1 was positively correlated with increased cytoplasmic but not reduced membranous beta-catenin expression (r = 0.239, p = 0.027 and r = 0.126, p = 0.089, respectively). These finding suggested that cytoplasmic HDPR1 protein expression was associated with tumor malignant progression via beta-catenin accumulation. It implicated that cytoplasmic HDPR1 expression may serve as a potential predictive factor for lymph node metastasis and tumor development in ESCC. PMID- 21525192 TI - The role of meta-analysis in the evaluation of the effects of early nutrition on mental and motor development in children. AB - The role of early nutrition as a cost-effective measure to ensure optimal infant growth, development, and long-term health is gaining attention. In particular, the role of supplementation with nutrients such as n-3 (omega-3) fatty acids, iron, zinc, and B vitamins, which are relevant to brain structure and function, is of interest. However, for all of these nutrients, there is a lack of clarity and no consensus regarding their role in the mental and motor development of children. Systematic reviews with or without a meta-analysis are a well established means of reviewing existing evidence and of integrating findings from various studies, including those related to infant nutrition. In this article, I provide an overview of the basic principles of systematic review and meta analysis of randomized controlled trials (RCTs) and summarize such evidence related to the effects of early nutrition on mental and motor development. The inclusion of only RCTs in a systematic review could be considered the major strength. Randomization is the only means to control for unknown and unmeasured differences between comparison groups as well as for those that are known and measured. However, even if only RCTs are included, reviews are not free of potential biases. An understanding of the strengths and limitations of the meta analytic approach, which I discuss in this article, is needed by everyone involved in decision making regarding interventions assessed by this approach. PMID- 21525191 TI - Urinary tract stone occurrence in the Women's Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements. AB - BACKGROUND: The Women's Health Initiative (WHI) randomized clinical trial (RCT) of calcium plus vitamin D (CaD) supplements found a 17% excess in urinary tract stone incidence in the supplemented group. This study evaluated whether this risk is modified by participant characteristics. OBJECTIVE: We examined the correlates of urinary tract stone occurrence in the CaD arm of the WHI trial. DESIGN: We analyzed an RCT involving 36,282 postmenopausal women aged 50-79 y from 40 WHI centers: 18,176 women received 500 mg calcium carbonate plus 200 IU vitamin D(3) twice daily (1000 mg and 400 IU daily, respectively), and 18,106 women received a matching placebo for an average of 7.0 y. The incidence of urinary tract stones was determined. RESULTS: The incidence of self-reported clinically diagnosed urinary tract stones was more common in the active CaD medication group than in the placebo group (hazard ratio: 1.17; 95% CI: 1.02, 1.34): 449 women in the CaD group and 381 women in the placebo group reported a stone during the trial. The rates of self-reported stones did not differ between various demographic, anthropomorphic, dietary, and other hypothesized risk factors according to randomization assignment. Neither the total calcium intake nor the use of calcium supplements at baseline was associated with the risk of stones. In sensitivity analyses that censored participants who were below 80% adherence, the findings were similar. CONCLUSIONS: Daily supplementation with CaD for 7 y was associated with an increase in the number of self-reported urinary tract stones. These findings have implications for CaD supplement use. This trial was registered with the WHI at clinicaltrials.gov as NCT00000611. PMID- 21525193 TI - Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss induced decrease in liver fat in humans. AB - BACKGROUND: The rs738409 C->G single nucleotide polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin) leads to a missense mutation (I148M), which is associated with increased liver fat but not insulin resistance. The I148M mutation impedes triglyceride hydrolysis in vitro, and its carriers have an increased risk of developing severe liver disease. OBJECTIVE: We explored whether the rs738409 PNPLA3 G allele influences the ability of weight loss to decrease liver fat or change insulin sensitivity. DESIGN: We recruited 8 subjects who were homozygous for the rs738409 PNPLA3 G allele (PNPLA3-148MM) and 10 who were homozygous for the rs738409 PNPLA3 C allele (PNPLA3-148II). To allow comparison of changes in liver fat, the groups were matched with respect to baseline age, sex, body mass index, and liver fat. The subjects were placed on a hypocaloric low-carbohydrate diet for 6 d. Liver fat content (proton magnetic resonance spectroscopy), whole-body insulin sensitivity of glucose metabolism (euglycemic clamp technique), and lipolysis ([(2)H(5)]glycerol infusion) were measured before and after the diet. RESULTS: At baseline, fasting serum insulin and C-peptide concentrations were significantly lower in the PNPLA3-148MM group than in the PNPLA3-148II group, as predicted by study design. Weight loss was not significantly different between groups (PNPLA3-148MM: -3.1 +/- 0.5 kg; PNPLA3 148II: -3.1 +/- 0.4 kg). Liver fat decreased by 45% in the PNPLA3-148MM group (P < 0.001) and by 18% in the PNPLA3-148II group (P < 0.01). CONCLUSION: Weight loss is effective in decreasing liver fat in subjects who are homozygous for the rs738409 PNPLA3 G or C allele. This trial was registered at www.hus.fi as 233775. PMID- 21525194 TI - Galactooligosaccharide supplementation reduces stress-induced gastrointestinal dysfunction and days of cold or flu: a randomized, double-blind, controlled trial in healthy university students. AB - BACKGROUND: Acute psychological stress induced by academic exams is associated with dysregulated gastrointestinal and immune function. OBJECTIVE: We examined whether supplementation with galactooligosaccharides reduced gastrointestinal dysfunction and the percentage of days with cold or flu in academically stressed undergraduate students. DESIGN: In a randomized, double-blind study, subjects (n = 427) received 0, 2.5, or 5.0 g galactooligosaccharides for 8 wk around the time of fall final exams. Levels of stress and cold or flu symptom intensity (SI; 0 = not experiencing to 3 = severe) were recorded daily. The SI from 9 cold or flu symptoms was summed with 1 d of cold or flu defined as a sum >6. The Gastrointestinal Symptom Response Scale was completed weekly. RESULTS: Stress was positively related to diarrhea, indigestion, and reflux syndromes and with abdominal pain, average daily cold or flu SI score, and the percentage of days with cold or flu. Gastrointestinal symptom scores for diarrhea (P = 0.0298), constipation (P = 0.0342), abdominal pain (P = 0.0058), and indigestion (P = 0.0003) syndromes were lower after galactooligosaccharide supplementation. The cold or flu SI score was affected by galactooligosaccharides and stress (P < 0.0001); 2.5 g was associated with a lower SI score across all levels of stress, but 5.0 g was protective only at lower levels of stress. The percentage of days with cold or flu was associated with galactooligosaccharides within different body mass index categories (P = 0.0002), wherein a 40% reduction in the percentage of days with cold or flu was observed in normal-weight individuals with 5.0 g galactooligosaccharides. This effect was not observed in overweight or obese individuals. CONCLUSIONS: Acute psychological stress was directly related to symptoms of gastrointestinal dysfunction and cold or flu. Galactooligosaccharide supplementation reduced these symptoms and the number of days with cold or flu. This trial was registered at clinicaltrials.gov as NCT01137760. PMID- 21525195 TI - Breastfeeding and body composition in children: will there ever be conclusive empirical evidence for a protective effect against overweight? AB - An increased prevalence of childhood overweight has been observed worldwide over the past decades, which indicates the need for strategies to prevent obesity. There is some evidence that risk of obesity is primed by exposures early in life. Among other factors, breastfeeding has been hypothesized as a potential priming factor against overweight. Although the properties of human milk suggest possible mechanisms for a protective effect of breastfeeding compared with formula feeding with respect to later overweight, empirical evidence is more difficult to establish. This article reviews the available epidemiologic literature on this topic. Several observational studies have shown evidence for a small protective effect with respect to overweight in childhood. Three meta-analyses reported significant protective effects of breastfeeding against overweight in later life, whereas another meta-analysis showed no effect of breastfeeding on mean body mass index (BMI) after adjustment for confounding factors. These seemingly inconsistent results might potentially be explained by different effects of breastfeeding in normal-weight compared with overweight children. Evidence from interventional studies is limited. A randomized trial failed to confirm an effect of a breastfeeding promotion on children's BMI, but this trial lacked statistical power because rates of breastfeeding were relatively similar in the intervention and control groups. In conclusion, protective priming effects of breastfeeding on later overweight appear to be possible but are difficult to prove. Although observational studies have to deal with confounding issues, interventional studies on breastfeeding promotion may lack power. PMID- 21525196 TI - Developmental origins of noncommunicable disease: population and public health implications. AB - Noncommunicable diseases (NCDs), including cardiovascular disease, diabetes, chronic lung disease, allergy, some forms of cancer, cognitive decline, osteoporosis, sarcopenia, and affective disorders, are the world's biggest killers. Eighty percent of these deaths occur in low- and middle-income countries, especially as these countries undergo socioeconomic improvement after reductions in infectious disease. The World Health Organization predicts a global increase of 17% in NCDs over the next decade. NCDs are preventable, but new initiatives are needed to institute such prevention, especially in early life. In this article, we emphasize that all children are affected by their early developmental conditions, not just children exposed to a very deficient environment, and that this has long-term consequences for their predisposition to NCDs. We highlight the biomedical implications of this developmental origins of health and disease (DOHaD) concept of NCDs and discuss the implications for health policy. PMID- 21525197 TI - Self-perceived lactose intolerance results in lower intakes of calcium and dairy foods and is associated with hypertension and diabetes in adults. AB - BACKGROUND: Self-perceived lactose intolerance may result in adverse dietary modifications; thus, more studies are needed to understand the prevalence of self perceived lactose intolerance and how it relates to calcium intake and selected health conditions. OBJECTIVE: The objective was to examine the effects of self perceived lactose intolerance as it relates to calcium intake and specific health problems that have been attributed to reduced intakes of calcium and dairy foods in a nationally representative multiethnic sample of adults. DESIGN: This was a cross-sectional study in a national sample of 3452 adults. The relation between self-perceived lactose intolerance, calcium intakes, and physician-diagnosed health conditions was analyzed by using linear regression analyses. RESULTS: Of the total sample, 12.3% of respondents perceived themselves to be lactose intolerant. The age-adjusted prevalence of self-perceived lactose intolerance was 7.8% for non-Hispanic whites, 20.1% for non-Hispanic blacks, and 8.8% for Hispanics. Respondents with self-perceived lactose intolerance had significantly lower (P < 0.05) average daily calcium intakes from dairy foods than did those without self-perceived lactose intolerance. A significantly higher (P < 0.05) percentage of respondents with self-perceived lactose intolerance than of respondents without self-perceived lactose intolerance reported having physician diagnosed diabetes and hypertension. The odds of self-reported physician diagnosed diabetes or hypertension decreased by factors of 0.70 and 0.60, respectively, for a 1000-mg increase in calcium intake from dairy foods per day. CONCLUSIONS: Self-perceived lactose-intolerant respondents had a significantly lower calcium intake from dairy foods and reported having a significantly higher rate of physician-diagnosed diabetes and hypertension. PMID- 21525198 TI - Correcting a marginal riboflavin deficiency improves hematologic status in young women in the United Kingdom (RIBOFEM). AB - BACKGROUND: Moderate riboflavin deficiency is prevalent in certain population groups in affluent countries, but the functional significance of this deficiency is not clear. Studies have indicated a role for riboflavin in the absorption and use of iron. OBJECTIVE: We investigated the effect of riboflavin supplementation on hematologic status in a group of moderately riboflavin-deficient women aged 19 25 y in the United Kingdom. DESIGN: One hundred twenty-three women with biochemical evidence of riboflavin deficiency [erythrocyte glutathione reductase activation coefficient (EGRAC) >1.40] were randomly assigned to receive 2 or 4 mg riboflavin or a placebo for 8 wk. Measurements of hematologic status were made pre- and postsupplementation, and dietary intakes were also assessed; iron absorption was measured in a subgroup of women. RESULTS: One hundred nineteen women completed the intervention. The use of a riboflavin supplement for 8 wk elicited a significant improvement in riboflavin status with a dose response (P < 0.0001). For women who received supplemental riboflavin, an increase in hemoglobin status correlated with improved riboflavin status (P < 0.02). Women in the lowest tertile of riboflavin status at baseline (EGRAC >1.65) showed a significantly greater increase in hemoglobin status in response to the supplement than did women in the first and second tertiles (P < 0.01). Dietary iron intake and iron absorption did not change during the study. CONCLUSIONS: Moderately poor riboflavin status can affect iron status: the lower the riboflavin status, the greater the hematologic benefits of improving status. The results also suggest that consideration should be given to raising the currently accepted EGRAC threshold for deficiency. This trial was registered at controlled-trials.com as ISRCTN35811298. PMID- 21525199 TI - Insights into the programming of bone development from the Avon Longitudinal Study of Parents and Children (ALSPAC). AB - We examined associations between proxy measures of in utero nutrition and total body bone mineral content (BMC), bone area (BA), and bone mineral density (BMD) assessed at age 9.9 y in the Avon Longitudinal Study of Parents and Children (ALSPAC). There were positive relations between birth weight and BMC, BA, and BMD. These associations were explained by the co-association of birth weight with body size in later childhood. In height- and weight-adjusted analyses, an inverse association was observed between birth weight and BMD at age 9.9 y, which suggests that birth weight had a negative influence on bone mass after relations with bone and body size were taken into account. In analyses of associations between bone mass at age 9 y and background ultraviolet B exposure during the third trimester of pregnancy (a proxy measure for maternal vitamin D status), maternal ultraviolet B exposure was positively related to BMC, BA, and BMD. After adjustment for height, these associations were only partially attenuated, which suggests that maternal ultraviolet B exposure affected skeletal size and mass independently of longitudinal growth, possibly by the increase of periosteal expansion. There was a positive relation between maternal folate intake and BMD of the spine subregion independent of body size. Although a co-association with folate intake in childhood could explain this relation, the maternal methylenetetrahydrofolate reductase (MTHFR) genotype affected spine BMD independently of the child MTHFR genotype, which suggests that maternal folate status has an independent effect on bone development of offspring. Together, these results confirm that there is a relation between bone development in childhood and several proxy measures for nutritional status in utero. PMID- 21525200 TI - Assessment of growth: variations according to references and growth parameters used. AB - Numerous studies have investigated associations between early growth and future risk of obesity, but the methods used varied considerably. Different growth references or parameters can be considered. Growth references from France, the United States (the Centers for Disease Control and Prevention), the Netherlands, Belgium, and the United Kingdom were compared with World Health Organization (WHO) standards. For the first 3 mo of life, all references showed markedly lower values for weight, length, and body mass index (BMI) compared with WHO standards, but after the age of 6 mo references were generally higher than WHO standards. Compared with nonbreastfed infants, the growth of breastfed infants was generally closer to that of WHO standards. Because data in the WHO standards were collected on infants who were breastfed, the difference between references and WHO standards might be mainly attributable to feeding practices. Epidemiologic and clinical studies evaluated the consequences of using either WHO standards or national references and showed differences according to the reference used. Analyses of children's weight curves by physicians showed significant differences in the interpretation of child growth and therefore in the advice given to parents. Finally, the effect of using different growth parameters to predict future risk of obesity was examined and showed that weight and length gains may be good candidates to study future risks. In conclusion, because the reference or parameters used to assess growth have an important effect on the interpretation of growth, it is crucial to be aware of the consequences of the methods used in clinical or epidemiologic contexts. PMID- 21525201 TI - Weight suppression and risk of future increases in body mass: effects of suppressed resting metabolic rate and energy expenditure. AB - BACKGROUND: Weight suppression, which reflects the difference between the highest previous weight and current weight, has predicted future increases in body mass index (BMI) and bulimic pathology; however, the mechanisms underlying these predictive effects are unclear. OBJECTIVE: The current study sought to test whether weight suppression predicts future increases in BMI and bulimic symptoms and whether suppressed resting metabolic rate (RMR) and suppressed total energy expenditure (TEE) drive these relations. DESIGN: A randomly selected subsample of 91 young women in their first year of college with body image concerns completed an RMR assessment--a doubly labeled water assessment of TEE--and provided data on weight suppression and change in BMI and bulimic symptoms over a 6-mo follow-up period. RESULTS: Weight suppression predicted future increases in BMI and correlated inversely with suppressed RMR and TEE, yet this predictive effect did not decrease when suppressed RMR and TEE were controlled for. Weight suppression, however, did not predict future increases in bulimic symptoms. CONCLUSIONS: The results provide additional evidence that weight suppression predicts future increases in BMI but not in bulimic symptoms. Weight suppression showed moderate relations with suppressed RMR and TEE, but these variables do not appear to drive the predictive effect on future increases in BMI. This trial was registered at clinicaltrials.gov as NCT00433680. PMID- 21525202 TI - Prenatal and early postnatal supplementation with long-chain polyunsaturated fatty acids: neurodevelopmental considerations. AB - It takes >20 y before the human brain obtains its complex adult configuration. Most dramatic neurodevelopmental changes occur prenatally and early postnatally, including a major transformation in cortical organization 3-4 mo after term. The long-lasting changes have practical implications for studies evaluating the effect of prenatal and early postnatal supplementation with long-chain polyunsaturated fatty acids (LC-PUFAs). Whether studies of the effect of supplementation will reveal an effect not only depends on the dosage and duration of supplementation but also on 1) the timing of supplementation, 2) the age at which the outcome is assessed, 3) the application of age-specific sensitive neurodevelopmental tools, and 4) the functional domain evaluated. Studies of the effects of prenatal supplementation with docosahexaenoic acid (DHA) or fish oil have provided inconsistent results. However, maternal and neonatal concentrations of DHA and arachidonic acid are associated with improved outcomes in early infancy, and concentrations of DHA are associated with favorable neurodevelopmental outcome beyond early infancy. Studies of LC-PUFA supplementation in preterm infants have not shown evidence of a positive effect on neurodevelopmental outcome. Similar studies in full-term infants have indicated that supplementation with 0.30% DHA (by wt) promotes neurodevelopmental outcome in early infancy, but positive effects on later outcome have not been shown. However, information on the effects on outcomes at school age or later is virtually absent. This article stresses the need for long-term longitudinal studies that apply age-specific, sensitive neurodevelopmental tools, which also take into account lifestyle habits, maternal prepregnancy nutritional status, and genetic variation in metabolism. PMID- 21525203 TI - Improving the assessment of iron status. PMID- 21525205 TI - Optimal cutoffs of percentage body fat for predicting obesity-related cardiovascular disease risk factors in Korean adults. AB - BACKGROUND: Obesity is a major health problem. It is associated with cardiovascular disease. The diagnosis of obesity is crucial to treating and preventing obesity-related medical problems. OBJECTIVE: The objective was to determine optimal percentage body fat cutoffs in Korean adults for predicting obesity-related cardiovascular disease risk factors. DESIGN: We evaluated the body composition and prevalence of obesity-related cardiovascular risk factors, such as hypertension, diabetes mellitus, and dyslipidemia, in 41,088 Korean adults aged 18-92 y. The optimal percentage body fat cutoffs for Korean adults were determined. Multivariable-adjusted odds ratios (ORs) of overweight and obesity were estimated by logistic regression. RESULTS: The first cutoffs in men and women were 17% and 32% body fat, respectively; the second cutoffs were 21% and 37% body fat, respectively. The percentages of obese men and women were 41.8% and 15.9%, respectively. The adjusted OR of at least one risk factor for overweight or obesity in men was 2.22 (95% CI: 2.07, 2.38) or 4.05 (95% CI: 3.78, 4.33). The adjusted OR for women was 1.95 (95% CI: 1.79, 2.07; P < 0.0001) or 3.21 (95% CI: 2.87, 3.57). CONCLUSIONS: Only one-fourth of Korean men had a normal body composition, whereas most of the Korean women had a normal body composition. We conclude that susceptibility to cardiovascular disease and its risk factors is higher in Korean men than in Korean women. The cutoffs are useful for providing adequate guidelines for treating and preventing cardiovascular disease. This was the first study to determine cutoffs of percentage body fat for Korean adults. PMID- 21525204 TI - A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission. AB - BACKGROUND: Zinc deficiency is a cause of immune dysfunction and infection. Previous human studies have shown that the activation of the acute phase response alters zinc metabolism. Whether the alteration in zinc metabolism is predictive of disease severity in the setting of critical illness is unclear. OBJECTIVE: We sought to determine whether differences occur in zinc metabolism at the onset of critical illness between infected (septic) and noninfected subjects. DESIGN: We conducted this prospective study in an adult medical intensive care unit (MICU) at a tertiary care hospital. Subjects were enrolled within 24 h of intensive care unit admission. Subjects who did not meet sepsis criteria were considered for the critically ill control (CIC) arm. After patient consent, blood was immediately collected to measure plasma zinc and cytokine concentrations and zinc transporter gene expression in peripheral blood monocytes. Clinical data during the MICU stay were also recorded. RESULTS: A total of 56 patients were evaluated (22 septic, 22 CIC, and 12 healthy subjects). Plasma zinc concentrations were below normal in CIC patients and further reduced in the septic cohort (57.2 +/- 18.2 compared with 45.5 +/- 18.1 MUg/dL). Cytokine concentrations increased with decreasing plasma zinc concentrations (P = 0.05). SLC39A8 gene expression was highest in patients with the lowest plasma zinc concentrations and the highest severity of illness. CONCLUSIONS: The alteration of zinc metabolism was more pronounced in septic patients than in noninfected critically ill patients. Specifically, sepsis was associated with lower plasma zinc concentrations and higher SLC39A8 mRNA expression, which correlated with an increased severity of illness, including cardiovascular dysfunction. PMID- 21525206 TI - Paw inflammation model in dogs for preclinical pharmacokinetic/pharmacodynamic investigations of nonsteroidal anti-inflammatory drugs. AB - The goal of the present study was to develop and validate a new canine model of inflammation. The motivation was to make available a scientifically appropriate and ethically acceptable model to conduct pharmacokinetic/pharmacodynamic investigations for testing nonsteroidal anti-inflammatory drugs in dogs. A kaolin induce paw inflammation model previously developed in cats was adapted to the dog. The paw inflammation developed within a few hours, reached maximum values 24 h and up to 3 days after kaolin administration, and then progressively resolved over 2 months. Five end points of clinical interest (body temperature, creeping time under a tunnel, paw withdrawal latency to a standardized thermal stimulus, lameness score, and vertical force developed during walking on a force plate) were measured regularly over the next 24 h and beyond to characterize the time development of the inflammation either in control conditions (placebo period) or after the administration of meloxicam (test period) according to a crossover design. Pharmacodynamic data were modeled using an indirect response pharmacokinetic/pharmacodynamic model. This model described three effects of meloxicam, namely, classic anti-inflammatory, analgesic, and antipyretic effects. The mean plasma meloxicam IC(50) values were 210 ng/ml for the antipyretic effect, 390 ng/ml for the analgesic effect, and 546 ng/ml for the vertical force exerted by the paw on the ground as measured by force plates. These in vivo IC(50) values require approximately 80 (antipyretic effect) to 90% (all other effects) cyclooxygenase-2 inhibition as calculated ex vivo whole-blood assay data. PMID- 21525207 TI - H9 avian influenza reassortant with engineered polybasic cleavage site displays a highly pathogenic phenotype in chicken. AB - In the field, highly pathogenic avian influenza viruses (HPAIV) originate from low-pathogenic strains of the haemagglutinin (HA) serotypes H5 and H7 that have acquired a polybasic HA cleavage site. This observation suggests the presence of a cryptic virulence potential of H5 and H7 low-pathogenic avian influenza viruses (LPAIV). Among all other LPAIV, the H9N2 strains are of particular relevance as they have become widespread across many countries in several avian species and have been transmitted to humans. To assess the potential of these strains to transform into an HPAIV, we introduced a polybasic cleavage site into the HA of a contemporary H9N2 isolate. Whereas the engineered polybasic HA cleavage site mutant remained a low-pathogenic strain like its parent virus, a reassortant expressing the modified H9 HA with engineered polybasic cleavage site and all the other genes from an H5N1 HPAIV became highly pathogenic in chicken with an intravenous pathogenicity index of 1.23. These results suggest that an HPAIV with a subtype other than H5 or H7 would only emerge under conditions where the HA gene could acquire a polybasic cleavage site and the other viral genes carry additional virulence determinants. PMID- 21525208 TI - Charged amino acid patterns of coreceptor use in the major subtypes of human immunodeficiency virus type 1. AB - Human immunodeficiency virus type 1 has several genetic subtypes and two coreceptor use phenotypes: R5 that uses CCR5, while X4 uses CXCR4. A high amino acid charge of the envelope glycoprotein 120 V3 region, common at positions 11 and 25, is important for CXCR4 use. We characterized charged V3 amino acids, retrieving all biologically phenotyped sequences from the HIV Sequence Database. Selecting individually unique ones randomly yielded 48 subtype A, 231 B, 180 C, 37 D and 32 CRF01_AE sequences; 482 were R5 and 46 were X4. Charged amino acids were conserved in both R5 and X4 with general and subtype-specific patterns. X4 viruses gained a higher charge from positive amino acids at positions other than in R5, and through the loss of negative amino acids. Other positions than 11/25 had a greater impact on charge (P<0.001). This describes how R5 evolves into X4 in a subtype-specific context, useful for computer-based predictions and vaccine design. PMID- 21525209 TI - PBMCs are additional sites of productive infection of bovine papillomavirus type 2. AB - Bovine papillomavirus type 2 (BPV-2) is an oncogenic virus infecting both epithelial and mesenchymal cells. Its life cycle, similar to other papillomaviruses (PVs), appears to be linked to epithelial differentiation. Human and bovine PVs have been known to reside in a latent, episomal form in PBMCs; therefore, it is believed that blood cells, like all mesenchymal cells, function as non-permissive carriers. Here, for the first time in veterinary and comparative medicine, the BPV-2 E5 oncoprotein and the major structural L1 capsid protein, known to be expressed only in productive infections, were shown to occur in defined subsets of PBMCs. E5 oncoprotein was detected in sorted T- and B-cells as well as in monocytes by flow cytometry and Western blot analysis. However, CD4(+) and CD8(+) lymphocytes appeared to be the main circulating targets of the virus, thus possibly representing the most important reservoir of active BPV-2 in blood. L1 protein was identified by flow cytometry in a population of blood cells recognized as lymphocytes by morphological scatter properties. Western blot analysis was performed on lysates obtained from the sorted subpopulations of PBMCs and detected L1 protein in CD4(+) and CD8(+) cells only. Thus, this study showed that CD4(+) and CD8(+) lymphocytes are permissive for BPV-2 and are new, hitherto unknown sites of productive PV infection. In light of these observations, the life cycle of PVs needs to be revisited to gain novel insights into the epidemiology of BPV infection and the pathogenesis of related diseases. PMID- 21525210 TI - First detection and analysis of a fish circovirus. AB - Circoviruses are present worldwide in birds and pigs but their occurrence in fish has not yet been reported. Recently, increased mortality was observed in barbel fry (Barbus barbus) in Hungary. This paper reports the detection of previously unknown circular viral DNA genomes in barbels by the use of a circovirus-specific wide-range nested PCR. The analysis of two complete genomes (Barbel circovirus, BaCV1 and BaCV2) indicated that they belonged into a new genetic group within the family Circoviridae, distinct from known circoviruses and circovirus-like genomes. Their genome size was 1957 bases and contained two major ORFs similar to the capsid and replication-associated protein genes of circoviruses. A connection between the presence of the virus and clinical manifestations of the infection could not be proved. PMID- 21525211 TI - A conserved arginine residue in the terminal protein domain of hepatitis B virus polymerase is critical for RNA pre-genome encapsidation. AB - Hepadnaviruses, including human hepatitis B virus (HBV) and duck hepatitis B virus (DHBV), replicate their DNA genome through reverse transcription. Although hepadnaviral polymerase (Pol) is distantly related to retroviral reverse transcriptases, some of its features are distinct. In particular, in addition to the reverse transcriptase and RNase H domains, which are commonly encoded by retroviral reverse transcriptases, the N-terminally extended terminal protein (TP) domain confers unique features such as protein-priming capability. Importantly, the TP domain is also essential for encapsidation of the viral RNA pre-genome. To gain further insight into the TP domain, this study used clustered charged residue-to-alanine mutagenesis of HBV Pol. Of the 20 charged residues examined, only one arginine (R105) was critical for RNA encapsidation. This result contrasts with previous findings for DHBV Pol regarding the critical residue of the TP domain required for RNA binding. Firstly, R128 of DHBV Pol, which corresponds to R105 of HBV Pol, was reportedly tolerable to alanine substitution for RNA binding. Secondly, the C-terminal arginine residue of the DHBV Pol TP domain (R183) was shown to be critical for RNA binding, whereas alanine substitution of the corresponding arginine residue of the HBV Pol TP domain (R160) remained able to support RNA encapsidation. Together, these data highlight the divergence between avian and mammalian hepadnaviral Pols with respect to an arginine residue critical for RNA encapsidation. PMID- 21525212 TI - The ADP-ribose-1''-monophosphatase domains of severe acute respiratory syndrome coronavirus and human coronavirus 229E mediate resistance to antiviral interferon responses. AB - Several plus-strand RNA viruses encode proteins containing macrodomains. These domains possess ADP-ribose-1"-phosphatase (ADRP) activity and/or bind poly(ADP ribose), poly(A) or poly(G). The relevance of these activities in the viral life cycle has not yet been resolved. Here, we report that genetically engineered mutants of severe acute respiratory syndrome coronavirus (SARS-CoV) and human coronavirus 229E (HCoV-229E) expressing ADRP-deficient macrodomains displayed an increased sensitivity to the antiviral effect of alpha interferon compared with their wild-type counterparts. The data suggest that macrodomain-associated ADRP activities may have a role in viral escape from the innate immune responses of the host. PMID- 21525213 TI - Evaluation of a loop-mediated isothermal amplification assay for diagnosis of Clostridium difficile infections. AB - A new assay (illumigene C. difficile; Meridian Bioscience), based on the original loop-mediated isothermal amplification (LAMP) assay, was evaluated with 472 unformed stools from patients suspected of Clostridium difficile infection. Compared to the toxigenic culture, the sensitivity, specificity, and positive and negative predictive values were 91.8, 99.1, 91.8, and 99.1% for the illumigene C. difficile assay and 69.4, 100, 100, and 96.6% for the cytotoxicity assay, respectively. PMID- 21525214 TI - Molecular characterization of drug-resistant Mycobacterium tuberculosis isolates circulating in China by multilocus PCR and electrospray ionization mass spectrometry. AB - We used multilocus PCR and electrospray ionization mass spectrometry (PCR/ESI-MS) to determine the genotype and drug resistance profiles for 96 Mycobacterium tuberculosis isolates circulating in regions of high and low tuberculosis (TB) endemicity in China. The dominant principal genetic group (PGG) circulating in China was PGG1, and drug-resistant gene mutations were more diversified in the region of low rather than high TB endemicity. PMID- 21525215 TI - Massilia timonae infection presenting as generalized lymphadenopathy in a man returning to Belgium from Nigeria. AB - We report a case of apparent malaria infection presented with a syndrome of painless, generalized lymphadenopathy without granulomas shortly after exposure to fresh water in rural West Africa. Residual infection with Massilia timonae was diagnosed and successfully treated with co-trimoxazole. PMID- 21525216 TI - Molecular characterization and antimicrobial susceptibility testing of Escherichia coli isolates from patients with urinary tract infections in 20 Chinese hospitals. AB - A total of 222 urinary Escherichia coli isolates from 20 tertiary hospitals in 15 different provinces and 4 municipalities in mainland China were characterized by antimicrobial susceptibility, phylogrouping, and the presence of plasmid-mediated quinolone resistance genes. A subset of 138 suspected extended-spectrum cephalosporinase (ESC) producers were examined for genes encoding cephalosporin resistance. Forty-three isolates harboring bla(CTX-M-14) or bla(CTX-M-15) were analyzed by pulsed-field gel electrophoresis (PFGE), and plasmids containing these genes were typed using PCR-based replicon typing (PBRT). Thirteen phylogroup B2 bla(CTX-M-14)- and bla(CTX-M-15)-positive isolates were analyzed by multilocus sequence typing (MLST). A frequent occurrence of resistance (>46%) was observed toward cephalosporins, gentamicin, and fluoroquinolones. Among the 222 isolates, 4 qnrS1, 4 qepA, and 16 aac(6')-Ib-cr genes were confirmed. Four major phylogroups (A, B1, B2, and D) and nontypeable isolates (NTs) were found among the isolates, with phylogroup D (54%) being the most common phylogroup. A total of 110 (80%) of the 138 screened isolates harbored bla(CTX-M) genes, with bla(CTX M-14) (71%) and bla(CTX-M-15) (24%) being the most prevalent of these genes. Nine of the 13 CTX-M-15- or CTX-M-14-containing B2 isolates belonged to ST131. PFGE typing showed a high level of diversity, and plasmid analysis indicated a very large pool of different resistance plasmids mediating the spread of bla(CTX-M) genes in mainland China. An equally very high frequency of resistance and equally high levels of diversity in phylogroups, PFGE types, and plasmids were observed among community- and hospital-acquired E. coli isolates, indicating the presence of a large reservoir in the community and a long-term spread of cephalosporin resistance in China. PMID- 21525217 TI - Use of bexB to detect the capsule locus in Haemophilus influenzae. AB - Haemophilus influenzae strains are classified as typeable or nontypeable H. influenzae (NTHI) based upon the presence or absence of capsule. In addition to serotyping, which is subject to false-positive results, typeable strains can be identified through the detection of the capsular export gene bexA and one of six capsule-specific genes, but this method is resource intensive, especially in characterizing large numbers of strains. To address these challenges, we developed a bexB-based method to differentiate true NTHI strains from typeable strains. We validated a PCR-based method to detect bexB in 10 strains whose capsule status was well defined. Among 40 strains that were previously serotype positive in clinical microbiology laboratories, 5 lacked bexA, bexB, and capsule type-specific genes by PCR analysis and thus likely represent false-positive serotyping results. Among 94 additional otitis media, commensal, and serotype b negative invasive strains, 85 were bexA and bexB negative and 9 contained either a complete or partial capsule locus, i.e., 8 were bexA and bexB positive and 1 was bexA negative but bexB positive. Finally, we adapted the method for use in a high-throughput DNA hybridization-based microarray method, which showed 98.75 and 97.5% concordance to the PCR methods for bexA and bexB, respectively. In addition, bexB showed 84% or greater nucleotide identity among strains containing the capsule locus. In this study, we demonstrate that bexB is a reliable proxy for the capsule locus and that its detection provides a simple and reliable method for differentiating strains that lack the entire capsule locus from those containing a partial or complete capsule locus. PMID- 21525218 TI - Comparison of automated processing of flocked swabs with manual processing of fiber swabs for detection of nasal carriage of Staphylococcus aureus. AB - The sensitivity of automated culture of Staphylococcus aureus from flocked swabs versus that of manual culture of fiber swabs was prospectively compared using nasal swabs from 867 patients. Automated culture from flocked swabs significantly increased the detection rate, by 13.1% for direct culture and 10.2% for enrichment culture. PMID- 21525219 TI - Blood cultures at central line insertion in the intensive care unit: comparison with peripheral venipuncture. AB - Blood cultures are a key diagnostic test for intensive care unit (ICU) patients; however, contaminants complicate interpretations and lead to unnecessary antibiotic administration and costs. Indications for blood cultures and central venous catheter (CVC) insertions often overlap for ICU patients. Obtaining blood cultures under the strict sterile precautions utilized for CVC insertion might be expected to decrease culture contamination. This retrospective study compared the results of blood cultures taken at CVC insertion, at arterial line insertion, and from peripheral venipuncture in order to validate the advantage of CVC insertion cultures. Cultures from indwelling lines were excluded. Results of 14,589 blood cultures, including 2,736 (19%) CVC, 1,513 (10%) arterial line, and 10,340 (71%) peripheral cultures taken over 5.5 years in two ICUs (general and medical) were analyzed. CVC cultures were contaminated more frequently than arterial line or peripheral cultures (225/2,736 [8%] CVC, 48/1,513 [3%] arterial line, and 378/10,340 (4%) peripheral cultures [P < 0.001 for CVC versus peripheral and CVC versus arterial line cultures]). True pathogens were found more frequently in CVC insertion cultures (334/2,736 [12%] CVC, 155/1,513 [10%] arterial line, and 795/10,340 [8%] peripheral cultures [P < 0.001 for CVC versus peripheral cultures; P = 0.055 for CVC versus arterial line cultures; P < 0.001 for peripheral versus arterial line cultures]). Contamination and true-positive rates were similar for culture sets from the two ICUs for each given culture source. Despite superior sterile precautions, cultures taken at the time of central line insertion had a higher contamination rate than did either peripheral or arterial line blood cultures. This may be related to the increased manipulations required for CVC insertion. PMID- 21525220 TI - Cutaneous diphtheria in the urban poor population of Vancouver, British Columbia, Canada: a 10-year review. AB - Between 1998 and 2007, records from 33 patients with cutaneous diphtheria from Vancouver's inner city were reviewed. Cases were associated with injection drug use and poverty. Coinfections with Staphylococcus aureus, Streptococcus pyogenes, and Arcanobacterium haemolyticum occurred. Corynebacterium diphtheriae is endemic in Vancouver's urban core, with strains of multilocus sequence type (MLST) 76 predominating. PMID- 21525222 TI - Rapid, cost-effective application of Tibilia TB rapid test for culture confirmation of live and heat-killed Mycobacterium tuberculosis. PMID- 21525221 TI - Clinical and molecular observations of two fatal cases of rotavirus-associated enteritis in children in Italy. AB - Two fatal cases of infantile rotavirus enteritis occurred in northern Italy in 2005. Both children were severely dehydrated, and death was related to severe cerebral edema. Histological examination demonstrated extensive damage of the intestinal epithelium, villous atrophy or blunting, and macrophage infiltration. The two rotavirus strains were of the G1P[8] type and the long electropherotype. The 2005 G1P[8] rotaviruses differed in the NSP4, VP3, VP4, and VP7 genes from G1P[8] rotaviruses circulating in 2004, suggesting the onset of a new G1P[8] strain in the local population. PMID- 21525223 TI - Virulence gene pool detected in bovine group C Streptococcus dysgalactiae subsp. dysgalactiae isolates by use of a group A S. pyogenes virulence microarray. AB - A custom-designed microarray containing 220 virulence genes of Streptococcus pyogenes (group A Streptococcus [GAS]) was used to test group C Streptococcus dysgalactiae subsp. dysgalactiae (GCS) field strains causing bovine mastitis and group C or group G Streptococcus dysgalactiae subsp. equisimilis (GCS/GGS) isolates from human infections, with the latter being used for comparative purposes, for the presence of virulence genes. All bovine and all human isolates carried a fraction of the 220 genes (23% and 39%, respectively). The virulence genes encoding streptolysin S, glyceraldehyde-3-phosphate dehydrogenase, the plasminogen-binding M-like protein PAM, and the collagen-like protein SclB were detected in the majority of both bovine and human isolates (94 to 100%). Virulence factors, usually carried by human beta-hemolytic streptococcal pathogens, such as streptokinase, laminin-binding protein, and the C5a peptidase precursor, were detected in all human isolates but not in bovine isolates. Additionally, GAS bacteriophage-associated virulence genes encoding superantigens, DNase, and/or streptodornase were detected in bovine isolates (72%) but not in the human isolates. Determinants located in non-bacteriophage related mobile elements, such as the gene encoding R28, were detected in all bovine and human isolates. Several virulence genes, including genes of bacteriophage origin, were shown to be expressed by reverse transcriptase PCR (RT PCR). Phylogenetic analysis of superantigen gene sequences revealed a high level (>98%) of identity among genes of bovine GCS, of the horse pathogen Streptococcus equi subsp. equi, and of the human pathogen GAS. Our findings indicate that alpha hemolytic bovine GCS, an important mastitis pathogen and considered to be a nonhuman pathogen, carries important virulence factors responsible for virulence and pathogenesis in humans. PMID- 21525224 TI - Impact of rpoB mutations on reduced vancomycin susceptibility in Staphylococcus aureus. AB - Of 38 vancomycin-intermediate Staphylococcus aureus (VISA) clinical strains, 27 (71%) possessed a mutation(s) in rpoB encoding the beta-subunit of RNA polymerase. Furthermore, 95.6% of the rifampin-resistant mutants obtained from 9 methicillin-resistant S. aureus (MRSA) clinical isolates showed decreased vancomycin susceptibilities. These data indicate the involvement of an rpoB mutation in VISA phenotype expression. PMID- 21525225 TI - Applied genomics: data mining reveals species-specific malaria diagnostic targets more sensitive than 18S rRNA. AB - Accurate and rapid diagnosis of malaria infections is crucial for implementing species-appropriate treatment and saving lives. Molecular diagnostic tools are the most accurate and sensitive method of detecting Plasmodium, differentiating between Plasmodium species, and detecting subclinical infections. Despite available whole-genome sequence data for Plasmodium falciparum and P. vivax, the majority of PCR-based methods still rely on the 18S rRNA gene targets. Historically, this gene has served as the best target for diagnostic assays. However, it is limited in its ability to detect mixed infections in multiplex assay platforms without the use of nested PCR. New diagnostic targets are needed. Ideal targets will be species specific, highly sensitive, and amenable to both single-step and multiplex PCRs. We have mined the genomes of P. falciparum and P. vivax to identify species-specific, repetitive sequences that serve as new PCR targets for the detection of malaria. We show that these targets (Pvr47 and Pfr364) exist in 14 to 41 copies and are more sensitive than 18S rRNA when utilized in a single-step PCR. Parasites are routinely detected at levels of 1 to 10 parasites/MUl. The reaction can be multiplexed to detect both species in a single reaction. We have examined 7 P. falciparum strains and 91 P. falciparum clinical isolates from Tanzania and 10 P. vivax strains and 96 P. vivax clinical isolates from Venezuela, and we have verified a sensitivity and specificity of ~100% for both targets compared with a nested 18S rRNA approach. We show that bioinformatics approaches can be successfully applied to identify novel diagnostic targets and improve molecular methods for pathogen detection. These novel targets provide a powerful alternative molecular diagnostic method for the detection of P. falciparum and P. vivax in conventional or multiplex PCR platforms. PMID- 21525226 TI - Comparison of the Flotac-400 dual technique and the formalin-ether concentration technique for diagnosis of human intestinal protozoon infection. AB - There is a need for accurate diagnosis of intestinal parasite infections in humans, but currently available copromicroscopic techniques have shortcomings, such as low sensitivity. We compared the diagnostic accuracy of a further modified version of the recently developed Flotac technique with that of the widely used formalin-ether concentration technique (FECT) for the detection of intestinal protozoa in human stool samples. Formaldehyde-preserved stool samples from 108 individuals in Cote d'Ivoire were subjected to the Flotac-400 dual technique, using two different flotation solutions (FS), and to the FECT. Stool samples were examined according to computer-generated random lists by an experienced laboratory technician blinded for the results of each method. Both methods detected the same eight intestinal protozoon species. While the Flotac 400 dual technique (results from both FS combined) found higher prevalences of Entamoeba coli (77.8% versus 71.3%, P < 0.001), Blastocystis hominis (20.4% versus 13.0%, P = 0.458), and Giardia intestinalis (8.3% versus 6.5%, P < 0.001), the FECT detected higher prevalences of Entamoeba histolytica/Entamoeba dispar (27.8% versus 20.4%, P = 0.019) and four species of nonpathogenic intestinal protozoa. The diagnostic agreement between the two methods differed considerably depending on the intestinal protozoon investigated (Cohen's kappa measures; range, 0.01 to 0.46). Our study confirmed that the Flotac-400 dual technique can be utilized for the diagnosis of intestinal protozoon infections in humans. Since Flotac is a sensitive technique for the detection of soil-transmitted helminths and Schistosoma mansoni, it might become a viable copromicroscopic technique for the concurrent diagnosis of helminths and intestinal protozoon infections. PMID- 21525227 TI - Shedding of Epstein-Barr virus and cytomegalovirus from the genital tract of women in a periurban community in Andhra Pradesh, India. AB - We found a large number of false-positive readings by visual inspection with acetic acid (VIA) in a study of cervical cancer screening strategies (VIA, human papillomavirus HPV DNA testing, and Pap cytology) in a periurban community in Andhra Pradesh, India. We evaluated whether these false-positive readings might be occurring as a result of infections with Epstein-Barr virus (EBV) or cytomegalovirus (CMV), prevalent latent herpesviruses known to be shed from the female genital tract. While we found that there was no association between VIA results and the presence of EBV or CMV in the cervix, we did find a high prevalence of both viruses: 20% for EBV and 26% for CMV. In multivariate analyses, CMV prevalence was associated with younger age, lack of running water in the home, and visually apparent cervical inflammation. EBV prevalence was associated with older age and a diagnosis of cervical intraepithelial neoplasia grade 1 or greater. The biological and clinical implications of these viruses at the cervix remain to be determined. The strong association between the presence of EBV and cervical disease warrants future exploration to determine whether EBV plays a causal role in disease development or if it is merely a bystander in the process. PMID- 21525228 TI - Solobacterium moorei bacteremia: identification, antimicrobial susceptibility, and clinical characteristics. AB - We present five cases of Solobacterium moorei bacteremia. The isolates were identified with 16S rRNA gene sequencing and were susceptible to common antibiotics used for anaerobic infections. Bacteremia with S. moorei seems to be associated with debilitating conditions, but the prognosis of the infection appears to be good. PMID- 21525229 TI - Persistent carriage and infection by multidrug-resistant Escherichia coli ST405 producing NDM-1 carbapenemase: report on the first Italian cases. AB - We report on the first detection of the NDM-1 carbapenemase in Italy, in Escherichia coli isolated in October 2009. Prolonged colonization and relapsing infection by NDM-1-positive E. coli were observed in a patient (index case) with an indirect epidemiological link with areas of endemicity. Transient colonization was apparently observed in another patient linked with the index case. PMID- 21525230 TI - Acinetobacter soli as a cause of bloodstream infection in a neonatal intensive care unit. AB - Acinetobacter soli is a new bacterial species described from forest soil. Five cases of bloodstream infection caused by A. soli clonal isolates are reported here for the first time. The patients were neonates admitted to an intensive care unit. This is a new neonatal pathogen with the potential to cause outbreaks. PMID- 21525231 TI - Sensitivity, specificity, and clinical value of human papillomavirus (HPV) E6/E7 mRNA assay as a triage test for cervical cytology and HPV DNA test. AB - There is evidence that testing for human papillomavirus (HPV) E6/E7 mRNA is more specific than testing for HPV DNA. A retrospective study was carried out to evaluate the performance of the PreTect HPV-Proofer E6/E7 mRNA assay (Norchip) as a triage test for cytology and HPV DNA testing. This study analyzed 1,201 women, 688 of whom had a colposcopy follow-up and 195 of whom had histology-confirmed high-grade intraepithelial neoplasia or worse (CIN2+). The proportion of positive results and the sensitivity and specificity for CIN2+ were determined for HPV mRNA in comparison to HPV DNA and cytology. All data were adjusted for follow-up completeness. Stratified by cytological grades, the HPV mRNA sensitivity was 83% (95% confidence interval [CI] = 63 to 94%) in ASC-US (atypical squamous cells of undetermined significance), 62% (95% CI = 47 to 75%) in L-SIL (low-grade squamous intraepithelial lesion), and 67% (95% CI = 57 to 76%) in H-SIL (high-grade squamous intraepithelial lesion). The corresponding figures were 99, 91, and 96%, respectively, for HPV DNA. The specificities were 82, 76, and 45%, respectively, for HPV mRNA and 29, 13, and 4%, respectively, for HPV DNA. Used as a triage test for ASC-US and L-SIL, mRNA reduced colposcopies by 79% (95% CI = 74 to 83%) and 69% (95% CI = 65 to 74%), respectively, while HPV DNA reduced colposcopies by 38% (95% CI = 32 to 44%) and by 15% (95% CI = 12 to 19%), respectively. As a HPV DNA positivity triage test, mRNA reduced colposcopies by 63% (95% CI = 60 to 66%), having 68% sensitivity (95% CI = 61 to 75%), whereas cytology at the ASC-US+ threshold reduced colposcopies by 23% (95% CI = 20 to 26%), showing 92% sensitivity (95% CI = 87 to 95%). In conclusion, PreTect HPV-Proofer mRNA can serve as a better triage test than HPV DNA to reduce colposcopy referral in both ASC-US and L-SIL. It is also more efficient than cytology for the triage of HPV DNA-positive women. Nevertheless, its low sensitivity demands a strict follow-up of HPV DNA positive-mRNA negative cases. PMID- 21525232 TI - A tile layer's nightmare. PMID- 21525233 TI - Retraction: Association of three bacterial species and periodontal status in Chinese adults: an epidemiological approach. PMID- 21525235 TI - Effects of high-fat diets rich in either omega-3 or omega-6 fatty acids on UVB induced skin carcinogenesis in SKH-1 mice. AB - Our previous studies reported that caffeine or voluntary exercise decreased skin tumor multiplicity, in part, by decreasing fat levels in the dermis. These data suggest that tissue fat may play an important role in regulating ultraviolet light (UV) B-induced skin tumor development. In the present study, we explored the effects of high-fat diets rich in either omega-3 or omega-6 fatty acids on UVB-induced skin carcinogenesis. SKH-1 mice were irradiated with 30 mJ/cm(2) of UVB once a day, two times per week for 39 weeks. During UVB treatment, one group of mice was given a high-fat fish oil (HFFO) diet rich in omega-3 fatty acids and the other group of mice was given a high-fat mixed-lipids (HFMLs) diet rich in omega-6 fatty acids. The results showed that, compared with HFML diet, HFFO treatment (i) increased latency for the development of UVB-induced skin tumors; (ii) decreased the formation of papilloma, keratoacanthoma and carcinoma by 64, 52 and 46%, respectively and (iii) decreased the size of papilloma, keratoacanthoma and carcinoma by 98, 80 and 83%, respectively. Mechanistic studies with antibody array revealed that compared with HFML diet, administration of HFFO to the mice significantly decreased the UVB-induced increases in the levels of TIMP-1, LIX and sTNF R1 as well as other several proinflammatory cytokines and stimulated the UVB-induced apoptosis in the epidermis. Our results indicate that omega-3 fatty acids in HFFO diet have beneficial effects against UVB-induced skin carcinogenesis, and these effects may be associated with an inhibition on UVB-induced inflammatory response. PMID- 21525236 TI - Spontaneous oscillations in a model for active control of microvessel diameters. AB - A new theory is presented for the origin of spontaneous oscillations in blood vessel diameters that are observed experimentally in the microcirculation. These oscillations, known as vasomotion, involve timevarying contractions of the vascular smooth muscle in the walls of arterioles. It is shown that such oscillations can arise as a result of interactions between the mechanics of the vessel wall and the dynamics of the active contraction of smooth muscle cells in response to circumferential tension in the wall. A theoretical model is developed in which the diameter and the degree of activation in a vessel are dynamic variables. The model includes effects of wall shear stress and oxygen-dependent metabolic signals on smooth muscle activation and is applied to a single vessel and to simplified network structures. The model equations predict limit cycle oscillations for certain ranges of parameters such as wall shear stress, arterial pressure and oxygen consumption rate. Predicted characteristics of the oscillations, including their sensitivity to arterial pressure, are consistent with experimental observations. PMID- 21525237 TI - Effects of catecholamines on hepatic and skeletal muscle mitochondrial respiration after prolonged exposure to faecal peritonitis in pigs. AB - Use of norepinephrine to increase blood pressure in septic animals has been associated with increased efficiency of hepatic mitochondrial respiration. The aim of this study was to evaluate whether the same effect could be reproduced in isolated hepatic mitochondria after prolonged in vivo exposure to faecal peritonitis. Eighteen pigs were randomized to 27 h of faecal peritonitis and to a control condition (n = 9 each group). At the end, hepatic mitochondria were isolated and incubated for one hour with either norepinephrine or placebo, with and without pretreatment with the specific receptor antagonists prazosin and yohimbine. Mitochondrial state 3 and state 4 respiration were measured for respiratory chain complexes I and II, and state 3 for complex IV using high resolution respirometry, and respiratory control ratios were calculated. Additionally, skeletal muscle mitochondrial respiration was evaluated after incubation with norepinephrine and dobutamine with and without the respective antagonists (atenolol, propranolol and phentolamine for dobutamine). Faecal peritonitis was characterized by decreasing blood pressure and stroke volume, and maintained systemic oxygen consumption. Neither faecal peritonitis nor any of the drugs or drug combinations had measurable effects on hepatic or skeletal muscle mitochondrial respiration. Norepinephrine did not improve the efficiency of complex I- and complex II-dependent isolated hepatic mitochondrial respiration [respiratory control ratio (RCR) complex I: 5.6 +/- 5.3 (placebo) vs. 5.4 +/- 4.6 (norepinephrine) in controls and 2.7 +/- 2.1 (placebo) vs. 2.9 +/- 1.5 (norepinephrine) in septic animals; RCR complex II: 3.5 +/- 2.0 (placebo) vs. 3.5 +/- 1.8 (norepinephrine) in controls; 2.3 +/- 1.6 (placebo) vs. 2.2 +/- 1.1 (norepinephrine) in septic animals]. Prolonged faecal peritonitis did not affect either hepatic or skeletal muscle mitochondrial respiration. Subsequent incubation of isolated mitochondria with norepinephrine and dobutamine did not significantly influence their respiration. PMID- 21525238 TI - Care transition experiences of spousal caregivers: from a geriatric rehabilitation unit to home. AB - The purpose of this study was to develop a theoretical framework about caregivers' experiences and the processes in which they engaged during their spouses' transition from a geriatric rehabilitation unit to home. We used a constructivist grounded theory methodology approach. Forty-five interviews were conducted across three points in time with 18 older adult spousal caregivers. A theoretical framework was developed within which reconciling in response to fluctuating needs emerged as the basic social process. Reconciling included three subprocesses (i.e., navigating, safekeeping, and repositioning), and highlighted how caregivers responded to the fluctuating needs of their spouse, to their own needs, and to those of the marital dyad. Reconciling was situated within a context shaped by a trajectory of prior care transitions and intertwined life events experienced by caregivers. Findings serve as a resource for scientists, rehabilitation clinicians, educators, and decision makers toward improving transitional care for spousal caregivers. PMID- 21525239 TI - Young people learning to live with inflammatory bowel disease: working with an "unclosed" diary. AB - In a longitudinal study we investigated how young people come to live with a chronic disease, and asked them to record an audio diary on a regular basis. We also interviewed each participant every 6 weeks. Our analysis focused within and across the diary sets of 6 young people diagnosed with inflammatory bowel disease. All were aged between 11 and 16 years, and their recordings provided an insight into the experience of living within and beyond disease, and of negotiating health in the context of adolescence. This data collection method, which became known as the unclosed diary, was well received by the young people, who made use of their diaries in different ways. Three key aspects of their diary use, immediacy and intimacy, conversation, and reflection, demonstrate the flexibility of the method both as a means of accessing young people's lives at a time of change and development, and as a personal resource for the participants. PMID- 21525241 TI - cTAGE5 mediates collagen secretion through interaction with TANGO1 at endoplasmic reticulum exit sites. AB - Cutaneous T-cell lymphoma-associated antigen 5 (cTAGE5), an originally identified tumor antigen, is overexpressed in various cancer cell lines. The cDNA encodes an integral membrane protein containing two coiled-coil motifs and a proline-rich domain. We show that cTAGE5 specifically localizes to the endoplasmic reticulum (ER) exit sites. In addition, cTAGE5 forms a complex with TANGO1 (MIA3), a previously characterized cargo receptor for collagen VII, by the interaction of their coiled-coil motifs. Of interest, cTAGE5, as well as TANGO1, is capable of interacting with the inner-layer coatomer of COPII Sec23/24 complex through their C-terminal proline-rich domains and required for collagen VII secretion. We propose that cTAGE5 acts as a coreceptor of TANGO1 for collagen VII export from the ER. PMID- 21525240 TI - Role of AP1 and Gadkin in the traffic of secretory endo-lysosomes. AB - Whereas lysosome-related organelles (LRO) of specialized cells display both exocytic and endocytic features, lysosomes in nonspecialized cells can also acquire the property to fuse with the plasma membrane upon an acute rise in cytosolic calcium. Here, we characterize this unconventional secretory pathway in fibroblast-like cells, by monitoring the appearance of Lamp1 on the plasma membrane and the release of lysosomal enzymes into the medium. After sequential ablation of endocytic compartments in living cells, we find that donor membranes primarily derive from a late compartment, but that an early compartment is also involved. Strikingly, this endo-secretory process is not affected by treatments that inhibit endosome dynamics (microtubule depolymerization, cholesterol accumulation, overexpression of Rab7 or its effector Rab-interacting lysosomal protein [RILP], overexpression of Rab5 mutants), but depends on Rab27a, a GTPase involved in LRO secretion, and is controlled by F-actin. Moreover, we find that this unconventional endo-secretory pathway requires the adaptor protein complexes AP1, Gadkin (which recruits AP1 by binding to the gamma1 subunit), and AP2, but not AP3. We conclude that a specific fraction of the AP2-derived endocytic pathway is dedicated to secretory purposes under the control of AP1 and Gadkin. PMID- 21525243 TI - Coupling among growth rate response, metabolic cycle, and cell division cycle in yeast. AB - We studied the steady-state responses to changes in growth rate of yeast when ethanol is the sole source of carbon and energy. Analysis of these data, together with data from studies where glucose was the carbon source, allowed us to distinguish a "universal" growth rate response (GRR) common to all media studied from a GRR specific to the carbon source. Genes with positive universal GRR include ribosomal, translation, and mitochondrial genes, and those with negative GRR include autophagy, vacuolar, and stress response genes. The carbon source specific GRR genes control mitochondrial function, peroxisomes, and synthesis of vitamins and cofactors, suggesting this response may reflect the intensity of oxidative metabolism. All genes with universal GRR, which comprise 25% of the genome, are expressed periodically in the yeast metabolic cycle (YMC). We propose that the universal GRR may be accounted for by changes in the relative durations of the YMC phases. This idea is supported by oxygen consumption data from metabolically synchronized cultures with doubling times ranging from 5 to 14 h. We found that the high oxygen consumption phase of the YMC can coincide exactly with the S phase of the cell division cycle, suggesting that oxidative metabolism and DNA replication are not incompatible. PMID- 21525242 TI - The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella. AB - Salmonella develops into resident bacteria in epithelial cells, and the autophagic machinery (Atg) is thought to play an important role in this process. In this paper, we show that an autophagosome-like double-membrane structure surrounds the Salmonella still residing within the Salmonella-containing vacuole (SCV). This double membrane is defective in Atg9L1- and FAK family-interacting protein of 200 kDa (FIP200)-deficient cells. Atg9L1 and FIP200 are important for autophagy-specific recruitment of the phosphatidylinositol 3-kinase (PI3K) complex. However, in the absence of Atg9L1, FIP200, and the PI3K complex, LC3 and its E3-like enzyme, the Atg16L complex, are still recruited to Salmonella. We propose that the LC3 system is recruited through a mechanism that is independent of isolation membrane generation. PMID- 21525244 TI - C4orf41 and TTC-15 are mammalian TRAPP components with a role at an early stage in ER-to-Golgi trafficking. AB - TRAPP is a multisubunit tethering complex implicated in multiple vesicle trafficking steps in Saccharomyces cerevisiae and conserved throughout eukarya, including humans. Here we confirm the role of TRAPPC2L as a stable component of mammalian TRAPP and report the identification of four novel components of the complex: C4orf41, TTC-15, KIAA1012, and Bet3L. Two of the components, KIAA1012 and Bet3L, are mammalian homologues of Trs85p and Bet3p, respectively. The remaining two novel TRAPP components, C4orf41 and TTC-15, have no homologues in S. cerevisiae. With this work, human homologues of all the S. cerevisiae TRAPP proteins, with the exception of the Saccharomycotina-specific subunit Trs65p, have now been reported. Through a multidisciplinary approach, we demonstrate that the novel proteins are bona fide components of human TRAPP and implicate C4orf41 and TTC-15 (which we call TRAPPC11 and TRAPPC12, respectively) in ER-to-Golgi trafficking at a very early stage. We further present a binary interaction map for all known mammalian TRAPP components and evidence that TRAPP oligomerizes. Our data are consistent with the absence of a TRAPP I-equivalent complex in mammalian cells, suggesting that the fundamental unit of mammalian TRAPP is distinct from that characterized in S. cerevisiae. PMID- 21525245 TI - Mitochondrial protein turnover: role of the precursor intermediate peptidase Oct1 in protein stabilization. AB - Most mitochondrial proteins are encoded in the nucleus as precursor proteins and carry N-terminal presequences for import into the organelle. The vast majority of presequences are proteolytically removed by the mitochondrial processing peptidase (MPP) localized in the matrix. A subset of precursors with a characteristic amino acid motif is additionally processed by the mitochondrial intermediate peptidase (MIP) octapeptidyl aminopeptidase 1 (Oct1), which removes an octapeptide from the N-terminus of the precursor intermediate. However, the function of this second cleavage step is elusive. In this paper, we report the identification of a novel Oct1 substrate protein with an unusual cleavage motif. Inspection of the Oct1 substrates revealed that the N-termini of the intermediates typically carry a destabilizing amino acid residue according to the N-end rule of protein degradation, whereas mature proteins carry stabilizing N terminal residues. We compared the stability of intermediate and mature forms of Oct1 substrate proteins in organello and in vivo and found that Oct1 cleavage increases the half-life of its substrate proteins, most likely by removing destabilizing amino acids at the intermediate's N-terminus. Thus Oct1 converts unstable precursor intermediates generated by MPP into stable mature proteins. PMID- 21525246 TI - Prophylactic application of bovine colostrum ameliorates murine colitis via induction of immunoregulatory cells. AB - Epidemiologic studies suggest a relationship between early weaning and the incidence of inflammatory bowel disease. Herein, we addressed the question whether bovine colostrum, the first milk produced by mammals, is able to prevent dextran sulfate sodium (DSS)-induced colitis in mice. Prior to induction of colitis with 5% DSS, Naval Medical Research Institute mice were fed bovine colostrum [BV-20 or 200 mg/kg body weight (BW)], BSA (20 mg/kg BW), or water (100 MUL) daily by oral gavage for 2 wk. The clinical severity of colitis was determined by scoring changes in BW and colon length reduction. Following 2 wk of observation, the colons were removed for histologic and immunohistochemical evaluation of inflammation. Flow cytometric phenotyping of leukocyte subsets was performed from peripheral blood, mesenteric lymph nodes, and spleens. Administration of bovine colostrum improved the clinical and histologic severity of colorectal inflammation. Compared with BSA-fed and water-fed controls, BV-20 pretreated mice had significantly less severe weight loss and decreased colon shortening. Beneficial effects were accompanied by redistribution of immunoregulatory, peripheral and splenic gammadelta TCR(+) cells, and CD11b(+)Gr1(+) cells. Higher colostrum doses did not affect disease activity. In summary, prophylactic administration of colostrum improved clinical symptoms of colorectal inflammation in a well-established mouse model of DSS-induced colitis. Further investigations will target the underlying immunomodulatory mechanisms to our approach. PMID- 21525247 TI - Prenatal DHA status and neurological outcome in children at age 5.5 years are positively associated. AB - Beneficial effects of perinatal DHA supply on later neurological development have been reported. We assessed the effects of maternal DHA supplementation on the neurological development of their children. Healthy pregnant women from Spain, Germany, and Hungary were randomly assigned to a dietary supplement consisting of either fish oil (FO) (500 mg/d DHA + 150 mg/d EPA), 400 MUg/d 5 methyltetrahydrofolate, both, or placebo from wk 20 of gestation until delivery. Fatty acids in plasma and erythrocyte phospholipids (PL) were determined in maternal blood at gestational wk 20 and 30 and in cord and maternal blood at delivery. Neurological development was assessed with the Hempel examination at the age of 4 y and the Touwen examination at 5.5 y. Minor neurological dysfunction, neurological optimality score (NOS), and fluency score did not differ between groups at either age, but the odds of children with the maximal NOS score increased with every unit increment in cord blood DHA level at delivery in plasma PL (95% CI: 1.094-2.262), erythrocyte phosphatidylethanolamine (95% CI: 1.091-2.417), and erythrocyte phosphatidylcholine (95% CI: 1.003-2.643). We conclude that higher DHA levels in cord blood may be related to a better neurological outcome at 5.5 y of age. PMID- 21525248 TI - Prolonged leucine supplementation does not augment muscle mass or affect glycemic control in elderly type 2 diabetic men. AB - The loss of muscle mass with aging has been, at least partly, attributed to a blunted muscle protein synthetic response to food intake. Leucine coingestion has been reported to stimulate postprandial insulin release and augment postprandial muscle protein accretion. We assessed the clinical benefits of 6 mo of leucine supplementation in elderly, type 2 diabetes patients. Sixty elderly males with type 2 diabetes (age, 71 +/- 1 y; BMI, 27.3 +/- 0.4 kg/m(2)) were administered 2.5 g L-leucine (n = 30) or a placebo (n = 30) with each main meal during 6 mo of nutritional intervention (7.5 g/d leucine or placebo). Body composition, muscle fiber characteristics, muscle strength, glucose homeostasis, and basal plasma amino acid and lipid concentrations were assessed prior to, during, and after intervention. Lean tissue mass did not change or differ between groups and at 0, 3, and 6 mo were 61.9 +/- 1.1, 62.2 +/- 1.1, and 62.0 +/- 1.0 kg, respectively, in the leucine group and 62.2 +/- 1.3, 62.2 +/- 1.3, and 62.2 +/- 1.3 kg in the placebo group. There also were no changes in body fat percentage, muscle strength, and muscle fiber type characteristics. Blood glycosylated hemoglobin did not change or differ between groups and was 7.1 +/- 0.1% in the leucine group and 7.2 +/- 0.2% in the placebo group. Consistent with this, oral glucose insulin sensitivity and plasma lipid concentrations did not change or differ between groups. We conclude that prolonged leucine supplementation (7.5 g/d) does not modulate body composition, muscle mass, strength, glycemic control, and/or lipidemia in elderly, type 2 diabetes patients who habitually consume adequate dietary protein. PMID- 21525249 TI - Bacteroides uniformis is a putative bacterial species associated with the degradation of the isoflavone genistein in human feces. AB - Inter-individual variation in isoflavone absorption depends on gut microbial degradation and affects the efficacy of these compounds. We hypothesized that inter-individual variation in fecal isoflavone disappearance coincided with variation in bacterial species. In vitro anaerobic fecal disappearance of isoflavones was measured from 33 participants by HPLC. Fecal microbial 16S rRNA variable region PCR products were obtained from 4 participants with the greatest and least genistein or glycitein degradation and were subjected to denaturing gradient gel electrophoresis. DNA bands with a homology of 90-95% to Bacteroides uniformis and Faecalibacterium prausnitzii were present in greater intensities in fecal samples showing a genistein disappearance rate constant of 1.47 +/- 0.14 h( 1) compared with those with a genistein disappearance rate constant of 0.15 +/- 0.03 h(-1) (P < 0.05). Human fecal bacterial species with DNA sequences 90-100% homologous to Tannerella forsythensis and 4 other species were present in greater intensities in fecal samples showing a glycitein disappearance rate constant of 0.57 +/- 0.30 h(-1) compared with fecal samples with a glycitein disappearance rate constant of 0.08 +/- 0.03 h(-1) (P < 0.05). In high degraders, B. uniformis may be a candidate for genistein degradation and T. forsythensis for glycitein degradation, based on fecal isoflavone degradation in the presence of these species. Bacteroides acidifaciens increased isoflavone disappearance in anaerobic human fecal incubations under nutrient-rich and -depleted conditions, suggesting this species as one responsible for the generally high degradation of isoflavones by humans. These fecal microbes are candidate biomarkers for interindividual variation in isoflavone uptake and efficacy. PMID- 21525250 TI - Dietary patterns are associated with levels of global genomic DNA methylation in a cancer-free population. AB - Animal studies have provided direct evidence that dietary factors induce changes in DNA methylation patterns. In humans, studies on diet and DNA methylation have yielded inconsistent findings. Because humans tend to consume foods and nutrients that are highly interrelated, study of dietary patterns may have improved the power of detecting the effect of diet on DNA methylation. Using data collected from 149 participants aged 45-75 y in the North Texas Healthy Heart Study, we examined the relationship between dietary patterns and levels of genomic DNA methylation in peripheral blood leukocytes. Dietary data were collected from study participants using the Block FFQ. Genomic DNA methylation was measured using bisulfite conversion of DNA and real-time PCR (MethyLight) for LINE-1. Two dietary patterns were identified using factor analysis: a "prudent" dietary pattern characterized by a high intake of vegetables and fruits, and a "Western" dietary pattern characterized by a high intake of meats, grains, dairy, oils, and potatoes. The prudent dietary pattern was associated with a lower prevalence of DNA hypomethylation (Q(4) vs. Q(1); OR = 0.33, 95% CI: 0.12-0.92) and the association was dose dependent (P-trend = 0.04). There was no apparent association between the Western dietary pattern and global leukocyte DNA methylation (Q(4) vs. Q(1); OR = 1.28, 95% CI: 0.47-3.47; P-trend = 0.55). Thus, a dietary pattern characterized by a high intake of vegetables and fruits may protect against global DNA hypomethylation. Future studies with a larger sample size need to confirm that this association holds longitudinally. PMID- 21525251 TI - Cobalamin status modifies the effect of zinc supplementation on the incidence of prolonged diarrhea in 6- to 30-month-old north Indian children. AB - The observed effect of zinc supplementation on diarrheal morbidity varies between trials and there is a need to identify subgroups most likely to benefit from improved zinc nutriture. In a randomized, double-blind trial in 2296 children in New Delhi, India, we assessed whether baseline cobalamin or folate status modified the effect of zinc supplementation on the incidence of prolonged (>= 7 d duration) and acute diarrhea. Children aged 6-30 mo received zinc or placebo daily for 4 mo. We measured plasma concentrations of folate, cobalamin, total homocysteine (tHcy), and methylmalonic acid (MMA) at enrollment and assessed the efficacy of zinc supplementation in subgroups based on these variables. The efficacy of zinc on reducing the risk of prolonged diarrhea was higher in those with plasma cobalamin concentrations below the 25th percentile and in those with tHcy and MMA concentrations above the 75th percentile. The OR (95% CI) for children below and above the 25th percentile for cobalamin were 0.53 (0.35-0.78) and 0.90 (0.73-1.11), respectively (P-interaction = 0.015). There were similar differences for the OR when comparing efficacy in those above and below the 75th percentile for tHcy and MMA (P-interaction = 0.045 and 0.188, respectively). Baseline folate status did not modify the effect of zinc on prolonged diarrhea. Neither cobalamin nor folate status influenced the effect of zinc on acute diarrhea. Children with poor cobalamin status benefited more from zinc supplementation for the prevention of prolonged diarrhea. PMID- 21525252 TI - A low-glycemic index diet and exercise intervention reduces TNF(alpha) in isolated mononuclear cells of older, obese adults. AB - Low-glycemic index diets and exercise independently improve glucose tolerance and reduce diabetes risk. However, the combined effect of a low-glycemic index diet and exercise on inflammation and glucose metabolism is not known. Therefore, we randomized 28 insulin-resistant adults (age: 66 +/- 1 y; BMI: 34.2 +/- 0.7 kg . m(-2)) to a 12-wk, low (LGI = 40) or high- (HGI = 80) glycemic index diet plus aerobic exercise (5 d . wk(-1), 60 min . d(-1), 80-85% heart rate(max)) intervention. All food and fluids were provided during the study. Inflammation was assessed from cytokine (TNFalpha and IL-6) secretion using peripheral blood mononuclear cells (MNC) stimulated overnight with LPS. Glycemic response was determined following ingestion of a 75-g glucose solution. Fasting blood samples were collected for additional cytokine [TNFalpha, IL-6, and monocyte chemoattractant protein 1 (MCP-1)] analysis. Both interventions decreased BMI (P < 0.001), fasting plasma glucose (P = 0.01), and insulin (P = 0.02). The glycemic response was reduced only in the LGI group (P = 0.04). Plasma and MNC-derived TNFalpha secretion were reduced in the LGI group (P = 0.02) but increased in the HGI group (P = 0.02). Secretion of IL-6 from MNC and plasma IL-6 and MCP-1 concentrations were reduced in the LGI group. The change in MNC-derived TNFalpha (r = 0.43; P = 0.04) and plasma MCP-1 (r = 0.44; P = 0.04) correlated with decreases in the glycemic response. These data highlight the importance of diet composition in the treatment and prevention of inflammation and hyperglycemia. A low-glycemic index diet has antiinflammatory and antidiabetogenic effects when combined with exercise in older, obese prediabetics. PMID- 21525253 TI - Consumption of high-oleic acid ground beef increases HDL-cholesterol concentration but both high- and low-oleic acid ground beef decrease HDL particle diameter in normocholesterolemic men. AB - On the basis of previous results from this laboratory, this study tested the hypothesis that ground beef high in MUFA and low in SFA would increase the HDL cholesterol (HDL-C) concentration and LDL particle diameter. In a crossover dietary intervention, 27 free-living normocholesterolemic men completed treatments in which five 114-g ground beef patties/wk were consumed for 5 wk with an intervening 4-wk washout period. Patties contained 24% total fat with a MUFA:SFA ratio of either 0.71 (low MUFA, from pasture-fed cattle) or 1.10 (high MUFA, from grain-fed cattle). High-MUFA ground beef provided 3.21 g more 18:1(n 9), 1.26 g less 18:0, 0.89 g less 16:0, and 0.36 g less 18:1(trans) fatty acids per patty than did the low-MUFA ground beef. Both ground beef interventions decreased plasma insulin and HDL(2) and HDL(3) particle diameters and increased plasma 18:0 and 20:4(n-6) (all P <= 0.05) relative to baseline values. Only the high-MUFA ground beef intervention increased the HDL-C concentration from baseline (P = 0.02). The plasma TG concentration was positively correlated with the plasma insulin concentration (r = 0.40; P < 0.001) and negatively correlated with HDL-C (r = -0.47; P < 0.001) and plasma 18:0 (r = -0.24; P < 0.01). Plasma insulin and HDL diameters were not correlated (r = 0.01; P > 0.50), indicating that reductions in these measures were not coordinately regulated. The data indicate that dietary beef interventions have effects on risk factors for cardiovascular disease that are independent (insulin, HDL diameters) and dependent (HDL-C) on beef fatty acid composition. PMID- 21525254 TI - Dietary protein and sugar differentially affect development and metabolic pools in ecologically diverse Drosophila. AB - We examined the effects of 3 diets differing in their relative levels of sugar and protein on development and metabolic pools (protein, TG, and glycogen) among sets of isofemale lines of 2 ecologically distinct Drosophila species, D. melanogaster and D. mojavensis. Our high protein:sugar ratio diet contained 7.1% protein and 17.9% carbohydrate, the EPS diet was 4.3% protein and 21.2% carbohydrate, and the LPS was only 2.5% protein and 24.6% carbohydrate. Larvae of D. melanogaster, a generalist fruit breeder, were able to survive on all 3 diets, although all 3 metabolic pools responded with significant diet and diet * line interactions. Development was delayed by the diet with the most sugar relative to protein. The other species, D. mojavensis, a cactus breeder ecologically unaccustomed to encountering simple sugars, completely failed to survive when fed the diet with the highest sugar and showed very poor survival even with the diet with equal parts of protein and sugar. Furthermore, the D. mojavensis adult metabolic pools of protein, TG, and glycogen significantly differed from those of D. melanogaster adults fed the identical diet. Thus, considerable within- and between-species differences exist in how diets are metabolized. Given that the genomes of both of these Drosophila species have been sequenced, these differences and their genetic underpinnings hold promise for understanding human responses to nutrition and for developing strategies for dealing with metabolic disease. PMID- 21525255 TI - Essential amino acids regulate both initiation and elongation of mRNA translation independent of insulin in MAC-T cells and bovine mammary tissue slices. AB - Current nutrient requirement models assume fixed efficiencies of absorbed amino acid (AA) conversion to milk protein. Regulation of mammary protein synthesis (PS) potentially violates this assumption by changing the relationship between AA supply and milk protein output. The objective of this study was to investigate the effects of essential AA (EAA) and insulin on cellular signaling and PS rates in bovine mammary cells. MAC-T cells were subjected to 0 or 100% of normal EAA concentrations in DMEM/F12 and 0 or 100 MUg insulin/L in a 2 * 2 factorial arrangement of treatments. Lactogenic bovine mammary tissue slices (MTS) were subjected to the same treatments, except low-EAA was 5% of normal DMEM/F12 concentrations. In MAC-T cells, EAA increased phosphorylation of mammalian target of rapamycin (mTOR; Ser2448), ribosomal protein S6 kinase 1 (S6K1; Thr389), eIF4E binding protein 1 (4EBP1; Thr37/46), and insulin receptor substrate 1 (IRS1; Ser1101), and reduced phosphorylation of eukaryotic elongation factor 2 (eEF2; Thr56) and eukaryotic initiation factor (eIF) 2-alpha (Ser51). In the presence of insulin, phosphorylation of Akt (Ser473), mTOR, S6K1, 4EBP1, and IRS1 increased in MAC-T cells. In MTS, EAA had similar effects on phosphorylation of signaling proteins and increased mammary PS rates. Insulin did not affect MTS signaling, perhaps due to inadequate levels. Effects of EAA and insulin were independent and additive for mTOR signaling in MAC-T cells. EAA did not inhibit insulin stimulation of Akt phosphorylation. PS rates were strongly associated with phosphorylation of 4EBP1 and eEF2 in MTS. EAA availability affected translation initiation and elongation control points to more strongly regulate PS than insulin. PMID- 21525256 TI - (n-3) long-chain PUFA differentially affect resistance to Pseudomonas aeruginosa infection of male and female cftr-/- mice. AB - The aim of this study was to determine whether oral supplementation with EPA/DHA (10.5 and 5.1% of fat, respectively) could improve the outcome of pulmonary P. aeruginosa infection in cftr(-/-) mice compared with wild-type (Wt) mice similarly treated. Because gender could influence the susceptibility of cftr deficient mice, results were analyzed by gender. Wt and (-/-) mice were randomized for 6 wk to consume a control or EPA/DHA diet, infected with endotracheal injection of 5 * 10(7) CFU/mouse of P. aeruginosa, and killed 24 h later. Cftr(-/-) mice were more susceptible to infection than were Wt mice; (-/-) males had more neutrophils (P < 0.01) and a higher keratinocyte-derived chemokine (KC) level (P < 0.05), and (-/-) females had greater lung injury and mortality (P < 0.05). Female (-/-) mice were more susceptible than (-/-) males with a higher mortality and lung injury (P < 0.05). The EPA/DHA diet reduced neutrophil numbers and KC and IL-6 levels (P < 0.05) in (-/-) males and reduced mortality rate (P < 0.001), lung permeability, and IL-6 level (P < 0.05) in (-/-) females compared with (-/-) mice fed the control diet. These results were associated with a reduction in the pulmonary bacterial load (P < 0.05), an increase in the EPA/DHA concentration in cell membranes of (-/-) males and females (P < 0.01), and an increased weight gain only in males compared with (-/-) mice fed the control diet (P < 0.01). In conclusion, EPA/DHA improves the host resistance of (-/-) mice, although the beneficial effect differed in males and females. PMID- 21525257 TI - Children are aware of food insecurity and take responsibility for managing food resources. AB - Child food insecurity is measured using parental reports of children's experiences based on an adult-generated conceptualization. Research on other child experiences (e.g. pain, exposure to domestic violence) cautions that children generally best report their own experiences, and parents' reports of children's experiences may lack adequate validity and impede effective intervention. Because this may be true of child food insecurity, we conducted semistructured interviews with mothers, children (age 9-16 y), and other household adults in 26 South Carolina families at risk for food insecurity. Interview transcripts were analyzed using a constant comparative process combining a priori with inductive coding. Child interviews revealed experiences of food insecurity distinct from parent experiences and from parent reports of children's experiences. Children experienced cognitive, emotional, and physical awareness of food insecurity. Children took responsibility for managing food resources through participation in parental strategies, initiation of their own strategies, and generation of resources to provide food for the family. Adults were not always aware of children's experiences. Where adult experiences of food insecurity are conditioned on inadequate money for food, child experiences were grounded in the immediate household social and food environment: quality of child/parent interactions, parent affect and behavior, and types and quantities of foods made available for children to eat. The new, child-derived understanding of what children experience that results from this study provides a critical basis from which to build effective approaches to identify, assess, and respond to children suffering from food insecurity. PMID- 21525258 TI - Food portion patterns and trends among U.S. children and the relationship to total eating occasion size, 1977-2006. AB - Food and beverage portion sizes are related to childhood obesity. We examined trends in food portion sizes and the association with total meal sizes among U.S. children. We selected children 2- to 18-y-old (n = 31,337) from 4 nationally representative surveys of food intake between 1977-1978 and 2003-2006. We assessed portion sizes (kcal and g) of selected key foods (soft/fruit drinks, salty snacks, desserts, French fries, burgers, pizzas, Mexican fast foods, and hot dogs), the total energy from eating occasions that included key foods, and portion sizes of the selected key foods by source (stores, restaurants, and fast food locations). These foods represented over one-third of children's energy intake in 2003-2006. Portion sizes increased significantly over the 30-y period and increases in pizza were particularly pronounced in the last decade [+176 kcal (736 kJ). Energy from eating occasions including pizzas and soft drinks increased, as did the proportion of energy from these foods in an eating occasion. Hamburgers and cheeseburgers increased in portion size and eating occasion size, but the proportion of these foods in the total eating occasions did not increase. Portion sizes of other key foods increased, although the total energy from eating events that included them remained constant (e.g. Mexican fast foods, French fries, fruit drinks) or decreased (e.g. salty snacks, desserts). Portion sizes increased across all food sources (stores, restaurants, and fast foods) for soft drinks and pizzas but only at fast-food locations for French fries. Portion sizes continue to grow for selected foods. Fast-food chains appear to be linked with less healthful portion size increases for selected foods. PMID- 21525259 TI - The Dietary Approaches to Stop Hypertension eating plan affects C-reactive protein, coagulation abnormalities, and hepatic function tests among type 2 diabetic patients. AB - Few studies exist regarding the effects of the Dietary Approaches to Stop Hypertension (DASH) diet on novel cardiovascular risk factors among type 2 diabetic patients. We evaluated the effects of the DASH eating pattern on C reactive protein (CRP) level, coagulation abnormalities, and hepatic function tests in type 2 diabetic patients. In this randomized, crossover clinical trial, 31 type 2 diabetic patients consumed a control diet or the DASH diet for 8 wk. The DASH diet was rich in fruits, vegetables, whole grains, and low-fat dairy products and low in saturated fat, total fat, cholesterol, refined grains, and sweets, with a total of 2400 mg/d sodium. The control diet was a standard diet for diabetic patients. There was a 4-wk washout between the 2 trial phases. The main outcome measures were CRP level, coagulation indices, and hepatic function tests. The mean percent change for plasma CRP level was -26.9 +/- 3.5% after the DASH diet period and -5.1 +/- 3.8% after the control diet period (P = 0.02). Decreases in both alanine aminotransferase and aspartate aminotransferase levels were greater after consuming the DASH diet compared with the control diet (-14.8 +/- 3.0% vs -6.6 +/- 3.4%; P = 0.001; -29.4 +/- 3.7% vs -5.9 +/- 1.4%; P = 0.001, respectively). The decrease in the plasma fibrinogen level during the DASH diet period (-11.4 +/- 3.6%) was greater than that during the control diet (0.5 +/- 3.4%) (P = 0.03). Among diabetic patients, the DASH diet can play an important role in reducing inflammation, plasma levels of fibrinogen, and liver aminotransferases. Future longer term studies are recommended. PMID- 21525260 TI - Green tea polyphenols provide photoprotection, increase microcirculation, and modulate skin properties of women. AB - Dietary constituents including polyphenols and carotenoids contribute to endogenous photoprotection and modulate skin characteristics related to structure and function of the tissue. Animal and in-vitro studies indicate that green tea polyphenols affect skin properties. In a 12-wk, double-blind, placebo-controlled study, 60 female volunteers were randomized to an intervention or control group. Participants consumed either a beverage with green tea polyphenols providing 1402 mg total catechins/d or a control beverage. Skin photoprotection, structure, and function were measured at baseline (wk 0), wk 6, and wk 12. Following exposure of the skin areas to 1.25 minimal erythemal dose of radiation from a solar simulator, UV-induced erythema decreased significantly in the intervention group by 16 and 25% after 6 and 12 wk, respectively. Skin structural characteristics that were positively affected included elasticity, roughness, scaling, density, and water homeostasis. Intake of the green tea polyphenol beverage for 12 wk increased blood flow and oxygen delivery to the skin. Likewise, in a separate, randomized, double-blind, single-dose (0.5, 1.0, and 2.0 g) study of green tea polyphenols, blood flow was maximized at 30 min after ingestion. In summary, green tea polyphenols delivered in a beverage were shown to protect skin against harmful UV radiation and helped to improve overall skin quality of women. PMID- 21525261 TI - Marginal zinc deficiency exacerbates experimental colitis induced by dextran sulfate sodium in rats. AB - We investigated the impact of Zn status on the maintenance of mucosal homeostasis. Rats were fed diets containing different amounts of Zn (30, 10, 5, <1 mg Zn/kg diet) for 21 d. Serum Zn concentrations were lower in rats fed marginally Zn-deficient (MZD; 5 mg Zn/kg diet) and severely Zn-deficient (<1 mg/kg) diets but not in those fed the marginally Zn-adequate diet (10 mg/kg) or the Zn-adequate (ZA; 30 mg/kg) group (P < 0.05). However, organ weights, colonic epithelial cell proliferation, and crypt fission did not differ between the MZD and ZA groups. We then evaluated whether MZD modulated dextran sulfate sodium (DSS)-induced colonic inflammation by administering 2% DSS to the MZD and ZA groups for 7 d. Myeloperoxidase activity and TNFalpha production increased in response to DSS in the MZD group (P < 0.03). Colonic permeability in the 2 groups did not differ after DSS administration. In a culture experiment using isolated mesenteric leukocytes, TNFalpha production was higher (P < 0.05) and TNF receptor type I (TNFR1) expression was detected in culture medium containing 20 and 30 MUmol/L of Zn compared with culture medium lacking Zn supplementation. These results suggest that MZD exacerbated colitis by modulating the immune response through the impairment of TNFalpha production and TNFR1 expression rather than through the impairment of epithelial barrier function. PMID- 21525262 TI - Dietary epicatechin promotes survival of obese diabetic mice and Drosophila melanogaster. AB - The lifespan of diabetic patients is 7-8 y shorter than that of the general population because of hyperglycemia-induced vascular complications and damage to other organs such as the liver and skeletal muscle. Here, we investigated the effects of epicatechin, one of the major flavonoids in cocoa, on health-promoting effects in obese diabetic (db/db) mice (0.25% in drinking water for 15 wk) and Drosophila melanogaster (0.01-8 mmol/L in diet). Dietary intake of epicatechin promoted survival in the diabetic mice (50% mortality in diabetic control group vs. 8.4% in epicatechin group after 15 wk of treatment), whereas blood pressure, blood glucose, food intake, and body weight gain were not significantly altered. Pathological analysis showed that epicatechin administration reduced the degeneration of aortic vessels and blunted fat deposition and hydropic degeneration in the liver caused by diabetes. Epicatechin treatment caused changes in diabetic mice that are associated with a healthier and longer lifespan, including improved skeletal muscle stress output, reduced systematic inflammation markers and serum LDL cholesterol, increased hepatic antioxidant glutathione concentration and total superoxide dismutase activity, decreased circulating insulin-like growth factor-1 (from 303 +/- 21 mg/L in the diabetic control group to 189 +/- 21 mg/L in the epicatechin-treated group), and improved AMP-activated protein kinase-alpha activity in the liver and skeletal muscle. Consistently, epicatechin (0.1-8 mmol/L) also promoted survival and increased mean lifespan of Drosophila. Therefore, epicatechin may be a novel food-derived, antiaging compound. PMID- 21525263 TI - Membrane raft organization is more sensitive to disruption by (n-3) PUFA than nonraft organization in EL4 and B cells. AB - Model membrane and cellular detergent extraction studies show (n-3) PUFA predominately incorporate into nonrafts; thus, we hypothesized (n-3) PUFA could disrupt nonraft organization. The first objective of this study was to determine whether (n-3) PUFA disrupted nonrafts of EL4 cells, an extension of our previous work in which we discovered an (n-3) PUFA diminished raft clustering. EPA or DHA treatment of EL4 cells increased plasma membrane accumulation of the nonraft probe 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate by ~50 70% relative to a BSA control. Forster resonance energy transfer imaging showed EPA and DHA also disrupted EL4 nanometer scale nonraft organization by increasing the distance between nonraft molecules by ~25% compared with BSA. However, changes in nonrafts were due to an increase in cell size; under conditions where EPA or DHA did not increase cell size, nonraft organization was unaffected. We next translated findings on EL4 cells by testing if (n-3) PUFA administered to mice disrupted nonrafts and rafts. Imaging of B cells isolated from mice fed low- or high-fat (HF) (n-3) PUFA diets showed no change in nonraft organization compared with a control diet (CD). However, confocal microscopy revealed the HF (n-3) PUFA diet disrupted lipid raft clustering and size by ~40% relative to CD. Taken together, our data from 2 different model systems suggest (n-3) PUFA have limited effects on nonrafts. The ex vivo data, which confirm previous studies with EL4 cells, provide evidence that (n-3) PUFA consumed through the diet disrupt B cell lipid raft clustering. PMID- 21525264 TI - Obesity in preschool children is more prevalent and identified at a younger age when WHO growth charts are used compared with CDC charts. AB - Our objective was to compare the prevalence and determinants of child obesity using the WHO child growth standards compared with the CDC growth reference. We used data from 143,787 2- to 5-y olds who participated in the Massachusetts Special Supplemental Food and Nutrition Program for Women, Infants and Children (WIC) program between 2001 and 2006. The prevalence of obesity (>95th percentile, BMI-for-age) was 23.3% when we used the WHO standards vs. 16.9% using the CDC reference; for obesity plus overweight (>85th percentile), the prevalence was 42.2 vs. 33.8%, respectively. The difference between the prevalence estimates was greatest at 24-36 mo of age. Multivariate logistic regression analysis indicated that child obesity (based on the WHO standards) was more common in boys, Hispanics, children of less educated mothers, and those born to obese mothers. These results confirm that the prevalence of child obesity is higher according to the WHO standards and indicate that the WHO charts allow for a more timely detection of obesity in childhood. PMID- 21525265 TI - Emerging evidence of connectomic abnormalities in schizophrenia. PMID- 21525266 TI - Stimulus selectivity in dorsal and ventral prefrontal cortex after training in working memory tasks. AB - The prefrontal cortex is known to represent different types of information in working memory. Contrasting theories propose that the dorsal and ventral regions of the lateral prefrontal cortex are innately specialized for the representation of spatial and nonspatial information, respectively (Goldman-Rakic, 1996), or that the two regions are shaped by the demands of cognitive tasks imposed on them (Miller, 2000). To resolve this issue, we recorded from neurons in the two regions, before and at multiple stages of training monkeys on visual working memory tasks. Before training, substantial functional differences were present between the two regions. Dorsal prefrontal cortex exhibited higher overall responsiveness to visual stimuli and higher selectivity for spatial information. After training, stimulus selectivity generally decreased, although dorsal prefrontal cortex retained higher spatial selectivity regardless of task performed. Ventral prefrontal cortex appeared to be affected to a greater extent by the nature of the task. Our results indicate that regional specialization for stimulus selectivity is present in the primate prefrontal cortex regardless of training. Dorsal areas of the prefrontal cortex are inherently organized to represent spatial information, and training has little influence on this spatial bias. Ventral areas are biased toward nonspatial information, although they are more influenced by training both in terms of activation and changes in stimulus selectivity. PMID- 21525267 TI - beta-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. AB - Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a beta-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b(+)/CD45(high)/Ly6C(high) macrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1beta and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes in microglia and macrophages were prevented by propranolol, a beta-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of beta adrenergic and IL-1 receptors. PMID- 21525268 TI - Integrin activation promotes axon growth on inhibitory chondroitin sulfate proteoglycans by enhancing integrin signaling. AB - Chondroitin sulfate proteoglycans (CSPGs) are upregulated after CNS lesions, where they inhibit axon regeneration. In order for axon growth and regeneration to occur, surface integrin receptors must interact with surrounding extracellular matrix molecules. We have explored the hypothesis that CSPGs inhibit regeneration by inactivating integrins and that forcing integrins into an active state might overcome this inhibition. Using cultured rat sensory neurons, we show that the CSPG aggrecan inhibits laminin-mediated axon growth by impairing integrin signaling via decreasing phosphorylated FAK (pFAK) and pSrc levels, without affecting surface integrin levels. Forcing integrin activation and signaling by manganese or an activating antibody TS2/16 reversed the inhibitory effect of aggrecan on mixed aggrecan/laminin surfaces, and enhanced axon growth from cultured rat sensory neurons (manganese) and human embryonic stem cell-derived motoneurons (TS2/16). The inhibitory effect of Nogo-A can also be reversed by integrin activation. These results suggest that inhibition by CSPGs can act via inactivation of integrins, and that activation of integrins is a potential method for improving axon regeneration after injury. PMID- 21525269 TI - Human dorsal striatal activity during choice discriminates reinforcement learning behavior from the gambler's fallacy. AB - Reinforcement learning theory has generated substantial interest in neurobiology, particularly because of the resemblance between phasic dopamine and reward prediction errors. Actor-critic theories have been adapted to account for the functions of the striatum, with parts of the dorsal striatum equated to the actor. Here, we specifically test whether the human dorsal striatum--as predicted by an actor-critic instantiation--is used on a trial-to-trial basis at the time of choice to choose in accordance with reinforcement learning theory, as opposed to a competing strategy: the gambler's fallacy. Using a partial-brain functional magnetic resonance imaging scanning protocol focused on the striatum and other ventral brain areas, we found that the dorsal striatum is more active when choosing consistent with reinforcement learning compared with the competing strategy. Moreover, an overlapping area of dorsal striatum along with the ventral striatum was found to be correlated with reward prediction errors at the time of outcome, as predicted by the actor-critic framework. These findings suggest that the same region of dorsal striatum involved in learning stimulus-response associations may contribute to the control of behavior during choice, thereby using those learned associations. Intriguingly, neither reinforcement learning nor the gambler's fallacy conformed to the optimal choice strategy on the specific decision-making task we used. Thus, the dorsal striatum may contribute to the control of behavior according to reinforcement learning even when the prescriptions of such an algorithm are suboptimal in terms of maximizing future rewards. PMID- 21525270 TI - Role of the hypocretin (orexin) receptor 2 (Hcrt-r2) in the regulation of hypocretin level and cataplexy. AB - Hypocretin receptor-2 (Hcrt-r2)-mutated dogs exhibit all the major symptoms of human narcolepsy and respond to drugs that increase or decrease cataplexy as do narcoleptic humans; yet, unlike narcoleptic humans, the narcoleptic dogs have normal hypocretin levels. We find that drugs that reduce or increase cataplexy in the narcoleptic dogs, greatly increase and decrease, respectively, hypocretin levels in normal dogs. The effects of these drugs on heart rate and blood pressure, which were considerable, were not correlated with their effects on cataplexy. Administration of these drugs to Hcrt-r2-mutated dogs produced indistinguishable changes in heart rate and blood pressure, indicating that neither central nor peripheral Hcrt-r2 is required for these cardiovascular effects. However, in contrast to the marked Hcrt level changes in the normal dogs, these drugs did not alter hypocretin levels in the Hcrt-r2 mutants. We conclude that Hcrt-r2 is a vital element in a feedback loop integrating Hcrt, acetylcholine, and norepinephrine function. In the absence of functional Hcrt-r2, Hcrt levels are not affected by monoaminergic and cholinergic drugs, despite the strong modulation of cataplexy by these drugs. Conversely, strong transient reductions of Hcrt level by these drugs do not produce episodes of cataplexy in normal dogs. The Hcrt-r2 mutation causes drug-induced cataplexy by virtue of its long-term effect on the functioning of other brain systems, rather than by increasing the magnitude of phasic changes in Hcrt level. A similar mechanism may be operative in spontaneous cataplexy in narcoleptic dogs as well as in narcoleptic humans. PMID- 21525271 TI - Molecular determinants controlling NMDA receptor synaptic incorporation. AB - Synaptic incorporation of NMDA receptors (NMDARs) is regulated by GluN2 subunits with different rules controlling GluN2A- and GluN2B-containing receptors; whereas GluN2B-containing receptors are constitutively incorporated into synapses, GluN2A incorporation is activity-dependent. We expressed electrophysiologically tagged NMDARs in rat hippocampal slices to identify the molecular determinants controlling the mode of synaptic incorporation of NMDARs. Expressing chimeric GluN2 subunits, we identified a putative N-glycosylation site present in GluN2B, but not in GluN2A, as necessary and sufficient to drive NMDARs into synapses in an activity-independent manner. This suggests a novel mechanism for regulating activity-driven changes and trafficking of NMDARs to the synapse. PMID- 21525272 TI - Caudal granular insular cortex is sufficient and necessary for the long-term maintenance of allodynic behavior in the rat attributable to mononeuropathy. AB - Mechanical allodynia, the perception of innocuous tactile stimulation as painful, is a severe symptom of chronic pain often produced by damage to peripheral nerves. Allodynia affects millions of people and remains highly resistant to classic analgesics and therapies. Neural mechanisms for the development and maintenance of allodynia have been investigated in the spinal cord, brainstem, thalamus, and forebrain, but manipulations of these regions rarely produce lasting effects. We found that long-term alleviation of allodynic manifestations is produced by discreetly lesioning a newly discovered somatosensory representation in caudal granular insular cortex (CGIC) in the rat, either before or after a chronic constriction injury of the sciatic nerve. However, CGIC lesions alone have no effect on normal mechanical stimulus thresholds. In addition, using electrophysiological techniques, we reveal a corticospinal loop that could be the anatomical source of the influence of CGIC on allodynia. PMID- 21525273 TI - PSD-95 is required to sustain the molecular organization of the postsynaptic density. AB - PSD-95, a membrane-associated guanylate kinase, is the major scaffolding protein in the excitatory postsynaptic density (PSD) and a potent regulator of synaptic strength. Here we show that PSD-95 is in an extended configuration and positioned into regular arrays of vertical filaments that contact both glutamate receptors and orthogonal horizontal elements layered deep inside the PSD in rat hippocampal spine synapses. RNA interference knockdown of PSD-95 leads to loss of entire patches of PSD material, and electron microscopy tomography shows that the patchy loss correlates with loss of PSD-95-containing vertical filaments, horizontal elements associated with the vertical filaments, and putative AMPA receptor-type, but not NMDA receptor-type, structures. These observations show that the orthogonal molecular scaffold constructed from PSD-95-containing vertical filaments and their associated horizontal elements is essential for sustaining the three-dimensional molecular organization of the PSD. Our findings provide a structural basis for understanding the functional role of PSD-95 at the PSD. PMID- 21525274 TI - Elapsed decision time affects the weighting of prior probability in a perceptual decision task. AB - Decisions are often based on a combination of new evidence with prior knowledge of the probable best choice. Optimal combination requires knowledge about the reliability of evidence, but in many realistic situations, this is unknown. Here we propose and test a novel theory: the brain exploits elapsed time during decision formation to combine sensory evidence with prior probability. Elapsed time is useful because (1) decisions that linger tend to arise from less reliable evidence, and (2) the expected accuracy at a given decision time depends on the reliability of the evidence gathered up to that point. These regularities allow the brain to combine prior information with sensory evidence by weighting the latter in accordance with reliability. To test this theory, we manipulated the prior probability of the rewarded choice while subjects performed a reaction-time discrimination of motion direction using a range of stimulus reliabilities that varied from trial to trial. The theory explains the effect of prior probability on choice and reaction time over a wide range of stimulus strengths. We found that prior probability was incorporated into the decision process as a dynamic bias signal that increases as a function of decision time. This bias signal depends on the speed-accuracy setting of human subjects, and it is reflected in the firing rates of neurons in the lateral intraparietal area (LIP) of rhesus monkeys performing this task. PMID- 21525275 TI - Biophysical mechanisms of multistability in resting-state cortical rhythms. AB - The human alpha (8-12 Hz) rhythm is one of the most prominent, robust, and widely studied attributes of ongoing cortical activity. Contrary to the prevalent notion that it simply "waxes and wanes," spontaneous alpha activity bursts erratically between two distinct modes of activity. We now establish a mechanism for this multistable phenomenon in resting-state cortical recordings by characterizing the complex dynamics of a biophysical model of macroscopic corticothalamic activity. This is achieved by studying the predicted activity of cortical and thalamic neuronal populations in this model as a function of its dynamic stability and the role of nonspecific synaptic noise. We hence find that fluctuating noisy inputs into thalamic neurons elicit spontaneous bursts between low- and high-amplitude alpha oscillations when the system is near a particular type of dynamical instability, namely a subcritical Hopf bifurcation. When the postsynaptic potentials associated with these noisy inputs are modulated by cortical feedback, the SD of power within each of these modes scale in proportion to their mean, showing remarkable concordance with empirical data. Our state-dependent corticothalamic model hence exhibits multistability and scale-invariant fluctuations-key features of resting-state cortical activity and indeed, of human perception, cognition, and behavior-thus providing a unified account of these apparently divergent phenomena. PMID- 21525276 TI - Nucleus accumbens MU-opioid receptors mediate social reward. AB - Positive social interactions are essential for emotional well-being and proper behavioral development of young individuals. Here, we studied the neural underpinnings of social reward by investigating the involvement of opioid neurotransmission in the nucleus accumbens (NAc) in social play behavior, a highly rewarding social interaction in adolescent rats. Intra-NAc infusion of morphine (0.05-0.1 MUg) increased pinning and pouncing, characteristic elements of social play behavior in rats, and blockade of NAc opioid receptors with naloxone (0.5 MUg) prevented the play-enhancing effects of systemic morphine (1 mg/kg, s.c.) administration. Thus, stimulation of opioid receptors in the NAc was necessary and sufficient for morphine to increase social play. Intra-NAc treatment with the selective MU-opioid receptor agonist [D-Ala(2),N MePhe(4),Gly(5)-ol]enkephalin (DAMGO) (0.1-10 ng) and the MU-opioid receptor antagonist Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) (0.3-3 MUg) increased and decreased social play, respectively. The delta-opioid receptor agonist DPDPE ([D Pen(2),D-Pen(5)]-enkephalin) (0.3-3 MUg) had no effects, whereas the kappa-opioid receptor agonist U69593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1 oxaspiro[4.5]dec-8-yl]acetamide) (0.01-1 MUg) decreased social play. Intra-NAc treatment with beta-endorphin (0.01-1 MUg) increased social play, but met enkephalin (0.1-5 MUg) and the enkephalinase inhibitor thiorphan (0.1-1 MUg) were ineffective. DAMGO (0.1-10 ng) increased social play after infusion into both the shell and core subregions of the NAc. Last, intra-NAc infusion of CTAP (3 MUg) prevented the development of social play-induced conditioned place preference. These findings identify NAc MU-opioid receptor stimulation as an important neural mechanism for the attribution of positive value to social interactions in adolescent rats. Altered NAc MU-opioid receptor function may underlie social impairments in psychiatric disorders such as autism, schizophrenia, or personality disorders. PMID- 21525277 TI - Trait-like characteristics of the sleep EEG across adolescent development. AB - Waking and sleep data in adults show high heritability and trait-like characteristics in EEG spectra. This phenomenon has not been examined in children and adolescents where brain development influences the EEG. The present study examines whether a trait-like sleep EEG pattern is detectable across adolescent development. Two consecutive nights of standard sleep recordings were performed in 19 9-10-year-old children and 26 15-16-year-old teens, and were repeated 1.5-3 years later. EEG spectra averaged across the night for non-rapid eye movement and rapid eye movement sleep separately were classified using hierarchical cluster analysis, which showed that all 4 nights of a participant clustered together for a majority of participants. Intraclass correlation coefficients were also very high (>0.7) across nights separated by several years, indicating a trait-like feature of the sleep EEG. In summary, our results, using two measures of stability, indicate that a "trait-like" aspect can be detected in the sleep EEG across adolescent development despite considerable neurodevelopmental changes. This finding indicates that the brain oscillators responsible for generating the sleep EEG signal remain relatively stable across adolescent development. PMID- 21525278 TI - Peripheral nervous system progenitors can be reprogrammed to produce myelinating oligodendrocytes and repair brain lesions. AB - Neural crest stem cells (NCSCs) give rise to the neurons and glia of the peripheral nervous system (PNS). NCSC-like cells can be isolated from multiple peripheral organs and maintained in neurosphere culture. Combining in vitro culture and transplantation, we show that expanded embryonic NCSC-like cells lose PNS traits and are reprogrammed to generate CNS cell types. When transplanted into the embryonic or adult mouse CNS, they differentiate predominantly into cells of the oligodendrocyte lineage without any signs of tumor formation. NCSC derived oligodendrocytes generate CNS myelin and contribute to the repair of the myelin deficiency in shiverer mice. These results demonstrate a reprogramming of PNS progenitors to CNS fates without genetic modification and imply that PNS cells could be a potential source for cell-based CNS therapy. PMID- 21525279 TI - Impairment of select forms of spatial memory and neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4. AB - Aquaporin-4 (AQP4) is the major water channel in the CNS and is primarily expressed in astrocytes. Little is known about the potential for AQP4 to influence synaptic plasticity, although many studies have shown that it regulates the response of the CNS to injury. Therefore, we evaluated long-term potentiation (LTP) and long-term depression (LTD) in AQP4 knock-out (KO) and wild-type mice. KO mice exhibited a selective defect in LTP and LTD without a change in basal transmission or short-term plasticity. Interestingly, the impairment in LTP in KO mice was specific for the type of LTP that depends on the neurotrophin BDNF, which is induced by stimulation at theta rhythm [theta-burst stimulation (TBS) LTP], but there was no impairment in a form of LTP that is BDNF independent, induced by high-frequency stimulation. LTD was also impaired in KO mice, which was rescued by a scavenger of BDNF or blockade of Trk receptors. TrkB receptors, which mediate effects of BDNF on TBS-LTP, were not altered in KO mice, but p75NTR, the receptor that binds all neurotrophins and has been implicated in some types of LTD, was decreased. The KO mice also exhibited a cognitive defect, which suggests a new role for AQP4 and astrocytes in normal cognitive function. This defect was evident using a test for location-specific object memory but not Morris water maze or contextual fear conditioning. The results suggest that AQP4 channels in astrocytes play an unanticipated role in neurotrophin-dependent plasticity and influence behavior. PMID- 21525280 TI - Dissociable effects of lesions to orbitofrontal cortex subregions on impulsive choice in the rat. AB - The orbitofrontal cortex (OFC) is implicated in a variety of adaptive decision making processes. Human studies suggest that there is a functional dissociation between medial and lateral OFC (mOFC and lOFC, respectively) subregions when performing certain choice procedures. However, little work has examined the functional consequences of manipulations of OFC subregions on decision making in rodents. In the present experiments, impulsive choice was assessed by evaluating intolerance to delayed, but economically optimal, reward options using a delay discounting paradigm. Following initial delay-discounting training, rats received bilateral neurotoxic or sham lesions targeting whole OFC (wOFC) or restricted to either mOFC or lOFC subregions. A transient flattening of delay-discounting curves was observed in wOFC-lesioned animals relative to shams--differences that disappeared with further training. Stable, dissociable effects were found when lesions were restricted to OFC subregions; mOFC-lesioned rats showed increased, whereas lOFC-lesioned rats showed decreased, preference for the larger-delayed reward relative to sham-controls--a pattern that remained significant during retraining after all delays were removed. When locations of levers leading to small-immediate versus large-delayed rewards were reversed, wOFC- and lOFC lesioned rats showed retarded, whereas mOFC-lesioned rats showed accelerated, trajectories for reversal of lever preference. These results provide the first direct evidence for dissociable functional roles of the mOFC and lOFC for impulsive choice in rodents. The findings are consistent with recent human functional imaging studies and suggest that functions of mOFC and lOFC subregions may be evolutionarily conserved and contribute differentially to decision-making processes. PMID- 21525281 TI - Variability of brain signals processed locally transforms into higher connectivity with brain development. AB - A number of studies have characterized the changes in variability of brain signals with brain maturation from the perspective of considering the human brain as a complex system. Specifically, it has been shown that complexity of brain signals increases in development. On one hand, such an increase in complexity can be attributed to more specialized and differentiated brain regions able to express a higher repertoire of mental microstates. On the other hand, it can be explained by increased integration between widely distributed neuronal populations and establishment of new connections. The goal of this study was to see which of these two mechanisms is dominant, accounting for the previously observed increase in signal complexity. Using information-theoretic tools based on scalp-recorded EEG measurements, we examined the trade-off between local and distributed variability of brain signals in infants and children separated into age groups of 1-2, 2-8, 9-24, and 24-66 months old. We found that developmental changes were characterized by a decrease in the amount of information processed locally, with a peak in alpha frequency range. This effect was accompanied by an increase in the variability of brain signals processed as a distributed network. Complementary analysis of phase locking revealed an age-related pattern of increased synchronization in the lower part of the spectrum, up to the alpha rhythms. At the same time, we observed the desynchronization effects associated with brain development in the higher beta to lower gamma range. PMID- 21525282 TI - State-dependent representation of amplitude-modulated noise stimuli in rat auditory cortex. AB - Cortical responses can vary greatly between repeated presentations of an identical stimulus. Here we report that both trial-to-trial variability and faithfulness of auditory cortical stimulus representations depend critically on brain state. A frozen amplitude-modulated white noise stimulus was repeatedly presented while recording neuronal populations and local field potentials (LFPs) in auditory cortex of urethane-anesthetized rats. An information-theoretic measure was used to predict neuronal spiking activity from either the stimulus envelope or simultaneously recorded LFP. Evoked LFPs and spiking more faithfully followed high-frequency temporal modulations when the cortex was in a desynchronized state. In the synchronized state, neural activity was poorly predictable from the stimulus envelope, but the spiking of individual neurons could still be predicted from the ongoing LFP. Our results suggest that although auditory cortical activity remains coordinated as a population in the synchronized state, the ability of continuous auditory stimuli to control this activity is greatly diminished. PMID- 21525284 TI - Anisotropic distribution of thalamocortical boutons in barrels. AB - A characteristic feature of the somatosensory cortex in rodents is the presence of discrete cellular aggregates in layer 4 (barrels) that process input from the mystacial vibrissae. Just like thalamic cells that relay vibrissal information to the barrels, barrel cells display directional preference to whisker motion. The present study examined whether the projection of single thalamic cells into a barrel is consistent with the existence of an orderly map of direction preference. The direction preference of single thalamic cells was assessed, and axonal projections were visualized after juxtacellular labeling with biotinylated dextran. Results show that the terminal field of individual thalamic neurons in a barrel is markedly anisotropic and that the location of boutons with respect to the somatotopic map is either positively or negatively correlated with the angular tuning of the thalamic neuron. These results indicate that angular tuning is not represented across a systematic map with fixed anteroposterior/mediolateral coordinates in a barrel. The actual significance of the direction-dependent segregation of thalamocortical terminals in barrels may only come to light in the context of active sensing. PMID- 21525283 TI - Protein kinase M maintains long-term sensitization and long-term facilitation in aplysia. AB - How the brain maintains long-term memories is one of the major outstanding questions in modern neuroscience. Evidence from mammalian studies indicates that activity of a protein kinase C (PKC) isoform, protein kinase Mzeta (PKMzeta), plays a critical role in the maintenance of long-term memory. But the range of memories whose persistence depends on PKMzeta, and the mechanisms that underlie the effect of PKMzeta on long-term memory, remain obscure. Recently, a PKM isoform, known as PKM Apl III, was cloned from the nervous system of Aplysia. Here, we tested whether PKM Apl III plays a critical role in long-term memory maintenance in Aplysia. Intrahemocoel injections of the pseudosubstrate inhibitory peptide ZIP (zeta inhibitory peptide) or the PKC inhibitor chelerythrine erased the memory for long-term sensitization (LTS) of the siphon withdrawal reflex (SWR) as late as 7 d after training. In addition, both PKM inhibitors disrupted the maintenance of long-term (>= 24 h) facilitation (LTF) of the sensorimotor synapse, a form of synaptic plasticity previously shown to mediate LTS of the SWR. Together with previous results (Bougie et al., 2009), our results support the idea that long-term memory in Aplysia is maintained via a positive-feedback loop involving PKM Apl III-dependent protein phosphorylation. The present data extend the known role of PKM in memory maintenance to a simple and well studied type of long-term learning. Furthermore, the demonstration that PKM activity underlies the persistence of LTF of the Aplysia sensorimotor synapse, a form of synaptic plasticity amenable to rigorous cellular and molecular analyses, should facilitate efforts to understand how PKM activity maintains memory. PMID- 21525285 TI - Gli3 is required for maintenance and fate specification of cortical progenitors. AB - Gli3, one of three vertebrate Gli transcription factors in Hedgehog (Hh) pathway, is processed into a repressor form (Gli3R) in the absence of Hh signal and acts as the major negative transducer of the pathway. Although the role of Gli3 in embryonic patterning has been extensively studied, its role in cortical neurogenesis, especially in the regulation of neural progenitors in proliferation and cell fate specification, is largely unknown. To bypass the patterning defects caused by loss of Gli3, we conditionally deleted Gli3 after patterning was complete in mouse. Our results from birthdating and in utero electroporation experiments demonstrate that the Gli3, specifically Gli3R, is critical for specifying the fate of cortical neurons that are generated following a stereotypical temporal order. Moreover, Gli3 is required for maintaining the cortical progenitors in active cell cycle, suggesting that cells may acquire differentiated status as they turn off Gli3 expression during neurogenesis. PMID- 21525286 TI - Impaired limbic gamma oscillatory synchrony during anxiety-related behavior in a genetic mouse model of bipolar mania. AB - Alterations in anxiety-related processing are observed across many neuropsychiatric disorders, including bipolar disorder. Though polymorphisms in a number of circadian genes confer risk for this disorder, little is known about how changes in circadian gene function disrupt brain circuits critical for anxiety-related processing. Here we characterize neurophysiological activity simultaneously across five limbic brain areas (nucleus accumbens, amygdala, prelimbic cortex, ventral hippocampus, and ventral tegmental area) as wild-type (WT) mice and mice with a mutation in the circadian gene, CLOCK (Clock-Delta19 mice) perform an elevated zero maze task. In WT mice, basal limbic gamma oscillatory synchrony observed before task performance predicted future anxiety related behaviors. Additionally, dynamic changes in limbic gamma oscillatory synchrony were observed based on the position of WT mice in the zero maze. Clock Delta19 mice, which displayed an increased propensity to enter the open section of the elevated maze, showed profound deficits in these anxiety-related circuit processes. Thus, our findings link the anxiety-related behavioral deficits observed in Clock-Delta19 mice with dysfunctional gamma oscillatory tuning across limbic circuits and suggest that alterations in limbic oscillatory circuit function induced by circadian gene polymorphisms may contribute to the behavioral manifestations seen in bipolar mania. PMID- 21525288 TI - Axon formation in neocortical neurons depends on stage-specific regulation of microtubule stability by the dual leucine zipper kinase-c-Jun N-terminal kinase pathway. AB - Studies using cultured neurons have established the critical role of microtubule regulators in neuronal polarization. The c-Jun N-terminal kinase (JNK) pathway is one of the candidate signaling pathways driving microtubule regulation during neuronal polarization. However, the significance of the JNK pathway in axon formation, a fundamental step in neuronal polarization, in vivo, remains unclear. Here, we provide evidence supporting the notion that the JNK pathway contributes to axon formation, in vivo, by identifying the genetic interactions between mouse JNK1 and dual leucine zipper kinase (DLK). Double mutants exhibited severe defects in axon formation in the cerebral neocortex. Moreover, RNA interference rescue experiments, in vitro, showed that DLK and JNK1 function in a common pathway to support neuronal polarization by promoting short-neurite and axon formation. Defects in axon formation caused by perturbations of the DLK-JNK pathway were significantly improved by Taxol. However, defects in short-neurite formation caused by perturbations of the DLK-JNK pathway were enhanced by Taxol. Together, these in vivo and in vitro observations indicate that the DLK-JNK pathway facilitates axon formation in neocortical neurons via stage-specific regulation of microtubule stability. PMID- 21525287 TI - Development, maturation, and necessity of transcription factors in the mouse suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) of the hypothalamus is the master mammalian circadian clock. The SCN is highly specialized because it is responsible for generating a near 24 h rhythm, integrating external cues, and translating the rhythm throughout the body. Currently, our understanding of the developmental origin and genetic program involved in the proper specification and maturation of the SCN is limited. Herein, we provide a detailed analysis of transcription factor (TF) and developmental-gene expression in the SCN from neurogenesis to adulthood in mice (Mus musculus). TF expression within the postmitotic SCN was not static but rather showed specific temporal and spatial changes during prenatal and postnatal development. In addition, we found both global and regional patterns of TF expression extending into the adult. We found that the SCN is derived from a distinct region of the neuroepithelium expressing a combination of developmental genes: Six3, Six6, Fzd5, and transient Rx, allowing us to pinpoint the origin of this region within the broader developing telencephalon/diencephalon. We tested the necessity of two TFs in SCN development, RORalpha and Six3, which were expressed during SCN development, persisted into adulthood, and showed diurnal rhythmicity. Loss of RORalpha function had no effect on SCN peptide expression or localization. In marked contrast, the conditional deletion of Six3 from early neural progenitors completely eliminated the formation of the SCN. Our results provide the first description of the involvement of TFs in the specification and maturation of a neural population necessary for circadian behavior. PMID- 21525289 TI - The lipid sulfatide is a novel myelin-associated inhibitor of CNS axon outgrowth. AB - CNS myelin is strongly inhibitory to growing axons and is thought to be a major contributor to CNS axon regenerative failure. Although a number of proteins present in myelin, including Nogo, MAG, and oligodendrocyte-myelin glycoprotein (OMgp), have been identified as myelin-associated inhibitors, studies of mice lacking these genes suggest that additional inhibitors present in CNS myelin remain to be identified. Here we have investigated the hypothesis that myelin lipids contribute to CNS regenerative failure. We identified sulfatide, a major constituent of CNS myelin, as a novel myelin-associated inhibitor of neurite outgrowth. Sulfatide, but not galactocerebroside or ceramide, strongly inhibited the neurite outgrowth of retinal ganglion cells (RGCs) when used as a purified lipid substrate. The mechanism involved in sulfatide-mediated inhibition may share features with other known inhibitors, because the Rho inhibitor C3 transferase lessened these effects. Myelin in which sulfatide was lacking or blocked using specific antibodies was significantly less inhibitory to RGC neurite outgrowth in vitro than was wild-type myelin, indicating that sulfatide is a major component of the inhibitory activity of CNS myelin. Mice unable to make sulfatide did not regenerate RGC axons more robustly after optic nerve crush than wild-type littermates under normal conditions but did exhibit a small but significant enhancement in the extent of zymosan-induced regeneration. These results demonstrate that specific lipids can powerfully inhibit axon growth, identify sulfatide as a novel myelin-associated axon growth inhibitor, and provide evidence that sulfatide inhibition contributes to axon regenerative failure in vivo. PMID- 21525290 TI - The canonical nuclear factor-kappaB pathway regulates cell survival in a developmental model of spinal cord motoneurons. AB - In vivo and in vitro motoneuron survival depends on the support of neurotrophic factors. These factors activate signaling pathways related to cell survival or inactivate proteins involved in neuronal death. In the present work, we analyzed the involvement of the nuclear factor-kappaB (NF-kappaB) pathway in mediating mouse spinal cord motoneuron survival promoted by neurotrophic factors. This pathway comprises ubiquitously expressed transcription factors that could be activated by two different routes: the canonical pathway, associated with IKKalpha/IKKbeta kinase phosphorylation and nuclear translocation RelA (p65)/p50 transcription factors; and the noncanonical pathway, related to IKKalpha kinase homodimer phosphorylation and RelB/p52 transcription factor activation. In our system, we show that neurotrophic factors treatment induced IKKalpha and IKKbeta phosphorylation and RelA nuclear translocation, suggesting NF-kappaB pathway activation. Protein levels of different members of the canonical or noncanonical pathways were reduced in a primary culture of isolated embryonic motoneurons using an interference RNA approach. Even in the presence of neurotrophic factors, selective reduction of IKKalpha, IKKbeta, or RelA proteins induced cell death. In contrast, RelB protein reduction did not have a negative effect on motoneuron survival. Together these results demonstrated that the canonical NF-kappaB pathway mediates motoneuron survival induced by neurotrophic factors, and the noncanonical pathway is not related to this survival effect. Canonical NF-kappaB blockade induced an increase of Bim protein level and apoptotic cell death. Bcl x(L) overexpression or Bax reduction counteracted this apoptotic effect. Finally, RelA knockdown causes changes of CREB and Smn protein levels. PMID- 21525291 TI - Chromatic bipolar cell pathways in the mouse retina. AB - Like most mammals, mice feature dichromatic color vision based on short (S) and middle (M) wavelength-sensitive cone types. It is thought that mammals share a retinal circuit that in dichromats compares S- and M-cone output to generate blue/green opponent signals, with bipolar cells (BCs) providing separate chromatic channels. Although S-cone-selective ON-BCs (type 9 in mouse) have been anatomically identified, little is known about their counterparts, the M-cone selective OFF-BCs. Here, we characterized cone connectivity and light responses of selected mouse BC types using immunohistochemistry and electrophysiology. Our anatomical data indicate that four (types 2, 3a/b, and 4) of the five mouse OFF BCs indiscriminately contact both cone types, whereas type 1 BCs avoid S-cones. Light responses showed that the chromatic tuning of the BCs strongly depended on their position along the dorsoventral axis because of the coexpression gradient of M- and S-opsin found in mice. In dorsal retina, where coexpression is low, most type 2 cells were green biased, with a fraction of cells (~ 14%) displaying strongly blue-biased responses, likely reflecting S-cone input. Type 1 cells were also green biased but did not comprise blue-biased "outliers," consistent with type 1 BCs avoiding S-cones. We therefore suggest that type 1 represents the green OFF pathway in mouse. In addition, we confirmed that type 9 BCs display blue-ON responses. In ventral retina, all BC types studied here displayed similar blue-biased responses, suggesting that color vision is hampered in ventral retina. In conclusion, our data support an antagonistically organized blue/green circuit as the common basis for mammalian dichromatic color vision. PMID- 21525293 TI - Distinct visual pathways mediate Drosophila larval light avoidance and circadian clock entrainment. AB - Visual organs perceive environmental stimuli required for rapid initiation of behaviors and can also entrain the circadian clock. The larval eye of Drosophila is capable of both functions. Each eye contains only 12 photoreceptors (PRs), which can be subdivided into two subtypes. Four PRs express blue-sensitive rhodopsin5 (rh5) and eight express green-sensitive rhodopsin6 (rh6). We found that either PR-subtype is sufficient to entrain the molecular clock by light, while only the Rh5-PR subtype is essential for light avoidance. Acetylcholine released from PRs confers both functions. Both subtypes of larval PRs innervate the main circadian pacemaker neurons of the larva, the neuropeptide PDF (pigment dispersing factor)-expressing lateral neurons (LNs), providing sensory input to control circadian rhythms. However, we show that PDF-expressing LNs are dispensable for light avoidance, and a distinct set of three clock neurons is required. Thus we have identified distinct sensory and central circuitry regulating light avoidance behavior and clock entrainment. Our findings provide insights into the coding of sensory information for distinct behavioral functions and the underlying molecular and neuronal circuitry. PMID- 21525292 TI - Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. AB - Orexin-A and orexin-B are hypothalamic neuropeptides that play critical roles in the maintenance of wakefulness. Intracerebroventricular (ICV) administration of orexin-A has been shown to promote wakefulness and suppress both rapid eye movement (REM) sleep and non-REM (NREM) sleep through the orexin receptor-1 (OX(1)R) and orexin receptor-2 (OX(2)R). Here, we elucidated the differential roles of orexin receptors in the regulation of sleep and wakefulness by comparing the effects of ICV orexin-A administration in wild-type, OX(1)R(-/-), and OX(2)R( /-) mice. The effects of orexin-A on wakefulness and NREM sleep were significantly attenuated in both knock-out mice as compared with wild-type mice, with substantially larger attenuation in OX(2)R(-/-) mice than in OX(1)R(-/-) mice. These results suggest that although the OX(2)R-mediated pathway has a pivotal role in the promotion of wakefulness, OX(1)R also plays additional roles in promoting arousal. In contrast, suppression of REM sleep by orexin-A administration was slightly and similarly attenuated in both OX(1)R(-/-) and OX(2)R(-/-) mice, suggesting a comparable contribution of the two receptors to REM sleep suppression. Histological studies demonstrated differential distributions of each receptor subtype in distinct neuronal populations with specific neurotransmitter identities in brainstem cholinergic/monoaminergic neurons. In the laterodorsal tegmental and pedunculopontine tegmental nuclei especially, cholinergic neurons exclusively expressed OX(1)R mRNA, but OX(2)R mRNA was expressed mainly in GABAergic putative interneurons. Thus, each orexin receptor subtype plays differential roles in gating NREM and REM sleep through distinct neuronal pathways. PMID- 21525294 TI - An equivalent noise investigation of saccadic suppression. AB - Visual stimuli presented just before or during an eye movement are more difficult to detect than those same visual stimuli presented during fixation. This laboratory phenomenon--behavioral saccadic suppression--is thought to underlie the everyday experience of not perceiving the motion created by our own eye movements-saccadic omission. At the neural level, many cortical and subcortical areas respond differently to perisaccadic visual stimuli than to stimuli presented during fixation. Those neural response changes, however, are complex and the link to the behavioral phenomena of reduced detectability remains tentative. We used a well established model of human visual detection performance to provide a quantitative description of behavioral saccadic suppression and thereby allow a more focused search for its neural mechanisms. We used an equivalent noise method to distinguish between three mechanisms that could underlie saccadic suppression. The first hypothesized mechanism reduces the gain of the visual system, the second increases internal noise levels in a stimulus dependent manner, and the third increases stimulus uncertainty. All three mechanisms predict that perisaccadic stimuli should be more difficult to detect, but each mechanism predicts a unique pattern of detectability as a function of the amount of external noise. Our experimental finding was that saccades increased detection thresholds at low external noise, but had little influence on thresholds at high levels of external noise. A formal analysis of these data in the equivalent noise analysis framework showed that the most parsimonious mechanism underlying saccadic suppression is a stimulus-independent reduction in response gain. PMID- 21525296 TI - Reduction of an afterhyperpolarization current increases excitability in striatal cholinergic interneurons in rat parkinsonism. AB - Striatal cholinergic interneurons show tonic spiking activity in the intact and sliced brain, which stems from intrinsic mechanisms. Because of it, they are also known as "tonically active neurons" (TANs). Another hallmark of TAN electrophysiology is a pause response to appetitive and aversive events and to environmental cues that have predicted these events during learning. Notably, the pause response is lost after the degeneration of dopaminergic neurons in animal models of Parkinson's disease. Moreover, Parkinson's disease patients are in a hypercholinergic state and find some clinical benefit in anticholinergic drugs. Current theories propose that excitatory thalamic inputs conveying information about salient sensory stimuli trigger an intrinsic hyperpolarizing response in the striatal cholinergic interneurons. Moreover, it has been postulated that the loss of the pause response in Parkinson's disease is related to a diminution of I(sAHP), a slow outward current that mediates an afterhyperpolarization following a train of action potentials. Here we report that I(sAHP) induces a marked spike frequency adaptation in adult rat striatal cholinergic interneurons, inducing an abrupt end of firing during sustained excitation. Chronic loss of dopaminergic neurons markedly reduces I(sAHP) and spike-frequency adaptation in cholinergic interneurons, allowing them to fire continuously and at higher rates during sustained excitation. These findings provide a plausible explanation for the hypercholinergic state in Parkinson's disease. Moreover, a reduction of I(sAHP) may alter synchronization of cholinergic interneurons with afferent inputs, thus contributing to the loss of the pause response in Parkinson's disease. PMID- 21525295 TI - Gap junctions between interneurons are required for normal spatial coding in the hippocampus and short-term spatial memory. AB - Gap junctions containing connexin 36 electrically couple interneurons in many brain regions and synchronize their activity. We used connexin-36 knock-out mice (Cx36(-/-)) to study the importance of electrical coupling between interneurons for spatial coding in the hippocampus and for different forms of hippocampus dependent spatial memory. Recordings in behaving mice revealed that the spatial selectivity of hippocampal pyramidal neurons was reduced and less stable in Cx36( /-) mice. Altered network activity was reflected in slower theta oscillations in the mutants. Temporal coding, assessed by determining the presence and characteristics of theta phase precession, had different dynamics in Cx36(-/-) mice compared with controls. At the behavioral level, Cx36(-/-) mice displayed impaired short-term spatial memory but normal spatial reference memory. These results highlight the functional role of electrically coupled interneurons for spatial coding and cognition. Moreover, they suggest that the precise spatial selectivity of place cells is not essential for normal performance on spatial tasks assessing associative long-term memory. PMID- 21525297 TI - Protein kinase C-mediated phosphorylation of a single serine residue on the rat glial glutamine transporter SN1 governs its membrane trafficking. AB - Molecular mechanisms involved in the replenishment of the fast neurotransmitters glutamate and GABA are poorly understood. Glutamine sustains their generation. However, glutamine formation from the recycled transmitters is confined to glial processes and requires facilitators for its translocation across the glial and neuronal membranes. Indeed, glial processes are enriched with the system N transporter SN1 (Slc38a3), which, by bidirectional transport, maintains steady extracellular glutamine levels and thereby furnishes neurons with the primary precursor for fast neurotransmitters. We now demonstrate that SN1 is phosphorylated by protein kinase Calpha (PKCalpha) and PKCgamma. Electrophysiological characterization shows that phosphorylation reduces V(max) dramatically, whereas no significant effects are seen on the K(m). Phosphorylation occurs specifically at a single serine residue (S52) in the N terminal rat (Rattus norvegicus) SN1 and results in sequestration of the protein into intracellular reservoirs. Prolonged activation of PKC results in partial degradation of SN1. These results provide the first demonstration of phosphorylation of SN1 and regulation of its activity at the plasma membrane. Interestingly, membrane trafficking of SN1 resembles that of the glutamate transporter GLT and the glutamate-aspartate transporter GLAST: it involves the same PKC isoforms and occurs in the same glial processes. This suggests that the glutamate/GABA-glutamine cycle may be modified at two key points by similar signaling events and unmasks a prominent role for PKC-dependent phosphorylation. Our data suggest that extracellular glutamine levels may be fine-tuned by dynamic regulation of glial SN1 activity, which may impact on transmitter generation, contribute to defining quantal size, and have profound effects on synaptic plasticity. PMID- 21525298 TI - beta3GnT2 maintains adenylyl cyclase-3 signaling and axon guidance molecule expression in the olfactory epithelium. AB - In the olfactory epithelium (OE), odorant receptor stimulation generates cAMP signals that function in both odor detection and the regulation of axon guidance molecule expression. The enzyme that synthesizes cAMP, adenylyl cyclase 3 (AC3), is coexpressed in olfactory sensory neurons (OSNs) with poly-N-acetyllactosamine (PLN) oligosaccharides determined by the glycosyltransferase beta3GnT2. The loss of either enzyme results in similar defects in olfactory bulb (OB) innervation and OSN survival, suggesting that glycosylation may be important for AC3 function. We show here that AC3 is extensively modified with N-linked PLN, which is essential for AC3 activity and localization. On Western blots, AC3 from the wild-type OE migrates diffusely as a heavily glycosylated 200 kDa band that interacts with the PLN-binding lectin LEA. AC3 from the beta3GnT2(-/-) OE loses these PLN modifications, migrating instead as a 140 kDa glycoprotein. Furthermore, basal and forskolin-stimulated cAMP production is reduced 80-90% in the beta3GnT2(-/-) OE. Although AC3 traffics normally to null OSN cilia, it is absent from axon projections that aberrantly target the OB. The cAMP-dependent guidance receptor neuropilin-1 is also lost from beta3GnT2(-/-) OSNs and axons, while semaphorin-3A ligand expression is upregulated. In addition, kirrel2, a mosaically expressed adhesion molecule that functions in axon sorting, is absent from beta3GnT2(-/-) OB projections. These results demonstrate that PLN glycans are essential in OSNs for proper AC3 localization and function. We propose that the loss of cAMP-dependent guidance cues is also a critical factor in the severe axon guidance defects observed in beta3GnT2(-/-) mice. PMID- 21525299 TI - The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. AB - Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP 1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APP(swe)/PS1(DeltaE9) (APP/PS1). Liraglutide was shown to cross the blood brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall beta-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40-50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP 1 analogs represent a novel treatment strategy for Alzheimer's disease. PMID- 21525300 TI - How soft is that pillow? The perceptual localization of the hand and the haptic assessment of contact rigidity. AB - A new haptic illusion is described, in which the location of the mobile object affects the perception of its rigidity. There is theoretical and experimental support for the notion that limb position sense results from the brain combining ongoing sensory information with expectations arising from prior experience. How does this probabilistic state information affect one's tactile perception of the environment mechanics? In a simple estimation process, human subjects were asked to report the relative rigidity of two simulated virtual objects. One of the objects remained fixed in space and had various coefficients of stiffness. The other virtual object had constant stiffness but moved with respect to the subjects. Earlier work suggested that the perception of an object's rigidity is consistent with a process of regression between the contact force and the perceived amount of penetration inside the object's boundary. The amount of penetration perceived by the subject was affected by varying the position of the object. This, in turn, had a predictable effect on the perceived rigidity of the contact. Subjects' reports on the relative rigidity of the object are best accounted for by a probabilistic model in which the perceived boundary of the object is estimated based on its current location and on past observations. Therefore, the perception of contact rigidity is accounted for by a stochastic process of state estimation underlying proprioceptive localization of the hand. PMID- 21525302 TI - Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity. AB - GH insensitivity (GHI) presents in childhood as growth failure and in its severe form is associated with dysmorphic and metabolic abnormalities. GHI may be caused by genetic defects in the GH-IGF-I axis or by acquired states such as chronic illness. This article discusses the former category. The field of GHI due to mutations affecting GH action has evolved considerably since the original description of the extreme phenotype related to homozygous GH receptor (GHR) mutations over 40 yr ago. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The role and mechanisms of the GH-IGF-I axis in normal human growth is discussed, followed by descriptions of mutations in GHR, STAT5B, PTPN11, IGF1, IGFALS, IGF1R, and GH1 defects causing bioinactive GH or anti-GH antibodies. These defects are associated with a range of genetic, clinical, and hormonal characteristics. Genetic abnormalities causing growth failure that is less severe than the extreme phenotype are emphasized, together with an analysis of height and serum IGF-I across the spectrum of different types of GHR defects. An overall view of genotype and phenotype relationships is presented, together with an updated approach to the assessment of the patient with GHI, focusing on investigation of the GH-IGF-I axis and relevant molecular studies contributing to this diagnosis. PMID- 21525301 TI - Dopamine transport by the serotonin transporter: a mechanistically distinct mode of substrate translocation. AB - The serotonin transporter (SERT) is the principal mechanism for terminating serotonin (5-HT) signals in the nervous system and is a site of action for a variety of psychoactive drugs including antidepressants, amphetamines, and cocaine. Here we show that human SERTs (hSERTs) and rat SERTs are capable of robust dopamine (DA) uptake through a process that differs mechanistically from 5 HT transport in several unanticipated ways. DA transport by hSERT has a higher maximum velocity than 5-HT transport, requires significantly higher Na(+) and Cl( ) concentrations to sustain transport, is inhibited noncompetitively by 5-HT, and is more sensitive to SERT inhibitors, including selective serotonin reuptake inhibitors. We use a thiol-reactive methane thiosulfonate (MTS) reagent to modify a conformationally sensitive cysteine residue to demonstrate that hSERT spends more time in an outward facing conformation when transporting DA than when transporting 5-HT. Cotransfection of an inactive or an MTS-sensitive SERT with wild-type SERT subunits reveals an absence of cooperative interactions between subunits during DA but not 5-HT transport. To establish the physiological relevance of this mechanism for DA clearance, we show using in vivo high-speed chronoamperometry that SERT has the capacity to clear extracellularly applied DA in the hippocampal CA3 region of anesthetized rats. Together, these observations suggest the possibility that SERT serves as a DA transporter in vivo and highlight the idea that there can be distinct modes of transport of alternative physiological substrates by SERT. PMID- 21525303 TI - Impact of weight on immune cell counts among HIV-infected persons. AB - Prior studies have shown that weight may impact immune cell counts. However, few data exist about the relationship of weight and immune cell counts among HIV infected patients. We examined documented HIV seroconverters (mean window, 15.7 months) in a prospective U.S. Military HIV Natural History Study (1 January 1986 to 20 January 2010). We estimated the association of the time-updated body mass index (BMI) category with changes in immune cell counts from HIV diagnosis across time (mean follow-up of 5.1 years) using multiply adjusted longitudinal linear mixed-effects models. Of 1,097 HIV seroconverters, 448 (41%) were overweight and 93 (8%) were obese at HIV diagnosis. Immune cell counts at HIV diagnosis did not significantly differ by BMI category. In the longitudinal models for those diagnosed before the advent of the highly active antiretroviral therapy (HAART) era, mean postdiagnosis decreases in the white cell count, total lymphocyte count, CD4 count, CD4 percentage, and CD4/CD8 ratio were less as the BMI category increased (all with P values of <0.05). Among HIV seroconverters diagnosed in the HAART era, obese compared to normal-weight patients had significantly smaller increases in CD4 counts, CD4 percentages, and the CD4/CD8 ratio (all with P values of <0.05). Similar findings were also noted among underweight versus normal-weight patients. In conclusion, although BMI was not associated with immune cell levels at the time of HIV diagnosis, weight appears to affect immune cells counts over the course of infection. In the HAART era, being either underweight or obese was associated with smaller increases in several important immune cell levels, including the CD4/CD8 ratio. PMID- 21525304 TI - Disulfide-mediated oligomer formation in Borrelia burgdorferi outer surface protein C, a critical virulence factor and potential Lyme disease vaccine candidate. AB - Borrelia burgdorferi OspC is an outer membrane lipoprotein required for the establishment of infection in mammals. Due to its universal distribution among B. burgdorferi sensu lato strains and high antigenicity, it is being explored for the development of a next-generation Lyme disease vaccine. An understanding of the surface presentation of OspC will facilitate efforts to maximize its potential as a vaccine candidate. OspC forms homodimers at the cell surface, and it has been hypothesized that it may also form oligomeric arrays. Here, we employ site-directed mutagenesis to test the hypothesis that interdimeric disulfide bonds at cysteine 130 (C130) mediate oligomerization. B. burgdorferi B31 ospC was replaced with a C130A substitution mutant to yield strain B31::ospC(C130A). Recombinant protein was also generated. Disulfide-bond-dependent oligomer formation was demonstrated and determined to be dependent on C130. Oligomerization was not required for in vivo function, as B31::ospC(C130A) retained infectivity and disseminated normally. The total IgG response and the induced isotype pattern were similar between mice infected with untransformed B31 and those infected with the B31::ospC(C130A) strain. These data indicate that the immune response to OspC is not significantly altered by formation of OspC oligomers, a finding that has significant implications in Lyme disease vaccine design. PMID- 21525305 TI - Comparison of two generations of the Panbio dengue NS1 capture enzyme-linked immunosorbent assay. AB - We compared two generations of Panbio (Brisbane, Australia) commercial kits for NS1 antigen capture for early diagnosis of dengue: the first-generation pan-E Dengue Early ELISA and the second-generation Dengue Early ELISA. The test improvement resulted in a highly sensitive and specific test suitable for use as a first-line test in the field. PMID- 21525307 TI - When is weight critical? PMID- 21525308 TI - Growth and the regulation of myotomal muscle mass in teleost fish. AB - Teleost muscle first arises in early embryonic life and its development is driven by molecules present in the egg yolk and modulated by environmental stimuli including temperature and oxygen. Several populations of myogenic precursor cells reside in the embryonic somite and external cell layer and contribute to muscle fibres in embryo, larval, juvenile and adult stages. Many signalling proteins and transcription factors essential for these events are known. In all cases, myogenesis involves myoblast proliferation, migration, fusion and terminal differentiation. Maturation of the embryonic muscle is associated with motor innervation and the development of a scaffold of connective tissue and complex myotomal architecture needed to generate swimming behaviour. Adult muscle is a heterogeneous tissue composed of several cell types that interact to affect growth patterns. The development of capillary and lymphatic circulations and extramuscular organs--notably the gastrointestinal, endocrine, neuroendocrine and immune systems--serves to increase information exchange between tissues and with the external environment, adding to the complexity of growth regulation. Teleosts often exhibit an indeterminate growth pattern, with body size and muscle mass increasing until mortality or senescence occurs. The dramatic increase in myotomal muscle mass between embryo and adult requires the continuous production of muscle fibres until 40-50% of the maximum body length is reached. Sarcomeric proteins can be mobilised as a source of amino acids for energy metabolism by other tissues and for gonad generation, requiring the dynamic regulation of muscle mass throughout the life cycle. The metabolic and contractile phenotypes of muscle fibres also show significant plasticity with respect to environmental conditions, migration and spawning. Many genes regulating muscle growth are found as multiple copies as a result of paralogue retention following whole-genome duplication events in teleost lineages. The extent to which indeterminate growth, ectothermy and paralogue preservation have resulted in modifications of the genetic pathways regulating muscle growth in teleosts compared to mammals largely remains unknown. This review describes the use of compensatory growth models, transgenesis and tissue culture to explore the mechanisms of muscle growth in teleosts and provides some perspectives on future research directions. PMID- 21525309 TI - Odometry and insect navigation. AB - Animals have needed to find their way about almost since a free-living life style evolved. Particularly, if an animal has a home--shelter or nesting site--true navigation becomes necessary to shuttle between this home and areas of other activities, such as feeding. As old as navigation is in the animal kingdom, as diverse are its mechanisms and implementations, depending on an organism's ecology and its endowment with sensors and actuators. The use of landmarks for piloting or the use of trail pheromones for route following have been examined in great detail and in a variety of animal species. The same is true for senses of direction--the compasses for navigation--and the construction of vectors for navigation from compass and distance cues. The measurement of distance itself- odometry--has received much less attention. The present review addresses some recent progress in the understanding of odometers in invertebrates, after outlining general principles of navigation to put odometry in its proper context. Finally, a number of refinements that increase navigation accuracy and safety are addressed. PMID- 21525310 TI - Bottles as models: predicting the effects of varying swimming speed and morphology on size selectivity and filtering efficiency in fishes. AB - We created physical models based on the morphology of ram suspension-feeding fishes to better understand the roles morphology and swimming speed play in particle retention, size selectivity and filtration efficiency during feeding events. We varied the buccal length, flow speed and architecture of the gills slits, including the number, size, orientation and pore size/permeability, in our models. Models were placed in a recirculating flow tank with slightly negatively buoyant plankton-like particles (~20-2000 MUm) collected at the simulated esophagus and gill rakers to locate the highest density of particle accumulation. Particles were captured through sieve filtration, direct interception and inertial impaction. Changing the number of gill slits resulted in a change in the filtration mechanism of particles from a bimodal filter, with very small (<= 50 MUm) and very large (>1000 MUm) particles collected, to a filter that captured medium-sized particles (101-1000 MUm). The number of particles collected on the gill rakers increased with flow speed and skewed the size distribution towards smaller particles (51-500 MUm). Small pore sizes (105 and 200 MUm mesh size) had the highest filtration efficiencies, presumably because sieve filtration played a significant role. We used our model to make predictions about the filtering capacity and efficiency of neonatal whale sharks. These results suggest that the filtration mechanics of suspension feeding are closely linked to an animal's swimming speed and the structural design of the buccal cavity and gill slits. PMID- 21525311 TI - Ontogenetic changes in jaw-muscle architecture facilitate durophagy in the turtle Sternotherus minor. AB - Differential scaling of musculoskeletal traits leads to differences in performance across ontogeny and ultimately determines patterns of resource use during development. Because musculoskeletal growth of the feeding system facilitates high bite-force generation necessary to overcome the physical constraints of consuming more durable prey, durophagous taxa are well suited for investigations of the scaling relationships between musculoskeletal growth, bite force generation and dietary ontogeny. To elucidate which biomechanical factors are responsible for allometric changes in bite force and durophagy, we developed and experimentally tested a static model of bite-force generation throughout development in the durophagous turtle Sternotherus minor. Moreover, we quantified the fracture properties of snails found in the diet to evaluate the relationship between bite force and the forces required to process durable prey. We found that (1) the static bite-force model accurately predicts the ontogenetic scaling of bite forces, (2) bite-force positive allometry is accomplished by augmenting muscle size and muscle pennation, and (3) the rupture forces of snails found in the diet show a similar scaling pattern to bite force across ontogeny. These results indicate the importance of muscle pennation for generating high bite forces while maintaining muscle size and provide empirical evidence that the allometric patterns of musculoskeletal growth in S. minor are strongly linked to the structural properties of their primary prey. PMID- 21525312 TI - Repeatability of standard metabolic rate, active metabolic rate and aerobic scope in young brown trout during a period of moderate food availability. AB - Standard metabolic rate (SMR) and active metabolic rate (AMR) are two fundamental physiological parameters providing the floor and ceiling in aerobic energy metabolism. The total amount of energy available within these two parameters confines constitutes the absolute aerobic scope (AAS). Previous studies on fish have found SMR to closely correlate with dominance and position in the social hierarchy, and to be highly repeatable over time when fish were provided an ad libitum diet. In this study we tested the temporal repeatability of individual SMR, AMR and AAS, as well as repeatability of body mass, in young brown trout (Salmo trutta L.) fed a moderately restricted diet (0.5-0.7% fish mass day-1). Metabolism was estimated from measurements of oxygen consumption rate (M(.)(O2)) and repeatability was evaluated four times across a 15-week period. Individual body mass was highly repeatable across the entire 15 week experimental period whereas residual body-mass-corrected SMR, AMR and AAS showed a gradual loss of repeatability over time. Individual residual SMR, AMR and AAS were significantly repeatable in the short term (5 weeks), gradually declined across the medium term (10 weeks) and completely disappeared in the long term (15 weeks). We suggest that this gradual decline in repeatability was due to the slightly restricted feeding regime. This is discussed in the context of phenotypic plasticity, natural selection and ecology. PMID- 21525313 TI - Activity of the claw retractor muscle in stick insects in wall and ceiling situations. AB - The activity of the middle part of the claw retractor muscle was examined in two species of stick insects (Carausius morosus and Cuniculina impigra). We performed electromyographic recordings while the animals were standing on a smooth or a rough surface of a platform in horizontal, vertical or inverted positions, as well as during rotations of the platform. We recorded tonic and phasic motor units. The tonic units were active all the time without significant differences in spike frequency, regardless of the position of the animals (although there was a tendency for higher discharge frequencies to occur during platform rotations). The phasic units were active almost exclusively during platform movement. In contrast to the tonic units, we detected significant differences in the activities of the phasic units; namely, higher spike frequencies during rotations compared with the stationary phases, especially for rotations into 'more awkward' positions. A comparison of the two species revealed no difference in muscle activity, despite differences in the animals' tarsal attachment structures. The same was true when comparing the muscle activity of the two species on both the smooth and the rough surfaces. PMID- 21525314 TI - How muscles define maximum running performance in lizards: an analysis using swing- and stance-phase muscles. AB - Maximum locomotor performance is crucial for capturing prey, escaping predators and many other behaviors. However, we know little about what defines maximum performance in vertebrates. Muscles drive the movement of the limbs during locomotion, and thus likely play a major role in defining locomotor capacity. For lizards, the iliofibularis, a swing-phase muscle, is often linked to ecology and/or performance. However, stance-phase muscles likely limit performance given that they propel the animal. Using a small semi-arboreal lizard (Sceloporus woodi), we compared how swing- and stance-phase muscles relate to maximum running speed and acceleration. We employed both a level and vertical trackway to elicit ecologically relevant locomotor performance. Six individuals were filmed at 250 frames s-1 in lateral view. Following performance trials, upper and lower hindlimbs were sectioned and assessed using histochemistry. Fast glycolytic, fast oxidative and slow oxidative fibers were detected and counted in the gastrocnemius (GA; stance phase) and iliofibularis (IF; swing phase) muscles. In addition, the mean fiber diameter for each fiber type in each muscle was determined, as was the fiber cross-sectional area. We found that properties of the GA, but not the IF, were positively correlated with performance. Interestingly, certain attributes of the GA were correlated with maximum vertical locomotion whereas others were correlated with maximum level locomotion. We conclude that stance phase, not swing phase, limits maximum performance in this species of lizard. In addition, we highlight the need to include properties of stance-phase muscles and a spectrum of ecologically relevant behaviors when attempting to correlate locomotor physiology with ecology and/or performance. PMID- 21525315 TI - The contractile sponge epithelium sensu lato--body contraction of the demosponge Tethya wilhelma is mediated by the pinacoderm. AB - Sponges constitute one of the two metazoan phyla that are able to contract their bodies despite a complete lack of muscle cells. Two competing hypotheses on the mechanisms behind this have been postulated to date: (1) mesohyl-mediated contraction originating from fusiform smooth muscle-like actinocytes ('myocytes') and (2) epidermal contraction originating in pinacocytes. No direct support exists for either hypothesis. The question of agonist-antagonist interaction in sponge contraction seems to have been completely neglected so far. In the present study we addressed this by studying sponge contraction kinetics. We also tested both hypotheses by carrying out volumetric studies of 3D synchrotron radiation based x-ray microtomography data obtained from contracted and expanded specimens of Tethya wilhelma. Our results support the pinacoderm contraction hypothesis. Should mesohyl contraction be present, it is likely to be part of the antagonist system. We conclude that epithelial contraction plays a major role in sponges. Contractile epithelia sensu lato may be regarded as part of the ground pattern of the Metazoa. PMID- 21525317 TI - Social interactions influence dopamine and octopamine homeostasis in the brain of the ant Formica japonica. AB - In ants, including Formica japonica, trophallaxis and grooming are typical social behaviors shared among nestmates. After depriving ants of either food or nestmates and then providing them with either food or nestmates, a behavioral change in type and frequency of social interactions was observed. We hypothesized that starvation and isolation affected levels of brain biogenic amines including dopamine (DA) and octopamine (OA) - neuromediators modifying various insect behaviors - and tested the relationship between brain biogenic amines and social behaviors of stressed ants. Ants starved for 7 days contained lower brain DA levels and they did not perform trophallaxis toward nestmates. Feeding starved ants sucrose solution re-established trophallaxis but not brain DA levels. The performance of trophallaxis induced recovery of brain DA content to the level of untreated ants. Ants that were isolated for 2 days displayed markedly increased OA levels, which following nestmate interactions, returned to levels similar to those of control (non-isolated) ants and ants isolated for 1 h. We conclude that: (1) starvation reduced brain DA level but had no significant effect on brain OA (trophallaxis recovered the brain DA levels), and (2) isolation increased brain OA level but had no effect on brain DA (trophallaxis and grooming events recovered the brain OA levels). We suggest that social interactions with nestmates influenced brain biogenic amine homeostasis in stressed F. japonica. PMID- 21525316 TI - Cross-linking by protein oxidation in the rapidly setting gel-based glues of slugs. AB - The terrestrial slug Arion subfuscus secretes a glue that is a dilute gel with remarkable adhesive and cohesive strength. The function of this glue depends on metals, raising the possibility that metal-catalyzed oxidation plays a role. The extent and time course of protein oxidation was measured by immunoblotting to detect the resulting carbonyl groups. Several proteins, particularly one with a relative molecular mass (M(r)) of 165 x 103, were heavily oxidized. Of the proteins known to distinguish the glue from non-adhesive mucus, only specific size variants were oxidized. The oxidation appears to occur within the first few seconds of secretion. Although carbonyls were detected by 2,4 dinitrophenylhydrazine (DNPH) in denatured proteins, they were not easily detected in the native state. The presence of reversible cross-links derived from carbonyls was tested for by treatment with sodium borohydride, which would reduce uncross-linked carbonyls to alcohols, but stabilize imine bonds formed by carbonyls and thus lead to less soluble complexes. Consistent with imine bond formation, sodium borohydride led to a 20-35% decrease in the amount of soluble protein with a M(r) of 40-165 (x 103) without changing the carbonyl content per protein. In contrast, the nucleophile hydroxylamine, which would competitively disrupt imine bonds, increased protein solubility in the glue. Finally, the primary amine groups on a protein with a M(r) of 15 x 103 were not accessible to acid anhydrides. The results suggest that cross-links between aldehydes and primary amines contribute to the cohesive strength of the glue. PMID- 21525318 TI - Effects of oxygen availability on maximum aerobic performance in Mus musculus selected for basal metabolic rate or aerobic capacity. AB - Maximum aerobic metabolism cannot increase indefinitely in response to demands for ATP production and, therefore, must be constrained by one (or many) of the steps of the oxygen transport and utilization pathways. To elucidate those constraints we compared peak metabolic rate elicited by running (V(.)(O2,run)) in hypoxia (14% O2), normoxia (21% O2) and hyperoxia (30% O2) of laboratory mice divergently selected for low and high basal metabolic rate (L-BMR and H-BMR, respectively), mice selected for maximum metabolic rate elicited by swimming (V(.)(O2,swim)) and mice from unselected lines. In all line types (V(.)(O2,run)) was lowest in hypoxia, intermediate in normoxia and highest in hyperoxia, which suggests a 'central' limitation of oxygen uptake or delivery instead of a limit set by cellular oxidative capacity. However, the existence of a common central limitation is not in agreement with our earlier studies showing that selection on high V(.)(O2,swim) (in contrast to selection on high BMR) resulted in considerably higher oxygen consumption during cold exposure in a He-O2 atmosphere than V(.)(O2,run). Likewise, between-line-type differences in heart mass and blood parameters are inconsistent with the notion of central limitation. Although responses of V(.)(O2,run) to hypoxia were similar across different selection regimens, the selection lines showed contrasting responses under hyperoxic conditions. V(.)(O2,run) in the H-BMR line type was highest, suggesting that selection on high BMR led to increased cellular oxidative capacity. Overall, between-line-type differences in the effect of the oxygen partial pressure on V(.)(O2,run) and in the components of O2 flux pathways are incompatible with the notion of symmorphosis. Our results suggest that constraints on V(.)(O2,max) are context dependent and determined by interactions between the central and peripheral organs and tissues involved in O2 delivery. PMID- 21525319 TI - Chronic social stress impairs thermal tolerance in the rainbow trout (Oncorhynchus mykiss). AB - When faced with limited resources, juvenile salmonid fish form dominance hierarchies that result in social stress for socially subordinate individuals. Social stress, in turn, can have consequences for the ability of the fish to respond to additional stressors such as pathogens or exposure to pollutants. In the present study, the possibility that social stress affects the ability of rainbow trout (Oncorhynchus mykiss) to tolerate acute increases in water temperature was investigated. To this end, we first evaluated physiological and cellular stress responses following a 1 h heat shock in juvenile fish in dominance hierarchies. We measured stress hormone (cortisol and catecholamines) concentrations and blood, brain and liver tissue levels of three heat shock proteins (HSPs), the stress inducible HSP70, the constitutive HSC70 and HSP90, in dominant and subordinate trout. No effects of social status on the hormonal response to the heat stress were detected, but the cellular heat shock response in the brain and liver of dominant and subordinate individuals was inhibited. We then assessed thermal tolerance in dominant and subordinate fish through critical thermal maximum temperature (CT(max)) trials and measured HSPs following the heat shock. Subordinate fish were less thermally tolerant than their dominant counterparts. We conclude that social stress impacts the ability of fish to respond, on a cellular scale and in a tissue-specific manner, to increases in water temperature, with likely consequences for overall fitness. PMID- 21525320 TI - Oxidative profile varies with personality in European greenfinches. AB - Where behavioural responses differ consistently between individuals, this is termed 'personality'. There is the suggestion, but with little supporting data, that personality traits reflect underlying variation in physiology. Here, we tested whether greenfinches Carduelis chloris differing in personality traits differed in various plasma indices of oxidative profile: antioxidant capacity (OXY), pro-oxidant status (reactive oxygen metabolites, ROMs), oxidative stress (OS) and an end-product of oxidative damage: malondialdehyde (MDA). We measured two personality traits: neophobia (latency to approach food near novel objects) and object exploration (latency to approach novel objects). These traits were uncorrelated. ROMs, OXY, OS and MDA were also uncorrelated with each other. Highly neophobic birds had lower OXY, higher ROMs and higher OS than less neophobic birds. Fast exploring birds had higher OXY than slow explorers, but did not differ in ROMs or OS. Variation in MDA was described by a quadratic relationship with neophobia: birds with extremely high or low neophobia had lower MDA than birds with intermediate neophobia, despite highly neophobic birds exhibiting lower OS than intermediately neophobic birds. Additively in that model, fast explorers had lower MDA than slower explorers. To conclude: first, personality types can differ in oxidative profile. Second, although physiological differences (e.g. hormonal stress responsiveness) between personality types generally range along a linear continuum, physiological costs may not. Finally, relationships with oxidative profile differed between neophobia and object exploration. Understanding how oxidative profile and thus physiological costs vary within and between personality traits may explain how differences in personality traits can predict fitness. PMID- 21525321 TI - Experimental evolution of sperm count in protandrous self-fertilizing hermaphrodites. AB - Sperm count evolution is driven by sexual selection, with an added role of selection on gamete resource allocation for hermaphrodite spermatogenesis. However, self-fertilization by hermaphrodites retards sexual selection and results in the evolution of reduced investment in sperm or pollen. In contrast to reproduction limited by female gametes (Bateman's Principle), self-fertilizing Caenorhabditis elegans hermaphrodites exhibit sperm-limited reproduction. Caenorhabditis elegans hermaphrodites are thought to experience a fitness trade off between lifetime fecundity and generation time: longer sperm production decreases the risk of self-sperm depletion, but at the same time delays the onset of selfing and thus increases egg-to-egg generation time. Theory predicts that shorter larval development will favor lower sperm counts and longer development will favor more sperm. To investigate how developmental trajectories affect the evolution of sperm production, we performed experimental evolution by directly competing alleles controlling hermaphrodite sperm count, conducted under different environmental conditions that alter development time. Results are partially consistent with theory: rapid larval development generally favored alleles encoding production of few sperm. However, we identify some previously unrecognized simplifications of the theory and its application to our experimental system. In addition, we evaluated the generality of sperm limitation in C. elegans. Although optimal growth conditions yield sperm limitation, non optimal conditions induce oocyte limitation, suggesting that this species might conform to Bateman's Principle under many natural settings. These findings demonstrate how developmental trajectories can shape the fitness landscape for the evolution of reproduction and sperm traits, even without sexual selection. PMID- 21525322 TI - ATP distribution and localization of mitochondria in Suberites domuncula (Olivi 1792) tissue. AB - The metabolic energy state of sponge tissue in vivo is largely unknown. Quantitative bioluminescence-based imaging was used to analyze the ATP distribution of Suberites domuncula (Olivi 1792) tissue, in relation to differences between the cortex and the medulla. This method provides a quantitative picture of the ATP distribution closely reflecting the in vivo situation. The obtained data suggest that the highest ATP content occurs around channels in the sponge medulla. HPLC reverse-phase C-18, used for measurement of ATP content, established a value of 1.62 MUmol ATP g-1 dry mass in sponge medulla, as opposed to 0.04 MUmol ATP g-1 dry mass in the cortex, thus indicating a specific and defined energy distribution. These results correlate with the mitochondria localization, determined using primary antibodies against cytochrome oxidase c subunit 1 (COX1) (immunostaining), as well as with the distribution of arginine kinase (AK), essential for cellular energy metabolism (in situ hybridization with AK from S. domuncula; SDAK), in sponge sections. The highest energy consumption seemed to occur in choanocytes, the cells that drive the water through the channel system of the sponge body. Taken together, these results showed that the majority of energetic metabolism in S. domuncula occurs in the medulla, in the proximity of aqueous channels. PMID- 21525323 TI - High background noise shapes selective auditory filters in a tropical cricket. AB - Because of call frequency overlap and masking interference, the airborne sound channel represents a limited resource for communication in a species-rich cricket community like the tropical rainforest. Here we studied the frequency tuning of an auditory neuron mediating phonotaxis in the rainforest cricket Paroecanthus podagrosus, suffering from strong competition, in comparison with the same homologous neuron in two species of European field crickets, where such competition does not exist. As predicted, the rainforest species exhibited a more selective tuning compared with the European counterparts. The filter reduced background nocturnal noise levels by 26 dB, compared with only 16 and 10 dB in the two European species. We also quantified the performance of the sensory filter under the different filter regimes by examining the representation of the species-specific amplitude modulation of the male calling song, when embedded in background noise. Again, the filter of the rainforest cricket performed significantly better in terms of representing this important signal parameter. The neuronal representation of the calling song pattern within receivers was maintained for a wide range of signal-to-noise ratios because of the more sharply tuned sensory system and selective attention mechanisms. Finally, the rainforest cricket also showed an almost perfect match between the filter for sensitivity and the peripheral filter for directional hearing, in contrast to its European counterparts. We discuss the consequences of these adaptations for intraspecific acoustic communication and reproductive isolation between species. PMID- 21525324 TI - Effects of fore-aft body mass distribution on acceleration in dogs. AB - The ability of a quadruped to apply propulsive ground reaction forces (GRF) during rapid acceleration may be limited by muscle power, foot traction or the ability to counteract the nose-up pitching moment due to acceleration. Because the biomechanics of acceleration change, both throughout the stride cycle and over subsequent strides as velocity increases, the factors limiting propulsive force production may also change. Depending on which factors are limiting during each step, alterations in fore-aft body mass distribution may either increase or decrease the maximum propulsive GRF produced. We analyzed the effects of experimental alterations in the fore-aft body mass distribution of dogs as they performed rapid accelerations. We measured the changes in trunk kinematics and GRF as dogs accelerated while carrying 10% body mass in saddlebags positioned just in front of the shoulder girdle or directly over the pelvic girdle. We found that dogs applied greater propulsive forces in the initial hindlimb push-off and first step by the lead forelimb in both weighted conditions. During these steps dogs appear to have been limited by foot traction. For the trailing forelimb, propulsive forces and impulses were reduced when dogs wore caudally placed weights and increased when dogs wore cranially placed weights. This is consistent with nose-up pitching or avoidance thereof having limited propulsive force production by the trailing forelimb. By the second stride, the hindlimbs appear to have been limited by muscle power in their ability to apply propulsive force. Adding weights decreased the propulsive force they applied most in the beginning of stance, when limb retractor muscles were active in supporting body weight. These results suggest that all three factors: foot traction, pitching of the body, and muscle power play roles in limiting quadrupedal acceleration. Digging in to the substrate with claws or hooves appears to be necessary for maximizing propulsion in the initial hindlimb push-off and first forelimb step. Shifting the center of mass forward, as occurred with the loss of the large and heavy tail in the evolution of mammals, is likely to increase the contribution of the forelimbs to acceleration. Hindlimb muscle power appears to play a greater role in limiting acceleration than does forelimb muscle power. As such, we might expect animals built for rapid acceleration to have an increased ratio of hindlimb to forelimb muscle mass. PMID- 21525326 TI - Molecular physiology and functional morphology of SO42- excretion by the kidney of seawater-adapted eels. AB - Marine teleosts actively excrete SO42- and keep the plasma concentration of this ion much lower than that of environmental seawater (SW). We used the eel as a model to study the excretory mechanism of SO42- because this euryhaline species changes SO42- regulation drastically after transfer from freshwater (FW) to SW. Time-course studies showed that plasma SO42- concentration decreased 3 days after transfer of eels from FW to SW, while urine SO42- concentration increased on 1 day. Detailed analyses showed that urine SO42- concentration increased linearly from 6 h after SW transfer; however, this did not immediately translate to increased SO42- excretion because the volume of urine was decreased. We identified five SO42- transporters in the eel kidney. Three of these (Slc26a1, Slc26a6b and Slc26a6c) are expressed in both SW- and FW-acclimated eels while Slc26a6a and Slc13a1 are expressed in SW-acclimated eels and FW-acclimated eels, respectively. We showed that changes in Slc26a6a and Slc13a1 gene expression occurred 1-3 days after SW transfer. In SW eel kidneys, immunohistochemistry using specific antisera against each transporter protein showed that Slc26a6a and Slc26a6c are localized on the apical membrane of the P1 segment of the proximal tubule, while Slc26a6b is localized on the apical membrane and Slc26a1 on the basolateral membrane of the P2 segment. The current study revealed complex molecular mechanisms of SO42- excretion in the SW eel kidney that involve segment specific localization of multiple Slc transporters in proximal tubules and modulation of their expression in different SO42- environments. This precise regulatory mechanism may endow the eel with euryhalinity. PMID- 21525325 TI - Histaminergic signaling in the central nervous system of Daphnia and a role for it in the control of phototactic behavior. AB - Daphnia magna and Daphnia pulex are well-established model organisms in the fields of ecotoxicology and toxicogenomics. Among the many assays used for determining the effects of environmental and anthropogenic stressors on these animals is monitoring for changes in their phototactic behavior. In most arthropods, histamine has been shown to play a key role in the visual system. Currently, nothing is known about histaminergic signaling in either D. magna or D. pulex. Here, a combination of immunohistochemistry and genome mining was used to identify and characterize the histaminergic systems in these daphnids. In addition, a behavioral assay was used to assess the role of histamine in their phototactic response to ultraviolet (UV) light exposure. An extensive network of histaminergic somata, axons and neuropil was identified via immunohistochemistry within the central nervous system of both daphnids, including labeling of putative photoreceptors in the compound eye and projections from these cells to the brain. Mining of the D. pulex genome using known Drosophila melanogaster proteins identified a putative ortholog of histidine decarboxylase (the rate limiting biosynthetic enzyme for histamine), as well as two putative histamine gated chloride channels (hclA and hclB orthologs). Exposure of D. magna to cimetidine, an H2 receptor antagonist known to block both hclA and hclB in D. melanogaster, inhibited their negative phototactic response to UV exposure in a reversible, time-dependent manner. Taken collectively, our results show that an extensive histaminergic system is present in Daphnia species, including the visual system, and that this amine is involved in the control of phototaxis in these animals. PMID- 21525328 TI - The induction of shared identity: the positive role of individual distinctiveness for groups. AB - This article examines inductive processes of social identity formation, the bottom-up processes by which individual group members influence a social identity, integrating it with work on entitativity. Three studies tested the prediction that feelings of individual distinctiveness mediate the relation between inductive social identity formation and entitativity and that entitativity in turn predicts identification. The studies provided consistent support for this theoretical model over alternative models, using a range of different social groups and methods. Study 1 found support for the model in self selected small groups. Study 2 supported it with a much broader set of groups that were not self-selected. Finally, Study 3 varied levels of inductive social identity formation systematically by varying group size and provided direct support for the hypothesized causal relations. PMID- 21525329 TI - The relationship between familial resemblance and sexual attraction: an update on Westermarck, Freud, and the incest taboo. AB - Foundational principles of evolutionary theory predict that inbreeding avoidance mechanisms should exist in all species--including humans--in which close genetic relatives interact during periods of sexual maturity. Voluminous empirical evidence, derived from diverse taxa, supports this prediction. Despite such results, Fraley and Marks claim to provide evidence that humans are sexually attracted to close genetic relatives and that such attraction is held in check by cultural taboos. Here, the authors show that Fraley and Marks, in their search for an alternate explanation of inbreeding avoidance, misapply theoretical constructs from evolutionary biology and social psychology, leading to an incorrect interpretation of their results. The authors propose that Fraley and Marks's central findings can be explained in ways consistent with existing evolutionary models of inbreeding avoidance. The authors conclude that appropriate application of relevant theory and stringent experimental design can generate fruitful investigations into sexual attraction, inbreeding avoidance, and incest taboos. PMID- 21525330 TI - The conflicting influences of religiosity on attitude toward torture. AB - This research examines the thesis that religiosity has conflicting influences on Americans' attitudes about the use of torture on terrorism suspects: an organic influence favoring opposition to torture and a discursively driven influence favoring support of torture. In each of two national samples, religiosity had both a direct effect toward opposition to torture and an indirect effect-via conservative political alignment-toward support of torture. Multiple-group analyses revealed that the direct effect toward opposition to torture did not vary across Americans with differing levels of exposure to political discourse, whereas the indirect effect toward support of torture via conservative political alignment was much stronger among Americans highly exposed to political discourse. Among such individuals, the indirect effect was so strong that it completely counteracted the competing direct effect. Discussion focuses on the competing influences that a single nonpolitical psychological characteristic may have on a political preference. PMID- 21525331 TI - Neuronal autophagy as a mediator of life and death: contrasting roles in chronic neurodegenerative and acute neural disorders. AB - Autophagy is a cellular mechanism for degrading proteins and organelles. It was first described as a physiological process essential for cellular health and survival, and this is its role in most cells. However, it can also be a mediator of cell death, either by the triggering of apoptosis or by an independent "autophagic" cell death mechanism. This duality is important in the central nervous system, where the activation of autophagy has recently been shown to be protective in certain chronic neurodegenerative diseases but deleterious in acute neural disorders such as stroke and hypoxic/ischemic injury. The authors here discuss these distinct roles of autophagy in the nervous system with a focus on the role of autophagy in mediating neuronal death. The development of new therapeutic strategies based on the manipulation of autophagy will need to take into account these opposing roles of autophagy. PMID- 21525332 TI - In situ distribution and speciation of toxic copper, nickel, and zinc in hydrated roots of cowpea. AB - The phytotoxicity of trace metals is of global concern due to contamination of the landscape by human activities. Using synchrotron-based x-ray fluorescence microscopy and x-ray absorption spectroscopy, the distribution and speciation of copper (Cu), nickel (Ni), and zinc (Zn) was examined in situ using hydrated roots of cowpea (Vigna unguiculata) exposed to 1.5 MUm Cu, 5 MUm Ni, or 40 MUm Zn for 1 to 24 h. After 24 h of exposure, most Cu was bound to polygalacturonic acid of the rhizodermis and outer cortex, suggesting that binding of Cu to walls of cells in the rhizodermis possibly contributes to the toxic effects of Cu. When exposed to Zn, cortical concentrations remained comparatively low with much of the Zn accumulating in the meristematic region and moving into the stele; approximately 60% to 85% of the total Zn stored as Zn phytate within 3 h of exposure. While Ni concentrations were high in both the cortex and meristem, concentrations in the stele were comparatively low. To our knowledge, this is the first report of the in situ distribution and speciation of Cu, Ni, and Zn in hydrated (and fresh) plant tissues, providing valuable information on the potential mechanisms by which they are toxic. PMID- 21525333 TI - Terpene down-regulation in orange reveals the role of fruit aromas in mediating interactions with insect herbivores and pathogens. AB - Plants use volatile terpene compounds as odor cues for communicating with the environment. Fleshy fruits are particularly rich in volatiles that deter herbivores and attract seed dispersal agents. We have investigated how terpenes in citrus fruit peels affect the interaction between the plant, insects, and microorganisms. Because limonene represents up to 97% of the total volatiles in orange (Citrus sinensis) fruit peel, we chose to down-regulate the expression of a limonene synthase gene in orange plants by introducing an antisense construct of this gene. Transgenic fruits showed reduced accumulation of limonene in the peel. When these fruits were challenged with either the fungus Penicillium digitatum or with the bacterium Xanthomonas citri subsp. citri, they showed marked resistance against these pathogens that were unable to infect the peel tissues. Moreover, males of the citrus pest medfly (Ceratitis capitata) were less attracted to low limonene-expressing fruits than to control fruits. These results indicate that limonene accumulation in the peel of citrus fruit appears to be involved in the successful trophic interaction between fruits, insects, and microorganisms. Terpene down-regulation might be a strategy to generate broad spectrum resistance against pests and pathogens in fleshy fruits from economically important crops. In addition, terpene engineering may be important for studying the basic ecological interactions between fruits, herbivores, and pathogens. PMID- 21525334 TI - FAR-RED INSENSITIVE219 modulates CONSTITUTIVE PHOTOMORPHOGENIC1 activity via physical interaction to regulate hypocotyl elongation in Arabidopsis. AB - FAR-RED INSENSITIVE219 (FIN219) in Arabidopsis (Arabidopsis thaliana) is involved in phytochrome A-mediated far-red (FR) light signaling. Previous genetic studies revealed that FIN219 acts as an extragenic suppressor of CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1). However, the molecular mechanism underlying the suppression of COP1 remains unknown. Here, we used a transgenic approach to study the regulation of COP1 by FIN219. Transgenic seedlings containing ectopic expression of the FIN219 amino (N)-terminal domain in wild-type Columbia (named NCox for the expression of the N-terminal coiled-coil domain and NTox for the N terminal 300-amino acid region) exhibited a dominant-negative long-hypocotyl phenotype under FR light, reflected as reduced photomorphogenic responses and altered levels of COP1 and ELONGATED HYPOCOTYL5 (HY5). Yeast two-hybrid, pull down, and bimolecular fluorescence complementation assays revealed that FIN219 could interact with the WD-40 domain of COP1 and with its N-terminal coiled-coil domain through its carboxyl-terminal domain. Further in vivo coimmunoprecipitation study confirms that FIN219 interacts with COP1 under continuous FR light. Studies of the double mutant fin219-2/cop1-6 indicated that HY5 stability requires FIN219 under darkness and FR light. Moreover, FIN219 levels positively regulated by phytochrome A can modulate the subcellular location of COP1 and are differentially regulated by various fluence rates of FR light. We conclude that the dominant-negative long-hypocotyl phenotype conferred by NCox and NTox in a wild-type background was caused by the misregulation of COP1 binding with the carboxyl terminus of FIN219. Our data provide a critical mechanism controlling the key repressor COP1 in response to FR light. PMID- 21525336 TI - RNA structural domains in noncoding regions of the foot-and-mouth disease virus genome trigger innate immunity in porcine cells and mice. AB - The induction of type I interferons (alpha/beta interferon [IFN-alpha/beta]) in response to viral infection is a crucial step leading to the antiviral state in the host. Viruses produce double-stranded RNA (dsDNA) during their replication cycle that is sensed as nonself by host cells through different receptors. A signaling cascade then is activated to block viral replication and spread. Foot and-mouth disease virus (FMDV) is a picornavirus that is highly sensitive to IFN, and it causes one of the world's most important animal diseases. In this study, we showed the ability of structural domains predicted to enclose stable dsRNA regions in the 5'- and 3'-noncoding regions (NCRs) of the FMDV genome to trigger an IFN-alpha/beta response in porcine kidney cultured cells and newborn mice. These RNAs, generated by in vitro transcription, were able to stimulate IFN-beta transcription and induce an antiviral state in SK-6 cells. The induction levels elicited by the different NCR RNAs were compared. Among them, the 3'NCR was identified as a potent IFN activator, and the features in this region involved in signaling have been analyzed. To address whether the FMDV NCR transcripts were able to trigger the innate immune response in vivo, Swiss suckling mice were inoculated intraperitoneally with the RNAs. All transcripts induced the innate response in transfected animals, measured as IFN-alpha/beta protein levels, antiviral activity in sera, and reduced susceptibility to FMDV infection. Our work provides new insight into innate responses against FMDV and identifies these small noninfectious RNA molecules as potential adjuvants for vaccine improvement and antiviral strategies against picornaviruses. PMID- 21525337 TI - Crystal structures of GII.10 and GII.12 norovirus protruding domains in complex with histo-blood group antigens reveal details for a potential site of vulnerability. AB - Noroviruses are the dominant cause of outbreaks of gastroenteritis worldwide, and interactions with human histo-blood group antigens (HBGAs) are thought to play a critical role in their entry mechanism. Structures of noroviruses from genogroups GI and GII in complex with HBGAs, however, reveal different modes of interaction. To gain insight into norovirus recognition of HBGAs, we determined crystal structures of norovirus protruding domains from two rarely detected GII genotypes, GII.10 and GII.12, alone and in complex with a panel of HBGAs, and analyzed structure-function implications related to conservation of the HBGA binding pocket. The GII.10- and GII.12-apo structures as well as the previously solved GII.4-apo structure resembled each other more closely than the GI.1 derived structure, and all three GII structures showed similar modes of HBGA recognition. The primary GII norovirus-HBGA interaction involved six hydrogen bonds between a terminal alphafucose1-2 of the HBGAs and a dimeric capsid interface, which was composed of elements from two protruding subdomains. Norovirus interactions with other saccharide units of the HBGAs were variable and involved fewer hydrogen bonds. Sequence analysis revealed a site of GII norovirus sequence conservation to reside under the critical alphafucose1-2 and to be one of the few patches of conserved residues on the outer virion-capsid surface. The site was smaller than that involved in full HBGA recognition, a consequence of variable recognition of peripheral saccharides. Despite this evasion tactic, the HBGA site of viral vulnerability may provide a viable target for small molecule- and antibody-mediated neutralization of GII norovirus. PMID- 21525338 TI - Multimerization of adenovirus serotype 3 fiber knob domains is required for efficient binding of virus to desmoglein 2 and subsequent opening of epithelial junctions. AB - Recently, we identified desmoglein 2 (DSG2) as the main receptor for a group of species B adenoviruses (Ads), including Ad3, a serotype that is widely distributed in the human population (H. Wang et al., Nat. Med. 17:96-104, 2011). In this study, we have attempted to delineate structural details of the Ad3 interaction with DSG2. For CAR- and CD46-interacting Ad serotypes, attachment to cells can be completely blocked by an excess of recombinant fiber knob protein, while soluble Ad3 fiber knob only inefficiently blocks Ad3 infection. We found that the DSG2-interacting domain(s) within Ad3 is formed by several fiber knob domains that have to be in the spatial constellation that is present in viral particles. Based on this finding, we generated a small recombinant, self dimerizing protein containing the Ad3 fiber knob (Ad3-K/S/Kn). Ad3-K/S/Kn bound to DSG2 with high affinity and blocked Ad3 infection. We demonstrated by confocal immunofluorescence and transmission electron microscopy analyses that Ad3-K/S/Kn, through its binding to DSG2, triggered the transient opening of intercellular junctions in epithelial cells. The pretreatment of epithelial cells with Ad3 K/S/Kn resulted in increased access to receptors that are localized in or masked by epithelial junctions, e.g., CAR or Her2/neu. Ad3-K/S/Kn treatment released CAR from tight junctions and thus increased the transduction of epithelial cells by a serotype Ad5-based vector. Furthermore, the pretreatment of Her2/neu-positive breast cancer cells with Ad3-K/S/Kn increased the killing of cancer cells by the Her2/neu-targeting monoclonal antibody trastuzumab (Herceptin). This study widens our understanding of how Ads achieve high avidity to their receptors and the infection of epithelial tissue. The small recombinant protein Ad3-K/S/Kn has practical implications for the therapy of epithelial cancer and gene/drug delivery to normal epithelial tissues. PMID- 21525339 TI - Strong human endogenous retrovirus-specific T cell responses are associated with control of HIV-1 in chronic infection. AB - Eight percent of the human genome is composed of human endogenous retroviruses (HERVs), which are thought to be inactive remnants of ancient infections. Previously, we showed that individuals with early HIV-1 infection have stronger anti-HERV T cell responses than uninfected controls. In this study, we investigated whether these responses persist in chronic HIV-1 infection and whether they have a role in the control of HIV-1. Peripheral blood mononuclear cells (PBMCs) from 88 subjects diagnosed with HIV-1 infection for at least 1 year (median duration of diagnosis, 13 years) were tested for responses against HERV peptides in gamma interferon (IFN-gamma) enzyme immunospot (ELISPOT) assays. Individuals who control HIV-1 viremia without highly active antiretroviral therapy (HAART) had stronger and broader HERV-specific T cell responses than HAART-suppressed patients, virologic noncontrollers, immunologic progressors, and uninfected controls (P < 0.05 for each pairwise comparison). In addition, the magnitude of the anti-HERV T cell response was inversely correlated with HIV-1 viral load (r(2) = 0.197, P = 0.0002) and associated with higher CD4(+) T cell counts (r(2) = 0.072, P = 0.027) in untreated patients. Flow cytometric analyses of an HLA-B51-restricted CD8(+) HERV response in one HIV-1-infected individual revealed a less activated and more differentiated phenotype than that stimulated by a homologous HIV-1 peptide. HLA-B51 tetramer dual staining within this individual confirmed two different T cell populations corresponding to these HERV and HIV-1 epitopes, ruling out cross-reactivity. These findings suggest a possible role for anti-HERV immunity in the control of chronic HIV-1 infection and provide support for a larger effort to design an HIV-1 vaccine that targets conserved antigens such as HERV. PMID- 21525340 TI - Evaluation of the Newcastle disease virus F and HN proteins in protective immunity by using a recombinant avian paramyxovirus type 3 vector in chickens. AB - Newcastle disease virus (NDV) belongs to serotype 1 of the avian paramyxoviruses (APMV-1) and causes severe disease in chickens. Current live attenuated NDV vaccines are not fully satisfactory. An alternative is to use a viral vector vaccine that infects chickens but does not cause disease. APMV serotype 3 infects a wide variety of avian species but does not cause any apparent disease in chickens. In this study, we constructed a reverse-genetics system for recovery of infectious APMV-3 strain Netherlands from cloned cDNAs. Two recombinant viruses, rAPMV3-F and rAPMV3-HN, were generated expressing the NDV fusion (F) and hemagglutinin-neuraminidase (HN) proteins, respectively, from added genes. These viruses were used to immunize 2-week-old chickens by the oculonasal route in order to evaluate the contribution of each protein to the induction of NDV specific neutralizing antibodies and protective immunity. Each virus induced high titers of NDV-specific hemagglutination inhibition and serum neutralizing antibodies, but the response to F protein was greater. Protective immunity was evaluated by challenging the immunized birds 21 days later with virulent NDV via the oculonasal, intramuscular, or intravenous route. With oculonasal or intramuscular challenge, all three recombinant viruses (rAPMV3, rAPMV3-F, and rAPMV3-HN) were protective, while all unvaccinated birds succumbed to death. These results indicated that rAPMV3 alone can provide cross-protection against NDV challenge. However, with intravenous challenge, birds immunized with rAPMV3 were not protected, whereas birds immunized with rAPMV3-F alone or in combination with rAPMV3-HN were completely protected, and birds immunized with rAPMV3-HN alone were partially protected. These results indicate that the NDV F and HN proteins are independent neutralization and protective antigens, but the contribution by F is greater. rAMPV3 represents an avirulent vaccine vector that can be used against NDV and other poultry pathogens. PMID- 21525341 TI - Human herpesvirus 6 suppresses T cell proliferation through induction of cell cycle arrest in infected cells in the G2/M phase. AB - Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus that primarily infects immune cells and strongly suppresses the proliferation of infected cells. However, the mechanisms responsible for the regulation and suppression mediated by HHV-6 are still unknown. In this study, we examined the ability of HHV-6A to manipulate cell cycle progression in infected cells and explored the potential molecular mechanisms. We demonstrated that infection with HHV-6A imposed a growth inhibitory effect on HSB-2 cells by inducing cell cycle arrest at the G(2)/M phase. We then showed that the activity of the Cdc2-cyclin B1 complex was significantly decreased in HHV-6A-infected HSB-2 cells. Furthermore, we found that inactivation of Cdc2-cyclin B1 in HHV-6A-infected cells occurred through the inhibitory Tyr15 phosphorylation resulting from elevated Wee1 expression and inactivated Cdc25C. The reduction of Cdc2-cyclin B1 activity in HHV-6-infected cells was also partly due to the increased expression of the cell cycle regulatory molecule p21 in a p53-dependent manner. In addition, HHV-6A infection activated the DNA damage checkpoint kinases Chk2 and Chk1. Our data suggest that HHV-6A infection induces G(2)/M arrest in infected T cells via various molecular regulatory mechanisms. These results further demonstrate the potential mechanisms involved in immune suppression and modulation mediated by HHV-6 infection, and they provide new insights relevant to the development of novel vaccines and immunotherapeutic approaches. PMID- 21525342 TI - Coxsackievirus B3-induced cellular protrusions: structural characteristics and functional competence. AB - Virus-induced alterations in cell morphology play important roles in the viral life cycle. To examine the intracellular events of coxsackievirus B3 (CVB3) infection, green monkey kidney (GMK) cells were either inoculated with the virus or transfected with the viral RNA. Various microscopic and flow cytometric approaches demonstrated the emergence of CVB3 capsid proteins at 8 h posttransfection, followed by morphological transformation of the cells. The morphological changes included formation of membranous protrusions containing viral capsids, together with microtubules and actin. Translocation of viral capsids into these protrusions was sensitive to cytochalasin D, suggesting the importance of actin in the process. Three-dimensional (3D) live-cell imaging demonstrated frequent contacts between cellular protrusions and adjacent cells. Markedly, in spite of an increase in the cellular viral protein content starting 8 h postinfection, no significant decrease in cell viability or increase in the amount of early apoptotic markers was observed by flow cytometry by 28 h postinfection. Comicroinjection of viral RNA and fluorescent dextran in the presence of neutralizing virus antibody suggested that these protrusions mediated the spread of infection from one cell to another prior to virus-induced cell lysis. Altogether, the CVB3-induced cellular protrusions could function as a hitherto-unknown nonlytic mechanism of cell-to-cell transmission exploited by enteroviruses. PMID- 21525343 TI - Sulfolobus turreted icosahedral virus c92 protein responsible for the formation of pyramid-like cellular lysis structures. AB - Host cells infected by Sulfolobus turreted icosahedral virus (STIV) have been shown to produce unusual pyramid-like structures on the cell surface. These structures represent a virus-induced lysis mechanism that is present in Archaea and appears to be distinct from the holin/endolysin system described for DNA bacteriophages. This study investigated the STIV gene products required for pyramid formation in its host Sulfolobus solfataricus. Overexpression of STIV open reading frame (ORF) c92 in S. solfataricus alone is sufficient to produce the pyramid-like lysis structures in cells. Gene disruption of c92 within STIV demonstrates that c92 is an essential protein for virus replication. Immunolocalization of c92 shows that the protein is localized to the cellular membranes forming the pyramid-like structures. PMID- 21525344 TI - Helper component proteinase of the genus Potyvirus is an interaction partner of translation initiation factors eIF(iso)4E and eIF4E and contains a 4E binding motif. AB - The multifunctional helper component proteinase (HCpro) of potyviruses (genus Potyvirus; Potyviridae) shows self-interaction and interacts with other potyviral and host plant proteins. Host proteins that are pivotal to potyvirus infection include the eukaryotic translation initiation factor eIF4E and the isoform eIF(iso)4E, which interact with viral genome-linked protein (VPg). Here we show that HCpro of Potato virus A (PVA) interacts with both eIF4E and eIF(iso)4E, with interactions with eIF(iso)4E being stronger, as judged by the data of a yeast two hybrid system assay. A bimolecular fluorescence complementation assay on leaves of Nicotiana benthamiana showed that HCpro from three potyviruses (PVA, Potato virus Y, and Tobacco etch virus) interacted with the eIF(iso)4E and eIF4E of tobacco (Nicotiana tabacum); interactions with eIF(iso)4E and eIF4E of potato (Solanum tuberosum) were weaker. In PVA-infected cells, interactions between HCpro and tobacco eIF(iso)4E were confined to round structures that colocalized with 6K2-induced vesicles. Point mutations introduced to a 4E binding motif identified in the C-terminal region of HCpro debilitated interactions of HCpro with translation initiation factors and were detrimental to the virulence of PVA in plants. The 4E binding motif conserved in HCpro of potyviruses and HCpro initiation factor interactions suggest new roles for HCpro and/or translation factors in the potyvirus infection cycle. PMID- 21525345 TI - Functional macroautophagy induction by influenza A virus without a contribution to major histocompatibility complex class II-restricted presentation. AB - Major histocompatibility complex (MHC) class II-presented peptides can be derived from both exogenous (extracellular) and endogenous (biosynthesized) sources of antigen. Although several endogenous antigen-processing pathways have been reported, little is known about their relative contributions to global CD4(+) T cell responses against complex antigens. Using influenza virus for this purpose, we assessed the role of macroautophagy, a process in which cytosolic proteins are delivered to the lysosome by de novo vesicle formation and membrane fusion. Influenza infection triggered productive macroautophagy, and autophagy-dependent presentation was readily observed with model antigens that naturally traffic to the autophagosome. Furthermore, treatments that enhance or inhibit macroautophagy modulated the level of presentation from these model antigens. However, validated enzyme-linked immunospot (ELISpot) assays of influenza-specific CD4(+) T cells from infected mice using a variety of antigen-presenting cells, including primary dendritic cells, revealed no detectable macroautophagy-dependent component. In contrast, the contribution of proteasome-dependent endogenous antigen processing to the global influenza CD4(+) response was readily appreciated. The contribution of macroautophagy to the MHC class II-restricted response may vary depending upon the pathogen. PMID- 21525346 TI - Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. AB - Preexposure prophylaxis (PrEP) with antiretroviral drugs is a novel human immunodeficiency virus (HIV) prevention strategy. It is generally thought that high systemic and mucosal drug levels are sufficient for protection. We investigated whether GS7340, a next-generation tenofovir (TFV) prodrug that effectively delivers tenofovir diphosphate (TFV-DP) to lymphoid cells and tissues, could protect macaques against repeated weekly rectal simian-human immunodeficiency virus (SHIV) exposures. Macaques received prophylactic GS7340 treatment 3 days prior to each virus exposure. At 3 days postdosing, TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) were about 50-fold higher than those seen with TFV disoproxil fumarate (TDF), and they remained above 1,000 fmol/10(6) cells for as long as 7 days. TFV-DP accumulated in lymphoid and rectal tissues, with concentrations at 3 days exceeding 500 fmol/10(6) mononuclear cells. Despite high mucosal and systemic TFV levels, GS7340 was not protective. Since TFV-DP blocks reverse transcription by competing with the natural dATP substrate, we measured dATP contents in peripheral lymphocytes, lymphoid tissue, and rectal mononuclear cells. Compared to those in circulating lymphocytes and lymphoid tissue, rectal lymphocytes had 100-fold higher dATP concentrations and dATP/TFV-DP ratios, likely reflecting the activated status of the cells and suggesting that TFV-DP may be less active at the rectal mucosa. Our results identify dATP/TFV-DP ratios as a possible correlate of protection by TFV and suggest that natural substrate concentrations at the mucosa will likely modulate the prophylactic efficacy of nucleotide reverse transcriptase inhibitors. PMID- 21525347 TI - Shifting hierarchies of interleukin-10-producing T cell populations in the central nervous system during acute and persistent viral encephalomyelitis. AB - Interleukin-10 (IL-10) mRNA is rapidly upregulated in the central nervous system (CNS) following infection with neurotropic coronavirus and remains elevated during persistent infection. Infection of transgenic IL-10/green fluorescent protein (GFP) reporter mice revealed that CNS-infiltrating T cells were the major source of IL-10, with minimal IL-10 production by macrophages and resident microglia. The proportions of IL-10-producing cells were initially similar in CD8(+) and CD4(+) T cells but diminished rapidly in CD8(+) T cells as the virus was controlled. Overall, the majority of IL-10-producing CD8(+) T cells were specific for the immunodominant major histocompatibility complex (MHC) class I epitope. Unlike CD8(+) T cells, a large proportion of CD4(+) T cells within the CNS retained IL-10 production throughout persistence. Furthermore, elevated frequencies of IL-10-producing CD4(+) T cells in the spinal cord supported preferential maintenance of IL-10 production at the site of viral persistence and tissue damage. IL-10 was produced primarily by the CD25(+) CD4(+) T cell subset during acute infection but prevailed in CD25(-) CD4(+) T cells during the transition to persistent infection and thereafter. Overall, these data demonstrate significant fluidity in the T-cell-mediated IL-10 response during viral encephalitis and persistence. While IL-10 production by CD8(+) T cells was limited primarily to the time of acute effector function, CD4(+) T cells continued to produce IL-10 throughout infection. Moreover, a shift from predominant IL-10 production by CD25(+) CD4(+) T cells to CD25(-) CD4(+) T cells suggests that a transition to nonclassical regulatory T cells precedes and is retained during CNS viral persistence. PMID- 21525349 TI - Delayed cytosolic exposure of Japanese encephalitis virus double-stranded RNA impedes interferon activation and enhances viral dissemination in porcine cells. AB - Interferon is a principal component of the host antiviral defense system. In this study, abortive focus formation by Japanese encephalitis virus (JEV) in primate cells was accompanied by early interferon induction, while productive focus formation in porcine cells was associated with a late interferon response. Neutralization antibodies against interferon relieved the restricted infection in primate cells, and increasingly larger foci were generated as treatment with exogenous interferon was delayed, thereby establishing a solid correlation between interferon response and viral dissemination. However, delayed interferon induction in JEV-infected porcine cells occurred in the absence of active inhibition by the virus. We further demonstrated that JEV mediates interferon activation through double-stranded RNA and cytosolic pattern recognition receptors. Immunofluorescence and subcellular fractionation studies revealed that double-stranded RNA is concealed in intracellular membranes at an early phase of infection but eventually appears in the cytosol at later periods, which could then allow detection by cytosolic pattern recognition receptors. Interestingly, cytosolic exposure of double-stranded RNA was delayed in porcine cells compared to primate cells, independent of total double-stranded RNA levels and in correlation with the timing of the interferon response. Furthermore, when double stranded RNA was artificially introduced into the cytosol of porcine cells, more rapid and robust interferon activation was triggered than in viral infection. Thus, cytosolic exposure of JEV double-stranded RNA is imperative for interferon induction, but in cell lines (e.g., porcine cells) with delayed emergence of cytosolic double-stranded RNA, the interferon response is late and viral dissemination is consequently enhanced. PMID- 21525352 TI - Varicella-zoster virus infection of differentiated human neural stem cells. AB - Primary varicella-zoster virus (VZV) infection in humans produces varicella (chickenpox), after which the virus becomes latent in ganglionic neurons. Analysis of the physical state of viral nucleic acid and virus gene expression during latency requires postmortem acquisition of fresh human ganglia. To provide an additional way to study the VZV-host relationship in neurons, we developed an in vitro model of infected differentiated human neural stem cells (NSCs). NSCs were induced to differentiate in culture dishes coated with poly-l-lysine and mouse laminin in the presence of fibroblast growth factor 2 (FGF-2), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), dibutyryl cyclic AMP, and retinoic acid. Immunostaining with neuronal (MAP2a and beta-tubulin), astrocyte (GFAP), and oligodendrocyte (CNPase) markers revealed that differentiated neurons constituted approximately 90% of the cell population. These neurons were maintained in culture for up to 8 weeks. No cytopathic effect (CPE) developed in neurons infected with cell-free VZV (Zostavax vaccine) compared to human fetal lung fibroblasts infected with VZV. Weeks later, VZV DNA virus-specific transcripts (open reading frames [ORFs] 21, 29, 62, and 63) were detected in infected neurons, and dual immunofluorescence staining revealed the presence of VZV IE63 and gE exclusively in healthy-appearing neurons, but not in astrocytes. Neither the tissue culture medium nor a homogenate prepared from VZV-infected neurons produced a CPE in fibroblasts. VZV induced apoptosis in fibroblasts, as shown by activation of caspase 3 and by terminal deoxynucleotidyltransferase mediated dUTP-biotin nick end labeling (TUNEL) staining, but not in neurons. This model provides a unique in vitro system to study the VZV-neuronal relationship. PMID- 21525351 TI - RAB11A is essential for transport of the influenza virus genome to the plasma membrane. AB - Influenza A virus assembly is a complex process that requires the intersection of pathways involved in transporting viral glycoproteins, the matrix protein, and viral genomes, incorporated in the viral ribonucleoprotein (vRNP) complex, to plasma membrane sites of virion formation. Among these virion components, the mechanism of vRNP delivery is the most incompletely understood. Here, we reveal a functional relationship between the cellular Rab11 GTPase isoform, RAB11A, and vRNPs and show that RAB11A is indispensable for proper vRNP transport to the plasma membrane. Using an immunofluorescence-based assay with a monoclonal antibody that recognizes nucleoprotein in the form of vRNP, we demonstrate association between RAB11A and vRNPs at all stages of vRNP cytoplasmic transport. Abrogation of RAB11A expression through small interfering RNA (siRNA) treatment or disruption of RAB11A function by overexpression of dominant negative or constitutively active proteins caused aberrant vRNP intracellular accumulation, retention in the perinuclear region, and lack of accumulation at the plasma membrane. Complex formation between RAB11A and vRNPs was further established biochemically. Our results uncover a critical host factor with an essential contribution to influenza virus genome delivery and reveal a potential role for RAB11A in the transport of ribonucleoprotein cargo. PMID- 21525350 TI - Proteomic characterization of pseudorabies virus extracellular virions. AB - Pseudorabies virus (PRV), a member of the Alphaherpesvirinae, has a complex multilayered extracellular virion that is structurally conserved among other herpesviruses. PRV virions contain a double-stranded DNA genome within a proteinaceous capsid surrounded by the tegument, a layer of viral and cellular proteins. The envelope layer, which encloses the capsid and tegument, contains viral transmembrane proteins anchored in a phospholipid bilayer. The viral and host proteins contained within virions execute important functions during viral spread and pathogenesis, but a detailed understanding of the composition of PRV virions has been lacking. In this report, we present the first comprehensive proteomic characterization of purified PRV virions by mass spectrometry using two complementary approaches. To exclude proteins present in the extracellular medium that may nonspecifically associate with virions, we also analyzed virions treated with proteinase K and samples prepared from mock-infected cells. Overall, we identified 47 viral proteins associated with PRV virions, 40 of which were previously localized to the capsid, tegument, and envelope layers using traditional biochemical approaches. Additionally, we identified seven viral proteins that were previously undetected in virions, including pUL8, pUL20, pUL32, pUL40 (RR2), pUL42, pUL50 (dUTPase), and Rsp40/ICP22. Furthermore, although we did not enrich for posttranslational modifications, we detected phosphorylation of four virion proteins: pUL26, pUL36, pUL46, and pUL48. Finally, we identified 48 host proteins associated with PRV virions, many of which have known functions in important cellular pathways such as intracellular signaling, mRNA translation and processing, cytoskeletal dynamics, and membrane organization. This analysis extends previous work aimed at determining the composition of herpesvirus virions and provides novel insights critical for understanding the mechanisms underlying PRV entry, assembly, egress, spread, and pathogenesis. PMID- 21525353 TI - Varicella-zoster virus (VZV) infection of neurons derived from human embryonic stem cells: direct demonstration of axonal infection, transport of VZV, and productive neuronal infection. AB - Study of the human neurotrophic herpesvirus varicella-zoster virus (VZV) and of its ability to infect neurons has been severely limited by strict viral human tropism and limited availability of human neurons for experimentation. Human embryonic stem cells (hESC) can be differentiated to all the cell types of the body including neurons and are therefore a potentially unlimited source of human neurons to study their interactions with human neurotropic viruses. We report here reproducible infection of hESC-derived neurons by cell-associated green fluorescent protein (GFP)-expressing VZV. hESC-derived neurons expressed GFP within 2 days after incubation with mitotically inhibited MeWo cells infected with recombinant VZV expressing GFP as GFP fusions to VZV proteins or under an independent promoter. VZV infection was confirmed by immunostaining for immediate early and viral capsid proteins. Infection of hESC-derived neurons was productive, resulting in release into the medium of infectious virions that appeared fully assembled when observed by electron microscopy. We also demonstrated, for the first time, VZV infection of axons and retrograde transport from axons to neuronal cell bodies using compartmented microfluidic chambers. The use of hESC-derived human neurons in conjunction with fluorescently tagged VZV shows great promise for the study of VZV neuronal infection and axonal transport and has potential for the establishment of a model for VZV latency in human neurons. PMID- 21525348 TI - Temporal variations in the hepatitis C virus intrahost population during chronic infection. AB - The intrahost evolution of hepatitis C virus (HCV) holds keys to understanding mechanisms responsible for the establishment of chronic infections and to development of a vaccine and therapeutics. In this study, intrahost variants of two variable HCV genomic regions, HVR1 and NS5A, were sequenced from four treatment-naive chronically infected patients who were followed up from the acute stage of infection for 9 to 18 years. Median-joining network analysis indicated that the majority of the HCV intrahost variants were observed only at certain time points, but some variants were detectable at more than one time point. In all patients, these variants were found organized into communities or subpopulations. We hypothesize that HCV intrahost evolution is defined by two processes: incremental changes within communities through random mutation and alternations between coexisting communities. The HCV population was observed to incrementally evolve within a single community during approximately the first 3 years of infection, followed by dispersion into several subpopulations. Two patients demonstrated this pattern of dispersion for the rest of the observation period, while HCV variants in the other two patients converged into another single subpopulation after ~9 to 12 years of dispersion. The final subpopulation in these two patients was under purifying selection. Intrahost HCV evolution in all four patients was characterized by a consistent increase in negative selection over time, suggesting the increasing HCV adaptation to the host late in infection. The data suggest specific staging of HCV intrahost evolution. PMID- 21525354 TI - Ubiquitin-specific peptidase 20 targets TRAF6 and human T cell leukemia virus type 1 tax to negatively regulate NF-kappaB signaling. AB - NF-kappaB plays a key role in innate and acquired immunity. Its activity is regulated through intricate signaling networks. Persistent or excessive activation of NF-kappaB induces diseases, such as autoimmune disorders and malignant neoplasms. Infection by human T cell leukemia virus type 1 (HTLV-1) causes a fatal hematopoietic malignancy termed adult T cell leukemia (ATL). The HTLV-1 viral oncoprotein Tax functions pivotally in leukemogenesis through its potent activation of NF-kappaB. Recent findings suggest that protein ubiquitination is crucial for proper regulation of NF-kappaB signaling and for Tax activity. Here, we report that ubiquitin-specific peptidase USP20 deubiquitinates TRAF6 and Tax and suppresses interleukin 1beta (IL-1beta)- and Tax-induced NF-kappaB activation. Our results point to USP20 as a key negative regulator of Tax-induced NF-kappaB signaling. PMID- 21525355 TI - The human T-cell leukemia virus type 1 oncoprotein tax controls forkhead box O4 activity through degradation by the proteasome. AB - Activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway by the viral Tax oncoprotein plays a pivotal role in clonal expansion of human T-cell leukemia virus type 1 (HTLV-1)-infected cells. As the Forkhead box O (FoxO) tumor suppressors act as downstream effectors of PI3K/Akt, they represent good candidate targets whose dysregulation by Tax might be involved in HTLV-1-mediated activation and transformation of infected cells. In this report, we provide evidence showing that Tax induces a dose-dependent degradation of FoxO4 by the ubiquitin-proteasome pathway. Consistent with that, we demonstrate that Tax expression increases the interaction between FoxO4 and Mdm2 E3 ligase, leading to a strong FoxO4 polyubiquitination. These processes require the phosphorylation of FoxO4 by Akt, since a mutant of FoxO4 with mutations on its three Akt phosphorylation sites appears to be resistant to Tax mediated degradation and ubiquitination. In addition, we show that Tax expression is associated with degradation and phosphorylation of endogenous FoxO4 in Jurkat T cells. Finally, we demonstrate that Tax represses FoxO4 transcriptional activity. Our study demonstrates that Tax can control FoxO4 protein stability and transcriptional activity and provides new insight into the subversion of cell signaling pathways during HTLV-1 infection. PMID- 21525356 TI - Regulation of the production of infectious genotype 1a hepatitis C virus by NS5A domain III. AB - Although hepatitis C virus (HCV) assembly remains incompletely understood, recent studies with the genotype 2a JFH-1 strain suggest that it is dependent upon the phosphorylation of Ser residues near the C terminus of NS5A, a multifunctional nonstructural protein. Since genotype 1 viruses account for most HCV disease yet differ substantially in sequence from that of JFH-1, we studied the role of NS5A in the production of the H77S virus. While less efficient than JFH-1, genotype 1a H77S RNA produces infectious virus when transfected into permissive Huh-7 cells. The exchange of complete NS5A sequences between these viruses was highly detrimental to replication, while exchanges of the C-terminal domain III sequence (46% amino acid sequence identity) were well tolerated, with little effect on RNA synthesis. Surprisingly, the placement of the H77S domain III sequence into JFH-1 resulted in increased virus yields; conversely, H77S yields were reduced by the introduction of domain III from JFH-1. These changes in infectious virus yield correlated well with changes in the abundance of NS5A in RNA-transfected cells but not with RNA replication or core protein expression levels. Alanine replacement mutagenesis of selected Ser and Thr residues in the C-terminal domain III sequence revealed no single residue to be essential for infectious H77S virus production. However, virus production was eliminated by Ala substitutions at multiple residues and could be restored by phosphomimetic Asp substitutions at these sites. Thus, despite low overall sequence homology, the production of infectious virus is regulated similarly in JFH-1 and H77S viruses by a conserved function associated with a C-terminal Ser/Thr cluster in domain III of NS5A. PMID- 21525357 TI - Ambivalent role of the innate immune response in rabies virus pathogenesis. AB - The neurotropic rabies virus (RABV) has developed several evasive strategies, including immunoevasion, to successfully infect the nervous system (NS) and trigger a fatal encephalomyelitis. Here we show that expression of LGP2, a protein known as either a positive or negative regulator of the RIG-I-mediated innate immune response, is restricted in the NS. We used a new transgenic mouse model (LGP2 TG) overexpressing LGP2 to impair the innate immune response to RABV and thus revealed the role of the RIG-I-mediated innate immune response in RABV pathogenesis. After infection, LGP2 TG mice exhibited reduced expression of inflammatory/chemoattractive molecules, beta interferon (IFN-beta), and IFN stimulated genes in their NS compared to wild-type (WT) mice, demonstrating the inhibitory function of LGP2 in the innate immune response to RABV. Surprisingly, LGP2 TG mice showed more viral clearance in the brain and lower morbidity than WT mice, indicating that the host innate immune response, paradoxically, favors RABV neuroinvasiveness and morbidity. LGP2 TG mice exhibited similar neutralizing antibodies and microglia activation to those of WT mice but showed a reduction of infiltrating CD4(+) T cells and less disappearance of infiltrating CD8(+) T cells. This occurred concomitantly with reduced neural expression of the IFN inducible protein B7-H1, an immunoevasive protein involved in the elimination of infiltrated CD8(+) T cells. Our study shows that the host innate immune response favors the infiltration of T cells and, at the same time, promotes CD8(+) T cell elimination. Thus, to a certain extent, RABV exploits the innate immune response to develop its immunoevasive strategy. PMID- 21525358 TI - The conserved YAGL motif in human metapneumovirus is required for higher-order cellular assemblies of the matrix protein and for virion production. AB - YXXL motifs in cellular and viral proteins have a variety of functions. The matrix (M) protein of the respiratory pathogen human metapneumovirus (hMPV) contains two such conserved motifs--YSKL and YAGL. We mutated these sequences to analyze their contributions to hMPV infectivity. The mutant clones were capable of intracellular replication; however, the YAGL but not YSKL mutants were defective at spreading in infected cultures. We improved the reverse genetics system for hMPV and generated cell lines that stably expressed selectable, replicating full-length genomes for both the wild type and the mutant clones, allowing microscopic and biochemical analyses of these viruses. YAGL mutants produced normal cellular levels of M protein but failed to release virions, while ectopic coexpression of wild-type M generated particles that were restricted to a single cycle of infection. The YAGL motif did not act as a late (L) domain, however, since hMPV budding was independent of the cellular endosomal sorting complex required for transport (ESCRT) machinery and because replacement of the YAGL motif with classical L domains generated defective viruses. Instead, the YAGL mutants had defective M assemblies lacking a normal filamentous appearance and showed poor extractability from the cell compared to the wild-type protein. The mutant proteins were not grossly misfolded, however, as they interacted with cellular membranes and coassembled with wild-type M proteins. Thus, the YAGL motif is an important determinant of hMPV assembly. Furthermore, the selectable hMPV genomes described here should extend the use of reverse genetics systems in the analysis of spreading-defective viruses. PMID- 21525359 TI - P bodies inhibit retrotransposition of endogenous intracisternal a particles. AB - mRNA-processing bodies (P bodies) are cytoplasmic foci that contain translationally repressed mRNA. Since they are important for the retrotransposition of Ty elements and brome mosaic virus in yeast cells, we assessed the role of P bodies in the movement of endogenous intracisternal A particles (IAPs) in mammalian cells. In contrast to the case for these other systems, their disruption via knockdown of RCK or eukaryotic initiation factor E transporter (eIF4E-T) increased IAP retrotransposition as well as levels of IAP transcripts, Gag proteins, and reverse transcription products. This increase was not mediated by impairing the microRNA pathway. Rather, the removal of P bodies shifted IAP mRNA from nonpolysomal to polysomal fractions. Although IAP mRNA localized to P bodies, Gag was targeted to the endoplasmic reticulum (ER), from which IAP buds. Thus, by sequestering IAP mRNA away from Gag, P bodies inhibit rather than promote IAP retrotransposition. PMID- 21525360 TI - Clathrin-mediated endocytosis in living host cells visualized through quantum dot labeling of infectious hematopoietic necrosis virus. AB - Infectious hematopoietic necrosis virus (IHNV) is an important fish pathogen that infects both wild and cultured salmonids. As a species of the genus Novirhabdovirus, IHNV is a valuable model system for exploring the host entry mechanisms of rhabdoviruses. In this study, quantum dots (QDs) were used as fluorescent labels for sensitive, long-term tracking of IHNV entry. Using live cell fluorescence microscopy, we found that IHNV is internalized through clathrin coated pits after the virus binds to host cell membranes. Pretreatment of host cells with chlorpromazine, a drug that blocks clathrin-mediated endocytosis, and clathrin light chain (LCa) depletion using RNA interference both resulted in a marked reduction in viral entry. We also visualized transport of the virus via the cytoskeleton (i.e., actin filaments and microtubules) in real time. Actin polymerization is involved in the transport of endocytic vesicles into the cytosol, whereas microtubules are required for the trafficking of clathrin-coated vesicles to early endosomes, late endosomes, and lysosomes. Disrupting the host cell cytoskeleton with cytochalasin D or nocodazole significantly impaired IHNV infectivity. Furthermore, infection was significantly affected by pretreating the host cells with bafilomycin A1, a compound that inhibits the acidification of endosomes and lysosomes. Strong colocalizations of IHNV with endosomes indicated that the virus is internalized into these membrane-bound compartments. This is the first report in which QD labeling is used to visualize the dynamic interactions between viruses and endocytic structures; the results presented demonstrate that IHNV enters host cells via clathrin-mediated endocytic, cytoskeleton-dependent, and low-pH-dependent pathways. PMID- 21525361 TI - Detection of chronic wasting disease prions in salivary, urinary, and intestinal tissues of deer: potential mechanisms of prion shedding and transmission. AB - Efficient horizontal transmission is a signature trait of chronic wasting disease (CWD) in cervids. Infectious prions shed into excreta appear to play a key role in this facile transmission, as has been demonstrated by bioassays of cervid and transgenic species and serial protein misfolding cyclic amplification (sPMCA). However, the source(s) of infectious prions in these body fluids has yet to be identified. In the present study, we analyzed tissues proximate to saliva, urine, and fecal production by sPMCA in an attempt to elucidate this unique aspect of CWD pathogenesis. Oropharyngeal, urogenital, and gastrointestinal tissues along with blood and obex from CWD-exposed cervids (comprising 27 animals and >350 individual samples) were analyzed and scored based on the apparent relative CWD burden. PrP(CWD)-generating activity was detected in a range of tissues and was highest in the salivary gland, urinary bladder, and distal intestinal tract. In the same assays, blood from the same animals and unseeded normal brain homogenate controls (n = 116 of 117) remained negative. The PrP-converting activity in peripheral tissues varied from 10(-11)- to 10(0)-fold of that found in brain of the same animal. Deer with highest levels of PrP(CWD) amplification in the brain had higher and more widely disseminated prion amplification in excretory tissues. Interestingly, PrP(CWD) was not demonstrable in these excretory tissues by conventional Western blotting, suggesting a low prion burden or the presence of protease-sensitive infectious prions destroyed by harsh proteolytic treatments. These findings offer unique insights into the transmission of CWD in particular and prion infection and trafficking overall. PMID- 21525362 TI - Acetylcholine and norepinephrine mediate GABAergic but not glycinergic transmission enhancement by melittin in adult rat substantia gelatinosa neurons. AB - GABAergic and glycinergic inhibitory synaptic transmissions in substantia gelatinosa (SG; lamina II of Rexed) neurons of the spinal dorsal horn play an important role in regulating nociceptive transmission from the periphery. It has not yet been well known whether each of the inhibitory transmissions plays a distinct role in the regulation. We report an involvement of neurotransmitters in GABAergic but not glycinergic transmission enhancement produced by the PLA(2) activator melittin, where the whole-cell patch-clamp technique is applied to the SG neurons of adult rat spinal cord slices. Glycinergic but not GABAergic spontaneous inhibitory postsynaptic current (sIPSC) was increased in frequency and amplitude by melittin in the presence of nicotinic, muscarinic acetylcholine, and alpha(1)-adrenergic receptor antagonists (mecamylamine, atropine, and WB 4101, respectively). GABAergic transmission enhancement produced by melittin was unaffected by the 5-hydroxytryptamine 3 receptor and P2X receptor antagonists (ICS-205,930 and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid, respectively). Nicotinic and muscarinic acetylcholine receptor agonists [(-) nicotine and carbamoylcholine, respectively] and norepinephrine, as well as melittin, increased GABAergic sIPSC frequency and amplitude. A repeated application of (-)-nicotine, carbamoylcholine, and norepinephrine, but not melittin, at an interval of 30 min produced a similar transmission enhancement. These results indicate that melittin produces the release of acetylcholine and norepinephrine, which activate (nicotinic and muscarinic) acetylcholine and alpha(1)-adrenergic receptors, respectively, resulting in GABAergic but not glycinergic transmission enhancement in SG neurons. The desensitization of a system leading to the acetylcholine and norepinephrine release is slow in recovery. This distinction in modulation between GABAergic and glycinergic transmissions may play a role in regulating nociceptive transmission. PMID- 21525364 TI - Interspike interval distributions of spiking neurons driven by fluctuating inputs. AB - Interspike interval (ISI) distributions of cortical neurons exhibit a range of different shapes. Wide ISI distributions are believed to stem from a balance of excitatory and inhibitory inputs that leads to a strongly fluctuating total drive. An important question is whether the full range of experimentally observed ISI distributions can be reproduced by modulating this balance. To address this issue, we investigate the shape of the ISI distributions of spiking neuron models receiving fluctuating inputs. Using analytical tools to describe the ISI distribution of a leaky integrate-and-fire (LIF) neuron, we identify three key features: 1) the ISI distribution displays an exponential decay at long ISIs independently of the strength of the fluctuating input; 2) as the amplitude of the input fluctuations is increased, the ISI distribution evolves progressively between three types, a narrow distribution (suprathreshold input), an exponential with an effective refractory period (subthreshold but suprareset input), and a bursting exponential (subreset input); 3) the shape of the ISI distribution is approximately independent of the mean ISI and determined only by the coefficient of variation. Numerical simulations show that these features are not specific to the LIF model but are also present in the ISI distributions of the exponential integrate-and-fire model and a Hodgkin-Huxley-like model. Moreover, we observe that for a fixed mean and coefficient of variation of ISIs, the full ISI distributions of the three models are nearly identical. We conclude that the ISI distributions of spiking neurons in the presence of fluctuating inputs are well described by gamma distributions. PMID- 21525363 TI - Optogenetic photochemical control of designer K+ channels in mammalian neurons. AB - Currently available optogenetic tools, including microbial light-activated ion channels and transporters, are transforming systems neuroscience by enabling precise remote control of neuronal firing, but they tell us little about the role of indigenous ion channels in controlling neuronal function. Here, we employ a chemical-genetic strategy to engineer light sensitivity into several mammalian K(+) channels that have different gating and modulation properties. These channels provide the means for photoregulating diverse electrophysiological functions. Photosensitivity is conferred on a channel by a tethered ligand photoswitch that contains a cysteine-reactive maleimide (M), a photoisomerizable azobenzene (A), and a quaternary ammonium (Q), a K(+) channel pore blocker. Using mutagenesis, we identify the optimal extracellular cysteine attachment site where MAQ conjugation results in pore blockade when the azobenzene moiety is in the trans but not cis configuration. With this strategy, we have conferred photosensitivity on channels containing Kv1.3 subunits (which control axonal action potential repolarization), Kv3.1 subunits (which contribute to rapid firing properties of brain neurons), Kv7.2 subunits (which underlie "M-current"), and SK2 subunits (which are Ca(2+)-activated K(+) channels that contribute to synaptic responses). These light-regulated channels may be overexpressed in genetically targeted neurons or substituted for native channels with gene knockin technology to enable precise optopharmacological manipulation of channel function. PMID- 21525365 TI - Inactivation and stimulation of the frontal pursuit area change pursuit metrics without affecting pursuit target selection. AB - The frontal pursuit area (FPA) lies posterior to the frontal eye fields in the frontal cortex and contains neurons that are directionally selective for pursuit eye movements. Lesions of the FPA (alternately called "FEFsem") cause deficits in pursuit acceleration and velocity, which are largest for movements directed toward the lesioned side. Conversely, stimulation of the FPA evokes pursuit from fixation and increases the gain of the pursuit response. On the basis of these properties, it has been hypothesized that the FPA could underlie the selection of pursuit direction. To test this possibility, we manipulated FPA activity and measured the effect on target selection behavior in rhesus monkeys. First, we unilaterally inactivated the FPA with the GABA agonist muscimol. We then measured the monkeys' performance on a pursuit-choice task. Second, we applied microstimulation unilaterally to the FPA during pursuit initiation while monkeys performed the same pursuit-choice task. Both of these manipulations produced significant effects on pursuit metrics; the inactivation decreased pursuit velocity and acceleration, and microstimulation evoked pursuit directly. Despite these changes, both manipulations failed to significantly alter choice behavior. These results show that FPA activity is not necessary for pursuit target selection. PMID- 21525366 TI - Modification of saccadic gain by reinforcement. AB - Control of saccadic gain is often viewed as a simple compensatory process in which gain is adjusted over many trials by the postsaccadic retinal error, thereby maintaining saccadic accuracy. Here, we propose that gain might also be changed by a reinforcement process not requiring a visual error. To test this hypothesis, we used experimental paradigms in which retinal error was removed by extinguishing the target at the start of each saccade and either an auditory tone or the vision of the target on the fovea was provided as reinforcement after those saccades that met an amplitude criterion. These reinforcement procedures caused a progressive change in saccade amplitude in nearly all subjects, although the rate of adaptation differed greatly among subjects. When we reversed the contingencies and reinforced those saccades landing closer to the original target location, saccade gain changed back toward normal gain in most subjects. When subjects had saccades adapted first by reinforcement and a week later by conventional intrasaccadic step adaptation, both paradigms yielded similar degrees of gain changes and similar transfer to new amplitudes and to new starting positions of the target step as well as comparable rates of recovery. We interpret these changes in saccadic gain in the absence of postsaccadic retinal error as showing that saccade adaptation is not controlled by a single error signal. More generally, our findings suggest that normal saccade adaptation might involve general learning mechanisms rather than only specialized mechanisms for motor calibration. PMID- 21525368 TI - Neuronal plasticity regulated by the insulin-like signaling pathway underlies salt chemotaxis learning in Caenorhabditis elegans. AB - Quantification of neuronal plasticity in a living animal is essential for understanding learning and memory. Caenorhabditis elegans shows a chemotactic behavior toward NaCl. However, it learns to avoid NaCl after prolonged exposure to NaCl under starvation conditions, which is called salt chemotaxis learning. Insulin-like signaling is important for this behavioral plasticity and functions in one of the salt-sensing sensory neurons, ASE right (ASER). However, how neurons including ASER show neuronal plasticity is unknown. To determine the neuronal plasticity related to salt chemotaxis learning, we measured Ca(2+) response and synaptic release of individual neurons by using in vivo imaging techniques. We found that response of ASER increased whereas its synaptic release decreased after prolonged exposure to NaCl without food. These changes in the opposite directions were abolished in insulin-like signaling mutants, suggesting that insulin-like signaling regulates these plasticities in ASER. The response of one of the downstream interneurons, AIB, decreased profoundly after NaCl conditioning. This alteration in AIB response was independent of the insulin-like signaling pathway. Our results suggest that information on NaCl is modulated at the level of both sensory neurons and interneurons in salt chemotaxis learning. PMID- 21525367 TI - Inhibition in the balance: binaurally coupled inhibitory feedback in sound localization circuitry. AB - Interaural time differences (ITDs) are the primary cue animals, including humans, use to localize low-frequency sounds. In vertebrate auditory systems, dedicated ITD processing neural circuitry performs an exacting task, the discrimination of microsecond differences in stimulus arrival time at the two ears by coincidence detecting neurons. These neurons modulate responses over their entire dynamic range to sounds differing in ITD by mere hundreds of microseconds. The well understood function of this circuitry in birds has provided a fruitful system to investigate how inhibition contributes to neural computation at the synaptic, cellular, and systems level. Our recent studies in the chicken have made significant progress in bringing together many of these findings to provide a cohesive picture of inhibitory function. PMID- 21525369 TI - Superior colliculus cells sensitive to active touch and texture during whisking. AB - Rats sense the environment through rhythmic vibrissa protractions, called active whisking, which can be simulated in anesthetized rats by electrically stimulating the facial motor nerve. Using this method, we investigated barrel cortex field potential and superior colliculus single-unit responses during passive touch, whisking movement, active touch, and texture discrimination. Similar to passive touch, whisking movement is signaled during the onset of the whisker protraction by short-latency responses in barrel cortex that drive corticotectal responses in superior colliculus, and all these responses show robust adaptation with increases in whisking frequency. Active touch and texture are signaled by longer latency responses, first in superior colliculus during the rising phase of the protraction, likely driven by trigeminotectal inputs, and later in barrel cortex by the falling phase of the protraction. Thus, superior colliculus is part of a broader vibrissa neural network that can decode whisking movement, active touch, and texture. PMID- 21525370 TI - Chemosensory burst coding by mouse vomeronasal sensory neurons. AB - The capabilities of any sensory system are ultimately constrained by the properties of the sensory neurons: the ability to detect and represent stimuli is limited by noise due to spontaneous activity, and optimal decoding in downstream circuitry must be matched to the nature of the encoding performed at the input. Here, we investigated the firing properties of sensory neurons in the accessory olfactory system, a distinct sensory system specialized for detection of socially relevant odors. Using multielectrode array recording, we observed that sensory neurons are spontaneously active and highly variable across time and trials and that this spontaneous activity limits the ability to distinguish sensory responses from noise. Sensory neuron activity tended to consist of bursts that maintained remarkably consistent statistics during both spontaneous activity and in response to stimulation with sulfated steroids. This, combined with pharmacological and genetic intervention in the signal transduction cascade, indicates that sensory transduction plays a role in shaping overall spontaneous activity. These findings indicate that as-yet unexplored characteristics of the sensory transduction cascade significantly constrain the representation of sensory information by vomeronasal neurons. PMID- 21525371 TI - Involvement of action-related brain regions in nicotine addiction. AB - The study of Wagner et al. (J Neurosci 31: 894-898, 2011) reveals the neural correlates of spontaneously activated action representations in smokers when subjects watch movie characters smoke. We stress the importance of differentiating how these representations are activated: while the anterior intraparietal sulcus and inferior frontal gyrus are part of the mirror neuron system of smokers, the middle frontal gyrus, premotor cortex, and superior parietal lobule represent the smoking-related tool use skills and action knowledge activated by smoking paraphernalia. PMID- 21525373 TI - Increased Na+ and K+ currents in small mouse dorsal root ganglion neurons after ganglion compression. AB - We investigated the effects of chronic compression (CCD) of the L3 and L4 dorsal root ganglion (DRG) on pain behavior in the mouse and on the electrophysiological properties of the small-diameter neuronal cell bodies in the intact ganglion. CCD is a model of human radicular pain produced by intraforaminal stenosis and other disorders affecting the DRG, spinal nerve, or root. On days 1, 3, 5, and 7 after the onset of compression, there was a significant decrease from preoperative values in the threshold mechanical force required to elicit a withdrawal of the foot ipsilateral to the CCD (tactile allodynia). Whole cell patch-clamp recordings were obtained, in vitro, from small-sized somata and, for the first time, in the intact DRG. Under current clamp, CCD neurons exhibited a significantly lower rheobase compared with controls. A few CCD but no control neurons exhibited spontaneous action potentials. CCD neurons showed an increase in the density of TTX-resistant and TTX-sensitive Na(+) current. CCD neurons also exhibited an enhanced density of voltage-dependent K(+) current, due to an increase in delayed rectifier K(+) current, without a change in the transient or "A" current. We conclude that CCD in the mouse produces a model of radicular pain, as we have previously demonstrated in the rat. While the role of enhanced K(+) current remains to be elucidated, we speculate that it represents a compensatory neuronal response to reduce ectopic or aberrant levels of neuronal activity produced by the injury. PMID- 21525372 TI - Reduced expression of SynGAP, a neuronal GTPase-activating protein, enhances capsaicin-induced peripheral sensitization. AB - Synaptic GTPase-activating protein (SynGAP) is a neuronal-specific Ras/Rap-GAP that increases the hydrolysis rate of GTP to GDP, converting Ras/Rap from the active into the inactive form. The Ras protein family modulates a wide range of cellular pathways including those involved in sensitization of sensory neurons. Since GAPs regulate Ras activity, SynGAP might be an important regulator of peripheral sensitization and pain. Therefore, we evaluated excitability, stimulus evoked release of the neuropeptide calcitonin gene-related peptide (CGRP), and nociception from wild-type (WT) mice and those with a heterozygous mutation of the SynGAP gene (SynGAP(+/-)). Our results demonstrate that SynGAP is expressed in primary afferent sensory neurons and that the capsaicin-stimulated CGRP release from spinal cord slices was two-fold higher from SynGAP(+/-) mice than that observed from WT mouse tissue, consistent with an increase in expression of the capsaicin receptor, transient receptor potential cation channel subfamily V member 1 (TRPV1), in SynGAP(+/-) dorsal root ganglia. However, there was no difference between the two genotypes in potassium-stimulated release of CGRP, the number of action potentials generated by a ramp of depolarizing current, or mechanical hypernociception elicited by intraplantar injection of capsaicin. In contrast, capsaicin-induced thermal hypernociception occurred at lower doses of capsaicin and had a longer duration in SynGAP(+/-) mice than WT mice. These results provide the first evidence that SynGAP is an important regulator of neuropeptide release from primary sensory neurons and can modulate capsaicin induced hypernociception, demonstrating the importance of GAP regulation in signaling pathways that play a role in peripheral sensitization. PMID- 21525374 TI - Regulation of learned vocal behavior by an auditory motor cortical nucleus in juvenile zebra finches. AB - In the process of song learning, songbirds such as the zebra finch shape their initial soft and poorly formed vocalizations (subsong) first into variable plastic songs with a discernable recurring motif and then into highly stereotyped adult songs. A premotor brain area critically involved in plastic and adult song production is the cortical nucleus HVC. One of HVC's primary afferents, the nucleus interface of the nidopallium (NIf), provides a significant source of auditory input to HVC. However, the premotor involvement of NIf has not been extensively studied yet. Here we report that brief and reversible pharmacological inactivation of NIf in juvenile birds leads to transient degradation of plastic song toward subsong, as revealed by spectral and temporal song features. No such song degradation is seen following NIf inactivation in adults. However, in both juveniles and adults NIf inactivation leads to a transient decrease in song stereotypy. Our findings reveal a contribution of NIf to song production in juveniles that agrees with its known role in adults in mediating thalamic drive to downstream vocal motor areas during sleep. PMID- 21525375 TI - A novel instrumented multipeg running wheel system, Step-Wheel, for monitoring and controlling complex sequential stepping in mice. AB - Motor control is critical in daily life as well as in artistic and athletic performance and thus is the subject of intense interest in neuroscience. Mouse models of movement disorders have proven valuable for many aspects of investigation, but adequate methods for analyzing complex motor control in mouse models have not been fully established. Here, we report the development of a novel running-wheel system that can be used to evoke simple and complex stepping patterns in mice. The stepping patterns are controlled by spatially organized pegs, which serve as footholds that can be arranged in adjustable, ladder-like configurations. The mice run as they drink water from a spout, providing reward, while the wheel turns at a constant speed. The stepping patterns of the mice can thus be controlled not only spatially, but also temporally. A voltage sensor to detect paw touches is attached to each peg, allowing precise registration of footfalls. We show that this device can be used to analyze patterns of complex motor coordination in mice. We further demonstrate that it is possible to measure patterns of neural activity with chronically implanted tetrodes as the mice engage in vigorous running bouts. We suggest that this instrumented multipeg running wheel (which we name the Step-Wheel System) can serve as an important tool in analyzing motor control and motor learning in mice. PMID- 21525376 TI - Postural preparation prior to stepping in patients with Parkinson's disease. AB - People with Parkinson's disease (PD) frequently have difficulties with generating anticipatory postural adjustments (APAs) for forward propulsion and lateral weight transfer when initiating gait. This impairment has been attributed to deficits in motor planning and preparation. This study examined the preparation of APAs prior to an imperative cue to initiate forward stepping. A startling acoustic stimulus (SAS) was used to probe the state of preparation of the APA in eight PD (off medication) and seven matched control subjects. Subjects performed visually cued trials involving a pre-cue light instructing them to prepare to step, followed 3.5 s later by a go-cue light to rapidly initiate stepping. In random trials, a SAS (124 dB) was presented at -1,500, -1,000, -500, -250, -100, or 0 ms before the go-cue. Subjects also performed self-initiated steps. Ground reaction forces (GRFs), center of pressure (CoP) changes, and electromyographic (EMG) signals were recorded. The SAS triggered APAs in 94 +/- 11% (PD) and 96 +/- 8% (control) of trials at latencies 89 +/- 4 ms (PD) and 97 +/- 3 ms (control) earlier than Control trials. The temporal profile of APA preparation was similar between groups. However, peak EMG, GRF, and mediolateral CoP amplitudes were reduced in PD. SAS-evoked APAs at 0 ms matched Control trial APAs and were enhanced compared with self-initiated stepping. These results demonstrate that people with mild to moderate PD can plan and prepare the appropriate APA sequence prior to the expected cue to initiate gait; however, the prepared APAs are underscaled in magnitude. PMID- 21525378 TI - From body form to biological motion: the apparent velocity of human movement biases subjective time. AB - In two experiments, we investigated time perception during apparent biological motion. Pictures of initial, intermediate, and final positions of a single movement were presented, with interstimulus intervals that were constant within trials but varied across trials. Movement paths were manipulated by changing the sequential order of body postures. Increasing the path length produced an increase in perceived movement velocity. To produce an implicit measure of apparent movement dynamics, we also asked participants to judge the duration of a frame surrounding the stimuli. Longer paths with higher apparent movement velocity produced shorter perceived durations. This temporal bias was attenuated for nonbody (Experiment 1) and inverted-body (Experiment 2) control stimuli. As an explanation for these findings, we propose an automatic top-down mechanism of biological-motion perception that binds successive body postures into a continuous perception of movement. We show that this mechanism is associated with velocity-dependent temporal compression. Furthermore, this mechanism operates on line, bridging the intervals between static stimuli, and is specific to configural processing of body form. PMID- 21525377 TI - Calcium-dependent phosphorylation regulates neuronal stability and plasticity in a highly precise pacemaker nucleus. AB - Specific types of neurons show stable, predictable excitability properties, while other neurons show transient adaptive plasticity of their excitability. However, little attention has been paid to how the cellular pathways underlying adaptive plasticity interact with those that maintain neuronal stability. We addressed this question in the pacemaker neurons from a weakly electric fish because these neurons show a highly stable spontaneous firing rate as well as an N-methyl-D aspartate (NMDA) receptor-dependent form of plasticity. We found that basal firing rates were regulated by a serial interaction of conventional and atypical PKC isoforms and that this interaction establishes individual differences within the species. We observed that NMDA receptor-dependent plasticity is achieved by further activation of these kinases. Importantly, the PKC pathway is maintained in an unsaturated baseline state to allow further Ca(2+)-dependent activation during plasticity. On the other hand, the Ca(2+)/calmodulin-dependent phosphatase calcineurin does not regulate baseline firing but is recruited to control the duration of the NMDA receptor-dependent plasticity and return the pacemaker firing rate back to baseline. This work illustrates how neuronal plasticity can be realized by biasing ongoing mechanisms of stability (e.g., PKC) and terminated by recruiting alternative mechanisms (e.g., calcineurin) that constrain excitability. We propose this as a general model for regulating activity dependent change in neuronal excitability. PMID- 21525379 TI - Microparticles (ectosomes) shed by stored human platelets downregulate macrophages and modify the development of dendritic cells. AB - Microparticles (MP) shed by platelets (PLT) during storage have procoagulant activities, but little is known about their properties to modify inflammation or immunity. In this study, we studied the capacity of MP present in PLT concentrates to alter the function of macrophages and dendritic cells (DC). The size of the purified MP was between 100 and 1000 nm, and they expressed phosphatidylserine; surface proteins of PLT (CD61, CD36, CD47), including complement inhibitors (CD55, CD59), but not CD63; and proteins acquired from plasma (C1q, C3 fragments, factor H). These characteristics suggest that the MP shed by PLT are formed by budding from the cell surface, corresponding to ectosomes. The purified PLT ectosomes (PLT-Ect) reduced the release of TNF-alpha and IL-10 by macrophages activated with LPS or zymosan A. In addition, PLT-Ect induced the immediate release of TGF-beta from macrophages, a release that was not modified by LPS or zymosan A. Macrophages had a reduced TNF-alpha release even 24 h after their exposure to PLT-Ect, suggesting that PLT-Ect induced a modification of the differentiation of macrophages. Similarly, the conventional 6 d differentiation of monocytes to immature DC by IL-4 and GM-CSF was modified by the presence of PLT-Ect during the first 2 d. Immature DC expressed less HLA-DP DQ DR and CD80 and lost part of their phagocytic activity, and their LPS-induced maturation was downmodulated when exposed to PLT-Ect. These data indicate that PLT-Ect shed by stored PLT have intrinsic properties that modify macrophage and DC differentiation toward less reactive states. PMID- 21525380 TI - IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. AB - Stimulation of naive mouse CD4(+)Foxp3(-) T cells in the presence of TGF-beta results in the induction of Foxp3 expression and T suppressor function. However, Foxp3 expression in these induced regulatory T cells (iTreg) is unstable, raising the possibility that iTreg would not be useful for treatment of autoimmune diseases. To analyze the factors that control the stability of Foxp3 expression in iTreg, we generated OVA-specific iTreg from OT-II Foxp3-GFP knockin mice. Following transfer to normal C57BL/6 mice, OT-II GFP(+) cells maintained high levels of Foxp3 expression for 8 d. However, they rapidly lost Foxp3 expression upon stimulation with OVA in IFA in vivo. This unstable phenotype was associated with a strong methylation of the Treg-specific demethylated region within the Foxp3 locus. Administration of IL-2/anti-IL-2 complexes expanded the numbers of transferred Foxp3(+) iTreg in the absence of Ag challenge. Notably, when the iTreg were stimulated with Ag, treatment with IL-2/anti-IL-2 complexes stabilized Foxp3 expression and resulted in enhanced demethylation of the Treg-specific demethylated region. Conversely, neutralization of IL-2 or disruption of its signaling by deletion of Stat5 diminished the level of Foxp3 expression resulting in decreased suppressor function of the iTreg in vivo. Our data suggest that stimulation with TGF-beta in vitro is not sufficient for imprinting T cells with stable expression of Foxp3. Administration of IL-2 in vivo results in stabilization of Foxp3 expression and may prove to be a valuable adjunct for the use of iTreg for the treatment of autoimmune diseases. PMID- 21525382 TI - Analyses of recombinant stereotypic IGHV3-21-encoded antibodies expressed in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) cells that use IgH encoded by IGHV3-21 and that have a particular stereotypic third CDR (HCDR3), DANGMDV (motif-1), almost invariably express Ig L chains (IgL) encoded by IGLV3-21, whereas CLL that use IGHV3-21-encoded IgH with another stereotypic HCDR3, DPSFYSSSWTLFDY (motif-2), invariably express kappa-IgL encoded by IGKV3-20. This nonstochastic pairing could reflect steric factors that preclude these IgH from pairing with other IgL or selection for an Ig with a particular Ag-binding activity. We generated rIg with IGHV3-21-encoded IgH with HCDR3 motif-1 or -2 and IgL encoded by IGKV3-20 or IGLV3-21. Each IgH paired equally well with matched or mismatched kappa- or lambda-IgL to form functional Ig, which we screened for binding to an array of different Ags. Ig with IGLV3-21-encoded lambda-IgL could bind with an affinity of ~ 2 * 10(-6) M to protein L, a cell-wall protein of Peptostreptococcus magnus, independent of the IgH, indicating that protein L is a superantigen for IGLV3-21 encoded lambda-IgL. We also detected Ig binding to cofilin, a highly conserved actin-binding protein. However, cofilin binding was independent of native pairing of IgH and IgL and was not specific for Ig with IgH encoded by IGHV3-21. We conclude that steric factors or the binding activity for protein L or cofilin cannot account for the nonstochastic pairing of IgH and IgL observed for the stereotypic Ig made by CLL cells that express IGHV3-21. PMID- 21525383 TI - DNAM-1 mediates epithelial cell-specific cytotoxicity of aberrant intraepithelial lymphocyte lines from refractory celiac disease type II patients. AB - In refractory celiac disease (RCD), intestinal epithelial damage persists despite a gluten-free diet. Characteristic for RCD type II (RCD II) is the presence of aberrant surface TCR-CD3(-) intraepithelial lymphocytes (IELs) that can progressively replace normal IELs and eventually give rise to overt lymphoma. Therefore, RCD II is considered a malignant condition that forms an intermediate stage between celiac disease (CD) and overt lymphoma. We demonstrate in this study that surface TCR-CD3(-) IEL lines isolated from three RCD II patients preferentially lyse epithelial cell lines. FACS analysis revealed that DNAM-1 was strongly expressed on the three RCD cell lines, whereas other activating NK cell receptors were not expressed on all three RCD cell lines. Consistent with this finding, cytotoxicity of the RCD cell lines was mediated mainly by DNAM-1 with only a minor role for other activating NK cell receptors. Furthermore, enterocytes isolated from duodenal biopsies expressed DNAM-1 ligands and were lysed by the RCD cell lines ex vivo. Although DNAM-1 on CD8(+) T cells and NK cells is known to mediate lysis of tumor cells, this study provides, to our knowledge, the first evidence that (pre)malignant cells themselves can acquire the ability to lyse epithelial cells via DNAM-1. This study confirms previous work on epithelial lysis by RCD cell lines and identifies a novel mechanism that potentially contributes to the gluten-independent tissue damage in RCD II and RCD associated lymphoma. PMID- 21525381 TI - Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. AB - Biofilms are complex communities of bacteria encased in a matrix composed primarily of polysaccharides, extracellular DNA, and protein. Staphylococcus aureus can form biofilm infections, which are often debilitating due to their chronicity and recalcitrance to antibiotic therapy. Currently, the immune mechanisms elicited during biofilm growth and their impact on bacterial clearance remain to be defined. We used a mouse model of catheter-associated biofilm infection to assess the functional importance of TLR2 and TLR9 in the host immune response during biofilm formation, because ligands for both receptors are present within the biofilm. Interestingly, neither TLR2 nor TLR9 impacted bacterial density or inflammatory mediator secretion during biofilm growth in vivo, suggesting that S. aureus biofilms circumvent these traditional bacterial recognition pathways. Several potential mechanisms were identified to account for biofilm evasion of innate immunity, including significant reductions in IL-1beta, TNF-alpha, CXCL2, and CCL2 expression during biofilm infection compared with the wound healing response elicited by sterile catheters, limited macrophage invasion into biofilms in vivo, and a skewing of the immune response away from a microbicidal phenotype as evidenced by decreases in inducible NO synthase expression concomitant with robust arginase-1 induction. Coculture studies of macrophages with S. aureus biofilms in vitro revealed that macrophages successful at biofilm invasion displayed limited phagocytosis and gene expression patterns reminiscent of alternatively activated M2 macrophages. Collectively, these findings demonstrate that S. aureus biofilms are capable of attenuating traditional host proinflammatory responses, which may explain why biofilm infections persist in an immunocompetent host. PMID- 21525384 TI - Analysis and modeling of the variable region of camelid single-domain antibodies. AB - Camelids have a special type of Ab, known as heavy chain Abs, which are devoid of classical Ab light chains. Relative to classical Abs, camelid heavy chain Abs (cAbs) have comparable immunogenicity, Ag recognition diversity and binding affinities, higher stability and solubility, and better manufacturability, making them promising candidates for alternate therapeutic scaffolds. Rational engineering of cAbs to improve therapeutic function requires knowledge of the differences of sequence and structural features between cAbs and classical Abs. In this study, amino acid sequences of 27 cAb variable regions (V(H)H) were aligned with the respective regions of 54 classical Abs to detect amino acid differences, enabling automatic identification of cAb V(H)H CDRs. CDR analysis revealed that the H1 often (and sometimes the H2) adopts diverse conformations not classifiable by established canonical rules. Also, although the cAb H3 is much longer than classical H3 loops, it often contains common structural motifs and sometimes a disulfide bond to the H1. Leveraging these observations, we created a Monte Carlo-based cAb V(H)H structural modeling tool, where the CDR H1 and H2 loops exhibited a median root-mean-square deviation to natives of 3.1 and 1.5 A, respectively. The protocol generated 8-12, 14-16, and 16-24 residue H3 loops with a median root-mean-square deviation to natives of 5.7, 4.5, and 6.8 A, respectively. The large deviation of the predicted loops underscores the challenge in modeling such long loops. cAb V(H)H homology models can provide structural insights into interaction mechanisms to enable development of novel Abs for therapeutic and biotechnological use. PMID- 21525386 TI - Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria. AB - Parasite burden predicts disease severity in malaria and risk of death in cerebral malaria patients. In murine experimental cerebral malaria (ECM), parasite burden and CD8(+) T cells promote disease by mechanisms that are not fully understood. We found that the majority of brain-recruited CD8(+) T cells expressed granzyme B (GzmB). Furthermore, gzmB(-/-) mice harbored reduced parasite numbers in the brain as a consequence of enhanced antiparasitic CD4(+) T cell responses and were protected from ECM. We showed in these ECM-resistant mice that adoptively transferred, Ag-specific CD8(+) T cells migrated to the brain, but did not induce ECM until a critical Ag threshold was reached. ECM induction was exquisitely dependent on Ag-specific CD8(+) T cell-derived perforin and GzmB, but not IFN-gamma. In wild-type mice, full activation of brain-recruited CD8(+) T cells also depended on a critical number of parasites in this tissue, which in turn, was sustained by these tissue-recruited cells. Thus, an interdependent relationship between parasite burden and CD8(+) T cells dictates the onset of perforin/GzmB-mediated ECM. PMID- 21525385 TI - Programmed death 1 regulates development of central memory CD8 T cells after acute viral infection. AB - The T cell response possesses a number of inhibitory receptors to regulate the extent of the antiviral response and prevent immune pathology. These receptors are generally transiently upregulated during an effector response and then downregulated during memory. Some inhibitory receptors, such as programmed death 1 (PD-1) and LAG-3, were shown to be aberrantly upregulated during memory to chronic lymphocytic choriomeningitis virus infection, limiting functional capabilities. However, little is known about the impact of inhibitory receptors on memory development during a normal CD8 T cell response to acute virus infection. Our previous data showed that PD-1 is aberrantly upregulated during a secondary response by memory CD8 T cells that were generated without CD4 T cell help. Therefore, we examined the role of PD-1 in memory differentiation during acute vaccinia virus infection in intact mice. In the absence of PD-1, the primary and memory CD8 T cell responses were enhanced. Moreover, there were distinct phenotypic and functional changes in the memory PD-1(-/-) CD8 T cells. Higher levels of CD62L, CD27, and CCR7 were detected; cells produced more IL-2 and made an enhanced secondary response. These changes indicate a skewing of the memory population toward the central memory phenotype in the absence of PD-1 signaling. PMID- 21525387 TI - Quantitative trait locus analysis, pathway analysis, and consomic mapping show genetic variants of Tnni3k, Fpgt, or H28 control susceptibility to viral myocarditis. AB - Coxsackievirus B3 (CVB3) infection is the most common cause of viral myocarditis. The pathogenesis of viral myocarditis is strongly controlled by host genetic factors. Although certain indispensable components of immunity have been identified, the genes and pathways underlying natural variation between individuals remain unclear. Previously, we isolated the viral myocarditis susceptibility 1 (Vms1) locus on chromosome 3, which influences pathogenesis. We hypothesized that confirmation and further study of Vms1 controlling CVB3 mediated pathology, combined with pathway analysis and consomic mapping approaches, would elucidate both pathological and protective mechanisms accounting for natural variation in response to CVB3 infection. Vms1 was originally mapped to chromosome 3 using a segregating cross between susceptible A/J and resistant B10.A mice. To validate Vms1, C57BL/6J-Chr 3(A)/NaJ (a chromosome substitution strain that carries a diploid A/J chromosome 3) were used to replicate susceptibility compared with resistant C57BL/6J (B6). A second segregating F2 cross was generated between these, confirming both the localization and effects of Vms1. Microarray analysis of the four strains (A/J, B10.A, C57BL/6J, and C57BL/6J-Chr 3(A)/NaJ) illuminated a core program of response to CVB3 in all strains that is comprised mainly of IFN-stimulated genes. Microarray analysis also revealed strain-specific differential expression programs and genes that may be prognostic or diagnostic of susceptibility to CVB3 infection. A combination of analyses revealed very strong evidence for the existence and location of Vms1. Differentially expressed pathways were identified by microarray, and candidate gene analysis revealed Fpgt, H28, and Tnni3k as likely candidates for Vms1. PMID- 21525388 TI - A new subset of CD103+CD8alpha+ dendritic cells in the small intestine expresses TLR3, TLR7, and TLR9 and induces Th1 response and CTL activity. AB - CD103(+) dendritic cells (DCs) are the major conventional DC population in the intestinal lamina propria (LP). Our previous report showed that a small number of cells in the LP could be classified into four subsets based on the difference in CD11c/CD11b expression patterns: CD11c(hi)CD11b(lo) DCs, CD11c(hi)CD11b(hi) DCs, CD11c(int)CD11b(int) macrophages, and CD11c(int)CD11b(hi) eosinophils. The CD11c(hi)CD11b(hi) DCs, which are CD103(+), specifically express TLR5 and induce the differentiation of naive B cells into IgA(+) plasma cells. These DCs also mediate the differentiation of Ag-specific Th17 and Th1 cells in response to flagellin. We found that small intestine CD103(+) DCs of the LP (LPDCs) could be divided into a small subset of CD8alpha(+) cells and a larger subset of CD8alpha( ) cells. Flow cytometry analysis revealed that CD103(+)CD8alpha(+) and CD103(+)CD8alpha(-) LPDCs were equivalent to CD11c(hi)CD11b(lo) and CD11c(hi)CD11b(hi) subsets, respectively. We analyzed a novel subset of CD8alpha(+) LPDCs to elucidate their immunological function. CD103(+)CD8alpha(+) LPDCs expressed TLR3, TLR7, and TLR9 and produced IL-6 and IL-12p40, but not TNF alpha, IL-10, or IL-23, following TLR ligand stimulation. CD103(+)CD8alpha(+) LPDCs did not express the gene encoding retinoic acid-converting enzyme Raldh2 and were not involved in T cell-independent IgA synthesis or Foxp3(+) regulatory T cell induction. Furthermore, CD103(+)CD8alpha(+) LPDCs induced Ag-specific IgG in serum, a Th1 response, and CTL activity in vivo. Accordingly, CD103(+)CD8alpha(+) LPDCs exhibit a different function from CD103(+)CD8alpha(-) LPDCs in active immunity. This is the first analysis, to our knowledge, of CD8alpha(+) DCs in the LP of the small intestine. PMID- 21525389 TI - Stat4 is critical for the balance between Th17 cells and regulatory T cells in colitis. AB - Th17 play a central role in autoimmune inflammatory responses. Th1 are also necessary for autoimmune disease development. The interplay of Th1 signals and how they coordinate with Th17 during inflammatory disease pathogenesis are incompletely understood. In this study, by adding Stat4 deficiency to Stat6/T-bet double knockout, we further dissected the role of Stat4 in Th1 development and colitis induction. We showed that in the absence of the strong Th2 mediator Stat6, neither Stat4 nor T-bet is required for IFN-gamma production and Th1 development. However, addition of Stat4 deficiency abolished colitis induced by Stat6/T-bet double-knockout cells, despite Th1 and Th17 responses. The failure of colitis induction by Stat4/Stat6/T-bet triple-knockout cells is largely due to elevated Foxp3(+) regulatory T cell (Treg) development. These results highlight the critical role of Stat4 Th1 signals in autoimmune responses in suppressing Foxp3(+) Treg responses and altering the balance between Th17 and Tregs to favor autoimmune disease. PMID- 21525390 TI - Priming of eosinophils by GM-CSF is mediated by protein kinase CbetaII phosphorylated L-plastin. AB - The priming of eosinophils by cytokines leading to augmented response to chemoattractants and degranulating stimuli is a characteristic feature of eosinophils in the course of allergic inflammation and asthma. Actin reorganization and integrin activation are implicated in eosinophil priming by GM CSF, but their molecular mechanism of action is unknown. In this regard, we investigated the role of L-plastin, an eosinophil phosphoprotein that we identified from eosinophil proteome analysis. Phosphoproteomic analysis demonstrated the upregulation of phosphorylated L-plastin after eosinophil stimulation with GM-CSF. Additionally, coimmunoprecipitation studies demonstrated a complex formation of phosphorylated L-plastin with protein kinase CbetaII (PKCbetaII), GM-CSF receptor alpha-chain, and two actin-associated proteins, paxilin and cofilin. Inhibition of PKCbetaII with 4,5-bis(4 fluoroanilino)phtalimide or PKCbetaII-specific small interfering RNA blocked GM CSF-induced phosphorylation of L-plastin. Furthermore, flow cytometric analysis also showed an upregulation of alpha(M)beta(2) integrin, which was sensitive to PKCbetaII inhibition. In chemotaxis assay, GM-CSF treatment allowed eosinophils to respond to lower concentrations of eotaxin, which was abrogated by the above mentioned PKCbetaII inhibitors. Similarly, inhibition of PKCbetaII blocked GM-CSF induced priming for degranulation as assessed by release of eosinophil cationic protein and eosinophil peroxidase in response to eotaxin. Importantly, eosinophil stimulation with a synthetic L-plastin peptide (residues 2-19) phosphorylated on Ser(5) upregulated alpha(M)beta(2) integrin expression and increased eosinophil migration in response to eotaxin independent of GM-CSF stimulation. Our results establish a causative role for PKCbetaII and L-plastin in linking GM-CSF-induced eosinophil priming for chemotaxis and degranulation to signaling events associated with integrin activation via induction of PKCbetaII-mediated L-plastin phosphorylation. PMID- 21525391 TI - The pleckstrin homology domain in the SKAP55 adapter protein defines the ability of the adapter protein ADAP to regulate integrin function and NF-kappaB activation. AB - Adhesion and degranulation promoting adapter protein (ADAP) is a multifunctional hematopoietic adapter protein that regulates TCR-dependent increases in both integrin function and activation of the NF-kappaB transcription factor. Activation of integrin function requires both ADAP and the ADAP-associated adapter Src kinase-associated phosphoprotein of 55 kDa (SKAP55). In contrast, ADAP-mediated regulation of NF-kappaB involves distinct binding sites in ADAP that promote the inducible association of ADAP, but not SKAP55, with the CARMA1 adapter and the TAK1 kinase. This suggests that the presence or absence of associated SKAP55 defines functionally distinct pools of ADAP. To test this hypothesis, we developed a novel SKAP-ADAP chimeric fusion protein and demonstrated that physical association of ADAP with SKAP55 is both sufficient and necessary for the rescue of integrin function in ADAP-deficient T cells. Similar to wild-type ADAP, the SKAP-ADAP chimera associated with the LFA-1 integrin after TCR stimulation. Although the SKAP-ADAP chimera contains the CARMA1 and TAK1 binding sequences from ADAP, expression of the chimera does not restore NF-kappaB signaling in ADAP(-/-) T cells. A single point mutation in the pleckstrin homology domain of SKAP55 (R131M) blocks the ability of the SKAP-ADAP chimera to restore integrin function and to associate with LFA-1. However, the R131M mutant was now able to restore NF-kappaB signaling in ADAP-deficient T cells. We conclude that integrin regulation by ADAP involves the recruitment of ADAP to LFA 1 integrin complexes by the pleckstrin homology domain of SKAP55, and this recruitment restricts the ability of ADAP to interact with the NF-kappaB signalosome and regulate NF-kappaB activation. PMID- 21525392 TI - Somatically diversified and proliferating transitional B cells: implications for peripheral B cell homeostasis. AB - The peripheral B cell compartment in mice and humans is maintained by continuous production of transitional B cells in the bone marrow. In other species, however, including rabbits, B lymphopoiesis in the bone marrow abates early in life, and it is unclear how the peripheral B cell compartment is maintained. We identified transitional B cells in rabbits and classified them into T1 (CD24(high)CD21(low)) and T2 (CD24(high)CD21(+)) B cell subsets. By neutralizing B cell-activating factor in vivo, we found an arrest in peripheral B cell development at the T1 B cell stage. Surprisingly, T1 B cells were present in GALT, blood, and spleen of adult rabbits, long after B lymphopoiesis was arrested. T1 B cells were distinct from their counterparts in other species because they are proliferating and the Ig genes are somatically diversified. We designate these newly described cells as T1d B cells and propose a model in which they develop in GALT, self renew, continuously differentiate into mature B cells, and thereby maintain peripheral B cell homeostasis in adults in the absence of B lymphopoiesis. PMID- 21525394 TI - Optimizing drug development and use in patients with kidney disease. PMID- 21525393 TI - The immunosuppressive role of IL-32 in lymphatic tissue during HIV-1 infection. AB - One pathological hallmark of HIV-1 infection is chronic activation of the immune system, driven, in part, by increased expression of proinflammatory cytokines. The host attempts to counterbalance this prolonged immune activation through compensatory mediators of immune suppression. We recently identified a gene encoding the proinflammatory cytokine IL-32 in microarray studies of HIV-1 infection in lymphatic tissue (LT) and show in this study that increased expression of IL-32 in both gut and LT of HIV-1-infected individuals may have a heretofore unappreciated role as a mediator of immune suppression. We show that: 1) IL-32 expression is increased in CD4(+) T cells, B cells, macrophages, dendritic cells, and epithelial cells in vivo; 2) IL-32 induces the expression of immunosuppressive molecules IDO and Ig-like transcript 4 in immune cells in vitro; and 3) in vivo, IL-32-associated IDO/Ig-like transcript 4 expression in LT macrophages and gut epithelial cells decreases immune activation but also may impair host defenses, supporting productive viral replication, thereby accounting for the correlation between IL-32 levels and HIV-1 replication in LT. Thus, during HIV-1 infection, we propose that IL-32 moderates chronic immune activation to avert associated immunopathology but at the same time dampens the antiviral immune response and thus paradoxically supports HIV-1 replication and viral persistence. PMID- 21525395 TI - A molecular and phenotypic integrative approach to identify a no-effect dose level for antiandrogen-induced testicular toxicity. AB - The safety assessment of chemicals for humans relies on identifying no-observed adverse effect levels (NOAELs) in animal toxicity studies using standard methods. With the advent of high information content technologies, especially microarrays, it is pertinent to determine the impact of molecular data on the NOAELs. Consequently, we conducted an integrative study to identify a no-transcriptomic effect dose using microarray analyses coupled with quantitative reverse transcriptase PCR (RT-qPCR) and determined how this correlated with the NOAEL. We assessed the testicular effects of the antiandrogen, flutamide (FM), in a rat 28 day toxicity study using doses of 0.2-30 mg/kg/day. Plasma testosterone levels and testicular histopathology indicated a NOAEL of 1 mg/kg/day. A no-effect dose of 0.2 mg/kg/day was established based on molecular data relevant to the phenotypic changes. We observed differential gene expression starting from 1 mg/kg/day and a deregulation of more than 1500 genes at 30 mg/kg/day. Dose related changes were identified for the major pathways (e.g., fatty acid metabolism) associated with the testicular lesion (Leydig cell hyperplasia) that were confirmed by RT-qPCR. These data, along with protein accumulation profiles and FM metabolite concentrations in testis, supported the no-effect dose of 0.2 mg/kg/day. Furthermore, the microarray data indicated a dose-dependent change in the fatty acid catabolism pathway, a biological process described for the first time to be affected by FM in testicular tissue. In conclusion, the present data indicate the existence of a transcriptomic threshold, which must be exceeded to progress from a normal state to an adaptative state and subsequently to adverse toxicity. PMID- 21525396 TI - Two roads diverge: weight loss interventions and circulating amino acids. AB - In this issue of Science Translational Medicine, Laferrere and colleagues describe a metabolite profiling approach to investigate changes in the circulating metabolome after equivalent weight loss spurred by either gastric bypass surgery (GBP) or dietary intervention. The results reveal that GBP enhances branched chain amino acid metabolism by mechanisms separate from weight loss. These observations raise the possibility that changes in circulating amino acids play a role in the correction of glycemic control observed shortly after GBP. PMID- 21525397 TI - The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. AB - Small-molecule compounds approved for use as drugs may be "repurposed" for new indications and studied to determine the mechanisms of their beneficial and adverse effects. A comprehensive collection of all small-molecule drugs approved for human use would be invaluable for systematic repurposing across human diseases, particularly for rare and neglected diseases, for which the cost and time required for development of a new chemical entity are often prohibitive. Previous efforts to build such a comprehensive collection have been limited by the complexities, redundancies, and semantic inconsistencies of drug naming within and among regulatory agencies worldwide; a lack of clear conceptualization of what constitutes a drug; and a lack of access to physical samples. We report here the creation of a definitive, complete, and nonredundant list of all approved molecular entities as a freely available electronic resource and a physical collection of small molecules amenable to high-throughput screening. PMID- 21525398 TI - Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells. AB - Although advanced-stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of antitumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred antitumor CD8(+) T lymphocytes (CTLs) have had limited life spans unless the host has been manipulated. To generate CTLs that have an intrinsic capacity to persist in vivo, we developed a human artificial antigen-presenting cell system that can educate antitumor CTLs to acquire both a central memory and an effector memory phenotype as well as the capacity to survive in culture for prolonged periods of time. We examined whether antitumor CTLs generated using this system could function and persist in patients. We showed that MART1-specific CTLs, educated and expanded using our artificial antigen-presenting cell system, could survive for prolonged periods in advanced-stage melanoma patients without previous conditioning or cytokine treatment. Moreover, these CTLs trafficked to the tumor, mediated biological and clinical responses, and established antitumor immunologic memory. Therefore, this approach may broaden the availability of adoptive cell therapy to patients both alone and in combination with other therapeutic modalities. PMID- 21525400 TI - Circulating tumor cell detection and transcriptomic profiles in early breast cancer patients. PMID- 21525399 TI - Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. AB - Glycemic control is improved more after gastric bypass surgery (GBP) than after equivalent diet-induced weight loss in patients with morbid obesity and type 2 diabetes mellitus. We applied metabolomic profiling to understand the mechanisms of this better metabolic response after GBP. Circulating amino acids (AAs) and acylcarnitines (ACs) were measured in plasma from fasted subjects by targeted tandem mass spectrometry before and after a matched 10-kilogram weight loss induced by GBP or diet. Total AAs and branched-chain AAs (BCAAs) decreased after GBP, but not after dietary intervention. Metabolites derived from BCAA oxidation also decreased only after GBP. Principal components (PC) analysis identified two major PCs, one composed almost exclusively of ACs (PC1) and another with BCAAs and their metabolites as major contributors (PC2). PC1 and PC2 were inversely correlated with pro-insulin concentrations, the C-peptide response to oral glucose, and the insulin sensitivity index after weight loss, whereas PC2 was uniquely correlated with levels of insulin resistance (HOMA-IR). These data suggest that the enhanced decrease in circulating AAs after GBP occurs by mechanisms other than weight loss and may contribute to the better improvement in glucose homeostasis observed with the surgical intervention. PMID- 21525401 TI - The presence of circulating tumor cells (CTCs) correlates with lymph node metastasis in nonresectable squamous cell carcinoma of the head and neck region (SCCHN). AB - BACKGROUND: The mechanisms regulating tumor cell dissemination in locally advanced squamous cell carcinoma of the head and neck region (SCCHN) are largely unresolved. We assessed the frequency of circulating tumor cells (CTCs), their association with clinicopathologic parameters and their kinetics during radiochemotherapy. PATIENTS AND METHODS: Peripheral blood samples from 42 patients with locally advanced SCCHN were included. CTCs were detected using flow cytometric analysis of CD45-epithelial cell adhesion molecule+cytokeratin+ cells and results were validated by nested RT-PCR analysis of circulating epidermal growth factor receptor transcripts. The association between the presence of CTCs and T stage, tumor volume, N stage and human papillomavirus status was evaluated. The influence of radiochemotherapy on CTC numbers was determined. RESULTS: CTCs were detected in 18 of 42 SCCHN patients (43%), with a mean +/- standard deviation of 1.7 +/- 0.9 CTCs per 3.75 ml blood. We observed no significant correlation between the presence of CTCs and T stage or tumor volume. However, a nodal stage of N2b or higher was associated with higher frequency of CTCs. Though concurrent radiochemotherapy reduced their frequency, CTCs persisted during treatment in 20% of cases. CONCLUSIONS: Detection of CTCs correlates with regional metastasis in inoperable SCCHN. Further follow-up is needed to evaluate the prognostic significance of CTC detection, in addition to clinical staging of lymph nodes, for regional or distant recurrence. PMID- 21525402 TI - Breast cancer subtypes and outcome after local and regional relapse. AB - BACKGROUND: To evaluate the outcome of breast cancer patients after locoregional recurrence (LRR) according to tumor biological features evaluated at first diagnosis and at the time of recurrence. PATIENTS AND METHODS: We collected information on all consecutive breast cancer patients operated at the European Institute of Oncology between 1994 and 2005. The tumor characteristics and subsequent outcome of patients who experienced LRR were analyzed. RESULTS: Two hundred and seventy nine patients with LRR were identified, 197 and 82 patients with local and regional recurrence respectively. The overall discordance rate between primary cancer and LRR was 9% for estrogen receptor expression, 22% for progesterone receptor and 4% for human epidermal growth factor receptor 2. For patients with regional recurrence, the risk of distant metastasis was significantly higher compared with local relapse in case of late recurrence (hazard ratio [HR] = 2.76; 95% CI 1.31-5.85). Patients with triple-negative breast cancer at LRR experienced a higher risk of subsequent relapse (HR 2.87 [1.67-4.91]) and death (HR 2.00 [1.25-3.19]). CONCLUSION: LRR correlates with a high risk of subsequent events and death in particular in patients with triple negative subtype. PMID- 21525403 TI - Risk of second cancers in Waldenstrom macroglobulinemia. AB - BACKGROUND: An increased incidence of second cancers has been reported in lymphoproliferative disorders. PATIENTS AND METHODS: We assessed the frequency, characteristics and predictive factors of second cancers in 230 patients with Waldenstrom macroglobulinemia (WM) and compared the incidence of second cancers in WM with that of an age- and sex-matched control population. RESULTS: Twenty two patients (10%) developed solid cancers and 10 (4%) second hematologic malignancies. In a competing risk model, the cumulative incidence of solid cancers was 12% at 10 years and 17% at 15 years while the incidence of hematologic malignancies was 6% and 8%, respectively. The overall risk of second cancer in WM was 1.69 times higher than expected (P = 0.002). WM patients were at increased risk for diffuse large B-cell lymphoma [standardized incidence ratio (SIR) 9.24, P < 0.0001], myelodisplastic syndrome/acute myeloid leukemia (SIR 8.4, P < 0.0001), brain cancer (SIR 8.05, P = 0.0004). The risk of a second hematologic malignancy was fourfold higher in patients previously treated, though not reaching statistical significance (P = 0.19). CONCLUSIONS: WM patients are at higher risk of second cancers as compared with the general population. The sample size does not allow firm conclusions about the effect of therapy on the development of second cancers. PMID- 21525404 TI - Rituxan is not associated with Stevens Johnson Syndrome. PMID- 21525405 TI - Different hepatitis B carrier categories need different management strategies in case of immunosuppressive chemotherapeutic regimens. PMID- 21525406 TI - Induction chemotherapy followed by concomitant radiotherapy and weekly cisplatin versus the same concomitant chemoradiotherapy in patients with nasopharyngeal carcinoma: a randomized phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation. AB - BACKGROUND: Concomitant administration of radiation therapy (RT) and chemotherapy with cisplatin (CCRT) is considered standard treatment in patients with locally advanced nasopharyngeal cancer (LA-NPC). The role of induction chemotherapy (IC) when followed by CCRT in improving locoregional control remains controversial. PATIENTS AND METHODS: Totally, 141 eligible patients with LA-NPC were randomized to either three cycles of IC with cisplatin 75 mg/m(2), epirubicin 75 mg/m(2) and paclitaxel (Taxol) 175 mg/m(2) (CEP) every 3 weeks followed by definitive RT (70 Gy) and concomitant weekly infusion of cisplatin 40 mg/m(2) (investigational arm, 72 patients) or to the same CCRT regimen alone (control arm, 69 patients). RESULTS: Sixty-two patients (86%) received three cycles of IC. No difference between the arms was observed in the number of patients who completed RT (61 versus 64, P = 018). Overall and complete response rates were very similar in the two arms and so were 3-year progression-free and overall survival rates. Grade III or IV toxic effects from IC were infrequent, apart of alopecia. Mucositis, weight loss and leukopenia were the most prominent side-effects from CCRT. CONCLUSION: IC with three cycles of CEP when followed by CCRT did not significantly improve response rates and/or survival compared with that of CCRT alone. PMID- 21525407 TI - TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. AB - The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and beta phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HT(1A) receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1(-/-) mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders. PMID- 21525408 TI - Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors. AB - Human embryonic stem cells (hESCs) hold enormous promise for regenerative medicine. Typically, hESC-based applications would require their in vitro differentiation into a desirable homogenous cell population. A major challenge of the current hESC differentiation paradigm is the inability to effectively capture and, in the long-term, stably expand primitive lineage-specific stem/precursor cells that retain broad differentiation potential and, more importantly, developmental stage-specific differentiation propensity. Here, we report synergistic inhibition of glycogen synthase kinase 3 (GSK3), transforming growth factor beta (TGF-beta), and Notch signaling pathways by small molecules can efficiently convert monolayer cultured hESCs into homogenous primitive neuroepithelium within 1 wk under chemically defined condition. These primitive neuroepithelia can stably self-renew in the presence of leukemia inhibitory factor, GSK3 inhibitor (CHIR99021), and TGF-beta receptor inhibitor (SB431542); retain high neurogenic potential and responsiveness to instructive neural patterning cues toward midbrain and hindbrain neuronal subtypes; and exhibit in vivo integration. Our work uniformly captures and maintains primitive neural stem cells from hESCs. PMID- 21525409 TI - Rapid evolution of disease resistance is accompanied by functional changes in gene expression in a wild bird. AB - Wild organisms are under increasing pressure to adapt rapidly to environmental changes. Predicting the impact of these changes on natural populations requires an understanding of the speed with which adaptive phenotypes can arise and spread, as well as of the underlying mechanisms. However, our understanding of these parameters is poor in natural populations. Here we use experimental and molecular approaches to investigate the recent emergence of resistance in eastern populations of North American house finches (Carpodacus mexicanus) to Mycoplasma galliseptum (MG), a severe conjunctivitis-causing bacterium. Two weeks following an experimental infection that took place in 2007, finches from eastern US populations with a 12-y history of exposure to MG harbored 33% lower MG loads in their conjunctivae than finches from western US populations with no prior exposure to MG. Using a cDNA microarray, we show that this phenotypic difference in resistance was associated with differences in splenic gene expression, with finches from the exposed populations up-regulating immune genes postinfection and those from the unexposed populations generally down-regulating them. The expression response of western US birds to experimental infection in 2007 was more similar to that of the eastern US birds studied in 2000, 7 y earlier in the epizootic, than to that of eastern birds in 2007. These results support the hypothesis that resistance has evolved by natural selection in the exposed populations over the 12 y of the epizootic. We hypothesize that host resistance arose and spread from standing genetic variation in the eastern US and highlight that natural selection can lead to rapid phenotypic evolution in populations when acting on such variation. PMID- 21525411 TI - Nitrososphaera viennensis, an ammonia oxidizing archaeon from soil. AB - Genes of archaea encoding homologues of ammonia monooxygenases have been found on a widespread basis and in large amounts in almost all terrestrial and marine environments, indicating that ammonia oxidizing archaea (AOA) might play a major role in nitrification on Earth. However, only one pure isolate of this group from a marine environment has so far been obtained, demonstrating archaeal ammonia oxidation coupled with autotrophic growth similar to the bacterial counterparts. Here we describe the cultivation and isolation of an AOA from soil. It grows on ammonia or urea as an energy source and is capable of using higher ammonia concentrations than the marine isolate, Nitrosopumilus maritimus. Surprisingly, although it is able to grow chemolithoautotrophically, considerable growth rates of this strain are obtained only upon addition of low amounts of pyruvate or when grown in coculture with bacteria. Our findings expand the recognized metabolic spectrum of AOA and help explain controversial results obtained in the past on the activity and carbon assimilation of these globally distributed organisms. PMID- 21525412 TI - Acetylation of lysine 120 of p53 endows DNA-binding specificity at effective physiological salt concentration. AB - Lys120 in the DNA-binding domain (DBD) of p53 becomes acetylated in response to DNA damage. But, the role and effects of acetylation are obscure. We prepared p53 specifically acetylated at Lys120, AcK120p53, by in vivo incorporation of acetylated lysine to study biophysical and structural consequences of acetylation that may shed light on its biological role. Acetylation had no affect on the overall crystal structure of the DBD at 1.9-A resolution, but significantly altered the effects of salt concentration on specificity of DNA binding. p53 binds DNA randomly in vitro at effective physiological salt concentration and does not bind specifically to DNA or distinguish among its different response elements until higher salt concentrations. But, on acetylation, AcK120p53 exhibited specific DNA binding and discriminated among response elements at effective physiological salt concentration. AcK120p53 and p53 had the highest affinity to the same DNA sequence, although acetylation reduced the importance of the consensus C and G at positions 4 and 7, respectively. Mass spectrometry of p53 and AcK120p53 DBDs bound to DNA showed they preferentially segregated into complexes that were either DNA(p53DBD)(4) or DNA(AcK120DBD)(4), indicating that the different DBDs prefer different quaternary structures. These results are consistent with electron microscopy observations that p53 binds to nonspecific DNA in different, relaxed, quaternary states from those bound to specific sequences. Evidence is accumulating that p53 can be sequestered by random DNA, and target search requires acetylation of Lys120 and/or interaction with other factors to impose specificity of binding via modulating changes in quaternary structure. PMID- 21525413 TI - Feed-forward mechanism of converting biochemical cooperativity to mitotic processes at the kinetochore plate. AB - The feed-forward mechanism is observed in some of the intracellular events, such as metabolic and transcriptional regulatory networks, but not in dynamic mitotic processes. Mammalian polo-like kinase 1 (Plk1) rapidly accumulates at centrosomes and kinetochores as cells enter mitosis. Plk1 function is spatially regulated through the targeting activity of the polo-box domain (PBD) that binds to a phosphoepitope generated by either cyclin dependent kinase 1 (Cdk1) (non-self priming) or Plk1 itself (self-priming). "Non-self-priming and binding" is thought to ensure the orderly execution of cell cycle events. The physiological significance of the "self-priming and binding" is unknown. Using a pair of ELISA, here we demonstrated that mutations of the self-priming site of a kinetochore component, PBIP1/MLF1IP/KLIP1/CENP-50/CENP-U (PBIP1), to a Cdk1-dependent non self-priming site abolished product-activated cooperativity in the formation of the Plk1-PBIP1 complex. Both PBD-dependent "two-dimensional" interaction with surface-restricted PBIP1 and subsequent phosphorylation of PBIP1 by anchored Plk1 were crucial to cooperatively generate the Plk1-PBIP1 complex. Highlighting the importance of this mechanism, failure in this process resulted in improper Plk1 recruitment to kinetochores, mitotic arrest, chromosome missegregation, and apoptosis. Thus, Plk1 PBD-dependent biochemical cooperativity is tightly coupled to mitotic events at the kinetochore plate through a product-activated, feed forward mechanism. Given the critical role of self-priming and binding in the recruitment of Plk1 to surface-confined structures, such as centrosomes, kinetochores, and midbody, we propose that the observed feed-forward mechanism serves as a fundamental biochemical process that ensures dynamic nature of Plk1 localization to and delocalization from these subcellular locations. PMID- 21525414 TI - Electron delocalization in the S1 and T1 metal-to-ligand charge transfer states of trans-substituted metal quadruply bonded complexes. AB - The singlet S(1) and triplet T(1) photoexcited states of the compounds containing MM quadruple bonds trans-M(2)(T(i)PB)(2)(O(2)CC(6)H(4)-4-CN)(2), where T(i)PB = 2,4,6-triisopropylbenzoate and M = Mo (I) or M = W (I(')), and trans M(2)(O(2)CMe)(2)((N[(i) Pr ])(2)CC = CC(6)H(5))(2), where M = Mo (II) and M = W (II(')), have been investigated by a variety of spectroscopic techniques including femtosecond time-resolved infrared spectroscopy. The singlet states are shown to be delocalized metal-to-ligand charge transfer (MLCT) states for I and I(') but localized for II and II(') involving the cyanobenzoate or amidinate ligands, respectively. The triplet states are MoModeltadelta* for both I and II but delocalized (3)MLCT for I(') and localized (3)MLCT for II('). These differences arise from consideration of the relative orbital energies of the M(2)delta or M(2)delta* and the ligand pi(*) as well as the magnitudes of orbital overlap. PMID- 21525415 TI - Equivalence of Heegaard Floer homology and embedded contact homology via open book decompositions. AB - We sketch the proof of the equivalence between the hat versions of Heegaard Floer homology and embedded contact homology (ECH). The key point is to express these two Floer homology theories in terms of an open book decomposition of the ambient manifold. PMID- 21525416 TI - Heat shock protein 90 from Escherichia coli collaborates with the DnaK chaperone system in client protein remodeling. AB - Molecular chaperones are proteins that assist the folding, unfolding, and remodeling of other proteins. In eukaryotes, heat shock protein 90 (Hsp90) proteins are essential ATP-dependent molecular chaperones that remodel and activate hundreds of client proteins with the assistance of cochaperones. In Escherichia coli, the activity of the Hsp90 homolog, HtpG, has remained elusive. To explore the mechanism of action of E. coli Hsp90, we used in vitro protein reactivation assays. We found that E. coli Hsp90 promotes reactivation of heat inactivated luciferase in a reaction that requires the prokaryotic Hsp70 chaperone system, known as the DnaK system. An Hsp90 ATPase inhibitor, geldanamycin, inhibits luciferase reactivation demonstrating the importance of the ATP-dependent chaperone activity of E. coli Hsp90 during client protein remodeling. Reactivation also depends upon the ATP-dependent chaperone activity of the DnaK system. Our results suggest that the DnaK system acts first on the client protein, and then E. coli Hsp90 and the DnaK system collaborate synergistically to complete remodeling of the client protein. Results indicate that E. coli Hsp90 and DnaK interact in vivo and in vitro, providing additional evidence to suggest that E. coli Hsp90 and the DnaK system function together. PMID- 21525417 TI - Drug-inducible gene recombination by the Dppa3-MER Cre MER transgene in the developmental cycle of the germ cell lineage in mice. AB - Germ cells ensure the diversification and totipotency of genetic information via the elaborate genetic and epigenetic regulation of the genome architecture during their development. To understand the mechanism underlying the regulation of genome function in germ cells, it is of primary importance to develop systems in which gene function can be regulated at desired time points during their development. Here, we report the generation of transgenic strains that express Cre recombinase flanked by the ligand-binding domains of murine estrogen receptor (MER Cre MER [MCM]) under the control of the regulatory elements of the Dppa3 (also known as Stella or Pgc7) gene. On the administration of 4-hydroxytamoxifen (4-OHT), the Dppa3-MCM strains recombined the sequence flanked by the loxP elements (the floxed sequence) specifically in primordial germ cells as early as Embryonic Day (E) 7.0, and this recombination became robust after E9.5. Furthermore, these strains exhibited efficient and specific recombination of the floxed sequence during the growth of oocytes and in preimplantation embryos in the 4-OHT-dependent manner. Thus, these Dppa3-MCM strains offer valuable opportunities to explore gene function in both loss-of-function and gain-of function experiments at a variety of time points during germ cell development. PMID- 21525418 TI - Improving quality of Food Frequency Questionnaire response in low-income Mexican American children. AB - The authors evaluated the validity and reliability of the Block Kids Food Frequency Questionnaire (BKFFQ) and the Block Kid Screener (BKScreener) in Mexican American children living along the Texas-Mexico border who participated in the National Institutes of Health-funded Proyecto Bienestar Laredo. The Bienestar/NEEMA health program is a school-based diabetes and obesity control program, and the Proyecto Bienestar Laredo is the translation of the Bienestar/NEEMA health program to 38 elementary schools in Laredo, Texas. Par ticipants included 2,376 eight-year-old boys (48%) and girls (52%) from two school districts in Laredo. Two Food Frequency Questionnaire (BKFFQ and BKScreener) dietary intakes were collected, and an expert panel of nutritionist assigned a classification response quality of "Good," "Questionable," and "Poor," based on playfulness (systematic or nonrandom) patterns and completion rates. In addition, both instruments were assessed for reliability (test-retest) in 138 students from a San Antonio School District. Children's height, weight, percentage body fat, reported family history of diabetes, and Texas Assessments of Knowledge and Skills in reading and mathematics scores were collected. This study showed that for Mexican American children living along the Texas-Mexico border, within the time constraints of the classroom, BKScreener yielded better data than the BKFFQ. PMID- 21525419 TI - Your body is the temple: impact of a spiritually based colorectal cancer educational intervention delivered through community health advisors. AB - Colorectal cancer (CRC) is third in cancer incidence and mortality, due in part to lack of awareness and low rates of screening. The purpose of the present study was to evaluate the efficacy of a spiritually based CRC educational intervention delivered by trained Community Health Advisors, in Alabama churches. The aim of the intervention was to increase knowledge and awareness of CRC and early detection, and to eventually increase CRC screening rates. Participants age eligible for screening (N = 122) completed baseline, 6-month, and 12-month surveys by telephone. Increases in CRC knowledge, perceived benefits of CRC screening, and awareness of the screening modalities and decreases in perceived barriers to screening suggested that this type of intervention may be promising for CRC control and should be examined further. PMID- 21525420 TI - Finding common ground: perspectives on community-based childhood obesity prevention. AB - To support successful and inclusive community organizing for childhood obesity prevention, this research identified stakeholder perspectives on what communities should do to prevent childhood obesity. It employed factor analysis on statement sorts (Q methodology) conducted by 95 people in an upstate New York community. These participants sorted 36 statements about the issue by how much he or she agreed or disagreed with each. Participants were recruited through strategic snowball sampling to sample a variety of perspectives. The four resulting factors, or perspectives, were interpreted in the context of presort demographic surveys and postsort interviews. This research found one stance that fits the environmental perspective common in public health. The other three factors indicate important variations among perspectives centered on individual responsibility, ranging from libertarian to technocratic views. However, overall, results revealed a substantial degree of agreement among the four perspectives, including on providing access to family activities and on making fruits and vegetables more available and affordable, for example, through subsidies. This article points to common ground for community action on childhood obesity prevention, highlights areas likely to generate considerable contention, and shows whose views are not being accounted for in, at least, this community's childhood obesity prevention project. PMID- 21525421 TI - Assessing the dependence of sensitivity and specificity on prevalence in meta analysis. AB - We consider modeling the dependence of sensitivity and specificity on the disease prevalence in diagnostic accuracy studies. Many meta-analyses compare test accuracy across studies and fail to incorporate the possible connection between the accuracy measures and the prevalence. We propose a Pearson type correlation coefficient and an estimating equation-based regression framework to help understand such a practical dependence. The results we derive may then be used to better interpret the results from meta-analyses. In the biomedical examples analyzed in this paper, the diagnostic accuracy of biomarkers are shown to be associated with prevalence, providing insights into the utility of these biomarkers in low- and high-prevalence populations. PMID- 21525422 TI - Bayesian evidence synthesis for a transmission dynamic model for HIV among men who have sex with men. AB - Understanding infectious disease dynamics and the effect on prevalence and incidence is crucial for public health policies. Disease incidence and prevalence are typically not observed directly and increasingly are estimated through the synthesis of indirect information from multiple data sources. We demonstrate how an evidence synthesis approach to the estimation of human immunodeficiency virus (HIV) prevalence in England and Wales can be extended to infer the underlying HIV incidence. Diverse time series of data can be used to obtain yearly "snapshots" (with associated uncertainty) of the proportion of the population in 4 compartments: not at risk, susceptible, HIV positive but undiagnosed, and diagnosed HIV positive. A multistate model for the infection and diagnosis processes is then formulated by expressing the changes in these proportions by a system of differential equations. By parameterizing incidence in terms of prevalence and contact rates, HIV transmission is further modeled. Use of additional data or prior information on demographics, risk behavior change and contact parameters allows simultaneous estimation of the transition rates, compartment prevalences, contact rates, and transmission probabilities. PMID- 21525423 TI - Looking into posterior cortical atrophy: providing insight into Alzheimer disease. PMID- 21525424 TI - Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution. AB - BACKGROUND/OBJECTIVE: Patients with posterior cortical atrophy (PCA) often have Alzheimer disease (AD) at autopsy, yet are cognitively and anatomically distinct from patients with clinical AD. We sought to compare the distribution of beta amyloid and glucose metabolism in PCA and AD in vivo using Pittsburgh compound B (PiB) and FDG-PET. METHODS: Patients with PCA (n = 12, age 57.5 +/- 7.4, Mini Mental State Examination [MMSE] 22.2 +/- 5.1), AD (n = 14, age 58.8 +/- 9.6, MMSE 23.8 +/- 6.7), and cognitively normal controls (NC, n = 30, age 73.6 +/- 6.4) underwent PiB and FDG-PET. Group differences in PiB distribution volume ratios (DVR, cerebellar reference) and FDG uptake (pons-averaged) were assessed on a voxel-wise basis and by comparing binding in regions of interest (ROIs). RESULTS: Compared to NC, both patients with AD and patients with PCA showed diffuse PiB uptake throughout frontal, temporoparietal, and occipital cortex (p < 0.0001). There were no regional differences in PiB binding between PCA and AD even after correcting for atrophy. FDG patterns in PCA and AD were distinct: while both groups showed hypometabolism compared to NC in temporoparietal cortex and precuneus/posterior cingulate, patients with PCA further showed hypometabolism in inferior occipitotemporal cortex compared to both NC and patients with AD (p < 0.05). Patients with AD did not show areas of relative hypometabolism compared to PCA. CONCLUSIONS: Fibrillar amyloid deposition in PCA is diffuse and similar to AD, while glucose hypometabolism extends more posteriorly into occipital cortex. Further studies are needed to determine the mechanisms of selective network degeneration in focal variants of AD. PMID- 21525425 TI - CSF biomarkers in posterior cortical atrophy. AB - OBJECTIVE: To describe CSF biomarker profiles in posterior cortical atrophy (PCA), which induces high-order visual deficits often associated with Alzheimer disease (AD) pathology, and relate these findings to clinical and neuropsychological assessment. METHODS: This prospective observational study included 22 patients with PCA who underwent CSF biomarker analysis of total tau (t-tau), phosphorylated tau on amino acid 181 (p-tau181), and amyloid beta (Abeta(42)). At group level, the CSF profiles of patients with PCA were compared to those of patients with typical AD and patients with other dementia (OD). Individually, the clinical presentation of patients with PCA was correlated to their CSF profile to assess the predictability of clinical features for diagnosis of underlying AD pathology. RESULTS: At group level, the PCA biomarker profile was not different from that of the AD group, but very different from that of the OD group (p < 0.001). More than 90% of patients with PCA had CSF profiles consistent with AD. All patients with PCA with either isolated higher-order visual deficit (n = 8) or visual deficit associated with memory impairment (n = 11) had CSF profiles consistent with AD. Only one of the 3 patients with PCA with asymmetric motor signs fulfilled biological CSF criteria for AD. CONCLUSIONS: PCA syndrome is usually associated with CSF biomarkers suggestive of AD, as shown by previous neuropathologic studies. This does not apply in case of motor signs suggesting associated corticobasal syndrome. CSF biomarkers help to discriminate AD from non-AD processes associated with this condition. PMID- 21525426 TI - Group patient visits for Parkinson disease: a randomized feasibility trial. AB - BACKGROUND: Group patient visits are medical appointments shared among patients with a common medical condition. This care delivery method has demonstrated benefits for individuals with chronic conditions but has not been evaluated for Parkinson disease (PD). METHODS: We conducted a 12-month, randomized trial of group patient visits vs usual (one-on-one) care for patients with PD. Visits were led by one of 3 study physicians, included patients and caregivers, and lasted approximately 90 minutes. Those receiving group visits had 4 sessions over 12 months. The primary outcome measure was feasibility as measured by the ability to recruit participants and by the proportion of participants who completed the study. The primary efficacy outcome was quality of life as measured by the PD Questionnaire-39. RESULTS: Thirty patients and 27 caregivers enrolled in the study. Thirteen of the 15 patients randomized to group patient visits and 14 of the 15 randomized to usual care completed the study. Quality of life measured 12 months after baseline between the 2 groups was not different (25.9 points for group patient visits vs 26.0 points for usual care; p = 0.99). CONCLUSIONS: Group patient visits may be a feasible means of providing care to individuals with PD and may offer an alternative or complementary method of care delivery for some patients and physicians. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that group patient visits did not improve quality of life for individuals with PD over a 1-year period. PMID- 21525428 TI - Group visits for Parkinson disease: "the doctor will see all of you now". PMID- 21525427 TI - Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease. AB - OBJECTIVE: Clinicopathologic phenotypes of dementia with Lewy bodies (DLB) and Alzheimer disease (AD) often overlap, making discrimination difficult. We performed resting state blood oxygen level-dependent (BOLD) functional connectivity MRI (fcMRI) to determine whether there were differences between AD and DLB. METHODS: Participants (n = 88) enrolled in a longitudinal study of memory and aging underwent 3-T fcMRI. Clinical diagnoses of probable DLB (n = 15) were made according to published criteria. Cognitively normal control participants (n = 38) were selected for the absence of cerebral amyloid burden as imaged with Pittsburgh compound B (PiB). Probable AD cases (n = 35) met published criteria and had appreciable amyloid deposits with PiB imaging. Functional images were collected using a gradient spin-echo sequence sensitive to BOLD contrast (T2* weighting). Correlation maps selected a seed region in the combined bilateral precuneus. RESULTS: Participants with DLB had a functional connectivity pattern for the precuneus seed region that was distinct from AD; both the DLB and AD groups had functional connectivity patterns that differed from the cognitively normal group. In the DLB group, we found increased connectivity between the precuneus and regions in the dorsal attention network and the putamen. In contrast, we found decreased connectivity between the precuneus and other task negative default regions and visual cortices. There was also a reversal of connectivity in the right hippocampus. CONCLUSIONS: Changes in functional connectivity in DLB indicate patterns of activation that are distinct from those seen in AD and may improve discrimination of DLB from AD and cognitively normal individuals. Since patterns of connectivity differ between AD and DLB groups, measurements of BOLD functional connectivity can shed further light on neuroanatomic connections that distinguish DLB from AD. PMID- 21525429 TI - Redox-dependent oligomerization through a leucine zipper motif is essential for MG53-mediated cell membrane repair. AB - We recently discovered that MG53, a muscle-specific tripartite motif (TRIM) family protein, functions as a sensor of oxidation to nucleate the assembly of cell membrane repair machinery. Our data showed that disulfide bond formation mediated by Cys242 is critical for MG53-mediated translocation of intracellular vesicles toward the injury sites. Here we test the hypothesis that leucine zipper motifs in the coiled-coil domain of MG53 constitute an additional mechanism that facilitates oligomerization of MG53 during cell membrane repair. Two leucine zipper motifs in the coiled-coil domain of MG53 (LZ1 - L176/L183/L190/V197 and LZ2 - L205/L212/L219/L226) are highly conserved across the different animal species. Chemical cross-linking studies show that LZ1 is critical for MG53 homodimerization, whereas LZ2 is not. Mutations of the conserved leucines into alanines in LZ1, not in LZ2, diminish the redox-dependent oligomerization of MG53. Live cell imaging studies demonstrate that the movement of green fluorescent protein (GFP)-tagged MG53 mutants (GFP-LA1 and GFP-LA2) is partially compromised in response to mechanical damage of the cell membrane, and the GFP LA1/2 double mutant is completely ineffective in translocation toward the injury sites. In addition to the leucine zipper-mediated intermolecular interaction, redox-dependent cross talk between MG53 appears to be an obligatory step for cell membrane repair, since in vivo modification of cysteine residues with alkylating reagents can prevent the movement of MG53 toward the injury sites. Our data show that oxidation of the thiol group of Cys242 and leucine zipper-mediated interaction among the MG53 molecules both contribute to the nucleation process for MG53-mediated cell membrane repair. PMID- 21525430 TI - Rab27b regulates exocytosis of secretory vesicles in acinar epithelial cells from the lacrimal gland. AB - Tear proteins are supplied by the regulated fusion of secretory vesicles at the apical surface of lacrimal gland acinar cells, utilizing trafficking mechanisms largely yet uncharacterized. We investigated the role of Rab27b in the terminal release of these secretory vesicles. Confocal fluorescence microscopy analysis of primary cultured rabbit lacrimal gland acinar cells revealed that Rab27b was enriched on the membrane of large subapical vesicles that were significantly colocalized with Rab3D and Myosin 5C. Stimulation of cultured acinar cells with the secretagogue carbachol resulted in apical fusion of these secretory vesicles with the plasma membrane. Evaluation of morphological changes by transmission electron microscopy of lacrimal glands from Rab27b(-/-) and Rab27(ash/ash)/Rab27b(-/-) mice, but not ashen mice deficient in Rab27a, showed changes in abundance and organization of secretory vesicles, further confirming a role for this protein in secretory vesicle exocytosis. Glands lacking Rab27b also showed increased lysosomes, damaged mitochondria, and autophagosome-like organelles. In vitro, expression of constitutively active Rab27b increased the average size but retained the subapical distribution of Rab27b-enriched secretory vesicles, whereas dominant-negative Rab27b redistributed this protein from membrane to the cytoplasm. Functional studies measuring release of a cotransduced secretory protein, syncollin-GFP, showed that constitutively active Rab27b enhanced, whereas dominant-negative Rab27b suppressed, stimulated release. Disruption of actin filaments inhibited vesicle fusion to the apical membrane but did not disrupt homotypic fusion. These data show that Rab27b participates in aspects of lacrimal gland acinar cell secretory vesicle formation and release. PMID- 21525432 TI - Multifocal animated imaging of changes in cellular oxygen and calcium concentrations and membrane potential within the intact adult mouse carotid body ex vivo. AB - Carotid body (CB) type I cell hypoxia-sensing function is assumed to be based on potassium channel inhibition. Subsequent membrane depolarization initiates an intracellular calcium increase followed by transmitter release for excitation of synapses with linked nerve endings. Several reports, however, contradict this generally accepted concept by showing that type I cell oxygen-sensing properties vary significantly depending on the method of their isolation. We report therefore for the first time noninvasive mapping of the oxygen-sensing properties of type I cells within the intact adult mouse CB ex vivo by using multifocal Nipkow disk-based imaging of oxygen-, calcium- and potential-sensitive cellular dyes. Characteristic type I cell clusters were identified in the compact tissue by immunohistochemistry because of their large cell nuclei combined with positive tyrosine hydroxylase staining. The cellular calcium concentrations in these cell clusters either increased or decreased in response to reduced tissue oxygen concentrations. Under control conditions, cellular potential oscillations were uniform at ~0.02 Hz. Under hypoxia-induced membrane depolarization, these oscillations ceased. Simultaneous increases and decreases in potential of these cell clusters resulted from spontaneous burstlike activities lasting ~1.5 s. type I cells, identified during the experiments by cluster formation in combination with large cell nuclei, seem to respond to hypoxia with heterogeneous kinetics. PMID- 21525431 TI - Abundance of TRPC6 protein in glomerular mesangial cells is decreased by ROS and PKC in diabetes. AB - The present study was performed to investigate the underlying mechanism, particularly the roles of reactive oxygen species (ROS) and protein kinase C (PKC), in the diabetes-induced canonical transient receptor potential 6 (TRPC6) downregulation. We found that high glucose (HG) significantly reduced TRPC6 protein expression in cultured mesangial cells (MCs). TRPC6 protein was also significantly reduced in the glomeruli but not in the heart or aorta isolated from streptozotocin-induced diabetic rats. In the cultured MCs, H(2)O(2) suppressed TRPC6 protein expression in a dose- and time-dependent manner, which emulated the HG effect. Catalase as well as superoxide dismutase were able to prevent the inhibitory effect of HG on TRPC6. The antioxidant effect observed in cultured cells was also observed in diabetic rats treated with tempol for 2 wk, which exhibited a preservation of TRPC6 in the glomeruli. Specific knockdown of Nox4, a component of NADPH oxidase, increased TRPC6 protein expression. Furthermore, the PKC activator phorbol 12-myristate 13-acetate (PMA), but not its analog 4alpha-phorbol 12, 13-didecanoate (4alpha-PDD), suppressed TRPC6 expression, and this PMA effect was not affected by catalase. Moreover, Go6976, but not LY333531, attenuated the negative effect of HG on TRPC6 expression. Go6976 also inhibited H(2)O(2) effect on TRPC6. Furthermore, either knockdown of TRPC6 or HG treatment significantly decreased ANG II-stimulated MC contraction, and the HG-impaired MC contraction was rescued by overexpression of TRPC6. These results suggest that hyperglycemia in diabetes downregulated TRPC6 protein expression in MCs through a NADPH oxidase Nox4-ROS-PKC pathway, proving a mechanism for impaired MC contraction in diabetes. PMID- 21525433 TI - Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries. AB - Chronic hypoxia (CH) activates the Ca(2+)-dependent transcription factor nuclear factor of activated T cells isoform c3 (NFATc3) in mouse pulmonary arteries. However, the mechanism of this response has not been explored. Since we have demonstrated that NFATc3 is required for CH-induced pulmonary arterial remodeling, establishing how CH activates NFATc3 is physiologically significant. The goal of this study was to test the hypothesis that endothelin-1 (ET-1) contributes to CH-induced NFATc3 activation. We propose that this mechanism requires increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca(2+) concentration ([Ca(2+)](i)) and stimulation of RhoA/Rho kinase (ROK), leading to calcineurin activation and actin cytoskeleton polymerization, respectively. We found that: 1) CH increases pulmonary arterial pre-pro-ET-1 mRNA expression and lung RhoA activity; 2) inhibition of ET receptors, calcineurin, L type Ca(2+) channels, and ROK blunts CH-induced NFATc3 activation in isolated intrapulmonary arteries from NFAT-luciferase reporter mice; and 3) both ET-1 induced NFATc3 activation in isolated mouse pulmonary arteries ex vivo and ET-1 induced NFATc3-green fluorescence protein nuclear import in human PASMC depend on ROK and actin polymerization. This study suggests that CH increases ET-1 expression, thereby elevating PASMC [Ca(2+)](i) and RhoA/ROK activity. As previously demonstrated, elevated [Ca(2+)](i) is required to activate calcineurin, which dephosphorylates NFATc3, allowing its nuclear import. Here, we demonstrate that ROK increases actin polymerization, thus providing structural support for NFATc3 nuclear transport. PMID- 21525434 TI - Membrane cholesterol modulates the fluid shear stress response of polymorphonuclear leukocytes via its effects on membrane fluidity. AB - Continuous exposure of polymorphonuclear leukocytes (PMNLs) to circulatory hemodynamics points to fluid flow as a biophysical regulator of their activity. Specifically, fluid flow-derived shear stresses deactivate leukocytes via actions on the conformational activities of proteins on the cell surface. Because membrane properties affect activities of membrane-bound proteins, we hypothesized that changes in the physical properties of cell membranes influence PMNL sensitivity to fluid shear stress. For this purpose, we modified PMNL membranes and showed that the cellular mechanosensitivity to shear was impaired whether we increased, reduced, or disrupted the organization of cholesterol within the lipid bilayer. Notably, PMNLs with enriched membrane cholesterol exhibited attenuated pseudopod retraction responses to shear that were recovered by select concentrations of benzyl alcohol (a membrane fluidizer). In fact, PMNL responses to shear positively correlated (R(2) = 0.96; P < 0.0001) with cholesterol-related membrane fluidity. Moreover, in low-density lipoprotein receptor-deficient (LDLr( /-)) mice fed a high-fat diet (a hypercholesterolemia model), PMNL shear responses correlated (R(2) = 0.5; P < 0.01) with blood concentrations of unesterified (i.e., free) cholesterol. In this regard, the shear-responses of PMNLs gradually diminished and eventually reversed as free cholesterol levels in blood increased during 8 wk of the high-fat diet. Collectively, our results provided evidence that cholesterol is an important component of the PMNL mechanotransducing capacity and elevated membrane cholesterol impairs PMNL shear responses at least partially through its impact on membrane fluidity. This cholesterol-linked perturbation may contribute to dysregulated PMNL activity (e.g., chronic inflammation) related to hypercholesterolemia and causal for cardiovascular pathologies (e.g., atherosclerosis). PMID- 21525436 TI - IMRT for breast cancer--balancing outcomes, patient selection, and resource utilization. PMID- 21525435 TI - Role of Rac1 in regulation of NOX5-S function in Barrett's esophageal adenocarcinoma cells. AB - We have shown that a novel NADPH oxidase isoform, NOX5-S, is the major isoform of NADPH oxidases in an esophageal adenocarcinoma (EA) cell line, FLO, and is overexpressed in Barrett's mucosa with high-grade dysplasia. NOX5-S is responsible for acid-induced reactive oxygen species production. In this study, we found that mRNA levels of NOX5-S were significantly higher in FLO EA cells than in the normal human esophageal squamous cell line HET-1A or in a Barrett cell line, BAR-T. The mRNA levels of NOX5-S were also significantly increased in EA tissues. The data suggest that NOX5-S may be important in the development of EA. Mechanisms of functional regulation of NOX5-S are not fully understood. We show that small G protein Rac1 was present in HET-1A cells, BAR-T cells, and EA cell lines FLO and OE33. Rac1 protein levels were significantly higher in FLO and OE33 cells than in HET-1A or BAR-T cells. Knockdown of Rac1 with Rac1 small interfering RNA significantly decreased acid-induced increase in H(2)O(2) production in FLO EA cells. Overexpression of constitutively active Rac1 significantly increased H(2)O(2) production, an increase that was blocked by knockdown of NOX5-S. By immunofluorescence staining and immunoprecipitation, we found that NOX5-S was present in the cytosol of FLO EA cells and colocalized with Rac1 and SERCA1/2 Ca(2+)-ATPase which is located in the endoplasmic reticulum membrane. We conclude that Rac1 may be important in activation of NOX5-S in FLO EA cells. PMID- 21525437 TI - Adoption of intensity-modulated radiation therapy for breast cancer in the United States. AB - BACKGROUND: Although intensity modulation of the radiation beam has been shown to lower toxic effects for patients receiving whole-breast irradiation, relatively simple techniques may suffice. It is thus controversial whether such treatment justifies billing for intensity-modulated radiation therapy (IMRT). METHODS: We used the claims data to determine billing for IMRT from Surveillance, Epidemiology, and End Results-Medicare records from 2001 to 2005 for 26,163 women aged 66 years or older with nonmetastatic breast cancer treated with surgery and radiotherapy. The impact of individual covariates (demographic, health services, tumor, and treatment factors) on cost of treatment was assessed using the Wilcoxon two-sample test. Two-sided multivariable logistic regression was used to identify predictors for IMRT use. Cost of radiation was calculated in 2005 dollars. All statistical tests were two-sided. RESULTS: The number of patients with IMRT billing claims increased from 0.9% (49 of 5196) of patients diagnosed in 2001 to 11.2% (564 of 5020) in 2005. In multivariable analysis, IMRT billing was more likely for patients with left-sided tumors (odds ratio [OR] = 1.30, 95% confidence interval [CI] = 1.16 to 1.45), for those residing in a health service area with high radiation oncologist density (OR = 2.32, 95% CI = 1.47 to 3.68), for those treated at freestanding radiation centers (OR = 1.36, 95% CI = 1.20 to 1.53), or for those residing in regions where the Medicare intermediary allowed breast IMRT (OR = 10.87, 95% CI = 9.26 to 12.76, all P < .001). The mean cost of radiation was $7179 without IMRT and $15 230 with IMRT. IMRT adoption contributed to an increase in the mean cost of breast radiation from $6334 in 2001 to $8473 in 2005. CONCLUSIONS: IMRT billing increased 10-fold from 2001 through 2005, contributing to a 33% increase in the cost of breast radiation. These findings suggest that reimbursement policy and practice setting strongly influenced adoption of IMRT billing for breast cancer. PMID- 21525438 TI - Impact of the U.S. Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs. PMID- 21525439 TI - The ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid trial: what we learn from subgroup analyses. PMID- 21525440 TI - Diabetes, hypertension, and outcome studies: overview 2010. PMID- 21525441 TI - Sibutramine on cardiovascular outcome. PMID- 21525442 TI - Postprandial hyperglycemia and glycemic variability: should we care? AB - The aim of this article is to evaluate the pros and cons of a specific impact of postprandial hyperglycemia and glycemic variability on the--mainly cardiovascular (CV)--complications of diabetes, above and beyond the average blood glucose (BG) as measured by HbA(1c) or fasting plasma glucose (FPG). The strongest arguments in favor of this hypothesis come from impressive pathophysiological studies, also in the human situation. Measures of oxidative stress and endothelial dysfunction seem to be especially closely related to glucose peaks and even more so to fluctuating high and low glucose concentrations and can be restored to normal by preventing those glucose peaks or wide glucose excursions. The epidemiological evidence, which is more or less confined to postprandial hyperglycemia and postglucose load glycemia, is also rather compelling in favor of the hypothesis, although certainly not fully conclusive as there are also a number of conflicting results. The strongest cons are seen in the missing evidence as derived from randomized prospective intervention studies targeting postprandial hyperglycemia longer term, i.e., over several years, and seeking to reduce hard CV end points. In fact, several such intervention studies in men have recently failed to produce the intended beneficial outcome results. As this evidence by intervention is, however, key for the ultimate approval of a treatment concept in patients with diabetes, the current net balance of attained evidence is not in favor of the hypothesis here under debate, i.e., that we should care about postprandial hyperglycemia and glycemic variability. The absence of a uniformly accepted standard of how to estimate these parameters adds a further challenge to this whole debate. PMID- 21525443 TI - Is hyperglycemia a cardiovascular risk factor? PMID- 21525444 TI - Hypoglycemia and cardiovascular risks. PMID- 21525445 TI - Heart in diabetes: not only a macrovascular disease. PMID- 21525446 TI - Heart in diabetes: a microvascular disease. PMID- 21525447 TI - Antiplatelet therapy for every diabetic person? PMID- 21525448 TI - Should C-reactive protein be a target of therapy? PMID- 21525449 TI - Type 2 diabetes in youth: epidemiology and pathophysiology. PMID- 21525450 TI - Obesity, autoimmunity, and double diabetes in youth. PMID- 21525451 TI - Childhood metabolic syndrome: must we define it to deal with it? PMID- 21525453 TI - The pros and cons of diagnosing diabetes with A1C. PMID- 21525452 TI - Treatment of type 2 diabetes in youth. PMID- 21525454 TI - Should A1C targets be individualized for all people with diabetes? Arguments for and against. PMID- 21525455 TI - Current application of continuous glucose monitoring in the treatment of diabetes: pros and cons. PMID- 21525457 TI - Long-term benefits from lifestyle interventions for type 2 diabetes prevention: time to expand the efforts. PMID- 21525456 TI - Type 2 diabetes can be prevented with early pharmacological intervention. AB - In the U.S., ~ 21 * 10(6) individuals have type 2 diabetes, and twice as many have impaired glucose tolerance (IGT). Approximately 40-50% of individuals with IGT will progress to type 2 diabetes over their lifetime. Therefore, treatment of high-risk individuals with IGT to prevent type 2 diabetes has important medical, economic, social, and human implications. Weight loss, although effective in reducing the conversion of IGT to type 2 diabetes, is difficult to achieve and maintain. Moreover, 40-50% of IGT subjects progress to type 2 diabetes despite successful weight reduction. In contrast, pharmacological treatment of IGT with oral antidiabetic agents that improve insulin sensitivity and preserve beta-cell function--the characteristic pathophysiological abnormalities present in IGT and type 2 diabetes--uniformly have been shown to prevent progression of IGT to type 2 diabetes. The most consistent results have been observed with the thiazolidinediones (Troglitazone in the Prevention of Diabetes [TRIPOD], Pioglitazone in the Prevention of Diabetes [PIPOD], Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication [DREAM], and Actos Now for the Prevention of Diabetes [ACT NOW]), with a 50-70% reduction in IGT conversion to diabetes. Metformin in the U.S. Diabetes Prevention Program (DPP) reduced the development of type 2 diabetes by 31% and has been recommended by the American Diabetes Association (ADA) for treating high-risk individuals with IGT. The glucagon-like peptide-1 analogs, which augment insulin secretion, preserve beta cell function, and promote weight loss, also would be expected to be efficacious in preventing the progression of IGT to type 2 diabetes. Because individuals in the upper tertile of IGT are maximally/near-maximally insulin resistant, have lost 70-80% of their beta-cell function, and have an ~ 10% incidence of diabetic retinopathy, pharmacological intervention, in combination with diet plus exercise, should be instituted. PMID- 21525458 TI - Safety of PPAR agonists. PMID- 21525459 TI - Pivotal role of timely basal insulin replacement after metformin failure in sustaining long-term blood glucose control at a target in type 2 diabetes. PMID- 21525461 TI - Multidrug treatment of type 2 diabetes: a challenge for compliance. PMID- 21525460 TI - Insulin: potential negative consequences of early routine use in patients with type 2 diabetes. PMID- 21525462 TI - Glucokinase activators for diabetes therapy: May 2010 status report. PMID- 21525463 TI - Role of bile acid sequestrants in the treatment of type 2 diabetes. PMID- 21525464 TI - Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. PMID- 21525465 TI - Incretin effects on beta-cell function, replication, and mass: the human perspective. PMID- 21525467 TI - Glycemic control impact on body weight potential to reduce cardiovascular risk: glucagon-like peptide 1 agonists. PMID- 21525466 TI - Therapy in the early stage: incretins. AB - The complex pathological mechanisms responsible for development of type 2 diabetes are not fully addressed by conventional drugs, which are also associated with inconvenient side effects such as weight gain or hypoglycemia. Two types of incretin-based therapies are now in use: incretin mimetics (glucagon-like peptide 1 [GLP-1] receptor agonists that bind specific receptors and mimic the action of natural GLP-1) and incretin enhancers (inhibitors of the enzyme that degrade the incretin hormones and thus prolong their activity). Both offer important advantages over previous agents. In addition to the proven glucose-lowering efficacy, they promote weight loss (or are weight neutral) by slowing gastric emptying and inducing satiety, inhibit glucagon secretion with maintenance of counterregulatory mechanisms, and exhibit cardiovascular benefits, while having a low risk profile. Importantly, short-term studies have shown that incretins/incretin-based therapies protect beta-cells (by enhancing cell proliferation and differentiation and inhibiting apoptosis) and stimulate their function (by recruiting beta-cells to the secretory process and increasing insulin biosynthesis/secretion). These therapies have the opportunity to interfere with the disease progression if used as an early intervention, when enough beta-cell mass/function can still be preserved or restored. PMID- 21525468 TI - DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. PMID- 21525469 TI - Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. PMID- 21525470 TI - Endothelial dysfunction in diabetes: the role of reparatory mechanisms. PMID- 21525471 TI - Endothelial factors and diabetic nephropathy. PMID- 21525473 TI - Antihypertensive treatment and blood pressure in diabetic and nondiabetic patients: the lower, the better? PMID- 21525472 TI - Benefits of tight blood pressure control in diabetic patients with hypertension: importance of early and sustained implementation of effective treatment strategies. AB - In 2008, when the UK Prospective Diabetes Study (UKPDS) group presented their 30 year findings concerning the possible sustained effects of improved glycemic control after 10 years of extended follow-up in type 2 diabetic patients, a so called "legacy effect" was reported to address the long-term emergent and/or sustained benefits of early improved glycemic control. Opposite results were obtained by the Hypertension in Diabetes Study (HDS) carried out in the frame of UKPDS, with no evidence of any legacy effect on cardiovascular (CV) outcomes for an initial 4-year period of tight blood pressure (BP) control. Thus, it was concluded that BP control has to be continued over time, since, although it had a short time-to-effect relationship in preventing stroke, BP control was associated with a short persistence of its clinical benefits once the intervention was discontinued. These findings are unique because, whereas most interventional trials in hypertension that included diabetic patients have shown a reduction in CV outcomes shortly after starting treatment, only the UKPDS-HDS specifically explored the possible persistence of clinical benefits after discontinuing intensive BP-lowering intervention. This article aims to provide a critical interpretation of the UKPDS findings of lack of BP legacy, in the context of the currently available evidence on the benefits of antihypertensive treatment. The importance of effective BP control in type 2 diabetic patients to prevent CV outcomes and other diabetes-related complications is underlined, with emphasis on early, tight, and continuous BP control to optimize patients' protection. PMID- 21525474 TI - Blood pressure: the lower, the better: the con side. PMID- 21525475 TI - Diuretic treatment of hypertension. PMID- 21525476 TI - RAS blockade for every diabetic patient: pro and con. PMID- 21525477 TI - Monitoring kidney function and albuminuria in patients with diabetes. PMID- 21525478 TI - Limitations and future treatment options in type 2 diabetes with renal impairment. PMID- 21525479 TI - Antimicrobial-sensing proteins in obesity and type 2 diabetes: the buffering efficiency hypothesis. PMID- 21525480 TI - Meal-related increases in microvascular vasomotion are impaired in obese individuals: a potential mechanism in the pathogenesis of obesity-related insulin resistance. PMID- 21525481 TI - Comparative efficiency and safety of pharmacological approaches to the management of obesity. PMID- 21525482 TI - Cure of type 2 diabetes by metabolic surgery? A critical analysis of the evidence in 2010. PMID- 21525483 TI - Bariatric surgery for type 2 diabetes reversal: the risks. PMID- 21525484 TI - Lipids in the wrong place: visceral fat and nonalcoholic steatohepatitis. PMID- 21525485 TI - Myocardial, perivascular, and epicardial fat. AB - Myocardial fat content refers to the storage of triglyceride droplets within cardiomyocytes. In addition, the heart and arteries are surrounded by layers of adipose tissue, exerting vasocrine and paracrine control of the subtending tissues. The rapid development of the field of noninvasive imaging has made it possible to quantify ectopic fat masses and contents with an increasing degree of accuracy. Myocardial triglyceride stores are increased in obesity, impaired glucose tolerance, and type 2 diabetes. The role of intramyocardial triglyceride accumulation in the pathogenesis of left ventricular (LV) dysfunction remains unclear. Increased triglyceride content is associated with states of fatty acid overload to the heart, saturating the oxidative capacity. It may initially serve as a fatty acid sink to circumscribe the formation of toxic lipid species and subsequently foster cardiac damage. Epicardial and perivascular fat depots may exert a protective modulation of vascular function and energy partition in a healthy situation, but their expansion turns them into an adverse lipotoxic, prothrombotic, and proinflammatory organ. They are augmented in patients with metabolic disorders and coronary artery disease (CAD). However, the progressive association between the quantity of fat and disease severity in terms of extent of plaque calcification or noncalcified areas, markers of plaque vulnerability, and number of vessels involved is less confirmed. Functional or hybrid imaging may contribute to a better definition of disease severity and unveil the direct myocardial and vascular targets of adipose tissue action. PMID- 21525487 TI - Introduction to the Third World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy): outcome studies versus clinical experience in the treatment of diabetes. PMID- 21525486 TI - Diabetes and cardiovascular disease: when it comes to lipids, statins are all you need. PMID- 21525488 TI - Sortase A as a tool for high-yield histatin cyclization. AB - Cyclic peptides are highly valued tools in biomedical research. In many cases, they show higher receptor affinity, enhanced biological activity, and improved serum stability. Technical difficulties in producing cyclic peptides, especially larger ones, in appreciable yields have precluded a prolific use in biomedical research. Here, we describe a novel and efficient cyclization method that uses the peptidyl-transferase activity of the Staphylococcus aureus enzyme sortase A to cyclize linear synthetic precursor peptides. As a model, we used histatin 1, a 38-mer salivary peptide with motogenic activity. Chemical cyclization of histatin 1 resulted in <= 3% yields, whereas sortase-mediated cyclization provided a yield of >90%. The sortase-cyclized peptide displayed a maximum wound closure activity at 10 nM, whereas the linear peptide displayed maximal activity at 10 MUM. Circular dichroism and NMR spectroscopic analysis of the linear and cyclic peptide in solution showed no evidence for conformational changes, suggesting that structural differences due to cyclization only became manifest when these peptides were located in the binding domain of the receptor. The sortase-based cyclization technology provides a general method for easy and efficient manufacturing of large cyclic peptides. PMID- 21525490 TI - Serum response factor expression is enriched in pancreatic beta cells and regulates insulin gene expression. AB - Serum response factor (SRF) is an essential regulator of myogenic and neurogenic genes and the ubiquitously expressed immediate-early genes. The purpose of this study is to determine SRF expression pattern in murine pancreas and examine the role of SRF in pancreatic gene expression. Immunohistochemical analysis of wild type pancreas and LacZ staining of pancreas from SRF LacZ knock-in animals showed that SRF expression is restricted to beta cells. SRF bound to the rat insulin promoter II (RIP II) serum response element, an element conserved in both rat I and murine I and II insulin promoters. SRF activated RIP II, and SRF binding to RIP II and the exon 5-encoded 64-aa subdomain of SRF was required for this activation. Transient or stable knockdown of SRF leads to down-regulation of insulin gene expression, suggesting that SRF is required for insulin gene expression. Further, SRF physically interacted with the pancreas and duodenum homeobox-1 (Pdx-1) and synergistically activated RIP II. Elevated glucose concentration down-regulated SRF binding to RIP II SRE, and this down-regulation was associated with decreased RIP II activity and increased SRF phosphorylation on serine 103. Together, our results demonstrate that SRF is a glucose concentration-sensitive regulator of insulin gene expression. PMID- 21525489 TI - Glial cell line-derived neurotrophic factor and endothelial cells promote self renewal of rabbit germ cells with spermatogonial stem cell properties. AB - Previous studies suggest that exogenous factors crucial for spermatogonial stem cell (SSC) self-renewal are conserved among several mammalian species. Since glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2) are critical for rodent SSC self-renewal, we hypothesized that they might promote self-renewal of nonrodent SSCs. Therefore, we cultured testicular germ cells from prepubertal rabbits in the presence of GDNF and FGF2 and found they proliferated indefinitely as cellular clumps that displayed characteristics previously identified for rodent SSCs. The rabbit germ cells could not be maintained on mouse embryonic fibroblast (STO) feeders that support rodent SSC self-renewal in vitro but were rather supported on mouse yolk sac-derived endothelial cell (C166) feeder layers. Proliferation of rabbit germ cells was dependent on GDNF. Of critical importance was that clump-forming rabbit germ cells colonized seminiferous tubules of immunodeficient mice, proliferated for at least 6 mo, while retaining an SSC phenotype in the testes of recipient mice, indicating that they were rabbit SSCs. This study demonstrates that GDNF is a mitogenic factor promoting self-renewal that is conserved between rodent and rabbit SSCs; with an evolutionary separation of ~ 60 million years. These findings provide a foundation to study the mechanisms governing SSC self-renewal in nonrodent species. PMID- 21525491 TI - Nonnutritive sweeteners, fructose, and other aspects of diet. PMID- 21525492 TI - Hypoglycemia in patients with diabetes on antidiabetic medications who fast for laboratory tests. PMID- 21525493 TI - Comment on: American Diabetes Association. Standards of medical care in diabetes- 2011. Diabetes Care 2011;34(Suppl. 1):S11-S61. PMID- 21525495 TI - Comment on: Chen et al. Utilizing the second-meal effect in type 2 diabetes: practical use of a soya-yogurt snack. Diabetes Care 2010;33:2552-2554. PMID- 21525497 TI - Comment on: Polonsky et al. Structured self-monitoring of blood glucose significantly reduces A1C levels in poorly controlled, noninsulin-treated type 2 diabetes: results from the structured testing program study. Diabetes Care 2011;34:262-267. PMID- 21525499 TI - Comment on: Boronat et al. Differences in cardiovascular risk profile of diabetic subjects discordantly classified by diagnostic criteria based on glycated hemoglobin and oral glucose tolerance test. Diabetes Care 2010;33:2671-2673. PMID- 21525502 TI - Medical expenditures associated with diabetes among privately insured U.S. youth in 2007. AB - OBJECTIVE: To estimate, among privately insured youth in the U.S., medical expenditures associated with diabetes and the difference in medical expenditures between individuals with insulin-treated diabetes mellitus (ITDM) and with non ITDM (NITDM). RESEARCH DESIGN AND METHODS: Using the 2007 MarketScan commercial claims and encounter database, we analyzed data for 49,356 youth (aged <= 19 years) who were continuously enrolled in fee-for-service health plans. Youth with diabetes (cases) were identified from inpatient, outpatient, and pharmaceutical drug claims. Each case was matched with five controls (without diabetes) by age (+/- 2 years), sex, census region, and urban versus rural residence. We used regression models to estimate medical expenditures in total and by component (inpatient, outpatient, and medication). RESULTS: The predicted mean annual total per-person medical expenditures were $9,061 for youth with diabetes and $1,468 for those without, an excess of $7,593 for those with diabetes; of which, 43% was for prescription drugs. The predicted mean annual total expenditures were $9,333 for ITDM youth and $5,683 for NITDM youth, respectively, an excess of $3,650 for those with ITDM diabetes, of which 59% was for prescription drugs. CONCLUSIONS: The excess medical expenditures associated with diabetes, ITDM in particular, among youth are substantial. Our estimates of excess expenditures can be used to assess the economic burden of diabetes overall and by diabetes treatment mode. Our estimated excess expenditure for NITDM may be used for evaluating the economic efficiency of interventions aimed at preventing type 2 diabetes in U.S. youth. PMID- 21525501 TI - Vitamin D levels, microvascular complications, and mortality in type 1 diabetes. AB - OBJECTIVE: To evaluate vitamin D as a predictor of all-cause mortality, progression from normoalbuminuria to micro- or macroalbuminuria, and the development of background or proliferative retinopathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A prospective observational follow-up study in which an inception cohort of type 1 diabetic patients was followed from onset of diabetes diagnosed between 1979 and 1984. Plasma vitamin D [25(OH)D3] levels were determined by high performance liquid chromatography/tandem mass spectrometry in 227 patients before the patients developed microalbuminuria. Values equal to or below the 10% percentile (15.5 nmol/L) were considered severe vitamin D deficiency. RESULTS: Median (range) vitamin D was 44.6 (1.7-161.7) nmol/L. Vitamin D level was not associated with age, sex, urinary albumin excretion rate (UAER), or blood pressure. During follow-up, 44 (18%) patients died. In a Cox proportional hazards model, the hazard ratio for mortality in subjects with severe vitamin D deficiency was 2.7 (1.1-6.7), P = 0.03, after adjustment for UAER, HbA(1c), and conventional cardiovascular risk factors (age, sex, blood pressure, cholesterol, smoking). Of the 220 patients, 81 (37%) developed microalbuminuria and 27 (12%) of these progressed to macroalbuminuria. Furthermore, 192 (87%) patients developed background retinopathy, whereas 34 (15%) progressed to proliferative retinopathy. Severe vitamin D deficiency at baseline did not predict the development of these microvascular complications. CONCLUSIONS: In patients with type 1 diabetes, severe vitamin D deficiency independently predicts all-cause mortality but not development of microvascular complications in the eye and kidney. Whether vitamin D substitution in type 1 diabetic patients can improve the prognosis remains to be investigated. PMID- 21525503 TI - Effects of exercise on cardiovascular risk factors in type 2 diabetes: a meta analysis. AB - OBJECTIVE: Exercise is a cornerstone of diabetes management and the prevention of incident diabetes. However, the impact of the mode of exercise on cardiovascular (CV) risk factors in type 2 diabetes is unclear. RESEARCH DESIGN AND METHODS: We conducted a systematic review of the literature between 1970 and October 2009 in representative databases for the effect of aerobic or resistance exercise training on clinical markers of CV risk, including glycemic control, dyslipidemia, blood pressure, and body composition in patients with type 2 diabetes. RESULTS: Of 645 articles retrieved, 34 met our inclusion criteria; most investigated aerobic exercise alone, and 10 reported combined exercise training. Aerobic alone or combined with resistance training (RT) significantly improved HbA(1c) -0.6 and -0.67%, respectively (95% CI -0.98 to -0.27 and -0.93 to -0.40, respectively), systolic blood pressure (SBP) -6.08 and -3.59 mmHg, respectively (95% CI -10.79 to -1.36 and -6.93 to -0.24, respectively), and triglycerides -0.3 mmol/L (95% CI -0.48 to -0.11 and -0.57 to -0.02, respectively). Waist circumference was significantly improved -3.1 cm (95% CI -10.3 to -1.2) with combined aerobic and resistance exercise, although fewer studies and more heterogeneity of the responses were observed in the latter two markers. Resistance exercise alone or combined with any other form of exercise was not found to have any significant effect on CV markers. CONCLUSIONS: Aerobic exercise alone or combined with RT improves glycemic control, SBP, triglycerides, and waist circumference. The impact of resistance exercise alone on CV risk markers in type 2 diabetes remains unclear. PMID- 21525504 TI - Diabetic retinopathy predicts all-cause mortality and cardiovascular events in both type 1 and 2 diabetes: meta-analysis of observational studies. AB - OBJECTIVE: The prognostic significance of diabetic retinopathy (DR) for death and cardiovascular (CV) outcomes is debated. We investigated the association of DR with all-cause mortality and CV events in patients with diabetes by a systematic review and meta-analysis. RESEARCH DESIGN AND METHODS: The electronic databases Medline and Embase were searched for cohort studies that evaluated DR in type 2 or type 1 diabetic patients and reported total mortality and/or fatal and nonfatal CV events, including myocardial infarction, angina pectoris, coronary artery bypass graft, ischemic changes on a conventional 12-lead electrocardiogram, transient ischemic attack, nonfatal stroke, or lower leg amputation. Data extraction was performed by two reviewers independently. Pooled effect estimates were obtained by using random-effects meta-analysis. RESULTS: The analysis included 20 studies that fulfilled the inclusion criteria, providing data from 19,234 patients. In patients with type 2 diabetes (n = 14,896), the presence of any degree of DR increased the chance for all-cause mortality and/or CV events by 2.34 (95% CI 1.96-2.80) compared with patients without DR. In patients with type 1 diabetes (n = 4,438), the corresponding odds ratio was 4.10 (1.50-11.18). These associations remained after adjusting for traditional CV risk factors. DR was also predictive of all-cause mortality in type 2 diabetes (odds ratio 2.41 [1.87-3.10]) and type 1 diabetes (3.65 [1.05-12.66]). CONCLUSIONS: The presence of DR was associated with an increased risk of all-cause mortality and CV events in both type 2 and type 1 diabetic patients. PMID- 21525505 TI - Vitamin D deficiency is not good for you. PMID- 21525507 TI - Magnetic resonance spectroscopy studies of human metabolism. PMID- 21525508 TI - How does type 1 diabetes develop?: the notion of homicide or beta-cell suicide revisited. PMID- 21525509 TI - Fractalkine: a cellular link between adipose tissue inflammation and vascular pathologies. PMID- 21525510 TI - Fractalkine is a novel human adipochemokine associated with type 2 diabetes. AB - OBJECTIVE: Leukocyte infiltration of adipose is a critical determinant of obesity related metabolic diseases. Fractalkine (CX3CL1) and its receptor (CX3CR1) comprise a chemokine system involved in leukocyte recruitment and adhesion in atherosclerosis, but its role in adipose inflammation and type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS: CX3CL1 mRNA and protein were quantified in subcutaneous adipose and blood during experimental human endotoxemia and in lean and obese human adipose. CX3CL1 cellular source was probed in human adipocytes, monocytes, and macrophages, and CX3CL1-blocking antibodies were used to assess its role in monocyte-adipocyte adhesion. The association of genetic variation in CX3CR1 with metabolic traits was determined in a community-based sample. Finally, plasma CX3CL1 levels were measured in a case-control study of type 2 diabetes. RESULTS: Endotoxemia induced adipose CX3CL1 mRNA (32.7-fold, P < 1 * 10(-5)) and protein (43-fold, P = 0.006). Obese subjects had higher CX3CL1 levels in subcutaneous adipose compared with lean (0.420 +/- 0.387 vs. 0.228 +/- 0.187 ng/mL, P = 0.04). CX3CL1 was expressed and secreted by human adipocytes and stromal vascular cells. Inflammatory cytokine induction of CX3CL1 in human adipocytes (27.5-fold mRNA and threefold protein) was completely attenuated by pretreatment with a peroxisome proliferator-activated receptor-gamma agonist. A putative functional nonsynonymous single nucleotide polymorphism (rs3732378) in CX3CR1 was associated with adipose and metabolic traits, and plasma CX3CL1 levels were increased in patients with type 2 diabetes vs. nondiabetics (0.506 +/- 0.262 vs. 0.422 +/- 0.210 ng/mL, P < 0.0001). CONCLUSIONS: CX3CL1-CX3CR1 is a novel inflammatory adipose chemokine system that modulates monocyte adhesion to adipocytes and is associated with obesity, insulin resistance, and type 2 diabetes. These data provide support for CX3CL1 as a diagnostic and therapeutic target in cardiometabolic disease. PMID- 21525512 TI - Mechanisms of protein retention in the Golgi. AB - The protein composition of the Golgi is intimately linked to its structure and function. As the Golgi serves as the major protein-sorting hub for the secretory pathway, it faces the unique challenge of maintaining its protein composition in the face of constant influx and efflux of transient cargo proteins. Much of our understanding of how proteins are retained in the Golgi has come from studies on glycosylation enzymes, largely because of the compartment-specific distributions these proteins display. From these and other studies of Golgi membrane proteins, we now understand that a variety of retention mechanisms are employed, the majority of which involve the dynamic process of iterative rounds of retrograde and anterograde transport. Such mechanisms rely on protein conformation and amino acid-based sorting signals as well as on properties of transmembrane domains and their relationship with the unique lipid composition of the Golgi. PMID- 21525513 TI - Evolutionary forces shaping the Golgi glycosylation machinery: why cell surface glycans are universal to living cells. AB - Despite more than 3 billion years since the origin of life on earth, the powerful forces of biological evolution seem to have failed to generate any living cell that is devoid of a dense and complex array of cell surface glycans. Thus, cell surface glycans seem to be as essential for life as having a DNA genetic code, diverse RNAs, structural/functional proteins, lipid-based membranes, and metabolites that mediate energy flux and signaling. The likely reasons for this apparently universal law of biology are considered here, and include the fact that glycans have the greatest potential for generating diversity, and thus evading recognition by pathogens. This may also explain why in striking contrast to the genetic code, glycans show widely divergent patterns between taxa. On the other hand, glycans have also been coopted for myriad intrinsic functions, which can vary in their importance for organismal survival. In keeping with these considerations, a significant percentage of the genes in the typical genome are dedicated to the generation and/or turnover of glycans. Among eukaryotes, the Golgi is the subcellular organelle that serves to generate much of the diversity of cell surface glycans, carrying out various glycan modifications of glycoconjugates that transit through the Golgi, en route to the cell surface or extracellular destinations. Here I present an overview of general considerations regarding the selective forces shaping evolution of the Golgi glycosylation machinery, and then briefly discuss the common types of variations seen in each major class of glycans, finally focusing on sialic acids as an extreme example of evolutionary glycan diversity generated by the Golgi. Future studies need to address both the phylogenetic diversity the Golgi and the molecular mechanisms for its rapid responses to intrinsic and environmental stimuli. PMID- 21525514 TI - Has psychopharmacology got a future? AB - Fifty years ago pharmacological discoveries transformed psychiatry but progress since then has been relatively slow and there is unease about the role of industry. Despite this, the possibilities of pharmacological treatment have improved in recent years but exploiting developments for the benefit of patients requires psychotherapeutic skill as well as a high level of scientific knowledge. PMID- 21525515 TI - More good news about the magic ion: lithium may prevent dementia. AB - Lithium is an established treatment for affective disorders with good evidence of antisuicidal properties. Alzheimer's disease rates are relatively reduced in patients with bipolar disorder on lithium and a recent trial of lithium in amnestic minimal cognitive impairment is indicative of potential benefits. This should stimulate further, larger-scale studies. PMID- 21525516 TI - Keeping therapies simple: psychoeducation in the prevention of relapse in affective disorders. AB - Psychological interventions for mood disorders can be divided into 'skilled' and 'simple'. Psychoeducation belongs to the latter group: a simple and illness focused therapy with prophylactic efficacy in all major mood disorders. Successful implementation of psychoeducation requires a proper setting, including open-door policy, team effort and empowerment of the therapeutic alliance. PMID- 21525517 TI - Clinical relevance of findings in trials of antipsychotics: systematic review. AB - BACKGROUND: There is concern over the methods used to evaluate antipsychotic drugs. AIMS: To assess the clinical relevance of findings in the literature. METHOD: A systematic review identified studies of antipsychotics that used the Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale (PANSS). A published method of translating these into Clinical Global Impression Change scale (CGI-C) scores was used to measure clinical relevance. RESULTS: In total 98 data-sets were included in the BPRS analysis and 202 data-sets in the PANSS analysis. When aggregated scores were translated into notional CGI-C scores, most drugs reached 'minimal improvement' on the BPRS, but few reached that level for PANSS. This was true of both first- and second-generation drugs, including clozapine. Amisulpride and olanzapine had better than average CGI-C scores. CONCLUSIONS: Our findings show improvements of limited clinical relevance. The CGI-C scores were better for the BPRS than for the PANSS. PMID- 21525518 TI - Lithium in drinking water and suicide mortality. AB - BACKGROUND: There is some evidence that natural levels of lithium in drinking water may have a protective effect on suicide mortality. AIMS: To evaluate the association between local lithium levels in drinking water and suicide mortality at district level in Austria. METHOD: A nationwide sample of 6460 lithium measurements was examined for association with suicide rates per 100,000 population and suicide standardised mortality ratios across all 99 Austrian districts. Multivariate regression models were adjusted for well-known socioeconomic factors known to influence suicide mortality in Austria (population density, per capita income, proportion of Roman Catholics, as well as the availability of mental health service providers). Sensitivity analyses and weighted least squares regression were used to challenge the robustness of the results. RESULTS: The overall suicide rate (R(2) = 0.15, beta = -0.39, t = -4.14, P = 0.000073) as well as the suicide mortality ratio (R(2) = 0.17, beta = -0.41, t = -4.38, P = 0.000030) were inversely associated with lithium levels in drinking water and remained significant after sensitivity analyses and adjustment for socioeconomic factors. CONCLUSIONS: In replicating and extending previous results, this study provides strong evidence that geographic regions with higher natural lithium concentrations in drinking water are associated with lower suicide mortality rates. PMID- 21525519 TI - Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. AB - BACKGROUND: Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimer's disease, although no benefits were obtained from short-term treatment. AIMS: To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI). METHOD: Forty-five participants with aMCI were randomised to receive lithium (0.25-0.5 mmol/l) (n = 24) or placebo (n = 21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (Abeta(42)), total tau (T-tau), phosphorylated-tau) (P-tau). TRIAL REGISTRATION: NCT01055392. RESULTS: Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P = 0.03) and better perform-ance on the cognitive subscale of the Alzheimer's Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%. CONCLUSIONS: The present data support the notion that lithium has disease modifying properties with potential clinical implications in the prevention of Alzheimer's disease. PMID- 21525520 TI - Annual high-dose vitamin D3 and mental well-being: randomised controlled trial. AB - BACKGROUND: Epidemiological evidence supports a relationship between vitamin D and mental well-being, although evidence from large-scale placebo-controlled intervention trials is lacking. AIMS: To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms; and if there is an association between serum 25-hydroxyvitamin D levels and mental health. METHOD: A double-blind, randomised, placebo-controlled trial of women aged 70 or older (the Vital D Study: ISRCTN83409867 and ACTR12605000658617). Participants were randomly assigned to receive 500 000 IU vitamin D(3) (cholecalciferol) orally or placebo every autumn/winter for 3-5 consecutive years. The tools utilised at various time points were the General Health Questionnaire, the 12-item Short Form Health Survey, the Patient Global Impression-Improvement scale and the WHO Well-Being Index. Serum 25 hydroxyvitamin D levels were measured in a subset of 102 participants. RESULTS: In this non-clinical population, no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health. Serum 25-hydroxyvitamin D levels in the vitamin D group were 41% higher than the placebo group 12 months following their annual dose. Despite this difference, scores from the questionnaires did not differ. Furthermore, there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups. CONCLUSIONS: The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D(3) is a practical intervention to prevent depressive symptoms in older community-dwelling women. PMID- 21525521 TI - Impact of screening for risk of suicide: randomised controlled trial. AB - BACKGROUND: Concerns have been expressed about the impact that screening for risk of suicide may have on a person's mental health. AIMS: To examine whether screening for suicidal ideation among people who attend primary care services and have signs of depression increases the short-term incidence of feeling that life is not worth living. METHOD: In a multicentre, single-blind, randomised controlled trial, 443 patients in four general practices were randomised to screening for suicidal ideation or control questions on health and lifestyle (trial registration: ISRCTN84692657). The primary outcome was thinking that life is not worth living measured 10-14 days after randomisation. Secondary outcome measures comprised other aspects of suicidal ideation and behaviour. RESULTS: A total of 443 participants were randomised to early (n = 230) or delayed screening (n = 213). Their mean age was 48.5 years (s.d. = 18.4, range 16-92) and 137 (30.9%) were male. The adjusted odds of experiencing thoughts that life was not worth living at follow-up among those randomised to early compared with delayed screening was 0.88 (95% CI 0.66-1.18). Differences in secondary outcomes between the two groups were not seen. Among those randomised to early screening, 37 people (22.3%) reported thinking about taking their life at baseline and 24 (14.6%) that they had this thought 2 weeks later. CONCLUSIONS: Screening for suicidal ideation in primary care among people who have signs of depression does not appear to induce feelings that life is not worth living. PMID- 21525522 TI - Working memory task performance and chunking in early Alzheimer's disease. AB - BACKGROUND: Chunking is a powerful encoding strategy that significantly improves working memory performance in normal young people. AIMS: To investigate chunking in patients with mild Alzheimer's disease and in a control group of elderly people without cognitive impairment. METHOD: People with mild Alzheimer's disease (n = 28) were recruited and divided according to Mini-Mental State Examination score into mild and very mild disease groups. A control group of 15 elderly individuals was also recruited. All participants performed digit and spatial working memory tasks requiring either unstructured sequences or structured sequences (which encourage chunking of information) to be recalled. RESULTS: The control group and both disease groups performed significantly better on structured trials of the digit working memory tasks, indicating successful use of chunking strategies to improve verbal working memory performance. The control and very mild disease groups also performed significantly better on structured trials of the spatial task, whereas those with mild disease demonstrated no significant difference between the structured and unstructured spatial conditions. CONCLUSIONS: The ability to use chunking as an encoding strategy to improve verbal working memory performance is preserved at the mild stage of Alzheimer's disease, whereas use of chunking to improve spatial working memory is impaired by this stage. Simple training in the use of chunking might be a beneficial therapeutic strategy to prolong working memory functioning in patients at the earliest stage of Alzheimer's disease. PMID- 21525523 TI - Lithium in drinking water and suicide rates across the East of England. AB - Lithium can be found naturally in drinking water. In clinical practice, it is widely used in pharmacological doses for the treatment of bipolar disorder; and may also prevent suicidal behaviour in people with mood disorders. In two studies, lithium levels in tap water have been significantly and negatively correlated with suicide. We measured lithium levels in tap water in the 47 subdivisions of the East of England and correlated these with the respective suicide standardised mortality ratio in each subdivision. We found no association between lithium in drinking water and suicide rates across the East of England from 2006 to 2008. PMID- 21525524 TI - Ward overcrowding and assaults on staff: cause and effect? PMID- 21525525 TI - Do we need to treat aggression? PMID- 21525526 TI - Circadian variations of infarct size in acute myocardial infarction. AB - BACKGROUND: The circadian clock influences a number of cardiovascular (patho)physiological processes including the incidence of acute myocardial infarction. A circadian variation in infarct size has recently been shown in rodents, but there is no clinical evidence of this finding. OBJECTIVE: To determine the impact of time-of-day onset of ST segment elevation myocardial infarction (STEMI) on infarct size. METHODS: A retrospective single-centre analysis of 811 patients with STEMI admitted between 2003 and 2009 was performed. Infarct size was estimated by peak enzyme release. The relationship between peak enzyme concentrations and time-of-day were characterised using multivariate regression splines. Time of STEMI onset was divided into four 6-hour periods in phase with circadian rhythms. RESULTS: Model comparisons based on likelihood ratio tests showed a circadian variation in infarct size across time-of-day as evaluated by peak creatine kinase (CK) and troponin-I (TnI) concentrations (p=0.015 and p=0.012, respectively). CK and TnI curves described similar patterns across time, with a global maximum in the 6:00-noon period and a local minimum in the noon-18:00 period. Infarct size was largest in patients with STEMI onset in the dark-to-light transition period (6:00-noon), with an increase in peak CK and TnI concentrations of 18.3% (p=0.031) and 24.6% (p=0.033), respectively, compared with onset of STEMI in the 18:00-midnight period. Patients with anterior wall STEMI also had significantly larger infarcts than those with STEMI in other locations. CONCLUSIONS: Significant circadian oscillations in infarct size were found in patients according to time-of-day of STEMI onset. The infarct size was found to be significantly larger with STEMI onset in the dark-to-light transition period (6:00-noon). If confirmed, these results may have a significant impact on the interpretation of clinical trials of cardioprotective strategies in STEMI. PMID- 21525527 TI - Changes in rates of violent child deaths in England and Wales between 1974 and 2008: an analysis of national mortality data. AB - BACKGROUND: This study used national data to determine if violent child death rates fell between 1974 and 2008. DESIGN: Using mortality data from the Office of National Statistics, categories potentially containing violent child deaths were analysed for children aged <1, 1-14 and 15-19 years. These data were compared with Home Office data on recorded homicides in children aged <1 and 1-15 years. RESULTS: Annual rates of infant deaths registered as due to assault fell between 1974 and 2008 from 5.6 to 0.7 per 100 000 infants; those in children (1-14 years) fell from 0.6 to 0.2 per 100 000. When these deaths are combined with those registered as undetermined intent, rates are higher but still show a decline in both groups. There is a slight fall in the rates of police recorded homicides in infants, but no observable change in childhood rates. In adolescents, the rates of death from assault fell during the 1970s and have since remained static in females but have risen in males. When these deaths are combined with those registered as undetermined intent, the rates for adolescent women have remained static at 2.0 per 100 000, while for young men they increased from 3.3 to 5.7 per 100 000 before declining to 4.2 per 100 000. CONCLUSION: These data provide evidence that rates of violent death in infancy and middle childhood have fallen over the past 30 years. In contrast, rates in adolescence have remained static or risen over the same period. PMID- 21525528 TI - The rising incidence of idiopathic pulmonary fibrosis in the U.K. AB - BACKGROUND: Previous studies have shown that the incidence of idiopathic pulmonary fibrosis (IPF) is rising in the U.K. and U.S.A. Death registrations and primary care data were used to determine the current trends in IPF incidence in the U.K. Because routine clinical data sets were used, the term IPF clinical syndrome (IPF-CS) is used to describe individuals in this study. METHODS: Age- and stratum-specific death registration rates between 1968 and 2008 were calculated and these were applied to the 2008 population to generate annual standardised expected number of deaths. Annual mortality rate ratios were calculated using Poisson regression. Computerised primary care records were used to determine incidence rates of IPF-CS between 2000 and 2008 stratified by age, sex and geographical region, and survival rates between calendar periods were compared. RESULTS: Annual death certificate recording of IPF-CS rose sixfold across the study period from 0.92 per 100,000 in the 1968-1972 calendar periods to 5.10 per 100,000 in the 2006-2008 calendar period, and were higher in men and the older age groups. The incidence of IPF-CS in primary care increased by 35% from 2000 to 2008, with an overall incidence rate of 7.44 per 100,000 person years (95% CI 7.12 to 7.77). Incidence was higher in men, the older population and in Northwest England. CONCLUSIONS: The incidence of IPF-CS in primary care and registered deaths from this cause in the U.K. continues to rise in the 21st century. The current findings suggest that there are >5000 new cases diagnosed each year in the U.K. PMID- 21525529 TI - Echinoderm phylogeny including Xyloplax, a progenetic asteroid. AB - Reconstruction of the phylogeny of the five extant classes of the phylum Echinodermata has proven difficult. Results concerning higher-level taxonomic relationships among echinoderms are sensitive to the choice of analytical parameters and methods. Moreover, the proposal of a putative sixth class based on a small enigmatic disc-shaped echinoderm, Xyloplax, from the deep seas of the Bahamas and New Zealand in the 1980s further complicated the problem. Although clearly an echinoderm, Xyloplax did not have clear affinity among known groups. Using molecular sequence and developmental data from recently collected Xyloplax adults and embryos, we show that rather than representing an ancient distinct lineage as implied by its status as a class, Xyloplax is simply a starfish that is closely related to the asteroid family Pterasteridae. Many members of the Pterasteridae and all Xyloplax inhabit deep or polar seas and brood young. Brooding pterasterids and Xyloplax hold their young in specialized adult chambers until the young reach an advanced juvenile stage after which they are released as free-living individuals. We hypothesize that the unique morphology of Xyloplax evolved via progenesis--the truncation of somatic growth at a juvenile body plan but with gonadal growth to maturity. Although the overall phylogeny of extant echinoderms remains sensitive to the choice of analytical methods, the placement of Xyloplax as sister to pterasterid asteroids is unequivocal. Based on this, we argue that the proposed class and infraclass status of Xyloplax should be suppressed. PMID- 21525531 TI - Enhancing proteotoxic stress as an anticancer strategy. PMID- 21525532 TI - [Surgical tactics at acute colonic bleedings]. AB - The analysis of complex clinical examination of 134 patients with acute colonic bleeding treated at Medical Centre "St. Grigor Lusavorich" in Yerevan during last 12 years is presented. It was found that causes of acute colonic bleeding are very diverse. The main ones are: cancer, colorectal cancer (28,4%), diverticulosis of the colon (14,9%), hemorrhagic erosive and erosive-ulcerative lesions of the colon (13,5%), colon polyps (11,9%). Technique of emergency colonoscopy with intubation of the colon is proposed and an increase in 18,2% sensitivity and 17,5% accuracy was observed. In cases of conservative hemostasis without application of endoscopic methods and a surgical intervention positive results were obtained in 26,5% cases of acute colic bleedings. Application of modern methods of endoscopic haemostasis reduced the number of emergency operations in 1,7 times; the recurrence rate of bleeding in 2,6 times. The differentiated surgical treatment of patients with acute colonic bleeding increases the number of simultaneous radical surgery on the colon by 23,9%, reduces postoperative complications by 26,3%, lethality - by 11,6%. PMID- 21525530 TI - A critical role of downstream RNA polymerase-promoter interactions in the formation of initiation complex. AB - Nucleation of promoter melting in bacteria is coupled with RNA polymerase (RNAP) binding to a conserved -10 promoter element located at the upstream edge of the transcription bubble. The mechanism of downstream propagation of the transcription bubble to include the transcription start site is unclear. Here we introduce new model downstream fork junction promoter fragments that specifically bind RNAP and mimic the downstream segment of promoter complexes. We demonstrate that RNAP binding to downstream fork junctions is coupled with DNA melting around the transcription start point. Consequently, certain downstream fork junction probes can serve as transcription templates. Using a protein beacon fluorescent method, we identify structural determinants of affinity and transcription activity of RNAP-downstream fork junction complexes. Measurements of RNAP interaction with double-stranded promoter fragments reveal that the strength of RNAP interactions with downstream DNA plays a critical role in promoter opening and that the length of the downstream duplex must exceed a critical length for efficient formation of transcription competent open promoter complex. PMID- 21525533 TI - Strategic aspects of stomach cancer surgery. AB - The aim of the research is to study both immediate and long-term results of treatment in patients with gastric cancer after extended and expanded-combined gastrectomy; assessment of quality of life of patients, depending on the methods of reconstruction. 90 extensive and extensively-combined gastrectomies have been performed. 23 patients have been given operations with overlaying reservoirs at the reconstructive stage. The post-operational complications were observed among 18 (20%) patients in the main group, mortality was constituted 5 (5,6%). In the control group the above mentioned rates was constituted 14 (17,1%) and 3 (3,37%) correspondingly. The difference between the obtained data is statistically non authentic (p>0,05). Reflux-oesophagitis was detected among 17 (25,37%) patients after standard reconstructions and 2 (7,69%) - after overlaying the reservoirs (p<0,01). In the main group an annual disease free period constituted 94,11%, 3 year - 58,82%, in the control group - 73,2% and 32,9%, respectively. 3- and 5 year survival rate in the main group constituted 70,59% and 37,65%, in the control group - 47,6% and 13,4% correspondingly (p<0,01). Extensive and extensively-combined gastrectomies improve distant results of the treatment among the patients with stomach cancer and aren't followed by increase in rate of post operational complications and mortality. Overlaying the reservoirs decrease the rate and intensity of reflux pathology. PMID- 21525534 TI - [Predictive value of some parameters of immune balance in preeclampsia]. AB - The goal of our research was to reveal correlation between pro- and anti inflammatory cytokines in preeclamptic women. The research was conducted on pregnant women with physiologic pregnancy and with preeclampsia. Parameters of immune system - pro-inflammatory cytokines (IL-2; TNF-alpha) and anti inflammatory cytokine (IL-10) were measured in venous blood by ELISA. The increase of TNF-alpha and decrease of IL-10 in blood of pregnant women with pre eclampsia after 20 weeks of gestation were observed; the content of IL-2 was in norm. The highest activation of inflammatory reactions was at the 20-28 weeks of gestation. It was found that women with preeclampsia had high levels of TNF- alpha in their blood. The increase of TNF- alpha has a prognostic significance. PMID- 21525535 TI - Acoustic neuroma diagnosis. AB - Pure tone audiometry, PTA, has been regarded as an initial step when starting acoustic neuroma, AN, diagnostic service. If observing unilateral/asymmetrical sensorineural hearing loss, electronystagmography, ENG, and registration of auditory brainstem responses, ABRs, are instructed to perform. The measures of the methods are listed appearing particularly effective for AN detecting. Efficacy of ENG and ABR approaches in verification of ANs of even initial stages has been stated to reach the absolute identification score, 100%. In tinnitus and/or vertigo complaints, ENG and ABR examinations are recommended to utilize under normal PTA even. The positive evidence of ANs via ENG and ABR has to validate by contrasting magnetic resonance imaging, MRI, while MRI data are advised to utilize for assessment of concrete strategy of surgical intervention. Under negative ENG and ABR outcomes, on the other hand, MRI is considered as a hardly urgent procedure. PMID- 21525536 TI - Peculiarities of the anatomo-morphological parameters of teeth and root canals in permanent dentition in Georgian population. AB - One of the main reasons that cause the failure of endodontic treatment is the lack of knowledge of complex anatomy of the tooth cavity. Numerous studies over the years have established a complex structure of the tooth root system, a particular configuration of which determines the uniqueness of each tooth.Numerous researches have laid the foundation for anatomical and morphological peculiarities of root system of the tooth, their classification and nomenclature indices. The anatomical picture of the tooth, its shape, root length - the "norms" have been established in the course of years. Statistical indices do not represent universal criteria due to the fact that anthropometric data are subjected to variations in accordance with national and geographic zones. The aim of our study is to establish anatomo-morphological peculiarities of the groups of teeth, roots and canals in Georgian population and to develop statistically reliable indicators on the basis of anthropological and clinical data. The obtained data will help to improve the effective endodontic treatment and avoid complications after obturation. PMID- 21525537 TI - [New possibilities for elimination of human papillomavirus from the organism]. AB - The variety of mechanisms of human papillomavirus (HPV) infection suggests that the success of treatment depends on the choice of a universal method, which combines the actions of etiotropic, pathogenetic and symptomatic approaches, without causing unwanted side effect. All these requirements are met by a drug based on the products of plant origin - Indinol. The observed patients with resistant forms of genital warts were divided into 3 groups: first group received the treatment according to the standard, conventional scheme; patients of the second group in addition to the standard scheme 2 times a day (for 90 days) received 2 capsules of Indinol (200 mg) and the patients of third group simultaneously with Indinol undergo infrared irradiation. The results of the observation have shown that the addition of Indinol to the standard treatment had a significant positive effect on the healing process of patients with resistant forms of genital warts. The effects of the Indinol in combination with infrared therapy revealed a statistically significant reduction (3 times) the frequency of relapses in cases of clinically sever forms of disease. Thus, during combined treatment of patients with recurrent, clinically severe forms of genital HPV, it is advisable to use the Indinol, which evidently has the well pronounced virus eliminative and anti-recurrent actions. PMID- 21525538 TI - [Clinical effectiveness of electrostatic vibration massages in fibromyalgia syndrome]. AB - The most frequent symptoms of fibromyalgia syndrome (FMS) are pains in the softpart and muscle. The Optimal treatment for management of FMS has not been reported yet. Current pharmacological therapies are often ineffective. The aim of the research is to present the results of treatment for FMS with vibration massage by deep oscillations. 70 patients with FMS were treated with deep oscillation. The efficiency of treatment were evaluated according to the assessment criteria (Fibromyalgia Impact Questionnaire, Visual Analogous Scale, the Pain Sensation Scale, as well as the Multidimensional Sensitive Questionnaire and the Mainz - Stadium Model Pain Chronification). This study demonstrated improvement of symptoms, quality of life, and reduction in pain during two months after treatment. Vibration massage by deep oscillations shows effectiveness for fibromyalgia. PMID- 21525539 TI - Changes in cognitive evoked potentials during non pharmacological treatment in children with attention deficit/hyperactivity disorder. AB - Attention deficit/hyperactivity disorder (ADHD) is one of the most widely spread condition of school aged children affecting 5% of children of this age. The unified consensus of the precise diagnosis of this condition is still absent. This fact encourages the researchers to seek the alternative neurometric tools which will help the clinicians in diagnosis making process of ADHD. The neurophysiologic approaches especially event-related potentials (ERPs) are mostly important from this point of view. The later response of ERPs (P3) reflects the most important parts of executive functioning frequently affected in ADHD children - the process of mental effortfullness to select the appropriate behavior and decision making. Besides the diagnosis the treatment of ADHD is also the point of concern of neurologists and neurophyschologists. In recent years EEG biofeedback ( Neurofeedback-NF) have become the alternative treatment as in some cases pharmacological drugs are non effective. The positive impact of NF was based on improvement detected by various questionnaires which are less valid but its effectiveness on ERPs parameters is still unknown. Thus we aimed to study the changes of ERPs after NF therapy. METHODS: We have studied 93 children with ADHD of combined subtype (ADHDcom) without any kind of pharmacological treatment. Age range 9-12 years. The children were divided into two subgroups: The first ADHDcom 1 (48 children) were children where NF treatment was carried out and the second subgroup of ADHDcom-2 (45 children) were non treated children. RESULTS: We have observed statistically significant improvement of parameters of later response like P3 in ADHD-1 compared with ADHD-2 whereas NF was non effective for earlier component like N1. CONCLUSIONS: NF can positively affect on the P3 parameters which is very important in ADHD children as P3 reflects the speed of information processing as well as selection of appropriate action and decision making which are frequently affected in ADHD children. PMID- 21525540 TI - Identification, management and complications of intra-abdominal hypertension and abdominal compartment syndrome in neonatal intensive care unit (a single centre retrospective analysis). AB - The abdominal compartment syndrome (ACS) is a result of increased intra-abdominal pressure (IAP) due to tissue edema or free fluid collecting in the abdominal cavity. Elevated pressure in the abdomen is referred to as intra-abdominal hypertension (IAH). The end result of ACS, if undetected and untreated, is multisystem organ failure and patient death. Intra-abdominal pressure monitoring should be strongly considered in all patients with this clinical presentation. Normal intra-abdominal pressure is 0-5 mm Hg. Physiologic compromise begins when the pressure rises above 8-10 mm Hg. Once the pressures increase beyond 20 mm Hg irreversible tissue injury occurs, ultimately resulting in ACS and multiple organ failure. Early recognition of rising abdominal pressure is critically important, because it allows prompt intervention which will prevent ACS from developing, leading to a much better prognosis for the patient. The purpose of the research was to: 1) Detect abdominal compartment syndrome in newborns with clinically suspicious intra-abdominal hypertension; 2) Identify intra-abdominal pressure numbers presented with clinical manifestation; 3) Measure and detect intra abdominal pressure numbers presented with abdominal compartment syndrome; 4) Find correlation between intra-abdominal hypertension grade and patient outcome. For completion of our goal we selected and reviewed medical records of 155 neonatal patients from 2008 to 2010, who stayed in surgical neonatal intensive care unit for more than 7 days. We monitored IAP in patients with suspected ACS and different clinical presentation. According to our research we may come to the following conclusion: Intra-abdominal hypertension was confirmed in most suspected cases. Intra-abdominal pressure of >10 mmHg in patients with clinical suspicion may be considered as intra-abdominal hypertension. Intra-abdominal hypertension is in close correlation with presence of fluid in abdominal cavity proved by ultrasound investigation. Intra-abdominal pressure of >=20 mmHg can be considered as a point of development of abdominal compartment syndrome. The grade of hypertension is in close correlation with patient outcome. PMID- 21525541 TI - [Stratification of risk factors of progressing of acute respiratory infection in children]. AB - The work purpose is the complex estimation of endogenous intoxication (change of optical density of plasma and erythrocytes), depressions of tissue hypoxia and functions of protective system, clinical and laboratory stratification of the risks-factors promoting progressing of disease and complication of pneumonia. There was carried cross-section study. The study included 36 patients from 1 to 7 years with an acute respiratory infection. The control group was made up of 19 healthy children. The comparative analysis of results of the specified factors and laboratory research set as the purpose to reveal the predictable negative risk factors. Evaluation of the quantitative findings of risks-factors was carried out in 95 % taking into account the confidence interval (CI). For the acute respiratory infection complicated with pneumonia, was determined strongly marked toxemia, and also high activity of antioxidant systems (SOD and catalase) and lysosomal enzymes (catepsin, RNA) was noted. The prognosis of the authentic risks-factors of acute respiratory disease was defined with following indicators: age of the child - before three years; hereditary background with a respiratory system pathology; the tobacco use in a family; low level of knowledge of parents; incomplete treatment; change of optical density of plasma and erythrocytes; fall (reduction) of redox-potential of the system of energy maintenance. We developed predictable model on probability of expected complications of respiratory system and groups of low, average and high risk were allocated. PMID- 21525542 TI - Environmental safety risk research. AB - Pilot epidemiology survey has been conducted with the aim to study the effect of occupational factors on workers in the Zestafoni Manganese Processing Plant. Overall 102 workers have been surveyed. They were selected from the list circulating in the plant ambulance. Selected workers have been surveyed through a standard questionnaire. The survey revealed that prevalence of such diseases as Radiculitis, hypertension, bronchitis, gastritis, and ulcer, ocular and nasal pharyngeal diseases are high among the workers of the Zestafoni Processing Plant. Study results have shown direct correlation between development of diseases and distance residence from the plant. Prevalence of hypertension, ocular and nasal pharyngeal diseases, bronchitis was higher among workers lived within distance of 2-5 kilometers from the plant. Positive correlation revealed between length of job and prevalence of bronchitis, ocular diseases, Radiculitis, hypertension, cardiac diseases and gastritis. Among plant workers revealed high prevalence of symptoms characterized the central nervous system disorders such as sleep disorder, insomnia, backache, walking disorders. The results proven correlation between occupational factors and diseases and different symptoms. PMID- 21525543 TI - Pancreatic D-cells in aging and intraislet effects of pancreatic somatostatin. AB - In old organisms pancreatic D-cells are not changed in number. During the aging in mentioned cells takes place the intensification of secretory and extrusive functions, which are more prominent in old organisms than in young ones. Peripherally situated D-cells are vascularly ineffective within the pancreatic islet and do not suppress locally B- and A-cells. D-cells' major target tissue may be pancreatic acinar cells. Functionally activated D-cells in old organisms may play the main role in the development of involutive processes in exocrine pancreas and in its atrophy. Stagnation of the secretory granules in pancreatic A and B-cells in old ages could not be caused by influence of paracrine effect of somatostatin. The given process could be considered as a result of reduction of energopotentials and suppression of signal ways for initiation of insulin and glucagon secretion. Respectively, extrusion impediment of secretory granules resulted in their stagnation could be explained by suppression of exocytosis as an energy- and signal-dependent process. We suppose that cytotopographic and microvascular peculiarities of pancreatic islets in human beings and rodents is a reflection of intensification of insulin apparatus and is directed to loose the B cells from the local (microvascular or paracrine) influences (effects of D- or A cells). The mentioned is of high physiological importance (especially in the process of aging) for the organisms of above-presented taxonomic groups due to rich amount of carbohydrates in their food ration. The above-mentioned fact gains the special importance in human beings, where evolutionary "solitary" (represented by single B-cells) insulin apparatus is faced with evolutionary "rooted" strong and diverse contrainsulin apparatus, leading to development of diabetes mellitus (type 2) in late ages. PMID- 21525544 TI - The spectrum of hemispheral cortex lesions in intrauterine alcoholic intoxication. AB - Aim of the study was to examine the specific morphological changes of brain cortex in fetal alcoholic intoxication model. The latter was performed in male and female animals by substituting water with 15% ethyl alcohol during 1 month period, which was followed by putting pregnant females on alcohol of the same concentration for the duration of the whole period of pregnancy (21 days). 24 experimental and 10 control (intact) animals were subjected to study overall. The study material applied the samples of brain convexital cortex from foetus and newborn rats. Paraffin-embedded slices (films) were dyed by the method of Nissle and hematoxylin eosin. After immersion fixation in 2.5% glutaraldehyde and 1% osmium acid solutions followed by double contrasting, the ultrathin slices were studied in the electron microscope Tesla BS 500. Macroscopic study demonstrated the hyperemia of pia with partial incorporation, different types of neuroorganogenesis disturbance, also, leptomeningeal heterotopia and microcephaly in 6 cases from 24 (25%) in the experimental group. Morphology of cortical damage to fetal brain in alcoholic intoxication was demonstrated by progressive massive destruction of neuronal mitochondria, involutional changes in dendrites and their processes and glial proliferation, which possibly account for the structural basis of energetic and informational deficit in neurons. Acquired data may be extrapolated on human model of alcoholic embryopathy with subsequent cognitive problems. PMID- 21525545 TI - [Study of toxicity of denture prosthetic appliance prothyl hot on the Jurkat cell model system]. AB - The aim of our study was the investigation of toxicity of denture prosthetic appliance Prothyl Hot on the model system of Jurkat cell culture. As a result of our study it was revealed that denture prosthetic appliance Prothyl Hot: - hadn't manifested toxic effects the viability Jurkat cells (that reviled by stability of activity of mitochondrial dehydrogenises and mean of mitochondrial membrane potential; - didn't influence on the balance of pro-and antyinflammatory cytokines, expressed by Jurkat cells; - induces intensification of oxidative metabolism in Jurkat cells, which may be considered as compensatory reaction developing in the cells. PMID- 21525546 TI - [Gummi armeniacae collected from apricot trees in armenia - perspective source of arabinogalactan]. AB - The subjects of this inquiry were apricot tree gums - Gummi armeniacae, collected from different regions of Republic Armenia. The samples of gums were analyzed by the method of gas-liquid chromatography. As a result arabinogalactans were revealed in apricot tree gums. Due to the presence of sufficient resources of Gummi armeniacae in Armenian flora their usage in the water soluble arabinogalactan's obtaining process is quite perspective. PMID- 21525547 TI - Real-time monitoring of complex moduli from micro-rheology. AB - We describe an approach to on-line analysis of micro-rheology data using a multi scale time-correlation method. The method is particularly suited to processing high-volume data streams and compressing the relevant information in real time. Using this, we can obtain complex moduli of visco-elastic media without our method suffering from the high-frequency artefacts that are associated with the truncation errors in the most widely used versions of micro-rheology. Moreover, the present approach obviates the need to choose the time interval for data acquisition beforehand. We test our approach first on an artificial data set and then on experimental data obtained both for an optically trapped colloidal probe in water and for a similar probe in polyethylene glycol solutions at various concentrations. In all cases, we obtain good agreement with the bulk rheology data in the region of overlap. We compare our method with the conventional Kramers-Kronig (KK) transform approach and find that the two methods agree over most of the frequency regime. For the same data set, the present approach is superior to the KK one at high frequencies and can be made to perform at least comparably at low frequencies. PMID- 21525548 TI - Magnetic-field-induced nematic-nematic phase separation and droplet formation in colloidal goethite. AB - We demonstrate the suitability of polarization microscopy to study the recently discovered (parallel) nematic-(perpendicular) nematic phase separation. This novel type of phase transition is induced by applying an external magnetic field to a nematic liquid crystal of boardlike colloidal goethite and is due to an interplay between the intrinsic magnetic properties of goethite and the collective effect of liquid crystal formation. It is shown that the intense ochre colour of goethite does not preclude the use of polarization microscopy and interference colours, and that dichroism can give valuable qualitative information on the nature of the phases, their anchoring and their sedimentation and order parameter profiles. We also apply these techniques to study 'nematic nematic tactoids': nematic droplets sedimenting within a nematic medium with mutually perpendicular orientations. PMID- 21525549 TI - How much does the core structure of a three-phase contact line contribute to the line tension near a wetting transition? AB - We initially simplify a three-phase contact line to a 'primitive' star-shaped structure formed by three planar interfaces meeting at a common line of intersection, and calculate the line tension associated with this primitive picture. Next, we consider the well-known more refined picture of the contact line that includes a 'core structure' consisting of interface deviations away from the planar interface picture. The corresponding contact line properties were calculated earlier, within mean-field theory, using an interface displacement model or a more microscopic density-functional theory. The question we ask is to what extent the thermodynamic line tension of the contact line near a wetting phase transition can be attributed to the core structure. To answer it we compare our result for the line tension contribution associated with the primitive structure to the known line tension of the full structure (within mean-field theory). While our primitive structure calculation provides a surprisingly useful upper bound to the known line tension near a critical wetting transition, the nontrivial core structure of the contact line near first-order wetting is found to be responsible for an important difference between the known line tension and the upper bound provided by the primitive picture calculation. This accounts also for the discrepancy between the line tensions calculated by two different methods in an earlier mean-field density-functional model of a first-order wetting transition. PMID- 21525550 TI - Phase behaviour of binary mixtures of diamagnetic colloidal platelets in an external magnetic field. AB - Using fundamental measure density functional theory we investigate paranematic nematic and nematic-nematic phase coexistence in binary mixtures of circular platelets with vanishing thicknesses. An external magnetic field induces uniaxial alignment and acts on the platelets with a strength that is taken to scale with the platelet area. At particle diameter ratio lambda = 1.5 the system displays paranematic-nematic coexistence. For lambda = 2, demixing into two nematic states with different compositions also occurs, between an upper critical point and a paranematic-nematic-nematic triple point. Increasing the field strength leads to shrinking of the coexistence regions. At high enough field strength a closed loop of immiscibility is induced and phase coexistence vanishes at a double critical point above which the system is homogeneously nematic. For lambda = 2.5, besides paranematic-nematic coexistence, there is nematic-nematic coexistence which persists and hence does not end in a critical point. The partial orientational order parameters along the binodals vary strongly with composition and connect smoothly for each species when closed loops of immiscibility are present in the corresponding phase diagram. PMID- 21525551 TI - Structural signature of slow dynamics and dynamic heterogeneity in two dimensional colloidal liquids: glassy structural order. AB - Glassy states are formed if crystallization is avoided upon cooling or increasing density. However, the physical factors controlling the ease of vitrification and the nature of glass transition remain elusive. Among various glass-forming systems, colloidal liquids are one of the most ideal glass-forming systems because of the simplicity and controllability of the interactions. We use numerical simulations of two-dimensional polydisperse and binary hard discs to tackle both of these longstanding questions. For polydisperse systems, we systematically control the polydispersity, which can be regarded as the strength of frustration effects on crystallization. We reveal that crystal-like hexatic order grows in size and lifetime with an increase in the colloid volume fraction or with a decrease in polydispersity (or frustration). We stress that hexatic ordering in hard disc systems is a direct consequence of dense packing and a manifestation of low configurational entropy. Our study suggests an intriguing scenario that the strength of frustration controls both the ease of vitrification and the nature of the glass transition. Vitrification may be a process of hidden crystal-like ordering under frustration for this system. This may provide not only a physical basis for glass formation, but also an answer to another longstanding question on the structure of amorphous materials: 'order in disorder' may be an intrinsic feature of a glassy state of many materials. For binary mixtures, on the other hand, the relevant structural feature linked to slow dynamics is not hexatic order, but an amorphous structure of low structural entropy. These results suggest that slow dynamics is associated with bond orientational order linked to the crystal for a weakly frustrated system, whereas to amorphous structures of low configurational entropy for a strongly frustrated system. This suggests an intrinsic link between structure and dynamics in glass forming materials: slow dynamics is linked to structuring ('glassy ordering') towards low configurational entropy. We discuss the nature of 'glassy order' responsible for slow dynamics. PMID- 21525552 TI - 3D structure of nematic and columnar phases of hard colloidal platelets. AB - We present small angle x-ray scattering data of single-domain nematic and columnar liquid crystal phases in suspensions of sterically stabilized gibbsite platelets. The measurements are performed with different sample orientations to obtain information about the three-dimensional structure of the liquid crystalline phases. With the x-ray beam incident along the director of the nematic phase a strong correlation peak is observed corresponding to the side-to side interparticle correlations, which suggests a columnar nematic structure. Upon sample rotation this side-to-side correlation peak of the nematic shifts to higher Q-values, suggesting the presence of strong fluctuations of small stacks of particles with different orientations, while the overall particle orientation is constant. In the hexagonal columnar phase, clear Bragg intercolumnar reflections are observed. Upon rotation, the Q-value of these reflections remains constant while their intensity monotonically decreases upon rotation. This indicates that the column orientation fluctuates together with the particle director in the columnar phase. This difference between the behaviour of the columnar and the nematic reflections upon sample rotation is used to assign the liquid crystal phase of a suspension consisting of larger platelets, where identification can be ambiguous due to resolution limitations. PMID- 21525553 TI - Structural searches using isopointal sets as generators: densest packings for binary hard sphere mixtures. AB - Algorithms to search for crystal structures that optimize some extensive property (energy, volume, etc) typically make use of random particle reorganizations in the context of one or more numerical techniques such as simulated annealing, genetic algorithms or biased random walks, applied to the coordinates of every particle in the unit cell, together with the cell angles and lengths. In this paper we describe the restriction of such searches to predefined isopointal sets, breaking the problem into countable sub-problems which exploit crystal symmetries to reduce the dimensionality of the search space. Applying this method to the search for maximally packed mixtures of hard spheres of two sizes, we demonstrate that the densest packed structures can be identified by searches within a couple of isopointal sets. For the A(2)B system, the densest known packings over the entire tested range 0.2 < r(A)/r(B) < 2.5, including some improvements on previous optima, can all be identified by searches within a single isopointal set. In the case of the AB composition, searches of two isopointal sets generate the densest packed structures over the radius ratio range 0.2 < r(A)/r(B) < 5.0. PMID- 21525554 TI - Polydispersity effects in colloid-polymer mixtures. AB - We study phase separation and transient gelation experimentally in a mixture consisting of polydisperse colloids (polydispersity: ~ 6%) and non-adsorbing polymers, where the ratio of the average size of the polymer to that of the colloid is ~ 0.062. Unlike what has been reported previously for mixtures with somewhat lower colloid polydispersity (~ 5%), the addition of polymers does not expand the fluid-solid coexistence region. Instead, we find a region of fluid solid coexistence which has an approximately constant width but an unexpected re entrant shape. We detect the presence of a metastable gas-liquid binodal, which gives rise to two-stepped crystallization kinetics that can be rationalized as the effect of fractionation. Finally, we find that the separation into multiple coexisting solid phases at high colloid volume fractions predicted by equilibrium statistical mechanics is kinetically suppressed before the system reaches dynamical arrest. PMID- 21525555 TI - The theory of delamination during drying of confined colloidal suspensions. AB - Recent experiments on the drying of colloidal films in confined thin rectangular geometries show an interesting new phenomenon: the delamination of the colloidal suspension from the cavity wall. The theory developed in this paper explains the phenomenon by applying the Griffith energy criteria to a poroelastic film of Hertzian spheres. Prior to delamination, flow due to drying compresses the film in the direction of flow and generates tension in the transverse direction. Delamination allows relaxation in both the transverse tensile stresses and the axial compression. Preliminary numerical solutions suggest that the elastic energy recovered should increase linearly with the length of the close-packed film. That suggests a simple analytical solution that predicts the advancing of the delamination as the length of the close-packed region increases and explains qualitatively the essential features of the phenomenon. PMID- 21525556 TI - Structure of colloidal sphere-plate mixtures. AB - In addition to containing spherical pigment particles, coatings usually contain plate-like clay particles. It is thought that these improve the opacity of the paint film by providing an efficient spacing of the pigment particles. This observation is counterintuitive, as suspensions of particles of different shapes and sizes tend to phase separate on increase of concentration. In order to clarify this matter a model colloidal system is studied here, with a sphere-plate diameter ratio similar to that found in paints. For dilute suspensions, small angle neutron scattering revealed that the addition of plates leads to enhanced density fluctuations of the spheres, in agreement with new theoretical predictions. On increasing the total colloid concentration the plates and spheres phase separate due to the disparity in their shape. This is in agreement with previous theoretical and experimental work on colloidal sphere-plate mixtures, where one particle acts as a depleting agent. The fact that no large scale phase separation is observed in coatings is ascribed to dynamic arrest in intimately mixed, or possibly micro-phase separated structures, at elevated concentration. PMID- 21525557 TI - Crystallization in suspensions of hard spheres: a Monte Carlo and molecular dynamics simulation study. AB - The crystallization of a metastable melt is one of the most important non equilibrium phenomena in condensed matter physics, and hard sphere colloidal model systems have been used for several decades to investigate this process by experimental observation and computer simulation. Nevertheless, there is still an unexplained discrepancy between the simulation data and experimental nucleation rate densities. In this paper we examine the nucleation process in hard spheres using molecular dynamics and Monte Carlo simulation. We show that the crystallization process is mediated by precursors of low orientational bond-order and that our simulation data fairly match the experimental data sets. PMID- 21525558 TI - Tuning the demixing of colloid-polymer systems through the dispersing solvent. AB - We report measurements on fluid-fluid phase separation in a colloid-polymer mixture by means of confocal scanning laser microscopy and we show that we can access the various coarsening regimes by tuning the properties of the solvent. By increasing the viscosity of the solvent we are able to access the diffusive hydrodynamic regime of spinodal decomposition. By matching the density of the solvent and colloids we are able to grow structures to large length scales before they are destroyed by buoyancy forces. Tuning the solvent's density furthermore gives control over which phase flows up and down, illustrating the flexibility of this particular system. PMID- 21525559 TI - Crystallization and aging in hard-sphere glasses. AB - We report new results from our programme of molecular dynamics simulation of hard sphere systems, focusing on crystallization and glass formation at high concentrations. First we consider a much larger system than hitherto, N = 86 400 equal-sized particles. The results are similar to those obtained with a smaller system, studied previously, showing conventional nucleation and growth of crystals at concentrations near melting and crossing over to a spinodal-like regime at higher concentrations where the free energy barrier to nucleation appears to be negligible. Second, we investigate the dependence on the initial state of the system. We have devised a Monte Carlo 'constrained aging' method to move the particles in such a way that crystallization is discouraged. After a period of such aging, the standard molecular dynamics programme is run. For a system of N = 3200, we find that constrained aging encourages caging of the particles and slows crystallization somewhat. Nevertheless, both aged and unaged systems crystallize at volume fraction phi = 0.61 whereas neither system shows full crystallization in the duration of the simulation at phi = 0.62, a concentration still significantly below that of random close packing. PMID- 21525560 TI - A systematic coarse-graining strategy for semi-dilute copolymer solutions: from monomers to micelles. AB - A systematic coarse-graining procedure is proposed for the description and simulation of AB diblock copolymers in selective solvents. Each block is represented by a small number, n(A) or n(B), of effective segments or blobs, containing a large number of microscopic monomers. n(A) and n(B) are unequivocally determined by imposing that blobs do not, on average, overlap, even if complete copolymer coils interpenetrate (semi-dilute regime). Ultra-soft effective interactions between blobs are determined by a rigorous inversion procedure in the low concentration limit. The methodology is applied to an athermal copolymer model where A blocks are ideal (theta solvent), B blocks self avoiding (good solvent), while A and B blocks are mutually avoiding. The model leads to aggregation into polydisperse spherical micelles beyond a critical micellar concentration determined by Monte Carlo simulations for several size ratios f of the two blocks. The simulations also provide accurate estimates of the osmotic pressure and of the free energy of the copolymer solutions over a wide range of concentrations. The mean micellar aggregation numbers are found to be significantly lower than those predicted by an earlier, minimal two-blob representation (Capone et al 2009 J. Phys. Chem. B 113 3629). PMID- 21525561 TI - Cholesteric order in systems of helical Yukawa rods. AB - We consider the interaction potential between two chiral rod-like colloids which consist of a thin cylindrical backbone decorated with a helical charge distribution on the cylinder surface. For sufficiently slender helical rods a simple scaling expression is derived which relates the chiral 'twisting' potential to the microscopic properties of the particles, such as the internal helical pitch, charge density and electrostatic screening parameter. To predict the behaviour of the macroscopic cholesteric pitch of the fluid bulk phase we invoke a simple second-virial theory generalized to treat anisotropic states with weakly twisted director fields. It is shown that, while particles with weakly coiled helices always form a cholesteric phase whose helical sense is commensurate with that of the internal helix, more strongly coiled rods lead to the formation of a cholesteric state of opposite sense. The correlation between the helical symmetry at the microscopic and macroscopic scale is found to be very sensitive to the pitch of the Yukawa helix. Mixing helical particles of sufficiently disparate length and internal pitch may give rise to a demixing of the uniform cholesteric phase into two fractions with a different macroscopic pitch. Our findings could be relevant to the interpretation of experimental observations in systems of cellulose and chitin microfibres, DNA and fd virus rods. PMID- 21525562 TI - Rheo-SAXS investigation of shear-thinning behaviour of very anisometric repulsive disc-like clay suspensions. AB - Aqueous suspensions of swelling clay minerals exhibit a rich and complex rheological behaviour. In particular, these repulsive systems display strong shear-thinning at very low volume fractions in both the isotropic and gel states. In this paper, we investigate the evolution with shear of the orientational distribution of aqueous clay suspensions by synchrotron-based rheo-SAXS experiments using a Couette device. Measurements in radial and tangential configurations were carried out for two swelling clay minerals of similar morphology and size, Wyoming montmorillonite and Idaho beidellite. The shear evolution of the small angle x-ray scattering (SAXS) patterns displays significantly different features for these two minerals. The detailed analysis of the angular dependence of the SAXS patterns in both directions provides the average Euler angles of the statistical effective particle in the shear plane. We show that for both samples, the average orientation is fully controlled by the local shear stress around the particle. We then apply an effective approach to take into account multiple hydrodynamic interactions in the system. Using such an approach, it is possible to calculate the evolution of viscosity as a function of shear rate from the knowledge of the average orientation of the particles. The viscosity thus recalculated almost perfectly matches the measured values as long as collective effects are not too important in the system. PMID- 21525563 TI - Brownian motion of a self-propelled particle. AB - Overdamped Brownian motion of a self-propelled particle is studied by solving the Langevin equation analytically. On top of translational and rotational diffusion, in the context of the presented model, the 'active' particle is driven along its internal orientation axis. We calculate the first four moments of the probability distribution function for displacements as a function of time for a spherical particle with isotropic translational diffusion, as well as for an anisotropic ellipsoidal particle. In both cases the translational and rotational motion is either unconfined or confined to one or two dimensions. A significant non Gaussian behaviour at finite times t is signalled by a non-vanishing kurtosis gamma(t). To delimit the super-diffusive regime, which occurs at intermediate times, two timescales are identified. For certain model situations a characteristic t(3) behaviour of the mean-square displacement is observed. Comparing the dynamics of real and artificial microswimmers, like bacteria or catalytically driven Janus particles, to our analytical expressions reveals whether their motion is Brownian or not. PMID- 21525564 TI - The Donnan equilibrium: I. On the thermodynamic foundation of the Donnan equation of state. AB - The thermodynamic equilibrium between charged colloids and an electrolyte reservoir is named after Frederic Donnan who first published on it one century ago (Donnan 1911 Z. Electrochem. 17 572). One of the intriguing features of the Donnan equilibrium is the ensuing osmotic equation of state which is a nonlinear one, even when both colloids and ions obey Van 't Hoff's ideal osmotic pressure law. The Donnan equation of state, nevertheless, is internally consistent; we demonstrate it to be a rigorous consequence of the phenomenological thermodynamics of a neutral bulk suspension equilibrating with an infinite salt reservoir. Our proof is based on an exact thermodynamic relation between osmotic pressure and salt adsorption which, when applied to ideal ions, does indeed entail the Donnan equation of state. Our derivation also shows that, contrary to what is often assumed, the Donnan equilibrium does not require ideality of the colloids: the Donnan model merely evaluates the osmotic pressure of homogeneously distributed ions, in excess of the pressure exerted by an arbitrary reference fluid of uncharged colloids. We also conclude that results from the phenomenological Donnan model coincide with predictions from statistical thermodynamics in the limit of weakly charged, point-like colloids. PMID- 21525565 TI - Phase stability of a reversible supramolecular polymer solution mixed with nanospheres. AB - Theory is presented for the phase stability of mixtures containing nanospheres and non-adsorbing reversible supramolecular polymers. This was made possible by incorporating the depletion thickness and osmotic pressure of reversible supramolecular polymer chains into generalized free-volume theory, recently developed for investigating the phase behaviour of colloidal spheres mixed with interacting polymers (Fleer and Tuinier 2008 Adv. Colloid Interface Sci. 143 1 47). It follows that the fluid-fluid phase stability region where reversible supramolecular polymer chains can be mixed with nanospheres is sensitive to the energy of scission between the monomers and to the nanoparticle radius. One can then expect the fluid-fluid coexistence curves to have a strong dependence on temperature and that shifting of phase boundaries within a single experimental system should be possible by varying the temperature. The calculations reveal the width of the stability region to be rather small. This implies that phase homogeneity of product formulations containing reversible supramolecular polymers is only possible at low nanoparticle concentrations. PMID- 21525566 TI - When depletion goes critical. AB - Depletion interactions in correlated fluids are investigated both theoretically and experimentally. A formally exact derivation of a general expression for depletion interactions is presented and then specialized to the case of critical correlations in the depletant by employing a long wavelength approximate analysis. A scaling expression is obtained in the critical region, suggesting a close connection to the critical Casimir effect. As a result we are able to compute the full scaling function of the critical Casimir effect in terms of the known scaling form of the depletant equation of state. These predictions are experimentally tested in a colloidal suspension with a micellar solution as depletion agent. Colloids are seen to aggregate reversibly when the micellar concentration exceeds a temperature dependent value which becomes remarkably small as the temperature approaches the lower consolution point of the micellar suspension. Continuity between the standard depletion picture at low temperature and the Casimir effect in the critical region is demonstrated by identifying several approximate scaling laws which compare favorably with the theoretical analysis. The transition line is seen to lie close to the curve of maximum susceptibility of the depletant. A model, analyzed within mean field approximation, is shown to reproduce the main qualitative features of the phenomenon. PMID- 21525567 TI - Modeling of equilibrium hollow objects stabilized by electrostatics. AB - The equilibrium size of two largely different kinds of hollow objects behave qualitatively differently with respect to certain experimental conditions. Yet, we show that they can be described within the same theoretical framework. The objects we consider are 'minivesicles' of ionic and nonionic surfactant mixtures, and shells of Keplerate-type polyoxometalates. The finite-size of the objects in both systems is manifested by electrostatic interactions. We emphasize the importance of constant charge and constant potential boundary conditions. Taking these conditions into account, indeed, leads to the experimentally observed qualitatively different behavior of the equilibrium size of the objects. PMID- 21525568 TI - Associating changes in output behavior with changes in parameter values in spiking and bursting neuron models. AB - Several recent studies have demonstrated that neuronal models allow multiple parameter value solutions for a given output. In the face of this variability of parameter values, what can be learned about neural function through parameter value differences? Here, in two different models, we examine this question by attempting to reconstruct the source of model output changes based on simple statistical analyses of parameter distributions generated by automated searches. We conclude that changes to parameter values or their associated distributions do not reliably reflect the specific mechanisms responsible for a given change in output. PMID- 21525569 TI - Modeling electroencephalography waveforms with semi-supervised deep belief nets: fast classification and anomaly measurement. AB - Clinical electroencephalography (EEG) records vast amounts of human complex data yet is still reviewed primarily by human readers. Deep belief nets (DBNs) are a relatively new type of multi-layer neural network commonly tested on two dimensional image data but are rarely applied to times-series data such as EEG. We apply DBNs in a semi-supervised paradigm to model EEG waveforms for classification and anomaly detection. DBN performance was comparable to standard classifiers on our EEG dataset, and classification time was found to be 1.7-103.7 times faster than the other high-performing classifiers. We demonstrate how the unsupervised step of DBN learning produces an autoencoder that can naturally be used in anomaly measurement. We compare the use of raw, unprocessed data--a rarity in automated physiological waveform analysis--with hand-chosen features and find that raw data produce comparable classification and better anomaly measurement performance. These results indicate that DBNs and raw data inputs may be more effective for online automated EEG waveform recognition than other common techniques. PMID- 21525570 TI - Drug discovery for neurodegenerative diseases: challenges and novel biochemical targets dedicated to the memory of Mark A. Smith for his inspiring contribution to Alzheimer's disease. PMID- 21525571 TI - Panama: Forging a path toward international science hub by Dr. Ruben Berrocal. PMID- 21525572 TI - Impact of cigarette smoking on kidney transplant recipients: a systematic review. AB - INTRODUCTION: Cigarette smoking has adverse effects on kidney transplant recipients, causing cardiovascular disease, kidney function impairment, and cancer. However, there are surprisingly few studies on the impact of cigarette smoking among kidney transplant recipients and its consequences after transplantation. We performed a systematic review of the literature to identify the effects of cigarette smoking on patient and graft survival rates among kidney transplant recipients. MATERIALS AND METHODS: We searched the PubMed from 1968 to 2009 to identify studies on the effect of cigarette smoking on kidney transplant recipients, using the following keywords: kidney transplantation, cigarette, smoking, tobacco, and nicotine. The electronic and manual searches yielded 357 articles, of which 39 were considered potentially relevant by titles and abstracts and were selected for full text review. Twenty-seven irrelevant reports were excluded. RESULTS: A total of 12 papers were selected for review, comprising of 1801 kidney transplant recipients with a history of smoking. The impact of cigarette smoking on kidney recipient survival was only evaluated by 6 studies and the relative risk of smoking for death was available in 3 reports, varying between 0.8 and 2.2. Cigarette smoking was an independent risk factor for patient death. In addition, on univariable and multivariable analyses, graft survival correlated with a history of cigarette smoking and the relative risk for graft failure ranged from 1.06 to 2.3. CONCLUSIONS: Cigarette smoking was associated with an increased risk of death and graft loss. Therefore, every attempt should be made to encourage kidney transplant candidates to stop smoking. PMID- 21525573 TI - Immunohistochemical detection of p53 protein expression as a prognostic factor in Wilms tumor. AB - INTRODUCTION: Histological typing, especially the evidence of anaplasia and stage of the tumor are two major prognostic indicators in Wilms tumor, but some genetic factors have recently been noted. Mutations in TP53, which is a tumor suppressor gene, have been demonstrated to be associated with poor prognosis in some malignancies. There are also few studies which have confirmed the correlation between p53 protein overexpression and advanced course in Wilms tumor. This study was conducted to determine the correlation p53 immunoexpression and prognosis and outcome of Wilms tumor. MATERIALS AND METHODS: The overexpression of p53 in 44 specimens of children (26 boys and 18 girls) with Wilms tumor (median age, 36 months; range, 4 to 96 months) was assessed in Mofid Children's Hospital, Tehran, Iran. The overexpression of p53 was determined by immunohistochemistry with antihuman p53 antibody. RESULTS: A positive immunostaining for p53 was detected in 24 of the 44 cases (54.7%). The grade of the tumor and anaplasia were associated with p53 positivity, but there was no association of p53 with the tumor stage. In comparison to p53 negatives, week-moderate and high p53 expressing tumors had significantly decreased the overall survival (hazard ratio, 3.75 and 8.61; P = .05 and P = .01, respectively). CONCLUSIONS: Overexpression of p53 protein in Wilms tumor is an indicator of poor pro gnosis, because it is correlated with unfavorable histology tumors and a shorter survival period. PMID- 21525574 TI - Soluble interleukine-2 receptor and MDR1 gene expression levels as inflammatory biomarkers for prediction of steroid response in children with nephrotic syndrome. AB - INTRODUCTION: Upregulation of interleukin-2 may be involved, not only in the pathophysiology of nephrotic syndrome, but also in steroid resistance treatment, by increasing expression of multidrug resistant gene-1 (MDR1) gene on lymphocytes and its product P-glycoprotein effluxing corticosteroid. Our aim was to assess the relation of serum soluble interleukin-2 receptor (sIL2R) levels and MDR1 gene expression on lymphocytes with nephrotic syndrome and its corticosteroids therapy. MATERIALS AND METHODS: We examined 40 children with nephrotic syndrome (15 cases of recent onset and 25 known cases with relapse) and 20 healthy children as a control group. We examined every patient twice at the time of disease activity and within 1 week of remission. RESULTS: A significant increase was found in sIL2R level and MDR1 gene in the patients in comparison with the control group whether in activity or remission, and they were significantly higher in activity than in remission. Levels of sIL2R and MDR1 gene expression in different subgroups were higher in known cases with relapse than in new onsets, both in activity and remission, and relatively higher in steroid-resistant than in steroid-sensitive ones. CONCLUSIONS: We propose sIL2R and MDR1gene expression levels as early predictors of steroid resistance in nephrotic syndrome for early control of disease by immediate introduction of cytotoxic drugs. This is the first report providing new insight into the use of sIL2R as a predictor of steroid resistance. Thus, wide-scale studies are needed to determine a cutoff level of sIL2R above which cytotoxic drugs are introduced. PMID- 21525575 TI - Role of high-dose hydrochlorothiazide in idiopathic hypercalciuric urolithiasis of childhood. AB - INTRODUCTION: The aim of this study was to evaluate the role of hydrochlorothiazide in pediatric calculus formers with hypercalciuria and define possible factors affecting response to treatment. MATERIALS AND METHODS: Nineteen pediatric calculus formers, 12 girls and 7 boys, aged 15 days to 60 months, with idiopathic hypercalciuria received high-dose hydrochlorothiazide (1 mg/kg/d to 2 mg/kg/d) and citric acid-potassium citrate (1 mEq/kg/d) and were evaluated in a 2 year period. Avoiding high-salt diets was recommended throughout the study and increasing fluid intake was encouraged. RESULTS: The patients received hydrochlorothiazide for 2.5 to 15 months (mean, 6 +/- 3 months), and 10 of them (52.6%) reached normacalciuria. Resolution of hypercalciuria was associated with decreased calculi sizes in 1 (5.3%) and stone-free condition in 4 (21.1%). No significant differences were found between responders and nonresponders with regard to age at presentation, gender, family history of calculus, and size and number of calculi. CONCLUSIONS: Our study showed that a combination of diet modification and hydrochlorothiazide has reasonable hypocalciuric effects; however, it is not very efficient in stopping calculus formation process. In addition, clinical and radiological data were not helpful to predict patients with better response to treatment. PMID- 21525576 TI - Carotid intima-media thickness in maintenance hemodialysis patients: role of cardiovascular risk factor. AB - INTRODUCTION: Carotid intima-media thickness (CIMT) has been introduced as a cardiovascular disease predictor which may increase in hamodialysis patients. As there are many risk factors in the uremic state that theoretically lead to increase in CIMT, this study was aimed to determine risk factors of CIMT increase in a group of hemodialysis patients. MATERIALS AND METHODS: Seventy-two hemodialysis patients with a mean age of 61.3 +/- 15.0 years and 49 individuals with no history of chronic disease (control group) underwent ultrasonography for measurement of CIMT. Correlation of demographic, clinical, and laboratory factors with CIMT was studied. Carotid intima-media thickness was measured by one radiologist in the bilateral common carotid artery, and the mean value of the two sides was reported. RESULTS: The mean duration on dialysis was 82.4 +/- 78.0 months. The mean CIMT was 0.96 +/- 0.25 mm (range, 0.4 to 1.7 mm) in hemodialysis patients and 0.76 +/- 0.06 mm (range, 0.58 to 0.91 mm) in the control group (P < .001). The mean CIMT was significantly higher in men compared to women on dialysis and in diabetic compared to nondiabetics patients. There was a positive correlation between CIMT and age (r = 0.266, P = .02) and serum cholesterol (r = 0.375, P = .002). No correlation was found between CIMT and other studied variables. CONCLUSIONS: Carotid intima-media thickness was greater in hemodialysis patients compared to the control group. It was mainly affected by traditional cardiovascular risk factors and uremic risk factors did not specifically affect CIMT. PMID- 21525577 TI - Validity and reliability of short form-12 questionnaire in Iranian hemodialysis patients. AB - INTRODUCTION: The aim of the study was to assess the validity and reliability of the SF-12 questionnaire in a sample of Iranian patients undergoing hemodialysis. MATERIALS AND METHODS: One hundred and forty-four hemodialysis patients were included from dialysis centers in Zanjan, Iran, and were asked to complete the SF 12 and SF-36 questionnaires. An initial test-retest reliability evaluation was performed on a sample of 70 patients from the total group, with a retest interval of 14 days. Reliability was estimated by internal consistency and validity was assessed using known-group comparisons and construct validity on the patient group as a whole. A linear regression analysis was used to assess any variation in the physical component summary and mental component summary scores of the SF 36 with the respective component summary scores of the SF-12. In addition, the factor structure of the questionnaire was extracted by performing a confirmatory factor analysis. RESULTS: Cronbach alpha for physical and mental component summaries were 0.89 and 0.90, respectively. The SF-12 showed a good discriminatory ability between subgroups of patients based on demographic and clinical variables. The confirmatory factor analysis for the original two-factor structure showed a good fit index (chi2 = 23.30, degrees of freedom = 13), goodness-of-fit index = 0.96, and root mean squared error of approximation = 0.079). CONCLUSIONS: In general, the SF-12 has good psychometric properties and can be used as a shorter version of the SF-36 questionnaire in future studies involving Iranian patients undergoing hemodialysis. PMID- 21525578 TI - Effect of hepatitis C virus on C-reactive protein and interleukin-6 in hemodialysis patients. AB - INTRODUCTION: Patients with end-stage renal disease are at a high risk of hepatitis C virus (HCV) infections. These patients are on maintenance hemodialysis where they are exposed to dialysis fluid and dialysis membrane that generate an acute-phase response, which leads to inflammation, reflected in increased inflammatory markers like C-reactive protein (CRP) and interleukin-6 (IL-6). The aim of this study was to investigate levels of IL-6 and CRP in patients on hemodialysis and to determine effects of HCV on these markers. MATERIALS AND METHODS: A total of 43 patients (39.5% men and 60.5% women; age range, 21 to 65 years) on maintenance hemodialysis for a period of at least 3 months were included. Twenty-four of them were HCV positive. Serum IL-6 and CRP were assessed in all patients. RESULTS: Of HCV-positive patients, 11 (45.8%) had high levels of CRP, while 13 (54.2%) had low levels and increased levels of IL-6 (1064 +/- 544.2 pg/mL, P = .19). Of 19 HCV-negative patients, 13 (68.4%) had high levels of CRP, while 6 (31.6%) had low levels, and all these patients had low levels of IL-6, as compared to HCV-positive patients. No significant correlation was observed between the levels of CRP or IL-6 and the duration of dialysis. CONCLUSIONS: In our study, we found high serum IL-6 and CRP levels in HCV positive hemodialysis patients, compared with HCV-negative ones. However, we failed to show the significance of these differences. More studies with large sample sizes and evaluation of the other inflammatory markers are warranted. PMID- 21525579 TI - CD86 +1057G>A polymorphism and susceptibility to acute kidney allograft rejection. AB - INTRODUCTION: CD86 is a costimulatory molecule that participates in the regulation of T-cell lymphocytes activation. Thus, we examined a genetic marker on the CD86 gene in kidney transplant outcome. MATERIALS AND METHODS: In our retrospective study, 168 kidney allograft recipients were genotyped by direct sequencing. Patients were classified into 2 groups of 29 human leukocyte antigen (HLA)-identical haplotype allograft recipients and 139 recipients showing one or more mismatches in the HLA haplotype. Forty-five patients (26.8%) developed at least 1 acute rejection (AR) episode, 7 in the first and 38 in the second group. RESULTS: Acute rejection was associated with the presence anti-HLA antibodies before transplantation (P = .03). The AA genotype and A allele at position +1057 in the CD86 gene were more frequent in patients without AR (9.75% and 28.5%, respectively) compared with those showing an AR (2.22% and 23.3%, respectively). This difference was statistically significant in the anti-HLA-positive recipients, as AA frequency was 31.3% in non-AR patients and zero in AR ones (P = .04) and A allele frequency was 46.9% and 20.8%, respectively (P = .04). Patients bearing AA genotype reached a higher graft survival time (9.84 years) than those carrying GA (8.21 years, P = .32) or GG (7.61 years, P = .72) genotypes. CONCLUSIONS: These results suggest that AA genotype and A allele of CD86 +1057G>A polymorphism may confer a protection against acute kidney allograft rejection in Tunisian patients. PMID- 21525580 TI - Preventive effect of garlic juice on renal reperfusion injury. AB - INTRODUCTION: Renal reperfusion injury is associated with increased mortality and morbidity due to acute kidney failure. Oxidative stress induced with renal reperfusion affects glomeruli and tubular epithelium through reactive oxygen species; therefore, the use of medicinal plants appears rational for improvement of reperfusion effects. The aim of present study was to examine the preventive effect of garlic juice (Allium sativum) on renal reperfusion injury in rats. MATERIALS AND METHODS: A total of 30 male Wistar rats were divided into 5 groups: control, garlic, sham (right nephrectomy), reperfusion, and reperfusion + garlic groups. After right nephrectomy, renal ischemia and reperfusion were induced. At the end of the experiment, all rats were killed and kidney function tests and histopathological examination were performed. Results. Reperfusion increased serum urea and fractional excretion of sodium levels, while it decreased urine potassium levels and creatinine clearance. However, garlic juice significantly decreased serum urea levels in the reperfusion + garlic group compared with the reperfusion group (P < .001). Preteatment with garlic juice also resulted in significant increase in urine potassium (P = .03) compared to reperfusion. Fractional excretion of sodium and creatinine clearance were also improved. On histological examination, rats pretreated with garlic juice had nearly normal morphology. CONCLUSIONS: The results of this study showed that garlic juice significantly prevented renal reperfusion-induced functional and histological injuries. PMID- 21525581 TI - Kidney function tests in children with beta-thalassemia minor in Zahedan, southeast of Iran. AB - There is little information regarding kidney function in patients with beta thalassemia minor. In this study we investigated kidney function tests in 50 children with beta-thalassemia minor (22 boys and 28 girls). Twenty-four-hour urine samples were collected and analyzed for sodium, potassium, calcium, magnesium, creatinine, phosphate, uric acid, protein, and beta2-microglobulin. Blood samples were obtained for hematologic and biochemical analyses including complete blood count, serum ferritin, sodium, potassium, calcium, phosphate, magnesium, creatinine, and uric acid. This group of children with beta thalassemia showed some evidence of tubulopathy such as proteinuria (32%), beta2 microglobulin excretion (36%), calciuria (4%), phosphaturia (4%), and uricosuria (20%). Our findings support the existence of renal tubular dysfunction in beta thalassemia minor. However, further studies in large series are needed to shed light on the possible relation of these two distinct diseases. PMID- 21525582 TI - Five patients with emphysematous pyelonephritis. AB - Emphysematous pyelonephritis is an acute necrotizing infection of the renal parenchyma, resulting in presence of gas within either in the collecting system or perinephric space. We herein report our experience with 5 cases of emphysematous pyelonephritis in 2 men and 3 women managed by broad spectrum antibiotics, supportive measures including hemodialysis (2 patients), ureteral stenting (2 patients), surgical drainage of perinephric collection (1 patient), and control of diabetes mellitus (4 patients). Four patients were discharged after a mean hospital stay of 18 days. A nondiabetic male patient with a nonobstructed kidney died on the second postoperative day due to persistent septicemia despite nephrectomy. Emphysematous pyelonephritis is a potentially fatal disease requiring careful and prompt diagnosis and individualized rational therapy. Ureteropelvic stenting should be used for drainage of pent-up collections as a lifesaving measure through relieving the obstruction. Perinephric fluid collection should be drained either percutaneously or surgically. PMID- 21525583 TI - Unusual presentation of renal tuberculosis. AB - Urogenital tuberculosis (TB) is a common late manifestation of an earlier symptomatic or asymptomatic pulmonary TB infection. A latency period ranging from 5 to 40 years between the time of the initial infection and the expression of urogenital TB frequently occurs. As one of the most common sites of involvement of extrapulmonary TB, urogenital TB accounts for 15% to 20% of the infections. We present a patient who had culture-negative active tubercular kidney disease due to silent tuberculous infection. Our case demonstrates the limitations of noninvasive testing in establishing the diagnosis of renal tuberculosis. PMID- 21525584 TI - Survey of microalbuminuria: a study in Thailand. PMID- 21525585 TI - Re: simple formulas for screening abnormal blood pressure in children and adolescents. PMID- 21525586 TI - Cyclosporine trough level monitoring. PMID- 21525589 TI - Biomedical instruments versus toys:a preliminary comparison of force platforms and the nintendo wii balance board - biomed 2011. AB - Biomedical sciences rely heavily on devices to acquire and analyze the physiological data needed to understand and model the biological processes of humans and animals. Therefore, the results of the investigations, clinical or academic, depend heavily on the instrumentation used. Unfortunately, all too often the users do not understand their instruments and end up compromising the results of their investigations by choosing an inadequate instrument or by not using it appropriately. One field where this is particularly apparent is posturography: the misconceptions about instruments are so widespread and deep that just recently there have been articles published in scientific journals suggesting the use of a ?toy?, the Nintendo Wii Balance Board, instead of instrument grade force platform to acquire posturographic data. Characterizing the tools used for research becomes the first and probably the most important step in producing sound research and clinical results, and in the case of posturographic force platforms and the Nintendo Wii Balance Board a simple experimental setup can be used to find their characteristics. Furthermore, based on the preliminary results of this investigation, a mathematical formula can be used to predict the behavior of a posturographic tool, once its noise characteristics and ?dead weight? response are known. PMID- 21525590 TI - Sunrise alarm clock for the hearing impaired - biomed 2011. AB - The Sunrise Alarm Clock is a device designed to be more effective than standard alarm clocks and more pleasant than specialty devices in waking the hearing impaired. This is accomplished with the inclusion of visual, physical, and audio alarms. The visual alarm stimulus is created by manipulating the light output of a bedside lamp to mimic the sunrise. This is achieved by varying the duty cycle of a pulse width modulated signal supplied through a standard three-prong receptacle located on the side of the alarm clock. Physical alarms are in the form of wristbands containing vibrating motors. Finally, audio alarms are provided with both volume and pitch control to match the user?s specific needs. The entire system is designed with two users in mind by providing two independently controlled receptacles, wristbands, and audio systems. At the conclusion of development, a nearly fully functional prototype has been produced. The prototype?s audio and physical alarm system along with one visual alarm are fully functional. Shortcomings include poor timekeeping accuracy and problems clearly displaying the time. Even so, this development in sleep technology is capable of performing its task and waking its user with all three alarm systems. PMID- 21525591 TI - Equipping an automated wheelchair with an infrared encoder wheel odometer - biomed 2011. AB - Assistive technology is a rapidly growing field that provides a degree of freedom and self-sufficiency to people of limited mobility. Smart wheelchairs are a subset of assistive technology, and are designed to be operated by people who are unable to use a traditional control system. Instead, smart wheelchairs are equipped with a combination of automated functionality and steering mechanisms specialized to meet a person?s individual needs. One feature common to the automated capabilities of smart wheelchairs is the tracking system. The wheelchair?s microcontroller needs to know how far the chair has travelled, its speed, and the rotational direction of its wheels in order to successfully navigate through an environment. The purpose of this research was to develop an odometer to track the motion of a motorized wheelchair. Due to federal regulations that prohibit changing the structure or internal mechanics of a medical device, the odometer had to be designed as a separate, removable part. The final design for the odometer consisted of two infrared sensors that measure edge transitions of a segmented black and white encoder wheel. The sensor output was then run through two comparator op amps and a high pass filter to produce a clean, crisp square wave signal output. The signal was then fed to an Atmel ATmega164P microcontroller. The microcontroller was programmed to compare the sensor signal with its internal clock, sense edge transitions, and thereby extrapolate the speed, travelled distance, and rotational direction of the wheelchair. PMID- 21525592 TI - Signal artifacts in a light-adapted, Musca domestica-based sensor system - biomed 2011. AB - The Musca domestica (common housefly) sensor project is an ongoing endeavor at the University of Wyoming. The project seeks to develop a sensor based on the rudimentary function of a fly?s eye, including the inherent hyperacuity (high sensitivity to motion) present in the insect?s vision. During the summer of 2010, several characterization tests were conducted on the latest sensor design at the University of Wyoming. It was found that the light-adaptation circuitry being utilized caused artifacts in the output signals. These artifacts, while initially bothersome, have a distinct use as a means to detect motion direction across the sensor?s field-of-view. This paper provides background information on the sensor design being considered, discusses one of the tests conducted, and offers results that illustrate the signal artifacts. The potential uses of these artifacts, as well as what causes them, is discussed in detail. PMID- 21525593 TI - A user-friendly application for the extraction of kubios hrv output to an optimal format for statistical analysis - biomed 2011. AB - The aim of the present manuscript is to present a user-friendly and flexible platform for transforming Kubios HRV output files to an .xls-file format, used by MS Excel. The program utilizes either native or bundled Java and is platform independent and mobile. This means that it can run without being installed on a computer. It also has an option of continuous transferring of data indicating that it can run in the background while Kubios produces output files. The program checks for changes in the file structure and automatically updates the .xls- output file. PMID- 21525594 TI - Comparison of isoinertial to simulated inertial force from a controlled resistance exercise device for spaceflight - biomed 2011. AB - Spaceflight leads to muscle and bone atrophy, and isoinertial (free-weight) exercises provide a sufficient stimulus to elicit increases in both muscle strength and bone mineral density in earth-based studies. Therefore, a computer controlled resistance exercise device is being developed for NASA that is able to simulate the inertial loading experienced when lifting a mass on earth. The ground reaction force with the device is compared to the ground reaction force measured during isoinertial dead-lifts over a full spectrum of resistance levels. Results indicate promise of adequately simulating the inertial effects experienced during terrestrial exercise by compensating for the difference by calibrating the control signal with the addition of (-7.27 + 0.03*desired resistance level) percent to the base desired resistance level. PMID- 21525595 TI - Evaluating antibiotic release profiles as a function of polymer coating formulation - biomed 2011. AB - To address persistent 1-3% infection rates associated with orthopedic implant surgeries, the next generation of bone graft filler materials will no longer pharmacologically silent being endowed as a local drug delivery vehicle to maintain locally high levels of antibiotic. Bone allograft material, used as a structural support to fill the avascular spaces in bone defects, revision surgeries, and traumatic injury, can be used as a drug depot to provide effective antibiotic delivery over the orthopedically relevant six-to-eight week time period. Passive antibiotic coatings, applied in the surgical theater, are quickly depleted from the site, inadvertently promoting the development of drug resistance. Alternatively, many promising controlled-delivery strategies provide an initial burst release of antibiotic within 24 to 72 hours; however, this remains inadequate to combat the onslaught of ubiquitous pathogens that can persist only to reemerge once drug concentrations fall below the minimal inhibitory concentration (MIC). To improve the longevity of this strategy, a variety of coating techniques were evaluated in which clinically-accepted, FDA recognized, degradable polycaprolactone (PCL) polymer acts as a rate-controlling membrane to retard the release of the antibiotic tobramycin from allograft bone. Using a combination of dipping and rapid drying, the drug-releasing polymer coating was applied concurrently maintaining the high surface area of the allograft bone; however, SEM imaging reveled an imperfect coating that negatively affected the release kinetics. Altering the drug-containing polymer formulation to incorporate water provided a smoother, more uniform coat and ultimately improved the drug-release profile and longevity out to 5 weeks using both bacteriostatic and bacteriocidal assays. Additionally, drug bioactivity was assessed and confirmed between 2 and 4 weeks in the absence of the water containing polymer. PMID- 21525596 TI - Macrophages under low oxygen culture conditions respond to ion parametric resonance magnetic fields - biomed 2011. AB - Macrophages, when entering inflamed tissue, encounter low oxygen tension due to the impairment of blood supply and/or the massive infiltration of cells that consume oxygen. Previously, we showed that such macrophages release more bacteriotoxic hydrogen peroxide (H2O2) when exposed in vitro to low oxygen than when cultured at usual ambient oxygen conditions. In this study, we use this low oxygen, inflammatory macrophage model to test the macrophages? response to low frequency magnetic fields. Low-frequency fields are clinically used for bone and wound healing and are emerging as therapy for inflammatory diseases. The acceptance of these non-invasive therapies is slow due to the lack of knowledge of the cellular targets for magnetic fields. One possible target is biologically relevant ions. The Ion Parametric Resonance (IPR) concept predicts that specific externally applied AC and DC magnetic fields will resonate with the cyclotron motion of ions. This concept is supported by experimental evidence, especially on a neuronal cell line. Using our macrophage model, we tested AC and DC magnetic fields at the amplitude ratio and frequency predicted by the IPR model for resonance with hydrogen, magnesium and manganese ions. Under these conditions, we found a significant increase in H2O2 release compared to control cells. Magnetic field exposure conditions in which parameters differed from the predictions of the IPR model showed no, or a smaller difference, with respect to the control cultures. These data indicate that magnetic fields can enhance H2O2 release of inflammatory macrophages, which is consistent with the predictions of the IPR model. PMID- 21525597 TI - The effect of low oxygen with and without steady-state hydrogen peroxide on cytokine gene and protein expression of monocyte-derived macrophages - biomed 2011. AB - An early event during inflammation and infection is the migration of monocytes into tissues where they differentiate into macrophages. Such monocyte-derived macrophages face an unfavorable environment characterized by extremely low oxygen tension and accumulation of reactive oxygen species such as hydrogen peroxide. Previous experiments showed that a macrophage cell line cultured under these conditions responded to inflammatory stimulants with an increased respiratory burst compared to cells kept at regular ambient oxygen conditions. The objective of the present study was to test if this effect was accompanied by an increased cytokine production. Using cytokine protein arrays and real time gene expression analysis, we indeed found that low oxygen exposure increased expression of characteristic macrophage inflammatory cytokines such as IL-1, IL-6, and TNF alpha. Interestingly, cells exposed to low oxygen and steady-state hydrogen peroxide levels did not show this increase, indicating different cell mechanisms might be involved in increasing macrophage hydrogen peroxide and cytokine release. PMID- 21525598 TI - Mechanical property and morphology changes in thin-film poly(dl-lactide-co glycolide) during degradation in aqueous environments - biomed 2011. AB - A protocol for spin-casting uniform Poly(DL-lactide-co-glycolide) (PLGA) thin films was developed and a variety of known solvents were evaluated for their impact on the quality of the films produced. Film thickness was quantified using a reflectometer and the elastic moduli were determined using a wavelength bucking technique. Qualitative observations of the films? morphological characteristics were made using optical microscopy. These parameters were then monitored over time as PLGA thin films were exposed to mildly agitated aqueous buffer solutions at 37 degrees C. Initial results suggest that over the course of several weeks films undergo a reduction in thickness with a concomitant change in film morphology. Current efforts are focused on determining how the changes in the mechanical properties of these films are correlated with the degradation process, in order to elucidate the mechanism and provide guidance on the use of PLGA in biological applications involving mechanical stresses. PMID- 21525599 TI - Image segmentation and registration algorithm to collect homologous landmarks for age-related thoracic morphometric analysis - biomed 2011. AB - Adults 65 years of age and older currently constitute more than 12% of the total population and the elderly population is projected to reach nearly 20% by 2030. Previous studies have shown that skeletal and physiological resilience decline with age, resulting in a decreased ability for the body to withstand traumatic insults. In the current study, an algorithm was developed to quantify age and gender-specific variations in the thoracic skeletal morphology. Normal chest CT scans of males and females ages 0-100 were collected from a radiological database. Image segmentation and subsequent image registration was used to collect landmark data from the ribs. Rigid, affine, and non-rigid, non-linear transformations are used to morph segmented ribs from different subjects to a ?rib atlas?. The atlas consists of a normal chest CT scan from an average male with over 100 landmarks placed per rib. The transformation matrices are used to map landmarks from the atlas coordinate system to the coordinate system of each CT scan, effectively allowing for collection of homologous (or comparable) rib landmarks across all subjects. Geometric morphometrics will be used in future work to analyze the landmark data to formulate age and gender-specific shape and size variation functions. These functions will be used to create a scalable finite element model of the thorax that will be used to predict thoracic injury response for different ages and genders. PMID- 21525600 TI - Stereoscopic visualization and haptic technology used to create a virtual environment for remote surgery - biomed 2011. AB - The objective of this research is to study the effectiveness of using a stereoscopic visualization system for performing remote surgery. The use of stereoscopic vision has become common with the advent of the da Vinci(r) system (Intuitive, Sunnyvale CA). This system creates a virtual environment that consists of a 3-D display for visual feedback and haptic tactile feedback, together providing an intuitive environment for remote surgical applications. This study will use simple in vivo robotic surgical devices and compare the performance of surgeons using the stereoscopic interfacing system to the performance of surgeons using one dimensional monitors. The stereoscopic viewing system consists of two cameras, two monitors, and four mirrors. The cameras are mounted to a multi-functional miniature in vivo robot; and mimic the depth perception of the actual human eyes. This is done by placing the cameras at a calculated angle and distance apart. Live video streams from the left and right cameras are displayed on the left and right monitors, respectively. A system of angled mirrors allows the left and right eyes to see the video stream from the left and right monitor, respectively, creating the illusion of depth. The haptic interface consists of two PHANTOM Omni(r) (SensAble, Woburn Ma) controllers. These controllers measure the position and orientation of a pen-like end effector with three degrees of freedom. As the surgeon uses this interface, they see a 3-D image and feel force feedback for collision and workspace limits. The stereoscopic viewing system has been used in several surgical training tests and shows a potential improvement in depth perception and 3-D vision. The haptic system accurately gives force feedback that aids in surgery. Both have been used in non-survival animal surgeries, and have successfully been used in suturing and gallbladder removal. Bench top experiments using the interfacing system have also been conducted. A group of participants completed two different surgical training tasks using both a two dimensional visual system and the stereoscopic visual system. Results suggest that the stereoscopic visual system decreased the amount of time taken to complete the tasks. All participants also reported that the stereoscopic system was easier to utilize than the two dimensional system. Haptic controllers combined with stereoscopic vision provides for a more intuitive virtual environment. This system provides the surgeon with 3-D vision, depth perception, and the ability to receive feedback through forces applied in the haptic controller while performing surgery. These capabilities potentially enable the performance of more complex surgeries with a higher level of precision. PMID- 21525601 TI - Analysis of trabecular structure in radiographic bone images using bi-dimensional empirical mode decomposition - biomed 2011. AB - Non-invasive assessment of bone strength is an important component of biomechanics research. Soft tissue structures like trabeculae in femur bones are to be assessed precisely for tissue modeling and fracture mechanics. The strength and architecture of these structures in femur bones are routinely analyzed by varied image based methods for diagnosis and monitoring of osteoporosis like metabolic disorders. In this work, an attempt has been made towards development of an automated system for analysis of trabecular femur bone architecture using spatial frequency decomposition method. Conventional Radiographic femur images recorded using standard protocols are used for the study. The compressive and tensile regions in the images are delineated using pre-processing procedures. The delineated images are decomposed into their corresponding Intrinsic Mode Functions using bi-dimensional empirical mode decomposition method. The characteristic feature vectors corresponding to regional variations are used for further analysis. The result shows that the extracted features are distinct for compressive and tensile regions and are found to be consistent for the first three modes. The values are high for compressive regions. The higher modes are not observed in tensile regions of abnormal images which are attributed to the loss of structural patterns. As the strength of the bone depend on architectural variation in addition to bone mass, this study seems to be clinically useful. The objectives, methodology and analysis are presented in this paper. PMID- 21525602 TI - Assessment of retinal vasculature abnormalities using slantlet transform based digital image processing - biomed 2011. AB - Vasculatures are imperative structures in a human retina and their varied manifestations are often associated with abnormal state of many disorders. Automatic detection and analysis of these structures assist in diagnosis of many diseases such as diabetes, hypertension and arteriosclerosis. In this work, human retinal images are analysed using image processing techniques and transform based method. Normal and abnormal digital fundus images recorded under controlled protocol are employed for the study. The acquired images are subjected to Slantlet transform and the corresponding zero moments and statistical parameters from those features were derived for analysis. The derived parameters are correlated with vessel density index to identify vascular density and its variations. Results demonstrate that Slantlet transform is capable of extracting variations in vascular density in normal and abnormal images. Varying magnitudes of positive and negative peaks are observed for normal images whereas variations are found to be uniform for abnormal images. The values of second zero moment, skewness and kurtosis are found to correlate with vessel to vessel free area index. The correlation values were high for abnormal images than normal images. It appears that Slantlet transform based study carried out in this work seems to differentiate normal and pathological retina. As the analysis of retinal vessel features are important for pathological states related with retinal vein occlusion and tortuosity, these studies seems to be clinically relevant. In this paper, the objectives, methodology, results and the correlation analysis of all the derived parameters are presented in detail. PMID- 21525603 TI - Pediatric occupants, restraint use, and injuries in motor vehicle crashes - biomed 2011. AB - Pediatric occupants are vulnerable in motor vehicle crashes (MVCs), and alternative restraints have been developed for their protection. This study sought to characterize injuries in MVCs for pediatric occupants and to identify scenarios that may benefit from enhanced vehicle safety. Using the NASS-CDS database (2000-2008), pediatric occupants (< 19 yr old) were characterized by their age and injuries to look at national averages in MVCs. There were over 14 million pediatric injuries and non-injured occupants in weighted NASS-CDS (out of over 70 million total). Of these pediatric cases, 60% sustained injuries, which was comparable to the percentage of all occupants injured (65%). Six percent of NASS-CDS pediatric occupants had AIS 2+ injuries, which is the injury inclusion criteria for CIREN pediatric cases. CIREN was used to investigate pediatric occupants and injuries resulting from incorrect positioning and restraints according to NHTSA suggestions. Results indicated that many injured pediatric occupants were not properly restrained, with over 100 in the front row of the vehicle under 13 years of age. There were also over 200 CIREN pediatric occupants under 4? 9? that were not seated in a child safety seat (CSS). The most frequently injured body region was the face, followed by the head and lower extremity. Eighty-six percent of head injuries and 82% of spinal injuries were AIS 2+. This study supports prior findings that demonstrate a need for enhanced public awareness for proper CSS use to reduce pediatric injuries in the future. PMID- 21525604 TI - Methods for validation of the mass distribution of a full body finite element model - biomed 2011. AB - Accurate mass distribution in computational human body models is essential for kinematic and kinetic validation. The purpose of this study was to validate the mass distribution of the 50th percentile male model (M50) developed as part of the Global Human Body Models Consortium (GHBMC) project. The body segment centers of gravity (CG) of M50 were compared against published data in two ways: using a homogeneous body surface CAD model, and a Finite Element Model (FEM). Both the CAD and FEM models were generated from image data collected from the same 50th percentile male subject. Each model was partitioned into 11 segments, using segment planes constructed from bony landmarks acquired from the subject. CG?s of the CAD and FEA models were computed using commercially available software packages. Deviation between the literature data CG?s and CG?s of the FEM and CAD were 5.8% and 5.6% respectively when normalized by a regional characteristic length. Deviation between the FEM and CAD CG?s averaged 2.4% when normalized in the same fashion. Unlike the CAD and literature which both assume homogenous mass distribution, the FEM CG data account for varying densities of anatomical structures by virtue of the assigned material properties. This analysis validates the CG?s determined from each model by comparing them directly to well-known literature studies that rely only on anthropometric landmarks to determine the CG?s measurements. The results of this study will help enhance the biofidelity of the GHBMC M50 model. PMID- 21525605 TI - Development and implementation of a custom program for post hoc strain tracking in biological specimens using cross-correlation - biomed 2011. AB - The research presented describes the development of a custom MATLAB(r) program designed to examine changes in surface strain based on digital image tracking, a technique that employs markerless tracking to access regional displacement in digital images. Strain tracking is accomplished through the analysis of successive images taken during testing using a dedicated black and white camera incorporated into a tensile testing system. In the tracking program a 2-D array of grid points is mapped on the initial image from a test. Each grid point consists of a pixel array (a sub-image corresponding to a ?marker?) which is then compared to consecutive images to determine the new grid point placement using cross correlation. By analyzing marker position post hoc, the number of grid points, the size of the sub-pixel array, and the spacing (longitudinal and/or regional) between grid points can be varied to account for differences in observed responses. Digital strain tracking allows for a test to be reanalyzed and eliminates the need to affix markers in specified patterns to a sample prior to testing. The new ?markerless? tracking approach has been compared to the classic procedure of applying physical surface markers for tracking strain, to determine the accuracy of this technique. Preliminary testing revealed that adding texture to the specimen may be necessary (especially for low texture samples like tendons and ligaments), through the use of glitter derivatives, to increase visual contrast between multiple grid points. PMID- 21525606 TI - Strength of a new method of achilles tendon repair in the rat - biomed 2011. AB - The rat Achilles tendon is frequently used as the model for tendon healing research. Several methods commonly employed in these studies may confound results. The Kessler method of suture repair requires immobilization of the operative extremity, which can be detrimental to healing. Determination of cross sectional area of tendons by caliper measurement may lead to significant errors in normalization of biomechanical data for stress and elastic modulus. New methods of suture repair of rat Achilles tendons and micro-CT scanning of tendons are presented as preferable techniques for tendon healing studies in rats. Operations involved transection of the right Achilles tendon at the mid-portion and suture repair using a 4-strand, looped locking technique. Groups were: positive control (no injury or treatment); negative control (injury, suture repair, no healing); 2 week repair; and 4 week repair. The cross-sectional area of the tendons was significantly higher (p<0.05) in the repair groups compared to controls. Peak stress and elastic modulus of repair groups were significantly lower than positive control. Strain of repair groups was not significantly different from control. Four weeks after repair, tendons bore significantly higher peak loads than positive control tendons. Based on these results, further studies of adjunct therapy for tendon healing may be placed in the context of normal (repair groups), ideal (positive control), and worst case (negative control) healing. The methods presented for new a new surgical technique and cross-sectional area calculation are reliable for animal studies and increase the validity and applicability of biomechanical results. PMID- 21525607 TI - Acetabular rim profile measurement in femoroacetabular impingement patients - biomed 2011. AB - Morphological variations in hip joint anatomy are a possible mechanism for femoroacetabular impingement (FAI) which leads to hip osteoarthritis. Significant geometric variations of the acetabular rim exist between patients including variations in depths of the postereosuperior depression (PSD) and psoas valley (PV). Computed tomographic scans of 48 FAI patients were segmented to create three-dimensional bone reconstructions. A pelvic plane was established using bony landmarks at the inferior iliac spines and the pubis. Placing a sphere on the articular surface of each acetabulum, the center of rotation was found. A curve was drawn on the acetabular rim to extract equally spaced points (0.67mm) to maximize output for an accurate representation of the profile. The acetabular plane was fit to the points using the least-squares method and translated to the center of rotation. The rim points were converted to cylindrical coordinates in degrees along the acetabulum and depth with respect to the mean acetabular plane. The mean depth of the PSD and PV were 7.27mm (SD 1.99) and 4.65mm (SD 2.12), respectively. The affected FAI hip was the right hip in 25 patients and the left hip in 23 patients. Comparisons were made on a per-patient basis between the acetabulum with FAI and without, and FAI hips had an increased coverage of the femoral head by the acetabulum. The appearance of cam and/or pincer impingement was also noted. The novel method of quantification of morphometric variations in the acetabular rim will further aid in understanding the development of FAI. PMID- 21525608 TI - Exogrip: assisted hand strength glove - biomed 2011. AB - A large number of American troops fighting in Afghanistan and Iraq have received wounds in their upper extremities leading to significant nerve damage and loss of strength. These injuries impair their ability to perform day-to-day tasks such as lifting a cup of coffee or opening a door. Although the cause of some injuries in service-people is often unique to their employment, civilian employees in other industries are also plagued with similar physical damage due to other kinds of injuries. Our goal is to develop a device to augment the strength of injured troops and civilian workers so they can perform everyday tasks despite their physical limitations. The ExoGrip is a glove designed to provide this necessary strength augmentation. The ExoGrip consists primarily of pressure sensors, linear actuators, and a microcontroller to provide a force multiplier based on a person?s strength. The goal of the first phase of the project was to conduct research and also produce a working prototype of one finger. This goal was achieved by a group of classmates who started the project a year before. Their research and feasibility analysis ended in the mechanical movement of a single finger when the sensors were activated. The next phase of this project is to design and integrate a working prototype that manipulates all four fingers, while keeping the thumb in a fixed position. This paper describes the integration of new microcontrollers, linear actuators utilizing pulse width modulation technology, and improved pressure sensors needed to manipulate the fingers, as well as laying the foundation for future testing and development of a final product. PMID- 21525609 TI - Qualitative femur bone tensile strength analysis in radiographic images using wavelets - biomed 2011. AB - In this work, the tensile strength of femur bone is qualitatively analyzed using radiographic images. The sub anatomic tensile regions were delineated from conventional planar radiographic femur images using digital image processing algorithms. The normal and abnormal images are then subjected to Daubechies5, coiflet5 and Haar wavelets decomposed at three levels to derive approximation and detail coefficients. The qualitative analyses were also performed on the delineated images to derive apparent mineralization and total area. The values of higher order energy parameter are derived for both approximation and detail coefficients in each level of decomposition and are correlated with apparent mineralization for analysis. Results show that the low values of energy correlates well with abnormalities in all levels of decomposition for all the three wavelets. Among all, the values of energy derived out of approximation coefficient using Haar wavelets show higher degrees of correlations in both primary tensile and secondary tensile regional strength. The variations between normal and abnormal were also found to be statistically significant. Poor correlation was observed in the case of detailed coefficients for all the wavelets irrespective of levels. Among all wavelets, the parameters decomposed at level one approximation coefficient of Haar wavelet appear to be a useful predictor for classifying normal and abnormal samples. This could be attributed to sensitivity of adopted wavelets to the architectural changes and discontinuities in regional distribution of trabecular pattern in tensile region. It appears that this methodology could be used for gross abnormality detection, micro-damage studies and modeling the mechanics of soft tissue in diseases. Thus wavelet extracted feature on tensile trabeculae regions of radiographic femur images could be a used as an index for automated screening of bone strength. PMID- 21525610 TI - Brain morphometry in autism spectrum disorders: a unified approach for structure specific statistical analysis of neuroimaging data - biomed 2011. AB - Autism spectrum disorders (ASD) are a neurodevelopmental condition with multiple causes, comorbid conditions, and a wide range in the type and severity of symptoms expressed by different individuals. This makes the neuroanatomy of autism inherently difficult to describe. It has been assumed in the scientific literature that deviations in regional brain size in clinical samples are directly related to maldevelopment or pathogenesis. The performed clinical studies analyzed specific brain structures that are assumed to be correlated to autistic brain behaviors. Examples of performed analyses, based upon manual or semi-automated segmentation from magnetic resonance imaging (MRI) scans, include volumetric measures of specific brain structures, or small groups of structures, as caudate, corpus callosum, putamen, hippocampus, nucleus accumbens, evaluating differences between groups of subjects with autism and control subjects. Nonetheless, the brain regions analyzed that differ between patients and control subjects have not been always consistent over the performed studies. This inconsistency might be due to the fact that the specific single volume differences that have been reported in the literature for the different brain structures under investigation may, instead, be not independent during pathogenesis. Hence, this issue comes into play in logically framing a comprehensive assessment of putative abnormalities in regional brain volumes. To this aim, a whole brain investigation system for a semi-automated morphometric statistical analysis of brain anatomy is presented in this paper and validated on a selected group of patients diagnosed with ASD that completed a 1.5 T magnetic resonance image (MRI) of the brain. The proposed system, which is mainly built basing upon the FreeSurfer and the 3D Slicer software frameworks for the volumetric analysis of brain imaging data, lies its foundations on the higher statistical power of the region of interest (ROI) approach, but equally aims at a higher exploratory power as it doesn?t restrict its focus to a small number of specific regions, thanks to a whole brain unified approach. PMID- 21525611 TI - Efforts toward an autonomous wheelchair - biomed 2011. AB - An autonomous wheelchair is in development to provide mobility to those with significant physical challenges. The overall goal of the project is to develop a wheelchair that is fully autonomous with the ability to navigate about an environment and negotiate obstacles. As a starting point for the project, we have reversed engineered the joystick control system of an off-the-shelf commercially available wheelchair. The joystick control has been replaced with a microcontroller based system. The microcontroller has the capability to interface with a number of subsystems currently under development including wheel odometers, obstacle avoidance sensors, and ultrasonic-based wall sensors. This paper will discuss the microcontroller based system and provide a detailed system description. Results of this study may be adapted to commercial or military robot control. PMID- 21525612 TI - Preliminary tests of a possible outdoor light adaptation solution for a fly inspired visual sensor: a biomimetic solution - biomed 2011. AB - Two previous papers, presented at RMBS in 2009 and 2010, introduced a fly inspired vision sensor that could adapt to indoor light conditions by mimicking the light adaptation process of the commonhousefly, Muscadomestica. A new system has been designed that should allow the sensor to adapt to outdoor light conditions which will enable the sensor?s use inapplications such as: unmanned aerial vehicle (UAV) obstacle avoidance, UAV landing support, target tracking, wheelchair guidance, large structure monitoring, and many other outdoor applications. A sensor of this type is especially suited for these applications due to features of hyperacuity (or an ability to achieve movement resolution beyond the theoretical limit), extreme sensitivity to motion, and (through software simulation) image edge extraction, motion detection, and orientation and location of a line.Many of these qualities are beyond the ability of traditional computervision sensors such as charge coupled device (CCD) arrays.To achieve outdoor light adaptation, a variety of design obstacles have to be overcome such as infrared interference, dynamic range expansion, and light saturation. The newly designed system overcomes the latter two design obstacles by mimicking the fly?s solution of logarithmic compression followed by removal of the average background light intensity. This paper presents the new design and the preliminary tests that were conducted to determine its effectiveness. PMID- 21525613 TI - Relationship between frequency and impedance change in an infusion rate measurement system employing a capacitance sensor - biomed 2011. AB - We have been searching for a suitable frequency range for an electrical impedance measurement infusion solution drip monitoring system, which we have previously reported. This electrical impedance, which is formed between two electrodes wrapped around the infusion supply polyvinyl-chloride tube and around the drip chamber, is changed by the growth and fall of each drop of fluid. Thus, the drip rate can be detected by measuring this impedance. However, many different kinds of infusion solutions such as glucose, amino acid, soya oil, and lactated Ringer?s solution are used in hospitals and care facilities. Therefore, it was necessary to find a suitable frequency for driving the capacitance-change sensor with a wide range of infusion solutions. In this study, the sensor electrical impedance change of 16 infusion solutions was measured from 1 kHz up to 1 MHz. The drip impedance produced by 5% glucose solution, 10% glucose solution and soya oil indicated the maximum sensor output change at 10 kHz, 20 kHz, and 70 kHz, respectively. The other 13 infusion solutions increased up to 10 kHz, and were constant from 10 kHz to 1 MHz. However, the growth, fall, and drip rate of the drops of all the infusion solutions were monitored by measuring the impedance change from 10 kHz to 30 kHz. Our experimental results indicated that most suitable excitation range for the infusion monitoring system is from 10 kHz to 30 kHz. Thus, we can now ?fine-tune? the system for optimal sensing. PMID- 21525614 TI - A mobile phone-based ecg and heart sound monitoring system - biomed 2011. AB - We have developed a telemedicine system to monitor a patient?s electrocardiogram (ECG) and heart sounds (PCG) during daily activity. The complete system, consisting of an ECG recorder, an accelerometer and a 2.4 GHz low power mobile phone, is mounted on three chest sensing electrodes. The accelerometer records the PCG produced by closing of the mitral and aortic valves (S1 and S2). The sampled ECG and PCG are stored in the system for two minutes and continuously updated. When a patient feels heart discomfort such as angina or an arrhythmia, he/she pushes the data transmission switch on the system. The ECG and PCG for the next two minutes are stored in the system, and then the system then sends the four minutes of stored data directly to a hospital server computer via the 1.9 GHz low power mobile phone. These data are stored on the server and then downloaded to the physician?s Java configured mobile phone. The physician can then check the patient?s cardiac condition, regardless of patient or physician locations, and then take appropriate actions. PMID- 21525615 TI - Miniature in vivo cameras for use in single-incision robotic surgery - biomed 2011. AB - Single-incision surgery provides numerous benefits over traditional open and laparoscopic surgery techniques including reduced pain, shortened recovery times, and minimal tissue scarring. The use of miniature in vivo robots inserted through a single incision offers additional advantages over conventional laparoscopy in improved maneuverability and dexterity. One consequence of performing surgical procedures through a small single incision is the loss of direct visualization through a large open incision or visualization via laparoscopic cameras inserted through additional ports. For this reason, a miniature in vivo actuated camera was designed to pass through a single incision and attach to a miniature in vivo robot, providing live video feedback at the control of the surgeon. The device was tested in a lab setting and porcine model surgery and demonstrated successful movement, control, and high-quality visualization, indicating the device?s functionality and feasibility for use in single-incision robotic surgery. PMID- 21525616 TI - Improved motion detection method using spot localization - biomed 2011. AB - The common house fly may be able to process certain features of images much faster than that of typical human vision. A computer model as well as a hardware model has been developed to simulate parts of the fly eye. One particular area of study in the software model has been motion detection. A new method is being developed that focuses on spot localization before motion detection. Models have been developed that can localize a spot in cylindrical coordinates with respect to the center receptor. Relative motion can be detected by analyzing the changes in the location of the spots. The advantage of this method is that it requires almost no memory. By reducing the memory required, faster frame rates can be achieved. Motion detection and spot localization will serve as the foundation for additional processing for segmentation and object recognition. PMID- 21525617 TI - Evaluation of the antimicrobial efficacy of green tea extract (egcg) against streptococcus pyogenes in vitro - biomed 2011. AB - S. pyogenes (GAS) is the agent that is involved in acute infections that can lead to devastating life-threatening invasive infections. S. pyogenes cell-surface components such as lipoteichoic acid, hyaluronic acid capsule, M proteins, and laminin and collagen binding proteins are responsible for adhesion to human cells. Natural compounds have been associated with decreased adherence of bacteria to cells. The most widely studies of these compounds has been cranberry juice which is thought to disrupt cellular adherence by altering the local cellular. The purpose of this study was to determine if pre-treating or post treating kidney epithelial cells (RMKEC) with Epigallocatechin Gallate (EGCG) alters GAS?s ability to adhere to the host cells. Our data indicates that pretreating or post treating the cells with EGCG (10uM, 30uM, or 50uM) inhibited the attachment of the bacteria to the cells in a dose dependent manner. The results also indicate that the remaining GAS bacteria attached to the cellular surface after a 24 hour period was unable to penetrate the epithelial cells. Additional studies also showed EGCG has antimicrobial properties at various concentrations. Our results indicate that EGCG can effectively reduce GAS bacteria cellular attachment and induce GAS cell death and can be used effectively as an adjunct to conventional antibiotic treatments. PMID- 21525618 TI - Biochemical and morphological changes associated with macrophages and osteoclasts when challenged with infection - biomed 2011. AB - Osteomyelitis is a bacterial infection of the bone that occurs frequently as a complication of open fractures and various kinds of orthopedic surgery. This infection can often lead to more extensive surgeries and even death of the patient. In animal models of osteomyelitis, the site of infection by Staphylococcus aureus was observed to have high numbers of both macrophages and osteoclasts, both of which may contribute to large amounts of osteolysis and tissue damage. In order to evaluate the immune response in both types of cells, two cells lines, a macrophage cell line and a macrophage cell line stimulated to become osteoclasts by the addition of receptor activator of nuclear-factor B (RANKL), were exposed to lipopolysaccharides, opsonized S. aureus, and unopsonized S. aureus. The results showed that both cell types activated a biochemical cascade that included the release of cytokines and nitric oxide associated with cell damage and death in response to infection. However, macrophages and osteoclasts differed in response magnitude, most likely due to differences in cell-membrane receptors. This data supports the growing body of research that links the immune and skeletal systems. Further understanding of biochemical pathways shared by the two systems could lead to significant advances in the treatment of osteomyelitis and the success of prostheses. PMID- 21525619 TI - Evaluation of the estrous cycle and ovarian function following sustained delivery of corticosteroid via tcpl delivery - biomed 2011. AB - Stress has been shown to impair reproduction in many species and the hypothalamic pituitary axis (HPA) has been shown to be the target. Most of the literature evaluated the effects of acute stress and focused solely on the HPA. The literature is lacking in the area of chronic administration of corticosteroid use and effects on the estrous cycle and long term effects on the ovary. The objectives of this study were to use tricalcium phosphate drug delivery systems to deliver corticosterone in a sustained supraphysiological level and follow the estrous cycle over a 28 day period; then, harvest the ovaries to evaluate the morphology. The results indicate prolonged administration of corticosterone in female rats cause alteration in the cyclic activity as evidenced by changes in the estrous as well as morphology of the ovaries. The mechanism appears to be disruption or interference of the HPA axis. Overall, ceramic drug delivery devices can be used effectively to deliver corticosteroid to induce pathophysiological changes associated with stress. PMID- 21525620 TI - Impact of supra-physiologic retinoids on ovalbumin-sensitized f344 lung tissue and reversal of related pathology by citral - biomed 2011. AB - The role of retinoids (All Trans Retinoic Acid; ATRA, and Retinyl Palmitate; RP) in the development of lung hypervitaminosis A pathology is not well understood or established in the literature. As well, the role of Citral (inhibitor of retinoid function) in the reversal of lung pathology is also not ascertained under an in vivo setting. Therefore, it is hypothesized that ovalbumin exposure will sensitize lung tissues to supra-physiologic levels of retinoids leading to tissue pathology and that Citral 1 and 2 will reverse or ameliorate the related pathological damage to lung tissues. Even though ovalbumin and retinoids have been previously applied through intra-tracheal route in cancer prevention and immunological research, the objective of this pilot study was to evaluate techniques, establish functional dosing and generate preliminary data before further experimentation. This IACUC approved in vivo study consist of twenty one (n = 21) Fischer 344 rats (200 to 400g) which were randomly assigned to controls and two ovalbumin-sensitized treatment groups (low; 0.15 mg/kg and high; 0.30 mg/kg, all sensitized by intra-peritoneal injection at day 1) and were also dosed at day 7 with 40 and 80 mg/kg each of ATRA or RP as well as 20 and 50 mg/kg each of Citrals 1 or 2 individually or in combination to represent low and high for all four chemicals, which were administered by intra-peritoneal injection. Citral is a non-toxic chemical that exists in two forms (diethyl; C1 or cis-trans dimethyl; C2). Positive and negative controls for each treatment were also included in the study. Animals were housed in rat cages at the JSU Research Animal Core Facilities and were placed on a 12:12 light?dark cycle. A standard rodent diet and water access were provided adlibidum. Rat weights were recorded on Day 1 and 21, all animals were sacrificed on day 21 and lung tissues were processed for histopathology. Slides were prepared and were digitized for comparison of tissues pathology. Results showed that even though C1 and C2 were not toxic individually, their combination at high dosing was lethal. As well, the combination of high dosing of RP and C1 was also lethal. Exposure of ovalbumin sensitized rats to ATRA showed various levels of lung tissue damage that was not ameliorated by Citrals. RP exposure caused various levels of tissue damage that was not reversed by either C1 or C2. Taken together, the study showed that there are variable pathologic responses from the interaction of ovalbumin, Citrals and retinoids and those Citrals failed in reversing tissue pathologies. These findings warrants further investigation as to the actual role of these interactions in relation to chronic lung disease and the possibility of reversing retinoid-mediated pathologies in the Fisher rat model. PMID- 21525621 TI - Assessing the survival of mrc-5 and a549 cell lines upon exposure to ascorbic Acid and sodium ascorbate - biomed 2011. AB - Lung cancer is among the highly prevalent and deadly cancers in the United States and worldwide. Cells that are cancerous exhibit higher rates of glycolysis as compared to normal cells. In an attempt to exploit this uniquely enhanced glucose dependent ATP generation phenomenon, the authors hypothesize that exposure of cancer cells to normal organic metabolites that are capable of inhibiting glycolysis would have a negative impact on survival by altering growth and viability characteristics vastly through decline in ATP build up essentially leading to collapse in energy supply; normal lung cells will not demonstrate such changes. The human lung fibroblast cell line MRC-5 and the cancerous human lung alveolar epithelial cell line A549 were utilized in this study as in vitro models of normal and cancerous lung cell lines respectively. Using standard methods, both cell lines were maintained in culture and exposed to ascorbic acid and sodium ascorbate reagents at concentration levels ranging from 31.3-2,000 ug/ml. Cell survival measurements using MTT andT4 Cellometric assays monitored with phase-contrast photo-imaging were carried out in quadruplicates. Results indicate that exposure characteristics to these metabolites followed concentration dependent cell mortality/survival curves by the cancerous versus normal cell lines respectively. Ascorbic acid and sodium ascorbate showed statistically significant (p<0.05) differential negative effects on the cancerous A549 cell line in comparison to unexposed controls as well as to effects measured with the normal lung MRC-5 cell line; this is highly indicative of a promising therapeutic potential. PMID- 21525622 TI - Defining the role of adenosine and glucocorticoids in down regulation of the inflammatory response associated with LPS activated macrophages - biomed 2011. AB - During infection and inflammation, macrophages play a pivotal role in the generation of inflammatory mediators and regulation of innate and adaptive immune responses. They also contribute to resolution of inflammation. It is generally accepted that monocytes are relatively short living cells which die spontaneously in the absence of appropriate stimuli. Proinflammatory factors like lipopolysaccharide (LPS) are known to enhance survival of proinflammatory monocytes, and the signals released from cells within the inflammatory site result in local accumulation of a population of activated macrophages. Glucocorticoids and adenosine are thought to play a role on the inflammatory macrophages. Macrophage-like cells were activated with LPS in the presence of glucocorticoids (GC) or adenosine. Glucocorticoid suppressed the nitric oxide and cytokine response associated with LPS activation of macrophages, while adenosine down regulated cytokine response. Signaling mechanism may be different depending upon receptor activation. PMID- 21525623 TI - Rosiglitazone-induced adipogenesis in a bone marrow mesenchymal stem cell line - biomed 2011. AB - In vitro modeling of adipose tissue is essential for the study of adipogenesis and related diseases as well as for the development of surgical reconstruction procedures and tissue-engineering applications. Peroxisome proliferator activated receptor ? (PPAR?) has been shown to play an integral role in stimulating adipogenesis. There are several established ligands for PPAR?, including rosiglitazone. D1 cells, a multipotential cell line derived from mouse bone marrow, were treated with increasing (0.1, 1, 10, and 30 uM) concentrations of rosiglitazone in DMEM for 48 hours followed by treatment by DMEM alone for up to 15 days. All doses of rosiglitazone stimulated the accumulation of lipids ,which was notable by day 6. The adipogenic effect of rosiglitazone was maximized at doses of 10 and 30 uM. Adipogenesis for rosiglitazone-treated cells was greater than that for cells treated with dexamethasone, a conventional method used to stimulate adipogenesis. Significantly higher levels of triglyceride-G (TG) and mature adipocyte markers (PPAR-, adipocyte fatty acid-binding protein) were observed with rosiglitazone treatment after 6 days. Cytokines in the supernatants were analyzed by multiplex-based ELISA assays at day 6 after treatment; these cells release adiponectin, resistin, PAI-1, MCP-1, and VEGF with either rosiglitazone or dexamethasone treatment. However, rosiglitazone treatment had lower osteocalcin release than did the control. This study provides evidence that rosiglitazone treatment is a reliable method that can be used to induce adipogenesis of D1 cells, a pluripotential cell line from mouse bone marrow. PMID- 21525624 TI - Role of plant-derived antioxidants on NF-kb expression in LPS-stimulated macrophages - biomed 2011. AB - The use of antioxidants has been shown to be beneficial in stimulating immune cells to increase phagocytosis and up-regulating the cellular processes to limit inflammation. Investigations into the specific mechanisms involved in the regulation of the inflammatory response in macrophages are broad; however, many researchers have found that regulating nuclear factor kappa B (NF-?B) may be a key component. The goal of this study was to assess the antioxidant potential of epigallocatechin-3-gallate (EGCG) (10uM) and thymoquinone (TQ) (10uM) on RAW 264.7 macrophages before and after being stimulated with lipopolysaccharide (LPS) (0.01 ug/mL). Our results showed that both EGCG and TQ, given individually, decreased NF-?B translocation in the nucleus when given before and after LPS stimulation. EGCG appeared to have the most impact on NF-?B in cells stimulated with LPS, but TQ was not as effective in inhibiting NF-?B in comparison to EGCG. The combination of EGCG and TQ showed a much higher level of NF-?B translocation compared to individual treatment, suggesting individual treatment may be more effective. In conclusion, we believe that EGCG and TQ may possibly block the upstream activation of mitogen activated protein kinase (MAPK) or inhibit the activity of the MAPK pathway, but further investigations are needed to understand the exact mechanisms of these observations. PMID- 21525625 TI - Androgen administration and macrophage behavior in the tissue-implant response - biomed 2011. AB - Macrophages are a critical component in the biocompatibility and function of implantable ceramic materials used in drug delivery applications. As part of the chronic inflammatory response, these cells surround the implant, establishing the tissue-implant interface and produce cytokines critical for recruitment of other complementary cells involved in the response. The purpose of this study was to evaluate the effect of androgens on behavior of the macrophage by further quantifying their presence in the fibrous tissue capsule of calcium phosphate (TCP) ceramic drug delivery systems with respect to their cytokine activity and release profile of the implant. Sixteen animals in four experimental groups were implanted with one TCP bioceramic each. Group I animals were implanted with a sham TCP ceramic not containing a steroid hormone (control group). Group II animals received the testosterone loaded TCP ceramic. Group III animals were implanted with the dihydrotestosterone loaded ceramic. Group IV animals received the androstenedione ceramic. At 90 days post-implantation, the animals were euthanized. The implants and fibrous tissue capsules were then extracted. Determination of macrophage populations and their behavior was conducted microscopically following H&E and IHC staining of antibodies to IL-1, IL-2, IL-6, and TNF- positive cells. All three of the hormones administered in this study, particularly androstenedione, significantly affect macrophage migration to the implant interface and surrounding fibrous tissue capsule when compared to the control group. In addition, these hormones limit the expression of cytokines severely limiting recruitment of other cells involved in the tissue-implant response. PMID- 21525626 TI - Utilizing computed tomography scans for analysis of motorcycle helmets in real world crashes - biomed 2011. AB - In 2008, there were more than 5,000 motorcycle crash fatalities in the United States. Many states have motorcycle helmet laws that are meant to protect riders during a crash. After recruiting motorcycle occupants injured in crashes, a protocol was established to scan three different types of motorcycle helmets commonly worn (cap, 3/4 shield, and full face shield) using a computed tomography (CT) scanner. The protocol developed was for a GE 64 slice PET/CT Discovery VCT scanner with axial images from anterior to posterior helmet acquired in helical mode. It had 512x512 resolution and the full face and 3/4 face shield helmets were scanned with greater voxels in the axial plane compared to the skull cap helmets. New helmets were scanned as exemplary images for comparison with helmets involved in motorcycle crashes. After CT scans were gathered, three-dimensional reconstructions were made to visualize scratches and impacts to the exterior of the helmets. Initial work was also conducted in analyzing interior components, and a trend was seen in decreased thickness between the interior foam and shell with sides of the exterior helmet thought to have contacted roadside barriers or the ground during motorcycle crashes. These helmet analysis methods have been established, and will be used to investigate multiple motorcycle crashes in conjunction with occupant injuries and direct head impacts to improve helmet design and the understanding of head injuries. This work also establishes the basis for development of finite element models of three of the most common helmet types. PMID- 21525627 TI - Amino Acid coated uhmw-pe implants modify macrophage migration in the tissue implant response - biomed 2011. AB - Polyethylene materials used in orthopedic applications are biocompatible and non immunogenic with host tissues. Recent studies in our laboratory have demonstrated the need for further study of these devices in vivo to further elucidate methods to modulate the tissue-implant response. The purpose of this investigation was to determine macrophage behavior after implantation of ultra high molecular weight polyethylene (UHMW-PE) rinsed with saline (control) and coated with poly-L-lysine (PLL), arginine-glycine-aspartic acid (RGD), and arginine-glycine-glutamic acid (RGE) into 16 adult male rats intraperitoneally (I/P). Implants and surrounding tissue were harvested at 90 days post-implantation. The animals were euthanized; and the UHMW-PE implants and the fibrous tissue capsules surrounding them were harvested. Microscopic examination of routinely stained sections (5 microns, Hematoxylin & Eosin) of the fibrous tissue capsules revealed macrophage counts were highest in the saline coated group (9.75+/-0.86 cells/high power field). Amino acid coated implants resulted in decreased mean macrophage counts per high power field for RGD (3.51+/-0.45), RGE (2.86+/-0.06), and PLL (4.2+/-0.55) compared to saline and the differences were statistically significant (ANOVA, p < 0.05). These findings indicate macrophage behavior at the tissue-implant interface and in surrounding fibrous tissue can be reduced using various amino acid combination coatings. In addition, these results provide evidence that the intensity of the chronic inflammatory reaction to UHMW-PE can be reduced and controlled to some extent. PMID- 21525628 TI - The effects of thymoquinone and green tea extract on wi-38 fibroblasts exposed to low-density lipoprotein - biomed 2011. AB - Previous research in cardiovascular disease (CVD) has indicated that differences exist among men and women. These differences are partially attributed to sex hormones, especially testosterone and estrogen. As CVD remains the leading cause of death for both men and women in the US and as healthcare costs continue to rise, researchers are seeking alternative methods of treating the disease. Consequently, the use of antioxidants for treatment of CVD has gained much attention in recent years. The specific aim of this study is to investigate the effects of the potential antioxidants thymoquinone and green tea extract on WI-38 (female) fibroblasts exposed to low-density lipoprotein (LDL). WI-38 fibroblasts were incubated with LDL in the presence of thymoquinone and/or green tea extract and were evaluated for signs of cellular damage. Results of this study suggest that thymoquinone and green tea extract may delay the progression of cellular damage caused by LDL challenge. PMID- 21525629 TI - Cellular effects of catabolic inflammatory cytokines on chondrocytes - biomed 2011. AB - The inhibitory effects of pro-inflammatory cytokines interleukin-1beta (IL 1beta), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) on articular chondrocyte growth dynamics are well documented. The cartilage remodeling process is mediated entirely by chondrocytes. Most importantly, the chondrocyte is responsible not only for the synthesis of the complex extracellular matrix of the articular cartilage, but it is also the source of proteinases and other precursors that degrade the damaged matrix to permit repair. IL-1beta and TNF-a appear to play important roles in affecting chondrocyte function. IL-1beta is extremely important to cartilage destruction contributing to increase production of matrix metalloproteinases (MMP?s) and other degradative products, while TNF-a appears to drive the inflammatory process. IL-6 has been proposed as a contributor to the pathogenesis of osteoarthritis. The objective of this study was to evaluate matrix degradation markers, apoptosis, cellular damage markers, and cellular morphology of chondrocytes following a challenge with these inflammatory cytokines. Human chondrosarcoma cells were exposed to IL-1beta, TNF a, and IL-6 for 24, 48, and 72 hours. Chondrocyte viability, proliferation, cellular damage, cellular function, and cellular morphology were evaluated after each time point. As early as 24 hours, chondrocytes exposed to IL-1beta and TNF-a resulted in a reduction in cell number, an increase in chondrocyte membrane damage, and a six-fold increase in MMP-13 production by chondrocytes. It was concluded that IL-1beta has the most significant effect on chondrocyte viability, proliferation and cellular function when compared to TNF-a and IL-6. PMID- 21525630 TI - Solid-state cryomilling for porogen mixing and porous scaffold fabrication - biomed 2011. AB - Several widely used techniques for the fabrication of three dimensional (3D) scaffolds utilize the particulate leaching method to achieve a porous structure. This method involves the selective leaching of a mineral or an organic compound to generate pores. However, scaffolds prepared by this technique tend to exhibit limited interconnectivity. Therefore, to enhance the interconnectivity of the scaffolds fabricated by particulate leaching, a polymeric porogen can be added during processing. Typically porogens are mixed into a polymer solution, powder, or melt. The mixture is subsequently cast, molded, or extruded, and then leaching the porogens results in porous scaffolds. Still, even though scaffold interconnectivity is improved through the addition of polymer porogens, particulate leaching does not yield scaffolds with uniform properties. This research introduces a new solventless approach, cryomilling, to blend porogens and attain interconnected porous scaffolds with uniform morphologies. To validate the efficacy of the suggested approach a comparison of the effect of various solid-state mixing approaches on scaffold morphology and mechanical properties will be made. In this study, salt particles and poly(ethylene oxide) (PEO) were mixed (manually or through cryomilling) with poly(e-caprolactone) (PCL) for the preparation of porous 3D PCL scaffolds, the mixtures were then compression molded, and subsequently, water was used to leach the porogens. Morphological and compressive properties of the resulting scaffolds will be discussed. This simple, novel, economical, organic solvent-free approach for the fabrication of 3D interconnected porous scaffolds holds promise for tissue engineering applications. PMID- 21525631 TI - Compression instrument for tissue experiments (cite) at the meso-scale: device validation - biomed 2011. AB - Liver sinusoidal endothelial cells (LSECs) are the primary site of numerous transport and exchange processes essential for liver function. LSECs rest on a sparse extracellular matrix layer housed in the space of Disse, a 0.5-1LSECs from hepatocytes. To develop bioengineered liver tissue constructs, it is important to understand the mechanical interactions among LSECs, hepatocytes, and the extracellular matrix in the space of Disse. Currently the mechanical properties of space of Disse matrix are not well understood. The objective of this study was to develop and validate a device for performing mechanical tests at the meso scale (100nm-100m), to enable novel matrix characterization within the space of Disse. The device utilizes a glass micro-spherical indentor attached to a cantilever made from a fiber optic cable. The 3-axis translation table used to bring the specimen in contact with the indentor and deform the cantilever. A position detector monitors the location of a laser passing through the cantilever and allows for the calculation of subsequent tissue deformation. The design allows micro-newton and nano-newton stress-strain tissue behavior to be quantified. To validate the device accuracy, 11 samples of silicon rubber in two formulations were tested to experimentally confirm their Young's moduli. Prior macroscopic unconfined compression tests determined the formulations of EcoFlex030 (n-6) and EcoFlex010 (n-5) to posses Young's moduli of 92.67+-6.22 and 43.10+-3.29 kPa respectively. Optical measurements taken utilizing CITE's position control and fiber optic cantilever found the moduli to be 106.4 kPa and 47.82 kPa. PMID- 21525632 TI - The metabolic effect of thyrotropin releasing hormone (trh) and norepinephrine (ne) in warm-acclimated obese rats - biomed 2011. AB - We have studied the effects of chronic peripheral infusion of thyrotropin releasing hormone (TRH) and norepinephrine (NE) alone and together. Do these hormones additively affect energy balance and body weight similarly in obese animals? 20 obese (fa/fa) Zucker strain rats were studied. Food intake, body weight and resting metabolic rate (RMR) were measured over a 14 day period. We confirmed that in these animals NE stimulated RMR, but with parallel stimulation of appetite so that weight gain continued; TRH stimulated RMR but inhibited food intake so that rate of weight gain was reduced. TRH and NE together acted to further enhance RMR, but the inhibitory and stimulatory effects on food intake cancelled out. Thus a negative energy balance resulted in this group of animals; however, resultant weight loss was moderate in obese compared to previously studied lean animals. We suggest like we previously reported that the relative insensitivity of the obese to TRH and NE together reflects the inability of their brown adipose tissue to respond to thermogenic agents, even when chronically administered. PMID- 21525633 TI - Human sexual function emulator - biomed 2011. AB - In this paper the author extends his computerized human nervous system function emulator (HNSFE) to include elements of courtship, pair bonding, erotic stimulation and sexual intercourse, producing a human sexual function emulator (HSFE). The HNSFE is a biologically-inspired, open systems, multitasking, multiprocessor, IEEE 1275 program which imitates many neural-cognitive operations of the human brain. It is the control element of the author?s robotic ?Android with Neural Network, Intellect and Emotions? (ANNIE). For this experiment two artificial people were created: a male (mANNIE) and a female (fANNIE). Their personality and memory files were customized to represent a stereotypical man and woman. The experimental apparatus included a display and camera for each individual, to enable facial gesture expression and recognition. Audio output and input was provided for speech synthesis and recognition. Bidirectional optical and radio frequency back-channels were supplied to facilitate subconscious interpersonal communications. Each individual was supplied with simulated erogenous zones and the means to stimulate them. Elements of normal human courtship as described by Devereux (1903) was included in the behavioral portion of this emulator, as well as the four phase model of the human sexual response cycle described by Masters and Johnson (1966) for each gender. RESULTS: depending on initial conditions set by the observer and a random factor, the male-female pair would show romantic interest in each other, engage in sexual behavior and attain an orgasmic outcome. If the results of an encounter were positive, subsequent encounters occurred with increased frequency; the reverse was also true. In conclusion, the author's HNSFE was shown to be adaptable to realistic emulation of human male-female courtship and sexual functioning. Reproduction of new artificial entities via the HSFE following simulated mating is discussed. PMID- 21525634 TI - A biomechanical modelof the arthrosis of the hip joint - biomed 2011. AB - The hip joint has been investigated in depth, but causes of algic (pain) phenomena, especially those apparently located at the knee (referred pain), still remain unclear. Using a bi-dimensional multi-body model we investigated the effect of arthrosis on the kinematic of the hip joint and its relationship to pain. The bone was modeled as a rigid structure whereas the capsule and cartilage were assumed to be deformable. The effects of arthrosis were simulated as reduction of the thickness of the deformable tissues and increased friction. The extension velocity of the rectus femori and the trajectory of the instantaneous center of rotation (ICR) were examined for both physiological conditions and advanced degrees of arthrosis.In physiological conditions, results show that the extension velocity of the muscle has slight irregularities but is nevertheless continuous. The presence of arthrosis leads to a localized increase in friction and the model shows a migration of the location of the ICR toward the acetabulum. Changes in the ICR due to irregular surface friction, cartilage erosion as well as lack of synovial fluid, which in normal conditions ensures boundary film lubrication, induce discontinuities in the extension velocity of the muscle which are detected by the proprioceptive system (e.g. Golgi tendon organ) generating algic phenomena.The results of the model confirmed these findings and how hip arthrosis, in producing changes in the extension velocity of the muscle and in the kinematic of the movement, results in muscle and tendon pain around the knee. PMID- 21525635 TI - Using computerized posturography to explore the connection between bmi and postural stability in long-term tai chi practitioners - biomed 2011. AB - Obesity is a major health concern because of its linkage to chronic diseases such as type 2 diabetes, heart disease, and cancer. Another less studied outcome is the observed increase in the incidence of accidental falls. According to CDC, medical costs associated with fall injuries exceeded $16 billion in 2000 and by 2020 will exceed $54 billion. To reduce the impact on society and individuals, it is essential to explore mechanisms to reduce the frequency of falls. For example, a short 12-week intervention of Tai Chi reduced the risk of accidental falls in an elderly population. However, there are few studies exploring the effect of the long-term practice of Tai Chi on postural stability, particularly in individuals with a BMI greater than 30. In this study, the connection between postural stability and BMI in long-term Tai Chi practitioners is investigated using a convenience sample study design. Participants at a 1-week Tai Chi workshop held in June of 2010 were contacted and forty-four individuals attending the workshop enrolled in the study (ranging in age from 22 to 84, mean age 61). The participants? weight distribution was similar to the general population with 38% having a BMI less than 25. Comparison between the normal and obese groups indicated that there were no differences in stability scores in the most challenging category: standing on a compliant surface with eyes closed. Additional studies are needed to determine whether Tai Chi is as an effective intervention to prevent falls in the obese population. PMID- 21525636 TI - Subjectivity of typical experiments used to investigate the existence of mirror neurons - biomed 2011. AB - Typical experiments used in investigating the mirror neuron theory involve a person executing a task, and an animal (usually a rhesus or nemestrina macaque primate), instrumented or under observation in some other manner, that is supposed to imitate the task. To evaluate if in fact the animal imitates the person and not the opposite, we asked a group of 70 first year veterinary medicine students with no experience with these type of experiments to evaluate two publicly available movies of two such experiments and to answer a multiple choice questionnaire. They were asked to judge if, in their opinion, the animal imitated the person or if it appeared that the person imitated or followed the animal. The order of the multiple choices was randomized to avoid biases. In one movie, the majority of the subjects found that the person seemed to follow the animal and not the opposite as it should have been. For the other movie, about 14% of the subjects also answered that the person followed the animal. This suggests there is a great deal of subjectivity in how these experiments are conducted and evaluated that might affect the conclusion of the investigations, raising doubts on their validity. We also raise some other questions about the validity of the experimental model in relation to other experiments used investigations about the hypothesized mirror neurons. This work is an invitation to caution with regards to proposing and accepting the mirror neuron theory based on the experiments conducted thus far. PMID- 21525637 TI - Fly eye based sensor model and animation using matlab - biomed 2011. AB - A new optical sensor based on the common house fly, Musca domestica, has been under development for some time at the University of Wyoming. Each sensor consists of a series of photodiodes with overlapping Gaussian field of views. The photodiodes share a common facet lens. This type of sensor provides higher movement detection and resolution than can be obtained in current charged-couple detector (CCD) arrays that are commonly used in digital imaging systems. The purpose of this research is to aid in the application and development of the fly based sensor by creating a MATLAB simulation tool to model and study the response signals from various input stimuli. In particular, the sensor detection capability and limits for line, edge and pulse stimuli will be modeled, and analyzed. Increased knowledge of the detection characteristics and limits of this type of sensor will provide insight and guidance to determine possible sensor applications. The signal analysis makes use of the Gaussian profiles that are created in MATLAB. A user-selectable input signal can be applied, while observing the output signal. The information is animated, and plotted for study and analysis. This interactive MATLAB model is a powerful tool to help understand the complex interactions of the optical signals. This sensor configuration has a variety of applications in wheelchair odometry, power line detection by unmanned aerial systems (AES), high speed railroad line inspection, and remote building monitoring. PMID- 21525638 TI - Macromolecular crystallography radiation damage research: what's new? AB - Radiation damage in macromolecular crystallography has become a mainstream concern over the last ten years. The current status of research into this area is briefly assessed, and the ten new papers published in this issue are set into the context of previous work in the field. Some novel and exciting developments emerging over the last two years are also summarized. PMID- 21525639 TI - Radiation damage in room-temperature data acquisition with the PILATUS 6M pixel detector. AB - The first study of room-temperature macromolecular crystallography data acquisition with a silicon pixel detector is presented, where the data are collected in continuous sample rotation mode, with millisecond read-out time and no read-out noise. Several successive datasets were collected sequentially from single test crystals of thaumatin and insulin. The dose rate ranged between ~ 1320 Gy s(-1) and ~ 8420 Gy s(-1) with corresponding frame rates between 1.565 Hz and 12.5 Hz. The data were analysed for global radiation damage. A previously unreported negative dose-rate effect is observed in the indicators of global radiation damage, which showed an approximately 75% decrease in D(1/2) at sixfold higher dose rate. The integrated intensity decreases in an exponential manner. Sample heating that could give rise to the enhanced radiation sensitivity at higher dose rate is investigated by collecting data between crystal temperatures of 298 K and 353 K. UV-Vis spectroscopy is used to demonstrate that disulfide radicals and trapped electrons do not accumulate at high dose rates in continuous data collection. PMID- 21525640 TI - Similarities and differences in radiation damage at 100 K versus 160 K in a crystal of thermolysin. AB - The temperature-dependence of radiation damage in macromolecular X-ray crystallography is currently much debated. Most protein crystallographic studies are based on data collected at 100 K. Data collection at temperatures below 100 K has been proposed to reduce radiation damage and above 100 K to be useful for kinetic crystallography that is aimed at the generation and trapping of protein intermediate states. Here the global and specific synchrotron-radiation sensitivity of crystalline thermolysin at 100 and 160 K are compared. Both types of damage are higher at 160 K than at 100 K. At 160 K more residue types are affected (Lys, Asp, Gln, Pro, Thr, Met, Asn) than at 100 K (Met, Asp, Glu, Lys). The X-ray-induced relative atomic B-factor increase is shown to correlate with the proximity of the atom to the nearest solvent channel at 160 K. Two models may explain the observed correlation: either an increase in static disorder or an increased attack of hydroxyl radicals from the solvent area of the crystal. PMID- 21525641 TI - Energy dependence of site-specific radiation damage in protein crystals. AB - It is important to consider radiation damage to crystals caused by data collection when solving structures and critical when determining protein function, which can often depend on very subtle structural characteristics. In this study the rate of damage to specific sites in protein crystals cooled at 100 K is found to depend on the energy of the incident X-ray beam. Several lysozyme crystals were each subjected to 3-26 MGy of cumulative X-ray exposure by collecting multiple data sets from each crystal at either 9 keV or 14 keV. The integrated electron density surrounding each S atom in the structure was calculated for each data set and the change in electron density was evaluated as a function of dose at the two energies. The rate of electron density decrease per cubic A per MGy was determined to be greater at 14 keV than at 9 keV for cysteine sulfurs involved in disulphide bridges; no statistically significant differences in the decay rates were found for methionine sulfurs. These preliminary results imply that it might be possible to minimize certain types of specific radiation damage by an appropriate choice of energy. Further experiments studying a variety of photolabile sites over a wider range of energies are needed to confirm this conclusion. PMID- 21525642 TI - Effective scavenging at cryotemperatures: further increasing the dose tolerance of protein crystals. AB - The rate of radiation damage to macromolecular crystals at both room temperature and 100 K has previously been shown to be reduced by the use of certain radical scavengers. Here the effects of sodium nitrate, an electron scavenger, are investigated at 100 K. For sodium nitrate at a concentration of 0.5 M in chicken egg-white lysozyme crystals, the dose tolerance is increased by a factor of two as judged from the global damage parameters, and no specific structural damage to the disulfide bonds is seen until the dose is greatly in excess (more than a factor of five) of the value at which damage appears in electron density maps derived from a scavenger-free crystal. In the electron density maps, ordered nitrate ions adjacent to the disulfide bonds are seen to lose an O atom, and appear to protect the disulfide bonds. In addition, results reinforcing previous reports on the effectiveness of ascorbate are presented. The mechanisms of action of both scavengers in the crystalline environment are elucidated. PMID- 21525643 TI - Correlated single-crystal electronic absorption spectroscopy and X-ray crystallography at NSLS beamline X26-C. AB - The research philosophy and new capabilities installed at NSLS beamline X26-C to support electronic absorption and Raman spectroscopies coupled with X-ray diffraction are reviewed. This beamline is dedicated full time to multidisciplinary studies with goals that include revealing the relationship between the electronic and atomic structures in macromolecules. The beamline instrumentation has been fully integrated such that optical absorption spectra and X-ray diffraction images are interlaced. Therefore, optical changes induced by X-ray exposure can be correlated with X-ray diffraction data collection. The installation of Raman spectroscopy into the beamline is also briefly reviewed. Data are now routinely generated almost simultaneously from three complementary types of experiments from the same sample. The beamline is available now to the NSLS general user population. PMID- 21525644 TI - Revealing low-dose radiation damage using single-crystal spectroscopy. AB - The structural information and functional insight obtained from X-ray crystallography can be enhanced by the use of complementary spectroscopies. Here the information that can be obtained from spectroscopic methods commonly used in conjunction with X-ray crystallography and best-practice single-crystal UV-Vis absorption data collection are briefly reviewed. Using data collected with the in situ system at the Swiss Light Source, the time and dose scales of low-dose X-ray induced radiation damage and solvated electron generation in metalloproteins at 100 K are investigated. The effect of dose rate on these scales is also discussed. PMID- 21525645 TI - Additional phase information from UV damage of selenomethionine labelled proteins. AB - Currently, selenium is the most widely used phasing vehicle for experimental phasing, either by single anomalous scattering or multiple-wavelength anomalous dispersion (MAD) procedures. The use of the single isomorphous replacement anomalous scattering (SIRAS) phasing procedure with selenomethionine containing proteins is not so commonly used, as it requires isomorphous native data. Here it is demonstrated that isomorphous differences can be measured from intensity changes measured from a selenium labelled protein crystal before and after UV exposure. These can be coupled with the anomalous signal from the dataset collected at the selenium absorption edge to obtain SIRAS phases in a UV-RIPAS phasing experiment. The phasing procedure for two selenomethionine proteins, the feruloyl esterase module of xylanase 10B from Clostridium thermocellum and the Mycobacterium tuberculosis chorismate synthase, have been investigated using datasets collected near the absorption edge of selenium before and after UV radiation. The utility of UV radiation in measuring radiation damage data for isomorphous differences is highlighted and it is shown that, after such measurements, the UV-RIPAS procedure yields comparable phase sets with those obtained from the conventional MAD procedure. The results presented are encouraging for the development of alternative phasing approaches for selenomethionine proteins in difficult cases. PMID- 21525646 TI - Experimental procedure for the characterization of radiation damage in macromolecular crystals. AB - A reliable and reproducible method to automatically characterize the radiation sensitivity of macromolecular crystals at the ESRF beamlines has been developed. This new approach uses the slope of the linear dependence of the overall isotropic B-factor with absorbed dose as the damage metric. The method has been implemented through an automated procedure using the EDNA on-line data analysis framework and the MxCuBE data collection control interface. The outcome of the procedure can be directly used to design an optimal data collection strategy. The results of tests carried out on a number of model and real-life crystal systems are presented. PMID- 21525647 TI - Assessment of radiation damage behaviour in a large collection of empirically optimized datasets highlights the importance of unmeasured complicating effects. AB - The radiation damage behaviour in 43 datasets of 34 different proteins collected over a year was examined, in order to gauge the reliability of decay metrics in practical situations, and to assess how these datasets, optimized only empirically for decay, would have benefited from the precise and automatic prediction of decay now possible with the programs RADDOSE [Murray, Garman & Ravelli (2004). J. Appl. Cryst. 37, 513-522] and BEST [Bourenkov & Popov (2010). Acta Cryst. D66, 409-419]. The results indicate that in routine practice the diffraction experiment is not yet characterized well enough to support such precise predictions, as these depend fundamentally on three interrelated variables which cannot yet be determined robustly and practically: the flux density distribution of the beam; the exact crystal volume; the sensitivity of the crystal to dose. The former two are not satisfactorily approximated from typical beamline information such as nominal beam size and transmission, or two dimensional images of the beam and crystal; the discrepancies are particularly marked when using microfocus beams (<20 um). Empirically monitoring decay with the dataset scaling B factor (Bourenkov & Popov, 2010) appears more robust but is complicated by anisotropic and/or low-resolution diffraction. These observations serve to delineate the challenges, scientific and logistic, that remain to be addressed if tools for managing radiation damage in practical data collection are to be conveniently robust enough to be useful in real time. PMID- 21525649 TI - Three-dimensional diffraction mapping by tuning the X-ray energy. AB - Three-dimensional reciprocal-space maps of a single SiGe island around the Si(004) Bragg peak are recorded using an energy-tuning technique with a microfocused X-ray beam with compound refractive lenses as focusing optics. The map is in agreement with simulated data as well as with a map recorded by an ordinary rocking-curve scan. The energy-tuning approach circumvents both the comparatively large sphere of confusion of diffractometers compared with nanostructures and vibrations induced by motors. Thus, this method offers new possibilities for novel combinations of three-dimensional micro- and nano-focused X-ray diffraction with complex in situ sample environments such as scanning probe microscopes. PMID- 21525648 TI - Radiation damage in single-particle cryo-electron microscopy: effects of dose and dose rate. AB - Radiation damage is an important resolution limiting factor both in macromolecular X-ray crystallography and cryo-electron microscopy. Systematic studies in macromolecular X-ray crystallography greatly benefited from the use of dose, expressed as energy deposited per mass unit, which is derived from parameters including incident flux, beam energy, beam size, sample composition and sample size. In here, the use of dose is reintroduced for electron microscopy, accounting for the electron energy, incident flux and measured sample thickness and composition. Knowledge of the amount of energy deposited allowed us to compare doses with experimental limits in macromolecular X-ray crystallography, to obtain an upper estimate of radical concentrations that build up in the vitreous sample, and to translate heat-transfer simulations carried out for macromolecular X-ray crystallography to cryo-electron microscopy. Stroboscopic exposure series of 50-250 images were collected for different incident flux densities and integration times from Lumbricus terrestris extracellular hemoglobin. The images within each series were computationally aligned and analyzed with similarity metrics such as Fourier ring correlation, Fourier ring phase residual and figure of merit. Prior to gas bubble formation, the images become linearly brighter with dose, at a rate of approximately 0.1% per 10 MGy. The gradual decomposition of a vitrified hemoglobin sample could be visualized at a series of doses up to 5500 MGy, by which dose the sample was sublimed. Comparison of equal-dose series collected with different incident flux densities showed a dose-rate effect favoring lower flux densities. Heat simulations predict that sample heating will only become an issue for very large dose rates (50 e(-)A(-2) s(-1) or higher) combined with poor thermal contact between the grid and cryo-holder. Secondary radiolytic effects are likely to play a role in dose-rate effects. Stroboscopic data collection combined with an improved understanding of the effects of dose and dose rate will aid single particle cryo-electron microscopists to have better control of the outcome of their experiments. PMID- 21525650 TI - Quantitative local structure determination in mica crystals: ab initio simulations of polarization XANES at the potassium K-edge. AB - An attempt to refine the local structure of a layered structure such as mica is made by combining angle-resolved XANES (AXANES) and single-crystal X-ray diffraction (SC-XRD) experiments. Ab initio calculations of AXANES spectra of several tri-octahedral micas have been used to further interpolate experimental data and to deduce physico/chemical effects. Structural distortions have been found highly correlated with the compositional disordering that arises from electronic interactions between anions and cations, and extend the interlayer entering deep into nearby tetrahedral and octahedral sheets. Multiple occupations at the same atomic site have been investigated in detail both in the parallel and perpendicular components of AXANES spectra. Finally, the best fit obtained, computed in the framework of the multiple-scattering theory, is presented and the limitations of the muffin-tin potential in layered systems are briefly discussed. PMID- 21525651 TI - Suppression of ring artefacts when tomographing anisotropically attenuating samples. AB - There are many objects for which the attenuation varies significantly as they are rotated during computerized X-ray tomography, for example plate samples. This can lead to significant ring artefacts in the subsequent tomographic reconstructions. In this paper a new method is presented that can successfully suppress such ring artefacts and is applicable to both parallel and cone-beam geometries. Rapid correction is achieved via an analytical formula which involves only a matrix vector multiplication, for which the matrix is known and depends on a regularization parameter. The efficacy of the method is demonstrated for a paleontological sample (calcified shark cartilage) and a carbon-carbon composite/Ti-SiC metal matrix composite test sample. PMID- 21525652 TI - Reconstruction of electron beam distribution using phase-retrieval algorithm. AB - The shapes of light sources such as electron beams can be reconstructed by inverse Fourier transformation of the complex degree of spatial coherency, which can be measured using Young's interferometer. The application of the phase retrieval algorithm to reduce phase measurement errors in the complex degree of spatial coherency is numerically studied using an electron beam with an asymmetric distribution. This application is demonstrated with experimental data measured at the diagnostic beamline at the Pohang Accelerator Laboratory. PMID- 21525653 TI - High-efficiency Fresnel zone plates for hard X-rays by 100 keV e-beam lithography and electroplating. AB - The fabrication and characterization of Fresnel zone plates (FZPs) for hard X-ray microscopy applications are reported. High-quality 500 nm- and 1 um-thick Au FZPs with outermost zone widths down to 50 nm and 70 nm, respectively, and with diameters up to 600 um were fabricated. The diffraction efficiencies of the fabricated FZPs were measured for a wide range of X-ray energies (2.8-13.2 keV) showing excellent values up to 65-75% of the theoretical values, reflecting the good quality of the FZPs. Spatially resolved diffraction efficiency measurements indicate the uniformity of the FZPs and a defect-free structure. PMID- 21525654 TI - In situ diffuse reflectance IR spectroscopy and X-ray absorption spectroscopy for fast catalytic processes. AB - A new instrument for synchronous in situ investigations of catalytic materials by IR and X-ray absorption spectroscopies was designed and built at the X18A beamline of the National Synchrotron Light Source of Brookhaven National Laboratory. It provides analytical tools for solving structural, electronic and kinetic problems in catalysis science by two complementary methods. Among the features attractive for catalysis research are the broad range of catalytically active elements that can be investigated (starting with Ni and beyond), the wide range of reaction conditions (temperatures up to 873 K, various reactive gases) and time scales (starting from tens of seconds). The results of several representative experiments that illustrate the attractive capabilities of the new set-up are discussed. PMID- 21525655 TI - Specific molecular and cellular events induced by irradiated X-ray photoactivatable drugs raise the problem of co-toxicities: particular consequences for anti-cancer synchrotron therapy. AB - Synchrotrons are capable of producing intense low-energy X-rays that enable the photoactivation of high-Z elements. Photoactivation therapy (PAT) consists of loading tumors with photoactivatable drugs and thereafter irradiating them at an energy, generally close to the K-edge of the element, that enhances the photoelectric effect. To date, three major photoactivatable elements are used in PAT: platinum (cisplatin and carboplatin), iodine (iodinated contrast agents and iododeoxyuridine) and gadolinium (motexafin gadolinium). However, the molecular and cellular events specific to PAT and the radiobiological properties of these photoactivatable drugs are still misknown. Here, it is examined how standard and synchrotron X-rays combined with photoactivatable drugs impact on the cellular response of human endothelial cells. These findings suggest that the radiolysis products of the photoactivatable drugs may participate in the synergetic effects of PAT by increasing the severity of radiation-induced DNA double-strand breaks. Interestingly, subpopulation of highly damaged cells was found to be a cellular pattern specific to PAT. The data show that the efficiency of emerging anti cancer modalities involving synchrotron photoactivation strongly depends on the choice of photoactivatable drugs, and important series of experiments are required to secure their clinical transfer before applying to humans. PMID- 21525656 TI - Fast X-ray microdiffraction techniques for studying irreversible transformations in materials. AB - A pair of techniques have been developed for performing time-resolved X-ray microdiffraction on irreversible phase transformations. In one technique capillary optics are used to focus a high-flux broad-spectrum X-ray beam to a 60 um spot size and a fast pixel array detector is used to achieve temporal resolution of 55 us. In the second technique the X-rays are focused with Kirkpatrick-Baez mirrors to achieve a spatial resolution better than 10 um and a fast shutter is used to provide temporal resolution better than 20 us while recording the diffraction pattern on a (relatively slow) X-ray CCD camera. Example data from experiments are presented where these techniques are used to study self-propagating high-temperature synthesis reactions in metal laminate foils. PMID- 21525657 TI - Calcifications in human osteoarthritic articular cartilage: ex vivo assessment of calcium compounds using XANES spectroscopy. AB - Calcium (Ca(2+))-containing crystals (CCs), including basic Ca(2+) phosphate (BCP) and Ca(2+) pyrophosphate dihydrate (CPPD) crystals, are associated with severe forms of osteoarthritis (OA). Growing evidence supports a role for abnormal articular cartilage mineralization in the pathogenesis of OA. However, the role of Ca(2+) compounds in this mineralization process remains poorly understood. Six patients, who underwent total knee joint replacement for primary OA, have been considered in this study. Cartilage from femoral condyles and tibial plateaus in the medial and lateral compartments was collected as 1 mm thick slices cut tangentially to the articular surface. First, CCs presence and biochemical composition were assessed using Fourier transform infrared spectroscopy (FT-IR). Next, Ca(2+) compound biochemical form was further assessed using X-ray absorption spectroscopy (XAS) performed at the Ca(2+) K-absorption edge. Overall, 12 cartilage samples were assessed. Using FT-IR, BCP and CPPD crystals were detected in four and three out of 12 samples, respectively. Ca(2+) compound biochemical forms differed between areas with versus without CCs, when compared using XAS. The complete set of data shows that XANES spectroscopy can be used to accurately characterize sparse CCs in human OA cartilage. It is found that Ca(2+) compounds differ between calcified and non-calcified cartilage areas. In calcified areas they appear to be mainly involved in calcifications, namely Ca(2+) crystals. PMID- 21525658 TI - Development of a hard X-ray delay line for X-ray photon correlation spectroscopy and jitter-free pump-probe experiments at X-ray free-electron laser sources. AB - A hard X-ray delay line capable of splitting and delaying single X-ray pulses has been developed with the aim of performing X-ray photon correlation spectroscopy (XPCS) and X-ray pump-probe experiments at hard X-ray free-electron laser sources. The performance of the device was tested with 8.39 keV synchrotron radiation. Time delays up to 2.95 ns have been demonstrated. The feasibility of the device for performing XPCS studies was tested by recording static speckle patterns. The achieved speckle contrast of 56% indicates the possibility of performing ultra-fast XPCS studies with the delay line. PMID- 21525659 TI - New developments in fabrication of high-energy-resolution analyzers for inelastic X-ray spectroscopy. AB - In this work new improvements related to the fabrication of spherical bent analyzers for 1 meV energy-resolution inelastic X-ray scattering spectroscopy are presented. The new method includes the use of a two-dimensional bender to achieve the required radius of curvature for X-ray analyzers. The advantage of this method is the ability to monitor the focus during bending, which leads to higher efficiency analyzers. PMID- 21525660 TI - High-resolution stress mapping of polycrystalline alumina compression using synchrotron X-ray diffraction. AB - The ability to achieve uniform stress in uniaxial compression tests of polycrystalline alumina is of significance for the calibration of piezospectroscopic coefficients as well as strength studies in ceramics. In this study high-energy X-rays were used to capture powder diffraction profiles over a half-section of a polycrystalline alumina parallelepiped sample under an increasing uniaxial compressive load. The data were converted to strain and results were used for stress mapping of the sample. Stress maps from the study quantify the higher stresses at the sample-platen contact interface and reveal the evolution of the stress distribution in these specimens with load. For the geometry of the samples used, at the center section of the specimen the overall magnitudes of the compressive stresses were found to be 20% higher compared with the average expected theoretical stress based on the applied load and cross sectional area. The observed compressive stresses at the corners of the parallelepiped specimen were 62% higher and shear stresses were observed at the specimen interface to the load mechanism. The effects, seen at the interface, can lead to premature failure at these locations and can affect the accuracy of calibration of spectral peaks with stress as well as compression strength measurements. The results provide important information that can be used to establish guidelines on material and geometry considerations in developing compression tests on high-strength ceramics. PMID- 21525661 TI - In situ powder diffraction study of belite sulfoaluminate clinkering. AB - Belite sulfoaluminate (BSA) cements have been proposed as environmentally friendly building materials, as their production may release up to 35% less CO(2) into the atmosphere when compared with ordinary Portland cement fabrication. However, their formation mechanism has not been studied in detail so far. Here, an in situ high-temperature high-resolution synchrotron X-ray powder diffraction study is reported. Two types of BSA clinkers have been characterized, both containing 50-60 wt% C(2)S and 20-30 wt% C(4)A(3)?underline{?rm S} as main phases. One type is iron-rich and a second type (with different phase assemblage) is aluminium-rich. Furthermore, the C(2)S phase reacts slowly with water, thus activation of this compound is desirable in order to enhance the mechanical strength development of the resulting cements. To do so, iron-rich BSA clinkers have been doped with minor amounts of B(2)O(3) and Na(2)O to promote stabilization of alpha-forms of C(2)S, which are more reactive with water. The decarbonated raw materials were loaded into Pt tubes and heated to between 973 K and 1673 K, and patterns were collected using a high-energy synchrotron beam of wavelength lambda = 0.30 A. The thermal stability of Klein's salt in these clinkers has been clarified. Several reactions have been followed: formation and decomposition of Klein's salt, melting of aluminates and ferrite, and polymorphic transformations of dicalcium silicate: alpha'H-C2S -> alpha-C(2)S. Changes in mineralogical phase assemblages at a given temperature owing to the addition of minor amounts of selected elements have also been determined. PMID- 21525662 TI - Geometrical layout and optics modelling of the surface science beamline station at the SESAME synchrotron radiation facility. AB - The layout and the optical performance of the SGM branch of the D09 bending magnet beamline, under construction at SESAME, are presented. The beamline is based on the Dragon-type design and delivers photons over the spectral range 15 250 eV. One fixed entrance slit and a movable exit slit are used. The performance of the beamline has been characterized by calculating the mirror reflectivities and the grating efficiencies. The flux and resolution were calculated by ray tracing using SHADOW. The grating diffraction efficiencies were calculated using the GRADIF code. The results and the overall shapes of the predicted curves are in reasonable agreement with those obtained using an analytical formula. PMID- 21525663 TI - X-ray collimation by crystals with precise parabolic holes based on diffractive refractive optics. AB - Two crystals with precise parabolic holes were used to demonstrate sagittal beam collimation by means of a diffractive-refractive double-crystal monochromator. A new approach is introduced and beam collimation is demonstrated. Two Si(333) crystals with an asymmetry angle of alpha = 15 degrees were prepared and arranged in a dispersive position (+,-,-,+). Based on theoretical calculations, this double-crystal set-up should provide tunable beam collimation within an energy range of 6.3-18.8 keV (Theta(B) = 71-18.4 degrees ). An experiment study was performed on BM05 at ESRF. Using 8.97 keV energy, the beam profile at various distances was measured. The experimental results are in good agreement with theoretical predictions. Owing to insufficient harmonic suppression, the collimated (333) beam was overlapped by horizontally diverging (444) and (555) beams. PMID- 21525664 TI - Use of Soller slits to remove reference foil fluorescence from transmission spectra. AB - Measurement of X-ray absorption spectroscopy (XAS) in transmission is the method of choice for strong or concentrated samples. In a typical XAS experiment above 5 keV the sample is placed between the first (I(0)) and second (I(1)) ion chambers and a standard foil is placed between the second (I(1)) and third (I(2)) ion chambers for simultaneous calibration of energy during sample analysis. However, some fluorescence from the foil may be registered in I(1), causing anomalies in the transmission signal of the sample, especially when the sample edge jump is relatively small. To remedy this, Soller slits were constructed and placed between the foil and I(1) to minimize back-fluorescence from the foil. A comparison of blank and standard samples, measured with or without Soller slits or under a worst-case scenario, demonstrates the advantages of Soller slits when analyzing weak signal samples via transmission XAS. PMID- 21525665 TI - Synchrotron-radiation-induced oxidation of selenite to selenate in coal-derived fly ash. AB - Systematic changes observed in consecutive XANES spectra of selenium in samples of fly ash from a power plant in Alberta, Canada, burning subbituminous coal have been interpreted as arising from synchrotron-radiation-induced oxidation of a selenite species to selenate. It was estimated that about 15-20% of the selenite was oxidized to selenate during the 2 h exposure of the fly ash to the synchrotron beam. In contrast, the XANES spectra of arsenic (and other trace elements not documented herein) showed no variation. It is believed that this is the first time that radiation-induced changes have been observed for an element in coal-derived fly ash. PMID- 21525668 TI - Assessment of microbial contamination of toothbrush head: an in vitro study. AB - BACKGROUND: The most common oral hygiene aid used to improve the oral health of an individual is toothbrush and it is often neglected to maintain in a proper aseptic condition, which could probably result in contamination by various micro organisms. AIMS: 1) To assess the microbial contamination of the hard deposit on the toothbrush head, between the bristle tufts, after 1 and 3 months of use. 2) To assess the microbial contamination of the hard deposit on the toothbrush head, between the bristle tufts, which were kept in the bathrooms with and without attached toilet. SETTING AND DESIGN: An in vitro study. MATERIALS AND METHODS: Twenty toothbrushes kept in the bathrooms with an attached toilet and 20 toothbrushes kept in the bathrooms without an attached toilet were collected from the participants, making it a total of 40. Among these 20 toothbrushes in each group, 10 were used for 1 month duration and 10 were used for 3 months duration. RESULTS: Streptococcus mutans, Staphylococcus aureus, Pseudomonas, Lactobacillus, Klebsiella, Candida species were isolated in 1 month and 3 months used toothbrushes kept in the bathrooms without attached toilet. Escherichia coli was found in 3 months used toothbrushes kept in the bathrooms with attached toilet. Micro-organisms were found in isolated form in toothbrushes used for 1 month, whereas in toothbrushes used for 3 months they are found in clumps. CONCLUSION: Hard deposit on the toothbrush head between bristle tufts is a nidus for growth of micro-organisms, which not only affects the oral health but also affects the general health of an individual. PMID- 21525669 TI - Estimation of relationship between psychosocial stress and periodontal status using serum cortisol level: a clinico-biochemical study. AB - AIMS AND OBJECTIVES: Psychological conditions, particularly psychosocial stress, have been implicated as risk indicators for periodontal disease. The aim of the present study was to explore the role of psychosocial stress that influences the periodontium with the use of a questionnaire data and serum cortisol level. MATERIALS AND METHODS: In this study 47 subjects, both male and female, were taken and divided into two groups. Group I comprised of 16 chronic periodontitis subjects. Their stress level was evaluated using a standard questionnaire method (social readjustment rating scale). Plaque index (PI), gingival index (GI), periodontal disease index (PDI) and serum cortisol level were also measured. Group II comprised of 31 stressed subjects and their clinical parameters PI, GI, PDI and cortisol level were recorded. STATISTICAL ANALYSIS USED: Spearman's rank correlation coefficient and unpaired 't' test. RESULTS: In group I statistically significant correlation (P<0.05) was found between cortisol and PDI; and cortisol and PI. In group II positive correlation was found between stress, cortisol, PI, GI and PDI. A statistically significant correlation was found between cortisol and smoking. CONCLUSION: Stress may be a contributing factor in periodontal disease. PMID- 21525670 TI - A comparative evaluation of smear layer removal using two rotary instrument systems with ethylenediaminetetraacetic acid in different states: a SEM study. AB - AIM: The aim of the study was to evaluate the ability of 17% ethylenediaminetetraacetic acid (EDTA) solution and 19% EDTA gel to remove debris, and smear layer produced during root canal preparation with two NiTi files systems, Mtwo and Protaper. MATERIALS AND METHODS: Twenty freshly extracted human anterior teeth with single root canal were collected. The crowns were sectioned at the cemento-enamel junction, and working length was measured. These samples were randomly divided into four groups of five samples each. In each group, 2 ml of 3 % sodium hypochlorite solution was used with first instrument. The groupings were as follows. Group 1: 2 ml of 17% EDTA solution and 2 ml of 3% NaOCl were used alternatively each time a new file was employed. This group was prepared with Mtwo rotary files. Group 2: The samples in this group was prepared with Mtwo rotary files. EDTA gel (19%) was used and the samples were irrigated with 2 ml of 3% NaOCl. NaOCl and EDTA gel were used alternatively. Group 3: Five samples were prepared with Protaper file. Irrigation regime was the same as in Group 1. Group 4: Five samples were prepared with Protaper files and irrigation regime was the same as in Group 2. SEM study was done and the collected data were submitted for statistical analysis. RESULTS: There was no statistically significant difference with the varied instruments used (Mtwo and Protaper files), and 17% EDTA solution and 19% EDTA gel. CONCLUSION: Both the NITI instruments produced a similar dentin surface on root canal wall when used with EDTA gel and EDTA solution. PMID- 21525671 TI - Morphological and ultrastructural characteristics of extracellular matrix changes in oral squamous cell carcinoma. AB - BACKGROUND: The biology of oral squamous cell carcinoma (OSCC), including its progression from dysplasia to carcinoma, "field effects", genetic changes in tumor associated mucosa (TAM) and effect of matrix metalloproteinases in breaking down of matrix proteins to facilitate invasion, has been well documented. However, what remains to be done is to extrapolate this knowledge to improve patient care. AIM: The aim of this study was to observe the extracellular matrix (ECM) changes with the routine histochemical stains available to most histopathologists. MATERIALS AND METHODS: The study includes 72 cases of OSCC in which the tumor and adjacent normal appearing areas were sampled to study the ECM changes with hematoxylin and eosin (H and E) and Verhoeff's-Van Gieson elastic stain (VVG). RESULTS: Basophilic fragmentation of collagen (H and E) and clumped short elastic fibers (VVG) were seen in 12 (16.7%) cases. Of the remaining cases, 18 (25%) had a dense lymphocytic infiltrate and had no demonstrable elastic fibers. Those cases with H and E changes were further studied and compared with normal mucosa for ultrastructural changes. The ultrastructural study demonstrated an increase in oxytalan, elaunin and elastic fibers and decrease in collagen fibers with some transformation changes associated with OSCCs and lymph node metastasis. CONCLUSION: Changes in transformation of collagen to elastic fibers and also the loss of both the fibers in areas of lymphocytic infiltration possibly indicate degradation of ECM fibers by factors released from the lymphocytes or tumor cells and the limiting effect on the tumor by ECM remodeling. PMID- 21525672 TI - Effect of endodontic irrigating solutions on the microhardness and roughness of root canal dentin: an in vitro study. AB - CONTEXT: To evaluate the effect of widely used endodontic irrigating solutions on root dentin microhardness and surface roughness. MATERIALS AND METHODS: One hundred twenty, non-carious extracted human permanent incisor teeth were selected. The crowns of the teeth were sectioned and the roots were separated longitudinally to get 240 specimens. These specimens were then divided into six groups according to the irrigating solutions used. The solutions used were 5% and 2.5% NaOCl solutions, 3% H2 O2 , 17% EDTA solution, 0.2% chlorhexidine gluconate, and distilled water. Then, the specimens were subjected to microhardness and roughness testing. The data were analyzed using ANOVA and Tukey's multiple comparison tests. RESULTS: The results of this study indicated that all irrigation solutions, except 0.2% chlorhexidine gluconate, decreased the microhardness of root dentin, and 3% H2 O2 and 0.2% chlorhexidine gluconate had no effect on surface roughness. CONCLUSIONS: Within the limitation of this study, it is concluded that 0.2% chlorhexidine gluconate seems to be an appropriate irrigation solution, because of its harmless effect on the microhardness and surface roughness of root canal dentin. PMID- 21525673 TI - Cephalometric norms for Central Indian population using Burstone and Legan analysis. AB - BACKGROUND: Lateral cephalometric standards of normal Central Indian adults having class I occlusion and acceptable facial profile were studied using the Burstone and Legan comprehensive cephalometric analyses that are specific for orthognathic surgery. AIM: To study normal dentofacial patterns of adult population belonging to Central India. MATERIALS AND METHODS: Cephalometric radiographs of 76 Central Indian adults (38 males and 38 females) having class I occlusion with acceptable facial profile were analyzed, and the mean values of their hard and soft tissue measurements were compared with those of Caucasian adults as reported in the literature. RESULTS: The Central Indian males demonstratedgreater anterior cranial base length and ramal length and a reduced chin depth. The inclination of the upper and lower incisors was also greater. The females demonstrated greater posterior cranial base length, increased upper anterior and posterior facial heights, and an increased maxillary length. Both mandibular body and ramal lengths were increased and there was greater mandibular protrusion and a reduced chin depth. The lower incisors were found to be proclinated. CONCLUSION: This study reveals that some of the cephalometric parameters in the Central Indian population are significantly different than that of the Caucasian population, especially in the females. PMID- 21525674 TI - Mechanism of oil-pulling therapy - in vitro study. AB - BACKGROUND: Oil pulling has been used extensively as a traditional Indian folk remedy without scientific proof for many years for strengthening teeth, gums and jaws and to prevent decay, oral malodor, bleeding gums and dryness of throat and cracked lips. AIM: The aim of this study was to evaluate the antibacterial activity of sesame oil and lignans isolated from sesame oil on oral microorganisms and to check whether saponification or emulsification occurs during oil-pulling therapy. MATERIALS AND METHODS: The in vitro study was carried out in three different phases: (1) Antibacterial activity of the lignans and sesame oil were tested by minimum inhibitory concentration assay by agar dilution method and agar well diffusion method, respectively. (2) Increase in free fatty acid level of oil and the quantity of sodium hydroxide (NaOH) used up in the titration are good indicators of saponification process. This was assessed using analytical tests for vegetable oils. (3) Swished oil was observed under light microscope to assess the status of the oil, presence of microorganisms, oral debris and foreign bodies. RESULTS: Sesamin and sesamolin isolated from sesame oil did not have any antibacterial effect against oral microorganisms like Streptococcus mutans, Streptococcus mitis and Streptococcus viridans. Emulsification of sesame oil occurs during oil-pulling therapy. Increased consumption of NaOH in titration is a definite indication of a possible saponification process. CONCLUSION: The myth that the effect of oil-pulling therapy on oral health was just a placebo effect has been broken and there are clear indications of possible saponification and emulsification process, which enhances its mechanical cleaning action. PMID- 21525675 TI - Melanin: a scavenger in gingival inflammation. AB - BACKGROUND: One of the major direct or indirect targets of ultraviolet exposure of skin is the melanocyte or the melanin -forming cell. Epidermal melanocytes act as a trap for free radicals. Based on the protective role of melanocytes in medical literature, the role of melanin pigmentation in gingiva needs to be elucidated. Periodontal pathogens and their products demonstrate the ability to induce the generation of reactive oxygen species. Hence purpose of this study was to unravel the protective role of melanin (if any) against the gingival inflammation. MATERIALS AND METHODS: A total of 80 subjects; 20 in each group were selected. The selection of subjects regarding gingival pigmentation was based on Dummett's scoring criteria 0, 3. A complete medical, dental history and an informed consent were obtained from the patients. After evaluation of clinical parameters the GCF was collected using microcapillary pipettes at the selected sites. IL-1beta levels were quantitated using ELISA. RESULTS: In non-pigmented healthy and gingivitis groups, there was a positive correlation between plaque index, gingival index and bleeding index versus IL-1beta level: indicating an increase in the biochemical mediator of inflammation corresponding to an increase in the clinical parameters of inflammation. Also a positive correlation was found between the gingival index and bleeding index versus the IL-1beta levels in the pigmented healthy group. The pigmented gingivitis groups showed a negative correlation between the plaque index, gingival index and bleeding index. CONCLUSIONS: The clinical markers of inflammation such as gingival index, bleeding index was of low numerical value in pigmented group than in the non pigmented group, supposedly due to the protective action of melanin. The negative correlation of clinical markers of inflammation to the IL-1beta levels in the pigmented gingivitis group could possibly be attributed to the protective role of melanins. PMID- 21525676 TI - Evaluation of demineralization adjacent to orthodontic bracket and bond strength using fluoride-releasing and conventional bonding agents. AB - BACKGROUND AND OBJECTIVES: One of the most difficult problems encountered in orthodontic treatment with fixed appliance is the control of enamel demineralization around the brackets. Fluoride-releasing bonding adhesives were introduced to aid in the prevention of demineralization adjacent to orthodontic brackets. Hence, an in vitro study was conducted to evaluate and compare demineralization adjacent to the orthodontic bracket and the bond strength using fluoride-releasing adhesive and conventional adhesive. MATERIALS AND METHODS: One hundred and twenty healthy extracted premolars were selected for the study and were divided into two groups, each group consisting of 60 teeth. Both groups were further divided into three subgroups consisting of 20 samples each. Samples of subgroups A and B were bonded with two prototypes of fluoride-releasing adhesives (i.e. Rely-a-bond and Tru-bond). Samples of subgroup C (ortho-one) were bonded with conventional non-fluoride-releasing adhesive. Group I samples were subjected to demineralization in an acidic medium (methyl cellulose buffered with acetic acid at a pH of 4.5) for 4 weeks, which were later observed under a stereomicroscope. Group II samples were tested for shear bond strength using the Instron Universal testing machine. RESULTS: Both fluoride-releasing adhesives showed statistically significant lower enamel demineralization around the bracket when compared with the conventional adhesive. There was no statistically significant difference on comparing the demineralization between the two prototypes of fluoride-releasing adhesive. Evaluation of shear bond strength revealed that there was no significant difference between the subgroups. CONCLUSION: Fluoride-releasing adhesives might aid in the prevention of demineralization adjacent to the orthodontic bracket with acceptable bond strength. PMID- 21525677 TI - A comparative study on microwave and routine tissue processing. AB - AIM AND OBJECTIVE: The present study was aimed at assessing the rapid microwave assisted tissue processing and staining to determine if it can replace standard formalin-fixed and paraffin-embedded processing and staining technique. MATERIALS AND METHODS: The study group consisted of 15 oral mucosal biopsies. The specimens were fixed in 10% formalin for 24 hours to ensure adequate fixation and their gross features were recorded, photographed, and then the specimens were cut into equal halves to be processed by both conventional and microwave histoprocessing methods and then subsequently stained with H and E by microwave and conventional methods. The stained slides in each group processed by both microwave and routine methods were randomly numbered for a blind study and circulated among six observers. All the observers were asked to grade each parameter into Excellent/Good/Average/Poor in a data sheet comprising a total of six parameters. These gradings were given a numerical value of 4, 3, 2 and 1, respectively. The parameters included in the data sheet were cellular clarity, cytoplasmic details, nuclear details, color intensity, interface of epithelium and connective tissue. Wilcoxon-matched pairs signed rank test (non-parametric) was used to calculate the test of significance (P value). RESULTS: The total processing time involved in microwave was 42 minutes and 270 minutes for the conventional method. H and E staining in microwave took 33 minutes and 40 minutes for conventional method. CONCLUSIONS: The individual scores by different observers regarding the various parameters included in the study were statistically insignificant, the overall quality of microwave-processed and microwave-stained slides appeared slightly better than conventionally processed and stained slides. PMID- 21525678 TI - Mineralized components and their interpretation in the histogenesis of peripheral ossifying fibroma. AB - BACKGROUND: Peripheral ossifying fibroma (POF) is a lesion of gingival tissue that predominantly affects women and is usually located in maxilla, anterior to molars. The definitive diagnosis is established by histopathological examination, which reveals the presence of cellular connective tissue with focal calcifications. OBJECTIVE: This study hypothesizes the histogenesis of POF by analyzing the diverse spectrum of mineralized components with a polarizing microscope. MATERIALS AND METHODS: A retrospective study was undertaken which involved a detailed review of clinical, radiographic and histopathological features of 22 cases of POF, retrieved from departmental archives. These cases were subsequently stained with a histochemical stain (van Gieson) and observed under a polarizing microscope. RESULTS: The study revealed that the most common age of occurrence was in second and third decades with a strong female predilection (73%), Interdental papilla of the maxillary anterior region was the most commonly afflicted site. About 90% cases showed no radiographic features.Histopathological examination showed that 73% cases consisted of a fibrocellular connective tissue stroma surrounding the mineralized masses. 50% mineralized masses comprised of woven bone, 18% showed combination of lamellar bone and cellular cementum, 18% showed only cementum (cellular and acellular), and remaining 13.6% exhibited a mixture of woven and lamellar bone under polarizing microscope. CONCLUSION: The study supports the theory that POF develops from cells of periodontal ligament (PDL)/periosteum as undifferentiated mesenchymal cells having an inherent proliferative potential to form bone or cementum, whose nature can be confirmed by polarizing microscope. PMID- 21525679 TI - Role of deeper sections in diagnostic oral histopathology: a retrospective study. AB - BACKGROUND: Histopathology is a gold standard diagnostic tool for many lesions. Interpretation of tissue sections is a pivotal step in giving the diagnosis. Usually, initial tissue sections may not show complete features of the lesion, so deeper sections of the specimen may play a significant role at times for final diagnosis. In small biopsy specimens, deeper sectioning is routinely used in many laboratories to enhance the sensitivity and accuracy of the diagnosis. AIM: To analyze the percentage of deeper sections taken and its significance in the final diagnosis of oral lesions. MATERIALS AND METHODS: A total of 500 cases from the files of Department of Oral and Maxillofacial Pathology, Vishnu Dental College, Bhimavaram, Andhra Pradesh were analyzed, and cases of deeper sections were selected. The present retrospective study involves comparison of initial histological findings with those seen in deeper tissue levels of same specimen. RESULTS: 40 cases (8%) were selected for our analysis. Out of these, 19 cases (47.5%) required deeper sections as the initial sections were superficial and undiagnostic. 21 (52.5%) cases were advised for additional sections to confirm, rule out or clarify certain diagnoses, out of which 15 (37.5%) disclosed additional pathological findings, whereas 6 cases (15%) showed the same histological features. CONCLUSIONS: Diagnostic laboratories must balance the utility of deeper levels with the additional time required and expense incurred and the impact on patient care. Deeper sections are inevitable in certain situations and periodical auditing of laboratory work will reduce the need for additional sections and delay in the dispatch of biopsy report. PMID- 21525680 TI - Antimicrobial effectiveness of different preparations of calcium hydroxide. AB - BACKGROUND: Intracanal medicaments have an antibacterial effect on the root canal flora. The effectiveness of such vehicles has to be tested and substantiated against the normal bacterial flora. The various vehicles that were tested for their effectiveness were commercially prepared calcium hydroxide (Metapex), saline, glycerine, CMCP, and Rexidine-M gel. The bacterial cultures tested for sensitivity were aerobes (Staphylococcus aureus, Streptococcus viridans, Streptococcus pyogens, Enterococcus faecalis), anaerobes (Lactobacillus, Bacteroides melaninogenicus) and a commonly found fungus (Candida albicans). One hundred and twenty-five samples were divided into five experimental groups consisting of 21 samples each and one control group of the same size. AIM: The aim of this study was to investigate in vitro the influence of four different vehicles on the effectiveness of calcium hydroxide against the commonly found aerobic and anaerobic bacteria in endodontic infections. MATERIALS AND METHODS: The samples were taken and transported using standardized techniques and pure growth of each bacterium was isolated. Petri dishes were prepared for the various calcium hydroxide combinations for each bacterium and incubated. The inhibition zone was recorded at three intervals of 24, 96 and 168 hours. Results were tabulated and sent for statistical analysis. RESULTS AND CONCLUSIONS: It was seen that calcium hydroxide and CMCP combination showed the maximum zone of inhibition, and maximum inhibitory effect was seen at 24 hours. The bacteria most susceptible was found to be S. aureus and the least susceptible was E. faecalis. Further clinical studies are required to substantiate these results. PMID- 21525681 TI - Flexural strength and hardness of resins for interim fixed partial dentures. AB - CONTEXT: Materials used for the fabrication of interim restorations must satisfy biological, esthetic, and functional needs. Strength and wear resistance are two important physical properties contributing to clinical efficiency. AIM: The objective of this in vitro study was to evaluate and compare the flexural strength and hardness of five resins used for the fabrication of interim fixed partial dentures. MATERIALS AND METHODS: Five groups containing ten specimens of each material were fabricated in customized brass split molds with dimensions 65 * 10 * 2.5 mm. The materials subjected to this study were Revotek LC (group RLC), Protemp II (group PSC), Acry-lux V with regular monomer (group AHC), Acry-lux V with self-cure monomer (group ASC), DPI self-cure tooth molding powder (group DSC). The specimens were polymerized according to the manufacturers' instructions and were evaluated for flexural strength using a universal testing machine and for hardness using a microhardness tester. STATISTICAL ANALYSIS: The mean of the five groups was compared using one way analysis of variance (ANOVA) and pair-wise comparison was done using Tukeys honesty significance difference (HSD) test. P <=.05 was considered to be statistically significant. RESULTS: Flexural test results showed that group AHC (79.8950 MPa) had the highest flexural strength followed, in descending order, by group PSC (77.9700 MPa), group ASC (63.7150 MPa), group RLC (58.8110 MPa), and group DSC (51.9840 MPa). Statistically, the difference was found to be highly significant among all the groups. The hardness tests showed that group AHC (17.6900 KHN) had the highest hardness value followed, in descending order, by group PSC (15.9400 KHN), group RLC (12.6000 KHN), group ASC (11.2500 KHN), and group DSC (8.7700 KHN). Statistically, the difference was found to be highly significant among all the groups. CONCLUSION: Group AHC, representing a heat-polymerizing resin, showed the highest flexural strength and hardness values as compared to auto-polymerizing resins and light polymerizing resin. PMID- 21525682 TI - Efficacy of CPP-ACP and CPP-ACPF on enamel remineralization - an in vitro study using scanning electron microscope and DIAGNOdent. AB - INTRODUCTION: Remineralization as a treatment procedure has received a lot of attention both from clinicians as well researchers. The objective of this in vitro study was to find out the efficacy of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and casein phosphopeptide-amorphous calcium phosphate fluoride (CPP-ACPF) in remineralizing enamel surface on which artificial caries lesion had been created. The changes were analyzed using DIAGNOdent (KaVo) and scanning electron microscope (SEM). MATERIALS AND METHODS: Ninety maxillary premolars were selected and divided into three groups of 30 teeth each: A (artificial saliva), B (CPP-ACP), and C (CPP-ACPF). All the samples were assessed using DIAGNOdent at the baseline and after demineralization and remineralization. Three samples were randomly selected from each group after remineralization for surface evaluation using SEM. RESULTS: Statistical analysis showed that group B {CPP-ACP (4.1 +/- 1.8)} and group C {CPP-ACPF (4.8 +/- 1.2)} had a significantly higher amount of remineralization than group A (1.7 +/- 0.7). CONCLUSION: All the three groups showed a statistically significant amount of remineralization. However, because of the added benefit of fluoride (NaF 0.2%), CPP-ACPF (Tooth Mousse-Plus) showed marginally more amount of remineralization than CPP-ACP (Tooth Mousse). PMID- 21525683 TI - Evaluation of the relative efficacy of copolymerized polylactic-polyglycolic acids alone and in conjunction with polyglactin 910 membrane in the treatment of human periodontal infrabony defects: a clinical and radiological study. AB - BACKGROUND: Absorbable synthetic biopolymers have been used as bone filler in Periodontology, proving effective stimulants to bone regeneration. AIM: Copolymerized polylactic and polyglycolic acid is used as a bone filler and polyglactin 910 as a guided tissue regeneration (GTR) membrane to achieve regeneration in periodontal infrabony defects. MATERIALS AND METHODS: Forty patients with two- or three-walled infrabony defects were selected and randomly divided into two groups. Group A included patients treated with polylactic polyglycolic acids 50:50 (Fisiograft ,Ghimsa SPA,Via Fucini, Italy) alone and Group B included patients treated with polylactic-polyglycolic acids (PLA PGA)50:50 in conjunction with polyglactin acid 910 (Vicryl Mesh Johnson&Johnson , U.S.A ). Evaluation of clinical parameters probing depth and attachment level and radiographs was done preoperatively and 12 and 24 weeks postoperatively. RESULTS: Both the groups showed statistically significant mean reduction in probing depth and gain in clinical attachment level and linear bone fill. CONCLUSIONS: Within the limit of this study, both the treatment modalities are beneficial for the treatment of infrabony defects. PMID- 21525684 TI - Comparative evaluation of frictional characteristics of coated low friction ligatures - Super Slick Ties with conventional uncoated ligatures. AB - BACKGROUND: Elastomeric ligatures have constituted a versatile method of securing the archwire to bracket slot, though self-ligating brackets have been a recent innovation. Coating elastomeric ligatures with a hydrophobic polymeric substance has been suggested as a methodology in reducing friction at the archwire-bracket interface and in repelling salivary adherends. A new polymeric coated ligature tie - Super Slick Ties (SST), manufactured using Metafasix technology, has been marketed by TP laboratories for potential reduction in treatment time. AIM: The basic in vitro design is to compare the frictional characteristics of the coated ligatures with those of uncoated ligatures in four different archwires, namely, stainless steel, NiTi, TMA, and Timolium. MATERIALS AND METHODS: Four archwires used are stainless steel archwires, TMA archwires, Timolium, NiTi archwires, and two types of elastomeric ligatures (the coated and uncoated ligatures) were used. The wires used were of 0.019 * 0.025 dimension. The evaluation of friction between the brackets and the archwire was carried out as per the test protocol described by Tidy. The values for kinetic friction were obtained and tabulated. Mean and standard deviation were calculated. Paired Student's "t" test was performed to analyze the significance of difference between means. RESULTS: The results indicate a significant difference in friction produced when coated and conventional uncoated ligatures were used. CONCLUSIONS: SST produced lower levels of friction (11%) for all archwire materials when compared to conventional uncoated ligatures (Dispense-A-Stix) and both conventional uncoated ligatures and coated ligatures gave a rank order of coefficient of kinetic friction (MUkf) among archwires, with stainless steel archwires exhibiting the least and TMA TM showing the highest. PMID- 21525685 TI - Frictional characteristics of the newer orthodontic elastomeric ligatures. AB - INTRODUCTION: Elastomeric ligatures reduce chairside time but increase friction. Polymeric coatings and 45 degrees angulations have been introduced to the ligature modules to combat its disadvantages and reduce friction. This in vitro study compared the frictional characteristics of six different types of the most commonly used elastomeric modules. MATERIALS AND METHODS: Thecoefficient of friction for six ligation methods: the non-coated Mini Stix? and coated Super Slick Mini Stix (TP Orthodontics), 45 degrees angulated but non-coated Alastik Easy-To-Tie (3M Unitek) elastomerics and non-angulated non-coated Alastik QuiK StiK FNx01 , 0.110'- and 0.120'-diameter elastomerics (Reliance Orthodontics) were measured in dry conditions utilizing a jig according to the protocol of Tidy. RESULTS: A significant difference was observed between the various types of elastomeric ligatures (P<.01). Among the six types of elastomeric ligatures, the 45 degrees angulated elastomeric ligatures produced the least friction, followed by the coated Super Slick elastomers. No difference in the friction was noted when the diameter of the elastomeric ligatures was varied. CONCLUSIONS: Polymeric surface coatings and introduction of angulations into elastomeric ligatures reduce the friction during sliding; however, the diameter of the ligature made no difference to sliding friction. PMID- 21525686 TI - Is palatal injection mandatory prior to extraction of permanent maxillary tooth: a preliminary study. AB - INTRODUCTION: Even after the invention of the modern injection techniques, palatal injection still remains a painful experience for patients, and this pain is attributed to the presence of rich nerve complement and displacement of palatal mucosa during anesthesia. OBJECTIVE: The aim of the present study was to demonstrate if lidocaine HCl could provide palatal anesthesia if given buccally during maxillary tooth removal without the need for a palatal injection. MATERIALS AND METHODS: The study group consisted of 75 patients, and 25 were controls. All the patients in the study group had unilateral extractions. In 75 patients, 2 ml of 2% lidocaine HCl with 1:80,000 epinephrine was injected into the buccal vestibule of tooth indicated for extraction without palatal injection. After 8 min, the extraction of maxillary tooth was carried out. Twenty-five subjects in the control group underwent same protocol with palatal injection. All the patients completed a faces pain scale (FPS) and a 100 mm visual analog scale (VAS) after extraction. STATISTICAL ANALYSIS USED: Unpaired t test and Chi-square test. RESULTS: According to VAS and FPS scores, when comparison was carried out between permanent maxillary tooth removal with and without palatal injection, the difference in the pain levels were not statistically significant (P>0.05). CONCLUSION: The extraction of permanent maxillary tooth is possible by depositing 2 mL of lidocaine to the buccal vestibule of the tooth without the need for palatal anesthesia. PMID- 21525687 TI - Effect of cavity varnish and intermediate restorative material on coronal microleakage in endodontically treated tooth. AB - AIM: Evaluation of microleakage in endodontically treated teeth that have been coronally sealed with eugenol and noneugenol containing zinc oxide cement, with and without the use of cavity varnish. MATERIALS AND METHODS: The crowns of single rooted teeth were removed at the cementoenamel junction (CEJ) and the root canals were prepared and obturated with gutta-percha points and zinc oxide eugenol (ZOE) sealer using lateral condensation technique. The samples were randomly divided into four groups-group 1, coronal seal was obtained with ZOE cement; in group 2, three coats of cavity varnish followed with coronal seal of ZOE cement; in group 3, Litark a (noneugenol cement) was placed in the prepared cavity as in group 1; and in group 4, cavity varnish and Litark were placed instead of ZOE as in group 2. The specimens were immersed in 2% methylene blue dye and examined under traveling microscope for evidence of dye penetration of the material. STATISTICAL ANALYSIS: In this study, Kruskal-Wallis test, Mann Whitney U, and Wilcoxon W tests were used. RESULTS: Kruskal-Wallis test with P=0.000 indicated that a significant difference exists between the four groups. Mann-Whitney U test and Wilcoxon W test showed a significant difference at 0.05 levels as follows: group 1 with group 3 and 4, group 2 with group 3 and 4, and group 3 with group 4. There was no significant difference at 0.05 levels between group 1 and group 2. CONCLUSION: Group 4 showed significant less amount of dye penetration as compared with other groups. PMID- 21525688 TI - Evaluation of the relative efficacy of autologous platelet-rich plasma in combination with beta-tricalcium phosphate alloplast versus an alloplast alone in the treatment of human periodontal infrabony defects: a clinical and radiological study. AB - BACKGROUND: Platelet-rich plasma (PRP) contains high levels of polypeptide growth factors that may enhance periodontal regeneration when combined with graft materials. AIM: The purpose of this study was to compare the efficacy of autologous PRP in combination with beta-tricalcium phosphate (beta-TCP) versus beta-TCP alone in the treatment of human infrabony defects. MATERIALS AND METHODS: Using a split-mouth design, 20 patients showing clinical evidence of almost identical bilateral infrabony defects were randomly selected. The right infrabony defects of the patient were designated as Group A and treated by the placement of beta-TCP alone. The left infrabony defects of the same patient were designated as Group B and treated by the placement of PRP mixed with beta-TCP. Clinical assessment of probing pocket depth and attachment level and radiographic evaluation of the defect depth were done preoperatively and at 12, 24 and 36 weeks postoperatively. The relative efficacy of two treatment modalities was evaluated using paired Student's t-test and the comparative evaluation between the two groups was done using independent Student's t-test. RESULTS: Both the groups exhibited a highly significant reduction in probing pocket depth, gain in clinical attachment level and linear bone fill at the end of 36 weeks postoperatively. Comparative evaluation between the two study groups revealed a significant reduction in probing pocket depth (P = 0.036FNx01), mean gain in clinical attachment level (P = 0.042FNx01) and linear bone fill (P = 0.014FNx01) in Group B as compared to Group A. CONCLUSIONS: Combination of PRP and beta-TCP led to a significantly more favorable clinical and radiographic improvement in infrabony periodontal defects. PMID- 21525689 TI - Immunohistochemical evaluation of mast cells and vascular endothelial proliferation in oral submucous fibrosis. AB - INTRODUCTION: Oral submucous fibrosis (OSMF) is a chronic, progressive, scarring disease that predominantly affects the people of south-east Asian origin. AIM: The present study is aimed at comparing and correlating the mast cell density (MCD) and micro vascular density (MVD) in normal mucosa and different grades of OSMF and to analyze their role in the disease progression. MATERIALS AND METHODS: MCD was assessed immunohistochemically using anti mast cell tryptase and MVD was assessed using anti-factor VIII related von Willebrand factor. RESULTS: The one way comparison of MVD and MCD in normal mucosa and among different grades of OSMF showed a significant increase in MCD and MVD among OSMF cases. Correlation analysis using Pearson correlation coefficient, showed positive correlation between MCD and MVD i.e. as MCD increases there is an exponential increase in MVD. CONCLUSION: The increase in MVD and MCD reveals their role in the pathogenesis of OSMF, a lesion characterized by progressive fibrosis in early stages and failure of degradation or remodeling in the advanced stages. PMID- 21525690 TI - Regenerative endodontics: a state of the art. AB - Scientific advances in the creation of restorative biomaterials, in vitro cell culture technology, tissue grafting, tissue engineering, molecular biology and the human genome project provide the basis for the introduction of new technologies into dentistry. Non-vital infected teeth have long been treated with root canal therapy (for mature root apex) and apexification (for immature root apex), or doomed to extraction. Although successful, current treatments fail to re-establish healthy pulp tissue in these teeth. But, what if the non-vital tooth could be made vital once again? That is the hope offered by regenerative endodontics, an emerging field focused on replacing traumatized and diseased pulp with functional pulp tissue. Restoration of vitality of non-vital tooth is based on tissue engineering and revascularization procedures. The purpose of this article is to review these biological procedures and the hurdles that must be overcome to develop regenerative endodontic procedures. PMID- 21525691 TI - Stem cell therapy: a challenge to periodontist. AB - Periodontitis is an inflammatory disease which manifests clinically as loss of supporting periodontal tissues including periodontal ligament, cementum, and alveolar bone, and periodontal therapy is aimed at achieving complete regeneration of these structures. To date, this goal has been tried to accomplish using various bone grafts, growth factors, and barrier membranes. Stem cells are the most fascinating area of biology today and have been used clinically in the field of medicine to treat many incurable diseases. Various human and animal studies have confirmed the presence of stem cells in dental tissues including periodontal ligament. This has opened new avenues aiming toward complete periodontal regeneration using cell-based therapies. This review provides an overview of various types of stem cells in medicine and dentistry and their potential uses especially pertaining to periodontal regeneration. PMID- 21525692 TI - Zirconium for esthetic rehabilitation: an overview. AB - The demand for esthetic restorations has resulted in an increased use of dental ceramics for anterior and posterior restorations. A few decades ago, all-ceramic restorations were restricted to treatment in the anterior region, but now all ceramic restorations can be made anywhere in the dentition. The properties of traditional ceramic materials, however, have limited their use to single crowns; larger restorations have been inadvisable because of insufficient strength. In attempts to meet the requirements for dental materials and improve strength and toughness, several new ceramic materials and techniques have been developed during the past few decades The paper reviews the current literature on dental zirconia with respect to survival, properties, marginal fit, cementation, esthetics and suggests clinical recommendations for their use. PMID- 21525693 TI - Dental insurance! Are we ready? AB - Dental insurance is insurance designed to pay the costs associated with dental care. The Foreign Direct Investment (FDI) bill which was put forward in the winter session of the Lok Sabha (2008) focused on increasing the foreign investment share from the existing 26% to 49% in the insurance companies of India. This will allow the multibillion dollar international insurance companies to enter the Indian market and subsequently cover all aspects of insurance in India. Dental insurance will be an integral a part of this system. Dental insurance is a new concept in Southeast Asia as very few countries in Southeast Asia cover this aspect of insurance. It is important that the dentists in India should be acquainted with the different types of plans these companies are going to offer and about a new relationship which is going to emerge in the coming years between dentist, patient and the insurance company. PMID- 21525694 TI - Eruption cyst: a literature review and four case reports. AB - Eruption cyst is a benign cyst associated with a primary or permanent tooth in its soft tissue phase after erupting through the bone. It is most prevalent in the Caucasian race. Intraoral examination of four patients revealed eruption cyst. Among these, in three patients it occurred in the maxillary arch and one had it in the mandibular arch. All were associated with permanent tooth. Surgical treatment was done in three cases and in one case the cyst disappeared gradually and tooth erupted in normal pattern. Four cases of eruption cyst from India are presented and literature on this condition is reviewed. It is clinically significant in that knowledge among general dentists is very essential regarding this developmental disturbance to reach the correct diagnosis and to provide proper treatment. PMID- 21525695 TI - Implant-supported auricular prosthesis. AB - Differences in the balance of shape, size, and position of body organs are immediately perceived as "looking wrong" and this perception can subject the individual to significant peer ridicule and social ostracism, often expressing as intense shame and anguish in the attitude of the afflicted. Rehabilitation of such patients can be remarkably beneficial on the individual's self-esteem and body image. The onus of the deed lies in the hands of a team that combines artistic excellence with surgical expertise, by combining the skills of anaplastologists, surgeons, and prosthodontists. This is a review of a few surgical and prosthetic considerations in the management of auricular defect and a case description of management of a patient of microtia following similar guidelines in fabrication of the epithesis. PMID- 21525696 TI - Keratocystic odontogenic tumor with impacted maxillary third molar involving the right maxillary antrum: an unusual case report. AB - The odontogenic keratocyst (OKC), first described by Phillipsen in 1956, has metamorphosized as a keratocystic odontogenic tumor (KCOT) as reported in WHO classification of head and neck tumors in 2005. KCOT is a benign intraosseous neoplasm of the jaw and its occurrence in maxilla is unusual and its appearance in maxillary antrum along with maxillary impacted third molar is very uncommon. This article reports a case of KCOT associated with impacted maxillary third molar in right maxillary antrum and describes its rare site of occurrence. PMID- 21525697 TI - Comparison of obturator design for acquired maxillary defect in completely edentulous patients. AB - The most challenging and appreciated area in the field of Prosthodontics is the rehabilitation of maxillary defects. Tumors of the head and neck are the common cause for acquired maxillofacial defects. Surgical consequences predispose the patient to hypernasal speech, fluid leakage into nasal cavity, impaired masticatory function, and cosmetic deformity. The Prosthodontists play a significant role in the intervention and improve the quality of life of such patients. The current article describes two clinical case reports of completely edentulous patients with acquired maxillary defects. PMID- 21525698 TI - Van der Woude syndrome with an unusual intraoral finding. AB - Orofacial manifestations of Van der Woude syndrome (VWS) include cleft lip or palate, lower lip pits, hypodontia, hypernasal voice, cleft or bifid uvula, syngnathia, narrow high arched palate, and ankyloglossia. Extraoral manifestations include limb anomalies, popliteal webs, accessory nipples, congenital heart defects, and Hirschsprung disease. We report an interesting case of VWS with characteristic orofacial features along with an unusual additional finding of fusion of primary mandibular left lateral incisor and canine in a 7 year-old boy. PMID- 21525699 TI - Submasseteric abscess: a rare head and neck abscess. AB - The objective of the article is to highlight and make people aware of a rare abscess which is often missed or misdiagnosed. As only a few cases have been reported, the authors feel that reporting such a case would help in proper management of the disease. We are presenting a 6.5-year-old male child with 3 weeks history of right facial swelling in the parotid region, with low-grade fever and trismus. Submasseteric abscess is a rare abscess which is often misdiagnosed as a parotid abscess or parotitis. Only a few cases have been reported. The cause is mostly dental in origin. Intravenous antibiotics often fail to alleviate the symptoms as this is a closed space and needs prompt drainage. Therefore, awareness of this complication of dental infections is vital for proper diagnosis and timely management. PMID- 21525700 TI - Multiple natal teeth: a rare case report. AB - A rare case report of multiple natal teeth in both maxillary and mandibular dental arches in a 21-day-old baby and its management is being presented here. PMID- 21525701 TI - Solitary bone cyst. AB - The solitary or traumatic bone cyst (TBC) is an uncommon non-epithelial lined cavity of the jaws. The lesion is mainly diagnosed in young patients most frequently during the second decade of life. The majority of them are located in the mandibular body between the canine and the third molar. Clinically, the lesion is asymptomatic and is often accidentally discovered on routine radiological examination. The definite diagnosis of traumatic cyst can only be determined at surgery. Often, the material for histological examination may be scanty or non-existent. We present a documented case of a solitary bone cyst involving the body of the mandible. A brief review of literature regarding the main characteristics of the lesion is provided. PMID- 21525702 TI - Are citations required for a biomedical review article? PMID- 21525703 TI - Reader's comment. PMID- 21525704 TI - Prevalence and socio-demographic correlates of dental anxiety among a group of adult patients attending a dental institution in Vadodara city, Gujarat, India. AB - CONTEXT: Anxiety is a subjective state of feelings. Dental anxiety is often reported as a cause of irregular dental attendance, delay in seeking dental care or even avoidance of dental care, resulting in poor oral health related quality of life. AIM: To assess the prevalence and socio-demographic correlates of dental anxiety among a group of adult patients attending a dental institution in Vadodara, Gujarat. PATIENTS AND METHODS: A total of 150 adult patients waiting in the out-patient Department of Oral Diagnosis of K.M. Shah Dental College and Hospital were included in the study. Subjects were selected by convenience sampling. Dental anxiety was assessed by using Modified Dental Anxiety Scale (MDAS) and self-designed, semi-structured questionnaire incorporating various demographic variables, type and nature of dental treatment. Statistical analysis was done using SPSS version 16. Descriptive analysis, unpaired t-test, one-way analysis of variance (ANOVA) test and multiple logistic regression were applied for statistical analysis. RESULTS: 46% of the participants were dentally anxious. Females were found to be significantly more anxious than males. Subjects residing in villages had significantly more score than those residing in city. Relative influence of age, education, type of dental treatment, and previous dental visit were not significantly associated with dental anxiety. However, those subjects who had past negative dental experience were found to be significantly more anxious. CONCLUSIONS: The study shows that dental anxiety was high among study subjects. It is recommended that this issue should be given due importance and addressed in a practical and meaningful manner. PMID- 21525705 TI - Comparative evaluation of the curve of Spee in two age groups and its relation to posterior teeth disclusion. AB - OBJECTIVES: This study aims to compare the curve of Spee in human permanent healthy dentitions in two age groups to the disclusion in the premolar and molar region during protrusion. MATERIALS AND METHODS: Sixty subjects were chosen and equally divided into two age groups of 18-25 years and 35-44 years. The left side of the mandibular dental casts was photographed using a digital camera to measure the curve of Spee. The canine cusp, mesiobuccal cusp of the first molar and the distal cusp of the second molar were marked and joined to form an arc. Using AUTOCAD software, the radius for this arc was obtained. A protrusive interocclusal record was made using rigid bite registration material to measure the amount of posterior disclusion during edge to edge protrusion. A dial gauge with an accuracy of 1/100 of a millimeter was used to measure the distance between the cusp tip indentations at the region of the buccal cusp of the mandibular 2nd premolar and distobuccal cusp of mandibular 1st molar. The results obtained were statistically analyzed. RESULTS: The radius of curve of Spee increased nonsignificantly with age. The mean disclusion values measured in premolar and molar region showed a nonsignificant decrease with age. CONCLUSION: As age advances, there is a flattening of the curve of Spee and a concurrent reduction in the disclusion values during protrusion. PMID- 21525706 TI - Mechanical properties of denture base resins: an evaluation. AB - BACKGROUND: Acrylic resin dentures are susceptible to fracture after clinical use, which is a problem of concern in prosthodontics. Impact failure outside the mouth and flexure fatigue failure in the mouth are two most important causes of fracture of denture base. AIM: This study evaluated the transverse deflection and transverse strength of four commercial brands of heat cure acrylic resin (Stellon, Acrylin-H, Trevalon and Trevalon-HI). MATERIALS AND METHODS: An experimental design was adapted. Twenty-four rectangular strip specimens, six for each group, were prepared. Strips were finished on the edges and equally from the both the molded surfaces to make strips of specific dimensions. The tests were conducted mainly in accordance with the American Dental Association Specification no. 12/ISO: 1567-1981 (ISO: 6887-1986) for denture base polymer. The transverse deflection and transverse strength were measured by Instron testing machine. Intergroup differences were assessed using student "t" test. RESULTS: The heat cure denture base material D (Trevalon "HI") had the minimum mean value of transverse deflection under different loads. Trevalon "HI" also had minimum value of mean transverse strength among different brands of acrylic resins. There was no statistically significant variation between Stellon, Acrylin-H and Trevalon, but variation was significantly higher with D (Trevalon "HI") vs. Stellon, Acrylin-H and Trevalon. CONCLUSION: The heat cure denture base material D (Trevalon "HI") was the strongest and C (Trevalon) was the weakest among all materials used in this study. The study showed that the deflection of various denture base resins (A to D) increases proportionately with the increase in load. PMID- 21525707 TI - Gold weight implantation as a treatment measure for correction of paralytic lagophthalmos. AB - Ocular complications from facial nerve paralysis can be quite devastating. Facial nerve paralysis results in cosmetic as well as functional problems. Paralysis of the upper eyelids leads to lagophthalmos, which results in incomplete closure of the lid over the cornea, leading to potential complication of corneal ulceration. The management of the affected eye in patients with facial palsy has been improved. Previously, ointment, eye drops, taping, partial or complete tarsorrhaphy was the primary treatment for inability to close the eyelid. Other mechanical techniques for reanimating lid closure are palpebral springs, encircling the upper and lower eyelids with silicone or fascia lata and temporalis muscle transfer. The most popular and widely used static procedure in facial nerve palsy is the upper eyelid gold weight implant. Gold eyelid implants are designed for the gravity assisted treatment of the functional defect of lagophthalmos resulting from facial paralysis. We report a case of a patient with facial paralysis who underwent gold weight implantation of the upper eyelid for correction of paralytic lagophthalmos. PMID- 21525708 TI - Massive keratocystic odontogenic tumor of mandible: a case report and review of literature. AB - Keratocystic odontogenic tumor (KCOT), also known as odontogenic keratocysts, as defined by World Health Organization (WHO), are known for their peculiar behavior, varied origin, debated development, unique tendency to recur, and disputed treatment modalities. We present a case of KCOT involving symphysis menti, right and left halves of the body of mandible in an 11-year-old girl treated with enucleation and open dressing (bismuth, iodoform, paraffin paste) with long-term follow-up. PMID- 21525709 TI - Development of a new selective medium for isolation of methicillin-resistant Staphylococcus aureus. AB - A new selective medium containing cephem antibiotics was developed for isolation of methicillin-resistant Staphylococcus aureus (MRSA). MRSA colonies on a medium containing ceftazidime (CAZ) were most easily identifiable and a medium containing cefoperazone (CPZ) was superior in suppressing the growth of other bacteria. With the medium containing a couple of CAZ and CPZ, MRSA and methicillin-resistant coagulase-negative staphylococci (MRCNS) were detected from 2 and 1 of 15 chicken meat samples respectively. The MRSA and MRCNS recovery test showed that the medium was effective for MRSA isolation, suppressing the growth of other bacteria efficiently. These results suggested that the medium containing a couple of CAZ and CPZ was useful for MRSA detection from foods and animals. PMID- 21525710 TI - Antimicrobial susceptibility of Escherichia coli isolates from wild mice in a forest of a natural park in Hokkaido, Japan. AB - To reveal the antimicrobial susceptibilities of Escherichia coli isolates from wild mice, 81 E. coli isolates were obtained from 109 voles (Clethrionomys spp.), 52 large Japanese field mice (Apodemus speciosus) and 19 small Japanese field mice (A. argenteus) captured in a forest of a natural park in Hokkaido, Japan. Seventy-eight of the 81 E. coli isolates were susceptible to all 10 antimicrobial agents tested. One E. coli isolate was resistant to ampicillin, dihydrostreptomycin, kanamycin, chloramphenicol and oxytetracycline. Two isolates were resistant to oxytetracycline. A low prevalence of antimicrobial resistance was maintained among wild mice that inhabited the forest. PMID- 21525711 TI - Expressions of protein oxidation markers, dityrosine and advanced oxidation protein products in acetaminophen-induced liver injury in rats. AB - The purpose of this study was to evaluate whether dityrosine and advanced oxidation protein products (AOPP) were useful as biomarkers for monitoring the development of acetaminophen-induced liver injury. Dityrosine immunoexpression in the liver along with plasma AOPP concentration was examined up to 24 hr post acetaminophen injection in rats. The histopathological changes in the liver appeared 3 hr after acetaminophen injection and became exacerbated with time. The immunohistological expression of dityrosine was also first detected in the damaged hepatocytes 3 hr after the injection and became more accentuated at 6, 12 and 24 hr in accompanying with the elevation of plasma AOPP concentration. These results suggested that dityrosine and AOPP expressions might be useful biomarkers for monitoring the development of acetaminophen-induced liver injury. PMID- 21525712 TI - Evaluation of serum and urine 1,5-anhydro-D-glucitol and myo-inositol concentrations in healthy dogs. AB - 1,5-anhydro-D-glucitol (1,5AG) is a pyranoid polyol compound found in human circulating blood. Myo-inositol (MI) is a stereoisomer of inositol and serves as a precursor of inositol phospholipids. 1,5AG and MI are filtered by the glomerulus and almost completely reabsorbed through the renal tubules. However, under hyperglycemic conditions, reabsorption through the renal tubules is competitively inhibited because the structures of 1,5AG and MI resemble that of glucose. In this study, we investigated the kinetics of serum and urine 1,5AG and MI levels in healthy dogs. We demonstrated that 1,5AG and MI exist in canine serum and urine by gas chromatography-mass spectrometry. Under continuous hyperglycemic conditions, the serum 1,5AG concentration in healthy dogs decreased while the serum MI concentration remained unchanged. Urinary excretion of 1,5AG and MI increased significantly after blood glucose concentrations reached 200 to 220 mg/dl. A significant negative correlation was observed between serum 1,5AG and glucose concentrations during hyperglycemia. However, no significant correlation was observed between serum MI and glucose concentrations. In this study, we demonstrated that serum and urine 1,5AG and MI levels were changed by blood glucose concentrations. The serum 1,5AG concentration was decreased by continuous hyperglycemia. However, the serum MI concentration does not reflect hyperglycemia. PMID- 21525713 TI - [Report immediately after earthquake--from a medium-scale hospital in the Sendai City where the emergency outpatient was done]. PMID- 21525714 TI - Laparoscopic management of spontaneous retroperitoneal hemorrhage. AB - Wunderlich's syndrome is a spontaneous nontraumatic massive retroperitoneal hemorrhage. It is usually secondary to a renal neoplasm, with angiomyolipoma being the most frequent followed by renal cell carcinoma. The management of spontaneous retroperitoneal bleeding varies depending on the hemodynamic status of the patient. We present the first report of a transperitoneal laparoscopic nephrectomy in a patient with spontaneous retroperitoneal active bleeding secondary to a right renal mass. PMID- 21525715 TI - MMP20 cleaves E-cadherin and influences ameloblast development. AB - Dental enamel development occurs in stages as observed by the changing morphology of the ameloblasts that are responsible for enamel formation. During the secretory stage of development, proteins including MMP20 are secreted into the enamel matrix. MMP20 is required for proper enamel formation as mutation of the Mmp20 gene causes autosomal recessive amelogenesis imperfecta. Here, we examined in detail the morphology of the Mmp20-null ameloblast cell layer. Intriguingly, we found that the Mmp20-null mouse secretory stage ameloblasts retract their Tomes' processes as if preparing to enter the maturation stage but later reextend their Tomes' processes as if resuming the secretory stage. We also demonstrated that MMP20 cleaves epithelial cadherin, i.e. E-cadherin. Cadherins are transmembrane proteins with extracellular domains that provide adhesive contacts between neighboring cells. Their intracellular domains bind to the cell cytoskeleton through catenins, including beta-catenin. When specific MMPs cleave the cadherin extracellular domain, beta-catenin is released and may locate to the cell nucleus as a transcription factor. Therefore, MMP20 may influence ameloblast developmental progression through hydrolysis of cadherin extracellular domains with associated release of transcription factor(s). PMID- 21525717 TI - Ultrastructure of the mantle of the gastropod Haliotis asinina and mechanisms of shell regionalization. AB - The ability of a biological system to drive the formation of a microstructure as complex and ordered as the molluscan shell is of immense interest to the fields of nanotechnology and biomedicine. Although recent studies have greatly expanded our knowledge of the genes involved in shell formation, the mechanism by which matrix proteins are regulated and directed to the appropriate region of the shell, a process critical for microstructure control, is still obscure. The formation of microstructure-specific compartments within the extrapallial cavity may be the outcome of precise regulation of the vesicle trafficking of shell components within secretory cells at the mineralization front and/or the overall organization and morphology of the mantle itself. Here, we investigate the ultrastructure of the mantle of the gastropod Haliotis asinina as current models put forward to describe molluscan shell formation are primarily based on observations from bivalves despite crystallographic and molecular studies indicating large differences between molluscan classes. We find that the H. asinina mantle is structurally complex and comprised of novel cells packed with a diversity of vesicle types consistent with a complex system to control the secretion of the shell matrix and associated factors. PMID- 21525718 TI - Enamel-calibrated lamellar bone reveals long period growth rate variability in humans. AB - Mammalian teeth exhibit incremental structures representing successive forming fronts of enamel at varying time scales, including a short daily increment called a cross striation and a long period called a stria of Retzius, the latter of which, in humans, occurs on average every 8-9 days. The number of daily increments between striae is called the repeat interval, which is the same period as that required to form one increment of bone, i.e. the lamella, the fundamental - if not archetypal - unit of bone. Lamellae of known formation time nevertheless vary in width, and thus their measures provide time-calibrated growth rate variability. We measured growth rate variability for as many as 6 years of continuously forming primary incremental lamellar bone from midshaft femur histological sections of sub-Saharan Africans of Bantu origin and known life history. We observed periodic growth rate variability in approximately 6- to 8 week intervals, and in some cases annual rhythms were visible. Endogenous biological periodicities, cycles manifest in the external environment, and/or perturbations of development are all potentially contained within growth rate variability studies of lamellar incremental patterns. Because lamellae are formed within defined periods of time, quantitative measures of widths of individual lamellae provide time-resolved growth rate variability that may reveal rhythms in human bone growth heretofore unknown. PMID- 21525716 TI - The cooperation of enamelin and amelogenin in controlling octacalcium phosphate crystal morphology. AB - Enamel matrix proteins, including the most abundant amelogenin and lesser amounts of enamelin, ameloblastin, and proteinases, play vital roles in controlling crystal nucleation and growth during enamel formation. The cooperative action between amelogenin and the 32-kDa enamelin is critical to regulating the growth morphology of octacalcium phosphate crystals. Using biophysical methods, we investigated the interaction between the 32-kDa enamelin and recombinant pig amelogenin 148 (rP148) at pH 6.5 in phosphate-buffered saline (PBS). Dynamic light scattering results showed a trend of increasing particle size in the mixture with the addition of enamelin to amelogenin. Upon addition of the 32-kDa enamelin, the shift and intensity decrease in the ellipticity minima of rP148 in the circular dichroism spectra of rP148 illustrated a direct interaction between the 2 proteins. In the fluorescence spectra, the maximum emission of rP148 was blue shifted from 335 to 333 nm in the presence of enamelin as a result of complexation of the 2 proteins. Our results demonstrate that the 32-kDa enamelin has a close association with amelogenin at pH 6.5 in PBS buffer. Our present study provides novel insights into the possible cooperation between enamelin and amelogenin in macromolecular coassembly and in controlling enamel mineral formation. PMID- 21525719 TI - In vitro analyses of the dysregulated R206H ALK2 kinase-FKBP12 interaction associated with heterotopic ossification in FOP. AB - A single recurrent mutation in the regulatory subdomain of a bone morphogenetic protein type I receptor kinase has been linked to heterotopic ossification in classic fibrodysplasia ossificans progressiva (FOP). As a result of a substitution at 1 residue by only 1 other side chain (Arg206His) in just 1 of the 4 type I BMP receptors (ALK2/ACVR1), soft connective tissues progressively metamorphose through an endochondral process into cartilage that is replaced by bone. The substitution of arginine for histidine, also a basic residue yet with the singular property of ionization/protonation over the physiological pH range, led to the hypothesis of an aberrant, pH-sensitive switch mechanism for the ligand-independent activation of BMP signaling through the mutant receptor kinase in patients presenting with classic FOP. To test a potential aspect of the putative pH-dependent mechanism, i.e. loss of autoinhibition of the kinase mediated by the inhibitory protein FKBP12, in vitrointeraction analyses with purified wild-type and R206H ALK2 kinase and FKBP12 proteins were performed. Interactions between the kinases and inhibitory proteins were analyzed qualitatively and quantitatively by native gel electrophoresis and HPLC size exclusion chromatography and with an optical biosensor (Octet; ForteBio). Binding of inhibitory protein by the R206H mutant was diminished 3-fold relative to the wild type kinase at a physiological pH, yet below this value (<~7.5) pronounced nonspecific interactions, particularly with the mutant, prevented comparative evaluations. In conclusion, substitution with histidine leads to partial loss of inhibition of the mutant type I receptor through diminished binding of FKBP12, which may act as a gradient reader in morphogenetic contexts. PMID- 21525721 TI - Thermal spread of vessel-sealing devices evaluated in a clinically relevant in vitro model. AB - INTRODUCTION: Bipolar vessel-sealing devices (VSDs) have advantages in urological surgeries (less hemorrhage, shorter operating time). However, these instruments can cause thermal injuries, which can result in neural damage and necrosis. The objectives of this study were to establish a reproducible in vitro model for standardized assessment of electrosurgical devices and to evaluate whether optimized placement of surgical instruments can reduce the thermal spread. METHODS: We evaluated thermal spread of two VSDs in vitro using thin bovine muscle strips. Thermal injury was measured using an infrared camera, temperature probes and histology. The recordings were made with the VSD alone and with a rectangular clamp next to the VSD. RESULTS: Both instruments showed a significant temperature spread of 2.5 mm lateral to the VSD. The placement of a metal clamp next to the VSD significantly reduced the temperature spread. Histological examinations were able to underline these findings. CONCLUSIONS: In this study we describe a straightforward clinically relevant in vitro model for the evaluation of future electrosurgical instruments. We demonstrated that the thermal spread of VSD could be further reduced by optimized placement of an additional surgical instrument. Our results could help surgeons protect sensitive structures like nerves in the vicinity of the VSD. PMID- 21525720 TI - Enamel pathology resulting from loss of function in the cystic fibrosis transmembrane conductance regulator in a porcine animal model. AB - Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a phosphorylation- and ATP-regulated anion channel. CFTR expression and activity is frequently associated with an anion exchanger (AE) such as AE2 coded by the Slc4a2 gene. Mice null for Cftr and mice null for Slc4a2 have enamel defects, and there are some case reports of enamel anomalies in patients with CF. In this study we demonstrate that both Cftr and AE2 expression increased significantly during the rat enamel maturation stage versus the earlier secretory stage (5.6- and 2.9-fold, respectively). These qPCR data im- ply that there is a greater demand for Cl(-) and bicarbonate (HCO3-) transport during the maturation stage of enamel formation, and that this is, at least in part, provided by changes in Cftr and AE2 expression. In addition, the enamel phenotypes of 2 porcine models of CF, CFTR-null, and CFTR-DeltaF508 have been examined using backscattered electron microscopy in a scanning electron microscope. The enamel of newborn CFTR-null and CFTR-DeltaF508 animals is hypomineralized. Together, these data provide a molecular basis for interpreting enamel disease associated with disruptions to CFTR and AE2 expression. PMID- 21525722 TI - Expression of ERbeta and its co-regulators p300 and NCoR in human transitional cell bladder cancer. AB - OBJECTIVE: Several data support a possible role of estrogens in bladder carcinogenesis, mediated mainly through estrogen receptor-beta (ERbeta). We study the expression of ERbeta and its co-regulators p300 and nuclear co-repressor (NCoR) in patients with bladder cancer. PATIENTS AND METHODS: One hundred and eleven consecutive patients (74 males and 37 females), aged 23-90 years (mean 70 +/- 10) diagnosed with transitional cell bladder cancer were included in this study. The control group consisted of 29 patients that underwent transurethral prostatectomy and consented to simultaneous bladder biopsies. Immunohistochemical studies took place on formalin-fixed, paraffin-embedded sections from the TUR (transurethral resection) specimens. We studied the expression of ERbeta, p300 and NCoR.chi(2) test was used to evaluate the relationship between the histological grade and ERbeta expression, grade and co-regulators expression and grade and gender. Spearman rank correlation coefficient (r) was used in order to estimate the direction and strength of correlations between histological grade and ERbeta-p300-NCoR expressions. The Cochran-Armitage test for trend was applied in order to examine possible trends across the ordered levels of histological grade. RESULTS: ERbeta was more frequently expressed in the nucleus of normal bladder epithelium compared to malignant bladder epithelium with statistical significant association (r = -0.25, p = 0.003). The p300 was expressed only in the nucleus of bladder cancer cells and a positive correlation between molecular expression and cancer progression was demonstrated (r = 0.55, p < 0.001). NCoR immunostaining was demonstrated in the nuclei of bladder cells. Nuclear staining was significantly higher in normal tissue than in cancer cells (r = -0.33, p < 0.001), with negative correlation. Furthermore, its expression in grade I tumors was significantly higher than in grade II (r = -0.46, p < 0.001) and grade III tumors (r = -0.51, p < 0.001). Thus, like ERbeta, NCoR expression in bladder epithelium decreased during cancer progression and loss of cell differentiation. There was no correlation between the levels of expression of the three proteins in normal bladder epithelium, but there was an inverse correlation between the nuclear expression of ERbeta and p300 in carcinomas (r = -3.88, p = 0.042). Statistical significant association was established when correlating ERbeta expression with NCoR expression (r = 0.273, p = 0.005), while co-regulators' nuclear expression did not correlate with each other (p > 0.05). CONCLUSIONS: In bladder carcinogenesis, we demonstrated inhibition in the expression of ERbeta and its co-repressor NCoR as well as increased expression of the co-activator p300. PMID- 21525723 TI - Clinical characteristics and outcomes of patients with primary signet-ring cell carcinoma of the urinary bladder. AB - OBJECTIVE: The aim of this study was to examine the epidemiology, natural history, treatment pattern and predictors of long-term survival of patients with signet-ring cell carcinoma (SRCC) of the urinary bladder based on the analysis of the national Surveillance, Epidemiology, and End Results (SEER) database. METHODS AND RESULTS: In total, 230 patients with pathologically confirmed SRCC of the urinary bladder were identified between 1973 and 2004. The mean age was 65 +/- 13 years. Overall, 75.7% of the patients had a poorly differentiated or undifferentiated histology grade, 26.5% presented with metastatic disease, 59 (25.7%) underwent transurethral resection for bladder tumor only and 107 (46.5%) had partial or radical cystectomy. The 1-, 3- and 10-year cancer-specific survival rates were 66.8, 40.6 and 25.8%, respectively. Using multivariable Cox proportional hazard model, age (HR 1.024; p = 0.004), stage (distant vs. local, HR 6.2; p < 0.001) and cystectomy (HR 0.53; p = 0.002) were identified as independent predictors for cancer-specific survival. CONCLUSIONS: Receipt of cystectomy was strongly associated with improved survival in the patients with SRCC of urinary bladder. However, many patients with localized tumors did not receive potentially curative cystectomy. Further studies to address the barriers to the delivery of appropriate care to these patients are warranted. PMID- 21525724 TI - Effect of long-term prazosin and yohimbine administration on c-Fos expression in spinal neurons: inhibitory effect of alpha-1 and alpha-2 adrenoceptors on afferents from the lower urinary tract. AB - INTRODUCTION: To investigate the effects of long-term administration of the alpha(1)-adrenoceptor antagonist prazosin and the alpha(2)-adrenoceptor antagonist yohimbine on afferent inputs from the lower urinary tract by evaluating c-Fos expression in the spinal cord. MATERIALS AND METHODS: Prazosin or yohimbine was administered for 4 weeks in rats using an osmotic pump. Effects of these agents on urodynamic parameters were determined by continuous cystometry in conscious rats. After cystometry, c-Fos expression in the dorsal horn of the L6 spinal cord was measured by immunohistochemistry. RESULTS: The administration of prazosin (0.12 mg/kg/day) or yohimbine (0.10 mg/kg/day) significantly increased micturition interval and bladder capacity, but did not affect micturition pressure and residual urine volume. The numbers of c-Fos-positive neurons in the dorsal horn were significantly lower in rats that received prazosin than in controls. Yohimbine reduced the number of c-Fos-positive neurons in part of the dorsal horn. CONCLUSIONS: Long-term administration of prazosin and yohimbine at clinically recommended doses can exert inhibitory effects on afferent pathways from the lower urinary tract during the storage phase. These reductions of the afferent input result in the increased bladder capacity and increased micturition interval. PMID- 21525725 TI - Impact of multidrug resistance on experimental empyema by Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa is a cause of infections of the lower respiratory tract among patients with chronic lung disorders. It is questionable whether virulence of this species may be influenced by multidrug resistance (MDR). OBJECTIVES: To define the impact of MDR in experimental lung infection. METHODS: Experimental empyema was induced in rabbits by MDR (group A, n = 16) and by susceptible isolates (group B, n = 10). Pleural fluid was sampled for quantitative culture and estimation of cell apoptosis and of tumor necrosis factor-alpha (TNFalpha) and malondialdehyde (MDA). Survival was recorded. Cytokine production was stimulated in U937 monocytes by samples of pleural fluid. Whole blood of rabbits was incubated with the isolates; induction of apoptosis was assessed. RESULTS: Survival of group A was prolonged compared to group B. This was accompanied by lower bacterial counts of the inoculated pathogens in pleural fluid and in the lungs of group A compared with group B. Early apoptosis of neutrophils of pleural fluid of group A was lower compared with group B. Pleural fluid concentrations of TNFalpha and MDA did not differ between the groups. Cytokine production by U937 monocytes after stimulation with pleural fluid was greater in group B than in group A. The susceptible isolate induced apoptosis of neutrophils in vitro at a greater rate than the MDR isolate. CONCLUSIONS: Experimental empyema by susceptible P. aeruginosa is accompanied by greater mortality compared with MDR P. aeruginosa. This phenomenon may be attributed to the different growth pattern of the pathogens or to their interaction with the innate immune system. PMID- 21525726 TI - A randomized controlled trial of hot versus cold biopsy forceps in the diagnosis of endobronchial lesions: strengths, pitfalls, and ethics points in the study designing. PMID- 21525728 TI - Improvement in antenatal diagnosis of critical congenital heart disease implications for postnatal care and screening. AB - OBJECTIVE: This observational study was performed to examine the current timing and mode of diagnosis of critical congenital heart disease (CCHD), since early detection of cardiac lesions can significantly improve morbidity and mortality. METHOD: Ninety cases of CCHD in infants born in Middle Tennessee in 2009 were identified by weekly review of admissions to a single cardiac referral center. CCHD is defined as lesions requiring admission or re-admission for surgical or medical intervention within 1 month of life. RESULTS: Overall, the observed antenatal detection rate of 49% is significantly greater than published values of 25%. Hypoplastic left heart syndrome was detected in 11/11, but only 5/16 coarctations were detected. CONCLUSION: Compared to earlier reports, our study showed a doubling of the antenatal detection rate. Perhaps efforts to improve early diagnosis of CCHD could focus on antenatal ultrasound screening techniques for lesions that are missed most often as well as on postnatal screening. PMID- 21525729 TI - Effect of SOM230 (pasireotide) on corticotropic cells: action in dogs with Cushing's disease. AB - SOM230 (pasireotide) is a multiligand somatostatin (SRIF) analog able to bind to somatostatin receptor (SSTR) subtypes 1, 2, 3 and 5, and trigger antisecretory and antiproliferative signaling cascades. Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing's disease in a spontaneous manner, due to adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Different levels of expression of SSTR2 and SSTR5 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells. The objective of this study was to evaluate whether SOM230 controls both tumor cell growth and hormone synthesis, therefore controlling the disease. SOM230 was tested in dogs suffering from Cushing's disease (10 animals were treated continuously during 6 months, and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2 month rest period). A significant decrease in ACTH, urinary cortisol creatinine ratio, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, without side effects. AtT20 cells treated with SOM230 suppressed pro-opiomelanocortin (POMC) promoter activity through SSTR2, via the G(i) alpha-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230, in addition to its well-described antisecretory effects, inhibits, as shown in AtT20 cells, ACTH synthesis at the POMC transcriptional level, an effect mediated mainly through SSTR2, and limits tumor growth. The controlled Cushing's disease in the dogs that received the treatment indicates that SOM230 has a potential therapeutic use in humans suffering from Cushing's disease. PMID- 21525730 TI - A noradrenergic sensitive endogenous clock is present in the rat pineal gland. AB - The aim of this study was to examine the occurrence of endogenous oscillations of Per1, Per2, Bmal1 and Rev-erbalpha genes in rat pineal explants and to investigate their regulation by adrenergic ligands. Our results show a significant and sustained rhythm of Per2,Bmal1 and Rev-erbalpha gene expression for up to 48 h in cultured pineal gland with a pattern similar to that observed in vivo. By contrast, the rhythms of Per1 and Aa-nat, the rate-limiting enzyme for melatonin synthesis, were strongly attenuated after 24 h in culture. Addition of the exogenous adrenergic agonist isoproterenol on cultured pineal glands induced a short-term increase in mRNA levels of Per1 and Aa-nat, but not those of Per2,Bmal1 and Rev-erbalpha. This study demonstrates that the rat pineal gland hosts a circadian oscillator as evidenced by the sustained, noradrenergic independent, endogenous oscillations of Per2, Bmal1 and Rev-erbalpha mRNA levels in cultured tissues. Only expression of Per1 was stimulated by adrenergic ligands suggesting that, in vivo, the adrenergic input could synchronize the pineal clock by acting selectively on Per1. PMID- 21525731 TI - Effects of aromatase or estrogen receptor gene deletion on masculinization of the principal nucleus of the bed nucleus of the stria terminalis of mice. AB - The principal nucleus of the bed nucleus of the stria terminalis (BNSTp) is a sexually dimorphic nucleus, and the male BNSTp is larger and has more neurons than the female BNSTp. To assess the roles of neuroestrogen synthesized from testicular androgen by brain aromatase in masculinization of the BNSTp, we performed morphometrical analyses of the adult BNSTp in aromatase knockout (ArKO), estrogen receptor-alpha knockout (alphaERKO), and estrogen receptor-beta knockout (betaERKO) mice and their respective wild-type littermates. In wild-type littermates, the BNSTp of males had a larger volume and greater numbers of neuronal and glial cells than did that of females. The volume and neuron number of the BNSTp in ArKO and alphaERKO males and glial cell number of the BNSTp in alphaERKO males were significantly smaller than those of wild-type male littermates, and they were not significantly different from those in female mice with either gene knockout. In contrast, there was no significant morphological difference in the BNSTp between betaERKO and wild-type mice. Next, we examined the BNSTp of ArKO males subcutaneously injected with estradiol benzoate (EB) on postnatal days 1, 2, and 3 (1.5 MUg/day). EB-treated ArKO males had a significantly greater number of BNSTp neurons than did oil-treated ArKO males. The number of BNSTp neurons in EB-treated ArKO males was comparable to that in wild-type males. These findings suggested that masculinization of the BNSTp in mice involves the actions of neuroestrogen that was synthesized by aromatase and that this estrogen mostly binds to ERalpha during the postnatal period. PMID- 21525732 TI - Transforming cytology. PMID- 21525733 TI - Digital cytology: current state of the art and prospects for the future. AB - The growth of digital methods in pathology is accelerating. Digital images can be used for a variety of applications in cytology, including rapid interpretations, primary diagnosis and second opinions, continuing education and proficiency testing. All of these functions can be performed using small static digital images, real-time dynamic digital microscopy, or whole-slide images. This review will discuss the general principles of digital pathology, its methods and applications to cytologic specimens. As cytologic specimens have unique features compared to histopathology specimens, the key differences will be discussed. Technical and administrative issues in digital pathology applications and the outlook for the future of the field will be presented. PMID- 21525734 TI - Fine-needle aspiration in suspected inflammatory breast cancer: case series with emphasis on approach to specimen adequacy. AB - OBJECTIVES: To highlight the utility of a tangential approach in the fine-needle aspiration (FNA) technique for obtaining cellular material adequate for a conclusive diagnosis in diffusely enlarged breast without a discrete lump. STUDY DESIGN: FNA was performed on 5 women clinically suspected to have inflammatory breast cancer (IBC). All had unilateral diffusely enlarged breasts with peau d'orange changes of the skin. No distinct lump was palpable. The procedure was performed using a 10 cm(3) syringe with a tangential approach of a 23-gauge needle in all 4 quadrants with extra passes in the antigravity areas. Rapid on site evaluation for adequacy was done. RESULTS: All women were of African descent within the age range of 34-57 years. One case had a recent history of lactation. FNA smears showed low-to-moderate cellularity. One case was suspicious and 4 were positive for ductal carcinoma. Core biopsy confirmed IBC in 3 cases. Two cases had a mastectomy; 1 of these cases had preoperative neoadjuvant chemotherapy. CONCLUSION: The approach of FNA used in these cases helped to establish the diagnosis of IBC in 4 women presenting with a diffusely enlarged and tender breast, resulting in the timely initiation of appropriate management. The technique needs to be assessed in a larger cohort of women with diffusely enlarged breast to evaluate its diagnostic utility. PMID- 21525735 TI - Morphological features of cell blocks prepared from residual liqui-PREP samples can distinguish between high-grade squamous intraepithelial lesions and squamous cell carcinomas. AB - OBJECTIVE: To evaluate the diagnostic value and compare morphological features of cell block sections of high-grade squamous intraepithelial lesions (HSIL) and squamous cell carcinomas (SCC). STUDY DESIGN: A total of 135 cell blocks were prepared from residual Liqui-PREP samples. Of these, 43 biopsy-confirmed cases (24 HSIL and 19 SCC) were reviewed. Morphological features determined included cell clusters, epithelial-stromal interface, stromal invasion and tumor necrosis. RESULTS: Ninety-three percent (40/43) of cell block diagnoses were consistent with histological diagnoses, which was better than the cytological diagnoses (81.4%; 35/43). The mean cell block size was 0.54 cm (range, 0.3-1.0 cm) for HSIL and 0.84 cm (range, 0.4-1.4 cm) for SCC (p < 0.0001). Cell clusters were present in 70.8% (17/24) of HSIL and 100% (19/19) of SCC (p < 0.0001). No epithelial stromal interface, stromal invasion or tumor necrosis was observed on HSIL cell block sections, which is in contrast to the 84.2% (16/19), 68.4% (13/19) and 42.1% (8/19) on SCC cell blocks, respectively (p < 0.05). CONCLUSION: Cell blocks may increase the diagnostic accuracy of liquid-based cytology. The presence of stromal invasion, epithelial-stromal interface and tumor necrosis on cell block sections may be useful for accurate SCC diagnosis. PMID- 21525736 TI - Infectious organisms on Papanicolaou smears should not influence the diagnosis of atypical squamous cells of undetermined significance. AB - BACKGROUND: Atypical squamous cells of undetermined significance (ASCUS) remain the center of diagnostic controversy and patients' stress despite recent advances in cervical cancer screening and the introduction of human papilloma virus (HPV) testing. The role of infectious agents in the induction of such changes is not well understood. AIM: We aim at reviewing the effect of the different infectious organisms in Papanicolaou (PAP) smears on the ASCUS diagnosis. MATERIAL: 133 ASCUS cases associated with variable infectious organisms (ASCUS-infection group) with secondary HPV testing and appropriate follow-up studies were reviewed. A control group of 310 ASCUS cases without any organisms (ASCUS-only group) was selected for comparison. RESULTS: The ASCUS-infection group had a significantly higher proportion of HPV-positive tests than the ASCUS-only group (p = 0.0027). There was no significant difference on follow-up PAPs and biopsies between the two groups (p = 0.4272). They showed an overall mean of 75% negative, 20% low grade lesions, and 5% high-grade lesions/carcinoma in situ on follow-up. CONCLUSION: Our study demonstrates no significant effect of infections on the cytological changes diagnostic of ASCUS. The cytologist should make this diagnosis neglecting any background infections even when predominant. PMID- 21525737 TI - Abnormal cervical cytology in the diagnosis of uterine papillary serous carcinoma: earlier detection of a poor prognostic cancer subtype? AB - OBJECTIVE: Early detection of uterine papillary serous (UPSC), clear cell (CCC), and grade 3 endometrioid carcinomas (G3EC) - all poor prognostic variants of endometrial carcinoma (EC) - is of particular clinical relevance. The study objective was to assess the utility of liquid-based cytology (Pap) in the detection of high-grade EC. STUDY DESIGN: A retrospective, two-institution analysis of patients diagnosed with UPSC, CCC, or G3EC with a preoperative Pap from 1999 to 2010 was conducted. RESULTS: One hundred and one patients were evaluated; 51.5% had UPSC, 27.7% had CCC, and 20.8% had G3EC. Stage I/II disease was found in 69.3% of patients, and 46/101 patients (45.5%) had abnormal Paps. Significantly more patients with UPSC had abnormal Paps (65.7%) than those with CCC (25%) or G3EC (23.8%; p < 0.001). An abnormal Pap was the only presenting clinical finding in a significant number of asymptomatic UPSC patients (26.9%) compared with 4% of patients with CCC and G3EC (p = 0.005). On multivariate analysis, UPSC histology was the only variable associated with an abnormal Pap. CONCLUSIONS: A high incidence of abnormal cervical cytology was observed in women with high-grade EC, particularly in UPSC patients. Although hypothesis generating, a proportion of asymptomatic UPSC patients had abnormal cytology, signifying that Pap smear screening may help detect the disease before the patient develops symptoms. PMID- 21525738 TI - The role of sediment cytology in ovarian neoplasm. AB - OBJECTIVE: It was our aim to study the role of sediment cytology in a diagnostic evaluation of ovarian neoplasm. METHODS: The present study was conducted in the Department of Pathology, Jawaharlal Nehru Medical College, AMU, Aligarh, India, over a span of 22 months. Cytological smears were prepared by centrifuging the sediment of fluid from the bottom of a container in which surgical specimens were received. Smears were fixed in 95% ethyl alcohol and then stained using hematoxylin-eosin and Papanicolaou stains. The cytological results were compared with histological diagnosis, taking the latter as gold standard. RESULTS: Out of 54 lesions studied by sediment cytology, 22 lesions were labeled as benign, 26 lesions as malignant and 6 lesions were inconclusive. Final histological diagnoses labeled 24 lesions as benign and 30 lesions as malignant. Comparing the diagnosis of the cytology smear with the histological section, 44 out of 54 cases were concordant. A sensitivity, specificity and diagnostic accuracy of 90.3, 92.3 and 90.3% was achieved, respectively. CONCLUSION: Biopsy sediment cytology is a good complementary method to histopathology in the study of ovarian biopsy material. In developing countries like ours, where the facility of frozen section is not available at many centers, this simple and cheap technique can be of much help in rapid diagnosis. PMID- 21525739 TI - Utility of napsin A and thyroid transcription factor 1 in differentiating metastatic pulmonary from non-pulmonary adenocarcinoma in pleural effusion. AB - OBJECTIVE: It was our aim to evaluate the usefulness of napsin A and thyroid transcription factor 1 (TTF-1) in the differential diagnosis of metastatic pulmonary and non-pulmonary adenocarcinomas (ACs) in pleural effusion. STUDY DESIGN: A total of 84 pleural effusion fluid cell blocks were collected from metastatic ACs. There were 53 pulmonary ACs and 31 non-pulmonary ACs. Immunohistochemical staining was performed with antibodies against napsin A and TTF-1. RESULTS: Napsin A was positive in 44/53 (83%) cases of pulmonary ACs, and TTF-1 was positive in 30/53 (57%) cases of pulmonary ACs. All non-pulmonary ACs were negative for napsin A and TTF-1. Napsin A showed a reactivity in >75% of the tumor cells in 36 of the 44 positive cases (82%), whereas TTF-1 showed a reactivity in >75% of the tumor cells only in 6 of the 30 positive cases (20%; p < 0.01). Poorly differentiated pulmonary ACs expressed napsin A (73%) more frequently than TTF-1 (53%), but this was not statistically significant (p = 0.45). CONCLUSION: We conclude that napsin A is superior to TTF-1 with regard to distinguishing between metastatic pulmonary and non-pulmonary ACs in cell blocks prepared from malignant pleural effusions. PMID- 21525741 TI - Preliminary study of a new, fully automated system for liquid-based cytology: the NovaPrep(r) processor system. AB - OBJECTIVE: To evaluate a fully automated system for liquid-based cytology (LBC): the NovaPrep(r) Processor System (NPS), which is based on the new concept of double decantation, versus conventional cytology (CC), the gold standard for cytology. STUDY DESIGN: We performed a preliminary comparative study involving 1,129 female patients who underwent sampling for a Pap test; the sample was first smeared for CC and then, using the remaining specimen on the brush, for LBC with the NPS. The performances of CC and NPS were evaluated for accuracy and compared using the gold standard of a combination of one of the two methods of pathological cytology with screening for positive human papilloma virus, quantification of cells (normal and pathological), and improvement in the quality of samples and reading time. RESULTS: The results showed improvement in sensitivity (3.81% for CC vs. 4.52% for NPS) with a specificity superior to 90% for both, a markedly decreased number of unsatisfactory specimens, notably samples containing too many inflamed cells (7.4% for CC vs. 0.5% for NPS), and a shortening of the reading time, which was three times less using NPS. CONCLUSION: This preliminary study showed a gain in sensitivity, a drop in the number of unsatisfactory specimens and a reduction in reading time with NPS. The results achieved using this fully automated LBC procedure are very promising and will hopefully reduce the overall cost of cervical cancer screening in the future. PMID- 21525740 TI - Quantitative automated image analysis system with automated debris filtering for the detection of breast carcinoma cells. AB - OBJECTIVE: To develop an intraoperative method for margin status evaluation during breast conservation therapy (BCT) using an automated analysis of imprint cytology specimens. STUDY DESIGN: Imprint cytology samples were prospectively taken from 47 patients undergoing either BCT or breast reduction surgery. Touch preparations from BCT patients were taken on cut sections through the tumor to generate positive margin controls. For breast reduction patients, slide imprints were taken at cuts through the center of excised tissue. Analysis results from the presented technique were compared against standard pathologic diagnosis. Slides were stained with cytokeratin and Hoechst, imaged with an automated fluorescent microscope, and analyzed with a fast algorithm to automate discrimination between epithelial cells and noncellular debris. RESULTS: The accuracy of the automated analysis was 95% for identifying invasive cancers compared against final pathologic diagnosis. The overall sensitivity was 87% while specificity was 100% (no false positives). This is comparable to the best reported results from manual examination of intraoperative imprint cytology slides while reducing the need for direct input from a cytopathologist. CONCLUSION: This work demonstrates a proof of concept for developing a highly accurate and automated system for the intraoperative evaluation of margin status to guide surgical decisions and lower positive margin rates. PMID- 21525742 TI - Triple immunocytochemical staining in fine-needle aspirate of a neck mass: a case report and review of the literature. AB - BACKGROUND: Immunocytochemistry involving single or double antibodies can be used to support or confirm a diagnosis in difficult cytology cases. There are a few reports on the application of a cocktail of 3 antibodies in the literature. We would like to report our experience using this technique in a difficult case of cervical lymph node fine-needle aspiration cytology (FNAC). CASE: A 75-year-old woman presented with a left neck mass for which FNAC was performed. The aspirates were cellular comprising atypical cells present in loose aggregates. The cells exhibited an ovoid and spindled morphology with no evidence of keratinization or any other differentiating features. The cytology was suggestive of metastatic poorly differentiated neoplasm; however, the presence of ovoid histiocytic looking cells required further assessment. Triple immunostaining using a cocktail of CK5/6, CK34, and CD68 was performed. The spindled atypical cells were positive for CK5/6 and CK34 (brown cytoplasmic staining) and the ovoid histiocytic-looking cells were positive for CD68 (red cytoplasmic staining). Based on immunostaining, the cytological diagnosis of metastatic squamous cell carcinoma was confirmed. CONCLUSION: In view of our findings, the utility of triple immunocytochemical staining in cytology smears of poorly differentiated malignancy and a brief review of the literature are highlighted in this report. PMID- 21525743 TI - Small cell carcinoma of the ovary presenting in a urine cytology specimen: a case report. AB - BACKGROUND: Small cell carcinoma (SMCC) is rarely diagnosed in urine specimens. Cytologically, this tumor is similar to pulmonary SMCC. However, clinicopathologic correlation may be required to differentiate between primary urinary bladder SMCC and metastatic SMCC from a remote primary or secondary bladder involvement by direct extension of the tumor from nearby organs (prostate, uterus, or ovary). A unique case of a rare pulmonary-type ovarian SMCC, the tumor cells of which were detected in a voided urine specimen, is described herein. CASE: A 79-year-old female presented to the urologic clinic with a history of metastatic SMCC of unknown primary with hematuria. The voided urine specimen examination revealed tumor cells cytomorphologically consistent with small cell neuroendocrine carcinoma. Following cytologic diagnosis, cystoscopic examination and bladder biopsy were performed. The histopathology revealed a widely invasive tumor with a morphology typical of SMCC. The overlying urothelium was unremarkable. By immunohistochemistry, tumor cells were found positive for neuroendocrine markers, EMA and WT-1. The morphologic and immunohistochemical features of the tumor were most consistent with urinary bladder involvement by pulmonary-type primary ovarian SMCC. CONCLUSION: It is justified to think that SMCC cell detection in urine specimens does not necessarily imply their origin from primary bladder malignancy. Performing additional studies may be prudent in order to exclude secondary involvement of the bladder in this tumor as the correct diagnosis has significant clinical implications. PMID- 21525744 TI - Primary amyloidosis involving mesenteric lymph nodes: diagnosis by fine-needle aspiration cytology. AB - BACKGROUND: Mesenteric lymph node amyloid deposits are rare and may be seen in isolated or secondary amyloidosis. The diagnosis of mesenteric amyloidosis has conventionally relied on histopathological examination following an exploratory laparotomy or a biopsy. CASE: A 72-year-old male previously diagnosed with Waldenstrom's macroglobulinemia and multiple other malignancies was admitted for abdominal pain. An abdominal computed tomography (CT) scan revealed diffuse retroperitoneal and mesenteric lymphadenopathy associated with bowel wall thickening. A CT-guided fine-needle aspiration (FNA) cytology and core biopsies of mesenteric lymph nodes were performed. The FNA smears revealed irregular, waxy, basophilic clumps on a Diff-Quik stain and cyanophilic clumps of amorphous material on a Papanicolaou stain. The lymph node aspirates showed positivity for the Congo red stain, confirming it as amyloid. In situ hybridization studies revealed a predominance of lambda light chains, and a diagnosis of primary amyloidosis involving mesenteric lymph nodes was made. Supplemental needle core biopsies showed positivity for Congo red and Crystal violet stains and exhibited the classic apple-green birefringence under polarized light. CONCLUSION: The involvement of lymph nodes in amyloidosis is not uncommon; however, the involvement of mesenteric lymph nodes in a setting of macroglobulinemia and its diagnosis by FNA cytology is novel to this case. PMID- 21525745 TI - Cytomorphology of crystal storing histiocytosis in the breast associated with lymphoma: a case report. AB - Crystal storing histiocytosis (CSH) is a very rare immunoglobulin (Ig) deposition disorder in which macrophages accumulate light chains or Ig crystalline inclusions. It is frequently associated with lymphoproliferative disorders, but can be seen in some reactive conditions too. This article reports the cytomorphologic, histopathologic, and ancillary study findings of a marginal zone B cell lymphoma of the breast with CSH in a 54-year-old woman. To the best of our knowledge, this is the first report describing CSH in the breast and one of a few reports describing the cytomorphology of CSH. In breast fine-needle aspiration biopsies, CSH can be confused with benign processes such as fat necrosis and histiocytic lesions. Thus, awareness of this rare entity and its frequent association with lymphoproliferative disorders is useful in order to triage a specimen appropriately and exclude the possibility of a lymphoproliferative process. PMID- 21525746 TI - Metabolic syndrome, components, and cardiovascular disease prevalence in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study. AB - BACKGROUND/AIMS: Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD. METHODS: We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study. RESULTS: Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non diabetics separately. CONCLUSION: The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses. PMID- 21525747 TI - Retinogeniculostriate pathway components scale with orbit convergence only in primates and not in other mammals. AB - Studies of the relative sizes of brain components in mammals suggest that areas responsible for sensory processing, including visual processing, are correlated with aspects of ecology, especially activity pattern. Some studies suggest that primate orbit convergence and binocular vision are correlated with the overall size of the brain as well as components of the visual pathway, such as the lateral geniculate nucleus. However, the question remains whether components of the visual pathway are correlated with orbit convergence and binocular visual field overlap in nonprimate mammals. Here, we examine the relationship between orbit convergence and the volumes of components of the visual pathway (optic tract, dorsal lateral geniculate nucleus and primary visual cortex). Data on orbit orientation are combined with those on overall brain volume as well as brain component volumes in a taxonomically diverse sample of mammals. Our results demonstrate that nonprimate mammals scale isometrically for component volumes along the visual pathway, whereas primates display negatively allometric relationships. However, only among primates is higher orbit convergence correlated with volumetrically larger lateral geniculate nuclei and visual cortices. Diurnal primates exhibit statistically larger visual pathway components when compared to nocturnal primates. Nonprimate mammals do not display activity pattern differences with the single exception of optic tract sizes. We conclude that binocular vision was a much stronger factor in the evolution of the visual system in primates than in other mammals. PMID- 21525748 TI - Comparison of area 17 cellular composition in laboratory and wild-caught rats including diurnal and nocturnal species. AB - In this study we examine the size of primary sensory areas in the neocortex and the cellular composition of area 17/V1 in three rodent groups: laboratory nocturnal Norway rats (Long-Evans; Rattus norvegicus), wild-caught nocturnal Norway rats (R. norvegicus), and laboratory diurnal Nile grass rats (Arvicanthis niloticus). Specifically, we used areal measures of myeloarchitecture of the primary sensory areas to compare area size and the isotropic fractionator method to estimate the number of neurons and nonneurons in area 17 in each species. Our results demonstrate that the percentage of cortex devoted to area 17 is significantly greater and the percentage of cortex devoted to S1 is significantly smaller in the diurnal Nile grass rat compared with the nocturnal Norway rat groups. Further, the laboratory rodent groups have a greater percentage of cortex devoted to auditory cortex compared with the wild-caught group. We also demonstrate that wild-caught rats have a greater density of neurons in area 17 compared to laboratory-reared animals. However, there were no other clear cellular composition differences in area 17 or differences in the percentage of brain weight devoted to area 17 between nocturnal and diurnal rats. Thus, there are differences in primary sensory area size between diurnal versus nocturnal and laboratory versus wild-caught rat groups and cellular density between wild-caught and laboratory rat groups. Our results demonstrate that the differences in the size and cellular composition of cortical areas do not fit with what would be expected based on brain scaling differences alone, and have a consistent relationship with lifestyle and sensory morphology. PMID- 21525749 TI - Evaluation of the effect of acetyl L-carnitine on experimental cisplatin ototoxicity and neurotoxicity. AB - INTRODUCTION: Cisplatin (CDDP) is an effective and widely used chemotherapeutic agent for pediatric tumors, and ototoxicity is one of the dose-limiting side effects. OBJECTIVE: It was the aim of our study to investigate the effect of acetyl L-carnitine (ALCAR) on experimental CDDP ototoxicity by audiologic tests, histomorphologic, immunohistochemical and ultrastructural examinations and to investigate the apoptotic pathways. MATERIALS AND METHODS: Wistar albino rats (n = 28) were studied. Baseline audiological tests were performed in 4 groups: group 1, control; group 2, ALCAR; group 3, CDDP; group 4, CDDP + ALCAR-administered rats. Control audiological tests were performed on the 3rd day, and then the rats were sacrificed. Ear and brain specimens were examined by transmission electron microscopy, and caspase 3, 8 and 9 activities were investigated. RESULTS: The CDDP-administered rats showed significant auditory brainstem response threshold shifts using all stimuli (clicks, 6-kHz and 8-kHz tone burst) compared with the control groups. The CDDP + ALCAR-administered rats showed significant auditory brainstem response threshold shifts by only click stimuli compared with the control groups. In the brain, spiral ganglion and organ of Corti, ultrastructural damage was prominent in group 3; the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive cells and caspase 3, 8 and 9 immunostaining cells was significantly high in group 3. CONCLUSION: ALCAR improves CDDP-induced auditory impairment, and also antioxidative and antiapoptotic properties of ALCAR on CDDP ototoxicity were supported by the findings. PMID- 21525750 TI - Floppy mitral valve and mitral valve prolapse: lack of precise definition (the Tower of Babel syndrome). PMID- 21525751 TI - The effect of chlorhexidine varnish on root caries: a systematic review. AB - OBJECTIVE: The aim of this study was to systematically review the present literature on the effect of chlorhexidine varnish (CHX-V) on root caries. MATERIALS AND METHODS: The MEDLINE-PubMed, the Cochrane-CENTRAL and EMBASE databases were searched through December 2010 to identify any appropriate studies. Root caries incidence and root caries activity were selected as outcome variables. RESULTS: An independent screening of the unique titles and abstracts of 24 MEDLINE-PubMed, 14 Cochrane-CENTRAL and 18 EMBASE papers resulted in 6 publications that met the eligibility criteria. Data extraction provided no conclusive evidence that the application of CHX-V is effective in patients when regular professional oral prophylaxis is performed. If effective, the 40% CHX-V was found to provide a benefit over a control or fluoride varnish. CHX-V at lower concentrations (1 and 10%) may provide protection against root caries in high risk patients (such as geriatric and xerostomia patients) in the absence of regular professional oral prophylaxis. CONCLUSION: Within the limitations of this review, it may be concluded that in the absence of regular professional tooth cleaning and oral hygiene instructions, CHX-V may provide a beneficial effect in patients in need of special care. The strength of this recommendation is graded as 'weak'. PMID- 21525752 TI - Liver and pancreatic diseases: consequences of chronic alcoholic consumption. PMID- 21525753 TI - Genetics of pancreatitis: a guide for clinicians. AB - It is now generally believed that pancreatitis results from pancreatic autodigestion. An inappropriate conversion of pancreatic zymogens to active enzymes within the pancreatic parenchyma is thought to initiate the inflammatory process. A key role has been attributed to the activation of trypsinogen to trypsin, converting all proteolytic proenzymes to their active form. Several gain of-function mutations in the cationic trypsinogen gene (PRSS1) have been identified in patients with chronic pancreatitis (CP). These mutations lead to enhanced intrapancreatic trypsinogen activation. In contrast, a variant in the anionic trypsinogen (PRSS2) gene, p.G191R, has been described that mitigates intrapancreatic trypsin activity and thereby plays a protective role. Beside trypsinogen mutations, loss-of-function variants in SPINK1, encoding a pancreatic trypsin inhibitor, are strongly associated with idiopathic CP. Approximately 15 40% of patients with so-called idiopathic CP carry p.N34S on one allele or on both alleles. Chymotrypsin C (CTRC) degrades all human trypsin isoforms with high specificity. Two CTRC alterations, p.R254W and p.K247_R254del, are significantly associated with idiopathic as well as alcohol-related CP. Functional analysis of the variants revealed impaired activity and/or reduced secretion. Thus, loss-of function mutations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Albeit the association between CFTR, the gene mutated in cystic fibrosis, and idiopathic CP is now well established, the pathogenic mechanisms are poorly understood. Nearly 25-30% of patients carry at least one CFTR mutation, but few patients only were compound-heterozygous. Several patients, however, are trans-heterozygous for a CFTR alteration and a PRSS1, SPINK1, or CTRC variant, respectively. PMID- 21525754 TI - Long-term, clinical follow-up in fatty liver patients. AB - The risk of progression to cirrhosis and death in patients with pure alcoholic (AFLD) and non-alcoholic steatosis (NAFLD) has only sparsely been studied. The aims of the present long-term follow-up study were to analyze for risks of progression to cirrhosis and death in a cohort of patients with histologically verified 'pure fatty liver'. 247 patients with biopsy verified AFLD and 170 patients with NAFLD without inflammation were included in the period from 1978 to 1987. Patients in the study cohort were linked through their personal identification number to The National Patient Registry (LPR) and The Causes of Death Registry. All admissions, discharge diagnoses, and causes of death were obtained from January 1, 1977 until death (2004) or December 31, 1999 in the registries. Surviving patients were offered a clinical follow-up in 2004. Survival was observed to be significantly higher (p < 0.01) in NAFLD for men as well as for women, which was not different from the Danish age- and gender matched population. Two (1.2%) patients with NAFLD developed cirrhosis, while 54 patients (21.9%) with AFLD developed cirrhosis. The degree of steatosis was the only histological parameter significantly associated with premature death in AFLD, but not in NAFLD patients. Risk of progression to cirrhosis and time to development was significantly associated to being of female gender. In conclusion, for patients with NAFLD, survival was good, while patients with AFLD had excess in mortality and risk of development of cirrhosis, which was associated with the degree of steatosis in the index biopsy and being of female gender. PMID- 21525755 TI - Induction of cross-linking and silencing of Sp1 by transglutaminase during liver injury in ASH and NASH via different ER stress pathways. AB - Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) share many histological similarities, but the molecular mechanisms responsible for hepatic apoptosis remain unclear. We previously reported that transglutaminase 2 (TG2), a protein cross-linking enzyme, is induced in the nucleus of ethanol treated hepatocytes, and cross-links and inactivates a general transcription factor Sp1, which eventually leads to reduced expression of c-Met and caspase independent hepatic apoptosis [Tatsukawa et al., Gastroenterology 2009;136:1783 1795]. In this study, we investigated if a similar change might be observed also in NASH and if yes how TG2 and cross-linked Sp1 (CLSp1) would be induced in NASH and ASH. We obtained elevated nuclear TG2 and CLSp1 formation in NASH patients, as well as in HepG2 cells treated with free fatty acids (FFAs). Biochemical analyses on this culture model revealed that both ethanol and FFAs provoked fat accumulation, endoplasmic reticulum (ER) stress, increased nuclear factor-kappaB (NFkappaB) and nuclear TG2, but the synergistic effect was not obvious between FFA and ethanol. Salubrinal, a selective inhibitor against dephosphorylation of eukaryotic initiation factor-2alpha in ER stress-induced pancreatic ER kinase (PERK) signal pathway, inhibited NFkappaB activation, nuclear TG2 expression and apoptosis only induced by FFAs, but not those induced by ethanol, while retinoid antagonist blocks ethanol induction of NFkappaB and TG2. These results suggest that FFA and ethanol may increase ER stress and lead to nuclear NFkappaB activation and TG2 induction through respectively distinctive pathways, leading to TG2-mediated apoptosis via cross-linking and inactivation of Sp1 and reduction in c-Met. PMID- 21525756 TI - New advances in cell physiology and pathophysiology of the exocrine pancreas. AB - This review provides some aspects on the physiology of stimulation and inhibition of pancreatic digestive enzyme secretion and the pathophysiology of pancreatic acinar cell function leading to pancreatitis. Cholecystokinin (CCK) stimulates both directly via CCK-A receptors on acinar cells and indirectly via CCK-B receptors on nerves, followed by acetylcholine release, pancreatic enzyme secretion. It is still not known whether CCK-A receptors exist in human acinar cells, in contrast to acinar cells of rodents where CCK-A receptors have been well described. CCK has numerous actions both in the periphery and in the central nervous systems. CCK inhibits gastric motility and regulates satiety. Another major function of CCK is stimulation of gallbladder contraction. This function enables that bile acids act simultaneously with pancreatic lipolytic enzymes. Secretin is a major stimulator of bicarbonate secretion. Trypsinogen is activated by the gut mucosal enzyme enterokinase. The other pancreatic proenzymes are activated by trypsin. Termination of enzyme secretion may be regulated by negative feedback mechanisms via destruction of CCK-releasing peptides by trypsin. Furthermore, the ileum may act as a brake by release of inhibitory hormones such as PYY and somatostatin. In the pathophysiology of acute pancreatitis, fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen is regarded as an initiation step. This activation of trypsinogen may be caused by the lysosomal enzyme cathepsin B. However, autoactivation of trypsinogen itself may be a possibility in pathogenesis. Autoactivation is enhanced in certain mutations of trypsinogen. Furthermore, an imbalance of protease inhibitors and active proteases may be involved. The role of pancreatic lipolytic enzymes, the role of bicarbonate secretion, and toxic Ca(2+) signals by excessive liberation from the endoplasmic reticulum have to be discussed in the pathogenesis of acute pancreatitis. PMID- 21525757 TI - Animal models of alcoholic liver disease. AB - The risk of alcohol-induced liver disease (ALD) increases dose- and time dependently with consumption of alcohol. The progression of the disease is well characterized; however, although the progression of alcohol-induced liver injury is well characterized, there is no universally-accepted therapy available to halt or reverse this process in humans. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of this disease, rational targeted therapy can be developed to treat or prevent it in the clinics. Several models for experimental ALD exist, including non-human primates, micropigs and rodents. However, most researchers employ rodent models of ALD. Furthermore, the advent of genetically modified strains of rodents (e.g. 'knockout' mice) has increased the specificity of the hypotheses that can be directly tested. Based on these models systems, several plausible hypotheses to explain the mechanism(s) by which alcohol leads to liver damage have been proposed, including consequences of alcohol metabolism, oxidative/nitrosative stress, altered inflammatory responses, and increased sensitivity to cytotoxic stimuli. These studies have also identified candidate genes for polymorphism studies to explain potential increased genetic risk in some individuals. However, despite significant advances in our understanding of the mechanisms by which ALD develops based on studies with these models, this work has yet to translate to a viable therapy for ALD in the clinics. This talk will also discuss potential reasons for these limitations to date and suggest future prospects to improve the translational utility of modeling ALD. PMID- 21525759 TI - Zinc and alcoholic liver disease. AB - Zinc deficiency is one of the most consistent nutritional/biochemical observations in alcoholic liver disease (ALD). The objectives of our research are to determine how alcohol interferes with cellular zinc homeostasis and if zinc deficiency is a causal factor in the development of ALD. Metallothionein (MT) is a major protein responsible for cellular zinc homeostasis. MT-transgenic (MT-TG) mice with hepatic overexpression of MT and elevation of zinc level were resistant to ethanol-induced liver injury. MT-knockout (MT-KO) mice with a reduction of hepatic zinc were more susceptible to alcohol toxicity. However, zinc treatment also provided beneficial effects on alcohol hepatoxicity in MT-KO mice, suggesting a MT-independent action. Dietary zinc supplementation normalized hepatic zinc level and attenuated the pathological changes in the liver of mice chronically fed alcohol. Several mechanisms were involved in zinc action against alcoholic cytotoxicity. Zinc enhanced cellular antioxidant capacity and corrected alcohol metabolic switch from alcohol dehydrogenase to cytochrome P4502E1. Zinc attenuated cytokine production and TNF-alpha receptor- and Fas-mediated cell death pathways. Zinc restored activities of hepatocyte nuclear factor-4alpha (HNF 4alpha) and peroxisome proliferation activator-alpha (PPAR-alpha), and enhanced hepatic fatty acid beta-oxidation and lipid secretion. Hepatoma cell cultures showed that zinc deprivation induces lipid accumulation via inactivating HNF 4alpha and PPAR-alpha. These results suggest that alcohol exposure interferes with hepatic zinc homeostasis, leading to cellular zinc deprivation. Inactivation of zinc proteins due to zinc release is likely an important molecular mechanism in the pathogenesis of ALD. PMID- 21525758 TI - Gut-liver axis and sensing microbes. AB - 'Detoxification' of gut-derived toxins and microbial products from gut-derived microbes is a major role of the liver. While the full repertoire of gut-derived microbial products that reach the liver in health and disease is yet to be explored, the levels of bacterial lipopolysaccharide (LPS), a component of Gram negative bacteria, is increased in the portal and/or systemic circulation in several types of chronic liver diseases. Increased gut permeability and LPS play a role in alcoholic liver disease where alcohol impairs the gut epithelial integrity through alterations in tight junction proteins. In addition, non alcoholic fatty liver disease is also associated with increased serum LPS levels and activation of the pro-inflammatory cascade plays a central role in disease progression. Microbial danger signals are recognized by pattern recognition receptors such as the Toll-like receptor 4 (TLR4). Increasing evidence suggests that TLR4-mediated signaling via the MyD88-dependent or MyD88-independent pathways may play different roles in liver diseases associated with increased LPS exposure of the liver as a result of gut permeability. For example, we showed that in alcoholic liver disease, the MyD88-independent, IRF3-dependent TLR4 cascade plays a role in steatosis and inflammation. Our recent data demonstrate that chronic alcohol exposure in the liver leads to sensitization of Kupffer cells to LPS via a mechanism involving upregulation of microRNA-155 in Kupffer cells. Thus, understanding the cell-specific recognition and intracellular signaling events in sensing gut-derived microbes will help to achieve an optimal balance in the gut-liver axis and ameliorate liver diseases. PMID- 21525760 TI - Role of the endocannabinoid system in alcoholic liver disease. AB - Alcohol abuse is a major cause of liver fibrosis and cirrhosis in developed countries. Alcoholic liver disease (ALD) is distinctively characterized by a pronounced inflammatory response due to elevated gut-derived endotoxin plasma levels, an augmented generation of oxidative stress with pericentral hepatic hypoxia and the formation of noxious ethanol metabolites (e.g. acetaldehyde or lipid oxidation products). These factors, based on a complex network of cytokine actions, together result in increased hepatocellular damage and activation of hepatic stellate cells, the key cell type of liver fibrogenesis. Recent studies suggest that the endocannabinoid system is a signaling system that also plays an important role in the pathogenesis of ALD. A study comparing chronic alcohol administration in cannabinoid receptor (CB) 1 or CB2 knockout versus wild-type mice revealed that CB1 signaling aggravated hepatic steatosis and fibrogenesis whereas CB2 protected the liver from ALD. These data suggested a protective role of CB2 (in contrast to CB1) in ALD. Similar results were found in global or hepatocyte-specific CB1 knockout mice that were resistant to ethanol-induced steatosis. Moreover, ethanol feeding upregulated the endocannabinoid 2 arachidonoyl glycerol and its biosynthetic enzyme diacylglycerol lipase-beta selectively in hepatic stellate cells and subsequently increased expression of CB1 receptors in hepatocytes of wild-type mice leading to CB1-dependent hepatic steatosis by activation of lipogenic pathways. This ethanol-induced upregulation of CB1 receptors was partly dependent on the ethanol metabolite acetaldehyde. Thus, the hepatic endocannabinoid system offers emerging options for therapeutic exploitation not only for liver disease in general, but also for ALD. PMID- 21525761 TI - MnSOD overexpression prevents liver mitochondrial DNA depletion after an alcohol binge but worsens this effect after prolonged alcohol consumption in mice. AB - Both acute and chronic alcohol consumption increase reactive oxygen species (ROS) formation and lipid peroxidation, whose products damage hepatic mitochondrial DNA (mtDNA). To test whether manganese superoxide dismutase (MnSOD) overexpression modulates acute and chronic alcohol-induced mtDNA lesions, transgenic MnSOD overexpressing (TgMnSOD(+++)) mice and wild-type (WT) mice were treated by alcohol, either chronically (7 weeks in drinking water) or acutely (single intragastric dose of 5 g/kg). Acute alcohol administration increased mitochondrial ROS formation, decreased mitochondrial glutathione, depleted and damaged mtDNA, durably increased inducible nitric oxide synthase (NOS) expression, plasma nitrites/nitrates and the nitration of tyrosine residues in complex V proteins and decreased complex V activity in WT mice. These effects were prevented in TgMnSOD(+++) mice. In acutely alcoholized WT mice, mtDNA depletion was prevented by tempol, a superoxide scavenger, L-NAME and 1400W, two NOS inhibitors, or uric acid, a peroxynitrite scavenger. In contrast, chronic alcohol consumption decreased cytosolic glutathione and increased hepatic iron, lipid peroxidation products and respiratory complex I protein carbonyls only in ethanol-treated TgMnSOD(+++) mice but not in WT mice. In chronic ethanol-fed TgMnSOD(+++) mice, but not WT mice, mtDNA was damaged and depleted, and the iron chelator, deferoxamine (DFO), prevented this effect. In conclusion, MnSOD overexpression prevents mtDNA depletion after an acute alcohol binge but aggravates this effect after prolonged alcohol consumption, which selectively triggers iron accumulation in TgMnSOD(+++) mice but not in WT mice. In the model of acute alcohol binge, the protective effects of MnSOD, tempol, NOS inhibitors and uric acid suggested a role of the superoxide anion reacting with NO to form mtDNA-damaging peroxynitrite. In the model of prolonged ethanol consumption, the protective effects of DFO suggested the role of iron reacting with hydrogen peroxide to form mtDNA-damaging hydroxyl radical. PMID- 21525763 TI - Pathophysiological similarities and synergisms in alcoholic and non-alcoholic steatohepatitis. AB - Chronic alcohol consumption is one of the main etiological factors for liver disease worldwide, however only a fraction of drinkers develop significant hepatic inflammation (alcoholic steatohepatitis), and even less progress to significant hepatic fibrosis and cirrhosis. The pathophysiological significance of hepatic lipid accumulation in the absence of significant alcohol consumption is also increasingly recognized. Non-alcoholic fatty liver disease (NAFLD) is regarded as the hepatic manifestation of the metabolic syndrome, and it is the most common cause of liver enzyme elevations in Western countries. Similarly to alcoholic liver disease, NAFLD encompasses mild hepatic steatosis to non alcoholic steatohepatitis with significant necroinflammation and progressive fibrosis. Several clinical studies suggest a strong causative link between the consumption of alcohol and progressive liver disease in individuals with high fat intake and/or diabetes. However, it is incompletely understood how alcohol and obesity interact and whether the combined effects on the progression of liver injury are additive or synergistic. This review describes single as well as combined effects of alcohol and (components of) the metabolic syndrome on hepatic steatosis, inflammation and fibrosis. In addition to direct effects on the liver, the view is expanded to other organs affected by chronic alcohol consumption or the metabolic syndrome, to understand also extrahepatic pathophysiological mechanisms involved in hepatocellular injury. Undoubtedly, alcohol and the metabolic syndrome appear as a dangerous mix, and there are important synergistic effects of either condition with regard to crucial triggers of liver injury. PMID- 21525762 TI - Alcohol abuse, endoplasmic reticulum stress and pancreatitis. AB - Alcohol abuse is a common cause of both acute and chronic pancreatitis. There is a wide spectrum of pancreatic manifestations in heavy drinkers from no apparent disease in most individuals to acute inflammatory and necrotizing pancreatitis in a minority of individuals with some progressing to chronic pancreatitis characterized by replacement of the gland by fibrosis and chronic inflammation. Both smoking and African-American ethnicity are associated with increased risk of alcoholic pancreatitis. In this review we describe how our recent studies demonstrate that ethanol feeding in rodents causes oxidative stress in the endoplasmic reticulum (ER) of the digestive enzyme synthesizing acinar cell of the exocrine pancreas. This ER stress is attenuated by a robust unfolded protein response (UPR) involving X-box binding protein-1 (XBP1) in the acinar cell. When the UPR activation is prevented by genetic reduction in XBP1, ethanol feeding causes significant pathological responses in the pancreas. These results suggest that the reason most individuals who drink alcohol heavily do not get significant pancreatic disease is because the pancreas mounts an adaptive UPR to attenuate the ER stress that ethanol causes. We hypothesize that disease in the pancreas results when the UPR is insufficiently robust to alleviate the ER stress caused by alcohol abuse. PMID- 21525764 TI - Protective role of HO-1 for alcohol-dependent liver damage. AB - BACKGROUND/AIMS: Alcoholic liver disease is continuously increasing in developed countries being a leading cause of death worldwide. Chronic ethanol consumption induces oxidative stress by accumulation of reactive oxygen intermediates (ROI) while reducing the cellular antioxidant defense. Induction of heme oxygenase-1 (HO-1) may protect primary human hepatocytes (hHeps) from such damage. Thus, the aim of this study was to investigate the potential of polyphenols to protect hHeps from ethanol-dependent oxidative damage. METHODS: hHeps were isolated by collagenase perfusion. ROI and cellular glutathione (GSH) were measured by fluorescent-based assays. Cellular damage was determined by lactate dehydrogenase (LDH) leakage and staining for apoptosis and necrosis. Nuclear translocation of Nrf2 and HO-1 expression were analyzed by Western blot. RESULTS: Ethanol and TGF beta rapidly increase ROI and reduce GSH in hHeps, causing apoptosis with a release of approximately 40% total LDH after 72 h. Similar to incubation with hemin preincubation and co-incubation of cells with nifedipine, verapamil and quercetin significantly reduce oxidative stress and resulting cellular damage, in a dose-dependent manner, by initiating nuclear translocation of Nrf2 which in turn induces HO-1 under the control of p38 and ERK. Blocking of HO-1 activity with ZNPP9 reverses the protective effect of all three substances. CONCLUSION: Our results suggest that increasing HO-1 activity in hHeps protects them from oxidative stress-dependent damage. As polyphenols have great potential to induce HO-1 expression, they may play an important role for future therapeutic strategies to protect liver from oxidative stress-dependent damage observed during chronic alcohol consumption. PMID- 21525765 TI - HCV, HBV and alcohol - the Dionysos study. AB - Population-based studies on the natural history of chronic viral liver disease that consider co-morbidity factors, such as alcohol or metabolic diseases, are lacking. We report here the contribution of ethanol intake and non-organ-specific autoantibodies (NOSA) to the course of chronic viral disease in the Dionysos cohort. As reported elsewhere, the Dionysos study was performed in two towns of Northern Italy, started in 1992 with 10 years of follow-up in 2002, and allowed us to quantify the burden of chronic liver disease in Northern Italy. We followed 139 subjects with chronic hepatitis C virus (HCV) infection and 61 with chronic hepatitis B virus (HBV) infection for a median (IQR) time of 8.4 (1.0) and 8.3 (0.9) years, respectively. The incidence and remission rates of steatosis were 9.0 and 29.7 per 1,000 person-years in the HCV cohort and 4.0 and 30.4 per 1,000 person-years in the HBV cohort. Progression to cirrhosis and hepatocarcinoma was more common in the HCV than in the HBV cohort. In the HCV cohort, ethanol intake was an independent predictor of liver cirrhosis and of death rate in both cohorts. We found no association between baseline NOSA and 8.4-year mortality. We conclude that morbidity and mortality rate of HBV and HCV infection in the general population is lower than that reported in secondary care populations, blood donors, or clinical series, and that ethanol intake >30 g/day is the most important and evitable risk factor for cirrhosis and death in patients with chronic HCV or HBV infection. PMID- 21525767 TI - Pancreas - non-alcoholic constituents and their effects. AB - Alcoholic beverages contain numerous non-alcoholic compounds that could have beneficial or pathological effects. For example, up to now in beer more than 2,000 and in wine more than 1,000 organic and inorganic constituents have been identified. Whereas the role of alcohol (ethanol) in the development of pancreatic diseases - in particular acute and chronic pancreatitis - has been intensively investigated, only little is known about the effects of non-alcoholic compounds in this context. Some of the non-alcoholic constituents have been shown to be biologically active, although discussions of the results in appropriate publications were often not performed with regard to their consumption as a mixture in alcoholic beverages. In this article we provide an overview about the newest data concerning the effect of non-alcoholic constituents of alcoholic beverages, especially of beer, on pancreatic secretion and their possible role in alcoholic pancreatitis. The data indicate that non-alcoholic constituents of beer stimulate pancreatic enzyme secretion in humans and rats, at least in part, by direct action on pancreatic acinar cells. However, there is accumulating evidence that non-alcoholic compounds of alcoholic beverages exert different effects on the pancreas. The effects and mechanisms of most single compounds and their combinations are still unknown and thus caution is required in attempting to draw firm conclusions on the effect of non-alcoholic compounds of alcoholic beverages on defining alcoholic etiology of pancreatitis. PMID- 21525766 TI - Role of CYP2E1 in ethanol-induced oxidant stress, fatty liver and hepatotoxicity. AB - BACKGROUND/AIMS: Several pathways contribute to mechanisms by which ethanol induces oxidant stress. While some studies support a role for cytochrome P450 2E1 (CYP2E1), others do not. There is a need to develop oral models of significant ethanol-induced liver injury and to evaluate the possible role of CYP2E1 in ethanol actions in such models. METHODS: We evaluated chronic ethanol-induced liver injury, steatosis and oxidant stress in wild-type (WT) mice, CYP2E1 knockout (KO) mice and in humanized CYP2E1 knockin (KI) mice, where the human 2E1 was added back to mice deficient in the mouse 2E1. WT mice and CYP2E1 KO and KI mice (both provided by Dr. F. Gonzalez, NCI) were fed a high-fat Lieber-DeCarli liquid diet for 3 weeks; pair-fed controls received dextrose. RESULTS: Ethanol produced fatty liver and oxidant stress in WT mice, but liver injury (transaminases, histopathology) was minimal. Ethanol-induced steatosis and oxidant stress were blunted in the KO mice (no liver injury) but restored in the KI mice. Significant liver injury was produced in the ethanol-fed KI mice with elevated transaminases and necrosis. This liver injury in the KI mice was associated with elevated oxidant stress and elevated levels of the human CYP2E1 compared to levels of the mouse 2E1 in WT mice. Activation of JNK was observed in the ethanol-fed KI mice compared to the other groups. Fatty liver in WT and KI mice was associated with lower levels of lipolytic PPAR-alpha. No such changes were found in the ethanol-fed KO mice. CONCLUSIONS: These results show that CYP2E1 plays a major role in ethanol-induced fatty liver and oxidant stress. Restoring CYP2E1 in the CYP2E1 KO mice restores ethanol-induced fatty liver and oxidant stress. PMID- 21525768 TI - Beneficial effects of probiotic bifidobacterium and galacto-oligosaccharide in patients with ulcerative colitis: a randomized controlled study. AB - BACKGROUND/AIM: In previous studies, we described the beneficial effects of bifidobacteria-fermented milk in patients with ulcerative colitis (UC). Here, we examined the effects of a live Bifidobacterium breve strain Yakult, a probiotic contained in bifidobacteria-fermented milk, and galacto-oligosaccharide (GOS) as synbiotics in UC patients. METHODS: Forty-one patients with mild to moderate UC were assigned to two groups; one group was treated with the synbiotics and the other was not (control). The treatment group ingested 1 g of the probiotic powder (10(9) CFU/g) three times a day, and 5.5 g of GOS once a day for one year. At the start and the end of this study, colonoscopic index and the amount of myeloperoxidase in a lavage solution were used as disease activity indices. Bacterial counts in the feces at the start and the end of this study were also examined. RESULTS: After a one-year treatment with the synbiotics, the clinical status of the UC patients as assessed by colonoscopy, significantly improved. Furthermore, the amount of myeloperoxidase in the lavage also decreased in these patients after the synbiotic treatment. The synbiotics significantly reduced the fecal counts of Bacteroidaceae and fecal pH. CONCLUSION: Administration of live B. breve strain Yakult and GOS can improve the clinical condition of patients with UC. These results encouraged us to perform a large-scale randomized, placebo controlled trial. PMID- 21525769 TI - Survival outcome associated with the screening interval for gastric cancer in Korea. AB - BACKGROUND/AIMS: Early gastric cancer (EGC) can be treated by endoscopic resection, which results in an excellent prognosis. Optimal screening intervals considering risk factors for gastric cancer have not been established. The aim of this study was to determine the maximum gastric cancer screening interval in terms of long-term survival. METHODS: Curative resection was performed in 561 patients with gastric cancer who had completed a questionnaire on their previous history of screening tests and risk factors. The association between EGC detection rate and previous screening history was evaluated, and 5-year disease free survival rates were compared between various screening intervals. RESULTS: Multivariate analysis showed that intestinal metaplasia [hazard ratio (HR) 9.690, 95% confidence interval (CI) 5.896-15.927] and previous screening history (HR 0.077, 95% CI 0.048-0.125) were independent factors associated with advanced gastric cancer. In patients without intestinal metaplasia, there was no significant difference in the extent of gastric cancer progression and the 5-year disease-free survival rate between groups with screening intervals of less than 3 years. In patients with intestinal metaplasia, the cutoff screening interval for detection of EGC and disease-free survival was 2 years. CONCLUSION: The optimum screening interval for disease-free survival for gastric cancer in a normal population is 3 years, but a screening interval of 2 years should be used for patients with intestinal metaplasia in Korea. PMID- 21525770 TI - Carotid intima-media thickness is increased not only in non-alcoholic fatty liver disease patients but also in alcoholic fatty liver patients. AB - BACKGROUND/AIMS: There are many reports of non-alcoholic fatty liver disease (NAFLD) patients with increased carotid intima-media thickness (IMT). However, there is little information about carotid IMT in alcoholic fatty liver disease (AFLD) patients. We aimed to compare the carotid IMT of NAFLD patients and AFLD patients. METHODS: The medical records of individuals who underwent carotid IMT measurement and abdominal ultrasonography between January 2006 and December 2008 at Korea University Ansan Hospital were retrospectively reviewed. The patients were divided into group A (no fatty liver without alcohol history), group B (NAFLD), group C (AFLD) and group D (no fatty liver with alcohol history). The carotid IMT results were compared across all groups. RESULTS: The mean carotid IMT was 0.55 +/- 0.1 mm for group A, 0.6 +/- 0.1 mm for group B, 0.59 +/- 0.1 mm for group C, and 0.54 +/- 0.1 mm for group D. There were significant differences between groups A and B, groups A and C, and groups C and D (p < 0.05), but there were no differences between groups B and C (p = 0.736). CONCLUSIONS: We determined that patients with fatty livers have an increased carotid IMT both in NAFLD and AFLD patients. PMID- 21525771 TI - Different ischemic preconditioning regimens affecting preservation injury of intestines. AB - Decreasing ischemia-reperfusion injury in intestinal transplantation is of paramount importance for improving graft recovery and function. This study explores the ability of two ischemic preconditioning (IPC) regimens to reduce preservation injury. Sprague-Dawley rats were divided into 3 groups (n = 11 each). In the controls (group C), intestinal grafts were harvested and preserved. IPC was performed either through 4 cycles of mesenteric ischemia of 4 min each followed by 10 min of reperfusion (group BIPC) or 2 ischemic cycles of 12 min each followed by 10 min of reperfusion (group LIPC). Grafts were stored in histidine-tryptophan-ketoglutarate, and samples were taken 0, 3, 6, 9, 12, 18, and 24 h after preservation. Preservation injury was scored using the Park/Chiu scale. Goblet cells (GC), enteroendocrine cells (EEC) and serotonin-producing EEC (SPEEC) were studied for evaluation of the graft conditions. Group C had the most advanced preservation injury followed by group BIPC. GC count was lowest in group C, followed by BIPC. Comparison between groups BIPC and LIPC showed superior parameters (preservation injury, GC, EEC, and SPEEC) in LIPC. In conclusion, an IPC regimen of 2 ischemic cycles of 12 min each followed by 10 min of reperfusion distinctly decreased the preservation injury of intestinal grafts compared with non-manipulated grafts. PMID- 21525772 TI - Neophobia and learning mechanisms: how captive orangutans discover medicinal plants. AB - Great apes sometimes feed on items of low nutritional value with bioactive secondary compounds. These molecules may be toxic and neophobia is presumed to be an essential factor in avoiding the ingestion of noxious items. The aim of this study is to investigate, in captive orangutans, individual and social learning involved in the discovery and ingestion of new items. We presented novel aromatic plants - 11 fresh plants and 4 infused plants - to 4 captive weaned Bornean orangutans, both under isolated and group conditions, and recorded their behaviour and interactions between group members. All animals tasted by nibbling or ingested most of the plants presented. Regardless of the experimental condition, individual responses did not vary visibly across the sessions, despite numerous close observations, and food transfers between individuals were observed. Our results suggest that a low level of neophobia and a strong propensity to look to conspecifics for information allow Bornean orangutans to expand their diet after weaning. Our results also provide some evidence that olfaction is a key sense in determining food edibility based on previous experience. PMID- 21525773 TI - Skeletal muscle gene expression profile is modified by dietary protein source and calcium during energy restriction. AB - BACKGROUND/AIMS: The potential of whey protein and calcium to modify skeletal muscle gene expression during energy restriction (ER) was investigated in a model of diet-induced obesity. METHODS: Obese C57BL/6J mice received casein (calcium 0.4%) and two different high-calcium (1.8%) whey protein-based [whey protein isolate (WPI)+Ca and alpha-lactalbumin+Ca] diets for ER. RESULTS: Compared to casein, WPI and alpha-lactalbumin-based diets altered 208 and 287 genes, respectively, of which 186 genes were common to WPI and alpha-lactalbumin diets. These genes represented 31 KEGG pathways. The Wnt signaling was the most enriched pathway among the 101 genes regulated by alpha-lactalbumin only, whereas the 22 genes regulated by WPI only were not associated with KEGG pathways. Unlike casein, WPI and alpha-lactalbumin diets decreased Aldh1a7, Fasn, leptin, Nr4a3 and Scd1 mRNA expression, indicating dietary protein source-dependent alterations in muscle lipid and fatty acid metabolism. Muscle weight or lean body mass maintenance did not differ between groups although modest changes in hypertrophy/atrophy signaling were found. CONCLUSION: The skeletal muscle gene expression profile is modified by the dietary protein source and calcium during ER which may explain, at least in part, the greater anti-obesity effect of whey proteins and calcium compared to casein. PMID- 21525774 TI - Prognostic implications of intraoperative radiotherapy for unresectable pancreatic cancer. AB - BACKGROUND/AIMS: To assess the prognostic effect of intraoperative radiotherapy (IORT) in unresectable pancreatic cancer. METHODS: We reviewed 198 patients with unresectable pancreatic cancer, which was found during experimental laparotomy. Liver metastasis was observed in 70 patients, peritoneal metastasis in 44, liver and peritoneal metastasis in 23 and locally advanced tumor in 61. Treatment consisted of IORT with or without postoperative chemotherapy. Overall survival (OS) and prognostic factors were evaluated for each pattern of disease spread. RESULTS: IORT was performed in 120 patients, and chemotherapy was administered in 80. Sixty patients did not receive either treatment. OS in the untreated group was significantly inferior to that for IORT alone and IORT plus gemcitabine (GEM) based chemotherapy. IORT and GEM-based chemotherapy were identified as independent prognostic factors [hazard ratio (HR) = 0.51, p < 0.001; HR = 0.43, p < 0.001]. IORT was an independent prognostic determinant for patients with peritoneal metastasis (HR = 0.24, p = 0.011) but not for those with liver metastasis (HR = 0.78, p = 0.381). CONCLUSION: IORT followed by GEM-based chemotherapy is the recommended treatment strategy in unresectable pancreatic cancer. and IAP. PMID- 21525775 TI - Idiopathic duct-centric pancreatitis: disease description and endoscopic ultrasonography-guided trucut biopsy diagnosis. AB - BACKGROUND/AIMS: Recent data demonstrate the presence of two autoimmune pancreatitis (AIP) subtypes. All existing endoscopic ultrasonography-guided trucut biopsy (EUS-TCB) data pertain to type 1 disease. Our aim is to determine if EUS-TCB samples are sufficient for diagnosing type 2 AIP. METHODS: This is a retrospective case series conducted in an academic tertiary care center. Patients included those with type 2 AIP (n = 5), retrospectively identified from a database of all patients with AIP, diagnosed by HISORt criteria (n = 125). The primary outcome measure was the diagnostic capability of EUS-TCB for type 2 AIP. RESULTS: 5 patients (4 male, 1 female; mean age 39.6 years) who underwent EUS-TCB were diagnosed with type 2 AIP. The serum IgG(4) level was elevated in 1 of the 4 patients tested. CT/MRI revealed diffuse pancreas enlargement (n = 3), a pancreas head mass (n = 1), and a normal pancreas (n = 1). Prior to EUS, AIP was not specifically suspected, but part of a broad differential (n = 3) or not suspected at all (n = 2). Fine-needle aspiration was negative for neoplasia and AIP. The TCB histology was definitive (n = 4) or suggestive (n = 1) for type 2 AIP. No complications developed. CONCLUSIONS: EUS-TCB may be safe and may provide sufficient material to definitively diagnose type 2 AIP. and IAP. PMID- 21525776 TI - Polyamine catabolism in relation to trypsin activation and apoptosis in experimental acute pancreatitis. AB - BACKGROUND: Overinduced polyamine catabolism (PC) in a transgenic rat model has been suggested to be a mediator of trypsin activation which is important in acinar cell necrosis. PC has also been observed in experimental taurodeoxycholate pancreatitis. We hypothesized that PC may be a mediator of trypsin activation in taurodeoxycholate pancreatitis. METHODS: Pancreatitis was induced in wild-type rats by 2 or 6% taurodeoxycholate infusion or in transgenic rats by overexpressing spermidine/spermine N(1)-acetyltransferase (SSAT). The time courses of necrosis, caspase-3 immunostaining, SSAT, polyamine levels, and trypsinogen activation peptide (TAP) were monitored. The effect of the polyamine analogue bismethylspermine (Me(2)Spm) was investigated. RESULTS: In a transgenic pancreatitis model, TAP and acinar necrosis increased simultaneously after the activation of SSAT, depletion of spermidine, and development of apoptosis. In taurodeoxycholate pancreatitis, necrosis developed along with the accumulation of TAP. SSAT was activated simultaneously or after TAP accumulation and less than in the transgenic model, with less depletion of spermidine than in the transgenic model. Supplementation with Me(2)Spm ameliorated the extent of acinar necrosis at 24 h, but contrary to previous findings in the transgenic model, in the taurodeoxycholate model it did not affect trypsin activation. Compared with the transgenic model, no extensive apoptosis was found in taurodeoxycholate pancreatitis. CONCLUSIONS: Contrary to transgenic SSAT-overinduced pancreatitis, PC may not be a mediator of trypsin activation in taurodeoxycholate pancreatitis. The beneficial effect of polyamine supplementation on necrosis in taurodeoxycholate pancreatitis may rather be mediated by other mechanisms than amelioration of trypsin activation. and IAP. PMID- 21525777 TI - Differences in base of articulation for consonants among Catalan dialects. AB - Electropalatographic data for several front lingual consonants, i.e., the dental /t/, the alveolars /n, l, s, r/ and the alveolopalatals /t?, ?, y, n/, show differences in constriction anteriority among Catalan dialects varying in the progression Valencian > Eastern, with the Majorcan dialect occupying an intermediate position. These differences do not conform to speaker- dependent differences in palate morphology and, to the extent that they operate on a varied range of consonants, may be attributed to base of articulation. Deviations from this pattern are associated with manner of articulation and symmetry demands. A specific dialect- dependent relationship between tongue dorsum contact and constriction fronting is interpreted assuming the existence of less laminal, more apical dental and alveolar stops, and less dorsal, more laminal alveolopalatals, in Valencian than in the other two dialects. These data are interpreted in terms of the articulatory characteristics for different tongue front settings which have been proposed in the literature. PMID- 21525778 TI - The interdependence of tonal and durational cues in the perception of rhythmic groups. AB - This experiment investigated whether rising fundamental frequency (f0) and increased duration are interdependent perceptual cues to rhythmic groups in speech, and whether this depends on listeners' native language. In a two alternative forced- choice decision task, listeners had to indicate whether they perceived a 3 + 2 or 2 + 3 grouping in 5- syllable- long series of various digits and letters, in which f0 and duration were manipulated in the second and/or third syllable. The listeners were native speakers of Swiss German, Swiss French, or French. These languages differ from each other in terms of prosodic properties involving f0 and duration. The results demonstrate that rising f0 and increased duration are interdependent cues to rhythmic groups, since the two cues were significantly more effective than one when heard simultaneously, but significantly less effective than one when heard in conflicting positions around the rhythmic- group boundary location. Moreover, listeners' native language influenced whether f0 or duration was the more effective cue. These findings are important not only for their insight into the perception of prosodic groups in speech, but also because they have implications for current research on speech rhythm. PMID- 21525779 TI - Language specificity in speech perception: perception of Mandarin tones by native and nonnative listeners. AB - The results reported in this paper indicate that native speakers of Mandarin Chinese rate the perceptual similarities among the lexical tones of Mandarin differently than do native speakers of American English. Mandarin listeners were sensitive to tone contour while English listeners attended to pitch levels. Chinese listeners also rated tones that are neutralized by phonological tone sandhi rules in Mandarin as more similar to each other than did English speakers- indicating a role of phonology in determining perceptual salience. In two further experiments, we found that some of these differences were eliminated when the listening task focused listeners' attention on the auditory properties of the stimuli, but, interestingly, a degree of language specificity remained even in the most purely psychophysical listening tasks with speech stimuli. PMID- 21525780 TI - Phase II trial of bevacizumab and dose/dense chemotherapy with cisplatin and metronomic daily oral etoposide in advanced non-small-cell-lung cancer patients. AB - Bevacizumab, is a humanized monoclonal antibody to vasculo-endothelial-growth factor, with anticancer activity in non-small-cell-lung cancer (NSCLC) patients. Our previous results from a dose/finding phase I trial in NSCLC patients, demonstrated the anti-angiogenic effects and toxicity of a newest bevacizumab based combination with fractioned cisplatin and daily oral etoposide. We designed a phase II trial to evaluate in advanced NSCLC patients the antitumor activity and the safety of this novel regimen. In particular, 45 patients (36 males and 9 females), with a mean age of 54 years, an ECOG <= 2, stage IIIB/IV and NSCLC (28 adenocarcinomas, 11 squamous-cell carcinomas, 2 large-cell carcinomas, 4 undifferentiated carcinomas), were enrolled. They received cisplatin (30 mg/sqm, days 1-3), oral etoposide (50 mg, days 1-15) and bevacizumab (5 mg/kg, day 3) every three weeks (mPEBev regimen). Patients who achieved an objective response or stable disease received maintenance treatment with bevacizumab in combination with erlotinib until progression. Grade I-II hematological, mucosal toxicity and alopecia were the most common adverse events. The occurrence of infections (17%), thromboembolic events (4.4%) and severe mood depression (6.7%) was also recorded. A partial response was achieved in 31 (68.8%) patients, disease remained stable in 8 (17.8%), and disease progressed in 6 (13.3%) with a progression-free survival of 9.53 months (95%CI, 7.7-11.46). Our bio-chemotherapy regimen resulted very active in advanced NSCLC, however, the toxicity associated with the treatment requires strict selection of the patients to enroll in future studies. PMID- 21525781 TI - Chemoresponse assay for evaluating response to sunitinib in primary cultures of breast cancer. AB - PURPOSE: Not all patient tumors respond equally to the same type of therapy. An in vitro chemoresponse assay that can suggest individualized tumor response to therapies, in this case sunitinib, can be a valuable guide for clinical decision making. RESULTS: The assay was shown to be sensitive and reproducible while differentiating renal cell lines based on sunitinib sensitivity and evaluating vendors' supply of the compound. Of the cultured breast cancer tumor specimens treated with sunitinib, ChemoFx classified 7.6% as responsive (R), 20.5% of specimens as intermediate responsive (IR), and 71.7% as non-responsive (NR). EXPERIMENTAL DESIGN: The ChemoFx((r)) drug response marker (DRM) (Precision Therapeutics, Inc.) was carried out on SK-OV-3 cells treated with sunitinib to establish appropriate dose ranges and assay thresholds, and to evaluate vendor supplies of sunitinib. Once reference values were determined, the assay was applied to eight different renal cell lines treated with sunitinib, each of which was subsequently classified into responsive, intermediate responsive, and non responsive groups. Next, ex vivo tumor samples from 39 clinically diagnosed breast cancer patients were grown in culture and assayed for their response to sunitinib using ChemoFx. CONCLUSIONS: Chemoresponse assay assessment is an effective tool for evaluating sunitinib sensitivity in cultured cell lines as well as ex vivo breast cancer samples. An in vitro assay that may indicate an individual patient's clinical response to a chemotherapeutic agent can be beneficial in time, cost, and clinical outcome when therapeutic options are considered. PMID- 21525783 TI - Long non-coding RNA-mediated mechanisms independent of the RNAi pathway in animals and plants. AB - Recent advances in the field of RNA research have provided compelling evidence implicating long non-coding RNA molecules in many diverse and substantial biological processes that include transcriptional and post-transcriptional regulation of gene expression, genomic imprinting, modulation of protein activity and subcellular localization and cellular structural maintenance. While long non coding RNAs have been most extensively studied in animal species, studies of long non-coding RNA in plants begin to emerge showing some conservation of mechanisms. This review aims to provide an overview of significant and recently identified long non-coding RNA-mediated mechanisms in both animal and plant species. PMID- 21525782 TI - Troglitazone suppresses c-Myc levels in human prostate cancer cells via a PPARgamma-independent mechanism. AB - Troglitazone is a ligand for the peroxisome proliferator activated receptor gamma (PPARgamma) that decreases growth of human prostate cancer cells in vitro and in vivo. However, the mechanism by which troglitazone reduces prostate cancer cell growth is not fully understood. To understand the signaling pathways involved in troglitazone-induced decreases in prostate cancer growth, we examined the effect of troglitazone on androgen-independent C4-2 human prostate cancer cells. Initial experiments revealed troglitazone inhibited C4-2 cell proliferation by arresting cells in the G(0)/G(1) phase of the cell cycle and inducing apoptosis. Since the proto-oncogene product c-Myc regulates both apoptosis and cell cycle progression, we next examined whether troglitazone altered expression of c-Myc. Troglitazone decreased c-Myc protein levels as well as expression of downstream targets of c Myc in a dose-dependent manner. In C4-2 cells, troglitazone-induced decreases in c-Myc protein involve proteasome-mediated degradation of c-Myc protein as well as reductions in c-Myc mRNA levels. It appears that troglitazone stimulates degradation of c-Myc by increasing c-Myc phosphorylation, for the level of phosphorylated c-Myc was elevated in prostate cancer cells exposed to troglitazone. While troglitazone dramatically decreased the amount of c-Myc within C4-2 cells, the PPARgamma ligands ciglitazone, rosiglitazone and pioglitazone did not reduce c-Myc protein levels. Furthermore the down-regulation of c-Myc by troglitazone was not blocked by the PPARgamma antagonist GW9662 and siRNA-mediated decreases in PPARgamma protein. Thus, our data suggest that troglitazone reduces c-Myc protein independently of PPARgamma. PMID- 21525784 TI - MicroRNA reins in embryonic and cancer stem cells. AB - MicroRNAs represents a new layer of gene regulation in stem cells by controlling the molecular mechanisms involved in modulating stem cell fate and behavior. Such a role of microRNA is seen in embryonic stem cell as well, maintaining a delicate balance between survival, proliferation, and self-renewal signals. Further, dysregulation of stem cell self-renewal is a likely requirement for the initiation and formation of cancer stem cells that probably pose resistance to current cancer treatments. In fact, the precise mechanism that regulates embryonic as well as cancer stem cell self-renewal and pluripotency remains largely unknown. Understanding the miRNA related stem cell biology and pathways offers great promise for improving stem cell mediated regenerative therapy as well as cancer therapies. Here we summarize some of the emerging evidences demonstrating the role of these molecular switches in embryonic and cancer stem cells. PMID- 21525786 TI - Genome-wide discovery and analysis of microRNAs and other small RNAs from rice embryogenic callus. AB - Small RNAs constitute a new and unanticipated layer of gene regulation present in the three domains of life. In plants, all organs are ultimately derived from a few pluripotent stem cells localized in specialized structures called apical meristems. The development of meristems involves a coordinated balance between undifferentiated growth and differentiation, a phenomenon requiring a tight regulation of gene expression. We used in vitro cultured embryogenic calli as a model to investigate the roles of meristem-associated small RNAs. Using high throughput sequencing, we sequenced 20 million short reads with size of 18-30 nt from rice undifferentiated and differentiated calli. We confirmed 50 known microRNA families, representing one third of annotated rice microRNAs. Using a specific computational pipeline for plant microRNA identification, we identified 24 novel microRNA families. Among them, 53 microRNA or microRNA* sequences appear to vary in expression between differentiated and undifferentiated calli, suggesting a role in meristem development. Our analysis also revealed a new class of plant small RNAs derived from 5' or 3' ends of mature tRNA analogous to the tRFs in human cancer cell. We independently verified the expression of these small RNAs from 5' end of mature tRNA using qRT-PCR. PMID- 21525787 TI - Morphogen gradient formation and action: insights from studying Bicoid protein degradation. AB - In a recent publication, we identified a novel F-box protein, encoded by fates shifted (fsd), that plays a role in targeting Bcd for ubiquitination and degradation. Our analysis of mutant Drosophila embryos suggests that Bcd protein degradation is important for proper gradient formation and developmental fate specification. Here we describe further experiments that lead to an estimate of Bcd half-life, < 15 min, in embryos during the time of gradient formation. We use our findings to evaluate different models of Bcd gradient formation. With this new estimate, we simulate the Bcd gradient formation process in our own biologically realistic 2-D model. Finally, we discuss the role of Bcd-encoded positional information in controlling the positioning and precision of developmental decisions. PMID- 21525788 TI - The insulin-like growth factor binding proteins 3 and 7 are associated with colorectal cancer and liver metastasis. AB - Over the last few decades, a great deal of attention has been directed to the IGF system for its vital role in regulating cell and tissue survival, growth and differentiation. The insulin-like growth factor binding proteins (IGFBPs), a main constituent of this system, have been implicated in the tumorigenesis of colorectal cancer (CRC). In this study, we intended to shed more light on two essential members; IGFBP3 as representative for the six main IGFBPs and IGFBP7 to represent their related proteins (IGFBP-rps). Our experiments on silencing IGFBP3 or IGFBP7 in the two human CRC cell lines SW480, Caco2, and in the rat CRC cell line CC531 show reduced proliferation, colony formation, and for IGFBP3, also reduced migration. The expression of both genes in 68 human CRC samples was higher in UICC stages II and III than in stages I and IV. Additionally, IGFBP3 was negatively correlated with age (p = 0.05) and positively related to IGFBP7 expression (p = 0.0001). Further, in a liver metastasis experiment, the expression of both genes was drastically increased in response to early metastatic growth in vivo. Since these high levels returned gradually to normal thereafter, it could be assumed that the up-regulation of IGFBPs is vital during the process of homing into the liver and early metastatic dissemination. Our results indicate that IGFBP3 and 7 cannot be simply considered as tumor suppressors but have additional properties, which become evident only during cancer progression and metastasis formation. PMID- 21525785 TI - Potential in vivo roles of nucleic acid triple-helices. AB - The ability of double-stranded DNA to form a triple-helical structure by hydrogen bonding with a third strand is well established, but the biological functions of these structures remain largely unknown. There is considerable albeit circumstantial evidence for the existence of nucleic triplexes in vivo and their potential participation in a variety of biological processes including chromatin organization, DNA repair, transcriptional regulation, and RNA processing has been investigated in a number of studies to date. There is also a range of possible mechanisms to regulate triplex formation through differential expression of triplex-forming RNAs, alteration of chromatin accessibility, sequence unwinding and nucleotide modifications. With the advent of next generation sequencing technology combined with targeted approaches to isolate triplexes, it is now possible to survey triplex formation with respect to their genomic context, abundance and dynamical changes during differentiation and development, which may open up new vistas in understanding genome biology and gene regulation. PMID- 21525789 TI - Bacteria-induced sexual isolation in Drosophila. AB - Commensal bacteria can induce sexual isolation between populations of Drosophila. This phenomenon has implications for speciation, and raises questions about its behavioral and developmental mechanisms, which are not yet known. In this Extra View, we discuss related work by others, bearing directly on these issues, and we speculate about how bacteria might influence fly behavior. There are many reports of interaction between Drosophila and their microbiota that significantly impacts mating preferences. Sexual isolation can be enhanced or reduced by altering the culture media, or the microbiota inhabiting those media. More dramatically, the endoparasite Wolbachia has induced strong mate preferences in some instances. While a sudden, ecologically induced shift in mating preferences falls far short of the changes required for speciation, it might be a first step in that direction. We hypothesize that bacteria-induced sexual isolation is caused by chemosensory cues. In our experiments, bacteria altered the profile of cuticular hydrocarbons, which function as sex pheromones. Commensal bacteria may act directly on these hydrocarbons, or they may affect their synthesis. Alternatively, bacterial metabolites might perfume the flies in ways that affect mate choice. In that event, habituation or conditioning likely plays a role. PMID- 21525790 TI - L-type calcium channel beta subunit modulates angiotensin II responses in cardiomyocytes. AB - Angiotensin II regulation of L-type calcium currents in cardiac muscle is controversial and the underlying signaling events are not completely understood. Moreover, the possible role of auxiliary subunit composition of the channels in Angiotensin II modulation of L-type calcium channels has not yet been explored. In this work we study the role of Ca(v)beta subunits and the intracellular signaling responsible for L-type calcium current modulation by Angiotensin II. In cardiomyocytes, Angiotensin II exposure induces rapid inhibition of L-type current with a magnitude that is correlated with the rate of current inactivation. Semi-quantitative PCR of cardiomyocytes at different days of culture reveals changes in the Ca(v)beta subunits expression pattern that are correlated with the rate of current inactivation and with Angiotensin II effect. Over-expression of individual b subunits in heterologous systems reveals that the magnitude of Angiotensin II inhibition is dependent on the Ca(v)beta subunit isoform, with Ca(v)beta(1b) containing channels being more strongly regulated. Ca(v)beta(2a) containing channels were insensitive to modulation and this effect was partially due to the N-terminal palmitoylation sites of this subunit. Moreover, PLC or diacylglycerol lipase inhibition prevents the Angiotensin II effect on L-type calcium channels, while PKC inhibition with chelerythrine does not, suggesting a role of arachidonic acid in this process. Finally, we show that in intact cardiomyocytes the magnitude of calcium transients on spontaneous beating cells is modulated by Angiotensin II in a Ca(v)beta subunit-dependent manner. These data demonstrate that Ca(v)beta subunits alter the magnitude of inhibition of L-type current by Angiotensin II. PMID- 21525791 TI - TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status. AB - A key player in prostate cancer development and progression is the androgen receptor (AR). Tumor-associated lipogenesis can protect cancer cells from carcinogenic- and therapeutic-associated treatments. Increased synthesis of fatty acids and cholesterol is regulated by androgens through induction of several genes in androgen-responsive cancer cells. Acetyl-CoA-carboxylase-alpha (ACCA) is a key enzyme in the regulation of fatty acids synthesis. Here we show that AR binds in vivo to intron regions of human ACCA gene. We also show that the level of ACCA protein in LNCaP depends on AR expression and that DHT treatment increases ACCA expression and fatty acid synthesis. Inhibition of ACCA by TOFA (5 tetradecyl-oxy-2-furoic acid) decreases fatty acid synthesis and induces caspase activation and cell death in most PCa cell lines. Our data suggest that TOFA can kill cells via the mitochondrial pathway since we found cytochrome c release after TOFA treatment in androgen sensitive cell lines. The results also imply that the pro-apoptotic effect of TOFA may be mediated via a decrease of neuropilin-1(NRP1) and Mcl-1expression. We have previously reported that Mcl-1 is under AR regulation and plays an important role in resistance to drug-induced apoptosis in prostate cancer cells, and NRP1 is known to regulate Mcl-1 expression. Here, we show for the first time that NRP1 expression is under AR control. Taken together, our data suggest that TOFA is a potent cell death inducing agent in prostate cancer cells. PMID- 21525792 TI - Evaluation of academic scientists' responses to situations that pose a conflict of interest. AB - The industry-academy relationship has many benefits, but it also has potential drawbacks, including potential conflicts of interest (e.g., when the profit motives of a private company unduly influence academic responsibilities). To date, policies intended to regulate or manage financial conflicts of interest appear to be unsatisfying and inadequate. The present study examined predictors of the responses of academic scientists and clinicians to hypothetical situations in which financial and other conflicts of interest may arise. Academic scientists and clinicians at five medical schools completed an anonymous survey that included vignettes that posed a potential conflict of interest. Participants indicated the likelihood that they would engage in specific actions to avoid conflicts of interest. Findings indicated that junior faculty and those whose departments received more federal grant money were more likely to respond in ways that could create conflicts of interest (ps < .05). These results suggest that various sub-groups of faculty may require different approaches to appropriately avoid or manage financial conflicts of interest. These findings may contribute to the development of new policies that deal more effectively with conflicts of interest. PMID- 21525793 TI - Effect of lectins from Diocleinae subtribe against oral Streptococci. AB - Surface colonization is an essential step in biofilm development. The ability of oral pathogens to adhere to tooth surfaces is directly linked with the presence of specific molecules at the bacterial surface that can interact with enamel acquired pellicle ligands. In light of this, the aim of this study was to verify inhibitory and antibiofilm action of lectins from the Diocleinaesubtribe against Streptococcus mutans and Streptococcus oralis. The inhibitory action against planctonic cells was assessed using lectins from Canavaliaensi formis (ConA), Canavalia brasiliensis (ConBr), Canavalia maritima (ConM), Canavalia gladiata (CGL) and Canavalia boliviana (ConBol). ConBol, ConBr and ConM showed inhibitory activity on S. mutans growth. All lectins, except ConA, stimulated significantly the growth of S. oralis. To evaluate the effect on biofilm formation, clarified saliva was added to 96-well, flat-bottomed polystyrene plates, followed by the addition of solutions containing 100 or 200 ug/mL of the selected lectins. ConBol, ConM and ConA inhibited the S. mutans biofilms. No effects were found on S. oralis biofilms. Structure/function analysis were carried out using bioinformatics tools. The aperture and deepness of the CRD (Carbohydrate Recognition Domain) permit us to distinguish the two groups of Canavalia lectins in accordance to their actions against S. mutans and S. oralis. The results found provide a basis for encouraging the use of plant lectins as biotechnological tools in ecological control and prevention of caries disease. PMID- 21525794 TI - The contribution of Elaine Ron PhD to radiation epidemiology. PMID- 21525795 TI - Congenital syndromes of severe insulin resistance. AB - Rare syndromes of severe insulin resistance (IR), caused by genetic defects in canonical insulin signalling or adipose tissue development, place patients at high, early risk of adverse clinical complications but are clinically challenging to manage. Prompt evaluation and diagnosis of these individuals not only facilitates more appropriate intervention but, together with identification of the underlying genetic defects, may provide valuable mechanistic insights into the pathogenesis of rare as well as common, obesity-associated IR. Although diagnosis of these syndromes is complicated by the variability of their natural history, several presenting features are common to all severe IR syndromes including disturbed glucose metabolism (either hypoglycaemia or hyperglycaemia), acanthosis nigricans and severe ovarian dysfunction in lean individuals. These features may be evident at birth, or appear during childhood or adolescence, so their recognition by paediatricians is essential. Here we review the general and specific features of syndromes of severe IR, summarise their classification, and recommend strategies for their subsequent investigation. PMID- 21525796 TI - Glucose meter accuracy and the impact on the care of diabetes in childhood and adolescence. AB - Blood glucose testing by point-of-care (POC) meters has become increasingly prevalent, and is an essential tool in diabetes management. But most of those who use the meters or rely upon their results for clinical decision-making are unaware of the significant limitations of these meters at present in both inpatient and outpatient settings. This review discusses the limitations of both strips and meters, in both hospital and outpatient settings, and the special problems when caring for diabetes in children and adolescents. It presents data that support the general concern among the experts that POC glucose meters are often inappropriate in critical care, as well reviewing when these meters are appropriate for use in other settings. The review discusses the problem of "outliers", glucose levels that deviate from the true glucose by a relatively large increment, and how these degrade clinical decision-making. Lastly, evidence based recommendations are provided for changes that are needed to improve the present situation. PMID- 21525797 TI - Effects of unintentional exposure of children to compounded transdermal sex hormone therapy. AB - Gynecomastia and rapid growth progressed in twin brothers and pubic hair in one, over a period of 2 years. A combination of contra- and isosexual development was induced by transdermal exposure to compounded estradiol, estrone, and testosterone creams applied to their mother's body as part of a hormone replacement regimen. PMID- 21525798 TI - Disorders of sex development-when and how to tell the patient. AB - Physicians and other providers are often confronted with difficult decisions in the area of disclosure. This article examines a hypothetical situation relevant to the practice of pediatric endocrinology. The parents of a child with a disorder of sex development (DSD) wish the physician to treat their child, but without revealing key medical information to the child. Herein, we will explore the legal and ethical responsibilities of a provider to disclose information to an under-age DSD patient and to provide insight on when and how to tell the patient. PMID- 21525799 TI - Impaired osmoregulation in anorexia nervosa: review of the literature. AB - BACKGROUND: Anorexia nervosa (AN) is a serious eating disorder associated with numerous medical complications, including alterations in water balance and impaired osmoregulation. OBJECTIVE: The aim of this paper is to review the evidence-based literature and discuss the potential pathophysiological mechanisms of impaired osmoregulation observed in patients with AN. MAIN DATA: Although limited, the evidence suggests that the pathophysiological mechanisms causing impaired osmoregulation in AN is multifactorial and includes abnormalities in osmoregulation of vasopressin, intrinsic renal defects and the influence of antidepressants often used in the treatment of patients with AN. Physicians treating patients with AN should be aware of this complication and the possible multifactorial etiology contributing to this medical complication. PMID- 21525800 TI - Experimental study of the mechanism of tolerance induction in dexamethasone treated dendritic cells. AB - BACKGROUND: The aim of this study was to investigate the mechanisms underlying tolerance induction of dexamethasone (Dex)-treated dendritic cells (DCs). MATERIAL/METHODS: Well-grown DC2.4 cells were randomly assigned to receive control, 50 ug/L, 100 ug/L, or 200 ug/L of dexamethasone and then were cultured for 6 days. The expressions of CD80, CD86, galectin-9, and PD-L1 on the surface of DC2.4 cells were analyzed with flow cytometry and the level of IL-12 secreted by DC2.4 cells was determined by ELISA. The stimulating activity of DC2.4 cells on allogeneic T cells was assessed with mixed lymphocyte reaction. Dexamethasone treated DC2.4 cells were co-cultured with allogeneic splenic lymphocytes and the Foxp3 expression in naive T lymphocytes was determined with flow cytometry. RESULTS: Compared with the control group, the expressions of CD80, CD86, galectin 9, and PD-L1 on the surface of DC2.4 cells exposed to different doses of dexamethasone showed no significant changes; however, dexamethasone treatment significantly reduced IL-12 secretion and inhibited DC2.4's stimulation on the proliferation of allogeneic T lymphocytes. Moreover, dexamethasone-treated DC2.4 cells effectively promoted FOXP3 expression in naive T lymphocytes. CONCLUSIONS: DC2.4 is a stable cell line with high expressions of CD80, CD86, and PD-L1. Dexamethasone does not significantly change the cell phenotype of DC2.4 cells, but inhibits the secretion of IL-12 cytokine and attenuates DC2.4's stimulation of the proliferation of allogeneic T cells. Dexamethasone-treated DC2.4 cells also effectively promote FOXP3 expression in naive T lymphocytes. PMID- 21525801 TI - Th17 response is augmented in OVA-induced asthmatic mice exposed to HDM. AB - BACKGROUND: It is widely accepted that T helper 2 (Th2) cells, Th17 cells and their cytokines orchestrate the feature of asthma. However, most of studies on asthma mechanisms use a single allergen challenge model. Actually, humans are concurrently exposed to various allergens, and the mechanism of asthma with complex allergen exposure is less well defined. To explore whether the mechanism would be altered if asthma patients are re-exposed to another allergen, we exposed the chicken egg albumin (OVA) induced-asthmatic mice to house dust mite (HDM). MATERIAL/METHODS: HE staining was used to analyze pathologic variation in lung tissue of mice in each sub-group: control group, HDM alone group, OVA alone group and OVA+HDM group. Th1, Th2 and Th17 associated gene mRNA expressions were detected by quantitative PCR; associated cytokines were determined by ELISA or immunohistochemistry. RESULTS: The severe of inflammatory cell infiltration, the augmentation of Th17 and Th2 related gene mRNA expressions and the increase of Th17 associated cytokines expression were shown in OVA+HDM group in comparison with OVA alone group. However, Th2 related cytokines were increased with no significant difference in OVA+HDM group compared with OVA alone group. CONCLUSIONS: We have found that Th17 response is connected with inflammation in the OVA-induced asthmatic mice exposed to HDM. When OVA-induced asthmatic mice are re-exposed to HDM, the pathomechanism is different from OVA alone exposure. HDM, indoor allergen, may be an important interferential factor for asthma therapy. It will give an important direction in the development of future asthma therapy. PMID- 21525803 TI - Phenotypic detection of broad-spectrum beta-lactamases in microbiological practice. AB - BACKGROUND: Enterobacteriaceae producing ESBL and AmpC enzymes can be associated with failure of antibiotic therapy and related morbidity and mortality. Their routine detection in microbiology laboratories is still a problem. The aim of this study was to compare the sensitivity of selected phenotypic methods. MATERIAL/METHODS: A total of 106 strains of the Enterobacteriaceae family were tested, in which molecular biology methods confirmed the presence of genes encoding ESBL or AmpC. In ESBL-positive strains, the sensitivity of the ESBL Etest (AB Biodisk) and a modified double-disk synergy test (DDST) were evaluated. AmpC strains were tested by a modified AmpC disk method using 3 aminophenylboronic acid. For simultaneous detection of ESBL and AmpC, the microdilution method with a modified set of antimicrobial agents was used. RESULTS: The sensitivity of the ESBL Etest was 95%; the modified DDST yielded 100% sensitivity for ESBL producers and the AmpC test correctly detected 95% of AmpC-positive strains. The sensitivity of the modified microdilution method was 87% and 95% for ESBL and AmpC beta lactamases, respectively. CONCLUSIONS: The detection of ESBL and AmpC beta lactamases should be based on specific phenotypic methods such as the modified DDST, ESBL Etest, AmpC disk test and the modified microdilution method. PMID- 21525802 TI - The inhibitory effect of Zingiber corallinum Hance essential oil on drug resistant bacteria and evaluation of its acute toxicity. AB - BACKGROUND: The excessive and irregular use of antibiotics could result in the generation and diffusion of drug-resistant bacteria. The aim of this study was to investigate the inhibitory effect of Zingiber corallinum Hance essential oil (ZCHO) on drug-resistant bacteria, especially on drug-resistant Acinetobacter baumannii. MATERIAL/METHODS: Susceptibility testing was used to evaluate the effect of ZCHO on growth inhibition of drug-resistant bacteria by paper disk method. Mice orally administered with ZCHO were used to observe acute toxicity and to determine median lethal dose (LD50) of ZCHO. Broth dilution method was used to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ZCHO on drug-resistant Acinetobacter baumannii. RESULTS: ZCHO exhibited an obvious inhibitory effect not only on gram-negative drug resistant bacteria including Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Acinetobacter baumannii, but also on gram-positive drug resistant bacteria including Staphylococcus aureus, Staphylococcus epidermidis and Staphylococcus haemolyticus. The ZCHO containing 79% terpinen-4-ol revealed better bacteriostatic effect than ZCHO with 34% terpinen-4-ol. The LD50 of ZCHO was 1790.427 mg/kg. The MIC and MBC of ZCHO on drug-resistant Acinetobacter baumannii were 1457.81 mg/L. CONCLUSIONS: ZCHO has obvious bacteriostasis and bactericidal effects, especially against drug-resistant Acinetobacter baumannii. Therefore, ZCHO is a promising natural bioactive component with antibacterial effect and satisfactory safety due to its low toxicity. PMID- 21525804 TI - Influence of pretreatment with H2 receptor antagonists on the cure rates of Helicobacter pylori eradication. AB - BACKGROUND: Pretreatment with a proton pump inhibitor (PPI) reportedly decreases the efficacy of Helicobacter pylori (H. pylori) eradication, however, the effect of pretreatment with an H2 receptor antagonist (H2RA) on H. pylori eradication has not yet been studied. We compared the efficacy of eradication regimen (lansoprazole/amoxicillin/clarithromycin) in patients with H. pylori infection with or without H2RA pretreatment. MATERIAL/METHODS: In this retrospective study conducted at three centers, 310 patients with H. pylori infection were treated. The diagnosis of H. pylori infection was made using the rapid urease test, bacterial cultures and histological examination of endoscopic biopsy specimens. The patients were assigned to receive an eradication regimen first or following pretreatment with H2RA. Eradication was assessed using the 13C-urea breath test more than 4 weeks after the completion of therapy. RESULTS: Overall, H. pylori was eradicated in 79.7% of the cases: the eradication rate was 81.6% in the pretreatment group, and 77.6% in the eradication first group (p=0.3799, chi square test). No significant difference in the eradication rate was observed between the two groups. CONCLUSIONS: Pretreatment with H2RA had no significant influence on the efficacy of H. pylori eradication therapy. PMID- 21525805 TI - Identification of cytosolic phosphodiesterases in the erythrocyte: a possible role for PDE5. AB - BACKGROUND: Within erythrocytes (RBCs), cAMP levels are regulated by phosphodiesterases (PDEs). Increases in cAMP and ATP release associated with activation of beta-adrenergic receptors (betaARs) and prostacyclin receptors (IPRs) are regulated by PDEs 2, 4 and PDE 3, respectively. Here we establish the presence of cytosolic PDEs in RBCs and determine a role for PDE5 in regulating levels of cGMP. MATERIAL/METHODS: Purified cytosolic proteins were obtained from isolated human RBCs and western analysis was performed using antibodies against PDEs 3A, 4 and 5. Rabbit RBCs were incubated with dbcGMP, a cGMP analog, to determine the effect of cGMP on cAMP levels. To determine if cGMP affects receptor-mediated increases in cAMP, rabbit RBCs were incubated with dbcGMP prior to addition of isoproterenol (ISO), a betaAR receptor agonist. To demonstrate that endogenous cGMP produces the same effect, rabbit and human RBCs were incubated with SpNONOate (SpNO), a nitric oxide donor, and YC1, a direct activator of soluble guanylyl cyclase (sGC), in the absence and presence of a selective PDE5 inhibitor, zaprinast (ZAP). RESULTS: Western analysis identified PDEs 3A, 4D and 5A. dbcGMP produced a concentration dependent increase in cAMP and ISO-induced increases in cAMP were potentiated by dbcGMP. In addition, incubation with YC1 and SpNO in the presence of ZAP potentiated betaAR-induced increases in cAMP. CONCLUSIONS: PDEs 2, 3A and 5 are present in the cytosol of human RBCs. PDE5 activity in RBCs regulates cGMP levels. Increases in intracellular cGMP augment cAMP levels. These studies suggest a novel role for PDE5 in erythrocytes. PMID- 21525806 TI - Palliative first-line therapy with weekly high-dose 5-fluorouracil and sodium folinic acid as a 24-hour infusion (AIO regimen) combined with weekly irinotecan in patients with metastatic adenocarcinoma of the stomach or esophagogastric junction followed by secondary metastatic resection after downsizing. AB - BACKGROUND: The aim of this retrospective study was to evaluate the efficacy and safety of weekly high-dose 5-fluorouracil (5-FU)/folinic acid (FA) as 24-h infusion (AIO regimen) plus irinotecan in patients with histologically proven metastatic gastroesophageal adenocarcinoma (UICC stage IV). MATERIAL/METHODS: From 08/1999 to 12/2008, 76 registered, previously untreated patients were evaluable. Treatment regimen: irinotecan (80 mg/m2) as 1-h infusion followed by 5 FU (2000 mg/m2) combined with FA (500 mg/m2) as 24-h infusion (d1, 8, 15, 22, 29, 36, qd 57). RESULTS: Median age: 59 years; male/female: 74%/26%; ECOG <=1: 83%; response: CR: 1%, PR: 16%, SD: 61%, PD: 17%, not evaluable in terms of response: 5%; tumor control: 78%; median OS: 11.2 months; median time-to-progression: 5.3 months; 1-year survival rate: 49%; 2-year survival rate: 17%; no evidence of disease: 6.6%; higher grade toxicities (grade 3/4): anemia: 7%, leucopenia: 1%, ascites: 3%, nausea: 3%, infections: 12%, vomiting: 9%, GI bleeding of the primary tumor: 4%, diarrhea: 17%, thromboembolic events: 4%; secondary metastatic resection after downsizing: 16 patients (21%), R-classification of secondary resections: R0/R1/R2: 81%/6%/13%, median survival of the 16 patients with secondary resection: 23.7 months. CONCLUSIONS: Combined 5-FU/FA as 24-h infusion plus irinotecan may be considered as an active palliative first-line treatment accompanied by tolerable toxicity; thus offering an alternative to cisplatin based treatment regimens. Thanks to efficient interdisciplinary teamwork, secondary metastatic resections could be performed in 16 patients. In total, the patients who had undergone secondary resection had a median survival of 23.7 months, whereas the median survival of patients without secondary resection was 10.1 months (p<=0.001). PMID- 21525807 TI - Comprehensive behavioral analysis of patients with a major depressive episode. AB - BACKGROUND: A major depressive episode diagnosed according to DSM-IV criteria can be accompanied by symptoms that DSM-IV does not include. These symptoms are sometimes classified as comorbidities. Our study assessed altered behavioral modes during a major depressive episode; ie, if 1 or more modes of behavior operated less or even not at all ("never"), or if the operation of others was more frequent or even constant ("always"). We hypothesize that these altered behavioral modes, especially the extreme positions "never" (hypomodes) and "always" (hypermodes) might correlate with depression scores and thus represent a typical symptom of depression. MATERIAL/METHODS: We used the 35-item Salzburg Subjective Behavioral Analysis (SSBA) questionnaire to measure altered behavioral modes in 63 depressed patients and 87 non-depressed controls. Depression was assessed using the Hamilton Depression Scale. RESULTS: In our test group (n=63) we found a total of 888 extreme positions. The mean number of extreme positions per patient was 11.15+/-5.173 (SD). Extreme positions were found in all 35 behavioral modes. The mean Hamilton score was 22.08+/-7.35 (SD). The association of the incidence of extreme positions and the Hamilton score in our test group was highly significant (Spearman's Rho=0.41; p=.001). In the control group (n=87), only 11 persons were found to display extreme positions, with a total of only 25. CONCLUSIONS: Although this study has several limitations, such as the small sample or the use of a questionnaire in the validation procedure, the significant correlation of extreme positions and the Hamilton score indicate that altered modes of behavior as detected with the SSBA might be typical symptoms in a major depressive episode. PMID- 21525808 TI - Impaired fetal adrenal function in intrahepatic cholestasis of pregnancy. AB - BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease of unknown etiology. The aim of this study was to investigate the change in maternal and fetal adrenal function in clinical and experimental ICP. MATERIAL/METHODS: The maternal and fetal serum levels of cortisol and dehydroepiandrosterone sulfate (DHEAS) were determined in 14 women with ICP and in pregnant rats with estrogen-induced intrahepatic cholestasis. RESULTS: In women with ICP, the fetal serum cortisol and DHEAS levels were significantly higher than those in women with normal pregnancy, after correcting the impact of gestational age at delivery. The relationship between fetal cortisol and maternal cholic acid levels was bidirectional; the fetal cortisol tended to increase in mild ICP, while it decreased in severe ICP. In pregnant rats with estrogen induced cholestasis, the fetal cortisol level was significantly lower in the group with oxytocin injection, compared with the group without oxytocin injection (191.92+/-18.86 vs. 272.71+/-31.83 ng/ml, P<0.05). In contrast, the fetal cortisol concentration was increased after oxytocin injection in normal control rats. CONCLUSIONS: The data indicate that fetal stress-responsive system is stimulated in mild ICP, but it is suppressed in severe ICP, which might contribute to the occurrence of unpredictable sudden fetal death. Further studies are warranted to explore the role of impaired fetal adrenal function in the pathogenesis of ICP and the clinical implications. PMID- 21525809 TI - Anxiety, depression and methods of stress coping in patients with nicotine dependence syndrome. AB - BACKGROUND: Nicotinism is the most common addiction in Poland. Nicotine dependence is the cause of numerous behavioral diseases, including ischemic heart disease, neoplasms and chronic obstructive pulmonary disease. A question arises whether a tendency to anxiety and depressive reactions, as well as the strategies of coping with stressful situations, is involved in the clinical presentation of this addiction. MATERIAL/METHODS: The study was conducted in a group of 88 nicotine addicts without serious systemic comorbidities and in 84 healthy subjects. All the participants were assessed with Beck Depression Inventory (BDI), Spielberger State-Trait Anxiety Inventory (STAI) and the Coping Inventory for Stressful Situations (CISS). RESULTS: The mean intensity of anxiety as a trait and anxiety as a state, as well as its level, were found to differ between the groups (Sten 6.28+/-1.52 and 4.86+/-1.05, p=0,0000 for the trait, and 6.09+/ 1.25 and 4.92+/-1.29, p=0.0000, for the state, respectively). Similarly, depression was demonstrated to be more intensive in nicotine addicts than in healthy subjects (12.76 points +/-4.77 vs. 10.76+/-4.83, p=0.007). Among the 5 scales assessed by CISS, smokers demonstrated higher prevalence of emotion oriented coping than controls (standard 9 6.27+/-1.70 in smokers vs. 5.67+/-1.57, p=0.019) and involvement in distracting activities (5.84+/-1.48 vs. 5.28+/-1.46, p=0.014). CONCLUSIONS: The obtained results indicate that anxiety and depression, as well as differences in coping with stress situations, distinguish nicotine addicts from non-smokers. PMID- 21525810 TI - Prognostic value of duration of untreated psychosis in long-term outcome of schizophrenia. AB - BACKGROUND: The goal of this prognostic study was to investigate whether the duration of untreated psychosis (DUP) may have a prognostic value with regard to the further course of the illness. MATERIAL/METHODS: Fifty-eight patients (77% of the original study group) diagnosed with DSM III schizophrenia and later re diagnosed with DSM IV T-R were assessed at 4 time points. Number of relapses, average time of inpatient treatment, number of inpatient readmissions, and severity of psychopathological symptoms were assessed at 1-, 3-, 7- and 12-year follow-ups. DUP information was obtained by clinical interview with patients and their families. The severity of symptoms was assessed using BPRS-SA, UCLA version. RESULTS: Increases in the number of relapses at follow-ups were more prominent in the group with a longer DUP (p<0.001). Decreases in the results of BPRS (symptom improvement) were more prominent in patients with a shorter DUP. The latter had significantly lower results than patients with a long DUP at each assessment except the index hospitalization (p equalled, respectively: 0.449; 0.002; 0.012; 0.034 and 0.014). Decreases in positive symptoms were greater in patients with a short DUP--significant at all except the 7-year follow-up (p equalled respectively: 0.230; <0.001; 0.011; 0.214; <0.001). CONCLUSIONS: 1) A positive correlation was found between DUP and the dynamics of general and positive symptoms and the number of relapses. 2) There was no significant relationship between DUP and the dynamics of negative symptoms, whereas the relationship between the time and number of re-hospitalizations was marginally significant. PMID- 21525811 TI - Inhibition of peripheral blood neutrophil oxidative burst in periodontitis patients with a homeopathic medication Traumeel S. AB - BACKGROUND: The anti-inflammatory effects of a homeopathic remedy, Traumeel S, have been observed in experimental and clinical studies; however, its antioxidant properties have not been elucidated. The aim of the present study was to evaluate the antioxidant effects of Traumeel S on peripheral blood neutrophils in patients with periodontitis. MATERIAL/METHODS: The study was performed using venous blood of 22 individuals with chronic periodontitis and 21 healthy subjects. The antioxidant effects of Traumeel S on the production of reactive oxygen species by unstimulated and stimulated with unopsonized E. coli neutrophils were investigated using luminol- and lucigenin-dependent chemiluminescence (CL). RESULTS: Polymorphonuclear leukocytes of periodontitis patients produced higher levels (p<0.01) of light output of lucigenin-dependent chemiluminescence and significantly reduced (p<0.01) light output of luminol-dependent chemiluminescence than analogous cells of healthy subjects. Highly diluted (10-4 of the stem solution) Traumeel S significantly (by approximately 50%) reduced superoxide-induced oxidation of lucigenin by unstimulated and stimulated with unopsonized E. coli polymorphonuclear leukocytes of periodontitis patients and had a tendency to intensify luminol-dependent chemiluminescence. Preincubation of the unstimulated and stimulated with unopsonized E. coli polymorphonuclear leukocytes of healthy subjects with Traumeel S exerts no inhibitory action on the luminol- and lucigenin-dependent chemiluminescence of the above-mentioned cells. CONCLUSIONS: This study indicates that Traumeel S may significantly reduce production of superoxide anion by unstimulated and stimulated peripheral blood polymorphonuclear neutrophils of periodontitis patients. PMID- 21525812 TI - Pseudo-patella baja after total knee arthroplasty. AB - BACKGROUND: One of the complications of total knee arthroplasty (TKA) which has not yet been directly addressed is pseudo-patella baja (PPB). True patella baja (PB) is present when the length of the patellar tendon becomes shorter. PPB is present when the patella tendon is not shortened, but the level of the joint line is elevated. This study was conducted to assess PPB in TKA. MATERIAL/METHODS: Sixty patients who had had a primary TKA at our center between 1995 and 2005 were included. The average follow-up was 27.5 months. The Knee Society Scoring (KSS), lateral knee x-rays and the Blackburne-Peel index were used for assessments. RESULTS: Out of the 60 patients, 43 (72%) demonstrated no joint line elevation or patellar tendon shortening (group A). Fifteen patients (25%) had joint line elevation (group B), and both PB and PPB were present in 2 (3%) patients (group C). KSS was lower in groups B and C compared with group A, but this difference was not statistically significant. The average range of motion (ROM) in group A was significantly higher compared with either group B or C, and patients in groups B and C showed significantly more severe pain compared with group A (P<0.001). CONCLUSIONS: PPB is not an uncommon finding after TKA and is associated with a statistically significant decrease in ROM and an increase in pain. Furthermore, KSS in the PPB group was less than in patients without PPB, although the difference was not statistically meaningful. PMID- 21525813 TI - Usefulness of 99mTc-ECD brain SPECT with voxel-based analysis in evaluation of perfusion changes early after carotid endarterectomy. AB - BACKGROUND: Association between preoperative perfusion pattern and reperfusion after carotid endarterectomy (CEA) is an important yet unexplored topic. Therefore, the aim of our study was to determine whether 99mTc-ECD single-photon emission computed tomography (SPECT) performed before carotid endarterectomy in patients with internal carotid artery (ICA) stenosis may be helpful in predicting early perfusion changes after revascularization. MATERIAL/METHODS: The examined group consisted of 30 patients (mean age 67.4+/-9.6 years) with ICA stenosis who underwent CEA. Infarction was demonstrated on computed tomography (CT) in 12 cases. Brain perfusion SPECT was performed 1-3 days before CEA and 3-5 days after the surgery. Voxel-based analysis was carried out with Brain SPECT Quantification software. For evaluation of preoperative interhemispheric asymmetry of perfusion, the percentage asymmetry index (AI) was calculated. For comparison of perfusion before and after CEA, the percentage relative difference (RD) was computed. RESULTS: Before CEA, cerebral hypoperfusion was seen in 26 cases, including 15 participants with normal CT. After CEA, the following changes of perfusion were observed: perfusion increase n=18 (ipsilateral and bilateral), deterioration n=1, mixed patterns n=2, no change n=9. In patients with preoperative ipsilateral hypoperfusion and perfusion increase after CEA, AI correlated significantly with RD (r=0.48, p=0.04). CONCLUSIONS: Our results suggest that perfusion increase 3-5 days after CEA is higher in patients with greater ipsilateral asymmetry index. Evaluation of preoperative AI may help to identify patients in whom rapid reperfusion is more likely. PMID- 21525814 TI - Bloodstream infections and mortality-related factors in febrile neutropenic cancer patients. AB - BACKGROUND: We performed a prospective observational cohort study to evaluate the causative bacteria and to identify risk factors for mortality in febrile neutropenic (FN) patients with blood stream infection (BSI). MATERIAL/METHODS: We conducted a prospective data collection on all patients with bacteremia or fungemia. The patients were assigned into low-risk and high-risk groups in accordance with the Multinational Association for Supportive Care in Cancer (MASCC) Risk Index. RESULTS: Throughout the study period, the patients developed 420 FN episodes. Out of 420 episodes, only 90 (21.4%) were found to have bloodstream infection. The mean age of the patients was 45.6+/-18.4 years and 55.6% of the patients were male. A total of 98 isolates were recovered from the cases of BSI. Coagulase-negative Staphylococcus spp (CoNS) were the most common isolates overall (33.7%). There was a significant increase in the rate of gram negative bacteria throughout the study period (p=0.028). Overall mortality was 33%. Multivariate analyses showed that MASCC risk scores (p=0.0001, OR=15.1, CI%95 4.5-50.7), ICU wards (p=0.0002, OR= 8.6, Cl%95 1.101-68,157) and CoNS (p=0.004, OR=12.12, CI%95 2.3-64.7) were independent risk factors associated with mortality. BSI due to CoNS was associated with lower mortality; however, MASCC high risk score and ICU stay were associated with higher mortality. CONCLUSIONS: The MASCC risk-index score and emergence of CoNS in positive blood cultures are valuable tools in the management of FN. PMID- 21525815 TI - Successful operative management of an intact second trimester abdominal pregnancy with additional preoperative selective catheter embolization and postoperative methotrexate therapy. AB - BACKGROUND: Abdominal pregnancy is a rare condition that may lead to severe complications. CASE REPORT: The authors report the case of a 17-week intact abdominal pregnancy diagnosed in the course of an investigation of lower abdominal pain. Ultrasonography and MR examination revealed an intact abdominal pregnancy. Subsequent angiography was performed to occlude the supportive artery of the pregnancy by selective embolization. The pregnancy was terminated safely by laparotomy a day later. The placenta was left in the abdominal cavity because of the high risk of massive and often uncontrollable bleeding, and treatment with methotrexate was applied postoperatively. CONCLUSIONS: Preoperative embolization and the postoperative methotrexate therapy facilitate the safe surgical treatment of abdominal pregnancy. PMID- 21525816 TI - Use of fondaparinux in a pregnant woman with pulmonary embolism and heparin induced thrombocytopenia. AB - BACKGROUND: A serious complication of heparin treatment, heparin-induced thrombocytopenia (HIT) is rarely observed in pregnant women. Drug therapy during pregnancy should always be chosen to minimize fetal risk. The management of HIT in pregnancy represents a medical challenge. Unlike heparins, the anticoagulants used in patients with HIT do cross the placenta, with unknown fetal effects. CASE REPORT: We present a case of a 24-year-old female presenting for care at 34 weeks of gestation with acute pulmonary embolism treated initially with unfractionated heparin (UFH) and low molecular weight heparin (LMWH), who developed HIT. She was then successfully treated with fondaparinux. CONCLUSIONS: To the best of our knowledge, this is one of the first case reports describing a successful use of fondaparinux in the treatment of HIT in a third-trimester pregnant woman, providing a novel approach for this subset of patients. PMID- 21525817 TI - Needle aspiration with surgical excision of an epithelial posttraumatic iris cyst -a case report. AB - BACKGROUND: The aim of this study was to report on epithelial posttraumatic iris cyst that was successfully treated with needle aspiration and surgical excision with surrounding iris tissue. CASE REPORT: A 30-year-old women was treated for a large fluid-filled cyst in the anterior chamber of the left eye; 25 years before, she had an open globe injury. She observed deterioration of her visual acuity 1 year before her visit to our clinic. During ophthalmological examination, an iris cyst was diagnosed. As a result, she had Nd: YAG laser puncture of the cyst in the left eye, performed 5 months before she came to our clinic. After a short time of decompression, the cyst rapidly grew in size (2/3 of the anterior chamber), and her visual acuity was getting worse due to an aggressive growth of the iris cyst. Visual acuity was 0.06. Needle aspiration with surgical excision of the cyst with surrounding iris tissue was performed. Histopathologic examination confirmed an epithelial cyst. At the 1-year follow-up, there was no evidence of recurrence of the iris cyst, and BCVA was 0.2. CONCLUSIONS: This case report provides evidence that needle aspiration with surgical excision of iris cyst seems to be an effective treatment method of this complication. PMID- 21525818 TI - SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. AB - Sirtuins are members of the silent information regulator 2 (Sir2) family, a group of Class III histone/protein deacetylases. There are 7 different sirtuins in mammals (SIRT1-7), of which SIRT1 is the best known and most studied. SIRT1 is responsible for the regulation of protein activation by means of deacetylating a variety of proteins that play important roles in the pathophysiology of metabolic diseases. Recently, it has been shown that SIRT1 plays key roles in the regulation of lipid and glucose homeostasis, control of insulin secretion and sensitivity, antiinflammatory effects, control of oxidative stress and the improvements in endothelial function that result due to increased mitochondrial biogenesis and beta-oxidation capacity. Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease, and it has been accepted as the hepatic component of metabolic syndrome. Recent studies have shown that SIRT expression in the liver is significantly decreased in an NAFLD model of rats fed a high-fat diet, and moderate SIRT1 overexpression protects mice from developing NAFLD. In addition to resveratrol, a natural SIRT1 activator, small-molecule pharmacologic SIRT1 activators have positive effects on metabolic diseases. These effects are particularly promising in the case of diabetes mellitus, for which phase studies are currently being performed. With this information, we hypothesized that the pharmacologic activation of SIRT1, which has been implicated in the pathogenesis of NAFLD, will be a potential therapeutic target for treating NAFLD. In this paper, we review the metabolic effects of SIRT1 and its association with the pathophysiology of NAFLD. PMID- 21525819 TI - Nosocomial infections and risk factors in the intensive care unit of a teaching and research hospital: a prospective cohort study. AB - BACKGROUND: To evaluate the incidence, risk factors and etiology of nosocomial infections (NIs) in the intensive care unit (ICU) of our hospital in order to improve our infection control policies. MATERIAL/METHODS: A 1-year prospective cohort study of nosocomial infection (NI) surveillance was conducted in our ICU in 2008. RESULTS: Out of 1134 patients hospitalized in the ICU for a period of 6257 days, 115 patients acquired a total of 135 NIs distributed as follows: 36.3% bacteremia, 30.4% ventilator-associated pneumonia (VAP), 18.5% catheter associated urinary tract infection, 7.4% central-line infection, 5.9% cutaneous infection, and 1.3% meningitis. The incidence rate of NI was 21.6 in 1000 patient days, and the rate of NI was 25.6%. Length of ICU stay, central venous catheterisation, mechanical ventilation and tracheostomy were statistically significant risk factors for NI. Of all NI, 112 (83%) were microbiologically confirmed and 68.8% of the isolates were Gram-negative, 27.6% were Gram-positive, and 3.6% were fungi. 23 (17%) were clinically-defined infections. The most frequently isolated organism was P. aeruginosa (25%), followed by S. aureus (21.4%), E. coli (18.7%) and A. baumannii (16.9%). CONCLUSIONS: The bloodstream was the most common site and Gram-negatives were the most commonly reported causes of ICU infections. PMID- 21525820 TI - Candidemia in children after complex congenital heart defects surgery treated with caspofungin--our own experience and a review of literature. AB - BACKGROUND: Invasive fungal infections due to Candida species constitute an increasing clinical problem. There are no guidelines for the management of candidemia in children undergoing surgical procedures for congenital heart defects (CHD). The aim of the study was to draw attention to the problem of candidemia in children who are operated on due to congenital heart defects. MATERIAL/METHODS: We retrospectively analyzed medical documentation of 307 children with congenital heart defects treated in 1 clinical centre in Poland, from whom we selected those diagnosed with candidemia during the postoperative period. Next, we analyzed in detail the clinical course of invasive candidiasis in each individual and we performed an analysis of risk factors that lead to candidemia. RESULTS: In the analyzed period, among 307 children who underwent surgical procedures, we observed 2 cases of candidemia (0.65%) which were effectively cured with caspofungin. No adverse effects were observed after treatment with the drug. CONCLUSIONS: Candidemia in children who undergo surgical treatment of congenital heart defects is an important factor that can influence final clinical results. Caspofungin may be an effective therapeutic option when treating candidemia in children after extensive cardiosurgical procedures. PMID- 21525821 TI - Management of temporomandibular ankylosis--compromise or individualization--a literature review. AB - Temporomandibular joint ankylosis is defined as bony or fibrous adhesion of the anatomic joint components accompanied by a limitation in opening the mouth, causing difficulties with mastication, speaking and oral hygiene as well as inadvertently influencing mandibular growth. Surgical treatment procedures include arthroplasty of the joint cavity with or without a reconstruction and a coronoidectomy, an autogenous costochondral rib graft, distraction osteogenesis and intensive mouth-opening exercise, corrective orthognathic surgery or alloplastic joint prostheses. The authors of this study would like to provide the reader with an evidence-based review of the literature in order to determine the most efficient way to manage TMJ ankylosis and re-ankylosis. The authors have concluded that in order to achieve a satisfactory and durable effective treatment, an individualized approach is necessary in each case. PMID- 21525822 TI - Current medical research with the application of coupled techniques with mass spectrometry. AB - The most effective methods of analysis of organic compounds in biological fluids are coupled chromatographic techniques. Capillary gas chromatography/mass spectrometry (GC-MS) allows the most efficient separation, identification and quantification of volatile metabolites in biological fluids. Liquid chromatography-mass spectrometry (LC-MS) is especially suitable for the analysis of non-volatile and/or thermally unstable compounds. A major drawback of liquid chromatography-mass spectrometry is that no standard spectral libraries such as NIST and Wiley for GC-MS are available to facilitate the identification of unknown compounds. Moreover, the identification of potential new compounds, especially new biomarkers in LC-MS, is much more challenging than in GC-MS. Capillary electrophoresis coupled with mass spectrometry (CE-MS) has been widely used to characterize metabolomes. Capillary electrophoresis is a powerful technique for the separation of charged metabolites, offering high analyte resolution. The advantages of CE-MS are applicability for hydrophilic metabolites, robust separation efficiency and short duration of analysis. This review provides an overview of current chromatographic methods--gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry--and their applications in current medical research. The focus is on the description of metabonomics research, strategies for biomarkers identification, medical diagnoses of diseases and research of drugs. PMID- 21525823 TI - Current and future assays for identifying recent HIV infections at the population level. AB - The precise diagnosis of recent human immunodeficiency virus (HIV) infection is crucial for estimating HIV incidence, defined as the number of new infections in a population, per person at risk, during a specified time period. Incidence assessment is considered to be a tool for surveillance, public health and research. Differentiating recent from long-term HIV infections is possible thanks to the evaluation of HIV-specific immune response development or viral markers measurement. Several methods that enable the recognition of recent HIV-1 infection with the use of a single blood specimen have been developed, and their value for use in population level studies has been demonstrated. However, they are still inadequate due to a variable window period and false recent rates among HIV clades and across populations. Application of these assays at an individual level is far more questionable because of person-to-person variability in the antibody response and the course of HIV infection, and because of the prospective regulatory approval requirements. In this article we review the principles and the limitations of the currently available major laboratory techniques that allow detection of recent HIV infection. The assays based on the alteration of serological parameters, as well as the newest method based on an increase of HIV genetic diversity with the progress of infection, are described. PMID- 21525824 TI - Simultaneous treatment of intractable pain and spasticity: observations of combined intrathecal baclofen-morphine therapy over a 10-year clinical experience. AB - AIM: Intrathecal therapy has separate indications for refractory pain and spasticity. Both entities have a relatively high prevalence in neurologic diseases. This study examines the potential efficacy of utilizing additive intrathecal morphine (ITM) therapy to a group of patients who had previously stabilized on intrathecal baclofen (ITB) therapy. METHODS: Pain intensity was assessed via VASPI; 183 individuals participated in ITB therapy from January 1998 to December 2007. Forty-seven individuals elected to add ITM to their intrathecal therapy regimen. Three patients were intolerant to ITM/ITB combination therapy. No significant demographic differences between the two groups existed with respect to gender and race. Non-traumatic and traumatic spinal cord injury patients were more likely to participate in combination therapy compared to other diagnoses. The average stabilized ITB dose for the monotherapy group was not statistically different for the combination therapy group. RESULTS: The average stabilized ITM for the combination therapy group was 1 730 MUg/day (range 27-10 500, SD 2 350). The average decrement in VASPI was 35%. Thirty out of 47 patients experienced a decrease greater than 30% in VASPI while 13 of the 47 patients experienced a decrease greater than 50% in Visual Analogue Scale of Pain Intensity (VASPI). There was no significant relationship between percent improvement in VASPI and morphine dosing. Eight of 47 combination patients experienced adverse events attributable to intrathecal morphine but were capable to utilize the combination therapy for a least one year. CONCLUSION: Reduction is pain intensity with combined therapy was variable. Intrathecal morphine can be a safe and effective adjunct pain therapy to patients utilizing intrathecal baclofen for spasticity. PMID- 21525826 TI - Treatment with daptomycin for Corynebacterium Jeikeium left-sided prosthetic valve endocarditis. AB - Prosthetic valve endocarditis (PVE) is a serious complication with potential fatal consequences, classified as early or late PVE, depending on whether typical symptoms occur within or later than 12 months from surgery. The incidence of early PVE is under 1%, but it carries high morbidity and mortality rates. There are few reported cases in literature of PVE due to Corynebacterium Jeikeium even though it is present in normal skin flora particularly in hospitalized patients. Corynebacterium species are, in fact, recognized as uncommon agents of endocarditis and little is known regarding species-specific risk factors and the outcome in this kind of endocarditis. Described is an unusual case report of a 57 year-old man who had early aortic PVE due to Corynebacterium Jeikeium infection complicated by dehiscence of the prosthesis, complete atrio-ventricular block, perforation of the interventricular septum and septic shock. Prompt diagnosis, choice of daptomycin as antibiotic therapy although it has only been approved by the European Medicine Agency (EMEA) for right-sided endocarditis and timely open heart surgery, resulted in a successful outcome. PMID- 21525827 TI - Managing patients whose family members are physicians. AB - The ethical complexities involving physicians who treat their own family members are well known and it is generally accepted that such practice should not occur. We present three anonymous cases in which patient family members who worked as physicians complicated the medical care of their hospitalized relatives. When a health care worker's family member becomes a hospital patient, the situation can be emotionally charged due to the medical insight the multiple parties have, as well as the desire of relatives to be protective of their family members. Clinician-relatives need to allow the medical team to assume the role of caretaker when their family members are hospitalized. Teams may need to employ limit setting in order to ensure fair and consistent care for all patients on the ward, and to prevent escalation of emotionally charged situations. PMID- 21525829 TI - An unusual cause of delayed awakening following coronary artery surgery. AB - Neurological deficits are a frequent complication of adult cardiac surgery. Dandy Walker malformation (DWM) is a rare posterior fossa malformation defined by hypoplasia and upward rotation of the cerebellar vermis, cystic dilation of the fourth ventricle and, on occasion, hydrocephalus. We report an incidental diagnosis of DWM in an adult following coronary artery surgery complicated by delayed awakening. PMID- 21525832 TI - Successful pre-emptive emergency management of a compromised airway with a ProsealTM Laryngeal Mask Airway followed by tracheostomy. AB - Following hemi-glossectomy and right neck dissection a 63-year-old female patient presented as an emergency with a large neck hematoma. There were significant concerns over difficulty in intubation and mask ventilation leading to deterioration into a cannot intubate cannot ventilate (CICV) situation. After careful discussion and planning with the surgical team, who planned a tracheostomy, the situation was salvaged using a ProSealTM Laryngeal Mask Airway (PLMA). The PLMA enabled rapid establishment of a clear airway early in anesthetic induction, controlled ventilation and safe airway maintenance during a difficult tracheostomy. PMID- 21525834 TI - Cesarean section during ECMO support. AB - This article presents the case of a pregnant woman affected by A/H1N1 flu progressed to ARDS requiring rescue therapy by VV ECMO. Due to the early gestational age, the patient was placed on ECMO before delivery. Four weeks after VV-ECMO placement, a Cesarean section was successfully performed while on ECMO support. One week after delivery, the patient was weaned from ECMO and at 8 weeks from admission she was discharged home without O2 support. The newborn is alive and was discharged at 40 days of age on neurological follow-up. PMID- 21525838 TI - A method for murine islet isolation and subcapsular kidney transplantation. AB - Since the early pioneering work of Ballinger and Reckard demonstrating that transplantation of islets of Langerhans into diabetic rodents could normalize their blood glucose levels, islet transplantation has been proposed to be a potential treatment for type 1 diabetes. More recently, advances in human islet transplantation have further strengthened this view. However, two major limitations prevent islet transplantation from being a widespread clinical reality: (a) the requirement for large numbers of islets per patient, which severely reduces the number of potential recipients, and (b) the need for heavy immunosuppression, which significantly affects the pediatric population of patients due to their vulnerability to long-term immunosuppression. Strategies that can overcome these limitations have the potential to enhance the therapeutic utility of islet transplantation. Islet transplantation under the mouse kidney capsule is a widely accepted model to investigate various strategies to improve islet transplantation. This experiment requires the isolation of high quality islets and implantation of islets to the diabetic recipients. Both procedures require surgical steps that can be better demonstrated by video than by text. Here, we document the detailed steps for these procedures by both video and written protocol. We also briefly discuss different transplantation models: syngeneic, allogeneic, syngeneic autoimmune, and allogeneic autoimmune. PMID- 21525839 TI - Studying the neural basis of adaptive locomotor behavior in insects. AB - Studying the neural basis of walking behavior, one often faces the problem that it is hard to separate the neuronally produced stepping output from those leg movements that result from passive forces and interactions with other legs through the common contact with the substrate. If we want to understand, which part of a given movement is produced by nervous system motor output, kinematic analysis of stepping movements, therefore, needs to be complemented with electrophysiological recordings of motor activity. The recording of neuronal or muscular activity in a behaving animal is often limited by the electrophysiological equipment which can constrain the animal in its ability to move with as many degrees of freedom as possible. This can either be avoided by using implantable electrodes and then having the animal move on a long tether (i.e. Clarac et al., 1987; Duch & Pfluger, 1995; Bohm et al., 1997; Gruhn & Rathmayer, 2002) or by transmitting the data using telemetric devices (Kutsch et al, 1993; Fischer et al., 1996; Tsuchida et al. 2004; Hama et al., 2007; Wang et al., 2008). Both of these elegant methods, which are successfully used in larger arthropods, often prove difficult to apply in smaller walking insects which either easily get entangled in the long tether or are hindered by the weight of the telemetric device and its batteries. In addition, in all these cases, it is still impossible to distinguish between the purely neuronal basis of locomotion and the effects exerted by mechanical coupling between the walking legs through the substrate. One solution for this problem is to conduct the experiments in a tethered animal that is free to walk in place and that is locally suspended, for example over a slippery surface, which effectively removes most ground contact mechanics. This has been used to study escape responses (Camhi and Nolen, 1981; Camhi and Levy, 1988), turning (Tryba and Ritzman, 2000a,b; Gruhn et al., 2009a), backward walking (Graham and Epstein, 1985) or changes in velocity (Gruhn et al., 2009b) and it allows the experimenter easily to combine intra- and extracellular physiology with kinematic analyses (Gruhn et al., 2006). We use a slippery surface setup to investigate the timing of leg muscles in the behaving stick insect with respect to touch-down and lift-off under different behavioral paradigms such as straight forward and curved walking in intact and reduced preparations. PMID- 21525840 TI - Electrophysiology of scorpion PEG sensilla. AB - We describe a modification of an existing tip-recording technique for electrophysiologically investigating short, peg-like sensory sensilla. On the mid ventral surface of all scorpions are two appendages called pectines, which have dense fields of mechano- and chemosensory peg sensilla. One method for assessing chemoresponsiveness of these sensilla uses a tungsten electrode for extracellularly recording neural activity within a sensillum as a volatile odorant is introduced to the sensory field. The limitations of this method include slow data collection and uncontrolled stimulant introduction to, and removal from, the peg field. To overcome these limitations, we developed a new tip-recording technique that uses nonpolar mineral oil as a medium through which to deliver water-based tastants to individual peg sensilla. We have successfully applied this method to obtain sensillar chemoresponses to citric acid, ethanol, and salt. Here we describe the experimental protocol for such a study. We think this new method may be useful for studying the response properties of other arthropod chemosensory systems, including those of insects and crustaceans. PMID- 21525841 TI - Using bioluminescent imaging to investigate synergism between Streptococcus pneumoniae and influenza A virus in infant mice. AB - During the 1918 influenza virus pandemic, which killed approximately 50 million people worldwide, the majority of fatalities were not the result of infection with influenza virus alone. Instead, most individuals are thought to have succumbed to a secondary bacterial infection, predominately caused by the bacterium Streptococcus pneumoniae (the pneumococcus). The synergistic relationship between infections caused by influenza virus and the pneumococcus has subsequently been observed during the 1957 Asian influenza virus pandemic, as well as during seasonal outbreaks of the virus (reviewed in (1, 2)). Here, we describe a protocol used to investigate the mechanism(s) that may be involved in increased morbidity as a result of concurrent influenza A virus and S. pneumoniae infection. We have developed an infant murine model to reliably and reproducibly demonstrate the effects of influenza virus infection of mice colonised with S. pneumoniae. Using this protocol, we have provided the first insight into the kinetics of pneumococcal transmission between co-housed, neonatal mice using in vivo imaging. PMID- 21525842 TI - Monitoring tumor metastases and osteolytic lesions with bioluminescence and micro CT imaging. AB - Following intracardiac delivery of MDA-MB-231-luc-D3H2LN cells to Nu/Nu mice, systemic metastases developed in the injected animals. Bioluminescence imaging using IVIS Spectrum was employed to monitor the distribution and development of the tumor cells following the delivery procedure including DLIT reconstruction to measure the tumor signal and its location. Development of metastatic lesions to the bone tissues triggers osteolytic activity and lesions to tibia and femur were evaluated longitudinally using micro CT. Imaging was performed using a Quantum FX micro CT system with fast imaging and low X-ray dose. The low radiation dose allows multiple imaging sessions to be performed with a cumulative X-ray dosage far below LD50. A mouse imaging shuttle device was used to sequentially image the mice with both IVIS Spectrum and Quantum FX achieving accurate animal positioning in both the bioluminescence and CT images. The optical and CT data sets were co registered in 3-dimentions using the Living Image 4.1 software. This multi-mode approach allows close monitoring of tumor growth and development simultaneously with osteolytic activity. PMID- 21525843 TI - Flow cytometry purification of mouse meiotic cells. AB - The heterogeneous nature of cell types in the testis and the absence of meiotic cell culture models have been significant hurdles to the study of the unique differentiation programs that are manifest during meiosis. Two principal methods have been developed to purify, to varying degrees, various meiotic fractions from both adult and immature animals: elutriation or Staput (sedimentation) using BSA and/or percoll gradients. Both of these methods rely on cell size and density to separate meiotic cells. Overall, except for few cell populations, these protocols fail to yield sufficient purity of the numerous meiotic cell populations that are necessary for detailed molecular analyses. Moreover, with such methods usually one type of meiotic cells can be purified at a given time, which adds an extra level of complexity regarding the reproducibility and homogeneity when comparing meiotic cell samples. Here, we describe a refined method that allows one to easily visualize, identify, and purify meiotic cells, from germ cells to round spermatids, using FACS combined with Hoechst 33342 staining. This method provides an overall snapshot of the entire meiotic process and allows one to highly purify viable cells from most stage of meiosis. These purified cells can then be analyzed in detail for molecular changes that accompany progression through meiosis, for example changes in gene expression and the dynamics of nucleosome occupancy at hotspots of meiotic recombination. PMID- 21525844 TI - Bimolecular fluorescence complementation. AB - Defining the subcellular distribution of signaling complexes is imperative to understanding the output from that complex. Conventional methods such as immunoprecipitation do not provide information on the spatial localization of complexes. In contrast, BiFC monitors the interaction and subcellular compartmentalization of protein complexes. In this method, a fluororescent protein is split into amino- and carboxy-terminal non-fluorescent fragments which are then fused to two proteins of interest. Interaction of the proteins results in reconstitution of the fluorophore (Figure 1). A limitation of BiFC is that once the fragmented fluorophore is reconstituted the complex is irreversible. This limitation is advantageous in detecting transient or weak interactions, but precludes a kinetic analysis of complex dynamics. An additional caveat is that the reconstituted flourophore requires 30min to mature and fluoresce, again precluding the observation of real time interactions. BiFC is a specific example of the protein fragment complementation assay (PCA) which employs reporter proteins such as green fluorescent protein variants (BiFC), dihydrofolate reductase, b-lactamase, and luciferase to measure protein:protein interactions. Alternative methods to study protein:protein interactions in cells include fluorescence co-localization and Forster resonance energy transfer (FRET). For co localization, two proteins are individually tagged either directly with a fluorophore or by indirect immunofluorescence. However, this approach leads to high background of non-interacting proteins making it difficult to interpret co localization data. In addition, due to the limits of resolution of confocal microscopy, two proteins may appear co-localized without necessarily interacting. With BiFC, fluorescence is only observed when the two proteins of interest interact. FRET is another excellent method for studying protein:protein interactions, but can be technically challenging. FRET experiments require the donor and acceptor to be of similar brightness and stoichiometry in the cell. In addition, one must account for bleed through of the donor into the acceptor channel and vice versa. Unlike FRET, BiFC has little background fluorescence, little post processing of image data, does not require high overexpression, and can detect weak or transient interactions. Bioluminescence resonance energy transfer (BRET) is a method similar to FRET except the donor is an enzyme (e.g. luciferase) that catalyzes a substrate to become bioluminescent thereby exciting an acceptor. BRET lacks the technical problems of bleed through and high background fluorescence but lacks the ability to provide spatial information due to the lack of substrate localization to specific compartments. Overall, BiFC is an excellent method for visualizing subcellular localization of protein complexes to gain insight into compartmentalized signaling. PMID- 21525845 TI - Fluorescence recovery after photobleaching (FRAP) of fluorescence tagged proteins in dendritic spines of cultured hippocampal neurons. AB - FRAP has been used to quantify the mobility of GFP-tagged proteins. Using a strong excitation laser, the fluorescence of a GFP-tagged protein is bleached in the region of interest. The fluorescence of the region recovers when the unbleached GFP-tagged protein from outside of the region diffuses into the region of interest. The mobility of the protein is then analyzed by measuring the fluorescence recovery rate. This technique could be used to characterize protein mobility and turnover rate. In this study, we express the (enhanced green fluorescent protein) EGFP vector in cultured hippocampal neurons. Using the Zeiss 710 confocal microscope, we photobleach the fluorescence signal of the GFP protein in a single spine, and then take time lapse images to record the fluorescence recovery after photobleaching. Finally, we estimate the percentage of mobile and immobile fractions of the GFP in spines, by analyzing the imaging data using ImageJ and Graphpad softwares. This FRAP protocol shows how to perform a basic FRAP experiment as well as how to analyze the data. PMID- 21525846 TI - Transfection of mouse retinal ganglion cells by in vivo electroporation. AB - The targeting and refinement of RGC projections to the midbrain is a popular and powerful model system for studying how precise patterns of neural connectivity form during development. In mice, retinofugal projections are arranged in a topographic manner and form eye-specific layers in the Lateral Geniculate Nucleus (dLGN) of the thalamus and the Superior Colliculus (SC). The development of these precise patterns of retinofugal projections has typically been studied by labeling populations of RGCs with fluorescent dyes and tracers, such as horseradish peroxidase. However, these methods are too coarse to provide insight into developmental changes in individual RGC axonal arbor morphology that are the basis of retinotopic map formation. They also do not allow for the genetic manipulation of RGCs. Recently, electroporation has become an effective method for providing precise spatial and temporal control for delivery of charged molecules into the retina. Current retinal electroporation protocols do not allow for genetic manipulation and tracing of retinofugal projections of a single or small cluster of RGCs in postnatal mice. It has been argued that postnatal in vivo electroporation is not a viable method for transfecting RGCs since the labeling efficiency is extremely low and hence requires targeting at embryonic ages when RGC progenitors are undergoing differentiation and proliferation. In this video we describe an in vivo electroporation protocol for targeted delivery of genes, shRNA, and fluorescent dextrans to murine RGCs postnatally. This technique provides a cost effective, fast and relatively easy platform for efficient screening of candidate genes involved in several aspects of neural development including axon retraction, branching, lamination, regeneration and synapse formation at various stages of circuit development. In summary we describe here a valuable tool which will provide further insights into the molecular mechanisms underlying sensory map development. PMID- 21525847 TI - Pseudofracture: an acute peripheral tissue trauma model. AB - Following trauma there is an early hyper-reactive inflammatory response that can lead to multiple organ dysfunction and high mortality in trauma patients; this response is often accompanied by a delayed immunosuppression that adds the clinical complications of infection and can also increase mortality. Many studies have begun to assess these changes in the reactivity of the immune system following trauma. Immunologic studies are greatly supported through the wide variety of transgenic and knockout mice available for in vivo modeling; these strains aid in detailed investigations to assess the molecular pathways involved in the immunologic responses. The challenge in experimental murine trauma modeling is long term investigation, as fracture fixation techniques in mice, can be complex and not easily reproducible. This pseudofracture model, an easily reproduced trauma model, overcomes these difficulties by immunologically mimicking an extremity fracture environment, while allowing freedom of movement in the animals and long term survival without the continual, prolonged use of anaesthesia. The intent is to recreate the features of long bone fracture; injured muscle and soft tissue are exposed to damaged bone and bone marrow without breaking the native bone. The pseudofracture model consists of two parts: a bilateral muscle crush injury to the hindlimbs, followed by injection of a bone solution into these injured muscles. The bone solution is prepared by harvesting the long bones from both hindlimbs of an age- and weight-matched syngeneic donor. These bones are then crushed and resuspended in phosphate buffered saline to create the bone solution. Bilateral femur fracture is a commonly used and well established model of extremity trauma, and was the comparative model during the development of the pseudofracture model. Among the variety of available fracture models, we chose to use a closed method of fracture with soft tissue injury as our comparison to the pseudofracture, as we wanted a sterile yet proportionally severe peripheral tissue trauma model. Hemorrhagic shock is a common finding in the setting of severe trauma, and the global hypoperfusion adds a very relevant element to a trauma model. The pseudofracture model can be easily combined with a hemorrhagic shock model for a multiple trauma model of high severity. PMID- 21525848 TI - Methods to quantify pharmacologically induced alterations in motor function in human incomplete SCI. AB - Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, recovery from SCI typically involves long term rehabilitation. While recovery of walking ability is a primary goal in many patients early after injury, those with a motor incomplete SCI, indicating partial preservation of volitional control, may have the sufficient residual descending pathways necessary to attain this goal. However, despite physical interventions, motor impairments including weakness, and the manifestation of abnormal involuntary reflex activity, called spasticity or spasms, are thought to contribute to reduced walking recovery. Doctrinaire thought suggests that remediation of this abnormal motor reflexes associated with SCI will produce functional benefits to the patient. For example, physicians and therapists will provide specific pharmacological or physical interventions directed towards reducing spasticity or spasms, although there continues to be little empirical data suggesting that these strategies improve walking ability. In the past few decades, accumulating data has suggested that specific neuromodulatory agents, including agents which mimic or facilitate the actions of the monoamines, including serotonin (5HT) and norepinephrine (NE), can initiate or augment walking behaviors in animal models of SCI. Interestingly, many of these agents, particularly 5HTergic agonists, can markedly increase spinal excitability, which in turn also increases reflex activity in these animals. Counterintuitive to traditional theories of recovery following human SCI, the empirical evidence from basic science experiments suggest that this reflex hyper excitability and generation of locomotor behaviors are driven in parallel by neuromodulatory inputs (5HT) and may be necessary for functional recovery following SCI. The application of this novel concept derived from basic scientific studies to promote recovery following human SCI would appear to be seamless, although the direct translation of the findings can be extremely challenging. Specifically, in the animal models, an implanted catheter facilitates delivery of very specific 5HT agonist compounds directly onto the spinal circuitry. The translation of this technique to humans is hindered by the lack of specific surgical techniques or available pharmacological agents directed towards 5HT receptor subtypes that are safe and effective for human clinical trials. However, oral administration of commonly available 5HTergic agents, such as selective serotonin reuptake inhibitors (SSRIs), may be a viable option to increase central 5HT concentrations in order to facilitate walking recovery in humans. Systematic quantification of how these SSRIs modulate human motor behaviors following SCI, with a specific focus on strength, reflexes, and the recovery of walking ability, are missing. This video demonstration is a progressive attempt to systematically and quantitatively assess the modulation of reflex activity, volitional strength and ambulation following the acute oral administration of an SSRI in human SCI. Agents are applied on single days to assess the immediate effects on motor function in this patient population, with long-term studies involving repeated drug administration combined with intensive physical interventions. PMID- 21525849 TI - Premature aging of circulating T cells in patients with end-stage renal disease. AB - Progressive loss of renal function is associated with a dysregulation of circulating T cells that may underlie their impaired T-cell immunity. Here we tested whether end-stage renal disease (ESRD)-related T-cell alterations are compatible with the concept of premature immunological aging. Younger patients (25-45 years old) with ESRD were found to resemble older healthy controls (60-80 years old) as they had a significant loss of naive T cells and a relative increase of memory T cells showing progressive terminal differentiation. A significant decrease in the content of T-cell receptor excision circles and telomere length in patients with ESRD confirmed these phenotypic data. The loss of naive T cells in patients with ESRD was associated with an excessive age related decrease of recent thymic emigrants, indicating a premature decline in thymic function. Additionally, increased homeostatic proliferation of naive T cells was found in patients with ESRD, similar to that of older healthy individuals, with an increased susceptibility for activation-induced apoptosis. Therefore, both decreased thymic output and increased susceptibility of naive T cells for apoptosis may play a role in the loss of naive T cells in ESRD patients. Thus, our results are compatible with premature aging of the T-cell system of patients with ESRD comparable with that of healthy individuals 20-30 years older. PMID- 21525850 TI - L-carnitine is an osmotic agent suitable for peritoneal dialysis. AB - Excessive intraperitoneal absorption of glucose during peritoneal dialysis has both local cytotoxic and systemic metabolic effects. Here we evaluate peritoneal dialysis solutions containing L-carnitine, an osmotically active compound that induces fluid flow across the peritoneum. In rats, L-carnitine in the peritoneal cavity had a dose-dependent osmotic effect similar to glucose. Analogous ultrafiltration and small solute transport characteristics were found for dialysates containing 3.86% glucose, equimolar L-carnitine, or combinations of both osmotic agents in mice. About half of the ultrafiltration generated by L carnitine reflected facilitated water transport by aquaporin-1 (AQP1) water channels of endothelial cells. Nocturnal exchanges with 1.5% glucose and 0.25% L carnitine in four patients receiving continuous ambulatory peritoneal dialysis were well tolerated and associated with higher net ultrafiltration than that achieved with 2.5% glucose solutions, despite the lower osmolarity of the carnitine-containing solution. Addition of L-carnitine to endothelial cells in culture increased the expression of AQP1, significantly improved viability, and prevented glucose-induced apoptosis. In a standard toxicity test, the addition of L-carnitine to peritoneal dialysis solution improved the viability of L929 fibroblasts. Thus, our studies support the use of L-carnitine as an alternative osmotic agent in peritoneal dialysis. PMID- 21525851 TI - Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric cardiac surgery. AB - In this multicenter, prospective study of 288 children (half under 2 years of age) undergoing cardiac surgery, we evaluated whether the measurement of pre- and postoperative serum cystatin C (CysC) improves the prediction of acute kidney injury (AKI) over that obtained by serum creatinine (SCr). Higher preoperative SCr-based estimated glomerular filtration rates predicted higher risk of the postoperative primary outcomes of stage 1 and 2 AKI (adjusted odds ratios (ORs) 1.5 and 1.9, respectively). Preoperative CysC was not associated with AKI. The highest quintile of postoperative (within 6 h) CysC predicted stage 1 and 2 AKI (adjusted ORs of 6 and 17.2, respectively). The highest tertile of percent change in CysC independently predicted AKI, whereas the highest tertile of SCr predicted stage 1 but not stage 2 AKI. Postoperative CysC levels independently predicted longer duration of ventilation and intensive care unit length of stay, whereas the postoperative SCr change only predicted longer intensive care unit stay. Thus, postoperative serum CysC is useful to risk-stratify patients for AKI treatment trials. More research, however, is needed to understand the relation between preoperative renal function and the risk of AKI. PMID- 21525852 TI - Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract. AB - Although the urinary tract is constantly challenged by microbial invasion, it remains free from colonization. Although little is known about how the urinary tract maintains sterility, the presence of antimicrobial peptides (AMPs) in the urine suggests that they may play a role in its protection from infection. Ribonuclease 7 (RNase 7) is a potent AMP that was first identified in the skin. Here, we characterize the expression and relevance of RNase 7 in the human kidney and urinary tract. Using RNA isolated from healthy human tissue, we performed quantitative real-time PCR and found basal RNASE7 expression in kidney and bladder tissue. Immunohistochemical and immunofluorescent analysis localized RNase 7 to the urothelium of the bladder, ureter, and the intercalated cells of the collecting tubules. In control urine samples from healthy individuals, the concentration of RNase 7 was found to be in the low micromolar range; very abundant for an AMP. Antibacterial neutralization assays showed that urinary RNase 7 has potent antimicrobial properties against Gram-negative and Gram positive uropathogenic bacteria. Thus, RNase 7 is expressed in the human kidney and urinary tract and it may have an important antimicrobial role in maintaining tract sterility. PMID- 21525853 TI - Higher recipient body mass index is associated with post-transplant delayed kidney graft function. AB - To examine whether a higher body mass index (BMI) in kidney recipients is associated with delayed graft function (DGF), we analyzed data from 11,836 hemodialysis patients in the Scientific Registry of Transplant Recipients who underwent kidney transplantation. The patient cohort included women, blacks, and diabetics; the average age was 49 years; and the mean BMI was 26.8 kg/m(2). After adjusting for relevant covariates, multivariate logistic regression analyses found that one standard deviation increase in pretransplant BMI was associated with a higher risk of DGF (odds ratio (OR) 1.35). Compared with patients with a pretransplant BMI of 22-24.99 kg/m(2), overweight patients (BMI 25-29.99 kg/m(2)), mild obesity patients (BMI 30-34.99 kg/m(2)), and moderate-to-severe obesity patients (BMI 35 kg/m(2) and over) had a significantly higher risk of DGF, with ORs of 1.30, 1.42, and 2.18, respectively. Similar associations were found in all subgroups of patients. Hence, pretransplant overweight or obesity is associated with an incrementally higher risk of DGF. PMID- 21525854 TI - Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. AB - Fibroblastic growth factor 23 (FGF23) is a bone-derived hormone that has a pivotal role in the pathogenesis of mineral disorders in chronic kidney disease. To study the effect of parathyroid hormone (PTH) on FGF23, rats were parathyroidectomized for a week and then implanted with constant-delivery infusion pumps to provide vehicle, a physiological, or a threefold supraphysiological dose of parathyroid hormone. Parathyroidectomy resulted in a significant decrease in blood ionized calcium, FGF23, and calcitriol along with an increase in phosphorus concentrations. PTH replacement produced a dose dependent increase in ionized calcium and FGF23 with decreased phosphorus. Calcitriol was also increased but there was no dose effect of PTH treatment. To maintain normal plasma calcitriol levels, two additional groups of parathyroidectomized rats were given calcitriol and temporarily treated with vehicle or the supraphysiological dose of PTH. FGF23 was significantly increased by calcitriol in the vehicle-treated rats but was not further increased above that in rats given the supraphysiological dose of PTH in the absence of calcitriol. Klotho expression in the kidney decreased after parathyroidectomy but was restored by hormone supplementation. Hence, our results show a direct and an indirect effect of PTH on FGF23 secretion, the latter through changes in calcitriol concentrations. PMID- 21525855 TI - Regulatory T cells control the Th1 immune response in murine crescentic glomerulonephritis. AB - Crescentic glomerulonephritis is mediated by inappropriate humoral and cellular immune responses toward self-antigens that may result from defects in central and peripheral tolerance. Evidence now suggests that regulatory T cells (Tregs) may be of pathophysiological importance in proliferative and crescentic forms of glomerulonephritis. To analyze the role of endogenous Tregs in a T cell-dependent glomerulonephritis model of nephrotoxic nephritis, we used 'depletion of regulatory T cell' (DEREG) mice that express the diphtheria toxin receptor under control of the FoxP3 (forkhead box P3) gene promoter. Toxin injection into these mice efficiently depleted renal and splenic FoxP3(+) Treg cells as determined by fluorescent-activated cell sorting (FACS) and immunohistochemical analyses. Treg depletion exacerbated systemic and renal interferon-gamma (IFNgamma) expression and increased recruitment of IFNgamma-producing Th1 cells into the kidney without an effect on the Th17 immune response. The enhanced Th1 response, following Treg cell depletion, was associated with an aggravated course of glomerulonephritis as measured by glomerular crescent formation. Thus, our results establish the functional importance of endogenous Tregs in the control of a significantly enhanced systemic and renal Th1 immune response in experimental glomerulonephritis. PMID- 21525856 TI - The ZNF804A gene: characterization of a novel neural risk mechanism for the major psychoses. AB - Schizophrenia and bipolar disorder share genetic risk, brain vulnerability, and clinical symptoms. The ZNF804A risk variant, rs1344706, confers susceptibility for both disorders. This study aimed to identify neural mechanisms common to both schizophrenia and bipolar disorder through this variant's potential effects on cortical thickness, white matter tract integrity, and cognitive function. Imaging, genetics, and cognitive measures were ascertained in 62 healthy adults aged between 18 and 59 years. High-resolution multimodal MRI/DTI imaging was used to measure cortical thickness and major frontotemporal and interhemispheric white matter tracts. The general linear model was used to examine the influence of the ZNF804A rs1344706 risk variant on cortical thickness, white matter tract integrity, and cognitive measures. Individuals homozygous for the risk variant ('A' allele) demonstrated reduced cortical gray matter thickness in the superior temporal gyrus, and in the anterior and posterior cingulate cortices compared with C-allele carriers. No effect of the risk variant on microstructural integrity of white matter tracts was found. Reduced attention control was found in risk allele homozygotes, aligning with findings in the anterior cingulate cortex. Our data provide a novel, genetically based neural risk mechanism for the major psychoses by effects of the ZNF804A risk variant on neural structures and cognitive function susceptible in both disorders. Our findings link genetic, imaging, and cognitive susceptibility relevant to both schizophrenia and bipolar disorder. PMID- 21525857 TI - Neuropeptide-S (NPS) receptor genotype modulates basolateral amygdala responsiveness to aversive stimuli. AB - Recent studies point to a role of neuropeptide-S (NPS) in the etiology of anxiety disorders. In animal models, NPS and its receptor (NPSR) were shown to be highly expressed in the amygdala, a central structure in the fear circuit, also known to be hyper-responsive in anxiety disorders. Recently, a functional polymorphism in the NPSR gene (rs324981 A/T) has been associated with panic disorder and anxiety sensitivity. However, the role of NPSR gene variation in the modulation of fear related amygdala responsiveness remains to be clarified. In 79 healthy subjects genotyped for NPSR rs324981, amygdala responses were assessed by means of fMRI. The participants were presented with fear-relevant faces in a robust emotion processing paradigm frequently used to study amygdala responsiveness. We observed a strong association of NPSR T-alleles with right amygdala responsiveness to fear relevant faces. The association peak was located in the BLA. Furthermore, responsiveness to aversive stimuli within this BLA cluster predicted a participant's self-reported harm avoidance but not depression level. We conclude that NPSR genotype is associated with increased amygdala responsiveness to fear relevant stimuli. Thereby, NPSR rs324981 apparently causes an indirect effect on anxiety-related traits and potentially contributes to the pathogenesis of anxiety disorders by shaping fear-related limbic activity. PMID- 21525858 TI - Cholecystokinin exerts an effect via the endocannabinoid system to inhibit GABAergic transmission in midbrain periaqueductal gray. AB - Cholecystokinin modulates pain and anxiety via its functions within brain regions such as the midbrain periaqueductal gray (PAG). The aim of this study was to examine the cellular actions of cholecystokinin on PAG neurons. Whole-cell patch clamp recordings were made from rat midbrain PAG slices in vitro to examine the postsynaptic effects of cholecystokinin and its effects on synaptic transmission. Sulfated cholecystokinin-(26-33) (CCK-S, 100-300 nM), but not non-sulfated cholecystokinin-(26-33) (CCK-NS, 100-300 nM) produced an inward current in a sub population of opioid sensitive and insensitive PAG neurons, which did not reverse over a range of membrane potentials. The CCK-S-induced current was abolished by the CCK1 selective antagonist devazepide (100 nM), but not by the CCK2 selective antagonists CI988 (100 nM, 1 MUM) and LY225910 (1 MUM). CCK-S, but not CCK-NS produced a reduction in the amplitude of evoked GABA(A)-mediated inhibitory postsynaptic currents (IPSCs) and an increase in the evoked IPSC paired-pulse ratio. By contrast, CCK-S had little effect on the rate and amplitude of TTX resistant miniature IPSCs under basal conditions and when external K(+) was elevated. The CCK-S-induced inhibition of evoked IPSCs was abolished by the cannabinoid CB1 receptor antagonist AM251 (3 MUM), the mGluR5 antagonist MPEP (10 MUM) and the 1, 2-diacylglycerol lipase (DAGLalpha) inhibitor tetrahydrolipstatin (10 MUM). In addition, CCK-S produced an increase in the rate of spontaneous non NMDA-mediated, TTX-dependent excitatory postsynaptic currents (EPSCs). These results suggest that cholecystokinin produces direct neuronal depolarisation via CCK1 receptors and inhibits GABAergic synaptic transmission via action potential dependent release of glutamate and mGluR5-induced endocannabinoid signaling. Thus, cholecystokinin has cellular actions within the PAG that can both oppose and reinforce opioid and cannabinoid modulation of pain and anxiety within this brain structure. PMID- 21525859 TI - Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus. AB - The aim of this prospective study was to investigate whether selective serotonin reuptake inhibitors (SSRIs) utilized by pregnant women influence fetal neurobehavioral development. In this observational study we investigated developmental milestones of fetal behavior during the pregnancy of women with psychiatric disorders who took SSRIs throughout gestation (medicated group; n=96) or who had discontinued medication early in gestation or before conception (unmedicated group; n=37). Healthy unexposed fetuses of women without mental disorders comprised the control group (n=130). Ultrasonographic observations of fetal behavior were made three times in pregnancy (T1-T3). Effects of SSRIs were studied over a wide range of dosages (low, standard, or high) and for different drug types. Fetuses exposed to standard or high SSRI dosages compared with control, unmedicated, or low-medicated fetuses showed significantly increased motor activity at the beginning (T1) and end of the second trimester (T2). They particularly exhibited disrupted emergence of non-rapid eye movement (non-REM; quiet) sleep during the third trimester, characterized by continual bodily activity and, thus, poor inhibitory motor control during this sleep state near term (T3). The SSRI effects on the fetus were dose related, but independent of SSRI type. The results demonstrate changes in fetal neurobehavioral development associated with standard and high SSRI dosages that are observable throughout gestation. A first-choice SSRI type was not apparent. Bodily activity at high rate during non-REM sleep in SSRI-exposed fetuses is an abnormal phenomenon, but its significance for postnatal development is unclear. PMID- 21525860 TI - Resting glutamate levels and rapid glutamate transients in the prefrontal cortex of the Flinders Sensitive Line rat: a genetic rodent model of depression. AB - Despite the numerous drugs targeting biogenic amines for major depressive disorder (depression), the search for novel therapeutics continues because of their poor response rates (~30%) and slow onset of action (2-4 weeks). To better understand role of glutamate in depression, we used an enzyme-based microelectrode array (MEA) that was selective for glutamate measures with fast temporal (2 Hz) and high spatial (15 * 333 MUm) resolution. These MEAs were chronically implanted into the prefrontal cortex of 3- to 6-month-old and 12- to 15-month-old Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats, a validated genetic rodent model of depression. Although no changes in glutamate dynamics were observed between 3 and 6 months FRL and FSL rats, a significant increase in resting glutamate levels was observed in the 12- to 15 month-old FSL rats compared with the 3- to 6-month-old FSL and age-matched FRL rats on days 3-5 post-implantation. Our MEA also recorded, for the first time, a unique phenomenon in all the four rat groups of fluctuations in resting glutamate, which we have termed glutamate transients. Although these events lasted only for seconds, they did occur throughout the testing paradigm. The average concentration of these glutamate-burst events was significantly increased in the 12- to 15-month-old FSL rats compared with 3- to 6-month-old FSL and age matched FRL rats. These studies lay the foundation for future studies of both tonic and phasic glutamate signaling in rat models of depression to better understand the potential role of glutamate signaling in depression. PMID- 21525861 TI - Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. AB - The gene encoding the dopamine transporter (DAT) has been implicated in CNS disorders, but the responsible polymorphisms remain uncertain. To search for regulatory polymorphisms, we measured allelic DAT mRNA expression in substantia nigra of human autopsy brain tissues, using two marker SNPs (rs6347 in exon 9 and rs27072 in the 3'-UTR). Allelic mRNA expression imbalance (AEI), an indicator of cis-acting regulatory polymorphisms, was observed in all tissues heterozygous for either of the two marker SNPs. SNP scanning of the DAT locus with AEI ratios as the phenotype, followed by in vitro molecular genetics studies, demonstrated that rs27072 C>T affects mRNA expression and translation. Expression of the minor T allele was dynamically regulated in transfected cell cultures, possibly involving microRNA interactions. Both rs6347 and rs3836790 (intron8 5/6 VNTR) also seemed to affect DAT expression, but not the commonly tested 9/10 VNTR in the 3'UTR (rs28363170). All four polymorphisms (rs6347, intron8 5/6 VNTR, rs27072 and 3'UTR 9/10 VNTR) were genotyped in clinical cohorts, representing schizophrenia, bipolar disorder, depression, and controls. Only rs27072 was significantly associated with bipolar disorder (OR = 2.1, p = 0.03). This result was replicated in a second bipolar/control population (OR = 1.65, p = 0.01), supporting a critical role for DAT regulation in bipolar disorder. PMID- 21525862 TI - Enhancement of LTP in aged rats is dependent on endogenous BDNF. AB - Long-term potentiation (LTP), considered the neurophysiological basis for learning and memory, is facilitated by brain-derived neurotrophic factor (BDNF), an action more evident when LTP is evoked by weak theta-burst stimuli and dependent on co-activation of adenosine A(2A) receptors (A(2A)R), which are more expressed in aged rats. As theta-burst stimuli also favor LTP in aged animals, we hypothesized that enhanced LTP in aging could be related to changes in neuromodulation by BDNF. The magnitude of CA1 LTP induced by a weak theta-burst stimuli delivered to the Schaffer collaterals was significantly higher in hippocampal slices taken from 36 to 38 and from 70 to 80-week-old rats, when compared with LTP magnitude in slices from 4 or 10 to 15-week-old rats; this enhancement does not impact in cognitive improvement as aged rats revealed an impairment on hippocampal-dependent learning and memory performance, as assessed by the Morris water maze tests. The scavenger for BDNF, TrkB-Fc, and the inhibitor of Trk phosphorylation, K252a, attenuated LTP in slices from 70 to 80 week-old rats, but not from 10 to 15-week-old rats. When exogenously added, BDNF significantly increased LTP in slices from 4 and 10 to 15-week-old rats, but did not further increased LTP in 36 to 38 or 70 to 80-week-old rats. The effects of exogenous BDNF on LTP were prevented by the A(2A)R antagonist, SCH58261 (7-(2 phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5 c]pyrimidine). These results indicate that the higher LTP magnitude observed upon aging, which does not translate into improved spatial memory performance, is a consequence of an increase in the tonic action of endogenous BDNF. PMID- 21525863 TI - Differential effects of dopamine receptor D1-type and D2-type antagonists and phase of the estrous cycle on social learning of food preferences, feeding, and social interactions in mice. AB - The neurobiological bases of social learning, by which an animal can 'exploit the expertise of others' and avoid the disadvantages of individual learning, are only partially understood. We examined the involvement of the dopaminergic system in social learning by administering a dopamine D1-type receptor antagonist, SCH23390 (0.01, 0.05, and 0.1 mg/kg), or a D2-type receptor antagonist, raclopride (0.1, 0.3, and 0.6 mg/kg), to adult female mice prior to socially learning a food preference. We found that while SCH23390 dose-dependently inhibited social learning without affecting feeding behavior or the ability of mice to discriminate between differently flavored diets, raclopride had the opposite effects, inhibiting feeding but leaving social learning unaffected. We showed that food odor, alone or in a social context, was insufficient to induce a food preference, proving the specifically social nature of this paradigm. The estrous cycle also affected social learning, with mice in proestrus expressing the socially acquired food preference longer than estrous and diestrous mice. This suggests gonadal hormone involvement, which is consistent with known estrogenic regulation of female social behavior and estrogen receptor involvement in social learning. Furthermore, a detailed ethological analysis of the social interactions during which social learning occurs showed raclopride- and estrous phase-induced changes in agonistic behavior, which were not directly related to effects on social learning. Overall, these results suggest a differential involvement of the D1-type and D2-type receptors in the regulation of social learning, feeding, and agonistic behaviors that are likely mediated by different underlying states. PMID- 21525864 TI - Fluoxetine alleviates behavioral depression while decreasing acetylcholine release in the nucleus accumbens shell. AB - Selective serotonin reuptake inhibitors, such as fluoxetine, have demonstrated the ability to alleviate behavioral depression in the forced swim test; however, the sites and mechanisms of their actions remain to be further elucidated. Previous studies have suggested that behavioral depression in the swim test is mediated in part by acetylcholine (ACh) stimulating the cholinergic M1 receptors in the nucleus accumbens (NAc) shell. The current study tested whether acute, local, and chronic, subcutaneous fluoxetine treatments increase escape motivation during the swim test while simultaneously lowering extracellular ACh in the NAc shell. Experiment 1: Fluoxetine (1.0 mM) infused unilaterally in the NAc shell for 40 min reduced extracellular ACh while simultaneously increasing swimming time. Experiment 2: Fluoxetine (0.2, 0.5, and 0.75 mM) infused bilaterally in the NAc shell on day 3 dose-dependently decreased immobility and increased the total escape attempts (swimming and climbing) compared with Ringer given on day 2. Experiment 3: Fluoxetine (0.5 mM) infused bilaterally in the NAc for 40 min did not affect activities in an open field. Experiment 4: Chronic systemic fluoxetine treatment decreased immobility scores and increased total escape attempt scores compared with control saline treatment. In all, 14 days after the initial swim test, basal extracellular ACh in the shell was still elevated in the saline treated group, but not in the fluoxetine-treated group. In summary, these data suggest that one of the potential mechanisms by which fluoxetine alleviates behavioral depression in the forced swim test may be to suppress cholinergic activities in the NAc shell. PMID- 21525865 TI - The gp41 epitope, QARVLAVERY, is highly conserved and a potent inducer of IgA that neutralizes HIV-1 and inhibits viral transcytosis. AB - Mucosal surfaces are the predominant site of human immunodeficiency virus (HIV)-1 transmission. For prophylactic approaches to effectively prevent HIV infection and subsequent dissemination, the induction of mucosally relevant protective immunity will be critical. Here, we have characterized the antibody (Ab) response generated by a highly conserved gp41epitope, QARVLAVERY, in an optimized immunization model that elicits potent epitope-specific Abs in the serum, vaginal washes, and fecal secretions of immunized mice. Our results show that QARVLAVERY is indeed a potent inducer of IgA and importantly, QARVLAVERY-specific IgA was effective in neutralizing HIV and inhibiting viral transcytosis. Intriguingly, QARVLAVERY also generated an approximate 1:1 ratio of IgG:IgA in the serum of immunized mice, independent of the delivery regimen and produced early systemic IgA, even before IgG. In light of the significantly high IgA induction by QARVLAVERY and the functionality of epitope-specific Abs in the inhibition of HIV infection and transcytosis, QARVLAVERY is an attractive epitope to be considered in mucosal vaccination strategies against HIV. PMID- 21525866 TI - Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the "COPA" pilot randomized trial. AB - Intestinal mucosal immune system is an early target for human immunodeficiency virus type 1 (HIV-1) infection, resulting in CD4(+) T-cell depletion, deterioration of gut lining, and fecal microbiota composition. We evaluated the effects of a prebiotic oligosaccharide mixture in highly active antiretroviral therapy (HAART)-naive HIV-1-infected adults. In a pilot double-blind, randomized, placebo-controlled study, 57 HAART-naive HIV-1-infected patients received a unique oligosaccharide mixture (15 or 30 g short chain galactooligosaccharides/long chain fructooligosaccharides/pectin hydrolysate derived acidic oligosaccharides (scGOS/lcFOS/pAOS) daily) or a placebo for 12 weeks. Microbiota composition improved significantly with increased bifidobacteria, decreased Clostridium coccoides/Eubacterium rectale cluster, and decreased pathogenic Clostridium lituseburense/Clostridium histolyticum group levels upon prebiotic supplementation. In addition, a reduction of soluble CD14 (sCD14), activated CD4(+)/CD25(+) T cells, and significantly increased natural killer (NK) cell activity when compared with control group were seen in the treatment group. The results of this pilot trial highly significantly show that dietary supplementation with a prebiotic oligosaccharide mixture results in improvement of the gut microbiota composition, reduction of sCD14, CD4(+) T-cell activation (CD25), and improved NK cell activity in HAART-naive HIV-infected individuals. PMID- 21525868 TI - Alendronate adherence and its impact on hip-fracture risk in patients with established osteoporosis in Taiwan. AB - A pharmacoepidemiology study was conducted using the health insurance database in Taiwan to assess compliance with osteoporosis drug regimens and the impact of compliance on the risk for secondary fractures. Patients >50 years of age with vertebral/hip fracture who had been started on alendronate therapy for the first time only after the fracture were included. Compliance was measured using the medication possession ratio (MPR) and was included as a time-dependent covariate in the Cox model to compare the difference between compliant (MPR >= 80%) and noncompliant patients (MPR <80%) with respect to risk for subsequent hip fractures. Only 38% of the study population remained compliant during the first year of treatment. Over the 4-year follow-up period, the risk of hip fracture among the compliant patients was 70% lower than that among the noncompliant ones (adjusted hazard ratio (HR) 0.30). Among patients with osteoporosis in Taiwan who had experienced a fracture and had started alendronate therapy, compliance with the dosage regimen was suboptimal. It was also found that compliance significantly reduced the risk of secondary hip fracture up to 4 years. PMID- 21525869 TI - Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine exposure. AB - The likelihood of significant exposure to drugs in infants through breast milk is poorly defined, given the difficulties of conducting pharmacokinetics (PK) studies. Using fluoxetine (FX) as an example, we conducted a proof-of-principle study applying population PK (popPK) modeling and simulation to estimate drug exposure in infants through breast milk. We simulated data for 1,000 mother infant pairs, assuming conservatively that the FX clearance in an infant is 20% of the allometrically adjusted value in adults. The model-generated estimate of the milk-to-plasma ratio for FX (mean: 0.59) was consistent with those reported in other studies. The median infant-to-mother ratio of FX steady-state plasma concentrations predicted by the simulation was 8.5%. Although the disposition of the active metabolite, norfluoxetine, could not be modeled, popPK-informed simulation may be valid for other drugs, particularly those without active metabolites, thereby providing a practical alternative to conventional PK studies for exposure risk assessment in this population. PMID- 21525870 TI - The multiple-specificity landscape of modular peptide recognition domains. AB - Modular protein interaction domains form the building blocks of eukaryotic signaling pathways. Many of them, known as peptide recognition domains, mediate protein interactions by recognizing short, linear amino acid stretches on the surface of their cognate partners with high specificity. Residues in these stretches are usually assumed to contribute independently to binding, which has led to a simplified understanding of protein interactions. Conversely, we observe in large binding peptide data sets that different residue positions display highly significant correlations for many domains in three distinct families (PDZ, SH3 and WW). These correlation patterns reveal a widespread occurrence of multiple binding specificities and give novel structural insights into protein interactions. For example, we predict a new binding mode of PDZ domains and structurally rationalize it for DLG1 PDZ1. We show that multiple specificity more accurately predicts protein interactions and experimentally validate some of the predictions for the human proteins DLG1 and SCRIB. Overall, our results reveal a rich specificity landscape in peptide recognition domains, suggesting new ways of encoding specificity in protein interaction networks. PMID- 21525871 TI - Origin of bistability underlying mammalian cell cycle entry. AB - Precise control of cell proliferation is fundamental to tissue homeostasis and differentiation. Mammalian cells commit to proliferation at the restriction point (R-point). It has long been recognized that the R-point is tightly regulated by the Rb-E2F signaling pathway. Our recent work has further demonstrated that this regulation is mediated by a bistable switch mechanism. Nevertheless, the essential regulatory features in the Rb-E2F pathway that create this switching property have not been defined. Here we analyzed a library of gene circuits comprising all possible link combinations in a simplified Rb-E2F network. We identified a minimal circuit that is able to generate robust, resettable bistability. This minimal circuit contains a feed-forward loop coupled with a mutual-inhibition feedback loop, which forms an AND-gate control of the E2F activation. Underscoring its importance, experimental disruption of this circuit abolishes maintenance of the activated E2F state, supporting its importance for the bistability of the Rb-E2F system. Our findings suggested basic design principles for the robust control of the bistable cell cycle entry at the R point. PMID- 21525876 TI - A commentary on for what am i participating? The need for communication after receiving consent from biobanking project participants: experience in Japan. PMID- 21525872 TI - Network modeling of the transcriptional effects of copy number aberrations in glioblastoma. AB - DNA copy number aberrations (CNAs) are a hallmark of cancer genomes. However, little is known about how such changes affect global gene expression. We develop a modeling framework, EPoC (Endogenous Perturbation analysis of Cancer), to (1) detect disease-driving CNAs and their effect on target mRNA expression, and to (2) stratify cancer patients into long- and short-term survivors. Our method constructs causal network models of gene expression by combining genome-wide DNA- and RNA-level data. Prognostic scores are obtained from a singular value decomposition of the networks. By applying EPoC to glioblastoma data from The Cancer Genome Atlas consortium, we demonstrate that the resulting network models contain known disease-relevant hub genes, reveal interesting candidate hubs, and uncover predictors of patient survival. Targeted validations in four glioblastoma cell lines support selected predictions, and implicate the p53-interacting protein Necdin in suppressing glioblastoma cell growth. We conclude that large scale network modeling of the effects of CNAs on gene expression may provide insights into the biology of human cancer. Free software in MATLAB and R is provided. PMID- 21525877 TI - Evaluation of next-generation sequencing software in mapping and assembly. AB - Next-generation high-throughput DNA sequencing technologies have advanced progressively in sequence-based genomic research and novel biological applications with the promise of sequencing DNA at unprecedented speed. These new non-Sanger-based technologies feature several advantages when compared with traditional sequencing methods in terms of higher sequencing speed, lower per run cost and higher accuracy. However, reads from next-generation sequencing (NGS) platforms, such as 454/Roche, ABI/SOLiD and Illumina/Solexa, are usually short, thereby restricting the applications of NGS platforms in genome assembly and annotation. We presented an overview of the challenges that these novel technologies meet and particularly illustrated various bioinformatics attempts on mapping and assembly for problem solving. We then compared the performance of several programs in these two fields, and further provided advices on selecting suitable tools for specific biological applications. PMID- 21525873 TI - D-Ornithine coopts pyrrolysine biosynthesis to make and insert pyrroline-carboxy lysine. AB - D-ornithine has previously been suggested to enhance the expression of pyrrolysine-containing proteins. We unexpectedly discovered that uptake of D ornithine results in the insertion of a new amino acid, pyrroline-carboxy-lysine (Pcl) instead of the anticipated pyrrolysine (Pyl). Our feeding and biochemical studies point to specific roles of the poorly understood Pyl biosynthetic enzymes PylC and PylD in converting L-lysine and D-ornithine to Pcl and confirm intermediates in the biosynthesis of Pyl. PMID- 21525878 TI - A single nucleotide polymorphism in the 3'-untranslated region of MyD88 gene is associated with Buerger disease but not with Takayasu arteritis in Japanese. AB - Buerger disease (BD) and Takayasu arteritis (TA) are rare vascular disorders. Although their etiology and pathogenesis have not been elucidated, several studies have suggested the involvement of innate immunity. Myeloid differentiation primary-response protein 88 (MyD88) is a key signaling adaptor for all Toll-like receptors, which have a central role in innate immunity. In the present study, we evaluated the association of MyD88 with BD and TA. We conducted case-control studies in Japanese populations composing of 131 BD cases, 90 TA cases and 270 healthy controls to be genotyped for a single nucleotide polymorphism rs7744 A>G in the 3'-untranslated region of MyD88 gene. The frequency of GG genotype was significantly lower in the BD patients than in the controls (6.9 vs 15.9%, P=0.011, odds ratio=0.39, 95% confidence interval; 0.19, 0.81), although there was no significant difference in the genotype frequencies between the TA patients and controls. It was suggested that MyD88 may confer resistance to BD in Japanese. Because this is the first report of the association between MyD88 and BD, replication studies in other cohorts are required. PMID- 21525879 TI - Pleiotropy of type 2 diabetes with obesity. AB - The risk of type 2 diabetes (T2D) increases with obesity. One possible explanation is that pleiotropic genes affect risk of both T2D and obesity. To identify pleiotropic genes, we performed bivariate analysis of T2D with waist-hip ratio (WHR) and with body mass index (BMI) in the African-American subset of the Genetics of NIDDM (GENNID) sample. Of 12 T2D loci identified through suggestive or higher univariate logarithm of the odds ratio (lod) scores, we inferred pleiotropy with obesity for six (chromosomes 1 at 17-19 Mb, 2 at 237-240 Mb, 7 at 54-73 Mb, 13 at 26-30 Mb, 16 at 26-47 Mb and 20 at 56-59 Mb). These findings provide evidence that at least some of the co-occurrence of obesity with T2D is because of pleiotropic genes. We also inferred four obesity loci through suggestive or higher lod scores for WHR (chromosomes 1 at 24-32 Mb, 2 at 79-88 Mb, 2 at 234-238 Mb and 3 at 148-159 Mb). PMID- 21525880 TI - Assessment of the relationship between coronary artery ectasia and erectile function score. AB - The relation between coronary artery ectasia (CAE) and erectile dysfunction (ED) has not been studied so far. Hence, we decided to investigate the erectile function score in patients with CAE. We investigated the international index of erectile function (IIEF)-5 score in 34 men with CAE, 38 men with coronary artery disease (CAD), and 30 male controls with normal coronary arteries whose mean ages were 53.2 +/- 5.6, 51.4 +/- 7.8, and 49.6 +/- 8.6 years, respectively. Erectile function was evaluated by the five-item version of the IIEF-5. Each question is scored from 0 to 5. CAE was defined as being without any stenotic lesions with a visual assessment of the coronary arteries showing a luminal dilatation 1.5-fold or more of the adjacent normal coronary segments. IIEF-5 scores in CAE group were found statistically significantly lower than the control group (P<0.001). There were no statistically significant differences in IIEF-5 scores between CAE and CAD groups (P=0.13). We have shown for the first time that patients with CAE have lower IIEF-5 scores compared with controls with normal coronary angiograms. Many studies reported that endothelial dysfunction in patients with CAE was more dominant than those with CAD. This study suggests that ED and CAE may be different manifestations of a common underlying vascular pathology and vasculogenic ED is frequently seen in CAE at least as much as in CAD. PMID- 21525881 TI - Culturing expressed breast milk: a costly and (mostly) useless procedure. PMID- 21525882 TI - Blueberry muffin rash, hyperbilirubinemia, and hypoglycemia: a case of hemolytic disease of the fetus and newborn due to anti-Kp(a). AB - Hemolytic disease of the fetus and newborn occurs when maternal IgG antibodies cross the placenta and cause hemolysis of fetal red blood cells. Kp(a) is a low frequency red blood cell antigen that has rarely been implicated in hemolytic disease of the fetus and newborn. The few reported cases attributed to anti-Kp(a) have typically had minimal clinical consequences. We report a critically ill neonate who presented with purpura, respiratory failure, severe liver dysfunction, hyperbilirubinemia, hypoglycemia and anemia. This case report broadens the spectrum of neonatal disease associated with anti-Kp(a), addresses the evaluation of hemolysis with liver failure in a neonate, and emphasizes the importance of screening for antibodies to low frequency red blood cell antigens in suspected hemolytic disease of the fetus and newborn. PMID- 21525883 TI - N-(3,5-dimethylphenyl)-3-methoxybenzamide (A(3)B(5)) targets TRP-2 and inhibits melanogenesis and melanoma growth. AB - Melanin protects the skin from harmful environmental factors such as UV light. However, excessive melanin production induces hyperpigmentation. Previously, N (3,5-dimethylphenyl)-3-methoxybenzamide (A(3)B(5)), a biaryl amide derivative, was identified for its ability to inhibit melanin production. However, its detailed mechanism of action has not been investigated. We elucidated the inhibitory mechanisms of A(3)B(5) in melanin production. Our results showed that A(3)B(5) had no effect on the production and activity of tyrosinase, an enzyme involved in melanogenesis. However, A(3)B(5) markedly decreased both constitutively expressed and UVB-induced tyrosinase-related protein 2 (TRP-2), which plays an important role along with tyrosinase in melanogenesis. The TRP-2 downregulation caused by A(3)B(5) may occur through proteasomal degradation because the A(3)B(5)-induced TRP-2 downregulation was inhibited by the ubiquitination inhibitor, MG-132. In addition, A(3)B(5) inhibited the proliferation of melanocytes and melanoma cells by arresting cells in the G1 stage of the cell cycle and moderately suppressed tumor growth in vivo. Taken together, our results indicate that A(3)B(5) downregulates melanin production and melanoma cell growth via proteosomal degradation of TRP-2 and suggest that A(3)B(5) can be a possible therapeutic agent that effectively regulates both hyperpigmentation and melanoma growth in the skin. PMID- 21525884 TI - A role for leukocyte-derived IL-1RA in DC homeostasis revealed by increased susceptibility of IL-1RA-deficient mice to cutaneous leishmaniasis. AB - Dendritic cell (DC)-derived IL-1alpha/beta plays a critical role in the induction of T helper type 1 (Th1)-dependent immunity against Leishmania. DCs from susceptible BALB/c mice produce less IL-1alpha/beta when compared with resistant C57BL/6 mice, contributing to aberrant Th2 development and ultimate death of infected mice. We have extended our studies of the role of IL-1 in leishmaniasis using IL-1RA(-/-) BALB/c mice that are characterized by upregulated IL-1 receptor signaling. Unexpectedly, infection of IL-1RA(-/-) mice led to significantly worsened disease outcome with larger lesions, dramatically higher parasite burdens, and decreased IFN-gamma production by antigen-specific T cells. We determined that IL-1RA(-/-) DCs were more mature already in the steady state, exhibited less phagocytotic capacity, and IL-12 production in response to various stimuli was impaired. Our data suggest that in addition to effects on Th education, IL-1alpha/beta signaling also modulates DC homeostasis with increased signaling, leading to downmodulation of IL-12 synthesis and worsened disease outcome after infection with Leishmania major. Thus, the complex regulation of various members of the IL-1 cytokine family mediated through effects on both DCs and T cells critically contributes to disease outcome against this important human pathogen. PMID- 21525887 TI - A watchdog with bite. PMID- 21525886 TI - Anti-TNFalpha therapy may lead to blood pressure reductions through improved endothelium-dependent microvascular function in patients with rheumatoid arthritis. PMID- 21525885 TI - Curcumin mediates both dilation and constriction of peripheral arterioles via adrenergic receptors. AB - Curcumin has wound healing attributes mediated through a plethora of biological activities that in general are not ascribed to specific receptors. Recently, we have demonstrated that intravenous administration of curcumin limits burn injury progression in a rat model. As decreased microvascular perfusion is a central element of burn injury progression, we hypothesized that curcumin may induce vasodilation in peripheral arterioles, to improve perfusion. Using mucosal microcirculation as an in situ assay, cheek pouch tissue was exteriorized in anesthetized (phentobarbital 70 mg kg(-1) intraperitoneal) male hamsters (N=60) to observe the terminal feed arterioles (~8 MUm diameter) and the immediately upstream arcade arterioles (~20 MUm). Curcumin (10(-12)-10(-4) mol l(-1)) was applied dose-wise (micropipette, 60 seconds). Subnanomolar curcumin dilated, whereas micromolar doses constricted, the arterioles. For the terminal arteriole: vasodilation logEC(50) -10.3+/-0.2, peak dilation +39+/-1%; vasconstriction logEC(50) -8.0+/-0.4, peak constriction -14+/-2%. Simultaneous atropine (muscarinic antagonist) or PD142893 (endothelin antagonist) had no effect. Propranolol (beta-adrenergic receptor (beta-Ad) antagonist) enhanced constriction by removing the vasodilation response to curcumin. Phentolamine (alpha-adrenergic receptor (alpha-Ad) antagonist) enhanced dilation to curcumin by removing the vasoconstriction response. Thus, the curcumin vasomotor activity on microcirculation was alpha-Ad and beta-Ad receptor-dependent and its net vasoactive effect was concentration- and time-dependent. PMID- 21525888 TI - A united front. PMID- 21525889 TI - Seeing REDD. PMID- 21525902 TI - Is FutureGen betting on the wrong rock? PMID- 21525890 TI - End the wasteful tyranny of reviewer experiments. PMID- 21525903 TI - Nuclear safety: Reactors, residents and risk. PMID- 21525904 TI - Astronomers mull merger of missions. PMID- 21525905 TI - California ponders cell-banking venture. PMID- 21525906 TI - Ancient DNA: Curse of the Pharaoh's DNA. PMID- 21525907 TI - The rise of people power. PMID- 21525913 TI - Bio-PIN could cut biobanking risks. PMID- 21525914 TI - Arab world needs its science diaspora. PMID- 21525915 TI - 'Plan B' for X-ray astronomy. PMID- 21525916 TI - 'No' to ban on stem-cell patents. PMID- 21525917 TI - Earth science: Lithosphere today ... PMID- 21525920 TI - Materials science: Colour without colourants. PMID- 21525918 TI - Immunology: A helping hand against autoimmunity. PMID- 21525921 TI - Animal behaviour: Large-scale cooperation. PMID- 21525923 TI - Astronomy: A new spin on the first stars. PMID- 21525922 TI - Materials chemistry: Polymer networks take a bow. PMID- 21525924 TI - Neuroscience: Sleepy neurons? PMID- 21525925 TI - On the role of the Agulhas system in ocean circulation and climate. AB - The Atlantic Ocean receives warm, saline water from the Indo-Pacific Ocean through Agulhas leakage around the southern tip of Africa. Recent findings suggest that Agulhas leakage is a crucial component of the climate system and that ongoing increases in leakage under anthropogenic warming could strengthen the Atlantic overturning circulation at a time when warming and accelerated meltwater input in the North Atlantic is predicted to weaken it. Yet in comparison with processes in the North Atlantic, the overall Agulhas system is largely overlooked as a potential climate trigger or feedback mechanism. Detailed modelling experiments--backed by palaeoceanographic and sustained modern observations--are required to establish firmly the role of the Agulhas system in a warming climate. PMID- 21525926 TI - Local sleep in awake rats. AB - In an awake state, neurons in the cerebral cortex fire irregularly and electroencephalogram (EEG) recordings display low-amplitude, high-frequency fluctuations. During sleep, neurons oscillate between 'on' periods, when they fire as in an awake brain, and 'off' periods, when they stop firing altogether and the EEG displays high-amplitude slow waves. However, what happens to neuronal firing after a long period of being awake is not known. Here we show that in freely behaving rats after a long period in an awake state, cortical neurons can go briefly 'offline' as in sleep, accompanied by slow waves in the local EEG. Neurons often go offline in one cortical area but not in another, and during these periods of 'local sleep', the incidence of which increases with the duration of the awake state, rats are active and display an 'awake' EEG. However, they are progressively impaired in a sugar pellet reaching task. Thus, although both the EEG and behaviour indicate wakefulness, local populations of neurons in the cortex may be falling asleep, with negative consequences for performance. PMID- 21525928 TI - Imprints of fast-rotating massive stars in the Galactic Bulge. AB - The first stars that formed after the Big Bang were probably massive, and they provided the Universe with the first elements heavier than helium ('metals'), which were incorporated into low-mass stars that have survived to the present. Eight stars in the oldest globular cluster in the Galaxy, NGC 6522, were found to have surface abundances consistent with the gas from which they formed being enriched by massive stars (that is, with higher alpha-element/Fe and Eu/Fe ratios than those of the Sun). However, the same stars have anomalously high abundances of Ba and La with respect to Fe, which usually arises through nucleosynthesis in low-mass stars (via the slow-neutron-capture process, or s-process). Recent theory suggests that metal-poor fast-rotating massive stars are able to boost the s-process yields by up to four orders of magnitude, which might provide a solution to this contradiction. Here we report a reanalysis of the earlier spectra, which reveals that Y and Sr are also overabundant with respect to Fe, showing a large scatter similar to that observed in extremely metal-poor stars, whereas C abundances are not enhanced. This pattern is best explained as originating in metal-poor fast-rotating massive stars, which might point to a common property of the first stellar generations and even of the 'first stars'. PMID- 21525927 TI - Structure and mechanism of the chromatin remodelling factor ISW1a. AB - Site-specific recognition of DNA in eukaryotic organisms depends on the arrangement of nucleosomes in chromatin. In the yeast Saccharomyces cerevisiae, ISW1a and related chromatin remodelling factors are implicated in establishing the nucleosome repeat during replication and altering nucleosome position to affect gene activity. Here we have solved the crystal structures of S. cerevisiae ISW1a lacking its ATPase domain both alone and with DNA bound at resolutions of 3.25 A and 3.60 A, respectively, and we have visualized two different nucleosome containing remodelling complexes using cryo-electron microscopy. The composite X ray and electron microscopy structures combined with site-directed photocrosslinking analyses of these complexes suggest that ISW1a uses a dinucleosome substrate for chromatin remodelling. Results from a remodelling assay corroborate the dinucleosome model. We show how a chromatin remodelling factor could set the spacing between two adjacent nucleosomes acting as a 'protein ruler'. PMID- 21525929 TI - Superconductor-insulator transition in La2 - xSrxCuO4 at the pair quantum resistance. AB - High-temperature superconductivity in copper oxides arises when a parent insulator compound is doped beyond some critical concentration; what exactly happens at this superconductor-insulator transition is a key open question. The cleanest approach is to tune the carrier density using the electric field effect; for example, it was learned in this way that weak electron localization transforms superconducting SrTiO(3) into a Fermi-glass insulator. But in the copper oxides this has been a long-standing technical challenge, because perfect ultrathin films and huge local fields (>10(9) V m(-1)) are needed. Recently, such fields have been obtained using electrolytes or ionic liquids in the electric double-layer transistor configuration. Here we report synthesis of epitaxial films of La(2- x)Sr(x)CuO(4) that are one unit cell thick, and fabrication of double-layer transistors. Very large fields and induced changes in surface carrier density enable shifts in the critical temperature by up to 30 K. Hundreds of resistance versus temperature and carrier density curves were recorded and shown to collapse onto a single function, as predicted for a two-dimensional superconductor-insulator transition. The observed critical resistance is precisely the quantum resistance for pairs, R(Q) = h/(2e) = 6.45 kOmega, suggestive of a phase transition driven by quantum phase fluctuations, and Cooper pair (de)localization. PMID- 21525930 TI - Continuing Colorado plateau uplift by delamination-style convective lithospheric downwelling. AB - The Colorado plateau is a large, tectonically intact, physiographic province in the southwestern North American Cordillera that stands at ~1,800-2,000 m elevation and has long been thought to be in isostatic equilibrium. The origin of these high elevations is unclear because unlike the surrounding provinces, which have undergone significant Cretaceous-Palaeogene compressional deformation followed by Neogene extensional deformation, the Colorado plateau is largely internally undeformed. Here we combine new seismic tomography and receiver function images to resolve a vertical high-seismic-velocity anomaly beneath the west-central plateau that extends more than 200 km in depth. The upper surface of this anomaly is seismically defined by a dipping interface extending from the lower crust to depths of 70-90 km. The base of the continental crust above the anomaly has a similar shape, with an elevated Moho. We interpret these seismic structures as a continuing regional, delamination-style foundering of lower crust and continental lithosphere. This implies that Pliocene (2.6-5.3 Myr ago) uplift of the plateau and the magmatism on its margins are intimately tied to continuing deep lithospheric processes. Petrologic and geochemical observations indicate that late Cretaceous-Palaeogene (~90-40 Myr ago) low-angle subduction hydrated and probably weakened much of the Proterozoic tectospheric mantle beneath the Colorado plateau. We suggest that mid-Cenozoic (~35-25 Myr ago) to Recent magmatic infiltration subsequently imparted negative compositional buoyancy to the base and sides of the Colorado plateau upper mantle, triggering downwelling. The patterns of magmatic activity suggest that previous such events have progressively removed the Colorado plateau lithosphere inward from its margins, and have driven uplift. Using Grand Canyon incision rates and Pliocene basaltic volcanism patterns, we suggest that this particular event has been active over the past ~6 Myr. PMID- 21525931 TI - Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'. AB - Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects beta-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate beta-glucan polymers, Dectin-1 signalling is only activated by particulate beta-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required. PMID- 21525932 TI - TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. AB - Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase machinery. However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to mouse macrophage bactericidal activity, although the mechanisms linking innate immune signalling to mitochondria for mROS generation remain unclear. Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results reveal a novel pathway linking innate immune signalling to mitochondria, implicate mROS as an important component of antibacterial responses and further establish mitochondria as hubs for innate immune signalling. PMID- 21525936 TI - Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase 12. AB - Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia-ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2alpha, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2alpha directed phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress. PMID- 21525937 TI - Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR. AB - We reported a relevant activity of the combination between sorafenib and octreotide long-acting release (LAR) in advanced hepatocellular carcinoma (HCC) patients. In this work, we have studied if oxidative stress in both serum and peripheral blood mononuclear cells (PBMC) and pERK activation status in PBMC could be predictive of response. In the 20 responsive patients, the decrease of reactive oxygen species levels was already detectable after 10 days (T10) from the beginning of sorafenib administration, and this effect was enhanced by the combined treatment with sorafenib+octreotide LAR (T21). This effect correlated with the modulation of superoxide dismutase (SOD) activity (physiological scavenger of O(2-)) and of serum nitric oxide (NO) levels. Sorafenib alone induced an increase of about 40% of NO levels and of about two-fold of SOD activity in responsive patients, and both effects were significantly potentiated by the combined treatment. We found a gradual reduction of Erk1/2 activity, as evaluated by cytofluorimetric analysis, in 15 responsive patients reaching about 50% maximal decrease at T21. On the other hand, in 17 resistant patients, Erk1/2 activity was about 80% increased at T21. The determination of both the oxidative stress status and pERK activity in PBMC has high value in the prediction of response to sorafenib+octreotide therapy in HCC patients. PMID- 21525938 TI - MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sezary syndrome. AB - Sezary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma and its pathogenesis is still unknown. Diagnosis/prognosis may strongly ameliorate the management of SS individuals. Here, we profiled the expression of 470 microRNAs (miRNAs) in a cohort of 22 SS patients, and we identified 45 miRNAs differentially expressed between SS and controls. Using predictive analysis, a list of 19 miRNAs, including miR-21, miR-214, miR-486, miR-18a, miR-342, miR-31 and let-7 members were also found. Moreover, we defined a signature of 14 miRNAs including again miR-21, potentially able to discriminate patients with unfavorable and favorable outcome. We validated our data for miR-21, miR-214 and miR-486 by qRT-PCR, including an additional set of array-independent SS cases. In addition, we also provide an in vitro evidence for a contribution of miR-214, miR 486 and miR-21 to apoptotic resistance of CTCL cell line. PMID- 21525939 TI - Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. AB - Gemcitabine (GEM, 2',2'-difluorodeoxycytidine) is currently used in advanced pancreatic adenocarcinoma, with a response rate of < 20%. The purpose of our work was to improve GEM activity by addition of cannabinoids. Here, we show that GEM induces both cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2) receptors by an NF-kappaB-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. The antiproliferative synergism is prevented by the radical scavenger N-acetyl-L cysteine and by the specific NF-kappaB inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-kappaB by GEM is required for this effect. In addition, we report that neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated with the enhancement of endoplasmic reticulum stress and autophagic cell death. Noteworthy, the antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects. These findings support a key role of the ROS-dependent activation of an autophagic program in the synergistic growth inhibition induced by GEM/cannabinoid combination in human pancreatic cancer cells. PMID- 21525940 TI - Each under his own vine and fig tree. PMID- 21525941 TI - Bad light stops play. PMID- 21525942 TI - Practicing biochemistry without a licence? PMID- 21525943 TI - Warheads and avoiding Star Wars. PMID- 21525944 TI - Human intuition in the quantitative age. The role of mathematics in biology is vital, but does it leave room for 'old-fashioned' observation and interpretation? PMID- 21525945 TI - Reading the tea leaves of Congress. With a new Republican majority in the House of Representatives, scientific research in the USA might face budget cuts. PMID- 21525946 TI - Hydrothermally generated aromatic compounds are consumed by bacteria colonizing in Atlantis II Deep of the Red Sea. AB - Hydrothermal ecosystems have a wide distribution on Earth and many can be found in the basin of the Red Sea. Production of aromatic compounds occurs in a temperature window of ~60-150 degrees C by utilizing organic debris. In the past 50 years, the temperature of the Atlantis II Deep brine pool in the Red Sea has increased from 56 to 68 degrees C, whereas the temperature at the nearby Discovery Deep brine pool has remained relatively stable at about 44 degrees C. In this report, we confirmed the presence of aromatic compounds in the Atlantis II brine pool as expected. The presence of the aromatic compounds might have disturbed the microbes in the Atlantis II. To show shifted microbial communities and their metabolisms, we sequenced the metagenomes of the microbes from both brine pools. Classification based on metareads and the 16S rRNA gene sequences from clones showed a strong divergence of dominant bacterial species between the pools. Bacteria capable of aromatic degradation were present in the Atlantis II brine pool. A comparison of the metabolic pathways showed that several aromatic degradation pathways were significantly enriched in the Atlantis II brine pool, suggesting the presence of aromatic compounds. Pathways utilizing metabolites derived from aromatic degradation were also significantly affected. In the Discovery brine pool, the most abundant genes from the microbes were related to sugar metabolism pathways and DNA synthesis and repair, suggesting a different strategy for the utilization of carbon and energy sources between the Discovery brine pool and the Atlantis II brine pool. PMID- 21525947 TI - Arterial stiffness, ambulatory blood pressure and low-grade albuminuria in non diabetic African and Caucasian men: the SABPA study. AB - Recent evidence suggests that low-grade urinary albumin excretion is a marker of early general attenuation of vascular function, but studies are limited to Caucasian population groups. We compared low-grade urinary albumin excretion (<3.5 mg mmol(-1) or 30 MUg mg(-1)) between non-diabetic African (aged, 41.7 years; n=70) and Caucasian (aged, 44.6 years; n=91) men and ethnic-specific associations thereof with arterial stiffness and ambulatory blood pressure. The albumin-to-creatinine ratio (ACR) was determined from an 8 h overnight urine collection. We recorded ambulatory blood pressure over 24 h during a typical workday and the carotid-dorsalis pedis pulse wave velocity measured the next morning after a controlled overnight stay. ACR was higher in Africans compared with Caucasians (P < 0.001), also after adjusting for 24 h systolic blood pressure, diastolic blood pressure and hypertension prevalence (P < 0.001) or when grouped by similar 24 h mean arterial pressures (P < 0.01 for all categories). Daytime (P=0.002) and night time (P < 0.001) systolic and daytime (P < 0.001) and night time (P < 0.001) diastolic blood pressures were higher in Africans compared with Caucasians, but no differences existed for daytime and night time pulse pressure and pulse wave velocity. In African men only, after adjustment for covariates, night time systolic blood pressure (beta=0.347; P=0.003), diastolic blood pressure (beta=0.298; P=0.010) and mean arterial pressure (beta=0.331; P=0.004) correlated positively with ACR. In addition, daytime (beta=0.265; P=0.032) and night time (beta=0.258; P=0.038) pulse pressure as well as pulse wave velocity (beta=0.271; P=0.032) correlated positively with ACR. In conclusion, arterial stiffness and ambulatory blood pressure are already associated with low-grade albuminuria in non-diabetic African men with normal kidney function. PMID- 21525948 TI - When the arteries get tough, the tougher do not get going. PMID- 21525949 TI - Association between physical activity and blood pressure in prepubertal children. AB - Elevated blood pressure (BP) during childhood and adolescence increases the risk of hypertension in later life. Although physical activity is known to positively moderate BP, data regarding this relationship are limited in prepubertal children. We aimed to assess the association between a range of physical activities (including indoor and outdoor activity) and BP in a large community based sample of prepubertal schoolchildren. Eligible year-1 schoolchildren (n=1765; mean age 6.7 +/- 0.4 years) from a random cluster sample of 34 schools in Sydney, Australia, were examined. Parents completed detailed questionnaires about their child's activity. Height and weight were measured, and body mass index (BMI) was calculated. BP was measured using a standard protocol, and elevated BP was defined using published guidelines. Physical activity was classified as low, medium or high (that is, as tertiles). After adjusting for age, sex, ethnicity, height, BMI, parental qualifications and family history of hypertension and/or cardiovascular disease, children in the highest tertile of outdoor and indoor activities had significantly lower diastolic BP (~1.5 mm Hg; P(trend)=0.01) and systolic BP (~1.3 mm Hg; P(trend)=0.03), respectively, compared with those in the lowest tertile (reference). Linearly, time spent in indoor activities (each hour per day) was associated with ~2.4 mm Hg decrease in diastolic BP (P=0.001). Physical activity was independently associated with lower BP in this sample of prepubertal children. The findings emphasize the importance of ensuring regular physical activity programs in primary schools to potentially reduce the risk of elevated BP in childhood and in later life. PMID- 21525950 TI - Increases in urinary albumin and beta2-microglobulin are independently associated with blood pressure in the Japanese general population: the Takahata Study. AB - Essential hypertension is a multifactorial disorder and a risk factor for renal failure and cardiovascular disease. Recently it was hypothesized that subtle acquired renal injury such as renal microvascular and tubulointerstitial damage induces salt-sensitive hypertension. The objective of this study was to examine the relationship between blood pressure and renal abnormalities in the Japanese general population. The participants in this community-based, cross-sectional study were 1,965 subjects over 40 years old, without renal insufficiency and antihypertensive medication. Urine albumin-creatinine ratio (UACR) and beta2 microglobulin-creatinine ratio (UBCR) were measured in single spot urine samples, as markers of renal microvascular and tubulointerstitial damage, respectively. Multiple linear regression analysis showed a significant positive correlation of blood pressure with UACR and UBCR, but not with estimated glomerular filtration rate. In multiple logistic regression analysis, the increases in UACR and UBCR were independently associated with hypertension, after adjustment for possible confounders. Higher levels of UACR (>= 5.9 mg g(-1)) and UBCR (>= 145 MUg g(-1)) were associated with a significantly higher risk of hypertension, compared with UACR <= 5.8 mg g(-1) and UBCR <= 84.5 MUg g(-1), respectively. Furthermore, there was a positive relationship between urinary sodium excretion and blood pressure in subjects with high UBCR tertile. This study showed that the increases in urinary albumin and beta2-microglobulin were independently associated with blood pressure in a general population. These renal abnormalities may be differentially related to the development of hypertension. PMID- 21525952 TI - MicroRNA therapeutics. AB - MicroRNAs (miRNAs) provide new therapeutic targets for many diseases, while their myriad roles in development and cellular processes make them fascinating to study. We still do not fully understand the molecular mechanisms by which miRNAs regulate gene expression nor do we know the complete repertoire of mRNAs each miRNA regulates. However, recent progress in the development of effective strategies to block miRNAs suggests that anti-miRNA drugs may soon be used in the clinic. PMID- 21525953 TI - Self-inactivating helper virus for the production of high-capacity adenoviral vectors. AB - Standard methods for producing high-capacity adenoviral vectors (HC-Ads) are based on co-infection with a helper adenovirus (HV). To avoid HV encapsidation, its packaging signal (Psi) is flanked by recognition sequences for recombinases expressed in the producing cells. However, accumulation of HV and low yield of HC Ad are frequently observed, due in part to insufficient recombinase expression. We describe here a novel HV (AdTetCre) in which Psi is flanked by loxP sites that can be excised by a chimeric MerCreMer recombinase encoded in the same viral genome. Efficient modulation of cleavage was obtained by simultaneous control of MerCreMer expression using a tet-on inducible system, and translocation to the nucleus by 4-hydroxytamoxifen (TAM). Encapsidation of AdTetCre was strongly inhibited by TAM plus doxycicline. Using AdTetCre and 293Cre4 cells for the production of HC-Ads, we found that cellular and virus-encoded recombinases cooperate to minimize HV contamination. The method was highly reproducible and allowed the routine production of different HC-Ads in a medium-scale laboratory setting in adherent cells, with titers >1010 infectious units and <0.1% HV contamination. The residual HVs lacked Psi and were highly attenuated. We conclude that self-inactivating HVs based on virally encoded recombinases are promising tools for the production of HC-Ads. PMID- 21525954 TI - The HARP domain dictates the annealing helicase activity of HARP/SMARCAL1. AB - Mutations in HepA-related protein (HARP, or SMARCAL1) cause Schimke immunoosseous dysplasia (SIOD). HARP has ATP-dependent annealing helicase activity, which helps to stabilize stalled replication forks and facilitate DNA repair during replication. Here, we show that the conserved tandem HARP (2HP) domain dictates this annealing helicase activity. Furthermore, chimeric proteins generated by fusing the 2HP domain of HARP with the SNF2 domain of BRG1 or HELLS show annealing helicase activity in vitro and, when targeted to replication forks, mimic the functions of HARP in vivo. We propose that the HARP domain endows HARP with this ATP-driven annealing helicase activity. PMID- 21525955 TI - The E3 ubiquitin ligase CTRIP controls CLOCK levels and PERIOD oscillations in Drosophila. AB - In the Drosophila circadian clock, the CLOCK/CYCLE complex activates the period and timeless genes that negatively feedback on CLOCK/CYCLE activity. The 24-h pace of this cycle depends on the stability of the clock proteins. RING-domain E3 ubiquitin ligases have been shown to destabilize PERIOD or TIMELESS. Here we identify a clock function for the circadian trip (ctrip) gene, which encodes a HECT-domain E3 ubiquitin ligase. ctrip expression in the brain is mostly restricted to clock neurons and its downregulation leads to long-period activity rhythms in constant darkness. This altered behaviour is associated with high CLOCK levels and persistence of phosphorylated PERIOD during the subjective day. The control of CLOCK protein levels does not require PERIOD. Thus, CTRIP seems to regulate the pace of the oscillator by controlling the stability of both the activator and the repressor of the feedback loop. PMID- 21525956 TI - Subtelomeric repetitive elements determine TERRA regulation by Rap1/Rif and Rap1/Sir complexes in yeast. AB - Telomeric repeat-containing RNA (TERRA) has been implicated in the control of heterochromatin and telomerase. We demonstrate that yeast TERRA is regulated by telomere-binding proteins in a chromosome-end-specific manner that is dependent on subtelomeric repetitive DNA elements. At telomeres that contain only X elements, the Rap1 carboxy-terminal domain recruits the Sir2/3/4 and Rif1/2 complexes to repress transcription in addition to promoting Rat1-nuclease dependent TERRA degradation. At telomeres that contain Y' elements, however, Rap1 represses TERRA through recruitment of Rif1 and Rif2. Our work emphasizes the importance of subtelomeric DNA in the control of telomeric protein composition and telomere transcription. PMID- 21525957 TI - Phosphorylation of Ser 402 impedes phosphatase activity of slingshot 1. AB - By using mass spectrometry, we have identified Ser 402 as a new phosphorylation site within the catalytic domain of human slingshot 1 (SSH1). Phosphorylation at this site inhibits substrate binding and, thus, phosphatase activity in vitro, resulting in enrichment of phosphorylated cofilin in monolayer cell culture. We further demonstrate that protein kinase D (PKD) is upstream from Ser 402 phosphorylation. Accordingly, expression of active PKD in Drosophila phenotypically mimics the loss of SSH activity by inducing accumulation of phosphorylated cofilin and filamentous actin. We thus identify a universal mechanism by which PKD controls SSH1 phosphatase activity. PMID- 21525958 TI - The ribosomal protein RACK1 is required for microRNA function in both C. elegans and humans. AB - Despite the importance of microRNAs (miRNAs) in gene regulation, it is unclear how the miRNA-Argonaute complex--or miRNA-induced silencing complex (miRISC)--can regulate the translation of their targets in such diverse ways. We demonstrate here a direct interaction between the miRISC and the ribosome by showing that a constituent of the eukaryotic 40S subunit, receptor for activated C-kinase (RACK1), is important for miRNA-mediated gene regulation in animals. In vivo studies demonstrate that RACK1 interacts with components of the miRISC in nematodes and mammals. In both systems, the alteration of RACK1 expression alters miRNA function and impairs the association of the miRNA complex with the translating ribosomes. Our data indicate that RACK1 can contribute to the recruitment of miRISC to the site of translation, and support a post-initiation mode of miRNA-mediated gene repression. PMID- 21525959 TI - Transplantation: Early switch from calcineurin inhibitors to mTOR inhibitors leads to improved renal graft function. PMID- 21525960 TI - Polycystic kidney disease: Urinary fingerprints unique to patients with ADPKD. PMID- 21525961 TI - Polycystic kidney disease: Renal transplantation in patients with ADPKD--the good, the bad and ugly. PMID- 21525962 TI - Mineral metabolism: Loop diuretics may contribute to secondary hyperparathyroidism. PMID- 21525964 TI - Association of a polymorphism of BTN2A1 with hypertension in Japanese individuals. AB - BACKGROUND: We previously showed that the C->T polymorphism (rs6929846) in butyrophilin, subfamily 2, member A1 gene (BTN2A1) was associated with myocardial infarction in Japanese individuals. Given that hypertension is a major risk factor for myocardial infarction, the association of rs6929846 of BTN2A1 with myocardial infarction might be attributable, at least in part, to its effect on susceptibility to hypertension. We have thus examined the relation of rs6929846 of BTN2A1 to hypertension in Japanese individuals. METHODS: A total of 8,567 Japanese individuals from two independent subject panels were examined: Subject panels A and B comprised 2,317 hypertensive individuals and 1,933 controls, and 2,911 hypertensive individuals and 1,406 controls, respectively. The genotype of rs6929846 was determined by a method that combines the PCR and sequence-specific oligonucleotide probes with suspension array technology. RESULTS: Multivariable logistic regression analysis with adjustment for covariates revealed that rs6929846 of BTN2A1 was significantly associated with hypertension in subject panel A (P = 2.6 * 10(-6); odds ratio, 1.69) and in subject panel B (P = 0.0284; odds ratio, 1.24), with the T allele representing a risk factor for hypertension. The rs6929846 was associated with systolic blood pressure (BP) in subject panels A (P = 0.0063) and B (P = 0.0115) and with diastolic BP in subject panel B (P = 0.0323), with the T allele being related to high BP. CONCLUSIONS: BTN2A1 may be a susceptibility gene for hypertension in Japanese individuals. Determination of genotype for this polymorphism may prove informative for assessment of the genetic risk for hypertension. PMID- 21525965 TI - Home and ambulatory blood pressure to identify white coat and masked hypertension in the pediatric patient. AB - OBJECTIVE: To evaluate the effect of the environment and the observer on the measurement of blood pressure (BP) as well as to compare home BP (HBP) and ambulatory BP (ABP) measurements in the diagnosis of white coat hypertension (WCH) and masked hypertension (MH) in children and adolescents with hypertension (HT). METHODS: BP of 40 patients with HT (75% of which had secondary HT and were on antihypertensive medication), mean age 12.1 years was evaluated through casual measurements at the clinic and at the HT unit, HBP for 14 days with the OMRON HEM 705 CP monitor (Omron, Tokyo, Japan) and ABP performed with SPACELABS 90207 (Spacelabs, Redmond, WA), for 24 h. RESULTS: HT was diagnosed at the doctor's office by ABP and HBP in 30/40, 27/40, and 31/40 patients, respectively. Based on office BP and ABP, 60% of patients were normotensive, 17.5% HT, 7.5% had WCH, and 15% had MH, whereas based on office BP and HBP 65, 12.5, 10, and 12.5% of patients were classified according to these diagnoses, respectively. There was considerable diagnostic agreement of HT by ABP and HBP (McNemar test, P < 0.01) (kappa = 0.56). CONCLUSION: In hypertensive children and adolescents, HBP and ABP present comparable results. HBP appears to be a useful diagnostic test for the detection of MH and WCH in pediatric patients. PMID- 21525966 TI - Association of masked hypertension and left ventricular remodeling with the hypertensive response to exercise. AB - BACKGROUND: A hypertensive response to exercise (HRE; defined as normal clinic blood pressure (BP) and exercise systolic BP (SBP) >=210 mm Hg in men or >=190 mm Hg in women, or diastolic BP (DBP) >=105 mm Hg) independently predicts mortality. The mechanisms remain unclear but may be related to masked hypertension. This study aimed to assess the prevalence of masked hypertension and its association with cardiovascular risk factors, including left ventricular (LV) mass, in patients with a HRE. METHODS: Comprehensive clinical and echocardiographic evaluation (including central BP, aortic pulse wave velocity by tonometry) and 24 h ambulatory BP monitoring (ABPM) were performed in 72 untreated patients with HRE (aged 54 +/- 9 years; 60% male; free from coronary artery disease confirmed by exercise stress echocardiography). Masked hypertension was defined according to guidelines as daytime ABPM >=135/85 mm Hg and clinic BP <140/90 mm Hg. RESULTS: Masked hypertension was present in 42 patients (58%). These patients had higher LV mass index (41.5 +/- 8.7 g/m(2.7) vs. 35.9 +/- 8.5 g/m(2.7); P = 0.01), LV relative wall thickness (RWT; 0.42 +/- 0.09 vs. 0.37 +/- 0.06; P = 0.004) and exercise SBP (222 +/- 17 mm Hg vs. 212 +/- 14 mm Hg; P = 0.01), but no significant difference in aortic pulse wave velocity or central pulse pressure (P > 0.05 for both). The strongest independent determinant of LV mass index was the presence of masked hypertension (unstandardized beta = 5.6; P = 0.007), which was also independently related to LV RWT (unstandardized beta = 0.04; P = 0.03). CONCLUSIONS: Masked hypertension is highly prevalent in HRE patients with a normal resting office BP and is associated with increased LV mass index and RWT. Clinicians should consider measuring ABPM or home BP in HRE patients. PMID- 21525967 TI - Management of blood pressure in patients with diabetes. AB - Hypertension is a major modifiable risk factor for cardiovascular morbidity and mortality in patients with diabetes. Lowering blood pressure (BP) to 135/85 mm Hg is the main goal of treatment. A nonpharmcologic approach is recommended in all patients. If BP levels remain above the target despite nonpharmacologic treatment, drug therapy should be initiated. Blockers of the renin-angiotensin aldosterone system (RAAS) represent the cornerstone of the antihypertensive drug arsenal; however, in most patients, combination therapy is required. For many patients, a combination of RAAS blocker and calcium antagonist is the combination preferred by the treating physician. Often three or even four drugs are needed. Treatment should be individualized according to concomitant risk factors and diseases and depending on the age and hemodynamic and laboratory parameters of the patient. In order to maximally reduce cardio renal risk, control of lipid and glycemic levels should also be ensured. PMID- 21525968 TI - Vitamin D, parathyroid hormone, and blood pressure in the National Health and Nutrition Examination Surveys . AB - BACKGROUND: Previous research shows serum 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) are each associated with blood pressure (BP), but it is unclear whether these associations are independent. METHODS: Cross-sectional data from the US National Health and Nutrition Examination Surveys (NHANES) during 2003-2006. Analyses were restricted to 7,561 participants aged >=20 years with measurements of 25(OH)D, PTH, BP, BP treatment, smoking, physical activity, serum calcium, and creatinine. Results were adjusted for these plus demographic variables. RESULTS: Serum 25(OH)D was more strongly associated (inversely) with systolic than diastolic BP. Adjusted mean (standard error) difference in BP for the lowest 25(OH)D quintile (<=13 ng/ml) was 3.5 (0.7) mm Hg for systolic BP and 1.8 (0.6) mm Hg for diastolic BP, compared with the highest quintile (>=30 ng/ml). In contrast, PTH was positively associated with both systolic and diastolic BP (P < 0.0001). Adjusted mean (standard error) difference in BP for the highest PTH quintile (>=59 ng/l) was 5.9 (0.8) mm Hg for systolic BP and 4.5 (0.5) mm Hg for diastolic BP, compared with the lowest quintile (<=27 ng/l). When both 25(OH)D and PTH were included in the same model, the associations of PTH with systolic and diastolic BP were unchanged. However, the associations between 25(OH)D and BP were attenuated, with mean (standard error) difference between the highest and lowest quintiles being 2.2 (0.6) mm Hg for systolic BP (P < 0.01) and 0.8 (0.6) mm Hg for diastolic BP. CONCLUSION: PTH may mediate most of the association between 25(OH)D and BP, which was not significant when also adjusting for body mass index. PMID- 21525969 TI - Combined effect of high-normal blood pressure and low HDL cholesterol on mortality in an elderly Korean population: the South-West Seoul (SWS) study. AB - BACKGROUND: It is unclear whether prehypertension by the seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) criteria (systolic blood pressure (SBP) 120-139 or diastolic blood pressure (DBP) 80-89 mm Hg) or high-normal blood pressure (HNBP) by the European Society of Hypertension and European Society of Cardiology (ESH/ESC) criteria (SBP 130-139 or DBP 85-89 mm Hg) predicts mortality in elderly Koreans. We compared the mortality risk between those with prehypertension and HNBP and evaluated whether the presence of components of metabolic syndrome (MetS) can improve the prediction of mortality in subjects with HNBP. METHODS: We analyzed all-cause and cardiovascular disease (CVD) mortality according to the JNC-7 and ESH/ESC categories using follow-up data of the South-West Seoul (SWS) Study, a prospective cohort study of 2,376 elderly Koreans, aged >60 years. RESULTS: During the median follow-up of 7.6 years, 353 deaths occurred from all causes, and 113 of these were attributed to CVD. Prehypertension was nonsignificantly associated with an increased risk of mortality (hazard ratio (HR): 1.06, 95% confidence interval (CI): 0.68-1.64). Subjects with HNBP exhibited a nonsignificantly higher risk of mortality compared with those with optimal blood pressure by the ESH/ESC guideline (HR: 1.35, 95% CI: 0.84-2.18). However, the combination of low high-density lipoprotein (HDL) cholesterol and HNBP showed a twofold higher risk of all-cause mortality (HR: 2.01, 95% CI: 1.11-3.64) independent of other risk factors. CONCLUSIONS: Although prehypertension was not associated with increased risk of mortality, individuals in the elderly Korean population with HNBP, especially when combined with low HDL cholesterol, showed a significantly increased risk of all-cause mortality. PMID- 21525970 TI - A clinical phenotype mimicking essential hypertension in a newly discovered family with Liddle's syndrome. AB - BACKGROUND: Liddle's syndrome (LS) is a monogenic form of hypertension simulating a mineralocorticoid excess, and is currently suspected in young hypokalemic hypertensives. The aims of the study were: (i) to evaluate the clinical phenotype of LS in a newly identified Italian family of Sicilian origin carrying a gain-of function mutation of the beta subunit of the epithelial sodium channel (ENaC) (P617L) previously reported by our group in an apparently unrelated Sicilian patient presenting the typical phenotype of LS including hypokalemia; (ii) to determine whether an unknown biological relationship exists between the newly identified family and the family of the proband previously reported. METHODS: Genetic analysis was performed in the present family, in the individual in which the betaP617L mutation was first observed, and in his relatives. RESULTS: betaP617L mutation was identified in the proband and in three maternal relatives. None of them showed hypokalemia. Mild to severe early onset hypertension and left ventricular hypertrophy were present in all of them. Analysis of mitochondrial DNA (mtDNA) and Y chromosome profiles in the present family and in the proband's family previously reported showed the absence of a relationship between them. The availability of only one carrier of the mutation in one of the two families meant that a genetic analysis able to assess a founder effect was not feasible. CONCLUSIONS: LS should be considered in all cases of early onset hypertension, independently of the plasma potassium concentration. The incidence of LS may be greater than is currently thought, because hypokalemia is not invariably present. PMID- 21525971 TI - Prognostic factors influencing survival after nephroureterectomy for transitional cell carcinoma of the upper urinary tract. AB - We analyzed the prognostic factors influencing survival after surgeries for upper urinary tract urothelial carcinoma (UUT-UC) with longer follow-up periods than in previous studies. Between January 2000 and December 2004, 386 patients underwent nephroureterectomy for UUT-UC. The data for the 221 patients with UUT-UC were retrospectively reviewed. Nine variables were evaluated for association with the survival outcomes of disease-specific survival. The prognostic significance was tested univariately with the log-rank test. The simultaneous effects of multiple prognostic factors were estimated by multiple regression analysis using the Cox proportional hazards model. The median follow-up was 38.4 months. The 5-year over all survival was 62.3%. Significant prognostic factors for disease-specific survival rate on univariate analysis were pathological stage (p<0.0001), tumor grade (p=0.0324), and venous invasion (p<0.0001). Multivariate analysis revealed that only venous invasion was significant for disease-specific survival rate (p=0.0205). Venous invasion was the only independent prognostic factor in pathologically localized UUT-UC. PMID- 21525972 TI - Cues for early social skills: direct gaze modulates newborns' recognition of talking faces. AB - Previous studies showed that, from birth, speech and eye gaze are two important cues in guiding early face processing and social cognition. These studies tested the role of each cue independently; however, infants normally perceive speech and eye gaze together. Using a familiarization-test procedure, we first familiarized newborn infants (n = 24) with videos of unfamiliar talking faces with either direct gaze or averted gaze. Newborns were then tested with photographs of the previously seen face and of a new one. The newborns looked longer at the face that previously talked to them, but only in the direct gaze condition. These results highlight the importance of both speech and eye gaze as socio communicative cues by which infants identify others. They suggest that gaze and infant-directed speech, experienced together, are powerful cues for the development of early social skills. PMID- 21525973 TI - A snapshot of the population structure of Branchiostoma lanceolatum in the Racou beach, France, during its spawning season. AB - A methodology for inducing spawning in captivity of the lancelet Branchiostoma lanceolatum has been developed recently with animals collected at the Racou beach, in the southern coast of France. An increasing amount of laboratories around the world are now working on the evolution of developmental mechanisms (Evo-Devo) using amphioxus collected in this site. Thus, today, the development of new aquaculture techniques for keeping amphioxus in captivity is needed and the study of the natural conditions at which amphioxus is exposed in the Racou beach during their spawning season becomes necessary. We have investigated the amphioxus distribution, size frequency, and population structure in the Racou beach during its natural spawning season using multivariate methods (redundancy analysis and multiple regression). We found a clear preference of amphioxus for sandy sites, something that seems to be a general behaviour of different amphioxus species around the world. We have also estimated the amphioxus growth rate and we show how the animals are preferentially localized in shallow waters during April and June. PMID- 21525974 TI - Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates. AB - BACKGROUND: Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels. RESULTS: Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation. CONCLUSION: We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants. PMID- 21525975 TI - Optimal resting-growth strategies of microbial populations in fluctuating environments. AB - Bacteria spend most of their lifetime in non-growing states which allow them to survive extended periods of stress and starvation. When environments improve, they must quickly resume growth to maximize their share of limited nutrients. Cells with higher stress resistance often survive longer stress durations at the cost of needing more time to resume growth, a strong disadvantage in competitive environments. Here we analyze the basis of optimal strategies that microorganisms can use to cope with this tradeoff. We explicitly show that the prototypical inverse relation between stress resistance and growth rate can explain much of the different types of behavior observed in stressed microbial populations. Using analytical mathematical methods, we determine the environmental parameters that decide whether cells should remain vegetative upon stress exposure, downregulate their metabolism to an intermediate optimum level, or become dormant. We find that cell-cell variability, or intercellular noise, is consistently beneficial in the presence of extreme environmental fluctuations, and that it provides an efficient population-level mechanism for adaption in a deteriorating environment. Our results reveal key novel aspects of responsive phenotype switching and its role as an adaptive strategy in changing environments. PMID- 21525976 TI - Factors influencing the emergence and spread of HIV drug resistance arising from rollout of antiretroviral pre-exposure prophylaxis (PrEP). AB - BACKGROUND: The potential for emergence and spread of HIV drug resistance from rollout of antiretroviral (ARV) pre-exposure prophylaxis (PrEP) is an important public health concern. We investigated determinants of HIV drug resistance prevalence after PrEP implementation through mathematical modeling. METHODOLOGY: A model incorporating heterogeneity in age, gender, sexual activity, HIV infection status, stage of disease, PrEP coverage/discontinuation, and HIV drug susceptibility, was designed to simulate the impact of PrEP on HIV prevention and drug resistance in a sub-Saharan epidemic. PRINCIPAL FINDINGS: Analyses suggest that the prevalence of HIV drug resistance is influenced most by the extent and duration of inadvertent PrEP use in individuals already infected with HIV. Other key factors affecting drug resistance prevalence include the persistence time of transmitted resistance and the duration of inadvertent PrEP use in individuals who become infected on PrEP. From uncertainty analysis, the median overall prevalence of drug resistance at 10 years was predicted to be 9.2% (interquartile range 6.9%-12.2%). An optimistic scenario of 75% PrEP efficacy, 60% coverage of the susceptible population, and 5% inadvertent PrEP use predicts a rise in HIV drug resistance prevalence to only 2.5% after 10 years. By contrast, in a pessimistic scenario of 25% PrEP efficacy, 15% population coverage, and 25% inadvertent PrEP use, resistance prevalence increased to over 40%. CONCLUSIONS: Inadvertent PrEP use in previously-infected individuals is the major determinant of HIV drug resistance prevalence arising from PrEP. Both the rate and duration of inadvertent PrEP use are key factors. PrEP rollout programs should include routine monitoring of HIV infection status to limit the spread of drug resistance. PMID- 21525977 TI - The structure of the NPC1L1 N-terminal domain in a closed conformation. AB - BACKGROUND: NPC1L1 is the molecular target of the cholesterol lowering drug Ezetimibe and mediates the intestinal absorption of cholesterol. Inhibition or deletion of NPC1L1 reduces intestinal cholesterol absorption, resulting in reduction of plasma cholesterol levels. PRINCIPAL FINDINGS: Here we present the 2.8 A crystal structure of the N-terminal domain (NTD) of NPC1L1 in the absence of cholesterol. The structure, combined with biochemical data, reveals the mechanism of cholesterol selectivity of NPC1L1. Comparison to the cholesterol free and bound structures of NPC1(NTD) reveals that NPC1L1(NTD) is in a closed conformation and the sterol binding pocket is occluded from solvent. CONCLUSION: The structure of NPC1L1(NTD) reveals a degree of flexibility surrounding the entrance to the sterol binding pocket, suggesting a gating mechanism that relies on multiple movements around the entrance to the sterol binding pocket. PMID- 21525978 TI - Face inversion reduces the persistence of global form and its neural correlates. AB - Face inversion produces a detrimental effect on face recognition. The extent to which the inversion of faces and other kinds of objects influences the perceptual binding of visual information into global forms is not known. We used a behavioral method and functional MRI (fMRI) to measure the effect of face inversion on visual persistence, a type of perceptual memory that reflects sustained awareness of global form. We found that upright faces persisted longer than inverted versions of the same images; we observed a similar effect of inversion on the persistence of animal stimuli. This effect of inversion on persistence was evident in sustained fMRI activity throughout the ventral visual hierarchy, including the lateral occipital area (LO), two face-selective visual areas--the fusiform face area (FFA) and the occipital face area (OFA)--and several early visual areas. V1 showed the same initial fMRI activation to upright and inverted forms but this activation lasted longer for upright stimuli. The inversion effect on persistence-related fMRI activity in V1 and other retinotopic visual areas demonstrates that higher-tier visual areas influence early visual processing via feedback. This feedback effect on figure-ground processing is sensitive to the orientation of the figure. PMID- 21525979 TI - The GBS PI-2a pilus is required for virulence in mice neonates. AB - BACKGROUND: Streptococcus agalactiae (Group B Streptococcus) is a leading cause of sepsis and meningitis in newborns. Most bacterial pathogens, including gram positive bacteria, have long filamentous structures known as pili extending from their surface. Although pili are described as adhesive organelles, they have been also implicated in many other functions including thwarting the host immune responses. We previously characterized the pilus-encoding operon PI-2a (gbs1479 1474) in strain NEM316. This pilus is composed of three structural subunit proteins: PilA (Gbs1478), PilB (Gbs1477), and PilC (Gbs1474), and its assembly involves two class C sortases (SrtC3 and SrtC4). PilB, the bona fide pilin, is the major component whereas PilA, the pilus associated adhesin, and PilC the pilus anchor are both accessory proteins incorporated into the pilus backbone. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the role of the major pilin subunit PilB was tested in systemic virulence using 6-weeks old and newborn mice. Notably, the non-piliated DeltapilB mutant was less virulent than its wild-type counterpart in the newborn mice model. Next, we investigated the possible role(s) of PilB in resistance to innate immune host defenses, i.e. resistance to macrophage killing and to antimicrobial peptides. Phagocytosis and survival of wild-type NEM316 and its isogenic DeltapilB mutant in immortalized RAW 264.7 murine macrophages were not significantly different whereas the isogenic DeltasodA mutant was more susceptible to killing. These results were confirmed using primary peritoneal macrophages. We also tested the activities of five cationic antimicrobial peptides (AMP-1D, LL-37, colistin, polymyxin B, and mCRAMP) and found no significant difference between WT and DeltapilB strains whereas the isogenic dltA mutant showed increased sensitivity. CONCLUSIONS/SIGNIFICANCE: These results question the previously described role of PilB pilus in resistance to the host immune defenses. Interestingly, PilB was found to be important for virulence in the neonatal context. PMID- 21525980 TI - Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks. AB - BACKGROUND: Micronuclei (MN) in mammalian cells serve as a reliable biomarker of genomic instability and genotoxic exposure. Elevation of MN is commonly observed in cells bearing intrinsic genomic instability and in normal cells exposed to genotoxic agents. DNA double-strand breaks are marked by phosphorylation of H2AX at serine 139 (gamma-H2AX). One subclass of MN contains massive and uniform gamma H2AX signals. This study tested whether this subclass of MN can be induced by replication stress. PRINCIPAL FINDINGS: We observed that a large proportion of MN, from 20% to nearly 50%, showed uniform staining by antibodies against gamma H2AX, a marker of DNA double-strand breaks (DSBs). Such micronuclei were designated as MN-gamma-H2AX (+). We showed that such MN can be induced by chemicals that are known to cause DNA replication stress and S phase arrest. Hydroxyurea, aphidicolin and thymidine could all significantly induce MN-gamma H2AX (+), which were formed during S phase and appeared to be derived from aggregation of DSBs. MN-gamma-H2AX (-), MN that were devoid of uniform gamma-H2AX signals, were induced to a lesser extent in terms of fold change. Paclitaxel, which inhibits the disassembly of microtubules, only induced MN-gamma-H2AX (-). The frequency of MN-gamma-H2AX (+), but not that of MN-gamma-H2AX (-), was also significantly increased in cells that experience S phase prolongation due to depletion of cell cycle regulator CUL4B. Depletion of replication protein A1 (RPA1) by RNA interference resulted in an elevation of both MN-gamma-H2AX (+) and MN-gamma-H2AX (-). CONCLUSIONS/SIGNIFICANCE: A subclass of MN, MN-gamma-H2AX (+), can be preferentially induced by replication stress. Classification of MN according to their gamma-H2AX status may provide a more refined evaluation of intrinsic genomic instabilities and the various environmental genotoxicants. PMID- 21525981 TI - Global changes in Staphylococcus aureus gene expression in human blood. AB - Staphylococcus aureus is a leading cause of bloodstream infections worldwide. In the United States, many of these infections are caused by a strain known as USA300. Although progress has been made, our understanding of the S. aureus molecules that promote survival in human blood and ultimately facilitate metastases is incomplete. To that end, we analyzed the USA300 transcriptome during culture in human blood, human serum, and trypticase soy broth (TSB), a standard laboratory culture media. Notably, genes encoding several cytolytic toxins were up-regulated in human blood over time, and hlgA, hlgB, and hlgC (encoding gamma-hemolysin subunits HlgA, HlgB, and HlgC) were among the most highly up-regulated genes at all time points. Compared to culture supernatants from a wild-type USA300 strain (LAC), those derived from an isogenic hlgABC deletion strain (LACDeltahlgABC) had significantly reduced capacity to form pores in human neutrophils and ultimately cause neutrophil lysis. Moreover, LACDeltahlgABC had modestly reduced ability to cause mortality in a mouse bacteremia model. On the other hand, wild-type and LACDeltahlgABC strains caused virtually identical abscesses in a mouse skin infection model, and bacterial survival and neutrophil lysis after phagocytosis in vitro was similar between these strains. Comparison of the cytolytic capacity of culture supernatants from wild-type and isogenic deletion strains lacking hlgABC, lukS/F-PV (encoding PVL), and/or lukDE revealed functional redundancy among two-component leukotoxins in vitro. These findings, along with a requirement of specific growth conditions for leukotoxin expression, may explain the apparent limited contribution of any single two-component leukotoxin to USA300 immune evasion and virulence. PMID- 21525982 TI - RAPD and internal transcribed spacer sequence analyses reveal Zea nicaraguensis as a section Luxuriantes species close to Zea luxurians. AB - Genetic relationship of a newly discovered teosinte from Nicaragua, Zea nicaraguensis with waterlogging tolerance, was determined based on randomly amplified polymorphic DNA (RAPD) markers and the internal transcribed spacer (ITS) sequences of nuclear ribosomal DNA using 14 accessions from Zea species. RAPD analysis showed that a total of 5,303 fragments were produced by 136 random decamer primers, of which 84.86% bands were polymorphic. RAPD-based UPGMA analysis demonstrated that the genus Zea can be divided into section Luxuriantes including Zea diploperennis, Zea luxurians, Zea perennis and Zea nicaraguensis, and section Zea including Zea mays ssp. mexicana, Zea mays ssp. parviglumis, Zea mays ssp. huehuetenangensis and Zea mays ssp. mays. ITS sequence analysis showed the lengths of the entire ITS region of the 14 taxa in Zea varied from 597 to 605 bp. The average GC content was 67.8%. In addition to the insertion/deletions, 78 variable sites were recorded in the total ITS region with 47 in ITS1, 5 in 5.8S, and 26 in ITS2. Sequences of these taxa were analyzed with neighbor-joining (NJ) and maximum parsimony (MP) methods to construct the phylogenetic trees, selecting Tripsacum dactyloides L. as the outgroup. The phylogenetic relationships of Zea species inferred from the ITS sequences are highly concordant with the RAPD evidence that resolved two major subgenus clades. Both RAPD and ITS sequence analyses indicate that Zea nicaraguensis is more closely related to Zea luxurians than the other teosintes and cultivated maize, which should be regarded as a section Luxuriantes species. PMID- 21525983 TI - Genetic transformation of an obligate anaerobe, P. gingivalis for FMN-green fluorescent protein expression in studying host-microbe interaction. AB - The recent introduction of "oxygen-independent" flavin mononucleotide (FMN)-based fluorescent proteins (FbFPs) is of major interest to both eukaryotic and prokaryotic microbial biologists. Accordingly, we demonstrate for the first time that an obligate anaerobe, the successful opportunistic pathogen of the oral cavity, Porphyromonas gingivalis, can be genetically engineered for expression of the non-toxic green FbFP. The resulting transformants are functional for studying dynamic bacterial processes in living host cells. The visualization of the transformed P. gingivalis (PgFbFP) revealed strong fluorescence that reached a maximum emission at 495 nm as determined by fluorescence microscopy and spectrofluorometry. Human primary gingival epithelial cells (GECs) were infected with PgFbFP and the bacterial invasion of host cells was analyzed by a quantitative fluorescence microscopy and antibiotic protection assays. The results showed similar levels of intracellular bacteria for both wild type and PgFbFP strains. In conjunction with organelle specific fluorescent dyes, utilization of the transformed strain provided direct and accurate determination of the live/metabolically active P. gingivalis' trafficking in the GECs over time. Furthermore, the GECs were co-infected with PgFbFP and the ATP-dependent Clp serine protease-deficient mutant (ClpP-) to study the differential fates of the two strains within the same host cells. Quantitative co-localization analyses displayed the intracellular PgFbFP significantly associated with the endoplasmic reticulum network, whereas the majority of ClpP- organisms trafficked into the lysosomes. Hence, we have developed a novel and reliable method to characterize live host cell-microbe interactions and demonstrated the adaptability of FMN green fluorescent protein for studying persistent host infections induced by obligate anaerobic organisms. PMID- 21525984 TI - Staphylococcus aureus protein A binds to osteoblasts and triggers signals that weaken bone in osteomyelitis. AB - Osteomyelitis is a debilitating infectious disease of the bone. It is predominantly caused by S. aureus and is associated with significant morbidity and mortality. It is characterised by weakened bones associated with progressive bone loss. Currently the mechanism through which either bone loss or bone destruction occurs in osteomyelitis patients is poorly understood. We describe here for the first time that the major virulence factor of S. aureus, protein A (SpA) binds directly to osteoblasts. This interaction prevents proliferation, induces apoptosis and inhibits mineralisation of cultured osteoblasts. Infected osteoblasts also increase the expression of RANKL, a key protein involved in initiating bone resorption. None of these effects was seen in a mutant of S. aureus lacking SpA. Complementing the SpA-defective mutant with a plasmid expressing spa or using purified protein A resulted in attachment to osteoblasts, inhibited proliferation and induced apoptosis to a similar extent as wildtype S. aureus. These events demonstrate mechanisms through which loss of bone formation and bone weakening may occur in osteomyelitis patients. This new information may pave the way for the development of new and improved therapeutic agents to treat this disease. PMID- 21525985 TI - Antigen-specific monoclonal antibodies isolated from B cells expressing constitutively active STAT5. AB - BACKGROUND: Fully human monoclonal antibodies directed against specific pathogens have a high therapeutic potential, but are difficult to generate. METHODOLOGY/PRINCIPAL FINDINGS: Memory B cells were immortalized by expressing an inducible active mutant of the transcription factor Signal Transducer and Activator of Transcription 5 (STAT5). Active STAT5 inhibits the differentiation of B cells while increasing their replicative life span. We obtained cloned B cell lines, which produced antibodies in the presence of interleukin 21 after turning off STAT5. We used this method to obtain monoclonal antibodies against the model antigen tetanus toxin. CONCLUSIONS/SIGNIFICANCE: Here we describe a novel and relatively simple method of immortalizing antigen-specific human B cells for isolation of human monoclonal antibodies. These results show that STAT5 overexpression can be employed to isolate antigen specific antibodies from human memory B cells. PMID- 21525986 TI - Association of plasma Abeta peptides with blood pressure in the elderly. AB - BACKGROUND: Abeta peptides are often considered as catabolic by-products of the amyloid beta protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion. We assess whether plasma Abeta peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively). METHODOLOGY/PRINCIPAL FINDINGS: Plasma Abeta(1-40) and Abeta(1-42) levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Abeta(1-42)/ Abeta(1-40) ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Abeta(1-42)/Abeta(1-40) ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Abeta(1-42)/ Abeta(1-40) ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37-0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Abeta(1-40). CONCLUSION: The plasma Abeta(1-42)/Abeta(1-40) ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Abeta peptides affect blood pressure in vivo. These results may be particularly relevant in Alzheimer's disease, in which a high Abeta(1-42)/Abeta(1-40) plasma ratio is reportedly associated with a decreased risk of incident disease. PMID- 21525987 TI - How group size affects vigilance dynamics and time allocation patterns: the key role of imitation and tempo. AB - In the context of social foraging, predator detection has been the subject of numerous studies, which acknowledge the adaptive response of the individual to the trade-off between feeding and vigilance. Typically, animals gain energy by increasing their feeding time and decreasing their vigilance effort with increasing group size, without increasing their risk of predation ('group size effect'). Research on the biological utility of vigilance has prevailed over considerations of the mechanistic rules that link individual decisions to group behavior. With sheep as a model species, we identified how the behaviors of conspecifics affect the individual decisions to switch activity. We highlight a simple mechanism whereby the group size effect on collective vigilance dynamics is shaped by two key features: the magnitude of social amplification and intrinsic differences between foraging and scanning bout durations. Our results highlight a positive correlation between the duration of scanning and foraging bouts at the level of the group. This finding reveals the existence of groups with high and low rates of transition between activities, suggesting individual variations in the transition rate, or 'tempo'. We present a mathematical model based on behavioral rules derived from experiments. Our theoretical predictions show that the system is robust in respect to variations in the propensity to imitate scanning and foraging, yet flexible in respect to differences in the duration of activity bouts. The model shows how individual decisions contribute to collective behavior patterns and how the group, in turn, facilitates individual-level adaptive responses. PMID- 21525988 TI - Modulation of activity in human visual area V1 during memory masking. AB - Neurons in the primary visual cortex, V1, are specialized for the processing of elemental features of the visual stimulus, such as orientation and spatial frequency. Recent fMRI evidence suggest that V1 neurons are also recruited in visual perceptual memory; a number of studies using multi-voxel pattern analysis have successfully decoded stimulus-specific information from V1 activity patterns during the delay phase in memory tasks. However, consistent fMRI signal modulations reflecting the memory process have not yet been demonstrated. Here, we report evidence, from three subjects, that the low V1 BOLD activity during retention of low-level visual features is caused by competing interactions between neural populations coding for different values along the spectrum of the dimension remembered. We applied a memory masking paradigm in which the memory representation of a masker stimulus interferes with a delayed spatial frequency discrimination task when its frequency differs from the discriminanda with +/-1 octave and found that impaired behavioral performance due to masking is reflected in weaker V1 BOLD signals. This cross-channel inhibition in V1 only occurs with retinotopic overlap between the masker and the sample stimulus of the discrimination task. The results suggest that memory for spatial frequency is a local process in the retinotopically organized visual cortex. PMID- 21525989 TI - Circulating FGF21 levels are progressively increased from the early to end stages of chronic kidney diseases and are associated with renal function in Chinese. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) is a hepatic hormone involved in the regulation of lipid and carbohydrate metabolism. This study aims to test the hypothesis that elevated FGF21 concentrations are associated with the change of renal function and the presence of left ventricular hypertrophy (LVH) in the different stages of chronic kidney disease (CKD) progression. METHODOLOGY/PRINCIPAL FINDINGS: 240 subjects including 200 CKD patients (146 outpatients and 54 long-term hemodialytic patients) and 40 healthy control subjects were recruited. All CKD subjects underwent echocardiograms to assess left ventricular mass index. Plasma FGF21 levels and other clinical and biochemical parameters in all subjects were obtained based on standard clinical examination methods. Plasma FGF21 levels were significantly increased with the development of CKD from early- and end-stage (P<0.001 for trend), and significantly higher in CKD subjects than those in healthy subjects (P<0.001). Plasma FGF21 levels in CKD patients with LVH were higher than those in patients without LVH (P = 0.001). Furthermore, plasma FGF21 level correlated positively with creatinine, blood urea nitrogen (BUN), beta2 microglobulin, systolic pressure, adiponectin, phosphate, proteinuria, CRP and triglyceride, but negatively with creatinine clearance rate (CCR), estimated glomerular filtrate rate (eGFR), HDL-c, LDL-c, albumin and LVH after adjusting for BMI, gender, age and the presence of diabetes mellitus. Multiple stepwise regression analyses indicated that FGF21 was independently associated with BUN, Phosphate, LVMI and beta2 microglobulin (all P<0.05). CONCLUSION: Plasma FGF21 levels are significantly increased with the development of early- to end-stage CKD and are independently associated with renal function and adverse lipid profiles in Chinese population. Understanding whether increased FGF21 is associated with myocardial hypertrophy in CKD requires further study. PMID- 21525990 TI - Global habitat suitability for framework-forming cold-water corals. AB - Predictive habitat models are increasingly being used by conservationists, researchers and governmental bodies to identify vulnerable ecosystems and species' distributions in areas that have not been sampled. However, in the deep sea, several limitations have restricted the widespread utilisation of this approach. These range from issues with the accuracy of species presences, the lack of reliable absence data and the limited spatial resolution of environmental factors known or thought to control deep-sea species' distributions. To address these problems, global habitat suitability models have been generated for five species of framework-forming scleractinian corals by taking the best available data and using a novel approach to generate high resolution maps of seafloor conditions. High-resolution global bathymetry was used to resample gridded data from sources such as World Ocean Atlas to produce continuous 30-arc second (~1 km(2)) global grids for environmental, chemical and physical data of the world's oceans. The increased area and resolution of the environmental variables resulted in a greater number of coral presence records being incorporated into habitat models and higher accuracy of model predictions. The most important factors in determining cold-water coral habitat suitability were depth, temperature, aragonite saturation state and salinity. Model outputs indicated the majority of suitable coral habitat is likely to occur on the continental shelves and slopes of the Atlantic, South Pacific and Indian Oceans. The North Pacific has very little suitable scleractinian coral habitat. Numerous small scale features (i.e., seamounts), which have not been sampled or identified as having a high probability of supporting cold-water coral habitat were identified in all ocean basins. Field validation of newly identified areas is needed to determine the accuracy of model results, assess the utility of modelling efforts to identify vulnerable marine ecosystems for inclusion in future marine protected areas and reduce coral bycatch by commercial fisheries. PMID- 21525991 TI - Climatic factors driving invasion of the tiger mosquito (Aedes albopictus) into new areas of Trentino, northern Italy. AB - BACKGROUND: The tiger mosquito (Aedes albopictus), vector of several emerging diseases, is expanding into more northerly latitudes as well as into higher altitudes in northern Italy. Changes in the pattern of distribution of the tiger mosquito may affect the potential spread of infectious diseases transmitted by this species in Europe. Therefore, predicting suitable areas of future establishment and spread is essential for planning early prevention and control strategies. METHODOLOGY/PRINCIPAL FINDINGS: To identify the areas currently most suitable for the occurrence of the tiger mosquito in the Province of Trento, we combined field entomological observations with analyses of satellite temperature data (MODIS Land Surface Temperature: LST) and human population data. We determine threshold conditions for the survival of overwintering eggs and for adult survival using both January mean temperatures and annual mean temperatures. We show that the 0 degrees C LST threshold for January mean temperatures and the 11 degrees C threshold for annual mean temperatures provide the best predictors for identifying the areas that could potentially support populations of this mosquito. In fact, human population density and distance to human settlements appear to be less important variables affecting mosquito distribution in this area. Finally, we evaluated the future establishment and spread of this species in relation to predicted climate warming by considering the A2 scenario for 2050 statistically downscaled at regional level in which winter and annual temperatures increase by 1.5 and 1 degrees C, respectively. CONCLUSIONS/SIGNIFICANCE: MODIS satellite LST data are useful for accurately predicting potential areas of tiger mosquito distribution and for revealing the range limits of this species in mountainous areas, predictions which could be extended to an European scale. We show that the observed trend of increasing temperatures due to climate change could facilitate further invasion of Ae. albopictus into new areas. PMID- 21525992 TI - Replication-fork stalling and processing at a single psoralen interstrand crosslink in Xenopus egg extracts. AB - Interstrand crosslink (ICL)-inducing agents block the separation of the two DNA strands. They prevent transcription and replication and are used in clinics for the treatment of cancer and skin diseases. Here, we have introduced a single psoralen ICL at a specific site in plasmid DNA using a triplex-forming oligonucleotide (TFO)-psoralen conjugate and studied its repair in Xenopus egg extracts that support nuclear assembly and replication of plasmid DNA. Replication forks arriving from either side stalled at the psoralen ICL. In contrast to previous observations with other ICL-inducing agents, the leading strands advanced up to the lesion without any prior pausing. Subsequently, incisions were introduced on one parental strand on both sides of the ICL. These incisions could be detected whether one or both forks reached the ICL. Using small molecule inhibitors, we found that the ATR-Chk1 pathway, but not the ATM Chk2 pathway, stimulated both the incision step and the subsequent processing of the broken replication intermediates. Our results highlight both similarities and differences in fork stalling and repair induced by psoralen and by other ICL forming agents. PMID- 21525993 TI - Quantifying the link between anatomical connectivity, gray matter volume and regional cerebral blood flow: an integrative MRI study. AB - BACKGROUND: In the graph theoretical analysis of anatomical brain connectivity, the white matter connections between regions of the brain are identified and serve as basis for the assessment of regional connectivity profiles, for example, to locate the hubs of the brain. But regions of the brain can be characterised further with respect to their gray matter volume or resting state perfusion. Local anatomical connectivity, gray matter volume and perfusion are traits of each brain region that are likely to be interdependent, however, particular patterns of systematic covariation have not yet been identified. METHODOLOGY/PRINCIPAL FINDINGS: We quantified the covariation of these traits by conducting an integrative MRI study on 23 subjects, utilising a combination of Diffusion Tensor Imaging, Arterial Spin Labeling and anatomical imaging. Based on our hypothesis that local connectivity, gray matter volume and perfusion are linked, we correlated these measures and particularly isolated the covariation of connectivity and perfusion by statistically controlling for gray matter volume. We found significant levels of covariation on the group- and regionwise level, particularly in regions of the Default Brain Mode Network. CONCLUSIONS/SIGNIFICANCE: Connectivity and perfusion are systematically linked throughout a number of brain regions, thus we discuss these results as a starting point for further research on the role of homology in the formation of functional connectivity networks and on how structure/function relationships can manifest in the form of such trait interdependency. PMID- 21525994 TI - A meta-analysis of studies of treatments for feline urine spraying. AB - Feline urine spraying inside the home is a common problem behaviour that owners seek advice for from veterinarians. Individual trials relating to a variety of interventions produce variable results, and to date, no consensus on the value of different treatments has emerged. This study therefore aimed to meta-analyse, current data from appropriate published clinical trials that evaluate treatments for feline urine spraying.Inclusion and exclusion criteria for study selection were predefined and methodological quality was assessed by two independent reviewers. Ten studies in nine publications that either evaluated pharmacotherapy or pheromonatherapy (the use of a synthetic analogue of the F3 facial fraction in the cat) were suitable for analysis. There was a significant (P<0.001) association between the use of any intervention and the number of cats that ceased or reduced urine spraying by at least 90%. Analysis by intervention type indicated that fluoxetine, clomipramine and pheromonatherapy may each assist in managing urine spraying beyond a placebo based intervention.This is the first time meta-analytical techniques have been used and reported to evaluate the efficacy of interventions used in veterinary behavioural medicine, and it has established confidence in the value of both conventional treatments (pharmacotherapy) and a more recently developed treatment modality (pheromonatherapy) as an adjunct to the management of this problem. It is suggested that future research into treatment efficacy for this problem uses the benchmark standard of randomised, controlled trials lasting for at least 8 weeks, with the outcome criteria of cessation of feline urine spraying or reduction by at least 90%. PMID- 21525995 TI - Evaluation of microwave steam bags for the decontamination of filtering facepiece respirators. AB - Reusing filtering facepiece respirators (FFRs) has been suggested as a strategy to conserve available supplies for home and healthcare environments during an influenza pandemic. For reuse to be possible, used FFRs must be decontaminated before redonning to reduce the risk of virus transmission; however, there are no approved methods for FFR decontamination. An effective method must reduce the microbial threat, maintain the function of the FFR, and present no residual chemical hazard. The method should be readily available, inexpensive and easily implemented by healthcare workers and the general public. Many of the general decontamination protocols used in healthcare and home settings are unable to address all of the desired qualities of an efficient FFR decontamination protocol. The goal of this study is to evaluate the use of two commercially available steam bags, marketed to the public for disinfecting infant feeding equipment, for FFR decontamination. The FFRs were decontaminated with microwave generated steam following the manufacturers' instructions then evaluated for water absorption and filtration efficiency for up to three steam exposures. Water absorption of the FFR was found to be model specific as FFRs constructed with hydrophilic materials absorbed more water. The steam had little effect on FFR performance as filtration efficiency of the treated FFRs remained above 95%. The decontamination efficacy of the steam bag was assessed using bacteriophage MS2 as a surrogate for a pathogenic virus. The tested steam bags were found to be 99.9% effective for inactivating MS2 on FFRs; however, more research is required to determine the effectiveness against respiratory pathogens. PMID- 21525996 TI - An allosteric mechanism inferred from molecular dynamics simulations on phospholamban pentamer in lipid membranes. AB - Phospholamban functions as a regulator of Ca(2+) concentration of cardiac muscle cells by triggering the bioactivity of sarcoplasmic reticulum Ca(2+)-ATPase. In order to understand its dynamic mechanism in the environment of bilayer surroundings, we performed long time-scale molecular dynamic simulations based on the high-resolution NMR structure of phospholamban pentamer. It was observed from the molecular dynamics trajectory analyses that the conformational transitions between the "bellflower" and "pinwheel" modes were detected for phospholamban. Particularly, the two modes became quite similar to each other after phospholamban was phosphorylated at Ser16. Based on these findings, an allosteric mechanism was proposed to elucidate the dynamic process of phospholamban interacting with Ca(2+)-ATPase. PMID- 21525997 TI - In vivo dioxin favors interleukin-22 production by human CD4+ T cells in an aryl hydrocarbon receptor (AhR)-dependent manner. AB - BACKGROUND: The transcription factor aryl hydrocarbon receptor (AhR) mediates the effects of a group of chemicals known as dioxins, ubiquitously present in our environment. However, it is poorly known how the in vivo exposure to these chemicals affects in humans the adaptive immune response. We therefore assessed the functional phenotype of T cells from an individual who developed a severe cutaneous and systemic syndrome after having been exposed to an extremely high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). METHODOLOGY/PRINCIPAL FINDINGS: T cells of the TCDD-exposed individual were studied for their capacity to produce cytokines in response to polyclonal and superantigenic stimulation, and for the expression of chemokine receptors involved in skin homing. The supernatants from T cells of the exposed individual contained a substantially increased amount of interleukin (IL)-22 but not of IL-17A, interferon (IFN)-gamma or IL-10 when compared to nine healthy controls. In vitro experiments confirmed a direct, AhR-dependent, enhancing effect of TCDD on IL-22 production by CD4+ T cells. The increased production of IL-22 was not dependent on AhR occupancy by residual TCDD molecules, as demonstrated in competition experiments with the specific AhR antagonist CH-223191. In contrast, it was due to an increased frequency of IL-22 single producing cells accompanied by an increased percentage of cells expressing the skin-homing chemokine receptors CCR6 and CCR4, identified through a multiparameter flow cytometry approach. Of interest, the frequency of CD4+CD25(hi)FoxP3+ T regulatory cells was similar in the TCDD-exposed and healthy individuals. CONCLUSIONS/SIGNIFICANCE: This case strongly supports the contention that human exposure to persistent AhR ligands in vivo induce a long-lasting effect on the human adaptive immune system and specifically polarizes CD4+ T cells to produce IL-22 and not other T cell cytokines with no effect on T regulatory cells. PMID- 21525998 TI - Enhanced auditory neuron survival following cell-based BDNF treatment in the deaf guinea pig. AB - Exogenous neurotrophin delivery to the deaf cochlea can prevent deafness-induced auditory neuron degeneration, however, we have previously reported that these survival effects are rapidly lost if the treatment stops. In addition, there are concerns that current experimental techniques are not safe enough to be used clinically. Therefore, for such treatments to be clinically transferable, methods of neurotrophin treatment that are safe, biocompatible and can support long-term auditory neuron survival are necessary. Cell transplantation and gene transfer, combined with encapsulation technologies, have the potential to address these issues. This study investigated the survival-promoting effects of encapsulated BDNF over-expressing Schwann cells on auditory neurons in the deaf guinea pig. In comparison to control (empty) capsules, there was significantly greater auditory neuron survival following the cell-based BDNF treatment. Concurrent use of a cochlear implant is expected to result in even greater auditory neuron survival, and provide a clinically relevant method to support auditory neuron survival that may lead to improved speech perception and language outcomes for cochlear implant patients. PMID- 21526001 TI - Temsirolimus is highly effective as third-line treatment in chromophobe renal cell cancer. AB - We report unexpectedly high efficacy of temsirolimus as third-line treatment in a patient with metastatic chromophobe renal cell carcinoma. After failure of two sequentially administered tyrosine kinase inhibitors, treatment with temsirolimus resulted in a prolonged partial remission of 14 months, and the response is still continuing. Up to now, no data from randomized clinical studies have been published addressing the question of efficacy of temsirolimus as third-line treatment after failure of tyrosine kinase inhibitors. The case presented here implies that temsirolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma. PMID- 21526000 TI - Fear and exploration in European starlings (Sturnus vulgaris): a comparison of hand-reared and wild-caught birds. AB - The revision of EU legislation will ban the use of wild-caught animals in scientific procedures. This change is partially predicated on the assumption that captive-rearing produces animals with reduced fearfulness. Previously, we have shown that hand-reared starlings (Sturnus vulgaris) indeed exhibit reduced fear of humans compared to wild-caught conspecifics. Here, we asked whether this reduction in fear in hand-reared birds is limited to fear of humans or extends more generally to fear of novel environments and novel objects. Comparing 6-8 month old birds hand-reared in the lab with age-matched birds caught from the wild as fledged juveniles a minimum of 1 month previously, we examined the birds' initial reactions in a novel environment (a small cage) and found that wild caught starlings were faster to initiate movement compared to the hand-reared birds. We interpret this difference as evidence for greater escape motivation in the wild-caught birds. In contrast, we found no differences between hand-reared and wild-caught birds when tested in novel object tests assumed to measure neophobia and exploratory behaviour. Moreover, we found no correlations between individual bird's responses in the different tests, supporting the idea that these measure different traits (e.g. fear and exploration). In summary, our data show that developmental origin affects one measure of response to novelty in young starlings, indicative of a difference in either fear or coping style in a stressful situation. Our data contribute to a growing literature demonstrating effects of early-life experience on later behaviour in a range of species. However, since we did not find consistent evidence for reduced fearfulness in hand-reared birds, we remain agnostic about the welfare benefits of hand-rearing as a method for sourcing wild birds for behavioural and physiological research. PMID- 21525999 TI - Genomic characterization and high prevalence of bocaviruses in swine. AB - Using random PCR amplification followed by plasmid subcloning and DNA sequencing, we detected bocavirus related sequences in 9 out of 17 porcine stool samples. Using primer walking, we sequenced the nearly complete genomes of two highly divergent bocaviruses we provisionally named porcine bocavirus 1 isolate H18 (PBoV1-H18) and porcine bocavirus 2 isolate A6 (PBoV2-A6) which differed by 51.8% in their NS1 protein. Phylogenetic analysis indicated that PBoV1-H18 was very closely related to a ~2 Kb central region of a porcine bocavirus-like virus (PBo LikeV) from Sweden described in 2009. PBoV2-A6 was very closely related to the porcine bocavirus genomes PBoV-1 and PBoV2 from China described in 2010. Among 340 fecal samples collected from different age, asymptomatic swine in five Chinese provinces, the prevalence of PBoV1-H18 and PBoV2-A6 related viruses were 45-75% and 55-70% respectively, with 30-47% of pigs co-infected. PBoV1-A6 related strains were highly conserved, while PBoV2-H18 related strains were more diverse, grouping into two genotypes corresponding to the previously described PBoV1 and PBoV2. Together with the recently described partial bocavirus genomes labeled V6 and V7, a total of three major porcine bocavirus clades have therefore been described to date. Further studies will be required to elucidate the possible pathogenic impact of these diverse bocaviruses either alone or in combination with other porcine viruses. PMID- 21526002 TI - Change in HER-2/neu Status from Negative to Positive following Treatment in Breast Cancer: A Case Report. AB - INTRODUCTION: Approximately 25-30% of breast cancers are assumed to be HER-2/neu positive. It is well known that HER-2/neu-positive cancers after treatment with trastuzumab can become HER-2/neu negative. Change in HER-2/neu status from negative to positive following treatment has not been well studied. We describe a patient with inflammatory breast cancer who was initially HER-2/neu negative but became positive after treatment. A 59-year-old postmenopausal white female saw her surgeon for violaceous discoloration of the left breast for 4 months. The surgeon palpated a mass measuring 6 cm in the patient's left breast. Additionally, there was violaceous discoloration involving two thirds of the breast. Biopsy of the breast mass and skin revealed inflammatory breast cancer. The tumor was estrogen receptor positive, progesterone receptor positive and HER 2/neu negative. The patient was given four cycles of chemotherapy with cyclophosphamide, doxorubicin and docetaxol. She subsequently underwent a mastectomy, excision of the skin over the chest wall and axillary node dissection. Of the axillary lymph nodes, 14/14 were involved. The tumor was still estrogen receptor positive and progesterone receptor positive, but HER-2/neu was 2+ by immunohistochemistry and amplified at 3.3 as detected by fluorescent in situ hybridization. The patient received trastuzumab along with chemotherapy followed by radiation therapy and letrozole. She is currently receiving trastuzumab and letrozole in the adjuvant setting and appears to be doing well. CONCLUSION: A breast cancer which was initially HER-2/neu negative can become positive following treatment. Therefore, re-biopsy may be necessary during the course of treatment of breast cancer to re-assess the HER-2/neu status. This gives the clinician the opportunity to include drugs like trastuzumab and lapatinib in the treatment of patients with a transformation to HER-2/neu positive cancer. PMID- 21526003 TI - Stereotactic body radiation therapy is effective and safe in patients with early stage non-small cell lung cancer with low performance status and severe comorbidity. AB - BACKGROUND: The purpose of this study was to assess stereotactic body radiation therapy (SBRT) results and toxicity for stage I non-small cell lung cancer patients with low performance status and severe comorbidity. PATIENTS AND METHODS: From September 2008 to April 2010, 36 patients with 38 lesions were treated with hypofractionated SBRT. All except one were medically inoperable, had low performance status and/or severe cardiovascular and/or cardiopulmonary comorbidity. The patients were immobilized in an Elekta stereotactic body frame to improve setup accuracy, and four-dimensional CT scans were used for target delineation. Fractions of 15 Gy were prescribed to cover the planning target volume, giving a total dose of 45 Gy, with 1 fraction every second day. Cone beam CT was applied at each fraction to correct for setup errors. The patients were followed with toxicity evaluation and radiographic follow-up. RESULTS: Median follow-up time was 13.8 months (0-21 months). The local tumor control after 12 months was 100%. Four patients developed regional relapse about 12 months after SBRT. The 1-year disease-free survival was 83%. The median tumor shrinkage at 1 year was 22 mm. Three patients experienced systemic relapse after 13 months. One patient developed grade 3 chest pain toxicity and 16 patients reported temporary grade 1 chest pain toxicity. Two patients reported temporary increased dyspnea. No patient experienced a reduction of the performance status after SBRT. CONCLUSION: SBRT is an effective and safe treatment modality for elderly patients with early-stage non-small cell lung cancer, having low performance status and severe comorbidity. It is possible to achieve high local control rates with good tolerance. PMID- 21526004 TI - Facial nerve palsy: an unusual presenting feature of small cell lung cancer. AB - Lung cancer is the second most common type of cancer in the world and is the most common cause of cancer-related death in men and women; it is responsible for 1.3 million deaths annually worldwide. It can metastasize to any organ. The most common site of metastasis in the head and neck region is the brain; however, it can also metastasize to the oral cavity, gingiva, tongue, parotid gland and lymph nodes. This article reports a case of small cell lung cancer presenting with metastasis to the facial nerve. PMID- 21526005 TI - Thyroglossal duct cyst papillary carcinoma. AB - Thyroglossal duct cysts are usually located in the midline of the neck. The coexistence of carcinomas in thyroglossal duct cysts is extremely rare, with most being papillary carcinomas. Usually, the diagnosis is only made postoperatively after excision of the cyst. Although the Sistrunk procedure is often regarded as adequate, controversies exist concerning the need for thyroidectomy depending on histopathological findings. We report the case of a 31-year-old man diagnosed with papillary carcinoma within a thyroglossal duct cyst, who underwent total thyroidectomy as has been recommended for differentiated papillary cancer. PMID- 21526006 TI - Correlation between Cancer Stem Cells and Circulating Tumor Cells and Their Value. AB - BACKGROUND: The scientific community has proven the value of circulating tumor cells (CTCs) as a prognostic factor in the development of cancer and progress to metastases [1, 2, 3, 4]. Simultaneously, a new type of cancer stem cell-like (CSC like) cells has also been established as a progenitor of metastases and relapses in cancer patients [5, 6]. The present research attempts to support the hypothesis that CTCs have all the cellular hallmarks of CSC-like cells which play a crucial role in cancer spreading. MATERIALS AND METHODS: TWO METHODS HAVE BEEN CHOSEN: a cellular-based and a molecular-based method. The first method is based on the fact that CSCs form microspheres in culture. In the second method, microspheres develop in the presence of specific markers that define the CSC phenotype [6]. RESULTS: In cellular-based assays, it has been shown that microspheres form in semi-suspension in a culture flask. In the second panel of the test, Nanog was chosen as a marker and the tested sample was positive when grown under specific conditions. CONCLUSION: Our analysis has demonstrated that in this particular case, CSCs-like cells are included in the vast majority of CTCs. PMID- 21526007 TI - Computational design optimization for microfluidic magnetophoresis. AB - Current macro- and microfluidic approaches for the isolation of mammalian cells are limited in both efficiency and purity. In order to design a robust platform for the enumeration of a target cell population, high collection efficiencies are required. Additionally, the ability to isolate pure populations with minimal biological perturbation and efficient off-chip recovery will enable subcellular analyses of these cells for applications in personalized medicine. Here, a rational design approach for a simple and efficient device that isolates target cell populations via magnetic tagging is presented. In this work, two magnetophoretic microfluidic device designs are described, with optimized dimensions and operating conditions determined from a force balance equation that considers two dominant and opposing driving forces exerted on a magnetic-particle tagged cell, namely, magnetic and viscous drag. Quantitative design criteria for an electromagnetic field displacement-based approach are presented, wherein target cells labeled with commercial magnetic microparticles flowing in a central sample stream are shifted laterally into a collection stream. Furthermore, the final device design is constrained to fit on standard rectangular glass coverslip (60 (L)*24 (W)*0.15 (H) mm(3)) to accommodate small sample volume and point-of care design considerations. The anticipated performance of the device is examined via a parametric analysis of several key variables within the model. It is observed that minimal currents (<500 mA) are required to generate magnetic fields sufficient to separate cells from the sample streams flowing at rate as high as 7 ml/h, comparable to the performance of current state-of-the-art magnet-activated cell sorting systems currently used in clinical settings. Experimental validation of the presented model illustrates that a device designed according to the derived rational optimization can effectively isolate (~100%) a magnetic-particle tagged cell population from a homogeneous suspension even in a low abundance. Overall, this design analysis provides a rational basis to select the operating conditions, including chamber and wire geometry, flow rates, and applied currents, for a magnetic-microfluidic cell separation device. PMID- 21526008 TI - Medical ethics in Libya: where to start? PMID- 21526009 TI - The burden of congenital heart disease in libya. PMID- 21526010 TI - Do we have a diabetes epidemic in Libya? PMID- 21526011 TI - Quantitative pathology: historical background, clinical research and application of nuclear morphometry and DNA image cytometry. PMID- 21526012 TI - Candidaemia in patients with haematological disorders and stem cell transplant. AB - The incidence of non-albicans species of Candida has recently increased, especially in patients with malignant haematological disorders receiving fluconazole prophylaxis. A retrospective study of patients who developed candidaemia at Riyadh Armed Forces Hospital between January 1992 and December 2002 was carried out. Thirty one episodes of candidaemia occurred in 27 patients with a variety of haematological disorders. Twenty-four episodes were caused by non-albicans species of Candida and only 7 episodes were caused by C.albicans. The most frequent underlying haematological disorders were acute myeloid leukaemia (AML) followed by acute lymphoblastic leukaemia (ALL). The main predisposing factors for the development of candidaemia were: broad spectrum antibiotics, central venous catheters, neutropenia, cytotoxic chemotherapy, coexisting bacterial infections, steroid therapy, relapsing or untreated primary disease and fluconazole prophylaxis.Eight episodes were complicated by chronic disseminated candidiasis. Amphotericin-B and amBisome were used in the treatment of Candida infections. The treatment was successful in 86% of the episodes of C. albicans and 50% of the episodes due to nonalbicans species of Candida. The highest mortality rate was encountered with C.tropicalis infections.Candidaemia is an important cause of mortality and morbidity in patients with malignant haematological disorders and stem cell transplant. The predominance of non albicans species of Candida especially C.krusei and C.tropicalis is alarming. The early administration of appropriate antifungal therapy and the removal of infected intravascular catheters improve the outcome considerably. PMID- 21526013 TI - Bilateral vocal cord injury following anterior cervical discectomy: could a better preoperative exam have prevented it? AB - We present a rare case of bilateral vocal cord injury (BVCI) following anterior cervical discectomy with fusion (ACD/F) in a 47 year old man. The patient experienced post-extubation stridor and whispering voice in the recovery room. Clinical assessment led to the diagnosis of BVCI. The patient was treated by tracheostomy and made a full recovery. What is unique about this case is that the patient had no reason for a preexisting unilateral vocal cord injury (UVCI) prior to this surgery. There have been only two similar cases in the English literature in which the patients had a preexisting unilateral vocal cord paralysis (UVCI). We recommend a more detailed preoperative airway exam to include a voice exam with specific voice fatigue questioning on all patients coming for ACD/F. Such detailed assessment may uncover hidden UVCI and allow a safer perioperative period. PMID- 21526014 TI - Libyan Boy with Autosomal Recessive Trait (P22-phox Defect) of Chronic Granulomatous Disease. AB - Chronic granulomatous disease (CGD) is a primary immune deficiency disorder of the phagocytes. In this disorder, phagocytic cells (polymorphonuclear leukocytes and monocytes) cannot produce active oxygen metabolites and, therefore, cannot destroy the ingested intracellular bacteria. Clinically, patients with CGD usually have recurrent bacterial and fungal infections causing abscess and granuloma formation in the skin, lymph nodes and visceral organs.In this report, we present a boy from Libya with a rare autosomal recessive trait of CGD (defect of p22-phox) who has chronic lung disease following multiple severe pneumonia attacks. The case we present suffered from bloody diarrhea since the third month of his life. He also had recurrent episodes of fever, and later, developed persistent cervical lymphadenitis and failure to gain weight. CGD is a very rare condition worldwide. It is also not recognized here in Libya, and usually not in the list of differential diagnosis for chronic pulmonary infections. We advise that pediatricians and general practitioners who treat chronic cases of lung diseases (with or without chronic diarrhea) should consider primary immunodeficiency disorders in the hope that early diagnosis and treatment may prevent chronic complications especially of the respiratory tract. Furthermore, we state that, to the best of our knowledge, this is the first documented case of CGD from Libya. PMID- 21526015 TI - Restless Legs Syndrome: The underrecognised condition. PMID- 21526016 TI - Basic Management of Diabetes Mellitus: Practical guidelines. AB - Diabetes mellitus is a major health problem associated with microvascular and macrovascular complications, leading to increased morbidity and mortality. It is rapidly growing worldwide with a huge economical and social burden. Although prevention and treatment of diabetes and its complications play a key role in reducing its morbidity and mortality, they require an integrated team approach at national and international levels. Early diagnosis, correct treatment, and effective follow-up are essential in any health care system to prevent complications of diabetes and ensure patients' well being. PMID- 21526017 TI - Complete atrio-ventricular septal defect and Wolf-Parkinson-White syndrome. PMID- 21526018 TI - Libyan Journal of Medicine: a humble, but a vital step! PMID- 21526019 TI - Diabetes mellitus and pregnancy. AB - Diabetes mellitus is the most common medical complication of pregnancy and it carries a significant risk to the foetus and the mother. Congenital malformations and perinatal morbidity remain common compared with the offspring of non diabetic pregnancies. Diabetic mothers are at risk of progression of microvascular diabetic complications as well as early pregnancy loss, pre-eclampsia, polyhydramnios and premature labour. Glycaemic control before and during pregnancy is critical and the benefit may result in a viable, healthy off spring. Gestational diabetes mellitus (GDM) which manifests for the first time during pregnancy is common and on the increase, its proper management will reduce the risk of neonatal macrosomia and hypoglycaemia. Post-partum evaluation of glucose tolerance and appropriate counselling in women with GDM may help decrease the high risk of subsequent type 2 diabetes in the longterm.This article will briefly review the changes in the carbohydrate metabolism that characterise normal pregnancy and will focus on a practical approach to the care of patients with pre existing diabetes as well as GDM. PMID- 21526020 TI - Colorectal cancer: from epidemiology to current treatment. PMID- 21526021 TI - Congenital cholesteatoma tract presenting as a postaural swelling. AB - The authors report a case of a three-year old boy, who presented with discharge from the site of a previously excised postaural lesion reported to have been an epidermoid cyst. It was found at operation that he had a fistulous connection between the site of the excised lesion and a congenital cholesteatoma sac in the mastoid bone. This case demonstrates the rare occurrence of congenital cholesteatoma eroding through the mastoid bone to the subcutaneous tissues and mimicking an epidermoid cyst. Such a presentation in a child has not previously been reported in the literature. The clinical, radiological, surgical and histological features of this case are discussed. PMID- 21526022 TI - Right hemithoracic pseudocyst with splenic artery aneurysm: two rare complications of an uncommon disease. PMID- 21526023 TI - Fiber-reinforced composites in fixed partial dentures. AB - Fiber-reinforced composite resin (FRC) prostheses offer the advantages of good aesthetics, minimal invasive treatment, and an ability to bond to the abutment teeth, thereby compensating for less-than-optimal abutment tooth retention and resistance form. These prostheses are composed of two types of composite materials: fiber composites to build the framework and hybrid or microfill particulate composites to create the external veneer surface. This review concentrates on the use of fiber reinforcement in the fabrication of laboratory or chairsidemade composite-fixed partial dentures of conventional preparation. Other applications of FRC in dentistry are briefly mentioned. The possibilities fiber reinforcement technology offers must be emphasized to the dental community. Rather than limiting discussion to whether FRC prostheses will replace metal ceramic or full-ceramic prostheses, attention should be focused on the additional treatment options brought by the use of fibers. However, more clinical experience is needed. PMID- 21526024 TI - Update on epidemiology classification, and management of thyroid cancer. PMID- 21526025 TI - A 22-year-old woman with recurrent gastrointestinal bleeding since childhood. PMID- 21526028 TI - Seroprevalence of lymphatic filariasis at Puducherry. AB - Lymphatic filariasis is a major vector borne disease prevalent in the tropics. This study was carried out to estimate the seroprevalence of lymphatic filariasis in and around Puducherry using indirect haemaggulutination test. Of the 5056 clinically suspected cases, 2214 (43.78%) were found to be positive, of whom majority were males (57.8%) belonging to the age group of 21-40 years, indicating that lymphatic filariasis mainly affects the adolescents and adults mainly. This high seroprevalence is a matter of immediate concern and necessary control programme is urgently required to check the transmission of filariasis. PMID- 21526026 TI - Drug targets in Leishmania. AB - Leishmaniasis is a major public health problem and till date there are no effective vaccines available. The control strategy relies solely on chemotherapy of the infected people. However, the present repertoire of drugs is limited and increasing resistance towards them has posed a major concern. The first step in drug discovery is to identify a suitable drug target. The genome sequences of Leishmania major and Leishmania infantum has revealed immense amount of information and has given the opportunity to identify novel drug targets that are unique to these parasites. Utilization of this information in order to come up with a candidate drug molecule requires combining all the technology and using a multi-disciplinary approach, right from characterizing the target protein to high throughput screening of compounds. Leishmania belonging to the order kinetoplastidae emerges from the ancient eukaryotic lineages. They are quite diverse from their mammalian hosts and there are several cellular processes that we are getting to know of, which exist distinctly in these parasites. In this review, we discuss some of the metabolic pathways that are essential and could be used as potential drug targets in Leishmania. PMID- 21526027 TI - Antiparasitic activity of methanolic extract of Acacia oxyphylla (Leguminosae) against Raillietina echinobothrida. AB - Acacia oxyphylla has been used traditionally by the natives of Mizoram against intestinal worm infections. In the present study, the crude methanolic extract of the plant was tested in vitro on the cestode parasite Raillietina echinobothrida to evaluate its potential anthelmintic efficacy. The test parasites were exposed to varying concentrations of the plant extract in phosphate buffered saline and they all slipped into a flaccid paralytic state at varying periods of time post incubation. Ultrastructural observations on the paralysed worms revealed wide scale destruction of the parasite tegument with intense vacuolization of the syncytium and swellings of the basal lamina accompanied by deformities in the cell organelles. To determine the exact mode of action of the botanicals on the parasite body surface, the tegumental enzymes viz. acid phosphatase (AcPase), alkaline phosphatase (AlkPase) and adenosine triphosphatase (ATPase) were investigated. A prominent decrease in the phosphatase activity, in comparison to the untreated control parasites was noticeable. In view of the alterations in the structural and functional integrity of the tegument, occurring in the treated parasites, it may be assumed that the changes transpire because of a compromise in the permeability of the tegument under the influence of the test plant-derived active chemical principles. PMID- 21526029 TI - Microhabitat distribution of some monogenoideans, parasitizing the gills of Wallago attu (Bl. and Sch., 1801) and their seasonal variation. AB - The parasitic microhabitat distribution of the monogenoideans Thaparocleidus wallagonoius Jain, 1952, Mizelleus indicus Jain, 1957and T. gomtius Jain, 1957 parasitizing the gills of a fresh-water demersal Wallago attu and their seasonal variations were investigated in the present study. The microhabitat preferences of these species were observed. The gill segments and gill areas were the most important factors segregating the monogenoidean parasites on gills, not their abundance. Low niche overlap was found within each of the four gill arches and parasites were segregated in the same microhabitats within each gill arch. The distribution of parasites was independent of the left or right side of gill. The distribution plots in our study indicated that the anterior segment of first and fourth gill arches were more preferred site of infection. Seasonal variation of parasites, recorded during 2006 & 2007, in male and female hosts was also investigated. Due to ectoparasitic nature and high host specificity exhibited by the species of monogenoidea, studies on their seasonal dynamics are very significant as they could contribute significantly to the understanding of their biological adaptations to their environment. PMID- 21526031 TI - A new myxosporean species Myxobolus sclerii sp. nov. and one known species M. stomum Ali et al. 2003 from two Indian major carp fishes. AB - The present communication deals with description of one new species of Myxobolus (Myxozoa: Myxosporea: Bivalvulida), M. sclerii sp. nov. infecting eye ball of Catla catla (Hamilton) and redescription of M. stomum infecting scales of Labeo rohita (Hamilton), two major carps of Kanjali and Ropar Wetlands respectively. Spores of M. sclerii sp. nov. measure 7.9-9.5(8.7 +/- 1.13) * 4.3-5.7(5 +/- 0.98) MUm in size. Parietal folds absent. Polar capsules two, equal and measuring 4 5.4(4.7 +/- 0.98) * 1-2.6(1.8 +/- 1.31) MUm in size. A rod-shaped medium-sized intercapsular process is present. Iodinophilous vacuole present measuring 2.19 4.13(3.16 +/- 1.37) MUm in diameter. Spores of M. stomum Ali et al.2003 measure 9.8-10.3(10.0 +/- 0.35) * 7.9-8.7(8.3 +/- 0.56) MUm in size, with rounded anterior and posterior end. Spore valves smooth, symmetrical, thick measuring 0.88 MUm in thickness. Parietal folds absent. Two anteriorly situated polar capsules are equal, pear-shaped measuring 4.8-5.2(5.0 +/- 0.28) * 1.5-2.3(1.9 +/- 0.56) MUm in size, each with a neck leading to a fine duct opening independently. Both polar capsules converge slightly anteriorly but diverge apart posteriorly occupying more than half of spore body. Intercapsular appendix is absent. Earlier, the parasite was recorded in the buccal cavity, muscles and lips of Plectorhynchus gaterinus (Forsskal), Egypt. A new locality-Ropar Wetland, a new location-scales and a new host- Labeo rohita (Hamilton) are recorded for this parasite. PMID- 21526030 TI - Evidence of new pathogenic Theileria species in dogs. AB - Babesiosis, caused by tick-borne haematozoan organisms of the genus Babesia, is a parasitic disease of domestic and wild mammals. Canine Babesidae have historically been classified as "large Babesia" (Babesia canis) and "small Babesia" (Babesia gibsoni) based on the size of their intraerythrocytic forms. Recent publications, however, suggest that the diversity of piroplasm species infecting dogs might be greater than previously appreciated. Sequencing and phylogenetic analysis of the ssrRNA gene has revealed that canine piroplasms are found in three clades, 'true' Babesia sp. (B. canis and B. gibsoni), Theileria annae and Theileria-like group (B. conradae). This newly recognised piroplasm T. annae appears to be hyperendemic in northwest Spain. The vector for this emergent canine infection remains undescribed, although the Ixodeshexagonus is suspected based on their presence upon the dogs in NW Spain and the relative absence of others. These observations have introduced a major change in the approach to the epidemiology of babesiosis in dogs. More clinical samples and data will need to be collected and analyzed to understand the importance of Theileria species in dogs. PMID- 21526032 TI - First record of a parasitic septate gregarines (Apicomplexa: Sporozoea) in the shrimp Peneaus monodon in Sundarbans of West Bengal. AB - Investigations on the incidence of septate gregarines in shrimp have immense importance because of severe pathogenicity of the parasite. The septate gregarines infect the midgut of shrimp Peneaus monodon and severe infection disturbs the intestinal tissues. Mostly gregarines of the genus Nematopsis have been identified from cultured peneaid shrimp. It has worldwide in distribution. In India, gregarine parasites have so far been reported from penaeid shrimps of Bombay and Kerala. The species which was isolated from the midgut of shrimp Peneaus monodon collected from Kharibari area of Sunderbans. 9 out of 20 i.e. 45% of the randomly sampled hosts were found to be infected with a species of the genus Nematopsis. Different developmental stages including trophozoites, sporadins, and gametocysts of the Nematopsis sp. infecting the shrimp have been isolated. No correlations have been established between incidence of infection and environmental parameters. PMID- 21526033 TI - Observation on prevalence of ectoparasites in carp fingerlings in two districts of West Bengal. AB - The present study has been carried out to find out the prevalence of ectoparasites of carp fingerlings during different months of the year 2008-2009. Four groups of ectoparasites viz. myxozoan, ciliophoran, monogenean and crustacean were recorded from 400 fingerlings of Rohu (Labeo rohita), Catla (Catla catla), Mrigal (Cirrhinus mrigala), Bata (Labeo bata), Common carp (Cyprinus carpio) and Lata (Channa punctatus) collected from different ponds of Nadia and Hooghly district of West Bengal from June 2008 to May 2009. The highest prevalence (51.66%) of infection has been recorded in ciliophorans and the lowest was in crustacean (17.5%) between the months of December and February. The highest ectoparasitic prevalence (36.85%) was recorded during winter season (December-February) while the lowest prevalence (9.16%) recorded during rainy season (June-August). PMID- 21526034 TI - Prevalence of Theileria annulata infection in Hyalomma anatolicum anatolicum in Punjab state, India. AB - The study was conducted to assess the prevalence of Theileria infection in tick vectors collected from healthy animals to record the natural infection level of theilerial parasite in the field condition. A total of 156 male and 110 semi engorged female of Hyalomma anatolicum anatolicum were collected from cattle and buffaloes of two different agro climatic zones of Punjab, dissected and their salivary glands were stained with Methyl Green Pyronin (MGP) stain. The prevalence, intensity and abundance of Theileria annulata infection were higher in female ticks (15.45%, 5.08 and 32.88, respectively) than male ticks (8.97%, 1.69 and 18.86, respectively). The ticks collected from cattle had a higher prevalence, abundance and intensity (15.15%, 5.38 and 35.53, respectively) of T. annulata infection than the ticks collected from buffaloes (9.58%, 1.74 and 18.13, respectively). Hot and dry climate favored the development of T. annulata sporozoites in H. a. anatolicum ticks as the prevalence, abundance and intensity of T. annulata infection were higher in ticks collected from Western semi arid zone of Punjab as compared to those collected from the central plain zone with hot and humid climate. PMID- 21526035 TI - Major lipid classes and their fatty acids in a parasitic nematode, Ascaridia galli. AB - The paper presents major lipid classes and their fatty acids investigated from Ascaridia galli, a nematode parasite of country fowl. Thin layer chromatography (TLC) reveals that the percent of total lipid, neutral lipid, phospholipids, and glycolipids are 1.94, 54.39, 26.95 and 18.66, respectively. Gas-liquid chromatography (GLC) analysis shows that the saturated fatty acids are the major components in all the lipid fractions followed by monoenes and dienes. Polyunsaturated fatty acids (PUFA) were present in low amount. Stearic acids (C(18)) were the chief components among all the fatty acids in all the lipid fractions. PMID- 21526036 TI - Immunoaffinity chromatographic analysis for purification of specific diagnostic antigens of Paramphistomum epiclitum. AB - Polypeptide profile of somatic antigen of Paramphistomum epiclitum (PSAg) and Gastrothylax crumenifer (GSAg) was studied by SDS-PAGE. PSAg and GSAg showed 14 and 19 polypeptides in the range of 14.9-95.5 and 13.7-129.6 kDa with six common polypeptides of mol wt 16.8, 21.8, 23.7, 35.5, 43.4 and 70.8 kDa. P. epiclitum experimentally infected sheep sera were used for identification of specific immuno-dominant peptide in the range of 37-40 kDa against P. epiclitum by western blotting. Hyperimmune sera (HIS) was raised in rabbit against the identified polypeptide, IgG was separated from HIS and an immunoaffinity column was constructed with a binding percentage of 83.74 of IgG with CNBr activated Sepharose 4B. Purification of somatic antigen (PSAg) was done with immunoaffinity chromatography and 37-40 kDa protein antigen was isolated in pure form with recovery percentage of 2.97%. This purified fraction of somatic antigen can be used as a candidate antigen for development of serological assay for early diagnosis of paramphistomosis among livestock. PMID- 21526038 TI - Visibility of Arab countries in the world biomedical literature. PMID- 21526037 TI - Post clubfoot release skin necrosis: a preventable disaster. AB - Complications of pedal wounds closed primarily after release of neglected cases of club foot are well known in literature. We treated a 12-year-old boy presenting with widespread necrosis involving medial aspect of foot after release of neglected talipes equinovarus. Such widespread necrosis is even known to end up in amputations and permanent disabilities. In our case, the foot was successfully salvaged by resorting to dedicated wound care, multiple debridements, use of topical negative pressure (vacuum-assisted closure - VAC), and skin grafting. Various means to prevent such adverse events are also presented. The aim of publishing this case is to stress the need to:Take proper measures preoperatively in neglected club feet to decrease the impact of deformity.To be aware of various different flaps and methods of closure as mentioned in literature and to reaffirm the fact that primary closures done under tension are bound to fail and end up in disasters.To be patient and use the modern concepts of wound management like topical negative pressure if such unfortunate complications do occur and thereby attempt to salvage the feet. PMID- 21526039 TI - Imaging in clinical medicine: traumatic pseudomeningocoele. PMID- 21526040 TI - The characteristics of adults with upper gastrointestinal bleeding admitted to Tripoli Medical Center: a retrospective case-series analysis. AB - BACKGROUND: Acute upper gastrointestinal bleeding (UGIB) is a common reason for hospital admissions worldwide. Aetiological causes of UGIB vary according to geographic region and socioeconomic status. However, despite the implementation of early endoscopy as the standard method for the diagnosis and treatment of UGIB, data on the characteristics of patients with UGIB in Libya are still minimal. In this study, we describe patient demographics, aetiological causes for UGIB, and possible risk factors for upper gastrointestinal bleeding in patients admitted to the Gastroenterology Department at Tripoli Medical Center from January 2001 through June 2006. METHOD: This is a retrospective case-series analysis of all adult patients with upper gastrointestinal bleeding admitted to the Gastroenterology Department at TMC. Patients' medical records were individually reviewed and relevant data abstracted. RESULTS: A total of 928 cases with diagnoses of UGIB were admitted to Tripoli Medical Center during the study period. Of these cases, 60.3% were males and 39.7% females (3:2) and males were significantly younger than females (49.6 years vs. 53.9 years, p=0.001). The most common cause of UGIB was peptic ulcer (37.1%) of which duodenal ulcer was the most common (30.7% of all UGIB), especially amongst male patients (36.4%). The second most common cause was bleeding due to varices (29.8%), especially amongst females (35.1%). Additionally, smoking and NSAIDs use were reported by 18.6% and 9.7% of cases and both were significantly associated with bleeding due to peptic ulcers. CONCLUSION: This study has investigated the characteristics of adults with UGIB at a tertiary referral center in Libya. The high frequency of bleeding due to varices amongst females mandates further investigations into the possible underlying hepatic causes and their management, and the potential impact on patient outcome and prognosis. PMID- 21526041 TI - Rotavirus in children with diarrhea in Tripoli, Libya. PMID- 21526042 TI - Evaluating the health of nations: a Libyan perspective. PMID- 21526043 TI - Angiogenesis in urinary bladder carcinoma as defined by microvessel density (MVD) after immunohistochemical staining for Factor VIII and CD31. AB - BACKGROUND: Among the patients with bladder cancer, a group is still at risk of disease recurrence, progression, and death from their cancer after curative treatment. Angiogenesis is a crucial pathogenic mechanism for this type of urothelial carcinoma and is a potential therapeutic target. OBJECTIVES: To quantify tumor angiogenesis in bladder cancer and determine whether it correlates with tumor stage and grade. PATIENTS AND METHODS: A series of 42 archival samples from carcinomas of the urinary bladder were graded, staged, and analyzed for microvessel density (MVD) by a double immunohistochemical technique using Factor VIII (FVIII) and CD31 antibodies. The correlation between MVD and histopathological grade and tumor stage was evaluated. RESULTS: FVIII and CD31 immunoreactivity was observed in 100% of cases and more intensely with CD31. Significantly higher MVD was determined in invasive tumors than in superficial tumors (p<0.05). MVD increased with tumor grade and stage (p<0.05); MVD was not affected by age or sex of the patients. CONCLUSION: These data demonstrate that MVD in bladder carcinoma correlates with the tumor grade and stage. Quantification of tumor angiogenesis may allow selection of the type of treatment for bladder cancer patients. PMID- 21526044 TI - Biomarkers in cancer: is 'omices' the way to go. PMID- 21526045 TI - Brazilian Bidens pilosa Linne yields fraction containing quercetin-derived flavonoid with free radical scavenger activity and hepatoprotective effects. AB - Bidens pilosa is a plant used by Amazonian and Asian folks for some hepatopathies. The hydroethanol crude extract and three fractions were assessed for antioxidant and hepatoprotective effects. Higher levels of scavenger activity on the 1,1-diphenyl-2-picrylhydrazyl radical, inhibition of deoxyribose oxidation and lipid peroxidation in vitro were detected for the ethyl acetate fraction (IC(50)~4.3-32.3 ug/ml) followed by the crude extract (IC(50)~14.2-98.0 ug/ml). The ethyl acetate fraction, again followed by the crude extract, showed high contents of total soluble polyphenols (3.6+/-0.2 and 2.1+/-0.2 GAE/mg, respectively) and presence of a quercetin-derived flavonoid identified as quercetin 3,3'-dimethyl ether 7-O-beta-D-glycopyranoside. Both products were assayed for hepatoprotector effects against CCl(4)-induced liver injury in mice. Markers of oxidative stress and hepatic injury were evaluated. The results showed that the 10-day pretreatments (15 mg/kg, p.o.) protected the livers against injury by blocking CCl(4)-induced lipid peroxidation and protein carbonylation and the DNA fragmentation was decreased (~60%). The pretreatments avoided the loss of the plasma ferric reducing/antioxidant power and the elevation of serum transaminases and lactate dehydrogenase activities. The results suggest that the main constituents responsible for the hepatoprotective effects with free radical scavenger power associated are well extracted by performing fractionation with ethyl acetate. The findings support the Brazilian traditional use of this plant and justify further evaluations for the therapeutic efficacy and safety of the constituents of the ethyl acetate fraction to treat some liver diseases. PMID- 21526046 TI - Increased heart rate and atherosclerosis: potential implications of ivabradine therapy. AB - Despite all the therapeutic advances in the field of cardiology, cardiovascular diseases, and in particular coronary artery disease, remain the leading cause of death and disability worldwide, thereby underlining the importance of acquiring new therapeutic options in this field. A reduction in elevated resting heart rate (HR) has long been postulated as a therapeutic approach in the management of cardiovascular disease. An increased HR has been shown to be associated with increased progression of coronary atherosclerosis in animal models and patients. A high HR has also been associated with a greatly increased risk of plaque rupture in patients with coronary atherosclerosis. Endothelial function may be an important link between HR and atherosclerosis. An increased HR has been shown experimentally to cause endothelial dysfunction. Inflammation plays a significant role in the pathogenesis and progression of atherosclerosis. In the literature, there is data that shows an association between HR and circulating markers of vascular inflammation. In addition, HR reduction by pharmacological intervention with ivabradine (a selective HR-lowering agent that acts by inhibiting the pacemaker ionic current I(f) in sinoatrial node cells) reduces the formation of atherosclerotic plaques in animal models of lipid-induced atherosclerosis. The aim of this editorial is to review the possible role of ivabradine on atherosclerosis. PMID- 21526048 TI - Chronic cola drinking induces metabolic and cardiac alterations in rats. AB - AIM: To investigate the effects of chronic drinking of cola beverages on metabolic and echocardiographic parameters in rats. METHODS: Forty-eight male Wistar rats were divided in 3 groups and allowed to drink regular cola (C), diet cola (L), or tap water (W) ad libitum during 6 mo. After this period, 50% of the animals in each group were euthanized. The remaining rats drank tap water ad libitum for an additional 6 mo and were then sacrificed. Rat weight, food, and beverage consumption were measured regularly. Biochemical, echocardiographic and systolic blood pressure data were obtained at baseline, and at 6 mo (treatment) and 12 mo (washout). A complete histopathology study was performed after sacrifice. RESULTS: After 6 mo, C rats had increased body weight (+7%, P < 0.01), increased liquid consumption (+69%, P < 0.001), and decreased food intake (-31%, P < 0.001). C rats showed mild hyperglycemia and hypertriglyceridemia. Normoglycemia (+69%, P < 0.01) and sustained hypertriglyceridemia (+69%, P < 0.01) were observed in C after washout. Both cola beverages induced an increase in left ventricular diastolic diameter (C: +9%, L: +7%, P < 0.05 vs W) and volumes (diastolic C: +26%, L: +22%, P < 0.01 vs W; systolic C: +24%, L: +24%, P < 0.05 vs W) and reduction of relative posterior wall thickness (C: -8%, L: -10%, P < 0.05 vs W). Cardiac output tended to increase (C: +25%, P < 0.05 vs W; L: +17%, not significant vs W). Heart rate was not affected. Pathology findings were scarce, related to aging rather than treatment. CONCLUSION: This experimental model may prove useful to investigate the consequences of high consumption of soft drinks. PMID- 21526047 TI - Vagal nerve stimulation in prevention and management of coronary heart disease. AB - Coronary heart disease (CHD) that is due to atherosclerosis is associated with low-grade systemic inflammation. Congestive cardiac failure and arrhythmias that are responsible for mortality in CHD can be suppressed by appropriate vagal stimulation that is anti-inflammatory in nature. Acetylcholine, the principal vagal neurotransmitter, is a potent anti-inflammatory molecule. Polyunsaturated fatty acids (PUFAs) augment acetylcholine release, while acetylcholine can enhance the formation of prostacyclin, lipoxins, resolvins, protectins and maresins from PUFAs, which are anti-inflammatory and anti-arrhythmic molecules. Furthermore, plasma and tissue levels of PUFAs are low in those with CHD and atherosclerosis. Hence, vagal nerve stimulation is beneficial in the prevention of CHD and cardiac arrhythmias. Thus, measurement of catecholamines, acetylcholine, various PUFAs, and their products lipoxins, resolvins, protectins and maresins in the plasma and peripheral leukocytes, and vagal tone by heart rate variation could be useful in the prediction, prevention and management of CHD and cardiac arrhythmias. PMID- 21526049 TI - Percutaneous approach to treatment of coronary disease in a patient with uremic cardiomyopathy. AB - Uremic cardiomyopathy is chronic ischemic left ventricular dysfunction characterized by heart failure, myocardial ischemia, hypotension in dialysis and arrhythmia. This nosologic entity represents a leading cause of morbidity and mortality among patients with end-stage renal disease receiving long-term hemodialysis. It is intuitive that revascularization in the presence of coronary artery disease in these patients represents an effective option for improving their prognosis. Although the surgical option seems to be followed by the best clinical outcome, some patients refuse this option and others are not good candidates for surgery. The present report describes the case of a patient affected by uremic cardiomyopathy and severe coronary artery disease in whom revascularization with percutaneous coronary angioplasty was followed by a significant improvement in quality of life. PMID- 21526051 TI - Management of drooling for patients in the north of Iran: Analysis of the surgical management. AB - BACKGROUND: Drooling is a common problem in children and adults with neuromuscular disorders. This problem is best dealt with using a multidisciplinary team approach. The objective of this paper is to assess the results following surgery at the Drooling Clinic of Amiralmomenin Hospital. METHODS: The results of the surgical protocol used between 1994 and 2007 at the Drooling Clinic of Amiralmomenin Hospital in Rasht, Iran, reported thirty-two patients underwent submandibular duct relocation and sublingual resection. The preoperative and postoperative levels of drooling were measured. The parents of the patients were contacted by telephone at least one year after operation. RESULTS: Of all the patients, eighteen were male and fourteen were female and were aged 6 years to 26 years. Of 30 patients with complete patients' chart, the mean drooling score fell from 7.59 to 2.71 after surgery (p < 0.0001). In 30 patients, results of operation were ascertained by telephone at average of 5.6 years after operation. In 78.1% of patients, long-term result was successful and none were considered worse after the procedure. There were few complications, none of which had any long-term adverse effects. Swelling of submandibular glands was frequently observed in the immediate post-operative period. Only one ranula was seen as delayed complication. CONCLUSIONS: Submandibular duct relocation with simultaneous sublingual gland excision is a safe and consistently efficient procedure for the treatment of chronic sialorrhea. It is believed that this operation is more physiological procedure than others. PMID- 21526050 TI - Molecular biology of heart disease. AB - Dr. Robert Roberts is currently Professor of Medicine and Director of the Ruddy Canadian Cardiovascular Genetics Centre along with being President and CEO of the University of Ottawa Heart Institute. Prior to this appointment, he was Chief of Cardiology for 23 years at Baylor College of Medicine, Houston, Texas. His original research was in cardiac enzymology which led to the development of the MBCK test which was the standard diagnostic assay for myocardial infarction for more than 3 decades. In the late 1970s, his research interests switched to molecular biology and the genetics of cardiomyopathies. He is regarded as one of the founders of molecular cardiology and has identified and sequenced more than 20 genes responsible for cardiovascular disorders. In the past 6 years, he has pursued genome-wide association studies to identify genes predisposing to coronary artery disease (CAD) and myocardial infarction. The first genetic variant for CAD, 9p21, was identified by Dr. Robert's laboratory and, in collaboration with the international consortium, CARDIoGRAM, has identified 13 novel genes for CAD. PMID- 21526052 TI - The efficacy of ilioinguinal and iliohypogastric nerve block for postoperative pain after caesarean section. AB - BACKGROUND: The effect of ilioinguinal and iliohypogastric (II-IH) nerve block on postoperative pain is well documented when performed before Caesarean section (CS) but the efficacy remains unclear when performed after the surgical procedure. The aim of this study is to investigate the effect of II-IH nerve block on postoperative pain and analgesic consumption in patients when performed after CS. METHODS: Sixty ASA I- II patients, scheduled for elective CS were included in the study. After general anaesthesia, patients were allocated into 2 groups randomly. In group I bilateral II-IH block has been performed after the skin closure, with 10 ml of 0.5% ropivacaine on each side. In group II sham block had been performed. For postoperative analgesia all patients received tramadol via i.v patient controlled analgesia. Visual analogue scale (VAS) scored tramadol consumption and side effects. RESULTS: The mean VAS scores in II-IH block group were significantly lower than in sham block group at 6(th), 8(th), 12(th), 24(th) hours at rest (p < 0.05) and at 6(th), 8(th) hours with movement (p < 0.05). Tramadol usage in II-IH block group was significantly less than in sham block group at all estimated time intervals (p < 0.05). Total tramadol consumption was 331 +/- 82 mg in II-IH block group and 622 +/- 107 mg in sham block group (p < 0.05). CONCLUSIONS: It was observed that II-IH nerve block when performed after the surgery may reduce analgesic consumption after CS. PMID- 21526053 TI - The predictive role of histopathological findings in renal insufficiency and complete remission in a sample of Iranian adults with primary focal segmental glomerulosclerosis. AB - BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) is defined by the presence of proteinuria, often in nephrotic range and pathologically by segmental scars (SS). The aim of this study is to identify the possible predictors of complete remission or progression to chronic kidney disease in Iranian adults with primary focal segmental glomerulosclerosis. METHODS: In this historical cohort study, pathological findings of 50 patients with primary FSGS were reviewed by single renal pathologist without knowing about patients' identities or outcomes. Patients were divided based on their histopathological findings and outcomes were compared among these groups. RESULTS: There were significant differences in the complete remission rate in subjects with and without mesangial hypercellularity (p < 0.05), and in patients with and without hyalinosis (p < 0.05). According to the cut off points based on ROC curve analysis for the quantitative data, there was significant difference in renal insufficiency between the patients with and without global scars more than 12% (p < 0.05). Also multiple logistic regression analysis strongly suggests the association of mesangial hypercellularity and global scar with no complete remission and progression to renal insufficiency, respectively. CONCLUSIONS: In the studied patients, presence of mesangial hypercellularity and hyalinosis has been suggested as prognostic factors for lower remission rate. According to multivariate analysis, only mesangial hypercellularity and global scar were found to act as independent prognostic predictors of lower complete remission rate and progression to renal insufficiency in patients with FSGS, respectively. PMID- 21526054 TI - Clinical and course indicators of bipolar disorder type I with and without opioid dependence. AB - BACKGROUND: The existing evidence about the clinical situations of the bipolar patients with opioid dependence is scarce. The present study was carried out to compare the clinical features and course of the bipolar disorder type I regarding the two subgroups of opioid dependent and non-dependent. METHODS: There were 178 adult patients with bipolar disorder type I consecutively referred to the Iran Hospital of Psychiatry, Tehran, Iran, from January 2008 to January 2009 who enrolled in the study. The Persian Structured Clinical Interview for DSM-IV axis I disorders (SCID-I), HDRS-17, and Y-MRS were administered for all patients. Other clinical information was gathered through the face-to-face interviews with the probands and the hospital records. The T test, Chi square test and logistic regression were used to analyze the data. RESULTS: The mean age of probands were 33.6 +/- 11.1 years old and they were mostly male. Among the evaluated indices, the factors gender, anxiety disorders comorbidity, non-adherence, and positive family history were different significantly and independently from the other studied factors between opioid dependent and non-dependent bipolar patients. CONCLUSIONS: Despite some differences, the opioid dependent and non-dependent bipolar patients did not have any significant difference regarding most of the examined clinical and course indices. PMID- 21526055 TI - Opium addiction and severity of coronary artery disease: a case-control study. AB - BACKGROUND: Coronary artery disease (CAD) is a leading cause of morbidity and mortality in the world. Determination of the risk factors and high risk groups plays an important role in the prevention and controlling programs. The present study aims to determine the relationship between opium consumption and severity of CAD. METHODS: In this hospital based case-control study, 299 patients who were candidates for coronary angiography from 2006 to 2007 were recruited. The patients' history of opium addiction was taken. Based on their history, they were categorized into three groups: non users, occasional users and current users. The relationship between opium addiction and severity of CAD was analyzed by a multiple logistic regression model, STATA v.10. RESULTS: According to angiographic data, patients were divided into 3 groups: 84 patients (28.09%) as non coronary artery disease, 81 patients (27.09%) as mild CAD and the remaining 134 patients (44.82%) as severe CAD. Univariate analysis showed that current opium users had higher odds of severe CAD compared with non users. Multivariate analysis showed a significant relationship between age, diabetes, hyperlipidemia, gender and severity of coronary artery stenosis. CONCLUSIONS: The findings indicated that current opium users - in comparison with non users - have a higher risk for severe CAD. But it is roughly confounded by other co-factors such as cigarette smoking, age and sex. A dose-response was noticed between the type of opium consumption and the severity of CAD. PMID- 21526056 TI - Differences in center of pressure trajectory between normal and steppage gait. AB - BACKGROUND: This pilot study aimed to assess the differences in center of pressure trajectory in neuropathic patients with steppage gait. Steppage gait has previously been evaluated by several biomechanical methods, but plantar pressure distribution has been much less studied. The purpose of this study was to analyze the changes in center of pressure trajectory using a force plate. METHODS: The steppage gait group was selected from the patients using drop foot brace (25 male) and the control group was selected from Isfahan university students (20 male). They walked at self- selected speed at a mean of ten trials (+2) to collect the center of pressure using a force plate. Center of pressure patterns were categorized into four patterns based on the center of pressure displacement magnitude (spatial features) through time (temporal features) when the longitudinal axis of the insole was plotted as the Y- axis and the transverse axis of the insole as X- axis during stance phase. RESULTS: The horizontal angle measured from center of pressure linear regression was positive in the control group (4.6 +/- 2.4) (p < 0.005), but negative in the patient group (- 2.3 +/- 1.6) (p < 0.005). CONCLUSIONS: The finding of this research measured center of pressure trajectory in steppage gait over time, which is useful for designing better shoe sole and also orthopaedic device and better understanding of stability in patients with drop foot. PMID- 21526057 TI - Perinatal depression in a cohort study on Iranian women. AB - BACKGROUND: Childbearing years in the women's life are associated with the highest risk of depression. In this study depression in third trimester of pregnancy and after delivery was studied. Depressive symptom score and the proportion of mothers above a threshold were compared to indicate probable depressive disorder at each stage. METHODS: This prospective cohort study was conducted in rural areas of Isfahan province of Iran from September 2007 to January 2008. Subjects were all in their third trimester and followed up from the beginning of the study to 6-8 weeks postpartum. At all, 2156 pregnant women completed the self report questionnaires but 258 were excluded because they were incomplete and final analysis was done with 1898 samples. At the final stage the sample size was decreased to 1291. RESULTS: The prevalence of depression based on BDI score greater than 20 in last trimester of pregnancy, was 22.8% and rate of depression based on EPD score greater than 12 between 6 to 8 weeks after delivery, was 26.3%. Incidence of Post Partum Depression (PPD) in 6 to 8 weeks after delivery in those who were not clinically depressed during pregnancy was 20.1%. Results showed that history of depression, unplanned pregnancy, being housewife and having 3 or more children had significant relation with ante partum depression. CONCLUSIONS: Two main risk factors for post partum depression are previous history of depression and depression during current pregnancy. It is important to assess these variables during pregnancy in order to facilitate timely identification of women at risk. PMID- 21526058 TI - A comparison of cerebral vasomotor reactivity in diabetic and nondiabetic Iranian patients. AB - BACKGROUND: Cerebral microangiopathy is one of the most important complications in diabetes. It may interfere with cerebral vasomotor reactivity (VMR) which may lead to disability, stroke or even death. The aim of the present study was to determine and compare VMR changes in diabetic and non- diabetic patients. METHODS: Fifty three diabetic and 51 non- diabetic patients (with no other vascular abnormality) were recruited. Vasomotor reactivity was evaluated with Trans- Cranial Doppler (TCD) before and after CO2 inhalation. RESULTS: There were 69 (66.30%) males. The mean age was 41.53 +/- 17.80 years. The general average of VMR was 5.79 +/- 3.00%, the figures in diabetic and nondiabetic patients were 5.31 +/- 2.60% and 6.62 +/- 2.00%, respectively (p = 0.02). The average of flow velocity (FV) change was 42.47+/- 29.00 in diabetics and 53.34 +/-16.70 in non- diabetic patients (p = 0.04). CONCLUSIONS: It is recommended that such non- invasive method is necessary for evaluation of cerebral vasculature in diabetic patients for better prevention. PMID- 21526059 TI - Textiloma, migration of retained long gauze from abdominal cavity to intestine. AB - Retaining of gauzes and surgical sponges in the abdomen is one of the most frequent medical errors usually manifesting as abscess or abdominocutaneus fistulas with no definite symptoms during lifetime. Here, we introduce a 35 year old woman with symptoms and signs of partial bowel obstruction and enterocutaneous fistulas caused by migration of retained gauze from abdominal cavity to terminal ileum, 9 months after cesarean section. This is called "Textiloma". There are several reports of gossypiboma worldwide but migration of retained gauze into intestine causing an enterocutaneous fistula is rare. PMID- 21526060 TI - Langerhans cell histiocytosis following Hodgkin lymphoma: a case report from Iran. AB - The occurrence of Langerhans Cell Histiocytosis (LCH) in a patient with lymphoma is an indication of a probable relationship between them. The two conditions have similarities both clinically and histopathologically. Occurrence of these two conditions in the same patient, particularly not simultaneously, is rare. According to different management and treatment of these conditions, exact histopathologic evaluation and even using immunohistochemistery (IHC) can prevent misdiagnosis. In this report, a 10 year old boy presented who afflicted with LCH 3 years after diagnosis and treatment of mixed cellularity Hodgkin lymphoma. PMID- 21526061 TI - Quality of life in patients with Parkinson's disease: Translation and psychometric evaluation of the Iranian version of PDQ-39. AB - BACKGROUND: Health related quality of life is an important outcome measure in studies involving patients with chronic neurological conditions. Disease specific patient reported outcome measures (PROMs) are increasingly used as primary end points in clinical trials. The most widely used disease specific PROM is the 39 item Parkinson's Disease Questionnaire (PDQ-39). The aim of this study was to determine validity and reliability of Persian PDQ-39. METHODS: Two hundred Parkinson's disease patients attending neurologic clinics of teaching hospitals were recruited. PD patients completed a translated version of the PDQ-39. Internal consistency reliability of the questionnaire was assessed by Cronbach's alpha coefficient. Reproducibility was assessed across the 3-week interval using the intraclass correlation coefficient. To assess convergent validity, results on the PDQ-39 were correlated with those gained on the SF-36. Discriminate validity of questionnaire was assessed by comparing PDQ-39 scores and the severity and the duration of disease. RESULTS: A value of 0.93 (Cronbach's alpha) was gained for the summary score (PDQ-SI), indicating high levels of internal reliability. Alpha value of seven domains was greater than 0.70. The intraclass correlation coefficient ranged from 0.47 to 0.90. The range of correlation coefficients between domains of SF-36 and PDQ-SI was from -0.40 to -0.61. There was a statistically significant difference between severity of disease and mean scores of PDSI. CONCLUSIONS: This study provides evidence that the Persian version of PDQ-39 is a valid and reliable measure of quality of life in PD. PMID- 21526063 TI - The effects of exercise training on maximum aerobic capacity, resting heart rate, blood pressure and anthropometric variables of postmenopausal women with breast cancer. AB - BACKGROUND: The aim of this study was to investigate the effects of exercise training on maximum aerobic capacity, resting heart rate (RHR), blood pressure and anthropometric variables of postmenopausal women with breast cancer. METHODS: Twenty nine women with breast cancer who received surgery, chemotherapy and radiotherapy with current hormone therapy were divided into two groups; intervention and control. Subjects in the intervention group performed 15 weeks combination exercise training including walking for 25 to 45 minutes (2 sessions per week) and resistance training for 60 minutes (2 sessions per week that were different from walking days). In pre and post tests, VO(2)max, RHR, blood pressure, body weight, body mass index (BMI) and waist to hip ratio (WHR) were measured in both groups. Data was analyzed using analysis of covariance (ANCOVA). RESULTS: Significant differences were observed for VO (2)max, RHR, body weight, BMI and WHR between intervention and control groups after 15 weeks (p < 0.05). In fact, exercise training had positive effects on the VO (2)max, RHR, body weight, BMI and WHR in postmenopausal women with breast cancer. No significant different was found for blood pressure between two groups (p > 0.05). CONCLUSIONS: It can be concluded that exercise training may improve maximum aerobic capacity, RHR and anthropometric variables in postmenopausal women with breast cancer. PMID- 21526062 TI - Effects of education on self-monitoring of blood pressure based on BASNEF model in hypertensive patients. AB - BACKGROUND: Hypertension is one of the most important health problems. Self monitoring may be an effective method for controlling this disease. The aim of this study is to determine the effectiveness of education on blood pressure self monitoring in patients with hypertension based on BASNEF model. METHODS: In this clinical trial, 150 outpatients with hypertension were randomly selected from those referred to private clinics in Yazd, Iran, during 2008. They were divided in two groups. The data were collected by a validated and reliable questionnaire. The implementing educational program was continued for 2 months and the pre-test and post-test had an interval of 2-months. BASNEF model was applied to explain the motivation of a behavior. Descriptive analysis, correlation test and also regression analysis were used to analyze data. RESULTS: The respondents acquired 17.72% of total score for self-monitoring behavior, 47.03% of attitude, 12.37% of subjective norms, 33.46% of intention and 50.95% of enabling factors. After intervention, there were significant increases in self-monitoring behavior (173.31%), attitude (62.60%), subjective norms (54.70%), intention (129.93%) and enabling factors (46.62%) in the intervention group. There was no significant difference between the constructs of BASNEF model in the control group after intervention compared to the baseline values (p > 0.05). CONCLUSIONS: The results of this study showed that the level of self-monitoring behavior in the patients was low. Educational programs are helpful and necessary to improve self monitoring behavior in patients with hypertension. PMID- 21526064 TI - Using functional Magnetic Resonance Imaging to differentiate between healthy aging subjects, Mild Cognitive Impairment, and Alzheimer's patients. AB - BACKGROUND: Alzheimer's disease is the most common form of dementia which is still difficult to be differentiated from other types of brain disorders. Moreover, Mild Cognitive Impairment refers to the presence of cognitive impairments that is not severe enough to meet the criteria of Alzheimer's, and its diagnosis in early stages is so critical. There is currently no distinct method available for diagnosing Alzheimer's or Mild Cognitive Impairment, and their diagnosis needs a combination of different methods and assessments. METHODS: The aim of this study was to evaluate the effectiveness of functional Magnetic Resonance Imaging (fMRI) in differentiating between Alzheimer's, Mild Cognitive Impairment (MCI) and healthy aging. To prove fMRI's ability, resting state brain activation patterns between these three groups of subjects were compared using Independent Component Analysis (ICA) algorithm. Forty age- and sex matched subjects, 15 elderly, 11 MCI and 14 Alzheimer's subjects were examined. RESULTS: The results showed that during a certain resting-state session, healthy aging brain benefits from larger area and greater intensity of activation (compared with MCI and Alzheimer's group) in Posterior Cingulate Cortex (PCC) region of the brain, as part of Default Mode Network. CONCLUSIONS: This difference in activation pattern can be used as a diagnostic criterion in using fMRI for differentiating between Alzheimer's Disease (AD), MCI and healthy aging. PMID- 21526065 TI - Does early-onset multiple sclerosis differ from adult-onset form in Iranian people. AB - BACKGROUND: Few studies have attempted to delineate the clinical profile of multiple Sclerosis (MS) among people of Asia. This study sought to identify the characteristics of early-onset Multiple Sclerosis (EOMS) comparison to adult onset form (AOMS) in Isfahan, IRAN. METHODS: This prospective study was conducted on 104 youths with multiple sclerosis beginning before the age of 16 years and 123 patients with adult-onset multiple sclerosis. Patients were observed for a mean period of 5 years. The common presenting symptoms, MRI finding, course of disease and disability score were compared between the two groups. RESULTS: The mean onset age of disease in youths and adults were 14 +/- 1.9 and 27.7 +/- 8.06 years, respectively. Female/male ratio was 4.47:1 in EOMS and 3.92:1 in AOMS, this ratio was 7:1 in early childhood MS (<= 10 year). The most common presenting symptom was optic neuritis in the EOMS group and paresthesia in AOMS. Optic neuritis was common in AOMS too, but brainstem/cerebellar signs were more common in EOMS than AOMS. Seizure occurred more frequently in EOMS than in the AOMS group (12.6% vs. 1.6%, respectively, p < 0.001). MRI showed that brainstem plaques were more prevalent in the EOMS compared with the AOMS group. CONCLUSIONS: It was concluded that early-onset MS does not significantly differ from adult form in terms of major clinical manifestation and course of disease, however Seizure is more common in EOMS, and brainstem and cerebellar symptoms as presenting symptom are more common. PMID- 21526066 TI - Pregnant women affected by thalassemia major: a controlled study of traits and personality. AB - BACKGROUND: The reproductive and sexual health issues concerning persons affected by thalassemia major are complex. The study was planned to investigate the psychological attitudes and expectations in a group of thalassemic pregnant women attending hospital for regular blood transfusion. METHODS: This is a preliminary cross-sectional study involving 20 consecutive thalassemic patients and a control group of 42 healthy pregnant volunteers. The personality structure was evaluated by Rorschach's test and the presence of psychic symptoms by SCL-90-R and STAI. RESULTS: Narcissism and sexual traumas are significantly higher in thalassemic women with respects to the control group. Also the percent of anxiety and depression observed with the SCL-90-R was significantly higher than in control group (45% vs. 3%, p < 0.001, mean and SD values are 1.65 +/- 0.15 vs. 0.43 +/- 0.18 for anxiety; 55% vs. 12%, p < 0.001, mean and SD values are 1.76 +/- 0.18 vs. 0.85 +/- 0.25 for depression). The score observed with the STAI shows that the trait of anxiety differed between thalassemic pregnant women and the control group, even though the score values aren't pathologic in neither group (87% vs. 42%, p < 0.05, mean and SD values are 33 +/- 0.8 vs. 22 +/- 0.2). CONCLUSIONS: This study addresses the need for developing, implementing and evaluating proper psychological support for thalassemic pregnant patients. Moreover, psychological screening and support prior to, during and following pregnancy would be indicated. PMID- 21526067 TI - Capture-recapture method for assessing publication bias. AB - BACKGROUND: Publication bias is an important factor that may result in selection bias and lead to overestimation of the intervention effect. In this study, the focus was on using capture-recapture method as a statistical procedure which may possibly be a practical means for measuring the amount of publication bias. METHODS: A systematic review was conducted to estimate the duration of protection provided by hepatitis B vaccine by measuring the anamnestic immune response to booster doses of vaccine and retrieved studies from three separate sources of electronic databases, reference lists of the studies, and conference databases as well as contact with experts and manufacturers. Capture-recapture and some conventional methods such as funnel plot, Begg test, Egger test, and trim and fill method were employed for assessing publication bias. RESULTS: Based on capture-recapture method, completeness of the overall search results was 87.2% [95% CI: 84.6% to 89.0%] and log-linear model suggested 5 [95% CI: 4.2 to 6.2] missing studies. The funnel plot was asymmetric while Begg and Egger tests results were statistically insignificant and trill and fill approach made no change in pooled effect. CONCLUSIONS: Capture-recapture method may be a useful practical approach for estimating the number of missing studies which are not usually detected by search strategy. As a result, use of capture-recapture method as an alternative approach could be suggested for estimating the extent of publication bias based on overlapping information rather than mirror image of extreme values on funnel plot. PMID- 21526068 TI - The seroepidemiology of the chronic infections in patients with myocardial infarction in North of Iran. AB - BACKGROUND: Recent studies have suggested that chronic infections with Chlamydia pneumoniae (Cpn) and Helicobacter pylori (Hp) may be associated with the risk of Myocardial Infarction (MI). METHODS: A cross sectional study was conducted on 140 citizens. Seroprevalence was assessed by ELISA tests measuring IgA and IgG antibodies to Cpn and Hp in sera. RESULTS: Among patients, %11.4 and %90.0 were seropositive for Anti-Cpn IgA and IgG respectively, and also %51.4 and %58.6 were seropositive for Anti-Hp IgA and IgG respectively. CONCLUSIONS: The present study shows that previous infection to Cpn in patients with MI is important. But there are no significant association between infection with Hp and MI. PMID- 21526069 TI - Pulmonary alveolar proteinosis in children: a case series. AB - Pulmonary alveolar proteinosis, (PAP) is a rare disease of unknown etiology, characterized by accumulation of intraalveolar proteinaceous material which is rich in lipid and positive on periodic acid-Schiff stain. Two clinically different pediatric types have been defined as congenital PAP which is fulminant and fatal, and a late-onset PAP which is similar to the adult form and less severe. Eight children with late-onset PAP were hospitalized from 1998 to 2005 in Mofid Children Hospital. Characteristics of these patients and the methods of diagnosis and treatment are presented in this case series. PMID- 21526070 TI - Treatment of atrophic cutaneous leishmaniasis scar using autologous fibroblasts and keratinocytes (a case report and literature review). PMID- 21526071 TI - The effectiveness of two energy drinks on selected indices of maximal cardiorespiratory fitness and blood lactate levels in male athletes. AB - BACKGROUND: Consumption of energy drinks has become widespread among athletes. The effectiveness of Red Bull and Hype energy drinks on selected indices of maximal cardiorespiratory fitness and blood lactate levels in male athletes was examined in this study. METHODS: TEN MALE STUDENT ATHLETES (AGE: 22.4 +/- 2.1 years, height: 180.8 +/- 7.7 cm, weight: 74.2 +/- 8.5 kg) performed three randomized maximal oxygen consumption tests on a treadmill. Each test was separated by four days and participants were asked to ingest Red Bull, Hype or placebo drinks 40 minutes before the exercise bout. The VO (2max), time to exhaustion, heart rate and lactate were measured to determine if the caffeine based beverages influence performance. ANOVA test was used for analyzing data. RESULTS: A greater value was observed in VO (2max)and time to exhaustion for the Red Bull and Hype trial compared to the placebo trial (p < 0.05). No significant difference was found in pre-and post-test heart rate for two drinks (p > 0.05). For blood lactate levels no significant changes were observed before and two minute after the test (p > 0.05). CONCLUSIONS: Ingestion of Red Bull and Hype prior to exercise testing is effective on some indices of cardiorespiratory fitness but not on the blood lactate levels. PMID- 21526072 TI - The assessment value of transcranial Doppler sonography versus magnetic resonance angiography in vertebrobasilar stroke. AB - BACKGROUND: The goal of this study was to determine the reliability of TCD in evaluation of vertebrobasilar arteries in comparison with brain MRA in patients suffering from acute vertebrobasilar stroke. METHODS: Samples were patients with definite clinical diagnosis of vertebrobasilar stroke. For all patients brain MRI, MRA and TCD were performed during the first 48 hours of admission. Basilar artery was insonated at the depth of 75 to 85 mm and vertebral arteries were insonated at the depth of 45 to 55 mm. On brain MRA, the degree of stenosis in vertebrobasilar arteries was graded from I (normal) to IV (total stenosis) and the correlation between the grade of stenosis and TCD indices were studied. RESULTS: Spearman correlation test revealed a significant correlation between mean flow velocity (MFV) and MRA grading (correlation coefficient = -0.486) as well as end diastolic velocity (EDV) and MRA grading (correlation coefficient = 0.323) with no significant correlation between pulsatility index, peak systolic velocity and MRA grading (p > 0.05). One way ANOVA analysis showed that there was only significant mean MFV and mean EDV difference between grade 1 and other grades. CONCLUSIONS: TCD was only able to differentiate between stenotic and normal pattern and could not assist in the grading of stenosis. On the other hand, in acute vertebrobasilar stroke that TCD performed blindly without visualization of arteries and in a fixed depth it might have limited value in the grading of vertebrobasilar system stenosis. PMID- 21526073 TI - Medical record information disclosure laws and policies among selected countries; a comparative study. AB - BACKGROUND: Hospitals have responsibility for responding to legitimate demands for release of health information while protecting the confidentiality of the patient health records. There have always been challenges concerning medical records confidentiality and their disclosure and release type in medical record departments. This study investigated and compared laws and policies of disclosure of health information in Iran and selected countries and tried to identify the differences and the similarities between them. METHODS: This is a descriptive and comparative study. The scope of study included related laws and policies of disclosure of health information in selected countries such as United States, Australia, England, Malaysia and Iran. Data were gathered from systematic internet search, library resources and communication with health information professionals. Data analysis was done using comparative tables and qualitative method. RESULTS: Study results showed that legislative institutions of each country have ordained laws and policies concerning disclosure and release of health information and in turn hospitals developed policies and procedures based on these laws. In Iran, however, there are few laws and policies concerning disclosure of health information in the form of formal letters and bylaws. There are no specific written policies and procedures for disclosure of health information in the hospitals. CONCLUSIONS: It is necessary to develop legitimate and appropriate laws and policies in different levels for information utilization by hospitals, medical universities and others. Meanwhile in all of the selected countries there are ordained limitations for release of health information for protecting health information in regard to patient rights. PMID- 21526074 TI - Serum lipid profiles in patients with beta-thalassemia major and intermedia in southern Iran. AB - BACKGROUND: Beta-thalassemia is considered to be the most frequent hereditary blood disorder worldwide. Lipid abnormalities have been detected in different types of beta-thalassemia. The aim of this study is to assess the lipid profiles in beta-thalassemia major (BTM) and beta-thalassemia intermedia (BTI) patients in southern Iran. METHODS: The study group consisted of 55 BTM patients and 50 BTI patients. The control group included 130 sex-and age-matched healthy participants. Serum lipids profiles (total cholesterol, triglycerides, LDL cholesterol, and HDL-cholesterol) as well as hemoglobin (Hb) and ferritin, were compared between the three groups. P value < 0.05 was considered statistically significant. RESULTS: There were no significant differences between BTM and BTI patients regarding age or sex. Mean triglyceride concentration was not significantly different between patients and controls. Total cholesterol and LDL cholesterol were significantly lower in patients with BTM and BTI in comparison with controls (p < 0.001). HDL-cholesterol was significantly lower in patients with BTI than in controls (p < 0.03). CONCLUSIONS: In patients with BTM and BTI, total cholesterol and LDL-cholesterol were lower than in control participants. The mechanisms that may account for these findings are increased erythropoiesis and cholesterol consumption in BTI, and iron overload and oxidative stress in BTM. PMID- 21526075 TI - Health problem behaviors in Iranian adolescents: a study of cross-cultural adaptation, reliability, and validity. AB - BACKGROUND: The main purpose of this study was to assess the factorial validity and reliability of the Iranian versions of the personality and behavior system scales (49 items) of the AHDQ (The Adolescent Health and Development Questionnaire) and interrelations among them based on Jessor's PBT (Problem Behavior Theory). METHODS: A multi-staged approach was employed. The cross cultural adaptation was performed according to the internationally recommended methodology, using the following guidelines: translation, back-translation, revision by a committee, and pretest. After modifying and identifying of the best items, a cross-sectional study was conducted to assess the psychometric properties of Persian version using calibration and validation samples of adolescents. Also 113 of them completed it again two weeks later for stability. RESULTS: The findings of the exploratory factor analysis suggested that the 7 factor solution with low self concept, emotional distress, general delinquency, cigarette, hookah, alcohol, and hard drugs use provided a better fitting model. The alpha range for these identified factors was 0.69 to 0.94, the ICC range was 0.73 to 0.93, and there was a significant difference in mean scores for these instruments in compare between the male normative and detention adolescents. The first and second-order measurement models testing found good model fit for the 7 factor model. CONCLUSIONS: Factor analyses provided support of existence internalizing and externalizing problem behavior syndrome. With those qualifications, this model can be applied for studies among Persian adolescents. PMID- 21526076 TI - Soft tissue augmentation by autologous cultured fibroblasts transplantation for treatment of wrinkles and scars: a case series of 20 patients. AB - BACKGROUND: There are many filler agents for augmentation of static wrinkles and atrophic scars from synthetic, bio-synthetic, cadaver, animal and human sources. METHODS: The current study presents 20 patients whose facial wrinkles and lines were treated by transplantation of autologous cultured fibroblasts. The fibroblast nature of cells was confirmed by immune-staining and flow cytometry. RESULTS: The mean of improvement for this procedure at the 6 month follow up was 41%. CONCLUSIONS: In conclusion autologous fibroblast transplantation can be an effective procedure for correction of wrinkles and atrophic scars. PMID- 21526077 TI - Effects of treadmill running on extracellular basal levels of glutamate and GABA at dentate gyrus of streptozotocin-induced diabetic rats. AB - BACKGROUND: The present study evaluated the effects of treadmill running on extracellular basal levels of glutamate and GABA at dentate gyrus of streptozotocin-induced diabetic rats. METHODS: After 12 weeks of diabetes induction and exercise period, extracellular levels of glutamate and GABA were investigated. RESULTS: The results showed that glutamate levels were significantly decreased in diabetes-rest group comparing to the control-rest and the diabetes-exercise groups. CONCLUSIONS: The findings support the possibility that treadmill running is helpful in alleviating neurotransmitter homeostasis and alterations in transmission in diabetes mellitus. PMID- 21526079 TI - Drug addiction in Gaza and the illicit trafficking of tramadol. PMID- 21526078 TI - Intravenous bisphosphonates for postmenopausal osteoporosis. AB - Numerous clinical studies have shown bisphoshonates (BPs) to be useful and cost effective options for the fractures prevention and postmenopausal bone loss. The use of oral bisphoshonates is an established option for managment of osteoporosis in postmenopausal women, but many of them complaint from gastrointestinal side effect or frequently dosed oral regimens. To improve upon the suboptimal therapeutic compliance in postmenopausal women, newer, longer-acting intravenous formulations of BPs has been approved for intermittent administration in postmenopausal women. These preparations would become an option for patients who can not tolerate oral BPs or it was ineffective in increasing their bone density.This article proposed to review effectiveness and tolerability of intravenous BPs in postmenopausal women with osteoporosis. PMID- 21526080 TI - Health Belief Model and HIV/AIDS among high school female students in Yazd, Iran. PMID- 21526081 TI - The influence of calcium supplement on body composition, weight loss and insulin resistance in obese adults receiving low calorie diet. AB - BACKGROUND: Obesity and diabetes are the most important problems of public health. Evidence from molecular animal research and epidemiologic investigations indicate that calcium intake may have an influence on body composition, weight and insulin resistance. The objective of this study was to determine the effects of calcium supplementation on body composition, weight, insulin resistance and blood pressure in the face of calorie restriction in obese adults. METHODS: A double blind randomized placebo-controlled trial on 40 adults with Body Mass Index > 25kg/m(2) was conducted. Subjects were maintained for 24 weeks on a balanced deficit diet (-500 kcal/d deficit) and randomly assigned into two groups with 1000 mg ca/d as calcium carbonate or placebo. RESULTS: There were no significant differences in variables at the 12th and 24th week between the two groups. The lean mass showed no significant increase in the calcium group at the 12th week compared to baseline and in placebo group at the 24th week compared to the 12th week. The insulin concentration showed a significant decrease in the calcium group at the 12th week compared to the baseline (p < 0.05). The diastolic blood pressure had a significant decrease at the 24th week compared to the 12th week in both groups (p = 0.013-0.009). CONCLUSIONS: Results from this study suggest that 24 weeks of supplementation with 1000 mg ca/d did not have any effect on weight, body composition, insulin resistance and blood pressure beyond what can be achieved in an energy restricted diet in obese adults. PMID- 21526082 TI - Activity of daily living and its associated factors in war survivors with no visual acuity. AB - BACKGROUND: War is a known cause of tremendous physical injuries to different body organs, and eyes are not exceptions. War-related no visual acuity (NVA) affects both the victim and the family. Activity of daily living (ADL) can display personal life independency and is considered as a morbidity index. This study was designed to investigate the ADL profile of war survivors with NVA. METHODS: This cross-sectional study was conducted in 2007 in Iran. In this study, 500 Iranian people with war related NVA were invited to take part in a camp in Mashhad city. ADL was evaluated using Barthel Index and demographic data were collected using a data sheet. Stepwise linear regression was used to determine the associates of ADL. RESULTS: The overall response rate to the invitation was 50%. From the total 250 participants 96.5% were male with a mean age of 43 +/- 8 years. Only 8.3% had no dependency in ADL and other 91.7% had some ranges of dependency in at least one of the daily living activities. ADL score was higher in highly educated participants, those younger than 50 years old, those with less co-morbid physical problems (hearing loss) and those with regular physical exercises. According to regression analysis, age and duration of war related NVA were significant predictors of ADL. CONCLUSIONS: According to the results, both age and the time passed from war related NVA increase the dependency of people with war related NVA. PMID- 21526083 TI - Comparison of divided sciatic nerve growth within dermis, venous and nerve graft conduit in rat. AB - BACKGROUND: Considering the common origin of skin and peripheral nervous system, a tube of dermal layer of skin hypothetically can be an ideal conduit for nerve reconstruction. An experimental study performed to evaluate the nerve regeneration of efficacy into a dermal tube. METHODS: Sixty male Wistar rats were used. A 10 mm gap was produced in right sciatic nerves. In group A the autogenous nerve grafts were used to bridge the defects. In group B vein conduit were use to reconstruct the gaps. In group C dermal tube were used to bridge the defects. Morphologic studies were carried out after 3 month. RESULTS: The density of nerve fibers was significantly higher in autogenous nerve graft group. The efficacy of nerve growth into the dermal tube group was significantly poor in comparison to other groups. CONCLUSIONS: In the present study, dermis was used as the nerve conduit for the first time. This study indicates that the dermal tube is not a suitable conduit for nerve regeneration till further studies to resolve the problems before clinical application. PMID- 21526084 TI - A comparison of the effect of intranasal desmopressin and intramuscular hyoscine N-butyl bromide combination with intramuscular hyoscine N-butyl bromide alone in acute renal colic. AB - BACKGROUND: Patients with acute renal colic usually require immediate diagnosis and treatment. In this clinical trial analgesic effect of hyoscine N-butyl bromide and desmopressin combination in comparison with hyoscine N-butyl bromide alone in patients with acute renal colic induced by urinary stones was assessed. METHODS: The study included 114 patients randomly allocated in two groups (A and B). Patients in group A received 20 mg intramuscular hyoscine N-butyl bromide at admission time and patients in group B received 20 MUg of intranasal desmopressin in combination with 20 mg intramuscular hyoscine N-butyl bromide. A visual analogue scale (VAS; a 10-cm horizontal scale ranging from "zero or no pain" to "10 or unbearable pain") was hired to assess the patients' pain severity at baseline, 30 and 60 minutes after the treatments. RESULTS: ON ADMISSION, THE PAIN LEVEL WAS SIMILAR IN BOTH GROUPS (GROUP A: 8.95 +/- 0.11 and group B: 8.95 +/- 0.12). In group A, the mean of pain level showed a decrease after 30 minutes (group A: 7.26 +/- 0.25 and group B: 5.95 +/- 0.28) but further decreasing did not occur; however in group B, the pain consistently decreased and the mean after 60 minutes was significantly decreased (group A: 6.80 +/- 0.31 and group B: 3.71 +/- 0.31). No side effects were detected in this study. CONCLUSIONS: The combination of hyoscine N-butyl bromide and desmopressin is more effective than hyoscine N-butyl bromide alone in patients with renal colic. Further studies are recommended to validate these findings and compare the different doses of desmopressin. PMID- 21526085 TI - The design and equipments of hospital pharmacies in Isfahan, Iran. AB - BACKGROUND: Nowadays pharmaceutical care departments located in hospitals are amongst the important pillars of the healthcare system. The aim of this study was to evaluate designing features and equipments of hospital drugstores affiliated with Isfahan University of Medical Sciences. METHODS: In this cross-sectional study a self-defined and validated questionnaire was used which included all the necessary and standard needed spaces and equipments of an ideal hospital pharmacy. The questionnaire was filled in by one of the researchers in all twelve hospital drugstores located in the teaching and non-teaching hospitals affiliated with Isfahan University of Medical Sciences. Data analysis was done using SPSS (version 14). RESULTS: Results showed that 56% of drugstore space allocations were unsuitable. Used pharmaceutical equipments in 75% of surveyed hospitals were not according to the standards. Almost all of these pharmacies had rather an enough space for storage, but cold storages were not designed in 58% of them. In 66% of perused hospitals, pharmaceutical services disposal level was admissible. The structural engineering parameters like size and dimensions, available spaces, availability of structural planes, existence of air conditioning systems and brightness controllers, adequate stores for drugs and safe places for narcotics were observed in 55% of pharmacies. CONCLUSIONS: There are apparent out of standard space allocations and shortages of needed equipments for offering drug services in studied drugstores that may probably lead to a waste of time and money. These issues may reduce the efficiency and safety of pharmaceutical services and drug administration in hospitals. PMID- 21526086 TI - Enhancement of the efficacy of cancer chemotherapy by the pineal hormone melatonin and its relation with the psychospiritual status of cancer patients. AB - BACKGROUND: The anti-oxidant and immunomodulating natural agents may enhance the efficacy of cancer chemotherapy. One of the most important agents is the pineal hormone melatonin (MLT) which may exert both anti-oxidant and antiproliferative immunostimulating anticancer effects. This study was performed to evaluate the efficacy of a biochemotherapeutic regimen in metastatic cancer patients, and its therapeutic activity in relation to the psychospiritual status of patients. METHODS: The study included 50 metastatic non-small cell lung cancer (NSCLC) patients and a control group of 100 patients. Chemotherapy consisted of cisplatin plus gemcitabine. MLT was given orally at 20 mg/day in the evening. Patients were subdivided into 5 psychic profiles, as follows: spiritual faith, rationale faith, anxiety, apathy, and accusation behavior. RESULTS: Tumor response rate was significantly higher in patients treated by chemotherapy plus MLT than in those treated by chemotherapy alone (21/50 vs. 24/100, p < 0.001). However, the percentage of objective tumor regressions obtained in patients with spiritual faith was significantly higher than that found in the overall other patients concomitantly treated by chemotherapy plus MLT (6/8 vs. 15/42, p < 0.01). CONCLUSIONS: In conclusion, the efficacy of chemotherapy may be enhanced by the pineal hormone MLT, by representing a new promising biochemotherapeutic combination; also despite its objective ability to enhance chemotherapy efficacy, the activity of MLT is depending at least in part on the psychospiritual status of cancer patients, and it is maximal in the presence of a real spiritual faith. PMID- 21526087 TI - Bipolar Disorder Patients Follow-up (BDPF): methods and materials. AB - BACKGROUND: The Bipolar Disorder Patients Follow-up (BDPF) project is a longitudinal, prospective and naturalistic study. The purpose of the present report is to introduce the project, elaborate its methods, and present the reliability data of the utilized symptoms rating scales. METHODS: The sampling started in May 2008 and is still in progress. The probands are assessed at the beginning of the sampling and then 2 and 6 months later and then every 6 months using several instruments to identify psychiatric comorbidities, symptoms severity, quality of life, attempted suicide rate, treatment compliance, and some other factors. RESULTS: The results could lead to increase the clinicians' awareness about the clinical picture of this disorder in Iranian patients. CONCLUSIONS: The present project could decrease to some extent the current shortcomings in Iran's psychiatric data at least about one of the major psychiatric disorders known as the eighth result which cause medical disability over the world. PMID- 21526088 TI - Characteristic and follow-up of subglottic hemangiomas in Iranian children. AB - Subglottic hemangiomas are very rare in compare with cutaneous form but can be life-threatening in the proliferating phase of tumor by airway obstruction. It should be considered in any child with recurrent, persistent and/or progressive, inspiratory or biphasic stridor, respiratory distress and feeding difficulties in the first months of life. It should be confirmed by endobronchoscopic evaluation. Affected infants are most likely to experience symptoms between the ages of 6 and 12 weeks. Infants who admitted and referred to our hospital with recurrent stridor, cough and respiratory distress were reviewed. PMID- 21526089 TI - Granulosa cell tumor in a six-year-old girl presented as precocious puberty. AB - Ovarian sex cord-stromal tumors, including granulose cell tumors (GCTs), are a group of neoplasms that occur rarely, especially in children. Only 0.1 percent of all ovarian tumors and 4-5 percent of GCTs occur in children. The most common presentation of these tumors in children is precocious puberty. We report a 6 years old girl with isosexual precocity, presented as premature thelarche and vaginal bleeding. Ultrasonography of pelvis showed a hypoechoic solid mass of left ovary.Microscopic features of the resected mass were characteristic of juvenile GCT. Although in most of girls with precocious puberty, the etiology is idiopathic, important causes, such as ovarian tumors must be considered. PMID- 21526090 TI - A survey on herpes simplex type 2 antibody among pregnant women in Isfahan, Iran. PMID- 21526091 TI - Essential trace metals and heavy metals in newly diagnosed schizophrenic patients and those on anti-psychotic medication. AB - BACKGROUND: Nutritional deprivation in the early stage of life increases the risk of developing schizophrenia. Oxidative stress, disturbed thinking and irrational behavior which are common to schizophrenic patients may be a result of changes in the levels of certain trace metals. METHODS: Twenty (20) healthy volunteers and a total of thirty-five (35) schizophrenic patients consisting of 20 on antipsychotic drugs for at least 2 weeks and 15 newly diagnosed but not taking antipsychotic drugs were considered. The plasma levels of trace metals were analyzed using atomic absorption spectrophotometer. RESULTS: Fe and Se were significantly reduced in newly diagnosed and medicated-schizophrenic patients compared with controls. Pb, Cd and Cr were significantly raised in newly diagnosed drug free schizophrenic patients compared with controls. While Cr and Cd were significantly raised in schizophrenic patients on treatment compared with the controls. CONCLUSIONS: Levels of certain nutritionally essential trace metals (Fe and Se) were reduced while levels of certain heavy metals (Pb, Cr and Cd) were raised in schizophrenic patients. PMID- 21526092 TI - Incidence of trapezius myofascial trigger points in patients with the possible carpal tunnel syndrome. AB - BACKGROUND: Patients with carpal tunnel syndrome (CTS) often complain of prominent pain in shoulder and arm, also there are patients that have pain in their shoulder and arm which is due to myofascial trigger point (MTP) located in their upper trapezius muscle. Despite the frequency of this observation, few studies have previously sought to establish possible relationship between the CTS and MTP in shoulder area. METHODS: Samples were 160 patients (221 hands) consist of 130 females and 30 males, with suspected diagnosis of CTS, from March 2008 to October 2008. In this study after performing electrodiagnosis searches, another evaluation was performed to find out if there was any sign of myofascial trigger point. The correlation between these two was sought. RESULTS: It was found that all of 36 hands with normal electrodiagnostic findings had myofascial trigger points in their upper trapezius muscle. Out of 185 hands, 130 hands (70%) with electrophysiological evidences of CTS showed myofascial trigger points in their trapezius muscles. Statistical analysis revealed significant (p < 0.001) reverse correlation between the severity of CTS and the presence of MTP. CONCLUSIONS: The findings of this study imply the significant correlation between occurrence of CTS and MTP. It is suggested that clinicians consider the probability of existence of MTP in patients referred for diagnosis of CTS. PMID- 21526093 TI - The efficacy of attendance and semi-attendance group cognitive-behavioral therapy (CBT) on the anxiety disorders of adolescent girls. AB - BACKGROUND: Anxiety disorders are one of the most psychiatric disorders in children and adolescents that can cause long life functional disability. The first line treatment for this disorder is cognitive behavioral therapy that has primary, secondary and tertiary preventive effect, but is expensive and long time. Today there is some effort to find short term, group, semi-attendance and low cost therapies. METHODS: Subjects were 42 girls (12- 17 y) with at least one anxiety disorder according to DSM-IV-TR with their parents who were divided into two groups randomly: group A which participated in 8 sessions and group B which participated in 4 sessions and the contents of sessions 3, 4, 6, and 7 were recorded on a CD for them. The tests used in this study were: SCARED, CATS, CAIS C, CAIS-P, conducted before (T0), just after (T1) and three months after the treatment (T2). The collected data were analyzed by multivariate analysis of covariance test using SPSS software package, version 15.0. RESULTS: There was no significant difference between efficacy of semi-attendance group CBT and attendance group CBT in T0, T1 and T2 according to 4 tests (p = 0.311). The difference between the scores of these tests between T0 andT1 and T0 and T2 was significant in both groups (p < 0.001) but the difference between T1 and T2 was not significant. (p = 0.771). CONCLUSIONS: The efficacy of semi-attendance group CBT and attendance group CBT is similar and would sustain after 3 months. PMID- 21526094 TI - Should the first degree relatives of type 2 diabetic patients with isolated impaired fasting glucose be considered for a diabetes primary prevention program? AB - BACKGROUND: The aim of this study is to investigate the need for diabetes primary prevention program in isolated impaired fasting glucose (i-IFG) of the first degree relatives of type 2 diabetics. METHODS: In a cross sectional study, 793 individuals with prediabetes [543 with i-IFG and 250 with isolated impaired glucose tolerance (i-IGT)] who were the first degree relatives of type 2 diabetic patients, were enrolled. Isolated IFG was considered as fasting plasma glucose between 100-125 mg/dl and 2 hour plasma glucose < 140 mg/dl and isolated IGT as FPG < 100 mg/dl and 2 hour plasma glucose between 140-199 mg/dl during an overnight fasting 75 g oral glucose tolerance test. Mean of the age, weight, waist circumference, body mass index, systolic and diastolic blood pressure, plasma glucose, HbA1C, and lipid profile were compared between two groups (i-IFG and i-IGT). The prevalence of cardiometabolic risk factors (BMI >= 25 kg/m2, hypertension, cholesterol >= 200 mg/dl, LDL-C >= 100 mg/dl, HDL-C <= 40 mg/dl, and triglyceride >= 150 mg/dl) adjusted by age, sex and BMI were compared. RESULTS: The prevalence of cardiometabolic risk factors is higher in i-IFG group than i-IGT. The mean level of LDL-C is significantly higher in i-IFG than i-IGT group. CONCLUSIONS: First degree relatives of T2DM with isolated impaired fasting glucose should probably be included in the primary preventive program for diabetes. However, longitudinal cohort study is required to show high progression of i-IFG to T2DM. PMID- 21526095 TI - Assessment of antioxidant enzyme activities in erythrocytes of pre-hypertensive and hypertensive women. AB - BACKGROUND: Few studies that have investigated hypertension have considered a state of oxidative stress that can contribute to the development of atherosclerosis and other hypertension induced organ damage. The aim of this study was to investigate whether pre-hypertension and hypertension status is associated with activities of erythrocyte antioxidant enzymes in a random sample of cardiovascular disease-free women. METHODS: In this case-control study, 53 pre hypertensive women, 32 hypertensive women and 75 healthy controls were included. General information was gathered using questionnaires and face-to-face interviews. Blood pressure and anthropometric measurements were measured for each subject. Venous blood samples were drawn from subjects and plasma was separated. Activities of erythrocyte antioxidant enzymes were also evaluated by measuring activities of copper zinc-superoxide dismutase (CuZn-SOD), glutathione peroxidase (GPX) and catalase (CAT) in selected subjects. RESULTS: Fifty-three (33.1%) and 32 (20%) participants were pre-hypertensive and hypertensive, respectively. The hypertensive and pre-hypertensive women had lower CuZn-SOD (p < 0.001) and GPX (p < 0.01) activities compared to normotensives. Furthermore, hypertensive women had lower CAT activity compared to pre-hypertensive and normotensive women (p < 0.001). Moreover, significant differences were also observed between hypertensive and pre-hypertensive women in erythrocyte CAT activity (p < 0.01). CONCLUSIONS: The present findings show that activities of erythrocyte antioxidant enzymes decrease in pre-hypertensive and hypertensive women, which may eventually lead to atherosclerosis and other high blood pressure related health problems. PMID- 21526096 TI - The growth inhibitory effects of cadmium and copper on the MDA-MB468 human breast cancer cells. AB - BACKGROUND: Cadmium chloride is an important occupational and environmental pollutant. However, it can also be anti-carcinogenic under certain conditions. Copper, an essential trace element, has the ability to generate reactive oxygen species and induce cell apoptosis. This study was aimed to determine the growth inhibitory effects of cadmium and copper on the MDA-MB468 human breast cancer cells. METHODS: By using MTT cell viability test, treatment of monolayer cell cultures with different metal concentrations (1-1000 uM) showed a significant dose dependent decrease (p < 0.05) of viable cells in different times. RESULTS: A considerable cytotoxicity was observed for CdCl2 at 200 uM and 1 uM after 48 and 72 hours incubations, respectively. The highest concentration of CuCl2 (1000 uM) had little cytotoxic effects after 48 hours incubation period, but 1 uM of CuCl2 revealed a considerable cytotoxicity after 72 hours. The maximum synergic cytotoxic effect was observed at 0.5 uM of both metals. CONCLUSIONS: The results of the present study indicate that cytotoxic effect of CuCl2 is somehow lesser than that of CdCl2. This may be due to vital role of copper which is not known for cadmium so far. PMID- 21526097 TI - Lack of HIV infection among truck drivers in Iran using rapid HIV test. AB - BACKGROUND: The aim of this study was to evaluate the prevalence of HIV infection in Iranian long distance truck drivers using rapid HIV test. METHODS: The study included 400 consecutive participants in Bazargan city, north-west of Iran in the late 2008 and the early 2009. RESULTS: No HIV infection was observed among these long distance truck drivers. CONCLUSIONS: Although results of this study is plausible compared to other similar studies, repeated surveys are necessary to know the trend of HIV infection in truckers in Iran. PMID- 21526098 TI - Esophageal cancer occurrence in Southeastern Iran. PMID- 21526099 TI - Observance of radiation protection principles in Iranian dental schools. PMID- 21526100 TI - Correlation of inflammatory and nutritional indexes in Isfahan hemodialysis patients. PMID- 21526101 TI - Trend of prostate cancer in Fars Province, Southern Iran, 2001-2007. PMID- 21526102 TI - Are there any differences between features of proteins expressed in malignant and benign breast cancers? AB - BACKGROUND: The most common cancer among women is breast cancer and it has been blamed as the second leading cause of cancer death in women; so far many approaches have been used to analyze and detect benign and malignant forms of cancer and understanding the features involved in proteins expressed by various types of breast cancers is crucial. METHODS: Herein features of proteins expressed in malignant, benign and both cancers were compared using different screening techniques, clustering methods, decision tree models and generalized rule induction (GRI) algorithms to look for patterns of similarity in two benign and malignant breast cancer groups. RESULTS: The findings showed that the N terminal amino acid was Met and 57 out of 838 proteins' features ranked as important (p > 0.05). The depth of the trees induced by tree induction models varied from 5 (in the Quest model) to 2 (in the C5.0 model) branches. The best performance evaluation found when C&RT model applied and the worst evaluation found when CHAID model applied. No significant difference in the percentage of correctness, performance evaluation, and mean correctness in tree induction algorithms was found when feature selection applied on datasets, but the number of peer groups reduced significantly (p < 0.05) when feature selection model applied. CONCLUSIONS: The frequency of Ile-Ile was the most important protein attributes in all tree and rule induction models. The importance of sequence based classification and the frequency of Ile-Ile in prediction of malignant and benign breast cancer have been discussed here. PMID- 21526103 TI - Efficacy of interferon alpha-2b with or without ribavirin in thalassemia major patients with chronic hepatitis C virus infection: A randomized, double blind, controlled, parallel group trial. AB - BACKGROUND: The aim of this study was to evaluate the effectiveness of monotherapy with interferon alpha-2b and combination therapy with interferon alpha-2b plus ribavirin on chronic hepatitis C infection in thalassaemic patients. METHODS: In parallel group randomized, double blind, controlled trial, 32 thalassaemic patients with chronic hepatitis C infection completed the study. In a random fashion, one group was treated with three million units of interferon alpha-2b three times a week plus ribavirin (800-1200 mg daily). The second group received interferon alpha-2b alone. Treatment duration was 24-48 weeks. Primary efficacy variables were HCV RNA after treatment and sustained viral response (SVR) six months after treatment. RESULTS: The mean age of patients was 22 +/- 7.4 years; 19 (59.4%) were male and 13 (40.6) were female. At the end of treatment, no statistically significant differences were found between the groups in HCV RNA and AST. The proportion of patients with SVR six months after treatment was significantly greater in the monotherapy group (90.9%) than in the combination therapy group (44.4%; p = 0.049). A significant difference in mean of ALT was also obtained at the end of treatment between monotherapy and combination therapy groups (30.4 +/- 19.2 and 60.1 +/- 48.9, respectively; p = 0.02). Response rates were not associated with genotype and severity of hepatitis C infection in both groups. CONCLUSIONS: These results suggest that monotherapy may be considered as the first-line therapy in patients with thalassemia. PMID- 21526104 TI - A cross-over trial on soy intake and serum leptin levels in women with metabolic syndrome. AB - BACKGROUND: Soy consumption may affect serum leptin levels and exert its beneficial effects in this way. The aim of this study was to evaluate the effect of soy consumption on serum leptin levels in postmenopausal women with metabolic syndrome. METHODS: In this clinical trial, 42 postmenopausal women with metabolic syndrome were included. The patients followed three kinds of diets: control diet (Dietary Approaches to Stop Hypertension= DASH), soy protein diet, or soy nut diet for eight weeks. Serum leptin level was measured by ELISA method. RESULTS: No significant weight change were seen in patients during three phases of trial. There was no significant difference between the end values of serum leptin concentrations following these diets (Geometric mean +/- SD: 16.9 +/- 2.5 ng/ml at the end of control diet, 16.1 +/- 1.6 ng/ml at the end of soy protein diet, and 15.9 +/- 1.7 ng/ml at the end of soy nut diet). Percent difference compared to control for serum leptin levels showed that neither soy protein nor soy nut diets could significantly alter this variable (p = 0.32). CONCLUSIONS: The results of the present study showed that neither soy protein, nor soy nut could affect weight and serum leptin levels in postmenopausal women with metabolic syndrome. PMID- 21526105 TI - The antibody titers to Helicobacter pylori in 7 - 12 year old iron deficiency anemic children, in Ilam. AB - BACKGROUND: It has recently been revealed that H. pylori infection is one the most important causes of anemia inhibiting iron uptake. The current study was designed to evaluate the correlation between the iron deficiency anemia and IgG to H. pylori in anemic children. METHODS: In this analytical study, 100 anemic children were analyzed using total Iron, Ferritin, TIBC and H. pylori IgG assay. Data were collected using a questionnaire including parameters of age, blood group, infancy nutrition, iron consumption, fatigue, weakness, height, weight, gastrointestinal infectious, parasitic and blood diseases, parent literacy, income, inhabitation, etc. Data were analyzed using Multivariate Regression Analysis Models, Pearson Correlation- test and Kolmogrov Smirnov. RESULTS: The most prevalent blood group detected in the study sample was group O (62%); 79% were breastfed, 9% were bottle- fed, 12% were both breastfed and bottle- fed. The history of gastrointestinal disorders was mentioned amongst 91% of the patients' family members. A significant relationship was observed between the iron level with serum, ferritin, level of TIBC and elevated level of IgG titer to H. pylori (p < 0.001). There was a significant association between the shared dishes, GI disorders, fatigue and weakness and level of TIBC, ferritin, Iron and IgG (p < 0.001). CONCLUSIONS: The significant relationship between the iron level, IgG titer and H. pylori infection rate can be referred to as important factors influencing the anemia rate. Therefore, H. pylori IgG test can be checked for anemia together with the other routine tests. PMID- 21526106 TI - The effect of hypocaloric diet enriched in legumes with or without L-arginine and selenium on anthropometric measures in central obese women. AB - BACKGROUND: Identifying new ways to decrease adiposity will be very valuable for health. The aim of this study was to find out whether L-Arginine (Arg) and selenium alone or together can increase the effect of hypocaloric diet enriched in legumes (HDEL) on anthropometric measures in healthy obese women. METHODS: This randomized, double-blind, placebo-controlled trial was undertaken in 84 healthy premenopausal women with central obesity. After 2 weeks of run-in on an isocaloric diet, participants were randomly considered to eat HDEL, Arg (5 g/d) and HDEL, selenium (200 ug/d) and HDEL or Arg, selenium and HDEL for 6 weeks. The following variables were assessed before intervention and 3 and 6 weeks after it: weight, waist circumference, hip circumference, waist to hip ratio (WHR), body mass index (BMI), and fasting nitrite/nitrate (NO(x)) concentrations. Other variables (arm, thigh, calf and breast circumferences, subscapular, triceps, biceps and suprailiac skinfold thicknesses, sum of skinfold thicknesses (SSF), body density (D) and estimated percent of body fat (EPF)) were assessed before and after intervention. RESULTS: HDEL showed a significant effect in reduction of waist, hip, arm, thigh, calf and breast circumferences, triceps, biceps, subscapular and suprailiac skinfold thicknesses, WHR, SSF, D and EPF. HDEL + Arg + selenium significantly reduced suprailiac skinfold thicknesses; and there was no significant effect of HDEL, Arg, selenium and Arg plus selenium on weight, BMI and fasting NO(x). CONCLUSIONS: The study indicates that HDEL + Arg + selenium reduce suprailiac skinfold thicknesses which represents the abdominal obesity reduction. PMID- 21526107 TI - Effect of decompressive hemicraniectomy on mortality of malignant middle cerebral artery infarction. AB - BACKGROUND: Increasing intracranial pressure (ICP) is one of the leading causes of mortality in patients with malignant infarction of the middle cerebral artery (MCA). We prospectively evaluated patients with MCA infarction for one month survival after decompressive hemicraniectomy. METHODS: This study was conducted at Alzahra University Hospital, Isfahan (Iran). Twenty patients with infarction in total MCA distribution area, resulting in midline shift of brain tissue for greater than 5mm, underwent decompressive hemicraniectomy. Mortality rate was estimated one month after surgery. RESULTS: Patients were 8 (40%) males and 12 (60%) females with a mean age of 49.9 +/- 3.8 (25 to 70) years. Left and right MCA were involved in 7 (35%) and 13 (65%) patients, respectively. Four (20%) patients died within one month after surgery (3 females and one male, mean age of 59.0 +/- 4.5 vs. 47.6 +/- 3.4 in survived patients, p < 0.001). The mean of baseline Glasscow Coma Scale (GCS) score estimated 8.60 +/- 1.55 in survived patients and 6.75 +/- 0.95 in patients who died (p < 0.05). CONCLUSIONS: The survival rate of malignant MCA infarction treated with decompressive hemicraniectomy was the same as previous reports. MCA infarction mortality increased with age and lower admission GCS score. PMID- 21526108 TI - Review of cellular and molecular pathways linking thrombosis and innate immune system during sepsis. AB - Cellular and molecular pathways link thrombosis and innate immune system during sepsis. Extrinsic pathway activation of protease thrombin through FVIIa and tissue factor (TF) in sepsis help activate its endothelial cell (EC) membrane Protease Activated Receptor 1 (PAR-1). Thrombin adjusts the EC cycle through activation of G proteins (G12/13), and later through Rho GEFs (guanine nucleotide exchange factors), and provides a path for Rho GTPases mediated cytoskeletal responses involved in shape change and permeability of the EC membrane leading to an increase of leakage of plasma proteins.At the same time, thrombin stimulates spontaneous mitogenesis by inducing activation of the cell cycle from G0-G1 to S by down-regulation of p27Kip1, a negative regulator of the cell cycle, in association with the up-regulation of S-phase kinase associated protein 2 (Skp2). After transport in cytoplasm, p27 Kip1 binds to RhoA thus prevent activation of RhoA by GEFs, thus inhibit GDP-GTP exchange mediated by GEFs. In cytoplasm, releasing factor (RF) p27-RF-Rho is able to free RhoA. P27 RF-Rho binds p27kip1 and prevents p27kip1 from binding to RhoA. Exposed RhoA is later able to increase the expression of the F-box protein Skp2, after its Akt triggered 14-3-3-beta dependent cytoplasm relocation. Skp2 increases cytoplasm ubiquitination-dependent degradation of p27Kip1. Additionally, after septic induction of canonical NF-kB pathway in EC through TLR4/IRAK4/TRAF/IkB, an IKKalpha dimer phosphorylates the p52 precursor NF-kB2/p100, leading to p100 processing and translocation of RelB/p52 to the nucleus. By controlling the NF-kB-RelB complex, IKKalpha signaling regulates the transcription of the Skp2 and correspondingly p27Kip1. PMID- 21526109 TI - Idiopathic thrombocytopenic purpura in women with breast cancer. AB - The association of solid tumors with idiopathic thrombocytopenic purpura (ITP) is rare. However, there have been some case reports indicating an association between breast cancer and ITP. In this article four patients with breast cancer and ITP are mentioned. The diagnosis of breast cancer was based on the results of biopsy or surgical sample. The ITP diagnosis criteria were 1) exclusion of drug induced thrombocytopenia, 2) platelet count less than 140 * 109 /l with normal or increased number of megakaryocytes on bone marrow samples, and 3) absence of splenomegaly. In this case report an association of breast cancer and ITP is shown. PMID- 21526110 TI - Endobronchial leiomyoma; report of a case successfully treated by bronchoscopic resection. AB - Bronchial leiomyoma is extremely rare. To date less than 60 cases have been reported in the world literature. The presented case here is a 30 year old woman who had been treated for bronchial asthma for several years. Her chest radiograph showed bulluos emphysematous changes in the right lung and computer tomography scan found the tumor in the right main bronchus near carina. Diagnosis was made by histological and immunohistochemical examination of the specimens obtained during bronchoscopy. The patient was treated by bonchoscopic resection of the 3 centimetre firm tumor and its removal through a tracheostomy incision. PMID- 21526111 TI - Normal olfaction range of Rasht residents using a new test designed for the region. PMID- 21526112 TI - A collaborative filtering approach for protein-protein docking scoring functions. AB - A protein-protein docking procedure traditionally consists in two successive tasks: a search algorithm generates a large number of candidate conformations mimicking the complex existing in vivo between two proteins, and a scoring function is used to rank them in order to extract a native-like one. We have already shown that using Voronoi constructions and a well chosen set of parameters, an accurate scoring function could be designed and optimized. However to be able to perform large-scale in silico exploration of the interactome, a near-native solution has to be found in the ten best-ranked solutions. This cannot yet be guaranteed by any of the existing scoring functions. In this work, we introduce a new procedure for conformation ranking. We previously developed a set of scoring functions where learning was performed using a genetic algorithm. These functions were used to assign a rank to each possible conformation. We now have a refined rank using different classifiers (decision trees, rules and support vector machines) in a collaborative filtering scheme. The scoring function newly obtained is evaluated using 10 fold cross-validation, and compared to the functions obtained using either genetic algorithms or collaborative filtering taken separately. This new approach was successfully applied to the CAPRI scoring ensembles. We show that for 10 targets out of 12, we are able to find a near-native conformation in the 10 best ranked solutions. Moreover, for 6 of them, the near-native conformation selected is of high accuracy. Finally, we show that this function dramatically enriches the 100 best-ranking conformations in near-native structures. PMID- 21526113 TI - Differential response of primary and immortalized CD4+ T cells to Neisseria gonorrhoeae-induced cytokines determines the effect on HIV-1 replication. AB - To compare the effect of gonococcal co-infection on immortalized versus primary CD4(+) T cells the Jurkat cell line or freshly isolated human CD4(+) T cells were infected with the HIV-1 X4 strain NL4-3. These cells were exposed to whole gonococci, supernatants from gonococcal-infected PBMCs, or N. gonorrhoeae-induced cytokines at varying levels. Supernatants from gonococcal-infected PBMCs stimulated HIV-1 replication in Jurkat cells while effectively inhibiting HIV-1 replication in primary CD4(+) T cells. ELISA-based analyses revealed that the gonococcal-induced supernatants contained high levels of proinflammatory cytokines that promote HIV-1 replication, as well as the HIV-inhibitory IFNalpha. While all the T cells responded to the HIV-stimulatory cytokines, albeit to differing degrees, the Jurkat cells were refractory to IFNalpha. Combined, these results indicate that N. gonorrhoeae elicits immune-modulating cytokines that both activate and inhibit HIV-production; the outcome of co-infection depending upon the balance between these opposing signals. PMID- 21526114 TI - Acrocephalus orinus: a case of mistaken identity. AB - Recent discovery of the Large-billed Reed Warbler (Acrocephalus orinus) in museums and in the wild significantly expanded our knowledge of its morphological traits and genetic variability, and revealed new data on geographical distribution of the breeding grounds, migration routes and wintering locations of this species. It is now certain that A. orinus is breeding in Central Asia; however, the precise area of distribution remains unclear. The difficulty in the further study of this species lies in the small number of known specimens, with only 13 currently available in museums, and in the relative uncertainty of the breeding area and habitat of this species. Following morphological and genetic analyses from Svensson, et al, we describe 14 new A. orinus specimens from collections of Zoological Museums of the former USSR from the territory of Central Asian states. All of these specimens were erroneously labeled as Blyth's Reed Warbler (A. dumetorum), which is thought to be a breeding species in these areas. The 14 new A. orinus specimens were collected during breeding season while most of the 85 A. dumetorum specimens from the same area were collected during the migration period. Our data indicate that the Central Asian territory previously attributed as breeding grounds of A. dumetorum is likely to constitute the breeding territory of A. orinus. This rare case of a re-description of the breeding territory of a lost species emphasizes the importance of maintenance of museum collections around the world. If the present data on the breeding grounds of A. orinus are confirmed with field observations and collections, the literature on the biology of A. dumetorum from the southern part of its range may have to be reconsidered. PMID- 21526115 TI - Neuroethics and fMRI: mapping a fledgling relationship. AB - Human functional magnetic resonance imaging (fMRI) informs the understanding of the neural basis of mental function and is a key domain of ethical enquiry. It raises questions about the practice and implications of research, and reflexively informs ethics through the empirical investigation of moral judgments. It is at the centre of debate surrounding the importance of neuroscience findings for concepts such as personhood and free will, and the extent of their practical consequences. Here, we map the landscape of fMRI and neuroethics, using citation analysis to uncover salient topics. We find that this landscape is sparsely populated: despite previous calls for debate, there are few articles that discuss both fMRI and ethical, legal, or social implications (ELSI), and even fewer direct citations between the two literatures. Recognizing that practical barriers exist to integrating ELSI discussion into the research literature, we argue nonetheless that the ethical challenges of fMRI, and controversy over its conceptual and practical implications, make this essential. PMID- 21526116 TI - Functional characterization of the plasmacytoma variant translocation 1 gene (PVT1) in diabetic nephropathy. AB - We previously observed association between variants in the plasmacytoma variant translocation 1 gene (PVT1) and end-stage renal disease (ESRD) attributed to both type 1 and type 2 diabetes, and demonstrated PVT1 expression in a variety of renal cell types. While these findings suggest a role for PVT1 in the development of ESRD, potential mechanisms for involvement remain unknown. The goal of this study was to identify possible molecular mechanisms by which PVT1 may contribute to the development and progression of diabetic kidney disease. We knocked-down PVT1 expression in mesangial cells using RNA interference, and analyzed RNA and protein levels of fibronectin 1 (FN1), collagen, type IV, alpha 1 (COL4A1), transforming growth factor beta 1 (TGFB1) and plasminogen activator inhibitor-1 (SERPINE1 or PAI-1) by qPCR and ELISA, respectively. PVT1 expression was significantly upregulated by glucose treatment in human mesangial cells, as were levels of FN1, COL4A1, TGFB1, and PAI-1. Importantly, PVT1 knockdown significantly reduced mRNA and protein levels of the major ECM proteins, FN1 and COL4A1, and two key regulators of ECM proteins, TGFB1 and PAI-1. However, we observed a higher and more rapid reduction in levels of secreted FN1, COL4A1, and PAI-1 compared with TGFB1, suggesting that at least some of the PVT1 effects on ECM proteins may be independent of this cytokine. These results indicate that PVT1 may mediate the development and progression of diabetic nephropathy through mechanisms involving ECM accumulation. PMID- 21526119 TI - Towards accurate estimation of the proportion of true null hypotheses in multiple testing. AB - BACKGROUND: Biomedical researchers are now often faced with situations where it is necessary to test a large number of hypotheses simultaneously, eg, in comparative gene expression studies using high-throughput microarray technology. To properly control false positive errors the FDR (false discovery rate) approach has become widely used in multiple testing. The accurate estimation of FDR requires the proportion of true null hypotheses being accurately estimated. To date many methods for estimating this quantity have been proposed. Typically when a new method is introduced, some simulations are carried out to show the improved accuracy of the new method. However, the simulations are often very limited to covering only a few points in the parameter space. RESULTS: Here I have carried out extensive in silico experiments to compare some commonly used methods for estimating the proportion of true null hypotheses. The coverage of these simulations is unprecedented thorough over the parameter space compared to typical simulation studies in the literature. Thus this work enables us to draw conclusions globally as to the performance of these different methods. It was found that a very simple method gives the most accurate estimation in a dominantly large area of the parameter space. Given its simplicity and its overall superior accuracy I recommend its use as the first choice for estimating the proportion of true null hypotheses in multiple testing. PMID- 21526117 TI - A novel strategy to screen Bacillus Calmette-Guerin protein antigen recognized by gammadelta TCR. AB - BACKGROUND: Phosphoantigen was originally identified as the main gammadelta TCR recognized antigen that could activate gammadelta T cells to promote immune protection against mycobacterial infection. However, new evidence shows that the gammadelta T cells activated by phosphoantigen can only provide partial immune protection against mycobacterial infection. In contrast, whole lysates of Mycobacterium could activate immune protection more potently, implying that other gammadelta TCR-recognized antigens that elicit protective immune responses. To date, only a few distinct mycobacterial antigens recognized by the gammadelta TCR have been characterized. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we established a new approach to screen epitopes or protein antigens recognized by the gammadelta TCR using Bacillus Calmette-Guerin- (BCG-) specific gamma TCR transfected cells as probes to pan a 12-mer random-peptide phage-displayed library. Through binding assays and functional analysis, we identified a peptide (BP3) that not only binds to the BCG-specific gammadelta TCR but also effectively activates gammadelta T cells isolated from human subjects inoculated with BCG. Importantly, the gammadelta T cells activated by peptide BP3 had a cytotoxic effect on THP-1 cells infected with BCG. Moreover, the oxidative stress response regulatory protein (OXYS), a BCG protein that matches perfectly with peptide BP3 according to bioinformatics analysis, was confirmed as a ligand for the gammadelta TCR and was found to activate gammadelta T cells from human subjects inoculated with BCG. CONCLUSIONS/SIGNIFICANCE: In conclusion, our study provides a novel strategy to identify epitopes or protein antigens for the gammadelta TCR, and provides a potential means to screen mycobacterial vaccines or candidates for adjuvant. PMID- 21526118 TI - The Nature Index: a general framework for synthesizing knowledge on the state of biodiversity. AB - The magnitude and urgency of the biodiversity crisis is widely recognized within scientific and political organizations. However, a lack of integrated measures for biodiversity has greatly constrained the national and international response to the biodiversity crisis. Thus, integrated biodiversity indexes will greatly facilitate information transfer from science toward other areas of human society. The Nature Index framework samples scientific information on biodiversity from a variety of sources, synthesizes this information, and then transmits it in a simplified form to environmental managers, policymakers, and the public. The Nature Index optimizes information use by incorporating expert judgment, monitoring-based estimates, and model-based estimates. The index relies on a network of scientific experts, each of whom is responsible for one or more biodiversity indicators. The resulting set of indicators is supposed to represent the best available knowledge on the state of biodiversity and ecosystems in any given area. The value of each indicator is scaled relative to a reference state, i.e., a predicted value assessed by each expert for a hypothetical undisturbed or sustainably managed ecosystem. Scaled indicator values can be aggregated or disaggregated over different axes representing spatiotemporal dimensions or thematic groups. A range of scaling models can be applied to allow for different ways of interpreting the reference states, e.g., optimal situations or minimum sustainable levels. Statistical testing for differences in space or time can be implemented using Monte-Carlo simulations. This study presents the Nature Index framework and details its implementation in Norway. The results suggest that the framework is a functional, efficient, and pragmatic approach for gathering and synthesizing scientific knowledge on the state of biodiversity in any marine or terrestrial ecosystem and has general applicability worldwide. PMID- 21526120 TI - Mature peripheral RPE cells have an intrinsic capacity to proliferate; a potential regulatory mechanism for age-related cell loss. AB - BACKGROUND: Mammalian peripheral retinal pigmented epithelium (RPE) cells proliferate throughout life, while central cells are senescent. It is thought that some peripheral cells migrate centrally to correct age-related central RPE loss. METHODOLOGY/PRINCIPAL FINDINGS: We ask whether this proliferative capacity is intrinsic to such cells and whether cells located centrally produce diffusible signals imposing senescence upon the former once migrated. We also ask whether there are regional differences in expression patterns of key genes involved in these features between the centre and the periphery in vivo and in vitro. Low density RPE cultures obtained from adult mice revealed significantly greater levels of proliferation when derived from peripheral compared to central tissue, but this significance declined with increasing culture density. Further, exposure to centrally conditioned media had no influence on proliferation in peripheral RPE cell cultures at the concentrations examined. Central cells expressed significantly higher levels of E-Cadherin revealing a tighter cell adhesion than in the peripheral regions. Fluorescence-labelled staining for E-Cadherin, F-actin and ZO-1 in vivo revealed different patterns with significantly increased expression on central RPE cells than those in the periphery or differences in junctional morphology. A range of other genes were investigated both in vivo and in vitro associated with RPE proliferation in order to identify gene expression differences between the centre and the periphery. Specifically, the cell cycle inhibitor p27(Kip1) was significantly elevated in central senescent regions in vivo and mTOR, associated with RPE cell senescence, was significantly elevated in the centre in comparison to the periphery. CONCLUSIONS: These data show that the proliferative capacity of peripheral RPE cells is intrinsic and cell-autonomous in adult mice. These differences between centre and periphery are reflected in distinct patterns in junctional markers. The regional proliferation differences may be inversely dependent to cell-cell contact. PMID- 21526121 TI - Sex-linked pheromone receptor genes of the European corn borer, Ostrinia nubilalis, are in tandem arrays. AB - BACKGROUND: Tuning of the olfactory system of male moths to conspecific female sex pheromones is crucial for correct species recognition; however, little is known about the genetic changes that drive speciation in this system. Moths of the genus Ostrinia are good models to elucidate this question, since significant differences in pheromone blends are observed within and among species. Odorant receptors (ORs) play a critical role in recognition of female sex pheromones; eight types of OR genes expressed in male antennae were previously reported in Ostrinia moths. METHODOLOGY/PRINCIPAL FINDINGS: We screened an O. nubilalis bacterial artificial chromosome (BAC) library by PCR, and constructed three contigs from isolated clones containing the reported OR genes. Fluorescence in situ hybridization (FISH) analysis using these clones as probes demonstrated that the largest contig, which contained eight OR genes, was located on the Z chromosome; two others harboring two and one OR genes were found on two autosomes. Sequence determination of BAC clones revealed the Z-linked OR genes were closely related and tandemly arrayed; moreover, four of them shared 181-bp direct repeats spanning exon 7 and intron 7. CONCLUSIONS/SIGNIFICANCE: This is the first report of tandemly arrayed sex pheromone receptor genes in Lepidoptera. The localization of an OR gene cluster on the Z chromosome agrees with previous findings for a Z-linked locus responsible for O. nubilalis male behavioral response to sex pheromone. The 181-bp direct repeats might enhance gene duplications by unequal crossovers. An autosomal locus responsible for male response to sex pheromone in Heliothis virescens and H. subflexa was recently reported to contain at least four OR genes. Taken together, these findings support the hypothesis that generation of additional copies of OR genes can increase the potential for male moths to acquire altered specificity for pheromone components, and accordingly, facilitate differentiation of sex pheromones. PMID- 21526122 TI - Staphylococcus aureus keratinocyte invasion is dependent upon multiple high affinity fibronectin-binding repeats within FnBPA. AB - Staphylococcus aureus is a commensal organism and a frequent cause of skin and soft tissue infections, which can progress to serious invasive disease. This bacterium uses its fibronectin binding proteins (FnBPs) to invade host cells and it has been hypothesised that this provides a protected niche from host antimicrobial defences, allows access to deeper tissues and provides a reservoir for persistent or recurring infections. FnBPs contain multiple tandem fibronectin binding repeats (FnBRs) which bind fibronectin with varying affinity but it is unclear what selects for this configuration. Since both colonisation and skin infection are dependent upon the interaction of S. aureus with keratinocytes we hypothesised that this might select for FnBP function and thus composition of the FnBR region. Initial experiments revealed that S. aureus attachment to keratinocytes is rapid but does not require FnBRs. By contrast, invasion of keratinocytes was dependent upon the FnBR region and occurred via similar cellular processes to those described for endothelial cells. Despite this, keratinocyte invasion was relatively inefficient and appeared to include a lag phase, most likely due to very weak expression of alpha(5)beta(1) integrins. Molecular dissection of the role of the FnBR region revealed that efficient invasion of keratinocytes was dependent on the presence of at least three high affinity (but not low-affinity) FnBRs. Over-expression of a single high-affinity or three low-affinity repeats promoted invasion but not to the same levels as S. aureus expressing an FnBPA variant containing three high-affinity repeats. In summary, invasion of keratinocytes by S. aureus requires multiple high-affinity FnBRs within FnBPA, and given the importance of the interaction between these cell types and S. aureus for both colonisation and infection, may have provided the selective pressure for the multiple binding repeats within FnBPA. PMID- 21526123 TI - Comparative analysis of 3D expression patterns of transcription factor genes and digit fate maps in the developing chick wing. AB - Hoxd13, Tbx2, Tbx3, Sall1 and Sall3 genes are candidates for encoding antero posterior positional values in the developing chick wing and specifying digit identity. In order to build up a detailed profile of gene expression patterns in cell lineages that give rise to each of the digits over time, we compared 3 dimensional (3D) expression patterns of these genes during wing development and related them to digit fate maps. 3D gene expression data at stages 21, 24 and 27 spanning early bud to digital plate formation, captured from in situ hybridisation whole mounts using Optical Projection Tomography (OPT) were mapped to reference wing bud models. Grafts of wing bud tissue from GFP chicken embryos were used to fate map regions of the wing bud giving rise to each digit; 3D images of the grafts were captured using OPT and mapped on to the same models. Computational analysis of the combined computerised data revealed that Tbx2 and Tbx3 are expressed in digit 3 and 4 progenitors at all stages, consistent with encoding stable antero-posterior positional values established in the early bud; Hoxd13 and Sall1 expression is more dynamic, being associated with posterior digit 3 and 4 progenitors in the early bud but later becoming associated with anterior digit 2 progenitors in the digital plate. Sox9 expression in digit condensations lies within domains of digit progenitors defined by fate mapping; digit 3 condensations express Hoxd13 and Sall1, digit 4 condensations Hoxd13, Tbx3 and to a lesser extent Tbx2. Sall3 is only transiently expressed in digit 3 progenitors at stage 24 together with Sall1 and Hoxd13; then becomes excluded from the digital plate. These dynamic patterns of expression suggest that these genes may play different roles in digit identity either together or in combination at different stages including the digit condensation stage. PMID- 21526124 TI - Differential proteome analysis of bone marrow mesenchymal stem cells from adolescent idiopathic scoliosis patients. AB - Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine. The cause and pathogenesis of scoliosis and the accompanying generalized osteopenia remain unclear despite decades of extensive research. In this study, we utilized two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS) to analyze the differential proteome of bone marrow mesenchymal stem cells (BM-MSCs) from AIS patients. In total, 41 significantly altered protein spots were detected, of which 34 spots were identified by MALDI-TOF/TOF analysis and found to represent 25 distinct gene products. Among these proteins, five related to bone growth and development, including pyruvate kinase M2, annexin A2, heat shock 27 kDa protein, gamma-actin, and beta-actin, were found to be dysregulated and therefore selected for further validation by Western blot analysis. At the protein level, our results supported the previous hypothesis that decreased osteogenic differentiation ability of MSCs is one of the mechanisms leading to osteopenia in AIS. In summary, we analyzed the differential BM-MSCs proteome of AIS patients for the first time, which may help to elucidate the underlying molecular mechanisms of bone loss in AIS and also increase understanding of the etiology and pathogenesis of AIS. PMID- 21526126 TI - A model for the evolution of nucleotide polymerase directionality. AB - BACKGROUND: In all known living organisms, every enzyme that synthesizes nucleic acid polymers does so by adding nucleotide 5'-triphosphates to the 3'-hydroxyl group of the growing chain. This results in the well known 5'->3' directionality of all DNA and RNA Polymerases. The lack of any alternative mechanism, e.g. addition in a 3'->5' direction, may indicate a very early founder effect in the evolution of life, or it may be the result of a selective pressure against such an alternative. METHODOLOGY/PRINCIPAL FINDINGS: In an attempt to determine whether the lack of an alternative polymerase directionality is the result of a founder effect or evolutionary selection, we have constructed a basic model of early polymerase evolution. This model is informed by the essential chemical properties of the nucleotide polymerization reaction. With this model, we are able to simulate the growth of organisms with polymerases that synthesize either 5'->3' or 3'->5' in isolation or in competition with each other. CONCLUSIONS/SIGNIFICANCE: We have found that a competition between organisms with 5'->3' polymerases and 3'->5' polymerases only results in a evolutionarily stable strategy under certain conditions. Furthermore, we have found that mutations lead to a much clearer delineation between conditions that lead to a stable coexistence of these populations and conditions which ultimately lead to success for the 5'->3' form. In addition to presenting a plausible explanation for the uniqueness of enzymatic polymerization reactions, we hope these results also provide an example of how whole organism evolution can be understood based on molecular details. PMID- 21526125 TI - Deficits in inhibitory control in smokers during a Go/NoGo task: an investigation using event-related brain potentials. AB - INTRODUCTION: The role of inhibitory control in addictive behaviors is highlighted in several models of addictive behaviors. Although reduced inhibitory control has been observed in addictive behaviors, it is inconclusive whether this is evident in smokers. Furthermore, it has been proposed that drug abuse individuals with poor response inhibition may experience greater difficulties not consuming substances in the presence of drug cues. The major aim of the current study was to provide electrophysiological evidence for reduced inhibitory control in smokers and to investigate whether this is more pronounced during smoking cue exposure. METHODS: Participants (19 smokers and 20 non-smoking controls) performed a smoking Go/NoGo task. Behavioral accuracy and amplitudes of the N2 and P3 event-related potential (ERP), both reflecting aspects of response inhibition, were the main variables of interest. RESULTS: Reduced NoGo N2 amplitudes in smokers relative to controls were accompanied by decreased task performance, whereas no differences between groups were found in P3 amplitudes. This was found to represent a general lack of inhibition in smokers, and not dependent on the presence of smoking cues. CONCLUSIONS: The current results suggest that smokers have difficulties with response inhibition, which is an important finding that eventually can be implemented in smoking cessation programs. More research is needed to clarify the exact role of cue exposure on response inhibition. PMID- 21526127 TI - Smooth muscle miRNAs are critical for post-natal regulation of blood pressure and vascular function. AB - Phenotypic modulation of smooth muscle cells (SMCs) plays a key role in vascular disease, including atherosclerosis. Several transcription factors have been suggested to regulate phenotypic modulation of SMCs but the decisive mechanisms remain unknown. Recent reports suggest that specific microRNAs (miRNAs) are involved in SMC differentiation and vascular disease but the global role of miRNAs in postnatal vascular SMC has not been elucidated. Thus, the objective of this study was to identify the role of Dicer-dependent miRNAs for blood pressure regulation and vascular SMC contractile function and differentiation in vivo. Tamoxifen-inducible and SMC specific deletion of Dicer was achieved by Cre-Lox recombination. Deletion of Dicer resulted in a global loss of miRNAs in aortic SMC. Furthermore, Dicer-deficient mice exhibited a dramatic reduction in blood pressure due to significant loss of vascular contractile function and SMC contractile differentiation as well as vascular remodeling. Several of these results are consistent with our previous observations in SM-Dicer deficient embryos. Therefore, miRNAs are essential for maintaining blood pressure and contractile function in resistance vessels. Although the phenotype of miR-143/145 deficient mice resembles the loss of Dicer, the phenotypes of SM-Dicer KO mice were far more severe suggesting that additional miRNAs are involved in maintaining postnatal SMC differentiation. PMID- 21526128 TI - vProtein: identifying optimal amino acid complements from plant-based foods. AB - BACKGROUND: Indispensible amino acids (IAAs) are used by the body in different proportions. Most animal-based foods provide these IAAs in roughly the needed proportions, but many plant-based foods provide different proportions of IAAs. To explore how these plant-based foods can be better used in human nutrition, we have created the computational tool vProtein to identify optimal food complements to satisfy human protein needs. METHODS: vProtein uses 1251 plant-based foods listed in the United States Department of Agriculture standard release 22 database to determine the quantity of each food or pair of foods required to satisfy human IAA needs as determined by the 2005 daily recommended intake. The quantity of food in a pair is found using a linear programming approach that minimizes total calories, total excess IAAs, or the total weight of the combination. RESULTS: For single foods, vProtein identifies foods with particularly balanced IAA patterns such as wheat germ, quinoa, and cauliflower. vProtein also identifies foods with particularly unbalanced IAA patterns such as macadamia nuts, degermed corn products, and wakame seaweed. Although less useful alone, some unbalanced foods provide unusually good complements, such as Brazil nuts to legumes. Interestingly, vProtein finds no statistically significant bias toward grain/legume pairings for protein complementation. These analyses suggest that pairings of plant-based foods should be based on the individual foods themselves instead of based on broader food group-food group pairings. Overall, the most efficient pairings include sweet corn/tomatoes, apple/coconut, and sweet corn/cherry. The top pairings also highlight the utility of less common protein sources such as the seaweeds laver and spirulina, pumpkin leaves, and lambsquarters. From a public health perspective, many of the food pairings represent novel, low cost food sources to combat malnutrition. Full analysis results are available online at http://www.foodwiki.com/vprotein. PMID- 21526129 TI - Factors defining the functional oligomeric state of Escherichia coli DegP protease. AB - Escherichia coli DegP protein is a periplasmic protein that functions both as a protease and as a chaperone. In the absence of substrate, DegP oligomerizes as a hexameric cage but in its presence DegP reorganizes into 12 and 24-mer cages with large chambers that house the substrate for degradation or refolding. Here, we studied the factors that determine the oligomeric state adopted by DegP in the presence of substrate. Using size exclusion chromatography and electron microscopy, we found that the size of the substrate molecule is the main factor conditioning the oligomeric state adopted by the enzyme. Other factors such as temperature, a major regulatory factor of the activity of this enzyme, did not influence the oligomeric state adopted by DegP. In addition, we observed that substrate concentration exerted an effect only when large substrates (full-length proteins) were used. However, small substrate molecules (peptides) always triggered the same oligomeric state regardless of their concentration. These results clarify important aspects of the regulation of the oligomeric state of DegP. PMID- 21526131 TI - Aerosolized Florida Red Tide Toxins and Human Health Effects. PMID- 21526130 TI - The genetic effect of copy number variations on the risk of type 2 diabetes in a Korean population. AB - BACKGROUND: Unlike Caucasian populations, genetic factors contributing to the risk of type 2 diabetes mellitus (T2DM) are not well studied in Asian populations. In light of this, and the fact that copy number variation (CNV) is emerging as a new way to understand human genomic variation, the objective of this study was to identify type 2 diabetes-associated CNV in a Korean cohort. METHODOLOGY/PRINCIPAL FINDINGS: Using the Illumina HumanHap300 BeadChip (317,503 markers), genome-wide genotyping was performed to obtain signal and allelic intensities from 275 patients with type 2 diabetes mellitus (T2DM) and 496 nondiabetic subjects (Total n = 771). To increase the sensitivity of CNV identification, we incorporated multiple factors using PennCNV, a program that is based on the hidden Markov model (HMM). To assess the genetic effect of CNV on T2DM, a multivariate logistic regression model controlling for age and gender was used. We identified a total of 7,478 CNVs (average of 9.7 CNVs per individual) and 2,554 CNV regions (CNVRs; 164 common CNVRs for frequency>1%) in this study. Although we failed to demonstrate robust associations between CNVs and the risk of T2DM, our results revealed a putative association between several CNVRs including chr15:45994758-45999227 (P = 8.6E-04, P(corr) = 0.01) and the risk of T2DM. The identified CNVs in this study were validated using overlapping analysis with the Database of Genomic Variants (DGV; 71.7% overlap), and quantitative PCR (qPCR). The identified variations, which encompassed functional genes, were significantly enriched in the cellular part, in the membrane-bound organelle, in the development process, in cell communication, in signal transduction, and in biological regulation. CONCLUSION/SIGNIFICANCE: We expect that the methods and findings in this study will contribute in particular to genome studies of Asian populations. PMID- 21526132 TI - Brain activation for reading and listening comprehension: An fMRI study of modality effects and individual differences in language comprehension. AB - The study compared the brain activation patterns associated with the comprehension of written and spoken Portuguese sentences. An fMRI study measured brain activity while participants read and listened to sentences about general world knowledge. Participants had to decide if the sentences were true or false. To mirror the transient nature of spoken sentences, visual input was presented in rapid serial visual presentation format. The results showed a common core of amodal left inferior frontal and middle temporal gyri activation, as well as modality specific brain activation associated with listening and reading comprehension. Reading comprehension was associated with more left-lateralized activation and with left inferior occipital cortex (including fusiform gyrus) activation. Listening comprehension was associated with extensive bilateral temporal cortex activation and more overall activation of the whole cortex. Results also showed individual differences in brain activation for reading comprehension. Readers with lower working memory capacity showed more activation of right-hemisphere areas (spillover of activation) and more activation in the prefrontal cortex, potentially associated with more demand placed on executive control processes. Readers with higher working memory capacity showed more activation in a frontal-posterior network of areas (left angular and precentral gyri, and right inferior frontal gyrus). The activation of this network may be associated with phonological rehearsal of linguistic information when reading text presented in rapid serial visual format. The study demonstrates the modality fingerprints for language comprehension and indicates how low- and high working memory capacity readers deal with reading text presented in serial format. PMID- 21526133 TI - Acute respiratory distress due to thymoma in a patient treated with TK inhibitor: a case report and review of the current treatment options. AB - Thymic malignancies are rare intrathoracic tumors that may be aggressive and difficult to treat in advanced stage. Surgery is the cornerstone of the management of thymomas: it is significant for the definite histopathological diagnosis and staging, and in most cases, it constitutes the first step of the treatment strategy. For patients with primary unresectable thymomas, the multimodal treatment schedule nowadays includes neoadjuvant chemotherapy, extensive surgery, adjuvant radiotherapy, and in some cases, adjuvant chemotherapy. A patient with a history of stage III COPD and an undiagnosed thoracic mass was admitted to the intensive care unit with acute respiratory distress. A radiologic evaluation by CT scan revealed a mass of 13 cm in diameter at the mediastinum. Fine needle aspiration was performed and revealed a thymoma. Due to poor performance status, the patient was not able to undergo surgery. He refused to be treated with neither chemotherapy nor radiotherapy, but due to EGFR overexpression, treatment with TK inhibitor was suggested. Fine needle aspiration biopsy is commonly used to identify metastasis to the mediastinum. However, it is less often employed as a primary diagnostic tool for tumors, particularly thymic neoplasms. The use of targeted therapies for the treatment of thymic malignancies has been described in the literature. Over the past years, significant efforts have been made to dissect the molecular pathways involved in the carcinogenesis of these tumors. Insights have been obtained following anecdotal clinical responses to targeted therapies, and large-scale genomic analyses have been conducted. PMID- 21526134 TI - Recurrent respiratory papillomatosis: a rare chronic disease, difficult to treat, with potential to lung cancer transformation: apropos of two cases and a brief literature review. AB - Recurrent respiratory papillomatosis (RRP), which is caused exclusively by human papilloma virus (HPV), is a rare condition characterized by recurrent growth of benign papillomata in the respiratory tract. The papillomata can occur anywhere in the aerodigestive tract but most frequently in the larynx, affecting both children and adults. The management of this entity remains still challenging since no specific definitive treatment exists. Nevertheless, novel surgical interventions as well as several adjuvant therapies have shown promising results in the long-term palliative management of this debilitating disease. Despite its mostly benign nature, RRP may cause significant morbidity and mortality because of its unpredictable clinical course and especially its tendency, albeit infrequent, for malignant transformation. In this article, we present two patients with RRP; one underwent bronchoscopic laser ablation in combination with inhaled interferon-alpha administration that led to a long-term regression of the disease while the other patient was diagnosed with transformation to squamous cell lung carcinoma with fatal outcome. We include a review of the current literature with special emphasis on RRP management and the potential role of HPV in the development of lung cancer. PMID- 21526135 TI - Elevated Serum CA-125 in a Patient with Follicular Lymphoma and a History of Ovarian Cancer. AB - A patient with a previous history of epithelial ovarian cancer presented to her physician with diffuse adenopathy. On subsequent evaluation, she was found to have a follicular lymphoma. Work-up revealed an elevated serum CA-125 antigen level, raising the question of whether the laboratory abnormality represented evidence of recurrence of the original epithelial cancer. The subsequent major decline in this tumor marker following treatment directed to the lymphoma provided strong support for the conclusion that the elevated CA-125 was secondary to this malignant process and not ovarian cancer. PMID- 21526136 TI - Leser-Trelat Sign without Internal Malignancy. AB - Leser-Trelat sign is characterized by the abrupt appearance of multiple seborrheic keratoses in association with underlying malignant disease. A case of Leser-Trelat sign in a 66-year-old healthy woman is presented. Evaluation and follow-up for the development of malignancy over a 2-year period failed to reveal any evidence of malignancy. To date, almost all cases of Leser-Trelat sign have been reported in association with an underlying malignancy. It is less known that Leser-Trelat sign can also occur in healthy individuals in the absence of internal malignancy. PMID- 21526137 TI - Well-differentiated liposarcoma, an atypical lipomatous tumor, of the mesentery: a case report and review of the literature. AB - Mesenteric liposarcoma is a rare neoplasm. Here, we report the case of a 73-year old Japanese man with a well-differentiated (WD) liposarcoma of the mesentery. Due to rapid growth of the abdominal mass and abdominal insufficiency, a tumorectomy was performed. The excised tumor was 12.4 * 9.6 cm in size and weighed 548 g. Cut sections showed a lobulated yellow and/or grayish-colored appearance. The histological features were predominantly those of the sclerotic and lipoma-like variants of WD liposarcoma. The cytoplasm of most spindle cells was diffusely immunoreactive for CD34, while fat cells were positive for S-100 protein. Some spindle cell nuclei were positive for CDK4, and a few were positive for MDM2. The average Ki-67 proliferation index in tumor cells was 10%, and androgen receptor expression was detected in tumor cell nuclei. The present case and 11 cases identified from a literature search were reviewed. The WD mesenteric liposarcomas developed in patients in the fourth to seventh decades of life (mean age 57.9 years). The patients consisted of 7 men and 5 women. All tumors were larger than 10 cm in diameter at the time of surgery. Complete resection might be the only curative therapy for WD liposarcomas of the mesentery, but long-term follow-up is needed because of the possibility of a local recurrence of the tumor. PMID- 21526138 TI - SPEECH PERCEPTION AS A TALKER-CONTINGENT PROCESS. AB - To determine how familiarity with a talker's voice affects perception of spoken words, we trained two groups of subjects to recognize a set of voices over a 9 day period. One group then identified novel words produced by the same set of talkers at four signal-to-noise ratios. Control subjects identified the same words produced by a different set of talkers. The results showed that the ability to identify a talker's voice improved intelligibility of novel words produced by that talker. The results suggest that speech perception may involve talker contingent processes whereby perceptual learning of aspects of the vocal source facilitates the subsequent phonetic analysis of the acoustic signal. PMID- 21526139 TI - Four aspects of self-image close to death at home. AB - Living close to death means an inevitable confrontation with one's own existential limitation. In this article, we argue that everyday life close to death embodies an identity work in progress. We used a narrative approach and a holistic-content reading to analyze 12 interviews conducted with three persons close to death. By illuminating the unique stories and identifying patterns among the participants' narratives, we found four themes exemplifying important aspects of the identity work related to everyday life close to death. Two of the themes, named "Inside and outside of me" and "Searching for togetherness," represented the core of the self-image and were framed by the other themes, "My place in space" and "My death and my time." Our findings elucidate the way the individual stories moved between the past, the present, and the future. This study challenges the idea that everyday life close to impending death primarily means limitations. The findings show that the search for meaning, new knowledge, and community can form a part of a conscious and ongoing identity work close to death. PMID- 21526140 TI - Elastography for hepatic fibrosis severity in chronic hepatitis B or C. AB - AIMS: To assess the value of transient elastography for predicting significant fibrosis or cirrhosis in chronic hepatitis B or C (CHB or CHC) patients. METHODS: 75 patients (CHB: 45, CHC: 32) were included. All underwent elastography and liver biopsy concurrently. Biopsies were evaluated using Ishak's classification. Fibrosis was mild, moderate or severe/cirrhosis when scores were 0-1 (n = 30), 2 3 (n = 20), 4-6 (n = 25), respectively. RESULTS: Median liver stiffness values were higher in patients with severe fibrosis or cirrhosis than in those with moderate or mild fibrosis (14.8 vs. 6.4 vs. 5.3 kPa, p < 0.001). The diagnostic accuracy of elastography for severe fibrosis and cirrhosis was excellent [area under the receiver operating characteristic (AUROC) curve 0.938 vs. 0.948], but it was not optimal for mild fibrosis (AUROC 0.78). Values of 7.5, 9.0 and 12 kPa had a sensitivity and specificity for severe fibrosis/cirrhosis of 96, 84 and 60%, and 76, 90 and 94%, respectively. The median stiffness value in cirrhotic patients (score 5-6) was 16.6 kPa (7.7-48). No differences in accuracy of elastography between CHB or CHC patients were found. Cutoff was 12.5 kPa for cirrhosis; 10/75 patients (13%) were misclassified. CONCLUSION: Transient elastography has an excellent diagnostic accuracy for severe fibrosis and cirrhosis in CHB and CHC, but the cutoffs need further evaluation. PMID- 21526141 TI - Usefulness of Real-Time 4D Ultrasonography during Radiofrequency Ablation in a Case of Hepatocellular Carcinoma. AB - We report a case of hepatocellular carcinoma (HCC) with chronic hepatitis C virus infection successfully treated with percutaneous radiofrequency ablation (RFA) under live four-dimensional (4D) echo guidance. A 65-year-old Japanese man had a HCC nodule in the liver S5 region 2.0 cm in diameter. We performed real-time 4D ultrasonography during RFA therapy with a LeVeen needle electrode. The echo guidance facilitated an accurate approach for the needle puncture. The guidance was also useful for confirming whether an adequate safety margin for the nodule had been obtained. Thus real-time 4D ultrasonography echo technique appears to provide safe guidance of RFA needles via accurate targeting of HCC nodules, thereby allowing real-time visualization when combined with echo contrast. Furthermore the position of the needle in a still image was confirmed in every area using a multiview procedure. PMID- 21526142 TI - A therapeutic chemical chaperone inhibits cholera intoxication and unfolding/translocation of the cholera toxin A1 subunit. AB - Cholera toxin (CT) travels as an intact AB(5) protein toxin from the cell surface to the endoplasmic reticulum (ER) of an intoxicated cell. In the ER, the catalytic A1 subunit dissociates from the rest of the toxin. Translocation of CTA1 from the ER to the cytosol is then facilitated by the quality control mechanism of ER-associated degradation (ERAD). Thermal instability in the isolated CTA1 subunit generates an unfolded toxin conformation that acts as the trigger for ERAD-mediated translocation to the cytosol. In this work, we show by circular dichroism and fluorescence spectroscopy that exposure to 4-phenylbutyric acid (PBA) inhibited the thermal unfolding of CTA1. This, in turn, blocked the ER to-cytosol export of CTA1 and productive intoxication of either cultured cells or rat ileal loops. In cell culture studies PBA did not affect CT trafficking to the ER, CTA1 dissociation from the holotoxin, or functioning of the ERAD system. PBA is currently used as a therapeutic agent to treat urea cycle disorders. Our data suggest PBA could also be used in a new application to prevent or possibly treat cholera. PMID- 21526143 TI - Gold mining in the Peruvian Amazon: global prices, deforestation, and mercury imports. AB - Many factors such as poverty, ineffective institutions and environmental regulations may prevent developing countries from managing how natural resources are extracted to meet a strong market demand. Extraction for some resources has reached such proportions that evidence is measurable from space. We present recent evidence of the global demand for a single commodity and the ecosystem destruction resulting from commodity extraction, recorded by satellites for one of the most biodiverse areas of the world. We find that since 2003, recent mining deforestation in Madre de Dios, Peru is increasing nonlinearly alongside a constant annual rate of increase in international gold price (~18%/yr). We detect that the new pattern of mining deforestation (1915 ha/year, 2006-2009) is outpacing that of nearby settlement deforestation. We show that gold price is linked with exponential increases in Peruvian national mercury imports over time (R(2) = 0.93, p = 0.04, 2003-2009). Given the past rates of increase we predict that mercury imports may more than double for 2011 (~500 t/year). Virtually all of Peru's mercury imports are used in artisanal gold mining. Much of the mining increase is unregulated/artisanal in nature, lacking environmental impact analysis or miner education. As a result, large quantities of mercury are being released into the atmosphere, sediments and waterways. Other developing countries endowed with gold deposits are likely experiencing similar environmental destruction in response to recent record high gold prices. The increasing availability of satellite imagery ought to evoke further studies linking economic variables with land use and cover changes on the ground. PMID- 21526144 TI - Late Byzantine mineral soda high alumina glasses from Asia Minor: a new primary glass production group. AB - The chemical characterisation of archaeological glass allows the discrimination between different glass groups and the identification of raw materials and technological traditions of their production. Several lines of evidence point towards the large-scale production of first millennium CE glass in a limited number of glass making factories from a mixture of Egyptian mineral soda and a locally available silica source. Fundamental changes in the manufacturing processes occurred from the eight/ninth century CE onwards, when Egyptian mineral soda was gradually replaced by soda-rich plant ash in Egypt as well as the Islamic Middle East. In order to elucidate the supply and consumption of glass during this transitional period, 31 glass samples from the assemblage found at Pergamon (Turkey) that date to the fourth to fourteenth centuries CE were analysed by electron microprobe analysis (EPMA) and by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). The statistical evaluation of the data revealed that the Byzantine glasses from Pergamon represent at least three different glass production technologies, one of which had not previously been recognised in the glass making traditions of the Mediterranean. While the chemical characteristics of the late antique and early medieval fragments confirm the current model of glass production and distribution at the time, the elemental make-up of the majority of the eighth- to fourteenth-century glasses from Pergamon indicate the existence of a late Byzantine glass type that is characterised by high alumina levels. Judging from the trace element patterns and elevated boron and lithium concentrations, these glasses were produced with a mineral soda different to the Egyptian natron from the Wadi Natrun, suggesting a possible regional Byzantine primary glass production in Asia Minor. PMID- 21526145 TI - The telomere binding protein TRF2 induces chromatin compaction. AB - Mammalian telomeres are specialized chromatin structures that require the telomere binding protein, TRF2, for maintaining chromosome stability. In addition to its ability to modulate DNA repair activities, TRF2 also has direct effects on DNA structure and topology. Given that mammalian telomeric chromatin includes nucleosomes, we investigated the effect of this protein on chromatin structure. TRF2 bound to reconstituted telomeric nucleosomal fibers through both its basic N terminus and its C-terminal DNA binding domain. Analytical agarose gel electrophoresis (AAGE) studies showed that TRF2 promoted the folding of nucleosomal arrays into more compact structures by neutralizing negative surface charge. A construct containing the N-terminal and TRFH domains together altered the charge and radius of nucleosomal arrays similarly to full-length TRF2 suggesting that TRF2-driven changes in global chromatin structure were largely due to these regions. However, the most compact chromatin structures were induced by the isolated basic N-terminal region, as judged by both AAGE and atomic force microscopy. Although the N-terminal region condensed nucleosomal array fibers, the TRFH domain, known to alter DNA topology, was required for stimulation of a strand invasion-like reaction with nucleosomal arrays. Optimal strand invasion also required the C-terminal DNA binding domain. Furthermore, the reaction was not stimulated on linear histone-free DNA. Our data suggest that nucleosomal chromatin has the ability to facilitate this activity of TRF2 which is thought to be involved in stabilizing looped telomere structures. PMID- 21526146 TI - O-GlcNAc-specific antibody CTD110.6 cross-reacts with N-GlcNAc2-modified proteins induced under glucose deprivation. AB - Modification of serine and threonine residues in proteins by O-linked beta-N acetylglucosamine (O-GlcNAc) glycosylation is a feature of many cellular responses to the nutritional state and to stress. O-GlcNAc modification is reversibly regulated by O-linked beta-N-acetylglucosamine transferase (OGT) and beta-D-N-acetylglucosaminase (O-GlcNAcase). O-GlcNAc modification of proteins is dependent on the concentration of uridine 5'-diphospho-N-acetylglucosamine (UDP GlcNAc), which is a substrate of OGT and is synthesized via the hexosamine biosynthetic pathway. Immunoblot analysis using the O-GlcNAc-specific antibody CTD110.6 has indicated that glucose deprivation increases protein O-GlcNAcylation in some cancer cells. The mechanism of this paradoxical phenomenon has remained unclear. Here we show that the increased glycosylation induced by glucose deprivation and detected by CTD110.6 antibodies is actually modification by N GlcNAc(2), rather than by O-GlcNAc. We found that this induced glycosylation was not regulated by OGT and O-GlcNAcase, unlike typical O-GlcNAcylation, and it was inhibited by treatment with tunicamycin, an N-glycosylation inhibitor. Proteomics analysis showed that proteins modified by this induced glycosylation were N GlcNAc(2)-modified glycoproteins. Furthermore, CTD110.6 antibodies reacted with N GlcNAc(2)-modified glycoproteins produced by a yeast strain with a ts-mutant of ALG1 that could not add a mannose residue to dolichol-PP-GlcNAc(2). Our results demonstrated that N-GlcNAc(2)-modified glycoproteins were induced under glucose deprivation and that they cross-reacted with the O-GlcNAc-specific antibody CTD110.6. We therefore propose that the glycosylation status of proteins previously classified as O-GlcNAc-modified proteins according to their reactivity with CTD110.6 antibodies must be re-examined. We also suggest that the repression of mature N-linked glycoproteins due to increased levels of N-GlcNAc(2)-modified proteins is a newly recognized pathway for effective use of sugar under stress and deprivation conditions. Further research is needed to clarify the physiological and pathological roles of N-GlcNAc(2)-modified proteins. PMID- 21526147 TI - Deep-sea nematodes actively colonise sediments, irrespective of the presence of a pulse of organic matter: results from an in-situ experiment. AB - A colonisation experiment was performed in situ at 2500 m water depth at the Arctic deep-sea long-term observatory HAUSGARTEN to determine the response of deep-sea nematodes to disturbed, newly available patches, enriched with organic matter. Cylindrical tubes,laterally covered with a 500 um mesh, were filled with azoic deep-sea sediment and (13)C-labelled food sources (diatoms and bacteria). After 10 days of incubation the tubes were analysed for nematode response in terms of colonisation and uptake. Nematodes actively colonised the tubes, however with densities that only accounted for a maximum of 2.13% (51 ind.10 cm(-2)) of the ambient nematode assemblages. Densities did not differ according to the presence or absence of organic matter, nor according to the type of organic matter added. The fact that the organic matter did not function as an attractant to nematodes was confirmed by the absence of notable (13)C assimilation by the colonising nematodes. Overall, colonisation appears to be a process that yields reproducible abundance and diversity patterns, with certain taxa showing more efficiency. Together with the high variability between the colonising nematode assemblages, this lends experimental support to the existence of a spatio temporal mosaic that emerges from highly localised, partially stochastic community dynamics. PMID- 21526148 TI - A cyclic undecamer peptide mimics a turn in folded Alzheimer amyloid beta and elicits antibodies against oligomeric and fibrillar amyloid and plaques. AB - The 39- to 42-residue amyloid beta (Abeta) peptide is deposited in extracellular fibrillar plaques in the brain of patients suffering from Alzheimer's Disease (AD). Vaccination with these peptides seems to be a promising approach to reduce the plaque load but results in a dominant antibody response directed against the N-terminus. Antibodies against the N-terminus will capture Abeta immediately after normal physiological processing of the amyloid precursor protein and therefore will also reduce the levels of non-misfolded Abeta, which might have a physiologically relevant function. Therefore, we have targeted an immune response on a conformational neo-epitope in misfolded amyloid that is formed in advance of Abeta-aggregation. A tetanus toxoid-conjugate of the 11-meric cyclic peptide Abeta(22-28)-YNGK' elicited specific antibodies in Balb/c mice. These antibodies bound strongly to the homologous cyclic peptide-bovine serum albumin conjugate, but not to the homologous linear peptide-conjugate, as detected in vitro by enzyme-linked immunosorbent assay. The antibodies also bound--although more weakly--to Abeta(1-42) oligomers as well as fibrils in this assay. Finally, the antibodies recognized Abeta deposits in AD mouse and human brain tissue as established by immunohistological staining. We propose that the cyclic peptide conjugate might provide a lead towards a vaccine that could be administered before the onset of AD symptoms. Further investigation of this hypothesis requires immunization of transgenic AD model mice. PMID- 21526149 TI - Breaking up the C complex spliceosome shows stable association of proteins with the lariat intron intermediate. AB - Spliceosome assembly requires several structural rearrangements to position the components of the catalytic core. Many of these rearrangements involve successive strengthening and weakening of different RNA:RNA and RNA:proteins interactions within the complex. To gain insight into the organization of the catalytic core of the spliceosome arrested between the two steps of splicing chemistry (C complex), we investigated the effects of exposing C complex to low concentrations of urea. We find that in the presence of 3M urea C complex separates into at least three sub-complexes. One sub-complex contains the 5'exon, another contains the intron-lariat intermediate, and U2/U5/U6 snRNAs likely comprise a third sub complex. We purified the intron-lariat intermediate sub-complex and identified several proteins, including U2 snRNP and PRP19 complex (NTC) components. The data from our study indicate that U2 snRNP proteins in C complex are more stably associated with the lariat-intron intermediate than the U2 snRNA. The results also suggest a set of candidate proteins that hold the lariat-intron intermediate together in C complex. This information is critical for further interpreting the complex architecture of the mammalian spliceosome. PMID- 21526150 TI - Deciphering the role of RND efflux transporters in Burkholderia cenocepacia. AB - Burkholderia cenocepacia J2315 is representative of a highly problematic group of cystic fibrosis (CF) pathogens. Eradication of B. cenocepacia is very difficult with the antimicrobial therapy being ineffective due to its high resistance to clinically relevant antimicrobial agents and disinfectants. RND (Resistance Nodulation-Cell Division) efflux pumps are known to be among the mediators of multidrug resistance in gram-negative bacteria. Since the significance of the 16 RND efflux systems present in B. cenocepacia (named RND-1 to -16) has been only partially determined, the aim of this work was to analyze mutants of B. cenocepacia strain J2315 impaired in RND-4 and RND-9 efflux systems, and assess their role in the efflux of toxic compounds. The transcriptomes of mutants deleted individually in RND-4 and RND-9 (named D4 and D9), and a double-mutant in both efflux pumps (named D4-D9), were compared to that of the wild-type B. cenocepacia using microarray analysis. Microarray data were confirmed by qRT-PCR, phenotypic experiments, and by Phenotype MicroArray analysis. The data revealed that RND-4 made a significant contribution to the antibiotic resistance of B. cenocepacia, whereas RND-9 was only marginally involved in this process. Moreover, the double mutant D4-D9 showed a phenotype and an expression profile similar to D4. The microarray data showed that motility and chemotaxis-related genes appeared to be up-regulated in both D4 and D4-D9 strains. In contrast, these gene sets were down-regulated or expressed at levels similar to J2315 in the D9 mutant. Biofilm production was enhanced in all mutants. Overall, these results indicate that in B. cenocepacia RND pumps play a wider role than just in drug resistance, influencing additional phenotypic traits important for pathogenesis. PMID- 21526152 TI - Electrostatic-assembly-driven formation of supramolecular rhombus microparticles and their application for fluorescent nucleic acid detection. AB - In this paper, we report on the large-scale formation of supramolecular rhombus microparticles (SRMs) driven by electrostatic assembly, carried out by direct mixing of an aqueous HAuCl(4) solution and an ethanol solution of 4,4'-bipyridine at room temperature. We further demonstrate their use as an effective fluorescent sensing platform for nucleic acid detection with a high selectivity down to single-base mismatch. The general concept used in this approach is based on adsorption of the fluorescently labeled single-stranded DNA (ssDNA) probe by SRM, which is accompanied by substantial fluorescence quenching. In the following assay, specific hybridization with its target to form double-stranded DNA (dsDNA) results in desorption of ssDNA from SRM surface and subsequent fluorescence recovery. PMID- 21526151 TI - Cdc48 and cofactors Npl4-Ufd1 are important for G1 progression during heat stress by maintaining cell wall integrity in Saccharomyces cerevisiae. AB - The ubiquitin-selective chaperone Cdc48, a member of the AAA (ATPase Associated with various cellular Activities) ATPase superfamily, is involved in many processes, including endoplasmic reticulum-associated degradation (ERAD), ubiquitin- and proteasome-mediated protein degradation, and mitosis. Although Cdc48 was originally isolated as a cell cycle mutant in the budding yeast Saccharomyces cerevisiae, its cell cycle functions have not been well appreciated. We found that temperature-sensitive cdc48-3 mutant is largely arrested at mitosis at 37 degrees C, whereas the mutant is also delayed in G1 progression at 38.5 degrees C. Reporter assays show that the promoter activity of G1 cyclin CLN1, but not CLN2, is reduced in cdc48-3 at 38.5 degrees C. The cofactor npl4-1 and ufd1-2 mutants also exhibit G1 delay and reduced CLN1 promoter activity at 38.5 degrees C, suggesting that Npl4-Ufd1 complex mediates the function of Cdc48 at G1. The G1 delay of cdc48-3 at 38.5 degrees C is a consequence of cell wall defect that over-activates Mpk1, a MAPK family member important for cell wall integrity in response to stress conditions including heat shock. cdc48-3 is hypersensitive to cell wall perturbing agents and is synthetic sick with mutations in the cell wall integrity signaling pathway. Our results suggest that the cell wall defect in cdc48-3 is exacerbated by heat shock, which sustains Mpk1 activity to block G1 progression. Thus, Cdc48-Npl4-Ufd1 is important for the maintenance of cell wall integrity in order for normal cell growth and division. PMID- 21526153 TI - Tradeoff between biomass and flavonoid accumulation in white clover reflects contrasting plant strategies. AB - An outdoor study was conducted to examine relationships between plant productivity and stress-protective phenolic plant metabolites. Twenty-two populations of the pasture legume white clover were grown for 41/2 months during spring and summer in Palmerston North, New Zealand. The major phenolic compounds identified and quantified by HPLC analysis were glycosides of the flavonoids quercetin and kaempferol. Multivariate analysis revealed a trade-off between flavonoid accumulation and plant productivity attributes. White clover populations with high biomass production, large leaves and thick tap roots showed low levels of quercetin glycoside accumulation and low quercetin:kaempferol ratios, while the opposite was true for less productive populations. The latter included stress-resistant ecotypes from Turkey and China, and the analysis also identified highly significant positive relationships of quercetin glycoside accumulation with plant morphology (root:shoot ratio). Importantly, a high degree of genetic variation was detected for most of the measured traits. These findings suggest merit for considering flavonoids such as quercetin as potential selection criteria in the genetic improvement of white clover and other crops. PMID- 21526154 TI - Elevated expression of squamous cell carcinoma antigen (SCCA) is associated with human breast carcinoma. AB - Squamous cell carcinoma antigen (SCCA) belongs to the serine protease inhibitor (Serpin) family of proteins. Elevated expression of SCCA has been used as a biomarker for aggressive squamous cell carcinoma (SCC) in cancers of the cervix, lung, head and neck, and liver. However, SCCA expression in breast cancer has not been investigated. Immunohistochemical analysis of SCCA expression was performed on tissue microarrays containing breast tumor tissues (n = 1,360) and normal breast epithelium (n = 124). SCCA expression was scored on a tiered scale (0-3) independently by two evaluators blind to the patient's clinical status. SCCA expression was observed in Grade I (0.3%), Grade II (2.5%), and Grade III (9.4%) breast cancers (p<0.0001). Comparing tissues categorized into the three non metastatic TNM stages, I-III, SCCA positivity was seen in 2.4% of Stage I cancers, 3.1% of Stage II cancers, and 8.6% of Stage III breast cancers (p = 0.0005). No positive staining was observed in normal/non-neoplastic breast tissue (0 out of 124). SCCA expression also correlated to estrogen receptor/progesterone receptor (ER/PR) double-negative tumors (p = 0.0009). Compared to SCCA-negative patients, SCCA-positive patients had both a worse overall survival and recurrence free survival (p<0.0001 and p<0.0001, respectively). This study shows that SCCA is associated with both advanced stage and high grade human breast carcinoma, and suggests the necessity to further explore the role of SCCA in breast cancer development and treatment. PMID- 21526155 TI - Associated factors for falls among the community-dwelling older people assessed by annual geriatric health examinations. AB - BACKGROUND: Falls are very common among the older people. Nearly one-third older people living in a community fall each year. However, few studies have examined factors associated with falls in a community-dwelling population of older Taiwanese adults. OBJECTIVES: To identify the associated factors for falls during the previous 12 months among the community-dwelling Taiwanese older people receiving annual geriatric health examinations. PARTICIPANTS: People aged sixty five years or older, living in the community, assessed by annual geriatric health examinations METHODS: 1377 community-dwellers aged >=65 years who received annual geriatric health examinations at one hospital in northern Taiwan between March and November of 2008. They were asked about their history of falls during the year prior to their most recent health examination. RESULTS: The average age of the 1377 participants was 74.9+/-6.8 years, 48.9% of which were women. Three hundred and thirteen of the participants (22.7%) had at least one fall during the previous year. Multivariate analysis showed that odds ratio for the risk of falling was 1.94 (95% CI 1.36-2.76) when the female gender group is compared with the male gender group. The adjusted odds ratios of age and waist circumference were 1.03 (95% CI 1.00-1.06) and 1.03 (95% CI 1.01-1.05) respectively. The adjusted odds ratios of visual acuity, Karnofsky scale, and serum albumin level were 0.34 (95% CI 0.15-0.76), 0.94 (95% CI 0.89-0.98), and 0.37 (95% CI 0.18 0.76) respectively. Larger waist circumference, older age, female gender, poorer visual acuity, lower score on the Karnofsky Performance Scale, and lower serum albumin level were the independent associated factors for falls. CONCLUSION: In addition to other associated factors, waist circumference should be included as a novel risk factor for falls. PMID- 21526156 TI - Eco-evolutionary trophic dynamics: loss of top predators drives trophic evolution and ecology of prey. AB - Ecosystems are being altered on a global scale by the extirpation of top predators. The ecological effects of predator removal have been investigated widely; however, predator removal can also change natural selection acting on prey, resulting in contemporary evolution. Here we tested the role of predator removal on the contemporary evolution of trophic traits in prey. We utilized a historical introduction experiment where Trinidadian guppies (Poecilia reticulata) were relocated from a site with predatory fishes to a site lacking predators. To assess the trophic consequences of predator release, we linked individual morphology (cranial, jaw, and body) to foraging performance. Our results show that predator release caused an increase in guppy density and a "sharpening" of guppy trophic traits, which enhanced food consumption rates. Predator release appears to have shifted natural selection away from predator escape ability and towards resource acquisition ability. Related diet and mesocosm studies suggest that this shift enhances the impact of guppies on lower trophic levels in a fashion nuanced by the omnivorous feeding ecology of the species. We conclude that extirpation of top predators may commonly select for enhanced feeding performance in prey, with important cascading consequences for communities and ecosystems. PMID- 21526157 TI - Artificial astrocytes improve neural network performance. AB - Compelling evidence indicates the existence of bidirectional communication between astrocytes and neurons. Astrocytes, a type of glial cells classically considered to be passive supportive cells, have been recently demonstrated to be actively involved in the processing and regulation of synaptic information, suggesting that brain function arises from the activity of neuron-glia networks. However, the actual impact of astrocytes in neural network function is largely unknown and its application in artificial intelligence remains untested. We have investigated the consequences of including artificial astrocytes, which present the biologically defined properties involved in astrocyte-neuron communication, on artificial neural network performance. Using connectionist systems and evolutionary algorithms, we have compared the performance of artificial neural networks (NN) and artificial neuron-glia networks (NGN) to solve classification problems. We show that the degree of success of NGN is superior to NN. Analysis of performances of NN with different number of neurons or different architectures indicate that the effects of NGN cannot be accounted for an increased number of network elements, but rather they are specifically due to astrocytes. Furthermore, the relative efficacy of NGN vs. NN increases as the complexity of the network increases. These results indicate that artificial astrocytes improve neural network performance, and established the concept of Artificial Neuron-Glia Networks, which represents a novel concept in Artificial Intelligence with implications in computational science as well as in the understanding of brain function. PMID- 21526158 TI - Association between the SERPING1 gene and age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese. AB - PURPOSE: Recently, a complement component 1 inhibitor (SERPING1) gene polymorphism was identified as a novel risk factor for age-related macular degeneration (AMD) in Caucasians. We aimed to investigate whether variations in SERPING1 are associated with typical AMD or with polypoidal choroidal vasculopathy (PCV) in a Japanese population. METHODS: We performed a case-control study in a group of Japanese patients with typical AMD (n = 401) or PCV (n = 510) and in 2 independent control groups--336 cataract patients without age-related maculopathy and 1,194 healthy Japanese individuals. Differences in the observed genotypic distribution between the case and control groups were tested using chi square test for trend. Age and gender were adjusted using logistic regression analysis. RESULTS: We targeted rs2511989 as the haplotype-tagging single nucleotide polymorphism (SNP) for the SERPING1 gene, which was reported to be associated with the risk of AMD in Caucasians. Although we compared the genotypic distributions of rs2511989 in typical AMD and PCV patients against 2 independent control groups (cataract patients and healthy Japanese individuals), SERPING1 rs2511989 was not significantly associated with typical AMD (P = 0.932 and 0.513, respectively) or PCV (P = 0.505 and 0.141, respectively). After correction for age and gender differences based on a logistic regression model, the difference in genotypic distributions remained insignificant (P>0.05). Our sample size had a statistical power of more than 90% to detect an association of a risk allele with an odds ratio reported in the original studies for rs2511989 for developing AMD. CONCLUSIONS: In the present study, we could not replicate the reported association between SERPING1 and either neovascular AMD or PCV in a Japanese population; thus, the results suggest that SERPING1 does not play a significant role in the risk of developing AMD or PCV in Japanese. PMID- 21526159 TI - Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. AB - T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. In this study, we examine the role and mechanism of Th17 cells in the pathogenesis of autoimmune hepatitis (AIH). The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. The hepatic expressions of IL-17, IL-23, ROR-gammat, IL-6 and IL-1beta in patients with AIH were also significantly increased and were associated with increased inflammation and fibrosis. IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis. PMID- 21526161 TI - Insects as stem engineers: interactions mediated by the twig-girdler Oncideres albomarginata chamela enhance arthropod diversity. AB - BACKGROUND: Ecosystem engineering may influence community structure and biodiversity by controlling the availability of resources and/or habitats used by other organisms. Insect herbivores may act as ecosystem engineers but there is still poor understanding of the role of these insects structuring arthropod communities. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the effect of ecosystem engineering by the stem-borer Oncideres albomarginata chamela on the arthropod community of a tropical dry forest for three consecutive years. The results showed that ecosystem engineering by O. albomarginata chamela had strong positive effects on the colonization, abundance, species richness and composition of the associated arthropod community, and it occurred mainly through the creation of a habitat with high availability of oviposition sites for secondary colonizers. These effects cascade upward to higher trophic levels. Overall, ecosystem engineering by O. albomarginata chamela was responsible for nearly 95% of the abundance of secondary colonizers and 82% of the species richness. CONCLUSIONS/SIGNIFICANCE: Our results suggest that ecosystem engineering by O. albomarginata chamela is a keystone process structuring an arthropod community composed by xylovores, predators and parasitoids. This study is the first to empirically demonstrate the effect of the ecosystem engineering by stem-boring insects on important attributes of arthropod communities. The results of this study have important implications for conservation. PMID- 21526160 TI - The AP-1 binding sites located in the pol gene intragenic regulatory region of HIV-1 are important for viral replication. AB - Our laboratory has previously identified an important intragenic region in the human immunodeficiency virus type 1 (HIV-1) genome, whose complete functional unit is composed of the 5103 fragment, the DNaseI-hypersensitive site HS7 and the 5105 fragment. These fragments (5103 and 5105) both exhibit a phorbol 12 myristate 13-acetate (PMA)-inducible enhancer activity on the herpes simplex virus thymidine kinase promoter. Here, we characterized the three previously identified AP-1 binding sites of fragment 5103 by showing the PMA-inducible in vitro binding and in vivo recruitment of c-Fos, JunB and JunD to this fragment located at the end of the pol gene. Functional analyses demonstrated that the intragenic AP-1 binding sites are fully responsible for the PMA-dependent enhancer activity of fragment 5103. Moreover, infection of T-lymphoid Jurkat and promonocytic U937 cells with wild-type and mutant viruses demonstrated that mutations of the intragenic AP-1 sites individually or in combination altered HIV 1 replication. Importantly, mutations of the three intragenic AP-1 sites led to a decreased in vivo recruitment of RNA polymerase II to the viral promoter, strongly supporting that the deleterious effect of these mutations on viral replication occurs, at least partly, at the transcriptional level. Single-round infections of monocyte-derived macrophages confirmed the importance of intragenic AP-1 sites for HIV-1 infectivity. PMID- 21526162 TI - The resonance frequency shift, pattern formation, and dynamical network reorganization via sub-threshold input. AB - We describe a novel mechanism that mediates the rapid and selective pattern formation of neuronal network activity in response to changing correlations of sub-threshold level input. The mechanism is based on the classical resonance and experimentally observed phenomena that the resonance frequency of a neuron shifts as a function of membrane depolarization. As the neurons receive varying sub threshold input, their natural frequency is shifted in and out of its resonance range. In response, the neuron fires a sequence of action potentials, corresponding to the specific values of signal currents, in a highly organized manner. We show that this mechanism provides for the selective activation and phase locking of the cells in the network, underlying input-correlated spatio temporal pattern formation, and could be the basis for reliable spike-timing dependent plasticity. We compare the selectivity and efficiency of this pattern formation to a supra-threshold network activation and a non-resonating network/neuron model to demonstrate that the resonance mechanism is the most effective. Finally we show that this process might be the basis of the phase precession phenomenon observed during firing of hippocampal place cells, and that it may underlie the active switching of neuronal networks to locking at various frequencies. PMID- 21526163 TI - Aberrant GABA(A) receptor-mediated inhibition in cortico-thalamic networks of succinic semialdehyde dehydrogenase deficient mice. AB - Aberrant gamma-aminobutyric acid type A (GABA(A)) receptor-mediated inhibition in cortico-thalamic networks remains an attractive mechanism for typical absence seizure genesis. Using the whole-cell patch clamp technique we examined 'phasic' and 'tonic' GABA(A) inhibition in thalamocortical neurons of somatosensory (ventrobasal, VB) thalamus, nucleus reticularis thalami (NRT) neurons, and layer 5/6 pyramidal neurons of the somatosensory (barrel) cortex of succinic semialdehyde dehydrogenase (SSADH) knock-out (SSADH(-/-)) mice that replicate human SSADH deficiency and exhibit typical absence seizures. We found increased sIPSC frequency in both VB and NRT neurons and larger sIPSC amplitude in VB neurons of SSADH(-/-) mice compared to wild-type animals, demonstrating an increase in total phasic inhibition in thalamus of SSADH(-/-) mice. mIPSCs in both VB and NRT neurons were no different between genotypes, although there remained a trend toward more events in SSADH(-/-) mice. In cortical layer 5/6 pyramidal neurons, sIPSCs were fewer but larger in SSADH(-/-) mice, a feature retained by mIPSCs. Tonic currents were larger in both thalamocortical neurons and layer 5/6 pyramidal neurons from SSADH(-/-) mice compared to WTs. These data show that enhanced, rather than compromised, GABA(A) receptor-mediated inhibition occurs in cortico-thalamic networks of SSADH(-/-) mice. In agreement with previous studies, GABA(A) receptor-mediated inhibitory gain-of-function may be a common feature in models of typical absence seizures, and could be of pathological importance in patients with SSADH deficiency. PMID- 21526164 TI - Co-crystal structures of PKG Ibeta (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding. AB - BACKGROUND: Cyclic GMP-dependent protein kinases (PKGs) are central mediators of the NO-cGMP signaling pathway and phosphorylate downstream substrates that are crucial for regulating smooth muscle tone, platelet activation, nociception and memory formation. As one of the main receptors for cGMP, PKGs mediate most of the effects of cGMP elevating drugs, such as nitric oxide-releasing agents and phosphodiesterase inhibitors which are used for the treatment of angina pectoris and erectile dysfunction, respectively. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the mechanism of cyclic nucleotide binding to PKG by determining crystal structures of the amino-terminal cyclic nucleotide-binding domain (CNBD A) of human PKG I bound to either cGMP or cAMP. We also determined the structure of CNBD-A in the absence of bound nucleotide. The crystal structures of CNBD-A with bound cAMP or cGMP reveal that cAMP binds in either syn or anti configurations whereas cGMP binds only in a syn configuration, with a conserved threonine residue anchoring both cyclic phosphate and guanine moieties. The structure of CNBD-A in the absence of bound cyclic nucleotide was similar to that of the cyclic nucleotide bound structures. Surprisingly, isothermal titration calorimetry experiments demonstrated that CNBD-A binds both cGMP and cAMP with a relatively high affinity, showing an approximately two-fold preference for cGMP. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that CNBD-A binds cGMP in the syn conformation through its interaction with Thr193 and an unusual cis-peptide forming residues Leu172 and Cys173. Although these studies provide the first structural insights into cyclic nucleotide binding to PKG, our ITC results show only a two-fold preference for cGMP, indicating that other domains are required for the previously reported cyclic nucleotide selectivity. PMID- 21526165 TI - A public health emergency of international concern? Response to a proposal to apply the International Health Regulations to antimicrobial resistance. PMID- 21526166 TI - IgE mediates killing of intracellular Toxoplasma gondii by human macrophages through CD23-dependent, interleukin-10 sensitive pathway. AB - BACKGROUND: In addition to helminthic infections, elevated serum IgE levels were observed in many protozoal infections, while their contribution during immune response to these pathogens remained unclear. As IgE/antigen immune complexes (IgE-IC) bind to human cells through FcepsilonRI or FcepsilonRII/CD23 surface molecules, the present study aimed to identify which functional receptor may be involved in IgE-IC interaction with human macrophages, the major effector cell during parasite infection. METHODOLOGY/PRINCIPAL FINDINGS: Human monocyte-derived macrophages were infected with Toxoplasma gondii before being incubated with IgE IC. IgE receptors were then identified using appropriate blocking antibodies. The activation of cells and parasiticidal activity were evaluated by mediator quantification and direct counting of infected macrophages. RNAs were extracted and cell supernatants were also collected for their content in tumor necrosis factor (TNF)-alpha, interleukin-10 (IL-10) and nitrites. Sera from symptomatic infected patients were also tested for their content of IgE, IL-10 and nitrites, and compared to values found in healthy donors. Results showed that IgE-IC induced intracellular elimination of parasites by human macrophages. IgE-mediated effect was FcepsilonRI-independent, but required cross-linking of surface FcepsilonRII/CD23, cell activation and the generation of nitric oxide (NO). Although TNF-alpha was shown to be produced during cell activation, this cytokine had minor contribution in this phenomenon while endogenous and exogenous IL-10 down-regulated parasite killing. Inverse relationship was found between IL-10 and NO expression by infected human macrophages at both mRNA and mediator levels. The relationship between these in vitro data and in vivo levels of various factors in T. gondii infected patients supports the involvement of CD23 antigen and IL-10 expression in disease control. CONCLUSION: Thus, IgE may be considered as immune mediator during antiprotozoal activity of human macrophages through its ability to trigger CD23 signaling. Increased cell activation by IgE-IC may also account for chronic inflammatory diseases observed in some patients. PMID- 21526167 TI - High affinity antigen recognition of the dual specific variants of herceptin is entropy-driven in spite of structural plasticity. AB - The antigen-binding site of Herceptin, an anti-human Epidermal Growth Factor Receptor 2 (HER2) antibody, was engineered to add a second specificity toward Vascular Endothelial Growth Factor (VEGF) to create a high affinity two-in-one antibody bH1. Crystal structures of bH1 in complex with either antigen showed that, in comparison to Herceptin, this antibody exhibited greater conformational variability, also called "structural plasticity". Here, we analyzed the biophysical and thermodynamic properties of the dual specific variants of Herceptin to understand how a single antibody binds two unrelated protein antigens. We showed that while bH1 and the affinity-improved bH1-44, in particular, maintained many properties of Herceptin including binding affinity, kinetics and the use of residues for antigen recognition, they differed in the binding thermodynamics. The interactions of bH1 and its variants with both antigens were characterized by large favorable entropy changes whereas the Herceptin/HER2 interaction involved a large favorable enthalpy change. By dissecting the total entropy change and the energy barrier for dual interaction, we determined that the significant structural plasticity of the bH1 antibodies demanded by the dual specificity did not translate into the expected increase of entropic penalty relative to Herceptin. Clearly, dual antigen recognition of the Herceptin variants involves divergent antibody conformations of nearly equivalent energetic states. Hence, increasing the structural plasticity of an antigen binding site without increasing the entropic cost may play a role for antibodies to evolve multi-specificity. Our report represents the first comprehensive biophysical analysis of a high affinity dual specific antibody binding two unrelated protein antigens, furthering our understanding of the thermodynamics that drive the vast antigen recognition capacity of the antibody repertoire. PMID- 21526168 TI - Evaluation of the efficacy and safety of rivaroxaban using a computer model for blood coagulation. AB - Rivaroxaban is an oral, direct Factor Xa inhibitor approved in the European Union and several other countries for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is in advanced clinical development for the treatment of thromboembolic disorders. Its mechanism of action is antithrombin independent and differs from that of other anticoagulants, such as warfarin (a vitamin K antagonist), enoxaparin (an indirect thrombin/Factor Xa inhibitor) and dabigatran (a direct thrombin inhibitor). A blood coagulation computer model has been developed, based on several published models and preclinical and clinical data. Unlike previous models, the current model takes into account both the intrinsic and extrinsic pathways of the coagulation cascade, and possesses some unique features, including a blood flow component and a portfolio of drug action mechanisms. This study aimed to use the model to compare the mechanism of action of rivaroxaban with that of warfarin, and to evaluate the efficacy and safety of different rivaroxaban doses with other anticoagulants included in the model. Rather than reproducing known standard clinical measurements, such as the prothrombin time and activated partial thromboplastin time clotting tests, the anticoagulant benchmarking was based on a simulation of physiologically plausible clotting scenarios. Compared with warfarin, rivaroxaban showed a favourable sensitivity for tissue factor concentration inducing clotting, and a steep concentration effect relationship, rapidly flattening towards higher inhibitor concentrations, both suggesting a broad therapeutic window. The predicted dosing window is highly accordant with the final dose recommendation based upon extensive clinical studies. PMID- 21526169 TI - Multiple changes in peptide and lipid expression associated with regeneration in the nervous system of the medicinal leech. AB - BACKGROUND: The adult medicinal leech central nervous system (CNS) is capable of regenerating specific synaptic circuitry after a mechanical lesion, displaying evidence of anatomical repair within a few days and functional recovery within a few weeks. In the present work, spatiotemporal changes in molecular distributions during this phenomenon are explored. Moreover, the hypothesis that neural regeneration involves some molecular factors initially employed during embryonic neural development is tested. RESULTS: Imaging mass spectrometry coupled to peptidomic and lipidomic methodologies allowed the selection of molecules whose spatiotemporal pattern of expression was of potential interest. The identification of peptides was aided by comparing MS/MS spectra obtained for the peptidome extracted from embryonic and adult tissues to leech transcriptome and genome databases. Through the parallel use of a classical lipidomic approach and secondary ion mass spectrometry, specific lipids, including cannabinoids, gangliosides and several other types, were detected in adult ganglia following mechanical damage to connected nerves. These observations motivated a search for possible effects of cannabinoids on neurite outgrowth. Exposing nervous tissues to Transient Receptor Potential Vanilloid (TRPV) receptor agonists resulted in enhanced neurite outgrowth from a cut nerve, while exposure to antagonists blocked such outgrowth. CONCLUSION: The experiments on the regenerating adult leech CNS reported here provide direct evidence of increased titers of proteins that are thought to play important roles in early stages of neural development. Our data further suggest that endocannabinoids also play key roles in CNS regeneration, mediated through the activation of leech TRPVs, as a thorough search of leech genome databases failed to reveal any leech orthologs of the mammalian cannabinoid receptors but revealed putative TRPVs. In sum, our observations identify a number of lipids and proteins that may contribute to different aspects of the complex phenomenon of leech nerve regeneration, establishing an important base for future functional assays. PMID- 21526170 TI - Sex differences in sand lizard telomere inheritance: paternal epigenetic effects increases telomere heritability and offspring survival. AB - BACKGROUND: To date, the only estimate of the heritability of telomere length in wild populations comes from humans. Thus, there is a need for analysis of natural populations with respect to how telomeres evolve. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that telomere length is heritable in free-ranging sand lizards, Lacerta agilis. More importantly, heritability estimates analysed within, and contrasted between, the sexes are markedly different; son-sire heritability is much higher relative to daughter-dam heritability. We assess the effect of paternal age on Telomere Length (TL) and show that in this species, paternal age at conception is the best predictor of TL in sons. Neither paternal age per se at blood sampling for telomere screening, nor corresponding age in sons impact TL in sons. Processes maintaining telomere length are also associated with negative fitness effects, most notably by increasing the risk of cancer and show variation across different categories of individuals (e.g. males vs. females). We therefore tested whether TL influences offspring survival in their first year of life. Indeed such effects were present and independent of sex-biased offspring mortality and offspring malformations. CONCLUSIONS/SIGNIFICANCE: TL show differences in sex-specific heritability with implications for differences between the sexes with respect to ongoing telomere selection. Paternal age influences the length of telomeres in sons and longer telomeres enhance offspring survival. PMID- 21526171 TI - Macrobenthic biomass relations in the Faroe-Shetland Channel: an Arctic-Atlantic boundary environment. AB - The Faroe-Shetland Channel, located in the NE Atlantic, ranges in depth from 0 1700 m and is an unusual deep-sea environment because of its complex and dynamic hydrographic regime, as well as having numerous different seafloor habitats. Macrofaunal samples have been collected on a 0.5 mm mesh sieve from over 300 stations in a wide area survey and on nested 0.5 and 0.25 mm mesh sieves along a specific depth transect. Contrary to general expectation, macrofauanl biomass in the Channel did not decline with increasing depth. When examined at phylum level, two main biomass patterns with depth were apparent: (a) polychaetes showed little change in biomass on the upper slope then increased markedly below 500 m to a depth of 1100 m before declining; and (b) other phyla showed enhanced biomass between 300-500 m. The polychaete response may be linked with a seafloor environment change to relatively quiescent hydrodynamic conditions and an increasing sediment mud content that occurs at c. 500 m. In contrast, the mid slope enhancement of other phyla biomass may reflect the hydrodynamically active interface between the warm and cold water masses present in the Channel at c. 300 500 m. Again contrary to expectation, mean macrofaunal body size did not decline with depth, and the relative contribution of smaller (>0.25 mm<0.5 mm) to total (>0.25 mm) macrobenthos did not increase with depth. Overall our total biomass and average individual biomass estimates appear to be greater than those predicted from global analyses. It is clear that global models of benthic biomass distribution may mask significant variations at the local and regional scale. PMID- 21526172 TI - Systematic mutational analysis of the intracellular regions of yeast Gap1 permease. AB - BACKGROUND: The yeast general amino acid permease Gap1 is a convenient model for studying the intracellular trafficking of membrane proteins. Present at the plasma membrane when the nitrogen source is poor, it undergoes ubiquitin dependent endocytosis and degradation upon addition of a good nitrogen source, e.g., ammonium. It comprises 12 transmembrane domains (TM) flanked by cytosol facing N- and C-terminal tails (NT, CT). The NT of Gap1 contains the acceptor lysines for ubiquitylation and its CT includes a sequence essential to exit from the endoplasmic reticulum (ER). PRINCIPAL FINDINGS: We used alanine-scanning mutagenesis to isolate 64 mutant Gap1 proteins altered in the NT, the CT, or one of the five TM-connecting intracellular loops (L2, -4, -6, -8 and -10). We found 17 mutations (in L2, L8, L10 and CT) impairing Gap1 exit from the ER. Of the 47 mutant proteins reaching the plasma membrane normally, two are unstable and rapidly down-regulated even when the nitrogen source is poor. Six others are totally inactive and another four, altered in a 16-amino-acid sequence in the NT, are resistant to ammonium-induced down-regulation. Finally, a mutation in L6 causes missorting of Gap1 from the secretory pathway to the vacuole. Interestingly, this direct vacuolar sorting seems to be independent of Gap1 ubiquitylation. CONCLUSIONS: This study illustrates the importance of multiple intracellular regions of Gap1 in its secretion, transport activity, and down regulation. PMID- 21526173 TI - A sodium leak current regulates pacemaker activity of adult central pattern generator neurons in Lymnaea stagnalis. AB - The resting membrane potential of the pacemaker neurons is one of the essential mechanisms underlying rhythm generation. In this study, we described the biophysical properties of an uncharacterized channel (U-type channel) and investigated the role of the channel in the rhythmic activity of a respiratory pacemaker neuron and the respiratory behaviour in adult freshwater snail Lymnaea stagnalis. Our results show that the channel conducts an inward leak current carried by Na(+) (I(Leak-Na)). The I(Leak-Na) contributed to the resting membrane potential and was required for maintaining rhythmic action potential bursting activity of the identified pacemaker RPeD1 neurons. Partial knockdown of the U type channel suppressed the aerial respiratory behaviour of the adult snail in vivo. These findings identified the Na(+) leak conductance via the U-type channel, likely a NALCN-like channel, as one of the fundamental mechanisms regulating rhythm activity of pacemaker neurons and respiratory behaviour in adult animals. PMID- 21526174 TI - The T7-related Pseudomonas putida phage phi15 displays virion-associated biofilm degradation properties. AB - Formation of a protected biofilm environment is recognized as one of the major causes of the increasing antibiotic resistance development and emphasizes the need to develop alternative antibacterial strategies, like phage therapy. This study investigates the in vitro degradation of single-species Pseudomonas putida biofilms, PpG1 and RD5PR2, by the novel phage phi15, a 'T7-like virus' with a virion-associated exopolysaccharide (EPS) depolymerase. Phage phi15 forms plaques surrounded by growing opaque halo zones, indicative for EPS degradation, on seven out of 53 P. putida strains. The absence of haloes on infection resistant strains suggests that the EPS probably act as a primary bacterial receptor for phage infection. Independent of bacterial strain or biofilm age, a time and dose dependent response of phi15-mediated biofilm degradation was observed with generally a maximum biofilm degradation 8 h after addition of the higher phage doses (10(4) and 10(6) pfu) and resistance development after 24 h. Biofilm age, an in vivo very variable parameter, reduced markedly phage-mediated degradation of PpG1 biofilms, while degradation of RD5PR2 biofilms and phi15 amplification were unaffected. Killing of the planktonic culture occurred in parallel with but was always more pronounced than biofilm degradation, accentuating the need for evaluating phages for therapeutic purposes in biofilm conditions. EPS degrading activity of recombinantly expressed viral tail spike was confirmed by capsule staining. These data suggests that the addition of high initial titers of specifically selected phages with a proper EPS depolymerase are crucial criteria in the development of phage therapy. PMID- 21526175 TI - Evolutionary analyses of entire genomes do not support the association of mtDNA mutations with Ras/MAPK pathway syndromes. AB - BACKGROUND: There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS) and related disorders (such as LEOPARD, neurofibromatosis type 1), although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45), most of them classified as NS patients (n = 42). METHODS/PRINCIPAL FINDINGS: The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of a typical Iberian dataset (including hgs H, T, J, and U). Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. CONCLUSIONS/SIGNIFICANCE: As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS. PMID- 21526176 TI - Host suitability of a gregarious parasitoid on beetle hosts: flexibility between fitness of adult and offspring. AB - Behavioral tactics play a crucial role in the evolution of species and are likely to be found in host-parasitoid interactions where host quality may differ between host developmental stages. We investigated foraging decisions, parasitism and related fitness in a gregarious ectoparasitoid, Sclerodermus harmandi in relation to two distinct host developmental stages: larvae and pupae. Two colonies of parasitoids were reared on larvae of Monochamus alternatus and Saperda populnea (Cerambycidae: Lamiinae). Paired-choice and non-choice experiments were used to evaluate the preference and performance of S. harmandi on larvae and pupae of the two species. Foraging decisions and offspring fitness-related consequences of S. harmandi led to the selection of the most profitable host stage for parasitoid development. Adult females from the two colonies oviposited more quickly on pupae as compared to larvae of M. alternatus. Subsequently, their offspring development time was faster and they gained higher body weight on the pupal hosts. This study demonstrates optimal foraging of intraspecific detente that can occur during host parasitoid interactions, of which the quality of the parasitism (highest fitness benefit and profitability) is related to the host developmental stage utilized. We conclude that S. harmandi is able to perfectly discriminate among host species or stages in a manner that maximizes its offspring fitness. The results indicated that foraging potential of adults may not be driven by its maternal effects, also induced flexibly with encountering prior host quality. PMID- 21526177 TI - Influence of Dll4 via HIF-1alpha-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditions. AB - Choroidal neovascularization (CNV) is the common pathological basis of irreversible visual impairment encountered in a variety of chorioretinal diseases; the pathogenesis of its development is complicated and still imperfectly understood. Recent studies indicated that delta-like ligand 4 (Dll4), one of the Notch family ligands might participate in the HIF-1alpha-VEGF pathway to regulate CNV angiogenesis. But little is known about the influence and potential mechanism of Dll4/Notch signals on CNV angiogenesis. Real-time RT-PCR, Western blotting were used to analyze the expression alteration of Dll4, VEGF and HIF-1alpha in hypoxic RF/6A cells. Immunofluorescence staining, a laser-induced rat CNV model and intravitreal injection techniques were used to confirm the relationships among these molecules in vitro and in vivo. RPE-RF/6A cell co culture systems were used to investigate the effects of Dll4/Notch signals on CNV angiogenesis. We found that the Dll4 was involved in hypoxia signaling in CNV angiogenesis. Results from the co-culture system showed that the enhancement of Dll4 expression in RF/6A cells led to the significantly faster proliferation and stronger tube forming ability, but inhibited cells migration and invasion across a monolayer of RPE cells in hypoxic environment, while siRNA-mediated Dll4 silencing caused the opposite effects. Pharmacological disruption of Notch signaling using gamma-secretase inhibitor (GSI) produced similar, but not identical effects, to that caused by the Dll4 siRNA. In addition, the expression of several key molecules involved in the angiogenesis of CNV was altered in RF/6A cells showing constitutively active Dll4 expression. These results suggest that Dll4 play an important role in CNV angiogenesis, which appears to be regulated by HIF-1alpha and VEGF during the progression of CNV under hypoxic conditions. Targeting Dll4/Notch signaling may facilitate further understanding of the mechanisms that underlie CNV angiogenesis. PMID- 21526178 TI - Effects of solution chemistry and aging time on prion protein adsorption and replication of soil-bound prions. AB - Prion interactions with soil may play an important role in the transmission of chronic wasting disease (CWD) and scrapie. Prions are known to bind to a wide range of soil surfaces, but the effects of adsorption solution chemistry and long term soil binding on prion fate and transmission risk are unknown. We investigated HY TME prion protein (PrP(Sc)) adsorption to soil minerals in aqueous solutions of phosphate buffered saline (PBS), sodium chloride, calcium chloride, and deionized water using western blotting. The replication efficiency of bound prions following adsorption in these solutions was also evaluated by protein misfolding cyclic amplification (PMCA). Aging studies investigated PrP(Sc) desorption and replication efficiency up to one year following adsorption in PBS or DI water. Results indicate that adsorption solution chemistry can affect subsequent prion replication or desorption ability, especially after incubation periods of 30 d or longer. Observed effects were minor over the short term (7 d or less). Results of long-term aging experiments demonstrate that unbound prions or prions bound to a diverse range of soil surfaces can readily replicate after one year. Our results suggest that while prion-soil interactions can vary with solution chemistry, prions bound to soil could remain a risk for transmitting prion diseases after months in the environment. PMID- 21526179 TI - Investigation outcomes of tuberculosis suspects in the health centers of Addis Ababa, Ethiopia. AB - BACKGROUND: Little is known about the prevalence of tuberculosis (TB) and HIV among TB suspects in primary health care units in Ethiopia. METHODS: In the period of February to March, 2009, a cross sectional survey was done in 27 health centers of Addis Ababa to assess the prevalence of TB and HIV among TB suspects who have > = 2 weeks symptoms of TB such as cough, fever and weight loss. Diagnosis of TB and HIV was based on the national guidelines. Information concerning socio-demographic variables and knowledge of the respondents about TB was collected using pretested questionnaire. RESULTS: Of the 545 TB suspects, 506 (92.7%) of them participated in the study. The prevalence of both pulmonary and extra pulmonary TB was 46.0% (233/506). The smear positivity rate among pulmonary TB suspect was 21.3%. Of the TB suspects, 298 (58.9%) of them were tested for HIV and 27.2% (81/298) were HIV seropositive. Fifty percent of the HIV positive TB suspects had TB. TB suspects who had a contact history with a TB patient in the family were 9 times more likely to have TB than those who did not have a contact history, [OR = 9.1, (95%CI:4.0, 20.5)]. Individuals who had poor [OR = 5.2, (95%CI: 2.3, 11.2)] and fair knowledge [OR = 3.7, (95%CI: 1.3, 10.4)] about TB were more likely to have TB than individuals who had good knowledge. CONCLUSION: In conclusion, the prevalence of TB among TB suspects with duration of 2 or more weeks is high. Fifty percent of the HIV positive TB suspects had TB. Case finding among TB suspects with duration of 2 or more weeks should be intensified particularly among those who have a contact history with a TB patient. PMID- 21526180 TI - SALL4, a stem cell factor, affects the side population by regulation of the ATP binding cassette drug transport genes. AB - Our previous work shows that the stem cell factor SALL4 plays a central role in embryonic and leukemic stem cells. In this study, we report that SALL4 expression was higher in drug resistant primary acute myeloid leukemic patients than those from drug-responsive cases. In addition, while overexpression of SALL4 led to drug resistance in cell lines, cells with decreased SALL4 expression were more sensitive to drug treatments than the parental cells. This led to our investigation of the implication of SALL4 in drug resistance and its role in side population (SP) cancer stem cells. SALL4 expression was higher in SP cells compared to non-SP cells by 2-4 fold in various malignant hematopoietic cell lines. Knocking down of SALL4 in isolated SP cells resulted in a reduction of SP cells, indicating that SALL4 is required for their self-renewal. The SP phenotype is known to be mediated by members of the ATP-binding cassette (ABC) drug transport protein family, such as ABCG2 and ABCA3. Using chromatin immunoprecipitation (ChIP), quantitative reverse transcription polymerase chain reaction (qRT-PCR) and electrophoretic mobility shift assay(EMSA), we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. Furthermore, SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples. Taken together, our results suggest a novel role for SALL4 in drug sensitivity, at least in part through the maintenance of SP cells, and therefore may be responsible for drug-resistance in leukemia. We are the first to demonstrate a direct link between stem cell factor SALL4, SP and drug resistance in leukemia. PMID- 21526181 TI - The LSD1-interacting protein GILP is a LITAF domain protein that negatively regulates hypersensitive cell death in Arabidopsis. AB - BACKGROUND: Hypersensitive cell death, a form of avirulent pathogen-induced programmed cell death (PCD), is one of the most efficient plant innate immunity. However, its regulatory mechanism is poorly understood. AtLSD1 is an important negative regulator of PCD and only two proteins, AtbZIP10 and AtMC1, have been reported to interact with AtLSD1. METHODOLOGY/PRINCIPAL FINDINGS: To identify a novel regulator of hypersensitive cell death, we investigate the possible role of plant LITAF domain protein GILP in hypersensitive cell death. Subcellular localization analysis showed that AtGILP is localized in the plasma membrane and its plasma membrane localization is dependent on its LITAF domain. Yeast two hybrid and pull-down assays demonstrated that AtGILP interacts with AtLSD1. Pull down assays showed that both the N-terminal and the C-terminal domains of AtGILP are sufficient for interactions with AtLSD1 and that the N-terminal domain of AtLSD1 is involved in the interaction with AtGILP. Real-time PCR analysis showed that AtGILP expression is up-regulated by the avirulent pathogen Pseudomonas syringae pv. tomato DC3000 avrRpt2 (Pst avrRpt2) and fumonisin B1 (FB1) that trigger PCD. Compared with wild-type plants, transgenic plants overexpressing AtGILP exhibited significantly less cell death when inoculated with Pst avrRpt2, indicating that AtGILP negatively regulates hypersensitive cell death. CONCLUSIONS/SIGNIFICANCE: These results suggest that the LITAF domain protein AtGILP localizes in the plasma membrane, interacts with AtLSD1, and is involved in negatively regulating PCD. We propose that AtGILP functions as a membrane anchor, bringing other regulators of PCD, such as AtLSD1, to the plasma membrane. Human LITAF domain protein may be involved in the regulation of PCD, suggesting the evolutionarily conserved function of LITAF domain proteins in the regulation of PCD. PMID- 21526182 TI - A comprehensive analysis of the dynamic biological networks in HCV induced hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, which is closely related to hepatitis C and cirrhosis. The molecular mechanisms underlying the hepatocarcinogenesis induced by HCV infection remain clarified from a standpoint of systems biology. By integrating data from protein-protein interactions, transcriptional regulation, and disease related microarray analysis, we carried out a dynamic biological network analysis on the progression of HCV induced hepatocarcinogenesis, and systematically explored the potentially disease-related mechanisms through a network view. The dysfunctional interactions among proteins and deregulatory relationships between transcription factors and their target genes could be causes for the occurrence and progression of this disease. The six pathologically defined disease stages in the development and progression of HCC after HCV infection were included in this study. We constructed disease-related biological networks for each disease stage, and identified progression-related sub-networks that potentially play roles in the developmental stage of the corresponding disease and participate in the later stage of cancer progression. In addition, we identified novel risk factors related to HCC based on the analysis of the progression-related sub-networks. The dynamic characteristics of the network reflect important features of the disease development and progression, which provide important information for us to further explore underlying mechanisms of the disease. PMID- 21526183 TI - Scoring protein relationships in functional interaction networks predicted from sequence data. AB - The abundance of diverse biological data from various sources constitutes a rich source of knowledge, which has the power to advance our understanding of organisms. This requires computational methods in order to integrate and exploit these data effectively and elucidate local and genome wide functional connections between protein pairs, thus enabling functional inferences for uncharacterized proteins. These biological data are primarily in the form of sequences, which determine functions, although functional properties of a protein can often be predicted from just the domains it contains. Thus, protein sequences and domains can be used to predict protein pair-wise functional relationships, and thus contribute to the function prediction process of uncharacterized proteins in order to ensure that knowledge is gained from sequencing efforts. In this work, we introduce information-theoretic based approaches to score protein-protein functional interaction pairs predicted from protein sequence similarity and conserved protein signature matches. The proposed schemes are effective for data driven scoring of connections between protein pairs. We applied these schemes to the Mycobacterium tuberculosis proteome to produce a homology-based functional network of the organism with a high confidence and coverage. We use the network for predicting functions of uncharacterised proteins. AVAILABILITY: Protein pair wise functional relationship scores for Mycobacterium tuberculosis strain CDC1551 sequence data and python scripts to compute these scores are available at http://web.cbio.uct.ac.za/~gmazandu/scoringschemes. PMID- 21526186 TI - One problem, many solutions: simple statistical approaches help unravel the complexity of the immune system in an ecological context. AB - The immune system is a complex collection of interrelated and overlapping solutions to the problem of disease. To deal with this complexity, researchers have devised multiple ways to measure immune function and to analyze the resulting data. In this way both organisms and researchers employ many tactics to solve a complex problem. One challenge facing ecological immunologists is the question of how these many dimensions of immune function can be synthesized to facilitate meaningful interpretations and conclusions. We tackle this challenge by employing and comparing several statistical methods, which we used to test assumptions about how multiple aspects of immune function are related at different organizational levels. We analyzed three distinct datasets that characterized 1) species, 2) subspecies, and 3) among- and within-individual level differences in the relationships among multiple immune indices. Specifically, we used common principal components analysis (CPCA) and two simpler approaches, pair-wise correlations and correlation circles. We also provide a simple example of how these techniques could be used to analyze data from multiple studies. Our findings lead to several general conclusions. First, relationships among indices of immune function may be consistent among some organizational groups (e.g. months over the annual cycle) but not others (e.g. species); therefore any assumption of consistency requires testing before further analyses. Second, simple statistical techniques used in conjunction with more complex multivariate methods give a clearer and more robust picture of immune function than using complex statistics alone. Moreover, these simpler approaches have potential for analyzing comparable data from multiple studies, especially as the field of ecological immunology moves towards greater methodological standardization. PMID- 21526184 TI - Change of positive selection pressure on HIV-1 envelope gene inferred by early and recent samples. AB - HIV-1 infection has been on the rise in Japan recently, and the main transmission route has changed from blood transmission in the 1980s to homo- and/or hetero sexual transmission in the 2000s. The lack of early viral samples with clinical information made it difficult to investigate the possible virological changes over time. In this study, we sequenced 142 full-length env genes collected from 16 Japanese subjects infected with HIV-1 in the 1980s and in the 2000s. We examined the diversity change in sequences and potential adaptive evolution of the virus to the host population. We used a codon-based likelihood method under the branch-site and clade models to detect positive selection operating on the virus. The clade model was extended to account for different positive selection pressures in different viral populations. The result showed that the selection pressure was weaker in the 2000s than in the 1980s, indicating that it might have become easier for the HIV to infect a new host and to develop into AIDS now than 20 years ago and that the HIV may be becoming more virulent in the Japanese population. The study provides useful information on the surveillance of HIV infection and highlights the utility of the extended clade models in analysis of virus populations which may be under different selection pressures. PMID- 21526185 TI - Absence of ataxin-3 leads to enhanced stress response in C. elegans. AB - Ataxin-3, the protein involved in Machado-Joseph disease, is able to bind ubiquitylated substrates and act as a deubiquitylating enzyme in vitro, and it has been involved in the modulation of protein degradation by the ubiquitin proteasome pathway. C. elegans and mouse ataxin-3 knockout models are viable and without any obvious phenotype in a basal condition however their phenotype in stress situations has never been described.Considering the role of ataxin-3 in the protein degradation pathway, we analyzed the effects of heat shock, a known protein homeostasis stressor, in C. elegans ataxin-3 (ATX-3) knockout animals. We found that ATX-3 mutants have an exacerbated stress response and survive significantly better than wild type animals when subjected to a noxious heat shock stimulus. This increased thermotolerance of mutants was further enhanced by pre-exposure to a mild heat shock. At a molecular level, ATX-3 mutants have a distinct transcriptomic and proteomic profile with several molecular chaperones abnormally up-regulated during heat shock and recovery, consistent with the observed resistance phenotype.The improved thermotolerance in ATX-3 mutants is independent of heat shock factor 1, the maestro of the heat shock response, but fully dependent on DAF-16, a critical stress responsive transcription factor involved in longevity and stress resistance. We also show that the increased thermotolerance of ATX-3 mutants is mainly due to HSP-16.2, C12C8.1 and F44E5.5 given that the knockdown of these heat shock proteins using RNA interference causes the phenotype to revert. This report suggests that the absence of ATX-3 activates the DAF-16 pathway leading to an overexpression of molecular chaperones, which yields knockout animals with an improved capacity for dealing with deleterious stimuli. PMID- 21526187 TI - Artificial modulation of the gating behavior of a K+ channel in a KvAP-DNA chimera. AB - We present experiments where the gating behavior of a voltage-gated ion channel is modulated by artificial ligand binding. We construct a channel-DNA chimera with the KvAP potassium channel reconstituted in an artificial membrane. The channel is functional and the single channel ion conductivity unperturbed by the presence of the DNA. However, the channel opening probability vs. bias voltage, i.e., the gating, can be shifted considerably by the electrostatic force between the charges on the DNA and the voltage sensing domain of the protein. Different hybridization states of the chimera DNA thus lead to different response curves of the channel. PMID- 21526188 TI - Intra-individual variability in Alzheimer's disease and cognitive aging: definitions, context, and effect sizes. AB - BACKGROUND/AIMS: To explore different definitions of intra-individual variability (IIV) to summarize performance on commonly utilized cognitive tests (Mini Mental State Exam; Clock Drawing Test); compare them and their potential to differentiate clinically-defined populations; and to examine their utility in predicting clinical change in individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: Sample statistics were computed from ADNI cohorts with no cognitive diagnosis, a diagnosis of mild cognitive impairment (MCI), and a diagnosis of possible or probable Alzheimer's disease (AD). Nine different definitions of IIV were computed for each sample, and standardized effect sizes (Cohen's d) were computed for each of these definitions in 500 simulated replicates using scores on the Mini Mental State Exam and Clock Drawing Test. IIV was computed based on test items separately ('within test' IIV) and the two tests together ('across test' IIV). The best performing definition was then used to compute IIV for a third test, the Alzheimer's Disease Assessment Scale-Cognitive, and the simulations and effect sizes were again computed. All effect size estimates based on simulated data were compared to those computed based on the total scores in the observed data. Association between total score and IIV summaries of the tests and the Clinician's Dementia Rating were estimated to test the utility of IIV in predicting clinically meaningful changes in the cohorts over 12- and 24-month intervals. RESULTS: ES estimates differed substantially depending on the definition of IIV and the test(s) on which IIV was based. IIV (coefficient of variation) summaries of MMSE and Clock-Drawing performed similarly to their total scores, the ADAS total performed better than its IIV summary. CONCLUSION: IIV can be computed within (items) or across (totals) items on commonly-utilized cognitive tests, and may provide a useful additional summary measure of neuropsychological test performance. PMID- 21526189 TI - Brain activity elicited by positive and negative feedback in preschool-aged children. AB - To investigate the processing of positive vs. negative feedback in children aged 4-5 years, we devised a prize-guessing game that is analogous to gambling tasks used to measure feedback-related brain responses in adult studies. Unlike adult studies, the feedback-related negativity (FRN) elicited by positive feedback was as large as that elicited by negative feedback, suggesting that the neural system underlying the FRN may not process feedback valence in early childhood. In addition, positive feedback, compared with negative feedback, evoked a larger P1 over the occipital scalp area and a larger positive slow wave (PSW) over the right central-parietal scalp area. We believe that the PSW is related to emotional arousal and the intensive focus on positive feedback that is present in the preschool and early school years has adaptive significance for both cognitive and emotional development during this period. PMID- 21526190 TI - Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis. AB - The CDKN2A/ARF locus encompasses overlapping tumor suppressor genes p16(INK4A) and p14(ARF), which are frequently co-deleted in human malignant mesothelioma (MM). The importance of p16(INK4A) loss in human cancer is well established, but the relative significance of p14(ARF) loss has been debated. The tumor predisposition of mice singly deficient for either Ink4a or Arf, due to targeting of exons 1alpha or 1beta, respectively, supports the idea that both play significant and nonredundant roles in suppressing spontaneous tumors. To further test this notion, we exposed Ink4a(+/-) and Arf(+/-) mice to asbestos, the major cause of MM. Asbestos-treated Ink4a(+/-) and Arf(+/-) mice showed increased incidence and shorter latency of MM relative to wild-type littermates. MMs from Ink4a(+/-) mice exhibited biallelic inactivation of Ink4a, loss of Arf or p53 expression and frequent loss of p15(Ink4b). In contrast, MMs from Arf(+/-) mice exhibited loss of Arf expression, but did not require loss of Ink4a or Ink4b. Mice doubly deficient for Ink4a and Arf, due to deletion of Cdkn2a/Arf exon 2, showed accelerated asbestos-induced MM formation relative to mice deficient for Ink4a or Arf alone, and MMs exhibited biallelic loss of both tumor suppressor genes. The tumor suppressor function of Arf in MM was p53-independent, since MMs with loss of Arf retained functional p53. Collectively, these in vivo data indicate that both CDKN2A/ARF gene products suppress asbestos carcinogenicity. Furthermore, while inactivation of Arf appears to be crucial for MM pathogenesis, the inactivation of both p16(Ink4a) and p19(Arf) cooperate to accelerate asbestos induced tumorigenesis. PMID- 21526191 TI - Relationship between gene body DNA methylation and intragenic H3K9me3 and H3K36me3 chromatin marks. AB - To elucidate the relationship between intragenic DNA methylation and chromatin marks, we performed epigenetic profiling of chromosome 19 in human bronchial epithelial cells (HBEC) and in the colorectal cancer cell line HCT116 as well as its counterpart with double knockout of DNMT1 and DNMT3B (HCT116-DKO). Analysis of H3K36me3 profiles indicated that this intragenic mark of active genes is associated with two categories of genes: (i) genes with low CpG density and H3K9me3 in the gene body or (ii) genes with high CpG density and DNA methylation in the gene body. We observed that a combination of low CpG density in gene bodies together with H3K9me3 and H3K36me3 occupancy is a specific epigenetic feature of zinc finger (ZNF) genes, which comprise 90% of all genes carrying both histone marks on chromosome 19. For genes with high intragenic CpG density, transcription and H3K36me3 occupancy were not changed in conditions of partial or intensive loss of DNA methylation in gene bodies. siRNA knockdown of SETD2, the major histone methyltransferase responsible for production of H3K36me3, did not reduce DNA methylation in gene bodies. Our study suggests that the H3K36me3 and DNA methylation marks in gene bodies are established largely independently of each other and points to similar functional roles of intragenic DNA methylation and intragenic H3K9me3 for CpG-rich and CpG-poor genes, respectively. PMID- 21526193 TI - Inter-individual variability in fear of humans and relative brain size of the species are related to contemporary urban invasion in birds. AB - BACKGROUND: Urbanization is the most prevailing cause of habitat transformation worldwide, differing from others by its intense levels of human activity. Despite its obvious impact on wildlife, it is still unclear why and how some species are able to adapt to urban settings. One possibility is that fear of humans and vehicles could preclude most species from invading cities. Species entering urban environments might be those that are more tolerant of human disturbance (i.e., tame species). Alternatively or in addition, urban invaders could be a fraction of variable species, with "tame" individuals invading urban habitats and other individuals remaining in rural areas. METHODOLOGY: Using the contemporary urban invasion by birds in a recently established South American city, we tested both hypotheses by relating interspecific differences in invasiveness to their flight initiation distances (i.e., the distances at which birds flee from approaching cars, FID), as well as to their relative brain size (RBS), a correlate of measures of behavioral flexibility. PRINCIPAL FINDINGS: Urban invasiveness was not significantly related to species' average rural FIDs but positively related to their RBS and inter-individual variability in FID. Moreover, FIDs were consistently lower in urban than in rural conspecifics, and the FIDs of urban individuals were within the lower-range distribution of their rural conspecifics. RBS indirectly influenced urban invasion through its positive effect on inter individual variability in FID. CONCLUSIONS/SIGNIFICANCE: Urban invaders do not appear to be individuals from apparently tame species, but rather tame individuals from species with a variable response regarding fear of people. Given the positive relationship between RBS and inter-individual variability in FID, our results suggest that behavioural flexibility should be regarded as a specific trait encompassing variability among individuals. Further research is needed to ascertain the neurophysiological mechanisms underlying the relationship between brain size and inter-individual variability in behavioural traits. PMID- 21526192 TI - The complete genome sequence of Fibrobacter succinogenes S85 reveals a cellulolytic and metabolic specialist. AB - Fibrobacter succinogenes is an important member of the rumen microbial community that converts plant biomass into nutrients usable by its host. This bacterium, which is also one of only two cultivated species in its phylum, is an efficient and prolific degrader of cellulose. Specifically, it has a particularly high activity against crystalline cellulose that requires close physical contact with this substrate. However, unlike other known cellulolytic microbes, it does not degrade cellulose using a cellulosome or by producing high extracellular titers of cellulase enzymes. To better understand the biology of F. succinogenes, we sequenced the genome of the type strain S85 to completion. A total of 3,085 open reading frames were predicted from its 3.84 Mbp genome. Analysis of sequences predicted to encode for carbohydrate-degrading enzymes revealed an unusually high number of genes that were classified into 49 different families of glycoside hydrolases, carbohydrate binding modules (CBMs), carbohydrate esterases, and polysaccharide lyases. Of the 31 identified cellulases, none contain CBMs in families 1, 2, and 3, typically associated with crystalline cellulose degradation. Polysaccharide hydrolysis and utilization assays showed that F. succinogenes was able to hydrolyze a number of polysaccharides, but could only utilize the hydrolytic products of cellulose. This suggests that F. succinogenes uses its array of hemicellulose-degrading enzymes to remove hemicelluloses to gain access to cellulose. This is reflected in its genome, as F. succinogenes lacks many of the genes necessary to transport and metabolize the hydrolytic products of non-cellulose polysaccharides. The F. succinogenes genome reveals a bacterium that specializes in cellulose as its sole energy source, and provides insight into a novel strategy for cellulose degradation. PMID- 21526195 TI - Distribution of country of origin in studies used in Cochrane Reviews. AB - BACKGROUND AND OBJECTIVE: Inclusion in systematic reviews is one important component in judging the potential impact of clinical studies upon practice and hence the 'value for money' of spending for clinical research. This study aims to quantify the distribution of countries of origin of clinical studies used in Cochrane Reviews (CRs), and to link these data to the size of a country and to its spending on research. METHODS: Random sample of publications used for CRs published in Issue 1 2008 and of publications used in CRs in the field of complementary and alternative medicine (CAM). Publications without original data were excluded. Likely countries of origin determined based on abstracts/full texts. CIA World Factbook (population data) and OECD database (economic data) were used. RESULTS: 1,000 random entries out of 140,005 references available in all specialities. In 876 (91.4%) of 959 eligible studies, country of origin was determined. The USA was the leading contributor (36.0% of the studies), followed by UK (13.4%), Canada (5.3%), Australia and Sweden (3.7%). In the CAM sample, country of origin was determined in 458 (93.5%) of 497 assessed studies. Again, the USA was the leading contributor (24.9%), with China also emerging as a significant contributor (24.7%) in this field. For both samples, the contribution of smaller countries (especially Scandinavian countries, Greece, and Ireland) became more noteworthy when considered in relation to population size and research spending. CONCLUSIONS: Our results support the leading roles of both the USA and the UK in publishing clinical papers. The emerging role of China can be seen, particularly related to CAM studies. Taking into account size of population and economic power, countries like France, Germany, Italy, and Spain provide small contributions. In contrast, smaller countries like Australia, Denmark, Finland, Ireland, New Zealand, and Sweden also play major roles. PMID- 21526194 TI - Innate and adaptive immune responses both contribute to pathological CD4 T cell activation in HIV-1 infected Ugandans. AB - HIV-1 disease progression is associated with persistent immune activation. However, the nature of this association is incompletely understood. Here, we investigated immune activation in the CD4 T cell compartment of chronically HIV-1 infected individuals from Rakai, Uganda. Levels of CD4 T cell activation, assessed as co-expression of PD-1, CD38 and HLA-DR, correlated directly to viral load and inversely to CD4 count. Deeper characterization of these cells indicated an effector memory phenotype with relatively frequent expression of Ki67 despite their PD-1 expression, and levels of these cells were inversely associated with FoxP3+ regulatory T cells. We therefore use the term deregulated effector memory (DEM) cells to describe them. CD4 T cells with a DEM phenotype could be generated by antigen stimulation of recall responses in vitro. Responses against HIV-1 and CMV antigens were enriched among the DEM CD4 T cells in patients, and the diverse Vbeta repertoire of DEM CD4 T cells suggested they include diverse antigen specificities. Furthermore, the levels of DEM CD4 T cells correlated directly to soluble CD14 (sCD14) and IL-6, markers of innate immune activation, in plasma. The size of the activated DEM CD4 T cell subset was predictive of the rate of disease progression, whereas IL-6 was only weakly predictive and sCD14 was not predictive. Taken together, these results are consistent with a model where systemic innate immune activation and chronic antigen stimulation of adaptive T cell responses both play important roles in driving pathological CD4 T cell immune activation in HIV-1 disease. PMID- 21526196 TI - Placenta-like structure of the aphid endoparasitic wasp Aphidius ervi: a strategy of optimal resources acquisition. AB - Aphidius ervi (Hymenoptera: Braconidae) is an entomophagous parasitoid known to be an effective parasitoid of several aphid species of economic importance. A reduction of its production cost during mass rearing for inundative release is needed to improve its use in biological control of pests. In these contexts, a careful analysis of its entire development phases within its host is needed. This paper shows that this parasitoid has some characteristics in its embryological development rather complex and different from most other reported insects, which can be phylogenetically very close. First, its yolkless egg allows a high fecundity of the female but force them to hatch from the egg shell rapidly to the host hemocoel. An early cellularisation allowing a rapid differentiation of a serosa membrane seems to confirm this hypothesis. The serosa wraps the developing embryo until the first instar larva stage and invades the host tissues by microvilli projections and form a placenta like structure able to divert host resources and allowing nutrition and respiration of embryo. Such interspecific invasion, at the cellular level, recalls mammal's trophoblasts that anchors maternal uterine wall and underlines the high adaptation of A. ervi to develop in the host body. PMID- 21526197 TI - Multiplexed immunoassay panel identifies novel CSF biomarkers for Alzheimer's disease diagnosis and prognosis. AB - BACKGROUND: Clinicopathological studies suggest that Alzheimer's disease (AD) pathology begins ~10-15 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset would, therefore, be invaluable for patient care and efficient clinical trial design. We utilized a targeted proteomics approach to discover novel cerebrospinal fluid (CSF) biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers (Abeta42, tau, p-tau181). METHODS AND FINDINGS: Using a multiplexed Luminex platform, 190 analytes were measured in 333 CSF samples from cognitively normal (Clinical Dementia Rating [CDR] 0), very mildly demented (CDR 0.5), and mildly demented (CDR 1) individuals. Mean levels of 37 analytes (12 after Bonferroni correction) were found to differ between CDR 0 and CDR>0 groups. Receiver-operating characteristic curve analyses revealed that small combinations of a subset of these markers (cystatin C, VEGF, TRAIL-R3, PAI-1, PP, NT-proBNP, MMP-10, MIF, GRO alpha, fibrinogen, FAS, eotaxin-3) enhanced the ability of the best-performing established CSF biomarker, the tau/Abeta42 ratio, to discriminate CDR>0 from CDR 0 individuals. Multiple machine learning algorithms likewise showed that the novel biomarker panels improved the diagnostic performance of the current leading biomarkers. Importantly, most of the markers that best discriminated CDR 0 from CDR>0 individuals in the more targeted ROC analyses were also identified as top predictors in the machine learning models, reconfirming their potential as biomarkers for early-stage AD. Cox proportional hazards models demonstrated that an optimal panel of markers for predicting risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) consisted of calbindin, Abeta42, and age. CONCLUSIONS/SIGNIFICANCE: Using a targeted proteomic screen, we identified novel candidate biomarkers that complement the best current CSF biomarkers for distinguishing very mildly/mildly demented from cognitively normal individuals. Additionally, we identified a novel biomarker (calbindin) with significant prognostic potential. PMID- 21526199 TI - The assembly of individual chaplin peptides from Streptomyces coelicolor into functional amyloid fibrils. AB - The self-association of proteins into amyloid fibrils offers an alternative to the natively folded state of many polypeptides. Although commonly associated with disease, amyloid fibrils represent the natural functional state of some proteins, such as the chaplins from the soil-dwelling bacterium Streptomyces coelicolor, which coat the aerial mycelium and spores rendering them hydrophobic. We have undertaken a biophysical characterisation of the five short chaplin peptides ChpD H to probe the mechanism by which these peptides self-assemble in solution to form fibrils. Each of the five chaplin peptides produced synthetically or isolated from the cell wall is individually surface-active and capable of forming fibrils under a range of solution conditions in vitro. These fibrils contain a highly similar cross-beta core structure and a secondary structure that resembles fibrils formed in vivo on the spore and mycelium surface. They can also restore the growth of aerial hyphae to a chaplin mutant strain. We show that cysteine residues are not required for fibril formation in vitro and propose a role for the cysteine residues conserved in four of the five short chaplin peptides. PMID- 21526198 TI - Differential expressions of adhesive molecules and proteases define mechanisms of ovarian tumor cell matrix penetration/invasion. AB - Epithelial ovarian cancer is an aggressive and deadly disease and understanding its invasion mechanisms is critical for its treatment. We sought to study the penetration/invasion of ovarian tumor cells into extracellular matrices (ECMs) using a fibroblast-derived three-dimensional (3D) culture model and time-lapse and confocal imaging. Twelve ovarian tumor cells were evaluated and classified into distinct groups based on their ECM remodeling phenotypes; those that degraded the ECM (represented by OVCAR5 cells) and those that did not (represented by OVCAR10 cells). Cells exhibiting a distinct ECM modifying behavior were also segregated by epithelial- or mesenchymal-like phenotypes and uPA or MMP-2/MMP-9 expression. The cells, which presented epithelial-like phenotypes, penetrated the ECM using proteases and maintained intact cell-cell interactions, while cells exhibiting mesenchymal phenotypes modified the matrices via Rho-associated serine/threonine kinase (ROCK) in the absence of apparent cell cell interactions. Overall, this study demonstrates that different mechanisms of modifying matrices by ovarian tumor cells may reflect heterogeneity among tumors and emphasize the need to systematically assess these mechanisms to better design effective therapies. PMID- 21526200 TI - The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells. AB - Tumors of the central nervous system represent a major source of cancer-related deaths, with medulloblastoma and glioblastoma being the most common malignant brain tumors in children and adults respectively. While significant advances in treatment have been made, with the 5-year survival rate for medulloblastoma at 70 80%, treating patients under 3 years of age still poses a problem due to the deleterious effects of radiation on the developing brain, and the median survival for patients with glioblastoma is only 15 months. The transcription factor, STAT3, has been found constitutively activated in a wide variety of cancers and in recent years it has become an attractive therapeutic target. We designed a non peptide small molecule STAT3 inhibitor, LLL12, using structure-based design. LLL12 was able to inhibit STAT3 phosphorylation, decrease cell viability and induce apoptosis in medulloblastoma and glioblastoma cell lines with elevated levels of p-STAT3 (Y705). IC(50) values for LLL12 were found to be between 1.07 uM and 5.98 uM in the five cell lines expressing phosphorylated STAT3. STAT3 target genes were found to be downregulated and a decrease in STAT3 DNA binding was observed following LLL12 treatment, indicating that LLL12 is an effective STAT3 inhibitor. LLL12 was also able to inhibit colony formation, wound healing and decreased IL-6 and LIF secretion. Our results suggest that LLL12 is a potent STAT3 inhibitor and that it may be a potential therapeutic treatment for medulloblastoma and glioblastoma. PMID- 21526201 TI - Hepatitis C virus protects human B lymphocytes from Fas-mediated apoptosis via E2 CD81 engagement. AB - HCV infection is often associated with B-cell regulatory control disturbance and delayed appearance of neutralizing antibodies. CD81 is a cellular receptor for HCV and can bind to HCV envelope protein 2 (E2). CD81 also participates to form a B cell costimulatory complex. To investigate whether HCV influences B cell activation and immune function through E2 -CD81 engagement, here, human Burkitt's lymphoma cell line Raji cells and primary human B lymphocytes (PHB) were treated with HCV E2 protein and cell culture produced HCV particles (HCVcc), and then the related cell phenotypes were assayed. The results showed that both E2 and HCVcc triggered phosphorylation of IkappaBalpha, enhanced the expression of anti apoptosis Bcl-2 family proteins, and protected Raji cells and PHB cells from Fas mediated death. In addition, both E2 protein and HCVcc increased the expression of costimulatory molecules CD80, CD86 and CD81 itself, and decreased the expression of complement receptor CD21. The effects were dependent on E2-CD81 interaction on the cell surface, since CD81-silenced Raji cells did not respond to both treatments; and an E2 mutant that lose the CD81 binding activity, could not trigger the responses of both Raji cells and PHB cells. The effects were not associated with HCV replication in cells, for HCV pseudoparticle (HCVpp) and HCVcc failed to infect Raji cells. Hence, E2-CD81 engagement may contribute to HCV-associated B cell lymphoproliferative disorders and insufficient neutralizing antibody production. PMID- 21526202 TI - An unusual splice defect in the mitofusin 2 gene (MFN2) is associated with degenerative axonopathy in Tyrolean Grey cattle. AB - Tyrolean Grey cattle represent a local breed with a population size of ~5000 registered cows. In 2003, a previously unknown neurological disorder was recognized in Tyrolean Grey cattle. The clinical signs of the disorder are similar to those of bovine progressive degenerative myeloencephalopathy (weaver syndrome) in Brown Swiss cattle but occur much earlier in life. The neuropathological investigation of an affected calf showed axonal degeneration in the central nervous system (CNS) and femoral nerve. The pedigrees of the affected calves suggested a monogenic autosomal recessive inheritance. We localized the responsible mutation to a 1.9 Mb interval on chromosome 16 by genome-wide association and haplotype mapping. The MFN2 gene located in this interval encodes mitofusin 2, a mitochondrial membrane protein. A heritable human axonal neuropathy, Charcot-Marie-Tooth disease-2A2 (CMT2A2), is caused by MFN2 mutations. Therefore, we considered MFN2 a positional and functional candidate gene and performed mutation analysis in affected and control Tyrolean Grey cattle. We did not find any non-synonymous variants. However, we identified a perfectly associated silent SNP in the coding region of exon 20 of the MFN2 gene. This SNP is located within a putative exonic splice enhancer (ESE) and the variant allele leads to partial retention of the entire intron 19 and a premature stop codon in the aberrant MFN2 transcript. Thus we have identified a highly unusual splicing defect, where an exonic single base exchange leads to the retention of the preceding intron. This splicing defect represents a potential explanation for the observed degenerative axonopathy. Marker assisted selection can now be used to eliminate degenerative axonopathy from Tyrolean Grey cattle. PMID- 21526203 TI - Fasting and high-fat diet alter histone deacetylase expression in the medial hypothalamus. AB - Increasing attention is now being given to the epigenetic regulation of animal and human behaviors including the stress response and drug addiction. Epigenetic factors also influence feeding behavior and metabolic phenotypes, such as obesity and insulin sensitivity. In response to fasting and high-fat diets, the medial hypothalamus changes the expression of neuropeptides regulating feeding, metabolism, and reproductive behaviors. Histone deacetylases (HDACs) are involved in the epigenetic control of gene expression and alter behavior in response to a variety of environmental factors. Here, we examined the expression of HDAC family members in the medial hypothalamus of mice in response to either fasting or a high-fat diet. In response to fasting, HDAC3 and -4 expression levels increased while HDAC10 and -11 levels decreased. Four weeks on a high-fat diet resulted in the increased expression of HDAC5 and -8. Moreover, fasting decreased the number of acetylated histone H3- and acetylated histone H4-positive cells in the ventrolateral subdivision of the ventromedial hypothalamus. Therefore, HDACs may be implicated in altered gene expression profiles in the medial hypothalamus under different metabolic states. PMID- 21526204 TI - Requirements for membrane attack complex formation and anaphylatoxins binding to collagen-activated platelets. AB - BACKGROUND: The activation of complement during platelet activation is incompletely understood. OBJECTIVES: We sought to explore the formation of C5b-9 and anaphylatoxins binding to collagen-activated platelets. METHODS: C5b-9, anaphylatoxins C3a, C4a and C5a, and anaphylatoxin receptors C3aR1 and C5aR were measured by flow cytometry and/or confocal microscopy. Platelet microparticles were quantified by flow cytometry, and their C5b-9 content was determined by western blot analyses. In all experiments, sodium citrate was used for blood anticoagulation. RESULTS: C5b-9 rapidly formed on the platelet surface following activation with collagen, TRAP, ADP or A23187, but was surprisingly restricted to a subset of platelets (1 to 15%) independently of P-selectin or phosphatidylserine exposure. Following collagen activation, C5b-9-positive platelets in thrombi were found associated with collagen fibres. C5b-9 formation was obliterated by Mg(2+)-EGTA and significantly reduced by the thrombin inhibitor hirudin (-37%, p<0.05), but was unaffected by chondroitinase, compstatin, SCH79797 (PAR-1 inhibitor), or in the PRP of a MBL-deficient donor. Compstatin and Mg(2+)-EGTA, but not hirudin, SCH79797 or chondroitinase, inhibited the formation of collagen-induced microparticles (-71% and -44%, respectively, p<0.04). These microparticles contained greater amounts of C5b-9 compared with the other agonists. Platelet activation by collagen or convulxin resulted in the strong binding of anaphylatoxins and the exposure of receptors C3aR1 and C5aR (CD88) on their surface. CONCLUSIONS: C5b-9 formation on collagen activated platelets is i) partially controlled by thrombin, ii) restricted to a subset of platelets, and iii) can occur without P-selectin expression or phosphatidylserine exposure. Activated platelets bind anaphylatoxins on their surface and express C3a and C5a receptors, which may contribute to the localization of inflammatory processes during thrombosis. PMID- 21526205 TI - Lhx1 is required for specification of the renal progenitor cell field. AB - In the vertebrate embryo, the kidney is derived from the intermediate mesoderm. The LIM-class homeobox transcription factor lhx1 is expressed early in the intermediate mesoderm and is one of the first genes to be expressed in the nephric mesenchyme. In this study, we investigated the role of Lhx1 in specification of the kidney field by either overexpressing or depleting lhx1 in Xenopus embryos or depleting lhx1 in an explant culture system. By overexpressing a constitutively-active form of Lhx1, we established its capacity to expand the kidney field during the specification stage of kidney organogenesis. In addition, the ability of Lhx1 to expand the kidney field diminishes as kidney organogenesis transitions to the morphogenesis stage. In a complimentary set of experiments, we determined that embryos depleted of lhx1, show an almost complete loss of the kidney field. Using an explant culture system to induce kidney tissue, we confirmed that expression of genes from both proximal and distal kidney structures is affected by the absence of lhx1. Taken together our results demonstrate an essential role for Lhx1 in driving specification of the entire kidney field from the intermediate mesoderm. PMID- 21526206 TI - Neural representations of personally familiar and unfamiliar faces in the anterior inferior temporal cortex of monkeys. AB - To investigate the neural representations of faces in primates, particularly in relation to their personal familiarity or unfamiliarity, neuronal activities were chronically recorded from the ventral portion of the anterior inferior temporal cortex (AITv) of macaque monkeys during the performance of a facial identification task using either personally familiar or unfamiliar faces as stimuli. By calculating the correlation coefficients between neuronal responses to the faces for all possible pairs of faces given in the task and then using the coefficients as neuronal population-based similarity measures between the faces in pairs, we analyzed the similarity/dissimilarity relationship between the faces, which were potentially represented by the activities of a population of the face-responsive neurons recorded in the area AITv. The results showed that, for personally familiar faces, different identities were represented by different patterns of activities of the population of AITv neurons irrespective of the view (e.g., front, 90 degrees left, etc.), while different views were not represented independently of their facial identities, which was consistent with our previous report. In the case of personally unfamiliar faces, the faces possessing different identities but presented in the same frontal view were represented as similar, which contrasts with the results for personally familiar faces. These results, taken together, outline the neuronal representations of personally familiar and unfamiliar faces in the AITv neuronal population. PMID- 21526207 TI - Melanoma spheroids grown under neural crest cell conditions are highly plastic migratory/invasive tumor cells endowed with immunomodulator function. AB - BACKGROUND: The aggressiveness of melanoma tumors is likely to rely on their well recognized heterogeneity and plasticity. Melanoma comprises multi-subpopulations of cancer cells some of which may possess stem cell-like properties. Although useful, the sphere-formation assay to identify stem cell-like or tumor initiating cell subpopulations in melanoma has been challenged, and it is unclear if this model can predict a functional phenotype associated with aggressive tumor cells. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the molecular and functional phenotypes of melanoma spheroids formed in neural crest cell medium. Whether from metastatic or advanced primary tumors, spheroid cells expressed melanoma associated markers. They displayed higher capacity to differentiate along mesenchymal lineages and enhanced expression of SOX2, NANOG, KLF4, and/or OCT4 transcription factors, but not enhanced self-renewal or tumorigenicity when compared to their adherent counterparts. Gene expression profiling attributed a neural crest cell signature to these spheroids and indicated that a migratory/invasive and immune-function modulating program could be associated with these cells. In vitro assays confirmed that spheroids display enhanced migratory/invasive capacities. In immune activation assays, spheroid cells elicited a poorer allogenic response from immune cells and inhibited mitogen dependent T cells activation and proliferation more efficiently than their adherent counterparts. Our findings reveal a novel immune-modulator function of melanoma spheroids and suggest specific roles for spheroids in invasion and in evasion of antitumor immunity. CONCLUSION/SIGNIFICANCE: The association of a more plastic, invasive and evasive, thus a more aggressive tumor phenotype with melanoma spheroids reveals a previously unrecognized aspect of tumor cells expanded as spheroid cultures. While of limited efficiency for melanoma initiating cell identification, our melanoma spheroid model predicted aggressive phenotype and suggested that aggressiveness and heterogeneity of melanoma tumors can be supported by subpopulations other than cancer stem cells. Therefore, it could be constructive to investigate melanoma aggressiveness, relevant to patients and clinical transferability. PMID- 21526208 TI - Increased short-term variability of the QT interval in professional soccer players: possible implications for arrhythmia prediction. AB - BACKGROUND: Sudden cardiac death in competitive athletes is rare but it is significantly more frequent than in the normal population. The exact cause is seldom established and is mostly attributed to ventricular fibrillation. Myocardial hypertrophy and slow heart rate, both characteristic changes in top athletes in response to physical conditioning, could be associated with increased propensity for ventricular arrhythmias. We investigated conventional ECG parameters and temporal short-term beat-to-beat variability of repolarization (STV(QT)), a presumptive novel parameter for arrhythmia prediction, in professional soccer players. METHODS: Five-minute 12-lead electrocardiograms were recorded from professional soccer players (n = 76, all males, age 22.0+/-0.61 years) and age-matched healthy volunteers who do not participate in competitive sports (n = 76, all males, age 22.0+/-0.54 years). The ECGs were digitized and evaluated off-line. The temporal instability of beat-to-beat heart rate and repolarization were characterized by the calculation of short-term variability of the RR and QT intervals. RESULTS: Heart rate was significantly lower in professional soccer players at rest (61+/-1.2 vs. 72+/-1.5/min in controls). The QT interval was prolonged in players at rest (419+/-3.1 vs. 390+/-3.6 in controls, p<0.001). QTc was significantly longer in players compared to controls calculated with Fridericia and Hodges correction formulas. Importantly, STV(QT) was significantly higher in players both at rest and immediately after the game compared to controls (4.8+/-0.14 and 4.3+/-0.14 vs. 3.5+/-0.10 ms, both p<0.001, respectively). CONCLUSIONS: STV(QT) is significantly higher in professional soccer players compared to age-matched controls, however, further studies are needed to relate this finding to increased arrhythmia propensity in this population. PMID- 21526209 TI - Association of FMR1 genotypes with in vitro fertilization (IVF) outcomes based on ethnicity/race. AB - The FMR1 gene, mapping to an area of the X chromosome closely associated with autoimmunity also affects ovarian reserve, with specific genotypes associated with distinct ovarian aging patterns. They, therefore, could also be associated with differences of in vitro fertilization (IVF) outcomes, reported between races/ethnicities. We analyzed 339 consecutive IVF patients, 232 Caucasian, 59 African and 48 Asian, for FMR1 genotypes, and tested by multiple logistic regressions for associations between race/ethnicity, FMR1 genotype, autoimmunity and pregnancy chances with IVF. FMR1 genotypes were predictive of pregnancy (P = 0.046), het-norm/low most significantly and with decreasing chance in comparison to norm genotypes (OR 0.44; 95% CI 0.23-0.85; P = 0.014). Race/ethnicity was, overall, independently associated (P = 0.03), African demonstrating decreased odds in comparison to Caucasian (OR 0.33. 95%CI 0.13-0.79; P = 0.014). Autoimmunity did not differ but interaction of autoimmunity with FMR1 genotype almost reached significance (P = 0.07). Logistic regression with race/ethnicity and interaction between FMR1 genotype and autoimmunity in the model, demonstrated 2.5-times the odds of being associated with autoimmune positivity (OR 2.5, 1.34 4.55; P = 0.004). FMR1 genotypes offer a possible explanation for differences in IVF outcomes between races/ethnicities. PMID- 21526210 TI - Adverse events post smallpox-vaccination: insights from tail scarification infection in mice with Vaccinia virus. AB - Adverse events upon smallpox vaccination with fully-replicative strains of Vaccinia virus (VACV) comprise an array of clinical manifestations that occur primarily in immunocompromised patients leading to significant host morbidity/mortality. The expansion of immune-suppressed populations and the possible release of Variola virus as a bioterrorist act have given rise to concerns over vaccination complications should more widespread vaccination be reinitiated. Our goal was to evaluate the components of the host immune system that are sufficient to prevent morbidity/mortality in a murine model of tail scarification, which mimics immunological and clinical features of smallpox vaccination in humans. Infection of C57BL/6 wild-type mice led to a strictly localized infection, with complete viral clearance by day 28 p.i. On the other hand, infection of T and B-cell deficient mice (Rag1(-/-)) produced a severe disease, with uncontrolled viral replication at the inoculation site and dissemination to internal organs. Infection of B-cell deficient animals (uMT) produced no mortality. However, viral clearance in uMT animals was delayed compared to WT animals, with detectable viral titers in tail and internal organs late in infection. Treatment of Rag1(-/-) with rabbit hyperimmune anti-vaccinia serum had a subtle effect on the morbidity/mortality of this strain, but it was effective in reduce viral titers in ovaries. Finally, NUDE athymic mice showed a similar outcome of infection as Rag1(-/-), and passive transfer of WT T cells to Rag1(-/-) animals proved fully effective in preventing morbidity/mortality. These results strongly suggest that both T and B cells are important in the immune response to primary VACV infection in mice, and that T-cells are required to control the infection at the inoculation site and providing help for B-cells to produce antibodies, which help to prevent viral dissemination. These insights might prove helpful to better identify individuals with higher risk of complications after infection with poxvirus. PMID- 21526212 TI - Association between alcohol consumption and cancers in the Chinese population--a systematic review and meta-analysis. AB - BACKGROUND: Alcohol consumption is increasing worldwide and is associated with numerous cancers. This systematic review examined the role of alcohol in the incidence of cancer in the Chinese population. METHODS: Medline/PubMed, EMBASE, CNKI and VIP were searched to identify relevant studies. Cohort and case-control studies on the effect of alcohol use on cancers in Chinese were included. Study quality was evaluated using the Newcastle-Ottawa Scale. Data were independently abstracted by two reviewers. Odds ratios (OR) or relative risks (RR) were pooled using RevMan 5.0. Heterogeneity was evaluated using the Q test and I-squared statistic. P<.01 was considered statistically significant. RESULTS: Pooled results from cohort studies indicated that alcohol consumption was not associated with gastric cancer, esophageal cancers (EC) or lung cancer. Meta-analysis of case-control studies showed that alcohol consumption was a significant risk factor for five cancers; the pooled ORs were 1.79 (99% CI, 1.47-2.17) EC, 1.40 (99% CI, 1.19-1.64) gastric cancer, 1.56 (99% CI, 1.16-2.09) hepatocellular carcinoma, 1.21 (99% CI, 1.00-1.46) nasopharyngeal cancer and 1.71 (99% CI, 1.20 2.44) oral cancer. Pooled ORs of the case-control studies showed that alcohol consumption was protective for female breast cancer and gallbladder cancer: OR 0.76 (99% CI, 0.60-0.97) and 0.70 (99% CI, 0.49-1.00) respectively. There was no significant correlation between alcohol consumption and lung cancer, colorectal cancer, pancreatic cancer, cancer of the ampulla of Vater, prostate cancer or extrahepatic cholangiocarcinoma. Combined results of case-control and cohort studies showed that alcohol consumption was associated with 1.78- and 1.40-fold higher risks of EC and gastric cancer but was not significantly associated with lung cancer. CONCLUSIONS: Health programs focused on limiting alcohol intake may be important for cancer control in China. Further studies are needed to examine the interaction between alcohol consumption and other risk factors for cancers in Chinese and other populations. PMID- 21526213 TI - Genetic markers of obesity risk: stronger associations with body composition in overweight compared to normal-weight children. AB - BACKGROUND: Genetic factors are important determinants of overweight. We examined whether there are differential effect sizes depending on children's body composition. METHODS: We analysed data of n = 4,837 children recorded in the Avon Longitudinal Study of Parents and Children (ALSPAC), applying quantile regression with sex- and age-specific standard deviation scores (SDS) of body mass index (BMI) or with body fat mass index and fat-free mass index at 9 years as outcome variables and an "obesity-risk-allele score" based on eight genetic variants known to be associated with childhood BMI as the explanatory variable. RESULTS: The quantile regression coefficients increased with increasing child's BMI-SDS and fat mass index percentiles, indicating larger effects of the genetic factors at higher percentiles. While the associations with BMI-SDS were of similar size in medium and high BMI quantiles (40th percentile and above), effect sizes with fat mass index increased over the whole fat mass index distribution. For example, the fat mass index of a normal-weight (50th percentile) child was increased by 0.13 kg/m(2) (95% confidence interval (CI): 0.09, 0.16) per additional allele, compared to 0.24 kg/m(2) per allele (95% CI: 0.15, 0.32) in children at the 90th percentile. The genetic associations with fat-free mass index were weaker and the quantile regression effects less pronounced than those on fat mass index. CONCLUSIONS: Genetic risk factors for childhood overweight appear to have greater effects on fatter children. Interaction of known genetic factors with environmental or unknown genetic factors might provide a potential explanation of these findings. PMID- 21526214 TI - Rosmarinic acid, active component of Dansam-Eum attenuates ototoxicity of cochlear hair cells through blockage of caspase-1 activity. AB - Cisplatin causes auditory impairment due to the apoptosis of auditory hair cells. There is no strategy to regulate ototoxicity by cisplatin thus far. Dansam-Eum (DSE) has been used for treating the central nerve system injury including hearing loss in Korea. However, disease-related scientific investigation by DSE has not been elucidated. Here, we demonstrated that DSE and its component rosmarinic acid (RA) were shown to inhibit apoptosis of the primary organ of Corti explants as well as the auditory cells. Administration of DSE and RA reduced the thresholds of the auditory brainstem response in cisplatin-injected mice. A molecular docking simulation and a kinetic assay show that RA controls the activity of caspase-1 by interaction with the active site of caspase-1. Pretreatment of RA inhibited caspase-1 downstream signal pathway, such as the activation of caspase-3 and 9, release of cytochrome c, translocation of apoptosis-inducing factor, up-regulation of Bax, down-regulation of Bcl-2, generation of reactive oxygen species, and activation of nuclear factor-kappaB. Anticancer activity by cisplatin was not affected by treatment with RA in SNU668, A549, HCT116, and HeLa cells but not B16F10 cells. These findings show that blocking a critical step by RA in apoptosis may be useful strategy to prevent harmful side effects of ototoxicity in patients with having to undergo chemotherapy. PMID- 21526215 TI - Increased inflammatory signaling and lethality of influenza H1N1 by nuclear thioredoxin-1. AB - BACKGROUND: Cell culture studies show that the antioxidant thiol protein, thioredoxin-1 (Trx1), translocates to cell nuclei during stress, facilitates DNA binding of transcription factors NF-kappaB and glucocorticoid receptor (GR) and potentiates signaling in immune cells. Excessive proinflammatory signaling in vivo contributes to immune hyper-responsiveness and disease severity, but no studies have addressed whether nuclear Trx1 mediates such responses. METHODOLOGY/PRINCIPAL FINDINGS: Transgenic mice (Tg) expressing human Trx1 (hTrx1) with added nuclear localization signal (NLS) showed broad tissue expression and nuclear localization. The role of nuclear Trx1 in inflammatory signaling was examined in Tg and wild-type (WT) mice following infection with influenza (H1N1) virus. Results showed that Tg mice had earlier and more extensive NF-kappaB activation, increased TNF-alpha and IL-6 expression, greater weight loss, slower recovery and increased mortality compared to WT. Decreased plasma glutathione (GSH) and oxidized plasma GSH/GSSG redox potential (E(h)GSSG) following infection in Tg mice showed that the increased nuclear thiol antioxidant caused a paradoxical downstream oxidative stress. An independent test of this nuclear reductive stress showed that glucocorticoid-induced thymocyte apoptosis was increased by NLS-Trx1. CONCLUSION/SIGNIFICANCE: Increased Trx1 in cell nuclei can increase severity of disease responses by potentiation of redox sensitive transcription factor activation. PMID- 21526211 TI - Barcoding bugs: DNA-based identification of the true bugs (Insecta: Hemiptera: Heteroptera). AB - BACKGROUND: DNA barcoding, the analysis of sequence variation in the 5' region of the mitochondrial cytochrome c oxidase I (COI) gene, has been shown to provide an efficient method for the identification of species in a wide range of animal taxa. In order to assess the effectiveness of barcodes in the discrimination of Heteroptera, we examined 344 species belonging to 178 genera, drawn from specimens in the Canadian National Collection of Insects. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of the COI gene revealed less than 2% intra-specific divergence in 90% of the taxa examined, while minimum interspecific distances exceeded 3% in 77% of congeneric species pairs. Instances where barcodes fail to distinguish species represented clusters of morphologically similar species, except one case of barcode identity between species in different genera. Several instances of deep intraspecific divergence were detected suggesting possible cryptic species. CONCLUSIONS/SIGNIFICANCE: Although this analysis encompasses 0.8% of the described global fauna, our results indicate that DNA barcodes will aid the identification of Heteroptera. This advance will be useful in pest management, regulatory and environmental applications and will also reveal species that require further taxonomic research. PMID- 21526216 TI - Solution structure of a repeated unit of the ABA-1 nematode polyprotein allergen of Ascaris reveals a novel fold and two discrete lipid-binding sites. AB - BACKGROUND: Nematode polyprotein allergens (NPAs) are an unusual class of lipid binding proteins found only in nematodes. They are synthesized as large, tandemly repetitive polyproteins that are post-translationally cleaved into multiple copies of small lipid binding proteins with virtually identical fatty acid and retinol (Vitamin A)-binding characteristics. They are probably central to transport and distribution of small hydrophobic compounds between the tissues of nematodes, and may play key roles in nutrient scavenging, immunomodulation, and IgE antibody-based responses in infection. In some species the repeating units are diverse in amino acid sequence, but, in ascarid and filarial nematodes, many of the units are identical or near-identical. ABA-1A is the most common repeating unit of the NPA of Ascaris suum, and is closely similar to that of Ascaris lumbricoides, the large intestinal roundworm of humans. Immune responses to NPAs have been associated with naturally-acquired resistance to infection in humans, and the immune repertoire to them is under strict genetic control. METHODOLOGY/PRINCIPAL FINDINGS: The solution structure of ABA-1A was determined by protein nuclear magnetic resonance spectroscopy. The protein adopts a novel seven-helical fold comprising a long central helix that participates in two hollow four-helical bundles on either side. Discrete hydrophobic ligand-binding pockets are found in the N-terminal and C-terminal bundles, and the amino acid sidechains affected by ligand (fatty acid) binding were identified. Recombinant ABA-1A contains tightly-bound ligand(s) of bacterial culture origin in one of its binding sites. CONCLUSIONS/SIGNIFICANCE: This is the first mature, post translationally processed, unit of a naturally-occurring tandemly-repetitive polyprotein to be structurally characterized from any source, and it belongs to a new structural class. NPAs have no counterparts in vertebrates, so represent potential targets for drug or immunological intervention. The nature of the (as yet) unidentified bacterial ligand(s) may be pertinent to this, as will our characterization of the unusual binding sites. PMID- 21526217 TI - Isolation of Trypanosoma brucei gambiense from cured and relapsed sleeping sickness patients and adaptation to laboratory mice. AB - BACKGROUND: Sleeping sickness due to Trypanosoma brucei (T.b.) gambiense is still a major public health problem in some central African countries. Historically, relapse rates around 5% have been observed for treatment with melarsoprol, widely used to treat second stage patients. Later, relapse rates of up to 50% have been recorded in some isolated foci in Angola, Sudan, Uganda and Democratic Republic of the Congo (DRC). Previous investigations are not conclusive on whether decreased sensitivity to melarsoprol is responsible for these high relapse rates. Therefore we aimed to establish a parasite collection isolated from cured as well as from relapsed patients for downstream comparative drug sensitivity profiling. A major constraint for this type of investigation is that T.b. gambiense is particularly difficult to isolate and adapt to classical laboratory rodents. METHODOLOGY/PRINCIPAL FINDINGS: From 360 patients treated in Dipumba hospital, Mbuji-Mayi, D.R. Congo, blood and cerebrospinal fluid (CSF) was collected before treatment. From patients relapsing during the 24 months follow-up, the same specimens were collected. Specimens with confirmed parasite presence were frozen in liquid nitrogen in a mixture of Triladyl, egg yolk and phosphate buffered glucose solution. Isolation was achieved by inoculation of the cryopreserved specimens in Grammomys surdaster, Mastomys natalensis and SCID mice. Thus, 85 strains were isolated from blood and CSF of 55 patients. Isolation success was highest in Grammomys surdaster. Forty strains were adapted to mice. From 12 patients, matched strains were isolated before treatment and after relapse. All strains belong to T.b. gambiense type I. CONCLUSIONS AND SIGNIFICANCE: We established a unique collection of T.b. gambiense from cured and relapsed patients, isolated in the same disease focus and within a limited period. This collection is available for genotypic and phenotypic characterisation to investigate the mechanism behind abnormally high treatment failure rates in Mbuji Mayi, D.R. Congo. PMID- 21526219 TI - Interferon-gamma release assay (modified QuantiFERON) as a potential marker of infection for Leishmania donovani, a proof of concept study. AB - BACKGROUND: In areas endemic for visceral leishmaniasis (VL), a large number of infected individuals mount a protective cellular immune response and remain asymptomatic carriers. We propose an interferon-gamma release assay (IFN-gammaRA) as a novel marker for latent L. donovani infection. METHODS AND FINDINGS: We modified a commercial kit (QuantiFERON) evaluating five different leishmania specific antigens; H2B, H2B-PSA2, H2B-Lepp12, crude soluble antigen (CSA) and soluble leishmania antigen (SLA) from L. donovani with the aim to detect the cell mediated immune response in VL. We evaluated the assay on venous blood samples of active VL patients (n = 13), cured VL patients (n = 15), non-endemic healthy controls (n = 11) and healthy endemic controls (n = 19). The assay based on SLA had a sensitivity of 80% (95% CI = 54.81-92.95) and specificity of 100% (95% CI = 74.12-100). CONCLUSION: Our findings suggest that a whole-blood SLA-based QuantiFERON assay can be used to measure the cell-mediated immune response in L. donovani infection. The positive IFN-gamma response to stimulation with leishmania antigen in patients with active VL was contradictory to the conventional finding of a non-proliferative antigen-specific response of peripheral blood mononuclear cells and needs further research. PMID- 21526218 TI - The Rose Bengal Test in human brucellosis: a neglected test for the diagnosis of a neglected disease. AB - Brucellosis is a highly contagious zoonosis affecting livestock and human beings. The human disease lacks pathognomonic symptoms and laboratory tests are essential for its diagnosis. However, most tests are difficult to implement in the areas and countries were brucellosis is endemic. Here, we compared the simple and cheap Rose Bengal Test (RBT) with serum agglutination, Coombs, competitive ELISA, Brucellacapt, lateral flow immunochromatography for IgM and IgG detection and immunoprecipitation with Brucella proteins. We tested 208 sera from patients with brucellosis proved by bacteriological isolation, 20 contacts with no brucellosis, and 1559 sera of persons with no recent contact or brucellosis symptoms. RBT was highly sensitive in acute and long evolution brucellosis cases and this related to its ability to detect IgM, IgG and IgA, to the absence of prozones, and to the agglutinating activity of blocking IgA at the pH of the test. RBT was also highly specific in the sera of persons with no contact with Brucella. No test in this study outperformed RBT, and none was fully satisfactory in distinguishing contacts from infected patients. When modified to test serum dilutions, a diagnostic titer >4 in RBT resulted in 87.4% sensitivity (infected patients) and 100% specificity (contacts). We discuss the limitations of serological tests in the diagnosis of human brucellosis, particularly in the more chronic forms, and conclude that simplicity and affordability of RBT make it close to the ideal test for small and understaffed hospitals and laboratories. PMID- 21526220 TI - Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. AB - Mitochondrial shape is determined by fission and fusion reactions catalyzed by large GTPases of the dynamin family, mutation of which can cause neurological dysfunction. While fission-inducing protein phosphatases have been identified, the identity of opposing kinase signaling complexes has remained elusive. We report here that in both neurons and non-neuronal cells, cAMP elevation and expression of an outer-mitochondrial membrane (OMM) targeted form of the protein kinase A (PKA) catalytic subunit reshapes mitochondria into an interconnected network. Conversely, OMM-targeting of the PKA inhibitor PKI promotes mitochondrial fragmentation upstream of neuronal death. RNAi and overexpression approaches identify mitochondria-localized A kinase anchoring protein 1 (AKAP1) as a neuroprotective and mitochondria-stabilizing factor in vitro and in vivo. According to epistasis studies with phosphorylation site-mutant dynamin-related protein 1 (Drp1), inhibition of the mitochondrial fission enzyme through a conserved PKA site is the principal mechanism by which cAMP and PKA/AKAP1 promote both mitochondrial elongation and neuronal survival. Phenocopied by a mutation that slows GTP hydrolysis, Drp1 phosphorylation inhibits the disassembly step of its catalytic cycle, accumulating large, slowly recycling Drp1 oligomers at the OMM. Unopposed fusion then promotes formation of a mitochondrial reticulum, which protects neurons from diverse insults. PMID- 21526221 TI - A cytoplasmic complex mediates specific mRNA recognition and localization in yeast. AB - In eukaryotes, hundreds of mRNAs are localized by specialized transport complexes. For localization, transcripts are recognized by RNA-binding proteins and incorporated into motor-containing messenger ribonucleoprotein particles (mRNPs). To date, the molecular assembly of such mRNPs is not well understood and most details on cargo specificity remain unresolved. We used ASH1-mRNA transport in yeast to provide a first assessment of where and how localizing mRNAs are specifically recognized and incorporated into mRNPs. By using in vitro interaction and reconstitution assays, we found that none of the implicated mRNA binding proteins showed highly specific cargo binding. Instead, we identified the cytoplasmic myosin adapter She3p as additional RNA-binding protein. We further found that only the complex of the RNA-binding proteins She2p and She3p achieves synergistic cargo binding, with an at least 60-fold higher affinity for localizing mRNAs when compared to control RNA. Mutational studies identified a C terminal RNA-binding fragment of She3p to be important for synergistic RNA binding with She2p. The observed cargo specificity of the ternary complex is considerably higher than previously reported for localizing mRNAs. It suggests that RNA binding for mRNP localization generally exhibits higher selectivity than inferred from previous in vitro data. This conclusion is fully consistent with a large body of in vivo evidence from different organisms. Since the ternary yeast complex only assembles in the cytoplasm, specific mRNA recognition might be limited to the very last steps of mRNP assembly. Remarkably, the mRNA itself triggers the assembly of mature, motor-containing complexes. Our reconstitution of a major portion of the mRNA-transport complex offers new and unexpected insights into the molecular assembly of specific, localization-competent mRNPs and provides an important step forward in our mechanistic understanding of mRNA localization in general. PMID- 21526223 TI - The 2010 gulf of Mexico oil well blowout: a little hindsight. PMID- 21526225 TI - A two-step process gets mRNA loaded and ready to go. PMID- 21526224 TI - Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells. AB - Hair cells of the mammalian cochlea are specialized for the dynamic coding of sound stimuli. The transduction of sound waves into electrical signals depends upon mechanosensitive hair bundles that project from the cell's apical surface. Each stereocilium within a hair bundle is composed of uniformly polarized and tightly packed actin filaments. Several stereociliary proteins have been shown to be associated with hair bundle development and function and are known to cause deafness in mice and humans when mutated. The growth of the stereociliar actin core is dynamically regulated at the actin filament barbed ends in the stereociliary tip. We show that Eps8, a protein with actin binding, bundling, and barbed-end capping activities in other systems, is a novel component of the hair bundle. Eps8 is localized predominantly at the tip of the stereocilia and is essential for their normal elongation and function. Moreover, we have found that Eps8 knockout mice are profoundly deaf and that IHCs, but not OHCs, fail to mature into fully functional sensory receptors. We propose that Eps8 directly regulates stereocilia growth in hair cells and also plays a crucial role in the physiological maturation of mammalian cochlear IHCs. Together, our results indicate that Eps8 is critical in coordinating the development and functionality of mammalian auditory hair cells. PMID- 21526226 TI - Nematodes: the worm and its relatives. PMID- 21526227 TI - A call for action: the application of The International Health Regulations to the global threat of antimicrobial resistance. PMID- 21526228 TI - Decline in diarrhea mortality and admissions after routine childhood rotavirus immunization in Brazil: a time-series analysis. AB - BACKGROUND: In 2006, Brazil began routine immunization of infants <15 wk of age with a single-strain rotavirus vaccine. We evaluated whether the rotavirus vaccination program was associated with declines in childhood diarrhea deaths and hospital admissions by monitoring disease trends before and after vaccine introduction in all five regions of Brazil with varying disease burden and distinct socioeconomic and health indicators. METHODS AND FINDINGS: National data were analyzed with an interrupted time-series analysis that used diarrhea-related mortality or hospitalization rates as the main outcomes. Monthly mortality and admission rates estimated for the years after rotavirus vaccination (2007-2009) were compared with expected rates calculated from pre-vaccine years (2002-2005), adjusting for secular and seasonal trends. During the three years following rotavirus vaccination in Brazil, rates for diarrhea-related mortality and admissions among children <5 y of age were 22% (95% confidence interval 6%-44%) and 17% (95% confidence interval 5%-27%) lower than expected, respectively. A cumulative total of ~1,500 fewer diarrhea deaths and 130,000 fewer admissions were observed among children <5 y during the three years after rotavirus vaccination. The largest reductions in deaths (22%-28%) and admissions (21%-25%) were among children younger than 2 y, who had the highest rates of vaccination. In contrast, lower reductions in deaths (4%) and admissions (7%) were noted among children two years of age and older, who were not age-eligible for vaccination during the study period. CONCLUSIONS: After the introduction of rotavirus vaccination for infants, significant declines for three full years were observed in under-5-y diarrhea-related mortality and hospital admissions for diarrhea in Brazil. The largest reductions in diarrhea-related mortality and hospital admissions for diarrhea were among children younger than 2 y, who were eligible for vaccination as infants, which suggests that the reduced diarrhea burden in this age group was associated with introduction of the rotavirus vaccine. These real-world data are consistent with evidence obtained from clinical trials and strengthen the evidence base for the introduction of rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea. PMID- 21526229 TI - Effect of a nutrition supplement and physical activity program on pneumonia and walking capacity in Chilean older people: a factorial cluster randomized trial. AB - BACKGROUND: Ageing is associated with increased risk of poor health and functional decline. Uncertainties about the health-related benefits of nutrition and physical activity for older people have precluded their widespread implementation. We investigated the effectiveness and cost-effectiveness of a national nutritional supplementation program and/or a physical activity intervention among older people in Chile. METHODS AND FINDINGS: We conducted a cluster randomized factorial trial among low to middle socioeconomic status adults aged 65-67.9 years living in Santiago, Chile. We randomized 28 clusters (health centers) into the study and recruited 2,799 individuals in 2005 (~100 per cluster). The interventions were a daily micronutrient-rich nutritional supplement, or two 1-hour physical activity classes per week, or both interventions, or neither, for 24 months. The primary outcomes, assessed blind to allocation, were incidence of pneumonia over 24 months, and physical function assessed by walking capacity 24 months after enrollment. Adherence was good for the nutritional supplement (~75%), and moderate for the physical activity intervention (~43%). Over 24 months the incidence rate of pneumonia did not differ between intervention and control clusters (32.5 versus 32.6 per 1,000 person years respectively; risk ratio = 1.00; 95% confidence interval 0.61-1.63; p = 0.99). In intention-to-treat analysis, after 24 months there was a significant difference in walking capacity between the intervention and control clusters (mean difference 33.8 meters; 95% confidence interval 13.9-53.8; p = 0.001). The overall cost of the physical activity intervention over 24 months was US$164/participant; equivalent to US$4.84/extra meter walked. The number of falls and fractures was balanced across physical activity intervention arms and no serious adverse events were reported for either intervention. CONCLUSIONS: Chile's nutritional supplementation program for older people is not effective in reducing the incidence of pneumonia. This trial suggests that the provision of locally accessible physical activity classes in a transition economy population can be a cost-effective means of enhancing physical function in later life. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 48153354. PMID- 21526230 TI - Non-esterified fatty acids generate distinct low-molecular weight amyloid-beta (Abeta42) oligomers along pathway different from fibril formation. AB - Amyloid-beta (Abeta) peptide aggregation is known to play a central role in the etiology of Alzheimer's disease (AD). Among various aggregates, low-molecular weight soluble oligomers of Abeta are increasingly believed to be the primary neurotoxic agents responsible for memory impairment. Anionic interfaces are known to influence the Abeta aggregation process significantly. Here, we report the effects of interfaces formed by medium-chain (C9-C12), saturated non-esterified fatty acids (NEFAs) on Abeta42 aggregation. NEFAs uniquely affected Abeta42 aggregation rates that depended on both the ratio of Abeta:NEFA as well the critical micelle concentration (CMC) of the NEFAs. More importantly, irrespective of the kind of NEFA used, we observed that two distinct oligomers, 12-18 mers and 4-5 mers were formed via different pathway of aggregation under specific experimental conditions: (i) 12-18 mers were generated near the CMC in which NEFAs augment the rate of Abeta42 aggregation towards fibril formation, and, (ii) 4-5 mers were formed above the CMC, where NEFAs inhibit fibril formation. The data indicated that both 12-18 mers and 4-5 mers are formed along an alternate pathway called 'off-pathway' that did not result in fibril formation and yet have subtle structural and morphological differences that distinguish their bulk molecular behavior. These observations, (i) reflect the possible mechanism of Abeta aggregation in physiological lipid-rich environments, and (ii) reiterate the fact that all oligomeric forms of Abeta need not be obligatory intermediates of the fibril formation pathway. PMID- 21526231 TI - Chemical defense by the native winter ant (Prenolepis imparis) against the invasive Argentine ant (Linepithema humile). AB - The invasive Argentine ant (Linepithema humile) is established worldwide and displaces native ant species. In northern California, however, the native winter ant (Prenolepis imparis) persists in invaded areas. We found that in aggressive interactions between the two species, P. imparis employs a potent defensive secretion. Field observations were conducted at P. imparis nest sites both in the presence and absence of L. humile. These observations suggested and laboratory assays confirmed that P. imparis workers are more likely to secrete when outnumbered by L. humile. Workers of P. imparis were also more likely to secrete near their nest entrances than when foraging on trees. One-on-one laboratory trials showed that the P. imparis secretion is highly lethal to L. humile, causing 79% mortality. The nonpolar fraction of the secretion was chemically analyzed with gas chromatography/mass spectrometry, and found to be composed of long-chain and cyclic hydrocarbons. Chemical analysis of dissected P. imparis workers showed that the nonpolar fraction is derived from the Dufour's gland. Based on these conclusions, we hypothesize that this chemical defense may help P. imparis to resist displacement by L. humile. PMID- 21526222 TI - A user's guide to the encyclopedia of DNA elements (ENCODE). AB - The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome. PMID- 21526233 TI - Capillary Stokes drift: a new driving mechanism for mixing in AC-electrowetting. AB - We studied the flow fields generated inside sessile drops that oscillate periodically between states of high and low contact angle under the influence of alternating electric fields of variable frequency and amplitude. Following the motion of dye patches, we show that the number of oscillation cycles required to achieve mixing scales logarithmically with the Peclet number as expected for chaotic mixing. High speed movies reveal an asymmetry of the drop shape between the spreading and receding phase of the oscillations. This results in net internal flow fields that we characterize by tracing the motion of colloidal seed particles. The strength and frequency dependence of the flow are explained in terms of Stokes drift driven by capillary waves that emanate from the oscillating contact line. PMID- 21526232 TI - Multiscale modeling of biological functions. AB - Recent years have witnessed a tremendous explosion in computational power, which in turn has resulted in great progress in the complexity of the biological and chemical problems that can be addressed by means of all-atom simulations. Despite this, however, our computational time is not infinite, and in fact many of the key problems of the field were resolved long before the existence of the current levels of computational power. This review will start by presenting a brief historical overview of the use of multiscale simulations in biology, and then present some key developments in the field, highlighting several cases where the use of a physically sound simplification is clearly superior to a brute-force approach. Finally, some potential future directions will be discussed. PMID- 21526234 TI - Okadaic acid induces morphological changes, apoptosis and cell cycle alterations in different human cell types. AB - Okadaic acid (OA) is a marine toxin produced by dinoflagellate species which is frequently accumulated in molluscs usual in the human diet. The exact action mechanism of OA has not been described yet and the results of most reported studies are often conflicting. The aim of this work was to evaluate the OA effects on morphology, cell cycle and apoptosis induction by means of light microscopy and flow cytometry, in three different types of human cells (leukocytes, HepG2 cells and SHSY5Y cells). Cells were treated with a range of OA concentrations in the presence and absence of S9 fraction. OA induced morphological changes in all the cell types studied, and cell cycle disruption only in leukocytes and neuronal cells. SHSY5Y cells were the most sensitive to OA assault. Results obtained in the presence and absence of metabolic activation were similar, suggesting that OA acts both directly and indirectly. Furthermore, OA was found to increase the subG(1) region in the flow cytometry cell cycle analysis, suggesting induction of apoptosis. These results were confirmed by the employment of specific methodologies for studying apoptosis such as caspase 3 activation and annexin V staining. Increases in the apoptosis rate were obtained in all the cells treated in the absence of S9 fraction, accompanied by increases in caspase 3 activation, suggesting that apoptosis induced by OA is a caspase 3 dependent process. Nevertheless, in the presence of S9 fraction no apoptosis was detected, indicating a metabolic detoxifying activity, although necrosis was observed in neuroblastoma cells. PMID- 21526235 TI - DNA-based logic gates operating as a biomolecular security device. AB - The first example of a nucleic acid-based molecular keypad lock has been constructed by taking advantage of the sequence-specific recognition ability of DNA and solid-phase substrates. PMID- 21526236 TI - Persistence time of charge carriers in defect states of molecular semiconductors. AB - Charge carriers in organic crystals are often trapped in point defects. The persistence time of the charge in these defect states is evaluated by computing the escape rate from this state using non-adiabatic rate theory. Two cases are considered (i) the hopping between separate identical defect states and (ii) the hopping between a defect state and the bulk (delocalized) states. We show that only the second process is likely to happen with realistic defect concentrations and highlight that the inclusion of an effective quantum mode of vibration is essential for accurate computation of the rate. The computed persistence time as a function of the trap energy indicates that trap states shallower than ~0.3 eV cannot be effectively investigated with some slow spectroscopic techniques such as THz spectroscopy or EPR commonly used to study the nature of excess charge in semiconductors. PMID- 21526237 TI - Diversity-driven chemical probe development for biomolecules: beyond hypothesis driven approach. AB - Bioprobes are indispensable tools for biological study and clinical diagnosis. A conventional strategy for probe development is hypothesis-driven approach based on known molecular mechanisms of recognition for individual analytes. However, even the most sophisticated rational design does not always guarantee the applicability of probes in complex biological systems, therefore the efficiency and scope of probe development has been intrinsically limited. Diversity-driven approach is a rapidly emerging alternative and has been employed for the development of new probes even in the absence of the knowledge about target recognition mechanism. This tutorial review summarizes the recent advances in probe development along with conceptual advantages and perspectives of the diversity-driven approach. PMID- 21526238 TI - A microfluidic-assisted microarray for ultrasensitive detection of miRNA under an optical microscope. AB - In this article, we report on direct detection of microRNAs (miRNAs) on a microarray by differential interference contrast (DIC) imaging technique. While the best resolution achieved with a fluorescence scanner is ~1 MUm, the DIC imaging technique adopted in our study offers the possibility of imaging individual reporting gold nanoparticles, or, in other words, individual miRNA strands. Due to its unrivalled resolution, the present technique could detect as low as 300 copies of target miRNAs in a sample volume of 1.0 MUl. With the greatly improved sensitivity, the amount of total RNA needed in the assay is reduced to only a few nanograms, offering an excellent opportunity for fast and direct miRNA profiling without engaging any labeling and amplification procedure. Expression patterns of hsa-let-7 family members in healthy versus cancer cells analyzed on our microarray, are found to be consistent with the patterns obtained on a commercial microarray and those reported in the literature. PMID- 21526247 TI - Characterisation of chondrogenic differentiation of human mesenchymal stem cells using synchrotron FTIR microspectroscopy. AB - A major limiting factor in stem cell therapy is the accurate identification of the differentiation state of cells destined for transplantation. This study aimed to evaluate the potential of synchrotron radiation Fourier transform infrared (SR FTIR) microspectroscopy as a novel technique to probe the differentiation state of human mesenchymal stem cells (hMSCs) to chondrocytes over a period of 7, 14 and 21 days of induction. The chondrogenic markers were determined using reverse transcription polymerase chain reaction, histology and immunohistochemistry. The changes of average spectra located near 1338-1230 and 1175-960 cm(-1) indicated increased levels of collagen and aggrecan, respectively, in chondrocyte-induced hMSCs compared with control cells. Classification of independent test spectra using partial least squares discriminant analysis (PLS-DA) could distinguish control and chondrocyte-induced cells with 100% accuracy. We conclude that the SR FTIR microspectroscopy technique is sensitive for monitoring the differentiation state of stem cells under chondrogenic induction particularly at an early stage. It provides biochemical information that is complimentary to that obtained from conventional techniques, and may give more unambiguous results particularly at the very early stage of cellular differentiation. In addition, the spectroscopic approach is more straightforward, non-destructive and requires less sample preparation compared with the conventional methodologies. PMID- 21526248 TI - Functionalization of luminescent cyclometalated iridium(III) polypyridine complexes with a fluorous moiety: photophysics, protein-binding, bioconjugation, and cellular uptake properties. AB - A new class of luminescent cyclometalated iridium(III) polypyridine fluorous complexes has been designed; the fluorous pendant not only plays an important role in the photophysical and biological properties of the complexes, but also allows the facile isolation of biomolecules labeled with these complexes with fluorous solid-phase extraction (FSPE). PMID- 21526249 TI - Enantiopure chiral coordination polymers of tetrahedral and octahedral cobalt(II) alternate chains exhibiting slow magnetic relaxation behavior. AB - The first two chiral homometallic coordination frameworks with homochiral helical [Co(Oct)O(Trp)Co(Td)O(Trp)](n) ferrimagnetic chains, exhibiting a unique coexistence of chirality and slow magnetic relaxation in one material, are reported. PMID- 21526250 TI - A specific chemodosimeter for fluoride ion based on a pyrene derivative with trimethylsilylethynyl groups. AB - Pyrene derivative 1 containing four trimethylsilylethynyl substituents was synthesized and investigated as a chromogenic and fluorescent chemodosimeter sensor for fluoride ions. 1 showed a high sensitivity and specific selectivity over a rapid response time toward fluoride anions compared to other anions, such as Cl(-), Br(-), ClO(4)(-), H(2)PO(4)(-) and HPO(4)(2-). TD-DFT calculations showed that the delocalization of the sigma-electrons of the silicon destabilized the HOMO energy level of 1, thus red shifting both its absorption and emission spectrum. The addition of F(-) removed the trimethylsilyl substituents and resulted in a blue shift of both the absorption and fluorescent spectra of 1, which could be monitored by the color change with the naked-eye. Moreover, an easy to prepare test paper, which was obtained by immersing a filter paper into a THF solution of 1, could be utilized to detect and estimate the concentration of fluoride anions in water. PMID- 21526251 TI - Non-classical diffusion in ionic liquids. AB - In this study the diffusion coefficient of neutral and cationic ferrocenyl derivatives have been characterised in a range of 1-alkyl-3-methylimidazolium ionic liquids of the general form [C(n)C(1)Im](+)[X](-). The electrochemistry of ferrocene, 1-ferrocenylmethylimidazole (FcC(1)Im), 1-ferrocenylmethylimidazolium bis(trifluoromethanesulfonyl)imide ([FcC(1)C(1)Im][Tf(2)N]) and N,N,N,N trimethylferrocenyl-methylammonium bis(trifluoromethanesulfonyl)imide ([FcC(1)NMe(3)][Tf(2)N]), in 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([C(2)C(1)Im][Tf(2)N]) was investigated. It was shown that the diffusion coefficients of each were not significantly affected by the presence and location of a positive charge on the ferrocenyl-derivative, suggesting that coulombic solvent-solute interactions did not hinder motion of these species in ionic liquids. The diffusion coefficients for [FcC(1)C(1)Im][Tf(2)N] in five [C(n)C(1)Im][X] ionic liquids were determined as a function of temperature and the data shown to disobey the Stokes-Einstein equation. This observation is consistent with the fact that ionic liquids are glass formers, systems in which non-Stokesian behaviour is well documented. Measured diffusion coefficient data was used to determine correlation length in the ionic liquid and was found to correlate with the average size of holes, or voids, within the ionic liquid. This interpretation suggests that a model by which a migrating species can jump between voids or holes within the liquid is highly appropriate and is consistent with the observed behaviour measured across a range of temperatures. PMID- 21526252 TI - On the diffusion of ferrocenemethanol in room-temperature ionic liquids: an electrochemical study. AB - The electrochemical behaviour of ferrocenemethanol (FcMeOH) has been studied in a range of room-temperature ionic liquids (RTILs) using cyclic voltammetry, chronoamperomery and scanning electrochemical microscopy (SECM). The diffusion coefficient of FcMeOH, measured using chronoamperometry, decreased with increasing RTIL viscosity. Analysis of the mass transport properties of the RTILs revealed that the Stokes-Einstein equation did not apply to our data. The "correlation length" was estimated from diffusion coefficient data and corresponded well to the average size of holes (voids) in the liquid, suggesting that a model in which the diffusing species jumps between holes in the liquid is appropriate in these liquids. Cyclic voltammetry at ultramicroelectrodes demonstrated that the ability to record steady-state voltammograms during ferrocenemethanol oxidation depended on the voltammetric scan rate, the electrode dimensions and the RTIL viscosity. Similarly, the ability to record steady-state SECM feedback approach curves depended on the RTIL viscosity, the SECM tip radius and the tip approach speed. Using 1.3 MUm Pt SECM tips, steady-state SECM feedback approach curves were obtained in RTILs, provided that the tip approach speed was low enough to maintain steady-state diffusion at the SECM tip. In the case where tip-induced convection contributed significantly to the SECM tip current, this effect could be accounted for theoretically using mass transport equations that include diffusive and convective terms. Finally, the rate of heterogeneous electron transfer across the electrode/RTIL interface during ferrocenemethanol oxidation was estimated using SECM, and k(0) was at least 0.1 cm s(-1) in one of the least viscous RTILs studied. PMID- 21526253 TI - Polyoxometalate-templated lanthanide-organic hybrid layers based on 6(3) honeycomb-like 2D nets. AB - The reaction of a double-betaine-containing ligand with LnPMo(12)O(40).nH(2)O (Ln = Dy, Tb and Er) led to the isolation of new polyoxometalate-templated lanthanide organic hybrid layers with the molecular formula [Ln(L)(1.5)(H(2)O)(5)][PMo(12)O(40)].1.5CH(3)CN.2H(2)O (Ln = Dy (1), Tb (2) and Er (3); L = 1,4-bis(pyridinil-4-carboxylato)-l,4-dimethylbenzene). All compounds were characterized by elemental analyses, TG analyses, IR and the single-crystal X-ray diffraction. Compounds 1-3 are isostructural and possess a 2D undulating cationic network [Ln(L)(1.5)(H(2)O)(5)](n)(3n+) with the honeycomb-like cavities. Interestingly, the interval 2D networks are further connected by the H-bonds to form a 3D supramolecular framework. Moreover, two of such identical supramolecular frameworks are 2-fold interpenetrated with each other and encapsulate the alpha-Keggin-type [PMo(12)O(40)](3-) anionic templates and the solvent molecules. These composite compounds display both luminescent properties (induced by organic ligands and/or lanthanide ions) and electrocatalytic activities towards the reduction of nitrite. PMID- 21526254 TI - Cascade polycyclisations in natural product synthesis. AB - The efficient, stereocontrolled construction of polycyclic ring systems has long presented a formidable challenge to synthetic chemists. Cascade reactions offer a 'quick fix'--building multiple rings in a single step--and often dramatically shorten a synthetic route. In this Emerging Area article, a selection of the most recent and impressive examples of applications of this tactic to natural product synthesis are discussed, which demonstrate the ambition and achievements of the modern synthetic chemist. PMID- 21526255 TI - Synthesis of novel N-hydroxy heterocycles via intramolecular reductive cyclization of diketoximes by NaBH3CN. AB - A simple and efficient protocol for the construction of substituted piperazines, piperidines, thiomorpholines, decahydroquinolines, perhydrocyclopenta[b]pyridine, and pyrrolidines bearing N-hydroxy substituents through intramolecular reductive cyclization of diketoximes using sodium cyanoborohydride is described. PMID- 21526256 TI - Identification of a source of size polydispersity and its solution in Brust Schiffrin metal nanoparticle synthesis. AB - The co-presence of thiol vs. disulfide in the well-known Brust-Schiffrin two phase synthesis has been identified as a source of size polydispersity in nanoparticles synthesized and a procedure has been proposed to address this long outstanding issue. PMID- 21526257 TI - Unprecedented copper(I)-catalyzed in situ double cycloaddition reaction based on 2-cyanopyrimidine. AB - The solvothermal in situ double cycloaddition reaction of 2-cyanopyrimidine, Cu(2)O and NaN(3) with aqueous ammonia additive generated a two dimensional copper(I) coordination polymer with 5-pyrimidyl-tetrazolate, 3,5-bispyrimidyl 1,2,4-triazolate and the cyano group as the ligands. This reaction can be tuned to yield two dimensional coordination polymers solely based on tetrazolate or 1,2,4-triazolate ligands. PMID- 21526258 TI - The anticancer drug cisplatin can cross-link the interdomain zinc site on human albumin. AB - Cisplatin, cis-[Pt(Cl(2)(NH(3))(2)], can crosslink residues His67 of domain I and His247 of domain II in human albumin, occupying the major binding site for the essential metal zinc on the protein. PMID- 21526259 TI - In situ monitoring of single molecule binding reactions with time-lapse atomic force microscopy on functionalized DNA origami. AB - Individual biomolecular binding events were recorded in situ by combining time lapse atomic force microscopy and DNA origami. Single streptavidin molecules bound to specifically biotinyated DNA origami were simply counted as a function of time to obtain a direct measure of the binding rate. PMID- 21526260 TI - A new route to alpha-alkyl-alpha-fluoromethylenebisphosphonates. AB - A new route to alpha-alkyl-alpha-fluoromethylenebisphosphonates, 2 has been developed starting from commercially available tetraethyl fluoromethylenebisphosphonate (1), and alkyl halides using either caesium carbonate in DMF or sodium dimsyl. De-esterification of 2 provided biologically important alpha-alkyl-alpha-fluoromethylenebisphosphonic acid, 3, while alkoxide induced carbon-phosphorus bond cleavage of 2 gave alpha-fluorophosphonates, 4, which are useful synthons in organic synthesis. PMID- 21526261 TI - Structural, spectroscopic and redox properties of uranyl complexes with a maleonitrile containing ligand. AB - The reaction of uranyl nitrate hexahydrate with the maleonitrile containing Schiff base 2,3-bis[(4-diethylamino-2-hydroxybenzylidene)amino]but-2-enedinitrile (salmnt((Et(2)N)(2))H(2)) in methanol produces [UO(2)(salmnt((Et2N)2))(H(2)O)] (1) where the uranyl equatorial coordination plane is completed by the N(2)O(2) tetradentate cavity of the (salmnt((Et(2)N)(2)))(2-) ligand and a water molecule. The coordinated water molecule readily undergoes exchange with pyridine (py), dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF) and triphenylphosphine oxide (TPPO) to give a series of [UO(2)(salmnt((Et(2)N)(2)))(L)] complexes (L = py, DMSO, DMF, TPPO; 2-5, respectively). X-Ray crystallography of 1-5 show that the (salmnt((Et(2)N)(2)))(2-) ligand is distorted when coordinated to the uranyl moiety, in contrast to the planar structure observed for the free protonated ligand (salmnt((Et(2)N)(2))H(2)). The Raman spectra of 1-5 only display extremely weak bands (819-828 cm(-1)) that can be assigned to the typically symmetric O=U=O stretch. This stretching mode is also observed in the infrared spectra for all complexes 1-5 (818-826 cm(-1)) predominantly caused by the distortion of the tetradentate (salmnt((Et(2)N)(2)))(2-) ligand about the uranyl equatorial plane resulting in a change in dipole for this bond stretch. The solution behaviour of 2-5 was studied using NMR, electronic absorption and emission spectroscopy, and cyclic voltammetry. Complexes 2-5 exhibit intense absorptions in the visible region of the spectrum due to intramolecular charge transfer (ICT) transitions and the luminescence lifetimes (< 5 ns) indicate the emission arises from ligand centred excited states. Reversible redox processes assigned to the {UO(2)}(2+)/{UO(2)}(+) couple are observed for complexes 2-5 (2: E(1/2) = -1.80 V; 3,5: E(1/2) = -1.78 V; 4: E(1/2) = -1.81 V : vs. ferrocenium/ferrocene {Fc(+)/Fc}, 0.1 M Bu(4)NPF(6)) in dichloromethane (DCM). These are some of the most negative half potentials for the {UO(2)}(2+)/{UO(2)}(+) couple observed to date and indicate the strong electron donating nature of the (salmnt((Et(2)N)(2)))(2-) ligand. Multiple uranyl redox processes are clearly seen for [UO(2)(salmnt((Et(2)N)(2)))(L)] in L (L = py, DMSO, DMF; 2-4: 0.1 M Bu(4)NPF(6)) indicating the relative instability of these complexes when competing ligands are present, but the reversible {UO(2)}(2+)/{UO(2)}(+) couple for the intact complexes can still be assigned and shows the position of this couple can be modulated by the solvation environment. Several redox processes were also observed between +0.2 and +1.2 V (vs. Fc(+)/Fc) that prove the redox active nature of the maleonitrile-containing ligand. PMID- 21526262 TI - High-throughput combinatorial cell co-culture using microfluidics. AB - Co-culture strategies are foundational in cell biology. These systems, which serve as mimics of in vivo tissue niches, are typically poorly defined in terms of cell ratios, local cues and supportive cell-cell interactions. In the stem cell niche, the ability to screen cell-cell interactions and identify local supportive microenvironments has a broad range of applications in transplantation, tissue engineering and wound healing. We present a microfluidic platform for the high-throughput generation of hydrogel microbeads for cell co culture. Encapsulation of different cell populations in microgels was achieved by introducing in a microfluidic device two streams of distinct cell suspensions, emulsifying the mixed suspension, and gelling the precursor droplets. The cellular composition in the microgels was controlled by varying the volumetric flow rates of the corresponding streams. We demonstrate one of the applications of the microfluidic method by co-encapsulating factor-dependent and responsive blood progenitor cell lines (MBA2 and M07e cells, respectively) at varying ratios, and show that in-bead paracrine secretion can modulate the viability of the factor dependent cells. Furthermore, we show the application of the method as a tool to screen the impact of specific growth factors on a primary human heterogeneous cell population. Co-encapsulation of IL-3 secreting MBA2 cells with umbilical cord blood cells revealed differential sub-population responsiveness to paracrine signals (CD14+ cells were particularly responsive to locally delivered IL-3). This microfluidic co-culture platform should enable high throughput screening of cell co-culture conditions, leading to new strategies to manipulate cell fate. PMID- 21526263 TI - Evaluation of foliar fungal endophyte diversity and colonization of medicinal plant Luehea divaricata (Martius et Zuccarini). AB - Endophyte microorganisms are organisms that live inside plants without causing any apparent damage to their hosts. Since all plants exhibit endophyte microorganisms, it is believed that mutual association is of great importance in nature. Luehea divaricata (Martius & Zuccarini), known popularly in Brazil as agoita-cavalo, is a big-sized tree with a wide distribution in the country that possesses medicinal qualities for: dysentery, leucorrhea, rheumatism, blennorrhoea, tumors, bronchitis, and depuration. This research aims at isolating and molecularly characterizing fungi isolates from L. divaricata by sequence analysis of ITS1-5.8S-ITS2 rDNA. Further, the colonization of endophyte in the host plant by Light and Scanning Electron Microscopy will also be investigated. Whereas, genera Alternaria, Cochliobolus, Diaporthe, Epicoccum, Guignardia, Phoma, and Phomopsis, were identified; rDNA sequence analysis revealed intra species variability among endophyte isolates of the genus Phomopsis sp. Light and Scanning Electron Microscopy techniques showed the presence of endophyte fungi inside L. divaricata leaves, inhabiting inter- and intra-cellular spaces. These types of extensive colonization and dissemination were reported throughout all the leaf parts in palisade parenchyma, esclerenchyma, spongy parenchyma, adaxial epidermis, and vascular bundle indicating colonization of endophytes in multiple structural sub-niches in the host plant. PMID- 21526264 TI - Development and characterization of two new cell lines from common carp, Cyprinus carpio (Linn). AB - Two new cell lines (CCF and CCH) were established from fin and heart tissues of common carp, Cyprinus carpio. The cells were optimally maintained in Leibovitz-15 medium supplemented with 10% fetal bovine serum (FBS) and 10 ng/ml of basic fibroblastic growth factor (bFGF). The effects of temperature, concentration of FBS and bFGF on the growth of CCF and CCH cells were examined. The temperature ranged from 24 to 32 degrees C for good growth of the cells. The growth rate of cells was higher in medium containing 10% FBS and the addition of bFGF to the medium significantly increased the growth rate. The CCF cells were found to be epithelial, while the CCH cells were fibroblastic in nature. The cytogenetic analysis of the cell lines revealed a diploid number of 100 chromosomes in C. carpio. The viability of CCF and CCH cell lines were 70 and 72%, respectively, after six months of storage in liquid nitrogen (-196 degrees C). Molecular characterization of the cell lines using 16S rRNA and Cytochrome Oxidase Subunit I (COI) revealed the origin of the cell lines. These new cell lines will be useful for isolation of fish viruses and other in vitro biotechnological studies. PMID- 21526265 TI - Network connectivity is shown to change in C57BL/6 mice during a continuing immune response subsequent to tetanus toxoid hyperimmunization. AB - We have already demonstrated (Stojanovic et al., 2009) a connection between tetanus toxoid (TTd) hyperimmunization and the induction of anti-phospholipid syndrome (APS) in BALB/c mice. Here we show that C57BL/6 mice subjected to an identical procedure do not exhibit any like pathology attributable to anti phospholipid antibodies; we explain that this absence results from idiotypic connectivity. Six groups of C57BL/6 mice were hyperimmunized with TTd in aluminum hydroxide or glycerol, with or without pretreatments. Pretreated mice had been injected with polyclonal or nonspecific immune stimulators, such as complete Freund's adjuvant (CFA) or glycerol. The epitope specificity of induced antibodies was tested by indirect ELISA using a tetanus toxoid immunogen and these autoantigens: phospholipids, gangliosides, laminin. Idiotypic connectivity was tested by competitive ELISA and gauged from the degree to which the interaction of idiotypic/anti-idiotypic complementary antibodies was inhibited in the presence of immunized sera antibodies. Higher idiotypic connectivity was noted amongst pretreated mice. There was a positive correlation between higher connectivity and autoantibody levels that acted to favor the participation of natural autoantibodies in the inhibitory process. We conclude that idiotypic connectivity plays a protective role in immunization-induced autoimmunity. PMID- 21526266 TI - The foliar trichomes of Hypoestes aristata (Vahl) Sol. ex Roem. & Schult var aristata (Acanthaceae) a widespread medicinal plant species in tropical sub Saharan Africa: with comments on its possible phylogenetic significance. AB - The micromorphology of foliar trichomes of Hypoestes aristata var. aristata was studied using stereo, light and scanning microscopy (SEM). This genus belongs to the advanced angiosperm family Acanthaceae, for which few micromorphological leaf studies exist. Results revealed both glandular and non-glandular trichomes, the latter being more abundant on leaf veins, particularly on the abaxial surface of very young leaves. With leaf maturity, the density of non-glandular trichomes decreased. Glandular trichomes were rare and of two types: long-stalked capitate and globose-like peltate trichomes. Capitate trichomes were observed only on the abaxial leaf surface, while peltate trichomes were distributed on both adaxial and abaxial leaf surfaces. PMID- 21526267 TI - Comparison of phenotypic and genetic performance of local silkworm groups and two commercial lines. AB - Five Iranian native silkworm groups: Baghdad, Khorasan Orange, Guilan Orange, Khorasan Pink, Khorasan Lemon, and 107 and 110 commercial lines (12 families from each breed) were randomly selected and reared during 2003-2005 (five generations in spring and autumn). In each family, 30 male and 30 female cocoons were individually recorded for weight, shell weight and shell ratio. From among the native groups, the highest average in all three traits belonged to Baghdad and Khorasan Pink, and the lowest to Khorasan Orange and Khorasan Lemon. From among the commercial lines, the highest average in all three traits belonged to 107. In comparing heritability for cocoon weight in native groups, the highest heritability belonged to Guilan Orange (0.5147) and Khorasan Orange (0.5036) and the lowest heritability belonged to Khorasan Pink (0.0967). In the two other traits, the highest heritability belonged to Khorasan Orange and Baghdad and the lowest to Khorasan Pink. In the commercial lines, line110 had higher heritability than line107 for cocoon weight and cocoon shell weight. In all the groups, genetic correlations between cocoon weight and cocoon shell weight were high, expect for the Baghdad group. There was medium or low genetic correlation among cocoon weight, cocoon shell weight and cocoon shell ratio. PMID- 21526268 TI - Anatomical root variations in response to water deficit: wild and domesticated common bean (Phaseolus vulgaris L). AB - Root anatomical responses to water deficit are diverse and regulation of water uptake strongly depends on plant anatomy. The ancestors of common bean (Phaseolus vulgaris L.) cultivars are the wild common beans. Because wild beans adapt and survive well in the natural environment, it is hypothesized that wild common bean roots are less affected than those of domesticated beans at low substrate water potential (psiW). A wild common bean accession from Chihuahua Mexico and cv. Bayomex were studied. Seedlings with a mean root length between 3 and 4 cm were maintained for 24 h in vermiculite at psiW of -0.03 (well hydrated), -0.65, -1.48 and -2.35 MPa (partially dry). Ten anatomical characteristics of differentiation and cell division in root regions were evaluated. Thickness of epidermis and protoderm diminished similarly in wild and domesticated beans growing at low substrate psiW (between -0.65 and -2.35 MPa). At the same time, parenchymatic cell area diminished by 71 % in the domesticated variety, but by only 32 % in the wild bean at -2.35 MPa. The number of cells in the cortex and the thickness of the xylem wall increased in both wild and domesticated beans at low substrate psiW; nevertheless, the effect was significantly lower in the wild bean. The number of xylem vessels increased in the cultivar (up to 40 %) while in the wild bean it decreased (up to 33 %). The diameter of xylem vessels and transverse root area diminished (15 and 57 %, respectively) in the cultivar, but in the wild common bean were not affected. Anatomical root characteristics and their modifications in both differentiation and cell division in root regions demonstrated that the wild bean reacted quite differently to substrate psiW than the domesticated common bean. PMID- 21526269 TI - Toxicity mechanisms of onion (Allium cepa) extracts and compounds in multidrug resistant erythroleukemic cell line. AB - Onion (Allium cepa) is being studied as a potential anticancer agent, but little is known regarding its effect in multidrug resistance (MDR) cells. In this work, the cytotoxicity of crude onion extract (OE) and fractioned extract (aqueous, methanolic and ethyl acetate), as well as some onion compounds (quercetin and propyl disulfide) were evaluated in Lucena MDR human erythroleukemic and its K562 parental cell line. The capacity of OE to induce apoptosis and/or necrosis in these cells, the possible participation of oxidative stress and DNA damage were also assessed. Similar sensitivities were obtained for both tumoral cells, however only OE caused significant effects in the cells. In K562 cells, a significant increase of apoptosis was verified while the Lucena cells experienced a significant increase of necrosis. An antioxidant capacity was verified for OE discarding oxidative damage. However, OE provoked similar significant DNA damage in both cell lines. Thus, the OE capacity to overcome the MDR phenotype suggests anti-MDR action of OE. PMID- 21526270 TI - Synthetic nanoemulsion resembling a protein-free model of 7-ketocholesterol containing low density lipoprotein: In vitro and in vivo studies. AB - 7-ketocholesterol (7-KC) differs from cholesterol by a functional ketone group at C7. It is an oxygenated cholesterol derivative (oxysterol), commonly present in oxidized low-density lipoprotein (LDL). Oxysterols are generated and participate in several physiologic and pathophysiologic processes. For instance, the cytotoxic effects of oxidized LDL have been widely attributed to bioactive compounds like oxysterols. The toxicity is in part due to 7-KC. Here we aimed to demonstrate the possibility of incorporating 7-KC into the synthetic nanoemulsion LDE, which resembles LDL in composition and behavior. This would provide a suitable artificial particle resembling LDL to study 7-KC metabolism. We were able to incorporate 7-KC in several amounts into LDE. The incorporation was evaluated and confirmed by several methods, including gel filtration chromatography, using radiolabeled lipids. The incorporation did not change the main lipid composition characteristics of the new nanoparticle. Particle sizes were also evaluated and did not differ from LDE. In vivo studies were performed by injecting the nanoemulsion into mice. The plasma kinetics and the targeted organs were the same as described for LDE. Therefore, 7-KC-LDE maintains composition, size and some functional characteristics of LDE and could be used in experiments dealing with 7-ketocholesterol metabolism in lipoproteins. PMID- 21526271 TI - The effects of Tynnanthus fasciculatus (Bignoniaceae) infusion on testicular parenchyma of adult Wistar rats. AB - Traditional medicine provides strong guidance for scientific experiments involving plant products used by the Brazilian people. The species "cipo-cravo" (Tynnanthus fasciculatus) is a plant commonly used either to combat indigestion and stomach aches, or as a general stimulant and aphrodisiac. In this study, the effects of "cipo-cravo" infusion were investigated within the testicular parenchyma of adult Wistar rats. Rats were divided into 3 groups: a control (distilled water) and two treated groups, which received the plant infusion (100 and 200mg/animal/day). The 200mg dose promoted a significant increase of the testicular parenchyma weight and of the volume and total length of the seminiferous tubules, as well as in total daily sperm production and sperm production per gram of testis. PMID- 21526273 TI - Antiulcer activity of ethanolic extract of Encholirium spectabile Mart. ex Schult & Schult f. (Bromeliaceae) in rodents. AB - This study evaluated the antiulcer activity of an ethanolic extract of Encholirium spectabile (ES-EtOH) by using different standard experimental models of induced acute gastric ulceration. ES-EtOH (100 mg/kg p.o) protected the gastric mucosa against ulceration that was induced by absolute ethanol (53%), ethanol/HCl (75%), ibuprofen (52 %) and ischemia/reperfusion (43 %). It also restored catalase activity and non-protein sulfhydryl group concentration in the gastric wall of mice that had been treated with ethanol. The pre-treatment of mice with N-nitro-L-arginine (70 mg/kg i.p.) abolished the protective activity of ES-EtOH, which indicates that prostaglandins, antioxidant compounds and nitric oxide synthase activity are involved in the gastroprotective activity of the extract. PMID- 21526272 TI - Gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves against acute gastric lesion models in rodents. AB - Parkia platycephala Benth. (Leguminosae--Mimosoideae), popularly known as "visgueira", fava bean tree or "fava-de-bolota", is widely found in the Northern and Northeastern regions of Brazil. Its pods are used as cattle food supplement in the drought period. Compounds with a gastroprotective activity were obtained from the genus Parkia. Therefore, this study aimed at investigating the gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves (Pp-EtOH), as well as evaluating its possible mechanisms of action in experimental ulcer induction models. Lesions were induced by absolute ethanol, ethanol-HCl, ischemia-reperfusion and indomethacin in rodents. Pp-EtOH showed a protective effect in the lesion models (66, 48 and 52%, respectively), but it was not able to protect gastric mucosa against indomethacin-induced lesions. Results show a possible participation of the NO-synthase pathway in the gastroprotection and an antioxidant activity, by the increase of the catalase activity. The participation of prostaglandins and potassium channels sensitive to ATP in the gastroprotective effect of Pp-EtOH seems less likely to occur. More comprehensive studies, therefore, should be carried out to elucidate the antiulcerative effects of this promising natural product against this gastrointestinal disorder. PMID- 21526274 TI - Divergent effects of nitric oxide on airway epithelial cell activation. AB - Nitric oxide (NO*) is a gaseous mediator synthesized by nitric oxide synthases. NO* is involved in the modulation of inflammation, but its role in airway inflammation remains controversial. We investigated the role of NO* in the synthesis of the chemokines interleukin-8 and monocyte chemotactic protein-1, and of intercellular adhesion molecule-1 by human airway epithelial cells. normal human bronchial epithelial cells and the bronchial epithelial cell line BEAS-2B were used. interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) secretion and intercellular adhesion molecule-1 (ICAM-1) expression were measured by ELISA. mRNA was assessed by semiquantitative RTI-PCR. Interleukin-8 secretion was significantly reduced after 24h incubation with the NO* donor, sodium nitroprusside. The effect was dose-dependent. Similar results were obtained with S-nitroso-N-D,L-penicillamine and S-nitroso-L-glutathione. Inhibition of endogenous NO* with the nitric oxide synthase inhibitor N-nitro-L-arginine-methyl ester caused an increase in IL-8 secretion by lipopolysaccharide- and cytokine stimulated BEAS-2B cells. Sodium nitroprusside also caused a reduction in monocyte chemotactic protein-1 secretion by both cell types. In contrast, intercellular adhesion molecule-1 expression was upregulated by sodium nitroprusside. RTI-PCR results indicate that the modulation of protein levels was paralleled by modification in mRNA levels. NO* has divergent effects on the synthesis of different inflammatory mediators in human bronchial epithelial cells. PMID- 21526275 TI - UL146 variability among clinical isolates of human cytomegalovirus from Japan. AB - Human cytomegalovirus (HCMV) is a herpesvirus associated with serious diseases in immunocompromised subjects. The region between ORF UL133 and UL151 from HCMV, named ULb' is frequently deleted in attenuated AD169 and in highly passaged laboratory strains. However, this region is conserved in low-passaged and more virulent HCMV, like the Toledo strain. The UL146 gene, which is located in the ULb' region, encodes a CXC-chemokine analogue. The diversity of UL146 gene was evaluated among fifty-six clinical isolates of HCMV from Japan. Results show that UL146 gene was successfully amplified by the polymerase chain reaction (PCR) in only 17/56 strains (30%), while the success rate for UL145/UL147 gene was 18/56 strains (32%). After DNA sequencing, the 35 amplified strains were classified into 8 groups. When compared, variability of UL146 ranged from 25.1% to 52.9% at the DNA level and from 34.5% to 67% at the amino acid level. Seven groups had the interleukin-8 (IL-8) motif ERL (Glu-Leu-Arg) CXC and one group had only the CXC motif, suggesting the absence of the IL-8 function of UL146. In conclusion, we found that UL146 gene of HCMV is hyper-variable in clinical strains from Japan suggesting the possibility of a different function in each sequence group. PMID- 21526276 TI - Internucleotide correlations and nucleotide periodicity in Drosophila mtDNA: new evidence for panselective evolution. AB - Analysis for the homogeneity of the distribution of the second base of dinucleotides in relation to the first, whose bases are separated by 0, 1, 2,... 21 nucleotide sites, was performed with the VIH-1 genome (cDNA), the Drosophila mtDNA, the Drosophila Torso gene and the human p-globin gene. These four DNA segments showed highly significant heterogeneities of base distributions that cannot be accounted for by neutral or nearly neutral evolution or by the "neighbor influence" of nucleotides on mutation rates. High correlations are found in the bases of dinucleotides separated by 0, 1 and more number of sites. A periodicity of three consecutive significance values (measured by the x29) was found only in Drosophila mtDNA. This periodicity may be due to an unknown structure or organization of mtDNA. This non-random distribution of the two bases of dinucleotides widespread throughout these DNA segments is rather compatible with panselective evolution and generalized internucleotide co-adaptation. PMID- 21526279 TI - [Since the local contribution el al control de la bacterial resistance in Chile]. PMID- 21526280 TI - [Bacteriological quality of air in a ward for sterile pharmaceutical preparations]. AB - BACKGROUND: An extremely clean area is required for preparation of sterile pharmaceutical compounds, in compliance with international standards, to minimize the probability of microbial contamination. AIM: To evaluate the bacteriological quality of the air in the Sterile Pharmaceutical Preparation Unit of the University of Chile's Clinical Hospital and to set up alerts and action levels of bacterial growth. METHODS: We studied eight representative sites of our Unit on a daily basis from January to February 2005 and twice a week from June 2005 to February 2006. We collected 839 samples of air by impact in the Petri dish. RESULTS: 474 (56.5%) samples were positive; 17 (3.5%) of them had an inappropriate bacterial growth (2% of total samples). The samples from sites 1 and 2 (big and small biosafety cabinets) were negative. The countertop and transfer area occasionally exceeded the bacterial growth limits. The most frequently isolated bacteria were coagulase-negative staphylococci, Micrococcus spp and Corynebacterium spp, from skin microbiota, and Bacillus spp, an environmental bacteria. CONCLUSIONS: From a microbiological perspective, the air quality in our sterile preparation unit complied with international standards. Setting institutional alerts and action levels and appropriately identifying bacteria in sensitive areas permits quantification of the microbial load and application of preventive measures. PMID- 21526281 TI - [Results of antimicrobial susceptibility surveillance in Chile: consolidating a network]. AB - Antimicrobial resistance is an increasing public health issue. Creation of surveillance networks is a matter of major importance for antimicrobial resistance understanding and monitoring. Also, they contribute to design actions for controlling its appearance and dissemination. In 2007 a colaborative group in antimicrobial resistance was formed, representing several health institutions across the country. In this paper we report the results of 2009 surveillance with emphasis in its interpretation, limitations and future perspectives. PMID- 21526282 TI - [Outbreak of multiresistant and extended spectrum beta-lactamase producing Klebsiella pneumoniae in a high risk neonatal unit]. AB - Klebsiella pneumoniae as a producer of extended spectrum beta-lactamase (ESBL) has played an important role as a cause of infection in the neonatal high risk unit (NHRU) of the Autonomous Hospital Institute of the Universidad de Los Andes (AHIULA). In this paper an outbreak caused by this bacterial specie that affected neonates hospitalized in this unit during February 2007 is described. Besides, the environment and the personnel were studied as possible sources of this organism. The strains of K. pneumonia isolated from the outbreak had the same resistance phenotype, produced ESBL type TEM and SHV and belonged to the same genotype as the isolated strains from the hands and the soapy solutions, possible sources of infection. This indicates that it was the same clone. The outbreak was resolved using two important measurements: reinforcing hand washing and with the opportune treatment of neonates with imipenem. PMID- 21526283 TI - [Bacteremia in patients with liver cirrhosis]. AB - Bacteremic infections are more frequent in patients with cirrhosis, as their immune system is compromised. Series of cirrhotic patients with bacteremia has seldom been reported in Chile. We retrospectively collected, from 2005 to 2008, 59 episodes of bacteremia in cirrhotics representing 9% of the overall number of bacteremic episodes seen in our center in the period. Spontaneous bacteremia accounted for 29% followed by those of pulmonary origin (22%). Grampositive cocci and gramnegative bacilli were responsible in 52% and 48% respectively, however gramnegative rods predominated in nosocomial bacteremias. Overall, the most frequent organisms were Staphylococcus aureus (24%) and Escherichia col i (22%). Mortality in bacteremic patients was significantly higher compared with all cirrhotic patients hospitalized in the period (37.0 vs 9.4%; p < 0.001) and MELD score was significantly correlated with mortality. CONCLUSION: bacteremia is a severe complication of cirrhosis and MELD score could be a useful tool to stratify risk in these patients. PMID- 21526285 TI - [Invasive candidiasis in critically ill adult patient]. AB - Invasive infections by Candida strains are a relevant pathology in critically ill patients. Candida should be considered where a high risk of infection is present for a critical early diagnosis. Despite the incorporation of new drugs in the therapeutic armamentarium over the last decade, mortality remains high. The key in improving clinical outcomes of these patients are the use of early effective therapies that offer coverage against different strains of Candida: C. albicans and non-albicans. Recent international guidelines suggest empiric therapy with echinocandins in suspected invasive candidiasis in this patient population. This group of drugs adequately documented clinical efficacy and safe use in these patients. The emergence of new echinocandins could improve access to these drugs by reducing their cost. PMID- 21526286 TI - [Cost analysis of early diagnosis of hydatidosis in children of 5 and 12 years old in the province of Nuble, Bio-Bio Region, Chile]. AB - This study conducted a cost analysis of different interventions in the early diagnosis of hydatidosis between the years 2006 -2007 in the Province of Nuble, Bio-Bio Region of Chile. The aim was to estimate the costs of early diagnosis of this condition. We included all children of 5 and 12 years old in rural areas of the province. Data collection activities were identified which included specific antibody measurements (indirect ELISA) and an abdominal ultrasound. For the determination of costs, direct and indirect costs were identified using the methodology of activity-based costs. The results demonstrate that the preventive diagnosis costs S17.183 Chilean pesos per child (S35 US dollars), thus making this intervention of lower cost than waiting until the person becomes ill with this disease. PMID- 21526287 TI - [Streptobacillus moniliformis]. PMID- 21526289 TI - [About prophylaxis of infectious diseases risks in travellers]. PMID- 21526288 TI - [Mass screening for hypothyroidism in a cohort of HIV infected patients in a Bogota hospital, Colombia]. AB - INTRODUCTION: The objective of this study was to evaluate the frequency of thyroid function alterations and its associated factors in a group of patients from a university hospital in Colombia. METHODS: From June 2007 through June 2008, 636 HIV patients were followed in order to assess the relation of thyroid function with the use of HAART. RESULTS: The overall prevalence of hypothyroidism (TSH > 4.6 MUUI/mL) was 15.5% (100/636). The association of hypothyroidism in the independent analysis showed significant relation only for the use of nevirapine (RR 1.6; CI 95% 1.1- 2.34) and stavudine (RR 1.5; CI 95%, 1 - 2.3). CONCLUSIONS: The prevalence of hypothyroidism was surprisingly high among the studied population. PMID- 21526290 TI - [Travellers to Africa]. PMID- 21526291 TI - [Travellers to Asia]. PMID- 21526292 TI - [Coexistence of plasmablastic lymphoma, Kaposi sarcoma and Castleman disease in a patient with HIV infection]. AB - Plasmablastic lymphoma (PL) is an uncommon B-cell lymphoma that is strongly associated with human immunodeficiency virus (HIV) infection, and displays distinctive affinity for extranodal presentation in the oral cavity. We report the case of a PL involving the stomach in a 36 year-old man HIV+ patient, associated with Kaposi sarcoma (KS) in sections adjacent to lymphoma. He had a positive history of Castleman disease and KS in a lymphoid node biopsy. PMID- 21526293 TI - [Some remarks on the evolution of medical language across the times]. AB - The language employed by the physicians in their communications has been suffering a continuous evolution through the times, from the sober beauty that in their conciseness and accuracy had the Greek and the Latin, to the verbosity and flowery of the Middle Age and posterior centuries, for ended in the poverty and monotony characteristics of the today publications. A brief selection of different papers and book's extracts is presented in order to illustrate these changes, including words of Hippocrates, Celsus, Leonardo, Van Leeunwenhoek, Spallanzani, Jenner, Koch, Laveran, Manson, Grassi and other less conspicuous, ending with the assertion that the scarce time for read adduced by physicians must not serves like an excuse for ignorance and lack of culture. PMID- 21526294 TI - [Myocardial lipids and creatine measured by magnetic resonance spectroscopy among patients with heart failure]. AB - BACKGROUND: Heart failure (HF) is characterized, among other features, by the development of alterations in myocardial energy metabolism, involving a decrease in glucose utilization and increased free fatty acid uptake by cardiomyocytes, associated with decreased deposits of high-energy phosphates (creatine phosphate/creatine transporter). Magnetic resonance (MR) imaging allows a direct and noninvasive assessment of myocardial metabolites. AIM: To measure myocardial creatine and lipids by MR spectroscopy among patients with HF. MATERIAL AND METHODS: Cardiac MR spectroscopy (1.5 Tesla) with Hydrogen antenna and single voxel acquisition was performed in five patients with non-ischemic heart failure, aged 58 +/- 9.7 years, (60% males) and 5 healthy volunteers matched for age and sex. We analyzed the signals of creatine (Cr), lipids (L) and water (W) in the interventricular septum, establishing the water/lipid (W/L) and water/creatine (W/Cr) index to normalize the values obtained. RESULTS: Among patients, left ventricular ejection fraction was 32 +/- 6.9%, 60% were in functional capacity II, 60% had hypertension and one was diabetic. Spectroscopic curves showed a depletion of total Cr, evidenced by the W/ Cr index, among patients with heart failure, when compared with healthy controls (1.46 +/- 1.21 and 5.96 +/- 2.25 respectively, p < 0,05). Differences in myocardial lipid content, measured as the W/L index, were not significant (5.06 +/- 2.66 and 1.80 +/- 1.62 respectively, p = 0.08). CONCLUSIONS: Among patients with heart failure of non-ischemic etiology, there is a depletion of creatine levels measured by MR spectroscopy. PMID- 21526295 TI - [Diagnostic yield of CT pulmonary angiography and venography for thromboembolic disease]. AB - BACKGROUND: CT pulmonary angiography is the diagnostic procedure of choice for non-massive pulmonary embolism. AIM: To assess the diagnostic yield for thromboembolic disease of CT pulmonary angiography and venography using a 64 slice multidetector tomography. MATERIAL AND METHODS: Prospective study of patients with a clinical suspicion of thromboembolic disease, subjected to CT pulmonary angiography and venography. The presence and location of pulmonary thromboembolism, of isolated or concomitant deep venous thrombosis and of other significant radiological findings, were registered. RESULTS: A 64-MDCT scanner was performed to 893 patients and thromboembolic disease was demonstrated in 240. Pulmonary thromboembolism was diagnosed in 218 patients. It was concomitant with deep venous thrombosis in 79 patients (36%) and isolated in the rest. Thirty five of the 218 patients with pulmonary thromboembolism had radiological evidence of right ventricular overload. Twenty two patients (10%) had an isolated deep venous thrombosis. In 65 patients with pulmonary thromboembolism (30%) a possibly new or old malignant lesion, was observed. Seventy one of 653 patients without evidence of thromboembolic disease had potentially pathological findings on CT. CONCLUSIONS: The combined use of CT pulmonary arteriography and venography using a 64 MDCT scanner increases the diagnostic yield of the procedure for thromboembolic disease. It also allows the diagnosis of other related conditions, specially malignant tumors. PMID- 21526296 TI - [Complications and mortality of extended gastrectomy for gastric cancer]. AB - BACKGROUND: Extended gastrectomy allows a complete tumor excision in patients with advanced gastric cancer. AIM: To compare the surgical results of extended (ER) and non-extended gastrectomy (NER) among patients with gastric cancer, and determine factors associated with complications and mortality. MATERIAL AND METHODS: Review of medical records of patients with gastric cancer who underwent complete resection between 2002 and 2008 in an oncological hospital. Demographics, patient-related and therapeutic features were compared between groups, and independent factors were established with multivariate analysis. RESULTS: Seventy four patients, (44 men, median age 62 years) underwent an ER and 103 patients, (56 men, median age 61 years) a NER. Specifically, ER included splenectomy alone in 27 patients, splenectomy associated with other procedure in 24, partial esophagectomy in 18, distal pancreatectomy in 13, hemicolectomy in 8, total esophagectomy in 7, partial hepatectomy in 4, and adrenalectomy in 1. Postoperative complications were observed in 19 patients treated with an ER (26%) and in 11 patients treated with a NER (11%), p < 0.05. Serious complications were higher in patients who underwent an ER compared with NER (6 patients (8%) vs. 4 (4%), respectively) p < 0.05. In the same way, mortality was higher in patients treated with ER when it was compared with NER (4 patients (5%) vs two (2%), respectively), p < 0.05. ER and serum albumin levels were independent factors associated to a higher risk of mortality and rate of complications. CONCLUSIONS: ER was associated with a higher rate of general and severe complications, and mortality. PMID- 21526297 TI - Correlation between clinical evaluation of liver size versus ultrasonography evaluation according to body mass index (BMI) and biotypes. AB - BACKGROUND: Body weight may influence liver size. AIM: To determine the correlation between clinical and ultrasound evaluation of the liver size according to body mass index (BMI). MATERIAL AND METHODS: A cross-sectional study of 81 subjects aged 25 +/- 6 years (43 females). Two percussion measurements were taken and ultrasonography was performed on the same site demarcated by percussion. RESULTS: Mean BMI was 23 +/- 4 kg/m2. Nineteen individuals (23.5%) had a BMI >= 25 kg/m2. There was a significant difference between the values of liver size obtained by clinical and ultrasound methods. The correlation coefficient between the liver size obtained by clinical and ultrasound methods was 0.419 (p < 0.01). No significant differences in liver size were observed, between subjects with a BMI below or over 25 kg/m2. In all subjects, regardless of BMI, there was a statistically significant difference between the mean sizes obtained by both methods. The correlation coefficients between both methods in subjects with a BMI <= 25 Kg/m2 and their counterparts with higher BMI were 0.47 and 0.03, respectively. CONCLUSIONS: There are significant differences in liver size obtained by clinical examination and ultrasound. Only in subjects with BMI <= 25 kg/m2, the correlation between the two techniques is significant. PMID- 21526298 TI - [Analysis of a scale for the assessment of attention deficit disorder with hyperactivity in Chilean children]. AB - BACKGROUND: Epidemiologic studies may be used as a starting point to improve interventions and improve diagnosis, with instruments that are both reliable and adequate. AIM: To analyze the psychometric properties of the Attention Deficit Disorder Evaluation Scale (ADDES) in Chilean primary and high school students. MATERIAL AND METHODS: The ADDES was applied by 142 teachers to 254 students. Attention Defcit Disorder was already diagnosed in 144 students. Explanatory and confirmatory factorial analyses were carried out. RESULTS: Confirmatory Factorial Analysis (CFA) proved that the model suggested by the authors could not be replicated in the Chilean sample. Exploratory Factorial Analysis (EFA) showed that three new factors came out of the analysis. CFA was applied to the new model and modification indexes suggested the introduction of new saturations. Based on the model with the best goodness-of-fit, psychometric characteristics were evaluated. CONCLUSIONS: The ADDES adapted to the Chilean context has a high reliability and a strong discrimination ability, allowing the evaluation of behavior disorders, hyperactivity/impulsivity and attention deficit. PMID- 21526299 TI - [Spermograms of healthy young subjects living in Arica, Chile]. AB - BACKGROUND: Semen analysis is one of the parameters used to predict male fertility. Semen can be altered by environmental pollutants; therefore it could be used as a biological marker of exposure in contaminated areas. AIM: To analyze the spermogram values in a sample of healthy young males, residing in Arica, Chile. MATERIAL AND METHODS: One hundred and two healthy university students volunteers aged 18 to 30 years answered a questionnaire about fertility, habits and andrologic diseases and provided a semen sample. Within three hours after ejaculation, semen volume, pH, sperm concentration, motility and morphology were analyzed. RESULTS: Six percent of volunteers had offspring, 1% declared to be infertile, 32% smoked and 78% consumed alcohol. Semen pH was 7.6 +/- 0.5, volume, 2.9 +/- 1.6 ml, sperm concentration, 62.8 +/- 62.3 x 10(6)/ml, normal morphology, 15.0 +/- 7.9%, overall motility, 42.2 +/- 23.2 % and grade A motility, 19.2 +/- 18.6%. The percentage of subjects that had normal semen values was 82% for total sperm count, 76% for sperm concentration, 72% for volume, 64% for vitality, 63% for pH, 57% for morphology, 38% for overall motility and 26% for grade A motility. CONCLUSIONS: This sample of healthy young males had a normal sperm count in comparison with international reports. However it is necessary to characterize the spermogram in uncontaminated areas of Chile to ensure that our results are within the expected values for the country. PMID- 21526300 TI - [The work environment as a source of exposure to secondhand smoke: a study in workers of bars and restaurants of Santiago, Chile]. AB - BACKGROUND: Secondhand smoke (SHS) is an established cause of morbidity and mortality among non-smokers. The workplace is an important source of exposure, especially among workers of restaurants, bars and nightclubs. AIM: To estimate the daily occupational exposure to SHS among non-smoking workers of bars and restaurants of Santiago, Chile. MATERIAL AND METHODS: Environmental vapor-phase nicotine was measured for 95 non-smoking workers of bars and restaurants of Santiago, using passive personal samplers during a daily work shift and outside the workplace. RESULTS: The median occupational exposure to air nicotine was 9.18 ug/m3 (P25-P75 3.15-25.67 ug/m3). Higher concentrations were found among workers of places with no smoking restrictions (22.72 ug/m3; P25-P75 5.73-34.85 ug/m3), bar workers (20.75 ug/m3, P25-P75 5.03-44.67 ug/m3), waiters (20.57 ug/m3, PP25 P75 5.66-42.73 ug/m3) and bartenders (10.37 ug/m3, P25-P75 9.75-25.67 ug/m3). The median concentration of nicotine outside the workplace was 1.79 ug/m3 (P25-P75 1.02-3.00 ug/m3). Occupational exposure was 4.77 times higher compared to the non work exposure. CONCLUSIONS: Workers of bars and restaurants are exposed to high levels of SHS at the workplace. Moreover, occupational exposure among these non smoking workers is, in most cases, the main source of daily exposure to this pollutant. PMID- 21526301 TI - [Frequency of prescription and transcription errors for intravenous medications in four pediatric services]. AB - BACKGROUND: Errors in the prescription and transcription of medications in pediatric services is a source of adverse events that can be prevented. AIM: To determine and compare the frequency of prescription and transcription errors for intravenous drugs in four pediatric services in a regional general hospital. MATERIAL AND METHODS: Cross sectional analysis of a probabilistic sample of 500 prescriptions of intravenous medications. Information was gathered using an instrument from the American Academy of Pediatrics. RESULTS: The detected prescription errors were illegible indications in 20%, lack of dosing indication in 11%, omission of the administration route in 24% and omission of the frequency of administration in 15%. Transcription errors were illegible transcription in 3%, not transcribing all indicated medications in 4% and transcription of medications that were not prescribed in 3%. Twenty one percent of prescriptions and 6% of transcriptions had at least one incorrect action. In the different services studied there was a significant association between the percentage of incorrect prescriptions and transcriptions and between illegible prescriptions and transcriptions. CONCLUSIONS: A high percentage of errors in prescription of intravenous medications and their transcriptions, was detected in these services. A better quality of care control is required. PMID- 21526302 TI - [Molecular and genetic studies for hereditary colon cancer in two patients and their families]. AB - BACKGROUND: About 30% of cases of colon cancer (CC) have a family history of CC, and only 5% are hereditary forms. Hereditary forms have an increased risk of CC and other tumors. AIM: To report the molecular and genetic study in two families with hereditary CC. MATERIAL AND METHODS: Molecular analysis of the adenomatous polyposis coli (APC) gene of familial adenomatous polyposis (FAP), was done in a patient with multiple benign polyps and his children. Molecular analysis was performed for MLH1 gene mutation of hereditary non-polyposis colon cancer (HNPCC) in an asymptomatic patient with family history of multiple cancers and his mother with a confirmed mutation in the MLH1 gene. RESULTS: The patient with FAP had an insertion of 17 base pairs in exon 9 of the APC gene and two of his children had the same mutation. The patient with history of HNPCC did not have the family mutation on MLH1. CONCLUSIONS: In the case of FAP, molecular study was performed in his children since manifestations in carriers of the mutation may begin in childhood. If the second patient would have had the mutation, the study of his children could have been postponed until the age of 18, when the risk for CC is increased. PMID- 21526303 TI - [Mesenteric cryptococcal lymphadenitis: report of one case]. AB - Cryptococcosis is an invasive mycotic infection caused by Cryptococcus neoformans, an encapsulated, yeast-like fungus. It is considered an opportunist infection, since it mainly affects immunocompromised subjects. However there are isolated reports of the infection in immunocompetent subjects. Cryptococcal infection of intra-abdominal organs or tissues is extremely rare. We report a 21 year-old HIV positive male that, during the treatment of a meningeal cryptococcosis, presented a clinical picture of an acute abdomen suggesting acute appendicitis. The patient was operated, finding enlarged mesenteric lymph nodes forming conglomerates and a macroscopically normal appendix. The conglomerated lymph nodes and the appendix were excised. The pathological study of the surgical piece revealed an intra abdominal cryptococcal lymphadenitis and a normal appendix. PMID- 21526304 TI - [Splenic gangrene due to Streptococcus anginosus after a sleeve gastrectomy. Report of one case]. AB - We report a 46-year-old woman, subjected to a laparoscopic sleeve gastrectomy, that had to be converted to open surgery due to the presence of adherences. She required an immediate new intervention due to a hemoperitoneum caused by a liver tear and venous bleeding from the splenic hilus. Both lesions were successfully repaired. In the postoperative period the patient had fever, leukocytosis and sialorrhea. A CAT scan showed a splenic infarction and a huge intra abdominal collection that communicated with the stomach. Streptococcus anginosus was isolated from the collection. The patient was managed with antimicrobials and percutaneous drainage with a favourable evolution and closure of the communication with the stomach. PMID- 21526305 TI - [Update on chronic obstructive pulmonary disease]. AB - Chronic obstructive pulmonary disease (COPD), mainly caused by smoking, is predicted to be the third most frequent cause of death in the world by 2020. It is a multicomponent, progressive, disabling condition that ultimately ends in respiratory failure and death. There is evidence that systemic inflammation and extra pulmonary effects are also common in COPD, although the association between systemic inflammation and systemic manifestations of COPD is still not entirely clear. COPD is not only preventable but also treatable and the past decade has witnessed great progress in COPD research. New drugs have been developed and tested and a growing base of scientific evidence now documents the efficacy of several therapies for symptoms and exacerbations. It is clear that many patients with the disease can benefit from an aggressive management, with a decrease in the frequency of hospitalizations and improvements in symptoms and quality of life. Moreover, basic and clinical scientists have now identified cells, mechanisms, and molecules that play key roles in its pathogenesis. The advent of newer and more effective therapies will lead to a decline in the contribution of this disease to worldwide disease burden. COPD is now viewed under a new paradigm as preventable and treatable. PMID- 21526306 TI - [Keynote address to the 19th congress of ALANAM]. AB - In his keynote address to the international seminar of the ALANAM (Association of Latin American National Academies of Medicine), held October 28-30, 2010, in Santiago, Chile, Dr. Alejandro Goic, President of the Chilean Academy of Medicine, discussed the state of health and of medical and health research in Latin American countries. He called attention to the fact that the National Academies of Medicine are learned and honorific institutions whose main function is to reflect on, and foster, medical practice, medical education, and public health. He noted that medical doctors bear a great individual and collective responsibility in the organization and management of sanitary services, but that health care as such concerns all citizens. Poverty is one of the most important factors conditioning the state of health in any society, particularly in developing countries. Because of the very nature of the medical profession, doctors are acquainted not only with the physical and mental ailments that afflict the poor, but also with their precarious housing, income, and labor conditions, as well as with how difficult it is for them to have access to good health care and education. He emphasized that health care is not only a technical, administrative and economic institution, but a moral one as well. When the economic considerations of the health care industry and its financial mechanisms prevail over the medical needs of the general population, a severe social problem arises to the extent that important segments of the population are denied access to health care, and preventable human suffering is left unattended. Society and governments have the responsibility of financing health services and ensure that the humanitarian ends of medicine are met in health care services and sanitary institutions. The superior aim in health care should always be to afford a humane, caring, and respectful relationship between health care professionals and all users of the health care system without exception. PMID- 21526307 TI - [The ALANAM statement on public health policy]. AB - The ALANAM (Association of Latin American National Academies of Medicine) statement on public health policy, issued following its 19th Congress, held October 28-30, 2010, in Santiago, Chile, declares that cardiovascular diseases, cancer, accidents and violence are the leading causes of death in the region, while in several of its member nations, emergent and re-emergent infectious diseases, malnutrition, and mother-child illnesses remain prevalent. The statement calls attention to the lack of functioning water supply and sewage systems in many villages and rural areas. After describing the social causes of the present state of public health in Latin America (poverty levels reaching upwards of 44% of the total population, or some 110 million people), it calls on governments, first, to spare no efforts in the task of eradicating extreme poverty in the short-term, and poverty in the long-term. Second, considering that about 15 million 3-to-6 year-olds have no access to education, it recommends extending educational services to these children, and to improve the quality of existing pre-school and primary education. Third, the statement calls for universal health care coverage and for equal access to good quality medical care for everyone, and for programs aimed at promoting healthy personal habits and self-care. In this regard, it also recommends that disease prevention programs be sustained over time, that national sanitary objectives be defined, and that its results be periodically reviewed. Fourth, it recommends that primary health care be extended to everyone, and that it be enhanced by improving coverage and coordination with secondary and tertiary level health care institutions. The statement lays special stress on the need for adopting public health policies aimed at lowering the cost of medicines; to this end, it calls for the creation of an official list of generic drugs. The statement ends by calling on governments to support public health research as a necessary step in tackling with greater efficiency the health problems still prevalent in the region. PMID- 21526308 TI - Neurofibromatosis type I and antiphospholipid syndrome. PMID- 21526309 TI - [Clinical ethics consultation in intensive care]. PMID- 21526311 TI - [The relevance and fate of abstracts presented in scientific meetings]. AB - Abstracts presented in scientific meetings are indispensable tools to diffuse the latest research in the field. They provide the authors with an opportunity to receive feedback from a critical audience so they can prepare a final manuscript to be submitted to a peer-reviewed journal. However, several studies in a wide range of medical specialties and other related sciences showed that no more than 50% of abstracts presented in annual meetings of learned societies are published in a 5-year follow up after the meeting. Therefore, abstracts are considered "preliminary publications" and it is recommended not to include them as bibliographic references unless they have been published recently (less than 3 years) in peer-reviewed journals (regular issues or supplements) or in their official websites. Databases dependent on the National Library of Medicine (USA) or SciELO do not index individual abstracts from a meeting. Authors and reviewers should be reminded that manuscripts that have shaped current knowledge probably had also been presented as abstracts in scientific meetings, sometime before their final publication. PMID- 21526312 TI - [Simultaneous kidney and pancreas transplantation (SKPT) in patients with type 1 diabetes and chronic renal failure: experience in 12 patients in Chile]. AB - BACKGROUND: Simultaneous kidney and pancreas transplantation (SKPT) is the best alternative for end stage renal disease among patients with insulin dependent diabetes mellitus. AIM: To report our experience with SKPT. MATERIAL AND METHODS: Retrospective analysis of 12 recipients of SKPT transplanted in one center starting in 1994, with a mean follow-up period of 6.8 years (2-15). RESULTS: Eleven of 12 recipients were in chronic hemodialysis before SKPT. Mean A, B, DR and HLA mismatch was 4.3. Mean preformed anti HLA antibodies was 3.3 %. Mean cold ischemia times for pancreas and kidney were 6 and 10 hours, respectively. In the first eight cases, the pancreas was drained to the bladder, and in the last four, an enteric drainage was performed. Eleven recipients were induced with antibodies, and maintenance immunosuppression consisted of cyclosporin or tacrolimus plus an antiproliferative agent. Ten year patient survival was 70%. Pancreas and kidney survival, defined by insulin and dialysis independence, were 72 and 73% respectively. Fifty percent of recipients experienced acute graft rejection (cellular or humoral), with good response to treatment except in one case. CONCLUSIONS: This experience shows that SKPT is associated with an excellent patient survival associated to insulin and dialysis independence in 70% of patients at 10 years. PMID- 21526313 TI - [Chilean results of the international registry of risk factors and treatment of unstable angina and non ST elevation myocardial infarction: ACCORD (ACute CORonary syndrome Descriptive study)]. AB - BACKGROUND: Guidelines for the management of unstable angina (UA) and non ST elevation myocardial infarction (NSTEMI) have been issued, however, current practices are unknown in Chile. AIM: To evaluate in a prospective cohort of NSTEMI patients the current practices, treatments and risk factors. MATERIAL AND METHODS: One year prospective International non interventional registry, conducted in Chile between January 2005 and November 2006. RESULTS: Two hundred thirty three Chilean NSTEMI patients were enrolled. Mortality was 5.5% at the end of the follow-up. Mean age was 61.6 years, and 30.6% were female. Most of the patients had at least one risk factor (98%): hypertension (84%), previous myocardial infarction (33%), dyslipidemia (54%), diabetes (33%), current smoking (30%). Main procedures during the hospitalization were coronary angiogram (67%), angioplasty (33%; 88% with stent) and coronary bypass surgery (7%). During procedures, 31% of patients received clopidogrel, and 4.2% glycoprotein Ilb/IIIa antagonists. Medical management was selected for 60% of patients. In comparison to men, women received less interventional procedures despite having more risk factors. Treatments prescribed at discharge were aspirin (97%), clopidogrel (49%), beta blockers (78%), diuretics (21%), lipid lowering agents (78%), oral hypoglycemic agents (13%) and insulin (9%). At the end of the 1-year follow-up, treatments were aspirin (84%), beta blockers (72%), diuretics (19%), and dual antiplatelet therapy with clopidogrel (16%). CONCLUSIONS: A high prevalence of multiple risk factors for cardiovascular disease in Chilean patients with NSTEMI was observed. More aggressive primary and secondary preventive measures are urgently needed. Use of therapies proposed in the guidelines is high, but dual antiplatelet therapy is less than 50% at discharge and decreases during the one year-follow-up. PMID- 21526314 TI - [Lymphomas associated with human immunodeficiency virus infection: retrospective review of medical records]. AB - BACKGROUND: The incidence of lymphoma increases enormously in patients infected with the human immunodeficiency virus (HIV). AIM: To describe the incidence, clinical and histological characteristics, treatments and survival of lymphomas associated with HTV infection. MATERIAL AND METHODS: Retrospective review of medical records of patients with HIV and lymphoma, treated in a public hospital, between January 2001 and June 2009. RESULTS: Twenty-two male patients were included but 14 had immunohistochemical confirmation of the lymphoma. The accumulated incidence for this period was 2.8%. The median age at lymphoma diagnosis was 39.5 years. Twelve patients (86%) had non-Hodgkin lymphoma (NHI) and two (14%) Hodgkin lymphoma. The main pathological type of non-Hodgkin lymphomas was diffuse large B cell in seven cases (50%). The mean CD4 cell count and viral load were 83 cell/mm3 (33.5-113.5) and 26.000 RNA copies/ml (1210 196500), respectively Twelve patients (86%) had B type symptoms of lymphoma at the moment of diagnosis. Eleven patients (29%) received chemotherapy with or without radiotherapy, one patient (7%) received radiotherapy alone and two patients (14%) received palliative symptomatic treatment. Six cases (43%) received highly active antiretroviral therapy simultaneously with chemotherapy. Global mortality in this series was 57% (8 patients) with a median survival time of 5.8 months (2.6-26.2). CONCLUSIONS: In this series of patients infected with HIV, a predominance of aggressive histological subtypes of lymphomas and low complete remission rates, were observed. PMID- 21526315 TI - Teaching of medical ethics: students' perception in different periods of the course. AB - BACKGROUND: Medical ethics is structured to guide doctors towards a better professional practice. However, its teaching in medical schools seems to be neglected. AIM: To evaluate the perception of Federal University of Sergipe medical students about ethical conflicts during their academic practice, in two different periods of a medical course. MATERIAL AND METHODS: A cross-sectional, analytic and observational study. Using a qualitative approach, analytic categories were identified using an open questionnaire answered by two groups of students, before and after attending the medical ethics course. RESULTS: In everyday practice, the participants referred embarrassment in front of patients. When considering the relationship with the professional/professor, they identified negligence and conflicts of interests in their practice. The students also detected bad infrastructure and professional relationship in public services, when compared to private ones. The conflicts experienced by the students in their own practice were insecurity, inability to cope with patients' problems and inadequate perception of medical confidentiality limits. According to the respondents, contribution of ethics teaching varied from adequate, when it was effective to orient their practice and provide confidence, to inadequate or absent because of an overall superficial approach. CONCLUSIONS: Major deficiencies related to the teaching of medical ethics were identified, pointing to the need to change current medical education model. PMID- 21526316 TI - [Development and validation of a questionnaire on perception of portfolio by undergraduate medical students]. AB - BACKGROUND: Portfolio is an innovative instrument that promotes reflection, creativity and professionalism among students. AIM: To describe the development and validation process of a questionnaire to evaluate the use of portfolio in undergraduate medical students. MATERIAL AND METHODS: Focus groups with students and teachers were employed to identify aspects related with portfolio in undergraduate teaching. The Delphi technique was used to prioritize relevant aspects and construct the questionnaire. The validated questionnaire, consisting of 43 items and 6 factors, was applied to 97 students (response rote of 99.9%) in 2007 and 100 students (99.2%) in 2008. Each question had to be answered using a Likert scale, from 0 (completely disagree) to 4 (completely agree) The validity and reliability of the questionnaire was evaluated. RESULTS: The questionnaire showed a high reliability (Cronbach alpha = 0.9). The mean total scores obtained in 2007 and 2008 were 106.2 +/- 21.2 (61.7% of the maximal obtainable score) and 104.6 +/- 34.0 (60.8% of the maximal obtainable score), respectively No significant differences were seen in the analysis by factors. Changes in portfolio during 2008 showed differences in items related with organization, evaluation and regulation. CONCLUSIONS: The questionnaire is a valid and highly reliable instrument, measuring perceptions about the portfolio by undergraduate medical students. The students perceived an improvement in their creativity and professionalism as one of the strengths of portfolio. The weaknesses identified during the implementation process helped us to focus changes in organization and evaluation to improve the portfolio as a dynamic process. PMID- 21526317 TI - [Transcranial sonography for the diagnosis of Parkinson disease]. AB - BACKGROUND: The detection of hyperechogenicity of the substantia nigra using trans cranial sonography can be predictive of the diagnosis of Parkinson Disease. AIM: To report an experience with transcranial sonography for the diagnosis of Parkinson disease. Material ana METHODS: One hundred sixteen patients with movement disorders were subjected to a transcranial sonography to detect the presence of hyperechogenicity of the substantia nigra and basal ganglia. Afterwards, two physicians, unaware of the results oft he sonography, examined the patients and reached a clinical diagnosis. The concordance between ultrasound results and the clinical diagnosis was analyzed. RESULTS: In 64 patients, a clinical diagnosis of Parkinson disease was reached. Of these, 52 patients had substantia nigra hyperechogenicity and in 12, it was normal. On the other hand ultrasound was normal in 42 of 43 patients without a clinical diagnosis of Parkinson disease. Therefore the sensitivity and specificity of trans cranial ultrasound for the diagnosis of Parkinson disease was 81 and 97%, respectively. CONCLUSIONS: Transcranial sonography has a good sensitivity and specificity for the diagnosis of Parkinson disease. PMID- 21526318 TI - [Effectiveness of a home visit program for adolescent mothers and their children]. AB - BACKGROUND: Home visiting is effective for the promotion and prevention of mother child health in other countries, especially in vulnerable populations such as pregnant teenagers. AIM: To evaluate the association between receiving a home visiting program during pregnancy and child development during the first year of life, maternal mental health, perception of social support and school attendance. MATERIAL AND METHODS: Cross sectional assessment of 132 teenage mother-sibling pairs. Of these, 87 received home visits and 45 were randomly assigned to a control group. The assessed variables were maternal mental health, perception of social support, life satisfaction, incorporation of mothers to school after delivery, child development and frequency of child abuse and neglect. RESULTS: Mothers that received home visits had a better mental health and went back to school in a higher proportion. No significant differences between groups were observed on perception of social support or child development. CONCLUSIONS: These results suggest the effectiveness of domiciliary visits performed by non professionals, to improve mental health and social integration of teenage mothers. PMID- 21526319 TI - [Nugent and Spiegel criteria for the diagnosis of bacterial vaginosis. Analysis of discordant specimens by the Ison and Hay method]. AB - BACKGROUND: Vaginal infection is the commonest cause of genital symptoms and has obstetric and gynecological implications. AIM: To compare the Nugent and Spiegel methods for the diagnosis of bacterial vaginosis (BV) and to analyze discordant specimens using Ison and Hay (Ison/Hay) criteria. MATERIAL AND METHODS: After discarding cases with Candidiasis, deficient specimens or those lacking bacteria, a total of 348 Gram-stained smears vaginal specimens received for the diagnosis of BV, were analyzed. RESULTS: Vaginal microbiota was classified as normal in 203 and 237 samples (58 and 68% of samples), according to Nugent and Spiegel criteria, respectively One hundred and five (30%) and 111 samples (32%), were classified as VB according to Nugent and Spiegel criteria, respectively. Both criteria were concordant in 308 samples (88.5%). The 40 (11.5%) discordant specimens were classified as intermediate microflora by the Nugent system and as normal or BV by Spiegel. Among these, the Ison/Hay procedure identified four categories of microbiota. Ten (25%) specimens were classified as grade II microbiota, confirming their categorization by Nugent as intermediate microbiota, six (15%) were classified in the III category, confirming the diagnosis of BV by Spiegel, 13 (32.5%) corresponded to the category III, that does not exist in the Nugent and Spiegel categorization systems. Finally, 11 specimens could not be assigned to one category due to microscopic limitations to distinguish bacterial morphotypes. CONCLUSIONS: The systems proposed by Spiegel, Nugent and Ison/Hay are comparable for the diagnosis of BV. However, we recommend the use of Ison/Hay procedure to evaluate vaginal microbiota, due to its wider range of categories, allowing a better discrimination of the vaginal microbiota. PMID- 21526320 TI - [Congenital malformations in Latin America in the period 1995-2008]. AB - BACKGROUND: The Latin American Study of Congenital Malformations (ECLAMC) has performed an epidemiological surveillance of congenital malformations since 1967. This allows to detect any unexpected change in the incidence of malformations, possibly caused by a new environmental teratogenic agent. AIM: To report a summary of the results thus far obtained in this study. MATERIAL AND METHODS: The ECLAMC database was analyzed and all live births and stillbirths of more than 500 grams in the period 1995-2008, were analyzed. RESULTS: There were 2,409,407 births in the nine participant countries. Of these 31,516 (1.3%) were stillbirths. The global rate of congenital malformations in this sample was 2.7%. In the studied period, there was a significant reduction in the rates of anencephaly and spina bifida in Chile and Argentina. In the rest of the countries, the global rates of malformations increased. Venezuela had the higher rate of teenage pregnancies (25%), followed by Colombia (23%). Chile had the higher percentage of women aged 35 years or more giving birth (14%), followed by Uruguay (13%). However, Chile had the higher rate of Down syndrome and Uruguay, the lowest (24.7 and 13.6 per 10000). CONCLUSIONS: There is a tendency towards an increase in the rates of congenital malformations in this sample, with significant differences among countries. PMID- 21526321 TI - [Recurrence of stress cardiomyopathy after an earthquake: report of one case]. AB - Stress-induced cardiomyopathy is characterized by transient systolic dysfunction of the apical or mid segments of the left ventricle that mimics myocardial infarction in the absence of obstructive coronary artery disease. Symptoms recur after a physical or emotional stress. We report a 77-year-old female that in 2004, suffered an episode of stress cardiomyopathy after an intense physical effort. In February 2010, immediately after the earthquake that occurred in Chile, the patient consulted for chest pain, ST segment elevation and enzyme elevation. An echocardiography showed a left ventricular anteroseptal akinesia with an ejection fraction of 35%. Coronary arteriography did not show significant alterations. PMID- 21526322 TI - [Combined periampullary adenocarcinoma and neuroendocrine tumor in type 1 neurofibromatosis: report of one case]. AB - Neurofibromatosis is a hereditary autosomal-dominant disease with high rates of de novo mutations, and carries a high risk of neoplasms. It affects both sexes and all races and ethnic groups. It is characterized by multiple cutaneous lesions and tumors, both benign and malignant, especially in the nervous system. We report a 52-year-old woman with a type 1 neurofibromatosis, presenting with fever, jaundice and weight loss. On physical examination, the patient was jaundiced and had "cafe au lait" spots in the skin. A magnetic resonance imaging showed bile duct dilation and a possible ampullar carcinoma. The patient was operated, during the exploration she presented a periampullary tumor and multiple small nodular lesions in the stomach, the tumor was resected with a pancreaticoduodenectomy and the nodular gastric lesions were biopsied. The pathological study revealed a combined adenocarcinoma and neuroendocrine duodenal tumor. The study of the stomach lesions revealed a gastrointestinal stromal tumor. Four months after surgery, the patient is in good condition. PMID- 21526323 TI - [Antagonism of tamoxifen and antidepressants among women with breast cancer]. AB - Tamoxifen is used as an adjuvant therapy to reduce breast cancer recurrence among women with estrogen receptor positive tumors. Antidepressants are also commonly used in such women, to treat depression or to manage hot flushes, a frequent tamoxifen secondary effect. Some antidepressants could potentially inhibit cytochrome P450 2D6, required to activate tamoxifen, interfering with its action. Although there is not a clear cut directive on the subject, it is nowadays recommended to treat women with antidepressants with the lower cytochrome P450 2D6 inhibition potential to avoid a possible antagonism that may reduce tamoxifen s prevention of breast cancer recurrence at least in some patients with CYP2D6 genetic variation. The recommended antidepressants are desvenlafaxine, milnacipran, venlafaxin, escitalopram and citalopram. PMID- 21526324 TI - [Autonomic disturbances in Parkinson disease]. AB - The current concept of Parkinson disease comprises a group of non-motor symptoms. Among these, dysautonomia is a common problem that deteriorates the quality of life of patients. In this article we review the most common dysautonomic manifestations that are observed in cardiovascular, gastrointestinal, urinary, genital and skin systems. Their possible role as risk factors, premotor symptoms and their implications in the pathogenesis of Parkinson disease are discussed. A general approach to the main syndromes, based in the available evidence and in our experience is also presented. PMID- 21526325 TI - [Injudicious and excessive use of antibiotics: public health and salmon aquaculture in Chile]. AB - Salmon aquaculture was one of the major growing and exporting industries in Chile. Its development was accompanied by an increasing and excessive use of large amounts of antimicrobials, such as quinolones, tetracyclines and florfenicol. The examination of the sanitary conditions in the industry as part of a more general investigation into the uncontrolled and extensive dissemination of the ISA virus epizootic in 2008, found numerous and wide-ranging shortcomings and limitations in management of preventive fish health. There was a growing industrial use of large amounts of antimicrobials as an attempt at prophylaxis of bacterial infections resulting from widespread unsanitary and unhealthy fish rearing conditions. As might be expected, these attempts were unsuccessful and this heavy antimicrobial use failed to prevent viral and parasitic epizootics. Comparative analysis of the amounts of antimicrobials, especially quinolones, consumed in salmon aquaculture and in human medicine in Chile robustly suggests that the most important selective pressure for antibiotic resistant bacteria in the country will be excessive antibiotic use in this industry. This excessive use will facilitate selection of resistant bacteria and resistance genes in water environments. The commonality of antibiotic resistance genes and the mobilome between environmental aquatic bacteria, fish pathogens and pathogens of terrestrial animals and humans suggests that horizontal gene transfer occurs between the resistome of these apparently independent and isolated bacterial populations. Thus, excessive antibiotic use in the marine environment in aquaculture is not innocuous and can potentially negatively affect therapy of bacterial infections of humans and terrestrial animals. PMID- 21526327 TI - [Pseudomonas aeruginosa septic arthritis of the temporomandibular joint in a young patient without malignant otitis externa]. PMID- 21526328 TI - Comparison of two different methods for performing combination analysis of force and posture risk factors in an epidemiological study. AB - OBJECTIVES: This study aimed to introduce a method of simultaneous combination analysis of multiple exposure parameters for large epidemiological studies of work-related upper-extremity musculoskeletal disorders (MSD) and compare this analysis method with the conventionally used job-level combination analysis method when applied in exposure-response analysis of work-related upper-extremity MSD. METHODS: Health outcome [carpal tunnel syndrome (CTS)] and physical exposure (forceful exertion and hand/wrist postures) data for 733 subjects were obtained from the baseline period of a 3-year work-related upper-extremity MSD study. Determinations of CTS cases were done based on a set of defined criteria. Physical exposure variables of several different types of forceful exertions and three different hand/wrist postures were collected onsite, processed, and analyzed using both a simultaneous combination and job-level combination analysis method. RESULTS: The commonly used job-level combination analysis method resulted in significantly different combination exposure distributions compared to the simultaneous combination analysis method, although the absolute differences were small. Both methods showed some significantly higher combined force-posture exposures among CTS cases than non-cases. CONCLUSIONS: The simultaneous combination method provides more realistic distribution information on combined exposure parameters compared to the job-level combination method that has been commonly used in epidemiological studies. The newly developed simultaneous combination analysis method needs to be used in larger scale work-related upper extremity MSD epidemiological studies to test its predictive power compared to the job-level combination analysis method. PMID- 21526329 TI - The mutual relationship between shift work and depressive complaints--a prospective cohort study. AB - OBJECTIVE: The aim of this study was to examine longitudinally the mutual relationship between shift work and depressive complaints. METHODS: Data from the ongoing Maastricht cohort study (1998-2008) were used. Firstly, the impact of shift work on the development of depressive complaints, defined as depressed mood, was studied. Both prospective and retrospective approaches were used, conducting, respectively, survival and logistic regression analyses, correcting for possible confounding factors. Secondly, the impact of depressed mood on changes in shift work at one-year follow-up was studied. All analyses were stratified for men and women and, where possible, for age (<45 versus >=45 years). RESULTS: Overall, the impact of shift work on the development of depressed mood over a ten-year period was rather small, although, male shift workers >=45 years did contribute to a higher risk of developing depressed mood [hazard risk (HR) 1.37, 95% confidence interval (95% CI) 1.01-1.86]. Retrospective analyses found higher odds of depressed mood and depressive disorder among former or current male shift workers than "never shift workers" [odds ratio (OR) 1.39, 95% CI 1.09-1.79 and OR 1.79, 95% CI 1.32-2.42, respectively]. Results lacked significance when correcting for demographic and work-related factors. Analyses studying the impact of depressed mood on changes in work schedules showed that the risk to change from shift to day work or from shift work to sick leave was higher when depressed mood was reported at baseline [relative risk (RR) shift to day work 1.98, 95% CI 1.13-3.47; RR shift work to sick leave 2.96, 95% CI 2.00-4.29]. CONCLUSIONS: Although shift work did not have a large impact on the development of depressed mood, results might be underestimated due to selection processes and possibly overcorrection. PMID- 21526330 TI - Quantitative grading using Grey Relational Analysis on ultrasonographic images of a fatty liver. AB - A quantitative graduation system based on Grey Relational Analysis is proposed to recognize fatty livers in B-scan ultrasonic images. We evaluated ultrasonography liver images from 95 subjects having fatty livers (Grade I, II, III) and 45 normal subjects, as diagnosed by an expert radiologist. In practice, ultrasonographical findings of fatty liver are based on the brightness level of the liver in comparison to the renal parenchyma. The development of a non invasive and accurate method would be of great clinical value as an alternative to diagnosing fatty liver based on the radiologist's visual perception. In this study, we also evaluated AST and ALT liver enzymes for fatty liver having different grades. A high correlation between enzymes and Grey Relational Grades were found. The Receiver Operating Characteristic (ROC) curves were obtained and yielded satisfactory classification results using sensitivity, specificity and area under the curve for computing graduation and distinguishing fatty livers from healthy livers. With the proposed method based on Grey Relational Analysis, not only misdiagnosis caused by subjective differences in clinical evaluation will be reduced, but also the early diagnosis fatty liver and quantitative assessment of its degree will be achieved. PMID- 21526331 TI - Barriers to physical activity: a study of self-revelation in an online community. AB - The importance of regular physical activity to overall health has been well established, yet adults in the United States are leading increasingly sedentary lives. Research suggests that lowering perceived barriers to exercise is an effective strategy for encouraging physical activity. This article describes the top barriers that emerged from a qualitative analysis of message board traffic from a three-month healthy lifestyle intervention that promoted physical activity and healthy eating. The findings further elaborate known barriers to physical activity-two of which are not reported as key barriers in prior research-and illustrate the value of a grounded approach to studying health and fitness behaviors. Based on our analysis, we identify design considerations for technologies that encourage and support physical activity. Understanding the needs of a population is a critical step in the design process, and this paper offers unique insights for those working in this growing domain. PMID- 21526332 TI - Deployment of secure mobile agents for medical information systems. AB - Changes in global population and demography, and advances in medicine have led to elderly population growth, creating aging societies from which elderly medical care has evolved. In addition, with the elderly susceptible to chronic diseases, this together with the changing lifestyles of young adults have not only pushed up patient numbers of chronic diseases, but also effected into younger patients. These problems have become the major focus for the health care industry. In response to patient demand and the huge shortage of medical resources, we propose remote healthcare medical information systems that combine patient physiological data acquisition equipment with real-time health care analyses. Since remote health care systems are structured around the Internet, in addition to considering the numerous public systems spread across insecure heterogeneous networks, compatibility among heterogeneous networks will also be another concern. To address the aforementioned issues, mobile agents are adopted. With a mobile agent's characteristics of easy adaptability to heterogeneity and autonomy, the problem of heterogeneous network environments can be tackled. To construct a hierarchical safe access control mechanism for monitoring and control of patient data in order to provide the most appropriate medical treatment, we also propose to use the Chinese Remainder Theorem and discrete logarithm to classify different levels of monitoring staff and hence, to grant permission and access according to their authorized levels. We expect the methods proposed can improve medical care quality and reduce medical resource wastage, while ensuring patient privacy. Finally, security analysis of the system is conducted by simulating a variety of typical attacks, from which it can be concluded that the constructed remote healthcare information system be secure. PMID- 21526333 TI - An efficient key-management scheme for hierarchical access control in e-medicine system. AB - In e-medicine system, the sharing of patients' medical histories scattered among medical institutions through the Internet is highly desirable. The most immediate cryptographic need certainly is an efficient key management method to solve dynamic access problems in a user hierarchy. In this paper, we propose a practical solution for dynamic access problem in a user hierarchy based on hybrid cryptosystems. When compared with Nikooghadam et al.'s scheme proposed most recently, the time complexity and the required storage space is reduced significantly. Moreover, it provides provable security, and is easy to implement. Therefore, our scheme is more suitable for e-medicine system. PMID- 21526335 TI - Neural mechanisms and models underlying joint action. AB - Humans, in particular, and to a lesser extent also other species of animals, possess the impressive capability of smoothly coordinating their actions with those of others. The great amount of work done in recent years in neuroscience has provided new insights into the processes involved in joint action, intention understanding, and task sharing. In particular, the discovery of mirror neurons, which fire both when animals execute actions and when they observe the same actions done by other individuals, has shed light on the intimate relationship between perception and action elucidating the direct contribution of motor knowledge to action understanding. Up to date, however, a detailed description of the neural processes involved in these phenomena is still mostly lacking. Building upon data from single neuron recordings in monkeys observing the actions of a demonstrator and then executing the same or a complementary action, this paper describes the functioning of a biologically constraint neural network model of the motor and mirror systems during joint action. In this model, motor sequences are encoded as independent neuronal chains that represent concatenations of elementary motor acts leading to a specific goal. Action execution and recognition are achieved through the propagation of activity within specific chains. Due to the dual property of mirror neurons, the same architecture is capable of smoothly integrating and switching between observed and self-generated action sequences, thus allowing to evaluate multiple hypotheses simultaneously, understand actions done by others, and to respond in an appropriate way. PMID- 21526334 TI - Non-invasive stimulation of the vibrissal pad improves recovery of whisking function after simultaneous lesion of the facial and infraorbital nerves in rats. AB - We have recently shown that manual stimulation of target muscles promotes functional recovery after transection and surgical repair to pure motor nerves (facial: whisking and blink reflex; hypoglossal: tongue position). However, following facial nerve repair, manual stimulation is detrimental if sensory afferent input is eliminated by, e.g., infraorbital nerve extirpation. To further understand the interplay between sensory input and motor recovery, we performed simultaneous cut-and-suture lesions on both the facial and the infraorbital nerves and examined whether stimulation of the sensory afferents from the vibrissae by a forced use would improve motor recovery. The efficacy of 3 treatment paradigms was assessed: removal of the contralateral vibrissae to ensure a maximal use of the ipsilateral ones (vibrissal stimulation; Group 2), manual stimulation of the ipsilateral vibrissal muscles (Group 3), and vibrissal stimulation followed by manual stimulation (Group 4). Data were compared to controls which underwent surgery but did not receive any treatment (Group 1). Four months after surgery, all three treatments significantly improved the amplitude of vibrissal whisking to 30 degrees versus 11 degrees in the controls of Group 1. The three treatments also reduced the degree of polyneuronal innervation of target muscle fibers to 37% versus 58% in Group 1. These findings indicate that forced vibrissal use and manual stimulation, either alone or sequentially, reduce target muscle polyinnervation and improve recovery of whisking function when both the sensory and the motor components of the trigemino facial system regenerate. PMID- 21526336 TI - Effects of movement stability and congruency on the emergence of spontaneous interpersonal coordination. AB - The current project evaluated the relationship between the stability of intrapersonal coordination and the emergence of spontaneous interpersonal coordination. Participants were organized into pairs, and each participant was instructed to produce either an inphase or antiphase pattern of intrapersonal bimanual coordination using two hand-held pendulums, while simultaneously performing an interpersonal puzzle task. At issue was whether the emergence and stability of spontaneous interpersonal rhythmic coordination is influenced by ("Experiment 1") the stability of the intrapersonal coordination patterns produced by co-actors and ("Experiment 2") the congruency of the intrapersonal coordination patterns produced by co-actors. The stability of intrapersonal movement coordination did not affect the emergence of spontaneous interpersonal coordination. The degree of interpersonal coordination observed was similar when both participants in a pair produced either inphase or antiphase patterns of intrapersonal bimanual coordination. Moreover, the congruency of the intrapersonal coordination patterns only slightly affected the emergence of interpersonal coordination, with only marginally lower inphase interpersonal entrainment when participants produced incongruent patterns of intrapersonal coordination (e.g., inphase-antiphase). Interestingly, movement observation and the emergence of interpersonal coordination did not affect the stability of intrapersonal bimanual coordination. The results suggest that interlimb rhythmic bimanual coordination reflects a single intrapersonal perceptual-motor synergy and that these bimanual synergies (not individual limbs) are what become spontaneously entrained interpersonally. PMID- 21526338 TI - Conflict with vision diminishes proprioceptive adaptation to muscle vibration. AB - Muscle vibration excites muscle spindles and creates illusory movement of a body part in a blindfolded individual. It is followed by an aftereffect, an illusion of return movement when vibration stops. The aftereffect reflects adaptation in the proprioceptive system. This adaptation is susceptible to attentional manipulations (Seizova-Cajic and Azzi in Exp Brain Res 203(1):213-219, 2010), but it is not known whether it is open to cross-modal influences unaided by those manipulations. We attempted to answer this question by allowing vision of the vibrated, stationary arm. We asked our participants (n = 20) to retain focus on the feeling of movement. They reported any illusory movement during 60-s biceps vibration (at 90 Hz), as well as following its offset, when vision of the arm was removed. During vibration, the proprioceptive movement illusion persisted, although the stationary arm was visible, but its duration and strength were much reduced in comparison with the no-vision condition. The movement aftereffect, experienced in total darkness following vibration offset, was also substantially weaker. The results show that proprioceptive adaptation is strongly modulated by vision. We propose that two processes contribute: perceptual (cross-modal binding with conflicting vision reduces the proprioceptive movement signal) and attentional (view of a stationary arm distracts from the proprioceptive movement signal). Our finding that during vibration, participants felt movement in the arm they could see, which was stationary, shows that cross-modal binding partially failed. This happened because the two percepts were too discrepant. However, only one-the visual-appeared real, and we argue that such an outcome is consistent with general principles of intersensory integration. PMID- 21526337 TI - Rhythmic movement in Parkinson's disease: effects of visual feedback and medication state. AB - Previous studies examining discrete movements of Parkinson's disease (PD) patients have found that in addition to performing movements that were slower than those of control participants, they exhibit specific deficits in movement coordination and in sensorimotor integration required to accurately guide movements. With medication, movement speed was normalized, but the coordinative aspects of movement were not. This led to the hypothesis that dopaminergic medication more readily compensates for intensive aspects of movement (such as speed), than for coordinative aspects (such as coordination of different limb segments) (Schettino et al., Exp Brain Res 168:186-202, 2006). We tested this hypothesis on rhythmic, continuous movements of the forearm. In our task, target peak speed and amplitude, availability of visual feedback, and medication state (on/off) were varied. We found, consistent with the discrete-movement results, that peak speed (intensive aspect) was normalized by medication, while accuracy, which required coordination of speed and amplitude modulation (coordinative aspect), was not normalized by dopaminergic treatment. However, our findings that amplitude, an intensive aspect of movement, was also not normalized by medication, suggests that a simple pathway gain increase does not act to remediate all intensive aspects of movement to the same extent. While it normalized movement peak speed, it did not normalize movement amplitude. Furthermore, we found that when visual feedback was not available, all participants (PD and controls) made faster movements. The effects of dopaminergic medication and availability of visual feedback on movement speed were additive. The finding that movement speed uniformly increased both in the PD and the control groups suggests that visual feedback may be necessary for calibration of peak speed, otherwise underestimated by the motor control system. PMID- 21526339 TI - Compression leggings modestly affect cardiovascular but not cerebrovascular responses to heat and orthostatic stress in young and older adults. AB - We tested the hypothesis that wearing commercially available compression leggings would attenuate postural reductions in mean arterial blood pressure (MAP) and cerebral perfusion during heat stress, particularly in older adults. Six older (70 years +/- 4) and six younger (29 years +/- 4) males were heated (esophageal temperature raised 0.5 degrees C) in a water-perfused suit whilst wearing compression or control leggings (>1 week apart, randomized order). Blood flow velocity in the middle cerebral artery (MCAv), blood pressure (photoplethysmography), total peripheral resistance (TPR; ModelFlow) and the partial pressure of end-tidal carbon dioxide were measured continuously before and during 3-min standing in each thermal state. When supine, compression leggings did not change any cardiorespiratory variables in either age group or thermal condition (P > 0.05). Upon standing, wearing compression leggings delayed (~15%; P = 0.044) the maximal drop (nadir) in MAP irrespective of age or thermal condition. During the last minute of standing, wearing compression leggings in normothermia increased TPR (+16%) in older participants but dropped TPR (-8%) in younger participants (P = 0.004 compression * age group). When standing and heated, wearing compression leggings lowered TPR in older and younger participants (~43%; P < 0.01) without changing MAP or MCAv (P > 0.05). In older adults, when standing, compression leggings maintained MAP by elevating TPR. In contrast, under combined heat and orthostatic stress, wearing compression leggings dropped TPR in both older and younger adults, though MAP and MCAv were maintained. PMID- 21526340 TI - NADPH regulates human NAD kinase, a NADP+-biosynthetic enzyme. AB - NAD kinase (NADK, EC 2.7.1.23) is the sole NADP(+)-biosynthetic enzyme that catalyzes phosphorylation of NAD(+) to yield NADP(+) using ATP as a phosphoryl donor, and thus, plays a vital role in the cell and represents a potentially powerful antimicrobial drug target. Although methods for expression and purification of human NADK have been previously established (Lerner et al. Biochem Biophys Res Commun 288:69-74, 2001), the purification procedure could be significantly improved. In this study, we improved the method for expression and purification of human NADK in Escherichia coli and obtained a purified homogeneous enzyme only through heat treatment and single column chromatography. Using the purified human NADK, we revealed a sigmoidal kinetic behavior toward ATP and the inhibitory effects of NADPH and NADH, but not of NADP(+), on the catalytic activity of the enzyme. These inhibitory effects provide insight into the regulation of intracellular NADPH synthesis. Furthermore, these attributes may provide a clue to design a novel drug against Mycobacterium tuberculosis in which this bacterial NADK is potently inhibited by NADP(+). PMID- 21526341 TI - Phosphorylation of human small heat shock protein HspB8 (Hsp22) by ERK1 protein kinase. AB - A number of phosphomimicking mutants (replacement of Ser/Thr residues by Asp) of human small heat shock protein HspB8 were obtained and phosphorylation of the wild type HspB8 and its mutants by ERK1 kinase was analyzed in vitro. Mutation S159D does not affect phosphorylation, whereas mutations S24D and S27D equally moderately inhibited and mutation T87D strongly inhibited phosphorylation of HspB8. The double mutations S24D/T87D and S27D/T87D induced very strong inhibitory effect and the triple mutations S24D/S27D/T87D completely prevented phosphorylation catalyzed by ERK1. Thus, Ser24 and Thr87, found to be phosphorylated in vivo, are among the sites phosphorylated by ERK1 in HspB8 in vitro. Mutations S24D and T87D affect intrinsic tryptophan fluorescence and susceptibility to chymotrypsinolysis of HspB8. Phosphomimicking mutations and phosphorylation promote concentration-dependent association of HspB8 subunits. Mutations S24D and S27D decrease, whereas mutation T87D increases the chaperone like activity of HspB8. It is concluded that phosphorylation catalyzed by ERK1 might affect the structure and chaperone-like activity of HspB8 and therefore can be important for regulation of interaction of HspB8 with different target proteins. PMID- 21526342 TI - MiR-126-3p regulates progesterone receptors and involves development and lactation of mouse mammary gland. AB - MicroRNAs (miRNAs) are small (18-22 nucleotide) non-coding, endogenous regulatory RNA molecules, and they regulate gene expression at the post-transcriptional level through binding to their target mRNAs by base-pairing and subsequently inducing either translational repression or mRNA destabilization by plants, animals, and some viruses. In this study, combining microarray techniques with qRT-PCR, we found that miR-126-3p expression showed significant difference in the mouse mammary cycle during pregnancy, particularly on transition from pregnancy to lactation. Bioinformatics were used to predict target gene of miR-126-3p, and luciferase activity assay to test it, it showed that the progesterone receptor (PGR) 3'UTR is directly targeted by miR-126-3p. In this study, mouse mammary epithelial cells as cell model in vitro were used to study the function of miR 126-3p. Using gene silencing and over-expression for miR-126-3p, the expression of PGR protein and the secretion of casein were detected by western blotting and HPLC, respectively. To determine whether miR-126-3p can affect mouse mammary epithelial cells viability, cells were analyzed by CASY-YY. In conclusion, PGR gene confirmed miR-126-3p target genes through luciferase activity and western blotting. And miR-126-3p could also inhibit proliferation of mouse mammary epithelial cells (P < 0.01) and expression of beta-casein (P < 0.01), and down regulate PGR protein (P < 0.05). Our results suggested that miR-126-3p inhibited expression of PGR protein level as well as the proliferation of mammary epithelial cells, therefore miR-126-3p could play an important role in the process of mammary gland development. PMID- 21526343 TI - SP1 suppresses phorbol 12-myristate 13-acetate induced up-regulation of human regucalcin expression in liver cancer cells. AB - There is a growing evidence that regucalcin (RGN) plays a multifunctional role in liver cancer cells. Previous reports showed that the presence of phorbol 12 myristate 13-acetate (PMA) caused a significant increase in RGN mRNA expression and promoter activity in rat hepatoma cells. In this study, we confirmed that human RGN is also up-regulated by PMA treatment independent of translation, and we identified the mechanism by which PMA up-regulates the expression of human RGN via driving SP1 away from a SP1 motif located within -188/-180 of the promoter in HepG2 cells. Overexpression of SP1 dramatically reduces PMA-induced up-regulation of both internal expression of mRNA and promoter activity, whereas knockdown of SP1 has the opposite effect. Therefore, the present study delineates the fundamental elements in the promoter which will be helpful in the future studies on the regulation of RGN expression in liver cancer. PMID- 21526344 TI - Increased JNK1 activity contributes to the upregulation of ApoD in the apocrine secretory gland cells from axillary osmidrosis. AB - Axillary osmidrosis is a benign disorder that causes functional and emotional problems in Asian patients. Recently, ApoD has been identified as an axillary odorant binding protein. The present study was designed to compare the expression of ApoD in normal and osmidrosis subjects. Compared with the normal subjects, osmidrosis subjects had a higher expression of AR and ApoD in the apocrine samples, both at mRNA and protein level. Further study showed that, consistent with the increased ApoD and AR, phosphorylated JNK1 was higher in apocrine samples from axillary osmidrosis subjects, while with no obvious differences of the total expression of JNK1. In the cultured apocrine epithelial cells from normal subjects, 5alpha-dihydrotestosterone (5alpha-DHT) increased the expression of ApoD in a dose dependent manner, which can be inhibited by the JNK1 inhibitor. In contrast, in the cultured apocrine epithelial cells from axillary osmidrosis subjects, inhibition of JNK1 significantly reduced the expression of ApoD. Taken together, our study here revealed that increased JNK1 activation in the apocrine cells from axillary osmidrosis contributes to the increased ApoD expression, which in turn involved in the process of axillary osmidrosis. PMID- 21526345 TI - Coupled expression of dipeptidyl peptidase-IV and fibroblast activation protein alpha in transformed astrocytic cells. AB - Dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein-alpha (FAP) are speculated to participate in the regulation of multiple biological processes, because of their unique enzymatic activity, as well as by non-hydrolytic molecular interactions. At present, the role of DPP-IV and FAP in the development and progression of various types of tumors, including glioblastoma, is intensively studied, and their functional crosstalk is hypothesized. In this article, we describe the correlative expression of DPP-IV and FAP mRNA in primary cell cultures derived from human glioblastoma and associated expression dynamics of both molecules in astrocytoma cell lines depending on culture conditions. Although the molecular mechanisms of DPP-IV and FAP co-regulations remain unclear, uncoupled expression of transgenic DPP-IV and the endogenous FAP suggests that it occurs rather at the transcriptional than at the posttranscriptional level. Understanding of the expressional and functional coordinations of DPP-IV and FAP may help clarify the mechanisms of biological roles of both molecules in transformed astrocytic cells. PMID- 21526346 TI - Curcumin induces DNA damage and caffeine-insensitive cell cycle arrest in colorectal carcinoma HCT116 cells. AB - Curcumin (CUR), a polyphenol derived from the plant Curcuma longa, displays potential anti-cancer activity. One of the mechanisms stems from its ability to elicit cell cycle arrest followed by suppression of cell proliferation. Herein, we reported that CUR significantly induced DNA damage and mediated S and G2/M phase arrest in colorectal carcinoma HCT116 cells. Unlike etoposide, a classical topoisomerase II inhibitor, CUR-triggered G2/M phase arrest was hardly reversed by caffeine (CAFF) which is an inhibitor of activated ataxia-telangiectasia mutated (ATM)/ATM- and Rad3-related (ATR), indicating that ATM and ATR signaling pathways may be not involved in CUR-mediated S and G2/M phase arrest in HCT116 cells. Furthermore, we demonstrated that CUR caused mitosis arrest in HCT116 cells by using mitotic protein monoclonal antibody-2 as a mitosis marker and the surface plasmon resonance assay. The findings provide new mechanisms of cell proliferation inhibition triggered by CUR in HCT116 cells. PMID- 21526348 TI - Motoneuron model of self-sustained firing after spinal cord injury. AB - Under many conditions spinal motoneurons produce plateau potentials, resulting in self-sustained firing and providing a mechanism for translating short-lasting synaptic inputs into long-lasting motor output. During the acute-stage of spinal cord injury (SCI), the endogenous ability to generate plateaus is lost; however, during the chronic-stage of SCI, plateau potentials reappear with prolonged self sustained firing that has been implicated in the development of spasticity. In this work, we extend previous modeling studies to systematically investigate the mechanisms underlying the generation of plateau potentials in motoneurons, including the influences of specific ionic currents, the morphological characteristics of the soma and dendrite, and the interactions between persistent inward currents and synaptic input. In particular, the goal of these computational studies is to explore the possible interactions between morphological and electrophysiological changes that occur after incomplete SCI. Model results predict that some of the morphological changes generally associated with the chronic-stage for some types of spinal cord injuries can cause a decrease in self-sustained firing. This and other computational results presented here suggest that the observed increases in self-sustained firing following some types of SCI may occur mainly due to changes in membrane conductances and changes in synaptic activity, particularly changes in the strength and timing of inhibition. PMID- 21526349 TI - Prosthetic vascular graft infections: a contemporary approach to diagnosis and management. AB - Improvements in manufacturing and implantation techniques, coupled with an increasing prevalence of atherosclerosis in an aging population, have led to increased utilization of prosthetic vascular grafts. The infection rates of vascular grafts are low. However, when they do occur, high rates of morbidity and mortality can be expected. The purpose of this article is to review the published literature regarding epidemiology, risk factors, pathogenesis, and clinical manifestations of prosthetic vascular graft infections. Moreover, we provide a practical approach to the diagnosis and management of these complicated infections based on empirically grounded evidence. PMID- 21526350 TI - Healthcare-associated bacterial meningitis. AB - Healthcare-associated bacterial meningitis may occur after neurosurgical procedures, head trauma, and following placement of external or internal ventricular catheters. The likely microorganisms that cause meningitis in this setting (ie, staphylococci and gram-negative bacilli) are different from those that cause meningitis in the community setting. Any clinical suspicion of healthcare-associated bacterial meningitis should prompt a diagnostic evaluation (neuroimaging and cerebrospinal fluid analysis) and appropriate management. Empiric antimicrobial therapy should be directed toward the likely infecting pathogen; based upon clinical response, intraventricular administration of specific agents may be required. With the emergence of resistant gram-negative bacilli (especially Acinetobacter baumannii) that may cause healthcare-associated meningitis, empiric therapy with a carbapenem, with or without an aminoglycoside administered by the intraventricular or intrathecal route, is recommended; colistin (given intravenously and/or intraventricularly) can be used if the organism is subsequently found to be resistant to carbapenems. PMID- 21526351 TI - The goal of blood pressure control for prevention of early diabetic microvascular complications. AB - Lowering blood pressure may confer a benefit to diabetic microvascular complications comparable with glycemic control. Hypertension is causally related to kidney outcomes and is a risk factor for the development of diabetic retinopathy. The prevalence of hypertension increases as kidney disease progresses, so that it coexists with diabetes in up to 80% of those with overt nephropathy. A significant number of patients have hypertension or rising blood pressures in earlier stages, or even before microvascular complications appear. Because microalbuminuria markedly increases the risk of overt nephropathy as well as of cardiovascular complications, primary prevention (i.e., preventing or delaying the onset of microalbuminuria) continues to be explored, predominantly through use of renin-angiotensin blockade. Available data reviewed suggest that primary prevention through blood pressure reduction is more likely to benefit select groups (those with hypertension, cardiovascular risks, or old age). This review discusses the relationship between hypertension, diabetes, and kidney disease, the rationale for primary prevention, and the data that led to that conclusion. PMID- 21526352 TI - Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells. AB - PURPOSE: To investigate the activity and myeloprotective properties of erufosine, a novel alkylphosphocholine (APC), on human malignant cells and normal bone marrow cells. METHODS: Human or mouse bone marrow cells were exposed to erufosine, miltefosine, perifosine, or edelfosine in CFU-GM assays. Human MDA-MB 231 breast carcinoma, Panc-1 pancreatic carcinoma, and RPMI8226 multiple myeloma cells were exposed to erufosine in colony formation assays. Colony formation of Panc-1 tumor cells and mouse bone marrow cells ex vivo were quantified following intravenous administration of erufosine to tumor-bearing mice. Western blotting methods were applied to human U87 glioblastoma cells exposed to erufosine to investigate Akt inhibition. RESULTS: Erufosine was less toxic to human and mouse bone marrow cells than perifosine, miltefosine, and edelfosine and was equally toxic to human and mouse CFU-GM. The human cancer cells MDA-MB-231 breast, Panc-1 pancreatic, and RPMI8226 MM cells were more sensitive to erufosine in a colony formation assay than were human bone marrow cells generating an approximately tenfold differential in IC(90) values. Erufosine injected intravenously significantly reduced Panc-1 tumor cell colony formation ex vivo but not mouse bone marrow CFU-GM. Erufosine inhibited Akt phosphorylation in human U87 glioblastoma cells. CONCLUSIONS: Erufosine offers potential as a novel therapeutic for cancer with a reduced toxicity profile to bone marrow cells compared with other agents in this class. Human cancer cells were more sensitive to erufosine than human or mouse bone marrow cells indicating a favorable therapeutic window for erufosine. PMID- 21526354 TI - The effects of caloric restriction on health and longevity. AB - OPINION STATEMENT: There is increasing evidence that restricting caloric intake may have considerable health benefits in humans. Significant evidence in non primate animals demonstrates that caloric restriction increases average and maximal life span. However, historically, caloric intake reduction in humans has been involuntary and accompanied by poverty, malnutrition, poor sanitation, and a lack of modern health care. As a result, caloric restriction in people typically has been accompanied by a reduction of both average and maximal life span. Conversely, improvements in standards of living usually are accompanied by an increased food supply and resultant improved health and longevity. The majority of the world is now in a new era where an abundance of caloric intake and its associated obesity are causing widespread chronic illness and premature death. What would happen if one were to institute caloric restriction with high-quality nutrition within an environment of modern sanitation and health care? This review argues that improved health and improved average life span would quite likely result. A lengthening of maximal human life span with this combination is perhaps possible but by no means certain. PMID- 21526353 TI - Phase I trial of capecitabine plus everolimus (RAD001) in patients with previously treated metastatic gastric cancer. AB - PURPOSE: Everolimus is a novel inhibitor of the mammalian target of rapamycin pathway, which is aberrantly activated in cancer cell. We conducted a phase I study of capecitabine plus everolimus (RAD001) in refractory gastric cancer patients. METHODS: Patients with metastatic gastric cancer and progression after prior chemotherapy were eligible. Four dose levels were planned as follows: Level 1, 5 mg bid/day of everolimus (D1-D21) and 500 mg/m(2) bid/day of capecitabine (D1-14); Level 2, 5 mg bid/day of everolimus (D1-D21) and 750 mg/m(2) bid/day of capecitabine (D1-14); Level 3, 5 mg bid/day of everolimus (D1-D21) and 1000 mg/m(2) bid/day of capecitabine (D1-14); and Level 4, 10 mg bid/day of everolimus (D1-D21) and 1000 mg/m(2) bid/day of capecitabine (D1-14). Treatment was repeated every 3 weeks until disease progression, patient refusal, or any serious adverse event. RESULTS: Fifteen patients were enrolled in this study between November 2009 and April 2010. Fifteen patients were enrolled (median age, 50 years; men, 9). Six patients had received two previous chemotherapy regimens; six patients had three previous chemotherapy regimens before the study treatment. Thus, the majority of patients were heavily pretreated. The dose-limiting toxicities were grade 3 infection, grade 3 mucositis, and grade 3 hyperglycemia and hyponatremia. After a median follow-up duration of 5.6 months (range, 2.3-8.1 months), median PFS was 1.8 months (95% CI, 0.8-2.8 months). The maximum best change observed was a 28.7% decrease in sum of longest diameters when compared with baseline. CONCLUSIONS: The combination of capecitabine and everolimus showed satisfactory toxicity profile and modest clinical benefit in patients with refractory gastric cancer. The recommended dose of capecitabine and everolimus was 650 mg/m(2) twice daily and 5 mg twice daily, respectively. PMID- 21526355 TI - A phase II study of the halichondrin B analog eribulin mesylate in gemcitabine refractory advanced pancreatic cancer. AB - BACKGROUND: Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics. Pre-clinical studies have suggested anti-tumor activity in pancreatic cancer. This phase II study of eribulin in patients with advanced pancreatic cancer previously treated with gemcitabine was conducted by the Princess Margaret Hospital Phase II consortium. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and previous treatment with gemcitabine. The study was a single arm phase II trial using a Simon 2-stage design. The primary endpoint was response rate, secondary endpoints included time to progression and overall survival. RESULTS: Fifteen patients were enrolled, 14 received treatment, and 12 were evaluable for response. The median age was 61, and the majority of patients were ECOG performance status 1. Grade 3 or greater adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses and therefore the study was closed after the first stage. The best response was stable disease in 5/12 (42%) of patients. Of these five patients, three had stable disease for 9 months or greater. Median time to progression was 1.4 months, and median overall survival was 6.1 months. CONCLUSION: Eribulin was well tolerated but did not result in any objective responses in gemcitabine refractory pancreatic cancer. However, several patients had prolonged stable disease, suggesting that further studies of eribulin in pancreatic cancer may be warranted. PMID- 21526356 TI - Response of fat-tailed Syrian Awassi ewes to accelerated lambing systems. AB - Fifty cyclic fat-tailed Syrian Awassi ewes aged 2-4 years, with a mean weight of 51.4 kg, were used for 4 years to assess the accelerated lambing system (three lambings in 2 years). Ewes were divided into two groups: treated (T) and untreated (C). Ewes in the T group were treated with flugestone acetate for 14 days and injected intramuscularly at sponge withdrawal with 500 IU of equine chorionic gonadotropin (eCG). Results indicated that ewes in the T group exhibited oestrus and were mated within 5 days post sponge removal compared to 11 days for ewes in the C group, and the difference in oestrus response between the two groups was significant (P < 0.001). Repeated hormonal treatments had no significant (P > 0.05) effect on the lamb birth weight. However, significant (P < 0.001) differences in the lamb birth weight were observed between singles and multiple births. In the treated ewes, the total number of lambs born was 211-157 parturitions, and the multiple birth rate reached 27.4%, whereas the rate in the untreated group was 6.3% with the difference being significant (P < 0.05). In the untreated ewes, the total number of lambs born was 14-13 parturitions (12 singles and 1 twin). Fecundity rates were 135.1% and 106.3% in the treated and untreated ewes, respectively, and the difference was significant (P < 0.05). Repeated administration of eCG had no negative effect on fertility of Syrian Awassi ewes. However, anti-eCG antibodies were produced following eCG injections with extremely high individual differences in the immune response among ewes. PMID- 21526357 TI - Prevalence of neuropathic pain among Black African patients suffering from common low back pain. AB - To study the prevalence and semiotic characteristics of neuropathic pain in the common low back pain to the Black African subject. This was a prospective cross sectional survey carried on from April 1 2009 to August 31 2009 in consultations of rheumatology, neurology, and neurosurgery at the University Hospital Yalgado Ouedraogo in Ouagadougou (Burkina Faso). All patients with a low back pain or a common lomboradiculalgie were included. DN4 questionnaire was used for the diagnosis of neuropathic pain. One hundred and seven patients have been recruited during the study period; Sixty-four (59.80%) were female (sex ratio M/F: 0.67). The average age was 34.11 +/- 13.46 years of age with extremes of 20 and 79. The average duration of disease was 48.53 months with extremes of 10 days and 50 years. Eighty-seven patients (81.31%) had a disease duration, which was 3 months longer. Sixty-six patients (61.70%) had a predominant lomboradiculalgie; among the remaining 41, low back pain predominated. Average intensity of pain was 62.81 +/- 22.43 (on a scale of 100). A sign of Laseque was present in the 41 (38.30%) patients. Fifty-three (49.5%) patients had a neuropathic pain. The prevalence of neuropathy signs according to the DN4 questionnaire was as follows: burning (n = 37; 34.58%), painful cold (n = 13; 12.15%), electric shocks (n = 31; 38.97%), pins and needles (n = 34; 31.77%), tingling (n = 35; 32.71%), numbness (n = 45; 42.05%), itching (n = 18; 16.82%), touch hypoesthesia (n = 35; 32.71%), pinprick (n = 33; 30.84%), and tactile allodynia (n = 21; 19.62%). Among the studied variables, the presence of a radiculalgy was statistically associated with neuropathic pain. The lomboradiculalgie of the Black African subject associates neuropathic pain observed in half of patients. Treatment must therefore always take account of this association. However, further studies are needed before any definitive conclusion. PMID- 21526358 TI - Polyarticular lipoma arborescens--a clinical and aesthetical case. AB - Lipoma arborescens is a benign tumor, but it may be a reactive process to other disorders, and its clinical, analytical, radiological and ultrasound presentation may be redundant to any synovial tumor. Despite the characteristic feature on magnetic resonance imaging (MRI), the correct differential diagnosis in atypical presentation, and the need for timely removal of the lesion to prevent joint damage, forces, ultimately, to invasive procedures. The clinical case reported here, fourth described in English language publications on the polyarticular form, also presented other specificities related to one of the swellings, in the knee. Because of its atypical location in the popliteal fossa, recurrent episodes of joint effusion, personal history of knee trauma, pulmonary tuberculosis, and family history of rheumatoid arthritis required particular attention. This process was hampered by the refusal of knee (and ankle) surgery by the patient. He accepted surgical removal of the swellings of the wrists, for aesthetical reasons, with pathologic confirmation of the diagnosis, and clinical success in that location. MRI of the knee showed the typical image of lipoma arborescens, but also other changes that compromise the prognosis. PMID- 21526360 TI - What role do mucins have in the development of laryngeal squamous cell carcinoma? A systematic review. AB - Mucins are the dominant component in the protective mucus layer on mucosal surfaces including the larynx. Hence, they are part of the first line of defence against external stimuli including effect of smoking in the larynx. We asked whether existing published evidence supported the hypothesis that alteration in mucins expression/production is related to the laryngeal neoplastic process. The objective of this study is to review published evidence for mucins having an important role in normal laryngeal physiology and the development of laryngeal squamous cell carcinoma (SCC). We aimed to review all available literature on mucins in the larynx in order to develop hypotheses to be tested by future research. Thereby, new potential means of prevention and treatment of laryngeal cancer may be developed. A systematic search of all published literature was conducted. Systematic searches were done in the following databases: AMED, BNI, EMBASE, HMIC, MEDLINE, PsycINFO, CINAHL and HEALTH BUSINESS ELITE from their respective inception up to 11 February 2011. The following keywords were used in combination: mucin, larynx and squamous cell carcinoma. Altogether, 53 studies were identified; 43 studies were excluded following screening of the titles and abstracts. Full text manuscripts for ten studies were obtained for detailed evaluation and five studies were included in this review. No single study fulfilled all relevant criteria. Based on the included studies, we now know that MUC1 is definitely expressed in SCC larynx. However, there is no definitive evidence to suggest that MUC1 and MUC2 are aberrantly expressed in SCC larynx as compared to normal larynx. Further studies using the best available detection technique to detect MUC1, MUC2 and other possible relevant mucins i.e., MUC4 on adequate numbers of normal and SCC specimens are needed to confirm the findings of this review. PMID- 21526359 TI - Intraperitoneal administration of poly(I:C) with polyethylenimine leads to significant antitumor immunity against murine ovarian tumors. AB - Ovarian cancer is currently the most lethal gynecologic cancer in the United States. There is an urgent need for the development of innovative therapies against ovarian cancer, such as immunotherapy. The toll-like receptor 3 ligand, polyriboinosinic:polyribocytidylic acid (poly(I:C), has emerged as a promising adjuvant for activating the host immune responses for the control of tumors. We reasoned that a strategy to enhance the intracellular uptake of poly(I:C) will likely improve the poly(I:C) adjuvant effect. Since polyethylenimine (PEI) has been shown to increase the transfection efficiency of nucleic acids, we characterized the antitumor effects in mouse ovarian surface epithelial cells (MOSEC) tumor-bearing mice treated intraperitoneally with poly(I:C) and PEI. We observed that tumor-bearing mice treated with poly(I:C) and PEI generated significantly better therapeutic antitumor effects against MOSEC tumors compared with treatment with poly(I:C) alone. Furthermore, we found that NK cells play a significant role in the antitumor effects generated by treatment with poly(I:C) in combination with PEI. Intraperitoneal administration of poly(I:C) with PEI led to the uptake of poly(I:C) mainly by CD11b+ macrophages, resulting in the high expression of MHC class II and IL-12 (M1 phenotype). In addition, adoptive transfer of CD11b+ macrophages from mice treated with poly(I:C) and PEI was found to lead to increased number of activated NK cells in the recipient mice. Taken together, our data indicate that PEI can potentially be used to improve the uptake of poly(I:C) by CD11b+ macrophages, leading to the activation of NK cells and the control of murine ovarian tumors. PMID- 21526361 TI - Attraction and electroantennogram responses of male Mediterranean fruit fly to volatile chemicals from Persea, Litchi and Ficus wood. AB - Trimedlure is the most effective male-targeted lure for the Mediterranean fruit fly, Ceratitis capitata (Wiedemann). A similar response is elicited by plant substances that contain alpha-copaene, a naturally-occurring sesquiterpene. alpha Copaene is a complex, highly-volatile, widely-distributed plant compound, and male C. capitata respond to material from both hosts (e.g., Litchi chinensis) and non-hosts (e.g., Ficus benjamina) that contain alpha-copaene. Avocado, Persea americana, recently was found to contain varying amounts of alpha-copaene in the bark and underlying cambial tissue. Short-range attraction bioassays and electroantennography (EAG) were used to quantify responses of sterile male C. capitata to samples of rasped wood from four avocado genotypes, L. chinensis, and F. benjamina. Gas chromatography-mass spectral (GC-MS) analysis was used to identify and quantify the major sesquiterpenes. Attraction and EAG amplitude were correlated, with L. chinensis eliciting the highest and F. benjamina the lowest responses. Responses to the avocado genotypes were intermediate, but varied among the four types. GC-MS identified 13 sesquiterpenes, including alpha-copaene, from all samples. Amounts of alpha-copaene in volatile collections from samples (3 g) ranged from 11.8 MUg in L. chinensis to 0.09 MUg in F. benjamina, which correlated with short-range attraction and EAG response. alpha-Copaene ranged from 8.0 to 0.8 MUg in the avocado genotypes, but attraction and EAG responses were not correlated with the amount of alpha-copaene. Differences in enantiomeric structure of the alpha-copaene in the different genotypes and/or presence of additional sesquiterpenes may be responsible for the variation in male response. EAG responses were correlated with the amount of several other sesquiterpenes including alpha-humulene, and this compound elicited a strong antennal response when tested alone. PMID- 21526362 TI - The implication of second-trimester amniotic fluid TNF-alpha, cytochrome C and cell death nucleosomes in the prediction of preterm labor and/or premature rupture of membranes. AB - AIM: The multifactorial pathway leading to preterm labor possibly includes the implication of apoptosis. This study aimed to clarify the role of amniotic fluid apoptotic molecules (TNF-alpha, cytochrome C and cell death nucleosomes) at midtrimester as possible predictors of preterm labor (PTL) and/or premature rupture of membranes (PROM). METHOD: In this case-control study, comprising 360 women undergoing genetic amniocentesis and out of whom 38 delivered preterm and 18 out of the latter after PROM, the above apoptotic molecules were determined by ELISA. The 38 cases with PTL and 18 cases with PROM were matched for age with 38 and 18 respective controls delivering at term, and the levels of apoptotic molecules were compared. RESULTS: Cell death nucleosome levels were found to be significantly associated with preterm delivery. Specifically, for every unit increase in nucleosomes, women were on average 0.2% more likely to deliver preterm (OR: 1.002, CI: 1.0-1.003, p = 0.018). In contrast, such an association was not found concerning the other two apoptotic molecules (TNF-a and Cytochrome C). CONCLUSION: Second-trimester amniotic fluid cell death nucleosomes' levels are significantly associated with preterm delivery and could possibly serve as predicting markers. PMID- 21526363 TI - Relative quantity judgments in South American sea lions (Otaria flavescens). AB - There is accumulating evidence that a variety of species possess quantitative abilities although their cognitive substrate is still unclear. This study is the first to investigate whether sea lions (Otaria flavescens), in the absence of training, are able to assess and select the larger of two sets of quantities. In Experiment 1, the two sets of quantities were presented simultaneously as whole sets, that is, the subjects could compare them directly. In Experiment 2, the two sets of quantities were presented item-by-item, and the totality of items was never visually available at the time of choice. For each type of presentation, we analysed the effect of the ratio between quantities, the difference between quantities and the total number of items presented. The results showed that (1) sea lions can make relative quantity judgments successfully and (2) there is a predominant influence of the ratio between quantities on the subjects' performance. The latter supports the idea that an analogue representational mechanism is responsible for sea lions' relative quantities judgments. These findings are consistent with previous reports of relative quantities judgments in other species such as monkeys and apes and suggest that sea lions might share a similar mechanism to compare and represent quantities. PMID- 21526364 TI - Phytochemical analysis of medicinal plants with kidney protective activities. AB - In view of the increasing number of patients undergoing kidney dialysis or transplant every year, a survey of the literature on renal protective medicinal plants was undertaken. Most of them are from traditional Chinese medicine (TCM). Although many of the medicinal herbs reported have not been investigated in terms of active chemical ingredients, some do have compounds well characterized. They fall into a wide range of structures. Several groups of compounds with well established activities are discussed. These include: antioxidant phenolic compounds like tannins, flavonoids, isoflavonoids, unsaturated organic acids and lignans; circulation enhancing compounds like saponins, and basic alkaloids with multiple targets (G-protein coupled receptors). Also presented are proinflammatory and antiinflammatory fatty acids like linoleic (n-6) and alpha linolenic (n-3) acids, respectively. Attention is also drawn to the plants containing nephrotoxic aristolochic acid. Different directions of future research are also presented. We hope that this review may provide some leads for new drug discovery and development, and more rational application of TCM. PMID- 21526365 TI - Systematic review on randomized controlled clinical trials of acupuncture therapy for neurovascular headache. AB - OBJECTIVE: To evaluate the effectiveness of acupuncture as a treatment for neurovascular headache and to analyze the current situation related to acupuncture treatment. METHODS: PubMed database (1966-2010), EMBASE database (1986-2010), Cochrane Library (Issue 1, 2010), Chinese Biomedical Literature Database (1979-2010), China HowNet Knowledge Database (1979-2010), VIP Journals Database (1989-2010), and Wanfang database (1998-2010) were retrieved. Randomized or quasi-randomized controlled studies were included. The priority was given to high-quality randomized, controlled trials. Statistical outcome indicators were measured using RevMan 5.0.20 software. RESULTS: A total of 16 articles and 1 535 cases were included. Meta-analysis showed a significant difference between the acupuncture therapy and Western medicine therapy [combined RR (random efficacy model)=1.46, 95% CI (1.21, 1.75), Z=3.96, P<0.0001], indicating an obvious superior effect of the acupuncture therapy; significant difference also existed between the comprehensive acupuncture therapy and acupuncture therapy alone [combined RR (fixed efficacy model)=3.35, 95% CI (1.92, 5.82), Z=4.28, P<0.0001], indicating that acupuncture combined with other therapies, such as points injection, scalp acupuncture, auricular acupuncture, etc., were superior to the conventional body acupuncture therapy alone. CONCLUSIONS: The inclusion of limited clinical studies had verified the efficacy of acupuncture in the treatment of neurovascular headache. Although acupuncture or its combined therapies provides certain advantages, most clinical studies are of small sample sizes. Large sample size, randomized, controlled trials are needed in the future for more definitive results. PMID- 21526366 TI - Blocking effect of salvianolic acid A on calcium channels in isolated rat ventricular myocytes. AB - OBJECTIVE: To study the effect of salvianolic acid A (SAA) on L-type calcium current (I-CaL) in isolated ventricular myocytes of Sprague-Dawley rats. METHODS: SAA powder was dissolved in normal Tyrode's solution to reach the concentrations of 1, 10, 100, and 1000 MUmol/L. The traditional whole-cell patch-clamp recording technique was employed to evaluate the effects of SAA on I-CaL in single ventricular myocytes which were prepared by Langendorff perfusion apparatus from Sprague-Dawley rats. RESULTS: SAA (1, 10, 100, and 1000 MUmol/L) inhibited I-CaL peak value by 16.23%+/-1.3% (n=6, P<0.05), 22.9%+/-3.6% (n=6, P<0.05), 53.4%+/ 3.0% (n=8, P<0.01), and 62.26%+/-2.9% (n=6, P<0.01), respectively. SAA reversibly inhibited I-CaL in a dose-dependent manner and with a half-blocking concentration (IC(50)) of 38.3 MUmol/L. SAA at 100 MUmol/L elevated the I-V curve obviously, and shifted the half-active voltage (V(0.5)) from (-15.78+/-0.86) mV to (-11.24 +/-0.77) mV (n=6, P<0.05) and the slope (K) from 5.33+/-0.74 to 4.35+/-0.74 (n=6, P>0.05). However, it did not alter the shapes of I-V curve, steady-state inactivation curve, or recovery from inactivation curve. CONCLUSIONS: SAA inhibited I-CaL in a dose-dependent manner. It shifted the steady-state activation curve to a more positive voltage, which indicated that the drug affected the activated state of calcium channels, and suggested that the Ca(2+) antagonistic effect of SAA be beneficial in the treatment of myocardial ischemia reperfusion injury. PMID- 21526367 TI - Effects of andrographolide on the activation of mitogen activated protein kinases and nuclear factor-kappaB in mouse peritoneal macrophage-derived foam cells. AB - OBJECTIVE: To observe the effect of andrographolide on the activation of mitogen activated protein kinases (MAPKs) and expression of nuclear factor-kappaB (NF kappaB) in macrophage foam cells. METHODS: The mouse peritoneal macrophages were cultured in the media in the presence of oxidized low-density lipoprotein (ox LDL), ox-LDL+andrographolide, or neither (control). The phosphorylation of MAPK molecules (p38MAPK, JNK, ERK1/2) and the expressions of NK-kappaB p65 were examined by Western blot. RESULTS: As compared with cells in the control group, the expressions of phospho-p38 and NF-kappaB p65 were increased in the cells cultured with either ox-LDL or ox-LDL+andrographolide (P<0.01), but attenuated significantly in the presence of ox-LDL+ andrographolide when compared with ox LDL (P<0.05). The phospho-JNK increased in the presence of either ox-LDL or ox LDL+andrographolide when compared with control cells (P<0.01), but no significant difference existed between ox-LDL and ox-LDL+andrographolide (P>0.05). The expression of phospho-ERK1/2 was increased in the presence of ox-LDL compared with the control cells (P<0.01), but no significant differences existed between the cells cultured in the presence of ox-LDL+andrographolide and the control medium (P>0.05). CONCLUSIONS: Andrographolide could inhibit the activation of ERK1/2, p38MAPK and NK-kappaB induced by ox-LDL in macrophage foam cells, which might be one of its mechanisms in preventing atherosclerosis. PMID- 21526368 TI - Realgar-induced apoptosis of cervical cancer cell line Siha via cytochrome c release and caspase-3 and caspase-9 activation. AB - OBJECTIVE: To explore the molecular mechanism of realgar-induced apoptosis of cervical cancer cells. METHODS: The cervical cancer cell line Siha was used to determine the cell viability and apoptosis after treatment with realgar using MTT assay and flow cytometry. The activities of caspase-3, -8, and -9 were detected by fluorescence resonance energy transfer technology and colorimetric assay, while the levels of Bcl-2, cytochrome c, and Bax were detected by Western blot method. RESULTS: Induction of apoptosis by realgar was detected in Siha cell line in a dose-dependent manner. The apoptosis was accompanied by a significant increase in cytochrome c release and activation of caspase-3 and caspase-9 but not caspase-8. Further, the realgar-induced apoptosis was inhibited by a broad spectrum caspase inhibitor, a caspase-3 inhibitor, and a caspase-9 inhibitor but not by a caspase-8 inhibitor. Bcl-2 and Bax protein expressions were not changed by realgar. CONCLUSION: The induction of apoptosis by realgar is mediated through a cytochrome c-dependent pathway, which sequentially activates caspase-9 and caspase-3. PMID- 21526369 TI - The qigong of 18 Luohan Hands and yoga for prevention of low back pain: A conceptual synthesis. AB - The practice of hathayoga is based on the following assumptions: complexity and multidimensionality of various positive influences on an individual's wholeness through the mind, body and their conscious control. On the other hand, the practice of the qigong of 18 Luohan Hands is based on slow movements designed to mobilise qi within the body. This article presents a conceptual integration of yoga and qigong when considering the congruence of beneficial effects for various systems of the body and prevention of low back pain (LBP). The author emphasizes the usefulness of qigong and yoga practice in clinical units and explains how the essence of these practices relates to each other. The justification of this fusion as well as differences between these two modalities are also described and explained. Within the scope of this article the existence of several similarities between these two practices has been suggested for both practitioners and researchers. They can obtain valuable and additional arguments through cross fertilization of ideas across presented studies united by shared, underlying biomechanical concepts and physiological effects. Such conceptual enrichment may be a useful source of inspiration for qigong and yoga practitioners who tend to prevent LBP and therapists (physiotherapists, occupational therapists, rehabilitants, nurses, bodywork and movement therapists or massage therapists) intended to manage their patients' back pains and overall health on a daily basis. PMID- 21526370 TI - EUS-FNA for suspected malignant biliary strictures after negative endoscopic transpapillary brush cytology and forceps biopsy. AB - BACKGROUND: Endoscopic transpapillary brush cytology and forceps biopsy are widely used for the pathological diagnosis of suspected malignant biliary strictures (MBS). However, the sensitivity of these methods remains insufficient, and it can be difficult to confirm the diagnosis. We aimed to evaluate the diagnostic ability of endoscopic ultrasound-guided fine-needle aspiration (EUS FNA) and the impact of this technique on clinical management in patients with suspected MBS where endoscopic brush cytology and biopsy yielded negative results. METHODS: This study included 225 consecutive patients with suspected MBS, who underwent endoscopic brush cytology and biopsy at our institutions. Negative results were obtained for these pathological tests in 75 patients, and EUS-FNA was performed in 22 of these patients. We retrospectively compared the EUS-FNA results with the final diagnosis and examined the influence of the EUS FNA diagnosis on treatment selection. RESULTS: FNA specimens were successfully obtained in all patients, and the pathological results confirmed malignancy in 16 cases and predicted that the other 6 cases were benign. Of the 6 cases that were suspected to be benign, 3 patients were diagnosed with xanthogranulomatous cholecystitis by surgical pathology, and the remaining 3 patients were diagnosed with benign diseases at a follow-up after 12-18 months. Thus, the EUS-FNA-based diagnosis was proven correct for all the patients. In addition, the treatment strategy was altered as a result of the EUS-FNA results in the above 6 patients (27%). CONCLUSIONS: EUS-FNA is a sensitive and safe diagnostic modality for patients with suspected MBS and can be an additional option in cases where endoscopic brush cytology and biopsy have produced negative results. PMID- 21526371 TI - Future aspects of therapy for hepatitis B virus infection: value of surrogate markers, innovative therapy, and global collaboration. AB - Both optimism and frustration exist regarding therapy for patients with chronic hepatitis B virus infection. Due to the recent advent of several drugs with potent antiviral capacities and comparatively low rates of adverse effects, considerable optimism has developed regarding the treatment of these patients. Chronic hepatitis B is now a treatable disease, and suppression of hepatitis B virus replication, normalization of alanine aminotransferase levels, seronegativity/seroconversion of hepatitis B e antigen and hepatitis B surface antigen, and decreased hepatic inflammation and liver fibrosis have been documented in chronic hepatitis B virus-infected patients treated with antiviral therapy. In contrast, many frustrations regarding antiviral therapy for chronic hepatitis B have arisen, because the disease, although treatable, is not curable. The present regimens of antiviral therapy modulate some intermediate parameters or so-called surrogate markers in chronic hepatitis B virus-infected patients, but usually fail to improve all intermediate parameters or ultimate clinical outcomes. In addition, major concerns remain about the applicability and use of antiviral drugs in developing and resource-constrained countries in which healthcare delivery systems do not support the proper use of antiviral therapy. New and more effective therapeutic regimens for chronic hepatitis B patients are needed that take into account potential surrogate markers of treatment outcomes and allow for effective collaboration between resource-constrained and advanced countries. PMID- 21526372 TI - Colonoscopic perforation: useful parameters for early diagnosis and conservative treatment. AB - OBJECTIVE: The purpose of this study is to determine useful parameters for the early diagnosis of colonoscopic perforation and to select those who would require surgical treatment. METHODS: We retrospectively reviewed the demographics, clinical and colonoscopic data, diagnostic-surgical interval, operative findings, complications, and hospital stay of patients who developed postcolonoscopy iatrogenic colonic perforation between January 2002 and December 2008. RESULTS: A retrospective multicentric study of patients diagnosed of colonoscopic perforation was performed. Fifty-four patients were found for final analysis (mean age, 71 years (26-91 years). Thirty-four were diagnostic and 20 were therapeutic colonoscopies. Most patients in whom the perforation was noticed during colonoscopy were treated surgically (p = 0.032) within 24 h (p = 0.004) and had a lesser degree of surgical peritonitis (p = 0.033). Those with deficient bowel preparation had more interventions (p < 0.05), ostomies (p = 0.015), and complications (p = 0.023) as well as major clinical (p < 0.001) and surgical peritonitis (p = 0.031). Patients with nonoperative management had fewer complications (p = 0.011) and lower hospital stay (p < 0.048). Surgical treatment within 24 h resulted in a lesser degree of surgical peritonitis (p < 0.001), fewer intestinal resections (p < 0.001), ostomies (p = 0.002) and complications (p < 0.047), and shorter hospital stay (p < 0.05). CONCLUSIONS: We recommend a conservative treatment for patients with the following conditions: good general health, unnoticed perforation during endoscopy, early diagnosis, no signs of diffuse peritonitis, proper colonic preparation, and a different injury mechanism to traction. Patients treated surgically after the first 24 h are likely to have a greater degree of peritonitis and more intestinal resections, ostomies, and complications. PMID- 21526373 TI - En bloc urinary bladder resection for locally advanced colorectal cancer: a 17 year experience. AB - BACKGROUND AND OBJECTIVES: En bloc bladder resection is often required for treating colorectal cancer with suspected urinary bladder invasion. Our aim was to review our institutional experience in en bloc resection of locally advanced colorectal cancer involving the urinary bladder over a period of 17 years. METHODS: The hospital records of 72 patients with locally advanced colorectal cancer who underwent en bloc urinary bladder resection at our institution between July 1987 and December 2004 were retrospectively reviewed. Clinical and oncologic outcomes were evaluated. RESULTS: The mean duration of follow-up was 64.3 months. Genuine tumor invasion into the urinary bladder was confirmed in 34 patients (47%) by histopathology. Forty patients (56%) underwent primary closure of the urinary bladder, while 32 patients (44%) required various kinds of urologic reconstructive procedures. Operative mortality occurred in four patients (6%). The overall postoperative morbidity rate was significantly higher in patients undergoing urologic reconstruction (81% vs. 45%, p = 0.002) when compared to that in patients undergoing primary closure. This was mostly attributable to significantly higher rates of urinary anastomotic leak (21.9% vs. 0%, p = 0.002) and urinary tract infection (50% vs. 18%, p = 0.003) in the urologic reconstruction group. For the 57 patients (79%) who underwent curative resection, the 5-year overall survival rate was 59%, and the local recurrence at 5 years was 15%. Both parameters were not significantly affected by the presence of pathologic bladder invasion or the extent of surgical procedures. CONCLUSIONS: En bloc bladder resection for locally advanced colorectal cancer involving the urinary bladder can produce reasonable long-term local control and patient survival. PMID- 21526374 TI - Preoperative risk evaluation of postoperative morbidity in IBD patients--impact of the POSSUM score. AB - BACKGROUND: The aim of this study was to assess the morbidity and mortality of patients undergoing surgery for inflammatory bowel disease (IBD) with special focus of the predictive value of the Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM) scoring system for preoperative risk adjustment of postoperative morbidity. METHODS: The operative notes and hospital files of 191 patients with IBD were analyzed. The POSSUM scoring system was used to predict morbidity rates after surgery. The physiological sub-score of the POSSUM score was analyzed with regard to its ability to predict postoperative complications. RESULTS: The overall complication rate was 27.7%, and the mortality was 0.5%. The morbidity rate predicted by POSSUM was 28.4% and the mortality rate 7.2%. The mean POSSUM-phys sub-score in patients without the major complications (anastomotic leakages, peritonitis, bleeding) was significant lower compared to patients with at least one of these complications (14.7 vs. 18.6; p < 0.001). Regarding the major complications separately, there were significant differences in the POSSUM-phys scores in patients developing a sepsis (14.1 vs. 23.4; p < 0.001) and/or a peritonitis (14.8 vs. 19.2; p = 0.05), whereas patients developing an anastomotic leakage/suture dehiscence or a postoperative bleeding did not differ significantly. CONCLUSION: POSSUM was an accurate predictor of morbidity in IBD patients and overpredicted mortality. The POSSUM-phys score is a promising instrument for identifying patients at increased risk of developing major postoperative complications after surgery for IBD. PMID- 21526375 TI - Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids. AB - BACKGROUND/PURPOSE: Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis. METHODS: Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined. RESULTS: The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression. CONCLUSIONS: The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes. PMID- 21526376 TI - Association of polymorphism in the promoter of the melatonin receptor 1A gene with schizophrenia and with insomnia symptoms in schizophrenia patients. AB - Schizophrenia patients commonly have sleep disturbances. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in the promoter region of the melatonin receptor genes (MTNR1A and MTNR1B) were associated with schizophrenia and with sleep problems such as insomnia and hypersomnia in schizophrenia patients. We genotyped two promoter SNPs [rs2119882 (-184T/C) of MTNR1A and rs4753426 (-1193C/T) of MTNR1B] using direct sequencing in 289 schizophrenia patients and 505 control subjects. We found that rs2119882 of MTNR1A was associated with schizophrenia in recessive model [CC vs. TT/TC, p = 0.013, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.12-2.55]. Interestingly, in an analysis of clinical phenotypes, we found that rs2119882 of MTNR1A was also associated with insomnia symptoms of schizophrenia (recessive model, p = 0.010, OR = 2.24, 95% CI = 1.21-4.14), but not with hypersomnia symptoms as determined using the Operational Criteria checklist. However, rs4753426 of MTNR1B was not associated with either schizophrenia or clinical phenotypes. Our results suggest that MTNR1A may be a susceptibility gene for schizophrenia and may be associated with insomnia symptoms exhibited in schizophrenia patients. PMID- 21526377 TI - Delayed treatment with vitamin C and N-acetyl-L-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib. AB - Bortezomib-induced peripheral neuropathy (BIPN) emerges as a disabling adverse effect. As rat models for BIPN have demonstrated damage in nerve Schwann cells, we screened for cytoprotective agents to devise a method of rescuing Schwann cells from the cytotoxic effects of bortezomib without compromising its anti myeloma effects. Schwann cells underwent macroautophagy along with cytoplasmic inclusion body and vacuole formation, and appeared much less susceptible to bortezomib-induced cytotoxicity than did myeloma cells. Vitamin C or N-acetyl-L cysteine (NAC) achieved near-complete rescue of Schwann cells treated with bortezomib at 30 nM or less, and these agents in combination are able to cooperatively inhibit the morphological changes and the cytotoxicity in Schwann cells with higher doses of bortezomib. The delayed addition of vitamin C and/or NAC after the exposure to bortezomib alleviated the cytotoxicity in Schwann cells but not myeloma cells. These results suggest that delayed treatment with these agents may be instrumental in prophylaxis of BIPN. PMID- 21526379 TI - Pain arising from the atlantooccipital joint. PMID- 21526378 TI - Potential nutritional conflicts in bariatric and renal transplant patients. AB - An increasing number of morbidly obese patients with end stage renal disease (ESRD) are sequentially undergoing bariatric surgery followed by renal transplantation. Discrepancies between the nutritional recommendations for obesity and chronic kidney disease (CKD) are often confusing for the obese patient in renal failure. However, when recommendations are structured according to stage and treatment of disease, a consistent plan can be clearly communicated to the patient. Therefore, to optimize patient and graft outcomes we present nutritional recommendations tailored to three patient populations: obese patients with ESRD, patients post Roux-en-Y gastric bypass (RYGBP) with ESRD, and patients post RYGBP and post renal transplantation. PMID- 21526380 TI - Do intramedullary spinal cord changes in signal intensity on MRI affect surgical opportunity and approach for cervical myelopathy due to ossification of the posterior longitudinal ligament? AB - Some controversy still exists over the optimal treatment time and the surgical approach for cervical myelopathy due to ossification of the posterior longitudinal ligament (OPLL). The aim of the current study was first to analyze the effect of intramedullary spinal cord changes in signal intensity (hyperintensity on T2-weighted imaging and hypointensity on T1-weighted imaging) on magnetic resonance imaging (MRI) on surgical opportunity and approach for cervical myelopathy due to OPLL. This was a prospective randomized controlled study. Fifty-six patients with cervical myelopathy due to OPLL were enrolled and assigned to either group A (receiving anterior decompression and fusion, n = 27) or group P (receiving posterior laminectomy, n = 29). All the patients were followed up for an average 20.3 months (12-34 months). The clinical outcomes were assessed by the average operative time, blood loss, Japanese Orthopedic Association (JOA) score, improvement rate (IR) and complication. To determine the relevant statistics, we made two factorial designs and regrouped the data of all patients to group H (with hyperintensity on MRI, n = 31), group L (with hypointensity on MRI, n = 19) and group N (no signal on MRI, n = 25), and then to further six subgroups as well: AH (with hyperintensity on MRI from group A, n = 15), PH (with hyperintensity on MRI from group P, n = 16), AL (with hypointensity on MRI from group A, n = 10), PL (with hypointensity on MRI from group P, n = 9), AN (no signal intensity on MRI from group A, n = 12) and PN (no signal intensity on MRI from group P, n = 13). Both hyperintensity on T2-weighted imaging and hypointensity on T1-weighted imaging had a close relationship with the JOA score and IR. The pre- and postoperative JOA score and postoperative IR of either group H or group L was significantly lower than that of group N (P < 0.05), regardless of whether the patients had received anterior or posterior surgery. On the other hand, both the JOA score and IR of subgroup AH were higher than those of subgroup PH at 1 week, 6 and 12 months postoperatively (P < 0.05), as well as between subgroup AL and PL; but in group N, there was no difference between the subgroup AN and PN (P > 0.05). In conclusion, regardless of hyperintensity on T2-weighted imaging or hypointensity on T1-weighted imaging in patients with OPLL, severe damage to the spinal cord is indicated. Surgical treatment should be provided before the advent of intramedullary spinal cord changes in signal intensity on MRI. The anterior approach is more effective than posterior approach for treating cervical myelopathy due to OPLL characterized by intramedullary spinal cord changes in signal intensity on MRI. PMID- 21526381 TI - Assessment of two novel surgical positions for the reduction of scoliotic deformities: lateral leg displacement and hip torsion. AB - Cobb angles and apical vertebral rotations (AVR) are two of the main scoliosis deformity parameters which spinal instrumentation and fusion techniques aim to reduce. Despite this importance, current surgical positioning techniques do not allow the reduction of these parameters. Two new surgical frame accessory prototypes have been developed: (1) a lateral leg displacer (LLD) allows lateral bending of a patient's legs up to 75 degrees in either direction and (2) a pelvic torsion device (PTD) which allows transverse plane twisting of a patient's pelvis at 30 degrees in either direction while raising the thoracic cushion, opposite to the raised side of the pelvis, by 5 cm. The objective of this study was to evaluate the ability of the LLD and PTD to reduce Cobb angles and AVR. Experimental testing was performed pre-operatively on 12 surgical scoliosis patients prone on an experimental surgical frame. Postero-anterior radiographs of their spines were taken in the neutral prone position on a surgical frame, and then again for 6 with their legs bent towards the convexity of their lowest structural curve, 4 with their pelvis raised on the convex side of their lowest structural curve and one each in opposite LLD and PTD intended use. Use of the LLD allowed for an average supplementary reduction of 16 degrees (39%) for Cobb angle and 9 degrees (33%) for AVR in the lowest structural curve. Use of the PTD allowed for an average supplementary reduction of 9 degrees (19%) for Cobb angle and 17 degrees (48%) for AVR in the lowest structural curve. Both devices were most efficient on thoraco-lumbar/lumbar curves. Opposite of intended use resulted in an increase in both Cobb angle and AVR. The LLD and PTD provide interesting novel methods to reduce Cobb angles and AVR through surgical positioning which can be used to facilitate instrumentation procedures by offering an improved intra-operative geometry of the spine. PMID- 21526382 TI - Epidemiology of acute poisonings during 2003-2007 in Toxicology Unit, Department of Occupational Medicine and Toxicology, Nofer Institute of Occupational Medicine, Lodz, Poland. AB - OBJECTIVES: The epidemiology of acute poisonings, observed in Toxicology Unit in Lodz, is the main objective of the study. The authors present frequency of respective kinds of poisoning cases and associated mortality. They discuss also the structure of poisonings with regard to type and causative agents over a period between 2003 and 2007. MATERIALS AND METHODS: The data used for the analysis were obtained from National Poison Information Center in Lodz. They were divided into two groups. The first one comprised information about patients treated at the Toxicology Unit (TU), whereas the other one included cases treated in other hospitals and only consulted by TU staff. RESULTS: Analysis of the data shows that overdosage of medications was the most frequent cause of hospitalization during 2006-2007. It constituted also the leading cause of deaths due to poisoning during 2003-2005. However, it was superseded during the subsequent period of 2006-2007 by intoxication with alcohols which was associated with the highest number of deaths in the latter period. Situation changed dynamically also with regard to the intention of poisoning. Suicidal poisonings constituted the largest group in 2003, whereas poisonings caused by abuse, including dependence-related abuse, were the most frequent in subsequent years. Patients between 15 and 30 years old formed the largest group among the total number of poisonings. CONCLUSIONS: The results of our study on epidemiology of acute poisoning in Lodz between 2003-2007 show that poisoning is a frequent cause of admission to hospital and constitutes a major health problem in Lodz district because of large number of hospital admissions, associated mortality and the high proportion of patients at young age. PMID- 21526383 TI - Assessment of nutritional status of selected group of children living in urban and rural areas in Upper Silesia, in the intervening five years. AB - OBJECTIVE: The aim of the paper is to assess changes in nutritional status of a selected group of children from urban and rural environment in Upper Silesia in the intervening 5 years. MATERIALS AND METHODS: The study was conducted twice - in 2003 and during the school year 2008/2009, and involved children from the town of Bytom and from the village Boronow. To assess the nutritional status, the following measurements were used - weight, height and thickness of subcutaneous fold. Body Mass Index (BMI) was also calculated. The results obtained were referred to the appropriate percentile charts. Measurement values, which were located below the 10th percentile or above the 90th percentile were treated as incorrect. Statistical analysis included only those children who participated in the I and II survey. The frequency of the anthropometric measurements and BMI exceeding the accepted limits of norms in both studied environments and between them, 5 years after the previous evaluation, were compared. RESULTS: In both environments, the number of pupils whose body mass exceeded the value of the 90th percentile increased. The number of pupils whose body mass was lower than the 10th percentile also increased in the city, but decreased in the country. Considering BMI, the percentage of children located above the norm increased as well in comparison to the first study. In addition, it was also found that the thickness of subcutaneous skin-fold difference between the studied communities was significant in both the first (p = 0.020) and the second survey (p = 0.015), as well as in each environment, after 5 years since the previous evaluation (Bytom: p = 0.001; Boronow: p = 0.32). CONCLUSION: In 5 years (2003-2008), the incidence of overweight of pupils increased in both groups. The percentage of pupils who weighed less than 10th percentile increased to a greater extent in urban environment than in rural areas. PMID- 21526384 TI - Survey of the opinions on the occupational health system in Turkey expressed by patients of the Istanbul hospital of occupational diseases. AB - OBJECTIVE: To examine the opinion of patients of an occupational diseases hospital on the quality of provision of occupational medicine services in Turkey. MATERIALS AND METHODS: A total of 189 patients were interviewed using a 13-item survey about their jobs and workplaces. RESULTS: The overall results of this study were as follows: 80.4% of the patients stated that physicians were located at their workplaces; 66.1% stated that inadequate attention was given to ensure the physical, psychological and social health of the employees; and 63.5% stated that sufficient protection against health risks was not provided. CONCLUSIONS: The quality of provision of occupational medicine services should be improved. PMID- 21526385 TI - Consequences of sickness presence and sickness absence on health and work ability: a Swedish prospective cohort study. AB - OBJECTIVE: To determine whether self-reported sickness presence (SP) and self reported sickness absence (SA) are specific risk factors for future health problems or reduced work ability in the active workforce. MATERIALS AND METHODS: The study population consisted of a cohort based on a random sample (n = 2181) with data for 2004, 2005, and 2006. The subjects were employees aged from 25 to 50 years in 2004. Cross-tabulations were calculated to identify significant background factors (sex, age, education, socioeconomic position), work factors (work demands, control, adjustment latitude), and outcome factors. Block-wise multiple logistic regression analyses were performed for outcome factors (SP, SA, self-rated health, physical complaints, work ability, mental well-being). RESULTS: SA and SP were found to have negative health consequences; this was particularly pronounced for those with frequent SP or SA. There was a dose response relationship between the degree of SA, SP and the different health outcomes. The health risks remained, after control for background factors, prior working conditions and initial health. SP also appeared to lead to SA, whereas SA did not have a significant impact on future SP. CONCLUSIONS: The results suggest that both SP and SA are strong predictors of future poor health, physical complaints, low mental well-being and low work ability. The detrimental influence of frequent SP was most pronounced in relation to work ability and physical complaints, although all of the measured health factors were affected. The negative effects of SA on the different health outcomes were similar. PMID- 21526387 TI - Bibliometric data in clinical cardiology revisited. The case of 37 Dutch professors. AB - In this paper, we assess the bibliometric parameters of 37 Dutch professors in clinical cardiology. Those are the Hirsch index (h-index) based on all papers, the h-index based on first authored papers, the number of papers, the number of citations and the citations per paper. A top 10 for each of the five parameters was compiled. In theory, the same 10 professors might appear in each of these top 10s. Alternatively, each of the 37 professors under assessment could appear one or more times. In practice, we found 22 out of these 37 professors in the 5 top 10s. Thus, there is no golden parameter. In addition, there is too much inhomogeneity in citation characteristics even within a relatively homogeneous group of clinical cardiologists. Therefore, citation analysis should be applied with great care in science policy. This is even more important when different fields of medicine are compared in university medical centres. It may be possible to develop better parameters in the future, but the present ones are simply not good enough. Also, we observed a quite remarkable explosion of publications per author which can, paradoxical as it may sound, probably not be interpreted as an increase in productivity of scientists, but as the effect of an increase in the number of co-authors and the strategic effect of networks. PMID- 21526388 TI - Degradation of the synthetic dye amaranth by the fungus Bjerkandera adusta Dec 1: inference of the degradation pathway from an analysis of decolorized products. AB - We examined the degradation of amaranth, a representative azo dye, by Bjerkandera adusta Dec 1. The degradation products were analyzed by high performance liquid chromatography (HPLC), visible absorbance, and electrospray ionization time-of flight mass spectroscopy (ESI-TOF-MS). At the primary culture stage (3 days), the probable reaction intermediates were 1-aminonaphthalene-2,3,6-triol, 4 (hydroxyamino) naphthalene-1-ol, and 2-hydroxy-3-[2-(4-sulfophenyl) hydrazinyl] benzenesulfonic acid. After 10 days, the reaction products detected were 4 nitrophenol, phenol, 2-hydroxy-3-nitrobenzenesulfonic acid, 4-nitrobenzene sulfonic acid, and 3,4'-disulfonyl azo benzene, suggesting that no aromatic amines were created. Manganese-dependent peroxidase activity increased sharply after 3 days culture. Based on these results, we herein propose, for the first time, a degradation pathway for amaranth. Our results suggest that Dec 1 degrades amaranth via the combined activities of peroxidase and hydrolase and reductase action. PMID- 21526386 TI - Engineering microbial factories for synthesis of value-added products. AB - Microorganisms have become an increasingly important platform for the production of drugs, chemicals, and biofuels from renewable resources. Advances in protein engineering, metabolic engineering, and synthetic biology enable redesigning microbial cellular networks and fine-tuning physiological capabilities, thus generating industrially viable strains for the production of natural and unnatural value-added compounds. In this review, we describe the recent progress on engineering microbial factories for synthesis of valued-added products including alkaloids, terpenoids, flavonoids, polyketides, non-ribosomal peptides, biofuels, and chemicals. Related topics on lignocellulose degradation, sugar utilization, and microbial tolerance improvement will also be discussed. PMID- 21526389 TI - Biochemical characterization of ethanol-dependent reduction of furfural by alcohol dehydrogenases. AB - Lignocellulosic biomass is usually converted to hydrolysates, which consist of sugars and sugar derivatives, such as furfural. Before yeast ferments sugars to ethanol, it reduces toxic furfural to non-inhibitory furfuryl alcohol in a prolonged lag phase. Bioreduction of furfural may shorten the lag phase. Cupriavidus necator JMP134 rapidly reduces furfural with a Zn-dependent alcohol dehydrogenase (FurX) at the expense of ethanol (Li et al. 2011). The mechanism of the ethanol-dependent reduction of furfural by FurX and three homologous alcohol dehydrogenases was investigated. The reduction consisted of two individual reactions: ethanol-dependent reduction of NAD(+) to NADH and then NADH-dependent reduction of furfural to furfuryl alcohol. The kinetic parameters of the coupled reaction and the individual reactions were determined for the four enzymes. The data indicated that limited NADH was released in the coupled reaction. The enzymes had high affinities for NADH (e.g., K ( d ) of 0.043 MUM for the FurX NADH complex) and relatively low affinities for NAD(+) (e.g., K ( d ) of 87 MUM for FurX-NAD(+)). The kinetic data suggest that the four enzymes are efficient "furfural reductases" with either ethanol or NADH as the reducing power. The standard free energy change (DeltaG degrees ') for ethanol-dependent reduction of furfural was determined to be -1.1 kJ mol(-1). The physiological benefit for ethanol-dependent reduction of furfural is likely to replace toxic and recalcitrant furfural with less toxic and more biodegradable acetaldehyde. PMID- 21526390 TI - Cupriavidus necator JMP134 rapidly reduces furfural with a Zn-dependent alcohol dehydrogenase. AB - Ethanol is a renewable biofuel, and it can be produced from lignocellulosic biomass. The biomass is usually converted to hydrolysates that consist of sugar and sugar derivatives, such as furfural. Yeast ferments sugar to ethanol, but furfural higher than 3 mM is inhibitory. It can take several days for yeast cells to reduce furfural to non-inhibitory furfuryl alcohol before producing ethanol. Bioreduction of furfural to furfuryl alcohol before fermentation may relieve yeast from furfural toxicity. We observed that Cupriavidus necator JMP134, a strict aerobe, rapidly reduced 17 mM furfural to less than 3 mM within 14 min with cell turbidity of 1.0 at 600 nm at 50 degrees C. The rapid reduction consumed ethanol. The "furfural reductase" (FurX) was purified, and it oxidized ethanol to acetaldehyde and reduced furfural to furfuryl alcohol with NAD(+) as the cofactor. The protein was identified with mass spectrometry fingerprinting to be a hypothetical protein belonging to Zn-dependent alcohol dehydrogenase family. The furX-inactivation mutant of C. necator JMP134 lost the ability to rapidly reduce furfural, and Escherichia coli producing recombinant FurX gained the ability. Thus, an alcohol dehydrogenase enabled bacteria to rapidly reduce furfural with ethanol as the reducing power. PMID- 21526391 TI - Production and properties of keratinolytic proteases from three novel Gram negative feather-degrading bacteria isolated from Brazilian soils. AB - The keratinolytic potential and protease properties of three novel Gram-negative feather-degrading bacteria isolated from Brazilian soils was described. Aeromonas hydrophila K12, Chryseobacterium indologenes A22 and Serratia marcescens P3 were able to degrade feather meal, producing high amounts of soluble proteins and forming thiol groups. The proteases of strains K12, A22 and P3 had optimal pH of 8.0, 7.5 and 6.0, respectively; this last is an uncommon feature for bacterial keratinases. The optimal temperature was in the range 45-55 degrees C. All three proteases were active towards azokeratin and were inhibited by EDTA, suggesting that they are keratinolytic metalloproteases. The proteolytic activity of K12 was stimulated by organic solvents and the detergent SDS, suggesting its potential application for detergent formulations and peptide synthesis. Strains A22, K12 and P3 have great potential for use in biotechnological processes involving hydrolysis of keratinous byproducts. PMID- 21526392 TI - Role of lymph node dissection in management of bladder cancer. AB - Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the gold standard for treatment of muscle-invasive bladder cancer. Recent retrospective series suggest that extended PLND provides a survival benefit, probably by removing undetected micrometastases. There have been several studies suggesting the survival benefit of extended PLND, not only for patients with node-negative disease but also for those who are node positive. The optimal boundaries of PLND seem to be at least up to the level of aortic bifurcation, including Marcille's fossa, under the present circumstances. Because retrieval of more lymph nodes may help to improve the prognosis of patients, careful approaches should be considered both surgically and pathologically. PLND should be performed for all patients who undergo RC. Prospective randomized studies will give us the answer to the question of whether extended PLND should be performed routinely. PMID- 21526393 TI - Serum human telomerase reverse transcriptase: a novel biomarker for breast cancer diagnosis. AB - BACKGROUND: Telomerase is a ribonucleoprotein complex composed mainly of a reverse transcriptase catalytic subunit, telomerase reverse transcriptase (hTERT). Expression of hTERT confers telomerase activity, indicating that hTERT is the rate-limiting component of human telomerase. The aim of the present study was to investigate the diagnostic implications of hTERT in the serum of breast cancer patients. METHODS: The study was conducted on 159 breast cancer patients and 41 healthy volunteers as controls. The evaluation of hTERT, cancer antigen 15.3 and carcinoembryonic antigen were performed by enzyme-linked immunosorbent assay, and analysed for their correlation with the patient's clinicopathological features. RESULTS: 27 of 52 (51.9%) patients with stage I breast cancer, 31 of 40 (77.5%) with stage II and 30 of 34 (88.2%) patients with stage III exhibited elevated hTERT levels. Serum hTERT levels showed significantly higher mean values in patients with breast cancer than healthy individuals. The sensitivity and specificity of hTERT in cancer diagnosis was 68.9 and 83.3%, respectively, which is significantly higher than conventional markers. The expression of serum hTERT was significantly correlated with telomerase activity in breast cancer tissues. Pretreatment serum hTERT levels showed a significant correlation with clinical stage, while correlation with nodal status and tumor size were marginal and no correlation was found with family history and age. CONCLUSION: Serum hTERT is useful for diagnosing and assessing the clinical stage of breast cancer and is superior to conventional markers. Therefore, serum hTERT could have a potential application as a novel biomarker for breast cancer diagnosis. PMID- 21526394 TI - Comparison of the Full Outline of UnResponsiveness and Glasgow Liege Scale/Glasgow Coma Scale in an intensive care unit population. AB - BACKGROUND: The Full Outline of UnResponsiveness (FOUR) has been proposed as an alternative for the Glasgow Coma Scale (GCS)/Glasgow Liege Scale (GLS) in the evaluation of consciousness in severely brain-damaged patients. We compared the FOUR and GLS/GCS in intensive care unit patients who were admitted in a comatose state. METHODS: FOUR and GLS evaluations were performed in randomized order in 176 acutely (<1 month) brain-damaged patients. GLS scores were transformed in GCS scores by removing the GLS brainstem component. Inter-rater agreement was assessed in 20% of the studied population (N = 35). A logistic regression analysis adjusted for age, and etiology was performed to assess the link between the studied scores and the outcome 3 months after injury (N = 136). RESULTS: GLS/GCS verbal component was scored 1 in 146 patients, among these 131 were intubated. We found that the inter-rater reliability was good for the FOUR score, the GLS/GCS. FOUR, GLS/GCS total scores predicted functional outcome with and without adjustment for age and etiology. 71 patients were considered as being in a vegetative/unresponsive state based on the GLS/GCS. The FOUR score identified 8 of these 71 patients as being minimally conscious given that these patients showed visual pursuit. CONCLUSIONS: The FOUR score is a valid tool with good inter-rater reliability that is comparable to the GLS/GCS in predicting outcome. It offers the advantage to be performable in intubated patients and to identify non-verbal signs of consciousness by assessing visual pursuit, and hence minimal signs of consciousness (11% in this study), not assessed by GLS/GCS scales. PMID- 21526395 TI - Mineral composition is altered by osteoblast expression of an engineered G(s) coupled receptor. AB - Activation of the G(s) G protein-coupled receptor Rs1 in osteoblasts increases bone mineral density by 5- to 15-fold in mice and recapitulates histologic aspects of fibrous dysplasia of the bone. However, the effects of constitutive G(s) signaling on bone tissue quality are not known. The goal of this study was to determine bone tissue quality in mice resulting from osteoblast-specific constitutive G(s) activation, by the complementary techniques of FTIR spectroscopy and synchrotron radiation micro-computed tomography (SRMUCT). Col1(2.3)-tTA/TetO-Rs1 double transgenic (DT) mice, which showed osteoblast specific constitutive G(s) signaling activity by the Rs1 receptor, were created. Femora and calvariae of DT and wild-type (WT) mice (6 and 15 weeks old) were analyzed by FTIR spectroscopy. WT and DT femora (3 and 9 weeks old) were imaged by SRMUCT. Mineral-to-matrix ratio was 25% lower (P = 0.010), carbonate-to phosphate ratio was 20% higher (P = 0.025), crystallinity was 4% lower (P = 0.004), and cross-link ratio was 11% lower (P = 0.025) in 6-week DT bone. Differences persisted in 15-week animals. Quantitative SRMUCT analysis revealed substantial differences in mean values and heterogeneity of tissue mineral density (TMD). TMD values were 1,156 +/- 100 and 711 +/- 251 mg/cm(3) (mean +/- SD) in WT and DT femoral diaphyses, respectively, at 3 weeks. Similar differences were found in 9-week animals. These results demonstrate that continuous G(s) activation in murine osteoblasts leads to deposition of immature bone tissue with reduced mineralization. Our findings suggest that bone tissue quality may be an important contributor to increased fracture risk in fibrous dysplasia patients. PMID- 21526396 TI - The protective effect of marriage for survival: a review and update. AB - The theory that marriage has protective effects for survival has itself lived for more than 100 years since Durkheim's groundbreaking study of suicide (Durkheim 1951 [1897]). Investigations of differences in this protective effect by gender, by age, and in contrast to different unmarried statuses, however, have yielded inconsistent conclusions. These investigations typically either use data in which marital status and other covariates are observed in cross-sectional surveys up to 10 years before mortality exposure, or use data from panel surveys with much smaller sample sizes. Their conclusions are usually not based on formal statistical tests of contrasts between men and women or between never-married, divorced/separated, and widowed statuses. Using large-scale pooled panel survey data linked to death registrations and earnings histories for U.S. men and women aged 25 and older, and with appropriate contrast tests, we find a consistent survival advantage for married over unmarried men and women, and an additional survival "premium" for married men. We find little evidence of mortality differences between never-married, divorced/separated, and widowed statuses. PMID- 21526397 TI - Targeted discovery of quantitative trait loci for resistance to northern leaf blight and other diseases of maize. AB - To capture diverse alleles at a set of loci associated with disease resistance in maize, heterogeneous inbred family (HIF) analysis was applied for targeted QTL mapping and near-isogenic line (NIL) development. Tropical maize lines CML52 and DK888 were chosen as donors of alleles based on their known resistance to multiple diseases. Chromosomal regions ("bins"; n = 39) associated with multiple disease resistance (MDR) were targeted based on a consensus map of disease QTLs in maize. We generated HIFs segregating for the targeted loci but isogenic at ~97% of the genome. To test the hypothesis that CML52 and DK888 alleles at MDR hotspots condition broad-spectrum resistance, HIFs and derived NILs were tested for resistance to northern leaf blight (NLB), southern leaf blight (SLB), gray leaf spot (GLS), anthracnose leaf blight (ALB), anthracnose stalk rot (ASR), common rust, common smut, and Stewart's wilt. Four NLB QTLs, two ASR QTLs, and one Stewart's wilt QTL were identified. In parallel, a population of 196 recombinant inbred lines (RILs) derived from B73 * CML52 was evaluated for resistance to NLB, GLS, SLB, and ASR. The QTLs mapped (four for NLB, five for SLB, two for GLS, and two for ASR) mostly corresponded to those found using the NILs. Combining HIF- and RIL-based analyses, we discovered two disease QTLs at which CML52 alleles were favorable for more than one disease. A QTL in bin 1.06 1.07 conferred resistance to NLB and Stewart's wilt, and a QTL in 6.05 conferred resistance to NLB and ASR. PMID- 21526398 TI - Comparison of FIB-4 and APRI in HIV-HCV coinfected patients with normal and elevated ALT. AB - BACKGROUND AND AIMS: Liver biopsy is standard for assessment of disease severity in patients with chronic HCV. However, associated risks have led to the development of simple non-invasive models. However, their utility in those with normal ALT is unknown. METHODS: FIB-4 and APRI were calculated for patients with HIV-HCV coinfection undergoing biopsy. The performance of each model and AUROC for predicting significant fibrosis (Ishak 4-6) were determined for the entire cohort and stratified by elevated (>=60 U/l in men and >=40 U/l in women) and normal ALT. RESULTS: Two-hundred and ninety-five liver biopsies from 237 patients were included. Elevated ALT was observed in 55, and 15% had significant fibrosis. The AUROC curve for patients with elevated ALT was 0.8 for FIB-4 and 0.76 for APRI, compared with 0.90 for the FIB-4 and 0.85-0.95 for the APRI in those with normal ALT. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FIB-4 were 1.0, 0.91, 0.50, and 1.0 for patients with normal ALT; the values were 0.67, 0.99, 0.67, and 0.99 for APRI. CONCLUSIONS: Both FIB-4 and APRI are useful for highly accurate identification of those without advanced fibrosis. However, because they have poor positive predictive value, liver biopsy will continue to be used for assessment of patients with coinfection. PMID- 21526399 TI - [Joint endoprosthesis pathology. Histopathological diagnostics and classification]. AB - Prosthesis durability has steadily increased with high 10-year rates of 88-95%. However, four pathogenetic groups of diseases can decrease prosthesis durability: (1) periprosthetic wear particle disease (aseptic loosening) (2) bacterial infection (septic loosening) (3) periprosthetic ossification, and (4) arthrofibrosis. The histopathological "extended consensus classification of periprosthetic membranes" includes four types of membranes, arthrofibrosis, and osseous diseases of endoprosthetics: The four types of neosynovia are: wear particle-induced type (type I), mean prosthesis durability (MPD) in years 12.0; infectious type (type II), MPD 2.5; combined type (type III) MPD 4.2; and indeterminate type (type IV), MPD 5.5. Arthrofibrosis can be determined in three grades: grade 1 needs clinical information to be differentiated from a type IV membrane, and grades 2 & 3 can be diagnosed histopathologically. Periprosthetic ossification, osteopenia-induced fractures, and aseptic osteonecrosis can be histopathologically diagnosed safely with clinical information. The extended consensus classification of periprosthetic membranes may be a diagnostic groundwork for a future national endoprosthesis register. PMID- 21526400 TI - Antibiotic resistance determinants in the interplay between food and gut microbiota. AB - A complex and heterogeneous microflora performs sugar and lactic acid fermentations in food products. Depending on the fermentable food matrix (dairy, meat, vegetable etc.) as well as on the species composition of the microbiota, specific combinations of molecules are produced that confer unique flavor, texture, and taste to each product. Bacterial populations within such "fermented food microbiota" are often of environmental origin, they persist alive in foods ready for consumption, eventually reaching the gastro-intestinal tract where they can interact with the resident gut microbiota of the host. Although this interaction is mostly of transient nature, it can greatly contribute to human health, as several species within the food microbiota also display probiotic properties. Such an interplay between food and gut microbiota underlines the importance of the microbiological quality of fermented foods, as the crowded environment of the gut is also an ideal site for genetic exchanges among bacteria. Selection and spreading of antibiotic resistance genes in foodborne bacteria has gained increasing interest in the past decade, especially in light of the potential transferability of antibiotic resistance determinants to opportunistic pathogens, natural inhabitants of the human gut but capable of acquiring virulence in immunocompromised individuals. This review aims at describing major findings and future prospects in the field, especially after the use of antibiotics as growth promoters was totally banned in Europe, with special emphasis on the application of genomic technologies to improve quality and safety of fermented foods. PMID- 21526401 TI - Palm tocotrienols decrease levels of pro-angiogenic markers in human umbilical vein endothelial cells (HUVEC) and murine mammary cancer cells. AB - Anti-angiogenic therapy is widely being used to halt tumour angiogenesis. In this study, the anti-angiogenic activity of palm tocotrienol-rich fraction (TRF) and its individual components (gamma- and delta-tocotrienol) were first investigated in vitro in human umbilical vein endothelial cells (HUVEC) and 4T1 mouse mammary cancer cells. Results showed reduced levels of Interkeukin (IL)-8 and IL-6, two pro-angiogenic cytokines in HUVEC treated with palm tocotrienols compared with alpha-tocopherol (alpha-T) and control cells (P < 0.05). The production of IL-8 and IL-6 was lowest in delta-tocotrienol (delta-T3)-treated cells followed by gamma-tocotrienol (gamma-T3) and TRF. There was significant (P < 0.05) reduction in IL-8 and vascular endothelial growth factor (VEGF) production in 4T1 cells treated with TRF or delta-T3. There was decreased expression of VEGF and its receptors; VEGF-R1 (fms-like tyrosine kinase, Flt-1) and VEGF-R2 (Kinase-insert domain-containing receptor, KDR/Flk-2) in tumour tissues excised from mice supplemented with TRF were observed. There was also decreased expression of VEGF R2 in lung tissues of mice supplemented with TRF. These observations correlate with the smaller tumour size recorded in the tocotrienol-treated mice. This study confirms previous observations that palm tocotrienols exhibit anti-angiogenic properties that may inhibit tumour progression. PMID- 21526402 TI - Long-term tracing of Rhizophagus irregularis isolate BEG140 inoculated on Phalaris arundinacea in a coal mine spoil bank, using mitochondrial large subunit rDNA markers. AB - During the last decade, the application of arbuscular mycorrhizal fungi (AMF) as bioenhancers has increased significantly. However, until now, it has been difficult to verify the inoculation success in terms of fungal symbiont establishment in roots of inoculated plants because specific fungal strains could not be detected within colonized roots. Using mitochondrial large subunit ribosomal DNA, we show that Rhizophagus irregularis (formerly known as Glomus intraradices) isolate BEG140 consists of two different haplotypes. We developed nested PCR assays to specifically trace each of the two haplotypes in the roots of Phalaris arundinacea from a field experiment in a spoil bank of a former coal mine, where BEG140 was used as inoculant. We revealed that despite the relatively high diversity of native R. irregularis strains, R. irregularis BEG140 survived and proliferated successfully in the field experiment and was found significantly more often in the inoculated than control plots. This work is the first one to show tracing of an inoculated AMF isolate in the roots of target plants and to verify its survival and propagation in the field. These results will have implications for basic research on the ecology of AMF at the intraspecific level as well as for commercial users of mycorrhizal inoculation. PMID- 21526403 TI - Characterization of Sarcocystis fusiformis based on sequencing and PCR-RFLP in water buffalo (Bubalus bubalis) in Iran. AB - Four Sarcocystis species, i.e., Sarcocystis fusiformis and Sarcocystis buffalonis with cats as definitive hosts, Sarcocystis levinei with dogs as definitive host, and Sarcocystis dubeyi with unknown definitive host, have previously been described from water buffalo (Bubalus bubalis). The aim of the present study was genetic characterization of the causative agent(s) of water buffalo sarcocystosis in Khuzestan Province, western Iran. RFLP-PCR and partial sequence analysis of 18S rDNA gene were used for the genetic characterization of the specimens directly obtained from water buffalo. In RFLP-PCR, four restriction enzymes (Dra1, Ssp1, Fok1 and Bsl1) were used for species discrimination of Sarcocystis spp. in this host. Comparison of the molecular sequencing results and RFLP-PCR pattern of the samples obtained in the present study with those previously reported for different Sarcocystis spp. revealed that all positive Sarcocystis samples represented S. fusiformis. To our knowledge, this is the first demonstration of the existence of S. fusiformis in the Iranian water buffalo population by a genetic approach. In addition, comparison between the alignments between the Iranian 18S rDNA sequences (HQ703791), made in this study, and those previously reported for S. fusiformis in different geographical location (accession nos. AF176927, AF176926, and U03071) showed the occurrence of local genetic polymorphisms and heterogeneity in this ribosomal locus. Despite the occurrence of some genetic variations in the hypervariable regions of the 18S rDNA in S. fusiformis, Dra I restriction site was conserved among all sequences available. According to the present study, it seems that cats have a more significant epidemiological role than dogs in transmission of sarcocystosis agent to water buffalo in Iran. PMID- 21526404 TI - Visualization of chromosomes in the binucleate intestinal parasite Giardia lamblia. AB - Mitosis of Giardia lamblia is a complex and rapid event that is poorly understood at the cellular and molecular levels. Therefore, we conducted this study to determine (1) whether the two nuclei have similar or different chromosomes, (2) the number of chromosomes of G. lamblia, and (3) the morphology and karyotype of the chromosomes. Trophozoites of the C2 and WB strains of G. lamblia were grown in modified TYI-S-33 medium at 37 degrees C. The trophozoites were collected, and sample slides were prepared for conventional light and scanning electron microscopy. Light microscopy revealed five pairs of chromosomes. The chromosomes were approximately 0.64-0.94 MUm long with a short rod-like shape and were usually arranged in pairs. Scanning electron microscopy yielded similar findings, and 10 chromosomes could be seen in each nucleus. Thus, the chromosome number of G. lamblia is 2n = 10. Chromosomes in pair 1 are submetacentric chromosomes, while pairs 2-5 are telocentric chromosomes. The present study shows that G. lamblia trophozoites have typical condensed chromosomes during mitosis and contains five pairs of chromosomes. The karyogram shows good fit to the formula 2n = 10 = 2sm + 8t revealed by scanning electron microscopy. PMID- 21526405 TI - Copper nanoparticles synthesized by polyol process used to control hematophagous parasites. AB - The present study was based on assessments of the anti-parasitic activities of the hematophagous (blood feeding) larvae of malaria vector, Anopheles subpictus Grassi, filariasis vector, Culex quinquefasciatus, Say (Diptera: Culicidae), and the larvae of cattle tick Rhipicephalus (Boophilus) microplus, Canestrini (Acari: Ixodidae). The metallic copper nanoparticles (Cu NPs) synthesized by polyol process from copper acetate as precursor and Tween 80 were used as both the medium and the stabilizing reagent. The efficacy of synthesized Cu NPs was tested against the larvae of blood-sucking parasites. UV-vis spectra characterization was performed, and peak was observed at 575 nm, which is the characteristic to the surface plasmon bond of Cu NPs. The strong surface plasmon absorption band observed at 575 nm may be due to the formation of non-oxidized Cu NPs. X-ray diffraction (XRD) spectral data showed concentric rings corresponding to the 26.79 (111), 34.52 (200), and 70.40 (220) reflections. XRD spectrum of the copper nanoparticles exhibited 2theta values corresponding to the copper nanocrystal. No peaks of impurities are observed in XRD data. The scanning electron micrograph (SEM) showed structures of irregular polygonal, cylindrical shape, and the size range was found to be 35-80 nm. The size of the Cu NPs was measured by atomic force microscope (AFM) in non-contact mode. For imaging by AFM, the sample was suspended in acetone and spins coated on a silicon wafer. The line profile image was drawn by the XEI software and the horizontal line at 6 MUm on a 2D AFM image. Research has demonstrated that metallic nanoparticles produce toxicity in aquatic organisms that is due largely to effects of particulates as opposed to release of dissolved ions. Copper acetate solution tested against the parasite larvae exposed to varying concentrations and the larval mortality was observed for 24 h. The larval percent mortality observed in synthesized Cu NPs were 36, 49, 75, 93,100; 32, 53, 63, 73, and 100 and 36, 47, 69, 88, 100 at 0.5, 1.0, 2.0, 4.0, and 8.0 mg/L against A. subpictus, C. quinquefasciatus and R. microplus, respectively. The larval percent mortality shown in copper acetate solution were 16, 45, 57, 66 and 100, 37, 58, 83, 87, and 100 and 41, 59, 79, 100, and 100 at 10, 20, 30, 40, and 50 mg/L against A. subpictus, C. quinquefasciatus, and R. microplus, respectively. The maximum efficacy was observed in Cu NPs and copper acetate solution against the larvae of A. subpictus, C. quinquefasciatus, and R. microplus with LC(50) and r (2) values of 0.95 and 23.47, 1.01 and 15.24, and 1.06 and 14.14 mg/L with r (2) = 0.766; 0.957 and 0.908; 0.946; and 0.816 and 0.945, respectively. The control (distilled water) showed nil mortality in the concurrent assay. The chi-square value was significant at p <= 0.05 level. This is the first report on anti-parasitic activity of the synthesized Cu NPs and copper acetate solution. PMID- 21526406 TI - Which McMaster egg counting technique is the most reliable? AB - This study focuses on the comparison of three selected modifications of the McMaster counting technique, namely the McMaster method modified by Wetzel (W) and Zajicek (Z), as well as the concentration McMaster technique according to Roepstorff and Nansen (R&N). These modifications differ in the weights of faeces examined (W, 2 g/Z, 1 g/R&N, 4 g), flotation solutions (W, NaCl/Z, MgSO(4) + Na(2)S(2)O(3)/R&N, NaCl + glucose), centrifugation (W, none/Z, 2,000 RPM for 2 min and 2,000 RPM for 1 min/R&N, 1,200 RPM for 5 min), number of McMaster chambers investigated (W, 3/Z, 2/R&N, 2), and multiplication factors used (W, 67/Z, 33/R&N, 20). To investigate the sensitivity and reliability of these methods, nematode eggs (Teladorsagia circumcincta) were used. Parasite elements are distributed through negative binomial distribution in naturally infected host faeces, and the number of parasite elements in a given amount of faeces sample is unknown to man. Therefore, we decided to prepare the exact number of eggs which were added to the parasite negative faeces; the faecal sample was then investigated. From this perspective, this is the first time a comparison of the McMaster methods has been so accurately investigated. This approach allows us to evaluate the real sensitivity and reliability of the tested method. As the findings of this study indicate, the highest sensitivity and reliability were obtained using the Roepstorff and Nansen modification. This McMaster modification is able to detect 20 eggs per sample (in 70% of samples). Concentrations of 200 and 500 eggs can be found in almost 100% of samples. Moreover, this method is simple, cheap and fast. For these reasons, we can recommend this method for routine veterinary practice. PMID- 21526407 TI - Coupling of gelatin to inner surfaces of pore walls in spongy alginate-based scaffolds facilitates the adhesion, growth and differentiation of human bone marrow mesenchymal stromal cells. AB - We have developed a novel wide-pore scaffold for cell 3D culturing, based on the technology of freeze-drying of Ca-alginate and gelatin. Two different preparation methodologies were compared: (i) freeze-drying of Na-alginate + gelatin mixed solution followed by the incubation of dried polymer in saturated ethanolic solution of CaCl2; (ii) freeze-drying of the Na-alginate solution followed by the chemical "activation" of polysaccharide core with divinylsulfone with subsequent gelatin covalent attachment to the inner surfaces of pore walls. The scaffolds produced using the first approach did not provide adhesion and proliferation of human bone marrow mesenchymal stromal cells (MSCs). Conversely, the second approach allowed to obtain scaffolds with a high adherence ability for the cells. When cultured within the latter type of scaffold, MSCs proliferated and were able to differentiate into adipogenic, osteogenic and chondrogenic cell lineages, in response to specific induction stimuli. The results indicate that Ca-alginate wide-pore scaffolds with covalently attached gelatin could be useful for stem cell-based bone, cartilage and adipose tissue engineering. PMID- 21526408 TI - Direct and interactive effects of three variables on properties of PMMA bone cement for vertebral body augmentation. AB - PMMA bone cements are widely used for vertebral body augmentation procedures vertebroplasty and balloon kyphoplasty. Although there are studies in the literature on the direct effects of relevant variables on the properties of these cements, there are none on the interactive effects. In the present work, such a study was performed on both types of effects, with the variables being the concentration of initiator (benzoyl peroxide), the concentration of crosslinker (ethylene glycol dimethacrylate), and the liquid-to-powder ratio used in preparing the cement; and the properties being the compressive strength, the compressive modulus, the doughing time, the setting time, and the maximum polymerization temperature. Two additional properties obtained from the viscosity versus-time curves, namely the time at the onset of curing, and the critical curing rate were also studied. Significant interactive effects between the amount of crosslinker and the amount of radical initiator were found to affect the doughing time and the critical curing rate. These effects were explained in terms of the reaction kinetics. It was concluded that interactive effects may exist and should be taken into account when designing bone cement formulations. PMID- 21526409 TI - Laser surface modification for synthesis of textured bioactive and biocompatible Ca-P coatings on Ti-6Al-4V. AB - A textured calcium phosphate based bio-ceramic coating was synthesized by continuous wave Nd:YAG laser induced direct melting of hydroxyapatite precursor on Ti-6Al-4V substrate. Two different micro-textured patterns (100 MUm and 200 MUm line spacing) of Ca-P based phases were fabricated by this technique to understand the alignment and focal adhesion of the bone forming cells on these surfaces. X-ray diffraction studies of the coated samples indicated the presence of CaTiO3, alpha-Ca3(PO4)2, Ca(OH)2, TiO2 (anatase) and TiO2 (rutile) phases as a result of the intermixing between the precursor and substrate material during laser processing. A two dimensional elemental mapping of the cross-section of the coated samples exhibited the presence of higher phosphorous concentration within the coating and a thin layer of calcium concentration only at the top of the coating. Improved in vitro bioactivity and in vitro biocompatibility was observed for the laser processed samples as compared to the control. PMID- 21526410 TI - Fabrication of nano-structured electrospun collagen scaffold intended for nerve tissue engineering. AB - Nerve tissue engineering is one of the most promising methods in nerve tissue regeneration. The development of blended collagen and glycosaminoglycan scaffolds can potentially be used in many soft tissue engineering applications. In this study an attempt was made to develop two types of random and aligned electrospun, nanofibrous scaffold using collagen and a common type of glycosaminoglycan. Ion chromatography test, MTT and attachment assays were conducted respectively to trace the release of glycosaminoglycan, and to investigate the biocompatibility of the scaffold. Cell cultural tests showed that the scaffold acted as a positive factor to support connective tissue cell outgrowth. The positive effect of fiber orientation on cell outgrowth organization was traced through SEM images. Porosity percentage calculation and tensile strength measurement of the webs specified analogous properties to the native neural matrix tissue. These results suggested that nanostructured porous collagen-glycosaminoglycan scaffold is a potential cell carrier in nerve tissue engineering. PMID- 21526411 TI - A multi-method evaluation of the Pharmacy First Minor Ailments scheme. AB - OBJECTIVES: To evaluate whether the Pharmacy First Minor Ailments scheme achieved its objectives in terms of improving access to medicines and reducing doctor workload for minor ailments by enhancing the role of community pharmacists in the management of minor ailments. SETTING: Nottingham, the United Kingdom. METHODS: A mixed-methods study was conducted, including semi-structured interviews with key stakeholders, a patient survey, and an analysis of the Nottingham City Primary Care Trust data. MAIN OUTCOME MEASURES: Stakeholders' acceptability of the scheme and scheme users' satisfaction with the scheme. RESULTS: Most health care professionals were positive about the implementation of the scheme, although they reported some problems, such as the restricted formulary. The majority of stakeholders perceived benefits of the scheme for both patients and health care professionals. The level of patient satisfaction with the scheme was high, particularly in terms of ease of access and convenience. The current structure of the scheme appears to be an acceptable way to run the scheme. Since its commencement the scheme has enabled the transfer of a substantial number of minor ailments consultations from general practices to community pharmacies. CONCLUSION: It appears that the Nottingham City Primary Care Trust is successful using community pharmacies to improve access to medicines and provide a greater choice in primary care for patients with minor ailments. Thus, the Primary Care Trust should continue the scheme, although there are some important issues (e.g. the restricted formulary, the lack of privacy in some pharmacies) that need to be addressed to improve and develop the service further. The Nottingham City Primary Care Trust should build on this success to further utilise the pharmacy in their primary care service development. PMID- 21526412 TI - Development of new concepts of non-adherence measurements among users of antihypertensives medicines. AB - OBJECTIVE: To identify various types of non-adherence among users of antihypertensive medications by establishing components of adherence measures and use these components for measuring the prevalence of non-adherence. SETTING: Twelve community pharmacies from the Danish county of Funen. METHOD: Users of antihypertensive medication were included in the study. 2,914 medication users received questionnaires by mail. Participating patients were asked to fill in two questionnaire regarding demographics, self-reported blood pressure, and various adherence measures. Two factor analyses were conducted based on responses to questions. MAIN OUTCOME MEASURES: Medication-taking behaviour and self-efficacy (beliefs about ability and capacity to accomplish a task), respectively. Other measures of non-adherence collected by questionnaire were also addressed in the data for comparison of prevalence with the developed concepts. RESULTS: 1,426 (49%) participants answered the questionnaires. The analyses resulted in two sets of components: three adherence behaviour measures and two self-efficacy measures which showed similarities in concepts. The adherence behaviour measures included two concepts of intentional nonadherence (associated with aspects of self regulation and effect concerns, respectively) and one measure of non-intentional non-adherence. Prevalence of the developed measures of behaviour related non adherence ranged from 10.3 to 34.9% depending on which type of non-adherence measure was used. Established measures of non-adherence resulted in prevalence between 2.2 and 39.6%. CONCLUSIONS: The study showed that concepts of non adherence measurements could be determined including self-efficacy aspects, unintentional non-adherence and intentional non-adherence related to self regulation and effect concerns respectively. The prevalence of the adherence behaviour components were found to be between 10.3 and 34.9%, which is in the range of expected values. Associations between the new concepts of non-adherence measurement and characteristics of nonadherers remain to be established and would be a subject for further studies. PMID- 21526413 TI - Frequency, types and severity of medication use-related problems among medical outpatients in Nigeria. AB - OBJECTIVES: To determine the frequency, types and severity of medications use related problems among medical outpatients in a tertiary care setting in southwestern Nigeria. SETTING: Medical outpatient clinics of a 900-bed Teaching Hospital located in Ibadan, Southwestern Nigeria. METHODS: A prospective cross sectional medication use review was conducted by ten pharmacists for 400 randomly selected medical outpatients over a 4 week period at a 900-bed premier teaching hospital located in Ibadan, Nigeria. Severity assessment of medication use related problems was done by 3 independent assessors with a modified severity index. MAIN OUTCOME MEASURE: Frequency, types and severity of medication use related problems identified through pharmacist-initiated medication use review. RESULTS: Of the 400 randomly selected patients, 324 (81.0%) consented and were interviewed. One hundred and sixty-three (50.3%) of the cohort were males and 161 (49.7%) were females; with mean ages 51.5 +/- 17.6 and 52.1 +/- 17.4 years respectively. Median no. of drugs prescribed per patient per day was 4 (Minimum Maximum, 1-7). About 27.5% were self medicating with orthodox (prescription-only and over-the-counter) and/or herbal medicines; and only 14.6% claimed disclosure to their physicians. The proportion of patients self medicating with orthodox medicines was significantly higher (P < 0.0001). Two hundred and twenty-six medication use-related problems were identified from 58.6% of patients, but the highest number (5) was identified among 2.6% of patients. The frequency of medication use-related problems appear strongly related to the number of medicines prescribed (r = 0.71, P = 0.006). The majority of medication use related problems were ranked as potentially harmful [Inter-rater reliability coefficient: Gwet AC1: 0.7214 (P <= 0.001)]. Non-adherence (43.8%), problems associated with self medication (39.3%) and adverse drug reactions (15.6%) were the most frequent. Unauthorized drug holidays (46.5%) and stoppage of prescribed prescription-only medications for local herbs (29.3%) were the major consequences of non-adherence. Potentially harmful drug-disease interactions were the most frequent medication use-related problems arising from self medication (40.4%). CONCLUSION: Potentially harmful medication use-related problems are frequently encountered among medical outpatients in Nigeria. The institutionalization of medication use review and the devolution of this task to pharmacists may prove beneficial in optimizing outcomes of medication use in Nigeria. PMID- 21526414 TI - The influence of lead on different proteins in gill cells from the freshwater bivalve, Corbicula fluminea, from defense to repair biomarkers. AB - The objective of this study was to evaluate the influence of lead (Pb) on regulatory proteins linked to mechanisms of animal adaptation to polluted environments (using in vivo and in vitro tests) and to validate the in vitro assay as a tool for environmental assessment. Specimens of the bivalve Corbicula fluminea were exposed to nominal concentrations of Pb 5 mg l(-1) for 96 h. Isolated gill cells were exposed to three concentrations (1, 10, and 100 MUM) for 5 h. Metal toxicity was evaluated by cell viability (trypan blue exclusion). We also analyzed Na+/K+ adenosine triphosphatase (ATPase) and carbonic anhydrase activity. Additionally, the multixenobiotic-resistance (MXR) phenotype was evaluated by the accumulation of rhodamine B (RB). Immunolabeling was used to quantify the expression of P-glycoproteins (C219) and proteins involved in ion transport, water movement, and cellular repair using antibodies against Na+/K+ ATPase, aquaporin 1, and heat-shock protein 70 (Hsp70). Pb was shown to be toxic in both in vivo and in vitro tests, in which cellular viability significantly decreased by approximately 25%. Cellular viability in the in vivo assays was determined by gill cell isolation after the entire animal was exposed to Pb. We observed that Na+/K+ ATPase activity was inhibited by 70%. Also, the expression of the MXR phenotype significantly increased in our in vivo tests. A statistically significant difference was observed in the expression of all proteins in the in vitro assays, whereas only Hsp70 increased in vivo. Employing these analyses, we could validate the sensitivity of the in vitro tests and can propose our in vitro model as a possible tool for environmental assessment. PMID- 21526416 TI - From RNAi screens to molecular function in embryonic stem cells. AB - The ability of embryonic stem (ES) cells to generate any of the around 220 cell types of the adult body has fascinated scientists ever since their discovery. The capacity to re-program fully differentiated cells into induced pluripotent stem (iPS) cells has further stimulated the interest in ES cell research. Fueled by this interest, intense research has provided new insights into the biology of ES cells in the recent past. The development of large-scale and high throughput RNAi technologies has made it possible to sample the role of every gene in maintaining ES cell identity. Here, we review the RNAi screens performed in ES cells to date and discuss the challenges associated with these large-scale experiments. Furthermore, we provide a perspective on how to streamline the molecular characterization following the initial phenotypic description utilizing bacterial artificial chromosome (BAC) transgenesis. PMID- 21526417 TI - Claudins and cancer stem cells. AB - It is now believed that most epithelial tumors are maintained by a subpopulation of cells called cancer stem cells (CSCs) or tumor initiating cells (TICs) with stem cell-like properties, including self-renewal and multilineage differentiation capacity. Recently new insights into this population have emerged in certain epithelial tumor types, including their Claudin(low) phenotype and its importance to the epithelial-mesenchymal transition (EMT) process. Taken together, CSCs, EMT and Claudins appear to constitute an axis-of-evil in cancer, for which better understanding may lead to new therapeutic platforms. PMID- 21526415 TI - Novel pathways in gonadotropin receptor signaling and biased agonism. AB - Gonadotropins play a central role in the control of male and female reproduction. Selective agonists and antagonists of gonadotropin receptors would be of great interest for the treatment of infertility or as non steroidal contraceptive. However, to date, only native hormones are being used in assisted reproduction technologies as there is no pharmacological agent available to manipulate gonadotropin receptors. Over the last decade, there has been a growing perception of the complexity associated with gonadotropin receptors' cellular signaling. It is now clear that the Gs/cAMP/PKA pathway is not the sole mechanism that must be taken into account in order to understand these hormones' biological actions. In parallel, consistent with the emerging paradigm of biased agonism, several examples of ligand-mediated selective signaling pathway activation by gonadotropin receptors have been reported. Small molecule ligands, modulating antibodies interacting with the hormones and glycosylation variants of the native glycoproteins have all demonstrated their potential to trigger such selective signaling. Altogether, the available data and emerging concepts give rise to intriguing opportunities towards a more efficient control of reproductive function and associated disorders. PMID- 21526418 TI - Langerhans cell histiocytosis in endoscopic biopsy: marked pinching artifacts by endoscopy. AB - Various diseases should be considered when evaluating a suprasellar mass. Diabetes insipidus has been reported as the primary manifestation in a patient with Langerhans cell histiocytosis involving the hypothalamopituitary axis (HPA) and can be helpful for the diagnosis. The use of endoscopic biopsy for suprasellar masses has increased. However, as it is difficult to make a diagnosis with endoscopic biopsy because of the many artifacts, pathologists must be careful. Langerhans cell histiocytosis involving the HPA as solitary lesions is rare. We report the eighth case that provides neurologists, radiologists, and pathologists with various implications. PMID- 21526419 TI - Diffuse in-stent restenosis of CYPHER(r) stent due to hypersensitivity reaction confirmed by pathohistological findings. AB - The use of drug-eluting stents (DES) reduces the risk of repeat revascularization without increase of death and myocardial infarction compared to standard bare metal stents. However, in-stent restenosis (ISR) after DES implantation still occurs. Here, we report a rare case with a diffuse ISR after CYPHER(r) stent implantation because of chronic inflammation and hypersensitivity reactions, confirmed by pathohistological findings. PMID- 21526420 TI - Independent no-reflow predictors in female patients with ST-elevation acute myocardial infarction treated with primary percutaneous coronary intervention. AB - Independent no-reflow predictors should be evaluated in female patients with ST segment elevation acute myocardial infarction (STEMI) and successfully treated with primary percutaneous coronary intervention (PPCI) in the current interventional equipment and techniques, thus to be constructed a no-reflow predicting model. In this study, 320 female patients with STEMI were successfully treated with PPCI within 12 h after the onset of AMI from 2007 to 2010. All clinical, angiographic, and procedural data were collected. Multiple logistic regression analysis was used to identify independent no-reflow predictors. The no reflow was found in 81 (25.3%) of 320 female patients. Univariate and multivariate stepwise logistic regression analysis identified that low SBP on admission <100 mmHg (OR 1.991, 95% CI 1.018-3.896; p = 0.004), target lesion length >20 mm (OR 1.948, 95% CI 1.908-1.990; p = 0.016), collateral circulation 0 1 (OR 1.952, 95% CI 1.914-1.992; p = 0.019), pre-PCI thrombus score >= 4 (OR 4.184, 95% CI 1.482-11.813; p = 0.007), and IABP use before PCI (OR 1.949, 95% CI 1.168-3.253; p = 0.011) were independent no-reflow predictors. The no-reflow incidence significantly increased as the numbers of independent predictors increased [0% (0/2), 10.8% (9/84), 14.5% (17/117), 37.7% (29/77), 56.7% (17/30), and 81.8% (9/11) in female patients with 0, 1, 2, 3, 4, and 5 independent predictors, respectively; p < 0.0001]. The five no-reflow predicting variables were admission SBP <100 mmHg, target lesion length >20 mm, collateral circulation 0-1, pre-PCI thrombus score >= 4, and IABP use before PCI in female patients with STEMI treated with PPCI. PMID- 21526421 TI - Impact of obesity on plasma B-type natriuretic peptide levels in Japanese community-based subjects. AB - The plasma B-type natriuretic peptide (BNP) concentration was recently shown to be inversely correlated with body mass index (BMI). However, very few attempts have been made to associate abdominal obesity and BNP in the Japanese general population. Here, we conducted a cross-sectional study, and examined 339 male and 429 female residents without heart disease in a rural Japanese community who received an annual health checkup in 2006. BNP was inversely associated with both BMI and abdominal circumference (AC) in the age-adjusted regression analysis (p < 0.05). Following adjustment for traditional risk factors, multiple regression analysis revealed that BNP was negatively correlated with AC (p < 0.05), but not BMI. Although metabolic syndrome was not associated with BNP levels, AC had an influence on low BNP levels in the multiple regression analysis using both AC and BMI concurrently (p < 0.05 for AC and p > 0.60 for BMI). These effects were more prominent in men than in women. Collectively, plasma BNP levels are inversely related with obesity, as measured by AC, in Japanese community-based subjects. PMID- 21526422 TI - Feral genetically modified herbicide tolerant oilseed rape from seed import spills: are concerns scientifically justified? AB - One of the concerns surrounding the import (for food and feed uses or processing) of genetically modified herbicide tolerant (GMHT) oilseed rape is that, through seed spillage, the herbicide tolerance (HT) trait will escape into agricultural or semi-natural habitats, causing environmental or economic problems. Based on these concerns, three EU countries have invoked national safeguard clauses to ban the marketing of specific GMHT oilseed rape events on their territory. However, the scientific basis for the environmental and economic concerns posed by feral GMHT oilseed rape resulting from seed import spills is debatable. While oilseed rape has characteristics such as secondary dormancy and small seed size that enable it to persist and be redistributed in the landscape, the presence of ferals is not in itself an environmental or economic problem. Crucially, feral oilseed rape has not become invasive outside cultivated and ruderal habitats, and HT traits are not likely to result in increased invasiveness. Feral GMHT oilseed rape has the potential to introduce HT traits to volunteer weeds in agricultural fields, but would only be amplified if the herbicides to which HT volunteers are tolerant were used routinely in the field. However, this worst-case scenario is most unlikely, as seed import spills are mostly confined to port areas. Economic concerns revolve around the potential for feral GMHT oilseed rape to contribute to GM admixtures in non-GM crops. Since feral plants derived from cultivation (as distinct from import) occur at too low a frequency to affect the coexistence threshold of 0.9% in the EU, it can be concluded that feral GMHT plants resulting from seed import spills will have little relevance as a potential source of pollen or seed for GM admixture. This paper concludes that feral oilseed rape in Europe should not be routinely managed, and certainly not in semi-natural habitats, as the benefits of such action would not outweigh the negative effects of management. PMID- 21526423 TI - Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer. AB - BACKGROUND: The tumor suppressor genes CADM1/TSLC1 and DAL-1/4.1B are frequently inactivated by promoter methylation in non-small cell lung cancer. The proteins they encode, CADM1 and 4.1B, form a complex in human epithelial cells and are involved in cell-cell adhesion. METHODS: Expression of CADM1 and 4.1B proteins was examined by immunohistochemistry in 67 primary breast cancer and adjacent noncancerous tissues. CADM1 and 4.1B messenger RNA (mRNA) was detected by reverse transcription polymerase chain reaction (RT-PCR). The methylation status of the CADM1 and 4.1B promoters was determined quantitatively by bisulfite treatment followed by pyrosequencing. RESULTS: CADM1 and 4.1B protein signals were detected along the cell membrane in normal mammary epithelia. By contrast, 47 (70%) and 49 (73%) of 67 primary breast cancers showed aberrant CADM1 and 4.1B staining, respectively. Aberrant CADM1 staining was more frequently observed in pT2 and pT3 tumors and for stages II and III (P = 0.045 and P = 0.020, respectively), while aberrant 4.1B staining was more often observed in tumors with lymph node metastasis, for pT2 and pT3 tumors, and for stages II and III (P = 0.0058, P = 0.0098, and P = 0.0007, respectively). Furthermore, aberrant CADM1 and 4.1B expression was preferentially observed in invasive relative to noninvasive lesions from the same specimen (P = 0.036 and P = 0.0009, respectively). Finally, hypermethylation of CADM1 and 4.1B genes was detected in 46% and 42% of primary breast cancers, respectively. CONCLUSIONS: Our findings suggest that aberrant CADM1 and 4.1B expression is involved in progression of breast cancer, especially in invasion into the stroma and metastasis. PMID- 21526424 TI - Safety of adjuvant trastuzumab for HER-2-overexpressing elderly breast cancer patients: a multicenter cohort study. AB - BACKGROUND: For targeting anti-HER-2, trastuzumab-incorporated chemotherapy is the standard for HER-2-overexpressing breast cancer in adjuvant settings. But there are few data on trastuzumab in elderly patients. We evaluated the incidence of adverse events among an elderly population of trastuzumab-treated HER-2 positive breast cancer patients in adjuvant settings. METHODS: Data on 39 elderly HER-2 overexpressing breast cancer patients treated with both curative surgery and adjuvant trastuzumab were retrospectively collected from a Japanese multicenter study. The loading dose was 8 mg/kg body weight, and the maintenance dose was 6 mg/kg every 3 weeks; or the loading dose was 4 mg/kg followed by 2 mg/kg weekly as maintenance. RESULTS: After a median follow-up of 20.0 (2.4-53.9) months, a total of 32 patients (82.1%) completed 1-year trastuzumab treatment. The median treatment duration was 12.0 months (range 2-12; mean 10.5). Adverse events occurred in 11 patients (28.2%). Four (10.2%) discontinued or interrupted treatment after experiencing toxicity. One patient died because of interstitial pneumonia. Three patients (7.7%) had congestive heart failure (CHF), one of whom had a history of angina. Three patients (7.7%) had a lower left ventricular ejection fraction (LVEF), and brain natriuretic peptide elevation was totally observed in three patients (7.7%). Three patients with lower LVEF had received chemotherapy containing doxorubicin before trastuzumab. Of the three patients, two discontinued therapy because of CHF, but all recovered with proper medication containing a diuretic agent. CONCLUSIONS: Elderly patients tolerated trastuzumab well, although careful management is needed. PMID- 21526425 TI - A case of metaplastic breast cancer that showed a good response to platinum-based preoperative chemotherapy. AB - Patients with metaplastic breast cancer (MBC) exhibit reduced response to chemotherapy and have poor prognosis. We investigated a case of MBC that showed a positive response to preoperative chemotherapy, resulting in near pathological complete response (pCR). A 59-year-old woman complained of a lump in her right breast. Magnetic resonance imaging (MRI) showed the presence of a solid mass that was 24 mm in diameter. The pathological diagnosis was MBC with cartilaginous differentiation. The clinical stage was T2N0M0, stage IIA according to the International Union against Cancer (UICC) criteria. To observe the response to chemotherapy, we gave her preoperative chemotherapy. The patient was monitored closely, since we realized that failure of chemotherapy carries a risk of tumor progression. Evaluation was carried out using ultrasound, MRI, fluorodeoxyglucose (FDG) positron emission tomography (PET), and a Ki-67 labeling index after the first cycle of chemotherapy, and ultrasound after each additional cycle. FDG-PET showed a positive response after the first cycle of chemotherapy. The patient underwent 4 cycles of docetaxel (75 mg/m(2)) and cisplatin (75 mg/m(2)) followed by 4 cycles of cyclophosphamide (500 mg/m(2)), doxorubicin (50 mg/m(2)), and cisplatin (50 mg/m(2)). Ultrasound showed decreases in tumor size after each cycle of chemotherapy. After chemotherapy, MRI showed nearly complete regression of the tumor. Partial mastectomy was performed. Pathological examination showed few cancer cells remaining, indicating near pCR. We report a case of MBC that responded well to platinum-based preoperative chemotherapy. We propose that preoperative chemotherapy may be an option for treatment of MBC in conjunction with careful monitoring. PMID- 21526426 TI - Eradication of breast cancer cells in patients with distant metastasis: the finishing touches? AB - Cytotoxic agents are significantly active in breast cancer cells, but their usefulness has been limited in treating metastatic breast cancer (MBC). This has facilitated the development of an approach using molecular-targeted agents. Intrinsic subtypes including luminal A, luminal B, human epidermal growth factor receptor type 2 (HER2)-enriched, basal-like, and claudin-low tumors exhibit original drug responsiveness and clinical prognosis. Anti-HER2 treatments, trastuzumab or lapatinib, have demonstrated clinically significant efficacy. Poly ADP-ribose polymerase-1 inhibitors act against BRCA1-disabled breast cancer. Cancer stem cells could be the major obstacle to achieving a cure in systemic treatment. Extensive investigations are underway to develop novel agents that act on the genes or signaling of Hedgehog, Wnt, and Notch, which regulate cancer stem cells. Cancer cells undergo epithelial-mesenchymal transition (EMT) and acquire invasive properties. Breast cancer cells alter their phenotype in blood and bone marrow, e.g., circulating tumor cells or disseminated tumor cells. Cancer stem cells, like normal stem cells, may exist at niches in bone marrow. To achieve a cure for MBC, it is necessary to disrupt cancer stem cell-niche interactions or eradicate cancer stem cells. Traditional treatments with cytotoxic or endocrine agents require development in relation to intrinsic subtypes, stem cells, or EMT. PMID- 21526427 TI - [Spectral domain OCT in patients with unclear uveitis]. AB - Presented here are two cases of patients with unclear visual loss. A diagnostic assessment with spectral domain optical coherence tomography (Sd-OCT), fluorescein angiography (FLA) and blood analyses was performed due to vitreous clouding. Characteristic FLA findings for papillitis and vasculitis and as yet undescribed morphological Sd-OCT changes in the photoreceptor layer and in the pigment epithelium were found. During the treatment of the diagnosed lues these changes were resolved. The Sd-OCT technique seems to be a useful and effective diagnostic tool for uveitis diagnostics. PMID- 21526428 TI - Kinetic and optical biosensor study of adrenodoxin mutant AdxS112W displaying an enhanced interaction towards the cholesterol side chain cleavage enzyme (CYP11A1). AB - In mammals, steroid hormones are synthesized from cholesterol that is metabolized by the mitochondrial CYP11A1 system leading to pregnenolone. The reduction equivalents for this reaction are provided by NADPH, via a small electron transfer chain, consisting of adrenodoxin reductase (AdR) and adrenodoxin (Adx). The reaction partners are involved in a series of transient interactions to realize the electron transfer from NADPH to CYP11A1. Here, we compared the ionic strength effect on the AdR/Adx and Adx/CYP11A1 interactions for wild-type Adx and mutant AdxS112W. Using surface plasmon resonance measurements, stopped flow kinetic investigations and analyses of the product formation, we were able to obtain new insights into the mechanism of these interactions. The replacement of serine 112 by tryptophan was demonstrated to lead to a dramatically decreased k (off) rate of the Adx/CYP11A1 complex, resulting in a four-fold decreased K (d) value and indicating a much higher stability of the complex involving the mutant. Stopped flow analysis at various ionic strengths and in different mixing modes revealed that the binding of reduced Adx to CYP11A1 seems to display the limiting step for electron transfer to CYP11A1 with pre-reduced AdxS112W being much more efficient than wild-type Adx. Finally, the dramatic increase in pregnenolone formation at higher ionic strength using the mutant demonstrates that the interaction of CYP11A1 with Adx is the rate-limiting step in substrate conversion and that hydrophobic interactions may considerably improve this interaction and the efficiency of product formation. The data are discussed using published structural data of the complexes. PMID- 21526429 TI - Economic burden of depression in South Korea. AB - BACKGROUND: A recent national survey in South Korea indicated that the 12-month prevalence rate of major depressive disorder was 2.5%. Depressive disorders may lead to disability, premature death, and severe suffering of patients and their families. This study estimates the economic burden of depression in Korea from a societal perspective. METHODS: Annual direct healthcare costs associated with depression were calculated based on the National Health Insurance database. Annual direct non-healthcare costs were estimated for transport. Annual indirect costs were estimated for the following components of productivity loss due to illness such as morbidity (absenteeism and presenteeism) and premature mortality. Indirect costs were estimated using the large national psychiatric epidemiological surveys in Korea. The human capital approach was used to estimate indirect costs. RESULT: The total cost of depression was estimated to be $4,049 million, of which $152.6 million represents a direct healthcare cost. Total direct non-healthcare costs were estimated to be $15.9 million. Indirect costs were estimated at $3,880.5 million. The morbidity cost was $2,958.9 million and the mortality cost was $921.6 million. The morbidity cost was identified as the largest component of overall cost. CONCLUSION: Depression is a considerable burden on both society and the individual, especially in terms of incapacity to work. The Korean society should increase the public health effort to prevent and detect depression in order to ensure that appropriate treatment is provided. Such actions will lead to a significant reduction in the total burden resulting from depression. PMID- 21526430 TI - Immunization with dendritic cells transfected in vivo with HIV-1 plasmid DNA induces HIV-1-specific immune responses. AB - We evaluated the importance of dendritic cells (DCs) in the induction of the immune response after immunization of mice with DNA plasmid Auxo-GTU((r)) MultiHIV. First, GTU((r))-encoded protein was shown to be expressed by DCs of the draining lymph nodes (LNs) following intradermal (i.d.) immunization. Next, donor mice were immunized with the MultiHIV DNA plasmid, and DCs were enriched and further used to immunize naive recipient mice. For the first time, the results show that i.d. immunization with Auxo-GTU((r))-MultiHIV transfects DCs in vivo, enabling them to present antigens and induce HIV-specific immune responses in recipient mice. PMID- 21526432 TI - Abstracts of the Twenty-First Meeting of the European Neurological Society. May 28-31, 2011. Lisbon, Portugal. PMID- 21526433 TI - [Abstracts of the 77th Annual Meeting of the German Society for Cardiology-Heart and Circulation Research. April 27-30, 2011. Mannheim, Germany]. PMID- 21526431 TI - Retrieval of total suspended matter (TSM) and chlorophyll-a (Chl-a) concentration from remote-sensing data for drinking water resources. AB - The concentrations of chlorophyll-a (Chl-a) and total suspended matter (TSM) are major water quality parameters that can be retrieved using remotely sensed data. Water sampling works were conducted on 15 July 2007 and 13 September 2008 concurrent with the Indian Remote-Sensing Satellite (IRS-P6) overpass of the Shitoukoumen Reservoir. Both empirical regression and back-propagation artificial neural network (ANN) models were established to estimate Chl-a and TSM concentration with both in situ and satellite-received radiances signals. It was found that empirical models performed well on the TSM concentration estimation with better accuracy (R (2) = 0.94, 0.91) than their performance on Chl-a concentration (R (2) = 0.62, 0.75) with IRS-P6 imagery data, and the models accuracy marginally improved with in situ spectra data. Our results indicated that the ANN model performed better for both Chl-a (R (2) = 0.91, 0.82) and TSM (R (2) = 0.98, 0.94) concentration estimation through in situ collected spectra; the same trend followed for IRS-P6 imagery data (R (2) = 0.75 and 0.90 for Chl-a; R (2) = 0.97 and 0.95 for TSM). The relative root mean square errors (RMSEs) from the empirical model for TSM (Chl-a) were less than 15% (respectively 27.2%) with both in situ and IRS-P6 imagery data, while the RMSEs were less than 7.5% (respectively 18.4%) from the ANN model. Future work still needs to be undertaken to derive the dynamic characteristic of Shitoukoumen Reservoir water quality with remotely sensed IRS-P6 or Landsat-TM data. The algorithms developed in this study will also need to be tested and refined with more imagery data acquisitions combined with in situ spectra data. PMID- 21526434 TI - Molecular dynamics as an approach to study prion protein misfolding and the effect of pathogenic mutations. AB - Computer simulation of protein dynamics offers unique high-resolution information that complements experiment. Using experimentally derived structures of the natively folded prion protein (PrP), physically realistic dynamics and conformational changes can be simulated, including the initial steps of misfolding. By introducing mutations in silico, the effect of pathogenic mutations on PrP conformation and dynamics can be assessed. Here, we briefly introduce molecular dynamics methods and review the application of molecular dynamics simulations to obtain insight into various aspects of the PrP, including the mechanism of misfolding, the response to changes in the environment, and the influence of disease-related mutations. PMID- 21526435 TI - Micromixing within microfluidic devices. AB - Micromixing is a crucial process within microfluidic systems such as micro total analysis systems (MUTAS). A state-of-art review on microstructured mixing devices and their mixing phenomena is given. The review first presents an overview of the characteristics of fluidic behavior at the microscale and their implications in microfluidic mixing processes. According to the two basic principles exploited to induce mixing at the microscale, micromixers are generally classified as being passive or active. Passive mixers solely rely on pumping energy, whereas active mixers rely on an external energy source to achieve mixing. Typical types of passive micromixers are discussed, including T- or Y-shaped, parallel lamination, sequential, focusing enhanced mixers, and droplet micromixers. Examples of active mixers using external forces such as pressure field, electrokinetic, dielectrophoretic, electrowetting, magneto-hydrodynamic, and ultrasound to assist mixing are presented. Finally, the advantages and disadvantages of mixing in a microfluidic environment are discussed. PMID- 21526436 TI - Flow control methods and devices in micrometer scale channels. AB - Recent advances in the fabrication of microflow devices using micro electromechanical systems (MEMS) technology are described. Passive and active liquid flow control and particle-handling methods in micrometer-scale channels are reviewed. These methods are useful in micro total analysis systems (MUTAS) and laboratory-on-a-chip systems. Multiple flow control systems (i.e., arrayed microvalves) for advanced high-throughput microflow systems are introduced. Examples of microflow devices and systems for chemical and biochemical applications are also described. PMID- 21526437 TI - Photocatalytic reduction of CO2: from molecules to semiconductors. AB - We are facing three serious problems related to fossil resources, i.e., shortage of energy, shortage of carbon resources, and the global worming problem. Development of practical systems for converting CO2 to useful chemicals using solar light, i.e., photocatalytic CO2 reduction systems, should be one of the best solutions for these problems. In this article, we review photocatalytic CO2 reduction systems, which are classified in two categories: (1) homogeneous reaction systems mainly using transition metal complexes, and (2) heterogeneous systems mainly using inorganic semiconductor as a light absorber. PMID- 21526438 TI - Deep sequencing of naupliar-, cyprid- and adult-specific normalised Expressed Sequence Tag (EST) libraries of the acorn barnacle Balanus amphitrite. AB - In order to improve the genetic characterisation of the barnacle Balanus amphitrite, normalised EST libraries for the developmental stages, viz. nauplius (a mix of instars I and II), cyprid and adult, were generated. The libraries were sequenced independently using 454 technologies and 575,666 reads were generated. For adults, 4843 unique isotigs were estimated and 6754 and 7506 in the cyprid and naupliar stage, respectively. It was found that some of the previously proposed cyprid-specific bcs genes were also expressed during the naupliar and adult stage. Furthermore, as lectins have been hypothesised to influence settlement cue recognition in barnacles, the database was searched for lectin like isotigs. Two proteins, uniquely expressed in either the cyprid or the adult stage, matched a mannose receptor, and their nucleotide sequences were 33% and 31% identical to a lectin (BRA-3) isolated from Megabalanus rosa. Further characterisation of these genes may suggest their involvement in settlement. PMID- 21526439 TI - Evidence of enzymatic catalysis of oxygen reduction on stainless steels under marine biofilm. AB - Cathodic current trends on stainless steel samples with different surface percentages covered by biofilm and potentiostatically polarized in natural seawater were studied under oxygen concentration changes, temperature increases, and additions of enzymic inhibitors to the solution. The results showed that on each surface fraction covered by biofilm the oxygen reduction kinetics resembled a reaction catalyzed by an immobilised enzyme with high oxygen affinity (apparent Michaelis-Menten dissociation constant close to K(O(2))(M) ~ 10 MUM) and low activation energy (W ~ 20 KJ mole(-1)). The proposed enzyme rapidly degraded when the temperature was increased above the ambient (half-life time of ~1 day at 25 degrees C, and of a few minutes at 50 degrees C). Furthermore, when reversible enzymic inhibitors (eg sodium azide and cyanide) were added, the cathodic current induced by biofilm growth was inhibited. PMID- 21526440 TI - The anti-biofouling effect of Lactobacillus fermentum-derived biosurfactant against Streptococcus mutans. AB - Biofouling in the oral cavity often causes serious problems. The ability of Streptococcus mutans to synthesize extracellular glucans from sucrose using glucosyltransferases (gtfs) is vital for the initiation and progression of dental caries. Recently, it was demonstrated that some biological compounds, such as secondary metabolites of probiotic bacteria, have an anti-biofouling effect. In this study, S. mutans was investigated for the anti-biofouling effect of Lactobacillus fermentum (L.f.)-derived biosurfactant. It was hypothesized that two enzymes produced by S. mutans, glucosyltransferases B and C, would be inhibited by the L.f.-biosurfactant. When these two enzymes were inhibited, fewer biofilms (or none) were formed. RNA was extracted from a 48-h biofilm of S. mutans formed in the presence or absence of L.f. biosurfactant, and the gene expression level of gtfB/C was quantified using the real-time polymerase chain reaction (RT-PCR). L.f. biosurfactant showed substantial anti-biofouling activity because it reduced the process of attachment and biofilm production and also showed a reduction in gtfB/C gene expression (P value < 0.05). PMID- 21526441 TI - Visual orientation in hospitalized boys with early onset conduct disorder and borderline intellectual functioning. AB - The aim of the present study is to investigate visual orientation in hospitalized boys with severe early onset conduct disorder and borderline intellectual functioning. It is tested whether boys with the dual diagnosis have a stronger action-oriented response style to visual-cued go signals than the norm. To this end, boys with the dual diagnosis were compared with a peer control group on Posner's (1980) visual-spatial detection test. Here, on each trial, a visual cue points either in the direction of the location of a subsequent go signal (valid cue), or points in the opposite direction away from the location of the subsequent go signal (invalid cue). Findings indicated superior orientation (a strong action-oriented response style) of children with the dual diagnosis in valid-cued trials as well as in invalid-cued trials in both the left and the right visual hemifield. Findings were controlled for attention scores on the Child Behavior Checklist -Teacher Form and IQ scores. PMID- 21526442 TI - The moderating effects of contamination sensitivity on state affect and information processing: examination of disgust specificity. AB - Although contamination sensitivity has been implicated in several disorders, there is a paucity of research examining the influence of this trait on various outcomes. Accordingly, the present study examined the extent to which individual differences in contamination sensitivity moderated state affect in response to a mood induction and subsequent information processing biases, as assessed by a lexical decision task (LDT). It was hypothesised that the moderating effects of contamination sensitivity would be specific to disgust responding to a negative but not positive mood induction, and to reaction times to disgust and fear compared to happy words on the LDT. The findings were largely consistent with this hypothesis, as contamination sensitivity predicted increased disgust and arousal to the negative mood induction. Contamination sensitivity was also a better predictor of reaction times to disgust and fear words than happy words. However, the moderating effect of contamination sensitivity on reaction times on the LDT was not mediated by its effects on response to the negative mood induction. Implications of these findings for conceptualising the role of contamination sensitivity and its association with disgust in specific disorders are discussed. PMID- 21526443 TI - Parenting magazines and obesity: how well do they trim the fat? AB - Magazines serve as an important source for health-related news, and this study examines the kinds of obesity-related messages that appear in magazines targeting parents and women. Coders examined 306 stories between 2002 and 2008 and found that messages focused on food more frequently than exercise or dieting. Women were more likely to appear in stories with food-related themes, while men were more likely to appear when supporting research or data were present. PMID- 21526444 TI - Nicotine effects on immediate and delayed verbal memory after substance use detoxification. AB - Decrements in verbal memory are commonly reported by detoxified treatment-seeking individuals. Although acute nicotine has been shown to improve attentional performance, its effects on verbal memory in substance abusers have not been addressed. Treatment-seeking alcohol-dependent (ALCs, n = 29; 14 male), illicit stimulant-dependent (predominantly cocaine; STIMs, n = 25; 15 male), and alcohol- and illicit-stimulant-dependent (ALC/STIMs, n = 50; 35 male) participants with comorbid nicotine dependence were studied. Subjects had been abstinent from their drugs of choice for 41 (+/-18) days and were in short-term abstinence from tobacco (~8-10 hours). Subjects received double-blind administration of either transdermal nicotine (high dose: 21/14 mg for men and women, respectively, or low dose: 7 mg) or placebo. The Logical Memory (LM) subtest from the Wechsler Memory Scale-Revised (WMS-R) was used to assess immediate and delayed verbal memory recall. Results indicated that STIMs receiving the high dose of nicotine recalled more words at immediate recall than STIMs who received placebo. Trend level differences were also noted at delayed recall between STIM nicotine and placebo doses. Nicotine failed to impact either recall in alcoholic subgroups. Although not the primary focus, results also revealed differences in the forgetting rates between the groups with the ALC/STIMs demonstrating the steepest forgetting slope. In summary, this study suggests that nicotine effects may be differentially experienced by substance-using subgroups; that nicotine may have a direct effect on memory; and that in considering neurocognitive processes (e.g., encoding vs. retrieval), underlying endpoint indicators (e.g., correct recall) may be critical in predicting outcomes. PMID- 21526445 TI - Evidence of reduced selective attention in schizotypal personality disorder. AB - It has been shown that high-schizotypy and schizophrenic participants demonstrate increased task-switching costs, although high-schizotypy participants present this pattern only in incongruent trials (Cimino & Haywood, 2008). In this study, we aim to explore whether this results from difficulties in selective attention or task control. A total of 18 participants with high levels of psychometrically defined schizotypy and 16 participants with low scores were tested in two different versions of a task-switching paradigm. Participants were asked to switch between attending to the color or the shape of bidimensional objects following a previous cue. Two versions of the task were investigated, one involving only switches in the perceptual dimension to attend (color or shape) and another also switching the response set. High-schizotypy subjects consistently showed increased switch costs in incongruent trials for both versions of the tasks, demonstrating a deficit in the selection of the perceptual dimension instead of the selection of the response rules. PMID- 21526446 TI - Brain activity patterns during phonological verbal fluency performance with varying levels of difficulty: a functional magnetic resonance imaging study in Portuguese-speaking healthy individuals. AB - A large number of functional neuroimaging studies have investigated the brain circuitry which is engaged during performance of phonological verbal fluency tasks, and the vast majority of these have been carried out in English. Although there is evidence that this paradigm varies depending on the language spoken, it is unclear if this difference is associated with differences in brain activation patterns. Also, there is neuroimaging evidence that the patterns of regional cerebral activation during verbal fluency tasks may vary with the level of task demanded. In particular, the engagement of the anterior cingulate cortex seems to be relative to cognitive demand. We compared functional magnetic resonance imaging data in healthy Portuguese-speaking subjects during overt production of words beginning with letters classified as easy or hard for word production in Portuguese. Compared to the baseline condition, the two verbal fluency tasks (with either easy or hard letters) engaged a network including the left inferior and middle frontal cortices, anterior cingulate cortex, putamen, thalamus and cerebellum (p < .001). The direct comparison between the two verbal fluency conditions showed greater cerebellar activation in the easy condition relative to the hard condition. In the anterior cingulate cortex, there was a direct correlation between activity changes and verbal fluency performance during the hard condition only. Despite grammatical differences, the changes in patterns of brain activity during verbal fluency performance observed in our study are in accordance with findings of previous neuroimaging studies of verbal fluency carried out in English and other languages, with recruitment of a set of distributed cerebral areas during word production. PMID- 21526447 TI - Electrokinetic transport of aerobic microorganisms under low-strength electric fields. AB - To investigate the feasibility of utilizing low strength electric fields to transport commonly available mixed cultures such as those from an activated sludge process, bench scale batch reactor studies were conducted in sand and sandy loam soils. A readily biodegradable substrate, dextrose, was used to test the activity of the transported microorganisms. Electric field strengths of 7V, 10.5V, and 14V were used. Results from this investigation showed that an electric field strength of 0.46 Volts per cm was sufficient to transport activated sludge microorganisms across a sandy loam soil across a distance of about 8 cm in 72 h. More importantly, the electrokinetically transported microbial culture remained active and viable after the transport process and was biodegrade 44% of the dextrose in the soil medium. Electrokinetic treatment without microorganisms resulted in removal of 37% and the absence of any treatment yielded a removal of about 15%. PMID- 21526448 TI - The effects of hydraulic loading and NaCl concentrations on the regeneration of exhausted homoionic natural zeolite. AB - A study of the suitable operational conditions for the regeneration of exhausted homoionic natural zeolite with ammonium was carried out. Laboratory-scale columns using NaCl solutions with concentrations of 2 and 4 mol/L and hydraulic loadings of 4, 6 and 8 bed volumes per hour (BV/h) were assessed. For both NaCl concentrations studied, the hydraulic load of 6 BV/h showed the highest ammonia nitrogen output from the exhausted zeolite bed. Results showed that the hydraulic load (BV/h) had a greater influence on the regeneration efficiency than the concentration of the regenerating solution. PMID- 21526449 TI - Performance of point-of-use devices to remove manganese from drinking water. AB - A recent epidemiological study reported significant cognitive deficits among children in relation with consumption of water with manganese concentrations in the order of 50-100 ug/L. Concerns for neurotoxic effects of manganese raises the need for evaluating the efficiency of domestic water treatment systems for removal of this metal. The objective of the present study was to determine whether POU devices are efficient at reducing dissolved manganese concentration in drinking water. Various devices were tested according to the NSF 53 protocol for general metals for high pH test water. Based on these assays, the pour through filters were identified as the most promising POU devices, with dissolved manganese removal greater than 60% at 100% rated capacity, and greater than 45% at 200% rated capacity (influent Mn ~1,000 MUg/L). Under-the-sink filters using cationic exchange resins (i.e., water softeners) were also efficient at removing dissolved manganese but over a shorter operating life. Manganese leaching was also observed beyond their rated capacity, making them less robust treatments. The activated carbon block filters and other proprietary technologies were found to be inappropriate for dissolved manganese removal. Further evaluation of POU devices performance should evaluate the impact of hardness on process performance. The impact of particulate Mn should also be evaluated. PMID- 21526450 TI - Spatial and temporal variations of manganese concentrations in drinking water. AB - The objective of this study was to assess the variability of manganese concentrations in drinking water (daily, seasonal, spatial) for eight communities who participated in an epidemiological study on neurotoxic effects associated with exposure to manganese in drinking water. We also assessed the performance of residential point-of-use and point-of-entry devices (POE) for reducing manganese concentrations in water. While the total Mn concentrations measured during this study were highly variable depending on the location (< 1-2,700 MUg/L), daily or seasonal variations were minimal. Flushing the tap for 5 minutes did not significantly reduce total manganese concentration for 4 out of 5 sampling locations. The efficiency of reverse osmosis and ion exchange for total Mn removal was consistently high while activated carbon provided variable results. The four POE greensand filters investigated all increased (29 to 199%) manganese concentration, indicating deficient operation and/or maintenance practices. Manganese concentrations in the distribution system were equal or lower than at the inlet, indicating that sampling at the inlet of the distribution system is conservative. The decline in total Mn concentration was linked to higher water residence time in the distribution system. PMID- 21526451 TI - Environmental monitoring study of linear alkylbenzene sulfonates and insoluble soap in Spanish sewage sludge samples. AB - In this work we present a monitoring study of linear alkylbenzene sulfonates (LAS) and insoluble soap performed on Spanish sewage sludge samples. This work focuses on finding statistical relations between LAS concentrations and insoluble soap in sewage sludge samples and variables related to wastewater treatment plants such as water hardness, population and treatment type. It is worth to mention that 38 samples, collected from different Spanish regions, were studied. The statistical tool we used was Principal Component Analysis (PC), in order to reduce the number of response variables. The analysis of variance (ANOVA) test and a non-parametric test such as the Kruskal-Wallis test were also studied through the estimation of the p-value (probability of obtaining a test statistic at least as extreme as the one that was actually observed, assuming that the null hypothesis is true) in order to study possible relations between the concentration of both analytes and the rest of variables. We also compared LAS and insoluble soap behaviors. In addition, the results obtained for LAS (mean value) were compared with the limit value proposed by the future Directive entitled "Working Document on Sludge". According to the results, the mean obtained for soap and LAS was 26.49 g kg(-1) and 6.15 g kg(-1) respectively. It is worth noting that LAS mean was significantly higher than the limit value (2.6 g kg(-1)). In addition, LAS and soap concentrations depend largely on water hardness. However, only LAS concentration depends on treatment type. PMID- 21526453 TI - The protective role of Lychnophora ericoides Mart. (Brazilian arnica) in 1,2 dimethylhydrazine-induced experimental colon carcinogenesis. AB - Aberrant crypt foci (ACF) and colon rectal mucosal epithelial cell proliferation have been shown to be increased in patients with colon cancer and have been largely used for early detection of factors that influence colorectal carcinogenesis in rats. Fifty male Wistar rats were randomly divided into 5 groups. The groups G1 to G4 were given 4 injections of the carcinogen 1,2 dimethylhydrazine (DMH). The G2 group received Lychnophora ericoides (LE) extracts for 6 wk. The groups G3 and G4 received LE for 4 wk and 2 wk, respectively, at the postinitiation and initiation phases of colonic carcinogenesis. The group G5 was the control. Forty-two days after the first injections of DMH for the neoplasic induction, we observed a statistically significant decrease in the number of aberrant crypt foci (ACF) and an attenuation of the increase in cell proliferation induced by DMH in all the LE treated groups. Thus, we concluded that Lychnophora ericoides extracts were effective against the development of cancer. These data suggest that LE has a protective influence on the process of colon carcinogenesis, suppressing both the initiation and the promotion of colonic carcinogenesis. PMID- 21526452 TI - Differential expression of thrombospondin (THBS1) in tumorigenic and nontumorigenic prostate epithelial cells in response to a chromatin-binding soy peptide. AB - The chemopreventive properties of the chromatin-binding soy peptide, lunasin, are well documented, but its mechanism of action is unclear. To elucidate the mechanism by which lunasin reduces tumor foci formation in cultured mammalian cells, nontumorigenic (RWPE-1) and tumorigenic (RWPE-2) human prostate epithelial cells were treated with lunasin followed by gene expression profiling and characterization of the chromatin acetylation status for certain chemopreventive genes. The genes HIF1A, PRKAR1A, TOB1, and THBS1 were upregulated by lunasin in RWPE-1 but not in RWPE-2 cells. Using histone acetyltransferase (HAT) assays with acid-extracted histones as templates, we showed that lunasin specifically inhibited H4K8 acetylation while enhanced H4K16 acetylation catalyzed by HAT enzymes p300, PCAF, and HAT1A. These results suggest a novel mechanism for lunasin-dependent upregulation of gene expression. Chromatin immunoprecipitation (ChIP) revealed hypoacetylation of H4K16 in RWPE-2 cells, specifically at the 5' end of THBS1 containing a CpG island. Moreover, bisulfite PCR (BSP) and subsequent DNA sequencing indicated that this CpG island was hypomethylated in RWPE-1 but hypermethylated in RWPE-2 cells. Histone hypoacetylation and DNA hypermethylation in the 5' region of THBS1 may explain the inability of lunasin to upregulate this gene in RWPE-2 cells. PMID- 21526455 TI - Similarity on the rebound: inhibition of similarity assessment leads to an ironic postsuppressional rebound. AB - A widely held but rarely tested assumption among cognitive scientists is that different cognitive tasks may rely upon a single basic cognitive process. Using an established methodology to examine the suppression and subsequent rebound of mental operations, the present research indicates that suppressing use of similarity in one domain results in the subsequent rebound of similarity assessment in a different domain, suggesting that both domains rely on the same underlying cognitive process. In two studies, we demonstrate that leading people to suppress natural similarity assessment in one task produces increased reliance on similarity in subsequent, different, and apparently unrelated tasks. In Experiment 1, participants led to suppress similarity in a concentration task subsequently made more errors in a false-memory paradigm than did control participants. In Experiment 2, participants suppressing similarity in a categorization task made more false-memory errors and perceived more similarity between word pairs than participants who did not suppress. The findings suggest that the cognitive process of similarity assessment may be a domain-general process, such that it is widespread across a number of different mental tasks. PMID- 21526454 TI - Meat consumption, cooking practices, meat mutagens, and risk of prostate cancer. AB - Consumption of red meat, particularly well-done meat, has been associated with increased prostate cancer risk. High-temperature cooking methods such as grilling and barbecuing may produce heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs), which are known carcinogens. We assessed the association with meat consumption and estimated HCA and PAH exposure in a population-based case-control study of prostate cancer. Newly diagnosed cases aged 40-79 years (531 advanced cases, 195 localized cases) and 527 controls were asked about dietary intake, including usual meat cooking methods and doneness levels. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate logistic regression. For advanced prostate cancer, but not localized disease, increased risks were associated with higher consumption of hamburgers (OR = 1.79, CI = 1.10-2.92), processed meat (OR = 1.57, CI = 1.04-2.36), grilled red meat (OR = 1.63, CI = 0.99-2.68), and well-done red meat (OR = 1.52, CI = 0.93-2.46), and intermediate intake of 2-amino-1-methyl1-6-phenylimidazo[4,5-b]pyridine (PhIP) (Quartile 2 vs. 1: OR = 1.41, CI = 0.98-2.01; Quartile 3 vs. 1: OR = 1.42, CI = 0.98-2.04), but not for higher intake. White meat consumption was not associated with prostate cancer. These findings provide further evidence that consumption of processed meat and red meat cooked at high temperature is associated with increased risk of advanced, but not localized, prostate cancer. PMID- 21526456 TI - [Not Available]. PMID- 21526457 TI - [Not Available]. PMID- 21526458 TI - [Pulmonary hypertension in end-stage renal disease: three case reports]. AB - HISTORY: Within three months, three patients with end-stage renal disease presented for evaluation of pulmonary hypertension (PH): a 72-year-old woman (case 1), a 67-year-old patient (case 2) and a 75-year-old patient (case 3), each with increasing dyspnea (WHO functional class III). INVESTIGATIONS: In all three cases, there was echocardiographic evidence of right heart failure; right heart catheterization was completed before and after dialysis. In case 1, we found a postcapillary PH (PH group 2 - PH with left heart diseases/diastolic dysfunction). Case 2 also showed a postcapillary PH and a high cardiac output of 9.7 l/min. In case 3, unmasked after dialysis, a precapillary, pulmonary arterial hypertension (PAH - group 1) was detected. TREATMENT AND COURSE: In patient 1, no relevant improvement of symptoms was observed, despite optimized cardiac therapy. There was a significant clinical improvement in patient 2 after surgical reduction of the arteriovenous shunt. In patient 3, relevant clinical and hemodynamic improvement was seen under treatment with bosentan. CONCLUSION: These cases confirm the role of right heart catheterization in the differential diagnosis of unclear PH in patients with end-stage renal failure. Moreover, the three cases point to three different causes. Specific therapies can result in significant symptomatic improvement. PMID- 21526459 TI - [Heart and kidney--only together they are strong. On the cardiorenal and renocardiac syndrome. Case 5/2011]. AB - HISTORY AND ADMISSION FINDINGS: We report on two patients with cardiorenal and renocardiac syndrome, respectively, who were treated with peritoneal dialysis. INVESTIGATIONS: Patient 1 suffered from dilated cardiomyopathy with an ejection fraction of 20%. There was no hint for an intrinsic renal disease, urinalysis showed microalbuminuria at the most. Due to progressive cardiac forward failure kidney dysfunction and diuretic-refractory volume retention developed. Patient 2 was admitted with an uremic syndrome and newly developed atrial fibrillation. Echocardiography revealed a hitherto unknown dilated cardiomyopathy. DIAGNOSIS, TREATMENT AND COURSE: Both patients were treated with continuous ambulatory peritoneal dialysis. This led to regression of the uremic complications. Sinus rhythm was restored in patient 2 after two weeks and cardiomyopathy was reversed after another 9 months. CONCLUSIONS: End-stage heart failure results in kidney dysfunction which can progress to a dialysis-dependent state. End-stage renal failure is often accompanied by cardiac dysfunction and failure. PMID- 21526460 TI - [Diagnosis and treatment of heparin-induced thrombocytopenia]. PMID- 21526461 TI - [Endocrine disruptors: hormone-active chemicals from the environment: a risk to humans?]. AB - Many substances from the technical and natural environment can cause damage to the endocrine system. Animal tests show that so-called endocrine disruptors (ED), such as pesticides, fungicides, plasticizers (phthalates), bisphenol A (BPA), and organotin compounds can interfere with the endocrine system. In humans, it is difficult to attribute such changes to specific ED. Nevertheless, in vitro studies with human cells and tissues clearly show that ED are able to interfere with endogenous hormones, i. e. affecting the steroid hormone metabolism and intracellular signaling. Several clinical studies show that humans are also affected, including reproductive disorders like reduction of spermatogenesis, decreased testosterone production or malformation of the genitals or induction of tumors like mammary carcinoma. Facing the body of reports documenting the effects of ED, the European Union supported--inter alia--COMPRENDO, a project addressing risk assessment of particular ED in human and wildlife species, while the FDA supports the industry's actions to stop producing BPA-containing baby bottles and infant feeding cups. Some ED show an u-shaped dose response curve and specific ED have effects at levels dramatically lower than thought relevant to traditional toxicology, a phenomenon termed "Low Dose Impact". Further research is needed to clarify whether the observed findings represent associations or causal results. PMID- 21526462 TI - [Cost structure of a telephone-based case management in primary care depression therapy]. AB - OBJECTIVES: Case management by health care assistants in small primary care practices has proven effective in improving depression symptoms in depressive patients. Resource consumption and costs of this intervention have not been evaluated yet. METHODS: Health care assistants and general practitioners of 15 participating practices were interviewed for intervention-related time expenditures. Intervention costs were based on individual labour costs. RESULTS: The annual time spent was 6.3 h per patient for health care assistants and 3.6 h for general practitioners (mean 8.9 patients per practice). The case management caused costs of ? 277 per patient and year. CONCLUSIONS: A telephone-based case management as add-on therapy improves quality of primary care depression therapy while causing only moderate costs for health care providers. PMID- 21526463 TI - [Diagnosis and treatment of iron deficiency and anaemia in inflammatory bowel diseases. Consensus of the Austrian IBD Working Party]. AB - Iron deficiency with and without anaemia is a common burden of patients with inflammatory bowel diseases (IBD) and has considerable impact on their quality of life and the ability to perform. The IBD working group of the Austrian Society of Gastroenterology and Hepatology developed five consensus statements on the following topics: (i) diagnosis of iron deficiency and (ii) anaemia, (iii) screening of iron deficiency, (iv) treatment of iron deficiency and (v) therapeutic goals. The clinical importance of intravenous iron replacement therapy in IBD with regard to effectiveness and compliance was discussed. PMID- 21526464 TI - [Factors that influence clinical outcome following autologous chondrocyte implantation for cartilage defects of the knee]. AB - AIM: Since its introduction in 1994, autologous chondrocyte implantation (ACI) has become an established surgical treatment for symptomatic isolated cartilage defects of the knee. Success rates vary between 80 and 95% and the clinical outcome seems to depend on various individual factors. The aim of the present review article is to summarise factors that affect clinical outcome following ACI for treatment of symptomatic cartilage defects of the knee based upon the scientific literature available on this topic. METHODS: The present publication represents a non-systematic review including publications which were considered relevant describing factors that influence clinical outcome following ACI for treatment of symptomatic full thickness cartilage defects of the knee. In order to identify relevant literature concerning complications following cartilage repair, medical databases including "medline", "ovid" and "web of science" were searched for the terms "autologous chondrocyte implantation", "autologous chondrocyte transplantation", "prognostic factor", "clinical outcome", "cartilage repair", "cartilage defect" and "cartilage regeneration". The literature search was performed in April 2010. RESULTS: Factors that influence clinical outcome following ACI for treatment of cartilage defects of the knee include patient specific parameters on the one hand, such as body mass index, nicotine abusus, patients age, prior surgical treatment, duration of symptoms and more, and defect characteristics such as containment, defect location, defect size, number of defects treated, on the other hand. Furthermore, surgical technique, cell quality and rehabilitation seem to significantly influence the clinical outcome following autologous chondrocyte implantation. Among all factors identified as relevant for clinical outcome, some of these parameters are fixed and cannot be changed by either the surgeon nor the patient, while others can be influenced and even changed during the treatment and rehabilitation of a patient who underwent ACI. CONCLUSION: Knowledge of all relevant parameters that influence clinical outcome following ACI is essential in order to achieve an optimal clinical outcome in patients with cartilage defects of the knee. This paper presents a review of the scientific literature available which focuses on the questions as to what parameters influence the outcome of a patient following ACI for treatment of cartilage defects of the knee. No isolated factors could be identified that influence the outcome following ACI alone, but it seems that clinical outcome is influenced by many different parameters. These parameters should be considered carefully, at the time of decision about what kind of treatment is applied. Furthermore, the patient should be informed especially about those parameters which can be influenced by him-/herself in order to create good prerequisites for the surgical treatment. PMID- 21526465 TI - [Vacuum-assisted closure therapy for the treatment of acute postoperative osteomyelitis]. AB - AIM: Vacuum-assisted closure is used frequently for the treatment of posttraumatic osteomyelitis of the extremities. After debridement and repeated VAC dressing changes, the wounds are closed by secondary suture, split-thickness skin grafts or local flaps. However, no objective parameters describe the time point for secondary wound closure. Our thesis was that negative microbiological results from bone specimens can indicate the time for secondary wound closure. Moreover, treatment course and clinical outcome after 3.4 years should be compared to those of other surgical approaches for acute postoperative osteomyelitis from the literature. PATIENTS AND METHODS: 43 patients with acute postoperative osteomyelitis of the extremities and the pelvis were treated by serial bone and soft tissue debridements and VAC therapy and analysed prospectively. Debridements were repeated until the wounds were macroscopically free from signs of infection (good granulation/no necrosis). During each revision a bone specimen was taken for microbiological analysis. Number of revisions, bacterial cultures, type of wound closure and recurrence of infection after 3 years and 5 months on average after the last surgery was analysed. RESULTS: 9.8 debridements on average were performed until eradication of infection and secondary wound closure. Despite the absence of macroscopic infection, bacteria were still found in bone samples from 15 of 43 patients. Three biopsies were free of bacteria for the first time right before wound closure, 25 samples had become negative during the treatment. Six recurrences (19.3 %) were noted after 3.4 years on average. Four patients from the group of negative bone biopsies (19 %) and two patients from the group of persisting bacteria before secondary closure (20 %) had a recurrence of infection. CONCLUSION: In about one third of the bone biopsies bacteria persisted. This bacterial load had no correlation to wound healing and rate of recurrence after over 3 years. In conclusion, microbiological bone samples are not suitable as an indicator for the time point of secondary wound closure. Compared to other treatment options in acute postoperative osteomyelitis from the literature (especially implantation of local antibiotics), no advantage of vacuum-assisted closure could be shown concerning number of debridements and rate of recurrences. PMID- 21526466 TI - [Clinical risk management in german hospitals - does size really matter?]. AB - PURPOSE: In the last years, German hospitals have implemented different measures to increase patient safety. Special importance has been attached to near miss reporting systems (critical incident reporting system, CIRS) as instruments for risk identification in health care, instruments that promise high potential for organisational learning. To gain insight into the current status of critical incident reporting systems and other instruments for clinical risk management, a survey among 341 hospitals was carried out in 2009. Questions covered a process of six steps: from risk strategy to methods for risk identification, to risk analysis and risk assessment, to risk controlling and risk monitoring. MATERIAL AND METHODS: Structured telephone interviews were conducted with 341 German hospitals, featuring in their statutory quality reports certain predefined key terms that indicated the concluded or planned implementation of clinical risk management. The main objective of those interviews was to check the relation between status/organisation of self-reported risk management and both operator (private, public, NPO) and size of hospital. RESULTS: The implementation of near miss reporting systems (CIRS) in German hospitals has been constantly rising since 2004: in 2009, 54 % of the interviewed hospitals reported an implemented CIRS; of these, 72 % reported the system to be hospital-wide. An association between CIRS and private, public or NPO-operator could not be detected (Fisher p = 1.000); however, the degree of CIRS implementation was significantly increasing with the size of the hospital, i.e., the number of beds (Fisher p = 0.008): only 38 % of the hospitals with less than 100 beds reported CIRS implementation against 52 % of those between 100 to 500 beds, and 67 % of those with more than 500 beds. While 62 % of the hospitals interviewed reported the maintenance of a risk management committee, only 14 % reported the implementation of risk analysing techniques. As to clinical risk management, 92 % of the hospitals see potential for internal improvement; 44 % have already communicated with external consultants. CONCLUSION: While identification of clinical risks with near miss and other incident reporting systems meets increasing acceptance, the learning potential based on incident reporting is not yet appropriately being used. There is a deficit regarding systematic and comprehensive risk assessment and controlling; this will have to be met by improving the organisational framework for clinical risk management. PMID- 21526468 TI - [What is your diagnosis? Exercise-associated hyponatremia]. PMID- 21526467 TI - [Etiologies of nephrotic syndrome]. PMID- 21526469 TI - [Focal points in tuberculosis research yesterday and today]. PMID- 21526470 TI - [Smoking behaviour and willingness to stop smoking in patients admitted in an internal medicine ward]. AB - Smoking is one of the leading preventable risk factors for the development of lung-, cardio-vascular diseases and cancer. We report results of a prospective survey regarding smoking behaviour and willingness to stop smoking in patients of an internal medicine clinic. Twenty percent of participants admitted smoking cigarettes in the previous 7 days. Smokers were more often males and were younger than non- or ex-smokers. Every second smoker reported being told to stop smoking by a physician before but only about a third was offered active support in doing so. About half of the smoking participants were interested to quit smoking and to participate in a hospital-based smoking cessation program. In patients admitted to the hospital, smoking behaviour and willingness to quit smoking should be recorded and help in quitting smoking should be offered actively. Beside recording smoking behaviour and willingness to quit, patients who are admitted in the hospital should be offered help to quit smoking or to join a proactive structured smoking cessation program. PMID- 21526471 TI - [Recommendations for the use of polyhexanide-containing products for the treatment of wounds]. AB - Polihexanide-containing wound products are often used for the treatment of acute and chronic wounds. Although information pertaining to the use of polihexanide can be found in the literature, the appropriate use of these products in clinical practice is not always clear. The goal of this short review is to provide clinically relevant recommendations to physicians and nurses treating patients with acute and chronic wounds. This review describes the clinically relevant characteristics of polihexanide and gives recommendations for the prophylaxis and treatment of wound infections. PMID- 21526472 TI - [Diagnosis of peripheral neuropathies]. PMID- 21526473 TI - [Refractory hypoxia]. AB - We report a case of refractory hypoxia in an 85 years old smoker patient, who is known for cardiac and pulmonary comorbidities. The whole clinical picture at the time of his admission to hospital was pointing to a cardiac failure or a pneumonia that were causing the respiratory insufficiency. Despite an optimal treatment which stabilised these conditions, the patient remained severely hypoxic, but with relatively few symptoms. The non response to the oxygen and the worsening of the oxygen saturation when changing from the lying to the sitting (or supine) position finally evoke the syndrome of platypnea-orthodeoxia caused by a cardiac right to left shunt; that diagnosis was confirmed by a cardiac ultrasound with contrast which revealed an important inter-auricular shunt. The patient didn't wish to undertake the curative treatment (shunt closure). PMID- 21526474 TI - [Help, I have crooked fingers - or the solution to a series of medical phenomena]. AB - We describe the case of a 23-year old man, who is himself a student of human medicine and who performed, thanks to his knowledge gained during his studies, a presumptive diagnosis of the Ehlers-Danlos-syndrome on himself. This fact was previously underdiagnosed by several physicians, who were consulted due to the manifestation of symptoms. PMID- 21526475 TI - [A penetrating volar foreign body: a wooden splinter beneath the flexor tendons]. AB - Hand injuries are among the most common injuries seen in general practitioner (GP) consultation hours and emergency departments and are most often affecting the dominant hand. We report on a case of unsuccessful primary exploration of the volar hand for a foreign body by the GP. In regard to detailed history of the injury mechanism, we performed the clinical examination and an additional ultrasound evaluation of the hand, suggesting evidence for a foreign body and a laceration of one of the flexor tendons. Figures are illustrating the mechanism of the injury and emphasize the need for determining the kinematics and course of the injury. The suspicion of a foreign body within the hand requires the consultation of a trained hand surgeon to adequately treat the injury and provide the after-care. PMID- 21526476 TI - [Assessment of osteoporotic fracture risk: FRAX is exactly as inadequate as simple models]. PMID- 21526477 TI - [Quadrivalent HPV vaccination in men is effective prevention against HPV infections and their associated anogenital lesions]. PMID- 21526479 TI - [CME ECG 33. Pacemaker rhythm or no pacemaker rhythm. Sinus rhythm with mainly normal conduction]. PMID- 21526482 TI - Proteomics of M-phase entry: 'Omen' vs. 'Omre', the battle for oocyte quality and beyond. AB - The understanding of cell cycle regulation benefited greatly from omic approaches. Because the cell cycle engine relies heavily on proteins, proteomic methods play a key role in identification of cell cycle players. The proteomic approach delivers an enormous volume of data, but it often lacks comprehensiveness. To ensure the comprehensiveness of results the discovery of novel proteins must be followed by functional analysis. Using Xenopus laevis oocytes in two different proteomic screens, we have recently identified a number of proteins whose behavior suggested specific and unexpected roles in M-phase entry. Functional analysis of EP45 identified in one of these screens has shown that M-phase entry is stimulated by Oocyte-Maturation-ENhancer ('Omen') activity. The second screen suggests the presence of an antagonistic activity, which we call 'Omre' (Oocyte- -Maturation-REpressor). The equilibrium between Omen and Omre activities may determine the quality of oocytes and further embryo development via participation in making the decision whether to enter oocyte maturation. It remains an open question whether similar activities operate during mitotic divisions in embryonic and adult cells. Identifying such activities in somatic cells might impact on cancer treatments. PMID- 21526483 TI - Similarities between oocytes and macrophages. An overview. AB - Oocytes behave as macrophages as they internalize solid and liquid substances required for their growth and competence. This activity is more pronounced in lower invertebrates. The slowing of endocytic activity may be caused by constraints imposed by surrounding nurse cells and by the amount of accumulated yolk precursors. The genes concerned with endocytic activity in oocytes are controlled by a negative feedback signal provided by accumulated yolk and/or by signal transduction. PMID- 21526484 TI - Cathepsin A activity of a parietal thrombus of an abdominal aortic aneurysm. AB - We evaluated the cathepsin A activity of a parietal thrombus of an abdominal aortic aneurysm. We compared this activity to that of a retracted blood clot homogenate. Cathepsin A of aneurysm parietal thrombus homogenate and blood clot homogenate showed the highest activity on Z-Phe-Ala. It was lower on Z-Phe-Phe, Z Glu-Tyr, Z-Glu-Phe, Z-Gly-Phe, and the lowest activity was on Z-Gly-Ala. We conclude that cathepsin A's activity on a parietal thrombus of an aneurysm is much higher than blood clot cathepsin A activity. PMID- 21526485 TI - Stem cells as therapy for cardiac disease - a review. AB - Acute myocardial infarction (AMI) is one of the most significant causes of morbidity and mortality worldwide. Stem cells represent an enormous chance to rebuild damaged heart tissue. Correct definition of the cardiac progenitors is necessary to understand heart development, and would pave the way for the use of cardiac progenitors in the treatment of heart disease. Identifying, purifying and differentiating native cardiac progenitor cells are indispensable if we are to overcome congenital and adult cardiac diseases. To understand their functions, physiology and action, cells are tested in animal models, and then in clinical trials. But because clinical trials yield variable results, questions about proper cardiac stem cells remain unanswered. Transplanted stem cells release soluble factors, acting in a paracrine fashion, which contributes to cardiac regeneration. Cytokines and growth factors have cytoprotective and neovascularizing functions, and may activate resident cardiac stem cells. Understanding all these mechanisms is crucial to overcoming heart diseases. PMID- 21526486 TI - The significance of Survivin and Nectin-4 expression in the prognosis of breast carcinoma. AB - To investigate the prognostic significance of Survivin and Nectin-4 expression in breast carcinomas. Imprint smears were obtained from 140 breast carcinoma specimens and studied immunocytochemically for the expression of Survivin and Nectin-4. The results were correlated with several clinicopathological parameters, including five-year survival. Increased Survivin staining pattern correlated with increased grade (p < 0.0001), increased lymph node invasion (p < 0.0001), increased tumor size and reduced survival (p < 0.0001). Elevated Nectin 4 expression also correlated significantly with increased grade (p < 0.0001), increased tumor size (p < 0.0001) and reduced survival (p < 0.0001). In addition, Survivin and Nectin-4 staining patterns correlated strongly with one another (p < 0.0001). However, on multivariate analysis, neither Survivin nor Nectin-4 expression seemed to have an independent impact on survival in our study cases. The findings of our study suggest that increased expression of Survivin and Nectin-4 may indicate a worse prognosis in breast cancer patients. The exact implications of the expression of these markers in breast cancer prognosis and treatment remain to be clarified. PMID- 21526487 TI - Effect of human papillomavirus on cell cycle-related proteins p16INK4A, p21waf1/cip1, p53 and cyclin D1 in sinonasal inverted papilloma and laryngeal carcinoma. An in situ hybridization study. AB - Human papillomavirus (HPV) infection is implicated as an important risk factor in the development of head and neck cancers. Many studies focusing on the relationships between HPV infection and cell cycle proteins immunoexpression in laryngeal lesions have provided contradictory results. The aim of this study was to evaluate the relationships between HPV DNA presence and p16INK4a, p21waf1/cip1, p53 and cyclin D1 immunoexpression in heterogenous HPV-positive and HPV-negative groups of laryngeal cancers and inverted papillomas. The HPV DNA expression was detected using an in situ hybridization method and immunoexpression of p16INK4a, p21waf1/cip1, p53 and cyclin D1 using immunohistochemistry. The immunoexpression of p21waf1/ /cip1 and p53 proteins was lower in the HPV-positive group compared to the HPV-negative group, although only the difference of p53 staining was statistically significant. The immunoexpression of p16INK4a and cyclin D1 was significantly increased in the HPV positive group compared to the HPV-negative group. The increased immunoexpression of p16INK4a and cyclin D1, and the lower immunoexpression of p21waf1/cip1 and p53 in the HPV-positive group compared to the HPV-negative group, supports the hypothesis that HPV may play an important role in cell cycle dysregulation. PMID- 21526488 TI - Immunohistochemical detection of metalloproteinase-9 (MMP-9), anti-oxidant like 1 protein (AOP-1) and synaptosomal-associated protein (SNAP-25) in the cerebella of dogs naturally infected with spontaneous canine distemper. AB - In most viral infections of the central nervous system (CNS), the integrity of brain extracelluar matrix (ECM), oxidative stress and dysfunction in neuronal transmission may contribute to the observed pathology. The purpose of this study was to investigate the role of these factors in demyelinating canine distemper virus (CDV) infections. Regardless of ECM integrity, the expression of metalloproteinase-9 (MMP-9) was visualized in microglial-like cells, whereas the expression of anti-oxidant like-1 (AOP-1) and synaptosomal associated protein (SNAP-25) was frequently detected in Purkinje cells (r(2) = 0.989; p < 0.05), regardless of whether the lesions were classified as acute or chronic. Increased numbers of immunolabeled microglia-like cells and reactive gliosis were observed in advanced cases of demyelinating CDV, suggesting that the expression of AOP-1 and SNAP-25 is correlated with the ultimate death of affected cells. Our findings bring a new perspective to understanding the role of the AOP-1, MMP-9 and SNAP-25 proteins in mediating chronic leukoencephalitis caused by CDV. PMID- 21526489 TI - ICOS gene polymorphisms in B-cell chronic lymphocytic leukemia in the Polish population. AB - There is strong evidence that altered immunological function entails an increased risk of B-cell chronic lymphocytic leukemia (B-CLL). The main mechanism of an anti-tumor response depends on T-cell activation. Unlike the constitutively expressed CD28, inducible costimulatory molecule (ICOS) is expressed on the T cell surface after activation. ICOS enhances all the basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, the upregulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B cells. ICOS is essential for both efficient interaction between T and B cells and normal antibody responses to T cell-dependent antigens. It does not upregulate the production of interleukin-2, but superinduces the synthesis of interleukin-10. Our previous results indicated the ICOS gene has a role as a susceptibility locus to B-CLL. Therefore an extended study was undertaken to evaluate the association between four ICOS polymorphisms (which were recently described as functional ones) and susceptibility to B-CLL in the Polish population. A case-control study of 296 individuals, including 146 B-CLL patients, was conducted on four polymorphisms in the ICOS gene. Genotyping of the polymorphisms ICOS ISV1+173T>C (rs10932029), ICOSc.1624C>T (rs10932037), ICOSc.2373G>C (rs4675379), and ICOSc.602A>C (rs10183087) was carried out using allelic discrimination methods with the TaqMan SNP Genotyping Assay. There were no statistically significant differences in the allele, genotype, or haplotype distributions between B-CLL patients and healthy controls for any of the investigated polymorphic markers in the ICOS gene. However, we noted that patients carrying genotype ICOS ISV1+173T>C [TT], ICOSc.602A>C [AA], ICOSc.1624C>T [CC], and ICOSc.2373G>C [GG] have a decreased frequency of progression to a higher Rai stage during 60-month follow-up (21.35% vs. 40.8%, p = 0.013) compared to other individuals. This indicates that the investigated polymorphisms do not modulate the risk of B-CLL in the Polish population, but are associated with disease dynamics, in particular with the time to Rai stage progression. PMID- 21526490 TI - Expression and localization of nerve growth factor (NGF) in the testis of alpaca (llama pacos). AB - During alpaca testis development and spermatogenesis, nerve growth factor (NGF) may play an important role. The main aim of this study was to determine the expression and localization of NGF in the alpaca testis, and to discuss the important role of NGF in alpaca reproductive characteristics. Immunohistochemical staining technique and real-time PCR were used. The expression of NGF in the same cells one-month old (newborn) alpacas 12-month, and 24-month old alpacas showed significant differences (p < 0.05); 12- and 24-month old alpacas showed no significant differences (p > 0.05); NGF at different cell stages showed no significant differences (p > 0.05). It suggests that NGF may be involved in the regulation of spermatogenesis, which provides direct evidence for NGF action in the alpaca testis during postnatal development and spermatogenesis. PMID- 21526491 TI - DHT deficiency perturbs the integrity of the rat seminiferous epithelium by disrupting tight and adherens junctions. AB - In rats with a DHT deficiency induced by finasteride, morphological changes in the seminiferous epithelium were observed. The structural alterations were manifested by the premature germ cells sloughing into the lumen of seminiferous tubules. The etiology of this disorder could be connected with intercellular junctions disintegration. We showed in the immunohistochemical study the changes in expression of some proteins building tight and adherens junctions. The depression of N-cadherin, beta-catenin and occludin immunoexpressions could be the reason for the release of immature germ cells from the seminiferous epithelium. However, the observed increase of the immunohistochemical reaction intensity of vinculin, one of the cadherin/catenin complex regulators, could be insufficient to maintain the proper function of adherens junctions. The hormonal imbalance appears to influence the pattern of expression of junctional proteins in the seminiferous epithelium. It could lead to untimely germ cells sloughing, and ultimately could impair fertility. PMID- 21526492 TI - Morphological aspects of the euphonic voice. AB - The high quality of a euphonic voice is the result of complex interactions between many organs and systems. Vibrating vocal folds play a crucial role in this process. Their physiological motion is conditioned by the presence of the layered structure of laryngeal mucosa. In this study, we assessed the degree of dysphonia according to the Union of European Phoniatrics (UEP) scale. Videoendoscopy (VLS) and videostroboscopic (VLSS) examination of the larynx was used to visualize the vibration of the vocal folds. Morphological assessment of the inter-membranous part of the vocal fold mucosa was carried out using material collected after surgical treatment (60%) or obtained from autopsy (40%). The samples were examined by light microscopy and transmission electron microscopy. In euphonic voices, 1 degrees of dysphonia (UEP) and the physiological endoscopic (VLS) and stroboscopic (VLSS) findings of vocal folds were registered. No morphological or ultramorphological changes were observed in the cells of the multilayered flat epithelium, basal membrane or in the stroma. Unchanged epithelial cells were situated on the basal membrane with folds. Moreover, numerous pericytes, vessels with multiplication of basal membranes, scanty collagenous fibers, plasmatic cells and lymphocytes were seen. Morphological changes with signs of atrophy and polypoid degeneration of the vocal fold mucosa were found in only 3 (15%) patients. PMID- 21526493 TI - The use of morphometric and fractal parameters to assess the effects of 5 fluorouracil, interferon and dexamethasone treatment on colonic anastomosis healing: an experimental study in rats. AB - Adjuvant chemotherapy and steroid therapy have been demonstrated to interfere with the wound healing process. The aim of this study was to evaluate the effects of 5-fluorouracil, interferon, and dexamethasone, on the healing of colon anastomosis by assessing morphometric and fractal parameters of the colonic wall. An experimental anastomosis of the ascending colon was performed in 60 male Wistar rats, which were then randomly assigned to four groups. On the second to sixth post-operative days, the rats were administered 5-fluorouracil, interferon alpha, dexamethasone, or 0.9% NaCl solution as a control. Macroscopic, histomorphometric and microbiological evaluation was performed in order to assess healing of the anastomosis. In three animals from the dexamethasone group, there was leakage of anastomosis; adhesion formation was highest in the interferon group, and significantly higher than in the control and 5-fluorouracil groups. Histomorphometric parameter alterations were most pronounced on the seventh and fourteenth post-operative days in all treatment groups, with submucosal thickness the most affected parameter. Connective tissue fractal dimension was significantly decreased in those animals treated with interferon and dexamethasone. All three pharmaceutical agents impaired healing of anastomosis, and promoted infection in the anastomosis and skin wound sites. As dexamethasone induced both morphometric and macroscopic alterations, it was considered the most detrimental in this study. PMID- 21526494 TI - Lymphatic vessel invasion detected by the endothelial lymphatic marker D2-40 (podoplanin) is predictive of regional lymph node status and an independent prognostic factor in patients with resected esophageal cancer. AB - The discovery of markers to lymphatic endothelial cells and the development of novel antibodies to these markers have brought increasing attention to the lymphatics and progress in the understanding of lymphangiogenesis and cancer metastasis. In this study, we investigate the presence of lymphatic vessel invasion (LVI) detected by D2-40 immunohistochemical staining in resected esophageal cancer and correlated with clinicopathologic data and patient survival. Sixty nine patients, who had a primary resection of esophageal cancer, were analyzed by univariate and multivariate logistic regression, and univariate and multivariate survival analysis. The total rate of LVI was 72% (50/69). Positive LVI was significantly correlated with lymph node metastasis (p < 0.001), tumor size (p < 0.001), histological grading (p = 0.017), tumor depth (p = 0.001), and stage (p < 0.001). Multivariate logistic analysis identified LVI (p = 0.036) as a predictor of regional lymph node metastasis. On univariate survival analysis, patients with LVI had a significantly shorter disease-free survival, cancer-specific survival and overall survival. Multivariate analysis proved that LVI diagnosed by D2-40 is an independent prognostic factor of both disease-free survival (p = 0.04) and overall survival (p = 0.032) in resected esophageal cancer. These results show that LVI assessment identifies patients at high risk for regional lymph node metastasis and that LVI is an independent prognostic factor in patients with esophageal cancer. PMID- 21526495 TI - Assessment of the pathway of apoptosis involving PAR-4, DAXX and ZIPK proteins in CLL patients and its relationship with the principal prognostic factors. AB - Par-4 (prostate apoptosis response-4) protein was originally found upregulated in prostate tumor cells undergoing apoptosis. Then it was further identified as a proapoptotic protein upregulated both in normal and leukemic lymphocytes. The aim of our study was to assess PAR-4 protein expression in the B cells of CLL patients and to examine its relationship with the expression of other proteins involved in the apoptosis process, such as DAXX, ZIPK and BCL-2. We found a positive relationship between PAR-4 and BCL-2 protein expression. Additionally, there was a positive correlation between PAR-4 and both DAXX and ZIPK protein expression. The results of our research were also analyzed in association with the principal CLL prognostic factors. There was a positive correlation between the expression of PAR-4 protein and the lactate dehydrogenase (LDH) serum concentration (p < 0.005). The expression of PAR-4 protein in B cells correlated positively with the percentage of CD38(+) cells (p < 0.05), as well as with CD38(+)/ZAP-70(+) cells (p < 0.05). Moreover, we found a close relationship between LPL protein expression or LPL/ADAM29 MFI ratio and PAR-4 protein expression. Our results confirm the significance of apoptosis deregulation in CLL, and suggest a possible relationship between PAR-4 expression and the clinical course of the disease. This however requires further investigation. PMID- 21526496 TI - Microvascular abnormalities in capillaroscopy correlate with higher serum IL-18 and sE-selectin levels in patients with type 1 diabetes complicated by microangiopathy. AB - Microvascular abnormalities are one of the most important causes of persistent diabetic complications. The aim of this study was to compare microvascular changes examined by nailfold capillaroscopy with serum concentrations of soluble E-selectin (sE-selectin) and IL-18 in type 1 diabetic patients with and without microangiopathy. Serum levels of sE-selectin and IL-18 were determined by an enzyme-linked immunosorbent assay in 106 patients with type 1 diabetes and in 40 healthy controls. All diabetic patients were evaluated by extensive clinical, laboratory and capillaroscopic studies. Morphological changes were observed by nailfold capillaroscopy in 86 out of 106 (81%) diabetic patients. Severe capillaroscopic changes were seen in 32 out of 54 (59%) patients with microangiopathy, but in only seven out of 52 (13%) patients without microangiopathy. Higher serum levels of sE-selectin (p < 0.001) and IL-18 (p < 0.05) were demonstrated in diabetic patients compared to controls. Significant differences of sE-selectin (p , 0.001) and IL-18 (p < 0.01) serum concentrations were observed between diabetic patients with microangiopathy and controls. Moreover, comparison between patients with and without microangiopathic complications showed a significantly higher capillaroscopic score and sE-selectin serum concentration in the group with microangiopathy (p < 0.001). Furthermore, diabetic patients with severe microvascular changes in capillaroscopy showed significantly higher IL-18 (p < 0.001) and sE-selectin (p < 0.05) serum levels than subgroups without changes or with mild abnormalities. Our findings suggest that abnormalities in nailfold capillaroscopy may reflect the extent of microvascular involvement and are associated with higher sE-selectin and IL-18 serum levels, as well as with microangiopathic complications in diabetic patients. PMID- 21526498 TI - Assessment of the influence of the inflammatory process on the activation of blood platelets and morphological parameters in patients with ulcerative colitis (colitis ulcerosa). AB - Ulcerative colitis (colitis ulcerosa) is a non-specific inflammatory bowel disease of unknown etiology. The symptoms which are observed in the course of ulcerative colitis are: an increase in the number of leukocytes and blood platelets, an increase in the concentration of IL-6 and anemia. Blood platelets are the key element, linking the processes of hemostasis, inflammation and the repair of damaged tissues. Activation of blood platelets is connected with changes in their shape and the occurrence of the reaction of release. P-selectin appears on the surfaces of activated blood platelets and the concentration level of soluble P-selectin increases in the blood plasma. The aim of this study was to define whether the increased number of blood platelets in patients with ulcerative colitis accompanies changes in their activation and morphology. A total of 16 subjects with ulcerative colitis and 32 healthy subjects were studied. Mean platelet count, morphological parameters of platelets and MPC were measured using an ADVIA 120 hematology analyzer. Concentrations of sP-selectin and IL-6 in serum were marked by immunoassay (ELISA). MPC, concentration of sP selectin and IL-6 were significantly higher in subjects with ulcerative colitis compared to those in the healthy group. There was a decrease of MPV in patients with ulcerative colitis, which is statistically significant. Chronic inflammation in patients with ulcerative colitis causes an increase in the number of blood platelets, a change in their morphology and activation. Decreased MPV value reflects activation and the role blood platelets play in the inflammatory process of the mucous membrane of the colon. A high concentration of sP-selectin, which is a marker of blood platelet activation, demonstrates their part in the inflammatory process. The increase in the concentration of sP-selectin correlated positively with the increase in concentration of IL-6. This is why it may be a useful marker of the activity of colitis ulcerosa. PMID- 21526497 TI - Expression of HOXA-10 and HOXA-11 in the endometria of women with idiopathic infertility. AB - In fertile women, HOXA-10 and HOXA-11 expression rises during the luteal phase, with the peak occurring during the implantation window, and stays at a high level until the end of the cycle. We evaluated the transcript and protein levels of HOXA-10 and HOXA-11 in the endometria of patients with idiopathic infertility (n = 15) and control patients (n = 10). The amounts of mRNA were determined by reverse transcription and real-time quantitative PCR. The protein levels were evaluated by Western blotting analysis. Using immunohistochemical techniques, we compared the localization of HOXA-10 and HOXA-11 proteins in the implantation window between the study and control groups. We observed statistically significantly decreased HOXA-10 and HOXA-11 transcript levels (p = 0.003, p = 0.012 respectively) in infertile patients compared to controls. There was no significant decrease in HOXA-10 protein levels between these groups (p = 0.074). However, we observed a significantly higher level of HOXA-11 protein in the endometria of infertile patients compared to controls (p = 0.015). HOXA-10 and HOXA-11 proteins were localized in the nuclei of the endometrial stromal cells. Immunohistochemical analyses did not reveal differences between amounts of HOXA 10 and HOXA-11 protein levels in infertility and control groups. Our results suggest that HOXA-10 and HOXA-11 gene expression in the endometrium during the implantation window may not be altered in patients with idiopathic infertility. PMID- 21526499 TI - Clinical significance of serum levels of matrix metalloproteinase 2 (MMP-2) and its tissue inhibitor (TIMP-2) in gastric cancer. AB - Matrix metalloproteinase 2 (MMP-2) is able to degrade type IV collagen, and thus plays a key role in the migration of tumor cells. MMP-2 activity is inhibited by its tissue inhibitor (TIMP-2). The imbalance between MMPs and TIMPs may facilitate progression of cancer cells. The aim of this study was to compare the clinical importance of MMP-2 and TIMP-2 to that of classical tumor markers, namely carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) in the diagnosis of gastric cancer (GC) by calculating the diagnostic criteria and estimating the levels of MMP-2, TIMP-2, CEA and CA 19-9 in GC patients in relation to clinicopathological features of cancer. We found that serum levels of MMP-2 and TIMP-2 were significantly lower, whereas serum tumor markers were higher, in GC patients than in healthy subjects. Moreover, concentrations of TIMP 2 and CEA correlated with gastric wall infiltration, while CA 19-9 levels correlated with gastric wall infiltration and the presence of nodal metastasis. None of the proteins tested was found to be an independent prognostic factor for GC patients' survival. The percentage of true positive results of TIMP-2 (61%) was higher than those of MMP-2 (54%) and the classical tumor markers CEA (21%) and CA 19-9 (31%). The highest diagnostic sensitivity was observed for the combined use of TIMP-2 with MMP-2 (77%). The results suggest the greater importance of serum MMP-2 and TIMP-2 than of the classical tumor markers CEA and CA 19-9 in the diagnosis of GC. But this issue requires further investigation. PMID- 21526500 TI - Concomitant hypermethylation of multiple genes in non-small cell lung cancer (NSCLC). AB - Primary lung cancer remains the leading cause of cancer death worldwide. Promoter hypermethylation is a major inactivation mechanism of tumor-related genes, and increasingly appears to play an important role in carcinogenesis. In the present study, we used quantitative methylation-specific PCR (Q-MSP) assays to analyze promoter hypermethylation of nine genes in a large cohort of well-characterized non-small cell lung cancer (NSCLC) and explore their associations with the clinicopathological features of tumor. We found that there were significant differences in methylation levels for six of nine gene promoters between cancerous and noncancerous lung tissues. More importantly, with 100% diagnostic specificity, high sensitivity, ranging from 44.9% to 84.1%, was found for each of the nine genes. Interestingly, promoter hypermethylation of most genes was closely associated with histologic type, which was more frequent in squamous cell carcinomas (SCC) than in adenocarcinomas (ADC). In addition, highly frequent concomitant methylation of multiple genes was found in NSCLC, particularly in SCC. Our data showed that multiple genes were aberrantly methylated in lung tumorigenesis, and that they were closely associated with certain clinicopathological features of NSCLC, particularly of the histologic type, suggesting that these hypermethylated genes could be potential biomarkers in early detection of NSCLC in high-risk individuals, as well as in evaluating the prognosis of NSCLC patients. PMID- 21526501 TI - Correlation between Fas and FasL proteins expression in normal gastric mucosa and gastric cancer. AB - The study's objective was to assess the expressions of Fas and FasL proteins in gastric cancer in correlation with chosen clinicohistological parameters. Fas and FasL expression was analyzed in 68 patients with gastric cancer, using the immunohistochemical method. The expression of Fas was found to be lower in gastric cancer cells than in healthy mucosa, both in the lining epithelium and in glandular tubes (28% vs. 48% and 44%; p < 0.001). The expression of FasL was also markedly lower in cancer cells than in glandular tubes, yet higher than in the lining epithelium (51% vs. 73% and 14%; p < 0.01). Positive expressions of FasL and Fas were lower in less advanced gastric cancer cells (T1, T2), than in more advanced tumors (T3, T4), but only in the case of FasL was this difference statistically significant (p < 0.05). Our findings seem to confirm the theory of the impact of apoptotic disorders at the level of Fas receptor and FasL protein in the process of gastric cancer formation and growth, which is manifested in the varied expressions of these proteins in gastric cancer and in the normal lining and glandular epithelium of the stomach. However, the lack of significant differences in the expressions of Fas and FasL in correlation to other clinicohistological parameters indicates the existence of mechanisms that have a greater impact on the process of differentiation of gastric cancers. This in our opinion eliminates these proteins as prognostic factors. PMID- 21526502 TI - Levetiracetam protects hippocampal neurons in culture against hypoxia-induced injury. AB - Many experimental studies indicate that some antiepileptic drugs possess neuroprotective properties in varied models of neuronal injury. Levetiracetam is a second-generation antiepileptic drug with a novel mechanism of action. In the present study, we evaluated the putative neuroprotective effect of levetiracetam on primary hippocampal cultures at seven day in vitro. Cell death was induced by incubation of neural cultures in hypoxic conditions over 24 hours. Neuronal injury was assessed by morphometric investigation of death/total ratio of neurons in light microscopy using Trypan blue staining and by evaluation of lactate dehydrogenase (LDH) release in the culture medium. Our results indicate that pre conditioning of hippocampal cultures with high concentrations of levetiracetam (100 MUM and 300 MUM) protects neurons against hypoxia-induced death. Two-fold higher number of neurons remained viable as compared to control cultures without drug. Lack of neuroprotective action of the drug on hippocampal neural cultures was observed, when a low concentration (10 MUM) of levetiracetam was used. PMID- 21526503 TI - Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. AB - Immunotherapy with dendritic cells (DC) may constitute a new and advantageous option for patients with chronic myeloid leukemia (CML) who respond to therapy with tyrosine kinase inhibitors (TKI), but do not reach complete cytogenetic or molecular remission. In this study, we evaluated the immunophenotype of DC generated from monocytes (Mo-DC) of patients with CML and the influence of TKI therapy on the results of CML-DC generation. We also measured the percentages of T regulatory cells (Tregs) as well as Th17 cells in 19 untreated patients suffering from CML, and in 28 CML patients treated with TKI. We found that DC can be reliably generated from the peripheral blood CD14+ cells of untreated CML patients. But we observed a persistent expression of CD14 monocyte marker on DC from CML patients, together with lower percentages of Mo-DC with expression of CD1a (p = 0.002), CD80 (p = 0.0005), CD83 (p = 0.0004), and CD209 (p = 0.02) compared to healthy donors. There was an adverse correlation between WBC count and the percentage of Mo-DC with co-expression of CD80 and CD86 (R = -0.63; p = 0.03). In patients treated with TKI, we observed higher efficacy of DC generation in seven-day cultures, compared to untreated patients. Expression of CD209 on DC was higher in patients treated with TKI (0.02). The duration of TKI therapy correlated adversely with MFI for CD1a (R = -0.49; p = 0.006) and positively with MFI for CD83 (R = 0.63; p = 0.01). Percentages of CD4+CD25highFoxP3+ cells (p = 0.0002) and Th17 cells (p = 0.02) were significantly higher in untreated CML patients compared to healthy controls. There was a significant correlation between the percentage of Treg cells and the percentage of peripheral blood basophiles (R = 0.821; p = 0.02). There were no changes in Tregs or Th17 cell percentages in CML patients after six months of TKI therapy. However, the expression of intracellular IL-17 in Th17 cells correlated negatively with the time of TKI therapy in the whole group of treated patients (R = -0.516; p = 0.04). We noted a correlation between IL-6 serum level and peripheral blood WBC count (R = 0.492; p = 0.04). There was also an inverse correlation between the serum level of IL-6 and the duration of TKI therapy (R = -0.66; p = 0.03). Taken together, our data shows that mature DC can be generated from CML patients treated with TKI, and that the yield of Mo-DC is higher in patients treated with TKI than in patients with active disease. This should encourage further trials with DC immunotherapy in patients with cytogenetic response after TKI therapy. We also found increased frequencies of T regulatory and Th17 cells in CML patients, which might suggest their potential role in immunity against this disease. Further studies are needed to determine if manipulation of these cell populations might improve the results of DC immunotherapy. PMID- 21526505 TI - Flow cytometric immunophenotypic characteristics of plasma cell leukemia. AB - The aim of this prospective study was to define the flow cytometric characteristics of simultaneously investigated bone marrow and peripheral blood plasma cells antigens expression in 36 plasma cell leukemia (PCL) patients. The immunophenotypic profile of plasma cells was determined with a panel of monoclonal antibodies. The antigen expression intensity was calculated as relative fluorescence intensity (RFI). Bone marrow plasma cells showed expression of particular antigens in the following proportion of cases: CD49d 100%, CD29 94%, CD54 93%, CD44 83%, CD56 60%, CD18 26%, CD11b 29%, CD11a 19%, CD117 27%, CD71 30%, CD126 100% and CD19 0%, while the expression of those antigens on peripheral blood plasma cells was present in the following percentage of patients: CD49d 100%, CD29 96%, CD54 93%, CD44 95%, CD56 56%, CD18 50%, CD11b 53%, CD11a 29%, CD117 26%, CD71 28%, CD126 100% and CD19 0%. The expression of CD54 was significantly higher than that of adhesion molecules belonging to the integrin b2 family: CD11a, CD18 and CD11b, on both bone marrow and peripheral blood cells (p < 0.01). Expression of CD18, CD11a and CD11b was differential between two cell compartments: lower on bone marrow and higher on peripheral blood cells. We found that plasma cells in the bone marrow of patients with plasma cell leukaemia showed significantly greater granularity and size than those in the peripheral blood (p = 0.0001 and p = 0.04, respectively). However, no differences in cell size or granularity were revealed between bone marrow plasma cells from patients with PCL and multiple myeloma. In conclusion, impaired expression of adhesion molecules such as CD11a/CD18 (LFA-1) or CD56 may explain hematogenic dissemination characterizing PCL. The following pattern of adhesion molecule expression according to the proportion of plasma cells expressing a given antigen in peripheral blood and bone marrow and arranged in diminishing order may be established: CD49d > CD44 > CD54 > CD29 > CD56 > CD18 > CD11b > CD11a. Immuno-phenotyping of plasma cells in PCL, as in multiple myeloma, might be useful in detecting minimal residual disease in cases with aberrant antigen expression and for selecting therapeutic agents towards specific membrane targets. PMID- 21526504 TI - Peptide vaccination induces profound changes in the immune system in patients with B-cell chronic lymphocytic leukemia. AB - Although the immune status of chronic lymphocytic leukemia (CLL) patients is mostly characterized by immunosuppression, there is an accumulation of in vivo (graft-versus-leukemia effect) and in vitro (spontaneous remissions after infections) data that indicates that CLL might be effectively targeted by T-cell based immunotherapy. Recently, we characterized receptor for hyaluronic acid mediated motility (RHAMM) as a preferential target for immunotherapy of CLL. We also completed a RHAMM-derived peptide vaccination phase I/II clinical trial in CLL. Here, we present a detailed immunological analysis of six CLL patients vaccinated with HLA-A2 restricted RHAMM-derived epitope R3 (ILSLELMKL). Beside effective induction of R3-specific cytotoxic T-cells, peptide vaccination caused profound changes in different T-cell subsets as well as cytokines. We present longitudinal analyses of Th17, CD8(+)CD103(+), CD8(+)CD137(+) and IL-17 producing CD8(+) T cells (CD8(+)IL- -17(+)) as well as important cytokines involved in regulation of immune response such as TGF-beta, IL-10, IL-2 and TNF throughout the peptide vaccination period. PMID- 21526506 TI - CD3+/CD16+CD56+ cell numbers in peripheral blood are correlated with higher tumor burden in patients with diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma is the commonest histological type of malignant lymphoma, and remains incurable in many cases. Developing more efficient immunotherapy strategies will require better understanding of the disorders of immune responses in cancer patients. NKT (natural killer-like T) cells were originally described as a unique population of T cells with the co-expression of NK cell markers. Apart from their role in protecting against microbial pathogens and controlling autoimmune diseases, NKT cells have been recently revealed as one of the key players in the immune responses against tumors. The objective of this study was to evaluate the frequency of CD3(+)/CD16(+)CD56(+) cells in the peripheral blood of 28 diffuse large B-cell lymphoma (DLBCL) patients in correlation with clinical and laboratory parameters. Median percentages of CD3(+)/CD16(+)CD56(+) were significantly lower in patients with DLBCL compared to healthy donors (7.37% vs. 9.01%, p = 0.01; 4.60% vs. 5.81%, p = 0.03), although there were no differences in absolute counts. The frequency and the absolute numbers of CD3(+)/CD16(+)CD56(+) cells were lower in advanced clinical stages than in earlier ones. The median percentage of CD3(+)/CD16(+)CD56(+) cells in patients in Ann Arbor stages 1-2 was 5.55% vs. 3.15% in stages 3-4 (p = 0.02), with median absolute counts respectively 0.26 G/L vs. 0.41 G/L (p = = 0.02). The percentage and absolute numbers of CD3(+)/CD16(+)CD56(+) cells were significantly higher in DL -BCL patients without B-symptoms compared to the patients with B symptoms, (5.51% vs. 2.46%, p = 0.04; 0.21 G/L vs. 0.44 G/L, p = 0.04). The percentage of CD3(+)/CD16(+)CD56(+) cells correlated adversely with serum lactate dehydrogenase (R= -445; p < 0.05) which might influence NKT count. These figures suggest a relationship between higher tumor burden and more aggressive disease and decreased NKT numbers. But it remains to be explained whether low NKT cell counts in the peripheral blood of patients with DLBCL are the result of their suppression by the tumor cells, or their migration to affected lymph nodes or organs. PMID- 21526507 TI - Identification of dendritic cells in the blood and synovial fluid of children with Juvenile Idiopathic Arthritis. AB - Childhood chronic arthritis of unknown etiology is known collectively as juvenile idiopathic arthritis (JIA) and consists of heterogeneous subtypes with unique clinical patterns of disease. JIA is the commonest rheumatic disease in children and may still result in significant disability, with joint deformity, growth impairment, and persistence of active arthritis into adulthood. Basic research is rather focused on rheumatoid arthritis, and this lead to small number of publications considering JIA. In this study we examine, by flow cytometry, the expression of dendritic cells (DCs) in the peripheral blood and synovial fluid of children with active JIA in a group of 220 patients. We reveal a significant decrease in the percentage of immature DCs in the blood of patients compared to control children. Surprisingly, we found higher percentages of mature circulating dendritic cells. Both populations of DCs, immature and mature, were accumulated in patients' synovial fluid. We also confirmed the presence of CD206+/CD209+ in JIA samples, which can represent a population of macrophages with dendritic cells morphology. Our results support the thesis that dendritic cells are crucial in the induction and maintenance of autoimmune response and local inflammation during juvenile idiopathic arthritis. PMID- 21526508 TI - I just turned 65. Do I still need a Pap smear for cervical cancer? PMID- 21526509 TI - The effectiveness of a community-based intervention for parents with FASD. AB - The purpose of this study was to evaluate the effectiveness of the Step by Step program in which mentors work with parents affected by Fetal Alcohol Spectrum Disorder (FASD) on a one-to-one basis. Mentors help clients identify and work towards meeting their needs and achieving their goals. Data from 24 closed client files was collected and analyzed and as predicted, the program was effective in helping clients reduce their needs and achieve their goals. The clients' reason for leaving the program as well as whether or not they had a formal FASD diagnosis had an impact on their success in the program. Data collected on additional mental health issues, experience of abuse and addictions helped to characterize the sample of clients and correlations were found between clients' experience of abuse and their past and/or present addictions issues. Limitations of this study as well as future implications were also discussed. PMID- 21526510 TI - Hot adaptation: for your gut only. PMID- 21526511 TI - Techniques and applications: how many sweets in the jar? PMID- 21526513 TI - Bacterial physiology: wrapped up in each other. PMID- 21526512 TI - Bacterial pathogenesis. Neisseria meningitidis: hit and run. PMID- 21526514 TI - Virology: viral capsids get stuffed. PMID- 21526515 TI - Horizontal gene transfer: eukaryotes under a new light. PMID- 21526516 TI - Cellular microbiology: bacterial networking. PMID- 21526517 TI - Cognitive symptoms during the menopausal transition and early postmenopause. AB - PURPOSES: To describe changes in levels of cognitive symptoms (forgetting and difficulty concentrating) during the menopausal transition (MT) stages and early postmenopause, including effects of age, MT-related factors(MT stages, estrone, follicle stimulating hormone (FSH), testosterone), symptoms (hot flush, sleep, mood), health-related factors (alcohol use, smoking, exercise, perceived health), stress-related factors (perceived stress, history of sexual abuse, cortisol, catecholamines) and social factors (partner and parenting status, education, employment). METHODS: A subset was studied of Seattle Midlife Women's Health Study participants who provided data during the late reproductive, early and late MT stages or postmenopause (n=292) including menstrual calendars for staging the MT, annual health questionnaires for social factors, morning urine samples assayed for estrone glucuronide (E1G), testosterone, FSH, cortisol and catecholamines and health diaries for rating symptoms several times each year. Multilevel modeling (R program) was used to test patterns of cognitive symptoms related to age, MT-related factors, symptoms, health-related, stress-related and social factors with as many as 6811 observations. RESULTS: As individual covariates and in the multivariate model, age, anxiety, depressed mood, night time awakening, perceived stress, perceived health, and employment were each significantly related to difficulty concentrating. Hot flushes, amount of exercise and history of sexual abuse had a significant effect as individual covariates but not in the final multivariate model. The best predictors of forgetfulness when analyzed as individual covariates and in the multivariate model were age, hot flushes, anxiety, depressed mood, perceived stress, perceived health and history of sexual abuse. Awakening during the night, although significant as an individual covariate, had no significant effect on forgetfulness in the final multivariate model. CONCLUSIONS: Menopausal transition related factors were not significantly associated with difficulty concentrating or forgetfulness. Consideration of women's ages and the context in which they experience the menopausal transition may be helpful in understanding women's experiences of cognitive symptoms. PMID- 21526519 TI - Bibliography. Therapeutics and toxicology. Current world literature. PMID- 21526518 TI - Bibliography. Nephrology. Current world literature. PMID- 21526520 TI - Bibliography. Xenotransplantation. Current world literature. PMID- 21526521 TI - Bibliography. Controversies in organ allocation. Current world literature. PMID- 21526522 TI - Training in the the Philippines. PMID- 21526523 TI - The impact of education in India. PMID- 21526525 TI - Hormone therapy: the next chapter. Is it time to rewrite the book on postmenopausal hormone use? PMID- 21526524 TI - Sexual barrier acceptability among multiethnic HIV-positive and at-risk women. AB - BACKGROUND: Sexual behavior interventions have been found to reduce sexual risk among HIV-seropositive and high-risk HIV-seronegative women. METHODS: This study examined the influence of ethnicity and HIV serostatus on sexual barrier acceptability and use at short-term and long-term follow-up among African American and Hispanic (n=457) women participating in a gender and culturally tailored sexual risk reduction intervention. We hypothesized that sexual barrier acceptability and use would differ between ethnic groups but that this difference would dissipate after intervention participation. We further postulated that HIV seropositive women would report greater acceptability and use of sexual barriers than seronegative women at baseline and that after participation in the intervention, acceptability and use would increase for both serostatus groups. RESULTS: We enrolled 317 African American and 140 Hispanic women, 273 (60%) seropositive and 184 (40%)seronegative. Ethnic differences in the frequency of male and female condom use existed at baseline but were not found at 12-month follow-up. Male condom acceptability was higher among African American women than Hispanic women at baseline and 12-month follow-up. Seropositive women reported higher levels of consistent male condom use, but both ethnic and serostatus groups reported high levels (positive, 40%; negative, 52%) of inconsistent condom use. Most women had little experience with female condoms or lubricating gels and suppositories at baseline. No differences between ethnicities were identified in lubricant use. CONCLUSIONS: Results support the use of a culturally tailored intervention among these populations to increase sexual barrier use and reduce sexual risk. PMID- 21526526 TI - Prolonged illness and grieving. When terminal illness last a long time, so does saying goodbye. PMID- 21526527 TI - What to do about gallstones. Gallstones are one of the most common digestive problems treated in women. PMID- 21526528 TI - Heart failure risk is lower in women who regularly eat modest amounts of chocolate. PMID- 21526529 TI - Ask the doctor. I recently had a right hip replacement and my doctor says I'm now ready to use a cane. Do you have any recommendations about the best way to use it? PMID- 21526530 TI - [Supporting and caring for the elderly]. PMID- 21526531 TI - [The debate on dependency is open]. PMID- 21526532 TI - [Fractures of the femur neck, more frequent and often fatal in patients with Alzheimer disease]. PMID- 21526534 TI - [A protocol in the form of small posters to assess the risks and the fragilities of elderly people in care homes]. AB - Nursing teams are obliged to have care protocols. Those which are presented in the form of small-size posters have the advantage of being pragmatic. A review of an experiment with a protocol which covers all the assessments which residents in care homes for dependent elderly people need. PMID- 21526533 TI - [Animal assisted therapy in a long-term care nursing home]. AB - Animal assisted therapy sessions have been set up at the Bellevaux nursing home in Besancon. The project has required a number of specific procedures and training courses to be put in place as well as the involvement of different departments. The sessions give real pleasure to the residents and produce interesting results. PMID- 21526535 TI - [Professor of adapted physical activities in geriatrics (interview by Anne-Marie Bonnery)]. PMID- 21526536 TI - [Campaign against mistreatment and initiative for kind treatment]. PMID- 21526537 TI - [Speaking outside.... about the inside]. PMID- 21526538 TI - [Growing old and dying in prison]. AB - French prisons are experiencing the same phenomenon observed across western societies, that of an ageing population. In addition to the structural inability of prisons to deal with inmates' loss of autonomy, it is the very sense in keeping highly vulnerable and dependent people behind bars which should be questioned. PMID- 21526539 TI - [The French general inspectorate of prisons]. AB - The French general inspectorate of prisons is an independent watchdog responsible for ensuring that inmates' fundamental rights are respected. An interview with Xavier Dupont, the secretary general, who assesses the objectives and methods of this institution. PMID- 21526540 TI - [Prison and the elderly]. PMID- 21526541 TI - [A determined team caring for an elderly detainee]. AB - The arrival of an elderly person in a remand centre reveals the extent to which the prison system is ill-equipped to deal with this type of detainee. The cooperation between the prison, nursing and social care teams however compensates for the many difficulties his case presents. PMID- 21526542 TI - [Maintaining autonomy, an issue in the care of elderly prisoners]. AB - Maintaining autonomy, an issue in the care of elderly prisoners. The ageing of the prison population means healthcare workers in prisons are having to care for inmates who are losing their autonomy. To guarantee the right to dignity, caregivers must adapt their practices and their organisation. PMID- 21526543 TI - [The needs of elderly or disabled inmates in Basse-Normandie]. AB - The Regional Healthcare Observatory has carried out a study of the health of elderly or disabled inmates in Basse-Normandie. Its objective is to identify more clearly the different situations of dependency and the difficulties expressed by professionals and inmates in order to draw up certain recommendations. PMID- 21526544 TI - [Different perspectives on old age in prison]. AB - The governor of Caen prison and two inmates describe the reality of the detention of elderly people. These inmates suffer from age-related pathologies or disabilities but still have the cognitive capability required to give their consent to take part in this interview. An opportunity for those who experience prison on a daily basis to express their views. PMID- 21526545 TI - [Bibliography]. PMID- 21526546 TI - [7/12. Organizing the therapeutic day]. PMID- 21526547 TI - [Specific treatments in oncology and the elderly]. PMID- 21526548 TI - [On 167 years of tradition--Military Medical Academy then, now and in the future]. PMID- 21526549 TI - [The Author of the Year 2010 by Vojnosanitetski Pregled]. PMID- 21526550 TI - [Voice analysis before and after vocal tiredness]. AB - BACKGROUND/AIM: A school teacher's occupation is one of the most vocal demanding professions. Vocal tiredness affects acoustic characteristics of voice, leads to the change in acoustic quality during vocal production. The aim of this study was to examine the influence of vocal tiredness on voice acoustic characteristics of school teachers. METHODS: The study included 36 school teachers (16 male and 20 female) of 27-58 years of age. Vocal tiredness was evaluated by analyzing acoustic parameters of voice, using computerized laboratory "Kay Elemetrics". The voices were recorded before the first class on the beginning of a working week and after the last class at the end of a working week. Signal, noise and tremor parameters were processed. In their analysis the methods of descriptive statistics, as well as the analytical statistics (Student's t-test for paired samples, chi2 test, Mann Whitney U-test and Pearson's correlation coefficient) were applied. RESULTS: The obtained results showed statistically significant differences in average values of parameters as a consequence of the vocal tiredness (p < 0.01), while gender, age and being smoker or not, did not have a significant effect on voice acoustic characteristics in this group of examinees (p > 0.05). CONCLUSION: The results of the study suggest a casual relationship between vocal tiredness and voice quality in vocal professionals. PMID- 21526551 TI - [Comparison of primary medicament therapy effects and primary argon laser trabeculoplasty on regulation of intraocular pressure and stability of perimetry findings in open angle glaucoma]. AB - INTRODUCTION/AIM: Argon Laser Trabeculoplasty (ALT) is a recognized method for reducing intraocular pressure (IOP) in patients with open angle glaucoma. The aim of this study was to compare the effects of primary medicament therapy and primary ALT on IOP regulation and stability of perimetry findings. METHODS: A total of 50 eyes of 35 patients were treated with primary ALT while 50 eyes of 36 patients were treated with primary medicament therapy with 0.5% timolol with 20, 0.005% latanoprost 18 and with 2% dorzolamid 12 eyes. IOP was controled at 3 months, and the visual field at 6 months during a 30-month follow-up period. RESULTS: In the first 24 months of follow-up there was no statistically significant difference in percentage of eyes with successfully regulated IOP. At 27th and 30th month, in the group primarily treated with medicaments a statistically significant higher percentage of successfully regulated IOP was observed in 98%, and 96% of the eyes, respectively, while in the group primarily treated with ALT the decline in the percentage of successfully regulated IOP was observed in 78% and 76% of the eyes, (chi2-test, p = 0.002, p = 0.140). Both therapy groups showed stability of perimetry findings without statistically significant difference in the values of mean deviation (MD) index until the end of the monitoring period. The dynamics of change in MD index value showed a statistically significant greater decline in this parameter in subjects who had been primarily treated with medications during the last six months of follow-up, (two-factor analysis of variance with a repeated measurement, factor of time x type of therapy, p = 0.030). CONCLUSION: Primary ALT equally successfully regulates IOP and restores stability of perimetry findings in patients with open angle glaucoma like the primary medicament therapy. PMID- 21526552 TI - [Mechanical ventilation in patients with most severe forms of influenza A H1N1]. AB - BACKGROUND/AIM: Pandemic of A H1N1 influenza is noted for its rapid spreading and life-threatening consequences like acute respiratory distress syndrome (ARDS) which requires mechanical ventilation (MV) and intensive therapy (IT).The aim of the study was to determine the significance of mechanical ventilation application in the presence of comorbidities on the outcome of the disease and patients with severe forms of acute influenza caused by A H1N1 virus. METHODS: Five patients with acute respiratory failure caused by A H1N1 influenza that required MV were included in the study. Course and outcome of the treatment were monitored in relation to age and sex of the patients, concomitant diseases, time of influenza beginning, a time of admittance in an intensive care unit, a time of an endotracheal intubation and MV beginning, MV duration and occurrence of secondary infections. RESULTS: Three patients were on a very prolonged MV (39, 43 and 20 days, respectively) and they all survived. Two patients with a significantly shorter duration of MV (14 and 12 days, respectively) died because of a very severe clinical course and concomitant diseases. Unexpectedly, we found a positive correlation between duration of MV and survival although two patients, who were on MV for the longest period of time (43 and 39 days, respectively), developed, as a complication, secondary bacterial pneumonia. CONCLUSION: Intensive therapy of patients with ARDS due to A H1N1 influenza virus requires MV which should be carried out according to guidelines of international expert forums. That is in accordance with our unexpected observation on negative correlation between duration of MV and fatal outcome. Intensive treatment of these patients, specially MV, can be very prolonged and, therefore, requires specialized teams of anesthesiologists, separate, isolated intensive therapy units and high level of medical staff protection, as was the case in this study, so no member of medical staff was infected. PMID- 21526553 TI - [Neurophysiological evaluation of patients with degenerative diseases of the cervical spine]. AB - BACKGROUND/AIM: Diagnostic protocol for patients with degenerative diseases of the cervical spine demands, in parallel with neuroimaging methods, functional evaluation through neurophysiological methods (somatosensitive and motor evoked potentials and electromyoneurography) aiming to evaluate possible subclinical affection of spinal medula resulting in neurological signs of long tract abnormalities. Considering diversities of clinical outcomes for these patients, complex diagnostic evaluation provides a prognosis of the disease progression. METHODS. The study included 21 patients (48.24 +/- 11.01 years of age) with clinical presentation of cervical spondylarthropathy, without neuroradiological signs of myelopathy. For each patient, in addition to conventional neurophysiological tests (somatisensory evoked potentials--SSEP, motor evoked potentials--MEP, electromyoneurography--EMG, nerve conduction studies), we calculated central motor conduction time (CMCT(F)), as well the same parameter in relation to a different position of the head (maximal anteflexion and retroflexion), so-called dynamic tests. RESULTS: Abnormalities of the peripheral motor neurone by conventional EMNeG was established in 2/3 of the patients, correponding to the findings of root condution time. Prolonged conventional CVMP(F) were found in 29% of the patients, comparing to 43% CVMP(F) abnormalities found with the dynamic tests. In addition, the SSEP findings were abnormal in 38% of the patients with degenerative diseases of the cervical spine. CONCLUSION: An extended neurophysiological protocol of testing corticospinal functions, including dynamic tests of central and periheral motor neurons are relevant for detection of subclinical forms of cervical spondylothic myelopathy, even at early stages. In addition to the conventional neurophysiological tests, we found useful to include the dynamic motor tests and root conduction time measurement in diagnostic evaluation. PMID- 21526554 TI - [Injuries of the thoracic aorta and its branches]. PMID- 21526555 TI - [Congenital intestinal lymphangiectasia]. AB - BACKGROUND: Congenital intestinal lymphangiectasia is a disease which leads to protein losing enteropathy. Tortuous, dilated lymphatic vessels in the intestinal wall and mesenterium are typical features of the disease. Clinical manifestations include malabsorption, diarrhea, steatorrhea, edema and effusions. Specific diet and medication are required for disease control. CASE REPORT: A 19-year old male patient was hospitalized due to diarrhea, abdominal swelling, weariness and fatigue. Physical examination revealed growth impairment, ascites, and lymphedema of the right hand and forearm. Laboratory assessment indicated iron deficiency anaemia, lymphopenia, malabsorption, inflammatory syndrome, and urinary infection. Enteroscopy and video capsule endoscopy demonstrated dilated lymphatic vessels in the small intestine. The diagnosis was confirmed by intestinal biopsy. The patient was put on high-protein diet containing medium-chain fatty acids, somatotropin and supportive therapy. CONCLUSION: Congenital intestinal lymphangiectasia is a rare disease, usually diagnosed in childhood. Early recognition of the disease and adequate treatment can prevent development of various complications. PMID- 21526556 TI - [Primary carcinoid of the ovary]. AB - BACKGROUND: Carcinoid tumors are distinct neuroendocrine neoplasms commonly located within the gastrointestinal tract and bronchopulmonary system. The aim of this case report was to present a patient with carcinoid tumor of the ovary as a less common form of this neoplasm. CASE REPORT: A 49 year old woman was admitted to the hospital with symptoms of diarrhea and abdominal pain and suspicion of neuroendocrine neoplasm, 4 month after bilateral salpingo-oophorectomy and total hysterectomy for ovarian tumor. Pathological diagnosis was typical for carcinoid tumor. At admission the patient had slightly eleveated levels of tumor marker CA 125 and highly elevated levels of 5- HIAA. Abdominal CT showed suspicious rest tumor in the pelvis. Relaparotomy was done and retroperitoneal fibrosis was found. Six months after the intervention the levels of 5-HIAA and CA 125 were normal, and NMR of the abdomen showed no signs of rest tumor. CONCLUSION: Carcinoid tumor of the ovary is rare form of ovarian tumors and less than 0.1% had malignant potential. Surgical therapy associated with a long-term followup was the treatment of choice. Consideration of unusual sites of carcinoid tumors facilitates appropriate diagnosis and treatment. PMID- 21526557 TI - [Aspirin resistance in patients with stable ischemic heart disease]. PMID- 21526558 TI - [Mitral valve remodeling in patients with acute myocardial infarction and ischemic mitral regurgitation]. AB - We have studied alterations of mitral valve geometry and quantitative parameters of mitral regurgitation in 130 patients with acute myocardial infarction in acute and subacute stages of the disease. Quantitative data of mitral regurgitation have been assessed using two quantitative Doppler techniques--proximal isovelocity surface area method (PISA-method) and quantitative Doppler technique (Q-DE-method). As a result of the research we have received data showing that in patients with acute myocardial infarction and ischemic mitral regurgitation mitral valve remodeling occurs with deformation of mitral structures inducing mitral regurgitation. We have observed correlation between degree of ischemic mitral regurgitation and structural valve alteration in patients with acute myocardial infarction. PMID- 21526559 TI - [Elevation of compliance and motivation to antihypertensive therapy in patients with arterial hypertension by way of educational programs and rational use of angiotensin converting enzyme perindopril. Results of the PRISMA study]. PMID- 21526560 TI - [Parameters of heart rhythm variability and QT-interval in patients with ischemic heart disease and type 2 diabetes]. AB - We studied parameters of heart rhythm variability and QT intervals in 141 patients (mean age 52.4 +/- 7.3 years) with unstable angina and acute myocardial infarction; 101 of these patients (71.6%) had type 2 diabetes. We found that in patients with diabetes parameters RRNN, LF and LF/HF were significantly lower. In patients with diabetes and risk of microangiopathy lowering of LF was maximal and correlated with elevation of glycosylated hemoglobin. In patients with diabetes and neuropathy significant reduction of power in HF range and increase of maximal corrected QT-interval value were observed. It is possible, that in patients with ischemic heart disease type 2 diabetes causes decrease of tone of vegetative nervous system mainly due to activity of parasympathetic part and this is accompanied by impaired repolarization of cardiac ventricles. PMID- 21526562 TI - [Unfavorable effect of the period of new year holidays on total and cardiovascular mortality]. AB - We studied effect of the period of new year holydays on parameters of total and cardiovascular mortality. We analyzed all registered deaths in Kemerovo from 01.01.1998 to 31.12.2001 using data of the Kemerovo registry office (ZAGS). In time interval from 21 December to January 10 of each year there were 1830 deaths (968 men and 862 women). Between January 1 and 5 compared with preceding and subsequent days total and cardiovascular mortality were 27% (p = 0.003) and 25% (p = 0.024), high respectively. We also noted dependence of the parameter studied on age and sex. Thus the period of New Year holydays is associated with increased total and cardiovascular mortality and this association can not be explained by the effect of low temperatures. PMID- 21526561 TI - [Causes of reoperations and their outcomes in patients with the Marfan's syndrome after correction of the ascending aorta aneurysm and aortic insufficiency]. AB - Aim of the study was to elucidate causes of repeat operations and their outcomes in patients with the Marfan's syndrome. Between December 1972 and January 2009 60 patients with Marfan's syndrome were operated for aneurysm of the ascending aorta and aortic insufficiency. All patients were subjected to ascending aorta and aortic valve replacement with valve containing conduit. Five of 60 patients (8.3%) were subjected to 7 repeat operations (2 patients were reoperated twice). Causes of repeat interventions were: conduit dysfunction (n=3), abdominal aortic aneurysm (n=3), mitral valve prolapse (n=1). Three patients died: 2 during surgery because of impaired conduit function, one - in 1 year after repeat operation of mitral valve replacement for mitral valve prolapse with pronounced mitral insufficiency. In all cases cause of death was progressive heart failure. As an example a case of a female patient who had been subjected to repetitive surgeries because of malfunctioning conduit is presented in this paper. Main reason for reoperations was the Marfan's syndrome itself. Progression of this disease might continue after operation, alteration of the aortic wall promote dissection in regions not subjected to prosthetics. Application of prostheses especially designed for replacement of the ascending aorta excludes such causes of reoperations and death as disruption of old sutured of two parts conduits. PMID- 21526563 TI - [Dynamics of prevalence of arterial hypertension and other risk factors of development of cardiovascular diseases in female population of Tallin (10 year prospective study)]. AB - Aim of the study was to assess dynamics of prevalence of arterial hypertension (AH) and main cardiovascular risk factors (RF) in a women population of Tallin during 10 years of follow up. In 2008-2009 we repeated measurements of arterial pressure (AP), electrocardiographic, echocardiographic, and complex laboratory examinations in 314 participants of epidemiological study undertaken in 1999 2000. Most prevalent RF was hypercholesterolemia. Rate of its detection substantially rose from 69.1 to 81.2%. Number of subjects who continuously took cholesterol lowering drugs and had target levels of lipid profile was sporadic. Prevalence of hypertriglyceridemia, obesity, and diabetes mellitus insignificantly increased. Only prevalence of smoking had tendency to reduction. AH was found in 28.7 and 44.6% of women in 1999-2000 and 2009, respectively. Obesity and hypercholesterolemia contributed significantly to development of new cases of AH. Among subjects with AH 25% of women received antihypertensive therapy and achieved target AP levels--3 times more than in 2000. Thus prevalence of AH and other main RF in female population of Tallin increased during 10 years follow-up. However control of AP in patients with AH notably improved. PMID- 21526564 TI - [Antioxidant and cardioprotective effects of N-tyrosol in myocardial ischemia with reperfusion in rats]. AB - We demonstrated in experiments on rats with left coronary artery occlusion that intravenous administration of 20 mg/kg n-tyrosol during ischemia limited manifestations of oxidative stress in myocardial tissue during early post reperfusion period: content of diene and triene conjugates lowered 16 and 20%, respectively. This was associated with higher preservation of cardiomyocytes and reduction of the infarction zone. PMID- 21526565 TI - [Comparative clinical and anatomic characteristic of patients with patent foramen ovale in cryptogenic and noncryptogenic stroke]. AB - In order to study anatomical and functional characteristics of patent foramen ovale (PFO) in patients with cryptogenic stroke and with other stroke subtypes we examined 56 stroke patients (male--35, female--21, age 46.7 +/- 16.5 years) with PFO and ischemic stroke. Diagnosis of PFO was made by transesophageal echocardiography (TEE), contrast transcranial Doppler monitoring (C-TCD), contrast transthoracic echocardiography (C-TTE). Group 1 was made up of patients with definite stroke cause (cardioembolic, lacunar, atherotrombotic) (n=40), and group 2--of patients with cryptogenic stroke (n=16). Patients in group 2 were younger than patients in group 1 (38.7 +/- 13.4 and 50.4 +/- 16.5 years, p < 0.05) and had slight neurological symptoms. These patients also more frequently had avalvular, or "window-like" anatomic types of PFO (2 [13%] and 4 [27%] patients, respectively), combination of large anatomic size (3 mm and larger) and functional level of PFO (3 degree of the right-to-left shunt by C-TCD) (p < 0.05). PMID- 21526566 TI - [Value of pleiotropic effects of angiotensin-converting enzyme inhibitors]. AB - Recently the pleiotropic effects of angiotensin-converting enzyme inhibitors which lay beyond their pure antihypertensive effects are widely discussed. Antiproliferative, antiatherosclerotic, antiproliferative and antiarrhythmic properties, as well as positive effects on hemostasis and endothelial function allows angiotensin-converting enzyme inhibitors to occupy very important position among other cardiovascular medications and to have a number of indications: arterial hypertension, congestive heart failure, myocardial infarction, left ventricular hypertrophy and patients with high risk of cardiovascular disease. PMID- 21526567 TI - [ACC/AHA warning on effectiveness of clopidogrel]. PMID- 21526568 TI - [Antianginal efficacy and tolerability of ivabradine in the therapy of patients with stable angina: results of the CONTROL study]. AB - Control of heart rate (HR) is an important target during treatment of patients with stable angina. In a number of cases it can be achieved by the use of beta adrenoblockers. But often a necessity arises to enhance pulse slowing therapy with the use of combinations of drugs exerting negative chronotropic effect. We present here results of the CONTROL study (n=1777), conducted with the aim of studying antianginal efficacy and tolerability of the If-channels blocker ivabradine used in combination with beta-adrenoblockers in patients with stable functional class II-III angina and frequency of attacks > or = 3/week and HR>70 bpm. The use of ivabradine for 12 weeks allowed to achieve greater reduction of frequency of anginal attacks (by 4 per week, 95% confidence interval 3-6) compared with the group of usual care (treatment at physicians discretion). At the end of the study in ivabradine group 43% of patients had no angina at all, HR lowering < or =60 bpm was noted in 46% of patients (in the comparison group14 and 6%, respectively, p < 0.001). Reduction of frequency of attacks of angina correlated with HR lowering, more with pulse rate measured by patients themselves (r = 0.411, p < 0.001), than with values measured at visits to physicians (r = 0.266, p < 0.001). Rate of lethal outcomes as well as rate of nonfatal cardiovascular complications (myocardial infarction, stroke, urgent revascularization) were similar in compared groups. In ivabradine group compared with usual care group there were less hospitalizations (5.0 and 8.6%, respectively, p = 0.021), calls for emergency service (13.3 and 25.4%), and sick leaves (6.6 and 13.1%, p = 0.018). Adverse reactions were noted in 130 patients (8.7%) in ivabradine group and in 29 patients (10.0%) in usual care group p = 0.580). PMID- 21526569 TI - [Reappraisal of old and introduction of novel indications to beta-adrenoblockers in the treatment of cardiovascular diseases]. PMID- 21526570 TI - [Detection of erectile dysfunction and peculiarities of its treatment in men with high cardiovascular risk]. AB - It has been demonstrated in a series of studies that erectile dysfunction (ED) appears to be one of risk factors and predictors of ischemic heart disease (IHD). According to the SSRC PM data in a cohort of 300 men with high cardiovascular risk ED was diagnosed in 61% of cases, while among 300 men with verified diagnosis of IHD was detected in 92.7% of cases. According to recommendations of the European Society of Urology changes of life style and correction of risk factors should precede therapy of ED or be components of complex therapy. It is known that some antihypertensive drugs (nonselective beta-adrenoblockers, thiazide diuretics) can negatively affect erectile function. According to data of comparative randomized clinical study average therapeutic doses of thiazide-like and thiazide diuretics in combination with ACE inhibitors do not worsen erectile function. Data on effect of lipid lowering therapy on erectile function are equivocal. Type 5 phosphodiesterase inhibitors (PDI) are first line preparations for the treatment of patients with ED. Safety of combination of type 5 PDI with main groups of antihypertensive drugs has been demonstrated in persons with risk factors of CVD and ED. The use of type 5 PDI in men depends on degree of compensation of cardiovascular system. In unstable cardiovascular events preparations of this group can be also carefully used. Simultaneous administration of nitrates is a contraindication for type 5 PDI. PMID- 21526572 TI - Retraction. The effect of the mus309 mutation, defective in DNA double-strand break repair, on crossing over in Drosophila melanogaster suggests a mechanism for interference. PMID- 21526571 TI - [Modern aspects of war against smoking: are there any opportunities left?]. AB - The war against smoking requires taking immediate measures because of the growing spread and severe consequences. All minuses and pluses of the Mass Media are underlined in this article. Anti-smoking technical means should to meet the following requirements: (1) each inhalation of cigarette smoke should be carried to the level of conscience; (2) each smoking act should be accompanied by unpleasant perceptions; (3) A conscientious registration number of cigarettes smoked is necessary. These problems have been solved by now. artery stiffness, defined by pulse wave propagation velocity increases after the act of smoking thus imitating aging. The smoker should be aware of this fact. PMID- 21526573 TI - Retraction. Effect of temperature shock treatment on crossing over in the mus309 mutant, deficient in DNA double-strand break repair, of Drosophila melanogaster suggests a two-phase control of crossover formation and interference. PMID- 21526575 TI - [Pathways of research in autism]. PMID- 21526574 TI - Comparison of functional fitness in elderlies with reference values by Rikli and Jones and after one-year of health intervention programs. AB - AIM: The purpose of this study was to characterize levels of physical fitness and compare our results with normative standards by Rikli and Jones to determine functional status of institutionalized elders. The effects of different intervention programs on physical fitness were also described. METHODS: A total of 148 institutionalized elders completed one-year health-promotion intervention programs: aerobic training (AT), strength training (ST), health education program and control. Habitual physical activity (MTI Actigraph), physical fitness (Senior Fitness Test), health related quality of life (MOS SF-36), and body composition (BMI) were assessed. RESULTS: Institutionalized elders performance has significantly deteriorated on functional fitness. Nevertheless, higher results than reference values were obtained on both body strength tests and aerobic endurance, specifically in men. Data of one-year intervention demonstrated that ST induced significant changes in body strength and flexibility test and the AT in lower body strength, aerobic endurance and agility/dynamic balance. The final multilevel model shows that AT Program compared with CG, education level, time of institutionalization and HRQoL were predictors for physical fitness score. CONCLUSION: These results suggest that participation in regular exercise programs (both aerobic and strength training) elicits a number of favorable responses that contribute to healthy aging and could play a role in prevention or reducing functional decline in elders. PMID- 21526576 TI - ICD-10 timetable: readiness assessments should be complete. PMID- 21526577 TI - Bridging the gap between ED and PCP. PMID- 21526578 TI - Five years without VAP? Two years without BSI? PMID- 21526579 TI - Collaborative uses data to bring uniformity. PMID- 21526580 TI - Addressing the health care needs of diverse populations. PMID- 21526581 TI - Time for healing: somatization among chronically mentally ill immigrants. AB - In a cross-sectional study, we examined demographic factors and acculturation level with somatization among chronically mentally ill groups of immigrants (Russians and Latinos). Ninety Russian and 90 Latino patients attending a university affiliated Day Treatment Program were assessed on somatoform symptoms and acculturation by the 12-item somatization subscale of the SCL-90-R and by a 12- items short acculturation scale, respectively. Higher somatization was significantly associated to women, Russian ethnicity, high school or above level of education, shorter length of residence in the U.S., and lower acculturation. Interaction by ethnic group showed that somatization was influenced by the length of residence in the U.S. among Russians but not among Hispanics. In a multivariate model, higher somatization corresponds to female, Russian, and shorter residence in the U.S. (only among Russians). Length of stay in the host country rather than the level of acculturation influence the frequency of somatic complaints, modified by ethnicity. PMID- 21526583 TI - Conflict, cultural marginalization, and personal costs of filial caregiving. AB - This study investigated the role of cultural marginalization as factor mediating the relationship between family conflict and the perceived personal costs associated with caring for an elderly parent. Participants included forty-seven Mexican American filial caregivers residing in Colorado. Using data from structured interviews, the results of regression analysis indicated that family conflict is a significant predictor of the personal costs of caregiving. Adding the variable of cultural marginalization to the regression equation increased the amount of explained variance; supporting an hypothesis that marginalization mediates the influence of family conflict on the perceived costs of caregiving. Practice implications for mental health professionals working with Mexican American caregivers are presented, as are study limitations and suggestions for future research. PMID- 21526582 TI - Willingness to participate in clinical trials among African Americans and whites previously exposed to clinical research. AB - The objective of this study was to identify racial differences in willingness to participate in a population with previous exposure to clinical research. A survey instrument was administered to community-dwelling whites and African Americans who were voluntarily receiving a lay research and health education newsletter from a local Boston geriatric clinical research institution. The survey instrument assessed willingness to participate in 3 hypothetical clinical trials (diet trial for obesity, medication trial for hypertension [HTN], chemotherapy trial for cancer). Surveys were received from 473 whites and 279 African Americans (53% response rate) with mean age 74 (SD +/- 9). In multivariate models, race was not significantly related to willingness to participate in the multivariate models for any of the 3 trials. Previous trial participation was related to a higher odds of willingness to participate in the diet trial only (OR 1.8, 95% CI 1.2, 2.6). Lower levels of trust in one's primary care physician were associated with a lower odds of willingness to participate in clinical trials for the diet and HTN trials (OR 0.5, 95% CI 0.3, 0.8 and OR 0.6, 95% CI 0.3, 0.9, respectively). These findings suggest that, within populations previously exposed to clinical research, African Americans are no less willing to participate in clinical trials compared to whites. PMID- 21526584 TI - Male infertility: an exploratory comparison of African American and white men. AB - PURPOSE: This study's purpose was to provide information regarding differences in AA and White men's attitude about not fathering a child, receipt and type of infertility services, and diagnosed infertility problem. METHODS: A descriptive study using Cycle 6 National Survey of Family Growth male interview data with Chi Square analysis was conducted. FINDINGS: There was a statistically significant difference in attitude about not fathering a child, but no other statistically significant differences. CONCLUSION: AA men have stronger attitudes about not fathering a child. Study limitations make other findings insufficient to conclude that infertility is the same for AA and White men. PMID- 21526585 TI - Use of Gilliam Asperger's disorder scale in differentiating high and low functioning autism and ADHD. AB - Little is known about the validity of Gilliam Asperger's Disorder Scale (GADS), although it is widely used. This study of 199 children with high functioning autism or Asperger's disorder, 195 with low functioning autism, and 83 with attention deficit hyperactivity disorder (ADHD) showed high classification accuracy (autism vs. ADHD) for clinicians' GADS Quotients (92%), and somewhat lower accuracy (77%) for parents' Quotients. Both children with high and low functioning autism had clinicians' Quotients (M=99 and 101, respectively) similar to the Asperger's Disorder mean of 100 for the GADS normative sample. Children with high functioning autism scored significantly higher on the cognitive patterns subscale than children with low functioning autism, and the latter had higher scores on the remaining subscales: social interaction, restricted patterns of behavior, and pragmatic skills. Using the clinicians' Quotient and Cognitive Patterns score, 70% of children were correctly identified as having high or low functioning autism or ADHD. PMID- 21526586 TI - Functional cerebral distance and the effect of emotional music on spatial rotation scores in undergraduate women and men. AB - The influence of listening to music on subsequent spatial rotation scores has a controversial history. The effect is unreliable, seeming to depend on several as yet unexplored factors. Using a large sample (167 women, 160 men; M age = 18.9 yr.), two related variables were investigated: participants' sex and the emotion conveyed by the music. Participants listened to 90 sec. of music that portrayed emotions of approach (happiness), or withdrawal (anger), or heard no music at all. They then performed a two-dimensional spatial rotation task. No significant difference was found in spatial rotation scores between groups exposed to music and those who were not. However, a significant interaction was found based on the sex of the participants and the emotion portrayed in the music they heard. Women's scores increased (relative to a no-music condition) only after hearing withdrawal-based music, while men's scores increased only after listening to the approach-based music. These changes were explained using the theory of functional cerebral distance. PMID- 21526587 TI - Work-family conflict and job burnout among correctional staff: a comment on Lambert and Hogan (2010)1. AB - Lambert and Hogan (2010) examined the relations between work-family conflict, role stress, and other noted predictors, on reported emotional exhaustion among a sample of 272 correctional staff at a maximum security prison. Using an ordinary least squares (OLS) regression model, the authors found work-on-family conflict, perceived dangerousness of the job, and role strain to have positive relations with emotional exhaustion. However, contrary to expectation they found that custody officers reported lower exhaustion than did their noncustody staff counterparts. Suggestions are provided for follow-up efforts designed to extend this line of research and correct methodological issues. PMID- 21526588 TI - Relationship between cynicism and job satisfaction: exploration of mechanisms. AB - Personality traits related to evaluation of other people and the world are important to study in relation to job satisfaction, which itself is an evaluation of various facets of a job, including the social dimensions. Accordingly, the relationship between cynicism and job satisfaction was studied. Cynicism was expected to be negatively related to job satisfaction, employees' perceptions of job enrichment, quality of leader-member exchange, and support from coworkers. Survey data from 105 employees in a diverse set of organizations (M age = 48 yr.; 50% women; M work experience = 28 yr.; 73% had >16 yr. education) were subjected to hierarchical regression. Individuals high in Cynicism were likely to have lower job satisfaction, job enrichment, quality of leader-member exchange, and perceptions of co-worker support. PMID- 21526589 TI - National anthems and suicide rates. AB - In a sample of 18 European nations, suicide rates were positively associated with the proportion of low notes in the national anthems and, albeit less strongly, with students' ratings of how gloomy and how sad the anthems sounded, supporting a hypothesis proposed by Rihmer. PMID- 21526590 TI - Student teachers' observations of unfavorable teacher behaviors exhibited in classrooms. AB - The aim of this study was to identify male and female teachers' misbehaviors in classrooms and determine the variance of those misbehaviors in schools in different socioeconomic areas. The study was conducted in 24 primary schools in Erzurum province with a total of 210 classroom teachers. Data were obtained through observations made by 210 student teachers. The data collected were analysed through descriptive analyses by the researcher. 661 misbehaviors were observed and classified into six different categories, namely, physical aggression, passive (verbal) aggression, constant nervousness, trouble in managing the classroom, class failures pertaining to instruction, and other. PMID- 21526591 TI - Subjective well-being and religiosity in Egyptian college students. AB - A sample of 224 Egyptian college students (101 men, 123 women) was recruited. Their ages ranged from 17 to 29 years (M = 18.9, SD = 1.5). They responded to the Arabic versions of the Oxford Happiness Inventory, the Love of Life Scale, and the Satisfaction with Life Scale, as well as five separate single-item self rating scales assessing physical health, mental health, happiness, satisfaction, and religiosity. All correlations between the measures and rating scales of subjective well-being and religiosity were statistically significant and positive, the largest between satisfaction and religiosity. Only one factor was retained in principal components factor analysis of the correlation matrix and labeled "Well-being and religiosity." It was concluded that religious persons in the present sample reported higher subjective well-being. PMID- 21526592 TI - Employee-oriented leadership and quality of working life: mediating roles of idiosyncratic deals. AB - Leader consideration has long been suggested to be conducive to quality of working life experienced by employees. The present study links this classic leadership dimension with more recent research on idiosyncratic deals, referring to personalized conditions workers negotiate in their employment relationships. A two-wave survey study (N = 159/142) among German hospital physicians suggests that authorizing idiosyncratic deals is a manifestation of employee-oriented leader behavior. Consideration had consistent positive effects on idiosyncratic deals regarding both professional development and working time flexibility. These two types had differential effects on two indicators of the quality of working life. Development related positively to work engagement, flexibility related negatively to work-family conflict. Cross-lagged correlations supported the proposed direction of influence between consideration and idiosyncratic deals in a subsample of repeating responders (n=91). The relation between development and engagement appeared to be reciprocal. Longitudinal results for the association between flexibility and work-family conflict were inconclusive. PMID- 21526593 TI - The role of peer groups in male and female adolescents' task values and physical activity. AB - The purpose of this longitudinal study was to examine the role of peer groups and sex in adolescents' task values and physical activity. The participants were 330 Finnish Grade 6 students (173 girls, 157 boys), who responded to questionnaires that assessed physical education task values during the spring semester (Time 1). Students' physical activity was assessed one year later (Time 2). The results indicated that adolescent peer groups were moderately homogeneous in terms of task values toward physical education and physical activity. Girls' peer groups were more homogeneous than those of boys in regards to utility and attainment values. Furthermore, the results for both girls and boys showed that particularly intrinsic task value typical for the peer group predicted group members' physical activity. The findings highlight the important role of peer group membership as a determinant of future physical activity. PMID- 21526594 TI - Love of life in Kuwaiti and American college students. AB - In samples of 198 Kuwaiti and 158 American college students, the Love of Life Scale appeared to have good reliability. The American students obtained slightly higher scores than the Kuwaiti students. PMID- 21526595 TI - Relationships between self-regulation skills and physical activity and fruit and vegetable consumption in obese adults: mediation of mood and self-efficacy. AB - In cognitive-behavioral treatments for obesity, self-regulation is thought to be a strong predictor of behavioral change, but it is rarely directly measured in intervention research. Thus, how self-regulation interacts with other psychological variables regarding treatment effects is largely unknown. In this preliminary field study, self-regulatory skills were directly measured and were found to be significantly associated with both volume of exercise and fruit and vegetable consumption in severely obese adults (N=116) enrolled in a behavioral weight management program. Significant partial and complete mediation of the relationship between self-regulation for physical activity and physical activity, and self-regulation for appropriate eating and fruit and vegetable intake, respectively, were found by reported negative mood. Self-efficacy was not found to be a significant mediator of these relationships. The bivariate relationship between baseline scores of self-regulation for physical activity and self regulation for appropriate eating was significant (r = .46), which supported the premise that self-regulation is a trait-like personal characteristic. Volume of exercise and fruit and vegetable consumption significantly predicted weight loss over 6 months (R2 = .35). Results were consistent with the few laboratory-based findings available and, after replication, may extend theory related to obesity treatment. PMID- 21526596 TI - Florida creativity index scores, conservatism, and openness in 268 U.S. regions. AB - This study assessed whether Florida's Creativity Index (2002) scores for 268 U.S. regions were related to levels of conservatism and openness in the states in which the regions were situated. State conservatism was measured as the percentage voting for Bush in 2000. State openness z scores were taken from a survey of 619,397 residents (Rentfrow, Gosling, & Potter, 2008). Creativity scores correlated negatively with conservatism (r = -.22) and positively with openness (r = .23). Regression showed that the two predictors accounted jointly (7%) and separately for significant variance in the Creativity Index. The findings contribute evidence for the construct validity of Florida's composite Creativity Index and some, albeit moderate to weak, support of the Rentfrow, et al. conclusion that state-aggregated openness reflects the unconventionality, tolerance, and creativity of a state. PMID- 21526597 TI - Using powerpoint to demonstrate human classical salivary conditioning in a classroom situation. AB - Classical conditioning is one of the most fundamental types of learning, yet demonstrating its principles in a classroom setting can be challenging. This study introduces using PowerPoint as a new, practical technique that can be used in a classroom setting to demonstrate classical conditioning. The PowerPoint file is flexible and easy to adapt for demonstrating various aspects of classical conditioning (including higher order conditioning) in a concrete manner. Moreover, this study was designed to measure salivation in a more objective and valid way which could be used by student researchers interested in measuring salivation as a conditioned response. PMID- 21526598 TI - Deliberate faking on personality and emotional intelligence measures. AB - This study examined the extent the Big Five personality traits and emotional intelligence can be faked. Using a student sample, the equivalence of measurement and theoretical structure of models in a faking and honest condition was tested. Comparisons of the models for the honest and faking groups showed the data fit better in the faking condition. These results suggest that faking does change the rank orders of high scoring participants. The personality dimensions most affected by faking were emotional stability and conscientiousness within the Big Five and the general mood and stress management dimensions of Bar-On's Emotional Quotient Inventory-Short Form (1997) measure of emotional intelligence. PMID- 21526599 TI - Suicide among foreign residents of Japan. AB - The suicide rate of Koreans living in Japan is twice as high as that of Koreans in South Korea. Reasons for this high suicide rate are discussed, including effects of economic crises and discrimination. PMID- 21526600 TI - Rape stereotypes and labeling: awareness of victimization and trauma. AB - For years, studies in the U.S. college population have described the phenomena of date and acquaintance rape. These phenomena have perpetuated myths regarding rape leading to the faulty labeling of the experience by the survivors themselves. Compared with the U.S., in Europe there are very few studies concerning this issue. This preliminary study in Italy comprised surveys of 210 participants who were asked to express their opinions on 2 scenarios of sexual assault (a forced rape and an acquaintance rape). Only 48% of the participants thought that acquaintance rape should be tried in a criminal court. PMID- 21526601 TI - Relative and absolute stability in perceived parenting behaviour: a longitudinal study with children and adolescents. AB - Patterns of relative and absolute stability in parental behaviour with children and adolescents are reported. The sample comprised 523 youth (58.7% girls). Data were collected at three time periods: T1 (M age = 11.1 yr.), T2 (M age = 12.2 yr.), and T3 (M age = 13.2 yr.), each separated by one year. According to children's reports, relative consistency was moderate in both mothers and fathers, particularly as regards communication and strict control. In contrast, as children got older, parental rearing practices related to strict control and hostility decreased. There was a similarity between fathers and mothers in terms of relative and absolute stability. Relative stability was affected by the child's sex, the parenting variable, and the time period; however, the patterns of absolute stability reveal no differences by sex. PMID- 21526602 TI - The effects of wearing a costume on charitable donations. AB - Although research has shown a general trend that people dressed in neat or professional clothes elicit more helping behavior from other people than when dressed in casual or sloppy clothes, no research has examined the effects of wearing a costume on helping behavior. In this experiment, confederates dressed either in a Santa suit or in street clothes as they volunteered for the Salvation Army as bell-ringers in front of retail stores. The hypothesis that donations would be greater while wearing the Santa suit was not supported by the data; the Santa suit and the street clothes elicited equal amounts of donations. PMID- 21526603 TI - Turkish children's Bender-Gestalt test performance: differences in public and private school children. AB - The present study was undertaken to provide data on the Bender-Gestalt test for children aged 5 to 11 in Turkey. Although it is well documented that sociocultural factors are important in cognitive evaluations, the effects of type of school and differing educational opportunities provided by these schools on the Bender-Gestalt test have not been previously investigated. The aim of the present study was to investigate the effect of age, sex, and school type on Bender-Gestalt performance. The test was individually administered to 484 children between the ages of 5 and 11 years. The children were enrolled in either public or private schools. Koppitz's Developmental Scoring System was utilized. The results indicated that older children performed with fewer errors. Girls performed with fewer errors than boys. Finally, as expected, private school children outperformed their public school peers. The results are discussed with respect to the importance of taking into account various educational factors in utilizing commonly used tests. PMID- 21526604 TI - A bibliography of articles of interest to teachers of psychology appearing in psychological reports 1955-2010. AB - Abibliography is presented of articles related to various aspects of the teaching of psychology that have appeared in Psychological Reports from 1955-2010. The 605 articles are classified into 21 sections including those devoted to history, psychology of the scientist, teaching tips, textbook evaluation, and evaluation of students and professors. PMID- 21526605 TI - The holistic theory of Andras Angyal: measuring the system principle. AB - Scales were devised to measure Andras Angyal's concepts of the trends toward autonomy and homonomy and the patterns of vicarious living and noncommitment. In a sample of 82 undergraduates (62 women, 20 men), scores for the trends were negatively associated with psychoticism scores (-.42 and -.39, respectively), while scores for the patterns were positively associated with neuroticism scores (.42 and .49, respectively). PMID- 21526606 TI - Measuring dispositional humility: a first approximation. AB - Humility is a psychological construct that has not received much empirical attention until recently. This new emphasis on positive psychology and humility has been both conceptual and empirical. The present study had two objectives: to review the literature briefly to verify the importance of humility and its positive perception by others, and to begin to develop a preliminary measure of humility. Results indicated that humility is held in high regard by others. Two factors emerged from exploratory factor analysis that appear to converge on measuring humility, with acceptable convergent and divergent validity and internal consistency reliability. These results are discussed in terms of the expected relationships among humility and other constructs (e.g., social desirability, narcissism, self-esteem). PMID- 21526607 TI - Reliability and validity of the kiddie mach scale in Chinese children. AB - The present study examined the psychometric properties of a translated Chinese version of the Kiddie Mach Scale in a sample of Chinese students (N=787) ages 9 to 13 years (416 boys, 371 girls; M age= 11.3 yr., SD = 1.3). Results of confirmatory factor analysis showed a three-factor structure to be the most adequate model: Distrust, Lack of faith in human nature, and Dishonesty. These results are similar to the English version, but not the Greek version. The Chinese version exhibited weak internal consistency, but acceptable 4-week test retest reliability. The Chinese version of the Kiddie Mach Scale was significantly associated with the Basic Empathy Scale. There was a sex effect on Kiddie Mach Scale scores with boys scoring higher on the Total scale and the Distrust subscale. Some items did not seem to function well in Chinese culture. More research will be needed to find items that represent, especially, distrust in Chinese settings. PMID- 21526608 TI - Role of self-esteem in the relationship between stress and ingratiation. AB - The relations among self-esteem, stress, and ingratiatory behaviors in the workplace were examined. Competing models for moderating and mediating effects of self-esteem on the relationship between stress and ingratiation were presented. Data from a sample of 136 employees at a state lottery organization were used to test the competing models. Support was found for the full mediation model, wherein self-esteem completely mediated the relationship between stress and ingratiation. PMID- 21526609 TI - Facilitated attentional disengagement from negative information in relation to self-reported depressive symptoms of Dutch female undergraduate students. AB - Prior research has shown that depressive symptoms are associated with an enhanced attention toward negative stimuli and difficulty of disengaging attention from negative stimuli. The current study was an extension of a 2005 study by Koster and colleagues. A different stimulus presentation time and word set were used. The whole range of depressive symptoms was included in this sample instead of creating dichotomized groups. The Exogenous Cueing Task with negative, positive, and neutral cues was administered to 85 female undergraduate university students. Participants completed the Beck's Depression Inventory-II-NL questionnaire to measure self-reported depression. Contrary to previous findings, depressive symptoms were related to a facilitated rather than impaired attentional disengagement from negative stimuli. An explanation for the discrepancy with findings from Koster, et al. may be the different stimulus presentation time (1000 msec. instead of 500 or 1500 msec.). PMID- 21526610 TI - Psychological profile of Polish skydivers. AB - To identify personality factors, personal values, time perspective, and attitude toward death of 53 Polish skydivers (M age = 28.4 yr., SD = 9.8) and 59 low-risk sport athletes (controls, M age = 27.3 yr., SD = 5.3), several scales were used. These were the Zuckerman-Kuhlman Personality Questionnaire, Schwartz's Value Survey, the Present and Future Time Perspective Questionnaire, and Death Attitude Questionnaire. It was found that skydivers scored higher on Impulsive Sensation Seeking, Hedonism, Stimulation, and Self-direction values, concentration on the present, preferring a fast death, and belief about controlling death in comparison to the control group. Skydivers also scored lower on Tradition, Universalism, and Benevolence values in comparison to the control group. PMID- 21526611 TI - An exploratory study to assess the impact of work demands and the anticipation of work on awakening saliva cortisol. AB - The goal was to investigate whether cortisol on awakening is higher on Monday relative to Sunday morning, and to assess whether responses vary with job demands and the anticipation of work. 77 white collar workers gave a sample of saliva on awakening Sunday and Monday mornings, and then rated their anticipation for work. Data showed that salivary cortisol concentration was greater on Monday compared to Sunday morning. There were no main effects of job demands or anticipation of work on cortisol secretion. There was a significant interaction between job demands and anticipation of work on Monday, relative to Sunday morning. Cortisol secretion was higher in those reporting high job demands together with a greater anticipation of work. It was concluded that increased awakening saliva cortisol secretion is not necessarily a result of working in a highly demanding environment. Anticipating the impending working day appears to be an important influence on adrenal-cortical activity. PMID- 21526612 TI - Opportunistic propensity hinders commitment to acts in conditions of forced compliance and compliance without pressure. AB - The psychosocial literature contains empirical evidence of the effects of personality variables on commitment to acts. The association of economic opportunism was explored with respect to postexperimental attitude change, intentions, and intrinsic motivation of individuals (N=132) toward acts with either forced compliance or compliance without pressure. In conditions of commitment and compliance without pressure, both intention and intrinsic motivation decreased as economic opportunism increased, while in conditions of commitment and forced compliance, intention increased as economic opportunism increased. Attitude change and economic opportunism did not appear to be associated in any experimental condition. These findings suggest that tendency to noncooperativeness predisposes to reduced concern for consistency and compliance with performed acts. PMID- 21526613 TI - Neurocognitive variability in high-functioning individuals: implications for the practice of clinical neuropsychology. AB - Knowledge of neurocognitive performance patterns of normal, healthy individuals is necessary, as clinicians may not always take into account normal intra individual variability, demonstrated here in a sample of 20 healthy individuals with particularly high educational achievement (i.e., holding doctorate degrees). The data indicate that neurocognitive abilities are not equally distributed within a given individual. Some participants in the sample achieved some test scores at the intellectually disabled to borderline range but also some scores in the high average to superior range. The practice of deductive reasoning in clinical neuropsychology may be prone to false positive conclusions about neurocognitive functioning where base rates of neurocognitive impairments are low and pre-existing educational achievements are high. PMID- 21526614 TI - Personality and mental health: an investigation of South African police trainees. AB - The relationship between personality and mental health was investigated in one cohort of police trainees at a South African police academy (1145 police recruits; 648 men, 497 women). Male trainees reported less somatisation, depression, anxiety, and phobic anxiety symptoms and lower harm avoidance as well as higher persistence than female trainees. A cluster analysis based on the personality scores was used to identify three clusters with personality profiles characterized as Vulnerable, Healthy, and Intermediate profiles. Sociodemographic variables and temperament and character domain scores contributed separately and differentially to the explanation of variance in mental health symptom scores. Selection tools should be developed to identify vulnerable individuals in terms of personality characteristics during selection and prior to training, to prevent later problems with stress reactions. Additional training modules focusing on coping skills could possibly reduce vulnerability to stress in some trainees. PMID- 21526615 TI - Factorial and cross-cultural validity of a Farsi version of the Anger Rumination Scale. AB - This study aimed to examine factorial and cross-cultural validity of a Farsi version of the Anger Rumination Scale. 933 undergraduate students (388 men, 545 women) from the University of Tehran participated. The Farsi version of the Anger Rumination Scale, the Tehran Multidimensional Anger Scale, and the Mental Health Inventory were completed by all participants. Results supported the four-factor structure, convergent and discriminant validity, internal consistency, and test retest reliability of the Farsi version of the Anger Rumination Scale. The factors found in the Farsi version of the Anger Rumination Scale are similar to the factors found in previous studies and were accordingly labeled as Angry Afterthoughts, Thoughts of Revenge, Angry Memories, and Understanding Causes. The results also provided evidence for applicability of the Farsi version of the Anger Rumination Scale and its cross-cultural validity. PMID- 21526616 TI - Moderation of participant characteristics in the relationships of changes in self regulation for exercise with self-regulation for controlled eating, and self efficacy for exercise with self-efficacy for controlled eating. AB - Research on the relationships of exercise with psychosocial predictors of controlled eating and weight loss may now be capable of informing the development of weight-management treatments. Thus, analysis of moderators of such relationships by personal characteristics is important. Moderation of the expected significant relationships of changes in self-regulation for exercise with self-regulation for controlled eating, and self-efficacy for exercise with self-efficacy for controlled eating was assessed by sex, age, and ethnicity. No significant moderation of the relationships was identified; however, it was suggested that extensions of this research also assess contextual aspects, administration method, and other demographic variables as possible moderators. With continued research, practical treatments based on relationships between exercise- and eating-related variables ultimately may prove to be efficacious, with positive effects that may generalize across participant types and settings. PMID- 21526618 TI - The medical professionals: a microcosm. PMID- 21526617 TI - Guideline for the management of chronic obstructive pulmonary disease--2011 update. AB - OBJECTIVE: To revise the South African Guideline for the Management of Chronic Obstructive Pulmonary Disease (COPD) based on emerging research that has informed updated recommendations. KEY POINTS: (1) Smoking is the major cause of COPD, but exposure to biomass fuels and tuberculosis are important additional factors. (2) Spirometry is essential for the diagnosis and staging of COPD. (3) COPD is either undiagnosed or diagnosed too late, so limiting the benefit of therapeutic interventions; performing spirometry in at-risk individuals will help to establish an early diagnosis. (4) Oral corticosteroids are no longer recommended for maintenance treatment of COPD. (5) A therapeutic trial of oral corticosteroids to distinguish corticosteroid responders from non-responders is no longer recommended. (6) Primary and secondary prevention are the most cost effective strategies in COPD. Smoking cessation as well as avoidance of other forms of pollution can prevent disease in susceptible individuals and ameliorate progression. Bronchodilators are the mainstay of pharmacotherapy, relieving dyspnoea and improving quality of life. (7) Inhaled corticosteroids are recommended in patients with frequent exacerbations and have a synergistic effect with bronchodilators in improving lung function, quality of life and exacerbation frequency. (8) Acute exacerbations of COPD significantly affect morbidity, health care units and mortality. (9) Antibiotics are only indicated for purulent exacerbations of chronic bronchitis. (10) COPD patients should be encouraged to engage in an active lifestyle and participate in rehabilitation programmes. OPTIONS: Treatment recommendations are based on the following: annual updates of the Global Obstructive Lung Disease (GOLD), initiative, that provide an evidence based comprehensive review of management; independent evaluation of the level of evidence in support of some of the new treatment trends; and consideration of factors that influence COPD management in South Africa, including lung co morbidity and drug availability and cost. OUTCOME: Holistic management utilising pharmacological and nonpharmacological options are put in perspective. EVIDENCE: Working groups of clinicians and clinical researchers following detailed literature review, particularly of studies performed in South Africa, and the GOLD guidelines. BENEFITS, HARMS AND COSTS. The guideline pays particular attention to cost-effectiveness in South Africa, and promotes the initial use of less costly options. It promotes smoking cessation and selection of treatment based on objective evidence of benefit. It also rejects a nihilistic or punitive approach, even in those who are unable to break the smoking addiction. RECOMMENDATIONS: These include primary and secondary prevention; early diagnosis, staging of severity, use of bronchodilators and other forms of treatment, rehabilitation, and treatment of complications. Advice is provided on the management of acute exacerbations and the approach to air travel, prescribing long-term oxygen and lung surgery including lung volume reduction surgery. VALIDATION: The COPD Working Group comprised experienced pulmonologists representing all university departments in South Africa and some from private practice, and general practitioners. Most contributed to the development of the previous version of the South African guideline. GUIDELINE SPONSOR: The meeting of the Working Group of the South African Thoracic Society was sponsored by an unrestricted educational grant from Boehringer Ingelheim and Glaxo-Smith-Kline. PMID- 21526619 TI - Aetiological profile of nasal trauma in Ilorin North-Central Nigeria. AB - BACKGROUND: The nose being the most prominent part of the face is easily traumatized in facial injuries and these has been found to be common among the Caucasians compared to the Africans and Asians. The aim is to highlight the Aetiological profile of nasal trauma in Ilorin north-central Nigeria. METHOD: A prospective study was carried out at the University of Ilorin Teaching Hospital Ilorin, Ilorin, north central Nigeria over a period of one and half years of all trauma cases seen at the A/E department of the hospital and those with nasal trauma were further studied. The data retrieved include demographic data, clinical presentation, and timing of presentation, examination findings, intervention offered and the outcome. Data were entered into SPSS 11.0 and analyzed descriptively. RESULTS: A total of one hundred and six (106) patients with nasal trauma were seen during the study period with a prevalence rate of 7%. The age range 6 months to 65 years with the majority of the patients in the age range 21-34 years (35.8%). The Male to female ratio was 1.7:1.0 and most patients were students (28.3%), followed by the traders (22.6%) the least were children (8.5%).Road traffic injury (RTI) constituted the highest cause of the nasal trauma (57.5%),assaults (17%), falls from heights (8.5%) and others were 17%.Majority of the patients presented within 1-6 hours of occurrence of the injury (61.3%) and only 24.5% presented less than an hour of the incidence. The common forms of presentation were epistaxis (40.6%), nasal lacerations and epistaxis (25.5%) and nasal fractures in only 10.4%. Involvement of both the passengers and the pedestrians was (57.5%) and most of them, 44.3% had surgical intervention and 40.6% had conservative treatment with a mortality rate of 0.9%. CONCLUSIONS: The pievalence of nasal trauma.is 7% with RTI being the commonest cause in nearly two thirds of cases and cases of assaults only accounted for 17%.The commonest forms of presentation were epistaxis,nasal lacerations and nasal fractures in that order and most of them were surgically treated. Measures should be adopted to reduce incidence of RTI, with regulations enforced to protect pedestrians most of whom were the victims of these injuries. PMID- 21526620 TI - Antiretroviral drug resistance--implications for HIV/AIDS reduction in sub Saharan Africa and other developing countries. AB - BACKGROUND: The introduction of the highly active antiretroviral therapy in the mid-1990s has significantly reduced morbidities and prolonged the lifespan of people living with HIV. However, the emergence of resistance to the antiretroviral drugs is becoming a major cause of treatment failure. While the problem of drug resistance is being tackled in developed countries, not much seem to be done in this regard in developing countries of Africa, Asia and Latin America. This review looked at the regional distribution of HIV groups and subtypes and how this has affected the pattern of antiretroviral resistance. METHODS: The review was sourced from papers presented at international conferences on HIV/AIDS and rational drug use, relevant journals and Medline search using the keywords--Antiretroviral drugs, drug resistance, HIV subtypes and resistance testing. RESULTS: The types, groups, subtypes, sub-subtypes and recombinant forms of HIV-1 have been identified according to their geographical distributions. The evolution of HIV viral mutations, process (es) involved in development of primary and secondary antiretroviral drug resistance, including the role of HIV genetic polymorphisms, and transmitted resistance have been discussed. CONCLUSION: The pitfalls in the current resistance testing based on HIV-1 subtype B have been highlighted. The design of resistance testing algorithm based on HIV-1 subtype non-B has been suggested for the developing world. PMID- 21526621 TI - Challenges of HIV treatment in resource-poor countries: a review. AB - BACKGROUND: The human immunodeficiency virus/acquired immunodeficiency syndrome pandemic have posed a significant public health challenge to the global community. Massive therapeutic interventions with antiretroviral drugs are being undertaken, yet problems and challenges exist. This review examines these problems and challenges as they affect the treatment of HIV infection in resource poor countries such as Nigeria. METHODS: The information was sourced from relevant literature using human immunodeficiency virus/acquired immunodeficiency syndrome journals, textbooks and Websites on human immunodeficiency virus/acquired immunodeficiency syndrome, highly active antiretroviral therapy, resource-poor countries as key words. RESULTS: Several studies have shown that the advent of highly active antiretroviral therapy in 1996 has significantly reduced morbidity and mortality among people living with HIV/AIDS (PLWHA). But in resource-poor countries, initiation and maintenance of highly active antiretroviral therapy has been associated with many challenges and problems such as: poor infrastructural base for the control programs; irregular or non availability of drugs; poor drug adherence; co-morbidities and opportunistic infections/malignancies; drug toxicities; drug/food and drug/drug interactions; laboratory monitoring of viral load; CD4 cell counts; full blood counts; electrolytes, kidney and liver functions. CONCLUSION: The review has shown that the solution to the pandemic lies in a multi-sectoral and holistic approach involving International and local agencies, and communities. PMID- 21526622 TI - Inguinal hernia: the quest for the best repair. AB - BACKGROUND: Inguinal hernia repair may be the most common procedure in general surgery. Many repairs have been described but none appears completely satisfactory. A brief look at the popular methods of repair from the traditional tissue approximation to the current mesh-based techniques is presented. METHODS: The PubMed database was searched for all English language literature. Further references were obtained through cross-referencing the bibliography cited in each work and using books from the authors' collection. CONCLUSION: The history of inguinal hernia is a rich one, from the traditional tissue approximation techniques to the current mesh-based repairs which are now performed as open or laparoscopic procedures. Recurrent rates have reduced but are still a problem. Perhaps the perfect repair remains elusive because the problem may also be with patients' collagen not just the surgical procedure. PMID- 21526623 TI - Non-Steroidal anti inflammatory drugs usage in orthopaedics and trauma practice. A guide and review. AB - BACKGROUND: Non steroidal anti-inflammatory drugs (NSAIDs) are a group of heterogeneous compounds with anti inflammatory, analgesic and often times anti pyretic properties. They are weak organic acids and are the most commonly used drugs in Orthopaedic/Trauma practice. They provide mild to moderate pain relief. NSAID share common therapeutic and side effects irrespective of the class or group to which an individual drug may belong. These side effects are many and varied and constitute a major concern in their usage since most of them are life threatening. The NSAIDs are also one of the most commonly abused drugs. The abuses stem mostly from poor prescription habit by the health professionals. The poor prescription habit by the professionals and laissez-a-faire attitude to NSAID Usage informed the need for this review which addresses the issues, controversies and preventive strategies to reduce the complications in Orthopedics/Trauma practice. METHODS: Literature on the subject was reviewed extensively using manual library internet search. Publications from local and international Journals spanning a period of over thirty years were reviewed. The internet search was done using pubmed and ortholink search engines. RESULTS: NSAIDs act locally at the site of origin of pain by inhibiting the cyclooxygenase enzymes and induce no change in mood and dependency The inhibition of the Cox enzymes can be reversible or irreversible and leads to inhibition of prostaglandin synthesis. All the therapeutic and most of the side effects of NSAIDs result from the inhibition of the cyclooxygenase pathway. Thus the Cox-2 selective inhibitors have lesser side effects than the non selective Cox inhibitors; though there is recent evidence linking them with adverse cardiovascular events. There is paucity of information in literature on the guidelines of the prescription/usage of NSAIDs, and the preventive strategies in orthopedics and traumatology. CONCLUSION: NSAIDs are the most commonly prescribed group of drugs in orthopedics and trauma practice. They constitute a great asset to any Doctor who deals with pains associated with inflammation which they relief quite effectively. NSAID Usage is froth with significant life threatening complications. A high index of suspicion of the possibility of occurrence of these complications, adherence to proper prescription guidelines and preventive strategies, change of the laissez-a-faire attitude of the professionals to NSAID prescription and appropriate monitoring of the patients on the drugs are paramount in improving their safety profiles. Orthopedic and Trauma surgeons need to be aware of the serious side effects and the role of preventive strategies in the use of NSAIDs. PMID- 21526624 TI - Audiometric findings in Waardenburg's syndrome amongst the institutionalised deaf/ blind in Kaduna-Nigeria. AB - INTRODUCTION: Waardenburg's syndrome is a rare inherited disorder of congenital hearing loss and Pigmentary disturbances of the eyes, hair, skin and neural crest derivatives. METHODOLOGY: 620 students in a deaf/blind school were examined end four had Waardenburg's syndrome with a frequency of 0.65%. 2 males and 2 females with Waardenburg's syndrome and age ranges between 1019 years (mean 15.75 years) All 4 subjects had complete blue irides, white forelock and sensorineural hearing loss, and thus met the diagnostic criteria. They were then subjected to Audiometric assessment. RESULTS: Otoscopy was essentially normal but Audiometry revealed sensorineural hearing loss [SNHL] in all the subjects ranging from severe to profound with one subject being stone deaf. CONCLUSION: Waardenburg's syndrome is a rare disorder in our environment although it may be under reported. Two of the subjects benefited from amplification and were given hearing Aids. Provision of early amplification cannot be over emphasized. PMID- 21526625 TI - Colposcopy and cytodiagnosis in the prevention of cervical malignancies. AB - BACKGROUND: The aim of this study was to establish the value of cytology, colposcopy, and pathohistology in the prevention of cervical malignancies. METHODOLOGY: A prospective study involving 750 patients hospitalized in the Obstetric-Gynecologic department during the period between January 2008 to January 2009 for different reasons in whom cervical dysplasia were noted on speculum examination or who showed typical clinical symptoms, direct biopsy was also obtained from 117 patients. RESULTS: 272 of the 750 patients (36.27%) showed clinical symptoms of cervical pathology. Atypical epithelial changes noted during colposcopy were more frequent in patients 31-40 years of age (60 patients, 32.09%) and 41-50 years of age (59 patients, 31.55%). Histopathological changes were noticed in 19 cases (16.24%) of cervical dysplasia at different stages, six cases (5.13%) of carcinoma in situ, and three cases (2.56%) of invasive carcinoma. CONCLUSIONS: The correct clinical evaluation of cervical epithelial alterations enables a prompt diagnosis and the timely implementation of appropriate therapeutic measures. PMID- 21526626 TI - Gender perspectives of sexual and reproductive practices of people living with HIV/AIDS in Enugu, South East Nigeria. AB - BACKGROUND: a major focus of attention in the efforts at controlling the spread of HIV infection has become the role of gender inequality. The objective of the study was to compare the sexual practices of HIV-positive male and female patients who received counselling and treatment at an Anti-retroviral Clinic in Enugu, South-East Nigeria. METHOD: A comparative cross-sectional descriptive study of patients attending the free anti-retroviral clinic at the University of Nigeria Teaching Hospital Enugu was done. RESULTS: A total of 146 males (30.8%) and 328 females (61.9%) were studied. Although there was no significant difference in the prevalence of sexual activity between the sexes, the reasons for sexual practices differed. Females indulged in risky sexual activity principally in obedience to the demands of their male partners and were more likely to have sexual partners who were unaware of their seropositivity than males. CONCLUSION: Risky sexual behaviour among women living with HIV/AIDS in Enugu despite exposure to intensive counselling was still mainly driven by the subordinate traditional gender roles of women in this culture. PMID- 21526627 TI - Frequency of cryptococcal meningitis in HIV-1 infected patients in north central Nigeria. AB - BACKGROUND: Cryptococcal meningitis (CM) is the most common severe life threatening fungal infection in AIDS patients. It is an important cause of morbidity and mortality There is paucity of data on the prevalence of CM in Nigeria. We aimed to determine the frequency of CM, the clinical presentation and immunological profile. METHODS: A cross sectional study was carried out at the Jos University Teaching Hospital (JUTH). A total of 100 HIV-1 infected patients suspected of having meningitis or meningoencephalitis were subjected to cerebrospinal fluid (CSF) analysis (including Indian ink preparation and fungal culture by conventional methods) and CD4 count was determined using flow cytometry (count bit Y-R 1004 Partec Muster Germany). RESULTS: The freguency of CM was 36% in our cohort. The commonest clinical presentation included headache (100.0%), neck stiffness (77.8%), fever (72.0%), vomiting 55.6%), personality changes (55.6%), photophobia (27.8%) and convulsions (27.8%). The mean duration of symptoms was 24 +/- 22 days with a median of 17 days. The mean CD4 count was 89 +/- 60 cells/mm3 with a median of 82 cells/mm3. CONCLUSION: The high prevalence of CM and the associated severe immunosuppression underscores the importance of early diagnosis of HIV infection which may reduce the incidence of CM. There is the urgent need for access to Amphotericin B and fluconazole in resource constrained settings in addition to a wide access to HAART. PMID- 21526628 TI - Magnitude and leading causes of in-hospital mortality at Aminu Kano Teaching Hospital, Kano, northern Nigeria: a 4-year prospective analysis. AB - BACKGROUND: Population based mortality data are scarce especially in developing countries including Nigeria. Despite its limitations, hospital mortality analysis assesses the quality of health-care delivery and provides a proximate measure of mortality. We reviewed the magnitude and causes of death among in-patients in a tertiary hospital in northern Nigeria. METHODS: Analysis of mortality rate and causes of death for the period 2005-2008 (inclusive) in Aminu Kano Teaching Hospital. Causes of death were prospectively entered on a database and classified according to the International Classification of Diseases (ICD- 10). RESULTS: Out of 51,975 patients admitted to the hospital, 4,029 of them died. This gives a mortality rate of 7.8% (95% Confidence Interval of 7.5% to 8.0%). Specifically, of the 15,484 males admitted, 2,361 died giving a mortality rate of 15.2% while of the 36,491 females admitted, 1,668 died giving a mortality rate of 4.6%. The median age for all patients that died was 32.4 years (range: less than 1 day to 101 years), but 36.1 years (range: less than 1 day to 101 years) for the male and 29.3 (range: less than 1 day to 87 years) for the female subsets. The ten most common causes of mortality were HIV/AIDS (8.3%), Septicaemia (6.8%), cerebrovascular disease (6.3%), chronic renal failure (3.9%) chronic liver disease (3.3%), diabetes mellitus (3.2), neonatal jaundice (2.9%), severe birth asphyxia (2.6%), prematurity (2.5%) and bronchopneumonia (2.4%). CONCLUSION: The mortality rate and causes of death are comparable to similar centres. Regular mortality audits could identify management errors and prevent recurrence of avoidable deaths. PMID- 21526629 TI - Occupational and environmental lead exposure in Port Harcourt, Nigeria: analysis of its association with renal function indices. AB - BACKGROUND: In spite of the high risk of lead exposure in Nigeria, there is a paucity of data on the occupational and environmental burden of lead exposure and its impact on human health especially its nephrotoxic effects. This study aims to assess the degree of occupational and environmental lead exposure in Port Harcourt Nigeria and the relationship between lead exposure and indices of renal function. METHODS: A cross sectional comparative study of 190 aduIt subjects with occupational lead exposure and 80 matched controls. Blood lead was used as the biomarker of lead exposure. Serum urea, creatinine, uric acid, urine albumin and glomerular filtration rate were the renal function indices measured. RESULTS: Occupationally lead exposed subjects had higher mean blood lead 50.37 +/- 24.58 ug/dI, than controls 41.40 +/- 26.85 ug/dl (p = 0.008). The mean values of serum urea, creatinine and uric acid were significantly higher in study subjects compared to controls 3.06 +/- 0.81 mmol/L vs. 2.7 +/- 0.84 mmol/L (p = 0.002), 87.2 +/- 14.30 umol/L vs. 80.68 +/- 14.70 umol/L (p = 0.001) and 271.93 +/- 71.18 umol/L vs. 231.1 +/- 62.70 umol/L (p = 0.000) respectively. Creatinine clearance was significantly lower in subjects compared to controls 98.86 +/- 21.26 mI/min/1.72m2 vs. 108.18 +/- 25.16 mI/min/1.72m2 (p = 0.002). Blood lead correlated positively only with blood urea [r = .031, r2 = .017, p = .031] and negatively [r = -.144, r2 = .02 1, p = .018] with serum phosphate. CONCLUSION: The level of environmental and occupational lead exposure in Port Harcourt, Nigeria is high, with occupational lead exposure increasing the risk of lead toxicity and renal function impairment. PMID- 21526630 TI - Abdominal tuberculosis in surgical practice in northern Nigeria. AB - BACKGROUND: Abdominal tuberculosis is a common complication of pulmonary tuberculosis. With the rising incidence of HIV, tuberculosis has become a major public health problem particularly in developing countries. METHODS: This is a retrospective study involving patients whose surgical specimens were processed at the central histopathology laboratory of the Ahmadu Bello University Teaching Hospital (ABUTH) Zaria--Nigeria, between January 1975 to December 2006. RESULTS: There were 68 males and 49 females, aged 12-70 years (mean 28.6 yrs 11 yrs). While paroxysmal dry cough was present in about 20 patients, abdominal pain and distension were very common. Concomitant pulmonary tuberculosis was confirmed in 15 patients (14%). The findings at Surgery in 66 patients are presented in fig. 2. Multiple deposits on the peritoneum and omentum were the commonest findings (48.7% and 26.2%) respectively CONCLUSION: Abdominal tuberculosis is not uncommon and there is need to establish an early less invasive diagnostic protocol. PMID- 21526631 TI - Profile of neurological admissions at the University of Nigeria Teaching Hospital Enugu. AB - BACKGROUND: The burden of Neurological diseases may be on the increase especially in developing countries. Improved outcome in these settings may require appreciation of the spectrum of Neurological diseases and the impediments to their management. We aim to determine the profile of neurological admissions and the challenges of managing these diseases at the University of Nigeria Teaching Hospital Enugu South East Nigeria. METHODS: Analysis of Neurological admissions into the medical wards of the University of Nigeria Teaching Hospital Enugu from January 2003 to December 2007. RESULTS: Neurological admissions comprise about 14.8% of medical admissions. There were 640 (51%) males and 609 (49%) females. The spectrum of neurological diseases were stroke 64.9%, central nervous system infections (21.8% ), HIV related neurological diseases 3.5%, hypertensive encephalopathy (3.4%), dementia (3%), subarachnoid haemorrhage (2.2%), Guillian Barre syndrome (1.2%), Parkinson's disease (1.1%), myasthenia gravis (1.0%), motor neurone disease and peripheral neuropathy and accounted for 0.8% and 0.6% respectively. Overall, noninfectious disease accounted for 78.2% of neurological admissions while infectious diseases accounted for 11.8%. CONCLUSION: A wide spectrum of neurological diseases occurs in our setting. The high incidence of CNS infections indicates that efforts should be geared towards preventive measures. A major challenge to be addressed in the management of neurological diseases in our setting is the lack of specialized facilities. PMID- 21526632 TI - Seroprevalence of hepatitis B surface antigen among patients attending Aminu Kano Teaching Hospital, Kano. AB - BACKGROUND: Hepatitis B virus infection has become a global public health problem. In Nigeria, several studies from different parts of the country have confirmed the endemicity of the infection. This study seeks examine the seroprevalence of Hepatitis B viral infection among patients attending Aminu Kano Teaching Hospital in Kano metropolis. METHOD: This is a retrospective study in which patients tested for hepatitis B virus using hepatitis B surface antigen (HBsAg) as a marker were reviewed over 3 years. A total of 6,395 patients comprising of 4,040 males and 2,355 females including adults and children were tested for HBsAg from January 2004 to December 2006. Over this period, 1,509 sera were tested in 2004, 2,322 in 2005 and 2,564 in 2006. RESULTS: Among the 6,395 patients, 703 (11.4%) comprising of 240 (10.2%) females and 490 (12.1%) males were positive for HBsAg. The highest prevalence was seen at the extremes of life in which 19.4% and 16.9% were seen among patients below 10 years and above 50 years respectively. The yearly trend of HBV surface antigenemia was 220 (14.6%) in 2004, 235 (10.1%) in 2005 and 275 (10.7%) in 2006. CONCLUSION: We conclude that the prevalence of HBsAg among patients attending Aminu Kano Teaching Hospital, Kano is high and highest prevalence is seen at the extremes of life. PMID- 21526633 TI - Serum C-reactive protein in Nigerians with type 2 diabetes mellitus. AB - BACKGROUND: C-reactive protein is an acute-phase proteins, produce in the liver, its release is stimulated by cytokines (interleukin 6 and tumour necrosis factor alpha). Elevated level of it is a risk factor for coronary heart disease. Baseline levels of C-reactive protein in apparently healthy men and women predict long-term risk of a first myocardial infarction. Diabetics are at increased risk for coronary heart disease, data from the Framingham Study showed a two- to three fold elevation in the risk of clinically evident atherosclerotic disease in patients with type II diabetes compared to those without diabetes. However, but data regarding CRP in Nigerian diabetic is lacking. METHOD: A cross-sectional study conducted among patients attending out patient clinic of the Obafemi Awolowo University Teaching Hospitals complex OAUTHC) Ile Ife, Osun State south western Nigeria. Measurement of C-reactive protein was based on the principle of solid phase enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 125 consecutive subjects were recruited comprising 75 patients with type II diabetes mellitus with or without hypertension and 50 apparently healthy age-and-sex comparable controls. There was a significant difference between the mean systolic and diastolic blood pressures of the patients and controls. The fasting blood glucose and C-reactive protein were significantly higher in diabetics compared to controls. there was a positive and significant correlation between FBG and CRP in both patients and controls. CONCLUSION: This study showed that diabetics have significantly higher serum C-reactive protein compared to the apparently controls. Also there was a positive and significant correlation between C reactive protein and fasting blood glucose among both patients and controls. PMID- 21526634 TI - Thyroid cancers amongst goiter population in a Nigerian tertiary hospital: surgical and radiographic perspective. AB - BACKGROUND: Goiters are commonly benign, but cases of malignancy can develop. Thyroid cancer is known to be commoner in whites than in blacks and in females than in males. Bone metastasis is a common occurrence and may be the initial manifestation in a small subset. We hope to determine the incidence and the cervical radiographic patterns of thyroid cancer amongst goiter population in Nigeria. METHOD: Surgical, histological and radiographic findings in patients with goiter who had thyroidectomy in our hospital from 1999 to 2006 were reviewed. Those with proven cancer were analyzed for sex, age and radiographic changes using SPSS 11.0 for windows. RESULTS: Thirteen (8.2%) cases out of the 160 goiters were malignant and distant metastases were present in 1.3% at presentation. The histological sub-types of malignant goiters were follicular (5.0%), papillary (1.9%) and poorly differentiated or anaplastic thyroid carcinoma (1.3%). As much as 30% of thyroid cancers demonstrated calcification on plain neck radiograph, which were commonly scattered or diffused. CONCLUSIONS: Carcinomatous goiters occurred in 9.3% of the goiter population studied with predominance of follicular variant. Surgery remains the main stay but was inappropriate in about 1.2% of population with goitre. Aside evidence of bony destruction, TC should be suspected in goiters with mixed (diffused or scattered) calcifications. PMID- 21526635 TI - Perinatal outcome of macrosomic births in Port Harcourt. AB - BACKGROUND: Macrosomic babies are at increased risk of adverse perinatal outcome and therefore constitute a high risk group of neonates and the incidence appears to be rising. The objective was to determine the incidence of fetal macrosomia, and the perinatal outcome of macrosomic babies, compare with matched term, appropriate weight neonates in the booked antenatal population of the UPTH. METHODS: It was a one year prospective study of the perinatal outcome of singleton babies whose birth weights were 4000 g and above (macrosomia) delivered to booked antenatal mothers in UPTH between 1st October 2003 and 30th September 2004, comparing them with term appropriate (2500-3999 g) weight babies. The birth weight, sex, perinatal and maternal complications documented from direct observations, questioning and other information extracted from patients' case notes, were entered into a personal computer, analysed and presented as frequency tables, percentages, Chi-square X2, calculated as appropriate using Epi info version 3.4.3 statistical software. P < 0.05 was considered statistically significant. RESULTS: Fetal macrosomia occurred in 354 out of 2417 singleton term deliveries, giving an incidence of 1 in 7 deliveries or 14.65%. The birth asphyxia (7.90% vs 2.60%, p = 0.011), Neonatal admission (29.54% vs 2.85%, p = 0.001) and perinatal mortality (48/1000 vs 23/1000 births, p = 0.001), caesarean delivery (55.70% vs 18.64%, p = 0.001) rates were significantly higher in the macrosomic than the control group. CONCLUSION: There is a high incidence of fetal macrosomia in Port Harcourt with associated relatively higher adverse perinatal outcome compared to singleton term normal weight babies. PMID- 21526636 TI - The incidence, pattern and management outcomes of early pregnancy losses at the Ebonyi State University Teaching Hospital, Abakaliki. AB - BACKGROUND: Early pregnancy losses are a source of deep emotional trauma to any woman, her family and the attttending Gynaecologist. This study evaluated the prelence, pattern and management outcomes of such losses at a tertiary Health Institution. METHODS: Data of all women who suffered early pregnancy losses between 1st January, 2002 and 31st December, 2004, were reviewed in a descriptive study. Information obtained from their case notes which related to the early pregnancy event, their socio demographics, obstetric history and management outcomes were collated. Univariate analysis was performed and frequency tables and figures were constructed where appropriate. RESULTS: Early pregnancy losses comprised miscarriages, molar pregnancy and ectopic gestations accounted for 32.1% of all gynaecological admissions during the period. Miscarriages were the commonest diagnosis and incomplete abortion constituted the bulk of this. Women of all parities were involved but rate of loss increased down the socio economic class strata. Majority were unbooked. A maternal mortality rate of 1.8% attended all forms of early pregnancy losses during the period. CONCLUSION: Early pregnancy loss constitutes a major gynaecological problem in our centre. Health care providers must institute prompt and appropriate clinical management for a good clinical outcome. PMID- 21526637 TI - Pattern of childhood injury presenting at General Hospital Aliero, Nigeria. AB - BACKGROUND: Injuries are important causes of morbidity and mortality in childhood. Children are vulnerable to injuries of any kind. METHOD: This is a prospective study of children with injuries who presented at General Hospital Aliero. Records were kept of injuries in children age fifteen years and below that occurred from February to November 2006 at General Hospital, Aliero. We aim to study the pattern of childhood injuries presenting at General Hospital Aliero, Nigeria. RESULT: Most of the injuries occurred at home 31 (48.4%) and on the road 28 (43.8%). Road traffic accidents occurred when a moving vehicle or motorcycle hit children or children falling from moving trucks. Boys 39 (60.9%) were more involved in injuries than girls 25 (39.1%). Mortality occurred in three injured children. CONCLUSION: Childhood injuries occur more in the boys and commonly Parents and guardians should not leave children unattended even for a moment. Children should always be in company of an adult when outside the home. Childhood injury can lead to serious work and financial problems for families. Health promoting and injury preventive interventions should be instituted to reduce the rate of injuries and their effects on children. PMID- 21526638 TI - Epidemiology of gastric cancer in Jos University Teaching Hospital Jos a 20 year review of cases. AB - BACKGROUND: Gastric cancer believed to be rare in the past in Africa, is now one of the leading cancer morbidity and mortality. It is now known gastric cancer is 2-3 times higher in males than females living in the same environment. We aim to describe the comprehensive histological characteristics of gastric cancer with age and sex distribution. METHODS: The study site was Jos University Teaching Hospital situated in the capital of Plateau State. The hospital has a bed capacity of 530. The study materials were obtained from all stained specimens of gastric cancer recorded in the histopathology laboratory of the teaching hospital between 1985 to 2004. The biopsy site was noted. These were divided into the following groups: Cardia, body and an thrum/pyloric regions respectively. Or the information included age and sex of the patients. RESULTS: There were a total of 205 gastric cancer histological confirmed, out of 5705 malignant tumours recorded in the same period. There were a total of 145 cases in male and 60 in females giving a male: female ratio 2.4:1. The highest frequencies of gastric cancers were located in the anthral and cardia regions which accounted for 79% of all the tumours. Well differentiated adenocarcinoma (intestinal type) was the most frequent histological subtypes 51.2%), this was followed by poorly and diffusely infiltrating carcinoma. Other cancers included signet ring carcinoma, Non Hodgkin's lymphoma and leiomyosarcoma in that order. The study has also demonstrated H pylori at the background of intestinal type adenocarcinoma which was seen in the body and an thrum. CONCLUSION: The study has shown that gastric cancer is not only common but it occur more males than females. The high proportion of H pylori in our environment might indicate a possible aetiological association. Therefore eradication of H pylori might reduce the prevalence of gastric carcinoma. PMID- 21526639 TI - Gender and psychiatric diagnosis: a 5-year retrospective study in a Nigerian Federal Medical Centre. AB - BACKGROUND: The role of gender in psychiatry disorders is becoming increasingly important. This study is therefore, aimed at identifying gender pattern of admissions to a public mental health centre with regards to demographic characteristic, psychiatry diagnosis and length of stay on admission. METHOD: In this retrospective study Hospital records of 388 patients admitted at the psychiatric section of the Federal Medical Centre (FMC) Makurdi, between January, 2004 and December, 2008 were studied for gender differences regarding demographic attributes, length of stay and psychiatry diagnoses. RESULTS: Findings revealed that more men than women were admitted overall. Most men (56%) were less than 30 years old whereas 60.6% of women were within 30-59 years aged bracket. For men the main diagnosis was schizophrenia (30.5%), followed by substance related disorders (16.5%) then depression (14.0%); for women the main diagnosis was also schizophrenia (30.3%), this was followed by depression (24.5%), only one woman was diagnosed with substance related disorder. A statistically significant association was also found between having a personality disorder and being a male (p = 0.009). Most female were single and belong to the lowest occupational group. There was no significant difference in the gender distribution of patients with respect to length of stay on admission (p = 0.161). CONCLUSION: The results revealed how psychiatry diagnosis is significantly influence by gender issues. We therefore recommend that; for a more effective psychiatry formulation, it is imperative to pay attention to gender issues that may affect the development of psychopathology. PMID- 21526640 TI - Obesity in adult Nigerians: a study of its prevalence and common primary co morbidities in a semi-urban Mission General Hospital in South-Eastern Nigeria. AB - BACKGROUND: Obesity is socially and culturally acceptable in Nigeria and therefore not usually recognized as a medical problem. This study is aimed at determining the prevalence of obesity using body mass index (BMI) criterion and its common primary comorbidities among adult Nigerians attending a semi-urban Mission General Hospital in Imo state, SouthEastern, Nigeria. METHODS: A descriptive study using primary data collection technique was carried out from October 2007 to December 2008. A total of 9296 consecutive new adult patients aged 18-88 years were screened for obesity using BMI criterion and 684 patients who had BMI = 30 kg/m2 met the inclusion criteria. The data collected included age, sex, marital status, education, occupation, weight (kilogram), height (meters), and blood pressure; fasting blood sugar and fasting lipid profile. Obese patients' perception of their obese condition and knowledge of lifestyle modification were also assessed. RESULTS: Six hundred and eighty-four (7.4%) out of a total of 9296 patients screened for obesity were obese. Hypertension (18.4%) was the commonest primary comorbidity, others include high triglyceridaemia (9.2%), high total cholesterol (8.2%), high LDL-cholesterol (6.0%) and diabetes mellitus (3.4%). One hundred and one (14.8%) obese patients were aware of their obese condition and majority, 72 (71.3%) of them were informed of their obese condition by healthcare professionals. Forty seven (46.5%) of those who were aware of their obese condition had knowledge of lifestyle modification. However, majority (72.3%) of those who had knowledge of lifestyle modification demonstrated low knowledge level of lifestyle modification. CONCLUSION: This study has shown the existence of obesity and its common primary co-morbidities among the study population. Anthropometric determination of obesity and screening for its common primary comorbidities should be integrated as part of clinic baseline assessment of adult Nigerians attending semi-urban hospitals. Those who had obesity-related primary co morbidities should become secondary target for risk reduction therapy and appropriate management. PMID- 21526641 TI - Morbidity of total abdominal hysterectomy at the University of Maiduguri Teaching Hospital, Maiduguri, Nigeria. AB - BACKGROUND: Total abdominal hysterectomy is a commonly performed gyneacological procedure. Although it is safe, it can still be associated with development of complication. The aim of this study was to determine morbidity associated with total abdominal hysterectomy in our environment. METHOD: All cases of total abdominal hysterectomy done over a five-year period (January 2003-December 2006) at the University of Maiduguri Teaching Hospital (UMTH) were reviewed. Information was obtained from the patients' case notes, gynaecology ward, and theatre records. The complications of the procedure were determined. Multiple logistic regression was used to find the factors that were independently associated with development of complications. RESULTS: During the study there were 101 cases of total abdominal hysterectomy out of 729 gynaecological operations, a rate of 13.8%. In majority of the cases 56 (68.3%) the indication of the hysterectomy was uterine fibroid (symptomatic). Overall 37 (45.1%) experience some form of complication out of which 26 (70.3%) was febrile morbidity Finding enlarged uterus intraoperatively {OR (95% CI) = 14.5 (1.84 114.6), p = 0.011}, blood transfusion {OR (95% CI) = 31.1(1.35-718.8), p = 0.032}and postoperative PCV < 30% {OR (95%CI) = 9.63 (1.14-81.3) p = 0.037} were found to be significantly associated with development of complication. conclusions: Total abdominal hysterectomy was associated with development of complications and enlarged uterus, increasing parity independent risk factors for development of the complication. PMID- 21526642 TI - Maternal HIV positive sero-prevalence at delivery at a tertiary hospital in South Eastern Nigeria. AB - BACKGROUND: The duo of HIV/AIDS infection has become a Global public health problem. This study was conducted to determine the maternal HIV positive seroprevalence at delivery at the Imo State University Teaching Hospital, Orlu. METHODS: A retrospective analysis of the case records of women (both booked and unbooked) who tested positive to Human Immune-deficiency Virus at delivery at the Imo State University Teaching Hospital (IMSUTH), Orlu from 1st May 2005 to 30th April 2010 was made. The biosocial, obstetric and fetal sex data were extracted and analysed. RESULTS: The maternal HIV positive sero-prevalence at delivery was 6.9%. The highest sero prevalence rate of 42.4% occurred in the age group of 31 35 years. Sixty three (68.5%) of the women were multiparous (para 1-4). The male: female birth ratio was 1:1.42. Forty one (44.6%) of the women were unbooked. None of the women were symptomatic of Acquired Immunodeficiency Syndrome (AIDS) on presentation. CONCLUSION: There is high maternal HIV seroprevalence at delivery at IMSUTH, Orlu. There should be improvement on interventions to reduce this ugly trend. There should also be early booking and adequate antenatal care services. PMID- 21526643 TI - Lower limb injuries arising from motorcycle crashes. AB - BACKGROUND: Motorcycle accidents are the second most common cause of road traffic accidents in both developing and developed countries. In this study we aim to look at the pattern and characteristics of lower limb injuries arising from motorcycle accidents and evaluate early outcome of treatment. METHODS: All the patients with lower limb injuries arising from motorcycle accidents who presented in our hospital between 1st October 2006 and 30th September 2007 were reviewed. History was obtained and detailed examination was done after resuscitation to determine the site, nature and the characteristics of injuries. Definitive treatment (conservative or operative) given was based on the pattern and type of injuries. Patients were followed up in the clinic for both clinical and radiological review. Functional outcome assessment was commenced after the onset of weight bearing. The data were recorded on a designated proforma and analyzed using a statistical programme. RESULTS: A total of 429 motorcycle accident victims were seen during this period and lower limb injuries represented the commonest type of injury (238, 55.5%). Male:female ratio was 2.2:1 with a mean age of 43.1years. Fractures were the commonest lower limb injuries (73.4%) and closed fractures were commoner than the open fractures. The commonest anatomical location of fractures in lower limbs was tibial shaft. Joint stiffness was found to be the commonest post treatment complication. CONCLUSION: Lower limb injuries represent the commonest form of injuries among the motorcycle accident victims. Fractures were the commonest type of injury seen and the most common location was shaft of tibia. PMID- 21526644 TI - Benign intermittent gastric outlet obstruction in an elderly: endoscopic management and brief review. AB - We describe the clinical scenario in an 80 year old female who presented with history of epigastric discomfort and postprandial fullness of three weeks duration without any alarming symptoms. On upper GI endoscopy she was found to have gastric polyp with a long stalk which was partially obstructing her pyloric ring giving rise to features of intermittent gastric outlet obstruction. Polypectomy was done with complete relief of symptoms. She is following our clinic for last 6 months now. Although possibility of malignant etiology in gastric outlet obstruction ranks high in the elderly some patients are lucky to have a benign cause as the index case. Report of the case and brief review is presented. PMID- 21526646 TI - Therapeutic potnetial of Anakinra in patients with left ventricular systolic dysfunction: a hypothesis. PMID- 21526645 TI - Idiopathic scrotal calcinosis; a rare scrotal tumour: a case report and review of literature. AB - Idiopathic scrotal calcinosis is a rare benign disease characterized by multiple, asymptomatic and painless nodules on the scrotum. We herein report this rare disease in a Nigerian adult male and briefly review the relevant literature. PMID- 21526647 TI - Potential utility of itraconazole as a novel enhancer and accelerator of bone healing. PMID- 21526648 TI - Discrimination and subjective well-being: protective influences of membership in a discriminated category. AB - BACKGROUND: Research reveals that discrimination has harmful effects on health and quality of life. Among the most frequent types of discrimination pertains gender and age discrimination. Research results show that discriminatory behaviours based on gender afflict predominantly women; age discrimination afflicts mainly older adults. At the same time, it has been found that members of these traditionally discriminated categories often use strategies that mitigate the effects of discrimination. HYPOTHESES: Discrimination will have detrimental effects on subjective well-being. But its effects will be most harmful for persons who are not members of the traditionally discriminated categories. METHODS: These hypotheses were tested on data from three waves of the European Social Survey that the Czech Republic also participated in. Data were analyzed in a series of multilevel random coefficients regression analyses with respondents nested within states and states nested within years of study. RESULTS: Both perceived gender discrimination and perceived age discrimination have negative effects on subjective well-being. However, gender discrimination had more harmful effects on the subjective well-being of men than women and age discrimination had the most harmful effects on the subjective well-being of people in their middle ages, not the elderly ones. CONCLUSION: Discrimination does not need to have most harmful effects on the quality of life of members of the categories that are discriminated against most often. PMID- 21526649 TI - Health-related quality of life: a population based study from Slovenia. AB - OBJECTIVES: Health status is represented by people's subjective assessment of their sense of well-being and ability to perform social roles and has been well accepted as a health indicator of different populations. The aim of this study was to determine health-related quality of life in Slovenian population. METHODS: We performed a cross-sectional postal survey in a random stratified sample of 1,000 adult Slovenian inhabitants. The questionnaire consisted of the respondents' demographic data (sex, age, education level, employment status, living environment), self-reported chronic conditions, self-reported use of health services and EQ-5D instrument for measuring quality of life. RESULTS: The response rate was 41% (53.1% men, mean age 51.5 years). Respondents reported most problems in the pain dimension of EQ-5D (59.3%), following by mobility (30.4%), anxiety/depression (30.3%), daily activities (29.8%) and self-care (9.0%). At least one moderate problem was reported by 272 (66.3%) respondents. Independent factors, associated with problems in any EQ-5D dimension were primary and vocational education, older age, high blood pressure, rheumatic diseases, back problems, anxiety/depression, a visit to the emergency department in the past year, and a house visit from a family doctor in the past year. CONCLUSIONS: The present study showed that the health-related quality of life of the Slovenian inhabitants is lower than the one found in some other European countries. This finding is surprising and also worrying. Because we cannot find any perceptible reason for this observation, larger and prospective studies are needed to confirm those results and to determine the reasons for that. PMID- 21526650 TI - The implications of nutrition services within the health care system on the quality of life and longevity, in developed countries: a re-analysis of 38 studies. AB - BACKGROUND: The United Nations' Global Population Pyramid is undertaking a shift from pyramid to cube. The concomitant decline in fertility and mortality rates produces a higher portion of older people, and, thus, an increased number of deaths due to cancer and cardiovascular disease (CVD). Limited studies have investigated the effect of health care services on longevity. In this work, findings from studies throughout the world are presented and re-analysed in order to evaluate the effect of health care services on population's health status. METHODS: Studies that have assessed the associations of nutritional and other health care services (i.e., physicians supply, technical support, inter collaboration) on longevity and health status were retrieved (searches in PubMed, EMBASE, Scopus, up to January 2010), and summarized here. RESULTS: Few studies, mostly located in the US and the UK, have evaluated the role of health care services on population's health status. The majority of the studies reported a beneficial association between the frequency of physicians and mortality, while some other studies reported weak or no associations between physician's supply and longevity. Also nutritional services (screening) seem to promote better clinical outcome. CONCLUSION: Although very few data are available, it seems that there is a positive correlation between the quality and quantity of health care services and longevity. Strong primary health care seems to be effective on the population's health outcome. Active health policy and enhancement of health and nutritional services within the health care system may contribute to improved population's health and their overall quality of life. PMID- 21526651 TI - Changes in surveillance of acute respiratory infections including influenza in the Slovak Republic during 1993-2008. AB - The authors evaluated surveillance of acute respiratory infections (ARI), influenza and influenza-like illnesses (ILI) in the Slovak Republic (SR). They analyze morbidity, age-specific morbidity, complications, mortality, number of influenza viruses isolations and vaccination coverage rates in the SR in the years 1993-2008. They focus mainly on the analysis during the epidemic. Most epidemics have been caused by influenza virus A subtype H3N2. The age group mostly affected by morbidity during the year were children at the age of 0-5, while during the epidemic, the highest morbidity was recorded among school children at the age of 6-14. A complicated clinical course of the disease was reported in 1,422,836 patients (5.1%). Since the 2002/2003 influenza season, the sentinel physicians have participated in taking biological material, which ensures monitoring of influenza viruses circulating in the SR. As of the 2006/2007 season, the ARI/ILI have been reported separately in the SR in accordance with the monitoring requirements set by the European Influenza Surveillance Scheme (EISS) project, and the calculation of morbidity is done from the number of persons, who are in care of the reporting physicians: Vaccination coverage in SR is still very low in comparison with other European Union (EU) countries. PMID- 21526652 TI - Hepatitis C virus antibody status, sociodemographic characteristics, and risk behaviour among injecting drug users in Croatia. AB - The study was conducted among 76 injecting drug users (IDU) from seven Croatian cities during a three-year period (2005-2007). Each participant completed a questionnaire on sociodemographic characteristics and potential risk factors for hepatitis C virurs (HCV) infection followed by anti-HCV and anti-HIV antibody testing. The mean patient age was 30. The majority of patients (69.8%) reported more than one potential exposure to HCV: 97.1% had shared injecting equipment, 75% reported risk sexual behaviour, and 56.3% reported a history of travelling abroad. The overall HCV seroprevalence was 51.3% (95% CI = 40-63%). HCV seroprevalence increased with increasing number of risk behaviours (p = 0.026). Needle sharing frequency was the most important risk factor for hepatitis C. The HCV seroprevalence rate ranged from 27.3% in IDUs who answered that they shared needles occasionally to 100% in IDUs who always shared needles (p < 0.001). No other risk factors (age, gender, educational level, marital and employment status, history of travelling abroad and sexual risk behaviour) were associated with HCV seropositivity. PMID- 21526653 TI - Racial/ethnic differences in predictors of PSA screening in a tri-ethnic population. AB - BACKGROUND: This study was carried out to identify racial/ethnic differences in predictors of prostate-specific antigen (PSA) screening in a group of prostate cancer patients. METHODS: In this cross-sectional study, a total of 935 prostate cancer patients were recruited from the Texas Medical Center, Houston, between 1996 and 2004. It included 372 Caucasians, 346 African Americans and 217 Hispanics. A structured questionnaire was used to collect data on socio demographic and life-style related variables, and self-reported PSA screening history through personal interview. RESULTS: African American (54.4%) and Hispanic patients (42.3%) were significantly less likely (p = 0.004 and p < 0.001, respectively) to report having had PSA screening than Caucasian patients (63.2%). Only annual check-up was found to be a significant predictor of PSA screening in Hispanics. Among Caucasians, education and annual check-up were significant predictors of PSA screening; whereas in African Americans, education, annual check-up, marital status and BMI were significant predictors of PSA screening. CONCLUSIONS: The rates of PSAscreening and its predictors varied by race/ethnicity in this tri-ethnic population. Health-education programs and culturally appropriate educational outreach efforts, especially targeted for high risk groups, are needed to reduce these disparities. PMID- 21526654 TI - Compliance to diabetes self-management in rural El-Mina, Egypt. AB - BACKGROUND: Diabetes is a serious public health problem that threatens the quality of life of patiens with diabetes, the success of long-term maintenance therapy for diabetes depends largely on the patients' compliance with a therapeutic plan. AIM OF THIS STUDY: To assess compliance of diabetic patients to diabetes self-Management in rural El Minia, and to determine the associated factors related to it. SUBJECTS AND METHOD: Cross sectional analytic study. Rural adults identified as having previously diagnosed diabetes were recruited to participate in this study. A total of 206 rural community diabetics were randomly chosen and subjected to interview questionnaire on history of diabetes, type of medication, self-management of diabetes as glucose examination, dietary modification, and eye examination. RESULTS: Mean age of participants was 54 +/- 6.3 years and mean duration of diabetes was 12 +/- 8 years. Nearly one third of the patients used insulin and more than half used oral hypoglycemic. The results of this study revealed that good adherence to diabetes self-management was reported among 41.7% of adult diabetic patients who show good adherence to diet instructions, but only 21.4% to blood glucose test. There was no gender difference regarding self care of diabetes. Younger age group had more glycemic control than older age; longer duration of diabetes was significantly associated with poor glycemic control. CONCLUSION: Compliance to self-management of diabetes is suboptimal among rural adult community diabetic. PMID- 21526655 TI - Action needed to reduce health impact of harmful alcohol use. PMID- 21526656 TI - Influence of sociodemographic factors on Helicobacter pylori prevalence variability among schoolchildren in Leipzig, Germany. A long-term follow-up study. AB - BACKGROUND: Until the beginning of this decade the assumption was that the Helicobacter pylori prevalence increases with the age of the population under consideration. More and more epidemiological studies have been suggestive of constancy in Helicobacter pylori prevalence, but to date there has been no long term follow-up study in a large group of children confirming this hypothesis. METHODS: Following up our study of H. pylori among school starters and 2nd graders in 1998 and 2000, we conducted a third phase of this study in 2006 using the [13C]-Urea Breath Test and a detailed parent-completed epidemiological questionnaire to evaluate the development of prevalence among the overall population of 8th graders in the city of Leipzig (n = 1,905), and especially of the subgroup of participants who took part in all three study phases (n = 751). RESULTS: The overall H. pylori prevalence was 6.5% and had not significantly changed since 1998 and 2000 (6.1%, 5.7% respectively). However, we noticed a significant lower prevalence in the subgroup that participated in all study phases (2.7%). Moreover, we observed a dependence of prevalence on distribution of sociodemographic risk factors such as foreign nationality of at least one parent, birth outside of Germany, low parental education and unemployment, and > or = 2 older siblings. CONCLUSION: The variability in prevalence is most likely a result of unequal sociodemographic family backgrounds. PMID- 21526657 TI - Characterization of the plasmidic or chromosomal cpe gene and metabolic activities in Clostridium perfringens isolates from food in San Luis--Argentina. AB - Food poisoning and non-food poisoning illnesses due to C. perfringens (by enterotoxin production) have been associated to chromosomal or plasmidic location of the cpe gene, respectively. Clostridial pathogenicity has been correlated to protease and azoreductase production. The aim of this work was: i) to assess the sanitary-hygienic quality of dehydrated soups (100 samples) consumed in San Luis Argentina; ii) to verify the presence of C. perfringens in these food products using the "Most Probable Number" method (MPN) and plate-counting methods; iii) to characterise enterotoxigenicity in strain isolates by RPLA; iv) to determine the chromosomal or plasmidic location of the cpe gene in enterotoxigenic strains previously isolated from food in our lab, using PCR; v) to correlate chromosomal cpe and spore heat-resistance; vi) to compare protease activity in cpe+ and cpe- strains; and vii) to compare azoreductase activity in cpe+ and cpe- strains. Twenty-six isolates had a count a 3-43 bacteria g(-1) count using MPN; 7.7% exceeded the Argentine Food Code (CAA) limit. All isolates showed protease activity: enterotoxigenic isolates had higher protease activity than non enterotoxigenic isolates. All isolates showed azoreductase activity: enterotoxigenic isolates had higher activity and shorter reducing times. Enterotoxigenic isolates showed chromosomal location for the gene responsible for the enterotoxin. PMID- 21526658 TI - Smoking practices in Jordanian people and their impact on semen quality and hormonal levels among adult men. AB - Despite worldwide anti-smoking campaigns, cigarette smoking prevalence is increasing in the third-world countries. It is now regarded as the most important public health issue. Here, we study the current smoking situation and investigate the impact of cigarette smoking on semen quality and hormonal levels among adult people. Furthermore, we suggest various strategies to reduce smoking consumption among young individuals. Across-sectional data from 804 adult smoker subjects (male n = 530 and female n = 274) aged between 15 and 45 years were analyzed. One hundred and eleven males were agreed for further evaluation of their semen quality and hormones compared with 93 age-matched non-smoking males. This study showed that the majorfactors initiating smoking among women were friends' influence (49%), life pressures (16%) and parental imitation (14%). The major reasons in men was friends' influence (65%). Furthermore, 61% ofwomen and 89% of men smoke in public implying social acceptance oreven encouragement of this habit. This study also found that low-income Jordanians consume more tobacco materials than those in the middle- and higher income. Furthermore, smokers had significantly lower (p < 0.001) sperm concentration and motility values and higher (p < 0.001) serum testosterone and luteinizing hormone (LH) levels than non-smokers. PMID- 21526659 TI - "Routine" preoxygenation before induction of and recovery from anesthesia (a safety precaution). PMID- 21526660 TI - Anesthetic management in a patient with Cornelia de Lange syndrome. PMID- 21526661 TI - Perioperative management of the patient with Goodpasture's syndrome. PMID- 21526662 TI - Target-controlled infusion anesthesia with propofol and remifentanil compared with manually controlled infusion anesthesia in mastoidectomy surgeries. AB - Target-controlled infusion (TCI) system is increasingly used in anesthesia to control the concentration of selected drugs in the plasma or at the site of drug effect (effect-site). The performance of propofol TCI delivery when combined with remifentanil in patients undergoing elective surgeries has been investigated. Our aim in this study was to assess the anesthesia profile of the propofol and remifentanil target controlled infusion (TCI) anesthesia as compared to the manually controlled infusion (MCI), in mastoidectomy surgery, where a bloodless field is of utmost importance to the surgeon. Sixty patients, aged 18-60 years ASA I-II enrolled in the study, were divided into two equal groups. Group MCI received propofol and remifentanil by conventional-dose-weight infusion method, and Group TCI received propofol 4 microg/ml and remifentanil 4 ng/ml as effect site target concentration. The hemodynamic variability, recovery profile, postoperative nausea and vomiting (PONV), surgeons satisfaction were assessed. Results were analyzed by SPSS version 11.5. The two groups were comparable with respect to age, ASA class, sex, weight, basal vital signs, operation time. The blood pressure and pulse were above desired levels in some data points in the MCI Group (P < or = 0.05). The PACU stay time to reach Aldret score of 10 was longer in the MCI Group (42.54 +/- 8 vs 59.01 +/- 6 min) (P < or = 0.05). The PONV was more common in the MCI Group (P < or = 0.05). Surgeon's satisfaction of the surgical field showed no significant differences except when described as "good", more common in the TCI Group. TCI is capable to induce and maintain anesthesia as well as MCI. In some stages of anesthesia, the TCI control of vital signs are better than the MCI. In some stages of anesthesia, the TCI control of vital signs are beter than the MCI. Recovery profile and complication rate and surgeon's satisfactions are more acceptable in the TCI than in the MCI Group. PMID- 21526663 TI - Airway management and hemodynamic response to laryngoscopy and intubation in supine and left lateral positions. AB - INTRODUCTION: Intubation in the lateral position is desirable in several conditions. We compared the technical ease and hemodynamic response to laryngoscopy and intubation in the lateral (group L) and supine (group S) positions in 120 patients with normal airway in a prospective randomized controlled study. METHODS: This was a randomized, controlled observational study. All intubations were performed by a single investigator experienced in lateral intubation. Ventilation score with bag and mask ventilation, laryngoscopy duration and attempts, application of external pressure and Cormac & Lehane grade were measured. Blood pressure and heart rate were observed before and after induction of anesthesia, after laryngoscopy/intubation and then at one minute interval for 6 minutes. RESULTS: 90% of patients in group S were ventilated by a single operator compared to 17% in group L. Duration oflaryngoscopy was significantly longer in group L (32 seconds) compared to group S (12 seconds) [p < 0.001]. 78% of the patients in group S had Cormack and Lehane grade 1 versus nil in group L. External pressure was required in 58% patients in group L and 5% in group S. In intra-group comparison at specified time lines no difference was observed in HR but the changes in BP were significantly higher in the lateral position (P-value < 0.001). CONCLUSION: Ventilation and intubation in lateral position was more difficult technically than in the suprine position, and the BP response was exaggerated in the lateral position. PMID- 21526664 TI - Fentanyl pretreatment for alleviation of perineal symptoms following preoperative administration of intravenous dexamethasone sodium phosphate--a prospective, randomized, double blind, placebo controlled study. AB - BACKGROUND: Corticosteroids have anti-inflammatory, analgesic and antiemetic effects but causes severe perineal symptoms when given intravenously. Simultaneous administration of dexamethasone and fentanyl have been known to decrease the duration of perineal pain but its role in alleviating perineal pain has not been studied. Therefore, we hypothesized that fentanyl pretreatment could prevent the perineal symptoms associated with the dexamethasone. MATERIAL AND METHODS: This prospective, randomized, double blind, placebo controlled study was done in 200 patients undergoing elective surgery requiring dexamethasone. The patients were randomized into two groups of 100 each. Group BD received 5 ml normal saline followed, 5 minutes later, by 8 mg dexamethasone bolus intravenously. Group FD received 1 microg/kg fentanyl diluted in saline to a volume of 5 ml followed by 8 mg dexamethasone bolus 5 minutes later. The time of onset, intensity, site, duration and nature of the pain after the drug administration were recorded. RESULTS: The demographic profile was comparable in the two groups. The incidence and severity of pain was more in females as compared to males (p value = 0). The pain was located especially in the perineal region and was expressed as itching (62%), burning (13%) or both (25%). The incidence of pain, its duration and severity were significantly reduced after pretreatment with fentanyl (p value = 0). DISCUSSION: Our study showed that the intravenous administration of dexamethasone sodium phosphate leads to significant perineal symptoms. These symptoms are alleviated by pretreatment with fentanyl (1 microg/kg) (incidence, severity and duration). The pharmacological mechanism explaining perineal pain with intravenous administration of dexamethasone remains poorly understood, but could be related to the phosphate ester. We conclude, that intravenous administration of dexamethasone sodium phosphate is associated with perineal pain and can be alleviated effectively by pretreatment with 1 microg/kg of fentanyl. PMID- 21526665 TI - Transient neurological symptoms following spinal anesthesia for cesarean section. AB - BACKGROUND: Transient neurological symptoms (TNS) are defined as symmetrical bilateral pain in the back or buttocks or pain radiating to the lower extremities after recovery from spinal anesthesia. About 80-85% of cesarean sections are performed under spinal anesthesia in our centre. Our aim was to determine the incidence of TNS, risk factors and outcome of management in pregnant women undergoing cesarean section. PATIENTS AND METHODS: Approval was obtained from the hospital ethic's committee, and consent from the patients. ASA 1 and 2 pregnant women undergoing cesarean section under spinal anesthesia formed the subjects of this prospective study. They were evaluated and pre-medicated by the attending anesthetists. Spinal anesthesia was performed at the L2-3 or L3-4 interspaces, using a 25G Quincke or 25G pencil point spinal needle with 0.5% heavy bupivacaine. The investigators interviewed the patients in the ward for three consecutive days, in order to identify those that developed TNS. RESULTS: One hundred and twenty consecutive patients were studied. TNS were documented in 12 (10%) patients. Backache was recorded in 8 patients (6.6%), pain in the thighs in 2 (1.7%) and pain in the buttocks in 2 (1.7%). Onset time of symptoms was recorded as 6-12 hrs in 5 (4.2%) patients, 12-24 hrs in 5 (4.2%) and 24-48 hrs in 2 (1.6%). The patients that developed TNS were managed accordingly with satisfactory outcome. CONCLUSION: A follow-up for all patients that receive spinal anesthesia for cesarean section should constitute a standard practice. PMID- 21526666 TI - Incidence of perioperative cardiac arrest: analysis of anesthetics over 18-year period. AB - OBJECTIVE: Several studies have surveyed perioperative cardiac arrests and their outcomes, regardless of whether patients were successfully resuscitated or died. No such studies have originated from the Kingdom of Saudi Arabia. This is a study of perioperative cardiac arrests and their outcome in a Saudi General Hospital, over an 18-year period. METHODS: Armed Forces Hospital, Wadi Al-Dawasir, Kingdom of Saudi Arabia, serves military personnel and their families, in addition to eligible civilian members of the community. Operating theaters' records were examined to collect details of patients who underwent some form of surgical procedure since the commission of the Hospital on 12.07.1992 up until 30.09.2010. Those surgical cases were traced in the Medical Records Department and the outcome of each case was reviewed. The numbers and causes of cardiac arrests and death occurring during the intraoperative and within the first postoperative 24 hours, were noted. RESULTS: There were 15,832 patients received anesthesia during the 18-year period. Five patients died during this period (an incidence of 0.03%), all were emergency cases and were due to non-anesthetic causes; four of them died intraoperatively and the fifth died within the first 24 hour postoperatively. CONCLUSION: There were 5 non-anesthetic deaths in the perioperative period during the 18-year period. The absence of anesthesia-related cardiac arrests in such patient population has demonstrated that adopting quality improvement measures, teamwork approach and applying strict, but updated and evidence-based, guidelines are essential in the prevention of such catastrophes. A multicentre similar survey is needed to include all types of surgical operations. PMID- 21526667 TI - Efficacy of ultrasound-guided transversus abdominis plane (TAP) block for postcesarean section delivery analgesia--a double-blind, placebo-controlled, randomized study. AB - BACKGROUND: Ultrasound-guided transversus abdominis plane (TAP) block has been used for intra-operative and postoperative analgesia. Here we evaluate the efficacy of TAP block for postoperative cesarean delivery analgesia. METHOD: A randomized, double-blind, placebo-controlled trial was performed at King Khalid University Hospital on 40 patients undergoing cesarean delivery under spinal anesthesia with bupivacaine and fentanyl. At the end of surgery they received bilateral ultrasound-guided TAP block either with bupivacaine 0.25% (B group) 20 patients, or saline (S group, or placebo group) 20 patients, followed by patient controlled analgesia with i.v. morphine only. Each patient was assessed 24 hours after delivery for pain, morphine consumption, nausea, vomiting, sedation, patient's satisfaction, and also pain relief during mobilization (24 hours post cesarean section). RESULTS: All 40 participants completed the study. Total morphine consumption was reduced more than 60% in the bupivacaine group; the bupivacaine group also reported improved satisfaction with their pain relief over 24 hours after surgery, reduced morphine consumption, less nausea, vomiting, and better patient's satisfaction. CONCLUSION: Ultrasound-guided TAP block improved postoperative analgesia, reduced morphine consumption and improved patient's satisfaction regarding analgesia after cesarean delivery. PMID- 21526668 TI - Complications and interventions associated with epidural analgesia for postoperative pain relief in a tertiary care hospital. AB - INTRODUCTION: Epidural analgesia is one of the commonly used methods of postoperative pain control despite its associated complications. Early recognition and intervention is required to minimize the effect of these complications. Present audit was conducted to find out the incidence of complications and type of interventions required to change the outcome. METHODOLOGY: The record of all the patients who had epidural catheter placed for postoperative pain management reviewed from the departmental acute pain management register. Parameters included level of insertion, drugs used, number of days infusion continued and complications like nausea, vomiting, motor block, sedation, dural tap, catheter pull out, hypotension and itching. In addition, the intervention done to manage these complications was also recorded. RESULTS: Total 1706 entries of epidurals were recorded in study period 2001 to 2007. The overall incidence of the complication was 26.6%. The common complications were motor block (13.4%), dural tap (1.2%), ineffective pain control (2.4%), accidental catheter pull outs (3.8%) and problems associated with the delivery system of drug (1.7%). The 12% of patients required intervention for the particular complications. The regime was discontinued in 28%, drug concentration changed in 21.5% while the other modes of pain management were used in 19% of patients. 0.9% of patients required epidural blood patch while 2% of patients required catheterization for urinary retention. CONCLUSION: This audit shows the importance of regular assessment and early intervention to manage epidural related complications in improving outcome. PMID- 21526669 TI - Cardiovascular responses to orotracheal intubation in patients undergoing coronary artery bypass grafting surgery. Comparing fiberoptic bronchoscopy with direct laryngoscopy. AB - BACKGROUND: The intubation by using fiberoptic brochoscop (FOB) can avoid the mechanical stimulus to oropharyngolaryngeal structures thereby it is likely to attenuate hemodynamic response during orotracheal intubation. Based on this hypothesis, we compared the hemodynamic responses to orotracheal intubation using an FOB and direct laryngoscope (DLS) in patients undergoing general anesthesia for coronary artery bypass grafting (CABG) surgery. METHODS: Fifty patients with ASA physical status II and Mallampati score I and II were scheduled for elective CABG surgery under general anesthesia requiring orotracheal intubation were randomly allocated to either DLS group (n = 25) or FOB group (n = 25). The same protocol of anesthetic medications was used. Invasive systolic and diastolic blood pressure (SBP & DBP) and heart rate (HR) were recorded before and after anesthesia induction, during intubation and in the first and second minutes after intubation. The differences among the hemodynamic variables recorded over time and differences in the circulatory variables between the two study groups were compared. RESULTS: Duration of intubation was shorter in DLS group (19.3 +/- 4.7 sec) compared with FOB group (34.9 +/- 9.8 sec; p = 0.0001). In both study groups basic SBP and DBP and HR were not significantly different (P > 0.05). During the observation, there were no significant differences between the two groups in BP or HR at any time points or in their maximal values (all p values > 0.05). CONCLUSION: We conclude that the FOB had no advantage in attenuating the hemodynamic responses to orotracheal intubation in patients undergoing CABG surgery. PMID- 21526670 TI - Effects of intraoperative-intrathecal sufentanil injection on postoperative pain management after single level lumbar discectomy. AB - BACKGROUND: For lumbar disc operation a chain of painful procedures including skin incision, muscle dissection and sometimes laminectomy should be performed. The combination of these manoeuvres results in significant post-operative pain. The standard way to reduce post-operative pain consist of intra-operative injection of local anaesthetic (Bupivicaine or Lidocaine) to the superficial tissues and intravenous, oral or rectal prescription of Opioid analgesics or other analgesics after operation, but inadequate analgesia, constipation and delayed mobilisation are frequent side effect of those treatments. The goal of this study was to reduce postoperative pain of patients which causes a reduction in analgesic consumption and eventually shortened hospital stay and acceleration in physical therapy programs and ambulation. MATERIALS AND METHODS: After ethical comitte approval, patients allocated in two groups A and B. Each group consisted 30 patients which all of them underwent general anesthesia. All of operations performed by same surgeon... After discectomy and at the end of surgery based on patients odd or even number of hospital admission, one group (group-A) received sufentanil (Iranian pharmaceutic company) 0.05/kg intrathecaly injected in surgical level and the placebo group (group-B) normal saline was injected. In recovery room when patients were sufficiently awake for pain assessment, patients were asked to score pain on the verbal pain assessment score In both groups we compaired pain scores pre and postoperativly. The total dose of opioid requirement for patients and its time after operation was recorded. RESULTS: Of the 60 patients (ASA classes I and II) entering the study, no one excluded during our study. 30 patients received intrathecal injection of sufentanil as group-A or case and 30 patients normal saline as group-B or control. Mean age between two groups showed no significant difference. 45.7 year (SD = 11.5) for group-A and 44.3 year (SD = 9.9) for group-B which did not differ between two groups (P = 0.617). Urinary retension happened in 3 patients of group-A and 3 patients of group-B (P = 1). Pruritis happened in 1 patient of group-A and no patient in group-B (P = 0.15). Patients in group-A had reduced analgesic requirments (P = 0.01). Preoperative low back pain based on NPS (numerical pain scores) criteria in group-A shows score 1, (n = 7) score 2, (n = 10) score 3, (n = 11) and score 4 (n = 2) (mean = 2.2667 and SD = 0.9072). These scores in group-B showed score 2 (n = 4) score 3 (n = 16) and score 4 (n = 10) (mean = 3.2 and SD = 0.6644) (P < 0.001). After surgery low back pain assessment in two groups shows in group-A three patients had score 1, score 2, (n = 7) score 3, (n = 11) score 4, (n = 8) score 5 (n = 1) (mean = 2.9 and SD = 1.0289) and in group-B score 4 (n = 17) score 5 (n = 13) (mean = 4.4333 and SD = 0.5040) (P < 0.001). Preoperative lower extremity radicular pain assessment in two groups shows a mean pain score of 8.3 with SD = 0.9523 in group-A and a mean of 8.3448 with SD = 1.1109 in group-B and after operation a mean pain score of 1.7333 with SD = 0.8277 in group-A and a mean of 4.1667 with SD = 0.7466 in group-B. In walking ability assessments pre and postoperatively based on Mann-Whitney test it is shown that in group-A walking ability is better than group-B (P < 0.001). CONCLUSION: In this study we studied the efficacy of intraoperative-intrathecal sufentanil injection versus placebo on post operative pain management. Our study showed that intrathecal (IT) sufentanil provided more effective analgesia postoperatively after single level discectomy. Urinary retention was equal in two groups. For more exact conclusions it is better to do a similar study on more patients. PMID- 21526671 TI - The effects of duration of Propofol injection on hemodynamics. AB - OBJECTIVES: The aim of study was to see whether increasing the time of injection of standard dose of Propofol during induction can prevent fall in blood pressure in female patients; as is commonly observed with this anesthetic agent. DESIGN: Comparative, non-interventional, prospective, and randomized and single blind study. PLACE AND DURATION: The study was carried out on female in-patients admitted and surgically operated at a specialized, tertiary care hospital and was completed with in 6-months. PATIENTS AND METHODS: The hemodynamic effects of Propofol were compared in three groups of patients undergoing minor surgical procedures. Each group comprised of 25 patients. A 2 mg/kg Propofol was administered for 30, 60 and 120 seconds in patients of group-A, group-B and group C respectively. Baseline heart rate, systolic blood pressure, diastolic blood pressure and mean arterial blood pressures were recorded before induction of anesthesia. The same hemodynamic variables were recorded after induction at one minute intervals for 10-minutes. Anesthesia was maintained with 1.5% enflurane and 60% nitrous oxide in oxygen. Complications such as pain on injection, dystonic movements, erythema, laryngeal spasm, episodes of desaturation, hypoventilation and the number of additional boluses required to induce hypnosis were also recorded. RESULTS: The fall in blood pressure was statistically insignificant between the three groups of patients. The incidence of dystonic movements was the highest in group-A while pain on injection was highest in group C. Additional boluses of Propofol to induce hypnosis were required for patients in group-B and group-C. CONCLUSION: Varying the speed of injection of Propofol during induction of anesthesia in adult female patients does not cause any major difference in the drop of their heart rate, systolic blood pressure, diastolic pressure and mean arterial pressure. PMID- 21526672 TI - Continual infusion of intrathecal baclofen (ITB): long-term effect on spasticity. AB - BACKGROUND: Spasticity is a disorder of muscular function causing muscular tightness or spasm which occurs when there is damage to the central nervous system whether it is of spinal cord or brain origin. This insult could be either pathological or traumatic. METHOD: Thirty-three patients had intrathecal Baclofen pumps implanted for severe spasticity. These patients either did not respond to or tolerate oral medications. RESULTS: All patients showed significant improvement in their spasms following the procedure. Improvement was noted not only in spasticity, but also in pain, management of sleep disturbance, activities of daily living, indoor and outdoor mobility and behavior. CONCLUSION: The number of complications was acceptable, and generally were not life-threatening. Infection was the significant complication in two patients and this led to explantation of their pumps. Patient satisfaction was very high and was related to improvement in the quality of life for the patients. PMID- 21526673 TI - The video laryngoscopes blind spots and possible lingual nerve injury by the Gliderite rigid stylet--case presentation and review of literature. AB - We report the first case of near serious lingual nerve injury in an 80-y-old female caused by the Rigid GlideScope Stylet. This complication was discovered during oral surgery and may have been missed if the site of surgery was not oral cavity. PMID- 21526674 TI - Subclavian vein injury and massive hemothorax requiring thoracotomy following insertion of tunneled dialysis catheter--a case report and review of literature. AB - Tunneled dialysis catheters are widely used for hemodialysis. Large caliber dilator is used for insertion of such catheter which can result in serious vascular injury leading to haemothorax. Here we report such an inadvertent central venous injury requiring thoracotomy following blind dilator advancement along with review of literature and recommendation to prevent such complication. PMID- 21526675 TI - Cesarean section under spinal anesthesia in a patient with ankylosing spondylitis -a case report. AB - INTRODUCTION: It is generally accepted that neuraxial anesthesia is difficult to establish in patients with ankylosing spondylitis. General anesthesia also has some disadvantages, especially with respect to airway control in patients with ankylosing spondylitis. We present herein a gravida with ankylosing spondylitis who had a cesarean delivery performed under spinal anesthesia. CASE: A 30-yr-old gravida at 38 weeks gestation with a 9 yr history of ankylosing spondylitis was admitted to our hospital in labor. She was scheduled for an elective repeat cesarean delivery. Spinal anesthesia was induced using a 22-gauge Quincke spinal needle with 1.8 mL of 0.5% heavy bupivacaine + 0.2 mL (10 microg) of fentanyl at the L3-4 interspace in the left lateral position by the median approach. Adequate sensory and motor blockade were achieved. The postoperative period was uneventful and she was discharged home on postoperative day 3. CONCLUSION: We suggest that spinal anesthesia can be safely and effectively used as an alternative to general anesthesia in patients with ankylosing spondylitis. Neuraxial techniques should not be regarded as unachievable in such patients; however, all necessary precautions should be taken to avoid complications of spinal anesthesia, and facilities to secure the airway should be available. PMID- 21526676 TI - Levosimendan as a rescue adjunct in amlodipine intoxication--a case report. PMID- 21526677 TI - Successful management of high-dose metformin intoxication. Role of vasopressin in the management of severe lactic acidosis. PMID- 21526678 TI - Awake craniotomy using initial sleep with laryngeal mask airway in depressed agitated patient--a case report. AB - Depressed patients with brain tumors are often not referred to awake craniotomy because of concern of uncooperation which may increase the risk of perioperative complications. This report describes an interesting case of Awake Craniotomy for frontal lobe glioma in 41 year old woman undergoing language and motor mapping intra-operatively. As she was fearful and apprehensive and was on antidepressant therapy to control depression the author adapted general anesthesia with laryngeal mask airway during initial stage of skull pinning and craniotomy procedures. Then patient reverted to awake state to continue the intended neurosurgical procedure. Patient tolerated the situation satisfactory and was cooperative till the finish without any event. PMID- 21526679 TI - Cardiac arrhythmia after succinylcholine administration in a patient with Guillain-Barre syndrome--a case report. AB - We report a case of cardiac arrhythmia occurring in a Guillain-Barre syndrome (GBS) patient after succinylcholine administration during third endotracheal intubation, on day 13 of illness. The probable cause of arrhythmia is succinylcholine-induced hyperkalemia. Of interest, this case demonstrated in the same patient that arrhythmia only occurred during third intubation, when duration of illness is prolonged, and not during previous two intubation episodes, despite succinylcholine was also being used. In GBS, muscle denervation resulted in up regulation of acetylcholine receptors at neuromuscular junctions, causing the muscle cell membrane to become supersensitive to succinylcholine, leading to severe hyperkalemia and arrhythmia when succinylcholine was administered. PMID- 21526680 TI - Conscious sedation for awake craniotomy in intra-operative magnetic resonance imaging operating theatre (IMRI OT) environment. AB - This technical report disrobes the first case in Intra-operative Magnatic Resonance Imaging operating theatre (iMRI OT) (BrainSuite), of Awake Craniotomy. The procedure was for frontal lobe glioma excision in 24 y. old man. He was scheduled to undergo eloquent cortex language mapping intra-operatively. He was motivated and was excited to see the operating theatre. He requested to take his photos while operated upon. The authors adapted conscious sedation technique with variable depth according to Ramsey's scale, in order to revert to awake state to perform the intended neurosurgical procedure. Patient tolerated the situation satisfactory and was cooperative till the finish without any event. We elicit in this report the special environment of iMRI OT for lengthy operation in pinned fixed patient having craniotomy. The text shows the special environment, its demands and its possible difficulties. PMID- 21526681 TI - Effective awake thoracic epidural anesthetic for major abdominal surgery in two high-risk patients with severe pulmonary disease--a case report. AB - Awake thoracic epidural anaesthesia as the sole anaesthetic technique was successfully employed for two high risk surgical patients with chronic obstructive pulmonary disease undergoing abdominal surgery. The procedure was tolerated well and the anaesthetic technique which has been shown to reduce intra operative and post-operative cardiac, respiratory and gastrointestinal complications, may have significantly contributed to the prompt, complication free recovery experienced by both patients. We report two cases of awake major abdominal surgery in two high-risk surgical patients with severe pulmonary disease, performed effectively under thoracic epidural anaesthesia as a sole technique. The first case was an elective open sigmoid colectomy in a sixty one year old cancerous patient with chronic obstructive pulmonary disease [COPD] and recent thoracotomy for a wedge resection of a bronchial adenocarcinoma [pT1NoMx]. The second case was an emergency open cholecystectomy in an adult patient with end-stage COPD. Reviewing the literature, no similar cases were reported recently. PMID- 21526682 TI - Variants of pheochromocytoma and their anesthetic implications--a case report and literature review. PMID- 21526683 TI - Anesthetic management of achondroplastic dwarf undergoing cesarean section--a case report. AB - There are more than 100 different types of dwarfism. Achondroplasia is the most common of these conditions. The aim of this report is to describe the anesthetic management of these patient, discussing the anesthetic considerations and emphasizing the difficulties encountered. A 32-year-old achondroplastic parturient underwent cesarean section under general anesthesia. We did not encounter problems related with airway management. The operation went without any complication. There are risks for both regional and general anesthesia in achondroplastic patients. The most important point is the careful preoperative assessment. Anesthesia plan should be specified to individual basis. PMID- 21526684 TI - And the patients that they serve. PMID- 21526685 TI - A call to action. PMID- 21526686 TI - The NHS academic vision: training the physicians to deliver it. PMID- 21526687 TI - Variation in lung cancer outcomes in the UK and Europe. PMID- 21526688 TI - Institutional partnerships in global health. PMID- 21526689 TI - Emergency medical readmission: long-term trends and impact on mortality. AB - There is increasing emphasis on prevention of emergency medical readmissions. The broad pattern of acute medical readmissions was studied over a seven-year period and the impact of any readmission on 30-day mortality was recorded. Significant predictors of outcome, including co-morbidity and illness severity score, were entered into a multivariate regression model, adjusting the univariate estimates of the readmission status on mortality. In total, 23,114 consecutive acute medical patients were admitted between 2002-8; the overall readmission rate was 27%. Readmission independently predicted an increased 30-day mortality; the odds ratio, was 1.12 (95% confidence interval (CI) 1.09 to 1.14). This fell to 1.05 (95% CI 1.02 to 1.08) when adjusted for outcome predictors including acute illness severity. The trend for readmissions was to progressively increase over time; the median times between consecutive admissions formed an exponential time series. Efforts to reduce or avoid readmissions may depend on an ability to modify the underlying chronic disease. PMID- 21526690 TI - UK rheumatology consultant workforce provision 2007-9: results from the BSR/Arthritis Research UK Consultant Workforce Register. AB - The objective of this study was to describe the provision of consultant rheumatology services and the pattern of inequalities in UK rheumatology service provision, and to summarise the five-year impact of the new NHS consultant contract and the Musculoskeletal Services Framework in England and Wales. All consultants on the British Society for Rheumatology/Arthritis Research UK Consultant Workforce Register in January 2007 and January 2009 were sent questionnaires about timetable and working conditions and the personal and job related details currently held about them on the register. Response rates were 87% in 2007 and 86% in 2009. The number of whole-time equivalent (WTE) rheumatologists in the UK increased from 470 to 531 (13%). Levels of provision in 2009 were lower in Scotland (1 WTE per 113,286 population) than the rest of the UK. There are now few regional variations in rheumatology consultant provision within the UK, and the number of WTE consultants is approaching recommended levels. PMID- 21526691 TI - Capitalising on leadership fellowships for clinicians in the NHS. AB - Clinical leadership has become a primary focus of the NHS with many leadership programmes, particularly those aimed at junior clinicians, being developed. This article illustrates the potential of these programmes but also urges caution when assessing the success of these schemes both from an individual and organisational perspective. PMID- 21526692 TI - Implementing an interprofessional patient record. AB - This paper describes the implementation of an interprofessional patient record (IPPR) at Sheffield Teaching Hospitals NHS Foundation Trust (STHFT). The IPPR was a two-year project, commencing in May 2008, aimed at creating a single IPPR to which all staff contribute. Prior to the IPPR, records were profession specific with nursing, medical and therapy staff keeping separate ones. This paper describes the process for the project including the stakeholder engagement plan, the development of IPPR standards, the education and training programme and the key measures used to assess implementation. The staff survey and clinical audit data suggest that the IPPR was successfully implemented with many of the perceived benefits realised. The keys to success of this major change project were: time spent engaging clinical staff, board level support, the appointment of a dedicated project team and the involvement and support of many staff involved in patient records throughout STHFT. PMID- 21526694 TI - Poster presentations at medical conferences: an effective way of disseminating research? AB - This study aimed to ascertain the value of posters at medical meetings to presenters and delegates. The usefulness of posters to presenters at national and international meetings was evaluated by assessing the numbers of delegates visiting them and the reasons why they visited. Memorability of selected posters was assessed and factors influencing their appeal to expert delegates identified. At both the national and international meetings, very few delegates (< 5%) visited posters. Only a minority read them and fewer asked useful questions. Recall of content was so poor that it prevented identification of factors improving their memorability. Factors increasing posters' visual appeal included their scientific content, pictures/graphs and limited use of words. Few delegates visit posters and those doing so recall little of their content. To engage their audience, researchers should design visually appealing posters by presenting high quality data in pictures or graphs without an excess of words. PMID- 21526693 TI - Helping the general physician to improve outcomes after PEG insertion: how we changed our practice. AB - During their careers, most general physicians are involved in the decision-making process for patients that potentially require percutaneous endoscopic gastrostomy (PEG) insertion. However, poor patient selection and less than favourable outcomes are frequently observed in this group. With the aim of identifying and addressing the underlying issues, the PEG service at University Hospital Llandough was radically changed over an eight-year period. The development of a nurse-led pre-assessment service and design of a specific referral form was successful in reducing the number of PEG referrals and consequently the 30-day mortality rate. Furthermore, the educational and training needs of general physicians of all grades regarding the issues surrounding PEG placement were identified and addressed at formal teaching sessions. A combination of these factors has positively impacted on our service, with more appropriate patient selection and a reduced 30-day mortality rate. PMID- 21526695 TI - Engaging trainees in shaping the future of health policy. AB - This paper presents an analysis of the views and ideas generated at a recent health policy discussion for doctors in training. This provides an illustration of the creativity and enthusiasm that trainees can bring to the policy sphere by providing unique insights and a fresh perspective. PMID- 21526696 TI - National pilot audit of intermediate care. AB - The National Service Framework for Older People resulted in the widespread introduction of intermediate care (IC) services. However, although these services have shared common aims, there has been considerable diversity in their staffing, organisation and delivery. Concerns have been raised regarding the clinical governance of IC with a paucity of data to evaluate the effectiveness, quality and safety of these services. This paper presents the results of a national pilot audit of IC services focusing particularly on clinical governance issues. The results confirm these concerns and provide support for a larger scale national audit of IC services to monitor and improve care quality. PMID- 21526697 TI - Non-invasive ventilation: established and expanding roles. AB - Non-invasive ventilation (NIV) has become the standard of care for most patients with ventilatory failure due to an acute exacerbation of chronic obstructive pulmonary disease (COPD). In all but a small minority, even of the very sickest, there is little to be lost by at least a short trial of NIV. In patients with acute cardiogenic pulmonary oedema, NIV results in a more rapid physiological improvement and resolution of dyspnoea, but the benefits in terms of survival have been called into question by two recent randomised controlled trials. There are no randomised controlled trials of NIV in patients with acute ventilatory failure due to obesity but the outcome from invasive ventilation is poor and the results of NIV encouraging. Finally, NIV may have a role during the transition from active care, aimed to extend life, to palliative care. PMID- 21526698 TI - Management of diabetic ketoacidosis. PMID- 21526699 TI - How do I manage a patient with suspected acute pulmonary embolism? AB - Acute PE is a cardiovascular emergency and early risk stratification is important in the management of these patients. Pre-test clinical prediction models together with D-dimer assays help select those who require imaging. Each hospital should develop a strategy for investigating patients with suspected PE depending on local expertise, resources and the patient population. PMID- 21526700 TI - Neurological aspects of falls in older adults. PMID- 21526701 TI - Normal pressure hydrocephalus (NPH): more about NPH by a physician who is the patient. AB - The incidence of idiopathic normal pressure hydrocephalus (INPH) is seen to be relatively rare, ie about two per million inhabitants per year. Five studies on the prevalence of INPH in elderly patients, from three countries, have been published between 1985 and 2009.1-5 Prevalence ranged from 0.41% to 2.94% (mean 0.8%), ie slightly less than one per 100 based on samples ranging from 170 to 982 subjects. This surprisingly high percentage was not found in a survey that attempted to identify every person with INPH in a small county in Norway with a population of 219,748. Attempts to identify all patients with INPH overlook many cases. INPH is actually a very common disease and its prevalence increases with age. PMID- 21526702 TI - Geriatrics. PMID- 21526703 TI - Growing up in ageing. PMID- 21526704 TI - Sarcopenia and some simple approaches to modifying the consequence of ageing. PMID- 21526705 TI - Yew tree poisoning: a near-fatal lesson from history. PMID- 21526706 TI - Non-alcoholic fatty liver disease: a massive problem. PMID- 21526707 TI - Pathogenesis and treatment of hepatic fibrosis: is cirrhosis reversible? PMID- 21526708 TI - Therapy for chronic viral hepatitis: current indications, optimal therapies and delivery of care. PMID- 21526709 TI - Managing alcohol dependence and alcohol-related liver disease: a problem for the hepatologist, psychiatrist or economist? PMID- 21526710 TI - Liver transplantation: filling the gap between supply and demand. PMID- 21526711 TI - Lesson of the month (1). Ictal asystole due to unsuspected cocaine abuse. AB - This lesson describes a patient who had a cardiac arrest during an episode of status epilepticus provoked by a first fit. This is an exceptional sequence of events and should lead to investigation for an underlying cause. Unsuspected cocaine abuse is common and may provoke prolonged status epilepticus, particularly if there is a low seizure threshold. A toxic screen should be undertaken in all patients presenting with unexplained status epilepticus even if abuse of illicit substances is denied. PMID- 21526712 TI - Lesson of the month (2). Angina without 'strangling and anxiety of the breast'. AB - Frequently patients with coronary artery disease (CAD) present with chest pain. Anginal equivalents such as dyspnoea and fatigue, or radiation of pain to the neck, jaw and arm, are also well described. Absence of chest pain with chronic left arm and neck pain is more unusual but demonstrates the heterogeneity of presentation. CAD should be considered in those anginal equivalents in the absence of 'strangling and anxiety of the breast'. PMID- 21526713 TI - Conversations with Charles. PMID- 21526714 TI - Early intervention can influence an outcome--time to introduce an alert system for all cancer patients? PMID- 21526715 TI - The preference of general practitioners for structured outpatient clinic letters. PMID- 21526716 TI - Reversible epigenetic modifications of the two cardiac myosin heavy chain genes during changes in expression. AB - The two genes of the cardiac myosin heavy chain (MHC) locus-alpha-MHC (aMHC) and beta-MHC (bMHC)--are reciprocally regulated in the mouse ventricle during development and in adult conditions such as hypothyroidism and pathological cardiac hypertrophy. Their expressions are under the control of thyroid hormone T3 levels. To gain insights into the epigenetic mechanisms that underlie this inducible and reversible switching of the aMHC and bMHC isoforms, we have investigated the histone modification patterns that occur over the two cardiac MHC promoters during T3-mediated reversible switching of gene expression. Mice fed a diet of propylthiouracil (PTU, an inhibitor of T3 synthesis) for 2 weeks dramatically reduce aMHC mRNA expression and increase bMHC mRNA levels to high levels, while a subsequent withdrawal of PTU diet for 2 weeks completely reverses the T3-mediated changes in MHC expression. Using hearts from mice treated in this way, we carried out chromatin immunoprecipitation-qPCR assays with antibodies against acetylated histone H3 (H3ac) and trimethylated histone (H3K4me3)-two well documented markers of activation. Our results show that the reexpression of bMHC is associated at the bMHC promoter with increased H3ac but not H3K4me3. In contrast, the silencing of aMHC is associated at its promoter with decreased H3K4me3, but not decreased H3ac. The epigenetic changes at the two MHC promoters are completely reversed when the gene expression returns to initial levels. These data indicate that during reciprocal and inducible gene expression H3ac parallels bMHC isoform expression while H3K4me3 parallels expression of the tightly linked aMHC isoform. PMID- 21526717 TI - Differential allelic distribution of V-ets erythroblastosis virus E26 oncogene homolog2 (ETS2) functional polymorphisms in different group of patients. AB - V-ets erythroblastosis virus E26 oncogene homolog2 (ETS2), located at chromosome 21 and overexpressed in Down's syndrome (DS), has known cancer regulatory functions. Because leukemia is of common occurrence in DS subjects while solid tumors are rare, we have explored the role of ETS2 functional genetic polymorphisms in this differential oncological development. In silico methods were used for identifying deleterious SNPs, tagged SNPs, and linkage disequilibrium followed by genotyping of 14 SNPs in Indo-Caucasoid individuals (N=668). Significantly different allelic frequencies for rs457705, rs1051420, and rs1051425 were observed in Indian controls (N=149) compared to other ethnic groups. A heterozygous "T" insertion, between chromosomal contig positions 40195541 and 40195542, was observed in DS subjects and their parents. rs461155 showed significant allelic and genotypic association in breast and oral cancer patients. Significantly higher occurrence of G-C haplotype (rs461155-rs1051425) was also observed in these patients compared to DS and leukemic patients. This is the first report on this type of allelic discrimination pattern of ETS2 under different disease conditions. From the data obtained it may be proposed that allelic discrimination of deleterious SNPs in ETS2 may play a regulatory role in the differential development of malignancy in DS subjects. PMID- 21526718 TI - RNAi silenced Dd-grp94 (Dictyostelium discoideum glucose-regulated protein 94 kDa) cell lines in Dictyostelium exhibit marked reduction in growth rate and delay in development. AB - Glucose-regulated 94 kDa protein (Grp94) is a resident of the endoplasmic reticulum (ER) of multicellular eukaryotes. It is a constitutively expressed protein that is overexpressed in certain abnormal conditions of the cell such as depletion of glucose and calcium, and low oxygen and pH. The protein is also implicated in diseased conditions like cancer and Alzheimer's disease. In this study, the consequences of downregulation of Grp94 were investigated at both unicellular and multicellular stages of Dictyostelium discoideum. Previous studies have shown the expression of Dd-Grp94 (Dictyostelium discoideum glucose regulated 94 kDa protein) in wild-type cells varies during development, and overexpression of Dd-Grp94 leads to abnormal cell shape and inhibition of development (i.e., formation of fruiting bodies). Grp94 is a known calcium binding protein and an efficient calcium buffer. Therefore, in the present study we hypothesized that downregulation of Dd-Grp94 protein would affect Dictyostelium cell structure, growth, and development. We found that Dd-grp94 RNAi recombinants exhibited reduced growth rate, cell size, and a subtle change in cell motility compared to the parental cells. The recombinants also exhibited a delay in development and small fruiting bodies. These results establish that Dd grp94 plays a crucial role in determining normal cell structure, growth and differentiation. PMID- 21526720 TI - Pediatric dentists and unaccompanied children in operatories. PMID- 21526721 TI - Doesn't buy 'dental home' idea. PMID- 21526722 TI - Our MDA dental PAC dollars at work. PMID- 21526719 TI - Intronic DNA elements regulate androgen-dependent expression of the murine Nkx3.1 gene. AB - Nkx3.1 is a well-conserved homeobox gene that is involved in development, differentiation and maintenance of prostate epithelial cells. Nkx3.1 expression is induced by androgen in prostate epithelia and, as such, our interest is to understand the mechanism(s) for this androgen-dependent expression in normal epithelial cells. In this report, we show that the region of DNA sequence 2.7 kilobases in front of the mouse Nkx3.1 gene drives enhanced transcription in prostate epithelia cells; however, this segment was not capable of androgen directed regulation. Among the multiple, potential androgen response elements (AREs) identified by scanning sequences near and within the gene, two sequences within the intron of the murine Nkx3.1 gene were demonstrated to confer androgen dependent transcription in reporter gene transfection experiments. Each of the elements, termed ARE A and ARE B, contained a 6-base pair core sequence, TGTTCT, that has been described as an androgen receptor half-site binding sequence, separated by 498 base pairs of DNA. Both of the intronic half-sites bind activated androgen receptor from a variety of sources, albeit with different apparent affinities. This region of the Nkx3.1 gene demonstrates a high degree of conservation among diverse species and mutagenesis experiments demonstrated that both elements are required for androgen stimulation. Taken together, our study shows that androgen-dependent transcription of the mouse Nkx3.1 gene is conferred through a noncanonical element within the intron of the gene. PMID- 21526723 TI - Patient abandonment issues when your employer closes the practice. PMID- 21526724 TI - Let's support the ADA's health screening program. PMID- 21526725 TI - Note to staff: a sick day is still an absence. PMID- 21526726 TI - 'Amalgam-free' dental practices: are they ethical? PMID- 21526727 TI - It's wise to understand the basics of life insurance. PMID- 21526728 TI - Just say 'no' to naysayers. PMID- 21526729 TI - Cone-beam computed tomography: strengths, weaknesses, and controversies. PMID- 21526730 TI - Why I belong to both the ADA and the AGD. PMID- 21526731 TI - Doxycycline-induced dizziness in a dental patient. AB - Many dentists are unaware of the documented adverse drug reaction of doxycycline induced dizziness. Because doxycycline is frequently prescribed in dentistry, it is important for dentists and patients to be aware of this significant adverse reaction to prevent medical complications. A clinical case is reported in which a patient developed dizziness after taking doxycycline that was prescribed following periodontal surgery. The dizziness resolved when the doxycycline was stopped. Patients and dentists should be educated to recognize the signs and symptoms of doxycycline's adverse reactions. PMID- 21526732 TI - A brief history of equine private practice in South Africa. AB - Horse breeding in South Africa started in 1652, shortly after the 1st European settlement in the Cape. African horsesickness posed a serious problem and after a devastating outbreak of the disease in 1719, horses were largely replaced by oxen for agricultural and transport purposes but remained important from a sporting and military point of view. Examples of the latter are the export of horses for military use to India in the mid-19th century and for use in the Crimean War in 1854, reaching a zenith in the Anglo-Boer war in which an estimated 450 000 horses succumbed. Research and disease control and initially also health services were the responsibility of state veterinary authorities. Private equine practice was pioneered by Jack Boswell in the late 1930s, mainly involving race horses and Thoroughbred studs as part of a general practice. Specialised equine private practices were only initiated 10 years later and developed further during the 2nd half of the 20th century. These developments are described in some detail, including resumes of the veterinarians involved, clinical challenges encountered, scientific advances as well as developments in the equine industry with the emphasis on Thoroughbreds and the racing community. The regulatory environment, especially regarding the import and export of horses, and the role of various organisations and associations are also briefly discussed. PMID- 21526733 TI - Summary of foot-and-mouth disease outbreaks reported in and around the Kruger National Park, South Africa, between 1970 and 2009. AB - Information with regard to foot-and-mouth disease (FMD) outbreaks that occurred in the Kruger National Park (KNP) and adjacent areas of South Africa between 1970 and 2009 was collected from reports and files of various government departments and collated into one report. The collected data were summarised in a table and assessed for patterns. Fifty-one FMD outbreaks occurred during this period in the target area, of which 16 were SAT 1, 31 were SAT 2,4 were SAT 3 and 3 were not serotyped. No pattern could be discerned although SAT 1 outbreaks occurred more frequently in the summer months while more SAT 2 outbreaks occurred in winter. PMID- 21526734 TI - Rabies in the Eastern Cape Province of South Africa--where are we going wrong? AB - Rabies is a growing problem in the Eastern Cape Province of South Africa. This study investigated dog ecology, vaccination coverage and rabies neutralising antibody levels in 203 randomly selected dogs within a local municipality in the former Transkei area. Responses to vaccination were also evaluated in 80 of these dogs. The population was remarkably uniform in size, breed and condition. Slightly over 1/5th of the population was between 6 weeks and 1 year of age, while very few dogs reached 10 years or older. According to owner responses, the Animal Health Technicians achieved a total vaccination coverage of 65% of owned dogs over several years, but only 56% within the previous 12 months. Only 32% of dogs had adequate circulating rabies virus neutralisation antibodies (> or = 0.5IU/l). After vaccination, 83% had seroconverted to this level. The magnitude of seroconversion was independent of body condition or age. This study proposes a different approach to vaccination strategies than those currently employed in certain areas of the province. PMID- 21526735 TI - The impact of ultrasound during emergency after-hour admissions of horses. AB - Clinical use of diagnostic ultrasound at point-of-care or emergency situations, although common, has not been well documented in veterinary medicine. Medical records of after-hour emergency equine admissions during a 10-year period were reviewed and horses that received ultrasound scans were identified. Data sheets for each ultrasound scan performed during emergency clinical evaluation were collected and reviewed. Data extracted included anatomical region imaged, body system affected, documented ultrasonographic diagnosis and final diagnosis. Six hundred and nine records were available of which 108 horses had an ultrasound diagnostic procedure performed. The most common reason for emergency ultrasonography was to investigate gastrointestinal abnormalities, the largest proportion of these being large intestinal disorders. A complete ultrasound report was documented in 57% of evaluations, of which 79% correlated with a final diagnosis. Incomplete reporting made accurate interpretation of records difficult. Results indicate that the use of ultrasound in the emergency setting may be of diagnostic benefit and impact on patient management. Ultrasound training should be provided to residents in order to gain proficiency, especially with regard to the gastrointestinal system. PMID- 21526736 TI - Prevalence of mixed Trypanosoma congolense infections in livestock and tsetse in KwaZulu-Natal, South Africa. AB - Trypanosoma congolense causes the most economically important animal trypanosomosis in Africa. In South Africa, a rinderpest pandemic of the 1890s removed many host animals, resulting in the near-eradication of most tsetse species. Further suppression was achieved through spraying with dichlorodiphenyltrichloroethane (DDT); however, residual populations of Glossina austeni and G. brevipalpis remained in isolated pockets. A total of 506 of these tsetse flies were captured in the Hluhluwe-iMfolozi Park, the St Lucia Wetland Park and Boomerang commercial farm. The polymerase chain reaction (PCR) was used to determine the infection rate and frequency of mixed infections of these flies. Additionally, 473 blood samples were collected from cattle at communal diptanks and a commercial farm in the area and each one examined by the haematocrit centrifugation technique (HCT). Furthermore, buffy coats from these blood samples were spotted onto FTA Elute cards and the DNA extracted from each one tested using 3 separate PCRs. The HCT revealed the presence of trypanosomes in only 6.6% of the blood samples; by contrast, species-specific PCR detected trypanosome DNA in 50% of the samples. The species-specific PCR detected trypanosome DNA in 17% of the tsetse flies, compared with the nested PCR targeting rDNA which detected trypanosome DNA in only 14% of the samples. Over time, the transmission of Savannah-type T. congolense and Kilifi-type T. congolense as mixed infections could have an impact on disease manifestation in different hosts in the area. PMID- 21526737 TI - Comparison of the effects of different transport conditions and lairage times in a Mediterranean climate in South Africa on the meat quality of commercially crossbred Large white x Landrace pigs. AB - Information on the effect of road transportation conditions and lairage times on the meat quality of pork under South African conditions is very sparse. In this investigation, the effects of 2 road conditions (rough road with frequent stops - A; smooth road, few stops - B) and 2 lairage holding periods (2 h and 24 h) on the physical meat quality attributes of commercially produced pigs during summer (ambient temperatures > 30 degrees C) in the Western Cape (South Africa) were investigated. Pig meat from pigs transported on a road that caused more stress (A), had lower pH 45 (measured 45 min post mortem) values after 2 h lairage than pigs transported over a smoother road. Pigs B had a lower muscle pH 24 (measured 24 h post mortem) than group A, indicating that they had more glycogen reserves available for post mortem glycolysis. Road conditions A were more stressful resulting in a higher incidence of PSE pork, as shown by the percentage drip loss and the L* values. When the lairage period was increased to 24 h prior to slaughter, pigs transported under road conditions A had time to replenish their energy reserves and the pH 45, drip loss and L* values were within an acceptable range. However, pigs transported under road conditions B had lower pH 45 and higher pH 24 values, indicating that the lairage period was too long and that energy reserves were depleted in order to adapt to the stressful conditions. Results from this investigation indicate that improvement of the transport/road conditions will result in better pork quality. PMID- 21526738 TI - Antimicrobial susceptibility in thermophilic Campylobacter species isolated from pigs and chickens in South Africa. AB - Campylobacter jejuni is one of the leading causes of sporadic food-borne bacterial disease in humans. In intensive poultry and pig rearing systems the use of oral antibiotics is essential to maintain health. Consequently, there is a high risk for the thermophilic Campylobacter jejuni and C. coli resident in the intestinal tract of food animals to develop resistance to commonly used antibiotics. Contamination of meat or eggs with pathogenic strains of resistant Campylobacter could, therefore, result in a form of campylobacteriosis in humans that is difficult to treat. The aim of this investigation was to determine the antimicrobial susceptibility of thermophilic Campylobacter spp. isolated from pigs and poultry by the broth microdilution minimum inhibitory concentration (MIC) test. A total of 482 samples from the Western Cape and Gauteng provinces was collected and analysed. Thirty-eight Campylobacter isolates were obtained. Analysis of data revealed that C. jejuni strains mainly of poultry origin were more resistant to the fluoroquinolones, macrolides and tetracyclines and the C. coli strains were more resistant to the macrolides and lincosamides. Multi resistance was also detected in 4 Campylobacter strains from the Western Cape. With the exception of tetracyclines, strains from high health Gauteng broiler farms were susceptible to antibiotics used to treat Campylobacter infections. PMID- 21526739 TI - Tick communities at the expanding wildlife/cattle interface in the Eastern Cape Province, South Africa: implications for Corridor disease. AB - Corridor disease, transmitted by the brown ear tick (Rhipicephalus appendiculatus), is one of Africa's most pathogenic tick-borne diseases for cattle. With a focus on this species, we investigated the community parameters (richness, diversity and abundance) of ticks in the Eastern Cape, South Africa, and how this may be linked to the increasing wildlife/cattle interface in the region. There were significantly more ticks of a greater diversity and richness at sites positioned at the wildlife/cattle interface ('treatment sites') compared to sites where wildlife was absent (controls). Significantly, R. appendiculatus was only found at the treatment sites. Therefore, it is believed that the wildlife/cattle interface may be playing a crucial role in increasing the occurrence, abundance and distribution of R. appendiculatus in the Eastern Cape. The implications of a Corridor disease outbreak in the region are discussed. PMID- 21526740 TI - Risk factors for smallholder dairy cattle mortality in Tanzania. AB - A retrospective cross-sectional study of mortality was conducted on smallholder dairy farms in 2 separate regions (Iringa and Tanga) of Tanzania during the period of January to April 1999. A total of 1789 cattle from 400 randomly sampled smallholder dairy farms (200 each from Iringa and Tanga regions) were included in the study. These animals contributed a total risk period of 690.4 and 653.95 years for Tanga and Iringa, respectively. The overall mortality rates were estimated to be 8.5 and 14.2 per 100 cattle years risk for Tanga and Iringa regions, respectively; 57.7% of the reported deaths were of young stock less than 12 months old; 45% of reported young stock deaths (< or = 12 months old) were due to tickborne diseases, mainly East Coast Fever (ECF) and anaplasmosis. Disease events including ECF were reported to occur in all months of the year. Survival analysis using Cox proportional hazard models indicated that, in both regions, death rate and risk was higher in young stock less than 12 months than in older animals (relative risk RR = 4.92, P < 0.001 for Iringa; RR = 5.03 P = 0.005 for Tanga). In the Tanga region reported mortality rates were significantly higher for male animals (RR = 3.66, P = 0.001) and F2 compared with F1 animals (RR = 3.04, P = 0.003). In the Iringa region, reported mortality rates were lower for cattle on farms where the owner had attended a dairy development project training course (RR = 0.47, P = 0.012). Farms located in Iringa urban district and Pangani were associated with higher risk (mortality risk 21% for Iringa urban and 34% for Pangani). Our findings suggest that timely health and management interventions on these factors are necessary to alleviate losses from disease and emphasise that understanding variation in mortality risk within a population can enhance early response to potential outbreaks, reducing losses. PMID- 21526741 TI - Macroscopic description of the coronary arteries in Swiss albino mice (Mus musculus). AB - A total of 25 (13 male, 12 female) adult, healthy Swiss albino mice were used to investigate the origin, course and anastomoses of coronary arteries. Coloured latex was injected into the aortic arch to enable these arteries to be clearly discerned. A. coronaria sinistra was larger than A. coronaria dextra. It was divided into a Ramus interventricularis paraconalis and a Ramus circumflexus sinister. However, in 2 specimens, the septal ramus, was observed to stem directly from the left coronary artery, and only 1 ventricular branch arose from the left circumflex. The collateral branches of the paraconal interventricular ramus had a larger diameter and more extensive distribution was observed in these specimens. The A. coronaria dextra was divided into a Ramus septalis and Ramus circumflexus dexter. The Ramus interventricularis subsinuosis was not detected in this study. The ventricular branches of the left coronary artery run intramyocardially whereas the branches of the right coronary artery course subendocardially. PMID- 21526742 TI - Steroid-sparing effect of mycophenolate mofetil in the treatment of a subepidermal blistering autoimmune disease in a dog. AB - A 7-year-old female Cocker spaniel-cross was referred with an 8-month history of mucocutaneous erosive dermatitis. On physical examination, skin lesions affected the eyelids and periocular area, lips and vulva. Lesions were symmetrical with small diffuse superficial ulcers, haemorrhagic crusts, adherent purulent exudation in haired skin, and alopecia with hyperpigmentation and scarring. Histopathologic evaluation showed multiple, non-intact dermoepidermal junction vesicles and ulceration associated with a dermal lichenoid infiltrate. Immunohistochemistry showed strong to moderate reactivity in the dermoepidermal junction for the antibodies directed against canine IgG, human IgG lambda light chains and C3, respectively. A diagnosis of autoimmune subepidermal blistering dermatosis was made. Treatment with oral prednisone at 2 mg/kg and mycophenolate mofetil (MMF) at 20 mg/kg twice daily was initiated and after 4 weeks the ulcers and erosions were cured. During the rest of treatment, MMF was maintained at 10 mg/kg twice daily and prednisone could be tapered to 0.25 mg/kg once every other day without recurrences. In conclusion, this case report shows that MMF was well tolerated and might be effective as steroid-sparing agent in the long-term treatment of this autoimmune subepidermal blistering disease. PMID- 21526743 TI - Infiltrative angiolipoma of the parotid salivary gland in a dog. AB - Solitary benign angiolipoma and infiltrative angiolipoma are rare tumours in dogs. Angiolipomata can be distinguished histologically from lipomata by the large number of tightly packed blood vessels seen between the adipocytes with multiple fibrin thrombi occupying some of the vessels' lumens. The dog presented with a solitary slow-growing mass in the cervical region. Histopathology revealed multifocal to coalescing single or clusters of blood-filled vessels lined by flattened endothelial cells with narrow, elongated, basophilic nuclei. These regions were embedded in adipose tissue with multifocal areas of intervascular remnants of differentiated serous salivary glandular tissue with multifocal small ducts. Fibrin thrombi occupied a few of the vessel lumens. A histological diagnosis of infiltrative angiolipoma was made. On computed tomography, the mass was bilobed with a suspected primary component involving the right parotid gland which was grossly enlarged. The mass had a slightly hypoattenuating mottled to lobulated appearance with a few hyperattenuating mineralised specks throughout. Hounsfield units of the mass ranged between 40 and 45, which was less than the 60 65 of the contralateral salivary glands and cranial musculature. Post contrast images showed no contrast enhancement of 90% of the mass with only a band of peripheral contrast uptake of the affected lateral lobe. PMID- 21526745 TI - Structural correspondence between uranyl chloride complexes in solution and their stability constants. AB - Pair-distribution functions (PDF)s were obtained from high-energy X-ray scattering (HEXS) data on a series of uranyl solutions as a function of chloride ion concentration. Analyses reveal that chloride forms only inner-sphere complexes with the uranyl, replacing inner-sphere waters such that the total uranyl coordination number decreases from 4.7 waters at [Cl(-)] = 0 m to 4.4 (1.7 water and 2.7 Cl(-)) at [Cl(-)] = 6.8 m. Some of the second-coordination sphere waters reorient upon uranyl inner-sphere chloride complexation in order to hydrogen bond with the bound anion. Similar data obtained on a series of solutions maintained at constant ionic strength are used to confirm structural assignments through determining stability constants for the addition of chloride to uranyl and comparison with published values. The stability constants, beta(1) = 1.5(10) m(-1), beta(2) = 0.8(4) m(-2), and beta(3) = 0.4(1) m(-3), obtained in a series of solutions with constant ionic strength of 5.3 m, are in reasonable agreement with previously published results determined by solvent extraction. The agreement of stability constants supports our peak assignments for the PDF and thus our structural model for uranyl chloride complexes in solution. Using coordination numbers and speciation determined here as a function of chloride ion concentration, the monochloro species is found to have four coordinating waters in the uranyl equatorial plane, the dichoro species is found to be an equilibrium of three and two coordinating waters, and the trichloro species has only a single water in the equatorial plane. These values correspond to total average coordination numbers of 5, 4.3, and 4 for the mono-, di-, and trichlorouranyl complexes. From the equilibrium value of the dichloro species, it can be further estimated that DeltaG = -0.5 kcal/mol for the conversion of five to four coordinate species. Overall, the HEXS data support the assertion that uranyl chloride correlations do exist and the results are not simply the result of solvent-ion effects. PMID- 21526746 TI - Supra-supra, supra-antara, and stepwise-diradical pathways for an observed 16 electron double-[4 + 4] cycloaddition within metal-templated dialkyne dimers (PtX2)2(MU-R2PCCCCPR2)2. AB - Quantum chemistry calculations are used to provide insight into the cycloaddition of two dialkyne chains in initially monocyclic organoplatinum dimers of the type (PtX(2))(2)(MU-R(2)PC(4)PR(2))(2), where X = Cl or Me and R = Ph or Me. Previous experimental studies showed that the cycloaddition occurs with {X, R} = {Cl, Ph} but not {Me, Ph}. Two concerted pericyclic paths, a D(2h)-symmetry double [pi4s+pi4s] "Huckel path" and a D(2)-symmetry double-[pi4s+pi4a] "Mobius path", were explored via orbital energy correlation diagrams (OECDs) computed using a singly occupied molecular orbital technique developed earlier. In accord with pericyclic reaction theory, the 16e(-) rearrangement is forbidden along the D(2h) Huckel path; four electrons would need to change their orbital symmetries. The D(2) Mobius path, afforded by the natural twist in the reactant structure which allows the desired Mobius orbital connectivity for a 4n rearrangement, is concluded to be a borderline forbidden pathway. This Mobius path creates avoided crossings in the OECD, which allows consistent orbital populations throughout the reaction, but it does not cause a change in intended orbital correlation, and the predicted activation barrier is rather high (~50 kcal mol(-1)). The avoided crossings show strong coupling, but a clear HOMO-LUMO gap for the reaction is not produced. A stepwise path is also presented, with evidence of its diradical character. PMID- 21526744 TI - Structure of even/odd trinucleotide repeat sequences modulates persistence of non B conformations and conversion to duplex. AB - Expansion of trinucleotide repeats (TNR) has been implicated in the emergence of neurodegenerative diseases. Formation of non-B conformations such as hairpins by these repeat sequences during DNA replication and/or repair has been proposed as a contributing factor to expansion. In this work we employed a combination of fluorescence, chemical probing, optical melting, and gel shift assays to characterize the structure of a series of (CTG)(n) sequences and the kinetic parameters describing their interaction with a complementary sequence. Our structure-based experiments using chemical probing reveal that sequences containing an even or odd number of CTG repeats adopt stem-loop hairpins that differ from one another by the absence or presence of a stem overhang. Furthermore, we find that this structural difference dictates the rate at which the TNR hairpins convert to duplex with a complementary CAG sequence. Indeed, the rate constant describing conversion to (CAG)(10)/(CTG)(n) duplex is slower for sequences containing an even number of CTG repeats than for sequences containing an odd number of repeats. Thus, when both the CAG and CTG hairpins have an even number of the repeats, they display a longer lifetime relative to when the CTG hairpin has an odd number of repeats. The difference in lifetimes observed for these TNR hairpins has implications toward their persistence during DNA replication or repair events and could influence their predisposition toward expansion. Taken together, these results contribute to our understanding of trinucleotide repeats and the factors that regulate persistence of hairpins in these repetitive sequences and conversion to canonical duplex. PMID- 21526747 TI - Modeling reaction pathways of low energy particle deposition on polymer surfaces via first principle calculations. AB - The chemical processes that lead to polystyrene surface modification via low energy deposition of C(2)H(+), C(2)F(+), CH(2), CH(2)(+), and H(+) radicals and ions are examined using first principles calculations. Specifically, the reaction mechanisms responsible for products identified in classical molecular dynamics with reactive empirical bond-order potentials are examined using density functional theory. In addition, these calculations consider how the presence of charges on the incident particles changes the result for the CH(2) system through the comparison of barriers, transition states, and final products for CH(2) and CH(2)(+). The structures of the reaction species and energy barriers are determined using the B3LYP hybrid functional. Finally, CCSD/6-31G(d,p) single point energy calculations are carried out to obtain optimized energy barriers. The results indicate that the large variety of reactions occurring on the polystyrene surface are a consequence of complex interactions between the substrate and the deposited particles, which can easily be identified and characterized using advanced computational methodologies, such as first principle calculations. PMID- 21526748 TI - Hydrolases in the stereoselective synthesis of N-heterocyclic amines and amino acid derivatives. PMID- 21526749 TI - Leukotriene receptors. PMID- 21526750 TI - Probing structural differences between PrP(C) and PrP(Sc) by surface nitration and acetylation: evidence of conformational change in the C-terminus. AB - We used two chemical modifiers, tetranitromethane (TNM) and acetic anhydride (Ac(2)O), which specifically target accessible tyrosine and lysine residues, respectively, to modify recombinant Syrian hamster PrP(90-231) [rSHaPrP(90-231)] and SHaPrP 27-30, the proteinase K-resistant core of PrP(Sc) isolated from brain of scrapie-infected Syrian hamsters. Our aim was to find locations of conformational change. Modified proteins were subjected to in-gel proteolytic digestion with trypsin or chymotrypsin and subsequent analysis by mass spectrometry (MALDI-TOF). Several differences in chemical reactivity were observed. With TNM, the most conspicuous reactivity difference seen involves peptide E(221)-R(229) (containing Y(225) and Y(226)), which in rSHaPrP(90-231) was much more extensively modified than in SHaPrP 27-30; peptide H(111)-R(136), containing Y(128), was also more modified in rSHaPrP(90-231). Conversely, peptides Y(149)-R(151), Y(157)-R(164), and R(151)-Y(162) suffered more extensive modification in SHaPrP 27-30. Acetic anhydride modified very extensively peptide G(90)-K(106), containing K(101), K(104), K(106), and the amino terminus, in both rSHaPrP(90-231) and SHaPrP 27-30. These results suggest that (1) SHaPrP 27-30 exhibits important conformational differences in the C-terminal region with respect to rSHaPrP(90-231), resulting in the loss of solvent accessibility of Y(225) and Y(226), very solvent-exposed in the latter conformation; because other results suggest preservation of the two C-terminal helices, this might mean that these are tightly packed in SHaPrP 27-30. (2) On the other hand, tyrosines contained in the stretch spanning approximately Y(149)-R(164) are more accessible in SHaPrP 27-30, suggesting rearrangements in alpha-helix H1 and the short beta sheet of rSHaPrP(90-231). (3) The amino-terminal region of SHaPrP 27-30 is very accessible. These data should help in the validation and construction of structural models of PrP(Sc). PMID- 21526751 TI - Neurotoxicity of silica nanoparticles: brain localization and dopaminergic neurons damage pathways. AB - Silica nanoparticles (SiO(2)-NPs) are being used increasingly in diagnosis, imaging, and drug delivery for the central nervous system. However, to date, little is known concerning the potential adverse effects on the brain associated with exposure to SiO(2)-NPs. The present study was conducted to trace, locate, and quantify SiO(2)-NPs in the brain by a radiolabeling approach after intranasal instillation with SiO(2)-NPs. The oxidative stress, inflammatory response, and levels of neurochemicals in the brain were also analyzed. Furthermore, in vitro studies were carried out to elucidate the pathway and mechanism of in vivo damage with a co-incubation model of dopaminergic neuron PC12 and SiO(2)-NPs. The results indicated that SiO(2)-NPs via intranasal instillation entered into the brain and especially deposited in the striatum. Exposure to SiO(2)-NPs also induced oxidative damage and an increased inflammatory response in the striatum. Meanwhile, results of in vitro studies demonstrated that exposure to SiO(2)-NPs decreased cell viability, increased levels of lactate dehydrogenase, triggered oxidative stress, disturbed cell cycle, induced apoptosis, and activated the p53 mediated signaling pathway. In addition, the in vivo injury of neurochemicals occurred as the SiO(2)-NPs appeared to induce depleted dopamine in the striatum, and the down-regulation of tyrosine hydroxylase protein was the main contribution. These data demonstrate that SiO(2)-NPs possibly have a negative impact on the striatum and dopaminergic neurons as well as a potential risk for neurodegenerative diseases. There is potential concern with SiO(2)-NPs' neurotoxicity in biomedical applications and occupational exposure in large-scale production. PMID- 21526752 TI - A serendipitous synthesis of (+)-gregatin B, second structure revisions of the aspertetronins, gregatins, and graminin A, structure revision of the penicilliols. AB - A (DHQN)(2)AQN-promoted asymmetric dihydroxylation (92% ee) of the allyl chloride derived from enynol (E)-13 and an 8-step sequence provided access to the hydroxyethylated furanone (R)-21. Oxidation with MnO(2) furnished 50% furanone (+)-(R)-2a and 2.7% isomeric furanone (+)-(R)-3a. (R)-2a possesses the accepted constitution of (+)-gregatin B but its spectra are different. Surprisingly, (+) (R)-3a equals the natural product. Analogous structure reassignments are due for the gregatins A and C-E, the aspertetronins A-B, graminin A, and the penicilliols A and B. PMID- 21526753 TI - Microfluidic device with chemical gradient for single-cell cytotoxicity assays. AB - Here, we report the fabrication of a chemical gradient microfluidic device for single-cell cytotoxicity assays. This device consists of a microfluidic chemical gradient generator and a microcavity array that enables entrapment of cells with high efficiency at 88 +/- 6% of the loaded cells. A 2-fold logarithmic chemical gradient generator that is capable of generating a serial 2-fold gradient was designed and then integrated with the microcavity array. High density single-cell entrapment was demonstrated in the device without cell damage, which was performed in 30 s. Finally, we validated the feasibility of this device to perform cytotoxicity assays by exposing cells to potassium cyanide (0-100 MUM KCN). The device captured images of 4000 single cells affected by 6 concentrations of KCN and determined cell viability by counting the effected cells. Image scanning of the microcavity array was completed within 10 min using a 10* objective lens and a motorized stage. Aligning cells on the microcavity array eases cell counting, observation, imaging, and evaluation of singular cells. Thus, this platform was able to determine the cytotoxicity of chemicals at a single-cell level, as well as trace the cytotoxicity over time. This device and method will be useful for cytotoxicity analysis and basic biomedical research. PMID- 21526754 TI - Elucidation of reaction mechanisms responsible for afterglow and reagent-ion formation in the low-temperature plasma probe ambient ionization source. AB - The development of ambient desorption/ionization mass spectrometry has shown promising applicability for the direct analysis of complex samples in the open, ambient atmosphere. Although numerous plasma-based ambient desorption/ionization sources have been described in the literature, little research has been presented on experimentally validating or determining the desorption and ionization mechanisms that are responsible for their performance. In the present study, established spectrochemical and plasma physics diagnostics in combination with spatially resolved optical emission profiles were applied to reveal a set of reaction mechanisms responsible for afterglow and reagent-ion formation of the Low-Temperature Plasma (LTP) probe, which is a plasma-based ionization source used in the field of ambient mass spectrometry. Within the dielectric-barrier discharge of the LTP probe, He(2)(+) is the dominant positive ion when helium is used as the plasma supporting gas. This helium dimer ion (He(2)(+)) has two important roles: First, it serves to carry energy from the discharge into the afterglow region in the open atmosphere. Second, charge transfer between He(2)(+) and atmospheric nitrogen appears to be the primary mechanism in the sampling region for the formation of N(2)(+), which is an important reagent ion as well as the key reaction intermediate for the formation of other reagent ions, such as protonated water clusters, in plasma-based ambient ionization sources. In the afterglow region of the LTP, where the sample is usually placed, a strong mismatch in the rotational temperatures of N(2)(+) (B (2)Sigma(u)(+)) and OH (A (2)Sigma(+)) was found; the OH rotational temperature was statistically identical to the ambient gas temperature (~300 K) whereas the N(2)(+) temperature was found to rise to 550 K toward the tail of the afterglow region. This much higher N(2)(+) temperature is due to a charge-transfer reaction between He(2)(+) and N(2), which is known to produce rotationally hot N(2)(+) (B (2)Sigma(u)(+)) ions. Furthermore, it was found that one origin of excited atomic helium in the afterglow region of the LTP is from dielectronic recombination of vibrationally excited He(2)(+) ions. PMID- 21526755 TI - Borotungstate polyoxometalates: multinuclear NMR structural characterization and conversions in solutions. AB - The unique heteropolyanion [H(3)BW(13)O(46)](8-) (BW(13)), previously suggested on the basis of indirect evidence, and protonated lacunary heteropolyanion [HBW(11)O(39)](8-) (BW(11)) have been identified in aqueous solutions at pH 5-7.5 from NMR spectra. The pattern of tungsten-tungsten connectivities based on the analysis of the (2)J(W-O-W) coupling satellites in the (183)W NMR spectrum of BW(11), containing six peaks of relative intensities ~2:2:2:1:2:2, indicates that the latter is the alpha isomer. The (17)O NMR spectrum confirms the protonated state of the polyanion with the proton delocalized on two out of four terminal O atoms surrounding the tungsten vacancy. The (183)W NMR spectrum of BW(13) contains seven peaks of relative intensities ~2:1:2:2:2:2:2 with additional large couplings due to the connectivity between BW(11) and [W(2)O(7)](2-) fragments. According to the (17)O NMR spectrum, two protons of [BW(13)O(46)H(3)](8-) are delocalized on the two terminal trans O atoms of the dimeric fragment while the third one is linked to its bridging O atom. The conversions of BW(11) and BW(13) in solution were followed by using (183)W NMR spectra at a "fingerprint" level. In the pH range from ~7.5 to 6, BW(11) transforms to BW(13), transforming further to [BW(12)O(40)](5-) (BW(12)) and [B(3)W(39)O(132)H(n)](n-21) (B(3)W(39)) in different ratios. Conversion of BW(13) to BW(12) proceeds through an intermediate complex of suggested composition [BW(11)O(39).WO(2)](7-). At high acidity (pH ~ 0), B(3)W(39) gradually decomposes into tungstic acid, BW(12) and H(3)BO(3). Polyanion BW(12) persists in the pH range ~0-7.5. PMID- 21526756 TI - Reaction of an oxoiron(IV) complex with nitrogen monoxide: oxygen atom or oxide(*1-) ion transfer? AB - Reaction of [FeO(tmc)(OAc)](+) with the free radical nitrogen monoxide afforded a mixture of two Fe(II) complexes, [Fe(tmc)(OAc)](+) and [Fe(tmc)(ONO)](+) (where tmc = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane and AcO(-) = acetate anion). The amount of nitrite produced in this reaction (ca. 1 equiv with respect to Fe) was determined by ESI mass spectrometry after addition of (15)N-enriched NaNO(2). In contrast to oxygen atom transfer to PPh(3), the NO reaction of [FeO(tmc)(OAc)](+) proceeds through an Fe(III) intermediate that was identified by UV-vis-NIR spectroscopy and ESI mass spectrometry and whose decay is dependent on the concentration of methanol. The observations are consistent with a mechanism involving oxide(*1-) ion transfer from [FeO(tmc)(OAc)](+) to NO to form an Fe(III) complex and NO(2)(-), followed by reduction of the Fe(III) complex. Competitive binding of AcO(-) and NO(2)(-) to Fe(II) then leads to an equilibrium mixture of two Fe(II)(tmc) complexes. Evidence for the incorporation of oxygen from the oxoiron(IV) complex into NO(2)(-) was obtained from an (18)O-labeling experiment. The reported reaction serves as a synthetic example of the NO reactivity of biological oxoiron(IV) species, which has been proposed to have physiological functions such as inhibition of oxidative damage, enhancement of peroxidase activity, and NO scavenging. PMID- 21526757 TI - On the origin of the relative stability of Wells-Dawson isomers: a DFT study of alpha-, beta-, gamma-, alpha*-, beta*-, and gamma*-[(PO4)2W18O54](6-) anions. AB - Density functional theory calculations have been carried out to investigate alpha , beta-, gamma-, alpha*-, beta*-, and gamma*-[(PO(4))(2)W(18)O(54)](6-) Wells Dawson isomers, which exhibited stability in the order of alpha > beta > gamma > gamma* > beta* > alpha*, reproduced the experimental observations (alpha > beta > gamma), and confirmed the hypothesis of Contant and Thouvenot (gamma* > beta* > alpha*). Energy decomposition analysis reveals that both the spatial arrangement of the host W(18)O(54) cage (eclipsed or staggered) and its structural distortion induced by the encapsulated guest anions are two dominant factors in control of the stability order, while the influences of host-guest interaction and distortion of the guest anions are very small. A building block decomposition approach is designed and provides an effective means to clarify the detailed relationship between the local distortion and energy. By using this method, it is found that the eclipsed belt, and in particular the staggered belt, significantly distort the two caps inside the Wells-Dawson structure. Notably, there is a direct relationship between the overall stability and distortion in the belts, which is proven to be partly originating from the dominance in the quantity of the belt building blocks over that of the caps (12:6). Besides, half-unit {XW(9)} decomposition confirms that [(XO(4))(2)W(18)O(54)](n-) (X = Si, Ge, Al, and Ga) are thermodynamically instable because of the notable electrostatic repulsion between two {XW(9)} units induced by the highly charged guest anions. PMID- 21526758 TI - Syntheses, crystal structures, magnetic and luminescent properties of two classes of molybdenum(VI) rich quaternary lanthanide selenites. AB - Hydrothermal reactions of lanthanide(III) oxide, molybdenum oxide, and SeO(2) at 230 degrees C lead to five new molybdenum-rich quaternary lanthanide selenites with two types of structures, namely, H(3)Ln(4)Mo(9.5)O(32)(SeO(3))(4)(H(2)O)(2) (Ln = La, 1; Nd, 2) and Ln(2)Mo(3)O(10)(SeO(3))(2)(H(2)O) (Ln = Eu, 3; Dy, 4; Er, 5). Compounds 1 and 2 feature a complicated three-dimensional (3D) architecture constructed by the intergrowth of infinite molybdenum selenite chains of [Mo(4.75)SeO(19)](5.5-) and one-dimensional (1D) lanthanide selenite chains. The structures of 3, 4, and 5 exhibit 3D network composed of 1D [Mo(3)SeO(13)](4-) anionic chains connected by lanthanide selenite chains. The molybdenum selenite chain of [Mo(4.75)SeO(19)](5.5-) in 1 and 2 is composed of a pair of [Mo(3)SeO(13)](4-) chains as in 3, 4, and 5 interconnected by a [Mo(1.75)O(8)](5.5-) double-strand polymer via corner-sharing. The lanthanide selenite chains in both structures are similar in terms of coordination modes of selenite groups as well as the coordination environments of lanthanide(III) ions. Luminescent studies at both room temperature and 10 K indicate that compound 2 displays strong luminescence in the near-IR region and compound 3 exhibits red fluorescent emission bands with a luminescent lifetime of 0.57 ms. Magnetic properties of these compounds have been also investigated. PMID- 21526759 TI - CuAAC macrocyclization: high intramolecular selectivity through the use of copper tris(triazole) ligand complexes. AB - A range of multivalent heteroaryl ligands, copper sources, and solvent systems have been investigated for use in CuAAC-mediated macrocyclization reactions. These studies have revealed the key factors governing selectivity for macrocyclization versus dimerization and identified a simple but specific set of reaction conditions capable of efficiently generating a diverse series of drug like macrocycles at modest dilution in up to 95% yield. PMID- 21526760 TI - Optical detection of the anesthetic agent propofol in the gas phase. AB - The anesthetic agent propofol (2,6-diisopropylphenol) is the most widely used intravenously administered drug in general anesthesia. However, a viable online capability to monitor metabolized levels of propofol in patients does not currently exist. Here we show for the first time that optical spectroscopy has good potential to detect metabolized propofol from patients' exhaled breath. We present quantitative absorption measurements of gas phase propofol both in the ultraviolet and middle-infrared spectral regions. We demonstrate that a detection limit in the subparts-per-billion concentration range can be reached with photoacoustic spectroscopy in the UV spectral region, paving the way for the development of future optical monitors. PMID- 21526762 TI - Lipophilized epigallocatechin gallate (EGCG) derivatives as novel antioxidants. AB - Epigallocatechin gallate (EGCG) is the major polyphenol in green tea and known to render many health benefits associated with tea consumption. EGCG was modified structurally to improve its lipophilicity, expand its application in lipophilic media, and enhance its cellular absorption in vivo. Esterification of the water soluble EGCG with selected long-chain saturated and unsaturated fatty acids was carried out, followed by a purification process. Ester derivatives of EGCG with stearic acid (SA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were prepared, and their enhanced lipophilicity was confirmed by octanol-water partition coefficient. The chemical structures of the EGCG derivatives, determined by HPLC-MS and 1H and 13C NMR, were EGCG-3',5',3'',5''-O-tetraesters of SA, EPA, and DHA. The lipophilized EGCG derivatives exhibited greater antioxidant activity in scavenging the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical than EGCG itself. The results suggest that EGCG derivatives may be used as potential lipophilic antioxidants in the food, cosmetic, and medicinal industries. PMID- 21526761 TI - Authentication of animal fats using direct analysis in real time (DART) ionization-mass spectrometry and chemometric tools. AB - A combination of direct analysis in real time (DART) ionization coupled to time of-flight mass spectrometry (TOFMS) and chemometrics was used for animal fat (lard and beef tallow) authentication. This novel instrumentation was employed for rapid profiling of triacylglycerols (TAGs) and polar compounds present in fat samples and their mixtures. Additionally, fat isolated from pork, beef, and pork/beef admixtures was analyzed. Mass spectral records were processed by principal component analysis (PCA) and stepwise linear discriminant analysis (LDA). DART-TOFMS profiles of TAGs were found to be more suitable for the purpose of discrimination among the examined fat types as compared to profiles of polar compounds. The LDA model developed using TAG data enabled not only reliable classification of samples representing neat fats but also detection of admixed lard and tallow at adulteration levels of 5 and 10% (w/w), respectively. The presented approach was also successfully applied to minced meat prepared from pork and beef with comparable fat content. Using the DART-TOFMS TAG profiles of fat isolated from meat mixtures, detection of 10% pork added to beef and vice versa was possible. PMID- 21526763 TI - Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity. AB - 78 kDa glucose-regulated protein (Grp78) is a heat shock protein (HSP) involved in protein folding that plays a role in cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and isothermal titration calorimetry. The most potent compounds were 13 (VER-155008) with K(D) = 80 nM and 14 with K(D) = 60 nM. X-ray crystal structures of Grp78 bound to ATP, ADPnP, and adenosine derivative 10 revealed differences in the binding site between Grp78 and homologous proteins. PMID- 21526764 TI - Asymmetric imine N-inversion in 3-methyl-4-pyrimidinimine. Molecular dipole analysis of solvation effects. AB - The thermal (E)/(Z)-isomerization of 3-methyl-4-pyrimidinimine, 3MePMI, has been studied in the gas phase at MP2/6-31G* and with the inclusion of medium effects using the polarizable continuum method, PCM(MP2/6-31G*), and the solvation model density method, SMD(MP2/6-31G*). For the free molecule and for 3MePMI in each of 14 solvents, the structures were determined of the (E)- and (Z)-isomers, of the transition state structure for isomerization ITS by asymmetric N-inversion, and of the second-order saddle point structure (SOSP) associated with in-plane N inversion. The results predict a reduction of the (E)-isomer preference energy of 3MePMI, an increase of the deformation energy DeltaE(def) = E(SOSP) - E(ITS), and an increase of the activation barrier E(act)(Z -> E) with increasing solvent polarity. Electronic effects associated with N-inversion are analyzed using molecular orbital theory, results of population analysis, and electrostatic potential maps. The molecular dipole moments are superior parameters for the description of electronic relaxation in the imine basin during N-inversion. In particular, the analysis of dipole moments explains the compatibility of the increase of local CN polarity during N-inversion with the negative solvation effect on the activation barrier. PMID- 21526765 TI - Heteroepitaxial growth of colloidal nanocrystals onto substrate films via hot injection routes. AB - Hot-injection synthesis of colloidal nanocrystals (NCs) in a substrate-bound form is demonstrated. We show that polycrystalline films submerged into hot organic solvents can nucleate the heteroepitaxial growth of semiconductor NCs, for which the ensuing lattice quality and size distribution are on the par with those of isolated colloidal nanoparticles. This strategy is demonstrated by growing lead chalcogenide NCs directly onto solvent-submerged TiO(2) substrates. The resulting PbX/TiO(2) (X = S, Se, Te) nanocomposites exhibit heteroepitaxial interfaces between lead chalcogenide and oxide domains and show an efficient separation of photoinduced charges, deployable for light-harvesting applications. The extendibility of the present method to other material systems was demonstrated through the synthesis of CdS/TiO(2) and Cu(2)S/TiO(2) heterostructures, fabricated from PbS/TiO(2) composites via cation exchange. The photovoltaic performance of nanocrystal/substrate composites comprising PbS NCs was evaluated by incorporating PbS/TiO(2) films into prototype solar cells. PMID- 21526766 TI - Update 1 of: Enantioselective enzymatic desymmetrizations in organic synthesis. PMID- 21526767 TI - Selective wrapping and supramolecular structures of polyfluorene-carbon nanotube hybrids. AB - We report on the photophysical properties of single-walled carbon nanotube (SWNT) suspensions in toluene solutions of poly[9,9-dioctylfluorenyl-2,7-diyl](PFO). Steady-state and time-resolved photoluminescence spectroscopy in the near infrared and visible spectral regions are used to study the interaction of the dispersed SWNTs with the wrapped polymer. Molecular dynamics simulations of the PFO-SWNT hybrids in toluene were carried out to evaluate the energetics of different wrapping geometries. The simulated fluorescence spectra in the visible region were obtained by the quantum chemical ZINDO-CI method, using a sampling of structures obtained from the dynamics trajectories. The tested schemes consider polymer chains aligned along the nanotube axis, where chirality has a minimal effect, or forming helical structures, where a preference for high chiral angles is evidenced. Moreover, toluene affects the polymer structure favoring the helical conformation. Simulations show that the most stable hybrid system is the PFO-wrapped (8,6) nanotube, in agreement with the experimentally observed selectivity. PMID- 21526768 TI - Redox reactions catalyzed by isolated enzymes. PMID- 21526769 TI - Thermodynamic compensation upon binding to exosite 1 and the active site of thrombin. AB - Several lines of experimental evidence including amide exchange and NMR suggest that ligands binding to thrombin cause reduced backbone dynamics. Binding of the covalent inhibitor dPhe-Pro-Arg chloromethyl ketone to the active site serine, as well as noncovalent binding of a fragment of the regulatory protein, thrombomodulin, to exosite 1 on the back side of the thrombin molecule both cause reduced dynamics. However, the reduced dynamics do not appear to be accompanied by significant conformational changes. In addition, binding of ligands to the active site does not change the affinity of thrombomodulin fragments binding to exosite 1; however, the thermodynamic coupling between exosite 1 and the active site has not been fully explored. We present isothermal titration calorimetry experiments that probe changes in enthalpy and entropy upon formation of binary ligand complexes. The approach relies on stringent thrombin preparation methods and on the use of dansyl-l-arginine-(3-methyl-1,5-pantanediyl)amide and a DNA aptamer as ligands with ideal thermodynamic signatures for binding to the active site and to exosite 1. Using this approach, the binding thermodynamic signatures of each ligand alone as well as the binding signatures of each ligand when the other binding site was occupied were measured. Different exosite 1 ligands with widely varied thermodynamic signatures cause a similar reduction in DeltaH and a concomitantly lower entropy cost upon DAPA binding at the active site. The results suggest a general phenomenon of enthalpy-entropy compensation consistent with reduction of dynamics/increased folding of thrombin upon ligand binding to either the active site or exosite 1. PMID- 21526770 TI - Stress-induced phosphorylation of PACT reduces its interaction with TRBP and leads to PKR activation. AB - PACT is a stress-modulated activator of interferon (IFN)-induced double-stranded (ds) RNA-activated protein kinase (PKR) and is an important regulator of PKR dependent signaling pathways. Stress-induced phosphorylation of PACT is essential for PACT's association with PKR leading to PKR activation. PKR activation by PACT leads to phosphorylation of translation initiation factor eIF2alpha, inhibition of protein synthesis, and apoptosis. In addition to positive regulation by PACT, PKR activity in cells is also negatively regulated by TRBP. In this study, we demonstrate for the first time that stress-induced phosphorylation at serine 287 significantly increases PACT's ability to activate PKR by weakening PACT's interaction with TRBP. A non-phosphorylatable alanine substitution mutant at this position causes enhanced interaction of PACT with TRBP and leads to a loss of PKR activation. Furthermore, TRBP overexpression in cells is unable to block apoptosis induced by a phospho-mimetic, constitutively active PACT mutant. These results demonstrate for the first time that stress-induced PACT phosphorylation functions to free PACT from the inhibitory interaction with TRBP and also to enhance its interaction with PKR. PMID- 21526771 TI - Ruthenium-catalyzed (2 + 2) intramolecular cycloaddition of allenenes. AB - We report a ruthenium-catalyzed (2 + 2) intramolecular cycloaddition of allenes and alkenes. We have found that the use of the ruthenium complex RuH(2)Cl(2)(P(i)Pr(3))(2), which has previously gone unnoticed in catalytic applications, is crucial for the observed reactivity. The reaction proceeds under mild conditions and is fully diastereoselective, providing a practical entry to a variety of bicyclo[3.2.0]heptane skeletons featuring cyclobutane rings. PMID- 21526772 TI - Silicon-(thio)urea Lewis acid catalysis. AB - We present a new class of catalysts based on the combination of N,N' diaryl(thio)ureas and weak silicon Lewis acids (e.g., SiCl(4)). Such silicon (thio)urea catalysts effectively catalyze the stereospecific rearrangement of epoxides to quaternary carbaldehydes. PMID- 21526773 TI - Supported-nanoparticle heterogeneous catalyst formation in contact with solution: kinetics and proposed mechanism for the conversion of Ir(1,5-COD)Cl/gamma-Al2O3 to Ir(0)(~900)/gamma-Al2O3. AB - A current goal in heterogeneous catalysis is to transfer the synthetic, as well as developing mechanistic, insights from the modern revolution in nanoparticle science to the synthesis of supported-nanoparticle heterogeneous catalysts. In a recent study (Mondloch, J. E.; Wang, Q.; Frenkel, A. I.; Finke, R. G. J. Am. Chem. Soc. 2010, 132, 9701-9714), we initialized tests of the global hypothesis that quantitative kinetic and mechanistic studies, of supported-nanoparticle heterogeneous catalyst formation in contact with solution, can provide synthetic and mechanistic insights that can eventually drive improved syntheses of composition-, size-, and possibly shape-controlled catalysts. That study relied on the development of a well-characterized Ir(1,5-COD)Cl/gamma-Al(2)O(3) precatalyst, which, when in contact with solution and H(2), turns into a nonaggregated Ir(0)(~900)/gamma-Al(2)O(3) supported-nanoparticle heterogeneous catalyst. The kinetics of the Ir(1,5-COD)Cl/gamma-Al(2)O(3) to Ir(0)(~900)/gamma Al(2)O(3) conversion were followed and fit by a two-step mechanism consisting of nucleation (A -> B, rate constant k(1)) followed by autocatalytic surface growth (A + B -> 2B, rate constant k(2)). However, a crucial, but previously unanswered question is whether the nucleation and growth steps occur primarily in solution, on the support, or possibly in both phases for one or more of the catalyst formation steps. The present work investigates this central question for the prototype Ir(1,5-COD)Cl/gamma-Al(2)O(3) to Ir(0)(~900)/gamma-Al(2)O(3) system. Solvent variation-, gamma-Al(2)O(3)-, and acetone-dependent kinetic data, along with UV-vis spectroscopic and gas-liquid-chromatography (GLC) data, are consistent with and strongly supportive of a supported-nanoparticle formation mechanism consisting of Ir(1,5-COD)Cl(solvent) dissociation from the gamma Al(2)O(3) support (i.e., from Ir(1,5-COD)Cl/gamma-Al(2)O(3)), solution-based nucleation from that dissociated Ir(1,5-COD)Cl(solvent) species, fast Ir(0)(n) nanoparticle capture by gamma-Al(2)O(3), and then subsequent solid-oxide-based nanoparticle growth from Ir(0)(n)/gamma-Al(2)O(3) and with Ir(1,5 COD)Cl(solvent), the first kinetically documented mechanism of this type. Those data disprove a solid-oxide-based nucleation and growth pathway involving only Ir(1,5-COD)Cl/gamma-Al(2)O(3) and also disprove a solution-based nanoparticle growth pathway involving Ir(1,5-COD)Cl(solvent) and Ir(0)(n) in solution. The present mechanistic studies allow comparisons of the Ir(1,5-COD)Cl/gamma Al(2)O(3) to Ir(0)(~900)/gamma-Al(2)O(3) supported-nanoparticle formation system to the kinetically and mechanistically well-studied, Ir(1,5 COD).P(2)W(15)Nb(3)O(62)(8-) to Ir(0)(~300).(P(2)W(15)Nb(3)O(62)(8-))(n)(-8n) solution-based, polyoxoanion-stabilized nanoparticle formation and stabilization system. That comparison reveals closely analogous, solution Ir(1,5-COD)(+) or Ir(1,5-COD)Cl-mediated, mechanisms of nanoparticle formation. Overall, the hypothesis supported by this work is that these and analogous studies hold promise of providing a way to transfer the synthetic and mechanistic insights, from the modern revolution in nanoparticle synthesis and characterization in solution, to the rational, mechanism-directed syntheses of solid oxide-supported nanoparticle heterogeneous catalysts, also in contact with solution. PMID- 21526774 TI - Nanotransfer printing using plasma etched silicon stamps and mediated by in situ deposited fluoropolymer. AB - This communication describes a simple method that uses a thin film of octafluorocyclobutane (OFCB) polymer for efficient nanoscale transfer printing (nTP). Plasma polymerization of OFCB produces a Teflon-like fluoropolymer which strongly adheres and conformally covers a 3-D inorganic stamp. The inherently low surface energy of in situ deposited OFCB polymer on nanoscale silicon features is demonstrated as a unique nanocomposite stamp to fabricate various test structures with improved nTP feature resolution down to sub-100 nm. PMID- 21526775 TI - Three-state trajectory surface hopping studies of the photodissociation dynamics of formaldehyde on ab initio potential energy surfaces. AB - Full-dimensional, three-state, surface hopping calculations of the photodissociation dynamics of formaldehyde are reported on ab initio potential energy surfaces (PESs) for electronic states S(1), T(1), and S(0). This is the first such study initiated on S(1) with ab initio-calculated spin-orbit couplings among the three states. We employ previous PESs for S(0) and T(1), and a new PES for S(1), which we describe here, as well as new spin-orbit couplings. The time dependent electronic state populations and the branching ratio of radical products produced from S(0) and T(1) states and that of total radical products and molecular products at three total energies are calculated. Details of the surface hopping dynamics are described, and a novel pathway for isomerization on T(1) via S(0) is reported. Final translational energy distributions of H + HCO products from S(0) and T(1) are also reported as well as the translational energy distribution and final rovibrational distributions of H(2) products from the molecular channel. The present results are compared to previous trajectory calculations initiated from the global minimum of S(0). The roaming pathway leading to low rotational distribution of CO and high vibrational population of H(2) is observed in the present calculations. PMID- 21526776 TI - Differentiation of O-H and C-H bond scission mechanisms of ethylene glycol on Pt and Ni/Pt using theory and isotopic labeling experiments. AB - Understanding and controlling bond-breaking sequences of oxygenates on transition metal catalysts can greatly impact the utilization of biomass feedstocks for fuels and chemicals. The decomposition of ethylene glycol, as the simplest representative of biomass-derived polyols, was studied via density functional theory (DFT) calculations to identify the differences in reaction pathways between Pt and the more active Ni/Pt bimetallic catalyst. Comparison of the computed transition states indicated three potentially feasible paths from ethylene glycol to C1 oxygenated adsorbates on Pt. While not important on Pt, the pathway to 1,2-dioxyethylene (OCH(2)CH(2)O) is favored energetically on the Ni/Pt catalyst. Temperature-programmed desorption (TPD) experiments were conducted with deuterated ethylene glycols for comparison with DFT results. These experiments confirmed that decomposition of ethylene glycol on Pt proceeds via initial O-H bond cleavage, followed by C-H and the second O-H bond cleavages, whereas on the Ni/Pt surface, both O-H bonds are cleaved initially. The results are consistent with vibrational spectra and indicate that tuning of the catalyst surface can selectively control bond breaking. Finally, the significant mechanistic differences in decomposition of polyols compared to that of monoalcohols and hydrocarbons serve to identify general trends in bond scission sequences. PMID- 21526777 TI - Persistent organic pollutants in Mediterranean seawater and processes affecting their accumulation in plankton. AB - The Mediterranean and Black Seas are unique marine environments subject to important anthropogenic pressures due to riverine and atmospheric inputs of organic pollutants. Here, we report the results obtained during two east-west sampling cruises in June 2006 and May 2007 from Barcelona to Istanbul and Alexandria, respectively, where water and plankton samples were collected simultaneously. Both matrixes were analyzed for hexaclorochyclohexanes (HCHs), hexachlorobenzene (HCB), and 41 polychlorinated biphenyl (PCB) congeners. The comparison of the measured HCB and HCHs concentrations with previously reported dissolved phase concentrations suggests a temporal decline in their concentrations since the 1990s. On the contrary, PCB seawater concentrations did not exhibit such a decline, but show a significant spatial variability in dissolved concentrations with lower levels in the open Western and South Eastern Mediterranean, and higher concentrations in the Black, Marmara, and Aegean Seas and Sicilian Strait. PCB and OCPs (organochlorine pesticides) concentrations in plankton were higher at lower plankton biomass, but the intensity of this trend depended on the compound hydrophobicity (K(OW)). For the more persistent PCBs and HCB, the observed dependence of POP concentrations in plankton versus biomass can be explained by interactions between air-water exchange, particle settling, and/or bioaccumulation processes, whereas degradation processes occurring in the photic zone drive the trends shown by the more labile HCHs. The results presented here provide clear evidence of the important physical and biogeochemical controls on POP occurrence in the marine environment. PMID- 21526778 TI - High recovery FASP applied to the proteomic analysis of microdissected formalin fixed paraffin embedded cancer tissues retrieves known colon cancer markers. AB - Proteomic analysis of samples isolated by laser capture microdissection from clinical specimens requires sample preparation and fractionation methods suitable for small amounts of protein. Here we describe a streamlined filter-aided sample preparation (FASP) workflow that allows efficient analysis of lysates from low numbers of cells. Addition of carrier substances such as polyethylene glycol or dextran to the processed samples improves the peptide yields in the low to submicrogram range. In a single LC-MS/MS run, analyses of 500, 1000, and 3000 cells allowed identification of 905, 1536, and 2055 proteins, respectively. Incorporation of an additional SAX fractionation step at somewhat higher amounts enabled the analysis of formalin fixed and paraffin embedded human tissues prepared by LCM to a depth of 3600-4400 proteins per single experiment. We applied this workflow to compare archival neoplastic and matched normal colonic mucosa cancer specimens for three patients. Label-free quantification of more than 6000 proteins verified this technology through the differential expression of 30 known colon cancer markers. These included Carcino-Embryonic Antigen (CEA), the most widely used colon cancer marker, complement decay accelerating factor (DAF, CD55) and Metastasis-associated in colon cancer protein 1 (MACC1). Concordant with literature knowledge, mucin 1 was overexpressed and mucin 2 underexpressed in all three patients. These results show that FASP is suitable for the low level analysis of microdissected tissue and that it has the potential for exploration of clinical samples for biomarker and drug target discovery. PMID- 21526780 TI - Binding ligands and cofactor to L-lactate dehydrogenase from human skeletal and heart muscles. AB - Binding affinities of cofactor and ligands to the active site of two different isoforms of lactate dehydrogenase (LDH), heart and skeletal muscles (H4 and M4, respectively), can be used for medical and biological applications. Herein, a hybrid QM/MM computational approach based on free energy perturbation methods has been carried out to estimate binding affinities and binding isotope effects (BIEs) for NADH/NAD(+) and oxamate, pyruvate, L-lactate, and D-lactate ligands to the M4 and H4 isoforms of L-LDH. Here, we show that determining how cofactor and ligands interact with the active site of LDH isoforms advanced the still open discussion on the intracellular lactate shuttle hypothesis. In our discussion we deny the key concept of this hypothesis showing, based on interaction energy values, that there is no evidence that the M4 type of LDH in the skeletal muscles cells served as a catalyst of the conversion of lactate to pyruvate. Additionally, theoretical determination of BIEs for H4 and M4 types of LDH shows that there is a way of using the BIEs as a tool capable to distinguish these isoforms, and for this purpose D-lactate labeled with deuterium in positions 11 or 7, 8, 9 ([11-2H]-BIE and [7,8,9-2H3]-BIE) or L-lactate labeled only in position 11 ([11-2H]-BIE) could be used. We propose the BIEs as a useful tool which can be applied in order to experimentally determine the types of LDH. PMID- 21526779 TI - Synthesis and macrophage activation of lentinan-mimic branched amino polysaccharides: curdlans having N-Acetyl-d-glucosamine branches. AB - N-Acetyl-d-glucosamine branches were incorporated at the C-6 position of curdlan, a linear beta-1,3-d-glucan, and the resulting nonnatural branched polysaccharides were evaluated in terms of the immunomodulation activities in comparison with lentinan, a beta-1,3-d-glucan having d-glucose branches at C-6. To incorporate the amino sugar branches, we conducted a series of regioselective protection deprotections of curdlan involving triphenylmethylation at C-6, phenylcarbamoylation at C-2 and C-4, and detriphenylmethylation. Subsequent glycosylation with a d-glucosamine-derived oxazoline, followed by deprotection gave rise to the branched curdlans with various substitution degrees. The products exhibited remarkable solubility in both organic solvents and water. Their immunomodulation activities were determined using mouse macrophagelike cells, and the secretions of both the tumor necrosis factor and nitric oxide proved to be significantly higher than those with lentinan. These results conclude that the amino sugar/curdlan hybrid materials are promising as a new type of polysaccharide immunoadjuvants useful for cancer chemotherapy. PMID- 21526781 TI - Determination of structural parameters of protein-containing reverse micellar solution by near-infrared absorption spectroscopy. AB - We present a method based on near-infrared absorption spectroscopy of the OH stretching vibration band of water around 3400 cm(-1) to examine whether the aqueous cavity size of a protein-unfilled reverse micelle is affected by solubilization of protein, and it has been found for AOT [= bis(2 ethylhexyl)sulfosuccinate] reverse micellar solution with myoglobin that the cavity size does not change before and after solubilization of the protein at water-to-surfactant molar ratios (w(0)) from 2 to ~18; that is, the w(0) values of the protein-filled and unfilled reverse micelles are the same as that of the reverse micellar solution, regardless of the size relationship between the aqueous cavity of the unfilled reverse micelle and the protein. On the basis of this experimental fact, we propose a model to determine the structural parameters of protein-filled reverse micelles, such as the aqueous cavity radius and the aggregation number of surfactant molecules constituting the micelle, and the molar concentration of the unfilled reverse micelle that exists with the protein filled reverse micelle in the reverse micellar solution, and derive their values for AOT reverse micellar solution with myoglobin in the w(0) range from 2 to 24. On the other hand, circular dichroic measurements and UV-visible absorption spectroscopy of myoglobin/AOT reverse micellar solution and myoglobin/AOT aqueous solution were carried out in order to examine the conformational state of myoglobin in the reverse micellar solution. These experimental results lead to the conclusion that myoglobin is located in the aqueous cavity of the reverse micelle, although the conformational state of the protein is to some extent distorted because of the interaction with AOT compared with that of native myoglobin. Finally, it is suggested that the proposed model is appropriate for reverse micellar solution with a hydrophilic protein molecule that is located in the aqueous cavity of the reverse micelle. PMID- 21526782 TI - Atomic force microscopy study of ganglioside GM1 concentration effect on lateral phase separation of sphingomyelin/dioleoylphosphatidylcholine/cholesterol bilayers. AB - The effect of monosialoganglioside GM1 (GM1) concentration on the lateral phase separation in the sphingomyelin/1,2-dioleoyl-sn-glycero-3 phosphocholine/cholesterol (SM/DOPC/Chol) bilayers was studied by using atomic force microscopy. The results show that, with the increase of GM1 mol fraction (x), the dominant composition of liquid-ordered (L(o)) domains changes from SM to SM/GM1 and finally to GM1. Meanwhile, the decrease of domain area (A) of the L(o) phase with the increase of x follows a scaling law of A ~ x(-3/2), for x > 0.005, indicating that the domain growth is pinned with high GM1 concentration. Results of in situ experiments of GM1 insertion into SM/DOPC/cholesterol bilayers further supported our observations. PMID- 21526783 TI - Taking advantage of unspecific interactions to produce highly active magnetic nanoparticle-antibody conjugates. AB - Several strategies for linking antibodies (Abs) through their Fc region in an oriented manner have been proposed at the present time. By using these strategies, the Fab region of the Ab is available for antigen molecular recognition, leading to a more efficient interaction. Most of these strategies are complex processes optimized mainly for the functionalization of surfaces or microbeads. These methodologies imply though the Ab modification through several steps of purification or the use of expensive immobilized proteins. Besides, the functionalization of magnetic nanoparticles (MNPs) turned out to be much more complex than expected due to the lack of stability of most MNPs at high ionic strength and non-neutral pH values. Therefore, there is still missing an efficient, easy and universal methodology for the immobilization of nonmodified Abs onto MNPs without involving their Fab regions during the immobilization process. Herein, we propose the functionalization of MNPs via a two-steps strategy that takes advantage of the ionic reversible interactions between the Ab and the MNP. These interactions make possible the orientation of the Ab on the MNP surface before being attached in an irreversible way via covalent bonds. Three Abs (Immunoglobulin G class) with very different isoelectric points (against peroxidase, carcinoembryonic antigen, and human chorionic gonadotropin hormone) were used to prove the general applicability of the strategy here proposed and its utility for the development of more bioactive NPs. PMID- 21526784 TI - Functionality mapping on internal surfaces of multidrug transporter AcrB based on molecular theory of solvation: implications for drug efflux pathway. AB - AcrB is a membrane protein and a multidrug efflux transporter. Although the recently solved X-ray crystal structures of AcrB provide a rough sketch of how drugs efflux, the pathway and mechanism have not been completely elucidated. In this study, a ligand-mapping method based on the 3D-RISM molecular theory of solvation, which we recently developed, is applied to AcrB in order to identify the drug efflux pathway. We use a fragment-based approach as a strategy to map chemical functionality on the internal surfaces. A few "multifunctional" ligand binding sites, which recognize various types of functional groups, are detected inside the porter domain. Spatial links between the multifunctional sites indicate a probable multidrug efflux pathway. The frustrated environment of the protein cavity constructed of weak interactions between ligand and protein may be a mechanism for allowing smooth transportation through the protein. Guided diffusion appears to be the main mechanism for efflux. PMID- 21526785 TI - Quantitative coherent anti-Stokes Raman scattering (CARS) microscopy. AB - The ability to observe samples qualitatively at the microscopic scale has greatly enhanced our understanding of the physical and biological world throughout the 400 year history of microscopic imaging, but there are relatively few techniques that can truly claim the ability to quantify the local concentration and composition of a sample. We review coherent anti-Stokes Raman scattering (CARS) as a quantitative, chemically specific, and label-free microscopy. We discuss the complicating influence of the nonresonant response on the CARS signal and the various experimental and mathematical approaches that can be adopted to extract quantitative information from CARS. We also review the uses to which CARS has been employed as a quantitative microscopy to solve challenges in material and biological science. PMID- 21526786 TI - Determination of malachite green residues in fish using a highly sensitive electrochemiluminescence method combined with molecularly imprinted solid phase extraction. AB - An electrochemiluminescence (ECL) inhibition method combined with molecularly imprinted solid phase extraction (MISPE) was developed for quantitative determination of malachite green (MG) residues in fish. It was found that MG could strongly inhibit the ECL signal of luminol. Under the optimized conditions, the quenched ECL intensity versus the logarithm of the concentration of MG was in good linear relationship over a concentration range from 20 to 5000 ppt. The method detection limit was found to be about 6 ppt. Molecularly imprinted polymers (MIPs) were synthesized as solid phase extraction (SPE) sorbents, and MISPE was used for the selective extraction and purification of MG. By carrying out the oxidation reaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), which could convert leucomalachite green (LMG) into MG, this method was successfully applied to determine MG residues in fish. A possible mechanism for the quenching effects of MG on luminol was also proposed. PMID- 21526787 TI - Solution-liquid-solid growth of semiconductor quantum-wire films. AB - We report the growth of cadmium-selenide (CdSe) quantum-wire (QW) films on a variety of substrates by the solution-liquid-solid (SLS) method. Our SLS syntheses employ size-controlled, near-monodisperse bismuth (Bi) nanoparticles (NPs) as the catalysts for QW growth, which offers several advantages over Bi NPs thermally generated from thin Bi films, including mean QW diameter control, narrow diameter distributions, small diameters in the quantum-confinement regime, and control of the QW density on the substrates. The Bi NPs are deposited on the substrates via drop casting of a Bi-NP solution and subsequently annealed in a reducing atmosphere, a key step to ensure firm attachment of the Bi NPs onto the substrates and maintenance of their catalytic activity for the QW-film growth. The QW growth density is proportional to the Bi-NP coating density, which is determined by the concentration of the Bi-NP deposition solution. Lower concentrations are used for small Bi NPs to reduce their high tendency for agglomeration and to achieve control over mean QW diameter and to produce narrow diameter distributions. Spectroscopic evidence of quantum confinement is provided. Related films of InP, InAs, and PbSe QWs are also described. PMID- 21526788 TI - Coarse-grained molecular dynamics simulation of DNA translocation in chemically modified nanopores. AB - Solid-state nanopores provide a direct means to detect and analyze DNA and proteins. In a typical setup, the DNA molecules travel through a nanopore under electrophoretic voltage bias. The nanopore is sandwiched between two chambers that are filled with ionic solution. A major challenge in using solid-state nanopores for DNA sequencing and gene detection is to improve their selectivity and detection sensitivity. To achieve these goals, one solution is to functionalize the nanopores by chemically modifying the pore walls with silanes or nucleic acids. However, little is known about molecular interactions in functionalized nanopores. This paper presents DNA translocation dynamics and the mechanism of DNA sequencing in a functionalized nanopore through a coarse-grained molecular dynamics model. The DNA nucleotide is coarse-grained into two interaction sites: one site corresponds to the base group and the other encompasses the phosphate and sugar groups. The water molecules are included in the model implicitly through Langevin dynamics. The coarse-grained model immensely improves the computational efficiency while still capturing the essential translocation dynamics. The model characterizes important physical properties of functionalized nanopores such as the effective pore diameter and effect of biasing voltage on the DNA translocation dynamics. The model reveals a nonlinear relationship between translocation speed of DNA and applied voltage. Moreover, DNA translocation in nanopores functionalized with hairpin-loop (HPL) DNA and single-stranded DNA (ss-DNA) shows significant differences: a target DNA is found to translocate through a ss-DNA coated nanopore 9 times faster than through an HPL coated one at a bias of 100 mV, putatively from lower stiffness of ss-DNA than that for HPL. The DNA translocation speed is also largely influenced by interaction potential between the DNA and surface-tethered molecules. The results reveal that such selective translocation, distinctly different translocation dynamics of target DNA molecules largely stem from the flexibility and orientation of the surface-tethered molecules. These findings can significantly impact the rational design of DNA transport experiments leading to rapid molecule-level diagnostics. PMID- 21526789 TI - Photoinduced electron transfer in a room temperature ionic liquid 1-butyl-3 methylimidazolium octyl sulfate micelle: a temperature dependent study. AB - The effect of temperature on the dynamics of photoinduced electron transfer (PET) between different coumarin dyes and N,N-dimethyl aniline in a room temperature ionic liquid 1-butyl-3-methylimidazolium octyl sulfate ([C(4)mim][C(8)SO(4)]) micelle have been investigated using steady-state and time-resolved fluorescence quenching measurements at four different temperatures: 208, 298, 308, and 318 K. The quenching rates (k(q)(TR)) of the PET process in this micellar system are found to be lower than the PET rate in sodium dodecyl sulfate and Triton-X 100 micelle and almost comparable to the dodecyl trimethyl ammonium bromide and cetyl trimethyl ammonium bromide micelle due to larger donor-acceptor separation in the micellar phase. The temperature dependent PET rates are well correlated with the Arrhenius type of correlation for all the coumarin dyes. Marcus type of inversion in PET rates has been observed at relatively lower exergonicity, and the correlation plots gradually move upward with the increase of temperature. PMID- 21526790 TI - The chemistry of cyclotides. AB - Cyclotides are head-to-tail cyclic peptides that contain a cystine knot motif built from six conserved cysteine residues. They occur in plants of the Rubiaceae, Violaceae, Cucurbitaceae, and Fabaceae families and, aside from their natural role in host defense, have a range of interesting pharmaceutical activities, including anti-HIV activity. The variation seen in sequences of their six backbone loops has resulted in cyclotides being described as a natural combinatorial template. Their exceptional stability and resistance to enzymatic degradation has led to their use as scaffolds for peptide-based drug design. To underpin such applications, methods for the chemical synthesis of cyclotides have been developed and are described here. Cyclization using thioester chemistry has been instrumental in the synthesis of cyclotides for structure-activity studies. This approach involves a native chemical ligation reaction between an N-terminal Cys and a C-terminal thioester in the linear cyclotide precursor. Since cyclotides contain six Cys residues their syntheses can be designed around any of six linear precursors, thus providing flexibility in synthesis. The ease with which cyclotides fold, despite their topologically complex knot motif, as well as the ability to introduce combinatorial variation in the loops, makes cyclotides a promising drug-design scaffold. PMID- 21526791 TI - Guided three-dimensional catalyst folding during metal-assisted chemical etching of silicon. AB - In recent years metal-assisted chemical etching (MaCE) of silicon, in which etching is confined to a small region surrounding metal catalyst templates, has emerged as a promising low cost alternative to commonly used three-dimensional (3D) fabrication techniques. We report a new methodology for controllable folding of 2D metal catalyst films into 3D structures using MaCE. This method takes advantage of selective patterning of the catalyst layer into regions with mismatched characteristic dimensions, resulting in uneven etching rates along the notched boundary lines that produce hinged 2D templates for 3D folding. We explore the dynamics of the folding process of the hinged templates, demonstrating that the folding action combines rotational and translational motion of the catalyst template, which yields topologically complex 3D nanostructures with intimately integrated metal and silicon features. PMID- 21526792 TI - InCl3/Me3SiBr-catalyzed direct coupling between silyl ethers and enol acetates. AB - A combined Lewis acid catalyst of InCl(3) and Me(3)SiBr promoted the direct use of enol acetates in the coupling with low-reactive silyl ethers, in which functional groups including ketones and aldehydes survived. Sterically hindered silyl ethers such as ROSiEt(3), ROSiPh(3), ROSit-BuMe(2), and ROSii-Pr(3) were also applicable. PMID- 21526793 TI - General statistical modeling of data from protein relative expression isobaric tags. AB - Quantitative comparison of the protein content of biological samples is a fundamental tool of research. The TMT and iTRAQ isobaric labeling technologies allow the comparison of 2, 4, 6, or 8 samples in one mass spectrometric analysis. Sound statistical models that scale with the most advanced mass spectrometry (MS) instruments are essential for their efficient use. Through the application of robust statistical methods, we developed models that capture variability from individual spectra to biological samples. Classical experimental designs with a distinct sample in each channel as well as the use of replicates in multiple channels are integrated into a single statistical framework. We have prepared complex test samples including controlled ratios ranging from 100:1 to 1:100 to characterize the performance of our method. We demonstrate its application to actual biological data sets originating from three different laboratories and MS platforms. Finally, test data and an R package, named isobar, which can read Mascot, Phenyx, and mzIdentML files, are made available. The isobar package can also be used as an independent software that requires very little or no R programming skills. PMID- 21526794 TI - Effect of side-chain structure of rigid polyimide dispersant on mechanical properties of single-walled carbon nanotube/cyanate ester composite. AB - Three kinds of polymer, polyimide without side-chain (PI), polyimide-graft glyceryl 4-nonylphenyl ether (PI-GNE), and polyimide-graft-bisphenol A diglyceryl acrylate (PI-BDA), have been synthesized and used to disperse single-walled carbon nanotubes (SWNTs) and to improve the interfacial bonding between SWNTs and cyanate ester (CE) matrix. Visual observation, UV-vis-near-IR (UV-vis-NIR) spectra, and atomic force microscopy (AFM) images show that both PI-GNE and PI BDA are highly effective at dispersing and debundling SWNTs in DMF, whereas PI is less effective. Interaction between SWNTs and PI, PI-GNE or PI-BDA was confirmed by computer simulation and Raman spectra. A series of CE-based composite films reinforced with different loadings of SWNTs, SWNTs/PI, SWNTs/PI-GNE and SWNTs/PI BDA were prepared by solution casting. It was found that, because of the unique side-chain structure of PI-BDA, SWNTs/PI-BDA disperse better in CE matrix than do SWNTs/PI-GNE, SWNTs/PI, and SWNTs. As a result, SWNTs/PI-BDA/CE composites have the greatest improvement in mechanical properties of the materials tested. These results imply that the choice of side-chain on a dispersant is very important to the dispersion of SWNTs in matrix and the filler/matrix interfacial adhesion, which are two key requirements for achieving effective reinforcement. PMID- 21526795 TI - Ground-state destabilization in orotate phosphoribosyltransferases by binding isotope effects. AB - Orotate phosphoribosyltransferases (OPRTs) form and break the N-ribosidic bond to pyrimidines by way of ribocation-like transition states (TSs) and therefore exhibit large alpha-secondary 1'-(3)H k(cat)/K(m) kinetic isotope effects (KIEs) [Zhang, Y., and Schramm, V. L. (2010) J. Am. Chem. Soc. 132, 8787-8794]. Substrate binding isotope effects (BIEs) with OPRTs report on the degree of ground-state destabilization for these complexes and permit resolution of binding and transition-state effects from the k(cat)/K(m) KIEs. The BIEs for interactions of [1'-(3)H]orotidine 5'-monophosphate (OMP) with the catalytic sites of Plasmodium falciparum and human OPRTs are 1.104 and 1.108, respectively. These large BIEs establish altered sp(3) bond hybridization of C1' toward the sp(2) geometry of the transition states upon OMP binding. Thus, the complexes of these OPRTs distort OMP part of the way toward the transition state. As the [1' (3)H]OMP k(cat)/K(m) KIEs are approximately 1.20, half of the intrinsic k(cat)/K(m) KIEs originate from BIEs. Orotidine, a slow substrate for these enzymes, binds to the catalytic site with no significant [1'-(3)H]orotidine BIEs. Thus, OPRTs are unable to initiate ground-state destabilization of orotidine by altered C1' hybridization because of the missing 5'-phosphate. However the k(cat)/K(m) KIEs for [1'-(3)H]orotidine are also approximately 1.20. The C1' distortion for OMP happens in two steps, half upon binding and half on going from the Michaelis complex to the TS. With orotidine as the substrate, there is no ground-state destabilization in the Michaelis complexes, but the C1' distortion at the TS is equal to that of OMP. The large single barrier for TS formation with orotidine slows the rate of barrier crossing. PMID- 21526796 TI - Triterpenoid glycosides from the leaves of two cultivars of Medicago polymorpha L. AB - The saponin composition of leaves from the Medicago polymorpha cultivars 'Santiago' and 'Anglona' belonging to the botanical varieties brevispina and vulgaris, respectively, was investigated by a combination of chromatographic, spectroscopic, and spectrometric techniques. Several compounds were detected and quantitated by HPLC analysis using the external standard method. Twelve triterpene saponins (1-12) were purified by reverse-phase chromatography and their structures elucidated by spectroscopic (1D and 2D NMR, ESI-MS/MS) and chemical methods. They were identified as glycosides of echinocystic acid, hederagenin, caulophyllogenin, bayogenin, and soyasapogenol B. Two of them (2, 10) were previously reported in M. polymorpha; five of them (4, 6, 7, 9, 12) were already identified in other Medicago species; and three of them (1, 8, 11) were found in other plant genera. The two saponins identified as 3-O-alpha-L arabinopyranosyl-28-O-[beta-D-glucopyranosyl(1->6)beta-D-glucopyranoside] echinocystic acid (3) and 3-O-alpha-L-arabinopyranosyl-28-O-beta-D glucopyranoside echinocystic acid (5) are newly identified natural compounds. The presence of echinocystic acid is reported here for the first time in the genus Medicago. Saponins from the cultivar 'Anglona' were characterized by a higher amount of echinocystic acid glycosydes, whereas saponins from the cultivar 'Santiago' were characterized by a higher amount of hederagenin glycosydes. PMID- 21526797 TI - A successful chemical strategy to induce oligothiophene self-assembly into fibers with tunable shape and function. AB - Functional supramolecular architectures for bottom-up organic nano- and microtechnology are a high priority research topic. We discovered a new recognition algorithm, resulting from the combination of thioalkyl substituents and head-to-head regiochemistry of substitution, to induce the spontaneous self assembly of sulfur overrich octathiophenes into supramolecular crystalline fibers combining high charge mobility and intense fluorescence. The fibers were grown on various types of surfaces either as superhelices or straight rods depending on molecular structure. Helical fibers directly grown on a field effect transistor displayed efficient charge mobility and intrinsic 'memory effect'. Despite the fact that the oligomers did not have chirality centers, one type of hand-helicity was always predominant in helical fibers, due to the interplay of molecular atropisomerism and supramolecular helicity induced by terminal substituents. Finally, we found that the new sulfur overrich oligothiophenes can easily be prepared in high yields through ultrasound and microwave assistance in green conditions. PMID- 21526798 TI - Study of antisite defects in hydrothermally prepared LiFePO4 by in situ X-ray diffraction. AB - Hydrothermal synthesis has proven to be a cost-effective, energy-efficient approach for the manufacture of lithium iron phosphate (LiFePO4) and its related materials. However, hydrothermally prepared LiFePO4 typically suffers from antisite defects, where some of the iron resides on lithium sites and restricts lithium-ion mobility. A post-heat-treatment temperature of around 700 degrees C is generally used to eliminate cation disorder, but little is known about these antisite defects or their concentration as a function of the post-heat-treatment temperature. In this study, time-resolved, synchrotron X-ray diffraction reveals that antisite defects are completely eliminated above 500 degrees C, suggesting that the electrochemical performance may be significantly enhanced by a milder postsynthesis heat treatment. The preliminary electrochemical results show a significant enhancement in the electrochemical capacity with the defect-free material, with the specific capacity increasing by approximately 60% at a C/20 rate. PMID- 21526799 TI - Accelerating two algorithms for large-scale compound selection on GPUs. AB - Compound selection procedures based on molecular similarity and diversity are widely used in drug discovery. Current algorithms are often time consuming when applied to very large compound sets. This paper describes the acceleration of two selection algorithms (the leader and the spread algorithms) on graphical processing units (GPUs). We first parallelized the molecular similarity calculation based on Daylight fingerprints and the Tanimoto index and then implemented the two algorithms on GPU hardware using the open source Thrust library. Experiments show that the GPU leader algorithm is 73-120 times faster than the CPU version, and the GPU spread algorithm is 78-143 times faster than the CPU version. PMID- 21526800 TI - Deconvolution of two-dimensional NMR spectra by fast maximum likelihood reconstruction: application to quantitative metabolomics. AB - We have developed an algorithm called fast maximum likelihood reconstruction (FMLR) that performs spectral deconvolution of 1D-2D NMR spectra for the purpose of accurate signal quantification. FMLR constructs the simplest time-domain model (e.g., the model with the fewest number of signals and parameters) whose frequency spectrum matches the visible regions of the spectrum obtained from identical Fourier processing of the acquired data. We describe the application of FMLR to quantitative metabolomics and demonstrate the accuracy of the method by analysis of complex, synthetic mixtures of metabolites and liver extracts. The algorithm demonstrates greater accuracy (0.5-5.0% error) than peak height analysis and peak integral analysis with greatly reduced operator intervention. FMLR has been implemented in a Java-based framework that is available for download on multiple platforms and is interoperable with popular NMR display and processing software. Two-dimensional (1)H-(13)C spectra of mixtures can be acquired with acquisition times of 15 min and analyzed by FMLR in the range of 2 5 min per spectrum to identify and quantify constituents present at concentrations of 0.2 mM or greater. PMID- 21526801 TI - Optical tuning of the fluorescence spectrum of a pi-conjugated polymer through excitation power. AB - The photophysical properties of a pi-conjugated polymer containing 2,2'-bipyridyl alternated with 2,5-dihexyloxyphenylene units (PBPyDHP) are investigated experimentally in terms of the conditions used (solvent, concentration, presence or absence of molecular oxygen, and optical excitation power). The experimental results have suggested that the fluorescence from PBPyDHP can be tuned by proper selection of the experimental conditions showing only one or two emission peaks: 445 nm (blue) and 555 nm (green). The observed effects were interpreted in terms of the twisted intramolecular charge transfer (TICT) theory. This is the first experimental report showing the interconversion of an usual fluorescence, called locally emission state (LE), to a TICT state in second scale time by varying the excitation power; that is, even though the torsion of only one fluorophore occurs in a nano or picosecond scale, the global change (the interconversion for all fluorophores) has occurred in the second time scale. PMID- 21526803 TI - Nanocontact electrification: patterned surface charges affecting adhesion, transfer, and printing. AB - Contact electrification creates an invisible mark, overlooked and often undetected by conventional surface spectroscopic measurements. It impacts our daily lives macroscopically during electrostatic discharge and is equally relevant on the nanoscale in areas such as soft lithography, transfer, and printing. This report describes a new conceptual approach to studying and utilizing contact electrification beyond prior surface force apparatus and point contact implementations. Instead of a single point contact, our process studies nanocontact electrification that occurs between multiple nanocontacts of different sizes and shapes that can be formed using flexible materials, in particular, surface-functionalized poly(dimethylsiloxane) (PDMS) stamps and other common dielectrics (PMMA, SU-8, PS, PAA, and SiO(2)). Upon the formation of conformal contacts and forced delamination, contacted regions become charged, which is directly observed using Kelvin probe force microscopy revealing images of charge with sub-100-nm lateral resolution. The experiments reveal chemically driven interfacial proton exchange as the dominant charging mechanism for the materials that have been investigated so far. The recorded levels of uncompensated charges approach the theoretical limit that is set by the dielectric breakdown strength of the air gap that forms as the surfaces are delaminated. The macroscopic presence of the charges is recorded using force distance curve measurements involving a balance and a micromanipulator to control the distance between the delaminated objects. Coulomb attraction between the delaminated surfaces reaches 150 N/m(2). At such a magnitude, the force finds many applications. We demonstrate the utility of printed charges in the fields of (i) nanoxerography and (ii) nanotransfer printing whereby the smallest objects are ~10 nm in diameter and the largest objects are in the millimeter to centimeter range. The printed charges are also shown to affect the electronic properties of contacted surfaces. For example, in the case of a silicon-on insulator field effect transistors are in contact with PDMS and subsequent delamination leads to threshold voltage shifts that exceed 500 mV. PMID- 21526802 TI - Application of the SCC-DFTB method to neutral and protonated water clusters and bulk water. AB - The self-consistent charge density functional tight-binding (SCC-DFTB) method has been actively employed to study proton-transfer processes in biological systems. Recent studies in the literature employing SCC-DFTB reported that the method favors the Zundel form of the hydrated proton over the Eigen form, both in gas phase water clusters and in bulk water, in disagreement with both higher-level calculations and experimental data. In this work, we explore the performance of SCC-DFTB for protonated gas-phase water clusters and bulk water (the latter both with and without an excess proton) with a modified O-H repulsive potential reported in our earlier work and with on-site third-order expansion of the DFT energy. Our results show that, with the proper set of published parameters, SCC DFTB does correctly favor the Eigen form of the hydrated proton as compared to the Zundel form, both in gas-phase clusters and in the bulk; the amphiphilic character of the hydrated proton discussed in the literature has also been observed. The analyses do, however, bring forth remaining limitations in terms of the solvation structure around the hydrated proton as well as the structure of bulk water, which can guide future improvements of the method. PMID- 21526804 TI - Hydrogen adsorption on Pd- and Ru-doped C60 fullerene at an ambient temperature. AB - Palladium- and ruthenium-doped C(60) fullerene compounds were synthesized by incipient wetness impregnation of C(60) fullerene with the corresponding metal acetylacetonate precursors. Transmission electron microscopy (TEM) imaging of the metal-doped C(60) fullerene samples showed different dispersion morphologies of palladium and ruthenium particles on the C(60) matrix. Raman spectra revealed a drastic decrease in peak intensity followed by disappearance of several bands indicating the distortion of the C(60) cage structure. The amorphous nature of the C(60) fullerene compounds was confirmed by the X-ray diffraction study. Hydrogen adsorption amount of 0.85 wt % and 0. 69 wt % on Pd-C(60) and Ru-C(60), respectively, as compared to 0.3 wt % on the pure C(60) fullerene were measured at 300 bar and 298 K. The enhancement in the hydrogen uptakes can be attributed to several factors, including adsorption of molecular H(2) on the defect sites, metallic hydride formation, spillover of hydrogen, and bond formation with atomic hydrogen with different active sites of carbon of host fullerene. The hydrogen adsorption isotherms are of type III and can be correlated by the Freundlich (for Ru-C(60)) and modified Oswin equations (for Pd-C(60) and pristine C(60)). PMID- 21526805 TI - Biomimetic membrane arrays on cast hydrogel supports. AB - Lipid bilayers are intrinsically fragile and require mechanical support in technical applications based on biomimetic membranes. Tethering the lipid bilayer membranes to solid substrates, either directly through covalent or ionic substrate-lipid links or indirectly on substrate-supported cushions, provides mechanical support but at the cost of small molecule transport through the membrane-support sandwich. To stabilize biomimetic membranes while allowing transport through a membrane-support sandwich, we have investigated the feasibility of using an ethylene tetrafluoroethylene (ETFE)/hydrogel sandwich as the support. The sandwich is realized as a perforated surface-treated ETFE film onto which a hydrogel composite support structure is cast. We report a simple method to prepare arrays of lipid bilayer membranes with low intrinsic electrical conductance on the highly permeable, self-supporting ETFE/hydrogel sandwiches. We demonstrate how the ETFE/hydrogel sandwich support promotes rapid self-thinning of lipid bilayers suitable for hosting membrane-spanning proteins. PMID- 21526806 TI - Use of IR thermography to investigate heated droplet evaporation and contact line dynamics. AB - In this paper we present the results of an experimental study investigating interfacial properties during the evaporation of sessile water droplets on a heated substrate. This study uses infrared thermography to map the droplet interfacial temperature. The measurements evidence nonuniform temperature and gradients that evolve in time during the evaporation process. A general scaling law for the interfacial temperature is deduced from the experimental observations. A theoretical analysis is performed to predict the local evaporation rates and their evolution in time. The use of energy conservation laws enabled us to deduce a general expression for the interfacial temperature. The comparison between the theory and experiments shows good agreement and allows us to rationalize the experimental observations. The thermography analysis also enabled the detection of the three-phase contact line location and its dynamics. To our knowledge, such measurements are performed for the first time using thermography. PMID- 21526807 TI - Surfactant-free miniemulsion polymerization as a simple synthetic route to a successful encapsulation of magnetite nanoparticles. AB - Due to the existing interest in new hybrid particles in the colloidal range based on both magnetic and polymeric materials for applications in biotechnological fields, this work is focused on the preparation of magnetic polymer nanoparticles (MPNPs) by a single-step miniemulsion process developed to achieve better control of the morphology of the magnetic nanocomposite particles. MPNPs are prepared by surfactant-free miniemulsion polymerization using styrene (St) as a monomer, hexadecane (HD) as a hydrophobe, and potassium persulfate (KPS) as an initiator in the presence of oleic acid (OA)-modified magnetite nanoparticles. The effect of the type of cross-linker used [divinylbenzene (DVB) and bis[2 (methacryloyloxy)ethyl] phosphate (BMEP)] together with the effect of the amount of an aid stabilizer (dextran) on size, particle size distribution (PSD), and morphology of the hybrid nanoparticles synthesized is analyzed in detail. The mixture of different surface modifiers produces hybrid nanocolloids with various morphologies: from a typical core-shell composed by a magnetite core surrounded by a polymer shell to a homogeneously distributed morphology where the magnetite is uniformly distributed throughout the entire nanocomposite. PMID- 21526808 TI - In situ STM imaging of bis-3-sodiumsulfopropyl-disulfide molecules adsorbed on copper film electrodeposited on Pt(111) single crystal electrode. AB - The adsorption of bis-3-sodiumsulfopropyldi-sulfide (SPS) on metal electrodes in chloride-containing media has been intensively studied to unveil its accelerating effect on Cu electrodeposition. Molecular resolution scanning tunneling microscopy (STM) imaging technique was used in this study to explore the adsorption and decomposition of SPS molecules concurring with the electrodeposition of copper on an ordered Pt(111) electrode in 0.1 M HClO(4) + 1 mM Cu(ClO(4))(2) + 1 mM KCl. Depending on the potential of Pt(111), SPS molecules could react, adsorb, and decompose at chloride-capped Cu films. A submonolayer of Cu adatoms classified as the underpotential deposition (UPD) layer at 0.4 V (vs Ag/AgCl) was completely displaced by SPS molecules, possibly occurring via RSSR (SPS) + Cl-Cu-Pt -> RS(-)-Pt(+) + RS(-) (MPS) + Cu(2+) + Cl(-), where MPS is 3 mercaptopropanesulfonate. By contrast, at 0.2 V, where a full monolayer of Cu was presumed to be deposited, SPS molecules were adsorbed in local (4 * 4) structures at the lower ends of step ledges. Bulk Cu deposition driven by a small overpotential (eta < 50 mV) proceeded slowly to yield an atomically smooth Cu deposit at the very beginning (<5 layers). On a bilayer Cu deposit, the chloride adlayer was still adsorbed to afford SPS admolecules arranged in a unique 1D striped phase. SPS molecules could decompose into MPS upon further Cu deposition, as a (2 * 2)-MPS structure was observed with prolonged in situ STM imaging. It was possible to visualize either SPS admolecules in the upper plane or chloride adlayer sitting underneath upon switching the imaging conditions. Overall, this study established a MPS molecular film adsorbed to the chloride adlayer sitting atop the Cu deposit. PMID- 21526809 TI - Stimuli responsive poly(1-[11-acryloylundecyl]-3-methyl-imidazolium bromide): dewetting and nanoparticle condensation phenomena. AB - A stimuli-responsive homopolymer poly(ILBr) is fabricated via a "two-phase" atom transfer radical polymerization (ATRP) process, where ILBr stands for the reactive ionic liquid surfactant, 1-[11-acryloylundecyl]-3-methyl-imidazolium bromide. An extraordinarily wide molecular weight distribution (PDI = 6.0) was obtained by introducing the initiator (4-bromomethyl methyl benzoate) in a heterogeneous two-phase process. The molecular weight distribution of poly(ILBr) was characterized by size-exclusion chromatography (SEC). The resulting homopolymer was found to be surface active and stimuli responsive. Poly(ILBr) films coated on quartz exhibit stimuli-responsive dewetting after ion exchange of Br(-) by PF(6)(-). This dewetting phenomenon can be understood in chain segmental terms as a stimuli-induced structural relaxation and appears to be the first such reported stimuli-responsive polymeric dewetting. Titrating aqueous poly(ILBr) with aqueous bis(2-ethylhexyl)sulfosuccinate induces nanophase separation and results in the condensation of nanoparticles 30-60 nm in diameter. PMID- 21526811 TI - Production of a biomimetic Fe(I)-S phase on pyrite by atomic hydrogen beam surface reactive scattering. AB - Molecular beam surface scattering and X-ray absorption spectroscopic experiments were employed to study the reaction of deuterium atoms with a pyrite, FeS(2) (100), surface and to investigate the electronic and geometric structures of the resulting Fe-S phases. Incident D atoms, produced by a radiofrequency plasma and expanded in an effusive beam, were directed at a pyrite surface held at various temperatures from ambient up to 200 degrees C. During exposure to the D-atom beam, D(2)S products were released with a thermal distribution of molecular speeds, indicating that the D atoms likely reacted in thermal equilibrium with the surface. The yield of D(2)S from the surface decreased approximately exponentially with exposure duration, suggesting that the surface accessible sulfur atoms were depleted, thus leaving an iron-rich surface. This conclusion is consistent with X-ray absorption measurements of the exposed surfaces, which indicated the formation of a layered structure, with elemental iron as the outermost layer on top of a formally Fe((I))-S phase as an intermediate layer and a formally Fe((II))-S(2) bulk pyrite layer at lower depths. The reduced Fe((I))-S phase is particularly remarkable because of its similarity to the catalytically active sites of small molecule metalloenzymes, such as FeFe-hydrogenases and MoFe nitrogenases. PMID- 21526812 TI - Sliding of water droplets on hydrophobic surfaces with various hydrophilic region sizes. AB - Four patterned surfaces with hydrophilic areas of different sizes were prepared using photolithography with a smooth octadecyltrimethoxysilane (ODS) hydrophobic coating. The hydrophilic area in the surfaces was aligned hexagonally with a constant area fraction. The sliding angle and contact angle hysteresis of the water droplets increased concomitantly with increasing pattern size. The increase of the contact line distortion between defects at the receding side plays an important role in this trend. The droplet sliding velocity also increased concomitantly with increasing pattern size. This trend was simulated by a simple flow model. The contribution of the interface between the ODS region and the hydrophilic area was deduced from this trend. This study demonstrated the different size dependency of the chemical surface defects for sliding behavior between the critical moment at which a droplet slides down and the period when a droplet is sliding. PMID- 21526810 TI - Conductive AFM patterning on oligo(ethylene glycol)-terminated alkyl monolayers on silicon substrates: proposed mechanism and fabrication of avidin patterns. AB - Micro- and nanopatterns of biomolecules on inert, ultrathin platforms on nonoxidized silicon are ideal interfaces between silicon-based microelectronics and biological systems. We report here the local oxidation nanolithography with conductive atomic force microscopy (cAFM) on highly protein-resistant, oligo(ethylene glycol) (OEG)-terminated alkyl monolayers on nonoxidized silicon substrates. We propose a mechanism for this process, suggesting that it is possible to oxidize only the top ethylene glycol units to generate carboxylic acid and aldehyde groups on the film surface. We show that avidin molecules can be attached selectively to the oxidized pattern and the density can be varied by altering the bias voltage during cAFM patterning. Biotinylated molecules and nanoparticles are selectively immobilized on the resultant avidin patterns. Since one of the most established methods for immobilization of biomolecules is based on avidin-biotin binding and a wide variety of biotinylated biomolecules are available, this approach represents a versatile means for prototyping any nanostructures presenting these biomolecules on silicon substrates. PMID- 21526813 TI - Quantitative classification of DNA damages induced by submicromolar cadmium using oligonucleotide chip coupled with lesion-specific endonuclease digestion. AB - Implementation of proper analytical tool for systematic investigation and quantitative determination of different classes of cadmium ion-induced DNA damages, especially at low metal ion concentrations, is still lacking. Using lesion-specific enzymes that cleave DNA at specific classes of damage and a fluorometric approach developed for quantifying fluorophore-labeled oligonucleotides bound to chip surfaces, we determined the frequencies of different lesions (strand breaks, oxidized purines, oxidized pyrimidines, or abasic sites) induced by submicromolar Cd(2+). Cd(2+)-treated oligonucleotide chips were digested with various endonucleases (Fpg protein, endonuclease III, endonuclease IV), producing a de novo single strand break (SSB) at their substrate modifications. The frequency of SSB and double strand break (DSB) was computed from the difference of pre- and post-Cd(2+)-treatment oligonucleotide coverage on the chip. While the frequency of SSBs and oxidized bases were successfully quantified even at 0.5 MUM of Cd(2+), DSB frequency could be easily quantitated at 8.7 MUM [Cd(2+)]. The numbers of abasic sites were below the oligonucleotide detection limit (2.4 amole; equivalent to 0.24 fM for a reaction volume of 100 MUL). SSBs were found to constitute about 85-90% of single strand damages, while oxidized bases comprise only 4-7% of the total at 0.9 to 8.7 MUM [Cd(2+)]. PMID- 21526814 TI - Cellular and transcriptional response of Pseudomonas stutzeri to quantum dots under aerobic and denitrifying conditions. AB - Pseudomonas stutzeri was exposed to quantum dots (QDs) with three different surface coatings (anionic polymaleic anhydride-alt-1-octadecene (PMAO), cationic polyethylenimine (PEI), and carboxyl QDs) under both aerobic and anaerobic (denitrifying) conditions. Under aerobic conditions, toxicity (assessed per growth inhibition) increased from PMAO to carboxyl to PEI QDs. The positive charge of PEI facilitated direct contact with negatively charged bacteria, which was verified by TEM analysis. Both PMAO and PEI QDs hindered energy transduction (indicated by a decrease in cell membrane potential), and this effect was most pronounced with PEI QDs under denitrifying conditions. Up-regulation of denitrification genes (i.e., nitrate reductase narG, periplasmic nitrate reductase napB, nitrite reductase nirH, and NO reductase norB) occurred upon exposure to subinhibitory PEI QD concentrations (1 nM). Accordingly, denitrification activity (assessed per respiratory nitrate consumption in the presence of ammonia) increased during sublethal PEI QD exposure. However, cell viability (including denitrification) was hindered at 10 nM or higher PEI QD concentrations. Efflux pump genes czcB and czcC were induced by PEI QDs under denitrifying conditions, even though Cd and Se dissolution from QDs did not reach toxic levels (exposure was at pH 7 to minimize hydrolysis of QD coatings and the associated release of metal constituents). Up-regulation of the superoxide dismutase (stress) gene sodB occurred only under aerobic conditions, likely due to intracellular production of reactive oxygen species (ROS). The absence of ROS under denitrifying conditions suggests that the antibacterial activity of QDs was not due to ROS production alone. Overall, this work forewarns about unintended potential impacts to denitrification as a result of disposal and incidental releases of QDs, especially those with positively charged coatings (e.g., PEI QDs). PMID- 21526815 TI - Capillary driven molten metal flow over topographically complex substrates. AB - A theoretical model of a capillary driven flow of liquid metal through topography features of rough surfaces has been verified by a study of molten solder (Sn-Pb) spreading over Cu(6)Sn(5)/Cu(3)Sn/Cu intermetallic (IMC) substrates. Flow through microgrooves over a rough IMC substrate is considered as spreading through an isotropic porous medium featuring a network of open microgrooves having predefined free-flow area cross sections. The relative margin of deviation between theoretically predicted and empirically determined locus of points of triple line locations is within the range of 5-15%. This margin supports the validity of the developed, analytically formulated square root power law model for a whole spreading domain in terms of (i) geometry of topographical features of the rough surface (i.e., effective intrinsic permeability, porosity/tortuosity, and microchannel cross section geometry), (ii) wetting/spreading features (equilibrium contact angle and filling factor), and (iii) molten metal/substrate properties (viscosity and surface tension). Experimental data involving triple line kinetics represent the data set of locations of the triple line versus time obtained by in situ monitoring of the spreading of molten metal systems over IMC substrates by using the controlled atmosphere hot stage microscopy. PMID- 21526816 TI - Use of a liter-scale microbial desalination cell as a platform to study bioelectrochemical desalination with salt solution or artificial seawater. AB - Bioelectrochemical desalination is potentially advantageous because of bioenergy production and integrated wastewater treatment and desalination. In this work, the performance and energy benefits of a liter-scale upflow microbial desalination cell (UMDC) were evaluated. The UMDC desalinated both salt solution (NaCl) and artificial seawater, and the removal rate of total dissolved solid (TDS) increased with an increased hydraulic retention time, although TDS reduction in artificial seawater was lower than that in salt solution. Our analysis suggested that electricity generation was a predominant factor in removing TDS (more than 70%), and that other factors, like water osmosis and unknown processes, also contributed to TDS reduction. It was more favorable given the high energy efficiency, when treating salt solution, to operate the UMDC under the condition of high power output compared with that of high current generation because of the amount of energy production; while high current generation was more desired with seawater desalination because of lower salinity in the effluent. Under the condition of the high power output and the assumption of the UMDC as a predesalination in connection with a reversal osmosis (RO) system, the UMDC could produce electrical energy that might potentially account for 58.1% (salt solution) and 16.5% (artificial seawater) of the energy required by the downstream RO system. Our results demonstrated the great potential of bioelectrochemical desalination. PMID- 21526817 TI - Geometry optimization of atomic clusters using a heuristic method with dynamic lattice searching. AB - In this paper, a global optimization method is presented to determine the global minimum structures of atomic clusters, where several already existing techniques are combined, such as the dynamic lattice searching method and two-phase local minimization method. The present method is applied to some selected large-sized Lennard-Jones (LJ) clusters and silver clusters described by the Gupta potential in the size range N = 13-140 and 300. Comparison with the results reported in the literature shows that the method is highly efficient and a lot of new global minima missed in previous papers are found for the silver clusters. The method may be a promising tool for the theoretical determination of ground-state structure of atomic clusters. Additionally, the stabilities of silver clusters are also analyzed and it is found that in the size range N = 13-140 there exist 12 particularly stable clusters. PMID- 21526818 TI - Statistical analysis of chemical transformation kinetics using Markov-Chain Monte Carlo methods. AB - For the risk assessment of chemicals intentionally released into the environment, as, e.g., pesticides, it is indispensable to investigate their environmental fate. Main characteristics in this context are transformation rates and partitioning behavior. In most cases the relevant parameters are not directly measurable but are determined indirectly from experimentally determined concentrations in various environmental compartments. Usually this is done by fitting mathematical models, which are usually nonlinear, to the observed data and such deriving estimates of the parameter values. Statistical analysis is then used to judge the uncertainty of the estimates. Of particular interest in this context is the question whether degradation rates are significantly different from zero. Standard procedure is to use nonlinear least-squares methods to fit the models and to estimate the standard errors of the estimated parameters from Fisher's Information matrix and estimated level of measurement noise. This, however, frequently leads to counterintuitive results as the estimated probability distributions of the parameters based on local linearization of the optimized models are often too wide or at least differ significantly in shape from the real distribution. In this paper we identify the shortcoming of this procedure and propose a statistically valid approach based on Markov-Chain Monte Carlo sampling that is appropriate to determine the real probability distribution of model parameters. The effectiveness of this method is demonstrated on three data sets. Although it is generally applicable to different problems where model parameters are to be inferred, in the present case for simplicity we restrict the discussion to the evaluation of metabolic degradation of chemicals in soil. It is shown that the method is successfully applicable to problems of different complexity. We applied it to kinetic data from compounds with one and five metabolites. Additionally, using simulated data, it is shown that the MCMC method estimates the real probability distributions of parameters well and much better than the standard optimization approach. PMID- 21526819 TI - Bottlenose dolphins as indicators of persistent organic pollutants in the western North Atlantic Ocean and northern Gulf of Mexico. AB - Persistent organic pollutants (POPs) including legacy POPs (PCBs, chlordanes, mirex, DDTs, HCB, and dieldrin) and polybrominated diphenyl ether (PBDE) flame retardants were determined in 300 blubber biopsy samples from coastal and near shore/estuarine male bottlenose dolphins (Tursiops truncatus) sampled along the U.S. East and Gulf of Mexico coasts and Bermuda. Samples were from 14 locations including urban and rural estuaries and near a Superfund site (Brunswick, Georgia) contaminated with the PCB formulation Aroclor 1268. All classes of legacy POPs in estuarine stocks varied significantly (p < 0.05) among sampling locations. POP profiles in blubber varied by location with the most characteristic profile observed in bottlenose dolphins sampled near the Brunswick and Sapelo estuaries along the Georgia coast which differed significantly (p < 0.001) from other sites. Here and in Sapelo, PCB congeners from Aroclor 1268 dominated indicating widespread food web contamination by this PCB mixture. PCB 153, which is associated with non-Aroclor 1268 PCB formulations, correlated significantly to human population indicating contamination from a general urban PCB source. Factors influencing regional differences of other POPs were less clear and warrant further study. This work puts into geographical context POP contamination in dolphins to help prioritize efforts examining health effects from POP exposure in bottlenose dolphins. PMID- 21526820 TI - Synthesis of a stereochemically diverse library of medium-sized lactams and sultams via S(N)Ar cycloetherification. AB - We have implemented an aldol-based "build/couple/pair" (B/C/P) strategy for the synthesis of stereochemically diverse 8-membered lactam and sultam scaffolds via S(N)Ar cycloetherification. Each scaffold contains two handles, an amine and aryl bromide, for solid-phase diversification via N-capping and Pd-mediated cross coupling. A sparse matrix design strategy that achieves the dual objective of controlling physicochemical properties and selecting diverse library members was implemented. The production of two 8000-membered libraries is discussed including a full analysis of library purity and property distribution. Library diversity was evaluated in comparison to the Molecular Library Small Molecule Repository (MLSMR) through the use of a multifusion similarity (MFS) map and principal component analysis (PCA). PMID- 21526821 TI - Adsorption of transgenic insecticidal Cry1Ab protein to silica particles. Effects on transport and bioactivity. AB - Bt crops are genetically modified to be resistant against insect pests by expressing insecticidal Cry proteins. The processes governing the fate and bioavailability of the expressed transgenic Cry proteins in soils are poorly understood. We studied adsorption of Cry1Ab to negatively charged silica (SiO(2)) particles, a major soil constituent and a model for negatively charged mineral surfaces, at pH 5 to 10 and ionic strengths I = 10 mM to 250 mM, both in solution depletion and saturated column transport experiments. Cry1Ab-SiO(2) interactions were dominated by patch-controlled electrostatic attraction (PCEA), as evident from increasing Cry1Ab attraction to SiO(2) with decreasing I at pH at which both Cry1Ab and SiO(2) were net negatively charged. Experimental and modeling evidence is provided that the surface heterogeneity of SiO(2) particles modulated PCEA, leading to a fraction of adsorption sites with slow Cry1Ab desorption kinetics. Desorption rates from these sites increased upon increasing the solution pH. In toxicity bioassays, we demonstrated that Cry1Ab retained insecticidal activity when adsorbed to SiO(2), suggesting high protein conformational stability during adsorption-desorption cycles. Models predicting Cry1A protein adsorption in soils therefore need to account for combined effects of the nonuniform protein surface charge distribution and of sorbent surface heterogeneity. PMID- 21526823 TI - Ortho-branched ladder-type oligophenylenes with two-dimensionally pi-conjugated electronic properties. AB - The synthesis, photochemical and electrochemical properties, and electronic structures of a series of star-shaped ladder-type oligophenylenes Sn (n = 7, 10, 13, 16, 19, and 22), including one multibranched case S19mb, are reported and compared with the linear para-phenylene ladders Rn (n = 2-5 and 8) and the stepladder analogues SFn (n = 10, 16, and 22). The n value refers to the number of pi-conjugated phenylene rings. Functionalized isotruxenes are the key synthetic building blocks, and S22 is the largest monodispersed ladder-type oligophenylene known to date. The Sn systems possess the structural rigidity of Rn and the ortho-para phenylene connectivity of SFn. Consequently, Sn represents the first class of branched chromophores with fully two-dimensional conjugation in both ground- and excited-state configurations. Evidences include the excellent linear correlations for the optical 0-0 energies or the first oxidation potentials of Sn and Rn against the reciprocal of their n values, delocalized HOMO and LUMO based on density functional theory calculations, and molecule-like fluorescence anisotropy. The resulting model of effective conjugation plane (ECP) for the two-dimensional pi-conjugated systems compliments the concept of effective conjugation length (ECL) for one-dimensional oligomeric systems. Other implications of the observed structure-property relationships are also included. PMID- 21526822 TI - Application of a sparse matrix design strategy to the synthesis of dos libraries. AB - We have implemented an interactive and practical sparse matrix design strategy for the synthesis of DOS libraries, which facilitates the selection of diverse library members within a user-defined range of physicochemical properties while still maintaining synthetic efficiency. The utility of this approach is illustrated with the synthesis of an 8000-membered library of stereochemically diverse medium-sized rings accessible via a build/couple/pair DOS strategy. Diverse library members were selected from a virtual library by applying the maximum dissimilarity method, while the selection of similar analogs around each diverse product was ensured by picking near neighbors algorithmically based on fingerprint comparison. Adjustable filters on compound properties, which can be tailored to suit the needs of the target biology, facilitated subset selection from the synthetically accessible compounds. PMID- 21526824 TI - Adsorption of oxygenates on alkanethiol-functionalized Pd(111) surfaces: mechanistic insights into the role of self-assembled monolayers on catalysis. AB - Recent work shows that coating a supported palladium catalyst with a self assembled monolayer (SAM) of alkanethiols can dramatically improve selectivity in the hydrogenation of 1-epoxy-3-butene (EpB) to 1-epoxybutane. Here, we present the results of surface-level investigations of the adsorption of EpB and related molecules on SAM-coated Pd(111), with an aim of identifying mechanistic explanations for the observed catalytic behavior. Alkanethiol SAM-covered Pd(111) surfaces were prepared by conventional techniques and transferred to ultrahigh vacuum, where they were characterized using Auger electron spectroscopy (AES) and temperature-programmed desorption (TPD) of EpB and other probe molecules. Whereas previous studies have shown that EpB undergoes rapid decomposition via epoxide ring opening on uncoated Pd(111), TPD studies show that EpB does not undergo substantial ring opening on SAM-covered surfaces but rather desorbs intact at temperatures less than 300 K. Systematic comparisons of EpB desorption spectra to spectra for other C(4) oxygenates suggest that the SAM creates a kinetic barrier to epoxide ring-opening reactions that does not exist on the uncoated surface. The EpB desorption spectra as a function of exposure show behavior similar to the desorption of olefins from Pd(111), indicating that the binding of the olefin functionality, in contrast to that of the epoxide ring, is not significantly perturbed. EpB desorption spectra from surfaces with less well-ordered SAMs show the presence of weakly bound states not observed on well-ordered SAM surfaces. The lower activity observed on catalysts covered with less well-ordered SAMs is hypothesized to occur due to partial confinement of adsorbates into these weakly bound, less active states. PMID- 21526825 TI - Triterpene cyclases from Oryza sativa L.: cycloartenol, parkeol and achilleol B synthases. AB - The gene products of AK121211, AK066327, and AK070534 from Oryza sativa encode cycloartenol, parkeol, and achilleol B synthases, respectively. Parkeol synthase is a unique enzyme that affords parkeol as a single product. Achilleol B synthase is the third seco-type triterpene cyclase identified to date, and triterpenes produced by this synthase include achilleol B (90%), tetracyclic (5.12%) and pentacyclic scaffolds (4.37%), and unidentified triterpenes (0.51%). The pathway for achilleol B biosynthesis is proposed. PMID- 21526826 TI - Mapping of local electrical properties in epitaxial graphene using electrostatic force microscopy. AB - Local electrical characterization of epitaxial graphene grown on 4H-SiC(0001) using electrostatic force microscopy (EFM) in ambient conditions and at elevated temperatures is presented. EFM provides a straightforward identification of graphene with different numbers of layers on the substrate where topographical determination is hindered by adsorbates. Novel EFM spectroscopy has been developed measuring the EFM phase as a function of the electrical DC bias, establishing a rigorous way to distinguish graphene domains and facilitating optimization of EFM imaging. PMID- 21526827 TI - Highly selective methods for synthesis of internal (alpha-) vinylboronates through efficient NHC-Cu-catalyzed hydroboration of terminal alkynes. Utility in chemical synthesis and mechanistic basis for selectivity. AB - Cu-catalyzed methods for site-selective hydroboration of terminal alkynes, where the internal or alpha-vinylboronate is generated predominantly (up to >98%) are presented. Reactions are catalyzed by 1-5 mol % of N-heterocyclic carbene (NHC) complexes of copper, easily prepared from N-aryl-substituted commercially available imidazolinium salts, and proceed in the presence of commercially available bis(pinacolato)diboron [B(2)(pin)(2)] and 1.1 equiv of MeOH at -50 to 15 degrees C in 3-24 h. Propargyl alcohol and amine and the derived benzyl, tert butyl, or silyl ethers as well as various amides are particularly effective substrates; also suitable are a wide range of aryl-substituted terminal alkynes, where higher alpha-selectivity is achieved with substrates that bear an electron withdrawing substituent. alpha-Selective Cu-catalyzed hydroborations are amenable to gram-scale procedures (1 mol % catalyst loading). Mechanistic studies are presented, indicating that alpha selectivity arises from the structural and electronic attributes of the NHC ligands and the alkyne substrates. Consistent with suggested hypotheses, catalytic reactions with a Cu complex, derived from an N-adamantyl-substituted imidazolinium salt, afford high beta selectivity with the same class of substrates and under similar conditions. PMID- 21526828 TI - Correction to "Machine learning-based method to improve docking scoring functions and its application to drug repurposing". PMID- 21526829 TI - Physicochemical mechanism for the enhanced ability of lipid membrane penetration of polyarginine. AB - Arginine-rich, cell-penetrating peptides (e.g., Tat-peptide, penetratin, and polyarginine) are used to carry therapeutic molecules such as oligonucleotides, DNA, peptides, and proteins across cell membranes. Two types of processes are being considered to cross the cell membranes: one is an endocytic pathway, and another is an energy-independent, nonendocytic pathway. However, the latter is still not known in detail. Here, we studied the effects of the chain length of polyarginine on its interaction with an anionic phospholipid large unilamellar vesicle (LUV) or a giant vesicle using poly-l-arginine composed of 69 (PLA69), 293 (PLA293), or 554 (PLA554) arginine residues, together with octaarginine (R8). zeta-potential measurements confirmed that polyarginine binds to LUV via electrostatic interactions. Circular dichroism analysis demonstrated that the transition from the random coil to the alpha-helix structure upon binding to LUV occurred for PLA293 and PLA554, whereas no structural change was observed for PLA69 and R8. Fluorescence studies using membrane probes revealed that the binding of polyarginine to LUV affects the hydration and packing of the membrane interface region, in which the degree of membrane insertion is greater for the longer polyarginine. Isothermal titration calorimetry measurements demonstrated that although the binding affinity (i.e., the Gibbs free energy of binding) per arginine residue is similar among all polyarginines the contribution of enthalpy to the energetics of binding of polyarginine increases with increasing polymer chain length. In addition, confocal laser scanning microscopy showed that all polyarginines penetrate across giant vesicle membranes, and the order of the amount of membrane penetration is R8 ~ PLA69 < PLA293 ~ PLA554. These results suggest that the formation of alpha-helical structure upon lipid binding drives the insertion of polyarginine into the membrane interior, which appears to enhance the membrane penetration of polyarginine. PMID- 21526830 TI - Atmospheric analytical chemistry. PMID- 21526831 TI - First principles study of the ignition mechanism for hypergolic bipropellants: N,N,N',N'-tetramethylethylenediamine (TMEDA) and N,N,N',N' tetramethylmethylenediamine (TMMDA) with nitric acid. AB - We report quantum mechanics calculations (B3LYP flavor of density functional theory) to determine the chemical reaction mechanism underlying the hypergolic reaction of pure HNO(3) with N,N,N',N'-tetramethylethylenediamine (TMEDA) and N,N,N',N'-tetramethylmethylenediamine (TMMDA). TMEDA and TMMDA are dimethyl amines linked by two CH(2) groups or one CH(2) group, respectively, but ignite very differently with HNO(3). We explain this dramatic difference in terms of the role that N lone-pair electrons play in activating adjacent chemical bonds. We identify two key atomistic level factors that affect the ignition delay: (1) The exothermicity for formation of the dinitrate salt from TMEDA or TMMDA. With only a single CH(2) group between basic amines, the diprotonation of TMMDA results in much stronger electrostatic repulsion, reducing the heat of dinitrate salt formation by 6.3 kcal/mol. (2) The reaction of NO(2) with TMEDA or TMMDA, which is the step that releases the heat and reactive species required to propagate the reaction. Two factors of TMEDA promote the kinetics by providing routes with low barriers to oxidize the C: (a) formation of a stable intermediate with a C-C double bond and (b) the lower bond energy for breaking the C-C single bond (by 18 kcal/mol comparing to alkane) between two amines. Both factors would decrease the ignition delay for TMEDA versus TMMDA. The same factors also explain the shorter ignition delay of 1,4-dimethylpiperazine (DMPipZ) versus 1,3,5-trimethylhexahydro 1,3,5-triazine (TMTZ). These results indicate that TMEDA and DMPipZ are excellent green replacements for hydrazines as the fuel in bipropellants. PMID- 21526832 TI - One-pot reductive amination and Suzuki-Miyaura cross-coupling of formyl aryl and heteroaryl MIDA boronates in array format. AB - Formyl-substituted aryl and heteroaryl MIDA boronates were prepared by a DMSO free method and used in the first reported one-pot reductive amination-Suzuki Miyaura cross-coupling sequence. This sequence was then carried out in parallel array format, using microwave-assisted in situ release cross-coupling of MIDA boronates to generate a library with diversity along two axes, affording rapid and convenient access to an array of druglike molecules. PMID- 21526833 TI - Heteronuclear single-quantum coherence nuclear magnetic resonance (HSQC NMR) characterization of acetylated fir (Abies sachallnensis MAST) wood regenerated from ionic liquid. AB - An ionic liquid, 1-butyl-3-methylimidazolium chloride ([Bmim]Cl), was used to dissolve Japanese fir (Abies sachallnensis MAST) wood. Milled woods prepared by planetary ball-milling for 8 h dissolved completely in [Bmim]Cl at 100 degrees C in 2 h. The dissolved woods were then subjected to in situ acetylation, and the fully acetylated woods were regenerated from [Bmim]Cl. (1)H-(13)C correlation heteronuclear single-quantum coherence (HSQC) nuclear magnetic resonance (NMR) experiments were successfully conducted with the acetylated woods in dimethyl sulfoxide (DMSO)-d(6). The acetylated lignin and polysaccharide signals dispersed reasonably well on the 2D spectra. Characterization of the NMR signals for the whole cell-wall components, including lignin, cellulose, and hemicelluloses, was achieved by comparison with isolated lignin and commercial cellulose and hemicelluloses (arabinoxylan, galactomannan, and glucomannan). The procedure used here is applicable for the characterization of cell-wall components in various plant biomasses. PMID- 21526834 TI - Zipper and layer-by-layer assemblies of artificial photosystems analyzed by combining optical and piezoelectric surface techniques. AB - Quartz crystal microbalance (QCM) and surface plasmon resonance (SPR) were used to study zipper and layer-by-layer multilayer assemblies of artificial photosystems based on naphthalenediimides (NDIs) attached to an oligophenylethynyl (OPE-NDI) or p-oligophenyl (POP-NDI) backbone in dry and wet state. For the most interesting OPE-NDI zipper, one obtains for the dry film a monolayer thickness of 1.85 nm and a density of 1.58 g/cm(3), while the wet film has a larger monolayer thickness of 3.6 nm with a water content of 36%. The dry thickness of a monolayer in OPE-NDI zippers corresponds to about one-half of the length of the OPE scaffold in agreement with the proposed structure of the zipper. The low water content of the OPE-NDI films confirms their compact structure. The dry monolayer thickness of the POP-NDI films of 1.45 nm is smaller than that for the OPE-NDI films, which is probably related to a tilt of the POP scaffolds within the adsorbed layer. The POP-NDI films swell in water much more substantially, suggesting a much more open structure. These features are in excellent agreement with the better photophysical performance of the OPE-NDI assemblies when compared to the POP-NDI films. PMID- 21526835 TI - Glycoprotein labeling using engineered variants of galactose oxidase obtained by directed evolution. AB - A directed evolution approach has been used for the generation of variants of galactose oxidase (GOase) that can selectively oxidize glycans on glycoproteins. The aldehyde function introduced on the glycans D-mannose (Man) and D-N-acetyl glucosamine (GlcNAc) by the enzyme variants could then be used to label the glycoproteins and also whole cells that display mannosides on their surface. PMID- 21526837 TI - Single excitons in InGaN quantum dots on GaN pyramid arrays. AB - Fabrication of single InGaN quantum dots (QDs) on top of GaN micropyramids is reported. The formation of single QDs is evidenced by showing single sub millielectronvolt emission lines in microphotoluminescence (MUPL) spectra. Tunable QD emission energy by varying the growth temperature of the InGaN layers is also demonstrated. From MUPL, it is evident that the QDs are located in the apexes of the pyramids. The fact that the emission lines of the QDs are linear polarized in a preferred direction implies that the apexes induce unidirected anisotropic fields to the QDs. The single emission lines remain unchanged with increasing the excitation power and/or crystal temperature. An in-plane elongated QD forming a shallow potential with an equal number of trapped electrons and holes is proposed to explain the absence of other exciton complexes. PMID- 21526836 TI - Zinc sparks are triggered by fertilization and facilitate cell cycle resumption in mammalian eggs. AB - In last few hours of maturation, the mouse oocyte takes up over twenty billion zinc atoms and arrests after the first meiotic division, until fertilization or pharmacological intervention stimulates cell cycle progression toward a new embryo. Using chemical and physical probes, we show that fertilization of the mature, zinc-enriched egg triggers the ejection of zinc into the extracellular milieu in a series of coordinated events termed zinc sparks. These events immediately follow the well-established series of calcium oscillations within the activated egg and are evolutionarily conserved in several mammalian species, including rodents and nonhuman primates. Functionally, the zinc sparks mediate a decrease in intracellular zinc content that is necessary for continued cell cycle progression, as increasing zinc levels within the activated egg results in the reestablishment of cell cycle arrest at metaphase. The mammalian egg thus uses a zinc-dependent switch mechanism to toggle between metaphase arrest and resumption of the meiotic cell cycle at the initiation of embryonic development. PMID- 21526838 TI - Pinpointing phosphorylation sites: Quantitative filtering and a novel site specific x-ion fragment. AB - Phosphoproteomics deals with the identification and quantification of thousands of phosphopeptides. Localizing the phosphorylation site is however much more difficult than establishing the identity of a phosphorylated peptide. Further, recent findings have raised doubts of the validity of the site assignments in large-scale phosphoproteomics data sets. To improve methods for site localization, we made use of a synthetic phosphopeptide library and SILAC-labeled peptides from whole cell lysates and analyzed these with high-resolution tandem mass spectrometry on an LTQ Orbitrap Velos. We validated gas-phase phosphate rearrangement reactions during collision-induced dissociation (CID) and used these spectra to devise a quantitative filter that by comparing signal intensities of putative phosphorylated fragment ions with their nonphosphorylated counterparts allowed us to accurately pinpoint which fragment ions contain a phosphorylated residue and which ones do not. We also evaluated higher-energy collisional dissociation (HCD) and found this to be an accurate method for correct phosphorylation site localization with no gas-phase rearrangements observed above noise level. Analyzing a large set of HCD spectra of SILAC-labeled phosphopeptides, we identified a novel fragmentation mechanism that generates a phosphorylation site-specific neutral loss derived x-ion, which directly pinpoints the phosphorylated residue. Together, these findings significantly improve phosphorylation site localization confidence. PMID- 21526839 TI - The 3D structure of thuricin CD, a two-component bacteriocin with cysteine sulfur to alpha-carbon cross-links. AB - Thuricin CD is an antimicrobial factor that consists of two peptides, Trn-alpha and Trn-beta, that exhibit synergistic activity against drug resistant strains of Clostridium difficile. Trn-alpha and Trn-beta each possess three sulfur to alpha carbon thioether bridges for which the stereochemistry is unknown. This report presents the three-dimensional solution structures of Trn-alpha and Trn-beta. Structure calculations were performed for the eight possible stereoisomers of each peptide based on the same NMR data. The structure of the stereoisomer that best fit the experimental data was chosen as the representative structure for each peptide. It was determined that Trn-alpha has L-stereochemistry at Ser21 (alpha-R), L-stereochemistry at Thr25 (alpha-R), and D-stereochemistry at Thr28 (alpha-S) (an LLD isomer). Trn-beta was also found to be the LLD isomer, with L stereochemistry at Thr21 (alpha-R), L-stereochemistry at Ala25 (alpha-R), and D stereochemistry at Tyr28 (alpha-S). PMID- 21526840 TI - Optimized preprocessing of ultra-performance liquid chromatography/mass spectrometry urinary metabolic profiles for improved information recovery. AB - Ultra-performance liquid chromatography coupled to mass spectrometry (UPLC/MS) has been used increasingly for measuring changes of low molecular weight metabolites in biofluids/tissues in response to biological challenges such as drug toxicity and disease processes. Typically samples show high variability in concentration, and the derived metabolic profiles have a heteroscedastic noise structure characterized by increasing variance as a function of increased signal intensity. These sources of experimental and instrumental noise substantially complicate information recovery when statistical tools are used. We apply and compare several preprocessing procedures and introduce a statistical error model to account for these bioanalytical complexities. In particular, the use of total intensity, median fold change, locally weighted scatter plot smoothing, and quantile normalizations to reduce extraneous variance induced by sample dilution were compared. We demonstrate that the UPLC/MS peak intensities of urine samples should respond linearly to variable sample dilution across the intensity range. While all four studied normalization methods performed reasonably well in reducing dilution-induced variation of urine samples in the absence of biological variation, the median fold change normalization is least compromised by the biologically relevant changes in mixture components and is thus preferable. Additionally, the application of a subsequent log-based transformation was successful in stabilizing the variance with respect to peak intensity, confirming the predominant influence of multiplicative noise in peak intensities from UPLC/MS-derived metabolic profile data sets. We demonstrate that variance stabilizing transformation and normalization are critical preprocessing steps that can benefit greatly metabolic information recovery from such data sets when widely applied chemometric methods are used. PMID- 21526841 TI - Cathodic preconcentration of f-elements on a mercury film carbon fiber disk microelectrode. AB - Field detection and quantification of f-elements is an important problem in radioanalytical chemistry requiring small, portable devices. Here, characterization of a 10 MUm Hg film carbon fiber disk microelectrode to accumulate f-elements is described. Accumulation was performed by cathodic deposition and evaluated by anodic stripping and subsequent ICPMS analyses. La(3+) was used as the model element, and subsequent studies were conducted on a 17 element mixture (Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, and Th). In the model studies, La(3+) undergoes a sorption phenomenon, and as in other studies and confirmed by ICPMS, a monolayer of atoms on the electrode surface is formed. Dissolved O(2) was found to have no effect on the cathodic accumulation of La(3+). Consideration of electrode reaction conditions is made, and reactions are hypothesized. The limit of detection (LOD) was found to be 10( 7) M with mass detection of 10(9) atoms, approximately 5 orders of magnitude less than at conventionally sized electrodes. To solve a dilution problem in follow-on analyses, a suggestion to use microelectrode chip-based sensors was made. PMID- 21526842 TI - Wetting behavior of oleophobic polymer coatings synthesized from fluorosurfactant macromers. AB - Architecturally similar monomers were copolymerized with a water-oil discriminate fluorosurfactant to create hydrophilic-oleophobic coatings. Acrylic acid, hydroxyethyl methacrylate, and methyl methacrylate were used as comonomers with the fluorosurfactant macromer. The homopolymers of the selected comonomers are water-soluble, water-swellable, and water-insoluble, respectively, thus coupling the surfactant monomer in varying concentration within polymers of varying hydrophilicity. Wetting behavior of water and hexadecane were examined as a function of copolymer composition, thus revealing critical structure-property relationships for the surfactant-based system. Acrylic acid copolymers and hydroxyethyl methacrylate copolymers both exhibited a hexadecane contact angle which exceeded the water contact angle. This condition predicted an ability to "self-clean" oil-based foulants. The most oleophobic of the self-cleaning copolymers had an advancing hexadecane contact angle of 73 degrees and an advancing water contact angle of 40 degrees . It was determined that the advancing and receding water and hexadecane contact angle response varies montonically for each copolymer type as the surface concentration of the surfactant is varied. Comparing between copolymer types revealed large differences in wetting response. Methyl methacrylate copolymers with 2.8 mol % surfactant had advancing water contact angle 82 degrees and advancing hexadecane contact angle 26 degrees , which is neither oleophobic nor self-cleaning. In contrast, acrylic acid copolymers with 3.1 mol % surfactant had advancing water contact angle of 44 degrees and advancing hexadecane contact angle of 52 degrees , creating a self-cleaning coating. Thus, the nature of the comonomer exerts a greater influence than the surfactant content on the wetting behavior and self cleaning ability of the final coating. PMID- 21526843 TI - MSSimulator: Simulation of mass spectrometry data. AB - Mass spectrometry coupled to liquid chromatography (LC-MS and LC-MS/MS) is commonly used to analyze the protein content of biological samples in large scale studies, enabling quantitation and identification of proteins and peptides using a wide range of experimental protocols, algorithms, and statistical models to analyze the data. Currently it is difficult to compare the plethora of algorithms for these tasks. So far, curated benchmark data exists for peptide identification algorithms but data that represents a ground truth for the evaluation of LC-MS data is limited. Hence there have been attempts to simulate such data in a controlled fashion to evaluate and compare algorithms. We present MSSimulator, a simulation software for LC-MS and LC-MS/MS experiments. Starting from a list of proteins from a FASTA file, the simulation will perform in-silico digestion, retention time prediction, ionization filtering, and raw signal simulation (including MS/MS), while providing many options to change the properties of the resulting data like elution profile shape, resolution and sampling rate. Several protocols for SILAC, iTRAQ or MS(E) are available, in addition to the usual label free approach, making MSSimulator the most comprehensive simulator for LC-MS and LC-MS/MS data. PMID- 21526844 TI - Identification of the strong vasorelaxing substance scirpusin B, a dimer of piceatannol, from passion fruit (Passiflora edulis) seeds. AB - Piceatannol is present in passion fruit (Passiflora edulis) seeds in high amounts. In this study, we isolated the second major polyphenolic compound of passion fruit seeds and identified it as scirpusin B, which is a dimer of piceatannol. We investigated the antioxidant activities and vasorelaxing effects of these polyphenols. Their antioxidant effects were measured using an in vitro 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, and their vasorelaxant effects were determined ex vivo in rat thoracic aorta. Both polyphenolic compounds exhibited potent antioxidant activities and significant vasorelaxant effects in endothelium-intact aortas. More specifically, scirpusin B exerted a greater antioxidant activity and vasorelaxant effect compared with that of piceatannol. Additionally, the vasorelaxation effects of the compounds were induced via the NO derived from the endothelium. This study provides the possibility that polyphenols in passion fruit seeds are effective against cardiovascular diseases (CVDs). PMID- 21526845 TI - Al2O3/silicon nanoISFET with near ideal nernstian response. AB - Nanoscale ISFET (ion sensitive field-effect transistor) pH sensors are presented that produce the well-known sub-nernstian pH-response for silicon dioxide (SiO(2)) surfaces and near ideal nernstian sensitivity for alumina (Al(2)O(3)) surfaces. Titration experiments of SiO(2) surfaces resulted in a varying pH sensitivity ~20 mV/pH for pH near 2 and >45 mV/pH for pH > 5. Measured pH responses from titrations of thin (15 nm) atomic layer deposited (ALD) alumina (Al(2)O(3)) surfaces on the nanoISFETs resulted in near ideal nernstian pH sensitivity of 57.8 +/- 1.2 mV/pH (pH range: 2-10; T = 22 degrees C) and temperature sensitivity of 0.19 mV/pH degrees C (22 degrees C <= T <= 40 degrees C). A comprehensive analytical model of the nanoISFET sensor, which is based on the combined Gouy-Chapman-Stern and Site-Binding (GCS-SB) model, accompanies the experimental results and an extracted DeltapK ~ 1.5 from the measured responses further supports the near ideal nernstian pH sensitivity. PMID- 21526846 TI - Microwave-assisted green synthesis of silver nanostructures. AB - Over the past 25 years, microwave (MW) chemistry has moved from a laboratory curiosity to a well-established synthetic technique used in many academic and industrial laboratories around the world. Although the overwhelming number of MW assisted applications today are still performed on a laboratory (mL) scale, we expect that this enabling technology may be used on a larger, perhaps even production, scale in conjunction with radio frequency or conventional heating. Microwave chemistry is based on two main principles, the dipolar mechanism and the electrical conductor mechanism. The dipolar mechanism occurs when, under a very high frequency electric field, a polar molecule attempts to follow the field in the same alignment. When this happens, the molecules release enough heat to drive the reaction forward. In the second mechanism, the irradiated sample is an electrical conductor and the charge carriers, ions and electrons, move through the material under the influence of the electric field and lead to polarization within the sample. These induced currents and any electrical resistance will heat the sample. This Account summarizes a microwave (MW)-assisted synthetic approach for producing silver nanostructures. MW heating has received considerable attention as a promising new method for the one-pot synthesis of metallic nanostructures in solutions. Researchers have successfully demonstrated the application of this method in the preparation of silver (Ag), gold (Au), platinum (Pt), and gold-palladium (Au-Pd) nanostructures. MW heating conditions allow not only for the preparation of spherical nanoparticles within a few minutes but also for the formation of single crystalline polygonal plates, sheets, rods, wires, tubes, and dendrites. The morphologies and sizes of the nanostructures can be controlled by changing various experimental parameters, such as the concentration of metallic salt precursors, the surfactant polymers, the chain length of the surfactant polymers, the solvents, and the operation reaction temperature. In general, nanostructures with smaller sizes, narrower size distributions, and a higher degree of crystallization have been obtained more consistently via MW heating than by heating with a conventional oil-bath. The use of microwaves to heat samples is a viable avenue for the greener synthesis of nanomaterials and provides several desirable features such as shorter reaction times, reduced energy consumption, and better product yields. PMID- 21526847 TI - Ligand field modification around Cu2+ ions in sodium borate glass by codoping. AB - Understanding the effect of codoping on the properties of photonic glasses is important for improving their properties. The effect of codoping on the ligand field around Cu(2+) ions in a sodium borate glass is examined using optical absorption spectroscopy, continuous-wave electron paramagnetic resonance, and three-pulse electron-spin-echo envelope-modulation. Glass with a composition of 0.1CuO.5Na(2)O.95B(2)O(3) was codoped with 2 mol % of Al(3+), Si(4+), P(5+), Zr(4+), or La(3+) oxide. Three codoping effects are found: strengthening the ligand field, as observed for Zr-codoping, which induces a large blue shift of the optical absorption peak of Cu(2+); weakening the ligand field, as observed for P-codoping, which causes a red shift of the Cu(2+) absorption peak; and almost no effect on the ligand field, which is observed for Al-, Si-, and La codoping. Coordination structure models based on local charge neutrality are proposed for the codoped glasses. The mechanism of the codoping effect is revealed by elucidating the local structure around Cu(2+). PMID- 21526848 TI - Carbon black nanoparticles impair acetylation of aromatic amine carcinogens through inactivation of arylamine N-acetyltransferase enzymes. AB - Carbon black nanoparticles (CB NPs) and their respirable aggregates/agglomerates are classified as possibly carcinogenic to humans. In certain industrial work settings, CB NPs coexist with aromatic amines (AA), which comprise a major class of human carcinogens. It is therefore crucial to characterize the interactions of CB NPs with AA-metabolizing enzymes. Here, we report molecular and cellular evidence that CB NPs interfere with the enzymatic acetylation of carcinogenic AA by rapidly binding to arylamine N-acetyltransferase (NAT), the major AA metabolizing enzyme. Kinetic and biophysical analyses showed that this interaction leads to protein conformational changes and an irreversible loss of enzyme activity. In addition, our data showed that exposure to CB NPs altered the acetylation of 2-aminofluorene in intact lung Clara cells by impairing the endogenous NAT-dependent pathway. This process may represent an additional mechanism that contributes to the carcinogenicity of inhaled CB NPs. Our results add to recent data suggesting that major xenobiotic detoxification pathways may be altered by certain NPs and that this can result in potentially harmful pharmacological and toxicological effects. PMID- 21526849 TI - ZrCl4-mediated regio- and chemoselective Friedel-Crafts acylation of indole. AB - An efficient method for regio- and chemoselective Friedel-Crafts acylation of indole using acyl chlorides in the presence of ZrCl(4) has been discovered. It minimizes/eliminates common competing reactions that occur due to high and multiatom-nucleophilic character of indole. In this method, a wide range of aroyl, heteroaroyl alkenoyl, and alkanoyl chlorides undergo smooth acylation with various indoles without NH protection and afford 3-acylindoles in good to high yields. PMID- 21526850 TI - Kinetic solvent effects on hydrogen abstraction reactions from carbon by the cumyloxyl radical. The importance of solvent hydrogen-bond interactions with the substrate and the abstracting radical. AB - A kinetic study of the hydrogen atom abstraction reactions from propanal (PA) and 2,2-dimethylpropanal (DMPA) by the cumyloxyl radical (CumO*) has been carried out in different solvents (benzene, PhCl, MeCN, t-BuOH, MeOH, and TFE). The corresponding reactions of the benzyloxyl radical (BnO*) have been studied in MeCN. The reaction of CumO* with 1,4-cyclohexadiene (CHD) also has been investigated in TFE solution. With CHD a 3-fold increase in rate constant (k(H)) has been observed on going from benzene, PhCl, and MeCN to TFE. This represents the first observation of a sizable kinetic solvent effect for hydrogen atom abstraction reactions from hydrocarbons by alkoxyl radicals and indicates that strong HBD solvents influence the hydrogen abstraction reactivity of CumO*. With PA and DMPA a significant decrease in k(H) has been observed on going from benzene and PhCl to MeOH and TFE, indicative of hydrogen-bond interactions between the carbonyl lone pair and the solvent in the transition state. The similar k(H) values observed for the reactions of the aldehydes in MeOH and TFE point toward differential hydrogen bond interactions of the latter solvent with the substrate and the radical in the transition state. The small reactivity ratios observed for the reactions of CumO* and BnO* with PA and DMPA (k(H)(BnO*)/k(H)(CumO*) = 1.2 and 1.6, respectively) indicate that with these substrates alkoxyl radical sterics play a minor role. PMID- 21526851 TI - Higher-order mass defect analysis for mass spectra of complex organic mixtures. AB - Higher-order mass defect analysis is introduced as a unique formula assignment and visualization method for the analysis of complex mass spectra. This approach is an extension of the concepts of Kendrick mass transformation widely used for identification of homologous compounds differing only by a number of base units (e.g., CH(2), H(2), O, CH(2)O, etc.) in complex mixtures. We present an iterative renormalization routine for defining higher-order homologous series and multidimensional clustering of mass spectral features. This approach greatly simplifies visualization of complex mass spectra and increases the number of chemical formulas that can be confidently assigned for given mass accuracy. The potential for using higher-order mass defects for data reduction and visualization is shown. Higher-order mass defect analysis is described and demonstrated through third-order analysis of a deisotoped high-resolution mass spectrum of crude oil containing nearly 13,000 peaks. PMID- 21526852 TI - Precise control and consecutive modulation of spin transition temperature using chemical migration in porous coordination polymers. AB - Precise control of spin transition temperature (T(c)) is one of the most important challenges in molecular magnetism. A Hofmann-type porous coordination polymer {Fe(pz)[Pt(II)(CN)(4)]} (1; pz = pyrazine) exhibited cooperative spin transition near room temperature (T(c)(up) = 304 K and T(c)(down) = 284 K) and its iodine adduct {Fe(pz)[Pt(II/IV)(CN)(4)(I)]} (1-I), prepared by oxidative addition of iodine to the open metal sites of Pt(II), raised the T(c) by 100 K. DSC and microscopic Raman spectra of a solid mixture of 1-I and 1 revealed that iodine migrated from 1-I to 1 through the grain boundary after heating above 398 K. We have succeeded in precisely controlling the iodine content of {Fe(pz)[Pt(CN)(4)(I)(n)]} (1-In; n = 0.0-1.0), which resulted in consecutive modulation of T(c) in the range 300-400 K while maintaining the hysteresis width. Furthermore, it was demonstrated that iodine migration in the solid mixture was triggered by the spin transition of 1-I. The magnetically bistable porous framework decorating guest interactive open-metal-site in the pore surface makes it possible to modulate T(c) ad arbitrium through unique postsynthetic method using iodine migration. PMID- 21526854 TI - Multilayer assembly of nanowire arrays for dye-sensitized solar cells. AB - Vertically ordered nanostructures synthesized directly on transparent conducting oxide have shown great promise for overcoming the limitations of current dye sensitized solar cells (DSCs) based on random networks of nanoparticles. However, the synthesis of such structures with a high internal surface area has been challenging. Here we demonstrate a convenient approach that involves alternate cycles of nanowire growth and self-assembled monolayer coating processes for synthesizing multilayer assemblies of ZnO nanowire arrays and using the assemblies for fabrication of DSCs. The assembled multilayer ZnO nanowire arrays possess an internal surface area that is more than 5 times larger than what one can possibly obtain with single-layer nanowire arrays. DSCs fabricated using such multilayer arrays yield a power conversion efficiency of 7%, which is comparable to that of TiO(2) nanoparticle-based DSCs. The ordered structure with a high internal surface area opens up opportunities for further improvement of DSCs. PMID- 21526853 TI - Pleiotropic impact of a single lysine mutation on biosynthesis of and catalysis by N-methyltryptophan oxidase. AB - N-Methyltryptophan oxidase (MTOX) contains covalently bound FAD. N Methyltryptophan binds in a cavity above the re face of the flavin ring. Lys259 is located above the opposite, si face. Replacement of Lys259 with Gln, Ala, or Met blocks (>95%) covalent flavin incorporation in vivo. The mutant apoproteins can be reconstituted with FAD. Apparent turnover rates (k(cat,app)) of the reconstituted enzymes are ~2500-fold slower than those of wild-type MTOX. Wild type MTOX forms a charge-transfer E(ox).S complex with the redox-active anionic form of NMT. The E(ox).S complex formed with Lys259Gln does not exhibit a charge transfer band and is converted to a reduced enzyme.imine complex (EH(2).P) at a rate 60-fold slower than that of wild-type MTOX. The mutant EH(2).P complex contains the imine zwitterion and exhibits a charge-transfer band, a feature not observed with the wild-type EH(2).P complex. Reaction of reduced Lys259Gln with oxygen is 2500-fold slower than that of reduced wild-type MTOX. The latter reaction is unaffected by the presence of bound product. Dissociation of the wild type EH(2).P complex is 80-fold slower than k(cat). The mutant EH(2).P complex dissociates 15-fold faster than k(cat,app). Consequently, EH(2).P and free EH(2) are the species that react with oxygen during turnover of the wild-type and mutant enzyme, respectively. The results show that (i) Lys259 is the site of oxygen activation in MTOX and also plays a role in holoenzyme biosynthesis and N methyltryptophan oxidation and (ii) MTOX contains separate active sites for N methyltryptophan oxidation and oxygen reduction on opposite faces of the flavin ring. PMID- 21526855 TI - Top-down sequencing of O-glycoproteins by in-source decay matrix-assisted laser desorption ionization mass spectrometry for glycosylation site analysis. AB - The sites of mucin-type O-glycosylation are largely unpredictable, making structural analysis by mass spectrometry (MS) indispensible. On the peptide level, a site localization and characterization of O-linked glycans in situ using tandem MS with electron-transfer dissociation or matrix-assisted laser desorption ionization (MALDI) MS with postsource decay have been reported. The top-down sequencing on the protein level by MALDI-MS is based on the in-source decay (ISD) of intact glycoproteins induced by hydrogen radical transfer from the matrix. It allows a ladder sequencing from both termini with assignment of O-glycosylation sites based on intense c-, y-, and z-type ions. The feasibility of ISD-MALDI-MS in the localization of O-glycosylation sites was demonstrated with synthetic O glycopeptides, the tandem repeat domain of recombinant MUC1, and the natural bovine glycoproteins asialofetuin and desialylated kappa-casein. Ladder sequencing of the 17-18.5 kD MUC1 hexarepeat domains revealed (1) cell-specific glycosylation site patterns on comparison of probes expressed in human HEK-293 or Drosophila S2 cells, and (2) a site-specific microheterogeneity at the Thr/Ser sites with variations of the glycan compositions from zero to four monosaccharides. Novel O-glycosylation sites in the C-terminal domains of fetuin (T334) and kappa-caseinoglycopeptide (S154 and T156) were assigned, the former representing a sequence conflict with the published T154. PMID- 21526856 TI - Mechanism of linear and nonlinear optical properties of the urea crystal family. AB - First-principles calculations of the second-order optical response functions and the dielectric functions of urea [CO(NH(2))(2)] and some of its derivatives such as monomethylurea (H(2)NCONHCH(3), MMU), and N,N'-dimethylurea (H(3)CHNCONHCH(3), DMU) crystals are performed. On the basis of the density functional theory (DFT) in the local-density approximation (LDA), the highly accurate full-potential projected augmented wave (FP-PAW) method was used to obtain the electronic structure. Over a wide frequency range (0.0-10.0 eV), the dielectric constants and second-harmonic generation (SHG) susceptibilities of the urea crystal family have been obtained, and the results are in good agreement with the experimental values. The origin of the linear and nonlinear optical (NLO) properties of the urea crystal family has been analyzed by coupling the calculated electronic structure and optical spectrum. The prominent spectra of chi((2)) are successfully correlated with the dielectric function epsilon(omega) in terms of single-photon and double-photon resonances. The virtual electron (VE) and virtual hole (VH) processes have also been performed for the urea crystal family. From the research into the electron deformation density, crystal configuration, substitutional group, and so forth, it is found that the origin of the SHG of the urea crystal family is the charge transfer due to the strong "()push-pull" effect along the hydrogen bond, which favors a head-to-tail arrangement of the molecules and enhances the SHG response. The electron-donating substitutional group supplies more electrons to the electron-accepting group, and helps to form large dipoles in molecules. The influence on the NLO properties of the local symmetry of the substitutional group is also discussed in detail. PMID- 21526857 TI - Bendable electronics and innovation centers. PMID- 21526858 TI - In situ analysis of three-dimensional electrolyte convection evolving during the electrodeposition of copper in magnetic gradient fields. AB - A novel three-dimensional particle tracking velocimetry technique was used to examine the flow during electrodeposition of Cu. For the first time electrode normal, circumferential, and radial velocities were spatially resolved during deposition in superimposed low and high magnetic gradient fields. In this way the complex interaction of magnetic field gradient force and Lorentz force induced convective effects could be measured and analyzed. Magnetic field gradient force induced electrolyte flow was detected only in high gradient magnetic fields, and it was found to be directed toward regions of gradient maxima. Since this electrode-normal flow causes enhanced transport of Cu(2+) ions from the bulk electrolyte to those regions of the working electrode where maxima of magnetic gradients are present, a structured deposit is formed during diffusion-limited electrodeposition. Lorentz force driven convection was observed during deposition in the low and the high magnetic gradient experiments. The overall fluid motion and the convection near the working electrode were determined experimentally and discussed with regard to the acting magnetic forces and numerical simulations. PMID- 21526859 TI - Thermodynamic and spectroscopic speciation to explain the blackening process of hematite formed by atmospheric SO2 impact: the case of Marcus Lucretius House (Pompeii). AB - After many decades exposed to a polluted environment, in some areas of Marcus Lucretius House, there are clear signs that plasters and hematite pigments are suffering deterioration. In the exhaustive analysis of the black layer covering the red pigment hematite it was possible to identify magnetite (Fe(3)O(4)) as responsible for the black colour, which always appears in combination with gypsum. Thermodynamic modelling stated that the presence of gypsum as well as the transformation of hematite into magnetite is a consequence of the attack of atmospheric SO(2). PMID- 21526860 TI - Benzotrithiophene--a planar, electron-rich building block for organic semiconductors. AB - Several functionalized benzo[1,2-b:3,4-b':5,6-d'']trithiophenes have been synthesized and characterized. The fully planar and highly electron-rich material shows great promise as the donor constituent in donor-acceptor type copolymers for use in organic electronics. As a proof of concept, a copolymer with the electron acceptor, 2,1,3-benzothiadiazole, has been prepared. Side-chain modifications have been employed to adjust both the electron-rich character of the monomer and the solubility and processability of the polymer. PMID- 21526861 TI - Metabolites in contact with the rat digestive tract after ingestion of a phenolic rich dietary fiber matrix. AB - Grape antioxidant dietary fiber (GADF) is a phenolic-rich dietary fiber matrix. The aim of this work was to determine which phenolic compounds come into contact with colonic epithelial tissue after the ingestion of GADF. By use of HPLC-ESI MS/MS techniques phenolic metabolites were detected in feces, cecal content, and colonic tissue from rats. Free (epi)catechin (EC) was detected in all three sources, and more than 20 conjugated metabolites of EC were also detected in feces. Fourteen microbially derived phenolic metabolites were also identified in feces, cecal content, and/or colonic tissue. These results show that during transit along the digestive tract, proanthocyanidin oligomers and polymers are depolymerized into EC units. After ingestion of GADF, free EC and its conjugates, as well as free and conjugated microbially derived phenolic metabolites, come into contact with the intestine epithelium for more than 24 h and may be partly responsible for the positive influence of GADF on gut health. PMID- 21526862 TI - Experimental and theoretical investigation of the kinetics of the reaction of atomic chlorine with 1,4-dioxane. AB - The rate coefficients for the reaction of 1,4-dioxane with atomic chlorine were measured from T = 292-360 K using the relative rate method. The reference reactant was isobutane and the experiments were made in argon with atomic chlorine produced by photolysis of small concentrations of Cl2. The rate coefficients were put on an absolute basis by using the published temperature dependence of the absolute rate coefficients for the reference reaction. The rate coefficients for the reaction of Cl with 1,4-dioxane were found to be independent of total pressure from p = 290 to 782 Torr. The experimentally measured rate coefficients showed a weak temperature dependence, given by k(exp)(T) = (8.4( 2.3)(+3.1)) * 10(-10) exp(-(470 +/- 110)/(T/K)) cm3 molecule (-1) s(-1). The experimental results are rationalized in terms of statistical rate theory on the basis of molecular data obtained from quantum-chemical calculations. Molecular geometries and frequencies were obtained from MP2/aug-cc-pVDZ calculations, while single-point energies of the stationary points were computed at CCSD(T) level of theory. The calculations indicate that the reaction proceeds by an overall exothermic addition-elimination mechanism via two intermediates, where the rate determining step is the initial barrier-less association reaction between the chlorine atom and the chair conformer of 1,4-dioxane. This is in contrast to the Br plus 1,4-dioxane reaction studied earlier, where the rate-determining step is a chair-to-boat conformational change of the bromine-dioxane adduct, which is necessary for this reaction to proceed. The remarkable difference in the kinetic behavior of the reactions of 1,4-dioxane with these two halogen atoms can be consistently explained by this change in the reaction mechanism. PMID- 21526863 TI - Stoichiometry-dependent chemical activity of supported MgO(100) films. AB - Here, we show that the stoichiometry and, consequently, the chemical activity toward hydroxylation of MgO(100) films grown by reactive deposition on Ag(100) strongly depend on the O(2) partial pressure during film growth. Oxygen-deficient films undergo dramatic relative oxygen uptake either by exposure to a partial pressure of water vapor or by aging in vacuum for a sufficiently long time. Conversely, on stoichiometric monolayer MgO islands, photoemission analysis of the O 1s level and scanning tunneling microscopy images are consistent with the prediction that dissociative adsorption of water occurs only at the borders of the islands. PMID- 21526864 TI - Degradable rosin-ester-caprolactone graft copolymers. AB - We have carried out the synthesis of side-chain rosin-ester-structured poly(epsilon-caprolactone) (PCL) through a combination of ring-opening polymerization and click chemistry. Rosin structures are shown to be effectively incorporated into each repeat unit of caprolactone. This simple and versatile methodology does not require sophisticated purification of raw renewable biomass from nature. The rosin properties have been successfully imparted to the PCL polymers. The bulky hydrophenanthrene group of rosin increases the glass transition temperature of PCL by >100 degrees C, whereas the hydrocarbon nature of rosin structures provides PCL excellent hydrophobicity with contact angle very similar to polystyrene and very low water uptake. The rosin-containing PCL graft copolymers exhibit full degradability and good biocompatibility. This study illustrates a general strategy to prepare a new class of renewable hydrocarbon rich degradable biopolymers. PMID- 21526865 TI - Rational design of organic asymmetric donors D1-A-D2 possessing broad absorption regions and suitable frontier molecular orbitals to match typical acceptors toward solar cells. AB - A series of donors have been designed based on three building blocks, i.e., triphenylamine (TPA), 4,7-di(thiophen-2-yl)benzo[c][1,2,5]thiadiazole (DBT), and oligothiophenes (5Th), to investigate suitable molecules toward solar cell materials. The donors are built by two donor fragments (TPA as D1 and 5Th as D2) and one acceptor fragment (DBT as A) in three topologies with or without linkages and electron-withdrawing groups. Their electronic and optical properties have been characterized by the PBE0/6-31G(d,p) and the TD-PBE0/6-31+G(d,p) approaches. The calculated results reveal that the asymmetric donor in the topology of D1-A D2 with vinyl linkage and -NO(2) groups is a rational strategy to design novel material possessing a small HOMO-LUMO gap, broad and intense absorption spectra, and higher charge transfer ability. The promising donors for [6,6]-phenyl-C(61) butyric acid methyl ester (PCBM), bisPCBM, and PC70BM as acceptors are recommended theoretically for the first time for solar cells based on the proper match for frontier molecular orbitals between donors and acceptors. PMID- 21526866 TI - DIBAL-mediated reductive transformation of trans-dimethyl tartrate acetonide into epsilon-hydroxy alpha,beta-unsaturated ester and its derivatives. AB - Stepwise, selective DIBAL reduction of the acetonide diester derived from tartaric acid followed by the Horner-Emmons reaction effectively provided desymmetrized hydroxy mono-olefination products in a one-pot operation. PMID- 21526867 TI - Fixed or invertible calixarene-based directional shuttles. AB - The first examples of rotaxanes based on calixarenes threaded by dialkylammonium ions, which also represent the first examples of calixarene-based molecular shuttles, are reported. The base/acid treatment demonstrated that these systems act as molecular shuttles, which move between three sites on the axle. When small OMe groups are appended at the calix[6]arene lower rim an unprecedented inversion of its shuttling direction is observed, which occurs through a cone-to-cone inversion of the macrocycle. PMID- 21526868 TI - Iron-catalyzed direct alkenylation of 2-substituted azaarenes with N-sulfonyl aldimines via C-H bond activation. AB - A novel iron-catalyzed alkenylation of 2-substituted azaarenes through sp(3) C-H bond activation has been developed. A favorable E2-elimination is proposed as a key step to cleavage of C-H and C-N bonds for the construction of a C?C bond in high stereoselectivity. This transformation represents an efficient way to synthesize 2-alkenylated azaarenes from simple starting materials. PMID- 21526869 TI - Acute on chronic liver failure and prognostic factors: time for reevaluation. PMID- 21526870 TI - Prognostic scores in cirrhotic patients admitted to a gastroenterology intensive care unit. AB - BACKGROUND: prognostic scores have been validated in cirrhotic patients admitted to general Intensive Care Units. No assessment of these scores was performed in cirrhotics admitted to specialized Gastroenterology Intensive Care Units (GICUs). AIM: to assess the prognostic accuracy of Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA), Model for End-stage Liver Disease (MELD) and Child-Pugh-Turcotte (CPT) in predicting GICU mortality in cirrhotic patients. METHODS: the study involved 124 consecutive cirrhotic admissions to a GICU. Clinical data, prognostic scores and mortality were recorded. Discrimination was evaluated with area under receiver operating characteristic curves (AUC). Calibration was assessed with Hosmer-Lemeshow goodness-of-fit test. RESULTS: GICU mortality was 9.7%. Mean APACHE II, SAPS II, SOFA, MELD and CPT scores for survivors (13.6, 25.4, 3.5,18.0 and 8.6, respectively) were found to be significantly lower than those of non-survivors (22.0, 47.5, 10.1, 30.7 and 12.5,respectively) (p < 0.001). All the prognostic systems showed good discrimination, with AUC = 0.860, 0.911, 0.868, 0.897 and 0.914 for APACHE II, SAPS II, SOFA, MELD and CPT, respectively. Similarly, APACHE II, SAPS II, SOFA, MELD and CPT scores achieved good calibration, with p = 0.146, 0.120, 0.686,0.267 and 0.120, respectively. The overall correctness of prediction was 81.9%, 86.1%, 93.3%, 90.7% and 87.7% for the APA-CHE II, SAPS II, SOFA, MELD and CPT scores, respectively. CONCLUSIONS: in cirrhotics admitted to a GICU, all the tested scores have good prognostic accuracy, with SOFA and MELD showing the greatest overall correctness of prediction. PMID- 21526871 TI - Pancreatic endocrine tumors or apudomas. AB - INTRODUCTION AND OBJECTIVE: pancreatic endocrine tumors (PET) are difficult to diagnose. Their accurate localization using imaging techniques is intended to provide a definite cure. The goal of this retrospective study was to review a PET series from a private institution. PATIENTS AND METHODS: the medical records of 19 patients with PETs were reviewed, including 4 cases of MEN-1, for a period of 17 years (1994-2010). A database was set up with ten parameters: age, sex, symptoms, imaging techniques, size and location in the pancreas, metastasis, surgery, complications, adjuvant therapies, definite diagnosis, and survival or death. RESULTS: a total of 19 cases were analyzed. Mean age at presentation was 51 years (range: 26-67 y) (14 males, 5 females), and tumor size was 5 to 80 mm (X: 20 mm). Metastatic disease was present in 37% (7/19). Most underwent the following imaging techniques: ultrasounds, computed tomography (CT) an magnetic resonance imaging (MRI). Fine needle aspiration punction (FNA) was performed for the primary tumor in 4 cases. Non-functioning: 7 cases (37%), insulinoma: 2 cases [1 with possible multiple endocrine neoplasia (MEN)], Zollinger-Ellison syndrome (ZES) from gastrinoma: 5 (3 with MEN-1), glucagonoma: 2 cases, 2 somatostatinomas; carcinoid: 1 case with carcinoide-like syndrome. Most patients were operated upon: 14/19 (73%). Four (4/14:28%) has postoperative complications following pancreatectomy: pancreatitis, pseudocyst, and abdominal collections. Some patients received chemotherapy (4), somatostatin (3) and interferon (2) before or after surgery. Median follow-up was 48 months. Actuarial survival during the study was 73.6% (14/19). CONCLUSIONS: age was similar to that described in the literature. Males were predominant. Most cases were non functioning (37%). Most patients underwent surgery (73%) with little morbidity (28%) and an actuarial survival of 73.6% at the time of the study. PMID- 21526872 TI - Radio induced cancer risk during ERCP. Is it a real clinical problem? AB - BACKGROUND: in recent years many factors have been shown to influence dose received by the patient during ERCP. Therefore it is necessary to update radio induced cancer risk. OBJECTIVES: to calculate lifetime attributable risk of cancer during ERCP. To compare the risk with the most common X-ray examinations. DESIGN: descriptive study with 393 consecutive ERCP performed at one center. Equipment used was Philips BV pulsera. In each exploration demographic and anthropometric variables of the patient were collected. Dosimetric quantities were calculated from exposure parameters. Effective dose was estimated using specific conversion factors. Organ doses and radio induced cancer incidence was estimated. RESULTS: dose area product was 0.82 mGym2(IQR 0.4-1.5) with an average fluoroscopy time of 2 minutes and 45 seconds. Entrance surface dose was 30.7 mGy (IQR 15-60.8) and effective dose was 0.44 mSv (IQR 0.2-0.9). Multivariate analysis identified that difficult papillary cannulation (beta 0.4; p = 0.009), patient age (beta-0.01; p = 0.001) and therapeutic applied (beta= 0.89; p < 0.001) influenced dose-area product. The ERCP dose would be equivalent to the radiation received by twenty chest radiographs and would be about fourteen times smaller than a barium enema or twenty times less than that received during an abdominal CT. Life-time attributable risk of cancer incidence was 4.08 and 16.81 per million procedures in diagnostic and therapeutic ERCP respectively. CONCLUSIONS: from the radiological point of view, ERCP is a safe technique that uses low exposure levels compared to other explorations commonly used in medicine. It implies a reasonably low risk of radio induced cancer. PMID- 21526873 TI - Predictors of in-hospital mortality in patients with non-variceal upper gastrointestinal bleeding. AB - OBJECTIVE: to determine the independent predictors of in-hospital death of Hispanic patients with nonvariceal upper gastrointestinal bleeding (NVUGB). EXPERIMENTAL DESIGN: prospective and observational trial. PATIENTS: in a period between 2000 and 2009, all patients with NVUGB admitted to our hospital were studied. Demographical and clinical characteristics, endoscopic findings and laboratory tests were evaluated chi2 and Mann-Whitney U analyses were per-formed for comparisons, and binary logistic regression was employed to identify independent predictors of in-hospital mortality. RESULTS: 1,067 patients were included, 65% male with a mean age of 58.8 years. Mean number of comorbidities per patient was 1.6 +/- 0.76. The most frequent cause of bleeding were gastric and duodenal ulcers (55.4%); 278 patients (25.8%) received endoscopic treatment of which 69.1% had combined therapy. Rebleeding occurred in 36 patients (3.4%) of which 50% died. In-hospital mortality was 10.2%, of which only 3.1% was associated to bleeding. When comparing causes of death among patients with and without comorbidities, only hypovolemic shock was found significative (48.3 vs. 25%; p = 0.020). Binary logistic regression found that the number of comorbidities, Rockall scale score; serum albumin < 2.6 g/dL on admission; rebleeding and length of hospital stay were independent risk factors of in hospital mortality. CONCLUSION: the number of comorbidities, the Rockall scales core, an albumin level < 2.6 g/dL, the presence of rebleeding and hospital stay were predictors of in-hospital mortality in patients with NVUGB. PMID- 21526874 TI - Ultrasonographic contrast agents versus sonoelastography in digestive diseases. AB - A review is made of the indications of ultrasonographic contrast enhancement as applied to conventional ultrasonography and endocopic ultrasonography (EUS) as opposed to the use of EUS-sonoelastography today. PMID- 21526875 TI - Kaposi's sarcoma of the rectum. PMID- 21526876 TI - Crohn's disease presenting as pyloric stenosis. PMID- 21526877 TI - Diagnosis of Whipple's disease using molecular biology techniques. AB - The diagnosis of Whipple's disease (WD) is based on the existence of clinical signs and symptoms compatible with the disease and in the presence of PAS positive diastase-resistant granules in the macrophages of the small intestine. If there is suspicion of the disease but no histological findings or only isolated extraintestinal manifestations, species-specific PCR using different sequences of the T. whippleii genome from different tissue types and biological fluids is recommended.This study reports two cases: the first patient had diarrhea and the disease was suspected after an endoscopic examination of the ileum, while the second patient had multi-systemic manifestations,particularly abdominal, thoracic, and peripheral lymphadenopathies. In both cases, the diagnosis was confirmed using molecular biology techniques to samples from the small intestine or from a retroperineal lymph node, respectively. PMID- 21526878 TI - [Endoscopy in liver diseases]. PMID- 21526879 TI - Acute gastric volvulus: a surgical emergency. PMID- 21526880 TI - Acute recurrent pancreatitis due to an intraductal papillary mucinous tumor of the pancreas. PMID- 21526881 TI - Laryngeal metastasis as first presentation of hepatocellular carcinoma. PMID- 21526882 TI - Benign pancreatic vipoma. PMID- 21526883 TI - [Gastric duplication cyst]. PMID- 21526884 TI - Evaluation of a dementia training workshop for health and social care staff in rural Scotland. AB - This short project report presents an evaluation of a training workshop for health and social-care staff working in one of the most rural areas in Scotland. The objective was to explore the learning needs and outcomes of training participants delivering services to people with dementia in a rural area. The training workshop encouraged health and social-care staff to discuss key challenges they experienced in their dementia care practice, as well as providing information on dementia care, services and rural dementia research. In a post training evaluation, despite barriers to implementing learning, participants rated their satisfaction with the workshop as high overall. Further training needs identified included: how to recognise dementia, what the diagnostic process entails, and the management of challenging behaviour. Health and social-care staff in rural areas of Scotland require further training on specific issues related to dementia to enable them to be confident in in the diagnostic process and delivery of post-diagnostic dementia services. PMID- 21526885 TI - Somatic classification of neonates based on birth weight, length, and head circumference: quantification of the effects of maternal BMI and smoking. AB - We defined neonates as small, appropriate, or large for gestational age (SGA, AGA, LGA) based on birth weight, length, and head circumference. We analyzed the effects on the somatic classification of maternal body mass index (BMI) (<18.5, 18.5-24.99, 25.0-29.99, >= 30) and smoking during pregnancy (0, 1-7, 8-14, >= 15 cigarettes daily). Data were from the German Perinatal Survey (1998-2000; 433,669 cases). The following refers to the classification by birth weight. In the normal maternal weight population SGA rates increased with cigarette consumption: 9.8%, 17.8%, 21.6%, and 25.4% for non-smokers, and smokers of 1-7, 8-14, and >= 15 cigarettes daily, respectively. In non-smoking underweight women the SGA rate was 17.4%. In underweight smokers of >= 15 cigarettes daily the SGA rate was 38.5% [odds ratio 5.77, 95% confidence interval 5.10-6.53, compared with normal weight non-smokers]. In the normal maternal weight population, LGA rates were 9.9%, 5.3%, 4.6%, and 3.5% for non-smokers, and smokers of 1-7, 8-14, and >= 15 cigarettes daily, respectively. In the obese, LGA rates were 20.9% (non-smokers) and 11.4% (>= 15 cigarettes). Similar findings were obtained for the somatic classifications based on birth length and head circumference. Results for the various combinations of maternal BMI and smoking status in the three classification systems are described. Our findings may assist in individualized risk assessment for SGA and LGA births. PMID- 21526886 TI - Classification of Iranian patients with Glanzmann's Thrombasthenia using a flow cytometric method. AB - Glanzmann's Thrombasthenia (GT) is a rare inherited autosomal recessive platelet disorder caused by a deficiency or dysfunction of the GPIIb-IIIa receptor on platelets, which is characterized by a lack of platelet aggregation in response to multiple physiologic agonists and a life-long bleeding disorder. Flow cytometry is a rapid and highly sensitive method that can detect reduced levels of receptors, as well as absolute deficiency. The aim of this study was to classify Iranian GT patients by a flow cytometric method, and to correlate these findings with the severity of clinical bleeding. The expression of GPIIb-IIIa on the platelet surface was assessed in 123 GT patients using quantitative flow cytometry to determine the most common subtype among these patients. We used a panel of antibodies to detect the expression of glycoproteins GPIb, GPIIb, GPIIIa, as well as Integrin alphav. Patients were also interviewed with regard to the severity and frequency of bleeding, according to history and gender, in order to evaluate the nature of their bleeding phenotype, and classify them as mild, moderate or severe bleeders, in accordance with the Glanzmann's Thrombasthenia Italian Team (GLATIT) protocol. In the detailed analysis of the results of our investigation, 95 out of 123 (77.5%) were classified as type I; 20 (16%) as type II with residual GPIIb-IIIa, and eight (6.5%) as GT variants. The variant type was diagnosed by the inability of GPIIb-IIIa to bind fibrinogen, as evidenced by the absence of platelet aggregation in response to physiologic agonists. There was no significant correlation between bleeding severity and different subtypes of GT. This study demonstrates that GT type I is the most common subtype among Iranian patients. There was no correlation between severity of symptoms and cytometric phenotype of the disease. The identification of families at risk may significantly decrease the incidence of the severe form of the disorder if genetic counseling is provided. PMID- 21526887 TI - Profound delayed thrombocytopenia presenting 16 days after Abciximab (Reopro(r)) administration. AB - Abciximab occasionally causes severe thrombocytopenia. This is variable in severity and usually occurs within hours of administration but has been reported to present up to 8 days later. This report describes a case of life-threatening thrombocytopenia 16 days following Abciximab administration. The patient required supportive transfusions and ultimately improved following dexamethasone and intravenous immunoglobulin. The case represents the longest delay between Abciximab administration and thrombocytopenia published to date. PMID- 21526888 TI - Statement of retraction. Gupta A, Chandra T, Kumar A. "Platelet storage lesion: current proteomics approach". PMID- 21526889 TI - The effects of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin. AB - Laropiprant (LRPT) is being developed in combination with Merck's extended release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD2 receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A2 receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time at 24 h post-dose (trough) was pre-specified as the primary pharmacodynamic endpoint in both studies. Two separate, double-blind, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose LRPT on the pharmacodynamics of multiple-dose clopidogrel or aspirin. Healthy subjects were randomized to once-daily oral doses of LRPT 40 mg or placebo to LRTP co administered with clopidogrel 75 mg or aspirin 81 mg for 7 days with at least a 21-day washout between treatments. In both studies, bleeding time and platelet aggregation were assessed 4 and 24 hours post-dose on Day 7. Comparability was declared if the 90% confidence interval for the estimated geometric mean ratio ([LRPT+clopidogrel]/clopidogrel alone or [LRPT+aspirin]/aspirin alone) for bleeding time at 24 hours post-dose on Day 7 was contained within (0.66, 1.50). Concomitant daily administration of LRPT 40 mg with clopidogrel 75 mg or aspirin 81 mg resulted in an approximate 4-5% increase in bleeding time at 24 hours after the last dose vs. bleeding time after treatment with clopidogrel or aspirin alone, demonstrating that the treatments had comparable effects on bleeding time. Percent inhibition of platelet aggregation was not significantly different between LRPT co-administered with clopidogrel or aspirin vs. clopidogrel or aspirin alone at 24 hours post-dose at steady state. At 4 hours after the last dose, co-administration of LRPT 40 mg resulted in 3% and 41% increase in bleeding time vs. bleeding time after treatment with aspirin or clopidogrel alone, respectively. Co-administration of LPRT with clopidogrel or aspirin was generally well tolerated in healthy subjects. Co-administration of multiple doses of LRPT 40 mg and clopidogrel 75 mg or aspirin 81 mg had no clinically important effects on bleeding time or platelet aggregation. PMID- 21526890 TI - Ca2+ leakage rate from agonist-sensitive intracellular pools is altered in platelets from patients with type 2 diabetes. AB - Platelets from patients with type 2 diabetes show abnormalities in intracellular Ca(2+) homeostasis that are involved in platelet hyperaggregability and the development of thrombotic complications. Different Ca(2+) transport mechanisms have been reported to be altered in platelets from patients with type 2 diabetes, including the sarcoendoplasmic and plasma membrane Ca(2+)-ATPases, plasma membrane Ca(2+) channels, or the Na(+)/Ca(2+) exchanger. Here, we have investigated whether passive Ca(2+) leak from the stores is altered in platelets from patients with type 2 diabetes. Resting cytosolic Ca(2+) concentration ([Ca(2+)](i)) was found to be greater in platelets from patients with type 2 diabetes than in healthy controls. In a Ca(2+)-free medium, platelet stimulation with thrombin or ADP evokes a rapid and transient increase in [Ca(2+)](i) that was found to be greater in patients with diabetes than in healthy controls. Sequential or combined inhibition of Ca(2+) extrusion and Ca(2+) sequestration into the stores reduced the difference between the responses to agonists in patients with diabetes and healthy controls, although agonist-induced Ca(2+) efflux from the stores was still significantly greater in patients with diabetes. Ca(2+) leak from the dense tubular system or the acidic stores, induced by a low concentration of thapsigargin or 2,5-di-(t-butyl)-1,4-hydroquinone (TBHQ), respectively, was clearly greater in patients with diabetes than in controls, and was not significantly modified by treatment with 2-APB. These findings indicate that passive Ca(2+) leakage rate from the intracellular stores in platelets is significantly enhanced in patients with type 2 diabetes mellitus and this might explain the increased resting [Ca(2+)](i). PMID- 21526891 TI - Yin and Yang in medicinal chemistry: what does drug-likeness mean? PMID- 21526892 TI - Promising FAAH inhibitor moves into clinical trials. PMID- 21526893 TI - The Screening Asia Conference 2010: an update. AB - The conference was the first of its kind in a series of trend-setting conferences conceived and organized by Select Biosciences. The conference was held in the state-of-the-art Matrix Building, Metropolis. The topics covered were grouped into the following half-day sessions: high-content screening, high-throughput screening, RNAi screening, novel drug-discovery techniques and assay development, and screening natural extracts and small molecules. Petr Bartunek (Group Leader, Institute of Molecular Genetics, Prague, Czech Republic), Rathnam Chaguturu (Director, High-Throughput Screening Laboratories, University of Kansas, USA) and Paul Orange (Business Leader, Bio-Discovery, PerkinElmer) were the keynote speakers. The conference attendees were from academia and the biotechnology and pharmaceutical sectors. The Screening Asia 2010 was designed to address, from a regional and international perspective, how best to approach the one issue that has been at the forefront of the drug-discovery endeavors: who is best suited among academia, biotechnology and pharmaceutics to discover chemical probes against key therapeutic targets, and how best one could implement the processes. PMID- 21526894 TI - Eliciting carbohydrate-specific immune response against sialosides: success and challenges. AB - Chemoenzymatic synthesis has been shown to be a powerful adjunct to carbohydrate chemistry since it allows chemists to prepare a wide range of complex carbohydrate analogs in large amounts and with unparalleled efficiency. Here we summarize investigations conducted in our group into the synthesis and immunochemistry of tumor-associated gangliosides and the development of a chemoenzymatic route to alpha(2->8)-linked oligosialosides by probing substrate binding to the enzyme, alpha(2->8)-sialyltransferase. PMID- 21526895 TI - Calcilytics: antagonists of the calcium-sensing receptor for the treatment of osteoporosis. AB - The only bone anabolic agents currently available on the market are based on the parathyroid hormone (PTH). Secretion of endogenous PTH is controlled by a calcium sensing receptor at the surface of the parathyroid glands. Antagonists of this receptor (calcilytics) induce the release of the hormone. Provided the effect of the calcilytic is of short duration, a bone anabolic effect should also result. Although the first calcilytic series became known approximately 10 years ago, the number of different structural types is still small today. This article outlines the quest from hits to potent development candidates of all relevant calcilytic series currently known. Even after the front-runners unexpectedly failed in the clinic, the approach for an oral alternative to parenteral PTH remains highly attractive. PMID- 21526897 TI - Signal transducer and activator of transcription 3 (STAT3): a promising target for anticancer therapy. AB - Signal transducer and activator of transcription 3 (STAT3) is an oncogenic protein whose inhibition is sought for the prevention and treatment of cancer. In this review, the validated therapeutic strategy to block aberrant activity of STAT3 in many tumor cell lines is evaluated by presenting the most promising inhibitors to date. The compounds are discussed in classes based on their different mechanisms of action, which are critically explained. In addition, their future clinical development as anticancer agents is considered. Furthermore, the efforts devoted to the comprehension of the structure-activity relationships and to the identification of the biological effects are brought to attention. The synthetic and technological approaches recently developed to overcome the difficulties in the obtainment of clinically suitable drugs are also presented. PMID- 21526896 TI - Small-molecule inhibitors of the PI3K signaling network. AB - The phosphoinositide 3-kinase (PI3K) signaling pathway controls a wide variety of cellular processes including cell death and survival, cell migration, protein synthesis and metabolism. Aberrant PI3K-dependent signaling, mediated by Akt kinase, has been implicated in many human diseases including cancer, inflammation, cardiovascular disease and metabolic diseases, making this pathway a principle target for drug development. In this article we will summarize the PI3K signaling network and discuss current strategies for pathway inhibition. We will also explore the importance and emerging relevance of Akt-independent PI3K signaling pathways and discuss attempts being made to harness these pathways by inhibiting the binding of a product of PI3K, phosphatidylinositol-(3,4,5) trisphosphate, to effector pleckstrin homology domains. PMID- 21526898 TI - The rise of metal radionuclides in medical imaging: copper-64, zirconium-89 and yttrium-86. AB - Positron emission tomography, with its high sensitivity and resolution, is growing rapidly as an imaging technology for the diagnosis of many disease states. The success of this modality is reliant on instrumentation and the development of effective and novel targeted probes. Initially, research in this area was focused on what we will define in this article as 'standard' PET isotopes (carbon-11, nitrogen-13, oxygen-15 and fluorine-18), but the short half lives of these isotopes limit radiopharmaceutical development to those that probe rapid biological processes. To overcome these limitations, there has been a rise in nonstandard isotope probe development in recent years. This review focuses on the biological probes and processes that have been examined, in additiom to the preclinical and clinical findings with nonstandard radiometals: copper-64, zirconium-89, and yttrium-86. PMID- 21526901 TI - Abstracts of the American Telemedicine Association Sixteenth Annual International Meeting and Exposition. May 1-3, 2011. Tampa, Florida, USA. PMID- 21526902 TI - Intramyocardial and intracoronary autologous bone marrow-derived mesenchymal stromal cell treatment in chronic severe dilated cardiomyopathy. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSC) may improve cardiac function following myocardial infarction. MSC can differentiate into cardiomyocytes and endothelial cells while exerting additional paracrine effects. There is limited information regarding the efficacy of route for MSC treatment of severe dilated cardiomyopathy (DCM). The aim of this study was to demonstrate the clinical safety, feasibility and efficacy of direct intramyocardial and intracoronary administration of autologous bone marrow-derived MSC treatment for no-option patients with chronic severe refractory DCM. METHODS: Ten symptomatic patients with DCM and refractory cardiac function, despite maximum medical therapy, were selected. Five had ischemic DCM deemed unlikely to benefit from revascularization alone and underwent bypass operations with concurrent intramyocardial MSC injection (group A). Two patients had previous revascularization and three had non-ischemic DCM and received intracoronary MSC injection (group B). RESULTS: Group A and B patients received 0.5-1.0 * 10(6) and 2.0-3.0 * 10(6) MSC/kg body weight, respectively. All patients remained alive at 1 year. There were significant improvements from baseline to 6 and 12 months in left ventricular ejection fraction and other left ventricular parameters. Scar reduction was noted in six patients by 12 months. CONCLUSIONS: Autologous bone marrow MSC treatment is safe and feasible for treating chronic severe refractory DCM effectively, via intracoronary or direct intramyocardial administration at prescribed doses. PMID- 21526899 TI - The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis. AB - Research efforts spanning the past two decades have established a clear link between nuclear receptor function, regulation of the circadian clock and lipid homeostasis. As such, this family of receptors represents an important area of research. Recent advances in the field have identified two nuclear receptor subfamilies, the REV-ERBs and the 'retinoic acid receptor-related orphan receptors' (RORs), as critical regulators of the circadian clock with significant roles in lipid homeostasis. In this review, the latest information garnered from cutting-edge research on these two nuclear receptor subfamilies will be discussed. Through direct targeting of the REV-ERBs and RORs with synthetic ligands, generation of novel tools aimed at characterizing their function in vivo have been developed, which may lead to novel therapeutics for the treatment of metabolic disorders. PMID- 21526903 TI - Aspergillus fumigatus infection as a delayed manifestation of prosthetic knee arthroplasty and a review of the literature. AB - Fungal infection after total joint arthroplasty is a very rare but serious complication and a challenge to the treating and consulting physicians. The literature includes little information about the treatment protocol for Aspergillus infection after total knee arthroplasty, since only 3 cases have been reported. We describe the case of a non-immunocompromised patient who lacked predisposing risk factors and presented with pain and swelling. An aspiration under sterile conditions revealed Aspergillus fumigatus. The patient was treated successfully with a 2-stage exchange reimplantation and 6-week course of liposomal amphotericin B. At 4 y after reimplantation, the patient had no evidence of infection or pain. PMID- 21526904 TI - Clinical and virological features of enterovirus 71 infections in Denmark, 2005 to 2008. AB - BACKGROUND: Since the late 1990s enterovirus 71 (EV71) has caused epidemics of hand, foot and mouth disease with fatal cases especially in the Asian Pacific region. The objective of this study was to describe the clinical and virological features of EV71 infections in Denmark. METHODS: All enterovirus-positive samples in Denmark are submitted to the National Poliovirus Laboratory for typing, and the EV71-positive samples are characterized by sequencing and phylogenetic analysis. Clinical information was gathered for the EV71-positive patients. RESULTS: During 2005-2008, EV71 was demonstrated in 29 patients. In 2007 EV71 was the second most common enterovirus type detected in Denmark. Twenty-one of the 29 patients were children aged <=1 y, 24 were hospitalized, and meningitis was the most common diagnosis. Gastroenteritis and hand, foot and mouth disease were other common clinical manifestations, but no fatal cases or cases of pulmonary oedema were seen. A novel subgenotype in Europe, B5, dominated the 2007 outbreak, but co-circulated with subgenotypes C1 and C2. CONCLUSIONS: In conclusion EV71 was among the common enterovirus types in Denmark, and in 2007 a novel subgenotype, B5, was observed. EV71 was mainly diagnosed in infants, and the majority of patients were hospitalized with meningitis. PMID- 21526905 TI - Identifying the affected branches of vestibular nerve in vestibular neuritis. AB - CONCLUSION: The inner ear monitoring system is useful for identifying the affected branches of the vestibular nerve in cases of vestibular neuritis, providing insight about the interval for the relief of vertigo. OBJECTIVE: This study conducted an inner ear monitoring system including audiometry, and caloric, ocular vestibular evoked myogenic potential (oVEMP), and cervical VEMP (cVEMP) tests in cases of vestibular neuritis for assessing the affected branches of the vestibular nerve. METHODS: Twenty patients with vestibular neuritis underwent caloric, oVEMP, and cVEMP tests. Type I indicates that one of the three tests is abnormal; type II indicates that two test results are abnormal; and type III indicates that no test result is normal. RESULTS: All patients had normal hearing, bilaterally. Nineteen (95%) of 20 patients had abnormal caloric responses, 11 patients (55%) had abnormal oVEMPs, and 5 patients (25%) had abnormal cVEMPs. Restated, of all 20 patients, 8 patients were classified as type I, 9 were type II, and 3 were type III. The mean intervals between presentation and relief of vertigo were significantly different among the three types. One year after treatment, caloric, oVEMP, and cVEMP tests returned to normal responses in three (60%) of five patients. PMID- 21526906 TI - Auditory and vestibular defects induced by experimental labyrinthitis following herpes simplex virus in mice. AB - CONCLUSION: Our herpes simplex virus (HSV) labyrinthitis mouse model suggests that HSV infection induces vestibular neuritis and sudden deafness. OBJECTIVE: Viral labyrinthitis has been postulated to play a role in vestibular neuritis and sudden deafness. We established a mouse model to investigate the pathogenesis of HSV-induced labyrinthitis. The relationship between HSV infection and apoptosis in the labyrinth was assessed. METHODS: HSV types 1 and 2 were inoculated into the middle ear of mice, and the function of the cochlear and vestibular nerves was assessed. Histopathological changes were examined with hematoxylin and eosin staining. Anti-HSV immunohistochemistry staining and TUNEL staining were done to investigate the relationship between HSV-infected cells and apoptotic cells. RESULTS: Hearing loss and vestibular dysfunction were observed in all mice after inoculation of HSV type 1 or 2. In the cochlear duct, columnar epithelial cells in the stria vascularis were infected with HSV, but only a portion of the infected cells underwent apoptosis. In contrast, many uninfected cells in the spiral organ of Corti were apoptotic. Vestibular dysfunction was observed when vestibular ganglion cells were largely infected, but not apoptotic. These findings recapitulate sudden deafness and vestibular neuritis described in patients. PMID- 21526907 TI - Astragaloside IV attenuates impulse noise-induced trauma in guinea pig. AB - CONCLUSION: These results suggest that the beneficial effect of astragaloside IV on impulse noise-induced hearing loss may be due to its ability to inhibit inducible nitric oxide synthase (iNOS) and prevent the formation of reactive nitrogen species (RNS). OBJECTIVE: Astragaloside IV is the major active constituent of Astragalus membranaceus, which has been widely used for the treatment of diseases in China due to its antioxidant properties. iNOS and RNS are involved in damage induced by impulse noise trauma. The purpose of the present study was to investigate if astragaloside IV has the potential to reduce cochlear damage from impulse noise. METHODS: Guinea pigs in the experimental group were administered astragaloside IV intragastrically. Auditory thresholds were assessed by sound-evoked auditory brainstem response (ABR) at click and tone bursts of 8, 16 and 32 kHz, 72 h before and after exposure to impulse noise. iNOS and nitrotyrosine were determined immunohistochemically. Hair cell damage was analyzed by scanning electron microscopy. RESULTS: Astragaloside IV significantly reduced ABR deficits, reduced hair cell damage, and decreased the expression of iNOS and RNS formation. PMID- 21526908 TI - Expression and distribution of endocan in human tissues. AB - Endocan is a novel human endothelial cell specific molecule. Its expression is regulated by cytokines and vascular endothelial growth factor (VEGF). The distribution of endocan in normal human tissues, however, remains unclear. We examined the expression of endocan in normal human tissue using immunohistochemical stains. Endocan was expressed in actively proliferative or neogeneic tissues and cells such as glandular tissues, endothelium of neovasculature, bronchial epithelium, germinal centers of lymph nodes etc. Endocan was not present in silent or resting tissues or cells such as endothelium of great arteries and spleen etc. Our findings suggest that endocan may act as a marker for angiogenesis or oncogenesis and could be regarded as a candidate gene for inflammatory tissue, neoplasia, tumor development and metastasis. The expression level of endocan may assist early diagnosis and prognosis of some tumors. PMID- 21526909 TI - Non-computer-assisted liquid-based cytology for diagnosis of oral squamous cell carcinoma. AB - The development of oral squamous cell carcinoma (OSCC) occasionally follows the neoplastic progression of other premalignant lesions. Although biopsy is the definitive diagnostic method, liquid-based cytology is an adequate method for screening suspicious lesions. We compared liquid-based cytology to histology for diagnosis of OSCC in patients with oral lesions that raised clinical suspicion of malignancy. Our sample consisted of 48 patients. Cytological samples were obtained by scraping the lesion superficially using Cytobrush(r). We conducted cytological and histopathological evaluation of all preparations. We estimated sensitivity and specificity levels as well as positive and negative predictive values. The degree of inter-observer agreement for both methods was assessed using the kappa index. Twenty-eight (58.3%) of the cases finally were diagnosed with OSCC and 20 (41.7%) were determined to be premalignant lesions. We observed eight false negatives and no false positives; OSCC prevalence was 56.5%. The values for diagnostic indices were: sensitivity, 69% (CI 95%, prevalence 51.87); specificity, 100%; positive predictive value, 100%; negative predictive value, 71% (CI 95% 54.82). A kappa index of 0.622 (CI 95% 0.93, 0.39) was observed. PMID- 21526910 TI - Immunohistochemical localization of C1 subunit of V-ATPase (ATPase C1) in oral squamous cell cancer and normal oral mucosa. AB - The ATP6V1C1 gene encodes the C1 subunit of the vacuolar-ATPase (V-ATPase) proton pump. This gene is over-expressed in oral squamous cell carcinoma (OSCC) as determined by real-time quantitative polymerase chain reaction. The aim of our study was to perform an immunohistochemical study of the distribution of the C1 subunit in normal epithelium of the oral cavity and in OSCC. We analyzed the expression of the C1 subunit in eight OSCC samples and two normal oral mucosa samples using polyclonal V-ATPase C1 antibody (clone H-300). In the normal oral mucosa samples, C1 subunit staining was observed in the basal and intermediate layers of the epithelium. No staining was visible in the keratinized superficial layers. More intense staining was observed in the OSCC samples, with the predominant expression at the periphery of tumor nests and absence of expression in dyskeratotic areas. C1 subunit expression in tumor cells was predominantly cytoplasmic, although there was perinuclear and nuclear expression in some samples. These findings demonstrate that V-ATPase is necessary for proper epithelial functioning and show its importance in the development of OSCC as evidenced by the over-expression of ATP6V1C1 in OSCC. PMID- 21526911 TI - Fungal aero-decontamination efficacy of mobile air-treatment systems. AB - Immunosuppressed patients are at high risk of acquiring airborne fungal infections, mainly caused by Aspergillus species. Although HEPA filters are recommended to prevent environmental exposure, mobile air-treatment units can be an alternative. However, many different models of mobile units are available but there are few data on their fungal aero-decontamination efficacy and usefulness in the prevention of Aspergillus infections. Thus, we developed a challenge test, based on the aerosolization of 10(6) Aspergillus niger conidia, in order to compare the particle and fungal decontamination efficacy of the following four mobile air-treatment systems; Plasmair T2006, Mobil'Air 1200 (MA1200), Mobil'Air 600 (MA600) combined with Compact AirPur Mobile C250 (C250), and the prototype unit Compact AirPur Mobile 1800 (C1800). The use of all these air-treatment systems was able to significantly decrease the concentration of particles or fungal viable conidia. ISO7 was the maximum particle class reached within 20 min with the Plasmair T2006 and MA1200, 1 h by the combined MA600/C250, and 1 h and 30 min with the C1800. After 2 h, fungal counts were significantly lower with Plasmair T2006, MA1200 and the combined MA600/C250 (2.2 +/- 1.9 to 5.0 +/- 3.7 CFU/m(3)) than achieved with the C1800 (23.8 +/- 12.8 CFU/m(3); P <= 6.0E-3). All the air-treatment systems were able to decrease aerial particle and fungal counts, but their efficacy was variable, depending on the units' air-treatment modalities and rates of air volume that was processed. This comparative study could be helpful in making an informed choice of mobile units, and in improving the prevention of air-transmitted fungal infections in non-protected areas. PMID- 21526912 TI - Recipient of kidney from donor with asymptomatic infection by Paracoccidioides brasiliensis. AB - The increase in solid organ transplantations may soon create a rise in the occurrence of endemic fungal diseases, such as paracoccidioidomycosis, due to the lack of rigorous screening of donors from endemic areas. Here we present the first case of an immunocompetent and asymptomatic kidney donor who had Paracoccidioides brasiliensis infected-adrenal tissue but no glandular dysfunction. PMID- 21526914 TI - Cardiac tissue engineering: a clinical perspective. AB - Engineered myocardium may be used to repair myocardial defects. Although not clinically applicable yet, initial studies in rodents have demonstrated the feasibility of tissue engineering based myocardial repair in vivo. In order for restorative treatment to evolve into a functional treatment modality, tissue engineers have to generate human myocardium of sufficient size and with relevant contractile function to replace/repair myocardial defects. This requires the identification of a scalable and ideally autologous cardiomyocyte source as well as the development of strategies to overcome size limitations. We will further address pivotal issues pertaining to the allocation of suitable human cells for myocardial tissue engineering and discuss the translation of present myocardial tissue engineering concepts into preclinical, as well as clinical, trials. PMID- 21526913 TI - Regulation of expression, activity and localization of fungal chitin synthases. AB - The fungal cell wall represents an attractive target for pharmacologic inhibition, as many of the components are fungal-specific. Though targeted inhibition of beta-glucan synthesis is effective treatment for certain fungal infections, the ability of the cell wall to dynamically compensate via the cell wall integrity pathway may limit overall efficacy. To date, chitin synthesis inhibitors have not been successfully deployed in the clinical setting. Fungal chitin synthesis is a complex and highly regulated process. Regulation of chitin synthesis occurs on multiple levels, thus targeting of these regulatory pathways may represent an exciting alternative approach. A variety of signaling pathways have been implicated in chitin synthase regulation, at both transcriptional and post-transcriptional levels. Recent research suggests that localization of chitin synthases likely represents a major regulatory mechanism. However, much of the regulatory machinery is not necessarily shared among different chitin synthases. Thus, an in-depth understanding of the precise roles of each protein in cell wall maintenance and repair will be essential to identifying the most likely therapeutic targets. PMID- 21526916 TI - The use of contrast echo to clear the left atrial appendage. PMID- 21526917 TI - Outcomes of acute heart failure associated with acute coronary syndrome versus other causes. AB - BACKGROUND: By and large, prior registries and randomized trials have not distinguished between acute heart failure (AHF) associated with acute coronary syndrome (ACS) versus other causes. AIMS: To examine whether the treatments and outcomes of ACS-associated AHF are different from non-ACS-associated AHF. METHODS: We examined in a prospective, nationwide hospital-based survey the adjusted outcomes of AHF patients with and without ACS as its principal cause. RESULTS: Of the 4102 patients in our national heart failure survey, 2336 (56.9%) had AHF, of whom 923 (39.5%) had ACS-associated AHF. These patients were more likely to receive intravenous inotropes and vasodilators and to undergo coronary angiography and revascularization, but less likely to receive intravenous diuretics. The unadjusted in-hospital, 30-day, one-year, and four-year mortality rates for AHF patients with or without ACS were 6.5% versus 5.0% (P = 0.13), 10.3% versus 7.5% (P = 0.02), 26.6% versus 31.0% (P = 0.02), and 55.3% versus 63.3% (P = 0.0001), respectively. In the multivariate analysis, the adjusted mortality risk for patients with ACS at the respective time points were 1.46 (0.99-2.10), 1.67 (1.22-2.30), 1.02 (0.86-1.20), and 0.93 (0.82-1.04). CONCLUSIONS: Patients with ACS-associated AHF seem to have a unique clinical course and perhaps should be distinguished from other AHF patients in future trials and registries. PMID- 21526918 TI - Transesophageal echo to help percutaneous closure of ventricular septal defect post acute myocardial infarction. AB - Ventricular septal defect after acute myocardial infarction (AMI) is a complication associated with poor outcome in the absence of intervention. We report a case of successful TEE guided transcatheter closure of a post myocardial infarction (MI) ventricular septal defect (VSD) with an Amplatzer occluder in a 79 years old male with cardiogenic shock. PMID- 21526919 TI - Routine upfront abciximab versus standard periprocedural therapy in patients undergoing primary percutaneous coronary intervention for cardiogenic shock: The PRAGUE-7 Study. An open randomized multicentre study. AB - BACKGROUND: The outcome of acute myocardial infarction (AMI) complicated with cardiogenic shock is poor. The aim of this study was to analyse, whether upfront abciximab administration could improve the outcomes of cardiogenic shock. METHODS: This multicentre open trial randomized 80 patients with AMI complicated by cardiogenic shock expected to undergo primary PCI into group A (routine upfront-pre-procedural-abciximab bolus followed by 12-h abciximab infusion) and group B (standard therapy). The study primary objective was 30-day combined outcome (death/reinfarction/stroke/new severe renal failure). RESULTS: PCI was technically successful in 90% (A) versus 87.5% (B) patients. Abciximab was used in 100% (A) versus 35% (B). The primary endpoint occurred in 17 group A patients (42.5%) and 11 group B patients (27.5%, P = 0.24). Ejection fraction among survivors after 30 days was 44 +/- 11% (A) versus 41 +/- 12% (B, P = 0.205). Major bleeding occurred in 17.5% (A) versus 7.5% (B, P = 0.310). No differences (A versus B) were found in TIMI-flow and MBG after PCI. CONCLUSIONS: This study did not show any benefit from routine pre-procedural abciximab when compared with a selective abciximab use during the intervention in patients with cardiogenic shock undergoing primary PCI. However, small sample size of the trial preclude any definitive conclusion, a larger prospective, randomized, multicentered trial is needed. PMID- 21526920 TI - Patient information for better health outcomes in primary care. PMID- 21526921 TI - Leadership in rural medicine: the organization on thin ice? AB - OBJECTIVE. To explore the personal experiences of and conceptions regarding leading rural primary care in Northern Norway. DESIGN. Qualitative content analysis of focus-group interviews. SETTING. Lead primary care physicians in the three northernmost counties. Subjects. Four groups with 22 out of 88 municipal lead physicians in the region. RESULTS. Three main categories were developed and bound together by an implicit theme. Demands and challenges included the wide leadership span of clinical services and public health, placed in a merged line/board position. Constraints of human resources and time and the ever changing organizational context added to the experience of strain. Personal qualifications indicates the lack of leadership motivation and training, which was partly compensated for by a leader role developed through clinical undergraduate training and then through the responsibilities and experiences of clinical work. In Exercising the leadership, the participants described a vision of a coaching and coordinating leadership and, in practice, a display of communication skills, decision-making ability, result focusing, and ad hoc solutions. Leadership was made easier by the features of the small, rural organization, such as overview, close contact with cooperating partners, and a supportive environment. There was incongruence between demands and described qualifications, and between desired and executed leadership, but nevertheless the organization was running. Leadership demonstrated a "working inadequacy". CONCLUSION. Under resource constraints, leadership based on clinical skills favours management by exception which, in the long run, appears to make the leadership less effective. Leadership training which takes into account the prominent features of rural and decentralized primary care is strongly needed. PMID- 21526922 TI - Occurrence of Cryptosporidium andersoni in Brazilian cattle. AB - Feces were collected from 68 dairy cattle, 1 to 12 mo of age, on 12 farms in the municipality of Campos dos Goytacazes, Rio de Janeiro, Brazil, and examined for the presence of Cryptosporidium sp. All samples were subjected to molecular analysis by polymerase chain reaction (nested PCR) of the 18S rRNA. Four positive samples (4.54%) were sequenced and identified as Cryptosporidium andersoni. This species represents a risk for Brazilian cattle because infection can affect cattle productivity. Moreover, C. andersoni is considered a zoonotic species. PMID- 21526924 TI - Bevacizumab versus ranibizumab for AMD. PMID- 21526926 TI - Nesting biology and fungiculture of the fungus-growing ant, Mycetagroicus cerradensis: new light on the origin of higher attine agriculture. AB - The genus Mycetagroicus is perhaps the least known of all fungus-growing ant genera, having been first described in 2001 from museum specimens. A recent molecular phylogenetic analysis of the fungus-growing ants demonstrated that Mycetagroicus is the sister to all higher attine ants (Trachymyrmex, Sericomyrmex, Acromyrmex, Pseudoatta, and Atta), making it of extreme importance for understanding the transition between lower and higher attine agriculture. Four nests of Mycetagroicus cerradensis near Uberlandia, Minas Gerais, Brazil were excavated, and fungus chambers for one were located at a depth of 3.5 meters. Based on its lack of gongylidia (hyphal-tip swellings typical of higher attine cultivars), and a phylogenetic analysis of the ITS rDNA gene region, M. cerradensis cultivates a lower attine fungus in Clade 2 of lower attine (G3) fungi. This finding refines a previous estimate for the origin of higher attine agriculture, an event that can now be dated at approximately 21-25 mya in the ancestor of extant species of Trachymyrmex and Sericomyrmex. PMID- 21526925 TI - Current methods of adipogenic differentiation of mesenchymal stem cells. AB - There has been a recent increase in our understanding in the isolation, culture, and differentiation of mesenchymal stem cells (MSCs). Concomitantly, the availability of MSCs has increased, with cells now commercially available, including human MSCs from adipose tissue and bone marrow. Despite an increased understanding of MSC biology and an increase in their availability, standardization of techniques for adipogenic differentiation of MSCs is lacking. The following review will explore the variability in adipogenic differentiation in vitro, specifically in 3T3-L1 and primary MSCs derived from both adipose tissue and bone marrow. A review of alternative methods of adipogenic induction is also presented, including the use of specific peroxisome proliferator activated receptor-gamma agonists as well as bone morphogenetic proteins. Finally, we define a standard, commonly used adipogenic differentiation medium in the hopes that this will be adopted for the future standardization of laboratory techniques--however, we also highlight the essentially arbitrary nature of this decision. With the current, rapid pace of electronic publications, it becomes imperative for standardization of such basic techniques so that interlaboratory results may be easily compared and interpreted. PMID- 21526927 TI - Wolbachia wSinvictaA infections in natural populations of the fire ant Solenopsis invicta: testing for phenotypic effects. AB - Wolbachia are intracellular bacteria that commonly infect many arthropods and some nematodes. In arthropods, these maternally transmitted bacteria often induce a variety of phenotypic effects to enhance their own spread within host populations. Wolbachia phenotypic effects generally either provide benefits to infected host females (cytoplasmic incompatibility, positive fitness effects) or bias host sex ratio in favor of females (male-killing, parthenogenesis, feminization), all of which increase the relative production of infected females in host populations. Wolbachia surveys have found infections to be exceedingly common in ants, but little is known at this juncture as to what phenotypic effects, if any, they induce in this group. Previous studies have demonstrated that individuals from native populations of the invasive fire ant Solenopsis invicta commonly harbor one or more of three Wolbachia variants. One of the variants, wSinvictaA, typically occurs at low prevalence in S. invicta populations, appears to have been transmitted horizontally into S. invicta three or more times, and has been lost repeatedly from host lineages over time. In order to determine the phenotypic effects and likely population dynamics of wSinvictaA infections in these ants, brood production patterns of newly mated fire ant queens were studied during simulated claustral founding and measured wSinvictaA transmission fidelity within mature single-queen families. No clear evidence was found for Wolbachia-induced cytoplasmic incompatibility, significant fitness effects, or male-killing. Maternal transmission was perfect to both virgin queens and males. Possible mechanisms for how this variant could be maintained in host populations are discussed. PMID- 21526928 TI - The role of body size and shape in understanding competitive interactions within a community of Neotropical dung beetles. AB - Geometric morphometrics is helpful for understanding how body size and body shape influence the strength of inter-specific competitive interactions in a community. Dung beetles, characterized by their use of decomposing organic material, provide a useful model for understanding the structuring of ecological communities and the role of competition based on their size and morphology. The relationship between body size and shape in a dung beetle community from the Atlantic Forest in Serra do Japi, Brazil was analyzed for 39 species. Fifteen anatomical landmarks on three-dimensional Cartesian coordinates were used to describe both the shape and the size of the body of each species on the basis of the centroid located along homologous points in all of the species. The first vector of a principal components analysis explained 38.5% of the morphological variation among species, and represents a gradient of body shape from elongated, flattened bodies with narrow abdomen to rounded or convex bodies. The second component explained 17.8% of the remaining variation in body shape, which goes from species with an abdomen that is larger than the elytra to species with constricted abdomens and large elytra. The relationship between body size and shape was analyzed separately for diurnal and nocturnal species. In both guilds not only were there differences in body size, but also in body shape, suggesting a reduction in their level of competition. PMID- 21526929 TI - Analysis of genetic variation and phylogeny of the predatory bug, Pilophorus typicus, in Japan using mitochondrial gene sequences. AB - Pilophorus typicus (Distant) (Heteroptera: Miridae) is a predatory bug occurring in East, Southeast, and South Asia. Because the active stages of P. typicus prey on various agricultural pest insects and mites, this species is a candidate insect as an indigenous natural enemy for use in biological control programs. However, the mass releasing of introduced natural enemies into agricultural fields may incur the risk of affecting the genetic integrity of species through hybridization with a local population. To clarify the genetic characteristics of the Japanese populations of P. typicus two portions of the mitochondrial DNA, the cytochrome oxidase subunit I (COI) (534 bp) and the cytochrome B (cytB) (217 bp) genes, were sequenced for 64 individuals collected from 55 localities in a wide range of Japan. Totals of 18 and 10 haplotypes were identified for the COI and cytB sequences, respectively (25 haplotypes over regions). Phylogenetic analysis using the maximum likelihood method revealed the existence of two genetically distinct groups in P. typicus in Japan. These groups were distributed in different geographic ranges: one occurred mainly from the Pacific coastal areas of the Kii Peninsula, the Shikoku Island, and the Ryukyu Islands; whereas the other occurred from the northern Kyushu district to the Kanto and Hokuriku districts of mainland Japan. However, both haplotypes were found in a single locality of the southern coast of the Shikoku Island. COI phylogeny incorporating other Pilophorus species revealed that these groups were only recently differentiated. Therefore, use of a certain population of P. typicus across its distribution range should be done with caution because genetic hybridization may occur. PMID- 21526930 TI - Fire ant decapitating fly cooperative release programs (1994-2008): two Pseudacteon species, P. tricuspis and P. curvatus, rapidly expand across imported fire ant populations in the southeastern United States. AB - Natural enemies of the imported fire ants, Solenopsis invicta Buren S. richteri Forel (Hymenoptera: Formicidae), and their hybrid, include a suite of more than 20 fire ant decapitating phorid flies from South America in the genus Pseudacteon. Over the past 12 years, many researchers and associates have cooperated in introducing several species as classical or self-sustaining biological control agents in the United States. As a result, two species of flies, Pseudacteon tricuspis Borgmeier and P. curvatus Borgmeier (Diptera: Phoridae), are well established across large areas of the southeastern United States. Whereas many researchers have published local and state information about the establishment and spread of these flies, here distribution data from both published and unpublished sources has been compiled for the entire United States with the goal of presenting confirmed and probable distributions as of the fall of 2008. Documented rates of expansion were also used to predict the distribution of these flies three years later in the fall of 2011. In the fall of 2008, eleven years after the first successful release, we estimate that P. tricuspis covered about 50% of the fire ant quarantined area and that it will occur in almost 65% of the quarantine area by 2011. Complete coverage of the fire ant quarantined area will be delayed or limited by this species' slow rate of spread and frequent failure to establish in more northerly portions of the fire ant range and also, perhaps, by its preference for red imported fire ants (S. invicta). Eight years after the first successful release of P. curvatus, two biotypes of this species (one biotype occurring predominantly in the black and hybrid imported fire ants and the other occurring in red imported fire ants) covered almost 60% of the fire ant quarantined area. We estimate these two biotypes will cover almost 90% of the quarantine area by 2011 and 100% by 2012 or 2013. Strategic selection of several distributional gaps for future releases will accelerate complete coverage of quarantine areas. However, some gaps may be best used for the release of additional species of decapitating flies because establishment rates may be higher in areas without competing species. PMID- 21526931 TI - Occurrence of different gynandromorphs and ergatandromorphs in laboratory colonies of the urban ant, Monomorium floricola. AB - Colonies of Monomorium floricola (Jerdon) in laboratory conditions showed gynandromorphic and ergatandromorphic specimens, the former with nine different combinations of male and female tissues and the latter with 6 different combinations. Their development from egg to adult was around 74.6 days for gynandromorphs, and 87.5 days for ergantandromorphs. PMID- 21526932 TI - Effects of temperature on the development and population growth of the sycamore lace bug, Corythucha ciliata. AB - The sycamore lace bug, Corythucha ciliata (Say) (Hemiptera: Tingidae), is an important invasive exotic pest of Platanus (Proteales: Platanaceae) trees in China. The objective of this study was to determine the effects of temperature on C. ciliata in the laboratory so that forecasting models based on heat accumulation units could be developed for the pest. Development and fecundity of C. ciliata reared on leaves of London plane tree (Platanus * acerifolia) were investigated at seven constant temperatures (16, 19, 22, 26, 30, 33, and 36 degrees C) and at a relative humidity of 80% with a photoperiod of 14:10 (L:D). The developmental time was found to significantly decrease with increasing temperature. The developmental time from egg hatching to adult emergence was respectively 47.6, 35.0, 24.1, 20.0, and 17.1 days at the temperatures of 19, 22, 26, 30, and 33 degrees C. C. ciliata could not complete full development at 16 degrees and 36 degrees C. The developmental threshold temperature (C) estimated for egg-to-adult was 11.17 degrees C, with a thermal constant of (K) 370.57 degree-days. Longevity of females was found to be the shortest, 17.7 days at 33 degrees C and the longest, 58.9 days at 16 degrees C, and that of males was the shortest, 19.7 days at 33 degrees C and the longest, 59.7 days at 16 degrees C. Fecundity was the highest at 30 degrees C, being 286.8 eggs per female over an oviposition period of 8.9 days. Female lifetime fecundity was reduced at other temperatures, being the lowest (87.7 eggs per female) at 19 degrees C. The population trend index (I) of C. ciliata was the highest (130.1) at 30 degrees C and the lowest (24.9) at 19 degrees C. Therefore, the optimal developmental temperature for C. ciliata was determined to be 30 degrees C. PMID- 21526933 TI - Parasitism of lepidopterous stem borers in cultivated and natural habitats. AB - Plant infestation, stem borer density, parasitism, and parasitoid abundance were assessed during two years in two host plants, Zea mays (L.) (Cyperales: Poaceae) and Sorghum bicolor (L.) (Cyperales: Poaceae), in cultivated habitats. The four major host plants (Cyperus spp., Panicum spp., Pennisetum spp., and Sorghum spp.) found in natural habitats were also assessed, and both the cultivated and natural habitat species occurred in four agroecological zones in Kenya. Across habitats, plant infestation (23.2%), stem borer density (2.2 per plant), and larval parasitism (15.0%) were highest in maize in cultivated habitats. Pupal parasitism was not higher than 4.7% in both habitats, and did not vary with locality during each season or with host plant between each season. Cotesia sesamiae (Cameron) and C. flavipes Cameron (Hymenoptera: Braconidae) were the key parasitoids in cultivated habitats (both species accounted for 76.4% of parasitized stem borers in cereal crops), but not in natural habitats (the two Cotesia species accounted for 14.5% of parasitized stem borers in wild host plants). No single parasitoid species exerted high parasitism rates on stem borer populations in wild host plants. Low stem borer densities across seasons in natural habitats indicate that cereal stem borer pests do not necessarily survive the non-cropping season feeding actively in wild host plants. Although natural habitats provided refuges for some parasitoid species, stem borer parasitism was generally low in wild host plants. Overall, because parasitoids contribute little in reducing cereal stem borer pest populations in cultivated habitats, there is need to further enhance their effectiveness in the field to regulate these pests. PMID- 21526934 TI - Factors of susceptibility of human myiasis caused by the New World screw-worm, Cochliomyia hominivorax in Sao Goncalo, Rio de Janeiro, Brazil. AB - This study was carried out between July 2007 and June 2008 and reports on the occurrence of human myiasis caused by the New World screwworm, Cochliomyia hominivorax (Coquerel) (Diptera: Calliphoridae) in Sao Goncalo in the state of Rio de Janeiro, Brazil. Liquid or solid vaseline was used to suffocate the larvae, which were then preserved in 70% ethanol and sent to the Instituto Oswaldo Cruz for identification. C. hominivorax were identified in all 22 cases of myiasis. There were 12 male and 10 female patients with ages ranging from 03 to 71. Ethnically the highest incidence was among black people, with 17 cases. Open wounds were the main cause of the parasitosis, whereas poor personal hygiene, the low educational level, alcoholism, bedridden patients, and physical or mental disability were possibly secondary factors; in addition to all these factors the income of the patients was very low. PMID- 21526935 TI - Assessment of attractiveness of cassava as a roosting plant for the melon fly, Bactrocera cucurbitae, and the Oriental fruit fly, B. dorsalis. AB - Application of bait spray to crop borders is a standard approach for suppression of melon fly, Bactrocera cucurbitae (Coquillett) (Diptera: Tephritidae) populations and may also be of value for suppression of oriental fruit fly, B. dorsalis (Hendel) populations. Establishment of preferred roosting hosts as crop borders may help to improve suppression of both fruit fly species by providing sites for bait spray applications. In an area-wide B. cucurbitae suppression trial, the question was raised as to whether cassava, Manihot esculenta Crantz (Euphorbiales: Euphorbiaceae), could be used as a B. cucurbitae roosting host. M. esculenta was of interest as a roosting host because, in contrast to many other identified preferred roosting hosts, it would also be a crop potentially increasing the productivity of the crop production system overall. As a short lived and shrubby perennial, M. esculenta potentially constitutes a crop with more persistent roosting foliage than an annual crop such as corn, Zea mays L. (Cyperales: Poaceae), that has often been planted as a roosting host for B. cucurbitae control. Using protein-baited traps set amidst potted plants placed adjacent to a papaya Carica papaya L. (Violales: Caricaceae) orchard known to have established populations of B. cucurbitae and B. dorsalis, the effectiveness of M. esculenta as a roosting host was assessed by comparing its attractiveness to that of castor bean, Ricinus communis L (Malpighiales: Euphorbiaceae), previously identified as one of the most attractive roosting hosts for B. cucurbitae, and to corn, a crop which has been planted as a roosting host for help in B. cucurbitae control. The results showed that use of M. esculenta as a roosting host is comparable to use of R. communis by both B. cucurbitae and B. dorsalis. These results provide encouragement to incorporate M. esculenta on a farm as a trap crop (i.e. site for bait spray application). This has the advantage of having the trap crop be a crop on its own (as opposed to castor bean) and, among prospective crops that could be used as a trap crop, has foliage more persistent than an annual trap crop such as corn. PMID- 21526936 TI - The reemergence of pertussis and infant deaths: is it time to immunize pregnant women? PMID- 21526938 TI - HIV-1 Vpr and G2 cell cycle arrest. AB - Evaluation of: Belzile J-P, Abrahamyan LG, Gerard FCA et al.: Formation of mobile chromatin-associated nuclear foci containing HIV-1 Vpr and VPRBP is critical for the induction of G2 cell cycle arrest. PLoS Pathog. 6(9), E1001080 (2010). All primate immunodeficiency viruses encode a unique set of accessory proteins to optimize their replication in hosts. In general, these proteins appear to be multifunctional for virus replication. Viral protein R (Vpr), one of the accessory proteins, has also been reported to exhibit distinct activities, but its exact role in the viral life cycle is still unclear and controversial. However, of particular note, Vpr-mediated G2 cell cycle arrest is conserved among primate immunodeficiency viruses. Belzile et al. have characterized and analyzed in detail the punctuate structures on the DNA of host cells formed by HIV-1 Vpr (Vpr nuclear foci). They demonstrate, mainly by confocal immunofluorescence analysis, that highly mobile chromatin-associated Vpr nuclear foci are critical for induction of the G2 cell cycle arrest. PMID- 21526940 TI - Chronic fatigue syndrome, XMRV and blood safety. AB - In the past few months, there has been public discussion relating to a new perspective on blood safety and specifically upon measures to prevent or discourage donation by individuals with a diagnosis of myalgic encephalopathy chronic fatigue syndrome. This reflects an intriguing interplay between science, public health and public concern and illustrates some of the difficulties of making decisions in the face of uncertainty and inadequate information. PMID- 21526939 TI - The Ying-Yang of the virus-host interaction: control of the DNA damage response. AB - Evaluation of: Nikitin PA, Yan CM, Forte E et al.: An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells. Cell. Host Microbe 8(6), 510-522 (2010). Viruses have evolved elegant strategies to manipulate the host while the host counters with defense systems including the interferon response, apoptosis and the DNA damage response (DDR). Viruses have multiple strategies for manipulating the DDR and the same virus can even activate or inhibit the DDR at different stages of infection. Epstein-Barr virus (EBV) is implicated in several human cancers, including Burkitt's lymphoma, nasopharyngeal carcinoma, post-transplant lymphoproliferative disease and HIV-associated lymphomas. Although multiple viral proteins have been implicated in EBV-associated malignancies, the cellular pathways that control EBV induced transformation and tumorigenesis remain incompletely understood. In this study, Nikitin et al. demonstrate that early EBV infection induces a cellular DDR that restricts virus-mediated transformation. The EBV-encoded EBNA3C protein subsequently attenuates this response to favor transformation and immortalization of host cells. PMID- 21526941 TI - Tularemia vaccines: recent developments and remaining hurdles. AB - Francisella tularensis subsp. tularensis is a facultative intracellular bacterial pathogen of humans and other mammals. Its inhaled infectious dose is very low and can result in very high mortality. Historically, subsp. tularensis was developed as a biological weapon and there are now concerns about its abuse as such by terrorists. A live attenuated vaccine developed pragmatically more than half a century ago from the less virulent holarctica subsp. is the sole prophylactic available, but it remains unlicensed. In recent years several other potential live, killed and subunit vaccine candidates have been developed and tested in mice for their efficacy against respiratory challenge with subsp. tularensis. This article will review these vaccine candidates and the development hurdles they face. PMID- 21526942 TI - Global spread of drug-resistant Acinetobacter baumannii: molecular epidemiology and management of antimicrobial resistance. AB - Acinetobacter baumannii is an opportunistic Gram-negative pathogen with increasing relevance in a variety of hospital-acquired infections especially among intensive care unit patients. Resistance to antimicrobial agents is the main reason for A. baumannii spread. A. baumannii outbreaks described worldwide are caused by a limited number of genotypic clusters of multidrug-resistant strains that successfully spread among hospitals of different cities and countries. In this article, we will focus on the mechanisms responsible for resistance to antimicrobials and disinfectants in A. baumannii and the epidemiology of drug-resistant A. baumannii in healthcare facilities. We will also discuss the therapeutic and infection control strategies for management of drug-resistant A. baumannii epidemics. PMID- 21526943 TI - Mycoplasma pneumoniae: susceptibility and resistance to antibiotics. AB - Mycoplasma pneumoniae is a pathogenic mycoplasma responsible for respiratory tract infections in humans, which occurs worldwide in children and adults. This article focuses on its antibiotic susceptibility profile and on the development of acquired resistance in this microorganism. The lack of a cell wall in mycoplasmas makes them intrinsically resistant to beta-lactams and to all antimicrobials that target the cell wall. M. pneumoniae is susceptible to macrolides and related antibiotics, tetracyclines and fluoroquinolones. Macrolides and related antibiotics are the first-line treatment for respiratory infections caused by M. pneumoniae. However, strains with acquired resistance to macrolides have recently emerged worldwide and have been spreading in Europe, USA and A sia especially, with more than 90% of Chinese isolates resistant to erythromycin and azithromycin. This acquired resistance can be detected by PCR methods directly from respiratory specimens and is related to 23S rRNA mutations. PMID- 21526944 TI - Pharmacokinetic/pharmacodynamic-based treatment of disseminated Mycobacterium avium. AB - Disseminated Mycobacterium avium complex (MAC) is treated with a macrolide and ethambutol. However, the kill rates are extremely slow so that therapy takes many months to years to achieve and even then more than 40% of patients are not completely cured. Recent studies have demonstrated that assays that detect extracellular MAC have a limited predictive value. Antibiotics kill at a much slower and more disappointing rate against bacilli within macrophages. Use of pharmacodynamic/pharmacokinetic models has resulted in design of new doses and dosing schedules for disseminated MAC, as well as new susceptibility breakpoints for ethambutol and moxifloxacin. PMID- 21526946 TI - Trans-splicing in trypanosomes: machinery and its impact on the parasite transcriptome. AB - In trypanosomes, all RNAs are processed by the concerted action of trans-splicing and polyadenylation. In trans-splicing, a common spliced leader (SL) is donated to all mRNAs from a small RNA molecule, the SL RNA. This article summarizes recent findings in the field focusing on SL RNA transcription, cap modifications and pseudouridylation. The role(s) of these modifications for splicing and gene expression are discussed. The recruitment of SL RNA to the spliceosome depends on splicing factors and recent progress in identifying such factors is described. A recent major advance in understanding the role of trans-splicing in the trypanosome transcriptome was obtained by whole-genome mapping of the SL and polyadenylation sites, revealing surprising heterogeneity and suggesting that gene regulation, especially during cycling between the two hosts of the parasite, involves alternative trans-splicing. Finally, the SL silencing mechanism, which is harnessed by the parasite to control gene expression under stress, is discussed. PMID- 21526948 TI - Adnexal clear cell carcinoma with comedonecrosis. PMID- 21526950 TI - When a protocol shows up at the door. PMID- 21526923 TI - Ranibizumab and bevacizumab for neovascular age-related macular degeneration. AB - BACKGROUND: Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. METHODS: In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. RESULTS: Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 MUm) than in the other groups (152 to 168 MUm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. CONCLUSIONS: At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.). PMID- 21526945 TI - Current perspectives on echinocandin class drugs. AB - It has been nearly a decade since caspofungin was approved for clinical use as the first echinocandin class antifungal agent, followed by micafungin and anidulafungin. The echinocandin drugs target the fungal cell wall by inhibiting the synthesis of beta-1,3-D-glucan, a critical cell wall component of many pathogenic fungi. They are fungicidal for Candida spp. and fungistatic for moulds, such as Aspergillus fumigatus, where they induce abnormal morphology and growth properties. The echinocandins have a limited antifungal spectrum but are highly active against most Candida spp., including azole-resistant strains and biofilms. As they target glucan synthase, an enzyme absent in mammalian cells, the echinocandins have a favorable safety profile. They show potent MIC and epidemiological cutoff values against susceptible Candida and Aspergillus isolates, and the frequency of resistance is low. When clinical breakthrough occurs, it is associated with high MIC values and mutations in Fks subunits of glucan synthase, which can reduce the sensitivity of the enzyme to the drug by several thousand-fold. Such strains were not adequately captured by an early clinical breakpoint for susceptibility prompting a revised lower value, which addresses the FKS resistance mechanism and new pharmacokinetic/pharmacodynamic studies. Elevated MIC values unlinked to therapeutic failure can occur and result from adaptive cell behavior, which is FKS-independent and involves the molecular chaperone Hsp90 and the calcineurin pathway. Mutations in FKS1 and/or FKS2 alter the kinetic properties of glucan synthase, which reduces the relative fitness of mutant strains causing them to be less pathogenic. The echinocandin drugs also modify the cell wall architecture exposing buried glucans, which in turn induce a variety of important host immune responses. Finally, the future for glucan synthase inhibitors looks bright with the development of new orally active compounds. PMID- 21526951 TI - An update in molecular diagnostics of solid tumors. PMID- 21526952 TI - Effects of preanalytical variables on the detection of proteins by immunohistochemistry in formalin-fixed, paraffin-embedded tissue. AB - CONTEXT: While formalin fixation and paraffin embedding has become a universal mechanism of tissue preservation and a gold standard for immunohistochemistry, fixation and processing variables that may confound assay effectiveness have received little attention from the scientific community. OBJECTIVE: To identify discrete steps in specimen fixation and processing that may impact immunostaining, assess the magnitude of reported effects in the literature, and highlight preanalytical variables that require further investigation. DATA SOURCES: Thirty-nine primary research articles that investigated immunohistochemical effects of 1 or more preanalytical variables were identified by our literature survey. Thresholds identified in the literature were then compared with published immunohistochemistry guidelines for formalin-fixed, paraffin-embedded specimens. CONCLUSIONS: Of the 62 preanalytical variables identified, 27 were examined in published research. Meta-analysis revealed 15 preanalytical variables that were capable of impacting immunohistochemistry (including fixation delay; fixative type; time in fixative; reagents and conditions of dehydration, clearing, and paraffin impregnation; and conditions of slide drying and storage) and 12 variables with no reported influence (including the type of processor used; the number and position of specimens during dehydration, clearing, and paraffin impregnation; and the duration of paraffin block storage). Variables with antigen-dependent or inconsistent effects were highlighted. Comparison of literature-supported thresholds with published recommendations revealed (1) strong agreement among preanalytical variables for optimal immunostaining, (2) discrepancies among thresholds for adequate immunostaining, and (3) the continued need for rigorous research and comprehensive guidelines on specimen fixation, processing, and storage. PMID- 21526953 TI - Molecular pathology of breast cancer: the journey from traditional practice toward embracing the complexity of a molecular classification. AB - CONTEXT: Adenocarcinoma of the breast is the most frequent cancer affecting women in both developed and developing regions of the world. From the moment of clinical presentation until the time of pathologic diagnosis, patients affected by this disease will face daunting questions related to prognosis and treatment options. While improvements in targeted therapies have led to increased patient survival, these same advances have created the imperative to accurately stratify patients to achieve maximum therapeutic efficacy while minimizing side effects. In this evolving era of personalized medicine, there is an ever-increasing need to overcome the limitations of traditional diagnostic practice. OBJECTIVE: To summarize the molecular diagnostics traditionally used to guide prognostication and treatment of breast carcinomas, to highlight published data on the molecular classification of these tumors, and to showcase molecular assays that will supplement traditional methods of categorizing the disease. DATA SOURCES: A review of the literature covering the molecular diagnostics of breast carcinomas with a focus on the gene expression and array studies used to characterize the molecular signatures of the disease. Special emphasis is placed on summarizing evolving technologies useful in the diagnosis and characterization of breast carcinoma. CONCLUSIONS: Available and emerging molecular resources will allow pathologists to provide superior diagnostic, prognostic, and predictive information about individual breast carcinomas. These advances should translate into earlier identification and tailored therapy and should ultimately improve outcome for patients affected by this disease. PMID- 21526954 TI - Molecular diagnostics of gliomas. AB - CONTEXT: Gliomas are the most common primary brain tumors of adults and include a variety of histologic types and morphologies. Histologic evaluation remains the gold standard for glioma diagnosis; however, diagnostic difficulty may arise from tumor heterogeneity, overlapping morphologic features, and tumor sampling. Recently, our knowledge about the genetics of these tumors has expanded, and new molecular markers have been developed. Some of these markers have shown diagnostic value, whereas others are useful prognosticators for patient survival and therapeutic response. OBJECTIVE: To review the most clinically useful molecular markers and their detection techniques in gliomas. DATA SOURCES: Review of the pertinent literature and personal experience with the molecular testing in gliomas. CONCLUSIONS: This article provides an overview of the most common molecular markers in neurooncology, including 1p/19q codeletion in oligodendroglial tumors, mutations in the isocitrate dehydrogenase 1 and 2 genes in diffuse gliomas, hypermethylation of the O(6)-methylguanine-DNA methyltransferase gene promoter in glioblastomas and anaplastic gliomas, alterations in the epidermal growth factor receptor and phosphatase and tensin homolog genes in high-grade gliomas, as well as BRAF alterations in pilocytic astrocytomas. Molecular testing of gliomas is increasingly used in routine clinical practice and requires that neuropathologists be familiar with these genetic markers and the molecular diagnostic techniques for their detection. PMID- 21526955 TI - Molecular diagnostics of thyroid tumors. AB - CONTEXT: Thyroid cancer is the most common type of endocrine malignancy and its incidence is steadily increasing. Papillary carcinoma and follicular carcinoma are the most common types of thyroid cancer and represent those tumor types for which use of molecular markers for diagnosis and prognostication is of high clinical significance. OBJECTIVE: To review the most common molecular alterations in thyroid cancer and their diagnostic and prognostic utility. DATA SOURCES: PubMed (US National Library of Medicine)-available review articles, peer-reviewed original articles, and experience of the author. CONCLUSIONS: The most common molecular alterations in thyroid cancer include BRAF and RAS point mutations and RET/PTC and PAX8/PPAR gamma rearrangements. These nonoverlapping genetic alterations are found in more than 70% of papillary and follicular thyroid carcinomas. These molecular alterations can be detected in surgically resected samples and fine-needle aspiration samples from thyroid nodules and can be of significant diagnostic use. The diagnostic role of BRAF mutations has been studied most extensively, and recent studies also demonstrated a significant diagnostic utility of RAS, RET/PTC, and PAX8/PPAR gamma mutations, particularly in thyroid fine-needle aspiration samples with indeterminate cytology. In addition to the diagnostic use, BRAF V600E mutation can also be used for tumor prognostication, as this mutation is associated with higher rate of tumor recurrence and tumor-related mortality. The use of these and other emerging molecular markers is expected to improve significantly the accuracy of cancer diagnosis in thyroid nodules and allow more individualized surgical and postsurgical management of patients with thyroid cancer. PMID- 21526956 TI - Molecular diagnostics of colorectal cancer. AB - CONTEXT: Of all gastrointestinal tract epithelial malignancies, molecular diagnostics has impacted colorectal cancer the most. Molecular testing can detect sporadic and inherited colorectal cancers that arise through the microsatellite instability pathway and can determine the efficacy of targeted drug therapy. OBJECTIVES: To review the microsatellite instability pathway of colorectal carcinoma carcinogenesis and to demonstrate the diagnostic utility of molecular testing in the detection of patients with Lynch syndrome, an inherited disorder of this pathway. Also, to review the significance of detection of KRAS and BRAF gene mutations in predicting the response to anti-epidermal growth factor receptor therapies. DATA SOURCES: This article is based on original publications and review articles that are accessible through the PubMed biomedical database (US National Library of Medicine). CONCLUSIONS: In modern pathology practice, molecular testing is a standard tool that is used to diagnose an inherited colorectal cancer predisposition syndrome (Lynch syndrome) and to help predict outcome and response to therapy for patients with advanced colorectal cancer. PMID- 21526957 TI - Molecular diagnostics of soft tissue tumors. AB - CONTEXT: Soft tissue pathology encompasses a remarkably diverse assortment of benign and malignant soft tissue tumors. Rendering a definitive diagnosis is complicated not only by the large volume of existing histologic subtypes (>100) but also frequently by the presence of overlapping clinical, histologic, immunohistochemical, and/or radiographic features. During the past 3 decades, mesenchymal tumor-specific, cytogenetic and molecular genetic abnormalities have demonstrated an increasingly important, ancillary role in mesenchymal tumor diagnostics. OBJECTIVES: To review molecular diagnostic tools available to the pathologist to further classify specific soft tissue tumor types and recurrent aberrations frequently examined. Advantages and limitations of individual approaches will also be highlighted. DATA SOURCES: Previously published review articles, peer-reviewed research publications, and the extensive cytogenetic and molecular diagnostic experience of the authors to include case files of The University of Nebraska Medical Center. CONCLUSIONS: Cytogenetic and molecular genetic assays are used routinely for diagnostic purposes in soft tissue pathology and represent a powerful adjunct to complement conventional microscopy and clinicoradiographic evaluation in the formulation of an accurate diagnosis. Care should be taken, however, to recognize the limitations of these approaches. Ideally, more than one technical approach should be available to a diagnostic laboratory to compensate for the shortcomings of each approach in the assessment of individual specimens. PMID- 21526958 TI - An update on molecular diagnostics of squamous and salivary gland tumors of the head and neck. AB - CONTEXT: Molecular testing in anatomic pathology is becoming standardized and can contribute valuable diagnostic, therapeutic, and prognostic information for the clinical management of patients. In head and neck pathology, recent advances in molecular testing have provided important targets in several different diagnostic areas, with particular emerging clinical applications in squamous and salivary gland pathology. In squamous mucosal-derived lesions, human papilloma virus has emerged as an important pathogenic etiology in a subset of oropharyngeal squamous cell carcinomas. Within the category of salivary gland tumors, 3 tumors have recently been recognized that contain oncogenic translocations. OBJECTIVE: To describe the current state of information about the molecular alterations in squamous lesions and in salivary gland tumors of the head and neck. DATA SOURCES: Published literature on squamous and salivary gland tumors of the head and neck. CONCLUSIONS: The different approaches to identification of viral-associated tumors include assays using polymerase chain reaction, in situ hybridization, and immunohistochemistry. Most mucoepidermoid carcinomas harbor MECT1-MAML2 gene rearrangement. The MYB-NFIB translocations have recently been identified in adenoid cystic carcinomas. Finally, a newly described tumor of salivary gland, mammary analogue secretory carcinoma, harbors the ETV6-NTRK3 translocation. Although these translocations are just emerging as diagnostic targets, future roles may evolve as potential therapeutic targets. PMID- 21526959 TI - Molecular diagnostics in urologic malignancies: a work in progress. AB - CONTEXT: Molecular diagnostic applications are now an integral part of the management algorithms of several solid tumors, such as breast, colon, and lung. In stark contrast, the current clinical management of urologic malignancies is lagging behind. Clinically robust molecular tests that can identify patients who are more likely to respond to a given targeted agent or even those in need of a more aggressive treatment based on well-validated molecular prognosticators are still lacking. Several promising biomarkers for detection, prognosis, and targeted therapeutics are being evaluated. OBJECTIVE: To discuss candidate biomarkers that may soon make the transition to clinical assay for patients in urologic oncology. DATA SOURCES: Selected original articles published in the PubMed service of the US National Library of Medicine. CONCLUSIONS: Recent understanding of the complex molecular alterations involved in the development and progression of urologic malignancies is yielding novel diagnostic and prognostic molecular tools and opening the doors for experimental targeted therapies in these prevalent, frequently lethal solid tumors. PMID- 21526960 TI - Molecular diagnostics of lung carcinomas. AB - CONTEXT: The development of targeted therapies in the treatment of lung carcinoma is a rapidly growing area that requires a precise histologic classification of lung carcinomas and the implementation into clinical practice of testing for predictive biomarkers of therapy response. Molecular testing has added another layer of complexity in the routine workup of rather limited diagnostic tumor tissue. OBJECTIVE: To review the most important lung carcinoma biomarkers predictive of response and to discuss proposed routine molecular testing in clinical practice. DATA SOURCES: PubMed (US National Library of Medicine) available review articles, peer-reviewed original articles, and experience of the author. CONCLUSIONS: Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) and other targeted therapies. Recently published results of large clinical trials indicate that mutational profiling, particularly identification of activating epidermal growth factor receptor (EGFR) mutations, is the best predictor for EGFR-TKI response. Despite all these observations, molecular profiling of lung carcinomas has not been standardized or validated in clinical practice. Rapid development of targeted therapies will probably require molecular testing for a panel of mutations to identify molecular subtypes of non-small cell lung carcinomas that will benefit from new therapeutic approaches in personalized patient care. PMID- 21526961 TI - Protocol for the examination of specimens from pediatric and adult patients with extragonadal germ cell tumors. PMID- 21526962 TI - Protocol for the examination of specimens from patients with primary pituitary tumors. AB - In an effort to improve the diagnosis of pituitary tumors, we propose a synoptic approach to pituitary pathology reporting that will provide clear information to endocrinologists, neurosurgeons, neuropathologists, and surgical pathologists to advance the diagnosis and classification of pituitary adenomas. PMID- 21526963 TI - Increased levels of nuclear factor kappaB and Fos-related antigen 1 in lung tissues from patients with acute respiratory distress syndrome. AB - CONTEXT: Both nuclear factor kappaB and Fos-related antigen 1 have been implicated in the pathogenesis of inflammatory lung diseases, including acute lung injury/acute respiratory distress syndrome. OBJECTIVE: To evaluate lung tissues from patients with acute respiratory distress syndrome for presence of nuclear factor kappaB and Fos-related antigen 1. DESIGN: Lung tissue sections from 5 patients with acute respiratory distress syndrome and sections of normal lung tissues of 4 patients were stained with antibodies against epithelial cell marker (surfactant protein B) and nuclear factor kappaB or Fos-related antigen 1. Samples were analyzed using confocal laser microscopy. RESULTS: We have detected significantly increased levels of activated nuclear factor kappaB and Fos-related antigen 1 in lung tissues from patients with acute respiratory distress syndrome compared with control tissues, suggesting that these transcription factors undergo activation in lungs of patients suffering from acute respiratory distress syndrome. CONCLUSIONS: Our data demonstrate that activated nuclear factor kappaB and Fos-related antigen 1 are elevated in epithelial cells in lung tissues of patients with acute respiratory distress syndrome. PMID- 21526964 TI - Reflex testing for epidermal growth factor receptor mutation and anaplastic lymphoma kinase fluorescence in situ hybridization in non-small cell lung cancer. AB - CONTEXT: Non-small cell lung cancer (NSCLC) is a poor-prognosis malignancy for which more effective treatments are needed, with accumulating clinical experiences supporting benefits of receptor tyrosine kinase inhibitors for patients with tumors harboring an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase ( ALK ) rearrangement. OBJECTIVE: To review completed and ongoing clinical trials of EGFR tyrosine kinase inhibitors for EGFR mutation-positive NSCLC and an ALK inhibitor for those with ALK rearrangement, while also exploring practical issues surrounding the implementation of molecular testing as a routine component of the diagnostic workup of NSCLC in the United States. DATA SOURCES: Published biomedical literature, abstracts presented at recent major oncology meetings, and ClinicalTrials.gov. CONCLUSIONS: Continually evolving evidence indicates the possible efficacy of molecularly targeted agents for the treatment of advanced NSCLC, especially adenocarcinoma. To identify patients who will most likely benefit from the targeted therapy, routine determination of the corresponding genetic alterations after histologic diagnosis of NSCLC (reflex molecular testing for EGFR mutations and ALK rearrangement) should be considered. PMID- 21526965 TI - Epithelioid angiomyolipoma: a morphologically distinct variant that mimics a variety of intra-abdominal neoplasms. AB - This review examines the histopathologic, immunohistochemical, ultrastructural, and molecular biologic features of epithelioid angiomyolipoma (EAML), with an emphasis on the differential diagnosis of intra-abdominal EAML. Epithelioid angiomyolipoma is an uncommon mesenchymal tumor with malignant potential, frequently associated with tuberous sclerosis complex. Histologically, EAML is characterized by sheets or nests of large polygonal epithelioid cells with abundant eosinophilic or occasionally clear cytoplasm, often with prominent nucleoli, and EAML may include multinucleated and markedly pleomorphic forms. As these tumors share a distinctive perivascular epithelioid cell phenotype, they belong to the PEComa tumor family. Nearly all EAMLs show immunoreactivity for both melanocytic and myoid markers. Ultrastructurally, EAMLs show evidence of melanogenesis by the presence of premelanosomes. Epithelioid angiomyolipoma can pose significant diagnostic challenges as it mimics morphologically a variety of neoplasms including renal cell carcinoma, renal oncocytoma, adrenal cortical neoplasm, epithelioid smooth muscle tumor, epithelioid peripheral nerve sheath tumor, epithelioid gastrointestinal stromal tumor, epithelioid melanoma, hepatoblastoma, and hepatocellular carcinoma. The variation in immunophenotype in these tumors requires a prudent use of immunohistochemistry, which may occasionally need complementation by electron microscopy to establish the correct diagnosis. PMID- 21526966 TI - Xanthogranulomatous pyelonephritis. AB - Xanthogranulomatous pyelonephritis is an uncommon chronic destructive granulomatous process of renal parenchyma in association with long-term urinary tract obstruction and infection. It affects females more often than males, with a wide range of age, from newborn to elderly. Almost all patients are symptomatic and the most common symptoms are flank or abdominal pain, lower urinary tract symptoms, fever, palpable mass, gross hematuria, and weight loss. The common laboratory findings are leukocytosis and anemia. Urine cultures most often reveal Escherichia coli and Proteus mirabilis . Computed tomography is the mainstay of diagnostic imaging for xanthogranulomatous pyelonephritis. Imaging studies may demonstrate diffuse or focal form. Histologically, xanthogranulomatous pyelonephritis presents a granulomatous inflammatory infiltrate composed of neutrophils, lymphocytes, plasma cells, xanthomatous histiocytes, and multinucleated giant cells. The differential diagnosis includes clear cell renal cell carcinoma, papillary renal cell carcinoma, sarcomatoid renal cell carcinoma, leiomyosarcoma, malakoplakia, and megalocytic interstitial nephritis. Both antibiotics and surgery can be treatment options depending on the patient's disease status. PMID- 21526967 TI - Connecting the plastid: transporters of the plastid envelope and their role in linking plastidial with cytosolic metabolism. AB - Plastids have a multitude of functions in eukaryotic cells, ranging from photosynthesis to storage, and a role in essential biosynthetic pathways. All plastids are of either primary or higher-order endosymbiotic origin. That is, either a photosynthetic cyanobacterium was integrated into a mitochondriate eukaryotic host cell (primary endosymbiosis) or a plastid-bearing eukaryotic cell merged with another eukaryotic cell (secondary or higher-order endosymbioses), thereby passing on the plastid between various eukaryotic lineages. For all of these endosymbioses to become functional, it was essential to establish metabolic connections between organelle and host cell. Here, we review the present understanding of metabolite exchange between plastids and the surrounding cytosol in the context of the endosymbiotic origin of plastids in various eukaryotic lineages. We show that only a small number of transporters that can be traced down to the primary endosymbiotic event are conserved between plastids of diverse origins. PMID- 21526968 TI - The BioCassava plus program: biofortification of cassava for sub-Saharan Africa. AB - More than 250 million Africans rely on the starchy root crop cassava (Manihot esculenta) as their staple source of calories. A typical cassava-based diet, however, provides less than 30% of the minimum daily requirement for protein and only 10%-20% of that for iron, zinc, and vitamin A. The BioCassava Plus (BC+) program has employed modern biotechnologies intended to improve the health of Africans through the development and delivery of genetically engineered cassava with increased nutrient (zinc, iron, protein, and vitamin A) levels. Additional traits addressed by BioCassava Plus include increased shelf life, reductions in toxic cyanogenic glycosides to safe levels, and resistance to viral disease. The program also provides incentives for the adoption of biofortified cassava. Proof of concept was achieved for each of the target traits. Results from field trials in Puerto Rico, the first confined field trials in Nigeria to use genetically engineered organisms, and ex ante impact analyses support the efficacy of using transgenic strategies for the biofortification of cassava. PMID- 21526969 TI - The cryptochromes: blue light photoreceptors in plants and animals. AB - Cryptochromes are flavoprotein photoreceptors first identified in Arabidopsis thaliana, where they play key roles in growth and development. Subsequently identified in prokaryotes, archaea, and many eukaryotes, cryptochromes function in the animal circadian clock and are proposed as magnetoreceptors in migratory birds. Cryptochromes are closely structurally related to photolyases, evolutionarily ancient flavoproteins that catalyze light-dependent DNA repair. Here, we review the structural, photochemical, and molecular properties of cry DASH, plant, and animal cryptochromes in relation to biological signaling mechanisms and uncover common features that may contribute to better understanding the function of cryptochromes in diverse systems including in man. PMID- 21526970 TI - Sex chromosomes in land plants. AB - Sex chromosomes in land plants can evolve as a consequence of close linkage between the two sex determination genes with complementary dominance required to establish stable dioecious populations, and they are found in at least 48 species across 20 families. The sex chromosomes in hepatics, mosses, and gymnosperms are morphologically heteromorphic. In angiosperms, heteromorphic sex chromosomes are found in at least 19 species from 4 families, while homomorphic sex chromosomes occur in 20 species from 13 families. The prevalence of the XY system found in 44 out of 48 species may reflect the predominance of the evolutionary pathway from gynodioecy towards dioecy. All dioecious species have the potential to evolve sex chromosomes, and reversions back from dioecy to various forms of monoecy, gynodioecy, or androdioecy have also occurred. Such reversals may occur especially during the early stages of sex chromosome evolution before the lethality of the YY (or WW) genotype is established. PMID- 21526971 TI - Chiasmatic infiltration secondary to late malignant transformation of retinoma. AB - PURPOSE: To report the lethal course of malignant transformation of retinoma in an adult. METHODS: Case report. A 40-year-old patient presented with retinoma in his right eye and retinoblastoma in his left eye. Enucleation was recommended but refused and the patient received whole eye radiotherapy elsewhere. Five years later he presented again, with temporal hemianopsia of the left eye secondary to chiasmatic invasion. RESULTS: Diagnosis of retinoblastoma infiltration was confirmed by stereotactic biopsy of the chiasmatic lesion. Treatment with intravenous and intrathecal chemotherapy led to partial remission, and was followed by stereotactic irradiation of the chiasmatic mass and right optic nerve. The left eye was enucleated. Death occurred one year later due to cerebrospinal fluid metastases. CONCLUSION: Extraocular extension of retinoblastoma diagnosed in adulthood has never, to our knowledge, been reported. This case stresses the importance of lifelong retinoma monitoring and the necessity for radical treatment in the event of malignant transformation. PMID- 21526973 TI - Amelioration of doxorubicin-induced cardiotoxicity by deferiprone in rats. AB - The therapeutic usefulness of doxorubicin (Dox), an anthracycline antibiotic used as an anticancer agent, is limited by its cardiotoxicity. Dox-induced cardiotoxicity is mainly attributed to accumulation of reactive oxygen species and interaction of Dox with cellular iron metabolism. The present study investigated the effects of the iron chelator deferiprone (Def) against Dox induced cardiotoxicity in rats. Dox (15 mg/kg) was injected intraperitoneally as a single dose, and Def (10 mg/kg) was administered orally for 10 days. Dox showed cardiotoxicity as evidenced by increased heart rate, elevated ST segment, prolonged QTc interval, and increased T wave amplitude. In addition, Dox enhanced aconitine cardiotoxicity by decreasing its dose, producing ventricular tachycardia. Administration of Def significantly attenuated Dox-induced electrocardiographic changes. Cardiotoxicity of Dox was confirmed biochemically by a significant elevation in serum creatine kinase-MB and lactate dehydrogenase activities as well as by myocardial malondialdehyde and reduced glutathione contents. Moreover, Dox caused a significant decrease in myocardial superoxide dismutase activity. Administration of Def significantly attenuated the biochemical changes. These results suggest that Def might be a potential cardioprotective agent against Dox-induced cardiotoxicity. PMID- 21526974 TI - Protective effect of neferine on endothelial cell nitric oxide production induced by lysophosphatidylcholine: the role of the DDAH-ADMA pathway. AB - Neferine, extracted from the seed embryo of Nelumbo nucifera Gaertn., has multiple cardiovascular pharmacological effects. The dimethylarginine dimethylaminohydrolase (DDAH) - asymmetric dimethylarginine (ADMA) system is a novel pathway for modulating nitric oxide (NO) production. The aim of this study was to investigate whether the protective effect of neferine on endothelial NO production was related to the DDAH-ADMA pathway. Human umbilical vein endothelial cells (HUVECs) were first exposed to neferine (0.1, 1.0, or 10.0 MUmol/L) for 1 h, and then incubated with lysophosphatidylcholine (LPC; 10 MUg/mL) in the presence of neferine for 24 h. The medium was collected for measuring the levels of NO, maleic dialdehyde (MDA), as well as ADMA. The endothelial cells were collected for measuring DDAH activity and the level of reactive oxygen species (ROS). LPC significantly decreased NO concentration and DDAH activity and increased the levels of ADMA, ROS, and MDA. Neferine could partially counteract the changes induced by LPC. These findings suggested that neferine could modulate the DDAH-ADMA pathway via its antioxidant properties, which was involved in its beneficial effect on endothelial NO production. PMID- 21526975 TI - Profound cardioprotection with timolol in a female rat model of aging-related altered left ventricular function. AB - Increasing evidence shows a marked beneficial effect with beta-blockers in heart dysfunction via scavenging reactive oxygen species. Previously we showed that chronic treatment with either timolol or propranolol possessed similar beneficial effects for heart function in male rats as age increased, whereas only timolol exerted similar benefits in female rats. Therefore, in this study, we aimed first to examine the cellular bases for age-related alterations in excitation contraction coupling in ventricular myocytes from female rats and, second, to investigate the hypothesis that age-related changes in [Ca(2+)](i) homeostasis and receptor-mediated system can be prevented with chronic timolol treatment. Chronic timolol treatment of 3-month-old female rats abolished age-related decrease in left ventricular developed pressure and the attenuated responses to beta-adrenoreceptor stimulation. It also normalized the altered parameters of [Ca(2+)](i) transients, decreased Ca(2+) loading of sarcoplasmic reticulum and increased basal [Ca(2+)](i), and decreased L-type Ca(2+) currents in 12-month-old female rats compared with the 3-month-old group. Adenylyl cyclase activity, beta adrenoreceptor affinity to its agonist, and beta-adrenoreceptor density of the 12 month-old group are normalized to those of the 3-month-old group. Moreover, timolol treatment prevented dysfunction of the antioxidant system, including increased lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and decreased activities of thioredoxin reductase and glucose-6 phosphate dehydrogenase, in the left ventricle of hearts from the 12-month-old group. Our data confirmed that aging-related early myocardial impairment is primarily related to a dysfunctional antioxidant system and impairment of Ca(2+) homeostasis, which can be prevented with chronic timolol treatment. PMID- 21526976 TI - The frequency of Le Fort I osteotomy in cleft patients. AB - OBJECTIVE: The aim of this research was to study the frequency of Le Fort I osteotomy (LFI) in cleft patients treated according to the protocol of the Erasmus University Medical Center, Rotterdam. DESIGN: Retrospective cohort study. Patients : 508 cleft patients born between January 1, 1983, and December 31, 1992, were evaluated. MAIN OUTCOME MEASURES: Frequency of LFI and correlations with type and extent of cleft, gender, number of previous surgical procedures, age during alveolar augmentation, and missing teeth, respectively. RESULTS: 251 patients met the inclusion criteria. Overall, 28 of the 251 patients (11.2%) required LFI: none for cleft lip (0.0%); 2 of 43 (4.7%) for cleft lip and alveolus; 24 of 100 (24.0%) for cleft lip, alveolus, and palate; 2 of 50 (4.0%) for cleft palate; and none for submucous clefts or the miscellaneous group (0.0%). The frequency of LFI increased with the severity of the cleft type. The number of previous surgical interventions is significantly higher in cases with an indication for LFI (p < .001). The frequency of LFI is significantly higher in male cleft patients (p < .05). CONCLUSIONS: The overall frequency of LFI in the study group was 11.2%; this increased with the severity of the cleft type. A significant difference was noted in the number of previous surgical interventions between patients with and without an indication for an LFI. Delayed closure of the hard palate in the protocol might have influenced the low frequency of LFI. PMID- 21526977 TI - The placental factor in spontaneous preterm labor with and without premature rupture of membranes. AB - AIM: The association between infection and inflammatory response in preterm labor (PTL) is well established. Our aim was to elucidate the roles of utero-placental perfusion and fetal component, in PTL. METHODS: Histopathologic findings in placentas from pregnancies complicated by preterm birth with or without premature rupture of membranes (ROM) (study group) were compared to placentas from pregnancies with delivery >34 weeks, with or without spontaneous ROM (control group). Placental lesions were classified as those consistent with maternal circulation abnormalities, maternal underperfusion, vascular or villous changes, and those consistent with fetal thrombo-occlusive disease, vascular or villous changes. Lesions were analyzed by maternal or fetal origin of inflammatory response. RESULTS: The study group of 68 women, had a higher rate of vascular lesions than controls (136 women, 26.5% vs. 11%, P=0.005) and of inflammatory lesions of maternal and fetal origin (P<0.001). Within the study group, inflammatory lesions were more common in those with ruptured membrane than in those without (P<0.001). CONCLUSIONS: Placentas from preterm birth demonstrate vascular lesions of maternal origin, in addition to the known inflammatory process. Preterm premature membrane rupture is associated with an increased rate of inflammatory lesions relative to spontaneous intact membranes-preterm birth, suggesting a different underlying mechanism. PMID- 21526978 TI - In utero exposure to Ureaplasma spp. is associated with increased rate of bronchopulmonary dysplasia and intraventricular hemorrhage in preterm infants. AB - AIMS: We determined the association between short-term neonatal morbidities, such as bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH), and Ureaplasma spp. in amniotic fluid, placental and amniotic membrane of preterm infants. METHODS: This study enrolled 257 patients who were born by cesarean section at <34 weeks' gestation. Patients were divided into two groups according to detection of Ureaplasma spp. by culture-based and/or polymerase chain reaction (PCR) techniques. RESULTS: Significant differences were observed between both groups for all IVH (P=0.032) and IVH grades III or IV (P=0.013), as wells as for BPD [odds ratio (OR) 5.46, 95% confidence interval (CI) 2.02-14.77], oxygen requirement at 28 days postnatal age (OR 1.93, 95% CI 1.00-3.70), and for death between 28 days and 36 postmenstrual weeks or BPD (OR 4.20, 95% CI 1.77-9.96). Ureaplasma spp. was a significant predictor (P<0.001) of BPD after correcting for birth weight (P=0.003) and positive pressure ventilation (P=0.001). CONCLUSIONS: In our study population Ureaplasma spp. was associated with BPD and IVH in preterm infants even after adjustment for multiple risk factors. PMID- 21526980 TI - Randomized control trials using a tablet formulation of hyperimmune bovine colostrum to prevent diarrhea caused by enterotoxigenic Escherichia coli in volunteers. AB - OBJECTIVE: Enterotoxigenic Escherichia coli (ETEC) is the leading cause of travelers' diarrhea. The aim of this study was to investigate the ability of a powdered extract of hyperimmune bovine colostrum to protect against diarrhea in volunteers challenged with ETEC. MATERIALS AND METHODS: Tablets were manufactured from a colostrum extract from cattle immunized with 14 ETEC strains, including serogroup O78. Two separate randomized, double-blind, placebo-controlled trials involving 90 healthy adult volunteers were performed to investigate the ability of different tablet formulations to protect against diarrhea following an oral challenge with an O78 ETEC strain. RESULTS: The first study with 30 participants evaluated the efficacy of tablets, containing 400 mg of colostrum protein, taken thrice daily with bicarbonate buffer. This regimen conferred 90.9% protection against diarrhea in the group receiving the active preparation compared with the placebo group (p = 0.0005). The second study examined the efficacy of tablets containing 400 mg colostrum protein given with buffer (83.3% protection; p = 0.0004) or without buffer (76.7% protection; p = 0.007), and tablets containing 200 mg colostrum protein given without buffer (58.3% protection; p = 0.02), compared with placebo. The difference between buffered and unbuffered treatments was not significant (p > 0.1). CONCLUSIONS: Active tablet formulations were significantly more effective than placebo in protecting volunteers against the development of diarrhea caused by ETEC. These results suggest that administration of a tablet formulation of hyperimmune bovine colostrum containing antibodies against ETEC strains may reduce the risk of travelers' diarrhea. PMID- 21526979 TI - Revealing histone variant induced changes via quantitative proteomics. AB - Histone variants are isoforms of linker and core histone proteins that differ in their amino acid sequences. These variants have distinct genomic locations and posttranslational modifications, thus increasing the complexity of the chromatin architecture. Biological studies of histone variants indicate that they play a role in many processes including transcription, DNA damage response, and the cell cycle. The small differences in amino acid sequence and the diverse posttranslational modification states that exist between histone variants make traditional analysis using immunoassay methods challenging. In recent years, a number of mass spectrometric techniques have been developed to identify and quantify histones at the whole protein or peptide levels. In this review, we discuss the biology of histone variants and methods to characterize them using mass spectrometry-based proteomics. PMID- 21526981 TI - Serum lipid/lipoprotein and arterial blood pressure among Chinese nonagenarians/centenarians. AB - OBJECTIVE: In the present study, we detected a relationship between serum lipid/lipoprotein [serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol] and arterial blood pressure among Chinese nonagenarians/centenarian. METHODS: The present study analyzed data from the survey that was conducted on all residents aged 90 years or more in a district; there were 2,311,709 inhabitants in 2005. Arterial blood pressure included systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: The subjects included in the statistical analysis were 217 men and 444 women. Subjects with hypertension (1.29 +/- 0.74 vs 1.13 +/- 0.45, t = 3.362, p = 0.001) or systolic hypertension (1.30 +/- 0.74 vs 1.12 +/- 0.45, t = 3.534, p < 0.0001) had higher levels of TG than those without. Subjects with abnormal levels of serum TG had higher SBP (145 +/- 22 vs 139 +/- 23, t = 2.223, p = 0.027). The Pearson correlation showed a significant relationship between SBP and serum TG levels (r = 0.088, p = 0.024). Unadjusted and adjusted multiple logistic regressions showed that hypertension or systolic hypertension was associated with an increased risk of abnormal of serum TG levels. CONCLUSIONS: In summary, we found that among Chinese nonagenarians and centenarians, the levels of serum lipid/lipoprotein were associated with arterial blood pressure. Hypertriglyceridemia was associated with SBP. PMID- 21526982 TI - Clinical and haemodynamic correlates of heart rate turbulence as a non-invasive index of baroreflex sensitivity in chronic heart failure. AB - HRT (heart rate turbulence), describing the heart rate changes following a premature ventricular contraction, has been regarded as an indirect index of baroreflex function. However, limited data are available on its relationship with invasive assessment by phenylephrine injection (Phe-slope). In the present study, we therefore compared these methodologies in a series of patients with HF (heart failure) in which both measures together with clinical and haemodynamic data were available. HRT parameters [TO (turbulence onset) and TS (turbulence slope)] were measured from 24-h Holter recordings obtained within 1 week of baroreflex sensitivity assessment and right heart haemodynamic evaluation (Swan-Ganz catheter). HRT was computable in 135 out of 157 (86%) patients who had both a phenylephrine test and haemodynamic evaluation. TO and TS significantly correlated with Phe-slope (r=-0.39, P<0.0001 and r=0.66, P<0.0001 respectively). Age, baseline heart rate, LVEF (left ventricular ejection fraction), PCP (pulmonary capillary pressure), CI (cardiac index) and sodium were significant and independent predictors of Phe-slope, accounting for 51% of its variability. Similarly, age, baseline heart rate and PCP, and NYHA (New York Heart Association) classes III-IV were independent predictors for TS and explained 48% of its variability, whereas only CI and LVEF were found to be significantly related to TO and explained a very limited proportion (20%) of the variability. In conclusion, these results suggest that HRT may be regarded as a surrogate measure of baroreflex sensitivity in clinical and prognostic evaluation in patients with HF. PMID- 21526983 TI - MicroRNA profiling in cancer. AB - The diagnosis of cancer has undergone major changes in the last 40 years. Once based purely on morphology, diagnosis has come to incorporate immunological, cytogenetic and molecular methods. Many cancers, especially leukaemias, are now defined by molecular markers. Gene expression profiling based on mRNA has led to further refinement of the classification and diagnosis of cancer. More recently, miRNAs (microRNAs), among other small non-coding RNA molecules, have been discovered and found to be major players in cell biology. miRNAs, having both oncogenic and tumour-suppressive functions, are dysregulated in many types of cancer. miRNAs also interfere with metastasis, apoptosis and invasiveness of cancer cells. In the present review, we discuss recent advances in miRNA profiling in human cancer. We discuss both frequent and rare tumour types and give an outlook on future developments. PMID- 21526984 TI - Hepatocyte growth factor incorporated chitosan nanoparticles augment the differentiation of stem cell into hepatocytes for the recovery of liver cirrhosis in mice. AB - BACKGROUND: Short half-life and low levels of growth factors in the niche of injured microenvironment necessitates the exogenous and sustainable delivery of growth factors along with stem cells to augment the regeneration of injured tissues. METHODS: Here, recombinant human hepatocyte growth factor (HGF) was incorporated into chitosan nanoparticles (CNP) by ionic gelation method and studied for its morphological and physiological characteristics. Cirrhotic mice received either hematopoietic stem cells (HSC) or mesenchymal stemcells (MSC) with or without HGF incorporated chitosan nanoparticles (HGF-CNP) and saline as control. Biochemical, histological, immunostaining and gene expression assays were carried out using serum and liver tissue samples. One way analysis of variance was used for statics application RESULTS: Serum levels of selected liver protein and enzymes were significantly increased in the combination of MSC and HGF-CNP (MSC+HGF-CNP) treated group. Immunopositive staining for albumin (Alb) and cytokeratin 18 (CK18), and reverse transcription-polymerase chain reaction (RT-PCR) for Alb, alpha fetoprotein (AFP), CK18, cytokeratin 19 (CK19) ascertained that MSC-HGF-CNP treatment could be an effective combination to repopulate liver parenchymal cells in the liver cirrhosis. Zymogram and western blotting for matrix metalloproteinases 2 and 9 (MMP2 and MMP9) revealed that MMP2 actively involved in the fibrolysis of cirrhotic tissue. Immunostaining for alpha smooth muscle actin (alphaSMA) and type I collagen showed decreased expression in the MSC+HGF-CNP treatment. These results indicated that HGF-CNP enhanced the differentiation of stem cells into hepatocytes and supported the reversal of fibrolysis of extracellular matrix (ECM). CONCLUSION: Bone marrow stem cells were isolated, characterized and transplanted in mice model. Biodegradable biopolymeric nanoparticles were prepared with the pleotrophic protein molecule and it worked well for the differentiation of stem cells, especially mesenchymal phenotypic cells. Transplantation of bone marrow MSC in combination with HGF-CNP could be an ideal approach for the treatment of liver cirrhosis. PMID- 21526985 TI - Case management in oncology rehabilitation (CAMON): the effect of case management on the quality of life in patients with cancer after one year of ambulant rehabilitation. a study protocol for a randomized controlled clinical trial in oncology rehabilitation. AB - BACKGROUND: Cancer diseases and their therapies have negative effects on the quality of life. The aim of this study is to assess the effectiveness of case management in a sample of oncological outpatients with the intent of rehabilitation after cancer treatment. Case management wants to support the complex information needs of the patients in addition to the segmented structure of the health care system. Emphasis is put on support for self-management in order to enhance health - conscious behaviour, learning to deal with the burden of the illness and providing the opportunity for regular contacts with care providers. We present a study protocol to investigate the efficacy of a case management in patients following oncology rehabilitation after cancer treatment. METHODS: The trial is a multicentre, two-arm randomised controlled study. Patients are randomised parallel in either 'usual care' plus case management or 'usual care' alone. Patients with all types of cancer can be included in the study, if they have completed the therapy with chemo- and/or radiotherapy/surgery with curative intention and are expected to have a survival time >1 year. To determine the health-related quality of life the general questionnaire FACT G is used. The direct correlation between self-management and perceived self-efficacy is measured with the Jerusalem & Schwarzer questionnaire. Patients satisfaction with the care received is measured using the Patient Assessment of Chronic Illness Care 5 As (PACIC-5A). Data are collected at the beginning of the trial and after 3, 6 and 12 months. The power analysis revealed a sample size of 102 patients. The recruitment of the centres began in 2009. The inclusion of patients began in May 2010. DISCUSSION: Case management has proved to be effective regarding quality of life of patients with chronic diseases. When it comes to oncology, case management is mainly used in cancer treatment, but it is not yet common in the rehabilitation of cancer patients. Case management in oncology rehabilitation is not well-established in Switzerland. A major challenge of the study will therefore probably be the recruitment of the patients due to the physicians' and patients' scarcely existing awareness of this issue. Trial registrationISRCTN41474586 PMID- 21526986 TI - Feasibility of the STarT back screening tool in chiropractic clinics: a cross sectional study of patients with low back pain. AB - The STarT back screening tool (SBT) allocates low back pain (LBP) patients into three risk groups and is intended to assist clinicians in their decisions about choice of treatment. The tool consists of domains from larger questionnaires that previously have been shown to be predictive of non-recovery from LBP. This study was performed to describe the distribution of depression, fear avoidance and catastrophising in relation to the SBT risk groups. A total of 475 primary care patients were included from 19 chiropractic clinics. They completed the SBT, the Major Depression Inventory (MDI), the Fear Avoidance Beliefs Questionnaire (FABQ), and the Coping Strategies Questionnaire. Associations between the continuous scores of the psychological questionnaires and the SBT were tested by means of linear regression, and the diagnostic performance of the SBT in relation to the other questionnaires was described in terms of sensitivity, specificity and likelihood ratios.In this cohort 59% were in the SBT low risk, 29% in the medium risk and 11% in high risk group. The SBT risk groups were positively associated with all of the psychological questionnaires. The SBT high risk group had positive likelihood ratios for having a risk profile on the psychological scales ranging from 3.8 (95% CI 2.3 - 6.3) for the MDI to 7.6 (95% CI 4.9 - 11.7) for the FABQ. The SBT questionnaire was feasible to use in chiropractic practice and risk groups were related to the presence of well-established psychological prognostic factors. If the tool proves to predict prognosis in future studies, it would be a relevant alternative in clinical practice to other more comprehensive questionnaires. PMID- 21526987 TI - Proteinortho: detection of (co-)orthologs in large-scale analysis. AB - BACKGROUND: Orthology analysis is an important part of data analysis in many areas of bioinformatics such as comparative genomics and molecular phylogenetics. The ever-increasing flood of sequence data, and hence the rapidly increasing number of genomes that can be compared simultaneously, calls for efficient software tools as brute-force approaches with quadratic memory requirements become infeasible in practise. The rapid pace at which new data become available, furthermore, makes it desirable to compute genome-wide orthology relations for a given dataset rather than relying on relations listed in databases. RESULTS: The program Proteinortho described here is a stand-alone tool that is geared towards large datasets and makes use of distributed computing techniques when run on multi-core hardware. It implements an extended version of the reciprocal best alignment heuristic. We apply Proteinortho to compute orthologous proteins in the complete set of all 717 eubacterial genomes available at NCBI at the beginning of 2009. We identified thirty proteins present in 99% of all bacterial proteomes. CONCLUSIONS: Proteinortho significantly reduces the required amount of memory for orthology analysis compared to existing tools, allowing such computations to be performed on off-the-shelf hardware. PMID- 21526988 TI - Regional and developmental brain expression patterns of SNAP25 splice variants. AB - BACKGROUND: SNAP25 is an essential SNARE protein for regulated exocytosis in neuronal cells. Differential splicing of the SNAP25 gene results in the expression of two transcripts, SNAP25a and SNAP25b. These splice variants differ by only 9 amino acids, and studies of their expression to date have been limited to analysis of the corresponding mRNAs. Although these studies have been highly informative, it is possible that factors such as differential turnover of the SNAP25 proteins could complicate interpretations based entirely on mRNA expression profiles. RESULTS: We report the generation and characterization of antibodies that distinguish between SNAP25a and SNAP25b isoforms, and their use to investigate the expression profile of these proteins in rat and human brain. In rat brain, SNAP25b protein expression increased dramatically during post-natal development, whereas the increase in SNAP25a expression was more modest and variable. The extent of this up-regulation in SNAP25b expression was similar across cortex, cerebellum and hippocampus. The SNAP25 isoforms also displayed distinct regional expression patterns, with SNAP25a very weakly expressed in both rat and human cerebellum. Quantitative analysis revealed that SNAP25b was the dominant isoform in all adult human brain regions examined. CONCLUSIONS: SNAP25a and SNAP25b display distinct developmental and regional expression profiles in rat and human brain. These differences might reflect distinct functions of these highly conserved isoforms in membrane fusion pathways in the brain. The antibodies generated and characterized in this study represent important tools for future analyses of these essential SNARE protein isoforms. PMID- 21526989 TI - Unexpected complexity of the reef-building coral Acropora millepora transcription factor network. AB - BACKGROUND: Coral reefs are disturbed on a global scale by environmental changes including rising sea surface temperatures and ocean acidification. Little is known about how corals respond or adapt to these environmental changes especially at the molecular level. This is mostly because of the paucity of genome-wide studies on corals and the application of systems approaches that incorporate the latter. Like in any other organism, the response of corals to stress is tightly controlled by the coordinated interplay of many transcription factors. RESULTS: Here, we develop and apply a new system-wide approach in order to infer combinatorial transcription factor networks of the reef-building coral Acropora millepora. By integrating sequencing-derived transcriptome measurements, a network of physically interacting transcription factors, and phylogenetic network footprinting we were able to infer such a network. Analysis of the network across a phylogenetically broad sample of five species, including human, reveals that despite the apparent simplicity of corals, their transcription factors repertoire and interaction networks seem to be largely conserved. In addition, we were able to identify interactions among transcription factors that appear to be species specific lending strength to the novel concept of "Taxonomically Restricted Interactions". CONCLUSIONS: This study provides the first look at transcription factor networks in corals. We identified a transcription factor repertoire encoded by the coral genome and found consistencies of the domain architectures of transcription factors and conserved regulatory subnetworks across eumetazoan species, providing insight into how regulatory networks have evolved. PMID- 21526990 TI - Pressure ulcer incidence in Dutch and German nursing homes: design of a prospective multicenter cohort study. AB - BACKGROUND: Pressure ulcers are a common and serious health care problem in all health care settings. Results from annual national pressure ulcer prevalence surveys in the Netherlands and Germany reveal large differences in prevalence rates between both countries over the past ten years, especially in nursing homes. When examining differences in prevalence and incidence rates, it is important to take into account all factors associated with the development of pressure ulcers. Numerous studies have identified patient related factors, as well as nursing related interventions as risk factors for the development of pressure ulcers. Next to these more process oriented factors, also structural factors such as staffing levels and staff quality play a role in the development of pressure ulcers. This study has been designed to investigate the incidence of pressure ulcers in nursing homes in the Netherlands and Germany and to identify patient related factors, nursing related factors and structural factors associated with pressure ulcer development. The present article describes the protocol for this study. METHODS/DESIGN: A prospective multicenter study is designed in which a cohort of newly admitted nursing home residents in 10 Dutch and 11 German nursing homes will be followed for a period of 12 weeks. Data will be collected by research assistants using questionnaires on four different levels: resident, staff, ward, and nursing home. DISCUSSION: The results of the study will provide information on the incidence of pressure ulcers in Dutch and German nursing homes. Furthermore, information will be gathered on the influence of patient related factors, nursing related factors and structural factors on the incidence of pressure ulcers. The present article describes the study design and addresses the study's strengths and weaknesses. PMID- 21526991 TI - Serum leptin is associated with cardiometabolic risk and predicts metabolic syndrome in Taiwanese adults. AB - BACKGROUND: Leptin is associated with cardiovascular disease (CVD); however, few studies have assessed its relationship with metabolic syndrome, especially in an Asian population. Therefore, the aim of the present study was to assess leptin levels and evaluate its association with CVD and metabolic syndrome. METHODS: In 2009, 957 subjects, who underwent a routine physical examination and choose leptin examination, were selected to participate. Participants (269 females and 688 males) were stratified according to leptin level quartiles. Metabolic syndrome was defined by NCEP ATP III using waist circumference cutoffs modified for Asian populations, and CVD risk was determined using the Framingham Heart Study profile. RESULTS: Leptin levels were correlated with CVD risk in men and women. With the exception of fasting plasma glucose, increased leptin levels were observed as factors associated with metabolic syndrome increased in both males and females. After adjusting for age, an association between leptin levels and metabolic syndrome was observed. After adjusting for age alone or with tobacco use, subjects in the highest leptin quartile had a higher risk of having metabolic syndrome than those in the lowest quartile (OR=6.14 and 2.94 for men and women, respectively). After further adjustment for BMI, metabolic syndrome risk remained significantly increased with increasing leptin quartiles in men. Finally, increased leptin levels were a predictor of metabolic syndrome in men and women. CONCLUSIONS: Serum leptin levels are correlated with CVD risk and metabolic syndrome. Analysis of leptin as part of routine physical examinations may prove beneficial for early diagnosis of metabolic syndrome. PMID- 21526993 TI - The personal and national costs of mental health conditions: impacts on income, taxes, government support payments due to lost labour force participation. AB - BACKGROUND: Mental health conditions have the ability to interrupt an individual's ability to participate in the labour force, and this can have considerable follow on impacts to both the individual and the state. METHOD: Cross-sectional analysis of the base population of Health&WealthMOD, a microsimulation model built on data from the Australian Bureau of Statistics' Survey of Disability, Ageing and Carers and STINMOD, an income and savings microsimulation model was used to quantify the personal cost of lost income and the cost to the state from lost income taxation, increased benefits payments and lost GDP as a result of early retirement due to mental health conditions in Australians aged 45-64 in 2009. RESULTS: Individuals aged 45 to 64 years who have retired early due to depression personally have 73% lower income then their full time employed counterparts and those retired early due to other mental health conditions have 78% lower incomes. The national aggregate cost to government due to early retirement from these conditions equated to $278 million (L152.9 million) in lost income taxation revenue, $407 million (L223.9 million) in additional transfer payments and around $1.7 billion in GDP in 2009 alone. CONCLUSIONS: The costs of mental health conditions to the individuals and the state are considerable. While individuals has to bear the economic costs of lost income in addition to the burden of the conditions itself, the impact on the state is loss of productivity from reduced workforce participation, lost income taxation revenue, and increased government support payments--in addition to direct health care costs. PMID- 21526992 TI - New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women. AB - BACKGROUND: Vaspin and omentin are recently described molecules that belong to the adipokine family and seem to be related to metabolic risk factors. The objectives of this study were twofold: to evaluate vaspin and omentin circulating levels and mRNA expression in subcutaneous and visceral adipose tissues in non diabetic morbidly obese women; and to assess the relationship of vaspin and omentin with anthropometric and metabolic parameters, and other adipo/cytokines. DESIGN: We analysed vaspin and omentin circulating levels in 71 women of European descent (40 morbidly obese [BMI>=40 kg/m2] and 31 lean [BMI<=25]). We assessed vaspin and omentin gene expression in paired samples of visceral and subcutaneous abdominal adipose tissue from 46 women: 40 morbidly obese and 6 lean. We determined serum vaspin and plasma omentin levels with an Enzyme-Linked Immunosorbent Assay and adipose tissue mRNA expression by real time RT-PCR. RESULTS: Serum vaspin levels in the morbidly obese were not significantly different from those in controls. They correlated inversely with levels of lipocalin 2 and interleukin 6. Vaspin mRNA expression was significantly higher in the morbidly obese, in both subcutaneous and visceral adipose tissue.Plasma omentin levels were significantly lower in the morbidly obese and they correlated inversely with glucidic metabolism parameters. Omentin circulating levels, then, correlated inversely with the metabolic syndrome (MS). Omentin expression in visceral adipose tissue was significantly lower in morbidly obese women than in controls. CONCLUSIONS: The present study indicates that vaspin may have a compensatory role in the underlying inflammation of obesity. Decreased omentin circulating levels have a close association with MS in morbidly obese women. PMID- 21526994 TI - Low fish oil intake improves insulin sensitivity, lipid profile and muscle metabolism on insulin resistant MSG-obese rats. AB - BACKGROUND: Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. METHODS: Monosodium glutamate (MSG) (4 mg/g body weight) was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C), coconut fat-treated normal weight group (CO), fish oil-treated normal weight group (FO), obese control group (Ob), coconut fat-treated obese group (ObCO) and fish oil-treated obese group (ObFO). Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day) for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. RESULTS: Obese animals (Ob) presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt) showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO) similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30%) and triacylglycerol (TG; 33%) compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. CONCLUSIONS: Low dose of fish oil supplementation (1 g/kg/day) was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms. PMID- 21526995 TI - PEX11beta induces peroxisomal gene expression and alters peroxisome number during early Xenopus laevis development. AB - BACKGROUND: Peroxisomes are organelles whose roles in fatty acid metabolism and reactive oxygen species elimination have contributed much attention in understanding their origin and biogenesis. Many studies have shown that de novo peroxisome biogenesis is an important regulatory process, while yeast studies suggest that total peroxisome numbers are in part regulated by proteins such as Pex11, which can facilitate the division of existing peroxisomes. Although de novo biogenesis and divisions are likely important mechanisms, the regulation of peroxisome numbers during embryonic development is poorly understood. Peroxisome number and function are particularly crucial in oviparous animals such as frogs where large embryonic yolk and fatty acid stores must be quickly metabolized, and resulting reactive oxygen species eliminated. Here we elucidate the role of Pex11beta in regulating peroxisomal gene expression and number in Xenopus laevis embryogenesis. RESULTS: Microinjecting haemagglutinin (HA) tagged Pex11beta in early embryos resulted in increased RNA levels for peroxisome related genes PMP70 and catalase at developmental stages 10 and 20, versus uninjected embryos. Catalase and PMP70 proteins were found in punctate structures at stage 20 in control embryos, whereas the injection of ectopic HA-Pex11beta induced their earlier localization in punctate structures at stage 10. Furthermore, the peroxisomal marker GFP-SKL, which was found localized as peroxisome-like structures at stage 20, was similarly found at stage 10 when co-microinjected with HA-Pex11beta. CONCLUSIONS: Overexpressed Pex11beta altered peroxisomal gene levels and induced the early formation of peroxisomes-like structures during development, both of which demonstrate that Pex11beta may be a key regulator of peroxisome number in early Xenopus embryos. PMID- 21526996 TI - Low back pain around retirement age and physical occupational exposure during working life. AB - BACKGROUND: Physical occupational exposure is a risk factor for low back pain in workers but the long term effects of exposure remain unclear. As several countries consider increasing the retirement age, further information on this topic is relevant. This study aimed to describe the prevalence of low back pain among middle aged and aging individuals in the general French population according to physical occupational exposure and retirement status. METHODS: The study population originated from the French national survey 'Enquete decennale sante 2002'. Low back pain for more than 30 days within the previous twelve months (LBP) was assessed using a French version of the Nordic questionnaire. Occupational exposure was self assessed. Subjects were classified as "exposed" if they were currently or had previously been exposed to handling of heavy loads and/or to tiring postures. The weighted prevalence of LBP was computed separately for men and women, for active (aged 45-59) and retiree (aged 55-74), according to 5-year age group and past/present occupational exposure. RESULTS: For active men, the prevalence of LBP was significantly higher in those currently or previously exposed (n = 1051) compared with those never exposed (n = 1183), respectively over 20% versus less than 11%. Among retired men, the prevalence of LBP tended towards equivalence with increasing age among those previously exposed (n = 748) and those unexposed (n = 599).Patterns were quite similar for women with a higher prevalence in exposed active women (n = 741) compared to unexposed (n = 1260): around 25% versus 15%. Similarly, differences between previously exposed (n = 430) and unexposed (n = 489) retired women tended to reduce with age. CONCLUSION: The prevalence of LBP in active workers was associated with occupational exposure. The link with past exposure among retirees decreased with age. These results should be considered for policies dealing with prevention at the workplace and retirement. PMID- 21526998 TI - The reliability of an Arabic version of the self-administered standardized chronic respiratory disease questionnaire (CRQ-SAS). AB - BACKGROUND: To produce a conceptually equivalent Arabic version to the original Self-Administered Chronic Respiratory Disease Questionnaire with standardized dyspnea domain (CRQ-SAS) and to assess its reliability. METHODS: The study was carried out in two stages: stage I which was the translation of the CRQ-SAS questionnaire from the English to the Arabic language, and stage II which represented the test-retest reliability for patients receiving usual care for COPD who were not yet admitted to the pulmonary rehabilitation program. RESULTS: Forty five patients with stable COPD were enrolled in this study. Strong test retest reliability was found for the four domains of the CRQ-SAS, with the intra class correlation coefficient of 0.97 for each of the domains. The association between most parameters and the four domains of CRQ-SAS were not found to be statistically significant, as measured by Pearson correlation. The number of exacerbations was negatively correlated with the dyspnea domain (correlation = 0.36, p-value = 0.02). The disease duration was negatively correlated with the domain fatigue (correlation = -0.35, p-value = 0.02). The correlation between FEV1/FVC ratio and emotion domain was -0.30 (p-value = 0.05). The mastery domain was negatively correlated with FEV1/FVC ratio with a correlation of -0.27 with borderline statistical significance (p-value = 0.07). CONCLUSION: The Arabic translation of the CRQ-SAS was found to be reliable to assess the quality of life among patients with COPD. PMID- 21526997 TI - Innate immunity and monocyte-macrophage activation in atherosclerosis. AB - Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review. PMID- 21526999 TI - Co-expression of AaPMT and AaTRI effectively enhances the yields of tropane alkaloids in Anisodus acutangulus hairy roots. AB - BACKGROUND: Tropane alkaloids (TA) including anisodamine, anisodine, hyoscyamine and scopolamine are a group of important anticholinergic drugs with rapidly increasing market demand, so it is significant to improve TA production by biotechnological approaches. Putrescine N-methyltransferase (PMT) was considered as the first rate-limiting upstream enzyme while tropinone reductase I (TRI) was an important branch-controlling enzyme involved in TA biosynthesis. However, there is no report on simultaneous introduction of PMT and TRI genes into any TA producing plant including Anisodus acutangulus (A. acutangulus), which is a Solanaceous perennial plant that is endemic to China and is an attractive resource plant for production of TA. RESULTS: In this study, 21 AaPMT and AaTRI double gene transformed lines (PT lines), 9 AaPMT single gene transformed lines (P lines) and 5 AaTRI single gene transformed lines (T lines) were generated. RT PCR and real-time fluorescence quantitative analysis results revealed that total AaPMT (AaPMT T) and total AaTRI (AaTRI T) gene transcripts in transgenic PT, P and T lines showed higher expression levels than native AaPMT (AaPMT E) and AaTRI (AaTRI E) gene transcripts. As compared to the control and single gene transformed lines (P or T lines), PT transgenic hairy root lines produced significantly higher levels of TA. The highest yield of TA was detected as 8.104 mg/g dw in line PT18, which was 8.66, 4.04, and 3.11-times higher than those of the control (0.935 mg/g dw), P3 (highest in P lines, 2.004 mg/g dw) and T12 (highest in T lines, 2.604 mg/g dw), respectively. All the tested samples were found to possess strong radical scavenging capacity, which were similar to control. CONCLUSION: In the present study, the co-expression of AaPMT and AaTRI genes in A. acutangulus hairy roots significantly improved the yields of TA and showed higher antioxidant activity than control because of higher total TA content, which is the first report on simultaneous introduction of PMT and TRI genes into TA-producing plant by biotechnological approaches. PMID- 21527000 TI - Possible gabapentin and ketamine interaction causing prolonged central nervous system depression during post-operative recovery following cervical laminoplasty: a case report. AB - INTRODUCTION: The drugs gabapentin and ketamine are used frequently in the peri operative setting. There is poor documentation whether or not gabapentin and ketamine interact to cause prolonged depression of the central nervous system. CASE PRESENTATION: The following is a case report in which a patient, a 58-year old African-American man, with a history of post-traumatic stress disorder and chronic pain underwent a cervical laminoplasty procedure. The patient presented post-operatively in a dissociative state with paralysis, anarthria and preservation of consciousness. All organic causes were excluded, with the exception of prolonged central nervous system depression from a gabapentin/ketamine drug interaction. A new onset conversion disorder could also not be excluded. CONCLUSION: Although this case by itself is not enough evidence to substantiate a true adverse reaction between gabapentin and ketamine, it is enough to warrant further investigation. PMID- 21527001 TI - Time course of collagen peak in bile duct-ligated rats. AB - BACKGROUND: One of the most useful experimental fibrogenesis models is the "bile duct-ligated rats". Our aim was to investigate the quantitative hepatic collagen content by two different methods during the different stages of hepatic fibrosis in bile duct-ligated rats on a weekly basis. We questioned whether the 1-wk or 4 wk bile duct-ligated model is suitable in animal fibrogenesis trials. METHODS: Of the 53 male Wistar rats, 8 (Group 0) were used as a healthy control group. Bile duct ligation (BDL) had been performed in the rest. Bile duct-ligated rates were sacrificed 7 days later in group 1 (10 rats), 14 days later in group 2 (9 rats), 21 days later in group 3(9 rats) and 28 days later in group 4 (9 rats). Eight rats underwent sham-operation (Sham). Hepatic collagen measurements as well as serum levels of liver enzymes and function tests were all analysed. RESULTS: The peak level of collagen was observed biochemically and histomorphometricly at the end of third week (P < 0.001 and P < 0.05). Suprisingly, collagen levels had decreased with the course of time such as at the end of fourth week (P < 0.01 and P < 0.05). CONCLUSION: We have shown that fibrosis in bile duct-ligated rats is transient, i.e. reverses spontaneously after 3 weeks. This contrasts any situation in patients where hepatic fibrosis is progressive and irreversible as countless studies performed by many investigators in the same animal model. PMID- 21527002 TI - Growth of breast cancer recurrences assessed by consecutive MRI. AB - BACKGROUND: Women with a personal history of breast cancer have a high risk of developing an ipsi- or contralateral recurrence. We aimed to compare the growth rate of primary breast cancer and recurrences in women who had undergone prior breast magnetic resonance imaging (MRI). METHODS: Three hundred and sixty-two women were diagnosed with breast cancer and had undergone breast MRI at the time of diagnosis in our institution (2005 - 2009). Among them, 37 had at least one prior breast MRI with the lesion being visible but not diagnosed as cancer. A linear regression of tumour volume measured on MRI scans and time data was performed using a generalized logistic model to calculate growth rates. The primary objective was to compare the tumour growth rate of patients with either primary breast cancer (no history of breast cancer) or ipsi- or contralateral recurrences of breast cancer. RESULTS: Twenty women had no history of breast cancer and 17 patients were diagnosed as recurrences (7 and 10 were ipsi- and contralateral, respectively). The tumour growth rate was higher in contralateral recurrences than in ipsilateral recurrences (growth rate [10(-3) days(-1)] 3.56 vs 1.38, p < .001) or primary cancer (3.56 vs 2.09, p = 0.01). Differences in tumour growth were not significant for other patient-, tumour- or treatment related characteristics. CONCLUSIONS: These findings suggest that contralateral breast cancer presents accelerated growth compared to ipsilateral recurrences or primary breast events. PMID- 21527003 TI - Rectal gel application of Withania somnifera root extract expounds anti inflammatory and muco-restorative activity in TNBS-induced inflammatory bowel disease. AB - BACKGROUND: Inflammatory Bowel Disease (IBD) is marked with chronic inflammation of intestinal epithelium driven by oxidative stress. Traditional treatments with plant extracts gained renewed interest due to their ability to ameliorate the multi factorial conditions like inflammation. We investigated the beneficial effects of Withania somnifera in Trinitro Benzyl Sulfonic Acid (TNBS) induced experimental IBD through a rectally applicable formulation. METHODS: The study included (i) preparation of gel formulation from aqueous Withania somnifera root extract (WSRE), (ii) biochemical assays to determine its performance potential, (iii) testing of formulation efficacy in TNBS-induced IBD rat model, and (iv) histo-patholgical studies to assess its healing and muco-regenerative effect in IBD-induced rats. For this purpose, concentration dependant antioxidant activity of the extracts were evaluated using biochemical assays like (a) inhibition of lipid peroxidation, (b) NO scavenging, (c) H2O2 scavenging, and (d) ferric reducing power assay. RESULTS: The extract, at 500 MUg/ml, the highest concentration tested, showed 95.6% inhibition of lipid peroxidation, 14.8% NO scavenging, 81.79% H2O2 scavenging and a reducing capacity of 0.80. The results were comparable with standard antioxidants, ascorbic acid and curcumin. WSRE treatment positively scored on histopathological parameters like necrosis, edema, neutrophil infiltration. The post treatment intestinal features showed restoration at par with the healthy intestine. In view of these results, gel formulation containing an aqueous extract of W. somnifera, prepared for rectal application was tested for its anti-inflammatory activity in TNBS-induced rat models for IBD. Commercially available anti-inflammatory drug Mesalamine was used as the standard in this assay. CONCLUSIONS: Dose of the rectal gel applied at 1000 mg of WSRE per kg rat weight showed significant muco-restorative efficacy in the IBD-induced rats, validated by histo-pathological studies. PMID- 21527004 TI - Laser confers less embryo exposure than acid tyrode for embryo biopsy in preimplantation genetic diagnosis cycles: a randomized study. AB - We compared two methods of zona pellucida drilling. 213 embryos were biopsied with acid Tyrode. Each biopsy took 3 minutes and the entire procedure ~29 minutes. 5% of blastomeres lysed, 49% of embryos became blastocyst and 36% of patients became pregnant. 229 embryos were biopsied with laser. Each biopsy took 30 seconds and the entire procedure ~7 minutes. 2.5% of blastomeres lysed, 50.6% of embryos became blastocyst and 47% of patients became pregnant. We can conclude that laser can be used for embryo biopsy. Reduction of embryo exposure and of removed blastomeres is associated with increased blastocysts available for transfer and a better clinical outcome. PMID- 21527005 TI - Using graph theory to analyze biological networks. AB - Understanding complex systems often requires a bottom-up analysis towards a systems biology approach. The need to investigate a system, not only as individual components but as a whole, emerges. This can be done by examining the elementary constituents individually and then how these are connected. The myriad components of a system and their interactions are best characterized as networks and they are mainly represented as graphs where thousands of nodes are connected with thousands of vertices. In this article we demonstrate approaches, models and methods from the graph theory universe and we discuss ways in which they can be used to reveal hidden properties and features of a network. This network profiling combined with knowledge extraction will help us to better understand the biological significance of the system. PMID- 21527006 TI - Validation of the post sleep questionnaire for assessing subjects with restless legs syndrome: results from two double-blind, multicenter, placebo-controlled clinical trials. AB - BACKGROUND: Because of the subjective nature of Restless Legs Syndrome (RLS) symptoms and the impact of these symptoms on sleep, patient-reported outcomes (PROs) play a prominent role as study endpoints in clinical trials investigating RLS treatments. The objective of this study was to validate a new measure, the Post Sleep Questionnaire (PSQ), to assess sleep dysfunction in subjects with moderate-to-severe RLS symptoms. METHODS: Pooled data were analyzed from two 12 week, randomized, placebo-controlled trials of gabapentin enacarbil (N = 540). At baseline and Week 12, subjects completed the PSQ and other validated health surveys: IRLS Rating Scale, Clinical Global Impression of Improvement (CGI-I), Profile of Mood States (POMS), Medical Outcomes Study Scale-Sleep (MOS-Sleep), and RLS-Quality of Life (RLSQoL). Pooled data were used post hoc to examine the convergent, divergent, known-group validity and the responsiveness of the PSQ. RESULTS: Convergent validity was demonstrated by significant correlations between baseline PSQ items and total scores of IRLS, POMS, RLSQoL, and the MOS-Sleep Scale (p <= 0.007 each). Divergent validity was demonstrated through the lack of significant correlations between PSQ items and demographic characteristics. Correlations (p < 0.0001) between RLS severity groups and PSQ items demonstrated known-group validity. Mean changes in investigator- and subject-rated CGI-I scores for each PSQ item (p < 0.0001) demonstrated the PSQ's responsiveness to patient change as reported by their care provider. CONCLUSIONS: Although these analyses were potentially limited by the use of clinical trial data and not prospective data from a study conducted solely for validation purposes, the PSQ demonstrated robust psychometric properties and is a valid instrument for assessing sleep and sleep improvements in subjects with moderate-to-severe RLS symptoms. TRIAL REGISTRATION: This study analyzed data from two registered trials, NCT00298623 and NCT00365352. PMID- 21527007 TI - A survey of orthopaedic journal editors determining the criteria of manuscript selection for publication. AB - BACKGROUND: To investigate the characteristics of editors and criteria used by orthopaedic journal editors in assessing submitted manuscripts. METHODS: Between 2008 to 2009 all 70 editors of Medline listed orthopaedic journals were approached prospectively with a questionnaire to determine the criteria used in assessing manuscripts for publication. RESULTS: There was a 42% response rate. There was 1 female editor and the rest were male with 57% greater than 60 years of age. 67% of the editors worked in university teaching hospitals and 90% of publications were in English. The review process differed between journals with 59% using a review proforma, 52% reviewing an anonymised manuscript, 76% using a routine statistical review and 59% of journals used 2 reviewers routinely. In 89% of the editors surveyed, the editor was able to overrule the final decision of the reviewers. Important design factors considered for manuscript acceptance were that the study conclusions were justified (80%), that the statistical analysis was appropriate (76%), that the findings could change practice (72%). The level of evidence (70%) and type of study (62%) were deemed less important. When asked what factors were important in the manuscript influencing acceptance, 73% cited an understandable manuscript, 53% cited a well written manuscript and 50% a thorough literature review as very important factors. CONCLUSIONS: The editorial and review process in orthopaedic journals uses different approaches. There may be a risk of language bias among editors of orthopaedic journals with under representation of non-English publications in the orthopaedic literature. PMID- 21527008 TI - Statistical methods for detecting periodic fragments in DNA sequence data. AB - BACKGROUND: Period 10 dinucleotides are structurally and functionally validated factors that influence the ability of DNA to form nucleosomes, histone core octamers. Robust identification of periodic signals in DNA sequences is therefore required to understand nucleosome organisation in genomes. While various techniques for identifying periodic components in genomic sequences have been proposed or adopted, the requirements for such techniques have not been considered in detail and confirmatory testing for a priori specified periods has not been developed. RESULTS: We compared the estimation accuracy and suitability for confirmatory testing of autocorrelation, discrete Fourier transform (DFT), integer period discrete Fourier transform (IPDFT) and a previously proposed Hybrid measure. A number of different statistical significance procedures were evaluated but a blockwise bootstrap proved superior. When applied to synthetic data whose period-10 signal had been eroded, or for which the signal was approximately period-10, the Hybrid technique exhibited superior properties during exploratory period estimation. In contrast, confirmatory testing using the blockwise bootstrap procedure identified IPDFT as having the greatest statistical power. These properties were validated on yeast sequences defined from a ChIP chip study where the Hybrid metric confirmed the expected dominance of period-10 in nucleosome associated DNA but IPDFT identified more significant occurrences of period-10. Application to the whole genomes of yeast and mouse identified ~21% and ~19% respectively of these genomes as spanned by period-10 nucleosome positioning sequences (NPS). CONCLUSIONS: For estimating the dominant period, we find the Hybrid period estimation method empirically to be the most effective for both eroded and approximate periodicity. The blockwise bootstrap was found to be effective as a significance measure, performing particularly well in the problem of period detection in the presence of eroded periodicity. The autocorrelation method was identified as poorly suited for use with the blockwise bootstrap. Application of our methods to the genomes of two model organisms revealed a striking proportion of the yeast and mouse genomes are spanned by NPS. Despite their markedly different sizes, roughly equivalent proportions (19-21%) of the genomes lie within period-10 spans of the NPS dinucleotides {AA, TT, TA}. The biological significance of these regions remains to be demonstrated. To facilitate this, the genomic coordinates are available as Additional files 1, 2, and 3 in a format suitable for visualisation as tracks on popular genome browsers. PMID- 21527009 TI - Identification and characterisation of a novel adhesin Ifp in Yersinia pseudotuberculosis. AB - BACKGROUND: In order to identify new virulence determinants in Y. pseudotuberculosis a comparison between its genome and that of Yersinia pestis was undertaken. This reveals dozens of pseudogenes in Y. pestis, which are still putatively functional in Y. pseudotuberculosis and may be important in the enteric lifestyle. One such gene, YPTB1572 in the Y. pseudotuberculosis IP32953 genome sequence, encodes a protein with similarity to invasin, a classic adhesion/invasion protein, and to intimin, the attaching and effacing protein from enteropathogenic (EPEC) and enterohaemorraghic (EHEC) Escherichia coli. RESULTS: We termed YPTB1572 Ifp (Intimin family protein) and show that it is able to bind directly to human HEp-2 epithelial cells. Cysteine and tryptophan residues in the C-terminal region of intimin that are essential for function in EPEC and EHEC are conserved in Ifp. Protein binding occurred at distinct foci on the HEp-2 cell surface and can be disrupted by mutation of a single cysteine residue at the C-terminus of the protein. Temporal expression analysis using lux reporter constructs revealed that ifp is expressed at late log phase at 37 degrees C in contrast to invasin, suggesting that Ifp is a late stage adhesin. An ifp defined mutant showed a reduction in adhesion to HEp-2 cells and was attenuated in the Galleria mellonella infection model. CONCLUSION: A new Y. pseudotuberculosis adhesin has been identified and characterised. This Ifp is a new member in the family of invasin/intimin outer membrane adhesins. PMID- 21527010 TI - Effects of in ovo electroporation on endogenous gene expression: genome-wide analysis. AB - BACKGROUND: In ovo electroporation is a widely used technique to study gene function in developmental biology. Despite the widespread acceptance of this technique, no genome-wide analysis of the effects of in ovo electroporation, principally the current applied across the tissue and exogenous vector DNA introduced, on endogenous gene expression has been undertaken. Here, the effects of electric current and expression of a GFP-containing construct, via electroporation into the midbrain of Hamburger-Hamilton stage 10 chicken embryos, are analysed by microarray. RESULTS: Both current alone and in combination with exogenous DNA expression have a small but reproducible effect on endogenous gene expression, changing the expression of the genes represented on the array by less than 0.1% (current) and less than 0.5% (current + DNA), respectively. The subset of genes regulated by electric current and exogenous DNA span a disparate set of cellular functions. However, no genes involved in the regional identity were affected. In sharp contrast to this, electroporation of a known transcription factor, Dmrt5, caused a much greater change in gene expression. CONCLUSIONS: These findings represent the first systematic genome-wide analysis of the effects of in ovo electroporation on gene expression during embryonic development. The analysis reveals that this process has minimal impact on the genetic basis of cell fate specification. Thus, the study demonstrates the validity of the in ovo electroporation technique to study gene function and expression during development. Furthermore, the data presented here can be used as a resource to refine the set of transcriptional responders in future in ovo electroporation studies of specific gene function. PMID- 21527011 TI - TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury. AB - BACKGROUND: Neuronal hyperexcitability is a crucial phenomenon underlying spontaneous and evoked pain. In invertebrate nociceptors, the S-type leak K(+) channel (analogous to TREK-1 in mammals) plays a critical role of in determining neuronal excitability following nerve injury. Few data are available on the role of leak K(2P) channels after peripheral axotomy in mammals. RESULTS: Here we describe that rat sciatic nerve axotomy induces hyperexcitability of L4-L5 DRG sensory neurons and decreases TRESK (K2P18.1) expression, a channel with a major contribution to total leak current in DRGs. While the expression of other channels from the same family did not significantly change, injury markers ATF3 and Cacna2d1 were highly upregulated. Similarly, acute sensory neuron dissociation (in vitro axotomy) produced marked hyperexcitability and similar total background currents compared with neurons injured in vivo. In addition, the sanshool derivative IBA, which blocked TRESK currents in transfected HEK293 cells and DRGs, increased intracellular calcium in 49% of DRG neurons in culture. Most IBA-responding neurons (71%) also responded to the TRPV1 agonist capsaicin, indicating that they were nociceptors. Additional evidence of a biological role of TRESK channels was provided by behavioral evidence of pain (flinching and licking), in vivo electrophysiological evidence of C-nociceptor activation following IBA injection in the rat hindpaw, and increased sensitivity to painful pressure after TRESK knockdown in vivo. CONCLUSIONS: In summary, our results clearly support an important role of TRESK channels in determining neuronal excitability in specific DRG neurons subpopulations, and show that axonal injury down-regulates TRESK channels, therefore contributing to neuronal hyperexcitability. PMID- 21527013 TI - The analysis of para-cresol production and tolerance in Clostridium difficile 027 and 012 strains. AB - BACKGROUND: Clostridium difficile is the major cause of antibiotic associated diarrhoea and in recent years its increased prevalence has been linked to the emergence of hypervirulent clones such as the PCR-ribotype 027. Characteristically, C. difficile infection (CDI) occurs after treatment with broad-spectrum antibiotics, which disrupt the normal gut microflora and allow C. difficile to flourish. One of the relatively unique features of C. difficile is its ability to ferment tyrosine to para-cresol via the intermediate para hydroxyphenylacetate (p-HPA). P-cresol is a phenolic compound with bacteriostatic properties which C. difficile can tolerate and may provide the organism with a competitive advantage over other gut microflora, enabling it to proliferate and cause CDI. It has been proposed that the hpdBCA operon, rarely found in other gut microflora, encodes the enzymes responsible for the conversion of p-HPA to p cresol. RESULTS: We show that the PCR-ribotype 027 strain R20291 quantitatively produced more p-cresol in-vitro and was significantly more tolerant to p-cresol than the sequenced strain 630 (PCR-ribotype 012). Tyrosine conversion to p-HPA was only observed under certain conditions. We constructed gene inactivation mutants in the hpdBCA operon in strains R20291 and 630Deltaerm which curtails their ability to produce p-cresol, confirming the role of these genes in p-cresol production. The mutants were equally able to tolerate p-cresol compared to the respective parent strains, suggesting that tolerance to p-cresol is not linked to its production. CONCLUSIONS: C. difficile converts tyrosine to p-cresol, utilising the hpdBCA operon in C. difficile strains 630 and R20291. The hypervirulent strain R20291 exhibits increased production of and tolerance to p cresol, which may be a contributory factor to the virulence of this strain and other hypervirulent PCR-ribotype 027 strains. PMID- 21527014 TI - Dilation of the ascending aorta in Turner syndrome - a prospective cardiovascular magnetic resonance study. AB - BACKGROUND: The risk of aortic dissection is 100-fold increased in Turner syndrome (TS). Unfortunately, risk stratification is inadequate due to a lack of insight into the natural course of the syndrome-associated aortopathy. Therefore, this study aimed to prospectively assess aortic dimensions in TS. METHODS: Eighty adult TS patients were examined twice with a mean follow-up of 2.4 +/- 0.4 years, and 67 healthy age and gender-matched controls were examined once. Aortic dimensions were measured at nine predefined positions using 3D, non-contrast and free-breathing cardiovascular magnetic resonance. Transthoracic echocardiography and 24-hour ambulatory blood pressure were also performed. RESULTS: At baseline, aortic diameters (body surface area indexed) were larger at all positions in TS. Aortic dilation was more prevalent at all positions excluding the distal transverse aortic arch. Aortic diameter increased in the aortic sinus, at the sinotubular junction and in the mid-ascending aorta with growth rates of 0.1 - 0.4 mm/year. Aortic diameters at all other positions were unchanged. The bicuspid aortic valve conferred higher aortic sinus growth rates (p < 0.05). No other predictors of aortic growth were identified. CONCLUSION: A general aortopathy is present in TS with enlargement of the ascending aorta, which is accelerated in the presence of a bicuspid aortic valve. PMID- 21527015 TI - PHQ-8 Days: a measurement option for DSM-5 Major Depressive Disorder (MDD) severity. AB - BACKGROUND: Proposed draft diagnostic criteria for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) suggest that dimensional assessments can supplement dichotomous diagnoses by incorporating measures of severity, frequency, and duration, providing the ability to monitor changes in symptoms over time and to guide appropriate treatment. METHODS: This report is based on data from the Behavioral Risk Factor Surveillance System 2006 from 198,678 survey participants who responded to all eight Patient Health Questionnaire (PHQ-8) items. We evaluated use of the days version of the PHQ-8 to determine an optimal cut-point for identifying respondents with depression and to evaluate the performance characteristics of the PHQ-8 at this cut-point. RESULTS: A PHQ-8 score of 55 or more days was determined to be the optimal cut-point when compared to the DSM-derived PHQ-8 algorithm for a major depressive episode (five or more symptoms present "more than half the days," at least one of which must be anhedonia or depression). In the full sample, the sensitivity and the specificity of this cut-point were 0.91 (0.90-0.93) and 0.99 (0.99-0.99), respectively. CONCLUSION: The days version of the PHQ-8 may be a valuable dimensional alternative to the traditional PHQ-8 by offering finer granularity of dimensionality (a score of 0 to 112). PMID- 21527012 TI - Biology and pathophysiology of the amyloid precursor protein. AB - The amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimer's disease in large part due to the sequential proteolytic cleavages that result in the generation of beta-amyloid peptides (Abeta). Not surprisingly, the biological properties of APP have also been the subject of great interest and intense investigations. Since our 2006 review, the body of literature on APP continues to expand, thereby offering further insights into the biochemical, cellular and functional properties of this interesting molecule. Sophisticated mouse models have been created to allow in vivo examination of cell type-specific functions of APP together with the many functional domains. This review provides an overview and update on our current understanding of the pathobiology of APP. PMID- 21527016 TI - Serum lipoprotein levels in takotsubo cardiomyopathy vs. myocardial infarction. AB - BACKGROUND: In the setting of myocardial infarction (MI) or acute coronary syndrome (ACS), current guidelines recommend early and aggressive lipid lowering therapy with statins, irrespective of the baseline lipoprotein levels. Takotsubo cardiomyopathy (TCM) patients have a clinical presentation similar to myocardial infarction and thus receive early and aggressive statin therapy during their initial hospitalization. However, the pathology of TCM is not atherosclerotic coronary artery disease and hence we assumed the lipid profiles in TCM would be healthier than coronary artery disease patients. METHODS: In this retrospective study, we assessed fasting serum lipoprotein levels of ten TCM patients and compared them with forty, age and sex-matched myocardial infarction (MI) patients. RESULTS: Comparing serum lipoprotein levels of TCM with MI group, there was no significant difference in mean total cholesterol between the two groups (174.5 mg/dL vs. 197.6 mg/dL, p = 0.12). However, in the TCM group, mean HDL-C was significantly higher (66.87 mg/dL vs. 36.5 mg/dL, p = 0.008), the mean LDL-C was significantly lower (89.7 mg/dL vs. 128.9 mg/dL, p = 0.0002), and mean triglycerides was also significantly lower (65.2 mg/dL vs. 166.8 mg/dL, p < 0.0001). CONCLUSIONS: In this study, TCM patients in comparison to MI patients had significantly higher levels of HDL-C, lower levels of LDL-C levels and triglycerides. The lipid profiles in TCM were consistent with the underlying pathology of non-atherosclerotic, non-obstructive coronary artery disease. As lipoproteins in most TCM patients were within the optimal range, we recommend an individual assessment of lipid profiles along with their coronary heart disease risk factors for considering long term lipid-lowering therapy. A finding of hyperalphalipoproteinemia or hypotriglyceridemia in 40% of TCM patients is novel but this association needs to be confirmed in future studies with larger sample sizes. These findings may provide clues in understanding the pathogenesis of takotsubo cardiomyopathy. PMID- 21527017 TI - Transcriptomic analysis of milk somatic cells in mastitis resistant and susceptible sheep upon challenge with Staphylococcus epidermidis and Staphylococcus aureus. AB - BACKGROUND: The existence of a genetic basis for host responses to bacterial intramammary infections has been widely documented, but the underlying mechanisms and the genes are still largely unknown. Previously, two divergent lines of sheep selected for high/low milk somatic cell scores have been shown to be respectively susceptible and resistant to intramammary infections by Staphylococcus spp. Transcriptional profiling with an 15K ovine-specific microarray of the milk somatic cells of susceptible and resistant sheep infected successively by S. epidermidis and S. aureus was performed in order to enhance our understanding of the molecular and cellular events associated with mastitis resistance. RESULTS: The bacteriological titre was lower in the resistant than in the susceptible animals in the 48 hours following inoculation, although milk somatic cell concentration was similar. Gene expression was analysed in milk somatic cells, mainly represented by neutrophils, collected 12 hours post-challenge. A high number of differentially expressed genes between the two challenges indicated that more T cells are recruited upon inoculation by S. aureus than S. epidermidis. A total of 52 genes were significantly differentially expressed between the resistant and susceptible animals. Further Gene Ontology analysis indicated that differentially expressed genes were associated with immune and inflammatory responses, leukocyte adhesion, cell migration, and signal transduction. Close biological relationships could be established between most genes using gene network analysis. Furthermore, gene expression suggests that the cell turn-over, as a consequence of apoptosis/granulopoiesis, may be enhanced in the resistant line when compared to the susceptible line. CONCLUSIONS: Gene profiling in resistant and susceptible lines has provided good candidates for mapping the biological pathways and genes underlying genetically determined resistance and susceptibility towards Staphylococcus infections, and opens new fields for further investigation. PMID- 21527018 TI - Identification and characterization of plant Haspin kinase as a histone H3 threonine kinase. AB - BACKGROUND: Haspin kinases are mitotic kinases that are well-conserved from yeast to human. Human Haspin is a histone H3 Thr3 kinase that has important roles in chromosome cohesion during mitosis. Moreover, phosphorylation of histone H3 at Thr3 by Haspin in fission yeast, Xenopus, and human is required for accumulation of Aurora B on the centromere, and the subsequent activation of Aurora B kinase activity for accurate chromosome alignment and segregation. Although extensive analyses of Haspin have been carried out in yeast and animals, the function of Haspin in organogenesis remains unclear. RESULTS: Here, we identified a Haspin kinase, designated AtHaspin, in Arabidopsis thaliana. The purified AtHaspin phosphorylated histone H3 at both Thr3 and Thr11 in vitro. Live imaging of AtHaspin-tdTomato and GFP-alpha-tubulin in BY-2 cells showed that AtHaspin tdTomato localized on chromosomes during prometaphase and metaphase, and around the cell plate during cytokinesis. This localization of AtHaspin overlapped with that of phosphorylated Thr3 and Thr11 of histone H3 in BY-2 cells. AtHaspin-GFP driven by the native promoter was expressed in root meristems, shoot meristems, floral meristems, and throughout the whole embryo at stages of high cell division. Overexpression of a kinase domain mutant of AtHaspin decreased the size of the root meristem, which delayed root growth. CONCLUSIONS: Our results indicated that the Haspin kinase is a histone H3 threonine kinase in A. thaliana. AtHaspin phosphorylated histone H3 at both Thr3 and Thr11 in vitro. The expression and dominant-negative analysis showed that AtHaspin may have a role in mitotic cell division during plant growth. Further analysis of coordinated mechanisms involving Haspin and Aurora kinases will shed new light on the regulation of chromosome segregation in cell division during plant growth and development. PMID- 21527019 TI - High protein diet maintains glucose production during exercise-induced energy deficit: a controlled trial. AB - BACKGROUND: Inadequate energy intake induces changes in endogenous glucose production (GP) to preserve muscle mass. Whether addition provision of dietary protein modulates GP response to energy deficit is unclear. The objective was to determine whether exercise-induced energy deficit effects on glucose metabolism are mitigated by increased dietary protein. METHODS: Nineteen men ([mean +/- SD] 23 +/- 2 y, VO2peak 59 +/- 5 ml.kg-1.min-1) were divided into three groups, two consuming moderate (MP; 0.9 g protein kg-1 d-1), and one high (HP; 1.8 g protein kg-1 d-1) protein diets (55% energy from carbohydrate) for 11 days. Following 4 days of energy balance (D1-4), energy expenditure was increased for 7 days (D5 12) in all groups. Energy intake was unchanged in two, creating a 1000 kcal d-1 deficit (DEF-MP, DEF-HP; n = 6, both groups), whereas energy balance was maintained in the third (BAL-MP, n = 7). Biochemical markers of substrate metabolism were measured during fasting rest on D4 and D12, as were GP and contribution of gluconeogenesis to endogenous glucose production (fgng) using 4-h primed, continuous infusions of [6,6-2H2]glucose (dilution-method) and [2 13C]glycerol (MIDA technique). Glycogen breakdown (GB) was derived from GP and fgng. RESULTS: Plasma beta-hydroxybutyrate levels increased, and plasma glucose and insulin declined from D4 to D12, regardless of group. DEF-MP experienced decreased plasma GP from D4 to D12 ([mean change +/- SD] 0.24 +/- 0.24 mg.kg 1.min-1), due to reduced GB from D4 (1.40 +/- 0.28 mg.kg-1.min-1) to D12 (1.16 +/ 0.17 mg.kg-1.min-1), P < 0.05. Conversely, BAL-MP and DEF-HP sustained GP from D4 to D12 ([mean change +/- SD] 0.1 +/- 0.5 and 0.0 +/- 0.2 mg.kg-1.min-1, respectively) by maintaining GB. CONCLUSION: Exercise-induced energy deficit decreased GP and additional dietary protein mitigated that effect. PMID- 21527020 TI - Seroprevalence of Human herpesvirus 8 (HHV-8) and incidence of Kaposi's sarcoma in Iran. AB - Seroepidemiological surveys show that the prevalence of human herpesvirus 8 (HHV 8) infection mostly varies in various geographical areas and reflects the local incidence of classic and endemic KS, being widespread in sub-Saharan Africa and Mediterranean countries and uncommon in the USA and Northern Europe. In the Middle East only few populations, such as Ashkenazi and Sephardic groups in Israel, have been adequately evaluated for HHV-8 seroprevalence. Among Iranian population a striking higher seroprevalence of HHV8 has been reported among haemodialysis (16.9%), renal transplant recipients (25%) and HIV (45.7%) patients compared to blood donors (2%). Kaposi's sarcoma (KS) is the rarest cancer in Iran, with an annual age-standardized incidence varying from 0.10 to 0.17 per 100,000 in males and from 0.06 to 0.08 per 100,000 in females. KS, however, is one of the most important malignancies in Iranian renal transplanted patients affecting up to 2.4% of organ recipients. The epidemiology of HHV8 and KS in Iran needs further evaluation. While the high prevalence of HHV-8 antibodies in HIV positive and haemodialysis individuals may be attributed to high-risk sexual behavior and polytransfusions, respectively, unknown determinants may be responsible for high seroprevalence of HHV8 and high incidence of KS in solid organ recipients. A global survey on HHV8 seroprevalence in Iran is mandatory to define co-factors associated with HHV8 infection and KS risk in the general Iranian population and in specific patient groups. PMID- 21527021 TI - Comparison between cardiovascular magnetic resonance and transthoracic Doppler echocardiography for the estimation of effective orifice area in aortic stenosis. AB - BACKGROUND: The effective orifice area (EOA) estimated by transthoracic Doppler echocardiography (TTE) via the continuity equation is commonly used to determine the severity of aortic stenosis (AS). However, there are often discrepancies between TTE-derived EOA and invasive indices of stenosis, thus raising uncertainty about actual definite severity. Cardiovascular magnetic resonance (CMR) has emerged as an alternative method for non-invasive estimation of valve EOA. The objective of this study was to assess the concordance between TTE and CMR for the estimation of valve EOA. METHODS AND RESULTS: 31 patients with mild to severe AS (EOA range: 0.72 to 1.73 cm2) and seven (7) healthy control subjects with normal transvalvular flow rate underwent TTE and velocity-encoded CMR. Valve EOA was calculated by the continuity equation. CMR revealed that the left ventricular outflow tract (LVOT) cross-section is typically oval and not circular. As a consequence, TTE underestimated the LVOT cross-sectional area (ALVOT, 3.84 +/- 0.80 cm2) compared to CMR (4.78 +/- 1.05 cm2). On the other hand, TTE overestimated the LVOT velocity-time integral (VTILVOT: 21 +/- 4 vs. 15 +/- 4 cm). Good concordance was observed between TTE and CMR for estimation of aortic jet VTI (61 +/- 22 vs. 57 +/- 20 cm). Overall, there was a good correlation and concordance between TTE-derived and CMR-derived EOAs (1.53 +/- 0.67 vs. 1.59 +/- 0.73 cm2, r = 0.92, bias = 0.06 +/- 0.29 cm2). The intra- and inter- observer variability of TTE-derived EOA was 5 +/- 5% and 9 +/- 5%, respectively, compared to 2 +/- 1% and 7 +/- 5% for CMR-derived EOA. CONCLUSION: Underestimation of ALVOT by TTE is compensated by overestimation of VTILVOT, thereby resulting in a good concordance between TTE and CMR for estimation of aortic valve EOA. CMR was associated with less intra- and inter- observer measurement variability compared to TTE. CMR provides a non-invasive and reliable alternative to Doppler-echocardiography for the quantification of AS severity. PMID- 21527022 TI - Expression of constitutively active erythropoietin receptor in pyramidal neurons of cortex and hippocampus boosts higher cognitive functions in mice. AB - BACKGROUND: Erythropoietin (EPO) and its receptor (EPOR) are expressed in the developing brain and their transcription is upregulated in adult neurons and glia upon injury or neurodegeneration. We have shown neuroprotective effects and improved cognition in patients with neuropsychiatric diseases treated with EPO. However, the critical EPO targets in brain are unknown, and separation of direct and indirect effects has remained difficult, given the role of EPO in hematopoiesis and brain oxygen supply. RESULTS: Here we demonstrate that mice with transgenic expression of a constitutively active EPOR isoform (cEPOR) in pyramidal neurons of cortex and hippocampus exhibit enhancement of spatial learning, cognitive flexibility, social memory, and attentional capacities, accompanied by increased impulsivity. Superior cognitive performance is associated with augmented long-term potentiation of cEPOR expressing neurons in hippocampal slices. CONCLUSIONS: Active EPOR stimulates neuronal plasticity independent of any hematopoietic effects and in addition to its neuroprotective actions. This property of EPOR signaling should be exploited for defining novel strategies to therapeutically enhance cognitive performance in disease conditions. PMID- 21527023 TI - Architectures of archaeal GINS complexes, essential DNA replication initiation factors. AB - BACKGROUND: In the early stage of eukaryotic DNA replication, the template DNA is unwound by the MCM helicase, which is activated by forming a complex with the Cdc45 and GINS proteins. The eukaryotic GINS forms a heterotetramer, comprising four types of subunits. On the other hand, the archaeal GINS appears to be either a tetramer formed by two types of subunits in a 2:2 ratio (alpha2beta2) or a homotetramer of a single subunit (alpha4). Due to the low sequence similarity between the archaeal and eukaryotic GINS subunits, the atomic structures of the archaeal GINS complexes are attracting interest for comparisons of their subunit architectures and organization. RESULTS: We determined the crystal structure of the alpha2beta2 GINS tetramer from Thermococcus kodakaraensis (TkoGINS), comprising Gins51 and Gins23, and compared it with the reported human GINS structures. The backbone structure of each subunit and the tetrameric assembly are similar to those of human GINS. However, the location of the C-terminal small domain of Gins51 is remarkably different between the archaeal and human GINS structures. In addition, TkoGINS exhibits different subunit contacts from those in human GINS, as a consequence of the different relative locations and orientations between the domains. Based on the GINS crystal structures, we built a homology model of the putative homotetrameric GINS from Thermoplasma acidophilum (TacGINS). Importantly, we propose that a long insertion loop allows the differential positioning of the C-terminal domains and, as a consequence, exclusively leads to the formation of an asymmetric homotetramer rather than a symmetrical one. CONCLUSIONS: The DNA metabolizing proteins from archaea are similar to those from eukaryotes, and the archaeal multi-subunit complexes are occasionally simplified versions of the eukaryotic ones. The overall similarity in the architectures between the archaeal and eukaryotic GINS complexes suggests that the GINS function, directed through interactions with other protein components, is basically conserved. On the other hand, the different subunit contacts, including the locations and contributions of the C-terminal domains to the tetramer formation, imply the possibility that the archaeal and eukaryotic GINS complexes contribute to DNA unwinding reactions by significantly different mechanisms in terms of the atomic details. PMID- 21527024 TI - Evaluating the health and economic impact of osteoarthritis pain in the workforce: results from the National Health and Wellness Survey. AB - BACKGROUND: There has been increasing recognition that osteoarthritis (OA) affects younger individuals who are still participants in the workforce, but there are only limited data on the contribution of OA pain to work productivity and other outcomes in an employed population. This study evaluated the impact of OA pain on healthcare resource utilization, productivity and costs in employed individuals. METHODS: Data were derived from the 2009 National Health and Wellness Survey. Univariable and multivariable analyses were used to characterize employed individuals (full-time, part-time, or self-employed) >= 20 years of age who were diagnosed with OA and had arthritis pain in the past month relative to employed individuals not diagnosed with OA or not experiencing arthritis pain in the past month. Work productivity was assessed using the Work Productivity and Activity Impairment (WPAI) questionnaire; health status was assessed using the physical (PCS) and mental component summary (MCS) scores from the SF-12v2 Health Survey and SF-6D health utilities; and healthcare utilization was evaluated by type and number of resources within the past 6 months. Direct and indirect costs were estimated and compared between the two cohorts. RESULTS: Individuals with OA pain were less likely to be employed. Relative to workers without OA pain (n = 37,599), the OA pain cohort (n = 2,173) was significantly older (mean age 52.1 +/ 11.5 years vs 41.4 +/- 13.2 years; P < 0.0001) and with a greater proportion of females (58.2% vs 45.9%; P < 0.0001). OA pain resulted in greater work impairment than among workers without OA pain (34.4% versus 17.8%; P < 0.0001), and was primarily due to presenteeism (impaired activity while at work). Health status, assessed both by the SF-12v2 and the SF-6D was significantly poorer among workers with OA pain (P < 0.0001), and healthcare resource utilization was significantly higher (P < 0.0001) than workers without OA pain. Total costs were higher in the OA pain cohort ($15,047 versus $8,175; P < 0.0001), driven by indirect costs that accounted for approximately 75% of total costs. CONCLUSIONS: A substantial proportion of workers suffer from OA pain. After controlling for confounders, the impact of OA pain was significant, resulting in lower productivity and higher costs. PMID- 21527025 TI - Identification of models of heterogeneous cell populations from population snapshot data. AB - BACKGROUND: Most of the modeling performed in the area of systems biology aims at achieving a quantitative description of the intracellular pathways within a "typical cell". However, in many biologically important situations even clonal cell populations can show a heterogeneous response. These situations require study of cell-to-cell variability and the development of models for heterogeneous cell populations. RESULTS: In this paper we consider cell populations in which the dynamics of every single cell is captured by a parameter dependent differential equation. Differences among cells are modeled by differences in parameters which are subject to a probability density. A novel Bayesian approach is presented to infer this probability density from population snapshot data, such as flow cytometric analysis, which do not provide single cell time series data. The presented approach can deal with sparse and noisy measurement data. Furthermore, it is appealing from an application point of view as in contrast to other methods the uncertainty of the resulting parameter distribution can directly be assessed. CONCLUSIONS: The proposed method is evaluated using artificial experimental data from a model of the tumor necrosis factor signaling network. We demonstrate that the methods are computationally efficient and yield good estimation result even for sparse data sets. PMID- 21527026 TI - Effect of anti-IgE therapy on food allergen specific T cell responses in eosinophil associated gastrointestinal disorders. AB - BACKGROUND: Anti-IgE therapy inhibits mast cell and basophil activation, blocks IgE binding to both FcepsilonRI and CD23 and down regulates FcepsilonRI expression by antigen (Ag) presenting cells (APCs). In addition to its classical role in immediate hypersensitivity, IgE has been shown in vitro to facilitate Ag presentation of allergens, whereby APC bound IgE preferentially takes up allergens for subsequent processing and presentation. The purpose of this study was to determine whether anti-IgE therapy, by blocking facilitated Ag presentation in vivo, attenuates allergen specific Th2 cell responses. METHODS: To test this hypothesis, food allergen specific T cell responses were examined during a 16-week clinical trial of omalizumab in nine subjects with eosinophilic gastroenteritis and food sensitization. Allergen specific T cell responses were measured using carboxyfluorescein succinimidyl ester dye dilution coupled with intracellular cytokine staining and polychromatic flow cytometry. Four independent indices of allergen specific T cell response (proliferation, Ag dose response, precursor frequency, and the ratio of Th2:Th1 cytokine expression) were determined. RESULTS: Eight of the 9 subjects had measurable food allergen specific responses, with a median proliferation index of 112-fold. Allergen specific T cell proliferation was limited to CD4 T cells, whereas CD8 T cell did not proliferate. Food allergen specific responses were Th2 skewed relative to tetanus specific responses in the same subjects. In contradistinction to the original hypothesis, anti-IgE treatment did not diminish any of the four measured indices of allergen specific T cell response. CONCLUSIONS: In sum, using multiple indices of T cell function, this study failed to demonstrate that anti-IgE therapy broadly or potently inhibits allergen specific T cell responses. As such, these data do not support a major role for IgE facilitated Ag presentation augmenting allergen specific T cell responses in vivo. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00084097. PMID- 21527027 TI - GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. AB - We describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets. PMID- 21527028 TI - Planning and problem-solving training for patients with schizophrenia: a randomized controlled trial. AB - BACKGROUND: The purpose of this study was to assess whether planning and problem solving training is more effective in improving functional capacity in patients with schizophrenia than a training program addressing basic cognitive functions. METHODS: Eighty-nine patients with schizophrenia were randomly assigned either to a computer assisted training of planning and problem-solving or a training of basic cognition. Outcome variables included planning and problem-solving ability as well as functional capacity, which represents a proxy measure for functional outcome. RESULTS: Planning and problem-solving training improved one measure of planning and problem-solving more strongly than basic cognition training, while two other measures of planning did not show a differential effect. Participants in both groups improved over time in functional capacity. There was no differential effect of the interventions on functional capacity. CONCLUSION: A differential effect of targeting specific cognitive functions on functional capacity could not be established. Small differences on cognitive outcome variables indicate a potential for differential effects. This will have to be addressed in further research including longer treatment programs and other settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT00507988. PMID- 21527030 TI - STSE: Spatio-Temporal Simulation Environment Dedicated to Biology. AB - BACKGROUND: Recently, the availability of high-resolution microscopy together with the advancements in the development of biomarkers as reporters of biomolecular interactions increased the importance of imaging methods in molecular cell biology. These techniques enable the investigation of cellular characteristics like volume, size and geometry as well as volume and geometry of intracellular compartments, and the amount of existing proteins in a spatially resolved manner. Such detailed investigations opened up many new areas of research in the study of spatial, complex and dynamic cellular systems. One of the crucial challenges for the study of such systems is the design of a well stuctured and optimized workflow to provide a systematic and efficient hypothesis verification. Computer Science can efficiently address this task by providing software that facilitates handling, analysis, and evaluation of biological data to the benefit of experimenters and modelers. RESULTS: The Spatio-Temporal Simulation Environment (STSE) is a set of open-source tools provided to conduct spatio-temporal simulations in discrete structures based on microscopy images. The framework contains modules to digitize, represent, analyze, and mathematically model spatial distributions of biochemical species. Graphical user interface (GUI) tools provided with the software enable meshing of the simulation space based on the Voronoi concept. In addition, it supports to automatically acquire spatial information to the mesh from the images based on pixel luminosity (e.g. corresponding to molecular levels from microscopy images). STSE is freely available either as a stand-alone version or included in the linux live distribution Systems Biology Operational Software (SB.OS) and can be downloaded from http://www.stse-software.org/. The Python source code as well as a comprehensive user manual and video tutorials are also offered to the research community. We discuss main concepts of the STSE design and workflow. We demonstrate it's usefulness using the example of a signaling cascade leading to formation of a morphological gradient of Fus3 within the cytoplasm of the mating yeast cell Saccharomyces cerevisiae. CONCLUSIONS: STSE is an efficient and powerful novel platform, designed for computational handling and evaluation of microscopic images. It allows for an uninterrupted workflow including digitization, representation, analysis, and mathematical modeling. By providing the means to relate the simulation to the image data it allows for systematic, image driven model validation or rejection. STSE can be scripted and extended using the Python language. STSE should be considered rather as an API together with workflow guidelines and a collection of GUI tools than a stand alone application. The priority of the project is to provide an easy and intuitive way of extending and customizing software using the Python language. PMID- 21527029 TI - The chlamydial periplasmic stress response serine protease cHtrA is secreted into host cell cytosol. AB - BACKGROUND: The periplasmic High Temperature Requirement protein A (HtrA) plays important roles in bacterial protein folding and stress responses. However, the role of chlamydial HtrA (cHtrA) in chlamydial pathogenesis is not clear. RESULTS: The cHtrA was detected both inside and outside the chlamydial inclusions. The detection was specific since both polyclonal and monoclonal anti-cHtrA antibodies revealed similar intracellular labeling patterns that were only removed by absorption with cHtrA but not control fusion proteins. In a Western blot assay, the anti-cHtrA antibodies detected the endogenous cHtrA in Chlamydia-infected cells without cross-reacting with any other chlamydial or host cell antigens. Fractionation of the infected cells revealed cHtrA in the host cell cytosol fraction. The periplasmic cHtrA protein appeared to be actively secreted into host cell cytosol since no other chlamydial periplasmic proteins were detected in the host cell cytoplasm. Most chlamydial species secreted cHtrA into host cell cytosol and the secretion was not inhibitable by a type III secretion inhibitor. CONCLUSION: Since it is hypothesized that chlamydial organisms possess a proteolysis strategy to manipulate host cell signaling pathways, secretion of the serine protease cHtrA into host cell cytosol suggests that the periplasmic cHtrA may also play an important role in chlamydial interactions with host cells. PMID- 21527031 TI - Eriocaulon buergerianum extract protects PC12 cells and neurons in zebrafish against 6-hydroxydopamine-induced damage. AB - BACKGROUND: Ericaulon buergerianum (Gujingcao) is an ophthalmic, anti inflammatory and antimicrobial Chinese medicinal herb. This study aims to investigate the neuroprotective effects of Ericaulon buergerianum ethanol extract (EBE) and to elucidate its underlying action mechanism. METHODS: The viability of dopaminergic (DA) neuron in zebrafish was examined by anti-tyrosine hydroxylase (TH) immunostaining. The locomotor activity of zebrafish was assessed with a digital video tracking system. The viability and cellular damage of the PC12 cells were determined by MTT and LDH assays respectively. The nuclear morphological changes in apoptotic cells were evaluated with DNA staining by Hoechst 33342 dye. Intracellular nitric oxide (NO) was quantified by DAF-FM diacetate staining. The expression of inducible nitric oxide synthase (iNOS) was determined by Western blot. RESULTS: EBE inhibited the 6-OHDA-induced decrease in total distance of movement in zebrafish. Pretreatments of EBE (25, 50, 100 and 200 MUg/ml) increased the viability of 6-OHDA-damaged PC12 cells in a dose dependent manner. Protection against 6-OHDA-induced nuclear fragmentation and accumulation of apoptotic bodies was also observed in EBE pretreated cells. Anti oxidative (inhibition of NO production and iNOS expression in PC12 cells in vitro) activities of EBE are related to its neuroprotective effects in 6-OHDA induced DA neuron damage. CONCLUSION: EBE exhibited significant neuroprotective activities in zebrafish, including recovery of dopaminergic neuron loss caused by 6-OHDA in a dose-dependent manner in vivo, inhibition of 6-OHDA-induced decrease of total distance in movement in zebrafish. The iNOS-NO pathway may be involved. PMID- 21527032 TI - Chinese herbal medicine research in eczema treatment. AB - Eczema is a chronic relapsing atopic dermatitis (AD) associated with pruritus, sleep disturbance and poor quality of life of the patient. Treatment of eczema includes use of emollient, topical and systemic antimicrobial agents, corticosteroid or immunomodulating agents. Many patients also seek alternative treatments such as dietary avoidance, supplementation or both. This article reviews the basic pathophysiology of eczema and clinical trials involving Chinese medicine in the treatment of eczema. Research reports on Chinese herbal medicine for eczema were retrieved from PubMed and the Cochrane Database for Systematic Reviews for this review. Only a few RCTs demonstrated the efficacy (or lack of efficacy) of Chinese medicinal herbs in treating atopic eczema. Further larger scale trials are warranted. PMID- 21527033 TI - Heterogeneous vancomycin-intermediate susceptibility in a community-associated methicillin-resistant Staphylococcus aureus epidemic clone, in a case of Infective Endocarditis in Argentina. AB - BACKGROUND: Community-Associated Methicillin Resistant Staphylococcus aureus (CA MRSA) has traditionally been related to skin and soft tissue infections in healthy young patients. However, it has now emerged as responsible for severe infections worldwide, for which vancomycin is one of the mainstays of treatment. Infective endocarditis (IE) due to CA-MRSA with heterogeneous vancomycin intermediate susceptibility-(h-VISA) has been recently reported, associated to an epidemic USA 300 CA-MRSA clone. CASE PRESENTATION: We describe the occurrence of h-VISA phenotype in a case of IE caused by a strain belonging to an epidemic CA MRSA clone, distinct from USA300, for the first time in Argentina. The isolate h VISA (SaB2) was recovered from a patient with persistent bacteraemia after a 7 day therapy with vancomycin, which evolved to fatal case of IE complicated with brain abscesses. The initial isolate-(SaB1) was fully vancomycin susceptible (VSSA). Although MRSA SaB2 was vancomycin susceptible (<= 2 MUg/ml) by MIC (agar and broth dilution, E-test and VITEK 2), a slight increase of MIC values between SaB1 and SaB2 isolates was detected by the four MIC methods, particularly for teicoplanin. Moreover, Sab2 was classified as h-VISA by three different screening methods [MHA5T-screening agar, Macromethod-E-test-(MET) and by GRD E-test] and confirmed by population analysis profile-(PAP). In addition, a significant increase in cell-wall thickness was revealed for SaB2 by electron microscopy. Molecular typing showed that both strains, SaB1 and SaB2, belonged to ST5 lineage, carried SCCmecIV, lacked Panton-Valentine leukocidin-(PVL) genes and had indistinguishable PFGE patterns (subtype I2), thereby confirming their isogenic nature. In addition, they were clonally related to the epidemic CA-MRSA clone (pulsotype I) detected in our country. CONCLUSIONS: This report demonstrates the ability of this epidemic CA-MRSA clone, disseminated in some regions of Argentina, to produce severe and rapidly fatal infections such as IE, in addition to its ability to acquire low-level vancomycin resistance; for these reasons, it constitutes a new challenge for the Healthcare System of this country. PMID- 21527034 TI - Multilevel Parallelization of AutoDock 4.2. AB - BACKGROUND: Virtual (computational) screening is an increasingly important tool for drug discovery. AutoDock is a popular open-source application for performing molecular docking, the prediction of ligand-receptor interactions. AutoDock is a serial application, though several previous efforts have parallelized various aspects of the program. In this paper, we report on a multi-level parallelization of AutoDock 4.2 (mpAD4). RESULTS: Using MPI and OpenMP, AutoDock 4.2 was parallelized for use on MPI-enabled systems and to multithread the execution of individual docking jobs. In addition, code was implemented to reduce input/output (I/O) traffic by reusing grid maps at each node from docking to docking. Performance of mpAD4 was examined on two multiprocessor computers. CONCLUSIONS: Using MPI with OpenMP multithreading, mpAD4 scales with near linearity on the multiprocessor systems tested. In situations where I/O is limiting, reuse of grid maps reduces both system I/O and overall screening time. Multithreading of AutoDock's Lamarkian Genetic Algorithm with OpenMP increases the speed of execution of individual docking jobs, and when combined with MPI parallelization can significantly reduce the execution time of virtual screens. This work is significant in that mpAD4 speeds the execution of certain molecular docking workloads and allows the user to optimize the degree of system-level (MPI) and node-level (OpenMP) parallelization to best fit both workloads and computational resources. PMID- 21527036 TI - Effect of age, impaction types and operative time on inflammatory tissue reactions following lower third molar surgery. AB - BACKGROUND: Postoperative mobidity following third molar surgery is affected by a number of factors. The study of these factors is essential for effective planning and limitation of morbidity. The aim of this study was to determine the effect of age, type of impaction and operative time on immediate postoperative tissue reactions following mandibular third molar surgery. METHODS: Consecutive patients with impacted mandibular third molar teeth were studied. All the third molars were classified according to Winter's classification. Surgical extraction was performed on all the patients by a single surgeon under local anaesthesia. The operation time was determined by the time lapse between incision and completion of suturing. Postoperative pain, swelling and trismus were evaluated. RESULTS: There were 120 patients with an age range of 19-42 years. Patients in the age range of 35-42 years recorded a lower pain score (p = 0.5) on day 1. The mouth opening was much better in the lower age group on day 2 and 5 (p = 0.007 and p = 0.01 respectively). Pain, swelling and trismus increased with increasing operative time. Distoangular impaction was significantly associated with higher VAS score on day 1 and 2 (p = 0.01, 0.0, 04). Distoangular and horizontal impaction are associated with a higher degree of swelling and reduced mouth opening on postoperative review days. Vertical impaction was associated with the least degree of facial swelling and best mouth opening. CONCLUSIONS: Increasing operating time and advancing age are associated with more postoperative morbidity, likewise distoangular and horizontal impaction types. PMID- 21527035 TI - The testosterone-dependent and independent transcriptional networks in the hypothalamus of Gpr54 and Kiss1 knockout male mice are not fully equivalent. AB - BACKGROUND: Humans and mice with loss of function mutations in GPR54 (KISS1R) or kisspeptin do not progress through puberty, caused by a failure to release GnRH. The transcriptional networks regulated by these proteins in the hypothalamus have yet to be explored by genome-wide methods. RESULTS: We show here, using 1 million exon mouse arrays (Exon 1.0 Affymetrix) and quantitative polymerase chain reaction (QPCR) validation to analyse microdissected hypothalamic tissue from Gpr54 and Kiss1 knockout mice, the extent of transcriptional regulation in the hypothalamus. The sensitivity to detect important transcript differences in microdissected RNA was confirmed by the observation of counter-regulation of Kiss1 expression in Gpr54 knockouts and confirmed by immunohistochemistry (IHC). Since Gpr54 and Kiss1 knockout animals are effectively pre-pubertal with low testosterone (T) levels, we also determined which of the validated transcripts were T-responsive and which varied according to genotype alone. We observed four types of transcriptional regulation (i) genotype only dependent regulation, (ii) T only dependent regulation, (iii) genotype and T-dependent regulation with interaction between these variables, (iv) genotype and T-dependent regulation with no interaction between these variables. The results implicate for the first time several transcription factors (e.g. Npas4, Esr2), proteases (Klk1b22), and the orphan 10-transmembrane transporter TMEM144 in the biology of GPR54/kisspeptin function in the hypothalamus. We show for the neuronal activity regulated transcription factor NPAS4, that distinct protein over-expression is seen in the hypothalamus and hippocampus in Gpr54 knockout mice. This links for the first time the hypothalamic-gonadal axis with this important regulator of inhibitory synapse formation. Similarly we confirm TMEM144 up-regulation in the hypothalamus by RNA in situ hybridization and western blot. CONCLUSIONS: Taken together, global transcriptional profiling shows that loss of GPR54 and kisspeptin are not fully equivalent in the mouse hypothalamus. PMID- 21527038 TI - Reconstruction of mandibular defects - clinical retrospective research over a 10 year period -. AB - BACKGROUND: Functional and cosmetic defects in the maxillofacial region are caused by various ailments and these defects are addressed according to their need. Simplicity of procedure, intact facial function and esthetic outcome with the least possible donor site morbidity are the minimum requirements of a good reconstruction. Oro-mandibular reconstruction, although a challenge for the head and neck reconstructive surgeon, is now reliable and highly successful with excellent long-term functional and aesthetic outcomes with the use of autogenous bone grafts. Reconstruction of trauma- or mandibular oncologic defects with bony free flaps is considered the gold standard. However the the optimal reconstruction of mandibular defects is still controversial in regards to reconstructive options which include the donor site selection and the timing of surgery. The purpose of this study was to determine the outcome of different osseous reconstruction options using autogenous bone grafts for mandibular reconstructions. METHODS: This study was carried out on 178 patients with mandibular bone defects. They were reconstructed with autogenous bone grafts from different donor sites. At post operative visits they were evaluated for functional and cosmetic results. RESULTS: The success rate found in this study was around 90%. Only 7.6% of the cases showed poor results regarding facial contours and mouth opening. All other patients were satisfied with their cosmesis and mouth opening at the recipient sites was in the normal range during last follow-up visits. Donor sites were primarily closed in all cases and there was no hypertrophic scar. CONCLUSION: Based on this study, autogenous bone grafts are a reliable treatment modality for the reconstruction of mandibular bone defects with predictable aesthetic and functional outcomes. As the free vascularized fibular flap has the least resorption and failure rate, it should be the first choice for most cases of mandiblular reconstruction. PMID- 21527037 TI - The use of microbead-based spoligotyping for Mycobacterium tuberculosis complex to evaluate the quality of the conventional method: providing guidelines for Quality Assurance when working on membranes. AB - BACKGROUND: The classical spoligotyping technique, relying on membrane reverse line-blot hybridization of the spacers of the Mycobacterium tuberculosis CRISPR locus, is used world-wide (598 references in Pubmed on April 8th, 2011). However, until now no inter-laboratory quality control study had been undertaken to validate this technique. We analyzed the quality of membrane-based spoligotyping by comparing it to the recently introduced and highly robust microbead-based spoligotyping. Nine hundred and twenty-seven isolates were analyzed totaling 39,861 data points. Samples were received from 11 international laboratories with a worldwide distribution. METHODS: The high-throughput microbead-based Spoligotyping was performed on CTAB and thermolyzate DNA extracted from isolated Mycobacterium tuberculosis complex (MTC) strains coming from the genotyping participating centers. Information regarding how the classical Spoligotyping method was performed by center was available. Genotype discriminatory analyses were carried out by comparing the spoligotypes obtained by both methods. The non parametric U-Mann Whitney homogeneity test and the Spearman rank correlation test were performed to validate the observed results. RESULTS: Seven out of the 11 laboratories (63%), perfectly typed more than 90% of isolates, 3 scored between 80-90% and a single center was under 80% reaching 51% concordance only. However, this was mainly due to discordance in a single spacer, likely having a non functional probe on the membrane used. The centers using thermolyzate DNA performed as well as centers using the more extended CTAB extraction procedure. Few centers shared the same problematic spacers and these problematic spacers were scattered over the whole CRISPR locus (Mostly spacers 15, 14, 18, 37, 39, 40). CONCLUSIONS: We confirm that classical spoligotyping is a robust method with generally a high reliability in most centers. The applied DNA extraction procedure (CTAB or thermolyzate) did not affect the results in this study. However performance was center-dependent, suggesting that training is a key component in quality assurance of spoligotyping. Overall, no particular spacer yielded a higher degree of deviating results, suggesting that errors occur randomly either in the process of re-using membranes, or during the reading of the results and transferring of data from the film to a digital file. Last, the performance of the microbead-based method was excellent as previously shown by Cowan et al. (J. Clin. Microbiol. 2004) and Zhang et al. (J. Med. Microbiol. 2009) and demonstrated the proper detection of spacer 15 that is known to occasionally give weak signals in the classical spoligotyping. PMID- 21527039 TI - Effects of childhood socioeconomic position on subjective health and health behaviours in adulthood: how much is mediated by adult socioeconomic position? AB - BACKGROUND: Adult socioeconomic position (SEP) is one of the most frequently hypothesised indirect pathways between childhood SEP and adult health. However, few studies that explore the indirect associations between childhood SEP and adult health systematically investigate the mediating role of multiple individual measures of adult SEP for different health outcomes. We examine the potential mediating role of individual measures of adult SEP in the associations of childhood SEP with self-rated health, self-reported mental health, current smoking status and binge drinking in adulthood. METHODS: Data came from 10,010 adults aged 25-64 years at Wave 3 of the Survey of Family, Income and Employment in New Zealand. The associations between childhood SEP (assessed using retrospective information on parental occupation) and self-rated health, self reported psychological distress, current smoking status and binge drinking were determined using logistic regression. Models were adjusted individually for the mediating effects of education, household income, labour market activity and area deprivation. RESULTS: Respondents from a lower childhood SEP had a greater odds of being a current smoker (OR 1.70 95% CI 1.42-2.03), reporting poorer health (OR 1.82 95% CI 1.39-2.38) or higher psychological distress (OR 1.60 95% CI 1.20 2.14) compared to those from a higher childhood SEP. Two-thirds to three quarters of the association of childhood SEP with current smoking (78%), and psychological distress (66%) and over half the association with poor self-rated health (55%) was explained by educational attainment. Other adult socioeconomic measures had much smaller mediating effects. CONCLUSIONS: This study suggests that the association between childhood SEP and self-rated health, psychological distress and current smoking in adulthood is largely explained through an indirect socioeconomic pathway involving education. However, household income, area deprivation and labour market activity are still likely to be important as they are intermediaries in turn, in the socioeconomic pathway between education and health. PMID- 21527040 TI - The methodology for developing a prospective meta-analysis in the family planning community. AB - BACKGROUND: Prospective meta-analysis (PMA) is a collaborative research design in which individual sites perform randomized controlled trials (RCTs) and pool the data for meta-analysis. Members of the PMA collaboration agree upon specific research interventions and outcome measures, ideally before initiation but at least prior to any individual trial publishing results. This allows for uniform reporting of primary and secondary outcomes. With this approach, heterogeneity among trials contributing data for the final meta-analysis is minimized while each site maintains the freedom to design a specific trial. This paper describes the process of creating a PMA collaboration to evaluate the impact of misoprostol on ease of intrauterine device (IUD) insertion in nulliparous women. METHODS: After the principal investigator developed a preliminary PMA protocol, he identified potential collaborating investigators at other sites. One site already had a trial underway and another site was in the planning stages of a trial meeting PMA requirements. Investigators at six sites joined the PMA collaborative. Each site committed to enroll subjects to meet a pre-determined total sample size. A final common research plan and site responsibilities were developed and agreed upon through email and face-to-face meetings. Each site committed to contribute individual patient data to the PMA collaboration, and these data will be analyzed and prepared as a multi-site publication. Individual sites retain the ability to analyze and publish their site's independent findings. RESULTS: All six sites have obtained Institutional Review Board approval and each has obtained individual funding to meet the needs of that site's study. Sites have shared resources including study protocols and consents to decrease costs and improve study flow. This PMA protocol is registered with the Cochrane Collaboration and data will be analyzed according to Cochrane standards for meta-analysis. CONCLUSIONS: PMA is a novel research method that improves meta-analysis by including several study sites, establishing uniform reporting of specific outcomes, and yet allowing some independence on the part of individual sites with respect to the conduct of research. The inclusion of several sites increases statistical power to address important clinical questions. Compared to multi-center trials, PMA methodology encourages collaboration, aids in the development of new investigators, decreases study costs, and decreases time to publication. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00613366, NCT00886834, NCT01001897, NCT01147497 and NCT01307111. PMID- 21527041 TI - Thick calcification from a GIST of the stomach penetrating into pericolic soft tissue--report of a case. AB - Thick calcification is a rare presentation of gastrointestinal stromal tumor (GIST). Penetration into gastric mucosa and pericolic soft tissue has never been reported. We report a case of gastric GIST with cystic degeneration and thick calcification in an 81-year old female, who presented with hematemesis and severe abdominal pain. Thick calcification of this tumor penetrating into pericolic soft tissue was noted and successfully treated by distal gastrectomy and partial colectomy. For gastrointestinal tumors with thick calcification, even with benign behavior, surgical intervention should be considered for both oncological considerations and prevention of catastrophes like perforation or penetration into surrounding soft tissue. PMID- 21527042 TI - Are we there yet? Australian road safety targets and road traffic crash fatalities. AB - BACKGROUND: Road safety targets are widely used and provide a basis for evaluating progress in road safety outcomes against a quantified goal. In Australia, a reduction in fatalities from road traffic crashes (RTCs) is a public policy objective: a national target of no more than 5.6 fatalities per 100,000 population by 2010 was set in 2001. The purpose of this paper is to examine the progress Australia and its states and territories have made in reducing RTC fatalities, and to estimate when the 2010 target may be reached by the jurisdictions. METHODS: Following a descriptive analysis, univariate time-series models estimate past trends in fatality rates over recent decades. Data for differing time periods are analysed and different trend specifications estimated. Preferred models were selected on the basis of statistical criteria and the period covered by the data. The results of preferred regressions are used to determine out-of-sample forecasts of when the national target may be attained by the jurisdictions. Though there are limitations with the time series approach used, inadequate data precluded the estimation of a full causal/structural model. RESULTS: Statistically significant reductions in fatality rates since 1971 were found for all jurisdictions with the national rate decreasing on average, 3% per year since 1992. However the gains have varied across time and space, with percent changes in fatality rates ranging from an 8% increase in New South Wales 1972-1981 to a 46% decrease in Queensland 1982-1991. Based on an estimate of past trends, it is possible that the target set for 2010 may not be reached nationally, until 2016. Unsurprisingly, the analysis indicated a range of outcomes for the respective state/territory jurisdictions though these results should be interpreted with caution due to different assumptions and length of data. CONCLUSIONS: Results indicate that while Australia has been successful over recent decades in reducing RTC mortality, an important gap between aspirations and achievements remains. Moreover, unless there are fairly radical ("trend breaking") changes in the factors that affect the incidence of RTC fatalities, deaths from RTCs are likely to remain above the national target in some areas of Australia, for years to come. PMID- 21527043 TI - Effect of grazers and viruses on bacterial community structure and production in two contrasting trophic lakes. AB - BACKGROUND: Over the last 30 years, extensive studies have revealed the crucial roles played by microbes in aquatic ecosystems. It has been shown that bacteria, viruses and protozoan grazers are dominant in terms of abundance and biomass. The frequent interactions between these microbiological compartments are responsible for strong trophic links from dissolved organic matter to higher trophic levels, via heterotrophic bacteria, which form the basis for the important biogeochemical roles of microbial food webs in aquatic ecosystems. To gain a better understanding of the interactions between bacteria, viruses and flagellates in lacustrine ecosystems, we investigated the effect of protistan bacterivory on bacterial abundance, production and structure [determined by 16S rRNA PCR-DGGE], and viral abundance and activity of two lakes of contrasting trophic status. Four experiments were conducted in the oligotrophic Lake Annecy and the mesotrophic Lake Bourget over two seasons (early spring vs. summer) using a fractionation approach. In situ dark vs. light incubations were performed to consider the effects of the different treatments in the presence and absence of phototrophic activity. RESULTS: The presence of grazers (i.e. <5-MUm small eukaryotes) affected viral production positively in all experiments, and the stimulation of viral production (compared to the treatment with no eukaryotic predators) was more variable between lakes than between seasons, with the highest value having been recorded in the mesotrophic lake (+30%). Viral lysis and grazing activities acted additively to sustain high bacterial production in all experiments. Nevertheless, the stimulation of bacterial production was more variable between seasons than between lakes, with the highest values obtained in summer (+33.5% and +37.5% in Lakes Bourget and Annecy, respectively). The presence of both predators (nanoflagellates and viruses) did not seem to have a clear influence upon bacterial community structure according to the four experiments. CONCLUSIONS: Our results highlight the importance of a synergistic effect, i.e. the positive influence of grazers on viral activities in sustaining (directly and indirectly) bacterial production and affecting composition, in both oligotrophic and mesotrophic lakes. PMID- 21527044 TI - Sequential interim analyses of survival data in DNA microarray experiments. AB - BACKGROUND: Discovery of biomarkers that are correlated with therapy response and thus with survival is an important goal of medical research on severe diseases, e.g. cancer. Frequently, microarray studies are performed to identify genes of which the expression levels in pretherapeutic tissue samples are correlated to survival times of patients. Typically, such a study can take several years until the full planned sample size is available.Therefore, interim analyses are desirable, offering the possibility of stopping the study earlier, or of performing additional laboratory experiments to validate the role of the detected genes. While many methods correcting the multiple testing bias introduced by interim analyses have been proposed for studies of one single feature, there are still open questions about interim analyses of multiple features, particularly of high-dimensional microarray data, where the number of features clearly exceeds the number of samples. Therefore, we examine false discovery rates and power rates in microarray experiments performed during interim analyses of survival studies. In addition, the early stopping based on interim results of such studies is evaluated. As stop criterion we employ the achieved average power rate, i.e. the proportion of detected true positives, for which a new estimator is derived and compared to existing estimators. RESULTS: In a simulation study, pre specified levels of the false discovery rate are maintained in each interim analysis, where reduced levels as used in classical group sequential designs of one single feature are not necessary. Average power rates increase with each interim analysis, and many studies can be stopped prior to their planned end when a certain pre-specified power rate is achieved. The new estimator for the power rate slightly deviates from the true power rate but is comparable to other estimators. CONCLUSIONS: Interim analyses of microarray experiments can provide evidence for early stopping of long-term survival studies. The developed simulation framework, which we also offer as a new R package 'SurvGenesInterim' available at http://survgenesinter.R-Forge.R-Project.org, can be used for sample size planning of the evaluated study design. PMID- 21527045 TI - Human saliva as a source of anti-malarial antibodies to examine population exposure to Plasmodium falciparum. AB - BACKGROUND: Antibody responses to malaria antigens reflect exposure to parasites, and seroprevalence correlates with malaria transmission intensity. Antibodies are routinely measured in sera or on dried blood spots but a non-invasive method would provide extra utility in sampling general populations. Saliva is already in use in the detection of plasma-derived IgM and IgG to viral infections. In this study, antibodies to Plasmodium falciparum merozoite antigens were compared between blood and saliva samples from the same individuals in unlinked surveys conducted in Tanzania and The Gambia. METHODS: In Tanzania, 53 individuals provided paired fingerprick blood and saliva sample using two commercially available sampling devices. In the Gambia, archived plasma and saliva samples collected from 200 children in the Farafenni area in a cross-sectional survey were analyzed.IgG antibodies against P. falciparum antigens, Merozoite Surface Protein-1 (MSP-119) and Apical membrane Antigen (AMA-1) were measured by ELISA in paired saliva and blood samples from both sites. Antibody levels were compared as continuous optical density (OD) values and by sero-positivity. RESULTS: Significant correlations between saliva and plasma antibody levels were seen in Tanzania for both antigens, AMA-1(r2 range 0.93 to 0.89, p < 0.001) and MSP-119 (r2 range 0.93 to 0.75, p < 0.001), with a weaker correlation for results from The Gambia (r2range 0.64 to 0.63, p < 0.01). When assessed as seropositivity and compared with plasma, sensitivity and specificity were good with saliva antibody levels to both AMA-1 and MSP-1(19) (sensitivity range 64-77% and specificity range 91-100% & 47-67% and 90-97% respectively) over the different sample sets. CONCLUSIONS: These data demonstrate anti-malarial antibodies can be detected in saliva and correlate strongly with levels in plasma. This non-invasive relatively simple collection method will be potentially useful for general population surveys, and particularly in migratory populations or those with infrequent contact with health services or opposed to blood withdrawal. Further studies will be needed to optimize collection methods, standardize volumes and content and develop controls. PMID- 21527046 TI - Promiscuity and preferences of metallothioneins: the cell rules. AB - Metalloproteins are essential for many cellular functions, but it has not been clear how they distinguish between the different metals to bind the correct ones. A report in BMC Biology finds that preferences of two metallothionein isoforms for two different cations are due to inherent properties of these usually less discriminating proteins. Here these observations are discussed in the context of the cellular mechanisms that regulate metal binding to proteins. PMID- 21527047 TI - Mapping meiotic breaks: Spo11 oligonucleotides precisely mark the spots. AB - Initiation sites for meiotic recombination have now been precisely mapped across the budding yeast genome using a widely applicable deep-sequencing approach. PMID- 21527048 TI - Butterfly eyespot serial homology: enter the Hox genes. AB - Hox genes modify serial homology patterns in many organisms, exemplified in vertebrates by modification of the axial skeleton and in arthropods by diversification of the body segments. Butterfly wing eyespots also appear in a serial homologous pattern that, in certain species, is subject to local modification. A paper in EvoDevo reports the Hox gene Antp is the earliest known gene to have eyespot-specific expression; however, not all Lepidoptera express Antp in eyespots, suggesting some developmental flexibility. PMID- 21527049 TI - [Myalgia during warming-up in a 12-year-old boy]. AB - INTRODUCTION: McArdle disease is a hereditary myopathy caused by muscle phosphorylase deficiency. Patients experience painful muscle cramps after strenuous exercise; the condition is sometimes associated with rhabdomyolysis, myoglobinuria and resulting acute renal failure. CASE DESCRIPTION: A 12-year-old boy visited the Paediatric and Neurology outpatients' departments with symptoms of leg myalgia, occurring during the warming-up phase of soccer practice, which disappeared after a short rest. Detailed history-taking revealed that he already experienced pain while walking during early childhood. An elevated serum creatine kinase concentration in combination with the typical presentation led to the presumptive diagnosis 'McArdle disease', which was confirmed by molecular genetic analysis. CONCLUSION: There is no effective gene therapy; a multidisciplinary approach by a neurologist, paediatrician, physiotherapist and nutritionist is advised. PMID- 21527051 TI - [Bad aftertaste caused by pine nuts]. AB - BACKGROUND: Dysgeusia caused by the consumption of pine nuts is not widely reported in the medical literature, although much is written about this condition on the Internet. CASE DESCRIPTION: We present the case of a 46-year-old male who complained of metallic and bitter dysgeusia that started 2 days after the ingestion of approximately 70 grams of pine nuts. A literature search revealed only 3 case reports on this subject. In all cases including ours, the complaints began a few days after the ingestion of pine nuts and had spontaneously resolved after a week. No medical sequelae are known, but patients may suffer social consequences. CONCLUSION: The cause of this condition is unknown. Possible causes include the presence of toxic or inedible components in the pine nuts. Physicians should be aware of this phenomenon in order to be able to reassure patients about this benign disorder. PMID- 21527050 TI - [Attrition and poor performance in general practice training: age, competence and knowledge play a role]. AB - OBJECTIVE: To investigate which determinants are related to poor performance and forced attrition in the first year residency in general practice (GP). DESIGN: Observational retrospective cohort study. METHOD: We collected data relating to personal characteristics such as age, sex and clinical experience from residents who started the GP training in Utrecht, the Netherlands, in the period March 2005 August 2007. We also collected competence scores from the domains 'medical expertise', 'doctor-patient communication' and 'professionalism', as well as scores on a national GP knowledge test. The outcome measures were 'poor performance' and 'forced attrition'. Multivariate logistic regression was used to analyse correlations between personal characteristics, competence scores on the 3 domains and knowledge scores in the first trimester on the one hand and poor performance or forced attrition on the other. RESULTS: 215 residents started the GP training. In the first trimester a quarter of the residents had an insufficient score in 1 or more of the domains. Competence scores were mutually correlated, but did not correlate with the knowledge score. 18 residents showed poor performance and 3 were forced to stop their training. Poor performance and forced attrition were correlated with age (adjusted odds ratio (OR): 1.1; 95% CI: 1.0-1.3), insufficient knowledge (adjusted OR: 8.9; 3.0-26.3) and medical expertise (adjusted OR: 2.1; 1.1-4.0) at the beginning of the training. CONCLUSION: Age, insufficient knowledge of general practice, and insufficient competence in the domain of 'medical expertise' at the beginning of the training are risk factors for poor performance by residents and attrition from their GP training. PMID- 21527052 TI - [Desensitisation to circumvent hypersensitivity reactions; treatment with docetaxel still possible]. AB - A 57-year-old woman with advanced non-small cell lung carcinoma developed hypersensitivity reactions to docetaxel. Measures taken to attempt the re administration of docetaxel failed. For the differential diagnosis, an IgE specific to docetaxel (in terms of cross-reactivity with Taxus baccata), the solubilizing agent polysorbate 80, as well as the possibility of the reaction being non-IgE-mediated, were all considered. The latter was thought to be most likely. Desensitisation has been reported to be safe and effective in protecting patients from severe hypersensitivity reactions in both IgE- and non-IgE-mediated reactions. Desensitisation in this context means the induction of temporary clinical unresponsiveness to the culprit drug. The gradual reintroduction of small doses of the drug at fixed time intervals eventually allows delivery of full therapeutic doses. Desensitisation to docetaxel was successfully carried out in a supervised setting a total of three times in this patient. PMID- 21527053 TI - [Insufficient medication compliance in Parkinson's disease]. AB - Medication compliance is generally suboptimal, particularly in patients with complex polypharmacy. This generic treatment problem is described here for Parkinson's disease (PD). We would expect patients with PD to have good medication compliance, since missed doses immediately result in worsening of symptoms. However, recent research has revealed that PD patients demonstrate poor medication compliance. Poor medication compliance is particularly undesirable for patients with PD because regular intake of medication is required for optimal treatment effect. Possible ways of improving medication compliance are pharmacotherapeutic measures and behavioural interventions. Modern methods of communication (text message reminders) and 'smart' pill dispensers may be beneficial, but the advantages of such interventions have not yet been scientifically studied. PMID- 21527054 TI - [Early detection of laryngeal carcinoma: limited improvement possible]. AB - In the majority of cases, laryngeal cancer is located in the glottis, which gives rise to symptoms of hoarseness at an early stage. These symptoms lead to a high rate (85%) of early detection of glottic cancer. Laryngeal carcinoma at other sites in the larynx is associated with symptoms of hoarseness, difficulties in swallowing and dyspnoea at a later stage. Improvements in awareness, speed of referral, identification of patients at risk and available techniques may result in earlier detection. However, if current Dutch national practice guidelines, of which a revised version has recently been published, are followed it would seem that the possibility of further improvements in early detection of laryngeal carcinoma is limited at this moment. PMID- 21527055 TI - [Can subarachnoid haemorrhage be recognised based on clinical characteristics?]. AB - Use of prediction rules may reduce the number of patients with acute headache undergoing a CT scan and lumbar puncture to rule in or rule out subarachnoid haemorrhage from a ruptured aneurysm. A Canadian study group that studied patients admitted to emergency departments from tertiary centres shows preliminary evidence that is theoretically promising. However, before such rules can be implemented they require prospective validation in the same and other health care systems and a cost-effectiveness analysis that balances the risks of missed instances of subarachnoid haemorrhage versus the risk of radiation-induced cancer. External validation particularly holds true for the Dutch health care system, where most of these patients are initially seen by a general practitioner. PMID- 21527056 TI - [Chagas disease in the Netherlands: an estimate of the number of patients]. AB - A total of 8-10 million persons are infected worldwide with Trypanosoma cruzi, the causative parasite of Chagas disease, most of whom are inhabitants of Latin America. Due to the increased migration of peoples, Chagas disease has been on the uprise outside Latin America, including in Europe. The course of Chagas, also called American trypanosomiasis, runs in 2 phases: an acute phase lasting approximately 2 months, and a chronic phase in which symptoms may appear years after infection. Without treatment, the patient will remain infected for life. The acute phase is usually asymptomatic; in the chronic phase of American trypanosomiasis, severe gastro-intestinal and cardiac abnormalities may develop, finally with fatal course. In the Netherlands, the number of immigrants who would serologically test positive for American trypanosomiasis is estimated to be between 726 and 2929. Healthcare providers in the Netherlands may encounter patients who have Chagas disease more and more frequently. The screening of pregnant women and blood donors at risk for American trypanosomiasis should be considered. PMID- 21527058 TI - [Autoimmune enteropathy in children]. AB - Autoimmune enteropathy is a rare syndrome which, in children in its most severe form, causes severe life-threatening diarrhoea and dehydration. The enteropathy seems to be part of a systemic disorder that can include neonatal diabetes mellitus, haematological abnormalities, severe allergies and eczema. The syndrome characterised by 'immuno-dysregulation, polyendocrinopathy, autoimmune enteropathy, X-linkage' (IPEX syndrome) is the most severe and also the best characterised form of autoimmune enteropathy. Recently, more has been discovered about the pathophysiology of autoimmune enteropathy. It would seem that an immunological defect exists, which is caused by the non-functioning of regulatory T cells. Characteristic of this disorder are circulating auto-antibodies that cause destruction of the intestinal wall. In a number of patients, this defect is caused by mutations in the Foxp3 gene on the X chromosome. The discovery of the molecular background for autoimmune enteropathy provides important new potential opportunities for diagnosis and therapy. Treatment options for this condition are immunosuppression and bone marrow transplantation. PMID- 21527059 TI - [Thromboprophylaxis with low-molecular-weight heparin insufficient in high-risk pregnancy]. AB - OBJECTIVE: To evaluate the efficacy and safety of thromboprophylaxis with a low of low-molecular-weight heparin (LMWH) in women with an intermediate to high risk of pregnancy-related venous thromboembolism (VTE). DESIGN: Retrospective cohort study. METHODS: We collected data from all pregnant women with an intermediate or high risk of VTE in the period 1996-2009. In accordance with protocol, pregnant women with an intermediate risk of VTE were treated with a prophylactic dose of LMWH for 6 weeks post partum, and pregnant women with a high risk were treated with a prophylactic dose of LMWH during the pregnancy and for 6 weeks post partum. Efficacy was defined as the incidence of VTE during pregnancy or < 3 months post partum, and safety as the incidence of post-partum haemorrhage (PPH) (> 500 ml blood loss) or severe PPH (> 1,000 ml blood loss). RESULTS: We analysed 34 women (44 pregnancies) with an intermediate risk and 57 women (82 pregnancies) with a high risk of VTE. The incidence of pregnancy-related VTE despite thromboprophylaxis was 5.5% (95% CI: 2.4-12.3). All VTEs occurred in high-risk women, and risk was higher post partum than ante partum: 7.0% (95% CI: 2.9-16.7) and 1.8% (95% CI: 0.4-9.2%), respectively. The risk of PPH was 21.6% (95% CI: 14.3-31.3) and of severe PPH 9.1% (95% CI: 4.7-16.9) and was comparable in women who used LMWH during pregnancy and those who started LMWH post partum. CONCLUSION: There was a considerable risk of pregnancy-related VTE in high-risk women despite a prophylactic dose of LMWH during pregnancy and in the post partum period. For these women thromboprophylaxis with a low, prophylactic dose of LMWH appeared to be insufficient. PMID- 21527060 TI - [Pay-for-performance in healthcare: effects are uncertain]. AB - A British pay-for-performance scheme to improve medical care has attracted the attention of Dutch health authorities. An extensive pay-for-performance policy was introduced in general practices in the UK in 2004. In British patients with hypertension, however, financial incentives for healthcare providers did not appear to improve the quality of patient care. A temporary effect was seen among patients with asthma and diabetes. Unintended consequences were detected. The quality of care for patients in general practice was already improving before the change in policy. Based on these results, careful consideration is needed before the introduction of extensive pay-for-performance in Dutch general practice. Quality of care has been an issue for Dutch GP's for many years. General practitioners and health insurance companies should cooperate to identify those aspects of care needing further improvement. More can probably be gained from trust in GPs and the facilitating role of health insurance companies than from a pay-for-performance scheme. PMID- 21527061 TI - East meets West: ethnic differences in epidemiology and clinical behaviors of lung cancer between East Asians and Caucasians. AB - Lung cancer is the leading cause of cancer death worldwide, with large variation of the incidence and mortality across regions. Although the mortality of lung cancer has been decreasing, or steady in the US, it has been increasing in Asia for the past two decades. Smoking is the leading cause of lung cancer, and other risk factors such as indoor coal burning, cooking fumes, and infections may play important roles in the development of lung cancer among Asian never smoking women. The median age of diagnosis in Asian patients with lung cancer is generally younger than Caucasian patients, particularly among never-smokers. Asians and Caucasians may have different genetic susceptibilities to lung cancer, as evidenced from candidate polymorphisms and genome-wide association studies. Recent epidemiologic studies and clinical trials have shown consistently that Asian ethnicity is a favorable prognostic factor for overall survival in non small cell lung cancer (NSCLC), independent of smoking status. Compared with Caucasian patients with NSCLC, East Asian patients have a much higher prevalence of epidermal growth factor receptor (EGFR) mutation (approximately 30% vs. 7%, predominantly among patients with adenocarcinoma and never-smokers), a lower prevalence of K-Ras mutation (less than 10% vs. 18%, predominantly among patients with adenocarcinoma and smokers), and higher proportion of patients who are responsive to EGFR tyrosine kinase inhibitors. The ethnic differences in epidemiology and clinical behaviors should be taken into account when conducting global clinical trials that include different ethnic populations. PMID- 21527062 TI - Next generation of antibody therapy for cancer. AB - Monoclonal antibodies (mAbs) have become a major class of therapeutic agents providing effective alternatives to treating various human diseases. To date, 15 mAbs have been approved by regulatory agencies in the world for clinical use in oncology indications. The selectivity and specificity, the unique pharmacokinetics, and the ability to engage and activate the host immune system differentiate these biologics from traditional small molecule anticancer drugs. mAb-based regimens have brought clinical benefits, including improvements in overall survival, to patients with a variety of cancers. Many challenges still remain, however, to fully realize the potential of these new medicines. With our further understanding of cancer biology, mechanism of antibody action, and advancement of antibody engineering technologies, many novel antibody formats or antibody-derived molecules are emerging as promising new generation therapeutics. Carefully designed and engineered, they retain the advantage of specificity and selectivity of original antibodies, but in the meantime acquire additional special features such as improved pharmacokinetics, increased selectivity, and enhanced anticancer efficacy. Promising clinical results are being generated with these newly improved antibody-based therapeutics. PMID- 21527064 TI - Proton therapy in clinical practice. AB - Radiation dose escalation and acceleration improves local control but also increases toxicity. Proton radiation is an emerging therapy for localized cancers that is being sought with increasing frequency by patients. Compared with photon therapy, proton therapy spares more critical structures due to its unique physics. The physical properties of a proton beam make it ideal for clinical applications. By modulating the Bragg peak of protons in energy and time, a conformal radiation dose with or without intensity modulation can be delivered to the target while sparing the surrounding normal tissues. Thus, proton therapy is ideal when organ preservation is a priority. However, protons are more sensitive to organ motion and anatomy changes compared with photons. In this article, we review practical issues of proton therapy, describe its image-guided treatment planning and delivery, discuss clinical outcome for cancer patients, and suggest challenges and the future development of proton therapy. PMID- 21527063 TI - Gastrointestinal stromal tumor and its targeted therapeutics. AB - Over the past 60 years, investigators of basic science, pathology, and clinical medicine have studied gastrointestinal stromal tumor (GIST) and made minor advances in patient care. Recent discoveries have led to an understanding of the biological role of KIT and platelet-derived growth factor receptor-alpha in GIST and the development of the tyrosine kinase inhibitor imatinib mesylate (Gleevec, formerly STI-571), one of the most exciting examples of targeted therapy to date. The success of targeted therapy in GIST has lead to new developments in our understanding of the medical and surgical management of the disease. Intense study of GIST may lead to new paradigms in the management of cancer. PMID- 21527066 TI - Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma. AB - Recent evidence suggests that the chemokine axis of CXC chemokine ligand-12 and its receptor CXC chemokine receptor-4 (CXCL12/CXCR4) is highly expressed in gynecological tumors and the axis of CXC chemokine ligand-16 and CXC chemokine receptor-6 (CXCL16/CXCR6) is overexpressed in inflammation-associated tumors. This study aimed to determine the relationship between CXCL12/CXCR4, CXCL16/CXCR6 and ovarian carcinoma's clinicopathologic features and prognosis. Accordingly, the expression of these proteins in ovarian tissues was detected by tissue microarray and immunohistochemistry. The expressions of CXCL12/CXCR4 and CXCL16/CXCR6 were significantly higher in epithelial ovarian carcinomas than in normal epithelial ovarian tissues or benign epithelial ovarian tumors. The expression of chemokines CXCL12 and CXCL16 were positively correlated with their receptors CXCR4 and CXCR6 in ovarian carcinoma, respectively (r = 0.300, P < 0.05; r = 0.395, P < 0.05). Moreover, the expression of CXCL12 was related to the occurrence of ascites (Chi2 = 4.76, P < 0.05), the expression of CXCR4 was significantly related to lymph node metastasis (Chi(2) = 4.37, P < 0.05), the expression of CXCR6 was significantly related to lymph node metastasis (Chi2 = 7.43, P < 0.05) and histological type (Chi2 = 33.48, P < 0.05). In univariate analysis, the expression of CXCR4 and CXCL16 significantly correlated with reduced median survival (Chi2 = 4.67, P < 0.05; Chi2 = 4.48, P < 0.05). Therefore, we conclude that the chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 may play important roles in the growth, proliferation, invasion, and metastasis of epithelial ovarian carcinoma. PMID- 21527065 TI - Lapatinib plus capecitabine in treating HER2-positive advanced breast cancer: efficacy, safety, and biomarker results from Chinese patients. AB - Overexpression of human epidermal growth factor receptor-2 (HER2) in metastatic breast cancer (MBC) is associated with poor prognosis. This single-arm open-label trial (EGF109491; NCT00508274) was designed to confirm the efficacy and safety of lapatinib in combination with capecitabine in 52 heavily pretreated Chinese patients with HER2-positive MBC. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), time to response (TTR), duration of response (DoR), central nervous system (CNS) as first site of relapse, and safety. The results showed that there were 23 patients with partial responses and 7 patients with stable disease, resulting in a CBR of 57.7%. The median PFS was 6.34 months (95% confidence interval, 4.93-9.82 months). The median TTR and DoR were 4.07 months (range, 0.03-14.78 months) and 6.93 months (range, 1.45-9.72 months), respectively. Thirteen (25.0%) patients had new lesions as disease progression. Among them, 2 (3.8%) patients had CNS disease reported as the first relapse. The most common toxicities were palmar plantar erythrodysesthesia (59.6%), diarrhea (48.1%), rash (48.1%), hyperbilirubinemia (34.6%), and fatigue (30.8%). Exploratory analyses of oncogenic mutations of PIK3CA suggested that of 38 patients providing a tumor sample, baseline PIK3CA mutation status was not associated with CBR (P = 0.639) or PFS (P = 0.989). These data confirm that the lapatinib plus capecitabine combination is an effective and well-tolerated treatment option for Chinese women with heavily pretreated MBC, irrespective of PIK3CA status. PMID- 21527067 TI - Expressions of Toll-like receptors 3, 4, 7, and 9 in cervical lesions and their correlation with HPV16 infection in Uighur women. AB - Recent findings show that Toll-like receptors (TLRs) expressed in immune cells play a crucial role in the innate immune response and the subsequent induction of adaptive immune responses against microbial infection on tissue injury. Furthermore, expression of TLRs in cancer cells is associated with tumor proliferation and invasion. To explore the role of TLRs expression in cervical carcinogenesis in Uighur women, we detected the expressions of TLR3, TLR4, TLR7, and TLR9 in 25 normal cervical tissues, 64 cervical intraepithelial neoplasia (CIN) tissues, and 63 cervical squamous cell carcinoma (CSCC) tissues using immunohistochemical staining, as well as human papillomavirus type 16 (HPV16) infection using PCR. All samples used in this study were from Xinjiang Uighur women. We found the expression levels of TLR4, TLR7, and TLR9 were significantly higher in CIN and CSCC than in normal controls (P < 0.05). Up-regulation of TLR4 and TLR7 were correlated with tumor differentiation but not FIGO stage or lymph node metastasis (P > 0.05). Up-regulation of TLR9 was correlated with lymph node metastasis (P < 0.05) but not tumor differentiation or FIGO stage (P > 0.05). We also analyzed the correlation between the expressions of TLRs and HPV16 infection and found that the expressions of TLR4 and TLR9 significantly correlated with HPV16 infection in CIN (r = 7.434, P = 0.006; r = 7.123, P = 0.008) and CSCC (r = 6.423, P = 0.001; r = 8.478, P = 0.004), whereas the expression of TLR3 was not significantly different in any of the three groups and had no significant correlation with HPV16 infection. Our results suggest that high expression of TLR4, TLR7, and TLR9 may play important roles in the development and progression of CIN and CSCC in Uighur women, and the expressions of TLR4 and TLR9 can be up regulated by HPV16 infection. PMID- 21527068 TI - Radiotherapy of unicentric mediastinal Castleman's disease. AB - Castleman's disease is a slowly progressive and rare lymphoproliferative disorder. Here, we report a 55-year-old woman with superior mediastinal Castleman's disease being misdiagnosed for a long term. We found a 4.3 cm mass localized in the superior mediastinum accompanied with severe clinical symptoms. The patient underwent an exploratory laparotomy, but the mass failed to be totally excised. Pathologic examination revealed a mediastinal mass of Castleman's disease. After radiotherapy of 30 Gy by 15 fractions, the patient no longer presented previous symptoms. At 3 months after radiotherapy of 60 Gy by 30 fractions, Computed tomography of the chest showed significantly smaller mass, indicating partial remission. Upon a 10-month follow-up, the patient was alive and free of symptoms. PMID- 21527069 TI - The intake of fruit and sweets in rural and urban Greenland--development from 1994 to 2006. AB - OBJECTIVES: The aim of this study is to explore the intake of fruit and sweets in Greenlandic schoolchildren aged 11, 13 and 15 years in villages, towns and the capital by cross-sectional data collected in 4 comparative surveys from 1994 to 2006. Study design. Repeated cross-sectional study. METHODS: Data from the Health Behaviour in School-aged Children survey, with responses from 1,302 students in 1994, 1,648 in 1998, 891 in 2002 and 1,366 in 2006, each in the age groups of 11, 13 and 15 years. RESULTS: From 1994 to 2006, the odds ratio for eating fruit daily showed a decline while odds for never eating fruit increased in children living in all types of habitations. For all survey years the intake of fruit was lowest in villages and in 2006 only about 15-20% of village children consumed fruit every day. No general trends were found in the daily intake of sweets or for never eating sweets. Only 6% or less of the respondents never ate sweets. Minor age group and gender differences were seen. For sweets, children in the capital in 2006 had a lower daily use than village children. CONCLUSION: Greenland is in the process of nutritional transition. The increase in the proportion of schoolchildren that do not meet the national recommendations for daily fruit consumption and the failure to reduce children's intake of sweets is worrying. The intake of fruit was, for all years, lowest in the villages and was probably related (among other things) to cost and access. The implications of the findings are discussed. PMID- 21527070 TI - Policy-relevant population health research: new approaches and opportunities. PMID- 21527071 TI - Developing a strategy to promote the generation and effective use of population health research for NSW Health: 2011-2015. AB - The Population Health Division of the NSW Department of Health has developed a 5 year strategy to improve the effectiveness of its resource investment in population health research. This paper describes the development of the strategy, Promoting the generation and effective use of population health research in NSW: a Strategy for NSW Health 2011-2015. A review of Australian and international strategic research documents and stakeholder interviews was conducted to support the development of the strategy. The findings from these two processes influenced the structure of the document and supported the inclusion of strategies and actions to assist with identifying research priorities, improving communication, enhancing networks and partnerships, supporting workforce development initiatives, providing research infrastructure, enhancing research and the use of research evidence and streamlining research governance and ethics processes. Small group discussions and a detailed review of literature were conducted to refine the thinking around four of the more complex aspects of the strategy. Finally, a broad consultation process was used to test the face validity of the proposed strategy content. PMID- 21527072 TI - Fostering population health research in NSW: the role of research infrastructure. PMID- 21527073 TI - The Physical Activity, Nutrition and Obesity Research Group: fostering population health research in NSW. PMID- 21527074 TI - The 45 and Up Study: fostering population health research in NSW. PMID- 21527075 TI - The Centre for Health Record Linkage: fostering population health research in NSW. PMID- 21527076 TI - Ensuring the policy relevance of population health research: experiences from the Drug Policy Modelling Program. AB - Illicit drugs are an important public health concern. A unique approach to tackling this problem is represented in the work of the Drug Policy Modelling Program which aims to improve evidence-informed policy by reducing the gap between research and policy. There are three elements to the Drug Policy Modelling Program: generating new knowledge; translating evidence into information of relevance for decision makers; and studying policy processes. Key aspects include the use of computer modelling as a translational tool and the focus on understanding policy processes such as the role of media and politics, important in contextualising the research-policy nexus. Other features of the Drug Policy Modelling Program approach include engagement of diverse disciplines, and government researcher partnerships. PMID- 21527077 TI - The Australian Rural Health Research Collaboration: building collaborative population health research in rural and remote NSW. AB - The health problems faced by rural and remote communities are complex and not amenable to simple or short-term solutions. The Australian Rural Health Research Collaboration, which comprises rural research centres, area health services and policy makers in NSW, investigates these problems. Founded in 2002, it has grown to become the leading rural research collaboration in Australia. It aims to: conduct high quality research; build the capacity of researchers and clinicians; and encourage the translation of research evidence into practice for the benefit of rural and remote communities. The success of the Collaboration is illustrated by the increase in research outputs, funds generated, the strength of the relationships between partners and the ability to address complex research problems such as the mental health of rural and remote communities often deemed too difficult or expensive to include in metropolitan-based research. Keys to success have been the inclusive public health ethos, the participation of senior researchers and service managers, the critical mass of researchers achieved through collaboration and effective leadership and governance. This demonstrates the value of supporting cooperative research and capacity building in rural and remote areas where the size of research groups is small and where effective multi disciplinary and co-operative research can pay dividends. PMID- 21527078 TI - Population Health Intervention Research Initiative for Canada: progress and prospects. AB - Actions in Canada are being designed to transform the way research evidence is generated and used to improve population health. Capacity is being built in population health intervention research. The primary target is more understanding and examination of policies and programs that could redress inequities in health. The Population Health Intervention Research Initiative for Canada is a loosely networked collaboration designed to advance the science of the field as well as the quantity, quality and use of population health intervention research to improve the health of Canadians. In the first few years there have been new training investments, new funding programs, new working guidelines for peer review, symposia and new international collaborations. This has been brought about by the strategic alignment of communication, planning and existing investments and the leveraging of new resources. PMID- 21527080 TI - Risk communication in public health. PMID- 21527081 TI - Communicable diseases report, NSW, November and December 2010. PMID- 21527083 TI - Self-monitoring of blood glucose and type 2 diabetes: new tricks for the old dog? PMID- 21527084 TI - Virtual reality technologies for research and education in obesity and diabetes: research needs and opportunities. AB - The rising rates, high prevalence, and adverse consequences of obesity and diabetes call for new approaches to the complex behaviors needed to prevent and manage these conditions. Virtual reality (VR) technologies, which provide controllable, multisensory, interactive three-dimensional (3D) stimulus environments, are a potentially valuable means of engaging patients in interventions that foster more healthful eating and physical activity patterns. Furthermore, the capacity of VR technologies to motivate, record, and measure human performance represents a novel and useful modality for conducting research. This article summarizes background information and discussions for a joint July 2010 National Institutes of Health - Department of Defense workshop entitled Virtual Reality Technologies for Research and Education in Obesity and Diabetes. The workshop explored the research potential of VR technologies as tools for behavioral and neuroscience studies in diabetes and obesity, and the practical potential of VR in fostering more effective utilization of diabetes- and obesity related nutrition and lifestyle information. Virtual reality technologies were considered especially relevant for fostering desirable health-related behaviors through motivational reinforcement, personalized teaching approaches, and social networking. Virtual reality might also be a means of extending the availability and capacity of health care providers. Progress in the field will be enhanced by further developing available platforms and taking advantage of VR's capabilities as a research tool for well-designed hypothesis-testing behavioral science. Multidisciplinary collaborations are needed between the technology industry and academia, and among researchers in biomedical, behavioral, pedagogical, and computer science disciplines. Research priorities and funding opportunities for use of VR to improve prevention and management of obesity and diabetes can be found at agency websites (National Institutes of Health: http://grants.nih.gov/grants/guide/index.html; Department of Defense: www.tatrc.org). PMID- 21527085 TI - Behavioral challenges in the management of childhood diabetes. AB - For many individuals, the diagnosis of diabetes is accompanied by the need for significant lifestyle changes, many of which seem difficult or impossible to implement. When diabetes is diagnosed in a child, those lifestyle changes may involve radical alterations in family life and significantly impact the child's normal growth and development as well as the family's social and economic status. This article describes some of the behavioral challenges associated with childhood diabetes and the importance of identifying strong, developmentally appropriate family support. Specific emphases are given to the complexity of the treatment regimens, the physiologic and emotional challenges associated with normal growth and development, and the family's role in ensuring successful diabetes management. Challenges inherent in both type 1 and type 2 diabetes mellitus are discussed as are factors important to ensuring adherence to the treatment plan. PMID- 21527086 TI - Behavioral science in video games for children's diet and physical activity change: key research needs. AB - Innovative intervention programs are needed to overcome the limitations in previous programs that promoted change in diabetes risk behaviors in children. Serious video games show promise of changing dietary and physical activity behaviors, but research is needed on the optimal design of behavior-change procedures in video games, the mechanisms that account for changes obtained, and the groups in which these interventions work best. Such research will permit the optimal design of serious video games for diabetes and obesity prevention in the future. PMID- 21527087 TI - Virtual reality and interactive gaming technology for obese and diabetic children: is military medical technology applicable? AB - The Telemedicine and Advanced Technology Research Center has pursued a number of technologies that may have application to the problems of obesity and diabetes management in children. Children are getting fatter because of increased caloric intake and less physical activity. Furthermore, technology advances have failed to significantly improve metabolic control of type 1 diabetes. Behavioral strategies should target video games, mobile phones, and other popular items used by children and seen by them as necessities. Exergaming is considerably more active than traditional video gaming and can be equivalent to moderate-intensity exercise. Diabetes equipment such as continuous glucose monitors and insulin pumps lack integration and live connectivity and suffer from a poor user interface. In contrast, mobile phones offer wireless connectivity, an excellent voice-enabled interface, and cloud connectivity that could possibly serve as a motivational and compliance tool for diabetes patients through text messaging to the patient, parents, and physician. Mobile phones have the potential to motivate and educate obese children as well. Exergaming for obese children could also be integrated into award systems of game consoles and game play time. The key to successful implementation of these strategies depends on the ability to integrate and connect the various technologies. PMID- 21527088 TI - Turning virtual reality into reality: a checklist to ensure virtual reality studies of eating behavior and physical activity parallel the real world. AB - Virtual reality (VR) provides a potentially powerful tool for researchers seeking to investigate eating and physical activity. Some unique conditions are necessary to ensure that the psychological processes that influence real eating behavior also influence behavior in VR environments. Accounting for these conditions is critical if VR-assisted research is to accurately reflect real-world situations. The current work discusses key considerations VR researchers must take into account to ensure similar psychological functioning in virtual and actual reality and does so by focusing on the process of spontaneous mental simulation. Spontaneous mental simulation is prevalent under real-world conditions but may be absent under VR conditions, potentially leading to differences in judgment and behavior between virtual and actual reality. For simulation to occur, the virtual environment must be perceived as being available for action. A useful chart is supplied as a reference to help researchers to investigate eating and physical activity more effectively. PMID- 21527089 TI - An overview of management issues in adult patients with type 2 diabetes mellitus. AB - Despite some progress in reducing the rate of diabetic complications, the epidemic rise in incidence of diabetes mellitus ensures that there will be an increasing number of patients in the coming decades with complex health care management issues who will need efficient and effective care. The management of patients with diabetes is an ever-challenging endeavor attributable to several factors. These include, among others, (1) limited provider expertise, (2) decreasing time of a patient visit, (3) increasing complexity of drug management, (4) limited use of self-monitoring of blood glucose by patients and/or providers, (5) clinical inertia, and (6) nonadherence. Technology-driven innovative solutions, including those using virtual reality, are desperately needed to assist both patients and their providers in overcoming the exigencies of this protean disease. PMID- 21527090 TI - The science of learning: breaking news. AB - We begin with a paradox. On one hand, not nearly enough is known about exactly how learning takes place in the brain, although exciting new results are emerging thanks to improved brain imaging and a greater focus on neuroscience by government and universities. But this research is just beginning, and a much larger effort and investment are needed to answer even the most basic questions. On the other hand, more than enough is already known about what best promotes learning to motivate and drive educational reform for years to come. This is a report from the front lines of both research and educational implementation. This information should prove of use to anyone--teachers, students, parents, patients, and health practitioners--who is concerned about how best to improve formal or informal teaching and learning, to help people remember complex instructions, or to change unhealthy habits and practices. PMID- 21527082 TI - Recommendations for the transfusion management of patients in the peri-operative period. II. The intra-operative period. PMID- 21527091 TI - Virtual reality and interactive digital game technology: new tools to address obesity and diabetes. AB - The convergence of the exponential advances in virtual reality (VR)-enabling technologies with a growing body of clinical research and experience has fueled the evolution of the discipline of clinical VR. This article begins with a brief overview of methods for producing and delivering VR environments that can be accessed by users for a range of clinical health conditions. Interactive digital games and new forms of natural movement-based interface devices are also discussed in the context of the emerging area of exergaming, along with some of the early results from studies of energy expenditure during the use of these systems. While these results suggest that playing currently available active exergames uses significantly more energy than sedentary activities and is equivalent to a brisk walk, these activities do not reach the level of intensity that would match playing the actual sport, nor do they deliver the recommended daily amount of exercise for children. However, these results provide some support for the use of digital exergames using the current state of technology as a complement to, rather than a replacement, for regular exercise. This may change in the future as new advances in novel full-body interaction systems for providing vigorous interaction with digital games are expected to drive the creation of engaging, low-cost interactive game-based applications designed to increase exercise participation in persons at risk for obesity. PMID- 21527092 TI - What virtual reality research in addictions can tell us about the future of obesity assessment and treatment. AB - Virtual reality (VR), a system of human-computer interaction that allows researchers and clinicians to immerse people in virtual worlds, is gaining considerable traction as a research, education, and treatment tool. Virtual reality has been used successfully to treat anxiety disorders such as fear of flying and post-traumatic stress disorder, as an aid in stroke rehabilitation, and as a behavior modification aid in the treatment of attention deficit disorder. Virtual reality has also been employed in research on addictive disorders. Given the strong evidence that drug-dependent people are highly prone to use and relapse in the presence of environmental stimuli associated with drug use, VR is an ideal platform from which to study this relationship. Research using VR has shown that drug-dependent people react with strong craving to specific cues (e.g., cigarette packs, liquor bottles) as well as environments or settings (e.g., bar, party) associated with drug use. Virtual reality has also been used to enhance learning and generalization of relapse prevention skills in smokers by reinforcing these skills in lifelike environments. Obesity researchers and treatment professionals, building on the lessons learned from VR research in substance abuse, have the opportunity to adapt these methods for investigating their own research and treatment questions. Virtual reality is ideally suited to investigate the link between food cues and environmental settings with eating behaviors and self-report of hunger. In addition, VR can be used as a treatment tool for enhancing behavior modification goals to support healthy eating habits by reinforcing these goals in life-like situations. PMID- 21527093 TI - Extending the reach of health care for obesity and diabetes using virtual worlds. AB - Today's epidemic of obesity and diabetes poses challenges to health care similar to those facing soldiers who return with postdeployment mental health issues. These include geographic barriers, social stigma, and the need for behavioral change. Researchers at University of Southern California's Institute for Creative Technologies are adapting their extensive experience in technological solutions for training to techniques that can aid veterans in need. These techniques show promise for concerns in the growing crisis of "diabesity." Virtual reality (VR) has already demonstrated itself as an impactful treatment method for several behavioral and mental health domains. Virtual worlds, the successor technology of original VR, inherited many of its predecessor's strengths but also presents the new affordances of accessibility, social connectivity, and avatar usage, which pave the way toward future treatment options on a broader scale. PMID- 21527094 TI - New directions in virtual environments and gaming to address obesity and diabetes: industry perspective. AB - Virtual reality is increasingly used for education and treatment in the fields of health and medicine. What is the health potential of virtual reality technology from the software development industry perspective? This article presents interviews with Ben Sawyer of Games for Health, Dr. Walter Greenleaf of InWorld Solutions, and Dr. Ernie Medina of MedPlay Technologies. Games for Health brings together researchers, medical professionals, and game developers to share information on the impact that game technologies can have on health, health care, and policy. InWorld is an Internet-based virtual environment designed specifically for behavioral health care. MedPlay Technologies develops wellness training programs that include exergaming technology. The interviewees share their views on software development and other issues that must be addressed to advance the field of virtual reality for health applications. PMID- 21527096 TI - Integrative gaming: a framework for sustainable game-based diabetes management. AB - Obesity and diabetes have reached epidemic proportions in both developing and developed nations. While doctors and caregivers stress the importance of physical exercise in maintaining a healthy lifestyle, many people have difficulty subscribing to a healthy lifestyle. Virtual reality games offer a potentially exciting aid in accelerating and sustaining behavior change. However, care needs to be taken to develop sustainable models of employing games for the management of diabetes and obesity. In this article, we propose an integrative gaming paradigm designed to combine multiple activities involving physical exercises and cognitive skills through a game-based storyline. The persuasive story acts as a motivational binder that enables a user to perform multiple activities such as running, cycling, and problem solving. These activities guide a virtual character through different stages of the game. While performing the activities in the games, users wear sensors that can measure movement (accelerometers, gyrometers, magnetometers) and sense physiological measures (heart rate, pulse oximeter oxygen saturation). These measures drive the game and are stored and analyzed on a cloud computing platform. A prototype integrative gaming system is described and design considerations are discussed. The system is highly configurable and allows researchers to build games for the system with ease and drive the games with different types of activities. The capabilities of the system allow for engaging and motivating the user in the long term. Clinicians can employ the system to collect clinically relevant data in a seamless manner. PMID- 21527095 TI - The key to unlocking the virtual body: virtual reality in the treatment of obesity and eating disorders. AB - Obesity and eating disorders are usually considered unrelated problems with different causes. However, various studies identify unhealthful weight-control behaviors (fasting, vomiting, or laxative abuse), induced by a negative experience of the body, as the common antecedents of both obesity and eating disorders. But how might negative body image--common to most adolescents, not only to medical patients--be behind the development of obesity and eating disorders? In this paper, I review the "allocentric lock theory" of negative body image as the possible antecedent of both obesity and eating disorders. Evidence from psychology and neuroscience indicates that our bodily experience involves the integration of different sensory inputs within two different reference frames: egocentric (first-person experience) and allocentric (third-person experience). Even though functional relations between these two frames are usually limited, they influence each other during the interaction between long- and short-term memory processes in spatial cognition. If this process is impaired either through exogenous (e.g., stress) or endogenous causes, the egocentric sensory inputs are unable to update the contents of the stored allocentric representation of the body. In other words, these patients are locked in an allocentric (observer view) negative image of their body, which their sensory inputs are no longer able to update even after a demanding diet and a significant weight loss. This article discusses the possible role of virtual reality in addressing this problem within an integrated treatment approach based on the allocentric lock theory. PMID- 21527097 TI - Learning in a virtual environment using haptic systems for movement re-education: can this medium be used for remodeling other behaviors and actions? AB - Robotic systems that are interfaced with virtual reality gaming and task simulations are increasingly being developed to provide repetitive intensive practice to promote increased compliance and facilitate better outcomes in rehabilitation post-stroke. A major development in the use of virtual environments (VEs) has been to incorporate tactile information and interaction forces into what was previously an essentially visual experience. Robots of varying complexity are being interfaced with more traditional virtual presentations to provide haptic feedback that enriches the sensory experience and adds physical task parameters. This provides forces that produce biomechanical and neuromuscular interactions with the VE that approximate real-world movement more accurately than visual-only VEs, simulating the weight and force found in upper extremity tasks. The purpose of this article is to present an overview of several systems that are commercially available for ambulation training and for training movement of the upper extremity. We will also report on the system that we have developed (NJIT-RAVR system) that incorporates motivating and challenging haptic feedback effects into VE simulations to facilitate motor recovery of the upper extremity post-stroke. The NJIT-RAVR system trains both the upper arm and the hand. The robotic arm acts as an interface between the participants and the VEs, enabling multiplanar movements against gravity in a three-dimensional workspace. The ultimate question is whether this medium can provide a motivating, challenging, gaming experience with dramatically decreased physical difficulty levels, which would allow for participation by an obese person and facilitate greater adherence to exercise regimes. PMID- 21527098 TI - Using virtual reality to improve walking post-stroke: translation to individuals with diabetes. AB - Use of virtual reality (VR) technology to improve walking for people post-stroke has been studied for its clinical application since 2004. The hardware and software used to create these systems has varied but has predominantly been constituted by projected environments with users walking on treadmills. Transfer of training from the virtual environment to real-world walking has modest but positive research support. Translation of the research findings to clinical practice has been hampered by commercial availability and costs of the VR systems. Suggestions for how the work for individuals post-stroke might be applied and adapted for individuals with diabetes and other impaired ambulatory conditions include involvement of the target user groups (both practitioners and clients) early in the design and integration of activity and education into the systems. PMID- 21527099 TI - New directions in the use of virtual reality for food shopping: marketing and education perspectives. AB - Virtual reality is used in marketing research to shape food selection and purchase decisions. Could it be used to counteract the marketing of less nutritious foods and teach healthier food selection? This article presents interviews with Raymond Burke, Ph.D., of Indiana University Bloomington, and Rachel Jones, M.P.H., of the University of Utah College of Health. Topics covered include new marketing research technologies, including virtual reality simulations; retailing and shopper behavior; and the use of virtual grocery stores to help students explore quality of diet and food/nutrient relationships. The interviewees discuss how the technologies they have developed fit into research and behavior change related to obesity and diabetes. PMID- 21527100 TI - Celebratory health technology. AB - There are numerous everyday health technologies (applications designed for people to use in their daily lives) that promote healthy eating habits. From educational games to monitoring applications, these systems often take a corrective approach in that they are designed to fix the problematic aspects of people's interactions with, and thoughts about, food. We propose a complementary approach, termed celebratory health technology design, in which systems promote healthy eating by highlighting positive food interactions, meanings, and values. We present a case study from our research to show the benefit and feasibility of designing celebratory health applications. Our goal is to encourage a more comprehensive approach to everyday health technology design, one that encompasses not only corrective systems, but celebratory applications as well. PMID- 21527101 TI - Pilot study of Aurora, a social, mobile-phone-based emotion sharing and recording system. AB - BACKGROUND: Emotion is a ubiquitous aspect of humanity that governs behavior in a number of ways and is linked inextricably with health. Pausing to evaluate one's emotional state in the face of decisions and reflecting on past patterns of emotion have been shown to improve behaviors. Further, social expression of emotion has been shown to directly improve health outcomes. While the virtual reality research community does not ignore emotion on the whole, there does exist a need to explore what roles emotional awareness and emotion sharing can play in this domain. METHODS: A mobile-phone-based social emotion recording and sharing system, Aurora, was developed to provide individuals with a means to pause and evaluate their emotional state, reflect on past emotions, share emotions with others, and participate in socially supportive activities with peers. A study was conducted with 65 subjects to evaluate Aurora as a tool to encourage emotional reflection and awareness as well as social sharing of emotion. RESULTS: Users of Aurora reported an increased comfort in socially expressing emotion and were encouraged to share emotions, even with strangers. Subjects also reported liking reflecting on their emotional state and found it valuable. Subjects' behavior also suggested that the system encouraged individuals to reach out to one another in acts of social support. CONCLUSIONS: The Aurora system offers a tool for encouraging emotional awareness, emotion sharing, and socially supportive behavior. Such a tool could be impactful in numerous health settings where emotion is considered to be an important indicator of or influence on outcome, such as for weight loss, alcohol cessation, or cancer sufferers. PMID- 21527102 TI - Application of virtual reality methods to obesity prevention and management research. AB - There is a great need for empirical evidence to inform clinical prevention and management of overweight and obesity. Application of virtual reality (VR) methods to this research agenda could present considerable advantages. Use of VR methods in basic and applied obesity prevention and treatment research is currently extremely limited. However, VR has been employed for social and behavioral research in many other domains where it has demonstrated validity and utility. Advantages of VR technologies as research tools include the ability to situate hypothetical research scenarios in realistic settings, tight experimental control inherent in virtual environments, the ability to manipulate and control any and all scenario elements, and enhanced behavioral measurement opportunities. The means by which each of these features could enhance obesity prevention and management research is discussed and illustrated in the context of an example research study. Challenges associated with the application of VR methods, such as technological limitations and cost, are also considered. By employing experimental VR methods to interrogate clinical encounters and other health related situations, researchers may be able to elucidate causal relationships, strengthen theoretical models, and identify potential targets for intervention. In so doing, researchers stand to make important contributions to evidence-based practice innovation in weight management and obesity prevention. PMID- 21527103 TI - The potential of virtual reality technologies to improve adherence to weight loss behaviors. AB - A significant proportion of the global population is obese, foreshadowing an epidemic of chronic disease. Self-monitoring (of diet, exercise, and body weight), decreasing energy intake, and increasing energy expenditure are robust predictors of successful weight loss. However, few individuals consistently practice these behaviors, making long-term weight loss and maintenance unlikely. Technologies afford unique opportunities to overcome barriers and increase the reach of traditional obesity interventions. In this article, we introduce ENGAGED, a technology-enhanced modification of the Diabetes Prevention Program designed to improve adherence to weight loss behaviors. Using a treatment implementation framework, we suggest how virtual reality technologies might further improve the delivery, receipt, and enactment of ENGAGED to maximize patient impact. PMID- 21527104 TI - Automated near-continuous glucose monitoring measured in plasma using mid infrared spectroscopy. AB - OBJECTIVE: There are increasing calls for a precise, automated system to enable tight glycemic control and to avoid hypoglycemia in an intensive care unit setting. OptiScan Biomedical has developed a glucose monitor based on mid infrared spectroscopy that withdraws blood samples (120 ul) and measures plasma glucose. The goal of this study was to validate the performance of the OptiScan Model 5000 over a wide range of glycemic levels in patients. RESEARCH DESIGN AND METHODS: Sixty people with type 1 (n = 18) or type 2 (n = 42) diabetes who were otherwise healthy were connected to OptiScanners. Their blood glucose concentrations were kept in a euglycemic, hypoglycemic (<75 mg/dl), and hyperglycemic (>180 mg/dl) range by intravenous administrations of insulin and glucose. OptiScanner venous blood samples were automatically withdrawn every 15 minutes. Reference measurements were done using the YSI 2300 glucose analyzer. RESULTS: The aggregate data points (1155 paired readings) were within International Organization for Standardization standards, with 98.6% of the glucose values within +/-20% above 75 mg/dl and +/-15 mg/dl below this value. A Clarke error grid analysis showed a total of 1139 points (98.6%) in zone A. Points outside of A exceeded the A zone boundary by an average of 4.3%. The r(2) was 0.99. The total coefficient for variance was 6.4%. CONCLUSIONS: These results show that the OptiScanner is highly accurate in healthy patients with diabetes across a wide range of glucose values. Mid-infrared spectroscopy may become the method of choice for highly accurate, high frequency, automated glucose measurements and may thus enable better glycemic control in critically ill patients. PMID- 21527105 TI - Assessment of blood glucose control in the pediatric intensive care unit: extension of the glycemic penalty index toward children and infants. AB - BACKGROUND: The glycemic penalty index (GPI) is a measure to assess blood glucose (BG) control in critically ill adult patients but needs to be adapted for children and infants. METHOD: The squared differences between a clinical expertise penalty function and the corresponding polynomial function are minimized for optimization purposes. The average of all penalties (individually assigned to all BG readings) represents the patient-specific GPI. RESULTS: Penalization in the hypoglycemic range is more severe than in the hyperglycemic range as the developing brains of infants and children may be more vulnerable to hypoglycemia. Similarly, hypoglycemia is also more heavily penalized in infants than in children. CONCLUSIONS: Extending the adult GPI toward the age-specific GPI is an important methodological step. Long-term clinical studies are needed to determine the clinically acceptable GPI cut-off level. PMID- 21527106 TI - Accuracy performance of the Medtronic NexSensorTM for 6 days in an inpatient setting using abdomen and buttocks insertion sites. AB - BACKGROUND: Users of continuous glucose monitoring are concerned with product accuracy and choice of insertion site. The Medtronic NexSensorTM was evaluated for accuracy during 6 days of wear when inserted in the abdomen and buttocks areas. METHODS: Adults (ages 18-75) with type 1 diabetes wore two sensors simultaneously for 6 days, one each inserted in the abdomen and buttocks. Subjects underwent a frequent blood sampling study for 12 hours, during which time reference blood glucose values were obtained every 15 minutes and compared to sensor values. RESULTS: Sixty-three subjects were enrolled, and 61 subjects completed the study. The mean agreement rate between sensor and blood glucose values was 75.5% [95% confidence interval (CI), 69.5, 81.4] at the abdomen site, 73.8% (95% CI, 68.8, 78.8) at the buttocks site, and 75.6% (95% CI, 70.8, 80.4) when sensor and reference data were combined between sites. Over 90% of paired sensor-reference values on Clarke error grids were within the A and B ranges. The mean absolute relative differences were 17.1% at the abdomen site, 16.5% at the buttocks site, and 16.8% when sites were combined. CONCLUSION: The NexSensor was accurate for inpatient, frequent-sample testing for 6 days when inserted into the abdomen and buttocks. The results of this study also provide evidence that both the abdomen and buttocks are suitable as sensor insertion sites. PMID- 21527107 TI - Analysis: accuracy performance of the Medtronic NexSensor for 6 days in an inpatient setting using abdomen and buttocks insertion sites. AB - In an article in this issue of Journal of Diabetes Science and Technology, Peoples and colleagues address the issue that, while continuous glucose sensors have been shown to improve hemoglobin A1c, they are still fraught with concerns regarding accuracy and flexibility in sensor placement. Their study aimed to evaluate whether NexSensor, an improved version of the already commercially available Sof-Sensor, can be used for 6 days instead of the 3 days approved for Sof-Sensor in the United States. Also, the article aims to compare the accuracy of wearing the sensor in the abdomen versus the buttocks, given that this offers more flexibility than the approved labeling for Sof-Sensor, which is only in the abdomen. The study demonstrated that NexSensor is both safe and accurate for 6 days at both insertion sites. There was no statistically significant difference between the sites. As far as improved accuracy, the authors find evidence in favor of NexSensor as compared to Sof-Sensor, although this evidence is preliminary and is not backed by statistical significance measures. PMID- 21527108 TI - A closed-loop artificial pancreas based on risk management. AB - BACKGROUND: Control algorithms that regulate blood glucose (BG) levels in individuals with type 1 diabetes mellitus face several fundamental challenges. Two of these are the asymmetric risk of clinical complications associated with low and high glucose levels and the irreversibility of insulin action when using only insulin. Both of these nonlinearities force a controller to be more conservative when uncertainties are high. We developed a novel extended model predictive controller (EMPC) that explicitly addresses these two challenges. METHOD: Our extensions to model predictive control (MPC) operate in three ways. First, they explicitly minimize the combined risk of hypoglycemia and hyperglycemia. Second, they integrate the effect of prediction uncertainties into the risk. Third, they understand that future control actions will vary if measurements fall above or below predictions. Using the University of Virginia/Padova Simulator, we compared our novel controller (EMPC) against optimized versions of a proportional-integral-derivative (PID) controller, a traditional MPC, and a basal/bolus (BB) controller, as well as against published results of an independent MPC (IMPC). The BB controller was optimized retrospectively to serve as a bound on the possible performance. RESULTS: We tuned each controller, where possible, to minimize a published blood glucose risk index (BGRI). The simulated controllers (PID/MPC/EMPC/BB) provided BGRI values of 2.99/3.05/2.51/1.27 as compared to the published IMPC BGRI value of 4.10. These correspond to 73/79/84/92% of BG values lying in the euglycemic range (70-180 mg/dl), respectively, with mean BG levels of 151/156/147/140 mg/dl. CONCLUSION: The EMPC strategy extends MPC to explicitly address the issues of asymmetric glycemic risk and irreversible insulin action using estimated prediction uncertainties and an explicit risk function. This controller reduces the avoidable BGRI by 56% (p < .05) relative to a published MPC algorithm studied on a similar population. PMID- 21527109 TI - Noninvasive polarimetric-based glucose monitoring: an in vivo study. AB - BACKGROUND: Since 1990, there has been significant research devoted toward development of a noninvasive physiological glucose sensor. In this article, we report on the use of optical polarimetry for the noninvasive measurement of physiological glucose concentration in the anterior chamber of the eye of New Zealand white (NZW) rabbits. METHOD: Measurements were acquired using a custom designed laser-based optical polarimetry system in a total of seven NZW rabbits anesthetized using an isoflurane-only anesthesia protocol. Aqueous humor-based polarimetric measurements were obtained by coupling light through the anterior chamber of the eye. Blood glucose levels were first stabilized and then altered with intravenous dextrose and insulin administration and measured every 3-5 min with a standard glucometer and intermittently with a YSI 2300 glucose analyzer. Acquired polarimetric glucose signals are calibrated to measured blood glucose concentration. RESULTS: Based on a total of 41 data points, Clarke error grid analysis indicated 93% in zone A, 7% in zone B, and 0% in zones C and D, with reference concentrations between 93 and 521 mg/dl. Errors in prediction are shown to be related to gross movement of the rabbit during the procedures, incurring time-varying corneal birefringence effects that directly affect the measured polarimetric signal. These effects can be compensated for with appropriate design modifications. CONCLUSIONS: An optical polarimetry technique was used for in vivo physiological glucose monitoring. The technique demonstrated provides a basis for the development of a noninvasive polarimetric glucose monitor for home, personal, or hospital use. PMID- 21527110 TI - Effects of a structured self-monitoring of blood glucose method on patient self management behavior and metabolic outcomes in type 2 diabetes mellitus. AB - BACKGROUND: The purpose of this study was to evaluate the effect of structured self-monitoring of blood glucose (SMBG) on patient self-management behavior and metabolic outcomes in patients with type 2 diabetes mellitus (T2DM). METHODS: From January to June 2009, 30 patients with basic diabetes education were followed for a period of 90 days. To provide assessment of glycemic control and frequency of dysglycemia, patients, underwent 3 consecutive days of seven-point SMBG during each month for 3 consecutive months, using the ACCU-CHEK 360 degrees View tool. Glucose profiles of the first and third month were used for comparison. RESULTS: Hemoglobin A1c (HbA1c) improved significantly during the 90 day period in all patients [confidence interval (CI) 95%, 0.32-1.64%, p < .05] and those with poor metabolic control (group B; CI 95%, 0.86-2.64%, p < .05). Mean blood glucose (MBG) values decreased significantly in group B (CI 95%, 0.56 24.78 mg/dl, p < .05) and all cases (CI 95%, 1.61-19.73 mg/dl, p < .05). Meanwhile, there was an average decrease of 15.7 mg/dl in fasting blood sugar (FBS) levels in the whole subjects. Mean postprandial blood glucose levels (MPP) decreased by 19.3 and 11.3 mg/dl in group B and in all cases, respectively. However, there were no significant changes in HbA1c, MBG, FBS, and MPP in people with good metabolic control. CONCLUSION: A structured SMBG program improves HbA1c, FBS, MPP, and MBG in people with poorly controlled diabetes. This improvement shows the importance of patient self-management behavior on metabolic outcomes in T2DM. PMID- 21527111 TI - Self-monitoring technologies for type 2 diabetes and the prevention of cardiovascular complications: perspectives from end users. AB - BACKGROUND: The objective of this study was to explore facilitators and barriers to the adoption of self-monitoring devices in individuals with type 2 diabetes mellitus (T2DM). METHODS: Individuals with T2DM who were currently using one or more devices to monitor their disease participated in focus groups. Transcripts of focus group meetings were coded into themes by two reviewers using NVivo qualitative software. RESULTS: Twenty-eight adults with T2DM reported using a blood glucose meter, and almost half reported monitoring their blood pressure. Few individuals consistently monitored other aspects of their cardiovascular health. Four major themes impacting device use/disuse were identified: knowledge gaps, relationships with health care providers, environment, and personal experience. Knowledge barriers included lack of information regarding diabetes and the associated risk of complications. Perceptions of inconvenience, pain, and financial restrictions were important factors influencing the adoption, use, and abandonment of self-monitoring devices. Community-run programs, as well as dieticians and pharmacists, were identified as important resources for accessing information related to T2DM. CONCLUSIONS: We identified the need for development of accessible and relevant education material; improved communication of disease specific information between patients and providers, as well as providers and community resources; and strategies to improve the convenience and cost of monitoring devices. PMID- 21527112 TI - Design of a decision support system to help clinicians manage glycemia in patients with type 2 diabetes mellitus. AB - OBJECTIVE: We sought to develop a computerized clinical decision support for clinicians treating patients with type 2 diabetes mellitus (T2DM). METHODS: We designed, developed, and tested a computer-assisted decision support (CADS) system using statistical analyses of self-monitoring of blood glucose data, laboratory data, medical and medication history, and individualized hemoglobin A1c goals. A rule-based expert system generated recommendations for changes in therapy and accompanying explanations. RESULTS: A clinical decision support system (CADS) was developed that considers 9 classes of medications and 69 regimens with combinations of up to 4 therapeutic agents. The preferred sequences of regimens can be customized. The program is integrated with a "comprehensive diabetes management system," electronic medical record systems, and a method for uploading data from memory glucose meters via telephone without use of a computer or the Internet. The software provides a report to the clinician regarding the overall quality of glycemic control and identifies problems, e.g., hypoglycemia, hyperglycemia, glycemic variability, and insufficient data. The program can recommend continuation of current therapy, adjustment of dosages of current medications, or change of regimen and can provide explanations for its recommendations. If the user rejects the recommendations, the program will recommend alternative approaches. The CADS also provides access to Food and Drug Administration-approved prescribing information, guidelines from professional organizations, and selections from the general medical literature. The system has been extensively tested with real and synthetic data and is ready for evaluation in multicenter clinical trials. CONCLUSION: A clinical decision support system to assist with the management of patients with T2DM was designed, developed, tested, and found to perform well. PMID- 21527113 TI - Perioperative hyperglycemia and postoperative infection after lower limb arthroplasty. AB - BACKGROUND: One of the most serious complications after major orthopedic surgery is deep wound or periprosthetic joint infection. Various risk factors for infection after hip and knee replacement surgery have been reported, including patients' comorbidities and surgical technique factors. We investigated whether hyperglycemia and diabetes mellitus (DM) are associated with infection that requires surgical intervention after total hip and knee arthroplasty. METHODS: We reviewed our computerized database for elective primary total hip and knee arthroplasty from 2000 to 2008. Demographic information, past medical history of patients, perioperative biochemistry, and postoperative complications were reviewed. Patients were divided into two groups: infected group (101 patients who had surgical intervention for infection at our institution within 2 years after primary surgery) and noninfected group (1847 patients with no intervention with a minimum of one year follow-up. The data were analyzed using t, chi-squared, and Fisher's exact tests. RESULTS: There were significantly more diabetes patients in the infected group compared with the noninfected group (22% versus 9%, p < .001). Infected patients had significantly higher perioperative blood glucose (BG) values: preoperative BG (112 +/- 36 versus 105 +/- 31 mg/dl, p = .043) and postoperative day (POD) 1 BG (154 +/- 37 versus 138 +/- 31 mg/dl, p < .001). Postoperative morning hyperglycemia (BG >200 mg/dl) increased the risk for the infection more than two-fold. Non-DM patients were three times more likely to develop the infection if their morning BG was >140 mg/dl on POD 1, p = .001. Male gender, higher body mass index, knee arthroplasty, longer operative time and hospital stay, higher comorbidity index, history of myocardial infarction, congestive heart failure, and renal insufficiency were also associated with the infection. CONCLUSIONS: Diabetes mellitus and morning postoperative hyperglycemia were predictors for postoperative infection following total joint arthroplasty. Even patients without a diagnosis of DM who developed postoperative hyperglycemia had a significantly increased risk for the infection. PMID- 21527114 TI - Indian Diabetes Risk Score helps to distinguish type 2 from non-type 2 diabetes mellitus (GDRC-3). AB - AIM: The aim of this study was to investigate whether the Indian Diabetes Risk Score (IDRS) could assist in classifying type 2 diabetes mellitus (T2DM) and non T2DM among patients attending clinics in India. METHODS: Patient records from 2006 through 2009 were taken from the clinical database of a tertiary care diabetes hospital in Chennai, Southern India. A total of 8747 patients with diabetes, diagnosed by a physician either as type 1 diabetes mellitus (T1DM), T2DM, or other types were included for analysis. The IDRS, based on age, abdominal obesity, family history of diabetes, and physical activity, was calculated for each patient at first visit to our clinic. Receiver operating characteristic (ROC) curves were generated to obtain optimal IDRS cut points for predicting T2DM and non-T2DM. RESULTS: Of the 8747 patient records analyzed, 204 (2.3%) were classified as non-T2DM and 8543 (97.7%) as T2DM. In ROC analysis, an IDRS >=60 [area under the curve (AUC), 0.894; sensitivity, 83.8%; specificity, 81.0%] was predictive of T2DM, while an IDRS <60 (AUC, 0.882; sensitivity, 79.9%; specificity, 83.8%) was predictive of non-T2DM. CONCLUSIONS: The IDRS, a simple, cost-effective risk score, can assist in classifying T2DM versus non-T2DM among clinic patients in India. PMID- 21527116 TI - Food and Drug Administration guidance: supervisory responsibilities of investigators. AB - Conducting clinical trials for diabetes can present researchers with a number of regulatory questions. The Food and Drug Administration (FDA) has increased regulatory enforcement at clinical sites, with an increased emphasis on oversight by principal investigators (PIs; referred to by the FDA as the clinical investigator). The FDA has issued a guidance document, "Guidance for Industry: Investigator Responsibilities-Protecting the Rights, Safety, and Welfare of Study Subjects" (2009), to assist investigators and sponsors. This guidance document breaks new ground regarding the FDA's expectations for investigator oversight of subinvestigators and study staff. The guidance document corresponds with a sharp increase in FDA warning letters to PIs for noncompliance with good clinical practice regulatory requirements. For the first time, an FDA guidance document discusses issues such as the delegation of authority, standard operating procedures, and training of study staff. The FDA provides specific examples with particular emphasis given to appropriate delegation of duties by the PI and ensuring that the clinical staff entrusted to carry out the trial has had adequate training and experience in order to allow them to perform the designated tasks. PMID- 21527115 TI - The fixed combination of pioglitazone and metformin improves biomarkers of platelet function and chronic inflammation in type 2 diabetes patients: results from the PIOfix study. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by a proinflammatory and procoagulant condition. This study investigates the impact of a pioglitazone plus metformin therapy on biomarkers of inflammation and platelet activation in comparison to a treatment with glimepiride plus metformin. METHODS: The study was designed as a multicenter, randomized, double-blinded two-arm trial. Patients with T2DM and dyslipidemia under metformin monotherapy with hemoglobin A1c value between 6.5% and 9.0% were eligible for trial participation. Blood was drawn at baseline and after 24 weeks of treatment from patients of five centers. Markers of inflammation and thrombocyte function (soluble CD40 ligand, thromboxane, vWillebrand factor, adhesion molecules, clotting reaction) were evaluated subsequently in a central laboratory. RESULTS: A total of 46 patients were included in the final analyses. Mean (+/- standard deviation) age was 58.5 +/- 9.0 years (13 women, 33 men; disease duration 6.3 +/- 5.0 years; body mass index 32.0 +/- 4.8 kg/m(2)). A total of 25 patients were treated with pioglitazone plus metformin, and 21 patients were in the glimepiride arm. There was a significant decline of E-selectin (-3.7 +/- 4.8 ng/ml, p < .001 versus baseline), vWillebrand factor (-19.5 +/- 32.0%, p < .05), and high-sensitivity C-reactive protein concentrations (-1.08 +/- 0.91 mg/liter, p < .05) in the metformin + pioglitazone arm only (metformin + glimepiride, -0.5 +/- 3.4 ng/ml, +1.4 +/- 33.2%, + 0.08 +/- 0.72 mg/liter, respectively, all not significant). Also, all other surrogate markers for platelet function and inflammation showed slight improvements in the metformin + pioglitazone arm but not in the metformin + glimepiride arm. CONCLUSIONS: The fixed metformin + pioglitazone combination treatment showed an overall improvement of laboratory surrogate markers, indicating improvement of platelet function and of chronic systemic inflammation, which was not seen with metformin + glimepiride. PMID- 21527117 TI - Prevalence and clinical profile of metabolic obesity and phenotypic obesity in Asian Indians. AB - BACKGROUND: We estimated the prevalence of metabolically obese nonobese (MONO), metabolically obese obese (MOO), and metabolically healthy obese (MHO) individuals and correlated this with the prevalence of coronary artery disease (CAD) compared to metabolically healthy nonobese (MHNO) in urban South Indians. METHOD: Study subjects (n = 2350) were recruited from the Chennai Urban Rural Epidemiology Study. Generalized obesity was defined as a body mass index (BMI) >=25 kg/m(2), based on the World Health Organization Asia Pacific guidelines. Metabolic syndrome (MS) was diagnosed based on the South Asian Modified-National Cholesterol Education Programme criteria. Coronary artery disease was defined by known myocardial infarction or Q waves on resting electrocardiogram. RESULTS: Metabolically obese nonobese was defined as nonobese subjects (BMI < 25 kg/m(2)) with MS, MOO as obesity (BMI >= 25 kg/m(2)) with MS, MHO as obese subjects (BMI >= 25 kg/m(2)) with no MS, and MHNO as no obesity or MS. Metabolically obese nonobese was identified in 355 (15.1%), MOO in 348 (14.8%), MHO in 312 (13.3%), and MHNO in 1335 (56.8%) subjects. The prevalence of CAD among the MONO, MOO, MHO, and MHNO was 5.5%, 4.2%, 1.4%, and 2.6%. However, when age standardization was done, there was no statistically significant increase in the risk of CAD among MONO [odds ratio (OR) = 1.300, 95% confidence interval (CI) 0.706-2.394, p = .339], MOO (OR = 1.651, 95% CI 0.852-3.199, p = .137), and MHO (OR = 0.524, 95% CI 0.250-2.130, p = .564) groups compared to MHNO, perhaps due to small numbers. CONCLUSION: Metabolic obesity may have different clinical implications than phenotypic obesity. PMID- 21527118 TI - GlyCulator: a glycemic variability calculation tool for continuous glucose monitoring data. AB - Glycemic variability has become a major concern over the years as growing evidence is gathered on its detrimental impact on the risk of diabetes complications. Glycated hemoglobin, although ubiquitous in clinical practice, does not adequately summarize short-term glycemic variability. This gap may be addressed through the use of continuous glucose monitoring, which continuously estimates glycemia based on interstitial fluid glucose concentration. As the amount of collected data is substantial, variability of the glycemic pattern can be analyzed in context of its direction, periodicity, and amplitude. As freely available variability calculation tools are limited in number and complexity, the authors have devised a simple-to-use Web-based application, "GlyCulator," allowing for rapid computation of glucose variability parameters from continuous glucose monitoring data. PMID- 21527119 TI - Treatment adherence in schizophrenia and schizoaffective disorder. AB - Medication nonadherence is common and difficult to detect in patients with schizoaffective disorder and schizophrenia. Roughly 50% of patients take less than 70% of prescribed doses. Many factors contribute to nonadherence, including poor illness insight, a negative attitude toward medication, substance abuse, and disorganization. Interventions to improve adherence consist of advising acceptance of illness, drawing analogies with treatment for chronic medical disease, and involving the patient in decision making. Clinicians must remain nonjudgmental, encouraging patients to disclose problems with adherence and anticipating that improvement in adherence may require a prolonged effort. Selection of medication is critical to avoid side effects and to provide a sense of well-being, which can result from improvement in insomnia, anxiety, or depression. Depot antipsychotics can improve adherence and provide the clinician with reliable information about the dosage of medication received for purposes of dose adjustments or to guide response to relapse. PMID- 21527120 TI - Challenges and algorithm-guided treatment in major depressive disorder. AB - Major depressive disorder is complicated and difficult to treat, primarily because of its chronic and recurrent nature and the poor efficacy of most pharmacologic treatment options. Until more effective treatments become available, clinicians must focus on optimizing patient outcomes through patient care. Implementing measurement-based care and using treatment algorithms can reduce symptoms of depression and help patients achieve and maintain remission. PMID- 21527121 TI - Performance improvement CME: adult ADHD. AB - Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders and is now understood to be a lifelong condition for most individuals. Unfortunately, many adults with ADHD are not being diagnosed, possibly due to insufficient diagnostic criteria, the complex presentation of the disorder, and a reluctance by physicians to diagnose the disorder in adults. Additionally, many of those who have been diagnosed with ADHD do not receive adequate treatment despite the availability of established and effective agents. Performance Improvement CME (PI CME) is an educational activity in which clinicians retrospectively assess their current clinical practice, choose areas for improvement and implement interventions based on treatment guidelines and health care standards, and then re-evaluate their clinical practice to assess the improvements made. This PI CME activity focuses on improving the diagnosis and treatment of adult ADHD. PMID- 21527122 TI - A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. AB - OBJECTIVE: To evaluate the efficacy, and further establish the safety profile, of oral once-daily vilazodone, a potent and selective serotonin 1A receptor partial agonist and reuptake inhibitor, in the treatment of major depressive disorder (MDD). METHOD: This phase 3, randomized, double-blind, placebo-controlled, 8-week study (conducted March 2008-February 2009) enrolled 481 adults with DSM-IV-TR defined MDD. Patients received vilazodone (titrated to 40 mg/d) or placebo. The primary efficacy endpoint was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to end of treatment. Secondary efficacy measures included MADRS and 17-item Hamilton Depression Rating Scale (HDRS-17) response and change in HDRS-17, HDRS-21, Hamilton Anxiety Rating Scale (HARS), Clinical Global Impressions-Severity of Illness (CGI-S), and Clinical Global Impressions-Improvement (CGI-I) scores. The Changes in Sexual Functioning Questionnaire (CSFQ) was administered at baseline and week 8. RESULTS: Vilazodone treated patients had significantly greater improvement (P = .009) according to the MADRS than placebo patients (intent-to-treat; least-squares mean changes: 13.3, -10.8). MADRS response rates were significantly higher with vilazodone than placebo (44% vs 30%, P = .002). Remission rates for vilazodone were not significantly different based on the MADRS (vilazodone, 27.3% vs placebo, 20.3%; P = .066) or HDRS-17 (vilazodone, 24.2% vs placebo, 17.7%; P = .088). Vilazodone treated patients had significantly greater improvements from baseline in HDRS-17 (P = .026), HDRS-21 (P = .029), HARS (P = .037), CGI-S (P = .004), and CGI-I (P = .004) scores than placebo patients. Rates of discontinuation due to adverse events were 5.1% (vilazodone) and 1.7% (placebo). The most common adverse events (vilazodone vs placebo) were diarrhea (31% vs 11%), nausea (26% vs 6%), and headache (13% vs 10%). Treatment-related effects on sexual function as measured by the CSFQ were small and similar to placebo. Effects on weight were no different from placebo. CONCLUSIONS: Vilazodone 40 mg/d was well tolerated and effective in adult patients with MDD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00683592. PMID- 21527123 TI - Exploratory analyses of efficacy data from major depressive disorder trials submitted to the US Food and Drug Administration in support of new drug applications. AB - OBJECTIVE: There has been concern about a high rate of placebo response and a substantial failure rate in recent clinical trials in major depressive disorder (MDD). This report explores differences in efficacy data from placebo-controlled MDD trials submitted in support of new drug applications (NDAs) over a 25-year period. METHOD: We compiled efficacy data from 81 randomized, double-blind clinical trials, with 21,611 evaluable patients, that were submitted to the US Food and Drug Administration as part of NDAs for an antidepressant claim between 1983 and 2008. Trial data were limited to completed, randomized, multicenter, double-blind, placebo-controlled clinical trials in adult patients diagnosed with MDD according to DSM-III or DSM-IV criteria. The database was further limited to patients who were involved in clinical trials for drugs widely viewed as effective antidepressants and for doses of these drugs also viewed as effective doses. Trials were rated as successful if they showed statistical superiority vs placebo for the investigational drug on change in Hamilton Depression Rating Scale (HDRS) score (last-observation-carried-forward data). (Trials with multiple investigational drug groups were successful if there was superiority in at least 1 drug group after adjustment for multiplicity.) In particular, we explored differences in effect size and success rate of these trials, based on when the studies were conducted, geographic location of the study sites (US vs non-US), trial duration, dosing regimen, study size, and baseline disease characteristics. RESULTS: Eighty-one percent of MDD patients were enrolled in US sites. Although the observed placebo and drug responses at non-US sites tended to be larger than at US sites, the treatment effect (drug-placebo difference) was similar (mean change from baseline of about -2.5 units in HDRS total score) in US and non-US trials. In both US and non-US trials, the placebo response showed a modest increase over the observation period (1983-2008). Treatment effect clearly diminished over this same period, at a similar rate for both US and non-US trials despite a marked increase in the sample size of the trials. Our analysis showed that 53% of all MDD trials in the last 25 years were successful. US trials had a higher success rate than non-US trials (58% vs 33%). Before 1995, the overall success rate was 55%, compared to 50% for trials in 1995 or later, and, in general, 6-week trials had a higher success rate than 8-week trials (55% vs 42%). It should be noted that the earlier trials were mostly 6 weeks, and the 6-week trials had higher mean baseline HDRS scores than the 8-week trials. Study size did not seem to influence trial success rates. Mean baseline HDRS total scores declined over the 25-year observation period for patients in both US and non-US trials, as did treatment effect in these trials, again, regardless of region. Fixed-dose trials had a numerically slightly greater success rate than flexible dose trials (57% vs 51%), although on average treatment effect was numerically larger in the flexible-dose trials than in fixed-dose trials (mean of -2.9 vs 2.0 on HDRS units). CONCLUSIONS: Treatment effect has declined over time in MDD trials, and there has been a high failure rate for these trials during the entire period, but the reasons for these findings remain elusive. Baseline disease severity seems to be a more important factor in study outcome than study duration, dosing regimen, sample size, time when studies were conducted, and regions where data were generated. Close attention is needed to a variety of factors in the design and conduct of these studies, including patient population, diagnostic considerations, patient assessment, and clinical practice differences. These considerations become increasingly important as globalization of clinical trials continues to increase. PMID- 21527124 TI - The impact of stimuli on affect in persons with dementia. AB - OBJECTIVE: To examine how presentation of different stimuli impacts affect in nursing home residents with dementia. METHOD: Participants were 193 residents aged 60 to 101 years from 7 Maryland nursing homes who had a diagnosis of dementia (derived from the medical chart or obtained from the attending physician). Cognitive functioning was assessed via the Mini-Mental State Examination (MMSE), and data pertaining to activities of daily living were obtained through the Minimum Data Set. Affect was assessed using observations of the 5 moods from Lawton's Modified Behavior Stream. Baseline observations of affect were performed for comparisons. During the study, each participant was presented with 25 predetermined engagement stimuli in random order over a period of 3 weeks. Stimuli were categorized as live social, simulated social, manipulative, work/task-related, music, reading, or individualized to the participant's self-identity. The dates of data collection were 2005-2007. RESULTS: Differences between stimulus categories were significant for pleasure (F(6,144) = 25.137, P < .001) and interest (F(6,144) = 18.792, P < .001) but not for negative affect. Pleasure and interest were highest for the live social category, followed by self-identity and simulated social stimuli for pleasure, and for manipulative stimuli in terms of the effect on interest. The lowest levels of pleasure and interest were observed for music. Participants with higher cognitive function had significantly higher pleasure (F(1,97) = 6.27, P < .05). Although the general trend of the impact of the different categories was similar for different levels of cognitive function, there were significant differences in pleasure in response to specific stimuli (interaction effect: F(6,92) = 2.31, P < .05). Overall, social stimuli have the highest impact on affect in persons with dementia. CONCLUSIONS: The findings of the present study are important, as affect is a major indicator of quality of life and this study is the first to systematically examine the impact of specific types of stimuli on affect. As live social stimuli are not always readily available, particularly in busy nursing home environments, simulated social stimuli can serve as an effective substitute, and other stimuli should have a role in the activity tool kit in the nursing home. The relative ranking of stimuli was different for interest and pleasure. The findings demonstrate the differential effect of presentation of different types of stimuli on the affect of persons with dementia, and that, while the impact is greater on persons with higher levels of cognitive function, there is a different effect of varying stimuli even in persons with MMSE scores of 3 or lower. Future research should attempt to ascertain a person's degree of interest in stimuli prior to developing an intervention. PMID- 21527125 TI - Risk of arrest in persons with schizophrenia and bipolar disorder in a Florida Medicaid program: the role of atypical antipsychotics, conventional neuroleptics, and routine outpatient behavioral health services. AB - OBJECTIVE: To examine (1) arrest outcomes for adults with schizophrenia and bipolar disorder who were treated with first-generation antipsychotics (FGAs) or second-generation atypical antipsychotics (SGAs) and (2) the interaction between medication class and outpatient services in a Florida Medicaid program. METHOD: In a secondary data analysis, Florida Medicaid data covering the period from July 1, 2002, to March 31, 2008, were used to identify persons diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder and to examine antipsychotic medication episodes lasting at least 60 days. There were 93,999 medication episodes in the population examined (N = 36,519). Medication episodes were coded as (1) SGA-aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, risperidone long-acting therapy, or ziprasidone; or (2) FGA-any other antipsychotic medication. Outpatient services were defined as the proportion of 30-day periods of each medication episode with at least 1 behavioral health visit. Survival analyses were used to analyze the data, and they were adjusted for the baseline propensity for receiving an SGA. RESULTS: Second-generation antipsychotic episodes were not associated with reduced arrests compared to FGA episodes; however, the interaction between outpatient services and SGA episodes was significant (hazard ratio [HR] = 0.68; 95% CI, 0.50-0.93; P = .02) such that an SGA episode with an outpatient visit during at least 80% of every 30-day period of the episode was associated with reduced arrests compared to SGA episodes with fewer outpatient services. There was no significant effect for concurrent FGA episodes and outpatient treatment (HR = 0.81; 95% CI, 0.60 1.10; P = .18). Substance use, poor refill compliance, and prior arrest increased risk of subsequent arrest. CONCLUSIONS: The interaction between outpatient visits and treatment with SGAs was significantly associated with reduced arrests. These findings indicate the importance of concurrent antipsychotic medications and outpatient services to affect arrest outcomes for adults with schizophrenia and bipolar disorder. PMID- 21527126 TI - Efficacy of antidepressants for dysthymia: a meta-analysis of placebo-controlled randomized trials. AB - OBJECTIVE: The authors sought to determine the efficacy of antidepressants in dysthymic disorder and to compare antidepressant and placebo response rates between major depressive disorder (MDD) and dysthymic disorder. DATA SOURCES: PubMed/MEDLINE databases were searched for double-blind, randomized, placebo controlled trials of antidepressants used as monotherapy for treatment of MDD or dysthymic disorder. We defined antidepressants as those with a letter of approval by the US, Canadian, or European Union drug regulatory agencies for treatment of MDD or dysthymic disorder, which included the following: amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, dothiepin, doxepin, lofepramine, amoxapine, maprotiline, amineptine, nomifensine, bupropion, phenelzine, tranylcypromine, isocarboxazid, moclobemide, brofaromine, fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, zimelidine, tianeptine, ritanserin, trazodone, nefazodone, agomelatine, venlafaxine, desvenlafaxine, duloxetine, milnacipran, reboxetine, mirtazapine, and mianserin. Eligible studies were identified by cross referencing the search term placebo with each of the above-mentioned agents. The search was limited to articles published between January 1, 1980, and November 20, 2009 (inclusive). To expand our database, we also reviewed the reference lists of the identified studies. STUDY SELECTION: We selected randomized, double blind, placebo-controlled trials of antidepressants for either MDD or dysthymic disorder according to preset criteria relating to comorbidities, patient age, drug formulation, study duration, diagnostic criteria, choice of assessment scales, and whether or not the study reported original data. Final selection of articles was determined by consensus among the authors. RESULTS: A total of 194 studies were found that were eligible for inclusion in our analysis. Of these, 177 focused on the treatment of MDD and 17 on the treatment of dysthymic disorder. We found that antidepressant therapy was significantly more effective than placebo in dysthymic disorder (risk ratio = 1.75; 95% CI, 1.49-2.04; P < .0001), while placebo response rates in dysthymic disorder trials were significantly lower compared to MDD trials (29.9% vs 37.9%, respectively; P = .042). Meta-regression suggested a statistically significant difference in the risk ratio of responding to antidepressants versus placebo when comparing studies either on dysthymic disorder or on MDD, suggesting a greater risk ratio for response in favor of antidepressant therapy versus placebo in patients with dysthymic disorder versus MDD (coefficient of -0.113; P = .007). CONCLUSIONS: These results support the utility of antidepressants for dysthymic disorder. In fact, the margin of efficacy of antidepressants for dysthymic disorder was larger than for MDD. Future studies providing longer-term data on the treatment of dysthymic disorder with antidepressants are essential. PMID- 21527127 TI - Brief eclectic psychotherapy for PTSD: a randomized controlled trial. PMID- 21527128 TI - Suicide sex ratios after the inception of charcoal-burning suicide in Taiwan and Hong Kong. PMID- 21527129 TI - Rapid resolution of obsessions after an infusion of intravenous ketamine in a patient with treatment-resistant obsessive-compulsive disorder. PMID- 21527130 TI - Agreement on a pandemic influenza preparedness framework for the sharing of viruses and benefit sharing. AB - On 16 April 2011, a working group of World Health Organization (WHO) member states agreed on a pandemic influenza preparedness framework. It regulates the sharing of viruses within the WHO Laboratory Global Influenza Surveillance Network (GISN) and the access to vaccines, antiviral drugs, diagnostic kits, and other benefits, in particular with regard to lower-income countries. It foresees mandatory regular contributions from industry partners. The four-year negotiations by 193 WHO member states began in November 2007, at a time when concerns about the fair distribution of benefits impaired the timely global sharing of influenza sequences. The agreed framework will be presented to the World Health Assembly in May 2011 for its consideration and approval. The agreement will strengthen global preparedness for potential future influenza pandemics. More detailed background information and a comment on the implications of this achievement has been published by the European Centre for Disease Prevention and Control. PMID- 21527131 TI - European risk assessment guidance for infectious diseases transmitted on aircraft -the RAGIDA project. AB - In order to assist national public health authorities in the European Union to assess the risks associated with the transmission of infectious agents on board aircrafts, the European Centre for Disease Prevention and Control initiated in 2007 the RAGIDA project (Risk Assessment Guidance for Infectious Diseases transmitted on Aircraft). RAGIDA consists of two parts: the production of a systematic review and a series of disease-specific guidance documents. The systematic review covered over 3,700 peer-reviewed articles and grey literature for the following diseases: tuberculosis, influenza, severe acute respiratory syndrome (SARS), invasive meningococcal disease, measles, rubella, diphtheria, Ebola and Marburg haemorrhagic fevers, Lassa fever, smallpox and anthrax. In addition, general guidelines on risk assessment and management from international aviation boards and national and international public health agencies were systematically searched. Experts were interviewed on case-based events by standardised questionnaires. Disease-specific guidance documents on tuberculosis, SARS, meningococcal infections, measles, rubella, Ebola and Marburg haemorrhagic fevers, Lassa fever, smallpox and anthrax were the result of consultations of disease-specific expert panels. Factors that influence the risk assessment of infectious disease transmission on board aircrafts and decision making for contact tracing are outlined. PMID- 21527132 TI - Contamination of the cold water distribution system of health care facilities by Legionella pneumophila: do we know the true dimension? AB - German water guidelines do not recommend routine assessment of cold water for Legionella in healthcare facilities, except if the water temperature at distal sites exceeds 25 degrees C. This study evaluates Legionella contamination in cold and warm water supplies of healthcare facilities in Hesse, Germany, and analyses the relationship between cold water temperature and Legionella contamination. Samples were collected from four facilities, with cases of healthcare-associated Legionnaires' disease or notable contamination of their water supply. Fifty-nine samples were from central lines and 625 from distal sites, comprising 316 cold and 309 warm water samples. Legionella was isolated from central lines in two facilities and from distal sites in four facilities. 17% of all central and 32% of all distal samples were contaminated. At distal sites, cold water samples were more frequently contaminated with Legionella (40% vs 23%, p <0.001) and with higher concentrations of Legionella (>=1,000 colony-forming unit/100 ml) (16% vs 6%, p<0.001) than warm water samples. There was no clear correlation between the cold water temperature at sampling time and the contamination rate. 35% of cold water samples under 20 degrees C at collection were contaminated. Our data highlight the importance of assessing the cold water supply of healthcare facilities for Legionella in the context of an intensified analysis. PMID- 21527133 TI - Imported extensively drug-resistant Mycobacterium tuberculosis Beijing genotype, Marseilles, France, 2011. AB - Multidrug- (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are reported to gradually spread across European countries with low TB prevalence including France. Some isolates may even accumulate traits of resistance in addition to the XDR profile, as a result of therapeutic mismanagement. We report here the first case of XDR TB in Marseilles and discuss the potential effectiveness of sulfamide treatment in such cases. PMID- 21527134 TI - Measles resurgence in Belgium from January to mid-April 2011: a preliminary report. AB - From 1 January to 14 April 2011, a total of 155 measles cases were notified in Belgium, whereas throughout 2010, there were only 40. Of the 103 cases with known vaccination status, 87% had not been vaccinated with measles-mumps-rubella vaccine. The resurgence of measles is the consequence of insufficient vaccine coverage in previous years. Efforts to communicate the benefits of measles vaccination to the public and to advise health professionals on control measures and outbreak management are ongoing. PMID- 21527135 TI - The six-item CTS symptoms scale and palmar pain scale in carpal tunnel syndrome. AB - PURPOSE: To evaluate measurement properties of 2 brief outcome measures for carpal tunnel syndrome: the 6-item carpal tunnel symptoms scale (CTS-6) and the 2 item palmar pain scale (measuring severity of pain in the scar/palm and pain related activity limitation). Our hypothesis was that the CTS-6 is responsive to change in symptoms after surgical treatment and the pain scale is a valid measure of surgery-related pain. METHODS: This study followed 447 consecutive patients with carpal tunnel syndrome undergoing open release; 308 completed the CTS-6 and the Disabilities of the Arm, Shoulder, and Hand-short form (QuickDASH) before surgery and the CTS-6, QuickDASH, palmar pain scale, and 2 items regarding global rating of change and treatment satisfaction once after surgery (range, 2-13 mo). The mean scores for the CTS-6 (range, 1-5) and QuickDASH and palmar pain scales (range, 0-100) were calculated (lower score is better). Responsiveness was assessed with the effect size (ES). We estimated the CTS-6 score change indicating minimal clinically important difference based on scores for patients with moderate self-rated improvement. RESULTS: The mean baseline CTS-6 score was 3.16, mean change after surgery was -1.54 (95% confidence interval [CI], -1.65 to -1.44), and ES was 2.0. The ES was large (2.5) in patients with the largest self rated improvement and decreased with lower self-rated improvement. A score change of 0.9 indicated a minimal clinically important difference. The mean change in QuickDASH score was -25.4 (95% CI, -27.8 to -23.0), and ES was 1.25. The mean palmar pain score for patients with time since surgery of less than 3 months was 38.5, at 3 to 6 months was 35.4, and greater than 6 months was 19.5; the mean score was significantly higher among patients with lower satisfaction. CONCLUSIONS: The CTS-6 is highly responsive to change in symptoms, and the palmar pain scale is a valid measure of surgery-related pain. These brief scales can be appropriate primary and secondary outcomes measures in clinical trials studying carpal tunnel syndrome. PMID- 21527136 TI - Repair of the motor branch of the ulnar nerve using a dorsal approach: case report. AB - We present the case of a young woman who sustained a stab injury to the left palm with a kitchen knife that entered the thenar eminence and exited dorsally between the index and middle metacarpals. We repaired the injured motor branch of the ulnar nerve using a dorsal approach and a proximal osteotomy of the index metacarpal. PMID- 21527137 TI - Influence of forearm rotation on proximal radioulnar joint congruency and translational motion using computed tomography and computer-aided design technologies. AB - PURPOSE: The contact areas of the articular surfaces in the proximal radioulnar joint (PRUJ) change, depending on the rotational position of the forearm. We investigated the in vivo congruency index of the PRUJ and translational motion of the radial head relative to the lesser sigmoid notch with forearm rotation. METHODS: Computed tomography scans of 12 healthy adult elbows were obtained in 3 forearm positions: full supination, neutral, and full pronation. The translation of the center of the radial head at the level of the PRUJ was measured using computer techniques, and a computer-aided design (CAD) program was used for analysis of the congruency index. The radius of the radial head and lesser sigmoid notch, as well as the distance between the radial head and lesser sigmoid notch, were used as parameters of the congruency index. RESULTS: The mean translation of the radial head was 1.17 mm. The mean ratio of the radius of the radial head to the lesser sigmoid notch was 0.83:1 in neutral position, 0.77:1 in pronation, and 0.92:1 in supination. In supination, the ratio of the radius was more congruent than in neutral and pronation. The mean ratio of the distance between the radial head and the lesser sigmoid notch was 0.15:1 in neutral position, 0.11:1 in pronation, and 0.10:1 in supination. In neutral position, the distance was significantly greater than those in the pronation and supination. CONCLUSIONS: In supination, the PRUJ was the most congruent, and the distance between the radial head and the lesser sigmoid notch was minimal (0.10:1). Our findings confirmed the changes of PRUJ congruency during forearm rotation, and this implies changes of intrinsic osseous stability of the PRUJ during forearm rotation. PMID- 21527138 TI - Steroid-induced osteonecrosis of bilateral distal humerus treated by arthroplasty using costal osteochondral graft: case report. AB - We report the case of a 43-year-old man with steroid-induced osteonecrosis of the distal humerus in both arms. Costal osteochondral autografts were used to restore both joints with satisfactory outcomes. PMID- 21527139 TI - Osteochondral autograft transplantation for osteochondritis dissecans of the scaphoid: case report. AB - This report presents the case of a 36-year-old man who was arthroscopically diagnosed with symptomatic osteochondritis dissecans of the scaphoid. We treated the condition using osteochondral autograft transplantation. PMID- 21527140 TI - A systematic review of outcomes and complications of treating unstable distal radius fractures in the elderly. AB - PURPOSE: As the population in developed countries continues to age, the incidence of osteoporotic distal radius fractures (DRFs) will increase as well. Treatment of DRF in the elderly population is controversial. We systematically reviewed the existing literature for the management of DRFs in patients aged 60 and over with 5 common techniques: the volar locking plate system, nonbridging external fixation, bridging external fixation, percutaneous Kirschner wire fixation, and cast immobilization (CI). METHODS: We reviewed articles retrieved from MEDLINE, Embase, and CINAHL Plus that met predetermined inclusion and exclusion criteria in 2 literature reviews. Outcomes of interest included wrist arc of motion, grip strength, functional outcome measurements, radiographic parameters, and the number and type of complications. We statistically analyzed the data using weighted means and proportions based on the sample size in each study. RESULTS: We identified 2,039 papers and selected 21 papers fitting the inclusion criteria in the primary review of articles with a mean patient age of 60 and older. Statistically significant differences were detected for wrist arc of motion, grip strength, and Disabilities of the Arm, Shoulder, and Hand score, although these findings may not be clinically meaningful. Volar tilt and ulnar variance revealed significant differences among groups, with CI resulting in the worst radiographic outcomes. The complications were significantly different, with CI having the lowest rate of complications, whereas the volar locking plate system had significantly more major complications requiring additional surgical intervention. CONCLUSIONS: This systematic review suggests that despite worse radiographic outcomes associated with CI, functional outcomes were no different from those of surgically treated groups for patients age 60 and over. Prospective comparative outcomes studies are necessary to evaluate the rate of functional recovery, cost, and outcomes associated with these 5 treatment methods. PMID- 21527141 TI - Repair of dorsal defects over the middle phalanx and proximal interphalangeal joint with a transposition flap from the dorsum of the proximal phalanx. AB - PURPOSE: We report the use of a transposition flap raised from the dorsum of the proximal phalanx for coverage of soft tissue defects on the dorsum of the middle phalanx and proximal interphalangeal joint involvement. METHODS: From October 2005 to November 2008, we treated 16 digits in 16 patients in our unit. There were avulsion (n = 3), third-degree burn (n = 7), and crush (n = 6) injuries. The mean flap size was 2.3 * 1.8 cm (range, 1.8 * 1.7 cm to 2.6 * 2.3 cm). The mean pedicle length was 1.7 cm (range, 1.0-2.3 cm). At follow-up, we measured active joint motion. The scar pain at the donor site was determined by the patient's self-reported assessment. We measured cold intolerance using the self administered Cold Intolerance Severity Score questionnaire. RESULTS: All flaps survived completely. At the final follow-up after 2 years, the mean active motion of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints were 90 degrees , 105 degrees , and 57 degrees , respectively. All scars on the donor sites were painless. All patients were mildly cold intolerant. CONCLUSIONS: This transposition flap raised from the dorsum of proximal phalanx is useful and reliable for coverage of a dorsal defect over the middle phalanx and proximal interphalangeal joint with minimal donor site morbidity. PMID- 21527142 TI - Shoulder and upper arm muscle architecture. AB - PURPOSE: To examine the architecture of the shoulder and upper arm muscles and generate data that could serve as a guide for comparison, compatibility, and relative performance among these muscles for use in transfer. METHOD: Eleven shoulder and arm muscles were dissected bilaterally in 5 fresh cadavers. Of these 110 potentially available muscles, 107 were suitable for evaluation and were grouped according to similarities in architecture. Resting muscle length, required excursion, muscle fiber length, pennation angle, and mass were determined. Physiologic cross-sectional area (PCSA) was then calculated from these parameters using a standard formula. RESULTS: Based on the gross appearance of muscle fiber orientation, the 11 muscles were subdivided into 3 groups. Required excursion was found to be less than fiber length in all muscles except for the teres major and middle deltoid with abduction. The middle deltoid muscle was found to have a short fiber length, complex multipennate structure, and high PCSA. Comparison showed the biceps and posterior deltoid to have fiber lengths greater than any portion of the triceps; however, neither demonstrated architectural features that would generate the force (represented by PCSA) determined for the combined triceps. CONCLUSIONS: Data presented in this study offer the opportunity for direct comparison of architectural features of select shoulder and arm musculature. PMID- 21527143 TI - Targeted muscle reinnervation of a muscle-free flap for improved prosthetic control in a shoulder amputee: case report. AB - We report a case of targeted muscle reinnervation of a muscle free flap for improved prosthetic control in a patient who had an amputation of the left upper extremity at the level of the shoulder after a severe electrical burn. The reinnervated muscle free flap receives signals from the brachial plexus, and these signals are amplified to provide an interface for a myoelectric prosthesis. This allows for more coordinated and efficient control of the artificial limb. PMID- 21527144 TI - Pronator syndrome. PMID- 21527145 TI - Percutaneous fasciotomy for Dupuytren's contracture. AB - Needle aponeurotomy (percutaneous needle fasciotomy) for Dupuytren's contracture can be performed in the office setting with local anesthesia. It is simple and inexpensive and has a low complication rate and rapid recovery compared with open fasciectomy. It can usually be repeated safely and effectively for recurrent disease. PMID- 21527146 TI - Optimization of volar percutaneous screw fixation for scaphoid waist fractures using traction, positioning, imaging, and an angiocatheter guide. AB - Percutaneous screw fixation of nondisplaced or reducible scaphoid fractures has become more popular as techniques and implants have improved. Many authors have advocated for the dorsal approach, citing difficulties with adequate screw placement from the volar approach. We have developed a straightforward and reproducible technique for volar percutaneous scaphoid screw fixation that mitigates most of the drawbacks of the approach. The wrist is held in extension and ulnar deviation with traction through the thumb. A 14-gauge angiocatheter needle is then used to localize the starting point and as a cannula for the guide wire. Specific fluoroscopic views help to confirm optimal guide wire placement. PMID- 21527147 TI - The role of the upper extremity surgeon in the management of tetraplegia. AB - Despite its demonstrated benefits, the majority of patients with tetraplegia do not have upper extremity surgery. Many upper extremity surgeons are unfamiliar with the techniques, long-term care providers are often unaware of the options or are biased against surgery, and patients might resist surgery based on lack of awareness, misinformation, or hope of a cure. Although it is not without its challenges, some consensus as to a general algorithm for the care of the tetraplegic patient does exist. At the recent 10th International Meeting on Surgical Rehabilitation of the Tetraplegic Upper Limb, there was little disagreement about when and what surgery to perform. The physical examination tools, clinical decision making, and surgical skills required to treat this population should, therefore, be accessible to the vast majority of hand surgeons who wish to take on these rewarding cases. Patients with specific, realistic, functional goals will realize the best self-perceived outcomes. PMID- 21527148 TI - The treatment of Dupuytren disease. AB - The treatment of progressive Dupuytren contractures has historically been and continues to be largely surgical. Although a number of surgical interventions do exist, limited palmar fasciectomy continues to be the most common and widely accepted treatment option. Until recently, nonsurgical options were limited and clinically ineffective. However, the commercial availability and recent approval of collagenase clostridium histolyticum now provides practitioners with a nonsurgical approach to this disease. This article presents a comprehensive review of the surgical and nonsurgical treatments of Dupuytren disease, with a focus on collagenase. PMID- 21527150 TI - Lunate revascularization in Kienbock's disease. PMID- 21527151 TI - Are we hand doctors or hand surgeons? PMID- 21527152 TI - Localized calcific constrictive pericarditis masquerading as a basal aneurysm. PMID- 21527154 TI - Stroke risk after coronary artery bypass graft surgery and extent of cerebral artery atherosclerosis. AB - OBJECTIVES: We aimed to define the relationship between cerebral atherosclerosis and stroke after coronary artery bypass grafting (CABG). BACKGROUND: Although cerebral atherosclerosis may play a crucial role in the advent of post-CABG stroke, only extracranial carotid artery disease has been extensively studied, and the effects of atherosclerosis on the mechanisms underlying post-CABG stroke remain unclear. METHODS: Pre-operative magnetic resonance angiography was performed on 1,367 consecutive CABG patients to assess intracranial and extracranial cerebral atherosclerosis. Disease severity was evaluated by atherosclerosis score, as determined by the number of steno-occlusions of cerebral arteries and the degree thereof. Post-CABG strokes (within 14 days) were classified as atherosclerotic (strokes attributable to pre-defined atherosclerosis) or other (strokes caused by other mechanisms). Associations between post-CABG stroke and each type of atherosclerotic disease (extracranial carotid artery disease, intracranial, extracranial, or extracranial and/or intracranial cerebral atherosclerosis), differentiated according to the involved arteries, were analyzed. RESULTS: Stroke occurred in 33 patients, and the atherosclerosis score was independently associated with stroke development (odds ratio: 1.35; 95% confidence interval: 1.16 to 1.56). Atherosclerotic stroke was defined in 15 (45%), and constituted >40% of both immediate (within 24 h) and delayed strokes. Intracranial, extracranial, and extracranial and/or intracranial cerebral atherosclerosis were significantly associated with stroke. CONCLUSIONS: Cerebral atherosclerosis was closely related to the occurrence of post-CABG stroke, being both an independent risk factor for and the cause of a significant proportion of strokes. Pre-operative evaluation of intracranial and extracranial cerebral arteries, apart from the extracranial carotid artery, may be useful to predict the likelihood of post-CABG stroke. PMID- 21527153 TI - Cardiac care for older adults. Time for a new paradigm. PMID- 21527155 TI - Post-coronary artery bypass grafting stroke: where is it coming from? PMID- 21527156 TI - Incidence, causes, and outcomes of out-of-hospital cardiac arrest in children. A comprehensive, prospective, population-based study in the Netherlands. AB - OBJECTIVES: This study sought to determine comprehensively the incidence of pediatric out-of-hospital cardiac arrest (OHCA) and its contribution to total pediatric mortality, the causes of pediatric OHCA, and the outcome of resuscitation of pediatric OHCA patients. BACKGROUND: There is a paucity of complete studies on incidence, causes, and outcomes of pediatric OHCA. METHODS: In this prospective, population-based study, OHCA victims younger than age 21 years in 1 province of the Netherlands were registered through both emergency medical services and coroners over a period of 4.3 years. Death certificate data on total pediatric mortality, survival status, and neurological outcome at hospital discharge also were obtained. RESULTS: With a total mortality of 923 during the study period and 233 victims of OHCA (including 221 who died and 12 who survived), OHCA caused 24% (221 of 923) of total pediatric mortality. Natural causes of OHCA amounted to 115 (49%) cases, with cardiac causes being most prevalent (n = 90, 39%). The incidence of pediatric OHCA was 9.0 per 100,000 pediatric person-years (95% confidence interval: 7.8 to 10.3), whereas the incidence of pediatric OHCA from cardiac causes was 3.2 (95% confidence interval: 2.5 to 3.9). Of 51 resuscitated patients, 12 (24%) survived; among survivors, 10 (83%) had a neurologically intact outcome. CONCLUSIONS: Out-of-hospital cardiac arrest accounts for a significant proportion of pediatric mortality, and cardiac causes are the most prevalent causes of OHCA. The vast majority of OHCA survivors have a neurologically intact outcome. PMID- 21527157 TI - Improved outcomes for cardiac arrest in children. Share the baton with the bystander. PMID- 21527158 TI - A prospective study of muscular strength and all-cause mortality in men with hypertension. AB - OBJECTIVES: This study sought to assess the impact of muscular strength on mortality in men with hypertension. BACKGROUND: Muscular strength is inversely associated with mortality in healthy men, but this association has not been examined in men with hypertension. METHODS: We followed 1,506 hypertensive men age 40 years and older enrolled in the Aerobics Center Longitudinal Study from 1980 to 2003. Participants received an extensive medical examination at baseline. Muscular strength was quantified by combining 1 repetition maximum (1-RM) measures for leg and bench press and cardiorespiratory fitness assessed by maximum exercise test on a treadmill. RESULTS: During an average follow-up of 18.3 years, 183 deaths occurred. Age-adjusted death rates per 10,000 person-years across incremental thirds of muscular strength were 81.8, 65.5, and 52.0 (p < 0.05 for linear trend). Multivariable Cox regression hazard ratios were 1.0 (reference), 0.81 (95% confidence interval [CI]: 0.57 to 1.14), and 0.59 (95% CI: 0.40 to 0.86) across incremental thirds of muscular strength. After further adjustment for cardiorespiratory fitness, those participants in the upper third of muscular strength still had a lower risk of death (hazard ratio [HR]: 0.66; 95% CI: 0.45 to 0.98). In the muscular strength and CRF combined analysis, men simultaneously in the upper third of muscular strength and high fitness group had the lowest mortality risk among all combination groups (HR: 0.49; 95% CI: 0.30 to 0.82), with men in the lower third of muscular strength and low fitness group as reference. CONCLUSIONS: High levels of muscular strength appear to protect hypertensive men against all-cause mortality, and this is in addition to the benefit provided by cardiorespiratory fitness. PMID- 21527159 TI - Distribution of coronary artery calcium scores by Framingham 10-year risk strata in the MESA (Multi-Ethnic Study of Atherosclerosis) potential implications for coronary risk assessment. AB - OBJECTIVES: By examining the distribution of coronary artery calcium (CAC) levels across Framingham risk score (FRS) strata in a large, multiethnic, community based sample of men and women, we sought to determine if lower-risk persons could benefit from CAC screening. BACKGROUND: The 10-year FRS and CAC levels are predictors of coronary heart disease. A CAC level of 300 or more is associated with the highest risk for coronary heart disease even in low-risk persons (FRS, <10%); however, expert groups have suggested CAC screening only in intermediate risk groups (FRS, 10% to 20%). METHODS: We included 5,660 Multi-Ethnic Study of Atherosclerosis participants. The number needed to screen (number of people that need to be screened to detect 1 person with CAC level above the specified cutoff point) was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using chi-square tests. RESULTS: CAC levels of more than 0, of 100 or more, and of 300 or more were present in 46.4%, 20.6%, and 10.1% of participants, respectively. The prevalence and amount of CAC increased with higher FRS. A CAC level of 300 or more was observed in 1.7% and 4.4% of those with FRS of 0% to 2.5% and of 2.6% to 5%, respectively (number needed to screen, 59.7 and 22.7, respectively). Likewise, a CAC level of 300 or more was observed in 24% and 30% of those with FRS of 15.1% to 20% and more than 20%, respectively (number needed to screen, 4.2 and 3.3, respectively). Trends were similar when stratified by age, sex, and race or ethnicity. CONCLUSIONS: Our study suggests that in very low-risk individuals (FRS <=5%), the yield of screening and probability of identifying persons with clinically significant levels of CAC is low, but becomes greater in low- and intermediate-risk persons (FRS 5.1% to 20%). PMID- 21527160 TI - Adenylyl cyclase 6 improves calcium uptake and left ventricular function in aged hearts. AB - OBJECTIVES: This study tested the hypothesis that activation of adenylyl cyclase 6 (AC6) expression in cardiac myocytes improves calcium uptake and left ventricular (LV) function in aging mice. BACKGROUND: Aging hearts exhibit impaired beta-adrenergic receptor signaling and LV dysfunction. METHODS: Twenty month-old mice with cardiac-directed and regulated AC6 expression were randomized into 2 groups, and AC6 expression was activated in 1 group (AC6-On) but not the other (AC6-Off). One month later, LV function and sarcoplasmic reticulum calcium uptake were assessed. RESULTS: AC6 expression was associated with increased LV contractility, as reflected by ejection fraction (p = 0.02), rate of pressure development (p = 0.002), and slope of the LV end-systolic pressure-volume relationship (p = 0.04). No changes in LV weight to tibial length ratio, LV fibrosis, and expression of fetal genes (atrial natriuretic factor, alpha skeletal muscle actin, and beta-myosin heavy chain) and collagens were observed between AC6-On and AC6-Off groups. However, LV samples from AC6-On mice showed increases in: isoproterenol-stimulated cAMP production (p = 0.04), cAMP-dependent protein kinase activity (p < 0.0004), phosphorylation of phospholamban (at Ser16 site; p = 0.04) and cardiac troponin I (at Ser23/24 sites; p = 0.01), velocity of sarcoplasmic reticulum calcium uptake (p < 0.0001), and sarcoplasmic reticulum calcium-ATPase2a (SERCA2a) affinity for calcium (p < 0.0001). Finally, we found that AC6 expression increased sarcoplasmic reticulum calcium storage in cardiac myocytes isolated from 23-month-old rats. In contrast, AC6 expression in 7-month old mice did not change LV function and calcium uptake. CONCLUSIONS: These results indicate that activation of cardiac AC6 expression improves impaired function of aged hearts through improved calcium uptake. PMID- 21527162 TI - President's page: too much of a good thing. PMID- 21527161 TI - Multi-imaging assessment of the congenital mitral arcade. PMID- 21527163 TI - Undernutrition: a major problem in nursing homes. PMID- 21527164 TI - Drug Enforcement Agency's dilemma in long-term care: delays in treatment, delays in solutions. PMID- 21527166 TI - Vitamin D: Lessons from the veterans population. AB - Vitamin D deficiency (25(OH)D < 20 ng/mL) is likely to be present in about 40% of veterans and is associated with much higher health care costs and service use. The prevalence of vitamin D deficiency is likely to be higher in certain subgroups such as ethnic minorities, those who are chronically ill, and nursing home residents. The lack of adequate sunlight exposure and poor dietary intake are common contributors to this deficient state. Moreover, vitamin D deficiency has also been noted in individuals taking vitamin D supplements within the recommended daily intake. To achieve a 25(OH)D value in the normal range (30-100 ng/mL), many studies indicate a much higher daily oral intake than currently recommended is needed. Inadequate vitamin D dosing may account for failure of some studies to show a benefit. Testing for vitamin D insufficiency levels remains suboptimal and serial monitoring in veterans to assess if a vitamin D replete state has been achieved also remains less than adequate. The lack of evidence-based guidelines for testing and monitoring has hampered optimal management of this very common condition. The cardiovascular, immunologic, anti infective, and oncologic benefits of a vitamin D-replete state are becoming recognized. Achieving a vitamin D-replete state may prolong longevity. Achieving adequate vitamin D status in US veterans is an important health measure that should be undertaken. PMID- 21527167 TI - DEA enforcement in long-term care: is a collaborative correction feasible? AB - The prescribing and dispensing of controlled substances within long-term care facilities is an important and complex issue from both the clinical and the public policy perspectives. This article reviews the regulatory background and clinical concerns regarding the enforcement of the Controlled Substances Act by the Drug Enforcement Administration within the institutional pharmacies serving long-term care facilities. The article argues that the processes implemented since 2009 in response to concerns about Drug Enforcement Administration enforcement are suboptimal at many levels. A robust solution that meets the needs of all parties involved will require multiple levels of collaboration and respect for several legitimate agendas pertinent to this issue. The comprehensive solution must address at least 4 concerns. It must ensure that (1) residents and patients of long-term care facilities receive appropriate and timely administration of controlled substances when they are part of their individualized plans of care; (2) long-term care facilities have rigorous processes in place to prevent diversion of controlled substances; (3) required processes for prescribing controlled substances are reasonable and not overly burdensome to the clinicians caring for this population; and (4) all parties are in compliance with statutory and regulatory requirements. The solution, however, will likely require legislative amendments to the Controlled Substances Act and regulatory revisions for optimal outcomes. The debate surrounding the enforcement of the Controlled Substances Act within long-term care facilities is ongoing and the parameters are in flux. This article provides a historical perspective and policy framework for understanding the topic, reviews various proposed solutions, and suggests a collaborative process for resolution. PMID- 21527168 TI - Physicians' attitudes toward guidelines for the treatment of hospitalized nursing home-acquired pneumonia. AB - OBJECTIVES: To assess physician awareness, attitudes, and barriers toward the 2005 American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines for the treatment of hospitalized nursing home-acquired pneumonia (NHAP). METHODS: We conducted a cross-sectional survey of 522 health care providers. The survey assessed the practice setting characteristics, physicians' attitudes, and reported awareness of the 2005 ATS/IDSA guidelines. Factor analysis was conducted to identify scales of variables, and a reliability analysis was performed to verify the reliability of the identified scales. RESULTS: Three hundred and ten completed the survey. Most responders (88%) reported familiarity with the practice guidelines in their field, but less than half were familiar with the ATS/IDSA NHAP guidelines. Although attitude scores regarding clinical practice guidelines did not differ significantly among various disciplines (P = .63), there were 2 characteristics that correlated with positive attitudes toward the 2005 ATS/IDSA guidelines in a multivariate analysis: being a pulmonary specialist (P <= .001) and time spent on CME activity per month (P = .03). The main barriers to the 2005 ATS/IDSA guidelines implementation were lack of awareness, concerns about practicality of using the recommended regimens, increased cost, lack of documented improved outcomes, and potential conflict with other guidelines. CONCLUSION: The study indicates low levels of awareness with the 2005 ATS/IDSA guidelines for treatment of hospitalized NHAP. Targeted intervention efforts including outcome assessment and cost-effective analysis may be necessary to improve adherence with the proposed guidelines. PMID- 21527165 TI - Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. AB - Sarcopenia, the age-associated loss of skeletal muscle mass and function, has considerable societal consequences for the development of frailty, disability, and health care planning. A group of geriatricians and scientists from academia and industry met in Rome, Italy, on November 18, 2009, to arrive at a consensus definition of sarcopenia. The current consensus definition was approved unanimously by the meeting participants and is as follows: Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multifactorial and can include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Although cachexia may be a component of sarcopenia, the 2 conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed less that 1 m/s(-1). Patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry with sarcopenia being defined using currently validated definitions. A diagnosis of sarcopenia is consistent with a gait speed of less than 1 m.s(-1) and an objectively measured low muscle mass (eg, appendicular mass relative to ht(2) that is <= 7.23 kg/m(2) in men and <= 5.67 kg/m(2) in women). Sarcopenia is a highly prevalent condition in older persons that leads to disability, hospitalization, and death. PMID- 21527169 TI - Energy intake compensation after 3 weeks of restricted energy intake in young and elderly men. AB - OBJECTIVES: Decreased energy intake in older persons poses these people at risk of progressive weight loss. It may result from a failure to regulate energy intake and expenditure after periods of underfeeding. The objective of this study was to investigate if a period of underfeeding differentially influences energy intake of older compared with young men and, additionally, to study potential underlying mechanisms, namely changes in gastric emptying rate and cholecystokinin (CCK) levels in blood. DESIGN/SETTING: Dietary intervention of 3 phases. After a phase of energy balance, we fed participants in phase 2 by a mean of 70% of their needs for 21 days. During phase 3, we assessed ad libitum energy intake of the participants during 9 days. At the end of phases 1 and 2, we assessed appetite, gastric emptying, and CCK levels in blood in response to a test meal. PARTICIPANTS: Fifteen young (age 24 years [range 20-34], body mass index 23.0 kg/m(2) +/- 2.3) and 17 older (age 68 years [64-85], body mass index 24.5 kg/m(2) +/- 1.9) men participated in this study. RESULTS: During energy balance, mean energy intake of young men (14.3 +/- 2.3 MJ/day) was significantly higher than that of older men (11.3 +/- 1.8 MJ/day, P < .001). After the period of underfeeding, energy intake in phase 3 amounted to 16.3 +/- 2.6 MJ/day in young men and to 14.4 +/- 3.2 MJ/day in older men. Ad lib energy intake after underfeeding did not differ between young and older men (analysis of covariance, with energy intake during phase 1 as covariate, P = .99). There were no differential changes in body weight, body composition, resting energy expenditure, gastric emptying rate, CCK-8 levels, and appetite between young and older men during the study. CONCLUSION: Our results do not indicate that older men have an impaired ability to control energy intake after a period of underfeeding compared with younger men. TRIAL REGISTRATION: NCT00561145. PMID- 21527170 TI - Undernutrition at baseline and health services utilization and mortality over a 1 year period in older adults receiving Medicare home health services. AB - OBJECTIVE: Older adults receiving Medicare home health services who experience undernutrition may be at increased risk of experiencing adverse outcomes. We sought to identify the association between baseline nutritional status and subsequent health service utilization and mortality over a 1-year period in older adults receiving Medicare home health services. DESIGN: This was a longitudinal study using questionnaires and anthropometric measures designed to assess nutritional status (Mini-Nutritional Assessment) at baseline and health services utilization and mortality status at 6-month and 1-year follow-ups. SETTING: Participants were evaluated in their homes. PARTICIPANTS: A total of 198 older adults who were receiving Medicare home health services. RESULTS: Based on Mini Nutritional Assessment, 12.0% of patients were malnourished, 51.0% were at risk for malnourishment, and 36.9% had normal nutritional status. Based on body mass index, 8.1% of participants were underweight, 37.9% were normal weight, 25.3% were overweight, and 28.8% were obese. Using multivariate binary logistic regression analyses, participants who were malnourished or at risk for malnourishment were more likely to experience subsequent hospitalization, emergency room visit, home health aide use, and mortality for the entire sample and hospitalization and nursing home stay for overweight and obese participants. CONCLUSIONS: Experiencing undernutrition at the time of receipt of Medicare home health services was associated with increased health services utilization and mortality for the entire sample, and with increased health services utilization only for the overweight and obese subsample. Opportunities exist to address risk of undernutrition in patients receiving home health services, including those who are overweight or obese, to prevent subsequent adverse health outcomes. PMID- 21527171 TI - Post-discharge nutritional support in malnourished elderly individuals improves functional limitations. AB - BACKGROUND: Older people are vulnerable to malnutrition, which leads to negative outcomes. This study evaluates the effectiveness of nutritional supplementation in malnourished elderly patients after hospital discharge. METHODS: Hospital admitted malnourished elderly patients (>= 60 years) were randomized to receive either nutritional supplementation (energy and protein enriched diet, oral nutritional support, calcium-vitamin D supplement, telephone counseling by a dietitian) for 3 months postdischarge or usual care. Outcomes were functional limitations, physical performance, physical activities, body weight, fat-free mass, and handgrip strength. Measurements were performed at hospital admission (baseline) and at 3 months after discharge. Data were analyzed according to the intention-to-treat principle. FINDINGS: A total of 210 patients were included, 105 in each group. Body weight increased more in the intervention group than in the control group; this was significant for the highest body weight category (mean difference 3.4 kg, 95% CI 0.2-6.6). Functional limitations decreased more (mean difference -0.5 (95% CI -1.0-0.1) in the intervention group than in the control group. When excluding patients who had already received nutritional support before the start of the study, this reached significance. No significant differences could be demonstrated for physical performance, physical activities, fat-free mass, or handgrip strength. INTERPRETATION: Three months of oral nutritional support to malnourished elderly decreased functional limitations and increased body weight. It can be questioned if a follow-up of only 3 months was not too short to detect differences on physical performance and physical activities as well. PMID- 21527172 TI - Nutritional status, energy, protein, and micronutrient intake of older service house residents. AB - OBJECTIVES: To examine the nutritional status and energy, protein, and micronutrient intake of aged residents living in service houses and to compare how they meet official recommendations. DESIGN: Cross-sectional study. PARTICIPANTS: Service house residents (n = 375) in the metropolitan region of Helsinki, Finland. MEASUREMENTS: The nutritional status of residents was assessed with the Mini Nutritional Assessment. Residents' energy, protein, and nutrient intake were calculated from 1-day food diaries and compared with the nutrition recommendations. RESULTS: The mean age of participants was 83 years; 82% were females. According to the Mini Nutritional Assessment, 65% were at risk for malnutrition and 21% were malnourished. Energy, protein, and nutrient intake varied greatly among residents. Inadequate energy, protein, and micronutrient intake was common among the oldest residents. Of the whole group, 46% received less than 1570 kcal/d of energy and 47% received less than 60 g/d of protein. Their intake of fiber, vitamin E, vitamin D, and folic acid was especially low. The percentages of residents receiving less than the recommended intake of these nutrients were 98%, 98%, 38%, and 86%, respectively. CONCLUSIONS: Taking into account the large number of aged residents suffering from malnutrition or being at risk for malnutrition, low energy, protein, and micronutrient intake was very common. Assessment-based nutritional care should be a significant part in supporting frail older people in service houses. PMID- 21527173 TI - Organization of the medication management process in Belgian nursing homes. AB - BACKGROUND: With the increase of the proportion of old (>80 years), frail people living in long-term care settings, concern about the quality of medication management processes in nursing homes is growing. OBJECTIVES: To characterize the organization of medication management processes in Belgian nursing homes. METHOD: This cross-sectional, observational study of a representative sample of 76 Belgian nursing homes was performed in November and December 2005. The results are based on structured interviews that were conducted with 76 facility directors and 112 head nurses, using 2 questionnaires. RESULTS: A self-reporting medication error system was set up in 69.7% of the nursing homes. Almost all nursing homes had a therapeutic drug formulary, but its use was not compulsory. Medications were mainly delivered from a community pharmacy (82.9%). The role of the pharmacist was often restricted to mere delivery of medications. Medications were not always administered by nurses, but also by care aides (67%) or nursing students (12.5%). The practice of postscription (i.e., prescribing medication after it has been dispensed by the pharmacist) was also found to be quite common (69.9%). CONCLUSION: This study provides a detailed description of the organization of medication management processes in Belgian nursing homes. Based on these results, problem areas can be identified and, consequently, targeted improvement actions can be investigated and implemented. PMID- 21527174 TI - God bless the Glendas. PMID- 21527175 TI - Deep vein thrombosis prophylaxis in long-term care facilities--perhaps less is more. PMID- 21527177 TI - Bacteremia in the elderly. PMID- 21527178 TI - Influenza vaccination in long-term care facilities: more than standing order programs? PMID- 21527180 TI - Comorbidities and their treatments. PMID- 21527183 TI - Clinical characterization of patients with macroprolactinemia and monomeric hyperprolactinemia. AB - Macroprolactinemia is often a cause of misdiagnosis, unnecessary expensive investigation, and unsuitable treatment. The aim of the present study was to investigate the clinical findings and the concentrations of macroprolactin in patients with hyperprolactinemia in our region. Eighty-four female hyperprolactinemic patients were screened for macroprolactinemia. Prolactin was measured by chemiluminescence method on an Immulite 2000 analyzer (Siemens Health Diagnostics, Deerfield, IL, USA). Recoveries less than or equal to 40% after polyethylene glycol precipitation were indicative of macroprolactinemia. Clinical features and biochemical values were compared in true hyperprolactinemic and macroprolactinemic patients. Macroprolactinemia was detected in 31 patients (36.9%), with 84 hyperprolactinemic female patients. There was no difference in frequency of galactorrhea and oligomenorrhea/amenorrhea between the two groups. When we evaluated the clinical features of patients according to prolactin levels, no significant difference was found between the groups. In conclusion, our initial data show that no clinical features could reliably differentiate macroprolactinemic from true hyperprolactinemic patients, but at least one of these symptoms was present in most macroprolactinemic patients. PMID- 21527182 TI - Expression of manganese superoxide dismutase in patients with breast cancer. AB - Breast cancer has become the second leading cancer among females in Taiwan. Even though the etiology of breast cancer is multifactorial, oxidative stress plays an important role in the carcinogenesis. The purpose of this study was to investigate the expression of manganese superoxide dismutase (MnSOD), one of the major antioxidant enzymes that is involved against oxidative stress, in adjacent cancer-free breast tissues and neoplasm tissues within the same patient. Sixty five breast cancer patients' formalin-fixed tissue blocks, including ductal carcinoma in situ (DCIS) tissues, invasive ductal carcinoma (IDC) tissues, and adjacent cancer-free tissues, were evaluated by immunohistochemical stain. Meanwhile, their demographic and clinical information was also collected. The combined scores of MnSOD-positive cell proportion and MnSOD staining intensity were compared for different tissues within the same patient. The results showed that the mean combined scores of MnSOD expression in adjacent cancer-free tissues (6.33), IDC (5.30), and DCIS (3.78) were significantly different when assessed by repeated-measurement analysis of variance (F=14.17, p<0.001). Additionally, the results revealed that the distribution of strong MnSOD protein expression was 80.0%, 72.3%, and 52.3% in adjacent cancer-free tissues, IDC, and DCIS, respectively. However, there was no statistically significant relationship between the expression of MnSOD and grades of breast cancer or other clinicopathologic variables. We suggest that the expression of MnSOD in neoplasm tissues, independent of the clinicopathologic characters, plays a critical role in breast cancer biology. PMID- 21527184 TI - Quality of life and its correlates among heroin users in Taiwan. AB - The aims of this study were to compare the quality of life (QOL) between subjects with and without heroin use and to examine the association of QOL with sociodemographic characteristics, characteristics of heroin use, family support, and depression among heroin users at entry to a methadone maintenance treatment program. A group of 123 heroin users who visited an outpatient addiction treatment clinic in southern Taiwan for methadone maintenance treatment were recruited into this study. We also recruited 106 subjects who had never used heroin as the control group. Their QOL status was assessed by the short form of the Taiwan Version of the World Health Organization Questionnaire on Quality of Life (the WHOQOL-BREF Taiwan version). The level of QOL between subjects with and without heroin use was compared, and the correlates of QOL among heroin users were examined. Heroin users had poorer QOL than nonusers in the physical, psychological, and social relationship domains but not the environment domain of the WHOQOL-BREF after controlling for the influences of other factors. In addition, heroin users with obvious depression had poorer QOL in all four domains than those without obvious depression. Also, heroin users who perceived higher family support had better QOL in the social relationship and environment domains. Heroin users had poorer QOL than nonusers in multiple domains. Relief of depressive symptoms and enhancement of family support should be important strategies to improve QOL in heroin users. PMID- 21527185 TI - Eosinophilic meningitis risk associated with raw Ampullarium canaliculatus snails consumption. AB - In Taiwan, Angiostrongylus cantonensis infection has been reported in foreign laborers who had consumed raw Ampullarium canaliculatus snails. This study analyzed three foreign laborers who had contracted enzyme-linked immunosorbent assay-confirmed A cantonensis infection while working in Taiwan. All three workers had consumed either roasted snails or raw snails flavored with seasoning while drinking wine. This study investigated possible risk factors for A cantonensis, including naturally occurring A cantonensis in A canaliculatus snails, viability of third-stage A cantonensis larvae in raw seasoned snails and in roasted snails, infectivity of larvae, and effects of alcohol while consuming snails. Positive infection rates in snails from five different irrigation canals in south Taiwan ranged from 12.3% to 29.4% and the average number of motile larvae per infected snail ranged from 36 to 65. The number of motile and coiled larvae in snail meat after 120 minutes seasoning was 93 (27.7%) and 233 (69.3%), respectively. After 20 minutes of roasting, most larvae in the snail meat were dead. The infectivities of motile and coiled larvae from snail meat after 60 minutes seasoning were 53.2% and 33.2%, respectively, and those from snail meat after 5 minutes roasting were 33.2% and 7.0%, respectively. Eating Taiwan A canaliculatus snails raw is extremely risky given their high infection rates and infection intensities. Even after 120 minutes seasoning or after 20 minutes roasting, snail meat should be considered unsafe for human consumption. Finally, experimental rodent studies indicated that consuming alcohol while ingesting larvae does not significantly reduced infectivity. PMID- 21527186 TI - Primary Sjogren's syndrome with minimal change disease--a case report. AB - Glomerular involvement in patients with primary Sjogren's syndrome (pSS) has rarely been reported. Among them, membranoproliferative glomerulonephritis and membranous nephropathy are the more common types. We report a middle-aged female presenting concurrently with nephrotic syndrome and microscopic hematuria, and her pSS was diagnosed by positive anti-Ro (SSA)/anti-La (SSB) autoantibodies, dry mouth, severely diffuse impaired function of both bilateral parotid and submandibular glands, and a positive Schirmer test. Renal pathology revealed minimal change disease and thin basement membrane nephropathy. The patient's nephrotic syndrome resolved after treatment with corticosteroids. To our knowledge, this is the first report of minimal change disease in a patient with pSS. PMID- 21527187 TI - Alcohol drinking triggers acute myocardial infarction in a case of hypertrophic obstructive cardiomyopathy. AB - Alcohol ingestion-related increased left ventricular outflow tract (LVOT) pressure gradient in hypertrophic obstructive cardiomyopathy (HOCM) has been reported in the literature; however, acute myocardial infarction (AMI) after alcohol drinking in this patient group is rarely reported. Herein, we report a 68 year-old man with chronic alcoholism suffering from AMI after alcohol drinking. Electrocardiography revealed complete left bundle branch block, and chest X-ray showed acute pulmonary edema. Intubation was done for respiratory failure and intra-aortic balloon pump was also inserted for unstable hemodynamics. However, emergent coronary angiography revealed normal coronary arteries. HOCM was diagnosed by a high pressure gradient over LVOT and systolic anterior motion of mitral valve by echocardiography. This patient became stable under intensive care and medical treatment. This case reminds physicians that alcohol ingestion might cause AMI in HOCM patients because of increased LVOT pressure gradient and decreased coronary perfusion despite normal coronary arteries. PMID- 21527188 TI - Extensive peritoneal calcification and small intestinal perforation in a peritoneal dialysis patient: a case report. AB - A 56-year-old woman was maintained on continuous ambulatory peritoneal dialysis (PD) for 12 years. The patient presented to our hospital with chief complaints of intermittent abdominal pain and frequent loose stool. Plain radiograph of abdomen revealed extensive peritoneal calcification. Computed tomography confirmed the extensive peritoneal calcification and revealed a large right ovarian cyst. Torsion of the right ovarian cyst was suspected. Right oophorectomy was performed. Small intestinal perforation developed 37 days after the operation. The patient expired because of peritonitis and sepsis. Extensive peritoneal calcification is a rare and serious complication after long-term PD. Intestinal perforation is a rare complication of PD. Pathognomic signs of imaging studies can be important in early diagnosis and treatment. PMID- 21527189 TI - Ectomesenchymal chondromyxoid tumor of the anterior tongue: a rare case. AB - Ectomesenchymal chondromyxoid tumor is a rare tumor seen in the anterior dorsal aspect of the tongue. Diagnosis of this lesion without a prediagnosis clinically is made only with histopathological findings including the immunohistochemical examinations. However, diverse results are being reported in the literature with keratin staining. While glial fibrillary acid protein positiveness maintain being a fixed repeating feature, we emphasized for our case of a 28-year-old Caucasian woman having the findings of qualities supporting the ectomesenchymal origin of the mentioned tumor. PMID- 21527190 TI - Poor sleep is associated with exaggerated cortisol response to the combined dexamethasone/CRH test in a non-clinical population. AB - Although sleep disturbance has been shown to be associated with psychological distress and the hypothalamic-pituitary-adrenal (HPA) axis function, the simultaneous relationship between sleep, distress and HPA axis function is less clear. Here we examined the relationship between sleep quality as assessed with the Pittsburgh Sleep Quality Index, psychological distress as assessed with the Hopkins Symptom Checklist, and cortisol responses to the dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test in 139 non-clinical volunteers. Poor sleep was significantly correlated with greater cortisol response to the combined DEX/CRH challenge, but not with the cortisol level just before CRH challenge. When subjects were divided into three groups based on the suppression pattern of cortisol (i.e., incomplete-, moderate-, and enhanced-suppressors), poor sleep was significantly associated with the incomplete suppression in women while no significant association was found between sleep and the enhanced suppression. The association between poor sleep and exaggerated cortisol response to the CRH challenge became more clear in the regression analysis where the confounding effect of psychological distress was taken into consideration. These results indicate that poor sleep would be associated with exaggerated cortisol reactivity. The observed association of poor sleep with reactive cortisol indices to the CRH challenge, but not with the cortisol level after DEX administration alone, might add to the well-established evidence demonstrating the role of CRH in the regulation of sleep. Our findings further suggest that the mediation model would work better than the bivariate approach in investigating the relationship between sleep, distress and HPA axis reactivity. PMID- 21527191 TI - Simplified surgical approach to congenital megaprepuce: fixing, unfurling and tailoring revisited. AB - PURPOSE: Megaprepuce is a congenital penile malformation that includes phimosis and severe ballooning of the internal prepuce. We combined the main technical details of 2 previously reported surgical techniques to simplify the surgical approach. We report the key points of this revisited surgical correction for megaprepuce and the long-term results. MATERIALS AND METHODS: Penile reconstruction was performed between March 2004 and March 2009 in 26 children 2 to 19 months old (median age 6) with congenital megaprepuce. Surgical repair consisted of limited preputial resection of the phimotic ring, wide dissection of the outer prepuce to the base of the penis, fixation of the proximal outer prepuce to Buck's fascia to create a new penoscrotal junction, and unfurling and wide tailoring of the inner prepuce in the ventral midline to resurface the whole elongated penile shaft. A bladder catheter was left in place for 5 or 6 days. Only patients with at least 6 months of followup were included in analysis. RESULTS: All patients underwent surgery on an outpatient basis. Operative time was between 50 and 85 minutes. Median followup was 17.6 months (range 6 to 59). Two patients had slight dehiscence of the ventral suture, which healed spontaneously without a scar. In 1 patient transient urethral meatal stenosis developed. The final cosmesis result was adequate in all patients. CONCLUSIONS: It is possible to correct megaprepuce and achieve an adequate genital aspect with a simple approach of resurfacing the penis with the unfurled, tailored inner prepuce. PMID- 21527192 TI - Effects of botulinum toxin type a in the bladder wall of children with neurogenic bladder dysfunction: a comparison of histological features before and after injections. AB - PURPOSE: Botulinum toxin type A has gained popularity in urology. Most reported studies have been in adults at urology centers and most have addressed long-term safety. Since botulinum toxin type A treatment for neurogenic bladder dysfunction requires repeat injections, verifying that such treatment does not induce fibrosis in children seems essential. MATERIALS AND METHODS: The study was approved by the institutional review board and patients were enrolled after we obtained written consent. Patients with neurogenic bladder dysfunction not responding to conventional treatment (anticholinergics and clean intermittent catheterization) were treated with 10 IU/kg botulinum toxin type A up to a maximum of 300 IU. Endoscopic cold cup biopsies were obtained from the posterolateral bladder wall 1.5 to 2 cm above the ureteral orifice. Bladder wall findings were categorized into 3 groups, including inflammatory infiltration, edema and fibrosis. Each criterion was then graded as mild or severe and analyzed by Fisher's exact test (p <0.05). RESULTS: A total of 46 bladder wall biopsies were obtained from 40 patients 2 to 18 years old. Biopsies were evaluated in groups 1 and 2, including group 1-20 from patients with no botulinum toxin type A injection and group 2-20 after botulinum toxin type A injection. Group 2 was subdivided into group 3-10 biopsies after 1 injection and group 4-10 after multiple injections. Six patients underwent biopsy twice, that is before the first and second treatments. Histological changes were present in all biopsies. When comparing groups 1 and 2, there was no statistically significant difference in inflammation and edema. However, there was a significant difference in fibrosis between groups 1 and 4 (p <0.05) with apparently decreased fibrosis after multiple injections. CONCLUSIONS: In our experience repeat botulinum toxin type A injections into the detrusor in children do not lead to increased fibrosis in the bladder wall. This study confirms the long-term safety of botulinum toxin type A in the pediatric population. PMID- 21527193 TI - Risk factors associated with chronic kidney disease in patients with posterior urethral valves without prenatal hydronephrosis. AB - PURPOSE: Postnatal diagnosis of posterior urethral valves continues despite the prevalence of prenatal ultrasound. We identified risk factors associated with chronic kidney disease in these children. MATERIALS AND METHODS: We retrospectively reviewed the medical records of boys with posterior urethral valves with clinical presentations other than prenatal hydronephrosis. We recorded presenting symptoms, age at presentation, and preoperative hydronephrosis and/or vesicoureteral reflux. Chronic kidney disease was defined as previous renal transplantation, dialysis dependence or glomerular filtration rate less than 60 ml per minute/1.73 m(2) at last followup. We used univariate survival analysis with the log rank test of equality for categorical variables and Cox proportional hazard regression for continuous variables to identify risk factors associated with progression to chronic kidney disease. RESULTS: We identified 141 boys with posterior urethral valves with a postnatal presentation. Median age at presentation was 46 months (range 0.3 to 174). Febrile urinary tract infection in 28% of patients and voiding complaints in 50% were the most common presentations. A total of 12 patients (9%) progressed to chronic kidney disease up to 23 years after initial presentation. Preoperative bilateral hydronephrosis, increased hydronephrosis severity and bilateral vesicoureteral reflux were associated with progression to chronic kidney disease. CONCLUSIONS: Approximately 10% of cases with postnatal presentation of posterior urethral valves progress to chronic kidney disease, sometimes decades after the initial presentations. Although all patients with posterior urethral valves should be counseled on the potential loss of renal function, children with risk factors warrant close followup into adulthood. PMID- 21527195 TI - Simplified open approach to surgical treatment of ureteropelvic junction obstruction in young children and infants. AB - PURPOSE: Indications for laparoscopic pyeloplasty for ureteropelvic junction obstruction are steadily growing but there is still a group of young children in whom open surgery continues to be the procedure most performed by pediatric urologists. We report our results in young children and infants with dismembered pyeloplasty done through a small flank incision on an outpatient basis or during a short hospital stay. MATERIALS AND METHODS: Between April 2001 and July 2009, 45 patients with a median age of 11.2 months (range 1 to 50), of whom 72.9% were male, with confirmed ureteropelvic junction obstruction underwent classic Anderson-Hynes dismembered pyeloplasty thorough a 2.5 to 3.5 cm flank incision. Obstruction was on the left side in 51.2% of the patients. Pyeloureteral anastomosis was performed with a continuous 7-zero polydioxanone suture over a 7Fr multiperforated pyelostomy self-designed catheter in 89% of the patients. A Double-J(r) catheter was used in only 4 patients with other associated conditions. The stent was removed in the office 7 to 12 days after surgery. RESULTS: Mean operative time was 92 minutes (range 60 to 150). Median hospital stay was 11.5 hours (range 6 to 35) in the whole group but it decreased to 9.4 hours in the last 22 cases. There was no reoperation due to recurrent ureteropelvic junction obstruction. Mean postoperative followup was 47.5 months. CONCLUSIONS: Ureteropelvic junction obstruction surgery in small children can be done safely through a small incision with a short hospital stay without morbidity and with good cosmesis. We believe that open pyeloplasty will continue to be the best standard treatment for ureteropelvic junction obstruction surgery in small children until miniaturization and better laparoscopic instruments allow us to reproduce these results. PMID- 21527194 TI - Pediatric testicular torsion: demographics of national orchiopexy versus orchiectomy rates. AB - PURPOSE: While the timely diagnosis and management of pediatric torsion can lead to testicular salvage, limited data exist on rates of orchiopexy vs orchiectomy and associated factors. Thus, we examined the Pediatric Health Information System database for torsion outcomes and demographics at American pediatric hospitals. MATERIALS AND METHODS: Using the Pediatric Health Information System database we performed a 7-year retrospective cohort study in children 1 to 17 years old with a primary ICD-9 diagnosis of torsion, assessing CPT codes for orchiopexy and orchiectomy. Data were analyzed with SPSS(r), version 17.0. RESULTS: Of 2,876 patients who underwent surgery for an ICD-9 diagnosis code of testicular torsion 918 (31.9%) underwent orchiectomy at a mean age of 10.7 years and 1,958 (68.1%) underwent orchiopexy at a mean age of 12.6 years (p <0.0001). In the age groups 1 to 9, 10 to 13 and 14 years or greater 274 (49.9%), 311 (29.4%) and 333 patients (26.2%), respectively, underwent orchiectomy. A higher orchiectomy rate was seen at age 1 to 9 vs 10 years or greater. Torsion and orchiectomy rates did not vary by season or geographic region. A higher orchiectomy rate was seen in black vs white children (37.6% vs 28.1%) and in patients without vs with private insurance (36.7% vs 27.0%). Multivariate analysis revealed an association of age (p <0.0001), race (p <0.0001) and insurance status (p <0.001) with orchiectomy. CONCLUSIONS: Nationally an average of 32% of the 411 pediatric torsion cases explored annually result in orchiectomy. Identified factors increasing the orchiectomy risk included age 1 to 9 years, black race and lack of private insurance. Efforts should continue to identify modifiable variables that can increase testicular salvage in patients with testicular torsion. PMID- 21527196 TI - Posterior urethral valve treatments and outcomes in children receiving kidney transplants. AB - PURPOSE: We evaluated the impact of surgical approaches to posterior urethral valves on renal transplant survival and compared transplant survival in children with vs without posterior urethral valves. MATERIALS AND METHODS: We reviewed the records of all children who underwent renal transplantation from January 1984 to March 2008 and performed univariate subgroup analysis in those with posterior urethral valves. We evaluated the ureteroneocystotomy method, immunosuppression and valve treatment. In patients with posterior urethral valves we regarded nocturnal and/or daytime incontinence, severe urgency and the need for intermittent catheterization or double voiding for increased post-void residual urine as signs of bladder dysfunction. RESULTS: The initial renal transplant was received by 418 children at a mean age of 5.6 years. The 59 boys with posterior urethral valves received a total of 69 kidneys. By 8-year followup the kidney had failed in 24 of 59 boys with and 143 of 359 without posterior urethral valves (OR 0.9665, 95% CI 0.5462-1.692, p = 0.9105). Immunosuppression was consistent in the 2 groups. Outcomes were similar across all ureteroneocystotomy techniques. Initial management for posterior urethral valves was valve ablation alone in 12 boys, vesicostomy in 7 and supravesical diversion in 11. There was no difference in transplant survival or bladder dysfunction based on valve intervention. In 18 boys (55%) we noted overlapping signs of bladder dysfunction, of whom 11 performed intermittent catheterization or had increased post-void residual urine, 4 had severe urgency, 4 had daytime incontinence and 7 had nocturnal incontinence. Bladder dysfunction did not predict increased graft loss (OR 3.306, 95% CI 0.7615-16.27, p = 0.1134). CONCLUSIONS: Of children who undergo renal transplantation boys with posterior urethral valves do not have a higher graft failure rate. Treatment for posterior urethral valves did not significantly impact transplant survival or bladder dysfunction. PMID- 21527197 TI - Management of the urinary tract in spina bifida cases varies with lesion level and shunt presence. AB - PURPOSE: The urinary and gastrointestinal tracts remain an enormous burden to the patient with spinal dysraphism. We examined our cases to determine the relationship between the level and type of spinal dysraphism, presence of a ventricular shunt, and urinary and gastrointestinal tract management. MATERIALS AND METHODS: After receiving ethics approval we reviewed the charts of 155 patients younger than 17 years with spinal dysraphism. We compiled all pertinent neurological, genitourinary and gastrointestinal outcomes from our pediatric and adolescent spina bifida clinic. RESULTS: Of our cohort 43% performed clean intermittent catheterization, including significantly more patients with myelomeningocele vs those with lipomeningocele or tethered cord (73% vs 19%, p <0.01). The intestinocystoplasty rate varied with lesion level and was significantly higher in cases of thoracic and thoracolumbar lesions than in cases of tethered cord, lipomeningocele and sacral myelomeningocele (p <0.005). Of the patients 52% older than 5 years were continent of urine but this varied significantly with lesion level and ventricular shunt presence. The urinary continence rate was highest in patients with a tethered spinal cord (57%), lipomyelomeningocele (65%) or sacral myelomeningocele (60%) (vs thoracic and lumbar myelomeningocele p <0.005). However, there was minimal difference between lumbar and thoracic lesions (25% and 26%, respectively). Of our patients 73% were also continent of feces, which did not vary with lesion level. CONCLUSIONS: Our data confirm the association of lesion level, a ventricular shunt and continence. PMID- 21527198 TI - Use of an inflatable silicone balloon improves the success rate of bladder autoaugmentation at long-term followup. AB - PURPOSE: Most groups have reported disappointing results with autoaugmentation or detrusor myectomy for low capacity/compliance neuropathic bladders. Failure may be due to an ischemic diverticulum or mucosal shrinkage. We investigated whether a Silimed(r) silicone balloon placed in the bladder after autoaugmentation could prevent these problems, improving surgical results. MATERIALS AND METHODS: We compared the results of standard bladder autoaugmentation in 12 children (group 1) with those in 10 (group 2) who underwent the same surgery using a bladder conformer. The conformer was a silicone balloon filled with saline that remained in the bladder for 2 weeks. All patients had a neuropathic bladder with poor capacity and compliance, resulting in urinary leakage between catheterizations. Preoperative and postoperative evaluation included a voiding diary, ultrasound, voiding cystourethrogram and urodynamics. RESULTS: In group 1 only 1 patient became dry, 4 had little improvement in continence, 4 remained unchanged and 3 became worse. In group 2, 6 patients (60%) become continent without medication, 2 (20%) become continent with oxybutynin and 2 remained unchanged. Bladder capacity and compliance did not change significantly in group 1. However, in group 2 capacity changed from a mean of 140 to 240 ml and mean +/- SD compliance increased from 15.6 +/- 16.8 to 34.3 +/- 22.8 ml/cm H(2)O (p = 0.02). CONCLUSIONS: The inflatable balloon improved our long-term results of bladder auto-augmentation. A larger series may be necessary to confirm procedure efficacy and safety. PMID- 21527199 TI - The BMP-7-Smad1/5/8 pathway promotes kidney repair after obstruction induced renal injury. AB - PURPOSE: Urinary tract obstruction causes hydroureteronephrosis and requires surgical intervention to prevent permanent renal injury. While many studies have focused on the development of renal injury, we examined the molecular mechanisms that promote renal recovery after correcting obstruction. MATERIALS AND METHODS: A reversible murine model of ureteral obstruction was used to examine the bone morphogenic protein-7 and transforming growth factor-beta signaling pathways during renal recovery after obstruction induced injury. Analysis was done using standard molecular techniques, including reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, immunoblotting and co immunoprecipitation. RESULTS: After correcting obstruction the up-regulation of bone morphogenic protein-7 inhibited the transforming growth factor-beta dependent profibrotic pathways that are central to renal injury pathogenesis. The inhibitory effects of bone morphogenic protein-7 were mediated in part by the activation of its downstream target proteins, SMA and MAD related proteins 1, 5 and 8, which suppress the activity of transforming growth factor-beta dependent Smad proteins and in turn inhibit the expression of transforming growth factor beta dependent genes. Activation of the bone morphogenic protein-7-Smad related protein 1/5/8 pathway during renal recovery promoted renal architecture restoration and fibrosis resolution in the kidney after correcting obstruction. CONCLUSIONS: Together these findings show that the bone morphogenic protein-7 Smad1/5/8 pathway promotes kidney repair after obstruction induced injury. Accordingly the pathway represents an important therapeutic target to stimulate this innate repair mechanisms of the kidney during treatment for obstruction induced renal injury. PMID- 21527200 TI - Cadaver donor kidney retransplantation in the pediatric patient: complications and long-term outcome. AB - PURPOSE: We compared the outcome of second and third kidney allografts with that of the first kidney allograft in pediatric recipients. MATERIALS AND METHODS: We classified 173 cadaveric kidney recipients into 2 groups. Group 1 comprised 120 first transplants and group 2 comprised 53 retransplants, including 43 second and 10 third transplants. We compared demographic characteristics and survival in groups 1 and 2. RESULTS: Group 1 consisted of 78 boys and 42 girls with a mean +/ SD age of 11.5 +/- 4.2 years. Group 2 consisted of 37 boys and 16 girls with a mean age of 10.4 +/- 4.7 years. One, 5, 10 and 15-year graft survival rates were 78.7%, 64.3%, 54.5% and 50.7% for first transplants vs 82.8%, 57.8%, 57.8% and 41.3%, respectively, for retransplants (p = 0.757). Patient survival at 1, 5 and 15-year was 95.8%, 89.6%, 84.9% in the first transplant group vs 93.6%, 93.6% and 93.6%, respectively, in the retransplant group (p = 0.0.63). Graft survival was significantly higher in patients who did vs did not receive calcineurin inhibitors in the 2 groups (p = 0.02). CONCLUSIONS: Kidney retransplantation in the pediatric population can yield excellent long-term outcomes, especially in patients treated with calcineurin inhibitors. PMID- 21527201 TI - Acquired undescended testes in boys with hypospadias. AB - PURPOSE: We determined the incidence of acquired undescended testes in boys with hypospadias. MATERIALS AND METHODS: We retrospectively reviewed the records of 566 boys with hypospadias who were referred to our outpatient clinic between January 2000 and September 2009. Acquired undescended testes were defined as testes that were documented at the bottom of the scrotum at least once after birth by the pediatric urologist at our institution but were subsequently documented to have moved from a satisfactory scrotal position by the same pediatric urologist or an equally experienced pediatric urologist. However, this definition did not include undescended testes after inguinoscrotal surgery. We excluded boys with gender development disorders with testicular dysgenesis, those who underwent bilateral inguinoscrotal surgery and those without congenital cryptorchidism who were followed less than 3 months. RESULTS: Of the 566 boys with hypospadias 100 met study exclusion criteria. Of the 466 boys included in analysis 29 (6.2%) had congenital cryptorchidism and 15 (3.2%) had acquired undescended testes. Urethroplasty was performed in 413 boys, including 91 with distal, 132 with mid and 181 with proximal hypospadias. The incidence of congenital cryptorchidism and acquired undescended testes in boys with proximal hypospadias was significantly higher than that in boys with other types of hypospadias (p = 0.03 and 0.001, respectively). CONCLUSIONS: Boys with proximal hypospadias are at a higher risk for acquired undescended testes than those with other mild types of hypospadias. Thus, testicular location should be monitored regularly until after puberty. PMID- 21527202 TI - Structural study of prepuce in hypospadias--does topical treatment with testosterone produce alterations in prepuce vascularization? AB - PURPOSE: Androgen stimulation before hypospadias surgery has resulted in increased penile size, fewer complications and improved cosmesis, and suggests increased neovascularization. To our knowledge the real effect on neovascularization remains to be proved. We studied the histological effects of testosterone on neovascularization. MATERIALS AND METHODS: A total of 26 boys with hypospadias were randomly allocated to 2 groups before surgical correction. Group 1 did not receive any treatment and group 2 received 1% testosterone propionate ointment twice daily for 30 days before surgery. During the surgical procedure a fragment of prepuce was excised and prepared for histological evaluation. The number and volume density of blood vessels were determined by labeling for von Willebrand's factor. Blood vessel quantification as volume density was done using a video microscopy system with a superimposed cycloid arch test system. RESULTS: The groups were similar in age and hypospadias classification. Testosterone treated prepuces (group 2) had an increased absolute number of blood vessels (mean +/- SD 8.5 +/- 1.3 vs 4.8 +/- 1.8 vessels per field) and increased blood vessel volume density (mean 50.5% +/- 7.8% vs 24.8% +/ 8.6% vessels per point) (each p <0.001) compared to those in untreated patients (group 1). CONCLUSIONS: The use of 1% testosterone propionate ointment before hypospadias surgery produces neovascularization in absolute numbers and in volume density. PMID- 21527203 TI - "Hanging" of the buccal mucosal graft for urethral stricture repair after failed hypospadias. AB - PURPOSE: Urethral stricture is the second most common complication of hypospadias repair after urethrocutaneous fistula. Usually more than 1 procedure is needed for correction due to a lack of available tissue after previous repairs. We evaluated 1-stage urethral stricture management after hypospadias repair using a ventral buccal mucosal graft. We describe the importance of graft hanging and coverage. MATERIALS AND METHODS: From August 2004 to April 2009, 15 patients 9 to 17 years old underwent urethral stricture repair after failed hypospadias surgery. Mean time after primary surgery was 7.2 years (range 4 to 13). Vascularized periurethral tissue around the stenotic part of the neourethra was dissected. The urethra was opened ventrally and a buccal mucosal graft of appropriate size was inserted to allow urethral augmentation. Using several U stitches the graft was anchored to the surrounding periurethral tissue to prevent its folding and retraction. Recurrent chordee in 12 patients and secondary vesicoureteral reflux in 3 were also corrected at this time. RESULTS: Mean followup was 37 months (range 17 to 73). Successful results were confirmed in all patients by urethrography and uroflowmetry. One urethral fistula was corrected 3 months later by minor surgery. Recurvature did not develop in this group. There was no recurrent reflux in endoscopically treated patients. CONCLUSIONS: Ventral buccal mucosal grafting is a simple, safe option for urethral stricture repair. Hanging the graft to periurethral tissue is important for its survival and to prevent postoperative folding and retraction. PMID- 21527204 TI - A simplified technique for botulinum toxin injections in children with neurogenic bladder. AB - PURPOSE: Botulinum toxin type A has revolutionized the treatment of neurogenic bladder dysfunction. The original injection technique used a rigid cystoscope and a flexible collagen needle. To date botulinum toxin type A injection techniques have not been standardized. We present our experience in pediatric patients using a new flexible injection system. MATERIALS AND METHODS: We treated 24 patients 3.8 to 17.5 years old who had neurogenic bladder dysfunction with botulinum toxin type A bladder and/or sphincter injection using a rigid cystoscope and the new N DOTM endo-injector needle system. Another 24 patients 3.6 to 17.8 years old were treated with a 3.7Fr standard flexible needle and served as controls. Operative time, hospital stay, complications and efficacy were considered. Selection criteria and treatment were the same in the 2 groups. The 10 IU/kg dose was determined according to European Association of Urology guidelines. RESULTS: All patients received botulinum toxin type A bladder injection while 11 patients in the endo-injector group and 5 controls also received urethral injection. In the endo-injector needle and control groups average operative time was 12.4 and 17.3 minutes for the bladder, and 5.1 and 10.1 minutes for the urethra, respectively (each p <0.05). All patients were discharged home the day after the procedure. No complications were observed. Urodynamics revealed an average maximum detrusor pressure decrease of 25 and 21 cm H(2)O, and an average bladder capacity increase of 75 and 80 ml in the endo-injector and control groups, respectively (p not significant). CONCLUSIONS: While retaining efficacy, the endo-injector needle technique appears to be more rapid than the standard procedure for botulinum toxin type A injection for neurogenic bladder dysfunction. Whether patients may be treated with sedation only remains to be clarified. PMID- 21527205 TI - The first World Congress of Pediatric Urology. PMID- 21527206 TI - Binding of the cell adhesive protein tropoelastin to PTFE through plasma immersion ion implantation treatment. AB - The interaction of proteins and cells with polymers is critical to their use in scientific and medical applications. In this study, plasma immersion ion implantation (PIII) was used to modify the surface of polytetrafluorethylene (PTFE), enabling the covalent binding of a cell adhesive protein, tropoelastin, without employing chemical linking molecules. Tropoelastin coating of untreated or PIII treated PFTE simultaneously promoted and blocked cell interactions respectively, i.e. PIII treatment of the PTFE surface completely inverses the cell interactive properties of bound tropoelastin. This activity persisted over long term storage of the PIII treated surfaces. The integrin binding C-terminus of tropoelastin was markedly less solvent exposed when bound to PIII treated PTFE than untreated PTFE, accounting for the modulation of cell adhesive activity. This presents a new methodology to specifically modulate cell behavior on a polymer surface using a simple one step treatment process, by adjusting the adhesive activity of a single extracellular matrix protein. PMID- 21527207 TI - Biochemical and phylogenetic analysis of CEBiP-like LysM domain-containing extracellular proteins in higher plants. AB - The chitin elicitor-binding protein (CEBiP) from rice was the first plant lysin motif (LysM) protein for which the biological and biochemical function had been established. It belongs to a plant-specific family of extracellular LysM proteins (LYMs) for which we analyzed the phylogeny. LYMs are present in vascular plants only, where an early gene duplication event might have resulted in two types which were retained in present day genomes. LYMs consist of a signal peptide, three consecutive LysMs, separated by cysteine pairs, and a C-terminal region without any known signature, whose length allows the distinction between the two types, and which may be followed by a glycosylphosphatidylinositol (GPI) anchor motif. We analyzed a representative of each type, MtLYM1 and MtLYM2, from Medicago truncatula at the biochemical level and with respect to their expression patterns and observed some similarities but also marked differences. MtLYM1 and MtLYM2 proved to be very different with regard to abundance and apparent molecular mass on SDS-PAGE. Both undergo several post-translational modifications, including N-glycosylation and the addition of a GPI anchor, which would position the proteins at the outer face of the plasma membrane. Only MtLYM2, but not MtLYM1, showed specific binding to biotinylated N acetylchitooctaose in a manner similar to CEBiP, which belongs to the same type. We postulate that LYM2-type proteins likely function in the perception of chitin related molecules, whereas possible functions of LYM1-type proteins remain to be elucidated. PMID- 21527208 TI - Human papillomavirus genotype distribution in oropharynx and oral cavity cancer in France--The EDiTH VI study. AB - BACKGROUND: The incidence of oropharyngeal cancers has gradually increased over the last decades. Recent studies suggest an association between human papillomavirus (HPV) infection and several head and neck cancers, especially oropharyngeal and oral cavity invasive carcinomas. OBJECTIVES: The objective was to assess the overall and type specific HPV prevalence in oropharyngeal and oral cavity carcinomas in France. STUDY DESIGN: Paraffin-embedded tumour specimens were retrospectively collected in 12 French centres and centrally tested for HPV detection and genotyping (INNO-LiPA assay). RESULTS: A total of 523 cases (77% males) were collected, among which 60% were oropharyngeal and 40% oral cavity carcinomas. The most frequent anatomical sites were tonsil (58.9%) and base of tongue (13.7%) for the oropharynx and floor of mouth (41.1%) and oral tongue (38.3%) for the oral cavity. Overall HPV prevalence was 46.5% in oropharyngeal carcinomas and 10.5% in oral cavity carcinomas and was higher in female than in male cases (63.5% vs 42.2% in oropharynx and 17.2% vs 8.0% in oral cavity). About 95% of HPV-positive cases were infected by a single HPV type. HPV 16 was the most prevalent type and was found in 89.7% and 95.5% of HPV-positive oropharyngeal and oral cavity carcinoma cases, respectively. All other HPV types had prevalence below 5%. CONCLUSIONS: Our results indicate that HPV is common among oropharyngeal and oral cavity carcinoma cases in France and emphasize the predominance of HPV 16. The potential benefit of HPV vaccination on the occurrence of head and neck carcinomas should be further evaluated. PMID- 21527209 TI - The PE and PPE proteins of Mycobacterium tuberculosis. AB - India already has earned the dubious distinction of being one of the countries with the highest incidence of tuberculosis (TB). The conventional control measures have had little impact on the relentless march of the TB epidemic. Potential solutions to this problem include the development of new drugs and an effective TB vaccine. In this perspective, identification of the mycobacterial components that have important role(s) in the establishment of the infection assumes crucial importance. Mycobacterium tuberculosis is an intracellular pathogen and it resides inside the macrophage, which is considered to be the most important component of the immune system. M. tuberculosis possesses two highly polymorphic sets of genes called the PE and PPE families. These unique families of proteins account for about 10% of the mycobacterial genome and have drawn considerable interest from different schools of M. tuberculosis researchers across the globe. In this review, we discuss the importance of these proteins in the regulation of dendritic cell and macrophage immune-effector functions, as well as the relevance of these proteins in the clinical manifestation of TB. This information may be helpful to better understand the immunological importance of PE/PPE proteins and their roles in mycobacterial virulence. PMID- 21527210 TI - Ventral corporal body grafting for correcting severe penile curvature associated with single or two-stage hypospadias repair. AB - PURPOSE: The literature on small intestinal submucosa for chordee correction in children is scarce. We reviewed our experience with 1 ply SIS for ventral corporal body grafting in cases of severe ventral penile curvature associated with proximal hypospadias in children. MATERIALS AND METHODS: From 04-2001 to 12 2007, 58 boys with proximal hypospadias and severe ventral curvature underwent single layered SIS graft to the corporal bodies to correct chordee. In 43 patients the surgery was done in the first stage of a planned 2-stage procedure. Fifteen patients underwent a 1-stage chordee correction with SIS and tubularized transverse preputial flap urethra. RESULTS: Mean follow-up was 4.8 years. A straight phallus with good cosmesis was achieved in 57/58 patients. In 51/58 patients an artificial erection was performed in the operating room as part of a second stage procedure or for complications associated with the one stage urethroplasty. One patient needed a second procedure to correct the curvature (chordee was over-corrected and needed a ventral Nesbitt plication). In fifteen patients that underwent a 1-stage genital reconstruction, the neourethral meatus was left in the lower part of the glans in 8 patients and at the coronal sulcus in 7. CONCLUSIONS: Corporal body grafting with single layer SIS is a viable option for correction of severe chordee associated with corporal body disproportion. SIS is a material with reliable results, easy availability and no donor site associated morbidity. As a result of penile elongation with a graft, simultaneous island flap urethroplasty became difficult in many patients. PMID- 21527211 TI - Outcomes and fate of the remnant moiety following laparoscopic heminephrectomy for duplex kidney: a multicenter review. AB - PURPOSE: To evaluate outcomes following laparoscopic heminephrectomy (LHN) in duplex kidneys in the pediatric population, focusing on the fate of the remnant moiety. METHODS: 142 patients underwent laparoscopic heminephrectomy for duplex kidney across 4 different institutions in the U.S. and Europe. Median age at surgery was 11.4 months. A retroperitoneoscopic approach was used in all patients, with 82 (57.7%) patients placed in posterior prone position (PPR), and 60 (42.3%) in lateral retroperitoneal (LRP). Follow up included routine ultrasound, and DMSA was performed in the event of abnormalities in ultrasound or postoperative course. RESULTS: Median operative time was 120 min. 11 patients (7.7%) required open conversion, the majority of which (8/11) occurred prior to 2000. Median hospital stay was 2 days and no major complications were observed. 7 patients (4.9%) developed a postoperative urinoma, and 1 patient required ureterectomy for urinary tract infection. With a median follow-up of 4.5 years, 7 children (4.9%) experienced significant loss of function in the remaining moiety, with 3 patients requiring completion nephrectomy. Of patients losing their remaining moiety, median age at surgery was 9 months [4 - 42], and all except 1 (6/7) had an upper pole heminephrectomy. Three patients in this group (42%) experienced an immediate postoperative complication (hematoma, UTI, urinoma). No consistent preoperative or technical factors were consistent in the renal loss group. CONCLUSIONS: LHN for duplex kidney produces satisfactory outcomes in the pediatric population. With a median follow up of 4.5 years, we demonstrate a non functioning renal moiety rate of 5%. We did not identify any clinical predictors of this outcome in our series, although upper pole heminephrectomy, patient age, and postoperative complications may be contributing factors. PMID- 21527212 TI - Quality of life in children with vesicoureteral reflux as perceived by children and parents. AB - PURPOSE: Significant research has been dedicated to the management of vesicoureteral reflux (VUR). However, few studies have been published to evaluate the impact of this disease on quality of life. The aim of this study was a prospective examination of the health-related quality of life (HRQoL) in children with VUR who have either been treated medically (antibiotics or surveillance) or by ureteral reimplant (UR) using a validated patient satisfaction survey. MATERIALS AND METHODS: A prospective, longitudinal study was conducted using a validated HRQoL questionnaire, the Pediatric Quality of Life Inventory (PedsQLTM 4.0 Generic Core). 353 children or parents of children with VUR, age 2-18 years, completed the survey. Statistical analysis was performed with significance set at p-value <= 0.05. RESULTS: Children and parents of children with VUR did not score lower on total or subscale domains of HRQoL when compared to a historical healthy control. On univariate analysis, patients who underwent UR scored lower on total as well as physical, social, and school subscale HRQoL domains, compared to patients managed medically. When controlling for gender, ethnicity, age, reflux grade, and antibiotic use, there was no difference in total HRQoL between patients who underwent UR compared to those managed medically. CONCLUSIONS: In terms of HRQoL, VUR is a benign clinical entity and neither antibiotic use nor UR is associated with lower HRQoL. Disease-specific quality of life surveys are needed to accurately evaluate patient and parent satisfaction in the management of VUR. PMID- 21527213 TI - Dysfunction elimination syndrome: is age at toilet training a determinant? AB - PURPOSE: To study the relationship between the age of completion of toilet training during daytime and the onset of dysfunctional elimination syndrome (DES). METHODS: The present study was designed as a case-control study. A total of 80 patients with DES were allocated to the case group and 80 patients age- and gender-matched without DES were allocated to the control group. The patients with DES were seen in a tertiary center and the control patients were seen in a primary care center. Early completion of toilet training was considered to be before 24 months. RESULTS: Patients were aged 3-17 years (mean: 7.55); 24 were male (30%) and 56 female (70%). The most frequent lower urinary tract symptoms were: urgency (77%), incontinence (75%), holding maneuvers (30%), high urinary frequency (61%) and low urinary frequency (16%). There was a history of urinary tract infection (UTI) in 62% of the DES group. The first UTI episode was before toilet training in 40%. The completion of toilet training was before the age of 2 years in 48% of DES patients and in 50% of the control group (p = 0.752) [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.49-1.62]. CONCLUSION: The completion of toilet training before 24 months of age was not associated with DES. Some patients had DES symptoms such as UTI, infrequent voiding and constipation before toilet training. These findings suggest that DES may precede toilet training and this possibility should be confirmed in further studies. PMID- 21527214 TI - Age and pro-inflammatory cytokine production: wound-healing implications for scar formation and the timing of genital surgery in boys. AB - PURPOSE: Fewer complications occur when hypospadias is repaired early in childhood. We hypothesize that the production of pro-inflammatory cytokines by fibroblasts from neonatal foreskin is decreased compared with fibroblasts from older boys. We believe that these age-related differences may explain the greater risk of complications following repair in older boys. MATERIALS AND METHODS: With IRB approval, we collected 15 samples of foreskin from boys undergoing elective circumcision. They were divided into one of three groups: a neonatal group (under 28 days), an intermediate age group (6 months-1 year), and an older age group (7 17-years-olds). Fibroblasts were cultured then incubated for 16 h with serum-free medium containing 0, 0.1, 1 or 10 ng/mL of PDGF. Supernatants were analyzed for production of IL-6 and IL-8 with quantitative ELISA. Fibroblasts had RT-PCR performed for IL-6, IL-8, IL-10, TGF-beta1, TGF-beta3 and TNF-alpha. RESULTS: Fibroblasts from neonatal foreskin produced significantly less IL-6 and IL-8 at baseline and following stimulation with PDGF compared to the intermediate and older age groups (P < 0.01). Real-time PCR revealed greater expression of IL-6, IL-8, TNF-alpha and TGF-beta1 mRNA in the older age groups (P < 0.05). CONCLUSIONS: There is a clear association between age and production of pro inflammatory cytokines by genitourinary fibroblasts. This relationship exists at baseline and following stimulation with PDGF. The dramatic difference in levels of pro-inflammatory factors may explain the observed age-associated differences in wound scarring and stricture formation following hypospadias repair. Further clinical studies are needed, however, to validate this finding. PMID- 21527215 TI - Long-term results with a one-stage complex primary hypospadias repair strategy (the three-in-one technique). AB - PURPOSE: Complex primary hypospadias repair that warrants urethral plate division is treated mostly in two steps, not necessarily in two surgeries. Our aim was to review long-term results with a one-stage strategy based on reconstruction of the urethral plate with buccal mucosa graft and onlay transverse preputial flap anastomosis protected by a tunica vaginalis flap (the three-in-one concept). MATERIAL AND METHODS: We were able to report on 35 patients operated for primary scrotal, penoscrotal and perineal hypospadias between March 2002 and June 2008. We reviewed all charts and had phone interviews with patients not seen for the last 24 months. We investigated parameters such as UTI occurrence, fistula, residual curvature, meatal stenosis, urethral diverticula, dehiscence, orchitis and parental perception. RESULTS: Surgical complications occurred in 13 patients (37%): 4 meatal stenosis, 4 diverticula, 5 fistulae and 2 residual penile curvatures (total 42%). Meatal dilatation was successful in 2 cases, reflected in fistula resolution. The reoperation rate was 31.5% consisting mostly of simple procedures like fistula closure, meatotomy and penile curvature release, and complex diverticula repair in 4 cases. Parental perception was excellent for 57% (20 patients) and good or acceptable for the remaining. Mean follow-up was 4.6 years. CONCLUSIONS: The one-step strategy is associated with 68.5% success in a single operation, whereas 31.5% will need a second repair. We recognize that meatal problems are mostly associated with fistulae and diverticula; therefore, we recommend a final acceptable proximal glandar opening that will not compromise the neourethra. PMID- 21527216 TI - Effectiveness of biofeedback for dysfunctional elimination syndrome in pediatrics: a systematic review. AB - PURPOSE: Dysfunctional elimination syndrome is associated with an inability to effectively empty the bladder and may present with UTI, incontinence, intestinal constipation or other voiding symptoms. Biofeedback has emerged as one potentially effective and non-invasive treatment. We sought to analyze if biofeedback is an effective method to treat children less than 18 years of age. METHODS: A literature search was conducted in MEDLINE, EMBASE, CINAHL, Cochrane Database, AUA, CUA, AAP and ESPU abstracts. Copies of all relevant articles were retrieved for quality assessment and data abstraction by two independent reviewers. Primary outcomes were UTIs and daytime incontinence. RESULTS: 27 studies were included (1 RCT and 26 case-series). The pooled estimate showed 83% (95% CI: 79%-86%) and 80% (95% CI: 76%-85%) improvement in UTI and daytime incontinence respectively. I(2) statistic showed "Low" (7%) and "High" (77%) heterogeneity across studies results for UTI and daytime incontinence. The only included RCT favored biofeedback over standard therapy (RR 1.4, 95% CI: 0.98 2.00) but this was not statistically significant. On analysis of all included studies there was also improvement in constipation (18%-100%), frequency (67% 100%), urgency (71%-88%) and VUR (21%-100%). PVR improvement ranged from 26 ml to 99 ml and Q(max) improvement was from 3.1 ml/s-4.7 ml/s. CONCLUSION: Based on this review, biofeedback is an effective, non-invasive method of treating dysfunctional elimination syndrome, and approximately 80% of children benefited from this treatment. However, most reports were of low level of evidence and studies of more solid design such as RCT should be conducted. PMID- 21527217 TI - Renal parenchymal fibrosis and atrophy are not correlated with upper tract dilatation: long-term study of partial unilateral ureteral obstruction in neonatal mice. AB - PURPOSE: The mechanism underlying the evolution of congenital obstructive hydronephrosis is still unclear. In a previous study, we have shown that it is possible to create renal lesions in newborn mice specific to partial ureteral obstruction. We aimed to study the long-term results of such partial obstruction. METHODS: Mice were operated on the third day of life. We created 2 groups: partial unilateral obstruction and control. We studied antero-posterior pelvis diameter, kidney length and volume on magnetic resonance imaging at day 10 and 3 months. We assessed ureteric patency by injecting Patent Blue dye. Kidney weight and fibrosis were histologically assessed. Fibrosis was assessed using Sirius Red staining and morphometry. RESULTS: Imaging showed parenchymal atrophy in the partially obstructed kidney and compensatory hypertrophy of the contralateral kidney. Pelvis dilatation was detected at day 10 but remained stable without significant increase at 3 months. The patency test confirmed the absence of total obstruction in the long term. There was no correlation between the degree of dilatation and parenchymal atrophy or the contralateral hypertrophy. Pathological studies at 3 months revealed fibrosis in the parenchyma without significant correlation with pelvis dilatation. CONCLUSIONS: Long-term results confirmed that partial ureteral obstruction in newborn mice produces fibrotic lesions of the renal parenchyma, which are not correlated with dilatation of the upper tract. These results could contribute to the clinical management of obstructive uropathy in children, emphasizing that follow up with simple evaluation of upper tract dilatation is insufficient to predict renal deterioration. PMID- 21527218 TI - In-vivo autologous bladder muscular wall regeneration: application of tissue engineered pericardium in a model of bladder as a bioreactor. AB - PURPOSE: Tissue-engineered pericardium (TEP) is a collagen-rich matrix that has previously been shown to promote in vivo and in vitro tissue regeneration. We evaluated the potential of TEP as a source for the in-vivo creation of bladder muscular wall grafts. We used bladder wall as a bioreactor to create a natural environment for cellular growth and differentiation. MATERIALS AND METHODS: Sixteen rabbits were divided into four groups. A control group underwent classical bladder autoaugmentation. Other groups underwent insertion of TEP between bladder mucosa and muscular layer: group 2 with insertion of TEP, group 3 with TEP over autologous bladder muscular wall fragments, and group 4 with autologous bladder smooth muscle cells (SMCs) seeded on TEP. After 4 and 8 weeks, grafts were biopsied for histopathological evaluations. RESULTS: Frames from groups 3 and 4 demonstrated more organized muscular wall generation with a significantly higher number of CD34 + endothelial progenitor cells and CD31 + microvessels, and maintenance of alpha-smooth muscle actin expression through immunohistochemistry. Group 4 showed significant enhancement of SMC penetration to TEP. Although the fragment-seeded group required a simpler procedure, the cell seeded group showed superior organization of the muscular layer on histopathology. We found a semi-organized muscular layer and new vessels in the margins of TEP in group 3, while there was a homogeneous pattern of SMCs and new vessels in both the margins and center of TEP in group 4. CONCLUSIONS: This preliminary work has important functional and clinical implications, as it indicates that use of the autologous SMC seeding method may enhance the properties of TEP in terms of bladder wall regeneration. PMID- 21527219 TI - Nephrectomy for hypertension in pediatric patients with a unilateral poorly functioning kidney: a contemporary cohort. AB - PURPOSE: A unilateral poorly or non-functioning kidney is a cause of hypertension in children. We report the outcomes of pediatric patients with unilateral renal parenchymal disease who underwent nephrectomy for hypertension. MATERIALS AND METHODS: Consecutive hypertensive children undergoing nephrectomy with a unilateral poorly or non-functioning kidney were retrospectively reviewed; preoperative and postoperative clinical variables were analyzed. RESULTS: From July 2002 to August 2009, 21 patients (8M:13F) with average age 3.5 years and average follow-up 17.8 months were studied. Eleven patients had multicystic dysplastic kidney, 8 had reflux nephropathy, and 2 had ureteropelvic junction obstruction. Fourteen of 21 (67%) had blood pressure normalization after nephrectomy. Seven of 11 with MCDK were normotensive postoperatively compared to 6/8 patients with reflux nephropathy, and 1/2 patients with UPJ obstruction. Of the 14 patients normotensive postoperatively, 7 were on antihypertensives prior to surgery. Four of 7 patients stopped their anti-hypertensive medications postoperatively, 2 decreased from 3 and 4 medications to 1, and 1 remained on an ACE inhibitor. There were 2 patients with contralateral renal scarring, both of which remained hypertensive postoperatively. CONCLUSIONS: Nephrectomy in hypertensive pediatric patients with a unilateral poorly functioning or non functioning kidney yielded hypertension resolution in 67% (14/21), permitting cessation or diminution of antihypertensives in many patients. Given the alternative of lifelong antihypertensives with the risk of medication non compliance and side-effects, nephrectomy is a logical option of care which can be offered to patients and families with informed knowledge of the potential for cure. PMID- 21527220 TI - Assessment of recoverability of kidney function in children with obstructive calcular anuria: multicenter study. AB - OBJECTIVE: Urolithiasis in children can cause considerable morbidity. Our aim was to evaluate the impact of intervention on the recoverability of kidney functions. MATERIALS AND METHODS: This prospective study included 93 children (66 boys and 27 girls) with median age of 3 years (range 0-14). Inclusion criteria were presence of anuria, oliguria, serum creatinine >2 mg% and/or hyperkalemia >= 6 mmol/L. The mean duration of anuria or oliguria was (mean +/- SE) 5.3 +/- 0.4 days. On presentation, mean plasma creatinine was 6.5 +/- 0.29 mg/dl with a mean estimated glomerular filtration rate (eGFR) of 14 ml/min and creatinine clearance (CC) of 8.24 ml/min. Dialysis was performed in 21 (22.6%) patients. When condition allowed, emergency surgery was performed. RESULTS: Mean follow up was 1.5 years with compliance of 82%. At the end of treatment, 83% of patients had complete clearance of calculi. Mean plasma creatinine after treatment was 3.3 +/- 0.35 mg/dl with an average GFR of 24.5 ml/min. After treatment renal function returned to normal in 57%, improved in 27% and deteriorated in 16% of children. Renal function recoverability rate was 94.6%. Chronic renal failure developed in 3 (3.2%) patients and 2 (2.2%) patients died. When absolute plasma creatinine concentration [P(cr)] improved 20-50% the eGFR and CC were doubled, and when improved 50-70% eGFR and CC tripled. Beyond 70% improvement in [P(cr)], eGFR and CC improved 7-8 times. Using Spearman's correlation, the mode of presentation and the type of management had a significant correlation with renal function outcome (P = 0.019 and 0.013 respectively). CONCLUSION: Urgent management of calcular anuria both medically and surgically is the cornerstone for favorable outcome. The mode of presentation and the type of management are significant factors affecting final renal function outcome. PMID- 21527221 TI - Renal autotransplantation for the treatment of renovascular hypertension in the pediatric population. AB - PURPOSE: To evaluate the effectiveness of renal autotransplantation (RA) for the treatment of renovascular hypertension (RVH) in a selected group of children in whom medical care, a percutaneous transluminal angioplasty or vascular reconstruction failed or was technically impossible, in addition to the short term and long-term morbidity. MATERIALS AND METHODS: A retrospective case review of 13 pediatric patients with severe or complicated RVH who underwent RA between May 1993 and August 2008 was conducted. We defined blood pressure (BP) response as follows: Cured: normal BP values with no need of antihypertensive medication (AM); Improved: normal BP values with AM requirements; Failed: abnormal BP values despite treatment with AM. RESULTS: 16 RA were performed in 7 female and 6 male patients. Bilateral RA were performed in 2 females and in 1 male. The average age at consultation for hypertension was 8.5 years (range 4-12 years) and the time of transplantation was 9.12 years (range 6-13 years). Etiological diagnoses were: Takayasu disease (n = 5); renal artery fibrodysplasia (n = 3); mid-aortic syndrome (n = 3) and neurofibromatosis type I (n = 2). Results after RA were: Cured: 61.5%; Improved: 38.5%. No patient presented therapeutic failure during follow up time (median = 53.4 months). Only 1 case presented a postoperative complication. CONCLUSIONS: RA is a procedure with no mortality and low morbidity rates that renders very satisfactory therapeutic results in the pediatric population. PMID- 21527222 TI - Z-plasty for sculpturing of the bifid scrotum in severe hypospadias associated with penoscrotal transposition. AB - PURPOSE: Bifid scrotum is usually associated with scrotal and perineal hypospadias. Conventional surgical repair involves rotation of two scrotal flaps, joining them in the midline, and vertical skin closure. Dimpling of skin can occur, resulting in suboptimal aesthetic results. We describe a technique whereby the bifid scrotum is rebuilt and contoured using single or multiple Z-plasties. METHODS: We repaired 43 children with scrotal, penoscrotal or perineal hypospadias and varying degrees of bifid scrotum. Age range was 5 months-18 years. Patients were divided into three groups: I) 26 children with primary perineoscrotal hypospadias who underwent two-stage hypospadias repair and had a Z scrotoplasty during either the first or second stage repair; II) 11 children who had previous hypospadias surgery with vertical closure of scrotum, and who underwent secondary Z-scrotoplasty; III) 6 children with primary posterior hypospadias who had their scrotum repaired with midline vertical closure, serving as control. RESULTS: 24 children in Group I and all patients in Group II achieved excellent aesthetic results, with rounded scrotum, no midline dimpling and no major complications. Midline dimple was encountered in 4 patients in Group III. CONCLUSIONS: In repairing bifid scrotum associated with hypospadias, the principle of Z-plasty can be incorporated in scrotal contouring. This elongates, relaxes and interrupts the longitudinal tension of the midline closure. Multiple Z-plasties avoid contracture and scar formation, which are apt to result in recurrence of bifid scrotum. PMID- 21527223 TI - Objective measurement of quality of life changes after ACE Malone using the FICQOL survey. AB - PURPOSE: There is little objective data demonstrating improved quality of life after a Malone antegrade continence enema (ACE) despite the dramatic subjective improvements seen by physicians and caretakers. METHODS: We utilized the FICQOL survey, a reliable and valid instrument for measuring the impact of fecal incontinence and constipation on quality of life (FICQOL) of caregivers and children with spina bifida. Between 2002 and 2009, 23 families were evaluated prospectively before and after an ACE procedure. Items on the survey were compared with Wilcoxon rank sum or signed rank test. RESULTS: After an ACE Malone the mean number of bowel movements (BM) per day decreased along with a decrease in number of accidents per week from 3.9 to 0.3. There was no change in the time committed to bowel care. The percentage of patients taking oral laxatives decreased from 44% to 6%. Both parent and child were less often prevented from leaving the house and the caretakers' bother, anxiety and depression due to bowel care decreased. Although factors regarding the child's social issues and parent's employment improved, the changes were not statistically significant. CONCLUSIONS: Among patients with spina bifida and fecal incontinence who underwent the ACE procedure at our institution, a significant improvement in fecal incontinence and QOL scores was observed using a validated instrument, FICQOL. Without changing the amount of time necessary for bowel care, the ACE procedure decreases the families' worries and anxieties and allows them to leave home with the confidence that their child will not have leakage of stool. PMID- 21527225 TI - Safety and efficacy of PCNL for management of staghorn calculi in pediatric patients. AB - OBJECTIVES: There are few reports on the use of PCNL for staghorn calculi in children. We evaluated the safety and efficacy of this technique, using adult equipment, in children below 16 years of age. METHODS: Data for pediatric patients undergoing PCNL for staghorn renal calculi was prospectively recorded. A staghorn calculus was defined as a branched stone occupying more than one part of the collecting system. A standard fluoroscopy guided PCNL was performed in the prone position using adult nephroscopes. Stone clearance was assessed on fluoroscopy and X-ray in all patients and an ultrasound or CT scan in selected cases. RESULTS: Beginning October 2007, 33 pediatric patients underwent 34 PCNLs at our center. 12 of these children had staghorn calculi. All patients had normal renal function and no metabolic abnormality. One child had a solitary kidney. In 5 children, the primary tract was placed into the superior calyx and 4 of these were above the 12th rib. A 21Fr nephroscope was used through a 24Fr tract in 9 children while a 26Fr nephroscope was used through a 30Fr tract in 3 cases. 10 children were managed through a single tract. One patient each required SWL and ureteroscopy for residual fragments. 11 patients had complete clearance while 1 had insignificant residue. One child required intravenous antibiotics for post operative fever while another developed an abdominal collection that was managed conservatively. CONCLUSIONS: PCNL is safe and effective in the management of pediatric staghorn calculi. PMID- 21527226 TI - Development of late, symptomatic abdominopelvic lymphoceles more than 10 years following pediatric reconstructive urologic procedures. AB - PURPOSE: Rare reports of symptomatic abdominopelvic lymphoceles following pediatric genitourinary reconstruction do exist; however there are no data regarding the development or management of late symptomatic lymphoceles. We report on the clinical presentation of these lymphoceles 10 or more years following initial urologic surgery. MATERIALS AND METHODS: We reviewed 480 patients following major intra-abdominal urologic reconstructive procedures from 1986 to 2009 for development of late, symptomatic abdominopelvic lymphoceles. A minimum of 10 years post-surgical follow up was required for inclusion. RESULTS: Late symptomatic lymphoceles developed in 4/480 (0.8%) patients. Median length of follow up post reconstruction was 13.5 years (range 10-17). Median time to lymphocele development was 12 years (range 8-16). Symptoms at presentation included abdominal distension (4/4, 100%), nausea and vomiting (3/4, 75%), flank pain/progressive hydroureteronephrosis (3/4, 75%), and obstructive pyelonephritis (1/4, 25%). Additional surgical procedures that may have contributed to lymphocele development were present in 100%. 75% (3/4) of the patients underwent open surgical drainage, with one electing observation for intermittent symptoms. Exploration revealed loculated fluid collections between bowel loops and dense adhesions; symptoms resolved although small asymptomatic recurrences developed in all patients. CONCLUSIONS: Late, symptomatic abdominopelvic lymphoceles following major pediatric urinary tract reconstruction or diversion develop in <1% patients. Many undergo subsequent abdominopelvic surgery, which may contribute to development of these late, pathologic lymphoceles. Open surgical drainage is usually required with excellent outcome. PMID- 21527227 TI - Comparative analysis of nephrolithiasis in otherwise healthy versus medically complex gastrostomy fed children. AB - PURPOSE: The purpose was to compare nephrolithiasis in healthy versus medically complex gastrostomy fed children. MATERIALS AND METHODS: Children with nephrolithiasis with and without gastrostomy were identified by database searches from 1999 to 2009. Gastrostomy fed stone formers (GSF) were compared to an age matched cohort of non-gastrostomy-fed stone formers (NGSF) for demographic and clinical data. RESULTS: 16 neurologically impaired GSF (10M:6F), mean age 10.4 years (range 1.7-17.5 years), were compared to 32 matched neurologically intact NGSF. Compared to NGSF, GSF had significantly higher urine pH (6.93 vs 6.23, p = 0.001) and larger stones (14.5 vs 6.9 mm, p = 0.02) more commonly composed of calcium phosphate (7/11, 64% vs 3/28, 11%, p = 0.002). 15/16 (94%) of GSF were immobile while 0% of NGSF were immobile. GSF had lower l-spine bone density Z scores (-3.02 vs -1, p = 0.002) but an equal rate of hypercalciuria (2/7, 29% vs 7/24, 29%, p = NS). Contributing lithogenic factors in 8/16 (50%) GSF included urinary tract infection (UTI) (5), lithogenic medications (2), and xanthinuria (1). CONCLUSIONS: Stone disease in GSF is multifactorial, and half of our study group had an identifiable risk factor for nephrolithiasis. A recurring pattern of alkaline urine and calcium phosphate stone formation was evident. GSF did not have higher rates of hypercalciuria despite chronic immobilization and markedly lower bone density. An awareness of the potential risk factors identified is mandatory for this vulnerable population. PMID- 21527229 TI - Pelvic fracture urethral distraction defects in children managed by anterior sagittal trans anorectal approach: a facilitating and safe access. AB - PURPOSE: Trauma injuries of the posterior urethra resulting from pelvic fracture in children tend to be complete ruptures, with upper dislocation of the prostate. This paper aims to show our experience in using an anterior sagittal transanorectal approach (ASTRA) in the treatment of such injuries. MATERIALS AND METHODS: The medical records of 11 patients with pelvic fracture urethral distraction defects who had undergone anastomotic urethroplasty through ASTRA between 1997 and 2009 were reviewed. Ages ranged from 1 year and 6 months to 23 years (mean age 11 years). Of the 11 patients, 8 had previously undergone failed urethroplasties. RESULTS: In 10 patients it was possible to perform tension free urethroplasty. One patient required inferior pubectomy and separation of the corpora cavernosa. Patients' follow-up time varied from 10 months to 10 years and 9 months (mean 41 months). One patient had a urethral fistula and evolved with a urethral diverticulum successfully managed by diverticulectomy. One patient presented a urethral stenosis managed by urethral dilatation. Of the 11 patients, 9 presented functional urethral flow and are continent. Two patients had no urethral flow. One is undergoing bladder catheterization through the Mitrofanoff principle and the other one through the urethra. No patient presented fecal incontinence or rectourethral fistula. CONCLUSION: This access, which is increasingly being used to approach posterior urethral diseases, has proved to be safe and effective in the treatment of pelvic fracture urethral distraction defects. PMID- 21527230 TI - Percutaneous nephrolithotomy for the management of stones in anomalous kidneys in children. AB - PURPOSE: We report percutaneous nephrolithotomy for the management of stones in anomalous kidneys in children. MATERIALS & METHODS: We performed PCNL on 6 children (one with bilateral stones), 3 boys and 3 girls with anomalous kidneys. Three had horseshoe kidneys, 2 malrotated kidneys, and one crossed fused ectopic kidney. Their age ranged from 5 to 12 years with a mean of 7.3 +/- 3 years. Two patients had previous failed ESWL, 4 underwent PCNL for large stone burden. Mean stone burden was 324.9 +/- 191.8 mm(2). Under fluoroscopic guidance we performed serial dilatation using Alken metal dilators. In 4 patients 17 Fr rigid nephroscope was used, in 2 patients 26 Fr nephroscope was utilized. Pneumatic lithotripsy was used for stone disintegration and forceps for stone extraction. RESULTS: A single stage PCNL resulted in complete stone clearance in 5 children, while one required a second look procedure. Operative time ranged from 25 to 70 min with a mean of 43.3 +/- 17.8 min. None of the patients required blood transfusion. Perforation of the renal pelvis occurred in one patient and was managed by prolonged insertion of nephrostomy tube. Hospital stay ranged from 1 to 6 days with a mean of 3 +/- 2 days. Postoperative fever occurred in one child and persisted for 3 days. All children were followed for 3 months and were stone free. Patient with bilateral stones performed ESWL on the contra lateral side. CONCLUSION: Children with stones in anomalous kidneys can be managed safely with PCNL when they are properly selected. PMID- 21527231 TI - The evaluation of combined standard urotherapy, abdominal and pelvic floor retraining in children with dysfunctional voiding. AB - PURPOSE: The aim of the study was to compare the treatment outcome of two urotherapy programs in children with dysfunctional voiding (DV) through analyzing the clinical manifestations and uroflowmetry parameters. MATERIALS AND METHODS: Eighty-six children with DV were randomly divided into two groups (A and B). Children in both groups were educated about the importance of regular voiding and hydratation, and about the appropriate posture during voiding. Simple voiding instructions were provided. In group A diaphragmatic breathing and pelvic floor muscles (PFM) retraining were additionally assigned to children. Constipation and recurrent urinary tract infections (UTIs) were treated in both groups. Selected children from both groups received pharmacotherapy (anticholinergics or desmopressin). Uroflowmetry with pelvic floor electromyography and ultrasound residual urine volumes were obtained before and at the end of the 12-month treatment period. RESULTS: After one year of therapy, urinary incontinence and nocturnal enuresis were cured in a significantly larger number of children in group A than in group B (P < 0.001; P < 0.05). Although more children with UTIs were cured in group A, the difference was not statistically significant compared to group B. There was a significant recovery constipation-wise in both groups. Post-treatment uroflowmetry parameters and curve pattern were markedly improved only in group A. CONCLUSIONS: Carefully planned and regularly controlled abdominal and PFM retraining is beneficial in children with DV for curing urinary incontinence, nocturnal enuresis, UTIs and normalizing urinary function. Further trials are needed to define the most effective treatment program for achieving the best treatment outcome. PMID- 21527232 TI - Bladder substitute reconstructed in a physiological pressure environment. AB - PURPOSE: Bladder reconstruction performed by enterocystoplasty or with bioengineered substitutes is still associated with complications, which led us to develop an autologous vesical equivalent (VE). This model has already proven its structural conformity. The challenge is to reconstruct our model in a more physiological environment, with the use of a bioreactor that mimics the dynamic of bladder filling and emptying, to acquire physiological properties. MATERIALS AND METHODS: Fibroblasts and urothelial cells evolved in a three-dimensional culture to obtain a reconstructed VE. This was then cultured in our bioreactor which delivers a cyclic pressure increase up to 15 cm H(2)O, followed by a rapid decrease, to achieve a dynamically cultured VE (dcVE). To compare with the statically cultured VE, the dcVE was characterized using histology and immunofluorescence. The mechanical resistance was evaluated by uniaxial tensile tests, and the permeability level was measured with 14C-urea. RESULTS: Compared to our static model, the dynamic culture led to a urothelium profile like that of native bladder. Permeability analysis displayed a profile comparable to native bladder, coinciding with basal cell organization in the dcVE, while an appropriate resistance for suturing and handling was shown. CONCLUSIONS: This new alternative method offers a promising avenue for regenerative medicine. It is distinguished by its autologous character and its efficiency as a barrier to urea. These properties could significantly reduce inflammation, necrosis, and therefore, possible rejection. PMID- 21527233 TI - Transpelvic anastomotic stenting: a good option for diversion after pyeloplasty in children. AB - PURPOSE: Several options are available to drain the renal pelvis after a dysmembered pyeloplasty. The purpose of our study was to review the results of transrenal pelvic transanastomotic stenting following ureteropelvic junction obstruction pyeloplasty (UPJO). PATIENTS AND METHODS: A retrospective chart review of 238 patients with UPJO (243 renal units) treated in 2004-2007. The patients were divided into 4 groups (1): renal units with very poor function (<10% uptake) having undergone nephrostomy tube placement, with pyeloplasty performed 1 month later for those with improved renal function, and nephrectomy for those with no improvement (2); pyeloplasty without diversion (3); pyeloplasty diverted with transrenal pelvis transanastomotic stenting (4); pyeloplasties diverted with both stents and Foley catheters; the stents used were 5 Fr or 6 Fr feeding tubes. RESULTS: Group 1: 13 nephrectomies and 31 pyeloplasties diverted with stents and Foley catheters; 1/31 re-do pyeloplasty. Group 2: 33 pyeloplasties that were performed without diversion or stenting; 2/33 required re do pyeloplasty. Group 3: 122 pyeloplasties diverted with only stents inserted through renal pelvis with 1 nephrostomy due to urine leakage, 2 prolonged urine leaks that ceased spontaneously, 1 urinary infection, no re-do pyeloplasty needed. Group 4: 44 pyeloplasties that were performed with stents and nephrostomy tubes, 2 delays of removal of Foley catheters, no re-do pyeloplasty needed. CONCLUSIONS: Transrenal pelvis transanastomotic stenting using a feeding tube is a good option for diverting urine following dysmembered pyeloplasty in children. PMID- 21527234 TI - Observation of infants with SFU grades 3-4 hydronephrosis: worsening drainage with serial diuresis renography indicates surgical intervention and helps prevent loss of renal function. AB - PURPOSE: Early pyeloplasty is indicated for ureteropelvic junction obstruction (UPJ) obstructions with reduced differential renal function (DRF) and/or no drainage on diuretic renography (DR). Optimal management of Society of Fetal Urology (SFU) Grades 3 and 4hydronephrosis with preservation of DRF and indeterminate drainage is less straightforward. We review our experience using serial DR to guide the management of kidneys with high-grade hydronephrosis, emphasizing preservation of DRF. METHODS: After IRB approval we reviewed the charts of 1398 patients <1-year-old referred for prenatal hydronephrosis. Only patients with SFU Grades 3 and 4 hydronephrosis without ureterectasis were included in the study. Initial evaluation included a baseline DR. Follow-up included DR or ultrasound (US). RESULTS: 115 patients (125 kidneys) were eligible for study inclusion. 27 kidneys underwent early surgery (median 64 days) due to reduced DRF and/or severely impaired drainage. 98 kidneys were initially observed. Of these, 21 underwent delayed surgery (median 487 days) due to worsening drainage. Only 2 patients had an irreversible decrease in DRF of >5%. 77 kidneys demonstrated improved drainage and stable DRF. Comparison of observation (n = 77) and surgery groups (n = 48) revealed more kidneys with SFU Grade 3 hydronephrosis in the observation group (p = 0.0001). CONCLUSION: Infants with Grades 3 and 4 hydronephrosis and preserved DRF may be safely followed with serial DR. Patients with SFU Grade 4 hydronephosis are more likely to require surgery. Worsening drainage on serial DR is a useful indicator for surgical intervention which limits the number of pyeloplasties while preserving DRF. PMID- 21527235 TI - Traumatic strictures of the posterior urethra in boys with special reference to recurrent strictures. AB - PURPOSE: We report 18 years' experience of traumatic urethral strictures in boys with emphasis on recurrent strictures. MATERIALS AND METHODS: Thirty-four boys with pelvic fracture urethral strictures underwent 35 repairs: 23 in the primary group (initial suprapubic cystostomy, but no urethral repair) and 12 in the re-do group (previously failed attempt(s) at urethroplasty elsewhere). The median age at operation and stricture length was 8.4 years and 3 cm in the primary and 9 years and 5.4 cm in the re-do group, respectively. Anastomotic urethroplasty was performed wherever possible, or failing this a substitution urethroplasty. Median follow up was 9 years for primary group and 8 years for re-do group. RESULTS: Primary group: urethroplasty was successful in 22/23, with 10 by perineal and 13 by additional transpubic approach. Two have stress incontinence. Erectile function is unchanged in all and upper tracts are maintained. One had recurrent stricture. Re-do group (12 including 1 recurrence from primary group): anastomotic urethroplasty was done in 5 and substitution urethroplasty in 7. Patients needing substitution had long stricture (>5 cm), stricture extending to distal bulb, or high riding bladder neck. All patients are voiding urethrally. Two patients with substitution required dilatation for early re-stenosis. One appendix substitution required delayed revision. Two have stress incontinence. Erectile function was unaffected. Upper tracts are maintained. CONCLUSIONS: Anastomotic urethroplasty was successful in over 95% of primary cases. In re-do cases it was viable in only 41% of cases; the rest required substitution urethroplasty. Urethral substitution also gave acceptable results. PMID- 21527236 TI - Epidemiologic trends in penile anomalies and hypospadias in the state of California, 1985-2006. AB - PURPOSE: Using statewide data, we evaluated whether the changing incidence of penile anomalies and hypospadias is reflected in the diverse California population of newborn males over the past 20 years. METHODS: Discharge data from all California hospitals, prepared by the OSHPD (Sacramento, CA) was reviewed for the years 1985-2006 for male infant births with an ICD-9 code (752.6) for hypospadias, epispadias or other penile anomalies. Trends were examined by Generalized Estimation Equations for Poisson regression. RESULTS: From 1985 to 2006, the birth incidence of newborn penile anomalies increased in California from 47 to 57 cases per 10,000 newborn discharges, yet the trend for hypospadias alone appears stable from 1997. The rates for penile anomalies in newborns increased 1.4% annually (p < 0.001). All racial/ethnic groups analyzed showed this increase (p < 0.001 for each). During the study period there was a 2% increase per year in plural births (p < 0.001). Interestingly, the rate of change in penile anomaly incidence was greater in males of plural births compared to their singleton cohorts (2% vs 1% annually) (p < 0.001). The birth incidence of cleft palate, another congenital anomaly known to be stable over time, remained unchanged over this period. CONCLUSIONS: From 1985 to 2006 in California the incidence of penile anomalies increased in a statistically significant manner, but the incidence of hypospadias appears stable for the last decade. Our data support the notion that different racial/ethnic groups have distinct incidences of penile anomaly formation and that an association with plural births appears to be present. PMID- 21527237 TI - Miniature pyeloplasty as a minimally invasive surgery with less than 1 day admission in infants. AB - PURPOSE: Open dismembered pyeloplasty is usually performed through flank, anterior subcostal or posterior lumbotomy incisions. These incisions are cosmetically less acceptable and may produce significant postoperative pain. We present the smallest incision for open pyeloplasty, called a 'miniature pyeloplasty'. The aim of this study was to reduce hospital stay and postoperative pain, along with enhanced cosmetic results. PATIENTS AND METHOD: 373 infants (mean age 4 months) with hugely dilated pelvises underwent the miniature pyeloplasty. The exact site of incision was determined by intraoperative renal ultrasonography and palpation. A muscle-splitting incision was made in the most dependent part of the lower quadrant. After meticulous dissection of the ureteropelvic junction component, the affected section was pulled out and underwent classic dismembered pyeloplasty without renal pelvis reduction. All children had long-duration stented anastomoses. Surgical incision size, operative time, hospital stay, postoperative analgesic use and complication rate were recorded. RESULTS: The operation was successful in all patients. The mean operative time was 53 min (range 43-75) and patients were discharged after 18 +/- 3 (mean +/- SD) h. Incision size ranged from 11 to 15 mm (mean 13). No narcotic analgesic was required postoperatively and there were no major complications during follow up. CONCLUSIONS: Miniature pyeloplasty is a safe and successful technique for ureteropelvic junction obstruction that avoids long operative time with negligible postoperative pain compared to the classic open pyeloplasty in infants. The exact incision site must be reconfirmed intraoperatively by physical examination or renal ultrasonography. PMID- 21527238 TI - The inguinal approach to extravesical ureteral reimplantation is safe, effective, and efficient. AB - INTRODUCTION: Minimally invasive surgery implies a percutaneous or endoscopic approach rather than an incision, regardless of size. However, open approaches to various procedures using a mini-incision should assume the same appellation. We report our experience with extravesical ureteral reimplant (EVR) performed through an inguinal mini-incision. MATERIALS AND METHODS: Patient characteristics of age, gender, and reflux grade were obtained, and outcomes of recurrent urinary tract infection, time of surgery, time of hospitalization and radiographic resolution were assessed. The technique involved a 2 cm incision made in the lowest inguinal skin crease, standard hernia exposure, opening of the floor of the inguinal canal to isolate the ureter, detrussorhaphy. RESULTS: 30 girls and 15 boys with a mean age of 64 months (range 20-180), and mean followup of 18 months (range 3-36) underwent unilateral inguinal mini-incision EVR. Reflux grades represented were 7, 13, 18, 5, and 2 for Grades I through V respectively. Common sheath reimplantations were performed in twelve duplicated systems, and tapering performed in three patients. The average time of surgery was 75 min. All but 2 patients were discharged within 24 h; postoperative imaging was normal in all cases. Three patients had febrile UTIs following discontinuation of prophylactic antibiotics. CONCLUSION: The inguinal approach to EVR is safe, effective, efficient, and well-tolerated. Through several maneuvers learned as the experience with EVR grew, we present a realizable approach to minimally invasive ureteral reimplantation with application in most pediatric urologic practice. PMID- 21527239 TI - Hypertensive disease in pregnancy. Preface. PMID- 21527240 TI - Analysing the generality of spatially predictive mosquito habitat models. AB - The increasing spread of multi-drug resistant malaria in African highlands has highlighted the importance of malaria suppression through vector control. Its historical success has meant that larval control has been proposed as part of an integrated malaria vector control program. Due to high operation costs, larval control activities would benefit greatly if the locations of mosquito habitats could be identified quickly and easily, allowing for focal habitat source suppression. Several mosquito habitat models have been developed to predict the location of mosquito habitats. However, to what extent these models can be generalised across time and space to predict the distribution of dynamic mosquito habitats remains largely unexplored. This study used mosquito habitat data collected in six different time periods and four different modelling approaches to establish 24 mosquito habitat models. We systematically tested the generality of these 24 mosquito habitat models. We found that although habitat--environment relationships change temporally, a modest level of performance was attained when validating the models using data collected from different time periods. We also describe flexible approaches to the predictive modelling of mosquito habitats, that provide novel modelling architecture for future research efforts. PMID- 21527241 TI - The activity of an ancient atypical protein kinase is stimulated by ADP-ribose in vitro. AB - The piD261/Bud32 protein kinases are universal amongst the members of the Eucarya and Archaea. Despite the fact that phylogenetic analyses indicate that the piD261/Bud32 protein kinases descend directly from the primordial ancestor of the "eukaryotic" protein kinase superfamily, our knowledge of their physiological role is relatively fragmentary and largely limited to two eucaryal representatives: piD261/Bud32 from yeast and the p53-related protein kinase from humans. A deduced archaeal homolog, SsoPK5, is encoded by open reading frame sso0433 from the acidothermophile Sulfolobus solfataricus. Recombinantly expressed SsoPK5 exhibited protein kinase activity, with a noticeable preference for phosphorylating proteins of acidic character and for Mn(2+) as cofactor. The protein kinase also can phosphorylate itself on serine and threonine residues. The activity of rSsoPK5 was increased several-fold upon preincubation with either millimolar concentrations of 5'-AMP or submicromolar concentrations of ADP ribose. Other mono- and di-nucleotides were ineffective. While activation was enhanced by the presence of ATP, no autophosphorylation of the protein kinase could be detected prior to addition of exogenous substrate proteins. We therefore suggest that ADP-ribose acts by evoking a conformational transition in the enzyme. Activation by ADP-ribose represents a potential regulatory link between chromatin remodeling and the activity of SsoPK5. PMID- 21527243 TI - Strand selections resulting from the combined template-independent DNA synthesis and clamp activities of HIV-1 reverse transcriptase. AB - The reverse transcriptase (RT) of HIV-1 has a non-templated addition (NTA) activity and can perform template switches with a very short (even two nucleotides) complementarity between the 3'-ends of the primer donor strand and the template acceptor strands. We have studied how the combination of several pivotal parameters can all lead to strand switches during DNA synthesis by HIV-1 RT. These include dNTP bias in the NTA step, the availability of acceptor strands with 3'-end sequences complementary to the de novo-generated primer tails and the stabilities of the clamped duplexes formed between these primer tails and the acceptor strands. PMID- 21527242 TI - 5- and 4'-Hydroxylated flavonoids affect voltage gating of single alpha-hemolysin pore. AB - Molecular mechanisms of the influence of flavonoids on the voltage gating of a single alpha-hemolysin channel in planar lipid membranes are studied. It is shown that the addition of flavonoids hydroxylated in position 5 of the A-ring and in position 4' of the B-ring into bilayer bathing solution shifts the voltage dependence of channel switching from high- to low-conductance states to voltages nearer zero. It is concluded that the effect is likely to be attributed to a specific interaction of at least three flavonoid molecules with the voltage sensor of an alpha-hemolysin pore. Possible flavonoid binding sites and identification of amino acid residues included into the voltage sensor domain of the alpha-hemolysin channel are discussed. PMID- 21527244 TI - Mouse FKBP23 mediates conformer-specific functions of BiP by catalyzing Pro117 cis/trans isomerization. AB - FK506-binding proteins (FKBPs) are cellular receptors for the immunosuppressant FK506 and rapamycin. They belong to the ubiquitous peptidyl-prolyl cis/trans isomerases (PPIases) family, which can catalyze the cis/trans isomerization of peptidyl-prolyl bond in peptides and proteins. In previous work, we revealed that mouse FKBP23 binds immunoglobulin binding protein (BiP), the major heat shock protein (Hsp) 70 chaperone in the ER, and the binding is interrelated with [Ca(2+)]. Furthermore, the binding can suppress the ATPase activity of BiP through the PPIase activity of FKBP23. In this work, FKBP23 is demonstrated to mediate functions of BiP by catalyzing the Pro(117)cis/trans conformational interconversion in the ATPase domain of BiP. This result may provide new understanding to the novel role of PPIase as a molecular switch. PMID- 21527246 TI - Real time monitoring of antigenicity development of HBsAg virus-like particles (VLPs) during heat- and redox-treatment. AB - The Hepatitis B virus major surface antigen (HBsAg) is a cysteine-rich, membrane bound protein which self-assembles into 22-nm spherical virus-like particles (VLPs). While this VLP based human vaccine has been demonstrated to be safe and efficacious since 1986, the structural and exact molecular basis for its antigenic determinants has not been elucidated. Maturation of the yeast-derived purified VLPs was characterized for the changes in 37 their biophysical properties. Using rapid and label-free surface plasmon resonance technique with a neutralizing monoclonal antibody - A1.2, the epitope evolution kinetics of purified VLPs was monitored in real time. Evidence supporting the mechanism that the correct disulfide bond pairing is the molecular basis for shaping up the native virion-like epitopes was obtained. At least 10-fold enhancement in antigenicity probed by A1.2 of the VLPs was achieved by heat-treatment (t(1/2) ~ 6-10 h), and another 2- to 3-fold enhancement was obtained when they were treated with redox buffer. This antigenicity development, presumably via disulfide formation/isomerization, was shown to be inhibited by a free radical scavenger and facilitated in the presence of light. Relative antigenicity determination with surface plasmon resonance was shown to be a valuable tool for process characterization in the kinetic monitoring mode or for final VLP product assessment in the end point antigenicity testing mode. PMID- 21527245 TI - Lifelong caloric restriction prevents age-induced oxidative stress in the sympathoadrenal system of Fischer 344 x Brown Norway rats. AB - Aging is associated with oxidative damage and an imbalance in redox signaling in a variety of tissues, yet little is known about the extent of age-induced oxidative stress in the sympathoadrenal system. Lifelong caloric restriction has been shown to lower levels of oxidative stress and slow the aging process. Therefore, the aims of this study were twofold: (1) to investigate the effect of aging on oxidative stress in the adrenal medulla and hypothalamus and (2) determine if lifelong 40% caloric restriction (CR) reverses the adverse effects of age-induced oxidative stress in the sympathetic adrenomedullary system. Adult (18months) and very old (38months) male Fischer 344 x Brown Norway rats were divided into ad libitum or 40% CR groups and parameters of oxidative stress were analyzed in the adrenal medulla and the hypothalamus. A significant age-dependent increase in lipid peroxidation (+20%, P<0.05) and tyrosine nitration (+111%, P<0.001) were observed in the adrenal medulla while age resulted in a reduction in the protein expression of key antioxidant enzymes, CuZnSOD (-27%, P<0.01) and catalase (-27%, P<0.05) in the hypothalamus. Lifelong CR completely prevented the age-induced increase in lipid peroxidation in the adrenal medulla and restored the age-related decline in antioxidant enzymes in the hypothalamus. These data indicate that aging results in a significant increase in oxidative stress in the sympathoadrenal system. Importantly, lifelong CR restored the age-related changes in oxidative stress in the adrenal medulla and hypothalamus. Caloric restriction could be a potential non-pharmacological intervention to prevent increased oxidative stress in the sympathetic adrenomedullary system with age. PMID- 21527247 TI - Interaction of a putative BH3 domain of clusterin with anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy. AB - Clusterin (CLU) is a multifunctional glycoprotein that is overexpressed in prostate and breast cancers. Although CLU is known to be involved in the regulation of apoptosis and cell survival, the precise molecular mechanism underlying the pro-apoptotic function of nuclear CLU (nCLU) remains unclear. In this study, we identified a conserved BH3 motif in C-terminal coiled coil (CC2) region of nCLU by sequence analysis and characterized the molecular interaction of the putative nCLU BH3 domain with anti-apoptotic Bcl-2 family proteins by nuclear magnetic resonance (NMR) spectroscopy. The chemical shift perturbation data demonstrated that the nCLU BH3 domain binds to pro-apoptotic BH3 peptide binding grooves in both Bcl-X(L) and Bcl-2. A structural model of the Bcl X(L)/nCLU BH3 peptide complex reveals that the binding mode is remarkably similar to those of other Bcl-X(L)/BH3 peptide complexes. In addition, mutational analysis confirmed that Leu323 and Asp328 of nCLU BH3 domain, absolutely conserved in the BH3 motifs of BH3-only protein family, are critical for binding to Bcl-X(L). Taken altogether, our results suggest a molecular basis for the pro apoptotic function of nCLU by elucidating the residue specific interactions of the BH3 motif in nCLU with anti-apoptotic Bcl-2 family proteins. PMID- 21527248 TI - A receptor tyrosine kinase inhibitor, Tyrphostin A9 induces cancer cell death through Drp1 dependent mitochondria fragmentation. AB - Mitochondria dynamics controls not only their morphology but also functions of mitochondria. Therefore, an imbalance of the dynamics eventually leads to mitochondria disruption and cell death. To identify specific regulators of mitochondria dynamics, we screened a bioactive chemical compound library and selected Tyrphostin A9, a tyrosine kinase inhibitor, as a potent inducer of mitochondrial fission. Tyrphostin A9 treatment resulted in the formation of fragmented mitochondria filament. In addition, cellular ATP level was decreased and the mitochondrial membrane potential was collapsed in Tyr A9-treated cells. Suppression of Drp1 activity by siRNA or over-expression of a dominant negative mutant of Drp1 inhibited both mitochondrial fragmentation and cell death induced by Tyrpohotin A9. Moreover, treatment of Tyrphostin A9 also evoked mitochondrial fragmentation in other cells including the neuroblastomas. Taken together, these results suggest that Tyrphostin A9 induces Drp1-mediated mitochondrial fission and apoptotic cell death. PMID- 21527249 TI - Co-repressor activity of scaffold attachment factor B1 requires sumoylation. AB - Sumoylation is an emerging modification associated with a variety of cellular processes including the regulation of transcriptional activities of nuclear receptors and their coregulators. As SUMO modifications are often associated with transcriptional repression, we examined if sumoylation was involved in modulation of the transcriptional repressive activity of scaffold attachment factor B1. Here we show that SAFB1 is modified by both the SUMO1 and SUMO2/3 family of proteins, on lysine's K231 and K294. Further, we demonstrate that SAFB1 can interact with PIAS1, a SUMO E3 ligase which mediates SAFB1 sumoylation. Additionally, SENP1 was identified as the enzyme desumoylating SAFB1. Mutation of the SAFB1 sumoylation sites lead to a loss of transcriptional repression, at least in part due to decreased interaction with HDAC3, a known transcriptional repressor and SAFB1 binding partner. In summary, the transcriptional repressor SAFB1 is modified by both SUMO1 and SUMO2/3, and this modification is necessary for its full repressive activity. PMID- 21527250 TI - Crystal structure and biophysical characterisation of Helicobacter pylori phosphopantetheine adenylyltransferase. AB - Helicobacter pylori is a bacterium that causes chronic active gastritis and peptic ulcers. Drugs targeting H. pylori phosphopantetheine adenylyltransferase (HpPPAT), which is involved in CoA biosynthesis, may be useful. Herein, we report the expression in Escherichia coli and purification of recombinant HpPPAT and describe a crystal structure for an HpPPAT/CoA complex. As is the case for E. coli PPAT (EcPPAT), HpPPAT is hexameric in solution and as a crystal. Each protomer has a well-packed dinucleotide-binding fold in which CoA binds. Structural characterisation demonstrated that CoA derived from the E. coli expression system bound tightly to HpPPAT, presumably to initiate feedback inhibition. However, the interactions between the active-site residues of HpPPAT and CoA are not identical to those of other PPATs. Finally, CoA binding affects HpPPAT thermal denaturation. PMID- 21527251 TI - Lack of Aquaporin 3 in bovine erythrocyte membranes correlates with low glycerol permeation. AB - In general, erythrocytes are highly permeable to water, urea and glycerol. However, expression of aquaporin isoforms in erythrocytes appears to be species characteristic. In the present study, human (hRBC) and bovine (bRBC) erythrocytes were chosen for comparative studies due to their significant difference in membrane glycerol permeability. Osmotic water permeability (P(f)) at 23 degrees C was (2.89 +/- 0.37) * 10(-2) and (5.12 +/- 0.61) * 10(-2)cms(-1) for human and bovine cells, respectively, with similar activation energies for water transport. Glycerol permeability (P(gly)) for human ((1.37 +/- 0.26) * 10(-5)cms(-1)) differed in three orders of magnitude from bovine erythrocytes ((5.82 +/- 0.37) * 10(-8)cms(-1)) that also showed higher activation energy for glycerol transport. When compared to human, bovine erythrocytes showed a similar expression pattern of AQP1 glycosylated forms on immunoblot analysis, though in slight higher levels, which could be correlated with the 1.5-fold larger P(f) found. However, AQP3 expression was not detectable. Immunofluorescence analysis confirmed the absence of AQP3 expression in bovine erythrocyte membranes. In conclusion, lack of AQP3 in bovine erythrocytes points to the lipid pathway as responsible for glycerol permeation and explains the low glycerol permeability and high E(a) for transport observed in ruminants. PMID- 21527252 TI - The human epithelial carcinoma antigen recognized by monoclonal antibody AE3 is expressed on a sulfoglycolipid in addition to neoplastic mucins. AB - The term human epithelial carcinoma antigen (HCA) has been applied collectively to mucin-type high molecular weight (>1000kDa) glycoproteins that are over expressed in epithelial cancers. Since the 1990s, over 40 monoclonal antibodies have been raised that recognize HCA. There has been evidence that the antigenic determinants are mostly carbohydrates, but details have been elusive. Here we have carried out carbohydrate microarray analyses of one of the monoclonal antibodies, AE3, that has been regarded the 'most carcinoma specific' in respect to its ability to detect HCA in sera of patients with epithelial cancers. The microarrays encompassed a series of 492 sequence-defined glycan probes in the form of glycolipids and neoglycolipids. We have thus established that the antigen recognized by antibody AE3 is a carbohydrate sequence distinct from the A, B, H, Lewis(a/b), Lewis(x/y) and T antigens, but that it is strongly expressed on the monosulfated tetra-glycosyl ceramide, SM1a, Galbeta1-3GalNAcbeta1-4(3-O sulfate)Galbeta1-4GlcCer. This is the first report of an anti-HCA to be characterized with respect to its recognition sequence and of the occurrence of the antigen on a glycolipid as well as on glycoproteins. Knowledge of a discrete glycan sequence as target antigen now opens the way to its exploration as a serologic cancer biomarker, namely to determine if the antigen elicits an autoantibody response in early non-metastatic cancer, or if it is shed and immunochemically detectable in more advanced disease. PMID- 21527253 TI - RANK signaling induces interferon-stimulated genes in the fetal thymic stroma. AB - Medullary thymic epithelial cells (mTECs) are essential for thymic negative selection to prevent autoimmunity. Previous studies show that mTEC development is dependent on the signal transducers TRAF6 and NIK. However, the downstream target genes of signals controlled by these molecules remain unknown. We performed a microarray analysis on mRNAs down-regulated by deficiencies in TRAF6 or functional NIK in an in vitro organ culture of fetal thymic stromata (2DG-FTOC). An in silico analysis of transcription factor binding sites in plausible promoter regions of differentially expressed genes suggests that STAT1 is involved in TRAF6- and NIK-dependent gene expression. Indeed, the signal of RANK, a TNF receptor family member that activates TRAF6 and NIK, induces the activation of STAT1 in 2DG-FTOC. Moreover, RANK signaling induces the up-regulation of interferon (IFN)-stimulated gene (ISG) expression, suggesting that the RANKL dependent activation of STAT1 up-regulates ISG expression. The RANKL-dependent expression levels of ISGs were reduced but not completely abolished in interferon alpha receptor 1-deficient (Ifnar1(-/-)) 2DG-FTOC. Our data suggest that RANK signaling induces ISG expression in both type I interferon-independent and interferon-dependent mechanisms. PMID- 21527254 TI - Deciphering the catalytic machinery in a universally conserved ribosome binding ATPase YchF. AB - YchF, a universally conserved protein, hitherto thought to be a GTPase, was shown to be an ATPase based on structural and biochemical studies on hOLA1, a human ortholog of YchF. However, the cellular role of YchF is unclear. Based on the presence of a RNA binding domain in this protein and significant homology to ribosome binding Obg family GTPases, we examined its ability to associate with the ribosome. Here, we show that Escherichia coli YchF binds the 50S and 70S ribosomal particles in a nucleotide independent manner and it hydrolyzes ATP utilizing a potassium dependent mechanism. A potassium mediated acceleration of hydrolysis activity was thus far known for a few GTPases. Like these, YchF too conserves the structural features required for K(+) coordination, making it a unique ribosome binding ATPase utilizing a similar mechanism. Furthermore, we show that Lys78 is an important determinant of the potassium dependent ATPase activity. PMID- 21527255 TI - Crystal structure of uroporphyrinogen III synthase from Pseudomonas syringae pv. tomato DC3000. AB - Uroporphyrinogen III synthase (U3S) is one of the key enzymes in the biosynthesis of tetrapyrrole compounds. It catalyzes the cyclization of the linear hydroxymethylbilane (HMB) to uroporphyrinogen III (uro'gen III). We have determined the crystal structure of U3S from Pseudomonas syringae pv. tomato DC3000 (psU3S) at 2.5A resolution by the single wavelength anomalous dispersion (SAD) method. Each psU3S molecule consists of two domains interlinked by a two stranded antiparallel beta-sheet. The conformation of psU3S is different from its homologous proteins because of the flexibility of the linker between the two domains, which might be related to this enzyme's catalytic properties. Based on mutation and activity analysis, a key residue, Arg219, was found to be important for the catalytic activity of psU3S. Mutation of Arg219 to Ala caused a decrease in enzymatic activity to about 25% that of the wild type enzyme. Our results provide the structural basis and biochemical evidence to further elucidate the catalytic mechanism of U3S. PMID- 21527256 TI - Assessment of urinary gamma-glutamyltransferase and alkaline phosphatase for diagnosis of diabetic nephropathy. AB - BACKGROUND: Urinary biomarkers of tubular damage can be useful for early diagnosis of diabetic nephropathy. Thus, the aim of this study was to test the diagnostic accuracy of the urinary excretion of gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) for diagnosis of diabetic nephropathy (DN). METHODS: Fasting glucose, fructosamine, serum creatinine, glomerular filtration rate (GFR), serum uric acid, serum albumin, and urinary albumin, creatinine, GGT and ALP were assessed in 74 type 2 diabetic patients without nephropathy and 38 type 2 diabetic patients with nephropathy. RESULTS: Urinary GGT and ALP were threefold higher in type 2 diabetic patients with nephropathy. Significant correlations were observed between urinary albumin and GGT (r=0.439, P<0.001) and urinary albumin and ALP (r=0.305, P<0.01). Areas under the curve for GGT and ALP were 0.7696 (P<0.001) and 0.7233 (P<0.001), respectively. At a cut-off value of 72U/g creatinine, GGT demonstrated a sensitivity of 96.0% and a specificity of 52.6%. At a cut-off value of 20U/g creatinine, ALP demonstrated a sensitivity and specificity of 83.8% and 36.8%, respectively. CONCLUSIONS: Urinary GGT and ALP have potential value in the diagnosis of nephropathy in type 2 diabetic patients, but GGT has a slightly higher ability to discriminate nephropathy than ALP. PMID- 21527257 TI - 3D reconstructions of quail-chick chimeras provide a new fate map of the avian scapula. AB - Limbed vertebrates have functionally integrated postcranial axial and appendicular systems derived from two distinct populations of embryonic mesoderm. The axial skeletal elements arise from the paraxial somites, the appendicular skeleton and sternum arise from the somatic lateral plate mesoderm, and all of the muscles for both systems arise from the somites. Recent studies in amniotes demonstrate that the scapula has a mixed mesodermal origin. Here we determine the relative contribution of somitic and lateral plate mesoderm to the avian scapula from quail-chick chimeras. We generate 3D reconstructions of the grafted tissue in the host revealing a very different distribution of somitic cells in the scapula than previously reported. This novel 3D visualization of the cryptic border between somitic and lateral plate populations reveals the dynamics of musculoskeletal morphogenesis and demonstrates the importance of 3D visualization of chimera data. Reconstructions of chimeras make clear three significant contrasts with existing models of scapular development. First, the majority of the avian scapula is lateral plate derived and the somitic contribution to the scapular blade is significantly smaller than in previous models. Second, the segmentation of the somitic component of the blade is partially lost; and third, there are striking differences in growth rates between different tissues derived from the same somites that contribute to the structures of the cervical thoracic transition, including the scapula. These data call for the reassessment of theories on the development, homology, and evolution of the vertebrate scapula. PMID- 21527258 TI - Members of the TEAD family of transcription factors regulate the expression of Myf5 in ventral somitic compartments. AB - The transcriptional regulation of the Mrf4/Myf5 locus depends on a multitude of enhancers that, in equilibria with transcription balancing sequences and the promoters, regulate the expression of the two genes throughout embryonic development and in the adult. Transcription in a particular set of muscle progenitors can be driven by the combined outputs of several enhancers that are not able to recapitulate the entire expression pattern in isolation, or by the action of a single enhancer the activity of which in isolation is equivalent to that within the context of the locus. We identified a new enhancer element of this second class, ECR111, which is highly conserved in all vertebrate species and is necessary and sufficient to drive Myf5 expression in ventro-caudal and ventro-rostral somitic compartments in the mouse embryo. EMSA analyses and data obtained from binding-site mutations in transgenic embryos show that a binding site for a TEA Domain (TEAD) transcription factor is essential for the function of this new enhancer, while ChIP assays show that at least two members of the family of transcription factors bind to it in vivo. PMID- 21527260 TI - Analysis of expressed sequence tags (ESTs) and gene expression changes under different growth conditions for the ciliate Anophryoides haemophila, the causative agent of bumper car disease in the American lobster (Homarus americanus). AB - The scuticociliate Anophryoides haemophila, causes bumper car disease in American lobster (Homarus americanus) in commercial holding facilities in Atlantic Canada. While the parasite has been recognized since the 1970s and much has been learned about its biology, minimal molecular characterization exists. With genome consortiums turning to model organisms like the ciliates Tetrahymena and Paramecium, the amount of relevant sequence data available has made sequence surveys more attractive for gene discovery in related ciliates. We sequenced 9984 expressed sequence tags (ESTs) from a non-normalized A. haemophila cDNA library to characterize gene expression patterns, functional gene distribution and to discover novel genes related to the parasitic life history. The A. haemophila ESTs were grouped into 843 clusters and singletons with 658 EST clusters having identifiable homologs, while 159 ESTs were unique and had no similarity to any sequences in the public databases. Not unexpectedly, about 67% of the A. haemophila ESTs have similarity to annotated and hypothetical genes from the related oligohymenophorean ciliate, Tetrahymena. Numerous cysteine proteases, hypothetical proteins and novel sequences possess putative secretory signal peptides suggesting that they may contribute to the pathogenesis of bumper car disease in lobster. Real time RT-qPCR analysis of cathepsin L and two homologs of cathepsin B did not show any changes in gene expression under varying in vitro growth conditions or during a modified-in vivo infection which may be suggestive of the opportunistic life history strategy of this ciliate. PMID- 21527259 TI - Tarsal-less peptides control Notch signalling through the Shavenbaby transcription factor. AB - The formation of signalling boundaries is one of the strategies employed by the Notch (N) pathway to give rise to two distinct signalling populations of cells. Unravelling the mechanisms involved in the regulation of these signalling boundaries is essential to understanding the role of N during development and diseases. The function of N in the segmentation of the Drosophila leg provides a good system to pursue these mechanisms at the molecular level. Transcriptional and post-transcriptional regulation of the N ligands, Serrate (Ser) and Delta (Dl) generates a signalling boundary that allows the directional activation of N in the distalmost part of the segment, the presumptive joint. A negative feedback loop between odd-skipped-related genes and the N pathway maintains this signalling boundary throughout development in the true joints. However, the mechanisms controlling N signalling boundaries in the tarsal joints are unknown. Here we show that the non-canonical tarsal-less (tal) gene (also known as pri), which encodes for four small related peptides, is expressed in the N-activated region and required for joint development in the tarsi during pupal development. This function of tal is both temporally and functionally separate from the tal mediated tarsal intercalation during mid-third instar that we reported previously. In the pupal function described here, N signalling activates tal expression and reciprocally Tal peptides feedback on N by repressing the transcription of Dl in the tarsal joints. This Tal-induced repression of Dl is mediated by the post-transcriptional activation of the Shavenbaby transcription factor, in a similar manner as it has been recently described in the embryo. Thus, a negative feedback loop involving Tal regulates the formation and maintenance of a Dl+/Dl- boundary in the tarsal segments highlighting an ancient mechanism for the regulation of N signalling based on the action of small cell signalling peptides. PMID- 21527261 TI - Probability distributions of ancestries and genealogical distances on stochastically generated rooted binary trees. AB - The stationary birth-only, or Yule-Furry, process for rooted binary trees has been analysed with a view to developing explicit expressions for two fundamental statistical distributions: the probability that a randomly selected leaf is preceded by N nodes, or "ancestors", and the probability that two randomly selected leaves are separated by N nodes. For continuous-time Yule processes, the first of these distributions is presented in closed analytical form as a function of time, with time being measured with respect to the moment of "birth" of the common ancestor (which is essentially inaccessible to phylogenetic analysis), or with respect to the instant at which the first bifurcation occurred. The second distribution is shown to follow in an iterative manner from a hierarchy of second order ordinary differential equations. For Yule trees of a given number n of tips, expressions have been derived for the mean and variance for each of these distributions as functions of n, as well as for the distributions themselves. In addition, it is shown how the methods developed to obtain these distributions can be employed to find, with minor effort, expressions for the expectation values of two statistics on Yule trees, the Sackin index (sum over all root-to-leaf distances), and the sum over all leaf-to-leaf distances. PMID- 21527262 TI - Neuroprotective effect of mithramycin against endoplasmic reticulum stress induced neurotoxicity in organotypic hippocampal slice cultures. AB - Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of various neurodegenerative diseases. Although the underlying mechanisms of these diseases have been suggested by many studies, therapeutic drugs have yet to be found. In this study, experiments were performed to examine the effect of mithramycin (MTM), a clinically approved guanosine-cytosine (GC)-rich DNA sequence-binding antitumor antibiotic, on ER stress-induced neurotoxicity in organotypic hippocampal slice cultures (OHCs). Time-dependent induction of the ER chaperones, glucose-regulated protein (GRP) 78 and GRP94, was observed after treatment with tunicamycin (TM) (80 MUg/mL). Western blot analysis showed that treatment of OHCs with TM increased the expression of CHOP and the cleaved forms of caspase-12. Simultaneous application of MTM suppressed TM-induced cell death in all areas of OHCs with a concomitant decrease in the level of CHOP. In contrast, MTM had no effect on excitotoxic cell death induced by ibotenic acid, a potent N-methyl-d-aspartate (NMDA) agonist in OHCs. Moreover, RNA interference to CHOP or simultaneous treatment with MTM attenuated TM-induced cell death in primary cultured hippocampal neurons. These results suggest that CHOP plays a critical role in the mechanisms underlying ER-stress-induced neurotoxicity in the hippocampus, and that MTM could be a protective agent against ER stress-induced hippocampal neuronal death through attenuation of ER stress-associated signal proteins. PMID- 21527263 TI - Dopamine-related drugs act presynaptically to potentiate GABA(A) receptor currents in VTA dopamine neurons. AB - Electrical activity of ventral tegmental area (VTA) dopamine (DA) neurons is immediately inhibited following in vivo administration of cocaine and other DA related drugs. While various forms of synaptic modulation were demonstrated in the VTA following exposure to DA-related drugs, comprehensive understanding of their ability to inhibit the activity of DA neurons, however, is still lacking. In this study, using whole-cell patch-clamp recordings from rat brain slices, a novel form of synaptic modulation induced by DA-related drugs was isolated. DA exposure was shown to cause potentiation of gamma-amino-butyric acid (GABA) receptor type A (GABA(A)R)-mediated evoked inhibitory postsynaptic currents (eIPSCs), recorded from VTA DA neurons, under conditions of potassium channels blockade. The potentiation of these eIPSCs lasted for more than twenty minutes, could be mimicked by activation of D2-like but not D1-like DA receptors, and was accompanied by an increase in the frequency of GABA(A)R-mediated spontaneous miniature inhibitory postsynaptic currents (mIPSCs). Furthermore, exposure to inhibitors of DA transporter (DAT) led to potentiation of GABA(A) currents in a manner similar to the DA-mediated potentiation. Finally, a prolonged presence of l-NAME, an inhibitor of nitric-oxide (NO) signaling was found to conceal the potentiation of GABA(A) currents induced by the DA-related drugs. Taken together, this study demonstrates a new modulatory form of VTA GABA(A) neurotransmission mediated by DA-related drugs. These results also suggest better understanding of the initial inhibitory action of DA-related drugs on the activity of DA neurons in the VTA. PMID- 21527264 TI - A microdialysis study of the medial prefrontal cortex of adolescent and adult rats. AB - The medial prefrontal cortex (mPFC) of the rat has become a key focus of studies designed to elucidate the basis of behavior involving attention and decision making, i.e. executive functions. The adolescent mPFC is of particular interest given the role of the mPFC in impulsivity and attention, and disorders such as attentional deficit disorder. In the present study we have examined the basal extracellular concentrations of the neurotransmitters 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE) in the ventral portion of the mPFC (vmPFC) in both adolescent (post-natal day 45-50) and adult, and male and female rats using in vivo microdialysis. We have also examined both the left and right vmPFCs given reports of laterality in function between the hemispheres. Basal extracellular concentrations of 5-HT differed significantly between male and female rats. Extracellular DA also differed significantly between male and female rats and between the left and the right vmPFC in adult males. No differences were seen in basal extracellular NE. There was a significant age difference between groups in the laterality of extracellular NE levels between right and left vmPFC. Infusion of 100 MUM methamphetamine through the dialysis probe increased the extracellular concentration of all the monoamines although there were no differences between groups in methamphetamine stimulated release. The findings from this study demonstrate that there are differences in monoaminergic input to the mPFC of the rat based on age, gender and hemisphere. This work sets the neurochemical baseline for further investigations of the prefrontal cortex during development. PMID- 21527265 TI - A right visual field advantage for tool-recognition in the visual half-field paradigm. AB - Neuropsychological and brain imaging studies have shown that the identification and use of tools mainly involve areas of the left hemisphere. We investigate whether this dominance can be observed in a behavioral visual half-field (VHF) task as well. To make sure that the VHF-effect was due to laterality and not due to attentional bias, we made use of two tasks: tool recognition and object recognition. On the basis of the existing literature, we predicted a right visual field (RVF) advantage for tool recognition, but not for object recognition. Twenty right-handed participants made judgments about whether one of two bilaterally presented stimuli was an object/non-object or a tool/non-tool. No VHF/hemisphere advantage was found for object recognition, whereas a significant RVF/left hemisphere advantage was observed for tool recognition. These findings show that VHF-tasks can be used as a valid laterality measure of tool recognition. PMID- 21527266 TI - Neurobiology of food anticipatory circadian rhythms. AB - Circadian rhythms in mammals can be entrained by daily schedules of light or food availability. A master light-entrainable circadian pacemaker located in the suprachiasmatic nucleus (SCN) is comprised of a population of cell autonomous, transcriptionally based circadian oscillators with defined retinal inputs, circadian clock genes and neural outputs. By contrast, the neurobiology of food entrainable circadian rhythmicity remains poorly understood at the systems and cellular levels. Induction of food-anticipatory activity rhythms by daily feeding schedules does not require the SCN, but these rhythms do exhibit defining properties of circadian clock control. Clock gene rhythms expressed in other brain regions and in peripheral organs are preferentially reset by mealtime, but lesions of specific hypothalamic, corticolimbic and brainstem structures do not eliminate all food anticipatory rhythms, suggesting control by a distributed, decentralized system of oscillators, or the existence of a critical oscillator at an unknown location. The melanocortin system and dorsomedial hypothalamus may play modulatory roles setting the level of anticipatory activity. The metabolic hormones ghrelin and leptin are not required to induce behavioral food anticipatory rhythms, but may also participate in gain setting. Clock gene mutations that disrupt light-entrainable rhythms generally do not eliminate food anticipatory rhythms, suggesting a novel timing mechanism. Recent evidence for non-transcriptional and network based circadian rhythmicity provides precedence, but any such mechanisms are likely to interact closely with known circadian clock genes, and some important double and triple clock gene knockouts remain to be phenotyped for food entrainment. Given the dominant role of food as an entraining stimulus for metabolic rhythms, the timing of daily food intake and the fidelity of food entrainment mechanisms are likely to have clinical relevance. PMID- 21527267 TI - UVS is rare in seabirds. AB - Ultraviolet-sensitive vision (UVS), believed to have evolved from an ancestral state of violet-sensitive vision (VS), is widespread among terrestrial birds, where it is thought to play a role in orientation, foraging, and sexual selection. Less is known, however, about the distribution and significance of UVS in seabirds. To date UVS has been definitively demonstrated only in two families (Laridae and Sternidae), although indirect evidence has been used to argue for a more widespread occurrence. In this study we analyzed short-wavelength sensitive (SWS1) opsin DNA sequences to determine the distribution of ancestral (VS) and derived (UVS) amino acid spectral tuning sites in 16 seabird species representing 8 families with diverse ecological niches. Our results revealed sequences associated with UVS pigments (UVSs) in the Black-backed gull (Larus dominicanus), providing further evidence of its widespread occurrence within the Laridae. The Caspian tern (Hydroprogne caspia) and White-fronted tern (Sterna striata), however, were found to have VSs, suggesting an evolutionary reversion to the ancestral state within Sternidae. VSs were also detected in an additional six families. Our results raise interesting questions about the functions of UV vision in marine environments. PMID- 21527268 TI - Developmental changes in the microgenesis of face perception revealed by effects of context and inversion. AB - Present studies on the development of face perception mechanisms are ambiguous about the question of whether holistic face vision arises early, or in the second decade of life (Crookes & McKone, 2009). Measuring the time course of face matching we assess effects of context and inversion as correlates of holistic processing in the microgenesis of face perception within the first 650 ms, and compare among 8- to 10-year-old children and adults. Results for adults indicate dominance of holistic viewing at brief timings, which is gradually replaced by feature selective strategies enabling them to selectively attend either internal or external features, as demanded by instruction. For children, however, effects of context and inversion are absent at brief timings, but gradually increase to strong levels with increasing viewing times. Moreover, we find a pronounced asymmetry in face matching performance with internal and external features. While face matching by attending external features is well developed and robust against variable facial contexts, face matching by attending internal features is generally poor, and strongly affected by interleaved congruent and incongruent contextual information. These results indicate that children and adults differ not only in the kind of featural information they preferentially encode in face perception, but also in the processing time they need to build holistic representations. While these are fast and automatic in adults' face vision, children's face representations are part based at brief timings, but develop to integrated wholes as more temporal resources are made available. PMID- 21527269 TI - Behavioural assessment of flicker fusion frequency in chicken Gallus gallus domesticus. AB - To interact with its visual environment, an organism needs to perceive objects in both space and time. High temporal resolution is hence important to the fitness of diurnally active animals, not least highly active aerial species such as birds. However, temporal resolution, as assessed by flicker fusion frequency (FFF; the stimulus frequency at which a flickering light stimulus can no longer be resolved and appears continuous) or critical flicker fusion frequency (CFF; the highest flicker fusion frequency at any light intensity) has rarely been assessed in birds. In order to further our understanding of temporal resolution as a function of light intensity in birds we used behavioural experiments with domestic chickens (Gallus gallus domesticus) from an old game breed 'Gammalsvensk dvarghona' (which is morphologically and behaviourally similar to the wildtype ancestor, the red jungle fowl, G. gallus), to generate an 'Intensity/FFF curve' (I/FFF curve) across full spectrum light intensities ranging from 0.2 to 2812 cd m-2. The I/FFF curve is double-branched, resembling that of other chordates with a duplex retina of both rods and cones. Assuming that the branches represent rod and cone mediated responses respectively, the break point between them places the transition between scotopic and photopic vision at between 0.8 and 1.9 cd m-2. Average FFF ranged from 19.8 Hz at the lowest light intensity to a CFF 87.0 Hz at 1375 cd m-2. FFF dropped slightly at the highest light intensity. There was some individual variation with certain birds displaying CFFs of 90-100 Hz. The FFF values demonstrated by this non-selected breed appear to be considerably higher than other behaviourally derived FFF values for similar stimuli reported for white and brown commercial laying hens, indicating that the domestication process might have influenced temporal resolution in chicken. PMID- 21527270 TI - Nicotine exposure during adolescence enhances behavioral sensitivity to nicotine during adulthood in Wistar rats. AB - RATIONALE: Drug use during adolescence is associated with an increased propensity for drug dependency during adulthood. Therefore, the effects of adolescent exposure to nicotine on adult behavioral responsiveness to nicotine are of particular importance. OBJECTIVES: The objective of the current study was to determine if adolescent nicotine exposure would enhance behavioral sensitivity and development of sensitization to nicotine during adulthood. MATERIALS AND METHODS: Male Wistar rats were assigned to one of three groups that received subcutaneous (s.c.) injections of nicotine (0, 0.25, or 0.5mg/kg) in the home cage for 12 consecutive days during adolescence, PD 31-42. Starting on PD 80, distance traveled, rearing, and stereotypy were recorded in locomotor activity chambers each day for 10 days, following s.c. injections of 0, 0.25, or 0.5mg/kg nicotine. One week later, a final challenge session took place during which rats were injected with 0.5mg/kg nicotine. RESULTS: Rats exposed to nicotine during adolescence displayed a greater locomotor response to a novel environment than saline-treated rats. Adolescent nicotine treatment also resulted in context independent sensitization to the acute locomotor activating properties of nicotine, including distance traveled and stereotypy, as measured on the first day of adulthood nicotine exposure. Adolescent nicotine-treated rats displayed increased sensitivity to repeated nicotine exposures during adulthood, compared to adolescent saline-treated rats, as measured by distance traveled, rearing, and stereotypic behaviors. Finally, rats treated with nicotine only during adolescence were more sensitive to a final nicotine challenge during adulthood than rats treated with nicotine only previously during adulthood. CONCLUSIONS: Overall, the results suggest that adolescent nicotine treatment predisposes adult rats to develop increased behavioral sensitivity to chronic nicotine treatment and to be more sensitive to the initial effects of nicotine. PMID- 21527271 TI - Prolonged chronic ethanol exposure alters neuropeptide Y and corticotropin releasing factor levels in the brain of adult Wistar rats. AB - There is evidence to suggest that alterations in neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) contribute to the escalated voluntary ethanol intake seen following long term chronic ethanol exposure. The present study assessed whether the duration of chronic ethanol exposure and abstinence alters brain levels of NPY and CRF in adult Wistar rats. NPY-like immunoreactivity (NPY-LI) and CRF-LI were determined in the amygdala (AMYG), frontal cortex (FCTX), hippocampus (HPC) and parietal cortex (PCTX) of adult Wistar rats after chronic ethanol exposure, and 24-h and 2-weeks following withdrawal (WD). Chronic ethanol exposure consisted of either a 2-week or an 8 week ethanol vapor regimen. No change in brain levels of NPY-LI, CRF-LI and the NPY-LI/CRF-LI ratio was observed 2-weeks following ethanol exposure, whereas, 8 weeks of ethanol exposure produced a significant effect on NPY-LI expression in the AMYG and FCTX. Moreover, an 8-week ethanol vapor regimen significantly increased CRF-LI levels in the HPC and PCTX. Findings from the present study suggest that a longer duration of ethanol vapor, similar to what is required to enhance voluntary drinking, is required to produce changes in NPY-LI and CRF-LI expression in the adult rat brain. PMID- 21527272 TI - Evidence that PGE2 in the dorsal and median raphe nuclei is involved in LPS induced anorexia in rats. AB - Anorexia is an element of the acute-phase immune response. Its mechanisms remain poorly understood. Activation of inducible cyclooxygenase-2 (COX-2) in blood brain-barrier endothelial cells and subsequent release of prostaglandins (e.g., prostaglandin E2, PGE2) may be involved. Therefore, we sought to relate the effects of prostaglandins on the anorexia following gram-negative bacterial lipopolysaccharide treatment (LPS) to neural activity in the dorsal and median raphe nuclei (DRN and MnR) in rats. COX-2 antagonist (NS-398, 10mg/kg; IP) administration prior to LPS (100MUg/kg; IP) prevented anorexia and reduced c-Fos expression the DRN, MnR, nucleus tractus solitarii and several related forebrain areas. These data indicate that COX-2-mediated prostaglandin synthesis is necessary for LPS anorexia and much of the initial LPS-induced neural activation. Injection of NS-398 into the DRN and MnR (1ng/site) attenuated LPS-induced anorexia to nearly the same extent as IP NS-398, suggesting that prostaglandin signaling in these areas is necessary for LPS anorexia. Because the DRN and MnR are sources of major serotonergic projections to the forebrain, these data suggest that serotonergic neurons originating in the midbrain raphe play an important role in acute-phase response anorexia. PMID- 21527273 TI - Socio-economic status and cardiovascular risk among Indians. PMID- 21527275 TI - Origin and evolution of TNF and TNF receptor superfamilies. AB - The tumor necrosis factor superfamily (TNFSF) and the TNF receptor superfamily (TNFRSF) have an ancient evolutionary origin that can be traced back to single copy genes within Arthropods. In humans, 18 TNFSF and 29 TNFRSF genes have been identified. Evolutionary models account for the increase in gene number primarily through multiple whole genome duplication events as well as by lineage and/or species-specific tandem duplication and translocation. The identification and functional analyses of teleost ligands and receptors provide insight into the critical transition between invertebrates and higher vertebrates. Bioinformatic analyses of fish genomes and EST datasets identify 14 distinct ligand groups, some of which are novel to teleosts, while to date, only limited numbers of receptors have been characterized in fish. The most studied ligand is TNF of which teleost species possess between 1 and 3 copies as well as a receptor similar to TNFR1. Functional studies using zebrafish indicate a conserved role of this ligand-receptor system in the regulation of cell survival and resistance to infectious disease. The increasing interest and use of TNFSF and TNFRSF modulators in human and animal medicine underscores the need to understand the evolutionary origins as well as conserved and novel functions of these biologically important molecules. PMID- 21527274 TI - Occurrence of a conserved domain in ATP diphosphohydrolases from pathogenic organisms associated to antigenicity in human parasitic diseases. AB - A polypeptide (r78-117) belonging to the potato apyrase was identified as a conserved domain shared with apyrase-like proteins from distinct pathogenic organisms, and was obtained as a 6xHis tag polypeptide (r-Domain B). By ELISA, high IgG, and IgG1 and IgG2a subtypes levels were detected in BALB/c mice pre inoculated with r-Domain B. In Schistosoma mansoni adult worm or Leishmania (V.) braziliensis promastigote preparation, anti-r-Domain B antibodies inhibit 22-72% of the phosphohydrolytic activities and when immobilized on Protein A-Sepharose immunoprecipitate 42-91% of them. Western blots of the immunoprecipitated resin antibody-antigen complexes identified bands of mw similar to those predicted for parasite proteins. Total IgG and subclasses of patients with leishmaniasis or schistosomiasis exhibited cross-immunoreactivity with r-Domain B. Therefore, the domain B within both S. mansoni SmATPDase 2 (r156-195) and L. (V.) braziliensis NDPase (r83-122) are potentially involved in the host immune response, and also seem to be conserved during host and parasites co-evolution. PMID- 21527276 TI - The high mobility group box 1 protein of Sciaenops ocellatus is a secreted cytokine that stimulates macrophage activation. AB - High mobility group box 1 protein (HMGB1) is a chromatin-associated nonhistone protein that is involved in nucleosome formation and transcriptional regulation. In addition, HMGB1 is also known as an extracellular cytokine that triggers inflammation and immune responses. HMGB1-like sequences have been identified in a number of fish species, however, the function of piscine HMGB1 remains uninvestigated. In this study, we reported the identification and analysis of SoHMGB1, an HMGB1 homologue from red drum (Sciaenops ocellatus). SoHMGB1 is 206 residues in length and contains two basic HMG boxes and a highly acidic C terminal domain. SoHMGB1 shares 71-87% overall sequence identities with the HMGB1 counterparts from human, rat, and several fish species. Quantitative real time RT PCR analysis showed that constitutive SoHMGB1 expression was detected in various tissues, with the lowest and highest levels found in kidney and muscle respectively. Bacterial challenge upregulated SoHMGB1 expression in head kidney (HK) and HK macrophages and induced extracellular secretion of SoHMGB1 by the activated macrophages. Recombinant SoHMGB1 (rSoHMGB1) purified from yeast exhibited no direct antimicrobial effect but was significantly stimulatory on the proliferation, activation, and bactericidal activity of HK macrophages. Taken together, these results indicate for the first time that a fish HMGB1, SoHMGB1, can function as a secreted cytokine in the event of bacterial infection and promote innate defense through the activation of macrophages. PMID- 21527277 TI - Escherichia coli K-12 pathogenicity in the pea aphid, Acyrthosiphon pisum, reveals reduced antibacterial defense in aphids. AB - To better understand the molecular basis underlying aphid immune tolerance to beneficial bacteria and immune defense to pathogenic bacteria, we characterized how the pea aphid Acyrthosiphon pisum responds to Escherichia coli K-12 infections. E. coli bacteria, usually cleared in the hemolymph of other insect species, were capable of growing exponentially and killing aphids within a few days. Red fluorescence protein expressing E. coli K-12 laboratory strain multiplied in the aphid hemolymph as well as in the digestive tract, resulting in death of infected aphids. Selected gene deletion mutants of the E. coli K-12 predicted to have reduced virulence during systemic infections showed no difference in either replication or killing rate when compared to the wild type E. coli strain. Of note, however, the XL1-Blue E. coli K-12 strain exhibited a significant lag phase before multiplying and killing aphids. This bacterial strain has recently been shown to be more sensitive to oxidative stress than other E. coli K-12 strains, revealing a potential role for reactive oxygen species-mediated defenses in the otherwise reduced aphid immune system. PMID- 21527278 TI - Formulations combining CpG containing oliogonucleotides and poly I:C enhance the magnitude of immune responses and protection against pancreas disease in Atlantic salmon. AB - Both CpG oligodeoxynucleotides and double-stranded RNA (poly I:C) have documented effects as treatments against several viral diseases in fish. However, as stand alone treatments their effects have been modest. We have tested here whether CpG and poly I:C, alone or in combination induce protection against Salmonid Alphavirus (SAV), the causative agent of pancreas disease in Atlantic salmon. Our results revealed a significant reduction of viraemia 2 weeks after ip injection of the combined treatment and 1 week after challenge with SAV subtype 3, followed by reduced SAV induced heart pathology 3 weeks later. The SAV titers in blood samples from the combination group were lower as compared to single treatments with either CpG or poly I:C. Surprisingly, reduced SAV levels could also be found in fish as long as 7 weeks after receiving the combination treatment. The expression of IFNgamma and to a lesser extent IFNa and Mx was up-regulated in head kidney and spleen 5 days after the fish had been treated with CpG and poly I:C. Furthermore, the complement factor C4 was depleted in serum 8 weeks post treatment, suggesting complement activation leading to C4 consumption. We hypothesize that the CpG/poly I:C-induced protection against SAV3 is mediated by mechanisms involving type I and type II IFN induced antiviral activity and complement mediated protective responses. PMID- 21527279 TI - Hydrogen peroxide is produced by E. coli challenged haemocytes and regulates phagocytosis, in the medfly Ceratitis capitata. The active role of superoxide dismutase. AB - Hydrogen peroxide (H(2)O(2)) participates as a second messenger in cell signaling. In this paper, the role of H(2)O(2) was investigated, in Escherichia coli phagocytosis by the haemocytes of the medfly Ceratitis capitata. Block of H(2)O(2) synthesis by specific enzymic inhibitors, namely N-ethylmaleimide (NEM) for NADPH oxidase and diethyldithiocarbamate (DDC) for SOD, resulted in the increase of E. coli phagocytosis. Immunoblot analysis, flow cytometry and confocal microscopy, revealed the constitutive expression of SOD, in the medfly haemocytes. Phagocytosis increased by small interfering RNA (siRNA) for SOD, revealing the active involvement of SOD and H(2)O(2). Immunoblot analysis showed an increase of the ERK1/2 phosphorylation, in the presence of the above H(2)O(2) synthesis enzymic inhibitors. In addition, confocal microscopy showed no co localization of SOD with beta integrin subunit. It appears that SOD participates in the regulation of bacterial phagocytosis, due to involvement of the produced H(2)O(2) in the differential phosphorylation of MAP kinases. PMID- 21527280 TI - Lipopolysaccharide enhances bactericidal activity in Dictyostelium discoideum cells. AB - Innate immune cells respond to invading microbes upon detection of pathogen associated molecular patterns (PAMPS). PAMP-recognition machinery is evolutionarily conserved, allowing for characterization in model organisms. The model organism Dictyostelium discoideum can exist as single-celled amoebae, which phagocytize bacteria for nutrients. Although D. discoideum is used extensively to study phagocytosis, it has not been determined if D. discoideum detects bacterial PAMPs using pattern-recognition machinery. Here we show that D. discoideum mounts responses against the bacterial cell wall PAMP, lipopolysaccharide (LPS). Upon treatment with LPS or its active component Lipid A, D. discoideum cells more efficiently clear phagocytized bacteria. LPS-enhanced bactericidal activity appears dependent both on MAPK signaling pathways as well as on the D. discoideum toll/interleukin-1 receptor domain-containing protein, TirA. These findings indicate that pattern-recognition machinery required to detect and respond to bacterial PAMPs may be conserved in D. discoideum. PMID- 21527281 TI - Characterization of a TnMAVS protein from Tetraodon nigroviridis. AB - A growing family of cellular proteins encoding for caspase activation and the recruitment domain (CARD) plays a crucial role in immunity by sensing viral infections and signaling antiviral immune defenses. We obtained a MAVS-like protein (named TnMAVS) from Tetradon nigroviridis, which contains a CARD domain, a pro-rich domain, and a TM domain similar to human MAVS. A fluorescence assay showed that TnMAVS was located in the cytoplasm and near by the membrane, and not the mitochondria in FHM cells. As such, it was considered as a new member of MAVS. The TnMAVS was highly expressed in the liver and muscle of T. nigroviridis. In the spleen, TnMAVS was down-regulated when the fish was treated with polyinosinic:polycytidylic acid or challenged with ISKNV, but was not affected by PGN or LPS. The dual luciferase reporter assay revealed that TnMAVS overexpression resulted in the activation of the interferon-sensitive response element and NF-kappaB signal pathways. In addition, a characteristic TRAF3 associated peptide PVQD was found in the TnMAVS sequence. Co-immunoprecipitation assays indicated that TnMAVS could interact with zfTRAF3 in eukaryotic cells. PMID- 21527282 TI - A comparative study of phenoloxidase activity in diseased and bleached colonies of the coral Acropora millepora. AB - In scleractinian (hard) corals, immune responses involving phenoloxidase (PO) activity are known to play a role in coral wound healing, but there have been no studies investigating their roles in mitigating either disease or bleaching in an Indo-Pacific coral. PO activity induces the release of reactive oxygen species leading to a cytotoxic cellular environment, which enhances resistance against pathogens, but is also likely to compound oxidative stress induced during bleaching. Antioxidants such as melanin, whose synthesis is activated by PO activity, and peroxidase are potentially important for mitigating the effects of oxidative stress. Therefore, PO activity was investigated in healthy and diseased colonies of Acropora millepora. PO activity levels were compared among tissues bordering white syndrome lesions (WS) and at two locations (mid and outer) at increasing distances from lesions. Equivalent locations were sampled for PO activity on visibly healthy colonies. Additionally, PO and peroxidase activity were compared between severely bleached and healthy colonies of A. millepora. Overall, PO activity of diseased colonies was significantly lower than that of healthy colonies, but with relatively higher activity at the WS lesion border. Severely bleached colonies had significantly lower PO activity than healthy colonies, and peroxidase was also lower, but not significantly. Lower PO activity in unhealthy colonies supports earlier suggestions that lower immune activity leads to increased susceptibility to disease and bleaching. Additionally, low enzyme activity levels may indicate a depletion of colony resources. Increased PO activity at lesion borders in diseased colonies confirms the relative up regulation of a key coral immune defense in response to WS in A. millepora. PMID- 21527283 TI - Dynamic evolution of CIKS (TRAF3IP2/Act1) in metazoans. AB - CIKS (TRAF3IP2/Act1) is important for inflammatory responses and autoimmunity control through its dual functions in CD40L/BAFF and IL17 signaling in mammalians. In this study, we performed comparative and evolutionary analyses of CIKSs from metazoans. Although nematode (Caenorabditis elegans) and sea urchin (Strongylocentrotus purpuratus) have IL17 and IL17 receptors, we found no CIKS in their genomes. The ancient CIKS-like (CIKSL) genes from the invertebrates lottia (Lottia gigantea) and amphioxus (Branchiostoma floridae) have an additional DEATH domain compared with other CIKSLs/CIKSs. Our data suggest that the ancient CIKSL evolved into early chordate CIKS possibly through gene tandem duplication and gene fission. Based on phylogenetic and synteny analyses, vertebrate CIKS genes are divided into two groups, one of which is orthologous to human CIKS and the other is paralogous. Expression analysis indicated that cephalochordata amphioxus IL17 together with CIKS might play an ancient and conserved role in host defense against bacterial infections. During the evolutionary process, the CIKS genes have obtained more and more functions through cooperation with other genes. PMID- 21527284 TI - The expression pattern of scygonadin during the ontogenesis of Scylla paramamosain predicting its potential role in reproductive immunity. AB - The antimicrobial peptide scygonadin (Scy) was first isolated from the gonad of Scylla serrata and its gene is predominantly expressed in the ejaculatory duct of adult males. Thus, its function was predicted to be associated with reproductive immunity, but this is still unclear and needs further investigation. In our study, the expression pattern of Scy at different developmental stages of both male and female S. paramamosain was investigated, so that the potential function of this peptide could be examined. Using real-time quantitative PCR, Scy mRNA transcripts were demonstrated obviously in the vulnerable embryos and larvae-zoea I but very weakly detected in the larvae-zoea III, megalops and juveniles. The gene expression pattern showed a decreasing trend during the early developmental stages. The Scy gene had low expression in the ejaculatory duct of small and medium crabs (100g and 200g in weight) whose gonads were underdeveloped. However, the level of Scy expression was significantly increased in large crabs (300g in weight), which had normally become sexually mature at this size. It was further observed that the numbers of Scy mRNA transcripts in sexually mature crabs were significantly more abundant than in immature ones. In addition, the Scy gene was significantly expressed in the ejaculatory duct of mature male crabs during the mating period (April and May) and reached their highest expression in May. Using immunohistochemistry, the Scy protein was strongly detected in the testis and seminal vesicle of small crabs. However, in large crabs, Scy protein was intensively present in more tissues than in small crabs, including the ejaculatory duct, posterior ejaculatory duct, gill and muscle of males, and also in the spermatheca, gill and muscle of females. It is also interesting to note that Scy mRNA transcripts were detected in other crab species and showed similar expression pattern to those in S. paramamosain. This study extended our knowledge concerning the antimicrobial peptide scygonadin, which has its function principally in the ejaculatory duct of males but which may also play a role at different developmental stages of S. paramamosain from embryogenesis to maturation, and is also widely distributed in other crabs. PMID- 21527285 TI - L-arginine enhances immunity to parasitoids in Drosophila melanogaster and increases NO production in lamellocytes. AB - Drosophila melanogaster was used as a model system to explore the link between nutrition and immunity, and to investigate the role of nitric oxide (NO) in enhancing immunity following dietary enhancement with L-arginine. First, we show that adding L-arginine to the food medium increases the ability of D. melanogaster larvae to encapsulate the eggs of the parasitoid Asobara tabida. Secondly, we show that the increase in immunity is specific to L-arginine, and not to an enhanced calorific content, and that immunity decreases when larvae are fed food with added L-NAME, an inhibitor of nitric oxide synthase. Finally, we show that parasitised larvae fed L-arginine have increased haemocyte numbers, and that the lamellocytes (haemocytes which play a key role in encapsulation) show evidence of an increased production of NO. These results suggest that NO plays a key role in immunity and that the effect of NO is mostly targeted via the lamellocytes. PMID- 21527286 TI - Mucosal dendritic cell subpopulations in the small intestine of newborn calves. AB - Mucosal dendritic cell development in the newborn is poorly understood despite evidence that distinct DC subpopulations populate individual mucosal surfaces. Therefore, we investigated DC phenotype and distribution in the small intestine of newborn calves. DC phenotype was analyzed using flow cytometry and DC distribution was investigated with immunohistochemistry. Purification of CD11c(Hi)MHC Class II(+) cells confirmed CD11c defined myeloid cells and a comparison of neonatal blood and intestine revealed distinct mucosal DC subpopulations. CD11c(Hi)CD14(+) cells were significantly more abundant in newborn ileum versus jejunum and CD335(+) NK cells were the only lymphoid population significantly different in ileum versus jejunum. Immunohistochemistry revealed unique patterns of myeloid cell distribution within the mucosal epithelium, lamina propria, and submucosa. CD11c(+) cells were present within the jejunal but absent from the ileal intraepithelial compartment. In contrast, CD11b(+) cells were present within the ileal but absent from the jejunal intraepithelial compartment. In conclusion, the neonatal small intestine is populated by diverse myeloid subpopulations and significant differences in regional distribution are established early in life. These observations may have significant implications for the response of the newborn to both commensal microflora and enteric pathogens. PMID- 21527287 TI - Animal models of obsessive-compulsive disorder: exploring pharmacology and neural substrates. AB - During the last 30 years there have been many attempts to develop animal models of obsessive-compulsive disorder (OCD). Most models have not been studied further following the original publication, and in the past few years, most papers present studies employing a few established animal models, exploring the neural basis of compulsive behavior and developing new treatment strategies. Here we summarize findings from the five most studied animal models of OCD: 8-OHDPAT (8 hydroxy-2-(di-n-propylamino)-tetralin hydrobromide) induced decreased alternation, quinpirole-induced compulsive checking, marble burying, signal attenuation and spontaneous stereotypy in deer mice. We evaluate each model's face validity, derived from similarity between the behavior in the model and the specific symptoms of the human condition, predictive validity, derived from similarity in response to treatment (pharmacological or other), and construct validity, derived from similarity in the mechanism (physiological or psychological) that induces behavioral symptoms and in the neural systems involved. We present ideas regarding future clinical research based on each model's findings, and on this basis, also emphasize possible new approaches for the treatment of OCD. PMID- 21527288 TI - The neurobiology of adolescence: changes in brain architecture, functional dynamics, and behavioral tendencies. AB - Adolescence is a period of increased behavioral and psychiatric vulnerabilities. It is also a time of dramatic structural and functional neurodevelopment. In recent years studies have examined the precise nature of these brain and behavioral changes, and several hypotheses link them together. In this review we discuss this research and recent electrophysiological data from behaving rats that demonstrate reduced neuronal coordination and processing efficiency in adolescents. A more comprehensive understanding of these processes will further our knowledge of adolescent behavioral vulnerabilities and the pathophysiology of mental illnesses that manifest during this period. PMID- 21527289 TI - The brain's emotional foundations of human personality and the Affective Neuroscience Personality Scales. AB - Six of the primary-process subcortical brain emotion systems - SEEKING, RAGE, FEAR, CARE, GRIEF and PLAY - are presented as foundational for human personality development, and hence as a potentially novel template for personality assessment as in the Affective Neurosciences Personality Scales (ANPS), described here. The ANPS was conceptualized as a potential clinical research tool, which would help experimentalists and clinicians situate subjects and clients in primary-process affective space. These emotion systems are reviewed in the context of a multi tiered framing of consciousness spanning from primary affect, which encodes biological valences, to higher level tertiary (thought mediated) processing. Supporting neuroscience research is presented along with comparisons to Cloninger's Temperament and Character Inventory and the Five Factor Model (FFM). Suggestions are made for grounding the internal structure of the FFM on the primal emotional systems recognized in affective neuroscience, which may promote substantive dialog between human and animal research traditions. Personality is viewed in the context of Darwinian "continuity" with the inherited subcortical brain emotion systems being foundational, providing major forces for personality development in both humans and animals, and providing an affective infrastructure for an expanded five factor descriptive model applying to normal and clinical human populations as well as mammals generally. Links with ontogenetic and epigenetic models of personality development are also presented. Potential novel clinical applications of the CARE maternal-nurturance system and the PLAY system are also discussed. PMID- 21527291 TI - A comparison of brain and behavioral effects of varenicline and nicotine in rats. AB - We evaluated the effects of the smoking cessation aid varenicline and nicotine on brain activation, locomotor sensitization and cognitive functioning in rats. Blood oxygenation level dependent (BOLD) activation on fMRI was measured in awake adult male Sprague-Dawley rats in response to their first dose of varenicline 0.04 mg/kg administered intravenously and compared to saline controls. Other groups of rats were pretreated with daily injections of either varenicline 0.04 mg/kg or saline administered subcutaneously over 5 days, and then imaged on the sixth day while receiving an intravenous dose. The initial dose of varenicline produced patterns of brain activation similar to those previously seen with nicotine, increasing BOLD activation in the auditory, cingulate, insular, prefrontal, retrosplenial, temporal and visual cortices, as well as the hippocampus, nucleus accumbens, septum, and ventral tegmental area. However, the sixth dose produced significantly less BOLD activation than the initial dose in the hippocampus, insular cortex, prefrontal cortex, and temporal cortex, suggesting tolerance. Repeated doses of varenicline have thus the opposite effect of repeated nicotine dosing at 24h intervals, previously shown to produce sensitization of brain activation under the same experimental conditions. We also assessed the effects of varenicline on locomotor sensitization and performance in the Morris water maze. Compared to saline controls, varenicline treated rats showed no evidence of locomotor activation or sensitization, and showed improved performance times on the water maze only on the first day. This study points to different effects of varenicline and nicotine on neuronal and behavioral indices. PMID- 21527292 TI - Cloning and characterization of novel tumor-targeting immunocytokines based on murine IL7. AB - We generated and characterized novel antibody-cytokine fusion proteins ("immunocytokines") based on murine interleukin-7 (IL7), an immunomodulatory protein which has previously shown anti-cancer activity in preclinical models and whose human counterpart is currently being investigated in clinical trials. The sequential fusion of the clinical-stage antibody fragment scFv(F8), specific to a tumor-associated splice isoform of fibronectin, yielded an immunocytokine (termed "F8-mIL7") of insufficient pharmaceutical quality and in vivo tumor targeting performance, with a striking dose dependence on tumor targeting selectivity. By contrast, a novel immunocytokine design (termed "F8-mIL7-F8"), in which two scFv moieties were fused at the N- and C-terminus of murine IL7, yielded a protein of excellent pharmaceutical quality and with improved tumor-targeting performance [tumor: blood ratio=16:1, 24h after injection]. Both F8-mIL7 and F8-mIL7-F8 could induce tumor growth retardation in immunocompetent mice, but were not able to eradicate F9 tumors. The combination of F8-mIL7-F8 with paclitaxel led to improved therapeutic results, which were significantly better compared to those obtained with saline treatment. The study indicates how the engineering of novel immunocytokine formats may help generate fusion proteins of acceptable pharmaceutical quality, for those immunomodulatory proteins which do not lend themselves to a direct fusion with antibody fragments. PMID- 21527293 TI - Quantification of cell infection caused by Listeria monocytogenes invasion. AB - Listeria monocytogenes causes a life-threatening food-borne disease known as Listeriosis. Elderly,immunocompromised, and pregnant women are primarily the victims of this facultative intracellular Gram-positive pathogen. Since the bacteria survive intracellularly within the human host cells they are protected against the immune system and poorly accessed by many antibiotics. In order to screen pharmaceutical substances for their ability to interfere with the infection, persistence and release of L. monocytogenes a high content as say is required. We established a high content screen (HCS) using the RAW 264.7 mouse macrophage cell line seeded into 96-well glass bottom microplates. Cells were infected with GFP-expressing L. monocytogenes and stained thereafter with Hoechst 33342.Automated image acquisition was carried out by the Scan(R) screening station. We have developed an algorithm that automatically grades cells in microscopy images of fluorescent-tagged Listeria for the severity of infection. The grading accuracy of this newly developed algorithm is 97.1% as compared to a 74.3%grading accuracy we obtained using the commercial Olympus Scan(R) software. PMID- 21527294 TI - Social modeling of food purchases at supermarkets in teenage girls. AB - Ample experimental research has demonstrated the impact of peer influence on food intake in adolescents and adults. However, none of these studies focused social modeling effects on food purchases in supermarkets. This study investigated whether the food purchase behavior of a confederate peer would be adopted by the participant. Teenage girls (N=89) were asked to perform a shopping task in a local supermarket. They had to shop with a same-sex confederate peer who had been instructed earlier to purchase either five low-kilocaloric food products, five average-kilocaloric or five high-kilocaloric food products. Significant main effects for the experimental purchase condition and hunger were found on the amount of kilocalories of the purchased food products. Teenage girls who shopped with a peer in the high-kilocaloric condition purchased higher kilocaloric food products relative to the girls who shopped with a peer in the low-kilocaloric condition. In addition, girls who reported to be hungry purchased higher kilocaloric food products in general. These findings might imply that teenage girls follow unhealthy food purchases of a peer during shopping. Health promotion might benefit from our findings by also focusing on food purchases and not only food intake. PMID- 21527295 TI - Effects of red wine on the electrical activity and functional coupling between prefrontal-parietal cortices in young men. AB - The effects of low-dose red wine on cortical electroencephalogram (EEG) and the functional coupling between the frontal and parietal cortices during the first minutes after ingestion were studied. In a first experiment, 38 male volunteers participated in a wine/water challenge protocol in which each subject served as his own control. Wine-induced EEG changes appeared immediately after ingestion and continued for 40 min. These changes were characterized by an increase in the absolute power (AP) and relative power (RP) of fast frequencies (alpha1, alpha2, beta1 and beta2), a decrease of low frequencies (delta and theta) and a specific decrease in the degree of coupling between cortices at 20 min after wine ingestion. To determine if EEG changes were produced by the alcohol in the red wine, in a second experiment, 24 male volunteers participated in an independent wine/placebo group protocol. At 20 min post-ingestion, the red wine group showed higher power in the alpha band, lower RP of low frequencies and decreased correlation, as compared to the placebo group. These findings show that low-dose red wine produces a rapid cortical activation and decreased synchronization between the prefrontal and parietal areas, which could be associated with aroused states or altered cognitive processes, as has been described in other studies. PMID- 21527290 TI - Psychopathological aspects of dopaminergic gene polymorphisms in adolescence and young adulthood. AB - Dopamine hypotheses of several psychiatric disorders are based upon the clinical benefits of drugs affecting dopamine transporter or receptors, and have prompted intensive candidate gene research within the dopaminergic system during the last two decades. The aim of this review is to survey the most important findings concerning dopaminergic gene polymorphisms in attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), obsessive compulsive disorder, and substance abuse. Also, genetic findings of related phenotypes, such as inattention, impulsivity, aggressive behavior, and novelty seeking personality trait are presented, because recent studies have applied quantitative trait measures using questionnaires, symptom scales, or other objective endophenotypes. Unfortunately, genetic variants with minor effects are problematic to detect in these complex inheritance disorders, often leading to contradictory results. The most consistent association findings relate to ADHD and the dopamine transporter and the dopamine D4 receptor genes. Meta-analyses also support the association between substance abuse and the D2 receptor gene. The dopamine catabolizing enzyme genes, such as monoamine oxidase (MAO) A and catechol-O-methyltransferase (COMT) genes, have been linked to aggressive behaviors. PMID- 21527296 TI - Effects of neuromedin-beta on caloric compensation, eating behaviours and habitual food intake. AB - We have previously shown that a missense mutation (p.P73T) located in the neuromedin-beta gene, a satiety peptide, was associated with higher levels of disinhibition, susceptibility to hunger, and body weight gain over time. In this study we compare caloric compensation, eating behaviour traits, food intake and adiposity between premenopausal women with (T73T) and without (P73P) mutation. Subjects (N=153) were screened to find homozygous women (T73T) that were matched for age, BMI and use of oral contraceptives with 7 women (P73P) not carrying the mutation. Eating behaviour traits were assessed with the Three-Factors Eating Questionnaire and habitual dietary intakes with a 3-day dietary record. A randomized single-blind cross-over design was used to test the effect of p.P73T on caloric compensation. We measured appetite sensations and ad libitum dietary intake following two different energy preloads. We found no difference in eating behaviour traits, adiposity, appetite sensations, ad libitum dietary intake and caloric compensation. However, T73T women had lower habitual energy and carbohydrate intakes than P73P. Differences in carbohydrate intakes disappeared when expressed in percentage of energy. These results suggest that the neuromedin beta p.P73T mutation modulates energy intake without effects on macronutrient. A lack of power resulting from our difficulty to recruit enough T73T women precludes any definitive conclusion regarding the impact of this mutation on caloric compensation. PMID- 21527297 TI - Neuropeptide Y, an orexigenic hormone, regulates phagocytic activity of lizard splenic phagocytes. AB - Present in vitro study in the wall lizard Hemidactylus flaviviridis, for the first time in ectothermic vertebrates, demonstrated the immunoregulatory role of neuropeptide Y (NPY) and its receptor-coupled downstream signaling cascade. NPY inhibited the percentage phagocytosis and phagocytic index of splenic phagocytes. The inhibitory effect of NPY on phagocytosis was completely antagonized by Y(2) and Y(5) receptor antagonists. This suggests that NPY mediated its effect on phagocytosis through Y(2) and Y(5) receptors. Further, NPY receptor-coupled downstream signaling cascade for NPY effect on phagocytosis was explored using the inhibitors of adenylate cyclase (SQ 22536) and protein kinase A (H-89). The SQ 22536/H-89 in a concentration-related manner decreased the inhibitory effect of NPY on phagocytosis. Further, an increase in intracellular cAMP level was observed in response to NPY. Taken together, it can be concluded that NPY via Y(2) and Y(5) receptor-coupled AC-cAMP-PKA pathway downregulated the phagocytic activity of lizard splenic phagocytes. PMID- 21527298 TI - Genetic variants of ghrelin in metabolic disorders. AB - An increasing understanding of the role of genes in the development of obesity may reveal genetic variants that, in combination with conventional risk factors, may help to predict an individual's risk for developing metabolic disorders. Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis and it is a reasonable candidate gene for obesity related co-morbidities. In cross-sectional studies low total ghrelin concentrations and some genetic polymorphisms of ghrelin have been associated with obesity-associated diseases. The present review highlights many of the important problems in association studies of genetic variants and complex diseases. It is known that population-specific differences in reported associations exist. We therefore conclude that more studies on variants of ghrelin gene are needed to perform in different populations to get deeper understanding on the relationship of ghrelin gene and its variants to obesity. PMID- 21527299 TI - The safety evaluation of adjuvants during vaccine development: the AS04 experience. AB - Novel adjuvants that contain immunoenhancer molecules are now present in human vaccines either registered or in clinical trials. These adjuvants have the potential to provide clear benefits in improving the magnitude and duration of various aspects of the adaptive immune response. However, the use of immunoenhancers in vaccine formulations may be perceived as introducing theoretical safety risks that need to be addressed during the course of vaccine development. In addition to classical clinical safety evaluation, the licensing authorities recommend that novel adjuvants should be evaluated in non-clinical toxicology studies, both as separate entities and as part of the final vaccine formulation. We present here our approach for the safety evaluation of adjuvanted vaccines using AS04-adjuvanted vaccines as example. This evaluation consists of three tiers: non-clinical toxicology, adjuvant mode-of-action investigations and clinical safety assessment in controlled clinical trials and post-marketing surveillance. We also discuss how the knowledge of adjuvant mode of action can support the current practice of safety evaluation. PMID- 21527300 TI - A history of Panton-Valentine leukocidin (PVL)-associated infection protects against death in PVL-associated pneumonia. AB - Panton-Valentine leukocidin (PVL) is a Staphylococcus aureus toxin associated with skin and soft-tissue infections (SSTIs) and life-threatening necrotizing pneumonia in humans. Recent reports have demonstrated that neutralizing antibody to PVL is not protective against SSTI recurrence, thus raising a controversy about the expected clinical benefits from the use of PVL as a vaccine target. To investigate the impact of pre-existing immunity to PVL on the outcome of necrotizing pneumonia, we conducted a retrospective study of 114 cases and searched for an association between the history of PVL-associated infection and outcome. Death and severity factors, such as the need for mechanical ventilation and inotrope support, were significantly less frequent in patients with prior PVL associated infection than in those without. These findings indicate a protective role of PVL-directed immunity in severe systemic PVL-associated disease, suggesting that anti-PVL vaccine could provide strong clinical benefits in this setting. PMID- 21527302 TI - Factors influencing uptake of influenza A (H1N1) vaccine amongst healthcare workers in a regional pediatric centre: lessons for improving vaccination rates. AB - BACKGROUND: Influenza A (H1N1) vaccination has been recommended for all frontline healthcare workers (HCWs) in the UK since October 2009, to protect individuals and their patients from infection. Understanding the factors influencing vaccine uptake by HCW may improve future vaccination programmes in current and subsequent years. AIMS: To assess the uptake of influenza A (H1N1) vaccine, and factors affecting vaccine uptake, in frontline healthcare workers in a large pediatric hospital. METHOD: A cross-sectional questionnaire survey conducted in a regional Pediatric Hospital in Scotland incorporating intensive care and ECMO services. One page, anonymised questionnaires were distributed to all frontline HCW in high risk departments of the hospital. RESULTS: 260 questionnaires were completed, capturing an estimated 52% of all staff. Vaccination rate was 49.6%, and was significantly higher amongst doctors (OR 2.4, 95% CI 1.3-4.5, P=0.005). Commonest reasons for vaccine uptake were high risk of contact with H1N1 (88%) and responsibility to protect patients (71%). Uncertainty about vaccine side-effects (47%), concern about vaccine safety (33%) and being too busy to attend the vaccine clinic (22%) were the commonest reasons for non-vaccination. Reasons for vaccination varied between staff grouping and department. 36% of non-vaccinated staff would accept the vaccine if offered. CONCLUSIONS: Vaccine uptake may be increased by addressing HCW knowledge and attitudes and access to vaccine. Future vaccination programmes should include targeted education and vaccine delivery, at the convenience of staff, and in their own department. PMID- 21527301 TI - Leishmania major MAP kinase 10 is protective against experimental L. major infection. AB - Leishmania, a protozoan parasite that resides and replicates obligatorily within macrophages, inflicts a complex of severe diseases known as leishmaniasis. The diseases have significant socio-economic impact through gross disfiguration, morbidity and mortality worldwide. Despite these problems, an effective anti leishmanial vaccine remains elusive. Herein, we have analyzed the immunogenicity and protective efficacy of L. major MAP kinase 10 (LmjMAPK10) against the challenge infection with the parasite. We observe significant protection against the infection by LmjMAPK10 priming of BALB/c mouse strain, a susceptible host. The resistance to the infection is generally associated with mixed Th1/Th2 responses to the infection following immunization with LmjMAPK10 DNA or protein or a combination of both DNA and protein. Therefore, LmjMAPK10 is a probable vaccine candidate against the infection. PMID- 21527303 TI - The effects of vaccine characteristics on adult women's attitudes about vaccination: a conjoint analysis study. AB - The number of current and future vaccines for adults has been steadily increasing. Yet, vaccine coverage rates for adult vaccinations have historically been low, and less is known about how adults in the mid-adult age range make vaccine decisions for themselves. The purpose of this study was to assess which vaccine characteristics affect vaccine decision-making among mid-adult women. Adult women, aged 27-55 (n=258) rated 9 hypothetical vaccine scenarios, each of which was defined along 4 dimensions: mode of transmission (STI or non-STI), severity of infection (curable, chronic, or fatal), vaccine efficacy (50%, 70%, or 90%), and availability of behavioral methods for prevention (available or not available). Ratings ranged from 0 to 100. Conjoint analysis was used to assess the effect of relative preferences for the vaccine scenario characteristics on participant ratings of scenarios. The mean vaccine scenario rating was 78.2. Nearly half (40%, n=104) of participants rated all nine scenarios the same, with the majority of those (84%) holding strongly positive views. Conjoint analysis of the other 154 participants who discriminated between scenarios indicated that the main drivers for vaccine acceptability were severity of the disease and the efficacy of the vaccine to prevent the disease. Mode of transmission and availability of a preventative behavioral measure did not play a significant role. Future studies should further assess how women's understanding of severity of the disease and efficacy of the vaccine to prevent disease may be useful for increasing vaccine acceptability. PMID- 21527304 TI - Phenotypic variability in childhood TB: implications for diagnostic endpoints in tuberculosis vaccine trials. AB - The endpoint definition for infant tuberculosis (TB) vaccine trials should match the TB disease phenotype expected in the control arm of the study population. Our aim was to analyse selected combinations of the clinical, radiological, and microbiological features of pulmonary TB among children investigated under vaccine trial conditions, in order to estimate case frequency for a range of expected TB phenotypes. Two thousand one hundred and eighty five South African children were investigated over a nine-year period (2001-2009). Evidence of TB exposure and classical symptoms were several times more common than chest radiography (CXR) compatible with TB, or positive Mycobacterium tuberculosis culture. Discordance between clinical, radiological, and microbiological features was common in individual children. Up to one third of children with compatible CXR, and up to half the children who were M. tuberculosis culture positive, were asymptomatic. The culture positive rate fell over time, although rates of TB exposure and compatible chest radiography increased. Consequently, the annual incidence of diagnostic combinations that included M. tuberculosis culture fell to <0.2%. However, in this study population (children <2 years of age), annual incidence of the TB disease phenotype that included the triad of TB exposure, symptoms, and compatible CXR, approached 1% (n=848 per 100,000). These findings allow modelling of expected TB case frequency in multi-centre infant TB vaccine trials, based upon benchmarking of diagnostic data against the key indicator variables that constitute the building blocks of a trial endpoint. PMID- 21527305 TI - Anaphylaxis following H1N1 pandemic vaccines: safety data in perspective. AB - We present here a detailed analysis of anaphylaxis cases reported to GlaxoSmithKline safety database following vaccination with its H1N1 pandemic influenza vaccines, PandemrixTM and ArepanrixTM. Cases were assessed according to the Brighton Collaboration Case Definition (BCCD) as either confirmed diagnosis (97/395, 24.6%), insufficient information to fulfil the minimal criteria of the case definition (117/395, 29.6%) or anaphylaxis excluded (181/395, 45.8%). There was no evidence that the rate of anaphylaxis following vaccination with PandemrixTM or ArepanrixTM is increased with respect to the rates of anaphylaxis for other vaccines. Our analysis also highlighted the challenges of reliably determining the rate of anaphylaxis as an adverse event in the postmarketing setting following mass vaccination, as anaphylaxis was excluded in 45.8% of reported cases. PMID- 21527306 TI - Exposure to 1-bromopropane causes degeneration of noradrenergic axons in the rat brain. AB - 1-Bromopropane (1-BP) has been used as an alternative to ozone-depleting solvents. Previous studies showed that 1-BP is neurotoxic in animals and humans. In humans, exposure to 1-BP caused various neurological and neurobehavioral symptoms or signs including depressive or irritated mood. However, the neurobiological changes underlying the depressive symptoms induced by 1-BP remain to be determined. The depressive symptoms are thought to be associated with degeneration of axons containing noradrenaline and serotonin. Based on this hypothesis, the present study examined the effects of repeated exposure to 1-BP on serotonergic and noradrenergic axons. Exposure to 1-BP induced dose-dependent decreases in the density of noradrenergic axons in the rat prefrontal cortex, but no apparent change in the density of serotonergic axons. The results suggest that depressive symptoms in workers exposed to 1-BP are due, at least in part, to the degeneration of noradrenergic axons in the brain. PMID- 21527307 TI - Unprecedented right- and left-handed quadruplex structures formed by heterochiral oligodeoxyribonucleotides. AB - CD and NMR studies on heterochiral oligodeoxynucleotides (d/l-ODNs) forming quadruplex structures are reported. Heterochiral ODNs, based on sequence TGGGGT, are able to form stable either right- or left-handed quadruplexes depending on d/l ratio and residues position. Results suggest that the 3'-end and the core of the G-run are more important than the 5'-end in determining the quadruplex handness. Particularly, oligonucleotide T(D)G(D)G(L)G(L)G(D)T(D) (L34) at low temperatures forms a well-defined left-handed quadruplex, notwithstanding it is mostly composed by natural d residues. This structure is characterized by three all-anti G-tetrads and one all-syn G-tetrad. PMID- 21527308 TI - Normalization of deranged signal transduction in lymphocytes of COPD patients by the novel calcium channel blocker H-DHPM. AB - Investigations on the role of intracellular Ca(2+) ion concentration in the mechanism of development of COPD in smokers and non-smokers were carried out. The intracellular Ca(2+) levels were found to be increased in human lymphocytes in patients with COPD as compared to non-smokers and smokers without COPD. The investigations reveal an association in altered intracellular Ca(2+) regulation in lymphocytes and severity of COPD, by means of significant activation of Protein kinase C and inducible nitric oxide synthase (iNOS). The effect of a novel calcium channel blocker ethyl 4-(4'-heptanoyloxyphenyl)-6-methyl-3,4 dihydropyrimidin-2-one-5-carboxylate (H-DHPM) as a potential candidate for the treatment of COPD was also investigated. H-DHPM treated cells showed a decrease in intracellular Ca(2+) level as compared to the control cells. Molecular studies were carried out to evaluate the expression profile of NOS isoforms in human lymphocytes and it was shown that H-DHPM decreases the increased iNOS in COPD along with reestablishing the normal levels of endothelial nitric oxide synthase (eNOS). The results of H-DHPM were comparable with those of Amlodipine, a known calcium channel blocker. Calcium channel blocker H-DHPM proves to be a potential candidate for the treatment of COPD and further clinical studies are required to prove its role in the treatment of pulmonary hypertension (PH). PMID- 21527309 TI - Binding properties of human telomeric quadruplex multimers: a new route for drug design. AB - Human telomeric G-quadruplex structures are known to be promising targets for an anticancer therapy. In the past decade, several research groups have been focused on the design of new ligands trying to optimize the interactions between these small molecules and the G-quadruplex motif. In most of these studies, the target structures were the single quadruplex units formed by short human DNA telomeric sequences (typically 21-26 nt). However, the 3'-terminal single-stranded human telomeric DNA is actually 100-200 bases long and can form higher-order structures by clustering several consecutive quadruplex units (multimers). Despite the increasing number of structural information on longer DNA telomeric sequences, very few data are available on the binding properties of these sequences compared with the shorter DNA telomeric sequences. In this paper we use a combination of spectroscopic (CD, UV and fluorescence) and calorimetric techniques (ITC) to compare the binding properties of the (TTAGGG)(8)TT structure formed by two adjacent quadruplex units with the binding properties of the (AG(3)TT)(4) single quadruplex structure. The three side-chained triazatruxene derivative azatrux and TMPyP4 cationic porphyrin were used as quadruplex ligands. We found that, depending on the drug, the number of binding sites per quadruplex unit available in the multimer structure was smaller or greater than the one expected on the basis of the results obtained from individual quadruplex binding studies. This work suggests that the quadruplex units along a multimer structure do not behave as completely independent. The presence of adjacent quadruplexes results in a diverse binding ability not predictable from single quadruplex binding studies. The existence of quadruplex-quadruplex interfaces in the full length telomeric overhang may provide an advantageous factor in drug design to enhance both affinity and selectivity for DNA telomeric quadruplexes. PMID- 21527311 TI - The ALS/PDC syndrome of Guam: potential biomarkers for an enigmatic disorder. AB - The ALS/parkinsonism-dementia complex of Guam is a long latency disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. It is remarkably similar to a syndrome localized to the Kii Peninsula of Japan. There are as yet no identified pathological features that will clearly distinguish the Guam or Kii ALS/PDC syndrome from other degenerative neurological disorders. At present, ALS/PDC of Guam and the Kii Peninsula can be confirmed only by postmortem examination. The most prominent pathological hallmark is the widespread occurrence of neurofibrillary tangles which express the same balance of 3R and 4R tau that is found in Alzheimer disease. They both show an increased prevalence of a peculiar retinal disorder termed linear retinal pigmentary epitheliopathy. The disorders are both highly familial. Several environmental factors have been proposed but no supportive evidence for an environmental or dietary factor has been found. Genome searches have so far failed to identify causative genes although two single nuclear polymorphisms related to MAPT that increase the risk of the Guam syndrome have been located. The two syndromes are clearly unique, and clues as to their causation could be beneficial in understanding the etiology of similar, but much more prevalent disorders in North America, Europe and Asia. Identification of biomarkers for premortem diagnosis would be helpful in management as well as in revealing the true etiology. PMID- 21527312 TI - Multimodal transcranial magnetic stimulation: using concurrent neuroimaging to reveal the neural network dynamics of noninvasive brain stimulation. AB - Since its introduction in the 1980s, Transcranial Magnetic Stimulation (TMS) has proven to be a versatile method to non-invasively study human brain function by reversibly altering ongoing neural processing. In addition, TMS has been explored as a therapeutic intervention in a number of neurological and neuropsychiatric conditions. However, our understanding of TMS-induced changes in neural activity patterns is still rather limited, particularly when it comes to changes in neural network dynamics beyond the cortical site directly targeted by TMS. In order to monitor both its local and remote neurophysiological effects, TMS has been combined with complementary neuroimaging methods that allow additional insights into how observed TMS effects at the behavioral level can be interpreted by taking into account the full scale of its impact throughout the brain. The current review provides a comprehensive overview of the existing multimodal TMS literature, covering studies in which TMS was combined with one of the three main neuroimaging modalities, namely Electroencephalography, Positron Emission Tomography, and functional Magnetic Resonance Imaging. Besides constituting a reflection of the status quo in this exciting multidisciplinary research field, this review additionally reveals both convergent and divergent observations across modalities that await corroboration or resolution, thereby further guiding ongoing basic research and providing useful constraints to optimize future clinical applications. PMID- 21527310 TI - The emerging role of forces in axonal elongation. AB - An understanding of how axons elongate is needed to develop rational strategies to treat neurological diseases and nerve injury. Growth cone-mediated neuronal elongation is currently viewed as occurring through cytoskeletal dynamics involving the polymerization of actin and tubulin subunits at the tip of the axon. However, recent work suggests that axons and growth cones also generate forces (through cytoskeletal dynamics, kinesin, dynein, and myosin), forces induce axonal elongation, and axons lengthen by stretching. This review highlights results from various model systems (Drosophila, Aplysia, Xenopus, chicken, mouse, rat, and PC12 cells), supporting a role for forces, bulk microtubule movements, and intercalated mass addition in the process of axonal elongation. We think that a satisfying answer to the question, "How do axons grow?" will come by integrating the best aspects of biophysics, genetics, and cell biology. PMID- 21527313 TI - Chronic treatment with ascorbic acid enhances cortical spreading depression in developing well-nourished and malnourished rats. AB - Ascorbic acid (AA) is an antioxidant molecule that is highly concentrated in the brain and can exert both anticonvulsant and proconvulsant effects in distinct models of experimental seizures. Herein, we investigated whether chronic AA administration alters cortical excitability as indexed by the cortical spreading depression (CSD). Well-nourished (W) and malnourished (M) rats were treated, by gavage, with 60mg/kg/day of l-AA from postnatal days 7-28, and CSD propagation was analyzed at 30-40 days. Compared to the W groups, M rats presented higher (p<0.05) CSD amplitudes and velocities of propagation. In both nutritional conditions, AA-treatment significantly increased CSD amplitudes and propagation velocities (p<0.05), as compared to non-treated ('naive'; Nv) and saline-treated (Sal) controls. The mean+/-standard deviation CSD velocities of propagation (in mm/min) for the Sal, AA and Nv groups were respectively 3.75+/-0.03, 4.26+/-0.08 and 3.81+/-0.04 for the W condition and 4.29+/-0.08, 4.51+/-0.04 and 4.30+/-0.04 for the M groups. The results demonstrate a CSD-facilitation by AA regardless of nutritional status. They also suggest that, at the dose of 60mg/kg/day chronically administered during brain development, AA may act as a prooxidant in brain, in view of the contrasting effect as compared with other antioxidants, which reduce CSD. PMID- 21527314 TI - Transcranial direct current stimulation influences the cardiac autonomic nervous control. AB - To investigate whether the manipulation of brain excitability by transcranial direct current stimulation (tDCS) modulates the heart rate variability (HRV), the effect of tDCS applied at rest on the left temporal lobe in athletes (AG) and non athletes (NAG) was evaluated. The HRV parameters (natural logarithms of LF, HF, and LF/HF) was assessed in 20 healthy men before, and immediately after tDCS and sham stimulation. After anodal tDCS in AG the parasympathetic activity (HF(log)) increased (P<0.01) and the sympathetic activity (LF(log)) and sympatho-vagal balance (LF/HF(log)) decreased (P<0.01), whereas no significant effects were detected in NAG (P>0.05). No significant changes in HRV indexes were provoked by sham stimulation in both AG and NAG (P>0.05). In conclusion, tDCS applied on the left temporal lobe significantly increased the overall HRV in AG, enhancing the parasympathetic and decreasing the sympathetic modulation of heart rate. Consequently the sympatho-vagal balance decreased at rest in AG but not in NAG. Releasing a weak electric current to stimulate selected brain areas may induce favorable effects on the autonomic control to the heart in highly fit subjects. PMID- 21527315 TI - Long-term object location memory in rats: effects of sample phase and delay length in spontaneous place recognition test. AB - This study investigates the effects of sample phase and delay length on discrimination performance in the spontaneous place recognition (SPR) test in rats. Rats were allowed to explore an arena where two identical objects were presented for 5-20 min (sample phase). After a delay interval, rats were placed again in the same arena but one of the two objects was moved to a novel place (test phase). Results showed that when the sample phase was as long as 20 min, rats preferentially explored the moved object during the test phase even after a 6-24h delay was interposed. Further sequential and cumulative analyses of the test phase revealed that the preference for the object in a novel place was evident in the first and 2nd min of the test phase in rats with a longer sample phase duration. Correlation analysis showed that locomotor activity and object exploration in the sample phase were not decisive factors in spatial memory performance. The present results demonstrate the importance of the sample phase exposure time and the test phase length. PMID- 21527316 TI - Prestimulus top-down reflection of obsessive-compulsive disorder in EEG frontal theta and occipital alpha oscillations. AB - It has recently been reported that prestimulus electroencephalogram (EEG) frontal theta and occipital alpha oscillations of healthy controls were modulated by the type of upcoming tasks, reflecting prestimulus top-down preparation. The present study explored the differences in dynamics of frontal theta and occipital alpha activities between obsessive-compulsive disorder (OCD) patients and healthy participants in terms of reflection of prestimulus top-down regulation. EEGs were recorded from 16 OCD patients and 16 healthy controls using a color and a shape discrimination task. The power and time course of oscillatory activity were calculated by convolving the EEG signals with Morlet wavelets. Although OCD patients yielded significantly lower total alpha and total theta power results than the normal controls, they demonstrated that significantly higher total alpha and total theta power preceded the difficult task (shape-task) as compared to the easy task (color-task). Furthermore, the frontal region, where OCD patients usually revealed abnormalities, showed significant differences in the prestimulus total theta power between the normal and OCD groups. Taken together, frontal theta and occipital alpha oscillations seem to be potent electrophysiological correlates reflecting impairment in the prestimulus top-down processing of OCD patients. PMID- 21527317 TI - Effects of extracellular calcium concentration on neurite outgrowth in PC12 cells by staurosporine. AB - Staurosporine as an inhibitor of protein kinases can induce neuronal differentiation in PC12 cells. We investigated the role of extracellular Ca(2+) on staurosporine inducing neurite outgrowth in PC12 cells. The cells were cultured during cell differentiation in the presence of 214 nM staurosporine with 0.0-0.7 Ca(2+)mM as treatment media. We obtained the fraction of neurite-bearing cells, total neurite length and the percentage of cytotoxiciy. The results showed that decrease or increase of extracellular calcium ions resulted in correspondingly significant decrease or increase in total neurite length and cell differentiation in treated cells. With an increase of extracellular calcium concentration from 0.0 to 0.7 mM, the percentage of cytotoxicity of the PC12 cells decreased (p<0.05). Our data suggest that staurosporine uses the extracellular calcium ions to affect on neurite outgrowth. PMID- 21527318 TI - GSK3beta genetic variability in patients with Multiple Sclerosis. AB - Glycogen synthase kinase-3 beta (GSK3beta) is a ubiquitous kinase that is part of multiple signaling pathways. It has neurotrophic/neuroprotective effects by mediating the actions of neurotrophic molecules in the brain, thus providing neuroprotection through modulation of energy metabolism. Notably, it has been demonstrated that GSK3beta is involved in Wnt-beta-catenin signaling, which contributes to the inhibition of myelination and remyelination processes in mammals. Three-hundred nineteen patients with MS and 294 age-matched controls were genotyped by allelic discrimination for four common GSK3beta variants (rs2199503, rs9826659, rs334558 and rs6438552) tagging about 100% of GSK-3beta variability. A statistically significant increased frequency of the rs334558 GG genotype was observed in patients as compared with controls (25.4% versus 17.7%, P=0.02; OR:1.58, 95%CI: 1.07-2.34). Stratifying MS patients according to the disease subtype, a statistically significant difference of rs334558 GG frequency was found between Relapsing Remitting (RR), but not Primary Progressive or Secondary MS, and controls (27.0% versus 17.7%, P=0.01; OR: 1.72, 95%CI: 1.13 2.61). GSK3beta rs334558 is a susceptibility factor for MS. As it is located in the promoter region, a possible explanatory mechanism could be an influence of the variant on the gene transcription rate. PMID- 21527319 TI - Aging-related alterations in the expression and distribution of GluR2 and PICK1 in the rat hippocampus. AB - Deficit in synaptic plasticity in the hippocampus frequently occurs during normal aging. Although the protein level and calcium permeability of AMPARs alter with aging, the alteration of AMPARs and their regulatory proteins during aging are far from understanding. Dynamics of GluR2 subunit are dependent on the function of protein interacting with Calpha kinase 1 (PICK1), PKCalpha and calcineurin (CaN). Here, we firstly show that the expression of PICK1 and CaN B decreased significantly in the hippocampus of old rats compared to that of young and adult rats. The decrease was accompanied by a reduction of GluR2 and PKCalpha and an increase in CaN A. Next, we found that in young and adult rats, the distribution of PICK1 and GluR2 diffused in the cytoplasm of hippocampal neurons, but closely around perinuclear in the hippocampal neurons of old rats. These results suggest that the expression of GluR2, PICK1, PKCalpha and CaN B significant decreased in the hippocampus and these alterations may lead to altered distribution of GluR2 and PICK1 during aging. PMID- 21527320 TI - Chronic restraint stress impairs endocannabinoid mediated suppression of GABAergic signaling in the hippocampus of adult male rats. AB - Chronic stress, a risk factor for the development of psychiatric disorders, is known to induce alterations in neuronal networks in many brain areas. Previous studies have shown that chronic stress changes the expression of the cannabinoid receptor 1 (CB1) in the brains of adult rats, but neurophysiological consequences of these changes remained unclear. Here we demonstrate that chronic restraint stress causes a dysfunction in CB1 mediated modulation of GABAergic transmission in the hippocampus. Using an established protocol, adult male Sprague Dawley rats were daily restrained for 21 days and whole-cell voltage clamp was performed at CA1 pyramidal neurons. When recording carbachol-evoked inhibitory postsynaptic currents (IPSCs) which presumably originate from CB1 expressing cholecystokinin (CCK) interneurons, we found that depolarization-induced suppression of inhibition (DSI) was impaired by the stress. DSI is a form of short-term plasticity at GABAergic synapses that is known to be CB1 mediated and has been suggested to be involved in hippocampal information encoding. Chronic stress attenuated the depolarization-induced suppression of the frequency of carbachol evoked IPSCs. Incubation with a CB1 receptor antagonist prevented this DSI effect in control but not in chronically stressed animals. The stress-induced impairment of CB1-mediated short-term plasticity at GABAergic synapses may underlie cognitive deficits which are commonly observed in animal models of stress as well as in patients with stress-related psychiatric disorders. PMID- 21527321 TI - Investigation of the extent of surface coating via mechanofusion with varying additive levels and the influences on bulk powder flow properties. AB - The objective of this study was to investigate if the coating extent created by a mechanofusion process corresponded with observed changes in bulk powder properties. A fine lactose powder (approximate median diameter 20 MUm) was dry coated with magnesium stearate using from 0.1 to 5% (w/w) content. An ultra-thin coating layer of magnesium stearate was anticipated, but previous attempts to determine such thin layers on these fine particles have had limited success, with poor resolution. In this study, the surface coating was examined using the state of-the-art XPS and ToF-SIMS systems. The powder flow was characterized by Carr index and shear cell testing. XPS was successfully applied to demonstrate variations in surface coverage, as a function of additive levels, and indicated near complete coating coverage at additive levels of 1% (w/w) and above. ToF-SIMS results supported such coating coverage assessment, and indicated coating uniformly across the fine particle surfaces. The flow metrics employed could then be related to the coating coverage metrics. The mechanofusion process also modified the apparent surface roughness observed by SEM and BET. It was suggested that the changes in the surface chemical composition exerted a more evident and direct impact on the powder cohesion and flow characteristics than the changes in the surface morphological properties after the mechanofusion in this study. PMID- 21527322 TI - A novel bottom-up process to produce nanoparticles containing protein and peptide for suspension in hydrofluoroalkane propellants. AB - To overcome the disadvantages of microemulsion and nanoprecipitation methods to produce protein-containing nanoparticles, a novel bottom-up process was developed to produce nanoparticles containing the model protein lysozyme. The nanoparticles were generated by freeze-drying a solution of lysozyme, lecithin and lactose in tert-butyl alcohol (TBA)/water co-solvent system and washing off excess lecithin in lyophilizate by centrifugation. Formulation parameters such as lecithin concentration in organic phase, water content in TBA/water co-solvent, and lactose concentration in water were optimized so as to obtain desired nanoparticles with retention of the bioactivity of lysozyme. Based on the results, 24.0% (w/v) of lecithin, 37.5% (v/v) of water content, and 0.56% (w/v) of lactose concentration were selected to generate spherical nanoparticles with approximately 200 nm in mean size, 0.1 in polydispersity index (PI), and 99% retained bioactivity of lysozyme. These nanoparticles rinsed with ethanol containing dipalmitoylphosphatidylcholine (DPPC), Span 85 or oleic acid (3%, w/v) could readily be dispersed in HFA 134a to form a stable suspension with good redispersibility and 98% retained bioactivity of lysozyme. The study indicates there is a potential to produce pressed metered dose inhaler (pMDI) formulations containing therapeutic protein and peptide nanoparticles. PMID- 21527323 TI - Assessment of fluidity of different invasomes by electron spin resonance and differential scanning calorimetry. AB - The aim of this study was to investigate the influence of membrane-softening components (terpenes/terpene mixtures, ethanol) on fluidity of phospholipid membranes in invasomes, which contain besides phosphatidylcholine and water, also ethanol and terpenes. Also mTHPC was incorporated into invasomes in order to study its molecular interaction with phospholipids in vesicular membranes. Fluidity of bilayers was investigated by electron spin resonance (ESR) using spin labels 5- and 16-doxyl stearic acid and by differential scanning calorimetry (DSC). Addition of 1% of a single terpene/terpene mixture led to significant fluidity increase around the C16 atom of phospholipid acyl chains comprising the vesicles. However, it was not possible to differentiate between the influences of single terpenes or terpene mixtures. Incorporation of mTHPC into the bilayer of vesicles decreased fluidity near the C16 atom of acyl chains, indicating its localization in the inner hydrophobic zone of bilayers. These results are in agreement with DSC measurements, which showed that terpenes increased fluidity of bilayers, while mTHPC decreased fluidity. Thus, invasomes represent vesicles with very high membrane fluidity. However, no direct correlation between fluidity of invasomes and their penetration enhancing ability was found, indicating that besides fluidity also other phenomena might be responsible for improved skin delivery of mTHPC. PMID- 21527324 TI - Weak bases and formation of a less soluble lauryl sulfate salt/complex in sodium lauryl sulfate (SLS) containing media. AB - This work reports on the solubility of two weakly basic model compounds in media containing sodium lauryl sulfate (SLS). Results clearly show that the presence of SLS in the media (e.g. simulated gastric fluid or dissolution media) can result in an underestimation of solubility of some weak bases. We systematically study this phenomenon and provide evidence (chromatography and pXRD) for the first time that the decrease in solubility is likely due to formation of a less soluble salt/complex between the protonated form of the weak base and lauryl sulfate anion. PMID- 21527326 TI - The development and evolution of a tonotopic organization in the cochlea. PMID- 21527325 TI - Inhibitory neurotransmission in animal models of tinnitus: maladaptive plasticity. AB - Tinnitus is a phantom auditory sensation experienced by up to 14% of the United States population with a smaller percentage experiencing decreased quality of life. A compelling hypothesis is that tinnitus results from a maladaptive plastic net down-regulation of inhibitory amino acid neurotransmission in the central auditory pathway. This loss of inhibition may be a compensatory response to loss of afferent input such as that caused by acoustic insult and/or age-related hearing loss, the most common causes of tinnitus in people. Compensatory plastic changes may result in pathologic neural activity that underpins tinnitus. The neural correlates include increased spontaneous spiking, increased bursting and decreased variance of inter-spike intervals. This review will examine evidence for chronic plastic neuropathic changes in the central auditory system of animals with psychophysically-defined tinnitus. Neurochemical studies will focus on plastic tinnitus-related changes of inhibitory glycinergic neurotransmission in the adult dorsal cochlear nucleus (DCN). Electrophysiological studies will focus on functional changes in the DCN and inferior colliculus (IC). Tinnitus was associated with increased spontaneous activity and altered response properties of fusiform cells, the major output neurons of DCN. Coincident with these physiologic alterations were changes in glycine receptor (GlyR) subunit composition, its anchoring/trafficking protein, gephyrin and the number and affinity of membrane GlyRs revealed by receptor binding. In the IC, the primary afferent target of DCN fusiform cells, multi-dimensional alterations in unit spontaneous activity (rate, burst rate, bursting pattern) were found in animals with behavioral evidence of chronic tinnitus more than 9 months following the acoustic/cochlear insult. In contrast, immediately following an intense sound exposure, acute alterations in IC spontaneous activity resembled chronic tinnitus related changes but were not identical. This suggests that long-term neuroplastic changes responsible for chronic tinnitus are likely to be responsible for its persistence. A clear understanding of tinnitus-related plasticity in the central auditory system and its associated neurochemistry may help define unique targets for therapeutic drug development. PMID- 21527327 TI - Effective compounds group of Mongolian prescriptions BAIMAI-SAN protect against peripheral neuropathy in lower limbs of rats through neuro protective effect. AB - ETHNOPHARMACOLOGICAL RELEVANCE: BAIMAI-SAN prescription is a famous Chinese minority complex prescription used for curing neuropathy. MATERIALS AND METHODS: The Effective Compounds Groups of BAIMAI-SAN (ECGBM) is determined by high through-put screening, and it includes picroside II, verbascose, taurine and ellagic acid and borneol. To research the potential protective effect of ECGBM on the function of peripheral neuropathy, diabetic rats with peripheral neuropathy were induced by streptozotocin and treated with ECGBM (0.1, 0.3, 0.9 mg/kg/day i.g.) for 75 days. Primary cortical neuronal cultures were subjected to high d glucitol, and treated with ECGBM prophylactically. RESULTS: The administration resulted in reductions in speed of sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV) and response speed to pain in the sciatic nerve fiber. Data from primary cortical neuronal cultures experiments indicated that neuronal survival rates were increased, and LDH release was decreased and the loss of neurite length was alleviated in ECGBM group. CONCLUSIONS: It is first report that ECGBM could protect the peripheral neuron in diabetic rat in vivo and in vitro. This activity may be associated with the neuron protective effect. PMID- 21527328 TI - Antiprotozoal activities of traditional medicinal plants from the Garhwal region of North West Himalaya, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In a search for new plant-derived biologically active compounds against protozoan parasites, an ethnopharmacological study was carried out to evaluate extracts from selected 17 traditional medicinal plants which were used by healers from the Garhwal region of North West Himalaya for the treatment of protozoal infections and fever including malaria. MATERIALS AND METHODS: In vitro activity against erythrocytic stages of Plasmodium falciparum was determined using a modified [3H]-hypoxanthine incorporation assay with the chloroquine- and pyrimethamine-resistant K1 strain. Activity against Trypanosoma brucei rhodesiense was performed on the STIB 900 strain and activity against Trypanosoma cruzi on infected rat skeletal myoblasts (L6 cells) seeded in 96-well microtitre plates while amastigotes of Leishmania donovani strain MHOM/ET/67/L82 were used to assess activity against Leishmania donovani. Cytotoxicity assays were performed against rat skeletal myoblasts (L6-cells). RESULTS AND CONCLUSIONS: Extracts of Artemisia roxburghiana, Roylea cinerea, Leucas cephalotes, Nepeta hindostana and Viola canescens showed good antiplasmodial activity (IC50<5 MUg/ml). The chloroform extract of Artemisia roxburghiana was the most active (IC50 value of 0.42 MUg/ml) and the most selective (SI=78) extract for Plasmodium falciparum among all plants extracts examined. The chloroform extract of Leucas cephalotes and the petroleum ether extract of Viola canescens exhibited substantial activities against Leishmania donovani with IC50 values of 3.61 MUg/ml (SI=8) and 0.40 MUg/ml (SI=30), respectively. The petroleum ether extract of Viola canescens exhibited activity against Trypanosoma cruzi with an IC50 value of 1.86 MUg/ml (SI=7). Methanol and water extracts from all plants under investigation were found inactive against all parasites tested. These results support investigation of components of traditional medicines as potential new antiprotozoal agents. On the other hand since herbalism has become the main stream throughout the world, investigation demonstrates that these non polar plant extracts of six of the plants examined in this study could play an important role in herbal formulations for the treatment of vector borne protozoal diseases. PMID- 21527329 TI - Effects of HuangKui capsules on glibenclamide pharmacokinetics in rats. AB - ETHNOPHARMACOLOGY: The main components of HuangKui capsules' are the total flavonoids extracted from the flowers of Abelmoschus manihot L medic. They have been widely used to treat chronic glomerulonephritis, diabetic nephropathy and nephrotic syndrome. The combination of HuangKui capsules and glibenclamide is a possible therapy for patients with diabetes mellitus and diabetic nephropathy. However, there is no report about effects of HuangKui capsules on the glibenclamide pharmacokinetics till now. AIM OF THE STUDY: This study was aimed investigating the effect of HuangKui capsules on pharmacokinetics of glibenclamide in rats. MATERIAL AND METHODS: Eight rats were administered with an oral dose of HuangKui capsules (0.75gkg(-1)) once daily for 10 consecutive days. All the rats were administered orally with the glibenclamide (1mgkg(-1)) before the first time and after the last time given HuangKui capsules. LC-MS/MS was utilized to determine the concentration of glibenclamide in rat plasma and to calculate the corresponding pharmacokinetic parameters. The statistical differences of the two cycles were evaluated by paired-samples t-test. RESULTS: In the rats treated with HuangKui capsules and glibenclamide, the t(1/2), the time point of maximum plasma concentration (T(max)) of glibenclamide increased obviously (p<0.05) compared with the glibenclamide alone, while maximum plasma concentrations (C(max)), area under the plasma concentration-time curve (AUC((0 t))) decreased significantly (p<0.05). There was no significant difference between other parameters. CONCLUSION: HuangKui capsules can reduce the absorption of glibenclamide and accelerate the metabolism of glibenclamide. PMID- 21527330 TI - Lysosomal membrane stabilization and anti-inflammatory activity of Clerodendrum phlomidis L.f., a traditional medicinal plant. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Clerodendrum phlomidis L.f., is used to treat several inflammatory diseases and arthritis in Indian traditional system and folk medicine. AIM OF THE STUDY: The aim of the present study was to evaluate the scientific basis of antiinflammatory activity of different organic solvent extracts of Clerodendrum phlomidis and to evaluate the active crude extract for its antiarthritic activity in FCA induced animal model. MATERIALS AND METHODS: The antiinflammatory activity of Clerodendrum phlomidis was studied using the carrageenan and cotton pellet induced inflammatory models. The crude ethanol extract was standardized with the known standard using HPLC. The antiarthritic activity was studied using Freund's complete adjuvant induced rat model. For antiarthritic activity, the active crude extract was administered at the concentrations of 100, 200 and 400mg/kg body weight. The effect of the ethanol extract on serum SGOT, SGPT, ALP, levels of pro-inflammatory cytokines, plasma lysosomal enzymes and protein bound carbohydrates of FCA arthritic animals were studied. RESULTS: The ethanol extract at 100, 200, and 400mg/kg, showed maximum inhibition of inflammation induced by carrageenan (100 mg/kg-47.73%; 200 mg/kg 54.00% and 400 mg/kg-65.15%). In cotton pellet induced granuloma, the ethanol extract at different concentrations showed significant reduction in granuloma weight. In FCA induced arthritis, the ethanol extract showed a significant reduction in paw thickness (100 mg/kg-51.71%; 200 mg/kg-57.58% and 400 mg/kg 62.48%). The levels of lysosomal enzymes and protein bound carbohydrates were significantly decreased in the ethanol extract treated groups compared with the arthritic control. The pro-inflammatory cytokine levels were significantly decreased in a dose dependent manner in all the Clerodendrum phlomidis treated groups. CONCLUSION: Clerodendrum phlomidis displays considerable potency in antiinflammatory action and has prominent antiarthritic effect on adjuvant induced arthritis. Future studies will provide new insights into the antiinflammatory activity of Clerodendrum phlomidis and isolation of compound from it may eventually lead to development of a new class of antiinflammatory agent. PMID- 21527331 TI - Effect of ginkgolide B on striatal extracellular amino acids in middle cerebral artery occluded rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba leaves are traditionally used in China for its health-promoting properties. There is substantial experimental evidence to support the view that Ginkgo biloba extracts have neuroprotective properties under conditions such as hypoxia/ischemia. Although a number of studies have investigated that ginkgolide B, a purified terpene lactone component extracted from Ginkgo biloba leaves, is available "platelet activating factor (PAF) receptors antagonist", "antioxidant" with a variety of actions, very little has been performed to explore the effect of ginkgolide B on extracellular amino acids in experimental animal of focal cerebral ischemia/reperfusion. In this study, the effect of ginkgolide B on the striatal extracellular levels of glutamate (Glu), aspartic acid (Asp), glycine (Gly) and gamma-aminobutyric acid (GABA) was evaluated in rats undergone middle cerebral artery occlusion (MCAO) for 1h followed by 23 h reperfusion. MATERIALS AND METHODS: The Sprague-Dawley (SD) rats received intraperitoneal injections of ginkgolide B dissolved at a dose of 10 mg kg(-1)d(-1), 20 mg kg(-1)d(-1), or normal saline (NS) of same volume 3d before the middle cerebral artery occlusion model establishment. Extracellular concentrations of glutamate, aspartic acid, glycine and GABA in striatum were monitored using in vivo microdialysis and analyzed using high-performance liquid chromatography. Excitotoxic index (EI) was calculated. Twenty-four hours after MCAO, the cerebral infarct volume was detected on 2,3,5-triphenyltetrazolium chloride-stained coronal sections. RESULTS: The result showed that administration of ginkgolide B (10 or 20 mg kg(-1)) before ischemia reduced the ischemia-induced elevation of levels of glutamate, aspartic acid and glycine, increased the elevation of extracellular GABA, decreased the excitotoxic index and diminished the volume of cerebral infarction, although a clear concentration-response relationship was not found. CONCLUSIONS: The present work provides the first evidence that ginkgolide B protects against cerebral ischemic injury by inhibiting excitotoxicity by modulating the imbalance of excitatory amino acids versus inhibitory amino acids, which may support the traditional use of Ginkgo biloba leaves for the treatment of stroke. PMID- 21527332 TI - Wound healing and antimicrobial potential of Carissa spinarum Linn. in albino mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Carissa spinarum Linn. (Apocynaceae), popularly known as Jungle karunda, has been traditionally used as wound healing agent. AIM OF THE STUDY: To investigate in vivo wound healing and antimicrobial properties of methanolic extract of Carissa spinarum. MATERIALS AND METHODS: The effect of methanolic extract of Carissa spinarum root extracted by cold maceration was evaluated on burn wound model in mice. The wound healing activity of 1% and 2.5% (w/w) extract was assessed by the rate of wound contraction, period of epithelization and hydroxyproline content. Histological study of the granulation tissue was carried out to know the extent of collagen formation in the wound tissue. The antimicrobial activity of extract was also studied against the bacterial and fungal strain using agar dilution method. RESULTS: The results showed that Carissa spinarum root extract has significant wound healing activity as evident from the rate of wound contraction and epithelization. Hydroxyproline expressions and histological parameters were also well correlated with the healing pattern observed. Methanolic extract also exhibited significant antimicrobial activity against all the tested microorganisms. CONCLUSIONS: The present study provides a scientific rationale for the traditional use of Carissa spinarum in the management of wounds. PMID- 21527333 TI - Pharmacokinetics of phenolic compounds of Danshen extract in rat blood and brain by microdialysis sampling. AB - AIM OF THE STUDY: To evaluate the pharmacokinetics of phenolic compounds after oral administration of Danshen extract in rat brain. MATERIALS AND METHODS: Blood and brain microdialysis probes were inserted into jugular vein and cerebral cortex of rat under anesthesia and perfused with ringer's solution at the rate of 2.0 and 0.8 MUL/min, respectively. Blank microdialysates were collected after 2h post-implantation equilibrium time. Danshen extract (danshensu 40 mg/kg BW, protocatechuic aldehyde 149 mg/kg BW, and salvianolic acid B 50mg/kg BW) was administrated intragastrically, and then blood and brain microdialysates were collected at 15 and 30 min time intervals for 4h, respectively. The concentrations of phenolic compounds were determined by high-performance liquid chromatography coupled with chemiluminescence detection. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: Danshensu and protocatechuic acid could be detected in both blood and brain microdialysates, while protocatechuic aldehyde and salvianolic acid B were not detected. Brain-to blood (AUC(brain)/AUC(blood)) distribution ratio were 0.25+/-0.04 and 0.09+/-0.02 for danshensu and protocatechuic acid, respectively. CONCLUSIONS: Danshensu can readily permeate the blood brain barrier after oral administration of Danshen extract, and protocatechuic acid is a potential oxidative metabolite of protocatechuic aldehyde. PMID- 21527334 TI - Treatment of Suqingwan watered pill reduces colon injury induced by experimental colitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sunqingwan watered pill (SWP) is a Chinese medicine compound, traditionally used in the treating UC symptoms like diarrhea, bloody and purulent stool, abdominal pain, etc. The present study aim to examine the effects of SWP on ulcerative colitis using the modern pharmacological models. MATERIALS AND METHODS: To address this question, we used two experimental models of colitis, mice induced by dextran sulfate sodium (DSS) as well as rats induced by 2,4-dinitrochlorobenzene (DNCB). For the mice with DSS-induced colitis, the disease activity index (DAI) and colon histological injuries were observed. For the rat models with DNCB-induced colitis, DAI, levels of nitric oxide (NO) in serum, macroscopic and histological colon injury were investigated. Besides, we also introduced a usually used model of ear swelling induced by xylene in mice to reveal the effect of SWP on acute inflammation. RESULT: In the mice with DSS induced colitis and the rats with DNCB-induced colitis, SWP could significantly decreased the DAI scores, which meant the body weights of animals were recovered and the gross rectal bleeding reduced. Under the microscope, the histology of colon was obviously changed in SWP administration groups. In the rat models with DNCB-induced colitis, SWP also significantly attenuated macroscopic and colon histological injury. The colon scores in SWP groups in rats was obviously lower than those in the control and similarly the serum levels of NO in the treatment groups were significantly lower than that of control group except for low dosage group of SWP. SWP with the dosages of 1.755 and 3.510 g/kg could inhibit the degree of ear swelling significantly compared with the blank control group (p<0.01), showing it owned good anti-inflammatory activity after 14 days administration. CONCLUSION: SWP is effective on treating UC, especially at the high dose and the mechanism may be related with adjusting the serum level of NO, inhibiting colonic mucosa damage and promoting ulcer repair. PMID- 21527335 TI - A single arm phase II study of a Far-Eastern traditional herbal formulation (sho sai-ko-to or xiao-chai-hu-tang) in chronic hepatitis C patients. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hepatitis C is a major public health problem internationally. Many patients cannot benefit from the current treatment regimen (interferon/ribavirin combinations) due to its side effects or ineffectiveness. Xiao-Chai-Hu-Tang or Sho-sai-ko-to (SST), a compound of seven botanical extracts used for liver diseases traditionally in East Asia, was shown to reduce transaminases and the incidence of hepatocellular carcinoma in hepatitis B patients. We conducted a phase II trial of SST in hepatitis C patients who were not candidates for interferon-based therapy to determine whether this agent is worthy of further study. MATERIALS AND METHODS: Twenty four chronic hepatitis C patients received SST at 2.5 g per os (p.o.) three times daily (t.i.d.) for 12 months. Liver function, hepatitis C virus (HCV) viral load and liver biopsy histology were assessed before and after the intervention. RESULTS: Improvement of aspartate aminotransferase (AST) was observed in 16 (67%) of study participants. Improvement of alanine aminotransferase (ALT) was seen in 18 (75%) patients. Viral load response was mixed, with 7 patients showing reductions, 10 increases and 7 indeterminate due to assay limitations. Among the 9 (38%) subjects who showed improvement per Knodell's histology activity index (HAI) scores in paired comparison of pre- and post-treatment liver biopsy (the primary endpoints of the study), 5 (21%) showed an improvement of 2 points or greater, meeting the pre-defined criteria for "response. CONCLUSIONS: Sho-sai-ko-to (SST or Xiao Chai Hu Tang) may improve liver pathology in selected hepatitis C patients who are not candidates for interferon based treatment. Larger, controlled studies of this botanical formulation may be warranted. PMID- 21527336 TI - Insecticidal and wormicidal plants from Aravalli hill range of India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Various plants are being used as ethnomedicines against insects and worms in Aravalli hill range of India. In this study, we are focusing upon intellectual traditional ecological knowledge with an objective of revaluation of ethnomedicinal data processing for the plants being utilized against insects and worms. These plants can be explored for drug discovery program against insects and worms. MATERIALS AND METHODS: An ethnobotanical survey was carried out to raise the information on plants against insects and worms from ethnic tribes. The information about the plant part used, dose & mode of administration was collected and verified by interviewing at different times, tribes and places within the study area. RESULTS: 67 remedies with 49 plants species belonging to 29 families are identified and reported with taxonomic description. Mitragyna parvifolia (Roxb.) Korth. is first time reported with ethnomedicinal claims (against insects and worms). CONCLUSION: These plants may specially be selected for the drug discovery program against insects and worms. Active ingredients from these plants may serve as novel drug molecules. Beside conservation efforts to these plants there is an urgent need to document the ethnomedicinal knowledge. The survey provides a veritable source of information for traditional medical practitioners and medicinal plant researchers and help in developing strategies for future conservation. PMID- 21527337 TI - Designs from the deep: marine organisms for bone tissue engineering. AB - Current strategies for bone repair have accepted limitations and the search for synthetic graft materials or for scaffolds that will support ex vivo bone tissue engineering continues. Biomimetic strategies have led to the investigation of naturally occurring porous structures as templates for bone growth. The marine environment is rich in mineralizing organisms with porous structures, some of which are currently being used as bone graft materials and others that are in early stages of development. This review describes the current evidence available for these organisms, considers the relative promise of each and suggests potential future directions. PMID- 21527339 TI - Gene expression of Pht cluster genes and a putative non-ribosomal peptide synthetase required for phaseolotoxin production is regulated by GacS/GacA in Pseudomonas syringae pv. phaseolicola. AB - Pseudomonas syringae pv. phaseolicola is the causal agent of halo blight disease of beans (Phaseolus vulgaris L.), which is characterized by watersoaked lesions surrounded by a chlorotic halo resulting from the action of a non-host specific toxin known as phaseolotoxin. This toxin inhibits the enzyme ornithine carbamoyltransferase involved in the arginine biosynthesis pathway. It was previously reported that genes within the Pht cluster were involved in the regulation and synthesis of phaseolotoxin. The GacS/GacA two-component signal transduction system controls important pathogenicity and virulence mechanisms in several Gram-negative bacteria. Tox(-) phenotype gacA(-) and gacS(-) mutants were obtained and gacA(-) transcriptome analysis revealed that this response activator controls expression of genes within the Pht cluster as well as another gene located in a different region in the bacterial chromosome and that has been unambiguously shown to be directly involved in phaseolotoxin biosynthesis. Results presented in this work suggest that phaseolotoxin biosynthesis involve elements within and outside the Pht Cluster, and that the GacS/GacA two-component system exerts control over them. PMID- 21527340 TI - Bacterial leaf symbiosis in Ardisia (Myrsinoideae, Primulaceae): molecular evidence for host specificity. AB - The association between bacteria and leaves in Ardisia has been described as a cyclic and obligate symbiosis in which bacteria are maintained throughout all stages of the plant's life cycle to guarantee normal growth and survival of the host. This intimate interaction suggests that both partners have co-diversified together. To test this co-speciation hypothesis, we constructed an endosymbiont (16S rDNA and gyrB) and host (rps16, trnL, matK and ITS) phylogeny. Phylogenetic analyses of the endosymbionts revealed a pattern of strict host specificity and recovered a single clade in the genus Burkholderia (beta-proteobacteria), which was closely related to the endosymbionts of leaf-nodulated Rubiaceae. Comparison of symbiont and host phylogenies suggests a single origin of bacterial leaf symbiosis in the nodulated ancestor of Ardisia and does not reject the co speciation hypothesis. PMID- 21527338 TI - The biological basis of injury and neuroprotection in the fetal and neonatal brain. AB - A compromised intrauterine environment that delivers low levels of oxygen and/or nutrients, or is infected or inflammatory, can result in fetal brain injury, abnormal brain development and in cases of chronic compromise, intrauterine growth restriction. Preterm birth can also be associated with injury to the developing brain and affect the normal trajectory of brain growth. This review will focus on the effects that episodes of perinatal hypoxia (acute, chronic, associated with inflammation or as an antecedent of preterm birth) can have on the developing brain. In animal models of these conditions we have found that relatively brief (acute) periods of fetal hypoxemia can have significant effects on the fetal brain, for example death of susceptible neuronal populations (cerebellum, hippocampus, cortex) and cerebral white matter damage. Chronic placental insufficiency which includes fetal hypoxemia, nutrient restriction and altered endocrine status can result in fetal growth restriction and long-term deficits in neural connectivity in addition to altered postnatal function, for example in the auditory and visual systems. Maternal/fetal inflammation can result in fetal brain damage, particularly but not exclusively in the white matter; injury is more pronounced when associated with fetal hypoxemia. In the baboon, in which the normal trajectory of growth is affected by preterm birth, there is a direct correlation between a higher flux in oxygen saturation and a greater extent of neuropathological damage. Currently, the only established therapy for neonatal encephalopathy in full term neonates is moderate hypothermia although this only offers some protection to moderately but not severely affected brains. There is no accepted therapy for injured preterm brains. Consequently the search for more efficacious treatments continues; we discuss neuroprotective agents (erythropoietin, N-acetyl cysteine, melatonin, creatine, neurosteroids) which we have trialed in appropriate animal models. The possibility of combining hypothermia with such agents or growth factors is now being considered. A deeper understanding of causal pathways in brain injury is essential for the development of efficacious strategies for neuroprotection. PMID- 21527341 TI - Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir. AB - The aim of this study was to evaluate the utility of biorelevant dissolution tests coupled with in silico simulation technology to forecast in vivo bioperformance of poorly water-soluble bases, using nelfinavir mesylate as a model compound. An in silico physiologically based pharmacokinetic (PBPK) model for poorly water-soluble, weakly basic drugs was used to generate plasma profiles of nelfinavir by coupling dissolution results and estimates of precipitation with standard gastrointestinal (GI) parameters and the disposition pharmacokinetics of nelfinavir. In vitro dissolution of nelfinavir mesylate film-coated tablets was measured in biorelevant and compendial media. Drug precipitation in the small intestine was estimated from crystal growth theory. GI parameters (gastric emptying rate and fluid volume) appropriate to the dosing conditions (fasting and fed states) were used in the PBPK model. The disposition parameters of nelfinavir were estimated by fitting compartmental models to the in vivo oral PK data. The in vivo performance in each prandial state was simulated with the PBPK model, and predicted values for AUC and C(max) were compared to observed values. Dissolution results in FaSSIF-V2 and FeSSIF-V2, simulating the fasting and fed small intestinal conditions, respectively, correctly predicted that there would be a positive food effect for nelfinavir mesylate, but overestimated the food effect observed in healthy human volunteers. In order to better predict the food effect, an in silico PBPK simulation model using STELLA(r) software was evolved. Results with the model indicated that invoking drug precipitation in the small intestine is necessary to describe the in vivo performance of nelfinavir mesylate in the fasted state, whereas a good prediction under fed state conditions is obtained without assuming any precipitation. In vitro-in silico-in vivo relationships (IVISIV-R) may thus be a helpful tool in understanding the critical parameters that affect the oral absorption of poorly soluble weak bases. PMID- 21527342 TI - Rat intestinal precision-cut slices as an in vitro model to study xenobiotic interaction with transporters. AB - ATP-binding cassette (ABC) proteins play key role in tissue defence by transporting metabolic waste and toxic chemicals out of the cells. Consequently, intact cell systems are required to study xenobiotic interactions with ATP dependent transporters. The aim of the present study was to set up an intestinal precision-cut slice technique to study the interactions of ABC transporters with xenobiotics. Rat intestinal slices were incubated with verapamil, indomethacin and glibenclamide, and the ability of the above-mentioned drugs to inhibit the multidrug resistance glycoprotein (MDR) and/or multidrug-resistance-associated protein (MRP) was assessed by measuring the intracellular conversion of calcein AM to fluorescent calcein. The ABC transporters' inhibitors caused a time dependent florescence increase which reached the maximum value at 30 min. Verapamil and glibenclamide promoted a concentration-dependent intracellular accumulation of calcein (IC(50) 8.1*10(-6) M, 1.9*10(-4) M, respectively). The effect of glibenclamide was fully reversed by washing the slices, suggesting the reversible nature of calcein accumulation. These data suggest that the precision cut intestinal slices are a reliable, simple and fast system to evaluate xenobiotic interactions with ABC transporters in rat and, hopefully, in human intestine. PMID- 21527344 TI - The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection. AB - Induced hypothermia is the only therapy with proven efficacy to reduce brain damage after perinatal asphyxia. While hypothermia down-regulates global protein synthesis and cell metabolism, low temperature induces a small subset of proteins that includes the RNA-binding protein RBM3 (RNA-binding motif protein 3), which has recently been implicated in cell survival. Here, immunohistochemistry of the developing postnatal murine brain revealed a spatio-temporal neuronal RBM3 expression pattern very similar to that of doublecortin, a marker of neuronal precursor cells. Mild hypothermia (32 degrees C) profoundly promoted RBM3 expression and rescued neuronal cells from forced apoptosis as studied in primary neurons, PC12 cells, and cortical organotypic slice cultures. Blocking RBM3 expression in neuronal cells by specific siRNAs significantly diminished the neuroprotective effect of hypothermia while vector-driven RBM3 over-expression reduced cleavage of PARP, prevented internucleosomal DNA fragmentation, and LDH release also in the absence of hypothermia. Together, neuronal RBM3 up-regulation in response to hypothermia apparently accounts for a substantial proportion of hypothermia-induced neuroprotection. PMID- 21527345 TI - Melatonin independent protective role of l-tryptophan in experimental reflux esophagitis in rats. AB - Melatonin is implicated in sustaining the esophageal integrity in gastro esophageal reflux disease. However, the role of its synthetic precursor l tryptophan is not clear in this pathology. The present study was designed to explore the effects of l-tryptophan on esophageal damage following reflux esophagitis (RE)-establishment and concurrent alterations in factors possibly influencing esophageal integrity such as esophageal melatonin level, luminal acidity, H(+)K(+)-ATPase activity, mucin and gastric PGE(2) levels. RE was established in rats by simultaneous ligation of pylorus region and fore-stomach. RE significantly decreased the esophageal-melatonin level and the expression of its synthesizing enzymes: arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT). Administration of l-tryptophan significantly decreased the RE-induced esophageal mucosal damage, without altering the levels of melatonin. l-Tryptophan pretreatment also normalized the esophageal mucosal damage caused by melatonin receptor antagonist-luzindole. Simultaneously, l-tryptophan significantly increased the RE-decreased expression of AA-NAT with insignificant effect on HIOMT gene expression. In contrast, l tryptophan per se caused a significant elevation in the esophageal melatonin level, with no significant effect on the expression of AA-NAT and HIOMT enzymes. Further, l-tryptophan significantly normalized the RE-induced changes in the gastric juice volume, acidity and pH. However, it did not significantly inhibit the H(+)K(+)-ATPase activity in vitro. Also, l-tryptophan significantly increased the RE-reduced mucin level, COX-2 activity and thereby PGE(2) levels. Interestingly, indomethacin (PGE(2) synthesis blocker), aggravated the RE-induced tissue injury with simultaneous changes in the gastric volume, acidity, pH and mucin content, which l-tryptophan failed to reverse, suggesting that the attenuating effect of l-tryptophan on gastric secretions could be PGE(2) driven. Thus the current study provide evidences that protective functions of l tryptophan against RE is independent of its conversion into melatonin, and possibly involve mobilization of factors such as COX-2 derived PGE(2) and mucin that counterbalance the detrimental effect of gastric acid on esophageal mucosa, signifying the therapeutic efficacy of l-tryptophan against the esophageal pathologies. PMID- 21527346 TI - Structural and functional analysis of bacterial flavin-containing monooxygenase reveals its ping-pong-type reaction mechanism. AB - A bacterial flavin-containing monooxygenase (bFMO) catalyses the oxygenation of indole to produce indigoid compounds. In the reductive half of the indole oxygenation reaction, NADPH acts as a reducing agent, and NADP(+) remains at the active site, protecting bFMO from reoxidation. Here, the crystal structures of bFMO and bFMO in complex with NADP(+), and a mutant bFMO(Y207S), which lacks indole oxygenation activity, with and without indole are reported. The crystal structures revealed overlapping binding sites for NADP(+) and indole, suggestive of a double-displacement reaction mechanism for bFMO. In biochemical assays, indole inhibited NADPH oxidase activity, and NADPH in turn inhibited the binding of indole and decreased indoxyl production. Comparison of the structures of bFMO with and without bound NADP(+) revealed that NADPH induces conformational changes in two active site motifs. One of the motifs contained Arg-229, which participates in interactions with the phosphate group of NADPH and appears be a determinant of the preferential binding of bFMO to NADPH rather than NADH. The second motif contained Tyr-207. The mutant bFMO(Y207S) exhibited very little indoxyl producing activity; however, the NADPH oxidase activity of the mutant was higher than the wild-type enzyme. It suggests a role for Y207, in the protection of hydroperoxyFAD. We describe an indole oxygenation reaction mechanism for bFMO that involves a ping-pong-like interaction of NADPH and indole. PMID- 21527343 TI - Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down syndrome: activation of beta1-adrenergic receptor by xamoterol as a potential cognitive enhancer. AB - Down syndrome (DS) is the most prevalent form of mental retardation caused by genetic abnormalities in humans. This has been successfully modeled in mice to generate the Ts65Dn mouse, a genetic model of DS. This transgenic mouse model shares a number of physical and functional abnormalities with people with DS, including changes in the structure and function of neuronal circuits. Significant abnormalities in noradrenergic (NE-ergic) afferents from the locus coeruleus to the hippocampus, as well as deficits in NE-ergic neurotransmission are detected in these animals. In the current study we characterized in detail the behavioral phenotype of Ts65Dn mice, in addition to using pharmacological tools for identification of target receptors mediating the learning and memory deficits observed in this model of DS. We undertook a comprehensive approach to mouse phenotyping using a battery of standard and novel tests encompassing: (i) locomotion (Activity Chamber, PhenoTyper, and CatWalk), (ii) learning and memory (spontaneous alternation, delayed matching-to-place water maze, fear conditioning, and Intellicage), and (iii) social behavior. Ts65Dn mice showed increased locomotor activity in novel and home cage environments. There were significant and reproducible deficits in learning and memory tests including spontaneous alternation, delayed matching-to-place water maze, Intellicage place avoidance and contextual fear conditioning. Although Ts65Dn mice showed no deficit in sociability in the 3-chamber test, a marked impairment in social memory was detected. Xamoterol, a beta1-adrenergic receptor (beta1-ADR) agonist, effectively restored the memory deficit in contextual fear conditioning, spontaneous alternation and novel object recognition. These behavioral improvements were reversed by betaxolol, a selective beta1-ADR antagonist. In conclusion, our results demonstrate that this mouse model of Down syndrome displays cognitive deficits which are mediated by an imbalance in the noradrenergic system. In this experimental model of Down syndrome a selective activation of beta1-ADR does restore some of these behavioral deficits. Further mechanistic studies will be needed to investigate the failure of noradrenergic system and the role of beta1-ADR in cognitive deficit and pathogenesis of DS in people. Restoring NE neurotransmission or a selective activation of beta1)-ADR needs to be further investigated for the development of any potential therapeutic strategy for symptomatic relief of memory deficit in DS. Furthermore, due to the significant involvement of noradrenergic system in the cardiovascular function further safety and translational studies will be needed to ensure the safety and efficacy of this approach. PMID- 21527347 TI - The physical basis of type 4 pilus-mediated microcolony formation by Vibrio cholerae O1. AB - The Vibrio cholerae toxin co-regulated pilus (TCP) is a type 4b pilus that mediates bacterial microcolony formation, which is essential for intestinal colonization. Structural analyses have defined a surface domain of the TcpA pilin subunit that is displayed repeatedly around the pilus filament surface and forms the molecular basis for pilus-pilus interactions required for microcolony formation. The physical attributes of this domain that lead to pilus-pilus association between bacteria are not known. Mutational analysis has revealed alterations within this domain that allow pilus-pilus interactions among pili expressed by individual bacteria, but do not allow pilus-pilus mediated association between bacteria. We characterized these altered strains using conventional microscopy, as well as three-dimensional high-resolution field emission scanning electron microscopy (FESEM), to reveal the physical difference between nonproductive and productive pilus associations that lead to interactions among multiple bacteria and result in microcolony formation. These findings pave the way towards investigation of the biophysical parameters involved in this basic bacterial property that promotes colonization of intestinal and other biological surfaces. PMID- 21527348 TI - Declarative memory deficits and schizophrenia: problems and prospects. AB - Cognitive deficits are among the most important factors leading to poor functional outcomes in schizophrenia, with deficits in declarative memory among the largest and most robust of these. Thus far, attempts to enhance cognition in schizophrenia have shown only modest success, which underlies increasing efforts to develop effective treatment strategies. This review is divided into three main parts. The first section delineates the nature and extent of the deficits in both patients with schizophrenia and in their adult, non-psychotic relatives. The second part focuses on structural and functional abnormalities in the hippocampus, both in people with schizophrenia and in animal studies that model relevant features of the illness. The third section views problems in declarative memory and hippocampal function from the perspective of elevated rates of common medical disorders in schizophrenia, with a focus on insulin insensitivity/diabetes. The likelihood that poor glucose regulation/availability contribute to declarative memory deficits and hippocampal abnormalities is considered, along with the possibility that schizophrenia and poor glucose regulation share common etiologic elements, and with clinical implications of this perspective for enhancing declarative memory. PMID- 21527349 TI - Re-assessment of phenotypic identifications of Bacteroides putredinis to Alistipes species using molecular methods. AB - Alistipes (previously Bacteroides) are strictly anaerobic gram-negative rods that resemble the Bacteroides fragilis group in that most species are bile-resistant and indole-positive; however, they are only weakly saccharolytic and most species produce light brown pigment only on laked rabbit blood agar. In this retrospective study, we re-identified 18 organisms previously identified phenotypically as "Bacteroides putredinis-like", but that did not produce pigment on routine media. The strains were identified with 16S rDNA sequencing and pigment production was evaluated on several different culture media. Only 12/18 strains had molecular identifications of Alistipes species, while the remaining strains phylogenetically resembled Butyricimonas and Odoribacter spp. Pigment production was not a reliable test for those Alistipes strains that are described as pigment producers. PMID- 21527350 TI - Membrane phospholipid composition of hemocytes in the Pacific oyster Crassostrea gigas and the Manila clam Ruditapes philippinarum. AB - The detailed sterol (free sterol proportions and compositions) and phospholipid (PL) compositions (relative proportions of PL classes and subclasses and their respective fatty acid (FA) compositions) of hemocyte membranes were investigated in two bivalve mollusks: the Pacific oyster Crassostrea gigas and the Manila clam Ruditapes philippinarum. Hemocyte membrane lipids of both species revealed similar general composition: i) their free sterol/PL ratio was above 0.4 and ii) their PL were predominated by the diacyl+alkyl forms of glycerophosphatidylcholine (PC), the plasmalogen form of glycerophosphatidylethanolamine (PE) and ceramide aminoethylphosphonate (CAEP). Free sterols were predominated by cholesterol in both species. Plasmalogen forms of PE and glycerophosphatidylserine (PS) represented 82-83% and 46-55% of total PE and PS, respectively. When compared to their respective diacyl+alkyl forms, plasmalogen forms of PE and PS were specifically enriched in non-methylene interrupted (NMI) FA and 20:1n-11, suggesting a functional significance of these PL molecular species in bivalve hemocytes. Lysoglycerophosphatidylcholine (LysoPC) levels were found to be fairly high in hemocytes, accounting for about 8% of the PL. Some species-specific features were also found. LysoPC and glycerophosphatidylinositol (PI) FA compositions differed between Ruditapes philippinarum and Crassostrea gigas. CAEP proportion was higher in R. philippinarum than in C. gigas (14.5% and 27.9% of the PL, respectively). Hemolymph cell monolayer observations and flow-cytometric analyses revealed species-specific hemocyte morphology and sub-populations which could account for some of the observed species-specific membrane lipid compositions. PMID- 21527351 TI - Rotational distortion in conventional allometric analyses. AB - Three data sets from the recent literature were submitted to new analyses to illustrate the rotational distortion that commonly accompanies traditional allometric analyses and that often causes allometric equations to be inaccurate and misleading. The first investigation focused on the scaling of evaporative water loss to body mass in passerine birds; the second was concerned with the influence of body size on field metabolic rates of rodents; and the third addressed interspecific variation in kidney mass among primates. Straight lines were fitted to logarithmic transformations by Ordinary Least Squares and Generalized Linear Models, and the resulting equations then were re-expressed as two-parameter power functions in the original arithmetic scales. The re-expressed models were displayed on bivariate graphs together with tracings for equations fitted directly to untransformed data by nonlinear regression. In all instances, models estimated by back-transformation failed to describe major features of the arithmetic distribution whereas equations fitted by nonlinear regression performed quite well. The poor performance of equations based on models fitted to logarithms can be traced to the increased weight and leverage exerted in those analyses by observations for small species and to the decreased weight and leverage exerted by large ones. The problem of rotational distortion can be avoided by performing exploratory analysis on untransformed values and by validating fitted models in the scale of measurement. PMID- 21527352 TI - The expression patterns of heat shock genes and proteins and their role during vertebrate's development. AB - Highly evolutionary conserved heat shock proteins (HSPs) act as molecular chaperones in regulation of cellular homeostasis and promoting survival. Generally they are induced by a variety of stressors whose effect could be disastrous on the organism, but they are also widely constitutively expressed in the absence of stress. Varied HSP expressions seem to be very essential in the critical steps of embryonic and extra-embryonic structures formation and may correspond to cell movements, proliferation, morphogenesis and apoptosis, which occur during embryonic development. While our knowledge of detailed HSP expression patterns is in constant progress, their functions during embryonic development are not yet fully understood. In the paper, we review available data on HSP expression and discuss their role during vertebrate development. PMID- 21527353 TI - Energy metabolism and the postprandial response of the Chilean tarantulas, Euathlus truculentus (Araneae: Theraphosidae). AB - One of the most ubiquitous consequences of feeding in animals is specific dynamic action (SDA), a drastic increment in metabolic rate after a meal, which lasts from a few hours to several days. According to a recent exhaustive review by Secor (2009), studies in SDA are abundant, encompassing all kinds of vertebrates and invertebrates. However, important exceptions are arachnids, as few studies have characterized SDA in this group. Here, we measured the standard metabolic rate (SMR) of the Chilean tarantulas Euathlus truculentus (body mass=7.32+/-0.7 g; N=32; T(A)=25 degrees C), its inter-individual variation (i.e., repeatability) and its SDA. We measured SMR three or four times in each individual, and we also conducted predation experiments where a prey was consumed by each spider, during a respirometry trial. The SMR of E. truculentus was 0.00049+/-0.000079 mlCO(2) g( 1) min(-1) which corresponds to 1524 MUW (assuming a protein-based diet), 108.4% of the predicted value for arachnids. According to the standard nomenclature for SDA studies, the scope of the SDA for a meal size of 1.26+/-0.04 g (18% of the spider size) was 6.55+/-1.1 times the baseline, the time to peak was 45 min, and the magnitude of the SDA was 0.28+/-0.03 kj, which is 85% of the expected value for invertebrates. Our SMR data are in concordance with previous findings suggesting remarkably low energy metabolism in arachnids, compared with other arthropods. On the other hand, the exceedingly high scope of the postprandial response contrasts with the comparatively low SDA. This fact suggests that spiders spend most of the energy for digestion in a short period after prey capture, which could be a consequence of their external digestion. PMID- 21527354 TI - Sequence variation of Epstein-Barr virus (EBV) BZLF1 gene in EBV-associated gastric carcinomas and nasopharyngeal carcinomas in Northern China. AB - Epstein-Barr virus (EBV) BZLF1 gene can trigger EBV from latent infection to lytic replicative phase. The functions of BZLF1 are well known, while little is known about its gene polymorphism. In order to elucidate the sequence variations of BZLF1 and its association with malignancies, we analyzed BZLF1 gene in 24 EBV associated gastric carcinomas, 41 nasopharyngeal carcinomas and 24 throat washing samples from healthy donors in Northern China using PCR-direct sequencing method. Three types and 8 subtypes of BZLF1 were identified. A dominant type BZLF1-A was found in 67 of 89 (75.3%) isolates. Type BZLF1-B was characterized by a common Ala deletion at residue 127, which was detected in 21 of 89 isolates (23.6%). Type BZLF1-C contained only one isolate (GC103), which had the same sequence with the prototype B95-8. Among 3 functional domains of BZLF1 protein, the transactivation domain had most mutations, followed by the bZIP domains (the DNA binding domain and dimerization domain). No prevalence of any subtypes or mutations in the functional domains among three specimen groups was found (P > 0.05). Our study indicates that BZLF1 subtypes and amino acid changes in functional domains are not preferentially associated with EBV-associated gastric carcinomas or nasopharyngeal carcinomas in Northern China. BZLF1 gene variations are geographically restricted rather than tumor-specific polymorphisms. PMID- 21527355 TI - Case report of primary retroperitoneal hydatid cyst. AB - Hydatid cyst develops in retroperitoneal space without accompanied lesion in other organs is defined as primary retroperitoneal hydatid cyst. It is extremely rare though hydatid cyst may affect every organ in human body. A 15 years old boy presented with a giant retroperitoneal cyst and hydatid cyst was suspected. Thorough examination did not revealed lesions in liver, lung, kidney or other organs. The diagnosis was confirmed through laparotomy. The diagnosis is difficult, but the possibility should be considered before operation to prevent spillage or fatal anaphylactic shock. Living in an endemic area, ultrasonography, CT or serology test is helpful in the diagnosis of this disease. Total cystectomy is the ideal surgery, if not possible or at high risk, partial pericystectomy is acceptable. PMID- 21527356 TI - Expression regulation triggers oncogenicity of xmrk alleles in the Xiphophorus melanoma system. AB - The Xiphophorus melanoma model has gained attention in biomedical research as a genetic model for tumor formation. Melanoma development in interspecific hybrids of Xiphophorus is connected to pigment cell specific overexpression of the mutationally activated receptor tyrosine kinase Xmrk. In purebred fish the oncogenic function of xmrk is suppressed by a so far unknown regulator locus R. To test the hypothesis that R is involved in transcriptional regulation of xmrk and consequently acts upstream of the xmrk signal, we performed a quantitative analysis of xmrk transcript levels in normal and melanoma tissues of different Xiphophorus genotypes carrying either a highly tumorigenic or a non-tumorigenic xmrk allele. Our results demonstrate that expression of the tumorigenic xmrk allele is highly increased in malignant melanomas compared to benign lesions, macromelanophore spots, and healthy skin. Transcription of the non-tumorigenic xmrk allele in pigment cells, in contrast, is not influenced by the presence or absence of R. These findings strongly indicate that differential transcriptional regulation of the xmrk promoter determines the tumorigenic potential of xmrk alleles in the Xiphophorus melanoma system, thereby supporting the hypothesis that R suppresses the oncogenic function of xmrk on the level of transcriptional control. PMID- 21527357 TI - Sequential patterns mining and gene sequence visualization to discover novelty from microarray data. AB - Data mining allow users to discover novelty in huge amounts of data. Frequent pattern methods have proved to be efficient, but the extracted patterns are often too numerous and thus difficult to analyze by end users. In this paper, we focus on sequential pattern mining and propose a new visualization system to help end users analyze the extracted knowledge and to highlight novelty according to databases of referenced biological documents. Our system is based on three visualization techniques: clouds, solar systems, and treemaps. We show that these techniques are very helpful for identifying associations and hierarchical relationships between patterns among related documents. Sequential patterns extracted from gene data using our system were successfully evaluated by two biology laboratories working on Alzheimer's disease and cancer. PMID- 21527358 TI - MRI in clinical trial: appropriateness? PMID- 21527359 TI - In search of the sample: recent experiences of a trial team in orthodontics. AB - Randomised clinical trials are commonly undertaken in medical and dental research. However, few authors discuss the difficulties associated with such studies, including costs, ethical issues and recruitment of an adequate number of patients. There is little information available on the number of studies which are terminated early as a result of these issues, but it seems likely that at least 10% of clinical studies never reach completion. This paper reviews two nationally funded clinical studies which were terminated early. It highlights the problems associated with patient recruitment and also some issues which may benefit researchers undertaking similar studies in the future. PMID- 21527360 TI - Rationale and design of a trial on the role of bosentan in Fontan patients: improvement of exercise capacity? AB - BACKGROUND: The Fontan circulation is a palliative procedure performed in patients with complex congenital heart disease (CHD), making transpulmonary blood flow dependent on the systemic venous pressure. In a Fontan circulation a low pulmonary vascular resistance (PVR) is crucial, as is epitomized by the observation that a high PVR is a strong predictor of mortality. Long-term follow up has shown that PVR may rise many years after the Fontan procedure has been performed, possibly due to micro-emboli from a dilated right atrium or from the venous system. Other mechanisms of increased PVR might be aging, obstructed airways caused by lymphatic dysfunction, lack of pulsatile pulmonary flow causing a release of endothelium-derived vasoactive molecules, and prolonged overexpression of vasoconstrictors such as endothelin-1. Mean plasma level of endothelin-1 has been shown to be significantly higher in Fontan patients compared to healthy controls. In patients with pulmonary arterial hypertension (PAH), therapy with bosentan, an endothelin-1 receptor antagonist, has demonstrated to improve exercise capacity and to reduce the elevated PVR. In addition, reduction of PVR is shown early and late after the Fontan procedure on treatment with exogenous NO, another advanced PAH therapy. However, the long term effect of reducing the PVR by bosentan treatment on exercise capacity in Fontan patients is still unknown. METHODS: We designed a prospective, multicenter, randomized open label trial to study the effect of bosentan in Fontan patients. The primary endpoint will be the change in maximum exercise capacity (peak V'O2). CONCLUSION: We hypothesize that treatment with bosentan, an endothelin-1 receptor antagonist, improves maximum exercise capacity and functional capacity in adult Fontan patients. PMID- 21527361 TI - Autoimmune bullous diseases the spectrum of infectious agent antibodies and review of the literature. AB - Pemphigus and bullous pemphigoid are two autoimmune diseases that have a similar pathogenesis. Both have a genetic predisposition which promotes the production of auto-antibodies targeted against different components of the epidermal desmosome and hemidesmosome. Environmental factors play an important role in the pathogenesis of this autoimmune disease. Among these, the role of infectious agents was debated as a causative factor. We sought to determine a possible connection between various infectious agents and autoimmune bullous disease (ABD). A cohort of 148 serum samples of patients with pemphigus, bullous pemphigoid and controls was screened for evidence of a prior infection with HBV, HCV, EBV, CMV, Helicobacter pylori, Toxoplasma gondii and Treponema pallidum, utilizing the Bio-Rad BioPlex 2200 system as well as ELISA assays to complete the panel. HBV, HCV, H. pylori, T. gondii and CMV were demonstrated to have significantly higher prevalence of antibodies in patients with pemphigus and bullous pemphigoid in comparison to controls. Among them, we found a novel association between H. pylori and ABD. Our study suggests a contributing role for HBV, HCV, H. pylori, T. gondii and CMV in inducing ABD in the genetically susceptible host. PMID- 21527362 TI - Anti-annexins autoantibodies: their role as biomarkers of autoimmune diseases. AB - Annexins are a group of 12 highly conserved proteins which exert several regulatory functions on cell biology. There are involved in numerous cell processes including vesicle trafficking, calcium signaling, cell growth, division, and apoptosis. Autoantibodies directed toward annexin I, II, V and XI have been reported, but their role and their clinical correlates are controversial. Annexin I exerts an anti-inflammatory effect by suppressing the generation of inflammatory mediators and anti-annexin I antibodies were detected in patients affected with rheumatoid arthritis, systemic (SLE) and cutaneous lupus erythematosus. Annexin II and V have a high affinity for phospholipids playing a pivotal role in the regulation of coagulation cascade. Anti-annexin II and anti-annexin V antibodies were found in patients with arterial or venous thrombosis, especially in those with autoimmune rheumatic diseases (ARD) such as SLE, primary antiphospholipid syndrome (APS) or systemic sclerosis. Anti-annexin V antibodies were also found in patients with pregnancy loss with or without APS. Annexin XI is involved in several biological pathways, particularly apoptosis and cell proliferation. Anti-annexin XI antibodies have been found in patients with SLE, undifferentiated connective tissue disease, rheumatoid arthritis, Sjogren's syndrome and APS. The metanalysis of studies published up to now showed that the Odds Ratio for having an ARD in anti-annexin XI positive patients was 5.08 (95% CI 2.06-12.58). PMID- 21527363 TI - Prenatal development of central rhythm generation. AB - Foetal breathing in mice results from prenatal activity of the two coupled hindbrain oscillators considered to be responsible for respiratory rhythm generation after birth: the pre-Botzinger complex (preBotC) is active shortly before the onset of foetal breathing; the parafacial respiratory group (e-pF in embryo) starts activity one day earlier. Transcription factors have been identified that are essential to specify neural progenitors and lineages forming each of these oscillators during early development of the neural tube: Hoxa1, Egr2 (Krox20), Phox2b, Lbx1 and Atoh1 for the e-pF; Dbx1 and Evx1 for the preBotC which eventually grow contralateral axons requiring expression of Robo3. Inactivation of the genes encoding these factors leads to mis-specification of these neurons and distinct breathing abnormalities: apneic patterns and loss of central chemosensitivity for the e-pF (central congenital hypoventilation syndrome, CCHS, in humans), complete loss of breathing for the preBotC, right left desynchronized breathing in Robo3 mutants. Mutations affecting development in more rostral (pontine) respiratory territories change the shape of the inspiratory drive without affecting the rhythm. Other (primordial) embryonic oscillators start in the mouse three days before the e-pF, to generate low frequency (LF) rhythms that are probably required for activity-dependent development of neurones at embryonic stages; in the foetus, however, they are actively silenced to avoid detrimental interaction with the on-going respiratory rhythm. Altogether, these observations provide a strong support to the previously proposed hypothesis that the functional organization of the respiratory generator is specified at early stages of development and is dual in nature, comprising two serially non-homologous oscillators. PMID- 21527364 TI - Dioxin exposure and age of pubertal onset among Russian boys. AB - BACKGROUND: Animal data demonstrate associations of dioxin, furan, and polychlorinated biphenyl (PCB) exposures with altered male gonadal maturation. It is unclear whether these associations apply to human populations. OBJECTIVES: We investigated the association of dioxins, furans, PCBs, and corresponding toxic equivalent (TEQ) concentrations with pubertal onset among boys in a dioxin contaminated region. METHODS: Between 2003 and 2005, 499 boys 8-9 years of age were enrolled in a longitudinal study in Chapaevsk, Russia. Pubertal onset [stage 2 or higher for genitalia (G2+) or testicular volume (TV) > 3 mL] was assessed annually between ages 8 and 12 years. Serum levels at enrollment were analyzed by the Centers for Disease Control and Prevention, Atlanta, Georgia, USA. We used Cox proportional hazards models to assess age at pubertal onset as a function of exposure adjusted for potential confounders. We conducted sensitivity analyses excluding boys with pubertal onset at enrollment. RESULTS: The median (range) total serum TEQ concentration was 21 (4-175) pg/g lipid, approximately three times higher than values in European children. At enrollment, boys were generally healthy and normal weight (mean body mass index, 15.9 kg/m2), with 30% having entered puberty by G2+ and 14% by TV criteria. Higher dioxin TEQs were associated with later pubertal onset by TV (hazard ratio = 0.68, 95% confidence interval, 0.49-0.95 for the highest compared with the lowest quartile). Similar associations were observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin concentrations for TV but not G2+. Results were robust to sensitivity analyses. CONCLUSIONS: Findings support an association of higher peripubertal serum dioxin TEQs and concentrations with later male pubertal onset reflected in delayed testicular maturation. PMID- 21527365 TI - [Concurrent whole-brain radiotherapy with trastuzumab for treatment of brain metastases in breast cancer patients: questions and answers]. AB - PURPOSE: We retrospectively assessed the use of trastuzumab concurrently with whole-brain radiotherapy (WBRT) for brain metastases. PATIENTS AND METHODS: From April 2001 to April 2007, 31 patients with brain metastases from HER2-positive breast cancer were referred for WBRT with concurrent trastuzumab. In most cases, concurrent WBRT delivered 30 Gy in 10 daily fractions. In six patients, other fractionations were chosen because of either poor performance status or patients' convenience. RESULTS: At time of brain progression, median age was 55 years (range: 38 to 73 years) and all patients had a performance status of 0 to 2. Median time to brain progression was 10.5 months. Following WBRT, radiological responses were observed in 23 patients (74.2%), including six patients (19.4%) with complete radiological responses and 17 patients (54.8%) with partial radiological response. Clinical responses were observed in 27 patients (87.1%). Median survival from the start of WBRT was 18 months (range: two to 65 months). No grade 2 or more acute toxicity was observed. CONCLUSION: Our results suggest that trastuzumab concurrently with WBRT may have a potential clinical impact with low toxicity. Although promising, these preliminary data warrant further validation of trastuzumab as radio sensitizer for WBRT in brain metastases from breast cancer in the setting of a clinical trial. Larger prospective studies are needed to confirm these results. PMID- 21527366 TI - [Brain metastasis of breast tumors and blood brain barrier]. AB - Brain metastases are prevalent in solid tumours and lymphomas. They are associated with poor survival. The brain is regarded as a sanctuary site for metastatic tumour cells where they exist partially protected from drugs by the blood brain barrier. Amongst the different molecular sub-types of breast cancer, HER2 positive tumours and triple negative tumours exhibit the highest incidence of brain metastasis. Specific strategies are needed to fight brain metastatic disease. Preclinical models for brain metastasis have been developed, yielding mechanistic molecular knowledge and new therapeutic approaches. PMID- 21527367 TI - Rituximab in pemphigus foliaceous with autoantibodies against both Desmoglein 1 and Desmoglein 3. PMID- 21527368 TI - Porokeratosis ptychotropica. PMID- 21527369 TI - Atypical large bullae caused by herpes simplex in a patient with thymoma. PMID- 21527370 TI - Recurrent annular erythema after thymectomy. PMID- 21527371 TI - Ten cases of drug reaction with eosinophilia and systemic symptoms (DRESS) treated with pulsed intravenous methylprednisolone. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, life threatening, drug-induced illness characterised by a widespread polymorphic eruption, fever and multivisceral involvement. There is little published on the management of DRESS. Prompt recognition and withdrawal of the causative drug is essential, along with supportive treatment. However, the condition commonly progresses despite these measures. Oral corticosteroids are usually given but the response can be suboptimal and result in a prolonged exposure to systemic glucocorticoid. We conducted a prospective single-centre study to determine the efficacy of pulsed intravenous methylprednisolone followed by a short reducing course of oral prednisolone in ten patients with confirmed DRESS. Rash and fever responded rapidly to methylprednisolone in all patients. Compared to pre treatment assessments, there was a significant reduction in eosinophil count at day 14 and AST level at day 90 post-treatment. One patient developed acute hepatic failure, necessitating a liver transplant, and died 4 months later. In the immediate post-treatment phase, 1 patient developed type 1 diabetes and 1 patient developed a corticosteroid-induced psychosis. Long-term follow-up on 8/10 revealed all patients to be well, although one patient had persistent pruritus. An aggressive corticosteroid regimen in the management of DRESS is associated with good clinical outcome and acceptable tolerance. PMID- 21527372 TI - Anti-inflammatory treatment for contact dermatitis by topical leptomycin B: inhibitory effects on the induced expression of matrix metalloproteinases (MMP)-9 and -3. PMID- 21527373 TI - Molecular characterization of 11 Italian patients with Darier disease. AB - Darier disease (DD) is an autosomal dominant genodermatosis characterized by multiple warty papules coalescing in seborrheic areas and specific histological skin changes. Heterozygous mutations in ATP2A2, encoding the sarco-endoplasmic reticulum calcium pumping ATPase type 2, are identified as the molecular basis of DD. In this study, molecular features in a large cohort of Italian patients are reported. Molecular data were collected along with the main clinical features. Genomic DNA was used for direct sequencing of ATP2A2. The effect of selected mutations was predicted by in silico analysis or investigated by gene expression studies. 10 different ATP2A2 mutations were identified. Three mutations (c.2300A>G, c.2794G>A, c.569delAins34) have been previously described, while 7, including 2 missense (c.545G>A and c.2116G>A), 2 nonsense (c.1372G>T and c.1675C>T), 1 small deletion (c.142delA), 1 duplication (c.2935_2949dup15) and 1 splice-site mutation (c.2742-1G>A), were novel. Collected data added new variants to the ATP2A2 repertoire and confirmed that ATP2A2 mutations are scattered over the entire gene and, in most cases, private. PMID- 21527374 TI - Anti-laminin-332 mucous membrane pemphigoid associated with recurrent metastatic prostate carcinoma: hypothesis for a paraneoplastic phenomenon. AB - Anti-epiligrin cicatricial pemphigoid is an autoimmune blistering disorder that has recently been associated with the development of solid organ malignancy. We describe a patient with recurrent metastatic prostate carcinoma who was diagnosed with this disorder. We provide a hypothesis as to the relationship between the development of this disease and its possible association with cancer pathogenesis. PMID- 21527375 TI - Jean Thivolet. PMID- 21527376 TI - 7th Congress of Update in Cardiology and Cardiovascular Surgery in association with TCT Mediterranean - March 2011. PMID- 21527377 TI - Avian metapneumovirus subtype B experimental infection and tissue distribution in chickens, sparrows, and pigeons. AB - Avian metapneumovirus (aMPV) is a respiratory virus that infects a range of avian hosts, including chickens and turkeys. Migratory and local wild birds are implicated in aMPV spread among farms, countries, and seasonal outbreaks of the disease. A subtype B aMPV isolate from commercial chicken flocks suffering from respiratory disease was experimentally inoculated oculonasally into 7-week old chickens, young pigeons, and sparrows. Chickens showed minimal tracheal rales, whereas pigeons and sparrows were asymptomatic. Shedding of aMPV was detected by reverse transcription polymerase chain reaction on homogenates from nasal turbinates. At 5 days postinfection, 5 of 5 chickens, 2 of 5 pigeons, and 1 of 5 sparrows were positive; at 10 or 15 days, none were positive. At 2 and 5 days, aMPV antigens were localized at the ciliated boarder of respiratory epithelium in nasal cavity and trachea of chickens, as well as to the conjunctival epithelium. Pigeons had detectable viral antigens in only the trachea at 2 and 5 days; sparrow tissues did not show any positive staining. At the end of the experiment, at 21 days postinfection, 14 of 15 inoculated chickens seroconverted against aMPV, but none of the inoculated pigeons or sparrows did. The authors believe that pigeons and sparrows have the ability to transmit the virus between chicken farms, although they do not consider pigeons and sparrows as natural hosts for aMPV, given that they failed to seroconvert. In conclusion, pigeons and sparrows are partially susceptible to aMPV infection, probably acting more as mechanical vectors because infection is only temporary and short-lived. PMID- 21527378 TI - An applet to estimate the IOP-induced stress and strain within the optic nerve head. AB - PURPOSE: The ability to predict the biomechanical response of the optic nerve head (ONH) to intraocular pressure (IOP) elevation holds great promise, yet remains elusive. The objective of this work was to introduce an approach to model ONH biomechanics that combines the ease of use and speed of analytical models with the flexibility and power of numerical models. METHODS: Models representing a variety of ONHs were produced, and finite element (FE) techniques used to predict the stresses (forces) and strains (relative deformations) induced on each of the models by IOP elevations (up to 10 mm Hg). Multivariate regression was used to parameterize each biomechanical response as an analytical function. These functions were encoded into a Flash-based applet. Applet utility was demonstrated by investigating hypotheses concerning ONH biomechanics posited in the literature. RESULTS: All responses were parameterized well by polynomials (R2 values between 0.985 and 0.999), demonstrating the effectiveness of our fitting approach. Previously published univariate results were reproduced with the applet in seconds. A few minutes allowed for multivariate analysis, with which it was predicted that often, but not always, larger eyes experience higher levels of stress and strain than smaller ones, even at the same IOP. CONCLUSIONS: An applet has been presented with which it is simple to make rapid estimates of IOP-related ONH biomechanics. The applet represents a step toward bringing the power of FE modeling beyond the specialized laboratory and can thus help develop more refined biomechanics-based hypotheses. The applet is available for use at www.ocularbiomechanics.com. PMID- 21527379 TI - Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study. AB - PURPOSE: To describe age and other risk factors for corneal infiltrative and inflammatory events (CIEs) in young, soft contact lens (SCL) wearers and to model the age-related risk. METHODS: A multicenter, retrospective chart review of 3549 SCL wearers (8-33 years at first observed visit, +8.00 to -12.00D, oversampling <18 years) captured CIEs from January 2006 to September 2009. The review noted age, sex, SCL worn, use of lens care products, and SCL wearing history. Event diagnoses were adjudicated to consensus by reviewers masked to wearer identity, age, and SCL parameters. Significant univariate risk factors for CIEs were subsequently tested in multivariate generalized estimating equations. RESULTS: Charts from 14,305 visits observing 4,663 SCL years yielded 187 CIEs in 168 wearers. Age was a significant nonlinear risk factor, peaking between 15 and 25 years (P < 0.008). Less than 1 year of SCL use was protective versus longer years of wear (P < 0.0003). Use of multipurpose care products (2.86*), silicone hydrogels (1.85*), and extended wear (2.37*) were significantly associated with CIEs in the multivariate model (P < 0.0001 each). CONCLUSIONS: Patient age, years of lens wear, use of multipurpose care products, silicone hydrogels, and extended wear were all significantly associated with CIEs with SCL wear. Use of SCLs in young patients aged 8 to 15 years was associated with a lower risk of infiltrative events compared with teens and young adults. In terms of safety outcomes, SCLs appear to be an acceptable method of delivering optics designed to manage myopia progression in children and young teens in the future. PMID- 21527380 TI - A prototype antifungal contact lens. AB - PURPOSE: To design a contact lens to treat and prevent fungal ocular infections. METHODS: Curved contact lenses were created by encapsulating econazole impregnated poly(lactic-co-glycolic) acid (PLGA) films in poly(hydroxyethyl methacrylate) (pHEMA) by ultraviolet photopolymerization. Release studies were conducted in phosphate-buffered saline at 37 degrees C with continuous shaking. The contact lenses and their release media were tested in an antifungal assay against Candida albicans. Cross sections of the pre- and postrelease contact lenses were characterized by scanning electron microscopy and by Raman spectroscopy. RESULTS: Econazole-eluting contact lenses provided extended antifungal activity against Candida albicans fungi. Fungicidal activity varied in duration and effectiveness depending on the mass of the econazole-PLGA film encapsulated in the contact lens. CONCLUSIONS: An econazole-eluting contact lens could be used as a treatment for fungal ocular infections. PMID- 21527381 TI - Evaluation of a computer-aided diagnosis system for diabetic retinopathy screening on public data. AB - PURPOSE: To evaluate the performance of a comprehensive computer-aided diagnosis (CAD) system for diabetic retinopathy (DR) screening, using a publicly available database of retinal images, and to compare its performance with that of human experts. METHODS: A previously developed, comprehensive DR CAD system was applied to 1200 digital color fundus photographs (nonmydriatic camera, single field) of 1200 eyes in the publicly available Messidor dataset (Methods to Evaluate Segmentation and Indexing Techniques in the Field of Retinal Ophthalmology (http://messidor.crihan.fr). The ability of the system to distinguish normal images from those with DR was determined by using receiver operator characteristic (ROC) analysis. Two experts also determined the presence of DR in each of the images. RESULTS: The system achieved an area under the ROC curve of 0.876 for successfully distinguishing normal images from those with DR with a sensitivity of 92.2% at a specificity of 50%. These compare favorably with the two experts, who achieved sensitivities of 94.5% and 91.2% at a specificity of 50%. CONCLUSIONS: This study shows, for the first time, the performance of a comprehensive DR screening system on an independent, publicly available dataset. The performance of the system on this dataset is comparable with that of human experts. PMID- 21527382 TI - Epidermal differentiation and loss of clonal growth potential of human limbal basal epithelial progenitor cells during intrastromal invasion. AB - PURPOSE: Intrastromal invasion by limbal basal epithelial progenitor cells in explant cultures is associated with epithelial-mesenchymal transition. It remains unclear whether intrastromal invasion is contingent on culturing conditions and whether invaded cells retain their progenitor status and original lineage. METHODS: Human limbal explants were cultured on various culture substrates, with or without air-lifting (AL), and subjected to hematoxylin and eosin staining and immunostaining to pan-cytokeratins, p63alpha, DeltaNp63, Pax6, CK10, and CK12. Single cells obtained by trypsin/EDTA from dispase-isolated epithelial sheets from both the outgrowth and the surface epithelium, or by collagenase from the remaining stroma, were seeded on 3T3 feeder layers. RESULTS: Intrastromal invasion was verified in all seven explant cultures by positive pan-cytokeratin staining. Immunofluorescence staining revealed that invaded epithelial cells were positive for p63alpha and DeltaNp63, with or without nuclear staining of Pax6. Double immunostaining to CK10 and CK12 revealed that squamous metaplasia induced by AL was noted on the surface epithelium but not in intrastromally invaded epithelial cells. On 3T3 feeder layers, both the outgrowth and the surface epithelium yielded significant numbers of holoclones and meroclones positive to DeltaNp63 but negative to CK10 and CK12. In contrast, intrastromally invaded epithelial cells generated only paraclones negative to DeltaNp63 and CK12 but positive to CK10 regardless of culturing conditions. CONCLUSIONS: Intrastromal invasion by limbal basal epithelial progenitor cells is universal in all explant culture conditions, explaining why there is a gradual decline of outgrowth potential. Alteration of the limbal stromal niche leads invaded epithelial cells to adopt an epidermal fate. PMID- 21527383 TI - A comparison of standard scoring versus Rasch scoring of the visual function index-14 in patients with cataracts. AB - PURPOSE: To compare the discriminatory ability and sensitivity to change of the standard summative score of the Visual Function Index (VF)-14 with two alternative Rasch-based scoring systems. METHODS: A total of 4335 prospective patients with cataracts completed the VF-14 before surgery and 3 months after surgery. Rasch analysis was applied to the VF-14 patient responses before surgery and the VF-14 joint patient responses before and after surgery. To study the discriminatory ability, the VF-14 patient responses were grouped according to the preoperative visual acuity (VA) and the presence of ocular morbidities besides cataracts. For analysis of the sensitivity to change, the overall mean change in VF-14 scores was calculated after surgery, and the patients were grouped according to the presence of other ocular morbidities, postoperative VA gain, and satisfaction with the surgical outcome. The relative precision (RP) index and the effect size were used to compare the different scoring systems. RESULTS: Rasch analysis confirmed the unidimensional structure of the VF-14. All items and scales adjusted well to the model (fit indices range, 0.71-1.34). The RP index for discrimination by ocular morbidity was 0.82 and by preoperative VA level, 1.02. Regarding sensitivity to change, the RP was 2.68 based on ocular morbidity and 1.78 with samples grouped by postoperative VA gain. CONCLUSIONS: For longitudinal studies in which change is the relevant outcome, Rasch scores should be used, rather than the traditional score. However, for cross-sectional studies, both scoring systems were similarly precise. PMID- 21527384 TI - Cognitive and motor mechanisms underlying older adults' ability to divide attention while walking. AB - BACKGROUND: An impaired ability to allocate attention to gait during dual-task situations is a powerful predictor of falls. OBJECTIVE: The primary purpose of this study was to examine the relative contributions of participant characteristics and motor and cognitive factors to the ability to walk while performing cognitive tasks. The impact of cognitive task complexity on walking also was examined. DESIGN: A cross-sectional, exploratory study design was used. METHODS: Seventy-seven community-dwelling older adults with a mean (SD) age of 75.5 (5.8) years completed comprehensive testing. Participant characteristics were assessed via questionnaires. The motor test battery included measures of strength (force-generating capacity), gait speed, and static and dynamic balance. The cognitive abilities test battery assessed psychomotor and perceptual speed, recall and working memory, verbal and spatial ability, and attention (sustained, selective, and divided). Time to walk while performing 4 cognitive tasks was measured. In addition, dual-task costs (DTCs) were calculated. Multiple hierarchical regressions explored walking under dual-task conditions. RESULTS: The ability to walk and perform a simple cognitive task was explained by participant characteristics and motor factors alone, whereas walking and performing a complex cognitive task was explained by cognitive factors in addition to participant and motor factors. Regardless of the cognitive task, participants walked slower under dual-task conditions than under single-task conditions. Increased cognitive task complexity resulted in greater slowing of gait: gait DTCs were least for the simplest conditions and greatest for the complex conditions. Limitations Walking performance was characterized by a single parameter (time), whereas other spatiotemporal parameters have been related to dual-task performance. However, this type of measurement (timed performance) will be easy to implement in the clinic. CONCLUSIONS: Two factors-participant characteristics and motor abilities-explained the majority of variance of walking under dual-task conditions; however, cognitive abilities also contributed significantly to the regression models. Rehabilitation focused on improving underlying balance and gait deficits, as well as specific cognitive impairments, may significantly improve walking under dual-task conditions. PMID- 21527385 TI - Cycling with functional electrical stimulation in an adult with spastic diplegic cerebral palsy. AB - BACKGROUND AND PURPOSE: Adults with cerebral palsy (CP) are at risk for decreased mobility and health complications, and exercise may combat some of these negative changes. Because people with CP have difficulty generating sufficient muscle force, exercise augmented with functional electrical stimulation (FES) is an option for increasing exercise intensity. This mixed-method (quantitative qualitative) case report describes the effects-across the International Classification of Functioning, Disability and Health (ICF) model-of cycling with FES (FES cycling) in an adult with CP. CASE DESCRIPTION: An ambulatory 49-year old man with spastic diplegic CP cycled with FES at home for 30 minutes, 3 times per week, for 12 weeks. Volitional efforts were augmented by FES of the bilateral quadriceps, gastrocnemius, and gluteal muscles. Testing was performed before and after the intervention and 4 weeks after intervention withdrawal. OUTCOMES: After training, quadriceps muscle strength (force-generating capacity) improved by 22.2%, hamstring muscle strength improved by 18.5%, and the Timed "Up & Go" Test time decreased from 11.9 to 9.0 seconds. The patient reported increased performance and satisfaction for self-identified goals at the ICF level of participation, and his score on the Medical Outcomes Study 36-Item Health Survey questionnaire increased from 62.1 to 77.6. However, he reported increased back pain, which he attributed to positioning while cycling. Qualitative interviews provided context (the patient's perspective) for some of the quantitative results. DISCUSSION: The patient made gains in body structure and function, activity, and participation (ICF levels) after FES cycling. The mixed-method approach provided insight into his experiences and perceptions about the measures assessed quantitatively. Further investigation on FES cycling in this population as well as positioning during cycling is warranted. PMID- 21527387 TI - Let them fall where they may: congruence analysis in massive phylogenetically messy data sets. AB - Interest in congruence in phylogenetic data has largely focused on issues affecting multicellular organisms, and animals in particular, in which the level of incongruence is expected to be relatively low. In addition, assessment methods developed in the past have been designed for reasonably small numbers of loci and scale poorly for larger data sets. However, there are currently over a thousand complete genome sequences available and of interest to evolutionary biologists, and these sequences are predominantly from microbial organisms, whose molecular evolution is much less frequently tree-like than that of multicellular life forms. As such, the level of incongruence in these data is expected to be high. We present a congruence method that accommodates both very large numbers of genes and high degrees of incongruence. Our method uses clustering algorithms to identify subsets of genes based on similarity of phylogenetic signal. It involves only a single phylogenetic analysis per gene, and therefore, computation time scales nearly linearly with the number of genes in the data set. We show that our method performs very well with sets of sequence alignments simulated under a wide variety of conditions. In addition, we present an analysis of core genes of prokaryotes, often assumed to have been largely vertically inherited, in which we identify two highly incongruent classes of genes. This result is consistent with the complexity hypothesis. PMID- 21527386 TI - An obese body mass increases the adverse effects of HIV/AIDS on balance and gait. AB - BACKGROUND: Balance and gait problems have been detected among patients with HIV/AIDS. The extent to which these problems are exacerbated by either frailty or obesity has not been examined. Objective The purpose of this study was to compare participants who differed in body mass and the presence or absence of HIV/AIDS. DESIGN: This was a cross-sectional study. METHODS: Quantitative measurements were obtained from 86 participants who were HIV-type 1 (HIV-1) seronegative and 121 participants who were seropositive divided into subgroups based on their body mass index (BMI <21, 21-29, or >29 kg/m(2)). RESULTS: Participants who were seropositive were impaired relative to seronegative controls on several indices, including the limit of stability, sway amplitude and sway strategy, gait initiation time, and gait speed during a fast pace condition. Participants who were obese also exhibited impairments, which were evident during assessments of the limit of stability, nonpreferred leg stance time, sway strategy, normal and fast gait speed, fast gait initiation time, and 360-degree turn time. Importantly, the analysis revealed that participants with both attributes were more impaired than those with either or neither attribute: patients who were obese and seropositive were more impaired in fast gait initiation time and cadence, nonpreferred leg stance time, 360-degree turn time, and sway strategy scores. Limitations The validity of BMI as a measure of body mass can be challenged. In addition, the validity of chair rise time and 360-degree turn time as estimates of lower-extremity strength (force-generating capacity) can be argued. CONCLUSIONS: The present findings have an obvious and unfortunate implication: as more patients who are HIV-1 seropositive join the seronegative community in becoming obese, the effects of obesity and their disease may summate and their risk for balance and gait problems may increase. PMID- 21527388 TI - Group beating related T-wave alternans in a patient with atrio-ventricular nodal reentrant tachycardia. PMID- 21527389 TI - Assessment of left ventricular dyssynchrony in pacing-induced left bundle branch block compared with intrinsic left bundle branch block. AB - AIMS: Although electrocardiographic and echocardiographic findings with right ventricular (RV) pacing mimic intrinsic left bundle branch block (LBBB), left ventricular (LV) mechanical activation pattern may differ. We compared mechanical activation pattern of the LV in RV-pacing-induced LBBB with intrinsic LBBB in symptomatic chronic heart failure patients. METHODS AND RESULTS: We studied 37 patients with chronic RV-pacing and 37 patients with intrinsic LBBB who were referred for cardiac resynchronization therapy. Echocardiographic study including 2D speckle tracking longitudinal strain and M-mode were performed at baseline. Patients with intrinsic LBBB were younger, had higher prevalence of ischaemic heart disease, and had more severe depressed LV function. The basal-septal segments were the earliest activated sites in 11% of patients in RV-pacing induced LBBB compared with 30% in intrinsic LBBB (P= 0.04). The mid- and basal lateral segments were the latest activated sites in 57% of patients in RV-pacing induced LBBB compared with 30% in intrinsic LBBB (P = 0.03). Left ventricular dyssynchrony, using longitudinal strain, time delay >= 130 ms between either mid septal or apico-septal and either basal or mid-lateral segments was present in 71% of patients with RV-pacing-induced LBBB compared with 59% in intrinsic LBBB (P = 0.03). Using M-mode, LV dyssynchrony was present in 11% of patients with RV pacing-induced LBBB compared with 59% in intrinsic LBBB (P = 0.02). CONCLUSION: Right ventricular-pacing results in less early basal activation and more often early mid-septal and late lateral wall activation in comparison with intrinsic LBBB. Imaging techniques that only visualize the basal- or mid-part of the LV may result in a serious underestimation of dyssynchrony in patients with pacing induced LBBB. PMID- 21527390 TI - Paravertebral echocardiographic views and thoracic aortic dissected aneurysm. PMID- 21527391 TI - Validity of generic scenarios used in derivation of exemption levels for surface contamination considering transport-specific aspects. AB - The exemption levels for surface contamination in units of Bq cm(-2) were derived by developing a new universal dose assessment model that consists of three generic scenarios assessed by considering manually, closely and remotely handled objects. In this paper, as part of the process of verifying the validity of these generic scenarios, annual doses that arise from transport-specific aspects are calculated. The maximum annual doses are found to be lower than 10 uSv, which is the bottom line of the exemption dose criterion. The result verifies the validity of the generic scenarios used in the previous derivation of exemption levels for surface contamination. PMID- 21527392 TI - Leber's hereditary optic neuropathy mutations associated with infantile-onset myoclonic epilepsy. AB - Epilepsy syndromes with onset in the first year of life, especially when they include myoclonic features, have special significance since they are associated with long-term developmental and neurological abnormalities. Dravet's severe myoclonic epilepsy in infancy is especially interesting as it is associated with fever-provoked seizures and mutations in the alpha subunit of the sodium channel (SCN1A) in about one-third of the cases. Here, we report 2 children who had clinical features of severe myoclonic epilepsy of infancy without mutations in the SCN1A gene who were found to have mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy. These 2 children demonstrated markers of mitochondrial dysfunction, drug-resistant epilepsy, and dysfunction of nonneurological systems. These cases demonstrate that mitochondrial DNA mutations, especially those associated with Leber's hereditary optic neuropathy, should be considered in cases of myclonic epilepsy starting in infancy, especially when mutations in the SCN1A gene are not found. PMID- 21527393 TI - Intellectual and behavioral functioning in a South african cohort of boys with duchenne muscular dystrophy. AB - The authors describe the neurocognitive and behavioral phenotype of 16 South African children (ages 4-16 years) with Duchenne muscular dystrophy, compared with 13 controls. The preschool group performed significantly worse than the controls in measures of general developmental performance. The school-age group showed no significant differences in general intellectual abilities. However, our data identified that boys with Duchenne muscular dystrophy experience mild cognitive dysfunction across multiple domains, including visual memory, and verbal and nonverbal executive functioning. Parental reports of 11 boys with the disorder revealed high rates of general behavioral problems (54.5%). The cognitive profile of boys with Duchenne muscular dystrophy in South Africa is similar to that described elsewhere in the world. Behavioral problems in our cohort were higher than previously reported. This may be partially explained by the poor socioeconomic background of the majority of the cohort. PMID- 21527394 TI - Psychiatric and autistic comorbidity in fragile X syndrome across ages. AB - Fragile X syndrome is caused by CGG trinucleotide repeat expansion within the fragile X mental retardation 1 gene, when repeat number exceeds 200. The typical psychiatric profile of fragile X syndrome patients includes cognitive and behavioral deficits, psychiatric comorbidity, and autistic characteristics. Specific psychiatric features have not yet been clarified, specifically in relationship to age and genetic characteristics. The objective of this study was to characterize psychiatric comorbidities in subjects with fragile X syndrome at different ages. Subjects with fragile X syndrome and their unaffected siblings were recruited and their parents filled out functional-behavioral and psychiatric comorbidities questionnaires. Adolescents with fragile X syndrome showed decreased prevalence of functional-behavioral deficits. Incidence and severity of most psychiatric comorbidities were lower in older subjects. Incidence of generalized anxiety disorder increased with age in the fragile X syndrome group. The typical profile of patients with fragile X syndrome changes with age. Unaffected siblings exhibit anxiety and motor tics. PMID- 21527396 TI - Cardiac involvement in nonketotic hyperglycinemia. AB - Nonketotic hyperglycinemia is an autosomal recessive disorder of glycine metabolism characterized by the accumulation of glycine in the serum and cerebrospinal fluid with elevated cerebrospinal fluid to serum glycine ratio. The disease primarily affects the central nervous system, and has not been previously associated with myocardial involvement. In this article, the authors report an infant with nonketotic hyperglycinemia, who was found to have progressive left ventricular hypertrophy and dysfunction. His older sibling, who had a similar neurologic presentation, died of dilated cardiomyopathy as stated by the parents. The authors speculate that glycine may have a role in the development of cardiac dysfunction. The incidence of cardiac involvement may be under-diagnosed. They suggest the need for a cardiac evaluation in confirmed cases of nonketotic hyperglycinemia. PMID- 21527395 TI - Reversible brainstem edema due to hypertensive encephalopathy in an 8-year-old girl. AB - The authors report an 8-year-old girl with refractory status epilepticus due to hypertensive encephalopathy, secondary to end-stage renal disease. Brain magnetic resonance imaging (MRI) in the acute phase showed striking hyperintensities in the brain stem and medial thalamus along with subtle cortical lesions. After successful control of hypertensive crisis and status epilepticus, the patient recovered to her baseline. Near total resolution of the lesions was noted on follow-up imaging performed 9 days later. Predominant brainstem involvement as a feature of posterior reversible encephalopathy syndrome due to hypertensive crisis is extremely rare in children and has not been well documented. PMID- 21527397 TI - A novel approach to wound management and prosthetic use with concurrent vacuum assisted closure therapy. AB - BACKGROUND AND AIM: Stump healing is critical to post amputation management. When healing is not optimal, immobility is prolonged and patients risk hospital acquired deconditioning. Two clinical cases with unhealed trans-femoral stump wounds are described. Vacuum assisted closure (VAC) dressing with concurrent prosthetic utilisation was undertaken successfully in both cases. TECHNIQUE: Fitting of the prosthetic socket included space for VAC dressing with modifications to allow the suction piping to exit the prosthesis. With VAC application, timely rehabilitation and mobility was enabled despite incomplete wound healing. DISCUSSION: The two clinical cases described made excellent progress. Discharge home was expedited with the provision of portable VAC pumps. Wounds healed fully without infection. Both patients were able to mobilise sooner than if they had to wait for complete wound closure and, importantly, the consequences of prolonged immobility were minimised. No extra costs were incurred using this novel therapy. CLINICAL RELEVANCE: Guidance for early mobilisation of trans-femoral amputees with open wounds is limited. These cases provide examples utilising VAC dressings with concurrent prosthetic rehabilitation, facilitating prompt ambulatory retraining, minimising deconditioning and optimising outcomes. PMID- 21527398 TI - Evidence for a conserved function of heart and neural crest derivatives expressed transcript 2 in mouse and human decidualization. AB - Previously, we showed that heart and neural crest derivatives expressed transcript 2 (Hand2) mRNA levels dramatically increase in mouse uterine endometrial stromal cells (ESCs) as they undergo decidualization in vivo. However, to date, little is known about the expression and function of this transcription factor in mouse or human uterus decidualization. Therefore, this study was conducted to provide a more detailed assessment of Hand2 gene expression and function in the mouse uterus during the peri-implantation period and also in mouse plus human ESCs during decidualization in vitro. The results show that Hand2 mRNA and protein levels increase in the mouse uterus during decidualization and this does not depend on the presence of a conceptus. Interestingly, Hand2 mRNA and protein are present in ESCs adjacent to the luminal epithelium in the uterus prior to the onset of implantation. We find that progesterone is likely a regulator of Hand2 expression during uterine sensitization of the mouse uterus. Finally, Hand2 expression increases in mouse and human fibroblast cells as they undergo decidualization in vitro. This expression is significantly increased in response to prostaglandin E(2). In particular, reduction of Hand2 expression in these cells using small hairpin RNA or small interfering RNA approaches results in the reduced extent of decidualization as shown by the reduced expression of a subset of decidualization markers. The results of this study support the hypothesis that Hand2 expression not only plays an important role in decidualization but may also play a role in obtaining proper progesterone-dependent uterine sensitization required for implantation to begin. PMID- 21527400 TI - Estimation of onset of analgesia from simulated data. PMID- 21527399 TI - Ontogeny of sulfonylurea-binding regulatory subunits of K(ATP) channels in the pregnant rat myometrium. AB - ATP-sensitive potassium channels (K(ATP) channels) are composed of sulfonylurea receptors (SURs) and potassium inward rectifiers (Kir(6.x)) that assemble to form a large octameric channel. This study was designed to examine the expression and role of sulfonylurea-binding regulatory subunits 1 (SUR1 (ABCC8)) and 2 (SUR2 (ABCC9)) of the K(ATP) channels in the pregnant rat myometrium with particular regard to the contractility. RT-PCR and western blot analyses were performed to detect the presence of SUR1 and SUR2. The SUR1 levels were markedly increased in the early stages of pregnancy. The highest level was detected on day 6 of pregnancy, whereas in the late stages, the levels of SUR1 were significantly decreased. The SUR2 level remained unchanged throughout pregnancy. The SUR non selective diazoxide and the SUR2-selective pinacidil inhibited oxytocin-induced contractions. Glibenclamide, a K(ATP) channel blocker, antagonized both pinacidil and diazoxide-induced relaxations. It was established that SURs are responsible for pharmacological reactivity of K(ATP) channel openers. We conclude that both SURs are involved in the K(ATP) channel in the pregnant rat myometrium. It may further be concluded that 'pinacidil-like' K(ATP) channel openers may be of therapeutic relevance as tocolytic agents in the future. PMID- 21527401 TI - Monocyte chemoattractant protein-1 derived from biliary innate immunity contributes to hepatic fibrogenesis. AB - AIMS: Monocyte chemoattractant protein-1 (MCP-1) is a major chemotactic factor for hepatic stellate cells (HSCs) associated with hepatic fibrosis. In this study, among several fibrogenetic factors derived from biliary epithelial cells (BECs), MCP-1 produced by the biliary innate immune system was found to be most critical in the histogenesis of hepatic fibrogenesis. METHODS: Using cultured human BECs, the expression of five fibrogenetic factors including MCP-1 on stimulation with Toll-like receptor ligands, inflammatory cytokines or bile acids was examined. Moreover, in situ detection of MCP-1 and alpha-smooth muscle actin proteins was performed using sections from normal and diseased livers by immunohistochemistry. RESULTS: All fibrogenetic factors were detected in BECs, but only MCP-1 expression was upregulated, by all the Toll-like receptor ligands, IL-1beta, and tumour necrosis factor-alpha. Proliferating bile ductules in interface areas expressed MCP-1 in diseased livers accompanying alpha-smooth muscle actin-positive activated HSCs. CONCLUSIONS: Bile ductules proliferate in various hepatobiliary diseases, and its significance is still unknown. This study demonstrated that BECs in bile ductules could produce MCP-1, particularly, via biliary innate immunity, suggesting that MCP-1 derived from BECs plays an important role in the recruitment of HSCs to interface areas and the activation of HSCs resulting in the progression of periportal fibrosis. PMID- 21527402 TI - The decline in ischaemic heart disease mortality in seven European countries: exploration of future trends. AB - BACKGROUND: To assess the implication of a possible continuation of the decline in ischaemic heart disease (IHD) mortality in the future. METHODS: Annual rates of decline in IHD mortality from 1980-2005 were determined for the national populations of the Netherlands, UK, France and four Nordic countries through regression analysis and used to extrapolate mortality rates until 2030. Through cause-elimination life tables we determined the impact of IHD on life expectancy at birth. RESULTS: In all countries, IHD mortality rates among both sexes declined incessantly until 2005. Age-adjusted mortality rates would have declined by about 50% in 2030 compared to 2005 if past trends were to continue. The impact of IHD on life expectancy at birth would decline by about 25-50% in most populations. The absolute numbers of IHD deaths would decline slowly or even increase in some countries mainly because of population ageing. CONCLUSIONS: If current IHD mortality trends continued, IHD would lose much of its importance as a cause of premature death in the near future. As the incidence and disabling impact of IHD might decline much less, prevention of IHD-related disability instead of mortality may become increasingly important in the future. PMID- 21527403 TI - Are we proper role models for students? Interns' perception of faculty and residents' professional behaviour. AB - AIM: This study was conducted to assess interns' level of exposure to different aspects of professional attitude and behaviour among faculty and residents. METHODS: In this descriptive study, 218 interns in surgery and internal medicine wards at four teaching hospitals of Tehran University of Medical Sciences were enrolled during the first semester of the 2007/2008 academic year. Each intern completed one questionnaire for faculty and one for residents in their ward. RESULTS: The questionnaire was completed by 150 students (68.8%) for faculty and by 139 students (63.7%) for residents. In terms of overall aspects of professionalism, the mean (+/-SD) score on observing professionalism was 52.9+/ 10 and 49.26+/-7.9 points out of 70 for faculty and residents, respectively. Students agreed that responsibility was observed better than other aspects of professionalism (119/150 (79.3%) and 115/139 (82.8%) students stated it was often or always observed by faculty and residents, respectively). In both groups, commitment to honour and integrity and excellence was less compared with other areas. CONCLUSION: Medical faculty and residents should be more aware of their behaviour and attitudes in practice, especially their interaction with colleagues so that students' professional behaviour can be improved. PMID- 21527404 TI - Mesenteric vasculitis with genitourinary tract involvement in systemic lupus erythematosus. PMID- 21527406 TI - Tobacco plain packaging legislation: a content analysis of commentary posted on Australian online news. AB - INTRODUCTION: In April 2010, the Australian government became the first to announce legislation mandating that tobacco products be sold in plain packaging. The announcement generated significant media coverage and public feedback. The increased readership of and community commentary on online news present an opportunity to assess the range of arguments most likely to be used by opponents to this policy. METHODS: A content analysis was conducted of reader commentary posted on Australian online news items about the plain packaging announcement. Reader opinion polls on the plain packaging were also recorded. All arguments opposed to plain packaging contained within reader comments were categorised into 11 debating frames. RESULTS: Of 117 relevant news items, 41 included 1818 reader comments. 1187 (65.3%) comments contained no reference to plain packaging, and mainly addressed a tobacco tax rise announced at the same time. The comments about plain packaging were more than 2.5 times more likely to oppose than support the policy. The dominant argumentative frame, comprising 27% of oppositional comments, was that plain packaging would be ineffective in reducing smoking. Online reader poll results showed equal support for and opposition to plain packaging. CONCLUSIONS: The results of this study can be used by tobacco control advocates to anticipate opposition and assist in reframing and counteracting arguments opposed to plain packaging. PMID- 21527405 TI - Impact of smoke-free legislation on children's exposure to secondhand smoke: cotinine data from the Health Survey for England. AB - OBJECTIVE: To examine the impact of the ban on smoking in enclosed public places implemented in England in July 2007 on children's exposure to secondhand tobacco smoke. DESIGN: Repeated cross-sectional surveys of the general population in England. SETTING: The Health Survey for England. PARTICIPANTS: Confirmed non smoking children aged 4-15 with measured saliva cotinine participating in surveys from 1998 to 2008, a total of 10,825 children across years. MAIN OUTCOME MEASURES: The proportion of children living in homes reported to be smoke-free; the proportion of children with undetectable concentrations of cotinine; geometric mean cotinine as an objective indicator of overall exposure. RESULTS: Significantly more children with smoking parents lived in smoke-free homes in 2008 (48.1%, 95% CI 43.0% to 53.1%) than in either 2006 (35.5%, 95% CI 29.7% to 41.7%) or the first 6 months of 2007, immediately before the ban came into effect (30.5%, 95% CI 19.7% to 43.9%). A total of 41.1% (95% CI 38.9% to 43.4%) of children had undetectable cotinine in 2008, up from 34.0% (95% CI 30.8% to 37.3%) in 2006. Geometric mean cotinine in all children combined was 0.21 ng/ml (95% CI 0.20 to 0.23) in 2008, slightly lower than in 2006, 0.24 ng/ml (95% CI 0.21 to 0.26). CONCLUSIONS: Predictions that the 2007 legislative ban on smoking in enclosed public places would adversely affect children's exposure to tobacco smoke were not confirmed. While overall exposure in children has not been greatly affected by the ban, the trend towards the adoption of smoke-free homes by parents who themselves smoke has received fresh impetus. PMID- 21527408 TI - Metrics associated with NIH funding: a high-level view. AB - OBJECTIVE: To introduce the availability of grant-to-article linkage data associated with National Institutes of Health (NIH) grants and to perform a high level analysis of the publication outputs and impacts associated with those grants. DESIGN: Articles were linked to the grants they acknowledge using the grant acknowledgment strings in PubMed using a parsing and matching process as embodied in the NIH Scientific Publication Information Retrieval & Evaluation System system. Additional data from PubMed and citation counts from Scopus were added to the linkage data. The data comprise 2,572,576 records from 1980 to 2009. RESULTS: The data show that synergies between NIH institutes are increasing over time; 29% of current articles acknowledge grants from multiple institutes. The median time lag to publication for a new grant is 3 years. Each grant contributes to approximately 1.7 articles per year, averaged over all grant types. Articles acknowledging US Public Health Service (PHS, which includes NIH) funding are cited twice as much as US-authored articles acknowledging no funding source. Articles acknowledging both PHS funding and a non-US government funding source receive on average 40% more citations that those acknowledging PHS funding sources alone. CONCLUSION: The US PHS is effective at funding research with a higher-than-average impact. The data are amenable to further and much more detailed analysis. PMID- 21527407 TI - Using the time and motion method to study clinical work processes and workflow: methodological inconsistencies and a call for standardized research. AB - OBJECTIVE: To identify ways for improving the consistency of design, conduct, and results reporting of time and motion (T&M) research in health informatics. MATERIALS AND METHODS: We analyzed the commonalities and divergences of empirical studies published 1990-2010 that have applied the T&M approach to examine the impact of health IT implementation on clinical work processes and workflow. The analysis led to the development of a suggested 'checklist' intended to help future T&M research produce compatible and comparable results. We call this checklist STAMP (Suggested Time And Motion Procedures). RESULTS: STAMP outlines a minimum set of 29 data/ information elements organized into eight key areas, plus three supplemental elements contained in an 'Ancillary Data' area, that researchers may consider collecting and reporting in their future T&M endeavors. DISCUSSION: T&M is generally regarded as the most reliable approach for assessing the impact of health IT implementation on clinical work. However, there exist considerable inconsistencies in how previous T&M studies were conducted and/or how their results were reported, many of which do not seem necessary yet can have a significant impact on quality of research and generalisability of results. Therefore, we deem it is time to call for standards that can help improve the consistency of T&M research in health informatics. This study represents an initial attempt. CONCLUSION: We developed a suggested checklist to improve the methodological and results reporting consistency of T&M research, so that meaningful insights can be derived from across-study synthesis and health informatics, as a field, will be able to accumulate knowledge from these studies. PMID- 21527409 TI - Why clinicians use or don't use health information exchange. PMID- 21527410 TI - The cell cycle profile test is a prognostic indicator for breast cancer patients treated with postoperative 5-fluorouracil-based chemotherapy. AB - OBJECTIVE: The cell cycle profile test is suggested to be an independent prognostic indicator for breast cancer patients. To further clarify the prognostic value, we applied this to breast cancer patients treated with postoperative 5-fluorouracil-based chemotherapy. METHODS: A total of 153 breast cancer patients, who were treated with postoperative 5-fluorouracil-based chemotherapies, were randomly selected. Specific activities of cyclin-dependent kinases 1 and 2 in the tumor samples were analyzed. Patients were divided into three categories (low, intermediate or high risk) based on cell cycle profile analysis. RESULTS: The proportions of the cell cycle profile categories were 39% for low risk, 10% for intermediate risk and 45% for high risk, respectively. Although the cell cycle profile test did not show a significant predictive power for relapse-free survival (high vs. low risk; P = 0.052), the cell cycle profile categories were significant prognostic factors in a subgroup of 98 patients with fewer than three involved nodes (high vs. low risk, P = 0.004). Multivariate analyses also indicated that a cell cycle profile parameter (high vs. low risk) was an independent prognostic indicator from the number of involved nodes and clinical stage in this subgroup (hazard ratio = 2.46, P = 0.01). Interestingly, the prognostic power of the cell cycle profile test was significant in 75 patients treated with oral 5-fluorouracil derivatives alone (hazard ratio = 6.29 for high vs. low risk, P = 0.02). CONCLUSIONS: These findings suggest that the cell cycle profile test is useful for predicting a higher risk of relapse in patients treated with postoperative 5-fluorouracil-based chemotherapy. PMID- 21527411 TI - Spontaneous regression of pulmonary metastases from a malignant phyllodes tumor. AB - We report a case of spontaneous regression of pulmonary metastases from a malignant phyllodes tumor. A 50-year-old woman was diagnosed with a breast phyllodes tumor. Computed tomography and positron emission tomography revealed multiple lung metastases. She underwent a mastectomy to control the pain of the enlarging breast mass. Histopathologic examination diagnosed a malignant phyllodes tumor. Without the administration of any adjuvant therapy, the follow up chest computed tomography scan and positron emission tomography scan showed disappearance of the lung metastases 2 months after surgery. PMID- 21527412 TI - Matrix-associated implantation of predifferentiated mesenchymal stem cells versus articular chondrocytes: in vivo results of cartilage repair after 1 year. AB - BACKGROUND: The use of predifferentiated mesenchymal stem cells (MSC) leads to better histological results compared with undifferentiated MSC in sheep. This raises the need for a longer term follow-up study and comparison with a clinically established method. HYPOTHESIS: We hypothesized that chondrogenic in vitro predifferentiation of autologous MSC embedded in a collagen I hydrogel leads to better structural repair of a chronic osteochondral defect in an ovine stifle joint after 1 year. We further hypothesized that resulting histological results would be comparable with those of chondrocyte-seeded matrix-associated autologous chondrocyte transplantation (MACT). STUDY DESIGN: Controlled laboratory study. METHODS: Predifferentiation period of ovine MSC within collagen gel in vitro was defined by assessment of several cellular and molecular biological parameters. For the animal study, 2 osteochondral lesions (7-mm diameter) were created at the medial femoral condyles of the hind legs in 9 sheep. Implantation of MSC gels was performed 6 weeks after defect creation. Thirty-six defects were divided into 4 treatment groups: (1) chondrogenically predifferentiated MSC gels (pre-MSC gels), (2) undifferentiated MSC gels (un-MSC gels), (3) MACT gels, and (4) untreated controls (UC). Histological, immunohistochemical, and radiological evaluations followed after 12 months. RESULTS: After 12 months in vivo, pre-MSC gels showed significantly better histological outcome compared with un-MSC gels and UC. Compared with MACT gels, the overall scores were higher for O'Driscoll and International Cartilage Repair Society (ICRS). The repair tissue of the pre-MSC group showed immunohistochemical detection of interzonal collagen type II staining. Radiological evaluation supported superior bonding of pre-MSC gels to perilesional native cartilage. Compared with previous work by our group, no degradation of the repair tissue between 6 and 12 months in vivo, particularly in pre-MSC gels, was observed. CONCLUSION: Repair of chronic osteochondral defects with collagen hydrogels composed of chondrogenically predifferentiated MSC shows no signs of degradation after 1 year in vivo. In addition, pre-MSC gels lead to partially superior histological results compared with articular chondrocytes. CLINICAL RELEVANCE: The results suggest an encouraging method for future treatment of focal osteochondral defects without donor site morbidity by harvesting articular chondrocytes. PMID- 21527413 TI - Auditory hallucinations elicit similar brain activation in psychotic and nonpsychotic individuals. AB - While auditory verbal hallucinations (AVH) are most characteristic for schizophrenia, they also occur in nonpsychotic individuals in the absence of a psychiatric or neurological disorder and in the absence of substance abuse. At present, it is unclear if AVH in these nonpsychotic individuals constitute the same phenomenon as AVH in psychotic patients. Comparing brain activation during AVH between nonpsychotic and psychotic individuals could provide important clues regarding this question. 21 nonpsychotic subjects with AVH and 21 matched psychotic patients indicated the presence of AVH during 3T functional magnetic resonance imaging (fMRI) scanning. To identify common areas of activation during the experience of AVH in both groups, a conjunction analysis was performed. In addition, a 2-sample t-test was employed to discover possible differences in AVH related activation between the groups. Several common areas of activation were observed for the psychotic and nonpsychotic subjects during the experience of AVH, consisting of the bilateral inferior frontal gyri, insula, superior temporal gyri, supramarginal gyri and postcentral gyri, left precentral gyrus, inferior parietal lobule, superior temporal pole, and right cerebellum. No significant differences in AVH-related brain activation were present between the groups. The presence of multiple common areas of AVH-related activation in psychotic and nonpsychotic individuals, in the absence of significant differences, implicates the involvement of the same cortical network in the experience of AVH in both groups. PMID- 21527414 TI - Minor salivary glands and labial mucous membrane graft in the treatment of severe symblepharon and dry eye in patients with Stevens-Johnson syndrome. AB - OBJECTIVE: To evaluate minor salivary glands and labial mucous membrane graft in patients with severe symblepharon and dry eye secondary to Stevens-Johnson syndrome (SJS). METHODS: A prospective, non-comparative, interventional case series of 19 patients with severe symblepharon and dry eye secondary to SJS who underwent labial mucous membrane and minor salivary glands transplantation. A complete ophthalmic examination including the Schirmer I test was performed prior to and following surgery. All patients had a preoperative Schirmer I test value of zero. RESULTS: Nineteen patients with severe symblepharon and dry eye secondary to SJS were included in the study. There was a statistically significant improvement in the best spectacle-corrected visual acuity in eight patients (t test; p=0.0070). Values obtained in the Schirmer I test improved significantly in 14 eyes (73.7%) 6 months following surgery (chi(2) test; p=0.0094). A statistically significant increase in tear production (Schirmer I test) was found in eyes that received more than 10 glands per graft compared with eyes that received fewer glands (chi(2) test; p=0.0096). Corneal transparency improved significantly in 11 (72.2%) eyes and corneal neovascularisation improved significantly in five eyes (29.4%) (McNemar test; p=0.001 and p=0.0005). The symptoms questionnaire revealed improvement in foreign body sensation in 53.6% of the patients, in photophobia in 50.2% and in pain in 54.8% (Kruskal-Wallis test; p=0.0167). CONCLUSION: Labial mucous membrane and minor salivary glands transplantation were found to constitute a good option for the treatment of severe symblepharon and dry eye secondary to SJS. This may be considered as a step prior to limbal stem cell and corneal transplantation in these patients. PMID- 21527415 TI - Spectral domain-optical coherence tomography analysis of choroidal osteoma. AB - BACKGROUND/AIMS: To assess spectral domain-optical coherence tomography (SD-OCT) contribution to choroidal osteoma characterisation. METHODS: A retrospective chart review of a series of patients diagnosed with choroidal osteoma, which included patient, clinical, ultrasonographic, photographic and SD-OCT imaging. RESULTS: 11 patients were included in this series. Their mean age was 42.5 years (median=43.0; range, 14-73). Using statistical analysis, the mean basal diameters of tumours as derived from fundus photographs (5.2 mm) and ultrasound images (6.4 mm) were significantly different (paired t-test, p=0.03). Tumours were SD-OCT hyporeflective in two cases, isoreflective in seven cases and hyper-reflective in two cases. Intrinsic reflectivity of the tumour was inhomogeneous in four cases. The overlying choroid was compressed by the tumour in eight cases and the retina exhibited degenerative changes in five cases. CONCLUSION: This study revealed that SD-OCT provided deeper and higher resolution images of choroidal osteoma when compared with previous studies using time domain-OCT. These findings offer new insights into the pathophysiology and diagnosis of choroidal osteoma. PMID- 21527416 TI - The effect of intravitreal ranibizumab on intraoperative bleeding during pars plana vitrectomy for diabetic traction retinal detachment. PMID- 21527417 TI - Relapsing migratory idiopathic orbital inflammation: six new cases and review of the literature. AB - AIMS: To present a case series of relapsing migratory idiopathic orbital inflammation. PATIENTS AND METHODS: Case series and review of the literature. The medical records of six patients with recurrent orbital myositis or idiopathic inflammation at different sites treated at the Goldschleger Eye Institute between April 2006 and December 2009 were collected and analysed; one patient treated at the orbital service in Priyamvada Birla Aravind Eye Hospital, Kolkata, India, was also included (June 2008 to August 2010). Orbital biopsy was performed in patients who failed to respond to steroids treatment. RESULTS: A total of six patients with recurrent episodes of orbital myositis or inflammation were identified. Four patients had orbital myositis of one extraocular muscle at the initial episode and recurrent myositis of a different extraocular muscle on the contralateral orbit. One patient had recurrent myositis of a different extraocular muscle on the same orbit. Two patients had a third episode of recurrence on a different site, that is, an extraocular muscle or an eyelid. One patient had eyelid and soft tissue involvement on one orbit and recurrence of orbital myositis on the contralateral eyelid. Histological findings in the latter case showed small perivascular lymphocytic aggregates and scattered histiocytes. The mean time for recurrence was 7.2 months. All patients were treated successfully with oral steroids and/or intralesional triamcinolone injection. CONCLUSIONS: Idiopathic orbital inflammation or orbital myositis can recur on a different extraocular muscle and on the contralateral orbit. These cases can be successfully treated with orally administered or intralesionally injected steroids. PMID- 21527418 TI - A double-flowered variety of lesser periwinkle (Vinca minor fl. pl.) that has persisted in the wild for more than 160 years. AB - BACKGROUND AND AIMS: Homeotic transitions are usually dismissed by population geneticists as credible modes of evolution due to their assumed negative impact on fitness. However, several lines of evidence suggest that such changes in organ identity have played an important role during the origin and subsequent evolution of the angiosperm flower. Better understanding of the performance of wild populations of floral homeotic varieties should help to clarify the evolutionary potential of homeotic mutants. Wild populations of plants with changes in floral symmetry, or with reproductive organs replacing perianth organs or sepals replacing petals have already been documented. However, although double-flowered varieties are quite popular as ornamental and garden plants, they are rarely found in the wild and, if they are, usually occur only as rare mutant individuals, probably because of their low fitness relative to the wild-type. We therefore investigated a double-flowered variety of lesser periwinkle, Vinca minor flore pleno (fl. pl.), that is reported to have existed in the wild for at least 160 years. To assess the merits of this plant as a new model system for investigations on the evolutionary potential of double-flowered varieties we explored the morphological details and distribution of the mutant phenotype. METHODS: The floral morphology of the double-flowered variety and of a nearby population of wild-type plants was investigated by means of visual inspection and light microscopy of flowers, the latter involving dissected or sectioned floral organs. KEY RESULTS: The double-flowered variety was found in several patches covering dozens of square metres in a forest within the city limits of Jena (Germany). It appears to produce fewer flowers than the wild-type, and its flowers are purple rather than blue. Most sepals in the first floral whorl resemble those in the wild-type, although occasionally one sepal is broadened and twisted. The structure of second-whorl petals is very similar to that of the wild type, but their number per flower is more variable. The double-flowered character is due to partial or complete transformation of stamens in the third whorl into petaloid organs. Occasionally, 'flowers within flowers' also develop on elongated pedicels in the double-flowered variety. CONCLUSIONS: The flowers of V. minor fl. pl. show meristic as well as homeotic changes, and occasionally other developmental abnormalities such as mis-shaped sepals or loss of floral determinacy. V. minor fl. pl. thus adds to a growing list of natural floral homeotic varieties that have established persistent populations in the wild. Our case study documents that even mutant varieties that have reproductive organs partially transformed into perianth organs can persist in the wild for centuries. This finding makes it at least conceivable that even double-flowered varieties have the potential to establish new evolutionary lineages, and hence may contribute to macroevolutionary transitions and cladogenesis. PMID- 21527419 TI - Evolution of oil-producing trichomes in Sisyrinchium (Iridaceae): insights from the first comprehensive phylogenetic analysis of the genus. AB - BACKGROUND AND AIMS: Sisyrinchium (Iridaceae: Iridoideae: Sisyrinchieae) is one of the largest, most widespread and most taxonomically complex genera in Iridaceae, with all species except one native to the American continent. Phylogenetic relationships within the genus were investigated and the evolution of oil-producing structures related to specialized oil-bee pollination examined. METHODS: Phylogenetic analyses based on eight molecular markers obtained from 101 Sisyrinchium accessions representing 85 species were conducted in the first extensive phylogenetic analysis of the genus. Total evidence analyses confirmed the monophyly of the genus and retrieved nine major clades weakly connected to the subdivisions previously recognized. The resulting phylogenetic hypothesis was used to reconstruct biogeographical patterns, and to trace the evolutionary origin of glandular trichomes present in the flowers of several species. KEY RESULTS AND CONCLUSIONS: Glandular trichomes evolved three times independently in the genus. In two cases, these glandular trichomes are oil-secreting, suggesting that the corresponding flowers might be pollinated by oil-bees. Biogeographical patterns indicate expansions from Central America and the northern Andes to the subandean ranges between Chile and Argentina and to the extended area of the Parana river basin. The distribution of oil-flower species across the phylogenetic trees suggests that oil-producing trichomes may have played a key role in the diversification of the genus, a hypothesis that requires future testing. PMID- 21527420 TI - Experimental growing of wild pea in Israel and its bearing on Near Eastern plant domestication. AB - BACKGROUND AND AIMS: The wild progenitors of the Near Eastern legumes have low germination rates mediated by hardseededness. Hence it was argued that cultivation of these wild legumes would probably result in no yield gain. Based on the meagre natural yield of wild lentil and its poor germination, it was suggested that wild Near Eastern grain legumes were unlikely to have been adopted for cultivation unless freely germinating types were available for the incipient farmers. Unlike wild cereals, data from experimental cultivation of wild legumes are lacking. METHODS: Replicated nurseries of wild pea (Pisum elatius, P. humile and P. fulvum) were sown during 2007-2010 in the Mediterranean district of Israel. To assess the effect of hardseededness on the yield potential, seeds of the wild species were either subjected to scarification (to ensure germination) or left intact, and compared with domesticated controls. KEY RESULTS: Sowing intact wild pea seeds mostly resulted in net yield loss due to poor establishment caused by wild-type low germination rates, while ensuring crop establishment by scarification resulted in net, although modest, yield gain, despite considerable losses due to pod dehiscence. Harvest efficiency of the wild pea plots was significantly higher (2-5 kg seeds h(-1)) compared with foraging efficiency in wild pea populations (ranging from a few grams to 0.6 kg h(-1)). CONCLUSIONS: Germination and yield data from 'cultivation' of wild pea suggest that Near Eastern legumes are unlikely to have been domesticated via a protracted process. Put differently, the agronomic implications of the hardseededness of wild legumes are incompatible with a millennia-long scenario of unconscious selection processes leading to 'full' domestication. This is because net yield loss in cultivation attempts is most likely to have resulted in abandonment of the respective species within a short time frame, rather than perpetual unprofitable cultivation for several centuries or millennia. PMID- 21527421 TI - MLN4924 is an efficient inhibitor of NEDD8 conjugation in plants. AB - The conjugation of the ubiquitin-like modifier NEURAL PRECURSOR CELL-EXPRESSED DEVELOPMENTALLY DOWN-REGULATED PROTEIN8/RELATED TO UBIQUITIN1 (NEDD8/RUB1; neddylation) is best known as an important posttranslational modification of the cullin subunits of cullin-RING-type E3 ubiquitin ligases (CRLs). MLN4924 has recently been described as an inhibitor of NEDD8-ACTIVATING ENZYME1 (NAE1) in human. Here, we show that MLN4924 is also an effective and specific inhibitor of NAE1 enzymes from Arabidopsis (Arabidopsis thaliana) and other plant species. We found that MLN4924-treated wild-type seedlings have phenotypes that are highly similar to phenotypes of mutants with a partial defect in neddylation and that such neddylation-defective mutants are hypersensitive to MLN4924 treatment. We further found that MLN4924 efficiently blocks the neddylation of cullins in Arabidopsis and that MLN4924 thereby interferes with the degradation of CRL substrates and their downstream responses. MLN4924 treatments also induce characteristic phenotypes in tomato (Solanum lycopersicum), Cardamine hirsuta, and Brachypodium distachyon. Interestingly, MLN4924 also blocks the neddylation of a number of other NEDD8-modified proteins. In summary, we show that MLN4924 is a versatile and specific neddylation inhibitor that will be a useful tool to examine the role of NEDD8- and CRL-dependent processes in a wide range of plant species. PMID- 21527422 TI - Carbon and nitrogen metabolism in mycorrhizal networks and mycoheterotrophic plants of tropical forests: a stable isotope analysis. AB - Most achlorophyllous mycoheterotrophic (MH) plants obtain carbon (C) from mycorrhizal networks and indirectly exploit nearby autotrophic plants. We compared overlooked tropical rainforest MH plants associating with arbuscular mycorrhizal fungi (AMF) to well-reported temperate MH plants associating with ectomycorrhizal basidiomycetes. We investigated (13)C and (15)N abundances of MH plants, green plants, and AMF spores in Caribbean rainforests. Whereas temperate MH plants and fungi have higher delta(13)C than canopy trees, these organisms displayed similar delta(13)C values in rainforests, suggesting differences in C exchanges. Although temperate green and MH plants differ in delta(15)N, they display similar (15)N abundances, and likely nitrogen (N) sources, in rainforests. Contrasting with the high N concentrations shared by temperate MH plants and their fungi, rainforest MH plants had lower N concentrations than AMF, suggesting differences in C/N of exchanged nutrients. We provide a framework for isotopic studies on AMF networks and suggest that MH plants in tropical and temperate regions evolved different physiologies to adapt in diverging environments. PMID- 21527423 TI - Identification of a novel gene, CIA6, required for normal pyrenoid formation in Chlamydomonas reinhardtii. AB - Chlamydomonas reinhardtii possesses a CO(2)-concentrating mechanism (CCM) that allows the alga to grow at low CO(2) concentrations. One common feature seen in photosynthetic organisms possessing a CCM is the tight packaging of Rubisco within the cell. In many eukaryotic algae, Rubisco is localized to the pyrenoid, an electron-dense structure within the chloroplast. In order to identify genes required for a functional CCM, insertional Bleomycin resistance (Ble(R)) mutants were generated and screened for growth on minimal medium under high CO(2) conditions (5% CO(2) in air) but only slow or no growth under very low CO(2) conditions (0.01% CO(2) in air). One mutant identified from this screen was named cia6. Physiological studies established that cia6 grows poorly on low levels of CO(2) and has an impaired ability to accumulate inorganic carbon. The inserted Ble(R) disrupted a gene encoding a protein with sequence similarity to proteins containing SET domain methyltransferase, although experiments using overexpressed CIA6 failed to demonstrate the methyltransferase activity. Electron microscopy revealed that the pyrenoid of cia6 mutant cells is highly disorganized. Complementation of the mutant restored the pyrenoid, the ability to grow under low-CO(2) conditions, and the ability to concentrate inorganic carbon. Quantitative reverse transcription-polymerase chain reaction data from a low CO(2) induction time-course experiment demonstrated that the up-regulation of several CCM components is slower in cia6 compared with the wild type. This slow induction was further confirmed at the protein level using western blots. These results indicated that CIA6 is required for the formation of the pyrenoid and further supported the notion that the pyrenoid is required for a functional CCM in C. reinhardtii. PMID- 21527424 TI - Regulatory hotspots are associated with plant gene expression under varying soil phosphorus supply in Brassica rapa. AB - Gene expression is a quantitative trait that can be mapped genetically in structured populations to identify expression quantitative trait loci (eQTL). Genes and regulatory networks underlying complex traits can subsequently be inferred. Using a recently released genome sequence, we have defined cis- and trans-eQTL and their environmental response to low phosphorus (P) availability within a complex plant genome and found hotspots of trans-eQTL within the genome. Interval mapping, using P supply as a covariate, revealed 18,876 eQTL. trans-eQTL hotspots occurred on chromosomes A06 and A01 within Brassica rapa; these were enriched with P metabolism-related Gene Ontology terms (A06) as well as chloroplast- and photosynthesis-related terms (A01). We have also attributed heritability components to measures of gene expression across environments, allowing the identification of novel gene expression markers and gene expression changes associated with low P availability. Informative gene expression markers were used to map eQTL and P use efficiency-related QTL. Genes responsive to P supply had large environmental and heritable variance components. Regulatory loci and genes associated with P use efficiency identified through eQTL analysis are potential targets for further characterization and may have potential for crop improvement. PMID- 21527425 TI - Willingness to Take a Free Home HIV Test and Associated Factors among Internet Using Men Who Have Sex with Men. AB - OBJECTIVES: Online HIV prevention studies have been limited in their ability to obtain biological specimens to measure study outcomes. We describe factors associated with willingness of men who have sex with men (MSM) to take a free home HIV test as part of an online HIV prevention study. METHODS: Between March and April 2009, we interviewed 6163 HIV-negative MSM and assessed the willingness to test for HIV infection using a home collection kit. RESULTS: Men reported being very likely (3833; 62%) or likely (1236; 20%) to accept a home HIV test as part of an online HIV prevention study. The odds of being willing to home test were higher for men who were offered incentives of $10 or $25, were black, had unprotected anal intercourse in the past 12 months, and were unaware of their HIV status. CONCLUSIONS: Home testing offered as part of online HIV prevention research is acceptable overall and in important subgroups of high-risk MSM. PMID- 21527426 TI - Adaptation of the Tokuyasu method for the ultrastructural study and immunogold labelling of filamentous fungi. AB - The study of filamentous fungi is fundamental not only to extend their biotechnological applications, but also to develop new drugs to fight pathological species. Morphological analyses are particularly relevant when investigating their development and differentiation. The need to maintain the orientation of hypahe and the presence of a cell wall, which hampers the sample infiltration with cryoprotectants and other reagents necessary to preserve the cell ultrastructure, creates difficulties with the use of electron microscopy (EM). Here, we present an immunoelectron microscopy (IEM) procedure that combines the Tokuyasu protocol adapted to yeast and the flat-embedding technique. While the first method leads to a fine resolution of the ultrastructure of Aspergillus nidulans because of both the cell wall permeabilization and the negative membrane coloration, the second permits us to preserve the spatial distribution of the hypahe of this fungus. The presented data demonstrate the advantages of this combination and the unprecedented potential of this relatively simple and rapid protocol in resolving the morphology of filamentous fungi and performing localization studies. PMID- 21527427 TI - The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response. AB - The discovery of a pharmacological treatment for phenylketonuria (PKU) raised new questions about function and dysfunction of phenylalanine hydroxylase (PAH), the enzyme deficient in this disease. To investigate the interdependence of the genotype, the metabolic state (phenylalanine substrate) and treatment (BH(4) cofactor) in the context of enzyme function in vitro and in vivo, we (i) used a fluorescence-based method for fast enzyme kinetic analyses at an expanded range of phenylalanine and BH(4) concentrations, (ii) depicted PAH function as activity landscapes, (iii) retraced the analyses in eukaryotic cells, and (iv) translated this into the human system by analyzing the outcome of oral BH(4) loading tests. PAH activity landscapes uncovered the optimal working range of recombinant wild type PAH and provided new insights into PAH kinetics. They demonstrated how mutations might alter enzyme function in the space of varying substrate and cofactor concentrations. Experiments in eukaryotic cells revealed that the availability of the active PAH enzyme depends on the phenylalanine-to-BH(4) ratio. Finally, evaluation of data from BH(4) loading tests indicated that the patient's genotype influences the impact of the metabolic state on drug response. The results allowed for visualization and a better understanding of PAH function in the physiological and pathological state as well as in the therapeutic context of cofactor treatment. Moreover, our data underscore the need for more personalized procedures to safely identify and treat patients with BH(4) responsive PAH deficiency. PMID- 21527428 TI - Intensive care unit palliative medicine: some issues-part II. PMID- 21527429 TI - Sexuality in patients with advanced cancer: a prospective study in a population admitted to an acute pain relief and palliative care unit. AB - The aim of this study was to characterize sexuality attitudes and feelings in a larger sample of patients with advanced cancer in comparison with their previous status before diagnosis. Of the 100 patients randomized, 65 patients answered to all the questions included in the questionnaire. Of these 65, 25 patients were male and 40 were female, with a mean Karnofsky of 58 (range 40-70) and a mean well-being sensation of 5.67 (range 2-10). In all, 60% of patients did not feel to be less attractive after disease, 30% of patients a little, and only 10% very much. Most patients (86.4%) considered important to talk about sexuality and to face such an issue with skilled people. About half of the patients (47%) reported that sexuality was very important for psychological well-being. Only 7.6% of patients had a good sexual intercourse, 15.2% had a light activity, 39.4% had an insufficient activity, and 37.8% did not have any activity. A significant relationship was observed with age (0.002), Karfnosky status (P = .024), and well being (P = .004). Only 12.1% of patients had a good sexual satisfaction, 12.1% experienced a mild satisfaction, 30.3% had insufficient satisfaction, and 45.5% had no sexual satisfaction. The difference was significant (P < .001). A significant relationship was observed with age (.047), Karfnosky status (P = .001), and well-being (P = .009). Only 3% of patients had a good frequency, 7.6% had a mild frequency, 37.9% had a limited frequency, and 51.5% had no sexual intercourses (P = .01). Emotional aspects maintained a relevant role in sexuality, as in 50% of patients these aspects were very important and for 12.1% important. Despite sexual activities decreased after the development of cancer, most patients considered important to talk about sexuality and to face such an issue with some experienced operators. Moreover, some patients were still able to maintain a sufficient sexual activity, in terms of quality and quantity. The emotional aspects had a relevant role in sexuality, possibly as a surrogate of impeded physical activity. The data gathered from this survey reveal how much sexuality continues to be present even though in different formality (satisfaction during the relationships) and different times (frequency of the relationships) in the life of the patients with advanced cancer. PMID- 21527430 TI - Precious moments. PMID- 21527431 TI - Adolescent optimistic bias toward HIV/AIDS in Seoul, South Korea. AB - The reported rates of HIV/AIDS cases and risky sexual behaviors have increased among adolescents in South Korea. This study reports the presence, impact, and development of optimistic bias toward HIV/AIDS in Korean adolescents. Survey data from 2996 participants were randomly collected from 8 high school and 8 middle school students in Seoul, South Korea. This study found that Korean high and middle school students had greater optimistic bias toward HIV/AIDS compared with their peers (P = .000). Involvement (r = -0.19; P < .01) decreased optimistic bias, whereas self-esteem (r = 0.13; P < .01) and self-control (r = 0.22; P < .01) increased it. Univariate analysis results indicated that gender and academic performance significantly influenced optimistic bias. However, according to hierarchical multiple regression, this significance was lost, and involvement, self-esteem, and self-control exerted a greater effect. Equipping Korean adolescents with involvement, awareness, and tailored interventions will reduce optimistic bias and yield greater protection against HIV/AIDS. PMID- 21527432 TI - Prevalence of metabolic syndrome and associated risk factors among Korean adolescents: analysis from the Korean national survey. AB - The aim of this study was to estimate the prevalence of metabolic syndrome (MS) and to identify the associated risk factors of MS among Korean adolescents. A total of 606 adolescents aged 12 to 18 years from the third Korea National Health and Nutrition Examination Survey (KNHNES) in 2005 participated in a community based and cross-sectional survey through face-to-face interviews. The authors defined pediatric MS using the modified National Cholesterol Educational Program Adult Treatment Panel III. The overall weighted prevalence of MS in Korean adolescents was 13.0% (15.4% boys, 10.0% girls). In multivariate logistic regression analysis, boys, adolescents with body mass index (BMI) greater than the 85th percentile, and adolescents who watched TV for more than 2 hours per day were significantly more likely to have MS. These findings suggest that lifestyle modification focusing on weight control by increasing physical activity is important for the prevention of MS in adolescents. PMID- 21527433 TI - Working-class Filipino women's perspectives on factors that facilitate or hinder prenatal micronutrients supplementation to prevent congenital anomalies. AB - The study was conducted to plan for a community-health campaign to inform working class Filipinos about the causes and prevention of orofacial clefting. Prenatal micronutrients may play a role in preventing orofacial clefting. Therefore, women's practices and perspectives on barriers to and facilitators of micronutrient supplementation were elicited. A total of 43 women and 22 health care workers were interviewed. Barriers to taking supplements included side effects, late prenatal care, the view that micronutrients are medications, inadequate supply, and health care workers who were unaware that prenatal vitamin supplements prevent congenital anomalies. The main facilitator was women's understanding that prenatal micronutrients improve the physical well-being of both mother and child. Given that women view having healthy babies as a reason to take micronutrients and that the health care workers lacked knowledge related to the use of micronutrients to prevent congenital anomalies, uptake of prenatal micronutrient supplementation programs may improve by specifically promoting the health benefit of preventing congenital anomalies. PMID- 21527434 TI - Promoting contraceptive use more effectively among unmarried male migrants in construction sites in China: a pilot intervention trial. AB - Poor sexual and reproductive health status has been reported among rural-to-urban migrants in China. Therefore, some effective and feasible interventions are urgently needed. The authors developed a workplace-based intervention to compare 2 young labor migrant service packages (A and B) on the knowledge, attitude related to contraception, and contraceptive use among unmarried male migrants in Chengdu. Fourteen construction sites were randomly assigned to either of the 2 intervention packages. Interventions were completed in 3 months, and data were collected in 2 rounds independently (before and after interventions). After the intervention, the median scores for knowledge and attitude in migrants in package B were significantly higher than in migrants in package A. Although migrants in both packages increased use of condom, the increase was pronounced in migrants in package B, with odds ratio (OR) = 9.65 (95% confidence interval [CI] = 1.41 66.28). The rate of unwanted pregnancies was reduced more significantly in migrants in package B than in migrants in package A (OR = 0.16; 95%CI = 0.03 0.45). Unmarried male migrants who received the comprehensive intervention (package B) were more willing to use condoms and avoid unwanted pregnancies effectively. PMID- 21527435 TI - Impact of the 1994 alcohol production and sales deregulation policy on traffic crashes and fatalities in Japan. AB - INTRODUCTION: . Many studies have demonstrated a strong relationship between alcohol availability and traffic crashes involving alcohol-impaired drivers. The present analysis focuses on the evaluation of the impact of alcohol availability on the Japanese population by comparing fatal and nonfatal motor vehicle crash rates before and after implementation of the alcohol deregulation policy in 1994. Participants and method. Poisson regression with robust standard error was used to model the before-to-after change in incidence rate ratios (IRRs) in the population. To control for potential confounders, per capita alcohol consumption, unemployment rate, and vehicle miles travelled (VMT) were also added to the model. The exponents of the fitted coefficients are equivalent to the IRRs. RESULTS: . Implementation of the policy deregulating alcohol sales and production did not appear to increase traffic fatalities and other traffic crashes in Japan. In the overall study results, nighttime fatalities were reduced statistically significantly by 6% since the implementation of the alcohol deregulation policy in 1994. Discussion. Contrary to previous research, the findings of this study demonstrated lower rates of fatalities and higher compliance with alcohol-related driving legislation. Further well-designed, nonaligned studies on alcohol availability and traffic fatalities in other countries are urgently needed. PMID- 21527436 TI - Identification of stable endogenous reference genes for real-time PCR in the human fetal gonad using an external standard technique. AB - Measurement of tissue mRNA transcript levels is critically dependent upon the normalization strategy used. For real-time polymerase chain reaction (PCR) (RT PCR) this commonly depends upon identification of stable (non-variable) endogenous reference genes, with housekeeping genes (HKGs) the most commonly used. In this report we describe the use of an external mRNA standard to identify stable HKGs in the human fetal gonad. Total RNA was extracted from second trimester human fetal gonads and a standard amount of luciferase mRNA was added at the start of the extraction process. Levels of luciferase were then measured relative to each of seven HKGs (SDHA, TBP, B2M, PMM1, SFRS4, HMBS and UBC) by RT PCR. When normalized to tissue weight, HKG expression was constant across fetal ages. Measurement of overall variation in transcript expression showed that PMM1 was the most stable HKG in the ovary while B2M was most stable in the testis. Re analysis of the data using GeNorm and NormFinder algorithms showed that two of the top three most stable HKGs were the same using all three methods. This study describes a method for identification of endogenous, stable reference genes for RT-PCR studies of transcript expression levels which is objective and not dependent on prior assumptions of HKG expression. This technique is likely to be applicable to most tissues and, in this case, identifies suitable HKGs for studies into human gonadal development. PMID- 21527437 TI - Systems biology approaches to heart development and congenital heart disease. AB - Even though the foundation of systems biology approaches to cardiac function was led more than fifty years ago, there has been slow progression over the last few decades. Systems biology studies were mainly focused on lower organisms, frequently on yeast. With the boost of high-throughput technologies, systems level analyses, building one backbone of systems biology, started to complement the single-gene focus in the fields of heart development and congenital heart disease. A challenge is to bring together the many uncovered molecular components driving heart development and eventually to establish computational models describing this complex developmental process. Congenital heart diseases represent overlapping phenotypes, reflecting the modularity of heart development. The aetiology of the majority of congenital heart disease is still unknown, and it is suggestive that understanding the biological network underlying heart development will enhance our understanding for its alteration. This review provides an overview of the framework for systems biology approaches focusing on the developing heart and its pathology. Recent methodological developments building the basis for future studies are highlighted and the knowledge gained is specified. PMID- 21527439 TI - Diabetic papillopathy: an uncommon cause of bilateral optic disc swelling. PMID- 21527438 TI - N-glycosylation controls trafficking, zymogen activation and substrate processing of proprotein convertases PC1/3 and subtilisin kexin isozyme-1. AB - The limited proteolysis of proteins by the proprotein convertases (PCs) is a common means of producing bioactive proteins or peptides. The PCs are associated with numerous human pathologies and their activity can be reduced through the use of specific inhibitors. Here, we demonstrate an alternative approach to inhibiting PCs by altering their N-glycosylation. Through site-directed mutagenesis, we show that the convertase PC1/3 contains two N-glycans, only one of which is critical for its prosegment cleavage. The exact structure of PC1/3 N glycans does not significantly affect its zymogen activation within endocrine cells, but glycosylation of Asn(146) is critical. Processing of the PC1/3's substrate proopiomelanocortin (POMC) was used in a cell-based assay to screen a collection of 45 compounds structurally related to known glycosidase inhibitors. Two 5-thiomannose-containing disaccharide derivatives were discovered to block PC1/3 and POMC processing into the analgesic peptide beta-endorphin. These compounds also reduced the zymogen activation of the convertase subtilisin kexin isozyme-1 (SKI-1), blocked the processing of its substrate the sterol regulatory element-binding protein SREBP-2 and altered its glycosylation. Thus, modification of PC glycosylation may also be a means of blocking their activity, an effect which, in the case of SKI-1, may be of possible therapeutic use since SREBP-2 regulates sterol levels including cholesterol biosynthesis and its metabolism. PMID- 21527440 TI - Identification of critical coronary artery disease. PMID- 21527441 TI - Basal cell carcinoma with a large central facial defect. PMID- 21527442 TI - Improvement of ultrasound appearances in carpal tunnel syndrome following treatment with oral corticosteroids. PMID- 21527443 TI - Tales from an academic RNAi screening facility; FAQs. AB - RNAi technology is now a well-established and widely employed research technique that has been adopted by many researchers for use in large-scale screening campaigns. Here, we offer our experience of genome-wide siRNA screening from the perspective of a facility providing screening as a service to a wide range of researchers with diverse interests and approaches. We have experienced the emotional rollercoaster of screening from the exuberant early promise of a screen, the messy reality of the data through to the recognition of screen data as a potential information goldmine. Here, we use some of the questions we most frequently encounter to highlight the initial concerns of many researchers embarking on a siRNA screen and conclude that an informed view of what can be reasonably expected from a screen is essential to the most effective implementation of the technology. Along the way, we suggest that for this area of research at least, either centralization of the resources or close and open collaboration between interested parties offers distinct advantages. PMID- 21527444 TI - Using impedance cardiography with postural change to stratify patients with hypertension. AB - BACKGROUND: Early detection of cardiovascular disease in patients with hypertension could initiate appropriate treatment to control blood pressure and prevent the progression of cardiovascular disease. OBJECTIVE: The goal of this study was to show how impedance cardiography waveform analysis with postural change can be used to detect subclinical cardiovascular disease in patients with high blood pressure. METHODS: Patients with high blood pressure had impedance cardiography data obtained in two positions, standing upright and supine. RESULTS: In 50 adults, impedance cardiography indicated that all patients had abnormal data, with 44 (88%) having multiple abnormalities. Impedance cardiography showed 32 (64%) had ventricular dysfunction, 48 (96%) had vascular load abnormalities, 34 (68%) had hemodynamic abnormalities, 2 (4%) had hypovolemia, and 3 (6%) had hypervolemia. CONCLUSIONS: Hypertensive patients have diverse cardiovascular abnormalities that can be quantified by impedance cardiography. By stratifying patients with ventricular, vascular, and hemodynamic abnormalities, treatment could be customized based on the abnormal underlying mechanisms with the potential to rapidly control blood pressure, prevent progression of cardiovascular disease, and possibly reverse remodeling. PMID- 21527445 TI - No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. AB - AIMS: In clopidogrel-treated patients undergoing coronary stenting, high on treatment platelet reactivity was linked to a higher risk of stent thrombosis (ST). Platelet response to clopidogrel is significantly influenced by genetic factors. Recently published findings showed a highly significant impact of a common polymorphism (Q192R) within the paraoxonase-1 (PON1) gene on clopidogrel treatment efficacy but no influence of the CYP2C19*2 genetic variant as previously demonstrated. The aim of this study was to assess the impact of the PON1 Q192R genotype in parallel to that of CYP2C19*2 on the antiplatelet effect of clopidogrel and the risk of ST in clopidogrel-treated patients. METHODS AND RESULTS: In 1524 patients undergoing percutaneous coronary intervention, ADP induced platelet aggregation was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. The clinical impact of genetic variants was investigated by comparing genotype frequencies of both genetic variants in a registry of 127 cases with early ST vs. an early ST-free control cohort (n = 1439). For PON1 Q192R genotypes, platelet aggregation values were similar across all genotype groups (P = 0.65). For CYP2C19*2 genotypes, significantly higher aggregation values were found in CYP2C19 wt/*2 and *2/*2 patients when compared with wt/wt allele carriers (P < 0.0001). Comparing genotype frequencies between ST cases and controls, no differences were observed for PON1 Q192R genotype distributions (P = 0.23), whereas the genotype distribution differed for CYP2C19*2 genotypes (P = 0.019). CONCLUSION: The PON1 Q192R genotype did not influence platelet response to clopidogrel or the risk of ST in clopidogrel-treated patients, whereas the CYP2C19*2 genotype impacted on both antiplatelet effect of clopidogrel and risk of coronary ST. PMID- 21527446 TI - Non-communicable diseases in sub-Saharan Africa: what we know now. AB - BACKGROUND: Sub-Saharan Africa (SSA) has a disproportionate burden of both infectious and chronic diseases compared with other world regions. Current disease estimates for SSA are based on sparse data, but projections indicate increases in non-communicable diseases (NCDs) caused by demographic and epidemiologic transitions. We review the literature on NCDs in SSA and summarize data from the World Health Organization and International Agency for Research on Cancer on the prevalence and incidence of cardiovascular diseases, diabetes mellitus Type 2, cancer and their risk factors. METHODS: We searched the PubMed database for studies on each condition, and included those that were community based, conducted in any SSA country and reported on disease or risk factor prevalence, incidence or mortality. RESULTS: We found few community-based studies and some countries (such as South Africa) were over-represented. The prevalence of NCDs and risk factors varied considerably between countries, urban/rural location and other sub-populations. The prevalence of stroke ranged from 0.07 to 0.3%, diabetes mellitus from 0 to 16%, hypertension from 6 to 48%, obesity from 0.4 to 43% and current smoking from 0.4 to 71%. Hypertension prevalence was consistently similar among men and women, whereas women were more frequently obese and men were more frequently current smokers. CONCLUSIONS: The prevalence of NCDs and their risk factors is high in some SSA settings. With the lack of vital statistics systems, epidemiologic studies with a variety of designs (cross sectional, longitudinal and interventional) capable of in-depth analyses of risk factors could provide a better understanding of NCDs in SSA, and inform health care policy to mitigate the oncoming NCD epidemic. PMID- 21527447 TI - Positive income shocks and accidental deaths among Cherokee Indians: a natural experiment. AB - BACKGROUND: Several studies in low-income populations report the somewhat counterintuitive finding that positive income gains adversely affect adult health. The literature posits that receipt of a large portion of annual income increases, in the short term, risk-taking behaviour and/or the consumption of health-damaging goods. This work implies the hypothesis that persons with an unexpected gain in income will exhibit an elevated risk of accidental death-the fifth leading cause of death in the USA. We test this hypothesis directly by capitalizing on a natural experiment in which Cherokee Indians in rural North Carolina received discrete lump sum payments from a new casino. METHODS: We applied Poisson regression to the monthly count of accidental deaths among Cherokee Indians over 204 months spanning 1990-2006. We controlled for temporal patterns in accidental deaths (e.g. seasonality and trend) as well as changes in population size. RESULTS: As hypothesized, the risk of accidental death rises above expected levels during months of the large casino payments (relative risk = 2.62; 95% confidence interval = 1.54-4.47). Exploratory analyses of ethnographic interviews and behavioural surveys support that increased vehicular travel and consumption of health-damaging goods may account for the rise in accident proneness. CONCLUSIONS: Although long-term income gains may improve health in this population, our findings indicate that acute responses to large income gains, in the short term, increase risk-taking and accident proneness. We encourage further investigation of natural experiments to identify causal economic antecedents of population health. PMID- 21527448 TI - The health care costs of violence against women. AB - The aim of this study is to analyze the health care costs of violence against women. For the study, we used a register-based approach where we identified victims of violence and assessed their actual health care costs at individual level in a bottom-up analysis. Furthermore, we identified a reference population. We computed the attributable costs, that is, the excess health care costs for victims compared to an identified reference population of nonvictims. Only costs within the health care sector were included, that is, somatic and psychiatric hospital costs, costs within the primary health care sector and costs of prescription pharmaceuticals. We estimated the attributable health care costs of violence against women in Denmark, using a generalized linear model where health care costs were modeled as a function of age, childbirth, and exposure to violence. In addition we tested whether socioeconomic status, multiple episodes of violence, and psychiatric contacts had any impact on health care costs. We found that the health care costs were about ?1,800 higher for victims of violence than for nonvictims per year, driven mostly by higher psychiatric costs and multiple episodes of violence. PMID- 21527449 TI - Hidden communicative competence: case study evidence using eye-tracking and video analysis. AB - A facilitated communication (FC) user with an autism spectrum disorder produced sophisticated texts by pointing, with physical support, to letters on a letterboard while their eyes were tracked and while their pointing movements were video recorded. This FC user has virtually no independent means of expression, and is held to have no literacy skills. The resulting data were subjected to a variety of analyses aimed at describing the relationship between the FC user's looking and pointing behaviours, in order to make inferences about the complex question of 'authorship'. The eye-tracking data present a challenge to traditional 'facilitator influence' accounts of authorship, and are consistent with the proposition that this FC user does indeed author the sophisticated texts that are attributed to him; he looks for longer at to-be-typed letters before typing them, and looks ahead to subsequent letters of words before the next letter of the word is typed. PMID- 21527452 TI - GP is accused of blurring roles of landlord and doctor. PMID- 21527454 TI - Psychiatrist is accused of undermining stability of 14 year old. PMID- 21527455 TI - Angiotensin receptor blockers and cardiovascular outcomes. PMID- 21527456 TI - Advising on travel during pregnancy. PMID- 21527457 TI - A theme issue in 2011 on unpublished evidence. PMID- 21527458 TI - General practitioner commissioning groups. PMID- 21527462 TI - Levothyroxine dose and fractures in older adults. PMID- 21527461 TI - Levothyroxine dose and risk of fractures in older adults: nested case-control study. AB - OBJECTIVE: To quantify the effect of levothyroxine dose on risk of fractures in older adults. DESIGN: Nested case-control study. SETTING: Population based health databases, Ontario, Canada. PARTICIPANTS: Adults aged 70 or more prescribed levothyroxine between 1 April 2002 and 31 March 2007 and followed for fractures until 31 March 2008. Cases were cohort members admitted to hospital for any fracture, matched with up to five controls from within the cohort who had not yet had a fracture. MAIN OUTCOME MEASURE: Primary outcome was fracture (wrist or forearm, shoulder or upper arm, thoracic spine, lumbar spine and pelvis, hip or femur, or lower leg or ankle) in relation to levothyroxine use (current, recent past, remote). Risk among current users was compared between those prescribed high, medium, and low cumulative levothyroxine doses in the year before fracture. RESULTS: Of 213,511 prevalent levothyroxine users identified, 22,236 (10.4%) experienced a fracture over a mean 3.8 years of follow-up, 18,108 (88%) of whom were women. Compared with remote levothyroxine use, current use was associated with a significantly higher risk of fracture (adjusted odds ratio 1.88, 95% confidence interval 1.71 to 2.05), despite adjustment for numerous risk factors. Among current users, high and medium cumulative doses (>0.093 mg/day and 0.044 0.093 mg/day) were associated with a significantly increased risk of fracture compared with low cumulative doses (<0.044 mg/day): 3.45 (3.27 to 3.65) and 2.62 (2.50 to 2.76), respectively. CONCLUSION: Among adults aged 70 or more, current levothyroxine treatment was associated with a significantly increased risk of fracture, with a strong dose-response relation. Ongoing monitoring of levothyroxine dose is important to avoid overtreatment in this population. PMID- 21527463 TI - Pituitary apoplexy with third cranial nerve palsy after off-pump coronary artery bypass grafting. AB - We present a rare case with pituitary apoplexy after three-vessel off-pump coronary artery bypass grafting (OPCAB). The patient exhibited right third cranial nerve palsy; ptosis of the right eye with completely dilated pupils and a loss of reflex to light after the effects of anesthesia completely subsided. The patient underwent endonasal transsphenoidal resection of the pituitary gland 14 days after the OPCAB, and the symptoms completely disappeared 40 days after the resection. OPCAB is recommended for patients with known pituitary tumor who require coronary artery bypass grafting, but OPCAB also has a risk of pituitary apoplexy. The present case report is the first to describe pituitary apoplexy after OPCAB. Pituitary apoplexy is a very rare complication after cardiac surgery, but cardiac surgeons should know the disease and quickly diagnose it to avoid severe brain injury. PMID- 21527464 TI - Health care disparity in the care of the vascular patient. AB - Peripheral vascular care continues to mature into a well-developed multidisciplinary subspecialty. Continued growth as a collaborative subspecialty will require delivering the highest quality medical care to all Americans. US census projections predict that greater than one half of all American citizens will identify themselves as ethnic or racial minorities by 2050. Evolving research has established significant health care disparity, or preventable differences in disease incidence and vascular procedure outcomes associated with socioeconomic, gender, language, geographic, racial, and ethnic variables. As a necessary step in the evolution of vascular care, practitioners, societies, and vascular departments should begin to adopt proven practices that enhance our ability to deliver equal care to an increasingly diverse American population. PMID- 21527465 TI - Successful total robotic-assisted aortobifemoral bypass for treatment of complicated aortoiliac occlusive disease. AB - Laparoscopic aortobifemoral bypass (AFB) for aortoiliac occlusive disease (AIOD) is a durable, minimally invasive procedure with comparable long-term outcomes to conventional open AFB. However, laparoscopic AFB requires advance training in laparoscopy with prolong learning curve to accomplish infrarenal aortic dissection and vascular reconstruction to minimize aortic clamp time and leg ischemia time. We describe another minimally invasive technique of total robotic assisted AFB for extensive, complicated AIOD in 3 patients who are not endovascular candidate or have failed endoluminal approach previously. PMID- 21527466 TI - Stent-assisted coil embolization of an intraparenchymal renal artery aneurysm in a patient with neurofibromatosis. AB - True renal artery aneurysms are rare. They are generally asymptomatic, however, a few may present with hypertension, rupture, or renal dysfunction secondary to distal embolization. Indications for intervention include aneurysm of >= 2.0 cm in diameter, renovascular hypertension, enlarging aneurysm, associated dissection /rupture, and aneurysms in women of child-bearing age/ pregnancy. Endovascular therapy through coil embolization or stent graft exclusion is the recommended management. Coil embolization of the first and second order branch aneurysms is often associated with distal parenchymal loss and current stent graft technology prohibits use of these endoprostheses in the branch renal arteries. In this report, we describe successful stent-assisted coil embolization of an intraparenchymal aneurysm while preserving the distal parenchyma in a young woman with Neurofibromatosis type 1. PMID- 21527467 TI - Longer time interval between carotid cross-clamping and shunting is associated with increased 30-day stroke and death rate. AB - BACKGROUND: The benefit of carotid endarterectomy (CEA) in patients with a significant (>70%) (a)symptomatic stenosis has been proven thoroughly in major trials. It is unknown whether, after cross-clamping the carotid artery, the time interval between determination that a shunt is needed and the actual functioning of the shunt, defined as the need for shunt-to-shunt time (NST), influences 30 day morbidity and mortality rate after CEA. METHODS: Experienced vascular surgeons performed 851 CEAs with a selective shunting protocol based on perioperative transcranial Doppler measurement and electroencephalographic findings, and data were analyzed retrospectively. The study included 156 shunted patients. RESULTS: Longer NST was associated with an increase in the 30-day stroke/death rate. A binary logistic regression model was used to determine a 2 tailed P value of .004 and an odds ratio of 1.5/min increase of the NST. There was no influence on stroke-death rate of gender, age, symptomatic or asymptomatic stenosis, the use of a patch or not, or the number of periprocedural microembolic signals. CONCLUSION: If CEA is performed with a selective shunting protocol, a longer NST increases the 30-day stroke/death rate. These results support a strong recommendation that shunt placement should be as quick as possible. PMID- 21527468 TI - Incomplete deployment of the Vena Tech LP filter--case series and concerns. AB - The Vena Tech LP vena cava filter (B Braun, Evanston, Illinois) has been FDA approved since 2001 and is a permanent vena cava filtration device. It replaced the previous Vena tech LGM filter also manufactured by B Braun. The LGM filter had 2 case series reporting a high incidence of incomplete deployment of the filter, especially when placed from a jugular approach. Design changes were made to this device and the LP filter introduced. The LP filter has also been reported to have incompletely deployed both in peer reviewed literature as well as the FDA MAUDE website. We present here 3 cases of incomplete deployment of the Vena Tech LP filter and review the cases previously described as well as attempt to present possible etiologies for incomplete deployment. PMID- 21527469 TI - The genome sequence of Bacillus subtilis subsp. spizizenii W23: insights into speciation within the B. subtilis complex and into the history of B. subtilis genetics. AB - The genome sequence of Bacillus subtilis subsp. spizizenii W23 has been determined. The sequence strongly suggests that W23 is a direct descendant of B. subtilis ATCC 6633. W23 shares a 3.6 Mb core genome with the intensively studied model organism B. subtilis subsp. subtilis 168, and gene order within this core has been strongly conserved. Additionally, the W23 genome has 157 accessory (that is, non-core) genome segments that are not found in 168, while the 168 genome has 141 segments not found in W23. The distribution of sequences similar to these accessory segments among other genomes of the B. subtilis species complex shows that those sequences having entered into the phylogeny of the complex more recently tend to be larger and more AT-rich than those having entered earlier. A simple model can account for these observations, in which parasitic or symbiotic DNAs are transferred into the genome and then are reduced in size and modified in base composition during speciation. PMID- 21527470 TI - Characterization of the Porphyromonas gingivalis conjugative transposon CTnPg1: determination of the integration site and the genes essential for conjugal transfer. AB - In our previous study, extensive genomic rearrangements were found in two strains of the Gram-negative anaerobic bacterium Porphyromonas (Por.) gingivalis, and most of these rearrangements were associated with mobile genetic elements such as insertion sequences and conjugative transposons (CTns). CTnPg1, identified in Por. gingivalis strain ATCC 33277, was the first complete CTn reported for the genus Porphyromonas. In the present study, we found that CTnPg1 can be transferred from strain ATCC 33277 to another Por. gingivalis strain, W83, at a frequency of 10(-7) to 10(-6). The excision of CTnPg1 from the chromosome in a donor cell depends on an integrase (Int; PGN_0094) encoded in CTnPg1, whereas CTnPg1 excision is independent of PGN_0084 (a DNA topoisomerase I homologue; Exc) encoded within CTnPg1 and recA (PGN_1057) on the donor chromosome. Intriguingly, however, the transfer of CTnPg1 between Por. gingivalis strains requires RecA function in the recipient. Sequencing analysis of CTnPg1-integrated sites on the chromosomes of transconjugants revealed that the consensus attachment (att) sequence is a 13 bp sequence, TTTTCNNNNAAAA. We further report that CTnPg1 is able to transfer to two other bacterial species, Bacteroides thetaiotaomicron and Prevotella oralis. In addition, CTnPg1-like CTns are located in the genomes of other oral anaerobic bacteria, Porphyromonas endodontalis, Prevotella buccae and Prevotella intermedia, with the same consensus att sequence. These results suggest that CTns in the CTnPg1 family are widely distributed among oral anaerobic Gram-negative bacteria found in humans and play important roles in horizontal gene transfer among these bacteria. PMID- 21527471 TI - Role of fimV in type II secretion system-dependent protein secretion of Pseudomonas aeruginosa on solid medium. AB - Although classical type II secretion systems (T2SSs) are widely present in Gram negative bacteria, atypical T2SSs can be found in some species. In Pseudomonas aeruginosa, in addition to the classical T2SS Xcp, it was reported that two genes, xphA and xqhA, located outside the xcp locus were organized in an operon (PaQa) which encodes the orphan PaQa subunit. This subunit is able to associate with other components of the classical Xcp machinery to form a functional hybrid T2SS. In the present study, using a transcriptional lacZ fusion, we found that the PaQa operon was more efficiently expressed (i) on solid LB agar than in liquid LB medium, (ii) at 25 degrees C than at 37 degrees C and (iii) at an early stage of growth. These results suggested an adaptation of the hybrid system to particular environmental conditions. Transposon mutagenesis led to the finding that vfr and fimV genes are required for optimal expression of the orphan PaQa operon in the defined growth conditions used. Using an original culturing device designed to monitor secretion on solid medium, the ring-plate system, we found that T2SS-dependent secretion of exoproteins, namely the elastase LasB, was affected in a fimV deletion mutant. Our findings led to the discovery of an interplay between FimV and the global regulator Vfr triggering the modulation of the level of Vfr and consequently the modulation of T2SS-dependent secretion on solid medium. PMID- 21527472 TI - Interaction of Bacteroides fragilis and Bacteroides thetaiotaomicron with the kallikrein-kinin system. AB - Many bacterial pathogens interfere with the contact system (kallikrein-kinin system) in human plasma. Activation of this system has two consequences: cleavage of high-molecular-mass kininogen (HK) resulting in release of the potent proinflammatory peptide bradykinin, and initiation of the intrinsic pathway of coagulation. In this study, two species of the Gram-negative anaerobic commensal organism Bacteroides, namely Bacteroides fragilis and Bacteroides thetaiotaomicron, were found to bind HK and fibrinogen, the major clotting protein, from human plasma as shown by immunoelectron microscopy and Western blot analysis. In addition, these Bacteroides species were capable of activating the contact system at its surface leading to a significant prolongation of the intrinsic coagulation time and also to the release of bradykinin. Members of the genus Bacteroides have been known to act as opportunistic pathogens outside the gut, with B. fragilis being the most common isolate from clinical infections, such as intra-abdominal abscesses and bacteraemia. The present results thus provide more insight into how Bacteroides species cause infection. PMID- 21527473 TI - Overlap of replication rounds disturbs the progression of replicating forks in a ribonucleotide reductase mutant of Escherichia coli. AB - Ribonucleotide reductase (RNR) is the only enzyme specifically required for the synthesis of deoxyribonucleotides (dNTPs). Surprisingly, Escherichia coli cells carrying the nrdA101 allele, which codes for a thermosensitive RNR101, are able to replicate entire chromosomes at 42 degrees C under RNA or protein synthesis inhibition. Here we show that the RNR101 protein is unstable at 42 degrees C and that its degradation under restrictive conditions is prevented by the presence of rifampicin. Nevertheless, the mere stability of the RNR protein at 42 degrees C cannot explain the completion of chromosomal DNA replication in the nrdA101 mutant. We found that inactivation of the DnaA protein by using several dnaAts alleles allows complete chromosome replication in the absence of rifampicin and suppresses the nucleoid segregation and cell division defects observed in the nrdA101 mutant at 42 degrees C. As both inactivation of the DnaA protein and inhibition of RNA synthesis block the occurrence of new DNA initiations, the consequent decrease in the number of forks per chromosome could be related to those effects. In support of this notion, we found that avoiding multifork replication rounds by the presence of moderate extra copies of datA sequence increases the relative amount of DNA synthesis of the nrdA101 mutant at 42 degrees C. We propose that a lower replication fork density results in an improvement of the progression of DNA replication, allowing replication of the entire chromosome at the restrictive temperature. The mechanism related to this effect is also discussed. PMID- 21527475 TI - Tuberculosis in goats on a farm in Ireland: epidemiological investigation and control. AB - This paper describes an outbreak of tuberculosis (TB) caused by Mycobacterium bovis in a dairy goat herd on a farm in Ireland, where 66.3 per cent of the herd tested positive to the single intradermal comparative tuberculin test (SICTT) at initial detection. An epidemiological investigation was conducted to determine the origin of the outbreak, considering issues such as animal movements and herd management practices. Infection was introduced with a consignment of goats, as determined by the variable number tandem repeat profile. Infection was eradicated using a test and cull programme involving the SICTT, the interferon-gamma assay and a multiplex immunoassay (Enferplex TB). PMID- 21527474 TI - Repression of N-glycosylation triggers the unfolded protein response (UPR) and overexpression of cell wall protein and chitin in Aspergillus fumigatus. AB - Aspergillus fumigatus is the most common airborne fungal pathogen, causing fatal invasive aspergillosis in immunocompromised patients. The crude mortality is 60 90 % and remains around 29-42 % even with treatment. The main reason for patient death is the low efficiency of the drug therapies. As protein N-glycosylation is involved in cell wall biogenesis in A. fumigatus, a deeper understanding of its role in cell wall biogenesis will help to develop new drug targets. The Afstt3 gene encodes the essential catalytic subunit of oligosaccharyltransferase, an enzyme complex responsible for the transfer of the N-glycan to nascent polypeptides. To evaluate the role of N-glycosylation in cell wall biosynthesis, we constructed the conditional mutant strain CPR-stt3 by replacing the endogenous promoter of Afstt3 with the nitrogen-dependent niiA promoter. Repression of the Afstt3 gene in the CPR-stt3 strain led to a severe retardation of growth and a slight defect in cell wall integrity (CWI). One of the most interesting findings was that upregulation of the cell wall-related genes was not accompanied by an activation of the MpkA kinase, which has been shown to be a central element in the CWI signalling pathway in both Saccharomyces cerevisiae and A. fumigatus. Considering that the unfolded protein response (UPR) was found to be activated, which might upregulate the expression of cell wall protein and chitin, our data suggest that the UPR, instead of the MpkA-dependent CWI signalling pathway, is the major compensatory mechanism induced by repression but not abolition of N glycosylation in A. fumigatus. Our finding is a key to understanding the complex compensatory mechanisms of cell wall biosynthesis and may provide a new strategy for drug development. PMID- 21527476 TI - Intradural vertebral disc herniation in a dog. PMID- 21527477 TI - Effect of eprinomectin treatment on milk yield and quality in dairy cows in South Tyrol, Italy. AB - The effect of treatment with eprinomectin on milk yield, milk composition and somatic cell counts (SCCs) was studied in 105 dairy cows located on seven farms in South Tyrol, Italy. On each farm, half of the animals were treated with eprinomectin and the other half were used as an untreated control group. Three test day records per animal were obtained before treatment (days -117, -75 and 33) and another three test day records were obtained after treatment (days 22, 62 and 131). Test day records comprised milk yield, milk composition, SCC and days in milk. On the day of treatment, blood samples and faecal samples were taken for parasitological analysis. Cows with positive faecal egg counts yielded less milk. A significant effect of eprinomectin on milk yield was observed after treatment and was most pronounced on the second and the third test days after treatment (+1.90 kg [P=0.002] and +2.63 kg [P<0.001], respectively). Furthermore, a significant decrease in SCC was observed on the second test day after treatment. PMID- 21527478 TI - Do testimonials improve parental perceptions and participation in parenting programmes? Results of two studies. AB - Despite the effectiveness of parenting interventions in both prevention and intervention with child emotional and behavioural problems, parental participation in evidence-based programmes remains low, limiting the benefit to the population. This research examines a new population parental engagement strategy for parenting programmes using video testimonials via two studies. The first study compared the use of parent versus expert testimonials, against a no testimonial condition on parenting programme evaluations with 70 parents. The second study compared expert testimonials which were framed in a fear or non-fear context, with 73 parents. Results indicated no significant effect of source of testimonial or content of testimonial on parental evaluations of the programme or behavioural outcomes. Trends favoured expert testimonials over parent testimonials. Implications for population level engagement strategies are discussed. PMID- 21527481 TI - Kennel Club's dog health group highlights the progress so far. PMID- 21527482 TI - Introducing the BSAVA's postgraduate certificates. PMID- 21527484 TI - Importing medicines: the VMD's special import and special treatment schemes. PMID- 21527485 TI - Assessing the risk of disease introduction in imports. PMID- 21527486 TI - Answers to some common questions on serum protein electrophoresis. PMID- 21527487 TI - Bovine mycoplasmosis: silent and deadly. AB - The first international conference on bovine mycoplasmosis, held in Saskatoon, Canada, in 2009, marked an official recognition of the importance of mycoplasmas in bovine respiratory disease, mastitis, arthritis and other disorders. Furthermore, bovine mycoplasmosis has been identified as a major emerging infectious disease by the European Community 7th Framework Programme under the EMIDA ERA-NET, which is funding a three-year study into the development of improved diagnosis and control of bovine mycoplasmosis involving the UK, Germany, Italy and Israel. These developments coincide with the publication of the complete sequence of the Mycoplasma bovis genome, which offers fresh insight into the properties of this tiny wall-less bacterium. With this in mind, it is an appropriate time to review our knowledge of cattle diseases caused by mycoplasmas. PMID- 21527488 TI - Rehabilitation medicine: Provision of canine hydrotherapy in the UK. PMID- 21527489 TI - Animal welfare: Cow welfare and 'quarter culling'. PMID- 21527491 TI - Bovine TB: Preventing TB fraud. PMID- 21527492 TI - Dangerous dogs: Handling and restraining aggressive dogs. PMID- 21527493 TI - Binary system thermodynamics to control pore architecture of PCL scaffold via temperature-driven phase separation process. AB - The use of scaffold-aided strategies for the regeneration of biological tissues requires the fulfilment of an accurate architectural design, that is, micro and macrostructure, with the final goal of realizing architectures to adopt as guidance for those cell activities specific to the formation of novel tissues. Here, highly porous scaffolds made up of biodegradable poly(epsilon-caprolactone) (PCL) have been realized by thermally induced phase separation (TIPS). Two different polymer/solvent systems, derived by the dissolution of PCL in dioxane and DMSO respectively, were investigated. The aim was to demonstrate the high potential of TIPS technique, in imprinting specific pore features to the polymer matrices, by a conscious selection of polymer/solvent systems. The investigation of pore architecture by SEM/mercury intrusion porosimetry/image analyses, firstly allow to detect remarkable variations in porosity (from 92% to 78%,) and pore sizes, ranging from micro-scale (ca 10 um) to macro-scale (greater than 100 um) as a function of the used polymer/solvent systems. Moreover, experimental and theoretical evidences referred to scaffold shaped in custom-made molds--a thin Teflon ring between two copper plates--allow exploring how the sensitivity of polymer solution features (i.e., crystallinity, thermal inertia) to the cooling temperature can affect the alignment of polymer phases and, ultimately, scaffold pore anisotropy. Analytical results supported by preliminary biological studies demonstrate the higher ability of PCL/dioxane solution to promote the formation of aligned pores which provide a morphological guidance to cell advance during the preliminary stage of culture. These findings, taken as a whole, put the basis for a better informed regeneration of structurally complex tissues based on the modeling of scaffold micro and macro-architecture by thermodynamic forces. PMID- 21527494 TI - Setting properties and biocompatibility of dicalcium silicate with varying additions of tricalcium aluminate. AB - This study sought to prepare biphasic mixtures by adding tricalcium aluminate (Ca3Al2O6) into dicalcium silicate (Ca2SiO4) and to evaluate the effect of Ca3Al2O6 on setting properties and biocompatibility of the Ca2SiO4/Ca3Al2O6 mixtures as compared to pure Ca2SiO4. The results indicated that the addition of Ca3Al2O6 into Ca2SiO4 reduced the setting time and improved the compressive strength. Furthermore, Ca2SiO4/Ca3Al2O6 mixtures were bioactive and biocompatible, and had a stimulatory effect on the L929 cell growth when the content of Ca3Al2O6 was below 10%. Therefore, the mixtures with 10% Ca3Al2O6 produced the best compromise between setting and in vitro biological properties. PMID- 21527495 TI - Improved synthesis of hyaluronic acid hydrogel and its effect on tissue augmentation. AB - HA-HMDA hydrogels were developed by direct amide bond formation between the carboxyl groups of hyaluronic acid (HA) and hexamethylenediamine (HMDA) with an optimized carboxyl group modification in the preliminary experiment. However, these HA-HMDA hydrogels transformed into an unstable liquid form after steam sterilization, and were problematic for application to actual dermal filler. A new method to overcome the problem of the previously developed HA-HMDA hydrogels is to prepare them by adjusting the pH in this study. Not only are these improved HA-HMDA hydrogels prepared with lower amounts of cross-linking and activation agents compared to the previously developed hydrogels, but they also maintain a stable form after steam sterilization. These improved HA-HMDA hydrogels showed higher viscoelasticity and longer lasting effects than the previous ones, despite the fact that the amount of the HMDA used as a cross-linking agent as well as 1 ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) and 1-hydroxybenzotriazole monohydrated (HOBt) used as activation agents were substantially reduced. According to an in vivo test using a wrinkled mouse model, the improved HA-HMDA hydrogels exhibited significantly improved tissue augmentation effects compared to a positive control of Restylane, which is widely used for the tissue augmentation throughout the world. Furthermore, histological analysis revealed excellent biocompatibility and safety of the improved synthesized HA-HMDA hydrogels. PMID- 21527496 TI - Intracellular pH distribution as a cell health indicator in Saccharomyces cerevisiae. AB - Internal pH regulation is vital for many cell functions, including transport mechanisms and metabolic enzyme activity. More specifically, transport mechanisms are to a wide degree governed by internal pH distributions. We introduce the term standard deviation of the intracellular pH (s.d.(pH(int))) to describe the internal pH distributions. The cellular pH distributional response to external stress such as heat has not previously been determined. In this study, the intracellular pH (pH(i)) and the s.d.(pH(int)) of Saccharomyces cerevisiae cells exposed to supralethal temperatures were measured using fluorescence ratio imaging microscopy (FRIM). An exponential decline in pH(i) was observed after an initial small decline. For the first time, we report the use of FRIM for determining in vivo plasma membrane proton permeability coefficients in yeast. Furthermore, the exponential decay of pH(i) and the rupture of the cell plasma membrane, as measured by propidium iodide staining, at 70 degrees C were not simultaneous but were separated by a significant temporal difference. Finally, a nonlinear relationship between the pH(i) and s.d.(pH(int)) was found; i.e. the s.d.(pH(int)) was significantly more sensitive to supralethal temperatures than pH(i). s.d.(pH(int)) is therefore proposed as an early health/vitality indicator in S. cerevisiae cells exposed to heat stress. PMID- 21527497 TI - Glucocorticoid receptor alpha isoform-selective regulation of antiapoptotic genes in osteosarcoma cells: a new mechanism for glucocorticoid resistance. AB - Glucocorticoids regulate a variety of physiological processes and are commonly used to treat disorders of inflammation, autoimmune diseases, and cancer. Glucocorticoid action is predominantly mediated through the classic glucocorticoid receptor (GR)alpha isoform. Recent data suggest that the mature GRalpha mRNA is translated into multiple N-terminal isoforms that have distinct biochemical properties and gene regulatory profiles. Interestingly, osteosarcoma cells stably expressing the GRalpha-D translational isoform are unique in that they are resistant to glucocorticoid-induced apoptosis. In this study, we investigate whether GRalpha isoform-specific differences in the regulation of antiapoptotic genes contribute to this resistant phenotype. We now show that GRalpha-D, unlike the other receptor isoforms, does not inhibit the activity of a nuclear factor kappaB (NF-kappaB)-responsive reporter gene and does not efficiently repress either the transcription or protein production of the antiapoptotic genes Bcl-xL, cellular inhibitor of apoptosis protein 1, and survivin. The inability of GRalpha-D to down-regulate the expression of these genes appears to be associated with a diminished interaction between GRalpha-D and NF-kappaB that is observed in cells, but not in vitro, and likely reflects the sequestration of GRalpha-D in the nucleus. Deletion of the GRalpha N-terminal amino acids 98-335 also results in a nuclear resident GR, which fails to interact with NF-kappaB in cells and promote apoptosis in response to glucocorticoids. These data suggest that the N-terminal translational isoforms of GRalpha selectively regulate antiapoptotic genes and that the GRalpha-D isoform may contribute to the resistance of certain cancer cells to glucocorticoid-induced apoptosis. PMID- 21527498 TI - Expanding the paradigm for estrogen receptor binding and transcriptional activation. AB - Estrogen receptor (ER) binds to a spectrum of functional estrogen response elements (ERE) within the human genome, including ERE half-sites (HERE), inverted and direct repeats. This has been confounding, because ER has been reported to bind weakly, if at all, to these sites in vitro. We show that ER binds strongly to these nonconventional EREs, and the binding is enhanced by the presence of high-mobility group protein B1 (HMGB1). Collectively, these and previous findings reinforce the notion of the plasticity of strong ER/ERE interactions, consistent with their broader range of observed binding specificity. In addition, transient transfection studies using luciferase reporter gene assays show that these EREs drive luciferase activity, and HMGB1 enhances transcriptional activity. Furthermore, HMGB1 gene expression knockdown results in a precipitous drop in luciferase activity, suggesting a prominent role for HMGB1 in activation of estrogen/ER-responsive genes. Therefore, these data advocate that the minimal target site for ER is a cHERE (consensus HERE) that occurs in many different contexts and that HMGB1 enhances both the binding affinity and transcriptional activity. This challenges the current paradigm for ER binding affinity and functional activity and suggests that the paradigm requires significant reevaluation and modification. These findings also suggest a possible mechanism for a cross talk between genes regulated by ER and class II nuclear receptors. PMID- 21527499 TI - Liver-derived IGF-I contributes to GH-dependent increases in lean mass and bone mineral density in mice with comparable levels of circulating GH. AB - The relative contributions of circulating and locally produced IGF-I in growth remain controversial. The majority of circulating IGF-I is produced by the liver, and numerous mouse models have been developed to study the endocrine actions of IGF-I. A common drawback to these models is that the elimination of circulating IGF-I disrupts a negative feedback pathway, resulting in unregulated GH secretion. We generated a mouse with near total abrogation of circulating IGF-I by disrupting the GH signaling mediator, Janus kinase (JAK)2, in hepatocytes. We then crossed these mice, termed JAK2L, to GH-deficient little mice (Lit). Compound mutant (Lit-JAK2L) and control (Lit-Con) mice were treated with equal amounts of GH such that the only difference between the two groups was hepatic GH signaling. Both groups gained weight in response to GH but there was a reduction in the final weight of GH-treated Lit-JAK2L vs. Lit-Con mice. Similarly, lean mass increased in both groups, but there was a reduction in the final lean mass of Lit-JAK2L vs. Lit-Con mice. There was an equivalent increase in skeletal length in response to GH in Lit-Con and Lit-JAK2L mice. There was an increase in bone mineral density (BMD) in both groups, but Lit-JAK2L had lower BMD than Lit Con mice. In addition, GH-mediated increases in spleen and kidney mass were absent in Lit-JAK2L mice. Taken together, hepatic GH-dependent production of IGF I had a significant and nonredundant role in GH-mediated acquisition of lean mass, BMD, spleen mass, and kidney mass; however, skeletal length was dependent upon or compensated for by locally produced IGF-I. PMID- 21527500 TI - The Leydig cell MEK/ERK pathway is critical for maintaining a functional population of adult Leydig cells and for fertility. AB - MAPK kinase (MEK)1 and MEK2 were deleted from Leydig cells by crossing Mek1(f/f);Mek2(-/-) and Cyp17iCre mice. Primary cultures of Leydig cell from mice of the appropriate genotype (Mek1(f/f);Mek2(-/-);iCre(+)) show decreased, but still detectable, MEK1 expression and decreased or absent ERK1/2 phosphorylation when stimulated with epidermal growth factor, Kit ligand, cAMP, or human choriogonadotropin (hCG). The body or testicular weights of Mek1(f/f);Mek2(-/ );iCre(+) mice are not significantly affected, but the testis have fewer Leydig cells. The Leydig cell hypoplasia is paralleled by decreased testicular expression of several Leydig cell markers, such as the lutropin receptor, steroidogenic acute regulatory protein, cholesterol side chain cleavage enzyme, 17alpha-hydroxylase, and estrogen sulfotransferase. The expression of Sertoli or germ cell markers, as well as the shape, size, and cellular composition of the seminiferous tubules, are not affected. cAMP accumulation in response to hCG stimulation in primary cultures of Leydig cells from Mek1(f/f);Mek2(-/-);iCre(+) mice is normal, but basal testosterone and testosterone syntheses provoked by addition of hCG or a cAMP analog, or by addition of substrates such as 22 hydroxycholesterol or pregnenolone, are barely detectable. The Mek1(f/f);Mek2(-/ );iCre(+) males show decreased intratesticular testosterone and display several signs of hypoandrogenemia, such as elevated serum LH, decreased expression of two renal androgen-responsive genes, and decreased seminal vesicle weight. Also, in spite of normal sperm number and motility, the Mek1(f/f);Mek2(-/-);iCre(+) mice show reduced fertility. These studies show that deletion of MEK1/2 in Leydig cells results in Leydig cell hypoplasia, hypoandrogenemia, and reduced fertility. PMID- 21527501 TI - Differential regulation and function of 5'-untranslated GR-exon 1 transcripts. AB - Alternative splicing serves to increase biological diversity and adaptation. Many genes, including the glucocorticoid receptor (GR), contain multiple 5' untranslated exons in their promoter regions that can give rise to various mRNA isoforms encoding the same protein. To date, information on the mouse GR promoter remains sparse. Here, we extensively characterize alternative first exons of the mouse GR to reveal homology to the rat and human. We further find that, although most promoters are broadly expressed in various tissues, transcription of individual promoters can be differentially regulated by growth factor- and depolarization-induced signaling. Moreover, in addition to selective promoter usage, the alternative first exon transcripts differentially control RNA stability and translation efficiency, indicative of their role in GR expression. In conclusion, the composite GR promoter enables multilayered adjustments in gene expression through transcriptional and posttranscriptional mechanisms that may serve varying physiological demands. PMID- 21527502 TI - LEF1 identifies androgen-independent epithelium in the developing prostate. AB - Lymphoid enhancer-binding factor (LEF)1 is a major mediator and a target in canonical Wnt/beta-catenin pathway. Interactions between the androgen receptor (AR) and canonical Wnt pathways have been implicated in the development of the genitourinary organs. Here, we investigated the localization and role of LEF1 positive cells during development of the prostate gland in human and in the murine model. We show that during human prostate development, LEF1 is restricted to the basal epithelial layer of the urogenital sinus. During mouse development, Lef1 is also present in the urogenital mesenchyme in addition to the basal epithelial layer of the urogenital sinus. In the course of elongation and branching of the prostatic ducts, Lef1 is localized to the proliferating epithelium at the distal tips of the buds. Notably, during branching morphogenesis, domains of Lef1 and AR are mutually exclusive. We further employed the TOPGAL reporter strain to examine the dynamics of Wnt signaling in the context of prostate regression upon a 7-d treatment with a competitive AR inhibitor, bicalutamide. We found that Wnt/Lef1-positive basal cells are not dependent upon androgen for survival. Furthermore, upon bicalutamide treatment, Wnt/Lef1-positive basal progenitors repopulated the luminal compartment. We conclude that Wnt/Lef1 activity identifies an androgen-independent population of prostate progenitors, which is important for embryonic development and organ maintenance and regeneration in the adult. PMID- 21527503 TI - Progesterone receptor directly inhibits beta-casein gene transcription in mammary epithelial cells through promoting promoter and enhancer repressive chromatin modifications. AB - Differentiated HC-11 cells ectopically expressing progesterone receptor (PR) were used to explore the molecular mechanisms by which progesterone suppresses beta casein gene transcription induced by prolactin (PRL) and glucocorticoids in the mammary gland. As detected by chromatin immunoprecipitation assays, treatment of cells with the progestin agonist R5020 induced a rapid recruitment (5 min) of PR to the proximal promoter (-235 bp) and distal enhancer (-6 kb upstream of transcription start site) of beta-casein. PR remained bound for 4 h and was dissociated by 24 h after treatment. Despite efficient binding, the hormone agonist-occupied PR did not stimulate transcription of the beta-casein gene. Recruitment of signal transducer and activator of transcription 5a, glucocorticoid receptor, and the CCAAT enhancer binding protein beta to the enhancer and proximal promoter of beta-casein induced by PRL and glucocorticoids was blocked by progestin cotreatment, whereas PR binding was induced under these conditions. PRL/glucocorticoid-induced histone acetylation and the recruitment of the coactivator p300 and RNA polymerase II required for gene activation were also inhibited by progestin. In addition, progestin prevented dissociation of the corepressors Yin and Yang 1 and histone deacetylase 3 from the promoter, and demethylation of lysine 9 of histone 3 induced by PRL and glucocorticoids. These studies are consistent with the conclusion that progesterone interferes with PRL/glucocorticoid induction of beta-casein transcription by a physical interaction of PR with the promoter and enhancer that blocks assembly of a transcriptional activation complex and dissociation of corepressors and promotes repressive chromatin modifications. These studies define a novel mechanism of steroid receptor-mediated transcriptional repression of a physiologically important gene in mammary gland development and differentiation. PMID- 21527504 TI - Class-C SOX transcription factors control GnRH gene expression via the intronic transcriptional enhancer. AB - GnRH is a pivotal hypothalamic neurohormone governing reproduction and sexual development. Because transcriptional regulation is crucial for the spatial and temporal expression of the GnRH gene, a region approximately 3.0 kb upstream of the mammalian GnRH promoter has been extensive studied. In the present study, we demonstrate a transcription-enhancer located in the first intron (intron A) region of the GnRH gene. This transcriptional enhancer harbors putative sex determining region Y-related high-mobility-group box (SOX) family transcription factor-binding sites, which are well conserved across many mammalian species. The class-C SOX member proteins (SOX-C) (SOX4 and SOX11) specifically augment this transcriptional activation by binding to these SOX-binding sites. In accordance, SOX11 is highly enriched in immortalized GnRH-producing GT1-1 cells, and suppression of its expression significantly decreases GnRH gene expression as well as GnRH secretion. Chromatin immunoprecipitation shows that endogenous SOX-C factors recognize and bind to the intronic enhancer in GT1-1 cells and the hypothalamus. Accompanying immunohistochemical analysis demonstrates that SOX4 or SOX11 are highly expressed in the majority of hypothalamic GnRH neurons in adult mice. Taken together, these findings demonstrate that SOX-C transcription factors function as important transcriptional regulators of cell type-specific GnRH gene expression by acting on the intronic transcriptional enhancer. PMID- 21527505 TI - Integrating ecology into macroevolutionary research. AB - On 9 March, over 150 biologists gathered in London for the Centre for Ecology and Evolution spring symposium, 'Integrating Ecology into Macroevolutionary Research'. The event brought together researchers from London-based institutions alongside others from across the UK, Europe and North America for a day of talks. The meeting highlighted methodological advances and recent analyses of exemplar datasets focusing on the exploration of the role of ecological processes in shaping macroevolutionary patterns. PMID- 21527506 TI - Multigene mutation analysis of metastatic lymph nodes in non-small cell lung cancer diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration. AB - BACKGROUND: The importance of biomarker analysis in patients with non-small cell lung cancer (NSCLC) is well known. The purpose of this study was to analyze the mutation status of multiple genes in metastatic lymph nodes obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and to examine the correlation between treatments and outcomes. METHODS: Genetic alterations were analyzed in metastatic hilar or mediastinal lymph nodes diagnosed by EBUS-TBNA in 156 patients with NSCLC. Epidermal growth factor receptor (EGFR) was analyzed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method (n = 156). V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) (exons 2-3) and tumor protein 53 (p53) (exons 4-8) were analyzed by direct sequencing (n = 113). In addition, retrospective chart review was performed for clinical data analysis. RESULTS: EGFR gene mutations were detected in 42 cases (26.9%). Twenty-three patients with EGFR mutations received gefitinib, with an overall response rate (partial response [PR]) of 54.5% and disease control rate (PR + stable disease) of 86.4% (Response Evaluation Criteria in Solid Tumors). K-ras gene mutations were detected in four cases (3.5%), and p53 gene mutations were detected in 47 cases (41.6%). Fifty-two patients underwent conventional chemotherapy (46 patients underwent platinum based chemotherapy). Patients with p53 gene mutations showed chemoresistance (progressive disease of 42.9%, P = .0339) and a relatively poor prognosis after chemotherapy (P = .1391). CONCLUSIONS: Multigene mutation analysis can be performed in EBUS-TBNA samples of metastatic lymph nodes from patients with NSCLC. EBUS-TBNA allows genetic evaluation of tumor cells within the metastatic node, which may allow physicians to better select treatments, particularly EGFR tyrosine kinase inhibitors. PMID- 21527508 TI - Atelectasis as a cause of postoperative fever: where is the clinical evidence? AB - BACKGROUND: Atelectasis is considered to be the most common cause of early postoperative fever (EPF) but the existing evidence is contradictory. We sought to determine if atelectasis is associated with EPF by analyzing the relevant published evidence. METHODS: We performed a systematic search in PubMed and Scopus databases to identify studies examining the association between atelectasis and EPF. RESULTS: A total of eight studies, including 998 cardiac, abdominal, and maxillofacial surgery patients, were eligible for analysis. Only two studies specifically examined our question, and six additional articles reported sufficient data to be included. Only one study reported a significant association between postoperative atelectasis and fever, whereas the remaining studies indicated no such association. The performance of EPF as a diagnostic test for atelectasis was also assessed, and EPF performed poorly (pooled diagnostic OR, 1.40; 95% CI, 0.92-2.12). The significant heterogeneity among the studies precluded a formal metaanalysis. CONCLUSION: The available evidence regarding the association of atelectasis and fever is scarce. We found no clinical evidence supporting the concept that atelectasis is associated with EPF. More so, there is no clear evidence that atelectasis causes fever at all. Large studies are needed to precisely evaluate the contribution of atelectasis in EPF. PMID- 21527507 TI - Increased adverse events after percutaneous coronary intervention in patients with COPD: insights from the National Heart, Lung, and Blood Institute dynamic registry. AB - BACKGROUND: Previous studies have demonstrated that patients with COPD are at higher risk for death after percutaneous coronary intervention (PCI), but other clinical outcomes and possible associations with adverse events have not been described. METHODS: Using waves 1 through 5 (1999-2006) of the National Heart, Lung, and Blood Institute Dynamic Registry, patients with COPD (n = 860) and without COPD (n = 10,048) were compared. Baseline demographics, angiographic characteristics, and in-hospital and 1-year adverse events were compared. RESULTS: Patients with COPD were older (mean age 66.8 vs 63.2 years, P < .001), more likely to be women, and more likely to have a history of diabetes, prior myocardial infarction, peripheral arterial disease, renal disease, and smoking. Patients with COPD also had a lower mean ejection fraction (49.1% vs 53.0%, P < .001) and a greater mean number of significant lesions (3.2 vs 3.0, P = .006). Rates of in-hospital death (2.2% vs 1.1%, P = .003) and major entry site complications (6.6% vs 4.2%, P < .001) were higher in pulmonary patients. At discharge, pulmonary patients were significantly less likely to be prescribed aspirin (92.4% vs 95.3%, P < .001), beta-blockers (55.7% vs 76.2%, P < .001), and statins (60.0% vs 66.8%, P < .001). After adjustment, patients with COPD had significantly increased risk of death (hazard ratio [HR] = 1.30, 95% CI = 1.01 1.67) and repeat revascularization (HR = 1.22, 95% CI = 1.02-1.46) at 1 year, compared with patients without COPD. CONCLUSIONS: COPD is associated with higher mortality rates and repeat revascularization within 1 year after PCI. These higher rates of adverse outcomes may be associated with lower rates of guideline recommended class 1 medications prescribed at discharge. PMID- 21527509 TI - Ethnic differences in fraction of exhaled nitric oxide and lung function in healthy young children. AB - BACKGROUND: Ethnic differences in lung function in school-aged children and adults are well recognized, but little is known about such differences in preschool children. We investigated whether differences exist in fraction of exhaled nitric oxide (Feno), multiple-breath washout (MBW) indices, specific airways resistance (sRaw), and spirometry indices between healthy preschool children of South Asian and white European origin. METHODS: Feno, MBW indices (lung clearance index, functional residual capacity, conductive airways inhomogeneity, and acinar airways inhomogeneity), sRaw, and spirometry were measured in healthy South Asian and white children aged 4 to 6 years, and comparisons were made between the two groups. Statistical analyses were by multiple linear regression and t tests. RESULTS: Thirty-seven white (mean age 5.8 +/- 0.7 years, 49% boys) and 31 South Asian children (mean age 5.4 +/- 0.8 years, 52% boys) were recruited. Feno was, on average, 36% higher (P < .05) in South Asian children compared with white children. FVC and FEV(1) and fractions thereof (FEV(0.75) and FEV(0.5)) z-scores were significantly lower in South Asian compared with white children by 0.69 (P = .01), 0.76 (P = .004), 0.76 (P = .009), and 0.85 (P = .002) z-scores, respectively, but there were no significant differences in FEV(1)/FVC, FEF(25-75), sRaw, or MBW indices. CONCLUSIONS: Differences in Feno and forced expiratory lung volumes between South Asian and white children exist from a very young age. Ethnic differences should be taken into account when interpreting lung function results in preschool children for effective management of respiratory conditions. PMID- 21527510 TI - Validation of a novel risk score for severity of illness in acute exacerbations of COPD. AB - BACKGROUND: Clinicians lack a validated tool for risk stratification in acute exacerbations of COPD (AECOPD). We sought to validate the BAP-65 (elevated BUN, altered mental status, pulse > 109 beats/min, age > 65 years) score for this purpose. METHODS: We analyzed 34,699 admissions to 177 US hospitals (2007) with either a principal diagnosis of AECOPD or acute respiratory failure with a secondary diagnosis of AECOPD. Hospital mortality and need for mechanical ventilation (MV) served as co-primary end points. Length of stay (LOS) and costs represented secondary end points. We assessed the accuracy of BAP-65 via the area under the receiver operating characteristic curve (AUROC). RESULTS: Nearly 4% of subjects died while hospitalized and approximately 9% required MV. Mortality increased with increasing BAP-65 class, ranging from < 1% in subjects in class I (score of 0) to > 25% in those meeting all BAP-65 criteria (Cochran-Armitage trend test z = -38.48, P < .001). The need for MV also increased with escalating score (2% in the lowest risk cohort vs 55% in the highest risk group, Cochran Armitage trend test z = -58.89, P < .001). The AUROC for BAP-65 for hospital mortality and/or need for MV measured 0.79 (95% CI, 0.78-0.80). The median LOS was 4 days, and mean hospital costs equaled $5,357. These also varied linearly with increasing BAP-65 score. CONCLUSIONS: The BAP-65 system captures severity of illness and represents a simple tool to categorize patients with AECOPD as to their risk for adverse outcomes. BAP-65 also correlates with measures of resource use. BAP-65 may represent a useful adjunct in the initial assessment of AECOPDs. PMID- 21527511 TI - Differences in ventilatory inefficiency between pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Measures of ventilatory efficiency during cardiopulmonary exercise testing (CPX) are increasingly being used as prognostic markers in heart failure and pulmonary hypertension (PH). Little is known about whether these measures can be applied to all forms of PH, in particular chronic thromboembolic pulmonary hypertension (CTEPH), wherein thrombotic vascular occlusion has an impact on gas exchange. METHODS: One hundred twenty-seven patients, 50 with CTEPH and 77 with pulmonary arterial hypertension (PAH), underwent incremental CPX. RESULTS: Physiologic ventilatory dead space fraction (Vd/Vtphys) measured at peak exercise with arterial blood gas analysis was higher in CTEPH than PAH (52.9% vs 41.8%, P < .001). The V(E)/V(CO(2)) slope was higher in patients with CTEPH than in patients with PAH (50.7 L/min/L/min vs 44.4 L/min/L/min, P = .024) and was mirrored by similar changes in the ventilatory equivalent for CO(2) at anaerobic threshold (Eqco(2)_AT) (47.7 L/min/L/min vs 42.0 L/min/L/min, P = .008). In a multivariate linear regression analysis, disease subtype was found to be an independent predictor of Vd/Vtphys (P < .001), V(E)/V(CO(2)) slope (P = .003), and Eqco(2)_AT (P < .001). These three measures could distinguish between World Health Organization functional classes I/II and III/IV in PAH but not CTEPH. CONCLUSION: Significant differences in gas exchange exist between CTEPH and PAH, due to differences in Vd/Vtphys likely as a result of vascular occlusion due to thromboembolic disease. This dissociates measures of ventilatory efficiency from disease severity and also contributes to our understanding of the differences in exercise limitation and breathlessness in PAH and CTEPH. Common prognostic end points from CPX cannot be applied to all forms of PH. PMID- 21527512 TI - Collective efficacy and major depression in urban neighborhoods. AB - Depression contributes substantially to the global burden of disease and disability. Population-level factors that shape depression may be efficient targets for intervention to decrease the depression burden. The authors aimed to identify the relation between neighborhood collective efficacy and major depression. Analyses were conducted on data from the New York Social Environment Study (n = 4,000), a representative study of residents of New York, New York, conducted in 2005. Neighborhood collective efficacy was measured as the average neighborhood response on a well-established scale. Major depression was assessed with the Patient Health Questionnaire. A marginal modeling approach was applied to present results on the additive scale relevant to public health and intervention. Analyses were adjusted for demographic and socioeconomic characteristics, recent life events that could contribute to both depression and change in residence, and individual perception of collective efficacy. Collective efficacy was related to major depression among older adults; marginal models estimated a 6.2% (95% confidence interval: 0.1, 17.5) lower prevalence of depression if all older adults (65 years and older) had lived in high versus low collective efficacy neighborhoods. Similar results were suggested among younger adults; however, the confidence interval crossed the null. These and other study findings suggest that community-randomized trials targeting collective efficacy merit consideration. PMID- 21527513 TI - Influence of physical inactivity on associations between single nucleotide polymorphisms and genetic predisposition to childhood obesity. AB - Childhood obesity is a complex disease that is influenced by both genetic and environmental factors. The authors' aim was to determine whether sedentary behavior and physical activity modulate the association between single nucleotide polymorphisms (SNPs) and obesity risk in Chinese children. A population-based study was carried out in 2,848 children (6-18 years of age) in Beijing, China, in 2004. It included 1,229 obese cases and 1,619 normal-weight controls. Lifestyle information was collected through the use of a validated questionnaire, and 6 SNPs were genotyped. The association between the 6 SNPs and obesity risk was modulated by sedentary behavior and physical activity. A higher risk of obesity was observed in children who carried the high-risk alleles of the 6 SNPs and engaged in sedentary behavior >=2 hours/day outside of school or participated in low or moderate physical activity. Most notably, the association between 5 SNPs (Fas apoptotic inhibitory molecule 2 rs7138803, Niemann-Pick disease, type C1 rs1805081, fat mass- and obesity-associated gene rs6499640, melanocortin 4 receptor gene rs17782313, and brain-derived neurotrophic factor rs6265) and obesity risk was only observed in children who had moderate-to-low physical activity levels or engaged in sedentary behavior, regardless of which risk alleles they carried. The results indicated that encouraging less sedentary behavior and higher levels of physical activity could alleviate the influence of risk alleles on genetic predisposition to childhood obesity, thereby serving as a promising prevention strategy. PMID- 21527514 TI - p90RSK2 is essential for FLT3-ITD- but dispensable for BCR-ABL-induced myeloid leukemia. AB - p90 ribosomal S6 kinase 2 (p90RSK2) is important in diverse cellular processes including gene expression, cell proliferation, and survival. We found that p90RSK2 is commonly activated in diverse leukemia cell lines expressing different leukemogenic tyrosine kinases, including BCR-ABL and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD). Interestingly, in a murine BM transplantation (BMT) model, genetic deficiency of RSK2 did not affect the pathogenesis or disease progression of BCR-ABL-induced myeloproliferative neoplasm (PN). In contrast, FLT3-ITD induced a T-cell acute lymphoblastic leukemia in BMT mice receiving RSK2 knockout (KO) BM cells, phenotypically distinct from the myeloproliferative neoplasm induced by FLT3-ITD using wild-type BM cells. In consonance with these results, inhibition of RSK2 by an RSK inhibitor, fmk, did not effectively induce apoptosis in BCR-ABL-expressing murine Ba/F3 cells, human K562 cells or primary tissue samples from CML patients, whereas fmk treatment induced significant apoptotic cell death not only in FLT3 ITD-positive Ba/F3 cells, human Molm14 and Mv(4;11) leukemia cells, but also in primary tissue samples from AML patients. These results suggest that RSK2 is dispensable for BCR-ABL-induced myeloid leukemia, but may be required for pathogenesis and lineage determination in FLT3-ITD-induced hematopoietic transformation. RSK2 may thus represent an alternative therapeutic target in the treatment of FLT3-ITD-positive leukemia. PMID- 21527515 TI - Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A. AB - The mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinib resistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1(-/-) MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib- or nilotinib-induced growth inhibition in primary CD34(+) mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, expressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK 1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type- or mutant-Bcr-Abl1 thereby overcoming drug resistance. PMID- 21527516 TI - Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. AB - The Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1 year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603). PMID- 21527518 TI - First-trimester low-dose prednisolone in refractory antiphospholipid antibody related pregnancy loss. AB - The objective of this study was to assess pregnancy outcome in women with a history of refractory antiphospholipid antibody-associated pregnancy loss(es) who were treated with early low-dose prednisolone in addition to aspirin and heparin. Eighteen women with antiphospholipid antibodies who had refractory pregnancy loss(es) were given prednisolone (10 mg) from the time of their positive pregnancy test to 14 weeks' gestation. Before low-dose prednisolone was given as treatment, 4 (4%) of 97 pregnancies had resulted in live births. Among 23 pregnancies supplemented with prednisolone, 9 women had 14 live births (61%), including 8 uncomplicated pregnancies. The remainder were complicated by preterm delivery, preeclampsia, and/or small-for-gestational-age infants. There were 8 first-trimester miscarriages and 1 ectopic pregnancy. There were no fetal deaths after 10 weeks' gestation and no evidence of maternal morbidity. The addition of first-trimester low-dose prednisolone to conventional treatment is worthy of further assessment in the management of refractory antiphospholipid antibody related pregnancy loss(es), although complications remain elevated. PMID- 21527517 TI - A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway. AB - JAK-STAT signaling is involved in the regulation of cell survival, proliferation, and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, whereas they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In the present study, we report that the kinase CK2 is a novel interaction partner of JAKs and is essential for JAK-STAT activation. We demonstrate that cytokine-induced activation of JAKs and STATs and the expression of suppressor of cytokine signaling 3 (SOCS-3), a downstream target, are inhibited by CK2 small interfering RNAs or pharmacologic inhibitors. Endogenous CK2 is associated with JAK2 and JAK1 and phosphorylates JAK2 in vitro. To extend these findings, we demonstrate that CK2 interacts with JAK2V617F and that CK2 inhibitors suppress JAK2V617F autophosphorylation and downstream signaling in HEL92.1.7 cells (HEL) and primary cells from polycythemia vera (PV) patients. Furthermore, CK2 inhibitors potently induce apoptosis of HEL cells and PV cells. Our data provide evidence for novel cross-talk between CK2 and JAK-STAT signaling, with implications for therapeutic intervention in JAK2V617F-positive MPDs. PMID- 21527519 TI - Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. AB - In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV >= 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P = .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P = .029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect -9 m; 95% confidence interval [95% CI] -56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531. PMID- 21527520 TI - Posttranscriptional deregulation of MYC via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia. AB - Cumulative evidence indicates that MYC, one of the major downstream effectors of NOTCH1, is a critical component of T-cell acute lymphoblastic leukemia (T-ALL) oncogenesis and a potential candidate for targeted therapy. However, MYC is a complex oncogene, involving both fine protein dosage and cell-context dependency, and detailed understanding of MYC-mediated oncogenesis in T-ALL is still lacking. To better understand how MYC is interspersed in the complex T-ALL oncogenic networks, we performed a thorough molecular and biochemical analysis of MYC activation in a comprehensive collection of primary adult and pediatric patient samples. We find that MYC expression is highly variable, and that high MYC expression levels can be generated in a large number of cases in absence of NOTCH1/FBXW7 mutations, suggesting the occurrence of multiple activation pathways in addition to NOTCH1. Furthermore, we show that posttranscriptional deregulation of MYC constitutes a major alternative pathway of MYC activation in T-ALL, operating partly via the PI3K/AKT axis through down-regulation of PTEN, and that NOTCH1(m) might play a dual transcriptional and posttranscriptional role in this process. Altogether, our data lend further support to the significance of therapeutic targeting of MYC and/or the PTEN/AKT pathways, both in GSI-resistant and identified NOTCH1-independent/MYC-mediated T-ALL patients. PMID- 21527521 TI - Protein kinase C mediates platelet secretion and thrombus formation through protein kinase D2. AB - Platelets are highly specialized blood cells critically involved in hemostasis and thrombosis. Members of the protein kinase C (PKC) family have established roles in regulating platelet function and thrombosis, but the molecular mechanisms are not clearly understood. In particular, the conventional PKC isoform, PKCalpha, is a major regulator of platelet granule secretion, but the molecular pathway from PKCalpha to secretion is not defined. Protein kinase D (PKD) is a family of 3 kinases activated by PKC, which may represent a step in the PKC signaling pathway to secretion. In the present study, we show that PKD2 is the sole PKD member regulated downstream of PKC in platelets, and that the conventional, but not novel, PKC isoforms provide the upstream signal. Platelets from a gene knock-in mouse in which 2 key phosphorylation sites in PKD2 have been mutated (Ser707Ala/Ser711Ala) show a significant reduction in agonist-induced dense granule secretion, but not in alpha-granule secretion. This deficiency in dense granule release was responsible for a reduced platelet aggregation and a marked reduction in thrombus formation. Our results show that in the molecular pathway to secretion, PKD2 is a key component of the PKC-mediated pathway to platelet activation and thrombus formation through its selective regulation of dense granule secretion. PMID- 21527523 TI - Controlled activation of morphogenesis to generate a functional human microvasculature in a synthetic matrix. AB - Understanding the role of the extracellular matrix (ECM) in vascular morphogenesis has been possible using natural ECMs as in vitro models to study the underlying molecular mechanisms. However, little is known about vascular morphogenesis in synthetic matrices where properties can be tuned toward both the basic understanding of tubulogenesis in modular environments and as a clinically relevant alternative to natural materials for regenerative medicine. We investigated synthetic, tunable hyaluronic acid (HA) hydrogels and determined both the adhesion and degradation parameters that enable human endothelial colony forming cells (ECFCs) to form efficient vascular networks. Entrapped ECFCs underwent tubulogenesis dependent on the cellular interactions with the HA hydrogel during each stage of vascular morphogenesis. Vacuole and lumen formed through integrins alpha(5)beta(1) and alpha(V)beta(3), while branching and sprouting were enabled by HA hydrogel degradation. Vascular networks formed within HA hydrogels containing ECFCs anastomosed with the host's circulation and supported blood flow in the hydrogel after transplantation. Collectively, we show that the signaling pathways of vascular morphogenesis of ECFCs can be precisely regulated in a synthetic matrix, resulting in a functional microvasculature useful for the study of 3-dimensional vascular biology and toward a range of vascular disorders and approaches in tissue regeneration. PMID- 21527524 TI - Serum hepcidin: reference ranges and biochemical correlates in the general population. AB - To date, concentrations of the promising biomarker hepcidin have only been assessed in serum of relatively small series of healthy volunteers and patients. We assessed age- and sex-stratified reference ranges of serum hepcidin concentration in a selected reference set and performed regression analyses to study associations between hepcidin and (biochemical) variables in a large, well phenotyped sample of the general population (n = 2998). All participants filled out a questionnaire on lifestyle, health status, and medical history. Serum measurements of iron parameters, liver enzyme alanine aminotransferase, creatinine and C-reactive protein were available. Serum hepcidin concentrations were lower for premenopausal than for postmenopausal women (median, 4.1 nM vs 8.5 nM, respectively). Hepcidin concentrations in men were constant over age (median, 7.8 nM). Serum hepcidin was strongly associated with serum ferritin in men and women: beta-coefficient of log-transformed variables (95% confidence interval): 0.78 (0.74-0.82) and 0.83 (0.78-0.88), respectively. Additional significant, though less strong, associations were observed for C-reactive protein and total iron binding capacity in men and for total iron binding capacity, alanine aminotransferase, and glomerular filtration rate in women. Our study provides age and sex-specific reference ranges of serum hepcidin concentration and indicates ferritin as the primary correlate of serum hepcidin concentration. PMID- 21527522 TI - Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis. AB - Corticosteroids and lenalidomide decrease red blood cell transfusion dependence in patients with Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome (MDS), respectively. We explored the effects of dexamethasone and lenalidomide, individually and in combination, on the differentiation of primary human bone marrow progenitor cells in vitro. Both agents promote erythropoiesis, increasing the absolute number of erythroid cells produced from normal CD34(+) cells and from CD34(+) cells with the types of ribosome dysfunction found in DBA and del(5q) MDS. However, the drugs had distinct effects on the production of erythroid progenitor colonies; dexamethasone selectively increased the number of burst-forming units-erythroid (BFU-E), whereas lenalidomide specifically increased colony-forming unit-erythroid (CFU-E). Use of the drugs in combination demonstrated that their effects are not redundant. In addition, dexamethasone and lenalidomide induced distinct gene-expression profiles. In coculture experiments, we examined the role of the microenvironment in response to both drugs and found that the presence of macrophages, the central cells in erythroblastic islands, accentuated the effects of both agents. Our findings indicate that dexamethasone and lenalidomide promote different stages of erythropoiesis and support the potential clinical utility of combination therapy for patients with bone marrow failure. PMID- 21527525 TI - Activation of factor XI by products of prothrombin activation. AB - The prothrombinase complex converts prothrombin to alpha-thrombin through the intermediate meizothrombin (Mz-IIa). Both alpha-thrombin and Mz-IIa catalyze factor (F) XI activation to FXIa, which sustains alpha-thrombin production through activation of FIX. The interaction with FXI is thought to involve thrombin anion binding exosite (ABE) I. alpha-Thrombin can undergo additional proteolysis to beta-thrombin and gamma-thrombin, neither of which have an intact ABE I. In a purified protein system, FXI is activated by beta-thrombin or gamma thrombin, and by alpha-thrombin in the presence of the ABE I-blocking peptide hirugen, indicating that a fully formed ABE I is not absolutely required for FXI activation. In a FXI-dependent plasma thrombin generation assay, beta-thrombin, gamma-thrombin, and alpha-thrombins with mutations in ABE I are approximately 2 fold more potent initiators of thrombin generation than alpha-thrombin or Mz-IIa, possibly because fibrinogen, which binds to ABE I, competes poorly with FXI for forms of thrombin lacking ABE I. In addition, FXIa can activate factor FXII, which could contribute to thrombin generation through FXIIa-mediated FXI activation. The data indicate that forms of thrombin other than alpha-thrombin contribute directly to feedback activation of FXI in plasma and suggest that FXIa may provide a link between tissue factor-initiated coagulation and the proteases of the contact system. PMID- 21527526 TI - Inhibition of cellular senescence by developmentally regulated FGF receptors in mesenchymal stem cells. AB - Bone-derived mesenchymal stem cells (MSCs) are important cells for use in cell therapy, tissue engineering, and regenerative medicine, but also to study bone development, homeostasis, and repair. However, little is known about their developmental ontology and in vivo identity. Because fibroblast growth factors (FGFs) play key roles in bone development and their receptors are developmentally regulated in bones, we hypothesized that MSCs should express FGF receptors (FGFRs), reflecting their developmental origin and potential. We show here that FGFR1/2 are expressed by rare mesenchymal progenitors in putative MSC niches in vivo, including the perichondrium, periosteum, and trabecular marrow. FGFR1+ cells often appeared as pericytes. These cells display a characteristic MSC phenotype in vitro when expanded with FGF-2, which appears to maintain MSC stemness by inhibiting cellular senescence through a PI3K/AKT-MDM2 pathway and by promoting proliferation. FGFRs may therefore be involved in MSC self-renewal. In summary, FGFR1/2 are developmentally regulated markers of MSCs in vivo and in vitro and are important in maintaining MSC stemness. PMID- 21527527 TI - SNP array-based karyotyping: differences and similarities between aplastic anemia and hypocellular myelodysplastic syndromes. AB - In aplastic anemia (AA), contraction of the stem cell pool may result in oligoclonality, while in myelodysplastic syndromes (MDS) a single hematopoietic clone often characterized by chromosomal aberrations expands and outcompetes normal stem cells. We analyzed patients with AA (N = 93) and hypocellular MDS (hMDS, N = 24) using single nucleotide polymorphism arrays (SNP-A) complementing routine cytogenetics. We hypothesized that clinically important cryptic clonal aberrations may exist in some patients with BM failure. Combined metaphase and SNP-A karyotyping improved detection of chromosomal lesions: 19% and 54% of AA and hMDS cases harbored clonal abnormalities including copy-neutral loss of heterozygosity (UPD, 7%). Remarkably, lesions involving the HLA locus suggestive of clonal immune escape were found in 3 of 93 patients with AA. In hMDS, additional clonal lesions were detected in 5 (36%) of 14 patients with normal/noninformative routine cytogenetics. In a subset of AA patients studied at presentation, persistent chromosomal genomic lesions were found in 10 of 33, suggesting that the initial diagnosis may have been hMDS. Similarly, using SNP-A, earlier clonal evolution was found in 4 of 7 AA patients followed serially. In sum, our results indicate that SNP-A identify cryptic clonal genomic aberrations in AA and hMDS leading to improved distinction of these disease entities. PMID- 21527528 TI - Tumor-associated macrophages as major source of APRIL in gastric MALT lymphoma. AB - Lymphoid hyperplasia of gastric mucosa associated with Helicobacter pylori (HP) infection represents a preneoplastic condition of the mucosa associated lymphoid tissue (MALT), which may evolve to a B-cell lymphoma. While it is well established that the initial neoplastic proliferation of B cells is antigen driven and dependent on the helper activity of HP-specific T cells, it needs to be elucidated which cytokine or soluble factor(s) promote B-cell activation and lymphomagenesis. Herein, we originally report that gastric MALT lymphoma express high levels of a proliferation inducing ligand (APRIL), a novel cytokine crucial in sustaining B-cell proliferation. By immunohistochemistry, we demonstrate that APRIL is produced almost exclusively by gastric lymphoma-infiltrating macrophages located in close proximity to neoplastic B cells. We also show that macrophages produce APRIL on direct stimulation with both HP and HP-specific T cells. Collectively, our results represent the first evidence for an involvement of APRIL in gastric MALT lymphoma development in HP-infected patients. PMID- 21527529 TI - Critical band 3 multiprotein complex interactions establish early during human erythropoiesis. AB - Band 3, the major anion transport protein of human erythrocytes, forms the core of a multiprotein complex in the erythrocyte membrane. Here we studied the spatiotemporal mechanisms of band 3 multiprotein complex assembly during erythropoiesis. Significant pools of intracellular band 3 and Rh-associated glycoprotein (RhAG) were found in the basophilic erythroblast. These intracellular pools decreased in the polychromatic erythroblast, whereas surface expression increased and were lowest in the orthochromatic erythroblast and reticulocytes. Protease treatment of intact cells to remove extracellular epitopes recognized by antibodies to band 3 and RhAG was used to study surface delivery kinetics and intracellular complex composition from the proerythroblast stage to the enucleated reticulocyte. Newly synthesized band 3 and protein 4.2 interact initially in the early stages of the secretory pathway and are found associated at the plasma membrane from the basophilic stage of erythropoiesis. Although we could successfully coimmunoprecipitate Rh with RhAG from plasma membrane pools at a similar stage, no intracellular interaction between these proteins was detectable. Knockdown of RhAG during early erythropoiesis was accompanied by a concomitant drop in membrane expression of Rh polypeptides. These data are consistent with assembly of major components of the band 3 macrocomplex at an early stage during erythropoiesis. PMID- 21527530 TI - Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia. AB - Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) that has a dismal outcome when treated with standard therapy. For improved diagnosis and risk stratification, the initiating genetic events need to be elucidated. To investigate the genetic basis of BCP-ALL, genomes of 94 iAMP21 patients were interrogated by arrays, FISH, and multiplex ligation-dependent probe amplification. Most copy number alterations targeted chromosome 21, reinforcing the complexity of this chromosome. The common region of amplification on chromosome 21 was refined to a 5.1-mb region that included RUNX1, miR-802, and genes mapping to the Down syndrome critical region. Recurrent abnormalities affecting genes in key pathways were identified: IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%), and RB1 (37%). Investigation of clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 rearrangements. Patient outcome was uniformly poor with standard therapy irrespective of the presence or absence of these changes. This study has provided evidence that chromosome 21 instability is the only anomaly among those so far investigated that is common to all iAMP21 patients, and therefore the initiating event is likely to be found among the complex structural rearrangements of this abnormal chromosome. PMID- 21527531 TI - Constitutive Notch pathway activation in murine ZMYM2-FGFR1-induced T-cell lymphomas associated with atypical myeloproliferative disease. AB - The ZMYM2-FGFR1 (formerly known as ZNF198-FGFR1) fusion kinase induces stem cell leukemia-lymphoma syndrome (SCLL), a hematologic malignancy characterized by rapid transformation to acute myeloid leukemia and T-lymphoblastic lymphoma. In the present study, we demonstrate frequent, constitutive activation of Notch1 and its downstream target genes in T-cell lymphomas that arose in a murine model of ZMYM2-FGFR1 SCLL. Notch up-regulation was also demonstrated in human SCLL- and FGFR1OP2-FGFR1-expressing KG-1 cells. To study the role of Notch in T-cell lymphomagenesis, we developed a highly tumorigenic cell line from ZMYM2-FGFR1 expressing cells. Pharmacologic inhibition of Notch signaling in these cells using gamma-secretase inhibitors significantly delayed leukemogenesis in vivo. shRNA targeting of Notch1, as well as c-promoter-binding factor 1 (CBF1) and mastermind-like 1 (MAML1), 2 essential cofactors involved in transcriptional activation of Notch target genes, also significantly delayed or inhibited tumorigenesis in vivo. Mutation analysis demonstrated that 5' promoter deletions and alternative promoter usage were responsible for constitutive activation of Notch1 in all T-cell lymphomas. These data demonstrate the importance of Notch signaling in the etiology of SCLL, and suggest that targeting this pathway could provide a novel strategy for molecular therapies to treat SCLL patients. PMID- 21527532 TI - Overexpression of microRNA-16-2 contributes to the abnormal erythropoiesis in polycythemia vera. AB - Deregulated expression of microRNAs is associated with neoplasia. Here, we show that mature miR-16 levels are abnormally increased in CD34(+) cells of patients with polycythemia vera as a consequence of preferential expression of miR-16-2 on chromosome 3 rather than of miR-16-1 on chromosome 13. Forced expression of miRNA 16 in normal CD34(+) cells stimulated erythroid cell proliferation and maturation. Conversely, exposure of polycythemia vera CD34(+) cells to small interfering RNA against pre-miR-16-2 reduced erythroid colonies and largely prevented formation of erythropoietin-independent colonies; myeloid progenitors remained unaffected. Experiments with knock down of JAK2 indicated that overexpression of miR-16 was independent of JAK/STAT pathway activation. Mice injected with an miR-16 antagomir showed a blunted erythroid response to exogenous erythropoietin, which indicates a role of miR-16 in normal erythropoiesis. These data suggest that deregulation of miR-16-2 contributes to abnormal expansion of erythroid lineage in polycythemia vera. However, the mechanisms for miR-16-2 overexpression remain to be elucidated, because no genetic abnormalities at the miR-16-2 locus were discovered. PMID- 21527533 TI - The cytochrome P450 4A/F-20-hydroxyeicosatetraenoic acid system: a regulator of endothelial precursor cells derived from human umbilical cord blood. AB - Endothelial progenitor cells (EPCs) contribute to physiological and pathological neovascularization. Previous data have suggested that the cytochrome P450 4A/F (CYP4A/F)-20-hydroxyeicosatetraenoic acid (20-HETE) system regulates neovascularization. Therefore, we studied whether the angiogenic effects of the CYP4A/F-20-HETE system involve regulation of EPC function. We extracted human umbilical cord blood and isolated EPCs, which express AC133(+)CD34(+) and kinase insert domain receptor (KDR) surface markers and contain mRNA and protein for CYP4A11 and CYP4A22 enzymes, as opposed to mesenchymal stem cells, which only express negligible amounts of CYP4A11/22. When EPCs were incubated with arachidonic acid, they produced 20-HETE, which stimulated the cells to proliferate and migrate, as did vascular endothelial growth factor. Incubation with 1 MUM N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET0016), a selective inhibitor of 20-HETE synthesis, reduced the proliferative and migratory effects of vascular endothelial growth factor and also significantly abolished EPC migration mediated by stroma-derived factor-1alpha, as did (6,15) 20 hydroxyeicosadienoic acid. Coculturing EPCs and endothelial cells on a Matrigel matrix led to tube formation, which in turn was inhibited by both HET0016 and 20 hydroxyeicosadienoic acid. We concluded that the CYP4A/F-20-HETE system is expressed in EPCs and can act as both an autocrine and a paracrine regulatory factor. PMID- 21527535 TI - The antithrombotic activity of EP224283, a neutralizable dual factor Xa inhibitor/glycoprotein IIbIIIa antagonist, exceeds that of the coadministered parent compounds. AB - EP224283 combines in a single molecule idraparinux and tirofiban, which allows obtaining a predictable and sustained antiplatelet effect through the transfer of the pharmacokinetics properties of idraparinux to the anti-alphaIIbbeta3 antagonist. The activity can be instantaneously neutralized by injection of avidin, a specific antidote. We have tested the effects of this new profile anticoagulant in various thrombosis models. The antithrombotic effect of EP224283 was compared with those of the parent compounds used alone or in association at doses achieving low to moderate inhibition of platelet aggregation ex vivo. In a model of systemic thromboembolism independent of thrombin generation, tirofiban and EP224283 had similar effects at equimolar doses. On the other hand, EP224283 was more potent than tirofiban or idraparinux under thrombin-dependent conditions. In a ferric chloride-induced thrombosis model, EP224283 was more potent than either parent compound or their combination. Similar results were obtained after atherosclerotic plaque rupture in ApoE(-/-) mice. Thus, the dual action of EP224283 exceeds that of the parent compounds used in combination. A possible explanation is that EP224283 could concentrate antithrombin inside the thrombus by binding to alphaIIbbeta3 through the tirofiban moiety, as shown by immunolabeling of the occluded vessel. No prolongation of the bleeding time was observed at doses achieving strong antithrombotic effects, suggesting that low to moderate alphaIIbbeta3 inhibition combined with factor Xa inhibition minimizes the bleeding risk. The favorable antithrombotic profile of EP224283 together with its possible neutralization by avidin makes it an interesting drug candidate for the treatment and prevention of acute ischemic events. PMID- 21527534 TI - Salt bridges overlapping the gonadotropin-releasing hormone receptor agonist binding site reveal a coincidence detector for G protein-coupled receptor activation. AB - G protein-coupled receptors (GPCRs) play central roles in most physiological functions, and mutations in them cause heritable diseases. Whereas crystal structures provide details about the structure of GPCRs, there is little information that identifies structural features that permit receptors to pass the cellular quality control system or are involved in transition from the ground state to the ligand-activated state. The gonadotropin-releasing hormone receptor (GnRHR), because of its small size among GPCRs, is amenable to molecular biological approaches and to computer modeling. These techniques and interspecies comparisons are used to identify structural features that are important for both intracellular trafficking and GnRHR activation yet distinguish between these processes. Our model features two salt (Arg(38)-Asp(98) and Glu(90)-Lys(121)) and two disulfide (Cys(14)-Cys(200) and Cys(114)-Cys(196)) bridges, all of which are required for the human GnRHR to traffic to the plasma membrane. This study reveals that both constitutive and ligand-induced activation are associated with a "coincidence detector" that occurs when an agonist binds. The observed constitutive activation of receptors lacking Glu(90)-Lys(121), but not Arg(38) Asp(98) ionic bridge, suggests that the role of the former connection is holding the receptor in the inactive conformation. Both the aromatic ring and hydroxyl group of Tyr(284) and the hydrogen bonding of Ser(217) are important for efficient receptor activation. Our modeling results, supported by the observed influence of Lys(191) from extracellular loop 2 (EL2) and a four-residue motif surrounding this loop on ligand binding and receptor activation, suggest that the positioning of EL2 within the seven-alpha-helical bundle regulates receptor stability, proper trafficking, and function. PMID- 21527536 TI - DARTs take aim at BiTEs. PMID- 21527537 TI - The metabolic cost of childhood ALL. PMID- 21527538 TI - Oxidative stress may cause ITP. PMID- 21527539 TI - To gel or not to gel. PMID- 21527541 TI - Outbreak of pneumocystis pneumonia occurring in late post-transplantation period. PMID- 21527542 TI - Effect of vitamin E administration on response to ischaemia-reperfusion of hearts from cold-exposed rats. AB - In both 3,5,3-triiodothyronine (T(3))-induced hyperthyroidism and cold-induced functional hyperthyroidism, the heart displays an increased susceptibility to oxidative challenge in vitro. Hearts from T(3)-treated rats also exhibit an increased susceptibility to ischaemia-reperfusion, a condition that raises free radical production. The present study was designed to establish whether cold exposed rats exhibit an increased cardiac susceptibility to ischaemia-reperfusion which can be attenuated by vitamin E. The following four groups of animals were used: C, control rats (n = 8, temperature 24 degrees C); C+VE, vitamin E-treated rats (n = 8, temperature 24 degrees C); CE, cold-exposed rats (n = 8, temperature 4 degrees C); and CE+VE, cold-exposed vitamin E-treated rats (n = 8, temperature 4 degrees C). Langendorff preparations from these animals were submitted to 20 min ischaemia followed by 25 min reperfusion. At the end of the ischaemia reperfusion protocol, homogenates and mitochondria were prepared and used for analytical procedures. With respect to control hearts, cold hearts showed a lower inotropic recovery and a higher oxidative stress, as inferred by higher levels of oxidized proteins and lipids and lower reduced glutathione levels. These changes were prevented when cold rats were treated with vitamin E. Evidence was also obtained that mitochondria are involved in the tissue derangement of cold hearts. Indeed, they display a faster production of reactive oxygen species, which causes mitochondrial oxidative damage and functional decline that parallel the tissue dysfunction. Moreover, vitamin E-linked improvement of tissue function was associated with a lower oxidative damage and a restored function of mitochondria. Finally, the mitochondrial population composition and Ca(2+)-induced swelling data indicate that the decline in mitochondrial function is in part due to a decrease in the amount of the highly functional heavy mitochondria linked to their higher susceptibility to oxidative damage and swelling. In conclusion, our work shows that vitamin E treatment attenuates harmful side-effects of the cardiac response to cold, such as oxidative damage and susceptibility to oxidants, thus preserving mitochondrial function and tissue recovery from ischaemia-reperfusion. PMID- 21527543 TI - Baroreflex and somato-reflex control of blood pressure, heart rate and renal sympathetic nerve activity in the obese Zucker rat. AB - It has been reported that the baroreflex control of heart rate (HR) and sympathetic nerve activity (SNA) is attenuated in obese Zucker rats (OZRs) compared with age-matched lean animals (LZRs). What is not known, however, is the extent to which the baroreflex control of mean arterial blood pressure (MAP) is altered in the OZR. In addition, it is not known whether the interactions of other sensory nerve inputs on autonomic control are altered in the OZR compared with the LZR. The aim of this study was to determine the baroreflex control of MAP, HR and renal SNA (RSNA) in the OZR and LZR using an open-loop baroreflex approach. In addition, the effect of brachial nerve stimulation (BNS) on the baroreflex control was determined in these animals. Age-matched, male LZRs and OZRs were anaesthetized, and the carotid baroreceptors were vascularly isolated, bilaterally. The carotid sinus pressure was increased in 20 mmHg increments from 60 to 180 mmHg using an oscillating pressure stimulus. Baroreflex function curves were constructed using a four-parameter logistic equation, and gain was calculated from the first derivative, which gave a measure of baroreceptor sensitivity, before and during BNS. The range over which the baroreflex could change MAP (28 +/- 6 versus 87 +/- 5 mmHg; mean +/- SEM), HR (17 +/- 4 versus 62 +/- 11 beats min(-1)) and normalized RSNA (NormNA; 22 +/- 4 versus 76 +/- 11%) was significantly decreased in the OZR compared with the LZR. Likewise, the maximal gain was lower in the OZR, as follows: MAP -0.88 +/- 0.22 versus -2.26 +/ 0.17; HR -0.42 +/- 0.18 versus -1.44 +/- 0.22 beats min(-1); and NormNA -0.54 +/ 0.14 versus -1.65 +/- 0.30% mmHg(-1). There was no difference in the mid-point of the baroreflex curve for each variable between the OZR and LZR. However, the minimal values obtained when the baroreceptors were maximally loaded were higher in the OZR (MAP 68 +/- 5 versus 53 +/- 4 mmHg; HR 455 +/- 7 versus 390 +/- 13 beats min(-1); and NormNA -19 +/- 4 versus -48 +/- 8%). Brachial nerve stimulation in the LZR resulted in an upward and rightward resetting of the baroreflex control of MAP and RSNA, and abolished baroreflex control of HR. The baroreflex control of RSNA in the OZR during BNS was further attenuated and reset upwards and to the right, while the HR response was abolished. With respect to MAP, the baroreflex curve reset upwards and to the right to a point comparable with the LZR during BNS. These data show that there is an attenuated baroreflex control in the OZR and that the ability to reset to higher arterial pressure during somatic afferent nerve stimulation is similar to that in the LZR. PMID- 21527544 TI - Hydrogen sulfide: its production and functions. AB - Endogenous levels of sulfide in the brain have been measured in rats, humans and bovines in 1989 and 1990, suggesting that H(2)S may have a physiological function. We demonstrated in 1996 that cystathionine beta-synthase can produce H(2)S in the brain and that H(2)S facilitates the induction of hippocampal long term potentiation by enhancing the activity of NMDA receptors. The following year, we showed that another H(2)S-producing enzyme, cystathionine gamma-lyase, is expressed in the thoracic aorta, portal vein and ileum and that H(2)S relaxes these tissues. We proposed that H(2)S may be a neuromodulator as well as a smooth muscle relaxant. In addition to a function as a signalling molecule, we demonstrated another function as a cytoprotectant in 2004. Hydrogen sulfide protects neurons from oxidative stress by reinstating the reduced glutathione levels. We recently demonstrated that a third H(2)S-producing enzyme, 3 mercaptopyruvate sulfurtransferase (3MST), is expressed in neurons and vascular endothelium. In addition to reinstating glutathione levels, H(2)S produced by 3MST, which is mainly localized to mitochondria, reduces reactive oxygen species generated in these organelles. PMID- 21527545 TI - Exercise training improves basal blood glucose metabolism with no changes of cytosolic inhibitor B kinase or c-Jun N-terminal kinase activation in skeletal muscle of Otsuka Long-Evans Tokushima fatty rats. AB - Redox-sensitive stress kinases and heat shock protein 72 (Hsp72) have been considered to be associated with the development of type 2 diabetes in skeletal muscle. However, the effect of exercise training on skeletal muscle of type 2 diabetic models is largely unknown. The purpose of this study was to investigate the effect of 12 weeks of exercise training on gastrocnemius of type 2 diabetic rats, by examining the activation of c-Jun N-terminal kinase (JNK), the nuclear factor B (NF-B) pathway and Hsp72. Total hydroperoxide and 4-hydroxynoneal, as oxidative stress markers, were also examined. Otsuka Long-Evans Tokushima fatty (OLEFT) rats were randomly divided into an exercise training group (Ex-OLETF, n = 8) and a sedentary group (Sed-OLETF, n = 8), while Long-Evans Tokushima Otsuka (LETO) rats were used as a control group (Con-LETO, n = 5). The Ex-OLETF rats were trained on a treadmill five times a week for 12 weeks. The levels of hydroperoxide and 4-hydroxynoneal in both Ex-OLETF and Sed-OLETF were significantly higher compared with Con-LETO, but there was no difference between Ex-OLETF and Sed-OLETF. Levels of inhibitor B kinase, JNK activation and p65 nuclear translocation followed a similar pattern to that observed in oxidative stress markers. The level of Hsp72 in Ex-OLETF was increased by exercise training, but it did not reach the level observed in Con-LETO. The NF-B DNA binding activity in Sed-OLETF was significantly higher compared with Con-LETO. Although it was not statistically significant, exercise training in Ex-OLETF showed a trend to reduce the activation of NF-B DNA binding activity compared with Sed-OLETF (P = 0.104). Our findings indicate that exercise training improves basal glucose metabolism without a change in stress kinases, and that nuclear regulation of NF-B activity in diabetic muscle could be regulated independently of the cytosolic pathway. Our study also suggests a possibility that exercise induced Hsp72 serves as a protective mechanism in skeletal muscle of OLETF rats. PMID- 21527546 TI - Hepatobiliary infections due to non-capsulated Haemophilus influenzae. AB - We present two cases of non-capsulated Haemophilus influenzae hepatobiliary infection and review the literature. Such cases are rare, and prior to routine immunization against H. influenzae serotype b invasive Haemophilus disease was largely caused by capsulated strains. The epidemiology of invasive Haemophilus infections has changed and the number of cases of intra-abdominal and hepatobiliary infection may be underestimated due to current microbiological processing practices. PMID- 21527547 TI - Generation and evaluation of A2-expressing Lactococcus lactis live vaccines against Leishmania donovani in BALB/c mice. AB - Leishmaniasis is a parasitic disease affecting over 12 million individuals worldwide. As current treatments are insufficient, the development of an effective vaccine is a priority. This study generated and assessed the efficacy of Leishmania vaccines engineered from the non-colonizing, non-pathogenic Gram positive bacterium Lactococcus lactis. A truncated, codon-optimized version of the A2 antigen from Leishmania donovani was engineered for expression in Lactococcus lactis in three different subcellular compartments: in the cytoplasm, secreted outside the cell or anchored to the cell wall. These three A2-expressing Lactococcus lactis strains were tested for their ability to generate A2-specific immune responses and as live vaccines against visceral Leishmania donovani infection in BALB/c mice. Subcutaneous immunization with live Lactococcus lactis expressing A2 anchored to the cell wall effectively induced high levels of antigen-specific serum antibodies. It was demonstrated that Lactococcus lactis based vaccines are a feasible approach in the generation of live vaccines against leishmaniasis. The Lactococcus lactis strains generated in this study provide an excellent foundation for further studies on live bacterial vaccines against leishmaniasis and other pathogens. PMID- 21527548 TI - Detection of Clostridium difficile in animals: comparison of real-time PCR assays with the culture method. AB - Clostridium difficile has emerged as a pathogen or commensal in food animals. There is overlap between isolates from animals, retail meats and humans, suggesting that animals may be a C. difficile reservoir. For direct detection of variant C. difficile strains in faecal samples of symptomatic and asymptomatic animals, we developed and validated a new TaqMan real-time PCR (TMrtPCR) assay targeting the tcdA, tcdB and cdtB genes. We compared it with the enrichment culture method and with two real-time PCR (rtPCR) assays, BrtPCR and PCRFast, targeting tcdB and tcdA/tcdB, respectively. All ten tested C. difficile toxinotypes, except one (XIa) with PCRFast and two (X, XIa) with BrtPCR, were detected with the test assays. A total of 340 (100 %) samples were cultured and amplified with TMrtPCR. Results correlated in 75.3 % samples. Forty (11.8 %) samples were culture positive/TMrtPCR negative, possibly because of the low numbers of bacteria in the samples or because of DNA extraction failure. Forty (11.8 %) samples were TMrtPCR positive/culture negative. Among 79 samples included in the rtPCR assays/culture comparison, 50.6 % were in complete concordance. The results showed that TMrtPCR performed better than BrtPCR and PCRFast, and 67 % of the culture-positive samples were TMrtPCR positive in comparison to 40 % of the samples positive in BrtPCR and 7 % of the samples positive in PCRFast, respectively. Another advantage of TMrtPCR over BrtPCR and PCRFast is its ability to detect a binary toxin gene. Therefore, the TMrtPCR results can provide the first information about the toxin type present in the sample. According to the results of our study, TMrtPCR could be a preferred screening method for the rapid detection of C. difficile in animal faecal samples, although an enrichment culture has to be performed for the specimens with negative or inconclusive rtPCR results. PMID- 21527549 TI - Exposure of sputum to phenol disinfectant in conjunction with universal sample processing solution provides safety to laboratory workers during smear microscopy. PMID- 21527550 TI - Identification and characterization of breakthrough contaminants associated with the conventional isolation of Mycobacterium tuberculosis. AB - Breakthrough contamination of tuberculosis (TB) cultures is a problem in that it allows the overgrowth of another bacterium present in the sputum specimen, which can potentially mask the presence of Mycobacterium tuberculosis. The aim of this study was to isolate and characterize the bacterial organisms responsible for such overgrowth and contamination, and to examine their susceptibility to (i) various chemical selective decontamination steps and (ii) antibiotics in liquid culture media, in an attempt to develop a method to help alleviate contamination problems associated with the conventional isolation of M. tuberculosis from routine patient sputum specimens. Bacterial contaminants from 102 routine sputum cultures were identified molecularly by 16S rRNA gene PCR and direct sequencing from contaminated Lowenstein-Jensen (LJ) slopes and BacT/Alert liquid medium. It was found that the contaminants from LJ slopes belonged to 11 different genera and were composed largely of Gram-negative organisms (84.9 %; 45/53), whereas the liquid culture contaminants belonged to 13 different genera, with 37/66 isolates (56.1 %) being Gram-negative. Pseudomonas aeruginosa was the dominant contaminant in both media. The effect of six different selective decontamination protocols was examined. Four of the six methods were effective at eliminating all culturable organisms present; these were 5 % oxalic acid, 5 % oxalic acid/2 % NaOH, 5 % oxalic acid/4 % NaOH and 1 % chlorhexidine. NaOH at a concentration of 2 or 4 % was less effective as it was unable to eliminate all organisms of each species tested, with the exception of P. aeruginosa. In conclusion, breakthrough contamination of TB cultures is due to a diverse range of at least 17 different bacterial genera, with P. aeruginosa and Staphylococcus epidermidis accounting for the dominant contaminating flora. Employment of chemical decontaminating protocols solely involving NaOH may lead to higher rates of contamination. Where such contamination is encountered, TB laboratories should consider the reprocessing of such sputum samples with an alternative decontamination method such as 1 % chlorhexidine. PMID- 21527551 TI - Combinatorial binding of transcription factors in the pluripotency control regions of the genome. AB - The pluripotency control regions (PluCRs) are defined as genomic regions that are bound by POU5F1, SOX2, and NANOG in vivo. We utilized a high-throughput binding assay to record more than 270,000 different DNA/protein binding measurements along incrementally tiled windows of DNA within these PluCRs. This high resolution binding map is then used to systematically define the context of POU factor binding, and reveals patterns of cooperativity and competition in the pluripotency network. The most prominent pattern is a pervasive binding competition between POU5F1 and the forkhead transcription factors. Like many transcription factors, POU5F1 is co-expressed with a paralog, POU2F1, that shares an apparently identical binding specificity. By analyzing thousands of binding measurements, we discover context effects that discriminate POU2F1 from POU5F1 binding. Proximal NANOG binding promotes POU5F1 binding, whereas nearby SOX2 binding favors POU2F1. We demonstrate by cross-species comparison and by chromatin immunoprecipitation (ChIP) that the contextual sequence determinants learned in vitro are sufficient to predict POU2F1 binding in vivo. PMID- 21527553 TI - Quantitative, noninvasive imaging of radiation-induced DNA double-strand breaks in vivo. AB - DNA double-strand breaks (DSB) are a major form of DNA damage and a key mechanism through which radiotherapy and some chemotherapeutic agents kill cancer cells. Despite its importance, measuring DNA DSBs is still a tedious task that is normally carried out by gel electrophoresis or immunofluorescence staining. Here, we report a novel approach to image and quantify DSBs in live mammalian cells through bifragment luciferase reconstitution. N- and C-terminal fragments of firefly luciferase genes were fused with H2AX and MDC1 genes, respectively. Our strategy was based on the established fact that at the sites of DSBs, H2AX protein is phosphoryated and physically associates with the MDC1 protein, thus bringing together N- and C-luciferase fragments and reconstituting luciferase activity. Our strategy allowed serial, noninvasive quantification of DSBs in cells irradiated with X-rays and (56)Fe ions. Furthermore, it allowed for the evaluation of DSBs noninvasively in vivo in irradiated tumors over 2 weeks. Surprisingly, we detected a second wave of DSB induction in irradiated tumor cells days after radiation exposure in addition to the initial rapid induction of DSBs. We conclude that our new split-luciferase-based method for imaging gamma H2AX-MDC1 interaction is a powerful new tool to study DSB repair kinetics in vivo with considerable advantage for experiments requiring observations over an extended period of time. PMID- 21527554 TI - Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth. AB - Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelter in complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and TERT [corrected] in human HCC. Finally, SIRT1 silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy. PMID- 21527556 TI - Protein kinase D3 sensitizes RAF inhibitor RAF265 in melanoma cells by preventing reactivation of MAPK signaling. AB - RAS mutations occur in more than 30% of all human cancers but efforts to directly target mutant RAS signaling as a cancer therapy have yet to succeed. As alternative strategies, RAF and MEK inhibitors have been developed to block oncogenic signaling downstream of RAS. As might be expected, studies of these inhibitors have indicated that tumors with RAS or BRAF mutations display resistance RAF or MEK inhibitors. In order to better understand the mechanistic basis for this resistance, we conducted a RNAi-based screen to identify genes that mediated chemoresistance to the RAF kinase inhibitor RAF265 in a BRAF (V600E) mutant melanoma cell line that is resistant to this drug. In this way, we found that knockdown of protein kinase D3 (PRKD3) could enhance cell killing of RAF and MEK inhibitors across multiple melanoma cell lines of various genotypes and sensitivities to RAF265. PRKD3 blockade cooperated with RAF265 to prevent reactivation of the MAPK signaling pathway, interrupt cell cycle progression, trigger apoptosis, and inhibit colony formation growth. Our findings offer initial proof-of-concept that PRKD3 is a valid target to overcome drug resistance being encountered widely in the clinic with RAF or MEK inhibitors. PMID- 21527555 TI - Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma. AB - Squamous cell carcinoma (SCC) is a treatment-refractory subtype of human cancer arising from stratified epithelium of the skin, lung, esophagus, oropharynx, and other tissues. A unifying feature of SCC is high-level expression of the p53 related protein p63 (TP63) in 80% of cases. The major protein isoform of p63 expressed in SCC is DeltaNp63alpha, an N-terminally truncated form which functions as a key SCC cell survival factor by mechanisms that are unclear. In this study, we show that DeltaNp63alpha associates with histone deacetylase 1 (HDAC1) and HDAC2 to form an active transcriptional repressor complex that can be targeted to therapeutic advantage. Repression of proapoptotic Bcl-2 family member genes including p53 upregulated modulator of apoptosis (PUMA) by p63/HDAC is required for survival of SCC cells. Cisplatin chemotherapy, a mainstay of SCC treatment, promotes dissociation of p63 and HDAC from the PUMA promoter, leading to increased histone acetylation, PUMA activation, and apoptosis. These effects are recapitulated upon targeting the p63/HDAC complex selectively with class I/II HDAC inhibitors using both in vitro and in vivo models. Sensitivity to HDAC inhibition is directly correlated with p63 expression and is abrogated in tumor cells that overexpress endogenous Bcl-2. Together, our results elucidate a mechanism of p63-mediated transcriptional repression and they identify the DeltaNp63alpha/HDAC complex as an essential tumor maintenance factor in SCC. In addition, our findings offer a rationale to apply HDAC inhibitors for SCC treatment. PMID- 21527557 TI - MMSET is highly expressed and associated with aggressiveness in neuroblastoma. AB - MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis. PMID- 21527559 TI - Functional parsing of driver mutations in the colorectal cancer genome reveals numerous suppressors of anchorage-independent growth. AB - Landmark cancer genome resequencing efforts are leading to the identification of mutated genes in many types of cancer. The extreme diversity of mutations being detected presents significant challenges to subdivide causal from coincidental mutations to elucidate how disrupted regulatory networks drive cancer processes. Given that a common early perturbation in solid tumor initiation is bypass of matrix-dependent proliferation restraints, we sought to functionally interrogate colorectal cancer candidate genes (CAN-genes) to identify driver tumor suppressors. We have employed an isogenic human colonic epithelial cell (HCEC) model to identify suppressors of anchorage-independent growth by conducting a soft agar-based short hairpin RNA (shRNA) screen within the cohort of CAN-genes. Remarkably, depletion of 65 of the 151 CAN-genes tested collaborated with ectopic expression of K-RAS(V12) and/or TP53 knockdown to promote anchorage-independent proliferation of HCECs. In contrast, only 5 of 362 random shRNAs (1.4%) enhanced soft agar growth. We have identified additional members of an extensive gene network specifying matrix-dependent proliferation, by constructing an interaction map of these confirmed progression suppressors with approximately 700 mutated genes that were excluded from CAN-genes, and experimentally verifying soft agar growth enhancement in response to depletion of a subset of these genes. Collectively, this study revealed a profound diversity of nodes within a fundamental tumor suppressor network that are susceptible to perturbation leading to enhanced cell-autonomous anchorage-independent proliferative fitness. Tumor suppressor network fragility as a paradigm within this and other regulatory systems perturbed in cancer could, in large part, account for the heterogeneity of somatic mutations detected in tumors. PMID- 21527558 TI - Enhancement of cancer vaccine therapy by systemic delivery of a tumor-targeting Salmonella-based STAT3 shRNA suppresses the growth of established melanoma tumors. AB - Cancer vaccine therapies have only achieved limited success when focusing on effector immunity with the goal of eliciting robust tumor-specific T-cell responses. More recently, there is an emerging understanding that effective immunity can only be achieved by coordinate disruption of tumor-derived immunosuppression. Toward that goal, we have developed a potent Salmonella-based vaccine expressing codon-optimized survivin (CO-SVN), referred to as 3342Max. When used alone as a therapeutic vaccine, 3342Max can attenuate growth of aggressive murine melanomas overexpressing SVN. However, under more immunosuppressive conditions, such as those associated with larger tumor volumes, we found that the vaccine was ineffective. Vaccine efficacy could be rescued if tumor-bearing mice were treated initially with Salmonella encoding a short hairpin RNA (shRNA) targeting the tolerogenic molecule STAT3 (YS1646-shSTAT3). In vaccinated mice, silencing STAT3 increased the proliferation and granzyme B levels of intratumoral CD4(+) and CD8(+) T cells. The combined strategy also increased apoptosis in tumors of treated mice, enhancing tumor-specific killing of tumor targets. Interestingly, mice treated with YS1646-shSTAT3 or 3342Max alone were similarly unsuccessful in rejecting established tumors, whereas the combined regimen was highly potent. Our findings establish that a combined strategy of silencing immunosuppressive molecules followed by vaccination can act synergistically to attenuate tumor growth, and they offer a novel translational direction to improve tumor immunotherapy. PMID- 21527560 TI - Product variability of the 'cineole cassette' monoterpene synthases of related Nicotiana species. AB - Nicotiana species of the section Alatae characteristically emit the floral scent compounds of the 'cineole cassette' comprising 1,8-cineole, limonene, myrcene, alpha-pinene, beta-pinene, sabinene, and alpha-terpineol. We successfully isolated genes of Nicotiana alata and Nicotiana langsdorfii that encoded enzymes, which produced the characteristic monoterpenes of this 'cineole cassette' with alpha-terpineol being most abundant in the volatile spectra. The amino acid sequences of both terpineol synthases were 99% identical. The enzymes cluster in a monophyletic branch together with the closely related cineole synthase of Nicotiana suaveolens and monoterpene synthase 1 of Solanum lycopersicum. The cyclization reactions (alpha-terpineol to 1,8-cineole) of the terpineol synthases of N. alata and N. langsdorfii were less efficient compared to the 'cineole cassette' monoterpene synthases of Arabidopsis thaliana, N. suaveolens, Salvia fruticosa, Salvia officinalis, and Citrus unshiu. The terpineol synthases of N. alata and N. langsdorfii were localized in pistils and in the adaxial and abaxial epidermis of the petals. The enzyme activities reached their maxima at the second day after anthesis when flowers were fully opened and the enzyme activity in N. alata was highest at the transition from day to night (diurnal rhythm). PMID- 21527561 TI - Inclusion of patients with brain metastases in phase I trials: an unmet need. AB - Patients with brain metastases are increasing in number; however, these patients are often excluded in phase I/II trials due to perceived poor prognosis, risk of hemorrhage, inefficient drug delivery, and confounding toxicities. Tsimberidou and colleagues demonstrate that selected patients can be appropriately enrolled in phase I trials and have outcomes representative of the general cancer population. PMID- 21527562 TI - Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I single-dose escalation trial. AB - PURPOSE: Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of (90)Y-clivatuzumab tetraxetan ((90)Y-labeled hPAM4) in patients with advanced pancreatic cancer. EXPERIMENTAL DESIGN: Twenty-one patients (4 stage III; 17 stage IV) received (111)In-hPAM4 for imaging and serum sampling before (90)Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). RESULTS: (111)In-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before (90)Y-hPAM4; otherwise, 20 patients received (90)Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m(2) (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v.3) grade 3 to 4 neutropenia and thrombocytopenia increasing with (90)Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m(2) encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m(2) as the maximal tolerated (90)Y dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32%-52% tumor diameter shrinkage). CONCLUSION: (90)Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated (90)Y dose, and is a potential new therapeutic for advanced pancreatic cancer. PMID- 21527563 TI - Prospective analysis of parametric response map-derived MRI biomarkers: identification of early and distinct glioma response patterns not predicted by standard radiographic assessment. AB - PURPOSE: Currently, radiologic response of brain tumors is assessed according to the Macdonald criteria 10 weeks from the start of therapy. There exists a critical need to identify nonresponding patients early in the course of their therapy for consideration of alternative treatment strategies. Our study assessed the effectiveness of the parametric response map (PRM) imaging biomarker to provide for an earlier measure of patient survival prediction. EXPERIMENTAL DESIGN: Forty-five high-grade glioma patients received concurrent chemoradiation. Quantitative MRI including apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired pretreatment and 3 weeks midtreatment on a prospective institutional-approved study. PRM, a voxel-by-voxel image analysis method, was evaluated as an early prognostic biomarker of overall survival. Clinical and conventional MR parameters were also evaluated. RESULTS: Multivariate analysis showed that PRM(ADC+) in combination with PRM(rCBV-) obtained at week 3 had a stronger correlation to 1-year and overall survival rates than any baseline clinical or treatment response imaging metric. The composite biomarker identified three distinct patient groups, nonresponders [median survival (MS) of 5.5 months, 95% CI: 4.4-6.6 months], partial responders (MS of 16 months, 95% CI: 8.6-23.4 months), and responders (MS has not yet been reached). CONCLUSIONS: Inclusion of PRM(ADC+) and PRM(rCBV-) into a single imaging biomarker metric provided early identification of patients resistant to standard chemoradiation. In comparison to the current standard of assessment of response at 10 weeks (Macdonald criteria), the composite PRM biomarker potentially provides a useful opportunity for clinicians to identify patients who may benefit from alternative treatment strategies. PMID- 21527564 TI - Isolation of circulating tumor cells in patients with hepatocellular carcinoma using a novel cell separation strategy. AB - PURPOSE: To establish a sensitive and specific isolation and enumeration system for circulating tumor cells (CTC) in patients with hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: HCC cells were bound by biotinylated asialofetuin, a ligand of asialoglycoprotein receptor, and subsequently magnetically labeled by antibiotin antibody-coated magnetic beads, followed by magnetic separation. Isolated HCC cells were identified by immunofluorescence staining using Hep Par 1 antibody. The system was used to detect CTCs in 5 mL blood. Blood samples spiked with Hep3B cells (ranging from 10 to 810 cells) were used to determine recovery and sensitivity. Prevalence of CTCs was examined in samples from HCC patients, healthy volunteers, and patients with benign liver diseases or non-HCC cancers. CTC samples were also analyzed by FISH. RESULTS: The average recovery was 61% or more at each spiking level. No healthy, benign liver disease or non-HCC cancer subjects had CTCs detected. CTCs were identified in 69 of 85 (81%) HCC patients, with an average of 19 +/- 24 CTCs per 5 mL. Both the positivity rate and the number of CTCs were significantly correlated with tumor size, portal vein tumor thrombus, differentiation status, and the disease extent as classified by the TNM (tumor-node-metastasis) classification and the Milan criteria. HER-2 gene amplification and TP53 gene deletion were detected in CTCs. CONCLUSION: Our system provides a new tool allowing for highly sensitive and specific detection and genetic analysis of CTCs in HCC patients. It is likely clinically useful in diagnosis and monitoring of HCC and may have a role in clinical decision making. PMID- 21527565 TI - Complications of the cut-and-push technique for percutaneous endoscopic gastrostomy tube removal. AB - The use of the "cut-and-push" technique for percutaneous endoscopic gastrostomy (PEG) removal has been recognized since 1991. This technique is used in patients who are thought to have no risk of distal adhesions or strictures. Its use in selected patients is supported by current British Society of Gastorenterology guidelines. However, the risk of complications has long been debated. This report describes a patient who developed complications as a result of PEG removal using the cut-and-push technique. The patient had undergone previous abdominal surgery, and removal of the PEG endoscopically was not possible. A barium follow-through was performed in light of the history, and it excluded any mechanical blockage. Follow-up x-ray showed passage of the remnant beyond the pylorus. Despite this, the remnant became lodged in the small bowel, eventually resulting in perforation and death. This case highlights the fact that impaction of the remnant can occur in patients without evidence of mechanical obstruction on investigation. This raises a question about the need for serial x-rays to ensure passage of the remnant if the patient cannot confirm this visually. PMID- 21527566 TI - Never say never again. PMID- 21527567 TI - Continuous positive airway pressure reduces postprandial lipidemia in obstructive sleep apnea: a randomized, placebo-controlled crossover trial. AB - RATIONALE: Dyslipidemia is common in Obstructive Sleep Apnea (OSA). Postprandial lipidemia (PPL) is a strong marker of cardiovascular risk. Evidence that OSA treatment improves PPL is lacking. OBJECTIVES: To investigate the effect of continuous positive airway pressure (CPAP) treatment on postprandial lipidemia (PPL) in patients with obstructive sleep apnea (OSA) in the upper moderate or severe range. METHODS: In this randomized, placebo-controlled crossover trial, we compared the effects of 2 months each of therapeutic and placebo CPAP on PPL. MEASUREMENTS AND MAIN RESULTS: PPL was determined from the area under the 24-hour triglyceride concentration curve (TAG-AUC(24)) using seven blood samples drawn across both the wake and sleep periods. Secondary outcomes were the difference in other 24-hour lipid profiles. Thirty-eight eligible patients were randomly assigned to a treatment order and 29 patients completed the trial. CPAP reduced PPL compared with placebo with a mean TAG-AUC(24) difference of -357 mmol/L/d (95% confidence interval [CI], -687.3 to -26.8; P = 0.035). During both the CPAP and placebo studies, TAG levels peaked during both wakefulness (2:00 p.m.) and sleep (3:00 a.m.). Both peaks were lower during CPAP than placebo: 2:00 p.m., 0.49 mmol/L (95% CI, -0.74 to -0.24; P < 0.0005) and 3:00 a.m., -0.40 mmol/L (95% CI, -0.65 to -0.15; P = 0.002). Moreover, mean 24-hour total cholesterol was 0.19 mmol/L lower on CPAP (95% CI, -0.27 to -0.11; P < 0.00001). CONCLUSIONS: This randomized trial demonstrated that treatment of severe OSA with CPAP improves postprandial TAG and total cholesterol levels. These effects may reduce the risk for cardiovascular events. The results imply that the association between OSA and cardiovascular disease may, in part, be caused by direct effects on dyslipidemia. Clinical trial registered with the Australian and New Zealand Clinical Trials Registry at www.anzctr.org.au (ACTRN 12605000066684). PMID- 21527568 TI - Comment on "global N-acetylaspartate declines even in benign multiple sclerosis". PMID- 21527569 TI - The treatment of unruptured cerebral aneurysms: cause for concern? PMID- 21527570 TI - A 3T MR imaging investigation of the topography of whole spinal cord atrophy in multiple sclerosis. AB - BACKGROUND AND PURPOSE: Spinal cord atrophy is a common feature of MS. However, it is unknown which cord levels are most susceptible to atrophy. We performed whole cord imaging to identify the levels most susceptible to atrophy in patients with MS versus controls and also tested for differences among MS clinical phenotypes. MATERIALS AND METHODS: Thirty-five patients with MS (2 with CIS, 27 with RRMS, 2 with SPMS, and 4 with PPMS phenotypes) and 27 healthy controls underwent whole cord 3T MR imaging. The spinal cord contour was segmented and assigned to bins representing each C1 to T12 vertebral level. Volumes were normalized, and group comparisons were age-adjusted. RESULTS: There was a trend toward decreased spinal cord volume at the upper cervical levels in PPMS/SPMS versus controls. A trend toward increased spinal cord volume throughout the cervical and thoracic cord in RRMS/CIS versus controls reached statistical significance at the T10 vertebral level. A statistically significant decrease was found in spinal cord volume at the upper cervical levels in PPMS/SPMS versus RRMS/CIS. CONCLUSIONS: Opposing pathologic factors impact spinal cord volume measures in MS. Patients with PPMS demonstrated a trend toward upper cervical cord atrophy. However patients with RRMS showed a trend toward increased volume at the cervical and thoracic levels, which most likely reflects inflammation or edema-related cord expansion. With the disease causing both expansion and contraction of the cord, the specificity of spinal cord volume measures for neuroprotective therapeutic effect may be limited. PMID- 21527571 TI - Peripheral nerve surgery: the role of high-resolution MR neurography. AB - High-resolution MRN is becoming increasingly available due to recent technical advancements, including higher magnetic field strengths (eg, 3T), 3D image acquisition, evolution of novel fat-suppression methods, and improved coil design. This review describes the MRN techniques for obtaining high-quality images of the peripheral nerves and their small branches and imaging findings in normal as well as injured nerves with relevant intraoperative correlations. Various microsurgical techniques in peripheral nerves, such as neurolysis, nerve repairs by using nerve grafts, and conduits are discussed, and MRN findings of surgically treated nerves are demonstrated. PMID- 21527573 TI - A novel "Y" stent flow diversion technique for the endovascular treatment of bifurcation aneurysms without endosaccular coiling. AB - BACKGROUND AND PURPOSE: Stent-assisted endovascular treatment and flow diversion techniques are increasingly used for the management of wide-neck intracranial aneurysms. We report our initial clinical experience using a new flow diversion technique for the endovascular management of bifurcation aneurysms. MATERIALS AND METHODS: Eight bifurcation aneurysms were treated by placing 2 stents in Y configuration with no accompanying endosaccular packing. This treatment technique aimed at flow diversion was selected in these cases because 1) the aneurysm was giant and causing mass effect, 2) the emanating branches were incorporated within the sac, or 3) the aneurysm was too small. Aneurysms were located at middle cerebral (5 aneurysms) and basilar artery bifurcations (3 aneurysms). Five aneurysms were small, 1 was large, and 2 were partially thrombosed giant. Closed cell stents were used in all Y-stent placement procedures. RESULTS: In all aneurysms, both stents could be placed at the intended locations without any procedural complication. Follow-up angiograms obtained at 3 months to 2 years demonstrated that all stents were patent except for one with asymptomatic P1 occlusion. Complete occlusion with remodelled bifurcation was observed in all middle cerebral artery bifurcation aneurysms and the large basilar tip aneurysm. Residual filling despite reduction in size was observed in both of the partially thrombosed giant aneurysms at 2-year and 3-month follow-up angiograms, respectively. CONCLUSIONS: Flow diversion with double stent placement in Y configuration provided successful and stable aneurysm occlusion. The technical and clinical results achieved are highly encouraging that this technique may contribute to the endovascular treatment of these complex bifurcation aneurysms. PMID- 21527574 TI - Perinatal Pitocin as an early ADHD biomarker: neurodevelopmental risk? AB - OBJECTIVE: To investigate a potential relationship between coincidental increases in perinatal Pitocin usage and subsequent childhood ADHD onset in an attempt to isolate a specific risk factor as an early biomarker of this neurodevelopmental disorder. METHOD: Maternal labor/delivery and corresponding childbirth records of 172 regionally diverse, heterogeneous children, ages 3 to 25, were examined with respect to 21 potential predictors of later ADHD onset, including 17 selected obstetric complications, familial ADHD incidence, and gender. ADHD diagnosis and history of perinatal Pitocin exposure distinguished groups for comparison. RESULTS: Results revealed a strong predictive relationship between perinatal Pitocin exposure and subsequent childhood ADHD onset (occurring in 67.1% of perinatal Pitocin cases vs. 35.6% in nonexposure cases, chi(2)=16.99, p<.001). Fetal exposure time, gestation length, and labor length also demonstrated predictive power, albeit significantly lower. CONCLUSION: The findings warrant further investigation into the potential link between perinatal Pitocin exposure and subsequent ADHD diagnosis. PMID- 21527575 TI - Dose response effects of lisdexamfetamine dimesylate treatment in adults with ADHD: an exploratory study. AB - OBJECTIVE: To explore dose-response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD. METHOD: This was a 4-week, randomized, double-blinded, placebo-controlled, parallel-group, forced-dose titration study in adult participants, aged 18 to 55 years, meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.) criteria for ADHD. RESULTS: Nearly all participants assigned to an LDX dose achieved their assigned dose with the exception of about 4% of participants assigned to the 50 mg or 14% assigned to the 70 mg doses. Higher doses of LDX led to greater improvements in ADHD-rating scale scores, independent of prior pharmacotherapy. This was evident for both inattentive and hyperactive-impulsive symptoms. The authors found some evidence for an interaction between LDX dose and baseline severity of ADHD symptoms. CONCLUSION: For LDX doses between 30 and 70 mg/d, the dose-response efficacy effect for LDX is not affected by prior pharmacotherapy, but patients with a greater severity of illness may benefit more from higher doses, especially for hyperactive-impulsive symptoms. The results do not provide information about doses above 70 mg/d, which is the maximum approved dose of LDX and the highest dose studied in ADHD clinical trials. PMID- 21527576 TI - Risks for persistence and progression by human papillomavirus type 16 variant lineages among a population-based sample of Danish women. AB - BACKGROUND: Little is known about factors determining HPV16 persistence and progression, but several studies have suggested that genetic variants may play a role. METHODS: HPV16-positive women with normal cytology in a large Danish cohort were reassessed for HPV16 status at 2 years and followed-up for cervical intraepithelial neoplasia 3 or worse (CIN3+) over 11 years through linkage with a national pathology database. Relative risks for clearance, persistence, and progression were compared with different HPV16 variant lineages based upon E6 gene sequencing. RESULTS: Sixty-two (23.7%) of 261 HPV16 infections were persistent at 2 years, and 32 (51.6%) persistent infections progressed to CIN3+. The majority of baseline infections belonged to the European lineage (97.3%), with EUR-350T and EUR-350G accounting for 61.3% and 36.0% of infections, respectively. At two years, the proportion of HPV16 infections that persisted was significantly higher for EUR-350T (28.2%) than EUR-350G (15.9%) variants (odds ratio = 2.06, 95% CI, 1.04-4.25). This increased risk for persistence was consistent both in the absence (OR = 2.16, 95% CI, 0.84-6.26) or presence (OR = 1.89, 95% CI, 0.76-5.15) of progression to CIN3+. Among persistent HPV16 infections, there was no significant difference in risk of progression to CIN3+ between EUR-350T and EUR-350G sub-lineages, which were both associated with a substantial absolute risk (>50%) of CIN3+. CONCLUSIONS: Significant differences in risk for persistence exist between the HPV16 variants that predominate in Europe. IMPACT: Understanding the genetic basis of HPV16 persistence and carcinogenicity may help unravel important interactions between HPV16 and the host immune system. PMID- 21527577 TI - Urinary biomarkers of meat consumption. AB - BACKGROUND: Meat intake has been positively associated with incidence and mortality of chronic diseases, including diabetes, heart disease, and several different cancers, in observational studies by using self-report methods of dietary assessment; however, these dietary assessment methods are subject to measurement error. One method to circumvent such errors is the use of biomarkers of dietary intake, but currently there are no accepted biomarkers for meat intake. METHODS: We investigated four analytes (creatinine, taurine, 1 methylhistidine, and 3-methylhistidine) specifically found in meat and excreted in urine. Twenty-four-hour urine samples were collected from 17 individuals on controlled diets containing varying levels of meat: vegetarian (0 g/d), low red meat (60 g/d), medium red meat (120 g/d), and high red meat (420 g/d), as part of two randomized crossover feeding studies. RESULTS: When compared with the low red meat diet or the vegetarian diet, the urinary levels of all four analytes were significantly higher in urine samples collected after 15 days of a high red meat diet (P < 0.0001). Only urinary 1-methylhistidine and 3-methylhistidine were statistically significantly different for every diet type, increasing as the amount of meat in the diet increased (P < 0.01 for 1-methylhistidine and P < 0.05 for 3-methylhistidine). Furthermore, urinary excretion of 1-methylhistidine and 3 methylhistidine elevated with increasing meat intake in every individual. CONCLUSION: Urinary 1-methylhistidine and 3-methylhistidine may be good biomarkers of meat intake. IMPACT: To determine the public health impact of red meat on cancer risk, biomarkers are crucial to estimate true intake; these potential biomarkers should be further investigated in free-living populations. PMID- 21527578 TI - Advanced glycation end products, soluble receptor for advanced glycation end products, and risk of colorectal cancer. AB - BACKGROUND: Advanced glycation end products (AGE) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE-ligand engagement. METHODS: We examined the association between N(epsilon)-(carboxymethyl)lysine (CML), a prominent AGE, and sRAGE and colorectal cancer risk in a prospective case-cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer 5 years after baseline (1985-1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI. RESULTS: Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI, 0.39-1.07; P(trend) = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR = 0.52; 95% CI, 0.30-0.89; P(trend) = 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR = 1.20; 95% CI, 0.64-2.26). CONCLUSIONS: Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers. IMPACT: This is the first epidemiologic study to implicate the receptor for AGEs in colorectal cancer development. PMID- 21527579 TI - CYP2D6 gene variants and their association with breast cancer susceptibility. AB - BACKGROUND: The gene encoding the phase I enzyme cytochrome P4502D6 (CYP2D6) has been previously investigated for its potential predictive role in the efficacy of breast cancer treatments such as tamoxifen, but its role in breast cancer susceptibility is unclear. This study aims to evaluate the association between germ line variations in CYP2D6 and breast cancer susceptibility. METHODS: DNA samples from 13,472 cases and controls were genotyped for seven known functional variants [minor allele frequency (MAF) >= 0.01] and five single nucleotide polymorphisms (SNP) that tag common genetic variation (MAF > 0.05) in CYP2D6. RESULTS: One relatively rare functional variant, CYP2D6*6, (MAF = 0.01) showed a modest increased association with breast cancer susceptibility (P(trend) = 0.02; OR = 1.32; 95% CI = 1.04-1.68). All other functional and tagSNPs showed no association with breast cancer susceptibility. CONCLUSIONS: Common variants of CYP2D6 do not play a significant role in breast cancer susceptibility. However, this study raises questions regarding the role of rare variants, such as CYP2D6*6, in breast cancer susceptibility which merit further investigation. IMPACT: This large case-control study, involving 13,472 women, found no evidence of any association between common CYP2D6 gene variants and breast cancer susceptibility. However, one relatively rare functional variant CYP2D6*6 showed a modest association with breast cancer susceptibility, indicating that the role of rare CYP2D6 variants in breast cancer risk is unclear and requires further investigation in an adequately powered study. PMID- 21527580 TI - The Association between cutaneous squamous cell carcinoma and betapapillomavirus seropositivity: a cohort study. AB - BACKGROUND: It is currently unclear whether betapapillomaviruses (betaPV) play a role in the etiology of cutaneous squamous cell carcinoma (SCC). We investigated the association between betaPV antibodies and subsequent SCC in a population based cohort study. METHODS: Serum samples were collected in 1992 and/or 1996 from 1,311 participants of the community-based Nambour Skin Cancer Study. These were tested for the presence of L1 antibodies against 21 different betaPV types. Histologically diagnosed SCCs were ascertained through three full-body skin examinations and linkage with the local pathology laboratories. We used age- and sex-adjusted Cox proportional hazards models to analyze the relationship between betaPV antibodies and SCC occurrence from 1992 until 2007. RESULTS: SCC was newly diagnosed in 150 people. No associations were found between the presence of any betaPV L1 antibodies and the occurrence of SCC (HR = 1.0), and stratification by sex, skin color, and sunburn propensity did not affect these results. However, among people who were less than 50 years old in 1992, the presence of betaPV antibodies was associated with a two-fold increased risk of SCC. There was no significant association between antibodies to any individual betaPV type examined and the later development of SCC. CONCLUSIONS: Whether betaPV infection of the skin, and indirectly betaPV antibodies, are involved in the oncogenic process in the general population remains unclear, and this longitudinal study provides only limited support. IMPACT: This study emphasizes the need for additional longitudinal studies of HPV (human papilloma virus) and SCC, to avoid the possibility of reverse causality in case--control studies. PMID- 21527581 TI - Age-stratified performance of the Cervista HPV 16/18 genotyping test in women with ASC-US cytology. AB - BACKGROUND: The objective of this study was to evaluate the clinical performance of the Cervista HPV 16/18 genotyping test for detection of human papilloma virus (HPV) 16 and 18 in cervical cytology specimens in women stratified by age. METHODS: In a multicenter, prospective clinical study, ThinPrep specimens were tested for the presence of HPV 16 and 18 using the HPV 16/18 genotyping test. Genotyping results from women with atypical squamous cells of undetermined significance or greater cytology were compared with local colposcopy and/or histology results. Sensitivity, specificity, and negative and positive predictive values (NPV and PPV) were determined. RESULTS: The prevalence of cervical intraepithelial neoplasia (CIN) 2(+) in subjects positive for HPV 16/18 was 6.6% and 4.1% for women <30 and >=30 years of age, respectively. The sensitivity of the test was 70.0% (95% CI: 54.6-81.9) and 66.7% (95% CI: 46.7-82.0) in women <30 and >=30 years, respectively. The NPV was 95.5% (95% CI: 93.4-97.6) in women <30 years and 96.6% (95% CI: 94.8-98.5) in women >=30 years. Specificity was higher in women >=30 years (79.9%; 95% CI: 74.9-84.2) than women <30 years (61.9%; 95% CI: 57.1-66.4). The PPV was 15.2% (95% CI: 12.7-19.1) in women <30 years and 21.9% (95% CI: 17.0-30.7) in women >=30 years. CONCLUSIONS: The performance of the Cervista HPV 16/18 genotyping test for predicting >=CIN 2 is what would be expected across the key >=CIN 2 age strata. IMPACT: HPV 16/18 genotyping may help further stratify women with a greater potential to develop cervical cancer. PMID- 21527582 TI - Serum 25-hydroxyvitamin D and risk of oropharynx and larynx cancers in Finnish men. AB - BACKGROUND: Published studies suggesting a relationship between vitamin D and some common cancers sparked interest in the association of vitamin D with head and neck cancers. Prolonged darker months in Finland are associated with lower levels of ultraviolet B radiation, raising concerns about low vitamin D levels. METHODS: We used a nested case--control study in the prospective Alpha-Tocopherol Beta Carotene (ATBC) Study of male smokers in Finland, to examine the relationship between serum 25(OH)D and risk of developing squamous cancers of the head and neck. Using conditional logistic regression, we calculated the multivariate adjusted ORs and CIs comparing those with serum 25(OH)D adequate levels of 50 to <75 nmol/L to those <25.0. RESULTS: We identified incident cancers of the oral cavity (n = 134), pharynx (n = 48), and larynx (n = 158). Median serum vitamin D was 31 nmol/L (interquartile range: 21-48), which is below the 50 nmol/L cutoff point was considered adequate for bone and overall health. Comparing those with serum 25(OH)D below 25 nmol/L to those 50 to <75 nmol/L as the referent, the OR was 1.35 (95% CI: 0.53-3.43, P(trend) = 0.65) for overall head and neck cancers. Stratification by cancer subsites of the oral cavity, pharynx, and larynx (P(trend) = 0.93, 0.78, 0.26, respectively) or by season of blood draw also showed no association. CONCLUSIONS: Our study showed no association between serum 25(OH)D and risk of head and neck cancers. IMPACT: This study does not support the hypothesis that greater vitamin D exposure would reduce the risk of developing head and neck squamous cancers. PMID- 21527583 TI - TGF-beta signaling pathway and breast cancer susceptibility. AB - BACKGROUND: TGF-beta acts as a suppressor of primary tumor initiation but has been implicated as a promoter of the later malignant stages. Here associations with risk of invasive breast cancer are assessed for single-nucleotide polymorphisms (SNP) tagging 17 genes in the canonical TGF-beta ALK5/SMADs 2&3 and ALK1/SMADs 1&5 signaling pathways: LTBP1, LTBP2, LTBP4, TGFB1, TGFB2, TGFB3, TGFBR1(ALK5), ALK1, TGFBR2, Endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, and SMAD7 [Approved Human Gene Nomenclature Committee gene names: ACVRL1 (for ALK1) and ENG (for Endoglin)]. METHODS: Three-hundred-fifty-four tag SNPs (minor allele frequency > 0.05) were selected for genotyping in a staged study design using 6,703 cases and 6,840 controls from the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) study. Significant associations were meta analyzed with data from the NCI Polish Breast Cancer Study (PBCS; 1,966 cases and 2,347 controls) and published data from the Breast Cancer Association Consortium (BCAC). RESULTS: Associations of three SNPs, tagging TGFB1 (rs1982073), TGFBR1 (rs10512263), and TGFBR2 (rs4522809), were detected in SEARCH; however, associations became weaker in meta-analyses including data from PBCS and BCAC. Tumor subtype analyses indicated that the TGFB1 rs1982073 association may be confined to increased risk of developing progesterone receptor negative (PR(-)) tumors [1.18 (95% CI: 1.09-1.28), 4.1 * 10(-5) (P value for heterogeneity of ORs by PR status = 2.3 * 10(-4))]. There was no evidence for breast cancer risk associations with SNPs in the endothelial-specific pathway utilizing ALK1/SMADs 1&5 that promotes angiogenesis. CONCLUSION: Common variation in the TGF-beta ALK5/SMADs 2&3 signaling pathway, which initiates signaling at the cell surface to inhibit cell proliferation, might be related to risk of specific tumor subtypes. IMPACT: The subtype specific associations require very large studies to be confirmed. PMID- 21527584 TI - B-cell stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B cell lymphoma. AB - BACKGROUND: The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine whether elevated serum levels of molecules associated with B-cell activation precede the diagnosis of AIDS-associated NHL (AIDS-NHL). METHODS: Serum levels of B-cell activation-associated molecules, interleukin (IL)6, IL10, soluble CD23 (sCD23), sCD27, sCD30, C-reactive protein (CRP), and immunoglobulin E were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to 3 time points per subject, 0 to 5 years prior to AIDS-NHL diagnosis. RESULTS: Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared with HIV+ controls or with AIDS controls, after adjusting for CD4 T-cell number. Elevated serum levels of B-cell activation-associated molecules were seen to be associated with the development of systemic [non-CNS (central nervous system)] NHL, but not with the development of primary CNS lymphoma. CONCLUSIONS: Levels of certain B-cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B-cell activation contributes to the development of these hematologic malignancies. IMPACT: Marked differences in serum levels of several molecules are seen for several years prediagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL. PMID- 21527585 TI - Differential activity of NADPH-producing dehydrogenases renders rodents unsuitable models to study IDH1R132 mutation effects in human glioblastoma. AB - The somatic IDH1(R132) mutation in the isocitrate dehydrogenase 1 gene occurs in high frequency in glioma and in lower frequency in acute myeloid leukemia and thyroid cancer but not in other types of cancer. The mutation causes reduced NADPH production capacity in glioblastoma by 40% and is associated with prolonged patient survival. NADPH is a major reducing compound in cells that is essential for detoxification and may be involved in resistance of glioblastoma to treatment. IDH has never been considered important in NADPH production. Therefore, the authors investigated NADPH-producing dehydrogenases using in silico analysis of human cancer gene expression microarray data sets and metabolic mapping of human and rodent tissues to determine the role of IDH in total NADPH production. Expression of most NADPH-producing dehydrogenase genes was not elevated in 34 cancer data sets except for IDH1 in glioma and thyroid cancer, indicating an association with the IDH1 mutation. IDH activity was the main provider of NADPH in human normal brain and glioblastoma, but its role was modest in NADPH production in rodent brain and other tissues. It is concluded that rodents are a poor model to study consequences of the IDH1(R132) mutation in glioblastoma. PMID- 21527586 TI - Expression of calcium binding proteins in mouse type II taste cells. AB - It is well established that calcium is a critical signaling molecule in the transduction of taste stimuli within the peripheral taste system. However, little is known about the regulation and termination of these calcium signals in the taste system. The authors used Western blot, immunocytochemical, and RT-PCR analyses to evaluate the expression of multiple calcium binding proteins in mouse circumvallate taste papillae, including parvalbumin, calbindin D28k, calretinin, neurocalcin, NCS-1 (or frequenin), and CaBP. They found that all of the calcium binding proteins they tested were expressed in mouse circumvallate taste cells with the exception of NCS-1. The authors correlated the expression patterns of these calcium binding proteins with a marker for type II cells and found that neurocalcin was expressed in 80% of type II cells, whereas parvalbumin was found in less than 10% of the type II cells. Calretinin, calbindin, and CaBP were expressed in about half of the type II cells. These data reveal that multiple calcium binding proteins are highly expressed in taste cells and have distinct expression patterns that likely reflect their different roles within taste receptor cells. PMID- 21527587 TI - First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07). AB - BACKGROUND: Oral temozolomide has shown similar efficacy to dacarbazine in phase III trials with median progression-free survival (PFS) of 2.1 months. Bevacizumab has an inhibitory effect on the proliferation of melanoma and sprouting endothelial cells. We evaluated the addition of bevacizumab to temozolomide to improve efficacy in stage IV melanoma. PATIENTS AND METHODS: Previously untreated metastatic melanoma patients with Eastern Cooperative Oncology Group performance status of two or more were treated with temozolomide 150 mg/m(2) days 1-7 orally and bevacizumab 10 mg/kg body weight i.v. day 1 every 2 weeks until disease progression or unacceptable toxicity. The primary end point was disease stabilisation rate [complete response (CR), partial response (PR) or stable disease (SD)] at week 12 (DSR12); secondary end points were best overall response, PFS, overall survival (OS) and adverse events. RESULTS: Sixty-two patients (median age 59 years) enrolled at nine Swiss centres. DSR12 was 52% (PR: 10 patients and SD: 22 patients). Confirmed overall response rate was 16.1% (CR: 1 patient and PR: 9 patients). Median PFS and OS were 4.2 and 9.6 months. OS (12.0 versus 9.2 months; P = 0.014) was higher in BRAF V600E wild-type patients. CONCLUSIONS: The primary end point was surpassed showing promising activity of this bevacizumab/temozolomide combination with a favourable toxicity profile. Response and OS were significantly higher in BRAF wild-type patients. PMID- 21527588 TI - Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience. AB - BACKGROUND: Majority of gastrointestinal stromal tumours (GISTs) are characterised by KIT-immunopositivity and the presence of KIT/platelet-derived growth factor receptor alpha (PDGFRA) activating mutations. PATIENTS AND METHODS: Spectrum and frequency of KIT and PDGFRA mutations were investigated in 427 GISTs. Univariate and multivariate analysis of relapse-free survival (RFS) was conducted in relation to tumours' clinicopathologic features and genotype. RESULTS: Mutations were found in 351 (82.2%) cases, including 296 (69.3%) KIT and 55 (12.9%) PDGFRA isoforms. Univariate analysis revealed higher 5-year RFS rate in women (37.9%; P = 0.028) and in patients with gastric tumours (46.3%; P < 0.001). In addition a better 5-year RFS correlated with smaller tumour size <= 5 cm (62.7%; P < 0.001), tumours with mitotic index <= 5/50 high-power fields (60%; P < 0.001), and characterised by (very) low/moderate risk (70.2%; P = 0.006). Patients with GISTs bearing deletions encompassing KIT codons 557/558 had worse 5 year RFS rate (23.8%) than those with any other KIT exon 11 mutations (41.8%; P < 0.001) or deletions not involving codons 557/558 (33.3%; P = 0.007). Better 5 year RFS characterised patients with KIT exon 11 point mutations (50.7%) or duplications (40%). By multivariate analysis, tumours with PDGFRA mutations and KIT exon 11 point mutations/other than 557/558 deletions had lower risk of progression than with KIT exon 11 557/558 deletions (both Ps = 0.001). CONCLUSIONS: KIT/PDGFRA mutational status has prognostic significance for patients' outcome and may help in management of patients with GISTs. PMID- 21527589 TI - Medical oncology recognized at EU level to allow free movement of doctors: progress and challenge. PMID- 21527591 TI - Vitamin D--new recommendations worthy of our consideration. PMID- 21527590 TI - A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. AB - PURPOSE: After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma. EXPERIMENTAL DESIGN: Patients > 14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided. RESULTS: Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (< 30% tumor shrinkage) and 12 (34%) stable diseases (SDs). For six patients (17%), PR/SD lasted >= 6 months. Noteworthy, tumor density reduction and [(18)F]2-fluoro-2-deoxy-d-glucose positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity. CONCLUSIONS: Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations. PMID- 21527592 TI - Ethical issues in nutrition support of severely disabled elderly persons: a guide for health professionals. AB - Providing or withholding nutrition in severely disabled elderly persons is a challenging dilemma for families, health professionals, and institutions. Despite limited evidence that nutrition support improves functional status in vulnerable older persons, especially those suffering from dementia, the issue of nutrition support in this population is strongly debated. Nutrition might be considered a basic need that not only sustains life but provides comfort as well by patients and their families. Consequently, the decision to provide or withhold nutrition support during medical care is often complex and involves clinical, legal, and ethical considerations. This article proposes a guide for health professionals to appraise ethical issues related to nutrition support in severely disabled older persons. This guide is based on an 8-step process to identify the components of a situation, analyze conflicting values that result in the ethical dilemma, and eventually reach a consensus for the most relevant plan of care to implement in a specific clinical situation. A vignette is presented to illustrate the use of this guide when analyzing a clinical situation. PMID- 21527593 TI - Vitamin D deficiency in patients with inflammatory bowel disease: association with disease activity and quality of life. AB - BACKGROUND: Vitamin D deficiency is common in inflammatory bowel disease (IBD). The aim of the study was to determine the prevalence and predictors of vitamin D deficiency in an IBD cohort. It was hypothesized that vitamin D deficiency is associated with increased disease activity and lower health-related quality of life (HRQOL). METHODS: This was a retrospective cohort study. Harvey-Bradshaw index and ulcerative colitis disease activity index were used to assess disease activity. Short Inflammatory Bowel Disease Questionnaire scores were used to assess HRQOL. Multivariate logistic regression was used to identify independent predictors of vitamin D deficiency and its association with disease activity and HRQOL. RESULTS: The study included 504 IBD patients (403 Crohn's disease [CD] and 101 ulcerative colitis [UC]) who had a mean disease duration of 15.5 years in CD patients and 10.9 years in UC patients; 49.8% were vitamin D deficient, with 10.9% having severe deficiency. Vitamin D deficiency was associated with older age (P = .004) and older age at diagnosis (P = .03). Vitamin D deficiency was associated with lower HRQOL (regression coefficient -2.21, 95% confidence interval [CI], -4.10 to -0.33) in CD but not UC (regression coefficient 0.41, 95% CI, -2.91 to 3.73). Vitamin D deficiency was also associated with increased disease activity in CD (regression coefficient 1.07, 95% CI, 0.43 to 1.71). CONCLUSIONS: Vitamin D deficiency is common in IBD and is independently associated with lower HRQOL and greater disease activity in CD. There is a need for prospective studies to assess this correlation and examine the impact of vitamin D supplementation on disease course. PMID- 21527594 TI - Effects of perioperative synbiotic treatment on infectious complications, intestinal integrity, and fecal flora and organic acids in hepatic surgery with or without cirrhosis. AB - BACKGROUND: The aim of this study was to assess the effect of preoperative and postoperative synbiotic treatment in hepatectomy patients with or without liver cirrhosis. METHODS: Sixty-one patients with hepatic cancer were assigned randomly to receive either oral synbiotics that consisted of Bifidobacterium, Lactobacillus, and galactooligosaccharides or no synbiotics (control) preoperatively for 14 days and postoperatively for 11 days. Infectious complications, intestinal mucosal integrity as measured by serum diamine oxidase (DAO) activity, and fecal flora and organic acid concentrations were compared between synbiotic treatment (n = 32) and control (n = 29) groups. RESULTS: Fecal flora culture and organic acid concentrations were changed after hepatectomy in both groups. The postsurgery decrease in DAO activity was less profound in the synbiotic-treated group (P < .01) and was correlated negatively with serum interleukin 6 and C-reactive protein concentrations (P < .001). Infectious complications occurred in 5 (17.2%) patients in the control group and no patients in the synbiotic-treated group (P < .05). CONCLUSION: Perioperative synbiotic treatment attenuated the decrease in intestinal integrity and reduced the rate of infectious complications in patients with or without liver cirrhosis who underwent hepatic surgery. PMID- 21527595 TI - Parenteral nutrition administration leads to specific alterations in the expression of adipocytokines and peroxisome proliferator-activated receptors in a rat model. AB - BACKGROUND: Similar to metabolic syndrome, parenteral nutrition (PN) administration has also been associated with biologic abnormalities of glucose and lipids. Such complications include hyperglycemia, hypertriglyceridemia, liver dysfunction, and hepatobiliary complications. Because metabolic syndrome has been associated with altered expression of adipocytokines, and peroxisome proliferator activated receptors (PPARs), the present study hypothesized that PN would also lead to alterations in adipocytokines and related gene abundances. METHODS: Male Wister rats received either intravenous (IV) saline and chow (control) or PN. To determine the contribution of lipids to metabolic changes, the following 2 PN groups were studied: PN with IV lipid (PN+L) and PN without lipid (PN-L). Rats were studied after 7 days. RESULTS: A marked increase in hepatic glycogen staining was found in the PN-L group, and conversely, a marked increase in hepatic lipid staining was observed in the PN+L group. Both PN groups demonstrated a 30% increase in serum adiponectin levels in comparison to controls. In the liver, ACDC mRNA expression significantly increased (10%-20%), while ADIPOR1 expression significantly declined in the PN groups compared with controls. PPAR expression significantly declined (10%-30%) in the PN+L group compared with controls. In contrast to metabolic syndrome, PN+L led to a decrease in tumor necrosis factor alpha and interleukin 6 levels in the liver. CONCLUSIONS: The study shows that PN led to specific alterations in the abundance of adipocytokines and PPARs. These changes give critical insight into many of the metabolic derangements in lipid metabolism, which patients may experience with PN. PMID- 21527597 TI - Efficacy of tube feeding in binge-eating/vomiting patients: a 2-month randomized trial with 1-year follow-up. AB - BACKGROUND: In many binge-eating/vomiting patients, abstinence could not be obtained from classical treatments. Since the authors showed that tube feeding (TF) reduced such episodes in anorexia nervosa (AN)-hospitalized patients, they carried out a randomized trial on the efficacy of TF plus cognitive behavioral therapy (CBT) vs CBT alone in AN and bulimia nervosa adult outpatients. METHODS: The authors randomly assigned 103 ambulatory patients to receive 16 sessions of CBT alone (n = 51) or CBT plus 2 months of TF (n = 52). The main goal was abstinence of binge-eating/vomiting episodes. Other criteria were gains in fat free mass and muscle mass improvements in nutrition markers, and quality of life (SF-36 Health Survey), depression (Beck Depression Inventory), and anxiety (Hamilton Anxiety Rating Scale) scores. Evaluations were performed at 1, 2 (end of treatment), 5, 8, and 14 months (analysis of variance). RESULTS: TF patients were rapidly and more frequently abstinent at the end of treatment (2 months) than the CBT patients: 81% vs 29% (P < .001). Fat-free mass, biological markers, depressive state (-58% vs -26%), anxiety (-48% vs -15%), and quality of life (+42% vs +13%) were more improved in the TF group than in the CBT group (P < .05). One year later, more TF patients remained abstinent (68% vs 27%, P = .02); they were less anxious, were less depressed, and had better quality of life than the CBT patients (P < .05). CONCLUSION: TF combined with CBT offered better results than CBT alone. PMID- 21527596 TI - Relationship between feeding tube site and respiratory outcomes. AB - BACKGROUND: It is unclear if placing feeding tubes postpylorically to prevent respiratory complications is worth the extra effort. This study sought to determine the extent to which aspiration and pneumonia are associated with feeding site (controlling for the effects of severity of illness, degree of head of-bed elevation, level of sedation, and use of gastric suction). METHODS: A retrospective analysis was performed on a large data set gathered prospectively to evaluate aspiration in critically ill, mechanically ventilated patients. Feeding site was designated by attending physicians and confirmed by radiography. Each patient participated in the study for 3 consecutive days, with pneumonia assessed by the simplified Clinical Pulmonary Infection Score on the fourth day. Tracheal secretions were assayed for pepsin in a research laboratory; the presence of pepsin served as a proxy for aspiration. A total of 428 patients were included in the regression analyses performed to address the research objectives. RESULTS: As compared with the stomach, the percentage of aspiration was 11.6% lower when feeding tubes were in the first portion of the duodenum, 13.2% lower when in the second/third portions of the duodenum, and 18.0% lower when in the fourth portion of the duodenum and beyond (all significant at P < .001). Pneumonia occurred less often when feedings were introduced at or beyond the second portion of the duodenum (P = .020). CONCLUSIONS: The findings support feeding critically ill patients with numerous risk factors for aspiration in the mid-duodenum and beyond to reduce the risk of aspiration and associated pneumonia. PMID- 21527598 TI - Prophylactic percutaneous endoscopic gastrostomy tube placement in treatment of head and neck cancer: a comprehensive review and call for evidence-based medicine. AB - BACKGROUND: Patients with head and neck cancers (HNCs) are at increased risk of experiencing malnutrition, which is associated with poor outcomes. Advances in the treatment of HNCs have resulted in improved outcomes that are associated with severe toxic oral side effects, placing patients at an even greater risk of malnutrition. Prophylactic placement of percutaneous endoscopic gastrostomy (PEG) tubes before treatment may be beneficial in patients with HNC, especially those undergoing more intense treatment regimens. PEG tube placement, however, is not without risks. METHODS: A comprehensive review of the literature was conducted. RESULTS: Systematic evidence assessing both the benefits and harm associated with prophylactic PEG tube placement in patients undergoing treatment for HNC is weak, and benefits and harm have not been established. CONCLUSIONS: More research is necessary to inform physician behavior on whether prophylactic PEG tube placement is warranted in the treatment of HNC. PMID- 21527599 TI - Pureed by gastrostomy tube diet improves gagging and retching in children with fundoplication. AB - BACKGROUND: Children with feeding disorders requiring Nissen fundoplication may develop gagging and retching following gastrostomy feedings. We developed a "pureed by gastrostomy tube" (PBGT) diet in an attempt to treat these symptoms and provide adequate nutrition and hydration. METHODS: Children post- fundoplication surgery with symptoms of gagging and retching with gastrostomy feedings were selected from our interdisciplinary feeding team. An individualized PBGT diet was designed to meet the child's nutrition goals. The child's weight gain was recorded at each follow-up visit. A telephone survey was performed to determine parents' perceptions of the child's symptoms and oral feeding tolerance. RESULTS: Thirty-three children (mean age, 34.2 months) participated in the trial. Average weight gain on the PBGT diet was 6.2 g/d. Seventeen children (52%) were reported to have a 76%-100% reduction in gagging and retching. Twenty four children (73%) were reported to have a >= 50% decrease in symptoms. No child had worsened symptoms on the PBGT diet. Nineteen children (57%) were reported to have an increase in oral intake on the PBGT diet. CONCLUSIONS: A PBGT diet is an effective means of providing nutrition to children with feeding disorders. In children post-fundoplication surgery, a PBGT diet may decrease gagging and retching behaviors. PMID- 21527600 TI - Commercial enteral formulas and nutrition support teams improve the outcome of home enteral tube feeding. AB - BACKGROUND: The benefits of home enteral tube feeding (HETF) provided by nutrition support teams (NSTs) have been questioned recently, given the growing costs to the healthcare system. This study examined the effect of a specialized home enteral nutrition program on clinical outcome variables in HETF patients. METHODS: The observational study included 203 patients (103 women, 100 men; mean age 52.5 years) receiving HETF with homemade diets for at least 12 months before starting a specialized home nutrition program for another 12 months consisting of provision of commercial enteral formulas and the guidance of an NST. Both study periods were compared regarding the number of hospital admissions, length of hospital and intensive care unit (ICU) stay, and costs of hospitalization. RESULTS: A specialized HETF program significantly reduced the number of hospital admissions and the duration of hospital and ICU stays. The need for hospitalization and ICU admission was significantly reduced, with odds ratios of 0.083 (95% confidence interval, 0.051-0.133, P < .001) and 0.259 (95% confidence interval, 0.124-0.539, P < .001), respectively. Specialized HETF was associated with a significant decrease in the prevalence of pneumonia (24.1% vs 14.2%), respiratory failure (7.3% vs 1.9%), urinary tract infection (11.3% vs 4.9%), and anemia (3.9% vs 0%) requiring hospitalization. The average yearly cost of hospital treatment decreased from $764.65 per patient to $142.66 per year per patient. CONCLUSIONS: The specialized HETF care program reduces morbidity and costs related to long-term enteral feeding at home. PMID- 21527601 TI - Omega-3-enriched lipid emulsion for liver salvage in parenteral nutrition-induced cholestasis in the adult patient. AB - The intrahepatic cholestasis attributed to parenteral nutrition (PN) in the adult patient is relatively rare and usually occurs in patients receiving long-term PN. This article reports the first case of an adult patient with cholestatic PN associated liver disease without sepsis who received almost all her nutrition requirements through PN. Administration of an omega-3-enriched lipid emulsion added to the PN regimen reversed cholestasis and demonstrated histologic improvement on serial liver biopsy. The patient had failed to respond to other modalities of treatment for this condition and was deeply jaundiced. Liver biochemistry profiles returned to baseline, and follow-up liver biopsy showed that cholestasis had resolved and that the only residual changes were mild portal inflammation with no histochemical or ultrastructural progression. The PN regimen for the patient was restored to provide total estimated energy requirements and remains the principle source of the patient's nutrition to date. PMID- 21527602 TI - Sterility of pediatric lipid emulsions repackaged by an automated compounding device. AB - BACKGROUND: The daily requirement of intravenous (IV) lipid in pediatric patients is often less than the volumes and sizes available in prepackaged, commercially available preparations. In clinical practice, IV lipid emulsions (IVLEs) have been repackaged into syringes to prevent infusions from exceeding 12 hours, to reduce waste, and to improve patient safety. Recent data suggest an increasing risk of contamination when these preparations are repackaged manually. This study investigates the sterility of small volumes of IVLE that have been repackaged into empty IV bags by means of an automated compounding device (ACD). METHODS: A total of 152 IVLE bags were repackaged with an ACD in an International Standards Organization class 5 environment. IVLE repackaging was conducted over a period of 3 weeks (week 1, n = 52; week 2, n = 52; week 3, n = 48). Forty commercially available bags of IVLE served as controls. At 0, 24, 48, and 120 hours after repackaging, IVLEs were filtered and placed onto blood agar medium. RESULTS: Microbial growth occurred in 12 of the 152 repackaged preparations compared with 0 of the 40 controls (7.9% vs 0%, P = .07). Positive cultures consisted of gram positive cocci (n = 5, 3.3%), gram-positive rods (n = 5, 3.3%), and yeast (n = 2, 1.3%). There was no difference in positive bacterial or yeast growth between weeks 1, 2, and 3, suggesting an absence of outside contamination during preparation. CONCLUSIONS: The positive microbial growth suggests a concerning incidence of contamination of IVLEs repackaged with an ACD. Additional research is needed to further identify and validate the clinical impact of these preparations. PMID- 21527604 TI - Albumin synthesis rates are not responsive to hyperglycemic hyperinsulinemia in postoperative patients. AB - BACKGROUND: Insulin regulates albumin synthesis in vitro and in various experimental models. The current study was undertaken to determine the effects of a physiologic hyperinsulinemia on albumin synthesis in postoperative patients in whom plasma albumin concentrations are decreased. METHODS: Studies were performed in postabsorptive patients after major abdominal operations. Mass spectrometry techniques were used to directly determine the incorporation rate of 1-[(13)C] leucine into albumin. Consecutive blood samples were taken during a continuous isotope (D-Glc) infusion (0.16 umol/kg/min). Isotopic enrichments were determined at baseline (period I) and after a 4-hour D-glucose (D-Glc) infusion at currently recommended rates (170 mg/kg/h, n = 10) or after infusion of saline (control group, n = 8) (period II). RESULTS: After D-Glc infusion, plasma insulin concentrations increased significantly (period I, 6.6 +/- 1.8 uU/mL; period II, 21.4 +/- 2.1 uU/mL; P < .01). In contrast, plasma insulin concentration remained constant in control patients (period I, 3.8 +/- 0.9 uU/mL(-1); period II, 5.9 +/- 1.1 uU/mL; not significant vs period I, but P < .005 vs the corresponding value at the end of period II in the control group). Hyperinsulinemia was without effect on fractional albumin synthesis (period I, 12.8% +/- 1.9%/d; period II, 11.9% +/- 1.9%/d; not significant), and synthesis rates corresponded to those measured in controls (period I, 13.0% +/- 1.2%/d; period II, 12.1% +/- 0.1%/d; not significant vs period I and vs D-Glc infusion). CONCLUSIONS: A standard D-Glc infusion is insufficient to increase albumin synthesis in postoperative patients. PMID- 21527603 TI - Correlation between exposure to phthalates and concentrations of malondialdehyde in infants and children undergoing cyclic parenteral nutrition. AB - BACKGROUND: Plasticizers such as di(2-ethylhexyl) phthalate (DEHP) are added to polyvinyl chloride (PVC) to confer flexibility. However, DEHP is associated with reproductive disorders in humans. Because of its noncovalent bond to the PVC matrix, this plasticizer tends to leach easily. Infants and children undergoing cyclic, long-term parenteral nutrition (PN) could be particularly at risk of potential toxicity from DEHP due to regular exposure. Malondialdehyde (MDA) is one of the most commonly used markers of free radical activity. The purpose of this study was to investigate how long-term exposure to phthalate affects the plasmatic rate of MDA. METHODS: Studies were performed on 7 randomized infants and children on regular cyclic, long-term PN, and the results were compared with those of 5 nontreated infants. The circulating concentrations of DEHP in children and infants during the PN therapy were measured by high-performance liquid chromatography. The concentrations were assessed before and after the PN session. In the same way, plasma MDA concentrations were measured. RESULTS: The circulating concentrations of DEHP before and after a 10- to 11-hour cyclic PN treatment in 7 infants and children under regular perfusion ranged widely, showing a significant increase after the treatment among all the patients. The same phenomenon observed with the rate of MDA showed that the 2 events are closely dependent. Therefore, long-term exposure to DEHP during cyclic PN raised plasma MDA levels, indicating increased oxidative stress. CONCLUSION: Long-term exposure to DEHP during PN increased free radical activity in vivo. PMID- 21527605 TI - Prediction of parenteral nutrition osmolarity by digital refractometry. AB - BACKGROUND: Infusion of high-osmolarity parenteral nutrition (PN) formulations into a peripheral vein will damage the vessel. In this study, the authors developed a refractometric method to predict PN formulation osmolarity for patients receiving PN. METHODS: Nutrients in PN formulations were prepared for Brix value and osmolality measurement. Brix value and osmolality measurement of the dextrose, amino acids, and electrolytes were used to evaluate the limiting factor of PN osmolarity prediction. A best-fit equation was generated to predict PN osmolarity (mOsm/L): 81.05 * Brix value--116.33 (R(2) > 0.99). To validate the PN osmolarity prediction by these 4 equations, a total of 500 PN admixtures were tested. RESULTS: The authors found strong linear relationships between the Brix values and the osmolality measurement of dextrose (R(2) = 0.97), amino acids (R(2) = 0.99), and electrolytes (R(2) > 0.96). When PN-measured osmolality was between 600 and 900 mOsm/kg, approximately 43%, 29%, 43%, and 0% of the predicted osmolarity obtained by equations 1, 2, 3, and 4 were outside the acceptable 90% to 110% confidence interval range, respectively. When measured osmolality was between 900 and 1,500 mOsm/kg, 31%, 100%, 85%, and 15% of the predicted osmolarity by equations 1, 2, 3, and 4 were outside the acceptable 90% to 110% confidence interval range, respectively. CONCLUSIONS: The refractive method permits accurate PN osmolarity prediction and reasonable quality assurance before PN formulation administration. PMID- 21527606 TI - The isolated mildly enlarged cisterna magna in the third trimester: much ado about nothing? PMID- 21527607 TI - Magnetic resonance volumetric assessments of brains in fetuses with ventriculomegaly correlated to outcomes. AB - OBJECTIVES: The purpose of this study was to correlate 2-dimensional magnetic resonance (MR) measurements of lateral ventricular width and 3-dimensional measurements of lateral ventricular and supratentorial parenchymal volumes to postnatal outcomes in fetuses with ventriculomegaly. METHODS: A total of 307 fetuses (mean gestational age, 26.0 weeks; range, 15.7-39.4 weeks) had MR volumetry after referral for ventriculomegaly. Fetuses were grouped into those with (n = 114) and without (n = 193) other central nervous system (CNS) anomalies. Pregnancy and postnatal neurodevelopmental outcomes up to 3 years of age were obtained. A subgroup analysis was performed excluding fetuses with other CNS anomalies. Logistic regression analysis was performed to assess which measurement was most predictive of outcomes. RESULTS: There were 50 terminations, 2 stillbirths, and 255 live births. Seventy-five cases were lost to follow-up. Among 180 live-born neonates with follow-up, 140 had abnormal and 40 had normal outcomes. Atrial diameter (P < .0001), frontal horn diameter (P < .0001), and ventricular volume (P = .04) were predictive of live birth, with 92% specificity at 60% sensitivity. Among fetuses without other CNS anomalies, 180 of 193 pregnancies (93%) resulted in live deliveries, with atrial diameter (P < .0001), frontal horn diameter (P = .003), and ventricular volume (P = .008) associated with live birth and atrial diameter having the highest specificity (>99% at 60% sensitivity). Parenchymal volume was not associated with normal or abnormal outcomes (either live birth versus death or normal versus abnormal neurodevelopmental outcome). Among live-born neonates, no age-adjusted threshold for any of the measurements reliably distinguished between normal and abnormal neurodevelopmental outcomes. CONCLUSIONS: Ventricular volume and diameter, but not parenchymal volume, correlate with live birth in fetuses with ventriculomegaly. However, once live born, neither 2- nor 3-dimensional measurements can distinguish a fetus that will have a normal outcome. PMID- 21527609 TI - Recurrent hepatocellular carcinoma after transcatheter arterial chemoembolization: planning sonography for radio frequency ablation. AB - OBJECTIVES: The purposes of this study were to evaluate the sonographic findings of recurrent hepatocellular carcinoma after transcatheter arterial chemoembolization and to determine how often the lesion conspicuity of the recurrent hepatocellular carcinoma makes it suitable for percutaneous sonographically guided radio frequency ablation. METHODS: A radiologist prospectively classified the echogenicity of recurrent hepatocellular carcinomas compared to that of the surrounding liver. In addition, the margin of the tumor was classified as follows: grade 1, absolutely indistinguishable; grade 2, less than 50%; grade 3, greater than 50%; and grade 4, clearly demarcated. The lesion conspicuity was also classified as follows: grade 1, absolutely invisible, thus ineligible for percutaneous sonographically guided radio frequency ablation; grade 2, poorly visible, thus unsuitable for ablation; and grade 3, visible and conspicuous, thus suitable for ablation. RESULTS: A total of 37 consecutive patients (31 men and 6 women; mean age, 59.4 years) with 38 hepatocellular carcinomas were enrolled. The echogenicity of the recurrent hepatocellular carcinomas varied, with the most common finding being a heterogeneous hypoechoic lesion (31.6%), followed by an isoechoic lesion (23.7%), a heterogeneous hyperechoic lesion (18.4%), a homogeneous hypoechoic lesion (13.2%), a lesion with a hypoechoic halo (10.5%), and a homogeneous hyperechoic lesion (2.7%). The margin of the recurrent hepatocellular carcinomas was clearly demarcated in only 28.9% of tumors, whereas 23.7% of the tumors were absolutely indistinguishable from the surrounding liver. The lesion conspicuity was classified as grade 3 in only 60.5% of the recurrent hepatocellular carcinomas. CONCLUSIONS: The echogenicity and margins of recurrent hepatocellular carcinomas after transcatheter arterial chemoembolization varied. The lesion conspicuity was suitable for sonographically guided radio frequency ablation in only 60.5% of cases. PMID- 21527608 TI - Percutaneous sonographically guided radio frequency ablation of hepatocellular carcinoma: causes of mistargeting and factors affecting the feasibility of a second ablation session. AB - OBJECTIVES: The purposes of this study were to evaluate the causes of mistargeting during percutaneous sonographically guided radio frequency ablation in patients with hepatocellular carcinoma and to determine factors affecting the feasibility of a second ablation session. METHODS: This study received Institutional Review Board approval, and informed consent was waived. Among 2213 percutaneous sonographically guided radio frequency ablations performed in our hospital, we searched for mistargeting cases and analyzed the causes of mistargeting. To determine which factors affected the feasibility of a second ablation session, univariate and multivariate analyses were performed. RESULTS: Forty-one cases of mistargeting occurred during the first ablation session, and 4 cases occurred during the second session. Of the 41 patients with mistargeted hepatocellular carcinomas during the first session, 39 who underwent replanning sonography were able to be analyzed for causes of mistargeting. The most common cause of mistargeting was confusion with cirrhotic nodules (87.2% [34 of 39]), followed by poor conspicuity of the hepatocellular carcinoma (69.2% [27 of 39]), a poor sonic window (28.2% [11 of 39]), a poor electrode path (7.7% [3 of 39]), and inaccurate electrode placement (2.6% [1 of 39]). Artificial ascites (P = .035) and the presence of more than 3 mistargeting causes (P = .017) were independent factors affecting feasibility. CONCLUSIONS: The most common cause of mistargeting was confusion with cirrhotic nodules, followed by poor conspicuity of the hepatocellular carcinoma, a poor sonic window, a poor electrode path, and inaccurate electrode placement. The use of artificial ascites and the presence of more than 3 mistargeting causes were factors affecting the feasibility of a second radio frequency ablation session. PMID- 21527610 TI - Evaluation of hepatocellular carcinoma by contrast-enhanced sonography: correlation with pathologic differentiation. AB - OBJECTIVES: The purpose of this study was to determine whether contrast-enhanced sonography can be used to differentiate histopathologic grades of hepatocellular carcinoma. METHODS: This study included 54 patients with hepatocellular carcinomas. All patients underwent fundamental and contrast-enhanced sonographic examinations. Auto-tracking contrast quantification software was used to determine the contrast arrival time, time to peak, peak intensity, contrast enhanced time, wash-out time, enhancement slope, and clearance slope of the lesions. All lesions were confirmed by surgery. The hepatocellular carcinoma lesions were divided into 2 groups according to the World Health Organization grading system: group 1 (well-differentiated hepatocellular carcinomas) and group 2 (moderately to poorly differentiated carcinomas). The enhancement parameters between the groups were compared using a Student t test. RESULTS: Fourteen of 20 well-differentiated lesions showed a "fast-in, slow-out" enhancement pattern, whereas 6 showed a "fast-in, fast-out" pattern. Thirty-three of 34 moderately to poorly differentiated lesions showed a fast-in, fast-out pattern, whereas only 1 showed a fast-in, slow-out pattern. The differences in the time to peak, contrast enhanced time, wash-out time, enhancement slope, and clearance slope between the groups were statistically significant (P < .05), whereas the differences in the arrival time and peak intensity were not significant (P > .05). CONCLUSIONS: The contrast patterns of well-differentiated and moderately to poorly differentiated hepatocellular carcinomas were quite different on contrast-enhanced sonography. The time to peak, contrast-enhanced time, and wash-out time of the well differentiated hepatocellular carcinomas were longer than those of the moderately to poorly differentiated carcinomas, whereas the enhancement slope and clearance slope of the well-differentiated lesions were lower those that of the moderately to poorly differentiated lesions. PMID- 21527611 TI - Acute outflow obstruction of hepatic veins in rabbits: quantitative analysis of hepatic perfusion with contrast-enhanced sonography. AB - OBJECTIVES: To compare time-enhancement curve parameters of contrast-enhanced sonography in acute partial hepatic venous outflow obstruction with those of a baseline study. METHODS: Contrast-enhanced sonography was performed in 11 rabbits with bolus administration of a sulfur hexafluoride contrast agent (0.1 mL/kg). After baseline scanning for 3 minutes, a 5.3F balloon catheter was placed into the left hepatic vein. Obstruction was artificially induced by 0.4-mL balloon inflation, and sonography was repeatedly performed thereafter. On images stored with 1-second intervals, 2 * 2-mm regions of interest were placed, and mean luminosity was measured. Time-enhancement curves were plotted, and contrast arrival times, peak enhancement values, peak enhancement times, 50% wash-out times, and 3-minute wash-out rates were obtained. Paired t tests were performed to evaluate the significance of differences in the parameters between baseline and obstruction. RESULTS: On baseline sonography, the median contrast arrival time, peak enhancement value, peak enhancement time, 50% wash-out time, and 3 minute wash-out rate were 6 (range, 4-8; mean +/- SD, 5.9 +/- 1.2) seconds, 188.5 (104.7-209.5; 178.4 +/- 33.1) arbitrary units, 19 (14-27; 19.8 +/- 4.1) seconds, 75 (60-101; 78.2 +/- 13.9) seconds, and 89.7% (81.3%-95.1%; 88.4% +/- 4.9%), respectively. With obstruction, those values were 7 (5-12; 6.9 +/- 2.3) seconds, 202.8 (98.2-215.1; 186.0 +/- 39.3) arbitrary units, 31 (17-59; 32 +/- 11.6) seconds, 101 (47-136; 96.2 +/- 23.6) seconds, and 79.2% (66.2%-88.8%; 79.1% +/- 7.6%). Compared with baseline, the peak enhancement time was significantly delayed from 19 to 31 seconds (P = .0027), 50% wash-out time significantly delayed from 75 to 101 seconds (P = .0209), and 3-minute wash-out rate significantly decreased from 89.7% to 79.2% (P < .0001) with obstruction, but there were no significant differences in contrast arrival times and peak enhancement values (P = .0756 and .2179). CONCLUSIONS: Contrast-enhanced sonography can provide quantitative assessment of microbubble congestion in partial hepatic venous outflow obstruction. The peak enhancement time and 50% wash-out time are delayed and 3-minute wash-out rate is decreased in rabbits with artificially induced obstruction compared with a baseline study. PMID- 21527612 TI - Comparison of real-time sonoelastography with T2-weighted endorectal magnetic resonance imaging for prostate cancer detection. AB - OBJECTIVES: The purpose of this study was to compare the value of real-time sonoelastography with T2-weighted endorectal magnetic resonance imaging (MRI) for prostate cancer detection. METHODS: Thirty-three patients with an elevated prostate-specific antigen level were investigated with real-time sonoelastography and T2-weighted endorectal MRI for prostate cancer diagnosis before systematic prostate biopsy. Real-time sonoelastography was performed to assess prostate tissue elasticity, and hard areas were considered suspicious for prostate cancer. Low-signal intensity nodules on T2-weighted endorectal MRI were considered suspicious for prostate cancer. Imaging findings were assigned to 6 areas of the peripheral zone (sextants), and their cancer detection rates were compared. RESULTS: Overall, prostate cancer was detected in 13 of 33 patients (39.4%). Both real-time sonoelastography and T2-weighted endorectal MRI detected 11 cancer positive patients (84.6%). Real-time sonoelastography showed 27 suspicious lesions in 198 sextants, and 15 (55.6%) were cancer positive. T2-weighted endorectal MRI showed 31 suspicious lesions in 198 sextants, and 13 (40.6%) were cancer positive. These findings resulted in sensitivity rates and negative predictive values per patient of 84.6% and 86.7%, respectively, for sonoelastography and 84.6% and 83.3% for MRI. The per-sextant analysis showed sensitivity rates and negative predictive values of 57.7% and 93.6% for sonoelastography and 50.0% and 92.2% for MRI. CONCLUSIONS: Real-time sonoelastography showed comparable results as T2-weighted endorectal MRI for prostate cancer detection. PMID- 21527613 TI - Sonography for determining the optic nerve sheath diameter with increasing intracranial pressure in a porcine model. AB - OBJECTIVES: This study investigated whether it is feasible to use sonography to monitor changes in the optic nerve sheath diameter in a porcine model. METHODS: A fiber-optic intracranial pressure transducer was surgically placed through the frontal sinus directly into the brain parenchyma of adult Yorkshire pigs (n = 5). A second bolt was placed on the contralateral side for intraparenchymal fluid infusion. Optic nerve sheath diameter measurements were acquired by each of 2 ultrasound operators around the leading edge of the nerve, 3 to 5 mm distal from the origin of the optic nerve. To induce a change in diameter, intracranial pressure was manipulated by injecting normal saline into the intraparenchymal infusion catheter located in the symmetric contralateral position as the pressure monitoring probe. RESULTS: Data from 1 pig were unusable because of a cerebrospinal fluid leak into the sinus and orbital fissure. Saline aliquots of 1 to 10 mL were able to generate intracranial pressures typically starting from 10 to 15 mm Hg and increasing to 75 to 90 mm Hg, which eventually evoked a Cushing response. Fluid injection was controlled to increase pressures by 60 mm Hg over a 15- to 20-minute period. Regression analysis of all animals showed that the optic nerve sheath diameter increased by 0.0034 mm/mm Hg of intracranial pressure; however, this slope ranged from 0.0025 to 0.0046, depending on the animal measured. There was no discernible effect of the ultrasound operator on the slope; however, measurements made by 1 operator were consistently higher than the others by about 8% of the overall diameter range. CONCLUSIONS: These results suggest that the use of the optic nerve sheath diameter to noninvasively confirm acute changes in intracranial pressure over 1 hour is feasible in a porcine model. We recommend that this method be validated in humans using direct intracranial pressure measurement where possible to confirm it as a screening tool for acute and chronically increased diameters secondary to elevated pressure in clinical settings. PMID- 21527614 TI - Differentiation of benign from malignant thyroid lesions: calculation of the strain ratio on thyroid sonoelastography. AB - OBJECTIVES: Initial data suggest that elastography can improve the specificity of sonography for differentiating benign and malignant thyroid lesions. The primary objective of this study was to compare quantitative sonoelastography to conventional qualitative sonoelastography and sonography for thyroid nodule characterization. METHODS: Ninety-eight thyroid masses (53 benign and 45 malignant) were examined with conventional sonography and sonoelastography. The images were classified into 4 patterns according to a previously proposed classification. In addition, strain ratios of thyroid tissue to the nodule were calculated. Receiver operating characteristic curve analysis was used to compare the diagnostic performance of the strain ratio and that of conventional sonography. The final diagnosis was obtained from histologic findings. RESULTS: When a cutoff point of 3.79 was introduced, significantly different strain ratios for benign (mean +/- SD, 2.97 +/- 4.35) and malignant (11.59 +/- 10.32) lesions was obtained (P < .0001). The strain ratio measurement had 97.8% sensitivity and 85.7% specificity. The area under the curve for the strain ratio was 0.92, whereas that for the 4-point scoring system was 0.85. Of the conventional sonographic patterns, microcalcification had the highest area under the curve, at 0.72. CONCLUSIONS: Strain ratio measurement of thyroid lesions is a fast standardized method for analyzing stiffness inside examined areas. Used as an additional tool with B-mode sonography, it helps increase the diagnostic performance of the examination. PMID- 21527615 TI - Use of sonography for rapid identification of esophageal and tracheal intubations in adult patients. AB - OBJECTIVES: The aim of this study was to investigate the usefulness of sonography for verifying tracheal tube placement within 3 seconds in adult surgical patients. METHODS: This was a blinded prospective randomized study. The anesthesiologist placed the tracheal tube randomly in the trachea (n = 75) or in the esophagus (n = 75) with direct laryngoscopy. A sonographer identified all tracheal and esophageal intubations. The transducer was placed transversely on the neck just superior to the suprasternal notch. The position of the tracheal tube was determined by the sonographer within 3 seconds of tracheal tube placement in the trachea or in the esophagus. RESULTS: We successfully identified 150 correct tracheal tube placements in tracheas and esophagi, resulting in sensitivity of 100% (95% confidence interval, 84%-100%) and specificity of 100% (95% confidence interval, 84%-100%). CONCLUSIONS: This investigation shows that sonography for confirming tracheal intubation is a fast and effective technique. PMID- 21527616 TI - Follow-up sonographic results for Graf type 2A hips: association with risk factors for developmental dysplasia of the hip and instability. AB - OBJECTIVES: The purpose of the study was to evaluate the association of sonographic worsening in type 2a hips with risk factors of developmental dysplasia of the hip, stability of the hip, and initial sonographic findings. METHODS: Among infants who were referred for hip sonography between 2007 and 2009, 3450 were included in this study. Sonographic examinations were performed by combining the static Graf technique and the dynamic Harcke technique. The rate of sonographic worsening in type 2a hips and the relationship between sonographic worsening and risk factors for developmental dysplasia, instability of the hip, lateralization (right or left) of immaturity, and the presence of unilateral and bilateral immature hips were evaluated. RESULTS: Type 2a hips were observed in 529 infants (15.3%; 780 hips [11.3%]). Of these, in 36 cases (6.8%; 44 hips [5.6%]), the sonographic results worsened. Twenty-five of these 36 cases (32 of 44 hips) were diagnosed as type 2 b; in others, the dysplasia worsened, and 6 cases (7 hips) were classified as type 2 c, 3 cases (3 hips) as type D, and 2 cases (2 hips) as type 3. Instability, unilateral type 2a hips, and associated central nervous system anomalies were found to be independent predictors of sonographic worsening in type 2a hips. CONCLUSIONS: Type 2a hips may worsen sonographically at a rate of 5.6%; hence, sonographic follow-up is needed. Instability, central nervous system anomalies, and unilateral type 2a hips were found to be independent predictors of sonographic worsening. Our study shows that cases with these risk factors should be followed more carefully. PMID- 21527617 TI - The thyroid nodule: fine-needle aspiration biopsy technique. AB - The initial portion of this article includes general comments regarding thyroid nodules, reference to 2 recent articles delineating guidelines for management of thyroid nodules, and discussion of several areas of disagreement with these articles and expansion of recommendations in areas not covered by the published guidelines. The main body of the article provides a detailed discussion of our technique for fine-needle aspiration biopsy of a thyroid nodule. PMID- 21527618 TI - Learning curve and factors influencing the feasibility of performing fetal echocardiography at the time of the first-trimester scan. AB - The purpose of this study was to assess the learning curve and factors influencing the feasibility of performing a complete fetal cardiac examination at the time of the first-trimester scan. The study included 103 fetuses undergoing first-trimester scans. The maternal body mass index, fetal crown-rump length, and 8 cardiac parameters were evaluated: 4-chamber view, tricuspid regurgitation, outflow tract crossover, bifurcating pulmonary artery, 3-vessel view, aortic arch, superior and inferior venae cavae on sagittal views, and Doppler images of the ductus venosus. All examinations were performed transabdominally by a single sonologist. The average times from the first to last cardiac images obtained were calculated. A complete examination was feasible in 55% of the cases: 15% of the first 52 and 94% of the last 51. Of the 8 cardiac parameters, 59.5% were seen in cases 1 to 21, 75.0% in cases 22 to 52, and 98.6% in the last 51 cases (P = .0001). The average times spent on the examinations increased from 4.37 to 9.3 minutes among the 3 groups (P = .032). There was no statistically significant influence for the crown-rump length (P = .899) or body mass index (P = .752). This study indicates that a fetal cardiac examination is feasible in the first trimester. Sonographer experience and the examination duration seem to be the most influential factors affecting the completeness of the examination. PMID- 21527619 TI - Sonographic findings of invasive cribriform carcinoma of the breast. AB - The purpose of this series was to evaluate the sonographic features of invasive cribriform carcinoma of the breast. Between 2004 and 2010, 3 patients had confirmed invasive cribriform carcinoma of the breast in our institution, and all of them underwent sonography. Sonograms showed masses with an oval (n = 2) or irregular (n = 1) shape, partially microlobulated (n = 2) or well-circumscribed (n = 1) margins, and a hypoechoic (n = 2) or an isoechoic (n = 1) internal echo texture. Sonographic assessments were classified as Breast Imaging Reporting and Data System category 4 in all 3 cases. Although invasive cribriform carcinoma is a rare breast malignancy, awareness of its sonographic features will be helpful for the diagnosis. PMID- 21527620 TI - Sonographic features of adrenal extramedullary hematopoiesis. PMID- 21527621 TI - An unusual complication of hysteroscopic sterilization. PMID- 21527622 TI - Atypical anomalous peroneal (fibularis) tendon: potential pitfall in musculoskeletal sonography. PMID- 21527623 TI - The thermal index: its strengths, weaknesses, and proposed improvements. AB - The thermal index (TI) has been used as a relative indicator of thermal risk during diagnostic ultrasound examinations for many years. It is useful in providing feedback to the clinician or sonographer, allowing assessment of relative, potential risks to the patient of an adverse effect due to a thermal mechanism. Recently, several shortcomings of the TI formulations in quantifying the risk to the patient have been identified by members of the basic scientific community, and possible improvements to address these shortcomings have been proposed. For this reason, the Output Standards Subcommittee of the American Institute of Ultrasound in Medicine convened a subcommittee to review the strengths of the TI formulations as well as their weaknesses and proposed improvements. This article summarizes the findings of this subcommittee. After a careful review of the literature and an assessment of the cost of updating the TI formulations while maximizing the quality of patient care, the Output Standards Subcommittee makes the following recommendations: (1) some inconsistencies in the current TI formulations should be resolved, and the break point distance should be redefined to take focusing into consideration; (2) an entirely new indicator of thermal risk that incorporates the time dependence not be implemented at this time but be included in continuing efforts toward standards or consensus documents; (3) the exponential dependence of risk on temperature not be incorporated into a new definition of the TI formulations at this time but be included in continuing efforts toward standards or consensus documents; (4) the TI formulations not be altered to include nonlinear propagation at this time but be included in continuing efforts toward standards or consensus documents; and (5) a new indicator for risk from thermal mechanisms should be developed, distinct from the traditional TI formulations, for new imaging modalities such as acoustic radiation force impulse imaging, which have more complicated pulsing sequences than traditional imaging. PMID- 21527624 TI - Differential drought-induced modulation of ozone tolerance in winter wheat species. AB - Recent reports challenge the widely accepted idea that drought may offer protection against ozone (O(3)) damage in plants. However, little is known about the impact of drought on the magnitude of O(3) tolerance in winter wheat species. Two winter wheat species with contrasting sensitivity to O(3) (O(3) tolerant, primitive wheat, T. turgidum ssp. durum; O(3) sensitive, modern wheat, T. aestivum L. cv. Xiaoyan 22) were exposed to O(3) (83ppb O(3), 7h d(-1)) and/or drought (42% soil water capacity) from flowering to grain maturity to assess drought-induced modulation of O(3) tolerance. Plant responses to stress treatments were assessed by determining in vivo biochemical parameters, gas exchange, chlorophyll a fluorescence, and grain yield. The primitive wheat demonstrated higher O(3) tolerance than the modern species, with the latter exhibiting higher drought tolerance than the former. This suggested that there was no cross-tolerance of the two stresses when applied separately in these species/cultivars of winter wheat. The primitive wheat lost O(3) tolerance, while the modern species showed improved tolerance to O(3) under combined drought and O(3) exposure. This indicated the existence of differential behaviour of the two wheat species between a single stress and the combination of the two stresses. The observed O(3) tolerance in the two wheat species was related to their magnitude of drought tolerance under a combination of drought and O(3) exposure. The results clearly demonstrate that O(3) tolerance of a drought-sensitive winter wheat species can be completely lost under combined drought and O(3) exposure. PMID- 21527626 TI - Variation in carbon isotope discrimination in Cleistogenes squarrosa (Trin.) Keng: patterns and drivers at tiller, local, catchment, and regional scales. AB - Understanding the patterns and drivers of carbon isotope discrimination in C(4) species is critical for predicting the effects of global change on C(3)/C(4) ratio of plant community and consequently on ecosystem functioning and services. Cleistogenes squarrosa (Trin.) Keng is a dominant C(4) perennial bunchgrass of arid and semi-arid ecosystems across the Mongolian plateau of the Eurasian steppe. Its carbon isotope discrimination (((13))Delta) during photosynthesis is relatively large among C(4) species and it is variable. Here the ((13))Delta of C. squarrosa and its potential drivers at a nested set of scales were examined. Within cohorts of tillers, ((13))Delta of leaves increased from 5.10/00 to 8.10/00 from old to young leaves. At the local scale, ((13))Delta of mature leaves varied from 5.80/00 to 8.40/00, increasing with decreasing grazing intensity. At the catchment scale, ((13))Delta of mature leaves varied from 6.20/00 to 8.50/00 and increased with topsoil silt content. At the regional scale, ((13))Delta of mature leaves varied from 5.50/00 to 8.90/00, increasing with growing-season precipitation. At all scales, ((13))Delta decreased with increasing leaf nitrogen content (N(leaf)). N(leaf) was positively correlated with grazing intensity and leaf position along tillers, but negatively correlated with precipitation. The presence of the correlations across a range of different environmental contexts strongly implicates N(leaf) as a major driver of ((13))Delta in C. squarrosa and, possibly, other C(4) species. PMID- 21527625 TI - Genetic dissection of vitamin E biosynthesis in tomato. AB - Vegetables are critical for human health as they are a source of multiple vitamins including vitamin E (VTE). In plants, the synthesis of VTE compounds, tocopherol and tocotrienol, derives from precursors of the shikimate and methylerythritol phosphate pathways. Quantitative trait loci (QTL) for alpha tocopherol content in ripe fruit have previously been determined in an Solanum pennellii tomato introgression line population. In this work, variations of tocopherol isoforms (alpha, beta, gamma, and delta) in ripe fruits of these lines were studied. In parallel all tomato genes structurally associated with VTE biosynthesis were identified and mapped. Previously identified VTE QTL on chromosomes 6 and 9 were confirmed whilst novel ones were identified on chromosomes 7 and 8. Integrated analysis at the metabolic, genetic and genomic levels allowed us to propose 16 candidate loci putatively affecting tocopherol content in tomato. A comparative analysis revealed polymorphisms at nucleotide and amino acid levels between Solanum lycopersicum and S. pennellii candidate alleles. Moreover, evolutionary analyses showed the presence of codons evolving under both neutral and positive selection, which may explain the phenotypic differences between species. These data represent an important step in understanding the genetic determinants of VTE natural variation in tomato fruit and as such in the ability to improve the content of this important nutriceutical. PMID- 21527627 TI - Effects of partial root-zone irrigation on hydraulic conductivity in the soil root system of maize plants. AB - Effects of partial root-zone irrigation (PRI) on the hydraulic conductivity in the soil-root system (L(sr)) in different root zones were investigated using a pot experiment. Maize plants were raised in split-root containers and irrigated on both halves of the container (conventional irrigation, CI), on one side only (fixed PRI, FPRI), or alternately on one of two sides (alternate PRI, APRI). Results show that crop water consumption was significantly correlated with L(sr) in both the whole and irrigated root zones for all three irrigation methods but not with L(sr) in the non-irrigated root zone of FPRI. The total L(sr) in the irrigated root zone of two PRIs was increased by 49.0-92.0% compared with that in a half root zone of CI, suggesting that PRI has a significant compensatory effect of root water uptake. For CI, the contribution of L(sr) in a half root zone to L(sr) in the whole root zone was ~50%. For FPRI, the L(sr) in the irrigated root zone was close to that of the whole root zone. As for APRI, the L(sr) in the irrigated root zone was greater than that of the non-irrigated root zone. In comparison, the L(sr) in the non-irrigated root zone of APRI was much higher than that in the dried zone of FPRI. The L(sr) in both the whole and irrigated root zones was linearly correlated with soil moisture in the irrigated root zone for all three irrigation methods. For the two PRI treatments, total water uptake by plants was largely determined by the soil water in the irrigated root zone. Nevertheless, the non-irrigated root zone under APRI also contributed to part of the total crop water uptake, but the continuously non-irrigated root zone under FPRI gradually ceased to contribute to crop water uptake, suggesting that it is the APRI that can make use of all the root system for water uptake, resulting in higher water use efficiency. PMID- 21527629 TI - The efficiency of C(4) photosynthesis under low light conditions: assumptions and calculations with CO(2) isotope discrimination. AB - Leakiness (Phi), the proportion of carbon fixed by phosphoenolpyruvate carboxylation that leaks out of the bundle-sheath cells, determines C(4) photosynthetic efficiency. Large increases in Phi have been described at low irradiance. The underlying mechanisms for this increase remain uncertain, but changes in photorespiration or the energy partitioning between the C(4) and C(3) cycles have been suggested. Additionally, values of Phi at low light could be magnified from assumptions made when comparing measured photosynthetic discrimination against (13)C (Delta) with the theoretical formulation for Delta. For example, several simplifications are often made when modelling Delta to predict Phi including: (i) negligible fractionation during photorespiration and dark respiration; (ii) infinite mesophyll conductance; and (iii) CO(2) inside bundle-sheath cells (C(s)) is much larger than values in mesophyll cells (C(m)). Theoretical models for C(4) photosynthesis and C(4) Delta were combined to evaluate how these simplifications affect calculations of Delta and Phi at different light intensities. It was demonstrated that the effects of photorespiratory fractionations and mesophyll conductance were negligible at low light. Respiratory fractionation was relevant only when the magnitude of the fractionation factor was artificially increased during measurements. The largest error in estimating Phi occurred when assuming C(s) was much larger than C(m) at low light levels, when bundle-sheath conductance was large (g(s)), or at low O(2) concentrations. Under these conditions, the simplified equation for Delta overestimated Phi, and compromised comparisons between species with different g(s), and comparisons across O(2) concentrations. PMID- 21527628 TI - Overexpression of a Harpin-encoding gene hrf1 in rice enhances drought tolerance. AB - Harpin proteins are well known as eliciters that induce multiple responses in plants, such as systemic acquired resistance, hypersensitive response, enhancement of growth, resistance to the green peach aphid, and tolerance to drought. Overexpression of Harpin-encoding genes enhances plant resistance to diseases in tobacco, rice, rape, and cotton; however, it is not yet known whether the expression of Harpin-encoding genes in vivo improves plant tolerance to abiotic stresses. The results of this study showed that overexpression of a Harpin-encoding gene hrf1 in rice increased drought tolerance through abscisic acid (ABA) signalling. hrf1- overexpression induces an increase in ABA content and promotes stomatal closure in rice. The hrf1 transgenic rice lines exhibited a significant increase in water retention ability, levels of free proline and soluble sugars, tolerance to oxidative stress, reactive oxygen species-scavenging ability, and expression levels of four stress-related genes, OsLEA3-1, OsP5CS, Mn SOD, and NM_001074345, under drought stress. The study confirmed that hrf1 conferred enhanced tolerance to drought stress on transgenic crops. These results suggest that Harpins may offer new opportunities for generating drought resistance in other crops. PMID- 21527630 TI - Hydraulic conductance as well as nitrogen accumulation plays a role in the higher rate of leaf photosynthesis of the most productive variety of rice in Japan. AB - An indica variety Takanari is known as one of the most productive rice varieties in Japan and consistently produces 20-30% heavier dry matter during ripening than Japanese commercial varieties in the field. The higher rate of photosynthesis of individual leaves during ripening has been recognized in Takanari. By using pot grown plants under conditions of minimal mutual shading, it was confirmed that the higher rate of leaf photosynthesis is responsible for the higher dry matter production after heading in Takanari as compared with a japonica variety, Koshihikari. The rate of leaf photosynthesis and shoot dry weight became larger in Takanari after the panicle formation and heading stages, respectively, than in Koshihikari. Roots grew rapidly in the panicle formation stage until heading in Takanari compared with Koshihikari. The higher rate of leaf photosynthesis in Takanari resulted not only from the higher content of leaf nitrogen, which was caused by its elevated capacity for nitrogen accumulation, but also from higher stomatal conductance. When measured under light-saturated conditions, stomatal conductance was already decreased due to the reduction in leaf water potential in Koshihikari even under conditions of a relatively small difference in leaf-air vapour pressure difference. In contrast, the higher stomatal conductance was supported by the maintenance of higher leaf water potential through the higher hydraulic conductance in Takanari with the larger area of root surface. However, no increase in root hydraulic conductivity was expected in Takanari. The larger root surface area of Takanari might be a target trait in future rice breeding for increasing dry matter production. PMID- 21527631 TI - Isomerization of the phytohormone precursor 12-oxophytodienoic acid (OPDA) in the insect gut: a mechanistic and computational study. AB - 12-Oxophytodienoic acid (OPDA) is isomerized in the gut of herbivorous insects to tetrahydrodicranenone B (iso-OPDA). The transformation is achieved by a glutathione S-transferase present in the gut epithelium. Experiments with 9 [(2)H]-iso-OPDA demonstrated the complete retention of the deuterium atom in the product 11-[(2)H]-OPDA consistent with an intramolecular 1,3-hydrogen shift. Homology modeling based on the x-ray structure of a glutathione S-transferase from Anopheles gambiae revealed that the co-factor glutathione does not covalently bind to the substrate but appears to be involved in the initial deprotonation and enolization of the OPDA. The transformation resembles that of a mammalian GST-catalyzed isomerization of Delta(5)-3-ketosteroids to Delta(4)-3 ketosteroids or the conversion of prostaglandin A(1) to the biologically inactive prostaglandin B(1). PMID- 21527632 TI - N-formylkynurenine as a marker of high light stress in photosynthesis. AB - Photosystem II (PSII) is the membrane protein complex that catalyzes the photo induced oxidation of water at a manganese-calcium active site. Light-dependent damage and repair occur in PSII under conditions of high light stress. The core reaction center complex is composed of the D1, D2, CP43, and CP47 intrinsic polypeptides. In this study, a new chromophore formed from the oxidative post translational modification of tryptophan is identified in the CP43 subunit. Tandem mass spectrometry peptide sequencing is consistent with the oxidation of the CP43 tryptophan side chain, Trp-365, to produce N-formylkynurenine (NFK). Characterization with ultraviolet visible absorption and ultraviolet resonance Raman spectroscopy supports this assignment. An optical assay suggests that the yield of NFK increases 2-fold (2.2 +/- 0.5) under high light illumination. A concomitant 2.4 +/- 0.5-fold decrease is observed in the steady-state rate of oxygen evolution under the high light conditions. NFK is the product formed from reaction of tryptophan with singlet oxygen, which can be produced under high light stress in PSII. Reactive oxygen species reactions lead to oxidative damage of the reaction center, D1 protein turnover, and inhibition of electron transfer. Our results are consistent with a role for the CP43 NFK modification in photoinhibition. PMID- 21527633 TI - High mobility group box-1 (HMGB1; amphoterin) is required for zebrafish brain development. AB - Hmgb1 (high mobility group box-1; amphoterin) is highly expressed in brain during early development of vertebrate and nonvertebrate species. However, its role in brain development remains elusive. Here we have cloned the zebrafish Hmgb1 and specifically manipulated Hmgb1 expression using injection of morpholino antisense oligonucleotides or Hmgb1 cRNA. The HMGB1 knockdown morphants produced by injection of three different morpholino oligonucleotides display a characteristic phenotype with smaller size, smaller brain width, and shorter distance between the eyes. Closer examination of the phenotype reveals severe defects in the development of the forebrain that largely lacks catecholaminergic neural networks. The HMGB1 morphant is deficient in survival and proliferation of neural progenitors and displays fewer cell groups expressing the transcription factor Pax6a in the forebrain and aberrant Wnt8 signaling. The mechanism of HMGB1 dependent progenitor survival involves the neuronal transmembrane protein AMIGO (amphoterin-induced gene and orf), the expression of which is regulated by HMGB1 in vivo. Our data demonstrate that HMGB1 is a critical factor for brain development, enabling survival and proliferation of neural progenitors that will form the forebrain structures. PMID- 21527634 TI - Structural and morphological characterization of aggregated species of alpha synuclein induced by docosahexaenoic acid. AB - The interaction of brain lipids with alpha-synuclein may play an important role in the pathogenesis of Parkinson disease (PD). Docosahexaenoic acid (DHA) is an abundant fatty acid of neuronal membranes, and it is presents at high levels in brain areas with alpha-synuclein inclusions of patients with PD. In animal models, an increase of DHA content in the brain induces alpha-synuclein oligomer formation in vivo. However, it is not clear whether these oligomeric species are the precursors of the larger aggregates found in Lewy bodies of post-mortem PD brains. To characterize these species and to define the role of fatty acids in amyloid formation, we investigated the aggregation process of alpha-synuclein in the presence of DHA. We found that DHA readily promotes alpha-synuclein aggregation and that the morphology of these aggregates is dependent on the ratio between the protein and DHA. In the presence of a molar ratio protein/DHA of 1:10, amyloid-like fibrils are formed. These fibrils are morphologically different from those formed by alpha-synuclein alone and have a less packed structure. At a protein/DHA molar ratio of 1:50, we observe the formation of stable oligomers. Moreover, chemical modifications, methionine oxidations, and protein-lipid adduct formations are induced by increasing concentrations of DHA. The extent of these modifications defines the structure and the stability of aggregates. We also show that alpha-synuclein oligomers are more toxic if generated in the presence of DHA in dopaminergic neuronal cell lines, suggesting that these species might be important in the neurodegenerative process associated with PD. PMID- 21527635 TI - Radiation-triggered tumor necrosis factor (TNF) alpha-NFkappaB cross-signaling favors survival advantage in human neuroblastoma cells. AB - Induced radioresistance in the surviving cancer cells after radiotherapy could be associated with clonal selection leading to tumor regrowth at the treatment site. Previously we reported that post-translational modification of IkappaBalpha activates NFkappaB in response to ionizing radiation (IR) and plays a key role in regulating apoptotic signaling. Herein, we investigated the orchestration of NFkappaB after IR in human neuroblastoma. Both in vitro (SH-SY5Y, SK-N-MC, and IMR-32) and in vivo (xenograft) studies showed that IR persistently induced NFkappaB DNA binding activity and NFkappaB-dependent TNFalpha transactivation and secretion. Approaches including silencing NFkappaB transcription, blocking post translational NFkappaB nuclear import, muting TNF receptor, overexpression, and physiological induction of either NFkappaB or TNFalpha precisely demonstrated the initiation and occurrence of NFkappaB -> TNFalpha -> NFkappaB positive feedback cycle after IR that leads to and sustains NFkappaB activation. Selective TNF dependent NFkappaB regulation was confirmed with futile inhibition of AP-1 and SP 1 in TNF receptor muted cells. Moreover, IR increased both transactivation and translation of Birc1, Birc2, and Birc5 and induced metabolic activity and clonal expansion. This pathway was further defined to show that IR-induced functional p65 transcription (not NFkappaB1, NFkappaB2, or c-Rel) is necessary for activation of these survival molecules and associated survival advantage. Together, these results demonstrate for the first time the functional orchestration of NFkappaB in response to IR and further imply that p65-dependent survival advantage and initiation of clonal expansion may correlate with an unfavorable prognosis of human neuroblastoma. PMID- 21527637 TI - Single cell time-resolved quorum responses reveal dependence on cell density and configuration. AB - Bacterial communication via quorum sensing has been extensively investigated in recent years. Bacteria communicate in a complex manner through the production, release, and reception of diffusible low molecular weight chemical signaling molecules. Much work has focused on understanding the basic mechanisms of quorum sensing. As more and more bacteria grow resistant to conventional antibiotics, the development of drugs that do not kill bacteria but instead interrupt their communication is of increasing interest. This study presents a method for analyzing bacterial communication by investigating single cell responses. Most conventional analysis methods for bacterial communication are based on the averaged response from many bacteria, masking how individual cells respond to their immediate environment. We applied a fiber-optic microarray to record cellular communication from single cells. Single cell quorum sensing systems have previously been employed, but the highly ordered array reported here is an improvement because it allows us to simultaneously investigate cellular communication in many different environments with known cellular densities and configurations. We employed this method to detect how genes under quorum regulation are induced or repressed over time on the single cell level and to determine whether cellular density and configuration are indicative of the single cell temporal patterns of gene expression. PMID- 21527636 TI - Phase advance of the light-dark cycle perturbs diurnal rhythms of brain-derived neurotrophic factor and neurotrophin-3 protein levels, which reduces synaptophysin-positive presynaptic terminals in the cortex of juvenile rats. AB - In adult rat brains, brain-derived neurotrophic factor (BDNF) rhythmically oscillates according to the light-dark cycle and exhibits unique functions in particular brain regions. However, little is known of this subject in juvenile rats. Here, we examined diurnal variation in BDNF and neurotrophin-3 (NT-3) levels in 14-day-old rats. BDNF levels were high in the dark phase and low in the light phase in a majority of brain regions. In contrast, NT-3 levels demonstrated an inverse phase relationship that was limited to the cerebral neocortex, including the visual cortex, and was most prominent on postnatal day 14. An 8-h phase advance of the light-dark cycle and sleep deprivation induced an increase in BDNF levels and a decrease in NT-3 levels in the neocortex, and the former treatment reduced synaptophysin expression and the numbers of synaptophysin positive presynaptic terminals in cortical layer IV and caused abnormal BDNF and NT-3 rhythms 1 week after treatment. A similar reduction of synaptophysin expression was observed in the cortices of Bdnf gene-deficient mice and Ca(2+) dependent activator protein for secretion 2 gene-deficient mice with abnormal free-running rhythm and autistic-like phenotypes. In the latter mice, no diurnal variation in BDNF levels was observed. These results indicate that regular rhythms of BDNF and NT-3 are essential for correct cortical network formation in juvenile rodents. PMID- 21527638 TI - Na+-translocating membrane pyrophosphatases are widespread in the microbial world and evolutionarily precede H+-translocating pyrophosphatases. AB - Membrane pyrophosphatases (PPases), divided into K(+)-dependent and K(+) independent subfamilies, were believed to pump H(+) across cell membranes until a recent demonstration that some K(+)-dependent PPases function as Na(+) pumps. Here, we have expressed seven evolutionarily important putative PPases in Escherichia coli and estimated their hydrolytic, Na(+) transport, and H(+) transport activities as well as their K(+) and Na(+) requirements in inner membrane vesicles. Four of these enzymes (from Anaerostipes caccae, Chlorobium limicola, Clostridium tetani, and Desulfuromonas acetoxidans) were identified as K(+)-dependent Na(+) transporters. Phylogenetic analysis led to the identification of a monophyletic clade comprising characterized and predicted Na(+)-transporting PPases (Na(+)-PPases) within the K(+)-dependent subfamily. H(+)-transporting PPases (H(+)-PPases) are more heterogeneous and form at least three independent clades in both subfamilies. These results suggest that rather than being a curious rarity, Na(+)-PPases predominantly constitute the K(+) dependent subfamily. Furthermore, Na(+)-PPases possibly preceded H(+)-PPases in evolution, and transition from Na(+) to H(+) transport may have occurred in several independent enzyme lineages. Site-directed mutagenesis studies facilitated the identification of a specific Glu residue that appears to be central in the transport mechanism. This residue is located in the cytoplasm membrane interface of transmembrane helix 6 in Na(+)-PPases but shifted to within the membrane or helix 5 in H(+)-PPases. These results contribute to the prediction of the transport specificity and K(+) dependence for a particular membrane PPase sequence based on its position in the phylogenetic tree, identity of residues in the K(+) dependence signature, and position of the membrane located Glu residue. PMID- 21527639 TI - Dislocation of ricin toxin A chains in human cells utilizes selective cellular factors. AB - Ricin is a potent A-B toxin that is transported from the cell surface to the cytosol, where it inactivates ribosomes, leading to cell death. Ricin enters cells via endocytosis, where only a minute number of ricin molecules reach the endoplasmic reticulum (ER) lumen. Subsequently, the ricin A chain traverses the ER bilayer by a process referred to as dislocation or retrograde translocation to gain access to the cytosol. To study the molecular processes of ricin A chain dislocation, we have established, for the first time, a human cell system in which enzymatically attenuated ricin toxin A chains (RTA(E177D) and RTA(Delta177 181)) are expressed in the cell and directed to the ER. Using this human cell based system, we found that ricin A chains underwent a rapid dislocation event that was quite distinct from the dislocation of a canonical ER soluble misfolded protein, null Hong Kong variant of alpha(1)-antitrypsin. Remarkably, ricin A chain dislocation occurred via a membrane-integrated intermediate and utilized the ER protein SEL1L for transport across the ER bilayer to inhibit protein synthesis. The data support a model in which ricin A chain dislocation occurs via a novel strategy of utilizing the hydrophobic nature of the ER membrane and selective ER components to gain access to the cytosol. PMID- 21527641 TI - GyrA interacts with MarR to reduce repression of the marRAB operon in Escherichia coli. PMID- 21527640 TI - Insecticidal toxin complex proteins from Xenorhabdus nematophilus: structure and pore formation. AB - Toxin complexes from Xenorhabdus and Photorhabdus spp. bacteria represent novel insecticidal proteins. We purified a native toxin complex (toxin complex 1) from Xenorhabdus nematophilus. The toxin complex is composed of three different proteins, XptA2, XptB1, and XptC1, representing products from class A, B, and C toxin complex genes, respectively. We showed that recombinant XptA2 and co produced recombinant XptB1 and XptC1 bind together with a 4:1:1 stoichiometry. XptA2 forms a tetramer of ~1,120 kDa that bound to solubilized insect brush border membranes and induced pore formation in black lipid membranes. Co expressed XptB1 and XptC1 form a tight 1:1 binary complex where XptC1 is C terminally truncated, resulting in a 77-kDa protein. The ~30-kDa C-terminally cleaved portion of XptC1 apparently only loosely associates with this binary complex. XptA2 had only modest oral toxicity against lepidopteran insects but as a complex with co-produced XptB1 and XptC1 had high levels of insecticidal activity. Addition of co-expressed class B (TcdB2) and class C (TccC3) proteins from Photorhabdus luminescens to the Xenorhabdus XptA2 protein resulted in formation of a hybrid toxin complex protein with the same 4:1:1 stoichiometry as the native Xenorhabdus toxin complex 1. This hybrid toxin complex, like the native toxin complex, was highly active against insects. PMID- 21527642 TI - Preparing emergency personnel in dialysis: a just-in-time training program for additional staffing during disasters. AB - BACKGROUND: There are 341 000 patients in the United States who are dependent on routine dialysis for survival. Recent large-scale disasters have emphasized the importance of disaster preparedness, including supporting dialysis units, for people with chronic disease. Contingency plans for staffing are important for providing continuity of care for a technically challenging procedure such as dialysis. PReparing Emergency Personnel in Dialysis (PREP-D) is a just-in-time training program designed to train individuals having minimum familiarity with the basic steps of dialysis to support routine dialysis staff during a disaster. METHODS: A 5-module educational program was developed through a collaborative, multidisciplinary effort. A pilot study testing the program was performed using 20 nontechnician dialysis facility employees and 20 clinical-year medical students as subjects. RESULTS: When comparing pretest and posttest scores, the entire study population showed a mean improvement of 28.9%, with dialysis facility employees and medical students showing improvements of 21.8% and 36.4%, respectively (P < .05 for all comparisons). CONCLUSIONS: PREP-D participants were able to demonstrate improved tests scores when taught in a just-in-time training format. The knowledge gained by using the PREP-D program during a staffing shortage may allow for continuity of care for critical services such as dialysis during a disaster. PMID- 21527643 TI - Cardiovascular function in nonclinical drug safety assessment: current issues and opportunities. AB - There are several recent examples where clinically significant, safety-related, drug effects on hemodynamics or cardiac function were not apparent until large clinical trials were completed or the drugs entered the consumer market. Such late-stage safety issues can have significant impact on patient health and consumer confidence, as well as ramifications for the regulatory, pharmaceutical, and financial communities. This manuscript provides recommendations that evolved from a 2009 HESI workshop on the need for improved translation of nonclinical cardiovascular effects to the clinical arena. The authors conclude that expanded and improved efforts to perform sensitive yet specific evaluations of functional cardiovascular parameters in nonclinical studies will allow pharmaceutical companies to identify suspect drugs early in the discovery and development process while allowing promising drugs to proceed into clinical development. PMID- 21527644 TI - Acute changes in pulmonary function following microinstillation inhalation exposure to soman in nonatropenized guinea pigs. AB - Barometric whole-body plethysmography (WBP) was used to examine pulmonary functions at 4 and 24 hours postexposure to soman (GD) in guinea pigs without therapeutics to improve survival. Endotracheal aerosolization by microinstillation was used to administer GD (280, 561, and 841 mg/m(3)) or saline to anesthetized guinea pigs. Significant increases in respiratory frequency (RF), tidal volume (TV), and minute volume (MV) were observed with 841 mg/m(3) GD at 4 hours and that were reduced at 24 hours postexposure. A dose-dependent increase in peak inspiration flow and peak expiration flow was present at 4-hour post-GD exposure that was reduced at 24 hours. Time of inspiration and expiration were decreased in all doses of GD exposure at 4 and 24 hours, with significant inhibition at 841 mg/m(3). End-expiratory pause (EEP) increased at 280 and 561 mg/m(3), but decreased in animals exposed 841 mg/m(3) at 24 hours postexposure. Pseudo-lung resistance (Penh) and pause followed similar patterns and increased at 4 hours, but decreased at 24 hours postexposure to 841 mg/m(3) of GD compared to control. These studies indicate GD exposure induces dose-dependent changes in pulmonary function that are significant at 841 mg/m(3) at 4 hours and remains 24 hours postexposure. Furthermore, at 4 hours, GD induces bronchoconstriction possibly due to copious airway secretion and ongoing lung injury in addition to cholinergic effects, while at 24 hours GD induces bronchodilation a possible consequence of initial compensatory mechanisms. PMID- 21527645 TI - Identification of circulating nonclassic human leukocyte antigen G (HLA-G)-like molecules in exudates. AB - BACKGROUND: HLA-G in biological fluids has been proposed to be useful as a tumor marker as both a diagnostic and prognostic factor. Most HLA-G measurement procedures are based on ELISA methods using highly specific antibodies. However, results of published studies are in conflict regarding the clinical utility and even the nature of HLA-G present in circulation. METHODS: We collected 118 exudates, 94 from cancer patients and 24 from patients without tumors. We measured HLA-G concentrations by ELISA using MEM-G/9 or G233 as capture antibody. Samples were immunoprecipitated with an anti-HLA-G antibody and analyzed by Western blot using a different anti-HLA-G antibody. RESULTS: Discrepancies in HLA G concentrations in exudates were observed depending on what capture anti-HLA-G antibody was used for ELISA (r = 0.376). These discrepancies were not observed when the ELISAs were performed using culture supernatants from HLA-G1-transfected cells (r = 0.983). Immunoprecipitation and Western blot of cell culture supernatants with 2 different anti-HLA-G antibodies produced the typical band at 39 kDa assigned to HLA-G. When the immunoprecipitation and western blot were performed with exudates, however, there were bands at 53 kDa and 70-76 kDa, higher molecular weights than those usually assigned to HLA-G. These HLA-G-like molecules were associated with beta(2)-microglobulin and could also form disulfide bridges with other HLA-G-like molecules. CONCLUSIONS: The main HLA-G antigenic molecules in exudates are HLA-G-like complexes, a factor that should be considered when analyzing HLA-G in biological fluids. PMID- 21527647 TI - Simultaneous pancreas-kidney transplants are appropriate in insulin-treated candidates with uremia regardless of diabetes type. PMID- 21527646 TI - Quality-of-life and mortality in hemodialysis patients: roles of race and nutritional status. AB - BACKGROUND AND OBJECTIVES: Maintenance hemodialysis (MHD) patients often have protein-energy wasting, poor health-related quality of life (QoL), and high premature death rates, whereas African-American MHD patients have greater survival than non-African-American patients. We hypothesized that poor QoL scores and their nutritional correlates have a bearing on racial survival disparities of MHD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined associations between baseline self-administered SF36 questionnaire-derived QoL scores with nutritional markers by multivariate linear regression and with survival by Cox models and cubic splines in the 6-year cohort of 705 MHD patients, including 223 African Americans. RESULTS: Worse SF36 mental and physical health scores were associated with lower serum albumin and creatinine levels but higher total body fat percentage. Spline analyses confirmed mortality predictability of worse QoL, with an almost strictly linear association for mental health score in African Americans, although the race-QoL interaction was not statistically significant. In fully adjusted analyses, the mental health score showed a more robust and linear association with mortality than the physical health score in all MHD patients and both races: death hazard ratios for (95% confidence interval) each 10 unit lower mental health score were 1.12 (1.05 1.19) and 1.10 (1.03-1.18) for all and African American patients, respectively. CONCLUSIONS: MHD patients with higher percentage body fat or lower serum albumin or creatinine concentration perceive a poorer QoL. Poor mental health in all and poor physical health in non-African American patients correlate with mortality. Improving QoL by interventions that can improve the nutritional status without increasing body fat warrants clinical trials. PMID- 21527648 TI - Associations among estimated glomerular filtration rate, proteinuria, and adverse cardiovascular outcomes. AB - BACKGROUND AND OBJECTIVES: Most studies of chronic kidney disease (CKD) and outcomes focus on mortality and ESRD, with limited data on other adverse outcomes. This study examined the associations among proteinuria, eGFR, and adverse cardiovascular (CV) events. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a population-based longitudinal study with patients identified from province-wide laboratory data from Alberta, Canada, between 2002 and 2007. Selected for this study from a total of 1,526,437 patients were 920,985 (60.3%) patients with at least one urine dipstick measurement and 102,701 patients (6.7%) with at least one albumin-creatinine ratio (ACR) measurement. Time to hospitalization was considered for one of four indications: congestive heart failure (CHF), coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), peripheral vascular disease (PVD), and stroke/transient ischemic attacks [TIAs] (cerebrovascular accident [CVA]/TIA). RESULTS: After a median follow-up of 35 months, in fully adjusted models and compared with patients with estimated GFR (eGFR) of 45 to 59 ml/min per 1.73 m(2) and no proteinuria, patients with heavy proteinuria by dipstick and eGFR >= 60 ml/min per 1.73 m(2) had higher rates of CABG/PCI and CVA/TIA. Similar results were obtained in patients with proteinuria measured by ACR. CONCLUSIONS: Risks of major CV events at a given level of eGFR increased with higher levels of proteinuria. The findings extend current data on risk of mortality and ESRD. Measurement of proteinuria is of incremental prognostic benefit at every level of eGFR. The data support use of proteinuria measurement with eGFR for definition and risk stratification in CKD. PMID- 21527650 TI - Sleep apnea in individuals with chronic kidney disease: a wake-up call. PMID- 21527649 TI - Serum fetuin-A levels are associated with vascular calcifications and predict cardiovascular events in renal transplant recipients. AB - BACKGROUND AND OBJECTIVES: Vascular calcifications predict cardiovascular disease, the major cause of death in renal transplant recipients (RTRs). We studied the determinants of fetuin-A, a potent circulating calcification inhibitor encoded by the AHSG gene, and tested its association with vascular calcifications and long-term survival and cardiovascular events (CVEs) in RTRs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Two hundred seventy-seven prevalent RTRs from a single center were included. CVEs and deaths were prospectively recorded during a 5-year follow-up. RESULTS: Independent determinants of lower serum fetuin-A levels were lower plasma cholesterol, the AHSG rs4918 G allele, and history of smoking. Low serum fetuin-A level was a determinant of aortic calcifications (assessed using spiral CT). Low fetuin-A levels (<=0.47 g/L, first quintile) were independently associated with CVEs and deaths (hazard ratio=1.83; 95% confidence interval, 1.07 to 3.04). The association was confirmed for all-cause mortality, and the major adverse cardiovascular endpoints were analyzed separately. Patients with low fetuin-A and high high-sensitivity C-reactive protein (>4.36 mg/L, fourth quintile) levels had a 3.5-fold increased risk of all-cause mortality and CVEs. In the presence of inflammation, CVE-free survival was influenced by common variants in the AHSG gene. CONCLUSIONS: These data show that low fetuin-A levels are independently associated with aortic calcifications and a higher risk of CVEs and mortality. They support fetuin-A as a circulating biomarker able to identify RTRs at risk for vascular calcifications and CVEs. PMID- 21527651 TI - C4d staining in renal allograft biopsies with early acute rejection and subsequent clinical outcome. AB - BACKGROUND AND OBJECTIVES: Diffuse C4d staining in peritubular capillaries (PTCs) during an acute rejection episode (ARE) is the footprint of antibody-mediated rejection. In current clinical practice, diffuse C4d+ staining during acute rejection is regarded as an inferior prognostic sign. This case-control study investigated the prognostic role of mere C4d staining for graft outcome during an ARE in a well defined cohort of similarly ARE-treated patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All kidney transplant recipients in the authors' center from January 1, 1995 to December 31, 2005 were reviewed. From these patients, 151 had a clinical ARE. Paraffin and/or frozen material was available for 128 patients showing a histologically proven ARE within the first 6 months after transplantation. All ARE patients were treated similarly with high-dose pulse steroids and in the case of steroid unresponsiveness with anti-thymocyte globulin. Biopsies were scored according to Banff criteria. Frozen and paraffin sections were stained by immunofluorescence (IF) and immunohistochemistry (IHC) for C4d, respectively, and scored for PTC positivity. RESULTS: Diffuse C4d+ staining in PTCs was found in 12.5% and 4.2% sections stained by IF or by IHC, respectively. Four patients showed diffuse positive staining with both methods but showed no different risk profile from other patients. No relation between C4d staining and clinical parameters at baseline was found. C4d staining was not associated with steroid responsiveness, graft, or patient survival. CONCLUSIONS: This study shows that C4d staining is not related to clinical outcome in this cohort of histologically proven early AREs. PMID- 21527652 TI - Increased cyclosporine concentrations in the absence of cyclosporine administration. PMID- 21527653 TI - Commentary. PMID- 21527654 TI - Commentary. PMID- 21527655 TI - What is your guess? The case of the milky white urine. PMID- 21527660 TI - ACE inhibition is renoprotective among obese patients with proteinuria. AB - Obesity may increase the risk for progression of CKD, but the effect of established renoprotective treatments in overweight and obese patients with CKD is unknown. In this post hoc analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, we evaluated whether being overweight or obese influences the incidence rate of renal events and affects the response to ramipril. Of the 337 trial participants with known body mass index (BMI), 105 (31.1%) were overweight and 49 (14.5%) were obese. Among placebo-treated patients, the incidence rate of ESRD was substantially higher in obese patients than overweight patients (24 versus 11 events/100 person-years) or than those with normal BMI (10 events/100 person-years); we observed a similar pattern for the combined endpoint of ESRD or doubling of serum creatinine. Ramipril reduced the rate of renal events in all BMI strata, but the effect was higher among the obese (incidence rate reduction of 86% for ESRD and 79% for the combined endpoint) than the overweight (incidence rate reduction of 45 and 48%, respectively) or those with normal BMI (incidence rate reduction of 42 and 45%, respectively). We confirmed this interaction between BMI and the efficacy of ramipril in analyses that adjusted for potential confounders, and we observed a similar effect modification for 24-hour protein excretion. In summary, obesity predicts a higher incidence of renal events, but treatment with ramipril can essentially abolish this risk excess. Furthermore, the reduction in risk conferred by ramipril is larger among obese than nonobese patients. PMID- 21527661 TI - Vagal-dependent nonlinear variability in the respiratory pattern of anesthetized, spontaneously breathing rats. AB - Physiological rhythms, including respiration, exhibit endogenous variability associated with health, and deviations from this are associated with disease. Specific changes in the linear and nonlinear sources of breathing variability have not been investigated. In this study, we used information theory-based techniques, combined with surrogate data testing, to quantify and characterize the vagal-dependent nonlinear pattern variability in urethane-anesthetized, spontaneously breathing adult rats. Surrogate data sets preserved the amplitude distribution and linear correlations of the original data set, but nonlinear correlation structure in the data was removed. Differences in mutual information and sample entropy between original and surrogate data sets indicated the presence of deterministic nonlinear or stochastic non-Gaussian variability. With vagi intact (n = 11), the respiratory cycle exhibited significant nonlinear behavior in templates of points separated by time delays ranging from one sample to one cycle length. After vagotomy (n = 6), even though nonlinear variability was reduced significantly, nonlinear properties were still evident at various time delays. Nonlinear deterministic variability did not change further after subsequent bilateral microinjection of MK-801, an N-methyl-D-aspartate receptor antagonist, in the Kolliker-Fuse nuclei. Reversing the sequence (n = 5), blocking N-methyl-D-aspartate receptors bilaterally in the dorsolateral pons significantly decreased nonlinear variability in the respiratory pattern, even with the vagi intact, and subsequent vagotomy did not change nonlinear variability. Thus both vagal and dorsolateral pontine influences contribute to nonlinear respiratory pattern variability. Furthermore, breathing dynamics of the intact system are mutually dependent on vagal and pontine sources of nonlinear complexity. Understanding the structure and modulation of variability provides insight into disease effects on respiratory patterning. PMID- 21527662 TI - Tracheal occlusion modulates the gene expression profile of the medial thalamus in anesthetized rats. AB - Conscious awareness of breathing requires the activation of higher brain centers and is believed to be a neural gated process. The thalamus could be responsible for the gating of respiratory sensory information to the cortex. It was reasoned that if the thalamus is the neural gate, then tracheal obstructions will modulate the gene expression profile of the thalamus. Anesthetized rats were instrumented with an inflatable cuff sutured around the trachea. The cuff was inflated to obstruct 2-4 breaths, then deflated for a minimum of 15 breaths. Obstructions were repeated for 10 min followed by immediate dissection of the medial thalamus. Following the occlusion protocol, 588 genes were found to be altered (P < 0.05; log(2) fold change >= 0.4), with 327 genes downregulated and 261 genes upregulated. A significant upregulation of the serotonin HTR2A receptor and significant downregulation of the dopamine DRD1 receptor genes were found. A pathway analysis was performed that targeted serotonin and dopamine receptor pathways. The mitogen-activated protein kinase 1 (MAPK1) gene was significantly downregulated. MAPK1 is an inhibitory regulator of HTR2A and facilitatory regulator for DRD1. Downregulation of MAPK1 may be related to the significant upregulation of HTR2A and downregulation of DRD1, suggesting an interaction in the medial thalamus serotonin-dopamine pathway elicited by airway obstruction. These results demonstrate an immediate change in gene expression in thalamic arousal, fear, anxiety motivation-related serotonin and dopamine receptors in response to airway obstruction. The results support the hypothesis that the thalamus is a component in the respiratory mechanosensory neural pathway. PMID- 21527663 TI - Skeletal muscle amino acid transporter expression is increased in young and older adults following resistance exercise. AB - Amino acid transporters and mammalian target of rapamycin complex 1 (mTORC1) signaling are important contributors to muscle protein anabolism. Aging is associated with reduced mTORC1 signaling following resistance exercise, but the role of amino acid transporters is unknown. Young (n = 13; 28 +/- 2 yr) and older (n = 13; 68 +/- 2 yr) subjects performed a bout of resistance exercise. Skeletal muscle biopsies (vastus lateralis) were obtained at basal and 3, 6, and 24 h postexercise and were analyzed for amino acid transporter mRNA and protein expression and regulators of amino acid transporter transcription utilizing real time PCR and Western blotting. We found that basal amino acid transporter expression was similar in young and older adults (P > 0.05). Exercise increased L type amino acid transporter 1/solute-linked carrier (SLC) 7A5, CD98/SLC3A2, sodium-coupled neutral amino acid transporter 2/SLC38A2, proton-assisted amino acid transporter 1/SLC36A1, and cationic amino acid transporter 1/SLC7A1 mRNA expression in both young and older adults (P < 0.05). L-type amino acid transporter 1 and CD98 protein increased only in younger adults (P < 0.05). eukaryotic initiation factor 2 alpha-subunit (S52) increased similarly in young and older adults postexercise (P < 0.05). Ribosomal protein S6 (S240/244) and activating transcription factor 4 nuclear protein expression tended to be higher in the young, while nuclear signal transducer and activator of transcription 3 (STAT3) (Y705) was higher in the older subjects postexercise (P < 0.05). These results suggest that the rapid upregulation of amino acid transporter expression following resistance exercise may be regulated differently between the age groups, but involves a combination of mTORC1, activating transcription factor 4, eukaryotic initiation factor 2 alpha-subunit, and STAT3. We propose an increase in amino acid transporter expression may contribute to enhanced amino acid sensitivity following exercise in young and older adults. In older adults, the increased nuclear STAT3 phosphorylation may be indicative of an exercise-induced stress response, perhaps to export amino acids from muscle cells. PMID- 21527664 TI - Changes in lower extremity muscle function after 56 days of bed rest. AB - Preservation of muscle function, known to decline in microgravity and simulation (bed rest), is important for successful spaceflight missions. Hence, there is great interest in developing interventions to prevent muscle-function loss. In this study, 20 males underwent 56 days of bed rest. Ten volunteers were randomized to do resistive vibration exercise (RVE). The other 10 served as controls. RVE consisted of muscle contractions against resistance and concurrent whole-body vibration. Main outcome parameters were maximal isometric plantar flexion force (IPFF), electromyography (EMG)/force ratio, as well as jumping power and height. Measurements were obtained before and after bed rest, including a morning and evening assessment on the first day of recovery from bed rest. IPFF (-17.1%), jumping peak power (-24.1%), and height (-28.5%) declined (P < 0.05) in the control group. There was a trend to EMG/force ratio decrease (-20%; P = 0.051). RVE preserved IPFF and mitigated the decline of countermovement jump performance (peak power -12.2%; height -14.2%). In both groups, IPFF was reduced between the two measurements of the first day of reambulation. This study indicates that bed rest and countermeasure exercises differentially affect the various functions of skeletal muscle. Moreover, the time course during recovery needs to be considered more thoroughly in future studies, as IPFF declined not only with bed rest but also within the first day of reambulation. RVE was effective in maintaining IPFF but only mitigated the decline in jumping performance. More research is needed to develop countermeasures that maintain muscle strength as well as other muscle functions including power. PMID- 21527665 TI - Imaging of the closed-chest mouse pulmonary circulation using synchrotron radiation microangiography. AB - Structural and functional changes of pulmonary circulation related to pathophysiology of pulmonary arterial hypertension (PAH) remain to be fully elucidated. Angiographic visualization in in vivo animals provided a powerful tool for assessing the major indexes associated with the pathogenesis of PAH. In this study, we have exploited the full potential of synchrotron radiation (SR) microangiography to show the ability to visualize pulmonary hemodynamics in a closed-chest mouse. Male adult mice were anesthetized and cannulated with a customized 24-gauge catheter into the right ventricle via the jugular vein for administering iodine contrast agent. The microangiography was performed on the left lung. We measured dynamic changes in vessel diameter in response to acetylcholine (ACh) and acute exposure to hypoxic gas (10% O(2)). Moreover, the pulmonary transit time was estimated by the time of contrast agent circulating. We were able to visualize the pulmonary arteries from the left pulmonary artery (LPA) to the third generation of branching (inner diameter <100 MUm). ACh and acute hypoxia induced vascular responses chiefly in the second and third branching vessels rather than the LPA and the first branching vessels. The transit time was only 0.83 s. These results demonstrate the effectiveness of SR for visualizing the pulmonary circulation in a closed-chest mouse. Future studies using SR microangiography on specific gene-targeted knockout and transgenic mice will provide new insights into the pathophysiology of pulmonary dysfunction and functional adaptation to survive in hypoxic condition. PMID- 21527666 TI - LIF is a contraction-induced myokine stimulating human myocyte proliferation. AB - The cytokine leukemia inhibitory factor (LIF) is expressed by skeletal muscle and induces proliferation of myoblasts. We hypothesized that LIF is a contraction induced myokine functioning in an autocrine fashion to activate gene regulation of human muscle satellite cell proliferation. Skeletal muscle LIF expression, regulation, and action were examined in two models: 1) young men performing a bout of heavy resistance exercise of the quadriceps muscle and 2) cultured primary human satellite cells. Resistance exercise induced a ninefold increase in LIF mRNA content in skeletal muscle, but LIF was not detectable in plasma of the subjects. However, electrically stimulated cultured human myotubes produced and secreted LIF, suggesting that LIF is a myokine with local effects. The well established exercise-induced signaling molecules PI3K, Akt, and mTor contributed to the regulation of LIF in cultured human myotubes as chemical inhibition of PI3K and mTor and siRNA knockdown of Akt1 were independently sufficient to downregulate LIF. Human myoblast proliferation was increased by recombinant exogenous LIF and decreased by siRNA knockdown of the endogenous LIF receptor. Finally, the transcription factors JunB and c-Myc, which promote myoblast proliferation, were induced by LIF in cultured human myotubes. Indeed, both JunB and c-Myc were also increased in skeletal muscle following resistance exercise. Our data suggest that LIF is a contraction-induced myokine, potentially acting in an autocrine or paracrine fashion to promote satellite cell proliferation. PMID- 21527668 TI - An amino acid mixture enhances insulin-stimulated glucose uptake in isolated rat epitrochlearis muscle. AB - Protein and certain amino acids (AA) have been found to lower blood glucose. Although these glucose-lowering AA are important modulators of skeletal muscle metabolism, their impact on muscle glucose uptake remains unclear. We therefore examined how an AA mixture consisting of 2 mM isoleucine, 0.012 mM cysteine, 0.006 mM methionine, 0.0016 mM valine, and 0.014 mM leucine impacts skeletal muscle glucose uptake in the absence or presence of a submaximal (sINS) or maximal insulin (mINS) concentration. The AA mixture, sINS, and mINS significantly increased 2-[(3)H]deoxyglucose (2-DG) uptake by 63, 79, and 298% above basal, respectively. When the AA mixture was combined with sINS and mINS, 2 DG uptake was further increased significantly by 26% (P = 0.028) and 14% (P = 0.032), respectively. Western blotting analysis revealed that the AA mixture increased basal and sINS Akt substrate of 160 kDa (AS160) phosphorylation, while AA mixture did not change phosphorylation of Akt or mammalian target of rapamycin (mTOR) under these conditions. Interestingly, addition of the AA mixture to mINS increased phosphorylation of mTOR, Akt as well as AS160, compared with mINS alone. These data suggest that certain AA increase glucose uptake in the absence of insulin and augment insulin-stimulated glucose uptake in an additive manner. Furthermore, these effects appear to be mediated via a pathway that is independent from the canonical insulin cascade and therefore may prove effective as an alternative therapeutic treatment for insulin resistance. PMID- 21527667 TI - Lactate threshold predicting time-trial performance: impact of heat and acclimation. AB - The relationship between exercise performance and lactate and ventilatory thresholds under two distinct environmental conditions is unknown. We examined the relationships between six lactate threshold methods (blood- and ventilation based) and exercise performance in cyclists in hot and cool environments. Twelve cyclists performed a lactate threshold test, a maximal O(2) uptake (Vo(2max)) test, and a 1-h time trial in hot (38 degrees C) and cool (13 degrees C) conditions, before and after heat acclimation. Eight control subjects completed the same tests before and after 10 days of identical exercise in a cool environment. The highest correlations were observed with the blood-based lactate indexes; however, even the indirect ventilation-based indexes were well correlated with mean power during the time trial. Averaged bias was 15.4 +/- 3.6 W higher for the ventilation- than the blood-based measures (P < 0.05). The bias of blood-based measures in the hot condition was increased: the time trial was overestimated by 37.7 +/- 3.6 W compared with only 24.1 +/- 3.2 W in the cool condition (P < 0.05). Acclimation had no effect on the bias of the blood-based indexes (P = 0.51) but exacerbated the overestimation by some ventilation-based indexes by an additional 34.5 +/- 14.1 W (P < 0.05). Blood-based methods to determine lactate threshold show less bias and smaller variance than ventilation based methods when predicting time-trial performance in cool environments. Of the blood-based methods, the inflection point between steady-state lactate and rising lactate (INFL) was the best method to predict time-trial performance. Lastly, in the hot condition, ventilation-based predictions are less accurate after heat acclimation, while blood-based predictions remain valid in both environments after heat acclimation. PMID- 21527669 TI - Limb-specific differences in the skin vascular responsiveness to adrenergic agonists. AB - In this study, to test the hypothesis that adrenergic vasoconstrictor responses of the legs are greater compared with the arms in human skin, cutaneous vascular conductance (CVC) in the forearm and calf were compared during the infusion of adrenergic agonists in healthy young volunteers. Under normothermic conditions, norepinephrine (NE, alpha- and beta-agonist, 1 * 10(-8) to 1 * 10(-2) M), phenylephrine (PHE, alpha(1)-agonist, 1 * 10(-8) to 1 * 10(-2) M), dexmedetomidine (DEX, alpha(2)-agonist, 1 * 10(-9) to 1 * 10(-4) M), and isoproterenol (ISO, beta-agonist, 1 * 10(-8) to 1 * 10(-3) M) were administered by intradermal microdialysis. Skin blood flow (SkBF) was measured by laser Doppler flowmetry, and the local temperature at SkBF-measuring sites was maintained at 34 degrees C throughout the experiments. CVC was calculated as the ratio of SkBF to blood pressure and expressed relative to the baseline value before drug infusion. The dose of NE at the onset of vasoconstriction and the effective dose (ED(50)) resulting in 50% of the maximal vasoconstrictor response for NE were lower (P < 0.001) in the calf than forearm. The ED(50) for PHE and DEX was also lower (P < 0.05) in the calf than forearm. Increases in CVC in response to ISO were potentially smaller in the calf, but the statistical differences in the responses were dependent on the expressions of CVC. These findings suggest that the cutaneous vasoconstrictor responsiveness to exogenous NE is greater in the legs than in the arms due to a higher alpha(1)- and alpha(2) adrenoceptor reactivity, while the beta-adrenoceptor function plays a minor role in regional differences in adrenergic vasoconstriction in normothermic humans. PMID- 21527671 TI - Role of polynucleotide phosphorylase in sRNA function in Escherichia coli. AB - In Escherichia coli, many small noncoding regulatory RNAs (sRNAs) post transcriptionally regulate gene expression by base-pairing to mRNAs in a process that is mediated by the RNA chaperone Hfq. Binding of the sRNA to the mRNA can lead to increased or decreased mRNA stability and/or translation. It is not known if proteins other than Hfq are necessary for this process. In order to identify additional genes required for the post-transcriptional regulation of gene expression by Hfq-dependent sRNAs, we developed a novel combined genetic selection and screen for mutants defective in sRNA regulation. In our combined genetic selection and screen, we isolated hfq mutants and mutants in pnp, encoding polynucleotide phosphorylase (PNPase). We show that loss-of-function mutations in pnp result in a decreased stability of several sRNAs including RyhB, SgrS, and CyaR and also decrease both the negative and positive regulation by sRNAs. The defect in stability of CyaR and in negative and positive regulation are suppressed by deletion mutations in RNase E. Altogether, our results suggest that the lack of sRNA-mediated regulation in the absence of an active form of PNPase is due to the rapid turnover of sRNA resulting from an increase in RNase E activity and/or an increase in access of other ribonucleases to sRNAs. PMID- 21527670 TI - Exercise, brain, and cognition across the life span. AB - This is a brief review of current evidence for the relationships between physical activity and exercise and the brain and cognition throughout the life span in non pathological populations. We focus on the effects of both aerobic and resistance training and provide a brief overview of potential neurobiological mechanisms derived from non-human animal models. Whereas research has focused primarily on the benefits of aerobic exercise in youth and young adult populations, there is growing evidence that both aerobic and resistance training are important for maintaining cognitive and brain health in old age. Finally, in these contexts, we point out gaps in the literature and future directions that will help advance the field of exercise neuroscience, including more studies that explicitly examine the effect of exercise type and intensity on cognition, the brain, and clinically significant outcomes. There is also a need for human neuroimaging studies to adopt a more unified multi-modal framework and for greater interaction between human and animal models of exercise effects on brain and cognition across the life span. PMID- 21527672 TI - Functional consequences of T-stem mutations in E. coli tRNAThrUGU in vitro and in vivo. AB - The binding affinities between Escherichia coli EF-Tu and 34 single and double base-pair changes in the T stem of E. coli tRNA(Thr)(UGU) were compared with similar data obtained previously for several aa-tRNAs binding to Thermus thermophilus EF-Tu. With a single exception, the two proteins bound to mutations in three T-stem base pairs in a quantitatively identical manner. However, tRNA(Thr) differs from other tRNAs by also using its rare A52-C62 pair as a negative specificity determinant. Using a plasmid-based tRNA gene replacement strategy, we show that many of the tRNA(Thr)(UGU) T-stem changes are either unable to support growth of E. coli or are less effective than the wild-type sequence. Since the inviable T-stem sequences are often present in other E. coli tRNAs, it appears that T-stem sequences in each tRNA body have evolved to optimize function in a different way. Although mutations of tRNA(Thr) can substantially increase or decrease its affinity to EF-Tu, the observed affinities do not correlate with the growth phenotype of the mutations in any simple way. This may either reflect the different conditions used in the two assays or indicate that the T-stem mutants affect another step in the translation mechanism. PMID- 21527673 TI - The 2010 Mw 8.8 Maule megathrust earthquake of Central Chile, monitored by GPS. AB - Large earthquakes produce crustal deformation that can be quantified by geodetic measurements, allowing for the determination of the slip distribution on the fault. We used data from Global Positioning System (GPS) networks in Central Chile to infer the static deformation and the kinematics of the 2010 moment magnitude (M(w)) 8.8 Maule megathrust earthquake. From elastic modeling, we found a total rupture length of ~500 kilometers where slip (up to 15 meters) concentrated on two main asperities situated on both sides of the epicenter. We found that rupture reached shallow depths, probably extending up to the trench. Resolvable afterslip occurred in regions of low coseismic slip. The low-frequency hypocenter is relocated 40 kilometers southwest of initial estimates. Rupture propagated bilaterally at about 3.1 kilometers per second, with possible but not fully resolved velocity variations. PMID- 21527674 TI - Imaging doped holes in a cuprate superconductor with high-resolution Compton scattering. AB - The high-temperature superconducting cuprate La(2-x)Sr(x)CuO(4) (LSCO) shows several phases ranging from antiferromagnetic insulator to metal with increasing hole doping. To understand how the nature of the hole state evolves with doping, we have carried out high-resolution Compton scattering measurements at room temperature together with first-principles electronic structure computations on a series of LSCO single crystals in which the hole doping level varies from the underdoped (UD) to the overdoped (OD) regime. Holes in the UD system are found to primarily populate the O 2p(x)/p(y) orbitals. In contrast, the character of holes in the OD system is very different in that these holes mostly enter Cu d orbitals. High-resolution Compton scattering provides a bulk-sensitive method for imaging the orbital character of dopants in complex materials. PMID- 21527675 TI - Human cytomegalovirus directly induces the antiviral protein viperin to enhance infectivity. AB - Viperin is an interferon-inducible protein that is directly induced in cells by human cytomegalovirus (HCMV) infection. Why HCMV would induce viperin, which has antiviral activity, is unknown. We show that HCMV-induced viperin disrupts cellular metabolism to enhance the infectious process. Viperin interaction with the viral protein vMIA resulted in viperin relocalization from the endoplasmic reticulum to the mitochondria. There, viperin interacted with the mitochondrial trifunctional protein that mediates beta-oxidation of fatty acids to generate adenosine triphosphate (ATP). This interaction with viperin, but not with a mutant lacking the viperin iron-sulfur cluster-binding motif, reduced cellular ATP generation, which resulted in actin cytoskeleton disruption and enhancement of infection. This function of viperin, which was previously attributed to vMIA, suggests that HCMV has coopted viperin to facilitate the infectious process. PMID- 21527676 TI - Spin-liquid ground state of the S = 1/2 kagome Heisenberg antiferromagnet. AB - We use the density matrix renormalization group to perform accurate calculations of the ground state of the nearest-neighbor quantum spin S = 1/2 Heisenberg antiferromagnet on the kagome lattice. We study this model on numerous long cylinders with circumferences up to 12 lattice spacings. Through a combination of very-low-energy and small finite-size effects, our results provide strong evidence that, for the infinite two-dimensional system, the ground state of this model is a fully gapped spin liquid. PMID- 21527677 TI - Early warnings of regime shifts: a whole-ecosystem experiment. AB - Catastrophic ecological regime shifts may be announced in advance by statistical early warning signals such as slowing return rates from perturbation and rising variance. The theoretical background for these indicators is rich, but real-world tests are rare, especially for whole ecosystems. We tested the hypothesis that these statistics would be early warning signals for an experimentally induced regime shift in an aquatic food web. We gradually added top predators to a lake over 3 years to destabilize its food web. An adjacent lake was monitored simultaneously as a reference ecosystem. Warning signals of a regime shift were evident in the manipulated lake during reorganization of the food web more than a year before the food web transition was complete, corroborating theory for leading indicators of ecological regime shifts. PMID- 21527679 TI - The new Egypt. PMID- 21527684 TI - International cooperation. U.S. spending bill limits joint efforts with China. PMID- 21527678 TI - Structural basis for methyl transfer by a radical SAM enzyme. AB - The radical S-adenosyl-L-methionine (SAM) enzymes RlmN and Cfr methylate 23S ribosomal RNA, modifying the C2 or C8 position of adenosine 2503. The methyl groups are installed by a two-step sequence involving initial methylation of a conserved Cys residue (RlmN Cys(355)) by SAM. Methyl transfer to the substrate requires reductive cleavage of a second equivalent of SAM. Crystal structures of RlmN and RlmN with SAM show that a single molecule of SAM coordinates the [4Fe 4S] cluster. Residue Cys(355) is S-methylated and located proximal to the SAM methyl group, suggesting the SAM that is involved in the initial methyl transfer binds at the same site. Thus, RlmN accomplishes its complex reaction with structural economy, harnessing the two most important reactivities of SAM within a single site. PMID- 21527685 TI - Astronomy. Peering back 13 billion years, through a gravitational lens. PMID- 21527686 TI - Medicine. Shortages of cancer drugs put patients, trials at risk. PMID- 21527687 TI - India. Faculties wither as higher education system rapidly expands. PMID- 21527688 TI - Infectious diseases. 'Breakthrough' deal on flu strains has modest provisions. PMID- 21527689 TI - Animal cognition. Are dolphins too smart for captivity? PMID- 21527690 TI - Social psychology. Using the psychology of evil to do good. PMID- 21527691 TI - Newsmaker interview. Jeremy Berg: an independent scientist departs NIH's ranks. PMID- 21527692 TI - Paleoanthropology Society & American Assoc. of Physical Anthropologists. Ancient footprints tell tales of travel. PMID- 21527693 TI - Paleoanthropology Society & American Assoc. of Physical Anthropologists. A new ancestor for Homo? PMID- 21527694 TI - Paleoanthropology Society & American Assoc. of Physical Anthropologists. Snapshots from the meeting. PMID- 21527695 TI - Prioritizing taxonomists. PMID- 21527696 TI - Peaceful collaborations deserve support. PMID- 21527697 TI - Toxicologists welcome assessment assistance. PMID- 21527698 TI - Life in science. Ichthyologists hooked on Facebook. PMID- 21527699 TI - Comment on "Erosion of lizard diversity by climate change and altered thermal niches". AB - Using a regionally calibrated model, Sinervo et al. (Reports, 14 May 2010, p. 894) predicted potential climate change impacts on lizard populations and estimated that many extinctions are under way. We argue that this model is not sufficient for predicting global losses in lizard species in response to anthropogenic climate change. PMID- 21527700 TI - Immunology. Damping by depletion. PMID- 21527701 TI - Applied physics. Phase-change memories on a diet. PMID- 21527702 TI - Biochemistry. The two faces of SAM. PMID- 21527703 TI - Physics. How do you want that insulator? PMID- 21527704 TI - Microbiology. Alternative actions for antibiotics. PMID- 21527705 TI - Retrospective. Thomas Eisner (1929-2011). PMID- 21527706 TI - SPORE series winner. Science Buddies: advancing informal science education. PMID- 21527707 TI - Microresonator-based optical frequency combs. AB - The series of precisely spaced, sharp spectral lines that form an optical frequency comb is enabling unprecedented measurement capabilities and new applications in a wide range of topics that include precision spectroscopy, atomic clocks, ultracold gases, and molecular fingerprinting. A new optical frequency comb generation principle has emerged that uses parametric frequency conversion in high resonance quality factor (Q) microresonators. This approach provides access to high repetition rates in the range of 10 to 1000 gigahertz through compact, chip-scale integration, permitting an increased number of comb applications, such as in astronomy, microwave photonics, or telecommunications. We review this emerging area and discuss opportunities that it presents for novel technologies as well as for fundamental science. PMID- 21527708 TI - Low-voltage, low-power, organic light-emitting transistors for active matrix displays. AB - Intrinsic nonuniformity in the polycrystalline-silicon backplane transistors of active matrix organic light-emitting diode displays severely limits display size. Organic semiconductors might provide an alternative, but their mobility remains too low to be useful in the conventional thin-film transistor design. Here we demonstrate an organic channel light-emitting transistor operating at low voltage, with low power dissipation, and high aperture ratio, in the three primary colors. The high level of performance is enabled by a single-wall carbon nanotube network source electrode that permits integration of the drive transistor and the light emitter into an efficient single stacked device. The performance demonstrated is comparable to that of polycrystalline-silicon backplane transistor-driven display pixels. PMID- 21527709 TI - Proton-catalyzed, silane-fueled Friedel-Crafts coupling of fluoroarenes. AB - The venerable Friedel-Crafts reaction appends alkyl or acyl groups to aromatic rings through alkyl or acyl cation equivalents typically generated by Lewis acids. We show that phenyl cation equivalents, generated from otherwise unreactive aryl fluorides, allow extension of the Friedel-Crafts reaction to intramolecular aryl couplings. The enabling feature of this reaction is the exchange of carbon-fluorine for silicon-fluorine bond enthalpies; the reaction is activated by an intermediate silyl cation. Catalytic quantities of protons or silyl cations paired with weakly coordinating carborane counterions initiate the reactions, after which proton transfer in the final aromatization step regenerates the active silyl cation species by protodesilylation of a quaternary silane. The methodology allows the high-yield formation of a range of tailored polycyclic aromatic hydrocarbons and graphene fragments. PMID- 21527710 TI - Surface-generated mesoscale eddies transport deep-sea products from hydrothermal vents. AB - Atmospheric forcing, which is known to have a strong influence on surface ocean dynamics and production, is typically not considered in studies of the deep sea. Our observations and models demonstrate an unexpected influence of surface generated mesoscale eddies in the transport of hydrothermal vent efflux and of vent larvae away from the northern East Pacific Rise. Transport by these deep reaching eddies provides a mechanism for spreading the hydrothermal chemical and heat flux into the deep-ocean interior and for dispersing propagules hundreds of kilometers between isolated and ephemeral communities. Because the eddies interacting with the East Pacific Rise are formed seasonally and are sensitive to phenomena such as El Nino, they have the potential to introduce seasonal to interannual atmospheric variations into the deep sea. PMID- 21527711 TI - Brain evolution triggers increased diversification of electric fishes. AB - Communication can contribute to the evolution of biodiversity by promoting speciation and reinforcing reproductive isolation between existing species. The evolution of species-specific signals depends on the ability of individuals to detect signal variation, which in turn relies on the capability of the brain to process signal information. Here, we show that evolutionary change in a region of the brain devoted to the analysis of communication signals in mormyrid electric fishes improved detection of subtle signal variation and resulted in enhanced rates of signal evolution and species diversification. These results show that neural innovations can drive the diversification of signals and promote speciation. PMID- 21527712 TI - Self-organizing and stochastic behaviors during the regeneration of hair stem cells. AB - Stem cells cycle through active and quiescent states. Large populations of stem cells in an organ may cycle randomly or in a coordinated manner. Although stem cell cycling within single hair follicles has been studied, less is known about regenerative behavior in a hair follicle population. By combining predictive mathematical modeling with in vivo studies in mice and rabbits, we show that a follicle progresses through cycling stages by continuous integration of inputs from intrinsic follicular and extrinsic environmental signals based on universal patterning principles. Signaling from the WNT/bone morphogenetic protein activator/inhibitor pair is coopted to mediate interactions among follicles in the population. This regenerative strategy is robust and versatile because relative activator/inhibitor strengths can be modulated easily, adapting the organism to different physiological and evolutionary needs. PMID- 21527713 TI - The spatial periodicity of grid cells is not sustained during reduced theta oscillations. AB - Grid cells in parahippocampal cortices fire at vertices of a periodic triangular grid that spans the entire recording environment. Such precise neural computations in space have been proposed to emerge from equally precise temporal oscillations within cells or within the local neural circuitry. We found that grid-like firing patterns in the entorhinal cortex vanished when theta oscillations were reduced after intraseptal lidocaine infusions in rats. Other spatially modulated cells in the same cortical region and place cells in the hippocampus retained their spatial firing patterns to a larger extent during these periods without well-organized oscillatory neuronal activity. Precisely timed neural activity within single cells or local networks is thus required for periodic spatial firing but not for single place fields. PMID- 21527714 TI - Reduction of theta rhythm dissociates grid cell spatial periodicity from directional tuning. AB - Grid cells recorded in the medial entorhinal cortex of freely moving rats exhibit firing at regular spatial locations and temporal modulation with theta rhythm oscillations (4 to 11 hertz). We analyzed grid cell spatial coding during reduction of network theta rhythm oscillations caused by medial septum (MS) inactivation with muscimol. During MS inactivation, grid cells lost their spatial periodicity, whereas head-direction cells maintained their selectivity. Conjunctive grid-by-head-direction cells lost grid cell spatial periodicity but retained head-direction specificity. All cells showed reduced rhythmicity in autocorrelations and cross-correlations. This supports the hypothesis that spatial coding by grid cells requires theta oscillations, and dissociates the mechanisms underlying the generation of entorhinal grid cell periodicity and head direction selectivity. PMID- 21527715 TI - A crystal structure of the complex between human complement receptor 2 and its ligand C3d. AB - The interaction of complement receptor 2 (CR2)--which is present on B cells and follicular dendritic cells--with its antigen-bound ligand C3d results in an enhanced antibody response, thus providing an important link between the innate and adaptive immune systems. Although a cocrystal structure of a complex between C3d and the ligand-binding domains of CR2 has been published, several aspects of this structure, including the position in C3d of the binding interface, remained controversial because of disagreement with biochemical data. We now report a cocrystal structure of a CR2(SCR1-2):C3d complex at 3.2 angstrom resolution in which the interaction interfaces differ markedly from the previously published structure and are consistent with the biochemical data. It is likely that, in the previous structure, the interaction was influenced by the presence of zinc acetate additive in the crystallization buffer, leading to a nonphysiological complex. Detailed knowledge of the binding interface now at hand gives the potential to exploit the interaction in vaccine design or in therapeutics directed against autoreactive B cells. PMID- 21527716 TI - Guanylyl cyclase activity in plants? PMID- 21527717 TI - Caenorhabditis elegans chromatin-associated proteins SET-2 and ASH-2 are differentially required for histone H3 Lys 4 methylation in embryos and adult germ cells. AB - Methylation of histone H3 lysine 4 (H3K4me), a mark associated with gene activation, is mediated by SET1 and the related mixed lineage leukemia (MLL) histone methyltransferases (HMTs) across species. Mammals contain seven H3K4 HMTs, Set1A, Set1B, and MLL1-MLL5. The activity of SET1 and MLL proteins relies on protein-protein interactions within large multisubunit complexes that include three core components: RbBP5, Ash2L, and WDR5. It remains unclear how the composition and specificity of these complexes varies between cell types and during development. Caenorhabditis elegans contains one SET1 protein, SET-2, one MLL-like protein, SET-16, and single homologs of RbBP5, Ash2L, and WDR5. Here we show that SET-2 is responsible for the majority of bulk H3K4 methylation at all developmental stages. However, SET-2 and absent, small, or homeotic discs 2 (ASH 2) are differentially required for tri- and dimethylation of H3K4 (H3K4me3 and me2) in embryos and adult germ cells. In embryos, whereas efficient H3K4me3 requires both SET-2 and ASH-2, H3K4me2 relies mostly on ASH-2. In adult germ cells by contrast, SET-2 serves a major role whereas ASH-2 is dispensable for H3K4me3 and most H3K4me2. Loss of SET-2 results in progressive sterility over several generations, suggesting an important function in the maintenance of a functional germ line. This study demonstrates that individual subunits of SET1 related complexes can show tissue specificity and developmental regulation and establishes C. elegans as a model to study SET1-related complexes in a multicellular organism. PMID- 21527718 TI - Alien introgressions represent a rich source of genes for crop improvement. PMID- 21527719 TI - Pheromone emergencies and drifting moth genomes. PMID- 21527720 TI - Unrepaired clustered DNA lesions induce chromosome breakage in human cells. AB - Clustered DNA damage induced by ionizing radiation is refractory to repair and may trigger carcinogenic events for reasons that are not well understood. Here, we used an in situ method to directly monitor induction and repair of clustered DNA lesions in individual cells. We showed, consistent with biophysical modeling, that the kinetics of loss of clustered DNA lesions was substantially compromised in human fibroblasts. The unique spatial distribution of different types of DNA lesions within the clustered damages, but not the physical location of these damages within the subnuclear domains, determined the cellular ability to repair the damage. We then examined checkpoint arrest mechanisms and yield of gross chromosomal aberrations. Induction of nonrepairable clustered damage affected only G2 accumulation but not the early G2/M checkpoint. Further, cells that were released from the G2/M checkpoint with unrepaired clustered damage manifested a spectrum of chromosome aberrations in mitosis. Difficulties associated with clustered DNA damage repair and checkpoint release before the completion of clustered DNA damage repair appear to promote genome instability that may lead to carcinogenesis. PMID- 21527721 TI - Engineering the embryo. PMID- 21527722 TI - Cysteine shotgun-mass spectrometry (CS-MS) reveals dynamic sequence of protein structure changes within mutant and stressed cells. AB - Questions of if and when protein structures change within cells pervade biology and include questions of how the cytoskeleton sustains stresses on cells- particularly in mutant versus normal cells. Cysteine shotgun labeling with fluorophores is analyzed here with mass spectrometry of the spectrin-actin membrane skeleton in sheared red blood cell ghosts from normal and diseased mice. Sheared samples are compared to static samples at 37 degrees C in terms of cell membrane intensity in fluorescence microscopy, separated protein fluorescence, and tryptic peptide modification in liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spectrin labeling proves to be the most sensitive to shear, whereas binding partners ankyrin and actin exhibit shear thresholds in labeling and both the ankyrin-binding membrane protein band 3 and the spectrin actin stabilizer 4.1R show minimal differential labeling. Cells from 4.1R-null mice differ significantly from normal in the shear-dependent labeling of spectrin, ankyrin, and band 3: Decreased labeling of spectrin reveals less stress on the mutant network as spectrin dissociates from actin. Mapping the stress dependent labeling kinetics of alpha- and beta-spectrin by LC-MS/MS identifies Cys in these antiparallel chains that are either force-enhanced or force independent in labeling, with structural analyses indicating the force-enhanced sites are sequestered either in spectrin's triple-helical domains or in interactions with actin or ankyrin. Shear-sensitive sites identified comprehensively here in both spectrin and ankyrin appear consistent with stress relief through forced unfolding followed by cytoskeletal disruption. PMID- 21527723 TI - Solid-state 2H NMR relaxation illuminates functional dynamics of retinal cofactor in membrane activation of rhodopsin. AB - Rhodopsin is a canonical member of the family of G protein-coupled receptors, which transmit signals across cellular membranes and are linked to many drug interventions in humans. Here we show that solid-state (2)H NMR relaxation allows investigation of light-induced changes in local ps-ns time scale motions of retinal bound to rhodopsin. Site-specific (2)H labels were introduced into methyl groups of the retinal ligand that are essential to the activation process. We conducted solid-state (2)H NMR relaxation (spin-lattice, T(1Z), and quadrupolar order, T(1Q)) experiments in the dark, Meta I, and Meta II states of the photoreceptor. Surprisingly, we find the retinylidene methyl groups exhibit site specific differences in dynamics that change upon light excitation--even more striking, the C9-methyl group is a dynamical hotspot that corresponds to a crucial functional hotspot of rhodopsin. Following 11-cis to trans isomerization, the (2)H NMR data suggest the beta-ionone ring remains in its hydrophobic binding pocket in all three states of the protein. We propose a multiscale activation mechanism with a complex energy landscape, whereby the photonic energy is directed against the E2 loop by the C13-methyl group, and toward helices H3 and H5 by the C5-methyl of the beta-ionone ring. Changes in retinal structure and dynamics initiate activating fluctuations of transmembrane helices H5 and H6 in the Meta I-Meta II equilibrium of rhodopsin. Our proposals challenge the Standard Model whereby a single light-activated receptor conformation yields the visual response--rather an ensemble of substates is present, due to the entropy gain produced by photolysis of the inhibitory retinal lock. PMID- 21527724 TI - Brain connectivity: gender makes a difference. AB - It has been well known that gender plays a critical role in the anatomy and function of the human brain, as well as human behaviors. Recent neuroimaging studies have demonstrated gender effects on not only focal brain areas but also the connectivity between areas. Specifically, structural MRI and diffusion MRI data have revealed substantial gender differences in white matter-based anatomical connectivity. Structural MRI data further demonstrated gender differences in the connectivity revealed by morphometric correlation among brain areas. Functional connectivity derived from functional neuroimaging (e.g., functional MRI and PET) data is also modulated by gender. Moreover, male and female human brains display differences in the network topology that represents the organizational patterns of brain connectivity across the entire brain. In this review, the authors summarize recent findings in the multimodal brain connectivity/network research with gender, focusing on large-scale data sets derived from modern neuroimaging techniques. The literature provides convergent evidence for a substantial gender difference in brain connectivity within the human brain that possibly underlies gender-related cognitive differences. Therefore, it should be mandatory to take gender into account when designing experiments or interpreting results of brain connectivity/network in health and disease. Future studies will likely be conducted to explore the interdependence between gender-related brain connectivity/network and the gender-specific nature of brain diseases as well as to investigate gender-related characteristics of multimodal brain connectivity/network in the normal brain. PMID- 21527726 TI - A role for transcription factor E2F2 in hepatocyte proliferation and timely liver regeneration. AB - E2F transcription factors are key regulators of the cell cycle although the relative contribution of each E2F member in regulating cellular proliferation is still poorly defined. Present evidence suggests that E2F2 may act both as a suppressor and promoter of proliferation, depending on the cellular context. We used a loss-of-function mutant mouse model to investigate the function of E2F2 in liver regeneration after partial hepatectomy, a paradigm of cell-cycle progression. Liver mass recovery and histology were examined over 9 days in 70% hepatectomized E2F2(-/-) and wild-type animals. Transcriptome analysis was performed in quiescent and 48-h regenerating liver samples. TIGR MultiExperiment Viewer was used for the statistical analysis of microarray data, significance was determined by Fischer, and P values were adjusted applying Benjamini-Hochberg multiple-testing correction. We show that E2F2 is required for adult hepatocyte proliferation and for timely liver regeneration, as disruption of the E2F2 gene in hepatocytes leads to a reduced rate of S-phase entry and to delayed liver regeneration. Transcriptome analysis followed by ontological classification of differentially expressed genes and gene-interaction network analysis indicated that the majority of genes involved in normal liver regeneration were related to biosynthetic and catabolic processes of all major biomolecules as well as cellular location and intracellular transport, confirming the complex nature of the regeneration process. Remarkably, transcripts of genes included in functional categories that are crucial for cell cycle, apoptosis and wound-healing response, and fibrosis were absent in the transcriptome of posthepatectomized E2F2(-/-) mice. Our results indicate that the transcriptional activity of E2F2 contributes to promote adult hepatocyte proliferation and liver regeneration. PMID- 21527725 TI - Hepatic stellate cells require a stiff environment for myofibroblastic differentiation. AB - The myofibroblastic differentiation of hepatic stellate cells (HSC) is a critical event in liver fibrosis and is part of the final common pathway to cirrhosis in chronic liver disease from all causes. The molecular mechanisms driving HSC differentiation are not fully understood. Because macroscopic tissue stiffening is a feature of fibrotic disease, we hypothesized that mechanical properties of the underlying matrix are a principal determinant of HSC activation. Primary rat HSC were cultured on inert polyacrylamide supports of variable but precisely defined shear modulus (stiffness) coated with different extracellular matrix proteins or poly-L-lysine. HSC differentiation was determined by cell morphology, immunofluorescence staining, and gene expression. HSC became progressively myofibroblastic as substrate stiffness increased on all coating matrices, including Matrigel. The degree rather than speed of HSC activation correlated with substrate stiffness, with cells cultured on supports of intermediate stiffness adopting stable intermediate phenotypes. Quiescent cells on soft supports were able to undergo myofibroblastic differentiation with exposure to stiff supports. Stiffness-dependent differentiation required adhesion to matrix proteins and the generation of mechanical tension. Transforming growth factor beta treatment enhanced differentiation on stiff supports, but was not required. HSC differentiate to myofibroblasts in vitro primarily as a function of the physical rather than the chemical properties of the substrate. HSC require a mechanically stiff substrate, with adhesion to matrix proteins and the generation of mechanical tension, to differentiate. These findings suggest that alterations in liver stiffness are a key factor driving the progression of fibrosis. PMID- 21527727 TI - The "cryptic" mechanism of action of glucagon-like peptide-2. AB - Glucagon-like peptide-2 (GLP-2) is a peptide hormone with multiple beneficial effects on the intestine, including expansion of the mucosal surface area through stimulation of crypt cell proliferation, as well as enhancement of nutrient digestion and absorption. Recent advances in clinical trials involving GLP-2 necessitate elucidation of the exact signaling pathways by which GLP-2 acts. In particular, the GLP-2 receptor has been localized to several intestinal cell types that do not include the proliferating crypt cells, and the actions of GLP-2 have thus been linked to a complex network of indirect mediators that induce diverse signaling pathways. The intestinotropic actions of GLP-2 on the colon have been shown to be mediated through the actions of keratinocyte growth factor and insulin-like growth factor (IGF)-2, whereas small intestinal growth has been linked to IGF-1, IGF-2, and ErbB ligands, as well as the IGF-1 receptor and ErbB. The cellular source of these mediators remains unclear, but it likely includes the intestinal subepithelial myofibroblasts. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are dependent on vasoactive intestinal polypeptide released from submucosal enteric neurons and nitric oxide, respectively. Finally, recent studies have suggested that GLP-2 not only modulates intestinal stem cell behavior but may also promote carcinogenesis in models of sporadic colon cancer. Further consideration of the molecular cross talk and downstream signaling pathways mediating the intestinotropic effects of GLP-2 is clearly warranted. PMID- 21527728 TI - SREBP2 mediates the modulation of intestinal NPC1L1 expression by curcumin. AB - Curcumin, the major phenolic compound in the spice turmeric, exhibits numerous biological effects, including lowering plasma cholesterol and preventing diet induced hypercholesterolemia. The mechanisms underlying the hypocholesterolemic effect of curcumin are not fully understood. In this regard, intestinal Niemann Pick C1-like 1 (NPC1L1) cholesterol transporter, the molecular target of intestinal cholesterol absorption inhibitor ezetimibe, plays an essential role in the maintenance of cholesterol homeostasis. The current studies were designed to investigate the effect of curcumin on NPC1L1 function, expression, and promoter activity in intestinal Caco-2 monolayers. NPC1L1 function was evaluated by the measurement of ezetimibe-sensitive [(3)H]cholesterol esterification. Relative abundance of NPC1L1 mRNA and protein was evaluated by real-time PCR and Western blotting, respectively. Luciferase assays were used to measure NPC1L1 promoter activity. Our results showed that curcumin significantly inhibited ezetimibe sensitive cholesterol esterification in a dose-dependent manner with a maximum decrease (by 52% compared with control) occurring at 50 MUM concentration. Curcumin treatment of Caco-2 monolayers also significantly decreased NPC1L1 mRNA and protein expression. Similarly, the promoter activity of the NPC1L1 gene was inhibited significantly (55%) by 50 MUM curcumin. The decrease in NPC1L1 promoter activity by curcumin was associated with a reduction in the expression and the DNA-binding activity of the sterol response element-binding protein 2 (SREBP2) transcription factor. Furthermore, the overexpression of active SREBP2 protected NPC1L1 from the inhibitory effect of curcumin. Our studies demonstrate that curcumin directly modulates intestinal NPC1L1 expression via transcriptional regulation and the involvement of SREBP2 transcription factor. PMID- 21527729 TI - Leptin and the central nervous system control of glucose metabolism. AB - The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders. PMID- 21527730 TI - Honeybees as a model for the study of visually guided flight, navigation, and biologically inspired robotics. AB - Research over the past century has revealed the impressive capacities of the honeybee, Apis mellifera, in relation to visual perception, flight guidance, navigation, and learning and memory. These observations, coupled with the relative ease with which these creatures can be trained, and the relative simplicity of their nervous systems, have made honeybees an attractive model in which to pursue general principles of sensorimotor function in a variety of contexts, many of which pertain not just to honeybees, but several other animal species, including humans. This review begins by describing the principles of visual guidance that underlie perception of the world in three dimensions, obstacle avoidance, control of flight speed, and orchestrating smooth landings. We then consider how navigation over long distances is accomplished, with particular reference to how bees use information from the celestial compass to determine their flight bearing, and information from the movement of the environment in their eyes to gauge how far they have flown. Finally, we illustrate how some of the principles gleaned from these studies are now being used to design novel, biologically inspired algorithms for the guidance of unmanned aerial vehicles. PMID- 21527731 TI - Physiology of microglia. AB - Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments. PMID- 21527732 TI - Axon physiology. AB - Axons are generally considered as reliable transmission cables in which stable propagation occurs once an action potential is generated. Axon dysfunction occupies a central position in many inherited and acquired neurological disorders that affect both peripheral and central neurons. Recent findings suggest that the functional and computational repertoire of the axon is much richer than traditionally thought. Beyond classical axonal propagation, intrinsic voltage gated ionic currents together with the geometrical properties of the axon determine several complex operations that not only control signal processing in brain circuits but also neuronal timing and synaptic efficacy. Recent evidence for the implication of these forms of axonal computation in the short-term dynamics of neuronal communication is discussed. Finally, we review how neuronal activity regulates both axon morphology and axonal function on a long-term time scale during development and adulthood. PMID- 21527733 TI - Epigenetic regulation of gene expression in physiological and pathological brain processes. AB - Over the past decade, it has become increasingly obvious that epigenetic mechanisms are an integral part of a multitude of brain functions that range from the development of the nervous system over basic neuronal functions to higher order cognitive processes. At the same time, a substantial body of evidence has surfaced indicating that several neurodevelopmental, neurodegenerative, and neuropsychiatric disorders are in part caused by aberrant epigenetic modifications. Because of their inherent plasticity, such pathological epigenetic modifications are readily amenable to pharmacological interventions and have thus raised justified hopes that the epigenetic machinery provides a powerful new platform for therapeutic approaches against these diseases. In this review, we give a detailed overview of the implication of epigenetic mechanisms in both physiological and pathological brain processes and summarize the state-of-the-art of "epigenetic medicine" where applicable. Despite, or because of, these new and exciting findings, it is becoming apparent that the epigenetic machinery in the brain is highly complex and intertwined, which underscores the need for more refined studies to disentangle brain-region and cell-type specific epigenetic codes in a given environmental condition. Clearly, the brain contains an epigenetic "hotspot" with a unique potential to not only better understand its most complex functions, but also to treat its most vicious diseases. PMID- 21527734 TI - Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. AB - The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review. PMID- 21527736 TI - Biology of human sodium glucose transporters. AB - There are two classes of glucose transporters involved in glucose homeostasis in the body, the facilitated transporters or uniporters (GLUTs) and the active transporters or symporters (SGLTs). The energy for active glucose transport is provided by the sodium gradient across the cell membrane, the Na(+) glucose cotransport hypothesis first proposed in 1960 by Crane. Since the cloning of SGLT1 in 1987, there have been advances in the genetics, molecular biology, biochemistry, biophysics, and structure of SGLTs. There are 12 members of the human SGLT (SLC5) gene family, including cotransporters for sugars, anions, vitamins, and short-chain fatty acids. Here we give a personal review of these advances. The SGLTs belong to a structural class of membrane proteins from unrelated gene families of antiporters and Na(+) and H(+) symporters. This class shares a common atomic architecture and a common transport mechanism. SGLTs also function as water and urea channels, glucose sensors, and coupled-water and urea transporters. We also discuss the physiology and pathophysiology of SGLTs, e.g., glucose galactose malabsorption and familial renal glycosuria, and briefly report on targeting of SGLTs for new therapies for diabetes. PMID- 21527737 TI - Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias. AB - RATIONALE: Posttranslational phosphorylation of connexin43 (Cx43) has been proposed as a key regulatory event in normal cardiac gap junction expression and pathological gap junction remodeling. Nonetheless, the role of Cx43 phosphorylation in the context of the intact organism is poorly understood. OBJECTIVE: To establish whether specific Cx43 phosphorylation events influence gap junction expression and pathological remodeling. METHODS AND RESULTS: We generated Cx43 germline knock-in mice in which serines 325/328/330 were replaced with phosphomimetic glutamic acids (S3E) or nonphosphorylatable alanines (S3A). The S3E mice were resistant to acute and chronic pathological gap junction remodeling and displayed diminished susceptibility to the induction of ventricular arrhythmias. Conversely, the S3A mice showed deleterious effects on cardiac gap junction formation and function, developed electric remodeling, and were highly susceptible to inducible arrhythmias. CONCLUSIONS: These data demonstrate a mechanistic link between posttranslational phosphorylation of Cx43 and gap junction formation, remodeling, and arrhythmic susceptibility. PMID- 21527738 TI - Exercise protects against myocardial ischemia-reperfusion injury via stimulation of beta(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols. AB - RATIONALE: Exercise training confers sustainable protection against ischemia reperfusion injury in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise protects the heart, but it is apparent that endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) play a role. OBJECTIVE: To determine the role of beta(3)-adrenergic receptors (beta(3)-ARs), eNOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of exercise. METHODS AND RESULTS: Here we show that voluntary exercise reduces myocardial injury in mice following a 4-week training period and that these protective effects can be sustained for at least 1 week following the cessation of the training. The sustained cardioprotective effects of exercise are mediated by alterations in the phosphorylation status of eNOS (increase in serine 1177 and decrease in threonine 495), leading to an increase in NO generation and storage of NO metabolites (nitrite and nitrosothiols) in the heart. Further evidence revealed that the alterations in eNOS phosphorylation status and NO generation were mediated by beta(3)-AR stimulation and that in response to exercise a deficiency of beta(3)-ARs leads to an exacerbation of myocardial infarction following ischemia-reperfusion injury. CONCLUSIONS: Our findings clearly demonstrate that exercise protects the heart against myocardial ischemia reperfusion injury by stimulation of beta(3)-ARs and increased cardiac storage of nitric oxide metabolites (ie, nitrite and nitrosothiols). PMID- 21527739 TI - Disruption of hexokinase II-mitochondrial binding blocks ischemic preconditioning and causes rapid cardiac necrosis. AB - RATIONALE: Isoforms I and II of the glycolytic enzyme hexokinase (HKI and HKII) are known to associate with mitochondria. It is unknown whether mitochondria bound hexokinase is mandatory for ischemic preconditioning and normal functioning of the intact, beating heart. OBJECTIVE: We hypothesized that reducing mitochondrial hexokinase would abrogate ischemic preconditioning and disrupt myocardial function. METHODS AND RESULTS: Ex vivo perfused HKII(+/-) hearts exhibited increased cell death after ischemia and reperfusion injury compared with wild-type hearts; however, ischemic preconditioning was unaffected. To investigate acute reductions in mitochondrial HKII levels, wild-type hearts were treated with a TAT control peptide or a TAT-HK peptide that contained the binding motif of HKII to mitochondria, thereby disrupting the mitochondrial HKII association. Mitochondrial hexokinase was determined by HKI and HKII immunogold labeling and electron microscopy analysis. Low-dose (200 nmol/L) TAT-HK treatment significantly decreased mitochondrial HKII levels without affecting baseline cardiac function but dramatically increased ischemia-reperfusion injury and prevented the protective effects of ischemic preconditioning. Treatment for 15 minutes with high-dose (10 MUmol/L) TAT-HK resulted in acute mitochondrial depolarization, mitochondrial swelling, profound contractile impairment, and severe cardiac disintegration. The detrimental effects of TAT-HK treatment were mimicked by mitochondrial membrane depolarization after mild mitochondrial uncoupling that did not cause direct mitochondrial permeability transition opening. CONCLUSIONS: Acute low-dose dissociation of HKII from mitochondria in heart prevented ischemic preconditioning, whereas high-dose HKII dissociation caused cessation of cardiac contraction and tissue disruption, likely through an acute mitochondrial membrane depolarization mechanism. The results suggest that the association of HKII with mitochondria is essential for the protective effects of ischemic preconditioning and normal cardiac function through maintenance of mitochondrial potential. PMID- 21527740 TI - The hemosteoblast: friend or foe? PMID- 21527735 TI - Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation. AB - This review addresses the cellular and molecular mechanisms of cadherin-based tissue morphogenesis. Tissue physiology is profoundly influenced by the distinctive organizations of cells in organs and tissues. In metazoa, adhesion receptors of the classical cadherin family play important roles in establishing and maintaining such tissue organization. Indeed, it is apparent that cadherins participate in a range of morphogenetic events that range from support of tissue integrity to dynamic cellular rearrangements. A comprehensive understanding of cadherin-based morphogenesis must then define the molecular and cellular mechanisms that support these distinct cadherin biologies. Here we focus on four key mechanistic elements: the molecular basis for adhesion through cadherin ectodomains, the regulation of cadherin expression at the cell surface, cooperation between cadherins and the actin cytoskeleton, and regulation by cell signaling. We discuss current progress and outline issues for further research in these fields. PMID- 21527742 TI - Multiple facets of NF-kappaB in the heart: to be or not to NF-kappaB. AB - The progression from cardiac injury to symptomatic heart failure has been intensely studied over the last decade, and is largely attributable to a loss of functional cardiac myocytes through necrosis, intrinsic and extrinsic apoptosis pathways and autophagy. Therefore, the molecular regulation of these cellular programs has been rigorously investigated in the hopes of identifying a potential cell target that could promote cell survival and/or inhibit cell death to avert, or at least prolong, the degeneration toward symptomatic heart failure. The nuclear factor (NF)-kappaB super family of transcription factors has been implicated in the regulation of immune cell maturation, cell survival, and inflammation in many cell types, including cardiac myocytes. Recent studies have shown that NF-kappaB is cardioprotective during acute hypoxia and reperfusion injury. However, prolonged activation of NF-kappaB appears to be detrimental and promotes heart failure by eliciting signals that trigger chronic inflammation through enhanced elaboration of cytokines including tumor necrosis factor alpha, interleukin-1, and interleukin-6, leading to endoplasmic reticulum stress responses and cell death. The underlying mechanisms that account for the multifaceted and differential outcomes of NF-kappaB on cardiac cell fate are presently unknown. Herein, we posit a novel paradigm in which the timing, duration of activation, and cellular context may explain mechanistically the differential outcomes of NF-kappaB signaling in the heart that may be essential for future development of novel therapeutic interventions designed to target NF kappaB responses and heart failure following myocardial injury. PMID- 21527743 TI - The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. AB - Recent studies suggest that the heart possesses an innate immune system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses, within the heart. The extant literature suggests that this intrinsic stress response system is mediated, at least in part, by a family of pattern recognition receptors, most notably the Toll-like receptors. Although the innate immune system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if innate immune signaling becomes sustained and/or excessive; in which case, the salutary effects of activation of these pathways are contravened by the known deleterious effects of inflammatory signaling. Herein, the biology of innate immune signaling in the heart is reviewed, as well as the literature suggesting that the innate immune system is involved in the pathogenesis of atherosclerosis, acute coronary syndromes, stroke, viral myocarditis, sepsis, ischemia/reperfusion injury, and heart failure. The review concludes by discussing new therapies that are being developed to modulate the innate immune system. PMID- 21527744 TI - Derivation of human induced pluripotent stem cells for cardiovascular disease modeling. AB - The successful derivation of human induced pluripotent stem cells (hiPSCs) by dedifferentiation of somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC derivatives offer incredible potential for new disease models and regenerative medicine therapies. However, many questions remain regarding the optimal starting materials and methods to enable safe, efficient derivation of hiPSCs suitable for clinical applications. Initial reprogramming experiments were carried out using lentiviral or retroviral gene delivery methods. More recently, various nonviral methods that avoid permanent and random transgene insertion have emerged as alternatives. These include transient DNA transfection using plasmids or minicircles, protein transduction, or RNA transfection. In addition, several small molecules have been found to significantly augment hiPSC derivation efficiency, allowing the use of a fewer number of genes during pluripotency induction. We review these various methods for the derivation of hiPSCs, focusing on their ultimate clinical applicability, with an emphasis on their potential for use as cardiovascular therapies and disease-modeling platforms. PMID- 21527745 TI - SUMO1 negatively regulates reactive oxygen species production from NADPH oxidases. AB - OBJECTIVE: Increased protein SUMOylation (small ubiquitin-related modifier [SUMO]) provides protection from cellular stress, including oxidative stress, but the mechanisms involved are incompletely understood. The NADPH oxidases (Nox) are a primary source of reactive oxygen species (ROS) and oxidative stress, and thus our goal was to determine whether SUMO regulates NADPH oxidase activity. METHODS AND RESULTS: Increased expression of SUMO1 potently inhibited the activity of Nox1 to Nox5. In contrast, inhibition of endogenous SUMOylation with small interfering RNA to SUMO1 or ubiquitin conjugating enzyme 9 or with the inhibitor anacardic acid increased ROS production from human embryonic kidney-Nox5 cells, human vascular smooth muscle cells, and neutrophils. The suppression of ROS production was unique to SUMO1, and it required a C-terminal diglycine and the SUMO-specific conjugating enzyme ubiquitin conjugating enzyme 9. SUMO1 did not modify intracellular calcium or Nox5 phosphorylation but reduced ROS output in an isolated enzyme assay, suggesting direct effects of SUMOylation on enzyme activity. However, we could not detect the presence of SUMO1 conjugation on Nox5 using a variety of approaches. Moreover, the mutation of more than 17 predicted and conserved lysine residues on Nox5 did not alter the inhibitory actions of SUMO1. CONCLUSIONS: Together, these results suggest that SUMO is an important regulatory mechanism that indirectly represses the production of ROS to ameliorate cellular stress. PMID- 21527746 TI - Triglycerides and heart disease: still a hypothesis? AB - The purpose of this article is to review the basic and clinical science relating plasma triglycerides and cardiovascular disease. Although many aspects of the basic physiology of triglyceride production, its plasma transport, and its tissue uptake have been known for several decades, the relationship of plasma triglyceride levels to vascular disease is uncertain. Are triglyceride-rich lipoproteins, their influence on high-density lipoprotein and low-density lipoprotein, or the underlying diseases that lead to defects in triglyceride metabolism the culprit? Animal models have failed to confirm that anything other than early fatty lesions can be produced by triglyceride-rich lipoproteins. Metabolic products of triglyceride metabolism can be toxic to arterial cells; however, these studies are primarily in vitro. Correlative studies of fasting and postprandial triglycerides and genetic diseases implicate very-low-density lipoprotein and their remnants and chylomicron remnants in atherosclerosis development, but the concomitant alterations in other lipoproteins and other risk factors obscure any conclusions about direct relationships between disease and triglycerides. Genes that regulate triglyceride levels also correlate with vascular disease. Human intervention trials, however, have lacked an appropriately defined population and have produced outcomes without definitive conclusions. The time is more than ripe for new and creative approaches to understanding the relationship of triglycerides and heart disease. PMID- 21527749 TI - Carotid artery longitudinal displacement predicts 1-year cardiovascular outcome in patients with suspected coronary artery disease. AB - OBJECTIVE: Total longitudinal displacement (tLoD) of the common carotid artery can be measured using the ultrasound-based velocity vector imaging (VVI) technique. This study aimed to investigate clinical correlates and the possible predictive value of tLoD for cardiovascular outcome. METHODS AND RESULTS: Four hundred forty-one patients referred for myocardial perfusion scintigraphy examination for suspected coronary artery disease were recruited and underwent VVI-assisted tLoD measurement. Patients were followed up with regard to major adverse cardiovascular event (MACE) 1 year later. Low tLoD (<= 0.055 mm) was associated with greater clinically determined myocardial ischemia (P<0.01). During a median follow-up time of 372 days, 61 MACEs occurred. In a Kaplan-Meier survival analysis, high tLoD (>0.055 mm) predicted 1-year event-free survival (P<0.01, highest versus lowest tertile odds ratio [OR] = 1.9). In a Cox regression model adjusting for age, gender, intima-media thickness, radial strain, pulse pressure, and percentage reversibility mass of myocardium, low tLoD remained a significant independent predictor of MACE (P = 0.03). Finally, low tLoD provided additional predictive value in subjects with increased intima-media thickness. CONCLUSIONS: VVI-derived tLoD seems to reflect cardiovascular status and predicts short-term event-free survival in medium- to high-risk patients. Finally, tLoD per se or in combination with intima-media thickness measurement may be a novel cardiovascular surrogate biomarker. PMID- 21527748 TI - Acrolein inhalation prevents vascular endothelial growth factor-induced mobilization of Flk-1+/Sca-1+ cells in mice. AB - OBJECTIVE: Acrolein is a toxic chemical present in tobacco, wood, and coal smoke, as well as automobile exhaust. Because exposure to these pollutants is associated with an increase in cardiovascular disease risk, we studied the effects of acrolein on Flk-1(+)/Sca-1(+) cells that are involved in vascular repair. METHODS AND RESULTS: In adult male C57BL/6 mice, inhalation of acrolein (1 part per million [ppm], 6 hours/day for 4 days or 5 ppm for 2 or 6 hours) led to the formation of protein-acrolein adducts in the bone marrow and diminished levels of plasma nitric oxide metabolites and circulating Flk-1(+)/Sca-1(+) but not Sca 1(+)-only cells. Acrolein exposure increased the number of apoptotic Flk-1(+)/Sca 1(+) cells in circulation and increased bone marrow-derived cells with endothelial characteristics (DiI-ac-low-density lipoprotein [DiI-acLDL]/UE-lectin and Flk-1(+)/Sca-1(+)) in culture. Deficits in the circulating levels of Flk 1(+)/Sca-1(+) cells were reversed after 7 days of recovery in acrolein-free air. Exposure to acrolein blocked vascular endothelial growth factor (VEGF)/AMD3100 stimulated mobilization of Flk-1(+)/Sca-1(+) but not Sca-1(+)-only cells and prevented VEGF-induced phosphorylation of Akt and endothelial nitric oxide synthase in the aorta. CONCLUSIONS: Inhalation of acrolein increases apoptosis and suppresses the circulating levels of Flk-1(+)/Sca-1(+) cells while increasing these cells in the bone marrow and preventing their mobilization by VEGF. Exposure to acrolein-rich pollutants could impair vascular repair capacity. PMID- 21527747 TI - Hemodynamic activation of beta-catenin and T-cell-specific transcription factor signaling in vascular endothelium regulates fibronectin expression. AB - OBJECTIVE: The goal of this study was to assess the activity of beta-catenin/T cell-specific transcription factor (TCF) signaling in atherosclerosis development and its regulation of fibronectin in vascular endothelium. METHODS AND RESULTS: Histological staining identified preferential nuclear localization of beta catenin in the endothelium of atheroprone aorta before and during lesion development. Transgenic reporter studies revealed that increased levels of TCF transcriptional activity in endothelium correlated anatomically with beta-catenin nuclear localization and fibronectin deposition. Exposure of endothelial cells to human-derived atheroprone shear stress induced nuclear localization of beta catenin, transcriptional activation of TCF, and expression of fibronectin. Activation of fibronectin expression required beta-catenin, TCF, and the transcriptional coactivator CRBP-binding protein. Finally, we identified platelet endothelial cell adhesion molecule-1 as a critical regulator of constitutive beta catenin and glycogen synthase kinase-3beta activities. CONCLUSIONS: These data reveal novel constitutive activation of the endothelial beta-catenin/TCF signaling pathway in atherosclerosis and regulation of fibronectin through hemodynamic shear stress. PMID- 21527750 TI - Joint effects of obesity and body height on the risk of venous thromboembolism: the Tromso Study. AB - OBJECTIVE: The goal of this study was to investigate the combined effect of obesity and body height on the risk of venous thromboembolism (VTE) in a prospective population-based study. METHODS AND RESULTS: Personal characteristics, including measures of obesity and body height, were collected in 26 714 men and women, aged 25 to 97 years, who participated in the Tromso Study in 1994 to 1995. Incident VTE events were registered through September 1, 2007. There were 461 incident VTE events during a median of 12.5 years of follow-up. A tall stature was associated with increased risk of VTE in normal-weight (body mass index <25 kg/m(2)) and obese (body mass index >=30 kg/m(2)) men, but not in women. The combination of obesity and tall stature synergistically increased the risk of VTE in both sexes. Tall (>=182 cm), obese men had a 5-fold (multivariable hazard ratio 5.16; 95% CI 2.39 to 11.14) increased risk of VTE compared with normal-weight men with short (<=172 cm) stature. Tall (>=168 cm), obese women had an almost 3-fold (multivariable hazard ratio 2.89; 95% CI 1.31 to 6.35) increased risk of VTE compared with normal-weight, short (<=159 cm) women. CONCLUSION: The combination of obesity and a tall stature was associated with a substantially increased risk of VTE, especially in men, suggesting synergistic effects of obesity and height on risk of VTE in both sexes. PMID- 21527751 TI - Endothelial fate and angiogenic properties of human CD34+ progenitor cells in zebrafish. AB - OBJECTIVE: The vascular competence of human-derived hematopoietic progenitors for postnatal vascularization is still poorly characterized. It is unclear whether, in the absence of ischemia, hematopoietic progenitors participate in neovascularization and whether they play a role in new blood vessel formation by incorporating into developing vessels or by a paracrine action. METHODS AND RESULTS: In the present study, human cord blood-derived CD34(+) (hCD34(+)) cells were transplanted into pre- and postgastrulation zebrafish embryos and in an adult vascular regeneration model induced by caudal fin amputation. When injected before gastrulation, hCD34(+) cells cosegregated with the presumptive zebrafish hemangioblasts, characterized by Scl and Gata2 expression, in the anterior and posterior lateral mesoderm and were involved in early development of the embryonic vasculature. These morphogenetic events occurred without apparent lineage reprogramming, as shown by CD45 expression. When transplanted postgastrulation, hCD34(+) cells were recruited into developing vessels, where they exhibited a potent paracrine proangiogenic action. Finally, hCD34(+) cells rescued vascular defects induced by Vegf-c in vivo targeting and enhanced vascular repair in the zebrafish fin amputation model. CONCLUSIONS: These results indicate an unexpected developmental ability of human-derived hematopoietic progenitors and support the hypothesis of an evolutionary conservation of molecular pathways involved in endothelial progenitor differentiation in vivo. PMID- 21527752 TI - Atheroprotective reverse cholesterol transport pathway is defective in familial hypercholesterolemia. AB - OBJECTIVE: Low high-density lipoprotein (HDL) cholesterol levels are frequently observed in familial hypercholesterolemia (FH) and might be associated with functional alterations of HDL particles that may influence their efficaciousness in the reverse cholesterol transport pathway. METHODS AND RESULTS: We evaluated key steps of the reverse cholesterol transport, ie, cellular free cholesterol efflux, cholesteryl ester transfer protein-mediated cholesteryl ester (CE) transfer from HDL to apolipoprotein B-containing lipoproteins, and hepatic HDL-CE uptake, in patients displaying FH (n = 12) and in healthy normolipidemic control subjects (n = 12). Large HDL2 particles isolated from FH patients displayed a reduced capacity to mediate free cholesterol efflux via both scavenger receptor BI- and ABCG1-dependent pathways. A significant inverse relationship between scavenger receptor-BI-dependent HDL2 efflux capacity and carotid intima-media thickness (r = -0.473; P = 0.0186), as well as between ABCG1-dependent HDL2 efflux capacity and carotid intima-media thickness (r = -0.485; P = 0.0212), was detected. We also observed an elevated cholesteryl ester transfer protein mediated CE transfer from HDL2 and HDL3 particles to low-density lipoprotein and a reduced capacity of HDL particles to deliver CEs to the liver. CONCLUSIONS: We demonstrated that the centripetal movement of cholesterol from peripheral tissues, including the vessel wall, to feces is defective in FH, thereby emphasizing its atherogenicity. PMID- 21527753 TI - Apoptosis signal-regulating kinase 1 deficiency accelerates hyperlipidemia induced atheromatous plaques via suppression of macrophage apoptosis. AB - OBJECTIVE: The pathogenic role of macrophage apoptosis in atherosclerosis is still debatable, but it is considered to be a suppressor of plaque progression in early stages but a promoter of plaque necrosis in advanced stages. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a pivotal role in stress-induced apoptosis. In the current study, we investigated the functions of ASK1 in hyperlipidemia-induced atherosclerosis. METHODS AND RESULTS: We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1(-/-)/apoE(-/-)) and analyzed atherosclerosis in ASK1(-/-)/apoE(-/-) mice fed a high-cholesterol diet for 12 weeks. ASK1(-/ )/apoE(-/-) mice had accelerated hyperlipidemia-induced atherosclerosis, which was characterized by less apoptosis of macrophages and fewer necrotic areas, and more macrophages and elastolysis compared with apoE(-/-) mice. Bone marrow transplantation from ASK1(-/-) or wild-type to apoE(-/-) mice confirmed the above observation that the recipient mice of ASK1(-/-) donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors. CONCLUSIONS: These findings suggest that ASK1 suppresses hyperlipidemia-induced atherosclerosis via increased macrophage apoptosis and that ASK1 may cause pronounced plaque vulnerability via necrotic core development. PMID- 21527754 TI - Amyloid beta enhances migration of endothelial progenitor cells by upregulating CX3CR1 in response to fractalkine, which may be associated with development of choroidal neovascularization. AB - OBJECTIVE: Deposits that accumulate beneath retinal pigment epithelium, called drusen, are early signs of age-related macular degeneration (AMD). We have shown that amyloid beta (Abeta) is present in drusen, and Abeta may be involved in AMD development. We have also shown that endothelial progenitor cells (EPCs) may contribute to the development of choroidal neovascularization (CNV). Thus, the purpose of this study was to investigate the role played by CX3CR1, a chemokine receptor, in EPC migration and CNV formation. METHODS AND RESULTS: EPCs collected from human umbilical cords were found to express higher levels of CX3CR1 than human umbilical vein endothelial cells, and exposure of EPCs to Abeta caused further upregulation of CX3CR1. This upregulation was decreased by blocking fractalkine, a ligand of CX3CR1. Exposure of EPCs to fractalkine increased their migration, but pretreatment with Abeta enhanced the migration. The fractalkine induced EPC migration was more inhibited by EPCs derived from CX3CR1(-/-) mice than wild-type mice. The area of laser-induced CNV was significantly smaller in wild-type mice that received bone marrow transplantation from CX3CR1(-/-) mice than in those that received transplantation from wild-type mice. CONCLUSIONS: These data suggest that Abeta enhances EPC migration through the upregulation of CX3CR1. This upregulation might play a role in development of CNV. PMID- 21527755 TI - Validity and reliability of the Barthel index administered by telephone. AB - BACKGROUND AND PURPOSE: We aimed to evaluate validity and reliability of the Barthel Index administered telephonically compared with face-to-face assessment in clinically stable patients with stroke. METHODS: One hundred thirty-one patients were interviewed twice by 2 registered nurses with identical training. Half of the patients were randomized to receive the telephone interview followed by the face-to-face interview and half the contrary. The sequence of interviewers was randomized. RESULTS: The median value of the Barthel Index score was 30 (first to third interquartile range, 15 to 80) by telephone and 35 (15 to 75) by face-to-face (P=0.29). The weighted kappa was 0.90 (95% CI, 0.85 to 0.94); kappa values ranged from 0.70 (0.58 to 0.82) for bowel control to 0.91 (0.83 to 0.99) for bathing. CONCLUSIONS: Telephone assessment of stroke disability with the Barthel Index is reliable in comparison to direct face-to-face assessment. PMID- 21527756 TI - Transfer delay is a major factor limiting the use of intra-arterial treatment in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: The development of comprehensive stroke centers within hub-and-spoke stroke networks offers the opportunity to increase the proportion of acute ischemic stroke patients treated with intra-arterial therapies (IAT). Interhospital transfer delays will be critical in evaluating the success of this strategy. METHODS: We collected data on consecutive patients who were transferred to our institution for possible IAT. We defined transfer time as time elapsed from initial transfer call to arrival at our hospital and assessed whether transfer time was a predictor of emergent angiography using multivariable logistic regression. RESULTS: Among 132 patients referred for IAT, 53 (40.2%) were excluded on clinical grounds. The remaining 79 (59.8%) patients (mean age, 61 years; median National Institutes of Health Stroke Scale score, 18; 49.4% male) were analyzed. Sixty-one of 79 (77%) patients underwent emergent angiography for IAT. The median hospital-to-hospital distance was 14.7 (interquartile range, 8.5-21.9) miles and median transfer time was 104 (interquartile range, 80-135) minutes. Transfer time was 33% lower among those who underwent emergent angiography (100.6 versus 149.0 minutes; P<0.001). Adjusting for relevant covariates, transfer time remained an independent predictor of emergent angiography (OR, 0.975; 95% CI, 0.956-0.995; P=0.014). The odds of treatment decrease by 2.5% for every minute of transfer time. CONCLUSIONS: Delay in hospital-to-hospital transfer is a common reason that acute ischemic stroke patients are excluded from interventional therapy. The likelihood of receiving IAT decreases rapidly by increasing transfer time. Specific goals for transfer time should be considered in future quality standards for hub-and spoke-organized stroke networks. PMID- 21527757 TI - Direct costs of patients with stroke can be continuously monitored on a national level: performance, effectiveness, and Costs of Treatment episodes in Stroke (PERFECT Stroke) Database in Finland. AB - BACKGROUND AND PURPOSE: Treatment of stroke consumes a significant portion of all healthcare expenditure. We developed a system for monitoring costs from individual patient data on a national level in Finland. METHODS: Multiple national administrative registers were linked to gain episode-of-care data on all hospital-treated patients with incident stroke over the years 1999 to 2007 (n = 94,316). Inpatient and specialist outpatient costs were evaluated with a cost database, long-term care costs with fixed prices, and medication costs with true retail prices. RESULTS: For the patients of Year 2007, the mean 1-year costs after an ischemic stroke were $29 580, after an intracerebral hemorrhage $36,220, and after a subarachnoid hemorrhage $42,570, valued in Year 2008 U.S. dollars. Only part of these costs are attributable to stroke, because the annual costs prior to stroke were significant, $8900 before ischemic stroke, $7600 before intracerebral hemorrhage, and $4200 before subarachnoid hemorrhage. Older patients with ischemic stroke, and, among patients with ischemic stroke and subarachnoid hemorrhage, women, incurred higher costs. The mean estimated lifetime costs were $130,000 after ischemic stroke or intracerebral hemorrhage and $80,000 after subarachnoid hemorrhage. Annually $1.6 billion is spent in the care of Finnish patients with stroke, which equals to 7% of the national healthcare expenditure, or 0.6% of the gross domestic product. Costs of patients with stroke are increasing with prolonged survival and the aging population. CONCLUSIONS: Treatment of patients with stroke is a large national investment. Setting up a nationwide system for continuous monitoring of stroke costs is feasible. Cost data should optimally be evaluated in conjunction with effectiveness and performance indicators. PMID- 21527758 TI - A new therapeutic strategy for acute ischemic stroke: sequential combined intravenous tPA-tenecteplase for proximal middle cerebral artery occlusion based on first results in 13 consecutive patients. AB - BACKGROUND AND PURPOSE: Intravenous tissue-type plasminogen activator (IV tPA) frequently fails to recanalize proximal middle cerebral artery (MCA-M1) obstructions, preventing favorable outcomes. Only neurointerventional procedures prevail in these cases, but well-equipped centers remain scarce. A new therapeutic strategy consisting of a second IV thrombolysis with low-dose tenecteplase was applied. METHODS: Consecutive patients with an MCA-M1 occlusion that did not reopen at the end of IV tPA perfusion received IV tenecteplase (0.1 mg/kg). Partial or complete thrombolysis in myocardial infarction recanalization (Thrombolysis In Myocardial Infarction grade 2/3) and intracerebral hemorrhage were assessed by magnetic resonance aging approximately 24 hours later. Clinical outcomes at 3 months were evaluated with the modified Rankin score. RESULTS: Among 40 patients with MCA-M1 occlusions who received IV tPA, 13 were treated according to the protocol of sequential combined IV thrombolytics. Baseline National Institutes of Health Stroke Scale score was 15. At a mean of 16.8 hours after IV thrombolysis, the recanalization rate was 100% (2 with Thrombolysis In Myocardial Infarction grade 2, 11 with Thrombolysis In Myocardial Infarction grade 3). Intracerebral hemorrhage occurred in 4 of 13 (31%) patients, with no symptomatic hemorrhage. Good clinical outcomes (modified Rankin score = 0/1) were achieved in 9 of 13 (69%) patients. Functional outcomes were very similar to those of 13 patients with early IV-tPA recanalization. Among 4 patients treated as protocol violations, 1 presented with a lack of recanalization and a parenchymal hematoma type 2. CONCLUSIONS: For patients with MCA-M1 occlusions treated with IV tPA but without early recanalization, a second bolus of IV tenecteplase (0.1 mg/kg) may be a relatively safe, effective, and easy option in carefully selected cases, but additional studies are needed to confirm these findings. PMID- 21527759 TI - Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. AB - Intracerebral hemorrhage (ICH) is an often fatal type of stroke that kills approximately 30,000 people annually in the United States. If the patient survives the ictus, then the resulting hematoma within brain parenchyma triggers a series of adverse events causing secondary insults and severe neurological deficits. This article discusses selected aspects of secondary brain injury after ICH and outlines key mechanisms associated with hematoma toxicity, oxidative stress, and inflammation. Finally, this review discusses the relevance of hematoma resolution processes as a target for ICH therapy and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with ICH injury. PMID- 21527760 TI - Heart rate contributes to the vascular effects of chronic mental stress: effects on endothelial function and ischemic brain injury in mice. AB - BACKGROUND AND PURPOSE: Vascular effects of mental stress are only partially understood. Therefore, we studied effects of chronic stress and heart rate (HR) on endothelial function and cerebral ischemia. METHODS: 129S6/SvEv mice were randomized to the I(f)-channel inhibitor ivabradine (10 mg/kg per day) or vehicle and underwent a chronic stress protocol for 28 days. RESULTS: Stress increased HR from 514 +/- 10 bpm to 570 +/- 14 bpm, this was prevented by ivabradine (485 +/- 7 bpm). Endothelium-dependent relaxation of aortic rings was impaired in mice exposed to stress. HR reduction restored endothelial function to the level of naive controls. Vascular lipid hydroperoxides were increased to 333% +/- 24% and vascular NADPH oxidase activity was upregulated to 223 +/- 38% in stressed mice, which was prevented by ivabradine. Stress reduced aortic endothelial nitric oxide synthase mRNA expression to 84% +/- 3% and increased AT1 receptor mRNA to 168% +/ 18%. Both effects were attenuated by HR reduction. In brain tissue, stress resulted in an upregulation of lipid hydroperoxides to 140% +/- 11%, which was attenuated by HR reduction. Ivabradine increased brain capillary density in naive and in stressed mice. Mice exposed to chronic stress before induction of ischemic stroke by transient middle cerebral artery occlusion exhibited increased lesion size (33.7 +/- 2.3 mm3 versus 23.9 +/- 2.4 mm3). HR reduction led to a marked reduction of the infarct volume to 12.9 +/- 3.3 mm3. CONCLUSIONS: Chronic stress impairs endothelial function and aggravates ischemic brain injury. HR reduction protects from cerebral ischemia via improvement of endothelial function and reduction of oxidative stress. These results identify heart rate as a mediator of vascular effects induced by chronic stress. PMID- 21527761 TI - Interobserver variability of grading scales for aneurysmal subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Worldwide, different scales are used to assess the clinical condition on admission after aneurysmal subarachnoid hemorrhage. In addition to the prognostic value, the inter-rater variability should be taken into account when deciding which scale preferably should be used. We assessed the interobserver agreement of the commonly used World Federation of Neurological Surgeons, the Hunt and Hess, and the Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scales. METHODS: In a cohort of 50 subarachnoid hemorrhage patients, 103 paired assessments were performed on the 3 admission scales by 2 independent observers per assessment with a total of 57 different raters. Patients were assessed during the first week after the hemorrhage. The interobserver agreement was calculated using quadratic (weighted) kappa statistics. RESULTS: The weighted kappa value of the Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scale was 0.64 (95% CI, 0.49-0.79), of the World Federation of Neurological Surgeons scale was 0.60 (95% CI, 0.48-0.73), and of the Hunt and Hess scale was 0.48 (95% CI, 0.36-0.59). CONCLUSIONS: The Hunt and Hess scale showed the lowest interobserver agreement, whereas agreement of the World Federation of Neurological Surgeons and Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scales was similar with overlapping CI. PMID- 21527762 TI - Seamless integrated stroke telemedicine systems of care: a potential solution for acute stroke care delivery delays and inefficiencies. PMID- 21527763 TI - Letter by Murphy et al regarding article, "Fugl-Meyer assessment of sensorimotor function after stroke: standardized training procedure for clinical practice and clinical trials". PMID- 21527764 TI - Does impaired cerebrovascular reactivity predict stroke risk in asymptomatic carotid stenosis? A prospective substudy of the asymptomatic carotid emboli study. AB - BACKGROUND AND PURPOSE: Improved methods are required to identify the subgroup of patients with asymptomatic carotid stenosis who will have stroke develop. It has been suggested that impaired cerebral reactivity (CVR) may predict high risk, but no multicenter studies have examined this. METHODS: In a preplanned substudy of Asymptomatic Carotid Emboli Study, 106 patients were recruited with >=70% asymptomatic carotid stenosis. Transcranial Doppler was used to measure CVR with a vasodilatory response of carbon dioxide or acetazolamide. A meta-analysis of the data with previously published studies was performed. RESULTS: Thirty-two of 106 (30.2%) had severely impaired CVR ipsilateral to the study artery. Mean follow-up was 680 days. There were no ipsilateral strokes. There was a nonsignificant trend to more secondary end points of any stroke/TIA in patients with severely impaired CVR. Three of 32 (9.4%) had impaired CVR compared with 2 of 74 (2.7%) without (hazard ratio, 2.54; 95% CI, 0.61-21.74; P=0.158). On meta analysis of the Asymptomatic Carotid Emboli Study data with previous studies, impaired CVR was associated with increased risk of ipsilateral stroke alone (OR, 6.14; 95% CI, 1.27-29.5; P=0.02), ipsilateral stroke or TIA (OR, 4.76; 95% CI, 1.86-12.16; P=0.001), and any stroke (OR, 4.66; 95% CI, 1.69-12.85; P=0.003). CONCLUSIONS: In this international multicenter study, we found no association between impaired CVR and recurrent events, but the study was underpowered because of the low event rate. Meta-analysis of available data suggested an association between impaired CVR and future risk. However, currently there are insufficient data to justify the routine clinical use of CVR to stratify risk in patients with asymptomatic carotid stenosis for selection for carotid endarterectomy. PMID- 21527765 TI - Letter by Makris et al regarding article, "Carotid artery stenting versus carotid endarterectomy: a comprehensive meta-analysis of short-term and long-term outcomes". PMID- 21527766 TI - Weighting components of composite end points in clinical trials: an approach using disability-adjusted life-years. AB - BACKGROUND AND PURPOSE: Conventional analysis of vascular prevention trials assigns equal weight to disparate vascular events in a composite end point at variance with the public's perception of their differential impact on health outcome. This study sought to apply the disability-adjusted life-year (DALY) metric to differential weighting individual vascular end points in trial analyses. METHODS: DALY values for the most common major end points in vascular prevention trials (nonfatal myocardial infarction, nonfatal stroke, and vascular death), were derived by using World Health Organization Global Burden of Disease Project methodology. The standardized DALYs for each event were applied to recent major primary and secondary vascular prevention trials and to hypothetical model trials. RESULTS: Standardized DALYs lost were 7.63 for nonfatal stroke, 5.14 for nonfatal myocardial infarction, and 11.59 for vascular death. In the published trials analyses, the direction of treatment effects was consistent between DALY and standard event analysis, but the rank order of treatment effect changed for 10 of 18 trials. The DALY analysis also permitted derivation of number-needed-to treat values to gain 1 DALY: 2.1 for anticoagulation in atrial fibrillation, 2.7 for carotid endarterectomy in symptomatic stenosis, and 4.7 for clopidogrel added to aspirin in acute coronary syndrome. Hypothetical trial analyses demonstrated that the DALY metric more finely discriminates treatment effects. CONCLUSIONS: Compared with a nonfatal myocardial infarction, a nonfatal stroke causes a 1.48 fold greater loss and vascular death a 2.25-fold greater loss of DALY. DALY analysis integrates these valuations in a summary metric reflecting the net impact of therapy on patient and societal health, complementing conventional end point analyses. PMID- 21527767 TI - Letter by Antonopoulos et al regarding article, "Carotid artery stenting versus carotid endarterectomy: a comprehensive meta-analysis of short-term and long-term outcomes". PMID- 21527768 TI - Letter by Huon and Wang regarding article, "Risk of stroke in patients hospitalized for isolated vertigo: a 4-year follow-up study". PMID- 21527769 TI - Frequency of increased blood pressure levels during systemic thrombolysis and risk of intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Significantly increased blood pressure (BP) is common in patients receiving intravenous thrombolysis (IVT). We aimed to investigate frequency of pre- and post-treatment elevated BP and its relation to intracerebral hemorrhage (ICH) and symptomatic ICH (sICH), respectively. METHODS: Data for patients treated with intravenous thrombolysis in the years 2007 to 2009 were retrospectively extracted from our prospectively conducted local stroke database. All documented BP levels from admission to follow-up imaging scan were analyzed. BP protocol violations were defined as systolic BP >185 mm Hg and/or diastolic BP >110 mm Hg. sICH was defined as ICH plus worsening of the National Institute of Health Stroke Scale >=4 points. RESULTS: BP protocol violation before IVT emerged in 12.6% and during the course of IVT in 40.1% of 427 patients. sICH occurred in 10 (2.3%) and ICH in general occurred in 51 (11.9%) of 427 patients. Proportions of BP protocol violations were similar in patients without ICH, with any ICH, and with sICH (3.1% versus 2.8% versus 3.2%). Systolic BP levels and mean arterial pressure did not differ between patients without ICH, patients with any ICH, and patients with sICH. In the multivariate analysis, only early CT findings independently predicted ICH (OR, 2.39; 95% CI, 1.25-4.61; P=0.009). CONCLUSIONS: BP protocol violations are common before and during the course of IVT, but neither the frequency of BP protocol violations nor the BP levels predicted ICH or sICH in univariate or multivariate analyses. PMID- 21527771 TI - Examination of hemiplasy, homoplasy and phylogenetic discordance in chromosomal evolution of the Bovidae. AB - Robertsonian chromosomal fusions predominate in shaping the genomes of many species of Bovidae. These and other cytogenetic data (from 52 taxa representing 51 species and 9 tribes of Bovidae) were (i) examined for usefulness in defining phylogenetic relationships and (ii) subsequently mapped to a consensus tree based on mitochondrial and nuclear DNA gene sequences with divergence dates of the corresponding species calculated from cytochrome b sequences. This permitted persistence time estimates for the various rearrangements. The chromosomal data resulted in an unsupported higher-level topology, but with recognition of the monophyly of some genera and tribes within Bovidae. The distribution and temporal spread of character states on the species tree is suggestive of a restricted role for hemiplasy (the retention of an ancestral chromosomal polymorphism through multiple speciation events) and for introgression (resulting from secondary contact among taxa), processes that can potentially lead to phylogenetic discordance. We conclude that the most probable interpretation for these data is that genuine karyotypic homoplasy predominates, but that hemiplasy (and/or introgression) is a realistic hypothesis for the observed patterns of several shared characters in Bovidae. PMID- 21527770 TI - Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. AB - BACKGROUND: Hypertension (HTN) is an on-target effect of the vascular endothelial growth factor pathway inhibitor, sunitinib. We evaluated the association of sunitinib-induced HTN with antitumor efficacy and HTN-associated adverse events in patients with metastatic renal cell carcinoma. METHODS: This retrospective analysis included pooled efficacy (n = 544) and safety (n = 4917) data from four studies of patients with metastatic renal cell carcinoma who were treated with sunitinib 50 mg/d administered on a 4-week-on 2-week-off schedule (schedule 4/2). Blood pressure (BP) was measured in the clinic on days 1 and 28 of each 6-week cycle. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods; hazard ratios (HRs) for survival were also estimated by a Cox proportional hazards models using HTN as a time-dependent covariate. Efficacy outcomes were compared between patients with and without HTN (maximum systolic BP [SBP] >=140 mm Hg or diastolic BP [DBP] >=90 mm Hg). Adverse events were also compared between patients with and without HTN (mean SBP >=140 mm Hg or mean DBP >=90 mm Hg). All P values were two-sided. RESULTS: Patients with metastatic renal cell carcinoma and sunitinib-induced HTN defined by maximum SBP had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval [CI] = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P < .001 for all). Similar results were obtained when comparing patients with vs without sunitinib induced HTN defined by maximum DBP. In a Cox proportional hazards model using HTN as a time-dependent covariate, PFS (HR of disease progression or death = .603, 95% CI = .451 to .805; P < .001) and OS (HR of death = .332, 95% CI = .252 to .436; P < .001) were improved in patients with treatment-induced HTN defined by maximum SBP; OS (HR of death = .585, 95% CI = .463 to .740; P < .001) was improved in patients with treatment-induced HTN defined by maximum DBP, but PFS was not. Few any-cause cardiovascular, cerebrovascular, ocular, and renal adverse events were observed. Rates of adverse events were similar between patients with and without HTN defined by mean SBP; however, hypertensive patients had somewhat more renal adverse events (5% vs 3%; P = .013). CONCLUSIONS: In patients with metastatic renal cell carcinoma, sunitinib-associated HTN is associated with improved clinical outcomes without clinically significant increases in HTN associated adverse events, supporting its viability as an efficacy biomarker. PMID- 21527772 TI - Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. AB - The aim of this study was to evaluate the suitability of global gene expression profiling for the characterization and identification of mutagens and promutagens in vitro. To enable detection of both mutagenic and promutagenic compounds, we cotreated HepG2 cells with a rat liver S9 fraction as metabolic activation system (MAS), supplementing the limited drug metabolic capability of HepG2 cells. Illumina BeadChip arrays were used to quantify gene expression changes after treatment with three well-known mutagenic, three promutagenic, as well as two non genotoxic reference compounds for a period of 24 or 48 h. Statistical data analysis revealed 91 genes being most representative for the (pro-)genotoxic response. Several processes such as cellular differentiation and the complex interactive regulation of the stress and DNA damage response via the transcriptional modulators STAT1, SP1, and P53 were differentially regulated. The gene set evaluated was further used to predict the genotoxic characteristics of N nitrosodiethylamine (DEN) after its metabolic activation. Although no clear response could be established in P53 activation experiments, DEN was classified correctly as nongenotoxic without S9 and genotoxic in the presence of the MAS by means of its transcriptomic pattern. Our data support that mechanistic profiling in vitro is a useful tool compared with single endpoint detections to predict genotoxicity. PMID- 21527773 TI - Necrotic concentrations of cisplatin activate the apoptotic machinery but inhibit effector caspases and interfere with the execution of apoptosis. AB - Cisplatin is a chemotherapeutic drug whose cytotoxicity is key to its therapeutic and side effects. Nephrotoxicity, mainly due to renal tubular injury, poses its most important therapeutic limitation. Tubular necrosis is derived from epithelial cell death by apoptosis and necrosis in the proximal and distal tubuli. The mode of cell death has been related to drug concentration, with necrosis occurring with high concentrations and apoptosis with lower concentrations. To fully understand the toxic effects of cisplatin to potentially improve its pharmaco-toxicological profile, it is necessary to unravel the cellular events and signaling pathways implicated in the appearance of both modes of cell death. We used cultured human lymphoma and renal tubule cells to investigate the biochemical and phenotypic characteristics of the death mode induced by increasing concentrations of cisplatin. Our results indicate that pronecrotic concentrations of cisplatin early activate the apoptotic machinery, which is in turn directly blocked by cisplatin at the level of effector caspases. Aborted apoptosis induces a death phenotype lacking some typical characteristics of this process, which more closely resembles necrosis. Furthermore, unidentified Bcl-2- and mitochondria-independent pathways are induced by pronecrotic and not by proapoptotic concentrations of cisplatin. Cisplatin-induced cell necrosis is the result of an aborted apoptosis at the level of effector caspases. Yet, Bcl-2 independent effects lead to cell death, which may pose potential targets for pharmacological intervention aimed at reducing cisplatin nephrotoxicity. PMID- 21527774 TI - The frequency of 1,4-benzoquinone-lysine adducts in cytochrome c correlate with defects in apoptosome activation. AB - Electrophile-mediated post-translational modifications (PTMs) are known to cause tissue toxicities and disease progression. These effects are mediated via site specific modifications and structural disruptions associated with such modifications. 1,4-Benzoquinone (BQ) and its quinone-thioether metabolites are electrophiles that elicit their toxicity via protein arylation and the generation of reactive oxygen species. Site-specific BQ-lysine adducts are found on residues in cytochrome c that are necessary for protein-protein interactions, and these adducts contribute to interferences in its ability to facilitate apoptosome formation. To further characterize the structural and functional impact of these BQ-mediated PTMs, the original mixture of BQ-adducted cytochrome c was fractionated by liquid isoelectric focusing to provide various fractions of BQ adducted cytochrome c species devoid of the native protein. The fractionation process separates samples based on their isoelectric point (pI), and because BQ adducts form predominantly on lysine residues, increased numbers of BQ adducts on cytochrome c correlate with a lower protein pI. Each fraction was analyzed for structural changes, and each was also assayed for the ability to support apoptosome-mediated activation of caspase-3. Circular dichroism revealed that several of the BQ-adducted cytochrome c species maintained a slightly more rigid structure in comparison to native cytochrome c. BQ-adducted cytochrome c also failed to activate caspase-3, with increasing numbers of BQ-lysine adducts corresponding to a greater inability to activate the apoptosome. In summary, the specific site of the BQ-lysine adducts, and the nature of the adduct, are important determinants of the subsequent structural changes to cytochrome c. In particular, adducts at sites necessary for protein-protein interactions interfere with the proapoptotic function of cytochrome c. PMID- 21527775 TI - PTEN limits alveolar macrophage function against Pseudomonas aeruginosa after bone marrow transplantation. AB - Hematopoietic stem cell transplant patients are susceptible to infection despite cellular reconstitution. In a murine model of syngeneic bone marrow transplantation (BMT), we previously reported that BMT mice have impaired host defense against Pseudomonas aeruginosa pneumonia due to overproduction of (PG)E(2) in lung. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an effector in the PGE(2) signaling pathway that negatively regulates alveolar macrophage (AM) phagocytosis and bacterial killing. Therefore, examined whether overproduction of PGE(2) after BMT inhibits AM host defense by up-regulating PTEN phosphatase activity. We found that PTEN activity is elevated in BMT AMs in response to increased PGE(2) signaling and that pharmacological inhibition of PTEN activity in BMT AMs fully restores phagocytosis of serum-opsonized P. aeruginosa but only partially restores phagocytosis of nonopsonized P. aeruginosa. In wild-type mice transplanted with myeloid-specific conditional PTEN knockout (PTEN CKO) bone marrow, bacterial clearance is improved after challenge with P. aeruginosa pneumonia. Furthermore, PTEN CKO BMT AMs display improved TNF alpha production and enhanced phagocytosis and killing of serum-opsonized P. aeruginosa despite overproduction of PGE(2). However, AM phagocytosis of nonopsonized P. aeruginosa is only partially restored in the absence of PTEN after BMT. This may be related to elevated AM expression of IL-1 receptor associated kinase (IRAK)-M, a molecule previously identified in the PGE(2) signaling pathway to inhibit AM phagocytosis of nonopsonized bacteria. These data suggest that PGE(2) signaling up-regulates IRAK-M independently of PTEN and that these molecules differentially inhibit opsonized and nonopsonized phagocytosis of P. aeruginosa. PMID- 21527776 TI - Overcoming redundancy: an RNAi enhancer screen for morphogenesis genes in Caenorhabditis elegans. AB - Morphogenesis is an important component of animal development. Genetic redundancy has been proposed to be common among morphogenesis genes, posing a challenge to the genetic dissection of morphogenesis mechanisms. Genetic redundancy is more generally a challenge in biology, as large proportions of the genes in diverse organisms have no apparent loss of function phenotypes. Here, we present a screen designed to uncover redundant and partially redundant genes that function in an example of morphogenesis, gastrulation in Caenorhabditis elegans. We performed an RNA interference (RNAi) enhancer screen in a gastrulation-sensitized double mutant background, targeting genes likely to be expressed in gastrulating cells or their neighbors. Secondary screening identified 16 new genes whose functions contribute to normal gastrulation in a nonsensitized background. We observed that for most new genes found, the closest known homologs were multiple other C. elegans genes, suggesting that some may have derived from rounds of recent gene duplication events. We predict that such genes are more likely than single copy genes to comprise redundant or partially redundant gene families. We explored this prediction for one gene that we identified and confirmed that this gene and five close relatives, which encode predicted substrate recognition subunits (SRSs) for a CUL-2 ubiquitin ligase, do indeed function partially redundantly with each other in gastrulation. Our results implicate new genes in C. elegans gastrulation, and they show that an RNAi-based enhancer screen in C. elegans can be used as an efficient means to identify important but redundant or partially redundant developmental genes. PMID- 21527777 TI - Implications of host genetic variation on the risk and prevalence of infectious diseases transmitted through the environment. AB - Previous studies have shown that host genetic heterogeneity in the response to infectious challenge can affect the emergence risk and the severity of diseases transmitted through direct contact between individuals. However, there is substantial uncertainty about the degree and direction of influence owing to different definitions of genetic variation, most of which are not in line with the current understanding of the genetic architecture of disease traits. Also, the relevance of previous results for diseases transmitted through environmental sources is unclear. In this article a compartmental genetic-epidemiological model was developed to quantify the impact of host genetic diversity on epidemiological characteristics of diseases transmitted through a contaminated environment. The model was parameterized for footrot in sheep. Genetic variation was defined through continuous distributions with varying shape and degree of dispersion for different disease traits. The model predicts a strong impact of genetic heterogeneity on the disease risk and its progression and severity, as well as on observable host phenotypes, when dispersion in key epidemiological parameters is high. The impact of host variation depends on the disease trait for which variation occurs and on environmental conditions affecting pathogen survival. In particular, compared to homogeneous populations with the same average susceptibility, disease risk and severity are substantially higher in populations containing a large proportion of highly susceptible individuals, and the differences are strongest when environmental contamination is low. The implications of our results for the recording and analysis of disease data and for predicting response to selection are discussed. PMID- 21527778 TI - Transcription initiation from within P elements generates hypomorphic mutations in Drosophila melanogaster. AB - Numerous transposable element insertions in Drosophila melanogaster cause hypomorphic mutations. We report that transcription initiation within a region found in many P-element constructs provides an explanation for why some gene function is retained. We detected evidence of this transcription in four different types of P constructs, regardless of whether the insertion was in a coding exon, intron, 5' untranslated region, or upstream of the gene span. PMID- 21527779 TI - Natural variation in CDC28 underlies morphological phenotypes in an environmental yeast isolate. AB - Morphological differences among individuals in a species represent one of the most striking aspects of biology, and a primary aim of modern genetics is to uncover the molecular basis of morphological variation. In a survey of meiosis phenotypes among environmental isolates of Saccharomyces cerevisiae, we observed an unusual arrangement of meiotic spores within the spore sac in a strain from Ivory Coast, West Africa. We mined population genomic data to identify CDC28 as the major genetic determinant of meiotic and budding cell shape behaviors in this strain. Molecular genetic methods confirmed the role of the Ivory Coast variant of CDC28 in the arrangement of spores after meiosis, in the shape of budding cells in rich medium and in the morphology of filamentous growth during nitrogen limitation. Our results shed new light on the role of CDC28 in yeast cell division, and our work suggests that with the growing availability of genomic data sets in many systems, a priori prediction of functional variants will become an increasingly powerful strategy in molecular genetics. PMID- 21527780 TI - A unified treatment of the probability of fixation when population size and the strength of selection change over time. AB - The fixation probability is determined when population size and selection change over time and differs from Kimura's result, with long-term implications for a population. It is found that changes in population size are not equivalent to the corresponding changes in selection and can result in less drift than anticipated. PMID- 21527782 TI - Cell lines derived from feline fibrosarcoma display unstable chromosomal aneuploidy and additionally centrosome number aberrations. AB - The purpose of the study was to evaluate clonality and presence of numerical chromosomal and centrosomal aberrations in 5 established feline fibrosarcoma cell lines and in a fetal dermal fibroblast cell line as a control. The clonality of all cell lines was examined using limited-dilution cloning. The number of chromosomes was counted in metaphase spreads. The immunocytochemical analysis of centrosome numbers was performed by indirect immunofluorescence using a monoclonal antibody that targets gamma-tubulin, a well-characterized component of centrosomes. Monoclonal cell populations could be established from all cell lines. In all feline fibrosarcoma cell lines, the number of chromosomes deviated abnormally from the normal feline chromosome number of 2n = 38, ranging from 19 to 155 chromosomes per cell. Centrosome hyperamplification was observed in all 5 feline fibrosarcoma cell lines with a proportion of cells (5.7 to 15.2%) having more than 2 centrosomes. In the control cell line, only 0.6% of the cells had more than 2 centrosomes. In conclusion, the examinations revealed that centrosome hyperamplification occurs in feline fibrosarcoma cell lines. The feline fibrosarcoma cell lines possessed 10 to 25 times as many cells with centrosome hyperamplification as the control cell line. These observations suggest an association of numerical centrosome aberrations with karyotype instability by increasing the frequency of chromosome missegregation. The results of this study may be helpful for further characterization of feline fibrosarcomas and may contribute to the knowledge of cytogenetic factors that may be important for the pathogenesis of feline fibrosarcomas. PMID- 21527781 TI - Toxic equine parkinsonism: an immunohistochemical study of 10 horses with nigropallidal encephalomalacia. AB - Chronic ingestion of yellow star thistle (Centaurea solstitialis) or Russian knapweed (Acroptilon repens) causes nigropallidal encephalomalacia (NPE) in horses with an abrupt onset of neurologic signs characterized by dystonia of lips and tongue, inability to prehend food, depression, and locomotor deficits. The objectives of this study were to reexamine the pathologic alterations of NPE and to conduct an immunohistochemistry study using antibodies to tyrosine hydroxylase and alpha-synuclein, to determine whether NPE brains show histopathologic features resembling those in human Parkinson disease. Results confirm that the NPE lesions are located within the substantia nigra pars reticulata, sparing the cell bodies of the dopaminergic neurons in the substantia nigra pars compacta, and in the rostral portion of the globus pallidus, with partial disruption of dopaminergic (tyrosine hydroxylase-positive) fibers passing through the globus pallidus. No abnormal cytoplasmic inclusions like the Lewy bodies of human Parkinson disease were seen in these NPE brains. These findings indicate that equine NPE may serve as a large animal model of environmentally acquired toxic parkinsonism, with clinical phenotype directly attributable to lesions in globus pallidus and substantia nigra pars reticulata rather than to the destruction of dopaminergic neurons. PMID- 21527783 TI - Gender differences in cardiac repolarization following intravenous sotalol administration. AB - BACKGROUND: Females are more susceptible to drug-induced torsade de pointes (TdP), which is associated with excessive prolongation of the heart rate corrected QT interval (QTc). Sotalol prolongs the cardiac action potential that can be observed as QT prolongation and can induce TdP. The aim of this study was to assess gender differences in sotalol-induced QTc prolongation. METHODS: A total of 15 healthy volunteers, 9 female and 6 male (age: 32 +/- 8 years) received 75 mg intravenous sotalol over 2.5 hours at a constant infusion rate. A 12-lead electrocardiograph (ECG) was recorded at baseline, 0.5, 1, 2, 3, 4, and 5 hours following the start of the infusion, and blood samples were collected simultaneously. QTc was calculated by the Fridericia and Framingham formulas. The 2 formulas resulted in virtually identical QTc intervals. The data analysis included repeated measures of analysis of variance (ANOVA), univariate analysis, and linear regression analysis. RESULTS: The longest average QTc intervals were observed at 2 hours of sotalol infusion in both genders. Compared to baseline, the increase was very significant in females (411 +/- 13 vs 438 +/- 13 ms, P < .001), while it was less significant in males (395 +/- 23 vs 413 +/- 27 ms, P < .05). The magnitude of individual changes from baseline were greater in females than in males (34 +/- 8 vs 21 +/- 12 ms, P < .05). In each gender, QTc and serum sotalol concentration strongly correlated (r = .93, P < .001). An upward shift of the regression line in females indicates a longer QTc at any concentration level. Males had greater body weight and body surface area than females (P < .05) but neither correlated with QTc or predicted QTc prolongation. The univariate analysis indicated that the single predictor for the greater QTc prolongation was female gender. CONCLUSION: Females had greater QTc prolongation than males following sotalol administration. This enhanced response to drug action may explain the higher incidence of drug-induced TdP seen in females. PMID- 21527784 TI - Contralateral delay activity reveals life-span age differences in top-down modulation of working memory contents. AB - Estimates of working memory (WM) capacity increase in children, peak in young adulthood, and decline thereafter. Despite this symmetry, the mechanisms causing capacity increments in childhood may differ from those causing decline in old age. The contralateral delay activity (CDA) of the electroencephalogram, an event related difference wave with a posterior scalp distribution, has been suggested as a neural marker of WM capacity. Here, we examine 22 children (10-12 years), 12 younger adults (20-25 years), and 22 older adults (70-75 years) in a cued change detection paradigm. Load levels and presentation times were varied within subjects. Behaviorally, we observed the expected life-span peak in younger adults and better performance with longer presentation times. With short presentation times, task load increased CDA amplitude and decreased behavioral performance in younger adults. Both effects were less pronounced in older adults. Children showed a unique pattern: Their behavioral load effects were as strong as those of younger adults, but their CDA was unaffected by load. With long presentation times, task load modulated the CDA in children and older adults but not in younger adults. These findings suggest that age-related differences in CDA reflect changes in the top-down control over WM representations. PMID- 21527785 TI - Modality-specific perceptual expectations selectively modulate baseline activity in auditory, somatosensory, and visual cortices. AB - Valid expectations are known to improve target detection, but the preparatory attentional mechanisms underlying this perceptual facilitation remain an open issue. Using functional magnetic resonance imaging, we show here that expecting auditory, tactile, or visual targets, in the absence of stimulation, selectively increased baseline activity in corresponding sensory cortices and decreased activity in irrelevant ones. Regardless of sensory modality, expectancy activated bilateral premotor and posterior parietal areas, supplementary motor area as well as right anterior insula and right middle frontal gyrus. The bilateral putamen was sensitive to the modality specificity of expectations during the unexpected omission of targets. Thus, across modalities, detection improvement arising from selectively directing attention to a sensory modality appears mediated through transient changes in pretarget activity. This flexible advance modulation of baseline activity in sensory cortices resolves ambiguities among previous studies unable to discriminate modality-specific preparatory activity from attentional modulation of stimulus processing. Our results agree with predictive-coding models, which suggest that these expectancy-related changes reflect top-down biases--presumably originating from the observed supramodal frontoparietal network--that modulate signal-detection sensitivity by differentially modifying background activity (i.e., noise level) in different input channels. The putamen appears to code omission-related Bayesian "surprise" that depends on the specificity of predictions. PMID- 21527786 TI - Changes in prefrontal neuronal activity after learning to perform a spatial working memory task. AB - The prefrontal cortex is considered essential for learning to perform cognitive tasks though little is known about how the representation of stimulus properties is altered by learning. To address this issue, we recorded neuronal activity in monkeys before and after training on a task that required visual working memory. After the subjects learned to perform the task, we observed activation of more prefrontal neurons and increased activity during working memory maintenance. The working memory-related increase in firing rate was due mostly to regular-spiking putative pyramidal neurons. Unexpectedly, the selectivity of neurons for stimulus properties and the ability of neurons to discriminate between stimuli decreased as the information about stimulus properties was apparently present in neural firing prior to training and neuronal selectivity degraded after training in the task. The effect was robust and could not be accounted for by differences in sampling sites, selection of neurons, level of performance, or merely the elapse of time. The results indicate that, in contrast to the effects of perceptual learning, mastery of a cognitive task degrades the apparent stimulus selectivity as neurons represent more abstract information related to the task. This effect is countered by the recruitment of more neurons after training. PMID- 21527787 TI - Automated analysis of spines from confocal laser microscopy images: application to the discrimination of androgen and estrogen effects on spinogenesis. AB - Accurate 3D determination of postsynaptic structures is essential to our understanding memory-related function and pathology in neurons. However, current methods of spine analysis require time-consuming and labor-intensive manual spine identification in large image data sets. Therefore, a realistic implementation of algorithm is necessary to replace manual identification. Here, we describe a new method for the automated detection of spines and dendrites based on analysis of geometrical features. Our "Spiso-3D" software carries out automated dendrite reconstruction and spine detection using both eigenvalue images and information of brightness, avoiding detection of pseudo-spines. To demonstrate the potential application of Spiso-3D automated analysis, we distinguished the rapid effects of androgen and estrogen on rapid modulation of spine head diameter in the hippocampus. These findings advance our understanding of neurotrophic function of brain sex steroids. Our method is expected to be valuable to analyze vast amounts of dendritic spines in neurons in the mammalian cerebral cortex. PMID- 21527788 TI - Prediction of motor recovery using initial impairment and fMRI 48 h poststroke. AB - There is substantial interpatient variation in recovery from upper limb impairment after stroke in patients with severe initial impairment. Defining recovery as a change in the upper limb Fugl-Meyer score (DeltaFM), we predicted DeltaFM with its conditional expectation (i.e., posterior mean) given upper limb Fugl-Meyer initial impairment (FM(ii)) and a putative functional magnetic resonance imaging (fMRI) recovery measure. Patients with first time, ischemic stroke were imaged at 2.5 +/- 2.2 days poststroke with 1.5-T fMRI during a hand closure task alternating with rest (fundamental frequency = 0.025 Hz, scan duration = 172 s). Confirming a previous finding, we observed that the prediction of DeltaFM by FM(ii) alone is good in patients with nonsevere initial hemiparesis but is not good in patients with severe initial hemiparesis (96% and 16% of the total sum of squares of DeltaFM explained, respectively). In patients with severe initial hemiparesis, prediction of DeltaFM by the combination of FM(ii) and the putative fMRI recovery measure nonsignificantly increased predictive explanation from 16% to 47% of the total sum of squares of DeltaFM explained. The implications of this preliminary negative result are discussed. PMID- 21527790 TI - Language learning under working memory constraints correlates with microstructural differences in the ventral language pathway. AB - The present study combined behavioral measures and diffusion tensor imaging to investigate the neuroanatomical basis of language learning in relation to phonological working memory (WM). Participants were exposed to simplified artificial languages under WM constraints. The results underscore the role of the rehearsal subcomponent of WM in successful speech segmentation and rule learning. Moreover, when rehearsal was blocked task performance was correlated to the white matter microstructure of the left ventral pathway connecting frontal and temporal language-related cortical areas through the extreme/external capsule. This ventral pathway may therefore play an important additional role in language learning when the main dorsal pathway-dependent rehearsal mechanisms are not available. PMID- 21527789 TI - Individual differences in the spontaneous recruitment of brain regions supporting mental state understanding when viewing natural social scenes. AB - People are able to rapidly infer complex personality traits and mental states even from the most minimal person information. Research has shown that when observers view a natural scene containing people, they spend a disproportionate amount of their time looking at the social features (e.g., faces, bodies). Does this preference for social features merely reflect the biological salience of these features or are observers spontaneously attempting to make sense of complex social dynamics? Using functional neuroimaging, we investigated neural responses to social and nonsocial visual scenes in a large sample of participants (n = 48) who varied on an individual difference measure assessing empathy and mentalizing (i.e., empathizing). Compared with other scene categories, viewing natural social scenes activated regions associated with social cognition (e.g., dorsomedial prefrontal cortex and temporal poles). Moreover, activity in these regions during social scene viewing was strongly correlated with individual differences in empathizing. These findings offer neural evidence that observers spontaneously engage in social cognition when viewing complex social material but that the degree to which people do so is mediated by individual differences in trait empathizing. PMID- 21527791 TI - Functional and dysfunctional brain circuits underlying emotional processing of music in autism spectrum disorders. AB - Despite intersubject variability, dramatic impairments of socio-communicative skills are core features of autistic spectrum disorder (ASD). A deficit in the ability to express and understand emotions has often been hypothesized to be an important correlate of such impairments. Little is known about individuals with ASD's ability to sense emotions conveyed by nonsocial stimuli such as music. Music has been found to be capable of evoking and conveying strong and consistent positive and negative emotions in healthy subjects. The ability to process perceptual and emotional aspects of music seems to be maintained in ASD. Individuals with ASD and neurotypical (NT) controls underwent a single functional magnetic resonance imaging (fMRI) session while processing happy and sad music excerpts. Overall, fMRI results indicated that while listening to both happy and sad music, individuals with ASD activated cortical and subcortical brain regions known to be involved in emotion processing and reward. A comparison of ASD participants with NT individuals demonstrated decreased brain activity in the premotor area and in the left anterior insula, especially in response to happy music excerpts. Our findings shed new light on the neurobiological correlates of preserved and altered emotional processing in ASD. PMID- 21527794 TI - Heeding the call to action. PMID- 21527792 TI - Comparative genomics of the odorant-binding and chemosensory protein gene families across the Arthropoda: origin and evolutionary history of the chemosensory system. AB - Chemoreception is a biological process essential for the survival of animals, as it allows the recognition of important volatile cues for the detection of food, egg-laying substrates, mates, or predators, among other purposes. Furthermore, its role in pheromone detection may contribute to evolutionary processes, such as reproductive isolation and speciation. This key role in several vital biological processes makes chemoreception a particularly interesting system for studying the role of natural selection in molecular adaptation. Two major gene families are involved in the perireceptor events of the chemosensory system: the odorant binding protein (OBP) and chemosensory protein (CSP) families. Here, we have conducted an exhaustive comparative genomic analysis of these gene families in 20 Arthropoda species. We show that the evolution of the OBP and CSP gene families is highly dynamic, with a high number of gains and losses of genes, pseudogenes, and independent origins of subfamilies. Taken together, our data clearly support the birth-and-death model for the evolution of these gene families with an overall high gene turnover rate. Moreover, we show that the genome organization of the two families is significantly more clustered than expected by chance and, more important, that this pattern appears to be actively maintained across the Drosophila phylogeny. Finally, we suggest the homologous nature of the OBP and CSP gene families, dating back their most recent common ancestor after the terrestrialization of Arthropoda (380--450 Ma) and we propose a scenario for the origin and diversification of these families. PMID- 21527793 TI - Structure-function analysis of the OB and latch domains of chlorella virus DNA ligase. AB - Chlorella virus DNA ligase (ChVLig) is a minimized eukaryal ATP-dependent DNA sealing enzyme with an intrinsic nick-sensing function. ChVLig consists of three structural domains, nucleotidyltransferase (NTase), OB-fold, and latch, that envelop the nicked DNA as a C-shaped protein clamp. The OB domain engages the DNA minor groove on the face of the duplex behind the nick, and it makes contacts to amino acids in the NTase domain surrounding the ligase active site. The latch module occupies the DNA major groove flanking the nick. Residues at the tip of the latch contact the NTase domain to close the ligase clamp. Here we performed a structure-guided mutational analysis of the OB and latch domains. Alanine scanning defined seven individual amino acids as essential in vivo (Lys-274, Arg 285, Phe-286, and Val-288 in the OB domain; Asn-214, Phe-215, and Tyr-217 in the latch), after which structure-activity relations were clarified by conservative substitutions. Biochemical tests of the composite nick sealing reaction and of each of the three chemical steps of the ligation pathway highlighted the importance of Arg-285 and Phe-286 in the catalysis of the DNA adenylylation and phosphodiester synthesis reactions. Phe-286 interacts with the nick 5'-phosphate nucleotide and the 3'-OH base pair and distorts the DNA helical conformation at the nick. Arg-285 is a key component of the OB-NTase interface, where it forms a salt bridge to the essential Asp-29 side chain, which is imputed to coordinate divalent metal catalysts during the nick sealing steps. PMID- 21527795 TI - A national website to track hospital discontinuation of formula sample pack distribution: accuracy of self-report. PMID- 21527797 TI - Defining lactation acuity to improve patient safety and outcomes. AB - While substantial evidence exists identifying risks factors associated with premature weaning from breastfeeding, there are no previously published definitions of patient acuity in the lactation field. This article defines evidence-based levels of lactation acuity based on maternal and infant characteristics. Patient acuity, matching severity of illness to intensity of care required, is an important determinant of patient safety and outcomes. It is often used as part of a patient classification system to determine staffing needs and acceptable workloads in health care settings. As acuity increases, more resources, including more skilled clinicians, are needed to provide optimal care. Developing an evidence-based definition of lactation acuity can help to standardize terminology, more effectively distribute health care staff resources, encourage research to verify the validity and reliability of lactation acuity, and potentially improve breastfeeding initiation and duration rates. PMID- 21527799 TI - New insights into excessive weight loss among breastfed newborns: the role of maternal intrapartum fluid balance. PMID- 21527796 TI - Infant formula, tea, and water supplementation of latino infants at 4-6 weeks postpartum. AB - The American Academy of Pediatrics recommends exclusive breastfeeding until 6 months-of-age. The authors examined prevalence and risk factors for use of infant formulas, water, and teas at 4-6 weeks in Latino infants in the San Francisco Bay Area, a group at high risk for future obesity. They recruited a cohort of pregnant Latina women (N = 201). Infant dietary recall and postpartum depressive symptoms were assessed at 4-6 weeks. The authors found that 105 women (53.1%) were feeding infant formulas and 48 (25.4%) were supplementing with tea or water. Of those providing water or tea, 60.0% were providing daily supplementation. In multivariate analyses, risk for infant supplementation with water or tea was associated with postpartum depressive symptoms (relative risk, 1.8; 95% confidence interval, 1.1-3.0), cesarean delivery (relative risk, 1.9; 95% confidence interval, 1.3-2.9), and infant formula use (relative risk, 1.3; 95% confidence interval, 1.1-1.6). Early supplementation with water or teas and infant formulas should be discouraged in Latinos, given the high frequency observed in this population. PMID- 21527800 TI - Striking "seesaw effect" between daptomycin nonsusceptibility and beta-lactam susceptibility in Staphylococcus haemolyticus. PMID- 21527801 TI - Obesity: is evolution to blame? PMID- 21527802 TI - Obesity: evolution of a symptom of affluence. AB - This paper delineates the evolutionary background of the unprecedented epidemic of obesity that has evolved over the last century. Some two million years ago, a change of climate in the habitat of our primate ancestors triggered dietary adaptations which allowed our brain to grow. A shift from principally carbohydrate-based to fish- and meat-based eating habits provided sufficient fuel and building blocks to facilitate encephalisation. Insulin resistance may have evolved simultaneously as a means to avert the danger of hypoglycaemia to the brain (in view of the reduction of carbohydrate intake). Ensuing cognitive capacities enabled the control of fire and the manufacturing of tools, which increased energy yield from food even further and eased the defence against predators. The latter development relieved the selective pressure to maintain an upper level of bodyweight (driven by predation of overweight ndividuals). Since then, random mutations allowing bodyweight to increase spread in the human gene pool by genetic drift. Also, (seasonal) food insecurity in hunter-gatherer societies spurred the evolution of thrifty genes to maximise nutrient intake and energy storage when food was available. The agricultural and industrial revolutions rapidly changed our habitat: virtually unlimited stocks of (refined) foodstuffs and mechanical substitutes of physical efforts push up energy balance, particularly in those of us who are still adapted to former environmental conditions: i.e. who carry thrifty genes and lack (genetic) protection against weight gain. Intrauterine epigenetic mechanisms potentially reinforce the impact of these genes on the propensity to grow obese. PMID- 21527803 TI - Gene expression profiling in acute myeloid leukaemia. AB - Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by clonal malignant haematopoiesis with a differentiation arrest and excessive proliferation of leukaemic blasts. Over the past decades, the heterogeneity of AML has been illustrated by evolving classifications based on morphology (French American-British classification (FAB classification), cytogenetic abnormalities (e.g. t(8;21), monosomies etc.), phenotype and/or molecular abnormalities (e.g. Fms-like tyrosine kinase 3 gene internal tandem duplication (FLT3-ITD), mutations in nucleophosmin 1 (NPM1) and the transcription factor CCAAT /enhancer binding protein a (CEBPA), etc.). The current World Health Organisation (WHO) 2008 classification has integrated these classification modalities. Clinically, dissection of AML into various subtypes allows better survival prediction, but has still limited impact on treatment strategies, with the exception of all-trans retinoic acid treatment for AML-M3 and no allogeneic haematopoietic cell transplantation in complete remission (CR1) for patients with normal karyotype bearing an NPM1 mutation without FLT3-ITD. However, enhanced understanding of the molecular biology of AML will likely result in more 'tailor-made' therapies, for example by adding specific tyrosine kinase inhibitors to standard chemotherapy. In this review, we summarise the variables currently used to classify AML. Specifically, the contribution of microarrays in classification, prognosis and understanding of pathobiology of AML is discussed. PMID- 21527804 TI - Autoimmune haemolytic anaemia - a practical guide to cope with a diagnostic and therapeutic challenge. AB - Autoimmune haemolytic anaemia (AIHA) is a rare disease. In clinical practice, diagnosis and treatment of AIHA turns out to be troublesome. Correct diagnosis is dependent on proper comprehension of the pathophysiology and the laboratory tests performed by the transfusion laboratory. The present review provides a short overview on the pathogenesis of autoimmune haemolytic anaemia. The diagnostic pitfalls will be discussed and a diagnostic algorithm for proper diagnosis of AI HA will be given. Moreover, a brief overview on the treatment of different forms of AIHA is given. PMID- 21527805 TI - A postoperative puzzle. PMID- 21527806 TI - A nonproductive cough that would give most people a headache, but not this patient! PMID- 21527807 TI - Cardiopulmonary events during primary colonoscopy screening in an average risk population. AB - BACKGROUND: Large colorectal cancer screening studies using primary colonoscopy have reported a low risk of major complications. Studies on diagnostic and therapeutic colonoscopy have pointed to a frequent occurrence of(minor) cardiopulmonary events, and with the steady increase of colonoscopy screening, it is important to investigate their occurrence in colonoscopy screening. METHODS: This study describes the frequency of bradycardia(pulse rate <60 min-1), hypotension (systolic blood pressure(SB P) <90 mmHg), hypoxaemia (blood oxygenation, SaO2<90%) and ECG changes during colonoscopy screening in an average risk population (hospital personnel, n=214,mean age 54.0+/-3.8, 39.3% male), without significant comorbidity) and aims at identifying subject-related and/or endoscopic factors associated with their occurrence. All data were collected prospectively. During 214 consecutive primary screening colonoscopies under conscious sedation(midazolam and pethidine), on top of pulse rate and SaO2,blood pressure and a three-channel ECG were recorded every five minutes. RESULTS: No major complications or relevant ECG changes occurred. Hypoxaemia occurred in 119 (55.6%),hypotension in 19 (8.9%) and bradycardia in 12 subjects(5.6%). In multivariate analysis, the sedation level 3 increased the risk of hypoxaemia (OR 4.8, CI 1.7-13.7), and incomplete colonoscopy (OR 5.3, CI 1.6-18.1) was associated with hypotension. Subjects with bradycardia had a longer mean procedure time (38+/-12 vs. 29+/-12 min, p<0.05), which did not turn out as a risk factor in a multivariate analysis. CONCLUSIONS: Mainly procedure-related and not subject-related factors were found to be associated with the occurrence of cardiopulmonary events in primary colonoscopy screening in this relatively healthy screening population. PMID- 21527808 TI - Cyclophosphamide-induced symptomatic hyponatraemia. AB - Cyclophosphamide is an alkylating agent used in antineoplastic and immunosuppressive therapies. Symptomatic hyponatraemia is a rare but life threatening complication in patients treated with cyclophosphamide. We report the case of a 64-year-old woman with breast cancer who developed severe symptomatic hyponatraemia with a generalised seizure and convulsions after a second cycle of adjuvant chemotherapy with 5-fluouracil, epirubicin and cyclophosphamide. She completely recovered after correction of the serum sodium concentration without neurological deficits. Physicians prescribing cyclophosphamide, irrespective of the treatment indication and dosage, should be aware of this potentially life threatening complication. PMID- 21527809 TI - Tropical fever. PMID- 21527810 TI - Leptospirosis in a Dutch catfish farm. AB - A 51-year-old farm worker presented with jaundice and fever. There had been a rat infestation around the farm ponds and in the shed. He was admitted to our hospital with acute renal and liver failure, thrombocytopenia and rhabdomyolysis. Because of the clinical clues, leptospirosis was suspected and diagnosed in blood by polymerase chain reaction and serology. Also his son, a co-worker on the farm, showed a positive serology. Clinicians should be aware of these occupational outbreaks and should recognise the clinical picture. PMID- 21527811 TI - The success of a weekly medical quiz. Test-based medical education. AB - BACKGROUND: Clinical images and tests are considered useful tools to enhance the memorisation of facts and information in medical education. Therefore, we initiated a weekly medical quiz for our department of Internal Medicine. METHODS: Every week, a new case on a single slide with relevant information and a representative image, is sent by e-mail to staff, residents and others. All are requested ona voluntary basis to e-mail the presumed diagnosis within one week. RESULTS: After two years, 100 cases were presented to 452 registered participants. On average, only 33 of 452 (range 14 to 59) participants (7.3%; 95% CI 4.9 to 9.7) responded per case. Most presumed diagnoses were submitted on the same day the case was sent (OR 0.81; 95% CI 0.69 to 0.94; p<0.01). Cases with a high response rate were associated with relatively more correct answers than cases with a low response rate. In addition, it was striking that participants in some subspecialities, particularly specialists in infectious diseases, were much more likely to respond to cases in their own subspecialty. CONCLUSION: Our experience with a weekly medical quiz demonstrates rather low response rates. This could be due to time restraints, but could also be due to the fact that doctors do not like to be wrong, and are afraid to fail among their peers. Hence, although images and tests may be helpful learning tools, the success and contribution of such clinical-based quizzes to medical education are difficult to determine. PMID- 21527812 TI - False elevation of chromogranin A due to proton pump inhibitors. PMID- 21527813 TI - Laser-assisted bioprinting for creating on-demand patterns of human osteoprogenitor cells and nano-hydroxyapatite. AB - Developing tools to reproduce and manipulate the cell micro-environment, including the location and shape of cell patterns, is essential for tissue engineering. Parallel to inkjet printing and pressure-operated mechanical extruders, laser-assisted bioprinting (LAB) has emerged as an alternative technology to fabricate two- and three-dimensional tissue engineering products. The objective of this work was to determine laser printing parameters for patterning and assembling nano-hydroxyapatite (nHA) and human osteoprogenitors (HOPs) in two and three dimensions with LAB. The LAB workstation used in this study comprised an infrared laser focused on a quartz ribbon that was coated with a thin absorbing layer of titanium and a layer of bioink. The scanning system, quartz ribbon and substrate were piloted by dedicated software, allowing the sequential printing of different biological materials into two and/or three dimensions. nHA printing material (bioink) was synthesized by chemical precipitation and was characterized prior and following printing using transmission electron microscopy, Fourier transformed infrared spectroscopy and x ray diffraction. HOP bioink was prepared using a 30 million cells ml(-1) suspension in culture medium and cells were characterized after printing using a Live/Dead assay and osteoblastic phenotype markers (alcaline phosphatase and osteocalcin). The results revealed that LAB allows printing and organizing nHA and HOPs in two and three dimensions. LAB did not alter the physico-chemical properties of nHA, nor the viability, proliferation and phenotype of HOPs over time (up to 15 days). This study has demonstrated that LAB is a relevant method for patterning nHA and osteoblastic cells in 2D, and is also adapted to the bio fabrication of 3D composite materials. PMID- 21527814 TI - Exceptional CO2 tolerance in white sturgeon (Acipenser transmontanus) is associated with protection of maximum cardiac performance during hypercapnia in situ. AB - White sturgeon rank among the most CO2-tolerant fish species examined to date. We investigated whether this exceptional CO2 tolerance extended to the heart, an organ generally viewed as acidosis intolerant. Maximum cardiac output (Q(max)) and maximum cardiac power output (PO(max)) were assessed using a working, perfused, in situ heart preparation. Exposure to a Pco2 of 3 kPa for 20 min had no significant effect on maximum cardiac performance, while exposure to 6-kPa Pco2 reduced heart rate, Q(max), PO(max), and rate of ventricular force generation (F(O)) by 23%, 28%, 26%, and 18%, respectively; however, full recovery was observed in all these parameters upon return to control conditions. These modest impairments during exposure to 6-kPa Pco2 were associated with partially compensated intracellular ventricular acidosis. Maximum adrenergic stimulation (500 nmol L-1 adrenaline) during 6-kPa Pco2 protected maximum cardiac performance via increased inotropy (force of contraction) without affecting heart rate. Exposure to higher CO2 levels associated with morbidity in vivo (i.e., 8-kPa Pco2) induced arrhythmia and a reduction in stroke volume during power assessment. Clearly, white sturgeon hearts are able to increase cardiac performance during severe hypercapnia that is lethal to other fishes. Future work focusing on atypical aspects of sturgeon cardiac function, including the lack of chronotropic response to adrenergic stimulation during hypercapnia, is warranted. PMID- 21527815 TI - Mechanisms associated with cellular desiccation tolerance in the animal extremophile artemia. AB - Using differential scanning calorimetry, we demonstrated the presence of biological glasses and measured the transition temperatures in dry encysted embryos (cysts) of the brine shrimp, Artemia franciscana. Cysts from the following three geographic locations were studied: San Francisco Bay (SFB); the Great Salt Lake, Utah (GSL); and the Mekong Delta, Vietnam (VN; these cysts were produced from previous sequential inoculations of SFB cysts into growth ponds). Values for the glass transition temperature, T(g), were highest in VN cysts. This study indicates that the composition and properties of these biological glasses can be altered by natural selection and thermal adaptation. To our knowledge, T(g) values for all three kinds of cysts were significantly higher than those for any other desiccation-tolerant animal system. To gain insight into the significance of T(g), we examined the thermal stability of these dry cysts at 80 degrees C. GSL cysts were the least tolerant, by far, with VN cysts being extremely tolerant and SFB cysts not far behind. Those results correlated with the thermal transition values. Also measured were alcohol-soluble carbohydrates, ~90% of which is the disaccharide trehalose, a known component of biological glasses. Amounts in the GSL cysts were significantly less than those in the other two kinds of cysts. Several stress proteins were measured in the three groups of cysts, with all of them being in lesser amounts in GSL cysts compared with the SFB and VN cysts. We interpret the data in terms of mechanisms involved with desiccation tolerance and thermal conditions at the sites of cyst collection. PMID- 21527817 TI - Interspecific comparisons of lymph volume and lymphatic fluxes: do lymph reserves and lymph mobilization capacities vary in anurans from different environments? AB - The femoral lymph sac volumes and lymph mobilization capacity were compared in three anuran species that span a range of environments, dehydration tolerance, ability to maintain blood volume with dehydration, and degrees of development of skeletal muscles putatively involved in moving lymph vertically to the posterior lymph hearts. The femoral lymph sac volume determined by Evans blue injection and dilution in the femoral lymph sac varied interspecifically. The semiaquatic species, Lithobates catesbeianus, had the greatest apparent lymph volume expressed either as 18.7 mL kg body mass-1 or 94 mL kg thigh mass-1, compared with both the terrestrial and aquatic species, Rhinella marina (7.3 mL kg body mass-1 and 57 mL kg thigh mass-1) and Xenopus laevis (6.5 mL kg body mass-1 and 40 mL kg thigh mass-1, respectively. Injections of Evans blue into the subvertebral lymph sac, which communicates with both pairs of lymph hearts, yielded the highest rates of lymph return to the circulation in all three species. The most terrestrial species had a greater rate of lymphatic return from the subvertebral lymph sac, compared with the other two species. The rate of lymph flux from the femoral sac varied interspecifically and was correlated with the number and development of skeletal muscles involved in lymph movement. The results indicated that the three species differ in both the volume of lymph present and the capacity to return lymph. Lymph flux was correlated with habitat and the ability to maintain blood volume when challenged by dehydration or hemorrhage, whereas femoral lymph volume was not correlated with these factors. PMID- 21527816 TI - On the evolution of saline tolerance in the larvae of mosquitoes in the genus Ochlerotatus. AB - We examined physiological and morphological parameters associated with saline tolerance in the larvae of 11 species of mosquito in the genus Ochlerotatus that were collected from the wild in a variety of sites around North America. Saline tolerance was assayed, and all of the species were osmoregulators. Six of the species examined were found to be physiologically restricted to freshwater habitats, while the other five could successfully osmoregulate in both freshwater and saline water, including seawater. All larvae that were obligate freshwater forms had only one rectal segment, while all of the euryhaline osmoregulators had two. We were interested in the evolutionary pathway by which saline tolerance arose in this lineage. DNA sequence data were obtained by polymerase chain reaction amplification and sequencing of the D2 region of the 28s rDNA gene in all of the freshwater and saline-tolerant Ochlerotatus species we studied. When the morphological and physiological characters were mapped on the resultant cladogram, they revealed a complex pattern, with freshwater and saline-water forms being adjacent and interspersed through the tree. The data also demonstrate that saline tolerance has been gained and then lost at least once in this lineage. Two possible evolutionary scenarios are presented, but the one we favor is that saline tolerance arose one time in this lineage and repeated reversions to the freshwater condition have occurred. PMID- 21527818 TI - Cutaneous water loss and the development of the stratum corneum of nestling house sparrows (Passer domesticus) from desert and mesic environments. AB - Evaporation through the skin contributes to more than half of the total water loss in birds. Therefore, we expect the regulation of cutaneous water loss (CWL) to be crucial for birds, especially those that live in deserts, to maintain a normal state of hydration. Previous studies in adult birds showed that modifications of the lipid composition of the stratum corneum (SC), the outer layer of the epidermis, were associated with changes in rates of CWL. However, few studies have examined the ontogeny of CWL and the lipids of the SC in nestling birds. In this study, we measured CWL and the lipid composition of the SC during development of nestlings from two populations of house sparrows, one from the deserts of Saudi Arabia and the other from mesic Ohio. We found that desert and mesic nestlings followed different developmental trajectories for CWL. Desert nestlings seemed to make a more frugal use of water than did mesic nestlings. To regulate CWL, nestlings appeared to modify the lipid composition of the SC during ontogeny. Our results also suggest a tighter regulation of CWL in desert nestlings, presumably as a result of the stronger selection pressures to which nestlings are exposed in deserts. PMID- 21527819 TI - Long-lasting consequences of elevated yolk testosterone for metabolism in the zebra finch. AB - Resting metabolic rate is a common way of quantifying the cost of living in endothermic animals. The trait often makes up a substantial part of an animal's energy budget and can also be related to sustainable peak work rate as well as to daily energy expenditure. Studies have shown that metabolic rates are often heritable, but much of the variation seems to be caused by other factors (e.g., environmental and maternal effects). In a previous study, in ovo exposure to increased levels of testosterone induced metabolic costs early in life. It is, however, unknown whether in ovo androgens also have long-term effects on individual metabolic rates. In this study, we show that experimentally increased levels of in ovo testosterone in zebra finches (Taeniopygia guttata) result in a 7% higher resting metabolic rate when they are adults. This shows that maternally transferred hormones can induce long-term effects on metabolic demands and potentially influence variation in life-history strategies among offspring. Variation in maternal hormone transfer may also explain some of the large interindividual variation observed in metabolic rates. PMID- 21527820 TI - Acute corticosterone administration during meiotic segregation stimulates females to produce more male offspring. AB - Birds have demonstrated a remarkable ability to manipulate offspring sex. Previous studies suggest that treatment with hormones can stimulate females to manipulate offspring sex before ovulation. For example, chronic treatments with corticosterone, the primary stress hormone produced by birds, stimulated significant skews toward female offspring. It has been suggested that corticosterone acts by influencing which sex chromosome is donated by the heterogametic female bird into the ovulated ovarian follicle. However, it is difficult to pinpoint when in developmental time corticosterone affects offspring sex, because in previous studies corticosterone treatment was given over a long period of time. We treated laying hens with acute high-dose corticosterone injections 5 h before the predicted time of ovulation and quantified the sexes of the subsequently ovulated eggs to determine whether mechanisms exist by which corticosterone can skew offspring sex ratios just before ovulation. We hypothesized that an injection of corticosterone coincident with segregation of the sex chromosomes would stimulate hens to produce more female than male offspring. Contrary to our predictions, hens injected with corticosterone produced a significant bias toward male offspring, nearly 83%. These results suggest that acute corticosterone treatment during meiosis I can influence primary sex ratios in birds, potentially through nonrandom chromosome segregation. Furthermore, acute corticosterone exposure, compared with chronic exposure, may act through different mechanisms to skew offspring sex. PMID- 21527821 TI - The importance of perivitelline fluid convection to oxygen uptake of Pseudophryne bibronii eggs. AB - The ciliated epithelium of amphibian embryos produces a current within the perivitelline fluid of the egg that is important in the convective transfer of oxygen to the embryo's surface. The effects of convection on oxygen uptake and the immediate oxygen environment of the embryo were investigated in Pseudophryne bibronii. Gelatin was injected into the eggs, setting the perivitelline fluid and preventing convective flow. Oxygen consumption rate (M(.)o2) and the oxygen partial pressure (Po2) of the perivitelline fluid were measured in eggs with and without this treatment. M(.)o2 decreased in eggs without convection at Gosner stages 17-19 under normoxia. The lack of convection also shifted embryos from regulators to conformers as environmental Po2 decreased. A strong Po2 gradient formed within the eggs when convection was absent, demonstrating that the loss of convection is equivalent to decreasing the inner radius of the capsule, an important factor in gas exchange, by 25%. M(.)o2 also declined in stage 26-27 embryos without cilia-driven convection, although not to the extent of younger stages, because of muscular movements and a greater skin surface area in direct contact with the inner capsule wall. This study demonstrates the importance of convective flow within the perivitelline fluid to gas exchange. Convection is especially important in the middle of embryonic development, when the perivitelline space has formed, creating a barrier to gas exchange, but the embryos have yet to develop muscular movements or have a large surface area exposed directly to the jelly capsule. PMID- 21527822 TI - Repeat swimming performance and its implications for inferring the relative fitness of asexual hybrid dace (Pisces: Phoxinus) and their sexually reproducing parental species. AB - While theories explaining the evolution and maintenance of sex are abundant, empirical data on the costs and benefits of asexual relative to sexual reproduction are less common. Asexually reproducing vertebrates, while few, provide a rare opportunity to measure differences in fitness between asexual and sexual species. All known asexually reproducing vertebrates are of hybrid origin, and hybrid disadvantage (i.e., reduced hybrid fitness) is thought to facilitate long-term coexistence between asexual and sexual species. We used repeat swimming performance as a proxy for fitness to compare the fitness of asexual hybrid dace (Pisces: Phoxinus) and their sexually reproducing parental species, finescale dace (Phoxinus neogaeus) and northern redbelly dace (Phoxinus eos). We tested the prediction that, given the widespread coexistence of these hybrid and parental dace, the parental species should show equivalent and perhaps superior repeat performance relative to hybrids. A repeat constant acceleration test (U(max)) was conducted at both acclimation temperature (16 degrees C) and at an elevated temperature (25 degrees C) to simulate the combined influence of a repeat swim and acute temperature change that fish might experience in the wild. The asexual hybrids performed more poorly than at least one of the parental species. There was a negative effect of temperature on repeat swimming performance in all fish, and the repeat performance of hybrids was more severely affected by temperature than that of finescale dace. No difference in the effect of temperature on repeat performance was detected between hybrids and northern redbelly dace. These results suggest that hybrids suffer physiological costs relative to the parentals or at least that the hybrids do not gain advantage from hybrid vigor, which probably contributes to the coexistence of asexual and sexual species in this system. PMID- 21527823 TI - Effects of air and water temperatures on resting metabolism of auklets and other diving birds. AB - For small aquatic endotherms, heat loss while floating on water can be a dominant energy cost, and requires accurate estimation in energetics models for different species. We measured resting metabolic rate (RMR) in air and on water for a small diving bird, the Cassin's auklet (Ptychoramphus aleuticus), and compared these results to published data for other diving birds of diverse taxa and sizes. For 8 Cassin's auklets (~165 g), the lower critical temperature was higher on water (21 degrees C) than in air (16 degrees C). Lowest values of RMR (W kg-1) averaged 19% higher on water (12.14 +/- 3.14 SD) than in air (10.22 +/- 1.43). At lower temperatures, RMR averaged 25% higher on water than in air, increasing with similar slope. RMR was higher on water than in air for alcids, cormorants, and small penguins but not for diving ducks, which appear exceptionally resistant to heat loss in water. Changes in RMR (W) with body mass either in air or on water were mostly linear over the 5- to 20-fold body mass ranges of alcids, diving ducks, and penguins, while cormorants showed no relationship of RMR with mass. The often large energetic effects of time spent floating on water can differ substantially among major taxa of diving birds, so that relevant estimates are critical to understanding their patterns of daily energy use. PMID- 21527824 TI - Comparative energetics of the giant hummingbird (Patagona gigas). AB - Hummingbirds (family Trochilidae) represent an extreme outcome in vertebrate physiological design and are the only birds capable of sustained hovering. The giant hummingbird (Patagona gigas) is the largest trochilid, with a mass of ~20 g, and is found over an altitudinal range from 0 to 4,500 m above sea level. We report here measurements of daily, basal, and hovering rates of oxygen consumption in the giant hummingbird; compare these values with data from smaller hummingbirds; and assess overall metabolic and allometric limits to trochilid body size. The sustained metabolic scope (i.e., the ratio of daily energy expenditure to basal metabolic rate) in the giant hummingbird is higher than that in smaller hummingbirds but lies below a proposed theoretical maximum value for endotherms. Scaling exponents in the allometric relationships for different modes of energetic expenditure were comparable, suggesting that the giant hummingbird, although a clear outlier in terms of body size, does not obviously deviate from metabolic relationships derived from other trochilid taxa. PMID- 21527825 TI - Asymmetric hearing loss. Extended abstracts from the Cochlear Science and Research Seminar. Interlaken, Switzerland. February 10-11, 2011. PMID- 21527826 TI - Identification and molecular characterization of the mammalian alpha-kleisin RAD21L. AB - Meiosis is a fundamental process that generates new combinations between maternal and paternal genomes and haploid gametes from diploid progenitors. Many of the meiosis-specific events stem from the behavior of the cohesin complex (CC), a proteinaceous ring structure that entraps sister chromatids until the onset of anaphase. CCs ensure chromosome segregation, participate in DNA repair, regulate gene expression, and also contribute to synaptonemal complex (SC) formation at meiosis by keeping long-range distant DNA interactions through its conserved structure. Studies from yeast to humans have led to the assumption that Scc1/RAD21 is the alpha-kleisin that closes the tripartite CC that entraps two DNA molecules in mitosis, while its paralog REC8 is essential for meiosis. Here we describe the identification of RAD21L, a novel mammalian CC subunit with homology to the RAD21/REC8 alpha-kleisin subfamily, which is expressed in mouse testis. RAD21L interacts with other cohesin subunits such as SMC1alpha, SMC1b, SMC3 and with the meiosis-specific STAG3 protein. Thus, our results demonstrate the existence of a new meiotic-specific CC constituted by this alpha-kleisin and expand the view of REC8 as the only specific meiotic alpha-kleisin. PMID- 21527827 TI - Pluripotency and lineages in the mammalian blastocyst: an evolutionary view. AB - Early mammalian development is characterized by a highly specific stage, the blastocyst, by which embryonic and extraembryonic lineages have been determined, but pattern formation has not yet begun. The blastocyst is also of interest because cell precursors of the embryo proper retain for a certain time the capability to generate all the cell types of the adult animal. This embryonic pluripotency is established and maintained by a regulatory network under the control of a small set of transcription factors, comprising Oct4, Sox2 and Nanog. This network is largely conserved in eutherian mammals, but there is scarce information about how it arose in vertebrates. We have analysed the conservation of gene regulatory networks controlling blastocyst lineages and pluripotency in the mouse by comparison with the chick. We found that few of elements of the network are novel to mammals; rather, most of them were present before the separation of the mammalian lineage from other amniotes, but acquired novel expression domains during early mammalian development. Our results strongly support the hypothesis that mammalian blastocyst regulatory networks evolved through rewiring of pre-existing components, involving the co-option and duplication of existing genes and the establishment of new regulatory interactions among them. PMID- 21527828 TI - FANCP/SLX4: a Swiss army knife of DNA interstrand crosslink repair. AB - Fanconi anemia (FA) is a rare genetic disease characterized by congenital abnormalities, bone marrow failure and heightened cancer susceptibility. The FA proteins are known to function in the cellular defense against DNA interstrand crosslinks (ICLs), a process that remains poorly understood. A recent spate of discoveries has led to the identification of one new FA gene, FANCP/SLX4, and two strong candidate FA genes, FAN1 and RAD51C. In this perspective we describe the discovery of FANCP/SLX4 and discuss how these new findings collectively refine our understanding of DNA ICL repair. PMID- 21527829 TI - Replication and spread of CJD, kuru and scrapie agents in vivo and in cell culture. AB - Transmissible Spongiform Encephalopathy (TSE) agents are defined by their virulence for particular species, their spread in the population, their incubation time to cause disease, and their neuropathological sequelae. Murine adapted human agents, including sporadic CJD (sCJD), New Guinea kuru, and Japanese CJD agents, display particularly distinct incubation times and maximal infectious brain titers. They also induce agent-specific patterns of neurodegeneration. When these TSE agents are transmitted to cultured hypothalamic GT1 cells they maintain their unique identities. Nevertheless, the human kuru (kCJD) and Japanese FU-CJD agents, as well as the sheep 22L and 263K scrapie agents display doubling times that are 8x to 33x faster in cells than in brain, indicating release from complex innate immune responses. These data are most consistent with a foreign viral structure, rather than an infectious form of host prion protein (PrP-res). Profound agent-specific inhibitory effects are also apparent in GT1 cells, and maximal titer plateau in kCJD and FU-CJD differed by 1,000-fold in a cell-based assay. Remarkably, the lower titer kCJD agent rapidly induced de novo PrP-res in GT1 cells, whereas the high titer FU-CJD agent replicated silently for multiple passages. Although PrP-res is often considered to be toxic, PrP-res instead may be part of a primal defense and/or clearance mechanism against TSE environmental agents. Limited spread of particular TSE agents through nanotubes and cell-to-cell contacts probably underlies the long peripheral phase of human CJD. PMID- 21527830 TI - DNA methylation: a transcriptional mechanism co-opted by the developed mammalian brain? AB - Forming and maintaining behavioral memories is a complex process that involves, among other requirements, transcriptional regulation and systems communication. Here we review recent studies exploring the role of DNA methylation in these critical processes. Further, we suggest that, perhaps, the adult brain controls and utilizes the mechanism of DNA methylation in non-traditional ways that are waiting to be explored. PMID- 21527832 TI - Bibliography--Editors' selection of current word literature. PMID- 21527831 TI - Tensin2 is a novel mediator in thrombopoietin (TPO)-induced cellular proliferation by promoting Akt signaling. AB - Thrombopoietin (TPO) and its receptor c-Mpl are essential in the regulation of the hematopoietic stem and progenitors cells as well as for the differentiation of megakaryocytes into mature platelets. Once TPO binds to its receptor, an intracellular signaling process is initiated through Janus kinase (JAK-2)-induced phosphorylation of the c-Mpl intracellular domain. Although some protein mediators that transmit the effects of TPO have been identified, many remain undiscovered. Using an unbiased approach with peptide microarrays that contained virtually every Src Homology (SH)2 and Phosphotyrosine Binding (PTB) domains in the human genome, we discovered a previously unreported interaction between c-Mpl at phospho-Tyrosine631 (pY 631) and Tensin2, a protein for which limited information is available. Confirming the findings of the microarrays, we discovered that Tensin2 co-precipitates with a pY 631 bearing peptide. Furthermore, we found that Tensin2 becomes phosphorylated in a TPO dependent manner. The functional consequence of Tensin2 was tested via knockdown of Tensin2, which dramatically decreased TPO-dependent cellular proliferation of UT7 TPO cell line as well as their activation of Akt signaling. These studies affirm the use of these arrays as an unbiased screening tool of protein-protein interactions. We conclude that Tensin2 is an important new mediator in TPO/c-Mpl pathway and has a positive affect on cellular growth, at least in part through its effect on the PI3K/Akt signaling. PMID- 21527833 TI - Editorial. PMID- 21527834 TI - Standard precautions: a KAP study among nurses in the dialysis unit in a University Hospital in Alexandria, Egypt. AB - BACKGROUND: Compliance with standard precautions measures is essential to prevent and control health-care-associated infections. OBJECTIVES: This study was conducted to determine the degree to which standard precautions were applied by nurses in a dialysis unit in terms of hand hygiene and use of personal protective equipments. It also aimed to assess nurses' knowledge and attitudes toward standard precautions. MATERIALS AND METHODS: This descriptive cross-sectional study was conducted in the dialysis unit of the Student University Hospital in Alexandria governorate. The study population included all nurses (17 nurses). An observational checklist was used to record practical activities performed by the nurses and a self-administered questionnaire was used to assess their knowledge and attitude toward standard precautions. A minimum required sample size was estimated to be 323 observations per shift. Each nurse was observed 19 times on different work shifts. RESULTS: During the study period, 1082 opportunities for applying standard precautions were recorded. None of the nurses (0%) washed hands before and after the different activities that required hand washing or used plastic aprons or face protection. In contrast, all of them (100%) wore nonsterile gloves before or after the different activities that required wearing of gloves. Less than half of nurses (47.1%) correctly knew that they had to wash their hands before and after caring for a patient. None of the nurses received training in infection control. Among the reported barriers for not applying standard precautions, inaccessibility of sinks, high workload or lack of appropriate staffing, and interference with the practice of care, were cited as the most important barriers. CONCLUSION AND RECOMMENDATIONS: The dialysis unit should revise staff compliance with dialysis unit precautions, and wherever necessary improve the precautions to be applied in the care of all patients and provide performance feedback to nurses. Training of health-care workers (preservice and inservice) about blood-borne infections and universal blood precautions should be regularly carried out. PMID- 21527835 TI - Antenatal care service utilization in tribal and rural areas in a South Indian district: an evaluation through mixed methods approach. AB - BACKGROUND: Maternal and child healthcare is one of the eight basic components of primary healthcare. Poor access and utilization of antenatal care (ANC) services continue to contribute to high maternal mortality and morbidity; and the services of primary healthcare are amenable for evaluation. AIM: To report the utilization of ANC services by women living in tribal and rural areas in the district of Visakhapatnam, Andhra Pradesh, India. MATERIALS AND METHODS: Both qualitative and quantitative methods were used in the study. Quantitative data on ANC were collected from women having a child aged less than a year (n=380) through a structured interview schedule. The qualitative data were collected through indepth interviews with key informants in the villages (n=12). RESULTS: The study reports higher utilization of ANC compared with the national average of India. A greater proportion of women living in tribal areas utilize the services from governmental sources (92%), whereas approximately 54% of the rural women seek services (paid services) from private practitioners. Health workers' visits match with the utilization of government health services. CONCLUSION AND RECOMMENDATIONS: The study showed relatively higher utilization of ANC services than the national average, but at the same time, child deliveries at home, which were mostly conducted by untrained elderly women, were also high. This gap is indicative of the target-oriented approach where quantity rather than the quality takes priority. In addition, the literacy levels of women, socioeconomic conditions and distance to the health facilities also played a role. To improve utilization and access, community health needs assessment has to be made, along with attempts to develop community participation. PMID- 21527836 TI - Gram-negative bacillary meningitis in Egypt. AB - BACKGROUND: Gram-negative bacillary meningitis (GNBM) is a rare disease with a high rate of mortality. OBJECTIVES: The aim of this study was to describe the clinical presentation and outcome of primary and secondary GNBM and to evaluate the efficacy of ceftriaxone (a third-generation cephalosporin) in the treatment of this disease. MATERIALS AND METHODS: A retrospective study was conducted including 95 patients with GNBM admitted to the Abbassia and Imbaba fever hospitals' meningitis wards in Egypt during the period from 1993 to the end of the year 2009. Their cerebrospinal fluid samples were subjected to conventional bacteriological methods for isolation of the causative Gram-negative bacilli. Forty-nine patients had primary GNBM (no predisposing cause of meningitis was detected) and 46 patients had secondary GNBM (with a predisposing cause of meningitis). RESULTS: Primary GNBM was characterized by an abrupt onset and was significantly associated with typical signs of meningeal irritation. The most common infecting organisms were Salmonella typhi in 16 (33%) patients and Escherichia coli in 15 (31%) patients. Of the patients with primary GNBM, 26 (53%) were cured, 11 (22%) developed neurological sequalae, and 12 (24%) patients died. Secondary GNBM was characterized by an insidious onset and significantly associated with unarousable coma. The most common infecting organisms were Proteus mirabilis in 17 (37%) patients and Pseudomonas aeruginosa in 16 (35%) patients. The most common predisposing factor of meningitis was otitis media and occurred in 26 (57%) patients. Of the patients with secondary GNBM, 15 (33%) were cured, 15 (33%) developed neurological sequalae, and 16 (35%) died. Primary GNBM was significantly associated with a higher cure rate than secondary GNBM. The duration of symptoms in patients with secondary GNBM was significantly higher than in those with primary GNBM. Ceftriaxone was the initial drug for treatment of these patients until the antibiotic sensitivity tests were reported. The overall resistance rate to the drug was 4%. CONCLUSION AND RECOMMENDATIONS: GNBM still has a high mortality rate and should be managed as a medical emergency. GNBM should be suspected in patients with otitis media, neurosurgical, and head trauma or who underwent spinal anesthesia and have disturbance in their level of consciousness, even if there are no signs of meningeal irritation. Ceftriaxone is still an effective drug and had a low rate of resistance in our study. PMID- 21527837 TI - Epidemiologic determinants of endometriosis among Egyptian women: a hospital based case-control study. AB - BACKGROUND: Advances in understanding the epidemiology of endometriosis have lagged behind other diseases because of methodological problems related to disease definition and control selection. AIM: To identify possible risk factors associated with the development of endometriosis among a sample of Egyptian women. MATERIALS AND METHODS: A case-control study was conducted in the University Maternity Hospital and some private hospitals in Alexandria. The sample included 110 cases recently diagnosed with endometriosis and 220 hospital based, age-matched controls. RESULTS: Using the logistic regression analysis, nulligravidae were four times more likely to develop endometriosis than gravid women [adjusted odds ratio (AOR)=4.0, 95% confidence interval (CI) (2.2-7.6)]. Short cycles were associated with approximately six times increase in risk of endometriosis [AOR=6.1, 95% CI (2.9-12.8)]. Women with irregular cycles were three times more likely to develop endometriosis than women with regular cycles [AOR=3.5, 95% CI (1.89-6.71)]. Similarly, women with a history of irritable bowel syndrome were twice as likely to develop endometriosis [AOR=1.9, 95% CI (1.03 3.87)]. Women who had one or more relatives with endometriosis were 1.2 times more likely to develop endometriosis [AOR=1.2, 95% CI (1.19-1.43)]. CONCLUSION AND RECOMMENDATIONS: Nulliparous and women reporting short and irregular cycles were at a significantly increased risk of developing endometriosis. A weak association between reported family history of endometriosis and history of irritable bowel syndrome and the development of endometriosis was also observed. Designing and implementing health education programs about endometriosis and its related risk factors should be a priority to ensure early diagnosis of the disease. PMID- 21527838 TI - What constitutes a good clinical teacher? AB - BACKGROUND: The practical part of medical studies occurs in clinical settings. The characteristics of a good clinical teacher have been reflected in a large number of medical educational studies, mainly within the western context. OBJECTIVES: To explore the views of medical students and staff with regard to the characteristics of a good clinical teacher, and to determine whether sex and type of department have any significant effect on this issue within the Saudi context. MATERIALS AND METHODS: A questionnaire was developed. It consists of 25 characteristics with four domains: professional, teaching skills, personal, and social. The study population included 85 fourth-year students and 36 faculty staff in the following three departments: respiratory technology, physical therapy, and medical laboratory technology, at the University of Dammam, Kingdom of Saudi Arabia. RESULTS: The questionnaire had high reliability and satisfactory content validity. There were statistically significant sex differences regarding the importance of one domain (professional, P<0.001) and seven individual characteristics. Female participants accorded higher mean ranks compared with men (25.3 vs. 32.5 in social domain). Faculty significantly accorded higher mean ranks in all domains compared with students. No statistically significant differences among students' views based on the type of department were observed. CONCLUSIONS AND RECOMMENDATIONS: There was a general agreement on the importance of all characteristics, but the degree of importance significantly varies. Faculty in general and female participants in particular viewed such attributes as more important than their counterparts. These characteristics should be incorporated in the teacher evaluation format/questionnaire currently used by the college, which will ultimately have a positive impact on teaching and learning in Saudi Arabia. PMID- 21527839 TI - Prevalence and characteristics of chronic pelvic pain among women in Alexandria, Egypt. AB - BACKGROUND: Chronic pelvic pain (CPP) is widespread among women with a significant impact on their health. The nature and severity of pain varies between different women and areas. OBJECTIVES: To estimate the prevalence CPP and associated dysmenorrhea, and dyspareunia among women attending Family Health Centers in Alexandria, Egypt and to describe the nature and severity of pain as reported by women. MATERIALS AND METHODS: A cross-sectional study was performed on a sample of 900 ever-married women aged (18-59) years attending three Family Health Centers in Alexandria, Egypt (2007-2008). Personal, social, reproductive, and medical data were collected using a modified Oxfordshire questionnaire. Severity of pain was assessed using both the Verbal Rating Scale and the Visual Analogue Scale. RESULTS: Prevalence of CPP was 26.6%, dysmenorrhea was 55.3%, and dyspareunia was 40.5%. The three types overlapped. Most women (92%) had CPP of intermittent type and 46.9% had this pain for more than 1 year (1-5 years). Pain was perceived as severe in approximately one third of them (32.2%). Their mean Visual Analog Scale for pain severity was 6.5+/-2.1. The most frequently mentioned types of pain were moderate cramping pain and moderate heaviness (40%). Factors that increase their pain were mainly full bladder, sexual intercourse, and loaded colon (60, 46.4, and 40%, respectively). Relieving factors were urination and sleep/rest (46.9 and 46.4%, respectively) and use of medications (40%). CONCLUSION AND RECOMMENDATIONS: The three types of pain were highly prevalent and overlapping among the women studied. CPP was perceived as severe and intermittent by many women. Pelvic pain should receive greater attention both in public education and in clinical practice. Primary care physicians should be prepared to initiate pain management to alleviate women's stress and disability. Women should be educated regarding the importance of seeking medical treatment early. PMID- 21527841 TI - Short-term outcomes of laparoscopic versus open colorectal cancer surgery. PMID- 21527843 TI - Post-discharge venous thromboembolism after cancer surgery: extending the case for extended prophylaxis. AB - OBJECTIVE: To (1) define the frequency of overall and postdischarge venous thromboembolism (VTE) after cancer surgery, (2) identify VTE risk for individual cancer operations, and (3) assess mortality rates in patients who experienced a VTE. SUMMARY AND BACKGROUND DATA: Cancer is a known risk factor for VTE but less is known about VTE risk after specific cancer operations. Moreover, most cancer patients routinely receive VTE prophylaxis postoperatively while in the hospital, but few receive prolonged prophylaxis despite strong evidence it reduces postdischarge events. METHODS: From 211 ACS NSQIP hospitals, 44,656 patients undergoing surgery for 9 cancers were identified (2006-2008). The frequency of VTE within 30-days of surgery was evaluated by cancer site and categorized as occurring before or after discharge. Multivariable logistic regression models were constructed to assess risk factors associated with VTE. RESULTS: VTE occurred in 1.6% of all patients, most frequently after esophagogastric (4.2%) and hepatopancreaticobiliary (3.6%) surgery. Overall, 33.4% of VTEs occurred postdischarge (from 17.9% for esophagogastric to 100% for endocrine operations). Factors associated with VTE were age (>=65 years), cancer/procedure type, metastatic disease, congestive heart failure, body mass index (BMI; >=25 kg/m(2)), ascites, thrombocytosis (>400,000 cells/mm(3)), albumin (<3.0 g/dL), and operation duration (>2 hours; all P < 0.001). Overall VTE was significantly more likely after gastrointestinal, lung, prostate, and ovarian/uterine operations (all P < 0.001). In those experiencing a VTE, mortality increased over 6-fold (8.0% vs. 1.3%; P < 0.001). CONCLUSION: One-third of VTE events in cancer surgery patients occurred postdischarge. Postoperative VTE was associated with operation type. Routine postdischarge VTE prophylaxis should be considered for high-risk patients. PMID- 21527844 TI - Is the seventh edition of the UICC/AJCC TNM staging system reasonable for patients with tumor deposits in colorectal cancer? AB - OBJECTIVE: To assess the rationality of the seventh edition of TNM staging system on tumor deposits (TDs) and propose a novel subclassification. SUMMARY BACKGROUND DATA: The TDs had been debated for many years. The seventh edition of TNM staging system proposed a "pN1c" concept. However, the value of the modification is still debated. METHODS: A total of 1541 patients with colorectal cancer were reviewed. Overall survival rates were compared between patients without LNM but TD (+), and those who were TD (-). The TDs were stratified into the "any T + any N" category. Two-step multivariate analysis was performed to identify significant prognostic factors. Univariate analysis was used to determine whether a correlation existed between the number of TDs and prognosis. RESULTS: There was a significant prognostic difference between patients without LNM or TDs compared with those with positive TDs. Only in T3N2bM0 there was a significant prognostic difference between LNM (+), TD (+) patients and TD (-) patients. The seventh edition of TNM staging system was substituted by the novel TNM staging system in 2-step multivariate analysis. Only in T3N1cM0 there was a significant prognostic difference between patients with only 1 TD and those with more than 1 TD. CONCLUSION: The seventh edition of TNM staging system on TDs satisfactorily predicts patients' outcome for those without LNM. Patients who categorized as T3N2bM0TD (+) and T4N2bM0TD (-/+) should be reclassified as stage IV. Number of TDs was not an independent prognostic parameter in the TNM staging system. PMID- 21527845 TI - Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria. AB - OBJECTIVE: To compare microvascular invasion (McVI) with parameters defined by the Milan criteria in predicting tumor recurrence and overall survival (OS) in patients with surgical resection (SR) for hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Although the Milan criteria is discriminatory for selecting patients with good outcomes in liver transplantation and SR for HCC, it neither adequately predict tumor recurrence nor explain differences in survival for patients with good liver function. McVI is a strong indicator of intrahepatic metastasis in HCC, but its relative significance for predicting clinical outcomes compared to the Milan criteria is unclear. METHODS: Patients undergoing SR with curative intent from January 2000 to March 2009 at the Singapore General Hospital were followed up for long-term outcomes till January 1, 2010. They were stratified first by the Milan criteria and then by the presence of McVI and compared relative to OS. RESULTS: Altogether, 454 of the 515 patients received curative SR. There were stratified into 4 groups (Milan+, McVI-), (Milan+, McVI+), (Milan-, McVI-), and (Milan-, McVI+). All pair-wise comparisons between groups relative to OS were significant except (Milan+, McVI-) (OS, 90%, 73%, and 60% at 1, 3, and 5 years) with (Milan-, McVI-) (OS, 86%, 71%, and 61% at 1, 3, 5 years) and (Milan+, McVI+) with (Milan-, McVI+). Multivariate Cox regression analysis showed that McVI was predictive of OS, after which Milan status did not add additional discriminative information. CONCLUSIONS: McVI is a better predictor of tumor recurrence and OS than the Milan criteria after SR for HCC. Assessment of McVI should aid in patient selection for adjuvant treatments to improve outcomes after SR. PMID- 21527846 TI - Involvement of mitochondrial and B-RAF/ERK signaling pathways in berberine induced apoptosis in human melanoma cells. AB - The natural isoquinoline alkaloid berberine exhibits a wide spectrum of biological activities including antitumor activity, but its mechanism of action remains to be fully elucidated. Here, we report that berberine induced apoptosis in human melanoma cells, through a process that involved mitochondria and caspase activation. Berberine-induced activation of a number of caspases, including caspases 3, 4, 7, 8, and 9. Pan-caspase inhibitor, z-VAD-fmk, and caspase-8 and caspase-9 inhibitors prevented apoptosis. Berberine also led to the generation of the p20 cleavage fragment of BAP31, involved in directing proapoptotic signals between the endoplasmic reticulum and the mitochondria. Treatment of SK-MEL-2 melanoma cells with berberine induced disruption of the mitochondrial transmembrane potential, release of cytochrome c and apoptosis-inducing factor from the mitochondria to the cytosol, generation of reactive oxygen species (ROS), and a decreased ATP/ADP ratio. Overexpression of bcl-xL by gene transfer prevented berberine-induced cell death, mitochondrial transmembrane potential loss, and cytochrome c and apoptosis-inducing factor release, but not ROS generation. N-acetyl-L-cysteine inhibited the production of ROS, but did not abrogate the berberine-induced apoptosis. Inhibition of extracellular signal regulated kinase (ERK) phosphorylation, by using the mitogen-activated protein kinase/ERK kinase inhibitor PD98059, and reduction of B-RAF levels by silencing RNA induced cell death of SK-MEL-2 cells, and diminished the berberine concentration required to promote apoptosis. These data show that berberine induced apoptosis in melanoma cells involves mitochondria and caspase activation, but ROS generation was not essential. Our results indicate that inhibition of B RAF/ERK survival signaling facilitates the cell death response triggered by berberine. PMID- 21527847 TI - Telecare is a valuable tool for hypertension management, a systematic review and meta-analysis. AB - There is an increasing interest for using telecare(TC) in the management of hypertension. A systematic review to the use of blood pressure (BP) measurement in TC has been performed (Medline/PubMed, Embase, and Cochrane Library), selecting randomized clinical trials that compared TC with usual care (UC) for hypertension management (treatment and/or coaching). Nine randomized clinical trials were selected (n=2501, 61.4+/-0.6 years, 42+/-2.7% males). Overall there was a significant larger decrease in the TC group than in the UC group for systolic (5.2+/-1.5 mmHg; P<0.001) and diastolic BP (2.1+/-0.8 mmHg; P<0.01). When studies were separated for antihypertensive treatment modification during the study (yes or no), systolic BP decrease difference between the TC and UC groups (DeltaTC-DeltaUC) tended to be significantly lower (5.1+/-2.9 mmHg lower) with treatment modification compared with nontreatment modification in which the DeltaTC-DeltaUC was 8.6+/-2.4 mmHg, P=0.07. TC led to a greater decrease in systolic and diastolic BP than UC. The differences between TC and UC for systolic BP tend to become larger when no treatment modification is applied. TC seems a valuable tool for hypertension management. PMID- 21527848 TI - Validation of the Welch Allyn ProBP 3400: a device for modern medical practice. AB - OBJECTIVES: As medical care evolves, automated sphygmomanometers must be able to provide accurate and timely blood pressure (BP) data to the healthcare provider. We evaluated the performance of a new hand-held, battery-operated device, the Welch Allyn ProBP 3400, to the AAMI SP 10 criteria. We also performed British Hypertension Society data analysis. METHODS: A total of 111 (97 adults, 14 children) participants were tested using blinded and paired observers performing auscultation of Korotkoff (K1 and K5) sounds. RESULTS: Ninety-two participants had acceptable data, giving 275 paired data sets for systolic BP (SBP) and diastolic BP (DBP) analyses. The mean +/- standard deviation of the observer/device differences were -1.1 +/- 7.5 mmHg for SBP and -2.1 +/- 6.0 mmHg for DBP. These passed the AAMI SP10 requirements. The ProBP 3400 achieved an A grade for both SBP and DBP. CONCLUSION: The ProBP 3400 passed the AAMI standard requirements and achieved A grade for both SBP and DBP. The device is less in cost and completely portable. It transmits BP data directly into the electronic medical record using a Universal Serial Bus connection. These features will improve the efficiency and accuracy of BP data available to clinicians, thus improving the quality of care. PMID- 21527850 TI - ANKRD11 gene deletion in a 17-year-old male. PMID- 21527849 TI - Chromosomal abnormalities resembling Joubert syndrome: two cases illustrating the diagnostic pitfalls. AB - We describe two patients with severe developmental delay, hypotonia and breathing abnormalities initially diagnosed with the autosomal recessive Joubert syndrome (JBS) who at a later stage appeared to carry chromosomal abnormalities. One case was due to a 4.8 Mb terminal 1q44 deletion, and the other due to a 15.5 Mb duplication of Xq27.2-qter containing the MECP2 gene. Critical evaluation of the clinical data showed that, retrospectively, the cases did not fulfil the diagnostic criteria for JBS, and that the diagnosis of JBS was incorrectly made. We discuss the diagnostic pitfalls and recommend adhering strictly to the JBS diagnostic criteria in the case of a negative molecular diagnosis. Critical assessment of the MRI findings by a specialized neuroradiologist is imperative. As chromosomal abnormalities may give rise to symptoms resembling JBS, we recommend array-based screening for segmental aneuploidies as an initial genetic test in all cases with a JBS-like phenotype. PMID- 21527851 TI - Ectopic varices in portal hypertension: computed tomographic angiography instead of repeated endoscopies for diagnosis. AB - Ectopic varices (EcV) accounting for 1-5% of all varices in portal hypertension are composed of dilated portosystemic collaterals located in unusual sites instead of the most known gastroesophageal region. The difficulty in localization of bleeding is a great burden on the management of these patients. Herein, we present patients with EcV as well as with portal hypertension and recurrent intestinal bleeding. The sites of EcV were identified with computed tomographic angiography, after a series of inconclusive endoscopies, and moreover a selective celiac arteriographic examination of one of the patients. PMID- 21527852 TI - Cytokine gene polymorphism in microscopic colitis association with the IL-6-174 GG genotype. AB - OBJECTIVES: Microscopic colitis (MC) is a chronic inflammatory disease with unknown pathogenesis. Very little is known about polymorphisms in the cytokine genes in MC. We have investigated the occurrence of well-characterized polymorphisms of interleukins (IL-6, IL-1beta, IL-1 receptor antagonist, IL-10) and CD14 in MC. We also determined the serum IL-6 levels. METHODS: We genotyped 81 patients with MC and 178 controls for polymorphisms of IL-6-174, IL-1beta-511, IL-1beta-3953, IL-1 receptor antagonist, IL-10-1082 and CD14-159. Serum concentration of IL-6 was measured in 72 patients. RESULTS: Genotype GG of IL-6 174 was more prevalent in MC compared with the controls (P=0.030; odds ratio: 1.941; confidence interval: 1.078-3.495), and the frequency of allele G of IL-6 174 was higher in MC (0.55 vs. 0.47; P=0.036; odds ratio: 1.514; confidence interval: 1.041-2.203). However, after correction for multiple comparisons, the difference became nonsignificant. IL-6 genotype and the serum IL-6 concentration showed no association. The concentration of IL-6 was higher in patients with collagenous colitis than in those with lymphocytic colitis (median 1.73 vs. 1.34 pg/ml, P=0.011). No association between polymorphisms of other cytokine genes and MC was seen. CONCLUSION: The IL-6-174 gene polymorphism has a possible association with MC, as the IL-6 GG genotype was more frequent in patients with the disease. As this genotype may be linked with an enhanced IL-6 production, we speculate that this polymorphism can influence the pathogenesis of MC by evoking a proinflammatory bias in the mucosal cytokines. The enhanced concentration of IL 6 in collagenous colitis compared with lymphocytic colitis supports a difference in the pathogenetic mechanisms between the two subgroups of MC. PMID- 21527853 TI - Blockage of TNF-alpha by infliximab reduces CCL2 and CCR2 levels in patients with rheumatoid arthritis. AB - OBJECTIVES: To investigate the mechanism in vivo for the regulation of inflammation of patients with RA by infliximab, we measured serum levels of chemokine ligand (CCL) 2, CCL3, CXCL8, and expression of CCL2 receptor chemokine receptor (CCR) 2 on CD4 T cells from patients with rheumatoid arthritis (RA). METHODS: Forty-four patients with were enrolled in our study. Twenty-four patients received infliximab combined with methotrexate. Twenty patients received methotrexate alone. Serum levels of the chemokines CCL2, CCL3, and CXCL8 were quantified using commercial enzyme-linked immunosorbent assay kits. Flow cytometry was used to analyze the expression of CCR2 on CD4 T cells. RESULTS: The mean CCL2 levels in the infliximab-treated patients decreased significantly from 885.20 +/- 323.52 pg/mL at pretreatment to 454.65 +/- 185.03 pg/mL (P < 0.05) at 30 weeks after the initial treatment. Fluorescence density of CCR2 expression on CD4 T cells were significantly reduced after infliximab treatment. CONCLUSIONS: CCL2/CCR2 system in patients with active RA may be sensitive to anti-tumor necrosis factor-alpha therapy and suggest that CCL2 plays a crucial role in the pathogenesis of RA. CCR2 may be an important target for therapy in RA. PMID- 21527854 TI - Simvastatin effects on androgens, inflammatory mediators, and endogenous pituitary gonadotropins among patients with PCOS undergoing IVF: results from a prospective, randomized, placebo-controlled clinical trial. AB - OBJECTIVE: To evaluate effects of simvastatin on selected biochemical parameters and reproductive outcome among patients with polycystic ovary syndrome (PCOS) who undergo in vitro fertilization (IVF). METHODS: Patients with PCOS were randomized to receive either oral simvastatin, 20 mg/d (n = 32), or placebo (n = 32) in a prospective, double-blind, randomized clinical trial (NCT 005-75601) in parallel with controlled ovarian hyperstimulation for IVF. All patients were determined to be at average risk for cardiovascular disease, based on high-sensitivity C reactive protein (hsCRP) measurement at entry. After an 8-week treatment interval concluding at periovulatory human chorionic gonadotropin administration, selected clinical and laboratory parameters were measured. RESULTS: Mean serum total testosterone level decreased by 25% in the simvastatin group, compared to a 10% reduction in the placebo group (P < 0.001). A trend of lower serum luteinizing hormone levels was noted in experimental and control groups (29% vs 22%, respectively), although this difference was not significant (P > 0.05). Neither fasting insulin nor quantitative insulin sensitivity check index were significantly impacted by simvastatin (P > 0.05). As expected, total cholesterol was not modified among placebo patients but was significantly reduced after simvastatin (P = 0.001). In addition, hsCRP and vascular cell adhesion protein-1 were both significantly lower after simvastatin therapy compared to controls (P <= 0.005 for both). At study completion, no important change in body mass index was observed in either group (P >= 0.60). Although oocyte maturation, fertilization, and clinical pregnancy rates were all higher after simvastatin, none of these improvements were statistically significant. CONCLUSIONS: This report presents data from the first prospective, randomized, placebo-controlled clinical investigation of simvastatin in the setting of PCOS and IVF. Simvastatin seems to be compatible with gonadotropin therapy for IVF and can offer beneficial endocrine and cardiovascular effects for patients with PCOS who undergo embryo transfer. Although the observed improvements in reproductive function were mild, the reductions in hsCRP and vascular cell adhesion protein-1 after simvastatin treatment were significant, suggesting the need for further clinical trials to clarify simvastatin's impact on reproductive physiology. PMID- 21527856 TI - Lupus erythematosus profundus and enophthalmos. PMID- 21527855 TI - Vitamin D and the immune system. AB - It is now clear that vitamin D has important roles in addition to its classic effects on calcium and bone homeostasis. As the vitamin D receptor is expressed on immune cells (B cells, T cells, and antigen-presenting cells), and these immunologic cells are all capable of synthesizing the active vitamin D metabolite, vitamin D has the capability of acting in an autocrine manner in a local immunologic milieu. Vitamin D can modulate the innate and adaptive immune responses. Deficiency in vitamin D is associated with increased autoimmunity and an increased susceptibility to infection. As immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D, the beneficial effects of supplementing vitamin D-deficient individuals with autoimmune disease may extend beyond the effects on bone and calcium homeostasis. PMID- 21527857 TI - Treatment of severe thoracolumbar kyphoscoliosis on the ground of ganglioneuroblastoma of the diaphragm: a case report. AB - The treatment of an unusual case with severe kyphoscoliotic deformity of the thoracolumbar spine, in association with a ganglioneuroblastoma invading the adjacent diaphragm, is presented in this report. Severe scoliotic deformity of the spine, associated with ganglioneuroblastoma of the diaphragm is a rare combination and treatment can be very challenging, as both entities require extensive surgery. To the best of our knowledge, only two reports related to a similar condition have been published in the literature so far. A 9-year-old girl had been treated in another institution since the age of 5 years for thoracolumbar kyphoscoliosis with bracing. She was referred to our department with a stiff right kyphoscoliotic curve at the thoracolumbar region (T8-L2), with measurements of 105 and 90 degrees for the scoliotic and kyphotic elements, respectively. There were no neurological signs detected at the preoperative work up, which included clinical and radiological evaluation (plain X-rays and computed tomographic scan). The patient was treated with a two-stage spinal fusion. During the anterior approach through a right thoracotomy, a tumor was discovered infiltrating half of the diaphragm and extended to the frontal surface of the lower thoracic vertebral bodies. The vertebrae were cleared of the tumorous masses and anterior discectomies (T8-L2) were successfully carried out according to the preoperative plan. The histopathology report indicated ganglioneuroblastoma in both the prevertebral material and the speciments excised from the diaphragm. A week later a T3-L4 posterior fusion was carried out and the deformity was corrected and fixed with an SFS instrumentation system. Both the scoliotic and the kyphotic curves were reduced to 46 degrees . Postoperatively the patient was referred to the oncology department of another hospital for the treatment of the diaphragm tumor. During the last follow-up (4 years), the scoliotic curve remains steady and the tumor shows no recurrence. Although there are cases of ganglioneuroblastoma associated with scoliotic deformity, the combination of this tumor infiltrating the diaphragm and a very severe deformity of the spine is extremely rare. Nevertheless, the treatment undertaken has proven to be successful so far. PMID- 21527858 TI - Endoscopically aided physeal bar takedown and guided growth for the treatment of angular limb deformity. AB - The treatment of physeal arrest after infection remains a challenge. This report describes localized endoscopic epiphysiolysis combined with guided growth in the treatment of partial physeal arrest and limb deformity in an infant after infection. Over a year's time, the valgus was corrected and the plate was removed. The patient returned to full activity. Physeal arrest may occur at anytime after physeal trauma, highlighting the importance of long-term follow-up. Endoscopic physeal bar takedown combined with guided growth of the distal femur can be an effective option for the treatment. PMID- 21527859 TI - Progression of idiopathic clubfoot correction using the Ponseti method. AB - The Ponseti technique involves sequential clubfoot correction by abduction, supination, and finally dorsiflexion. Although shown to be effective, correction progression has not been examined. The Dimeglio/Bensahel classification system was used to analyze heel equinus, varus, midfoot rotation, adduction, posterior crease, medial crease, and cavus initially and after each casting. From 2000 to 2008, 123 patients (185 feet) with idiopathic clubfeet, aged below 60 days, without prior treatment were grouped by number of casts required. Successive castings achieved goals of reducing cavus and medial crease first, then gradually correcting midfoot rotation, adduction, and heel varus. Unexpectedly, heel equinus improved simultaneously with midfoot variables, as well as with final casting. PMID- 21527863 TI - "Is Chiari-I malformation associated with fibromyalgia?" revisited. PMID- 21527865 TI - A model for early prediction of facial nerve recovery after vestibular schwannoma surgery. AB - OBJECTIVE: To identify early predictors of long-term facial nerve function after vestibular schwannoma resection. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Subjects with facial nerve weakness despite anatomic preservation of the nerve after removal of vestibular schwannoma. INTERVENTION: Surgical resection of vestibular schwannoma. MAIN OUTCOME MEASURE: Facial function after 1 postoperative year. Independent variables included patient demographics, presenting symptoms, tumor size and location, and serial postoperative function within the first year. RESULTS: Among 281 patients with postoperative facial weakness, 81% improved to a House Brackmann (HB) III or better (good outcome) after 12 months of recovery, whereas 12% remained HB IV or worse (poor outcome). For patients starting with HB V or VI function, recovery rate was the most reliable predictor of poor outcome after 1 year. The resulting predictive model using rate of functional improvement as the independent variable was found to anticipate poor outcome before 1 year in more than 50% of cases with 97% sensitivity and 97% specificity. Although associated with facial nerve outcome, tumor size, tumor vascularity, preoperative facial function, age at surgery, and ability to stimulate the nerve intraoperatively did not contribute significantly to the predictive model. CONCLUSION: The rate of recovery within the first postoperative year serves as a useful early predictor of long-term facial nerve function. We present a novel predictive model using rate of recovery that can be used to select candidates for reanimation surgery sooner than the traditional waiting period of 1 year, potentially improving the outcome of this intervention. PMID- 21527866 TI - Unusual electroacoustic device failure and electroacoustic reimplantation with hearing preservation. AB - OBJECTIVE: To document the preservation of hearing after electroacoustic (EAS) cochlear reimplantation and to report on a method of managing recurrent air accumulation under the posterior skin flap. STUDY DESIGN: Retrospective case report. PATIENTS: A single patient report. INTERVENTION: After successful EAS cochlear implantation with hearing preservation, patient developed recurrent air accumulation under his posterior flap and a subsequent device failure. The patient was reimplanted using EAS protocol and a myringotomy tube used to prevent reaccumulation of air. MAIN OUTCOME MEASURE: Preservation of hearing. RESULTS: Hearing was preserved after reimplantation, and air accumulation was avoided. CONCLUSION: Hearing can be preserved in EAS reimplantation using EAS surgical techniques. Air accumulation can be avoided or treated with a myringotomy tube. PMID- 21527867 TI - Neuroendocrine adenoma of the middle ear. PMID- 21527868 TI - Connexin implication in the control of the murine beta-cell mass. AB - Diabetes develops when the insulin needs of peripheral cells exceed the availability or action of the hormone. This situation results from the death of most beta-cells in type 1 diabetes, and from an inability of the beta-cell mass to adapt to increasing insulin needs in type 2 and gestational diabetes. We analyzed several lines of transgenic mice and showed that connexins (Cxs), the transmembrane proteins that form gap junctions, are implicated in the modulation of the beta-cell mass. Specifically, we found that the native Cx36 does not alter islet size or insulin content, whereas the Cx43 isoform increases both parameters, and Cx32 has a similar effect only when combined with GH. These findings open interesting perspectives for the in vitro and in vivo regulation of the beta-cell mass. PMID- 21527869 TI - Assessing instrument handling and operative consequences simultaneously: a simple method for creating synced multicamera videos for endosurgical or microsurgical skills assessments. AB - INTRODUCTION: There has been an increasing interest in assessment of technical skills in most medical and surgical disciplines. Many of these assessments involve microscopy or endoscopy and are thus amenable to video recording for post hoc review. An ideal skills assessment video would provide the reviewer with a simultaneous view of the examinee's instrument handling and the operative field. Ideally, a reviewer should be blinded to the identity of the examinee and whether the assessment was performed as a pretest or posttest examination, when given in conjunction with an educational intervention. METHODS: We describe a simple method for reliably creating deidentified, multicamera, time-synced videos, which may be used in technical skills assessments. We pilot tested this method in a pediatric airway endoscopy Objective Assessment of Technical Skills (OSATS). Total video length was compared with the OSATS administration time. RESULTS: Thirty-nine OSATS were administered. There were no errors encountered in time syncing the videos using this method. Mean duration of OSATS videos was 11 minutes and 20 seconds, which was significantly less than the time needed for an expert to be present at the administration of each 30-minute OSATS (P < 0.001). CONCLUSIONS: The described method for creating time-synced, multicamera skills assessment videos is reliable and may be used in endosurgical or microsurgical skills assessments. Compared with live review, post hoc video review using this method can save valuable expert reviewer time. Most importantly, this method allows a reviewer to simultaneously evaluate an examinee's instrument handling and the operative field while being blinded to the examinee's identity and timing of examination administration. PMID- 21527870 TI - A randomized trial of simulation-based deliberate practice for infant lumbar puncture skills. AB - BACKGROUND: Infant lumbar puncture (LP) is mandated by the Accreditation Council for Graduate Medical Education for all pediatric trainees. Current training usually involves the apprenticeship model of "see one, do one, teach one" where a trainee's first LP attempt occurs in a high-stakes environment. Simulation training promotes skill development in a safe environment before patient contact. OBJECTIVE: To demonstrate that deliberate practice simulation-based training after audiovisual training (AV) improves infant LP skills compared with a control group receiving AV training only. DESIGN/METHODS: This was a randomized trial of simulation-based training + AV versus AV only for pediatric residents. On enrollment, the subjects' infant LP skills were evaluated through their performance on a simulator. A questionnaire and brief quiz were administered to collect information on the subjects' infant LP experience, knowledge, and confidence. All subjects viewed an educational AV presentation. The intervention group went on to participate in a simulation-based deliberate practice session on the infant LP simulator while the control group did not. Our primary outcome was self-reported clinical success on the first infant LP after training. Secondary outcomes were rates of traumatic clinical LPs, infant LP skills (measured via observed structured clinical examinations on the simulator 6 months after training), and change in participants' knowledge and confidence. RESULTS: Fifty one residents reported 32 clinical encounters. Sixteen of 17 subjects (94%) in the intervention group who performed a clinical infant LP obtained cerebrospinal fluid compared with 7 of 15 subjects (47%) in the control group (difference = 47%; 95% CI = 16%-70%). There was no difference between groups at 6 months on observed structured clinical examination performance, knowledge, or confidence. CONCLUSIONS: Participation in a simulation-based deliberate practice intervention can improve infant LP skill. PMID- 21527871 TI - Proteomic analysis reveals innate immune activity in intestinal transplant dysfunction. AB - BACKGROUND: Many patients with intestinal failure require intestinal transplantation (ITx) to survive. Acute cellular rejection poses a challenge in ITx because its biologic components are incompletely understood. New methodologies for its integrative and longitudinal analysis are needed. METHODS: In this study, we characterized episodes of acute cellular rejection in ITx recipients using a noninvasive proteomic analysis. Ostomy effluent was obtained from all patients undergoing ITx at University of California, Los Angeles from July 2008 to September 2009 during surveillance endoscopies in the first 8 weeks post-ITx. Effluent was analyzed using 17-plex Luminex technology and matrix assisted laser desorption/ionization proteomics. RESULTS: Of 56 ostomy effluent samples from 17 ITx recipients, 14% developed biopsy-proven rejection at a median of 25 days post-ITx. Six had mild rejection, two were indeterminate for rejection, and no graft loss was seen in the first 3 months posttransplantation. Effluent levels of five innate immune cytokines were elevated in the posttransplantation phase: granulocyte colony-stimulating factor, interleukin-8, tissue necrosis factor-alpha, interleukin-1beta, and interferon-gamma. Proteomic analysis revealed 17 protein features differentially seen in rejection, two identified as human neutrophil peptide 1 and 2. This was confirmed by the presence of human neutrophil peptide-positive lamina propria neutrophils in biopsy tissue samples. CONCLUSIONS: Proteomic and cytokine analysis of ostomy effluents suggests an early and unappreciated role of innate immune activation during rejection. PMID- 21527872 TI - Longer-term outcomes after kidney transplantation from seronegative deceased donors at increased risk for blood-borne viral infection. AB - BACKGROUND: Transmission of human immunodeficiency virus and hepatitis C to transplant recipients has drawn attention of the use of allografts from seronegative donors at increased risk for blood-borne viral infection (DIRVI). METHODS: We performed a cohort study of 7803 kidney transplant recipients whose kidneys were recovered through one of two organ procurement organizations from 1996 to 2007. Detailed organ procurement organization data on donor risk factors were linked to recipient data from the Organ Procurement and Transplantation Network. RESULTS: Median recipient follow-up was 3.9 years. Three hundred sixty eight (5%) patients received DIRVI kidneys, a third of which were procured from donors with a history of injection drug use or commercial sex work. Compared with standard criteria kidney recipients, DIRVI kidney recipients were more likely to be human immunodeficiency virus positive or black. In multivariable Cox regression, using DIRVI recipients as the reference, recipients of standard criteria donor kidneys had lower mortality (hazard ratio [HR] 0.71, P<0.01) and no difference in death-censored allograft failure (HR 1.09, P=0.62), whereas recipients of expanded criteria donor kidneys had no significant difference in mortality (HR 0.98, P=0.83) but a higher allograft failure rate (HR 1.93, P<0.01). High-quality data on posttransplant recipient viral testing were not available. CONCLUSIONS: DIRVI kidney recipients experienced higher mortality than standard criteria kidney recipients. This finding could be explained if sicker patients received DIRVI kidneys (i.e., residual confounding) or the less likely possibility of undetected transmission of viral infections. Given the limitations of registry data used in this analysis, prospective studies are needed to further elucidate these findings. PMID- 21527873 TI - Point of view: Q&A with Peter W. Carmel, MD, president-elect, American Medical Association. PMID- 21527874 TI - The expansion of post-traumatic stress disorder: some issues regarding diagnosis and treatment. PMID- 21527875 TI - An ongoing physician-patient relationship defines New Jersey's unique Medicinal Marijuana Program. PMID- 21527876 TI - Hospital branding in challenging and uncertain times. PMID- 21527877 TI - Gestation of a simulation training facility: the Northern New Jersey Perinatal Simulation Training Center at Saint Barnabas. PMID- 21527878 TI - Announcing the 2011 Edward J. Ill Excellence in Medicine Awards. PMID- 21527879 TI - Protecting your practice: filling the gaps. PMID- 21527880 TI - An interview with William J. O'Byrne, executive director of NJ-HITEC. Interview by Carol V. Brown. PMID- 21527881 TI - Microwave-assisted one-step synthesis of fenamic acid hydrazides from the corresponding acids. AB - A facile and efficient method for synthesis of fenamic acid hydrazides from their acids in one-step reaction under microwave irradiation and solvent-free conditions was developed. Compared with the two-step conventional heating method, the process was simple, the reaction time was very short and the yields were almost quantitative. PMID- 21527882 TI - Diterpene glycosides from Stevia rebaudiana. AB - Three novel diterpene glycosides were isolated for the first time from the commercial extract of the leaves of Stevia rebaudiana, along with several known steviol glycosides, namely stevioside, rebaudiosides A-F, rubusoside and dulcoside A. The new compounds were identified as 13-[(2-O-beta-D-glucopyranosyl 3-O-beta-D-glucopyranosyl-beta-D-glucopyranosyl)oxy] ent-kaur-15-en-19-oic acid, 13-[(2-O-beta-D-glucopyranosyl-3-O-beta-D-glucopyranosyl-beta-D glucopyranosyl)oxy]-16beta-hydroxy-ent-kauran-19-oic acid and 13-methyl-16-oxo-17 nor-ent-kauran-19-oic acid-beta-D-glucopyranosyl ester on the basis of extensive 2D NMR and MS spectroscopic data as well as chemical studies. PMID- 21527883 TI - Reduction of nitroarenes to azoxybenzenes by potassium borohydride in water. AB - The synthesis of the azoxybenzenes by the reduction of nitroarenes with reducing agent potassium borohydride in water was reported for the first time. PEG-400 was used as a phase transfer catalyst and could effectively catalyze the reduction. The electronic effects of substituent groups play an important role in determining the reduction efficiencies. Electron-withdrawing substituents promote the formation of the azoxybenzene products, while electron-releasing groups retard the reductions to various degrees depending on the extent of their electron-donating ability. PMID- 21527884 TI - Chromium (VI) ion adsorption features of chitosan film and its chitosan/zeolite conjugate 13X film. AB - This research evaluated the importance of the adsorption properties of chitosan a chitosan/zeolite conjugate film for the removal of Cr(VI) ions from solutions in the 5-260 mg/L concentration range, when the pH was adjusted to 4.0 and 6.0. The uptake capacities of the films formed by chitosan and by the chitosan/zeolite conjugate were calculated by mass balance. The equilibrium isotherms were fitted to the Langmuir, Freundlich and Redlich-Peterson models. The chitosan film seems to be a good sorbent for Cr(VI) at pH 4, but its physical instability suggests the need for a more resilient support. Due to this fact zeolite was added to the chitosan matrix in solution and a chitosan/zeolite (CS/Zeo) film was thus formed. The solubility of the film and the characterization of the different matrices by FTIR, TGA and X-Ray showed that a cross-linked structure was formed between the chitosan and zeolite and the solubility of the film increased. In this study, the low manufacturing cost of the CS/Zeo matrix, the good uptake of Cr(VI) at acidic pH (17.28 mg/g) and the non desorption of Cr(VI) from the film in water suggests this combination should be tested in industrial environment. PMID- 21527885 TI - Synthesis of some phenylpropanoid glycosides (PPGs) and their acetylcholinesterase/xanthine oxidase inhibitory activities. AB - In this research, three categories of phenylpropanoid glycosides (PPGs) were designed and synthesized with PPGs isolated from Rhodiola rosea L. as lead compounds. Their inhibitory abilities toward acetylcholinesterase (AChE) and xanthine oxidase (XOD) were also tested. Some of the synthetic PPGs exhibited excellent enzyme inhibitory abilities. PMID- 21527886 TI - Occupational highway transportation deaths --- United States, 2003--2008. AB - Highway transportation crashes are the leading cause of fatal injuries in the United States for both workers and the general population (1,2). Prevention of work-related highway transportation deaths, and highway transportation deaths in general, are long-standing public health priorities (1,3). To assess trends and help guide the prevention of occupational highway transportation deaths, CDC analyzed data from the Census of Fatal Occupational Injuries (CFOI) for 2003 2008. PMID- 21527887 TI - Nonfatal occupational injuries and illnesses among older workers --- United States, 2009. AB - Older workers (defined as those aged >= 55 years) represented 19% of the U.S. workforce in 2009* and are the nation's fastest growing segment of the working population (1). To identify occupational safety issues affecting older workers, an analysis of data from the Bureau of Labor Statistics (BLS) Survey of Occupational Injuries and Illnesses (SOII) was conducted by CDC, BLS, and several state partners. This report summarizes the results of that analysis, which indicated that, based on employer reports, an estimated 210,830 nonfatal occupational injuries and illnesses among older workers in 2009 resulted in lost workdays. Although older workers had similar or lower rates for all injuries and illnesses combined compared with younger workers, the length of absence from work increased steadily with age and was highest for older workers (medians of 11 and 12 days for workers aged 55-64 years and >= 65 years, respectively). Older workers had higher rates of falls on the same level, fractures, and hip injuries compared with younger workers and workers of all ages. Public health and research agencies should conduct research to better understand the overall burden of occupational injuries and illnesses on older workers, aging-associated risks, and effective prevention strategies. Employers and others should take steps to address specific risks for older workers such as falls (e.g., by ensuring floor surfaces are clean, dry, well-lit, and free from tripping hazardS.) PMID- 21527888 TI - Prevalence of obesity among adults with arthritis --- United States, 2003--2009. AB - Obesity and arthritis are critical public health problems with high prevalences and medical costs. In the United States, an estimated 72.5 million adults aged >= 20 years are obese, and 50 million adults have arthritis. Medical costs are estimated at $147 billion for obesity and $128 billion for arthritis each year (1 3). Obesity is common among persons with arthritis (2) and is a modifiable risk factor associated with progression of arthritis, activity limitation, disability, reduced quality-of-life, total joint replacement, and poor clinical outcomes after joint replacement (4,5). To assess obesity prevalence among adults with doctor-diagnosed arthritis, CDC analyzed data from the Behavioral Risk Factor Surveillance System (BRFSS) for the period 2003-2009. This report summarizes the results of that analysis, which determined that, among adults with arthritis, 1) obesity prevalence, on average, was 54% higher, compared with adults without arthritis, 2) obesity prevalence varied widely by state (2009 range: 26.9% in Colorado to 43.5% in Louisiana), 3) obesity prevalence increased significantly from 2003 to 2009 in 14 states and Puerto Rico and decreased in the District of Columbia (DC), and 4) the number of U.S. states with age-adjusted obesity prevalence >= 30.0% increased from 38 (including DC) in 2003 to 48 in 2009. Through efforts to prevent, screen, and treat obesity in adults, clinicians and public health practitioners can collaborate to reduce the impact of obesity on U.S. adults with arthritis. PMID- 21527889 TI - Rotavirus surveillance --- worldwide, 2009. AB - Rotavirus is the leading cause of severe diarrhea worldwide among children aged <5 years (1). An estimated 527,000 children in this age group died from rotavirus in 2004, and approximately 85% of those deaths occurred in South Asia and sub Saharan Africa (2). In 2009, the World Health Organization (WHO) recommended inclusion of rotavirus vaccination in all national immunization programs (3). Disease burden data generated from surveillance are important for making decisions regarding whether to introduce rotavirus vaccine into a country, and establishing surveillance platforms is essential to enable monitoring of vaccine impact. WHO coordinates a global surveillance network for rotavirus that uses standardized case definitions and laboratory methods at sentinel hospitals to identify cases of rotavirus in children with diarrhea. This report summarizes an assessment of data from the global surveillance network for 2009, which found that, among 43 participating countries that tested >= 100 stool specimens and reported results for all 12 months in 2009, a median of 36% of enrolled and tested children aged < 5 years hospitalized with diarrhea (range: 25%-47% among the six WHO regions) tested positive for rotavirus. These data illustrate the important etiologic role of rotavirus in hospitalizations for diarrhea in children worldwide, which can be prevented by rotavirus vaccination. PMID- 21527890 TI - County-level trends in vaccination coverage among children aged 19-35 months - United States, 1995-2008. AB - PROBLEM/CONDITION: Estimated trends in county-level vaccination coverage compared with national health objectives and associated with other variables (e.g., access to care, economic conditions, and demographic characteristics) have not been reported previously. REPORTING PERIOD: 1995-2008. DESCRIPTION OF SYSTEM: The National Immunization Survey (NIS) is an ongoing, random-digit-dialed telephone survey that gathers vaccination coverage data from households with children aged 19-35 months in 50 states and selected urban areas and territories. RESULTS: During 1995-2008, 185,336 children aged 19-35 months sampled by NIS had adequate provider data and lived in one of the 257 counties where the combined sample size for at least one of the seven biennial periods during 1995-2008 was >=35. Statistically significant increases in estimated vaccination coverage occurred in 27 of 233 counties (12%) with >=4 doses of diphtheria and tetanus toxoids and acellular pertussis (DTaP); for 38 of 233 counties (16%) with >=3 doses of polio vaccine; eight of 233 counties (3%) with >=1 dose of measles, mumps, and rubella (MMR); nine of 233 counties (4%) with >=3 doses of Haemophilus influenzae type B (Hib) vaccine; 193 of 233 counties (83%) with >=3 doses of hepatitis B vaccine; 228 of 232 counties (98%) with >=1 dose of varicella vaccine; and 187 of 192 counties (97%) with >=4 doses of 7-valent pneumococcal conjugate vaccine (PCV7). Six of 233 (2%) counties had significant decreases in vaccination coverage for Hib. During the 2007-2008 biennial period, the percentage of 193 counties with estimated vaccine coverage that achieved the Healthy People 2010 objective of 90% vaccination coverage was 8% for DTaP/DTP vaccines, 93% for polio vaccine, 86% for MMR vaccine, 71% Hib vaccine, 94% for hepatitis B vaccine, 50% for varicella vaccine, and <1% for PCV7. Among 104 counties, the estimated percentage of children aged 6-23 months who were administered >=1 dose of the seasonal influenza vaccine during the 2007-2008 influenza vaccination season was 39.0% (range: 22.2%-68.8%). For most vaccines and vaccine series, higher levels of county-level vaccination coverage correlated with a higher number of pediatricians per capita, a higher number of people living in group quarters (e.g., college residence halls, residential treatment centers, skilled nursing facilities, group homes, military barracks, correctional facilities, workers' dormitories, and facilities for persons experiencing homelessness) per capita, higher per capita income, a higher number of Hispanics per capita, and having a service-dependent economy. Lower levels of county-level vaccination coverage correlated with higher number of persons in poverty per capita, a higher percentage of black children among children aged <5 years, higher levels of housing stress (i.e., >=30% income for rent or mortgage and certain inadequate housing characteristics), a higher number of pediatric intensive care beds per capita, and designation as a nonmetropolitan county with an economy dependent on recreation activities. INTERPRETATION: During 1995-2008, significant increases in vaccination coverage for individual vaccines occurred in many counties for the newly recommended vaccines, varicella and PCV7. PUBLIC HEALTH ACTIONS: In counties that did not meet the Healthy People 2010 vaccination coverage objectives, states should evaluate strategies to achieve these objectives. The Guide to Community Preventive Services provides a summary of interventions that increase community vaccination coverage, including provider reminder-recall systems that remind parents to return to clinics to administer missed doses to children and assessment and feedback on the performance of vaccination providers. In counties where significant decreases in Hib vaccination coverage occurred, additional research is warranted to determine whether the recent shortage in the Hib vaccine was the sole cause of these decreases. In counties with a high proportion of children living in poverty, interventions to increase vaccination coverage among these children are needed. Additional research is required to understand potential barriers to increased coverage with these vaccines, the role of vaccination providers and their resource constraints, and factors associated with access to health care among children. PMID- 21527891 TI - Blood pressure and heart rate effects, weight loss and maintenance during long term phentermine pharmacotherapy for obesity. AB - There is a perception that phentermine pharmacotherapy for obesity increases blood pressure and heart rate (HR), exposing treated patients to increased cardiovascular risk. We collected data from phentermine-treated (PT) and phentermine-untreated (P0) patients at a private weight management practice, to examine blood pressure, HR, and weight changes. Records of 300 sequential returning patients were selected who had been treated with a low-carbohydrate ketogenic diet if their records included complete weight, blood pressure, and HR data from seven office examinations during the first 12 weeks of therapy. The mean time in therapy, time range, and mode was 92 (97.0), 12-624, and 52 weeks. 14% were normotensive, 52% were prehypertensive, and 34% were hypertensive at their first visit or had a previous diagnosis of hypertension. PT subjects systolic blood pressure/diastolic blood pressure (SBP/DBP) declined from baseline at all data points (SBP/DBP -6.9/-5.0 mm Hg at 26, and -7.3/-5.4 at 52 weeks). P0 subjects' declines of SBP/DBP at both 26 and 52 weeks were -8.9/-6.3 but the difference from the treated cohort was not significant. HR changes in treated/untreated subjects at weeks 26 (-0.9/-3.5) and 52 (+1.2/-3.6) were not significant. Weight loss was significantly greater in the PT cohort for week 1 through 104 (P = 0.0144). These data suggest phentermine treatment for obesity does not result in increased SBP, DBP, or HR, and that weight loss assisted with phentermine treatment is associated with favorable shifts in categorical blood pressure and retardation of progression to hypertension in obese patients. PMID- 21527892 TI - Role of sleep timing in caloric intake and BMI. AB - Sleep duration has been linked to obesity and there is also an emerging literature in animals demonstrating a relationship between the timing of feeding and weight regulation. However, there is a paucity of research evaluating timing of sleep and feeding on weight regulation in humans. The goal of this study was to evaluate the role of sleep timing in dietary patterns and BMI. Participants included 52 (25 females) volunteers who completed 7 days of wrist actigraphy and food logs. Fifty-six percent were "normal sleepers" (midpoint of <5:30 AM) and 44% were "late sleepers" (midpoint of sleep >=5:30 AM). Late sleepers had shorter sleep duration, later sleep onset and sleep offset and meal times. Late sleepers consumed more calories at dinner and after 8:00 PM, had higher fast food, full calorie soda and lower fruit and vegetable consumption. Higher BMI was associated with shorter sleep duration, later sleep timing, caloric consumption after 8:00 PM, and fast food meals. In multivariate models, sleep timing was independently associated with calories consumed after 8:00 PM and fruit and vegetable consumption but did not predict BMI after controlling for sleep duration. Calories consumed after 8:00 PM predicted BMI after controlling for sleep timing and duration. These findings indicate that caloric intake after 8:00 PM may increase the risk of obesity, independent of sleep timing and duration. Future studies should investigate the biological and social mechanisms linking timing of sleep and feeding in order to develop novel time-based interventions for weight management. PMID- 21527893 TI - A comparison of the metabolic response to abdominal obesity in two Canadian Inuit and First Nations population. AB - Inuit and Cree populations are known for high obesity rates despite markedly different rates of type 2 diabetes (T2DM). To document this apparent discrepancy we evaluated the impact of body size parameters and fasting insulin (FI) on several T2DM risk factors among Inuit and Cree populations (Quebec, Canada). A total of 1,104 adults (>=18 years) Inuit and Cree individuals participated in a cross-sectional investigation. Interestingly, across both genders, across all levels of waist circumference (WC), Inuit showed lower levels of FI (age adjusted, P < 0.0001) and fasting glucose (P < 0.0001) than Cree individuals. In both groups, a comparison of multi-sample structural equation models confirmed the predominant influence of WC on other traditional risk factors, compared to BMI. A preponderant direct impact of WC was observed on blood pressure (BP) parameters (P < 0.0001), high-density lipoprotein cholesterol (HDL-C) (P < 0.0001), and FI (P < 0.0001). Fasting glucose level appear to be influenced by WC via FI in both ethnic groups (P < 0.0001), while triacylglycerol (TAG) level was predominantly impacted by WC via FI, but only in Cree individuals (P < 0.0001). The main ethnic difference found was the strength of the impact of WC on FI, which was considerably higher among the Cree (lambda = 2.4, P < 0.0001) than the Inuit (lambda = 1.8, P < 0.0001). These results confirm the predominant role of abdominal adiposity in the complex and tenuous links of different traditional T2DM determinants. However, the ethnic difference in the impact of abdominal obesity on insulin levels across all WCs needs to be explored further. PMID- 21527894 TI - Markers of inflammation and fat distribution following weight loss in African American and white women. AB - Changes in markers of inflammation (MOI) and fat distribution with weight loss between African-American (AA) and white (W) women have yet to be characterized. The purpose of this study was to examine potential ethnic differences in MOI and regional fat distribution with weight loss, and identify the associations between these markers and changes in regional fat distribution with weight loss among AA and W women. Subjects were 126 healthy, premenopausal women, BMI 27-30 kg/m(2). They were placed on a weight-loss intervention consisting of diet and/or exercise until a BMI <25 was achieved. Fat distribution was measured with computed tomography, and body composition with dual-energy X-ray absorptiometry. Serum concentrations of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor-I (sTNFR-I), sTNFR-II, C-reactive protein (CRP), and interleukin-6 (IL-6) were assessed. All MOI and adiposity measures significantly decreased with weight loss. Significant ethnic differences with weight loss were observed for fat mass, body fat, intra-abdominal adipose tissue (IAAT), sTNFR-I, and sTNFR-II. Mixed model analysis indicated that adjusting for change in IAAT explained ethnic differences in change in TNF-alpha and the decrease in TNF-alpha with weight loss, while total fat mass only explained the decrease in sTNFR-I and sTNFR-II with weight loss. In conclusion, all MOI decreased following weight loss among W, whereas only IL-6 and CRP decreased following weight loss in AA. The most distinct phenotypic difference observed was a greater impact of weight loss on TNF-alpha in W compared to AA, which was directly associated with IAAT in W. PMID- 21527895 TI - Melanocortin receptor 4 deficiency affects body weight regulation, grooming behavior, and substrate preference in the rat. AB - Obesity is caused by an imbalance between energy intake and expenditure and has become a major health-care problem in western society. The central melanocortin system plays a crucial role in the regulation of feeding and energy expenditure, and functional loss of melanocortin receptor 4 (MC4R) is the most common genetic cause of human obesity. In this study, we present the first functional Mc4r knockout model in the rat, resulting from an N-ethyl-N-nitrosourea mutagenesis induced point mutation. In vitro observations revealed impaired membrane-binding and subsequent nonfunctionality of the receptor, whereas in vivo observations showed that functional loss of MC4R increased body weight, food intake, white adipose mass, and changed substrate preference. In addition, intracerebroventricular (ICV) administration of Agouti-Related Protein(79-129) (AgRP(79-129)), an MC4R inverse agonist, or Melanotan-II (MTII), an MC4R agonist, did affect feeding behavior in wild-type rats but not in homozygous mutant rats, confirming complete loss of MC4R function in vivo. Finally, ICV administration of MTII induced excessive grooming behavior in wild-type rats, whereas this effect was absent in homozygous mutant rats, indicating that MTII-induced grooming behavior is exclusively regulated via MC4R pathways. Taken together, we expect that the MC4R rat model described here will be a valuable tool for studying monogenic obesity in humans. More specifically, the relative big size and increased cognitive capacity of rats as compared to mice will facilitate complex behavioral studies and detailed mechanistic studies regarding central function of MC4R, both of which ultimately may help to further understand the specific mechanisms that induce obesity during loss of MC4R function. PMID- 21527896 TI - Predictors of long-term weight loss in adults with modest initial weight loss, by sex and race. AB - Effective weight management interventions could reduce race-sex disparities in cardiovascular disease (CVD), yet little is known about factors associated with successful weight loss maintenance in race-sex subgroups. In the Weight Loss Maintenance trial (WLM), overweight/obese (BMI 25-45 kg/m(2)) adults who lost >=4 kg in a 6-month behavioral weight loss intervention (phase I) were randomized into one of three 30-month maintenance interventions (phase II). To investigate predictors in subgroups, randomized groups were combined for this analysis. Of 1,685 phase I participants, 1,032 (61%) entered phase II, including 12% black men (BM), 26% black women (BW), 25% white men (WM), and 37% white women (WW). Weight change over the 36-month study ranged from -2.3% (95% confidence interval = -3.1 to -1.5%) in BW to -4.5% (95% confidence interval = -5.7 to -4.0%) in WM, the result of differential weight loss during phase I. Within race, men lost significantly more weight than women, but within sex group, weight loss did not differ significantly between races. Although participants regained weight during phase II, regain did not differ by race-sex group, and mean weight at the end of the study was significantly lower than phase I entry weight for each subgroup. In regression models, phase I weight loss predicted overall 36-month weight loss in all race-sex groups. Healthy dietary pattern at entry, improvement in dietary pattern, or both were predictive in three of four race-sex groups. Few other variables other than initial weight loss and dietary pattern were predictive. Future research should identify additional modifiable influences on long-term maintenance after a modest weight loss. PMID- 21527897 TI - A QTL for genotype by sex interaction for anthropometric measurements in Alaskan Eskimos (GOCADAN Study) on chromosome 19q12-13. AB - Variation in anthropometric measurements due to sexual dimorphism can be the result of genotype by sex interactions (G*S). The purpose of this study was to examine the sex-specific genetic architecture in anthropometric measurements in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Maximum likelihood-based variance components decomposition methods, implemented in SOLAR, were used for G*S analyses. Anthropometric measurements included BMI, waist circumference (WC), waist/height ratio, percent body fat (%BF), and subscapular and triceps skinfolds. Except for WC, mean values of all phenotypes were significantly different in men and women (P < 0.05). All anthropometric measures were significantly heritable (P < 0.001). In a preliminary analysis not allowing for G*S interaction, evidence of linkage was detected between markers D19S414 and D19S220 on chromosome 19 for WC (logarithm of odds (lod) = 3.5), %BF (lod = 1.7), BMI (lod = 2.4), waist/height ratio (lod = 2.5), subscapular (lod = 2.1), and triceps skinfolds (lod = 1.9). In subsequent analyses which allowed for G*S interaction, linkage was again found between these traits and the same two markers on chromosome 19 with significantly improved lod scores for: WC (lod = 4.5), %BF (lod = 3.8), BMI (lod = 3.5), waist/height ratio (lod = 3.2), subscapular (lod = 3.0), and triceps skinfolds (lod = 2.9). These results support the evidence of a G*S interaction in the expression of genetic effects resulting in sexual dimorphism in anthropometric phenotypes and identify the chromosome 19q12-13 region as important for adiposity-related traits in Alaskan Eskimos. PMID- 21527898 TI - Changing BMI categories and healthcare expenditures among elderly Medicare beneficiaries. AB - To examine the association between changes in BMI categories and health-care expenditures among elderly Medicare beneficiaries using longitudinal data of the Medicare Current Beneficiary Survey (MCBS) 2000-2005. Changes in BMI were (i) Stayed Normal: individuals with a normal BMI at baseline and follow-up; (ii) Stayed Overweight individuals with overweight BMI at baseline and follow-up; (iii) Stayed Obese individuals with obese BMI at baseline and follow-up; (iv) Normal-Overweight: individuals with normal BMI at baseline and overweight BMI at follow-up; (v) Overweight-Obese: individuals with overweight BMI at baseline and obese BMI at follow-up; (vi) Overweight-Normal: individuals with overweight BMI at baseline and normal BMI at follow-up; (vii) Obese-Overweight: individuals with obese BMI at baseline and overweight BMI at follow-up. Ordinary Least Squares (OLS) models on logged Year 3 expenditures were used to analyze changes in expenditures between BMI categories. Overall, 35% Stayed Normal, 34% Stayed Overweight, 18% Stayed Obese, 4% gained weight from Normal-Overweight BMI, 3% gained weight from Overweight-Obese BMI, 5% lost weight from Overweight-Normal BMI, and 3% lost weight from Obese-Overweight BMI. Adjusted models revealed those who Stayed Obese had increased total and multiple expenditure types that were significantly higher than Stayed Normal including total (11%), outpatient (25%), prescription (9%), and medical provider (4%). Compared to Stayed Normal, total expenditures were both 26% higher for Obese-Overweight and Overweight-Obese. The current findings highlight the importance of maintaining a normal BMI in the elderly. PMID- 21527900 TI - Elevated serum 25(OH)D concentrations, vitamin D, and calcium intakes are associated with reduced adipocyte size in women. AB - Recent studies have suggested a beneficial effect of vitamin D and calcium on adipocyte metabolism and the metabolic profile. Our objective was to examine associations of vitamin D intake, calcium and dairy products as well as serum 25(OH)D concentration with adiposity measures and adipocyte size in women. Omental and subcutaneous adipose tissue samples were obtained from 43 women undergoing gynecological surgeries. Adipocyte size was measured using adipocyte suspensions from collagenase-digested fat tissues. Total and visceral adiposity were assessed by dual-energy X-ray absorptiometry and computed tomography, respectively. Serum 25(OH)D was measured by radioimmmunoassay. Dietary intakes were assessed using a food frequency questionnaire. Women consuming two or more dairy product portions daily had smaller adipocytes in the omental depot compared to women consuming less than two portions daily (79 +/- 12 vs. 94 +/- 16 um, P <= 0.01). Dietary intakes of calcium (r = -0.55) and vitamin D (r = -0.43) as well as serum 25(OH)D (r = -0.35) were also inversely and significantly associated with omental adipocyte size (P <= 0.05 for all). Dietary vitamin D intake was inversely associated with visceral adipose tissue area (r = -0.34, P <= 0.05). Serum 25(OH)D was also inversely associated with visceral adipose tissue area (r = -0.32) as well as with total adipose tissue area (r = -0.44), subcutaneous adipose tissue area (r = -0.36), BMI (r =-0.43) and total body fat mass (r = 0.41, P <= 0.05 for all). In conclusion, elevated dietary vitamin D intake and serum 25(OH)D values are related to lower visceral adiposity and omental adipocyte size in women. PMID- 21527899 TI - Fasting induces an anti-inflammatory effect on the neuroimmune system which a high-fat diet prevents. AB - The neuroimmunological and behavioral consequences of a high-fat diet (HFD) are not well delineated. This is especially true when short term (24 h) fasting is used as a physiologic stressor. In this study, we examined the impact of a HFD on learning and memory and depressive-like behaviors to understand how fasting impacts neuroimmunity and whether obesity modulates the response. Mice were fed diets containing either 10% (low-fat diet (LFD) mice) or 60% (HFD mice) calories from fat for 10-12 weeks. Gene transcripts for 26 pro-/anti-inflammatory cytokines and markers of macrophage activation were examined in adipose tissue and whole brain. Mouse learning and memory (spontaneous alternation, novel object) and depressive-like behaviors (saccharin preference, burrowing, forced swim) were studied in the fed and fasted state as were gene transcripts for F4/80, CD11b, interleukin-1alpha (IL-1alpha), IL-1beta, IL-1R1, IL-1R2, IL-1RA, IL-6 and tumor necrosis factor-alpha in cortex, hippocampus and hypothalamus. In the fed state, HFD mice compared to LFD mice had reduced locomotor activity, and were adverse to saccharin and burrowed less. After fasting, LFD mice vs. HFD mice lost 18 vs. 5% of their body weight, respectively. In addition, HFD mice failed to downregulate gene transcripts for the myeloid-cell associated proteins F4/80, CD11b and IL-1alpha in the brain, failed to appropriately explore a novel object, failed to reduce locomotor activity and had increased saccharin consumption and burrowing. These data indicate that fasting induces an anti-inflammatory effect on the neuroimmune system which a HFD prevents. This breakdown appears linked to the IL-1 system because of the association of this cytokine with memory and learning. PMID- 21527902 TI - The impact of certificate of need programs on neonatal intensive care units. AB - OBJECTIVE: To determine the impact of state certificate of need programs (CON) on the number of hospitals with neonatal intensive care units (NICU) and the number of NICU beds. STUDY DESIGN: The presence of a CON program was verified from each state's department of health. Multivariable regression models determined the association between the absence of a CON program and each outcome after controlling for socioeconomic and demographic differences between states. RESULT: A total of 30 states had CON programs that oversaw NICUs in 2008. Absence of such programs was associated with more hospitals with a NICU (Rate Ratio (RR) 2.06, 95% CI 1.74 to 2.45) and NICU beds (RR 1.96, 95% CI 1.89 to 2.03) compared with states with CON legislation, and increased all-infant mortality rates in states with a large metropolitan area. CONCLUSION: There has been an erosion of CON programs that oversee NICUs. CON programs are associated with more efficient delivery of neonatal care. PMID- 21527901 TI - Early-onset neonatal sepsis: rate and organism pattern between 2003 and 2008. AB - OBJECTIVE: Organisms causing early-onset neonatal sepsis (EONS) have consistently changed over time. The distribution of organisms in EONS helps to influence the appropriate type of antibiotic prophylaxis strategy during labor and the antibiotics used in neonates with suspected sepsis. STUDY DESIGN: To compare the organisms distribution for EONS between 2003 and 2008 for infants admitted to neonatal intensive care units (NICUs) in Canada. Data were retrieved from infants with a positive bacterial blood or cerebrospinal fluid culture in the first 72 h after birth who were admitted to NICUs participating in the Canadian Neonatal Network from 2003 to 2008. Comparisons of incidence rate, demographics and causative organisms were carried out between earlier cohort (2003 to 2005) and later cohort (2006 to 2008). RESULT: A total of 405 infants had positive blood and/or cerebral spinal fluid cultures over the study period. The EONS rate was 6.8/1000 admissions (n=24969) in the earlier cohort compared with 6.2/1000 admissions (n=37484) in the later cohort (P=0.36). Rate of clinical chorioamnionitis was higher in the later cohort (38 vs 26%; P=0.02). For term infants, coagulase-negative Staphylococcus (CONS) (2.4/1000) followed by group B Streptococcus (GBS) (1.9/1000) were the most common organisms identified. For preterm infants, CONS (2.5/1000) followed by Escherichia coli (2.6/1000) were the most common organisms identified. There was a significant reduction in GBS EONS over time (P<0.01) and a trend toward an increase in other organisms. CONCLUSION: Although the rate of EONS among neonates admitted to NICUs has not changed, the pattern of infection has changed over the past 6 years. With the increased use of prophylactic antibiotics to mothers, careful surveillance of the changing trend of bacterial organisms among neonates is warranted. PMID- 21527904 TI - Non-invasive measurement of local tissue perfusion and its correlation with hemodynamic indices during the early postnatal period in term neonates. AB - OBJECTIVE: Monitoring the changes in buccal tissue oxygen saturation (StO(2)) may aid in early diagnosis of circulatory compromise. Our objective was to define the normal value of buccal StO(2) and its correlation to the middle cerebral artery (MCA) flow indices and cardiac output in healthy term infants during the first 48 h after birth. STUDY DESIGN: In this prospective study, we assessed buccal StO(2) by visible light spectroscopy and assessed the left ventricular output (LVO) and MCA flow indices by ultrasound on postnatal days 1 and 2. We enrolled 20 term neonates. The Wilcoxon-matched pairs signed-rank test and Pearson correlation were used to analyze the data. RESULT: Median (range) buccal StO(2) readings were 68% (62 to 72) on day 1 and 66% (61 to 69) on day 2 (P=0.03). A weak but significant positive correlation was found between buccal StO(2) and LVO (r=0.37, P=0.023). There was no correlation between buccal StO(2) and MCA mean velocity or pulsatility index. CONCLUSION: Under a physiological state, buccal StO(2) in resting healthy neonates is 61 to 72%, regardless of variability in systemic and cerebral blood flow. Because of its ease of use and non-invasive nature, the use of visible light spectroscopy in conditions with circulatory compromise needs to be further investigated. PMID- 21527903 TI - Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics. AB - OBJECTIVE: To examine the relationship between high-risk human leukocyte antigen (HLA) genotypes for type 1 diabetes and birth size in combination with prenatal ch aracteristics in different countries. STUDY DESIGN: Four high-risk HLA genotypes were enrolled in the Environmental determinants of Diabetes in the Young study newborn babies from the general population in Finland, Germany, Sweden and the United States. Stepwise regression analyses were used to adjust for country, parental physical characteristics and environmental factors during pregnancy. RESULT: Regression analyses did not reveal differences in birth size between the four type 1 diabetes high-risk HLA genotypes. Compared with DQ 4/8 in each country, (1) DQ 2/2 children were heavier in the United States (P=0.028) mostly explained however, by parental weight; (2) DQ 2/8 (P=0.023) and DQ 8/8 (P=0.046) children were longer in Sweden independent of parents height and as well as (3) in the United States for DQ 2/8 (P=0.023), but again dependent on parental height. CONCLUSION: Children born with type 1 diabetes high-risk HLA genotypes have comparable birth size. Longitudinal follow-up of these children should reveal whether birth size differences between countries contribute to the risk for islet autoimmunity and type 1 diabetes. PMID- 21527905 TI - Safety and efficacy of Trans-warmer mattress for preterm neonates: results of a randomized controlled trial. AB - OBJECTIVE: To compare the admission temperatures, incidence of hypothermia and discharge outcomes of preterm neonates managed with Trans-warmer mattress (TWM) initiated in the delivery room (DR) and controls. STUDY DESIGN: A prospective quasi-randomized controlled trial was performed between January and November 2009 on preterm neonates <32 weeks gestation. Infants in the intervention group were resuscitated and transported to neonatal intensive care unit (NICU) on a TWM, in addition to other measures recommended by the Neonatal Resuscitation Program. RESULT: The mean (s.d.) gestational age 28.7 (3) vs 28.7 (2.4) weeks and birth weight 1151 (407) vs 1175 (413) g) were comparable in the intervention (n=53) and control (n=49) groups. Temperature of the DR, maternal temperature, 5 min Apgar score, mode of delivery, cord pH and need for resuscitation were similar in both groups. Temperature of neonates in the DR (36.3 vs 36.0 degrees C) was also similar. Admission temperature in the NICU was significantly higher 36.2 degrees C (0.8) vs 35.7 degrees C (0.8) and incidence of hypothermia (temperatures <36 degrees C) lower in the intervention group (34 vs 57%, P<0.05). TWM use was not associated with any adverse effects. On logistic regression, low birth weight, lack of use of TWM and low DR temperature were independently associated with admission hypothermia. CONCLUSION: In this quasi-randomized controlled trial, the admission temperatures of preterm neonates on whom TWM was used were significantly higher compared to controls with a reduction in the incidence of hypothermia. A TWM initiated in the DR may be a simple efficacious method of reducing hypothermia in preterm neonates. PMID- 21527906 TI - Is a small platelet mass associated with intraventricular hemorrhage in very low birth-weight infants? AB - OBJECTIVE: We sought to determine whether, among very low-birth-weight (VLBW) neonates, the platelet mass was associated with common perinatal factors, and whether a low platelet mass in the first days following birth was associated with a higher incidence and/or severity of intraventricular hemorrhage (IVH). STUDY DESIGN: This was a cross-sectional, retrospective cohort analysis of VLBW infants admitted to a level 3 neonatal intensive care unit from June 2003 to July 2006, n=408. Platelet mass was calculated and recorded on the day of birth and for 2 consecutive days thereafter. All neonates had a screening cranial sonogram on day 4 of life. Statistical analysis included analysis of variance and Mann-Whitney U test. RESULT: Neonates born to mothers with pre-eclampsia had a smaller platelet mass (1921 fl/nl +/- 603 vs 2297 fl/nl +/- 747; P<0.01). The same was found among neonates with intrauterine growth restriction (IUGR). In contrast, neonates born after histological chorioamnionitis had a larger platelet mass (2400 fl/nl +/- 749 vs 2036 fl/nl +/- 674; P<0.01). No effect of platelet mass, measured on the day of birth, was observed related the outcomes of IVH, severe IVH or death. However, those with a platelet mass <10th percentile on the 2 subsequent days following birth were more likely to have severe IVH or death. CONCLUSION: Among VLBW neonates, pre-eclampsia and IUGR are associated with a lower platelet mass, owing to their effect on platelet count. Histological chorioamnionits is associated with a larger platelet mass. A mass <10th percentile on the days following birth was associated with severe IVH and/or death, but it remains unclear whether this is a cause of, or an effect of, the IVH. PMID- 21527907 TI - Genetic variations in fetal and maternal tumor necrosis factor-alpha and interleukin 10: is there an association with preterm birth or periventricular leucomalacia? AB - OBJECTIVE: The aim of the study was to identify whether tumor necrosis factor alpha (TNF-alpha) (-308) and interleukin (IL)-10 (-1082; -819) genotypes were associated with preterm delivery and cystic periventricular leucomalacia (PVL). STUDY DESIGN: Venous blood, buccal swabs or cord blood were collected from mother/child pairs with infants born at term (200) or preterm (106) in the presence and absence of neonatal PVL and of premature infants with PVL (7). Extracted genomic DNA served as template for determination of IL-10 (-1082), IL 10 (-819) and TNF-alpha (-308) genotypes by allele-specific PCR. RESULT: No significant difference was observed in the frequencies of IL-10 (-1082), IL-10 ( 819) and TNF-alpha (-308) genotypes in mothers or in children of term versus preterm deliveries with or without PVL. CONCLUSION: Maternal and infant IL-10 ( 1082, -819) and TNF-alpha (-308) genotypes are not indicative for an increased risk of preterm birth or the development of PVL in premature newborns. PMID- 21527908 TI - Antenatal diagnosis of congenital anomaly: a really traumatic experience? AB - OBJECTIVE: With increasing use of routine prenatal ultrasound, prenatal counseling after diagnosis of congenital malformations is frequently offered to prospective parents. We aimed to assess if the communication of diagnosis of a congenital anomaly in the fetus meets American Psychiatric Association (APA) criteria for trauma in parents. STUDY DESIGN: In the period ranging from 2003 to 2009 a preliminary investigation was conducted with 165 prospective mothers and 91 prospective fathers being interviewed after communication of diagnosis. Analysis of statements was made independently by two psychologists considering the APA definition of trauma. RESULT: A total of 145 mothers and 76 fathers experienced the communication of diagnosis in their fetus as a traumatic event. There was no correlation between type of malformation and trauma nor was there statistical difference between mother and father regarding the stressor. CONCLUSION: Communication of diagnosis of a fetal anomaly can be a traumatic event and should be dealt with consequently. Given the therapeutic value of sharing traumatic experience such practice should be encouraged as part of the consultation process. PMID- 21527909 TI - Does phenobarbital improve the effectiveness of therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy? AB - OBJECTIVE: To determine whether phenobarbital (PB) given before therapeutic hypothermia to infants with hypoxic-ischemic encephalopathy (HIE) augments the neuroprotective efficacy of hypothermia. STUDY DESIGN: Records of 68 asphyxiated infants of ?36 weeks' gestation, who received hypothermia for moderate or severe HIE were reviewed. Some of these infants received PB prophylactically or for clinical seizures. All surviving infants had later brain magnetic resonance imaging (MRI). The composite primary outcome of neonatal death related to HIE with worsening multiorgan dysfunction despite maximal treatment, and the presence of post-hypothermia brain MRI abnormalities consistent with hypoxic-ischemic brain injury, were compared between the infants who received PB before initiation of hypothermia (PB group, n=36) and the infants who did not receive PB before or during hypothermia (No PB group, n=32). Forward logistic regression analysis determined which of the pre-hypothermia clinical and laboratory variables predict the primary outcome. RESULT: The two groups were similar for severity of asphyxia as assessed by Apgar scores, initial blood pH and base deficit, early neurologic examination, and presence of an intrapartum sentinel event. The composite primary outcome was more frequent in infants from the PB group (PB 78% versus No PB 44%, P=0.006, odds ratio 4.5, 95% confidence interval 1.6 to 12.8). Multivariate analysis identified only the PB receipt before initiation of hypothermia (P=0.002, odds ratio 9.5, 95% confidence interval 2.3 to 39.5), and placental abruption to be independently associated with a worse primary outcome. CONCLUSION: PB treatment before cooling did not improve the composite outcome of neonatal death or the presence of an abnormal post-hypothermia brain MRI, but the long-term outcomes have not yet been evaluated. PMID- 21527910 TI - Chromatin: constructing the big picture. AB - Chromatin is the ensemble of genomic DNA and a large number of proteins. Various genome-wide mapping techniques have begun to reveal that, despite the tremendous complexity, chromatin organization is governed by simple principles. This review discusses the principles that drive the spatial architecture of chromatin, as well as genome-wide-binding patterns of chromatin proteins. PMID- 21527911 TI - ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity. AB - Mutations in the ClC-7/Ostm1 ion transporter lead to osteopetrosis and lysosomal storage disease. Its lysosomal localization hitherto precluded detailed functional characterization. Using a mutated ClC-7 that reaches the plasma membrane, we now show that both the aminoterminus and transmembrane span of the Ostm1 beta-subunit are required for ClC-7 Cl(-)/H(+)-exchange, whereas the Ostm1 transmembrane domain suffices for its ClC-7-dependent trafficking to lysosomes. ClC-7/Ostm1 currents were strongly outwardly rectifying owing to slow gating of ion exchange, which itself displays an intrinsically almost linear voltage dependence. Reversal potentials of tail currents revealed a 2Cl(-)/1H(+)-exchange stoichiometry. Several disease-causing CLCN7 mutations accelerated gating. Such mutations cluster to the second cytosolic cystathionine-beta-synthase domain and potential contact sites at the transmembrane segment. Our work suggests that gating underlies the rectification of all endosomal/lysosomal CLCs and extends the concept of voltage gating beyond channels to ion exchangers. PMID- 21527912 TI - Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia and associated with progressive deposition of amyloid beta-peptides (Abeta) in the brain. Abeta derives by sequential proteolytic processing of the amyloid precursor protein by beta- and gamma-secretases. Rare mutations that lead to amino-acid substitutions within or close to the Abeta domain promote the formation of neurotoxic Abeta assemblies and can cause early-onset AD. However, mechanisms that increase the aggregation of wild-type Abeta and cause the much more common sporadic forms of AD are largely unknown. Here, we show that extracellular Abeta undergoes phosphorylation by protein kinases at the cell surface and in cerebrospinal fluid of the human brain. Phosphorylation of serine residue 8 promotes formation of oligomeric Abeta assemblies that represent nuclei for fibrillization. Phosphorylated Abeta was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non phosphorylated Abeta. Phosphorylation of Abeta could represent an important molecular mechanism in the pathogenesis of the most common sporadic form of AD. PMID- 21527914 TI - An efficient factor-depleted mammalian in vitro translation system. AB - Much of the regulation of gene expression occurs at the level of protein synthesis. In addition to the canonical translation factors, a multitude of proteins and microRNAs (miRNAs) act as regulatory trans-acting factors. Mechanistic analysis of translational control benefits from functional cell-free systems that can be depleted of the responsible regulatory factors. Although antisense oligonucleotides facilitate the functional sequestration of the regulatory RNAs, immunodepletion of protein factors is technically challenging. Here we describe a simple and robust alternative protocol for the preparation of factor-depleted in vitro translation system derived from HeLa cells. The procedure relies on RNA interference-mediated knockdown of the factor of interest prior to extract preparation, and it overcomes problems with the availability and specificity of antibodies, as well as with the co-depletion of proteins associated with the factor under study. The complete procedure can normally be conducted within 1 week and carried out in parallel for multiple (candidate) factors. PMID- 21527913 TI - LMP1 association with CD63 in endosomes and secretion via exosomes limits constitutive NF-kappaB activation. AB - The ubiquitous Epstein Barr virus (EBV) exploits human B-cell development to establish a persistent infection in ~90% of the world population. Constitutive activation of NF-kappaB by the viral oncogene latent membrane protein 1 (LMP1) has an important role in persistence, but is a risk factor for EBV-associated lymphomas. Here, we demonstrate that endogenous LMP1 escapes degradation upon accumulation within intraluminal vesicles of multivesicular endosomes and secretion via exosomes. LMP1 associates and traffics with the intracellular tetraspanin CD63 into vesicles that lack MHC II and sustain low cholesterol levels, even in 'cholesterol-trapping' conditions. The lipid-raft anchoring sequence FWLY, nor ubiquitylation of the N-terminus, controls LMP1 sorting into exosomes. Rather, C-terminal modifications that retain LMP1 in Golgi compartments preclude assembly within CD63-enriched domains and/or exosomal discharge leading to NF-kappaB overstimulation. Interference through shRNAs further proved the antagonizing role of CD63 in LMP1-mediated signalling. Thus, LMP1 exploits CD63 enriched microdomains to restrain downstream NF-kappaB activation by promoting trafficking in the endosomal-exosomal pathway. CD63 is thus a critical mediator of LMP1 function in- and outside-infected (tumour) cells. PMID- 21527915 TI - Dynamic suspension culture for scalable expansion of undifferentiated human pluripotent stem cells. AB - Human pluripotent (embryonic or induced) stem cells (hPSCs) have many potential applications, not only for research purposes but also for clinical and industrial uses. While culturing these cells as undifferentiated lines, an adherent cell culture based on supportive layers or matrices is most often used. However, the use of hPSCs for industrial or clinical applications requires a scalable, reproducible and controlled process. Here we present a suspension culture system for undifferentiated hPSCs, based on a serum-free medium supplemented with interleukins and basic fibroblast growth factor, suitable for the mass production of these cells. The described system supports a suspension culture of hPSC lines, in both static and dynamic cultures. Results showed that hPSCs cultured with the described dynamic method maintained all hPSC features after 20 passages, including stable karyotype and pluripotency, and increased in cell numbers by 25 fold in 10 d. Thus, the described suspension method is suitable for large-scale culture of undifferentiated hPSCs. PMID- 21527916 TI - Generation of chemically engineered ribosomes for atomic mutagenesis studies on protein biosynthesis. AB - The protocol describes the site-specific chemical modification of 23S rRNA of Thermus aquaticus ribosomes. The centerpiece of this 'atomic mutagenesis' approach is the site-specific incorporation of non-natural nucleoside analogs into 23S rRNA in the context of the entire 70S ribosome. This technique exhaustively makes use of the available crystallographic structures of the ribosome for designing detailed biochemical experiments aiming at unraveling molecular insights of ribosomal functions. The generation of chemically engineered ribosomes carrying a particular non-natural 23S rRNA residue at the site of interest, a procedure that typically takes less than 2 d, allows the study of translation at the molecular level and goes far beyond the limits of standard mutagenesis approaches. This methodology, in combination with the presented tests for ribosomal functions adapted to chemically engineered ribosomes, allows unprecedented molecular insight into the mechanisms of protein biosynthesis. PMID- 21527917 TI - Controlling gene loss of function in newts with emphasis on lens regeneration. AB - Here we describe a protocol for gene loss of function during regeneration in newts, specifically applied to lens regeneration. Knockdown with the use of morpholinos can be achieved both in vitro and in vivo, depending on the experimental design. These methods achieve desirable levels of gene knockdown, and thus can be compared with methods developed for use in other animals, such as zebrafish. The technology has been applied to study molecular mechanisms during the process of lens regeneration by knocking down genes at specific stages and examining their effects on other genes and lens differentiation. The protocol can take a few days or up to 20 d to complete, depending on the duration of the experiment. PMID- 21527918 TI - Expressing exogenous genes in newts by transgenesis. AB - The great regenerative abilities of newts provide the impetus for studies at the molecular level. However, efficient methods for gene regulation have historically been quite limited. Here we describe a protocol for transgenically expressing exogenous genes in the newt Cynops pyrrhogaster. This method is simple: a reaction mixture of I-SceI meganuclease and a plasmid DNA carrying a transgene cassette flanked by the enzyme recognition sites is directly injected into fertilized eggs. The protocol achieves a high efficiency of transgenesis, comparable to protocols used in other animal systems, and it provides a practical number of transgenic newts (~20% of injected embryos) that survive beyond metamorphosis and that can be applied to regenerative studies. The entire protocol for obtaining transgenic adult newts takes 4-5 months. PMID- 21527919 TI - Analysis of methanotroph community composition using a pmoA-based microbial diagnostic microarray. AB - Microbial diagnostic microarrays (MDMs) are highly parallel hybridization platforms containing multiple sets of immobilized oligonucleotide probes used for parallel detection and identification of many different microorganisms in environmental and clinical samples. Each probe is approximately specific to a given group of organisms. Here we describe the protocol used to develop and validate an MDM method for the semiquantification of a range of functional genes- in this case, particulate methane monooxygenase (pmoA)--and we give an example of its application to the study of the community structure of methanotrophs and functionally related bacteria in the environment. The development and validation of an MDM, following this protocol, takes ~6 months. The pmoA MDM described in detail comprises 199 probes and addresses ~50 different species-level clades. An experiment comprising 24 samples can be completed, from DNA extraction to data acquisition, within 3 d (12-13 h bench work). PMID- 21527920 TI - Characterization of bacterial spore germination using phase-contrast and fluorescence microscopy, Raman spectroscopy and optical tweezers. AB - This protocol describes a method combining phase-contrast and fluorescence microscopy, Raman spectroscopy and optical tweezers to characterize the germination of single bacterial spores. The characterization consists of the following steps: (i) loading heat-activated dormant spores into a temperature controlled microscope sample holder containing a germinant solution plus a nucleic acid stain; (ii) capturing a single spore with optical tweezers; (iii) simultaneously measuring phase-contrast images, Raman spectra and fluorescence images of the optically captured spore at 2- to 10-s intervals; and (iv) analyzing the acquired data for the loss of spore refractility, changes in spore specific molecules (in particular, dipicolinic acid) and uptake of the nucleic acid stain. This information leads to precise correlations between various germination events, and takes 1-2 h to complete. The method can also be adapted to use multi-trap Raman spectroscopy or phase-contrast microscopy of spores adhered on a cover slip to simultaneously obtain germination parameters for multiple individual spores. PMID- 21527921 TI - OLIG gene targeting in human pluripotent stem cells for motor neuron and oligodendrocyte differentiation. AB - Pluripotent stem cells can be genetically labeled to facilitate differentiation studies. In this paper, we describe a gene-targeting protocol to knock in a GFP cassette into key gene loci in human pluripotent stem cells (hPSCs), and then use the genetically tagged hPSCs to guide in vitro differentiation, immunocytochemical and electrophysiological profiling and in vivo characterization after cell transplantation. The Olig transcription factors have key roles in the transcription regulatory pathways for the genesis of motor neurons (MNs) and oligodendrocytes (OLs). We have generated OLIG2-GFP hPSC reporter lines that reliably mark MNs and OLs for monitoring their sequential differentiation from hPSCs. The expression of the GFP reporter recapitulates the endogenous expression of OLIG genes. The in vitro characterization of fluorescence-activated cell sorting-purified cells is consistent with cells of the MN or OL lineages, depending on the stages at which they are collected. This protocol is efficient and reliable and usually takes 5-7 months to complete. The genetic tagging-differentiation methodology used herein provides a general framework for similar work for differentiation of hPSCs into other lineages. PMID- 21527922 TI - Purification and direct transformation of epithelial progenitor cells from primary human prostate. AB - Epithelial cell transformation has been demonstrated in numerous animal models for the study of solid tumor biology. However, little evidence exists for human epithelial cell transformation without previous immortalization via genetic influences such as SV40 T-antigen, thus limiting our knowledge of the events that can transform naive human epithelium. Here we describe a system developed in our laboratory to directly transform freshly isolated primary human prostate epithelial cells without previous culture or immortalization. Prostate tissue is obtained from patients and benign tissue is separated from malignant tissue. Benign and malignant tissues are mechanically and enzymatically dissociated to single cells overnight, and immune cells and epithelial subsets are isolated on the basis of differential expression of surface antigens. Epithelial progenitor cells are transduced with lentiviruses expressing oncogenes and combined with inductive stroma for in vivo studies. At 8-16 weeks after transplantation into immune-deficient mice, the development of lesions, histologically classified as benign prostate, prostatic intraepithelial neoplasia and adenocarcinoma, can be evaluated. PMID- 21527923 TI - Rapid isolation of antigen-specific antibody-secreting cells using a chip-based immunospot array. AB - Here we report a new method for isolating antigen-specific antibody-secreting cells (ASCs) using a microwell array chip, which offers a rapid, efficient and high-throughput (up to 234,000 individual cells) system for the detection and retrieval of cells that secrete antibodies of interest on a single-cell basis. We arrayed a large population of lymphoid cells containing ASCs from human peripheral blood on microwell array chips and detected spots with secreted antibodies. This protocol can be completed in less than 7 h, including 3 h of cell culture. The method presented here not only has high sensitivity and specificity comparable with enzyme-linked immunospot (ELISPOT) but it also overcomes the limitations of ELISPOT in recovering ASCs that can be used to produce antigen-specific human monoclonal antibodies. This method can also be used to detect cells secreting molecules other than antibodies, such as cytokines, and it provides a tool for cell analysis and clinical diagnosis. PMID- 21527924 TI - Chemical toxicity testing in vitro using cytochrome P450-expressing cell lines, such as human CYP1B1. AB - This protocol describes how to use cytochrome P450-dependent monooxygenase (CYP) expressing cell lines in toxicity testing of chemicals in vitro. Selected cells amenable to permanently grow in culture are genetically manipulated to stably express single CYP enzymes originating from any species of interest. This expression can be characterized by, for example, determining CYP mRNA content, CYP protein level (western blotting or in situ immunofluorescence) and CYP mediated enzyme activity (substrate conversion assays). These cells can be used to determine substrate specificities and species differences, e.g., in the bioactivation of drugs. Once constructed, CYP-expressing cells can serve as a straightforward and reliable tool in toxicity testing and the corresponding assays could be adapted for high-throughput analysis. Using these cells, enzyme assays can be performed in a matter of hours. This protocol is exemplified with V79 fibroblasts from Chinese hamster (Cricetulus griseus), modified to express human cytochrome P450 1B1 (CYP1B1). These cells are characterized for their CYP1B1-linked properties by in situ immunofluorescence and their activity in the 7-ethoxyresorufin-O-deethylase enzyme assay. This is followed by an assay showing metabolic activation of the polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene by CYP1B1, along with the toxicological endpoints of cytotoxicity and micronucleus formation. PMID- 21527925 TI - Scalable expansion of human pluripotent stem cells in suspension culture. AB - Routine commercial and clinical applications of human pluripotent stem cells (hPSCs) and their progenies will require increasing cell quantities that cannot be provided by conventional adherent culture technologies. Here we describe a straightforward culture protocol for the expansion of undifferentiated human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) in suspension culture. This culture technique was successfully tested on two hiPSC clones, three hESC lines and on a nonhuman primate ESC line. It is based on a defined medium and single-cell inoculation, but it does not require culture preadaptation, use of microcarriers or any other matrices. Over a time course of 4-7 d, hPSCs can be expanded up to sixfold. Preparation of a high-density culture and its subsequent translation to scalable stirred suspension in Erlenmeyer flasks and stirred spinner flasks are also feasible. Importantly, hPSCs maintain pluripotency and karyotype stability for more than ten passages. PMID- 21527926 TI - PhymmBL expanded: confidence scores, custom databases, parallelization and more. PMID- 21527928 TI - Shining a new light into molecular workings. PMID- 21527929 TI - Keeping things simple. PMID- 21527930 TI - High-content screening: getting more from less. PMID- 21527931 TI - Two-photon absorption properties of fluorescent proteins. AB - Two-photon excitation of fluorescent proteins is an attractive approach for imaging living systems. Today researchers are eager to know which proteins are the brightest and what the best excitation wavelengths are. Here we review the two-photon absorption properties of a wide variety of fluorescent proteins, including new far-red variants, to produce a comprehensive guide to choosing the right fluorescent protein and excitation wavelength for two-photon applications. PMID- 21527932 TI - Bmi1 is essential for leukemic reprogramming of myeloid progenitor cells. AB - The polycomb group (PcG) proteins, particularly Bmi1, have an essential role in maintaining the self-renewing capacity of leukemic stem cells (LSCs). Although one of their major targets in LSCs is known to be the Ink4a/Arf tumor suppressor gene locus, the role of PcG proteins in the leukemic reprogramming of target cells into LSCs is not well characterized. In this study, Bmi1(-/-) granulocyte/macrophage progenitors (GMPs) were transformed with the leukemic fusion gene MLL-AF9. Although Bmi1 was not essential to the immortalization of GMPs in vitro, Bmi1(-/-) cells showed enhanced differentiation and retained less LSCs. A number of genes were derepressed in the absence of Bmi1 including potential tumor suppressor genes. Transplantation assays demonstrated that Bmi1 was indispensable for the development of leukemia in vivo and deletion of both the Ink4a and Arf genes only partially restored the leukemogenic capacity of Bmi1(-/-) LSCs. Of note, the complementation of immortalized Bmi1(-/-)Ink4a-Arf( /-) GMPs with Bmi1 failed to restore the expression of the majority of deregulated genes and leukemogenic activity in vivo. These findings indicate that Bmi1 is essential for the faithful reprogramming of myeloid progenitors into LSCs and unveil that leukemic fusion genes require PcG proteins exerting an effect in concert to establish LSC-specific transcriptional profiles, which confer full leukemogenic activity on LSCs. PMID- 21527933 TI - Stem cell self-renewal: lessons from bone marrow, gut and iPS toward clinical applications. AB - The hematopoietic stem cell (HSC) is the prototype organ-regenerating stem cell (SC), and by far the most studied type of SC in the body. Currently, HSC-based therapy is the only routinely used SC therapy; however, advances in the field of embryonic SCs and induced pluripotent SCs may change this situation. Interest into in vitro generation of HSCs, including signals for HSC expansion and differentiation from these more primitive SCs, as well as advances in other organ specific SCs, in particular the intestine, provide promising new applications for SC therapies. Here, we review the basic principles of different SC systems, and on the basis of the experience with HSC-based SC therapy, provide recommendations for clinical application of emerging SC technologies. PMID- 21527934 TI - Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. AB - This systematic review and meta-analysis compared the efficacy and toxicity of dexamethasone (DEX) versus prednisone (PRED) for induction therapy in childhood acute lymphoblastic leukemia (ALL). We searched biomedical literature databases and conference proceedings for randomized controlled trials comparing DEX and PRED during induction therapy for childhood ALL. A total of eight studies were eligible for inclusion in this meta-analysis. DEX, in comparison with PRED, reduced events (that is, death from any cause, refractory or relapsed leukemia, or second malignancy; risk ratio (RR) 0.80; 95% confidence interval (CI), 0.68 0.94) and central nervous system relapse (RR 0.53; 95% CI, 0.44-0.65), but did not alter bone marrow relapse (RR 0.90; 95% CI, 0.69-1.18) or overall mortality (RR 0.91; 95% CI, 0.76-1.09). Patients receiving DEX had a higher risk of mortality during induction (RR 2.31; 95% CI, 1.46-3.66), neuro-psychiatric adverse events (RR 4.55; 95% CI, 2.45-8.46) and myopathy (RR 7.05; 95% CI, 3.00 16.58). There was no statistically significant difference in the risk of osteonecrosis, sepsis, fungal infection, diabetes or pancreatitis. DEX in induction therapy for children with ALL is more efficacious than PRED. However, DEX is also associated with more toxicity, and currently it remains unclear whether short-term superiority of DEX will also result in better overall survival. PMID- 21527935 TI - Acute lymphoblastic leukemia cells treated with CpG oligodeoxynucleotides, IL-4 and CD40 ligand facilitate enhanced anti-leukemic CTL responses. AB - Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the majority of patients initially respond to upfront chemotherapy, relapses with poor prognosis occur in approximately 20% of cases. Thus, novel therapeutic strategies are required to improve long-term survival. B-cell precursor (BCP)-ALL cells express low levels of immunogenic molecules and, therefore, are poorly recognized by the immune system. In the present study, we investigated the effect of various combinations of potent B-cell stimulators including CpG, Interleukin (IL)-2 family cytokines and CD40 ligand (CD40L) on the immunogenicity of primary BCP-ALL cells and a series of BCP-ALL cell lines. The combination of CpG, IL-4 and CD40L was identified as most effective to enhance expression of immunogenic molecules on BCP-ALL cells, resulting in an increased capacity to induce both allogeneic and autologous cytotoxic T lymphocytes (CTL). Importantly, such CTL exhibited significant anti-leukemic cytotoxicity not only towards treated, but also towards untreated BCP-ALL cells. Our results demonstrate that the combination of CpG with other B-cell stimulators is more efficient than CpG alone in generating immunogenic BCP-ALL cells and anti leukemic CTL. Our results may stimulate the development of novel adoptive T cell transfer approaches for the management of BCP-ALL. PMID- 21527936 TI - Role of autophagy in disease resistance and hypersensitive response-associated cell death. AB - Ancient autophagy pathways are emerging as key defense modules in host eukaryotic cells against microbial pathogens. Apart from actively eliminating intracellular intruders, autophagy is also responsible for cell survival, for example by reducing the deleterious effects of endoplasmic reticulum stress. At the same time, autophagy can contribute to cellular suicide. The concurrent engagement of autophagy in these processes during infection may sometimes mask its contribution to differing pro-survival and pro-death decisions. The importance of autophagy in innate immunity in mammals is well documented, but how autophagy contributes to plant innate immunity and cell death is not that clear. A few research reports have appeared recently to shed light on the roles of autophagy in plant-pathogen interactions and in disease-associated host cell death. We present a first attempt to reconcile the results of this research. PMID- 21527937 TI - miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. AB - We examined the effect of reactive oxygen species (ROS) on MicroRNAs (miRNAs) expression in endothelial cells in vitro, and in mouse skeletal muscle following acute hindlimb ischemia. Human umbilical vein endothelial cells (HUVEC) were exposed to 200 MUM hydrogen peroxide (H(2)O(2)) for 8 to 24 h; miRNAs profiling showed that miR-200c and the co-transcribed miR-141 increased more than eightfold. The other miR-200 gene family members were also induced, albeit to a lower level. Furthermore, miR-200c upregulation was not endothelium restricted, and occurred also on exposure to an oxidative stress-inducing drug: 1,3-bis(2 chloroethyl)-1nitrosourea (BCNU). miR-200c overexpression induced HUVEC growth arrest, apoptosis and senescence; these phenomena were also induced by H(2)O(2) and were partially rescued by miR-200c inhibition. Moreover, miR-200c target ZEB1 messenger RNA and protein were downmodulated by H(2)O(2) and by miR-200c overexpression. ZEB1 knockdown recapitulated miR-200c-induced responses, and expression of a ZEB1 allele non-targeted by miR-200c, prevented miR-200c phenotype. The mechanism of H(2)O(2)-mediated miR-200c upregulation involves p53 and retinoblastoma proteins. Acute hindlimb ischemia enhanced miR-200c in wild type mice skeletal muscle, whereas in p66(ShcA -/-) mice, which display lower levels of oxidative stress after ischemia, upregulation of miR-200c was markedly inhibited. In conclusion, ROS induce miR-200c and other miR-200 family members; the ensuing downmodulation of ZEB1 has a key role in ROS-induced apoptosis and senescence. PMID- 21527938 TI - HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis. AB - Of critical importance in the stress response is the post-transcriptional control of the expression of important genes involved in the control of cell survival and apoptosis. Here we report that miR-19, an oncogenic component of the miR-17 92/Oncomir-1 microRNA polycistron, regulates the expression of Ras homolog B (RhoB) in keratinocytes upon exposure to ultraviolet (UV) radiation. Strikingly, we could not find any evidence for deregulated expression of miR-19 during UV treatment. However, we show that miR-19-mediated regulation of antiapoptotic RhoB expression requires the binding of human antigen R (HuR), an AU-rich element binding protein, to the 3'-untranslated region of the rhoB mRNA. We propose that the loss of the interdependent binding between HuR and miR-19 to the rhoB mRNA upon UV exposure relieves this mRNA from miR-19-dependent inhibition of translation and contributes to the apoptotic response. PMID- 21527942 TI - Tubular biomarkers to assess progression of diabetic nephropathy. AB - Despite aggressive management, many patients with diabetic nephropathy still develop end-stage renal disease. Accompanying tubulointerstitial damage is important in the progression of diabetic nephropathy. Markers of tubular damage, such as NGAL, KIM-1, and LFABP, have been proposed for monitoring the effectiveness of therapy. However, Nielsen et al. report a lack of an independent correlation between these biomarkers and glomerular filtration rate. Therefore, these markers seem to offer no improvement in the management of diabetic nephropathy. PMID- 21527943 TI - Phosphate, oxidative stress, and nuclear factor-kappaB activation in vascular calcification. AB - Phosphate-induced vascular calcification, characterized by induction of osteogenic programs, mineral vesicle release, and apoptosis, is prevalent in patients with kidney disease. Zhao et al. provide a mechanistic link between phosphate-induced calcification and increased mitochondrial membrane potential, increased mitochondrial reactive oxygen species, activation of the nuclear factor kappaB pathway, and subsequent expression of osteogenic genes and vascular mineralization. This link clarifies the intracellular mechanism of vascular calcification and may allow exploration of antioxidants as therapeutic agents for vascular calcification. PMID- 21527944 TI - How to use biomarkers efficiently in acute kidney injury. AB - We discuss the performance of novel biomarkers in acute kidney injury (AKI). Comparison of the areas under the receiver operating characteristic curves of several biomarkers with some clinical and/or routine biochemical outcome parameters reveals that none of the biomarkers has demonstrated a clear additional value beyond the traditional approach in clinical decision making in patients with AKI. Unscrutinized use of these biomarkers may distract from adequate clinical evaluation and carries the risk of worse instead of better patient outcome. PMID- 21527945 TI - Meta-analyses and the art of medicine: strange bedfellows? PMID- 21527946 TI - Waist circumference and mortality in dialysis patients: steps to go. PMID- 21527949 TI - Microfilariae-associated nephrotic range proteinuria. PMID- 21527950 TI - Neuronal networks: networking in the visual cortex. PMID- 21527951 TI - Stem Cells: Zooming in on schizophrenia. PMID- 21527952 TI - Autophagy: shaping the fate of mitochondria. PMID- 21527954 TI - Evaluation of the motion of surgical instruments during intraocular surgery. AB - PURPOSE: Robot assistance in ocular microsurgery could improve precision, dexterity, save time or prevent complications by task automation, and provide access to ocular surgery in undeserved countries by teleoperation. However, to design robotic devices, the range of motion of surgical instruments needs to be precisely quantified. METHODS: An electromagnetic tracking system was developed for intraocular surgery in order to quantify the movements of ophthalmic surgeons. Kinematics of surgical steps during phacoemulsification and pars plana vitrectomy procedures were determined by measuring the maximum translation and angular range of motion of intraocular surgical tools in the three planes. CONCLUSION: Important variations in amplitudes of rotation and translation were measured between both hands and between surgical tasks. These parameters may be used to develop a robotic intraocular surgical system or to improve training. PMID- 21527953 TI - Mitotic catastrophe: a mechanism for avoiding genomic instability. AB - The improper distribution of chromosomes during mitosis compromises cellular functions and can reduce cellular fitness or contribute to malignant transformation. As a countermeasure, higher eukaryotes have developed strategies for eliminating mitosis-incompetent cells, one of which is mitotic catastrophe. Mitotic catastrophe is driven by a complex and poorly understood signalling cascade but, from a functional perspective, it can be defined as an oncosuppressive mechanism that precedes (and is distinct from) apoptosis, necrosis or senescence. Accordingly, the disruption of mitotic catastrophe precipitates tumorigenesis and cancer progression, and its induction constitutes a therapeutic endpoint. PMID- 21527955 TI - X-linked retinoschisis maculopathy treated with topical dorzolamide, and relationship to genotype. AB - PURPOSE: To correlate the response of topical dorzolamide (Trusopt; Merck) in patients with X-linked retinoschisis (XLRS) with genotype. METHODS: We carried out a retrospective evaluation of four patients (seven eyes) with XLRS, treated with topical dorzolamide. The change in best-corrected visual acuity (VA) and central macular thickness (CMT; central 1 mm subfield thickness) from optical coherence tomography (OCT) was analysed over the follow-up period, using Student's t-test. Each patient also had genetic analysis for mutations in the retinoschisisgene (RS1). RESULTS: The mean age at the start of treatment was 14.7+/-11 years, and mean follow-up duration was 21.7+/-7.7 months. Mean CMT at the final follow-up was significantly better than at baseline (291+/-123 vs 352+/ 119 MUm, P=0.007); however, mean VA was worse (0.38+/-0.25 vs 0.31+/-0.24 logMAR score, P=0.041). All four patients had a mutation in the RS1gene; there was no apparent association between the type of mutation and the response to topical dorzolamide. CONCLUSION: Topical dorzolamide may have some effect in reducing central macular thickness in patients with XLRS, but this does not necessarily correlate with improvement in VA. In our case series, genotypic information did not predict the response to this treatment. PMID- 21527956 TI - Avulsed retinal vessels accompanying posterior vitreous detachment: a late complication of retinopathy of prematurity. PMID- 21527957 TI - A review of safety incidents in England and Wales for vascular endothelial growth factor inhibitor medications. AB - PURPOSE: To learn from patient safety incidents (PSIs) following recent introduction of vascular endothelial growth factor inhibitor medications (anti VEGF) in ophthalmic care, as reported via a national incident reporting database. METHODS: Thematic retrospective review of anti-VEGF medications PSIs as reported via clinical incident reporting methods in NHS care in England and Wales from 2003 to 2010, ascertained from database mining at the National Patient Safety Agency (NPSA). RESULTS: In all, 166 relevant anti-VEGF incidents were reported. Reports have increased year on year from 2006. Incident severity as reported: 10 were reported as 'severe harm' and 23 as 'moderate harm'. The remainder were 'low' or 'no harm' events. The incident themes and/or causes found and by order of severity included: intra-ocular inflammation/endophthalmitis (n=16); treatment or follow-up delays (n=45); wrong medication (n=26); wrong eye/patient injection (n=17); missing records (n=12). Other problems included medication availability and refrigeration failures. We reflect on potential solutions for addressing the matters found. Systemic safety matters, stroke, subdural hemorrhage, and myocardial infarction (total n=3) followed anti-VEGF treatments. CONCLUSION: Although infrequent, anti-VEGF medication PSIs or errors do occur and are thus a threat to quality. This review also provides supporting evidence to existing concerns and challenges surrounding age-related macular degeneration service pressures and provision. Lessons for improvement of care from a national incident reporting database for a frequently undertaken and recently introduced ophthalmic procedure were found. Suggestions are proposed for improving quality by reducing such problems based on analysis of such reports. Endophthalmitis reports following intra-vitreal injections suggest rigorous infection control measures are required. PMID- 21527958 TI - The analysis of lacquer crack in the assessment of myopic choroidal neovascularization. AB - OBJECTIVE: The aim of this study was to clarify the characteristic findings in myopic choroidal neovascularization (CNV) and the relationship with lacquer crack (LC). METHODS: In all, 66 consecutive myopic CNV patients treated with photodynamic therapy and/or intravitreal anti-vascular endothelial growth factor injection in one eye were reviewed. Data from fluorescein angiography (FA) and indocyanine green angiography (ICGA), obtained simultaneously using the Heidelberg retina angiograph 2 (HRA2), were analyzed. RESULTS: LCs were associated with a relatively large extent (>=3000 MUm) of peripapillary choroidal atrophy and a dark rim, the proliferation of retinal pigment epithelial cells surrounding the neovascular membrane was accompanied by a small extent. Myopic CNV usually developed in the LC area surrounded by tiny crack fragments. In all, 35 patients with LCs received FA and ICGA at least twice during follow-up. LC progression was observed in nine (25.7%) treated eyes and six (23.1%) non-CNV fellow eyes. Crack fragments progressed in three distinct forms such as elongation, branching, or bridging pattern. Newly diagnosed myopic CNV was reported in 18 treated eyes and 3 fellow eyes. Progression of LCs and development of CNV occurred simultaneously in eight eyes. By multivariate Cox's regression, a statistically significant association was observed between recurrence of myopic CNV and the absence of a dark rim on ICGA. CONCLUSIONS: The HRA2 instrument affords detailed high-resolution images of FA and ICGA. Notably, recurrence of myopic CNV developed in areas surrounded by new small crack fragments and LCs are considered to be important in the development of myopic CNV. PMID- 21527959 TI - Increased intraocular pressure on the first postoperative day following resident performed cataract surgery. AB - PURPOSE: The aim of this study was to investigate the incidence of intraocular pressure (IOP) elevation after resident-performed cataract surgery and to determine variables, which influence postoperative day 1 (POD1) IOP. METHODS: In all, 1111 consecutive cataract surgeries performed only by training residents between 1 July 2001 and 30 June 2006 were included. Elevated IOP was defined as >=23 mm Hg. Surgeries were classified according to the presence of POD1-IOP elevation. Fisher's exact test and Student t-test were used to compare both groups. Multivariate analyses using generalized estimating equations were performed to investigate predictor variables associated with POD1-IOP elevation. RESULTS: The average preoperative IOP was 16.0+/-3.2 mm Hg and the average POD1 IOP was 19.3+/-7.1 mm Hg, reflecting a significant increase in IOP (P<0.001, paired t-test). The incidence of POD1-IOP elevation >=23 mm Hg was 22.0% (244/1111). Presence of glaucoma and ocular hypertension, higher preoperative IOP, and longer axial length were frequently encountered variables in the POD1 IOP elevation group (all P<0.05). Using a multivariate analysis, presence of glaucoma (P=0.004, OR=2.38; 95% confidence interval (95% CI)=1.31-4.30), presence of ocular hypertension (P=0.003, OR=6.09; 95% CI=1.81-20.47), higher preoperative IOP (P<0.001, OR=3.73; 95% CI=1.92-7.25), and longer axial length (P=0.01, OR=1.15; 95% CI=1.03-1.29) were significant predictive factors for POD1-IOP elevation. CONCLUSIONS: IOP elevation on the first postoperative day following resident-performed cataract surgery occurred frequently (22.0%). Increased early postoperative IOP was associated with presence of glaucoma and ocular hypertension, higher preoperative IOP, and longer axial length. PMID- 21527961 TI - [Burnout syndrome among medical residents during the influenza A H1N1 sanitary contigency in Mexico]. AB - OBJECTIVE: To measure the degree of stress among medical residents at a Third Level Hospital in Mexico City during the sanitary contingency caused by the AH1N1 influenza virus. METHODS: A transversal descriptive study with a non probabilistic sample of 99 medical residents with different fields of specialization related to respiratory medicine. Researchers applied the Maslach Burnout Inventory questionnaire to evaluate three dimensions: emotional fatigue, depersonalization, and personal fulfillment. The survey was self-administered and anonymous, and the study was conducted during the first AH1N1 influenza virus outbreak (April 23 to May 10, 2009). During that period, the hospital underwent a process of reorganization that included cancelling vacation periods for all medical residents and adjusting duty rosters. RESULTS: The highest proportion of medical residents with burnout syndrome was those in their second year of specialization in the area of pneumology. Results also showed that medical residents under 30 years of age had a higher probability of presenting burnout syndrome. No significant differences were found regarding the residents' place of origin. PMID- 21527960 TI - Optic neuritis. AB - AIMS: The aim of this study is to provide a clinical update on optic neuritis (ON), its association with multiple sclerosis (MS), and neuromyelitis optica (NMO). METHODS: This study included a PubMed review of the literature written in the English language. RESULTS: ON in adults is typically idiopathic or demyelinating, and is characterised by unilateral, subacute, painful loss of vision that is not associated with any systemic or other neurological symptoms. Demyelinating ON is associated with MS, and we review the key studies of ON including the ON treatment trial and several other MS treatment trials and NMO. CONCLUSION: Acute demyelinating ON can occur in isolation or be associated with MS. Typical ON does not require additional evaluation other than cranial magnetic resonance imaging. NMO is likely a separate disorder from MS and the ON in NMO has a different treatment and prognosis. METHODOLOGY: The authors conducted an English language search using Pubmed from the years 1964 to 2010 using the search terms 'ON', 'MS' and 'NMO'. The authors included original articles, review articles, and case reports, which revealed new aspects as far as epidemiology, histopathology, clinical manifestations, imaging, genetics, and treatment of ON. Titles were reviewed for topicality and full references were obtained. Letters to the editor, unpublished work, and abstracts were not included in this review. PMID- 21527962 TI - [Videofluoroscopic evaluation of adenoid hypertrophy and velopharyngeal closure during speech]. AB - BACKGROUND: Adenoid hypertrophy is a common cause of upper airway obstruction in children. Traditionally, adenoid size has been evaluated using a conventional lateral skull film. Flexible endoscopy is now the gold standard for the evaluation of the upper airway. In small children, this study is not always adequately tolerated. OBJECTIVE: Determine specificity and sensitivity of videofluoroscopy for evaluating adenoid size and velopharyngeal closure during speech, as compared with lateral skull film, using videonasopharyngoscopy as gold standard. METHODS: Prospective study analyzing 70 patients with clinical data of upper airway obstruction, ages 5-10 years old. Videofluoroscopy, videonasopharyngoscopy, and lateral skull film were performed in all cases. Patients were divided into children with and without adenoid hypertrophy. Specificity, sensitivity, and predictive values were calculated. Also, data concerning comfort during the three procedures were obtained. RESULTS: Videofluoroscopy showed sensitivity of 100% and specificity of 93%. Lateral skull film showed sensitivity of 70% and specificity of 52%. A Spearman correlation coefficient demonstrated a significant correlation (p < 0.05) between videofluoroscopy and videonasopharyngoscopy. A non-significant correlation was found between lateral skull film and videonasopharyngoscopy. Parents or legal guardians considered the lateral skull film as a comfortable procedure. Seventy one percent of the parents considered videofluoroscopy as a comfortable procedure and 29% reported "mild discomfort". Ten percent evaluated videonasopharyngoscopy as "extremely uncomfortable". The rest reported "minor" and "moderate" discomforts. CONCLUSIONS: Videofluoroscopy seems a reliable method without serious complications for evaluating adenoid hypertrophy and velopharyngeal closure in children,besides being a well-tolerated procedure. PMID- 21527963 TI - [Relationship between the ankle-arm index determined by Doppler ultrasonography and cardiovascular outcomes and amputations, in a group of patients with type 2 diabetes mellitus from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran]. AB - BACKGROUND: An ankle/arm index < 0.90 and >= 1.41 is considered as abnormal. This study was aimed to investigate the prevalence of peripheral arterial disease through the identification of the ankle/arm index using Doppler ultrasound, and the possible association between pathological ankle/arm index and the micro- and macrovascular complications of diabetes and amputation. METHODS: The ankle/arm index was determined in outpatient type 2 diabetic subjects. There were the following variables: age and cardiovascular outcomes. To find if the ankle/arm index is related to the cardiovascular outcomes or with the presence of micro- or macrovascular complications we determined the index of correlation of Pearson and also used logistic regression methods to analyze the association between ankle/arm index with the categorical variables. RESULTS: We calculated the ankle/arm index in 242 patients. The prevalence of ischemic ankle/arm index (< 0.90) was 13.6%. The Pearson correlation coefficient for ankle/arm index pathological and cardiovascular outcomes was 0.180 (p = 0.005), amputation 0.130 (p < 0.05), retinopathy 0.132 (p < 0.05), and nephropathy 0.158 (p = 0.01). In logistic regression analysis, the factors associated with pathological ankle/arm index were age > 51 years, cardiovascular outcomes, and amputation. With the Mann Whitney U test we found that a relationship exists between pathological and amputation iliotibial band (p < 0.05). CONCLUSIONS: Diabetic patients have a high prevalence of pathological ankle/arm index. PMID- 21527965 TI - [The curriculum of the faculty of medicine in the XXI century]. PMID- 21527964 TI - [Microbiology of the diabetic foot: is the swab culture useful?]. AB - BACKGROUND: The microbiology of the diabetic foot is complex, making swab culture controversial; biopsy culture is the gold standard. OBJECTIVE: To determine the diagnostic utility of swab culture in diabetic foot ulcers. METHODS: Comparative study of diagnostic utility. Diabetic foot ulcers were classified according to the University of Texas scale. Cultures by biopsy and swabbing were performed. Bacterial identification was performed by standard biochemical methods. Antimicrobial susceptibility was determined by the plate diffusion method. An analysis of the diagnostic test was made, reporting descriptive measures of frequencies. RESULTS: We obtained specimens for culture from 118 patients. Grade II and III lesions were the most frequently occurring (80%). Overall, 132 organisms were isolated from biopsies and 118 from swabs, with those of the Enterobacteriaceae family being the most frequent (56% from biopsies and 60% from swabs). Swab culture had a calculated sensitivity of 0.85, specificity of 0.86, positive predictive value of 0.98, negative predictive value of 0.43, positive likelihood ratio of 5.9, and negative likelihood ratio of 0.2. CONCLUSION: Swab culture is a reasonable option to determine the diabetic foot microbiology. PMID- 21527966 TI - [Towards a new curriculum for the faculty of medicine of the National University of Mexico (UNAM)]. AB - The 2010 undergraduate medical degree curriculum at the Faculty of Medicine of the Universidad Nacional Autonoma de Mexico (UNAM) is the result of eight years of collegiate work, which started under the leadership of Dr. Jose Narro Robles, our current Dean. In order to fulfill the aim of integrally developing a physician in the scientific, technical, social and human aspects, this academic plan considered the adaptations from a self-assessment test, the opinions expressed during academic workshops with professors from different disciplines, the work of committees and the results of external evaluations, as well as national and international health issues. New areas of knowledge that arose from whirling changes were also included in this plan, new technologies were adopted, the student was considered responsible for his own learning, and the development of unprecedented competences was considered. All this resulted in a departmental infrastructure that is our Faculty of Medicine's strength.An education model was defined by subjects with an outline of two years of basic sciences and two-and-a half years of clinical work aside from internship and social service. In order to achieve this and seek a better curricular organization, three curricular axes were settled: bio- and sociomedical clinic integration, medicine/information technology link, and the ethical/humanistic professional combination. We are certain that the 2010 Academic Curriculum will draw the graduates we need to train and to the professional requisites for our society in the XXI century. PMID- 21527967 TI - [Reflexions about the curricula at the faculty of medicine in the XXI century]. AB - In this paper we review the main medical programs from the Universidad Nacional Autonoma de Mexico (UNAM) faculty of medicine in the first seventy-five years of twentieth century. We have selected those instances that are representative of special moments in the development of Mexican medical knowledge, and also corresponding to the need to prepare medical students in view of social demands. The first programs are those of Ignacio Chavez in 1934, concerned mainly with the introduction into the curricula of medical specialties such as cardiology or neurology. After those, the 1956 and 1960 programs are mentioned and briefly analyzed; both were founded on the concern to develop a clinical reasoning in the student. Finally, the 1974 Integral General Medicine Program directed its interest to social and environmental themes. PMID- 21527968 TI - [Diagnosis on the unique curriculum of the medical career at the National University of Mexico]. AB - The analysis of the Plan Unico de Estudios of the medical career was the result of five years of collegiate work in which commissions consisting of academic staff of different departments from the faculty of medicine at the Universidad Nacional Autonoma de Mexico (UNAM) participated. The most significant conclusions derived from this analysis are: to adjust the graduate's profile in order to face the emerging health problems of the twenty-first century in our country; to update the academic curricula of the different subjects, including new ones; to create a nuclear curricula; as well as to strengthen the basic-clinic and the clinic-basic. With regard to the teaching/learning process, we acknowledged the need to develop self-cognitive and self-motivational skills in students as well as to consider a different evaluation for students and teachers. PMID- 21527970 TI - [Curricular adjustments in the clinical fields]. AB - The 2010 undergraduate medical degree curriculum at the National Autonomous University of Mexico (UNAM) faculty of medicine is based on the reality of the operating structure of the medical care units qualified for teaching. The clinical teaching/learning is based on the cooperative work of the professor and student; this means, it is based on the institutional physician responsible for medical care in a professor/assistant action together with the student being brought up. Therefore, the permanent education and training of all medical teams in the institutions offering teaching is essential. Teaching must be one distinctive characteristic of excellence for the units of the Health Ministry as it is teaching the central factor that raises the quality of medical care. The clinical evaluation must be permanent, improving the value of the daily action in front of a patient at the formative level and as a means to allow the assessment for its development, as it is the clinical aspect that is the essence of medicine. PMID- 21527969 TI - [Modifications to the faculty of medicine core curriculum at the National University of Mexico: adjusting the basic sciences program]. AB - In order to identify the core curriculum of each course from the faculty of medicine's study plan at the Universidad Nacional Autonoma de Mexico (UNAM), 22 workshops were organized. A total of 505 professors of 22 different subjects participated to identify the core content of each course: to define essential and necessary contents; to relate each objective's course with some of the eight established competences; and to apply an individual questionnaire where the professor suggests strategies for the vertical and horizontal integration among similar courses. At the end of these workshops, several meetings were carried out to incorporate the work done in order to design an integrated and modified program with the essential and necessary knowledge, eliminating the obsolete one. We also managed to integrate two courses in both horizontal and vertical ways to avoid repetition of topics. RESULTS: Twenty-two courses were reviewed, from which two of them were horizontally and vertically integrated. The content of six courses was modified and one course was divided into three programs. This resulted in the achievement of our goal: to have an academic program with essential and necessary contents that integrates the essential core curriculum, which in turn leads to the achievement of the intermediate and final competences. PMID- 21527971 TI - [The 2010 curriculum of the faculty of medicine at the National University of Mexico]. AB - The 2010 undergraduate medical degree curriculum at the faculty of medicine of the Universidad Nacional Autonoma de Mexico (UNAM) constitutes an important curricular reform of medical education in our country. It is the result of an institutional reflective process and academic dialog, which culminated in its approval by UNAM's Academic Council for the Biology, Chemistry, and Health Sciences areas on February 2nd, 2010. Some distinguishing characteristics of the new academic curriculum are: organization by courses with a focus on outcome competencies; three curricular axes that link three knowledge areas; four educational phases with achievement profiles; new courses (biomedical informatics, basic-clinical and clinical-basic integration, among others); and core curriculum. The aforementioned curriculum was decided within a framework of effective teaching strategies, competency oriented learning assessment methods, restructuring of the training of teaching staff, and establishment of a curriculum committee follow-up and evaluation of the program. Curricular change in medical education is a complex process through which the institution can achieve its mission and vision. This change process faces challenges and opportunities, and requires strategic planning with long-term foresight to guarantee a successful dynamic transition for students, teachers, and for the institution itself. PMID- 21527972 TI - [Citomegalovirus reactivation in critical ill intensive care patients]. AB - Cytomegalovirus (CMV) is a beta herpesvirus and a significant human pathogen. After primary infection establishes life long latency. In immunocompetent individuals cell-mediated host immune responses prevent the development of overt CMV disease. It has increasingly come to be recognized that critically ill patients are at risk for CMV reactivation from the latency. The risk factors associated to CMV reactivation in the critically ill are infection, sepsis, trauma, transfusions, major surgery, prolonged mechanical ventilation, steroids and vasopressors. In the pathogenesis are involved immunodysfunction and imbalance in immunomodulatory mediators principally tumor necrosis factor (TNF) and nuclear factor kappaB (NF-kappaB). Several studies have shown an association between CMV reactivation in immunocompetent critically ill patients and poor clinical outcomes. Further studies are warranted to identify subsets of patients who are at risk of developing CMV reactivation and to determine the role of antiviral agents on clinically outcomes in critically ill patients. PMID- 21527973 TI - [A 33 year old woman with a six-year history of slight thoracic-abdominal pain]. AB - We present a case of a benign hybrid nerve sheath tumor showing features of both cellular schwannoma and perineurioma.The patient was a 33 year-old female who presented with a 6 month history of pain in the thorax-lumbar region.Axial CT and MIR images showed and homogeneously enhancing solid oval mass involving the left paravertebra region in contact with the vertebral foramina T9-T11. Morphologically the tumor presented a well formed capsule and showed a uniform highly spindle cell proliferation. The spindle cells were arranged in whorls and intersecting fascicles with focal intervening sclerosis and relatively uniform cellularity with a prominent perivascular lymphocytic infiltrate. No cytological atypia, necrosis or mitoses were present. A second cell component was present composed of spindle-shaped cells with inconspicuous bipolar, pale, eosinophilic cytoplasm with oval nuclei. By immunohistochemistry there was a diffuse staining for S-100, and the elongated bipolar cells were EMA, Glut-1 and Claudin-1. To our knowledge this is the first reported case of a hybrid cellular schwannoma/perineurioma. PMID- 21527974 TI - [Spontaneous pneumothorax due to pulmonary coccidioidomycosis]. AB - Coccidioidomycosis is a systemic infection caused by the soil fungus Coccidioides immitis. It is endemic in northern Mexico and the southwest part of the United States. Radiologic manifestations are varied. Rupture of a coccidioidal pulmonary cavity with subsequent pneumothorax is a rare clinical event, even in endemic areas. We present a case with a brief review of this rare condition. PMID- 21527975 TI - [Prevention of mitochondrial diseases: a hope through assisted reproductive technologies]. AB - Mitochondrial diseases are a heterogenic and poorly studied group of diseases, considered serious in most cases and currently without treatment. Although assisted reproduction proposed strategies to prevent them, such as pre implantation genetic diagnosis, these techniques are not sufficiently successful. However, the recent publication of two assistedreproduction techniques - meiotic spindle transfer in nonhuman primates and pronuclear transfer in humans - generate a clear ray of hope for the prevention of these diseases. This review analyzes the characteristics and meaning of these new findings and their future clinical implications. PMID- 21527976 TI - [Gregorio Maranon, a pioneer of endocrinology, 50 years after his death]. AB - Gregorio Maranon born and dead in Madrid (1887-1960), was a Spanish physician, scientist, historian, philosopher, humanist, and writer, considered one of the most brilliant Spanish intellectuals of the 20th century. He was also a Republican and fought the Primo de Rivera dictatorship, though later expressed his disagreement with communism. Maranon participated closely with the process of exile of Alfonso XIII. From a very early age he learned several foreign languages and was an avid reader, hence he became in contact with the intellectual circles of the time and cultivated a close friendship with Perez Galdos, Menendez-Pelayo, Ortega y Gasset, Pio Baroja, Unamuno, Lerroux among several outstanding and eminent figures of the famous Generation of 14. In Medical School he had great teachers such as Santiago Ramon y Cajal, and later he specialized in endocrinology and became professor of the specialty in the Complutense University in Madrid, moreover he founded the Institute of Medical Pathology and the Department of Experimental Endocrinology, henceforth he contributed to establish the relationship between endocrinology and psychology. At the beginning of the instauration of the Republic, Maranon became a member of the constituent assembly and the parliament, but soon became disillusioned of communism and left Spain before the initiation of the Civil War, remaining in France until 1942 when he returned to Spain to reestablish his private practice, and soon the medical teaching at the hospital which now bears his name. Late work about history, poetry was elaborated at his Toledo Cigarral de Menores. PMID- 21527979 TI - Antitumor and HIV-1 Reverse Transcriptase Inhibitory Activities of a Hemagglutinin and a Protease Inhibitor from Mini-Black Soybean. AB - Protease inhibitors (PIs) and hemagglutinins are defense proteins produced by many organisms. From Chinese mini-black soybeans, a 17.5-kDa PI was isolated using chromatography on Q-Sepharose, SP-Sepharose, and DEAE-cellulose. A 25-kDa hemagglutinin was purified similarly, but using Superdex 75 instead of DEAE cellulose in the final step. The PI inhibited trypsin and chymotrypsin (IC(50) = 7.2 and 8.8 MUM). Its trypsin inhibitory activity was stable from pH 2 to pH 13 and from 0 degrees C to 70 degrees C. The hemagglutinin activity of the hemagglutinin was stable from pH 2 to pH 13 and from 0 degrees C to 75 degrees C. The results indicated that both PI and hemagglutinin were relatively thermostable and pH-stable. The trypsin inhibitory activity was inhibited by dithiothreitol, signifying the importance of the disulfide bond to the activity. The hemagglutinating activity was inhibited most potently by D (+)-raffinose and N acetyl-D-galactosamine, suggesting that the hemagglutinin was specific for these two sugars. Both PI and hemagglutinin inhibited HIV-1 reverse transcriptase (IC(50) = 3.2 and 5.5 MUM), proliferation of breast cancer cells (IC(50) = 9.7 and 3.5 MUM), and hepatoma cells (IC(50) = 35 and 6.2 MUM), with relatively high potencies. PMID- 21527980 TI - Molecular and Biological Characterization of Chinese Sacbrood Virus LN Isolate. AB - Chinese sacbrood virus (CSBV) was purified from diseased insects, and its genome was cloned and sequenced. The genomic RNA of CSBV is 8863 nucleotides in length and contains a single large open reading frame encoding a 319.614 kDa polyprotein. The coding sequence is flanked by a 178-nucleotide 5' nontranslated leader sequence and a 142-nucleotide 3' nontranslated region, followed a poly(A) tail. Four major structural proteins, VP1,VP2, VP3 and VP4, were predicted in the N-teminal of the polyprotein. The C-terminal part of the polyprotein contains sequence motifs which is a typical and well-characterized picornavirus nonstructural proteins: an RNA helicase, a chymotrypsin-like 3C protease, and an RNA-dependent RNA polymerase. Genetic analysis shows that the CSBV-LN had a 13 amino-acid deletion at amino acid positions 710-719 and 727-729 in comparison with CSBV-GZ and SBV-UK, and the SBV-UK had a 7-amino-acid deletion at amino acid positions 2124-2132 in comparison with CSBV-GZ and CSBV-LN, and the CSBV-GZ and CSBV-LN had a 6-amino-acid deletion at amino acid positions 2143-2150 in comparison with SBV-UK. Phylogenetic analysis using RdRp of selected picorna-like viruses shows that CSBV/SBV and Deformed Wing Virus (DWV) tend to group together, which possesses an RNA of similar size and gene order. PMID- 21527981 TI - Network models: an underutilized tool in wildlife epidemiology? AB - Although the approach of contact network epidemiology has been increasing in popularity for studying transmission of infectious diseases in human populations, it has generally been an underutilized approach for investigating disease outbreaks in wildlife populations. In this paper we explore the differences between the type of data that can be collected on human and wildlife populations, provide an update on recent advances that have been made in wildlife epidemiology by using a network approach, and discuss why networks might have been underutilized and why networks could and should be used more in the future. We conclude with ideas for future directions and a call for field biologists and network modelers to engage in more cross-disciplinary collaboration. PMID- 21527982 TI - Thromboelastography to monitor clotting/bleeding complications in patients treated with the molecular adsorbent recirculating system. AB - Background. The Molecular Adsorbent Recirculating System (MARS) has been shown to clear albumin-bound toxins from patients with liver failure but might cause bleeding complications potentially obscuring survival benefits. We hypothesized that monitoring clotting parameters and bed-side thromboelastography allows to reduce bleeding complications. Methods. Retrospective analysis of 25 MARS sessions during which clotting parameters were monitored by a standardized protocol. Results. During MARS therapy median INR increased significantly from 1.7 to 1.9 platelet count and fibrinogen content decreased significantly from 57 fL(-1) to 42 fL(-1) and 2.1 g/L to 1.5 g/L. Nine relevant complications occurred: the MARS system clotted 6 times 3 times we observed hemorrhages. Absent thrombocytopenia and elevated plasma fibrinogen predicted clotting of the MARS system (ROC 0.94 and 0.82). Fibrinolysis, detected by thromboelastography, uniquely predicted bleeding events. Conclusion. Bed-side thromboelastography and close monitoring of coagulation parameters can predict and, therefore, help prevent bleeding complications during MARS therapy. PMID- 21527983 TI - In Vitro Selection of Cathepsin E-Activity-Enhancing Peptide Aptamers at Neutral pH. AB - The aspartic protease cathepsin E has been shown to induce apoptosis in cancer cells under physiological conditions. Therefore, cathepsin E-activity-enhancing peptides functioning in the physiological pH range are valuable potential cancer therapeutic candidates. Here, we have used a general in vitro selection method (evolutionary rapid panning analysis system (eRAPANSY)), based on inverse substrate-function link (SF-link) selection to successfully identify cathepsin E activity-enhancing peptide aptamers at neutral pH. A successive enrichment of peptide activators was attained in the course of selection. One such peptide activated cathepsin E up to 260%, had a high affinity (K(D); ~300 nM), and had physiological activity as demonstrated by its apoptosis-inducing reaction in cancerous cells. This method is expected to be widely applicable for the identification of protease-activity-enhancing peptide aptamers. PMID- 21527984 TI - A Suitable Approach to Estimate Cancer Incidence in Area without Cancer Registry. AB - Objective. Use of cancer cases from registries and PMSI claims database to estimate Departement-specific incidence of four major cancers. Methods. Case extraction used principal diagnosis then surgery codes. PMSI cases/registry cases ratios for 2004 were modelled then Departement-specific incidence for 2007 estimated using these ratios and 2007 PMSI cases. Results. For 2007, only colon rectum and breast cancer estimations were satisfactorily validated for infranational incidence not ovary and kidney cancers. For breast, the estimated national incidence was 50,578 cases and the incidence rate 98.6 cases per 100,000 person per year. For colon-rectum, incidence was 21,172 in men versus 18,327 in women and the incidence rate 38 per 100,000 versus 24.8. For ovary, the estimated incidence was 4,637 and the rate 8.6 per 100,000. For kidney, incidence was 6,775 in men versus 3,273 in women and the rate 13.3 per 100.000 versus 5.2. Conclusion. Incidence estimation using PMSI patient identifiers proved encouraging though still dependent on the assumption of uniform cancer treatments and coding. PMID- 21527985 TI - Applicability of three alternative instruments for food authenticity analysis: GMO identification. AB - Ensuring foods are correctly labelled for ingredients derived from genetically modified organisms (GMOs) is an issue facing manufacturers, retailers, and enforcement agencies. DNA approaches for the determination of food authenticitys often use the polymerase chain reaction (PCR), and PCR products can be detected using capillary or gel electrophoresis. This study examines the fitness for purpose of the application of three laboratory electrophoresis instruments (Agilent Bioanalyzer 2100, Lab901 TapeStation, and Shimadzu MCE-202 MultiNA) for the detection of GMOs using PCR based on a previously validated protocol. Whilst minor differences in the performance characteristics of bias and precision were observed, all three instruments demonstrated their applicability in using this protocol for screening of GMO ingredients. PMID- 21527987 TI - Previously undocumented diversity and abundance of cryptic species: a phylogenetic analysis of Indo-Pacific Arminidae Rafinesque, 1814 (Mollusca: Nudibranchia) with descriptions of 20 new species of Dermatobranchus. AB - The phylogenetic relationships amongst the Arminidae were analysed based upon morphological characters of 58 presently described species or nudibranchs, including 35 previously described Arminidae and 20 new species of Dermatobranchus. From the literature review and anatomical examinations, 43 characters were considered for 78 taxa. These characters were polarized using Berthella canariensis as the outgroup taxon and the type species of several other genera identified from recent publications. The resulting phylogeny supports the monophyly of Arminidae, Dermatobranchus, Doridina, and Proctonotidae. The paraphyly of the Arminina is further demonstrated in this study. Two previously described, but poorly known, species of Indo-Pacific Armina are redescribed, Armina magnaBaba, 1955 and Armina paucifoliataBaba, 1955. The anatomy and taxonomic status of nine previously described species of Dermatobranchus were examined in this study. The anatomy of Dermatobranchus pustulosus (van Hasselt, 1824) has been overlooked since Bergh (1888) illustrated the radula of van Hasselt's specimen. It is redescribed and its range is extended to several new localities in the western Pacific. Dermatobranchus pulcherrimus Miller & Willan, 1986 is considered here as a new synonym of Dermatobranchus rubidus (Gould, 1852). The following 20 species of Dermatobranchus are new and are described in the present paper: Dermatobranchus albineus sp. nov., Dermatobranchus arminus sp. nov., Dermatobranchus caesitius sp. nov., Dermatobranchus caeruleomaculatus sp. nov., Dermatobranchus cymatilis sp. nov., Dermatobranchus dendonephthyphagus sp. nov., Dermatobranchus diagonalis sp. nov., Dermatobranchus earlei sp. nov., Dermatobranchus fasciatus sp. nov., Dermatobranchus funiculus sp. nov., Dermatobranchus kalyptos sp. nov., Dermatobranchus kokonas sp. nov., Dermatobranchus leoni sp. nov., Dermatobranchus microphallus sp. nov., Dermatobranchus oculus sp. nov., Dermatobranchus phyllodes sp. nov., Dermatobranchus piperoides sp. nov., Dermatobranchus rodmani sp. nov., Dermatobranchus semilunus sp. nov., and Dermatobranchus tuberculatus sp. nov. Eighteen of these new taxa are found in the Indo-Pacific tropics and two are found in temperate South Africa, D. albineus and D. arminus. Unique combinations of morphological characters distinguish these as new species of Dermatobranchus. Several species that are externally similar have radically divergent internal morphology, are members of different clades of Dermatobranchus, and represent cryptic species. Especially important is the radular morphology, which shows remarkable diversity of form, probably related directly to the diversification of feeding of members of this clade on various octocorals. PMID- 21527986 TI - Genital HSV detection among HIV-1-infected pregnant women in labor. AB - OBJECTIVE: To compare genital HSV shedding among HIV-positive and HIV-negative women. METHODS: Women with and without known HIV infection who delivered at the University of Washington Medical Center between 1989-1996 had HSV serologies done as part of clinical care. Genital swabs from HSV-2-seropositive women were evaluated by real-time quantitative HSV DNA PCR. RESULTS: HSV-2 seroprevalence was 71% and 30% among 75 HIV-positive and 3051 HIV-negative women, respectively, (P < .001). HSV was detected at delivery in the genital tract of 30.8% of HIV seropositive versus 9.5% of HIV-negative women (RR = 3.2, 95% CI 1.6 to 6.5, P = .001). The number of virion copies shed per mL was similar (log 3.54 for HIV positive versus 3.90 for HIV negative, P = .99). CONCLUSIONS: Our study demonstrated that HIV-, HSV-2-coinfected women are more likely to shed HSV at delivery. PMID- 21527988 TI - Microsurgical excisions of vestibular schwannomas: A tumor-size-based analysis of neurological outcomes and surgical complications. AB - INTRODUCTION: Vestibular schwannomas (VS) are benign tumors originating from Schwann cells in vestibulocochlear nerve. This study aimed at evaluating outcomes of microsurgical resections of VS based on tumor sizes in a South Asian country. METHODS: The chart notes of 71 patients who underwent microsurgical resections of VS at a single academic center over a 20-year period (1990-2009) were reviewed, and relevant information was extracted. For analyzing outcomes, patients were divided into two groups based on tumor size at initial presentation: (1) Group A (tumor size <= 4 cm) and (2) Group B (tumor size > 4 cm). Pearson's chi-square and Fisher's exact tests were used for comparison of proportions; the independent sample t-test was used for comparison of means. RESULTS: The average tumor diameter was 4.1 +/- 1.5 (range, 1-6.6) cm. Complete resection was achieved more frequently in patients in Group A (P < 0.001). Duration of hospital stay and cost of treatment were significantly higher in Group B patients (P < 0.003 and P < 0.04, respectively). The severity of postoperative facial nerve injury, assessed by House-Brackmann grading system, was significantly higher in Group B (P < 0.01). Cerebrospinal fluid (CSF) leak and lower cranial nerve deficits also occurred more frequently after resection in Group B (P = 0.031 and P = 0.003, respectively). CONCLUSION: We conclude that advanced stage tumors suggestive of delayed presentation are fairly common in Pakistan, and limit curative resection in the majority of patients. Postoperative morbidity is significantly higher in patients with tumor size > 4 cm. PMID- 21527989 TI - The epithelium-molecular landscaping for an interactive barrier. PMID- 21527990 TI - Nestin reporter transgene labels multiple central nervous system precursor cells. AB - Embryonic neuroepithelia and adult subventricular zone (SVZ) stem and progenitor cells express nestin. We characterized a transgenic line that expresses enhanced green fluorescent protein (eGFP) specified to neural tissue by the second intronic enhancer of the nestin promoter that had several novel features. During embryogenesis, the dorsal telencephalon contained many and the ventral telencephalon few eGFP+ cells. eGFP+ cells were found in postnatal and adult neurogenic regions. eGFP+ cells in the SVZ expressed multiple phenotype markers, glial fibrillary acidic protein, Dlx, and neuroblast-specific molecules suggesting the transgene is expressed through the lineage. eGFP+ cell numbers increased in the SVZ after cortical injury, suggesting this line will be useful in probing postinjury neurogenesis. In non-neurogenic regions, eGFP was strongly expressed in oligodendrocyte progenitors, but not in astrocytes, even when they were reactive. This eGFP+ mouse will facilitate studies of proliferative neuroepithelia and adult neurogenesis, as well as of parenchymal oligodendrocytes. PMID- 21527991 TI - The expression of alphaA- and betaB1-crystallin during normal development and regeneration, and proteomic analysis for the regenerating lens in Xenopus laevis. AB - PURPOSE: To explore the expression of the lens crystallins (alphaA- and betaB1 crystallin) in Xenopus laevis embryonic lens development and regeneration and to analyze the order of different crystallins generated in the regenerating lens. METHODS: Real Time-PCR, Immunofluorescence, and 2D-PAGE were used to analyze the expressions of alphaA-crystallin and betaB1-crystallin, and related factors during embryonic lens development and regeneration in Xenopus laevis. RESULTS: alphaA-crystallin and betaB1-crystallin were first detected at stage 29/30 during normal development, and the two crystallins were simultaneously detected in regeneration. During embryonic lens development, the relative expression level of the betaB1-crystallin gene was higher than that of the alphaA-crystallin gene. In the process of the lens regeneration, however, the relative expression level of the betaB1-crystallin gene was lower than that of the alphaA-crystallin gene. Throughout embryonic lens development, the two crystallin transcripts showed the same variation trends, and similar occurrence did in the regeneration process. Crystallins showed different localization and distribution during the ontogeny and regeneration, especially in the lens fiber region. 2D-electrophores revealed the patterns of the sequential synthesis of crystallins, with regard to the different classes and apparent variations of some auxiliary regulatory factors. CONCLUSIONS: The ontogeny and localization of the crystallins during embryonic lens development and regeneration indicated a different development program, although they have identical origins, the ectoderm. The expression level of crystallin transcripts displayed a consistent variation tendency, but the presence of appreciable differences was still exposed. In addition to stably producing the crystallins of different classes in accordance with established procedure, these auxiliary factors may perform the function, to some extent, because of significant changes in their expression throughout the process of lens regeneration. PMID- 21527992 TI - A DNA pooling-based case-control study of myopia candidate genes COL11A1, COL18A1, FBN1, and PLOD1 in a Chinese population. AB - PURPOSE: We examined the relationship between high myopia and common polymorphisms in four candidate genes: collagen, type XI, alpha 1 (COL11A1); collagen, type XVIII, alpha 1 (COL18A1); fibrillin 1 (FBN1); and procollagen lysine 1,2-oxoglutarate 5-dioxygenase 1 (PLOD1). These genes were selected because rare pathogenic mutations in these genes cause disease syndromes that have myopia, usually high myopia, as one of the common presenting features. METHODS: This study recruited 600 unrelated Han Chinese subjects including 300 cases with high myopia (spherical equivalent or SE<=-8.00 diopters) and 300 controls (SE within +/-1.00 diopter). A total of 66 tag single nucleotide polymorphisms (SNPs) were selected for study from these four candidate genes. The study adopted a DNA pooling strategy with an initial screen of DNA pools to identify putatively positive SNPs and then confirmed the "positive" SNPs by genotyping individual samples forming the original DNA pools. DNA pools were each constructed by mixing equal amounts of DNA from 50 individuals with the same phenotype status. Six case pools were prepared from 300 cases and six control pools from 300 controls. Allele frequencies of DNA pools were estimated by analyzing the primer-extended products with denaturing high performance liquid chromatography and compared between case pools and control pools with nested ANOVA. RESULTS: In the first stage, 60 SNPs from the 4 candidate genes were successfully screened using the DNA pooling approach. Of these, 6 SNPs showed a statistical significant difference in estimated allele frequencies between case pools and controls at p<0.10. In the second stage, these "positive" SNPs were followed up by individual genotyping, but failed to be confirmed via standard single-marker and haplotype analyses. CONCLUSIONS: Common polymorphisms in these four candidate genes (COL11A1, COL18A1, FBN1 and PLOD1) were unlikely to play important roles in the genetic susceptibility to high myopia. PMID- 21527993 TI - Dietary zerumbone prevents mouse cornea from UVB-induced photokeratitis through inhibition of NF-kappaB, iNOS, and TNF-alpha expression and reduction of MDA accumulation. AB - PURPOSE: Ultraviolet B (UVB) irradiation activates nuclear factor-kappa B (NF kappaB) and inducible nitric oxide synthase (iNOS) in the cornea, resulting in inflammatory responses and malondialdehyde (MDA) accumulation. This study aims to determine the effect of zerumbone, a potent NF-kappaB inhibitor and inflammation modulators, on UVB-induced corneal damages in a mouse model. METHODS: Fifty female imprinting control region (ICR) mice were randomly divided into five groups. The mice were anaesthetized with their ocular surfaces exposed to UVB light (0.72J/cm(2)/daily), followed by daily dietary zerumbone supplements at 0, 1, 10, and 100 mg/kg of bodyweight. Mice without zerumbone supplements were used as treatment controls and mice without UVB irradiation as blank controls. Corneal surface damages were graded according to smoothness, opacity, and the extent of lissamine green staining. Histopathological changes were also examined, along with the expression of NF-kappaB, iNOS, and tumor necrosis factor-alpha (TNF alpha). MDA accumulation and the levels of two antioxidant enzymes, glutathione (GSH) and GSH reductase (GR) were also examined. RESULTS: UVB irradiation caused significant damages to cornea, including sustained inflammation, apparent corneal ulcer, and severe epithelial exfoliation, leading to thinning of corneal epithelial layer, and infiltration of polymorphonuclear leukocytes. NF-kappaB expression was highly activated with nuclear translocation. The expression of iNOS and TNF-alpha were increased. MDA accumulation was also increased in both the corneal epithelial layer and the stroma. With dietary zerumbone, corneal damages were ameliorated in a dose-dependent manner. NF-kappaB activation and its nuclear translocation were blocked with decreased expression of iNOS and TNF alpha. Infiltration of polymorphonuclear leukocytes was also blocked by dietary zerumbone. Besides, MDA accumulation was reduced with concomitant increase of GSH and GR levels. CONCLUSIONS: Dietary zerumbone prevents UVB-induced corneal damages by inhibition of NF-kappaB, iNOS, and TNF-alpha, with concomitant reduction of MDA accumulation and increase of GSH and GR levels in the mouse model. Results of this study suggest that dietary zerumbone may be used as a prophylactic agent against UVB-induced photokeratitis. PMID- 21527994 TI - A novel mutation in gammaD-crystallin associated with autosomal dominant congenital cataract in a Chinese family. AB - PURPOSE: To identify the pathogenic gene mutation in a Chinese family with autosomal dominant congenital nuclear cataract. METHODS: After obtaining informed consent, detailed ophthalmic examinations were performed and genomic DNAs were obtained from eleven family members in a three-generation Chinese family with five affected. All exons of candidate genes associated with congenital nuclear cataract were amplified by polymerase chain reaction (PCR) and the PCR products were sequenced in both directions. The hydrophobic property of the mutant protein was analyzed with bioinformatics program ProtScale. The structure homology modeling of the mutant protein was based on Swiss-Model Serve, and its structure was displayed and compared with native gammaD-crystallin (CRYGD) using the RasMol software. RESULTS: By sequencing the encoding regions of the candidate genes, a novel mutation (c.110G>C) was detected in exon 2 of CRYGD, which resulted in the substitution of a highly conserved arginine by proline at codon 36 (p.R36P). The mutation co-segregated with all patients and was absent in 100 normal Chinese controls. Bioinformatics analysis showed an obvious increase of the local hydrophilicity of the R36P mutant gammaD-crystallin. The homology modeling showed that the structure of the mutant protein was similar with that of native human gammaD-crystallin. CONCLUSIONS: The study identified a novel mutation (c. 110G>C) in CRYGD associated with autosomal dominant congenital cataract in a Chinese family. It expands the mutation spectrum of CRYGD in association with congenital cataract. PMID- 21527995 TI - Novel serum proteomic signatures in a non-human primate model of retinal injury. AB - PURPOSE: To identify candidate protein biomarkers in sera indicative of acute retinal injury. METHODS: We used laser photocoagulation as a model of acute retinal injury in Rhesus macaques. In a paired-control study design, we collected serum from each animal (n=6) at 4 h, 1 day, and 3 days following a mock procedure and then again following retinal laser treatment that produced mild lesions. Samples were fractionated by isoelectric focusing, digested with trypsin, and analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Spectral counting was used to determine relative protein abundances and identify proteins with statistically significant differences between control and treated sera. RESULTS: Mild retinal injury was confirmed by fundus photography and histological examination. The average number of total proteins detected by LC-MS/MS was 908+/ 82 among samples from all three time points. Following statistical analysis and employing stringent filtering criteria, a total of 19 proteins were identified as being significantly more abundant in sera following laser-induced retinal injury, relative to control sera. Many of the proteins detected were unique to one time point. However, four proteins (phosphoglycerate kinase 1, keratin 18, Lewis alpha 3-fucosyltransferase, and ephrin receptor A2) showed differences that were significant at both 4 h and 1 day after laser treatment, followed by a decrease to baseline levels by day 3. CONCLUSIONS: A serum biomarker response to mild retinal laser injury was demonstrated in a primate model. Among the proteins detected with highest significant differences, most are upregulated within 24 h, and their appearance in the serum is transient. It is conceivable that a panel of these proteins could provide a means for detecting the acute-phase response to retinal injury. Further investigation of these candidate biomarkers and their correlation to retinal damage is warranted. PMID- 21527996 TI - Protective effect of a JNK inhibitor against retinal ganglion cell loss induced by acute moderate ocular hypertension. AB - PURPOSE: To correlate retinal ganglion cell (RGC) loss and optic nerve (ON) damage with the duration of acute glaucoma attacks in a rat experimental model and to determine whether the c-Jun N-terminal kinase (JNK) inhibitor SP600125 protects against such attacks. METHODS: To model an acute glaucoma attack, rat intraocular pressure (IOP) was elevated by a controllable compression method using pulleys and specific weights. Intraocular pressure was measured with a TonoLab(r) rebound tonometer. Time-dependent ocular hypertension-induced damage was evaluated by ON morphology, retina morphology (both retina layer thickness in cross-sections and RGC counts in Dextran tetramethylrhodamine crystals [DTMR] labeled flatmounts), and scotopic flash electroretinography (ERG). A c-Jun N terminal kinase (JNK) inhibitor, SP600125 (0, 1.5, 5, or 15 mg/kg), was administered by intraperitoneal injection immediately before and after induction of ocular hypertension, then once daily for seven days. Retinal cross-sections were measured to determine the thickness of various retinal layers and the cell density in the ganglion cell layer (GCL). Retinal flatmounts immunolabeled with anti-rat Brn-3a primary antibody were used to quantify RGC numbers. RESULTS: Elevated rat IOP induced by corneal limbus compression correlated with the different weights. Elevation to 45 mmHg for up to 7 h did not significantly affect the thicknesses of the outer nuclear layer, outer plexiform layer, or inner nuclear layer. Amplitudes of A- and B-waves were not affected. However, elevation to 45 mmHg for up to 7 h decreased the inner retinal thickness and caused ON damage. Most importantly, IOP elevation induced a time-dependent RGC loss. Cell density in the GCL decreased to 70%, 62%, and 49% of that of the control after 5 h, 6 h, and 7 h, respectively, of pressure increases. In retinal flatmount studies, labeled RGCs were reduced 56+/-4% (mean+/-SEM) versus the control (p<0.001) after 7 h of ocular hypertension. SP600125 dose-dependently protected against ocular hypertension-induced RGC loss. The difference in RGC density between the vehicle and SP600125-treated (15 mg/kg) groups was statistically significant (p<0.001). CONCLUSIONS: The correlation of inner retinal morphological changes with the duration of the application of 45 mmHg IOP was demonstrated. Treatment with SP600125 significantly protected RGC survival against this insult. Inhibitors of JNK may be an interesting pharmacological class for treating glaucoma. PMID- 21527997 TI - Pre-corneal tear film thickness in humans measured with a novel technique. AB - PURPOSE: The purpose of this work was to gather preliminary data in normals and dry eye subjects, using a new, non-invasive imaging platform to measure the thickness of pre-corneal tear film. METHODS: Human subjects were screened for dry eye and classified as dry or normal. Tear film thickness over the inferior paracentral cornea was measured using laser illumination and a complementary metal-oxide-semiconductor (CMOS) camera. A previously developed mathematical model was used to calculate the thickness of the tear film by applying the principle of spatial auto-correlation function (ACF). RESULTS: Mean tear film thickness values (+/-SD) were 3.05 MUm (0.20) and 2.48 MUm (0.32) on the initial visit for normals (n=18) and dry eye subjects (n=22), respectively, and were significantly different (p<0.001, 2-sample t-test). Repeatability was good between visit 1 and 2 for normals (intraclass correlation coefficient [ICC]=0.935) and dry eye subjects (ICC=0.950). Tear film thickness increased above baseline for the dry eye subjects following viscous drop instillation and remained significantly elevated for up to approximately 32 min (n=20; p<0.05 until 32 min; general linear mixed model and Dunnett's tests). CONCLUSIONS: This technique for imaging the ocular surface appears to provide tear thickness values in agreement with other non-invasive methods. Moreover, the technique can differentiate between normal and dry eye patient types. PMID- 21527998 TI - Sequence variants in COL4A1 and COL4A2 genes in Ecuadorian families with keratoconus. AB - PURPOSE: Keratoconus (KTCN) is a non-inflammatory, usually bilateral disorder of the eye which results in the conical shape and the progressive thinning of the cornea. Several studies have suggested that genetic factors play a role in the etiology of the disease. Several loci were previously described as possible candidate regions for familial KTCN; however, no causative mutations in any genes have been identified for any of these loci. The purpose of this study was to evaluate role of the collagen genes collagen type IV, alpha-1 (COL4A1) and collagen type IV, alpha-2 (COL4A2) in KTCN in Ecuadorian families. METHODS: COL4A1 and COL4A2 in 15 Ecuadorian KTCN families were examined with polymerase chain reaction amplification, and direct sequencing of all exons, promoter and intron-exon junctions was performed. RESULTS: Screening of COL4A1 and COL4A2 revealed numerous alterations in coding and non-coding regions of both genes. We detected three missense substitutions in COL4A1: c.19G>C (Val7Leu), c.1663A>C (Thr555Pro), and c.4002A>C (Gln1334His). Five non-synonymous variants were identified in COL4A2: c.574G>T (Val192Phe), c.1550G>A (Arg517Lys), c.2048G>C (Gly683Ala), c.2102A>G (Lys701Arg), and c.2152C>T (Pro718Ser). None of the identified sequence variants completely segregated with the affected phenotype. The Gln1334His variant was possibly damaging to protein function and structure. CONCLUSIONS: This is the first mutation screening of COL4A1 and COL4A2 genes in families with KTCN and linkage to a locus close to these genes. Analysis of COL4A1 and COL4A2 revealed no mutations indicating that other genes are involved in KTCN causation in Ecuadorian families. PMID- 21527999 TI - Influence of blue light on photoreceptors in a live retinal explant system. AB - PURPOSE: The present study was performed to investigate the early effects of blue light irradiation of photoreceptors in retinal explant cultures. METHODS: Murine retinal explant cultures were irradiated with visible blue light (405 nm) with an output power of 1 mW/cm2. Dihydroethidium was used to determine the production of reactive oxygen species. Morphological alterations of photoreceptor outer segments were determined by live imaging microscopy with mitochondrial dye JC-1. Transmission and scanning electron microscopy were used for ultrastructural evaluations. Cell death in the retina was assessed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) assay method. RESULTS: Live retinal explants displayed an increase in reactive oxygen species production, as revealed by fluorescent dihydroethidium products in photoreceptor cells after 30 min of blue light exposure. After 3 h of exposure, blue light caused disorganization of the normally neatly stacked outer segments of living photoreceptors. Ultrastructural analysis revealed breaks in the cell membrane surrounding the outer segments, especially in the middle section. The outer segments appeared tortuous, and the lamellar structures had been disrupted. TUNEL-staining revealed that long-term blue light exposure induced photoreceptor cell death. CONCLUSIONS: In vitro blue light irradiation of retinal explants is a suitable model system for investigating early ultrastructural changes, as well as damage that leads to cell death in photoreceptor cells. PMID- 21528000 TI - KH906, a recombinant human VEGF receptor fusion protein, is a new effective topical treatment for corneal neovascularization. AB - PURPOSE: The purpose of the current study was to investigate the effect of topical administration of KH906 on corneal neovascularization (NV). METHODS: To induce corneal neovascularization, chemical cauterization of the corneas of the right eyes of forty-eight New Zealand white rabbits was performed by touching the central cornea with an 8-mm-diameter NaOH-soaked Whatman filter paper for 60 s. On the next day after modeling, the rabbits were randomly and equally divided into six groups: PBS control group, 0.1% dexamethasone group, 10 mg/ml Avastin group, 5 mg/ml KH906 group, 10 mg/ml KH906 group, and 20 mg/ml KH906 group. The rabbits in the six groups received topical administration of 50 MUl of the different solutions on the cornea four times per day for 14 days. Corneal neovascularization was analyzed by slit-lamp biomicroscopy 10 and 14 days after chemical cauterization. Corneal fluorescein staining was performed to evaluate the extent of corneal epithelial defect on the 7th, 10th, and 14th days. The VEGF level of the cornea was evaluated by ELISA assay. RESULTS: On the 10th and 14th days after chemical cauterization, the length of the longest new vessel and the areas of corneal neovascularization in all KH906-treated groups were significantly reduced compared to those of the PBS-treated group (p<0.05). The VEGF level of the cornea in all KH906-treated groups was significantly decreased compared to that of the PBS-treated group (p<0.05). Corneal fluorescein staining showed that KH906 had no effect on corneal epithelial healing. CONCLUSIONS: Topical administration of KH906 significantly inhibited alkali burn-induced corneal neovascularization in rabbits. The new eye drops of KH906 may have a broad application for human corneal neovascularization in the near future. PMID- 21528001 TI - Investigation of the association between SLC1A3 gene polymorphisms and normal tension glaucoma. AB - PURPOSE: To investigate whether the solute carrier family 1, member 3 (SLC1A3) gene, which encodes the glutamate aspartate transporter, is associated with normal tension glaucoma (NTG) in Japanese patients. METHODS: Two hundred and ninety-five Japanese patients with NTG and 518 Japanese healthy controls were recruited. Patients exhibiting comparatively early NTG onset were selected because early onset suggests that genetic factors may show stronger involvement. We genotyped 5 single-nucleotide polymorphisms (SNPs) in SLC1A3 and assessed the allelic and genotypic diversity among cases and controls. RESULTS: There were no statistically significant differences in the frequency of SLC1A3 alleles and genotypes between cases and controls. CONCLUSIONS: Our study showed no association between SLC1A3 and NTG, suggesting that the SLC1A3 gene may not be an associated factor in NTG pathogenesis. PMID- 21528002 TI - High-resolution analysis of DNA copy number alterations in patients with isolated sporadic keratoconus. AB - PURPOSE: To determine whether patients with sporadic, non-familial keratoconus and no pathogenic mutations in the visual system homeobox 1 (VSX1) gene have evidence of chromosomal copy number alterations. METHODS: Twenty Saudi Arabian patients with isolated keratoconus, no family history of the disease and no mutations in VSX1 were recruited. Additionally, 10 ethnically-matched healthy controls were also recruited for this study. We screened patients for chromosomal copy number aberrations using the Agilent Human Genome CGH 244A Oligo Microarray Chip. RESULTS: None of the keratoconus patients screened had evidence of chromosomal copy number alterations when compared to normal ethnically matched controls. CONCLUSIONS: Chromosomal deletions and/or duplications were not detected in any of the patients tested here. Other chromosomal imbalances such as translocations, inversions, and some ploidies cannot be detected by current array CGH technology and other nuclear genetic or epigenetic factors cannot be excluded as a possible contributing factor to keratoconus pathogenesis. PMID- 21528003 TI - Functional analysis of disease-associated polymorphism LRP5.Q89R. AB - PURPOSE: The canonical wingless and Int1 (Wnt) signaling pathway plays key roles in multiple biologic events. The pathway co-receptor, low density lipoprotein receptor-related protein 5 (LRP5), is involved in the pathogenesis of retinal diseases and has been implicated in glaucoma. We studied whether a disease associated polymorphism LRP5.Q89R, which is located in the second blade of the first beta-propeller domain, directly alters Wnt signaling activity with cell based assays. METHODS: The LRP5.Q89R polymorphism was evaluated by transfection of HEK293T or GTM3 cells with expression vectors. LRP5 expression and interaction with the molecular chaperone mesoderm development (MESD) were determined by western immunoblotting and co-immunoprecipitation analyses. To compare membrane associated LRP5 proteins, surface proteins were labeled with biotin and pulled down with avidin beads followed by western immunoblotting. TCF-reporter plasmid based luciferase assays were used to determine whether LRP5.Q89R affects the canonical Wnt signaling, or has altered efficacy to suppression by Dickkopf-1 (DKK-1). RESULTS: Cell-based assays showed that this polymorphism did not change protein expression, interaction with the molecular chaperone MESD, protein trafficking, Wnt signaling transduction, or its efficacy in DKK1-mediated inhibition. CONCLUSIONS: Our data suggest that this specific polymorphism does not appear to alter the canonical Wnt signaling pathway. Further studies of LRP5 polymorphisms are needed to elucidate their roles in various associated diseases. PMID- 21528005 TI - Contemporary issues in head and neck pathology and radiology. PMID- 21528004 TI - Serial analysis of gene expression (SAGE) in normal human trabecular meshwork. AB - PURPOSE: To identify the genes expressed in normal human trabecular meshwork tissue, a tissue critical to the pathogenesis of glaucoma. METHODS: Total RNA was extracted from human trabecular meshwork (HTM) harvested from 3 different donors. Extracted RNA was used to synthesize individual SAGE (serial analysis of gene expression) libraries using the I-SAGE Long kit from Invitrogen. Libraries were analyzed using SAGE 2000 software to extract the 17 base pair sequence tags. The extracted sequence tags were mapped to the genome using SAGE Genie map. RESULTS: A total of 298,834 SAGE tags were identified from all HTM libraries (96,842, 88,126, and 113,866 tags, respectively). Collectively, there were 107,325 unique tags. There were 10,329 unique tags with a minimum of 2 counts from a single library. These tags were mapped to known unique Unigene clusters. Approximately 29% of the tags (orphan tags) did not map to a known Unigene cluster. Thirteen percent of the tags mapped to at least 2 Unigene clusters. Sequence tags from many glaucoma-related genes, including myocilin, optineurin, and WD repeat domain 36, were identified. CONCLUSIONS: This is the first time SAGE analysis has been used to characterize the gene expression profile in normal HTM. SAGE analysis provides an unbiased sampling of gene expression of the target tissue. These data will provide new and valuable information to improve understanding of the biology of human aqueous outflow. PMID- 21528006 TI - Medicinal plants used as antitumor agents in Brazil: an ethnobotanical approach. AB - WE DESCRIBE THE MEDICINAL PLANTS THAT HAVE BEEN REPORTED TO BE ANTITUMOR AGENTS AND THAT HAVE BEEN USED IN ETHNOBOTANIC RESEARCH IN BRAZIL TO ANSWER THE FOLLOWING QUESTIONS: what is the abundance of plants reported to be antitumor in Brazil? Have the plant species used for tumor treatment in traditional Brazilian medicine been sufficiently examined scientifically? Our analysis included papers published between 1980 and 2008. A total of 84 medicinal plant species were reported to be used for cancer and tumor prevention or treatment; 69.05% of these were cited as being used for the treatment of tumors and cancer in general and 30.95% for specific tumors or cancers. The plants that were cited at a higher frequency were Aloe vera, Euphorbia tirucalli, and Tabebuia impetiginosa. At least, one pharmacological study was found for 35.71% of the species. Majority of the studies selected were conducted in rural communities and urban areas and in areas with traditional healers in Brazil. We found the following molecules to be the most studied in vitro and in vivo: silibinin, beta-lapachone, plumbagin and capsaicin. The species addressed here constitute interesting objects for future studies to various professionals in the field of natural products. PMID- 21528007 TI - MYC, TP53, and chromosome 17 copy-number alterations in multiple gastric cancer cell lines and in their parental primary tumors. AB - We evaluated whether MYC, TP53, and chromosome 17 copy-number alterations occur in ACP02, ACP03, and AGP01 gastric cancer cell lines and in their tumor counterpart. Fluorescence in situ hybridization for MYC and TP53 genes and for chromosome 17 was applied in the 6th, 12th, 60th, and 85th passages of the cell lines and in their parental primary tumors. We observed that three and four MYC signals were the most common alterations in gastric cell lines and tumors. ACP02 presented cells with two copies of chr17 and loss of one copy of TP53 more frequently than ACP03 and AGP01. Only ACP03 and AGP01 presented clonal chr17 trisomy with three or two TP53 copies. The frequency of MYC gain, TP53 loss, and chromosome 17 trisomy seems to increase in gastric cell lines compared to their parental tumors. Our findings reveal that these cell lines retain, in vitro, the genetic alterations presented in their parental primary tumors. PMID- 21528009 TI - Studies of intramolecular Diels-Alder reactions of nitroalkenes for the stereocontrolled synthesis of trans-decalin ring systems. AB - Studies of thermal IMDA cyclizations of (1E,7E)-1-nitro-deca-1,7,9-trienes and (1E,3Z,7E)-1-nitro-deca-1,3,7,9-tetraenes have been examined. Reactions of these nitroalkenes proceed via transition states featuring characteristics of asymmetric stretch asynchronicity and result in stereoselective formation of trans-fused decalin products. A substantial rate acceleration is observed for IMDA cyclizations exemplified by triene 14 due to steric repulsions of substituents in the tethering chain which promote facile stereocontrolled formation of trans-fused 26. PMID- 21528010 TI - Dose Imaging Detectors for Radiotherapy Based on Gas Electron Multipliers. AB - New techniques in charged particle therapy and widespread use of modern dynamic beam delivery systems demand new beam monitoring devices as well as accurate 2D dosimetry systems to verify the delivered dose distribution. We are developing dose imaging detectors based on gas electron multipliers (GEM) with the goal of improving dose measurement linearity, position and timing resolution, and to ultimately allow pre-treatment verification of dose distributions and dose delivery monitoring employing scanning beam technology. A prototype 10*10 cm(2) double-GEM detector has been tested in the 205 MeV proton beam using electronic and optical readout modes. Preliminary results with electronic cross-strip readout demonstrate fast response and single-pixel (4 mm) position resolution. In optical readout mode, the line spread function of the detector was found to have sigma=0.7 mm. In both readout modes, the detector response was linear up to dose rates of 50 Gy/min, with adequate representation of the Bragg peak in depth-dose profile measurements. PMID- 21528008 TI - Neural mirroring systems: exploring the EEG MU rhythm in human infancy. AB - How do human children come to understand the actions of other people? What neural systems are associated with the processing of others' actions and how do these systems develop, starting in infancy? These questions span cognitive psychology and developmental cognitive neuroscience, and addressing them has important implications for the study of social cognition. A large amount of research has used behavioral measures to investigate infants' imitation of the actions of other people; a related but smaller literature has begun to use neurobiological measures to study of infants' action representation. Here we focus on experiments employing electroencephalographic (EEG) techniques for assessing mu rhythm desynchronization in infancy, and analyze how this work illuminates the links between action perception and production prior to the onset of language. PMID- 21528012 TI - Characterization of Nonpolar Lipids and Selected Steroids by Using Laser-Induced Acoustic Desorption/Chemical Ionization, Atmospheric Pressure Chemical Ionization, and Electrospray Ionization Mass Spectrometry. AB - Laser-induced acoustic desorption (LIAD) combined with ClMn(H(2)O)(+) chemical ionization (CI) was tested for the analysis of nonpolar lipids and selected steroids in a Fourier-transform ion cyclotron resonance mass spectrometer (FT ICR). The nonpolar lipids studied, cholesterol, 5alpha-cholestane, cholesta-3,5 diene, squalene, and beta-carotene, were found to solely form the desired water replacement product (adduct-H(2)O) with the ClMn(H(2)O)(+) ions. The steroids, androsterone, dehydroepiandrosterone (DHEA), estrone, estradiol, and estriol, also form abundant adduct-H(2)O ions, but less abundant adduct-2H(2)O ions were also observed. Neither (+)APCI nor (+)ESI can ionize the saturated hydrocarbon lipid, cholestane. APCI successfully ionizes the unsaturated hydrocarbon lipids to form exclusively the intact protonated analytes. However, it causes extensive fragmentation for cholesterol and the steroids. The worst case is cholesterol that does not produce any stable protonated molecules. On the other hand, ESI cannot ionize any of the hydrocarbon analytes, saturated or unsaturated. However, ESI can be used to protonate the oxygen-containing analytes with substantially less fragmentation than for APCI in all cases except for cholesterol and estrone. In conclusion, LIAD/ClMn(H(2)O)(+) chemical ionization is superior over APCI and ESI for the mass spectrometric characterization of underivatized nonpolar lipids and steroids. PMID- 21528011 TI - The History of the Discovery of the Molybdenum Cofactor and Novel Aspects of its Biosynthesis in Bacteria. AB - Biosynthesis of the molybdenum cofactor in bacteria is described with a detailed analysis of each individual reaction leading to the formation of stable intermediates during the synthesis of molybdopterin from GTP. As a starting point, the discovery of molybdopterin and the elucidation of its structure through the study of stable degradation products are described. Subsequent to molybdopterin synthesis, the molybdenum atom is added to the molybdopterin dithiolene group to form the molybdenum cofactor. This cofactor is either inserted directly into specific molybdoenzymes or is further modified by the addition of nucleotides to the molybdopterin phosphate group or the replacement of ligands at the molybdenum center. PMID- 21528013 TI - Methods for the Analysis of High Precision Differential Hydrogen Deuterium Exchange Data. AB - Hydrogen/deuterium exchange (HDX) mass spectrometry has been widely applied to the characterization of protein dynamics. More recently, differential HDX has been shown to be effective for the characterization of ligand binding. Previously we have described a fully automated HDX system for use as a ligand screening platform. Here we describe and validate the required data analysis workflow to facilitate the use of HDX as a robust approach for ligand screening. Following acquisition of HDX data at a single on-exchange time point (n >= 3), one way analysis of variance in conjunction with the Tukey multiple comparison procedure is used to establish the significance of any measured difference. Analysis results are graphed with respect to a single peptide, ligand or group of ligands, or displayed as an overview within a heat map. For the heat map display, only Delta%D values with a Tukey-adjusted P value less than 0.05 are colored. Hierarchical clustering is used to bin compounds with highly similar HDX signatures. The workflow is evaluated with a small data set showing the ligand binding domain (LDB) of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) screened against 10 functionally selective ligands. More significantly, data for the vitamin D receptor (VDR) in complex with 87 ligands are presented. To highlight the robustness and precision of our automated HDX platform we analyzed the data from 4191 replicate HDX measurements acquired over an eight month timeframe. Ninety six percent of these measurements were within 10 percent of the mean value. Work has begun to integrate these analysis and graphing components within our HDX software suite. PMID- 21528014 TI - ICE SLURRY APPLICATIONS. AB - The role of secondary refrigerants is expected to grow as the focus on the reduction of greenhouse gas emissions increases. The effectiveness of secondary refrigerants can be improved when phase changing media are introduced in place of single phase media. Operating at temperatures below the freezing point of water, ice slurry facilitates several efficiency improvements such as reductions in pumping energy consumption as well as lowering the required temperature difference in heat exchangers due to the beneficial thermo-physical properties of ice slurry. Research has shown that ice slurry can be engineered to have ideal ice particle characteristics so that it can be easily stored in tanks without agglomeration and then be extractable for pumping at very high ice fraction without plugging. In addition ice slurry can be used in many direct contact food and medical protective cooling applications. This paper provides an overview of the latest developments in ice slurry technology. PMID- 21528016 TI - Acquisition of the syntax-discourse interface: The expression of point of view. AB - This study examines the proposal that the syntax-discourse interface is particularly vulnerable, and therefore components of this interface are acquired later than those of the syntax-semantics interface. The proposal is examined using data from the native language acquisition of markers of point of view in American Sign Language and Brazilian Sign Language, known as constructed action (CA). CA was observed in the spontaneous production of two case studies from as early as 1 year, 7 months of age, with the correct eye-gaze, facial expression, and manner of movement. However, the children sometimes failed to indicate the referent whose point of view was being expressed, and were not skilled at maintaining point of view marking across discourse. The results are interpreted as providing support for the vulnerability of the syntax-discourse interface, and for the interpretation of this vulnerability in connection with children's relatively poor ability to assume an identical discourse context with their interlocutor. PMID- 21528015 TI - Microbial Pathogens in the Fungal Kingdom. AB - The fungal kingdom is vast, spanning ~1.5 to as many as 5 million species diverse as unicellular yeasts, filamentous fungi, mushrooms, lichens, and both plant and animal pathogens. The fungi are closely aligned with animals in one of the six to eight supergroups of eukaryotes, the opisthokonts. The animal and fungal kingdoms last shared a common ancestor ~1 billion years ago, more recently than other groups of eukaryotes. As a consequence of their close evolutionary history and shared cellular machinery with metazoans, fungi are exceptional models for mammalian biology, but prove more difficult to treat in infected animals. The last common ancestor to the fungal/metazoan lineages is thought to have been unicellular, aquatic, and motile with a posterior flagellum, and certain extant species closely resemble this hypothesized ancestor. Species within the fungal kingdom were traditionally assigned to four phyla, including the basal fungi (Chytridiomycota, Zygomycota) and the more recently derived monophyletic lineage, the dikarya (Ascomycota, Basidiomycota). The fungal tree of life project has revealed that the basal lineages are polyphyletic, and thus there are as many as eight to ten fungal phyla. Fungi that infect vertebrates are found in all of the major lineages, and virulence arose multiple times independently. A sobering recent development involves the species Batrachochytrium dendrobatidis from the basal fungal phylum, the Chytridiomycota, which has emerged to cause global amphibian declines and extinctions. Genomics is revolutionizing our view of the fungal kingdom, and genome sequences for zygomycete pathogens (Rhizopus, Mucor), skin-associated fungi (dermatophytes, Malassezia), and the Candida pathogenic species clade promise to provide insights into the origins of virulence. Here we survey the diversity of fungal pathogens and illustrate key principles revealed by genomics involving sexual reproduction and sex determination, loss of conserved pathways in derived fungal lineages that are retained in basal fungi, and shared and divergent virulence strategies of successful human pathogens, including dimorphic and trimorphic transitions in form. The overarching conclusion is that fungal pathogens of animals have arisen repeatedly and independently throughout the fungal tree of life, and while they share general properties, there are also unique features to the virulence strategies of each successful microbial pathogen. PMID- 21528018 TI - The Local Geometry of Multiattribute Tradeoff Preferences. AB - Existing representations for multiattribute ceteris paribus preference statements have provided useful treatments and clear semantics for qualitative comparisons, but have not provided similarly clear representations or semantics for comparisons involving quantitative tradeoffs. We use directional derivatives and other concepts from elementary differential geometry to interpret conditional multiattribute ceteris paribus preference comparisons that state bounds on quantitative tradeoff ratios. This semantics extends the familiar economic notion of marginal rate of substitution to multiple continuous or discrete attributes. The same geometric concepts also provide means for interpreting statements about the relative importance of different attributes. PMID- 21528017 TI - Nucleic Acid Charge Transfer: Black, White and Gray. AB - Theoretical studies of charge transport in deoxyribonucleic acid (DNA) and peptide nucleic acid (PNA) indicate that structure and dynamics modulate the charge transfer rates, and that different members of a structural ensemble support different charge transport mechanisms. Here, we review the influences of nucleobase geometry, electronic structure, solvent environment, and thermal conformational fluctuations on the charge transfer mechanism. We describe an emerging framework for understanding the diversity of charge transport mechanisms seen in nucleic acids. PMID- 21528019 TI - Solid-State Nuclear Magnetic Resonance Studies of Electrochemically Discharged CF(x). AB - Electrochemical studies of three types of CF(x) (F - Fiber based, C - Petroleum coke based, G - Graphite based) have demonstrated different electrochemical performances types in previous work, with fiber based CF(x) delivering superior performance over those based on petroleum coke and graphite. (13)C and (19)F MAS (Magic Angle Spinning) NMR techniques are employed to identify the atomic/molecular structural factors that might account for differences in electrochemical performance among the different types of CF(x). Small quantitative variations of covalent CF and LiF are noted as a function of discharge and sp(3) bonded carbons are detected in discharged F type of CF(x). PMID- 21528020 TI - Cohabitation: parents following in their children's footsteps? AB - As cohabitation has risen dramatically in the past few decades among adults of all ages, it is possible that middle-and older-aged parents are "learning" cohabitation from their young adult children. The present study uses this theory as a guiding framework to determine if parents are more likely to cohabit themselves following the start of a young adult child's cohabitation. Using three waves of the National Survey of Families and Households (N = 275), results show that union formation patterns are influenced by young adult children among parents who are single at their child's 18th birthday. Parents are less likely to marry than remain single and are much more likely to cohabit than marry if they have a young adult child who cohabits. These results show support for the hypotheses. PMID- 21528021 TI - Racial disparities in risk of second primary cancers in endometrial cancer patients: Analysis of SEER Data. AB - INTRODUCTION: Endometrial cancer (EC) is the most common gynecologic cancer in the United States. Racial disparities in the incidence and mortality of this cancer are apparent; black women are less likely to develop this malignancy, and yet are more likely to die when diagnosed. Racial differences of second primary cancer (SPC) have not been examined and are the goal of this study. METHODS: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results database, SPC risk in white and black EC cases was compared to the general population and to women with other primary cancers. Standardized incidence ratios (SIRs) of SPC (overall and by tumor site) with 95% confidence intervals were calculated. Poisson regression was used to estimate the race-specific risk of SPC in EC cases treated with radiotherapy vs. non-irradiated cases. RESULTS: The analysis included 11,047 EC cases diagnosed between 1973 and 2007 that developed a SPC. Overall risk of SPC in white EC cases was significantly lower than the general population (SIR=0.85, 95% CI: 0.84, 0.87), but significantly higher in black EC cases (SIR=1.19, 95% CI: 1.08, 1.31). White EC cases treated with radiotherapy were more likely to develop SPC compared to non-irradiated cases (IRR=1.18, 95% CI: 1.14, 1.23). CONCLUSIONS: This is the first analysis of race specific SPC risk in EC cases and it suggests differences between white and black cases. Although exploratory, these data provide important clues about the etiology of SPC in patients with EC. This analysis also highlights the need for careful monitoring following diagnosis and treatment of EC. PMID- 21528022 TI - Comparative study of number and distribution of IgG cells in oral lichen planus and oral lichenoid lesions. AB - BACKGROUND: Oral lichen planus is a common mucocutaneous disorder with unknown etiology. While current data suggest that oral lichen planus is a cell-mediated disease, differential diagnosis of this disease and oral lichenoid lesions is very problematic, both clinically and histopathologically. This study aimed to compare immunohistochemical features of these similar diseases. METHODS: This was a descriptive-analytic study in which formalin-fixed and paraffin-embedded tissue sections of 30 oral lichen planus and 30 oral lichenoid lesions were immunohistochemically analyzed for number and distribution of IgG(+) cells. A standard biotin-streptavidin procedure after antigen retrieval was used. Data were analyzed in SPSS software using Mann-Whitney U test. RESULTS: There were some significant differences in distribution of IgG (+)cells among different locations in oral lichen planus and also in oral lichenoid lesions separately; but the differences between distribution of IgG(+) cells between the two groups of oral lichen planus and oral lichenoid lesions were not significant. CONCLUSION: There was no significant difference in number and distribution of IgG(+) cells between the two groups. So, this study can suggest that location of IgG is similar in samples of oral lichen planus and oral lichenoid lesions and consequently, this marker cannot help us differentiate them from each other. Other markers can be analyzed in further studies in order to find an appropriate distinguisher between the two lesions. PMID- 21528023 TI - Comparative Evaluation of Metal Ions Release from Titanium and Ti-6Al-7Nb into Bio-Fluids. AB - BACKGROUND: The study was designed to investigate the effects of pH, chloride ions and nature of some bio-fluids on the amount of metal ions released from titanium and TiAl(6)Nb(7) plates following incubation in actual and simulated bio fluids over time. METHODS: The amounts of released metal ions from commercially pure titanium (CpTi) and TiAl(6)Nb(7)of surgical grade on immersion in 20 mL Hank's solution of pH 4.0 or 7.0, Hank's solution of high chloride ions concentration, Whole Blood Serum (WBS) and Phosphate Buffered Saline (PBS) at 37 degrees C were determined over an incubation time of 20 weeks using atomic absorption spectrophotometry. The levels of released metal ions were compared by two-way ANOVA and Duncan's post-hoc tests. The amounts of titanium ions released by the samples were analyzed by Pearson's correlation. RESULTS: TiAl(6)Nb(7) plate showed no release of Ti ions into the test solutions until after 12 weeks of incubation, while Ti ions were released from the CpTi plate from the 1 day immersion time. The release of measurable amount of Al ions from TiAl(6)Nb(7)was after 12 weeks of incubation. The rate of release of Ti and Al ions from the samples increased initially with incubation time and then stabilized due to adsorption-desorption equilibrium. CONCLUSION: The results showed that variations in pH and chloride ions of the test media has a significant effect on the amounts of Ti ions released, while increase in chloride ions concentration significantly elevates the release of Al ions into the biofluids. PMID- 21528024 TI - Changes in Children's Oral Health Related Quality of Life Following Dental Treatment under General Anesthesia. AB - BACKGROUND: Children's oral health related quality of life (OHRQoL) evaluates the impacts of oral daily activities of children and family on quality of life. Oral health related quality of life as outcome can be used to evaluate the dental health services. This study aimed to assess the extent to which dental treatment under general anesthesia affects quality of life of children and their families. METHODS: One hundred parents of 3-10 year-old children who needed dental treatment under general anesthesia completed a parent-children perception questionnaire (P-CPQ) and family impact scale (FIS) before, and 4 weeks after dental treatment under general anesthesia. The questionnaire had statements related to oral health, functional limitation, emotional state and well being social well-being and family issues. Data were analyzed using SPSS version 11.5. RESULTS: The mean scores and standard deviations of oral health quality of life of the children before and after dental treatment were 43.3 +/- 7.14 and 39.24 +/ 5.47 respectively. The mean scores of FIS before and after dental treatment were 8.00 +/- 3.21 and 3.66 +/- 2.62, respectively. The effect size of mean differences in P-CPQ and FIS scores were 1.84 +/- 1.64 and 1.35 +/- 4.34, respectively. CONCLUSION: Provision of dental treatment under general anesthesia for uncooperative, young children with extensive dental problems had significant effects on quality of life of both children and their families. PMID- 21528025 TI - Influence of intermediary filling material on microleakage of intracoronally bleached and restored teeth. AB - BACKGROUND: Failure of composite restorations in terms of microleakage after intracoronal bleaching has been reported. The purpose of this study was to assess in vitro effect of sodium ascorbate and calcium hydroxide as intermediary filling materials to repair the microleakage associated with adhe-sive restoration following intracoronal bleaching. METHODS: Sixty endodontically-treated incisors with access cavities extended to the cementoenamel junction in gingival margin were randomly divided into five equal groups. In group 1, cavities were restored by applying Single Bond and Z100 composite resin. In groups 2-5, 35% hydrogen peroxide gel was placed into the pulp chamber and sealed for 5 days. In group 2, teeth were then restored as in group 1. In groups 3 and 4, 10% sodium ascorbate gel and calcium hydroxide paste were applied in the pulp chamber for 40 hours, removed, rinsed and then, restored. In group 5, the cavities were incu-bated for 7 days and then, restored. Samples were thermocycled, immersed in basic fuschin, and sec-tioned. Dye penetration was scored using a stereomicroscope. Data were analyzed using Kruskal- Wallis and Mann-Whitney U tests (alpha = 0.05). RESULTS: There was no significant difference in enamel margins (P = 0.163). In dentinal margins (P = 0.003), groups 1, 3 and 5 exhibited similar leakage patterns, each one of groups 1, 3 and 5 had sig-nificant differences with each one of groups 2 and 4. CONCLUSION: Intracoronal bleaching using 35% H2O2 gel increases the microleakage in dentinal margins. Application of the antioxidant agent or a seven day delay following bleaching may improve the marginal integrity. Applying calcium hydroxide might jeopardize dentinal sealing. PMID- 21528026 TI - Candida Colonization on the Denture of Diabetic and Non-diabetic Patients. AB - BACKGROUND: Oral candidiasis is a common opportunistic infection in diabetic patients. Presence of denture in the oral cavity of diabetic patients can promote Candida colonization and results in the higher incidence of oral and systemic candidiasis. The general purpose of the present study was to evaluate and compare Candida colonization in denture of diabetic patients and non-diabetic control group. METHODS: In current case-control study, samples for mycological examinations were collected from the palatal impression surface of maxillary dentures from 92 edentulous patients including 46 dia-betic and 46 non-diabetic denture wearers. All samples were cultured directly on sabouraud agar me-dium and isolated colonies were counted and identified based on specific tests. Data were statistically analyzed using Mann-Whitney and Spearman correlation tests. RESULTS: The higher density of isolated colonies was seen in diabetic group in compare with control group (P = 0.0001). There was a statistically significant correlation between the blood glucose level (P = 0.0001) and the duration of denture usage (P = 0.022) with the colonization of Candida on denture of diabetic patients. C. albicans was the most common isolated Candida species in both groups, though diabetic patients with dentures had more non-albicans Candida isolated from their dentures compared to non-diabetic patients. CONCLUSIONS: Mycological findings from the present study revealed that diabetes mellitus can in-crease colonization of Candida in denture and mouth. By elimination of local and systemic factors in diabetic patients and improving their oral health care, Candida colonization and the risk of oral and systemic candidiasis will be decreased. PMID- 21528027 TI - Effect of storage time, thermocycling and resin coating on durability of dentin bonding systems. AB - BACKGROUND: Along with development of different dental adhesives, concerns about hydrolytic deg-radation of the adhesive components have arisen. The purpose of this study was to evaluate the in vitro influence of thermocycling, water storage and resin coating on the microshear bond strength of total etch and self etch adhesive systems to dentin. METHODS: The superficial coronal dentin of eighty intact third molars were exposed and divided into 5 equal groups. Dental adhesives including Scotch Bond Multi Purpose (SBMP), Single Bond (SB), Clearfil SE Bond (CSE), Prompt L-Pop (PLP), and Prompt L-Pop plus Margin bond (PLPM) were applied according to the manufacturers' instructions on prepared surfaces in the study groups, respectively. Then composite cylinders were bonded and specimens were divided into two subgroups. One subgroup was stored in water for 24 hours. The second subgroup was subjected to 3000 thermocycle shocks and then was stored in 37 degrees C water for 3 months. Finally, all teeth were subjected to the microshear bond strength test. Data were analyzed using two-way ANOVA and Tukey HSD tests. One specimen similar to each subgroup was also prepared for SEM evaluation. RESULTS: After one-day storage, the SBMP showed the highest bond strength followed by CSE, PLPM, SB and PLP. After three months storage, the highest bond strength was observed in SBMP followed by PLPM, CSE, SB, and PLP. CONCLUSION: SBMP showed the best bond strength while CSE represented acceptable bond durability. Resin coating on PLP improved bond strength and durability. PMID- 21528028 TI - Effect of axial groove and resin luting cements on the retention of complete cast metal crowns. AB - BACKGROUND: The design of the tooth preparation and the cementing medium are important consid-erations in the retention of crowns and fixed partial dentures. The purpose of this invitro study was to determine the effect of axial groove on the retention of complete cast metal crowns using two resin luting cements. METHODS: Forty freshly extracted intact human molar teeth were prepared in their long axis to receive complete cast metal crowns. The specimens were randomly divided into two groups (one control and one study group). An axial groove of uniform size and shape was made on the prepared teeth under the study group. Axial surface area of prepared teeth specimens was measured. Complete cast metal crowns were fabricated for each specimen. Specimens of each group were divided into subgroups of 10 samples and were cemented with two resin luting cements, RelyX Unicem(r) and Calibra(r), re-spectively. The cemented crowns were loaded in tension using a Universal Instron testing machine. The maximal tensile strength was recorded. Data were compared using the Mann-Whitney U test (alpha=0.05). RESULTS: NO SIGNIFICANT DIFFERENCES IN THE TENSILE STRESS VALUES WERE NOTED BETWEEN THE CONTROL (MEAN: 5.76+/-0.392 MPa) and study (mean: 5.93+/-0.751 MPa) groups cemented with RelyX Unicem. No significant differences in the tensile stress values were noted between the control (mean: 4.92+/-0.641 MPa) and study (mean: 5.15 +/-0.478 MPa) groups cemented with Calibra. However, significant dif ference in the tensile stress values was found between the two resin cements in the control and study groups. CONCLUSION: Axial groove placed in tooth preparations for resin bonded complete cast metal crowns had no statistically significant effect on retention. The use of (RelyX Unicem(r)) yielded greater retention values when compared to Calibra(r). PMID- 21528029 TI - Peripheral giant cell granuloma: a review of 123 cases. AB - BACKGROUND: Peripheral giant cell granuloma is one of the reactive hyperplastic lesions of the oral cavity, which originates from the periosteum or periodontal membrane following local irritation or chronic trauma. The purpose of this study was to present the clinical characteristics of peripheral giant cell granuloma in a group of Iranian population. METHODS: A series of 123 consecutive confirmed cases of peripheral giant cell granuloma after biopsy were evaluated. Age, sex, anatomic location, consistency, etiologic factor, pain and bleeding history, color, surface texture, and pedicle situation were recorded and were analyzed by chi-square test and values were considered to be significant if P < 0.05. RESULTS: Age ranged from 6 to 75 years (mean 33 years). Women affected more than men (M/F 1:1.1). Peripheral giant cell granuloma was seen in the mandible more than in the maxilla and in the anterior region more than in the posterior region. In most cases, lesions were pink, pedunculated and had non-ulcerated surface. In less than half of the cases, there was no history of bleeding and also pain was rarely reported. Calculus was the most common etiologic factor. CONCLUSION: The results confirmed that the clinical features of peripheral giant cell granuloma in a group of Iranian population are almost similar to those reported by other investigators. PMID- 21528030 TI - Functionally generated amalgam stops for single complete denture: a case report. AB - Single complete denture opposing natural dentition is a common occurrence in clinical practice. This article reports a case of a single complete denture with a technique of occlusal refinement by functionally generated amalgam stops condensed in prepared resin teeth after initial balancing of the denture with semi-adjustable articulator. This technique provides intimacy of contact in all excursions by carving the amalgam in plastic stage. Amalgam stops improve the efficiency of the resin teeth. Dentures fabricated using this technique require fewer and simpler post-insertion adjustments. PMID- 21528031 TI - A comparative study of density of obturated root canals by conventional and mechanical lateral condensation techniques. AB - BACKGROUND: The purpose of this study was to compare the weight of root canal filling material used in a new lateral condensation technique named mechanical lateral condensation (MLC) with that of conventional lateral condensation technique (LC). This new technique uses reciprocal handpiece. METHODS: In this experimental study, 40 human extracted straight canine teeth were used. After crown amputation, root canals were prepared with 18 mm in length. The teeth were randomly divided into four experimental groups; each group was consisting of 10 teeth. The teeth in groups IA and IB were filled by LC technique. The teeth in groups IIA and IIB were filled by MLC technique and using a finger spreader that placed in a reciprocating-action handpiece to laterally condense cold gutta percha, creating space for accessory cones. All of the roots were weighted before and after obturation and the difference demonstrated the weight of gutta-percha mass. The data were analyzed by t-test. RESULTS: The mean weight for MLC obturations was 10.82 +/- 0.025 g compared with 7.37 +/- 0.035 g for that of LC technique. The difference was statistically significant (P = 0.001). CONCLUSION: This study showed that MLC technique requires more gutta-percha mass than LC technique. PMID- 21528032 TI - Three dimensional finite element analysis to detect stress distribution in spiral implants and surrounding bone. AB - BACKGROUND: The aim of research was to study spiral family implant by finite element analysis (FEA) inserted in different bone qualities connected with abutments of different angulations. METHODS: The biomechanical behaviour of 4.2 * 13 mm dental implants, connecting screw, straight and 15 degrees and 25 degrees angulated abutments subjected to static loads, in contact with high and poor bone qualities was evaluated by FEA. RESULTS: The lowest stress value was found in the system composed by implants and straight abut-ments loaded with a vertical force, while the highest stress value was found in implants with 15 degrees angulated abutment loaded with an angulated force. In addition, we found the lower the bone quality, the higher the distribution of the stress within the bone. CONCLUSION: Spiral family implants can be used successfully in low bone quality but applying a straight force is recommended. PMID- 21528033 TI - Association of parental stress and early childhood caries. AB - BACKGROUND: Little research has been carried out on whether the parental stress affects children's oral health in general and dental caries in particular. This study aimed to investigate the association between parental stress and early childhood caries (ECC). METHODS: A cross-sectional study was designed that included 250 children of 4-6 year-old; 127 ones attended the pediatric department of Isfahan School of Dentistry who had early childhood caries and a comparison group of 123 caries free children attended five kindergartens and pre-schools in Isfahan city. Clinical examinations were conducted to evaluate the caries status. The parents of the two study groups completed the self-administrated long form of the Parenting Stress Index questionnaire. Details of their socio-demographic status were gathered too. The collected data were analyzed by SPSS version 11.5. The nonparametric Mantel-Haenszel test for correlation statistics was used to determine bivariate associations between total parenting stress and their domains scores in the two groups; i.e., those with early childhood caries and the caries free group. RESULTS: Mean score of PSI in the early childhood caries and caries free group were 286.66 +/- 66.26 and 273.87 +/- 31.03, respectively. There was not any significant relationship between total parental stress and ECC. The scores of the following domains of PSI demonstrated significant differences between ECC and CF groups: child reinforcement, child distractibility, child deficit attention, life stress and relationship with spouse (P = 0.01, 0.01, 0.001, 0.005 respectively). CONCLUSION: Findings of this study did not show any significant association between total parenting stress score and prevalence of early childhood caries. PMID- 21528034 TI - Association of trauma from occlusion with localized gingival recession in mandibular anterior teeth. AB - BACKGROUND: There have been passing references in history that excessive occlusal forces might be a causative factor in gingival recession. The purpose of the present cross-sectional study was to explore the role of trauma from occlusion on the development of gingival recession. METHODS: Three hundred patients reporting to the department of Periodontics were screened for the presence of gingival recession in the lower incisors. A single trained examiner carried out clinical examination for signs of trauma from occlusion, such as fremitus test, presence of wear facets and mobility. The data were analyzed by chi square test. RESULTS: No statistically significant relationship was observed between the presence of a positive fremitus and wear facets with gingival recession. However, a significant association was observed between patients who experienced mobility and gingival recession. CONCLUSION: There does appear to be a relationship between fremitus and tooth wear with gingival recession based on the results of the present study, though not conclusive. However, the sign of tooth mobility, which is a feature of trauma from occlusion, appeared to be a predictor of positive association with gingival recession. PMID- 21528035 TI - Fluoride release by glass ionomer cements, compomer and giomer. AB - BACKGROUND: To measure the amounts of fluoride released from fluoride-containing materials, four glass ionomer cements (Fuji IX, Fuji VII, Fuji IX Extra and Fuji II LC), a compomer (Dyract Extra) and a giomer (Beautifil) were used in this study. METHODS: Twenty cylindrical specimens were prepared from each material. The amount of released fluoride was measured during the first week and on the days 14 and 21 by using specific fluoride electrode and an ionanalyzer. The results were statistically analyzed using analysis of variance (two-way ANOVA) and Tukey Kramer multiple comparison tests (p=0.05). RESULTS: Significant differences were seen in fluoride release of different days and materials (p<0.05). The maximum cumulative fluoride release of days 1-7 was related to Fuji VII, followed by Fuji IX Extra, Fuji II LC, Fuji IX, Dyract Extra and Beautifil in descending order and this order remained the same until the 21(st) day. CONCLUSION: Fuji IX, Fuji VII, Fuji IX Extra, and Fuji II LC released higher amounts of fluoride compared to Beautifil and Dyract Extra in this study. It seems that the extent of the glass ionomer matrix plays an important role in determining the fluoride releasing ability of glass ionomer cement materials. PMID- 21528036 TI - Human papilloma virus as a possible factor in the pathogenesis of oral lichen planus. AB - BACKGROUND: Oral lichen planus (OLP) is a common chronic inflammatory mucocutaneous disease. Clinical diagnosis of OLP requires clinical work-up and histologic examination to rule out possible dysplasia and carcinoma. It is possible that oral mucosal viral infections including HPV infection may have a causative role in OLP pathogenesis. The aim of this study was to examine the coincidence of human papilloma virus type 18 and oral lichen planus. METHODS: This study was a case-control study. Twenty nine paraffinized specimens of previously diagnosed oral lichen planus and 14 paraffinized specimens of nonpathogenic mucosa were studied. Polymerase Chain Reaction (PCR) analyze used for detection of DNA HPV 18. The data were analyzed with SPSS software and Fisher's exact test was used to find the possible relation between HPV18 infection and oral lichen planus. RESULTS: Nine out of 29 (31.0%) lichen planus samples and one out of 14 (7.1%) controls were HPV 18 positive. No significant correlation (P = 0.128) was observed between HPV18 infection and oral lichen planus. CONCLUSION: According to the findings there might be a co-incidence of human papilloma virus type 18 and oral lichen planus. PMID- 21528037 TI - An in vitro antimicrobial activity of ten Iranian-made toothpastes. AB - BACKGROUND: Antimicrobial agents have been used as a chemotherapeutic agent to improve oral health. This in vitro study was carried out to determine the antimicrobial activity of ten Iranian-made toothpastes against commonly found bacteria in the oral cavity. METHODS: The microorganisms used in this study were Streptococcus mutans, Streptococcus sanguis, Actinomyces viscosus and Candida albicans. Sterile discs impregnated with 10 Iranian-made toothpastes; Paveh, Saviz, Latifeh II, Bath, Darugar II, Darugar I, Close up, Tage, Pooneh III and Nasim, which were separately used on agar plates. Crest Cavity Protection toothpaste and Sterile pyrogenfree distilled water were used as positive and negative controls, respectively. The samples were tested in triplicate, at full strength, 1:1 and 1:3 dilutions. Inhibition zones were measured in millimeter after 48 hr. The data were analyzed by the ANOVA and t-test. RESULTS: All tested toothpastes demonstrated an antimicrobial activity. The antimicrobial activity of Bath on S. mutans, Paveh on S. sanguis, Paveh, Saviz, Latifeh III and Darugar II on C. albicans were similar to the activity of Crest Cavity Protection. The antimicrobial activity of Pooneh III and Nasim on S. mutans, Bath on S. sanguis and A. viscosus, and Bath and Pooneh III on C. albicans were significantly higher and the others were significantly lower than the positive control. While, the activity of Crest Cavity Protection was the same as Pooneh III, it showed a weaker activity compared with Bath. CONCLUSION: Apart from Bath and Pooneh III, the other Iranian-made toothpastes tested in this study showed a lower antimicrobial activity compared to Crest Cavity Protection. PMID- 21528038 TI - The Single-tooth Implant Treatment of Congenitally Missing Maxillary Lateral Incisors Using Angled Abutments: A Clinical Report. AB - The maxillary lateral incisor is the second most common congenitally absent tooth. There are several treatment options for replacing the missing maxillary lateral incisor, including canine substitution, tooth-supported restoration, or single-tooth implant. Dental implants are an appropriate treatment option for replacing missing maxillary lateral incisor teeth in adolescents when their dental and skeletal development is complete. This case report presents the treatment of a patient with congenitally missing maxillary lateral incisors using dental implants with angled abutments. PMID- 21528039 TI - Intraoral epithelioid hemangioendothelioma: an intermediate vascular tumor- a case report. AB - Vascular neoplasms, other than benign are characterized as intermediate or malignant. They are often enshrouded in controversy, because the same neoplasm could show variability in biologic behavior that may not be correlated with microscopic features. The intermediate grade vascular neoplasm is named as epithelioid hemangioendothelioma (EHE). Epithelioid hemangioendothelioma of the oral cavity has been infrequently reported. To the best of our knowledge, the review of the English literature revealed a total of 30 cases of intraoral EHE reported till today. We report such a rare case in a 20 year old male, presented with a growth in lower anterior lingual gingiva since five months before the diagnosis with a history of similar swelling, twice in the same area. The differential diagnosis and brief review of literature is also discussed in the current article. PMID- 21528040 TI - Gastro-hep news. PMID- 21528041 TI - Direct-acting antiviral medications for chronic hepatitis C virus infection. AB - Treatment of hepatitis C virus has traditionally been difficult because of low rates of treatment success and high rates of treatment discontinuation due to side effects. Current standard therapy consists of pegylated interferon alpha and ribavirin, both of which have nonspecific and largely unknown mechanisms of action. New therapies are in development that act directly on the hepatitis C virus at various points in the viral life cycle. Published clinical trial data on these therapies are summarized in this paper. A new era of hepatitis C virus treatment is beginning, the ultimate goals of which will be directly targeting the virus, shortening the length of therapy, improving sustained virologic response rates, and minimizing side effects. PMID- 21528042 TI - Crohn's disease: the first visit. AB - A Crohn's disease patient's first visit to a new practice is the optimal time to collect important clinical data and identify appropriate therapies. A methodologic approach to this visit is crucial. The focus of this visit should be on preparing the patient for the initiation of treatment, with particular attention to the necessary steps prior to the use of immunosuppressive and biologic agents. This paper is intended to provide recommendations and a checklist for the initial assessment and evaluation of patients with Crohn's disease. PMID- 21528043 TI - Management and prevention of postoperative Crohn's disease. PMID- 21528044 TI - Antireflux surgery: efficacy, side effects, and other issues. PMID- 21528045 TI - Rifaximin for treatment of irritable bowel syndrome. PMID- 21528046 TI - Exploring the possibility of an interferon-free treatment regimen for hepatitis C virus infection. PMID- 21528047 TI - Update on endoscopist-administered propofol sedation for endoscopic procedures. PMID- 21528048 TI - An unusual case of SIADH. PMID- 21528049 TI - Strongyloidiasis: a multifaceted disease. PMID- 21528050 TI - Inguinodynia following Lichtenstein tension-free hernia repair: a review. AB - Chronic groin pain (Inguinodynia) following inguinal hernia repair is a significant, though under-reported problem. Mild pain lasting for a few days is common following mesh inguinal hernia repair. However, moderate to severe pain persisting more than 3 mo after inguinal herniorrhaphy should be considered as pathological. The major reasons for chronic groin pain have been identified as neuropathic cause due to inguinal nerve(s) damage or non-neuropathic cause due to mesh or other related factors. The symptom complex of chronic groin pain varies from a dull ache to sharp shooting pain along the distribution of inguinal nerves. Thorough history and meticulous clinical examination should be performed to identify the exact cause of chronic groin pain, as there is no single test to confirm the aetiology behind the pain or to point out the exact nerve involved. Various studies have been performed to look at the difference in chronic groin pain rates with the use of mesh vs non-mesh repair, use of heavyweight vs lightweight mesh and mesh fixation with sutures vs. glue. Though there is no convincing evidence favouring one over the other, lightweight meshes are generally preferred because of their lesser foreign body reaction and better tolerance by the patients. Identification of all three nerves has been shown to be an important factor in reducing chronic groin pain, though there are no well conducted randomised studies to recommend the benefits of nerve excision vs preservation. Both non-surgical and surgical options have been tried for chronic groin pain, with their consequent risks of analgesic side-effects, recurrent pain, recurrent hernia and significant sensory loss. By far the best treatment for chronic groin pain is to avoid bestowing this on the patient by careful intra operative handling of inguinal structures and better patient counselling pre- and post-herniorraphy. PMID- 21528052 TI - Hepatitis B and C infection and liver disease trends among human immunodeficiency virus-infected individuals. AB - AIM: To examine trends in and correlates of liver disease and viral hepatitis in an human immunodeficiency virus (HIV)-infected cohort. METHODS: The multi-site adult/adolescent spectrum of HIV-related diseases (ASD) followed 29 490 HIV infected individuals receiving medical care in 11 U.S. metropolitan areas for an average of 2.4 years, and a total of 69 487 person-years, between 1998 and 2004. ASD collected data on the presentation, treatment, and outcomes of HIV, including liver disease, hepatitis screening, and hepatitis diagnoses. RESULTS: Incident liver disease, chronic hepatitis B virus (HBV), and hepatitis C virus (HCV) were diagnosed in 0.9, 1.8, and 4.7 per 100 person-years. HBV and HCV screening increased from fewer than 20% to over 60% during this period of observation (P < 0.001). Deaths occurred in 57% of those diagnosed with liver disease relative to 15% overall (P < 0.001). Overall 10% of deaths occurred among individuals with a diagnosis of liver disease. Despite care guidelines promoting screening and vaccination for HBV and screening for HCV, screening and vaccination were not universally conducted or, if conducted, not documented. CONCLUSION: Due to high rates of incident liver disease, viral hepatitis screening, vaccination, and treatment among HIV-infected individuals should be a priority. PMID- 21528051 TI - Role of conventional therapies in the era of biological treatment in Crohn's disease. AB - Outstanding progress regarding the pathophysiology of Crohn's disease (CD) has led to the development of innovative therapeutic concepts. Numerous controlled trials have been performed in CD. This review concentrates on the results of randomized, placebo-controlled trials, and meta-analyses when available, that provide the highest degree of evidence. Current guidelines on the management of CD recommend a step-up approach to treatment involving the addition of more powerful therapies as the severity of disease and refractoriness to therapy increase. The advent of biological drugs has opened new therapeutic horizons for treating CD, modifying the treatment goals. However, the large majority of patients with CD will be managed through conventional therapy, even if they are a prelude to biological therapy. PMID- 21528053 TI - X-ray diagnosis of synchronous multiple primary carcinoma in the upper gastrointestinal tract. AB - AIM: To analyze the radiological features of multiple primary carcinoma (MPC) in the upper gastrointestinal (GI) tract, study its biological characteristics and evaluate X-ray examination in its diagnosis. METHODS: Hypotonic double-contrast GI radiography was performed in 59 multiple primary carcinoma cases, pathologically proved by surgery or endoscopy biopsy. Radiological findings were analyzed. RESULTS: Of the 59 cases, esophageal MPC (EMPC) was seen in 24, esophageal and gastric MPC (EGMPC) in 27 and gastric MPC (GMPC) in 8. Of the 49 lesions found in 24 EMPC, hyperplastic type was seen in 23, medullary type in 9. The lesions were located at the upper (n = 17), middle (n = 19) or lower (n = 13) segment of the esophagus. In 27 EGMPC, the esophageal lesions were located at the middle (n = 16) or lower (n = 11) segment of the esophagus, while the gastric lesions were located at the gastric cardia (n = 16), fundus (n = 1), body (n = 3) and antrum (n = 7). The esophageal lesions were mainly of the hyperplastic type (n = 12) or medullary type (n = 7), while the gastric lesions were mainly of the hyperplastic type (n = 18). A total of 119 lesions in the 59 patients with synchronous multiple carcinoma were proved by surgery or endoscopy biopsy, and preoperative upper radiographic examination detected 100 of them (84.03% sensitivity). Eighteen (52.94%) of the T(1) lesions were found during preoperative diagnosis by radiographic examination. Moreover, only 3 (3.53%) of the T(2-4) lesions were misdiagnosed. CONCLUSION: Hypotonic double-contrast upper gastrointestinal examination, providing accurate information about lesion morphology, location and size, can serve as a sensitive technique for the preoperative diagnosis of MPC. PMID- 21528054 TI - Breviscapine attenuates acute pancreatitis by inhibiting expression of PKCalpha and NF-kappaB in pancreas. AB - AIM: To study the effect of breviscapine (Bre) on activity of protein kinase Calpha (PKCalpha) and nuclear factor (NF)-kappaB in pancreas, and the mechanism of Bre attenuating acute pancreatitis (AP). METHODS: One hundred and eight rats were randomly divided into acute necrotizing pancreatitis (ANP) group, Bre group (ANP + Bre group) and sham operation (SO) group, 36 rats in each group. ANP model was induced by a retrograde injection of 4% sodium deoxycholate into the bilio pancreatic duct. Fifteen minutes after the ANP model was induced, the rats in Bre group were intraperitoneally injected with Bre (0.4 mg/100 g body weight or 0.1 mL/100 g body weight). Survival time and mortality of rats were calculated. Serum amylase and malondialdehyde levels were measured, volume of ascites was recorded and morphology of pancreas and lung was evaluated at 1, 5 and 10 h, after the ANP model was induced, respectively. Expressions of PKCalpha and subunit p65 of NF kappaB in pancreas were detected by immunohistochemistry and Western blotting. RESULTS: The life span of rats was longer and the mortality was lower in Bre group than in ANP group 13.51 +/- 5.46 vs. 25.36 +/- 8.11 (P < 0.05). The amylase and MDA levels as well as the volume of ascites were lower and the pathological changes in pancreas and lung were less in Bre group than ANP group (P < 0.05), indicating that the pancreatitis is less severe in Bre group than ANP group. The activation of PKCalpha and NF-kappaB p65 in pancreas was induced rapidly and reached their peak at 1 h or 5 h after ANP, but their activity in Bre group was significantly inhibited. CONCLUSION: Bre exerts its therapeutic effect on AP by inhibiting the activation of PKCalpha and NF-kappaB p65 in pancreas. PMID- 21528055 TI - Predictive factors of clinical response in steroid-refractory ulcerative colitis treated with granulocyte-monocyte apheresis. AB - AIM: To identify factors predicting the clinical response of ulcerative colitis patients to granulocyte-monocyte apheresis (GMA). METHODS: Sixty-nine ulcerative colitis patients (39 F, 30 M) dependent upon/refractory to steroids were treated with GMA. Steroid dependency, clinical activity index (CAI), C reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), values at baseline, use of immunosuppressant, duration of disease, and age and extent of disease were considered for statistical analysis as predictive factors of clinical response. Univariate and multivariate logistic regression models were used. RESULTS: In the univariate analysis, CAI (P = 0.039) and ESR (P = 0.017) levels at baseline were singled out as predictive of clinical remission. In the multivariate analysis steroid dependency [Odds ratio (OR) = 0.390, 95% Confidence interval (CI): 0.176 0.865, Wald 5.361, P = 0.0160] and low CAI levels at baseline (4 < CAI < 7) (OR = 0.770, 95% CI: 0.425-1.394, Wald 3.747, P = 0.028) proved to be effective as factors predicting clinical response. CONCLUSION: GMA may be a valid therapeutic option for steroid-dependent ulcerative colitis patients with mild-moderate disease and its clinical efficacy seems to persist for 12 mo. PMID- 21528056 TI - Gastrointestinal stromal tumors: thirty years experience of an institution. AB - AIM: To report our experience of gastrointestinal stromal tumors (GISTs) during the last 29 years. METHODS: Thirty two cases of GIST referred to our Institution from the 1st January 1981 to the 10th June 2010 were reviewed. Metastases, recurrence and survival data were collected in relation to age, history, clinical presentation, location, size, resection margins and cellular features. RESULTS: Mean age was 63.7 years (range, 40-90) and incidence was slightly higher in males (56%). R0 resection was performed in 90.7% of cases, R1 in 6.2% (2 cases) and R2 in 3.1% (one case). Using Fletcher's classification 8/32 (25%) had high risk, 9/32 (28%) intermediate and 15/32 (47%) low risk tumors. Follow-up varied from 1 mo to 29 years, with a median of 8 years; overall survival was 75% (24/32), disease-free survival was 72% and tumor-related mortality was 9.3%. Three patients with high risk GIST were treated with imatinib mesylate: one developed a recurrence after 36 mo, and 2 are free from disease at 41 mo. CONCLUSION: Surgical treatment remains the gold standard therapy for resectable GISTs. Pathological and biological features of the neoplasm represent the most important factors predicting the prognosis. PMID- 21528057 TI - Feasibility of a finger prick-based self-testing kit in first- and second-degree relatives of children with coeliac disease. AB - AIM: To assess feasibility of a finger prick-based kit as method for self-testing of first and second-degree relatives of coeliac disease (CD) patients. METHODS: A total number of 379 subjects were invited to participate in this study, consisting of 197 first-degree and 182 second-degree relatives of CD patients. The self-testing kit (BiocardTM) was sent out with included instructions for use. Completed tests were sent back to the study coordinator for assessment. RESULTS: One hundred and ninety-six invited relatives carried out the BiocardTM test at home. Amongst these, 70% were children. In 97% of the cases the test was performed correctly. Three tests revealed a positive result, all of which were later confirmed by serology and histology as coeliac disease. CONCLUSION: Our study indicates that BiocardTM test is a reliable, easy to use and well-accepted tool for home testing of first- and second-degree relatives of CD patients. PMID- 21528058 TI - Role of ERCP in the era of laparoscopic cholecystectomy for the evaluation of choledocholithiasis in sickle cell anemia. AB - AIM: To evaluate the role of endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis in patients with sickle cell anemia (SCA) in the era of laparoscopic cholecystectomy (LC). METHODS: Two hundred and twenty four patients (144 male, 80 female; mean age, 22.4 years; range, 5-70 years) with SCA underwent ERCP as part of their evaluation for cholestatic jaundice (CJ). The indications for ERCP were: CJ only in 97, CJ and dilated bile ducts on ultrasound in 103, and CJ and common bile duct (CBD) stones on ultrasound in 42. RESULTS: In total, CBD stones were found in 88 (39.3%) patients and there was evidence of recent stone passage in 16. Fifteen were post-LC patients. These had endoscopic sphincterotomy and stone extraction. The remaining 73 had endoscopic sphincterotomy and stone extraction followed by LC without an intraoperative cholangiogram. CONCLUSION: In patients with SCA and cholelithiasis, ERCP is valuable whether preoperative or postoperative, and in none was there a need to perform intraoperative cholangiography. Sequential endoscopic sphincterotomy and stone extraction followed by LC is beneficial in these patients. Endoscopic sphincterotomy may also prove to be useful in these patients as it may prevent the future development of biliary sludge and bile duct stones. PMID- 21528059 TI - Thrombotic microangiopathy-like disorder after living-donor liver transplantation: a single-center experience in Japan. AB - AIM: To investigate thrombotic microangiopathy (TMA) in liver transplantion, because TMA is an infrequent but life-threatening complication in the transplantation field. METHODS: A total of 206 patients who underwent living donor liver transplantation (LDLT) were evaluated, and the TMA-like disorder (TMALD) occurred in seven recipients. RESULTS: These TMALD recipients showed poor outcomes in comparison with other 199 recipients. Although two TMALD recipients successfully recovered, the other five recipients finally died despite intensive treatments including repeated plasma exchange (PE) and re-transplantation. Histopathological analysis of liver biopsies after LDLT revealed obvious differences according to the outcomes. Qualitative analysis of antibodies against a disintegrin-like domain and metalloproteinase with thrombospondin type 1 motifs (ADAMTS-13) were negative in all patients. The fragmentation of red cells, the microhemorrhagic macules and the platelet counts were early markers for the suspicion of TMALD after LDLT. Although the absolute values of von Willebrand factor (vWF) and ADAMTS-13 did not necessarily reflect TMALD, the vWF/ADAMTS-13 ratio had a clear diagnostic value in all cases. The establishment of adequate treatments for TMALD, such as PE for ADAMTS-13 replenishment or treatments against inhibitory antibodies, must be decided according to each case. CONCLUSION: The optimal induction of adequate therapies based on early recognition of TMALD by the reliable markers may confer a large advantage for TMALD after LDLT. PMID- 21528060 TI - Characteristics of non-erosive gastroesophageal reflux disease refractory to proton pump inhibitor therapy. AB - AIM: To investigate whether potent acid inhibition is effective in non-erosive reflux disease (NERD) refractory to standard rabeprazole (RPZ) treatment. METHODS: We treated 10 Japanese patients with NERD resistant to standard dosages of RPZ: 10 mg or 20 mg od, 20 mg bid, or 10 mg qid for 14 d. All patients completed a frequency scale for symptoms of gastroesophageal reflux disease questionnaire frequency scale for the symptoms of GERD (FSSG); and underwent 24 h pH monitoring on day 14. RESULTS: With increased dosages and frequency of administration of RPZ, median intragastric pH significantly increased, and FSSG scores significantly decreased. With RPZ 10 mg qid, potent acid inhibition was attained throughout 24 h. However, five subjects were refractory to RPZ 10 mg qid, although the median intragastric pH in these subjects (6.6, range: 6.2-7.1) was similar to that in the remaining five responsive subjects (6.5, range: 5.3 7.3). With baseline RPZ 10 mg od, FSSG scores in responsive patients improved by > 30%, whereas there was no significant decrease in the resistant group. CONCLUSION: NERD patients whose FSSG score fails to decrease by > 30% after treatment with RPZ 10 mg od for 14 d are refractory to higher dosage. PMID- 21528061 TI - Clinicopathologic significance of GLUT1 expression and its correlation with Apaf 1 in colorectal adenocarcinomas. AB - AIM: To investigate the role of glucose transporter 1 (GLUT1) expression in colorectal carcinogenesis and evaluate the correlation with clinicopathological parameters and apoptosis-activating factor-1 (Apaf-1) expression in colorectal adenocarcinomas. METHODS: We used tissue microarrays consisting of 26 normal mucosa, 50 adenomas, 515 adenocarcinomas, and 127 metastatic lesions. Medical records were reviewed and clinicopathological analysis was performed. RESULTS: GLUT1 expression was absent in normal mucosa and low or moderately apparent in 19 cases (38.0%) of 50 adenomas. However, GLUT1 expression was detected in 423 (82.1%) of 515 adenocarcinomas and in 96 (75.6%) of 127 metastatic lesions. GLUT1 expression was significantly correlated with female gender (P = 0.009), non mucinous tumor type (P = 0.045), poorer differentiation (P = 0.001), lymph node metastasis (P < 0.001), higher AJCC and Dukes stage (P < 0.001 and P < 0.001, respectively). There was a significant inverse correlation between GLUT1 expression and Apaf-1 expression (P = 0.001). In univariate survival analysis, patients with GLUT1 expression demonstrated poor overall survival and disease free survival (P = 0.047 and P = 0.021, respectively, log-rank test). CONCLUSION: GLUT1 expression was frequently increased in adenocarcinomas and metastatic lesions. GLUT1 expression was significantly correlated with poorer clinicopathologic phenotypes and survival of patients with colorectal adenocarcinomas. PMID- 21528062 TI - Acoustic radiation force impulse elastography for hepatocellular carcinoma associated radiofrequency ablation. AB - AIM: To evaluate the potential usefulness of acoustic radiation force impulse (ARFI) images for evaluation of hepatocellular carcinomas (HCC)-associated radiofrequency ablation. METHODS: From January 2010 to June 2010, a total of 38 patients with HCC including recurred HCCs after RFA underwent ARFI elastography. The brightness of tumor was checked and the shear wave velocity was measured for the quantification of stiffness. According to the brightness, the tumors were classified as brighter, same color and darker compared with adjacent parenchyma. Using the same methods, 8 patients with recurred HCCs after RFA state were evaluated about the brightness compared with adjacent RFA ablation area. RESULTS: In the 38 patients with HCCs, 20 (52.6%) were brighter than surrounding cirrhotic parenchyma. Another 13 (34.2%) were darker. The others (5 cases, 13.2%) were seen as the same color as the adjacent liver parenchyma. Post-RFA lesions were darker than previous tumor and surrounding parenchyma in all 38 cases. However, recurred HCCs were brighter than the treated site in all 8 cases. CONCLUSION: Using ARFI technique is helpful for differential diagnosis in order to detect recurred HCCs more easily in patients with confusing status. PMID- 21528063 TI - Cetuximab plus irinotecan in pretreated metastatic colorectal cancer patients: the ELSIE study. AB - AIM: To evaluate the efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients from South East Asia and Australia. METHODS: In this open-label, phase II study, the main eligibility criteria were epidermal growth factor receptor-positive mCRC with progressive disease within 3 mo of an irinotecan-based regimen as the most recent chemotherapy. Patients received cetuximab 400 mg/m2 initially, then 250 mg/m2 every week, with the same regimen of irinotecan on which the patients had progressed (4 pre-defined regimens allowed). The primary objective was evaluation of progression-free survival (PFS) at 12 wk. Secondary objectives included a further investigation of PFS, and an assessment of the overall response rate (ORR), duration of response, time to treatment failure (TTF), overall survival and the safety profile. RESULTS: One hundred and twenty nine patients were enrolled from 25 centers in the Asia-Pacific region and of these 123 received cetuximab plus irinotecan. The most common recent irinotecan regimen used was 180 mg/m2 every 2 wk which had been used in 93 patients (75.6%). The PFS rate at 12 wk was 50% (95% confidence interval (CI, 41-59) and median PFS time was 12.1 wk (95% CI: 9.7-17.7). The ORR was 13.8% (95% CI: 8.3-21.2) and disease control rate was 49.6% (95% CI: 40.5-58.8). Median duration of response was 31.1 wk (95% CI: 18.0-42.6) and median overall survival was 9.5 mo (95% CI, 7.5-11.7). The median TTF was 11.7 wk (95% CI: 9.1-17.4). Treatment was generally well tolerated. The most common grade 3/4 adverse events were diarrhea (13.8%), neutropenia (8.9%), rash (5.7%) and vomiting (5.7%). CONCLUSION: In patients from Asia and Australia, this study confirms the activity and safety of cetuximab plus irinotecan observed in previous studies in Europe and South America. PMID- 21528064 TI - Risk factors for residual tumor after resection of hepatocellular carcinoma. AB - AIM: To identify the clinicopathological risk factors correlated with residual tumor in hepatocellular carcinoma (HCC) patients after resection. METHODS: From January 2001 to April 2007, 766 HCC patients who had undergone resection were included in this research. Lipiodol angiography was performed within 2 mo after surgery and followed by post-Lipiodol computed tomography (CT) 4 wk later for all 766 patients to monitor tumor in the remnant liver. Tumor detected within the first 3-mo postoperative period was defined as residual tumor. Patients were divided into 2 groups: disease or disease-free within the first 3 mo after surgery. Risk factors for residual tumor were investigated among various clinicopathological variables. RESULTS: A total of 63 (8.22%) patients were found to have residual tumor after surgery. Three independent factors associated with residual tumor were identified by multivariate analysis: preoperative serum alpha -fetoprotein (AFP) level [odds ratio (OR) = 1.68 (95% confidence interval (CI): 1.20-2.36)], tumor size [OR = 1.73 (95% CI: 1.29-2.31)] and microvascular invasion [OR = 1.91 (95% CI: 1.12-3.24)]. CONCLUSION: Residual tumor is related to AFP level, tumor size and microvascular invasion. Patients at high risk should undergo closer follow-up and could be candidates for multimodality therapy. PMID- 21528065 TI - Down-regulation of miR-622 in gastric cancer promotes cellular invasion and tumor metastasis by targeting ING1 gene. AB - AIM: To evaluate the biological and clinical characteristics of miR-622 in gastric cancer. METHODS: We analyzed the expression of miR-622 in 57 pair matched gastric neoplastic and adjacent non-neoplastic tissues by quantitative real-time polymerase chain reaction. Functional analysis of miR-622 expression was assessed in vitro in gastric cancer cell lines with miR-622 precursor and inhibitor. The roles of miR-622 in tumorigenesis and tumor metastasis were analyzed using a stable miR-622 expression plasmid in nude mice. A luciferase reporter assay was used to assess the effect of miR-622 on inhibitor of growth family, member 1 (ING1) expression. RESULTS: Expression of miR-622 was down-regulated in gastric cancer. MiR-622 was found involved in differentiation and lymphatic metastasis in human gastric cancer. Ectopic expression of miR-622 promoted invasion, tumorigenesis and metastasis of gastric cancer cells both in vitro and in vivo. ING1 is a direct target of miR-622. CONCLUSION: These findings help clarify the molecular mechanisms involved in gastric cancer metastasis and indicate that miR 622 modulation may be a bona fide treatment of gastric cancer. PMID- 21528066 TI - Salvianolate inhibits cytokine gene expression in small intestine of cirrhotic rats. AB - AIM: To study the effect of salvianolate on expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 mRNA in small intestine of cirrhotic rats. METHODS: Cirrhosis in rats was induced using CCl4 (0.3 mL/kg). Rats were randomly divided into non-treatment group, low-dose salvianolate (12 mg/kg) treatment group, medium-dose salvianolate (24 mg/kg) treatment group, and high-dose salvianolate (48 mg/kg) treatment group, and treated for 2 wk. Another 10 healthy rats served as a normal control group. Mortality of cirrhotic rats in each group was evaluated after treatment with salvianolate. Serum samples were taken from portal vein for the detection of endotoxin. Morphological changes in tissue samples from the ileocecum were observed under a light microscope. Expression of TNF-alpha and IL-6 mRNA in the small intestine of rats was analyzed by real-time reverse-transcriptase polymerase chain reaction. RESULTS: The mortality of cirrhotic rats in the non-treatment group was 37.5%. No cirrhotic rat died in the high-dose salvianolate treatment group. The serum endotoxin level was significantly higher in the non-treatment group than in the salvianolate treatment and normal control groups. The intestinal mucosal and villous atrophy, necrosis and shedding of the intestinal mucosal epithelium, observed in the non treatment group, were reversed in different salvianolate treatment groups. The TNF-alpha and IL-6 mRNA expression levels in small intestine were significantly lower in different salvianolate treatment groups than in the non-treatment group. CONCLUSION: Salvianolate can reduce the endotoxin level, ameliorate the injury of intestinal mucosa, and inhibit the expression of TNF-alpha and IL-6 mRNA in small intestine of cirrhotic rats. PMID- 21528067 TI - Computational prediction and experimental validation of novel markers for detection of STEC O157:H7. AB - AIM: To identify and assess the novel makers for detection of Shiga toxin producing Escherichia coli (STEC) O157:H7 with an integrated computational and experimental approach. METHODS: High-throughput NCBI blast (E-value cutoff e-5) was used to search homologous genes among all sequenced prokaryotic genomes of each gene encoded in each of the three strains of STEC O157:H7 with complete genomes, aiming to find unique genes in O157:H7 as its potential markers. To ensure that the identified markers from the three strains of STEC O157:H7 can serve as general markers for all the STEC O157:H7 strains, a genomic barcode approach was used to select the markers to minimize the possibility of choosing a marker gene as part of a transposable element. Effectiveness of the markers predicted was then validated by running polymerase chain reaction (PCR) on 18 strains of O157:H7 with 5 additional genomes used as negative controls. RESULTS: The blast search identified 20, 16 and 20 genes, respectively, in the three sequenced strains of STEC O157:H7, which had no homologs in any of the other prokaryotic genomes. Three genes, wzy, Z0372 and Z0344, common to the three gene lists, were selected based on the genomic barcode approach. PCR showed an identification accuracy of 100% on the 18 tested strains and the 5 controls. CONCLUSION: The three identified novel markers, wzy, Z0372 and Z0344, are highly promising for the detection of STEC O157:H7, in complementary to the known markers. PMID- 21528068 TI - Oxidative stress and hypoxia-induced factor 1alpha expression in gastric ischemia. AB - AIM: To investigate the relation of reactive oxygen species (ROS) to hypoxia induced factor 1alpha (HIF-1alpha) in gastric ischemia. METHODS: The animal model of gastric ischemia reperfusion was established by placing an elastic rubber band on the proximal part of the bilateral lower limb for ligature for 3 h and reperfusion for 0, 1, 3, 6, 12 or 24 h. Ischemic post-conditioning, three cycles of 30-s reperfusion and 30-s femoral aortic reocclusion were conducted before reperfusion. Histological and immunohistochemical methods were used to assess the gastric oxidative damage and the expression of HIF1-alpha in gastric ischemia. The malondialdehyde (MDA) content and superoxide dismutase (SOD), xanthine oxidase (XOD) and myeloperoxidase (MPO) activities were determined by colorimetric assays. RESULTS: Ischemic post-conditioning can reduce post-ischemic oxidative stress and the expression of HIF-1alpha of gastric tissue resulting from limb ischemia reperfusion injury. MDA, SOD, XOD and MPO were regarded as indexes for mucosal injuries from ROS, and ROS was found to affect the expression of HIF-1alpha under gastric ischemic conditions. CONCLUSION: ROS affects HIF 1alpha expression under gastric ischemic conditions induced by limb ischemia reperfusion injury. Therefore, ROS can regulate HIF-1alpha expression in gastric ischemia. PMID- 21528069 TI - Intraductal papillary neoplasm of the bile duct in liver cirrhosis with hepatocellular carcinoma. AB - A case of intraductal papillary neoplasm of the bile duct (IPNB) arising in a patient with hepatitis B-related liver cirrhosis with hepatocellular carcinoma (HCC) is reported. A 76-year-old man was admitted to our hospital with recurrent HCC. Laboratory data showed that levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were elevated. He died of progressive hepatic failure. At autopsy, in addition to HCCs, an intraductal papillary proliferation of malignant cholangiocytes with fibrovascular cores was found in the dilated large bile ducts in the left lobe, and this papillary carcinoma was associated with an invasive mucinous carcinoma (invasive IPNB). Interestingly, extensive intraductal spread of the cholangiocarcinoma was found from the reactive bile ductular level to the interlobular bile ducts and septal bile ducts and to the large bile ducts in the left lobe. Neural cell adhesion molecule, a hepatic progenitor cell marker, was detected in IPNB cells. It seems possible in this case that hepatic progenitor cells located in reactive bile ductules in liver cirrhosis may have been responsible for the development of the cholangiocarcinoma and HCC, and that the former could have spread in the intrahepatic bile ducts and eventually formed grossly visible IPNB. PMID- 21528070 TI - An overview of occult hepatitis B virus infection. AB - Occult hepatitis B virus (HBV) infection (OBI), alternatively defined as occult hepatitis B (OHB), is a challenging clinical entity. It is recognized by two main characteristics: absence of HBsAg, and low viral replication. The previous two decades have witnessed a remarkable progress in our understanding of OBI and its clinical implications. Appropriate diagnostic techniques must be adopted. Sensitive HBV DNA amplification assay is the gold standard assay for detection of OBI. Viral as well as host factors are implicated in the pathogenesis of OBI. However, published data reporting the infectivity of OBI by transfusion are limited. Several aspects including OBI transmission, infectivity and its relation to the development of chronic liver diseases and hepatocellular carcinoma have to be resolved. The aim of the present review is to highlight recent data on OBI with a focus on its virological diagnosis and clinical outcome. PMID- 21528071 TI - Perianal Crohn's disease: is there something new? AB - Perianal lesions are common in patients with Crohn's disease, and display aggressive behavior in some cases. An accurate diagnosis is necessary for the optimal management of perianal lesions. Treatment of perianal Crohn's disease includes medical and/or surgical options. Recent discoveries in the pathogenesis of this disease have led to advances in medical and surgical therapy with good results. Perianal lesions in Crohn's disease remain a challenging aspect for both gastroenterologists and surgeons and lead to a greatly impaired quality of life for all patients affected by this disease. A multidisciplinary approach is mandatory to obtain the best results. PMID- 21528072 TI - Tetracycline-inducible protein expression in pancreatic cancer cells: effects of CapG overexpression. AB - AIM: To establish stable tetracycline-inducible pancreatic cancer cell lines. METHODS: Suit-2, MiaPaca-2, and Panc-1 cells were transfected with a second generation reverse tetracycline-controlled transactivator protein (rtTA2S-M2), under the control of either a cytomegalovirus (CMV) or a chicken beta-actin promoter, and the resulting clones were characterised. RESULTS: Use of the chicken (beta-actin) promoter proved superior for both the production and maintenance of doxycycline-inducible cell lines. The system proved versatile, enabling transient inducible expression of a variety of genes, including GST-P, CYP2E1, S100A6, and the actin capping protein, CapG. To determine the physiological utility of this system in pancreatic cancer cells, stable inducible CapG expressors were established. Overexpressed CapG was localised to the cytoplasm and the nuclear membrane, but was not observed in the nucleus. High CapG levels were associated with enhanced motility, but not with changes to the cell cycle, or cellular proliferation. In CapG-overexpressing cells, the levels and phosphorylation status of other actin-moduating proteins (Cofilin and Ezrin/Radixin) were not altered. However, preliminary analyses suggest that the levels of other cellular proteins, such as ornithine aminotransferase and enolase, are altered upon CapG induction. CONCLUSION: We have generated pancreatic-cancer derived cell lines in which gene expression is fully controllable. PMID- 21528074 TI - Assay of ghrelin concentration in infant formulas and breast milk. AB - AIM: To test if total ghrelin is present in infant formulas. METHODS: Using a radioimmunoassay, we measured total ghrelin concentrations in 19 samples of commercial infant formulas and in 20 samples of human milk. We also determined ghrelin concentration in the serum of infants and lactating mothers. RESULTS: Ghrelin concentrations were significantly higher in artificial milk (2007.1 +/- 1725.36 pg/mL) than in human milk (828.17 +/- 323.32 pg/mL) (P = 0.005). The mean ghrelin concentration in infant serum (n = 56) was 1115.86 +/- 42.89 pg/mL, and was significantly higher (P = 0.023) in formula-fed infants (1247.93 +/- 328.07 pg/mL) than in breast-fed infants (1045.7 +/- 263.38 pg/mL). The mean serum ghrelin concentration (mean +/- SD) in lactating mothers (n = 20) was 1319.18 +/- 140.18 pg/mL. CONCLUSION: This study provides evidence that total ghrelin is present in infant formulas. This finding raises diverse questions regarding the uptake, absorption and metabolic effects of this hormone. PMID- 21528073 TI - Unusual histopathological findings in appendectomy specimens: a retrospective analysis and literature review. AB - AIM: To document unusual findings in appendectomy specimens. METHODS: The clinicopathological data of 5262 patients who underwent appendectomies for presumed acute appendicitis from January 2006 to October 2010 were reviewed retrospectively. Appendectomies performed as incidental procedures during some other operation were excluded. We focused on 54 patients who had unusual findings in their appendectomy specimens. We conducted a literature review via the PubMed and Google Scholar databases of English language studies published between 2000 and 2010 on unusual findings in appendectomy specimens. RESULTS: Unusual findings were determined in 54 (1%) cases by histopathology. Thirty were male and 24 were female with ages ranging from 15 to 84 years (median, 32.2 +/- 15.1 years). Final pathology revealed 37 cases of enterobiasis, five cases of carcinoids, four mucinous cystadenomas, two eosinophilic infiltrations, two mucoceles, two tuberculosis, one goblet-cell carcinoid, and one neurogenic hyperplasia. While 52 patients underwent a standard appendectomy, two patients who were diagnosed with tuberculous appendicitis underwent a right hemicolectomy. All tumors were located at the distal part of the appendix with a mean diameter of 6.8 mm (range, 4-10 mm). All patients with tumors were alive and disease-free during a mean follow-up of 17.8 mo. A review of 1366 cases reported in the English literature is also discussed. CONCLUSION: Although unusual pathological findings are seldom seen during an appendectomy, all appendectomy specimens should be sent for routine histopathological examination. PMID- 21528075 TI - Factors associated with irritable bowel syndrome symptoms in hemodialysis patients. AB - AIM: To investigate clinical characteristics associated with the presence of irritable bowel syndrome (IBS) symptoms in hemodialysis (HD) patients. METHODS: This was a cross-sectional study. A questionnaire based on the Bowel Disease Questionnaire that records gastrointestinal symptoms was given to 294 patients in 4 dialysis centers. A total of 196 (67%) subjects returned the survey. A multivariable logistic regression model was used to identify factors significantly associated with IBS symptoms. RESULTS: Symptoms compatible with IBS were present in 27 (13.8%) subjects and independently associated with low post dialysis serum potassium [OR = 0.258, 95% CI (0.075-0.891), P = 0.032], paracetamol use [OR = 3.159, 95% CI (1.214-8.220), P = 0.018], and Kidney Disease Quality of Life (KDQOL) cognitive function score [OR = 0.977, 95% CI (0.956 0.999), P = 0.042]. Univariate regressions were also performed and the reported significance is for multivariate analysis. No association was detected for age, gender, depressed mood, smoking (present or past), body mass index, albumin level, Kt/V, sodium pre- or post-dialysis level, change in potassium level during HD, proton pump inhibitor or H2 blocker use, aspirin use, residual diuresis, hepatitis B or C infection, diabetes mellitus, marital status and education level. CONCLUSION: This study examined potential risk factors for symptoms compatible with IBS in HD patients and identified an association with paracetamol use, post-dialysis potassium level and KDQOL-cognitive function score. PMID- 21528076 TI - Viscosity of food boluses affects the axial force in the esophagus. AB - AIM: To study the effect of viscosity on axial force in the esophagus during primary peristalsis using a newly validated impedance-based axial force recording technique. METHODS: A probe able to simultaneously measure both axial force and manometry was positioned above the lower esophageal sphincter. Potable tap water and three thickened fluids were used to create boluses of different viscosities. Water has a viscosity of 1 mPa.s. The three thickened fluids were made with different concentrations of Clinutren Instant thickener. The viscous fluids were in appearance comparable to pudding (2 kPa.s), yogurt (6 kPa.s) and slush ice (10 kPa.s). Six healthy volunteers swallowed 5 and 10 mL of boluses multiple times. RESULTS: The pressure amplitude did not increase with the bolus viscosity nor with the bolus volume whereas the axial force increased marginally with bolus volume (0.1 > P > 0.05). Both techniques showed that contraction duration increased with bolus viscosity (P < 0.01). Association was found between axial force and pressure but the association became weaker with increasing viscosity. The pressure amplitude did not increase with the viscosity or bolus volume whereas the axial force increased marginally with the bolus size. CONCLUSION: This indicates a discrepancy between the physiological functions that can be recorded with axial force measurements and pressure measurements. PMID- 21528077 TI - Pancreatic duct guidewire placement for biliary cannulation in a single-session therapeutic ERCP. AB - AIM: To investigate the technical success and clinical complication rate of a cannulated pancreatic duct with guidewire for biliary access. METHODS: During a five-year study period, a total of 2843 patients were included in this retrospective analysis. Initial biliary cannulation method consisted of single guidewire technique (SGT) for up to 5 attempts, followed by double-guidewire technique (DGT) when repeated unintentional pancreatic duct cannulation had taken place. Pre-cut papillotomy technique was reserved for when DGT had failed or no pancreatic duct cannulation had been previously achieved. Main outcome measurements were defined as biliary cannulation success and post-endoscopic retrograde cholangiopancreatography (ERCP) complication rate. RESULTS: SGT (92.3% success rate) was characterized by statistically significant enhanced patient outcome compared to either the DGT (43.8%, P < 0.001), pre-cut failed DGT (73%, P < 0.001) or pre-cut as first step method (80.6%, P = 0.002). Pre-cut as first step method offered a statistically significantly more favorable outcome compared to the DGT (P < 0.001). The incidence of post-ERCP pancreatitis did not differ in a statistically significant manner between either method (SGT: 5.3%, DGT: 6.1%, Pre-cut failed DGT: 7.9%, Pre-cut as first step: 7.5%) or with patients' gender. CONCLUSION: Although DGT success rate proved not to be superior to SGT or pre-cut papillotomy, it is considered highly satisfactory in terms of safety in order to avoid the risk of a pre-cut when biliary therapy is necessary in difficult-to cannulate cases. PMID- 21528078 TI - Microscopic colitis as a missed cause of chronic diarrhea. AB - AIM: To determine the prevalence of increased intraepithelial lymphocytes, using immunohistochemistry in patients with normal colonoscopy and near normal biopsy. METHODS: We retrospectively reviewed all non-malignant colon mucosal biopsies between 2005 and 2007, reported as normal, chronic inflammation or melanosis coli in patients who were undergoing routine colonoscopy. Immunohistochemistry using CD3 was performed on all mucosal biopsies and an intraepithelial lymphocyte count (IEL) was determined. Cases with an IEL count of >= 20 IELs per 100 surface epithelial cells were correlated with demographic, clinical and follow-up data. A further subgroup was evaluated for lymphocytic colitis. RESULTS: Twenty (8.3%) of 241 cases revealed an IEL count >= 20. Six (2.5%) patients were identified as having lymphocytic colitis (P < 0.001), of whom, five were missed on initial evaluation (P = 0.01). Four of these five patients were labeled with diarrhea predominant irritable bowel syndrome (IBS). On follow-up, three of the remaining 20 cases were diagnosed with malignancy (renal cell carcinoma and myelodysplastic syndrome) and one had an unknown primary tumor with multiple liver metastases. Two cases of collagenous colitis with an IEL count < 10 were included in this study. Increased IELs were not confined to patients with diarrhea as a primary presenting symptom, but were also present in patients with abdominal pain (n = 7), constipation (n = 3) and loss of weight (n = 1). CONCLUSION: Immunohistochemistry using CD3 is of value in identifying and quantifying IELs for the presence of microscopic colitis in patients with diarrhea-predominant IBS. PMID- 21528079 TI - Extracapsular invasion as a risk factor for disease recurrence in colorectal cancer. AB - AIM: To evaluate the presence of extracapsular invasion (ECI) in positive nodes as a predictor of disease recurrence disease in colorectal cancer. METHODS: Two hundred and twenty-eight consecutive patients who underwent colorectal resection were identified for inclusion in this study, of which 46 had positive lymph nodes. Among 46 cases with stage IIIcolorectal cancer, 16 had ECI at positive nodes and 8 had disease recurrence. The clinical and pathological features of these cases were reviewed. RESULTS: In the univariate analysis, the number of positive lymph nodes and depth of tumor invasion were significantly associated with the presence of ECI at positive nodes. Multivariate analysis demonstrated that only ECI was a predictor of recurrence. The recurrence-free interval differed significantly among patients with ECI at positive nodes. CONCLUSION: Our results suggest that ECI at metastatic nodes can identify which cases are at high risk of short-term disease recurrence in colorectal cancer. PMID- 21528080 TI - Impact of disease severity on gastric residual volume in critical patients. AB - AIM: To investigate whether illness severity has an impact on gastric residual volume (GRV) in medical critically ill patients. METHODS: Medical intensive care unit (ICU) patients requiring nasogastric feeding were enrolled. Sequential Organ Failure Assessment (SOFA) score was assessed immediately preceding the start of the study. Acute Physiology and Chronic Health Evaluation (APACHE) II scores were recorded on the first, fourth, seventh, and fourteenth day of the study period. GRV was measured every 4 h during enteral feeding. The relationship between mean daily GRV and SOFA scores and the correlation between mean daily GRV and mean APACHE II score of all patients were evaluated and compared. RESULTS: Of the 61 patients, 43 patients were survivors and 18 patients were non-survivors. The mean daily GRV increased as SOFA scores increased (P < 0.001, analysis of variance). Mean APACHE II scores of all patients correlated with mean daily GRV (P = 0.011, Pearson correlation) during the study period. Patients with decreasing GRV in the first 2 d had better survival than patients without decreasing GRV (P = 0.017, log rank test). CONCLUSION: GRV is higher in more severely ill medical ICU patients. Patients with decreasing GRV had lower ICU mortality than patients without decreasing GRV. PMID- 21528081 TI - Effect of multidisciplinary team treatment on outcomes of patients with gastrointestinal malignancy. AB - AIM: To evaluate the effect of multidisciplinary team (MDT) treatment modality on outcomes of patients with gastrointestinal malignancy in China. METHODS: Data about patients with gastric and colorectal cancer treated in our center during the past 10 years were collected and divided into two parts. Part 1 consisted of the data collected from 516 consecutive complicated cases discussed at MDT meetings in Peking University School of Oncology (PKUSO) from December 2005 to July 2009. Part 2 consisted of the data collected from 263 consecutive cases of resectable locally advanced rectal cancer from January 2001 to January 2005. These 263 patients were divided into neoadjuvant therapy (NT) group and control group. Patients in NT group received MDT treatment, namely neoadjuvant therapy + surgery + postoperative adjuvant therapy. Patients in control group underwent direct surgery + postoperative adjuvant therapy. The outcomes in two groups were compared. RESULTS: The treatment strategy was altered after discussed at MDT meeting in 76.81% of gastric cancer patients and in 58.33% of colorectal cancer patients before operation. The sphincter-preservation and local control of tumor were better in NT group than in control group. The 5-year overall survival rate was also higher in NT group than in control group (77.23% vs 69.75%, P = 0.049). CONCLUSION: MDT treatment modality can significantly improve the outcomes of patients with gastrointestinal malignancy in China. PMID- 21528082 TI - Gastric cancer cells induce human CD4+Foxp3+ regulatory T cells through the production of TGF-beta1. AB - AIM: To elucidate the molecular and cellular features responsible for the increase of regulatory T cells (Tregs) in gastric cancer. METHODS: The frequencies of CD4(+)Foxp3(+) Tregs and the level of transforming growth factor beta1 (TGF-beta1) were analyzed from 56 patients with gastric cancer by flow cytometry and enzyme-linked immunosorbent assay respectively. Foxp3 gene expression was analyzed by real-time polymerase chain reaction. The gastric cancer microenvironment was modeled by establishing the co-culture of gastric cancer cell line, MGC-803, with sorting CD4(+) T cells. The normal gastric mucosa cell line, GES-1, was used as the control. The production of TGF-beta1 was detected in supernatant of MGC and GES-1. The carboxyfluorescein diacetatesuccinimidyl ester (CFSE) dilution assay was performed to evaluate the proliferation characteristics of induced Tregs. Neutralizing anti-TGF-beta1 antibody was added to the co-culture system for neutralization experiments. RESULTS: The level of serum TGF-beta1 in gastric cancer patients (15.1 +/- 5.5 ng/mL) was significantly higher than that of the gender- and age-matched healthy controls (10.3 +/- 3.4 ng/mL) (P < 0.05). Furthermore, the higher TGF-beta1 level correlated with the increased population of CD4(+)Foxp3(+) Tregs in advanced gastric cancer (r = 0.576, P < 0.05). A significant higher frequency of CD4(+)Foxp3(+) Tregs was observed in PBMCs cultured with the supernatant of MGC than GES-1 (10.6% +/- 0.6% vs 8.7% +/- 0.7%, P < 0.05). Moreover, using the purified CD4(+)CD25(-) T cells, we confirmed that the increased Tregs were mainly induced from the conversation of CD4(+)CD25(-) naive T cells, and induced Tregs were functional and able to suppress the proliferation of effector T cells. Finally, we demonstrated that gastric cancer cells induced the increased CD4(+)Foxp3(+) Tregs via producing TGF-beta1. Gastric cancer cells upregulated the production of TGF-beta1 and blockade of TGF-beta1 partly abrogated Tregs phenotype. CONCLUSION: Gastric cancer cell can induce Tregs development via producing TGF-beta1, by which the existence of cross-talk between the tumor and immune cells might regulate anti-tumor immune responses. PMID- 21528083 TI - SPARCL1, Shp2, MSH2, E-cadherin, p53, ADCY-2 and MAPK are prognosis-related in colorectal cancer. AB - AIM: To investigate the expression of markers that are correlated with the prognosis of colorectal cancer (CRC) patients. METHODS: One hundred and fifty-six CRC patients were followed up for more than 3 years after radical surgery. Immunohistochemical (IHC) analysis was performed to detect the expression of 14 pathway-related markers (p53, APC, p21ras, E-cadherin, endothelin-B receptor, Shp2, ADCY-2, SPARCL1, neuroligin1, hsp27, mmp-9, MAPK, MSH2 and rho) in specimens from these patients. Bioinformatics analysis involving a Support Vector Machine (SVM) was used to determine the best prognostic model from combinations of these markers. RESULTS: Seven markers (SPARCL1, Shp2, MSH2, E-cadherin, p53, ADCY-2 and MAPK) were significantly related to the prognosis and clinical pathological features of the CRC patients (P < 0.05). Prognostic models were established through SVM from combinations of these 7 markers and proved able to differentiate patients with dissimilar survival, especially in stage II/III patients. According to the best prognostic model, the p53/SPARCL1 model, patients having high p53 and low SPARCL1 expression had about 50% lower 3-year survival than others (P < 0.001). CONCLUSION: SPARCL1, Shp2, MSH2, E-cadherin, p53, ADCY-2 and MAPK are potential prognostic markers in CRC. A p53/SPARCL1 bioinformatics model may be used as a supplement to tumor-nodes-metastasis staging. PMID- 21528084 TI - DEC1 nuclear expression: a marker of differentiation grade in hepatocellular carcinoma. AB - AIM: To investigate the expression patterns of human differentiated embryo chondrocyte 1 (DEC1) in hepatocellular carcinoma (HCC) and corresponding adjacent non-tumor and the normal liver tissues, the association between DEC1 expression and histopathological variables and the role of DEC1 in hepatocarcinogenesis. METHODS: The expression of DEC1 was detected immunohistochemically in 176 paraffin-embedded sections from 63 patients with HCC and 50 subjects with normal liver tissues. RESULTS: DEC1 protein was persistently expressed in the cytoplasm of hepatocytes in normal liver and HCC tissues. Compared with adjacent non-tumor liver tissues, HCC tissues showed high nuclear expression of DEC1 protein. However, high DEC1 nuclear expression was more frequently detected in well differentiated (83.3%) than in moderately (27.3%) and poorly differentiated HCC (16.7%). Low DEC1 expression was associated with poor histological differentiation and malignancy progression. A correlation was found between the nuclear expression of DEC1 protein and histological differentiation (r = 0.376, P = 0.024). CONCLUSION: DEC1 is expressed in the cytoplasm of hepatocytes and because nuclear DEC1 expression is decreased with decreasing differentiation status of HCC, nuclear DEC1 might be a marker of HCC differentiation. PMID- 21528085 TI - Apoptotic bone marrow CD34+ cells in cirrhotic patients. AB - AIM: To access the frequency and level of apoptotic CD34+ cells isolated from the marrow fluid of patients with post-hepatitis cirrhosis. METHODS: The frequency of bone marrow CD34+ cells and apoptotic bone marrow CD34+ cells in 31 in-patients with post-hepatitis cirrhosis (cirrhosis group), and 15 out-patients without liver or blood disorders (control group) was calculated by flow cytometry. Parameters were collected to evaluate liver functions of patients in cirrhosis group. RESULTS: The percentage of normal bone marrow CD34+ cells was 6.30% +/- 2.48% and 1.87% +/- 0.53% (t = 3.906, P < 0.01) while that of apoptotic marrow CD34+ cells was 15.00% +/- 15.81% and 5.73% +/- 1.57% (t = 2.367, P < 0.05) in cirrhosis and control groups, respectively. The percentage of apoptotic marrow CD34+ cells was 6.25% +/- 3.30% and 20.92 +/- 18.5% (t = 2.409, P < 0.05) in Child-Pugh A and Child-Pugh B + C cirrhotic patients, respectively. The percentage of late apoptotic marrow CD34+ cells was positively correlated with the total bilirubin and aspartate aminotransferase serum levels in patients with cirrhosis. CONCLUSION: The status of CD34+ marrow cells in cirrhotic patients may suggest that the ability of hematopoietic progenitor cells to transform into mature blood cells is impaired. PMID- 21528086 TI - A case-control study on the relationship between salt intake and salty taste and risk of gastric cancer. AB - AIM: To investigate the relationship between salt intake and salty taste and risk of gastric cancer. METHODS: A 1:2 matched hospital based case-control study including 300 patients with gastric cancer and 600 cancer-free subjects as controls. Subjects were interviewed with a structured questionnaire containing 80 items, which elicited information on dietary, lifestyle habits, smoking and drinking histories. Subjects were tested for salt taste sensitivity threshold (STST) using concentrated saline solutions (0.22-58.4 g/L). Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CI). RESULTS: Alcohol and tobacco consumption increased the risk of gastric cancer [OR (95% CI) was 2.27 (1.27-4.04) for alcohol and 2.41 (1.51-3.87) for tobacco]. A protective effect was observed in frequent consumption of fresh vegetable and fruit [OR (95% CI) was 0.92 (0.58-0.98) for fresh vegetable and 0.87 (0.67-0.93) for fruit]. Strong association was found between STST >= 5 and gastric cancer [OR = 5.71 (3.18-6.72)]. Increased STST score was significantly associated with salted food intake and salty taste preference (P < 0.05). CONCLUSION: A high STST score is strongly associated with gastric cancer risk. STST can be used to evaluate an inherited characteristic of salt preference, and it is a simple index to verify the salt intake in clinic. PMID- 21528087 TI - Laparoscopic repair of hiatal hernia with mesenterioaxial volvulus of the stomach. AB - Although mesenterioaxial gastric volvulus is an uncommon entity characterized by rotation at the transverse axis of the stomach, laparoscopic repair procedures have still been controversial. We reported a case of mesenterioaxial intrathoracic gastric volvulus, which was successfully treated with laparoscopic repair of the diaphragmatic hiatal defect using a polytetrafluoroethylene mesh associated with Toupet fundoplication. A 70-year-old Japanese woman was admitted to our hospital because of sudden onset of upper abdominal pain. An upper gastrointestinal series revealed an incarcerated intrathoracic mesenterioaxial volvulus of the distal portion of the stomach and the duodenum. The complete laparoscopic approach was used to repair the volvulus. The laparoscopic procedures involved the repair of the hiatal hernia using polytetrafluoroethylene mesh and Toupet fundoplication. This case highlights the feasibility and effectiveness of the laparoscopic procedure, and laparoscopic repair of the hiatal defect using a polytetrafluoroethylene mesh associated with Toupet fundoplication may be useful for preventing postoperative recurrence of hiatal hernia, volvulus, and gastroesophageal reflux. PMID- 21528088 TI - Treatment of advanced rectal cancer after renal transplantation. AB - Renal transplantation is a standard procedure for end-stage renal disease today. Due to immunosuppressive drugs and increasing survival time after renal transplantation, patients with transplanted kidneys carry an increased risk of developing malignant tumors. In this case report, 3 patients with advanced rectal cancer after renal transplantation for renal failure were treated with anterior resection or abdominoperineal resection plus total mesorectal excision, followed by adjuvant chemotherapy. One patient eventually died of metastasized cancer 31 mo after therapy, although his organ grafts functioned well until his death. The other 2 patients were well during the 8 and 21 mo follow-up periods after rectal resection. We therefore strongly argue that patients with advanced rectal cancer should receive standard oncology treatment, including operation and adjuvant treatment after renal transplantation. Colorectal cancer screening in such patients appears justified. PMID- 21528089 TI - Pancreatic hyperechogenicity on endoscopic ultrasound examination. AB - There is an ongoing discussion on how to diagnose a hyperechogenic pancreas and what is the clinical significance of diffusely hyperechogenic pancreas. Computerized tomography and magnetic resonance imaging are the more appropriate methods to diagnose pancreatic hyperechogenicity when compared with transcutaneous or endoscopic ultrasound examination. More importantly, pancreatic hyperechogenicity may not be a certain indicator of pancreatic fat infiltration. Even if it is true, we do not know the clinical significances of pancreatic fat accumulation. Some suggested that excess fat in the pancreas is associated with chronic pancreatitis. However, several histological studies on human alcoholic chronic pancreatitis did not prove the presence of fatty pancreas in such cases. Thus, except for aging, it is very rare to have truly steatotic pancreas in the absence of certain human diseases. PMID- 21528092 TI - Primary gastric signet ring cell carcinoma presenting as cardiac tamponade. AB - Primary gastric signet ring cell carcinoma presenting as cardiac tamponade is difficult to diagnosis early. Patients are generally asymptomatic until the disease is advanced. General practitioners usually focus on the initial symptoms related to pericarditis and pericardial effusion. We report a case of signet-ring cell carcinoma of the stomach presenting as cardiac tamponade with pericarditis and pericardial effusion but without any gastrointestinal symptoms. A 49-year old woman was admitted because of progressive dyspnea and cough. Chest X-ray revealed an increased cardiothoracic ratio and a small amount of bilateral pleural effusion. Two dimensional ultrasonographic echocardiography pericardial effusions with atrial and right ventricular early diastolic collapse were found, establishing the diagnosis of cardiac tamponade. Pericardiocentesis was performed and 420 mL of bloody fluid was taken. The patient died of respiratory failure and cardiac arrest on October 28, 2009. Post-mortem examination revealed diffuse gastric mucosa erosion and edema with stomach mucosa incrassation in the greater curvature. The primary lesion was histopathologically diagnosed as signet-ring cell carcinoma of the stomach. PMID- 21528091 TI - Chemotherapy plus percutaneous radiofrequency ablation in patients with inoperable colorectal liver metastases. AB - AIM: To access the efficacy of chemotherapy plus radiofrequency ablation (RFA) as one line of treatment in inoperable colorectal liver metastases. METHODS: Eligible patients were included in three Phase II studies. In the first study percutaneous RFA was used first followed by 6 cycles of 5-fluorouracil, leucovorin and irinotecan combination (FOLFIRI) (adjunctive chemotherapy trial). In the other two, chemotherapy (FOLFIRI or 5-fluorouracil, leucovorin and oxaliplatin combination) up to 12 cycles was used first with percutaneous RFA offered to responding patients (primary chemotherapy trials). RESULTS: Thirteen patients were included in the adjunctive chemotherapy trial and 17 in the other two. At inclusion they had 1-4 liver metastases (up to 6.5 cm in size). Two patients died during chemotherapy. All patients in the adjunctive chemotherapy trial and 44% in the primary chemotherapy studies had their metastases ablated. Median PFS and overall survival in the adjunctive study were 13 and 24 mo respectively while in the primary chemotherapy studies they were 10 and 21 mo respectively. Eighty one percent of the patients had tumour relapse in at least one previously ablated lesion. CONCLUSION: Chemotherapy plus RFA in patients with low volume inoperable colorectal liver metastases seems safe and relatively effective. The high local recurrence rate is of concern. PMID- 21528090 TI - Markers of bile duct tumors. AB - Biliary tract carcinomas are relatively rare, representing less than 1% of cancers. However, their incidence has increased in Japan and in industrialized countries like the USA. Biliary tract tumors have a poor prognosis and a high mortality rate because they are usually detected late in the course of the disease; therapeutic treatment options are often limited and of minimal utility. Recent studies have shown the importance of serum and molecular markers in the diagnosis and follow up of biliary tract tumors. This review aims to introduce the main features of the most important serum and molecular markers of biliary tree tumors. Some considerable tumor markers are cancer antigen 125, carbohydrate antigen 19-9, carcinoembryonic antigen, chromogranin A, mucin 1, mucin 5, alpha fetoprotein, claudins and cytokeratins. PMID- 21528093 TI - Classification and management of bile duct injuries. AB - To review the classification and general guidelines for treatment of bile duct injury patients and their long term results. In a 20-year period, 510 complex circumferential injuries have been referred to our team for repair at the Instituto Nacional de Ciencias Medicas y Nutricion "Salvador Zubiran" hospital in Mexico City and 198 elsewhere (private practice). The records at the third level Academic University Hospital were analyzed and divided into three periods of time: GI-1990-99 (33 cases), GII- 2000-2004 (139 cases) and GIII- 2004-2008 (140 cases). All patients were treated with a Roux en Y hepatojejunostomy. A decrease in using transanastomotic stents was observed (78% vs 2%, P = 0.0001). Partial segment IV and V resection was more frequently carried out (45% vs 75%, P = 0.2) (to obtain a high bilioenteric anastomosis). Operative mortality (3% vs 0.7%, P = 0.09), postoperative cholangitis (54% vs 13%, P = 0.0001), anastomosis strictures (30% vs 5%, P = 0.0001), short and long term complications and need for reoperation (surgical or radiological) (45% vs 11%, P = 0.0001) were significantly less in the last period. The authors concluded that transition to a high volume center has improved long term results for bile duct injury repair. Even interested and tertiary care centers have a learning curve. PMID- 21528094 TI - Small intestine diverticula: Is there anything new? AB - AIM: To globally approach the clinical entity of small bowel diverticulosis and, at the same time, set out the treatment options. METHODS: We analysed 77 cases of diverticula located in the duodenum, jejunum and ileum that were treated in our department, evaluating the symptoms, diagnostic approach and offered treatment. RESULTS: Almost half of the diverticula (46.7%) were incidentally discovered and Meckel's diverticula represented the majority (43%) that were actually the only true diverticula. A high complication rate (53%) which included inflammation with or without perforation (22%), bleeding (10%) or obstructive ileus (12%) due to small bowel diverticulosis was reported. The preoperative diagnosis was often impossible (44% of complicated cases). CONCLUSION: Although small bowel diverticulosis has a low incidence, it should be in the clinician's mind in order to avoid misdiagnosis. PMID- 21528095 TI - Trichobezoar: A rare cause of bowel obstruction. AB - A bezoar is an intraluminal mass formed by the accumulation of undigested material in the gastrointestinal tract. A trichobezoar is a bezoar made up of hair and is a rare cause of bowel obstruction of the proximal gastrointestinal tract. They are seen mostly in young women with trichotillomania and trichotillophagia and symptoms include epigastric pain, nausea, loss of appetite and bowel or gastric outlet obstruction. We herein describe a case of a trichobezoar that presented as a gastric outlet obstruction and was subsequently successfully removed via a laparotomy. PMID- 21528096 TI - Transanal polypectomy using single incision laparoscopic instruments. AB - Transanal excision of rectal polyps with laparoscopic instrumentation and a single incision laparoscopic port is a novel technique that uses technology originally developed for abdominal procedures from the natural orifice of the rectum. Transanal endoscopic microsurgery (TEM) is a well established surgical approach for certain benign or early malignant lesions of the rectum, under specific indications. Our technique is a hybrid technique of transanal surgery, a reasonable method for polyp resection without the need of the sophisticated and expensive instrumentation of TEM which can be applied whenever endoscopic or conventional transanal surgical removal is not feasible. PMID- 21528097 TI - Gender and Psychological Essentialism. AB - When individuals reason in an essentialist way about social categories, they assume that group differences reflect inherently different natures (Gelman, 2003; Rothbart & Taylor, 1992). This paper describes the psychological and social implications of essentialist beliefs, and examines the extent to which children exhibit psychological essentialism when reasoning about gender. The authors discuss reasons young children as well as older children show essentialist reasoning in some contexts, but not in others. Finally, the authors suggest directions for future research, and discuss a primary challenge to many working in this field: reduction of rigid gender beliefs. PMID- 21528098 TI - Influenza immunization with trehalose-stabilized virus-like particle vaccine using microneedles. AB - Morbidity and mortality due to seasonal and pandemic influenza could be reduced by simpler vaccination methods that enable improved vaccination coverage. In this study, solid metal microneedles coated with influenza virus-like particle (VLP) vaccine were inserted into skin for intradermal immunization. Microneedles were applied to the skin by hand and designed for simple administration with little or no training. Inclusion of trehalose in the coating formulation significantly increased vaccine stability during coating by maintaining hemagglutination activity. Mice vaccinated with stabilized microneedles developed strong antibody responses comparable to conventional intramuscular vaccination and were fully protected against subsequent viral challenge. Whereas, coating microneedles with a coating solution lacking trehalose led to only partial protection against lethal viral challenge. Therefore, our results show that microneedles coated with trehalose-stabilized VLP vaccine can be a promising tool for improving influenza vaccination. PMID- 21528099 TI - Both Sides of the Coin: Randomization from the Perspectives of Physician Investigators and Patient-Subjects. AB - Randomization is the "gold standard" design for clinical research trials, and is accepted as the best way to reduce bias. Although some controversy remains over this matter, we believe equipoise is the fundamental ethical requirement for conducting a randomized clinical trial. Despite much attention to the ethics of randomization, the moral psychology of this study design has not been explored. This paper analyzes the ethical tensions that arise from conducting these studies, and examines the moral psychology of this design from the perspectives of physician-investigators and patient-subjects. We conclude with a discussion of the practical implications of this analysis. PMID- 21528100 TI - A Drug Court Outcome Evaluation Comparing Arrests in a Two Year Follow-up Period. AB - Since the first drug court in Miami in 1989, the drug court movement has spread throughout the United States, influencing how drug-involved offenders are treated in the criminal justice system. This paper reports on an outcome evaluation of a drug court in San Mateo County, California. Arrest rates were compared for drug court participants (N=618) and non-participants (N=75), and for graduates (N=257) and non-graduates (N=361). Factors associated with rearrest were assessed for participants in both groups. During a two-year follow-up period, there were no significant differences in rearrest rates between the participant and non participant groups. Comparisons between graduates and non-graduates showed lower rearrest rates for graduates (19% vs. 53%, chi(2)(1)=73.5, p<0.01). In a model including participants and non-participants, only a prior history of conviction predicted an increased likelihood of rearrest whereas being female and older decreased the likelihood of rearrest. In addition, among drug court participants only, graduating decreased the likelihood of rearrest. PMID- 21528101 TI - Towards a dynamical network view of brain ischemia and reperfusion. Part IV: additional considerations. AB - The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the fourth in a series of four papers whose purpose is to work towards a revision of the concept of brain ischemia by applying network concepts to develop a bistable model of brain ischemia. Here we consider additional issues to round out and close out this initial presentation of the bistable network view of brain ischemia. Initial considerations of the network architecture underlying the post-ischemic state space are discussed. Network and differential equation models of brain ischemia are compared. We offer a first look at applying the bistable model to focal cerebral ischemia. The limitations of the present formulation of the bistable model are discussed. This work concludes with a series of questions by which to direct future efforts. PMID- 21528102 TI - Towards a dynamical network view of brain ischemia and reperfusion. Part I: background and preliminaries. AB - The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the first in a series of four papers whose purpose is to work towards a revision of the concept of brain ischemia by applying network concepts to develop a bistable model of brain ischemia. This first paper sets the stage for developing the bistable model of brain ischemia. Necessary background in network theory is introduced using examples from developmental biology which, perhaps surprisingly, can be adapted to brain ischemia with only minor modification. Then, to move towards a network model, we extract two core generalizations about brain ischemia from the mass of empirical data. First, we conclude that all changes induced in the brain by ischemia can be classified as either damage mechanisms that contribute to cell death, or stress responses that contribute to cell survival. Second, we move towards formalizing the idea of the "amount of ischemia", I, as a continuous, nonnegative, monotonically increasing quantity. These two generalizations are necessary precursors to reformulating brain ischemia as a bistable network. PMID- 21528103 TI - Multilevel Confirmatory Factor Analysis of a Scale Measuring Interagency Collaboration of Children's Mental Health Agencies. AB - Multilevel confirmatory factor analysis was used to evaluate the factor structure underlying the 12-item, three-factor Interagency Collaboration Activities Scale (IACS) at the informant level and at the agency level. Results from 378 professionals (104 administrators, 201 service providers, and 73 case managers) from 32 children's mental health service agencies supported a correlated three factor model at each level and indicated that the item loadings were not significantly (p < .05) different across levels. Reliability estimates of the three factors (Financial and Physical Resource Activities, Program Development and Evaluation Activities, and Collaborative Policy Activities) at the agency level were .81, .60, and .72, respectively, while these estimates were .79, .82, and .85 at the individual level. These multilevel results provide support for the construct validity of the scores from the IACS. When the IACS was examined in relation to level-1 and level-2 covariates, results showed that participants' characteristics (i.e., age, job role, gender, educational level, and number of months employed) and agency characteristics (i.e., state location and number of employees) were not significantly (p > .05) related to levels of interagency collaboration. PMID- 21528104 TI - The importance of scale for spatial-confounding bias and precision of spatial regression estimators. AB - Residuals in regression models are often spatially correlated. Prominent examples include studies in environmental epidemiology to understand the chronic health effects of pollutants. I consider the effects of residual spatial structure on the bias and precision of regression coefficients, developing a simple framework in which to understand the key issues and derive informative analytic results. When unmeasured confounding introduces spatial structure into the residuals, regression models with spatial random effects and closely-related models such as kriging and penalized splines are biased, even when the residual variance components are known. Analytic and simulation results show how the bias depends on the spatial scales of the covariate and the residual: one can reduce bias by fitting a spatial model only when there is variation in the covariate at a scale smaller than the scale of the unmeasured confounding. I also discuss how the scales of the residual and the covariate affect efficiency and uncertainty estimation when the residuals are independent of the covariate. In an application on the association between black carbon particulate matter air pollution and birth weight, controlling for large-scale spatial variation appears to reduce bias from unmeasured confounders, while increasing uncertainty in the estimated pollution effect. PMID- 21528105 TI - Rosuvastatin counteracts vessel arterialisation and sinusoid capillarisation, reduces tumour growth, and prolongs survival in murine hepatocellular carcinoma. AB - Background and Aims. An arterial blood supply and phenotypic changes of the sinusoids characterise the liver vasculature in human hepatocellular carcinoma (HCC). We investigated the effects of rosuvastatin on liver vessel anomalies, tumour growth and survival in HCC. Methods. We treated transgenic mice developing HCC, characterized by vessel anomalies similar to those of human HCC, with rosuvastatin. Results. In the rosuvastatin group, the survival time was longer (P < .001), and liver weight (P < .01) and nodule surface (P < .01) were reduced. Rosuvastatin decreased the number of smooth muscle actin-positive arteries (P < .05) and prevented the sinusoid anomalies, with decreased laminin expression (P < .001), activated hepatic stellate cells (P < .001), and active Notch4 expression. Furthermore, rosuvastatin inhibited endothelial cell but not tumour hepatocyte functions. Conclusions. Rosuvastatin reduced the vessel anomalies and tumour growth and prolonged survival in HCC. These results represent new mechanisms of the effects of statin on tumour angiogenesis and a potential target therapy in HCC. PMID- 21528106 TI - A New Type of Motor: Pneumatic Step Motor. AB - This paper presents a new type of pneumatic motor, a pneumatic step motor (PneuStep). Directional rotary motion of discrete displacement is achieved by sequentially pressurizing the three ports of the motor. Pulsed pressure waves are generated by a remote pneumatic distributor. The motor assembly includes a motor, gearhead, and incremental position encoder in a compact, central bore construction. A special electronic driver is used to control the new motor with electric stepper indexers and standard motion control cards. The motor accepts open-loop step operation as well as closed-loop control with position feedback from the enclosed sensor. A special control feature is implemented to adapt classic control algorithms to the new motor, and is experimentally validated. The speed performance of the motor degrades with the length of the pneumatic hoses between the distributor and motor. Experimental results are presented to reveal this behavior and set the expectation level. Nevertheless, the stepper achieves easily controllable precise motion unlike other pneumatic motors. The motor was designed to be compatible with magnetic resonance medical imaging equipment, for actuating an image-guided intervention robot, for medical applications. For this reason, the motors were entirely made of nonmagnetic and dielectric materials such as plastics, ceramics, and rubbers. Encoding was performed with fiber optics, so that the motors are electricity free, exclusively using pressure and light. PneuStep is readily applicable to other pneumatic or hydraulic precision motion applications. PMID- 21528107 TI - Error Estimation of Nanoindentation Mechanical Properties Near a Dissimilar Interface via Finite Element Analysis and Analytical Solution Methods. AB - Nanoindentation methods are well suited for probing the mechanical properties of a heterogeneous surface, since the probe size and contact volumes are small and localized. However, the nanoindentation method may introduce errors in the computed mechanical properties when indenting near the interface between two materials having significantly different mechanical properties. Here we examine the case where a soft material is loaded in close proximity to an interface of higher modulus, such as the case when indenting bone near a metallic implant. Results are derived from both an approximate analytical quarter-space solution and a finite element model, and used to estimate the error in indentation determined elastic modulus as a function of the distance from the apex of contact to the dissimilar interface, for both Berkovich and spherical indenter geometries. Sample data reveal the potential errors in mechanical property determination that can occur when indenting near an interface having higher stiffness, or when characterizing strongly heterogeneous materials. The results suggest that caution should be used when interpreting results in the near interfacial region. PMID- 21528108 TI - Word Learning in Children Following Cochlear Implantation. AB - An experimental procedure was developed to investigate word-learning skills of children who use cochlear implants (CIs). Using interactive play scenarios, 2- to 5-year olds were presented with sets of objects (Beanie Baby stuffed animals) and words for their names that corresponded to salient perceptual attributes (e.g., "horns" for a goat). Their knowledge of the word-object associations was measured immediately after exposure and then following a 2-hour delay. Children who use cochlear implants performed more poorly than age-matched children with typical hearing both receptively and expressively. Both groups of children showed retention of the word-object associations in the delayed testing conditions for words that were previously known. Our findings suggest that although pediatric CI users may have impaired phonological processing skills, their long-term memory for familiar words may be similar to children with typical hearing. Further, the methods that developed in this study should be useful for investigating other aspects of word learning in children who use CIs. PMID- 21528109 TI - Screening for Mood Disorder in Pregnant Substance-dependent Patients. AB - The Addiction Severity Index (ASI) and Beck Depression Inventory (BDI) were compared as screening tests for current mood disorder in pregnant substance dependent patients (N = 187). Mean ASI psychiatric Interviewer Severity Rating (ISR) and BDI scores for Diagnostic and Statistical Manual of Mental Disorder-IV diagnosed current mood disorder patients (n = 51) were 4.4 and 17.1, respectively, and for those without current mood disorder (n = 136) were 2.7 and 14.0, respectively. Areas under receiver operating characteristic curves were 0.73 (ASI) and 0.59 (BDI). The ASI psychiatric ISR predicted mood disorder with better sensitivity and specificity versus the BDI (0.82 and 0.49 for scores >=4 vs. 0.49 and 0.62 for scores >=17, respectively). PMID- 21528110 TI - Beliefs about racism and health among African American women with diabetes: a qualitative study. AB - Exposure to racism has been linked to poor health outcomes. Little is known about the impact of racism on diabetes outcomes. This study explored African American women's beliefs about how racism interacts with their diabetes self-management and control. Four focus groups were conducted with a convenience sample of 28 adult African American women with type 2 diabetes who were recruited from a larger quantitative study on racism and diabetes. The focus group discussions were transcribed verbatim and analyzed by the authors. Women reported that exposure to racism was a common phenomenon, and their beliefs did in fact link racism to poor health. Specifically, women reported that exposure to racism caused physiological arousal including cardiovascular and metabolic perturbations. There was consensus that physiological arousal was generally detrimental to health. Women also described limited, and in some cases maladaptive, strategies to cope with racist events, including eating unhealthy food choices and portions. There was consensus that the subjective nature of perceiving racism and accompanying social prohibitions often made it impossible to address racism directly. Many women described anger in such situations and the tendency to internalize anger and other negative emotions, only to find that the negative emotions would be reactivated repeatedly with exposure to novel racial stressors, even long after the original racist event remitted. African American women in this study believed that racism affects their diabetes self-management and control. Health beliefs can exert powerful effects on health behaviors and may provide an opportunity for health promotion interventions in diabetes. PMID- 21528111 TI - Community Partners in Care: Leveraging Community Diversity to Improve Depression Care for Underserved Populations. AB - Research suggests that the quality and outcomes of depression treatment for adults can be substantially improved through "collaborative care" programs. However, there is a lack of resources required to implement such programs in vulnerable communities. Our paper examines the planning phase of the Community Partners in Care (CPIC) initiative, which addresses this problem through a unique approach in which academic institutions partner directly with a wide range of community-based and service organizations in all phases of the project fielded in two underserved communities in Los Angeles. CPIC offers a unique opportunity to understand how diverse organizations can work together to address community depression care needs and to analyze the potential strengths and tradeoffs of coordinating among such varied entities. This article focuses on intra-group dynamics that surround the process of participatory research and reports results of the first wave of process evaluation of the planning phase of the CPIC initiative. Our analysis explores two main themes: Community-Partnered Participatory Research and benefits and challenges of collaboration in diverse groups. PMID- 21528112 TI - Synlabia after severe monilia infections: a case report. AB - CASE: A 25-year-old woman presented with acute urine retention with overflow 6 months after an inadequate treatment of severe monilia infections. Examination revealed complete adhesion between both labia majora. Division of adhesion was done with reconstruction by labial mucocutaneous flap. Complete recovery was achieved with good cosmetic outcome. CONCLUSION: Labial adhesions whatever their severity is can be surgically divided with complete correction by locally designed flap to reconstruct the introuitus with rapid recovery, good healing, and good cosmetic outcome. PMID- 21528113 TI - Screen-printed carbon electrodes modified by rhodium dioxide and glucose dehydrogenase. AB - The described glucose biosensor is based on a screen-printed carbon electrode (SPCE) modified by rhodium dioxide, which functions as a mediator. The electrode is further modified by the enzyme glucose dehydrogenase, which is immobilized on the electrode's surface through electropolymerization with m-phenylenediamine. The enzyme biosensor was optimized and tested in model glucose samples. The biosensor showed a linear range of 500-5000 mg L(-1) of glucose with a detection limit of 210 mg L(-1) (established as 3sigma) and response time of 39 s. When compared with similar glucose biosensors based on glucose oxidase, the main advantage is that neither ascorbic and uric acids nor paracetamol interfere measurements with this biosensor at selected potentials. PMID- 21528114 TI - Healthcare applications and services in converged networking environments. PMID- 21528115 TI - Enzymes as additives or processing AIDS in food biotechnology. PMID- 21528116 TI - Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: a voxel-based morphometry study. AB - AIMS: To use magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to search for evidence of altered brain morphology in patients with temporomandibular disorders (TMD). METHODS: Using VBM, regional gray and white matter volume was investigated in nine TMD patients and nine carefully matched healthy controls. RESULTS: A decrease in gray matter volume occurred in the left anterior cingulate gyrus, in the right posterior cingulate gyrus, the right anterior insular cortex, left inferior frontal gyrus, as well as the superior temporal gyrus bilaterally in the TMD patients. Also, white matter analyses revealed decreases in regional white matter volume in the medial prefrontal cortex bilaterally in TMD patients. CONCLUSION: These data support previous findings by showing that TMD, like other chronic pain states, is associated with changes in brain morphology in brain regions known to be part of the central pain system. PMID- 21528117 TI - Adolescents with temporomandibular disorder pain-the living with TMD pain phenomenon. AB - AIMS: To acquire a deeper understanding of adolescents' experiences of living with temporomandibular disorder (TMD) pain. METHODS: Twenty-one adolescents with TMD pain, aged 15 to 19, were strategically selected from a group of patients referred to an orofacial pain clinic. The patients were examined and received diagnoses per the Research Diagnostic Criteria for TMD. One-on-one interviews that followed a semistructured protocol focused on the patient's experiences of living with TMD pain. The interviews were recorded and transcribed verbatim, followed by content analysis to obtain a deeper understanding of adolescents' experiences living with TMD pain. RESULTS: Content analysis led to the overall theme "Adolescents with TMD live with recurrent pain; physical problems and daily demands form a vicious circle that causes adolescents to oscillate between hope and despondency." The latent content forming the theme is grounded in three categories that evolved from 13 subcategories. For instance, five subcategories headache; headache on awakening; jaw and tooth pain; constant thoughts of pain; and popping, cracking, clicking, and locking-formed the category that was labeled TMD pain is recurrent. The latent interpretation, ie, the meaning, of this category was that adolescents with TMD pain constantly thought about the pain, even when it was absent. CONCLUSION: TMD pain is a substantial problem for affected adolescents and has consequences for all aspects of their lives. In this study, the adolescents were able to talk openly and introduce issues outside of the interview protocol. Qualitative analysis deepens our understanding of the adolescent patient with TMD pain. PMID- 21528118 TI - Differences in psychosocial functioning and sleep quality between idiopathic continuous orofacial neuropathic pain patients and chronic masticatory muscle pain patients. AB - AIM: To examine differences between idiopathic continuous orofacial neuropathic pain (ICONP) patients and chronic masticatory muscle pain (MMP) patients for psychosocial functioning and sleep quality. METHODS: Archival data were used to compare 81 ICONP patients to 81 age- and sex-matched chronic MMP patients on pain severity, life interference, life control, and affective distress measures from the Multidimensional Pain Inventory (MPI), a global severity index of psychological symptoms from the Symptom Checklist-90-R (SCL-90-R), Posttraumatic Stress Disorder Checklist-Civilian (PCL-C), and overall sleep quality from the Pittsburgh Sleep Quality Index (PSQI). MANOVA, MANCOVA, and chi-square analysis were used to investigate differences between the two groups in the psychosocial and sleep variables. RESULTS: The ICONP group reported greater pain severity (P = .013) and more life interference (P = .032) than the MMP group, while the MMP group reported higher levels of global psychological symptoms (P = .005) than the ICONP group. After controlling for pain severity, however, the MMP group demonstrated greater affective distress (P = .014) than the ICONP group, and life interference was no longer significantly different between the groups. ICONP patients were more likely to report a traumatic life event (P = .007). CONCLUSION: Although ICONP patients are likely to present more intense pain and report that their pain causes more interference in their lives, MMP patients are more likely to present with higher levels of overall psychological symptoms. The greater levels of pain severity reported by ICONP patients appear to be partially responsible for their higher levels of reported life interference. PMID- 21528119 TI - Combined topical and systemic clonazepam therapy for the management of burning mouth syndrome: a retrospective pilot study. AB - AIMS: To evaluate retrospectively the efficacy of administering an anticonvulsant medication, clonazepam, by dissolving tablets slowly orally before swallowing, for the management of burning mouth syndrome (BMS). METHODS: A retrospective clinical records audit was performed of patients diagnosed with BMS between January 2006 and June 2009. Patients were prescribed 0.5 mg clonazepam three times daily, and changes were made to this regimen based on their individual response. Patients were asked to dissolve the tablet orally before swallowing and were reviewed over a 6-month period. Pain was assessed by patients on an 11-point numerical scale (0 to 10). A nonparametric (Spearman) two-tailed correlation matrix and a two-tailed Mann-Whitney test were performed. RESULTS: A total of 36 patients (27 women, 9 men) met the criteria for inclusion. The mean (+/- SEM) pain score reduction between pretreatment and final appointment was 4.7 +/- 0.4 points. A large percentage (80%) of patients obtained more than a 50% reduction in pain over the treatment period. One patient reported no reduction in pain symptoms, and one third of the patients had complete pain resolution. Approximately one third of patients experienced side effects that were transient and mild. CONCLUSION: This pilot study provides preliminary evidence that the novel protocol of combined topical and systemic clonazepam administration provides an effective BMS management tool. PMID- 21528120 TI - Unexplained somatic comorbidities in patients with burning mouth syndrome: a controlled clinical study. AB - AIMS: To evaluate the prevalence of unexplained extraoral symptoms in a group of patients with burning mouth syndrome (BMS) and compare the prevalence with that in patients with oral lichen planus (OLP) and age- and gender-matched controls. METHODS: The occurrence of extraoral symptoms was analyzed in a group of 124 BMS patients, a group of 112 oral lichen planus (OLP) patients, and a group of 102 healthy patients. Oral symptoms were collected by a specialist in oral medicine and a general dentist, while data concerning unexplained extraoral symptoms were gathered by each specialist ward, ie, ophthalmology, gynecology, otolaryngology, gastroenterology, neurology, cardiology, internal medicine, and dermatology. A Fisher exact test (alpha = .05) and Kruskal-Wallis test (alpha = .05) were performed for statistical analysis. RESULTS: In the BMS group, 98 (96.1%) patients reported unexplained extraoral symptoms, while 4 (3.9%) patients reported only oral symptoms. A painful symptomatology in different bodily regions was reported more frequently by BMS patients (83.3%) than by OLP patients (1.8%) and healthy patients (11.7%) (P < .0001). The differences in the overall unexplained extraoral symptoms between BMS (96.1%) and OLP patients (9.3%) (P < .0001) and between BMS (96.1%) and healthy patients (15.7%) (P < .0001) were statistically significant. The unexplained extraoral symptoms in BMS patients consisted of pain perceived in different bodily areas (odds ratio [OR]: 255; 95% confidence interval [CI]: 58.4-1112), ear-nose-throat symptoms (OR: 399.7; 95%CI: 89.2-1790), neurological symptoms (OR: 393; 95% CI: 23.8-6481), ophthalmological symptoms (OR: 232.3; 95% CI: 14.1-3823), gastrointestinal complaints (OR: 111.2; 95% CI: 42.2-293), skin/gland complaints (OR: 63.5; 95% CI: 3.8-1055), urogenital complaints (OR: 35; 95% CI: 12-101), and cardiopulmonary symptoms (OR: 19; 95% CI: 4.5-82). CONCLUSION: The great majority of BMS patients presented with several additional unexplained extraoral comorbidities, indicating that various medical disciplines should be involved in the BMS diagnostic process. Furthermore, the results suggest that BMS may be classified as a complex somatoform disorder rather than a neuropathic pain entity. PMID- 21528121 TI - Oral pain and eating problems in Spanish adults and elderly in the Spanish National Survey performed in 2005. AB - AIMS: To analyze and quantify the sociodemographic, behavioral, and clinical factors influencing the oral pain and eating difficulties reported by Spanish 35- to 44-year-old adults and more elderly people in the most recent Spanish National Oral Health Survey. METHODS: Pain and chewing difficulties were gathered in a Likert-scale format from a representative sample of the Spanish general population between the ages of 35 and 44 years (n = 540) and 65 to 74 years (n = 540). Risk factors were identified using bivariate analysis, after which the crude association between risk factors (sociodemographic, behavioral, and clinical) and outcome variables (pain and eating problems) was assessed by adjusted odds ratios, calculated by means of multivariate logistic regression. RESULTS: In the 35- to 44-year-old adults, eating problems were mainly associated with caries and prosthetic treatment needs and oral pain by the number of decayed teeth. In the more elderly individuals, eating problems and oral pain were influenced by prosthetic needs and the number of missing teeth. Female sex was seen to be a risk factor for suffering pain and eating restrictions. Additionally, several independent variables such as social class, place of residence, brushing habits, or periodontal needs became nonsignificant after logistic regression modelling. CONCLUSION: According to this high-specificity regression model, caries and prosthetic treatment needs should be considered key factors in determining the oral well-being of the Spanish population. Missing teeth represent the most relevant influencing factor for the elderly and decayed teeth for younger adults. PMID- 21528122 TI - Risk factors for anterior disc displacement with reduction and intermittent locking in adolescents. AB - AIMS: To test the hypothesis that oral parafunctions and symptomatic temporomandibulair joint (TMJ) hypermobility are risk factors in adolescents for both anterior disc displacement with reduction (ADDR) and intermittent locking. METHODS: Participants were two hundred sixty 12- to 16-year-old adolescents (52.3% female) visiting a university clinic for regular dental care. ADDR and symptomatic TMJ hypermobility were diagnosed using a structured clinical examination. During the anamnesis, reports of intermittent locking and of several parafunctions were noted, eg, nocturnal tooth grinding, diurnal jaw clenching, gum chewing, nail biting, lip and/or cheek biting, and biting on objects. The adolescents' dentitions were examined for opposing matching tooth-wear facets as signs of tooth grinding. Risk factors for ADDR and intermittent locking were first assessed using univariate logistic regression and then entered into a stepwise backward multiple model. RESULTS: While in the multiple model, ADDR was weakly associated only with increasing age (P = .02, explained variance 8.1%), intermittent locking was weakly correlated to diurnal jaw clenching (P = .05, explained variance 27.3%). CONCLUSION: In adolescence, diurnal clenching may be a risk factor for intermittent locking while age may be a risk factor for ADDR. Symptomatic TMJ hypermobility seems to be unrelated to either ADDR or to intermittent locking. PMID- 21528123 TI - Quantitative sensory testing in the trigeminal region: site and gender differences. AB - AIMS: To establish a quantitative sensory testing (QST) profile in the trigeminal (V) area and test for site and gender differences in healthy humans. METHODS: A standardized QST protocol was applied on 15 healthy men (age range: 18 to 25 years old) and 15 age-matched women, and the sensitivity was examined bilaterally in facial sites supplied by the infraorbital (V2) and mental (V3) nerves. The cold detection threshold (CDT), cold pain threshold (CPT), warm detection threshold (WDT), heat pain threshold (HPT), thermal sensory limen (TSL), mechanical detection threshold (MDT), mechanical pain sensitivity (MPS), mechanical pain threshold (MPT), dynamic mechanical allodynia (ALL), windup ratio (WUR), pressure pain threshold (PPT), and vibration detection threshold (VDT) were determined. Data were tested with ANOVAs for repeated measures and post-hoc comparisons were calculated using Bonferroni tests. RESULTS: There were significant gender differences with lower threshold (higher sensitivity) in women for CDT (P = .030) and PPT (P = .006). A significantly lower threshold (higher sensitivity) was detected for HPT (P < .001), and significantly higher thresholds (lower sensitivity) for VDT (P < .001) and CDT (P < .001) in V2 compared to V3. There were no significant right-to-left side differences for any of the QST parameters. CONCLUSION: Application of this standardized QST protocol may allow for a better understanding of the underlying mechanisms from somatosensory phenotypes and provide basic information for the study of sensory dysfunctions in the V area. PMID- 21528124 TI - Nighttime facial pain induced by myxoma of the maxillary sinus: a case report. AB - Myxomas of the maxillary sinus are uncommon benign tumors arising from the primitive mesenchyme. They may be related to dental malformations or missing teeth but may also occur without any abnormalities. They usually result in facial deformity manifested by slow, painless bony expansion. Although these tumors are well-circumscribed, they are more extensive than they appear due to their local aggressiveness and bone erosion. Therefore, it should be widely resected with maximal preservation of surrounding structures to prevent recurrence. This article reports a case of myxoma of the maxillary sinus and nighttime facial pain in a 33-year-old male who underwent curettage following debridement with a microdebrider via an intranasal endoscopic approach and surgery involving a modified Caldwell-Luc approach. PMID- 21528126 TI - Interpenetrated metal-organic frameworks of self-catenated four-connected mok nets. AB - We describe two cobalt metal-organic frameworks built by amide derivative and organodicarboxyl co-ligands, displaying 3-fold interpenetration of 6(5).8-mok nets which are 4-connected self-catenated nets described theoretically in the early nineties. PMID- 21528125 TI - Artificial lantipeptides from in vitro translations. AB - We have devised a protocol for enzyme-free insertion of dehydroalanine, dehydrobutyrine and thioether crosslinks into translated peptides. In vitro translation using 4-selenalysine and 4-selenoisoleucine as substitutes for lysine and isoleucine yields peptides that can be converted to polycyclic structures using mild chemistry in water. This methodology presents a gateway for exploring the potential of artificial lantipeptides as scaffolds for drug development. PMID- 21528127 TI - Triterpenoids. AB - This review covers the isolation and structure determination of triterpenoids, including squalene derivatives, protostanes, lanostanes, holostanes, cycloartanes, dammaranes, euphanes, tirucallanes, tetranortriterpenoids, quassinoids, lupanes, oleananes, friedelanes, ursanes, hopanes, serratanes and saponins; 278 references are cited. PMID- 21528128 TI - Intrinsic disorder in S100 proteins. AB - Although the members of the largest subfamily of the EF-hand proteins, S100 proteins, are evolutionarily young, their functional diversity is extremely broad, partly due to their ability to adapt to various targets. This feature is a hallmark of intrinsically disordered proteins (IDPs), but none of the S100 proteins are recognized as IDPs. S100 are predicted to be enriched in intrinsic disorder, with 62% of them being predicted to be disordered by at least one of the predictors: 31% are recognized as 'molten globules' and 15% are shown to be in extended disordered form. The disorder level of predicted disordered S100 regions is conserved compared to that of more structured regions. The central disordered stretch corresponds to the major part of pseudo EF-hand loop, helix II, hinge region, and an initial part of helix III. It contains about half of known sites of enzymatic post-translational modifications (PTMs), confirming that this region can be flexible in vivo. Most of the internal residues missing in tertiary structures belong to the hinge. Both hinge and pseudo EF-hand loop correspond to the local maxima of the PONDR(r) VSL2 score and are shown to be evolutionary hotspots, leading to gain of new functional properties. The action of PTMs is shown to be destabilizing, in contrast with the effect of metal binding or S100 dimerization. Formation of the S100 heterodimers relies on the interplay between the structural rigidity of one of the S100 monomers and the flexibility of another monomer. The ordered regions dominate in the S100 homodimerization sites. Target-binding sites generally consist of distant regions, drastically differing in their disorder level. The disordered region comprising most of the hinge and the N-terminal half of helix III is virtually not involved into dimerization, being intended solely for target recognition. The structural flexibility of this region is essential for recognition of diverse target proteins. At least 86% of multiple interactions of S100 proteins with binding partners are attributed to the S100 proteins predicted to be disordered. Overall, the intrinsic disorder is inherent to many S100 proteins and is vital for activity and functional diversity of the family. PMID- 21528129 TI - Molecular adaptability of nucleoside diphosphate kinase b from trypanosomatid parasites: stability, oligomerization and structural determinants of nucleotide binding. AB - Nucleoside diphosphate kinases play a crucial role in the purine-salvage pathway of trypanosomatid protozoa and have been found in the secretome of Leishmania sp., suggesting a function related to host-cell integrity for the benefit of the parasite. Due to their importance for housekeeping functions in the parasite and by prolonging the life of host cells in infection, they become an attractive target for drug discovery and design. In this work, we describe the first structural characterization of nucleoside diphosphate kinases b from trypanosomatid parasites (tNDKbs) providing insights into their oligomerization, stability and structural determinants for nucleotide binding. Crystallographic studies of LmNDKb when complexed with phosphate, AMP and ADP showed that the crucial hydrogen-bonding residues involved in the nucleotide interaction are fully conserved in tNDKbs. Depending on the nature of the ligand, the nucleotide binding pocket undergoes conformational changes, which leads to different cavity volumes. SAXS experiments showed that tNDKbs, like other eukaryotic NDKs, form a hexamer in solution and their oligomeric state does not rely on the presence of nucleotides or mimetics. Fluorescence-based thermal-shift assays demonstrated slightly higher stability of tNDKbs compared to human NDKb (HsNDKb), which is in agreement with the fact that tNDKbs are secreted and subjected to variations of temperature in the host cells during infection and disease development. Moreover, tNDKbs were stabilized upon nucleotide binding, whereas HsNDKb was not influenced. Contrasts on the surface electrostatic potential around the nucleotide-binding pocket might be a determinant for nucleotide affinity and protein stability differentiation. All these together demonstrated the molecular adaptation of parasite NDKbs in order to exert their biological functions intra parasite and when secreted by regulating ATP levels of host cells. PMID- 21528130 TI - Identification of a high-affinity network of secretagogin-binding proteins involved in vesicle secretion. AB - Secretagogin is a hexa EF-hand Ca(2+)-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. The protein has been noted for its expression in specific neuronal subtypes in the support of hierarchical organizing principles in the mammalian brain. Secretagogin has previously been found to interact with SNAP25 involved in Ca(2+)-induced exocytosis. Here, the cellular interaction network of secretagogin has been expanded with nine proteins: SNAP-23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2, based on screening of a high content protein array and validation and quantification of binding with surface plasmon resonance and GST pulldown assays. All targets have association rate constants in the range 10(4)-10(6) M(-1) s(-1), dissociation rate constants in the range 10(-3)-10(-5) s(-1) and equilibrium dissociation constants in the 100 pM to 10 nM range. The novel target SNAP23 is an essential component of the high affinity receptor for the general membrane fusion machinery and an important regulator of transport vesicle docking and fusion. Complementary roles in vesicle trafficking are known for ARFGAP2 and DOC2alpha in regulating fusion of vesicles to membranes, kinesin 5B and tubulin for transport of vesicles in the cell, while rootletin builds up the rootlet believed to function as a scaffold for vesicles. The identification of a discrete network of interacting proteins that mediate secretion and vesicle trafficking suggests a regulatory role for secretagogin in these processes. PMID- 21528131 TI - Dynamic control of 3D chemical profiles with a single 2D microfluidic platform. AB - Dynamic control of three-dimensional (3D) chemical patterns with both high precision and high speed is important in a range of applications from chemical synthesis, flow cytometry, and multi-scale biological manipulation approaches. A central challenge in controlling 3D chemical patterns is the inability to create rapidly tunable 3D profiles with simple and direct approaches that avoid complicated microfabrication. Here, we present the ability to rapidly and precisely create 3D chemical patterns using a single two-dimensional (2D) microfluidic platform. We are not only able to create these 3D patterns, but can rapidly switch from one mode to another (e.g. from a focused to a defocused pattern in less than 1 second) via simple changes in inlet pressures. A feedback control scheme with a pressure modulation mechanism controls the pressure changes. In addition to experiments, we conducted computational simulations for guiding the optimum design of the channels as well as revealing the sensitivity of the patterns to the channel dimensions; these simulations have high experimental correlations. We also show that microvortices play an important role in creating these tunable 3D patterns in this microfluidic platform. We quantitatively determine the degrees of the focused patterns in 2D cross-sections using a focus index with a 2D Gaussian function. Our integrated approach combining feedback control with simple microfluidics will be useful for researchers in diverse disciplines including chemistry, engineering, physics, and biology. PMID- 21528132 TI - Monosubstituted arylimido hexamolybdates containing pendant amino groups: synthesis and structural characterization. AB - Three novel rigid-rod conjugated organic-POM hybrids (1, 2 and 3) containing pendant amino terminus, with different rod lengths and different substituents on the rod, have been respectively synthesized via one-pot reaction of hexamolybdate and the corresponding aromatic diamine (for 1 and 2) and reaction of octamolybdate and the corresponding aromatic diamine dihydrochloride (for 3) with N,N'-dicyclohexylcarbodiimide (DCC) as a dehydrating agent. These complexes have been characterized by UV/Vis, IR, (1)H NMR, ESI and single-crystal X-ray diffraction techniques. The influences of the rod length and substituents on the properties of these compounds have been systematically investigated, which provide necessary information for further preparations of complicated hybrid materials via reactions with pendant amino groups. PMID- 21528133 TI - Magnetic properties of isostructural M(H2O)4[Au(CN)4]2-based coordination polymers (M = Mn, Co, Ni, Cu, Zn) by SQUID and MUSR studies. AB - A series of isomorphous M(H(2)O)(4)[Au(CN)(4)](2).4H(2)O (M = Mn, Co, Ni, Zn; Cu is similar) coordination polymers was synthesized from the reaction of M(II) with KAu(CN)(4); they consist of octahedrally coordinated metal centres with four equatorial water molecules and trans-axial N-cyano ligands from [Au(CN)(4)](-) moieties, generating a linear 1-D chain of M(H(2)O)(4)[Au(CN)(4)]-units. An additional interstitial [Au(CN)(4)](-) unit forms AuN and hydrogen bonds with adjacent chains. The Cu(II) system readily loses water to yield Cu[Au(CN)(4)](2)(H(2)O)(4), which was not structurally characterized. The magnetic properties of these polymers were investigated by a combination of SQUID magnetometry and zero-field muon spin relaxation (ZF-MUSR). Only weak antiferromagnetic interactions along the chains are mediated by the [Au(CN)(4)] units, but the ZF-MUSR data indicates that interchain interactions yield a phase transition to a magnetically ordered state for Cu[Au(CN)(4)](2)(H(2)O)(4) below 0.6 K, while for M(H(2)O)(4)[Au(CN)(4)](2).4H(2)O (M = Co), depopulation of zero field split Kramer's doublets to an effective "S = 1/2" ground state yields a transition to a spin-frozen magnetic state below 0.26 K. On the other hand, only a simple slowing-down of spins above 0.02 K is observed for the more weakly zero field split M(H(2)O)(4)[Au(CN)(4)](2).4H(2)O (M = Mn, Ni) complexes. PMID- 21528134 TI - Comparison of the SidePak personal monitor with the Aerosol Particle Sizer (APS). AB - The aim of this study was to compare the performance of the TSI Aerodynamic Particle Sizer (APS) and the TSI portable photometer SidePak to measure airborne oil mist particulate matter (PM) with aerodynamic diameters below 10 MUm, 2.5 MUm and 1 MUm (PM(10), PM(2.5) and PM(1)). Three SidePaks each fitted with either a PM(10), PM(2.5) or a PM(1) impactor and an APS were run side by side in a controlled chamber. Oil mist from two different mineral oils and two different drilling fluid systems commonly used in offshore drilling technologies were generated using a nebulizer. Compared to the APS, the SidePaks overestimated the concentration of PM(10) and PM(2.5) by one order of magnitude and PM(1) concentrations by two orders of magnitude after exposure to oil mist for 3.3-6.5 min at concentrations ranging from 0.003 to 18.1 mg m(-3) for PM(10), 0.002 to 3.96 mg m(-3) for PM(2.5) and 0.001 to 0.418 mg m(-3) for PM(1) (as measured by the APS). In a second experiment a SidePak monitor previously exposed to oil mist overestimated PM(10) concentrations by 27% compared to measurements from another SidePak never exposed to oil mist. This could be a result of condensation of oil mist droplets in the optical system of the SidePak. The SidePak is a very useful instrument for personal monitoring in occupational hygiene due to its light weight and quiet pump. However, it may not be suitable for the measurement of particle concentrations from oil mist. PMID- 21528138 TI - Enhanced electrocatalytic performance of functionalized carbon nanotube electrodes for oxygen reduction in proton exchange membrane fuel cells. AB - Although nitrogen doped CNTs (N-CNTs) are considered as a promising alternative to platinized carbon for the oxygen reduction reaction (ORR) in polymer electrolyte membrane fuel cells (PEMFCs), the origin of the enhanced ORR activity with N-CNTs is not clear at present. Among several plausible reasons, the exposure of edge plane and creation of impurity band/surface states near the Fermi level are considered as major causes behind the catalytic activity. However, CNTs without nitrogen doping are not known to catalyze the ORR. In this work, we study the ORR activity of functionalized carbon nanotubes with different functional groups, such as sulfonic acid and phosphonic acid, in order to understand the role of surface functionalities in catalyzing the reaction. Functionalized CNTs show significantly enhanced activity towards the ORR, while CNTs without such surface functional groups do not reveal any such special ORR activity. Linear sweep voltammetry experiments with different rotation rates show diffusion controlled limiting current values for functionalized CNTs, and the 'n' values derived from Koutecky-Levich plots are 3.3 and 1.7 for S-MWCNTs and P MWCNTs, respectively. This work demonstrates the ORR activity of functionalized MWCNTs, which opens up new strategies for electrocatalyst design in PEMFCs. PMID- 21528139 TI - Synthesis and characterisation of group nine transition metal complexes containing new mesityl and naphthyl based azaindole scorpionate ligands. AB - Two novel boron-based flexible scorpionate ligands based on 7-azaindole, Li[HB(azaindolyl)(2)(1-naphthyl)] and Li[HB(azaindolyl)(2)(mesityl)] {Li[(Naphth)Bai] and Li[(Mes)Bai] respectively}, have been prepared (mesityl = 2,4,6-trimethylphenyl). These salts have been isolated in two forms, either as dimeric structures which contain bridging hydride interactions with the lithium centres or as crystalline material containing mono nuclear bis-acetonitrile solvates. The newly formed ligands have been utilised to prepare a range of group nine transition metal complexes with the general formula [M(COD){kappa(3)-NNH-HB (azaindolyl)(2)(Ar)}] (where M = rhodium, iridium; Ar = 1-naphthyl, mesityl; COD = 1,5-cyclooctadiene) and [Rh(NBD){kappa(3)-NNH-HB (azaindolyl)(2)(Ar)}] (where NBD = 2,5-norbornadiene; Ar = 1-naphthyl, mesityl). These new complexes have been compared to the previously reported compounds which contain the related scorpionate ligands Li[HB(azaindolyl)(2)(phenyl)] and K[HB(azaindolyl)(3)] {Li[(Ph)Bai] and K[Tai] respectively}. Structural characterisation of the complexes [Rh(COD){kappa(3)-NNH-HB (azaindolyl)(2)(mesityl)}], [Ir(COD){kappa(3) NNH-HB (azaindolyl)(2)(mesityl)}] and [Rh(NBD){kappa(3)-NNH-HB (azaindolyl)(2)(naphthyl)}] confirm the expected kappa(3)-NNH coordination mode for these new ligands. Spectroscopic analysis suggests strong interactions of the B-H functional group with the metal centres in all cases. PMID- 21528141 TI - Metal-induced aggregation of mononucleotides-stabilized gold nanoparticles: an efficient approach for simple and rapid colorimetric detection of Hg(II). AB - A new approach for simple and rapid colorimetric detection of Hg(2+) in aqueous solution is proposed based on Hg(2+)-induced aggregation of mononucleotides stabilized gold nanoparticles. PMID- 21528140 TI - Sialic acid C-glycosides with aromatic residues: investigating enzyme binding and inhibition of Trypanosoma cruzi trans-sialidase. AB - Several alpha-configured C-sialosides were synthesised by cross metathesis and further synthetic derivatisation to obtain ligands for Trypanosoma cruzi trans sialidase (TcTS), a key enzyme in Chagas disease. Affinities of these compounds to immobilised TcTS were measured by surface plasmon resonance (SPR). The K(D) values thus obtained are in the lower millimolar range and will be discussed. The results show the importance of addressing Tyr(119) and Trp(312) side chains of TcTS in target oriented ligand synthesis, since these amino acids constitute the acceptor binding region in the active site of TcTS. The best ligand showed a significant decrease of TcTS activity in a preliminary NMR based inhibition assay. PMID- 21528142 TI - Enantioselective formal hydration of alpha,beta-unsaturated acceptors: asymmetric conjugate addition of silicon and boron nucleophiles. AB - The direct enantioselective 1,4-addition of water to alpha,beta-unsaturated acceptors is an open challenge in asymmetric catalysis. Enantioselective conjugate addition of either silicon or boron nucleophiles and subsequent enantiospecific oxidative degradation of the carbon-element bond represents, however, an attractive detour. A single extra step thereby enables an indirect enantiocontrolled construction of (in a broader sense) aldols from alpha,beta unsaturated carbonyl and carboxyl compounds. While that strategy had been obvious for a long time, it was recent stunning progress in transition metal-catalysed activation of interelement linkages that brought about the solution to that long standing problem. A concise introduction of existing protocols for stereoselective 1,4-addition of oxygen nucleophiles is followed by a comprehensive summary of the recent rapid advances in transition metal-catalysed (and metal-free) asymmetric conjugate transfer of nucleophilic silicon and boron onto alpha,beta-unsaturated acceptors. PMID- 21528143 TI - From titanium oxydifluoride (TiOF2) to titania (TiO2): phase transition and non metal doping with enhanced photocatalytic hydrogen (H2) evolution properties. AB - Single-crystalline TiOF(2) crystals with cubical morphology were prepared via a facile solvothermal method and their transformation to anatase TiO(2) under different calcination conditions such as pure argon, moist argon and pure hydrogen sulfide (H(2)S) was explored by using XRD/Raman/UV-Vis/SEM/TEM/SAED. The non-metal sulfur doping was successfully fulfilled and the doped TiO(2) microcubes showed the best photocatalytic H(2) evolution property. PMID- 21528144 TI - Modular 'click' sensors for zinc and their application in vivo. AB - Although the central role that zinc plays in many biological processes and important disease states is now well-established, there remains a pressing need to develop an absolute understanding of the underlying biology of zinc trafficking in terms of its dynamic and quantitative processing in specific organelles. Here we describe the modular synthesis of zinc sensors using a 'click' approach and demonstrate the applicability of our new sensors in vivo using a zebrafish model. PMID- 21528146 TI - Fundamental studies and perceptions on the spillover mechanism for hydrogen storage. AB - In this feature article, the atomic-scale understanding of the hydrogen spillover mechanism for hydrogen storage in metal-doped carbon materials and metal-organic frameworks is discussed by critically assessing recent computational and experimental studies. It is argued that the spillover mechanism involves: (a) the generation and desorption of mobile H atoms on the metal nanoparticles (b) the diffusion of H atoms in weakly-bound states on the support (c) the sticking and immobilization of H atoms at preferential locations of the receptor where barriers to sticking are decreased, and, (d) the Eley-Rideal recombination of the adsorbed H atoms with diffusing mobile H atoms to form H(2). The implications and open questions on the mechanism and effectiveness of hydrogen storage by spillover are critically assessed. PMID- 21528145 TI - Tambjamine alkaloids and related synthetic analogs: efficient transmembrane anion transporters. AB - The tambjamine alkaloids and related synthetic analogs are potent transmembrane anion tranporters promoting bicarbonate/chloride exchange in model phospholipid liposomes and discharging pH gradients in living cells. PMID- 21528147 TI - Chemical functionalization of electrodes for detection of gaseous nerve agents with carbon nanotube field-effect transistors. AB - An innovative sensor for the detection of nerve agents in the gas phase based on a carbon nanotube field-effect transistor was developed. A high sensitivity to organophosphorus gases was obtained by modifying gold electrodes with specific tailor-made self-assembled monolayers. PMID- 21528148 TI - Surface chemical modifications and surface reactivity of nanodiamonds hydrogenated by CVD plasma. AB - The present study focuses on the interaction of hydrogen microwave CVD plasma with nanodiamonds (NDs). Hydrogen treated NDs (H-NDs) were characterized using electron spectroscopies (XPS, AES) without air exposure. A surface temperature higher than 700 degrees C is needed to remove the oxygen present on raw NDs. The kinetics of oxygen removal were investigated. Moreover, UHV annealings of H-NDs after ageing in ambient air clearly underline that 75% of the oxygen is related to physisorbed species. Finally, H-NDs were efficiently grafted using photochemical reaction with alkenes and a spontaneous coupling of aryldiazonium salts. These results confirm similar electronic surface properties between bulk and nano diamond materials. PMID- 21528149 TI - Dependence of pKa on solute cavity for diprotic and triprotic acids. AB - A systematic study of DeltaG(aq)/pK(a) for monoprotic, diprotic, and triprotic acids has been carried out based on DFT/aug-cc-pVTZ combined with CPCM and SMD solvation modeling. All DFT/cavity set combinations considered showed similar accuracy for DeltaG(aq)(1)/pK(a1) (70% within +/-2.5 kcal mol(-1) of experiment) while only the M05-2X/Pauling cavity combination gave reasonable results for DeltaG(aq)(2)/pK(a2) when both pK(a) values are separated by more than three units (70% within +/-5.0 kcal mol(-1) of experiment). The choice of experimental data is critical to the interpretation of the calculated accuracy especially for several inorganic acids. For the calculation of DeltaG(aq)(3)/pK(a3), the larger experimental uncertainty and an unrealistic orbital population of diffuse function for trianions in the gas phase hinders an evaluation of the predictive performance. We find the M05-2X functional with the Pauling cavity set is the best choice for DeltaG(aq)(2)/pK(a2) prediction in aqueous media while all DFT/cavity sets considered were competitive for DeltaG(aq)(1)/pK(a1). PMID- 21528150 TI - Recent developments and perspectives in palladium-catalyzed cyanation of aryl halides: synthesis of benzonitriles. AB - The palladium-catalyzed cyanation of Ar-X (X = I, Br, Cl, OTf, and H) allows for an efficient access towards benzonitriles. After its discovery in 1973 and following significant improvements in recent decades, this methodology has become nowadays the most popular for preparation of substituted aromatic nitriles. In this critical review, we summarize the important developments in this area from 2000 until 2010 (151 references). PMID- 21528151 TI - General synthesis and characterization of a family of layered lanthanide (Pr, Nd, Sm, Eu, and Gd) hydroxide nanowires. AB - A family of layered lanthanide (Pr, Nd, Sm, Eu, and Gd) hydroxide nanowires (NWs) has been synthesized via a hydrothermal route. These NWs are ~8 nm in diameter and a few micrometres in length. The obtained Eu- and Gd-based layered hydroxide NWs consist of layered structure with two interlayer spacings. The effects of hydrothermal temperature and time on the transition of the layered structure were investigated. Photoluminescence of the Eu-based layered hydroxide NWs was also studied. These layered lanthanide hydroxide NWs combine the advantages of lanthanide and layered hydroxides, which will expand the inorganic layered materials and can be expected to be used as building blocks for further fabrication of functional nanostructures. PMID- 21528152 TI - Semiconductor nanostructure-based photovoltaic solar cells. AB - Substantial efforts have been devoted to design, synthesize, and integrate various semiconductor nanostructures for photovoltaic (PV) solar cells. In this article, we will review the recent progress in this exciting area and cover the material chemistry and physics related to all-inorganic nanostructure solar cells, hybrid inorganic nanostructure-conductive polymer composite solar cells, and dye-sensitized solar cells. PMID- 21528153 TI - A family of multicyclic indolosesquiterpenes from a bacterial endophyte. AB - Three novel indolosesquiterpenes, xiamycin B (1b), indosespene (2), and sespenine (3), along with the known xiamycin A (1a) were isolated from the culture broth of Streptomyces sp. HKI0595, a bacterial endophyte of the widespread mangrove tree Kandelia candel. Agar diffusion assays revealed moderate to strong antimicrobial activities against several bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, while no cytotoxicity against human tumor cell lines was observed. Together with the previously reported oridamycin, the endophyte metabolites represent the first indolosesquiterpenes isolated from prokaryotes. PMID- 21528154 TI - Asporin expression is highly regulated in human chondrocytes. AB - A significant association between a polymorphism in the D repeat of the gene encoding asporin and osteoarthritis, the most frequent of articular diseases, has been recently reported. The goal of the present study was to investigate the expression of this new class I small leucine-rich proteoglycan (SLRP) in human articular chondrocytes. First, we studied the modulation of asporin (ASPN) expression by cytokines by Western blot and reverse transcription-polymerase chain reaction. Interleukin-1beta and tumor necrosis factor-alpha downregulated ASPN, whereas transforming growth factor-beta1 (when incubated in a serum-free medium) upregulated it. Similarly to proinflammatory cytokines, chondrocyte dedifferentiation induced by a successive passages of cells was accompanied by a decreased asporin expression, whereas their redifferentiation by three dimensional culture restored its expression. Finally, we found an important role of the transcription factor Sp1 in the regulation of ASPN expression. Sp1 ectopic expression increased ASPN mRNA level and promoter activity. In addition, using gene reporter assay and electrophoretic mobility shift assay, we showed that Sp1 mediated its effect through a region located between -473 and -140 bp upstream of the transcription start site in ASPN gene. In conclusion, this report is the first study on the regulation of asporin expression by different cytokines in human articular chondrocytes. Our data indicate that the expression of this gene is finely regulated in cartilage and suggest a major role of Sp1. PMID- 21528155 TI - All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from Autism spectrum disorder. AB - Deficits in social behavior in mice lacking the CD38 gene have been attributed to impaired secretion of oxytocin. In humans, similar deficits in social behavior are associated with autistic spectrum disorder (ASD), for which genetic variants of CD38 have been pinpointed as provisional risk factors. We sought to explore, in an in vitro model, the feasibility of the theory that restoring the level of CD38 in ASD patients could be of potential clinical benefit. CD38 transcription is highly sensitive to several cytokines and vitamins. One of these, all-trans retinoic acid (ATRA), a known inducer of CD38, was added during cell culture and tested on a large sample of N = 120 lymphoblastoid cell (LBC) lines from ASD patients and their parents. Analysis of CD38 mRNA levels shows that ATRA has an upmodulatory potential on LBC derived from ASD patients as well as from their parents. The next crucial issue addressed in our study was the relationship between levels of CD38 expression and psychological parameters. The results obtained indicate a positive correlation between CD38 expression levels and patient scores on the Vineland Adaptive Behavior Scale. In addition, analysis of the role of genetic polymorphisms in the dynamics of the molecule revealed that the genotype of a single-nucleotide polymorphism (rs6449182; C>G variation) in the CpG island of intron 1, harboring the retinoic-acid response element, exerts differential roles in CD38 expression in ASD and in parental LBC. In conclusion, our results provide an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids. PMID- 21528156 TI - Time of diagnosis of oral clefts: a multicenter study. AB - OBJECTIVE: To determine the time of diagnosis of typical orofacial clefts in different Brazilian regions and its influence on age at surgical correction. METHOD: This was a prospective, descriptive, cross-sectional study conducted in medical centers in the Southeast, South, and Northeast of Brazil. Trained speech therapists and geneticists interviewed the parents of affected children using a previously validated questionnaire. Epi-Info and SPSS were used for data analysis. Significance level was set at 5% (p <= 0.05). RESULTS: The sample consisted of 215 interviews conducted in the following regions: 21.9% (47) in the Southeast, 51.1% (110) in the South, and 27% (58) in the Northeast. Monthly family income was higher in the Southeast (p <= 0.05). Cleft lip and palate were found in 61.4% (132) of cases, cleft palate in 20.9% (45), and cleft lip in 17.7% (38). Diagnosis occurred in the maternity ward in 75.3% (162) of cases, during the prenatal period in 14% (30), and after hospital discharge in 10.2% (22). The Southeast had a higher frequency of prenatal diagnosis (27.7%), possibly related to greater purchasing power in this region and greater availability of prenatal investigation. Of all cases diagnosed in the maternity ward, 74.4% occurred in the Northeast. However, no significant difference was found when comparing time of diagnosis, region, and age at first surgery. CONCLUSION: Considering that diagnosis is more common in the maternity ward, local health care teams should be trained in order to effectively improve the initial care of these patients. Although time of diagnosis did not affect age at surgery, it favors the planning of neonatal care and treatment of affected infants. PMID- 21528158 TI - Statistical quality control charts: new tools for studying the body mass index of populations from the young to the elderly. AB - BACKGROUND AND AIMS: Statistical quality control charts (SQCCs) have been widely used in numerous manufacturing processes to keep fluctuations within the acceptable limits but no applications have been applied to weight management studies yet. The aims of the present study were (1) to show that using the mean Body Mass Index (BMI) values as the only indicator to assess the weight status of populations might be misleading in clinical weight management studies; and (2) to introduce a powerful tool, SQCCs, to keep fluctuations in BMIs within acceptable limits in a given population for healthy aging. METHODS: The study design was cross-sectional. The distributions of individual BMIs (n=829) between specified limits (USL=24.9 and LSL=18.5) and the pattern of BMI change by age were studied using X-charts, tolerance charts and a capability analysis. RESULTS: The mean BMI increased in both genders by age. In some groups, although a significant number of people were outside the normal weight BMI limits the mean BMI values were within the normal limits (18.5=20 ng/ml were found to be associated with better lower extremity muscle function and strength. Forty- six % of participants had 25OHD levels >=20 ng/ml. Women with 25OHD levels >=20 ng/ml scored higher on the muscle function tests (11.2+/-0.9 vs.10.0+/-2.1; p<0.003) and had stronger knee extensor (13.4+/-2.7 vs.11.6+/-2.5 Kg.; p<0.03) and hip abductor (8.3+/-2.7 vs. 7.3+/-3.1 Kg; p<0.04) muscles; strength of their hip flexors tended to be higher but did not reach significantly different values (17.0+/-3.3 vs. 15.4+/-2.8 Kg.; 0.1>p>0.05). Negative correlation was observed between iPTH and muscle function (r= -0.436; p<0.02). CONCLUSION: 25OHD levels >=20 ng/ml are needed for a better muscle function and strength. Assessing vitamin D nutritional status in adults aged >= 65 years would allow correcting hypovitaminosis D and improve muscle function and strength. PMID- 21528161 TI - Unawareness of memory impairment and behavioral abnormalities in patients with Alzheimer's disease: relation to professional health care burden. AB - OBJECTIVES: The present study investigates the impact of unawareness of deficit (anosognosia) in patients with Alzheimer's disease upon professional health care burden. DESIGN: Cross-sectional study with a consecutive clinical sample from an Alzheimer day-care hospital in France. SUBJECTS: 65 patients with probable AD, aged from 75 to 94 years old, consecutively admitted at the Alzheimer Day Hospital to complete a program of cognitive stimulation and psychosocial rehabilitation. MEASUREMENTS: Each patient was submitted to a standardized evaluation including clinical investigation, cerebral imagery, and neuropsychological assessment. Anosognosia of memory deficit and anosognosia of behavioral disturbances were measured as the "discrepancy scores" between patients' self-reports and family member ratings of patient memory performance and behavioral disturbances. Professional health care burden was assessed with the Professional Health Care Dementia Burden Index (PCDBI; maximal score: 12), designed for this study. Multiple linear regressions were used to examine the correlations between the PCDBI and the severity of anosognosia. RESULTS: The findings showed a significant positive correlation between the PCDBI and both anosognosia of memory impairment and behavioral abnormalities (both p at least less than 0.05). However, there was no significant correlation between the severity of the burden and the severity of cognitive decline or functional impairment (both p at least>0.05). CONCLUSION: Anosognosia in Alzheimer disease patients has a negative impact upon the professional caregivers' burden over and above the cognitive deficit and the functional impairments. PMID- 21528162 TI - Diagnosis of Alzheimer's disease patients with rapid cognitive decline in clinical practice: interest of the Deco questionnaire. AB - BACKGROUND: Patients with Alzheimer's disease (AD) who deteriorate rapidly are likely to have a poorer prognosis. There is a clear need for a clinical assessment tool to detect such a decline in newly diagnosed patients. OBJECTIVE: To identify the predictive factors of rapid cognitive decline (RCD) in a cohort of patients with mild to moderate AD ; and to validate a self-questionnaire for caregivers as a diagnostic tool for rapid decline. DESIGN AND ANALYSIS: An open label, observational, 12-month, multicenter, French study. Physicians were asked to record data of three eligible rivastigmine naive (or on rivastigmine for < 1 year) AD patients. Risk factors of RCD and the detection power of the Deterioration Cognitive Observee scale (Deco), a 19 item self-questionnaire for caregivers, were assessed at endpoint using regression analyses. RESULTS: Out of the 361 patients enrolled in the study, 91 (25.2%) were excluded due to loss of follow-up. Among subjects using cholinesterase inhibitors or memantine, 161 (59.6%) experienced a stabilization (29.2%) or an improvement (30.4%) in global functioning as measured by the CGI-C. Sixty of the remaining 204 patients retained for analysis (29.6%, CI 95% [23.4; 35.8]) lost three or more points on the MMSE score between the inclusion and one of the follow-up visit. In the multivariate logistic regression analysis, institutionalization, higher level of education and the loss of 3 points or more on the MMSE were found to be significant predictors of a rapid cognitive loss in this population. The threshold which maximizes the predictive values of the Deco score as a diagnostic tool of rapid cognitive decline was significantly different according to the age of the patient (below or over 75 years old). A score below 16 for patients < 75 years old and below 14 for patients >= 75 years old consistently predicted a RCD within the next year. CONCLUSION: The Deco test appears to be a simple tool to alert the physician to the possibility of an aggressive course of the disease which warrants particular management. PMID- 21528163 TI - Assessment of analytical methods used to measure changes in body composition in the elderly and recommendations for their use in phase II clinical trials. AB - It is estimated that in the next 20 years, the amount of people greater than 65 years of age will rise from 40 to 70 million, and will account for 19% of the total population. Age-related decreases in muscle mass and function, known as sarcopenia, have been shown to be related to functional limitation, frailty and an increased risk of morbidity and mortality. Therefore, with an increasing elderly population, interventions that can improve muscle mass content and/or function are essential. However, analytical techniques used for measurement of muscle mass in young subjects may not be valid for use in the elderly. Therefore, the purpose of this review is to examine the applied specificity and accuracy of methods that are commonly used for measurement of muscle mass in aged subjects, and, to propose specific recommendations for the use of body composition measures in phase II clinical trials of function-promoting anabolic therapies. PMID- 21528164 TI - The anabolic response to resistance exercise and a protein-rich meal is not diminished by age. AB - OBJECTIVES: The synergistic effect of resistance exercise and protein ingestion on muscle protein anabolism in young adults has been well described. However, it is unclear if this relationship is maintained in older adults who are at greater risk of sarcopenic muscle loss. To this end, we sought to determine if the synergistic response to a bout of resistance exercise and a protein-rich lean beef meal was altered by age. SETTING: The University of Texas Medical Branch, Clinical Research Center, Galveston, Texas. PARTICIPANTS: Healthy young (n=7, 29+/-3 y) and older (n=7, 67+/-2 y) adults. DESIGN: Mixed muscle fractional synthesis rate (FSR) was calculated during a 3 h post-absorptive/rest period and again during a 5 h period following ingestion of a protein-rich meal (340 g lean beef) and bout of resistance exercise (6 sets of 8 repetitions of isotonic knee extension exercise at 80% one repetition maximum). MEASUREMENTS: Venous blood samples and vastus lateralis muscle biopsy samples were obtained during a primed (2.0 umol/kg) constant infusion (0.08 umol?kg(-1)min(-1)) of L- [ring-13C6] phenylalanine. RESULTS: Mixed muscle FSR increased by approximately 108% in both young [pre: 0.073+/-0.008; post: 0.156+/-0.021(SE) %/h, p<0.001] and older adults (pre: 0.075+/-0.004; post: 0.152+/-0.017 %/h, p=0.003) following the meal and resistance exercise bout. CONCLUSION: Aging does not diminish the increase in muscle protein synthesis following a high-quality protein rich meal and bout of resistance exercise. PMID- 21528165 TI - Effect of accelerometry on the functional mobility of older rehabilitation inpatients as measured by functional independence measure--locomotion (FIM) gain: a retrospective matched cohort study. AB - OBJECTIVES: To examine the effect of wearing an accelerometer (without provision of feedback) on the mobility of older rehabilitation inpatients, using the locomotion component of the FIM at admission and discharge. DESIGN: A retrospective matched cohort study of patients aged >60 years admitted to a rehabilitation unit between 1 January 2008 and 1 January 2009. PARTICIPANTS: The exposed group was 17 patients who had worn an accelerometer daily during their rehabilitation stay. These patients were matched with 17 controls (the unexposed group) identified from the unit database using the following variables: age (within 5 years), sex, admission Functional Independence Measure (locomotion) score and reason for admission to rehabilitation. DATA ANALYSIS: The median length of stay, median FIM (locomotion) gain and median FIM (locomotion) efficiency for the two groups were compared using the Wilcoxon Signed Ranks Test. RESULTS: There were no statistically significant differences between the two groups at baseline. There was a trend towards a greater FIM-locomotion gain in the accelerometer group (mean 2.88+/- 2.12, median 3.00) compared with the no accelerometer group (mean 2.53+/- 2.07, median 3.00), but this did not reach statistical significance (p=0.08). There was no significant difference in the FIM -locomotion efficiency for the accelerometer group (mean 0.08 +/- 0.07, median 0.05) compared with the no accelerometer group(mean 0.01 +/- 0.09, median 0.06) (p= 0.33). CONCLUSION: In the absence of feedback and goal setting, wearing a monitoring device does not significantly increase physical activity. PMID- 21528166 TI - Nutritional status and associations with falls, balance, mobility and functionality during hospital admission. AB - OBJECTIVES: To explore associations between nutritional status, falls and selected falls risk factors amongst older hospitalized people. Lengths of stay amongst fallers and the malnourished were assessed. DESIGN: An observational longitudinal cohort study. SETTING: Geriatric Assessment and Rehabilitation Unit (GARU) of a tertiary teaching hospital. PARTICIPANTS: Admissions to the GARU during a six-month period were included. MEASUREMENTS: Associations between nutritional status and falls during hospitalization, reported preadmission history of falls, functional status, balance and mobility during GARU admission were analysed. Associations between nutritional status or experiencing a hospital fall and length of stay were also examined. RESULTS: Malnutrition prevalence was 39% (75/194, 95% CI 32-46%) with odds of falling during admission being 1.49 (95%CI: 0.81, 2.75), p< 0.20). Patients assessed as malnourished were older (p<0.001) and more likely to have a poorer score on both the admission (p<0.05) and discharge (p<0.009) timed "Up and Go" test. Malnutrition was associated with reduced mobility (p<0.05). Those who fell during admission had statistically greater lengths of stay compared with non-fallers [median (range): 57.0 (7-127) vs 35.0 (5-227) days; p<0.002]. CONCLUSION: Evidence of reduced mobility was evident during GARU admission amongst older people assessed as malnourished. Considering the results, a larger study concerning nutritional status, functionality and falls in the hospitalized population is warranted. The influence of nutritional status upon a person's physical functioning should be considered more broadly in falls research. PMID- 21528167 TI - Measures of body composition and risk of heart failure in the elderly: the Rotterdam study. AB - OBJECTIVES: The incidence of heart failure increases with aging. Aim of the present study was to determine whether measures body composition predict incident heart failure in older adults. SETTING: Prospective community-based cohort study. 5, 868 men and women aged 55 years and older participating the Rotterdam study. Measures of body mass index and waist circumference were obtained at baseline. Information on incident heart failure was obtained during follow-up. Cox regression analyses were performed to investigate the possible association between measure of body composition and incident heart failure. RESULTS: During a mean follow up of 10.9 (SD +/-4.4) years, 765 participants had heart failure. After adjustment for age and gender, 1-standard deviation of body mass index, waist circumference and the waist-hip ratio predicted heart failure (HR 1.25; 95% CI 1.17-1.34; HR 1.26; 95% CI 1.18-1.36; and HR 1.17; 95% CI 1.08-1.27), respectively. In age-stratified analyses, 1-standard deviation of body mass index (1.17; 95% CI 1.06- 1.29) and waist circumference (1.16; 95% CI 1.05- 1.29) were still associated with the risk of heart failure in the oldest participants, whereas the waist-hip ratio was not (1.06; 95% CI 0.945-1.18). CONCLUSION: Although estimates decrease with age, measures of overall and central adiposity predict incident heart failure among community dwelling older adults. PMID- 21528168 TI - Predictors of institution admission in the year following acute hospitalisation of elderly people. AB - OBJECTIVES: The aim of the study was to identify factors related to institutionalisation within one-year follow up of subjects aged 75 or over, hospitalised via the emergency department (ED). DESIGN: Prospective multicentre cohort. SETTING: Nine French university teaching hospitals. PARTICIPANTS: One thousand and forty seven (1 047) non institutionalised subjects aged 75 or over, hospitalised via ED. A sub-group analysis was performed on the 894 subjects with a caregiver. MEASUREMENTS: Patients were assessed using Comprehensive Geriatric Assessment (CGA) tools. Cox survival analysis was performed to identify predictors of institutionalisation at one year. RESULTS: Within one year after hospital admission, 210 (20.1%) subjects were institutionalised. For the overall study population, age >85 years (HR 1.6; 95%CI 1.1-2.1; p=0.005), inability to use the toilet (HR 1.6; 95%CI 1.1-2.4; p=0.007), balance disorders (HR 1.6; 95%CI 1.1-2.1; p=0.005) and presence of dementia syndrome (HR 1.9; 95%CI 1.4-2.6; p<0.001) proved to be independent predictors of institutionalisation; while a greater number of children was inversely linked to institutionalisation (HR 0.8; 95%CI 0.7-0.9; p<0.001). Bathing was of borderline significance (p=.09). For subjects with a caregiver, initial caregiver burden was significantly linked to institutionalisation within one year, in addition to the predictors observed in the overall study population. CONCLUSIONS: CGA performed at the beginning of hospitalisation in acute medical wards is useful to predict institutionalisation. Most of the predictors identified can lead to targeted therapeutic options with a view to preventing or delaying institution admission. PMID- 21528170 TI - Identification of the main domains for quality of care and clinical research in nursing homes. PMID- 21528169 TI - Nutritional approach for inhibiting bone resorption in institutionalized elderly women with vitamin D insufficiency and high prevalence of fracture. AB - BACKGROUND: Nutritional approach to the deterioration of bone integrity and increased fracture risk appears to be particularly appropriate in elderly women living in nursing homes. OBJECTIVE: To investigate the beneficial effect of the consumption of soft plain cheese on bone resorption markers in institutionalized elderly women. DESIGN: Prospective, randomized crossover controlled study. SETTING: Six French nursing homes or other institutions for elderly. PARTICIPANTS: Institutionalized women >= 65 years old with low vitamin D status and calcium intake below 700 mg/day. INTERVENTION: Consumption of soft plain cheese made of semi-skimmed milk which was fortified by both vitamin D3 (+1.25 ug/100g) and milk extracted Ca, thus achieving a total Ca content of 151 mg/100g as compared to about 118 mg/100g for standard fresh cheese. Two servings were taken every day during the 6 weeks that preceded or followed a period of 6 weeks without soft plain cheese consumption. MEASUREMENTS: The primary end point was the change in serum carboxy terminal cross-linked telopeptide of type I collagen (CTX) selected as a marker of bone resorption. RESULTS: 29 women aged 73-94 yr were selected, 21 of them with mean age 87.2+/-6.1 years remained compliant. The intervention increased calcium and protein intakes by 51% (904+/-228 vs. 599+/ 122 mg/d) and 33 % (74.2+/-17.1 vs. 55.6+/-12.7 g/d, mean+/-SD), respectively. The dietary intervention was associated with a statistically significant increase in serum levels of both 25OHD and IGF-I, while those of [corrected] CTX and TRAP5b were significantly reduced. Compliance was 93,4 %. The daily consumption of two servings of soft plain cheese was well accepted in terms of tastiness and appetite suited portion size. CONCLUSION: This randomized crossover controlled trial demonstrates that in elderly women living in nursing homes, the consumption of soft plain cheese increasing the supply of vitamin D, calcium and proteins, could reduce bone resorption and thereby reduce the risk of incidental fragility fractures in the long term. PMID- 21528171 TI - Sickness absence associated with shared and open-plan offices--a national cross sectional questionnaire survey. AB - OBJECTIVE: The aim of this study was to examine whether shared and open-plan offices are associated with more days of sickness absence than cellular offices. METHODS: The analysis was based on a national survey of Danish inhabitants between 18-59 years of age (response rate 62%), and the study population consisted of the 2403 employees that reported working in offices. The different types of offices were characterized according to self-reported number of occupants in the space. The log-linear Poisson model was used to model the number of self-reported sickness absence days depending on the type of office; the analysis was adjusted for age, gender, socioeconomic status, body mass index, alcohol consumption, smoking habits, and physical activity during leisure time. RESULTS: Sickness absence was significantly related to having a greater number of occupants in the office (P<0.001) when adjusting for confounders. Compared to cellular offices, occupants in 2-person offices had 50% more days of sickness absence [rate ratio (RR) 1.50, 95% confidence interval (95% CI) 1.13-1.98], occupants in 3-6-person offices had 36% more days of sickness absence (RR 1.36, 95% CI 1.08-1.73), and occupants in open-plan offices (>6 persons) had 62% more days of sickness absence (RR 1.62, 95% CI 1.30-2.02). CONCLUSION: Occupants sharing an office and occupants in open-plan offices (>6 occupants) had significantly more days of sickness absence than occupants in cellular offices. PMID- 21528172 TI - The effects of sleep duration on the incidence of cardiovascular events among middle-aged male workers in Japan. AB - OBJECTIVES: Although previous epidemiological studies have investigated the relationship between sleep duration and various cardiovascular events, the results have been inconsistent. Accordingly, we conducted a follow-up survey to investigate the relationship between sleep duration and cardiovascular events among male workers, accounting for occupational factors that might confound the true relationship. METHODS: A total of 2282 male employees aged 35-54 years based in a factory in Japan were followed for 14 years. The risk of cardiovascular events was compared among 4 groups stratified based on sleep duration at baseline (<6, 6-6.9, 7-7.9, and >=8 hours). Cardiovascular events included stroke, coronary events and sudden cardiac death. The hazard ratios for events were calculated using a Cox proportional hazards model, with the 7-7.9-hour group serving as a reference. The model was adjusted for potential confounders including traditional cardiovascular risk factors and working characteristics. RESULTS: During 14 years of follow-up, 64 cardiovascular events were recorded including 30 strokes, 27 coronary events and 7 sudden cardiac deaths. After adjustment for possible confounders, the hazard ratios for cardiovascular and coronary events in the <6-hour group were 3.49 [95% confidence interval (95% CI) 1.30-9.40] and 4.95 (95% CI 1.31-18.73), respectively. There was no significant increment in the risk of stroke for any sleep duration groups. CONCLUSION: Short sleep duration (<6 hours) was a significant risk factor for coronary events in a Japanese male working population. PMID- 21528173 TI - Mammary-derived growth inhibitor (MDGI) cloned from human breast epithelial cells is expressed in fully differentiated lobular structures. AB - Mammary-derived growth inhibitor (MDGI), an inducer of rodent mammary differentiation and suppressor of human breast cancer cell growth, has been cloned from bovine and rodent mammary glands. The present study reports the cloning of MDGI from cultured human breast epithelial cells (HBEC-MDGI) as a cDNA fragment encoding a protein of 133 amino acids identical to heart fatty acid binding protein. Expression of HBEC-MDGI, as detected by in situ hybridization in paraffin-embedded normal breast tissues, was maximal in the most differentiated lobules type 4, low in the moderately differentiated lobules type 3, and absent in the least differentiated lobules types 1 and 2. HBEC-MDGI was not expressed in breast tissues that contained ductal hyperplasia, carcinoma in situ or invasive carcinomas. Our results indicate that HBEC-MDGI is a biomarker of lobular differentiation in the human breast, and its expression is silenced in poorly differentiated lobules as well as in the early and late stages of breast cancer progression. PMID- 21528174 TI - Inhibition of telomerase activity correlates with a decrease in the RNA component of telomerase during differentiation. AB - In most normal somatic cells the telomeres of human chromosomes shorten with each cell division because of low expression or lack of telomerase activity. Telomerase, a ribonucleoprotein that synthesizes telomeric DNA onto chromosomal ends, is reactivated or upregulated in tumor cells and maintains the stability of telomere length. We previously showed that treatment of HL60 leukemia cells with differentiation-inducing agents resulted in inhibition of telomerase activity. In the present study, we found that the decrease in telomerase activity did not temporally correlate with the expression of a differentiation marker, CD11b, on the cell surface. Mixing of protein extracts from telomerase-negative differentiated HL60 cells with those from parental HL60 cells did not result in inhibition of telomerase activity, suggesting that a diffusible cellular telomerase inhibitor was not produced in the differentiated cells. However, a decrease in telomerase activity correlated with a selective decrease of telomerase RNA expression, a decrease in the levels of total cellular RNA, and an increase in cells at G(0) phase. PMID- 21528175 TI - Frequent gains and losses of specific chromosome segments in human ovarian carcinomas shown by comparative genomic hybridization. AB - Total genomic DNA obtained from 24 ovarian carcinomas was examined for genomic imbalances by comparative genomic hybridization (CGH). A varying number of gains and losses (1 up to 31) of specific chromosomal segments was detected per tumor. Chromosomal segments which were most often present in increased copy numbers were (in decreasing order): 1q21, 8q24, 8q23, 3q26, 12p12-p13, 20q, 7q31, and 7q33 qter. Loss of material was found most frequently at 16q12, 13q13-q14, Xq, 8p21 p22, 5q13-q14, and 5q21. All these chromosomal segments involved in gains and losses may carry gene loci playing a more or less causal role in the process of ovarian malignancies. Based on these findings CGH can be regarded as a valuable tool for rapid screening of genomic imbalances in human tumors. PMID- 21528176 TI - High-dose chemotherapy with bone marrow transplantation for advanced colorectal cancer. AB - A chemotherapy regimen based on high doses of BCNU and mitomycin C with autologous bone marrow transplantation was used in 18 patients with advanced colorectal carcinoma. Haematological toxicity was manageable, with a short nadir for white blood cells and platelets. The response rate was 33%, with a prevalence in peritoneal lesions compared to liver or lung metastases. Extra-haematological toxicity appeared in 16% of cases: a case of veno-occlusive disease of the liver and two cases of lung impairment are discussed. Although the response rate obtained with the regimen was satisfactory, the more extensive use of high-dose chemotherapy followed by autologous bone marrow transplantation requires the identification of less toxic protocols. PMID- 21528177 TI - Inhibition of MAP kinase by sphingosine and its methylated derivative, N,N dimethylsphingosine. AB - Endogenous sphingolipid metabolites such as ceramides and sphingosines have been increasingly recognized as lipid mediators of cell growth, differentiation and apoptosis. We have previously studied the ability of sphingosine (Sph) and N,N dimethylsphingosine (DMS) to induce apoptosis in a variety of solid tumor cell lines. Here we report that in tumor cell lines displaying high mitogen-activated protein kinase activity (MAPK), treatment with 5 mu M of these sphingolipids significantly inhibited MAPK activity within 2-5 min (p < 0.005-0.01 as compared to controls) and induced apoptosis within hours. In contrast, untransformed cells and those tumor cell lines with low MAPK activity showed no significant change in activity and no apoptosis. High concentrations of C2-ceramide (50-100 mM), which induced apoptosis in the solid tumor cells, did not show significant effect on MAPK activity. MAPK activity was not directly inhibited in vitro, but tyrosine phosphatase activity was increased 2-4 fold in solid tumor cells by Sph or DMS (p < 0.01-0.05), suggesting that a phosphatase may play an important role in sphingolipid-directed MAPK regulation. Sph/DMS-induced apoptosis, but not MAPK inhibition, was blocked by protease inhibitors, indicating that MAPK inhibition is an earlier step of Sph/DMS-induced apoptosis than proteolysis. Furthermore, in human breast carcinoma MDA468 cells and human epidermal carcinoma A431 cells, both of which overexpress the epidermal growth factor (EGF) receptor, 20-200 nM EGF inhibited MAPK (p < 0.005-0.01) and induced apoptosis. These observations suggest that inhibition of the MAPK cascade may be involved in apoptotic signaling by Sph/DMS in some solid tumor cells, or by EGF in some cancer cells which overexpress the EGF receptor. Finally, the PKC-specific inhibitor, calphostin C, under conditions in which PKC is completely suppressed, inhibited MAPK activity and induced apoptosis only weakly in these solid tumor cells, whereas the non-specific PKC inhibitor staurosporine induced both apoptosis and MAPK inhibition significantly, suggesting that MAPK inhibition and apoptosis by Sph/DMS occurs independently of PKC in these cell lines, although these pathways may act cooperatively in other cell types. This study provides insight into possible mechanisms involved in sphingolipid-induced apoptosis in solid cancer tumor cell lines. PMID- 21528178 TI - Microsatellite instability of D17S513 on chromosome 17 is associated with progression of breast cancer. AB - Genetic abnormalities of chromosome 17 are frequently found in human breast cancer. Recently, loss of heterozygosity (LOH) and microsatellite instability (MSI) studies have shown evidence for the presence of at least several unknown tumor suppressor genes (TSG) on chromosome 17, in addition to the well known TP53 and the breast cancer susceptibility gene BRCA1. We have previously reported the establishment of a transformed human breast epithelial cell (HBEC) system induced by benzo(a)pyrene in vitro that is tumorigenic in an exogenous host. This has allowed us to develop a cell line designated BP1E-Tp cells. Further studies have shown that various regions of chromosome 17 in these cells expressed genomic changes in the forms of LOH and/or MSI, indicating that putative TSGs anchoring in these regions might have been the targets for the carcinogenic induction. In the present work, we report that normal chromosome 17, upon introduced into the BP1E-Tp cells, was able to partially reverse the transformed phenotypes in vitro as well as the tumorigenic phenotypes in vivo, providing direct functional evidence that chromosome 17 does harbor unknown TSGs. Moreover, we discovered that the MSI of D17S513 (located distal to TP53 at 17p13.1), pre-existing in BP1E Tp? cells and derived tumors, was abrogated in the BP1E-Tp cell-chromosome 17 microcell hybrids, or BPIE-Tp-17neo cells, and the derived tumors. The reversion of this MSI was in association with the phenotypic reversion observed in these cells, thus suggesting that MSI of D17S513 might represent an important event in the progression of breast carcinogenesis. We further confirmed this by analyzing two groups of primary human breast cancers, one group consisted of tumors less than 2 cm in diameter with negative lymph node, and another group of tumors larger than 5 cm in diameter with positive lymph nodes. We found that MSI of D17S513 occurred significantly more frequently in the second group of breast cancers (80%) than in the first group (18%). These results led us to conclude that chromosome 17 harbors putative TSGs, whose inactivation partially accounted for the expression of neoplastic phenotypes of the BP1E-Tp cells, and that MSI of D17S513 represents a genomic change occurring at the late stage of the neoplastic transformation of HBECs as well as during the progression of breast cancers. PMID- 21528179 TI - Differential expression and characterization of proto-oncogene product Ha-Ras GTPase in camel tissues. AB - Pas proto-oncogene product is known to be involved in transducing signals for growth, differentiation and oncogenesis in mammalian cells. Using a monoclonal antibody to human Ha-Ras, a camel homolog of Ha-Ras protein having an apparent molecular mass of 21 kDa was identified. The expression level of Ha-Ras protein in various tissues of camel was compared with that of mouse tissues. In camel it was found that expression of Ha-Ras protein was highest in the kidney and moderate in the liver. Expression of Ha-Ras in camel lung, testis, spleen, heart, brain, intestine and muscle was found to be very low. While Ha-Ras expression in mouse was found to be highest in the intestine. A moderate expression of Ha-Ras was found in mouse testis, kidney and heart. The kidney tissue extract of camel was immunoprecipitated using the same human Ha-Ras antibody. Biochemical characterization of the immunoprecipitate revealed that like most other G proteins, the camel homolog of Ras is a GTPase. The GTPase activity was found to be stimulated specifically by recombinant human Ras GAP p120 and neurofibromin. It suggests that both camel and human share the same Ras mediated growth signaling process and that human Ras GAP might be able to complement camel Ras GAP function. Camel homolog of Raf-1 and MAP kinase (member of Ras signaling pathway) were also identified by immunoblot. This is the first demonstration showing the existence of a Ras mediated growth signal transduction pathway in camel. PMID- 21528180 TI - Genetic predisposition and specific chromosomal defects associated with Sinclair swine malignant melanomas. AB - Cytogenetic abnormalities are the hallmarks of most cancers and cutaneous melanomas are no exception. The purpose of this study was to determine whether nonrandom chromosomal abnormalities are associated with development and spontaneous regression of congenital cutaneous melanoma in Sinclair miniature swine. Careful analyses of the peripheral blood lymphocytes, skin fibroblasts, and melanoma cell lines of Sinclair swine indicated telomeric association, genetic instability, and clonal marker formations involving swine chromosomes 2, 3, 6, 7, 12, and 17. PMID- 21528181 TI - Caffeic acid phenethyl ester profoundly modifies protein synthesis profile in type 5 adenovirus-transformed cloned rat embryo fibroblast cells. AB - Caffeic acid phenethyl ester (CAPE), an active component of propolis from bee hives, exerts a plethora of biological changes in diverse systems. These include antimitogenic, anticarcinogenic, anti-inflammatory and immunomodulatory responses. CAPE directly induces programmed cell death (apoptosis) in type 5 adenovirus (Ad5)-transformed cloned rat embryo fibroblast cells, wt3A. To identify the gene and protein expression changes induced by CAPE in wt3A cells we used a strategy involving in vitro translation of mRNAs followed by high resolution two-dimensional (2D) gel electrophoresis. This approach results in the detection of 745 spots, including 172 displaying differences in expression upon exposure to CAPE. A high proportion of spots show profound changes in spot intensity (42 spots with increased and 27 spots with decreased intensity) following CAPE treatment. These studies provide a basis for comparing these changes to known protein patterns of various cell populations with an ultimate aim of identifying families of polypeptides responsible for the up- and down regulation of cellular proteins during CAPE-induced apoptosis. Specific newly appearing or completely disappearing spots (52 and 51 molecular species, respectively) will be used to attempt to identify and retrieve their cDNA counterparts from an ordered cDNA library. These approaches represent a novel strategy for cloning genes associated with and potentially mediating apoptosis. PMID- 21528182 TI - Microcirculation and metastasis in a new mouse mammary tumor model system. AB - Two new metastatic mouse mammary tumor transplant lines have been established in nude mice. The Met-1 line, with the polyoma virus middle T (PyV-MT) transgene, metastasized with 100% efficiency. The Db-7 line, expressing a PyV-MT transgene mutated at positions 315 and 322, metastasized with 8.8% efficiency. Histology and computer-assisted intravital microscopy demonstrated that internal microcirculation in Met-1 was more complex than Db-7; Met-1 exhibited higher microvessel density and tortuosity (P < 0.0001). These indices of microvascular complexity correlated with the higher Met-1 metastatic rate (P < 0.0001). These two transplantable lines will be useful for investigating the complex relationship between angiogenesis and metastasis. PMID- 21528183 TI - Bacillus Calmette-Guerin (BCG) in the treatment of superficial bladder cancer. AB - Intravesical therapy is currently being used in the management of superficial transitional cell carcinoma of the urinary bladder. Its main objectives constitute treatment of existing or residual tumor, prevention of recurrence of tumor, prevention of disease progression, and prolongation of survival. The initial clinical stage and grade of bladder cancer remains the main determinant factors in survival, irrespective of the treatment. Intravesical chemotherapy has shown a decrease in short-term tumor recurrence rates, but has had no positive impact on disease progression or prolongation of survival. Bacillus Calmette Guerin (BCG) immunotherapy remains the most effective treatment and prophylaxis modality for superficial bladder cancer and results in a positive outcome on tumor recurrence, disease progression, and prolongation of survival. Although therapy by intravesical BCG instillation is widely accepted as the therapy of choice, the development of BCG-resistant bladder cancer remains a major setback. Thus, there is an urgent need for a major effective therapy for bladder cancer patients who are unresponsive to BCG therapy. This review summarizes briefly the recent highlights and advances in the therapy of superficial bladder cancer. This review also describes our preliminary findings achieved in in vitro model systems and our proposed new approaches to overcome the resistance of bladder cancer cells and render bladder cancer cells responsive to these new therapies. PMID- 21528184 TI - Homologous T and B cells immortalized in vitro by the Epstein-Barr virus exhibit differential genetical and functional features. AB - After in vitro EBV infection of peripheral blood lymphocytes (PBL), we previously obtained IL-2-independent T-cell lines expressing EBNA1 and LMP1 viral latent genes. One tumorigenic clone, NC5, was further characterized for chromosomal abnormalities, rearrangement and expression of oncogenes, and constitutive or induced activation of cellular transduction pathways. NC5 as well as TC cells derived from an NC5-induced tumor exhibited the same few chromosomal abnormalities absent in normal PBL and B-cell lines (LCLs) from the same donor. No rearrangement or altered expression of C-MYC, BCL-2 and NF-KB2 oncogenes could be detected. In contrast, we found high levels of BCL-X and thioredoxin (TRX), as markers of EBV infection or T-cell activation/transformation status. No constitutive activation of NF-kappa B or STAT transcriptional complexes was observed in these cells. For NF-kappa B, this was in apparent contradiction with its reported inducibility mediated by LMP1, taking into account that NF-kappa B was still inducible by TNF alpha or PMA and ionomycin. Our results highlight independence of EBV protein-mediated transformation towards classical cellular pathways in T-lymphocytes. PMID- 21528185 TI - p53 overexpression in normal and dysplastic tissues adjacent to p53 negative squamous cell carcinomas of the head and neck. AB - p53 overexpression was present in the normal or dysplastic epithelium, but absent in the adjacent invasive cancers of five patients with head and neck squamous cell carcinomas (HNSCC), when p53 immunostaining (IHC) was performed. In three of the five p53 immunoreactive dysplasias and adjacent p53 negative invasive cancers single stranded conformation polymorphism (SSCP) results from exon 7 and 8 were also obtained. Bandshifts in exon 7 were detected in two dysplasias, and bandshifts in exon 8 were found in a third. Sequencing of exon 7 in the first dysplasia with bandshift indicated a deletion of codon 241-242 (loss of CT) resulting in a frame shift. In the second dysplasia with bandshift a mutation was observed in codon 244 resulting in a Gly-->Arg substitution in the protein sequence. In the adjacent IHC p53 negative invasive cancer lesions, no bandshifts could be observed by SSCP, and sequencing did not reveal any mutated p53. WAF1/p21 (IHC) expression was assayed to study p53 function. Image cytometry (ICM) DNA analysis, estimating genetic instability, showed progress in DNA aberration for invasive cancer lesions as compared with the dysplasias. Human papillomavirus (HPV DNA) was not detected by a polymerase chain reaction (PCR) in any of the five cancers thus excluding possible p53 degradation caused by HPV protein. In conclusion, the finding of p53 mutations in mild, moderate, and severe dysplasia indicates that p53 mutation, not only p53 immunoreactivity, can be an early event in HNSCC carcinogenesis. The lack of p53 immunoreactivity in the invasive cancers adjacent to p53 positive dysplasias could possibly be attributed to loss of the mutant allele, or clonal heterogeneity. PMID- 21528186 TI - Association of tumor induced vascularization with clinicopathological parameters in cervical neoplasm. AB - Angiogenic properties have been shown in preinvasive cervical lesions. Our goal was to determine the angiogenesis in cervical intraepithelial neoplasms (CIN), the relationship between microvessel counts, histopathological parameters and the clinical outcome in invasive cervical carcinoma. Comparison of microvessel counts from normal epithelium with that from CIN and invasive carcinoma showed significant increases in pre-cancerous lesions and invasive cancer (p < 0.0001). Microvessel density, assessed by CD31 immunostaining, was found to be associated with the overall survival in women with clinical stage IB cervical carcinoma (p < 0.03). There was a significant association of microvessel density (p < 0.05) with relapse-free survival in patients with regional lymph node metastasis. PMID- 21528187 TI - Reconstruction of the two-dimensional distribution of p53 positive staining patches in sun-exposed morphologically normal skin. AB - 1,320 serial sections were microscopically examined from 11 excisions of human skin with a variety of neoplastic lesions. In total about 1 cm(2) of morphologically normal epidermis was scrutinized. The emphasis was on the topography of epidermal 'p53 patches' of morphologically normal keratinocytes apparently driven into clonal expansion by a mutation of the p53 gene or an analogous mechanism causing constitutive nuclear accumulation of p53. The p53 patches were only rarely in contact with dysplasia or carcinoma in situ supporting previous somatic genetic evidence that patches are not common precursors of squamous cell neoplasia. The size of the p53 patches varied from 0.03 to at least 12 mm(2). About 34% of epidermis was covered by p53 patches deduced to be originally derived from an average of 40 cells per cm(2) by clonal expansion. This implies that a large number of skin cells are at risk of contracting further mutations in the p53 gene and other parts of the genome, if the 'guardian of the genome hypothesis' of the p53 gene is correct and exposure to sun-light continues. This finding together with calculations based on number of basal cells/mm(2) skin area suggest that prevalence of mutations which apparently drive stem cells into clonal growth is about 1:15,000 stem cells in 70 80 years old Caucasian sun-exposed skin at latitude 60 degrees North. PMID- 21528188 TI - Expression of human beta 1,4-galactosyltransferase in gynecological cancer cell lines. AB - We examined the expression of beta 1,4-GT gene products in 11 gynecological cancer cell lines. A 4.7 kb mRNA and protein (54,000 Da and 57,000 Da) were detected by Northern blot and Western blot. Immunocytochemical staining revealed that beta 1,4-GT was localized in the Golgi or ER of tumor cells. An intense beta 1,4-GT mRNA signal was detected in ovarian and cervical cancer cells, whereas the level of beta 1,4-GT mRNA was very low in uterine endometrial cancer cells. We also confirmed that expression of beta 1,4-GT mRNA corresponded to expression of beta 1,4-GT protein. These results suggest that expression of the beta 1,4-GT gene products is higher in human cervical and ovarian cancer cells than in uterine endometrial cancer cells. PMID- 21528189 TI - Epothilone A induces apoptosis in neuroblastoma cells with multiple mechanisms of drug resistance. AB - Epothilone A, a novel macrolide antibiotic, is produced by the myxobacterium Sorangium cellulosum. Similarly to paclitaxel (Taxol), epothilone A inhibits cell proliferation and induces apoptosis by binding to tubulin and stabilizing of microtubuli. Like paclitaxel, epothilone A induced apoptosis in neuroblastoma cells which exhibit constitutive cytoplasmic sequestration of p53 and, hence, an impaired DNA-damage-dependent apoptosis. However, in contrast to paclitaxel, epothilone A was also effective against a constitutively Pgp-expressing, multidrug resistant neuroblastoma cell line (SK-N-SH). Moreover, the efficacy of epothilone A was not impaired even though the Pgp level was further increased during treatment with the drug. PMID- 21528190 TI - Correlation between the immunohistochemical and mRNA expression of glutathione S transferase-pi and cisplatin plus etoposide chemotherapy response in patients with untreated primary non-small cell lung cancer. AB - Patients who have inoperable lung cancer usually undergo chemotherapy and have problems such as a resistance against chemotherapeutic agents during the treatment. Glutathione S-transferase (GST) is one of the detoxication-related enzymes. We studied the relationship between immunohisto-chemical staining of GST pi type and cisplatin + etoposide chemotherapy in patients with untreated primary non-small cell lung cancer (NSCLC). Of patients diagnosed as having primary lung cancer, 60 cases (49 men, 11 women; median age, 75.2 years, 35 squamous cell carcinomas and 25 adenocarcinomas) with stage, which were not surgically treatable, were examined immunohistochemically by using anti-GST-pi antibody. Chemotherapy (cisplatin 100 mg/m(2) i.v. day 1, etoposide 100 mg/m(2) i.v. days 1 3) was administered for all 60 patients and was repeated at 28 days for two cycles. After two courses of treatment, the therapeutic response was evaluated. Of 60 cases, 36 (60%) were GST-pi positive and 24 (40%) negative at pretreatment. In 24 patients with GST-pi negative expression, the chemo-therapeutic response rate was 66.7% (16/24), while the response rate was 25% (9/36) in the 36 GST-pi positive patients. The mRNA levels of GST-pi were similar to the immunohistochemical expressions in some of these cases by using reverse transcription-polymerase chain reaction analysis. The results suggest that GST pi: expression in cancer tissues is related to response to cisplatin + etoposide chemotherapy in untreated primary NSCLC patients, and may be useful as a predictor of chemotherapy response. PMID- 21528191 TI - p53 tumor suppressor gene and ras oncogene mutations in hypopharyngeal squamous cell carcinomas. AB - To examine the potential role of p53 and ras gene mutations in hypopharyngeal tumorigenesis, twenty-eight primary hypopharyngeal carcinomas, obtained at biopsy or total pharyngolaryngectomy, were investigated. Exons 5 through 9 of the p53 gene and exons 1 and 2 of the H-, K-, N-ras gene were screened using a combination of immunohistochemistry and single-strand conformation polymorphism analysis of polymerase chain reaction products (PCR-SSCP). The targeted DNA sequences coding for p53 and ras were confirmed by direct DNA sequencing. Point mutations of p53 were found in 9 (32.1%) of the 28 cases, including one with a double mutation, 3 in exon 5, 1 in exon 6, 2 in exon 7 and 4 in exon 8. Positive nuclear immunostaining for p53 was evident in 14 (50.0%) lesions. Seven (25.0%) of the 28 demonstrated point mutations in the H-rns gene, and 11 (39.3%) showed positive cytoplasmic staining for I as. The 5-year survival rate was worse with than without p53 overexpression (p <0.05). The present results suggest that gene mutations, although they occur at a relatively low incidence, are involved in hypopharyngeal tumorigenesis with p53 expression being a prognostic factor. PMID- 21528192 TI - Alteration of telomeric repeat length in hepatocellular carcinoma is independent of telomerase activity. AB - Length of terminal restriction fragments (TRFs) was examined in 34 samples from hepatocellular carcinoma (HCC) patients. TRF length alterations (reduction or elongation) were found in 18 of 34 (53%) HCC nodules (13 cases reduced, 5 cases elongated). The incidence of TRF alteration was significantly higher in HCC exceeding 3 cm in diameter, moderately- or poorly-differentiated in histology, or with microscopic aggressive lesions (P<0.05). The survival rates were significantly higher in patients without alterations in TRFs (P<0.05). Specifically, all 5 cases with elongated TRFs recurred within 1 year after resection and had a poor prognosis. In contrast, the presence of telomerase activity was not associated with alterations in TRF length. The incidence of TRF length alterations increased with HCC tumor progression. PMID- 21528193 TI - Surface plasmon resonance for real-time detection of molecular interactions between chromomycin and target DNA sequences. AB - DNA-binding drugs interfere with the activity of a large variety of transcription factors, leading to an alteration of transcription. This and similar effects could have important practical applications in the experimental therapy of many human pathologies, including neoplastic diseases. The analysis of sequence selectivity of DNA-binding drugs by footprinting, gel retardation studies, polymerase chain reaction and in vitro transcription does not allow an easy study of kinetics of binding and dissociation. The recent development of biosensor technologies for biospecific interaction analysis (BIA) enables the monitoring of a variety of molecular reactions in real-time by surface plasmon resonance (SPR). In this report we demonstrate that molecular interactions between the DNA-binding drug chromomycin and a biotinylated GC-rich Ha-ras oligonucleotide probe immobilized on a sensor chip is detectable by SPR technology using the BIAcore(TM) biosensor. This approach appears of interest in the development of drugs exhibiting differential affinity for target DNA sequences for the following reasons: a) results are obtained within one hour; b) unlike footprinting and gel retardation studies, this technology does not require P-32-labelled probes; c) BIA allows kinetic studies of both association and dissociation. PMID- 21528194 TI - Preoperative prediction of postoperative reserve hepatic function for liver surgery for hepatobiliary, pancreatic cancer. AB - To perform safer hepatic resection for hepatobiliary-pancreatic cancer, the possibility of preoperative prediction of postoperative reserve hepatic function was assessed using hepatobiliary scintigraphy. After intravenous administration of Tc-99m-pyridoxyl-5-methyltryptophan in 23 patients, the time-activity curves of region of interest over the heart and liver were generated, and peak and one fourth clearance times were calculated, which were compared with biochemical data. The parameters were significantly related to protein syntheses (prothrombine time and hepaplastin test) and indocyanine-green dye excretion, but not to hepatobiliary enzymes. So we hypothesized 'when the curve left by subtracting the resected area from the whole liver was larger than one-third of the total liver curve, the surgery would be safe', which we applied to another eight patients, clarifying the hypothesis. Hepatobiliary scintigraphy can be a promising procedure in the assessment of partial liver function, and the study will contribute to a safer liver surgery. PMID- 21528195 TI - Inhibition of tumor promoter induced transformation by expression of the small GTP-binding protein Rac in JB6 cells. AB - The small GTP-binding protein rac-1 has been reported to be a mediator for tumor promoter, growth factor and serum-induced cell membrane ruffling. We have stably overexpressed rac-1 in JB6 P+ cells. In contrast to rac-1 expressing NIH/3T3 cells, all JB6 transfectants expressing rac-1 did not show tumorigenic transformation (forward progression) but instead showed anti-oncogenic effects (backward progression). Transfectants expressing high levels of rac-1 were blocked for TPA-, EGF- and serum-induced transformation, while transfectants expressing lower levels of rac-1 were completely blocked for EGF- and serum induced transformation but only partially inhibited for TPA-induced transformation compared with vector control transfectants. PMID- 21528196 TI - Effects of aromatase complex selective inhibition on insulin-like growth factor 1 and insulin-like growth factor binding protein 3 circulating levels in breast cancer. AB - The aim of our study is to evaluate insulin-like growth factor (IGF) and IGF binding protein (IGFBP)-3 circulating levels in postmenopausal women treated with type I aromatase inhibitor formestane for breast cancer. Sixty-three patients at their first relapse entered the trial and were randomly given formestane at 250 mg or 500 mg i.m. fortnightly. Effects of the endocrine treatment on IGF-1 and IGFBP-3 were measured before and during therapy at scheduled times. IGF-1 and IGFBP-3 seems to slightly increase in both the dose groups, but only IGFBP-3 levels showed statistically significant fluctuation (baseline vs 4 weeks, p=0.01925; baseline vs 10 weeks, p=0.04537). These modifications are unlikely to be related to clinical status because they were observed both in responsive and unresponsive patients. This report demonstrates that hormonal treatments for breast cancer (particularly, aromatase inhibitor administration) can modify growth factor disposition to tumour. PMID- 21528197 TI - Human papillomavirus type-16 (HPV-16) major transforming proteins functionally interact with interferon signaling mechanisms. AB - Since the IFN system has been implicated in cell growth and differentiation control mechanisms, we evaluated the influence of the expression of HPV-16 E6 and E7 oncoproteins on IFN signaling by using cotransfection experiments. Both viral oncoproteins differentially interfered with the inducibility of IFN-beta promoter by Sendai virus. The activation by IFN-gamma of a GBP ISRE reporter was dramatically affected by both viral proteins suggesting a disruption of STATs/IRFs function. Further, the inducibility of 6-16 gene ISRE reporter by IFN alpha was decreased to varying degrees by both viral oncoproteins, implying that ISGF3 function is also impaired. Taken together, these observations suggest that HPV-16 negatively interacts with cellular targets of the IFN system, and these interactions may be implicated in cellular transformation caused by HPVs and their refractory response to IFN treatment. PMID- 21528198 TI - Phase I study of carboplatin, cisplatin, and cyclophosphamide without and with lenograstim for the treatment of ovarian cancer. AB - Cisplatin and carboplatin are both active in ovarian cancer with different toxicity profiles; thus, dose intensification may be possible by combining them. The aim of the present study was to determine the maximum tolerated dose of carboplatin combined with fixed doses of cisplatin and cyclophosphamide without and with support of lenograstim. Cisplatin (60 mg/m(2)), cyclophosphamide (600 mg/m(2)) and carboplatin (starting dose 200 mg/m(2)) were given on day 1 every 3 weeks for 4 cycles. Escalated dose levels for carboplatin were planned by increments of 50 mg/m(2) per level. Lenograstim (L) (150 mu g/m(2)/day subcutaneously) was given in case of grade 4 leukopenia (levels without support) or from day 5 up to leukocyte >10,000/mm(3) after nadir (levels with support). Four levels were studied (200, 250, 250 + lenograstim, 300 + lenograstim) with 7, 7, 8, and 7 patients enrolled, respectively. Unacceptable toxicity was induced in 1 patient at the level I (grade 4 thrombocytopenia), in 4 patients at the level 2 (2 prolonged grade 2 leukopenia, 1 grade 4 leukopenia with concomitant grade 4 thrombocytopenia and 1 grade 4 thrombocytopenia), in 1 patient at the level 2 + L (grade 4 thrombocytopenia) and in 3 patients at the level 3 + L (3 grade 4 thrombocytopenia). Thus, 200 mg/m(2) and 250 mg/m(2) were defined as carboplatin MTDs without and with lenograstim support, respectively. Median total platinum (cisplatin + 1/4 carboplatin) delivered dose-intensities were 33, 32, 38 and 44 mg/m(2)/week at the four levels, respectively. Hematological toxicity was overall mild. In no case was febrile neutropenia recorded. Grade 4 thrombocytopenia was always transient and never symptomatic. Grade 3 vomiting was the only severe non hematological toxicity reported in 5 patients. Out of 16 patients with measurable disease, 11 objective responses were obtained (5 complete and 6 partial) for an overall response rate of 69% (95% exact CL 41-89%). Recommended dose of carboplatin is 200 mg/m(2) without and 250 mg/m(2) with support of lenograstim when combined with cisplatin 60 mg/m(2) and cyclophosphamide 600 mg/m(2). Dose limiting toxicity is persistent leukopenia without and grade 4 thrombocytopenia with support of lenograstim. PMID- 21528199 TI - Differentiating and growth inhibitory effects of diallyl disulfide on cancer cells. AB - Diallyl disulfide caused growth inhibition and differentiation of DS19 mouse erythroleukemic cells as judged by hemoglobin synthesis and induction of acetylcholinesterase activity. There was a 50% inhibition of cell division at about 0.25 mM diallyl disulfide which was much more effective than diallyl sulfide. K562 human erythroleukemia cells and mouse melanoma cells were more resistant to the action of diallyl disulfide. Thymidine incorporation into DNA in 7800NJ and 7288CTC rat hepatoma cells and in T47D and MCF7 human breast cancer cells was inhibited by 1-2 mM diallyl disulfide. Administration of diallyl disulfide to rats bearing Morris hepatomas caused marked inhibitory effects on precursor incorporation into DNA and protein in both hepatomas and in livers after a dose of 400 mg/kg body weight, but only small differences were seen at a less toxic dose of 200 mg/kg. PMID- 21528200 TI - Increased hepatic ferritin-H messenger RNA levels correlate with those of c-myc in human hepatocellular carcinoma. AB - Serum ferritin is elevated in many cancers. Using the subtraction-enhanced display technique, we isolated several cDNA clones including ferritin-H which is overexpressed in rat hepatocellular carcinoma (HCC) induced by diethylnitrosamine. We investigated hepatic messenger RNA (mRNA) levels of ferritin-H in patients with HCC, adenoma, cirrhosis and healthy controls in relation to those of oncogene c-myc. Ferritin-H mRNA levels were 2-12 fold higher in tumor tissues than in adjacent non-tumor tissues in 12 of 17 patients with HCC, irrespective of coexisting cirrhosis or viral hepatitis. However, no difference in ferritin-H mRNA levels was found in patients with adenoma, cirrhosis and healthy controls. c-myc mRNA levels were 2-5 ford increased in 11 of 17 HCC patients, and correlated significantly with those of ferritin-H (p<0.001). In situ hybridization showed that the overexpressed ferritin-H mRNA was restricted to the tumor nodules in HCC livers. These findings suggest that overexpression of ferritin-fl in HCC patients, correlated with c-myc, is phenotypically associated with HCC, and could become a useful molecular indicator for human HCC. PMID- 21528201 TI - Overexpression of insulin-like growth factor binding protein 4 (IGFBP-4) in MCF-7 breast cancer cells is associated with reduced responsiveness to insulin-like growth factors in vitro and reduced tumour growth in vivo. AB - Insulin-like growth factors (IGF-I and IGF-II) are potent mitogens for breast cancer cells. IGF bioactivity is influenced by IGF binding proteins (IGFBPs). In vitro, most breast cancer cell lines express and secrete IGFBP-4. Sense and antisense complementary DMA of human IGFBP-4 were ligated into a mammalian expression vector and transfected into MCF-7 cells in order to investigate the role of IGFBP-4 on breast cancer cell proliferation in vitro and in vivo. IGFBP-4 concentrations were 4-8-fold higher in conditioned media (CM) of sense IGFBP-4 transfected cells compared to control cells, while IGFBP-4 concentrations in the CM of antisense IGFBP-4 transfected cells were lower than those present in the CM of control cells. Basal growth of sense IGFBP-4 transfected cells (S11) in media supplemented with 0.5% fetal bovine serum was significantly lower (P<0.01) than that of a vector-transfected control (C13) and antisense IGFBP-4 transfected cells (AS4). Loss of IGF but not EGF responsiveness in S11 cells was observed 48 h after exposure to these mitogens. Equal response to Des (1-3) IGF-I (an IGF-I analogue with reduced affinity for IGF binding proteins) was observed for C13, S11 and AS4 cells, suggesting that loss of responsiveness to IGFs by S11 cells is a consequence of IGFBP-4 expression. The in viva proliferation of S11 was significantly (P<0.01) less than that of control C13 and AS4 cells in both lit/lit (IGF-I deficient) or lit/+ (IGF-I replete) hosts. These data demonstrate that IGFBP-4 expression influences breast cancer behaviour. PMID- 21528202 TI - Concurrent carboplatin and iodine-125 brachytherapy for recurrent glioblastoma multiforme. AB - Toxicity and safety study of concurrent carboplatin chemotherapy and iodine-125 (I-125) brachytherapy. I-125 brachy therapy has an established albeit limited role in surgically accessible recurrent gliomas. Carboplatin has anti-tumoral; activity against gliomas and demonstrated sensitization of tumor to radiotherapy. In 15 patients (age range 30-77 years; median 53) with recurrent glioblastoma multiforme, stereotactically placed catheters were afterloaded with I-125 sources. A median 50 Gy minimum treatment volume dose was delivered during a 100 h period in conjunction with continuous infusion carboplatin (100 mg/m(2)/20 h x 5). Tumor volumes ranged from 13 to 63 cm(3) (median, 32 cm(3)). Early complications included: headache (n=7), transient exacerbations of pre existing neurologic deficits (n=5), seizures (n=2), nausea/vomiting (n=2), myelosuppression (n=2) and a catheter site wound CSF leak (n=1). Late complications included: steroid dependency (n=10), carcinomatous meningitis in association with hydrocephalus (n=1) and radiation-induced necrosis requiring reoperation (n=6). All patients were evaluable with a median survival of 10 months. In 12 patients, best clinical and neuroradiographic response was stable disease all of whom died of recurrent tumor (local recurrence in 11; CSF dissemination in 1). In 3 patients best response was either complete (n=2) or partial (n=1) all of whom are alive with a median follow-up of 31 months. I-125 brachytherapy with concurrent carboplatin chemotherapy is associated with an acceptable level of toxicity, has anti-tumoral activity and warrants further investigation in carefully selected patients with recurrent gliomas. PMID- 21528204 TI - Intra-pinna induction of specific antitumor immune T cell functions. AB - Upon inoculation of highly metastatic ESb lymphoma cells into the ear pinna of syngeneic mice a potent specific antitumor immune response is induced which prevents the outgrowth of the tumor cells at this particular site. When the tumor cell inoculated pinna was resected at different times after antigen application, systemic protective antitumor immunity, tested by s.c. tumor challenge 7 days later, could still be induced. This was true even for a situation in which the pinna was resected as early as two hours after tumor cell inoculation. Protective antitumor immunity was found to be even augmented when the pinna was removed three days after tumor cell inoculation as compared to the non-resected situation. Pinna resection had no effect on the induction of a tumor specific cytotoxic T lymphocyte response while resection after 48 h had an augmenting effect on the delayed type hypersensitivity (DTH) response. An explanation for some of these findings was found when lacZ-labeled lymphoma cells were used for single cell detection in tissue sections. As early as 15 min after intra-pinna inoculation disseminated single tumor cells were detected in the local draining lymph node as well as in the spleen. Whether these tumor cells can prime T cells for protective immunity directly or only after processing and presentation by specialized host cells remains to be elucidated. PMID- 21528203 TI - Adenovirus-mediated p53 gene therapy in nasopharyngeal cancer. AB - EBV-associated nasopharyngeal cancer (NPC) occurs with high frequency in China and is a major cause of morbidity and mortality. To explore the potential use of adenovirus-mediated tumor suppressor p53 gene therapy In NPC, we first examined the in vitro effects of p53 introduced into the NPC cell lines RPMI 2650, Fadu and Detroit 562. p21(WAF1/CIP1) induction by chemotherapy was used as a functional assay which revealed that RPMI 2650 expresses wild-type p53 whereas Fadu and Detroit 562 encode mutant p53. Infection with p53-expressing adenovirus (Ad-p53) induced apoptosis and inhibited cell growth in all three NPC cell lines, regardless of the endogenous p53 status. Adenovirus infectivity was greatest in RPMI 2650 cells, with 100% of the cells expressing beta-galactosidase following Ad-LacZ infection using an MOI of 100, as compared to 20-30% infectivity with the other NPC lines. Using RPMI 2650 cells injected into nude mice, we developed an animal model for nasopharyngeal cancer. Established tumors (0.6-0.8 cm) were injected with 5x10(9) PFU Ad-LacZ, Ad-p53 or PBS in a 100 mu l volume. We found evidence for in vivo expression of beta-galactosidase or p53 and p21 up to two weeks following Ad-LacZ or Ad-p53 virus injection respectively. Objective regression of tumor size was observed at two weeks in 4/6 Ad-p53-treated tumors, but not in Ad-LacZ or PBS-treated tumors. The results provide an animal model for human nasopharyngeal cancer, and indicate a potential use of p53 in its therapy in vivo. PMID- 21528205 TI - Differential expression of the neu transgene in murine mammary tissues. AB - The mammary glands of control FVB and mice with MTV-LTR promoted transgenes were stained using immunohistochemistry to detect neu expression. Neu expression in the terminal end buds of developing mammary glands and during early pregnancy in FVB mice was confirmed by in situ hybridization. Neu was expressed in all tumors from mice with the neu transgene but not in tumors expressing transforming growth factor alpha (TGF alpha) or polyoma virus middle T (PyV-MT). Neu was also expressed sporadically in non-neoplastic mammary cells of transgenic neu mice. However, most mammary cells expressing neu were dysplastic. The differential expression of the neu transgene has important implications for the interpretation of transgenic biology. PMID- 21528206 TI - Bromelain proteases suppress growth, invasion and lung metastasis of B16F10 mouse melanoma cells. AB - The thiolprotease bromelain, isolated from pine apple stem, was suggested for use in adjuvant tumor therapy. This study examined the in vitro effects of crude bromelain, bromelain F9 and papain on B16F10 mouse melanoma cell lung colonization, in vitro cell proliferation, invasion through matrigel and CD44 expression. In vitro treatment of the melanoma cells with bromelain F9 and papain before i.v. injection into mice prevented lung colonization. The lung weight at day 20 was significantly reduced from 5.1% (untreated cells) to 1.6% (bromelain F9 treated cells). Papain was as effective as bromelain F9. However, there was no difference in the lung weight between bromelain F9 treated and the untreated group at day 27. Protease removal and further incubation of the B16F10 cells retained their capacity to induce lung tumor metastases. The proteases inhibited growth of the melanoma cells in a dose dependent manner. Crude bromelain was most active with a half maximal value of 7.5 mu g/ml. However, the antiproliferative effects did not correlate with the proteolytic activity. In a matrigel invasion assay, the proteases reduced the invasive capacity of the melanoma cells maximally by about 30%. Using flow cytometry, the proteases were found to reduce the CD44 density, present on the melanoma cells, to a different degree: crude bromelain was more active than bromelain F9 and papain, which had higher proteolytic activity. Crude bromelain was most active in abolishing the CD44 re expression after protease treatment. PMID- 21528207 TI - Adoptive transfer via immune T-lymphocytes of effective anti-tumor immunity against a malignant rat glioma in the brain. AB - The aim of the present study was to develop an animal model to test the therapeutic potential of purified CD4 and CD8 T-lymphocytes against the intracerebrally implanted rat glioma cell line TZ363. Peripheral immunization of donor rats was performed by subcutaneous injection of viable TZ363 tumor cells while control animals received buffer injection. Donor splenic T-lymphocytes were prepared 14 days later and enriched by immune-bead MACS sorting. FACScan analysis revealed that of the pooled and sorted cells 91% of the tumor immune group were T lympocytes and from the control animals 96%. The purified immune CD4/CD8 T lymphocytes (1.2 to 5x10(7) cells) were injected intraperitoneally into 12 adult rats (three groups; each four animals), which were challenged five days later by an intracerebral injection of 5x10(4) TZ363 glioma cells. Four rats received 1.4x10(7) T-cells from control animals. While 3 of 4 animals developed a brain tumor and died in the control group, all animals, which received 5x10(7) immune T cells survived the intracerebral tumor challenge. In the other groups survival rate depended on the amount of T-cells given. All other rats were sacrificed 32 days after intracerebral grafting. No tumor was found in these animals. Our data demonstrate that an anti-tumor T-cell response can be raised against the malignant rat glioma TZ363 and that purified CD4 and CD8 T-lymphocytes from tumor immunized donors can transfer protective immunity across the blood-brain barrier into recipient rats which are tumor challenged intracerebrally. PMID- 21528208 TI - Peroxisome proliferators increase ethanol catabolism through utilization of the catalase pathway. AB - We investigated the effects of ciprofibrate, a potent peroxisome proliferator, on ethanol metabolism in mice. The blood alcohol levels of mice fed a liquid diet containing both ciprofibrate and ethanol were markedly depressed compared with mice fed the ethanol-containing diet alone. Ciprofibrate markedly induced enoyl CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, hydrogen peroxide, and to a lesser extent catalase in both control and ethanol-diet fed mice. Northern blot analysis indicated no significant upregulation of cytochrome P450IIE1 mRNA by ciprofibrate. Our study suggests that peroxisome proliferators increase ethanol catabolism through hydrogen peroxide production, thus allowing utilization of the catalase pathway. These findings indicate that catalase has the potential to provide a significant pathway for ethanol metabolism under conditions of peroxisome proliferation. PMID- 21528209 TI - Antisense galectin-3 alters thymidine incorporation in human MDA-MB435 breast cancer cells. AB - Galectin-3 is a 30-kDa galactose-binding protein member of the galectin family. Galectin-3 is involved in multiple intracellular and extracellular biological functions, e.g. interactions with laminin and with nucleic acids. This latter property is consistent with the presence of 3. serum-response factor-like domain at the amino-terminal part of the protein. Galectin-3 expression is upregulated during serum-mediated induction of proliferation. In order to examine the role of galectin-3 in breast cancer cell proliferation, we examined in this study the influence of antisense galectin-3 complementary DNA stable transfection on the in vitro thymidine incorporation of human breast cancer MDA-MB435 cells. Two stable transfectants, clones 5.24 and 5.29, were selected based both on the presence of a complete CMV promoter-antisense galectin-3 cDNA cassette as assayed by polymerase chain reaction, and on efficient down-regulation of galectin-3 protein expression as determined by Western blotting. Thymidine incorporation experiments showed that both clones were characterized by significantly decreased values of DNA incorporation compared to wild-type transfectants (55 to 68%, and 71 to 82% of the control clone values). Our data demonstrate for the first time that galectin-3 decreases thymidine incorporation in breast cancer cells. The mechanism underlying this property of galectin-3 and its importance during breast cancer development remain to be elucidated. PMID- 21528210 TI - Lisofylline as an adjuvant to high dose cytotoxic therapy. AB - Lisofylline, a dimethylxanthine derivative, has been shown to block the induction of hematopoietic growth inhibitors produced in response to cytotoxic anticancer therapy. In the current study, mice bearing established EMT-6 mammary carcinoma were treated with high dose cyclophosphamide, melphalan, BCNU, 5-fluorouracil or with total body radiation alone or with peripheral blood cells. The effect of lisofylline and/or G-CSF on leukocyte recovery was examined. Lisofylline was as effective as G-CSF in accelerating the recovery of white blood cells and granulocytes after treatment with high dose chemotherapy or total body radiation. Lisofylline alone or along with G-CSF was effective in protecting animals from the weight loss caused by high dose melphalan but not from weight loss caused by other cytotoxic therapies. Administration of lisofylline did not alter the killing of bone marrow CFU-GM by single doses of cyclophosphamide, melphalan or BCNU. However, administration of lisofylline increased the killing of EMT-6 tumor cells taken from the same animals. Administration of lisofylline had no effect on EMT-6 tumor growth. However, treatment with lisofylline along with high dose cyclophosphamide: melphalan, BCNU or 5-fluorouracil significantly increased the tumor growth delay produced by these agents. Overall, in the high dose therapy/EMT-6 mammary carcinoma model, lisofylline selectively enhanced hematopoietic recovery and increased tumor response to cytotoxic therapy. PMID- 21528211 TI - Familial cancer in Sweden. AB - Studies on familial clustering of cancer have usually followed transmission of a trait or mutant gene from one parental line. However, an access to families with two affected parents may additionally contribute to the models of carcinogenesis. The combined effect of parental cancer on the cancer risk of the offspring was tested in a large population-based data set. A family-cancer data base was constructed from the nationwide Swedish registries to include over 21,000 cancers in offspring diagnosed at ages 15-51 and their parents. Cancer risk in the offspring was assessed when the parents had different combinations of site specific cancers. The risk in the offspring was increased only moderately, at most 1.1 times when the father or the mother had cancer. If both parents had cancer the risks were higher and reached statistical significance for the following paternal/maternal site-specific combinations: colorectum/colorectum, prostate/colorectum, colorectum/breast, prostate/breast, melanoma/breast and skin (squamous cell carcinoma)/breast. These results on young and middle-aged adults indicate that cancer in both parents increase cancer risk in the offspring at many sites. A likely molecular explanation is that both parents contribute with different mutant genes to the set of genes constituting the multistage pathway to carcinogenesis. PMID- 21528212 TI - Increased growth inhibition of human chronic myelogenous leukemic cells by a combination of c-myb antisense oligonucleotide and 4 hydroxyperoxycyclophosphamide in vitro. AB - Human chronic myelogenous leukemia (CML) is a unique malignancy in its cellular and molecular phenotypes. High dose therapy followed by stem cell transplantation seems to be one of the most effective treatment modalities for CML. However, allogeneic stem cell transplantation, a curative treatment modality, is limited due to the availability of matched siblings. On the other hand, the autologous stem cell harvests are contaminated with leukemic cells, and therefore a significant reduction of leukemic cells is desired before using the harvest for transplantation. Therefore in the present study, effects of a combination of a suboptimal concentration of 4-hydroxyperoxycyclophosphamide (4HC) and an optimal concentration of c-myb antisense oligonucleotide on the growth of K562 human chronic myelogenous leukemic cells in vitro were determined. The combination significantly (p<0.05) inhibited the growth of K562 cells in vitro when compared to the effects of c-myb oligonucleotide or 4HC alone. The c-myb oligonucleotide alone or in combination with low dose 4HC decreased the expression of c-myb gene as determined by RT-PCR techniques. Cellular uptake and retention of fluoresceinated oligonucleotide in control and treated K562 cells was studied using plain field laser microscopy and flow cytometry. There was an increase in cellular uptake of c-myb oligonucleotide in K562 cells as measured by plain field laser microscopy in the presence of 4HC. The combination of oligonucleotides and 4HC did not significantly decrease the number of hematopoietic stem/progenitor cells from normal hematopoietic stem cell harvests as determined by in vitro colony assays. The combination of low dose 4HC and c-myb antisense oligonucleotides can potentially be applied in CML patients, particularly for purging leukemic cells present in their hematopoietic stem cell harvests. PMID- 21528213 TI - Monoclonal antibodies to a MUC 4 peptide react with lung cancer. AB - The cDNA of mucin 4 (MUC 4) has been cloned from human tracheo-bronchial cDNA library and MUG 4 was demonstrated to be expressed in normal tracheobronchial and colonic mucosa. However, as there are no antibodies available, there is little information on the distribution of MUC 4 on normal and malignant tissues. A 22 amino-acid peptide (M4.22), derived from the MUC 4 cDNA sequence was synthesized and used to immunise mice and 2 monoclonal antibodies were produced and characterized by ELISA, immunoperoxidase staining and flow cytometry. By ELISA the two anti-MUG 4 mAbs reacted with the immunizing peptide (M4.22), but not with peptides derived from other mucins. By immunoperoxidase staining the mAbs reacted with native mucin expressed in normal colon and to a lesser extent with stomach, but not with normal lung. By contrast, the mAbs reacted most strongly (similar to 70%) with lung cancers. Using six-mer overlapping peptides the minimum number of amino acids in the epitopes detected by the mAbs were TPL (M4.171) and PLPV (M4.275). MUC 4 detected by the mAbs was of a molecular mass (180 kDa) by Western blotting. Using anti-MUC 4 mAbs non-large cell lung cancers were found to be MUC 4 positive compared with normal lung tissues which were negative. By contrast, normal colon was strongly positive but the expression was decreased in colon cancer. These findings could have diagnostic and therapeutic implication for lung cancer. PMID- 21528214 TI - Proliferation markers and cell cycle associated expression of prosomes in breast cancers of Parsis and non-Parsis. AB - The present study has focused attention essentially on the Parsis, an ethnic group with high breast cancer incidence. We have investigated the potential use of prosomes, compared to Ki-67 and PCNA, as an additional cell proliferation marker. We also addressed the question whether or not breast tumors of Parsis differed in their DNA index and in the proportion of the S-phase fraction, compared to that of non-Parsi and European patients. We observed that the benign tumors of Parsis and non-Parsis were hyperdiploids, whereas in case of malignant tumors the Parsis showed essentially diploid characteristics while hyperdiploidy prevailed in the non-Parsis. Tetraploidy was seen as a common feature in the non Parsis, whereas aneuploidy seemed to be the more common type in the Parsis. The cell cycle analysis also revealed some interesting differences between the cell proliferation compartments of these two populations. A high number of cells in G2+M and S-phases was seen for non-Parsi malignant tumors while only the S-phase had a large cell count in the Parsis malignant tumors. The malignant tumors of Parsis and non-Parsis showed, as would be expected, a high expression of Ki-67 in the proliferation compartment. Surprisingly high Ki-67 expression was also a feature seen in the benign tumors of Parsis only and not any other group. We observed that expression of Ki-67, a proliferation marker directly related to the degree of malignancy, paralleled that of prosomal protein expression. In addition the prosomal monoclonal antibodies appeared to be more sensitive than Ki-67 in detecting a larger quantum of cells in the proliferation compartment. PMID- 21528215 TI - p53 mutations of lung cancer are not significantly affected by CYP1A1 or GSTM1 polymorphisms. AB - Cytochrome p4501A1 gene (CYP1A1) and glutathione S-transferase mu gene (GSTM1) are involved in the metabolic activation or detoxification of environmental carcinogens including benzo[a]pyrene in tobacco smoke. Individuals with both Val/Val and C type of CYP1A1 (CYP1A1; Val/Val and CYP1A1; C) or homozygous null ( /-) genotype of GSTM1 gene (GSTM1; -/-) show increased susceptibility to lung cancer. The incidence of p53 gene mutations are related to the smoking index of the lung cancer patients. Therefore we determined genotypes of these enzymes and screened p53 gene mutations in 123 non-small cell lung cancer (NSCLC) patients. p53 gene mutations were found in 35% (43/123) of the patients. The incidence of p53 gene mutation CYP1A1; Val/Val (60.0%), CYP1A1; C (50.0%) tended to be higher than those of CYPIAI; Ile/Ile and Ile/Val (40.4%) or CYP1A1; A and B (40.5%). We conclude that the incidence of the p53 mutations does not seem to be significantly affected by only CYP1A1 or GSTM1 polymorphisms in lung cancer patients. PMID- 21528216 TI - Allelic imbalance at the beta-catenin gene (CTNNB1 at 3p22-21.3) in various human tumor types. AB - beta-catenin is a multifunctional protein: it plays a central role in the cell cell adhesive junctions, and participates in transduction of the morphogenic Wingless/Wnt-signal. Upon detailed analysis of the human beta-catenin gene, an intragenic polymorphic microsatellite marker could be identified. This marker shows 62% heterozygosity and was used in a study of eleven different tumor types. A high level of beta-catenin allelic imbalance was observed for small cell lung carcinoma, squamous cell lung carcinoma and cervix carcinoma. Other microsatellite markers on 3p24-21 could demonstrate frequent but not invariable codeletion of flanking chromosomal loci. This intragenic polymorphic marker will allow selection of tumor types and tumor samples possibly bearing recessive mutations in the remaining allele of the beta-catenin gene. PMID- 21528217 TI - In vitro and in vivo MRS study of human glioma metabolites. AB - In this study an in vitro multinuclear magnetic resonance spectroscopy (MRS) characterization of water soluble metabolites and of the lipid fraction obtained from 19 human gliomas (12 glioblastomas, 3 anaplastic astrocytomas, 2 anaplastic oligodendrogliomas and 2 oligodendrogliomas) with a total of 27 surgical specimens, is reported. Moreover, some in vivo H-1 MRS results are shown. The regional metabolic heterogeneity of glioblastomas, according to their morphological heterogeneity, is documented. For glioblastomas a specific in vitro H-1 MRS metabolite profile cannot be defined. Low and high grade oligodendrogliomas showed characteristic choline/creatine and alanine/creatine metabolite ratios. The spectroscopical characterization of histopathological factors concerning malignant gliomas is shown. PMID- 21528218 TI - Immunoliposomes as targeted delivery vehicles for cancer therapeutics (Review). AB - Advances in liposome technology over the last decade has seen the development of stealth liposomes for drug delivery and cationic liposomes for gene delivery. Many of these liposome formulations are now in clinical trials for the treatment of a variety of malignancies. Whilst some clinical efficacy has been demonstrated, the goal of specific tumor targeting is yet to be attained. For this reason, antibodies have been attached to the surface of liposomes to produce immunoliposomes. These liposomes have shown preferential binding to specific tumor cells in animal models. The construction of the immunoliposome, and in particular the optimal method of antibody coupling to its surface is, however, yet to be determined. Despite these difficulties, immunoliposomes have demonstrated anti-tumor properties, both in vitro and in vivo, and show great promise as targeted delivery vehicles for the treatment of cancer. PMID- 21528219 TI - Health-related quality of life during post-induction chemotherapy in children with acute lymphoblastic leukemia in remission. AB - Using a multi-attribute approach, we and others have reported on the comprehensive health status of survivors of cancer in childhood, after completion of therapy. However, there is a dearth of information about health status and associated health-related quality of life (HRQL) in children and adults with cancer, during the treatment process; a deficit which this study was intended to redress. All children (n=18) receiving 'maintenance' chemotherapy for acute lymphoblastic leukemia (ALL) at a single institution were assessed prospectively through a single cycle of therapy. Patients, family members and health care professionals used global ratings, the health utilities index mark 2 (HUI2) and mark 3 (HUI3) classification systems, and detailed descriptions of temporary states of health, to provide independent assessments of health status at weekly intervals. Utility scores were derived for each comprehensive health state and for single attribute levels of the HUI2 system, and for the temporary health state descriptions. The classification of the subjects into the most appropriate temporary health states was challenging even for older children and some of the parents. The HUI instruments were used much more easily and produced highly comparable information. The most frequently affected attributes were pain, emotion and mobility/ambulation; in that order. The global (p=0.005) and specific morbidity burdens were, as predicted, greatest in the middle of the cycle of chemotherapy, reflecting the toxicity of steroid use. HUI2 global utility scores demonstrated moderate responsiveness with an intra-class correlation coefficient of 0.43. Cyclical administration of therapy, in particular corticosteroids, produces important changes in health status and HRQL in children with ALL. The HUI are valid and responsive systems for quantifying the burden of morbidity during the treatment of cancer in childhood. These are sensitive tools which can be used in a wide array of other circumstances to quantify changes in health status. PMID- 21528220 TI - Targeted adenoviral vectors for cancer gene therapy (Review). AB - In order to realise the full potential of gene therapy as a rational approach to the treatment of cancer, it will be necessary to achieve delivery of the therapeutic gene selectively to target tumour cells. Such cancer cell-specific gene delivery is mandated in the context of locoregional or compartmentalised carcinomas, and is also an absolute requirement for the treatment of disseminated disease. Moreover, underlying any cancer gene therapy approach is the need to achieve a high level of efficiency of gene transfer to the target cells. Of the existing viral and nonviral gene delivery vehicles, the adenoviral vector uniquely fulfils two requirements of an intravenously administered vector for cancer gene therapy: systemic stability and the ability to accomplish efficient transduction of cancer cells. However, it is necessary to modify native adenoviral tropism in order to achieve selective transduction of target tumour cells. A number of strategies have been developed for this purpose, involving genetic or immunological modifications to either of two adenoviral capsid proteins, the fibre and penton base. These strategies are designed to generate a targetable, injectable vector which would represent a major advance in the field of cancer gene therapy. PMID- 21528221 TI - A possible role of cytokines in the formation of peritoneal dissemination. AB - The earliest event in the formation of peritoneal dissemination is considered through the process of the attachment of intraperitoneal free cancer cells to the submesothelial basement membrane, exposed after contraction of mesothelial cells. We studied the mechanisms of the contraction of mesothelial cells using a. highly metastatic sell line (MKN-45-P) to the peritoneum. Four hours after intraperitoneal inoculation of MKN-45-P, mouse mesothelial cells began to contract, and submesothelial basement membrane was widely exposed after 24 h. The same changes developed four hours after i.p. injection of IL-6, TNF-alpha and IL 8, and were most prominently observed in mice treated with IL-8. However, no significant changes were observed after treatment of HGF, EGF and TGF-beta. Furthermore, IL-1 alpha, IL-6, IL-8, TNF and EGF increased the number of intercellular gaps of a human mesothelial cell monolayer, which was incubated on Matrigel coated dishes. Normal mesothelial cells form a contiguous monolayer of closely apposed polygonal cells, each of which had prominent and peripheral bands of F-actin. After incubation with IL-1 alpha, IL-6, IL-8, TNF and EGF, peripheral actin bands became indistinct and the central stress fibers became numerous. However, no significant changes were found in mesothelial cells, which were treated with TGF-beta and HGF. In addition, the number of attached MKN-45-P cells on a mesothelial cell monolayer after treatment of IL-1 alpha (0.1-1 ng/ml), IL-8 (10-100 ng/ml), and TNF-alpha (100 ng/ml) was significantly larger than that of control and TGF-beta significantly reduced the number of attached cells. Concentration of IL-8 in the serum-free medium of MKN-45-P cells was high (3.4 ng/ml), but IL-1 alpha, IL-6, TNF-alpha, TGF-beta, EGF and HGF could not be detected. None of these cytokines were detected in the conditioning medium of human mesothelial cells. Based on these results, mesothelial cell contraction may be mediated by IL-1 alpha, IL-6, IL-8, TNF-alpha, and EGF, and these cytokines may be produced from cancer cells and/or intraperitoneal inflammatory cells. In contrast, TGF-beta have an inhibitory effect on the mesothelial cell contraction and attachment of cancer cells to a mesothelial monolayer. The attachment of free cancer cells on the peritoneum may be controlled with these cytokines. PMID- 21528222 TI - Negative and positive transcriptional control during cell proliferation (Review). AB - A significant amount of experimental evidence has demonstrated that progression of the cell cycle in mammalian cells is associated with periodic transcriptional activation/ repression of growth-regulatory genes. We summarize our current knowledge and views on the role of the critical cell cycle regulators such as the retinoblastoma proteins in transcription repression and their functional connections with various different transcription factors. In addition, we discuss the role of oncogenes such as TIF1 alpha, PML and RFL which belong to a characteristic subgroup of RING finger proteins that contain the RING finger (C3HC4 zinc finger) the B-boxes and a putative coiled-coil (RBCC configuration) as mediators of transcription repression. PMID- 21528223 TI - Risk factors for the development of severe cisplatin neurotoxicity. AB - Cisplatin sensory neuropathy is not equally severe in all patients and may progress even after drug withdrawal. A major goal in cisplatin chemotherapy would be the identification of early predictors of an unfavorable neurological outcome in order to adjust the schedules of administration. The final neurological outcome of 63 women treated with the same schedule of cisplatin (CDDP) was compared with the general demographic and oncological parameters and with the baseline neurological results. No definite association could be drawn between any of the parameters evaluated and peripheral neuropathy. Further studies are needed to investigate the individual factors which are at the basis of the remarkable variability of this severe side effect of CDDP. PMID- 21528224 TI - Concurrent chemotherapy and thoracic radiation therapy for limited-stage small cell lung cancer. AB - We conducted a phase II study of therapy for limited-stage small cell lung cancer (LD-SCLC). The chemotherapy regimen consisted of a three-week cycle of cisplatin (80 mg/m(2), given intravenously on day 1) and etoposide (100 mg/m(2), given intravenously on days 1, 3 and 5), given three to four times. Fifty Cy thoracic irradiation was administered in standard fractions simultaneously without a treatment break. A total of 19 patients with SCLC were entered into the study, and 18 were eligible. This concurrent treatment produced 39% complete-response and 89% overall-response rates in the eligible patients. The median response duration was 36 weeks, and the median survival time was 67 weeks. A local relapse within the irradiation field was observed in 28% of the eligible patients. Brain metastasis as the first relapse was seen in 33% of the eligible patients. Myelosuppression represented by grade 3 and 4 leukopenia was experienced in 79% of the entered patients. We conclude that the concurrent modality with cisplatin and etoposide (PE) chemotherapy and early thoracic radiation therapy without split is a feasible and beneficial therapy. PMID- 21528225 TI - Evidence for reduced drug influx in multidrug resistant CEM cells by a fluorescent dye. AB - Multidrug resistance (MDR) in cancer cells is commonly ascribed to a reduced drug accumulation mediated by an ATP dependent efflux pump. We have developed a new, rapid and quantitative method for measuring influx of BCECF-AM in sensitive (CEM) and MDR cells (CEM/VLB100). The fluorescence of intracellular accumulated BCECF after hydrolysis of BCECF-AM is rapidly visualized by spectrofluorometry. The rate of BCECF-AM entry into CEM/VLB100 cells is considerably lower than that found in CEM cells, similar to 10-fold after 10 min of incubation. This phenomenon is not in relation with a difference of esterase activities, it is not energy or intracellular pH-dependent, and BCECF efflux is negligible. CEM cells exhibited diffuse fluorescence within cytoplasm in contrast with numerous spots of intense labelling, related to the presence of the cytoplasmic vesicles in CEM/VLB100 cells demonstrated by Nomarski's microscopy. MDR modulators such as verapamil, sodium orthovanadate, chlorpromazine or trifluoperazine induce an enhanced influx in CEM/VLB100 cells (150+/-4%; 204+/-17%; 410+/-17% and 229+/-7% respectively) whereas no major differences were noted with the parental sensitive cells. Vinblastine (under conditions close to IC50) increases the influx only in MDR cells (481+/-6%) by a process that is not linked to competitive inhibition of the P170 efflux pump. These results suggest that reduced influx of drugs could be a major defect in MDR cells, a possible role for P170-membrane lipids interactions is discussed. PMID- 21528226 TI - Detection of differentially expressed genes in human bladder cancer cells using arbitrarily primed PCR of RNA. AB - The aim of the present study was to detect differentially expressed genes in human bladder cancer cell lines using a non-radioactive RNA fingerprinting technique (arbitrarily primed polymerase chain reaction of RNA, RAP-PCR). The two clonal urothelial cancer cell lines, RT4 and J82, show different growth kinetics upon stimulation with EGF. By RAP-PCR we detected changes in band patterns for J82 cells treated with EGF but not for RT4 cells. Polymorphic fragments were further characterized and sequences from two of these gave a perfect match to the coding sequence of the human tropomyosin gene TM30(pl) and the human MAC30 gene, respectively. In accordance with the results of RAP-PCR downregulation in EGF stimulated J82 cells could be demonstrated by reverse transcription PCR. PMID- 21528227 TI - Adoptive immunotherapy of intracranial tumors by systemic transfer of tumor draining lymph node cells (Review). AB - T lymphocytes, reactive against tumor antigens, mediate the regression of established tumors upon adoptive transfer. We have developed an effective therapy for experimental brain tumors by systemic intravenous transfer of ex vivo activated T cells derived from tumor-draining lymph nodes. Both CD4 and CD8 T cells are required to mediate tumor regression which is exquisitely specific and confers immunologic memory. Several factors influencing the efficacy of adoptive immunotherapy for brain tumors are markedly different than for optimal treatment of tumors at other visceral sites. A similarly designed phase I clinical trial has been initiated for the treatment of malignant astrocytomas. PMID- 21528228 TI - Molecular mechanisms of retinoid action in acute promyelocytic leukemia (Review). AB - Acute promyelocytic leukemia (APL) is, at present, the first and only example of leukemia which can be induced into remission with a single cyto-differentiating agent. This is due to the fact that APL is exquisitely sensitive to the differentiating action of all-trans retinoic acid (ATRA). Thus, the APL model offers a unique opportunity to study the cyto-differentiating action of ATRA and synthetic retinoids in a clinically relevant setting. This review article summarizes the work relating to the molecular mechanisms underlying the action of retinoic acid and retinoids in APL cells, and focuses on: a) genes which are expressed and regulated by ATRA; b) synthetic retinoids as cyto-differentiating agents; c) rational combinations between retinoids and cytokines or other cyto differentiating agents; d) cellular paradigms of retinoic acid resistance. It is our aim to give an updated, about nonexhaustive, account of some of the most recent development regarding the pharmacological action of retinoic acid and its derivatives in APL cells. PMID- 21528229 TI - The role of desmoglein 2 and E-cadherin in the invasion and motility of human breast cancer cells. AB - Loss of adhesion is a fundamental step in the metastatic cascade. Desmosomal cadherins, Desmoglein (Dsg) and Desmocollin (Dsc) are a novel group of adhesion molecules. Aims were to demonstrate expression of Dsg2 and E-cadherin in breast cancer cells and assess their role in invasion and motility. Immunofluorescence and Western blotting were used to demonstrate expression of Dsg2 and E-cadherin in 3 breast cancer cell lines (MDA MB 231, MCF7 and BT474). Functional studies included cell-cell aggregation, in vitro invasion and colloidal gold phagokinetic tracking assays. All 3 cell lines expressed Dsg2. MCF7 and BT474 cells were E cadherin positive, MDA 231 was negative. Cell aggregation was reduced, in vitro invasion and motility were increased in Dsg2 or E-cadherin Mab pre-treated cells. Dsg2 present in breast cancer cells may act as a tumour suppressor molecule. PMID- 21528230 TI - Apoptosis and cell cycle effects induced by extracts of the Chinese herbal preparation PC SPES. AB - A herbal preparation denoted PC SPES(R) is available in 'natural food' or 'health food' stores in the United States. This mixture (patent pending, US Serial number 08/697,920) consists of extracts from 8 different herbs, 7 originating from China and one from America, and is sold as a dietary supplement. Although several components of this herbal mixture were reported to have antiproliferative and/or antitumor activity little is known about the possible in vitro cytostatic or cytotoxic properties of the formulation. Composition of PC SPES is standardized by HPLC; the ethanol extract is characterized by the presence of 6 distinct components, reproducible from batch to batch. This extract suppressed cell proliferation and reduced the clonogenicity of a variety of human tumor cell lines, including PC-3 and LNCaP prostate carcinomas, MCF-7 and T47-D breast carcinomas, SK-N-MC neuroepithelioma, Cole 38 melanoma, U937 histiomonocytic lymphoma, as well as HL-60 and MOLT-4 leukemias. The sensitivity to PC SPES was different for particular cell lines, with MCF-7 cells being the most sensitive (IC50 = 20 nl/ml) and Cole 38 the most resistant (IC50 = 430 nl/ml) in clonogenicity assays. The predominant cell cycle effect induced by PC SPES was the prolongation of G(1) phase. Apoptosis was observed after exposure of tumor cells to PC SPES for 48 h and longer. PC SPES also downregulated expression of bcl-2, the gene protecting cells against apoptosis (studied in U937 cells) and sensitized these cells to gamma-irradiation. The cell cycle progression of mitogen stimulated human lymphocytes was not affected at PC SPES concentrations which induced cytotoxic and cytostatic effects in tumor cells. The data indicate that PC SPES is cytostatic and cytotoxic for different tumor cell lines and modulates the cell's propensity to undergo apoptosis. PMID- 21528231 TI - An in vitro chemosensitivity test for solid human tumors using collagen gel droplet embedded cultures. AB - In vitro chemosensitivity testing using a collagen gel droplet embedded culture drug sensitivity test (CD-DST), was conducted with several types of solid cancer. The overall evaluable rate was 80% (443/554), including 76% for lung (n=243), 78% for breast (n=110), 87% for gastric (n=62), 83% for colorectal (n=107) cancers and 88% for 32 metastatic brain tumors. The in vitro sensitivity of breast, gastric and colorectal cancers to mitomycin C (MMC), cisplatin (CDDP), 5 fluorouracil (5-FU) and doxorubicin (DXR) was similar to the efficacy rates reported for each drug. This was also observed with lung cancer, the sensitivity of which to MMC, CDDP, vindesine (VDS) and etoposide (VP-16) was similar to the clinical efficacy. The clinical response to chemotherapy was compared with the results of in vitro chemosensitivity testing in Il patients: the clinical correlation was 91%, with a 80% true positive and 100% true negative rate. These results suggest that the CD-DST may be clinically useful by allowing the prediction of clinical response in various solid cancers. PMID- 21528232 TI - Inhibition of integrin mediated cell adhesion of human head and neck squamous cell carcinoma to extracellular matrix laminin by monoclonal antibodies. AB - We recently reported that three members of the integrin family of cell adhesion molecules, designated alpha 2 beta 1, alpha 3 beta 1, and alpha 6 beta 4, are expressed at increased levels within the tumors and cell lines of patients with SCC. These three integrins have been reported to serve as receptors for laminin isoforms, and we also previously observed that laminins are secreted by SCC cell lines isolated from patients. In this study, the expression and localization of the three integrins and laminin in situ was evaluated in ten tumor specimens from patients with SCC by immunohistochemistry using integrin subunit-specific monoclonal antibodies. The ability of the antibodies to inhibit laminin attachment of a human squamous cell carcinoma line was determined by in vitro cell adhesion assay. Laminin and the three integrins were co-localized along the invasive border of the tumor parenchyma in 10/10 patient tumor specimens. Attachment of the UM-SCC-38 cell line to laminin was strongly inhibited by specific mAbs to alpha 2 and alpha 6 integrin subunits alone, or completely using a combination of alpha 2, alpha 3, and alpha 6 subunit specific mAbs. The co localization of the three abnormally expressed integrins and laminin in patient tumor specimens indicates the potential for interaction of these receptors and ligand in vivo. The results of the cell adhesion assays using a patient SCC cell line that expresses the same repertoire of integrins confirms that SCC attach to laminin isoforms primarily through the alpha 2, alpha 3 and alpha 6 subunit containing integrins. These findings provide a basis for undertaking experimental studies to obtain small molecule receptor antagonists to determine the role of these integrins in tumor formation, growth, invasion and metastasis in vivo. PMID- 21528233 TI - Mutational analysis of the hMSH2 gene in a wide variety of tumors. AB - The hMSH2 gene participates in DNA mismatch repair and its mutation can result in genetic instability of the human genome which is an important feature of tumorigenesis. In this study, genetic alterations of the hMSH2 gene were examined in 43 ovarian, 36 non-small cell lung (NSCL), 31 poorly differentiated gastric, 15 endometrial, and 11 colon cancers, nine gastric cancer cell lines, 41 adult T cell leukemias (ATLs), two ATL cell lines, and 37 non-Hodgkin's lymphomas (NHLs), using polymerase chain reaction-single strand conformation polymorphism (PCR SSCP) technique. Microsatellite instability (MSI) was also investigated for ovarian, NSCL, and colon cancers. The incidence of MSI was 1/36 (3%) for NSCL, 2/23 (9%) for ovarian, and 1/11 (9%) for colon cancers. Missense base changes of the hMSH2 gene were identified in two gastric cancer patients (ATG to ATA resulting in Met changing to Ile at codon 688 in exon 13 and ACA to GCA resulting in Thr changing to Ala at codon 803 in exon 14). These mutations were found in samples with no MSI. One ovarian and one gastric cancer, and six ATL samples showed two types of polymorphisms of hMSH2 (CTT to TTT resulting in Leu changing to Phe at codon 390 in exon 7 and CAG to AAG resulting in Gin to Arg at codon 419 in exon 7). Our data suggest that MSI and hMSH2 mutations are uncommon in sporadic tumors. PMID- 21528234 TI - SH2-containing phosphotyrosine phosphatase SHP-1 is involved in BCR-ABL signal transduction pathways. AB - The BCR-ABL fusion protein is strongly implicated in the malignant process of Philadelphia (Ph-1)-positive leukemia. The BCR-ABL fusion protein exhibits a deregulated tyrosine kinase activity capable of phosphorylating different cellular substrates in vivo and in vitro. SHP-1 (SHPTP1, PTP1C, HCP, SHP) is an SH2 domain-containing tyrosine phosphatase expressed predominantly in hematopoietic cells. The association of the murine motheaten phenotype of severe hematopoietic dysregulation with loss of SHP-1 tyrosine phosphatase activity indicates a critical role of SHP-1 in the regulation of hematopoietic cell growth and differentiation. Experiments were performed to determine whether SHP-1 might form specific complexes with BCR-ABL signaling pathway. We found that SHP-1 was highly and constitutively tyrosine phosphorylated in 32DCl3 and TF-1 cells transfected with BCR-ABL expression vector. Furthermore, SHP-1 and BCR-ABL formed stable complexes in BCR-ABL expressing cells. Direct binding between SHP-1 and Grb2 was observed in vitro. Expression of BCR-ABL in TF-1 cells resulted in a two fold increase in SHP-1 phosphatase activity. BCR-ABL tyrosine kinase was able to phosphorylate recombinant SHP-1 protein in vitro. SHP-1 therefore has the capacity to bind and potentially modulate the signaling effectors involved in activation of Ras, and accordingly, regulation of cellular transformation of BCR ABL. PMID- 21528235 TI - Expression of p53 in pediatric lymphomas from Mexico. AB - Eighty-five cases of pediatric non-Hodgkin's lymphomas (NHLs) from Mexico have been reviewed and classified according to histologic type and immunophenotype using a panel of markers which included CD20, CD45RO-(UCHLI), CD3 and Tdt. Twenty five cases were classified as lymphoblastic lymphoma (LBL) of precursor cell origin and forty-nine cases as non-lymphoblastic lymphomas. Eleven cases could not be satisfactorily classified due to insufficient tissue or on technical grounds. All these lymphomas were subjected to immunohistochemistry (IHC) for detecting p53 expression. p53 was detectable in 7 (28%) lymphoblastic lymphomas, in 36 (73.4%) non-lymphoblastic lymphomas and in 4 (36.3%) of the lymphomas that could not be classified. Our results indicate that in contrast to adults with NHL and children with acute leukemia, p53 expression is relatively frequent in pediatric NHLs, although it is higher in lymphomas of B cell phenotype than in those of T cell type. PMID- 21528236 TI - Detection of somatic mutations of the bcl-2 oncogene in B cell lymphomas with the t(14;18). AB - The incidence of mutations within the first 582 bp of the open reading frame of the bcl-2 gene, has been investigated in presentation lymph node samples, from 7 cases with follicular non-Hodgkin's lymphoma (NHL), 1 case with centroblactic NHL, the DOHH, cell line derived from the immunoblastic transformation of a follicular NHL and one case with benign follicular hyperplasia. A total number of 43 point mutations within the examined portion of the bcl-2 gene were detected in the cases analysed including the DOHH, cell line. Similar analysis of peripheral blood lymphocytes from 2 normal individuals that lacked the t(14;18), revealed no mutations in one case and a single 101 bp A-->G transition in clone, in the other. Missense mutations were detected in 7/8 NHLs, the DOHH2 cell line and the case of benign follicular hyperplasia. There was a significantly higher frequency of mutations within the region corresponding to the BH1, one of the two known functional domains, of the bcl-2 protein. The same position, 445 bp of the bcl-2 gene, was found to be involved in missense mutations affecting the DOHH2 cell line and 3 cases with follicular NHL. PMID- 21528237 TI - Modulation of fibronectin expression and proteolytic activity associated with the invasive and metastatic phenotype in two new murine mammary tumor cell lines. AB - Two cell lines obtained by sequential subcultures from primary cultures of the murine mammary adenocarcinomas M3 and MM3 were characterized. During LM3 cell line evolution an increase in the anchorage-independent growth ability, a displacement towards a triploid level in the chromosomic distribution and a loss of fibronectin (FN) expression were observed. LMM3 cell line showed a tetraploid chromosomic number and was unable to produce FN, behaving in a similar way as its parental tumor MM3. The local invasive ability as well as the spontaneous metastatic capacity of LM3 cells inoculated subcutaneously (s.c.) increased with the passage number and were associated with the progressive loss of FN expression as well as to the appearence of membrane bound uPA. LMM3 cells, which did not express FN, maintained the high spontaneous metastasic capacity already shown by the parental tumor MM3 but acquired a higher local invasive phenotype. PMID- 21528238 TI - Enhanced albumin uptake by rat tumors. AB - Albumin dominates the nitrogen and energy resources in blood. However, only limited data is available on its accumulation and catabolism by tumors. This was caused by the lack of suitable radiolabels for long-term follow-up of protein catabolism in vivo. Conventional radiolabels like radioiodine are metabolically unstable. After lysosomal degradation diffusible tracer residues are rapidly released from catabolic sites, Tumors with high metabolic activity evade detection. To study the uptake of rat serum albumin (RSA) by tumors a conventional radioiodine label and two residualizing radiolabels were chosen. It is known that residualizing I-131-tyramine-deoxisorbitol and In-111-DTPA protein labels remain trapped at catabolic sites after lysosomal degradation of their carrier proteins. We were able to show by scintigraphy and after organ removal that a Walker-256 carcinosarcoma with a turner size of about 5% of the body weight accumulated more than 20% of the initially injected dose of a In-111-DTPA RSA within 24 h. Tumor uptake rates for albumin exceeded those of the kidneys by about 4 times, and those of the liver by about 3 times. It was estimated that about one out of two albumin molecules trapped by an ovarian-342 tumor must have been degraded during 72 h. High uptake and degradation rates would make albumin an alternative nitrogen and energy source for these tumors. Although an unfavorable time-frame limits the use of residualizingly labeled albumin for scintigraphic tumor diagnosis in man, albumin might be an interesting carrier for delivering covalently attached chemotherapeutic agents into tumors by an alternative lysosomal route. PMID- 21528239 TI - Novel germline mutations in Swedish von Hippel-Lindau disease patients. AB - We have used a combination of different mutation detection systems in analyzing two Swedish families with von Hippel-Lindau disease (VHL). The methods employed were single-stranded conformation polymorphism (SSCP), heteroduplex analysis, and direct sequencing. The families were both shown to carry constitutional mutations in the VHL gene not reported earlier. Both were frameshift mutations (i.e. nt761delC and nt732insAA) predicted to give a premature stop codon. The correlation of mutation data to different clinical features of VHL is discussed. PMID- 21528240 TI - Enhanced tumorigenic and metastatic potential of an androgen-sensitive human prostate cancer cell line, LNCaP, by intratesticular inoculation in SCID mice. AB - To establish a prostate cancer model expressing prostate-specific antigen (PSA) with metastatic potential, LNCaP or PC-3 cells were inoculated into the testis of SCID mice, resulting in a 100% rate of tumor formation. A significant increase in serum PSA was found in mice with LNCaP xenografts. Circulating tumor cells and micrometastases to organs such as lung, liver, spleen, and omentum were detected for both cell lines by PCR of the human beta-globin gene. Lymph node metastases occurred more frequently with PC-3 than LNCaP cells. This is the first report showing stable growth of LNCaP cells in mice with metastases to the regional lymph nodes. This model of prostate cancer should help to assess treatment strategies targeting PSA. PMID- 21528241 TI - Morphological and molecular characterization of an undifferentiated soft tissue sarcoma cell line and derivative clones. AB - From an undifferentiated soft tissue sarcoma (STS) a cell line designated US8-93 has been established. At subcloning the cell line US8-93 three different lines (US8-93A, B and C) could be set up. In a subsequent study characteristics for ultrastructure, growth, cell cycle distribution, karyotype, protein overexpression detected by immunohistochemistry (IHC) and p53 mutational status were determined. The cell line US8-93 as well as subclones contain mainly bipolar spindle-shaped cells and additionally some polygonal and multinucleated cells. Cells possess the characteristics of primitive mesenchymal cells based on their positive reactions with anti-vimentin and negative reactions for desmin, cytokeratin, myoglobin, S100, and NSE, implying a classification as an undifferentiated STS. Cytogenetic analysis revealed nearly diploid cells with several structural and numerical aberrations for chromosomes 1, 3, 4, 6, 9, 10, 12, 13, 15 and 18. IHC positivity was found for the tumor suppressor proteins p53 and Rb, the oncogene products Bcl-2, K-ras, N-ras, P-glycoprotein Mdr-1 and MDM 2. In the p53 gene a nonsense mutation in exon 4 was detected, that was confirmed in the original primary tumor and in three derivative clonal lines. The described STS cell line represents a valuable supplementation to the relatively small number of human STS cell lines currently available and may also provide a good in vitro model for studies of STS tumorigenesis in respect to a mutated p53 gene. PMID- 21528242 TI - A fast and simple in situ PCR method to detect human papilloma virus infection in archival paraffin-embedded tissues. AB - We describe a simple and fast method for the detection and localization of low copy numbers of HPV DNA in formalin-fixed and paraffin-embedded archival tissues. We have developed a protocol for direct bl situ-PCR in order to demonstrate its convenience in rapid and reproducible assessment of HPV infection in unknown biopsies. The morphological aspect of the tissues has been maintained, despite the multiple steps of fixation, permeabilization and thermal cycling, and positivity has been detected only in virus target cells. PMID- 21528243 TI - Local recurrence of colorectal tumors after endoscopic mucosal resection. AB - We evaluated intramucosal local recurrences of 114 colorectal tumors which were removed by endoscopic mucosal resection (EMR). Removals of all these lesions were judged as successful by endoscopic absence of residual tumor immediately after EMR. The presence of residual tumor was determined by histologic and stereomicroscopic examinations in the lateral margin of resected specimen. There was no evidence of intramucosal local recurrence in 91 lesions with negative margin. However, intramucosal local recurrence occurred in 3 of 23 lesions (13%) with positive margin. Consequently endoscopic follow-up is mandatory in patients with lateral margin positive for tumor tissue in the EMR specimen. PMID- 21528244 TI - Loss of DNA mismatch repair due to knockout of MSH2 or PMS2 results in resistance to cisplatin and carboplatin. AB - Loss of DNA mismatch repair is a common finding in hereditary nonpolyposis colon cancer as well as in many types of sporadic human tumors. The effect of loss of DNA mismatch repair activity on sensitivity to cisplatin and carboplatin was tested using MSH2 and PMS2 knockout cell lines. The knockout dMsh2 embryonic stem cell line was 2.1-fold more resistant to cisplatin and 1.7-fold more resistant to carboplatin when compared to the isogenic wild-type wt-2 cell line. Likewise, the PMS2(-/-) mouse fibroblasts were 1.9-fold more resistant to cisplatin and 1.5 fold more resistant to carboplatin when compared to the isogenic PMS2(+/+) fibroblasts. These findings demonstrate that loss of mismatch repair due to knockout of either MSH2 or PMS2 results in low-level resistance to cisplatin and carboplatin, drugs that form the same types of adducts in DNA. These data validate results previously obtained using non-isogenic mismatch repair proficient and -deficient cell lines, and indicate that simple recognition of the cisplatin adduct by the MSH2/MSH6 heterodimer is not sufficient for full detector function, but that PMS2 is also required for the pro-apoptotic signal to be generated from this detector. PMID- 21528245 TI - The accumulation of H-1 MR-visible lipid in human glioma cells is independent of the cell cycle. AB - The human glioma cell line, 2607, was observed with proton magnetic resonance spectroscopy (MRS) in the presence of a number of cell-cycle blockers (cysteamine, desferrioxamine, ADR 529). MR spectra of the arrested cells revealed a correlation between the intensity of the lipid methylene resonance at 1.3 ppm and the percentage of cells in G(2)/M. However, subsequent time course studies using ADR 529 on cells partially synchronised by contact inhibition showed that the emergence of the lipid signal in drug-treated cells is not strictly cell cycle dependent but increases with continuing exposure to ADR 529. This indicates that the accumulation of MR-visible lipid arises from drug cell interactions that specifically affect lipid metabolism in a non cell cycle dependent manner. PMID- 21528246 TI - Mutation and microsatellite instability analysis of the androgen receptor gene in human prostate cancer. AB - To investigate the mechanism for the development of human prostate cancer, examination was made of structural abnormality of the androgen receptor (AR) gene in 29 human prostate cancer. AR gene mutations from exons A to H were examined by PCR-SSCP and microsatellite instability analysis using (CAG)n and (GGN)n polymorphic markers in AR gene exon A. A point mutation was found in the exon D hormone-binding domain of AR leading to substitution of glutamine (GAG) for wild type arginine (CGG) at codon 629 in 1 (3.4%) hormone-independent stage D2 patient. Microsatellite instability was detected in 5 of the 27 (18.5%) patients, 1 of 6 (16.7%) hormone-independent stage D2 and 4 of 21 (19.0%) hormone-dependent and non-treated prostate cancer patients. AR mutations may possibly be involved in the transition from androgen-dependent to independent stages during androgen ablation therapy. PMID- 21528247 TI - Structure and function of plasminogen activator inhibitor-2. AB - Serine proteinase inhibitors (serpins) are well known regulators of extracellular proteolytic pathways. A recently identified group of intracellular serpins of mammalian and viral origin, designated ovalbumine-like serpins, modify intracellular proteolytic pathways involved in the regulation of apoptosis and inflammation. This review focuses on plasminogen activator inhibitor-2 (PAI-2) in terms of the molecular structure-function relationships and its intracellular functions, in particular in relation to apoptosis. PAI-2 inhibits apoptosis in cell lines challenged with tumor necrosis factor or certain viruses. The intracellular proteinases which PAI-2 act upon are still unknown. During myeloid apoptosis, PAI-2 proteolytically modified to a smaller but still proteinase inhibitory form. PAI-2 is unique among the serpins with respect to its large CD domain localized between alpha-helices C and D. Recent data show that two domains in PAI-2 are required for its antiapoptotic activity, the CD-domain and the proteinase reactive site. We have shown the CD-domain is involved in covalent and reversible interactions with cytosolic proteins, e.g. the annexins. These intracellular PAI-2-reactive proteins might represent participants in signalling pathways involved in the regulation of cell survival. PMID- 21528248 TI - Oxygen radicals in lung carcinogenesis accompanying phagocytosis of diesel exhaust particles. AB - We sought to examine the involvement of oxygen radicals derived from phagocytosis process in lung carcinogenesis induced by diesel exhaust particles (DEP). The carcinogenic response and formation of 8-hydroxydeoxyguanosine (8-OHdG) were examined in the lungs of mice intratracheally injected with washed DEP (WDEP), DEP, or nontoxic control particles of titanium dioxide (TiO2). After 10 weekly treatments with these particles, the formation of 8-OHdG in the lungs of mice treated with WDEP or DEP showed a significant increase, but not in those treated with TiO2. After 12 months, the incidence of lung tumors in mice treated with WDEP or DEP was higher than that of mice treated with vehicle by 2.3- and 3.1 fold, respectively. A significant difference in the incidence of tumors was found between the vehicle group and DEP-treated group. Treatment with TiO2 had no effect on the incidence of lung tumors. The formation of 8-OHdG in mice treated with these particles was significantly correlated with the development of lung tumors. These results suggest that the induction of DNA damage by oxygen radicals may be an important factor in the initiation of WDEP- and DEP-induced lung carcinogenesis, and that oxygen radicals derived from the phagocytic process may play a role in 8-OHdG formation induced by DEP. PMID- 21528249 TI - Vascular endothelial growth factor in patients with hepatocellular carcinoma. AB - The main aims of this study were to analyze the significance of serum vascular endothelial growth factor (VEGF) levels in the development of hepatocellular carcinoma, and the effect of transcatheter arterial embolization treatment on the production of VEGF. Serum VEGF levels in hepatocellular carcinoma were significantly higher than in liver cirrhosis (P<0.01) but not significantly different from normal controls. Serum VEGF levels in cirrhosis decreased gradually as the Pugh-Child grade increased in severity. In hepatocellular carcinoma serum VEGF levels were not related to the tumor stage or serum levels of the tumor markers, cr-fetoprotein and des-gamma-carboxy prothrombin. In 18 patients who underwent transcatheter arterial embolization, serum VEGF increased gradually and reached a peak at day 7, although serum interleukin-6 and hepatocyte growth factor levels peaked at days 1-3 and then decreased. VEGF levels were elevated significantly in patients who did not respond to transcatheter arterial embolization treatment as compared to those who responded to this treatment (P<0.05). Serum VEGF levels may be useful in the assessment of hepatocellular carcinoma patients and may indicate responsiveness to transcatheter arterial embolization. PMID- 21528250 TI - Effects of estrogen and tamoxifen on the MAP kinase cascade in experimental rat breast cancer. AB - The mitogen-activated protein kinase (MAPK) cascade, which includes MAPK, MAP kinase kinase (MAPKK) and Raf-l, is involved in the signal transduction of growth factor receptors. We found that the MAPK and Raf-l proteins are increased in human breast cancer. Activated MAPKK was also observed. We then investigated whether the MAPK cascade is activated when 7,12-dimethylbenz(a) anthracene (DMBA) induced rat mammary cancer is treated with 17 beta-estradiol (E-2). Ovariectomy suppressed MAPK expression in tumors, and E-2 administration induced the activation of MAPK in ovariectomized rats. We also investigated the effects of tamoxifen (TAM) on proliferation and the MAPK cascade in DMBA-induced rat mammary cancers. Although tumor size was reduced significantly by TAM, the expression of the MAPK and Raf-l proteins did not decrease. Additionally, MAPK and Raf-l protein expression increased in tumors of ovariectomized rats given TAM, despite a reduction in the size of the tumors. These results suggest that the activated MAPK cascade is important in human breast cancer, and is an important mechanism in the estrogen-dependent growth of DMBA-induced rat mammary cancer. TAM shows E 2-antagonistic effects on tumor proliferation, and E-2-agonistic effects on the MAPK cascade. PMID- 21528251 TI - p53 is involved in the inhibition of cell proliferation mediated by activin A in cultured human prostate cancer LNCaP cells. AB - Activin A in a concentration ranging from 0.7 to 75 ng/ml specifically inhibited cell growth of an androgen-sensitive human prostate cancer line, LNCaP, but had no effects on two androgen-insensitive human prostate cancer lines, PC3 and DU 145. This activin-mediated inhibition of cell growth in LNCaP cells results from a decrease of cell proliferation and an increase of apoptosis. Northern blot analysis of mRNA expression encoding human p53 in untreated and activin-treated LNCaP cells resulted in upregulation of p53 gene expression. We conclude that autocrine inhibition of cell growth in LNCaP cells by activin is in part related to the expression of the p53 gene. PMID- 21528253 TI - Gonadotrophin releasing hormone (GnRH) receptor and steroid receptors in human uterine leiomyoma, myometrium and endometrium. AB - The present study evaluated the presence of GnRH-R in leiomyomas, in associated, non-involved uterine tissues (myometrium and endometrium) and the possible relationships between GnRH-R and the receptors for estrogen and progesterone in the same tissues. GnRH-R was found in all uterine tissues and both GnRH and the GnRH analog, goserelin, displaced its binding consistent with a single type of high affinity receptor (Kd approximate to 10(-8) M). GnRH-R were found more frequently in myometrium (81% of samples) than in endometrium (58%) or leiomyoma (42%). However, the mean receptor content was lowest in myometrium (139+/-19 fmol/mg protein) with both leiomyomas (288+/-77 fmol/mg protein) and endometrium (372+/-96 fmol/mg protein) having significantly higher values. Endometrial GnRH binding varied from 596+/-42 in uteri that were GnRH-R positive in the endothelium alone to 231+/-49 when GnRH-R was present also in the other tissues. Endometrium negative for the GnRH-R had significantly higher levels of estrogen receptor than all the other uterine samples (266+/-25 vs 61+/-7.5 fmol/mg protein, respectively). Endometrial GnRH-R seem to be dependent on its presence and/or level in other uterine tissues. Further, when GnRH-R is absent in the endometrium this tissue expresses greatly increased levels of steroid receptors. PMID- 21528252 TI - Differential expression of vacuolar-type H+-ATPase between normal human pancreatic islet B-cells and insulinoma cells. AB - Recent studies have shown that bafilomycin A(1)-sensitive vacuolar type H+-ATPase (V-ATPase) is responsible for the acidification of intracellular compartments in eukaryotic cells. B-cells of pancreatic islets also are known to include acidifying secretory vesicles which are the major cellular site of proinsulin to insulin conversion. This study was designed to examine immunohistochemically the level of V-ATPase protein expression in normal pancreas (five cases) and benign insulinoma (six cases), using mouse monoclonal antibody raised against the 116 kDa subunit of human V-ATPase. Light microscopic immunohistochemistry revealed that moderate to marked V-ATPase expression was observed in normal islet B-cells, while insulinoma cells in each case expressed V-ATPase faintly or not at all. By immunoelectron microscopy, the majority of secretory vesicles in insulinoma cells did not express V-ATPase protein at their endomembranes, although mild to marked V-ATPase expression was noted at the endomembrane of secretory vesicles in normal islet B-cells. Thus, differential expression of V-ATPase protein at the endomembrane of secretory vesicles was observed between normal islet B-cells and insulinoma cells. These findings suggest that the reduced activity of V-ATPase per insulin secretory vesicle in insulinoma cells have a profound effect on the efficiency of proteolytic cleavage of proinsulin. PMID- 21528254 TI - Cell-cell and cell-stromal interactions in breast cancer invasion and metastasis (review). AB - Tumour cell invasion and metastasis is a highly orchestrated process in which the malignant cells exhibit an altered relationship to the surrounding host stroma. This is reflected in a change in expression pattern of the receptors which mediate cell-cell and cell-stromal interactions. Down regulation of E-cadherin and of many integrin receptors is associated with tumour development. Conversely, up-regulation or de novo expression of certain integrin receptors enhances tumour cell invasion. It is of fundamental importance to elucidate the mechanisms controlling expression of cell adhesion molecules, and the effects of their altered expression. Cell adhesion molecule expression may be altered by changes in cytoskeletal protein interactions, and there is evidence that both integrin and possibly E-cadherin mediated signalling can modulate expression of matrix degrading proteases, which would further influence invasive and metastatic behaviour. PMID- 21528255 TI - Serum anti-p53 antibodies in patients with squamous cell carcinoma of the esophagus. AB - Immunoassay of serum anti-p53 antibodies was performed in a series of 63 patients with squamous cell carcinoma of the esophagus. p53 alterations were also analyzed with DGGE to detect gene mutations (n=53) and by immunohistochemistry to assess overexpression of p53 (n=43). An immune response was observed in 16 sera (25%). The corresponding biopsies all had a p53 gene mutation or overexpression of protein p53. We were unable to demonstrate any significant relationship between habitual tumor parameters (localization, cell differentiation, TNM stage) and development of p53 alterations. However, none of the patients with a localized tumor developed an immune response, while some of them had a muted gene or overexpressed p53. PMID- 21528256 TI - Interferon-alpha and gemcitabine (2',2'-difluorodeoxycytidine) in adult and pediatric renal tumors. AB - 2',2'-difluorodeoxycytidine (dFdC) is an active anticancer drug in different human malignancies. The present study aimed to evaluate if the activity of dFdC in renal tumors could be improved by interferon-alpha (IFN-alpha). The influence of IFN-alpha (4 h) on the cytotoxicity of dFdC was analyzed in vitro by a colorimetric assay. in vivo, nude mice with xenografts from human nephroblastoma (AC-KLxe-12) and renal cell cancer (ACHN, SN12C) were treated by dFdC +/- IFN alpha. IFN-alpha alone resulted in no growth inhibition in vitro, but pretreatment with IFN-alpha sensitized SN12C and ACHN cells against dFdC. The additional treatment with IFN-alpha increased the CR rate of ACHN- and SN12C-mice (40%; 7%) compared to dFdC alone (20%; 0%). Xenografts from AC-KLxe-12 did all progress. In conclusion, IFN-alpha increased cytotoxicity of dFdC in vitro and tumor responses of renal cell cancer (RCC) in xenografts. Since therapy lacked activity in nephroblastoma, further studies should focus on RCC to compare the efficacy of dFdC and interferons with other types of biochemotherapy. PMID- 21528257 TI - Expression of bcl-2 protein in nephroblastomas. AB - Bcl-2 expression has been shown to relate to prognosis in several neoplasms. A study of 139 cases of nephroblastomas was undertaken to ascertain the prognostic value of bcl-2 immunoexpression. Archival formalin-fixed, paraffin-embedded tissue sections were stained with monoclonal anti-bcl-2 antibody using a peroxidase-labelled streptavidin biotin kit. 75.5% of cases showed bcl-2 immunoreactivity, however, heterogeneous staining was observed within each case. No statistically significant correlation was found when bcl-2 expression was compared to histology (P=0.451), disease status (P=0.375) and disease stage (P=0.875). A statistically significant difference in bcl-2 protein was noted when comparing tumours treated with and those not treated with pre-operative chemotherapy (P=0.002). Further analysis of the cases that were treated with pre operative chemotherapy showed a striking difference in survival periods between bcl-2 positive (shorter) and negative tumours (longer). Although not statistically significant, we think that this finding requires further investigation in other series. The results of bcl-2 immunoexpression in nephroblastomas may have prognostic implications that impact on patient treatment protocols. PMID- 21528258 TI - beta-catenin-cell adhesion and beyond (review). AB - beta-catenin was originally identified as a cytosolic cell protein required for the correct function of the cadherin cell-cell adhesion complex. However, recent studies have identified the presence of intracellular pools of beta-catenin that are cadherin-independent and that beta-catenin is also involved in Wnt-1, src and Tcf-Lef mediated intracellular pathways. Thus, this molecule functions not only as a regulator of cell-cell adhesion, but as a mediator of intracellular signalling cascades resulting in cell growth and proliferation. Furthermore, its association with other proteins such as the tumour suppressor gene product APC may implicate it in the processes of tumour progression. PMID- 21528259 TI - Acute leukemia. AB - The acute leukemias continue to present a formidable challenge for which there is not yet a reliably curative 'standard approach' for the majority of adults with this family of diseases. In order to make progress in terms of curing these devastating diseases, we must understand leukemia biology on the clinical, cellular and molecular levels, with exploitation of the leukemia-associated molecular targets in designing strategies aimed at eradicating the leukemic clone. In this review, we will discuss a few key mechanisms of leukemogenesis that represent convergent pathways of malignant transformation and, as such, present pivotal molecular targets for therapy. Specifically, we focus on normal and leukemic hematopoietic cell cycle regulation, issues surrounding DNA damage and repair, programmed cell death (apoptosis) and drug responsiveness, and multidrug resistance as a marker for stem cell involvement and as a novel target for intervention. When functioning normally, such mechanisms determine a cell's ability to respond to DNA damage, traverse the cell cycle and maintain genomic integrity. And in addition to the target cell itself, there are crucial extracellular determinants of hematopoietic cell proliferation and differentiation that modulate net signalling activity and gene expression, cell cell contact and growth-modulating factors for instance. The molecular dissection of these intersecting pathways, from the extracellular milieu to the genes themselves, in both the normal and transformed states will elucidate the means by which cells escape treatment-induced death. Such understanding should, in turn, lead to the development of targeted therapeutic strategies that exploit differences between normal and malignant cells, overcome the mechanisms by which leukemic cells acquire drug resistance, and enhance the curability of these devastating diseases. PMID- 21528260 TI - Schedule-dependent modulation of idarubicin cytotoxicity by lonidamine in human lymphoma cell lines. AB - The ability of lonidamine (LND), an energolytic derivative of indazol-carboxylic acid, to modulate the cytotoxic activity of idarubicin (IDA) and doxorubicin (DX) was investigated in two human lymphoma cell lines (H9 and U937). A different pattern of interaction between the drugs was observed as a function of treatment sequence. Specifically, a 24-h postincubation with a non-cytotoxic concentration of LND (75 mu M) increased the activity of a 1-h anthracycline treatment in both cell lines. However, the extent of potentiation for IDA was more than twofold that of DX. No enhancement of anthracycline activity was observed when LND preceded IDA. For comparative purposes, the modulating effect of all-trans retinoic acid (ATRA) on the cytotoxicity of IDA was evaluated according to different treatment schemes in both lymphoma cell lines. In U937 cells, which undergo monocytic differentiation after exposure to retinoids, a marked increase in LDA activity was obtained following a 48-h postincubation with 1.5 mu M ATRA. No potentiation of anthracycline activity was obtained using the opposite drug sequence. In H9 cells, no significant interference between ATRA and IDA was observed independent of the modality of drug administration. The ability of LND to potentiate IDA activity, and the consideration that LND causes side effects different from those caused by anthracyclines, make this compound an attractive candidate for multidrug combination therapy in hematological neoplasms. PMID- 21528261 TI - Do lymphocytes contain chromosomal lesions that are also stable markers in cancer cells? AB - The initiation and metastatic progression of human cancers are genetically controlled. We therefore sought to identify specific chromosomal changes associated with the development of a melanoma and its metastasis to the bladder in a 57-year-old Caucasian man by analyzing his lymphocytes and metastatic melanoma cells. Approximately 4% of the patient's PHA-stimulated lymphocytes showed constitutional abnormalities of chromosomes 1, 2, 3, 4, 7, 9, 10, 12, 14 and 19. On the other hand, his melanoma cells showed clonal markers involving chromosomes 2, 4, 5, 6, 7, 9, 10, 14, 16, 17 and 20 plus many more. Our results indicate that both primary chromosome abnormalities and some of the secondary cytogenetic defects of melanoma cells can be identified in lymphocyte cultures and that such abnormalities may be possible markers for early diagnosis and treatment. PMID- 21528262 TI - Characterization of a cellular RNA that activates PKR in 3T3-F442A cells. AB - The double-stranded RNA dependent eIF-2 alpha kinase (PKR) has been implicated in the regulation of a number of cellular processes including cell growth and differentiation. Previous studies using embryonic mouse 3T3-F442A cells have indicated that PKR undergoes phosphorylation and activation in vivo. This activation of PKR has been attributed to a subset of poly(A)(+)-rich cellular RNA (R-RNA) having sufficient secondary structure to interact with the kinase. To characterize the R-RNA activity, a cDNA was prepared which, when transcribed in vitro, gave rise to an RNA transcript that retained its property to activate PKR. The ability of the transcript to activate PKR was sensitive to ribonuclease V1 and was abolished by the addition of high concentrations of poly(I).poly(C). The cloned cDNA was utilized for liquid RNA/DNA hybridization experiments, which disrupted the secondary structure of the R-RNA and for Northern blot analysis. The results from these studies indicated that the measurable RRNA activity was represented in a specific cellular RNA which was responsible for the activation of PKR. Furthermore it was found that the R-RNA was specifically associated with PKR and that this complex could be detected directly in cell extracts. The nucleotide sequence of the cDNA was determined. We propose that this novel cellular RNA may play a critical role in regulating the activation of PKR and thus be an important component in the control of cell growth and differentiation. PMID- 21528263 TI - Intra-and inter-individual heterogeneity in exon 2 of the MDR1 gene in primary breast carcinoma and healthy individuals. AB - Increased expression of P-glycoprotein, encoded by the MDR1 gene, is considered to be responsible for chemotherapy failure in a number of human cancers. Although it is clear that mutations in the MDR1 gene affect substrate specificity of the transporter in multidrug-resistant cell lines, scant interest has been directed at whether mutations have a unique clinical presentation. To address this question, we studied exon 2 of the MDR1 gene in 9 patients with primary breast carcinoma and 9 healthy controls using PCR and DNA sequence analysis. In order to reduce the possibility of nucleotide misincorporations introduced by Tag polymerase, sequencing of six subclones of each DNA specimen was performed. A mutation was seen as a substitution from G to A at position -1 in two patients and one control. An A to G nucleotide substitution giving rise to an amino acid substitution (Asn-->Asp) in codon 21 at the first potential N-glycosylation site of the P-glycoprotein was seen in primary tumors from four patients and in an axillar lymph node metastases from one of these patients. This mutation was also seen in two healthy individuals, which similar to the patients, both seem to be heterozygous for this MDR1 exon 2 allele. Three other mutations were also found in the patients; a substitution of A to G at position 23 and A to G at position 52 in the same patient and in another patient, G at position 42 was changed to A. However, the last three mutations were not confirmed by repeating analysis of the original genomic sample. The results revealed different distribution of a point mutation between various parts of the same primary tumor and between a lymph node metastasis and the primary tumor tissue. Thus, demonstrating both intra-and inter tumor heterogeneity. The results also emphasized constitutional allelic variation in the MDR1 gene. Whether this might affect sensitivity to chemotherapy has to be further evaluated. PMID- 21528264 TI - Correlation between reduced p21(WAF1/CIP1) expression and abnormal p53 expression in esophageal carcinomas. AB - p21(WAF1/CIP1) is a potent inhibitor of various cyclin-dependent kinases, the expression of which is transcriptionally regulated by tumor suppressor gene product p53. We immunohistochemically examined the expression of p53 and p21(WAF1/CIP1) in 61 esophageal squamous cell carcinomas. p53 protein was expressed in 37 (61%) of 61 carcinomas. p21(WAF1/CIP1) was consistently expressed in the normal stratified esophageal mucosa. In the carcinomas, the expression of p21(WAF1/CIP1) protein was markedly reduced or not expressed in 33 (54%) cases. Clinicopathologic analyses revealed that no significant correlation exists either between p53-positive and -negative cases or between p21(WAF1)/(CIP1)-positive and -negative cases. Twenty-four cases were p53-positive/p21(WAF1/CIP1) negative, 15 were p53-negative/p21(WAF1/CIP1)-positive, 13 were positive for both and 9 were negative for both, and these findings thus showed an inverse correlation of the positivity between p53 and p21(WAF1/CIP1) (p<0.05). Furthermore, of the 13 cases with positive staining for both, the distribution of the expression was mutually exclusive in 6 cases and coincidental in the remaining 7 cases. These findings showed the p53-dependent expression of p21(WAF1/CIP1) was observed in esophageal squamous cell carcinomas, while the lack of an absolute correlation between abnormal p53 expression and p21(WAF1/CIP1) expression suggested that the p53 independent expression of p21(WAF1/CIP1) might also occur in some portions of the esophageal squamous carcinomas, suggesting that the molecular mechanisms of esophageal carcinogenesis appear to be complicated. PMID- 21528265 TI - Concurrent use of multiple chemotherapy resistance modulators with etoposide in patients with resistant malignancies. AB - Since chemotherapy resistance is probably multifactorial, we studied the toxicity and efficacy of adding to etoposide in sequence 5 resistance modulators in the treatment of resistant solid tumors. In cohort 1, metronidazole and ketoconazole were given with i.v. etoposide 100 mg/m(2)/day x 5 days. Because of excessive toxicity, cohort 2 received just metronidazole with etoposide, and metronidazole doses were reduced. Subsequent patient cohorts had the following drugs added to etoposide plus metronidazole: ketoconazole (cohort 3), dipyridamole (cohort 4), tamoxifen [cohort 5 (with etoposide 75 mg/m(2)/day) and 6 (with etoposide 60 mg/m(2)/day)], and cyclosporin (cohort 7). Hence, cohort 7 received daily x 5 i.v. etoposide 60 mg/m(2)/day plus 5 resistance modulators. Forty patients were treated, of whom 38 were evaluable for toxicity. Metronidazole resulted in augmentation of both central neurotoxicity and peripheral neuropathy. Sequential addition of each of dipyridamole, tamoxifen, and cyclosporin appeared to increase hematological toxicity. Some patients also experienced reversible hepatic and renal toxicity. Partial responses were seen in adrenocortical and small cell lung cancers, and minor responses with symptomatic improvement were seen in adrenocortical, small cell lung, non-small cell lung and colorectal carcinomas. Further evaluation of this approach may be warranted in patients with minimal prior chemotherapy exposure. PMID- 21528266 TI - SV40-transformation of embryonic human diploid fibroblasts results in multiple molecular changes. AB - Attempts were made to identify the cellular and molecular changes associated with SV40-transformation of human fibroblasts, MRC-5. SV40-transformed human fibroblasts, MRC-5V1, displayed a polygonal to round morphology, grew slowly, had reduced plating efficiencies but high saturation densities. However, they could be propagated in low serum-containing medium and grew very efficiently in soft agar. These altered growth properties of MRC-5V1 suggested that SV40 induced changes in cell adhesion and growth factor requirements. Indeed, MRC-5V1 expressed markedly reduced levels of cellular fibronectin, high levels of tPA and the expression of procollagen alpha 2(I) and decorin were absent. Moreover, MRC 5V1 did not express HGF/SF, a paracrine effector of epithelial cells and expressed very low levels of EGF receptor. However, SV40 induced the expression of TGF alpha, one of the ligands of the EGF receptor, TGF beta 1 and TGF beta 2, all of which are associated with cellular transformation. Given the establishment of autocrine loops in MRC-5V1 and the fact that decorin interacts with fibronectin and collagens and negatively regulates the activity of TGF beta s, these changes could account for the altered growth and transformation properties of MRC-5V1. Several studies have provided a link between oncogenic transformation, transcriptional and translational control. SV40 markedly reduced the expression of junB but not c-jun in MRC-5V1 and the expression of EIF-4E and EF1 delta were not significantly affected. The data shows that SV40 transformation of human fibroblasts is associated with multiple genetic changes affecting the expression of genes involved in cell adhesion, signal transduction and transcription, hence suggesting the breakdown of several cellular control mechanisms. PMID- 21528267 TI - Overexpression of activin A inhibits growth, induces apoptosis, and suppresses tumorigenicity in an androgen-sensitive human prostate cancer cell line LNCaP. AB - The effects of overexpression of activin A in the androgen-sensitive human prostate cancer cell line LNCaP were studied. A full-length cDNA of activin beta A coding region was inserted into a eukaryotic expression vector and transfected into the LNCaP cells. Overexpression of activin BA significantly inhibited growth of this cell line. An increased death rate was also noted in these activin overproducing cells, which was believed to be due to apoptosis as manifested by morphological change, DNA laddering, and FAGS analysis. The expression of bcl-2 was suppressed and the expression of c-myc was stimulated in these cells. In addition, the efficiency of soft agar colony formation and the tumorigenicity in the nude mice were suppressed for the activin producing LNCaP cells. PMID- 21528268 TI - Molecular analysis of INK4 genes in breast carcinomas. AB - Cell cycle regulators have recently been implicated in oncogenic transformation of cells, including the cyclins active in the G1 phase of the cell cycle and their respective cyclin-dependent kinases (CDK) whose activities are regulated by a set of inhibitors of CDK (CDKI). Since CDKIs can inhibit cell proliferation, they may have a role as tumor suppressor genes. To determine if alterations of CDKI genes may be involved in tumorigenesis of breast cancer, we examined the mutational status of p16(INK4A), p15(INK4B), p18(INK4C), p19(INK4D) CDKI genes in 36 primary breast carcinomas and 9 breast cancer cell lines using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP), direct DNA sequencing, and Southern blot analysis. Furthermore, amplification of cyclin D1, D2, D3 genes were also examined in these samples. One mutation of p15(INK4B) gene occurred, resulting in change of aspartic acid to asparagine at codon 85. Since aspartic acid at this position is conserved between all four human and murine INK4 proteins, this missense mutation may have functional significance. The sample with a p15(INK4B) point mutation was accompanied by amplification of the cyclin D1 gene. A deletion of the p18(INK4C) gene was found in a primary tumor. Three deletions of the p16(INK4A) gene and two deletions of the p15(INK4B) gene were found in the cell lines. Also, we found amplification of the p15(INK4B) and p16(INK4A) loci in a clinical sample as well as amplification of the p19(INK4D) in another sample, and amplification of the myeloperoxidase (MPO) gene in one cell line and two primary tumors. We suspect that a critical gene for breast cancer is amplified near the MPO gene. These data indicate that CDKI mutations are moderately rare in breast cancer and are often associated with the simultaneous alteration of more than one cell-cycle regulatory gene. PMID- 21528269 TI - Differential cellular zinc levels in metastatic and primary nasopharyngeal carcinoma. AB - Zinc levels are known to be elevated in certain cancer tissues. In this study, zinc content in metastatic and primary nasopharyngeal carcinoma (NPC) cells were quantitated by X-ray microanalysis at the ultrastructural level. Zinc levels of cancer cells derived from the cervical lymph node of a patient with metastatic carcinoma and that from the nasopharynx biopsy of another NPC patient with no clinical evidence of secondary spread, were analyzed. X-ray microanalysis revealed significantly higher cellular zinc levels in metastatic NPC cells. Zinc is a known anti-apoptotic agent and tumor response to radiotherapy is linked with apoptosis or programmed cell death. Raised zinc levels observed here could provide the biological basis for the observation of a higher percentage of distant metastasis in cervical node positive NPC patients treated by radiotherapy (the mainstay of treatment for NPC) as compared to those without regional nodal disease. PMID- 21528270 TI - Production and characterization of a monoclonal antibody (MSN-3) for uterine endometrial and endocervical adenocarcinoma. AB - A monoclonal antibody (MSN-3) was raised using HEC-108 cells derived from poorly differentiated endometrial carcinoma as the immunogen. The immunoglobulin subclass of MSN-3 was IgGr1. The target antigen of MSN-3 was a protein with a molecular weight of 77 kDa, and it was shown to be localized in the cytoplasm. MSN-3 only reacted with 14% of normal proliferative endometrium cells, but it showed a high positivity rate of 66% for endometrial carcinoma. The target antigen of MSN-3 increased as endometrial cells became more malignant, and the possibility of changes in localization was also suggested. Moderately and poorly differentiated endometrial carcinoma showed a high positivity rate for MSN-3. MSN 3 reacted rarely or not at all with normal cervical glandular tissue, but the positivity rate for cervical adenocarcinoma (especially endocervical adenocarcinoma) was a high rate of 59%. The patterns of staining of endocervical adenocarcinoma by MSN-3 included diffuse staining of the whole cytoplasm and not only that near the glandular lumen, as well as staining of the basal cytoplasm. Changes in the localization of the target antigen were clearly associated with carcinogenesis of the cervical glandular cells. The MSN-3-positive rate was high in patients with lymph node metastasis and vascular invasion. Among the staining patterns, the basal and diffuse patterns tended to increase with malignacy. The basal pattern of staining was characteristic of MSN-3, suggesting that it might assist in the diagnosis of cervical adenocarcinoma. PMID- 21528271 TI - Echistatin inhibits Lewis lung carcinoma cell-matrix adhesion in vitro and experimental metastasis in vivo. AB - Echistatin, a low molecular weight, RGD-containing protein isolated from the venom of Echis carinatus, inhibited Lewis lung carcinoma cell (3LL) adhesion to immobilized fibronectin and laminin. The inhibition was specific, noncytotoxic, dose-dependent and fully reversible. Echistatin showed a stronger activity in inhibiting cell adhesion to fibronectin rather than to laminin and it resulted about 3-fold more effective than kistrin, an other ROD-snake venom protein, in inhibiting 3LL cell attachment to both substrates. The ability of echistatin to modulate experimental metastasis formation in vivo was also evaluated. A 20% inhibition of the lung metastasis spread with respect to controls was observed when 3LL cells and echistatin were coinjected i.m. into male C57BL/6NCr1BR mice. When echistatin was administered i.p. 1 mu g/g of body weight/72 h x 4 doses into mice bearing Lewis lung carcinoma, it promoted only a 15% inhibition of tumor growth but inhibited by 45% lung metastasis formation. These results demonstrate that echistatin is able to inhibit metastasis attachment and spreading in experimental system in vivo independently by its effect on the primary tumor. PMID- 21528272 TI - Study of nm23 gene expression in an N-methyl-N-nitrosourea transformed human breast epithelial cell line. AB - In the present study we pinpoint the time of nm23 down-regulation during the chemical transformation of the human breast epithelial cell line HBL100. The non malignant HBL100 was transformed by exposing it to N-methyl-N-nitrosourea (MNU). We subsequently injected the transformed cells (HBL-T-MNU) into nude mice, resulting in tumor growth. With a second passage of these tumors in mice we observed lung and extra-regional node metastases. The expression of nm23 in the non-tumorigenic HBL100 cells was compared to the tumorigenic KBL-T-MNU cells as well as to the metastatic cell line HBL-T2(MNU) derived from the tumor induced by HBL-T-MNU cells. By using immunohistochemistry and Western blot analysis we documented the downregulation of nm23 expression in the tumorigenic HBL-T-MNU and metastatic HBL-T2(MNU) cell lines, as compared to the parental line HBL100. Once downregulated, nm23 expression in this model remains constant during the subsequent progression. These results suggest that nm23 down-regulation may indeed be associated with early neoplastic transformation and is maintained throughout neoplastic progression and metastatic stage. PMID- 21528273 TI - A comparison of the expression of the malignant phenotype in two androgen independent human prostate cancer cell lines after orthotopic implantation in nude mice. AB - Expression of some features of the malignant phenotype were compared in the DU145 and PC-3M human prostate cancer cell lines after their intraprostatic growth in nude mice. At necropsy, 27/74 (36%) mice injected with DU145 cells and 41/75 (55%) injected with PC-3M cells had either invasive macroscopic tumors, or microscopic intraprostatic tumor cell nests (p = 0.02). Para-aortic lymph node metastases had occurred in 19% of the DU145 cell, and 44% of the PC-3M cell tumor bearing animals (p = 0.033). Immunohistochemical staining showed high mutant p53 and vascular endothelial growth factor (VEGF) expression by DU145 cells; PC-3M cells did not express detectable p53, and had relatively low VEGF immunohistochemical reactivity. Assays by ELISA established a statistically significant difference in VEGF levels between the cell lines (p < 0.001). Urokinase-like plasminogen activator (uPA) levels, determined by ELISA, were ten fold higher in the PC-3M cell tumors, as were matrix metalloproteinase-9 (MMP-9) activities assessed by zymography. These findings of high expression of uPA and MMP-9, two key proteolytic enzymes in the invasive/metastatic process, by PC-3M cell prostatic tumors are consistent with their aggressive behavior; the low VEGF levels compared with those in the poorly metastatic DU145 cell tumors suggest that other angiogenic factors may be critical for prostate cancer cell progression in this model. PMID- 21528274 TI - Use of lonidamine to potentiate the effect of cisplatin and carboplatin on platinum resistant human ovarian cancer cells. AB - Lonidamine (LND), an indazole-3-carboxylic-acid derivative, is a new, relatively non-toxic, chemotherapeutic agent. LND, which interferes with energy metabolism, has been shown to potentiate the antineoplastic effects of chemotherapeutic agents and radiation. In this study, we evaluated the effect of LND in combination with cisplatin (DDP) or carboplatin (CARBO) on platinum resistant ovarian cancer cells. The ovarian cancer cell line BG-1 was selected as platinum resistant cell line, defined as cell line with survival fraction >50% at 0.5 peak plasma concentration (PPC). Cells were treated during the proliferative phase of cell growth with DDP and CARBO using doses between 0.1 and 1x (x = PPC). PPC of DDP = 2.5 mu g/ml, PPC of CARBO = 28 mu g/ml. Cells were also treated with LND at doses varying between 10 and 100 mu g/ml (PPC 20-50 mu g/ml). Drugs were used as single agents and in combination. Experiments were performed by treating the cells with DDP or CARBO for 90 min and with LND continuous exposure or 90 min only. The ATP cell viability assay was used to assess the antiproliferative effect of the drugs tested. Experiments were repeated at least 3 times. The synergistic interaction formula for anticancer agents and the t-test were used for the analysis of the results. LND was shown to be effective when used in continuous exposure only (IC50 = 0.58). The IC50 of DDP was 1.1 and the IC50 of CARBO was 0.64. Significant dose related antiproliferative effect of LND alone, as well as DDP and CARBO cytotoxicity potentiation was observed (p<0.05). LND was shown to have synergistic effect when combined with platinum compounds to treat ovarian cancer cells at doses of 20 and 30 mu g/ml. These doses are achievable in patients. LND, a relatively new antineoplastic agent with good clinical tolerance, has been shown to synergistically potentiate the antiproliferative effect of platinum compounds on platinum resistant ovarian cancer cells. LND is an agent of potential use for the treatment of ovarian cancer patients in combination with DDP or CARBO. PMID- 21528275 TI - A monoclonal antibody CF703 raised against human fetal lung recognizes a novel onco-fetal mucin. AB - To obtain murine monoclonal antibodies (MAb), mice were immunized with the extract of a human fetal lung from the first trimester of gestation as initial immunogen followed by booster immunization with a human lung cancer cell line. MAb CF703 which reacted to the booster material was screened and selected. In adults, expression of the antigen defined by MAb CF703, CF703 antigen, was shown immunohistochemically in 78% of gastric carcinomas (14/18), 59% of ovarian adenocarcinomas (10/17), 50% of pancreatic carcinomas (5/10), 17% of lung carcinomas (4/24), 50% of uterine cervical adenocarcinomas (2/4), 20% of endometrial adenocarcinomas (1/5) and 10% of renal cell carcinomas (1/10). Other malignant tumors failed to demonstrate the reactivity. MAb CF703 was weakly reactive with only three adult normal tissues including surface lining of gastric mucosa, Brunner's glandular epithelia of the duodenum and columnar epithelia in the uterine endocervix. In fetal tissues, 5 of 23 tissues including squamous epithelia in lower portion of the;esophagus, surface epithelia of gastric mucosae and goblet cells in the small and large intestine were reactive. The CF703 antigen had a molecular weight over 500 kDa and its epitope was carbohydrate in nature by reason of the resistance to proteinase digestion and sensitivity to periodate oxidation, neuraminidase and alkaline-borohydrite. MAb CF703 recognizes probably a unique epitope in oncodevelopmental mucin glycoprotein. Additionally, this immunization method has the advantage of rapid acquirement of MAbs with restricted, narrow cancer spectrum and is a worthy strategy for generating the new MAbs. PMID- 21528276 TI - Epidermal growth factor-DNA conjugate for two-step targeting. AB - An epidermal growth factor (EGF) conjugate, with potential for selective delivery of DNA-binding compounds to malignancies overexpressing the EGF receptor, is presented. The development of a two-step targeting principle implies that, after cellular binding and internalisation, the conjugate should be degraded and the released toxic agents should be in such chemical forms that they bind to the cellular DNA. Boronated compounds with proved DNA-intercalation, earlier developed for boron neutron capture therapy, could be most suitable as the toxic agents. In this study the amino terminus of I-125-EGF was coupled to the 5' end of double stranded DNA, constructed of a 30-mer self-complementary oligonucleotide, to generate a I-125-EGF-DNA conjugate. Binding, internalisation and retention of the conjugate were investigated in vitro on human glioma cells overexpressing the EGF receptor. The generated I-125-EGF-DNA conjugate was shown to bind specifically to the EGF receptor. The conjugate was thereafter internalised and degraded efficiently. The results indicate that the I-125-EGF DNA conjugate has suitable biological properties for the planned tests of selective delivery of DNA-binding toxic compounds in a two-step targeting process. PMID- 21528277 TI - Rapamycin inhibits substance P-induced protein synthesis and phosphorylation of PHAS-I (4E-BP1) and p70 S6 kinase (p70(S6K)) in human astrocytoma cells. AB - The mitogenic substance P receptor (NK-1 subtype) is expressed in many primary human tumors with the highest frequency of expression appearing in astrocytomas and glioblastomas (75% and 100%, respectively). Recently, we showed that substance P neuropeptide induces DNA synthesis in the human astrocytoma U-373MG cells by activating the mitogen-activated protein (MAP) kinase pathway leading to the induction of c-Fos and c-Myc expression. The induction of these immediate early genes is necessary for the progression of cells form G1 to S phase of the cell cycle. In this study, we demonstrate that U-373MG cells are highly sensitive to the growth-inhibitory action of rapamycin at nanomolar concentrations (IC50 <1 ng/ml). We also show that SP peptide stimulates protein synthesis in the U-373MG cell line by activating a rapamycin-sensitive signaling pathway. Further, we demonstrate that SP is potent in stimulating PHAS-I protein (also known as 4E BP1) phosphorylation and p70 S6 kinase (p70(S6K)) phosphorylation and enzymatic activity, and that this stimulation is inhibited by subnanomolar concentrations of rapamycin. In contrast, rapamycin was not at all effective in repressing SP induced activation of MAP kinase pathway, c-Fos phosphoprotein expression, and DNA synthesis in U-373MG astrocytoma cells. PMID- 21528278 TI - Growth stimulatory effect of interleukin (IL)-1 alpha produced by oral squamous carcinoma cell lines. AB - The expression of IL-1 alpha and its effect on the cell growth were examined in six human oral squamous carcinoma cell lines. All the cell lines expressed IL-1 alpha mRNA and protein at various levels. Particularly, HSC-2 and HSC-3 cells showed high level of the mRNA expression and secreted large amounts of IL-1 alpha into the culture fluid. Scatchard plot analysis of IL-1 alpha binding revealed that HSC-2 cells had high-and low-affinity receptors, whereas IL-1 alpha receptors on HSC-3 cells were of undetectable level. The cell growth of HSC-2 and HSC-3 cells was stimulated by IL-1 alpha and inhibited by anti-IL-1 alpha antibody or IL-1 receptor antagonist. The expression of IL-1 alpha mRNA by these cell lines was induced by either IL-1 alpha, epidermal growth factor (EGF) or transforming growth factor alpha (TGF-alpha). On the other hand, IL-1 alpha promoted the mRNA expression of TGF-alpha and EGF receptor. These findings indicate that IL-1 alpha acts as an autocrine growth stimulator for oral squamous carcinoma cells in vitro and its interaction with EGF/TGF-alpha/receptor system may play a role in this enhanced growth by IL-1 alpha. PMID- 21528279 TI - Inhibitory effect of a serine protease inhibitor, FOY-305 on the invasion and metastasis of human pancreatic cancers. AB - We examined the inhibitory effect of a serine protease inhibitor, FOY-305, on the invasion and metastasis of human pancreatic cancers. The in vitro matrigel invasion assay showed that the invasiveness of Capan-1 human pancreatic cancer cells was inhibited by FOY-305 treatment in a dose-dependent manner at concentrations greater than 100 nM. Intrasplenic injection of Capan-1 cells in nude mice resulted in frequent metastases to liver, however, its incidence was significantly decreased by FOY-305 treatment. These findings suggest that a serine protease inhibitor, FOY-305 can inhibit tumor invasion and metastasis by blocking the serine protease-mediated activation cascade. PMID- 21528280 TI - Role of ras oncogene in adriamycin resistance in human prostate tumor cells. AB - We have previously isolated a drug-resistant, [PC3(R)], variant of human prostate PC3 cell line, which showed significant resistance (>10-fold) to adriamycin. No known mechanisms of drug resistance were found; however, resistant cells expressed more bcl2, c-myc, and ms oncogenes compared to the sensitive cells. In this study, we found that buthionine sulfoximine (BSO), an inhibitor of gamma glutamyl-cysteine synthetase, decreased glutathione levels by 80-90% in both cell lines. BSO treatment down-modulated Ras protein only in PC3(R) cells and caused a 4-fold sensitization of PC3(R) cells to adriamycin without affecting PC3(W) cells. Farnesol treatment also inhibited expression of Ras protein and concomitantly reversed adriamycin resistance in PC3(R) cells, indicating that altered levels of ras expression plays an important role in drug resistance in PC3(R) cells. PMID- 21528281 TI - Protein tyrosine phosphatases. AB - Protein tyrosine phosphatases (PTPases) balance the action of tyrosine kinases to maintain a set level of cellular tyrosine phosphorylation. Increases in tyrosine phosphorylation produced by transformation with constitutively active tyrosine kinases can initiate cellular proliferation. PTPases may act as tumor suppressors to counteract the transforming potential of oncogenic kinases. However, recent evidence suggests that PTPases have the potential to act as positive mediators of mitogenic signaling. If PTPases are acting as tumor suppressors, the expression of an inactive PTPase may cause an increase in overall tyrosine phosphorylation of cellular proteins, resulting in cellular transformation. Alternatively, overexpression of PTPases that play a positive role in signal transduction might also lead to proliferation. The role that each PTPase plays may depend in the cellular context in which it is expressed. PMID- 21528282 TI - Dimethylsilane polyamines, a new class of potential anticancer drugs. AB - Several members of a new class of structural analogues of the natural polyamines which contain a S1(CH3)(2)- group in the central carbon chain have previously been found to be potent cytostatics to various tumor cell lines. These compounds have been tested with regard to their ability to inhibit the growth of Lewis lung carcinoma grafts in DBA/2 mice. All compounds exerted consistently antitumor effects, however,growth inhibition was only partial at one or two daily doses of 25 mu mol/kg of the drugs. Among the dimethylsilane tetramines only (6-amino-3 azahexyl),(7-amino-4-azaheptyl)-dimethylsilane (AzhexAzhepSi) reduced tumor growth to a significant degree. A major central nervous system pharmacologic effect of the compounds, hypothermia, limitates the administrable amount of the compounds. The dimethylsilane amines have polyamine antagonist properties, and are weak polyamine mimetics, as became obvious from their effect on tumor cells in culture and the present in vivo experiments. PMID- 21528283 TI - Phosphorylation of signaling proteins in factor-independent myeloid leukemia cell lines. AB - We investigated the mechanisms of factor-independent growth of four human myeloid leukemia cell lines. The autocrine mechanisms were ruled out by RT-PCR method examining growth factor mRNA. The immunoblotting method showed that many proteins were tyrosine phosphorylated irrespective of the stimulation with growth factors (G-CSF and GM-CSF) in factor-independent cell lines while the phosphorylation was induced stimulation dependently in a factor-dependent cell line. MAP kinase was constitutively phosphorylated in factor-independent cell lines. JAK2 protein was not tyrosine phosphorylated before the stimulation. It was significantly phosphorylated after the stimulation in three factor-independent cell lines although the stimulation did not affect their growth. JAK1 protein was not phosphorylated either before or after the stimulation. In conclusion, constitutive phosphorylation of signaling proteins seemed to be related to factor independent growth. MAP kinase was involved in the phosphorylation, while JAK1 and JAK2 were not. PMID- 21528284 TI - VLA(3)/integrin expression in breast carcinomas evaluated by automated and quantitative immunohistochemistry. AB - VLA, expression was immunohistochemically investigated in 145 breast carcinomas. Frozen tissue sections were probed with monoclonal anti-VLA, using automated (Ventana ES 320 system) and quantitative (SAMBA 2005 image processor) immunoperoxidase. A positive anti-VLA, immunoreaction was observed in 86 tumors (23.5%) within epithelial cells of carcinomas. The positive surface in tumors varied from 3% to 38% (mean = 13.8%, SD=11.5) and was independent of the tumor size, grade, type and aneuploidy, and of nodal status. VLA(2) was significantly correlated with VCAM (p<0.01), VLA(2) (p<0.01), E cadherin (p=0.025), and CD44 v (p<0.01), and an inverse relationship was observed with Ki67/MIB 1 (p=0.0024) and P-53 (p=0.034). In contrast VLA, expression proved to be independent of Bcl-2, c erbB-2, cathepsin D, tenascin, CD31, ELAM, RE, RP, PS2 immunohistochemical expression. The results suggest that VLA, expression in tumors is related to the regulation of other adhesion molecules involved in the metastasis process, but the prognostic significance and clinical relevance of VLA, immunodetection in breast carcinomas remain to be demonstrated. PMID- 21528285 TI - The tumorigenic phenotype of a mutated form of Fc gamma RIIB1, lacking the ability to generate soluble receptor and allowing a low-level of ligand binding. AB - Non immunohematopoietic murine tumor cells ectopically expressing Fc gamma RIIB1 (B1) were recently shown to express a higher tumorigenicity phenotype than cells not expressing this receptor. Utilizing a genetic approach we studied the possible contribution of a soluble form of B1 to tumor enhancement. A mutated form of the B1, lacking the cleavage site responsible for the generation of soluble B1 was produced using gene splicing by overlap extension PCR. A deletion confirmed by sequence analysis from 172 to 178 residues was generated. Stable transfectants expressed the B1 deleted form (B1 Delta) both as specific RNA and as a membrane protein receptor allowing a low level of ligand binding. The soluble form of B1 was undetectable in tissue culture supernatants of Bib transfected cells while it was present in supernatants of wild type B1 transfectants. Stable B1 Delta transfectants were significantly more tumorigenic than negative control transfectants. Tumor incidence was almost as high as that of intact B1 and lagged in the latency period before the appearance of palpable tumors. It is suggested that the soluble B1 has a minimal contribution to tumor enhancement. PMID- 21528286 TI - Proto-oncogene products as target antigens for cancer vaccines. AB - Enthusiasm for cancer vaccines has undoubtedly been fueled by the success of vaccines against infectious diseases. The underlying principle of antibacterial or antiviral vaccines is the induction of an immune response to foreign (non self) antigen(s) encoded by the invading microorganism. Until recently, the premise of a response to nonself antigen would have seemed the sine qua non of any vaccine, so self evident as to scarcely merit remark. In fact, the vaccine concept discussed here eschews this premise in favor of a response to self antigen as an anti-tumor modality. Vaccination would target proteins encoded by protooncogenes. As measured relative to their expression in normal cells, proto oncogene-encoded proteins are overexpressed in the tumor cells of a number of human cancers. Any vaccine intended to target self antigen must manage to both circumvent a possible tolerogenicity of the antigen and, at the same time, avoid the induction of autoimmune pathology. For the vaccine concept discussed here, the difference in levels of proto-oncogene expression between tumor cells and normal cells provides a basis for satisfying both of these requirements and hence a basis for the immune-mediated destruction of tumor tissue. PMID- 21528287 TI - Synergy between cisplatin and an inhibitor of S-adenosylmethionine dependent transmethylation in human ovarian adenocarcinoma cells. AB - Selection of cells for resistance to cisplatin results in resistance to arsenite and selenite. Mammalian cells detoxify arsenite and selenite by S adenosylmethionine dependent methylation. We aimed to investigate whether S adenosylmethionine dependent methylation is involved in the cellular metabolism of cisplatin. Treatment of human ovarian cancer cells 2008 and the cisplatin resistant subline 2008/C13*5.25 with the S-adenosylhomocysteine hydrolase inhibitor adenosine-dialdehyde, an indirect inhibitor of transmethylation, resulted in a significant elevation (16-fold in 2008, 6-fold in 2008/C13*5.25) in the cellular content of S-adenosylhomocysteine without changing S adenosylmethionine. Adenosine dialdehyde synergistically enhanced the cytotoxicity of cisplatin and carboplatin as evidenced by combination indices <1 using the combination index-isobologram method in clonogenic assays with 2008 human ovarian adenocarcinoma cells. However, the cellular accumulation, efflux, steady state content, and the formation of DNA adducts of the cisplatin [H-3]-DEP were not affected by adenosine-dialdehyde. Sodium arsenite was significantly more toxic in mice pretreated with adenosine-dialdehyde, whereas the toxicity of cisplatin remained unchanged. These studies suggest that inhibition of S adenosylmethionine dependent transmethylation enhanced the toxicity of cisplatin and carboplatin to human ovarian carcinoma cells in vitro without directly affecting the metabolism of either platinum drug. PMID- 21528288 TI - Altered expression of the genes regulating apoptosis in multidrug resistant human myeloid leukemia cell lines overexpressing MDR1 or MRP gene. AB - Development of multidrug resistance (MDR) in cancer cells is associated with an overexpression of ATP-binding cassette proteins [e.g. P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP)] and with decreased chemotherapeutic agent-induced apoptosis. In this study, we investigated whether MDR in cancer cells was associated with altered expression of genes regulating apoptosis using a drug sensitive human myeloid leukemia cell line (HL60), and its MDR sublines, overexpressing MRP (HL60/AR) or P-gp (HL60/taxol). Expression of apoptotic Genes was examined at the protein level by flow cytometry and at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR). We observed that the MDR cells either did not express or expressed a reduced level of the apoptosis promoters Fas, Bcl-x(s), and Bax, whereas expression of the apoptosis repressor Bcl-x, was increased. Both vincristine and anti-Fas monoclonal antibody induced apoptosis in HL60 cells but failed to do so in both MDR cell lines. These data suggest that acquired MDR in cancer cells, regardless of the type of overexpressed ABC transporter, may be associated with increased expression of antipeptidic genes and decreased expression of pro-apoptotic Genes. PMID- 21528289 TI - Effective introduction of T cell costimulatory molecules into virus modified tumor cell vaccines by modification with bispecific antibodies. AB - This report describes the generation of bispecific antibodies which bind with one arm to virus modified tumor cell vaccines and introduce with the other arm anti murine CD28 T cell costimulatory molecules. This is an effective alternative to somatic gene therapy strategies using genes coding for ligands of CD28 such as CD80 (B7-1) or CD86 (B7-2). While these B7 molecules interact not only with CD28 but also with CLTA-4, thereby generating a negative signal, agonistic anti CD28 antibodies only bind to CD28 and therefore deliver only positive costimulatory signals. The new bispecific antibody (bsAb) HN x CD28 allows the introduction of anti-CD28 antibodies into the tumor cell vaccine ATV-NDV, an autologous tumor cell vaccine already modified by infection with Newcastle Disease Virus (NDV). The bsAb HN x CD28 attaches with its anti-HN binding site to the NDV derived hemagglutinin-neuraminidase (HN) molecule which serves as a common foreign anchoring molecule in the vaccine. NDV infected tumor cells which were further modified with HN x CD28 on their cell surface (bs-vaccine), showed increased T cell stimulatory capacity in vitro. This was revealed by augmented proliferation as well as augmented CTL activity. When syngeneic mice were injected with aggressive murine ESb lymphoma cells which were infected with NDV and further modified with the bsAb HN x CD28, delayed tumor development and prolonged survival was observed in comparison to respective controls. PMID- 21528290 TI - Clinical significance of integrin alpha 6 mRNA expression in gastric carcinoma. AB - Integrin alpha 6 is believed to be involved in malignant biological development. High tumor/normal (T/N) ratio of integrin alpha 6 was observed in intestinal type tumors in gastric carcinoma. In an immunohistochemical study, an intense and continuous staining was seen at the basement layer in the intestinal type tumors. Concerning the variant, there was a significant correlation between the expression ratio of variant B/variant A and the depth of tumor invasion. In conclusion, i) integrin alpha 6 expression was intimately correlated with histologic differentiation, and ii) the overexpression of variant B may be correlated with tumor invasion of gastric carcinoma. PMID- 21528291 TI - Up-regulation of nm23/NDP kinase expression in regenerating hepatocytes. AB - We analyzed the kinetics and subcellular localization of nm23-M1 and nm23-M2 in in vivo proliferating mouse liver cells after partial hepatectomy. Along with the regenerative growth rate measured by mitotic index, the expression of both nm23 M1 and nm23-M2 was altered with distinct kinetics. Among the subcellular fractions of regenerating hepatocytes, the increase in the quantity of nm23-M1 and nm23-M2 was the most dominant in the nuclear fractions. In in vitro proliferating human hepatocellular carcinoma cells (PLC/PRF/5) stimulated by hepatocyte growth factor, both nm23-H1 and nm23-H2 were dominantly accumulated around nuclear membranes. PMID- 21528292 TI - Modulation of growth relative to division regulates expression of a Theileria annulata infection associated antigen in HL-60 cells differentiating towards granulocytes. AB - The protozoan parasite Theileria annulata has the ability to immortalise the bovine leukocyte in which it resides. Immortalisation is known to be associated with a number of molecular and antigenic alterations to the host cell. In this study cells of related lineage were compared with T. annulata infected cells, using a monoclonal antibody which detects an infection associated glycoprotein on the host cell surface. The results show that this antibody recognises a 160 kDa antigen in HL-60 cells, and that expression of this antigen is up-regulated as cells are induced to differentiate towards granulocytes, but not macrophages. Up regulation was observed to proceed in a quantitative manner, with progression through an intermediate phase, before full antigen expression and granulocyte formation was observed. Limited incubation with inducer (DMSO) for 18 h indicated that intermediate cells could revert to negative cells, while longer exposure resulted in conversion to high level antigen expression and a commitment to differentiate. Alteration of cell culture conditions and modulation of division (DNA synthesis) relative to growth (protein synthesis) by incubation in aphidicolin resulted in an increase in the number of cells expressing antigen at both the intermediate level and the level associated with commitment. Based on these results and related studies we present a model which proposes that differentiation is initiated, and then progresses to a quantitative commitment threshold, by altering the level of key regulators of gene expression relative to their DNA templates. PMID- 21528293 TI - Expression of retinoic acid receptor-beta 2 mRNA in normal cervical epithelium and cervical squamous cell carcinoma. AB - Retinoids have antiproliferative effects on epithelial cells and have been used as chemopreventive and chemotherapeutic agents for several human cancers. Retinoid/interferon combinations have demonstrated activity in advanced stage cervical cancer. The objective of this study was to quantify and localize the expression of RAR-beta 2, a retinoid inducible receptor, in normal cervix and cervical squamous cell carcinoma by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ RT-PCR. Specimens where obtained from 11 patients enrolled in a clinical trial to test all-trans retinoic acid (tRA) in combination with interferon-alpha 2a (IFN-alpha 2a) in the treatment of metastatic or recurrent cervical carcinoma. Expression of RAR-beta 2 in cervical carcinoma and normal cervix was measured by quantitative RT-PCR. DNA competitors were used to estimate the relative expression level of RAR-beta 2. Expression of RAR-beta 2 was examined in normal cervix by in situ RT-PCR. Expression of RAR beta 2 in cervical carcinoma ranged from 0.33 to 1.40 with a mean of 0.89+/-0.13 vs. 1.0+/-0.13 for normal cervix (NS) with RAR-beta 2 reduced to less than or equal to 65% in five cases. Irt situ RT-PCR identified RAR-beta 2 most prominently in basal and para-basal epithelial cell layers of normal exocervix; stromal expression was markedly decreased. This is the first report to localize expression of RAR-beta 2 mRNA in normal cervical epithelium and quantify expression in normal cervix and cervical squamous cell carcinoma. Because retinoid receptors are the proximate mediators of retinoid action on gene expression, alteration of their expression or function could result in cancer development. PMID- 21528294 TI - Correlation between apoptosis and tumor-associated macrophages in human invasive ductal breast carcinoma. AB - The relationship between apoptosis and tumor-associated macrophages (TAM) was studied in situ in 60 breast carcinomas (18 G1, 28 G2 and 14 G3 carcinomas) using simultaneous apoptosis (TUNEL method) and macrophage staining (anti-CD68 antibody). Apoptotic tumor cell rate (ATCR), total TAM content (TAM(TOT)) and the proportion of TAM that had either cell-to-cell contact with apoptotic tumor cells or that were phagocytosing them (TAM/APO cells) were quantified. ATCR correlated significantly with TAM(TOT). Within all apoptotic tumor cells, the proportion of TAM/APO cells was lower than 20%. Considering the fact that cell-to-cell contact is essential for macrophage-mediated tumor cell killing, our data suggest that the majority of apoptoses occurring in breast cancer may not be caused by macrophage tumoricidal activity. TAM/APO cells accounted for only 1.7% of all TAM. Thus, tumor cell killing and apoptotic tumor cell phagocytosis seem to be quantitatively less important functions of TAM in human breast cancer in vivo. PMID- 21528295 TI - Radiation induced G2/M block and apoptosis in two human sarcoma cell lines with different p53 gene status. AB - We investigated a wild-type (wt) p53 rhabdomyosarcoma (A-204) and a mutated (mt p53) undifferentiated sarcoma cell line (US8-93) for their response to X-rays. The observation period was 0 to 96 h after irradiation. Both cell lines showed a strikingly delayed G2/M arrest and an induction of apoptosis after irradiation. Compared with the cell line A-204 (wt p53), the cell line US8-93 (mt p53) revealed a stronger G2/M arrest. In agreement with this, in terms of viability as well as the rate of apoptosis, A-204 (wt p53) showed a stronger response to irradiation than US8-93 (mt p53). We suggest that the different p53 gene status might be the cause for a different response to irradiation. PMID- 21528296 TI - Dexamethasone apoptosis induction and glucocorticoid receptor levels in cultured normal and neoplastic cell lines. AB - The deletion with apoptotic mechanisms, of different normal and neoplastic cell lines [Jurkat leukemic cells, EUE epithelioid cells, normal (FG) and transformed rat fibroblasts (SGS/3A)] cultured in vitro in presence of dexamethasone, have been studied combining morphocytochemical (fluorescence microscopy), cytometric (flow cytometry) and biochemical (Radio Receptor Assay) analyses. It has been found that the synthetic glucocorticoid hormone induces an antiproliferative effect with accumulation of cells in the G1 phase and a cell loss by programmed death in some cell lines. The apoptotic incidence was found to be inversely proportional to the cytostatic effect of the hormone: the highest in EUE and Jurkat cells (in EUE cells not only affecting the G0/G1 phase of the cell cycle), the lowest in SGS/3A cells and absent in frbroblasts FG. The apoptotic degeneration, in all the cell lines studied, was characterized, morphologically and cytochemically by: a) decrease in stainability/content of cell DNA and proteins; b) condensation of cytoplasm; c) preservation of mitochondrial membrane functional integrity. In conclusion, in the presence of dexamethasone, programmed cell death was found to play a variable role during the maintenance of culture turnover in different cell lines and the incidence of degenerative phenomena does not appear to be related to glucocorticoid receptor levels. PMID- 21528297 TI - Measurement of the range of HIV-LTR transactivating activity of HIV in vitro. AB - Tat is known to act both in a 'cell autonomous' and in 'cell non-autonomous' manner, i.e. Tat can function as a powerful transcription factor both inside the cell in which it is expressed and also in cells not expressing Tat. However, the distance at which Tat can act by the cell non-autonomous mechanism is not yet known. To estimate the range of Tat action and to understand the mechanism underlying its exocrine action, we used HeLa cells stably expressing chloramphenicol-acetyltransferase (CAT) as a reporter gene under the control of the HIV-LTR. These cells were transiently co-transfected by the Kalashnikov bombardment technique with a plasmid carrying the beta-galactosidase reporter gene under the control of the HIV-LTR together with a plasmid expressing the Tat gene. The cells were then analyzed for expression of both CAT (LTR transactivation marker) and beta-galactosidase (Tat expression marker). The results indicate that Tat can act by inducing the expression of LTR-CAT not only in the Tat producing cells, but also in neighboring cells up to 6-10 cells distance from the producer cell. Furthermore, we demonstrate that the Tat-RDC motif is essential for this paracrine action of Tat, since a Tat protein carrying a deletion of the RDG sequence was unable to activate either adjacent or distant cells. These results suggest the presence of different mechanisms through which exocrine Tat can exert its action. PMID- 21528298 TI - Differential immunohistochemical localization of xanthine oxidase in normal and neoplastic human breast epithelium. AB - Xanthine oxidase (XO) and xanthine dehydrogenase (XDH) are alternate enzymatic forms of the XO/XDH protein that catalyzes the oxidation of hypoxanthine to xanthine, and xanthine to uric acid, and in the process XO/XDH generates reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals. We hypothesize that XO/XDH, which is expressed in mammary epithelium, contributes to the development of breast cancers by virtue of its ability to generate genotoxic ROS. In this study, we produced human XO/XDH protein at high levels in Spodoptera frugiperda (Sf9) insect cells using the baculovirus vector to confirm the specificity of antibodies used for immunostaining of human breast tissues. Immunoblot analysis demonstrated that the full length 143 kDa polypeptide was partially processed into a 87 kDa and 59 kDa fragments. The overexpressed XO/XDH protein was identified in the cytoplasm of insect cells by immunofluorescence staining. Using these antibodies we analyzed normal and neoplastic breast epithelium for the presence of XO/XDH. Immunohistochemical analysis of normal human breast revealed the presence of XO/XDH in the cytoplasm of epithelium lining terminal ducts. The intensity of XO/XDH staining was markedly enhanced in alveolar epithelium of lactating mammary lobules. In contrast, no immunohistochemically detectable XO/XDH was observed in intraductal in situ carcinomas and in invasive carcinomas of the breast. Further studies are necessary to confirm the utility of the loss of XO/XDH expression as a marker for neoplastic change in the breast and investigate the functional role of this enzyme in the pathogenesis of breast cancer. PMID- 21528299 TI - p53 overexpression as a prognostic factor in patients with Dukes B colorectal adenocarcinoma. AB - To investigate the relationship of p53 overexpression with clinicopathological factors and prognosis, we examined p53 expression in 257 colorectal adenocarcinomas by immunohistochemistry using monoclonal antibody DO-1. Nuclear p53 staining was detected in 113 tumors. p53 overexpression was increased in DNA non-diploid tumors (p=0.004) and in the tumors with higher proliferative activity (p=0.02). Overexpression of p53 predicted unfavorable prognosis in patients with Dukes B tumors in both univariate (p=0.02) and multivariate analyses including DNA ploidy (p=0.04). No correlation was found between p53 expression and patient sex and age, tumor site, stage, differentiation or growth pattern. Our results indicate that p53 overexpression detected by antibody DO-I might be a useful tool in optimizing care of patients with Dukes B tumors. PMID- 21528300 TI - Differential mechanisms of multidrug resistance are expressed during stepwise selection of KB-3-1 cells with adriamycin. AB - A major limitation of cancer chemotherapy is development of resistance. In this study, we analyzed KB-3-1 cells and adriamycin-selected multidrug resistant sublines KB-A1 and KB-A10 cells for mechanisms of resistance. KB-A10 cells are 10 fold more resistant than KB-A1 cells but have lower P-glycoprotein. Of the known mechanisms of multidrug resistance, topoisomerase II and lung-resistance-related protein were altered between the resistant cell lines. Glutathione-S-transferase activity and multidrug-resistance-related protein levels were higher in the resistant cell lines compared to the sensitive cells but were similar in KB-A1 and KB-A10 cells. Results indicate differential regulation of mechanisms of resistance with stepwise selection. PMID- 21528301 TI - Characterization and purification of angiogenic factor derived from highly liver metastatic colon cancer cells. AB - We investigated the effects of serum-free conditioned medium (SFCM) of colon cancer cells on human umbilical vein endothelial cells (HUVECs). SFCM of highly liver metastatic cell line (LM-HS) strongly enhanced proliferation, migration and tube formation of HUVECs. Moreover, it was suggested that a main angiogenic factor derived from LM-H5 may be VEGF based on HPLC, SDS-PAGE analysis and neutralizing experiment using anti-growth factor antibodies. These findings suggest that angiogenesis is related to the processes of metastasis of colon cancer, and that VEGF synthesized by colon cancer cells acts as a key factor inducing angiogenesis. PMID- 21528302 TI - Enhancing 5-fluorouracil cytotoxicity by inhibiting dihydropyrimidine dehydrogenase activity with uracil in human tumor cells. AB - We analyzed dihydropyrimidine dehydrogenase (DPD) activity (radioenzymatic assay) and 5-fluorouracil (5-FU) cytotoxicity (MTT test) in the absence or presence of uracil in two human cancer cell lines, MIAPaCa-2 (pancreas tumor) and HuTu80 (duodenum tumor). Basal DPD activities in both were comparatively high; MIAPaCa 2, 101 and HuTu80, 153 pmol/min/mg protein, respectively. Twenty mu g/ml of uracil, a dose which did not influence cell proliferation, enhanced 5-FU cytotoxicity; MIAPaCa-2, 2.0-fold and HuTu80, 1.5-fold, respectively. Uracil inhibited both DPD activity and cell growth in a concentration-dependent manner, and exhibited maximum effect at molar ratios to 5-FU of more than 10 (DPD activity, almost complete inhibition; growth-inhibitory effect, about a 30% increase). In addition, the cytosolic DPD activity of OCC-1 human head and neck tumors, collected following the oral administration of ss mg/kg of uracil to tumor-bearing nude mice, decreased to about 50% of that of OCC-1 tumors not treated with uracil. These findings suggested that combined fluoropyrimidine and uracil treatment of tumors with high basal DPD, elicits a greater antitumor effect than fluoropyrimidines alone, since uracil could inhibit the degradation of 5-FU in the tumor. UFT, an oral fluoropyrimidine combined with uracil, is expected to be more effective in such tumors. PMID- 21528303 TI - MRP-1/CD9 and KAI1/CD82 expression in normal and various cancer tissues. AB - As part of our evaluation of MRP-1/CD9 and KAI1/CD82 as prognostic predictors among patients with cancer, we have extended our studies to solid tumors of a variety of anatomical sites. Normal tissues were included for comparison. Immunohistochemical techniques were used throughout. Our results indicate that MRP-1/CD9 was strongly expressed by many normal tissues, including the epithelium of the gastrointestinal tract, alveolar epithelium of the lung, urothelium and smooth muscle. Expression was weak in the pituitary gland, spleen and hepatocytes, and absent in testes and spinal cord. KAI1/CD82 was also expressed by many normal tissues, but was absent in some MRP-1/CD9-positive tissues (e.g., smooth muscle, adrenal cortex, urothelium, myelin of peripheral nerves, epithelium of amnion). On the other hand, KAI1/CD82 was strongly expressed in spinal cord gray matter, which was MRP-1/CD9-negative. Expression of these glycoproteins was detected in almost all types of tumors examined. In certain cancers, MRP-1/CD9 and KAI1/CD82 positivity was inversely related to lymph node involvement. Whereas lymph node metastases were present in 22.2% of lung cancer patients whose tumors were MRP-1/CD9 and KAI1/CD82-positive, 65.5% of patients with MRP-1/CD9 and KAI1/CD82-reduced/negative tumors had lymph node metastases. A similar inverse relationship was seen in colon cancer and breast cancer patients with respect to MRP-1/CD9 expression. The present data, together with our previous results suggest that evaluating the MRP1/CD9 and KAI1/CD82 status of cancers of the lung, breast and colon may provide useful information on the metastatic potential of the tumors. PMID- 21528304 TI - Molecular epidemiology in cancer research (review). AB - In recent years, a new tool known as 'molecular epidemiology' has been developed for cancer research. This approach evaluates molecular phenomena of the carcinogenesis process as related to exogenous and endogenous risk factors. Modern laboratory methodologies make available for similar studies many applicable endpoints. These techniques may be applied directly in tissues bearing risk for cancer development (target tissues) or in 'surrogate' tissues more easily recoverable but not prone to neoplastic transformation. Possible useful endpoints are related to metabolic cell activities, presence of toxic substances metabolites in various cell compartments, genotypic lesions or phenotypic alterations. The present article reports and briefly comments the main laboratory techniques used in molecular epidemiology studies, with particular reference to results obtained in humans undergoing environmental exposure to cancer risk factors. It is concluded that each single end point possesses specific attributes highlighting only. some aspects of the complex carcinogenesis process. Therefore, molecular epidemiology studies comparing multiple endpoints normally produce the most reliable and useful data, and should represent the gold standard in the field. PMID- 21528305 TI - Overexpression of the human c-erbB (EGF receptor) protooncogene fails to alter the lifespan or promote tumourigenic growth of normal and SV40-transformed human fibroblasts. AB - c-erbB was introduced into normal human fibroblasts, MRC-5, which expressed normal levels of EGF receptor and in a SV40-transformed cell line, MRC-5V1, derived from them, which expressed markedly reduced levels of EGF receptor mRNA. MRC-5 overexpressing c-erbB, responded mitogenically to EGF. However, addition of high EGF concentrations markedly reduced DNA synthesis and resulted in the inhibition of cellular growth. In contrast, MRC-5V1 exhibited an increase in DNA synthesis in an EGF-dependent manner which was enhanced by overexpression of c erbB. These cells, unlike MRC-5, also produced TGF alpha, an EGF receptor ligand which is often associated with cellular transformation. Ligand-activation of EGF receptor did not alter the lifespan, induce focus formation or anchorage independence of MRC-5 and all the cell types remained non-tumourigenic in nude mice. However, c-erbB induced the expression of tPA, c-jun and junB in both MRC-5 and MRC-5V1. The data suggest that overexpression and activation of c-erbB is unlikely to play a role in immortalisation of human diploid fibroblasts but it may contribute to cellular transformation. PMID- 21528306 TI - Therapeutic value of intraperitoneal hyperthermic peritoneal perfusion for patients with gastric cancer. AB - To evaluate the prognostic factors of patients with gastric cancer invading the serosa, 14 factors (age, sex, maximum diameter of tumor, histologic type, growth pattern, lymph node status, lymphatic invasion, vascular invasion, surgical method, lymph node dissection, chemotherapy, expression of p53 protein, expression of p21 protein, and DNA ploidy pattern of tumor) were analyzed in 156 patients who underwent curative operation between 1983 and 1992. By multivariate survival analysis, 6 factors (maximum diameter of tumor, lymph node status, vascular invasion, lymph node dissection, expression of p53 protein, and expression of p21 protein) were found as independent prognostic factors. Although no statistically significant difference was observed, postoperative intraperitoneal hyperthermo-chemotherapy prolonged the survival rate of patients who had p21-positive tumors or that of patients who had dipoid tumors. These results indicate that tumors with expression of p21 protein or with DNA diploidy may be more sensitive to anti-cancer drugs than tumors without expression of p21 protein or with DNA aneuploidy. PMID- 21528307 TI - Altered P53 conformation. AB - The p53 protein is a transcription factor that is frequently mutated in human malignancies. Using the MCF10AT model for early human breast cancer we show that P53 protein is unmutated indicating that mutations are not necessary for alterations in growth and morphology that accompany preneoplastic stages of breast tumor progression. Although p53 protein is wild-type in cells of the MCF10AT model system, it exists predominantly in a conformationally altered state that is defective in its ability both to bind DNA in a sequence-specific manner and to induce transcriptional activation from the WAF-1 promoter. This contrasts with P53 from the non-tumorigenic parental MCF10A cells which is predominantly conformationally normal and functionally active. The possibility that stabilized wild-type but conformationally altered P53 plays a role in the neoplastic progression of preneoplastic MCF10AT system cells is discussed. PMID- 21528308 TI - v-erb A and v-erb B do not cooperate in quail myoblasts. AB - We have previously shown that v-erb A stimulates quail myoblast differentiation in a T3 independent, cell-specific manner. In this work, we have studied the influence of v-erb B (the second oncogene carried in the AEV genome) upon quail myoblast proliferation and differentiation. v-erb B expression,moderately stimulates myoblast proliferation, and inhibits differentiation. Moreover, this oncoprotein fully inhibits the v-erb A myogenic influence. These data provide evidence that these two oncogenes do not cooperate in avian myoblasts. Consequently, in contrast to results obtained in other cell-types, coexpression of both oncogenes does not transform quail myoblasts. PMID- 21528309 TI - High prevalence of hepatitis C virus infection in schistosomiasis japonica patients associated with hepatocellular carcinoma. AB - Schistosomiasis japonica (SCJ) patients frequently develop hepatocellular carcinoma (HCC). This study investigated relationship between SCJ infection, hepatitis virus infection, and incidence of HCC, in 25 patients with chronic SCJ infection and HCC (SCJ with HCC group), 51 patients with chronic SCJ infection without HCC (SCJ group) and 65 HCC patients without SCJ (HCC group). Number of patients who were positive to HBsAg or hepatitis B virus DNA were 4 (16.0%) in the SCJ with HCC group, none (0%) in the SCJ group, and 5 (7.9%) in the HCC group; while number of patients who were positive to anti-hepatitis C virus antibody were 21 (87.5%) in the SCJ with HCC group, 3 (5.9%) in the SCJ group, and 58 (84.6%) in the HCC group. Biopsy was performed for all patients, and background histological features of each specimen were evaluated based on the histological activity index scoring system. Mean scores of inflammatory changes in both the portal area and parenchyma in the SCJ with HCC group were significantly higher than those in the SCJ group. Nodular formation which is common in post-viral hepatitis was frequently observed in the SCJ with HCC group, and histological changes in non-cancerous area of the SCJ with HCC group showed the characteristics of chronic viral hepatitis. We conclude that infection of hepatitis virus, particularly hepatitis C virus, affects synergistically on the hepatocarcinogenesis in patients having SCJ infection. PMID- 21528310 TI - Aberrant expression of p53 and retinoblastoma gene products in human esophageal squamous cell carcinoma. AB - The aberrant expression of p53 and RB proteins was investigated by immunohistochemistry in 73 patients with esophageal SCC, who underwent esophageal resection. Fresh tumor tissues from 21 patients were also tested for p53 mutations in exons 4 through 9 by direct sequencing. Positive nuclear staining with p53 antibody in cancer cells was found in 49.3% (36/73) of the tumors. Mutations in the p53 gene were detected in 66.7% (14/21) by direct sequencing. Nuclear staining with RB antibody in cancer cells was diffuse in 11.0% (8/73) and heterogeneous in 57.5% (42/73) of cases. Ten patients with p53-positive but RB negative tumors had a significantly higher incidence of stage IV disease than the other patients studied. In addition, 8 patients with tumors with diffuse nuclear staining for RB antibody had a significantly lower survival rate than the other patients. These findings demonstrate that aberrant expression of RB and/or p53 protein is frequent in human esophageal SCC, and is probably associated with tumor progression and unfavorable prognosis. PMID- 21528311 TI - Rapamycin-induced apoptosis is p53-independent in human prostate carcinoma PC-3 cells. AB - We have investigated the mechanisms of rapamycin-induced growth inhibition and apoptosis in the PC-3 prostate carcinoma cell line. Rapamycin induced apoptosis as well as the expression of p21(waf1) mRNA and protein, independent of p53. Rapamycin treatment also resulted in: a decrease in cdk2 kinase activity; an increase in hypophosphorylated retinoblastoma protein (pRb); a dephosphorylation of p70 S6 kinase; and, growth-arrest in G(1)-phase of cell cycle. These data suggest that rapamycin-induced growth arrest and apoptosis occur through the p53 independent induction of p21(waf1). Since this induction occurred soon after rapamycin treatment, possibly, the early induction of p21(waf1) and G(1)-arrest are important components of the mechanism by which rapamycin induces apoptosis in PC-3 cells. PMID- 21528312 TI - Control of cell cycle regulatory protein expression by 1,25-dihydroxyvitamin D-3 in human promyelocytic HL-60 leukemic cells cultured in serum-free medium. AB - 1,25-Dihydroxyvitamin D-3 (herein referred to as vitamin D-3), the natural vitamin D-3 formed by successive hydroxylation of cholecalciferol at the 25 and 1 alpha position, and numerous vitamin D-3 analogs, have been reported to decrease proliferation and promote terminal differentiation from several types of human malignant cells, including the human promyelocytic HL-60 leukemic cells. The purpose of this study was to determine if and to what extent the cell culture conditions affect the sensitivity of the HL-60 cells to vitamin D-3, both in terms of cell growth, differentiation, and changes in expression of specific proteins. Addition of 10 nM and 100 nM vitamin D-3 to HL-60 cells cultured in the serum-free, chemically defined medium of insulin/transferrin/selenium (ITS) effected cell growth differently than cells maintained in a fetal bovine serum supplemented medium. In addition to the greater degree of growth suppression by 100 nM vitamin D-3, cells maintained in serum-free medium also displayed significantly higher levels of monocytic differentiation. Furthermore, Western blot analysis showed that a pronounced arrest of cell cycling at the G(1)-to-S phase transition, concomitant with a corresponding 36% down-regulation of cyclin D1 and, in parallel, a similar decreased hyperphosphorylation of pRb, was elicited by 100 nM vitamin D-3. These results indicate that the sensitivity of HL 60 cells to vitamin D-3 is dependent on the availability of serum. PMID- 21528313 TI - Enhancement of thermal damage in murine tumors by hydralazine-induced modification of blood flow and oxygen tension. AB - We investigated changes in blood flow in normal muscle and in SCC-VII tumors treated by hyperthermia combined with hydralazine, to evaluate the enhancement of thermal tumor damage by hydralazine. We studied SCC-VII tumor-bearing C3H/He mice. Hydralazine was administered by intraperitoneal injection, and tumors were heated by a water bath. We measured blood flow using the laser Doppler method, and oxygen tension using polarography. The response of tumors to therapy was assessed using a growth delay analysis. In tumors, blood flow and O-2 tension significantly decreased with increasing doses of hydralazine. Compared to tumors treated by hydralazine alone or by hyperthermia alone, tumor blood flow was significantly decreased in the group treated by hyperthermia with hydralazine. In tumors treated by hyperthermia with hydralazine, blood flow was significantly decreased with increasing Hyd doses, heat durations, and temperatures. In normal muscle, no decrease in blood flow was induced by hyperthermia, hydralazine, or their combination. In tumors treated by hyperthermia (43 degrees C, 20 min) with hydralazine, a maximum additional growth delay was observed. Our results suggest that a decrease in tumor blood flow caused by hydralazine plays an important role in enhancement of the hyperthermic antitumor effect. PMID- 21528314 TI - Rare mutations of the growth suppressor genes involved in negative regulation of the cell cycle. AB - The growth suppressing activity of the retinoblastoma susceptibility gene product, pRb, is down regulated by cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) whose activity is negatively regulated by CDK inhibitors of the p16 family. We have previously reported point mutations of the p16/CDKN2 gene in 4 (57%) of 7 oral squamous cell carcinoma (SCC) cell lines. In the current study, we examined the mutational status of CDK inhibitors, including 3 genes of the p16 family (p16, p15 and p18), in 50 human oral SCCs, and also additional results concerning their loss of heterozygosity in the regions of the p16, p15 and p18 genes. Our results demonstrated that 2 of 50 (4%) primary oral SCCs had nonsense mutations of the p16 gene, and 2 of 50 (4%) showed frameshift mutations of the p18 gene. However, we detected no mutation of the p15 gene in any of the 50 oral SCCs. In addition, no evidence of hypermethylation of the p16 gene was found in our series. To better understand the extent of alterations affecting chromosomes 9p21 (location of the p15/p16 genes) and 1p32 (location of the p18 gene), loss of heterozysity (LOH) on these locations was examined. LOH was detected in 16 of 34 (47%) informative samples that had no detectable mutation of the p15/p16 genes on 9p21, but we found no LOH at 1p32. These results strongly suggest that a putative tumor suppressor gene for oral SCC may be present on chromosome 9p21-22, while the p16, p15 and p18 genes play a minor role in the oncogenesis of this cancer. PMID- 21528315 TI - Induction of erythroid differentiation is associated with inhibition of glycolysis and a decrease in fructose 2,6-bisphosphate levels. AB - The fraction of glucose metabolized to lactate is dramatically reduced during erythroid differentiation of mouse erythroleukemia (MEL) cells induced by dimethyl sulfoxide (DMSO), hexamethylene bisacetamide (HMBA), or sodium butyrate treatment. In order to determine the mechanism of the reduction in lactate production, several enzymatic steps in glucose catabolism were investigated. No changes in glycolytic enzyme levels were found during differentiation that could account for the alteration in lactate production and alterations in pyruvate kinase activity are known not to occur during MEL cell differentiation. Further, utilizing D-mannoheptulose, a specific inhibitor of hepatic-/tumor-specific glucokinase, no dependence on the activity of this enzyme for growth or differentiation was observed. Therefore, the possibility was entertained that the decrease in lactate production reflected a decrease in fructose 2,6-bisphosphate (F-2,6-P-2) which is a major regulator of the lactate production due to its ability to allosterically stimulate phosphofructokinase-1 (PFK-1) activity. PFK-1 cannot function in the absence of F-2,6-P-2 when only a suboptimal concentration of one of its substrates, fructose-6-phosphate (F-6-P), is present. When assayed under limiting F-6-P concentrations, it was found that following DMSO- or HMBA induced differentiation, PFK-1 activity was decreased 7-20-fold. This finding suggested that F-2,6-P-2 levels might be controlling lactate production in this system. In keeping with this idea, marked decreases in F-2,6-P-2 levels were found to occur during DMSO- or HMBA-induced differentiation. These data suggest that decreasing F-2,6-P-2 levels account for the decrease in lactate accumulation that occurs during MEL cell differentiation. PMID- 21528316 TI - The role of dietary factors in prevention of chemically-induced cancers (review). AB - The role of dietary factors in prevention of chemically-induced cancer was reviewed on two models: i) the role of high fiber diets in prevention of colon cancer and ii) the role of high fat diets in prevention of mammary gland cancer, i) Experiments in colon cancer showed that 20% cellulose content decreased tumor incidence caused by 1,2-dimethylhydrazine (DMH) to 33% compared with 92% of tumors developed in animals fed a fiber-free diet. The tumor-preventive effect of a cellulose diet was accompanied by increased enzyme concentrations, such as ornithine decarboxylase, thymidine kinase and beta-glucuronidase. Corncob fiber (15%), treated with the fungus Pleurotus os., had a significant protective effect against DMH-induced rat colon cancer. This effect was accompanied by activation of some cellular mechanisms, i.e. apoptosis, proliferating cell nuclear antigen (PCNA) and p53 protein synthesis. A high positive correlation was found between tumor grade and p53 protein in the serum (r=0.97) or in the cell cytoplasm (r=0.77), and between tumor grade and PCNA (r=0.81). An inverse relationship was found between tumor grade and apoptosis (r=-0.63). ii) Experiments in mammary gland cancer showed that a 15% olive-oil diet reduced tumor incidence caused by 9,10-dimethyl-1,2-benzanthracene to 30%, compared with 55% in the control group. The antitumor effect of the olive oil diet was connected to its content of monounsaturated fatty acids, such as oleic and palmitic acids. The promotive tumorigenic effects of other high-fat diets (avocado, soybeans) were associated with high content of some polyunsaturated fatty acids (linoleic and alpha linolenic). We concluded that different diets have different targets. The effect of the same diet depends on its content of anti-tumor substances. PMID- 21528317 TI - Wild-type p53 is not sufficient for serum starvation-induced apoptosis in cancer cells but accelerates apoptosis in sensitive cells. AB - According to the conflicting growth signal model, cells that are driven to proliferate by certain oncogenes undergo apoptosis but not growth arrest upon withdrawal of growth factors. However, we found that the majority of human cancer cell lines continued to proliferate and did not undergo apoptosis following serum withdrawal. As an exeption, wild-type (wt) p53-expressing HCT116 human colon cancer cells underwent apoptosis within 24-36 h of serum deprivation. p53 degradation in human papilloma virus EG-expressing HCT116 cells led to enhanced survival that was not due to growth arrest. These results are consistent with a role for p53 in starvation-induced death in HCT116 cells. However, other cell lines did not undergo apoptosis despite their expression of wt p53. Thus, H460 cells (wt p53) were resistant to starvation-induced death but introduction of the adenovirus EIA oncoprotein induced p53 and also increased sensitivity to serum withdrawal. p53 was not stabilized by E1A and resistance to starvation-induced cell death was observed in E6-expressing H460 cells. These results suggest that although p53 contributes to starvation-induced apoptosis in sensitive (HCT116 and E1A-expressing H460) cancer cell lines, most cancer cells survived despite the presence of wt p53. We conclude that naturally selected human cancer cell lines suppress apoptosis due to conflicting growth signals. PMID- 21528318 TI - The biological effects of antisense mos expression in fibroblasts. AB - In order to determine the physiological significance of c-mos RNA expression in somatic cells, we introduced antisense c-mos under the control of an inducible promoter. NIH/3T3 cells were stably transfected with antisense mos under the control of the mouse mammary tumor virus long terminal repeat (MMTV-LTR). Positive transfectants were selected under G418 conditions. Following selection, NIH/3T3 cells that received the antisense mos failed to form foci, whereas sense mos transfected cells grew normally. Moreover, v-mos-transformed cells were unaffected by antisense mos transfection. Of: interest, NIH/3T3 antisense mos transfectants that survived selection were growth-arrested. Nuclear abnormalities and the extrusion of microvesicles containing cellular material were observed in these cells. In order to rescue these cells from growth inhibition, the v-mos gene was introduced into cells by acute infection with Moloney murine sarcoma virus. Following infection, these cells resumed growth and became rapidly transformed. In other experiments, mouse C2 cells stably transfected with antisense mos showed a slower growth rate and gross morphological changes. C2 cells containing antisense mos under the control of mouse metallothionein-1 promoter had a large and flattened morphology and a relatively high percentage (30%) of binucleated cells. Our results indicate that basal level expression of antisense mos (under uninduced conditions) results in either arrested or retarded cell growth. The phenotypes exhibited in both cell lines leads us to suggest that the c-mos expression may play a role in mitotic progression in some somatic cells, in particular affecting cytokinesis. PMID- 21528319 TI - Elevated expression of ETS-1 gene in a metastatic, tumorigenic human prostate epithelial cell line transformed by the v-Ki-ras oncogene. AB - A suitable in vitro model system to investigate mechanisms of human prostate carcinogenesis is much needed. We have previously demonstrated that an immortal, but non-tumorigenic, human prostate epithelial cell line (267B(1)) can be malignantly transformed by the v-Ki-ras oncogene, and it can serve as a useful model for investigation of the progression steps of prostate carcinogenesis. In this study, we report for the first time the invasive/metastatic phenotype of the v-Ki-ras transformed 267B, cells (267B(1)/Ki-ras). In addition, comparing non tumorigenic 267B, and metastatic tumorigenic 267B(1)/Ki-ras human prostate epithelial cell lines, we have found that expression of ETS-1 and ERGB mRNA was elevated to 2-5 fold in the metastatic and tumorigenic 267B(1)/Ki-ras cell line. A specific ETS-1 monoclonal antibody E44 also revealed that the expression of ETS 1 protein level in 267B(1)/Ki-ras cell line was higher than those in 267B, cell line. However, other members of the ETS gene family such as ETS-2, GABP alpha and their mRNA expression levels were similar in both cell lines. The activation of MAP kinase, a downstream target for Ki-ras, was also shown. The expression of urokinase plasminogen activator (u-PA) was also increased in the metastatic 267B(1)/Ki-ras line. An obvious capability of invasion was observed in the 267B(1)/Ki-ras cell line, but not in the 267B(1) line using BioCoat Matrigel invasion chamber assay system. The present study has provided evidence that the v Ki-ras oncogene may activate the nuclear target gene, ETS-1 gene, to mediate tumorigenic and metastatic capacity of the v-Ki-ras transformed prostate epithelial cells. PMID- 21528320 TI - TGF-beta 3 expression correlates with epithelial cell death in normal, hyperplastic and malignant prostate. AB - Cytokines of the TGF beta family are thought to be involved in cellular growth control and are therefore likely candidates to regulate homeostasis of the prostate. We have analyzed immunohistochemically the expression of TGF-beta 3 in normal prostate (NP), benign prostate hyperplasia (BPH) and prostate cancer (PCa). Its expression was correlated to cell death and cell proliferation using double labeling techniques with terminal transferase and anti-Ki67 antibodies, respectively. TGF-beta 3 expression, localized to the basal cell layer of glandular epithelium, was found in NP and BPH. In TGF-beta 3 positive regions cell death was frequently detected, while proliferating cells were only observed in TGF-beta 3 negative areas. Moreover, cell death was not observed in the absence of TGF-beta 3. PCa was characterized by high cell proliferation and the absence of cell death. TGF-beta 3 expression could not be detected in PCa. Hormonal ablation is the main therapeutic protocol used today suffering, however, from a high relapse rate. We have used the rat as a model system to show that castration, resulting in massive cell death of glandular epithelial cells, induces overall expression of TGF-beta 3 in the basal cell layers. Interestingly, investigation of tumor material from patients received after hormonal ablation revealed the simultaneous presence of TGF-beta 3 positive, hyperplastic regions undergoing cell death and TGF-beta 3 negative highly proliferating malignant foci. Our results suggest that the expression of TGF-beta 3 strictly correlates with cell death in normal and hyperplastic prostate and that disappearance of TGF beta 3 indicates high cell proliferation and the establishment of the malignant phenotype. PMID- 21528321 TI - Correlative study of angiogenesis in endometrial cancer assessed by the color Doppler ultrasound and by the chick embryo chorioallantoic membrane. AB - Angiogenesis is required for both tumor growth and progression and the degree of vascularization seems to correlate with prognosis in several human tumors including uterine malignant neoplasms. In this study we have investigated if three Doppler parameters, such as peak systolic velocity (PSV), resistance index (RI) and pulsatily index (PI), measured in patients with endometrial cancer, were correlated to the angiogenic response induced by grafting of bioptic specimens obtained from the same patients onto the chick embryo chorioallantoic membrane (CAM), a useful in vivo model for such an investigation. Results showed that only PSV was directly correlated to the degree of angiogenesis measured by means of the CAM assay. Moreover, these two parameters were also directly correlated to the malignancy grade of the disease. PMID- 21528322 TI - Immunocytologic staining of cytokeratin in bone marrow aspirates to detect micrometastatic cells fails in patients with metastatic urologic carcinoma. AB - The detection of cytokeratin-positive cells in bone marrow of patients with various carcinomas is considered an adverse marker. To establish a routine diagnostic procedure to detect these cells in patients with urologic carcinoma, we evaluated different immunocytological techniques in parallel. The study included 50 patients with urologic carcinoma (16 with metastatic disease) and 10 healthy volunteers. Bone marrow was aspirated from the iliac crest; after density centrifugation, cytocentrifuged specimens were stained according to optimized modifications of conventional immunocytologic techniques. Overall only 3% of patients with locally restricted carcinoma and only 19% with metastatic disease showed cytokeratin-positive bone marrow cells. Nonspecific labeling of bone marrow cells in the immunoglobulin isotype controls was a major problem, demonstrating the need for numerous detailed controls. If all nonspecific reactions were excluded, up to 20% of the healthy controls yielded positive results as well. The presence of cytokeratin-positive cells in bone marrow aspirates shows only slight correlation with systemic metastasis. The biologic and clinical relevance of this immunocytologic marker must be judged cautiously. PMID- 21528323 TI - Analysis of K-ras, p53, bcl-2 and Rb expression in non-small cell lung cancer cell lines. AB - Six non-small cell lung cancer (NSCLC) cell lines (A-549, Ca-Lu-6, SK-Lu-1, Ca-Lu 1, SK-Mes-1 and LX-1) were studied to assess the presence of multiple concomitant alterations of different oncogenes (K-ras, bcl-2) and tumor suppressor genes (p53, Rb) in NSCLC. K-ras (exon 1) and p53 (exons 5-8) gene mutations were determined via a PCR-based-DGGE (Denaturing Gradient Gel Electro-phoresis) and by sequencing approach. Different mutations were found in the Ist exon of K-ras gene in 5 of 6 cell lines examined. Five of six cell lines contained K-ras mutations at codon 12 (A-549, SK-Lu-1, LX-1) or codon 13 (SK-Mes-1, Ca-Lu-1). In addition, 5 of 6 cell lines showed p53 mutations of exon 8 (SK-Mes-1, Ca-Lu-1 cod. 280; LX 1 cod. 273) or exon 6 (Ca-Lu-6 cod. 196; SK-Lu-1 cod. 193). In 4 of these cell lines, p53 protein nuclear expression was also confirmed with DO-7 mAb immunocytochemistry. Expression of cytoplasmic bcl-2 protein, by anti-bcl-2 mAb flow cytometric analysis, was found in A-549, Ca-Lu-1, SK-Lu-1, SK-Mes-1 cell lines. In contrast, RT-PCR analysis of Rb gene could not identify any change in the cell lines examined. In conclusion, most NSCLC cell lines tested displayed concomitant multiple oncogene/tumor suppressor gene alterations. PMID- 21528324 TI - Cisplatin-induced cell death in human glioma. AB - It has been reported that apoptosis is a predominant mode of death of tumor cells treated with cisplatin. It is unclear, however, whether cells of all tumor types, without exception, respond to cisplatin by apoptosis. In particular, the mode of death of glioma cells has not been investigated. In the present study human glioma U251 MG cells were treated in vitro with 1 or 10 mu g/ml cisplatin and their mode of death was analyzed by flow cytometry, DNA gel electrophoresis, examination of cell morphology following their staining with Giemsa and electron microscopy. The absence of a sub-G1 peak on the DNA content frequency histogram, the absence of DNA laddering on agarose gels, no nuclear fragmentation but distinct mitochondrial swelling were the features of U251 MG cells dying in the presence of cisplatin. Since these features are characteristic of necrosis rather than apoptosis the data indicate that the mode of cell death of some tumors treated with cisplatin may be necrosis. PMID- 21528325 TI - Tumour vaccines expressing IL-2, CD80, and IL-2 plus CD80 gene. AB - Experiments were designed to investigate immunogenicity and therapeutic efficacy of tumour vaccines constructed by transfection of poorly immunogenic murine sarcoma Mc12 with synergistic CD80 and IL-2 genes. Immunization/challenge experiments demonstrated that both, IL-2(+) and IL-2(+) plus CD80(+) live cell vaccines can exert an immunizing stimulus, the IL-2(+) plus CD80(+) vaccine being superior to the IL-2(+) vaccine. Live CD80(+) Mc12 cell vaccine could not be tested, since the vaccine was highly tumorigenic in the doses required for immunization. Preimmunization with IL-2(+) and IL-2(+) plus CD80(+) vaccines induced regressions of a proportion of the parental Mc12 challenge inocula after their temporary growth. Areas of necrosis and extensive infiltration with Mac1(+) and CD4(+) leukocytes have been observed in the regressing sarcomas. When the therapeutic efficacy of the irradiated CD80(+), IL-2(+), and mixed CD80(+) plus IL-2(+) vaccines was compared, it was found that the insertion of the IL-2, but not CD80 gene alone was efficient. The mixed IL-2(+) plus CD80(+) tumour vaccine was able to protect and prolong survival of a higher proportion of mice than the IL-2(+) tumour vaccine. PMID- 21528326 TI - Microfluorometry and image analysis of peritoneal mast cells reveal differences in the morphology and content of sulfated polyanions between normal and tumor bearing mice. AB - Mast cells (MC) are frequently increased in neoplasias. Recently, we observed that MC from peritoneal cavity of normal mice (NMC) and one of their mediators (heparin) decreased M3 tumor incidence and tumor cell proliferation in vitro, while MC from peritoneal cavity of tumor-bearing mice (TMC) had no effect. The purpose of this study was to evaluate the differences in morphology and content of sulfated glycosaminoglycans between NMC and TMC. Both were stained with Mayer's haematoxylin-Rubipy [tris (2,2'-bipyridine) ruthenium (II)] sequence, a specific technique to detect sulfated polysaccharides. Image processing and analysis (IPA) confirmed densitometric and microfluorometric studies and revealed several structural characteristics of MC. TMC were partially degranulated with smaller surface and greater perimeter than NMC. Shape factor, which reflects the sphericity grade of the cell (1 = spherical), was three-fold increased in TMC in relation to NMC (6.15 vs 1.76, respectively). Also, TMC had less than a half sulfated polysaccharides compared to NMC. We conclude that subcutaneous tumor grafts mediate degranulation of MC from peritoneal cavity with the consequent release of MC mediators such as heparin. This may be one of the factors for the absence of antitumoral effect of TMC. PMID- 21528327 TI - Effects of dietary supplementation of N-acetylcysteine on cigarette smoke-related DNA adducts in rat tissues. AB - Cigarette smoking plays a major role in the etiology of several human cancers. It is believed that formation of DNA adducts is an initial step in the carcinogenic process. In this study, we have examined the ability of dietary N-acetylcysteine (NAG) to inhibit the formation of cigarette smoke-related DNA adducts in various tissues of rats. Female Sprague-Dawley rats were exposed to cigarette smoke (10 mg TPM/m(3)) in a whole-body exposure chamber for 6 h per day, seven days a week for four weeks. The smoke-exposed groups were provided either an unrefined diet or diets supplemented with low (5,000 ppm) or high (20,000 ppm) dose of NAG. A sham group was given control diet and maintained on filtered ambient air. Tissue DNA analysis of smoke-exposed rats by nuclease P1-version of the P-32 postlabeling assay showed up to 6 adducts in the following descending order expressed as total adducts/10(10) nucleotides: 1 predominant (no. 5) and 4 (no. 1 no. 4) minor adducts in the (219 +/- 36), 6 minor adducts in the heart (93 +/- 11), 5 adducts in the trachea (50 +/- 16), and 4 adducts in the bladder (50 +/- 3.5); sham-treated animals showed 2 or 3 adducts in each tissue but at 4-20-fold lower levels. Dietary intervention with either high or low dose of NAC did not affect the levels of most adducts, except for the following: a 30-40% increase (P<0.05) for adducts 3 and 4 in the lung; a 40-50% decrease (P<0.05) for adduct 2 in the trachea; and a 30% increase (P<0.05) for adduct 2 in the bladder. In a second experiment conducted under identical conditions, most major and minor adducts remained unaffected with NAC intervention, except for adduct 2 in the trachea which was somewhat diminished. These results suggest that dietary NAC intervention does not significantly influence the levels of most major and minor adducts. However, some minor adducts in the lung, trachea and bladder were modulated differentially. PMID- 21528328 TI - Irinotecan and radiation in vitro and in vivo. AB - Topoisomerase I inhibitors have shown positive effects in combination with radiation therapy in some studies. Normally oxygenated and hypoxic human MCF-7 breast carcinoma-cells were exposed to irinotecan (100 mu M or 250 mu M) or to SN 38 (10 mu M or 25 mu M) for 1 h prior to, during and for 3 h after radiation. Irinotecan and SN-38 showed little or no radiation sensitization of normally oxygenated MCF-7 cells but were effective radiation sensitizers of hypoxic cells. Both irinotecan and SN-38 diminished or eliminated the shoulder of the radiation survival curves of both the normally oxygenated and hypoxic cells indicating inhibition of the repair of sublethal radiation damage to DNA. Irinotecan (20 mg/kg or 30 mg/kg) was administered to mice bearing the EMT-6 mammary carcinoma on days 7 through 11 just prior to fractionated radiation (5x3 Gray). The tumor growth delays obtained with the combination regimens were greater than expected for simple additivity of the two treatments. Treatment with irinotecan resulted in decreased expression of topoisomerase I mRNA and increased expression of topoisomerase II mRNA in EMT-6 tumor tissue. Irinotecan treatment did not alter the protein levels for topoisomerase I or II in the tumor tissue; however, the combination of radiation therapy and irinotecan administration resulted in decreased topisomerase I and increased topoisomerase II protein in the tumor tissue. These results suggest that with appropriate scheduling of a topoisomerase I inhibitor and a topoisomerase II inhibitor with fractionated radiation therapy maximal cyto-reduction can be achieved. PMID- 21528329 TI - Intracellular acidification is associated with, but not required for caspase activation, DNA fragmentation or apoptosis. AB - Apoptosis is characterized by DNA digestion mediated by either a Ca2+/Mg2+ dependent endonuclease or the acid-activated deoxyribonuclease II (DNase II). However, DNA digestion frequently does not correlate with changes in Ca2+ whereas intracellular acidification is a consistent marker of apoptosis. To confirm the role of low pH in regulating DNA digestion, ML-I cells were damaged with etoposide then incubated at various extracellular pH (pH,). When pH, was 8.1, DNA digestion still occurred, and intracellular pH still decreased but only to 7.2, a pH at which DNase LT is inactive. In contrast, low pH, inhibited the DNA digestion and apoptosis induced by etoposide. An upstream event in apoptosis is the activation of proteases known as caspases. The activity of caspases was inhibited at low pH, demonstrating that the pH-sensitive step is upstream of caspase action. Similar results have been obtained in other models of apoptosis. Hence, both DNase II and Ca2+/Mg2+-dependent endonuclease appear unlikely to cause DNA digestion in apoptosis, unless their ion dependence is modified by, for example, proteolytic cleavage. PMID- 21528330 TI - Inhibition of migration of MDA-MB-231 cells by methyl-3,5-diiodo-4-(4' methoxyphenoxy)benzoate (DIME). AB - The GTPase activity of purified dimeric tubulin (alpha+beta) at 5 mu M was insensitive to methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME), in contrast to nocodazole which activated GTPase. Cellular motility of MDA-MB-231 (human mammary cancer) cells migrating through 12-mu m pores was inhibited by DIME similar to nocodazole in a drug concentration-and DIME structure-dependent manner. An increase of cytoplasmic ATPase activity of DIME-treated cells without a decrease in ATP contents of intact cells suggests that DIME may also influence additional as yet unidentified ATP-dependent system(s) probably also involved in cell motility. These results show that DIME not only arrests cells in M phase but also inhibits cell motility in interphase. However the cellular mode of action of DIME is different from the action of other toxic tubulin-targeted drugs, despite the fact that DIME in a concentration-dependent manner disrupts microtubule structures in intact cells. PMID- 21528331 TI - Coordinate up-regulation of cyclin-dependent kinase 4 and its inhibitor p16(INK4) in human glioma cells following chloroethylnitrosourea-induced DNA damage. AB - Anomalies in the genes of the cell cycle regulators, p16(INK4) and CDK4 are highly frequent in human gliomas and other cancers, however, the extent to which these defects are involved in regulating the response of tumor cells to DNA damaging agents is not clear. In this study, using three human malignant glioma cell lines, MGR1, MGR3, and U87MG, we examined changes in gene expression of p16 and/or of its specific target CDK4 following damage of the cellular genome by the chemotherapeutic bifunctional alkylating agent, 1,3-bis (2-chloroethyl)-1 nitrosourea (BCNU). Exposure of the cells to 50 mu M BCNU for 24 h induced a significant level of DNA interstrand cross-links in all cell lines. In MCR1 cells (p16(+), Rb+), over the 24 h period, a steady increase in p16 (mRNA and protein) and CDK4 (protein) was observed. The increase in CDK4 and p16 proteins occurred in parallel, and that the two proteins accumulated in complex with each other, resulting in marked inhibition of CDK4 kinase activity. In MGR3 and U87MG cells, both of which lack functional p16 protein (p16(-), Rb+), BCNU, however increased the CDK4 protein levels. In all three cell lines, despite the differences in p16 gene status, BCNU exposure caused significant blockade of the cells at G(2)/M phase of the cell cycle. The coordinated enhancement of the target (CDK4) and the inhibitor (p16) in cellular response to genomic injury may reflect an attempt of the cells to continue progression through the cell cycle (via CDK4), while triggering the cell cycle arrest (via p16), required for the orderly repair of the damage to the genome. PMID- 21528332 TI - Inhibition of liver metastasis formation by anti-CD44 variant exon 9 monoclonal antibody. AB - The overexpression of variants of the glycoprotein CD44 is thought to be associated with the tumorigenesis and progression of human cancers. We examined the role of the variant CD44v8-10 in the metastasis of the human colon cancer cell line HT29 using a monoclonal antibody (mAb 44-1V) reactive with the v9 product. After immunization with mAb 44-1V, the growth of HT29m cells in vitro was not retarded. Six-to 8-week-old mice were divided into 4 groups for liver metastasis assay. All animals in control groups injected with intrasplenic HT29m developed metastases. In contrast, only one of the animals injected with HT29m that reacted with mAb 44-1V developed a metastatic tumor in the liver. The intravenous administration of mAb 44-1V after intrasplenic HT29m injection did not inhibit the formation of liver metastasis. In addition, the adhesiveness of the HT29m cells to the basement membrane matrix was decreased by treatment with the anti-CD44v9 mAb. These findings indicated that a CD44 variant containing the products of variants of exons v8-10 may play an important role in adhesion of tumor cells to the capillaries of distant organs in the metastatic process. PMID- 21528333 TI - In vitro characterization of an end-end coupled mEGF-dextran conjugate using a cultured human glioma cell line. AB - The cellular binding properties of a new conjugate, I-125-mEGF-dextran, in which the amino terminus on mEGF was covalently coupled by reductive amination to the reducing end of dextran D14 were analysed. The coupling molar ratio was 1:1 since dextran only contains one aldehyde group and mEGF only has one free amino group available; the amino terminus. The conjugates were I-125-labelled and tested for their receptor binding properties using cultured human glioma, U-343MGaC12:6, cells. The conjugate reached maximal binding around 1.5 or 2 h when incubated at 37 degrees C or 4 degrees C, respectively. The binding was receptor specific since it could be displaced by free mEGF. Dissociation constants were determined at 4 degrees C by using mEGF to displace I-125-mEGF and non-radioactive mEGF dextran to displace I-125-mEGF-dextran and were 6.6 x 10(-10) and 7.1 x 10(-9) M respectively. Cellular internalisation was studied at 37 degrees C for both I-125 mEGF-dextran and I-125-mEGF and most of the radioactivity was internalized in both cases. However, there was a difference regarding the retention time pattern. It took less than 1 h for the internalised radioactivity delivered with mEGF to decrease to 50% of the initial level while it took about 2.5 h for the conjugate. The studies on this new form of EGF-containing conjugate serve as a model for the design of future dextran containing conjugates employing, for example, antibody fragments or small ligands with tumour specificity. PMID- 21528335 TI - Long-term results of thermoradiotherapy for superficial, subsurface tumors using a 430 MHz microwave heating system. AB - Superficial, subsurface tumors of 93 patients were treated with thermoradiotherapy using a 430 MHz microwave heating system (HTS-100). All patients had malignant tumors, and all were treated with a combination of hyperthermia and radiation. Satisfactory temperature data for each thermal parameter were achieved within a 5 cm depth for each tumor. The overall complete response (CR) rate was 39.8%; in the less than or equal to 3 cm (depth of tumor), the CR rate was 66.7%, in the 3-5 cm group, the CR rate was 42.9%. In the multivariate analysis, duration of local control correlated with tumor responses (CR). There were no instances of prominent late complications that were observed for greater than or equal to 6 months. This study suggests that the HTS-100 may improve tumor response and the duration of local control of superficial and subsurface tumors. PMID- 21528334 TI - Involvement of bcl-2 and bax gene expression in apoptosis and differentiation of the non-tumorigenic murine hematopoietic cell line, 32DC13(G). AB - 32DCl3(G) is an interleukin-3 (IL-3) dependent, non-tumorigenic murine hematopoietic cell line which undergoes terminal differentiation into granulocytes when exposed to granulocyte-colony stimulating factor (G-CSF). This line therefore offers a convenient system to study the expression of genes involved in apoptosis and differentiation. In our experiments we have acquired evidence that during the differentiation pathway, likewise in apoptosis induced by IL-3 deprivation, detectable levels of bax mRNA appear, while bcl-2 expression decreases. These events are under the control of the p53 tumor-suppressor gene. In these cells, an overexpression of exogenous wild-type p53 leads to a decrease in bcl-2 mRNA and to the appearance of box mRNA, which instead is absent in the parental cells growing in IL-3 conditioned medium. Furthermore, results from experiments on p53 transfected cells demonstrate that excess wild-type p53 activity, on its own, fails to elicit apoptosis as long as IL-3 is present and does not induce differentiation if G-CSF is not added to the culture medium. We conclude that in apoptosis and differentiation of 32DCl3(G) the alterate ratio of bcl-2 and box gene expression, modulated by p53, is an early event dependent on IL-3 withdrawal and that the appearance of bax and the decrease of bcl-2 expression are necessary, but not sufficient for the acquisition of a completely mature granulocytic phenotype. PMID- 21528336 TI - Mutational state of tumor suppressor genes (DCC, DPC4) and alteration on chromosome 18q21 in human oral cancer. AB - In order to investigate the roles of two candidate tumor suppressor genes, DCC (deleted in colorectal carcinoma) and DPC4 (deleted in pancreatic carcinoma 4) genes in oral squamous cell carcinoma (SCC), we examined 32 primary SCCs by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Additionally, 32 pairs of normal and tumor DNA from 32 patients with oral SCCs were also analyzed for loss of heterozygosity (LOH) using 10 microsatellite markers on chromosome 18q21 where DCC and DPC4 genes are localized. We detected point mutations of DPC4 gene in two cases by PCR-SSCP analysis and sequencing. One case showed an AGC (Ser) to ACC (Thr) missense mutation at codon 1061 and the other the substitution C for A of the intron between exons 7 and 8. No mutation of DCC gene was observed in our cases. LOH at 18q21 was observed in 14 of the 32 cases (43.8%). The highest frequency (33.3%) of LOH was found at D18S46, and this was significantly correlated with the pathological results. These findings suggest that DCC and DPC4 gene may play minor roles in the genesis of oral SCC, and that another tumor suppressor gene involved in the development of oral SCC may exist in the region of D18S46 of this chromosome. PMID- 21528337 TI - Genetic alterations in thyroid carcinomas and adenomas detected by restriction landmark genomic scanning. AB - Alterations of genomic DNAs in 9 papillary thyroid carcinomas and 3 follicular thyroid adenomas were examined by restriction landmark genomic scanning, a 2 dimensional gel analysis that allows detection of deletions, amplifications and other rearrangements of genomic DNA. DNAs from both thyroid tumors and associated non-tumorous glandular tissues were cleaved with the restriction enzyme NotI end labeled with P-32 and size-fractionated by 2-dimensional electrophoresis using HinfI in a second digestion. The altered spots in carcinomas and adenomas were compared with those in nontumorous samples. Five and 4 spots were commonly amplified in carcinomas and adenomas, respectively. One amplified spot was apparently specific only for carcinoma and was not detected in any of adenomas examined. In contrast, 12 spots reduced in intensity were frequently observed in tumors, although a subset of 5 were more sporadically affected in adenomas. The results indicate both common and distinct genetic abnormalities occurring in thyroid tumors, which may relate to the different biological behaviors of malignant and benign neoplasms. PMID- 21528338 TI - Human papillomavirus type 16 E5 protein (review). AB - The association of certain human papillomavirus (HPV) types with malignancies of the anogenital tract is well established. The virus type most frequently associated with cellular transformation is HPV 16, as has been shown in epidemiological studies. Its transforming capacity has also been demonstrated in many in vitro cell transformation experiments. The most potent oncogenes of HPV 16 are the E6 and E7 proteins, but the E5 protein, whose homologue is the main oncogene of bovine papillomavirus, has recently been identified as an oncogene also for HPV. On the basis of epidemiological and clinical data from tumor material as well as from in vitro data it has been suggested, that the HPV 16 E5 protein would have a function at the early stages of cervical carcinogenesis. The E5 protein enhances growth factor-mediated signal transduction to the nucleus and consequently augments cellular proliferation. Expression of the E5 protein enables the infected cell to escape growth control provided by surrounding cells by inhibiting gap junctional intercellular communication in epithelial cells. This viral oncogene seems to interfere with the control mechanisms of cellular growth and proliferation and thus facilitate the function of the E6 and E7 proteins and further steps towards epithelial cell transformation. PMID- 21528339 TI - Biological and clinical significance of hepatocyte growth factor in breast cancer. AB - Hepatocyte growth factor (HGF) is a mesenchyme- or stroma-derived multipotent factor that regulates the growth, motility, and morphogenesis of various types of cells, including cancer cells. We investigated the effect of HGF on human breast cancer cells, and measured the concentration of HGF in the sera of breast cancer patients. When BT-20 cells were stimulated with HGF, the transmigration of cancer cells was markedly accelerated. In a checkboard assay, pronounced chemotaxic locomotion of BT-20 cells is expressed, corresponding to HGF concentrations. HGF treatment of BT-20 cells resulted in enhanced expression of alpha 2, alpha 3 and beta 1 integrin subunits, and augmented the binding activity to immobilized collagen. The c-met protein was expressed on the cancer cells in 48 of the 97 (49.5%) breast cancer primary tumors. In the serum, the advanced and recurrent cancer group showed a high level of this protein in comparison with the other patient groups. The mean value of serum HGF was 0.65 ng/ml in patients with distant metastases and 0.27 ng/ml in those with no such evidence. Thus, the HGF concentration becomes significantly elevated in the sera of patients with distant metastases. These findings suggest that HGF is involved in invasion and metastasis of breast cancer, and that serum HGF is useful as a tumor marker with a close correlation to the metastatic state of breast cancer. PMID- 21528340 TI - Bioflavonoids, type II [H-3]estradiol binding sites and prostatic cancer cell proliferation. AB - Previous studies from this laboratory have shown that bioflavonoids including luteolin and quercetin possess antiestrogenic activity in the female reproductive tract and appear to elicit this activity by interaction with type II [H 3]estradiol binding sites in the cell nucleus. Studies by a number of laboratories including our own have shown that type II sites are present in the rodent prostate gland and therefore, we suspected that administration of bioflavonoids such as luteolin may antagonize prostate growth through type LT site binding interactions as well. The studies presented in this report demonstrate that the mouse prostatic tissue does contain nuclear type II sites and that oral administration of luteolin for 14 days results in a significant (p<0.01) reduction in prostatic weight in intact male mice without significant effects on the seminal vesicular, testis or body weights of these animals. These results suggest that luteolin is a prostate specific antagonist under these experimental conditions. In vitro studies with LNCaP and PC-3 human prostate cancer cell lines demonstrated that luteolin treatment resulted in a dose dependent inhibition of prostate cancer cell proliferation which was maximum 4-8 days following treatment. Whole cell binding studies demonstrated that both LNCaP and PC-3 cells contained very high concentrations of type II [H-3]estradiol binding sites (>200,000 sites/cell) relative to levels previously reported for other tissues and cells and luteolin was capable of interacting with these sites in prostate cancer cells. In fact, there was a direct correlation between the type II site occupancy by luteolin and the inhibition of LNCaP or PC-3 prostatic cancer cell proliferation by this bioflavonoid. Flow cytometric analysis revealed that luteolin treatment caused an accumulation of LNCaP cells in G(2)/M (p<0.01) and reduced the fractions of LNCaP cells in S-phase undergoing apoptosis (p<0.01). Similarly, luteolin treatment also arrested PC-3 cells in G(2)/M (p<0.01) and reduced the proportion of cells in G(0)/G(1) (p<0.05). This being the case, it is not surprising that this bioflavonoid also blocked the growth of subcutaneous PC-3 cell xenografts in athymic nude mice. These data demonstrate that naturally occurring type TI site antagonists such as luteolin are capable of inhibiting normal and malignant prostatic cell growth and proliferation in vitro and in viva and may possess prophylactic as well as therapeutic activities against prostatic proliferative diseases including benign prostatic hyperplasia (BPH) and prostate cancer. PMID- 21528341 TI - Differential regulation of matrix metalloproteinases in human cancer cells by exogenous factors. AB - Matrix degradation by cancer cells is an important attribute of malignant behaviour. We have postulated that during invasion and metastasis, matrix metalloproteinase (MMP) production by cancer cells is modulated by microenvironmental factors. To determine this, we screened human cancer cell lines of diverse histogenesis for their secreted MMP profile following exposure to a diversity of soluble and insoluble agents. Enzymatic changes were observed in the presence of phorbol ester (TPA) and hydrogen peroxide (H2O2). More specifically, we observed: (a) increased secretion and/or activation of gelatinases A (MMP-2) and B (MMP-9) after exposure of 8 cell lines to 10(-6) M TPA; (b) increased activation of interstitial collagenase (MMP-1) caseinolysis after stimulation of 3 cancer cell lines with 10(-7) M TPA; and (c) increased activation of MMP-2 after exposure of 2 cell lines to 0.5 mM H3O2. In functional assays, exposure of lung Calu-6 carcinoma cells to 0.5 mM H2O2 and PC-3 cells to TPA, increased their ability to degrade radiolabelled endothelial cell-derived and osteoblast-like-derived basement membranes, respectively. RNA hybridization studies confirmed and further documented these observations. We conclude that modulation of MMP activity in human cancer cells is a common phenomenon regardless of lineage. Modulatory mechanisms such as increased de novo pro-enzyme synthesis and/or release, and enhanced proenzyme activation may be involved. Furthermore, our results provide evidence that extracellular matrix degradation by human cancer cells during invasion and metastasis may be stimulated by soluble matrix-derived factors in a cell type-specific fashion. PMID- 21528342 TI - Expression of E-cadherin/catenin complexes in breast cancer. AB - Expression of E-cadherin, alpha-, beta- and gamma-catenins were studied in 100 patients with primary breast cancer compiled of 57 invasive ductal carcinomas (IDC) and 43 invasive lobular carcinomas (ILC) by means of immunohistochemistry. Loss of E-cadherin was observed in 26 (45.6%), and alpha-, beta- and gamma catenin expression was lacking in 22 (38.6%), 27 (47.4%) and 22 (38.6%) IDCs, respectively. The expression in ILCs was significantly lower, as compared to IDCs (p<0.001). Immunostaining of both E-cadherin and catenins was completely lacking in 27 (47.4%) IDCs and 30 (93.8%) ILCs. Go-expression of E-cadherin/beta-catenin or E-cadherin/gamma-catenin was preserved more frequently than that of E cadherin/alpha-catenin complexes. E-cadherin/catenin complex expression showed significant positive correlation with histological differentiation (p=0.037), ER (p=0.017) and PR expression (p=0.052), and negative correlation with c-erbB-2 receptor overexpression (p=0.046). Patients with tumours showing adhesion complexes containing alpha-catenin had an increased overall survival rate compared to other patients. Expression of either E-cadherin or alpha-catenin only, without the formation of entire adhesion complexes, was not correlated with overall survival. Thus, determination of both E-cadherin and catenins is suggested to add further information to estimate the prognosis of breast cancer patients. PMID- 21528343 TI - Rel/NF-kappa B transcription factors and cancer. AB - The transcription factors of the Rel/NF-kappa B family play a central role in immune regulation. In addition, they may be involved in the pathogenesis of certain tumors, especially those of hematopoietic origin. In this review evidence is summarized indicating an association between dysregulated NF-kappa B-dependent gene expression and tumorigenesis. Furthermore, possible molecular mechanisms through which NF-kappa B might exert these effects, such as disturbance of cell cycle control or apoptosis, are outlined. Potential therapeutic approaches based on these findings are also described. Rel/NF-kappa B factors are presented here as an important example of the growing number of transcription factors possibly involved in oncogenesis. PMID- 21528344 TI - Levels of p21(WAF1/CIP1) do not affect radiation-induced cell death in human breast epithelial cells. AB - Loss of the wild-type p53 activity and/or overexpression of the proto-oncogene bcl-2 are frequently detected in breast cancer and suggested to be related to chemotherapy and radiation therapy resistance. To identify the downstream signaling molecules for anti-proliferative and apoptotic activities of p53 and to investigate the interaction of bcl-2 with p53 in human breast epithelial cells, we have used the MCF10A cell line. We previously showed that overexpression of bcl-2 downregulates expression of p21(WAF1/CIP1) (a cyclin dependent kinase inhibitor which mediates p53 dependent G(1) arrest) and suppresses DNA damage induced apoptosis in MCF10A cells. In the present study, we constitutively overexpressed p21(WAF1/CIP1) in bcl-2 overexpressing MCF10A cells to determine whether downregulation of p21(WAF1/CIP1) is necessary for the anti apoptotic activity of bcl-2, and to investigate the roles of p21(WAF1/CIP1) in p53-mediated cell death upon irradiation. Overexpression of p21(WAF1/CIP1) resulted in growth inhibition, but had no effect on bcl-2 inhibition of apoptosis following irradiation. Also, overexpression of p21(WAF1/CIP1) did not affect the dose dependent radiation-induced cell lethality as determined by a clonogenic survival assay. These results suggest that bcl-2 downregulation of p21(WAF1/CIP1) is independent of the anti-apoptotic activity of bcl-2, and that p21(WAF/CIP1) is not involved in the p53-mediated cell death pathway. PMID- 21528345 TI - Effect of continuous intravenous administration of high-dose G-CSF on hematologic recovery following autologous purged bone marrow transplantation. AB - Delay in peripheral blood recovery is a common complication of autologous purged bone marrow transplantation. To overcome this problem, we examined the effect of continuous intravenous administration of high-dose G-CSF on hematologic recovery following autologous bone marrow transplantation (auto-BMT) with purged bone marrow. Continuous intravenous administration of high dose G-CSF significantly facilitated the recovery of platelet counts and reticulocyte counts compared to one-hour bolus intravenous injection of the usual-dose G-CSF, although both ways of administration facilitated the recovery of leukocyte counts. The results showed continuous intravenous administration of high-dose G-CSF was useful to facilitate the recovery of not only leukocytes but also reticulocytes and platelets following auto-BMT with purged bone marrow in certain situations. Continuous i.v. administration of high-dose G-CSF may be one of the safest and most useful modes facilitating the hematopoietic recovery following auto-BMT with purged bone marrow. PMID- 21528346 TI - Kaposi's sarcoma before and during the HIV epidemic in Tanzania. AB - The Tanzania cancer registry recorded 39,920 cancer cases from 1968 to 1995. Kaposi's sarcoma (KS) constituted 4% of the cases of which 79.9% were males. During the AIDS period changes in the demographics of KS were noted showing an increase in the diagnosis of KS (p=0.0001). There was an overall decrease in the mean age from 41.7 years before to 37.3 years during the AIDS epidemic (p=0.002). In males this decreased from 42.7 to 38.8 years (p=0.01) but was not statistically significant in females (p=0.06). In both periods the cases were observed in the sexually active age groups. The narrowing of the male/female ratio during the AIDS period (p=0.0004), and an increase in extra-limb lesions from 19.7% before to 48.7% during the AIDS epidemic indicates the emergence of an aggressive form of KS in Tanzania, suggesting a co-factor role of HIV in KS pathogenesis. PMID- 21528347 TI - Tetraploid arrest with overexpressed non-mutated p53 in germ cell cancers. AB - Immunocytochemical study of 40 germ cell cancers, 31 bladder cancers and 27 squamous head and neck cancers using monoclonal antibodies (Mab) specific for p53, Bcl-2 and HSP70 was carried out. The results showed that 89% of germ cell cancer compared to 7% of bladder and 2% of squamous head and neck cancers were positive for p53 using Mab 240. In contrast only 60% of germ cell cancers (20% strong) but 100% of bladder (80% strong) and head and neck (75% strong) were positive for Bcl-2. There was a higher p53 positivity for the more chemoradiosensitive seminoma (82%, n=17) compared to non-seminoma (33%, n=6) and the inverse for Bcl-2 (53% vs. 83%). Taken together with emerging data that the putative stem cell for all germ cell cancers, the tetraploid pachytene primary spermatocyte normally expresses p53, these results support the view that near tetraploid overexpression of functional p53 in germ cell cancer may be a factor in why germ cell cancers are more chemosensitive than the common adult cancers. They also highlight the need for better understanding of the cell cycle check points during meiosis as possible molecular targets that would increase the chemosensitivity of non-germ cell cancers. PMID- 21528348 TI - The effect of thrombospondin on hepatocellular carcinoma cell proliferation. AB - We report the effects of thrombospondin (TSP) on the proliferation of four different human hepatocellular carcinoma (HCC) cell lines (HuH-7, KIM-I, KYN-2, and KYN-3) and report the proliferative activity of HuH-7 cell using microspectrophotometry. The addition of anti-TSP neutralizing antibody (150, 1500, or 15000 ng/ml) to cultured medium showed marked suppression of cell proliferation in all cell lines. On the other hand, the addition of exogenous TSP (20 or 40 mu g/ml) to culture medium stimulated cell proliferation, in KYN-2 and KYN-3 but not in HuH-7 or KTM-1. Furthermore, in DNA measurements on HuH-7 cells, the effect of the anti-TSP neutralizing antibody induced growth arrest in the G(0)/G(1) phase of the cell cycle and decreased DNA synthesis. In conclusion, TSP promoted the proliferation of HCC cells, and based on our results it is predicted that TSP might act through an autocrine or paracrine growth-supportive mechanism in the extracellular matrix. PMID- 21528349 TI - In vitro schedule-dependent interaction between paclitaxel and vinorelbine in A2780 parental and multidrug-resistant human ovarian cancer cell lines. AB - Paclitaxel, a taxane, and vinorelbine, a semisynthetic vinca alkaloid drug, have tubulin as their common intracellular target but inhibit growth by acting with opposed mechanisms of action and binding to different sites. The purpose of this study was to evaluate in vitro the cytotoxicity of these two drugs as single agents, in combination and in sequence, against a human carcinoma ovarian cell line A2780S and its doxorubicin-resistant subline A2780R. The cell growth inhibitions were determined by the MTT assay. The cytotoxic effect of drug combinations at the IC50 level were analysed by the isobologram method of Steel and Peckham. On simultaneous exposure to paclitaxel and vinorelbine, synergistic effects were observed in A2780S and A2780R cell lines. On sequential exposure to paclitaxel first followed by vinorelbine or vice versa, a strong antagonistic interaction was observed. These data demonstrate that the interactions of vinorelbine and paclitaxel are highly schedule-dependent. These findings could have implications for the design of further clinical protocols and suggest that the simultaneous administration of the two agents may be the most suitable sequence while sequential administration may be avoided. Further preclinical and clinical studies are required to elucidate the relationship between vinorelbine and paclitaxel with regard to both anti-tumor activity and toxicity. PMID- 21528350 TI - Cancer prevention through sensible nutrition (commentary). AB - Because of the constant inflow of information and educational efforts by many organizations, public attention is increasingly focused in finding information about strategies for prevention of cancer. Because of the research efforts of the last twenty years it is now increasingly appreciated that changes in dietary habits may result in cancer incidence. In addition, the usefulness of dietary substances in affording prevention against the occurrence of cancer is increasingly recognized as one practical. approach in this direction. The general public through media efforts and through educational efforts by many organizations is becoming aware of the fact that certain dietary substances can increase the risk for cancer development whereas certain others can lower it. This awareness, most likely, will have practical implications in reducing cancer risk because unlike the carcinogenic environmental factors that are difficult to control, individuals can make decisions to modify their choice for the food and beverage they consume. This commentary deals with issues related to cancer prevention through sensible nutrition. PMID- 21528352 TI - Silencing suppressors: viral weapons for countering host cell defenses. AB - RNA silencing is a conserved eukaryotic pathway involved in the suppression of gene expression via sequence-specific interactions that are mediated by 21-23 nt RNA molecules. During infection, RNAi can act as an innate immune system to defend against viruses. As a counter-defensive strategy, silencing suppressors are encoded by viruses to inhibit various stages of the silencing process. These suppressors are diverse in sequence and structure and act via different mechanisms. In this review, we discuss whether RNAi is a defensive strategy in mammalian host cells and whether silencing suppressors can be encoded by mammalian viruses. We also review the modes of action proposed for some silencing suppressors. PMID- 21528353 TI - Genetic variants of 6q25 and breast cancer susceptibility: a two-stage fine mapping study in a Chinese population. AB - A recent genome-wide association study identified a novel single nucleotide polymorphism (SNP), rs2046210, in the 6q25 region as a breast cancer susceptibility locus in Chinese and subsequently replicated in a multicenter study. Further fine-mapping of this region may help identify the potential causative SNPs of breast cancer. We employed a block-based fine mapping analysis to investigate the tagging SNPs in a 41 kb block with the marker-SNP rs2046210 in the 6q25 region, and also extended our study by including two potentially functional SNPs (rs2234693 and rs1801132) within the ESR1 gene by a two-stage case-control study with 1,792 breast cancer cases and 1,867 controls (878 cases and 900 controls in the testing set and 914 cases and 967 controls in the validation set). Significant associations with breast cancer risk were observed for rs1038304, rs6929137, rs2046210, and rs10484919 in the 41 kb block of the 6q25 region in the testing set after controlling multiple testing. Together with the validation set samples, these four SNPs were all significantly associated with increased risk of breast cancer (additive OR from 1.25 to 1.34, additive P from 4.84 * 10(-6) to 7.17 * 10(-9)). After conditional regression and linkage disequilibrium analyses, rs6929137 and rs10484919 tend to be susceptible markers of breast cancer in this region and both of them were located at sites of histone modification according to the UCSC (http://genome.ucsc.edu/) genome database. Our results support that the 6q25 region is an important susceptibility region for breast cancer in Chinese women, and rs6929137 and rs10484919 are causative or marker SNPs for this region. PMID- 21528351 TI - Calcium regulation of nucleocytoplasmic transport. AB - Bidirectional trafficking of macromolecules between the cytoplasm and the nucleus is mediated by the nuclear pore complexes (NPCs) embedded in the nuclear envelope (NE) of eukaryotic cell. The NPC functions as the sole pathway to allow for the passive diffusion of small molecules and the facilitated translocation of larger molecules. Evidence shows that these two transport modes and the conformation of NPC can be regulated by calcium stored in the lumen of nuclear envelope and endoplasmic reticulum. However, the mechanism of calcium regulation remains poorly understood. In this review, we integrate data on the observations of calciumregulated structure and function of the NPC over the past years. Furthermore, we highlight challenges in the measurements of dynamic conformational changes and transient transport kinetics in the NPC. Finally, an innovative imaging approach, single-molecule superresolution fluorescence microscopy, is introduced and expected to provide more insights into the mechanism of calcium-regulated nucleocytoplasmic transport. PMID- 21528354 TI - Microcephaly in ancient Greece-the "Minoan" microcephalus of Zakros. PMID- 21528355 TI - Computed tomography recovers data from historical amber: an example from huntsman spiders. AB - Computed tomography (CT) methods were applied to a problematic fossil spider (Arachnida: Araneae) from the historical Berendt collection of Eocene (ca. 44-49 Ma) Baltic amber. The original specimens of Ocypete crassipes Koch and Berendt 1854 are in dark, oxidised amber and the published descriptions lack detail. Despite this, they were subsequently assigned to the living Pantropical genus Heteropoda Latreille, 1804 and are ostensibly the oldest records of huntsman spiders (Sparassidae) in general. Given their normally large size, and presumptive ability to free themselves more easily from resin, it would be surprising to find a sparassid in amber and traditional (optical) methods of study would likely have left O. crassipes as an equivocal record--probably a nomen dubium. However, phase contrast enhanced X-ray CT revealed exquisite morphological detail and thus 'saved' this historical name by revealing characters which confirm that it's a bona fide member both of Sparassidae and the subfamily Eusparassinae. We demonstrate here that CT studies facilitate taxonomic equivalence even between recent spiders and unpromising fossils described in older monographs. In our case, fine structural details such as eye arrangement, cheliceral dentition, and leg characters like a trilobate membrane, spination and claws, allow a precise referral of this fossil to an extant genus as Eusparassus crassipes (Koch and Berendt 1854) comb. nov. PMID- 21528356 TI - Preparation of decellularized and crosslinked artery patch for vascular tissue engineering application. AB - There is an urgent clinical need of tissue-engineering (TE) vascular grafts, so this study was for developing a fast and simple way of producing TE vascular scaffold. The TE vascular scaffold was prepared with pepsin, DNase and RNase enzymatic decellularization and crosslinked with 0.1, 1, 5% glutaraldehyde (GA), respectively. The samples were underwent analyses of burst pressure; suture strength; cytotoxicity; enzymatic degradation in vitro; degradation in vivo; rehydration; biocompatibilities detected with hematoxylin and eosin (H&E), scan electron microscope, immunohistochemistry both in vivo and in vitro; macrophage infiltration and calcification using Von Kossa staining. After being decellularized the scaffold had a complete removal of cellular components, an intact collagen structure. The burst pressure and suture strength were similar to native artery. 0.1% GA crosslinked scaffold showed less cytotoxicity than 1 and 5% GA groups (P < 0.05) and was resistance to enzymatic degradation in vitro. Once being implanted, 0.1% GA group was resistant to degradation and formed endothelium, smooth muscle and adventitia with few macrophages infiltration. However, there appeared calcification in implants compared with that in native artery. This study demonstrated that DVPs producing methods by enzymatic decellularizing and crosslinking with 0.1% GA could be used for clinical TE vascular graft manufacture. PMID- 21528357 TI - Inhibition of inflammatory mediators and related signaling pathways by macrophage stimulating protein in rheumatoid arthritis synovial fibroblasts. AB - OBJECTIVE: To evaluate the mechanism of macrophage-stimulating protein (MSP) mediated inhibition of inflammatory cytokine and chemokine production in rheumatoid arthritis synovial fibroblasts (RASF). MATERIALS AND METHODS: RASF were treated with different concentrations (0, 0.5, 1, 5 and 10 ng/ml) of MSP with or without 1 MUg/mL lipopolysaccharide (LPS). The protein expressions of IL 1beta, TNF-alpha, IL-18, MIP-1, MCP-1, RANTES and PGE(2) were analyzed by enzyme linked immunosorbent assays (ELISA). The total nitric oxide (NO) concentration was determined using the Griess reaction. The protein expressions of iNOS, COX-2, NF-kappaB(p-p65), IKB-alpha, IKB-beta, p-P38, p-Erk1/2 (P-P42/44) and p-AKT were detected by Western blotting. RESULTS: MSP markedly inhibited expression of inflammatory cytokines (IL-1beta, TNF-alpha and IL-18), chemokines (MIP-1, MCP-1 and RANTES) and iNOS, NO, COX-2 and PGE(2) in RASF stimulated by LPS. MSP treatment decreased expressions of p-IkappaBalpha, p-IKBbeta and p-P65 in RASF in a concentration-dependent manner. Expressions of p-AKT, p-p38 and p-Erk1/2 were also inhibited markedly in RASF stimulated by LPS after treatment with MSP in a concentration-dependent manner. CONCLUSION: MSP could inhibit the inflammatory cycle by suppressing inflammatory mediators and activation of NF-kappaB as well. The inhibitory effect of MSP on LPS-stimulated RASF may act through suppression of multiple signals such as the PI3K/AKT and/or MAPK pathways. PMID- 21528358 TI - Folic acid inhibits lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages by suppressing MAPKs and NF-kappaB activation. AB - OBJECTIVE: The aim of the present study was to investigate the effects of folic acid on the inflammatory responses to lipopolysaccharide (LPS) in RAW264.7 cells and the signal transduction pathways involved. METHODS: RAW264.7 macrophages were used. The production of nitric oxide (NO) was determined by the Griess test. The protein levels and mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) were determined by ELISA and RT-PCR, respectively. The phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear nuclear factor-kappa B (NF-kappaB) p65 protein were analyzed by Western blotting. RESULTS: Folic acid inhibited LPS-induced production of NO, TNF-alpha and IL 1beta with decreased mRNAs of inducible nitric oxide synthase (iNOS), TNF-alpha and IL-1beta. Further study showed that folic acid inhibited the LPS-induced phosphorylation of MAPKs and the nuclear translocation of NF-kappaB. CONCLUSION: Folic acid inhibits the inflammatory response of RAW 264.7 cells to LPS through inhibiting the MAPKs and NF-kappaB pathways. PMID- 21528359 TI - Trans-theta logistics: a new family of population growth sigmoid functions. AB - Sigmoid functions have been applied in many areas to model self limited population growth. The most popular functions; General Logistic (GL), General von Bertalanffy (GV), and Gompertz (G), comprise a family of functions called Theta Logistic ([Formula: see text] L). Previously, we introduced a simple model of tumor cell population dynamics which provided a unifying foundation for these functions. In the model the total population (N) is divided into reproducing (P) and non-reproducing/quiescent (Q) sub-populations. The modes of the rate of change of ratio P/N was shown to produce GL, GV or G growth. We now generalize the population dynamics model and extend the possible modes of the P/N rate of change. We produce a new family of sigmoid growth functions, Trans-General Logistic (TGL), Trans-General von Bertalanffy (TGV) and Trans-Gompertz (TG)), which as a group we have named Trans-Theta Logistic (T [Formula: see text] L) since they exist when the [Formula: see text] L are translated from a two parameter into a three parameter phase space. Additionally, the model produces a new trigonometric based sigmoid (TS). The [Formula: see text] L sigmoids have an inflection point size fixed by a single parameter and an inflection age fixed by both of the defining parameters. T [Formula: see text] L and TS sigmoids have an inflection point size defined by two parameters in bounding relationships and inflection point age defined by three parameters (two bounded). While the Theta Logistic sigmoids provided flexibility in defining the inflection point size, the Trans-Theta Logistic sigmoids provide flexibility in defining the inflection point size and age. By matching the slopes at the inflection points we compare the range of values of inflection point age for T [Formula: see text] L versus [Formula: see text] L for model growth curves. PMID- 21528360 TI - Management of osteoporosis in fracture liaison service associated with long-term adherence to treatment. AB - SUMMARY: Adherence to osteoporosis treatment is not satisfactory. Our study evaluated persistence and compliance with these treatments prescribed specifically in the context of a fracture liaison service (FLS), an internal health care network, and showed that this type of organization in our institution was associated with high level of adherence. INTRODUCTION: Medical management of patients with a fragility fracture has been improved by health care internal network or FLS organized in large hospitals. However, treatment effectiveness is not only related to larger initiation rate but also to better long-term adherence. Therefore, we evaluated persistence and compliance in the context of osteoporosis treatment initiated in our institution's FLS, among postmenopausal women with a peripheral fragility fracture. METHODS: Patients with a specific osteoporosis treatment prescribed while visiting our FLS were contacted by phone to answer an evaluation questionnaire. A simplified questionnaire was sent to their general physicians when we were not able to reach patients on the phone. RESULTS: Of the 279 selected patients, 155 were evaluated. Of them, 90.3% had actually started their treatment and 80% were still under treatment after 1 year. After 27.4 +/- 11.7 months of follow-up, 67.7% of patients were persistent with their treatment. In addition, 87% of the persistent patients declared to respect both treatment posology and administration conditions. Occurrence of adverse events was the first cause of treatment interruption within the first 6 months. CONCLUSIONS: Our data showed a high level of persistence with osteoporosis treatment when initiation was performed in an FLS, even on a long-term basis. Since follow-up and renewal of treatment were under routine daily practise, our study underlines how important the first prescription conditions are and provides additional interest in medical care network such as FLS. PMID- 21528361 TI - Predictive values of calcaneal quantitative ultrasound and dual energy X ray absorptiometry for non-vertebral fracture in older men: results from the MrOS study (Hong Kong). AB - Calcaneal QUS is comparable to DXA in predicting non-vertebral fractures in older Chinese men. INTRODUCTION: The predictive values of calcaneal quantitative ultrasound (QUS) and dual-energy X-ray absorptiometry (DXA) for non-vertebral fractures in older Chinese men were examined. METHODS: One thousand nine hundred twenty-one Chinese men aged 65-92 years had calcaneal QUS and axial DXA bone mineral density (BMD) measurements. The incidence of non-vertebral fractures was documented. Cox regression and receiver operating curve (ROC) analysis were used to examine the associations of QUS parameters and BMD with the incidence of non vertebral fractures. RESULTS: The duration of follow-up was (mean +/- SD) 6.5 +/- 1.7 years. One hundred thirty-one non-vertebral fractures were recorded, 71 of which were major fragility fractures. Broadband ultrasound attenuation (BUA) and quantitative ultrasound index (QUI) were significantly associated with non vertebral fractures and major fragility fractures, with age and fracture history adjusted hazard ratio (95% CI) of 1.23 (1.03, 1.47) and 1.32 (1.10, 1.59) per standard deviation reduction, respectively, for non-vertebral fractures; 1.32 (1.04, 1.68) and 1.43 (1.11, 1.84), respectively, for major fragility fractures. Age and fracture history-adjusted areas under ROC curves of hip or spine BMDs were significantly greater than that of BUA or QUI in predicting major fragility fractures, but not in predicting all non-vertebral fractures. The addition of BUA or QUI had no effect on AUCs of total hip BMD alone. CONCLUSIONS: The ability of calcaneal QUS to predict non-vertebral fractures was comparable to that of axial BMD by DXA, but was inferior to BMD in predicting major fragility fractures in older Chinese men. PMID- 21528362 TI - Measuring health-related quality of life (HRQOL) in osteoporotic males using the Male OPAQ. AB - The Male Osteoporosis Assessment Questionnaire (OPAQTM) is a health-related quality of life (HRQOL) instrument that can differentiate between men with and without fracture. The Male OPAQTM is a reliable and validated instrument that may be utilized in clinical trials seeking to include male populations. INTRODUCTION: Men with osteoporosis (OP) experience poorer clinical outcomes than do women with the disorder, but little is known about the impact of OP on men's HRQOL. This study aimed to test the validity, reliability, and ability to differentiate between men with and without fracture of an HRQOL for men with osteoporosis, the Male OPAQTM. METHODS: The OPAQ and OPAQ-SV were tested for face validity in interviews with male OP patients, and a revised, male-specific instrument was developed. Thirty-seven men ages 50+ completed the Male OPAQTM and SF-12 at baseline and a two-week retest of the Male OPAQTM. To analyze both the domain and dimension scores, a normalization procedure was performed on the data to determine health status scores from 0 to 100. Descriptive statistics were calculated for each item and site. Reliability and validity of the Male OPAQTM were assessed using Pearson's r. RESULTS: The Male OPAQTM can discriminate between men with and without fracture, and men who have more fractures have poorer scores. Instrument domains correspond to those of the SF-12. CONCLUSIONS: The Male OPAQ(TM) is a brief and sensitive tool for measuring HRQOL in men with OP. Further testing in a more diverse and large sample is warranted. PMID- 21528363 TI - [The man behind the prize: scientific prizes - meaningful control mechanism or "vanity fair"?]. PMID- 21528364 TI - [Men in a critical age: Kurt Mendel and the controversy over the male climacterium]. AB - Since the 1990s, with concepts like the male climacterium, andropause or PADAM, the idea of a"change of life" in men has gone through a spectacular reinvention. Recent research has focused upon the ways when, how and why these concepts emerged, thus taking cultural and historical approaches into account. This paper contributes to the growing corpus of such works. It sheds new light on the early decades of the twentieth century - a period that was decisive in establishing the modern, endocrinological understanding of the climacteric period as a result of hormonal deficiencies. Concurrently, this period saw several initiatives to conceptualize the male climacterium as a new and important diagnostic entity for health problems of men in their middle and later life. In Germany, the most important advocate was the Berlin neurologist Kurt Mendel, who published an influential article in 1910 entitled "The Change of Life in Men (Climacterium virile)". Mendel's concept evoked considerable interest and was much debated across medical disciplines, including neurology, psychiatry, sexology, endocrinology and urology. This article revisits and reassesses Mendel's concept of the male climacterium, discusses its specific status and significance, and places it within the historical context. Furthermore this, the paper argues that a historical approach is indispensable for a more nuanced understanding of the current arguments given to legitimize (or delegitimize) the status of a climacteric period in men. PMID- 21528366 TI - [Functional MRI and neurophysiological aspects of obesity]. AB - Functional magnetic resonance imaging studies have revealed that metabolic signals and food stimuli activate the mesocorticolimbic neural network involved in processing the reward system. Activation is influenced by obesity and hunger and many recent brain imaging studies have detected that food and drug stimuli activate many of the same reward circuits. These findings have implications for obesity prevention and therapy. Educational efforts need to be directed towards those at increased risk of becoming obese and the food industry has to be involved in providing and promoting healthier food options. Given that visual food stimuli are potent triggers of desire, seductive advertising of high calorie foods directed towards children should be curtailed. The application of non invasive brain imaging methodologies to the study of hedonic and homeostatic eating behavior represents a novel and important experimental approach. Further advances in imaging technology and improved experimental designs will provide new and important insights into human ingestive behavior that may lead to new developments in behavioral and pharmacological therapies. PMID- 21528367 TI - Time-dependent alterations of VEGF and its signaling molecules in acute lung injury in a rat model of sepsis. AB - Molecular mechanisms of sepsis-associated acute lung injury (ALI) are poorly defined. Since vascular endothelial growth factor (VEGF) is a potent vascular permeability and mitogenic factor, it might contribute to the development of ALI in sepsis. Thus, using lipopolysaccharide (LPS)-induced (15 mg/kg, intraperitoneal) endotoxemic rat model, we studied the timeline (1, 3, 6, and 10 h) of pulmonary VEGF expression and its signaling machinery. Levels of pulmonary VEGF and its angiogenic-mediating receptor, Flk-1, were downregulated by LPS in a time-dependent manner; levels of plasma VEGF and its permeability-mediating receptor, Flt-1, in contrast, was upregulated with time. In addition, blockade of Flt-1 could improve the downregulated pulmonary VEGF level and attenuate the elevated plasma and pulmonary levels of TNF-alpha, followed by improvement of arterial oxygenation and wet-to-dry weight ratio of the lung. Expression of signaling, pro- and or apoptotic factors after LPS administration were as follows: phosphorylated Akt, a downstream molecule was downregulated time dependently; endothelial nitric oxide synthase levels were significantly reduced; pro-apoptotic markers caspase 3 and Bax were upregulated whereas levels of Bcl-2 were downregulated. The present findings show that VEGF may play a role through the expression of Flt-1 in LPS-induced ALI. Moreover, downregulation of VEGF signaling cascade may account for LPS-induced apoptosis and impaired physiological angiogenesis in lung tissues, which in turn may contribute to the development of ALI induced by LPS. PMID- 21528368 TI - Multiple cystic brain metastases from adenocarcinoma mimicking cysticercosis. Case report. PMID- 21528365 TI - [Urinary diversion in childhood: special attention to the long-term consequences and complications]. AB - For reconstruction of the urinary tract almost all bowel segments have been used. Today ileal and colonic segments are used for bladder augmentation, substitution, continent or incontinent urinary diversion. In patients with a competent anal sphincter and normal renal function, the rectosigmoid pouch is an option. Urinary diversion in the paediatric age group is mostly performed in patients with dilated upper urinary tracts. Consequently the complication rate is increased with reoperation rates of up to 42%.Incorporation of bowel segments into the urinary tract can have metabolic consequences. Each bowel segment has its own characteristic and specific complications. These relate to the acid-base balance, absorption of vitamins and reabsorption of bile acids (causing diarrhoea) from the small bowel. Due to the risk of secondary malignancies, lifelong surveillance of the patients is mandatory, especially in those with continent anal diversion and after bladder augmentation. PMID- 21528369 TI - Differential diagnosis of cerebral hemispheric pathology: multimodal approach. AB - This article gives a comprehensive review and illustrations of the imaging features of various pathological conditions and clinical syndromes associated with cerebral hemispheric involvement. The various conditions are described and defined to provide a basis for the differential diagnostics. The hypotheses relating to the pathology of the various syndromes are discussed with special emphasis on excitotoxic mechanisms for explaining the subsequent cerebral hemiatrophy. PMID- 21528370 TI - Progressive multilocal supratentorial hemorrhages as a rare complication of artificial CSF drainage after lumbar disc surgery. PMID- 21528371 TI - The growth pattern of transplanted normal and nodular hepatocytes. AB - Overt neoplasia is often the end result of a long biological process beginning with the appearance of focal lesions of altered tissue morphology. While the putative clonal nature of focal lesions has often been emphasized, increasing attention is being devoted to the possible role of an altered growth pattern in the evolution of carcinogenesis. Here we compare the growth patterns of normal and nodular hepatocytes in a transplantation system that allows their selective clonal proliferation in vivo. Rats were pre-treated with retrorsine, which blocks the growth of resident hepatocytes, and were then transplanted with hepatocytes isolated from either normal liver or hepatocyte nodules. Both cell types were able to proliferate extensively in the recipient liver, as expected. However, their growth pattern was remarkably different. Clusters of normal hepatocytes integrated in the host liver, displaying a normal histology; however, transplanted nodular hepatocytes formed new hepatocyte nodules, with altered morphology and sharp demarcation from surrounding host liver. Both the expression and distribution of proteins involved in cell polarity, cell communication, and cell adhesion, including connexin 32, E-cadherin, and matrix metalloproteinase-2, were altered in clusters of nodular hepatocytes. Furthermore, we were able to show that down-regulation of connexin 32 and E-cadherin in nodular hepatocyte clusters was independent of growth rate. These results support the concept that a dominant pathway towards neoplastic disease in several organs involves defect(s) in tissue pattern formation. PMID- 21528372 TI - [Diffuse anterior retinoblastoma]. AB - Retinoblastoma is the most common primary intraocular tumor in childhood. Diffuse anterior retinoblastoma is an uncommon variant and usually occurs in comparatively older children. Typically, there is an extensive infiltration of the anterior segment by tumor cells clinically mimicking anterior uveitis with pseudohypopyon. The actual retinal focus is often very small and may not be detected despite a thorough histological examination. In this case report the clinical and histological findings of a diffuse anterior retinoblastoma are described. PMID- 21528373 TI - [A 25-year-old patient with corneal infiltration]. AB - Filamentous fungal keratitis represents a serious infection of the eye. When corneal infiltrates appear, particularly in those who wear contact lenses, mycological assessment should already be performed initially so that filamentous fungal keratitis can be recognized early and treated. Keratitis caused by Fusarium responds well in most cases to topical therapy with ketoconazole or other antimycotic agents so that surgical intervention is only necessary in advanced or treatment-refractory cases. PMID- 21528374 TI - [Pancreatic necrosis: pro-endoscopic therapy]. AB - The transmural endoscopic debridement and other minimally invasive therapies of infected postpancreatic necroses have been developed over the last decade as alternatives to open surgery. In several clinical centers the endoscopic approach has become standard therapy. The mortality rate in published series is in the range 0-15% and additional surgery is needed in 0-40%.Out of 73 own patients treated endoscopically between 2006 and 2010, 4 were operated because of bleeding, 2 with an acute abdomen and 3 with sepsis. Of the patients 6 died because of multi-organ failure and in 3 cases despite surgery. Main complications such as bleeding (n=20) and acute abdomen (n=7) were mostly treated conservatively. There was no procedure-related mortality. The endoscopic therapy was successful in 59 patients (80%) of whom 7 required further transmural endoscopic interventions for cystic relapses.At present, finding the best combination of endoscopic-transmural, percutaneous, laparoscopic and sometimes finally open surgical therapy remains an interdisciplinary challenge. The only randomized study published in this context clearly indicates that such a step-up approach is the most favorable. PMID- 21528376 TI - [Interventional therapy at the interface between surgery and gastroenterology]. PMID- 21528375 TI - [Inguinal and femoral hernia repair]. AB - With an incidence of 200,000 new cases per year in Germany, inguinal hernia has a significant socioeconomic impact. The 2009 guidelines from the European Hernia Society established treatment recommendations. Hernia repair is based on reinforcing the posterior wall of the inguinal canal by suture or mesh repair by an anterior or posterior approach. Lightweight mesh reduces recurrence rates and is the treatment of choice even in primary hernias. Laparoscopic hernia repair is associated with specific risks but is superior in postoperative pain and earlier return to work. PMID- 21528377 TI - [Single incision in minimally invasive surgery]. PMID- 21528378 TI - What do people include when they self-rate their health? Differential associations according to health status in community-dwelling older adults. AB - AIMS: Self-rated health (SRH) is widely regarded a valid and reliable indicator of health status. The validity of self-rated health has been demonstrated in many studies, for example by predicting mortality over and above medical and epidemiological data. However, the meaning of SRH can differ between individuals, especially in elderly individuals with considerable individual differences in their physical health states. It is thus important to determine whether predictors of self-rated health vary according to physical health status in order to interpret self-rated health data. METHODS: In a representative survey study, 1174 individuals over 65 years of age rated their health and filled in questionnaires on subjective well-being, control beliefs, depressive symptoms, and functional health. Structural equation modeling with latent moderated structural equations was used to determine whether health status (number of illnesses) moderated the association of self-rated health with these predictors. RESULTS: Self-rated health was predicted by positive affect, depressive symptoms, control beliefs, and physical functioning. Moderated effects were found for positive affect and physical functioning, suggesting that there are stronger associations with positive affect in healthier individuals and stronger associations with physical functioning in less healthy individuals. CONCLUSIONS: This implies that SRH has differential associations depending on health status, which should be taken into account in interpreting any research with SRH as predictor or criterion. PMID- 21528379 TI - Development of a high-throughput G4-FID assay for screening and evaluation of small molecules binding quadruplex nucleic acid structures. AB - G4-FID (G-quadruplex fluorescent intercalator displacement) is a simple and fast method that allows to evaluate the affinity of a compound for G-quadruplex DNA and its selectivity towards duplex DNA. This assay is based on the loss of fluorescence of thiazole orange (TO) upon competitive displacement from DNA by a putative ligand. We describe here the development of a high-throughput version of this assay performed in 96-well microplates, and fully transposable to 384-well microplates. The test was calibrated with a set of G-quadruplex ligands characterized for their ability to bind quadruplex within a large range of affinity. The comparison of the results obtained in microplates and in cuvettes was conducted indicating a full agreement. Additionally, the spectral range of the test was enlarged using two other fluorescent on/off probes whose absorption are red-shifted (TO-PRO-3) and blue-shifted (Hoechst 33258) as compared to that of TO. These labels enable to screen a large diversity of compounds with various optical properties, which was exemplified by evaluation of affinity and selectivity of the porphyrin TMPyP4 that could not be evaluated previously. Altogether, our study demonstrates that the HT-G4-FID assay offers the possibility to label a large variety of G-quadruplexes of biological interest and should enable screening of collections of putative G4-ligands of high structural diversity. It thus represents a powerful tool to bring into light new ligands able to discriminate between quadruplexes of different structures. PMID- 21528380 TI - The prevalence of human papillomavirus in oral premalignant lesions and squamous cell carcinoma in comparison to cervical lesions used as a positive control. AB - BACKGROUND: Previous reports concerning the prevalence of human papillomavirus (HPV) in oral squamous cell carcinoma (OSCC) have observed varied results. The aim of this study was to evaluate the prevalence of HPV in oral premalignant lesions (OPL) and OSCC. For accurate HPV detection in oral lesions, comparative analysis was performed on cervical lesions as positive controls. METHODS: Fifty seven cases with OPL and 50 with OSCC were selected. Twenty-nine control cases were selected from cervical lesions. The HPV infection rate was analysed by consensus polymerase chain reaction (PCR) using the My09/My11 and Gp5+/Gp6+ primers, and genotyping detection was employed using a PCR-based micro-array. Immunohistochemical staining for p16(INK4a) was performed. RESULTS: Twenty-eight (96.6%) cases of cervical lesions were positive for HPV by consensus PCR and 24 cases (82.8%) were positive by genotyping. The total HPV-positive rate in cervical lesions was 96.6%. HPV-DNA was detected in nine cases (15.8%) of OPL and six cases (12.0%) of OSCC by consensus PCR. Six cases (10.5%) of OPL and three cases (6.0%) of OSCC were positive by genotyping. The total HPV-positive rate in oral lesions was 22.4% (26.3% of OPL and 18.0% of OSCC). In cervical lesions, immunohistochemistry of p16(INK4a) identified 27 cases (93.1%) as positive. Fifteen cases (26.3%) of OPL and eight cases (16.0%) of OSCC were positive for p16(INK4a). CONCLUSIONS: The HPV infection and p16(INK4a)-positive rates in oral lesions are lower than previously reported. This suggests that HPV may not play a major role in oral lesions although its involvement cannot completely be ruled out. PMID- 21528381 TI - Predicted effects of pulse width programming in spinal cord stimulation: a mathematical modeling study. AB - To understand the theoretical effects of pulse width (PW) programming in spinal cord stimulation (SCS), we implemented a mathematical model of electrical fields and neural activation in SCS to gain insight into the effects of PW programming. The computational model was composed of a finite element model for structure and electrical properties, coupled with a nonlinear double-cable axon model to predict nerve excitation for different myelinated fiber sizes. Mathematical modeling suggested that mediolateral lead position may affect chronaxie and rheobase values, as well as predict greater activation of medial dorsal column fibers with increased PW. These modeling results were validated by a companion clinical study. Thus, variable PW programming in SCS appears to have theoretical value, demonstrated by the ability to increase and even 'steer' spatial selectivity of dorsal column fiber recruitment. It is concluded that the computational SCS model is a valuable tool to understand basic mechanisms of nerve fiber excitation modulated by stimulation parameters such as PW and electric fields. PMID- 21528382 TI - Comparison of QuantiFERON-TB Gold and the tuberculin skin test for detecting previous tuberculosis infection evaluated by chest CT findings in Japanese rheumatoid arthritis patients. AB - The aim of the study was to compare the usefulness of the QuantiFERON-TB Gold (QFT-2G) with that of the tuberculin skin test (TST) for detecting previous infection of tuberculosis (TB) in Japanese rheumatoid arthritis (RA) patients. Before receiving biologic therapy, 97 RA patients were divided into two groups based on their chest computed tomography (CT) findings: the TB past infection group (n = 48), with old inflammatory changes due to prior pulmonary TB; and the non-TB infection group (n = 49), without such findings. The QFT-2G was not affected by methotrexate or prednisolone. Indeterminate results with a positive control had a low incidence (5.2%). A positive QFT-2G for the TB past infection group at cutoffs of 0.35 and 0.1 IU/ml (intermediate range) was seen in 5.8% and 20.8%, respectively. A TST >20 mm was significantly higher in the non-TB infection group (31%) than in the TB past infection group (13%). The correlation between the QFT-2G and TST was poor among all patients. Disagreement between these tests in the non-TB infection group was caused by the false-positive TST induced by previous Bacillus Calmette-Guerin (BCG) vaccination. Only 12 (12.4%) of 97 patients had a positive QFT-2G (>=0.1 IU/ml) and a negative TST (<20 mm), but in this subgroup, a high incidence (10, 83.3%) was detected in the TB past infection group. QFT-2G may be a good alternative to the TST to evaluate previous TB infection when it is necessary to determine whether isoniazid (INH) prophylaxis is needed before biologic therapy is begun. PMID- 21528383 TI - Abbott RealTime PCR assay is useful for evaluating virological response to antiviral treatment for chronic hepatitis C. AB - This study was done to evaluate the utility of the Abbott RealTime PCR assay (ART) for the monitoring of chronic hepatitis C patients. The serum samples of 183 patients infected with hepatitis C virus (HCV) genotype 1b who had completed a 48-week period of pegylated interferon (PEG-IFN) alpha-2b plus ribavirin treatment were prospectively analyzed. Serum HCV RNA levels were measured both by ART and by the Roche COBAS Amplicor Monitor test, version2.0 (CAM) at baseline and at weeks 4, 12, 24, 36, and 48 of treatment, and at 24 weeks after the end of treatment (EOT). A significant positive correlation of pretreatment HCV RNA levels was found between ART and CAM (r = 0.595, P < 0.0001). Of the 183 patients, 66 (36.0%) achieved a sustained virological response (SVR). The logarithmic decline of the HCV RNA level from the pretreatment level determined by ART in SVR patients was significantly higher than that in non-SVR patients at all time points tested. The logarithmic decline determined by CAM in SVR patients was significantly higher than that in non-SVR patients only at week 4, but there was no significant difference at other weeks. Of 124 patients who were HCV RNA negative at EOT by ART, 58 (46.8%) had a relapse of viremia at 24 weeks after EOT, whereas 77 of 143 patients (53.8%) who were HCV RNA-negative at EOT by CAM had a relapse. The relapse rate was lower when determined by ART than by CAM, but not significantly so. ART is more useful than CAM for evaluating the virological response to antiviral treatment for chronic hepatitis C. PMID- 21528384 TI - Is the replacement strategy, as it exists today in the EU for cosmetics, the way forward ? PMID- 21528385 TI - Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). AB - INTRODUCTION: Kratom (Mitragyna speciosa) is a common medical plant in Thailand and is known to contain mitragynine as the main alkaloid. According to an increase in published reports and calls at German poison control centers, it has been used more frequently as a drug of abuse in the western hemisphere during the last couple of years. Despite this increase, reports of severe toxicity are rare within the literature. CASE REPORT: We describe a case of a young man who presented with jaundice and pruritus after intake of kratom for 2 weeks in the absence of any other causative agent. Alkaloids of M. speciosa were detected in the urine. CONCLUSION: While M. speciosa is gaining in popularity among illicit drug users, its adverse effects remain poorly understood. This is the first published case of intrahepatic cholestasis after kratom abuse. PMID- 21528386 TI - Washout of 82Rb as a marker of impaired tissue integrity, obtained by list-mode cardiac PET/CT: relationship with perfusion/metabolism patterns of myocardial viability. AB - PURPOSE: Myocardial washout of the potassium analogue (82)Rb may indicate tissue impairment. Few studies have evaluated its usefulness for viability assessment, and controversial results were reported. We revisited this topic using list-mode positron emission tomography (PET)/CT. METHODS: A total of 22 patients with chronic ischemic cardiomyopathy (ICM) and 11 control subjects with normal CT coronary angiogram were studied. Rest (82)Rb PET/CT studies were acquired in list mode and resampled to static, gated, and dynamic images. Using a 17-segment model, (82)Rb washout was determined by monoexponential fitting of myocardial time-activity curves. In ICM patients, (18)F-fluorodeoxyglucose (FDG) studies were obtained in the same session and segments were classified as normally perfused, mismatch, or matched defect. RESULTS: (82)Rb washout was minimal and homogeneous in control subjects. Normally perfused segments of ICM did not differ (p = 0.33). ICM patients had a left ventricular ejection fraction (LVEF) of 25 +/ 12%, 25/353 mismatched, and 46/353 matched defect segments. (82)Rb washout was higher in hypoperfused vs normal segments (p < 0.05), but not different between mismatch and matched defect (p = 0.18). Intraindividual analysis in nine patients showing both FDG mismatch and matched defect confirmed absence of differences. Overall, segmental (82)Rb washout correlated inversely with (82)Rb uptake (r = 0.70; p < 0.05) and less well with FDG uptake (r = -0.31; p < 0.05). CONCLUSION: Using state-of-the-art PET/CT technology for myocardial viability assessment, (82)Rb washout does not distinguish between perfusion/metabolism patterns of hibernating myocardium and scar. Tissue integrity may be at least partially impaired in hibernation. PMID- 21528387 TI - Comparison of biological stability and metabolism of CCK2 receptor targeting peptides, a collaborative project under COST BM0607. AB - PURPOSE: Stability of radiolabelled cholecystokinin 2 (CCK2) receptor targeting peptides has been a major limitation in the use of such radiopharmaceuticals especially for targeted radionuclide therapy applications, e.g. for treatment of medullary thyroid carcinoma (MTC). The purpose of this study was to compare the in vitro stability of a series of peptides binding to the CCK2 receptor [selected as part of the COST Action on Targeted Radionuclide Therapy (BM0607)] and to identify major cleavage sites. METHODS: Twelve different 1,4,7,10 tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-minigastrin/CCK conjugates were provided within an European COST Action (BM0607) by different laboratories and radiolabelled with (177)Lu. Their in vitro stabilities were tested in fresh human serum. Radiochemical yields (RCY) and intact radioligands for half-life calculations were determined by radio-HPLC. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) analysis of metabolites was performed to identify cleavage products using conjugates labelled with excess stable (nat)Lu, incubated in serum at 37 degrees C. Urine metabolite analysis after injection in normal mice was performed by radio-HPLC analysis. RESULTS: Variable stability in human serum was found for the different peptides with calculated half-lives between 4.5 +/- 0.1 h and 198 +/- 0.1 h (n = 2). In urine of normal mice only metabolised peptide fragments were detected even at short times after injection for all peptides. MALDI-TOF MS revealed a major cleavage site of all minigastrin derivatives between Asp and Phe-NH(2) at the C terminal end. CONCLUSION: Development of CCK2 receptor ligands especially for therapeutic purposes in patients with MTC or small cell lung cancer (SCLC) is still ongoing in different laboratories. This comparative study provided valuable insight into the importance of biological stability especially in the context of other results of this comparative trial within the COST Action BM0607. PMID- 21528388 TI - A new method for continuous monitoring of chest wall movement to characterize hypoxemic episodes during HFOV. AB - INTRODUCTION: Monitoring ventilated infants is difficult during high-frequency oscillatory ventilation (HFOV). This study tested the possible causes of hypoxemic episodes using a new method for monitoring chest wall movement during HFOV in newborn infants. METHODS: Three miniature motion sensors were attached to both sides of the chest and to the epigastrium to measure the local tidal displacement (TDi) at each site. A >20% change in TDi was defined as deviation from baseline. RESULTS: Eight premature infants (postmenstrual age 30.6 +/- 2.6 weeks) were monitored during 10 sessions (32.6 h) that included 21 hypoxemic events. Three types of such events were recognized: decrease in TDi that preceded hypoxemia (n = 11), simultaneous decrease in TDi and SpO2 (n = 6), and decrease in SpO(2) without changes in TDi (n = 4). In the first group, decreases in TDi were detected 22.4 +/- 18.7 min before hypoxemia, and were due to airway obstruction by secretions or decline in lung compliance. The second group resulted from apnea or severe abdominal contractions. In the third group, hypoxia appeared following a decrease in FiO2. CONCLUSIONS: Monitoring TDi may enable early recognition of deteriorating ventilation during HFOV that eventually leads to hypoxemia. In about half of cases, hypoxemia is not due to slowly deteriorating ventilation. PMID- 21528389 TI - Cost-effectiveness of statins revisited: lessons learned about the value of innovation. AB - BACKGROUND: The economic evaluation of statins has undergone a development from risk-factor-based models to modeling of hard end points in clinical trials with a shift back to risk-factor models after increased confidence in their predictive power has now been established. At this point, we can look back on the historical economic data on simvastatin to see what lesson regarding reimbursement we can learn. METHODS: Historical data on the usage and sales of simvastatin in Sweden were combined with published epidemiological and clinical data to calculate the social value of simvastatin to the present day and to make projection until projected until 2018. The distribution of the social surplus was calculated by taking the costs born by society and the producer of the drug into consideration. RESULTS: The cost of simvastatin fell drastically following patent expiration, although the number of treated patients has continued to grow. Presently, the use of simvastatin is close to cost neutrality taking direct and indirect cost savings from reduced morbidity into account. However, the major part of the social surplus generated comes from the value of improved quality-adjusted survival. Of the social surplus generated, the producer appropriated 20-43% of the value during the on-patent period, a figure dropping to 1% following loss of exclusivity. The total producer surplus between 1987 and 2018 is 2-5% of the total social surplus. CONCLUSION: Only a small part of the surplus value generated was appropriated by the producer. A regulatory and reimbursement approach that favors early market access and coverage with evidence development as opposed to long-term trials as a pre-requisite for launch is more attractive from both a company and social perspective. PMID- 21528390 TI - Do corticosteroids affect lumbar spinal fusion? A rabbit model using high-dose methylprednisolone. AB - BACKGROUND: The effect of corticosteroids on spinal fusion healing has not yet been determined. To evaluate the effect of corticosteroids on lumbar spinal fusion we designed a randomized, placebo-controlled animal study using high-dose methylprednisolone sodium succinate, which is widely used in patients with spinal cord injury who are undergoing spinal fusion. METHODS: Two groups of 18 rabbits underwent a postero-lateral fusion at L5-L6 with autologous bone graft. After surgery, the animals were assigned to receive: (a) methylprednisolone sodium succinate 30 mg/kg over 15 min, followed by an intravenous infusion of 5.4 mg/kg/h for 23 h, or (b) normal saline in the same volume. Animals were killed 8 weeks after surgery; the presence of fusion was analyzed by use of two different methods: a manual palpation test and an antero-posterior radiograph. RESULTS: Both groups of animals were comparable in weight. Fusion was achieved in 5/18 rabbits (27.8%) in the methylprednisolone group and in 9/18 animals (50%) in the control group (p = 0.17). CONCLUSION: In a lumbar posterolateral fusion rabbit model, high-dose methylprednisolone sodium succinate reduced the success of lumbar fusion; however, our data did not reach statistical significance. PMID- 21528392 TI - Hiatal hernias: a review of the pathophysiologic theories and implication for research. AB - BACKGROUND: The pathophysiology of hiatal hernias is incompletely understood. This study systematically reviewed the literature of hiatal hernias to provide an evidence-based explanation of the pathogenetic theories and to identify any risk factors at the molecular and cellular levels. METHODS: A systematic search of the Medline and Pubmed databases on the pathophysiology of hiatal hernias was performed to identify English-language citations from the database inception to December 2010. RESULTS: Although few studies have examined the relationship of molecular and cellular changes of the diaphragm to the pathogenesis of hiatal hernias, there appear to be three dominant pathogenic theories: (1) increased intraabdominal pressure forces the gastroesophageal junction (GEJ) into the thorax; (2) esophageal shortening due to fibrosis or excessive vagal nerve stimulation displaces the GEJ into the thorax; and (3) GEJ migrates into the chest secondary to a widening of the diaphragmatic hiatus in response to congenital or acquired molecular and cellular changes, such as the abnormalities of collagen type 3 alpha 1. CONCLUSIONS: The pathogenesis of hiatal hernias at the molecular and cellular levels is poorly described. To date, no single theory has proved to be the definitive explanation for hiatal hernia formation, and its pathogenesis appears to be multifactorial. PMID- 21528391 TI - Odor detection threshold, but not odor identification, is impaired in children with autism. AB - The aim of our study was to examine odor detection thresholds and odor identification in autistic subjects. Thirty-five patients with Asperger's syndrome and high functioning autism (mean age 10.8 +/- 3.6 years; 31 boys) were compared with 35 healthy control subjects (mean age 10.4 +/- 2.4 years; 28 boys). There were no significant differences between groups with regard to mean age (p = 0.598) and gender proportion (p = 0.324). Olfactory testing used the Sniffin' Sticks test (threshold and identification parts only). Participants with Asperger's syndrome and high functioning autism, in comparison with healthy controls, were significantly impaired relative to odor detection thresholds (6.3 +/- 3.1 vs. 7.9 +/- 2.0; p = 0.025). Autistic participants were significantly better in correctly identifying the odor of an orange (94 vs. 63%; p < 0.05) and significantly worse at correctly identifying the odor of cloves (40 vs. 74%; p < 0.05). With regard to identification of fourteen other substances, there were no significant differences. There was no significant difference between autistic and control subjects on the total score of olfactory identification (p = 0.799). Odor identification ability (as expressed by this total score) correlated significantly with age in the control group (p = 0.049), but not in the autism group (p = 0.103). We found impaired odor detection and almost normal odor identification in children with autism. Implications for further research are discussed. PMID- 21528393 TI - Is the implantation of an artificial urinary sphincter with a large cuff in women with severe urinary incontinence associated with worse perioperative complications and functional outcomes than usual? AB - INTRODUCTION AND HYPOTHESIS: As the subsequent risks of complications and explantation increase with the size of the cuff, we aimed to assess functional outcomes after the implantation of an artificial urinary sphincter (AUS) with a large cuff (>=8 cm) in women with severe urinary incontinence. METHODS: Fifty women underwent an AUS placement with a large cuff between 1984 and 2007. Forty three (86%) had previously undergone anti-incontinence procedures. The AUS was implanted with an open surgical technique using a transverse abdominal approach. The cuff was placed around the bladder neck between the periurethral fascia and the vagina. Perioperative complications were reviewed. To assess the resolution of urinary incontinence, all patients were seen at 1, 3, 6 and 12 months and yearly thereafter. RESULTS: The mean age was 59 +/- 12.4 years (26-81). The mean BMI was 27.3 +/- 5.1 (19-37). The mean pre-operative closure pressure was 19.1 +/ 9.4 cmH(2)O (3-46). The mean hospital stay was 14.1 +/- 5 days (5-28). The mean follow-up was 8 +/- 5.6 years. Incontinence was completely resolved in 34 women (68%). The protective factors to avoid explantation were a number of gestations less than two (p = 0.04), a closure pressure higher than 19 cmH(2)O (p = 0.04) and a cuff size equivalent to 8 cm (p = 0.005). CONCLUSIONS: Specific anatomical conditions can sometimes lead to AUS implantation with a large cuff with encouraging outcomes. Thus, surgeons should not be reluctant to place a large cuff when the situation requires it. PMID- 21528394 TI - [Proximal tibial fractures]. AB - Only 1-4% of all long bone fractures in children involve the proximal tibia. To evaluate these fractures appropriately, it is mandatory to differentiate between articular fractures and metaphyseal fractures. Articular fractures of the proximal physis are rare and include Salter Harris type III and IV injuries. The reconstruction of the articular surface is the fundamental goal of therapy. Injuries of the anterior crucial ligament which typically appear as an avulsion of the tibial spine and the avulsion fracture of the tibial tubercle apophysis can involve the articular surface. Dislocated fractures should be reduced and stabilized. Extraarticular fractures include Salter Harris type I and II fractures. Other types of metaphyseal fractures are the complete fracture, the compression fracture and the bending fracture of the proximal tibia. Care should be taken while treating bending fractures, especially a valgus deformity must be excluded. Due to unequal growth stimulation during remodelling, a progressive valgus deformity frequently develops. Small deformities in the sagittal plane can be compensated by spontaneous remodelling during further growth. Dislocated fractures should be reduced and stabilized by K-wires. The retention of bending fractures by a compression plate or external fixator for medial compression might be more beneficial. PMID- 21528395 TI - [Traumatic physeal separations of the distal tibia. Occurrence, forms, treatment strategies]. AB - Traumatic physeal separations (SH I/II) of the lower extremities are rare. Complications are reported in 2.2-39.6%. The current study is intended to provide recent data concerning epidemiology and treatment decisions in physeal separation of the distal tibia. All patients who suffered a physeal separation of the distal tibia in a 36-month period were included in a multicenter study. Age, gender, mechanism of injury, classification, therapeutic decision, and early complications were recorded online. There were 150 cases (64.6% male, 35.4% female, average age 11.8 years). The most frequent mechanism of injury was sportive activity (42%); 76% of cases needed reduction. Antecurvation was tolerated up to 10 degrees (p=0.0021) and valgus up to 7 degrees (p=0.0155). Tolerance ranges up to 5 degrees of retrocurvation and varus were not statistically significant. The investigation confirmed epidemiological data of former studies. For the first time data concerning the treatment reality of physeal separations of the distal tibia were recorded. They consistently follow the recommendations of the appropriate literature. PMID- 21528396 TI - [The mature twoplane and triplane fracture. Transitional fractures of the distal tibia combined with typical fracture patterns of adults]. AB - Physiologic closure of the growth plate of the distal tibia occurs between the ages of 12 and 14 years in girls and 1 year later in boys. The closure of the tibial physis starts eccentrically at the ventrolateral zone of the medial malleolus extending dorsally and ends laterally. Therefore, the anterolateral zone is the last to ossify. The process of closure lasts about 18 months. During this period the growth plate loses its joint-protective function and transitional fractures may occur. The more the closure progresses the more lateral the location of the fracture. In addition to the typical transitional fractures, typical fracture patterns of adults in the ossified physis are possible due to a mature bone structure. We report two cases of transitional fractures combined with typical fracture patterns of adults due to a dorsomedial ossified physis in the distal tibia. PMID- 21528397 TI - Modulation of short intra-cortical inhibition during action reprogramming. AB - Actions are selected in the context of environmental demands and internal goals. Since both change continuously it is often necessary to inhibit a prepared action plan in favour of an alternative, a process we refer to as action reprogramming. Previous studies have established that a frontal/basal ganglia network exerts top down control over the primary motor cortex (M1) during action reprogramming. The current study focuses on the role of M1 itself during action reprogramming. Participants were asked to perform a behavioural task that required them to either execute a prepared response or to reprogram an alternative response. Paired-pulse TMS was used to investigate short-interval intra-cortical inhibition (SICI) during these action execution and action reprogramming trials. Normal action execution was associated with sustained SICI in the M1 during both trials in which the contralateral hand was to respond and trials in which the ipsilateral hand was to respond. In contrast, reprogramming towards an alternative action was associated with a progressive release of SICI in M1 involved in the execution of the novel response. This release started 125 ms after the cue telling the participants to reprogram their action. This time point is consistent with previous results showing a facilitatory influence of the pre supplementary motor area (pre-SMA) on the M1 at the same delay. Hence, SICI might be a potential candidate mechanism through which frontal lobe areas could influence primary motor cortex output. PMID- 21528399 TI - The Great Recession's impact on children. AB - Since that first day of the millennium the United States has experienced two recessions. The first recession began in 2001 and lasted for 10 months. The second, now referred to as the Great Recession, began in December of 2007, was approximately 18 months in duration and was followed by a weak and jobless recovery that has persisted into the second decade of this century. This commentary will examine how low-income children have fared in regard to economic security, food insecurity and housing instability as a result of the Great Recession and recent economic downturn. It concludes with a call to action for a renewed investment in our children through a Children's Recovery and Stimulus Initiative. PMID- 21528398 TI - Endovascular treatment of severe vasospasm in nonaneurysmal perimesencephalic subarachnoid hemorrhage. AB - BACKGROUND: Nonaneurysmal perimesencephalic subarachnoid hemorrhage (SAH) has usually a benign prognosis and uneventful course; however, recent reports suggest that these patients may develop severe symptomatic vasospasm. METHODS: Description of the clinical course of one patient with nonaneurysmal perimesencephalic SAH who required intraarterial infusion of calcium antagonists and transluminal balloon angioplasty for treatment of symptomatic vasospasm. The perimesencephalic clot burden was quantified to determine if there is a relationship with the development of symptomatic vasospasm. RESULTS: Despite maximized clinical management, the patient described in this report developed vasospasm and delayed cerebral ischemia (DCI), requiring multiple endovascular interventions. The volumetric quantification of subarachnoid blood was 15.4 ml, and was mostly localized in the cisternal space. CONCLUSIONS: Nonaneurysmal perimesencephalic SAH may have a "malignant" course requiring close neurocritical care monitoring and multiple clinical and endovascular interventions. Moreover, large cisternal hemorrhage was correlated with the development of DCI in this patient with non-aneurysmal SAH. PMID- 21528400 TI - Surgical techniques and return to work following carpal tunnel release: a systematic review and meta-analysis. AB - INTRODUCTION: This systematic review was conducted to evaluate return to work (RTW) following minimally invasive carpal tunnel surgery versus open carpal tunnel release. This study also assesses how RTW as an outcome measure was examined in previous randomized controlled trials (RCTs). METHODS: The bibliographic databases Medline, AMED and CINAHL were systematically searched. We found 15 relevant RCTs. Meta-analysis was possible only for four studies. RESULTS: The result indicates that minimally invasive surgery offers earlier return to work compared to open carpal tunnel release (mean difference -7.2 days; 95% CI -10 to -4.4 days). There were remarkable inconsistencies in how return to work as an outcome measure was examined in different RCTs. CONCLUSIONS: Calculating standardised mean difference in future RCTs would allow future reviews to be more inclusive of the evidence. The authors suggest more consistent approach for evaluating work-related features in future studies. We recommend that new fit note categories introduced by UK Department of Work and Pension (unfit for all work/return to modified work or work adaptations/return to normal work) would be used to identify different levels of return to work. PMID- 21528402 TI - Ethical and regulatory issues with conducting sexuality research with LGBT adolescents: a call to action for a scientifically informed approach. AB - Lesbian, gay, bisexual, and transgender (LGBT) adolescents experience disparities in mental and sexual health. There is also a lack of research on this population relative to other adolescents, which limits our ability to effectively address these health disparities. Researchers may unfortunately avoid conducting research with this population because of anticipated or actual experiences with difficulties in obtaining IRB approval. A case example is provided to illustrate the ethical and regulatory issues related to research with LGBT adolescents. Relevant U.S. federal and local regulations related to research on sexual and mental health with adolescents is then reviewed. Data are presented demonstrating that requiring parental consent for LGBT youth under age 18 would likely alter study result. Data are also presented on participants' appraisals of the risks and discomforts associated with research participation. The provision of such empirical data on the risks of research participation is consistent with the goal of moving the IRB process of risk/benefit assessment from being entirely subjective to being evidence-based. Finally, recommendations are provided on how to approach these issues in IRB applications and investigators are called to help to build a corpus of scholarship that can advance empirical knowledge in this area. PMID- 21528401 TI - Differentiation of localization of spinal hemangioblastomas based on imaging and pathological findings. AB - Intramedullary + extramedullary hemangioblastomas with largely extramedullary growth are rare and often incorrectly assigned as intradural-extramedullary tumors preoperatively. Preoperative evaluation of the precise tumor location is important for total resection of tumor and improving the surgical outcome. The aim of this study was to provide the first identification of the key differences among of preoperative MR images of hemangioblastomas in different locations and to correlate these with pathological findings. The subjects were 26 patients with surgery for spinal hemangioblastoma in our department, including 6 with an intramedullary tumor who were complicated with von Hippel Lindau disease. Intramedullary, intramedullary + extramedullary, and intradural-extramedullary tumors were present in 22, 3 and 1 cases, respectively. Sagittal MR images showed that intramedullary and intramedullary + extramedullary tumors gave intramedullary T2 high intensity areas (HIAs) spreading toward the craniocaudal sides of the tumor, whereas such findings were absent for the intradural extramedullary tumor. All the tumors showed strong contrast on axial images, with focal enhancement of hemangioblastomas limited to the intramedullary region (focal type); smooth boundary lines between the spinal cord and the extramedullary tumor (smooth type); and a snowman sign for intramedullary + extramedullary tumors, which provided a key characteristic for differentiating intramedullary + extramedullary tumors from those limited to the extramedullary region. In pathological findings, the Ki67 activity was less than 1% for intramedullary and intradural-extramedullary tumors, but 18-25% in all cases with an intramedullary + extramedullary tumor. In conclusion, on preoperative MRI, a change in the intramedullary HIAs spreading the craniocaudal sides of the tumor on sagittal T2 weighted image (T2WI) and a snowman sign on contrast axial T1WI may be important for differentiation among spinal hemangioblastomas in different locations. Pathologically, we found that intramedullary + extramedullary hemangioblastoma has high cell proliferative activity, which may suggest that enlargement of this tumor occurs faster than that of intramedullary hemangioblastoma. PMID- 21528404 TI - Expression of OsDREB2A transcription factor confers enhanced dehydration and salt stress tolerance in rice (Oryza sativa L.). AB - Stress responsive transcriptional regulation is an adaptive strategy of plants that alleviates the adverse effects of environmental stresses. The ectopic overexpression of Dehydration-Responsive Element Binding transcription factors (DREBs) either in homologous or in heterologous plants improved stress tolerance indicating the DRE/DREB regulon is conserved across plants. We developed 30 transgenic T(0) rice plants overexpressing OsDREB2A which were devoid of any growth penalty or phenotypic abnormalities during stressed or non-stressed conditions. Integration of T-DNA in the rice genome and stress inducible overexpression of OsDREB2A had occurred in these transgenic lines. Functional analyses of T(1)-3 and T(1)-10 lines revealed significant tolerance to osmotic, salt and dehydration stresses during simulated stress conditions with enhanced growth performance as compared to wild type. OsDREB2A, thus, confers stress tolerance in homologous rice system that failed in the heterologous Arabidopsis system earlier. PMID- 21528403 TI - The antinociceptive effects of estradiol on adjuvant-induced hyperalgesia in rats involve activation of adrenergic and serotonergic systems. AB - PURPOSE: Estradiol is a female hormone required for maintaining pregnancy and developing follicles in the ovary. Estradiol has been shown to perform a variety of physiological activities, including pain reduction. In this study, we tested the hypothesis that estradiol exerts antinociceptive effects in a rat model of inflammatory hyperalgesia. METHODS: We established a subacute hyperalgesia model using plantar injection of Freund's complete adjuvant (FCA) in Sprague-Dawley rats. We administered estradiol every 24 h, beginning 12 h after FCA administration, and used the plantar test to determine its effect on hyperalgesia. To determine the mechanism of action of estradiol, we evaluated the role of the opioid antinociceptive system using naloxone and the role of the descending pain inhibitory system using the alpha-2-receptor antagonist yohimbine and the serotonin receptor antagonist methysergide. RESULTS: Administration of FCA induced hyperalgesia, which was significantly reduced by estradiol treatment compared to controls. Moreover, this effect was not antagonized by naloxone, but was attenuated by alpha-2-receptor and serotonin-receptor antagonists. CONCLUSION: Estradiol is known to perform a variety of physiological functions. Our findings suggest that one such function is antinociception via an interaction with alpha-2 receptors and serotonin receptors. PMID- 21528405 TI - Secondary metabolites of soil Bacillus spp. AB - Bacillus species produce secondary metabolites that are the object of natural product chemistry studies. The wide structural variability of these compounds has attracted the curiosity of chemists and their biological activities have inspired the pharmaceutical industry to search for lead structures in microbial extracts. Screening of microbial extracts reveals the large structural diversity of natural compounds with broad biological activities, such as antimicrobial, antiviral, immunosuppressive, and antitumor activities, that enable the bacterium to survive in its natural environment. These findings widen the potential industrial importance of Bacillus spp., particularly of B. thuringiensis, beyond insecticidal usage and may help explain the role of Bacillus spp. in the soil ecosystem. PMID- 21528406 TI - Small intestinal vascular malformation bleeding: diagnosis by double-balloon enteroscopy combined with abdominal contrast-enhanced CT examination. AB - AIM: The purpose of this study was to explore the value of double-balloon enteroscopy combined with abdominal vascular-enhanced CT examination for the diagnosis of intestinal vascular malformation bleeding, to explore a simple and effective method for the diagnosis of small intestinal vascular malformation bleeding. METHODS: Ten patients with intestinal bleeding were first examined with double-balloon enteroscopy. If active bleeding considered as vascular malformation was observed, the patient underwent abdominal vascular-enhanced CT examination. If no active bleeding was observed with double-balloon enteroscopy, the patient also underwent abdominal vascular-enhanced CT examination. When intestinal vascular malformation bleeding was diagnosed with double-balloon enteroscopy and/or abdominal vascular-enhanced CT examination, the patient underwent surgical operation and vascular malformation was confirmed with pathologic diagnosis. RESULTS: In ten patients who underwent double-balloon enteroscopy examination, active intestinal bleeding was observed in seven patients and no active bleeding was observed in three patients. All ten patients underwent abdominal vascular-enhanced CT examination and vascular malformation was detected in all the patients with confirmation by pathologic diagnosis. CONCLUSION: Double-balloon enteroscopy combined with abdominal vascular enhanced CT examination is a simple and effective method for the diagnosis of intestinal vascular malformation bleeding. PMID- 21528407 TI - Soluble Fas and Fas ligand and prognosis in children with acute lymphoblastic leukemia. AB - The soluble forms of Fas and its ligand (sFas and sFasL) correlate with disease progression in various malignancies. We compared serum levels of sFas and sFasL in children with acute lymphoblastic leukemia and healthy children to determine the prognostic significance of these molecules. Serum levels of sFas and sFasL were measured with an enzyme-linked immunosorbent assay in 48 patients with newly diagnosed childhood acute lymphoblastic leukemia and 38 healthy children. Cut-off values of sFas and sFasL levels were based on their levels in controls. Clinical and laboratory characteristics were recorded on admission. The mean serum concentration of sFas was 243 +/- 40 pg/mL in patients and 238 +/- 29 pg/mL in controls. Serum levels of sFasL were 4.33 +/- 0.25 ng/mL in patients and 4.27 +/- 0.11 ng/mL in controls. Neither difference was significant. Based on the cut-off value, 12.5% of the patients were positive for sFas, and 16.6% were positive for sFasL. Survival was significantly longer in sFasL-positive patients (394 +/- 69.6 vs. 254 +/- 24.3 days) and the duration of complete remission was also longer (380 +/- 65.0 vs. 246 +/- 26.0 days) than in sFasL-negative patients (P < 0.02), indicating the important role of this molecule in the response to therapy. Higher sFas levels were associated with hepatosplenomegaly (P < 0.047). In conclusion, sFasL positivity was associated with a favorable outcome in ALL patients. PMID- 21528409 TI - Co-existence of t(6;13)(p21;q14.1) and trisomy 12 in chronic lymphocytic leukemia. AB - We report a case of a 57-year-old man diagnosed with chronic lymphocytic leukemia (CLL) and presence of a rare t(6;13)(p21;q14.1) in association with an extra copy of chromosome 12. Classical cytogenetic analysis using the immunostimulatory combination of DSP30 and IL-2 showed the karyotype 47,XY,t(6;13)(p21;q14.1), +12 in 75% of the metaphase cells. Spectral karyotype analysis (SKY) confirmed the abnormality previously seen by G-banding. Additionally, interphase fluorescence in situ hybridization using an LSI CEP 12 probe performed on peripheral blood cells without any stimulant agent showed trisomy of chromosome 12 in 67% of analyzed cells (134/200). To the best of our knowledge, the association of t(6;13)(p21;q14.1) and +12 in CLL has never been described. The prognostic significance of these new findings in CLL remains to be elucidated. However, the patient has been followed up since 2009 without any therapeutic intervention and has so far remained stable. PMID- 21528408 TI - Classical CMF regimen as adjuvant chemotherapy for triple-negative breast cancer may be more effective compared with anthracycline or taxane-based regimens. AB - Patients suffering from triple-negative breast cancer (TNBC) have poor prognosis mainly because no standard treatment is currently available. Our objectives were to explore the prognostic factors for first relapse of patients with TNBC. A cohort of 687 patients with TNBC, diagnosed and treated between January 1995 and December 2008 at Sun Yat-sen University Cancer Center, were retrospectively analyzed. Cox proportional hazards models were fitted to explore factors that predict relapse development. Survival rate was computed using the Kaplan-Meier product limit method. The median age of the 687 patients was 46 (range 16-76 years), and 64.8% of the patients were pre-menopausal. The median follow-up time was 56 months (range 14-156 months), in which 194 patients had recurrence, and 115 died. The median recurrence-free time was 25 months (range 4-143 months), with 118 (60.8%) of the cases first relapsing at a single site. The three- and five-year disease-free survival rates were 79.7 and 72.6%, respectively. Primary tumor size at diagnosis, lymph node status, and type of regimen used in the (neo)adjuvant chemotherapy were considered independent predictors of first relapse. CMF-containing adjuvant chemotherapy significantly decreased recurrence compared with the anthracycline- or taxane-based regimens (RR = 0.66, 95%; CI 0.45-0.96; P = 0.030). The median time from first relapse to death was 26 months (range 2-121 months). The two- and five-year survival rates were 60.6 and 36.6%, respectively. Liver metastasis at first recurrence and progression-free survival over 12 months after first-line therapy were two important factors that affected survival rate after recurrence. The median relapse time of TNBC was about 2 years after diagnosis. CMF regimens for TNBC patients may be more effective than anthracycline- or taxane-based regimens. Liver metastasis at first recurrence signifies unfavorable prognosis. PMID- 21528411 TI - Exercise-induced laryngeal obstructions: prevalence and symptoms in the general public. AB - Respiratory difficulties caused by exercise-induced laryngeal obstructions (EILOs) are reported with increasing frequency. The aim of this study was to assess the prevalence and symptoms of EILOs and their relation to airway hyperresponsiveness (AHR). In total, 556 randomly selected youths in Copenhagen aged 14-24 years were invited over a 2-year period. The study included a mailed questionnaire and two visits: day 1 (an interview-based questionnaire, methacholine bronchial provocation test and physical exertion test); and day 2 [an exercise test with continuous laryngoscopic recordings (CLE test)]. The diagnosis of EILOs was based on the CLE test. In total, 237 answered the mailed questionnaire and 150 participated on day 1 whereof 98 participated on day 2 also. AHR was verified in 23 (4.1% of invitees) and EILOs in 42 (7.5% of invitees). Co-morbidity was verified in 6 cases (26.1% of verified AHR cases). No symptoms were found specific for either AHR or EILOs. The minimum prevalence of EILOs in this cohort was 7.5%. EILOs were verified in 26.1% of participants with AHR. Questionnaires could not differentiate between AHR and EILOs. PMID- 21528412 TI - Alcoholic fermentation by wild-type Hansenula polymorpha and Saccharomyces cerevisiae versus recombinant strains with an elevated level of intracellular glutathione. AB - The ability of baker's yeast Saccharomyces cerevisiae and of the thermotolerant methylotrophic yeast Hansenula polymorpha to produce ethanol during alcoholic fermentation of glucose was compared between wild-type strains and recombinant strains possessing an elevated level of intracellular glutathione (GSH) due to overexpression of the first gene of GSH biosynthesis, gamma-glutamylcysteine synthetase, or of the central regulatory gene of sulfur metabolism, MET4. The analyzed strains of H. polymorpha with an elevated pool of intracellular GSH were found to accumulate almost twice as much ethanol as the wild-type strain during glucose fermentation, in contrast to GSH1-overexpressing S. cerevisiae strains, which also possessed an elevated pool of GSH. The ethanol tolerance of the GSH overproducing strains was also determined. For this, the wild-type strain and transformants with an elevated GSH pool were compared for their viability upon exposure to exogenous ethanol. Unexpectedly, both S. cerevisiae and H. polymorpha transformants with a high GSH pool proved more sensitive to exogenous ethanol than the corresponding wild-type strains. PMID- 21528410 TI - Study on predictive role of AR and EGFR family genes with response to neoadjuvant chemotherapy in locally advanced breast cancer in Indian women. AB - Locally advanced breast cancer (LABC) remains a clinical challenge as the majority of patients with this diagnosis develop distant metastases despite appropriate therapy. We analyzed expression of steroid and growth hormone receptor genes as well as gene associated with metabolism of chemotherapeutic drugs in locally advanced breast cancer before and after neoadjuvant chemotherapy (NACT) to study whether there is a change in gene expression induced by chemotherapy and whether such changes are associated with tumor response or non response. Fifty patients were included with locally advanced breast cancer treated with cyclophosphamide, adriamycin, 5-fluorouracil (CAF)-based neoadjuvant chemotherapy before surgery. Total RNA was extracted from 50 match samples of pre and post-NACT tumor tissues. RNA expression levels of epidermal growth factor receptor family genes including EGFR, ERBB2, ERBB3, androgen receptor (AR), and multidrug-resistance gene 1 (MDR1) were determined by quantitative real-time reverse transcriptase-polymerase chain reaction. Responders show significantly high levels of pre-NACT AR gene expression (P = 0.016), which reduces following NACT (P = 0.008), and hence can serve as a useful tool for the prediction of the success of neoadjuvant chemotherapy in individual cancer patients with locally advanced breast carcinoma. Moreover, a significant post-therapeutic increase in the expression levels of EGFR and MDR1 gene in responders (P = 0.026 and P < 0.001) as well as in non-responders (P = 0.055, P = 0.001) suggests that expression of these genes changes during therapy but they do not have any impact on tumor response, whereas a post-therapeutic reduction was observed in AR in responders. This indicates an independent predictive role of AR with response to NACT. PMID- 21528413 TI - Engineering lower inhibitor affinities in beta-D-xylosidase of Selenomonas ruminantium by site-directed mutagenesis of Trp145. AB - beta-D-Xylosidase/alpha-L-arabinofuranosidase from Selenomonas ruminantium is the most active enzyme reported for catalyzing hydrolysis of 1,4-beta-D xylooligosaccharides to D-xylose. One property that could use improvement is its relatively high affinities for D-glucose and D-xylose (K (i) ~ 10 mM), which would impede its performance as a catalyst in the saccharification of lignocellulosic biomass for the production of biofuels and other value-added products. Previously, we discovered that the W145G variant expresses K(i)(D glucose) and K(i)(D-xylose) twofold and threefold those of the wild-type enzyme. However, in comparison to the wild type, the variant expresses 11% lower k(cat)(D xylobiose) and much lower stabilities to temperature and pH. Here, we performed saturation mutagenesis of W145 and discovered that the variants express K (i) values that are 1.5-2.7-fold (D-glucose) and 1.9-4.6-fold (D-xylose) those of wild-type enzyme. W145F, W145L, and W145Y express good stability and, respectively, 11, 6, and 1% higher k(cat)(D-xylobiose) than that of the wild type. At 0.1 M D-xylobiose and 0.1 M D-xylose, kinetic parameters indicate that W145F, W145L, and W145Y catalytic activities are respectively 46, 71, and 48% greater than that of the wild-type enzyme. PMID- 21528414 TI - Effect of biostimulation on the microbial community in PCB-contaminated sediments through periodic amendment of sediment with iron. AB - Reductive dehalogenation of polychlorinated biphenyls (PCBs) by indigenous dehalorespiring microorganisms in contaminated sediments may be enhanced via biostimulation by supplying hydrogen generated through the anaerobic corrosion of elemental iron added to the sediment. In this study, the effect of periodic amendment of sediment with various dosages of iron on the microbial community present in sediment was investigated using phospholipid fatty acid analysis (PLFA) over a period of 18 months. Three PCB-contaminated sediments (two freshwater lake sediments and one marine sediment) were used. Signature biomarker analysis of the microbial community present in all three sediments revealed the enrichment of Dehalococcoides species, the population of which was sustained for a longer period of time when the sediment microcosms were amended with the lower dosage of iron (0.01 g iron per g dry sediment) every 6 months as compared to the blank system (without iron). Lower microbial stress levels were reported for the system periodically amended with 0.01 g of iron per g dry sediment every 6 months, thus reducing the competition from other hydrogen-utilizing microorganisms like methanogens, iron reducers, and sulfate reducers. The concentration of hydrogen in the system was found to be an important factor influencing the shift in microbial communities in all sediments with time. Periodic amendment of sediment with larger dosages of iron every 3 months resulted in the early prevalence of Geobacteraceae and sulfate-reducing bacteria followed by methanogens. An average pH of 8.4 (range of 8.2-8.6) and an average hydrogen concentration of 0.75% (range of 0.3-1.2%) observed between 6 and 15 months of the study were found to be conducive to sustaining the population of Dehalococcoides species in the three sediments amended with 0.01 g iron per g dry sediment. Biostimulation of indigenous PCB dechlorinators by the periodic amendment of contaminated sediments with low dosages of iron metal may therefore be an effective technology for remediation of PCB-contaminated sediments. PMID- 21528415 TI - Bilateral endoscopic total extraperitoneal (TEP) inguinal hernia repair does not induce obstructive azoospermia: data of a retrospective and prospective trial. PMID- 21528416 TI - Awareness of dengue and practice of dengue control among the semi-urban community: a cross sectional survey. AB - Primary prevention is the most effective measure in dengue prevention and control. The objectives were (i) to determine the level of knowledge and practice of dengue control amongst the study community, and (ii) to explore the factors affecting practice of dengue control in the study area. A cross-sectional study was conducted in a semi-urban Town of Malaysia, using a structured questionnaire covering sociodemography, knowledge related to dengue, knowledge related to Aedes mosquito and preventive measures against the disease. For comparison of survey responses, chi-square test was applied for categorical data. To explore the factors affecting the practice of dengue control, a linear regression model was introduced. Almost all of the respondents (95%) had heard about dengue. Overall, misconceptions of dengue transmission were identified and the practice of dengue control in the study population was insufficient. About half (50.5%) had misconceptions that Aedes can breed in dirty water and the preferred biting time is dusk or sunset (45.6%). Only 44.5% of the households surveyed had covered their water containers properly. Significant associations were found between knowledge scores of dengue and age (P = 0.001), education level (P = 0.001), marital status (P = 0.012), and occupation (P = 0.007). In regression analysis, only the knowledge of dengue was significantly and positively associated with practice on dengue control. A future study with larger samples and more variables to assess the knowledge, attitudes and practices of dengue control is recommended. PMID- 21528418 TI - [Psychiatry as a cultural science: considerations according to Max Weber]. PMID- 21528417 TI - Inhibition of aconitase in citrus fruit callus results in a metabolic shift towards amino acid biosynthesis. AB - Citrate, a major determinant of citrus fruit quality, accumulates early in fruit development and declines towards maturation. The isomerization of citrate to isocitrate, catalyzed by aconitase is a key step in acid metabolism. Inhibition of mitochondrial aconitase activity early in fruit development contributes to acid accumulation, whereas increased cytosolic activity of aconitase causes citrate decline. It was previously hypothesized that the block in mitochondrial aconitase activity, inducing acid accumulation, is caused by citramalate. Here, we investigated the effect of citramalate and of another aconitase inhibitor, oxalomalate, on aconitase activity and regulation in callus originated from juice sacs. These compounds significantly increased citrate content and reduced the enzyme's activity, while slightly inducing its protein level. Citramalate inhibited the mitochondrial, but not cytosolic form of the enzyme. Its external application to mandarin fruits resulted in inhibition of aconitase activity, with a transient increase in fruit acidity detected a few weeks later. The endogenous level of citramalate was analyzed in five citrus varieties: its pattern of accumulation challenged the notion of its action as an endogenous inhibitor of mitochondrial aconitase. Metabolite profiling of oxalomalate-treated cells showed significant increases in a few amino acids and organic acids. The activities of alanine transaminase, aspartate transaminase and aspartate kinase, as well as these of two gamma-aminobutyrate (GABA)-shunt enzymes, succinic semialdehyde reductase (SSAR) and succinic semialdehyde dehydrogenase (SSAD) were significantly induced in oxalomalate-treated cells. It is suggested that the increase in citrate, caused by aconitase inhibition, induces amino acid synthesis and the GABA shunt, in accordance with the suggested fate of citrate during the acid decline stage in citrus fruit. PMID- 21528419 TI - [Was the expert medical opinion rendered by B. von Gudden regarding King Ludwig II of Bavaria correct?]. AB - Even today the deaths of King Ludwig II of Bavaria and the Munich-based psychiatrist Bernhard von Gudden on 13 June 1886 remain something of a mystery. In his psychiatric expertise von Gudden had rated Ludwig as insane and incapable of governing. Ludwig was placed under tutelage, deposed and interned under the supervision of guards. After the catastrophe witnesses and the press were silenced by strict censorship under threat of heavy penalties. Even today obstacles to free information still exist, aiding and abetting the birth of legends and the preservation of leading traditional views. We report on the results of a 5-year research project conducted at the Heidelberg Academy of Sciences and Humanities and based on information derived from private and public archives in Germany and abroad. Reference is made to comparable analyses. Neither von Gudden's expertise nor Ludwig's behaviour provide reliable cues to his alleged insanity. The reasons and motives behind the king's deposition are discussed. Apart from von Gudden's tragic death, this was not a singular case of a psychiatric expertise commissioned in the monarchist culture of the nineteenth and the early twentieth century. PMID- 21528420 TI - Investigation of a fatal airplane crash: autopsy, computed tomography, and injury pattern analysis used to determine who was steering the plane at the time of the accident. A case report. AB - A fatal accident is reported in which a small single-engine light airplane crashed. The airplane carried two persons in the front seats, both of whom possessed valid pilot certificates. Both victims were subject to autopsy, including post-mortem computed tomography scanning (PMCT) prior to the autopsy. The autopsies showed massive destruction to the bodies of the two victims but did not identify any signs of acute or chronic medical conditions that could explain loss of control of the airplane. PMCT, histological examination, and forensic chemical analysis also failed to identify an explanation for the crash. A detailed review of an airplane identical to the crashed airplane was performed in collaboration with the Danish Accident Investigation Board and the Danish National Police, National Centre of Forensic Services. The injuries were described using the abbreviated injury scale, the injury severity score, 3 dimensional reconstructions of the PMCT, and an injury pattern analysis. We describe how, on basis of these data, we reached a conclusion about which of the two victims was the most likely to have been in control of the airplane at the time of accident. Furthermore, we argue that all victims of fatal airplane crashes should be subject to forensic autopsy, including PMCT and forensic chemical analysis. The continuous accumulation of knowledge about injury patterns from "simple" accidents is the foundation for the correct analysis of "difficult" accidents. PMID- 21528421 TI - Development of a fish cell culture model to investigate the impact of fish oil replacement on lipid peroxidation. AB - Fish oils are rich in omega-3 long-chain polyunsaturated fatty acids (n-3 LC PUFA), predominantly 20:5n-3 and 22:6n-3, whereas vegetable oils contain abundant C(18)-PUFA, predominantly 18:3n-3 or 18:2n-6. We hypothesized that replacement of fish oils with vegetable oils would increase the oxidative stability of fish lipids. Here we have used the long established and easily cultivated FHM cell line derived from the freshwater fish species fathead minnow (Pimephales promelas) to test this hypothesis. The FHM cells were readily able to synthesize 20:5n-3 and 24:6n-3 from 18:3n-3 but 22:6n-3 synthesis was negligible. Also, they were readily able to synthesize 20:3n-6 from 18:2n-6 but 20:4n-6 synthesis was negligible. Mitochondrial beta-oxidation was greatest for 18:3n-3 and 20:5n-3 and the rates for 16:0, 18:2n-6, 22:6n-3 and 18:1n-9 were significantly lower. Fatty acid incorporation was predominantly into phospholipids (79-97%) with very little incorporation into neutral lipids. Increasing the fatty acid concentration in the growth medium substantially increased the concentrations of 18:3n-3 and 18:2n-6 in the cell phospholipids but this was not the case for 20:5n-3 or 22:6n-3. When they were subjected to oxidative stress, the FHM cells supplemented with either 20:5n-3 or 22:6n-3 (as compared with 18:3n-3 or saturated fatty acids) exhibited significantly higher levels of thiobarbituric reactive substances (TBARS) indicating higher levels of lipid peroxidation. The results are discussed in relation to the effects of fatty acid unsaturation on the oxidative stability of cellular lipids and the implications for sustainable aquaculture. PMID- 21528422 TI - Reduced isotope dose and imaging time with a high-efficiency CZT SPECT camera. AB - BACKGROUND: In light of recent focus on diagnostic imaging, cardiac SPECT imaging needs to become a shorter test with lower radiation exposure to patients. Recently introduced Cadmium Zinc Telluride (CZT) cameras have the potential to achieve both goals. METHODS: During a 2-month period patients presenting for a Tc 99m sestamibi SPECT MPI study were imaged using a CZT camera using a low-dose rest-stress protocol (5 mCi rest and 15 mCi stress doses). Patients >=250 lbs or a BMI >=35 kg/m(2) were excluded. Rest images were processed at 5- and 8-minute acquisition times and stress images at 3- and 5-minute acquisition times. A subset of patients had stress imaging performed using both conventional and CZT SPECT cameras. Image acquisition times and SPECT camera images were compared based on total counts, count rate, image quality, and summed rest and stress scores. Twelve month clinical follow-up was also obtained. RESULTS: 131 patients underwent the study protocol (age 64.9 +/- 9.8 years, 54.2% male). There was no significant difference in image quality and mean summed scores between 5- and 8 minute rest images and between 3- and 5-minute stress images. When compared to a conventional SPECT camera in 27 patients, total rest and stress perfusion deficits and calculated LVEF were similar (r = 0.94 and 0.96, respectively). At 12 months there was a benign prognosis in patients with normal perfusion. The effective dose was 5.8 mSv for this protocol which is 49.2% less than conventional Tc-99m studies and 75.7% less than conventional Tl-201/Tc-99m dual isotope studies. CONCLUSIONS: New SPECT camera technology with low isotope dose significantly reduces ionizing radiation exposure and imaging times compared to traditional protocols while maintaining image quality and diagnostic accuracy. PMID- 21528424 TI - Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheumatic drugs. AB - To evaluate the prevalence of past infection with hepatitis B virus (HBV) in patients with rheumatoid arthritis (RA) and the incidence of its reactivation under treatment with biological and/or nonbiological disease-modifying antirheumatic drugs (DMARDs), 239 patients receiving DMARD therapy were consecutively enrolled and tested for HBV-DNA, using a real-time polymerase chain reaction assay, HBV serology including hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc), and serum levels of aminotransferase. Data prior to DMARD therapy and during follow-up were examined by reviewing medical records. Two patients (0.8%) were positive for HBsAg at the start of therapy. Sixty patients (25.1%) showed HBsAg-negative and anti-HBc-positive serology indicative of past HBV infection. Among these 60 patients, 2 patients (3.3%) experienced reactivation of viral replication (<2.1 log copies/ml) during DMARD therapy. One had been receiving tacrolimus, prednisolone, and methotrexate (MTX); the other had been treated with adalimumab, prednisolone, and MTX. Their serum aminotransferase levels remained normal, and HBsAg was negative. Ten weeks after reactivation of viral replication had been noted, the HBV-DNA titer in the former patient had increased to 2.9 log copies/ml, and HBsAg and hepatitis B e antigen had become weakly positive. In contrast, the latter patient had become negative for viral DNA without any antiviral prophylaxis. In conclusion, the use of biological and nonbiological DMARDs is relatively safe in most RA patients with past HBV infection, even when no anti-HBV prophylaxis is administered. Considering the high prevalence of past infection in RA patients and the high cost of prophylaxis against HBV reactivation, universal prophylaxis is impractical. Regular monitoring of serum viral DNA seems to be the most rational approach to preventing the development of clinically apparent hepatitis. PMID- 21528425 TI - Acoustic and perceptual measurement of expressive prosody in high-functioning autism: increased pitch range and what it means to listeners. AB - Are there consistent markers of atypical prosody in speakers with high functioning autism (HFA) compared to typically-developing speakers? We examined: (1) acoustic measurements of pitch range, mean pitch and speech rate in conversation, (2) perceptual ratings of conversation for these features and overall prosody, and (3) acoustic measurements of speech from a structured task. Increased pitch range was found in speakers with HFA during both conversation and structured communication. In global ratings listeners rated speakers with HFA as having atypical prosody. Although the HFA group demonstrated increased acoustic pitch range, listeners did not rate speakers with HFA as having increased pitch variation. We suggest that the quality of pitch variation used by speakers with HFA was non-conventional and thus not registered as such by listeners. PMID- 21528426 TI - Parameter validation of analytical methods of insecticide residue analyses in foods of animal origin, feed and water. AB - The study was conducted to examine the interrelationship and coherence of analytical parameters in method validation. Recovery, sensitivity, linearity, precision and limits of detection (LOD) were tested in six methods for organochlorine and organophosphate insecticides. Compounds that fell out of the stipulated recovery, 70-120%, in a matrix have concurrently failed to meet the requirements for sensitivity (>= 0.7), linearity (R2 > 0.99) and precision (< 0.2) in the same matrix. Highest LOD was recorded in those compounds and matrices. Different from the conventional point estimate, a new approach was introduced for setting upper and lower confidence limits of the LOD in quantitative analyses. PMID- 21528427 TI - Influence of bioassay volume, water column height, and octanol-water partition coefficient on the toxicity of pesticides to rainbow trout. AB - Effects of water volume and water column height on toxicity of cypermethrin, carbaryl, dichlorvos, tetradifon, maneb, captan, carbosulfan endosulfan and HgCl2 to juvenile rainbow trout (Oncorhynchus mykiss, 3.2 +/- 0.7 g) were evaluated in different glass aquaria under static conditions. When fish were exposed to the chemical compounds in 23 cm water column height (25 L), their mortality ranged between 0% and 58%. At the same water volume, but lower water column height (9 cm), mortality of fish increased significantly and was in a range from 60% to 95%. At the same water column height, toxic effects of chemicals were significantly higher in 25 L water volume than that of 8.5 L, water except maneb which has lowest (-0.45) octanol-water partition coefficient value. Mortality rates ratio of 9 and 23 cm water column height ranged between 1.12 and 90 while mortality rates ratio of 9 and 25 L water volume ranged between 1.20 and 4.0. Because actual exposure concentrations were not affected by either water volume or water column height, we propose that increased pesticides' toxicity was related to an increase in bioassay volume, since more pesticide molecules were able to interact with or accumulate the fish. However, there seem to be no relationship between the effects of water volume, water column height and Kow value of chemicals with regard to toxicity in juvenile rainbow trout. PMID- 21528428 TI - An analysis on the research ethics cases managed by the Committee on Publication Ethics (COPE) between 1997 and 2010. AB - The growing emphasis on the importance of publishing scientific findings in the academic world has led to increasing prevalence of potentially significant publications in which scientific and ethical rigour may be questioned. This has not only hindered research progress, but also eroded public trust in all scientific advances. In view of the increasing concern and the complexity of research misconduct, the Committee on Publication Ethics (COPE) was established in 1997 to manage cases with ethical implications. In order to review the outcomes of cases investigated by COPE, a total of 408 cases that had been managed by COPE were successfully extracted and analysed with respect to 7 distinct criteria. The results obtained indicate that the number of ethical implications per case has not changed significantly (p > 0.01) since the year COPE was instigated. Interestingly, the number of ethical cases, and to some extent, research misconduct, is not diminishing. Therefore, journal editors and publishers need to work closely together with COPE to inculcate adoption of appropriate research ethics and values in younger researchers while discouraging others from lowering standards. It is hoped that with a more concerted effort from the academic community and better public awareness, there will be fewer incidences of ethically and scientifically challenged publications. The ultimate aim being to enhance the quality of published works with concomittant public trust in the results. PMID- 21528430 TI - Overlap-coefficient for the relationship between mesh size and defect size in laparoscopic ventral hernia surgery. PMID- 21528429 TI - A 79 year old man with chronic lymphocytic leukemia and nephrotic syndrome. PMID- 21528431 TI - The correlation of common carotid arterial diameter with atherosclerosis and diabetic retinopathy in patients with type 2 diabetes mellitus. AB - The clinical significance of the diameter of the common carotid artery (CCA) measured ultrasonographically in diabetic practice has not been sufficiently established. The objective of this study was to investigate the relationship of the ultrasonic CCA diameter with atherosclerotic measures and diabetic retinopathy as a microvascular complication in patients with type 2 diabetes mellitus (T2DM). This hospital-based cross-sectional study included 102 patients with T2DM (men: 65%, mean age: 57 years) who had no apparent carotid arterial stenosis and no history of cardiovascular or severe renal disease. The current smoking status, body mass index, blood pressure, hemoglobin A1c, serum low density lipoprotein cholesterol, and ultrasonic measures of carotid arteries (CCA diameter, intima-media thickness (IMT), plaque score) were measured. The cardio ankle vascular index (CAVI) and the presence of diabetic retinopathy were also assessed. The CCA diameter showed a significant positive correlation with the mean IMT or plaque score. The CAVI had a significant positive correlation with the mean IMT, plaque score, and CCA diameter, while diabetic retinopathy had a significant positive correlation with the CCA diameter, but not the mean IMT or plaque score. These results were unaltered after adjusting for multiple confounders. The CCA diameter may serve as a useful marker for atherosclerosis and diabetic retinopathy, and in particular, may be a marker associated with diabetic retinopathy more clearly than the carotid IMT and plaque score, in patients with T2DM. PMID- 21528432 TI - Lipid partitioning after uninephrectomy. AB - This longitudinal study addressed the sequential events and metabolic consequences of lipid partitioning following uninephrectomy. Adult male Sprague Dawley rats were randomized into sham operation (n = 15) or left uninephrectomy (UNX, n = 18). At 1 and 3 months post nephrectomy, three rats from each group were killed for histopathological examination of adipocyte differentiation and lipid accumulation. Renal protein expression of the lipogenic peroxisome proliferator-activated receptor-gamma (PPAR-gamma), HMG-CoA reductase (HMGCR), and adiponectin receptor was detected by Western blot and immunofluorescence microscopy. Blood lipids, glucose, insulin, and renal functions were longitudinally measured up to 10 months after operation. The UNX rats progressively developed lipodystrophy of subcutaneous and visceral adipose depots with failure of adipocyte differentiation and lipid storage, followed by blood lipid elevation and ectopic lipid deposition with cellular lipid peroxidation, and renal adipogenesis with chronic inflammatory infiltration. Despite having standard diet, normal food consumption and normal body weight, the uninephrectomized rats with defective lipid partitioning manifested a myriad of homeostatic disturbances including insulin resistance, hyperglycemia, adiponectin resistance, and upregulation of PPAR-gamma and HMGCR. Abnormal lipid partitioning from adipose depots to circulation and non-adipose tissues and non-adipocytic cells contributes to homeostatic disturbances and lipogenic activation. PMID- 21528434 TI - [Midcarpal fusion with the spider plate]. AB - OBJECTIVE: Pain relief while preserving wrist motion in advanced carpal collapse. INDICATIONS: Advanced carpal collapse stage II/III due to scaphoid non-union, scapholunate ligament tear, idiopathic radiocarpal osteoarthritis, aseptic osteonecrosis of the scaphoid (Preisser's disease). A relative indication is chronic midcarpal instability. CONTRAINDICATIONS: Osteoarthrisis of the lunate. Radiocarpal instability with ulnar translation of the wrist. SURGICAL TECHNIQUE: Dorsal curved incision between the 3rd and 4th dorsal extensor compartment. Partial wrist denervation (posterior interosseous nerve). Raising of a radial pedicled capsule flap. Complete extirpation of the scaphoid without fragmentation. Cartilage removal of all the joint facets for arthrodesis. Reduction of the lunate and temporary fixation with K wires between the triquetrum and capitate and the triquetrum and lunate. Milling the plate hole exactly in central position of the four carpal bones. The plate should not protrude from the bone to avoid impingement with the dorsal limb of the radius. Transferring of spongiosa harvested from the removed scaphoid into the arthrodesis gap. Fixation of the 8-hole plate with 2 screws in each of the four carpal bones. Fluoroscopy of the screw fitting. Control of the correct wrist articulation (motion test). Lavage of the wrist. Suture of the capsule flap. Redon drain, wound closure, dorsal splinting. POSTOPERATIVE MANAGEMENT: Dorsal splint for 3 weeks; finger mobilization up to complete fist closure starting on postoperative day 1. From week 4-6, active wrist motion, from week 7-10 with increasing load. Return to work after 11-12 weeks. CT scan in cases of delayed union, abnormal function, or persistence of pain. RESULTS: Between 2002 and 2008, 36 four-corner fusions (32 male, 4 female) with the spider plate were performed in 24 right and 12 left wrists. The mean age of the patients at surgery was 48 years (range 32-71 years). Follow-up examinations were performed in 11 patients. The Krimmer and Rudolf scores were determined: 1 excellent, 7 good, 2 satisfactory, and 1 poor result were found. The mean grip strength was 51% relative to the opposite wrist. The mean range of motion (ROM) for wrist extension/flexion was 56% of the opposite side. Wrist extension/flexion averaged 24/0/32 degrees and ulnar/radial deviation was on average 20/0/19 degrees . Pain during activity was on average 2.2 based on the visual analogue scale (0-10). One delayed bony union due to a screw breakage, which required total wrist fusion, was observed. PMID- 21528433 TI - Glycemic control and pregnancy outcomes in women with type 2 diabetes from Poland. The impact of pregnancy planning and a comparison with type 1 diabetes subjects. AB - The number of pregnancies complicated by type 2 diabetes mellitus (T2DM) is growing; however, their clinical characteristics remain incomplete. We aimed to assess clinical characteristics, glycemic control, and selected pregnancy outcomes in pregestational T2DM from Poland and to compare them with those of T1DM. We analyzed 415 consecutive singleton pregnancies; among them, there were 70 women with T2DM and 345 with T1DM. As compared to T1DM patients, women with T2DM were older (mean age 33.1 years vs. 27.8, respectively), heavier before pregnancy (mean BMI 30.8 kg/m2 vs. 23.9), and had a shorter duration of diabetes (mean 3.3 years vs. 11.4); ( P<0.0001 for all comparisons). The gestational age at the first visit was higher in T2DM (mean 11.4 weeks vs. 8.6; P=0.0004). Nevertheless, they had better glycemic control in the first trimester (mean HbA1c 6.2% vs. 7.0; P=0.003); in subsequent months, the differences in HbA1c were no longer significant. T2DM women gained less weight during pregnancy (mean 9.9 kgs vs. 14.1; P<0.0001). The proportion of miscarriages (10.0 vs. 7.3%; P=0.32), preterm deliveries (12.7 vs. 17.8%; P=0.32), combined infant deaths, and congenital malformations were similar in both groups (9.5 vs. 8.8%; P=0.4) as was the frequency of caesarean sections (58.7 vs. 64.1%; P=0.30). Macrosomic babies were more than twice less frequent in T2DM and the difference reached borderline significance (7.9 vs. 17.5%, P=0.07). Pregnancy planning in T2DM had a significant impact on HbA1c in the first trimester (5.7 vs. 6.4% in the planning vs. the not planning group, P=0.02); the difference was not significant in the second and third trimester. T2DM women had better glycemic control in the first trimester than T1DM subjects and gained less weight during pregnancy. This could have been the reason for the slightly lower number of macrosomic babies but did not affect other outcomes. In T2DM, pregnancy planning had a beneficial glycemic effect in the first trimester. PMID- 21528435 TI - Lifetime risk and age of onset distributions of psychiatric disorders: analysis of national sample survey in South Korea. AB - BACKGROUND: The present study represents the first attempt at examining variation across Korean cohorts with respect to lifetime risk of DSM-IV psychiatric disorders. AIMS: To present data on lifetime prevalence and projected lifetime risk, as well as age of onset (AOO) and demographic correlates of DSM-IV psychiatric disorders as assessed in the nationwide survey of a representative sample of Korean adults. METHOD: The survey was based on a multistage area probability sample of non-institutionalized Koreans aged 18-64 years. The Korean version of the Composite International Diagnostic Interview 2.1 (K-CIDI 2.1) was administered by lay interviewers. RESULTS: Lifetime prevalence of any disorder was 24.6%. Alcohol abuse (9.2%), alcohol dependence (7.0%), major depressive disorder (5.6%), specific phobia (3.8%), and GAD (1.6%) were the most common disorders. The median AOO was earliest for anxiety disorders (age 29), latest for mood disorders (age 47), and intermediate for alcohol use disorders (age 31). Compared to observed lifetime prevalence (24.6%), 35.0% of Koreans will eventually experience one of these disorders. Further, half of the population who present with a psychiatric disorder do so by the age of 32 and younger cohorts are at greater risk for most disorders. CONCLUSIONS: About one-third of the Korean adult population will meet the criteria for a DSM-IV psychiatric disorder at some time during their life. The median age of onset varies from disorder to disorder and younger cohorts appear to be at greater risk for most disorders. PMID- 21528436 TI - Are children improving? Results from outcome measurement in a large mental health system. AB - Standardized outcome assessment was implemented in a large county mental health system. This study examines changes in children's emotional and behavioral problems after 6 months of treatment and identifies factors associated with treatment improvement. Results from 3,215 youth indicated that externalizing and internalizing problems significantly decreased from intake to 6 months and that ethnicity, gender, and age were associated with caregiver-reported changes in symptomatology. While there was improvement associated with entry into treatment, the magnitude of symptom reduction was small to medium and not associated with amount of care, providing only limited support for the impact of routine out patient care. PMID- 21528437 TI - Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction. AB - NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are known to be involved in angiotensin II-induced hypertension and endothelial dysfunction. Several Nox isoforms are expressed in the vessel wall, among which Nox2 is especially abundant in the endothelium. Endothelial Nox2 levels rise during hypertension but little is known about the cell-specific role of endothelial Nox2 in vivo. To address this question, we generated transgenic mice with endothelial specific overexpression of Nox2 (Tg) and studied the effects on endothelial function and blood pressure. Tg had an about twofold increase in endothelial Nox2 levels which was accompanied by an increase in p22phox levels but no change in levels of other Nox isoforms or endothelial nitric oxide synthase (eNOS). Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates. Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine induced vasorelaxation. Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose. These results indicate that an increase in endothelial Nox2 levels contributes to angiotensin II-induced endothelial dysfunction, vascular remodeling and hypertension. PMID- 21528439 TI - [Abstracts of the 95th Annual Meeting of the German Society of Pathology. June 16 19, 2011. Leipzig, Germany]. PMID- 21528438 TI - Step-wise integration of single-port laparoscopic surgery into routine colorectal surgical practice by use of a surgical glove port. AB - INTRODUCTION: The cost associated with single-port laparoscopic access devices may limit utilisation of single-port laparoscopic surgery by colorectal surgeons. This paper describes a simple and cheap access modality that has facilitated the widespread adoption of single-port technology in our practice both as a stand alone procedure and as a useful adjunct to traditional multiport techniques. METHODS: A surgical glove port is constructed by applying a standard glove onto the rim of the wound protector/retractor used during laparoscopic resectional colorectal surgery. To illustrate its usefulness, we present our total experience to date and highlight a selection of patients presenting for a range of elective colorectal surgery procedures. RESULTS: The surgical glove port allowed successful completion of 25 single-port laparoscopic procedures (including laparoscopic adhesiolysis, ileo-rectal anastomosis, right hemicolectomy, total colectomy and low anterior resection) and has been used as an adjunct in over 80 additional multiport procedures (including refashioning of a colorectal anastomosis made after specimen extraction during a standard multiport laparoscopic anterior resection). CONCLUSIONS: This simple, efficient device can allow use of single-port laparoscopy in a broader spectrum of patients either in isolation or in combination with multiport surgery than may be otherwise possible for economic reasons. By separating issues of cost from utility, the usefulness of the technical advance inherent within single-port laparoscopy for colorectal surgery can be better appreciated. We endorse the creative innovation inherent in this approach as surgical practice continues to evolve for ever greater patient benefit. PMID- 21528440 TI - Genetics of prion disease. AB - Prion diseases or transmissible spongiform encephalopathies (TSEs) are neurodegenerative disorders of humans and animals for which there are no effective treatments or cure. They include Creutzfeldt-Jakob disease (CJD) in humans and sheep scrapie, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in cervids. The prion protein (PrP) is central to the disease process. An abnormal form of PrP is generally considered to be the sole or principal component of the infectious agent and a multimeric isomer (PrP(Sc)) is deposited in affected brains. Inherited prion diseases are caused by over 30 mutations in the prion protein gene (PRNP) and common polymorphisms can have a considerable affect on susceptibility and phenotype. Susceptibility and incubation time are also partly determined by other (non-PRNP) genetic modifiers. Understanding how these other genes modify prion diseases may lead to insights into biological mechanisms. Several approaches including human genome wide association studies (GWAS), mouse mapping and differential expression studies are now revealing some of these genes which include RARB (retinoic acid receptor beta), the E3 ubiquitin ligase HECTD2 and SPRN (Shadoo, shadow of prion protein gene). PMID- 21528441 TI - Electrorheological fluid and its applications in microfluidics. AB - Microfluidics is a low-cost technique for fast-diagnosis and microsynthesis. Within a decade it might become the foundation of point-of-care and lab-on-a-chip applications. With microfluidic chips, high-throughput sample screening and information processing are made possible. The picoliter droplet runs in microfluidic chips are ideal miniaturized vessels for microdetection and microsynthesis. Meanwhile, individual manipulation of microdroplets remains a challenge: the shortcomings in automatic, reliable, and scalable methods for logic control prevent further integration of microfluidic applications. The giant electrorheological fluid (GERF), which is a kind of "smart" colloid, has tunable viscosity under the influence of external electric field. Therefore, GERF is introduced as the active controlling medium, with real-time response in on-chip fluid control. This review article introduces the working principles and fabrication methods of different types of electrorheological fluid, and extensively describes the strategies of GERF-assisted microfluidic controlling schemes. PMID- 21528443 TI - Purification of native Argonaute complexes from the fission yeast Schizosaccharomyces pombe. AB - Small interfering (si) RNAs, produced by the RNA interference (RNAi)-mediated processing of long double-stranded (ds) RNAs, can inhibit gene expression by post transcriptional or transcriptional gene silencing mechanisms. At the heart of all small RNA-mediated silencing lies the key RNAi effector protein Argonaute, which once loaded with small RNAs can recognize its target transcript by siRNA-RNA Watson-Crick base pairing interactions. In the fission yeast Schizosaccharomyces pombe, the formation of the epigenetically heritable centromeric heterochromatin requires RNAi proteins including the sole fission yeast Argonaute homolog, Ago1. Two distinct native Ago1 complexes have been purified and studied extensively, both of which are required for siRNA production and heterochromatin formation at the fission yeast centromeres. The purification and analysis of the Argonaute siRNA chaperone (ARC) complex and RNA-induced transcriptional silencing (RITS) complex have provided insight into the mechanism of siRNA-Ago1 loading and the cis recruitment of silencing complexes at fission yeast centromeres, respectively. These discoveries have been instrumental in shaping the current models of RNA-mediated epigenetic silencing in eukaryotes. Below, we describe the protocol used for affinity purification of the native Ago1 complexes from S. pombe. PMID- 21528444 TI - Chromatin immunoprecipitation in fission yeast. AB - A tremendous amount of information regarding the nature and regulation of heterochromatin has emerged in the past 10 years. This rapid progress is largely due to the development of techniques such as chromatin immunoprecipitation or "ChIP," which allow analysis of chromatin structure. Further technological advances such as microarray analysis and, more recently, deep sequencing technologies, have made ChIP an even more powerful tool. ChIP allows the investigator to identify protein interactions and/or the presence of various chromatin modifications at specific genomic loci. PMID- 21528445 TI - Biochemical analyzes of endogenous argonaute complexes immunopurified with anti Argonaute monoclonal antibodies. AB - Argonaute proteins are key factors in RNA silencing. After association with small RNAs of 20-30 -nucleotides, Argonaute proteins are targeted to homologous RNA molecules that are to be silenced. To understand the functional contributions of Argonaute proteins to RNA silencing at a biochemical level, immunoisolation of Argonaute proteins from living cells of various organisms has been performed. This has enabled the analysis of Argonaute-associated proteins and RNAs. Identifying the small RNAs that associate with individual Argonaute proteins, for instance, could help to elucidate the silencing pathways in which particular Argonaute proteins are involved. However, it is also necessary to note that the results obtained through such biochemical analyzes are greatly affected by the quality and properties of the antibodies used, as well as by the immunoprecipitation conditions employed, including buffer contents and/or salt concentration. In this chapter, we describe fundamental methods for immunoprecipitating Argonaute proteins using monoclonal antibodies as well as for detecting associated proteins and small RNAs. Furthermore, we will also explain how various parameters, such as antibody properties and buffer conditions, can alter the production and interpretation of experimental data. PMID- 21528446 TI - Mapping of Ago2-GW182 functional interactions. AB - MicroRNA (miRNA)-mediated posttranscriptional regulation of gene expression has become a major focus in understanding fine-tuning controls in many biological processes. Argonaute 2 protein (Ago2), a core component of RNA-induced silencing complex, directly binds miRNA and functions in both RNAi and miRNA pathways. GW182 is a marker protein of GW bodies (GWB, also known as mammalian P-bodies) and is known to bind the Ago2 protein. This Ago2-GW182 interaction is crucial for Ago2-miRNA-mediated translational silencing as well as the recruitment of Ago2 into GWB. Translational silencing of tethered Ago2 to a 3'UTR reporter requires GW182 for function, whereas tethered GW182 exerts a stronger repression than tethered Ago2 and does not apparently require Ago2. This chapter describes in detail the methods used in mapping Ago2-GW182 interactions. PMID- 21528447 TI - Continuous density gradients to study Argonaute and GW182 complexes associated with the endocytic pathway. AB - Most complexes involved in RNA silencing were thought to be concentrated in cytoplasmic sites called P-bodies in the absence of stress. Accumulating evidence suggests that distinct cellular organelles or sites may be involved in the maturation of RNA-induced silencing complexes (RISC), decapping and deadenylation of miRNA-repressed mRNA, transport of translationally repressed mRNA, and disassembly of RISC complexes. Significant fractions of proteins essential for RNA silencing associate with membranes in general (GW182, AGO, and DICER), or more specifically with endoplasmic reticulum and Golgi (AGO), or endosomes and multivesicular bodies (AGO, GW182). In contrast, mRNA decapping and decay occur mainly in the cytoplasm. Continuous density gradients capable of partitioning these cellular compartments are valuable tools in efforts to decipher the complexes, trafficking and regulation of RISC throughout its biogenesis, action and turnover. PMID- 21528448 TI - In vitro RISC cleavage assay. AB - RNA interference (RNAi) is a widely used tool for the analysis of gene expression. In this process, short-interfering RNAs (siRNAs) guide the RNA induced silencing complex (RISC) to complementary target RNA molecules, which are sequence-specifically cleaved by the RISC. In vitro cleavage assays have proved to be powerful tools for the characterization of the RNAi pathway in many different organisms. Therefore, this chapter provides a detailed protocol for in vitro RISC assays. PMID- 21528449 TI - Native gel analysis for RISC assembly. AB - Small-interfering RNAs (siRNAs) and microRNAs (miRNAs) regulate expression of their target mRNAs via the RNA-induced silencing complex (RISC). A core component of RISC is the Argonaute (Ago) protein, which dictates the RISC function. In Drosophila, miRNAs and siRNAs are generally loaded into Ago1-containing RISC (Ago1-RISC) and Ago2-containing RISC (Ago2-RISC), respectively. We developed a native agarose gel system to directly detect Ago1-RISC, Ago2-RISC, and their precursor complexes. Methods presented here will provide powerful tools to biochemically dissect the RISC assembly pathways. PMID- 21528450 TI - Purification and assembly of human Argonaute, Dicer, and TRBP complexes. AB - The RNA-induced silencing complex (RISC) is a programmable gene-silencing machine involved in many aspects of eukaryotic biology. In humans, RISC is programmed or "loaded" with a small-guide RNA by the action of a tri-molecular assembly termed the RISC-loading complex (RLC). The human RLC is composed of the proteins Dicer, TRBP, and Argonaute2 (Ago2). To facilitate structural and biochemical dissection of the RISC-loading process, we have developed a system for the in vitro reconstitution of the human RLC. Here, we describe in detail methods for the expression and purification of recombinant Dicer, TRBP, and Ago2 and protocols for the assembly of RLCs and RLC subcomplexes. We also describe several simple assays to observe the biochemical activities of the assembled protein complexes. PMID- 21528452 TI - Imaging the cellular dynamics of Drosophila Argonaute proteins. AB - Drosophila melanogaster is used extensively as a model system to uncover genetic and molecular pathways that regulate various cellular activities. There are five members of the Argonaute protein family in Drosophila. Argonautes have been found to be localized to cytoplasmic ribonucleoprotein containing structures in both cultured Drosophila cells and developing embryos. However, in fixed cell preparations some Drosophila Argonaute family proteins co-localize with structures containing known as RNA processing (P) body components while others do not. The ability to image Argonaute family proteins in live Drosophila cells, (both cultured and within developing embryos) allows for accurate genetic dissection of the pathways involved in the assembly, mobility, disassembly, and other dynamic processes of Argonaute-containing bodies. Here we describe a method of rapidly creating vectors for, and assay the activity of, fluorescently tagged Argonaute proteins in cultured Drosophila cells and embryos. PMID- 21528453 TI - Live cell imaging of Argonaute proteins in mammalian cells. AB - The central effector of mammalian RNA interference (RNAi) is the RNA-induced silencing complex (RISC). Proteins of the Argonaute family are the core components of RISC. Recent work from multiple laboratories has shown that Argonaute family members are associated with at least two types of cytoplasmic RNA granules: GW/Processing bodies and stress granules. These Argonaute containing granules harbor proteins that function in mRNA degradation and translational repression in response to stress. The known role of Argonaute proteins in miRNA-mediated translational repression and siRNA-directed mRNA cleavage (i.e., Argonaute 2) has prompted speculation that the association of Argonautes with these granules may reflect the activity of RNAi in vivo. Accordingly, studying the dynamic association between Argonautes and RNA granules in living cells will undoubtedly provide insight into the regulatory mechanisms of RNA-based silencing. This chapter describes a method for imaging fluorescently tagged Argonaute proteins in living mammalian cells using spinning disk confocal microscopy. PMID- 21528451 TI - Detection of human Dicer and Argonaute 2 catalytic activity. AB - The microRNA (miRNA)-guided RNA silencing pathway is a central and well-defined cellular process involved in messenger RNA (mRNA) translational control. This complex regulatory process is achieved by a well orchestrated machinery composed of a relatively few protein components, among which the ribonuclease III (RNase III) Dicer and Argonaute 2 (Ago2) play a central role. These two proteins are essential and it is of particular interest to measure and detect their catalytic activity under various situations and/or conditions. In this chapter, we describe different protocols that aim to study and determine the catalytic activity of Dicer and Ago2 in cell extracts, immune complexes, and size-fractionated cell extracts. Another protocol aimed at assessing miRNA binding to Ago2 is also described. These experimental approaches are likely to be useful to researchers investigating the main steps of miRNA biogenesis and function in human health and diseases. PMID- 21528454 TI - Reporter-based assays for analyzing RNA interference in mammalian cells. AB - RNA interference (RNAi) is a process whereby small RNAs serve as effectors to direct posttranscriptional regulation of gene expression. The effector small RNAs can arise from various sources including plasmids that express short-hairpin RNAs (shRNAs) or microRNA (miRNAs), or alternatively, from synthetic small-interfering RNAs (siRNAs). These small RNAs enter a protein complex that binds directly to mRNA targets and this results in transcript-specific inhibition of protein expression. Though the key core components of the mammalian RNAi processing and effector complexes have been identified, accessory and regulatory factors are less well-defined. Reporter assays that can quantitatively assess RNAi activity can be used to identify modulators of RNAi. We present two methods to quantitatively analyze RNAi activity that have overlapping and distinct utility. The first method uses an eGFP reporter in transiently transfected cells to identify RNAi modulators. The second method uses cells that express luciferase based reporters in a stable fashion. This assay can easily be conducted in 96 well plate format. Both methods can be used to identify novel proteins or small molecules that modulate RNAi activity. PMID- 21528455 TI - Artificial tethering of Argonaute proteins for studying their role in translational repression of target mRNAs. AB - Small RNAs such as microRNAs (miRNAs) and small-interfering RNAs (siRNAs) associate with members of the RNA-binding Argonaute family proteins. Together they participate in transcriptional and posttranscriptional gene silencing mechanisms. The fate of the target mRNA is determined, in part, by the degree of complementarity with the small RNA. To examine the exact role of the Argonaute protein in the silencing complex, human Argonautes were artificially recruited to reporter mRNAs in a small RNA-independent manner by the BoxB-N-peptide tethering system. Tethering of Argonaute proteins to a reporter mRNA leads to the inhibition of translation, mimicking the repression seen with miRNAs. Similar tethering experiments were performed with fly and fission yeast Argonaute proteins and other components of the small RNP (ribonucleoprotein) complex, uncovering their specific roles in the silencing complexes containing them. PMID- 21528456 TI - An efficient system for let-7 microRNA and GW182 protein-mediated deadenylation in vitro. AB - Experiments with cell cultures have been useful in analyzing microRNA action. However, miRNA-mediated effects are often assayed many hours or days after miRNA target recognition. Consequently, this has made it difficult to analyze early events of miRNA-mediated repression. The development of cell-free systems that recapitulate miRNA action in vitro has been instrumental in dissecting the molecular mechanisms of miRNA action. Here we describe such a system, derived from mouse Krebs II ascites carcinoma cells, termed Krebs cell-free system. As an example, the protocol for assaying let-7 and GW182 (TNRC6) protein-mediated deadenylation of mRNA in vitro is described. PMID- 21528457 TI - Cell-free microRNA-mediated translation repression in Caenorhabditis elegans. AB - In vitro recapitulation has recently led to significant advances in the understanding of the molecular functions of microRNAs. Cell-free systems allow a direct perspective on the different steps involved, and provide the experimenter with the opportunity to directly interfere with, or alter the implicated factors. In this chapter, we describe a cell-free translation system based on Caenorhabditis elegans embryo, which faithfully recapitulates miRNA-mediated translation repression. Because of the genetic and transgenic flexibility of this animal model, such a system provides a unique experimental resource to study the mechanism and the functions of miRNAs, the Argonautes, and the RISC. PMID- 21528458 TI - Argonaute pull-down and RISC analysis using 2'-O-methylated oligonucleotides affinity matrices. AB - During the last decade, several novel small non-coding RNA pathways have been unveiled, which reach out to many biological processes. Common to all these pathways is the binding of a small RNA molecule to a protein member of the Argonaute family, which forms a minimal core complex called the RNA-induced silencing complex or RISC. The RISC targets mRNAs in a sequence-specific manner, either to induce mRNA cleavage through the intrinsic activity of the Argonaute protein or to abrogate protein synthesis by a mechanism that is still under investigation. We describe here, in details, a method for the affinity chromatography of the let-7 RISC starting from extracts of the nematode Caenorhabditis elegans. Our method exploits the sequence specificity of the RISC and makes use of biotinylated and 2'-O-methylated oligonucleotides to trap and pull-down small RNAs and their associated proteins. Importantly, this technique may easily be adapted to target other small RNAs expressed in different cell types or model organisms. This method provides a useful strategy to identify the proteins associated with the RISC, and hence gain insight in the functions of small RNAs. PMID- 21528459 TI - Cloning Argonaute-associated small RNAs from Caenorhabditis elegans. AB - Small RNA pathways fulfill a plethora of gene-regulatory functions in a variety of organisms. In the nematode worm, Caenorhabditis elegans, a number of endogenous small RNA pathways have been described, including the microRNA pathway, the 21U/piRNA pathway, the 26G-RNA pathways, and the 22G-RNA pathways. Argonaute proteins are key effector molecules of each pathway that, together with their small RNA cofactors regulate various processes including developmental timing, fertility, transposon silencing, and chromosome segregation. Although several of the 26 Argonautes in the worm have been studied to date, a number have yet to be fully characterized or their small RNA binding complement defined. The identification of small RNAs that copurify with an Argonaute family member is central to understanding the targets and assessing the function of that Argonaute. Here we discuss the rationale for generating reagents to immunoprecipitate Argonaute complexes and provide a cohesive protocol for the cloning and Illumina deep-sequencing of Argonaute-associated small RNAs in C. elegans. PMID- 21528460 TI - Immunoprecipitation of piRNPs and directional, next generation sequencing of piRNAs. AB - Piwi interacting RNAs (piRNAs) are small (~25 to ~30 nucleotide) and are expressed in the germline. piRNAs bind to the Piwi subclade of Argonaute proteins and form the core ribonucleoproteins (RNPs) of piRNPs. We describe a method for the massive identification of piRNAs from immunopurified piRNPs. This strategy may also be used for immunopurification and directional sequencing of RNAs from other RNPs that contain small RNAs. PMID- 21528462 TI - Whole cell proteome regulation by microRNAs captured in a pulsed SILAC mass spectrometry approach. AB - Since gene expression is controlled on many different levels in a cell, capturing a comprehensive snapshot of all regulatory processes is a difficult task. One possibility to monitor effective changes within a cell is to directly quantify changes in protein synthesis, which reflects the accumulative impact of regulatory mechanisms on gene expression. Pulsed stable isotope labeling by amino acids in cell culture (pSILAC) has been shown to be a viable method to investigate de novo protein synthesis on a proteome-wide scale (Schwanhausser et al., Proteomics 9:205-209, 2009; Selbach et al., Nature 455:58-63, 2008). One application of pSILAC is to study the regulation of protein expression by microRNAs. Here, we describe how pSILAC in conjunction with shotgun mass spectrometry can assess differences in the protein profile between cells transfected with a microRNA and non-transfected cells. PMID- 21528461 TI - Generation of an inducible mouse ES cell lines deficient for Argonaute proteins. AB - Argonautes (Agos) are core effectors of RNA silencing. In several nonmammalian organisms, multiple Agos are known to exhibit specialized functions for distinct RNA silencing pathway. Mammals have four closely related Agos. To examine the functions of mammalian Agos in the microRNA silencing pathway, we generated mouse embryonic stem (ES) cells that are nullizygous for all Agos. This chapter describes a variety of techniques including BAC recombineering, gene targeting, and inducible Cre-loxP recombination, used to generate inducible Ago knock-out ES cells. The Ago-deficient ES cells provide an important tool for the study of mammalian RNA silencing. PMID- 21528463 TI - Gender-related ADL performance of old people recently admitted to a Swiss nursing home. A cross-sectional study. AB - QUESTIONS UNDER STUDY: The aim of this paper was to establish gender-specific associations between the characteristics of residents recently admitted to Swiss nursing homes (NH) and their activities of daily living (ADL) performance. METHODS: A sample of 17'331 NH residents living in 90 Swiss NHs received a Resident Assessment Instrument Minimum Data Set (RAI-MDS) shortly after NH entry, in the period from 1997 to 2007. ADL performance was assessed using the MDS-ADL long-form scale that measures self-performance in the seven following tasks: bed mobility, transfer, locomotion, dressing, eating, toilet use and personal hygiene. Associations between ADL performance and health and personal characteristics of the residents were then investigated using bivariate and multivariate analyses. RESULTS: A total of 40% of the residents recently admitted to Swiss NHs were completely dependent for ADL. Absence of physical activity and having been admitted to a NH before 2003 were gender-specific variables associated with poorer ADL. Incontinence, poor balance, impaired cognition and vision as well as low BMI were important factors associated with poorer ADL performance in both genders. CONCLUSION: The general scheme of ADL impairment was quite similar for both genders, but females tended to do slightly but significantly better than males. Overall, strategies improving balance, continence, cognition and sensory function including treatment of vision impairment, promoting healthy nutrition as well as physical activity- particularly among elderly women with musculoskeletal conditions--may facilitate care in recently admitted residents and/or delay NH admission. PMID- 21528464 TI - Accuracy of serum LDH elevation for the diagnosis of Pneumocystis jiroveci pneumonia. AB - In 328 immunocompromised patients, 105 with and 193 without Pneumocystis jiroveci pneumonia (PCP), serum lactate dehydrogenase (LDH) was analysed retrospectively, taking into consideration the time interval from the onset of symptoms to the start of specific therapy. 97 of the 105 PCP patients were negative for human immunodeficiency virus (HIV). Eight were positive. Of the 193 patients without PCP 134 were HIV-negative and 59 were HIV-positive. In HIV-negative patients the sensitivity of LDH elevation was 63% and specificity 43%. In HIV-positive patients sensitivity was 100% and specificity 47%. The overall accuracy of LDH for the diagnosis of PCP was 52%, 51% in HIV-negative and 58% in HIV-positive patients. Except for its sensitivity in HIV-positive patients, the value of LDH for the diagnosis of PCP should not be overestimated. PMID- 21528465 TI - Are immigrant children admitted to intensive care at increased risk? AB - BACKGROUND: Racial and ethnic disparities in health care are significant predictors of the quality of health care received. Studies documenting these disparities are largely based on an adult chronic care model. There are only few reports in paediatric populations. Our objective was to evaluate the severity of illness of immigrants at admission to PICU, the proportion of immigrants in PICU compared to the general population and the quality of care they receive, in order to examine whether there are disparities in health care. METHODS: Prospectively collected data of 1009 sequential first admissions in 2007 to a multidisciplinary, 19-bed, PICU of a university children's hospital in Switzerland. The main outcome measures were expected mortality, standardised mortality ratio, proportion of immigrants in general population and in PICU. RESULTS: Children with an immigrant background are overrepresented in PICU compared with their proportion in the general population. Parents of these children are more likely to be in the lowest strata of socio-professional status than parents of Swiss children hospitalised in PICU (relative risk 9.82, 95% CI 5.16 to 18.7). However, the distribution of immigrant children and Swiss children along the strata of illness severity is equal and there is no difference in standardised mortality ratio between these two groups. CONCLUSIONS: These findings indicate that disparities may exist at a lower level of illness severity, due to many possible reasons (for example shortcomings in primary health care). However, once a child enters tertiary health care, nationality and socio-economic factors no longer influence quality of health care delivery. PMID- 21528466 TI - Mannan-binding lectin (MBL) and MBL-associated serine protease-2 in children with cancer. AB - QUESTIONS UNDER STUDY: Mannan-binding lectin (MBL) and MBL-associated serine protease-2 (MASP-2) are two key components of the lectin-pathway of complement activation. Information on the potential role of lectin-pathway components in carcinogenesis versus immune surveillance of cancer is scarce. This study aimed to determine if serum concentrations of MBL and MASP-2 differ between children with cancer and healthy age-matched controls. METHODS: In this retrospective multicentre study, MBL and MASP-2 were measured by commercially available ELISA in frozen remnants of serum taken at diagnosis in paediatric patients with cancer. For six diagnostic groups, these concentrations were compared with serum concentrations of age-matched healthy controls using exact Wilcoxon signed-rank tests. RESULTS: MBL and MASP-2 were measured in serum of 372 patients. MBL was significantly higher in patients with solid tumours vs. controls (median, 2,799 vs. 1,917 MUg/L; P = 0.008), and MASP-2 was significantly higher in patients with acute lymphoblastic leukaemia (406 vs. 317 MUg/L; P = 0.009), Non-Hodgkin lymphoma (361 vs. 293 MUg/L; P = 0.037) and CNS tumors (463 vs. 296 MUg/L; P = 0.002). CONCLUSIONS: These results may indicate a role of MBL and MASP-2 in the initiation or progression of specific paediatric cancers, while other mechanisms remain possible as well. Larger, disease-specific studies are warranted for confirmation and for elucidation of the underlying mechanisms. PMID- 21528467 TI - [MR imaging of the Achilles tendon: evaluation of criteria for the differentiation of asymptomatic and symptomatic tendons]. AB - PURPOSE: The purpose of this study was to develop quantitative and qualitative MRI criteria to differentiate between healthy and pathological Achilles tendons. MATERIALS AND METHODS: 364 Achilles tendons were examined on a 1.5 T MRI scanner. 264 patients had Achilles tendon complaints, 100 asymptomatic Achilles tendons served as a control. T 1-weighted, T 2-weighted and a STIR sequence were performed in sagittal and axial orientation. Images were evaluated in consensus by two radiologists. Quantitative and qualitative criteria were assessed. A Mann Whitney-U-Test and a regression analysis were used for statistical analysis. RESULTS: There were statistically significant differences between the patients with disorders and the control group concerning the depth (12.0 mm and 6.3 mm, p < 0.001) and length (83.2 mm and 45.9 mm, p < 0.001) of the tendon, the area of the tendon cross section (1.60 mm (2) and 061 mm (2), p < 0.001), as well as the length of the bursa retrocalcanea (8.3 mm and 5.3 mm, p < 0.001). There was a sensitivity of 97 % and a specificity of 91 % using a formula including the 3 criteria: tendon depth (A4), length of bursa (A5) and area of tendon (F). CONCLUSION: The measurement of the Achilles tendon and the binary-logistic regression analysis allow differentiation between normal and pathological Achilles tendons. PMID- 21528468 TI - [Modfied technique for intramedullary femur nail removal]. AB - BACKGROUND: The indication of implant removal of intramedullary nails is a subject of much discussion. The main concern is the increased morbidity of the preparation of the proximal nail end which can cause postoperative discomfort. The aim of the present study was to develop a soft-tissue protecting extraction technique and to evaluate it in comparison to the standard procedure. MATERIAL AND METHODS: With the modified technique the proximal end of the nail is preparated by a guidewire and the standard reamer used for implantation. This allows a soft-tissue protection with reduced morbidity, especially in patients with ossification. The outcome was assessed 4-20 weeks postoperatively and the operation times compared with those of 10 patients operated with the conventional technique. RESULTS: From 5/09 to 12/10 we treated 9 patients with the mentioned technique. The operation time was reduced from a mean of 74.8 minutes to 32.0 minutes. Eight of nine patients had reduced or no discomfort postoperatively. Eight of nine patients stated that they had a benefit from the operation. CONCLUSION: The modified operation technique is capable of reducing operation time and morbidity in the implant removal of intramedullary nails. PMID- 21528469 TI - Aortic arch repair: let it beat! AB - Objective aortic arch repair (AAR) on the beating heart may reduce cross-clamping times and offer improved postoperative cardiac function.Methods A single-center review of all patients (n = 24) who underwent surgical AAR during biventricular repair between 01/2006 and 01/2008 was done. All patients were operated on under cardiopulmonary bypass (CPB) with antegrade cerebral perfusion (ACP). During AAR, 13 patients (group 1) received cardioplegic arrest, and were compared to 11 patients (group 2) who underwent a beating-heart modification with selective myocardial perfusion. Seventeen patients had additional intracardiac lesions and underwent simultaneous correction during the procedure.Results Durations of CPB, AAR and ACP did not differ statistically between groups. Cardioplegic arrest time was significantly lower in group 1 (34 +/- 13 vs. 76 +/- 11 min, p = 0.02) and resulted in a subsequent reduction of myocardial ischemic damage as borne out by lower postoperative levels of troponin T and CK-MB (2.5 +/- 0.7 vs. 7.1 +/- 1.4 ng/mL, p = 0.02; 68.7 +/- 11.5 vs. 149.1 +/- 27.2 U/l, p = 0.03). We observed an enhanced patient recovery with shorter inotropic and ventilatory support times (p < 0.05).Conclusion Pediatric aortic arch correction on a CPB beating heart with selective myocardial perfusion is technically feasible and safe. The reduction of the myocardial ischemic time is effective and results in less myocardial damage. PMID- 21528470 TI - Comparison between Sequential Organ Failure Assessment score (SOFA) and Cardiac Surgery Score (CASUS) for mortality prediction after cardiac surgery. AB - BACKGROUND: Our purpose was to evaluate and compare the accuracy of the "Sequential Organ Failure Assessment" score (SOFA) and the "Cardiac Surgery Score" (CASUS) for the prediction of mortality after cardiac surgery. METHODS: Between January 1, 2007 and December 31, 2008 we prospectively included all consecutive adult patients admitted to our intensive care unit (ICU) after cardiac surgery. Both scoring systems were calculated daily from the 1st day in the ICU (day of operation) until the 7th ICU day. We evaluated the ICU mortality prediction of both models using calibration and discrimination statistics. RESULTS: 2801 patients (29.6% females) were included. Mean age was 66.9 +/- 10.7 years. Intensive care unit mortality was 5.2%. The calibration of the "Sequential Organ Failure Assessment Score" and "Cardiac Surgery Score" was reliable for all days (p >= 0.05). CASUS was more accurate in predicting survival and mortality compared to SOFA for all days, as evidenced by the larger areas under the Receiver Operating Characteristic curves. CONCLUSIONS: Both CASUS and SOFA are reliable mortality prediction tools after cardiac surgery. However, CASUS was more accurate in predicting the individual patient's risk of mortality. Thus, use of the CASUS in cardiac surgery intensive care units is recommended. PMID- 21528471 TI - Are metabolic syndrome and its components in obese children influenced by the overweight status or the insulin resistance? AB - INTRODUCTION: The aim of this study was to determine which factors increase the risk of metabolic syndrome (MS) and its components in obese children and adolescents. MATERIAL AND METHODS: In 78 obese children (42 girls, 36 boys), mean age 14.6 +/- 3.5 years, blood pressure, total cholesterol, triglycerides, HDL cholesterol (HDL), insulin and glucose at fasting state as well as in OGTT were measured. Body mass index (BMI) Z-score, LDLcholesterol, and insulin resistance indices (FIGR, R-HOMA) were calculated. RESULTS: Metabolic syndrome was diagnosed in ten (12.8%) children. Hyperinsulinaemia was present in 42 (53.8%) subjects, increased FIGR in eight (10.3%) and increased R-HOMA in 49 (62.3%). Significant correlations between BMI Z-score >= 2.5 and MS occurrence and its components (hypertriglyceridaemia, isolated systolic and diastolic hypertension) were found. Hypertriglyceridaemia, low HDL and hypertension, as well as MS occurrence, correlated significantly with stimulated hyperinsulinaemia and increased FIGR. Risk of hypertension was increased 5.6 times by fasting hyperinsulinaemia. Stimulated hyperinsulinaemia increased the risk of hypertriglyceridaemia 3.7 times, risk of low HDL 14.4 times and risk of MS 10.3 times. These risks did not change significantly when adjusted for BMI Z-score. CONCLUSIONS: Our study results show that both BMI Z-score and OGTT stimulated hyperinsulinaemia are good predictors of MS occurrence in obese children and adolescents. The risk of dyslipidaemia and hypertension increase significantly with hyperinsulinaemia and insulin resistance, with low HDL cholesterol being the most affected. PMID- 21528472 TI - Impact of vertical banded gastroplasty on body weight, insulin resistance, adipocytokine, inflammation and metabolic syndrome markers in morbidly obese patients. AB - INTRODUCTION: Diet, exercise, and pharmacological therapy have been shown to be unsatisfactory treatments for severe obesity in the long term. Bariatric surgery is the most effective means to achieve weight loss in morbidly obese subjects. The aim of this study was to evaluate the action of a number of adipocytokines, as well as the metabolic syndrome parameters of obese patients, before and after vertical banded gastroplasty (VBG). MATERIAL AND METHODS: The test subjects comprised eight males and 20 females (total 28 patients) aged from 20 to 59 years (43.7 +/- 10.0) with simple obesity and the presence of metabolic syndrome, both before and 3, 6, 12, and 24 months after bariatric surgery (six patients were also checked after 36 and 48 months). RESULTS: After surgical treatment (at 24 months), the values of body weight, BMI, waist circumference, blood pressure (RR S, RR-D), HOMA-IR and blood concentrations of CRP, TG, IRI, AUC-IRI, and AUC-GLU gradually decreased. We did not observe any significant differences of fasting glucose, leptin, total cholesterol and LDL-cholesterol concentrations before or after surgery. The blood levels of HDL, adiponectin, resistin, and ghrelin gradually increased after treatment. CONCLUSIONS: The significant decrease of body weight after vertical banded gastroplasty, as well as improvement of the main metabolic syndrome parameters and some adipocytokine blood levels, indicate the use of bariatric surgery as a valuable method of treating morbidly obese patients. PMID- 21528473 TI - The utility of the gonadotrophin releasing hormone (GnRH) test in the diagnosis of polycystic ovary syndrome (PCOS). AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is characterised by increased frequency of hypothalamic GnRH pulses leading to a relative increase in LH synthesis by the pituitary. As GnRH stimulation can reveal a relative LH excess, we have endeavoured to assess whether GnRH test might be useful in the diagnosis of PCOS. MATERIAL AND METHODS: The study involved 185 subjects: a PCOS group, n = 151, all with oligo- or amenorrhoea, aged (mean +/- SD) 24.8 +/- +/- 5.4 years, BMI 24.5 +/- 6.0 kg/m2; and regularly menstruating controls, n = 34, aged 26.6 +/ 5.0 years, BMI 24.6 +/- 5.5 kg/m2. In 121 subjects with PCOS and in 32 controls, serum LH and FSH were measured before (0 minutes) and 30 and 60 minutes after GnRH stimulation (100 MUg i.v.). Insulin resistance was assessed by HOMA and Insulin Resistance Index derived from glucose and insulin concentrations during 75 gram oral glucose tolerance test. RESULTS: Women with PCOS had higher testosterone (p = 0.0002), androstendione (p = 0.0021), 17OH-progesterone (p < 0.0001) and were more insulin resistant. Raised concentrations of at least one androgen were, however, found only in 58.1% of women with PCOS. Baseline and stimulated LH concentrations were higher in PCOS (9.09 +/- 5.56 vs 4.83 +/- 1.71 IU/L, 35.48 +/- 31.4 vs 16.30 +/- 6.68 IU/L, 33.86 +/- 31.8 vs 13.45 +/- 5.2 IU/L, at 0, 30 and 60 mins post GnRH, respectively, p < 0.0001). There was no difference in baseline or stimulated FSH concentrations between groups. Relative increases of LH or FSH in comparison to respective baseline values were similar in both groups. There was, however, a marked increase in LH/FSH ratio in PCOS in comparison to controls (LH0 min/FSH(0 min) 1.59 +/- 0.95 vs 0.76 +/- 0.2, LH(30 min) /FSH(30 min) 4.07 +/- 3.0 vs 1.89 +/- 0.79, LH(60 min)/FSH(60 min) 3.56 +/- 2.58 vs 1.55 +/- 0.63, p < 0.0001 at all time points). Further analysis revealed that LH30 min/FSH(30 min) > 2.11 or LH(60 min)/FSH(60 min) > 1.72 had 78.3% and 87.5% sensitivity and 81.7% and 81.3% specificity for the diagnosis of PCOS, respectively. CONCLUSIONS: Women with PCOS have higher baseline and GnRH stimulated LH concentrations. GnRH stimulation results in an increase in LH/FSH ratio in women with PCOS. Therefore we postulate that this phenomenon might be potentially useful as an additional tool in the diagnosis of PCOS. PMID- 21528475 TI - Association between environmental factors and risk of type 1 diabetes - a case control study. AB - INTRODUCTION: While many studies support the theory that environmental factors play a role in the development of type 1 diabetes mellitus (T1DM), controversy exists as to the contribution of any individual factor. The aim of the present study was therefore to investigate the associations of T1DM with several environmental factors. MATERIAL AND METHODS: A case-control study was conducted on children L 16 years old who were diagnosed with T1DM and healthy age and sex matched controls. Data regarding the socio-demographic status, gestational and neonatal risk factors were evaluated. RESULTS: One hundred and one children with T1DM (41 males and 60 females), and the same number of age- and sex-matched controls, were included in the present study (mean age 10.3 +/- 4.5 years). On multivariable logistic regression analysis, maternal age > 35 years at delivery, duration of > 6 months of cow milk feeding, lack of vitamin D supplementation and caesarean delivery were significantly associated with diabetes. CONCLUSION: In the present case-control study, certain environmental risk factors were associated with the development of T1DM. PMID- 21528474 TI - Hormonal abnormalities in first-degree relatives of women with polycystic ovary syndrome (PCOS). AB - INTRODUCTION: A body of evidence points to a familial aggregation of hormonal abnormalities in first-degree relatives of women with polycystic ovary syndrome (PCOS). The aim of this study was to determine whether siblings of women with PCOS had evidence of hormonal abnormalities typical of PCOS. MATERIAL AND METHODS: Eighty-six siblings of women with PCOS (44 sisters, 42 brothers) were recruited. Two control groups consisted of 70 healthy women and 30 healthy men. Anthropometric, hormonal (testosterone, androstenedione, DHEA-S, LH, FSH) parameters and SHBG were assessed in all subjects. RESULTS: Mean testosterone and DHEA-S levels were higher in sisters of women with PCOS than in the control women. In eight of the 44 (18.2%) sisters, a diagnosis of PCOS was made. Mean testosterone and androstenedione levels, and free androgen index (FAI) were significantly higher in sisters with PCOS compared to the sisters without PCOS. Brothers of women with PCOS had higher DHEA-S level than the control men. Eleven of the 42 (26.2%) brothers had alopecia occurring before the age of 30. Prematurely balding brothers did not differ from the non-balding brothers in hormonal parameters. CONCLUSIONS: Siblings of women with PCOS are predisposed to hormonal abnormalities typical of PCOS. The symptom of premature balding under the age of 30 in brothers of women with PCOS should not be considered as a male PCOS equivalent. PMID- 21528476 TI - Involvement of the auditory organ in type 1 diabetes mellitus. AB - INTRODUCTION: The aim of this study was to evaluate auditory organ function in relatively young type 1 diabetic patients, with short duration of the disease and without overt hearing loss. The impact of age, diabetes duration and metabolic control on hearing function was also analysed. MATERIAL AND METHODS: Thirty-one patients with type 1 diabetes, aged below 45 years (mean 29.1 +/- 7.1 years), with diabetes duration of less than 120 months (mean 54.7 +/- 32.5 months), and no evident hearing impairment, were compared to 26 age-matched (30.3 +/- 7.8 years, p = 0.567) healthy volunteers. In all subjects, pure-tone audiometry, transient evoked otoacoustic emissions (TEOAE), and auditory brainstem responses (ABR) were performed, after an ENT examination. RESULTS: In diabetic patients, compared to healthy subjects, the mean hearing threshold in the pure-tone audiometry was significantly higher at high frequencies, the mean amplitude of TEOAE was lower (7.75 +/- 4.43 dB v. 10.00 +/- 4.01 dB, p < 0.001), and latency times of wave V and interval I-V in ABR were longer (5.78 +/- 0.25 ms v. 5.69 +/- 0.18 ms, p = 0.025 and 4.03 +/- 0.20 ms v. 3.95 +/- 0.17 ms, p = 0.017 respectively). In the diabetic group, the hearing threshold showed positive linear correlation with age, whereas TEOAE was inversely correlated with this parameter. In ABR latency, times of wave V and interval I-V were negatively correlated with diabetes duration. CONCLUSIONS: This study confirms the involvement of the auditory organ in type 1 diabetes mellitus. To determine the prognostic and predictive values of this finding, and methods of possible prevention of hearing loss, further prospective observations are required. PMID- 21528477 TI - The effect of nutritional habits and addictions on the incidence of thyroid carcinoma in the Olsztyn province of Poland. AB - INTRODUCTION: The aim of this study was to investigate the roles of nutritional habits and addictions in the incidence of thyroid carcinoma. MATERIAL AND METHODS: The study of risk factors affecting the incidence of thyroid carcinoma was conducted in patients included in a register of thyroid carcinoma. For that purpose, a questionnaire was prepared. The questionnaire covered: personal information, medical history, individual risk factors of thyroid carcinoma such as nutritional habits, alcohol consumption and smoking. Statistical analysis was conducted. RESULTS: The register comprised 297 patients with thyroid carcinoma (89% women) and 589 healthy subjects. 46% of patients declared frequent consumption of milk and dairy products. The patients with thyroid carcinoma consumed cruciferous plants significantly more often than healthy subjects (p = 0.0001) whereas egg consumption among both groups of patients was similar. Low consumption of fish and average table salt consumption was typical of both groups. Alcohol consumption was similar in both groups and was, respectively, 42.18% and 47.59%. The patients with thyroid cancer smoked less frequently than subjects from the control group. Logistic regression analysis showed that carcinoma risk increased in patients who consumed cruciferous vegetables (brassicas). Their regular intake was related to a 1.5-fold (CI 1.19-1.96) higher risk of thyroid carcinoma incidence. Despite the demonstrated decreased risk of thyroid cancer, smoking (OR 0.54) was not considered a protective factor. CONCLUSIONS: 1. It is not possible to determine unequivocally the causative factors for the growth in the incidence of thyroid cancer in Olsztyn province. 2. It appears that one of the environmental factors causing the increase is overconsumption of cruciferous vegetables. PMID- 21528478 TI - Angiotensin II as a factor modulating protein tyrosine kinase activity in two breast cancer lines - MCF-7 and MDA-MB-231. AB - INTRODUCTION: Angiotensin II (AngII), a peptide that regulates the water electrolytic balance and blood pressure, is also known to influence cell proliferation. It can either induce cell growth, when binding to angiotensin type I receptor, or trigger growth inhibition via angiotensin type-II receptor. AngII stimulates proliferation of some normal and tumour cell lines, e.g. pituitary, adrenal glands and breast cancer. MATERIAL AND METHODS: The aim of this study was to evaluate possible AngII effect on the growth of two breast cancer cell lines - hormone-dependent MCF-7 and hormone-independent MDA-MB-231. We measured tyrosine kinase activity as a potential proliferation marker. We also estimated the influence of 17b-oestradiolon AngII-induced changes. RESULTS: In the MDA-MB-231 line, AngII radically slowed the activity of tyrosine kinases and 17b-oestradiol only at a concentration of 10-6 M, while it enhanced the effect of angiotensin II at a concentration of 10-9 M. In MCF-7, Ang II had a strong inhibitory effect in the presence of oestradiol (10-6 M). Oestradiol alone decreased the activity of examined enzymes in both cell lines. AngII receptor type 1 was found in both studied lines, but type 2 only in MDA-MB-231. CONCLUSIONS: Our results show that AngII can modulate tyrosine kinase activity in breast tumour cell lines. PMID- 21528479 TI - Alternative splicing and its role in pathologies of the endocrine system. AB - Alternative splicing of pre-mRNA is a process in which noncoding regions of primary transcript are removed and coding regions are joined in different manners to produce mRNA molecules of different sequences. Alternative splicing affects nearly all human genes and is a key source of diversity of proteins coded by a relatively small number of genes. Since alternative splicing is of crucial importance for the proper functioning of cells, including those involved in hormonal signalling, aberrations of alternative splicing can lead to disruption of cellular mechanisms and in consequence result in serious endocrine pathologies. Disturbances of alternative splicing include mutations of consensus splice regulatory sites and improprieties in the action of splicing factors, the proteins involved in regulating the process. In consequence of disturbed alternative splicing, improperly spliced mRNA and protein isoforms can be produced which can lead to disruption of function of their wild type counterparts. This review aims to discuss the role of alternative splicing in pathologies of the endocrine system and gives examples that highlight the importance of this process in the proper functioning of hormones, hormone receptors and other factors involved in hormonal regulation. The examples given include endocrine-related tumours (pituitary tumours, cancers of the thyroid, prostate, ovary and breast, and insulinoma), isolated growth hormone deficiency, and Frasier syndrome. Non-endocrine pathologies in which aberrant alternative splicing of transcripts of genes involved in hormonal signalling have been detected are also described. Finally, we discuss future perspectives on the possible usage of alternative splicing in diagnostics and therapy. PMID- 21528480 TI - Diabetic pulmonary microangiopathy - fact or fiction? AB - Elevated levels of serum glucose have deleterious effects on the walls of blood vessels, leading to microangiopathy. Such a destructive process involves also pulmonary circulation, where it is referred to as diabetic pulmonary microangiopathy. This hypothesis has been confirmed in histopathologic examinations of pulmonary parenchyma, as well as in pulmonary function tests. However, so far there have been no clinical implications of these findings. Another phenomenon requiring further discussion involves diabetics with clinically silent respiratory dysfunction. That may result from significant vascular and ventilation reserves that compensate for partial loss of pulmonary parenchyma in the course of diabetes. In this review, we present an overview of the available publications on pulmonary microangiopathy and its influence on the functioning of the respiratory system. PMID- 21528481 TI - Wernicke-Korsakoff syndrome in the course of thyrotoxicosis - a case report. AB - Wernicke-Korsakoff syndrome (also called Wernicke's encephalopathy) is a potentially fatal, neuropsychiatric syndrome caused most frequently by thiamine deficiency. The three classic symptoms found together are confusion, ataxia and eyeball manifestations. Memory disturbances can also be symptoms. Wernicke's encephalopathy mainly results from alcohol abuse, but also from malnutrition, cancer, chronic dialysis, thyrotoxicosis and, in well-founded cases, encephalopathy associated with autoimmune thyroid disease (EAATD). The coexistence of many factors makes a proper diagnosis difficult, delays appropriate treatment and consequently reduces the chance of complete recovery. We present the case of a 53 year-old female with Wernicke's encephalopathy caused by chronic malnutrition, surgical operation, as well as thyrotoxicosis. She received treatment with intravenous thiamine administration and also anti-thyroid treatment which caused satisfactory regression of her neurological symptoms. PMID- 21528482 TI - A case of Cushing's syndrome in pregnancy. AB - Cushing's syndrome (also known as hypercortisolemia) is rare in pregnant women due to the menstrual disturbances and infertility in women with hypercortisolism. A diagnosis of pathological hypercortisolism in pregnant women is often difficult as some symptoms of the disease may be associated with a complicated pregnancy. Hypercortisolemia leads to serious complications for mother and foetus, and is associated with premature labour and high foetal mortality. Hormonal and radiological diagnostics in pregnancy are limited. The results of hormonal measurements and dynamic tests are difficult to interpret due to the physiological changes in the hypothalamo-pituitaryadrenal axis connected with pregnancy. The optimal time and method of treatment should be chosen cautiously case by case because of the possibility of maternal and foetal complications. In this paper, we present a case of Cushing's syndrome secondary to adrenal adenoma in which the diagnosis was made in the 22(nd) week of pregnancy. Due to the advanced gestational status and mild symptoms of hypercortisolism, only symptomatic treatment was introduced. The patient was under continuous obstetric and endocrinological care. At 35 weeks of gestation, the pregnancy was terminated by emergency caesarean section because of premature detachment of the placenta. A male infant weighing 2,450 g was delivered; neither adrenal insufficiency in the child nor hypercortisolemia complications in the mother were observed. PMID- 21528483 TI - Pregnancy in a patient with adrenocortical carcinoma during treatment with Mitotane - a case report. AB - We present the case of a female patient with virilising adrenocortical carcinoma treated surgically who conceived during adjuvant treatment with mitotane. We discuss the frequently erroneous routine treatment with oral hormonal contraception without thorough differential diagnosis in female patients with oligo-/amenorrhea and subsequent delay in the proper diagnosis of adrenocortical carcinoma. PMID- 21528484 TI - Gynecomastia - a difficult diagnostic problem. AB - Gynecomastia is a benign, abnormal, growth of the male breast gland which can occur unilaterally or bilaterally, resulting from a proliferation of glandular, fibrous and adipose tissue. Gynecomastia is characterised by the presence of soft, 2-4 cm in diameter, usually discusshaped enlargement of tissues under the nipple. It is estimated that this pathology occurs in 32-65% of men over the age of 17. Gynecomastia is a psychosocial problem and may lead to a perceived lowering of quality of life. The main cause of gynecomastia is a loss of equilibrium between oestrogens and androgens. Increased sensitivity for oestrogens of the breast gland, or local factors (e.g. an excessive synthesis of oestrogens in breast tissues or changes in oestrogen and androgen receptors) may cause gynecomastia. Also, prolactin, thyroxine, cortisol, human chorionic gonadotropin, leptin and receptors for human chorionic gonadotropin, prolactin and luteinizing hormone localised in tissues of the male breast may participate in the etiopathogenesis of gynecomastia. Usually three types of gynecomastia are distinguished: physiological, idiopathic and pathological gynecomastia. The latter is the consequence of relative or absolute excess of oestrogens. In this paper, frequent as well as casuistic causes of gynecomastia will be described. A diagnosis of gynecomastia is usually possible after a palpation examination. Ultrasonographic, mammographic or histopathological examinations are useful in aiding diagnosis. The five degree scale devised by Tanner and Marshall is useful in estimating disease progression. PMID- 21528485 TI - Summary from the European Meeting of WHO Collaborating Centres for Nutrition, Krakow, 23-24 June 2010. AB - In June 2010, the WHO Regional Office for Europe, in co-operation with the WHO Collaborating Centre for Nutrition at the Department of Endocrinology, Jagiellonian University, Collegium Medicum, organized in Krakow the 1st Conference of the WHO European Collaborating Centres for Nutrition. Taking part were representatives of the WHO Regional Office for Europe Nutrition, Dr Joao Breda (Programme Manager - Nutrition, Physical Activity and Obesity Programme) and representatives of the WHO Collaborating Centres for Nutrition from Denmark, Greece, Holland, the UK and Poland, as well as representatives of co-operating institutes from Portugal, Switzerland and the UK. The main objective of the meeting was to discuss the ongoing work of each Collaborating Centre and the development of a strategic plan for the coming years in the most important areas of interest: the prevention of obesity, type 2 diabetes and other NCD, nutrition and inequalities, capacity building in nutrition as well as micronutrient deficiencies (namely iodine deficiency). A final report summarising the Network Meeting is being prepared and will be released in due course. PMID- 21528487 TI - Inhibitory activities of microalgal extracts against Epstein-Barr virus DNA release from lymphoblastoid cells. AB - This study aimed to assess the inhibitory activities of methanol extracts from the microalgae Ankistrodesmus convolutus, Synechococcus elongatus, and Spirulina platensis against Epstein-Barr virus (EBV) in three Burkitt's lymphoma (BL) cell lines, namely Akata, B95-8, and P3HR-1. The antiviral activity was assessed by quantifying the cell-free EBV DNA using real-time polymerase chain reaction (PCR) technique. The methanol extracts from Ankistrodesmus convolutus and Synechococcus elongatus displayed low cytotoxicity and potent effect in reducing cell-free EBV DNA (EC(50)<0.01 ug/ml) with a high therapeutic index (>28000). After fractionation by column chromatography, the fraction from Synechococcus elongatus (SEF1) reduced the cell-free EBV DNA most effectively (EC(50)=2.9 ug/ml, therapeutic index>69). Upon further fractionation by high performance liquid chromatography (HPLC), the sub-fraction SEF1'a was most active in reducing the cell-free EBV DNA (EC(50)=1.38 ug/ml, therapeutic index>14.5). This study suggests that microalgae could be a potential source of antiviral compounds that can be used against EBV. PMID- 21528488 TI - Up-regulation of mitochondrial antioxidation signals in ovarian cancer cells with aggressive biologic behavior. AB - OBJECTIVE: Recently, a high frequency of mutations in mitochondrial DNA (mtDNA) has been detected in ovarian cancer. To explore the alterations of proteins in mitochondria in ovarian cancer, a pair of human ovarian carcinoma cell lines (SKOV3/SKOV3.ip1) with different metastatic potentials was examined. METHODS: Cancer cells SKOV3.ip1 were derived from the ascitic tumor cells of nude mice bearing a tumor of ovarian cancer cells SKOV3. SKOV3.ip1 exhibited a higher degree of migration potential than its paired cell line SKOV3. The proteins in the mitochondria of these two cells were isolated and separated by 2-D gel electrophoresis. The differently expressed proteins were extracted and identified using matrix assisted laser desorption ionisation/time-of-flight/time-of-flight (MALDI-TOF/TOF), and finally a selected protein candidate was further investigated by immunohistochemistry (IHC) method in nude mice bearing tumor tissues of these two cells. RESULTS: A total of 35 spots with different expressions were identified between the two cells using 2D-polyacrylamide gel electrophoresis (PAGE) approach. Among them, 17 spots were detected only in either SKOV3 or SKOV3.ip1 cells. Eighteen spots expressed different levels, with as much as a three-fold difference between the two cells. Twenty spots were analyzed using MALDI-TOF/TOF, and 11 of them were identified successfully; four were known to be located in mitochondria, including superoxide dismutase 2 (SOD2), fumarate hydratase (FH), mitochondrial ribosomal protein L38 (MRPL38), and mRNA turnover 4 homolog (MRTO4). An increased staining of SOD2 was observed in SKOV3.ip1 over that of SKOV3 in IHC analysis. CONCLUSIONS: Our results indicate that the enhanced antioxidation and metabolic potentials of ovarian cancer cells might contribute to their aggressive and metastatic behaviors. The underlying mechanism warrants further study. PMID- 21528489 TI - Value of T-tube in biliary tract reconstruction during orthotopic liver transplantation: a meta-analysis. AB - OBJECTIVE: To compare biliary complications after biliary tract reconstruction with or without T-tube in orthotopic liver transplantation. METHODS: Randomized control trials (RCTs) and comparative studies were identified by a computerized literature search of the Cochrane Library, MEDLINE (1966/1-2010/4), Scopus (1980/1-2010/4), ClinicalTrials.gov (2010/4), the Cochrane Hepato-Biliary Group Controlled Trials Register, and the Cochrane Central Register of Controlled Trials. Studies and data were extracted and assessed independently. Dichotomous outcomes were reported as odds ratios (ORs) and weighted mean difference with 95% confidence intervals (CI). RESULTS: Five RCTs and eight comparative studies with a total of 1 608 subjects were identified. The data showed that the operation with T-tube had better outcomes for duct stenosis (P=0.01, OR=0.45, 95% CI 0.24 0.85). The operations with or without T-tube had equivalent outcomes as follows: overall biliary complications (P=0.85, OR=1.15, 95% CI 0.28-4.72), bile leaks (P=0.38, OR=0.75, 95% CI 0.39-1.42), and cholangitis (P=0.24, OR=4.64, 95% CI 0.36-60.62). These results were strengthened by the analysis of all thirteen non randomized and randomized studies. CONCLUSIONS: Our systematic review and meta analysis suggest that the insertion of a T-tube reduces the incidence of biliary stenosis without increasing the incidence of other biliary complications. PMID- 21528490 TI - Association between moderately oxidized low-density lipoprotein and high-density lipoprotein particle subclass distribution in hemodialyzed and post-renal transplant patients. AB - Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed (HD) and post-renal transplant (Tx) patients are proatherogenic, but elevated concentrations of plasma high-density lipoprotein (HDL) reduce the risk of cardiovascular disease. We investigated the concentrations of lipid, lipoprotein, HDL particle, oxidized low-density lipoprotein (ox-LDL) and anti-ox LDL, and paraoxonase-1 (PON-1) activity in HD (n=33) and Tx (n=71) patients who were non-smokers without active inflammatory disease, liver disease, diabetes, or malignancy. HD patients had moderate hypertriglyceridemia, normocholesterolemia, low HDL-C, apolipoprotein A-I (apoA-I) and HDL particle concentrations as well as PON-1 activity, and increased ox-LDL and anti-ox-LDL levels. Tx patients had hypertriglyceridemia, hypercholesterolemia, moderately decreased HDL-C and HDL particle concentrations and PON-1 activity, and moderately increased ox-LDL and anti-ox-LDL levels as compared to the reference, but ox-LDL and anti-ox-LDL levels and PON-1 activity were more disturbed in HD patients. However, in both patient groups, lipid and lipoprotein ratios (total cholesterol (TC)/HDL-C, LDL C/HDL-C, triglyceride (TG)/HDL-C, HDL-C/non-HDL-C, apoA-I/apoB, HDL-C/apoA-I, TG/HDL) were atherogenic. The Spearman's rank coefficient test showed that the concentration of ox-LDL correlated positively with HDL particle level (R=0.363, P=0.004), and negatively with TC (R=-0.306, P=0.012), LDL-C (R=-0.283, P=0.020), and non-HDL-C (R=-0.263, P=0.030) levels in Tx patients. Multiple stepwise forward regression analysis in Tx patients demonstrated that ox-LDL concentration, as an independent variable, was associated significantly positively with HDL particle level. The results indicated that ox-LDL and decreased PON-1 activity in Tx patients may give rise to more mildly-oxidized HDLs, which are less stable, easily undergo metabolic remodeling, generate a greater number of smaller pre-beta-HDL particles, and thus accelerate reverse cholesterol transport, which may be beneficial for Tx patients. Further studies are necessary to confirm this. PMID- 21528492 TI - Malignant peritoneal mesothelioma presenting with persistent high fever. AB - Malignant peritoneal mesothelioma (MPM) is a rare tumor that develops in the peritoneum. In this paper, we describe an extremely rare case of MPM metastasizing to the appendix in a 48-year-old female who initially presented with a persistent high fever. The woman reported a slight lower abdominal discomfort which had been relieved by urination for four months. She had lost 5 kg of weight. There was no nausea, vomiting, diarrhea, abdominal pain, or abdominal distension. Many broad spectrum antibiotics were given without relief of fever. Computed tomography (CT) scans revealed a thickened omentum majus and diffused multiple omental nodules. An omentectomy, appendectomy, and adnexectomy were carried out. A gross pathologic specimen of omentum tissue revealed a firm gray-white mass. Microscopic and immunohistochemical examinations confirmed the diagnosis of appendiceal and bilateral adnexal metastases of an MPM. These results suggest that MPM should be considered in the differential diagnosis of unexplained persistent high fever. Awareness of such atypical presentations of mesothelioma may help to make a correct diagnosis. PMID- 21528491 TI - Plasticity of human menstrual blood stem cells derived from the endometrium. AB - Stem cells can be obtained from women's menstrual blood derived from the endometrium. The cells display stem cell markers such as Oct-4, SSEA-4, Nanog, and c-kit (CD117), and have the potent ability to differentiate into various cell types, including the heart, nerve, bone, cartilage, and fat. There has been no evidence of teratoma, ectopic formation, or any immune response after transplantation into an animal model. These cells quickly regenerate after menstruation and secrete many growth factors to display recurrent angiogenesis. The plasticity and safety of the acquired cells have been demonstrated in many studies. Menstrual blood-derived stem cells (MenSCs) provide an alternative source of adult stem cells for research and application in regenerative medicine. Here we summarize the multipotent properties and the plasticities of MenSCs and other endometrial stem cells from recent studies conducted both in vitro and in vivo. PMID- 21528493 TI - Antitumor and antimicrobial activities of endophytic fungi from medicinal parts of Aquilaria sinensis. AB - The purpose of this study was to isolate and characterize endophytic fungi from the stem tissue which can produce fragrant ingredients in Aquilaria sinensis (also called agarwood) to determine their antitumor and antimicrobial activities. Twenty-eight fungal endophytes were isolated from agarwood by strict sterile sample preparation and were classified into 14 genera and 4 taxonomic classes (Sordariomycetes, Dothideomycetes, Saccharomycetes, and Zygomycetes) based on molecular identification. Of the 28 isolates, 13 (46.4%) showed antimicrobial activity against at least one of the test strains by the agar well diffusion method, and 23 isolates (82.1%) displayed antitumor activity against at least one of five cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The diameters of inhibition zones of YNAS07, YNAS14, HNAS04, HNAS05, HNAS08, and HNAS11 were equal to or higher than 14.0 mm against Staphylococcus aureus, Escherichia coli, Bacillus subtilis, B. subtilis, Aspergillus fumigatus, and B. subtilis, respectively. The inhibition rates of YNAS06, YNAS08, and HNAS06 were not less than 60% to 293-T, 293-T, and SKVO3 cells, respectively. These results suggest that the endophytic fungi associated with agarwood will provide us with not only useful micro-ecological information, but also potential antimicrobial and antitumor agents. PMID- 21528494 TI - Molecular authentication of geo-authentic Scrophularia ningpoensis. AB - Scrophularia ningpoensis has long been used in the Chinese Materia Medica for inflammation. Like other herbal medicines, S. ningpoensis collected from different localities may considerably differ in their therapeutic efficacy, and the one grown in Zhejiang Province is recognized as geo-authentic. However, it is difficult to confirm the geographical authenticity by similar morphological characteristics. In the present study, inter-simple sequence repeat (ISSR) markers were conducted to detect S. ningpoensis from different origins. A 1 259 bp fragment amplified by primer UBC874 was found only in geo-authentic ones. By cloning and sequencing that specific band, sequence characterized amplified region (SCAR) markers were designed to distinguish geo-authentic S. ningpoensis from others. This is a rapid and easy method that can be used to identify the geographical authenticity of S. ningpoensis. PMID- 21528495 TI - Genotypic differences in callus induction and plant regeneration from mature embryos of barley (Hordeum vulgare L.). AB - An efficient induction system and regeneration protocol based on mature barley embryos were developed. Embryos isolated from mature seeds, dehusked by hand and inoculated with longitudinally bisected sections, showed low contamination and high primary callus-forming capability. The influences of nine culture media on primary callus induction and germination from the mature embryos of barley cultivars Golden Promise and Zaoshu 3 were analyzed. The results showed that the two cultivars had much higher values of primary callus induction in the B16M6D medium as compared to the other eight medium formulations, with a frequency of 74.3% and 78.4% for Golden Promise and Zaoshu 3, respectively. Furthermore, Zaoshu 3 demonstrated particularly high stability in callus induction over the different media, indicating its potential utilization in callus induction and regeneration for its good agronomic traits and wide adaption. There were significant differences amongst 11 barley genotypes in terms of primary callus induction in the optimum medium, with percentages of callus induction and germination response ranging from 17.9% to 78.4% and 2.8% to 47.4%, respectively. Green plantlets of Dong 17, Golden Promise, and Zaoshu 3 were successfully developed from primary calli through embryogenesis, with green plant differentiation frequencies ranging from 9.7% to 21.0% across genotypes. PMID- 21528498 TI - Abstracts of 4th Asia Pacific Regional Meeting of the International Society for the Study of Xenobiotics (ISSX). T'ainan, Taiwan. April 22-25, 2011. PMID- 21528496 TI - Characterization of (68)Zn uptake, translocation, and accumulation into developing grains and young leaves of high Zn-density rice genotype. AB - Zinc (Zn) is an essential micronutrient for humans, but Zn deficiency has become serious as equally as iron (Fe) and vitamin A deficiencies nowadays. Selection and breeding of high Zn-density crops is a suitable, cost-effective, and sustainable way to improve human health. However, the mechanism of high Zn density in rice grain is not fully understood, especially how Zn transports from soil to grains. Hydroponics experiments were carried out to compare Zn uptake and distribution in two different Zn-density rice genotypes using stable isotope technique. At seedling stage, IR68144 showed higher (68)Zn uptake and transport rate to the shoot for the short-term, but no significant difference was observed in both genotypes for the long-term. Zn in xylem sap of IR68144 was consistently higher, and IR68144 exhibited higher Zn absorption ratio than IR64 at sufficient (2.0 umol/L) or surplus (8.0 umol/L) Zn supply level. IR64 and IR68144 showed similar patterns of (68)Zn accumulation in new leaves at seedling stage and in developing grains at ripening stage, whereas (68)Zn in new leaves and grains of IR68144 was consistently higher. These results suggested that a rapid root-to shoot translocation and enhanced xylem loading capacity may be the crucial processes for high Zn density in rice grains. PMID- 21528497 TI - [One year outcomes of total hip prostheses]. PMID- 21528499 TI - [Abstracts of the 5th Conference of the French-Speaking Clinical Epidemiology. May 5-6, 2011. Marseille, France]. PMID- 21528500 TI - Abstracts of the Canadian Conference on Medical Education. May 7-11, 2011. Toronto, Ontario, Canada. PMID- 21528501 TI - Nuclear agency faces reform calls. PMID- 21528502 TI - Dravet syndrome. Proceedings of an international workshop. October 4-5, 2009. Verona, Italy. PMID- 21528503 TI - Skeletal Complications of Cancer. Special Issue dedicated to Gregory Robert Mundy. Proceedings of the 10th International Conference on Cancer-Induced Bone Disease. Sheffield, United Kingdom. September 22-25, 2010. PMID- 21528505 TI - Proceedings of the 4th National Conference of the Association of Psychologists in Academic Health Centers (APAHC). October 15-17, 2009. St. Louis, Missouri, USA. PMID- 21528504 TI - Abstracts of the 13th Scientific Meeting in Optometry and 7th Optometric Educators Meeting. University of New South Wales, Australia. September 10-12, 2010. PMID- 21528506 TI - [Not Available]. PMID- 21528507 TI - [Not Available]. PMID- 21528508 TI - Acute decompensated heart failure secondary to thiamine deficiency: often a missed diagnosis. PMID- 21528509 TI - Where there is no resident neurologist: a case for a neurology attachment for acute medicine trainees. PMID- 21528510 TI - DHATS--an upper Michigan perspective. PMID- 21528511 TI - Plasma cell leukemia mimicking chronic lymphocytic leukemia. PMID- 21528512 TI - What's so great about fiber? PMID- 21528513 TI - The future of telemedicine. How technology might help you get better--and more convenient--healthcare. PMID- 21528514 TI - Beat back depression after heart surgery. CABG frequently leads to a bout with the "black dog," but you can fight it. PMID- 21528515 TI - Five steps to more accurate blood sugar readings. If you have diabetes, these simple strategies will help you stay on top of your condition. PMID- 21528516 TI - STDs in baby boomers and beyond. What you need to know about sexually transmitted diseases and why they're on the rise. PMID- 21528517 TI - Why can't I see at night and in low light as well as I used to? PMID- 21528518 TI - [Neonatal diabetes mellitus]. AB - Instead of type 1 diabetes, the underlying cause in diabetes with an onset before the age of six months is more likely to be monogenic. Approximately half of the permanent cases of neonatal diabetes are due to mutations in genes coding for the potassium ATP channel proteins essential to insulin secretion. Identification of the cause of a monogenic form of diabetes is important, since it will affect the mode of treatment, prognosis and hereditability. It is especially important to detect neonatal diabetes caused by K-ATP channel genes, as insulin therapy can then usually be replaced by oral sulfonylurea medication. PMID- 21528519 TI - [Exercise laryngoscopy: a new method for the differential diagnosis of dyspnea on exertion]. AB - Exertional dyspnea originating from the laryngeal level can be established with certainty only if the paradoxical vocal cord adduction is observed during dyspnea. We have developed a novel diagnostic method, exercise laryngoscopy, which involves observation of the larynx with a flexible endoscope applied via the nose during a bicycle ergometry test. It has been our aim to improve the differential diagnosis of dyspnea on exertion and thus also reduce unnecessary antiasthmatic medication. Exercise laryngoscopy allows examination in the out patient clinics because the method is well tolerated. PMID- 21528520 TI - [Acute renal failure]. AB - Acute renal failure occurs in intensive care units as part of multiple organ injuries as well as in connection with sepsis and other severe diseases. The corresponding mortality rate remains high. High age and blood pressure, vascular diseases and diabetes are its risk factors. Angiotensin convertase inhibitors and angiotensin receptor blockers cause a functional "nephrectomy", especially when combined with anti-inflammatory drugs in situations of fluid deficit. Acute ischemic tubular necrosis is the most common cause. Treatment involves usually correction of hemodynamic abnormalities, fluid and other supportive therapy, elimination of obstructions, and dialysis. PMID- 21528521 TI - [From injections to pills--neonatally diagnosed diabetes of mother and baby]. AB - The genetic background of neonatally diagnosed diabetes has begun to become clear only in the last few years. Recognition of the disease mechanism has often allowed the replacement of insulin therapy by sulfonylurea, which has improved the patients' quality of life and diabetes control. We describe a male infant diagnosed with neonatal diabetes, and his mother, who has had a disease considered to be type 1 diabetes since infancy. Both were diagnosed with a mutation in the KCNJ11 gene coding for the beta cell potassium channel and causing neonatal diabetes. The patients were treated with sylfonylurea. PMID- 21528522 TI - [Update on current care guidelines: preterm birth]. AB - Prevention of preterm birth includes recognition of infections and other risk factors at outpatient clinics. If a woman presents with imminent preterm labour, 1. maternal corticosteroid prophylaxis should be administered if fewer than 35 gestational weeks have elapsed, 2. broad spectrum antibiotics should be administered if membranes have ruptured, 3. foetal distress and clinical chorioamnionitis should be ruled out, as they indicate immediate delivery. Deliveries less than 30 weeks of pregnancy should be centralised in tertiary units, since this improves the prognosis of newborns. Delivery can be postponed through tocolytic therapy, in order to enable corticosteroid prophylaxis and hospital referral. PMID- 21528523 TI - [Active surveillance of prostatic cancer]. AB - Overdiagnosis of prostatic cancer easily leads to overtreatment, whereby the patients are also exposed to the adverse effects of the treatments. Active surveillance has been raised as an alternative to the treatments of prostatic cancer with a good prognosis. Active surveillance means that instead of immediate curative treatment, a patient suited for radical treatments by his age and condition is under careful monitoring. Active surveillance aims to pick out from the wide group of prostatic cancer patients those, who present sings of progressive disease, and to provide the curative treatment later, whereby harm free lifetime will be extended. PMID- 21528524 TI - [Treatment of benign prostatic hyperplasia]. AB - Due to the changing population structure, the proportion of aged men has increased, whereby there is an increasing need for the treatment of prostatic hyperplasia. Most men can be treated with medication within the primary health care. Although the disease is mostly mild in nature and merely lowering the quality of life, it may cause severe complications in the urinary tract, if left untreated. In the treatment of severe cases, the common transurethral prostatic resection has maintained an important status, but has been accompanied by several mini-invasive treatment methods. PMID- 21528525 TI - [Prostatic pain]. AB - Prostatic pain usually refers to male chronic pelvic pain syndrome (CPPS), chronic abacterial prostatitis. It has a prevalence of 14% among Finnish men, and it is characterised by chronic pain in the pelvis, genital and inguinal area, lower abdomen and perineum, often accompanied by various urinary symptoms. The aetiology and pathophysiology of CPPS are poorly understood. Most likely, the aetiology is multifactorial and there is evidence of neuroinflammation in the development of the chronic pain associated with CPPS. Alpha-blockers, 5-alpha reductase inhibitors and possibly extracorporeal shock wave therapy (ESWT) are beneficial for treating CPPS. Antibiotics and antiinflammatory agents seem to be beneficial only in short-term treatment. PMID- 21528526 TI - [Has time already passed the open radical prostatectomy?]. AB - Besides radiotherapy, open radical prostatectomy is an established therapy for localized prostatic cancer. Continuous improvements have been made to the surgical technique, with constantly improving results. Erection is preserved in approximately half of the operated patients, and the risk of urinary incontinence is about 3%. In recent years, open surgery has become rivalled by less invasive forms of surgery, laparoscopic prostatectomy and, above all, robotic laparoscopic prostatectomy, by producing slight reductions in the length of the hospital stay and in surgical bleeding. Even so, the costs of surgical operations may increase even twofold, especially with robotic laparoscopic prostatectomy. PMID- 21528528 TI - [Prevent malaria]. PMID- 21528527 TI - [Robotic laparoscopic radical prostatectomy]. AB - Robotic laparoscopic radical prostatectomy is an established method in the treatment of localized prostatic cancer. The equipment comprises a separate control console that makes ergonomic working possible. The optics creates a three dimensional view and 10 to 15-fold magnification, thus enabling accurate operation. Recovery from the procedure is quicker and the number of blood transfusions lower than in open radical prostatectomy. The methods do not differ in regard to oncological results. Regardless of technique, radical prostatectomy is a demanding operation, in which the surgeon's skills and experience are decisive for the final result. PMID- 21528530 TI - [Anticholinergic drugs in the therapy of obstructive airway diseases]. AB - The anticholinergic effects from botanical preparations of the deadly nightshade family have been used for hundreds of years for the treatment of obstructive airway diseases. Nowadays, derivatives of the plant alkaloids with quaternary ammonium structure, ipratropium bromide and tiotropium bromide, are used, which retain the bronchodilator properties of the parent compounds but are much safer since they are poorly absorbed across biologic membranes. They are the bronchodilators of choice in the management of chronic obstructive pulmonary disease (COPD). However, ipratropium is considered a second-line agent in the treatment of asthma as the bronchodilatory effects seen with ipratropium are less than those seen with beta-adrenergic drugs. Tiotropium is only approved for use in COPD. Though, a recent study provides some evidence that this agent may be an alternative to long-acting beta agonists as an add-on therapy to inhaled glucocorticoids for asthma. PMID- 21528529 TI - [Use of mTOR-inhibitors in solid tumors]. AB - mTOR-inhibitors are part of targeted agents and are already in use in the clinic, especially for treatment of metastatic renal cell carcinoma. Distinct from conventional chemotherapeutics, targeted agents imply chronic treatment, which has changed our perspective on the commerce of adverse events (AE). In principle, mTOR-inhibitors are associated with a broad number of AEs. The occurrence of stomatitis, infection, pneumonitis, hyperlipidemia and hyperglycemia are considered major class effects of mTOR-inhibitors. However, severe adverse events remain scarce among mTOR-inhibitors and support chronic use of these agents. Based on their good clinical tolerability mTOR-inhibitors are prone to be developed in combinational therapies. However, the hepatic metabolism of these agents may limit their use to partners with a distinct metabolism in order to avoid drug interaction. Meanwhile about 40 different trials use mTOR-inhibitors in different tumor entities. The use of mTOR-inhibitors in neuroendocine tumors of the intestine, mantle cell lymphoma and sarcomas has hereby shown to be very promising. The mainstay of therapy already incorporates the use of everolimus in second line and temsirolimus in first line treatment in patients with metastatic renal cell carcinoma. PMID- 21528531 TI - [Should patients on daily levothyroxine have thyroid hormone analysis?]. PMID- 21528532 TI - [Biological and phylogenetic analysis of first isolate of Tahyna virus in China]. AB - In 2006, the first Chinese Tahyna virus isolate (XJ0625) was obtained in Xinjiang province and human infection were found in the same region. In this study, cell culture, animal experiments, electron microscopy, immunofluorescence assay and cross neutralization tests were performed to see the cell susceptibility, animal pathogenicity, morphology and antigenic and other biological characteristics of XJ0625. In addition, molecular biology software was used to analyze the characteristics of molecular evolution. The results showed that BHK-21 cell line was susceptible to XJ0625 and the virus was lethal to suckling mice when injected by intracranial ways. Similar to the other Bunyavirus, Tahyna virus is spherical enveloped virus under electron microscopy. XJ0625 infected cells showed strong fluorescent signal and could be neutralized by immune asities fluid with immnity to protype Tahyna virus Bardos 92. The sequence of the S and M segments showed 91.8% and 81.9% homology with Bardos 92. PMID- 21528533 TI - [Establishment of a mouse-lethal model for pandemic H1N1 influenza virus]. AB - To establish the mouse-lethal model for pandemic H1N1 influenza virus, provide an animal model for studying the pathogenicity and host adaptation of 2009 pandemic H1N1 influenza virus, and find out the key amino acid mutations which may affect viral virulence and replication. A pandemic H1N1 influenza virus strain, A/Sichuan/SWL1/2009 (H1N1, SC/1) was passaged in mouse lung by 15 cycles with intranasal infection. The passaged viruses were all propagated in MDCK cells and sequenced. Based on the sequencing results, four mice in each group were inoculated with 6 selected viruses and their weight and survival rate were monitored during the following 14 days after infection. Additionally, SC/1-MA P14 and P15 viruses were sequenced after purification by Plague Assay. Viral virulence was increased after serial passages and the mortality of 100% was detected after 7 passages. Several amino acid residue mutations of passaged viruses which may contribute to the enhanced virulence were observed. The increased virulence of passaged viruses and mammalian host adaptation maybe associated with amino acid mutations in viral functional proteins. Finally, we established a mouse-lethal model. PMID- 21528534 TI - [Antagonism of baicalin on cell cyclical distribution and cell apoptosis in A549 cells infected with influenza A (H1N1) virus]. AB - To observe the inhibitive effect of Baicalin against influenza A H1N1 virus infection in epithelial cell line A549, the cell proliferation and cytotoxicity were assayed by MTT, the cell cycle and the apoptosis were analyzed by flowcytometer using PI staining, the morphology of cellular nucleolus was observed by Hoechst 33258 staining and the effects of activation on caspase 3 and caspase 8/9 were also detected by immunofluorescent staining with a fluorescence microscope. The results showed that Baicalin exerted an inhibitive effect on CPE after influenza A H1N1 virus infection. The FACS with PI staining showed that the cell cycle of the infected cell was arrested at S phase, the Baicalin-treated group decreased S phase cell ratio and subG0 phase peak in comparison with the control (P < 0.05) and significantly promoted cell proliferation (# P < 0.05). Hoechst33258 staining suggested that Baicalin protected the cellular nucleolus against the influenza virus-induced apoptosis. Observation under the immunofluorescent microscope suggested that the activities of caspase-8 and caspase-3 were enhanced at 36 h post the influenza virus infection, but 100 microg/mL Baicalin suppressing the activation of caspase-8 and caspase-3 rather than that of caspase-9. In summary, this research confirmed that Baicalin inhibited the influenza A H1N1 virus strain infection in vitro, the drug obviously protected cells from apoptosis damages through regulating cell cycle and suppressed the activation of caspase-8 and caspase-3. The down-regulation was significant and showed a dose-dependent relationship. PMID- 21528535 TI - [Genetic characterization of HA1 gene of influenza H3N2 virus isolates during 2008-2009 in Zhuhai, China]. AB - To understand the HA1 genetic variation characterization of influenza H3N2 virus isolates in Zhu-hai during 2008-2009, we selected 20 of H3N2 Influenza strains cultured in MDCK cell. Viral RNAs were extracted and amplified by using RT-PCR. The amplified products were purified after identified by gel electrophoresis and then the nucleotide sequences of the amplicons were determined. The results were analyzed by the software ClustalX and MEGA4. 1. When compared with the amino acid sequences of the epitopes of HA1 district of H3N2 influenza vaccine recommended by WHO in 2008, changes were found in those of H3N2 influenza strains in Zhuhai in 2008: K140I in all of H3N2 influenza strains, L157S in 08-0343 and 08-0677, K158R in 08-0466, 08-0620 and 08-0667, K173E in 08-0466 and 08-0620, K173N in 08 0667, and I192T in 08-0667. The epitopes of HA1 district of H3N2 influenza strains in Zhuhai in 2009 are different from that of H3N2 influenza vaccine during the same time: K173Q and P194L occur in all of H3N2 influenza strains, N144K, K158N, and N189K occur in the strains except the strain 09-0056. HA1 domain of H3N2 influenza strains in 2009 has lost a glycosylation site at amino acid position 144 while the glycosylation sites of HA1 domain of H3N2 influenza stains isolated in 2008 remained. This study suggested that H3N2 influenza virus in Zhuhai in 2008 was not evolved a novel variant and H3N2 influenza variant in 2009 was attributed to antigenic drift in HA1 district. PMID- 21528536 TI - [Sequence and phylogenetic analysis of the haemagglutinin genes of H9N2 avian influenza viruses isolated in central China during 1998-2008]. AB - The purpose of this study is to explore the effects of the HA sequence variation on the pathogenicity and antigenicity of avian influenza virus(AIV). Haemagglutinin (HA) genes from, 6 of 25 avian influenza viruses (AIVs) H9N2 strains with different pathogenicity isolated in central China during last 10 years were amplified by reverse transcriptase PCR (RT-PCR), completely sequenced and phylogenetically analyzed. The purpose of this study was to explore the effects of the HA sequence variation on the pathogenicity and antigenicity of AIV. The results showed that all 6 representative H9N2 isolates belong to low pathogenic AIVs, since none of the amino acid sequences at the cleavage site of the HA of the isolates possessed the basic motif required for highly pathogenic viruses (R-X-R/K-R). There were eight potential glycosylation sites in HA of the isolates, except that 3# and 12# had an extra one. The higher pathogenicity of 3# and 12# was probably due to the extra glycosylation site (145aa-147aa) in HA1, which might alter the conformational structure of HA resulting in the mutation or deletion of the binding sites of anti-HA antibody, and has effects on receptor binding sites thus changed the antigenicity of the virus. Our results suggested that attention should be paid to the transmission and natural evolution of H9N2 AIV in order to control AIV H9N2. PMID- 21528537 TI - [HIV-1 infection affects the expression of host cell factor TSG101 and Alix]. AB - To investigate the effects of HIV-1 infection on the expression of host factors TSG101 (Tumor Susceptibility Gene 101) and Alix (ALG-2-interacting protein X). HIV-1 infectious clone pNL4-3 was used to infect TZM-bl, PM1, Jurkat cell lines and human peripheral blood mononuclear cells (PBMC). Twenty-four hours post infection, the infected or uninfected cells were harvested respectively for extraction of total RNAs and total cellular proteins, which were subsequently used in RT-PCR and Western-blotting respectively to quantify TSG101 and Alix, respectively. Our data showed that HIV-1 infection resulted in various influences on the expression of TSG101 and Alix in the cell lines and the primary PBMC. A down-regulation was mainly observed in the cell lines, whereas an up-regulation of TSG101 was identified in primary PBMC. Three patterns were observed for down regulation, including dual down-regulation of TSG101 and Alix for Jurkat cells, single down-regulation of Alix for TZM-bl cells and marginal or no influence on PM1 cells. The dual down-regulation of Alix and TSG101 in Jurkat cells coincided with less expression of HIV-1 p24 protein. This is the first-line evidence that HIV-1 infection affects the expression of host factors TSG101 and Alix, the down regulation of these molecules may influence the HIV-1 replication. The underlying mechanism remains to be addressed. PMID- 21528538 TI - [The non-replicating recombinant vaccinia virus expressing six genes of HIV-1 can be passaged stably in CEF]. AB - To investigate the genetic stability (including the vector of vaccinia virus and six foreign genes: gp160, gag, pol, rev, tat and nef) of the HIV-1 non replicating recombinant vaccinia virus (rNTV-C). rNTV-C was serially passaged to passage 25 (P25) in primary chicken embryo fibroblast (CEF). P9, P12, P15 and P25 were selected to study the genetic stability in four aspects, including the genetic stability of viral vector, the genetic stability of six foreign genes, the expressing stability of foreign genes and the genetic loss of foreign genes. The results showed that the viral vector was non-replicated vaccinia virus of Tiantan strain and was passaged stably; foreign gene sequences matched with designed sequences, the insert sites were right, and the nucleotide mutation rate was less than one over ten thousands within different passages of rNTV-C; the target proteins could be expressed effectively, and the expression level was stable within different passages of rNTV-C; the genetic loss of gag and nef was less than 5% within different passages of rNTV-C. The above results provided important data for the vaccine production. PMID- 21528539 TI - [Prokaryotic expression for fusion protein of human metapneumovirus and its preliminary application as an antigen for antibody detection]. AB - To understand the effectiveness of prokaryotic expression of fusion protein (F) of human metapneumovirus (hMPV) and its application as antigen, F proteins from different genotypes of hMPV were expressed in prokaryotic expression system and purified by Ni-NTA affinity chromatography column. According to the hydrophobicity, antigen index and surface probability of F protein, the subunit 1 (F1) region of F protein was generated and expressed in E. Coil. BL21(DE3). The 6 His-F1 proteins with molecular weight of approximately 37 kD generated from hMPV of two genotypes were expressed efficiently mainly in inclusion body. The antigenicity and specificity of the expressed proteins were tested and confirmed by Western Blot using polyclonal antibody against hMPV and one serum specimen from a patient with confirmed hMPV acute infection,and polyclonal antibodies against human respiratory syncytial virus and parainfluenza virus 2 and 3. The results of preliminary use of the expressed proteins for detecting antibodies against hMPV in 457 serum specimens collected from different age groups in Beijing indicated that 66%-67% of sera in all age groups were positive. The positive rate of antibodies declined in children in age groups from birth to 2 year-old and then rose along with the increase in age, in which the lowest was in age group from 1 to 2-year-old and the highest in newborn and people older than 60 years. The data indicated the existence of maternal transferred antibodies against hMPV in infants and the risk of hMPV infections in children younger than 2 years old. PMID- 21528540 TI - [Cloning and expression of gp85 gene of subgroup J avian leukosis virus isolated from hemangiomas]. AB - During July to November in 2007, several outbreaks of Hemangiomas in Hy-line Brown laying hens were observed in China. The virus that infected these flocks was identified in cultured DF-1 cells by PCR and indirect fluorescent assay (IFA) with ALV-J specific monoclonal antibody JE-9. The gp85 gene of one strain named WS0705 of ALV-J was cloned and expressed. Phylogenetic analysis showed that gp85 amino sequences of WS0705 strain had the highest homology with that of the prototype HPRS-103. The gp85 gene from a constructed plasmid pMD18-T-WS0705gp85 was cloned into baculovirus transfer vector. rBac-WS0705gp85 was obtained by the Bac-to-Bac baculovirus expression system. The rBac-WS0705gp85 protein was analyzed by indirect immunofluor escence assay and Western blot. The results showed that positive green fluorescent was present in Sf9 cells infected with the recombinant virus and a 35 kD band was present in western blot. It is concluded that WS0705 gp85 gene was expressed in Sf9 cells infected with the recombinant virus and the SU protein of WS0705 can bind specifically to JE9 MAb of ALV-J. The expressed protein can be used to detect hemangiomas induced by ALV-J. PMID- 21528541 TI - [Characterization of an iridovirus detected in rock bream (Oplegnathus fasciatus; Temminck and Schlegel)]. AB - During the summer of 2009, mass mortality was observed in cage-cultured Rock Bream (Oplegnathus fasciatus; Temminck and Schlegel) in the Liaoning Province. Histopathogic studies of the affected fish showed enlarged basophilic cells in the kidney and spleen. These necrotic cells were stained purple using haematoxylin and eosin (HE). GF cell cultures showed advanced cytopathic effects after infection with virus supernatants from diseased fish homogenate. Transmission electron microscopy revealed hexagonal outlines virions in the cytoplasm of the spleen, kidney, liver, intestine cells. The viral particles consisted of a central nucleocapsid (100-110 nm) and envelope, and were 150-180 nm in diameter. These results suggested that the virus belonged to the Iridoviridae. Using polymerase chain reaction (PCR), approximately 570-bp fragments were amplified from the viral DNA in spleen, kidney, gill, intestine, heart and brain of diseased fish with the primers derived from red sea bream Iridovirus (RSIV). In addition, a specific fragment of 1 400 bp of the major capsid protein (MCP) gene of the Iridovirus was amplified by PCR. A phylogenetic tree was constructed to compare the corresponding genetic sequences in Megalocytivirus. The tree demonstrated that RSIV-LN09 virus existed in the same branch as the RSIV-U1 et al. Our present results indicated that RSIV was the causative agent. PMID- 21528542 TI - [Sequencing and analysis of the complete genome sequence of WU polyomavirus in Fuzhou, China]. AB - WU polyomavirus (WUPyV), a new member of the genus Polyomavirus in the family Polyomaviridae, is recently found in patients with respiratory tract infections. In our study, the complete genome of the two WUPyV isolates (FZ18, FZTF) were sequenced and deposited in GenBank (accession nos. FJ890981, FJ890982). The two sequences of the WUPyV isolates in this study varied little from each other. Compared with other complete genome sequences of WUPyV in GenBank (strain B0, S1 S4, CLFF, accession nos. EF444549, EF444550, EF444551, EF444552, EF444553, EU296475 respectively), the sequence length in nucleotides is 5228bp, 1bp shorter than the known sequences. The deleted base pair was at nucleotide position 4536 in the non-coding region of large T antigen (LTAg). The genome of the WUPyV encoded for five proteins. They were three capsid proteins: VP2, VP1, VP3 and LTAg, small T antigen (STAg), respectively. To investigate whether these nucleotide sequences had any unique features, we compared the genome sequence of the 2 WUPyV isolates in Fuzhou, China to those documented in the GenBank database by using PHYLIP software version 3.65 and the neighbor-joining method. The 2 WUPyV strains in our study were clustered together. Strain FZTF was more closed to the reference strain B0 of Australian than strain FZ18. PMID- 21528543 TI - [Molecular technology for identification of novel viruses]. PMID- 21528544 TI - [Research and development of M2- and M2e-based broad-spectrum influenza A vaccines]. PMID- 21528545 TI - [Progress about genetic and variant study of rabies virus glycoprotein gene]. PMID- 21528546 TI - [The progress in research on foamy virus Tas protein]. PMID- 21528547 TI - [Uncertainty analysis of emission inventory for volatile organic compounds from anthropogenic sources in China]. AB - This study analyzed the uncertainties in the Chinese anthropogenic volatile organic compound (VOC) emission inventory. The uncertainty evaluation system for input information including activity data and emission factors was established to provide the probability density function of each input datum. Monte Carlo method was applied to propagate the uncertainties of emissions' input data and calculate the probability density function of total VOC emissions. The results indicated that the Chinese national anthropogenic VOC emissions in year 2005 had a log normal distribution, with a relative standard deviation of 52%, and with 95% confidence interval of [- 51%, + 133%]. However, if the traditional method for error analysis was used based on the same input information, the uncertainty of the 2005 VOC emission inventory calculated was 40% lower than the former results. In addition, sensitivity analysis was conducted to identify the 20 most sensitive inputs influencing the uncertainty of emissions, which will be helpful to improve the accuracy of VOC emission inventory in the future. PMID- 21528548 TI - [Size distribution and characterization of EC and OC in aerosols during the Olympics of Beijing, China]. AB - Samples of airborne PM with different size were collected by cascade impactor (Andersen) in Beijing during the Beijing Olympics. Organic carbon (OC) and elemental carbon (EC) in particles were determined by DRI Model 2001 A t carbon analyzer of USA. PM (56%), OC (55%) and EC (73%) were associated with the fine particle below 2.1 microm. OC and EC account for 25% and 5% of particle below 2.1 microm, respectively, which indicates that carbonaceous aerosols are key components for controlling fine particles pollution in Beijing. It is found that Beijing auto measures were effective in abatement of carbonaceous aerosols. The ratios of OC/EC indicated that the main origins of carbonaceous aerosols in fine particle were automobile exhaust fumes and coal combustion and in coarse particle were biomass burning and cooking. The average percentage of estimated secondary OC (OC(sec)) in the total OC (OC(tot)) in TSP was 74%. The results of correlation analysis show that the correlation coefficient between the OC and secondary water soluble ions (SO4(2-), NO3-, NH4+, NO2-) were very high in PM2.1 (R2 = 0.88), while the correlation coefficient was very faint in particles greater than 2.1 microm (R2 = 0.21). PMID- 21528549 TI - [Study on atmospheric particles and their long-term trend in Beijing cleaning area]. AB - Observational data in clean area provides important references for evaluating environmental impact both from natural and anthropogenic sources. Atmospheric particulate matter of different size were closely examined using dustfall data during 1980-2009, TSP data during 1991-2009 and PM10 data since 2000 at Dingling station (DL), which was located in the clean area of Beijing. It was shown that dustfall amount at DL was on decrease in the last 30 years, by reasons of anthropogenic emission control and ecological environment improvement; meanwhile there was a 5-6 years' cycle of variation in yearly dustfall amount partly caused by dust storms. Similarly TSP and PM10 concentrations changed greatly but had a decreasing trend since 2000. Furthermore, the ratios of Pb and BaP in TSP at DL, namely Pb/TSP and BaP/TSP, were analyzed for anthropogenic influence. It was proved that the ratios were increasing and there was stronger influence of regional pollutant transport from urban areas. Lastly, it was also found that the coarser atmospheric particles were, the stronger their seasonal fluctuations in mass were, which were mainly affected by local sources rather than regional, and vice verse. PMID- 21528550 TI - [Characterizing spatial patterns of NO(x), SO2 and O3 in Pearl River Delta by passive sampling]. AB - Concentrations of NO(x), SO2 and O3 were measured by passive sampling within 200km x 200km grid in Pearl River Delta (PRD). Sampling period was two weeks in November, 2009. Spatial distributions of NO(x), SO2 and O3 were obtained by Kriging interpolation method. The results were compared with emission inventories and modeling results. The transportations of O3 were evaluated by using backward trajectories of air parcels. During the sampling period, the mean concentrations of NO(x), SO2 and O3 were 75.9 microg/m3, 37.3 microg/m3 and 36.2 microg/m3, respectively. And the highest concentrations of NO(x), SO2 and O3 were 195.7 microg/m3, 95.9 microg/m3 and 81.8 microg/m3. Comparing with routine measurements from the regional monitoring network in PRD, the results by passive method were 18.6%, 33.5% and 37.5% lower for NO(x), SO2 and O3, respectively. The spatial patterns demonstrated that higher NO(x) concentrations often appeared in cities such as Guangzhou, Foshan and Shenzhen. SO2 concentrations were higher in west and lower in east. High SO2 concentrations are mainly from emission of power plants and industrial sources. Concentrations of O3 showed the highest levels in the south of PRD. Backward trajectory analysis for higher ozone areas indicated that 53% of the air masses were from the region with high concentration of NO(x). The horizontal transportation caused higher ozone in the south while lower in north in PRD. PMID- 21528551 TI - [Effect of developing tourism on chemical characteristic of precipitation: taking Lijiang for example]. AB - 1090 precipitation samples were collected from 1989 to 2006 at Lijiang City. The analyzed results indicate that the average pH value is 6.08 at study period, which is higher than the average pH value (5.0) during 1987 to 1989, and the annual pH value show an increasing trend, suggesting there are more alkaline mass input to air after 1989. the concentrations of major ions Cl-, SO4(2-), NO3-, Na+, Ca2+, Mg2+ and NH4+ are 11.56, 32.64, 3.63, 2.54, 50.19, 7.73 and 11.36 microeq x L(-1), respectively. By computed the correlation coefficients and sources contribution among major ions, it find that Ca2+ and Mg2+ are from soil derived sources, and about 57.2% of SO4(2-) also come from soil-derived sources; 95.4% of total NO3- and 41.9% of SO4(2-) come from anthropogenic sources, and only Na+ and 25.7% of Cl- come from sea source, meaning that the chemical composition of precipitation at Lijiang region is main influenced by regional sources. According to the variation of tour scale at Lijiang city, it can be divided into 3 periods of 1987-1989, 1989-1996 and 1997-2006. The percent of soil derived ions at different periods is 40%, 53% and 72%, respectively, showing a significant increase trend; but the percent of anthropology-derived ions at different periods is 39%, 36% and 15%, respectively, showing a decrease trend. It explains that more dust input to the air by expending city scale, changing the land form and overusing water resources. But in order to develop tourism, the pollutants related to industries are controlled well. PMID- 21528552 TI - [Influence of biomass burning in Central Asia on nitrate concentrations in Urumqi Glacier No. 1, eastern Tianshan Mountains, China]. AB - Influence of biomass burning in Kazakhstan on nitrate concentrations in eastern Tianshan Mountains was studied. 52 samples of surface snow and snow pits were collected from Glacier No. 1 at the headwater of Urumqi River in eastern Tianshan Mountains, China. Nitrate concentrations in these samples were measured and atmospheric transmission was reconstructed with HYSPLIT air trajectory model. The objectives of this study were to identify the relationship between steppes fire and nitrate concentration in snow, and develop deposition process of nitrate caused by biomass burning in alpine glacier at high altitude. Results indicated that nitrate in surface snow could be regarded as a subsidiary indicator of biomass burning for long distance. Correlations for NO3- and K+ were 0.74 from mid September to late October 2002, which was obviously higher than mean concentration. It took 2-6 days from fire spots in Kazakhstan to sampling site. Whether the information in air mass with biomass burning products can be recorded or not, was mostly depend on local temperature and precipitation. Eluviation process was prominent at Glacier No. 1 in wet season, so postdepositional effect should be considered in paleoclimate reconstruction by ice core. PMID- 21528553 TI - [In-situ measurement on volatilization loss of ammonia in the vegetable field and its influencing factors]. AB - In order to obtain ammonia volatilization flux and volatilization loss rate in the vegetable field and investigate their relationship with environmental factors, an on-line monitoring system was used to measure the ammonia volatilization in the vegetable (Brassica rapa L. and lettuce) field after urea application during January to September, 2009. The system included a wind tunnel system, a gas collector and an online analyzer system with ion chromatography. The time resolution of measurement was 15 min. The recovery of the system was (92.6 +/- 3.4)%; the accumulated ammonia volatilization within 15 d continuous sampling after fertilization was regarded as the total loss. The accumulated ammonia volatilization of 12 d continuous sampling after fertilization accounted for (85.4 +/- 5.2)% of the total volatilization. The ammonia volatilization loss of broadcasting basal dressing and top dressing for Brassica rapa L. were 23.6% and 21.3%, respectively. The ammonia volatilization loss of holing basal dressing and top dressing for lettuce were 17.6% and 24.0%, respectively. The ammonia volatilization in the vegetable field mostly occurred in the first 2-3 weeks after fertilization. The ammonia volatilization flux had significant positive correlation with the nitrogen application rate, while the ammonia volatilization loss rate had negative correlation with the nitrogen application rate. The ammonia volatilization flux was positively correlated with the soil temperature (r = 0.041, p < 0.05) and the air temperature (r = 0.049, p < 0.01), while not significantly associated with the air humidity and the soil moisture. Temperature was found to be a main factor influencing the ammonia volatilization in the vegetable field. PMID- 21528554 TI - [Characterization of photochemical smog chamber and initial experiments]. AB - A self-made new indoor environmental chamber facility for the study of atmospheric processes leading to the formation of ozone and secondary organic aerosols has been introduced and characterized. The characterization experiments include the measurements of wall effects for reactive species and the determination of chamber dependent * OH radical sources by CO-NO(x) irradiation experiments. Preliminary ethene-NO(x) and benzene-NO(x) experiments were conducted as well. The results of characterization experiments show that the wall effects for O3 and NO2 in a new reactor are not obvious. Relative humidity has a great effect on the wall losses in the old reactor, especially for O3. In the old reactor, the rate constant for O3 wall losses is obtained to be 1.0 x 10(-5) s( 1) (RH = 5%) and 4.0 x10(-5) s(-1) (RH = 91%), whereas for NO2, it is 1.0 x 10( 6) s(-1) (RH = 5%) and 0.6 x 10(-6) s(-1) (RH = 75%). The value for k(NO2 --> HONO) determined by CO-NO(x) irradiation experiments is (4.2-5.2) x 10(-5) s(-1) and (2.3-2.5) x 10(-5) s(-1) at RH = 5% and RH 75% -77%, respectively. The average *OH concentration is estimated to be (2.1 +/- 0.4) x 10(6) molecules/cm3 by using a reaction rate coefficient of CO and * OH. The sensitivity of chamber dependent auxiliary reactions to the O3 formation is discussed. Results show that NO2 --> HONO has the greatest impact on the O3 formation during the initial stage, N2O5 + H2O --> 2HNO3 has a minus effect to maximum O3 concentration, and that the wall losses of both O3 and NO2 have little impact on the O3 formation. The results from the ethene-NO(x) and benzene-NO(x) experiments are in good agreement with those from the MCM simulation, which reflects that the facility for the study of the formation of secondary pollution of ozone and secondary organic aerosols is reliable. This demonstrates that our facility can be further used in the deep-going study of chemical processes in the atmosphere. PMID- 21528555 TI - [Relationship between groundwater level in riparian wetlands and water level in the river]. AB - The development and degradation processes of riparian wetlands are significantly affected by river hydrological processes. By observing the variation of groundwater levels in riparian wetlands at the Kouma section of the Yellow River Wetland, especially that during the period of regulation for water and sediment at the Xiaolangdi Reservoir, relationship between groundwater level in riparian wetlands and flood water level in the river is studied. The results show that groundwater level in riparian wetlands is significantly affected by water level in the river investigated. There is a negative exponential relationship between groundwater level and the distance between wells and river. The correlation coefficient shows the maximum (R2 > 0.98) during the period of regulation for water and sediment. Affected by the cultivation system in the flooding area, distance between monitoring wells and river bank, water level in the river variation of groundwater level in the wetland changed greatly. In artificial wetland, which is far from the river, the inter-annual variation in groundwater levels show a " (see symbol)" shape, while in the farmland, which is close to the river, the inter-annual variation of groundwater levels show a big peak. The groundwater level 400 m from the river is affected by flood events obviously, that in the area which is less than 200 m from the river is significantly affected by flood events in the area which is especially less than that in the area that is less than 100 m from the river, the groundwater level is affected by flood events intensively. The result indicated that there was a very close relationship between groundwater and surface water, and it was the hydrological ecotone between groundwater of riparian wetlands and the river. It is very important that rational protection for this region (very important for the area which is less than 100 m from the river, important for the area that is between 100 m and 200 m from the river) is critical for the conservation of water quality in the river and groundwater quality. PMID- 21528556 TI - [Phosphorus forms of the suspended particulate matter in the Yellow River downstream during water and sediment regulation 2008]. AB - Suspended particulate matter samples were collected from Lijin Station on the Yellow River during the 2008 water and sediment regulation. Using water elutriation method, samples were physically separated according to grain size, and phosphorus forms were detected by the improved SEDEX technology. Results show that authigenic apatite phosphorus and organic phosphorus are the dominant forms of the particulate phosphorus. During water and sediment regulation, concentrations of total particulate phosphorus, loosely adsorbed phosphorus, organic phosphorus and refractory phosphorus are lower than those in other time of the year, while the concentration of detrital fluorapatite phosphorus is higher than that in other time. Grain size is the primary variable in the determination of the content of various particulate phosphorus forms. In fine particles, loosely adsorbed phosphorus, organic phosphorus and refractory phosphorus concentrations are high, while detrital fluorapatite phosphorus concentration is high in coarse particles. About 28.3% of the total particulate phosphorus is in the form of bio-available phosphorus, of which organic phosphorus is the major component. During the water and sediment regulation, the fluxes of sediment, particulate phosphorus and particulate bio-available phosphorus are 6.63 x 10(7) t, 3.42 x 10(4) t, and 8.30 x 10(3) t, which are 83.2%, 78.6%, and 80.2% each of the total fluxes in 2008. PMID- 21528557 TI - [Research the biogeochemical processes of nutrients in Minjiang Estuary]. AB - The variations in the concentration and distribution of nutrients and influencing factors in the Minjiang Estuary with a tidal cycle were investigated based on the data obtained during field observations in May 2007. The results showed the suspended sediment, dissolved inorganic nitrogen and silicate were opposite to the change of tidal, while the water level and salinity were consistent with tidal. The buffer mechanism of phosphate was controlled by suspended sand and water. The concentrations of silicate, phosphate and inorganic nitrogen were ranged 0.63-9.00 mg/L, 0.013-0.075 mg/L, 0.33-4.24 mg/L respectively. The contents of dissolved inorganic nitrogen in water mass increased remarkably comparing 1980s because of agriculture, industry and living. The research indicated that the nitrate and silicate were conservative, but phosphate was non conservative in the biogeochemical processes of nutrients in Minjiang Estuary. The diluted water carried abundant inorganic nitrogen, silicate nutrients to Minjiang Estuary and thus phosphate was similar between diluted water and sea water. Based on the results of nutrient ratios, it was suggested that phosphate was a limiting factor for phytoplankton growth in the Minjiang Estuary. PMID- 21528558 TI - [Simulation and evaluation on TIN and PO4(3-) -P reduction in Deep Bay, China]. AB - Environmental Fluid Dynamics Code (EFDC), three-dimensional hydrodynamic and water quality models, are employed to simulate the transport of total inorganic nitrogen (TIN) and orthophosphate (PO4(3-) -P) in Deep Bay, China under different hydrologic conditions. It shows that, the computational results of TIN and PO4(3 ) -P match very well with monthly-averaged field data in dry and wet seasons. The results of TIN and PO4(3-) -P reduction scenarios show that, it is necessary to reduce TIN concentration in Pearl River to Grade III to guarantee TIN in Deep Bay comply with the marine functional zonation requirement of the standard of Grade III. TIN and PO4(3-) -P concentrations in Deep Bay could comply with the marine functional zonation requirement if 95% TIN and PO4(3-) -P loading are reduced from the inflow when degradation ignores. When the degradation is considered, TIN could comply with the marine functional zonation requirement if 83% TIN loading are reduced from the inflow. PMID- 21528559 TI - [Seasonal succession of phytoplankton function groups in the Xiaojiang (Pengxi) River backwater area, Three Gorges Reservoir]. AB - Phytoplankton function classification came from the physiological characteristics and habitat adaption of specific phytoplankton species, matching the growth strategy of the species with the habitat template. The phytoplankton functional groups were classified based on the C-R-S growth strategy and its favored habitat. Phytoplankton function classification was applied in this study to the backwater area of Xiaojiang (Pengxi) River (XBA) of the Yangtze in the Three Gorges Reservoir. 26 functional groups were classified based on the phytoplankton species data from May, 2007 to April, 2009. J/F/H1/P/Lo/LM/B/Y/G/C was the major functional groups in the 2-year survey, while functional groups of MP/D/X1/X2/W1/W2 were also dominant and frequently detected. The succession traits among 5 sampling spots were generally the same. Succession series of the functional groups between the 2 years showed distinct. However, seasonal succession of functional groups based on the C-R-S strategy showed to have some in common: S/CS type dominated in the spring, while in the summer flood season a co-occurrence of S/CS type and R/CR type was evident. From autumn, the succession from S/CS type to R/CR type which dominated in winter was remarkable. In the February to March, the shift from R/CR type in winter to S/CS type in the early spring was completed in a relatilve short time span. PMID- 21528560 TI - [Analysis of meteorological factors of forming feculent and anaerobic water aggregation induced by algal bloom in Taihu Lake]. AB - The water quality pollution problem about feculent and anaerobic water aggregation (FAWA) induced by algal bloom in Taihu Lake, which is often called 'hufan' in Chinese, was studied. Its forming process is divided into 3 phases, i. e., material elements forming of FAWA, anaerobic products to be brought to the water surface and the maintaining of FAWA in the water surface. The conventional observational data from Wuxi meteorological station was analyzed. The result shows that there are similar meteorological characteristics of two FAWA phenomena in Taihu Lake in May, 2007 and May, 2008. A numerical simulation was performed to prove the analysis results. It indicates that propitious meteorological condition is one of the necessary forming factors of FAWA, which provides thermal and dynamical environment for FAWA. During the first phase, the weather conditions, such as high air temperature, gentle breeze and nearly invariable wind direction, maintain for more than 3 days and cause algal bloom to aggregate, then die, sink and anaerobic decay near lake bank. All these provide the precondition for FAWA. During the second phase, when the cold air mass passes across the Taihu basin, almost counter-direction wind, which maintains for more than 1 day with higher speed and lower air temperature, makes anaerobic products to be brought to the water surface by uplifted current. This is the trigger mechanism of FAWA. During the last phase, continual high air temperature and gentle breeze is favorable for FAWA in the water surface. Because meteorological factors are predictable, this research provides a way and basis for the further study of warning and controlling approaches of FAWA. PMID- 21528561 TI - [Influence of scum of algal bloom on the release of N and P from sediments of Lake Taihu]. AB - Sediment cores were sampled in macrophyte dominated zone, phytoplankton dominated zone and river mouth in Lake Taihu and incubated with one half of them added algae in laboratory in August to reveal the influence of algal accumulation on the release of nitrogen and phosphorus in sediments. Concentrations of dissolved oxygen (DO), total nitrogen (TN), total phosphorus (TP), ammonium, phosphate and other parameters were determined during cultivation of the sediment cores in dark. There were differences in release of TN and TP in sediments and significant variations in changes of DO, ammonium, phosphate in overlying water after adding algae. When DO declined to nearly zero, the changes of release of TN, TP in sediments differed from different ecological types of Lake Taihu with minus numbers of -0.1, -3.01 mg x (m2 x d)(-1) in macrophyte dominated zone, larger numbers of 31.1, 0.75 mg x (m2 x d)(-1) in phytoplankton dominated zone and 9.5, 2.46 mg x (m2 x d)(-1) in river mouth. The concentrations of ammonium in overlying water increased 3.62, 5.10, 6.57 mg/L and phosphate increased 53, 219, 418 microg/L in macrophyte dominated zone, phytoplankton dominated zone, river mouth, respectively. The changes of nutrients have good correlations with the decrease of DO and duration. The release of nutrients from sediments caused by accumulation and decay of algae may be the way that algal bloom satisfied itself. PMID- 21528562 TI - [Influences of Potamogeton crispus population on the lake water quality distribution]. AB - A continuing 26-hour monitoring is given on the physical and chemical indicators of the water around the Potamogeton crispus population in Xuanwu Lake, Nanjing City to study the consequent environmental effects. The result shows that both the highest (11.85 mg/L) and the lowest (9.90 mg/L) DO concentrations occur in the population, while the DO concentration decreases with increasing distance from the population. The DO concentration difference of the surface and bottom waters within the population and the open waters is slight, yet it is more obvious in the junction between the population and the open waters. The pH value declines from the population to the open waters. The maximum pH value of the surface water within the population is 10.3, and the minimum value outside the population is 9.2. The pH value of surface water is higher than the bottom within the population, but there is no such difference in the open waters. The TDS content increases with increasing distance from the population, which shows the maximum is 216.9 mg/L of the surface water and the minimum is 177.7 mg/L outside the population. The TDS value of the surface is lower than that in the bottom. The TN, NO2(-) -N, NO3(-) -N contents also increase with the increasing distance from the population, in that the TN content is lower than 2.00 mg/L within the population while the outside is higher than 2.00 mg/L; the NO2(-) -N content is less than 0.026 mg/L within the population while the outside is higher than 0.026 mg/L; the NO3(-) -N content is lower than 1.25 mg/L within the population while the outside is mostly higher than 1.25 mg/L. The TN, NO2(-) -N, NO3(-) -N contents of the surface water are lower than those in the bottom, but the difference is insignificant (p > 0.05). There is no significant difference of the NH4(+) -N content between the inner population and the external and the surface and the bottom. The TP and PO4(3-) -P contents of the surface water are lower than those in the bottom within the population, in that the TP, PO4(3-) -P contents of the highest point of the surface water within the population are 90.9% and 69.64% higher than the lowest point outside the population. The TP and PO4(3-) -P contents of the bottom water are significantly higher than those of the surface within the population, but the difference is slight from outside the population. Therefore, the Potamogeton crispus population plays an important role in improving the lake water quality. PMID- 21528563 TI - [Dynamic change of non-point source pollution exported from Heigou watershed in Three Gorges Reservoir area]. AB - Sediment and its associated pollutants entering a water body can be very destructive to the ecological health of that system. Based on GIS and AnnAGNPS model, A total of 60 combinations of various management treatments including five fertilizer levels (FL1-existing, FL2-70% of existing, FL3-recommended, FLA-70% of recommended, FL5-30% of recommended), four tillage practices (CT-conventional tillage, NT-no tillage, CS-contour strip cropping, RC-residue cover) and three kinds of annual rainfall (deficit, normal, abundant) have been evaluated. Results from model simulations indicate that runoff and sediment yield were not affected due to change in fertilizer doses, but there was a significant positive correlation between nutrient losses and fertilizer application rates; Conservation tillage practices such as NT, CS and RC would reduce sediment and sediment-bound nutrient losses significantly, they have very little benefit on soluble nitrogen and phosphorus losses. This is primarily because the increased infiltration rates resulting from those practices leads to greater losses of subsurface and return flow in the watershed. In view of feasibility and efficiency, the combination of FL3 + NT was found to be the best scenario as the reductions of nutrient losses and sediment yield were about 40% and 45%, respectively. PMID- 21528564 TI - [Comparative study of N, P output and eutrophication risk in runoff water in cross ridge and longitudinal ridge]. AB - Field in-situ rainfall simulation tests with two rainfall intensities (40 mm x h( 1) and 70 mm x h(-1)), which were conducted at typical sloping cropland in Yimeng mountainous area, were designed to analyze the output characteristics of dissolved inorganic nitrogen, Inorganic-N (NO3(-)-N, NH4(+) -N) and dissolved phosphorus (DP) in runoff water, as well as to compare the eutrophication risk in this water by calculating three ratios of Inorganic-N/DP, NO3(-) -N/DP, and NH4(+)-N/DP, respectively, in cross ridge and longitudinal ridge tillage methods. Results showed that, under the same rainfall intensity, the DP level in runoff water was higher in cross ridge than longitudinal ridge, while the change of different Inorganic-N level between the two tillage methods were not consistent. Cross ridge could effectively reduce runoff and the output rate of Inorganic-N and DP when compared to the longitudinal ridge tillage, which would be more outstanding with the increases of rainfall intensities. The losses of Inorganic-N and DP in runoff water were 43% and 5% less, respectively, in cross ridge than longitudinal ridge at the 40 mm x h(-1) rainfall intensity, and were 68% and 55%, respectively, at 70 mm x h(-1). The higher Inorganic-N/DP and NO3(-) -N/DP ratios suggest that runoff water from either cross ridge or longitudinal ridge tillage have a certain eutrophication risk, which present an increasing trend during the precipitation-runoff process. Compared with longitudinal ridge, cross ridge can not only hinder the increasing trend of eutrophication risk, but also can significantly lower it, and thus effectively reduce the effect of sloping cropland runoff on the eutrophication processes of receiving waters. PMID- 21528565 TI - [Distribution and potential ecological risk assessment of heavy metals in surface sediments of Hongze Lake]. AB - In order to investigated horizontal distribution patterns of heavy metals in surface sediments of Hongze Lake, heavy metal contents in every samples were measured by Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) and Atomic Fluorescence spectrometry (AFS) and the potential ecological risks of each heavy metals were analyzed. The average contents of heavy metals Cu, Zn, Pb, Cd, Cr, Hg, As, Fe, Al and Mn are 34.99 mg/kg, 72.44 mg/kg, 18.82 mg/kg, 3.24 mg/kg, 57.59 mg/kg, 0.07 mg/kg, 23.67 mg/kg, 29.63 mg/g, 37.19 mg/g and 0.69 mg/g, respectively. Horizontal distribution patterns of every heavy metals (Cu, Zn, Pb, Cd, Fe, Al, Cr, Hg, Mn and As) in surface sediments were very similar. By impact of hydodynamical and topographical condition, the contents of heavy metals were significantly lower in the inflow river mouth areas than that of open water area in the eastern part of the lake, and that of bays and outflow river mouth areas. This distribution pattern belongs to Turbidity Flood Model. These heavy metals are highly related with each other positively, indicating that they are from the same pollution source. The geo-accumulation index (I(geo)) and the Hakanson potential ecological risk index were applied for assessing the status of sediment heavy metal enrichment and the extent of potential ecological risk. The pollution extent of heavy metals followed the order: Cd > As > Cu > Cr > Zn > Hg > Pb, while the single potential ecological risk of heavy metals followed the order: Cd > As > Hg > Cu > Pb > Cr > Zn. The pollution extent and potential ecological risk of Cd were the most serious among all heavy metals. The distribution pattern of Cd individual potential ecological risk indices is exactly the same as that of general potential ecological risk indices for all heavy metals, indicating the important contribution of Cd in the general indices. Analysis showed that heavy metal pollution and the potential ecological risk existed in three risk regions: the central open water area and outflow river mouth region (S9, S1 and S8), the northern bay region (S6) and the western bay region (S5). PMID- 21528566 TI - [Distribution characteristics of trace pollutants in benthic mussels from the coastal areas of Bohai Sea and North Yellow Sea]. AB - Based on the recent monitoring results, the concentration and distribution of persistent toxic substances in the benthic mussels from the coastal areas of Bohai Sea and North Yellow Sea were determined. The results indicated that, at over 36% of the total sampling sites, the tissue concentrations of petroleum hydrocarbons were higher than the Category I value (15 microg/g, wet weight) of the national marine biological quality standards, especially at the sites near Dalian Bay and Xincun in Hebei Province, the tissue concentrations even exceeded the Category III level (80 microg/g, wet weight). Moreover, higher tissue concentration of PHCs (over the Category I level) during recent years remained in the most monitoring sea areas. At minor sites (mariculture zone in Yantai and Laizhou Bay), the tissue concentrations of As and Pb were relatively higher, and the high levels of Cd (above the Category II value of 2000 ng/g, wet weight) and Hg (above the Category II value of 100 ng/g, wet weight) in mussel bodies presented at several sites situated in coastal areas near Dalian Bay and Xincun of Hebei Province. Additionally, at the sampling sites near Liaodong Bay and Shandong Peninsula, the tissue concentration of Hg showed an annual increase during recent years. At all the monitoring sites, the tissue concentrations of PCBs and HCHs were usually low, while as the case of Hg, the tissue concentrations of PCBs and HCHs in Liaodong Bay increased gradually in these years. The new monitoring results indicated that, most sites with DDTs levels in benthic mussels higher than the Category I value (10 ng/g, wet weight) were located in the coastal areas of Hebei Province belonged to Bohai Bay (such as Zhaojiapu and Xincun). The continuous monitoring in these sea areas demonstrated that, in addition to the historical residues, there may be some fresh input sources of DDT nearby. Consequently, in the neighboring sea areas of Dalian Bay and Xincun, the tissue concentrations of PHCs, Cd and Hg were fairly high (all over their Category II values), and these sea areas could be of relatively stronger potential ecological risk. In view of the gradual increases in tissue concentrations (e. g., Hg, PCBs and HCHs) during the recent years, the coastal areas, for example, of Liaodong Bay and Shandong Peninsula should be addressed with sufficient concern. PMID- 21528567 TI - [Spectral absorption coefficients of optically active substances in Lake Dianchi]. AB - A field investigation in Lake Dianchi was carried out in November, 2009, and a dataset including absorption coefficients and concentration of water components was collected. Absorption properties and its spatial distribution of Lake Dianchi have been systematically analyzed, the results show that: (1) Absorption spectral curve of total particles (a(p)) are similar with that of phytoplankton (a(ph)), which indicates that phytoplankton absorption dominates absorption of total suspended particles; (2) Significant relationships are found between a(ph) (440), a(ph) (624), a(ph) (675) and concentration of chla, and cyanophyta dominats the quantity of the algae in water columns; (3) There are more phytoplankton existed in northern lake than other areas because of higher level of eutrophication. Comparing with other water columns, discrepancies mainly appear as below: (1) The mean value of slope of absorption spectral curve of non-algal particles (S(d)) in Lake Dianchi is much bigger than that in other case-II waters; (2) The mean value of slope of absorption spectral curve of chromophoric dissolved organic matter (CDOM) S(g) in Lake Dianchi is much smaller than that in other case-II waters; (3) Specific absorption of phytoplankton (a(ph)*) at 440 nm and 675 nm is at intermediate level, and a(ph)* value is susceptible to different regions, seasons, population structure of phytoplankton and so on. PMID- 21528568 TI - [Estimating of backscattering rate in Lake Chaohu based on bio-optical model]. AB - Backscattering rate is the important factor of above water spectra. A bio-optical model simplified in near-infrared bands was constructed to estimate backscattering rate in Lake Chaohu by using the in-situ data measured in June 2009. The results show that the maximum value of backscattering rate in Lake Chaohu is 0.059, the minimum value is 0.001 4 and the mean value is 0.023 6. Backscattering rate and spatial differences in the west of Lake Chaohu are all greater than that in the east. In addition, particle refractive index of each sampling site was calculated by using backscattering rate. The dominant factors of in-water particles were determined according to the change scopes of refractive index. The results show that 74% of all sampling sites are dominated by inorganic particles, 18.5% of all sampling sites are dominated by both phytoplankton and inorganic particles, and the rest of sampling sites which accounts only for 7.4% of all sampling sites are dominated by phytoplankton. This indicates that backscattering character of Chaohu Lake is mainly affected by inorganic particles, while the effect of algae particle is relatively small. PMID- 21528569 TI - [Retrieve phycocyanin concentrations based on semi-analytical model in the Dianchi Lake, China]. AB - Phycocyanin (PC) in the blue-green algae is usually used to detective the quantity of the blue-green algae, because of its special absorption at band 620 nm. A semi-analytical model retrieving phycocyanin concentrations is been built, based on a nested semi-empirical band ratio algorithm, using the data sets collected in September 19 and September 20, 2009 from Dianchi Lake. The empirical relationship between the specific absorption coefficient at band 620 nm [a(PC)* (620)] and the absorption coefficient at band 620 nm [a(PC) (620)] reduces the impact of the variability of a(PC)* (620) in the model built by Simis. The new semi-analytical model is proved well done in retrieving phycocyanin concentrations and has a mean relative error (MRE) 21.63% by the dataset collected on December 1, 2009 from Dianchi Lake. The model error analysis prove that the main reason of the error is caused by the component and concentrations of pigments changing seasonally in the blue-green algae. PMID- 21528570 TI - [Uptake 14CO2 from air and accumulation of 14C in hornwort]. AB - Uptake 14CO2 from air and accumulation of 14C in the hornwort were studied by using the isotope-tracer techniques in order to get a better understanding of the environmental behavior of 14CO2. And the possibility of hornwort used as the indicator plant in the supervisor of 14CO2 air pollution was discussed. The results show that the hornwort could uptake 14CO2 from the air by some way and formed an accumulating trend. The main way was that the hornwort absorbed free 14CO2 and H 14CO3- from the water through photosynthesis. During the introducing 14CO2, the increasing rate of 14C specific activity in dry hornwort and fresh hornwort were between 91.9-95.6 Bq/(g x d) and 6.1-6.3 Bq/(g x d), respectively, which was roughly equal to the increasing rate in the wheat. The results indicate that the hornwort had strong ability of absorbing 14CO2 indirectly through water. The hornwort has an certain concentration of 14CO2. And the concentration factor (CF) values rise with the introduction of 14CO2 and decline slowly after it reached the maximum value. Owing to its accumulation of 14CO2, hornwort can be used as the indicator plant in the supervisor of 14CO2 air pollution. PMID- 21528571 TI - [Effect of PCP on the living cell content and distribution in biofilms]. AB - The phospholipids method for the determination of the living cell content in the biofilm was established to study the wastewater biofilm. With the micro-slicing technology, the biofilm was divided into 150 microm-layer for the phospholipids analysis. Results showed the phospholipids were approximately normal distribution along the biofilm depth without no addition of pentachlorophenol (PCP). The absolute values were between (1 246.2 +/- 217.4) microg/L and (527.2 +/- 95.3) microg/L with the maximum occurring at the depth of (0.60 +/- 0.15) microm, indicating the highest concentrations of the living cell in the biofilm. With the PCP concentrations of 5 microg/L, 10 microg/L and 20 microg/L and the exposure times of 2 h, 6 h and 24 h, respectively, the results of the orthogonal experiments showed the value of phospholipids decreased greatly along the biofilm depth only with the exception of 5 microg/L PCP concentration and 2 h exposure time, with a concentration decline by up to 70% especially close to the peak of phospholipids distribution. Results proved that PCP has an adversely influence on the living cells, and the influence can be enhanced with the increase of PCP amount and the exposure time. PMID- 21528572 TI - [Investigation on simultaneous determination of dihydroxybenzene isomers in water samples using multi-walled carbon nanotube modified screen-printed electrode]. AB - A disposable electrode, multi-walled carbon nanotube modified screen printed electrode (MWCNT/SPE), had been fabricated using screen printing technology and drop-coating method to determine dihydroxybenzene isomers (hydroquinone, catechol and resorcinol). The cyclic voltammetry behavior of dihydroxybenzene isomers had been investigated with the MWCNT/SPE. The results reveal that MWCNT/SPE, which shows a strong electrocatalytic activity for the oxidation of dihydroxybenzenes, can entirely separate the oxidation peaks of them. According to differential pulse voltammetry tests, the peak currents of dihydroxybenzene isomers are linear to their concentrations at the range of 8.20 x 10(-6) -1.00 x 10(-3), 8.20 x 10( 6) -1.00 x 10(-3) and 1.64 x 10(-5) -1.16 x 10(-3) mol x L(-1), with the detection limits of 4.34 x 10(-6), 3.42 x 10(-6) and 6.70 x 10(-6) mol x L(-1) for hydroquinone, catechol and resorcinol, respectively. For the determination of dihydroxybenzene isomers in water samples, the value of recovery found by standard addition method was in the range of 96.2%-104.9%. These results indicate MWCNT/SPE can be applied to rapid in-situ determination of dihydroxybenzenes polluted water samples. PMID- 21528573 TI - [Effect of physico-chemical characteristics of activated carbon on the adsorption of organic pollutants in natural water]. AB - In this paper, the adsorption characteristics of two synthetic organic compounds (SOCs), i. e., methyl parathion(MP) and trichloroethylene (TCE), and natural organic matter (NOM) on powdered activated carbons (PAC) in natural water were studied. On the basis of fully characterizing the physical and chemical characteristics of PAC, the effect of physical and chemical properties of PAC on the adsorption of low molecular weight SOCs in natural water was studied by correlation analysis. The effect of molecular weight fractionation on the adsorption of NOM on PAC was investigated using high performance size exclusion chromatography (HPSEC). It was found that, compared to the surface chemistry, the physical property (pore properties) of PAC was the critical factor to determine its adsorption capacity of MP and TCE in natural water. The adsorption of the low molecular weight SOC and NOM with apparent molecular weight (AMW) < 500 on PAC was primarily impacted by the micropore surface area, and that of NOM with 500 < AMW < 3 000 was affected by the mesopore surface area combined with the mesopore size distribution. PMID- 21528574 TI - [Characteristic of ammonia nitrogen adsorption on karst underground river sediments]. AB - Karst aquifers are one of the most important aquifers in Southwestern China. One of the characteristics of karst aquifers is the enhanced permeability permits high flow velocities are capable of transporting suspended and bedload sediments. Mobile sediment in karst may act as a vector for the transport of contaminates. 14 sediment samples were collected from two underground rivers in two typical karst areas in Liuzhou city, Guangxi Autonomous Region, China. According to simulated experiment methods, characteristic of adsorption of ammonia nitrogen on sediment was studied. The results of ammonia nitrogen adsorption dynamics on sediments showed that the maximum adsorption velocity was less than 2 h. The adsorption balance quantity in 5 h accounted for 71% - 98% of the maximum adsorption quantity. The maximum adsorption quantity of ammonia nitrogen was 385.5 mg/kg, which was sediment from a cave in the middle areas of Guancun underground river system. The study of isotherm adsorption indicated adsorption quantity of NH4+ increase followed by incremental balance concentration of NH4+ in the aquatic phase. Adsorption quantity of ammonia nitrogen in sediments has a relative linear relationship with adsorption balance concentrations. Adsorption desorption balance concentrations were all low, indicating sediments from underground rivers have great adsorption potential. Under the condition of low and high concentrations of ammonia nitrogen in overlying water, Langmuir and Tempkin couldn't simulate or simulate results couldn't reach remarkable level, whilst Linear and Freundlich models could simulate well. Research on different type sediments, sampling times and depths from two underground rivers shows characteristic of ammonia nitrogen adsorption on karst underground river sediments doesn't have good correspondence with the type of sediments. One of the reasons is there is no big difference between sediments in the development of climate, geology, hydrological conditions and pollution history. The other reason maybe the article is lack of research on pH, salinity and others factors which may affect adsorption and desorption. PMID- 21528575 TI - [Effect of powdered activated carbon on the sludge mixed liquor characteristics and membrane fouling of MBR]. AB - Effect of dosing powder activated carbon (PAC) on the characteristics of the sludge mixed liquor in membrane bioreactor (MBR) was investigated by parallel tests. And the reason that PAC mitigated membrane fouling was also explored. The results showed that PAC could decrease mixture viscosity and increase sludge particle size, which led to less trans-membrane pressure developing. Extracellular polymer substances (EPS) content, sludge specific resistance and cake layer resistance (R(c)) had a good correlation. Adding PAC could decrease EPS concentration, sludge specific resistance and then slow down the increase of R(c), which mitigated membrane fouling. Membrane pore blocking resistance (R(p)) increased exponentially with increasing of the soluble microbial products (SMP) concentration in the supernatant. Dosing PAC reduced the SMP concentration and slowed down the growth rate of R(p), which was helpful to mitigating membrane fouling. R(c) and R(p) increased along with the operation of MBRs and R(c)/R(f) (26.32% -63.16%) was always greater than R(p)/R(f) (7.89% -35.32%) which suggested the R(c) was the main factor in membrane fouling. Moreover, it was also found that controlling of dosing PAC on R(c) was better than it on R(p). PMID- 21528576 TI - [Bioavailability of nickel and its complexes during anaerobic digestion]. AB - The biouptake of nickel and its complexes for methanogenic enrichment in the presence of different chelators during batch methane fermentation were investigated in this paper. The results showed that the chelators had obvious effects on anaerobic digestion. At sodium acetate concentration of 85 mmol/L, sulfides concentration of 1 mmol/L, nickel concentration of 200 micromol/L and temperature was 35 degrees C, methane production in the NTA added system were 15% and 9% which was higher than that in CA and EDTA amended ones. While nickel concentration was 100 micromol/L, methane production in NTA added system were 43% and 57% which was higher than that in CA and EDTA amended ones. The biouptake of nickel for methanogenic enrichment related to the species of nickel complexes. NTA was the best chelator for stimulating nickel biouptake in the anaerobic reactors, and EDTA was the better one. The biouptake of Ni-CA complexes was the minimum for the methanogenic enrichment. PMID- 21528577 TI - [Start-up of a thermophilic anaerobic sludge digester]. AB - Anaerobic digestion is one of the most widely-used technologies of the sludge reduction and stabilization, in which thermophilic digestion has advantage of fast stabilization. But it is lack of operation experience in China. Thus start up of a thermophilic anaerobic sludge digester treating excess activated sludge was investigated. The digester was an internal circulation anaerobic sludge digester. It belongs to upflow reactor and its hydrodynamic conditions can be controlled by backflow biogas. A multistep strategy was applied to the start-up to enhance anaerobic bacteria to adapt the changes of temperature, reactor and treated sludge, including: to feed the digester with easily-degraded glucose to enhance bacteria reproduce at the first beginning with COD organic loading of 2.4 kg/(m3 x d); to accelerate the internal circulation; to control pH within a optimal range; to gradually increase excess sludge flow rate as well as to initiate pydrohydrolysis to enhance hydrolysis. The start-up took 63 days and when it finished, the VSS organic loading reached 1.60 kg/(m3 x d), the average VSS biogas rate was 0.51 L/g, i. e. 15.3 m3/m3 sludge (96% water content), VSS and SS removals were 60.8% and 45.8%. This shows that the strategy is valid. PMID- 21528578 TI - [Utilizing the wastewater treatment plant sludge for the production of eco cement]. AB - The aim of this paper was to study the effect on cement property by using of municipal sewage as additive in the process of clinker burning. Based on the standard sample P. 042. 5 from cement plant, the properties of eco-cement samples adding municipal sewage to unit raw material by 0%, 0.50%, 1.00%, 1.50%, 2.00%, 2.50% respectively and the standard sample from the cement plant were compared. According to the analysis of X-ray diffraction, microstructure, the particles size determination material change, the setting time, specific surface area, leaching toxicity and strength of cement mortar of the cement, respectively, it showed that the strength of the productions were similar to the P. 042.5 standard sample. The metal ion concentrations of Al, Fe, Ba, Mn and Ti in clinkers and raw material decreased, the initial and setting time increased, as well as the strength of the paste within the curing time of 3 days decreased with the increase of municipal sewage ratio. However, after the curing of 7 days, the strength was similar to non-sludge-mortar or even higher. PMID- 21528579 TI - [Impact of depth and moisture to diesel degradation in sand layer of vadose zone]. AB - Through the experiment simulated sand columns, the biodegradation characteristics of diesel in sand layers (including fine sand, medium sand and coarse sand) with different depths and moisture contents were studied. The results show that the depth and moisture content of medium are important factors in affecting the efficiency of diesel degradation. In the same medium conditions, the higher moisture content of the medium, the higher biological activity, and biological degradation efficiency of diesel are observed. The nature of medium affects the efficiency of diesel degradation in vadose zone. The finer particles of the medium, the higher ability of diesel degradation is. It is expressed as: fine sand > medium sand > coarse sand. Volatilization and biodegradation are important factors in affecting natural attenuation of diesel in vadose zone. PMID- 21528580 TI - [Characteristics of biodegradation of triphenyltin by Rhodopseudomonos spheroids]. AB - The biodegradation of triphenyltin (TPT) by Rhodopseudomonos spheroids was investigated in this study. The results illuminated that R. spheroids was an effective strain for the biodegradation of TPT. The maximum removal ratio was attained when the growth temperature of R. spheroids was 30 degrees C. After treating for 3 hours, the removal ratios of 3 mg x L(-1) TPT were 13.82% to 47.29% using 0.49 g x L(-1) (based on dry weight) biomass of R. spheroids. The experiments on biodegradation of TPT were carried out in double-distilled water, simulated seawater,culture medium and river water, respectively. The results demonstrated that river water was optimal for the biodegradation since the indigenous microorganisms in water synergistically increased the removal ratios of TPT. Extracellular enzyme produced by R. spheroids was also effective on the degradation of TPT, and 71.64% of TPT was degraded by this way within 24 hours. The experiments also revealed that the biodegradation process of TPT included biosorption by cell wall, TPT entering cells, and initial degradation by intracellular enzyme, then the TPT and intermediate products backing out of cells to be degraded by extracellular enzyme. PMID- 21528581 TI - [Isolation and degradation characteristics of acetochlor-degrading strain A-3]. AB - The strain A-3 which could use acetochlor as the sole nitrogen source was isolated from soils contaminated with acetochlor and the sludge of pesticide factory by enrichment culture. The strain was identified as Ensifer adhaerens according to the results of morphology, physiology,and the phylogenetical analyses of 16S rRNA sequence. It was observed that the degradation rate of acetochlor by strain A-3 was 33.6% after 10 days culture at the concentration of 10 mg/L. The composition of the culture could affect the growth of A-3 and the degradation of acetochlor. The growth and degradation ability of strain A-3 were different with the different carbon sources. The strain had the strangest growth capability with the D600 value of 0.55, but the degradation rate was only 9.4% when using sucrose as carbon source. However, the strain A-3 had the highest degradation rate up to 29.2%, although the D600 value was only 0.3 when using glucose as carbon source. When the NaCl concentration was 0.5%, the strain A-3 grew best and had the highest degradation rate of 35%, but when the NaCl concentration was higher than 7%, the growth of A-3 was inhibited and the degradation rate was reduced to 2.6%. The results showed that the strain A-3 could degrade acetochlor effectively and the growth and degradation process was affected by environmental media, and the degradation of acetochlor could be controlled by changing the composition of the culture. PMID- 21528582 TI - [Optimization of two-dimensional electrophoresis conditions for proteomics of Issatchenkia orientalis in degrading dyes]. AB - Total protein of the yeast Issatchenkia orientalis was extracted and separated by two-dimensional electrophoresis (2-DE) before and after the dye Reactive Brilliant Red K-2BP was degraded by this yeast, respectively. Different protein extraction methods, different volumes of sample loaded and different staining techniques were tested and compared for the 2-DE. Among three different protein extraction methods, the final protein concentrations of 3.4 mg/mL, 1.8 mg/mL and 5.6 mg/mL were obtained by single ultrasonication, ultrasonication TCA/acetone,and ultrasonication-ammonium sulfate precipitation, respectively. The best electrophoresis pattern could be gotten by loading 150 microg protein samples from the method of ultrasonication-ammonium sulfate precipitation, using IPG strips of pH 4-7 for the first dimensional electrophoresis and staining with silver nitrate. This electrophoresis pattern had high resolution and good repetition. It was detected to have 730 +/- 30 protein points by preliminary image analysis. This research results provided a technical support for screening dye-degrading enzymes from the yeast of I. orientalis. PMID- 21528583 TI - [Bioaugmented treatment of atrazine by genetically engineered microorganism in different bioreactors]. AB - Removal of atrazine was investigated when genetically engineered microorganism (GEM) was inoculated into membrane bioreactor (MBR) and hybrid bioreactor for bioaugmentation. The performances of atrazine removal in two bioreactors were explored. The variations of GEM density and atzA gene abundance in two bioreactors were also determined. The results indicated that removal activities of COD and ammonia nitrogen were inhibited a little by atrazine and recovered after bioaugmentation by inoculated GEM. The better removal performance of COD and ammonia nitrogen was obtained in MBR. The biological removal efficiency of atrazine was improved significantly when bioaugmented treatment by GEM was applied. The atrazine removal increased gradually and the average removal rates reached up to 38.94% in MBR and 29.36% in hybrid bioreactor in the later running period. After inoculated, GEM densities in two bioreactors decreased rapidly and then tended to be constant. The stable GEM densities in MBR, suspended sludge and adherent biofilm of hybrid bioreactor were 5 x 10(3) CFU/mL, 1.1 x 10(3) CFU/mL and 0.4 x 10(3) CFU/mL, respectively. Fluorescence in situ hybridization (FISH) was used to detect azA gene in two bioreactors and the result indicated that the average relative abundances of atzA gene decreased initially and increased subsequently. The largest average relative abundance of atzA gene was obtained in MBR. The average relative abundance of atzA gene in adherent biofilm is larger than that in suspended sludge in the hybrid bioreactor. The horizontal transfer of atzA gene was the possible important reason responsible for high gene abundance. PMID- 21528584 TI - [Isolation of phenol-degrading bacteria from coking wastewater and their degradation gene]. AB - Phenol and phenolic compounds are main pollutants in wastewater of coking factories. To identify the bacteria responsible for phenol removal in the activated sludge of a coking factory, we isolated bacteria from the sludge directly or after enrichment. From two samples from the aerobic and anaerobic pools, 28 strains belonging to 28 species of 20 genera were obtained after identification with BOX-PCR and further 16S rDNA sequence analyses. Most of them belonged to beta- and gamma-Proteobacteria, four of which are potential novel species of low 16S rDNA sequence similarity to corresponding type strains. From the m-cresol enrichment community, two strains identified and named as Pseudomonas monteilii GCS-AE-J-1 and Pseudomonas plecoglossicida GCS-AN-J-3 were obtained as the efficient degraders; The former can remove 94.6% m-cresol (791 mg/L) in just 48 h; while the latter metabolized 92.2% m-cresol (763 mg/L). Furthermore, the phenol hydroxylase gene was surveyed by PCR from the phenol degrading strains,and 4 were positively detected. Summarily, quite diverse bacteria were proved of high capability to degrade phenol and phenolic compounds in this report, which play important role in biotreatment of phenol compounds. PMID- 21528585 TI - [Effects of soil HHCB and Cd contamination on the growth of wheat seedlings (Triticum aestivum) and the pollutants accumulation in plants]. AB - Using outdoor pot-culture experiment,biomasses of wheat seedlings and accumulation of HHCB and/or Cd in parts of wheat seedlings cultured in alluvial soil and cinnamon soil were investigated. The biomasses of wheat seedlings in different treatments followed the order as single HHCB treatment > HHCB and Cd treatment > single Cd treatment. The accumulation of HHCB in wheat seedlings cultured in alluvial soil was more than that in cinnamon soil, and effect of Cd on accumulation of HHCB in wheat seedlings cultured in alluvial soil was different to that in cinnamon soil. In alluvial soil, the accumulation of HHCB in different parts of wheat seedlings followed the sequence that root > stem > leaf. Cd significantly induced the accumulation of HHCB in wheat roots, but inhibited that of HHCB in wheat stems and leaves, and the highest inhibition rate was 44.07%. In cinnamon soil, the accumulation of HHCB in different parts of wheat seedlings followed the sequence that root > leaf > stem. The effect of Cd on accumulation of HHCB in wheat roots was not significant, but the median and high concentrations of Cd induced accumulation of HHCB in wheat stems and leaves significantly, and the highest induction rate was 35.95%. Besides, the accumulation of Cd in alluvial soil was lower than that in cinnamon soil, and HHCB could significantly induce the accumulation of Cd in wheat seedlings cultured in two different soils. The increasing rates of Cd accumulation in roots, stems and leaves in alluvial soil were 30.84%, 61.82% and 61.82%, and those in cinnamon soil were 41.53%, 184.16% and 206.18%, respectively. It is indicated that HHCB in cinnamon soil induced more accumulation of Cd in wheat seedlings than that in alluvial soil. PMID- 21528586 TI - [Effect of fertilization on the absorption, partition and accumulation of carbon and nitrogen of rice under the equal N conditions]. AB - In this study, the assimilation, partition and accumulation of carbon (C) and nitrogen (N), as well as the relationship between C and N accumulation of rice, were studied from typical paddy ecosystems under long-term fertilizer applications with equal N inputs in subtropical China. The results showed that chemical fertilizer plus low organic manure (LOM) could promote effectively the distribution of C in the rice plant. The N content in the stem-leaf and grain of rice under organic-inorganic fertilization was 8.9-10.2 g x kg(-1) and 11.9-14.8 g x kg(-1) respectively. It was much higher than under other treatments, with about 13% - 53% and 9% - 19% higher than under the chemical fertilization (NPK), separately and 12% - 77% and 23% - 32% higher than under the control treatment (CK), respectively. The C and N storages of rice were mainly accumulated in the aboveground part. Organic-inorganic fertilization treatment possessed higher storages of C (3467.8-4 323.9 kg x hm(-2)) and N (120.3-135.2 kg x hm(-2)) in the rice grain,which was about 13% - 23% of C and 26% - 45% of N higher than under NPK treatment. It indicated that rice grain was the main sink of C and N. The organic-inorganic fertilization was in favor of C accumulation and N absorption in the rice plant and it still possesses an obvious potential in C and N sequestration and absorption in subtropical paddy field. PMID- 21528587 TI - [Effect and mechanism of immobilization of cadmium and lead compound contaminated soil using new hybrid material]. AB - The effect of new hybrid material and its compound treatments with phosphate on immobilization of cadmium and lead in contaminated soil was investigated using a pot-culture experiment, and the immobilization mechanism of hybrid material was clarified through analysis of heavy metal fractions, sorption equilibration experiment and X-ray photoelectron spectroscopy (XPS). The single treatments of hybrid material could not significantly promote growth of Brassica chinensis, while the compound treatments of hybrid material and phosphate markedly increased dry biomass of shoots and roots, with maximal increases of 75.53% and 151.22%, respectively. Different hybrid material treatments could significantly reduce Cd and Pb concentrations in shoots, with maximal reductions of 66.79% and 48.62%, respectively, and the compound amendment treatments appeared more efficient than the single amendment treatments in reducing Cd and Pb uptake of B. chinensis. Different hybrid material treatments could significantly decrease concentrations of toxicity characteristic leaching procedure (TCLP) extractable Cd and Pb, and the compound hybrid material treatments appeared more efficient than the single treatments in reducing TCLP extractable Cd and Pb. Through the formation of bidentate ligand between metal ions and surface sulfhydryl by complexing reaction, the hybrid material could absorb and fix mobile fractions of Cd and Pb in soil, and promote transformation of acid extractable Cd and Pb into residual fraction, resulting in significant reduction of heavy metals bioavailability and mobility and then fixing remediation of contaminated soil. In summary, the compound treatment of hybrid material and phosphate is the most effective treatment for immobilization of Cd and Pb in contaminated soils, and the hybrid material inactivates Cd and Pb in soil mainly through special chemical adsorption. PMID- 21528588 TI - [Effects of soil trituration size on adsorption of oxytetracycline on soils]. AB - In order to understand the effects of soil trituration size on adsorption of oxytetracycline (OTC) on soils, two contrasting soils including moisture soil and purplish soil were selected to investigate adsorption of OTC on these soils, at the scales of no more than 0.20 mm, 0.84 mm, 0.25 mm and 0.15 mm, using the method of batch equilibrium experiments respectively. The results presented as the following: (1) Adsorption amount of OTC on moisture soil and purplish soil increased with the sampling time, and reached to equilibration at 24 h. First order kinetic model, second-order kinetic model, parabolic-diffusion kinetic model, Elovich kinetic model, and two-constant kinetic model could be used to fit the changes in adsorption on soils with sampling time. Adsorption of OTC on two soils consisted of two processes such as quick adsorption and slow adsorption. Quick adsorption process happened during the period of 0-0.5 h. The adsorption rates of OTC on soils were higher at the small trituration size than those at the large trituration size, and at the same trituration size, the k(f) of purplish soil was about two times higher than those of moisture soil. (2) Adsorption isotherms of OTC on two soils with different trituration sizes were deviated from the linear model. The data were fitted well to Freundlich and Langmuir models, with the correlation coefficients between 0.956 and 0.999. The values of k(f) and q(m) for purplish soil were higher than those for moisture soil. At the same soil, adsorption amount of OTC increased with the decreases of soil trituration size. The results suggested that it is important to select the appropriate trituration size, based on the physical and chemical properties such as soil particle composition and so on, when the fate of antibiotics on soils was investigated. PMID- 21528589 TI - [Selective recovery of copper, zinc and nickel from printed circuit boards by ammonia leaching under pressure]. AB - The ammonia/ammonium leaching process using oxygen as oxidant in autoclave was studied to extract copper, zinc and nickel from printed circuit board. Parameters such as leaching time, concentration of leaching reagents, stirring speed, oxygen pressure and temperature were optimized. The best results were achieved when the leaching was carried out at 55 degrees C for 150 minutes, using 4 mol/L NH4OH and 1 mol/L (NH4)2CO3 as leaching solution, with 700 r/min stirring speed and 0.2 MPa oxygen. With this method, Zn, Cu and Ni could be effectively recovered from printed circuit boards by 100%, more than 99% and more than 64%, respectively. The kinetics of Cu leaching behavior was studied and it was found that the shrinking core model described it well. It was a diffusion control process and the apparent activation energy was 14.68 kJ/mol. PMID- 21528590 TI - [Phosphorus flow analysis of civil food production and consumption system]. AB - With the method of substance flow analysis (SFA), the study provided an analytical framework for phosphorus cycle on civil food production and consumption system that was demonstrated by four life stages-food production, food processing, consumption and waste handling. Furthermore, a case study was carried out in Hefei City, for the year 2008. The SFA results show that the total demand of phosphorus reaches 5 475.86 t in the food production and consumption of Hefei City in 2008; approximately 242.57 t P leaves the system, and around 1 710.84 t P is emitted via waste discharge to the surface water, the rest is transformed as the stocks in the system. The effluent of excessive fertilizer in agriculture plays an important role for the huge phosphorus load, as well as the civil sewage. In the end, the study provided some suggestions on improving the use efficiency of phosphorus and reducing phosphorus discharge into surface water. PMID- 21528591 TI - [Acupuncture and moxibustion for peripheral facial palsy at different stages: multi-central large-sample randomized controlled trial]. AB - OBJECTIVE: To explore the best intervention time of acupuncture and moxibustion for peripheral facial palsy (Bell's palsy) and the clinical advantage program of selective treatment with acupuncture and moxibustion. METHODS: Multi-central large-sample randomized controlled trial was carried out. Nine hundreds cases of Bell's palsy were randomized into 5 treatment groups, named selective filiform needle group (group A), selective acupuncture + moxibustion group (group B), selective acupuncture + electroacupuncture (group C), selective acupuncture + line-up needling on muscle region of meridian group (group D) and non-selective filiform needle group (group E). Four sessions of treatment were required in each group. Separately, during the enrollment, after 4 sessions of treatment, in 1 month and 3 months of follow-up after treatment, House-Brackmann Scale, Facial Disability Index Scale and Degree of Facial Nerve Paralysis (NFNP) were adopted for efficacy assessment. And the efficacy systematic analysis was provided in view of the intervention time and nerve localization of disease separately. RESULTS: The curative rates of intervention in acute stage and resting stage were 50.1% (223/445) and 52.1% (162/311), which were superior to recovery stage (25.9%, 35/135) separately. There were no statistical significant differences in efficacy in comparison among 5 treatment programs at the same stage (all P > 0.05). The efficacy of intervention of group A and group E in acute stage was superior to that in recovery stage (both P < 0.01). The difference was significant statistically between the efficacy on the localization above chorda tympani nerve and that on the localization below the nerve in group D (P < 0.01). The efficacy on the localization below chorda tympani nerve was superior to the localization above the nerve. CONCLUSION: The best intervention time for the treatment of Bell's palsy is in acute stage and resting stage, meaning 1 to 3 weeks after occurrence. All of the 5 treatment programs are advantageous to Bell's palsy. In the condition of the limited medical sources, the simple filiform needle therapy is recommended in acute stage. For the patients with the disorder above chorda tympani nerve, the line-up needling on muscle region of meridian is not recommended. PMID- 21528592 TI - [Randomized controlled trial on comorbid anxiety and depression treated with electroacupuncture combined with rTMS]. AB - OBJECTIVE: To compare the efficacy differences between integrative therapy of electroacupuncture and repetitive transcranial magnetic stimulation (rTMS) and simple rTMS only in the treatment of comorbid anxiety and depression (CAD). METHODS: Eighty-five cases of CAD were randomized into two groups. The observation group (40 cases) was treated with electroacupuncture at Baihui (GV 20), Yintang (EX-HN 3), Shenting (GV 24), Shenmen (HT 7) and Neiguan (PC 6) mainly, combined with rTMS. The control group (45 cases) was treated with simple rTMS. Separately, before treatment, after 5 days and 10 days treatment, Hemilton Depression Scale (HAMD) and Hemilton Anxiety Scale (HAMA) were used for the scoring of depression and anxiety. Additionally, the efficacies were compared between two groups. RESULTS: After 5 days, 10 days treatment, the scores of HAMA, HAMD were reduced remarkably as compared with those before treatment in two groups (all P < 0.001), HAMA score in observation group was lower than that in control group after 10 days treatment (P < 0.05). The remarkable effective rates of depression and anxiety in observation group those 10 days that treatment were 87. 1% (27/31) and 90.3% (28/31) respectively, which were higher apparently than 61.8% (21/34) and 61.8% (21/34) in control group separately (both P < 0.05). CONCLUSION: The integrative therapy of electroacupuncture and rTMS is definitely effective on CAD. This method is better than simple rTMS. PMID- 21528593 TI - [Effect on blood pressure and microcirculation of nail fold in primary hypertension patients treated with acupuncture according to syndrome differentiation]. AB - OBJECTIVE: To verify the efficacy of primary hypertension treated with acupuncture at acupoints selected according to syndrome differentiation and probe into the mechanism of acupuncture for primary hypertension. METHODS: One hundred and thirty-five cases of primary hypertension were randomized into an observation group (108 cases) and a control group (27 cases). In either group, Fengchi (GB 20), Quchi (LI 11), Zusanli (ST 36) and Sanyinjiao (SP 6) were selected conventionally. In observation group, on the basis of the acupoints selected above, the supplementary points were selected according to syndrome differentiation in Chinese medicine and the control group was selected main points only, once per day. After 15 days acupuncture, the efficacy and changes in microcirculation of nail fold were observed. RESULTS: The remarkable effective rate and the total effective rate were 29.6% (32/108) and 84.2% (91/108) in observation group respectively, which were superior to 18. 5% (5/27) and 70.4% (19/27) as compared with control group separately (both P < 0.05). After treatment, the microcirculation of nail fold was all improved in two groups, of which blood flow state integral, peripheral capillary loop state integral and the total integral were all improved obviously (all P < 0.05). The improvements in observation group were much more significant than those in control group (all P < 0.05). CONCLUSION: Acupuncture is effective significantly on primary hypertension and the point selection according to syndrome differentiation can improve the efficacy, which is probably relevant with the reduction in the peripheral vascular resistance due to the improvements of microcirculatory state in mechanism. PMID- 21528594 TI - [Preliminary comparison on the time-effect rule of pain-relieving in the treatment of moderate dysmenorrhea between acupuncture on single-point and acupuncture on multi-point]. AB - OBJECTIVE: To compare the time-effect rule of pain-relieving in moderate dysmenorrhea in the treatment between acupuncture on single-point and acupuncture on multi-point so as to determine the best time of needle retaining on single point and multi-point as well as provide the reference evidences of acupuncture frequency in the treatment. METHODS: Sixty-three cases of moderate dysmenorrhea were randomized into a single-point group (31 cases) and a multi-point group (32 cases). During the attack of dysmenorrhea, in single-point group, Shiqizhui (EX-B 8) was punctured; in multi-point group, Shiqizhui (EX-B 8), Diji (SP 8), Ciliao (BL 32) and Sanyinjiao (SP 6) were punctured and the needles were retained for 30 min. Visual Analogue Scale (VAS) values were recorded in the immediate time before acupuncture, in 5 min, 10 min, 20 min and 30 min after needle insertion, as well as in 30 min, 60 min and 120 min after needle withdrawal separately. RESULTS: After needling, analgesia was generated rapidly in either group. During 30 min of needle retaining, analgesia was enhanced persistently till needle withdrawal in either group. In 10 min after needle insertion, the immediate analgesia in multi-point group was superior obviously to single-point group (P < 0.05) and this effect was maintained in 2 h after needle withdrawal. In 30 min after needle withdrawal, acupuncture analgesia was declined to the maximum. CONCLUSION: Either single-point acupuncture at Shiqizhui (EX-B 8) or multi-point acupuncture at Shiqizhui (EX-B 8) and other acupoints has apparent immediate analgesia on primary dysmenorrhea of moderate degree, but the effect of multi point acupuncture is better than that of acupuncture at Shiqizhui (EX-B 8). No matter with acupuncture at Shiqizhui (EX-B 8) or at multi-point, the time of needle retaining should not be shorten than 30 min. It is suitable to give acupuncture, twice per day for the patients with moderate and persistent pain. PMID- 21528595 TI - [Therapeutic effect of acupoint catgut embedding on irritable bowel syndrome of diarrhea type]. AB - OBJECTIVE: To observe the therapeutic effects of irritable bowel syndrome of diarrhea type (deficiency of spleen and stomach) treated with acupoint catgut embedding therapy. METHODS: Sixty cases of irritable bowel syndrome of diarrhea type were randomly divided into an acupoint catgut embedding group and a medication group. In acupoint catgut embedding group, acupoint catgut embedding therapy was given at Tianshu (ST 25), Dachang shu (BL 25) and Zusanli (ST 36), etc., once treatment every 10 days and 3 treatments in all. In medication group, Pinaverium Bromide was orally taken for 50 mg, 3 times a day and 30 days in all. The therapeutic effects were compared after 3Q days treatment and the recurrence rates were observed after 3 months in both groups. RESULTS: The total effective rate was 86.7% (26/30) in acupoint catgut embedding group, superior to that of 56.7% (11/30) in medication group (P < 0.05). The recurrence rate was 15.4% (4/26) in acupoint catgut embedding group, which was lower than that of 64. 7% (11/17) in medication group after 3 months (P < 0.05). CONCLUSION: The curative effect of irritable bowel syndrome of diarrhea type (deficiency of spleen and stomach) treated by acupoint catgut embedding is superior to that by Pinaverium Bromide, with low recurrence rate. PMID- 21528596 TI - [Postmenopausal osteoporosis of liver and kidney deficiency type treated with acupoint catgut embedding by stages]. AB - OBJECTIVE: To explore the better treatment of postmenopausal osteoporosis of liver and kidney deficiency type. METHODS: One hundred and five cases were randomly divided into an observation group, a control group A and a control group B equally. In control group A, Calcichew D3 tablets were taken with oral administration; in control group B, Calcichew D3 tablets and Xianling Gubao capsule were taken with oral administration. In observation group, Calcichew D3 tablets and acupoint catgut embedding were applied; Shenshu (BL 23), Ganshu (BL 18), Jiaji (EX-B 2) and Weizhong (BL 40) etc. were selected at acute stage; Shenshu (BL 23) and Ganshu (BL 18) etc. were selected at remission stage, once every half a month and 6 months treatment in all. The Visual Analogue Scale (VAS), bone mineral density(BMD), estradiol (E2) and clinical effects were compared among groups. RESULTS: After 3 and 6 months treatment, the scores of VAS were reduced among groups (all P < 0.01); the reduction in observation group and control group B was superior to that in control group A (all P < 0.001), and it was more obvious in observation group than that in control group B (both P < 0.001). After 6 months treatment, lumbar BMD and the serum level of Ez improved obviously in observation group and control group B (all P < 0.01). The comparison among groups after treatment showed that the BMD in observation group and control group B was superior o o that in control group A (P < 0.01, P < 0.05); the serum level of E2 in observation group was superior to that in control group B and control group A (both P < 0.001), and it in control group B was superior to that in control group A. The total effective rate was 91.4% (32/35) in observation group, superior to that in control group A (57.1%, 20/35); and the total effective rate was 82. 9% (29/35) in control group B, superior to that in control group A. CONCLUSION: Calcichew D3 tablets and acupoint catgut embedding therapy can relieve the pain caused by postmenopausal osteoporosis of liver and kidney deficiency, improve the bone mineral density and serum level of estradiol; in brief, it is the better method. PMID- 21528597 TI - [Randomized controlled study on chronic functional constipation treated with grain-shaped moxibustion and acupuncture]. AB - OBJECTIVE: To compare the therapeutic effect differences of chronic functional constipation treated with the combined therapy of grain-shaped moxibustion and acupuncture and simple acupuncture therapy. METHODS: One hundred cases of constipation were randomly divided into an acupuncture and moxibustion group and an acupuncture group by fifty-fifty. Both groups were treated by acupuncture therapy with acupoints of two groups alternatively. Group 1: Tianshu (ST 25), Daheng (SP 15), Qihai (CV 6), Guanyuan (CV 4), Zusanli (ST 36), Shangjuxu (ST 37) and Sanyinjiao (SP 6). Group 2: Zhongliao (BL 33), Xialiao (BL 34), Dachangshu (BL 25), Shenshu (BL 23) and Pishu (BL 20). In acupuncture group, all the acupoints, were punctured; in acupuncture and moxibustion group, grain-shaped moxibustion was given at Qihai (CV 6), Susanli (ST 36), Dachangshu (BL 25) and Pishu (BL 20), and others were treated by puncture. The clinical therapeutic effect, and the changes of clinical score of constipation, quality of life and psychological symptoms score were observed before and after treatment. RESULTS: The total effective rate in acupuncture and moxibustion group was 74.0% (37/50), superior to that (52.0%, 26/50) in acupuncture group (P < 0.05). The clinical score of constipation, the quality of life and psychological symptoms score in both groups improved after treatment; in clinical score of constipation, the improvement of difficulty of defecation, defecation time, abdominal pain, exsufflation difficulty, endless sensation of defecation, obstruction sense of anus, purgative prescription dependence, quality of life score and psychological symptoms score in acupuncture and moxibustion group were superior to those in acupuncture group (P < 0.05, P < 0.01). CONCLUSION: For treating chronic functional constipation, the combined therapy of both grain-shaped moxibustion and acupuncture is safe and effective, superior to the simple acupuncture therapy. PMID- 21528598 TI - [Observation of therapeutic effect on post stroke depression treated by differentiation of spleen and stomach]. AB - OBJECTIVE: To explore the clinical effect of post stroke depression treated by differentiation of spleen and stomach, so as to search better treatment. METHODS: Sixty-three cases were randomly divided into an acupuncture and moxibustion group and a medication group. In acupuncture and moxibustion group, acupuncture and grain sized moxibustion were given at Zhongwan (CV 12), Zhangmen (LV 13), Zusanli (ST 36), Yinlingquan (SP 9), Pishu (BL 20) and Weishu (BL 21); in medication group, Fluoxetine was orally taken for 20 mg after breakfast. Both groups were treated for 4 weeks. Prospective information of spleen and stomach syndrome was collected before treatment; the therapeutic effects and adverse reactions were evaluated by integral scale of spleen and stomach syndrome, Hamilton Depression (HAMD) Scale and Treatment Emergent Symptom Scale (TESS) at the first, second and fourth weekend of treatment. RESULTS: The prospective information collection of spleen and stomach syndrome before treatment indicated that among these 63 cases of post stroke depression, poor appetite, constipation and less drinking appeared for many times. The cured and markedly effective rate was 81.8% (27/33) in acupuncture and moxibustion group and 63.3% (19/30) in medication group, manifesting the same curative effect (P > 0. 05); the integral scale of spleen and stomach syndrome reduced in both groups (P < 0.001, P < 0.05), and it was superior in acupuncture and moxibustion group to that in medication group. In acupuncture and moxibustion group, HAMD score reduced obviously at the 1st and 2nd week and after treatment ( all P < 0.001), and it was superior to that in medication group at the 1st and 2nd week (P < 0.05, P < 0.01). The TESS showed that the adverse reactions intervention in acupuncture and moxibustion group was superior to that in medication group at the 1st and 2nd week (both P < 0.05). CONCLUSION: The patients who get post stroke depression commonly suffer from varying degrees of spleen and stomach functional disturbance. The curative effect of post stroke depression treated by differentiation of spleen and stomach is quick and stable, with less adverse reaction and high safety. PMID- 21528599 TI - [Key contents of disease prevention in Chinese medicine: to understand, regulate and take care of meridians]. AB - The key contents of disease prevention through 3 aspects of understanding, regulating and taking care of meridians were expounded in this article. It discussed how to understand meridian through its main functions of relating with life and death, concerning various diseases, regulating deficient and excessive conditions, and also the importance of being kept smooth. It also expounded how to check the affected meridians through the diagnostic methods of inspection, pulse feeling, pressing along meridians, fixed pressing and palpation, how to regulate meridians through scribing, sucking, cutting, pulling and twisting etc., and how to take care of meridians through removing stagnation from meridians and collaterals, regulating emotions, diet and living style, so as to reach the aim of diseases prevention and inherite and develop the theory of meridians and collaterals of the past generations. PMID- 21528600 TI - [Ashi points, Ashi method and pressing reaction]. AB - The nomination of Ashi points was reviewed, and the meaning of Ashi method was discussed in this article. On the base of further study on Huangdi Neijing (The Yellow Emperor's Canon of Internal Medicine), the general meaning of palpation at acupoints, meridians and collaterals to the process of acupoint locating were expounded. The concept of pressing reaction was proposed as well. It is held that Ashi points are a category of acupoints without specific names and definite locations. They are a kind of manifestation of reactions of acupoints, meridians and collaterals, which embody their dynamic features. Pressing reaction mainly manifested by sensations of comfort, pain, and moreover, relieving of the primary symptoms. It is the most basic evidence for us to estimate Ashi points. PMID- 21528601 TI - [Effects of reinforcing and reducing methods by twirling and rotating the needle on contents of CGRP and NO in rats with stress-induced hypertension]. AB - OBJECTIVE: To explore the different effects of reinforcing and reducing methods by twirling and rotating the needle on stress-induced hypertension and its mechanism. METHODS: Sixty male Wistar rats were randomly divided into a nomal group (group A), a model group (group B), an acupuncture control group (group C), an acupuncture with reinforcing method group (group D)and an acupuncture with reducing method group (group E), 12 rats in each group. The model of stress induced hypertension was established by foot-shock and noise stimulation in the other groups except group A. Group C was treated by acupuncture at left "Taichong" (LR 3) with no manipulation, group D with twirling reinforcement method and group E with twirling reducing method at the same acupoint, respectively, and group A and B with no acupuncture treatment. The contents of calcitonin gene-related peptide (CGRP) and nitrogen monoxidum (NO) in blood plasma and hypothalamus after 7 days were observed. RESULTS: After acupuncture treatment, the contents of CGRP in blood plasma and hypothalamus were (375.9 +/- 36.5) pg/mL and (213.6 +/- 50.1) pg/mg in group A, which were higher than (261.0 +/- 20.1) pg/mL and (156.0 +/- 21.8) pg/mg in group B , and (255.3 +/- 33.6) pg/mL and (154.3 +/- 47.3) pg/mg in group C (all P < 0.05), and (465.9 +/- 53.2) pg/mL and (250.74 +/- 47.7) pg/mg in group E higher than those in group C and (283.3 +/- 29.8) pg/mL and (164.6 +/- 47.4) pg/mg in group D (all P < 0.05), and there was no significant difference among group B, C and D (all P > 0.05). After acupuncture treatment, the contents of NO in blood plasma and hypothalamus were (43.7 +/- 5.5) micromol/L and (23.3 +/- 2.9) micromol/g in group B, (46.5 +/- 6.4) micromol/L and (23.1 +/- 3.3) micromol/g in group C, (45.8 +/- 6.7) micromol/L and (25.0 +/- 2.7) micromol/g in group D, which were all lower than (64.5 +/- 9.9) micromol/L and (30.7 +/- 1.6) micromol/g in group A (all P < 0.05), (55.9 +/- 4.6) micromol/L and (30.4 +/- 2.1) micromol/g in group E higher than those in group C and group D (all P < 0.05), and there was no significant difference among group B, C and D either (all P > 0.05). CONCLUSION: Acupuncture with twirling reducing method can increase the contents of CGRP and NO in rats with stress-induced hypertension, thereby causing a fall in blood pressure, however, no significant influence with twirling reinforcing method. Reinforcing or reducing method by twirling and rotating the needle has different efficacy. PMID- 21528602 TI - [Effects of moxibustion at "Shenque" (CV 8) on superoxide dismutase (SOD) in rabbits with kidney-yang deficiency]. AB - OBJECTIVE: To explore the influence of moxibustion at Shenque (CV 8) point on aging and its mechanism. METHODS: Forty-eight health rabbits were randomly divided into 8 groups, ie., group I (normal control group), group II (model group), group III (prevention with moxibustion at Shenque (CV 8) group), group lY (prevention with moxibustion both at Shenque (CV 8) and Zusanli (ST 36) group), group V (prevention with moxibustion both at Shenque (CV 8) and Mingmen (GV 4) group), group VI (treatment with moxibustion at Shenque (CV 8) group), group XII (treatment with moxibustion both at Shenque (CV 8) and Zusanli (ST 36) group), and group VIII (treatment with moxibustion both at Shenque (CV 8) and Mingmen (GV 4) group). The rabbit models of kidney-yang deficiency were created by pouring Hydroxyurea. The serum superoxide dismutase (SOD) activity was detected and the effect of the moxibustion from both prevention and treatment aspects were compared. And then the effect of different compatibility of acupoints was observed. RESULTS: After modeling, obvious symptoms of kidney-yang deficiency and decrease of SOD activity (all P < 0.01) were found in groups II, VI, VII and VIII. After the moxibustion treatment, the syndromes of kidney-yang deficiency were significantly improved (all P < 0.01) and SOD activities were increased obviously in groups VI, VII and VIII (all P < 0.01); a few syndromes of kidney yang deficiency were found in groups III, IV and V after modeling, but with no significant changes of SOD activity (all P > 0.05). There was no significant difference in three moxibustion treatment groups (all P > 0.05). CONCLUSION: Three acupoints compatibilities of moxibustion treatment can all regulate serum SOD activity in rabbits with kidney-yang deficiency effectively and have the significant effect both at prevention and treatment aspects and there is close relationship between their mechanisms on aging and regulating serum SOD activity. PMID- 21528603 TI - [Effects of magnetic auricular point-sticking on adjuvant anesthesia and postoperative recovery of body function]. AB - OBJECTIVE: To prove analgesia and sedative effect of adjuvant anesthesia with magnetic auricular point-sticking on abdominal gynecological operation and its effect on postoperative recovery of body function. METHODS: Ninety-two patients with abdominal gynecological operation were randomly divided into 3 groups. The auricular point-sticking group (APS group, n=31) was pasted and pressed by plasters with magnetic beads at bilateral Shenmen, Pizhixia (subcortex), Zigong (uterus) and Penqiang (pelvic cavity), etc. the night before operation. The placebo group (n=31) was pasted by plasters without magnetic beads. The blank group (n=30) was given no intervention. The mental and gastrointestinal functional changes before and 3 days after the operation were observed. RESULTS: As compared with those in the control group and the blank group, the postoperative score of Self rating Anxiety Scale (SAS) was less (25.5 +/- 0.81 vs. 28.9 +/- 3.19, 28.3 +/- 2.36, both P < 0.01), with lower-dose of Innovar [(2.5 + 1.1) mL vs. (3.4 + 1.8) mL, (3.2 + 1.6) mL, both P < 0.05], earlier exsufflation after the operation [(34.2 + 12.1) h vs. (46.3 + 10.9) h, (43.2 + 14.8) h, both P < 0.01] and higher level serum of beta-endorphin before and after the operation in the APS group (all P < 0.05). CONCLUSION: The magnetic auricular point-sticking has sedative, analgesic and function-regulating effects on the abdominal gynecological operation. PMID- 21528604 TI - [Preliminary study on syndrome differentiation types and acupuncture for whiplash injuries]. AB - Whiplash injury is a relatively common injury of clinical acupuncture and moxibustion in the United States. The mechanism and clinical manifestation of whiplash injuries as well as its pathogenesis described in TCM were analyzed in this present article. The authors introduced the TCM syndrome differentiation of whiplash injuries and claimed that both the location and the stage of disease should be considered. For the different injury locations, the meridian musculature differentiation was applied to classify the whiplash injuries as Taiyang, Yangming, Shaoyang and Shaoyin Meridian syndromes. Considering the duration of the injury, qi stagnation and blood stasis types were classified in the acute stage and phlegm accumulation, insufficiency of the liver and kidney and qi and blood deficiencies types were classified during the chronic stage. An acupuncture protocol for whiplash injuries and typical cases were also introduced. PMID- 21528605 TI - [Therapeutic effects of common cold of wind-cold type at early stage treated by different cupping duration]. AB - OBJECTIVE: To observe the differences of therapeutic effects on common cold of wind-cold type at early stage treated by different cupping duration. METHODS: Sixty cases of common cold of wind-cold type were randomly divided into an observation group and a control group by fifty-fifty. Flash cupping was applied at Dazhui (GV 14), Fengmen (BL 12), Feishu (BL 13), Xinshu (BL 15) and Geshu (BL 16), etc., and the cupping was retained for 25-30 min in the observation group and 15 min in the control group. The therapeutic effects were compared after twice treatments. RESULTS: The total effect rate was 93.3% (28/30) in observation group, superior to that 66.7% (20/30) in control group (P < 0.01). CONCLUSION: The therapeutic effect of common cold of wind-cold type at early stage treated with cupping for 25-30 min is obvious, superior to that for 15 min. PMID- 21528606 TI - [Current situation of courses on diagnosis and treatment with acupuncture]. AB - The current situation of courses on diagnosis and treatment with acupuncture both domestically and internationally were analyzed in this article. It explored the methods of enhancing the dialectical thinking method in clinic through specific cases, and proposed suggestions for editions of the textbooks and examination papers on acupuncture education. It is held that the effect of courses on acupuncture diagnosis and treatment may directly influence the ability of student on application of acupuncture in disease prevention and treatment. Acupuncture education abroad is featured with flexibility and practicability. However, attention attached on theory is not enough. Oppositely, domestic courses focus more on theoretical study, but neglect the hands-on ability. Although certain result has been achieved by various forms of the domestic education reform, it still needs to be further perfected. PMID- 21528607 TI - [Intermediate structure of the interior-exterior relationship between lung and large intestine]. AB - Through analysis and study of ancient literatures, it is primarily approved that there existed a connective subject, namely intermediate structure, between the "lung-lung meridian" and the "large intestine-large intestine meridian", which can promote the interior-exterior close relationship between the two. It mainly includes intermediate of the organism (throat, supraclavicular fossa, the bone formed elbow joint, nose, anus and skin), intermediate of acupoints (Luo connecting points) and intermediate of zang-fu, meridians and collaterals (stomach and the Stomach Meridian of Foot-Yangming, liver and Liver Meridian of Foot-Jueyin). The theory provides new thoughts for study on the interior-exterior relationship between the corresponding zang and fu organs. PMID- 21528608 TI - [Thinkings on the key brain region activated by needling with the baseline state fMRI]. AB - After reviewing the literatures in recent years, it is of importance to investigate on the key brain region activated by needling with the baseline state fMRI in research of acupoint specificity and brain fMRI. It is valuable to define two ways to determine the key brain region: one is the so called Seek True, while the other one is the so called Prove Wrong, and some examples of applications of the two methods are given in order to prove that the methods are feasible on determining the key brain region. PMID- 21528609 TI - [Contribution of Zhenjiu jiayi jing (A-B classic of acupuncture and moxibustion) to surface anatomy]. AB - The knowledge of surface anatomy in the ancient classic Zhenjiu Jiayi Jing (A-B Classic of Acupuncture and Moxibustion) is expounded in this article through comprehensive reading of the book and study of surface anatomy. The description and application of body surface landmarks,recording of the length of skeleton at the surface of the body,location of the viscera,palpation on arteries at the surface of the body and dynamic selection of acupoints are studied as well,which provide basis for locating and selecting of acupoints. PMID- 21528610 TI - [Health care and disease prevention in Jiujing Tu (Illustration of moxibustion) of the Dunhuang caves]. AB - Figure four of the Jiujing Tu (Illustration of Moxibustion) of the Dunhuang Caves is the earliest and the most complete recording of treatment for five kinds of strain and seven kinds of impairments in the history of acupuncture and moxibustion. Figure 12 is held as a mystery since it only provided illustrations without indications. Through analysis and approved by clinical experiences, it is held that the two figures are companion illustrations on prevention and treatment of five kinds of strain and seven kinds of impairments as well as health keeping with moxibustion. The point prescriptions in these two figures are defined according to the tri-gram in Yijing (The Book of Change), which allowed the maximization of harmony between the human and the nature. Recovery and health are thus fulfilled through regulation on points at the head, trunk and four extremities of the body. And it is considered to have great significance for promoting the development of the present acupuncture and moxibustion theory since it is effective in both preventing and curing diseases caused by deficient and stagnation conditions such as the wei (flaccidity) syndrome, bi (arthralgia) syndrome, paralysis, dementia, asthma and so on. PMID- 21528611 TI - [Recent developments of the study on the energy metabolism in the meridians]. AB - Based on the literatures retrieved on CNKI and PubMed database in recent twenty years, the major indices of meridian activities, for instance, ATP, oxygen partial pressure, transcutaneous CO2 emission, pH value, temperature, and the energy metabolic characters along the meridians, are analyzed and summarized in this paper. The selection requirements of study subjects, the acupoint selection principles, and research methods are introduced in great detail according to selecting appropriate pathological model, applying the specifity of acupoints and the physiologic characteristics of meridians in order to establish cooperation among relevant fields. PMID- 21528612 TI - The successful "Guthrie test" celebrates its 10th birthday in Brazil! PMID- 21528613 TI - Facing type 2 diabetes in the healthcare reform era. AB - One of the greatest challenges facing healthcare systems today is the management of chronic disease. Patients with chronic diseases often require multiple medications, frequent physician visits and monitoring, and even hospitalization. Diabetes is one of the most prevalent chronic conditions in the United States, affecting over 20 million Americans. Diabetes causes significant morbidity and mortality and places a tremendous strain on the American healthcare system. One of the greatest contributing factors to the increase in diabetes prevalence is the increased incidence of obesity; in 2000, almost 20% of Americans were considered obese. In order to fight the growing prevalence of diabetes, numerous guidelines and consensus statements have been issued to lay the groundwork for the management and prevention of this chronic disease. Despite these efforts, significant barriers remain. These barriers may only be overcome through significant change within the healthcare system. Value-based insurance design is one method that has the potential to bring about the necessary change to fight chronic diseases such as diabetes. Further investigation of clinical practice and payer models is necessary to resolve some of the interrelated clinical and economic issues associated with its implementation. PMID- 21528614 TI - Introduction: Evaluating the role of incretin-based therapies in the management of type 2 diabetes. PMID- 21528615 TI - [50 years of the SVTF]. PMID- 21528616 TI - [Interview with Bela Buda by Fekete Sandor, Tenyi Tamas and Osvath Peter]. PMID- 21528617 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); TRICARE Young Adult. Interim final rule with comment period. AB - This interim final rule implements Section 702 of the Ike Skelton National Defense Authorization Act for Fiscal Year 2011 (NDAA for FY11). It establishes the TRICARE Young Adult (TYA) program to provide an extended medical coverage opportunity to most unmarried children under the age of 26 of uniformed services sponsors. The TRICARE Young Adult program is a premium-based program. PMID- 21528618 TI - The seroprevalence of Lawsonia intracellularis in horses in The Netherlands. AB - Equine proliferative enteropathy caused by Lawsonia intracellularis is an emerging disease of weanling foals and affects their growth and development. The prevalence of Lawsonia intracellularis in The Netherlands is not known. The aim of the study was to investigate the seroprevalence of Lawsonia intracellularis in horses in The Netherlands. Blood samples were taken from healthy foals before and after weaning and from healthy yearlings and mature horses on farms throughout The Netherlands. These samples were analysed for the presence of Lawsonia intracellularis-specific antibodies with a blocking ELISA. White blood cell count, packed cell volume, and total protein concentration were also measured in all foals. Information regarding housing, pasture access, and contact with pig manure on the premises was obtained for all animals. The prevalence of Lawsonia intracellularis antibodies in foals increased significantly from 15% before weaning to 23% after weaning (p = 0.019); it was 89% in yearlings and 99% in horses older than 2 years. There was no significant difference in seroprevalence between the pasture-kept and stable-confined adult horses (97% and 100%, respectively), and there was no significant influence of contact with pig manure. None of the sampled animals showed clinical disease. In conclusion, the results suggest that Lawsonia intracellularis is widespread in The Netherlands and that seropositivity is not necessarily associated with clinical problems. The high seroprevalence in adult horses suggests long-term persistence of antibodies against Lawsonia intracellularis or constant exposure to the bacterium. PMID- 21528619 TI - A call to action: The 2010 survey of employment of Americans with disabilities. PMID- 21528620 TI - Spinal cord injury in Manitoba: a provincial epidemiological study. AB - OBJECTIVE: To define the epidemiological trends and identify populations at risk of traumatic and non-traumatic spinal cord injury (NTSCI) for the province of Manitoba, Canada. METHODS: We reviewed records retrospectively for subjects in three cohorts (1981-1985, 1998-2002, and 2003-2007). A total of 553 individuals with spinal cord injury (SCI) were studied for variables such as age, level of injury, severity of injury, First Nations (FN) status, and etiology of injury. RESULTS: Incidence of overall SCi has increased from 22.0 to 46.5 per million (P< 0.001). Incidence of NTSCI increased from 3.12 per million to 16.7 per million (P < 0.001). Incidence of traumatic spinal cord injury (TSCI) has increased from the 17.1 per million to 25.6 per million (P<0.001). There was a significant increase in the mean age at injury from 30.23 to 45.768 years of age (P < 0.0001). Female and NTSCI have a higher mean and median age at injury. There was a significant (P = 0.0008) increase in the proportion of females with a most recent male/female ratio of 3.4:1. A temporal increase in incomplete injuries was observed (P < 0.0001). Incomplete and thoracic level injuries are more common with NTSCI. CONCLUSION: The results demonstrate that there are significant differences between NTSCI and TSCI in Manitoba, and that Manitoba trends in SCI are in keeping with those seen on a national and an international level. There is a high risk of SCI in Manitoba FN, for which preventive strategies need to be put in place, and higher resource structure geared towards. Additionally, the trend of older age at injury has significant implications for structuring acute care and rehabilitation programs for these individuals, enhancing the need for treating older and more medically complicated individuals with SCI. PMID- 21528621 TI - Treatment of urinary tract infection in persons with spinal cord injury: guidelines, evidence, and clinical practice. A questionnaire-based survey and review of the literature. AB - OBJECTIVES: To investigate current clinical practice in the treatment of urinary tract infections (UTIs) in persons with spinal cord injury (SCI) in SCI centers where German is spoken and to compare it with current guidelines and evidence based standards evaluated by a literature review. METHODS: A standardized questionnaire was mailed to 16 SCI rehabilitation centers. The results were compared with a literature review RESULTS: Of the 16 centers, 13 responded. Indications for UTI treatment, medications, and treatment duration differed substantially among the individual centers and from the existing guidelines. Antibiotic treatment is regarded as the method of choice. Compared with the existing literature, patients in two center were undertreated, whereas they were overtreated in seven centers. CONCLUSION: Even in specialized centers, treatment of UTI in patients with SCI is based more on personal experience of the treating physicians than on published evidence. This may at least partly be due to the paucity of evidence-based data. The observed tendency toward overtreatment with antibiotics carries substantial future risks, as this strategy may well lead to the induction of multiresistant bacterial strains. Therefore, developing guidelines would be an important step toward a unification of the different treatment strategies, thus reducing unnecessary antibiotic treatment. Furthermore, evidence-based studies evaluating the success of antibiotic treatment as well as the usefulness of alternative strategies are urgently needed. PMID- 21528622 TI - Providers' beliefs and behaviors regarding antibiotic prescribing and antibiotic resistance in persons with spinal cord injury or disorder. AB - CONTEXT: Persons with spinal cord injury or disorder (SCI/D) are at increased risk for antibiotic resistance because of recurrent infections and subsequent use of antibiotics. However, there are no studies focused on providers who care for these patients and their perceptions regarding antibiotic use and resistance. OBJECTIVE: To characterize SCI/D provider behavior and attitudes about antibiotic prescribing and resistance. DESIGN/METHODS: Anonymous internet-based, cross sectional survey. PARTICIPANTS: A total of 314 SCI/D clinicians who prescribe antibiotics (physicians, physician assistants, and nurse practitioners). RESULTS: A total of 118 providers responded (37.6% response rate) including 80 physicians, 20 nurse practitioners, and 18 physician assistants. The majority of respondents agreed with statements regarding the societal impact of antibiotic resistance; only 17.8% agreed that they prescribed antibiotics more than they should, but 61.0% agreed that patient demand was a major reason for prescribing unnecessary antibiotics. The most frequent problematic organisms reported were: methicillin resistant Staphylococcus aureus (83.1%), multidrug-resistant Pseudomonas (61.0%), and Clostridium difficile (57.6%). The most frequent antibiotics selected for outpatient treatment of community-acquired pneumonia treatment, based on a clinical scenario were azithromycin (36.4%) and respiratory fluoroquinolones (22.9%). CONCLUSION: These data show that the respondents are aware of and concerned with the problem of antibiotic resistance in their practice. Clinician respondents also endorsed the need to improve their own knowledge and that of their colleagues regarding appropriate antibiotic prescribing. These findings suggest that interventions should focus on provider education, particularly regarding appropriate antibiotic prescribing. PMID- 21528623 TI - Epidemiology of clostridium difficile and vancomycin-resistant Enterococcus colonization in patients on a spinal cord injury unit. AB - BACKGROUND/OBJECTIVE: Patients with spinal cord injury (SCI) are at risk of acquiring colonization with Clostridium difficile and vancomycin-resistant Enterococcus (VRE) due to prolonged hospitalization and frequent antimicrobial use. We examined the frequency of stool, skin, and environmental contamination with C. difficile and VRE in hospitalized patients with SCl. METHODS: We performed a cross-sectional study of 22 hospitalized patients with SCI with no symptoms of C. difficile infection. Stool samples, skin, and environmental sites were cultured for C. difficile and VRE, and polymerase chain reaction ribotyping was performed for C. difficile isolates. Fisher's exact test was used to compare the proportions of skin and environmental contamination among stool carriers and non-carriers. Univariate analysis was used to assess factors associated with asymptomatic carriage of C. difficile. RESULTS: Of 22 asymptomatic patients, 11 (50%) were asymptomatic carriers of toxigenic C. difficile and 12 (55%) were carriers of VRE. In comparison with non-carriers, asymptomatic carriers of toxigenic C. difficile had higher rates of skin (45 versus 9%) (P = 0.07) and environmental contamination (55 versus 9%) (P = 0.03) and longer length of stay (median, 57 versus 6 days; P = 0.04). A majority of skin and environmental C. difficile isolates from individuals were identical to isolates from stool. In comparison with non-carriers, patients with VRE stool colonization had non significant trends toward more frequent skin (27 versus 9%) and environmental (18 versus 9%) contamination. CONCLUSION: Asymptomatic stool carriage of toxigenic C. difficile and VRE was common on an acute-care SCI unit. Asymptomatic carriers of toxigenic C. difficile had frequent skin and environmental contamination, suggesting the potential to contribute to transmission. PMID- 21528624 TI - Adherence with the National Cholesterol Education Program guidelines in men with chronic spinal cord injury. AB - OBJECTIVE: Describe the management of dyslipidemia and adherence to the National Cholesterol Educational Program (NCEP) guidelines in men with Spinal Cord Injury (SCI). RESEARCH: Cross-sectional study of a consecutive sample of men with SCI presenting to a single site for coronary heart disease (CHD) risk assessment. PARTICIPANTS/METHODS: Men age 45 to 70 with traumatic SCI (ASIA A, B, and C) at least 10 years prior to participation in the study with no prior history of clinical CHD. Medical history, blood-pressure, and fasting lipid panel were used to calculate risk for CHD using NCEP guidelines and the Framingham Risk Score (FRS). Adherence to treatment recommendations and adequacy of control were assessed based on the NCEP guidelines. RESULTS: 38 men were assessed; 15/38 (39.5%, 95% CI: 24.0-56.6%) had dyslipidemia, defined as an LDL-C above their LDL C treatment threshold (n=6) or being on treatment for dyslipidemia (n=9, for a 60% treatment rate (9/15, 95% CI: 32.3-83.7%)). Of the 9 individuals on treatment, 6 (66.7%) met their treatment goals (for a 40% overall control rate (6/15, 95% CI: 16.3-67.7%)). Dyslipidemia was well controlled in low risk individuals, but control was less common in higher risk individuals. CONCLUSIONS: Dyslipidemia is common in men age 45-70 with chronic SCI and no evidence of clinical cardiovascular disease. Rates of treatment and control of dyslipidemia in this population are far from optimal, especially among the intermediate- and high-risk groups. PMID- 21528625 TI - Smoking behavior and delivery of evidence-based care for veterans with spinal cord injuries and disorders. AB - OBJECTIVE: Little is known about those veterans with spinal cord injuries and disorders (SCI/D) who smoke cigarettes. This study identified the factors associated with smoking in this population, motivations for smoking, and the readiness for smoking cessation. Current practices for the delivery of evidence based tobacco cessation were also examined. DESIGN: Methods included surveys of veterans with SCI/D, medical record reviews of current smokers, and telephone interviews with SCI/D providers. SETTING: Six Veterans Health Administration facilities with SCI centers and one SCI clinic. PARTICIPANTS: Survey data were analyzed for 1210 veterans, 256 medical records were reviewed, and 15 providers served as key informants. INTERVENTIONS: Observational study. OUTCOME MEASURES: Veterans self-reported smoking status, quit attempts, methods and care received, motivation for smoking, and health care conditions. Medical record review and informant interviews examined the tobacco cessation care provided. RESULTS: Whereas 22% of the respondents were current smokers; 51% were past smokers. Current smokers more often reported respiratory illnesses and/or symptoms, alcohol use, pain, and depression than past or never smokers, and approximately half made quit attempts in the past year. Smokers received referral to counseling (57%) and/or prescription for medication/nicotine replacement (23%). Key informants identified difficulty of providing follow-up and patients' unwillingness to consider quitting as barriers. CONCLUSION: Veterans with SCi/D who smoke also had other health problems. Providers offer counseling and medication, but often have difficulty following patients to arrange/provide support. Identifying other support methods such as telehealth, considering the use of combination cessation therapies, and addressing other health concerns (e.g., depression) may affect tobacco cessation in this population. PMID- 21528626 TI - Do vascular risk factors contribute to the prevalence of pressure ulcer in veterans with spinal cord injury? AB - OBJECTIVE: The overall goal of this observational study was to determine whether modifiable vascular risk factors contribute to the prevalence of pressure ulcers (PrU) in veterans with traumatic spinal cord injury (SCI). BACKGROUND: Given the increasingly limited financial resources in hospitals and clinics, identifying risk factors associated with the development of PrU in persons with SCI will be a major step in reducing the cost of care for these individuals, and may improve their quality of life. METHOD: We retrospectively reviewed the electronic charts of 87 veterans with SCI who are being followed regularly in our SCI clinic and are enrolled in the SCI registry. The data collected included the basic demographics, presence of modifiable vascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and current smoking; presence of incontinence and depression; and results from blood drawn for hemoglobin level, blood urea nitrogen, creatinine, and albumin levels and lipid profile on veteran's initial enrollment. Local Institution Review Board approval was obtained for the protocol. RESULTS: Of the 87 veterans with SCI, 27 had PrU. Comparisons between those with and without PrU found no significant differences for the demographic variables of age, gender, age of SCI onset, or SCI duration, but there was a trend for the groups to differ in ethnicity (P = 0.05). Similarly, the presence of modifiable vascular risk factors including hypertension, diabetes mellitus, hyperlipidemia, and current smoking did not differ between those with and without PrU. There were 36 pressure ulcer sites observed in 27 people. The proportion of pressure ulcer sites (of the 36) significantly differed by SCI severity based on the American Spinal Injury Association (ASIA) score (P < 0.0001). CONCLUSION: This study suggests that the presence of PrU was influenced by the severity of the SCl without any contribution from modifiable vascular risk factors. PMID- 21528628 TI - Long-term outcomes of adults with pediatric-onset spinal cord injuries as a function of neurological impairment. AB - OBJECTIVE: To identify outcomes of participation, life satisfaction, and medical complications as a function of impairment in adults with pediatric-onset spinal cord injury (SCI). METHODS: Study participants were adults who sustained SCI at age 18 years or younger and were interviewed at age 24 years or older (M = 26.9, SD = 3.5). The telephone interview included a questionnaire and several standardized measures: FIM instrument (FIM), Craig Handicap Assessment and Reporting Technique (CHART), SF-12 Health Survey, and Satisfaction with Life Scale. Using the International Standards for Neurological Classification of Spinal Cord Injury and the American Spinal Injury Association (ASIA) Impairment Scale (AIS), subjects were grouped into four impairment categories: C1-C4 ABC, C5 C8 ABC, T1-L4 ABC, and AIS D. RESULTS: Of the 410 participants, 62% were male, 54% had tetraplegia, 70% had AIS A lesions, and average age at injury was 14 years (SD = 4.3). Of the 407 subjects who had complete neurological information, 59 had C1-C4 ABC, 140 had C5-C8 ABC, 168 had T1-L4 ABC, and 40 had AIS D lesions. The outcomes were delineated for education, employment, independent living and driving, marriage, participation, medical complications, health-related quality of life, and global life satisfaction, in addition to the ASIA motor score and FIM motor scores, for each of the four impairment groups. CONCLUSIONS: This information should help focus interventions that facilitate positive outcomes in relationship to the severity of impairment. In addition, these data can provide a level of expectation about long-term outcomes for newly injured children and their parents. PMID- 21528627 TI - Transmission of low-intensity vibration through the axial skeleton of persons with spinal cord injury as a potential intervention for preservation of bone quantity and quality. AB - BACKGROUND/OBJECTIVE: Persons with spinal cord injury (SCI) develop marked bone loss from paralysis and immobilization. Low-intensity vibration (LIV) has shown to be associated with improvement in bone mineral density in post-menopausal women and children with cerebral palsy. We investigated the transmissibility of LIV through the axial skeleton of persons with SCI as an initial approach to determine whether LIV may be used as a clinical modality to preserve skeletal integrity. METHODS: Transmission of a plantar-based LIV signal (0.27 +/- 0.11 g; 34 Hz) from the feet through the axial skeleton was evaluated as a function of tilt-table angle (15, 30, and 45 degrees) in seven non-ambulatory subjects with SCI and ten able-bodied controls. Three SCI and five control subjects were also tested at 0.44 +/- 0.18 g and 34 Hz. Transmission was measured using accelerometers affixed to a bite-bar to determine the percentage of LIV signal transmitted through the body. RESULTS: The SCI group transmitted 25, 34, and 43% of the LIV signal, and the control group transmitted 28, 45, and 57% to the cranium at tilt angles of 15, 30, and 45 degrees, respectively. No significant differences were noted between groups at any of the three angles of tilt. CONCLUSION: SCI and control groups demonstrated equivalent transmission of LIV, with greater signal transmission observed at steeper angles of tilt. This work supports the possibility of the utility of LIV as a means to deliver mechanical signals in a form of therapeutic intervention to prevent/reverse skeletal fragility in the SCI population. PMID- 21528629 TI - Towards personalized care for persons with spinal cord injury: a study on patients' perceptions. AB - OBJECTIVE/BACKGROUND: A newly designed Spinal Cord Unit (SCU) was set up at the Orthopedic Traumatology Center (OTC), Turin, Italy, in July 2007. With the relocation of the SCU came the need to reorganize and improve the delivery of its services. The study reported here is a preliminary part of a project entitled 'Experimentation and evaluation of personalized healthcare for patients with spinal cord injury', which is a component of an overarching program of targeted research into healthcare funded by the Piedmont Region in 2006. The aim of this study was to assess the perception of care by patients with spinal cord injury (SCI) by collecting important data in order to determine whether an integrated and personalized care pathway could be effective both in hospital and in a rehabilitation setting. DESIGN: Qualitative research study. The interview format was based on a narrative approach. METHODS: Qualitative in-depth semi-structured interviews were conducted with 21 patients with SCI. Qualitative content analysis was used to identify categories and themes arising from the data. RESULTS: Six main categories emerged from the perspectives of patients: expectations of rehabilitation care, impact and welcome, relationship with nurses and their involvement in treatment, relationship with physical therapists and participation in rehabilitation programs, relationship with physicians and their availability and attendance, and imparting of information on injury and rehabilitation outcomes. Care was the aspect new patients admitted to the SCU found most important. When closer relationships with staff formed, the healthcare professionals became an essential support. Patients with SCI commonly stated that receiving explicit information was necessary for accepting their condition. CONCLUSIONS: Analysis of the patients' perceptions revealed a wealth of details on their experience in the SCU and the need for flexible planning of care time in particular. Incorporating the patients' perceptions into a new care model could increase professionals' awareness of patients' needs and provide a useful basis for constructing a personalized care plan. PMID- 21528631 TI - Dysphagia in individuals with tetraplegia: incidence and risk factors. AB - BACKGROUND/OBJECTIVE: Dysphagia following cervical spinal cord injury (SCI) can increase risk for pulmonary complications that may delay the rehabilitative process. The objective of this study was to identify risk factors for dysphagia after cervical SCI. DESIGN: Prospective cohort study. METHODS: Individuals with cervical SCI within 31 days of injury underwent a bedside swallow evaluation (BSE) followed by a videofluoroscopy swallow study (VFSS) within 72 hours of the BSE. Subjects were diagnosed as having dysphagia if they had positive findings in either BSE or VFSS. RESULTS: Twenty-nine patients (7 female and 22 male) were enrolled. Of these, 21 (72%) had high cervical tetraplegia (C4 or higher) and 8 (38%) had lower cervical tetraplegia. A tracheostomy was present in 18 (62%) patients; 15 (52%) subjects were on ventilators. Dysphagia was diagnosed in 12 (41%) subjects. Dysphagia was noted in 62% of the subjects with tracheostomy and 53% of the subjects on the ventilator, but only tracheostomy resulted in a statistically significant association with dysphagia (P = 0.047). All three subjects who had nasogastric tubes were diagnosed with dysphagia (P = 0.029). The relationships between dysphagia and gender, high versus low tetraplegia, presence of halo or collar, head injury, and ventilator use were not statistically significant, but age was a significant risk factor (P = 0.028). CONCLUSIONS: Dysphagia is present in about 41% of individuals with acute tetraplegia. Only age, tracheostomy, and nasogastric tubes were identified as significant risk factors for dysphagia for individuals with tetraplegia. No relationship between dysphagia and level of SCI, spine surgery, collar, and ventilator use was found to exist. PMID- 21528630 TI - Effect of technique and timing of tracheostomy in patients with acute traumatic spinal cord injury undergoing mechanical ventilation. AB - OBJECTIVE: To assess the effect of timing and techniques of tracheostomy on morbidity, mortality, and the burden of resources in patients with acute traumatic spinal cord injuries (SCls) undergoing mechanical ventilation. DESIGN: Review of a prospectively collected database. SETTING: Intensive and intermediate care units of a monographic hospital for the treatment of SCI. PARTICIPANTS: Consecutive patients admitted to the intensive care unit (ICU) during their first inpatient rehabilitation for cervical and thoracic traumatic SCI. A total of 323 patients were included: 297 required mechanical ventilation and 215 underwent tracheostomy. OUTCOME MEASURES: Demographic data, data relevant to the patients' neurological injuries (level and grade of spinal cord damage), tracheostomy technique and timing, duration of mechanical ventilation, length of stay at ICU, incidence of pneumonia, incidence of perioperative and early postoperative complications, and mortality. RESULTS: Early tracheostomy (<7 days after orotracheal intubation) tracheostomy was performed in 101 patients (47%) and late (> or = 7 days) in 114 (53%). Surgical tracheostomy was employed in 119 cases (55%) and percutaneous tracheostomy in 96 (45%). There were 61 complications in 53 patients related to all tracheostomy procedures. Two were qualified as serious (tracheoesophageal fistula and mediastinal abscess). Other complications were mild. Bleeding was moderate in one case (late, percutaneous tracheostomy). Postoperative infection rate was low. Mortality of all causes was also low. CONCLUSION: Early tracheostomy may have favorable effects in patients with acute traumatic SC. Both techniques, percutaneous and surgical tracheostomy, can be performed safely in the ICU. PMID- 21528632 TI - Cervical spinal cord multiple sclerosis: evaluation with 2D multi-echo recombined gradient echo MR imaging. AB - OBJECTIVE: The two-dimensional multi-echo recombined gradient echo (MERGE) technique automatically acquires and sums multiple gradient echoes at various echo times in cervical spine magnetic resonance (MR) imaging. This technique increases the grey-white matter contrast within the spinal cord and should also improve the depiction of cervical cord lesions. The aim of this study was to qualitatively and quantitatively evaluate MERGE imaging compared with T2-weighted fast spin-echo (T2WFSE) imaging for depicting multiple sclerosis (MS) lesions in the cervical cord. METHODS: Nineteen consecutive patients (10 males and 9 females; age range 22-62 years, mean age 43.6 years) with clinically diagnosed MS were examined with cervical spinal cord MR imaging at 3 T including both MERGE and T2WFSE imaging. Qualitative evaluation for MS lesion conspicuity was performed. The quantitative criterion utilized to compare MERGE imaging with T2WFSE imaging was the lesion-to-background contrast-to-noise ratio (CNR). RESULTS: MERGE imaging showed 79 lesions and missed 1 that was depicted on T2WFSE imaging. T2WFSE imaging showed 46 lesions and missed 34 that were depicted on MERGE imaging. MERGE imaging was markedly superior to T2WFSE imaging in rendering greater lesion conspicuity. In the quantitative evaluation, the lesion-to background CNR upon MERGE imaging was significantly higher than that upon T2WFSE imaging (P < 0.001, paired t-test). CONCLUSIONS: MERGE imaging in the cervical spinal cord increases detection and conspicuity of MS lesions. Strong consideration should be given to utilizing axial MERGE images in the diagnosis and follow-up study of cervical cord MS. PMID- 21528633 TI - Influence of motor complete spinal cord injury on visceral and subcutaneous adipose tissue measured by multi-axial magnetic resonance imaging. AB - OBJECTIVE: Abdominal obesity conveys substantial health risks, in association with high levels of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and an increased proportion of VAT to SAT. The purposes were to determine the influence of spinal cord injury (SCI) on the associations between single axial cross-sectional area (CSA) slices and the average CSA or volumes of VAT and SAT across multi-axial slices of magnetic resonance imaging (MRI); and the relationships relative to the whole body composition and anthropometrics. METHODS: Thirteen healthy male participants with traumatic motor complete SCI underwent fast spin-echo MRI to measure VAT and SAT across multi-axial slices, followed by dual-energy X-ray absorptiometry to measure whole body fat-free mass (FFM) and fat mass (FM). Waist circumference (WC) was also measured in the seated position. RESULTS: The trunk CSAs of VAT and SAT were 99 +/- 51 and 164 +/- 69 cm2, respectively, and the ratio of VAT to SAT was 0.68 +/- 0.33. The CSAs of VAT and SAT at a single slice strongly predicted the average CSA and modestly predicted the volumes across multi-axial slices. VAT and SAT represented 5.7 +/- 1.8% and 9.7 +/- 3.2% of the total body FM, respectively. Percent body FFM was negatively related to VAT and SAT volumes, but not to a single axial CSA. CONCLUSION: A single slice CSA can modestly predict the volume of multi-axial slices in individuals with SCI, yet it is not related to any of the body composition variables. Increased percent FFM is associated with a reduction in VAT and SAT volumes measured across multi-axial slices. The ratio of VAT to SAT is greater than 0.4, suggesting that individuals with SCI are at high risk of developing metabolic sequelae. PMID- 21528634 TI - Evaluation of activity monitors in manual wheelchair users with paraplegia. AB - OBJECTIVE: The aim of this study was to evaluate the performance of SenseWear (SW) and RT3 activity monitors (AMs) in estimating energy expenditure (EE) in manual wheelchair users (MWUs) with paraplegia for a variety of physical activities. METHODS: Twenty-four subjects completed four activities including resting, wheelchair propulsion, arm-ergometry exercise, and deskwork. The criterion EE was measured by a K4b2 portable metabolic cart. The EE estimated by the SW and RT3 were compared with the criterion EE by the absolute differences and absolute percentage errors. Intraclass correlations and the Bland and Altman plots were also used to assess the agreements between the two AMs and the metabolic cart. Correlations between the criterion EE and the estimated EE and sensors data from the AMs were evaluated. RESULTS: The EE estimation errors for the AMs varied from 24.4 to 125.8% for the SW and from 22.0 to 52.8% for the RT3. The intraclass correlation coefficients (ICCs) between the criterion EE and the EE estimated by the two AMs for each activity and all activities as a whole were considered poor with all the ICCs smaller than 0.75. Except for deskwork, the EE from the SW was more correlated to the criterion EE than the EE from the RT3. CONCLUSION: The results indicate that neither of the AMs is an appropriate tool for quantifying physical activity in MWUs with paraplegia. However, the accuracy of EE estimation could be potentially improved by building new regression models based on wheelchair-related activities. PMID- 21528635 TI - Unilateral right occipital condyle to C2 level spinal cord infarction associated with ipsilateral vertebral artery stenosis and contralateral vertebral artery dissection: a case report. AB - OBJECTIVES: To illustrate the clinical presentation, diagnosis, management, and outcome of unilateral right occipital condyle to C2 level spinal cord infarction. SETTING: A teaching hospital in Taiwan. FINDINGS: A 37-year-old man presented with acute-onset severe right neck pain before weakness developed in both right limbs. Early diagnosis was delayed due to mild intervertebral herniation of the C4-C5 disk. Magnetic resonance imaging revealed unilateral right occipital condyle to C2 level infarction. Angiography showed stenosis of the right vertebral artery (foraminal and intradural segments), and dissection of the left vertebral artery at the C1-C2 level. At discharge, he walked with assistance; 2 weeks later, he walked independently. CONCLUSIONS: An early diagnosis is difficult but important, as it facilitates appropriate treatment for better functional and survival outcomes. Accurate early diagnosis can be made with adequate knowledge of spinal cord infarction and high index of suspicion for this condition. PMID- 21528636 TI - A case report on the use of sustained release platelet-rich plasma for the treatment of chronic pressure ulcers. AB - BACKGROUND/OBJECTIVES: Chronic pressure ulcers affect patient health, emotional state, and quality of life, causing considerable morbidity and mortality in addition to contributing to significant health care costs from lengthy hospitalizations to advanced home care and surgical care costs. The conventional treatment of these wounds can be slow due to their chronic inflammatory state and the senescence of local reparative cells. Platelet-rich plasma (PRP) therapy has been growing as a viable treatment alternative for a number of clinical applications and has potential benefit for use in chronic wounds. The sustained release of large quantities of autologous growth factors, cytokines, and other mediators found in PRP plus the favorable mononuclear cell profile of PRP may help us to stimulate wound healing and resolve chronic inflammation. METHODS: Three veterans with spinal cord injury (SCI), presenting with chronic stage IV pressure ulcers, were treated with a sustained release PRP therapy to stimulate wound healing. RESULTS: PRP treatment consistently resulted in the formation of granulation tissue and improved vascularity for each of the three patients treated, while reducing the overall ulcer area and volume. CONCLUSION: The controlled release of growth factors from PRP demonstrated a positive stimulatory effect on the healing rate of chronic pressure ulcers in individuals with SCI. PMID- 21528637 TI - Determination of glyceryl trinitrate and its two main metabolites in human plasma using a new sensitive gas chromatography method. AB - The aim of the present study was to determine the concentrations of nitroglycerin (glyceryl trinitrate, GTN, CAS 55-63-0) and its two main stable metabolites; 1,2 dinitroglycerin (1,2-glyceryl dinitrate, GDN, CAS 621-65-8) and 1,3 dinitroglycerin (1,3-GDN, CAS 623-87-0) in human plasma using a capillary gas chromatography method with an electron capture detection. Using the GC conditions, linear calibrations were obtained for 1,3-GDN from 0.14 to 3 ng/mL, for 1,2-GDN from 0.06 to 6 ng/mL, and for GTN from 0.01 to 0.3 ng/mL in plasma samples by the following calibration curve equations: [y = 0.1924x - 0.0088 (r = 0.999)], [y = 0.2273x + 0.0164 (r = 0.995)], [y = 17.434x - 0.0751] for 1,3-GDN, 1,2-GDN, and GTN respectively. The calculated limits of quantification values for GTN, 1,2-GDN, and 1,3-GDN were 0.03 ng/mL, 0.2 ng/mL, and 0.15 ng/mL respectively. This method was verified with a bioequivalence study of an Iranian brand of oral sustained release nitroglycerin with an innovator formulation. PMID- 21528638 TI - Effect of 20(S)-protopanaxatriol and its epimeric derivatives on myocardial injury induced by isoproterenol. AB - OBJECTIVE: It was reported Panax ginseng had diverse components and multifaceted pharmacological functions. This study aims to investigate the effect of 20(S) protopanaxatriol (PT, CAS 179799-20-3) and its epimeric derivatives (20S, 24R epoxy-dammarane-3beta, 6alpha, 12beta, 25-tetraol, PTD1 and 20S, 24S-epoxy dammarane-3beta, 6alpha, 12beta, 25-tetraol, PTD2) on myocardial injury induced by isoproterenol in rats. METHODS: Male Wistar rats were administered orally 20(S)-protopanaxatriol or its epimeric derivatives for 7 days. Four days after treatment, all rats, except those in the control group, were subcutaneously injected with isoproterenol (20 mg/kg) for 3 consecutive days. Two hours after the last isoproterenol injection, the rats were anaesthetized and sacrificed. The biochemical parameters were assayed and pathological examination of the heart tissues was performed. RESULTS: Administration of PT and PTD1 resulted in a reduction in creatine kinase and lactate dehydrogenase. PT and PTD1 Inhibited not only the elevation of malondialdehyde content, but also the reduction of superoxide dismutase activity, glutathione peroxidase and total antioxIdant capacity. The pathohistological changes induced by isoproterenol were also ameliorated by PT and PTD1. CONCLUSION: The present findings suggest that PT and PTD1 exerted cardioprotective effects against myocardial ischemic injury by enhancing the anti-free-radical actions of heart tissues. Furthermore the results indicated that the configuration of C-24 of the funan ring was involved in the phannacological action of the epimeric derivatives of 20(S)-protopanaxatriol. PMID- 21528639 TI - Study on the bioequivalence of two formulations of eplerenone in healthy volunteers under fasting conditions: data from a single-center, randomized, single-dose, open-label, 2-way crossover bioequivalence study. AB - BACKGROUND: Eplerenone (CAS 107724-20-9) prevents the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone-system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular disease and is indicated, in addition to standard therapy including beta blockers, to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (LVEF < or = 40%) and clinical evidence of heart failure after recent myocardial infarction. OBJECTIVE: The aim of this study was to assess the bioequivalence of a new eplerenone 50 mg formulation (test formulation) vs. the reference product, as required by European regulatory authorities for the marketing of a generic product. METHODS: This was a single-center, randomized, single-dose, open-label, 2-way crossover study in healthy volunteers under fasting conditions. Plasma samples were collected up to 24 h post-dosing and plasma eplerenone levels were determined by reversed phase high performance liquid chromatography and by tandem mass spectrometry detection (ie, the LC-MS/MS method). Pharmacokinetic parameters were calculated using non compartmental analysis. Area under the concentration-time curve from time zero to time of last non-zero concentration (AUClast) and maximum observed concentration (Cmax) were the main evaluation criteria. All of the above-mentioned pharmacokinetic parameters were analyzed using 90% geometric confidence interval of the ratio (T/R) of least-squares means from the ANOVA of the 1n-transformed parameter. Tolerability was monitored using physical examination, including vital sign measurements and laboratory analysis. RESULTS: According to the classical approach, the 90% geometric confidence intervals obtained by analysis of variance for AUClast and Cmax were within the predefined ranges (80.00-125.00%). CONCLUSION: Bioequivalence between test and reference formulations, both in terms of rate and extension of absorption, under fasting conditions was concluded according to European guidelines. Both formulations were well tolerated. PMID- 21528640 TI - Antihypertensive efficacy and safety of benidipine and its effects on cardiac structure and function in elderly Chinese patients with mild to moderate hypertension: an open-label, long-term study. AB - Benidipine (CAS 91599-74-5) has been reported as an effective antihypertensive treatment and its cardioprotective effects have been shown in several basic and clinical studies. However, the long-term efficacy and safety of benidipine remain unknown in elderly Chinese patient with hypertension. In this prospective, multicenter, open-label clinical trial, 152 eligible patients aged 60 to 75 years with mild to moderate essential hypertension (sitting systolic blood pressure (BP) > or = 140 mmHg and/or sitting diastolic BP > or = 90 mmHg) entered a 52 week study. All patients initially received benidipine 2-4 mg once a day, followed by titration to benidipine 8 mg/day to achieve the target BP (< 140/90 mmHg in non-diabetics and <130/80 mmHg in diabetics). Add-on hydrochlorothiazide (CAS 58-93-5) and/or metoprolol tartaric acid (CAS 3750-58-6) were permitted during the study. Overall, 132 patients completed the 52-week treatment with benidipine as monotherapy or combination therapy. It showed that the regimen based on benidipine provided an obvious mean trough BP reduction of 13.8 +/- 12.4/8.3 +/- 9.2 mmHg (p < 0.001), and 62.5% of patients reached the target BP. In patients with left ventricular hypertrophy, the left ventricular mass index significantly decreased from 147.1 +/- 27.6 g/m2 at baseline to 136.0 +/- 17.5 g/m2 at 52 weeks (p = 0.036). Clinical adverse events (AEs) were found in 15.1% of all patients, and six patients discontinued the treatment due to drug-related AEs during the entire trial. Patients' compliance was an average of 98.7%. Benidipine, with a favorable tolerability profile, provides a long-term antihypertensive effect and potential benefit for the heart in elderly patients with mild to moderate hypertensive, suggesting that it is suitable for elderly patients with hypertension. PMID- 21528641 TI - Pharmacokinetics and bioequivalence study of two mosapride citrate formulations after single-dose administration in healthy Chinese male volunteers. AB - The pharmacokinetics and relative bioavailability/bioequivalence of two formulations of mosapride citrate (CAS 112885-42-4) were assessed in this study. The study was conducted in 20 healthy Chinese male volunteers according to an open, randomized, single-blind, 2-way crossover study design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 12 h post-dose, and mosapride citrate plasma concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Based on the plasma concentration-time data of each individual during two periods, pharmacokinetic parameters, Cmax, AUCo-t,, AUCo-infinity, and t1/2, were calculated by applying non-compartmental analysis. Pharmacokinetic data for test and reference formulations were analyzed statistically to test for bioequivalence of the two formulations. After oral administration, the values of Cmax, Tmax, t1/2, AUCo-t, AUCo-infinity for test and reference formulations were 68.48 +/- 22.95 and 70.69 +/- 23.78 ng/mL, 0.46 +/- 0.20 and 0.49 +/- 0.21 h, 2.30 +/- 0.30 and 2.24 +/- 0.28 h, 161.17 +/- 52.75 and 171.37 +/- 59.02 ng x h/mL, 165.76 +/- 54.34 and 175.77 +/- 60.54 ng x h/mL, respectively. Both primary target parameters, AUCo-infinity and AUCo-t, were tested parametrically by analysis of variance (ANOVA). Relative bioavailabilities were 95.3 +/- 11.3% for AUCo infinity and 95.2 +/- 11.3% for AUo-t. Bioequivalence between test and reference formulations was demonstrated for both parameters, AUJCo-infinity and AUCo-t. The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80-125%. That means that the test formulation is bioequivalent to the reference formulation of mosapride citrate. PMID- 21528642 TI - Beneficial effects of colchicine on 17alpha-ethynylestradiol-induced cholestasis in rats. AB - Colchicine (CAS 64-86-8) is considered to have a hepatoprotective effect and play a role in biliary excretion. 17alpha-Ethynylestradiol (EE) (5 mg/kg, subcutaneously, daily, for 5 days) causes intrahepatic cholestasis by reducing both the influx and efflux of bile acid in hepatocytes, resulting in a decrease in bile flow. The objective of this study was to evaluate whether colchicine has any effect on EE-induced cholestasis. The effects of colchicine treatment on EE induced cholestasis in rats for 5 consecutive days were evaluated. The serum components and enzymatic activity were assayed. In addition, the bile flow and biliary excretion were determined. Furthermore, western blot analysis was used to measure the expression of farnesoid X receptor (FXR), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and cholesterol 7alpha hydroxylase (CYP7A1). Colchicine not only significantly inhibited the elevation of cholestasis-related serum components and enzyme activity but also significantly attenuated the decrease of the bile flow and biliary excretion. Colchicine also remarkably increased the hepatic expression of FXR, BSEP and MRP2, but decreased that of CYP7A1. Our data indicates that colchicine treatment attenuated EE-induced cholestasis in rats, most likely by promoting bile flow and biliary excretion, and reduced the synthesis of bile acids. PMID- 21528643 TI - Design and synthesis of certain mesoionic sydnonyl styrylketones as potential nonsteroidal antiinflammatory agents. AB - In an attempt to develop effective and safer analgesic anti-inflammatory agents, nine compounds belonging to 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(4 methoxyphenyl) sydnones, containing the structural features of mesoionic sydnone and styrylketone, have been designed and synthesized by condensing 4-acetyl-3-(4 methoxyphenyl) sydnone with various substituted aryl aldehydes and characterized by spectral studies. They have been tested for analgesic activity by acetic acid induced writhing in mice and for anti-inflammatory activity by carrageenan induced rat paw edema at 100 mg/kg body weight p.o. The compounds containing furyl and chloro substituents showed highly significant analgesic effect, while those with dimethylamino, chloro and nitro substituents exhibited highly significant anti-inflammatory effect at the end of 3 h. The compounds that showed good analgesic and anti-inflammatory activities were evaluated for ulcerogenicity in rats to assess their gastric side effects at 100 mg/kg body weight p.o. They were found to be less ulcerogenic than the standard drug. PMID- 21528644 TI - Synthesis and screening of cyclooxygenase inhibitory activity of some 1,3 dioxoisoindoline derivatives. AB - In this study, 15 compounds bearing N,N-phthaloylacetamide structure designed by the molecular simplification approach based on thalidomide structure were synthesized and evaluated for inhibitory potencies against cyclooxgenase (COX) isoenzymes, namely COX-1 and COX-2. The results suggested that the N,N phthaloylacetamide structure, as a primary amide, has inhibitory activity against cyclooxygenase isoenzymes with a higher COX-1 selectivity. The conversion of the primary amide to secondary or tertiary derivatives lowered the potency but favored the COX-2 selectivity thus yielding the compounds with stronger COX-2 inhibiting activity. PMID- 21528645 TI - Pharmacokinetic properties of a once-daily formulation of tacrolimus in patients with renal transplantation. AB - The present study was designed to determine the pharmacokinetic profiles of a once-daily formulation of tacrolimus (CAS 104987-11-3; TAC-once) in patients before and after introduction of renal transplantation. Pharmacokinetic parameters for tacrolimus were almost comparable among patients receiving TAConce before, 2 weeks after and 3 weeks after renal transplantation. Among various parameters, C(trough) correlated most closely with the area under the concentration-time curve during 24 h (AUCo-24) (R2 = 0.82, P < 0.001), while no consistent correlation was observed between AUCo_24 and concentrations at 2 h or 4 h, or the dose of TAC-once. The clinical outcomes such as the incidence of acute re-jection, renal tissue injury and cytomegalovirus infection were evaluated during the first 3 weeks and 3 months after transplantation, and the data were compared with the historical data obtained from patients who had received the conventional twice-daily formulation of tacrolimus (TAC-twice). There were no significant differences in the incidence of such clinical outcomes between the two groups. These findings suggest that C(trough) is useful for therapeutic monitoring of tacrolimus in patients receiving TAC-once. In addition, pharmacokinetics and clinical outcomes were comparable between TAC-once and TAC twice formulations. PMID- 21528646 TI - Improved RP-HPLC method to determine biapenem in human plasma/urine and its application to a pharmacokinetic study. AB - Existing methods to determine biapenem (CAS 120410-24-4), a carbapenem, either lacked sensitivity/reproducibility or had no internal standard as a control. Here an improved reversed-phase high-performance liquid chromatographic (RP-HPLC) method was established in human plasma and urine. After adding p-aminobenzoic acid as the internal standard to plasma or urine, plasma samples were ultra filtrated and urine samples were diluted directly. Chromatographic separations were carried out on a 4.6 mm x 150 mm column with acetonitrile-0.1 mol/l sodium acetate (2:98, v:v; pH 4.38 or 4.00) as mobile phase and UV detection at 300 nm. The extraction recovery was 91.51% for biapenem at the concentration level of 5 microg /ml in human plasma. The linear quantification range of the method was 0.1 to approximately 50 microg /ml for plasma and urine, with linear correlation coefficients greater than 0.998. The intra-day and inter-day relative standard deviations (R.S.D.) for biapenem at low, middle and high levels in human samples were less than 12.51% for plasma and less than 7.05% for urine. The RP-HPLC method was successfully applied to pharmacokinetic studies, in which healthy subjects received multiple doses of biapenem (300 mg, i.v., b.i.d., for 5 continuous days). The pharmacokinetic results are presented. PMID- 21528647 TI - The need to assess and transform the nursing profession. PMID- 21528648 TI - What would happen if the federal healthcare bill was repealed or defunded--what nurses need to know. PMID- 21528649 TI - Advancing membrane electrodes and optical ion sensors. AB - While potentiometric sensors experienced a golden age in the 1970s that drove innovation and implementation in the clinical laboratory as sensors of choice, it has been only fairly recently that a theoretical understanding coupled with modern materials approaches transformed the area of membrane electrodes from a playful, yet empirical field to one firmly rooted in scientific understanding. This paper summarizes key progress in the field during the past two decades, emphasizing that the key impulses at the time originated from the emerging field of optical ion sensors. This simplified and transformed the underlying theory of their potentiometric membrane electrode counterparts, where subsequently substantial progress was made, including the realization of ultra-trace detection limits. The better understanding of zero-current ion fluxes and transport processes in turn allowed the development of approaches utilizing dynamic electrochemistry principles, thereby drastically expanding the field of membrane electrodes and making available a range of new methodologies that would have been difficult to predict only a few years ago. These significant developments are now starting to come back and influence the field of optical sensors, where the control and triggering of dynamic processes, away from simpler equilibrium principles, are becoming a highly promising field of research. PMID- 21528650 TI - Organic synthesis without stoichiometric reagents: a guiding principle for reaction development. AB - A common theme of our research program is the development of new organic transformations that operate under catalytic conditions or as ligation reactions that do not require the addition of any reagents or other additives. Our catalysis program features the transient generation of reactive species from alpha-functionalized aldehydes via intramolecular redox reactions using N heterocyclic carbenes as multifunctional catalysts. This approach makes possible the catalytic generation of enolates, homoenolates, and activated carboxylates and their application to diastereo- and enantioselective transformation. Intermolecular redox couplings are key to a general, highly chemoselective amide forming ligation reaction and its use for oligopeptide synthesis. The concepts behind these transformation and examples of their use as well as current and future directions of our research program are presented. PMID- 21528651 TI - Shining light at working interfaces and chiral nanoparticles. AB - In this article we present an overview of our recent research in the fields of in situ spectroscopy, nanomaterials and chirality. Our research focuses around the spectroscopic investigation of chemical reactions taking place at solid-liquid interfaces. This research goes hand in hand with the development of experimental techniques that enable us to study interface phenomena in situ. Using such techniques we try to shed light on photocatalytic reactions like the decomposition of organic pollutants in water or the reduction of carbon dioxide. We are moreover interested in chiral surfaces and their ability to discriminate between enantiomers. Again this relies on special techniques that highlight the enantiodiscriminating surface-adsorbate interactions. We furthermore seek to transfer chirality from adsorbates to metal nanoparticles. The latter are probed by chiroptical techniques, particularly also vibrational circular dichroism (VCD). Finally, we aim at preparing metamaterials with tailored optical properties by organizing plasmonic particles in two and three dimensions. PMID- 21528652 TI - Access to macrocycles with an endo aryl ether and an endo aryl-aryl bond, development and application. AB - Macrocyclization methodologies allowing access to macrocycles having an endo aryl ether and an endo aryl-aryl bond, especially those based on an intramolecular S(N)Ar reaction and the Suzuki-Miyaura reaction, are summarized. Total synthesis of complestatin, a bis-macrocyclic natural product, featuring these two technologies are presented. PMID- 21528653 TI - Microencapsulated fragrances in melamine formaldehyde resins. AB - The process for making melamine formaldehyde microcapsules containing fragrant oil is well-known. Recently, this technology has been used to enhance the olfactory performance on fabrics. However keeping the fragrance in the capsule during storage, improving the olfactory benefit and releasing a low amount of formaldehyde is highly challenging. To answer these challenges, Givaudan has developed its own melamine formaldehyde microcapsule, called Mechacaps, which is described in this article. PMID- 21528654 TI - Membranes for specific adsorption: immobilizing molecularly imprinted polymer microspheres using electrospun nanofibers. AB - Molecularly imprinted polymer microspheres were immobilized within a polymer nanofiber membrane by electrospinning. Such membranes simplify the handling of functional microspheres and provide specific recognition capabilities for solid phase extraction and filtration applications. In this study, microspheres were prepared by precipitation polymerization of methacrylic acid and divinylbenzene as a cross-linker with the target molecule (-)-cinchonidine and then, they were electrospun into a non-woven polyacrylonitrile nanofiber membrane. The composite membrane showed specific affinity for (-)-cinchonidine which was attributed to the functional microspheres as confirmed by Raman microscopy. The target molecule capturing capacity of the composite membrane was 5 mg/g or 25 mg/g immobilized functional microsphere. No difference in target affinity was observed between the immobilized microspheres and the free microspheres. These results reveal that electrospun composite membranes are a feasible approach to immobilizing functional microspheres. PMID- 21528655 TI - Postoperative radiotherapy in prostate cancer: acquired certainties and still open issues. A review of recent literature. AB - It is recognized that radiation therapy can eradicate microscopic tumor disease, even in postoperative prostate cancer patients, when extracapsular extension, positive surgical margins or increased prostate-specific antigen is found in surgical specimens. This review of recent literature analyzes and discusses acquired certainties and still open questions regarding type, timing, doses, techniques, toxicities, and associated hormonal therapies of radiotherapy prescribed after radical prostatectomy. PMID- 21528656 TI - Lung cancer risk and residence in the neighborhood of a sewage plant in Italy. A case-control study. AB - AIMS AND BACKGROUND: Environmental pollution originating in sewage and industrial plants can be associated with lung cancer risk, as ecological and case-control studies have indicated. In the present study, the association between lung cancer occurrence and residence near a sewage plant in Prato (Italy) was investigated. A previous geographic study in the same area had shown an increasing trend of lung cancer mortality and incidence with propinquity to the plant. METHODS: A case control study was carried out in the male population of Prato. Incident cases in the period 1987-1997 were identified from the Tuscan Cancer Registry (no. 918). Controls were randomly extracted from the Registry Office of the Municipality of Prato (no. 1852). For all subjects, the residential history was reconstructed. A weighted average distance from the plant was computed and used as a proxy variable of exposure. Two analyses were performed: on the whole data set and on a subset of subjects for whom information on tobacco exposure and education was obtained through a postal questionnaire (response rate, 41.1%). Logistic regression models were applied to estimate odds ratios and 95% CI. RESULTS: Both analyses showed a significantly elevated lung cancer risk for subjects living within 1.5 km (ORwhole= 1.56, 1.06-2.28; ORsubset= 2.28, 1.06-4.86) and suggested a risk increase with a decrease of weighted average distance from the plant. CONCLUSIONS: The findings highlight a possible role, in lung cancer occurrence, for environmental pollution spread from the plant. Due to drawbacks of the study, further analyses are needed to evidence a noncontroversial etiological conclusion. When environmental data are not available, results of epidemiological studies using residential histories may be useful in preventive policies regarding point source emissions. PMID- 21528657 TI - Is cancer overtaking cardiovascular diseases as the killer number one in men in Tuscany? AB - AIMS AND BACKGROUND: For the first time in 2006, cancer became the main cause of death in men in Italy, exceeding cardiovascular disease. The aim of the study was to verify whether the overtaking of cancer male mortality occurred also in Tuscany or in some of its 12 subregional areas and whether there was a geographical trend. METHODS: Age-standardized mortality rates from the Tuscan Regional Mortality Registry, 1987-2008, were calculated for neoplasms, cardiovascular diseases, and respiratory diseases, considering the whole region and its 12 areas. Joinpoint analyses were carried out to study temporal trend. RESULTS: Up to 2008, the number of male deaths for neoplasms (6786) in Tuscany did not exceed deaths from cardiovascular disease (7065). Instead, overtaking occurred in some subregional areas from 2004 onwards. When we compared age standardized mortality rates, cancer became the first cause of death in Tuscany from 2004 onwards (age-standardized mortality rates for cancer 236.5 per 100,000; for cardiovascular disease 227.8 per 100,000). Age-standardized mortality rates for cardiovascular disease recorded an annual 2.4% decrease until 1998, then a 3.5% decrease. Age-standardized mortality rates for all cancers recorded an annual 1.6% decrease in the whole period. CONCLUSIONS: Our study confirmed a geographical trend in cancer overtaking as the main cause of death in males: from the more urbanized areas in northern Tuscany, where the phenomenon occurred earlier, to the southern part. PMID- 21528658 TI - Hepatic arterial infusion chemotherapy for liver metastases from gastric cancer: an analysis in Western patients. AB - AIMS AND BACKGROUND: The advantage of administering chemotherapy by hepatic arterial infusion is the achievement of high drug concentrations in the liver. Oxaliplatin, irinotecan and 5-flourouracil are active agents in advanced gastric cancer. Therefore a retrospective analysis was performed to investigate the effects of these drugs administered by hepatic arterial infusion in heavily pretreated gastric cancer patients with predominant hepatic metastases. Very limited data about hepatic arterial infusion exist in western gastric cancer patients. METHODS: Seven patients with advanced gastric cancer were included in the retrospective analysis. All patients had proven progressive disease prior to initiation of hepatic arterial infusion. All had an ECOG performance status of < or =2 and had received at least two previous systemic chemotherapy regimens, including the combination of cisplatin/5-fluorouracil. Patients were given chemotherapy by hepatic arterial infusion: 5-fluorouracil, 600 mg/m2, together with folinic acid, 300 mg/m2/2 h, followed by oxaliplatin, 85 mg/m2/2 h, every 2 weeks. RESULTS: Fifty-four cycles of hepatic arterial infusion (range, 2-21) with a median treatment duration of 6 cycles were administered in 7 patients. The treatment was feasible and safe, no grade 3-4 toxicity was observed. One patient showed stabilization of liver metastases over 7 months. In 6 of the 7 patients there was radiologically proven progressive disease after a median treatment time of 10 weeks. CONCLUSIONS: Chemotherapy by hepatic arterial infusion is modestly effective in heavily pretreated gastric cancer patients. Hepatic arterial infusion has a very favorable toxicity profile and can be safely administered even in elderly patients. It might be an additional therapeutic option and should be further investigated. The literature on hepatic arterial infusion in gastric cancer patients is reviewed. PMID- 21528660 TI - Chemotherapy use at the end of life. A retrospective single centre experience analysis. AB - AIMS AND BACKGROUND: The aim of the study was to evaluate the attitude at our institution in using chemotherapy at the end of life in oncology patients. We compared our habits with other clinical patterns in medical oncology, calculating the temporal interval between the last chemotherapy administration and death of the patient. PATIENTS AND METHODS: We selected and analyzed 102 patients who received chemotherapy for metastatic or advanced solid tumors (breast, colon, gastric, pancreatic and lung cancers) and who died either in or out of a hospital or hospice from June 2007 to the end of 2009. RESULTS: We compared 51 patients enrolled in clinical trials with 51 patients not enrolled in clinical trials. Patients of both groups died with advanced cancer between June 2007 and 2009. The following solid tumor types were represented: 48% colorectal cancer, 22% breast cancer, 30% other solid tumors (pancreatic, lung and gastric cancer). The median age at death was 62 years (range, 39 to 84), the male/female ratio was 52:50, and 69% of the patients were married. Most patients, 54%, received 2-3 lines of chemotherapy, 25% received more than 3 lines, and the remaining 21% one line only of chemotherapy. Of the 102 patients identified, 16 (16%) received chemotherapy in the last month of life, and 6 (6%) of these in the last 2 weeks. We speculated that the presence of palliative care services in the territory of residence of patients could influence the time interval between the last chemotherapy and death. We found that 52 patients (51%) lived in areas where palliative care services were not available, 27 (52%) of them received chemotherapy in the last 3 months, 8 (15%) in the last month, and 5 (10%) within the last 2 weeks of life. In contrast, of the 49 patients living in the territory served by palliative care units or a hospice, none received chemotherapy during the last 2 weeks of life and 37% received it during the last 3 months of life (P = 0.003). CONCLUSIONS: Among selected patients who died for advanced cancer in our Operative Unit from 2007 to 2009, 50% received chemotherapy in the last 3 months of life. The availability of palliative care services in the territory of residence of patients can influence the interval between the last chemotherapy administration and death. PMID- 21528659 TI - Systemic chemotherapy with pemetrexed and cisplatin for malignant peritoneal mesothelioma: a single institution experience. AB - BACKGROUND AND AIMS: Primary malignant peritoneal mesothelioma is a rare malignancy with an unfavorable prognosis. Pemetrexed has proven effective in the treatment of malignant mesothelioma, alone or in combination with platinum agents. In the present study, chemo-naive patients were evaluated for the efficacy and safety of the pemetrexed-cisplatin combination. METHODS: Six patients with diffuse peritoneal mesothelioma were treated with 6 cycles of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2). Chemotherapy was administered on an outpatient basis every 3 weeks. RESULTS: Complete response was observed in 2 patients (33%) and partial response was observed in 3 patients (50%). The estimated median overall survival was 24 months and the estimated median time to disease progression was 9.5 months. The regimen was well tolerated. CONCLUSIONS: Though our data reflect a small sample size, pemetrexed plus cisplatin accomplished a particularly high clinical benefit rate on chemo-naive patients. PMID- 21528661 TI - Small nodular melanoma: the beginning of a life-threatening lesion. A clinical study on 11 cases. AB - AIMS AND BACKGROUND: Because of its high thickness, nodular melanoma often bears a poor prognosis. Thus, an earlier diagnosis of this type of lesion while it is still thin would be an important step in secondary prevention. The principal aim of the present study was to better define the initial clinical features of nodular melanoma to allow an early diagnosis. A secondary aim was to establish the prognosis of this type of lesion. METHODS: We retrospectively studied and illustrated the clinical features of 11 small (< or = 6 mm maximum diameter) cutaneous nodular melanomas seen and treated during a 10-year period. Prognostic characteristics of the various lesions were also described. RESULTS: The results of the study help to describe a small nodular melanoma as a dark and/or pink/red raised lesion, which may be evenly or unevenly colored, with well-defined borders, that often appears de novo. A correct clinical diagnosis was made in 7 of the cases. During a median follow-up of 6 years, none of the patients had local or distant relapses. CONCLUSIONS: Detection of small nodular melanoma is feasible by accurate visual inspection, provided that physicians are aware of this type of lesion and maintain the index of suspicion at a high level to bring about curative surgery. PMID- 21528662 TI - Alkaline phosphatase levels as a prognostic factor in metastatic colorectal cancer treated with the FOLFOX 4 regimen: a monoinstitutional retrospective study. AB - AIMS AND BACKGROUND: Metastatic colorectal cancer has a heterogeneous behavior, and a set of patients will have minimal response and rapid disease progression. To understand this heterogeneity, studies have evaluated biological and clinical prognostic factors. Alkaline phosphatase seems to be a key prognostic factor, so we have reviewed the outcomes of our patients with respect to alkaline phosphatase levels. METHODS AND STUDY DESIGN: Between January 2003 and December 2008, we treated with the FOLFOX 4 regimen 103 consecutive patients with metastatic colorectal cancer. Thirty-two patients had alkaline phosphatase > or =300 U/l. RESULTS: Median time to progression was 4 months for patients with high alkaline phosphatase levels and 8 months for those with low alkaline phosphatase levels. Median overall survival was 8 and 17.5 months, respectively. Only 3 patients in the high alkaline phosphatase group obtained partial response (9.4%) compared to 3 complete responses and 24 partial responses (41.5%) in low alkaline phosphatase group. Toxicity was substantially different, with more grade 3-4 neutropenia, diarrhea and oral mucositis in the high than low alkaline phosphatase group. CONCLUSIONS: Alkaline phosphatase is an uncomplicated and potent prognostic factor. Patients with high alkaline phosphatase levels had a poor prognosis. PMID- 21528663 TI - Image-guided stereotactic body radiation therapy for localized prostate cancer. AB - PURPOSE: We report the results of a retrospective study of stereotactic body radiation therapy (SBRT) using CyberKnife for localized prostate cancer. The study focused on the safety and feasibility of this treatment modality. MATERIALS AND METHODS: Between October 2002 and December 2007, 44 patients suffering from localized adenocarcinoma of the prostate were treated with SBRT using CyberKnife at the Korea Cancer Center Hospital. The patients were divided into 3 groups: a low-risk group (5 patients), an intermediate-risk group (10 patients), and a high risk group (29 patients). Five patients received 32 Gy in 4 fractions, 28 patients received 34 Gy in 4 fractions, and 11 patients received 36 Gy in 4 fractions. RESULTS: The median age of the patients was 69 years (range, 53-79 years) and the median duration of follow-up 40 months (range, 12-78 months). There were 6 acute and 3 late grade 2 urinary toxicities, and 4 acute and 5 late grade 2 rectal toxicities, but there were no grade 3 or higher treatment-related toxicities. The 5-year cause-specific survival rate and progression-free survival rate were both 100%. At last follow-up, the biochemical failure-free rate of the low-risk, intermediate-risk and high-risk patients was 100%, 100% and 90.8%, respectively. CONCLUSION: SBRT using CyberKnife for localized prostate cancer is safe and well tolerated. We obtained promising results with 34 Gy in a 4-fraction regimen especially for the high-risk patients. PMID- 21528664 TI - Efficacy of eradicative radiotherapy for limited nodal metastases detected with choline PET scan in prostate cancer patients. AB - AIMS AND BACKGROUND: In patients with recurrent prostate cancer, discriminating local or systemic recurrence is critical to decide second-line treatment. We investigated the capability of stereotactic body radiotherapy to treat limited nodal recurrences, detected using choline PET scan. METHODS AND STUDY DESIGN: Seventy-one patients with biochemical failure were studied after prostate cancer treatment: prostatectomy (28), radiotherapy (15) or both (28). Following computed tomography and choline PET imaging, stereotactic body radiotherapy was delivered on pathological lymphatic areas by 6 MV Linac, using dynamic micromultileaf collimation and intensity-modulated arc therapy optimization. Sixty days post treatment, choline PET/CT imaging was carried out. RESULTS: Median follow-up was 29 months (range, 14.4-48). Choline PET detected recurrences in 39 of 71 patients. Median PSA velocity was 0.40 ng/ml/year in PET-negative patients and 2.88 ng/ml/year in PET-positive subjects (P < 0.05). Twenty-five patients with limited nodal recurrences, out of the 71 submitted to choline PET, received eradicative radiotherapy. Persistent regression was recorded in 13; early spread to bone was found in 2 cases; lymph node recurrences in 8, all in sites outside the irradiated areas; 2 patients were lost to follow-up. At the 3-year follow-up, overall survival, disease-free survival and local control rates were 92%, 17% and 90%, respectively. In patients with a complete regression, PSA fell from 5.65 to 1.40 ng/ml (median). PSA nadir value (median 1.06 ng/ml) was maintained for 5.6 months (median). CONCLUSIONS: Stereotactic body radiotherapy was effective in disease eradication of limited nodal recurrences from prostate cancer, saving patients from, or at least postponing, systemic treatments. PMID- 21528665 TI - Treatment of recurrent glioblastoma with stereotactic radiotherapy: long-term results of a mono-institutional trial. AB - AIMS AND BACKGROUND: Few clinical data exist concerning normal brain tissue tolerance to re-irradiation. The present study evaluated long-term outcome of 22 recurrent glioblastoma patients re-irradiated with radiosurgery or fractionated stereotactic radiotherapy. METHODS: Twenty-two patients were treated with radiosurgery (13, 59%) or fractionated stereotactic radiotherapy (9, 41%) for 24 lesions of recurrent glioblastoma. The male/female ratio was 14:8, median age 55 years (range, 27-81), and median Karnofsky performance status 90 (range, 70-100). The majority of the cases (77%) was in recursive partitioning analysis classes III or IV Radiosurgery or fractionated stereotactic radiotherapy was chosen according to lesion size and location. RESULTS: Median time between primary radiotherapy and re-irradiation was 9 months. Median doses were 17 Gy and 30 Gy, whereas median cumulative normalized total dose was 141 Gy and 98 Gy for radiosurgery and fractionated stereotactic radiotherapy, respectively. All patients submitted to radiosurgery had a cumulative normalized total dose of more than 100 Gy, whereas only a few (44%) of fractionated stereotactic radiotherapy patients had a cumulative normalized total dose exceeding 100 Gy. Median follow up from re-irradiation was 54 months. At the time of analysis, all patients had died. After re-irradiation, 1 (4%) lesion was in partial remission, 16 (67%) lesions were stable, and the remaining 7 (29%) were in progression. Median duration of response was 6 months, and median survival from re-irradiation 11 months. Three of 13 (23%) patients submitted to radiosurgery developed asymptomatic brain radionecrosis. The cumulative normalized total dose for the 3 patients was 122 Gy, 124 Gy, and 141 Gy, respectively. In one case, the volume of the lesion was large (14 cc), and in the other 2 the interval between the first and second cycle of radiotherapy was short (5 months). CONCLUSIONS: Re irradiation with radiosurgery and fractionated stereotactic radiotherapy is feasible and effective in recurrent glioblastoma patients. Apart from the importance of an accurate patient selection, cumulative radiotherapy dose and a correct indication for radiosurgery or fractionated stereotactic radiotherapy must be taken into account to avoid brain toxicity. PMID- 21528666 TI - Accuracy of intraoperative macroscopic diagnosis of sentinel node metastases in breast cancer: is accurate prediction possible? AB - BACKGROUND: Accurate intraoperative diagnosis of sentinel lymph node (SLN) metastases enables the selection of patients who require axillary lymph node dissection, thus avoiding an additional operation. In this study we investigated the accuracy of intraoperative macroscopic diagnosis of SLN metastases in patients with breast cancer. METHODS: SLNs from 276 breast cancer patients with clinically negative nodes were analyzed by macroscopic examination. The results of intraoperative macroscopic diagnosis were compared with those of frozen section analysis. RESULTS: The sensitivity, specificity, overall accuracy, and false negative rate of SLN biopsy in the assessment of node status were 82.1%, 100%, 96.4%, and 17.9%, respectively, for frozen section analysis, and 57.1%, 95.5%, 87.7%, and 42.9%, respectively, for macroscopic evaluation. Even in patients with node metastasis >7 mm, the false negative rate of macroscopic evaluation was 11.1%. CONCLUSIONS: Our results suggest that macroscopic diagnosis is less effective in predicting lymph node status in breast cancer than frozen section analysis. These findings imply that intraoperative macroscopic evaluation of sentinel nodes is never predictive of the final pathology. PMID- 21528667 TI - Surgical therapy of vertebral metastases. Are there predictive parameters for intraoperative excessive blood loss despite preoperative embolization? AB - AIMS AND BACKGROUND: Preoperative embolization of vertebral metastases has been shown to lower intraoperative blood loss. Nevertheless, excessive up to life threatening blood loss can occur despite embolization. We therefore decided to evaluate possible parameters for predicting significant blood loss in a surgically homogeneous group of patients with vertebral metastases. METHODS: Patients with vertebral metastases of the thoracic and thoracolumbar spine who underwent preoperative embolization were included. All patients had existing or impending neurological deficit as the main indication for direct metastasis reduction. The parameters evaluated were the technical feasibility of embolization, vascularization grade of metastasis, success of embolization, tumor type in relation to blood loss, and interval between embolization and surgery. RESULTS: Twenty-seven patients fullfilled the inclusion criteria. Technically complete embolization was feasible in 14 patients (52%) and fully successful embolization was obtained in 10 patients (37%). Eighty-three percent of the renal cell carcinomas were hypervascularized, but also 67% of the breast carcinoma patients had hypervascularized tumors. No permanent complications occurred during embolization, but two patients had pain and another two experienced a transient burning sensation. A significant difference in intraoperative blood loss was only found between patients achieving partially or fully successful embolization in the subgroup of hypervascularized grade III metastases. CONCLUSIONS: The success of embolization in the group of hypervascularized grade III metastases was the only predictor for the extent of blood loss in our study. Due to the inaccuracy of predicting high blood loss in general all possible precautions for excessive blood loss should be taken despite preoperative embolization. Further randomized studies to determine the indications and results of embolization seem desirable. PMID- 21528668 TI - Lymph node harvesting in colorectal carcinoma specimens. AB - INTRODUCTION: Adequate lymph node evaluation is an important determinant of prognosis in patients with colorectal cancer. Current guidelines recommend evaluation of at least 12 lymph nodes; however, a significant number of patients fail to meet these criteria. AIM: To investigate the factors that influence adequate recovery and evaluation of lymph nodes in colorectal cancer. METHODS: We retrospectively analyzed 454 consecutive cases of colorectal cancer surgically treated from September 2000 to September 2006. Univariate and multivariate linear and logistic regression analysis was used to study the effect of various factors in lymph node recovery. RESULTS: The number of lymph nodes retrieved ranged from 0 to 62 with a median of 13 nodes. Overall, 189 (41.6%) patients had fewer than 12 nodes removed. Patient age, tumor stage, location and size were associated with lymph node retrieval. Multivariable regression revealed that the aforementioned variables, including gender and hospital type, explained 17% of the observed variance of the lymph node number. CONCLUSION: Patient and tumor characteristics, although important, are only partly responsible for the variation of lymph node yield. Quality of surgical resection and/or the thoroughness of examination of the tissue by the pathologist might explain the wider proportion of this variance. Training in colorectal node evaluation could help to improve the quality of cancer care. PMID- 21528669 TI - Prognostic significance of p53 protein and X-ray repair cross-complementing protein 1 in non-small cell lung cancer. AB - OBJECTIVES: p53 and XRCC1 protein expression were evaluated in 54 samples of nonsmall cell lung cancer. PATIENTS AND METHODS: The immunohistochemical method was used for detection of the monitored proteins. Tissue samples were divided according to histopathological tumor type. The results were then compared with basic clinical and histopathological parameters (histopathological type, nuclear grade and TNM tumor stage IA, IB). RESULTS: Statistically significant correlations were found between histopathological type and p53 expression, since P < 0.05 (P = 0.015). Comparing p53 expression with grade resulted in a strong positive correlation (P < 0.0396, R2 = 0.9223). The percentage of p53-positive tumors progressively increased from 0% in grade 1 to 75% in grade 4. No correlation was found between p53 expression and tumor stage. In case of XRCC1, the highest level was found in squamous cell lung carcinoma, where 71% of samples was positive. In case of large cell carcinoma samples, it was 67%, and in adenocarcinoma 52% of samples showed XRCC1 immunoreactivity. No statistically significant correlation was found between histopathological type, grade or early stage (IA, IB) of non-small cell lung cancer and expression of XRCC1 protein profile without neoadjuvant therapy. CONCLUSIONS: We found a statistically significant correlation between p53 expression and histopathological tumor type. It is possible that stabilized p53 protein plays an important role in the development of squamous and large cell carcinoma. Our findings also suggest that p53 expression cumulates with the dedifferentiation of cancer cells. It is possible that the expression of XRCC1 is not fixed and could be changed by the status of cancer cells and in relation to therapy. Relevant data about pre- versus post-chemotherapy and XRCC1 expression are needed to evaluate the influence of XRCC1 on drug resistance. PMID- 21528671 TI - Basic fibroblast growth factor affects the expression of angiogenin and cell proliferation in A375 human melanoma cells. AB - AIMS AND BACKGROUND: Human malignant melanoma is a very aggressive and highly angiogenesis-dependent tumor. Basic fibroblast growth factor and angiogenin are the potentially important angiogenic factors for melanoma progression and metastasis. Many studies have mainly focused on how they induce angiogenesis. In the present study, we investigated the effects of basic fibroblast growth factor on the expression of angiogenin and melanoma cell growth. METHODS AND STUDY DESIGN: Angiogenin mRNA and protein expression were investigated by means of semi quantitative reverse transcriptase polymerase chain reaction assay and western blotting. We analyzed cell proliferation using MTT, flow cytometry and soft agar assay. Immunofluorescence staining was applied to investigate co-localization and nuclear translocation. RESULTS: We found that basic fibroblast growth factor negatively affected the expression of angiogenin in A375 cells. The result showed that down-regulation of basic fibroblast growth factor induced decreased cell proliferation ofA375 cells, and in basic fibroblast growth factor up-regulated cells, cell proliferation was increased. We demonstrated that basic fibroblast growth factor protein was co-localized with angiogenin and that it underwent nuclear translocation in A375 cells. CONCLUSION: These findings suggest that there is a cooperation mechanism between basic fibroblast growth factor and angiogenin in A375 cells, and the cooperation mechanism affects the progress of tumor cell proliferation and angiogenesis. PMID- 21528670 TI - Expression analysis of angiogenesis-related genes in Bulgarian patients with early-stage non-small cell lung cancer. AB - AIMS AND BACKGROUND: Angiogenesis is a key process in the early stages of tumor development. In this study we aimed to evaluate the expression of a panel of angiogenesis-related genes in a group of Bulgarian patients with early-stage non small cell lung cancer (NSCLC). METHODS AND STUDY DESIGN: We analyzed the expression of 84 genes associated with the angiogenic process in 12 NSCLCs of two histological subtypes: 7 adenocarcinomas and 5 squamous cell carcinomas. Eight peripheral nontumorous tissues were used as controls. We performed real-time PCR on pathway-specific gene arrays (SABiosciences). RESULTS: Our pilot study identified upregulated genes in early-stage NSCLC including growth factors (TGFA and EFNA3), the adhesion molecule THBS2, cytokines and chemokines (MDK, CXCL9, CXCL10), and the serine protease PLAU. Several genes showed downregulation including one growth factor (FIGF), the receptors for growth factors TEK and S1PR1 as well as adhesion molecules (COL4A3 and CDH5), the cytokine IL6, the matrix protein LEP and the transcription factor NOTCH4. The study demonstrated deregulated genes specific for the two histological subtypes including the transcription factor HAND2, which was overexpressed in squamous cell carcinomas but not adenocarcinomas. CONCLUSIONS: Despite the limited number of patients, our results demonstrated the potential of angiogenesis-related genes as biomarkers in the early stages of NSCLC development. PMID- 21528672 TI - Immunohistochemical assessment of MGMT expression and p53 mutation in glioblastoma multiforme. AB - AIMS AND BACKGROUND: The prognosis of glioblastoma multiforme (GBM) remains poor despite advances in surgery and adjuvant therapies. TP53 and O6-methylguanine-DNA methyltransferase (MGM) are tumor suppressor genes that are implicated in GBM resistance to radiation and chemotherapy. In order to assess the expression of the protein products of these two genes, 50 GBM samples were analyzed in this study. METHODS: Demographic and clinical data along with postsurgery tumor samples from 50 GBM patients were collected from the pathology archive. MGMT and p53 protein expression was evaluated by immunohistochemistry. RESULTS: 52% of cases had mutated p53, predominantly expressed in the nuclei of tumor cells. MGMT immunohistochemistry was negative in 35 (70%) patients and positive in 15 (30%) others. Immunohistochemistry-negative specimens for MGMT expression showed a significantly higher expression of mutant p53 (P = 0.03). CONCLUSION: MGMT expression was significantly lower in cells bearing p53 mutation. This indicates that there is a tendency for p53 activity to decline with MGMT inactivation. However, this study could not deduce which protein was the regulator of the other. PMID- 21528673 TI - Serum beta-HCG and CA-125 as tumor markers in a patient with osteosarcoma: case report. AB - BACKGROUND: Elevated beta-HCG serum levels are usually an indication of pregnancy or pregnancy-related disorders, but beta-HCG can also be elevated in testis and germ cell tumors. HCG expression by osteosarcoma is a rare phenomenon, with a few documented cases. CA-125 is commonly used to monitor disease progression and treatment response in ovarian cancer. CA-125 expression in patients with osteosarcoma has not previously been documented. CASE REPORT: Elevated beta-HCG and CA-125 serum levels were observed in a female patient of 57 years of age with metastatic osteosarcoma during screening investigations prior to participation in a phase I clinical trial. Pregnancy was excluded. Immunohistochemical studies revealed the tumor to be the source of the elevated beta-HCG serum levels. We found no CA-125 expression in tumor tissue. The patient was treated with E7080, a novel oral multi-targeted tyrosine kinase inhibitor. We measured serum beta-HCG and CA-125 to monitor treatment response. She had a significant clinical and radiological response after two cycles of treatment, but developed progressive disease after the third cycle. The beta-HCG serum levels seemed to better reflect her disease status than those of the other tumor marker, CA-125. CONCLUSIONS: When elevated, beta-HCG serum levels in patients with osteosarcoma might be used to monitor treatment. Treatment of advanced osteosarcoma with tyrosine kinase inhibitors, including E7080, warrants further investigation. PMID- 21528674 TI - Capecitabine in combination with oxaliplatin as first-line therapy for advanced gastric cancer: a case report. AB - Gastric cancer is one of the most common cancers worldwilde. The five-year survival for stage IV gastric cancer is around 5-10% in Western countries. Advanced gastric cancer is sensitive to numerous agents, but there is no generally accepted standard regimen. Here we report on a case of advanced gastric cancer occurring in a 72-year-old man who underwent treatment with capecitabine plus oxaliplatin, achieving a complete response. PMID- 21528676 TI - Filgrastim helps to heal herpes zoster faster: two case reports. AB - Herpes zoster is an infectious disease caused by varicella-zoster virus that may occur sporadically at any age. We report on two patients with herpes zoster who received chemotherapy for breast cancer. Both patients were immunocompromised and received filgrastim therapy for the management of neutropenia. Zoster occurred during filgrastim therapy but the symptoms were alleviated rapidly in the course of therapy. We conclude that granulocyte colony-stimulating factor therapy helped symptom alleviation and accelerated the recovery from herpes zoster in our chemotherapy-treated patients. PMID- 21528675 TI - Effectiveness of interferon-beta therapy for recurrent glioblastoma: a case report. AB - AIMS AND BACKGROUND: Glioblastoma has a poor prognosis, with few therapeutic options if it recurs. We report a case in which we were able to inhibit the growth of a recurrent glioblastoma by weekly single-dose administration of interferon-beta. CASE REPORT: A patient with recurrent glioblastoma after radiation and chemotherapy was treated with nimustine and interferon-beta. After 2 cycles of nimustine, the patient's leukocyte, neutrophil, and platelet counts showed grade 4 toxicity according to the National Cancer Institute's Common Toxicity Criteria. The patient was treated with a weekly single dose of interferon-beta at 6 x 10(6) IU. The tumor showed no remarkable changes after 18 months, and the patient's Karnofsky performance status remained at 50%. CONCLUSIONS: The administration of interferon-beta produced long-term control in one case of glioblastoma and may be an effective therapy. PMID- 21528677 TI - Precursor B-cell acute lymphoblastic leukemia after thymoma and myasthenia gravis: report of a case and review of the literature. AB - The association of thymoma, myasthenia gravis (MG) and pure red cell aplasia (PRCA) is well recognized. The association of T-cell lymphoblastic lymphoma and thymoma/MG/PRCA is less distinctive but reported occasionally. We present a 35 year-old female patient who was diagnosed with thymoma and myasthenia gravis. She underwent a thymectomy shortly after the diagnosis. One year later she developed precursor B-cell acute lymphoblastic leukemia (ALL). Complete remission was achieved after induction chemotherapy but the disease relapsed and she expired two years after the diagnosis of ALL despite allogeneic stem cell transplantation. This association has never before been reported and the pathogenesis needs to be clarified. Aberrant thymus function in myasthenia gravis, immunosuppressive therapy and thymectomy are considered to account for the leukemia development in this patient. PMID- 21528678 TI - Metastatic melanoma: an unusual presentation. AB - In this report we describe a case of a malignant cutaneous melanoma metastasizing to the pleural surface and peritoneal cavity 5 years after surgical resection of the primary lesion. Malignant cutaneous melanoma is a very aggressive cancer able to metastasize anywhere in the body. Pleural secondary lesions represent a rare event described only in a small number of patients and the association with peritoneal localizations may suggest an uncommon pattern of spread that we discuss. PMID- 21528679 TI - CIGNOweb.it. AB - We introduce CIGNOweb.it, a database of oncology resources for patients, the general public and healthcare professionals. It builds on the previous Italian cancer resource Azaleaweb and offers quality-evaluated content. It meets international bibliographic and technical standards such as the Open Archives Initiative (OAI) for web content interoperability and the Functional Requirements for Bibliographic Records (FRBR) for bibliographic description with respect to the different media, applications, and user needs. Database content is supplied in collaboration with non-profit associations, libraries and the network of Cancer Information Points that is currently being established all over Italy. Expert and customer evaluation and feedback are provided for in the system. The graphic layout has been painstakingly designed to be user-friendly for a non expert public. CIGNOweb.it is multicentric and will in time offer health information outside the field of oncology. It is designed to become a multilingual tool to organize, optimize and access patient information produced in the languages of the "newer" European countries. It is hoped that CIGNOweb.it will support other European nations in enhancing the structure and organization of their own-language patient health information and will contribute towards making a common health information portal of the European Union a reality. PMID- 21528680 TI - Fatigue testing of laser treated endosseous implants with an internal trilobe connection. AB - This study investigated the effect of laser treatment on the fatigue resistance of a 3.5-mm diameter implant with an internal trilobe connection. Twenty two implants were embedded into acrylic resin blocks. Half the specimens were used as control group, and the other half were laser treated circumferentially around the 1.5-mm polished collar with argon shielding. Implants were fatigue tested using a step-stress accelerated lifetime test in a servo-hydraulic test machine. Despite the trend pointing towards higher fatigue resistance of laser treated specimens versus controls, step-stress analysis did not determine significant differences in the fatigue lifetimes. PMID- 21528681 TI - Bonding of a gingival shade composite to a denture base resin using a chemically activated 4-meta resin. AB - The purpose of the present study was to determine an effective surface preparation for the bonding of a gingival shade composite resin to a denture base resin. The flat surfaces of a heat-processed denture base resin were prepared in various ways. A highly filled gingival shade composite resin was applied and polymerized. Shear testing was performed in a universal testing machine, and the maximum fracture load values were determined. The application of chemically activated 4-META resin using the brush-dip technique was an effective surface preparation for the bonding of a gingival shade composite resin to a denture base resin. PMID- 21528683 TI - Comparison of linear dimensional change, surface hardness and surface roughness of refractory model prepared from two different duplicating media. AB - The aim of this study was to evaluate and compare the linear dimensional change, surface hardness and surface roughness of the refractory casts poured against different duplicating media. Polyvinyl siloxane and Agar-agar were used for duplicating the stainless steel die. Sixty refractory models were prepared which were divided into two groups: I and II with 30 samples each respectively. Each group was subdivided into 3 subgroups with 10 samples each which were treated differently. All the specimens were measured for the linear dimensional change and surface hardness and the obtained data was statistically analyzed. Surface roughness was evaluated qualitatively taking SEM photomicrographs. Statistical analysis of linear dimensional change using one-way ANOVA showed statistically significant difference between subgroups of group I and non-significant difference between subgroups of group II. One-way ANOVA for Brinell hardness number showed statistically significant difference between the subgroups of group I & II. Student's 't' test results for linear dimensional change among different subgroups of group I & II showed significant difference between IA-IIA, IB-IIB, IC-IIC. Similarly 't'-test results for Brinell hardness number showed significant difference between subgroups IA-IIA, IB-IIB, and IC-IIC. Surface characteristics of the refractory casts poured against polyvinyl siloxane duplicating media were found to be better than the Agar media. PMID- 21528682 TI - The fatigue life of a cobalt-chromium alloy after laser welding. AB - The aim of this study was to investigate the fatigue life of laser welded joints in a commercially available cast cobalt-chromium alloy. Twenty rod shaped specimens (40 mm x 1.5 mm) were cast and sand blasted. Ten specimens were used as controls and the remaining ten were sectioned and repaired using a pulsed Nd: YAG laser welder. All specimens were subjected to fatigue testing (30N - 2Hz) in a controlled environment. A statistically significant difference in median fatigue life was found between as-cast and laser welded specimens (p < 0.001). Consequently, the technique may not be appropriate for repairing cobalt chromium clasps on removable partial dentures. Scanning electron microscopy indicated the presence of cracks, pores and constriction of the outer surface in the welded specimens despite 70% penetration of the weld. PMID- 21528684 TI - Flabby alveolar ridges: a modified technique to treat this clinical challenge. AB - Flabby tissues are common clinical finding which poses no problem of pain and discomfort but adversely affect the support, retention and stability of complete dentures. This paper presents a nonsurgical alternative to such cases focusing on a modified impression technique to record the flabby tissue in its undisplaced form. The custom tray was made in two parts, the first part of which contains a "lattice-work", which strengthens the tray followed by a second tray, which adequately supports the final impression. A standard neutral zone technique was additionally employed for the mandibular ridge as it was severely resorbed. PMID- 21528685 TI - Fracture resistance of endodontically treated premolars with fibre-reinforced composite restorations. AB - This study investigated the fracture resistance and failure mode of endodontically treated premolars restored with a glass fibre-reinforced composite resin. Endodontically treated maxillary premolars were divided in 4 groups: group O: occlusal access opening restored with direct composite; group O+: as group O but with fibre reinforcement; group MOD: occlusal access opening and mesio-distal (MOD) cavity restored with direct composite; group MOD+: as group MOD but with additional fibre reinforcement. Pairwise comparisons of the fracture force among all groups was performed (95% confidence level). Fractures were classified in 4 groups depending on the type of fracture. Group O was the strongest (452.7N) and group MOD the weakest (292.4N). Fracture resistance was significantly different among all groups, except between groups O+ and MOD+. The majority of the unreinforced teeth displayed unfavourable fractures, while the reinforced teeth displayed more favourable fractures. The incorporation of glass fibre weakened endodontically treated but otherwise intact premolars; premolars with MOD restorations were stronger if reinforced with fibres. Fibre reinforcement led to more favourable fractures. PMID- 21528686 TI - An in vitro study to assess glucose microleakage along fiber posts cemented with 2- and 3-step etch-and-rinse resin adhesive systems. AB - The aim of the study is to compare the sealing ability of two adhesive systems. Thirty teeth were endodontically treated and were randomly assigned to 2 groups: G 1 - 3-step adhesive (Solobond-Plus) and G 2 - 2-step adhesive (Solobond-M). Posts containing glass fiber were cemented using the adhesive technique recommended by the manufacturer. All samples were mounted on a glucose leakage model. A 10 microL aliquot of solution was drawn from the glass bottle using a micropipette. The samples were then analyzed in a UV-Vis spectrophotometer. The two tested adhesive systems presented a similar capacity to prevent the glucose infiltration. PMID- 21528687 TI - Correlation of prosthetic status with the GOHAI and TMD indices. AB - This study sought to find a correlation between the prosthetic status and TMD and between the prosthetic status and self-perception of oral health in a Brazilian elderly population (n = 400). Prosthetic status was recorded in clinical examinations, and TMD was determined by applying the Helkimo index. Self perception of oral health was evaluated based on the Geriatric Oral Health Assessment Index (GOHAI). The most prevalent prosthetic status was edentulous using complete dentures (47.5%). Absence of subjective TMD symptoms was found in 69.5%, and of clinical TMD signs in 38.3% of the population. The average GOHAI score was 33.02 +/- 2.85. A correlation was found between prosthetic status and TMD subjective symptoms (P = 0.017), but prosthetic status and TMD objective signs were uncorrelated (P = 0.061). Prosthetic status and self-perception of oral health were positively correlated (P = 0.001). PMID- 21528688 TI - An investigation into the effects of metal primer and surface topography on the tensile bond strength between cobalt chromium alloy and composite resin. AB - This study examined the influence of surface preparation and metal primer on the tensile bond strength between cobalt chromium alloy and composite resin. The bond strength between 168 cobalt chromium alloy dumb-bells with one of three test surfaces (beaded, machined or sandblasted) to composite resin were tested. Half of each group were treated with metal primer. The weakest bond strength was produced by the unprimed machined surface, many specimens failing before testing. The metal primer increased the bond strengths of all groups tested. The greatest bond strengths were achieved with the primed beaded and sandblasted surfaces. Within the limits of the study it has been shown that the surface preparation of the cobalt-chromium alloy did influence tensile bond strengths with composite resin and Metal Primer II increased the tensile bond strengths for all groups tested. The sandblasted surface treated with Metal Primer II is recommended for the bonding of composite resin to cobalt chromium alloy. PMID- 21528689 TI - Invertebrate immunity. Preface. PMID- 21528690 TI - Cnidarian immunity: a tale of two barriers. AB - The phylum Cnidariais one of the earliest branches in the animal tree of life providing crucial insights into the early evolution of immunity. The diversity in cnidarian life histories and habitats raises several important issues relating to immunity. First, in the absence of specific immune cells, cnidarians must have effective mechanisms to defend against microbial pathogens. Second, to maintain tissue integrity, colonial forms have to rely on their capacity of self/nonself discrimination to rapidly detect approaching allogeneic cells as foreign and to eliminate them. And third, since cnidarians are colonized by complex bacterial communities and in many cases are home to algal symbionts, successful growth means for cnidarians to be able to distinguish between beneficial symbionts and pathogenic intruders. The aim of this chapter is to review the experimental evidence for innate immune reactions in Cnidaria. We show that in these diploblastic animals consisting of only two cell layers; the epithelial cells are able to mediate all innate immune responses. The endodermal epithelium appears as a chemical barrier employing antimicrobial peptides while the ectodermal epithelium is a physicochemical barrier supported by a glycocalix. Microbial recognition is mediated by pattern recognition receptors such as Toll- and Nod like receptors. Together, the data support the hypothesis that the establishment of epithelial barriers represents an important step in evolution of host defense in eumetazoan animals more than 600 million years ago. PMID- 21528691 TI - Gastropod immunobiology. AB - Over their 500 million yearhistory, gastropods have radiated into marine, freshwater and terrestrial environments and adopted life styles ranging from herbivory to carnivory to endoparasitism to symbiont-mediated chemoautotrophy. They contend with many pathogens, including several lineages of specialized eukaryotic parasites. Their immunobiology is as yet poorly known, in part because most studies focus on a very small segment of gastropod diversity. Gastropod genome sequences are now forthcoming but synthetic overviews of the gastropod immunome are not yet available. Most immunological studies focus on interactions between gastropods and the larval stages of digenetic trematodes (digeneans) such as the medically important schistosomes. Digeneans elicit demonstrable and relevant snail defense responses and provide insights, augmented by the recently available schistosome genome sequences, for how gastropod responses are subverted. Survival of digeneans in snails depends at least in part on their ability to mimic host glycotopes, to overcome the immediate attack ofreactive oxygen and nitrogen species produced by host hemocytes, and to induce long-term down-regulation of immune functions. Gastropods can mount distinct responses to different categories of pathogens, and can orchestrate effective elevated secondary responses under certain circumstances. Defense responses of at least one gastropod species, Biomphalaria glabrata, involve hemolymph lectins that are diversified by a variety of processes, including somatic diversification. Such observations have played a role in revising our general concept of invertebrate defense to include the possibility of more sophisticated and diversified responses beyond the production of limited repertoires of invariant pattern recognition molecules. The study of gastropod immunobiology is thus of basic interest and has several applied uses as well, including our need to conserve imperiled gastropod diversity. PMID- 21528692 TI - Bivalve immunity. AB - Bivalves are comprised of animals unclosed in two shell valves, such as mussels oysters, scallops and clams. There are about 7,500 bivalve species and some ofthem are of commercial importance. Recently, interest in bivalve immunity has increased due to the importance in worldwide aquaculture and their role in aquatic environmental science and their position in phylogenetic research. This chapter provides a short review of bivalve immunity, including cellular and humoral immunity and the key components and the interactions involved in humoral immunity. PMID- 21528693 TI - Earthworm immunity. AB - Earthworms belonging to oligochaete annelids became a model for comparative immunologists in the early sixties with the publication of results from transplantation experiments that proved the existence of self/nonself recognition in earthworms. This initiated extensive studies on the earthworm immune mechanisms that evolved to prevent the invasion of pathogens. In the last four decades important cellular and humoral pathways were described and numerous biologically active compounds were characterized and often cloned. PMID- 21528694 TI - Leech immunity: from brain to peripheral responses. AB - In the present chapter, we will emphasize the immune response in two compartments (Central nervous system and peripheral system) in two blood sucking leeches i.e., the medicinal leech and the bird leech Theromyzon tessulatum. In the medicinal leech, the neuroimmune response has been described in the context of septic trauma at the cellular and humoral levels through microglia, Toll-like, cannabinoids and chemoattractant factors activation and modulation. In the bird leech, the antimicrobial responses have been dissected at the cellular and molecular levels. Altogether, this chapter presents a complete integrate immune response from the brain and the systemic compartments with high similarity to the vertebrates one. These points that the neuroimmune and immune responses evolved sooner than can be expected. PMID- 21528695 TI - Innate immunity in C. elegans. AB - The nematode Caenorhabditis elegans is proving to be a powerful invertebrate model to study host-pathogen interactions. In common with other invertebrates, C. elegans relies solely on its innate immune system to defend itself against pathogens. Studies of the nematode response to infection with various fungal and bacterial pathogens have revealed that the innate immune system of C. elegans employs evolutionary conserved signalling pathways. They regulate the expression of various effectors molecules, some of which are also conserved. Here, we summarize the current knowledge of the pathways and effector molecules involved in the nematode immune response, with a particular focus on the antifungal immune response of the C. elegans epidermis. PMID- 21528696 TI - Immunocompetent molecules and their response network in horseshoe crabs. AB - Horseshoe crab hemocyte selectively responds to bacterial lipopolysaccharides (LPS), which depends critically on the proteolytic activity of the LPS-responsive serine protease zymogen factor C. In response to stimulation by LPS, the hemocyte secretes several kinds of immunocompetent proteins. The coagulation cascade triggered by LPS or beta-1,3-D-glucans (BDG) results in the formation of coagulin fibrils that are subsequently stabilized by transglutaminase (TGase)-dependent cross-linking. Invading pathogens are recognized and agglutinated by lectins and then killed by antimicrobial peptides. Moreover, LPS-triggered hemocyte exocytosis is enhanced by a feedback mechanism in which the antimicrobial peptides serve as endogenous mediators. Factor C also acts as an LPS-sensitive complement C3 convertase. In addition, a sub-cuticular epidermis-derived protein forms a TGase-stabilized mesh at sites of injury. Horseshoe crabs have a sophisticated innate immune response network that coordinately effects pathogen recognition and killing, prophenoloxidase activation, complement activation and TGase-dependent wound healing. PMID- 21528697 TI - Tick innate immunity. AB - Ticks are blood feeding parasites transmitting a wide variety of pathogens to their vertebrate hosts. The vector competence of ticks is tightly linked with their immune system. Despite its importance, our knowledge of tick innate immunity is still inadequate and the limited number of sufficiently characterized immune molecules and cellular reactions are dispersed across numerous tick species. The phagocytosis of microbes by tick hemocytes seems to be coupled with a primitive complement-like system, which possibly involves self/nonself recognition by fibrinogen-related lectins and the action of thioester-containing proteins. Ticks do not seem to possess a pro-phenoloxidase system leading to melanization and also coagulation of tick hemolymph has not been experimentally proven. They are capable of defending themselves against microbial infection with a variety of antimicrobial peptides comprising lysozymes, defensins and molecules not found in other invertebrates. Virtually nothing is known about the signaling cascades involved in the regulation of tick antimicrobial immune responses. Midgut immunity is apparently the decisive factor of tick vector competence. The gut content is a hostile environment for ingested microbes, which is mainly due to the antimicrobial activity of hemoglobin fragments generated by the digestion of the host blood as well as other antimicrobial peptides. Reactive oxygen species possibly also play an important role in the tick-pathogen interaction. The recent release of the Ixodes scapularis genome and the feasibility of RNA interference in ticks promise imminent and substantial progress in tick innate immunity research. PMID- 21528698 TI - Beetle immunity. AB - Genetic studies have elegantly characterized the innate immune response in Drosophila melanogaster. However, these studies have a limited ability to reveal the biochemical mechanisms underlying the innate immune response. To investigate the biochemical basis of how insects recognize invading microbes and how these recognition signals activate the innate immune response, it is necessary to use insects, from which larger amounts of hemolymph can be extracted. Using the larvae from two species of beetle, Tenebrio molitor and Holotrichia diomphalia, we elucidated the mechanisms underlying pathogenic microbe recognition. In addition, we studied the mechanism of host defense molecule amplification. In particular, we identified several pattern recognition proteins, serine proteases, serpins and antimicrobial peptides and examined how these molecules affect innate immunity. PMID- 21528699 TI - Immunity in lepidopteran insects. AB - Lepidopteran insects provide important model systems for innate immunity of insects, particularly for cell biology of hemocytes and biochemical analyses of plasma proteins. Caterpillars are also among the most serious agricultural pests, and understanding of their immune systems has potential practical significance. An early response to infection in lepidopteran larvae is the activation of hemocyte adhesion, leading to phagocytosis, nodule formation, or encapsulation. Plasmatocytes and granular cells are the hemocyte types involved in these responses. Infectious microorganisms are recognized by binding of hemolymph plasma proteins to microbial surface components. This "pattern recognition" triggers phagocytosis and nodule formation, activation of prophenoloxidase and melanization and the synthesis of antimicrobial proteins that are secreted into the hemolymph. Many hemolymph proteins that function in such innate immune responses of insects were first discovered in lepidopterans. Microbial proteinases and nucleic acids released from lysed host cells may also activate lepidopteran immune responses. Hemolymph antimicrobial peptides and proteins can reach high concentrations and may have activity against a broad spectrum of microorganisms, contributing significantly to clearing of infections. Serine proteinase cascade pathways triggered by microbial components interacting with pattern recognition proteins stimulate activation of the cytokine Spatzle, which initiates the Toll pathway for expression of antimicrobial peptides. A proteinase cascade also results inproteolytic activation of phenoloxidase and production of melanin coatings that trap and kill parasites and pathogens. The proteinases in hemolymph are regulated by specific inhibitors, including members of the serpin superfamily. New developments in lepidopteran functional genomics should lead to much more complete understanding of the immune systems of this insect group. PMID- 21528700 TI - Fly immunity: recognition of pathogens and induction of immune responses. AB - Despite the lack of adaptive immunity based on gene rearrangement such as that in higher vertebrates, flies are able to defend themselves from a wide array of pathogens using multiple innate immune responses whose molecular mechanisms are strikingly similar to those of the innate immune responses of other multicellular organisms, including humans. Invading pathogens passing through the epithelial barriers, the first line of self-defense, are detected by pattern recognition receptors that identify pathogen-associated molecular patterns in the hemolymph or on the immune cell surface and are eliminated by humoral and cellular responses. Some pathogens escape recognition and elimination in the hemolymphby invading the host cell cytoplasm. Some of these intracellular pathogens, however, such as Listeria monocytogenes, are identified by pattern recognition receptors in the cytoplasm and are eliminated by intracellular responses, including autophagy, an intracellular degradation system. Although some of these pattern recognition receptors are encoded in the germ-line as protein families, another type of receptor in the immunoglobulin-superfamily is extensively diversified by alternative splicing in somatic immune cells in Drosophila. PMID- 21528701 TI - Mosquito immunity. AB - Throughout their lifetime, mosquitoes are exposed to pathogens during feeding, through breaks in their cuticle and following pathogen-driven cuticular degradation. To resist infection, mosquitoes mount innate cellular and humoral immune responses that are elicited within minutes of exposure and can lead to pathogen death via three broadly defined mechanisms: lysis, melanization and hemocyte-mediated phagocytosis. This chapter reviews our current understanding of the mosquito immune system, with an emphasis on the physical barriers that prevent pathogens from entering the body, the organs and tissues that regulate immune responses and the mechanistic and molecular bases of immunity. PMID- 21528702 TI - Crustacean immunity. AB - This chapter provides are view of recent progress in the elucidation of innate immune mechanisms in crustaceans. Mainly due to the importance of crustacean aquaculture interest in this field is large and the subject for extensive research efforts. Here, we provide detailed data on the molecular characterisation of lectins, antiviral reactions, hemocyte formation and differentiation and on the regulation of innate immune pathways. PMID- 21528703 TI - Echinoderm immunity. AB - A survey for immune genes in the genome for the purple sea urchin has shown that the immune system is complex and sophisticated. By inference, immune responses of all echinoderms maybe similar. The immune system is mediated by several types of coelomocytes that are also useful as sensors of environmental stresses. There are a number of large gene families in the purple sea urchin genome that function in immunity and of which at least one appears to employ novel approaches for sequence diversification. Echinoderms have a simpler complement system, a large set of lectin genes and a number of antimicrobial peptides. Profiling the immune genes expressed by coelomocytes and the proteins in the coelomic fluid provide detailed information about immune functions in the sea urchin. The importance of echinoderms in maintaining marine ecosystem stability and the disastrous effects of their removal due to disease will require future collaborations between ecologists and immunologists working towards understanding and preserving marine habitats. PMID- 21528704 TI - Urochordate immunity. AB - This chapter provides a short review of the immune system of urochordates, the closest living relative of vertebrates. Since adaptive immunity is a unique property of vertebrates, urochordates rely exclusively on innate immunity to recognize and eliminate pathogens. Here we discuss three immune systems of urochordates which show different evolutionary relationship with the vertebrate immune system. Urochordate Toll-like receptors (TLR) show a clear orthologous relationship with vertebrate counterparts, although they show unique characteristics most likely gained in the urochordate lineage. The urochordate complement system also shows orthologous relationship with the vertebrate complement system. From the structural and functional viewpoints, it seems to represent a more primitive state ofthe vertebrate complement system without any major deviation. In contrast, the allorecognition systems of urochordates show no evolutionary relationship with any invertebrate or vertebrate systems, suggesting that they were invented in the urochordate lineage. PMID- 21528705 TI - Density of tumor-associated macrophages (TAMs) and expression of their growth factor receptor MCSF-R and CD14 in canine mammary adenocarcinomas of various grade of malignancy and metastasis. AB - Several years ago, the presence of macrophages in the tumor microenvironment was thought to be an inflammatory response to kill the cancer cells. Now, this is clear that the inflammatory cells that exit blood vessels and migrate to the tumor tissue play an important role in cancer progression. Various cells present in the tumor microenvironment enhance cancer growth and invasiveness by secretion of tumor-enhancing products. That is why tumors should not be treated as only aggregates of cancer cells but as separate structures. Macrophages form a major component of the inflammatory infiltration in tumors, where they are termed tumor associated macrophages (TAMs). To the best of our knowledge, up-to-date there were no studies on tumor associated macrophages and the role of the tumor microenvironment in tumor invasion/metastasis in dogs. This is the first study performed to asses if the number of TAMs and expression of MCSF-R (macrophages colony stimulating factor receptor) and CD14 (LPS co-receptor) are associated with the grade of tumor malignancy and its ability to metastasize. We have performed immunohistochemical analysis of 50 canine mammary adenocarcinomas of various grade of malignancy (1st, 2nd, 3rd) and tumors that gave local or distant metastases. The results indicate that in dogs, similarly to humans and mice, the number of tumor associated macrophages is related to the cancer ability to metastasize. Our results also indicate that the expression of MCSF-R and, what is particularly new finding, CD14 is associated with tumor malignancy and its ability to metastasize. Hence, these molecules play a role in tumor progression, metastasis and microenvironment interactions. These results show that in dogs we should treat the tumor as a whole organ rather than just try to eliminate the cancer cells. PMID- 21528706 TI - Gene expression pattern in canine mammary osteosarcoma. AB - Canine mammary sarcomas are usually very aggressive and easily metastasize. Unfortunately the biology of this type of tumor is not well known because they are a very rare type of tumors. The aim of this study was to find differences in gene expression patterns in canine mammary osteosarcomas (malignant) versus osteomas (benign) using DNA microarrays. Our microarray experiment showed that 11 genes were up-regulated in osteosarcoma in comparison to osteoma whereas 36 genes were down-regulated. Among the up-regulated genes were: PDK1, EXT1, and EIF4H which are involved in AKT/PI3K and GLI/Hedgehog pathways. These genes play an important role in cell biology (cancer cell proliferation) and may be essential in osteosarcoma formation and development. Analyzing the down-regulated genes, the most interesting seemed to be HSPB8 and SEPP1. HSPB8 is a small heat shock protein that plays an important role in cell cycle regulation, apoptosis, and breast carcinogenesis. Also SEPP1 may play a role in carcinogenesis, as its down regulation may induce oxidative stress possibly resulting in carcinogenesis. The preliminary results of the present study indicate that the up-regulation of three genes EXT1, EIF4H, and PDK1 may play an essential role in osteosarcoma formation, development and proliferation. In our opinion the cross-talk between GLI/Hedgehog and PI3K/AKT pathways may be a key factor to increase tumor proliferation and malignancy. PMID- 21528707 TI - Boar variability affects sperm metabolism activity in liquid stored semen at 5 degrees C. AB - Metabolic activity of boar spermatozoa, liquid stored for three days at 5 degrees C, was measured using bioluminescence for ATP content, fluorescent assay (JC fluorochrome) of mitochondrial activity and oxygen consumption. Sperm motility and plasma membrane integrity (PMI) were simultaneously analyzed. Apart from the statistically significant effect (P < 0.001) of semen storage time, the importance of the individual source of the ejaculate for the analyzed parameters of metabolic efficiency of spermatozoa was shown. This phenomenon was manifested in the interaction of the individual source of the ejaculate with spermatozoa motility, integrity of their membranes and metabolic activity with the passing time of semen preservation. Recorded results indicate that the individual factor may have a significant influence on the technological usefulness of boar spermatozoa for liquid storage. Quality analyses conducted on boar semen stored at 5 degrees C may be used for pre-selection of boars producing sperm with an enhanced tolerance to cold shock. PMID- 21528708 TI - Molecular forms of selected antioxidant enzymes in dog semen--electrophoretical identification. AB - The aim of the study was the electrophoretical identification of molecular forms of selected antioxidant enzymes in dog semen. Ejaculates to be studied were chosen from five dogs, aged from two to eight years. Polyacrylamide gel electrophoresis was carried out under non-denaturing conditions and then gels were stained for the activity of the following enzymes: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Sperm homogenates and all fractions (pre-spermatic, spermatic and post-spermatic) of dog ejaculate demonstrated one protein band with SOD activity characterized by low electrophoretic mobility. Based on the confirmed sensitivity to H2O2, it can be assumed that the detected SOD is an enzyme containing ions of Zn2+ and Cu2+ (Cu,Zn SOD). In sperm homogenates one protein band with GPx activity was characterized by high electrophoretic mobility, whereas in the spermatic and post spermatic fractions of dog ejaculate three protein bands with different (low, medium and high) electrophoretic mobility were identified. CAT molecular forms were not found in either sperm homogenates or in the analyzed fractions of ejaculate. PMID- 21528709 TI - Effect of sperm concentration in an ejaculate on morphometric traits of spermatozoa in Duroc boars. AB - The experimental material consisted of 75 ejaculates collected form 8 Duroc boars. The ejaculates were divided into three groups according to sperm concentration in an ejaculate. An ejaculate was obtained from each boar monthly and it was used to make microscopic preparations to examine spermatozoa morphology. In each preparation morphometric measurements were taken of fifteen randomly selected spermatozoa characterized by normal morphology. The following measurements of spermatozoa were taken: length and width of the spermatozoa head, head area, length of the flagellum, perimeter of the spermatozoon head and total spermatozoon length. The results were used to calculate indicators of spermatozoa morphology. Moreover, assessments were made of frequency of morphological defects to isolate spermatozoa with primary and secondary abnormalities following the Blom classification system. It was found that the concentration of spermatozoa in the ejaculate influenced the morphometric characteristics of spermatozoa. Ejaculates with low sperm concentrations are characterized by larger spermatozoa as compared to ejaculates with high sperm concentrations. However, sperm concentration in the ejaculate does not much influence the shape of spermatozoa. PMID- 21528710 TI - Survival of Staphylococcus aureus exposed to UV radiation on the surface of ceramic tiles coated with TiO2. AB - The aim of this study was to determine and compare the antimicrobial activity of UV radiation of wavelength 253.7 nm (used in typical germicidal lamps) against Staphylococcus aureus on the surfaces of conventionally produced white ceramic wall tiles (matt and shiny) and the same tiles coated with TiO2 using three different methods: RF diode sputtering, atmospheric pressure chemical vapour deposition (APCVD) and spray pyrolysis deposition (SPD). Results clearly indicate that the bactericidal action of UV radiation is much stronger on the surfaces of tiles coated with TiO2 than on the tiles uncovered. The strongest bactericidal effect of UV radiation was found for film prepared by APCVD. Results of experiments for shiny and matt tiles did not differ statistically. The use of ceramic wall tiles coated with TiO2 films in hospitals, veterinary clinics, laboratories, food processing plants and other places where UV radiation is applied for disinfection should greatly improve the efficiency of this treatment. PMID- 21528711 TI - Slaughter value, meat quality, creatine kinase activity and cortisol levels in the blood serum of growing-finishing pigs slaughtered immediately after transport and after a rest period. AB - The experimental materials comprised 44 hybrid [female (Polish Large White x Polish Landrace) x male Duroc] growing-finishing pigs. The animals were randomly divided into two groups: 24 pigs were slaughtered immediately after transport and 20 pigs were slaughtered after a 24-hour rest period in the lairage. The meat content of pork carcasses, carcass dressing percentage, the proximate chemical composition, physicochemical and sensory properties of meat and shear force values were determined. Serum creatine kinase activity and cortisol levels were determined in blood samples collected before transport and during carcass bleeding. Pigs slaughtered immediately after transport, compared with those slaughtered after a 24-hour rest period, were characterized by a higher meat content of the carcass and a higher carcass dressing percentage. Pre-slaughter handling had no effect on pork quality. The incidence of normal-quality meat, partially PSE (pale, soft, exudative) meat and PSE meat was similar in both groups. Chemical analysis showed that the content of dry matter, total protein, fat and minerals in meat was comparable in both groups. As regards the functional properties of the pork, samples from the carcasses of pigs that had rested before slaughter had a higher contribution of the red color component. Meat from pigs slaughtered immediately after transport had more desirable sensory properties. Pre-slaughter resting had a significant effect on those analyzed physiological parameters which were found to be good indicators of pre-slaughter stress. Serum creatine kinase activity and cortisol levels were higher in blood samples collected after transport (during carcass bleeding) than in samples collected before transport, pointing to a strong stress response of animals to pre slaughter treatment. The decrease in serum cortisol levels in blood samples collected during bleeding from the carcasses of pigs slaughtered after a 24-hour rest period, compared with samples collected from animals slaughtered immediately after transport, suggests that rest before slaughter alleviated stress induced by pre-slaughter handling operations. PMID- 21528712 TI - Effects of different starch sources on metabolic profile, production and fertility parameters in dairy cows. AB - The objective of the study was to determine the effect of replacing triticale (high rumen degradable starch) with maize grain (low rumen degradable starch) during the transition period and the first 120 days of lactation on metabolic and hormonal profile indices, milk production and fertility performance in cows. Forty-eight Holstein-Friesian dairy cows were divided into 4 groups: TT (2.5 kg triticale grain/cow per day supplemented from 14 days prepartum to day 120 postpartum), TM (2.5 kg triticale grain/cow per day supplemented from day 14 before parturition to calving, and then 2.5 kg maize grain to 120 days of lactation), MT (2.5 kg maize grain/cow per day supplemented from day 14 before parturition to calving, and then 2.5 kg triticale grain to 120 days of lactation), MM (2.5 kg maize grain/cow per day supplemented from 14 days prepartum to day 120 postpartum). Blood samples were collected 3 weeks and 1 week before calving and on days 14, 56 and 70 of lactation, and they were analyzed in terms of concentrations of glucose, insulin, leptin, insulin-like growth factor I, nonesterified fatty acids, triglycerides, cholesterol, blood urea nitrogen and activities of aspartate aminotransferase and gamma glutamyl transpeptidase. Milk samples were collected twice a day at weekly intervals and analyzed for fat, protein and lactose. Milk yield and individual dry mater intake were recorded at weekly intervals. Body condition was estimated 3 weeks before calving, on parturition day and on days 14, 56 and 120 of lactation. Replacing triticale grain with maize grain in the transition period and during lactation positively affected fertility of lactating cows. An increased first service conception rate and shortening of the days open period was observed in MM and TM groups in comparison to those found in group MT (P < or = 0.05). The lowest number of services per conception was recorded in groups MM and TM (P < or = 0.05). Although the impact of milk production and the most of the blood indices were not significantly affected by this treatment, the results of the study suggest that maize grain in the transition period and lactation might be a more effective energy source for dairy cows than triticale grain. PMID- 21528713 TI - Enzymatic activity of yeasts isolated from the inflamed mammary secretion in dairy cows. AB - The aim of the study was to evaluate enzymatic activities of yeasts isolated from inflammatory mammary secretion. The yeasts isolated from cows with clinical and sub-clinical mastitis (134 strains) included: Candida krusei (62 strains), Candida kefyr (48 strains), Candida lusitaniae (17 strains) and Candida famata (7 strains). The API ZYM system was used containing substrates to assess 19 hydrolytic enzymes. Substantial differences in the number and activity of hydrolyses were demonstrated in individual species. In Candida krusei, acid phosphatase showed the highest activity (4.36 points), in Candida kefyr and Candida lusitaniae--leucine arylamidase (4.93 and 4.25 points, respectively), in Candida famata--alpha-glucosidase (4.75 points). No activity of trypsin, chymotrypsin, alpha-galactosidase, beta-glucuronidase, alpha-mannosidase or alpha fucosidase was observed in any of the yeasts examined. PMID- 21528714 TI - Histopathologic and immunohistochemical lesions in liver of mink infected with Aleutian disease virus. AB - Parvovirus of Aleutian disease causes mainly damage to kidneys, but immune complexes deposition and damage may occur also in other organs. In mink farms of Latvia the liver dystrophy or hepatic lipidosis of mink is widely distributed. The goal of this study was to examine probability of liver damage and regeneration of mink infected with Aleutian disease virus. Liver injury was assessed histologically. The mink liver demonstrated inflammation of liver parenchyma and foci of fatty liver. In immunohistochemistry, during liver regeneration the matrix metalloproteinases MMP-9, vascular endothelial growth factor and beta-defensin 2 expressions were lower, but MMP-2 and nerve growth factor receptor p75 expression was increased. PMID- 21528715 TI - Influence of the wing-of-the-nostrils correction procedure on the change of the acid-base balance parameters and oxygen concentration in the arterial blood in French bulldogs. AB - Brachycephalic syndrome develops as a result of a specific build of splanchnocranium. In dogs of brachycephalic breeds, an impairment of correct gas exchange occurs. 5 French bulldogs at the age of 11-14 months, which suffered from continuous mixed-type dispnoea and lowered effort tolerance, were examined. Apart from the above-mentioned symptoms, the occurrence of strong external nostril stenosis was noted in the clinical examination. The symptoms observed together with the nostril stenosis indicated a possibility of an occurrence of the brachycephalic syndrome. 1 ml of full blood was drawn from the femoral artery. Acid-base balance parameters were determined in the arterial blood: pH, pCO2, HCO3-, and pO2. The wing-of-the-nostrils correction procedure were carried out in general anaesthesia. In premedication, the patients received medetomidine and after 15 minutes, fentanyl together with atropine. The induction of propofol was carried out. After four weeks from the procedure, blood was collected and the acid-base balance and pO2 parameters were again determined. The obtained values of the acid-base balance and pO2 parameters showed a noticeable influence of the wing-of-the-nostrils correction procedure on the values of the parameters determined. The results of the blood gasometry obtained prior to the procedure clearly indicate the occurrence of respiratory acidosis. The correction of wings of the nostrils significantly influenced saturation of the arterial blood with oxygen and the symptoms of dispnoea observed by the owners and episodes of apnoea and the loss of consciousness entirely subsided. PMID- 21528716 TI - The state of bioelements in the hair of free-ranging European bisons from Bialowie a Primeval Forest. AB - Human or animal hair is considered to be a good indicator of the content of bioelements or toxic elements in human and animal organism. Its analysis is a good alternative for the arduous obtaining blood or biopsy samples. The aim of the performed research was the assessment of some chosen bioelements in the organism of European bison on the basis of their analysis in hair. The investigation material comprised hair samples obtained from 22 animals. All animals were divided into groups according to gender (males, females) and age (calves up to one year of age and animals older than 2 years). Samples were mineralized in nitric acid, under pressure in the microwave apparatus. The content of phosphorus, sulphur, magnesium, iron, titanium and vanadium were determined in hair samples. The content of these elements was determined using the ICP-AES method in accredited laboratory. The accuracy of determinations was tested using the standard reference material. The mean content of phosphorus in hair amounted to 245.14 mg x kg(-1), SD 65.00, magnesium 97.32 mg x kg(-1), SD 33.16, iron 119.48 mg x kg(-1), SD 83.31 and titanium 2.368 mg x kg(-1), SD 2.097. In case of these elements, differences depending on gender and age were statistically insignificant. Mean content of sulphur in the European bison hair amounted to 3.41% with equalized content in the herd (SD 0.22%). Here also statistically insignificant differences depending on gender were observed. However, a statistically significant difference (p < or = 0,05) was demonstrated which depended on animal age. Mature European bisons had more sulphur in hair as compared to calves. The concentration of vanadium (0.362 mg x kg(-1), SD 0.396 on the average) significantly differed in hair depending on the European bison age with much higher values in adult animals (calves 0.260 mg x kg(-1), animals older than 2 years 0.686 mg x kg(-1)). Similar data were obtained while investigating hair of sea mammals. PMID- 21528717 TI - Laboratory diagnosis of Mycoplasma infection in young cattle. AB - The aim of this study was to detect Mycoplasma species in the respiratory tract of 110, 310 and 510 day-old groups of cattle by serological, bacteriological and histopathological investigations. Antibodies against M. bovis were found in 75% of the 110 day-old, in 50%--of the 310 day-old and in 55%--of the 510 day-old groups of cattle. Bacteriological examination of the samples from nasal cavities revealed that Mycoplasma carriers were found in 60% of the 110 day-old group of cattle, 40% of the 310 day-old and 40% of the 510 day-old group of cattle. Using the PCR method Mycoplasma was isolated from 25% of lung samples of the 510 day old group of cattle. Mycoplasma bovis and Mycoplasma dispar were confirmed by serological investigations. Foci of bronchointerstitial pneumonia were determined by histopathological examination in 27.5% of lung samples. Mycoplasma bovis was isolated in 72.7% of bronchointerstitial pneumonia cases. Data processing with an SPSS 13.0 statistical package led to the conclusion that Mycoplasma bovis was found more frequently in the 110 day-old group of cattle (the youngest age group in this study) rather than in the 310 and 510 day-old groups of cattle (chi2 = 6.531; p = 0.038). The results obtained led to the conclusion that serological, bacteriological and histopathological examinations are important in detecting particular animal--carriers of Mycoplasma. PMID- 21528718 TI - The results of intradermal skin tests (IDST) in dogs with atopic dermatitis from the Lublin voivodeship. AB - The purpose of this study was to assess the positive immediate reactions received from intradermal skin tests (IDST) which confirmed the presence of IgE-dependent hypersensitivity in dogs with atopic dermatitis, which were patients of the Dermatology Consulting Section at the University of Life Sciences in Lublin between 2007 and 2009. Intradermal skin tests were performed on 142 dogs (72 females and 70 males) from the Lublin voivodeship of different breeds ranging in age from 1 to 6 years (average 2.8 years). The allergen set used in this study was the Artuvetrin Test (ARTU Biologicals Europe B.V, Holland). The owners of 84 dogs observed the presence of skin lesions all year round regardless of season, while 58 dog owners noted them only in spring and summer. Most immediate positive reactions were ascertained from mite allergens (70.61%), fewer from pollen allergens (19.55%), and the fewest from animal (4.15%) and mould allergens (1.66%). Immediate positive reactions for a flea allergen (4.03% of all positive reactions) were also ascertained. In 98.6% of dogs polysensitization was found. PMID- 21528719 TI - The influence of administration of biotin and zinc chelate (Zn-methionine) to cows in the first and second trimester of lactation on their health and productivity. AB - In cattle, the prevention of diseases might be possible using dietary methods, with nutritional optimization of feed rations. For years significant influence has been associated with the addition of biotin, methionine and zinc (each given individually, or as chelate - Zn-methionine). The aim of this study was to evaluate the influence of biotin or biotin + Zn-methionine additives on the health and performance of cows, in the first and second trimester of lactation. This study was carried out in 3 groups of cows, 30 animals in each group. In the first group cows were fed the usual fodder used on the farm. In the second group biotin at 10 mg/day/cow was added. In the third group both biotin at 10 mg/day/cow and Zn-methionine at 5 g/day/cow were added. The administration of biotin increased the milk yield and reduced the occurrence of retained placenta, as well as endometritis puerperalis. However, the high doses of biotin suppressed ovulation and oestrus symptoms in the investigated cows (low progesterone levels on days 15, 21 and 45 after calving). Zn-methionine in comparison to biotin had a lower effect on the milk yield in the cows. Moreover, its supplementation improved the milk content, as well as some of the blood parameters; it also decreased the number of somatic cells in milk. The concurrent administration of biotin and zinc-methionine seemed to be a good method for the prophylaxis of subacute mastitis and for the improvement of the high yielding dairy cows' productivity. PMID- 21528720 TI - Usefulness of PCR/RFLP and ERIC PCR techniques for epidemiological study of Haemophilus parasuis infections in pigs. AB - Haemophilus parasuis belongs to opportunistic microorganisms of undefined virulence. The purpose of the studies was to compare suitability of PCR/RFLP in our modification and ERIC PCR for epidemiological study of domestic strains of H. parasuis. The results were evaluated taking into account two different aspects: suitability of the tests for isolating the highest possible number of clone groups and subjective evaluation of the method judged with respect to the following criteria: difficulty, availability of equipment and reagents as well as time and cost of the study. The results obtained in the present study show that the two methods used for typing of H. parasuis had high discriminatory power. Taking into account this parameter it can be concluded that ERIC PCR is more suitable than PCR/RFLP. This justifies the use of ERIC PCR for routine epidemiological analyses of mentioned pathogen. Taking into account the complexity of method used, ERIC-PCR based on random amplification of DNA, proved to be comparable to PCR/RFLP. The last mentioned technique is relatively less expensive and labour-consuming, especially when diagnostic PCR method is used for the epidemiological studies. PMID- 21528721 TI - Effect of benzoic acid and combination of benzoic acid with a probiotic containing Bacillus cereus var. Toyoi in weaned pig nutrition. AB - The purpose of this study was to assess the efficacy of a probiotic containing Bacillus cereus var. Toyoi spores (Toyocerin) and benzoic acid (VevoVitall) on growth performance and diarrhoea in weaning pigs, against negative controls. The trial groups were as follows: (a) NC group (Negative Controls): No treatment (b) TOYO group: Same feed as in the controls plus Toyocerin at a dose of 1 x 10(9) Bacillus cereus var. Toyoi spores/kg feed, (c) BA group: Same feed as in the controls plus VevoVitall at a dose of 5 g/kg feed (5000 ppm benzoic acid) and (d) TOYO+BA group: Same feed as in the controls plus Toyocerin at a dose of 1 x 10(9) Bacillus cereus var. Toyoi spores and VevoVitall at a dose of 5 g/kg feed. In conclusion, the results of this study indicated that administration of Bacillus cereus var. Toyoi spores at 1 x 10(9)/kg feed or benzoic acid at a dose of 5000 ppm or the combination of 1 x 10(9) Bacillus cereus var. Toyoi spores and 5000 ppm of benzoic acid/kg feed, improved the growth performance parameters and reduced the severity of diarrhoea in weaning pigs. PMID- 21528722 TI - Cellular immune response of pigeons in the conditions of endotoxin fever and pyrogenic tolerance. AB - The aim of this study was to investigate changes in selected parameters of cellular immune response in the conditions of endotoxin fever and pyrogenic tolerance in pigeons. On the first day of observation the experimental birds (n = 18) were intravenously injected with Escherichia coli LPS at a dose of 10 microg/kg b.w., while the control animals (n = 6) received apyrogenic physiological saline also in the form of injection. On the second and the third day of the experiment LPS was injected additionally at 24 h intervals. Four and a half hours after the saline and pyrogen administration blood samples were collected from the control and experimental pigeons. The following immunological assays were performed: WBC, leucogram and immunophenotyping of lymphocyte subsets in peripheral blood, i.e. CD 3+ (T lymphocytes), CD 4+ (T helper lymphocytes) and CD 8+ (T suppressor/cytotoxic lymphocytes) cells. In the conditions of endotoxin fever (i.e. after the first LPS injection) leucopenia, monocytopenia, heterophilia and eosinophilia were observed. Additionally, the immunophenotyping of peripheral blood lymphocytes indicated an increase in percentage of CD 3+, CD 4+ and CD 8+ cells in response to the single injection of LPS. In contrast, the consecutive injections of LPS, which created a pyrogenic tolerance effect, caused a decrease in WBC value, heteropenia, eosinopenia and lymphocytosis. Moreover, during this state an increase in percentage of CD 3+ and CD 8+ cells was demonstrated in contrast to the percentage of CD 4+ lymphocytes. The general tendencies in cellular immune response of the affected pigeons in the conditions of endotoxin fever and pyrogenic tolerance aim at activation of defence mechanisms against LPS for its prompt elimination from the animal's organism. PMID- 21528723 TI - A survey of anti-Ostertagia ostertagii antibody levels in bulk tank milk samples (BTM) in dairy herds in Lower Silesia Region (Poland). AB - This work presents serological evidence of cattle ostertagiosis in the Lower Silesia Region (Poland), based on the measurement of antibodies in bulk tank milk (BTM) samples. It represents the first evidence of this parasite examined with the use of the ELISA test and milk samples in Poland. The prevalence of Ostertagia ostertagii antibodies was determined in BTM from 32 dairy cattle herds. Antibodies to O. ostertagii were demonstrated in all herds. The optical density ratio (ODR) varied from -0.088 to 1.024. The mean ODR value in the examined region was 0.53. PMID- 21528724 TI - Restoration of fractured canines in ferrets after one-step root canal treatment. AB - This article describes a one-step root canal treatment and restoration of canine teeth in ferrets. Standard brass posts were used for the reconstruction of the teeth. The procedures were performed by dentists according to all rules and procedures used in root canal treatment in humans. The teeth were immediately restored anatomically. The procedures were successfully performed in four ferrets aged between 6 and 20 months of age, in three upper and one lower canines. PMID- 21528725 TI - Isolation of an atypical pigeon paramyxovirus type 1 in Poland. AB - In this study, a pigeon paramyxovirus type 1 (PPMV-1) isolated from a flock of ornamental pigeons in Poland in 2010 is described. The PPMV-1/Poland/H2/10 isolate showed the amino acid sequence at the cleavage site of F2/F1 112KRQKRF117 i.e. typical of virulent strains. Despite having the monoclonal antibody binding pattern typical of pigeon variants PPMV-1 (antigenic group "P"), the Polish isolate clustered into genetic sublineage 4a, which is usually associated with PMV-1 isolated from poultry. PMID- 21528726 TI - Optimization of Salmonella enteritidis recombinant heat shock protein 60 production. AB - The aim of the study was to optimize conditions for producing Salmonella Enteritidis recombinant heat shock protein 60 (rHsp60). Seven Escherichia coli host strains (Rosetta, Turner, C41, C43, Origami, BL21pLys, Rosetta pLys) were transformed by a recombinant plasmid containing Hsp60 gene from Salmonella Enteritidis, and then cultured and induced by isopropyl-beta-D thiogalactopyranoside (IPTG). The highest S. Enteritidis rHsp60 yield was obtained using E. coli strain C41. Induction of this strain using IPTG allowed the yield 400 microg of S. Enteritidis Hsp60 protein/2L of culture, but by autoinduction the yield exceeded 800 microg/2L. PMID- 21528728 TI - Nuclear progesterone receptor isoforms and their functions in the female reproductive tract. AB - Progesterone (P4), which is produced by the corpus luteum (CL), creates proper conditions for the embryo implantation, its development, and ensures proper conditions for the duration of pregnancy. Besides the non-genomic activity of P4 on target cells, its main physiological effect is caused through genomic action by the progesterone nuclear receptor (PGR). This nuclear progesterone receptor occurs in two specific isoforms, PGRA and PGRB. PGRA isoform acts as an inhibitor of transcriptional action of PGRB. The inactive receptor is connected with chaperone proteins and attachment of P4 causes disconnection of chaperones and unveiling of DNA binding domain (DBD). After receptor dimerization in the cells' nucleus and interaction with hormone response element (HRE), the receptor coactivators are connected and transcription is initiated. The ratio of these isoforms changes during the estrous cycle and reflects the different levels of P4 effect on the reproductive system. Both isoforms, PGRA and PGRB, also show a different response to the P4 receptor antagonist activity. Connection of the antagonist to PGRA can block PGRB, but acting through the PGRB isoform, P4 receptor antagonist may undergo conversion to a strongly receptor agonist. A third isoform, PGRC, has also been revealed. This isoform is the shortest and does not have transcriptional activity. Alternative splicing and insertion of additional exons may lead to the formation of different PGR isoforms. This paper summarizes the available data on the progesterone receptor isoforms and its regulatory action within the female reproductive system. PMID- 21528727 TI - The effects of soybean selenium proteinate on tissue selenium and meat quality traits in finishing pigs. AB - The purpose of the present study was to evaluate the effects of soybean selenium proteinate on Se tissue retention and meat quality in pigs. In group A (n = 11) the mixtures were supplemented with soybean selenium proteinate, in group B (n = 11) with sodium selenite and in group C (n = 11) with Se-enriched yeast (0.3 mg Se per kg in all groups). The use of soybean selenium proteinate resulted in lower retention of Se in tissues (liver, heart, muscle) compared to Se-enriched yeast. Selenium concentrations in tissues achieved by soybean selenium proteinate and sodium selenite were comparable. No differences in serum Se, serum GSH-Px and meat quality traits were found among the groups. PMID- 21528729 TI - The carcinogenic effects of benzoquinones produced by the flour beetle. AB - Humans and animals come into contact with various compounds in their natural environment. Most of the encountered substances are neutral, yet some may carry adverse health effects. The ingested food may be a source of harmful substances, including benzoquinones which, as shown by research results cited in this paper, demonstrate toxic, carcinogenic and enterotoxic activity. This group of compounds is inclusive of 2-methyl-1,4-benzoquinone (MBQ) and 2-ethyl-1,4-benzoquinone (EBQ), defensive secretions of the confused flour beetle (Tribolium confusum J. du V) and the red flour beetle (Tribolium castaneum Herbst). Benzoquinones have a carcinogenic effect, they are inhibitors of growth of various microorganisms, they produce a self-defense mechanism in threat situations and affect population aggregation. As noted by the referenced authors, the properties of benzoquinones have not been fully researched to this date. PMID- 21528730 TI - Treatment of inflammatory bowel disease (IBD) in dogs and cats. AB - The treatment of inflammatory bowel disease (IBD) possesses numerous difficulties owing to the unclear etiology of the disease. This article overviews the drugs used in the treatment of IBD depending on the intensity of clinical symptoms (Canine Inflammatory Bowel Disease Activity Index and Canine Chronic Enterophaty Clinical Activity Index). Patients demonstrating mild symptoms of the disease are usually placed on an appropriate diet which may be combined with immunomodulative or probiotic treatment. In moderate progression of IBD, 5-aminosalicylic acid (mesalazine or olsalazine) derivatives may be administered. Patients showing severe symptoms of the disease are usually treated with immunosuppressive drugs, antibiotics and elimination diet. Since the immune system plays an important role in the pathogenesis of the disease, the advancements in biological therapy research will contribute to the progress in the treatment of canine and feline IBD in the coming years. PMID- 21528731 TI - Patients' decisions to die: the emerging Australian jurisprudence. AB - A series of decisions by McDougall J in Hunter and New England Area Health Service v. A (2009) 74 NSWLR 88; Martin CJ in Brightwater Care Group (Inc) v. Rossiter (2009) 40 WAR 84; Higgins CJ in Australian Capital Territory v. JT (2009) 232 FLR 322; and Kourakis J in H Ltd v. J (2010) 240 FLR 402 has built upon prior decisions in New South Wales, Queensland and Victoria. The combination of authority has provided a reasonably homogeneous set of principles on the basis of which future decision-making can take place by clinicians, institutions and courts. It is apparent that, wherever possible, effect will be given to competent patients' wishes in relation to cessation of treatment, nutrition and hydration. However, scrutiny will be applied to patients' capacity in order to examine not the rationality or correctness of their decisions per se but their capacity to make them. It is probable that a rigorous approach will be taken both to whether patients' mental ill health deprives them of capacity and to whether they are provided with sufficient information to understand the consequences and processes of deprivation of nutrition, hydration and medication. PMID- 21528732 TI - Priority-setting processes for medicines: the United Kingdom, Australia and New Zealand. AB - The agencies involved in the assessment and prioritisation of medicines for public subsidy purposes in Australia, England and Wales, and New Zealand are compared in terms of their processes; ultimate decision-maker and political involvement in decisions; price-setting processes; decision criteria and inclusion of economic assessment of cost-effectiveness; provision for the rule of rescue and separate treatment of potentially life-saving medicines and cancer drugs; levels of access; extent of consumer participation in processes and decisions; and provision for appeal from decisions. All countries face the key challenge of expanding access to important new treatments, while maintaining cost effectiveness as a key criterion for public funding and safeguarding the affordability and sustainability of their programs into the future. New Zealand's model may have led to a greater focus on cost-containment and overall affordability than those of the other two agencies. Despite controversial decisions that have led on occasion to disappointment and challenge, the Australian and New Zealand agencies have survived and appear to have managed to date to maintain public and political support. By contrast, the United Kingdom's National Institute for Healthcare and Clinical Excellence is facing major changes to its role that could see it become more of an advisory organisation. PMID- 21528733 TI - Death from minor head trauma and alcohol. AB - Sudden death in association with minor or otherwise insignificant head injury is increasingly being recognised in the forensic medical literature. While the exact mechanism of the cardiorespiratory arrest that appears to occur in these cases is unclear, a number of mechanisms have been postulated. Animal studies have provided evidence that alcohol can be associated with an increased period of apnoea following minor physical brain injury and cardiac changes have also been identified. The limited information in the community about the risk of alcohol in association with minor head injury causing death may be relevant in homicide cases where this issue is raised. PMID- 21528734 TI - Embracing the new professionalism: self-regulation, mandatory reporting and their discontents. AB - In response to perceived failures in medical self-regulation in Australia, first in two States (for doctors) and now under the National Registration and Accreditation Scheme (for all health practitioners), mandatory reporting of peer status or practice that poses risks to patients has been introduced. Yet now, in response to the lobbying of State and federal health ministers by the medical profession, mainly in relation to the impairment provisions, this is to be reviewed. This column argues that claims concerning the negative consequences for practitioners of mandatory reporting are illogical and lack supporting evidence. There is, however, evidence that the medical profession does not consistently act in accordance with its professed positions in the area of physician impairment and departure from accepted clinical standards. The call for a review of mandatory reporting reflects an outdated model of regulation that does not align with increasing calls for a "new professionalism". In its own interests, but primarily in the interests of patients, the medical profession should embrace new attitudes and practices that will at first appear to threaten the privilege of self-regulation, but on proper scrutiny will be seen as necessary to retain it. PMID- 21528735 TI - Psychotherapy, suicide and foreseeable risks of decompensation by the vulnerable. AB - Utilising the findings and recommendations in a 2010 coronial inquest in New South Wales into the death of Rebekah Lawrence, a person who had recently completed a personal development course incorporating confronting techniques of regression, run by persons without formal psychotherapeutic skills, this column scrutinises issues arising in relation to unregistered therapies. The evidentiary bases upon which coronial findings of suicide can be made are also examined, along with the effects of the ancient presumption against findings of suicide. In addition, the existence of regulatory controls, as recommended by the New South Wales Deputy State Coroner, are discussed. The grim conclusion arrived at is that the potential exists for further deaths of vulnerable people in the aftermath of the wielding of powerful psychological techniques by persons ill equipped to do so and to identify and respond to the sequelae of their therapies. PMID- 21528736 TI - What makes a real man? Gender norms and Western Australia v. AH [2010] WASCA 172. AB - In Western Australia v AH [2010] WASCA 172 the Western Australian Court of Appeal denied two female-to-male applicants for gender reassignment certificates the right to be legally recognised as men. In so doing, an opportunity was lost for Australia to be one of the first jurisdictions in the world to legally provide a reassignment of gender without requiring permanent sterilising surgery. This column examines not only the legal issues considered in the case but the broader ethical and human rights issues associated with denying female-to-male gender reassignment applicants who have not undergone a permanent sterilisation or genitalia alteration procedure, the right to be identified as males. PMID- 21528737 TI - The legal role of medical professionals in decisions to withhold or withdraw life sustaining treatment: part 1 (New South Wales). AB - This is the first article in a series of three that examines the legal role of medical professionals in decisions to withhold or withdraw life-sustaining treatment from adults who lack capacity. This article considers the position in New South Wales. A review of the law in this State reveals that medical professionals play significant legal roles in these decisions. However, the law is problematic in a number of respects and this is likely to impede medical professionals' legal knowledge in this area. The article examines the level of training medical professionals receive on issues such as advance directives and substitute decision-making, and the available empirical evidence as to the state of medical professionals' knowledge of the law at the end of life. It concludes that there are gaps in legal knowledge and that law reform is needed in New South Wales. PMID- 21528738 TI - The legal role of medical professionals in decisions to withhold or withdraw life sustaining treatment: part 2 (Queensland). AB - This is the second article in a series of three that examines the legal role of medical professionals in decisions to withhold or withdraw life-sustaining treatment from adults who lack capacity. This article considers the position in Queensland, including the parens patriae jurisdiction of the Supreme Court. A review of the law in this State reveals that medical professionals play significant legal roles in these decisions. However, the law is problematic in a number of respects and this is likely to impede medical professionals' legal knowledge in this area. The article examines the level of training medical professionals receive on issues such as advance health directives and substitute decision-making, and the available empirical evidence as to the state of medical professionals' knowledge of the law at the end of life. It concludes that there are gaps in legal knowledge and that law reform is needed in Queensland. PMID- 21528739 TI - Serving two masters? Recent legal developments regarding the professional obligations of medical administrators in Australia. AB - Medical administration is a recognised medical specialty in Australia. Historically, medical administrators have rarely been subjected to litigation or disciplinary hearings relating specifically to their administrative functions. However, the legal landscape for medical administrators in Australia appears to be shifting. In 2009, the Queensland Health Practitioners Tribunal heard two separate cases involving the professional conduct of medical administrators who were implicated in the scandal surrounding Dr. Jayant Patel at Bundaberg Hospital. In September 2010, judgment in one of those cases was delivered. This article reviews the tribunal's decision through the lens of relevant United Kingdom authorities and recent legislative changes in Australia regulating the health professions. PMID- 21528740 TI - Who shall live when not all can live? Intellectual property in accessing and benefit-sharing influenza viruses through the World Health Organisation. AB - This article addresses the development of the World Health Organisation's (WHO) arrangements for accessing viruses and the development of vaccines to respond to potential pandemics (and other lesser outbreaks). It examines the ongoing "conflict" between the United Nations' Convention on Biological Diversity (CBD) and the World Trade Organisation's Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS) in the context of the debates about the paramountcy of intellectual property, and the potential for other (equity and development) imperatives to over-ride respect for intellectual property and TRIPS. The article concludes that the same intellectual property fault lines are evident in the WHO forum as those apparent at the CBD and the WTO fora, and an ongoing failure to properly address questions of equity and development. This poses a challenge for the Australian Government in guaranteeing a satisfactory pandemic influenza preparation and response. PMID- 21528741 TI - Access to medicine and the dangers of patent linkage: lessons from Bayer Corp v. Union of India. AB - In February 2010, the Delhi High Court delivered its decision in Bayer Corp v Union of India in which Bayer had appealed against an August 2009 decision of the same court. Both decisions prevented Bayer from introducing the concept of patent linkage into India's drug regulatory regime. Bayer appealed to the Indian Supreme Court, the highest court in India, which agreed on 2 March 2010 to hear the appeal. Given that India is regarded as a global pharmaceutical manufacturer of generic medications, how its judiciary and government perceive their international obligations has a significant impact on the global access to medicines regime. In rejecting the application of patent linkage, the case provides an opportunity for India to further acknowledge its international human rights obligations. PMID- 21528742 TI - Police use of TASERs in the restraint and transport of persons with a mental illness. AB - The mentally ill are overrepresented in the statistics of individuals killed or injured by police and it is understandable that police would seek a weapon, such as a TASER, that is less lethal than a firearm. However, it appears that use of TASERs is not without risk, especially in certain groups, including the mentally ill. The risk of injury to vulnerable people with a mental illness from TASER weapons must be weighed against the risk that escalation to lethal force may cause if a person with an acute mental illness requires restraint. When police officers are carrying out their duties under mental health legislation it is recommended that TASERs be used only when an individual is imminently likely to sustain or to cause grievous bodily harm. This article recommends changes to the Western Australian Police TASER training programs and proposes mandatory medical assessments after the use of TASER restraint. PMID- 21528743 TI - Abortion laws and medical developments: a medico-legal anomaly in Queensland. AB - In October 2010 the District Court sitting in Cairns, Queensland, found Tegan Leach not guilty of attempting to procure her own abortion and Sergie Brennan not guilty of supplying Leach with the drugs Mifepristone and Misoprostol to procure an abortion. Brennan obtained the drugs from his sister in the Ukraine through the regular postal system. R v Brennan and Leach was the first case in Queensland's history where a woman was charged with procuring her own abortion. The drugs are accepted by the medical profession worldwide for medical abortions. A prosecution witness gave evidence that Mifepristone is not harmful or injurious to the health of a woman and it is listed as an essential medicine by the World Health Organisation and approved for use by the Australian Therapeutic Goods Administration. The jury found the defendants not guilty because they were not satisfied beyond reasonable doubt that the combination of the drugs Mifepristone and Misoprostol was a "noxious" substance under the Criminal Code (Old). This article concludes that there is no regulatory miracle which will stop the traffic of Mifepristone and Misoprostol into Australia and therefore an intelligent regulatory response is required which would make it unnecessary for women to seek Mifepristone and Misoprostol from overseas networks and the internet. Among other things, this would include the repeal of confusing, inappropriate and ineffective abortion laws. PMID- 21528744 TI - The criminal act of commercial surrogacy in Australia: a call for review. AB - Australian surrogacy legislation punishes the pursuit of a commercial surrogacy arrangement as a criminal offence. Such legislation was first introduced in Victoria in 1986 and has since been applied in every Australian jurisdiction except for the Northern Territory. The current application of criminal law is based upon this 1980s policy which has never been subject to public debate. This article argues that the continued application of criminal penalties to commercial surrogacy requires review. PMID- 21528745 TI - Surrogacy: is it harder to relinquish genes? AB - Surrogacy has produced some positive outcomes by creating an opportunity for otherwise childless couples to realise their dream of parenthood. However, it has also been problematic, particularly where the surrogate mother fails to relinquish a child born as a result of the surrogacy arrangement. This article examines whether a surrogate mother who is genetically related to the child she delivers is less likely to relinquish the child than one who has no genetic ties. An examination of empirical evidence provides support for this argument. Legislation and case law in Australia, the United States and the United Kingdom are examined to determine which, if any, of these jurisdictions take into account the existence, or otherwise, of a genetic link between the surrogate mother and the child she bears. The article concludes that surrogacy legislation should, subject to exceptional circumstances, encourage surrogacy arrangements where the child and the surrogate are not genetically related. PMID- 21528746 TI - Mesenteric ischemia--a complex disease requiring an interdisciplinary approach. A review of the current literature. AB - Mesenteric ischemia is caused by a reduction in intestinal blood flow with potential catastrophic clinical consequences: sepsis, bowel infarction, and death. In the recent years, the incidence of mesenteric ischemia increased, now accounting for 0.1% of hospital admissions. Among the multiple factors responsible for this change is the heightened awareness for the diagnoses, the advanced mean age of the population and the increasing number of critically ill patients. Acute mesenteric ischemia is a potentially fatal vascular emergency, with overall mortality of 60-80%; prompt diagnosis and treatment are paramount. A high index of suspicion in the setting of a compatible history and physical examination serves as the cornerstone to early diagnosis of mesenteric ischemia. Restoration of intestinal blood flow, as rapidly as possible, is the main goal of treatment in patients with acute mesenteric ischemia. This may be achieved by medical means, endovascular procedures and by surgery. Chronic mesenteric ischemia is an uncommon process that occurs only when severe atherosclerotic narrowing of a major splanchnic vessel exists in association with occlusion of one or two of the remaining vessels. Its diagnosis is mainly based on the characteristic clinical picture, on the presence of an occlusive lesion in the splanchnic vessels and on the absence of other common causes of abdominal pain. The means available for mesenteric revascularization are the surgical techniques of flow restoration and the more recently developed percutaneous transluminal procedures. PMID- 21528747 TI - The management of patients with peripheral arterial disease and intermittent claudication. Actual recommendations. AB - In the general context of increasing prevalence of cardiovascular risk factors in European population, we face with a significant rise of the incidence of atherothrombotic diseases. Peripheral arterial disease (PAD) represented for a long time a peripheral interest for cardiologist. The epidemiological studies in the latest years determine a reconsideration of the medical attitude in respect of PAD, motivated by an increase in its prevalence and, on the other hand, by the significant cardiovascular risk this disease carries with. Taking into account that fact and aiming at a better medical approach of these patients, we realized a review regarding therapeutic methods in patients with PAD and intermittent claudication based on the latest medical publications and in accord with the guide in force at the moment. PMID- 21528748 TI - Celiac disease--a continuous challenge. AB - Celiac disease (CD) is an immune mediated enteropathy with an increasing prevalence worldwide. It is estimated that 1% of general population in Europe is suffering from this ailment. The clinically silent form affects the majority of patients. Hence, diarrhea, nutritional deficiencies and weight loss are symptoms which are not very often seen. Nonspecific complaints like headaches and joint pain have the potential to delay the diagnosis. The high risk groups have been identified to be those patients suffering from autoimmune insulin-dependent diabetes mellitus, osteoporosis, Sjogren's syndrome and the first degree relatives of CD patients. Those patients should be screened for CD. The association of CD with several autoimmune ailments has various explanations ranging from common genotypes to systemic immune reactions triggered by food antigens. CD is, nevertheless, an autoimmune disorder triggered by an environmental antigen (gluten) but, as opposed to other autoimmune disorders in which the pathogenic process is self-sustained, the removal of gluten from diet results in relatively fast resolution of histological and serological markers. PMID- 21528749 TI - Diagnosis and treatment in Helicobacter pylori infection. AB - In our days, Helicobacter pylori is considered to be the bacterium responsible for the most frequent and persistent chronic infection worldwide, involving half of the entire world population. Untreated, the infection is lasting for the whole life. In Romania, the number of carrying people is variable between 90-94%, while in western countries, the prevalence of this infection is much lower, under 50 60%, with a high tendency to decrease, due both to the higher socio-economic level and to advanced methods of diagnosis and treatment, with a special focus on prevention. Because a percentage of 10-11% of the infected people develop in time an ulcerous disease, and 5-6% will have premalignant changes on the gastric mucosa and even gastric cancer in 1% of the cases, the goal to detect and treat H. pylori infection is, in our opinion, very much justified by both theoretical and practical reasons. Diagnosis methods for the infection's detection are numerous and diverse, the choice for one or another depending on several factors, among which: accessibility, advantages and disadvantages specific to each method (particularly the method's invasive or non invasive character), the cost, the aim (diagnosis, epidemiological, the treatment's efficiency, etc.). From a clinical point of view the patient's age, antecedents and digestive symptoms, as well as his psychological state and associated treatments are also important. Once the diagnosis of infection is proved, the treatment of the Helicobacter pylori infection supposes the simultaneous administration of antibiotics and proton pump inhibitors. The idea to create a vaccine for Helicobacter pylori is the evident result of the need to avoid the costs imposed by the diagnosis and treatment of the infection, especially in view of the high percentage of failure in eradicating the infection. If we add to these the socio-economic costs brought by the treatment of gastric ulcers and cancers, the idea of using a vaccine with double role, both in preventing, as well as in treating the infection, is even more attractive. PMID- 21528750 TI - The role of radiofrequency ablation as a first line therapy in the treatment of atrial flutter. AB - Cavo-tricuspid isthmus radiofrequency (RF) ablation is an efficient option in the treatment of atrial flutter. In the case of a well-tolerated, first episode of atrial flutter, it has a class II indication, level of evidence B, the current first-line therapeutic option being electrical cardioversion, pharmacological cardioversion or atrial overdrive pacing followed by long-term antiarrhythmic therapy. The purpose of this study was to evaluate, in a prospective manner, the recurrence rate of these two different therapeutic options after the treatment of a first episode of atrial flutter. MATERIAL AND METHODS: Between January 2007 and May 2009, for 99 patients admitted to the hospital for a first episode of atrial flutter, cardioversion was attempted either by RF ablation (group 1-42 patients), or by electrical cardioversion, pharmacological cardioversion or atrial overdrive pacing followed by long-term Amiodarone therapy (group 21-57 patients). We compared the recurrence rate of atrial flutter in the 2 groups after a follow-up period of one year. RESULTS: In group 1, sinus rhythm was achieved in all patients, with bidirectional isthmic block being obtained for 37 patients (88.1%). In group 2, conversion to sinus rhythm was obtained in all cases. The recurrence rate was 6 times higher in group 2 vs group 1 (57.9% = 33 patients vs 9.5% = 4 patients) (p = 0.01). CONCLUSION: RF ablation should be considered as a therapeutic option in the treatment of the first episode of atrial flutter, due to its significant efficiency in maintaining sinus rhythm and to its low recurrence rate. PMID- 21528751 TI - T helper 17 cell population in lupus erythematosus. AB - Lupus erythematosus (LE) is an autoimmune inflammatory disease that involves many organs and systems. Immunological factors seem to play a key-role in LE pathogenesis. LE patients have T lymphocytes dysfunctions.Th17 is implicated in the pathogenesis of various autoimmune diseases like psoriasis, multiple sclerosis or rheumatoid arthritis. The purpose of this study was to evaluate the circulating Th17 cell population in LE patients. MATERIAL AND METHODS: A total of 15 LE patients were recruited and divided into three groups: systemic lupus erythematosus (SLE), discoid lupus (DLE) and subacute lupus (SCLE). Serum IL-17A, IL-17F and IL-23 were detected. Th17 circulating cells were evaluated by flow cytometry. RESULTS: Serum IL-17A and IL-17F levels were higher in SLE, DLE and SCLE patients compared to healthy controls. The number of Th17 cells were higher in SLE and DLE patients (p<0.05). the number of CD3+IL-17+ cells were higher in SLE, DLE and SCLE patients (p<0.05). CONCLUSION: Th17 lymphocytes are implicated in LE pathogenesis. Our findings suggest that IL-17 is implicated not only in SLE but also in DLE and SCLE immunopathogenesis. PMID- 21528752 TI - Immunohistochemical aspects of apoptosis in subcutaneous lupus erythematosus. AB - Lupus erythematosus (LE) has a broad clinical spectrum from exclusively skin damage (chronic discoid lupus-DLE or subacute lupus erythematosus-SCLE) to systemic, multiorgan disease (involving skin, joints, kidney, central nervous system). LE is characterized by an autoimmune component. SCLE is characterized by erythemato-squamous lesions mainly in photoexposed areas. Apoptosis (programmed cellular death) is essential for normal embryogenesis and for normal tissue homeostasis and control. Inefficient apoptotic cell clearance has been correlated with inflammatory diseases and autoimmunity outburst. This study evaluates histological and immunohistochemical expression ofpro-apoptotic markers in patients with SCLE. MATERIALS AND METHODS: 20 patients with SCLE and 10 healthy controls were selected. Biopsies from skin lesions were performed. Biopsies were evaluated for immunohistochemical expression of caspase 3, CD25, CD35, CD21, CD36, CD68, CD31, IgM detection, T and B cell markers. RESULTS: In the inflammatory cells population we distinguished T lymphocytes, rare B lymphocytes, dendritic cells and macrophages. Within the lymphocyte population IL-2 receptor (CD25) expression was low but caspase 3 expression was intense in lymphocytes, epithelial cells and pericytes. Basal epithelial vacuolations were common. Phagocytic-cell and lymphocytic expression of CD35 (complement receptor 1-CR1) and CD21 (complement receptor 2-CR2) were lower when compared to healthy controls. CONCLUSIONS: In SCLE patients we observed lymphocytic, epithelial and pericytal cell apoptosis and CR1 and CR2 expression are lower in professional phagocytes, suggesting a delay in the uptake of apoptotic bodies. PMID- 21528753 TI - Detection of serum of IgG anti-neuronal antibodies in systemic lupus erythematosus patients with central nervous system manifestations. AB - The objective of the study was to assess the frequence of serum IgG anti-neuronal antibodies (NA) in SLE patints with CNS manifestations. Serum anti-NA antibodies were measured in 47 patients with SLE with CNS manifestations (CNS-SLE), age 33 52 years, mean age 38.6 years, 18 men and 29 women, as compared to 31 patients with SLE without CNS manifestations, age 28-56 years, mean age 41.2 years, 13 men and 18 women and 56 healthy subjects. Serum IgG antineuronal antibodies were measured by indirect immunofluorescent assay. Thirty-five of out 47 CNS-SLE patients presented anti-NA (74.6%). Anti-NA were observed in 15 out of 15 patients with acute confusional state (100%), in 8 of 8 patients with cerebrovascular disease (100%), in 5 out of 7 patients with seizure disorder (76.3%), and in 4 out of 5 patients in intractable headache (86.8%). Out of 31 nonCNS-SLE patients 1 patient presented anti-NA (3.9%). Serum anti-NA were more frequently observed in CNS-SLE patients as compared to controls (p < 0.000001). The frequence of serum anti-NA was significantly higher in CNS-SLE patients as compared to non CNS-SLE patients (p < 0.00001). In conclusion, serum anti neuronal antibodies are associated with CNS-SLE. These antibodies are more frequent in CNS-SLE than in nonCNS-SLE patients, demonstrating a strong association between serum anti-NA and CNS involvement of SLE. The presence of serum anti-NA could be a useful diagnostic tool for CNS-SLE, the test could help to distinguish SLE from other diseases with similar symptoms. Further studies are needed to evaluate the predictive value of anti-NA in SLE. PMID- 21528754 TI - E-cadherin and beta-catenin expression in gastric neoplastic and non-neoplastic lesions--correlations with H. pylori infection. AB - Gastric cancer is one of the most aggressive malignancies, as incidence and as evolution as well. Although, due to the new findings about etiology, carcinogenesis, precancerous conditions and their detection, as well as the treatment, in the latest decade, there is an improvement in these data, gastric cancer remains a redoubtable enemy because of its incidence, prevalence and mortality. Researches are focusing on early detection of precursor lesions and on establishing their reversibility potential by bringing more clinical and statistical information and by setting new clinical hypotheses. In this context, the present article is trying to study immunohistochemical expression of two oncogenic markers, the cell adhesion protein antibodies E-cadherin and beta catenin. Cell to cell and cell to extracellular matrix interactions are crucial for neoplastic transformation and for metastasizing process. The importance of these antibodies in maintaining cell adhesion suggests that their abnormal expression is playing an important role in tumorigenesis. In this article, authors are presenting a study about E-cadherin and beta-catenin expression in 75 patients who underwent gastrectomy for suspicions of gastric malignancies. The variables of the study are the presence or absence of Helicobacter pylori, type I carcinogenetic agent for gastric carcinoma (especially intestinal type adenocarcinoma) and the presence of tumoral or non-tumoral gastric lesions. PMID- 21528755 TI - Evaluation of inter-relationship between behavioral inhibition, behavioral activation, avoidance, daily stressors and oral health. AB - The aim of the present study was to evaluate the interrelationship between behavioral inhibition, behavioral activation, avoidance, oral health status and behaviour. MATERIAL AND METHODS: The present study sample consisted of213 first year dental students. The questionnaire included information about socio demographic factors, behavioral variables and self-reported oral health status. The Cognitive-Behavioral Avoidance Scale (CBAS; Ottenbreit & Dobson, 2004), BIS/BAS Scale (Carver & White 1994) and DISE scale (Daily Inventory of Stressful Experiences; Almeida et al., 2002) were also used. RESULTS: Self-reported oral health status significantly correlated with BIS (P < 0.05), BAS (P < 0.05) and DISE (P < 0.01). Satisfaction by appearance of own teeth and self-reported gingival condition were also correlated with BIS (P < 0.05, respectively P < 0.01) and DISE (P < 0.05, respectively P < 0.05). Participants with high BIS sensitivity reported more frequently to never use dental flossing than those with low BIS (P = 0.025), while the students with high BAS (Reward Responsiveness and Drive scales) scores showed lower frequency of never using mouthrinse (P = 0.043) and visited their dentist more frequently than those with low BAS scores. 12.5% of the individuals with high levels of avoidance have done last dental visit more than 2 years ago comparing with 6.9% of those with lower levels of avoidance. A high level of daily stressors was linked to an impaired dental health, insatisfaction by appearance of own teeth, toothache during last 3 months, impaired gingival condition and self-reported gum bleeding (P < 0.05). CONCLUSIONS: . Our results have important implications for the focus and content of(preventive) oral health behaviour interventions, emphasizing on teaching patients strategies to counter their difficult behavioral patterns. PMID- 21528756 TI - Restrictive cardiomyopathy--an outdated concept? AB - Restrictive cardiomyopathy is probably the least common of all cardiomyopathies, with a nonspecific clinical presentation and a frequently unknown cause. The concept of RCM has changed tremendously over time. Today it includes a large panel of disorders characterized by a non-hypertrophied, non-dilated cardiac phenotype and a restrictive ventricular filling pattern. Several unsuccessful attempts to define and classify cardiomyopathies have been made, but they all proved problematic due to the contradiction in terms and the overlap between classical patterns. Advances in disease pathology, genomics and molecular biology are emerging as the framework of a new revolutionary classification system, focused on the dynamic interaction between genotype and phenotype. In this context, RCM is evolving as a self-contained hemodynamic and pathophysiological concept, although questionable due to its uncertain practical utility. PMID- 21528757 TI - Carcinogenesis and infection with Helicobacter pylori. AB - It was accepted several years ago that, in the carcinogenesis process of human cancers, biologic agents, especially the viruses, are playing an etiologic role. This is the case of lymphomas (retroviruses), hepatocarcinoma (hepatic viruses) and cervical carcinoma (papilloma viruses). Helicobacter pylori is the first bacteria recognized as a first class carcinogen for gastric cancer. Nevertheless, comparing with the most validated human carcinogens, the activity of H. pylori is very little studied. As a consequence, at this moment, in its case, explanation of carcinogenesis mechanism is more or less hypothetical. PMID- 21528758 TI - Oxidative stress in diabetic kidney disease. AB - Diabetic Kidney Disease (DKD) represents a worldwide public health problem, due to its ever growing incidence and high costs connected to the imposed therapies regarding substitution of kidney functions. DKD includes all the anatomical, clinical and functional alterations that occur at kidney level in a patient with Diabetes Mellitus (DM), as a result of numerous metabolic and haemodynamic factors at the level of kidney microcirculation, based on a polygenous genetical polymorphism that generates an individual susceptibility for this complication. DKD is found in 20-40% of DM patients and it represents the main cause of chronic kidney disease. In DKD pathogeny, an important part is played by the oxidative stress determined by hyperglycemia. Among the mechanisms by which hyperglycemia may affect the kidney we may enumerate polyol pathway activation, C protein kinase activation (PKC), non-enzymatic protein glycosylation. Out of the highly reactive molecules involved in the oxidative stress of DKD, an important role is attributed to *O2-, *NO and ONOO-. The role of oxidative stress played in DKD pathogeny is also supported by the promising results of some antioxidant therapies in DKD: AGE inhibitors (pyridorin, 2,3 diamino-phenazine, bromo phenylacetic thiazolium, aminoguanidine/pimagedine), diacylglycerol pathway inhibitors (vitamin E, thiamine, benfotiamine, aminoguanidine), PKC inhibitors (ruboxistaurin), transketolase activators (thiamine and benfotiamine). PMID- 21528759 TI - Cardiovascular risk in patients with diabetic kidney disease. AB - In the past decades, chronic kidney disease has become a public health problem all over the world. Both the incidence and the prevalence are continually increasing. Diabetic nephropathy is, by far, the most frequent cause of CKD, with a prevalence of 40% in patients with end-stage renal disease (ESRD). Present studies have shown the fact that microalbuminuria and chronic kidney disease are independently associated to a high risk of cardiovascular events, as well as to a high mortality rate of all causes and also of cardiovascular cause, both in the general population and also in patients with high risk or an already present cardiovascular disease. There is a permanent association between the level of urinary albumin excretion and the risk for cardiovascular disease, macroalbuminuria and clinical nephropathy being associated to a higher risk for cardiovascular events than microalbuminuria. Due to the importance of clinical data and low cost, microalbuminuria and glomerular filtration rate should be introduced in the clinical practice for the evaluation of cardiovascular risk, especially in the patients with previously known heart disease. An early identification of the factors that determine the emergence and progression of diabetes complications is essential, in order to reduce the cardiovascular mortality and morbidity. PMID- 21528760 TI - Blood pressure pattern and heart rate variability in normotensive patients with type 2 diabetes mellitus. AB - Ambulatory blood pressure monitoring (ABPM) has shown that almost one third of presumed normotensive patients with type 2 diabetes mellitus have instead masked hypertension. There is also a relationship between cardiovascular autonomic neuropathy and blood pressure patterns even in normotensive patients with diabetes mellitus. The aim of the present study was to analyze the blood pressure patterns in type 2 diabetic patients without any history of hypertension and to establish the connection between heart rate variability parameters, ultrasound parameters and ABPM parameters. MATERIAL AND METHODS: Fifty-two subjects with type 2 diabetes, aged 59 (+/- 6), were consecutively recruited at the Internal Medicine Department of the County Hospital in Cluj. Informed consent was obtained from all participants. A control group of 47 subjects, age and sex matched, was also analyzed. RESULTS: More than half of the patients had a non-dipping pattern, despite the fact that they are considered normotensive patients. Heart rate variability parameters are lower in the non-dipping group, but the difference is significant only for vagal activity. Left ventricle is thicker in non-dipping group. The mean age of the non-dipping group (61.23 +/- 2.02 years) was significantly higher than the age of the dipping group (55.11 +/- 3.88 years) (p < 0.01). DISCUSSIONS AND CONCLUSION: We found a great number of patients with diabetes mellitus and with altered patterns of blood pressure, even if they were previously considered as normotensive. The non-dipping pattern is associated with abnormal values of heart rate variability parameters and with thicker left ventricle walls, but the differences are not always statistically significant. It is important to closely monitorize the patients with diabetes mellitus even if they have normal office blood pressure determinations, mainly those with a history of more than 5 years of the disease. PMID- 21528761 TI - Study of endothelin-1 in acute ischemic stroke. AB - Endothelins (ETs) are potent vasoconstrictor and may play a role in the pathophysiology of several cardiovascular diseases. Endothelin-mediated vasoconstriction may enhance ischemic neuronal damage. The study aimed to find out whether the plasma ET-1 levels may serve as marker of early ischemic stroke. Plasma ET-1 levels were tested in 20 patients with acute ischemic stroke, mean age 63.7 +/- 5.03 years, 12 men and 8 women, within 24 hours of stroke onset as compared to 10 sex- and age-matched control subjects; only the patients with normal CT-scan at admission were included in the study. Plasma ET-1 was measured by ELISA. The results were statistically analyzed by Student test and a p < 0.05 (95% CI) was considered statistically significant. ET-1 levels in patients with hemiplegia and normal CT-scan at admission were significantly higher as compared to control group (0.0910 +/- 0.0256 pg/mL vs. 0.0490 +/- 0.0185 pg/mL, p < 0.0001) (95% CI). Ischemic stroke is associated with acute and marked increased levels of ET-1 in plasma. This may reflect enhanced production by damaged endothelial cells within the infarcted lesion. ET-1 may be used as additional marker of cerebral ischemia in selected cases to distinguish between the onset of an ischemic stroke and other non-vascular diseases presenting similar symptoms. PMID- 21528762 TI - Relationship of humour with oral health status and behaviours. AB - A sense of humor and an ability to laugh reduces stress, enhances hope, relieves tension, and stimulates the immune system. This study explored the role of humour on oral health status and behaviors. The factor structure and the construct validity of the Romanian version of the Multidimensional Sense of Humour Scale (MSHS) was also assessed. MATERIAL AND METHODS: The present study sample consisted of 213 first year dental students. The questionnaire included information about socio-demographic factors, behavioral variables and self reported oral health status. Sense of humour was assessed using the Multidimensional Sense of Humour Scale (MSHS) (Thorson and Powell, 1993). RESULTS: There was no significant gender difference with regard to total MSHS scale of humour; however, a detailed analysis of the factors and items reveals some differences in constructions of sense of humor between males and females. We have compared the highest and the lowest 30% of individuals with respect to their MSHS humour scores, in order to test the hypothesis that persons in high humour groups would report higher levels of good health than those in low humour groups. It was revealed that four of the dependent variables, oral health status, gingival health status, toothbrushing frequency and dental visit frequency differed significantly among the two groups. It was also shown that participants who flossed their teeth or used mouthwash once a month presented significant lower values of humour thon those who used everyday dental floss or oral mouthrinses. The independent variables (demographic variables [age, gender, tobacco usage] and humour) were regressed on each of the dependent oral health status and behaviour scales. Although the multiple regression analysis on gingival status was non-significant overall, humour contributed a small, but significant 1.51% of the predictive variance, P < 0.05. CONCLUSIONS: Further research is required in order to gain a better understanding of the concept of humour and its uses in healthcare. PMID- 21528763 TI - Autonomic neuropathy and plasma catecholamine in patients with diabetes mellitus. AB - BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a common form of autonomic dysfunction in diabetes mellitus (DM) patients, but it can be asymptomatic for years. Low baseline plasma noradrenaline levels have been found in diabetic patients, but this decrease seems to associate clinically severe autonomic neuropathy. PURPOSE: To evaluate the impact of DM on heart rate variability (HRV) parameters and to determine the correlations with plasma adrenaline and noradrenaline, as a possible mechanism of early disruption in HRV. METHODS: A group of 34 patients with type 2 diabetes mellitus, without clinical signs of CAN, was enrolled. HRV (as a measure of autonomic balance) was measured using a 24 hour ECG monitoring system in all subjects during normal daily activity. Plasma catecholamines and other laboratory markers were measured. RESULTS: HRV parameters are lower in DM group as compared with control group. More than half of the patients had HRV parameters below the normal range (54%). There are lower levels of noradrenaline value in DM, as compared with controls, but the difference is not statistically significant (p = 0.08). Adrenaline levels were similar in both groups. DISCUSSION AND CONCLUSION: CAN is best evaluated using heart rate variability (HRV) on 24 hours recordings. There is a tendency for HRV parameters to decrease even in asymptomatic patients, especially after years of evolution. We did not find significant correlations between HRV and plasma catecholamine, even if noradrenaline was lower in DM patients. Holter monitoring remains a reliable method for early diagnosis of CAN. PMID- 21528764 TI - Ankylosing spondylitis or Crohn's disease? Case report and review of the literature. AB - A 27-year-old male with a 2 year history of ankylosing spondylitis (AS) was investigated for intermittent episodes of diarrhea and found to have granulomatous ileitis. Differential diagnosis, discussions regarding similarities in immune alterations in both AS and Crohn's disease and therapeutic options are presented in this paper. PMID- 21528765 TI - Right renal artery occlusion as a complication of fibromuscular dysplasia. AB - Renovascular hypertension is defined as elevated blood pressure levels due to the stenosis/ occlusion of the renal artery caused by fibromuscular dysplasia or atherosclerosis. We present the case of a 59-year old female patient with recently diagnosed arterial hypertension due to renal artery occlusion through intimal fibromuscular dysplasia. In this case, arterial blood pressure levels have not been controlled by maximum doses of antihypertensive drugs, used in association; rapid deterioration of the renal function, as well as important kidney damage, proven by imaging explorations, motivated the laparoscopic nephrectomy. PMID- 21528766 TI - At the dawn of a new era in treating angina pectoris, or just another antianginal drug? Some considerations about ranolazine. AB - Ranolazine is a new compound that has been approved by the FDA for use in patients who have chronic stable angina refractory to conventional antianginal medications. Ranolazine proved to be effective also as monotherapy in patients with stable angina and as part of a combination regimen. This review is inspired by the presentation that legendary figures in contemporary cardiology, such as Braunwald, Komajda and Camm made recently at the Congress of the European Society of Cardiology held in Stockholm, Sweden, last September. PMID- 21528767 TI - Stress vulnerability in patients with drug allergy--psychological aspects revealed from some personal studies. AB - Previous studies revealed the fact that patients with allergic-type reactions to drugs display very frequently psychical disturbances, possibly in relation to the large amount of stress perceived by them. Some of these patients with psychiatric comorbidity show a disproportionate reaction, manifested as extensive psychosomatic disturbances, mimicking the psychic and somatic symptoms of a previous anaphylactic or anaphylactoid reaction, when a new drug or even when placebo preparations are given. The neurotic symptoms, very frequently encountered in patients with allergic-type reactions to drugs (including asthma patients) appear to be secondarily-induced by the anxious experience of the drug provoked accident. The vulnerability to psychic stress, together with many life stressors events may represent a potential risk for developing drug allergy. Their main problem is the risk of repeating the allergic accidents, especially in patients with various comorbidity which need medication. PMID- 21528768 TI - Protein aggregation in inclusion body myositis, a sporadic form among protein aggregate myopathies, and in myofibrillar myopathies--a comparative study. AB - Protein aggregation has been identified in muscle fibres and, thus, in certain neuromuscular disorders. There are certain similarities between IBM and DRM: midlife or late-onset clinical symptoms, apparently of both sporadic and genetic background, morphologically autophagocytosis by vacuole formation, which is frequent in IBM though rare in DRM, and presence of tubulofilamentous aggregates, which is almost regular in IBM but scantily found in DRM as beta-amyloid components have been identified as accruing proteins, both in IBM and DRM. Previous studies pointed to the hypothesis that clear morphological borders between the two types of diseases--hereditary inclusion body myopathies/myositis and desmin-related myopathies may not exist. Therefore, we analysed and morphologically characterised the spectrum of proteins accumulating in both types of disorders in order to compare them and more clearly define similarities and dissimilarities between these two different groups of protein aggregate myopathies. Previous studies showed that there is an overlap among some of the proteins accruing in these diseases, but there might also be differences in that a large number of proteins found aggregated in desmin-related myopathies had not yet been described in IBM. The aim of describing the comparative protein profiles is to give more insights into the mechanism of protein aggregation within muscle fibres. MATERIAL & METHODS: We studied diagnostic muscle biopsies from 10 sIMB patients and 6 MM patients with histological, histochemical, enzyme histochemical, ultrastructural and immunohistochemical techniques using a large number of antibodies. RESULTS: We noticed a partial overlap of protein expression in the two cohorts of patients for sarcomeric, chaperone and mostly for cytoskeletal proteins. In both of the cohorts, the nuclear proteins were absent in the cytoplasmic bodies. A different pattern of immunolabelling was noted for trans-sarcolemmal proteins, constantly enhanced in the inclusion bodies in MM, but never found in IBM, except for delta-sarcoglycan, dysferlin and caveolin. CONCLUSIONS: The partial overlap among some of the proteins accruing in these diseases raise the hypothesis that clear nosological borders between s-IBM and MM may not always exist. There are also dissimilarities in the pattern of protein aggregation, suggesting that other additional factors are involved in the pathogenesis. PMID- 21528769 TI - Oxidative stress during abdominal aortic aneurysm repair--biomarkers and antioxidant's protective effect: a review. AB - BACKGROUND AND OBJECTIVES: Oxidative stress during abdominal aortic aneurysm (AAA) repair is likely to result as a response to an ischemia-reperfusion injury (IRI) to the lower limbs and gastrointestinal tract. This paper reviews the oxidative stress during AAA repair, with specific reference to biological markers and the potential antioxidant's protective effect. EVIDENCE AND INFORMATION SOURCES: The current literature (1966 to July 2010) was reviewed specifically for all articles describing human studies relevant with the particular subject: oxidative stress in patients with AAA repair. Key-words used as single or combined searches included "abdominal aortic aneurysm", "open repair", "EVAR", "oxidative stress", "oxidation" and "antioxidant". RESULTS: A total of 14 relevant human studies were identified. In the majority of studies all samples (blood samples or/and muscle biopsies) were obtained from the patients using regional sampling techniques before or after anaesthesia, during aortic clamping or balloon occlusion (ischemic time) and after aortic clamp removal (reperfusion time) in different time intervals up to 24 or 48 hours. The oxidative status during AAA repair operation was evaluated by measuring quantitative changes of different substances including mainly vascular endothelial adhesion molecules, lipid peroxidation by-products or reactive oxygen species (ROS) and their metabolites. Two studies compared two groups of patients with AAA treated either by open or endovascular repair (EVAR), while four studies used different types of antioxidant supplementation in order to correlate it with a reduction in oxidative stress and damage in the antioxidant group of patients. PERSPECTIVES AND CONCLUSIONS: Current evidence suggests that there is a high-grade oxidative stress during AAA repair operation. This was higher in cases of open repair beside EVAR and in cases with ruptured AAAs beside elective cases. The beneficial effect of an antioxidant supplementation in reducing the oxidative stress during AAA repair was also demonstrated. The use of a biological marker as a predictor of the development of systemic complications could also give a therapeutic advantage. PMID- 21528770 TI - Long-term enzyme replacement therapy in a severe case of mucopolysaccharidosis type II (Hunter syndrome). AB - Hunter syndrome or mucopolysaccharidosis II (MPS II) is a rare X-linked disease caused by a deficiency of the iduronate-2-sulphatase (12S) lysosomal enzyme, resulting in a progressive accumulation of glycosaminoglycans (GAGs). Enzyme replacement therapy (ERT) with recombinant human 12S idursulfase has been used infrequently in children < 5 years. We present the case of a 7 years and 10 months-old child, who was diagnosed with a severe form of MPS II at the age of 3 years, and who began a 36 months' treatment with idursulfase at 4 years 10 months. After 10 months, GAG urinary excretion was normal, but after just 4 months the liver and spleen had decreased in size, returning to normal limits by 36 months. Significant bone remodeling was noted after 16 months. Cardiac and neurological development, however, progressively deteriorated. The only adverse reactions were episodic inflammations of the upper and/or lower respiratory tract, but there was no otitis. Early use of ERT, presuming good treatment adherence, can significantly improve bone abnormalities. PMID- 21528772 TI - Obesity is associated with a higher level of pro-inflammatory cytokines in follicular fluid of women undergoing medically assisted procreation (PMA) programs. AB - INTRODUCTION: Cytokines are glycoproteins that modulate reproductive function through a series of various mechanisms (by both conditioning gonadal steroidogenesis and contributing to the preservation of an inflammatory microenvironment). AIM OF THE STUDY: To evaluate the impact of certain clinical variables (i.e., age, obesity, insulin resistance index, serum antithyroid antibodies serum levels) on the serum concentrations of cytokines TNF-alpha, IL 6, and IL-10 in the follicular fluid of women undergoing a medically assisted procreation (PMA) cycle. MATERIALS AND METHODS: A total of 40 female patients undergoing an intracytoplasmic sperm injection (ICSI) in oocytes, following ovarian stimulation by purified FSH and hCG carried out after suppression of ovarian function. The follicular fluid, obtained by surgical ultrasonography guided withdrawal, was stored at -30 degrees C. Subsequently the cytokines were assayed by ELISA technique. RESULTS: Women suffering from class II obesity showed follicular levels of TNF-alpha significantly higher (p < 0.05) than women with a normal body mass index (BMI). Significantly higher concentrations of TNF-alpha and IL-6 were found in women with HOMA index > 2.5. Women clinically presenting with concomitant obesity and high serum levels of antithyroid antibodies were found to have higher follicular levels of TNF-alpha and IL-6 (p < 0.05) in comparison with women suffering from obesity only or low antithyroid antibodies levels only, or from both these conditions. CONCLUSION: Obesity is a common clinical condition associated with a higher concentration of inflammatory substances in the follicular fluid of infertile women. It is not understood, as yet, the possible pejorative role exerted by the presence of other clinical conditions, such as insulin resistance and high levels of antithyroid antibodies, that are conditions frequently encountered in the clinical practice. PMID- 21528773 TI - The issue of applying marketing on the pharmaceutical market in Serbia. AB - The issue of applying marketing on the pharmaceutical market has the features of subject-based approach, with the intention to appreciate the specific nature of the products, as well as the special characteristics of the complexly formed demand. The relevance of the issue is related to the above-average performance of the pharmaceutical industry, its role in the generation of humanity's demographic transition, and specific development routes of marketing as a scientific and practical discipline. The sensitive nature of a pharmaceutical product on the one hand generates the intense legislation on this market, whereas on the other, the circumstances of its use generate a specific environment in which the production/consumption of the products of pharmaceutical industry is intensively reflected as a specific medical, cultural, economic and even political phenomenon. PMID- 21528771 TI - Nutritional status in a multicenter study among institutionalized patients in Spain. AB - INTRODUCTION: The aim of our study was to investigate and evaluate, in a multicenter study, the prevalence of malnutrition as well as the relationship between different anthropometric and biochemical markers with Mininutritional assessment (MNA) scores. SUBJECTS AND METHODS: A representative sample of the institutionalized Spanish population aged 65 and older (stricly speaking, born in 1942 or earlier), is covered in this cross-sectional survey. Anthropometric variables, MNA test and biochemical evaluation were performed by Geriatrics Units specialists. RESULTS: The percentage of patients classified as well nourished (27.8%) was larger in the 85-94 (39.4%) range than in the 65-74 (26.2%), 75-84 (24%) and > 95 (14.8%) age ranges. A population of 254 patients (49.6%) were at risk of undernutrition, a number which was larger in 75-84 (52%), 65-74 (53.8%) and > 95 (53.7%) than in the 85-94 (44.1%) ones. On the other hand, undernourishment (22.5%) was larger in those of 95 and older (31.5%) than in 85 94 (16.5%), 75-84 (24%) and 65-74 (20%) patients. According to our investigation females are worse nourished (Odd's Ratio 0.51 CI 95%: 0.33-0.79) and, consequently, more undernourished (Odd's Ratio 2.36 CI 95%: 1.48-3.74) than males. No significant differences in the "at risk of undernutrition category" (Odd's Ratio 0.76 CI 95%: 0.52-1.10) were observed but, in transferrin, iron, haemoglobin and total cholesterol, statistical differences among MNA classification were detected. MNA scores were correlated with iron, total cholesterol, albumin, transferrin, age and haemoglobin. CONCLUSION: In this multicenter study, institutionalized patients have a high prevalence of undernutrition or are at-risk, as well as females are more undernourished than males. PMID- 21528774 TI - Protective effect of gum acacia against the aspirin induced intestinal and pancreatic alterations. AB - OBJECTIVES: The current study was carried out to examine the influence of aspirin (400 mg/kg of body weight) and gum acacia (one g/day) and their combination on pancreatic, intestinal mucosal enzymes, intestinal tissue iron and zinc after 21 days of treatment on experimental rats. MATERIALS AND METHODS: The treated rats were sacrificed and the pancreatic and intestinal lipase and amylase were measured photometrically. Moreover, zinc and iron level were determined using atomic absorption spectrometry. Intestinal sections were stained with hematoxylin and eosin. RESULTS: The results showed that treatment with aspirin caused a marked decrease in pancreatic lipase and amylase compared with that of the control group. This decrease in aspirin treated group was accompanied by significant increase in the intestinal amylase, lipase, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) compared with the control group. On the other hand, gum combined with aspirin caused a significant increase in pancreatic and intestinal lipase, amylase accompanied with significant increase in intestinal ALP and LDH compared with that of the control group. Concentration of Zn in wet weight of intestine showed a significant decrease in aspirin and aspirin combined with gum groups but it was increased significantly in gum acacia treated group. Histological analysis revealed intestinal epithelial damage in aspirin treated rats, this damage was not noticed with gum acacia treatment. Co administration of gum in combination with aspirin indicated some changes of denuded intestinal mucosal cells compared with that of the control. CONCLUSIONS: Gum acacia exhibited a protective property that can ameliorate the alterations induced hazardous effect of aspirin treatment. PMID- 21528775 TI - In vitro study of antibacterial activity of the alga Sargassum oligocystum from the Persian Gulf. AB - BACKGROUND AND OBJECTIVES: With due attention to the development of drug resistant bacteria, discovering of new antibacterial compounds is needed. Algae produce numerous bioactive substances which may have pharmacological properties such as antibacterial activity. The objective of this investigation was to in vitro study of antibacterial activity of brown alga Sargassum oligocystum collected along the Bushehr coast of Persian Gulf (south west of Iran). MATERIALS AND METHODS: Hot water extract, cold water extract, and hot glycerin extract were prepared. The effect of the extracts were investigated on Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis (ATCC 14990), Pseudomonas aeruginosa (ATCC 27853), and Escherichia coli (ATCC 25922). RESULTS: Hot water extract exhibited antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa. Cold water extract and hot glycerin extract did not show antibacterial activity on any of the four test bacteria. The minimum inhibitory concentration (MIC) of hot water extract for both Staphylococcus aureus and Staphylococcus epidermidis was 3.175 mg/ml. However, the MIC of this extract for Pseudomonas aeruginosa was 9.556 mg/ml. DISCUSSION: In this study gram-positive bacteria were more susceptible to hot water extract than gram-negative bacteria. Extract of Sargassum oligocystum could be a candidate for purification and further in vivo studies. PMID- 21528776 TI - Dupuytren's contracture as result of prolonged administration of phenobarbital. AB - Dupuytren's disease is a fibroproliferative condition involving the superficial palmar fascia, leading to a progressive and irreversible flexion of the fingers. In literature, there are different opinions regarding the phenobarbital, a common antiepileptic drug, and its effective role in the genesis and development of Dupuytren's disease. In this retrospective investigation the association between phenobarbital and Dupuytren's contracture is discussed. Three patients in treatment with phenobarbital who had no others significant risk factors for Dupuytren's contracture were included in this study. The disease occurred after one to four years of drug therapy, at dosage of 100 mg/day. After surgery, Dupuytren's disease showed different evolutions in relation to dosage and type of antiepileptic drug used. Phenobarbital causes a dose and time-dipendent profibrotic effect. A clinical regression was observed when phenobarbital was substituted by carbamazepine, maintaining the same dosage (100 mg/day). This data confirms that not all the antiepileptic drugs are implicated in palmar fibrosis, and suggests that, according to the efficacy and adverse effects, the administration of benzodiazepine reduces the risk of Dupuytren's recurrence. PMID- 21528778 TI - Rapid detection of Streptococcus pyogenes in throat swab specimens by fluorescent in situ hybridization. AB - BACKGROUND AND OBJECTIVES: Streptococcus pyogenes (S. pyogenes) is an important cause of pharyngitis. Rapid detection of this microorganism in throat specimens is essential to promptly start antibiotic therapy which could be lead to prevent complications and stop transmission of infection to other individuals. In the present study, fluorescent in situ hybridization (FISH) was compared with culture method for the detection of S. pyogenes in throat swab specimens. MATERIALS AND METHODS: One hundred eleven patients with pharyngitis were included in this study. The throat swab specimens of these patients were investigated by both conventional culturing and FISH. RESULTS: Based on the results of this investigation, the sensitivity and specificity of FISH were 88.9% and 97.8%, respectively. Strikingly, in the specimen of one patient who had received antibiotic previous to clinical sampling, S. pyogenes was detected by means of FISH, whereas the culture method could not detect this bacterium. CONCLUSIONS: It seems that FISH is a suitable method for quick identification of S. pyogenes in throat swab specimens. When FISH is positive, culturing is not necessary. But because of the limited sensitivity of FISH for detection of S. pyogenes in throat swab specimens, culturing shoud be performed if FISH was negative. PMID- 21528777 TI - Curative effect of the Egyptian marine Erugosquilla massavensis extract on carbon tetrachloride-induced oxidative stress in rat liver and erythrocytes. AB - OBJECTIVES: The purpose of the present work was to investigate the effect of marine crustacean extract (MCE) from marine mantis shrimp Erugosquilla massavensis and silymarin on oxidative stress induced by carbon tetrachloride (CCl4) in rat liver and erythrocytes. MATERIALS AND METHODS: Male rats were randomly divided into 3 main groups, (1) control group which administered olive oil orally for 2 days, followed by distilled water for 7 consecutive days, (2) MCE group in which rats administered orally MCE, 250 mg/kg body weight for 9 consecutive days and (3) CCl4-treated group in which rats given CCl4 orally (2.5 ml/kg body weight) for 2 days. This group then subdivided into 5 subgroups. All subgroups treated orally for 7 consecutive days with distilled water (subgroup I), silymarin, 150 mg/kg body weight (subgroup II) and MCE at three tested doses 50, 100 and 250 mg/kg body weight (subgroups III, IV and V). RESULTS: The MCE and silymarin produced significant hepatoprotective effect by decreasing the activity of serum aminotransferases (ASAT and ALAT) and alkaline phosphatase (ALP) as well as malondialdehyde (MDA) level, and increasing the serum total protein, glutathione reduced (GSH) levels and the activities of glutathione-S-transferase (GST) and catalase (CAT). The MCE and silymarin also showed the same antioxidant effect on erythrocytes. CONCLUSIONS: The results of the present study, suggested that, the MCE could protect the liver and erythrocytes injuries perhaps, by its antioxidative effect, hence eliminating the deleterious effect of toxic metabolites from CCl4. PMID- 21528779 TI - Exophiala oligosperma involved in a refractory chronic rhinosinusitis. AB - Fungal rhinosinusitis refers to a wide variety of conditions caused by fungal infections of the paranasal sinuses. Allergic fungal rhinosinusitis and sinus fungus balls are mostly noted in healthy individuals. Aspergillus species are supposed to be the most common etiologic agents of the disorder, but melanized fungi also occur, and these potentially are able to lead to fatal dissemination into brain parenchyma. We report on a case of fungus ball in a 20-year-old female with refractory chronic rhinosinusitis (RCRS) and bronchial asthma due to the black yeast Exophiala oligosperma which was confirmed by mycological and molecular (sequences of ITS rDNA) investigations. Exophiala oligosperma has previously not been reported to cause fungus balls or invasive fungal rhinosinusitis. Patient underwent functional endoscopic sinusitis surgery and the hypertrophic mucosa was removed completely. Without antifungal therapy, successful cure was achieved after spray therapy with corticosteroids for 1 month, without any relapse after a 6 month-follow up. PMID- 21528780 TI - Docetaxel plus prednisone in patients with metastatic hormone-refractory prostate cancer: an Italian clinical experience. AB - AIMS AND BACKGROUND: We investigated the efficacy of docetaxel plus prednisone in Italian patients with metastatic hormone-refractory prostate cancer (mHRPC). METHODS: Twenty four patients with mHRPC received docetaxel 75 mg/m2 every 3 weeks plus prednisone 5 mg twice daily for up to six cycles. The primary endpoint was efficacy measured by a reduction in serum prostate specific antigen (PSA) levels and measurable disease. Evaluation of toxicity, quality of life and reduction of pain were secondary endpoints. RESULTS: PSA response was seen in 18 patients (75%). We observed a partial response in 2 patients (8.3%), stable disease in 10 patients (41.7%), and disease progression in 12 patients (50%). Severe neutropenia was reported in 12.5% of patients. CONCLUSIONS: Treatment with docetaxel every three weeks is an effective and well tolerated therapeutic option in patients with mHRPC. PMID- 21528781 TI - A preliminary study of the local treatment of preneoplastic and malignant skin lesions using methyl jasmonate. AB - BACKGROUND: Jasmonates are plant stress hormones. These small hydrophobic compounds exhibit anti-cancer activities, in vitro and in vivo, against cancer cells of various histological origins. Moreover, they show a selective activity against transformed cells and affect drug-resistant cells as well. AIM: The aim of this study was to evaluate the activity of a powerful jasmonate derivative, that is methyl jasmonate. MATERIAL AND METHODS: Methyl jasmonate was applied topically on cancerous and pre-cancerous skin lesions from eight patients. RESULTS: Methyl jasmonate did not cause any meaningful local or systemic side effects. Three patients exhibited positive responses. Two patients had complete recovery and one had a recurrence of the lesion three months post treatment. CONCLUSIONS: Methyl jasmonate is a potentially promising novel topical treatment for prcancerous and cancerous skin lesions. Methyl jasmonate should be evaluated in a larger series of patients. PMID- 21528782 TI - Association of invasive breast carcinoma and multicentric high grade astrocytoma: a case report with a review. AB - Breast cancer is the most common cancer in women. Multicentric gliomas are uncommon lesions of the central nervous system (CNS) with an unprecise rate of occurrence that diffusely infiltrate large portions of the brain. High grade astrocytoma is the most agressive form of gliomas and often has a distinct neuroimaging pattern with a poor prognosis. We report a case of a 29-year-old woman patient with primary breast carcinoma and high grade astrocytoma subsequently developed. The woman was treated by mastectomy and 20 months post diagnosis of the cancer she exhibited a transient facial paralysis. Magnetic resonance imaging (MRI) revealed two cranial masses suspicious of metastasis. A complete tumor removal from the brain was performed. On histological examination, this tumor was a high grade astrocytoma. PMID- 21528783 TI - A thoracic mass infiltrating the chest wall. AB - A case of thoracic mass infiltrating the chest wall mimicking a pulmonary invasive neoplasm is reported. Differential diagnosis and characteristic radiological and histological imaging had a decisive role in the case management. Actinomycosis is caused by a gram-positive, filamentous, microaerophilic bacteria. About 15% of the infections caused by Actinomyces involve the thorax. If not promptly diagnosed and treated thoracic actinomycosis may determine contiguous and systemic involvement. Actinomycosis is an anaerobic-to microaerophilic bacteria and direct identification and isolation are difficult to obtain. In depth discussion diagnostic and therapeutic features are described in this report. PMID- 21528784 TI - Epidemiology of rotavirus and cholera in children aged less than five years in rural Bangladesh. AB - Despite the known presence of rotavirus-associated diarrhoea in Bangladesh, its prevalence, including records of hospitalization in rural health facilities, is largely unknown. In a systematic surveillance undertaken in two government-run rural health facilities, 457 children, aged less than five years, having acute watery diarrhoea, were studied between August 2005 and July 2007 to determine the prevalence of rotavirus. Due to limited financial support, the surveillance of rotavirus was included as an addendum to an ongoing study for cholera in the same area. Rotavirus infection was detected in 114 (25%) and Vibrio cholerae in 63 (14%) children. Neither rotavirus nor V cholerae was detected in 280 (61%) samples; these were termed 'non-rotavirus and non-cholera' diarrhoea. Both rotavirus and cholera were detected in all groups of patients (<5 years). The highest proportion (41%; 47/114) of rotavirus was in the age-group of 6-11 months. In children aged less than 18 months, the proportion (67%; 76/114) of rotavirus was significantly (p < 0.001) higher than that of cholera (16%; 10/63). By contrast, the proportion (84%; 53/63) of cholera was significantly (p < 0.001) higher than that of rotavirus (33%; 38/114) in the age-group of 18-59 months. During the study period, 528 children were hospitalized for various illnesses. Thirty-eight percent (202/528) of the hospitalizations were due to acute watery diarrhoea, and 62% were due to non-diarrhoeal illnesses. Rotavirus accounted for 34% of hospitalizations due to diarrhoea. Severe dehydration was detected in 16% (74/457) of the children. The proportion (51%; 32/63) of severe dehydration among V cholerae-infected children was significantly higher (p < 0.001) compared to the proportion (16%; 18/114) of rotavirus-infected children. The study revealed that 12-14% of the hospitalizations in rural Bangladesh in this age-group were due to rotavirus infection, which has not been previously documented. PMID- 21528785 TI - The 2010 outbreak of cholera among workers of a jute mill in Kolkata, West Bengal, India. AB - On 10 March 2010, an outbreak of diarrhoeal disease was reported among workers of a jute mill in Kolkata, West Bengal, India. The cluster was investigated to identify the agent(s) and the source of infection and make recommendations. A suspected case of cholera was defined as having >3 loose watery stools in a 24 hour period and searched for case-patients in the workers' colony. The outbreak was described by time, place, and person, and a case-control study was conducted to identify the source of infection. Rectal swabs were collected from the hospitalized case-patients, and the local water-supply system was assessed. In total, 197 case-patients were identified among 5,910 residents of the workers' colony (attack rate 3.33%). Fifteen of 24 stool samples were positive for Vibrio cholerae O1. The outbreak started on 7 March, peaked on 11 March, and ended on 16 March 2010. Compared to 120 controls, 60 cases did not differ in terms of age and socioeconomic status. Drinking-water from the reservoir within the mill premises was associated with an increased risk of illness [odds ratio: 26.7, 95% confidence interval (CI) 11.4-62.6) and accounted for most cases (population attributable risk percentage = 82%, 95% CI 70.8-92.9). An outbreak of cholera occurred among workers of the jute mill due to contamination of the drinking water reservoir. It occurred within a few days of re-opening of the mill after the workers' strike. Health authorities need to enforce disinfection of drinking water and regularly test its bacteriological quality, particularly before re opening of the mill after the strike. PMID- 21528786 TI - Clinical profile of HIV/AIDS-infected patients admitted to a new specialist unit in Dhaka, Bangladesh--a low-prevalence country for HIV. AB - This paper describes the clinical features of a series of patients admitted to the specialist HIV/AIDS unit (Jagori) of the Dhaka Hospital, ICDDR,B (International Centre for Diarrhoeal Disease Research, Bangladesh) during May 2008-February 2010. Data were collected from a review of documents and electronic case-records and collation of laboratory results with respect to CD4 counts. One hundred and nine patients were admitted during this period. Their mean age was 33.4 years, and 62% were male. On admission, the mean CD4 count +/- standard deviation (SD) was 244 +/- 245 (range 2-1,549). The death rate was 12%. The patients were classified as World Health Organization clinical stage 1: 23%, stage 2: 30%, stage 3: 23%, and stage 4: 24% during the admission. The commonest diagnosis recorded was tuberculosis (TB) (23%), which was also the commonest cause of death (38%). Even for those clinicians with limited experience of managing AIDS cases, the commonest problem encountered in this patient group was TB, reflecting the continued high burden of TB on health services in Bangladesh. Additional challenges to managing TB/HIV co-infection include atypical presentations in HIV-infected persons and the complex drug interaction with antiretroviral therapy. PMID- 21528787 TI - Evaluation of the performance of nitrate reductase assay for rapid drug susceptibility testing of mycobacterium tuberculosis in north India. AB - The objective of the study was to evaluate the performance of nitrate reductase assay (NRA) as a rapid, reliable and inexpensive method for drug-susceptibility testing (DST) of Mycobacterium tuberculosis against first-line antitubercular drugs, such as rifampicin (RIF), isoniazid (INH), streptomycin (STR), and ethambutol (EMB). In total, 286 isolates were subjected to test by proportion method (PM) and NRA. By comparing the results of NRA with those of the gold standard PM, sensitivities and specificities were 98.4%, 97%, 88.5%, and 94.2% and 100%, 100%, 94%, and 99% for RIF, INH, STR, and EMB respectively. The positive predictive values were 100%, 100%, 95%, and 98% for RIF, INH, STR, and EMB respectively. The negative values were 99%, 98%, 87%, and 96% for RIF, INH, STR, and EMB respectively. The median time of obtaining results was shorter using NRA (10 days) compared to PM (28 days). An excellent agreement was observed between the two phenotypic tests with the K values of 0.98, 0.97, 0.81, and 0.93 for RIF, INH, STR, and EMB respectively. The results demonstrated that NRA is suitable for the early determination of INH and RIF resistance and has the potential to be a useful tool for rapid drug-sensitivity test of M. tuberculosis in resource-constrained settings. PMID- 21528788 TI - Prevalence of Listeria monocytogenes in raw meats marketed in Bangkok and characterization of the isolates by phenotypic and molecular methods. AB - Listeria monocytogenes causes listeriosis characterized by septicaemia, encephalitis, and abortion or stillbirth. Regular monitoring of its prevalence in food and characterization of its phenotypes and genotypes are necessary for disease surveillance and tracing the epidemic outbreaks. In this study, the prevalence of L. monocytogenes in raw meats marketed in Bangkok was 15.4%. The bacteria isolated from meat were serotyped and genotyped using enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR). Their virulence-associated genes, antimicrobial susceptibility, and ability to invade intestinal epithelial cells were studied. All 22 L. monocytogenes strains isolated from 104 raw meat samples carried virulence-associated genes, such as actA, flaA, hlyA, lap, inlA, inlB, and prfA. These were serotype 4b, suggesting their pathogenic and epidemic potential. These isolates could be classified into six ERIC-PCR groups: A-E The majority (59.1%) of the isolates belonged to Group A, and three isolates were Group D which was closely related to the Group A. Two isolates each were Group C and E, and one isolate each was group B and F. Although the isolates belonged to the same serotype and genotype and were all equipped with the virulence-associated genes, they showed a different cell invasion capability and antibiotic susceptibility. All the isolates were susceptible to ampicillin, amikacin, chloramphenicol, gentamicin, imipenem, penicillin G, sulphamethoxazole-trimethoprim, and tetracycline. However, one isolate showed only intermediate susceptibility to tetracycline. The data provide the first molecular insight into the L. monocytogenes isolates in Thailand and elucidate a potential risk of people contracting listeriosis. PMID- 21528789 TI - Does dietary intake by Tehranian adults align with the 2005 dietary guidelines for Americans? Observations from the Tehran lipid and glucose study. AB - The aim of this study was to compare dietary intakes by Tehranian adults with recent dietary guidelines for the Americans. The study made a cross-sectional assessment of the dietary patterns of Tehranian adults using a validated food frequency questionnaire. It included 2,510 subjects (1,121 men and 1,389 women) aged 19-70 years. They were the participants of the third follow-up survey of the Tehran Lipid and Glucose Study (2005-2008). The dietary patterns were assessed using the latest World Health Organization (WHO)'s nutritional goals and Dietary Guidelines for the Americans Adherence Index (DGAI) 2005. The mean [standard deviation (SD)] DGAI score for this population was 8.31 (1.9). Participants in the highest quartile category of DGAI were more likely to be female, older, non smoking, and physically active than those in the lowest quartile category (p < 0.001). Percentage of participants meeting the DGA recommendations was low, especially for starchyvegetables (2.3%), orange vegetables (16.2%), lean meat (9.2%), grains (12.0%), and legumes (6.4%). Over-consumption of grains was observed in almost half of the participants while approximately 20% of the subjects over-consumed milk and meat groups. Intakes of most nutrients examined were significantly associated with the DGAI 2005 score (p < 0.001), except for vitamin E, vitamin B12, and vitamin D. The least adherence with the WHO goals was observed with n-3 PUFAs, sodium, fruit, and vegetable intakes. The results revealed that the dietary patterns of most Tehranian adults did not comply with the 2005 DGA and nutritional goals of WHO/Food and Agriculture Organization. PMID- 21528790 TI - Correlation between fitness and fatness in 6-14-year old Serbian school children. AB - Lack of physical activity and/or physical fitness are some reasons epidemiologists suggest for increase in childhood obesity in the last 20 years, with clear correlation between body composition and physical activity and/or physical fitness yet to be determined. The objectives of the study were to (a) investigate the prevalence of overweight and obesity among Serbian school children and (b) determine the relationship between indicators of physical activity and body fatness in Serbian school children aged 6-14 years. The study subjects included a representative sample of Serbian elementary school children (n = 1,121-754 boys and 367 girls-aged 6.2-14.1 years), all of whom were recruited in the OLIMP (Obesity and Physical Activity among Serbian School Children) study. Anthropometric and physical fitness values, including body mass index (BMI), waist-circumference, body-fat, and aerobic capacity, were measured in all the children. Significant differences were found between male and female children regarding the prevalence of obesity (6.8% vs 8.2%, p < 0.05, boys and girls respectively). Boys had significantly lower body mass, BMI, waist circumference, sum of six skinfolds, and body-fat compared to their female counterparts (p < 0.05). The highest level of weight, BMI, body-fat, and waist circumference observed in a 14-year old girl (96.3 kg, 40.5 kg/m2, 54.5%, 91.4 cm respectively) implies the existence of extreme obesity in Serbian school children. The negative relationship between body-fat and maximal oxygen (VO2max) uptake was moderately high (r = -0.76; p < 0.05). The study has shown a high prevalence of adiposity among Serbian school children, with a strong negative relationship between aerobic fitness and body fatness. Data of the study emphasize the necessity to identify children with weight problems and to develop early interventions to improve physical activity in children and prevent the increase of childhood obesity. PMID- 21528792 TI - Trends in choosing place of delivery and assistance during delivery in Nanded district, Maharashtra, India. AB - Delivery in a medical institution promotes child survival and reduces the risk of maternal mortality. Many initiatives under the National Rural Health Mission (NRHM) focus on increasing the institutional deliveries. This study describes the trends in choosing place of delivery in Nanded district at the end of the first phase of the mission. Key informants were interviewed to document the initiatives under NRHM implemented in the district. A cross-sectional descriptive study was conducted in 30 villages selected using one stage cluster-sampling method. A house-to-house survey was conducted in June 2009. A set of structured open-ended questionnaire was used for interviewing all women who had delivered during January 2004-May 2009. The outcomes studied were place of delivery and assistance during delivery. Analysis was done by calculating chi-square test and odds ratio. Interventions to improve the quality of health services and healthcare-seeking behaviour were implemented successfully in the district. The proportion of institutional deliveries increased from 42% in 2004 to 69% in 2009. A significant increase was observed in the proportion of institutional deliveries [60% vs 45%; chi2 = 173.85, p < 0.05, odds ratio (OR) = 1.8 (95% confidence interval (CI) 1.65 1.97)] in the NRHM period compared to the pre-NRHM period. The deliveries in government institutions and in private institutions also showed a significant rise. The proportion of deliveries assisted by health personnel increased significantly during the NRHM period [62% vs 49%; chi2 = 149.39; p < 0.05, OR = 1.73, 95% CI 1.58-1.89]. However, less than 10% of the deliveries in the home (range 2-9%) were assisted by health personnel throughout the study period. There was a wide geographic variation in place of delivery among the study villages. The results showed a significant increase in the proportion of institutional deliveries and deliveries assisted by health personnel in the NRHM period. Since a less proportion of deliveries in the home is conducted by health personnel, the focus should be on increasing the institutional deliveries. Special and innovative interventions should be implemented in the villages with a less proportion of institutional deliveries. PMID- 21528791 TI - Healthcare-seeking behaviour for common infectious disease-related illnesses in rural Kenya: a community-based house-to-house survey. AB - Community surveys of healthcare-use determine the proportion of illness episodes not captured by health facility-based surveillance, the methodology used most commonly to estimate the burden of disease in Africa. A cross-sectional survey of households with children aged less than five years was conducted in 35 of 686 census enumeration areas in rural Bondo district, western Kenya. Healthcare sought for acute episodes of diarrhoea or fever in the past two weeks or pneumonia in the past year was evaluated. Factors associated with healthcare seeking were analyzed by logistic regression accounting for sample design. In total, 6,223 residents of 981 households were interviewed. Of 1,679 children aged less than five years, 233 (14%) had diarrhoea, and 736 (44%) had fever during the past two weeks; care at health facilities was sought for one-third of these episodes. Pneumonia in the past year was reported for 64 (4%) children aged less than five years; 88% sought healthcare at any health facility and 48% at hospitals. Seeking healthcare at health facilities was more likely for children from households with higher socioeconomic status and with more symptoms of severe illness. Health facility and hospital-based surveillance would underestimate the burden of disease substantially in rural western Kenya. Seeking healthcare at health facilities and hospitals varied by syndrome, severity of illness, and characteristics of the patient. PMID- 21528793 TI - Is screening of TORCH worthwhile in women with bad obstetric history: an observation from eastern Nepal. AB - This pilot case-control study at a tertiary-care hospital over a four-month period was aimed at evaluating the possible usefulness of screening of TORCH (Toxoplasma gondii, rubella virus, cytomegalovirus, and Herpes simplex virus) in females with bad obstetric history. The study included 12 women with bad obstetric history and a similar number of matched controls with previous normal pregnancies. A serological evaluation of TORCH infections was carried out by detecting IgG and IgM antibodies against these infections by ELISA test-kit. Statistical analysis was not done to compare the results relating to the two groups due to a small number of cases and controls included in the study. Ten (83.3%) of the 12 cases with bad obstetric history and two (16.7%) of the 12 healthy controls were serologically positive at least for one of the TORCH agents. The seropositivity rate in women with bad obstetric history was quite high compared to that in the normal healthy controls. The results suggest that a previous history of pregnancy wastage and the serological evaluation of TORCH infections during current pregnancy must be considered while managing cases with bad obstetric history. PMID- 21528794 TI - Health and sports law collide: do professional athletes have an unfettered choice to accept risk of harm? AB - Is there a positive duty at law to prevent an athlete with a serious medical disability from performance, despite the player accepting the risk? Is high risk of serious injury or death in the athletic context equivalent to euthanasia? Euthanized death is a predictable consequence of deliberate action. Accepting high risk in the athletic context is distinguishable. Athletes are often more likely able to make voluntary decisions without the burdens of incurable pain and clouding medications. Should policy reasons, nonetheless, preclude athletes from accepting high or uncertain risks of serious injury or death? What standard of medical certainty or legal certainty is appropriate regarding the "right to risk"? The higher the risk of serious injury or death and the less the medical uncertainty the more tort law might trump contract principles. In contrast, medically certain outcomes are easier to knowingly and voluntarily assume by way of contract. Waivers are contracts and present a conflict between a person's rights to have freedom to contract and negligence. Contracts shift the risk. An athlete can be disqualified to avoid a significant risk of injury that cannot be eliminated through reasonable medical accommodations. The problem is that physicians tend to be conservative and without any input from informed athletes, many otherwise disabled players would be refused participation, albeit with a high risk. If an athlete is able to seek medical treatment that reduces the risk and does so, an athlete's will to return should not be ignored. The team must substantiate the restriction by justifying a relatively certain and substantial risk. An athlete may agree to accept high risk of serious injury or death through a contractual waiver to insulate others from liability in negligence. Independent legal advice and advice from medical experts ensure that such waivers are legally enforceable. As medical law has broad application, dealing with improving the rights, rules and policies of health care as it relates to the use of advanced medical technologies in potentially vulnerable persons and consequently the right to accept risk, is as important both evaluative and meritorious exercise for all health and legal systems throughout the world. PMID- 21528795 TI - Surrogate motherhood as a medical treatment procedure for women's infertility. AB - The content of this work is conceived on the research of the consequences of surrogate motherhood as a process of assisted procreation, which represent a way of parenthood in cases when it is not possible to realize parenthood through a natural way. Surrogate motherhood is a process in which a woman (surrogate mother) agrees to carry a pregnancy with the intent to give the child to the couple with whom she has made a contract on surrogate maternity after the birth. This process of conception and birth makes the determination of the child's origin on its mother's side hard to determine, because of the distinction of the genetic and gestation phases of the two women. The concept of surrogate motherhood is to appear in two forms, depending on the existence or the non existence of the genetic link between the surrogate mother and the child she gives birth to. There are gestation (full) and genetic (partial) surrogates each with different modalities and legal and ethical implications. In Serbia, Infertility Treatment and the Bio-medically Assisted Procreation Act from 2009 explicitly forbids surrogate motherhood, despite the fact that an infertile couple decides to use it, as a rule, after having tried all other treatment procedures, in cases when there is a diagnosis but the conventional treatment applied has not produced the desired results. Given the fact that no one has the right to ignore the sufferings of people who cannot procreate naturally, the medical practice and legal science in our country plead for a formulation of a legal framework in which to apply surrogate motherhood as an infertility treatment, under particular conditions. PMID- 21528796 TI - Medical error in Ukraine. AB - A medical error is conditioned in most cases by the absence of doctors' experience or by overvaluation of their knowledge and experience. It is necessary to conduct the proper control and set of events which will train them to feel the responsibility, to adhere to the standards of diagnostics and treatment, also to take into account the individual features of the flow of illness for patients. PMID- 21528797 TI - The role of a professional dental organization in the resolution of malpractice claims the professional dentist college in the region of Murcia (Spain). AB - The aim of this paper is to study the role of a professional dental organization in the resolution of malpractice claims in Murcia (southeast of Spain). We analysed all the claims presented to the College of Dentists during the last sixteen years (n = 84). Professional behaviour was demonstrated as adequate in 29 cases and as malpractice in 55 (32 cases were considered technically correct but with information failures and in 23 cases technical errors were observed). The written informed consent was absent in 40 cases, although information was supplied verbally in 30 cases of the 40. The distribution of the dental interventions performed in the claim cases was: surgery, 20 cases (23.80%), prosthetic, 36 cases (42.85%) and endodontic, 28 cases (33.33%). Only in 22 cases (26.19%) was a final agreement reached between the parties. The Dental College could improve these results, acting as a real arbitral court and minimizing the problems for professionals and the claimers. PMID- 21528798 TI - Ethics at Israeli universities: unlearned lessons from professional ethics. AB - At the practical level, sustained attention to ethical issues in academia in Israel is inadequate. This paper suggests that professional models of ethics education and training present constructive alternatives. The author views this topic from the dual perspective of a professional clinical psychologist and a committed faculty member. After a brief introduction, the paper opens with a case vignette of ethical violations of trust in academia, its handling, and how a similar case 25 years later illustrates the lack of progress in preparing the academic community for such things. A discussion of normative actions and behavioral norms in academia follows. Three lessons from the professions are offered: 1) the importance of involving members in the process of identifying ethical violations; 2) the value of adopting for academia current practices preparing persons for work in research, (for example the standardization of online modules for training in ethics); and c) the significance of addressing self-interest and its limits. If silence around a code of ethics is being practiced, that silence should be broken. PMID- 21528799 TI - Bioethics education on deliberation--a view of a novel: Blue Gold, by Clive Cussler. AB - Since the focus of Bioethics is the bridge between Humanities and the Life Sciences and bearing in mind that this bridge is often difficult to build, those who believe that this dialogue is important in our days should promote it through Education. By educating in Bioethics it is possible to improve the participation of the citizens in debates on the ethical issues raised by new technologies and scientific research. It is our conviction that literary texts are laboratories of ethical judgment, where the ethical questions concerning specific scientific/ technological issues are addressed in an imaginary world. Therefore our purpose is to present a framework for ethical deliberation through the use of literature. Fiction allows us to "practise" ethical decision making, by focusing on the particular cases of the characters of the story and by checking how the principles/theories working in the background apply to the narrated cases. PMID- 21528800 TI - Informed consent under the European Convention on Biomedicine and the UNESCO Declaration on Bioethics. AB - The desirability of obtaining freely given consent is universally accepted. The point, however, is that there is no unanimity on the definition of informed consent or its application in bioethics. Whether informed consent is based on principalism or casuistry or the virtue theory, the problem is how to handle the ethically complex situation created in the interface between informed consent and social justice under international biomedical instruments. This article will proceed by offering detailed historical and critical analyses of informed consent under the European Convention on Human Rights and Biomedicine 1997 and The UNESCO Universal Declaration on Bioethics and Human Rights 2005. Three conceptions of justice will be utilised to show that the doctrine of informed consent has driven the ethos of research on human beings and shaped the physician-patient relationship; and that casuistry and virtue theory are consistent with and not rivals of a principle-based account of informed consent. PMID- 21528801 TI - Dissemination of information on the off-label (unapproved) use of medication: a comparative analysis. AB - "Off-label" in relation to the use of medication means that a medicine is used in another way or for indications other than those specified in its conditions of registration and reflected in its labelling. The off-label use of medication accounts for an estimated 21 per cent of drug use overall and is an important part of mainstream, legitimate medical practice worldwide. In South Africa, legislation prohibits the dissemination of information regarding the off-label use of medication. There are diverging views on whether pharmaceutical companies should be allowed to distribute scientific publications on off-label uses of approved drugs. Current policy in the United States of America (USA) eases restrictions on the dissemination of information of this nature. The prohibitions existing in South Africa, however, are more comparable with those in European countries. After analysing the different legal positions on the issue, it is submitted that pharmaceutical companies should not be allowed to disseminate information on off-label uses, but that the regulatory authority play an active and leading role in providing the latest, objective medical and scientific information, as well as guidelines on the off-label use of medication. Other related recommendations are also made. PMID- 21528802 TI - International means for protecting humans as ends in medicine. AB - According to Kant human beings should use their humanity, whether in their own person or the person of any other, 'always at the same time as an end never simply as a means' (1786, p429). This has traditionally been broken down into an imperfect duty of virtue to promote both one's own ends and the ends of others as if they were one's own (the means by which perfection can be achieved) and the more narrow but perfect duty not to treat oneself and others as mere means. This article critically examines how the latter duty is interpreted and enforced in the health field, particularly via general and health specific international human rights instruments. PMID- 21528803 TI - The assessment of expert testimony relevance and admissibility in medical malpractice cases in the Czech Republic. Can American judicial practice help us? AB - The relevance and admissibility of expert medical testimony in relation to medical malpractice suits requires a more successful development of formal criteria and a more intentional compliance with efficient judicial procedures. The American judicial system provides an excellent model for implementation of a critical approach to knowledge collection, the evaluation of the validity of scientifically sound information, and the examination of expert's testimony on the basis of a sound methodology. An analysis of the assessment and application of reliability yields evidence that assuring standards to improve the quality of expert medical testimony will increase the overall probability of a fair outcome during the judicial process. Applying these beneficial strategies in medical malpractice cases will continue to support further considerations of promoting justice and solving problems through sufficient scientific means. PMID- 21528804 TI - Sex steroid priming for growth hormone (GH) provocative tests: an endless debate with insufficient solutions. PMID- 21528805 TI - Not ready for prime time. PMID- 21528806 TI - Sex hormone priming. PMID- 21528808 TI - Images in pediatric endocrinology: vitamin D deficiency rickets and other nutritional deficiencies in a 12-month-old infant. PMID- 21528807 TI - Pros of priming in the diagnosis of growth hormone deficiency. AB - Priming with sex steroids in stimulation tests for the diagnosis of GHD is still under debate. Most of the data on utility of priming during GH stimulation so far seem to support its use in the diagnosis of GHD in childhood. There is a propensity to treat growth retarded children who test subnormally to stimulation tests with GH. However, some studies analyzing the final height or height gain during GH treatment in such children failed to show any improvement in height. This paper summarizes previous studies on priming to analyze the utility of priming as a valid method to better the diagnostic capacity of the test. PMID- 21528809 TI - The influence of an educational program on the HbA(1c)-level of adolescents with type 1 diabetes mellitus: a retrospective study. AB - OBJECTIVES: Adherence to diabetes management tasks in type 1 diabetes mellitus (T1DM) patients deteriorates during puberty. This causes glycemic dysregulation, which accelerates the development of long-term complications. METHODS: The data of 25 poorly regulated T1DM-patients were compared before and 3 and 9 months after a psycho-educational program. Data were extracted from patient's records. The psycho-educational program consisted of three sessions for the patients and one for the parents in a 3-month period. RESULTS: HbA(1c)-levels at baseline (10.0 +/- 0.72%), decreased by 0.65% after 9 months follow-up (p = 0.08). A subgroup of 15 patients showed a clinical significant HbA(1c)-reduction of > or = 0.5% at 9 months follow-up (subgroup A), with a mean reduction of 1.6%. CONCLUSIONS: These encouraging results show that a psychoeducational program can be of benefit in improving HbA(1c)-levels in poorly regulated adolescents with T1DM. More research with a larger population is necessary to evaluate the value of psycho-educational programs in this age-group. PMID- 21528810 TI - Contribution of clinical, metabolic, and genetic factors on hypertension in obese children and adolescents. AB - The role of ACE gene insertion (I) or deletion (D) polymorphism on blood pressure phenotype is not clear in children. The aim of this work is to examine the association between hypertension and ACE I/D polymorphism, as well as the contribution of clinical and metabolic parameters on blood pressure. The study participants were 199 obese children. Forty-four of them were hypertensive. The hypertensive subjects were older than the normotensive and most of them were pubertal. The prevalence of hypertension in obese subjects with II, ID, and DD genotype was similar. There was no difference between the hypertensive and the normotensive group according to ACE I/D genotype, BMISDS, sex, blood glucose level and total cholesterol levels. In obese children, high IR-HOMA values, puberty, presence of family history for hypertension, hypertriglyceridemia, and low HDL-cholesterol, high triglyceride/HDL-cholesterol ratio were found as increased risk factors of hypertension. In obese children and adolescents, blood pressure did not differ by ACE I/D genotype. The presence of family history, puberty, insulin resistance and hypertriglyceridemia constitute important risk factors for developing hypertension. PMID- 21528811 TI - Hyperphosphatemic tumoral calcinosis: a 10-year follow-up. AB - OBJECTIVE: To report a case of primary hyperphosphatemic tumoral calcinosis (TC) and its long-term 10-year follow-up. PATIENT: The patient was an 18-year-old male, who had been diagnosed with TC at the age of 8 years. In spite of nine surgeries for tumoral resection and medical treatments (i.e., aluminum hydroxide, non-steroidal anti-inflammatory agents) the lesions continued to progress. Physical examination showed calcified masses on shoulders, hip, elbows and right foot. PTH, calcitonin, 25(OH) vitamin D, 1,25(OH)2 vitamin D, renal and liver function, electrolytes, alkaline phosphatase, calcium and magnesium were normal. Serum phosphorus was elevated. FGF-23 (C-terminal): 1960 RU/mL (<180) Radiological and histological studies were compatible with TC. CONCLUSION: This long-term follow-up illustrates the morbidity and difficulty in treating these patients due to the progressive and recurrent nature of the calcified masses, for which there is no effective treatment as yet. The discovery of FGF-23 as the factor responsible for the hyperphosphatemic type of TC paves the way for forthcoming therapies. PMID- 21528813 TI - Evaluation of children with nutritional rickets. AB - AIM: To evaluate the clinical findings, risk factors, therapy and outcome in 946 children with nutritional rickets. PATIENTS AND METHODS: This retrospective study included a review of medical records of patients with nutritional rickets between March 2004 and 2009. Patients who displayed both the biochemical inclusion criteria and the clinical signs/symptoms or radiological signs of rickets were included in the study. RESULTS: The present study included 946 patients aged between 4 months and 15 years. Distribution of the cases showed a density between December and May. The age at diagnosis, showed two peaks and most of the patients were in the age range 0-23 months and 12.0-15 years. In infants and young children, most of the patients had been admitted to the hospital due to infectious diseases. In older children, short stature and obesity were the most common complaints. CONCLUSION: Children aged between 0-23 months and 12.0-15 years were under most risk for nutritional rickets, especially in winter and spring and vitamin D should be given to them as supplementation dose. PMID- 21528812 TI - Vitamin D deficiency and insulin resistance in obese African-American adolescents. AB - OBJECTIVE: The study aim determined if low 25-hydroxy vitamin D levels correlated with low levels of adiponectin and insulin resistance in African American adolescents with body mass index > or = 85th %. PATIENTS AND METHODS: Fasting blood levels of adiponectin, 25-hydroxy vitamin D, insulin, glucose, lipid, leptin and glycosylated hemoglobin were measured in a total of 34 (19 study and 15 control) African American adolescents between the ages of 10 and 20 years. Nutritional vitamin D intake and body composition measurements were assessed. Insulin resistance was calculated using the homeostasis model assessment. RESULTS: Adiponectin, fasting insulin, glucose, leptin, triglycerides, HDL, and 25-hydroxy vitamin D levels all reached statistical significance in the group with body mass index > or = 85th percentile when compared to the control population. There was no difference in vitamin D intake between the two groups. CONCLUSIONS: Low vitamin D levels correlated with low adiponectin levels and obesity and insulin resistance. PMID- 21528814 TI - The effects of delivery route and anesthesia type on early postnatal weight loss in newborns: the role of vasoactive hormones. AB - OBJECTIVE: To investigate the effects of delivery route and maternal anesthesia type and the roles of vasoactive hormones on early postnatal weight loss in term newborns. METHODS: Ninety-four term infants delivered vaginally (group 1, n=31), cesarean section (C/S) with general anesthesia (GA) (group 2, n=29), and C/S with epidural anesthesia (EA) (group 3, n=34) were included in this study. All infants were weighed at birth and on the second day of life and intravenous (IV) fluid infused to the mothers for the last 6 h prior to delivery was recorded. Serum electrolytes, osmolality, N-terminal proANP (NT-proANP), brain natriuretic peptide (BNP), aldosterone and plasma antidiuretic hormone (ADH) concentrations were measured at cord blood and on the second day of life. RESULTS: Our research showed that postnatal weight loss of infants was higher in C/S than vaginal deliveries (5.7% vs. 1.3%) (p < 0.0001) and in EA group than GA group (6.8% vs. 4.3%) (p < 0.0001). Postnatal weight losses were correlated with IV fluid volume infused to the mothers for the last 6 h prior to delivery (R = 0.814, p = 0.000) and with serum NT-proANP (R = 0.418, p = 0.000), BNP (R = 0.454, p = 0.000), and ADH (R = 0.509, p = 0.000) but not with aldosterone concentrations (p > 0.05). CONCLUSION: Large amounts of IV fluid given to the mothers who were applied EA prior to the delivery affect their offsprings' postnatal weight loss via certain vasoactive hormones. PMID- 21528815 TI - Abdominal obesity is associated with cardiovascular risk in Japanese children and adolescents. AB - BACKGROUND: Metabolic syndrome is listed as a risk for atherosclerosis. However, changes in that risk during childhood and adolescence have not been well documented. It is also unclear whether individuals with abdominal obesity, but with as yet undiagnosed metabolic syndrome, have cardiovascular risks. METHODS AND RESULTS: Ninety-two patients were studied at the Hamamatsu University School of Medicine Department of Pediatrics. Physical measurements including abdominal circumference (AC), body mass index (BMI), body fat (BF), intima media thickness (IMT), arterial elasticity: beta index (Beta), carotid artery compliance (CAC), and Young's elastic modulus (YEM) using ultrasonography were taken. A positive correlation between systolic blood pressure, AC, BMI, and BF was observed (AC, r = 0.717, p < 0.001; BMI, r = 0.672, p < 0.001; BF, r = 0.518, p < 0.001). IMT showed a weak positive correlation with AC, BMI and BF (AC, r = 0.211, p = 0.044; BMI, r = 0.233, p = 0.025; BF, r = 0.232, p = 0.026). The relationship between AC, BMI, BF and arterial elasticity, especially in AC, positively correlated with beta index and YEM but negatively correlated with CAC. CONCLUSION: We suggest that AC is the most sensitive marker in the detection of arterial elasticity, even in school age children. Earlier pre-diagnostic intervention, especially in the prevention of abdominal obesity, may reduce the incidence of metabolic syndrome in children and adolescents. PMID- 21528816 TI - PPAR-gamma2 pro12Ala polymorphism is associated with post-challenge abnormalities of glucose homeostasis in children and adolescents with obesity. AB - AIM: The aim of the study was to investigate the association between PPAR-gamma2 Pro12Ala polymorphism and laboratory characteristics of carbohydrate metabolism in children and adolescents with obesity. In addition, serum levels of tumor necrosis factor (TNF)-alpha, and soluble form of its receptors (sTNFR1 and sTNFR2) were assessed. METHODS: In a cross-sectional study, 79 obese children and adolescents of Caucasian origin were investigated. PPAR-gamma2 Pro12Ala polymorphism was determined using polymerase chain reaction--restriction fragment length polymorphism technique. Serum levels of TNF-alpha, sTNFR1 and sTNFR2 were measured by enzyme amplified sensitivity immunoassay. RESULTS: The minor Ala allele frequency was found to be 14.56% in our cohort. No significant differences in age, BMI, waist circumference, blood pressure, serum lipid, uric acid, TNF alpha, sTNFR1 and sTNFR2 values were found between carriers of the Ala allele (Pro/Ala and Ala/Ala; n=21) vs. homozygous carriers of the Pro allele (Pro/Pro; n=58). However, post-challenge (120 min) plasma glucose and insulin values were significantly lower in Ala allele carriers vs. homozygous Pro allele carriers (6.56 +/- 0.26 vs. 7.36 +/- 0.25 mmol/L and 65.9 +/- 13.8 vs. 111.8 +/- 20.7 microU/mL, respectively; p < 0.05); while no significant differences were found at fasting state. CONCLUSIONS: The association between PPAR-gamma2 Prol2Ala polymorphism and glucose metabolism is already present in children and adolescents with obesity who might be at the very beginning of the natural course of type 2 diabetes. At this stage, higher insulin sensitivity can be detected in Ala allele carriers compared to homozygous Pro subjects at post-challenge but not in fasting state; however, the TNF-system seems not to be involved in the alteration of glucose homeostasis due to PPAR-gamma2 Pro12Ala polymorphism. PMID- 21528817 TI - The relationship between pubertal gynecomastia, prostate specific antigen, free androgen index, SHBG and sex steroids. AB - OBJECTIVE: To investigate the relationships between pubertal gynecomastia, prostate-specific antigen (PSA), free androgen index (FAI), sex hormone-binding globulin (SHBG) and sex steroids. METHODS: A total of 61 male adolescents (10-17 years old; mean: 13.67 +/- 1.08) with gynecomastia were enrolled into the study group. A total of 65 healthy age-matched adolescents were included in the control group. Body mass index (BMI), Tanner staging, testis volume, stretched penis length (SPL) and bone age were evaluated. Serum follicle-stimulating hormone, luteinizing hormone (LH), estradiol (E2), testosterone, free testosterone, SHBG, PSA levels were determined and FAI was calculated. RESULTS: In the study group, free testosterone (p = 0.012) and FAI (p = 0.05) were significantly lower than the control group. In the control group, SHBG levels decreased (p < 0.05) and FAI increased (p < 0.05) significantly with increasing Tanner stages; however, no such difference was observed in the study group (p > 0.05). High FAI was found to decrease the risk of gynecomastia (odds ratio: 0.211, 95% confidence interval: 0.064-0.694, p = 0.01). PSA showed a positive correlation with FAI, free testosterone, Tanner staging, testosterone, E2 and LH levels. CONCLUSIONS: PSA is a good indicator of androgen activity during puberty. However, owing to FAI remaining as the single significant variable for pubertal gynecomastia, we suggest that it is still the best parameter to elucidate the etiopathogenesis of gynecomastia as well as other pubertal developmental abnormalities in male adolescents, and further longitudinal studies are needed to investigate the relationships between PSA and FAI in puberty. PMID- 21528818 TI - Severe hypercalcemia associated with Williams syndrome successfully treated with pamidronate infusion therapy. AB - Infantile hypercalcemia becomes manifest in 15% of patients with Williams syndrome (WS) and generally is not clinically severe. However, some patients with WS can have severe hypercalcemia and do not respond well to traditional therapies. Recently, pamidronate has been used in the treatment of childhood hypercalcemia associated with many disorders, but there is little experience with the treatment of hypercalcemia with bisphosphonates in patients with WS. We present a 17-month-old female patient, who had been diagnosed as WS by genetic analysis, admitted to our clinic for the investigation of severe hypercalcemia (4.02 mmol/L). Because the patient did not respond very well to fluid administration, furosemide infusion, and dietary calcium restriction, pamidronate infusion was performed and calcium levels returned to normal within 2 days. This case report is presented to point out that pamidronate therapy seems to be a safe and efficient way of treating life-threatening hypercalcemia in WS. PMID- 21528819 TI - The subtle signs of Wolfram (DIDMOAD) syndrome: not all juvenile diabetes is type 1 diabetes. AB - Wolfram syndrome (also known as DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, deafness) is an autosomal recessive disorder characterized by the association of childhood non-immune insulin-dependent diabetes mellitus (DM) with progressive bilateral optic atrophy. Additional symptoms including signs of severe neurodegeneration and psychiatric illness are likely to evolve over time resulting in premature death. We report on two siblings of Turkish origin from our diabetes clinic who were diagnosed with Wolfram syndrome after 6 years and 2 years duration of DM, respectively. Subtle symptoms such as attitude changes, growing reading difficulties in the history of children or adolescents with antibody negative and ketone negative DM should alert the treating physician and lead to re-evaluation of the diagnosis, keeping in mind that not all juvenile DM is type 1 DM. PMID- 21528820 TI - The frequency of Hashimoto thyroiditis in children and the relationship between urinary iodine level and Hashimoto thyroiditis. AB - The aim of this study was to determine the frequency of thyroid autoimmunity in second grade primary school students and to examine the relationship between iodine and Hashimoto thyroiditis (HT). This was a cohort study performed with 1000 students. Urinary iodine levels, antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies were determined in all children. Children with anti-TPO or anti-Tg antibody positivity or with goiter were summoned for detailed examinations. In total, 36 cases (3.6%) were diagnosed as HT. The goiter frequency was found in 17.5% of the whole cohort. Additionally, iodine deficiency was found in 64.2% of all children. The median urinary iodine excretion was determined as 132 microg/L (range 382 microg/L) in the HT group, whereas it was 73 microg/L (range 390 microg/L) in children with goiter but without HT and 81 microg/L (range 394 microg/L) in normal children. The urinary iodine level of HT cases was significantly higher than the other two groups (p < 0.001). HT was also determined in 2% of patients with low urinary iodine levels, in 6.2% of patients with normal urinary iodine levels, and in 7.5% of patients with high urinary iodine levels. Our data demonstrates the close relationship between excessive iodine levels and autoimmunity. PMID- 21528821 TI - The relationship between serum phosphate levels with childhood obesity and insulin resistance. AB - AIM: To investigate the relationship between serum phosphate levels with obesity and insulin resistance in childhood. METHODS: A total of 298 children and adolescents (190 obese subjects and 108 controls) were included in the study. Serum glucose, insulin, phosphate, calcium and alkaline phosphatase levels were measured after 12 h fasting at 08:00-08:30 h. We assessed insulin sensitivity by using the HOMA-IR (homeostasis model of insulin resistance) index as a surrogate marker of insulin resistance. RESULTS: Serum levels of phosphate were significantly lower in the 6- to 12-year-old obese subjects than controls (p = 0.02, p < 0.05). At the same time, there was a moderate negative correlation between serum phosphate levels and the HOMA-IR index in the 6- to 12-year-old IR (-) obese children (r = -0.26, p = 0.02). CONCLUSIONS: Low serum phosphate levels could contribute to the development of insulin resistance in 6- to 12-year-old obese children. PMID- 21528822 TI - The relationship of salivary and cord blood cortisol in preterm infants. AB - Recent studies reveal that salivary cortisol measurements accurately reflect blood cortisol levels in older children and adults; yet, the relationship between the two values in premature infants has not been established. This study explores the use of salivary cortisol as an accurate measure of adrenal steroid concentrations in premature infants to provide a reliable and less invasive tool for investigating hormonal stress response. Premature infants (n=51) were recruited, with saliva and blood collected immediately after birth, and cortisol levels measured by radioimmunoassay. A linear relationship emerged between cord plasma and salivary cortisol values in the 102 paired samples [(salivary cortisol) = 0.546 +/- 0.192 x (plasma cortisol), r = 0.481 and p = 0.0003]. Findings demonstrated that salivary and plasma cortisol levels were correlated in premature infants. This information will be useful in future studies that assess use of salivary cortisol to evaluate neonatal stress axis function. PMID- 21528823 TI - A comparison of referral patterns to the pediatric endocrine clinic before and after FDA approval of growth hormone for idiopathic short stature. AB - BACKGROUND: Short stature is a common reason for referral to the pediatric endocrine clinic. In 2003, the US Food and Drug Administration (FDA) approved the use of growth hormone (GH) for the treatment of children with idiopathic short stature (ISS). OBJECTIVE: To explore if this indication changed referrals for short stature (SS). DESIGN/METHODS: A retrospective chart review of children seen for SS in the pediatric endocrine clinic between July 1998 and June 1999 (interval one, n=138) and July 2005-June 2006 (interval two, n=268) was performed. Variables collected included age, gender, height (h), and parental heights. RESULTS: Average height standard deviation score (HT-SDS) was -2.11 +/- 0.9 in interval one and -2.14 +/- 0.83 in interval two (p=ns). No differences in age, gender distribution, relationship between child and parental heights, the proportion of subjects started on GH for ISS or in the HT-SDS of those treated between the two intervals were identified. Nearly half of all children referred in each interval did not meet the technical criteria for short stature. CONCLUSIONS: No differences in referral patterns for SS in our area following FDA approval of GH for ISS were identified. Although referrals appear unchanged, additional investigation of GH prescribing patterns before and after this new indication is needed. Continued education of primary care physicians and the general public regarding the definition of SS and the eligibility for GH therapy should be pursued. PMID- 21528824 TI - Benign transient hyperphosphatasemia in infants and children: a prospective cohort. AB - A total of 20 children with benign transient hyperphosphatasemia were prospectively evaluated with no additional investigations recommended except repeat serologic evaluation in 2-3 months. The average age of our patients was 2.5 years (range: 1 year 2 months-5 years 10 months). The serum levels of alkaline phosphatase averaged 2383 IU/L (range: 1013-5700 IU/L). Levels returned to normal within several months. This condition should be recognized by the clinician in order not to put patients through lengthy, expensive and unnecessary investigations. PMID- 21528825 TI - Carotid arterial stiffness in overweight and obese Indian children. AB - OBJECTIVE: The aim of the study was to evaluate carotid arterial stiffness and intima media thickness (IMT) in obese children in comparison with healthy children, and to examine associations of lipid profile and blood pressure with carotid artery morphology. METHODS: Anthropometric and blood parameters were assessed in 44 overweight, 95 obese (6-17 years) and 69 healthy age-matched normal children. Percent body fat was measured by dual-energy X-ray absorptiometry and stiffness and IMT of the common carotid artery were evaluated using Aloka alpha 10 equipment. RESULTS: Anthropometric and lipid parameters were significantly higher in overweight and obese than in normal children (p < 0.05). Stiffness (beta), pulse wave velocity (PWV), elastic modulus (Ep) and blood pressure were significantly higher in obese and overweight children than in normal children (p < 0.05). However, overweight and obese children did not show any significant difference in IMT compared with normal children (p > 0.1). Significant positive correlation of PWV, beta and Ep and negative correlation of arterial compliance with body fat and triglyceride was noted (p < 0.05). Different multinomial regression models for each e-Tracking parameter indicated that the relative risk of hypertension was highest with high PWV, followed by LDL cholesterol, Ep and body fat. CONCLUSION: PWV may be considered an important marker for evaluation of early functional changes of the carotid artery in children and adolescents. PMID- 21528826 TI - Association study in Taiwanese girls with precocious puberty. AB - BACKGROUND: The timing of puberty has a genetic component. Recently, genome-wide association studies have identified that rs314280 on 6q21 (near the LIN28B gene) and rs2090409 on 9q31.2 (in an intergenic region) are associated with age at menarche. In this study, we aimed to determine whether the two loci were associated with the timing of puberty in Taiwanese girls. RESULTS: A total of 117 girls were divided into two groups: (1) precocious puberty (n=50) and (2) normal control subjects (n=45). The genotype proportions and allele frequencies in both groups were not significantly different. CONCLUSION: These data suggest that rs314280 and rs2090409 polymorphisms are not a useful marker for prediction of the susceptibility of precocious puberty. PMID- 21528827 TI - A homozygous recurring mutation in WISP3 causing progressive pseudorheumatoid arthropathy. AB - WISP3 is a member of the CCN (for CTGF, CYR61, and NOV) gene family, which encodes cysteine-rich secreted proteins with roles in cell growth and differentiation. Mutations in the WISP3 gene are associated with the autosomal recessive skeletal disorder, also known as progressive pseudorheumatoid arthropathy of childhood (PPAC). We diagnosed three siblings from a non consanguineous family with PPAC. The patients were asymptomatic in early childhood. Signs and symptoms of disease that include progressive joint stiffness, swelling of the finger joints, and osteopenia, and slow linear growth developed between 2 and 8 years of age. PCR amplification and direct sequencing of the WISP3 gene revealed a homozygous mutation at nucleotide 156 of the WISP3 gene, resulting in a Cys52-to-ter substitution. This mutation has previously been reported in French, Italian, and Arab families. Interestingly, the C52X mutation was found to be associated with a c.248G-->A (G83E) variation, suggesting the existence of a founder effect. By contrast, the presence of the same aberration in three different ethnic groups could imply that this particular site is prone to mutation. Basal fasting concentrations of growth hormone, insulin-like growth factor-1, and insulin-like growth factor binding protein-3, as well as glucose and insulin levels revealed no aberrations. In conclusion, consideration of this rare disease that causes significant morbidity with short stature, osteopenia and arthritic complaints would prevent unnecessary examinations and treatment attempts. Testing for this specific mutation in suspected cases could provide a rapid and definitive diagnosis. PMID- 21528828 TI - Two pediatric patients with Von Hippel-Lindau disease type 2b: from patient to screening, from screening to patient. AB - Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor susceptibility disease characterized by the development of hemangioblastomas of the brain, spinal cord and retina; pheochromocytomas and renal cell carcinoma. The disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3p26-p25. In this paper, we present two patients with VHL disease type 2B confirmed by genetic analysis. Diagnosis in the first patient was based on demonstration of retinal hemangioblastoma in association with bilateral pheochromocytoma. Family screening revealed renal cell carcinoma in her father and uncle. The second patient was discovered during family screening of another index case in adult age. VHL disease should be clinically suspected in any individual with a pheochromocytoma especially when there is bilateral and/or multifocal disease or family history. Screening of patients and at-risk family members for VHL-associated tumors should be essential in management of VHL. PMID- 21528829 TI - Growth hormone and mortality: the anatomy of a global scare. PMID- 21528830 TI - An examination of contemporary financing practices and the global financial crisis on nonprofit multi-hospital health systems. AB - This study examines the impact of the 2008 global financial crisis on large US nonprofit health systems. We proceed from an analysis of the contemporary capital financing practices of 25 of the nation's largest nonprofit hospitals and health systems. We find that these institutions relied on operating cash flows, public issues of insured variable rate debt, and accumulated investment to meet their capital financing needs. The combined use of these three financial instruments provided these organizations with $22.4 billion of long-term capital at favorable terms and the lowest interest rates. Our analysis further indicates that the extensive utilization of bond insurance, auction rate debt, and interest rate derivatives created significant risk exposures for these health systems. These risks were realized by the broader global financial crisis of 2008. Findings indicate these health systems incurred large losses from the early retirement of their variable rate debt. In addition, many organizations were forced to post nearly $1 billion of liquid collateral due to the falling values of their interest rate derivatives. Finally, the investment portfolios of these large nonprofit health systems suffered millions of dollars of unrealized capital losses, which may minimize their ability to finance future capital investment requirements. PMID- 21528831 TI - Interactive financial decision support for clinical research trials. AB - The purpose of this article is to describe a decision support approach useful for evaluating proposals to conduct clinical research trials. Physicians often do not have the time or background to account for all the expenses of a clinical trial. Their evaluation process may be limited and driven by factors that do not indicate the potential for financial losses that a trial may impose. We analyzed clinical trial budget templates used by hospitals, health science centers, research universities, departments of medicine, and medical schools. We compiled a databank of costs and reviewed recent research trials conducted by the Department of Cardiothoracic Surgery in a major academic health science center. We then developed an interactive spreadsheet-based budgetary decision support approach that accounts for clinical trial income and costs. It can be tailored to provide quick and understandable data entry, accurate cost rates per subject, and clear go/no-go signals for the physician. PMID- 21528832 TI - The role of financial market performance in hospital capital investment. AB - Many not-for-profit hospitals hold large portfolios of financial investments, making them vulnerable to fluctuations in market performance. This article examines the association of bond and equity market performance with investment in property, plant, and equipment by 194 not-for-profit general hospitals in California over the period 1997 to 2006. The study combines retrospective panel data from the California Office of Statewide Health Planning and Development with year-end returns on the S&P 500 and ten-year US Treasury bonds. Using fixed effects regression, we find a significant positive association between S&P 500 performance and hospitals' capital investment; investment is not correlated with ten-year Treasury bond performance. PMID- 21528833 TI - Nursing home safety: does financial performance matter? AB - OBJECTIVES: This study examines the relationship between financial performance and selected safety measures of nursing homes in the State of Florida. METHODS: We used descriptive analysis on a total sample of 1,197. Safety information was from the Online Survey, Certification and Reporting (OSCAR) data of 2003 to 2005, while the financial performance measures were from the Medicare cost reports of 2002 to 2004. Finally, we examined the most frequently cited deficiencies as well as the relationship between financial performance and quality indicators. RESULTS: Nursing homes in the bottom quartile of financial performance perform poorly on most resident-safety measures of care; however, nursing homes in the top two financial categories also experienced a higher number of deficiencies. Nursing homes in the next to lowest quartile of financial performance category best perform on most of these safety measures. CONCLUSIONS: The results reinforce the need to monitor nursing home quality and resident safety in US nursing homes, especially among facilities with poor overall financial performance. PMID- 21528834 TI - Cigarette taxes and respiratory cancers: new evidence from panel co-integration analysis. AB - Using a set of state-level longitudinal data from 1954 through 2005, this study investigates the "long-run equilibrium" relationship between cigarette excise taxes and the mortality rates of respiratory cancers in the United States. Statistical tests show that both cigarette excise taxes in real terms and mortality rates from respiratory cancers contain unit roots and are co integrated. Estimates of co-integrating vectors indicated that a 10 percent increase in real cigarette excise tax rate leads to a 2.5 percent reduction in respiratory cancer mortality rate, implying a decline of 3,922 deaths per year, on a national level in the long run. These effects are statistically significant at the one percent level. Moreover, estimates of co-integrating vectors show that higher cigarette excise tax rates lead to lower mortality rates in most states; however, this relationship does not hold for Alaska, Florida, Hawaii, and Texas. PMID- 21528835 TI - Revisiting the cost of medical student education: a measure of the experience of UT Medical School-Houston. AB - This study uses a cost construction model to estimate the cost of a four-year undergraduate medical education at the University of Texas-Houston Medical School (UT-Houston) in 2006-2007 compared to 1994-1995. The model computes the cost by measuring increasingly inclusive definitions of the educational mission: instructional (direct-contact teaching), educational (instructional plus general supervision), and milieu (educational plus research costs). Using the model and adjusting for inflation, annual cost per student enrolled decreased by 16 percent in 2006-2007 compared to 1994-1995 and total cost decreased by 9 percent. Additionally, the model predicted 190 full-time equivalent (FTE) faculty and 187 FTE residents for 2006-2007 compared to 201 FTE faculty and 258 FTE residents for 1994-1995. Decreases in the cost of educating medical students were driven by (1) the reduction in the number of educator contact hours required for curriculum delivery; (2) change in the mix of educators; and (3) an increase in medical school class size. PMID- 21528836 TI - Cost-volume-profit analysis and expected benefit of health services: a study of cardiac catheterization services. AB - AIM: Academic research investigating health care costs in the Palestinian region is limited. Therefore, this study examines the costs of the cardiac catheterization unit of one of the largest hospitals in Palestine. We focus on costs of a cardiac catheterization unit and the increasing number of deaths over the past decade in the region due to cardiovascular diseases (CVDs). METHODS: We employ cost-volume-profit (CVP) analysis to determine the unit's break-even point (BEP), and investigate expected benefits (EBs) of Palestinian government subsidies to the unit. RESULTS: Findings indicate variable costs represent 56 percent of the hospital's total costs. Based on the three functions of the cardiac catheterization unit, results also indicate that the number of patients receiving services exceed the break-even point in each function, despite the unit receiving a government subsidy. CONCLUSIONS: Our findings, although based on one hospital, will permit hospital management to realize the importance of unit costs in order to make informed financial decisions. The use of break-even analysis will allow area managers to plan minimum production capacity for the organization. The economic benefits for patients and the government from the unit may encourage government officials to focus efforts on increasing future subsidies to the hospital. PMID- 21528837 TI - Some aromatic amines, organic dyes, and related exposures. PMID- 21528838 TI - Nucleophilic deoxyfluorination of catechols. AB - Nucleophilic deoxyfluorinaiton of one of the two hydroxyl groups of catechols has been developed via the Umpolung concept. This method was successively applied to naturally occurring catechols, such as catechins and dopamine, to produce novel fluorinated analogues. PMID- 21528839 TI - A reproducible SERS substrate based on electrostatically assisted APTES functionalized surface-assembly of gold nanostars. AB - A SERS active gold nanostar layer on the surface of ITO glass slip has been prepared by a low-cost electrostatically assisted APTES-functionalized surface assembly method for SERS analysis. The two-dimensional morphology of the SERS substrate was examined by scanning electron microscopy. Comparative analysis revealed that the optical characteristics and SERS efficiency of these substrates varied as a function of nanostar morphology. It was found that the substrate assembled with the longest branches of nanostars generated the best SERS efficiency, whether the excitation source is 785 or 633 nm. The potential use of these substrates in detection applications was also investigated by using Nile blue A and Rhodamine 6G. The detection limits are 5 * 10(-11) M and 1 * 10(-9) M, respectively, when using the 785 nm excitation source. Apart from this high enhancement effect, the substrate here also shows extremely good reproducibility at the same time. All of these indicate that gold nanostars are a very good structure for SERS substrate assembly. PMID- 21528840 TI - Adding fingers to an engineered zinc finger nuclease can reduce activity. AB - Zinc finger nucleases (ZFNs) have been used to direct precise modifications of the genetic information in living cells at high efficiency. An important consideration in the design of ZFNs is the number of zinc fingers that are required for efficient and specific cleavage. We examined dimeric ZFNs composed of [1]+[1], [2]+[2], [3]+[3], [4]+[4], [5]+[5], and [6]+[6] zinc fingers, targeting 6, 12, 18, 24, 30, and 36 bp, respectively. We found that [1]+[1] and [2]+[2] fingers supported neither in vitro cleavage nor single-strand annealing in a cell-based recombination assay. An optimal ZFN activity was observed for [3]+[3] and [4]+[4] fingers. Surprisingly, [5]+[5] and [6]+[6] fingers exhibited significantly reduced activity. While the extra fingers were not found to dramatically increase toxicity, directly inhibit recombination, or perturb the ZFN target site, we demonstrate the ability of subsets of three fingers in six finger arrays to bind independently to regions of the target site, possibly explaining the decrease in activity. These results have important implications for the design of new ZFNs, as they show that in some cases an excess of fingers may actually negatively affect the performance of engineered multifinger proteins. Maximal ZFN activity will require an optimization of both DNA binding affinity and specificity. PMID- 21528841 TI - Reprogramming virus nanoparticles to bind metal ions upon activation with heat. AB - We have reprogrammed the stimulus-responsive conformational change property of a virus nanoparticle (VNP) to enable the surface exposure of metal binding motifs upon activation with heat. The VNP is based on the widely investigated adeno associated virus (AAV). An intrinsic bioactive functionality of AAV was genetically replaced with a hexahistidine (His) tag. The peptide domain with the inserted His tag is normally inaccessible. Upon external stimulation with heat, the VNP undergoes a conformational change, resulting in externalization of His tag-containing domains and the conferred ability to bind metal. We show that beyond this newfound functionality of the capsid, the VNPs maintain many of the wild-type capsid properties. Our work lays the groundwork for developing stimulus responsive VNPs that can be used as "smart" building blocks for the creation of higher order structures. PMID- 21528842 TI - Crystal structure and spectroscopic studies of a stable mixed-valent state of the hemerythrin-like domain of a bacterial chemotaxis protein. AB - The bacterial chemotaxis protein of Desulfovibrio vulgaris DcrH (DcrH-Hr) functions as an O(2)-sensing protein. This protein has a hemerythrin-like domain that includes a nonheme diiron center analogous to the diiron center of the hemerythrin (Hr) family. Interestingly, the O(2) affinity of DcrH-Hr is 3.3 * 10(6) M(-1), a value 25-fold higher than that of the Pectinaria gouldii Hr. This high affinity arises from the fast association of the O(2) ligand with DcrH-Hr (k(on) = 5.3 * 10(8) M(-1) s(-1)), which is made possible by a hydrophobic tunnel that accelerates the passage of the O(2) ligand to the diiron site. Furthermore, the autoxidation kinetics indicate that the rate of autoxidation of DcrH-Hr is 54 fold higher than that of P. gouldii Hr, indicating that the oxy form of DcrH-Hr is not stable toward autoxidation. More importantly, a mixed-valent state, semimet(R), which was spectroscopically observed in previous Hr studies, was found to be stable for over 1 week and isolable in the case of DcrH-Hr. The high resolution crystal structures of the semimet(R)- (1.8 A) and met-DcrH-Hr (1.4 A) indicate that the semimet(R)- and met-DcrH-Hr species have very similar coordination geometry at the diiron site. PMID- 21528843 TI - Long-term bioethanol system and its implications on GHG emissions: a case study of Thailand. AB - The study evaluates greenhouse gas (GHG) emissions performance of future bioethanol systems in Thailand to ascertain whether bioethanol for transport could help the country mitigate a global warming impact. GHG emission factors of bioethanol derived from cassava, molasses, and sugar cane are analyzed using 12 scenarios covering the critical variables possibly affecting the GHG performance, i.e., (1) the possible direct land use change caused by expanding feedstock cultivation areas; (2) types of energy carriers used in ethanol plants; and (3) waste utilization, e.g., biogas recovery and dry distillers grains with solubles (DDGS) production. The assessment reveals that GHG performance of a Thai bioethanol system is inclined to decrease in the long run due to the effects from the expansion of plantation areas to satisfy the deficit of cassava and molasses. Therefore, bioethanol will contribute to the country's strategic plan on GHG mitigation in the transportation sector only if the production systems are sustainably managed, i.e., coal replaced by biomass in ethanol plants, biogas recovery, and adoption of improved agricultural practices to increase crop productivity without intensification of chemical fertilizers. Achieving the year 2022 government policy targets for bioethanol with recommended measures would help mitigate GHG emissions up to 4.6 Gg CO(2)-eq per year. PMID- 21528844 TI - Spatial modeling for groundwater arsenic levels in North Carolina. AB - To examine environmental and geologic determinants of arsenic in groundwater, detailed geologic data were integrated with well water arsenic concentration data and well construction data for 471 private wells in Orange County, NC, via a geographic information system. For the statistical analysis, the geologic units were simplified into four generalized categories based on rock type and interpreted mode of deposition/emplacement. The geologic transitions from rocks of a primary pyroclastic origin to rocks of volcaniclastic sedimentary origin were designated as polylines. The data were fitted to a left-censored regression model to identify key determinants of arsenic levels in groundwater. A Bayesian spatial random effects model was then developed to capture any spatial patterns in groundwater arsenic residuals into model estimation. Statistical model results indicate (1) wells close to a transition zone or fault are more likely to contain detectible arsenic; (2) welded tuffs and hydrothermal quartz bodies are associated with relatively higher groundwater arsenic concentrations and even higher for those proximal to a pluton; and (3) wells of greater depth are more likely to contain elevated arsenic. This modeling effort informs policy intervention by creating three-dimensional maps of predicted arsenic levels in groundwater for any location and depth in the area. PMID- 21528845 TI - Two-step synthesis of novel, bioactive derivatives of the ubiquitous cofactor nicotinamide adenine dinucleotide (NAD). AB - We report the design and concise synthesis, in two steps from commercially available material, of novel, bioactive derivatives of the enzyme cofactor nicotinamide adenine dinucleotide (NAD). The new synthetic dinucleotides act as sirtuin (SIRT) inhibitors and show isoform selectivity for SIRT2 over SIRT1. An NMR-based conformational analysis suggests that the conformational preferences of individual analogues may contribute to their isoform selectivity. PMID- 21528846 TI - Total synthesis of dolabelide C: a phosphate-mediated approach. AB - The first synthesis of dolabelide C (1), a cytotoxic marine macrolide, is reported utilizing a phosphate tether-mediated approach. Bicyclic phosphates (S,S,S(P))-5 and (R,R,R(P))-5 serve as the central building blocks for the construction of two major 1,3-anti-diol subunits in 1 through selective cleavage pathways, regioselective olefin reduction, and cross-metathesis. Overall, phosphate-mediated processes provided copious amounts of both major subunits allowing for a detailed RCM macrocyclization study to the 24-membered macrolactone 1. PMID- 21528847 TI - Asymmetric synthesis of cis-2-aminocyclopropanols by intramolecular Mannich addition of silyloxy benzyl carbanions. AB - An efficient, highly diastereoselective method for the preparation of protected cis-2-aminocyclopropanols from N-tert-butanesulfinyl ketimines and various aryl acylsilanes is described. A tandem process for carbon-carbon bond formation via nucleophilic addition to acylsilanes, Brook rearrangement, and intramolecular Mannich reaction has been developed. PMID- 21528849 TI - Graphene for controlled and accelerated osteogenic differentiation of human mesenchymal stem cells. AB - Current tissue engineering approaches combine different scaffold materials with living cells to provide biological substitutes that can repair and eventually improve tissue functions. Both natural and synthetic materials have been fabricated for transplantation of stem cells and their specific differentiation into muscles, bones, and cartilages. One of the key objectives for bone regeneration therapy to be successful is to direct stem cells' proliferation and to accelerate their differentiation in a controlled manner through the use of growth factors and osteogenic inducers. Here we show that graphene provides a promising biocompatible scaffold that does not hamper the proliferation of human mesenchymal stem cells (hMSCs) and accelerates their specific differentiation into bone cells. The differentiation rate is comparable to the one achieved with common growth factors, demonstrating graphene's potential for stem cell research. PMID- 21528848 TI - Optimization of a cyclic peptide inhibitor of Ser/Thr phosphatase PPM1D (Wip1). AB - PPM1D (PP2Cdelta or Wip1) was identified as a wild-type p53-induced Ser/Thr phosphatase that accumulates after DNA damage and classified into the PP2C family. It dephosphorylates and inactivates several proteins critical for cellular stress responses, including p38 MAPK, p53, and ATM. Furthermore, PPM1D is amplified and/or overexpressed in a number of human cancers. Thus, inhibition of its activity could constitute an important new strategy for therapeutic intervention to halt the progression of several different cancers. Previously, we reported the development of a cyclic thioether peptide with low micromolar inhibitory activity toward PPM1D. Here, we describe important improvements in the inhibitory activity of this class of cyclic peptides and also present a binding model based upon the results. We found that specific interaction of an aromatic ring at the X1 position and negative charge at the X5 and X6 positions significantly increased the inhibitory activity of the cyclic peptide, with the optimized molecule having a K(i) of 110 nM. To the best of our knowledge, this represents the highest inhibitory activity reported for an inhibitor of PPM1D. We further developed an inhibitor selective for PPM1D over PPM1A with a K(i) of 2.9 MUM. Optimization of the cyclic peptide and mutagenesis experiments suggest that a highly basic loop unique to PPM1D is related to substrate specificity. We propose a new model for the catalytic site of PPM1D and inhibition by the cyclic peptides that will be useful both for the subsequent design of PPM1D inhibitors and for identification of new substrates. PMID- 21528850 TI - Chiral imprinting of diblock copolymer single-chain particles. AB - This Article reports the molecular imprinting of polymer single-chain particles that have a radius ~3.7 nm. For this, the template L-phenylalanine anilide or L PhiAA and a diblock copolymer PtBA-b-P(CEMA-r-CA) were used. Here, PtBA denotes poly(tert-butyl acrylate), and P(CEMA-r-CA) denotes a random block consisting of cinnamoyloxyethyl methacrylate (CEMA) and carboxyl-bearing (CA) units. In CHCl(3)/cyclohexane (CHX) with 64 vol % of CHX or at f(CHX) = 64%, a block selective solvent for PtBA, PtBA-b-P(CEMA-r-CA) formed spherical micelles. The core consisted of the insoluble P(CEMA-r-CA) block and L-PhiAA, which complexed with the CA groups. Pumping slowly this micellar solution into stirred CHCl(3)/(CHX) at f(CHX) = 64% triggered micelle dissociation into single-chain micelles, which comprised presumably a solubilized PtBA tail and a collapsed P(CEMA-r-CA)/L-PhiAA head. Because the solvent reservoir was under constant UV irradiation, the photo-cross-linkable units in the P(CEMA-r-CA) head cross linked, and the single-chain micelles were converted into cross-linked single chain micelles or tadpoles. Synchronizing the micelle addition and photoreaction rates allowed the preparation, from this protocol, of essentially pure tadpoles at high final polymer concentrations. Imprinted tadpoles were procured after L PhiAA was extracted from the tadpole heads. Under optimized conditions, the produced imprinted tadpoles had exceptionally high binding capacity and high selectivity for L-PhiAA. In addition, the rates of L-PhiAA release from and rebinding by the particles were high. PMID- 21528851 TI - Phospholipid membrane encapsulation of nanoparticles for surface-enhanced Raman scattering. AB - Lipid-encapsulated surface-enhanced Raman scattering (SERS) nanoparticles, with promising applications in biomedical diagnostics, were produced. Gold nanoparticles, 60 nm in diameter, were coated with a ternary mixture of DOPC, sphingomyelin, and cholesterol. The lipid layer is versatile for engineering the chemical and optical properties of the particles. The stability of the lipid encapsulated particles is demonstrated over a period of weeks. The versatility of the layer is demonstrated by the incorporation of three different Raman-active species using three different strategies. The lipid layer was directly observed by TEM, and the SERS spectrum of the three dye species was confirmed by Raman spectroscopy. UV-vis absorption and dynamic light scattering provide additional evidence of lipid encapsulation. The encapsulation is achieved in aqueous solution, avoiding phase transfer and possible contamination from organic solvents. Furthermore, when fluorescent dye-labeled lipids were employed in the encapsulant, the fluorescence and SERS activity of the particles were controlled by the use of dissolved ions in the preparation solution. PMID- 21528852 TI - Comparison of Pickering and network stabilization in water-in-oil emulsions. AB - We compared the efficacy of Pickering crystals, a continuous phase crystal network, and a combination thereof against sedimentation and dispersed phase coalescence in water-in-oil (W/O) emulsions. Using 20 wt % water-in-canola oil emulsions as our model, glycerol monostearate (GMS) permitted Pickering-type stabilization, whereas simultaneous usage of hydrogenated canola oil (HCO) and glycerol monooleate (GMO) primarily led to network-stabilized emulsions. A minimum of 4 wt % GMS or 10 wt % HCO was required for long-term sedimentation stability. Although there were no significant differences between the two in mean droplet size with time, the free water content of the network-stabilized emulsions was higher than Pickering-stabilized emulsions, suggesting higher instability. Microscopy revealed the presence of crystal shells around the dispersed phase in the GMS-stabilized emulsions, whereas in the HCO-stabilized emulsion, spherulitic growth in the continuous phase and on the droplet surface occurred. The displacement energy (E(disp)) to detach crystals from the oil-water interface was ~10(4) kT, and was highest for GMS crystals. Thermal cycling to induce dispersed phase coalescence of the emulsions resulted in desorption of both GMS and GMO from the interface, which we ascribed to solute-solvent hydrogen bonding between the emulsifier molecules and the solvent oil, based on IR spectra. Overall, Pickering crystals were more effective than network crystals for emulsion stabilization. However, the thermal stability of all emulsions was hampered by the diffusion of the molten emulsifiers from the interface. PMID- 21528853 TI - Influence of air oxidation on the surfactant-assisted purification of single walled carbon nanotubes. AB - Arc discharge single-walled carbon nanotube (SWCNT) soot was treated under different experimental conditions including gas- and liquid-phase oxidation, heat treatment in an inert gas, and hydrogen gasification. Afterward, the samples were dispersed in a surfactant and centrifuged at a moderately high speed. Near infrared spectra of all the dispersions were compared with that of raw SWCNT soot. The relative intensity of SWCNT characteristic spectral bands strongly increased for air-oxidized samples after centrifugation, while it did not substantially change for samples oxidized with nitric acid or reduced with hydrogen. The relative SWCNT spectral intensity was associated to the sample purity through the so-called purity index, which was calculated from the S(22) band transition of semiconducting SWCNTs. Air-oxidized samples experienced a 7 fold increase in the purity index during centrifugation, while it increased by only 2-3 times for nonoxidized samples. Air oxidation specifically improves the preferential stability of SWCNTs over carbonaceous impurities in the dispersions, leading to the highest purity index values reported so far. PMID- 21528854 TI - Biofunctionalization of anisotropic nanocrystalline semiconductor-magnetic heterostructures. AB - Asymmetric binary nanocrystals (BNCs) formed by a spherical gamma-Fe(2)O(3) magnetic domain epitaxially grown onto a lateral facet of a rodlike anatase TiO(2) nanorod have been functionalized with PEG-terminated phospholipids, resulting in a micellar system that enables the BNC dispersion in aqueous solution. The further processability of the obtained water-soluble BNC including PEG lipid micelles and their use in bioconjugation experiments has been successfully demonstrated by covalently binding to bovine serum albumin (BSA). The whole process has also been preliminarily performed on spherical iron oxide nanocrystals (NCs) and TiO(2) nanorods (NRs), which form single structural units in the heterostructures. Each step has been thoroughly monitored by using optical, structural, and electrophoretic techniques. In addition, an investigation of the magnetic behavior of the iron oxide NCs and BNCs, before and after incorporation into PEG lipid micelles and subsequently bioconjugation, has been carried out, revealing that the magnetic characteristics are mostly retained. The proposed approach to achieving water-soluble anisotropic BNCs and their bioconjugates has a large potential in catalysis and biomedicine and offers key functional building blocks for biosensor applications. PMID- 21528855 TI - Nonequilibrium water transport in a nonionic microemulsion system. AB - We used microsecond time scale atomistic simulations to study the relaxation dynamics of the microemulsion water/octane/C(9)E(3) system. In order to determine what transport mechanism occurs under the conditions of surfactant excess, we studied the system under a wide range of temperatures (7-88 degrees C) and showed that the surfactant acts as an effective solvent for water and carries out passive water transport through oil. Interestingly, most of surfactant solubilized water is situated between surfactant and oil layers and is not homogeneously distributed in the surfactant-oil slab. With raising the temperature, the larger aggregates are allowed to travel through the oil layer, increasing overall water presence in oil. Also, our cluster analysis indicates that most complexes do not form a dense water core, supporting the "hydrated surfactants" transport mechanism. PMID- 21528856 TI - Influence of degree of gas saturation on multibubble sonoluminescence intensity. AB - The influence of the degree of saturation (DOS) of a gas in a solution on the intensity of multibubble sonoluminescence (MBSL) excited by ultrasound with a frequency of 261 kHz is investigated at various ultrasonic powers and with different concentrations of ethanol, which is added as a volatile solute. At relatively low powers and a high DOS, low ethanol concentrations give higher sonoluminescence (SL) intensities than those obtained with pure water. This intensity enhancement decreases as sonication proceeds because the SL intensity for pure water increases with time, whereas it remains almost constant or decreases slightly in solutions containing ethanol. At relatively low powers, a partially degassed solution has a higher SL intensity than a solution with a high DOS for both pure water and solutions containing ethanol. The reason why the DOS decreases more when ethanol is added is considered mainly to be the accumulation of hydrocarbon products and the promotion of rectified diffusion. Adding an alcohol to a solution enhances ultrasonic degassing. PMID- 21528857 TI - Pressure-induced isostructural phase transition and correlation of FeAs coordination with the superconducting properties of 111-type Na(1-x)FeAs. AB - The effect of pressure on the crystalline structure and superconducting transition temperature (T(c)) of the 111-type Na(1-x)FeAs system using in situ high-pressure synchrotron X-ray powder diffraction and diamond anvil cell techniques is studied. A pressure-induced tetragonal to tetragonal isostructural phase transition was found. The systematic evolution of the FeAs(4) tetrahedron as a function of pressure based on Rietveld refinements on the powder X-ray diffraction patterns was obtained. The nonmonotonic T(c)(P) behavior of Na(1 x)FeAs is found to correlate with the anomalies of the distance between the anion (As) and the iron layer as well as the bond angle of As-Fe-As for the two tetragonal phases. This behavior provides the key structural information in understanding the origin of the pressure dependence of T(c) for 111-type iron pnictide superconductors. A pressure-induced structural phase transition is also observed at 20 GPa. PMID- 21528858 TI - Predictable stereoselective and chemoselective hydroxylations and epoxidations with P450 3A4. AB - Enantioselective hydroxylation of one specific methylene in the presence of many similar groups is debatably the most challenging chemical transformation. Although chemists have recently made progress toward the hydroxylation of inactivated C-H bonds, enzymes such as P450s (CYPs) remain unsurpassed in specificity and scope. The substrate promiscuity of many P450s is desirable for synthetic applications; however, the inability to predict the products of these enzymatic reactions is impeding advancement. We demonstrate here the utility of a chemical auxiliary to control the selectivity of CYP3A4 reactions. When linked to substrates, inexpensive, achiral theobromine directs the reaction to produce hydroxylation or epoxidation at the fourth carbon from the auxiliary with pro-R facial selectivity. This strategy provides a versatile yet controllable system for regio-, chemo-, and stereoselective oxidations at inactivated C-H bonds and demonstrates the utility of chemical auxiliaries to mediate the activity of highly promiscuous enzymes. PMID- 21528859 TI - Selective biomolecular nanoarrays for parallel single-molecule investigations. AB - The ability to direct the self-assembly of biomolecules on surfaces with true nanoscale control is key for the creation of functional substrates. Herein we report the fabrication of nanoscale biomolecular arrays via selective self assembly on nanopatterned surfaces and minimized nonspecific adsorption. We demonstrate that the platform developed allows for the simultaneous screening of specific protein-DNA binding events at the single-molecule level. The strategy presented here is generally applicable and enables high-throughput monitoring of biological activity in real time and with single-molecule resolution. PMID- 21528860 TI - Local covariance order diffusion-ordered spectroscopy: a powerful tool for mixture analysis. AB - Diffusion-ordered spectroscopy (DOSY) is an important tool in NMR mixture analysis that has found use in most areas of chemistry, including organic synthesis, drug discovery, and supramolecular chemistry. Typically the aim is to disentangle the overlaid, and often overlapped, NMR spectra of individual mixture components and/or to obtain size and interaction information from their respective diffusion coefficients. The most common processing method, high resolution DOSY, breaks down where component spectra overlap; here multivariate methods can be very effective, but only for small numbers (2-5) of components. In this study, we present a hybrid method, local covariance order DOSY (LOCODOSY), that breaks a spectral data set into suitable windows and analyzes each individually before combining the results. This approach uses a multivariate algorithm (e.g., SCORE or DECRA) to resolve only a small number of components in any given window. Because a small spectral region should contain signals from only a few components, even when the spectrum as a whole contains many more, the total number of resolvable chemical components rises dramatically. It is demonstrated here that complete resolution of component spectra can be achieved for mixtures that are much more complex than could previously be analyzed with DOSY. Thus, LOCODOSY is a powerful, flexible tool for processing NMR diffusion data of complex mixtures. PMID- 21528861 TI - Population of nonnative states of lysozyme variants drives amyloid fibril formation. AB - The propensity of protein molecules to self-assemble into highly ordered, fibrillar aggregates lies at the heart of understanding many disorders ranging from Alzheimer's disease to systemic lysozyme amyloidosis. In this paper we use highly accurate kinetic measurements of amyloid fibril growth in combination with spectroscopic tools to quantify the effect of modifications in solution conditions and in the amino acid sequence of human lysozyme on its propensity to form amyloid fibrils under acidic conditions. We elucidate and quantify the correlation between the rate of amyloid growth and the population of nonnative states, and we show that changes in amyloidogenicity are almost entirely due to alterations in the stability of the native state, while other regions of the global free-energy surface remain largely unmodified. These results provide insight into the complex dynamics of a macromolecule on a multidimensional energy landscape and point the way for a better understanding of amyloid diseases. PMID- 21528862 TI - Petroleum analysis. PMID- 21528863 TI - Proteomic characterization of engineered nanomaterial-protein interactions in relation to surface reactivity. AB - Adsorption of proteins onto an engineered nanoparticle surface happens immediately after particles come in contact with a biological fluid. However, at the moment very little is known about the mechanisms of interactions between biomolecules and nanomaterials. In this study, eleven thoroughly characterized materials were first investigated in vitro for their ability to enter human lung epithelial cells and human monocyte-derived macrophages. All tested materials were taken up by primary macrophages and epithelial cells. Some of the engineered nanomaterials (ENM) were found in the cytoplasm. Large quantitative and qualitative variation in the binding efficiencies to cellular proteins was observed between different tested nanoparticles. Pulmonary surfactant components significantly reduced the overall protein adsorption on the surface of ENMs. Fibrinogen chains were attached to all materials after exposure to plasma proteins. Common ENM-bound cytoplasmic protein identifications were peroxiredoxin 1, annexin A2, and several ribosomal and cytoskeletal proteins. The underlying mechanism of the ENM-plasma protein interaction may diverge from that of cell lysate proteins, as the binding efficiency to cell lysate proteins appears to depend on the characteristics of the ENM surface, whereas the adsorbed plasma proteins are involved in particle phagocytosis and seem to cover ENMs independently of the their surface properties. Identification of the composition of the nanomaterial-protein complex is crucial for understanding of the uptake mechanisms, biodistribution, and clearance of ENMs, knowledge which is required for safety evaluation and biomedical applications of these materials. PMID- 21528864 TI - Comparing conventional and biotechnology-based pest management. AB - Pest management has changed dramatically during the past 15 years by the introduction of transgenes into crops for the purpose of pest management. Transgenes for herbicide resistance or for production of one or more Bt toxins are the predominant pest management traits currently available. These two traits have been rapidly adopted where available because of their superior efficacy and simplification of pest management for the farmer. Furthermore, they have substantially reduced the use of environmentally and toxicologically suspect pesticides while reducing the carbon footprint of pest management as reduced tillage became more common, along with fewer trips across the field to spray pesticides. The most successful of these products have been glyphosate-resistant crops, which cover approximately 85% of all land occupied by transgenic crops. Over-reliance on glyphosate with continual use of these crops has resulted in the evolution of highly problematic glyphosate-resistant weeds. This situation has resulted in some farmers using weed management methods similar to those used with conventional crops. Evolution of resistance has not been a significant problem with Bt crops, perhaps because of a mandated resistance management strategy. Transgenic crops with multiple genes for resistance to different herbicides and resistance to additional insects will be available in the next few years. These products will offer opportunities for the kind of pest management diversity that is more sustainable than that provided by the first generation of transgenic crops. PMID- 21528866 TI - Controllable photoluminescence properties of an anion-dye-intercalated layered double hydroxide by adjusting the confined environment. AB - This article reports a novel method to tune the photoluminance properties of ammonium 1-anilinonaphthalene-8-sulfonate (ANS) in a 2D matrix of layered double hydroxide (LDH) by changing the interlayer microenvironment. ANS and a series of surfactants with different alkyl chain lengths (pentanesulphonate (PES), hexanesulphonate (HES), heptanesulphonate (HPS), decanesulphonate (DES), and dodecylsulphonate (DDS)) were respectively cointercalated into the galleries of ZnAl-LDH by the anion exchange method. Thin films of ANS/surfactant-LDHs obtained by the solvent evaporation method possess good c orientation as revealed by XRD and SEM. It was found that the ANS/HPS-LDH film showed the maximum fluorescence efficiency and the longest intensity-average lifetime among these ANS/surfactant LDH composites owing to the "size-matching" rule between the organic dye and surfactant. Moreover, the fluorescence properties can be tuned by changing the relative molar ratio of ANS/HPS, and the film containing 20% ANS (molar percentage, expressed as ANS(20%)/HPS-LDH) exhibits the maximum fluorescence efficiency, the longest average lifetime, and significantly enhanced photo and thermal stability. In addition, the composite films show fluorescence anisotropy, attributed to the preferential orientation of ANS in the LDH gallery. Therefore, this work demonstrates a feasible approach to tuning the photoluminescence properties of a dye confined in an inorganic 2D matrix via changing the interlayer microenvironment, which may be considered to be a good candidate for solid photoluminescence materials, nonlinear optics, and polarized luminescence materials. PMID- 21528865 TI - Surface engineering of iron oxide nanoparticles for targeted cancer therapy. AB - Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired response. Of the nanomaterials studied, iron oxide nanoparticles have emerged as one of top candidates for cancer therapy. Their intrinsic superparamagnetism enables noninvasive magnetic resonance imaging (MRI), and their biodegradability is advantageous for in vivo applications. A therapeutic superparamagnetic iron oxide nanoparticle (SPION) typically consists of three primary components: an iron oxide nanoparticle core that serves as both a carrier for therapeutics and contrast agent for MRI, a coating on the iron oxide nanoparticle that promotes favorable interactions between the SPION and the biological system, and a therapeutic payload that performs the designated function in vivo. Often, the design may include a targeting ligand that recognizes the receptors over-expressed on the exterior surface of cancer cells. The body is a highly complex system that imposes multiple physiological and cellular barriers to foreign objects. Thus, the success of a therapeutic SPION largely relies on the design of the iron oxide core to ensure its detection in MRI and the coatings that allow the nanoparticles to bypass these barriers. Strategies to bypass the physiological barriers, such as liver, kidneys, and spleen, involve tuning the overall size and surface chemistry of the SPION to maximize blood half-life and facilitate the navigation in the body. Strategies to bypass cellular barriers include the use of targeting agents to maximize uptake of the SPION by cancer cells and the employment of materials that promote desired intracellular trafficking and enable controlled drug release. The payload can be genes, proteins, chemotherapy drugs, or a combination of these molecules. Each type of therapeutic molecule requires a specific coating design to maximize the loading and to achieve effective delivery and release. In this Account, we discuss the primary design parameters in developing therapeutic SPIONs with a focus on surface coating design to overcome the barriers imposed by the body's defense system. We provide examples of how these design parameters have been implemented to produce SPIONs for specific therapeutic applications. Although there are still challenges to be addressed, SPIONs show great promise in the successful diagnosis and treatment of the most devastating cancers. Once the critical design parameters have been optimized, these nanoparticles, combined with imaging modalities, can serve as truly multifunctional theranostic agents that not only perform a therapeutic function but also provide instant clinical feedback, allowing the physician to adjust the treatment plan. PMID- 21528867 TI - Single step hybrid coating process to enhance the electrosteric stabilization of inorganic particles. AB - We report on a single-step coating process and the resulting colloidal stability of silica-coated spindle-type hematite nanoparticles (NPs) decorated with a layer of poly(acrylic acid) (PAA) polyelectrolyte chains that are partially incorporated into the silica shell. The stability of PAA coated NPs as a function of pH and salt concentration in water was compared to bare hematite particles and simple silica-coated hematite NPs, studying their electrophoretic mobility and the hydrodynamic radius by dynamic light scattering. Particles coated with this method were found to be more stable upon the addition of salt at pH 7, and their aggregation at the pH of the isoelectric point is reversible. The hybrid coating appears to increase the colloidal stability in aqueous media due to the combination of the decrease of the isoelectric point and the electrosteric stabilization. This coating method is not limited to hematite particles but can easily be adapted to any silica-coatable particle. PMID- 21528868 TI - Rate enhanced olefin cross-metathesis reactions: the copper iodide effect. AB - Copper iodide has been shown to be an effective cocatalyst for the olefin cross metathesis reaction. In particular, it has both a catalyst stabilizing effect due to iodide ion, as well as copper(I)-based phosphine-scavenging properties that apply to use of the Grubbs-2 catalyst. A variety of Michael acceptors and olefinic partners can be cross-coupled under mild conditions in refluxing diethyl ether that avoid chlorinated solvents. This effect has also been applied to chemistry in water at room temperature using the new surfactant TPGS-750-M. PMID- 21528869 TI - On intermolecular dipolar coupling in two strongly polar liquids: dimethyl sulfoxide and acetonitrile. AB - The paper presents the results of studies of the electric and dielectric properties of dimethyl sulfoxide (DMSO) and acetonitrile (ACN), two strongly polar liquids composed of the molecules of the same dipole moment value (MU ~ 4 D) but of a quite different static dielectric permittivity (epsilon(S)(DMSO) >> epsilon(S)(ACN)). It was shown that the activation energies for both the dc ionic conductivity (sigma(DC)) and the viscosity (eta) are two times higher for DMSO than for ACN; however, for both of the liquids, the temperature dependence of the product sigma(DC)eta is quite close to the prediction of the Stokes-Einstein relation. The dielectric results are interpreted in terms of the intermolecular dipole-dipole coupling. An exceptional behavior of DMSO most certainly results from its "monomolecularity", i.e., from the lack of the dipolar coupling in that strongly polar liquid. The effect is a consequence of a very specific structure of the DMSO molecule where its rotational dynamics makes the intermolecular dipole-dipole coupling very unfavorable, in contrast to the ACN molecules. PMID- 21528871 TI - Mechanism and kinetics of the water-assisted formic acid + OH reaction under tropospheric conditions. AB - In this work, we have revisited the mechanism of the formic acid + OH radical reaction assisted by a single water molecule. Density functional methods are employed in conjunction with large basis sets to explore the potential energy surface of this radical-molecule reaction. Computational kinetics calculations in a pseudo-second-order mechanism have been performed, taking into account average atmospheric water concentrations and temperatures. We have used this method recently to study the single water molecule assisted H-abstraction by OH radicals (Iuga, C.; Alvarez-Idaboy, J. R.; Reyes, L.; Vivier-Bunge, A. J. Phys. Chem. Lett. 2010, 1, 3112; Iuga, C.; Alvarez-Idaboy, J. R.; Vivier-Bunge, A. Chem. Phys. Lett. 2010, 501, 11; Iuga, C.; Alvarez-Idaboy, J. R.; Vivier-Bunge, A. Theor. Chem. Acc. 2011, 129, 209), and we showed that the initial water complexation step is essential in the rate constant calculation. In the formic acid reaction with OH radicals, we find that the water-acid complex concentration is small but relevant under atmospheric conditions, and it could in principle be large enough to produce a measurable increase in the overall rate constant. However, the water-assisted process occurs according to a formyl hydrogen abstraction, rather than abstraction of carboxylic hydrogen as in the water-free case. As a result, the overall reaction rate constant is considerably smaller. Products are different in the water-free and water-assisted processes. PMID- 21528870 TI - Asymmetric enzymatic glycosylation of mitoxantrone. AB - Using a uniquely promiscuous engineered glycosyltransferase (GT) derived from the macrolide-inactivating GT OleD, a single-step asymmetric glucosylation of one 'arm' of the drug mitoxantrone was efficiently achieved in high stereo- and regiospecificity. The synthesis, structural elucidation, and anticancer activity of the corresponding mitoxantrone 4'-beta-D-glucoside are described. PMID- 21528872 TI - Stereochemistry and solvent role in protein folding: nuclear magnetic resonance and molecular dynamics studies of poly-L and alternating-L,D homopolypeptides in dimethyl sulfoxide. AB - The competing interactions folding and unfolding protein structure remain obscure. Using homopolypeptides, we ask if poly-L structure may have a role. We mutate the structure to alternating-L,D stereochemistry and substitute water as the fold-promoting solvent with methanol and dimethyl sulfoxide (DMSO) as the fold-denaturing solvents. Circular dichroism and molecular dynamics established previously that, while both isomers were folded in water, the poly-L isomer was unfolded and alternating-L,D isomer folded in methanol. Nuclear magnetic resonance and molecular dynamics establish now that both isomers are unfolded in DMSO. We calculated energetics of folding-unfolding equilibrium with water and methanol as solvents. We have now calculated interactions of unfolded polypeptide structures with DMSO as solvent. Methanol was found to unfold and water fold poly L structure as a dielectric. DMSO has now been found to unfold both poly-L and alternating-L,D structures by strong solvation of peptides to disrupt their hydrogen bonds. Accordingly, we propose that while linked peptides fold protein structure with hydrogen bonds they unfold the structure electrostatically due to the stereochemical effect of the poly-L structure. Protein folding to ordering of peptide hydrogen bonds with water as canonical solvent may thus involve two specific and independent solvent effects-one, strong screening of electrostatics of poly-L linked peptides, and two, weak dipolar solvation of peptides. Correspondingly, protein denaturation may involve two independent solvent effects one, weak dielectric to unfold poly-L structure electrostatically, and two, strong polarity to disrupt peptide hydrogen bonds by solvation of peptides. PMID- 21528873 TI - A stereoselective formal synthesis of leucascandrolide A. AB - A stereoselective formal synthesis of leucascandrolide A was accomplished through the tandem and organocatalytic oxa-Michael reactions, which were promoted by the gem-disubstituent effect, in conjunction with the dithiane coupling reaction. PMID- 21528874 TI - Vibrational properties of the disulfur dinitride molecule, S2N2: IR and Raman spectra of the matrix-isolated molecule. AB - The IR and Raman spectra of disulfur dinitride, S(2)N(2), are reported not only for the solid condensate but also for the molecules isolated in solid noble gas, N(2), or CH(4) matrices at low temperatures. The results imply that the isolated S(2)N(2) molecule has much the same geometry as in the crystalline solid with a virtually square-planar structure conforming to D(2h) symmetry, a conclusion confirmed by isotopic enrichment in (15)N and by the results of earlier as well as fresh quantum chemical calculations. These calculations also support the results of normal coordinate analysis of the experimental data in giving potential constants suggestive of a relatively rigid S(2)N(2) molecule consistent with its description as a 2pi-electron aromatic, while appearing to maintain a formal S-N bond order close to 1. PMID- 21528875 TI - Direct observations of conformational distributions of intrinsically disordered p53 peptides using UV Raman and explicit solvent simulations. AB - We report the first experimental measurements of Ramachandran Psi-angle distributions for intrinsically disordered peptides: the N-terminal peptide fragment of tumor suppressor p53 and its P27S mutant form. To provide atomically detailed views of the conformational distributions, we performed classical, explicit-solvent molecular dynamics simulations on the microsecond time scale. Upon binding its partner protein, MDM2, wild-type p53 peptide adopts an alpha helical conformation. Mutation of Pro27 to serine results in the highest affinity yet observed for MDM2-binding of the p53 peptide. Both UV resonance Raman spectroscopy (UVRR) and simulations reveal that the P27S mutation decreases the extent of PPII helical content and increases the probability for conformations that are similar to the alpha-helical MDM2-bound conformation. In addition, UVRR measurements were performed on peptides that were isotopically labeled at the Leu26 residue preceding the Pro27 in order to determine the conformational distributions of Leu26 in the wild-type and mutant peptides. The UVRR and simulation results are in quantitative agreement in terms of the change in the population of non-PPII conformations involving Leu26 upon mutation of Pro27 to serine. Finally, our simulations reveal that the MDM2-bound conformation of the peptide is significantly populated in both the wild-type and mutant isolated peptide ensembles in their unbound states, suggesting that MDM2 binding of the p53 peptides may involve conformational selection. PMID- 21528876 TI - Macromolecular design of aliphatic polyesters with maintained mechanical properties and a rapid, customized degradation profile. AB - An innovative type of triblock copolymer that maintains and even increases the mechanical properties of poly(l-lactide) (PLLA) and poly(epsilon-caprolactone) (PCL) with a controlled, predictable, and rapid degradation profile has been synthesized. Elastic triblock copolymers were formed from the hydrophobic and crystalline PLLA and PCL with an amorphous and hydrophilic middle block of poly(but-2-ene-1,4-diyl malonate) (PBM). The polymers were subjected to degradation in PBS at 37 degrees C for up to 91 days. Prior to degradation, ductility of the PLLA-PBM-PLLA was approximately 4 times greater than that of the homopolymer of PLLA, whereas the modulus and tensile stress at break were unchanged. A rapid initial hydrolysis in the amorphous PBM middle block changed the microstructure from triblock to diblock with a significant reduction in ductility and molecular weight. The macromolecular structure of the triblock copolymer of PLLA and PBM generates a more flexible and easier material to handle during implant, with the advantage of a customized degradation profile, demonstrating its potential use in future biomedical applications. PMID- 21528878 TI - Anticoagulant surface of 316 L stainless steel modified by surface-initiated atom transfer radical polymerization. AB - Polished 316 L stainless steel (SS) was first treated with air plasma to enhance surface hydrophilicity and was subsequently allowed to react with 2-(4 chlorosulfonylphenyl)ethyltrimethoxysilane to introduce an atom transfer radical polymerization (ATRP) initiator. Accordingly, the surface-initiated atom transfer radical polymerization of polyethylene glycol methacrylate (PEGMA) was carried out on the surface of the modified SS. The grafting progress was monitored by water contact angle measurements, X-ray photoelectron spectroscopy and atomic force microscopy. The polymer thickness as a function different polymerization times was characterized using a step profiler. The anticoagulative properties of the PEGMA modified SS surface were investigated. The results showed enhanced anticoagulative to acid-citrate-dextrose (ACD) blood after grafting PEGMA on the SS surface. PMID- 21528877 TI - Highly conductive boron nanotubes: transport properties, work functions, and structural stabilities. AB - The transport properties, work functions, electronic structure, and structural stability of boron nanotubes with different lattice structures, radii, and chiralities are investigated theoretically. As the atomic structure of boron nanotubes and the related sheets is still under debate, three probable structural classes (nanotubes derived from the alpha-sheet, the buckled triangular sheet, and the distorted hexagonal sheet) are considered. For comparison with recent transport measurements [J. Mater. Chem. 2010, 20, 2197], the intrinsic conductance of ideal nanotubes with large diameters (D ~ 10 nm) is determined. All considered boron nanotubes are highly conductive, irrespective of their lattice structures and chiralities, and they have higher conductivities than carbon nanotubes. Furthermore, the work functions of the three sheets and the corresponding large-diameter nanotubes are determined. It is found that the value of the nanotubes obtained from the alpha-sheet agrees well with the experiment. This indirectly shows that the atomic structure of boron nanotubes is related to the alpha-sheet. The structural stability of nanotubes with diameters > 2 nm approaches that of the corresponding boron sheets, and alpha-sheet nanotubes are the most stable ones. However, for smaller diameters the relative stabilities change significantly, and for diameters < 0.5 nm the most stable structures are zigzag nanotubes of the buckled triangular sheet. For structures related to the distorted hexagonal sheet the most stable nanotube is discovered to have a diameter of 0.39 nm. PMID- 21528879 TI - Microwave-assisted, divergent solution-phase synthesis of 1,3,6-trisubstituted pyrazolo[3,4-d]pyrimidines. AB - A concise and highly divergent synthetic route has been developed to rapidly access 1,3,6-trisubstituted pyrazolopyrimidines. The synthesis features a microwave assisted one-pot N1-alkylation/Suzuki-Miyaura reaction as the key step. The sequence of the synthetic scheme can be varied to selectively modify the N1, C3, or C6 position at a late synthetic stage, thereby providing a highly efficient approach to explore the structure-activity relationships of pyrazolopyrimidine derivatives. The scope of these reactions has also been explored. PMID- 21528880 TI - Synthesis of a drug-like focused library of trisubstituted pyrrolidines using integrated flow chemistry and batch methods. AB - A combination of flow and batch chemistries has been successfully applied to the assembly of a series of trisubstituted drug-like pyrrolidines. This study demonstrates the efficient preparation of a focused library of these pharmaceutically important structures using microreactor technologies, as well as classical parallel synthesis techniques, and thus exemplifies the impact of integrating innovative enabling tools within the drug discovery process. PMID- 21528881 TI - Photoexcited state properties of H2-porphyrin/C60-based rotaxanes as studied by time-resolved electron paramagnetic resonance spectroscopy. AB - Light-driven intramolecular electron transfer (ET) and energy transfer (EnT) processes in two rotaxanes, the first containing two free base porphyrins and C(60) fullerene moieties incorporated around a Cu(I)bisphenanthroline core ((H(2)P)(2)-Cu(I)(phen)(2)-C(60)) and a second lacking the fullerene moiety ((H(2)P)(2)-Cu(I)(phen)(2)), were studied by X-band (9.5 GHz) time-resolved electron paramagnetic resonance (TREPR) spectroscopy. The experiments were performed in frozen toluene and ethanol and different phases of the nematic liquid crystal (E-7). It is demonstrated that the ET and EnT processes in the (H(2)P)(2)-Cu(I)(phen)(2)-C(60) rotaxane in different media result in the formation of the same charge-separated state, namely (H(2)P)(2)(*+) Cu(I)(phen)(2)(*-)-C(60), while photoexcitation of the (H(2)P)(2)-Cu(I)(phen)(2) rotaxane does not induce noticeable transfer processes in these matrices. The results are discussed in terms of the high conformational mobility of the rotaxanes, which enables changes in the molecular topography and resultant modification of the rates and routes of photoinduced processes occurring in these systems. The parameters of the transfer processes are compared with those obtained in our previous study of (ZnP)(2)-Cu(I)(phen)(2)-C(60) and (ZnP)(2) Cu(I)(phen)(2) rotaxanes under the same experimental conditions. PMID- 21528882 TI - Synthesis of the stenine ring system from pyrrole. AB - The skeleton of the stemona alkaloid, stenine, has been synthesized starting from pyrrole, employing an asymmetric organocatalyzed cyclization, Sonogashira coupling, a diastereoselective intramolecular propargylic Barbier reaction, cyclocarbonylation, and diastereoselective alkene reduction. Modulation of the electron-rich nature of the pyrrole nucleus by employing an alpha-trifluoroacetyl group is essential. The alpha-trifluoroacetyl group may be rapidly removed under carefully defined, mild conditions. PMID- 21528883 TI - Real-time monitoring of invertase activity immobilized in nanoporous aluminum oxide. AB - In this work, we demonstrate the activity of enzyme invertase immobilized in the pores of nanoporous anodized 3 MUm thick aluminum oxide (AA). The porous anodic alumina has uniform nanosized pores with an interpore distance of p = 100 nm, with pore diameters on the order of 60-65 nm. The pores trap the enzyme and continuous monitoring of the activity is carried out in a flow cell where the substrate is made to flow and the product is detected. The activity of the immobilized enzyme has been determined for the different concentrations of sucrose and for pH ranging from 3 to 6.5. Maximum activity was found for pH 4.5. Adsorption of the enzyme followed by its interaction with the substrate have been analyzed using confocal laser scanning microscopy (CLSM) and surface plasmon spectroscopy (SPR) and the results obtained show excellent correlation. SPR results show a biphasic kinetics for the adsorption of the enzyme as well as its interaction with the substrate with rates of adsorption for the enzyme at k = 2.9 * 10(5) M(-1) s(-1) and 1.17 * 10(5) M(-1) s(-1). The rate of interaction of the substrate with the invertase is initially rapid with k = 4.49 * 10(5) M(-1) s(-1) followed by a slower rate 1.43 * 10(4) M(-1) s(-1). PMID- 21528884 TI - Monte Carlo simulations of high-pressure phase equilibria of CO2-H2O mixtures. AB - Histogram-reweighting grand canonical Monte Carlo simulations were used to obtain the phase behavior of CO(2)-H(2)O mixtures over a broad temperature and pressure range (50 degrees C <= T <= 350 degrees C, 0 <= P <= 1000 bar). We performed a comprehensive test of several existing water (SPC, TIP4P, TIP4P2005, and exponential-6) and carbon dioxide (EPM2, TraPPE, and exponential-6) models using conventional Lorentz-Berthelot combining rules for the unlike-pair parameters. None of the models we studied reproduce adequately experimental data over the entire temperature and pressure range, but critical assessments were made on the range of T and P where particular model pairs perform better. Away from the critical region (T <= 250 degrees C), the exponential-6 model combination yields the best predictions for the CO(2)-rich phase, whereas the TraPPE/TIP4P2005 model combination provides the most accurate coexistence composition and pressure for the H(2)O-rich phase. Near the critical region (250 degrees C < T <= 350 degrees C), the critical points are not accurately estimated by any of the models studied, but the exponential-6 models are able to qualitatively capture the critical loci and the shape of the phase envelopes. Local improvements can be achieved at specific temperatures by introducing modification factors to the Lorentz-Berthelot combining rules, but the modified combining rule is still not able to achieve global improvements over the entire temperature and pressure range. Our work points to the challenge and importance of improving current atomistic models so as to accurately predict the phase behavior of this important binary mixture. PMID- 21528885 TI - Layered perovskite-like Pb2Fe2O5 structure as a parent matrix for the nucleation and growth of crystallographic shear planes. AB - The Pb(2)Fe(2)O(5) compound with a layered intergrowth structure has been prepared by a solid-state reaction at 700 degrees C. The incommensurate compound crystallizes in a tetragonal system with a = 3.9037(2) A, c = 3.9996(4) A, and q = 0.1186(4)c*, or when treated as a commensurate approximant, a = 3.9047(2) A, c = 36.000(3) A, space group I4/mmm. The crystal structure of Pb(2)Fe(2)O(5) was resolved from transmission electron microscopy data. Atomic coordinates and occupancies of the cation positions were estimated from high-angle annular dark field scanning transmission electron microscopy data. Direct visualization of the positions of the oxygen atoms was possible using annular bright-field scanning transmission electron microscopy. The structure can be represented as an intergrowth of perovskite blocks and partially disordered blocks with a structure similar to that of the Bi(2)O(2) blocks in Aurivillius-type phases. The A-cation positions at the border of the perovskite block and the cation positions in the Aurivillius-type blocks are jointly occupied by Pb(2+) and Fe(3+) cations, resulting in a layer sequence along the c axis: -PbO-FeO(2)-PbO-FeO(2) Pb(7/8)Fe(1/8)-O(1-x)-Fe(5/8)Pb(3/8)-O(2)-Fe(5/8)Pb(3/8)-. Upon heating, the layered Pb(2)Fe(2)O(5) structure transforms into an anion-deficient perovskite modulated by periodically spaced crystallographic shear (CS) planes. Considering the layered Pb(2)Fe(2)O(5) structure as a parent matrix for the nucleation and growth of CS planes allows an explanation of the specific microstructure observed for the CS structures in the Pb-Fe-O system. PMID- 21528886 TI - Clusters of proteins in biomembranes: insights into the roles of interaction potential shapes and of protein diversity. AB - It has recently been proposed that proteins embedded in lipidic biomembranes can spontaneously self-organize into stable small clusters, or membrane nanodomains, due to the competition between short-range attractive and longer-range repulsive forces between proteins, specific to these systems. In this paper, we carry on our investigation, by Monte Carlo simulations, of different aspects of cluster phases of proteins in biomembranes. First, we compare different long-range potentials (including notably three-body terms) to demonstrate that the existence of cluster phases should be quite generic. Furthermore, a real membrane contains hundreds of different protein species that are far from being randomly distributed in these nanodomains. We take this protein diversity into account by modulating protein-protein interaction potentials both at short and longer range. We confirm theoretical predictions in terms of biological cluster specialization by deciphering how clusters recruit only a few protein species. In this respect, we highlight that cluster phases can turn out to be an advantage at the biological level, for example by enhancing the cell response to external stimuli. PMID- 21528887 TI - Cluster-driven dynamical arrest in concentrated lysozyme solutions. AB - We present a detailed experimental and numerical study of the structural and dynamical properties of salt-free lysozyme solutions. In particular, by combining small-angle X-ray scattering (SAXS) data with neutron spin echo (NSE) and rheology experiments, we are able to identify that an arrest transition takes place at intermediate densities, driven by the slowing down of the cluster motion. Using an effective pair potential among proteins, based on the combination of short-range attraction and long-range repulsion, we account remarkably well for the peculiar volume fraction dependence of the effective structure factor measured by SAXS. We show that a transition from a monomer to a cluster-dominated fluid happens at volume fractions larger than phi ? 0.05 where the close agreement between NSE measurements and Brownian dynamics simulations confirms the transient nature of the clusters. Clusters even stay transient above the geometric percolation found in simulation at phi > 0.15, though NSE reveals a cluster lifetime that becomes increasingly large and indicates a divergence of the diffusivity at phi ? 0.26. Macroscopic measurements of the viscosity confirm this transition where the long-lived-nature of the clusters is at the origin of the simultaneous dynamical arrest at all length scales. PMID- 21528888 TI - Global trends and diversity in pentachlorophenol levels in the environment and in humans: a meta-analysis. AB - Pentachlorophenol (PCP) was banned or restricted in many countries worldwide because of its adverse effects on the ecological environment and humans. However, the endocrine disrupting effects caused by low environmental PCP exposure levels has warranted more analysis. We reviewed 80 studies conducted in 21 countries and published between 1967 and 2010, using meta-regression analysis to examine the time trends and regional differences in PCP levels. The results suggested that in indoor air, bodies of water, freshwater sediments in western countries, invertebrates and freshwater vertebrates, PCP levels had declined over time, with half-lives ranging from 2.0 years to 11.1 years. However, in marine sediments/vertebrates and Chinese surface water/sediments, PCP levels increased over time. PCP levels in human blood and urine had decreased since the 1970s, with population half-lives of 3.6 years and 5.7 years, respectively. The intervals for global population blood and urine reference values decreased to 1.1 6.3 MUg/L (2002-2008) and 2.5-7 MUg/L (1995-2003), respectively. The possible thyroid disrupting effects and other health risks correlated with low environmental PCP exposure should be concerning. This study can help to ascertain the effects of the banning/restriction policy, providing data for cost-benefit analysis in policy-making and further control of health risks caused by low environmental exposure to PCP. PMID- 21528890 TI - Reduction of charge recombination by an amorphous titanium oxide interlayer in layered graphene/quantum dots photochemical cells. AB - The effect of an amorphous TiO(x) interlayer on layered graphene/quantum dots photochemical cells has been investigated. The addition of the TiO(x) interlayer eliminates the decay of photocurrent in the initial seconds after light illumination and significantly increases the slope of the steady-state photocurrent versus the light intensity. The open-circuit voltage decay measurements further illustrate a longer electron lifetime when an amorphous TiO(x) interlayer is applied. Consequently, the photocurrent and photovoltage of the photovoltaic cell with a TiO(x) interlayer are greatly increased. This work demonstrates that the graphene/amorphous TiO(x) composite structure effectively inhibits charge recombination while enhancing charge transfer, providing a promising scaffold for quantum dots and dye-sensitized photovoltaic cells. PMID- 21528891 TI - Rational design of new class of BH3-mimetics as inhibitors of the Bcl-xL protein. AB - The Bcl-2 family of proteins plays an important role in the intrinsic pathway of cell apoptosis. Overexpression of pro-survival members of this family of proteins is often associated with the development of many types of cancer and confers resistance against conventional therapeutic treatments. Accordingly, antagonism of its protective function has emerged as an encouraging anticancer strategy. In the present work, we use a pharmacophore for describing interaction between the BH3 domain of different pro-apoptotic members and the pro-survival protein Bcl x(L) in order to identify new lead compounds. In the strategy followed in the present work, the pharmacophore was derived from molecular dynamics studies of different Bcl-x(L)/BH3 complexes. This pharmacophore was later used as query for 3D database screening. Hits obtained from the search were computationally assessed, and a subset proposed for in vitro testing. Two of the 15 compounds assayed were found able to disrupt the Bcl-x(L)/Bak(BH3) complex with IC(50) values in the lower micromolar range. Finally, docking studies were performed to explore the binding mode of these compounds to Bcl-x(L) for further modifications. PMID- 21528889 TI - Gold nanocages: from synthesis to theranostic applications. AB - Gold nanostructures have garnered considerable attention in recent years for their potential to facilitate both the diagnosis and treatment of cancer through their advantageous chemical and physical properties. The key feature of Au nanostructures for enabling this diverse array of biomedical applications is their attractive optical properties, specifically the scattering and absorption of light at resonant wavelengths due to the excitation of plasmon oscillations. This phenomenon is commonly known as localized surface plasmon resonance (LSPR) and is the source of the ruby red color of conventional Au colloids. The resonant wavelength depends on the size, shape, and geometry of the nanostructures, providing a set of knobs to manipulate the optical properties as needed. For in vivo applications, especially when optical excitation or transduction is involved, the LSPR peaks of the Au nanostructures have to be tuned to the transparent window of soft tissues in the near-infrared (NIR) region (from 700 to 900 nm) to maximize the penetration depth. Gold nanocages represent one class of nanostructures with tunable LSPR peaks in the NIR region. These versatile nanostructures, characterized by hollow interiors and ultrathin, porous walls, can be prepared in relatively large quantities using a remarkably simple procedure based on the galvanic replacement between Ag nanocubes and aqueous chloroauric acid. The LSPR peaks of Au nanocages can be readily and precisely tuned to any wavelength in the NIR region by controlling their size, wall thickness, or both. Other significant features of Au nanocages that make them particularly intriguing materials for biomedical applications include their compact sizes, large absorption cross sections (almost five orders of magnitude greater than those of conventional organic dyes), and their bio-inertness, as well as a robust and straightforward procedure for surface modification based on Au-thiolate chemistry. In this Account, we present some of the most recent advances in the use of Au nanocages for a broad range of theranostic applications. First, we describe their use as tracers for tracking by multiphoton luminescence. Gold nanocages can also serve as contrast agents for photoacoustic (PA) and mutimodal (PA/fluorescence) imaging. In addition, these nanostructures can be used as photothermal agents for the selective destruction of cancerous or diseased tissue. Finally, Au nanocages can serve as drug delivery vehicles for controlled and localized release in response to external stimuli such as NIR radiation or high-intensity focused ultrasound (HIFU). PMID- 21528892 TI - Top-gated graphene field-effect transistors with high normalized transconductance and designable dirac point voltage. AB - High-performance graphene field-effect transistors (G-FETs) are fabricated with carrier mobility of up to 5400 cm(2)/V.s and top-gate efficiency of up to 120 (relative to that of back gate with 285 nm SiO(2)) simultaneously through growing high-quality Y(2)O(3) gate oxide at high oxidizing temperature. The transconductance normalized by dimension and drain voltage is found to reach 7900 MUF/V.s, which is among the largest of the published graphene FETs. In an as fabricated graphene FET with a gate length of 310 nm, a peak transconductance of 0.69 mS/MUm is realized, but further improvement is seriously hindered by large series resistance. Benefiting from highly efficient gate control over the graphene channel, the Dirac point voltage of the graphene FETs is shown to be designable via simply selecting a gate metal with an appropriate work function. It is demonstrated that the Dirac point voltage of the graphene FETs can be adjusted from negative to positive, respectively, via changing the gate material from Ti to Pd. PMID- 21528893 TI - Synthesis of silver nanorods by low energy excitation of spherical plasmonic seeds. AB - Plasmon excitation of Ag seed particles with 600-750 nm light in the presence of Ag(+) and trisodium citrate was used to synthesize penta-twinned nanorods. Importantly, the excitation wavelength can be used to control the reaction rate and, consequently, the aspect ratio of the nanorods. When the excitation wavelength is red-shifted from the surface plasmon resonance of the spherical seed particles, the rate of Ag(+) reduction becomes slower and more kinetically controlled. Such conditions favor the deposition of silver onto the tips of the growing nanorods as compared to their sides, resulting in the generation of higher aspect ratio rods. However, control experiments reveal that there is only a range of low energy excitation wavelengths (between 600 and 750 nm) that yields monodisperse nanorods. This study further highlights the utility of using wavelength to control the size and shape of growing nanoparticles using plasmon mediated methods. PMID- 21528894 TI - Softened elastic response and unzipping in chemical vapor deposition graphene membranes. AB - We use atomic force microscopy to image grain boundaries and ripples in graphene membranes obtained by chemical vapor deposition. Nanoindentation measurements reveal that out-of-plane ripples effectively soften graphene's in-plane stiffness. Furthermore, grain boundaries significantly decrease the breaking strength of these membranes. Molecular dynamics simulations reveal that grain boundaries are especially weakening when subnanometer voids are present in the lattice. Finally, we demonstrate that two graphene membranes brought together form membranes with higher resistance to breaking. PMID- 21528895 TI - Improved administrative system to ensure China's nuclear security. PMID- 21528896 TI - Solvent assisted inlet ionization: an ultrasensitive new liquid introduction ionization method for mass spectrometry. AB - A new inlet ionization method requiring no voltage or laser, and using water, methanol, or water/organic solvent mixtures, is shown to produce mass spectra similar to those obtained with electrospray ionization (ESI) for small molecules, peptides, and proteins, at least as large as carbonic anhydrase, with sensitivity that surpasses ESI. With the use of wide mass range acquisitions at 100,000 mass resolution on an Orbitrap Exactive, detection limits below parts per trillion are obtained for small molecules such as arginine, ciprofloxacin, and acetaminophen. Low attomoles of bovine insulin consumed produced a multiply charged mass spectrum. Ions are generated, even using pure water as solvent, within the heated inlet tube linking atmospheric pressure with the first vacuum stage of the Orbitrap Exactive. The extremely high sensitivity observed at this early stage of solvent assisted inlet ionization (SAII) development suggests that inlet ionization may surpass nanoelectrospray in sensitivity but without the need for extremely low solvent flows. PMID- 21528897 TI - Edge effects determine the direction of bilayer bending. AB - We elucidate the reason for preferential bending along the long edge in thin rectangular bilayers in which one of the layers is isotropically strained. While this preference has been observed previously, the physical basis for this preference has not been understood. We find that the bending direction is determined by the existence of doubly curved regions at the curled edges, which lower the energy. This energy difference between "spiral" and "cigar" shapes increases with aspect ratio. PMID- 21528898 TI - Mass transport in a micro flow-through vial of a junction-at-the-tip capillary electrophoresis-mass spectrometry interface. AB - When coupling capillary electrophoresis with postcolumn detection methods, such as mass spectrometry, the presence of postcolumn band broadening must be considered. The band broadening effects introduced by junction-at-the-tip CE-MS interfaces using a postcolumn micro flow-through vial are investigated by studying the hydrodynamic flow patterns and mass transport process inside the micro vial at the end of the CE separation capillary. Simulation results obtained by solving the Navier-Stokes and mass balance equations provide insights into the velocity field and concentration distribution of the analytes in the micro vial and demonstrate that, with a low flow rate of chemical modifier solution, the laminar flow streams confine the analyte molecules to the central part of the micro vial and thus maintain major features of the peak shapes. Peaks detected by UV and MS under similar experimental conditions were compared to verify the numerical prediction that the main features of the UV peak can be retained in the MS peak. Experiments also show that band broadening can be minimized when an appropriate chemical modifier flow rate is selected. PMID- 21528899 TI - Effects of crystal phase mixing on the electrical properties of InAs nanowires. AB - We report a systematic study of the relationship between crystal quality and electrical properties of InAs nanowires grown by MOVPE and MBE, with crystal structure varying from wurtzite to zinc blende. We find that mixtures of these phases can exhibit up to 2 orders of magnitude higher resistivity than single phase nanowires, with a temperature-activated transport mechanism. However, it is also found that defects in the form of stacking faults and twin planes do not significantly affect the resistivity. These findings are important for nanowire based devices, where uncontrolled formation of particular polytype mixtures may lead to unacceptable device variability. PMID- 21528900 TI - Isobaric peptide termini labeling utilizing site-specific N-terminal succinylation. AB - Recently, we introduced a novel approach for protein quantification based on isobaric peptide termini labeling (IPTL). In IPTL, both peptide termini are dervatized in two separate chemical reactions with complementary isotopically labeled reagents to generate isobaric peptide pairs. Here, we describe a novel procedure for the two chemical reactions to enable a cost-effective and rapid method. We established a selective N-terminal peptide modification reaction using succinic anhydride. Dimethylation was used as second chemical reaction to derivatize lysine residues. Both reactions can be performed within 15 min in one pot, and micropurification of the peptides between the two reactions was not necessary. For data analysis, we developed the force-find algorithm in IsobariQ which searches for corresponding peaks to build up peak pairs in tandem mass spectrometry (MS/MS) spectra where Mascot could not identify opposite sequences. Utilizing force-find, the number of quantified proteins was improved by more than 50% in comparison to the standard data analysis in IsobariQ. This was applied to compare the proteome of HeLa cells incubated with S-trityl-L-cysteine (STLC) to induce mitotic arrest and apoptosis. More than 50 proteins were found to be quantitatively changed, and most of them were previously reported in other proteome analyses of apoptotic cells. Furthermore, we showed that the two complementary isotopic labels coelute during liquid chromatography (LC) separation and that the linearity of relative IPTL quantification is not affected by a complex protein background. Combining the optimized reactions for IPTL with the open source data analysis software IsobariQ including force-find, we present a straightforward and rapid approach for quantitative proteomics. PMID- 21528901 TI - Effect of acid deposition on quantity and quality of dissolved organic matter in soil-water. AB - The aim of this study was to explore how acid deposition may affect the concentration and quality of dissolved organic matter (DOM) in soil-water. This was done by a small-scale acidification experiment during two years where 0.5 * 0.5 m(2) plots were artificially irrigated with water with different sulfuric acid content, and soil-water was sampled using zero-tension lysimeters under the O-horizon. The DOM was characterized using absorbance, fluorescence, and size exclusion chromatography analyses. Our results showed lower mobility of DOM in the high acid treatment. At the same time, there was a significant change in the DOM quality. Soil-water in the high acid treatment exhibited DOM that was less colored, less hydrophobic, less aromatic, and of lower molecular weight, compared to the low acid treatment. This supports the hypothesis that reduction in sulfur deposition is an important driver behind the ongoing brownification of surface waters in many regions. PMID- 21528902 TI - Effect of set potential on hexavalent chromium reduction and electricity generation from biocathode microbial fuel cells. AB - Setting a biocathode potential at -300 mV improved the subsequent performance of an MFC for Cr(VI) reduction compared to a control (no set potential). With this set potential, the startup time was reduced to 19 days, the reduction of Cr(VI) was improved to 19.7 mg/L d, and the maximum power density was increased to 6.4 W/m(3) compared to the control (26 days, 14.0 mg/L d and 4.1 W/m(3)). Set potentials of -150 mV and -300 mV also improved system performance and led to similarly higher utilization of metabolic energy gained (PMEG) than set potentials of +200 mV and -450 mV. We observed putative pili at -150 and -300 mV potentials, and aggregated precipitates on bacterial surfaces in both poised and nonpoised controls. These tests show that there are optimal potentials that can be set for developing a Cr(VI) biocathode. PMID- 21528903 TI - Analysis of a homologous series of perfluorocarboxylates from American Red Cross adult blood donors, 2000-2001 and 2006. AB - The purpose of this study was to determine the concentration trends of a nine target-analyte homologous series of perfluorocarboxylates from six American Red Cross adult blood donor centers. A total of 645 serum and 600 plasma samples were obtained in 2000-2001 and 2006, respectively, with samples stratified for each 10 year (20-69) age- and sex-group per each location. Samples were extracted by protein precipitation and quantified by using tandem mass spectrometry. The nine perfluorocarboxylates were perfluorobutanoate (PFBA, C(3)F(7)CO(2)(-)), perfluoropentanoate (PFPeA, C(4)F(9)CO(2)(-)), perfluorohexanoate (PFHxA, C(5)F(11)CO(2)(-)), perfluoroheptanoate (PFHpA, C(6)F(13)CO(2)(-)), perfluorooctanoate (PFOA, C(7)F(15)CO(2)(-)), perfluorononanoate (PFNA, C(8)F(17)CO(2)(-)), perfluorodecanoate (PFDA, C(9)F(19)CO(2)(-)), perfluoroundecanoate (PFUnA,C(10)F(21)CO(2)(-)), and perfluorododecanoate (PFDoA, C(11)F(23)CO(2)(-)). The majority of measurements were less than the lower limit of quantitation for PFPeA, PFHxA, and PFDoA. For the remaining targeted analytes, the geometric mean serum and plasma concentrations (ng/mL) for 2000-2001 and 2006 were, respectively, as follows: PFBA 2.61 vs 0.33, PFHpA 0.13 vs 0.09, PFOA 4.70 vs 3.44, PFNA 0.57 vs 0.97, PFDA 0.16 vs 0.34, and PFUnA 0.10 vs 0.18. Estimates of the 95th percent tolerance limits (ng/mL) were as follows: PFBA 5.3 vs 1.4, PFHpA 0.4 vs 0.4, PFOA 12.3 vs 7.7, PFNA 1.4 vs 2.2, PFDA 0.4 vs 0.8, and PFUnA 0.3 vs 0.5. Important observations were the decline in PFBA and increase in PFNA, PFDA, and PFUnA concentrations between 2000-2001 and 2006. The longer chain length perfluorocarboxylates were also highly correlated with each other. PMID- 21528904 TI - Ni-catalyzed ketene cycloaddition: a system that resists the formation of decarbonylation side products. AB - Ni-phosphine complexes were used as catalysts for the cycloaddition of various ketenes and diynes. In general, 2,4-cyclohexadienones were formed instead of products arising from decarbonylation of the ketenes. PMID- 21528905 TI - The multiple multicomponent approach to natural product mimics: tubugis, N substituted anticancer peptides with picomolar activity. AB - The synthesis of a new generation of highly cytotoxic tubulysin analogues (i.e., tubugis) is described. In the key step, the rare, unstable, and synthetically difficult to introduce tertiary amide-N,O-acetal moiety required for high potency in natural tubulysins is replaced by a dipeptoid element formed in an Ugi four component reaction. Two of the four components required are themselves produced by other multicomponent reactions (MCRs). Thus, the tubugis represent the first examples of the synthesis of natural-product-inspired compounds using three intertwined isonitrile MCRs. PMID- 21528906 TI - NONOates--polyethylenimine hydrogel for controlled nitric oxide release and cell proliferation modulation. AB - In recent years, numerous research activities have been devoted to the controlled release of nitric oxide (NO) due to its potential as a restenosis inhibitor which inhibits the proliferation of vascular smooth muscle cells, the apoptosis of vascular endothelial cells, and aggregation of platelets. This work has demonstrated the development of a novel NO-conjugated gel system comprising of thermosensitive Pluronic F127, branched polyethylenimine (BPEI), and diazeniumdiolates (NONOates). Synthesis of conjugated Pluronic-BPEI-NONOates involved coupling of activated F127 to BPEI followed by the installation of NONOates at the secondary amine sites of branched PEI backbone under high pressure. NO-conjugated gel system, F127-BPEI-NONOates, reduced the initial burst of NO release and prolonged NO release. Furthermore, F127-BPEI-NONOates polymer coated on cell culture dish displayed much higher increase of endothelial cell proliferation and reduction of smooth muscle cell proliferation than that exhibited by non-NO releasing control. Such an NO-releasing device can operate locally and has a great potential in several biomedical applications due to high biocompatibility imparted by the conjugated F127. PMID- 21528907 TI - Detection of a cyclic perfluorinated acid, perfluoroethylcyclohexane sulfonate, in the Great Lakes of North America. AB - Perfluoroethylcyclohexanesulfonate (PFECHS) is a cyclic perfluorinated acid (PFA) mainly used as an erosion inhibitor in aircraft hydraulic fluids. It is expected to be as recalcitrant to environmental degradation as aliphatic PFAs including perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS). For the first time, PFECHS is reported in top predator fish (=10-fold selectivity for human P2Y(4) over P2Y(2) and P2Y(6) receptors (EC(50) values 23, 62, and 73 nM, respectively). delta-3-Chlorophenyl phosphoester 21 of Up(4) activated P2Y(2) but not P2Y(4) receptor. Selected nucleotides tested for chemical and enzymatic stability were much more stable than UTP. Agonist docking at CXCR4-based P2Y(2) and P2Y(4) receptor models indicated greater steric tolerance of N(4)-phenylpropoxy group at P2Y(4). Thus, distal structural changes modulate potency, selectivity, and stability of extended uridine tetraphosphate derivatives, and we report the first P2Y(4) receptor-selective agonists. PMID- 21528912 TI - Membrane topology of the colicin E1 channel using genetically encoded fluorescence. AB - The membrane topology of the colicin E1 channel domain was studied by fluorescence resonance energy transfer (FRET). The FRET involved a genetically encoded fluorescent amino acid (coumarin) as the donor and a selectively labeled cysteine residue tethered with DABMI (4-(dimethylamino)phenylazophenyl-4' maleimide) as the FRET acceptor. The fluorescent coumarin residue was incorporated into the protein via an orthogonal tRNA/aminoacyl-tRNA synthetase pair that allowed selective incorporation into any site within the colicin channel domain. Each variant harbored a stop (TAG) mutation for coumarin incorporation and a cysteine (TGT) mutation for DABMI attachment. Six interhelical distances within helices 1-6 were determined using FRET analysis for both the soluble and membrane-bound states. The FRET data showed large changes in the interhelical distances among helices 3-6 upon membrane association providing new insight into the membrane-bound structure of the channel domain. In general, the coumarin-DABMI FRET interhelical efficiencies decreased upon membrane binding, building upon the umbrella model for the colicin channel. A tentative model for the closed state of the channel domain was developed based on current and previously published FRET data. The model suggests circular arrangement of helices 1-7 in a clockwise direction from the extracellular side and membrane interfacial association of helices 1, 6, 7, and 10 around the central transmembrane hairpin formed by helices 8 and 9. PMID- 21528913 TI - Forensic science. PMID- 21528914 TI - Identification of presenilin 1-selective gamma-secretase inhibitors with reconstituted gamma-secretase complexes. AB - Accumulation of the beta-amyloid (Abeta) peptides is one of the major pathologic hallmarks in the brains of Alzheimer's disease (AD) patients. Abeta is generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) catalyzed by beta- and gamma-secretases. Inhibition of Abeta production by gamma secretase inhibitors (GSIs) is thus being pursued as a target for treatment of AD. In addition to processing APP, gamma-secretase also catalyzes proteolytic cleavage of other transmembrane substrates, with the best characterized one being the cell surface receptor Notch. GSIs reduce Abeta production in animals and humans but also cause significant side effects because of the inhibition of Notch processing. The development of GSIs that reduce Abeta production and have less Notch-mediated side effect liability is therefore an important goal. gamma Secretase is a large membrane protein complex with four components, two of which have multiple isoforms: presenilin (PS1 or PS2), aph-1 (aph-1a or aph-1b), nicastrin, and pen-2. Here we describe the reconstitution of four gamma-secretase complexes in Sf9 cells containing PS1--aph-1a, PS1--aph-1b, PS2--aph-1a, and PS2- aph-1b complexes. While PS1--aph-1a, PS1--aph-1b, and PS2--aph-1a complexes displayed robust gamma-secretase activity, the reconstituted PS2--aph-1b complex was devoid of detectable gamma-secretase activity. gamma-Secretase complexes containing PS1 produced a higher proportion of the toxic species Abeta42 than gamma-secretase complexes containing PS2. Using the reconstitution system, we identified MRK-560 and SCH 1500022 as highly selective inhibitors of PS1 gamma secretase activity. These findings may provide important insights into developing a new generation of gamma-secretase inhibitors with improved side effect profiles. PMID- 21528915 TI - Sodium nitrite catalyzed aerobic oxidative deoximation under mild conditions. AB - A mild, simple process for the effective deoximation of a wide range of ketoximes and aldoximes has been developed, which utilizes available NaNO(2) as the catalyst and molecular oxygen as the green oxidant. Notably Amberlyst-15, which acts as the initiator of NaNO(2), can be reused without regeneration. This environmentally benign protocol could provide a valuable synthetic method for practical applications. PMID- 21528916 TI - Glutaraldehyde-activated chitosan matrix for immobilization of a novel cysteine protease, procerain B. AB - Proteases have several applications in the food industry. We report the immobilization of procerain B, a novel cysteine protease, on glutaraldehyde activated chitosan beads through covalent attachment. Glutaraldehyde not only serves as a cross-linking agent but also links the procerain B on the surface of bead through primary amine group (either lysine side chain or N-terminal) by Schiff base linkage. Immobilized procerain B was characterized for optimum functional range and stability with respect to pH and temperature. The chitosan immobilized procerain B has broad pH and thermal optima. The effects of substrate concentration and reusability of immobilized beads were also studied. It showed nearly 50% activity until the 10th use. PMID- 21528917 TI - Comparison of the volatile profile and sensory analysis of 'Golden Reinders' apples after the application of a cold air period after ultralow oxygen (ULO) storage. AB - All efforts to improve fruit quality are rewarded when consumers are satisfied after tasting the fruit. Apples are often stored under controlled atmosphere conditions to preserve them over time, but this frequently results in a loss of flavor. The aim of this work, which was based on two seasons, was to evaluate the influence of a period of short-term air storage (periods of 2 and 4 weeks) after removal from ultralow oxygen (ULO) storage (1 kPa of O(2)/1 kPa of CO(2)) with respect to increases in volatile compound emissions and the effect on standard and sensory quality in 'Golden Reinders' apples. The results showed that emissions of 26 volatile compounds increased as a result of ULO + 2 weeks or ULO + 4 weeks of storage. However, the results of tastings involving a panel of consumers and trained experts revealed that this increase was not matched by corresponding increases in either the degree of consumer preference or flavor attributes. PMID- 21528918 TI - Volatile analysis of ground almonds contaminated with naturally occurring fungi. AB - Aflatoxigenic aspergilli inflict major economic damage to the tree nut industry of California, with the highest negative impact to almonds. Aspergilli and fungi in general are known to emit volatiles in varying quantity and composition dependent upon their growth media. The goal of the study was to determine the volatile emission of whole and blanched almonds that had been picked out and labeled as inedible by processors. The aflatoxin content and number of colony forming units of each sample were also determined. A total of 23 compounds were consistently detected and identified. Several volatiles from the blanched almonds demonstrated significant increases when compared to the emissions of whole almonds. Several of these volatiles are considered fatty acid decomposition products and included hexanal, heptanal, octanal, nonanal, 3-octen-2-one, tetramethylpyrazine, and decanal. The almond samples investigated were characteristic of a typical postharvest environment and illustrative of potential contamination within a stockpile or transport container. Volatiles indicative of fatty acid decomposition were predominant in the samples that underwent some form of blanching. The emission amounts of hexanal, heptanal, octanal, and hexanoic acid increased 3-fold in samples contaminated with aflatoxin; however, due to variability between samples they could not be considered as indicator volatiles for aflatoxin content. The emission profile of volatiles from almond kernels contaminated with naturally occurring aspergilli and associated fungi is heretofore unreported. PMID- 21528919 TI - Dianthra[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DATT): synthesis, characterization, and FET characteristics of new pi-extended heteroarene with eight fused aromatic rings. AB - A novel highly pi-extended heteroarene with eight fused aromatic rings, dianthra[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DATT), was selectively synthesized via a newly developed synthetic strategy, fully characterized by means of single crystal X-ray structural analysis, and examined as an organic semiconductor in thin film transistors. Even with its highly extended acene-like pi-system, DATT is a fairly air-stable compound with IP of 5.1 eV. Single crystal X-ray structural analysis revealed its planar molecular structure and the lamella-like layered structure with typical herringbone packing. Theoretical calculations of the solid state electronic structure based on the bulk single crystal structure suggest that DATT affords almost comparable intermolecular orbital couplings between HOMOs (t(HOMO)) with those of dinaphtho[2,3-b:2',3'-f]thieno[3,2 b]thiophene (DNTT), implying its good potential as an organic semiconductor for organic field-effect transistors. In fact, field-effect mobilities as high as 3.0 cm(2) V(-1) s(-1) were achieved with vapor-processed DATT-based devices, which is comparable with that of DNTT-based devices. The molecular ordering of DATT in the thin film state, however, turned out to be not completely uniform; as elucidated by in-plane and out-of-plane XRD measurements, the face-on molecular orientation was contaminated in the edge-on orientation, the former of which is not optimal for efficient carrier transport and thus could limit the mobility. PMID- 21528920 TI - Application of sequential Cu(I)/Pd(0)-catalysis to solution-phase parallel synthesis of combinatorial libraries of dihydroindeno[1,2-c]isoquinolines. AB - Parallel solution-phase synthesis of combinatorial libraries of dihydroindenoisoquinolines employing a sequential Cu(I)/Pd(0)-catalyzed multicomponent coupling and annulation protocol was realized. The scope and limitations of the protocol with respect to the substitution pattern in the aryl ring of the indene core, as well as the N-substituent have been defined, revealing that the methodology is compatible with a wide-range of aliphatic linear, branched, and ester functionalized N-substituents. Unexpectedly, the formation of regioisomers featuring a 1,2,3-contiguous substitution pattern in the aromatic ring of the indene core was observed. Three distinct combinatorial libraries with a total of 111 of members were synthesized, and 80 highly substituted dihydroindenoisoquinolines structurally related to known medicinal agents including some consisting of mixtures of two regioisomers were made available for biological activity testing. PMID- 21528921 TI - Gradients with depth in electrospun fibrous scaffolds for directed cell behavior. AB - A major obstacle in creating viable tissue-engineered constructs using electrospinning is the lack of complete cellularization and vascularization due to the limited porosity in these densely packed fibrous scaffolds. One potential approach to circumvent this issue is the use of various gradients of chemical and biophysical cues to drive the infiltration of cells into these structures. Toward this goal, this study focused on creating durotactic (mechanical) and haptotactic (adhesive) gradients through the thickness of electrospun hyaluronic acid (HA) scaffolds using a unique, yet simple, modification of common electrospinning protocols. Specifically, both mechanical (via cross-linking: ranging from 27-100% modified methacrylated HA, MeHA) and adhesive (via inclusion of the adhesive peptide RGD: 0-3 mM RGD) gradients were each fabricated by mixing two solutions (one ramping up, one ramping down) prior to electrospinning and fiber collection. Gradient formation was verified by fluorescence microscopy, FTIR, atomic force microscopy, and cellular morphology assessment of scaffolds at different points of collection (i.e., with scaffold thickness). To test further the functionality of gradient scaffolds, chick aortic arch explants were cultured on adhesive gradient scaffolds for 7 days, and low RGD-high RGD gradient scaffolds showed significantly greater cell infiltration compared with high RGD-low RGD gradients and uniform high RGD or uniform low RGD control scaffolds. In addition to enhanced infiltration, this approach could be used to fabricate graded tissue structures, such as those that occur at interfaces. PMID- 21528922 TI - Stabilizing effect of propionic acid derivative of anthraquinone--polyamine conjugate incorporated into alpha-beta chimeric oligonucleotides on the alternate stranded triple helix. AB - Two types of anthraquinone conjugates were synthesized as non-nucleosidic oligonucleotide components. These include an anthraquinone derivative conjugated with 2,2-bis(hydroxymethyl)propionic acid and an anthraquinone--polyamine derivative conjugated with 2,2-bis(hydroxymethyl)propionic acid. The conjugates were successfully incorporated into the "linking-region" of the alpha-beta chimeric oligonucleotides via phosphoramidite method as non-nucleosidic backbone units. The resultant novel alpha-beta chimeric oligonucleotides possessed two diastereomers that were generated by the introduction of the anthraquinone conjugate with a stereogenic carbon atom. The isomers were successfully separated by a reversed-phase HPLC. UV-melting experiments revealed that both stereoisomers formed a substantially stable alternate-strand triple helix, irrespective of the stereochemistry of the incorporated non-nucleosidic backbone unit. However, the enhancing effect on thermal stability depended on the length of the alkyl linker connecting anthraquinone moiety and the propionic acid moiety. The sequence discrimination ability of the chimeric oligonucleotides toward mismatch target duplex was also examined. The T(m) values of the triplexes containing the mismatch target were substantially lower than the T(m) values of those containing the full-match target. The thermodynamic parameters (DeltaH degrees , DeltaS degrees , and DeltaG degrees ) required for the dissociation of the triplexes into the third strand and target duplex were also measured. PMID- 21528923 TI - Enhanced intracellular delivery and chemotherapy for glioma rats by transferrin conjugated biodegradable polymersomes loaded with doxorubicin. AB - A brain drug delivery system for glioma chemotherapy based on transferrin conjugated biodegradable polymersomes, Tf-PO-DOX, was made and evaluated with doxorubicin (DOX) as a model drug. Biodegradable polymersomes (PO) loaded with doxorubicin (DOX) were prepared by the nanoprecipitation method (PO-DOX) and then conjugated with transferrin (Tf) to yield Tf-PO-DOX with an average diameter of 107 nm and surface Tf molecule number per polymersome of approximately 35. Compared with PO-DOX and free DOX, Tf-PO-DOX demonstrated the strongest cytotoxicity against C6 glioma cells and the greatest intracellular delivery. It was shown in pharmacokinetic and brain distribution experiments that Tf-PO significantly enhanced brain delivery of DOX, especially the delivery of DOX into brain tumor cells. Pharmacodynamics results revealed a significant reduction of tumor volume and a significant increase of median survival time in the group of Tf-PO-DOX compared with those in saline control animals, animals treated with PO DOX, and free DOX solution. By terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling, Tf-PO-DOX could extensively make tumor cell apoptosis. These results indicated that Tf-PO-DOX could significantly enhance the intracellular delivery of DOX in glioma and the chemotherapeutic effect of DOX for glioma rats. PMID- 21528924 TI - Synthesis of PAMAM dendrimer derivatives with enhanced buffering capacity and remarkable gene transfection efficiency. AB - In this study, we introduced histidine residues into l-arginine grafted PAMAM G4 dendrimers to enhance proton buffering capacity and evaluated the physicochemical characteristics and transfection efficacies in vitro. The results showed that the synthesized PAMAM G4 derivatives effectively delivered pDNA inside cells and the transfection level improved considerably as the number of histidine residues increased. Grafting histidine residues into the established polymer vector PAMAM G4-arginine improved their proton buffering capacity. The cytotoxicity of PAMAM G4 derivatives was tested and it was confirmed that they displayed relatively lower cytotoxicity compared to PEI25KD in various cell lines. Also, confocal microscopy results revealed that PAMAM G4 derivatives effectively delivered pDNA into cells, particularly into the nucleus. These PAMAM dendrimer derivatives conjugated with histidines and arginines may provide a promising polymeric gene carrier system. PMID- 21528925 TI - Simultaneous electrokinetic and hydrodynamic injection for high sensitivity bacteria analysis in capillary electrophoresis. AB - A repeatable preconcentration electrophoretic methodology for the analysis of bacteria was developed. This method is based on an isotachophoretic mode coupled with a simultaneous hydrodynamic-electrokinetic injection in conditions of field amplified sample injection. This electrophoretic method allows the quantification of Enterobacter cloacae (studied as a model of Gram negative bacteria) with a limit of detection of 2 * 10(4) cells/mL. With the optimized conditions, a preconcentration factor of about 500-fold was obtained as compared to a standard hydrodynamic injection. The RSD (n = 5) on the migration time and on the peak area were 3% and 5%, respectively. This capillary electrophoretic methodology has been applied for the quantification of microbes in natural water (river and natural spring waters). Filtration of the sample prior to injection was required to remove ions present in the water and to keep the field-amplified sample injection condition at the injection. Filtrated bacteria were then recovered in terminating electrolyte diluted 10 times with water. Good agreements were obtained between cellular ATP measurements and the proposed CE methodology for the quantification of bacteria in waters. PMID- 21528926 TI - Targeted nuclear delivery using peptide-coated quantum dots. AB - Core/shell quantum dots (CdSe/Zns) conjugated with various nuclear localization signaling (NLS) peptides, which could facilitate the transportation of quantum dots across the plasma membrane into the nucleus, have been utilized to investigate the uptake mechanism of targeted delivery. Because of their brightness and photostability, it was possible to trace the trajectories of individual quantum dots in living cells using both confocal and total internal reflection microscopes. We found that, when the quantum dots were added to a cell culture, the peptide-coated quantum dots entered the cell nucleus while the uncoated quantum dots remained in the cytoplasm. At 8 nM, most of the peptide coated quantum dots were found in the cytoplasm due to aggregation. However, at a lower concentration (0.08 nM), approximately 25% of the NLS peptide-coated quantum dots entered the cell nucleus. We also found that some quantum dots without NLS coating could also enter the nucleus, suggesting that the size of the quantum dots may play an important role in such a process. PMID- 21528927 TI - Photoluminescent hyperbranched poly(amido amine) containing beta-cyclodextrin as a nonviral gene delivery vector. AB - Hyperbranched poly(amido amine)s (HPAAs) containing different amounts of beta cyclodextrin (beta-CD) (HPAA-CDs) were synthesized in one-pot by Michael addition copolymerization of N,N'-methylene bisacrylamide, 1-(2-aminoethyl)piperazine, and mono-6-deoxy-6-ethylenediamino-beta-CD. In comparison to pure HPAA, the fluorescence intensity of HPAA-CDs was enhanced significantly while the cytotoxicity became lower. Ascribed to plenty of amino groups and strong photoluminescence, HPAA-CDs could be used as nonviral gene delivery vectors, and the corresponding gene transfection was evaluated. The experimental results indicated that HPAA-CDs condensed the plasmid DNA very well. By utilizing the fluorescent properties of HPAA-CDs, the cellular uptake and gene transfection processes were tracked by flow cytometry and confocal laser scanning microscopy without any fluorescent labeling. The transfection efficiencies of HPAA-CDs were similar to that of pure HPAA. In addition, the inner cavities of beta-CDs in HPAA CDs could be used to encapsulate drugs through host--guest interaction. Therefore, the HPAA-CDs may have potential application in the combination of gene therapy and chemotherapy. PMID- 21528928 TI - Evidence for an extracellular acid proteolytic activity secreted by living cells of Saccharomyces cerevisiae PlR1: impact on grape proteins. AB - In this work, Saccharomyces cerevisiae PlR1, a strain isolated from Pinot noir grapes in the Champagne area, was shown to secrete an acid proteolytic activity against bovine serum albumin. This proteolytic activity was detectable in cell free culture supernatants at the beginning of the exponential growth phase and increased with yeast growth. Using a zymography method, only one protease band with a molecular mass of 72 kDa was observed. This extracellular proteolytic activity was detected in the pH range from 2 to 4 with a maximal value at pH 2.5 and 38 degrees C and was completely inhibited by pepstatin A. The secretion of this protease did not need any protein inducer and seemed to be insensitive to nitrogen catabolic repression. S. cerevisiae PlR1 was also able to secrete this proteolytic activity during alcoholic fermentation, and it was found to be active against grape proteins, with a molecular mass around 25 kDa, at optimal conditions of 38 degrees C, pH 3.5. PMID- 21528929 TI - Inhibition of buckwheat starch digestion by the formation of starch/bile salt complexes: possibility of its occurrence in the intestine. AB - During the digestion of starch in foods, starch is mixed with bile in the duodenum. Because fatty acids and some kinds of polyphenols could bind to starch, it was postulated that bile salts might also bind to starch. The purpose of this paper is to study the effects of bile and bile salts on starch/iodine complex formation and pancreatin-induced starch digestion. Bile suppressed starch/iodine complex formation and inhibited pancreatin-induced starch digestion slightly in control buckwheat starch, but did so significantly in buckwheat starch from which fatty acids and polyphenols had been extracted. Such significant suppression and inhibition by bile were also observed in a reagent soluble starch. The effects of cholate and taurocholate on the starch/iodine complex formation and the pancreatin-induced starch digestion were essentially the same as those of bile. Bile, cholate, and taurocholate suppressed amylose/iodine complex formation more significantly than amylopectin/iodine complex formation and inhibited pancreatin induced amylose digestion more effectively than the digestion of amylopectin. It is concluded from the results that bile salts could bind to starch, especially amylose, the helical structures of which were not occupied by other molecules such as fatty acids and polyphenols, and that the binding resulted in the inhibition of starch digestion by pancreatin. The conclusion suggests that the function of bile salts can be discussed from the point of not only lipid digestion but also starch digestion. PMID- 21528930 TI - Directed covalent immobilization of fluorescently labeled cytokines. AB - Cytokines are important mediators coordinating inflammation and wound healing in response to tissue damage and infection. Therefore, immobilization of cytokines on the surface of biomaterials is a promising approach to improve biocompatibility. Soluble cytokines signal through receptors on the cell surface leading to cell differentiation, proliferation, or other effector functions. Random immobilization of cytokines on surfaces will result in a large fraction of inactive protein due to impaired cytokine--receptor interaction. We developed a strategy that combined (i) directed covalent coupling of cytokines, (ii) quantification of coupling efficiency through fluorescence detection, and (iii) a reliable protease cleavage assay to control orientation of coupling. For this purpose, fusion proteins of the SNAP-tag followed by an enterokinase recognition site, yellow fluorescent protein (YFP), and the cytokine of interest being either interleukin-6 (IL-6) or oncostatin M (OSM) were generated. The SNAP-tag is a derivative of O(6)-alkylguanine-DNA alkyltransferase that couples itself covalently to benzylguanine. Bioactivities of the SNAP-YFP-cytokines were shown to be comparable with the nontagged cytokines. Efficient coupling of SNAP-YFP cytokines to benzylguanine-modified beads was demonstrated by flow cytometry. The fact that enterokinase treatment released most of the fluorescence from the beads is indicative for directed coupling and only marginal adsorptive binding. Cellular responses to SNAP-YFP-cytokine beads were analyzed in cellular lysates and by confocal microscopy indicating that the directionally immobilized cytokines are fully signaling competent with respect to the activation of ERK and STAT3. The strategy presented here is generally applicable for the directed covalent immobilization of fluorescently labeled proteins including the convenient and reliable control of coupling efficiency and orientation. PMID- 21528932 TI - Assembly of single-walled carbon nanohorn supported liposome particles. AB - Nanoparticle-supported liposomes can be a promising platform for drug delivery, vaccine development, and biomedical imaging. Single-walled carbon nanohorns are a relatively new carbon nanomaterial, and they could be used as carriers of drug and imaging reagents. Assembling lipids around carbon nanohorns would confer this nanomaterial much broader applications such as vaccine development and targeted drug delivery by embedding a target protein or immunogenic protein into the lipid bilayer structure. Here, we show the assembly of functionalized single-walled carbon nanohorns (-CH(2)-CH(2)-COOH(x), ~100 nm) with positively charged lipids through a freeze and thaw cycle. The assembled complex particles can be readily separated from individual nanohorns or liposomes under specific centrifugation conditions. The results from transmission electronic microscopy, flow cytometry through nitrobenzoxadiazole labeled lipids, and zeta potential analysis clearly show that the nanohorns are encapsulated by liposomes with a median size of ca. 120 nm. PMID- 21528931 TI - RS-predictor: a new tool for predicting sites of cytochrome P450-mediated metabolism applied to CYP 3A4. AB - This article describes RegioSelectivity-Predictor (RS-Predictor), a new in silico method for generating predictive models of P450-mediated metabolism for drug-like compounds. Within this method, potential sites of metabolism (SOMs) are represented as "metabolophores": A concept that describes the hierarchical combination of topological and quantum chemical descriptors needed to represent the reactivity of potential metabolic reaction sites. RS-Predictor modeling involves the use of metabolophore descriptors together with multiple-instance ranking (MIRank) to generate an optimized descriptor weight vector that encodes regioselectivity trends across all cases in a training set. The resulting pathway independent (O-dealkylation vs N-oxidation vs Csp(3) hydroxylation, etc.), isozyme-specific regioselectivity model may be used to predict potential metabolic liabilities. In the present work, cross-validated RS-Predictor models were generated for a set of 394 substrates of CYP 3A4 as a proof-of-principle for the method. Rank aggregation was then employed to merge independently generated predictions for each substrate into a single consensus prediction. The resulting consensus RS-Predictor models were shown to reliably identify at least one observed site of metabolism in the top two rank-positions on 78% of the substrates. Comparisons between RS-Predictor and previously described regioselectivity prediction methods reveal new insights into how in silico metabolite prediction methods should be compared. PMID- 21528933 TI - Influence of biological media on the structure and behavior of ferrocene containing cationic lipid/DNA complexes used for DNA delivery. AB - Biological media affect the physicochemical properties of cationic lipid-DNA complexes (lipoplexes) and can influence their ability to transfect cells. To develop new lipids for efficient DNA delivery, the influence of serum-containing media on the structures and properties of the resulting lipoplexes must be understood. To date, however, a clear and general picture of how serum-containing media influences the structures of lipoplexes has not been established. Some studies suggest that serum can disintegrate lipoplexes formed using certain types of cationic lipids, resulting in the inhibition of transfection. Other studies have demonstrated that lipoplexes formulated from other lipids are stable in the presence of serum and are able to transfect cells efficiently. In this article, we describe the influence of serum-containing media on lipoplexes formed using the redox-active cationic lipid bis(n-ferrocenylundecyl)dimethylammonium bromide (BFDMA). This lipoplex system promotes markedly decreased levels of transgene expression in COS-7 cells as serum concentrations are increased from 0 to 2, 5, 10, and 50% (v/v). To understand the cause of this decrease in transfection efficiency, we used cryogenic transmission electron microscopy (cryo-TEM) and measurements of zeta potential to characterize lipoplexes in cell culture media supplemented with 0, 2, 5, 10, and 50% serum. Cryo-TEM revealed that in serum free media BFDMA lipoplexes form onionlike, multilamellar nanostructures. However, the presence of serum in the media caused disassociation of the intact multilamellar lipoplexes. At low serum concentrations (2 and 5%), DNA threads appeared to separate from the complex, leaving the nanostructure of the lipoplexes disrupted. At higher serum concentration (10%), disassociation increased and bundles of multilamellae were discharged from the main multilamellar complex. In contrast, lipoplexes characterized in serum-free aqueous salt (Li(2)SO(4)) medium and in OptiMEM cell culture medium (no serum) did not exhibit significant structural changes. The zeta potentials of lipoplexes in serum-free media (salt medium and cell culture medium) were similar (e.g., approximately -35 mV). Interestingly, the presence of serum caused the zeta potentials to become less negative (about -20 mV in OptiMEM and -10 mV in Li(2)SO(4)), even though serum contains negatively charged entities that have been demonstrated to lead to more negative zeta potentials in other lipoplex systems. The combined measurements of zeta potential and cryo-TEM are consistent with the proposition that DNA threads separate from the lipoplex in the presence of serum, resulting in a decrease in the net negative charge of the surface of the lipoplex. PMID- 21528934 TI - Zwitteration as an alternative to PEGylation. AB - A direct, head-to-head comparison of the efficacy of a zwitterionic versus a poly(ethylene glycol), PEG, coating in preventing protein adsorption to silica and aggregation of silica nanoparticles is presented. The same siloxane coupling chemistry was employed to yield surfaces with similar coverages of both types of ligand. Nanoparticle and planar surfaces were challenged with salt, serum, lysozyme, and serum albumin at 25 and 37 degrees C. While both types of surface modification are highly effective in preventing protein adsorption and nanoparticle aggregation, the zwitterion provided monolayer-type coverage with minimal thickness, whereas the PEG appeared to yield a more three-dimensional coating. The mechanism for adsorption resistance is thought to be based on preventing ion pairing between protein and surface charges, which releases counterions and water molecules, an entropic driving force enough to overcome a disfavored enthalpy of adsorption. PMID- 21528935 TI - Formation of molecular monolayers on TiO2 surfaces: a surface analogue of the Williamson ether synthesis. AB - Strategies to modify metal oxide surfaces are important because of the increasing applications of metal oxides in catalysis, sensing, electronics, and renewable energy. Here, we report the formation of molecular monolayers on anatase nanocrystalline TiO(2) surfaces at near-ambient temperatures by a simple one-step immersion. This is achieved by an analogue of the Williamson ether synthesis, in which the hydroxyl groups of the TiO(2) surface react with iodo-alkane molecules to release HI and form a Ti-O-C surface linkage. The grafted molecules were characterized by Fourier-transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS) to confirm the formation of covalently bonded monolayers. Kinetic studies yielded an activation barrier of ~59 kJ/mol for the grafting reaction. Measurements of hydrolytic stability of the grafted molecules in water show that approximately half the molecules are removed within minutes to hours at temperatures of 25-100 degrees C with an activation energy of ~82 kJ/mol, while the remaining molecules are stable for much longer periods of time. These different stabilities are discussed in terms of the different types of Ti-O C bonds that can form on TiO(2) surfaces. PMID- 21528936 TI - Mutual capture of dipolar molecules at low and very low energies. II. Numerical study. AB - The low-energy rate coefficients of capture of two identical dipolar polarizable rigid rotors in their lowest nonresonant (j(1) = 0 and j(2) = 0) and resonant (j(1) = 0, 1 and j(2) = 1, 0) states are calculated accurately within the close coupling (CC) approach. The convergence of the quantum rate coefficients to their quantum-classical counterparts is studied. A comparison of the present accurate numerical with approximate analytical results (Nikitin, E. E.; Troe, J. J. Phys. Chem. A 2010, 114, 9762) indicates a good performance of the previous approach which was based on the interpolation between s-wave fly wheel quantal and all wave classical adiabatic channel limits. The results obtained apply as well to the formation of transient molecular species in the encounter of two atoms at very low collision energy interacting via resonance dipole-dipole interaction. PMID- 21528937 TI - Synthesis of nine-membered azlactones by palladium-catalyzed ring-expansion of gamma-methylidene-delta-valerolactones with aziridines. AB - A palladium-catalyzed formal [6 + 3] cyclization of gamma-methylidene-delta valerolactones with aziridines has been developed to produce 1,4-oxazonan-9-ones, a class of nine-membered azlactones that are not easily accessible by existing methods. The products thus obtained can also be further functionalized with ease. PMID- 21528938 TI - Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual Orexin inhibitor Suvorexant (MK-4305). AB - The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines. PMID- 21528940 TI - Manidipine for hypertension not controlled by dual therapy in patients with diabetes mellitus: a non-comparative, open-label study. AB - BACKGROUND AND OBJECTIVE: Little is known about the effects of the calcium channel antagonist manidipine when it is added as a third drug in non-controlled hypertensive patients with diabetes mellitus receiving dual antihypertensive therapy. The aim of this study was to evaluate the response in terms of blood pressure (BP) and microalbuminuria when manidipine is administered to patients with type 2 diabetes and uncontrolled hypertension who are already being treated with a combination of a low-dose diuretic plus an ACE inhibitor or an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]). We also evaluated the effects of addition of manidipine on plasma fasting glucose, glycosylated haemoglobin (HbA(1c)), serum uric acid, the lipid profile, serum creatinine and creatinine clearance. METHODS: This was a non-comparative, open label study of hypertensive diabetic patients with systolic/diastolic BP >130/80 mmHg. All patients had been receiving treatment for >=3 months with stable doses of a diuretic plus an ACE inhibitor or ARB. Manidipine 10 mg/day was added, increasing to 20 mg/day if the target BP was not reached after 3 months' treatment. The follow-up period was 6 months. Patient compliance was verified by tablet count. The doses of statins being taken by patients prior to commencement of the trial were not modified during the study. All patients were treated with oral antihyperglycaemic agents only; patients receiving insulin were excluded from the study. RESULTS: 136 patients were enrolled in the trial and completed the study; 41.9% of the patients were males, the mean +/- SD age of the study population was 64.4 +/- 12.3 years, and the mean +/- SD body mass index was 30.2 +/- 4.9 kg/m(2). The mean +/- SD BP at baseline was 158.6 +/- 15.6/86.7 +/- 11.2 mmHg compared with 136.8 +/- 12.0/78.0 +/- 11.2 (-21.8/-8.7, respectively) mmHg at the end of the study period (p < 0.001). A total of 63.6% of the patients attained a BP of <140/90 mmHg and 20.9% attained a BP of <130/80 mmHg. The mean +/- SD heart rate decreased from 75.1 +/- 11.2 at baseline to 72.8 +/- 11.2 beats/min at the end of the study (p = 0.06; not significant). Fifty percent (95% CI 41.6, 58.4) of the patients had microalbuminuria at baseline compared with 31.3% (95% CI 23.0, 39.6) at study end (p = 0.006). Reductions in mean +/- SD fasting glucose levels (-10.2 +/- 50.3 mg/dL; p < 0.05), HbA(1c) (-0.19 +/- 0.97%; p = 0.05), total cholesterol (-11.9 +/- 35.2 mg/dL; 95% CI -18.1, -5.8; p < 0.005), triglycerides (-10.8 +/- 51.1 mg/dL; 95% CI -19.7, -1.8; p = 0.018) and low-density lipoprotein-cholesterol (-8.1 +/- 27.7 mg/dL; 95% CI -13.2, -2.9; p = 0.002) were observed. No patients dropped out of the study because of adverse effects. The most frequent adverse effect encountered was malleolar oedema (9%). CONCLUSION: Manidipine added as the third drug to a renin-angiotensin system inhibitor plus a low dose of diuretic significantly reduces BP, improves renal function, has favourable effects on the lipid and glucose profiles, and reduces microalbuminuria in uncontrolled hypertensive patients with type 2 diabetes. Long term trials are necessary to evaluate time-related effects. PMID- 21528939 TI - Long-term renal safety of tenofovir disoproxil fumarate in vertically HIV infected children, adolescents and young adults: a 60-month follow-up study. AB - BACKGROUND AND OBJECTIVE: Sporadic cases of renal toxicity have been reported in HIV-infected children treated with tenofovir disoproxil fumarate (TDF). We assessed the long-term renal safety of TDF in a cohort of vertically HIV-infected children, adolescents and young adults. METHODS: We evaluated 26 HIV-infected children, adolescents and young adults, aged 4.9-17.4 years at baseline, every 6 months for 60 consecutive months. At the baseline visit, they had an undetectable viral load and a good immune reconstitution and were being treated with lamivudine, stavudine and a protease inhibitor (PI). At the same visit, stavudine was replaced with TDF and the PI with efavirenz. Serum creatinine, estimated glomerular filtration rate (GFR), urine protein to creatinine ratio, serum phosphate, ratio of the maximum rate of tubular phosphate reabsorption to the GFR (TmPO(4)/GFR), urine glucose, and urine alpha(1)-microglobulin to creatinine ratio were used as markers of renal function. The outcome-time relationships were studied using generalized estimating equations (GEEs). In addition to time (continuous, ten equally spaced intervals), sex, age at baseline and CD4+ T-cell count were used as covariates. RESULTS: A moderate reduction in GFR was observed only once in an underweight female patient. There was no occurrence of proteinuria, hypophosphataemia or glycosuria. Moreover, TmPO(4)/GFR was stable and the urine alpha(1)-microglobulin to creatinine ratio was always within normal limits. CONCLUSION: TDF had an excellent renal safety profile in HIV-infected children, adolescents and young adults regularly followed up for 60 months. PMID- 21528941 TI - Activity and safety of dasatinib as second-line treatment or in newly diagnosed chronic phase chronic myeloid leukemia patients. AB - Dasatinib is an oral dual tyrosine kinase inhibitor active against ABL1 and SRC family kinases. The US FDA approved it for the treatment of chronic myeloid leukemia (CML) patients in chronic, accelerated, or blastic phase with resistance or intolerance to imatinib therapy. Dasatinib is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia who have become resistant to or intolerant of other treatments. The agent is now also approved for newly diagnosed chronic phase (CP) patients. This article reviews the pharmacokinetic and pharmacodynamic properties of dasatinib as well as clinical data limited to CP-CML patients. Four-year follow-up of a phase III dose optimization trial confirmed that better progression-free survival (66%) and overall survival (82%) were obtained with a dose of 100 mg once daily (od) than with the standard 70 mg twice daily dosing (65% and 75%, respectively). The 100 mg od dosing schedule was also associated with the highest benefit-risk ratio for CP patients with resistant, intolerant, or suboptimal response. Recent results of a phase III trial in newly diagnosed patients demonstrated that dasatinib 100 mg od has superiority in terms of confirmed cytogenetic and molecular responses, with faster responses and high activity in high Sokal risk patients compared with standard-dose imatinib. PMID- 21528942 TI - Influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphism on the pharmacokinetics of the prolonged-release, once-daily formulation of tacrolimus in stable renal transplant recipients. AB - BACKGROUND AND OBJECTIVE: Tacrolimus is metabolized by cytochrome P450 (CYP) 3A5. The objective of this study was to investigate the influence of the genetic polymorphism of CYP3A5 on the pharmacokinetics of a new modified-release, once daily formulation of tacrolimus (Advagraf(r)) after a switch from the immediate release formulation (Prograf(r)). PATIENTS AND METHODS: This was a prospective, single-centre, open-label study in stable kidney transplant recipients. Seventeen 'expressor' patients (CYP3A5*1/*3 or *1/*1) were matched to 15 'non-expressor' patients (CYP3A5*3/*3). Exposure variables (concentrations and area under the blood concentration-time curve from 0 to 24 hours [AUC(24)]) were obtained before and 15 days after the switch. Delay since grafting was similar for both groups of patients (expressors: 49 +/- 24 months; non-expressors: 45 +/- 22 months). RESULTS: During administration of tacrolimus as Prograf(r) or Advagraf(r), the mean tacrolimus daily dose was significantly higher and the dose-adjusted AUC(24) was significantly lower in the expressor group. Following the switch to Advagraf(r), there was a significant decrease in the dose-adjusted AUC(24) for both non-expressor (5910 +/- 3019 vs 5334 +/- 2668 ng.h/mL per mg/kg/day; p = 0.041) and expressor patients (3701 +/- 1409 vs 3273 +/- 1372 ng.h/mL per mg/kg/day; p = 0.03). In the non-expressor group, mean blood trough concentration (C(0)) was comparable for both formulations while it decreased significantly in the expressor group after the switch (8.2 +/- 2.2 vs 6.3 +/- 2.5 ng/mL; p = 0.02). However, a good correlation between AUC(24) and C(0) was observed for both Advagraf(r) and Prograf(r) regardless of CYP3A5 genotype. CONCLUSION: Tacrolimus exposure significantly decreases after a switch from Prograf(r) to Advagraf(r), on a milligram-for-milligram basis, in CYP3A5 expressor recipients. Consequently, these patients should be carefully monitored. PMID- 21528943 TI - Communication: Comment on the effective temporal and spectral resolution of impulsive stimulated Raman signals. AB - A compact correlation-function expression for time-resolved stimulated Raman signals, generated by combining a spectrally narrow (picosecond) with a broad (femtosecond) pulse, is derived using a closed time path loop diagrammatic technique that represents forward and backward time evolution of the vibrational wave function. We show that even though the external spectral and temporal parameters of the pulses may be independently controlled, the effective temporal and spectral resolution of the experiment may not exceed the fundamental bandwidth limitation. PMID- 21528944 TI - Anharmonic rovibrational analysis for disilacyclopropenylidene (Si2CH2). AB - The global minimum on the Si(2)CH(2) electronic singlet potential energy surface has been theoretically predicted to be a peculiar hydrogen bridged (Si...H...Si) disilacyclopropenylidene structure (Si(2)CH(2)). An accurate quartic force field for Si(2)CH(2) has been determined employing ab initio coupled-cluster theory with single and double excitations and a perturbative treatment for triple excitations [CCSD(T)], in combination with the correlation consistent core valence quadruple zeta (cc-pCVQZ) basis set. The vibration-rotation coupling constants, equilibrium and zero-point vibration corrected rotational constants, centrifugal distortion constants, and harmonic and fundamental vibrational frequencies for six isotopologues of Si(2)CH(2) are predicted using vibrational second-order perturbation theory (VPT2). The anharmonic corrections for the vibrational motions involving the H bridged bonds are found to be more than 5% with respect to the corresponding harmonic vibrational frequencies. In this light, an experimental detection and characterization of disilacyclopropenylidene (Si(2)CH(2)) is highly desired. PMID- 21528945 TI - A natural orbital functional for multiconfigurational states. AB - An explicit formulation of the Piris cumulant lambdaDelta,Pi matrix is described herein, and used to reconstruct the two-particle reduced density matrix (2-RDM). Then, we have derived a natural orbital functional, the Piris Natural Orbital Functional 5, PNOF5, constrained to fulfill the D, Q, and G positivity necessary conditions of the N-representable 2-RDM. This functional yields a remarkable accurate description of systems bearing substantial (near)degeneracy of one particle states. The theory is applied to the homolitic dissociation of selected diatomic molecules and to the rotation barrier of ethylene, both paradigmatic cases of near-degeneracy effects. It is found that the method describes correctly the dissociation limit yielding an integer number of electrons on the dissociated atoms. PNOF5 predicts a barrier of 65.6 kcal/mol for the ethylene torsion in an outstanding agreement with Complete Active Space Second-order Perturbation Theory (CASPT2). The obtained occupation numbers and pseudo one-particle energies at the ethylene transition state account for fully degenerate pi orbitals. The calculated equilibrium distances, dipole moments, and binding energies of the considered molecules are presented. The values obtained are accurate comparing those obtained by the complete active space self-consistent field method and the experimental data. PMID- 21528946 TI - Application of a semiclassical model for the second-quantized many-electron Hamiltonian to nonequilibrium quantum transport: the resonant level model. AB - A semiclassical approach is developed for nonequilibrium quantum transport in molecular junctions. Following the early work of Miller and White [J. Chem. Phys. 84, 5059 (1986)], the many-electron Hamiltonian in second quantization is mapped onto a classical model that preserves the fermionic character of electrons. The resulting classical electronic Hamiltonian allows for real-time molecular dynamics simulations of the many-body problem from an uncorrelated initial state to the steady state. Comparisons with exact results generated for the resonant level model reveal that a semiclassical treatment of transport provides a quantitative description of the dynamics at all relevant timescales for a wide range of bias and gate potentials, and for different temperatures. The approach opens a door to treating nontrivial quantum transport problems that remain far from the reach of fully quantum methodologies. PMID- 21528948 TI - Unusual ground states via monotonic convex pair potentials. AB - We have previously shown that inverse statistical-mechanical techniques allow the determination of optimized isotropic pair interactions that self-assemble into low-coordinated crystal configurations in the d-dimensional Euclidean space R(d). In some of these studies, pair interactions with multiple extrema were optimized. In the present work, we attempt to find pair potentials that might be easier to realize experimentally by requiring them to be monotonic and convex. Encoding information in monotonic convex potentials to yield low-coordinated ground-state configurations in Euclidean spaces is highly nontrivial. We adapt a linear programming method and apply it to optimize two repulsive monotonic convex pair potentials, whose classical ground states are counterintuitively the square and honeycomb crystals in R(2). We demonstrate that our optimized pair potentials belong to two wide classes of monotonic convex potentials whose ground states are also the square and honeycomb crystal. We show that these unexpected ground states are stable over a nonzero number density range by checking their (i) phonon spectra, (ii) defect energies and (iii) self assembly by numerically annealing liquid-state configurations to their zero-temperature ground states. PMID- 21528947 TI - A strategy for reducing gross errors in the generalized Born models of implicit solvation. AB - The "canonical" generalized Born (GB) formula [C. Still, A. Tempczyk, R. C. Hawley, and T. Hendrickson, J. Am. Chem. Soc. 112, 6127 (1990)] is known to provide accurate estimates for total electrostatic solvation energies DeltaG(el) of biomolecules if the corresponding effective Born radii are accurate. Here we show that even if the effective Born radii are perfectly accurate, the canonical formula still exhibits significant number of gross errors (errors larger than 2k(B)T relative to numerical Poisson equation reference) in pairwise interactions between individual atomic charges. Analysis of exact analytical solutions of the Poisson equation (PE) for several idealized nonspherical geometries reveals two distinct spatial modes of the PE solution; these modes are also found in realistic biomolecular shapes. The canonical GB Green function misses one of two modes seen in the exact PE solution, which explains the observed gross errors. To address the problem and reduce gross errors of the GB formalism, we have used exact PE solutions for idealized nonspherical geometries to suggest an alternative analytical Green function to replace the canonical GB formula. The proposed functional form is mathematically nearly as simple as the original, but depends not only on the effective Born radii but also on their gradients, which allows for better representation of details of nonspherical molecular shapes. In particular, the proposed functional form captures both modes of the PE solution seen in nonspherical geometries. Tests on realistic biomolecular structures ranging from small peptides to medium size proteins show that the proposed functional form reduces gross pairwise errors in all cases, with the amount of reduction varying from more than an order of magnitude for small structures to a factor of 2 for the largest ones. PMID- 21528949 TI - Use of correlated potential harmonic basis functions for the description of the 4He trimer and small clusters. AB - A correlated many-body basis function is used to describe the (4)He trimer and small helium clusters ((4)He(N)) with N = 4-9. A realistic helium dimer potential is adopted. The ground state results of the (4)He dimer and trimer are in close agreement with earlier findings. But no evidence is found for the existence of Efimov state in the trimer for the actual (4)He-(4)He interaction. However, decreasing the potential strength we calculate several excited states of the trimer which exhibit Efimov character. We also solve for excited state energies of these clusters which are in good agreement with Monte Carlo hyperspherical description. PMID- 21528950 TI - Molecular dynamics scheme for precise estimation of electrostatic interaction via zero-dipole summation principle. AB - We propose a novel idea, zero-dipole summation, for evaluating the electrostatic energy of a classical particle system, and have composed an algorithm for effectively utilizing the idea for molecular dynamics. It conceptually prevents the nonzero-charge and nonzero-dipole states artificially generated by a simple cutoff truncation. The resulting energy formula is nevertheless represented by a simple pairwise function sum, which enables facile application to high performance computation. By following a heuristic approach to derive the current electrostatic energy formula, we developed an axiomatic approach to construct the method consistently. Explorations of the theoretical details of our method revealed the structure of the generated error, and we analyzed it by comparisons with other methods. A numerical simulation using liquid sodium chloride confirmed that the current method with a small damping factor yielded sufficient accuracy with a practical cutoff distance region. The current energy function also conducts stable numerical integration in a liquid MD simulation. Our method is an extension of the charge neutralized summation developed by Wolf et al. [J. Chem. Phys. 110, 8254 (1999)]. Furthermore, we found that the current method becomes a generalization of the preaveraged potential method proposed by Yakub and Ronchi [J. Chem. Phys. 119, 11556 (2003)], which is based on a viewpoint different from the neutrality. The current study presents these relationships and suggests possibilities for their further applications. PMID- 21528951 TI - Embedded density functional theory for covalently bonded and strongly interacting subsystems. AB - Embedded density functional theory (e-DFT) is used to describe the electronic structure of strongly interacting molecular subsystems. We present a general implementation of the Exact Embedding (EE) method [J. Chem. Phys. 133, 084103 (2010)] to calculate the large contributions of the nonadditive kinetic potential (NAKP) in such applications. Potential energy curves are computed for the dissociation of Li(+)-Be, CH(3)-CF(3), and hydrogen-bonded water clusters, and e DFT results obtained using the EE method are compared with those obtained using approximate kinetic energy functionals. In all cases, the EE method preserves excellent agreement with reference Kohn-Sham calculations, whereas the approximate functionals lead to qualitative failures in the calculated energies and equilibrium structures. We also demonstrate an accurate pairwise approximation to the NAKP that allows for efficient parallelization of the EE method in large systems; benchmark calculations on molecular crystals reveal ideal, size-independent scaling of wall-clock time with increasing system size. PMID- 21528952 TI - Fluctuations in the ensemble of reaction pathways. AB - The dominant reaction pathway is a rigorous framework to microscopically compute the most probable trajectories, in nonequilibrium transitions. In the low temperature regime, such dominant pathways encode the information about the reaction mechanism and can be used to estimate nonequilibrium averages of arbitrary observables. On the other hand, at sufficiently high temperatures, the stochastic fluctuations around the dominant paths become important and have to be taken into account. In this work, we develop a technique to systematically include the effects of such stochastic fluctuations, to order k(B)T. This method is used to compute the probability for a transition to take place through a specific reaction channel and to evaluate the reaction rate. PMID- 21528953 TI - Ab initio lattice dynamics of nonconducting crystals by systematic fragmentation. AB - A systematic method for approximating the ab initio electronic energy of crystal lattices has been improved by the incorporation of long range electrostatic and dispersion interactions. The effect of these long range interactions on the optimization of the crystal structure is reported. The harmonic lattice dynamics have been evaluated to give phonon frequencies and neutron scattering intensities. Exemplary results are reported for diamond, silicon, and alpha quartz using Hartree-Fock, Moller-Plesset perturbation, and coupled-cluster levels of ab initio theory. PMID- 21528954 TI - The photodissociation dynamics of tetrachloroethylene. AB - We present a direct current slice imaging study of tetrachloroethylene (C(2)Cl(4)) photodissociation, probing the resulting ground state Cl ((2)P(3/2)) and spin-orbit excited state Cl* ((2)P(1/2)) products. We report photofragment images, total translational energy distributions and the product branching ratio of Cl*/Cl following dissociation at 235 and 202 nm, obtained using a two-color reduced-Doppler dissociation/probe. Near 235 nm, the Cl translational energy distribution shows a peak at the limit of the available energy, indicating a direct dissociation through a sigma*(C-Cl) <- pi (C=C) transition, which is superimposed on a broader underlying distribution. The ground state Cl image and associated translational energy distribution at 202 nm is broad and peaked at lower energy, suggesting either internal conversion to the ground state or a lower excited state prior to dissociation. The Cl* images are similarly broad at both wavelengths. The branching ratio is presented as a function of recoil energy, but after integration shows a near-statistical average of Cl:Cl* as 70:30 at both wavelengths. All the images are largely isotropic, with anisotropy parameters (beta) of 0.05 +/- 0.03. PMID- 21528955 TI - Two-dimensional resonance enhanced multiphoton ionization of H(i)Cl; i = 35, 37: state interactions, photofragmentations and energetics of high energy Rydberg states. AB - Mass spectra were recorded for (2 + n) resonance enhanced multiphoton ionization (REMPI) of HCl as a function of resonance excitation energy in the 88865-89285 cm(-1) region to obtain two-dimensional REMPI data. Band spectra due to two photon resonance transitions to number of Rydberg states (Omega' = 0, 1, and 2) and the ion-pair state V((1)Sigma(+)(Omega' = 0)) for H(35)Cl and H(37)Cl were identified, assigned, and analyzed with respect to Rydberg to ion-pair interactions. Perturbations show as line-, hence energy level-, shifts, as well as ion signal intensity variations with rotational quantum numbers, J', which, together, allowed determination of parameters relevant to the nature and strength of the state interactions as well as dissociation and ionization processes. Whereas near-resonance, level-to-level, interactions are found to be dominant in heterogeneous state interactions (DeltaOmega ? 0) significant off-resonance interactions are observed in homogeneous interactions (DeltaOmega = 0). The alterations in Cl(+) and HCl(+) signal intensities prove to be very useful for spectra assignments. Data relevant to excitations to the j(3)Sigma(0(+)) Rydberg states and comparison with (3 + n) REMPI spectra allowed reassignment of corresponding spectra peaks. A band previously assigned to an Omega = 0 Rydberg state was reassigned to an Omega = 2 state (nu(0) = 88957.6 cm(-1)). PMID- 21528956 TI - Characterization of C4H in the A2Pi and X2Sigma+ states by double resonance four wave mixing. AB - The B(2)Pi-X(2)Sigma(+) electronic spectrum of C(4)H has been studied by degenerate and double resonance four-wave mixing. The technique identifies vibrational levels in the X(2)Sigma(+) ground state. Its sensitivity and unique characteristics permit detection of new levels. The A(2)Pi state lying 222 cm(-1) above the X(2)Sigma ground state is also observed, confirming the analysis from anion photoelectron spectroscopy but with improved accuracy. Vibrational level determination in the A(2)Pi electronic manifold up to 700 cm(-1) above v = 0 is made. A Renner-Teller analysis is carried out for the two lowest bending modes v(6) and v(7) in the A(2)Pi state by diagonalization of the effective Hamiltonian matrix. The Renner-Teller parameters ?(6), ?(7), and ?(67), the vibrations omega(6) and omega(7) and the spin-orbit coupling constant A(so) are determined. PMID- 21528957 TI - First-principles determination of the structure of NaN and NaN- clusters with up to 80 atoms. AB - We have performed an extensive computational search for the global minimum (GM) structures of both neutral and anionic sodium clusters with up to 80 atoms. The theoretical framework combines basin hopping unbiased optimizations based on a Gupta empirical potential (EP) and subsequent reoptimization of many candidate structures at the density functional theory level. An important technical point is that the candidates are selected based on cluster shape descriptors rather than the relative stabilities of the EP model. An explicit comparison of the electronic density of states of cluster anions to experimental photoemission spectra suggests that the correct GM structures have been identified for all but two sizes (N = 47 and 70). This comparison validates the accuracy of the proposed methodology. Furthermore, our GM structures either match or improve over the results of previous works for all sizes. Sodium clusters are seen to accommodate strain very efficiently because: (a) many structures are based on polyicosahedral packing; (b) others are based on Kasper polyhedra and show polytetrahedral order; (c) finally, some (N + 1)-atom structures are obtained by incorporating one adatom into the outermost atomic shell of a compact N-atom cluster, at the cost of increasing the bond strain. GM structures of neutrals and anions differ for most sizes. Cluster stabilities are analyzed and shown to be dominated by electron shell closing effects for the smaller clusters and by geometrical packing effects for the larger clusters. The critical size separating both regimes is around 55 atoms. Some implications for the melting behavior of sodium clusters are discussed. PMID- 21528958 TI - Cr(CO)6 photochemistry: semi-classical study of UV absorption spectral intensities and dynamics of photodissociation. AB - The UV absorption spectrum of Cr(CO)(6) (chromium hexacarbonyl) in gas phase is investigated by theoretical methods with focus on the absorption intensities. It is shown that in spite of good predictions for the excitation energies, the most frequently employed methods for excited-state calculations produce poor predictions for oscillator strengths and absorption cross sections. In particular, time-dependent DFT predicts relative intensities for the two main spectral bands to be up to five times larger than the experimental results depending on the functional. The best results are obtained by a multireference configuration interaction method based on DFT (DFT/MRCI). Spectral shoulders caused by vibronic-coupling absorption are assigned based on symmetry-restricted spectrum simulations. The dynamics of Cr(CO)(6) photodissociation was also considered at TDDFT/B3LYP level. The estimated time constants for the Cr(CO)(6) relaxation and dissociation are in excellent agreement with experimental values. The time constant for internal conversion, however, is longer than the experimentally observed by factor 2, presumably due to an underestimation of the experimental analysis. PMID- 21528959 TI - H(D) -> D(H) + Cu(111) collision system: molecular dynamics study of surface temperature effects. AB - All the channels of the reaction dynamics of gas-phase H (or D) atoms with D (or H) atoms adsorbed onto a Cu(111) surface have been studied by quasiclassical constant energy molecular dynamics simulations. The surface is flexible and is prepared at different temperature values, such as 30 K, 94 K, and 160 K. The adsorbates were distributed randomly on the surface to create 0.18 ML, 0.28 ML, and 0.50 ML of coverages. The multi-layer slab is mimicked by a many-body embedded-atom potential energy function. The slab atoms can move according to the exerted external forces. Treating the slab atoms non-rigid has an important effect on the dynamics of the projectile atom and adsorbates. Significant energy transfer from the projectile atom to the surface lattice atoms takes place especially during the first impact that modifies significantly the details of the dynamics of the collisions. Effects of the different temperatures of the slab are investigated in this study. Interaction between the surface atoms and the adsorbates is modeled by a modified London-Eyring-Polanyi-Sato (LEPS) function. The LEPS parameters are determined by using the total energy values which were calculated by a density functional theory and a generalized gradient approximation for an exchange-correlation energy for many different orientations, and locations of one- and two-hydrogen atoms on the Cu(111) surface. The rms value of the fitting procedure is about 0.16 eV. Many different channels of the processes on the surface have been examined, such as inelastic reflection of the incident hydrogen, subsurface penetration of the incident projectile and adsorbates, sticking of the incident atom on the surface. In addition, hot-atom and Eley-Rideal direct processes are investigated. The hot-atom process is found to be more significant than the Eley-Rideal process. Furthermore, the rate of subsurface penetration is larger than the sticking rate on the surface. In addition, these results are compared and analyzed as a function of the surface temperatures. PMID- 21528960 TI - Measurement of the electric quadrupole moment of CO. AB - Measurements of the temperature dependence of the Buckingham effect (electric field-gradient-induced birefringence, EFGIB) for gaseous carbon monoxide are presented. The measurements span the temperature range 301.2-473.9 K, which allows for separation of the temperature-independent hyperpolarizability contribution from the temperature-dependent quadrupole contribution. It is demonstrated that in the case of carbon monoxide, quantization of the rotational motion of the molecules needs to be considered, the analysis yielding a quadrupole moment of Theta = (-8.77 +/- 0.31) * 10(-40) C m(2) and a hyperpolarizability term of b' = (-0.1243 +/- 0.0078) * 10(-60) C(3) m(4) J(-2). For dipolar molecules, the quadrupole moment is origin dependent, and the value reported here is referred to an origin called the effective quadrupole center. Comparison of this value with the center-of-mass quadrupole moment obtained from other experiments yields information about the dynamic dipole-quadrupole and dipole-magnetic dipole polarizabilities. The temperature-independent term, which contributes (7.0 +/- 0.6)% to the EFGIB at room temperature, is by no means insignificant, and must necessarily be accounted for if the quadrupole moment is to be definitively established. The measured Theta and b' are compared with the best available ab initio calculated values. PMID- 21528961 TI - Coherent control of indirect photofragmentation in the weak-field limit: control of transient fragment distributions. AB - We demonstrate theoretically that laser-induced coherent quantum interference control of asymptotic states of dissociating molecules is possible--even in the (one-photon) weak-field limit starting from a single vibrational eigenstate--when resonances are in play. This is illustrated for the NaI molecule, where it is shown that the probability of observing atomic fragments as well as the distribution of their relative momenta can be changed by a phase modulated pulse with a fixed bandwidth. This type of control is restricted to finite times during the indirect fragmentation. PMID- 21528962 TI - Molecular dynamics study on evaporation and condensation of n-dodecane at liquid vapor phase equilibria. AB - Molecular dynamics simulations are performed to study the evaporation and condensation of n-dodecane (C(12)H(26)) at temperatures in the range 400-600 K. A modified optimized potential for liquid simulation model is applied to take into account the Lennard-Jones, bond bending and torsion potentials with the bond length constrained. The equilibrium liquid-vapor n-dodecane interface thickness is predicted to be ~1.2-2.0 nm. It is shown that the molecular chains lie preferentially parallel to the interface in the liquid-vapor transition region. The predicted evaporation/condensation coefficient decreased from 0.9 to 0.3 when temperature increased from 400 to 600 K. These values can be used for the formulation of boundary conditions in the kinetic modeling of droplet heating and evaporation processes; they are noticeably different from those predicted by the transition state theory. We also present the typical molecular behaviors in the evaporation and condensation processes. The molecular exchange in condensation, typical for simple molecules, has never been observed for n-dodecane molecular chains. PMID- 21528963 TI - Electronic spectra of GdF reanalyzed by decomposing state functions according to f-shell angular momentum. AB - The electronic structure of the GdF molecule was studied by means of four component relativistic configuration interaction (CI) calculations [S. Yamamoto, H. Tatewaki, and T. Saue, J. Chem. Phys. 129, 244505 (2008)]. To analyze the electronic spectra more accurately, the CI wave function is decomposed according to the angular momentum (Omega(f)) generated from the (4f)(7) electrons. The weight of a specified Omega(f) is referred to as the "f-shell Omega component weight." This Omega(f) plays a crucial role in classifying the strong electronic transitions from the upper states (0.7 eV-3.0 eV) to the lower states (~0.55 eV). For these transitions, the upper and lower states have almost identical Omega(f) weights. This appears to be a necessary condition for a transition to be strong. The same condition is expected to hold for other lanthanide linear molecules. A point charge model is also studied, acting as a simplified model of GdF; it successfully reproduces the spectra of GdF, justifying studies based on ligand field theory. PMID- 21528964 TI - Discriminating the structure of exo-2-aminonorbornane using nuclear quadrupole coupling interactions. AB - The intrinsic conformational and structural properties of the bicycle exo-2 aminonorbornane have been probed in a supersonic jet expansion using Fourier transform microwave (FT-MW) spectroscopy and quantum chemical calculations. The rotational spectrum revealed two different conformers arising from the internal rotation of the amino group, exhibiting small (MHz) hyperfine patterns originated by the (14)N nuclear quadrupole coupling interaction. Complementary ab initio (MP2) and DFT (B3LYP and M05-2X) calculations provided comparative predictions for the structural properties, rotational and centrifugal distortion data, hyperfine parameters, and isomerization barriers. Due to the similarity of the rotational constants, the structural assignment of the observed rotamers and the calculation of the torsion angles of the amino group were based on the conformational dependence of the (14)N nuclear quadrupole coupling hyperfine tensor. In the most stable conformation (ss), the two amino N-H bonds are staggered with respect to the adjacent C-H bond. In the second conformer (st), only one of the N-H bonds is staggered and the other is trans. A third predicted conformer (ts) was not detected, consistent with a predicted conformational relaxation to conformer ss through a low barrier of 5.2 kJ mol(-1). PMID- 21528965 TI - Conformer-specific vibronic spectroscopy and vibronic coupling in a flexible bichromophore: bis-(4-hydroxyphenyl)methane. AB - The vibronic spectroscopy of jet-cooled bis-(4-hydroxyphenyl)methane has been explored using fluorescence excitation, dispersed fluorescence (DFL), UV-UV hole burning, UV depletion, and fluorescence-dip infrared spectroscopies. Calculations predict the presence of three nearly isoenergetic conformers that differ in the orientations of the two OH groups in the para positions on the two aromatic rings (labeled uu, dd, and ud). In practice, two conformers (labeled A and B) are observed, with S(0)-S(1) origins at 35,184 and 35,209 cm(-1), respectively. The two conformers have nearly identical vibronic spectra and hydride stretch infrared spectra. The low-frequency vibronic structure is assigned to bands involving the phenyl torsions (T and T), ring-flapping (R and R), and butterfly (beta) modes. Symmetry arguments lead to a tentative assignment of the two conformers as the C(2) symmetric uu and dd conformers. The S(0)-S(2) origins are assigned to bands located 132 cm(-1) above the S(0)-S(1) origins of both conformers. DFL spectra from the S(2) origin of the two conformers display extensive evidence for vibronic coupling between the two close-lying electronic states. Near-resonant coupling from the S(2) origin occurs dominantly to S(1) R(1) and S(1) R(1)beta(1) levels, which are located -15 and +31 cm(-1) from it. Unusual vibronic activity in the ring-breathing (nu(1)) and ring-deformation (nu(6a)) modes is also attributed to vibronic coupling involving these Franck Condon active modes. A multimode vibronic coupling model is developed based on earlier theoretical descriptions of molecular dimers [Fulton and Gouterman, J. Chem. Phys. 35, 1059 (1961)] and applied here to flexible bichromophores. The model is able to account for the ring-mode activity under conditions in which the S(2) origin is strongly mixed (60%/40%) with S(1) 6a(1) and 1(1) levels. The direct extension of this model to the T/T and R/R inter-ring mode pairs is only partially successful and required some modification to lower the efficiency of the S(1)/S(2) mixing compared to the ring modes. PMID- 21528966 TI - On the properties of X...N noncovalent interactions for first-, second-, and third-row X atoms. AB - In addition to a structure with a PH...N H-bond, a second complex of greater stability is formed when the PH(3) is rotated such that its P-H bond is pointing away from the approaching N lone pair of NH(3). Quantum calculations are applied to examine whether such a complex is characteristic only of P, or may occur as well for other atoms of the first, second, or third rows of the periodic table. The molecules PH(3), H(2)S, HCl, AsH(3), and NH(3) are all paired with NH(3) as electron donor. While NH(3) will not engage in an N...N attraction, all the others do form a X...N complex. The energetics, geometries, and other properties of these complexes are relatively insensitive to the nature of the X atom. This uniformity contrasts sharply with the H-bonded XH...N complexes where a strong sensitivity to X is observed. The three-dimensional nature of the electrostatic potential, in conjunction with the striving for a linear H-X...N orientation that maximizes charge transfer, serves as an excellent tool in understanding both the shape of the potential energy surface and the proclivity to engage in a X...N interaction. PMID- 21528967 TI - Density functional theory of inhomogeneous liquids. IV. Squared-gradient approximation and classical nucleation theory. AB - The squared-gradient approximation to the modified-core Van der Waals density functional theory model is developed. A simple, explicit expression for the SGA coefficient involving only the bulk equation of state and the interaction potential is given. The model is solved for planar interfaces and spherical clusters and is shown to be quantitatively accurate in comparison to computer simulations. An approximate technique for solving the SGA based on piecewise linear density profiles is introduced and is shown to give reasonable zeroth order approximations to the numerical solution of the model. The piecewise-linear models of spherical clusters are shown to be a natural extension of classical nucleation theory and serve to clarify some of the nonclassical effects previously observed in liquid-vapor nucleation. Nucleation pathways are investigated using both constrained energy-minimization and steepest-descent techniques. PMID- 21528968 TI - Isotope effects in liquid water by infrared spectroscopy. V. A sea of OH4 of C2v symmetry. AB - The two water gas OH stretch vibrations that absorb in the infrared (IR) near 3700 cm(-1) are redshifted to near 3300 cm(-1) upon liquefaction. The bathochromic shift is due to the formation of four H-bonds: two are from the labile hydrogen atoms to neighbors and two are received from neighbors by the oxygen free electron pairs. Therefore, the water oxygen atom is surrounded by four hydrogen atoms, two of these make covalent bonds that make H-bonds and two are oxygen H-bonded. However, these permute at rate in the ps range. When the water molecules are isolated in acetonitrile (MeCN) or acetone (Me(2)CO), only the labile hydrogen atoms make H-bonds with the solvent. The bathochromic shift of the OH stretch bands is then almost 130 cm(-1) with, however, the asymmetric (nu(3)) and symmetric (nu(1)) stretch bands maintained. When more water is added to the solutions, the oxygen lone doublets make H-bonds with the available labile hydrogen atoms from neighboring water molecules. With one bond accepted, the bathochromic shift is further displaced by almost 170 cm(-1). When the second oxygen doublet is filled, another bathochromic shift by almost 100 cm(-1) is observed. The total bathochromic shift is near 400 cm(-1) with a full width at half height of near 400 cm(1). This is the case of pure liquid water. Notwithstanding the shift and the band broadness, the nu(3) and nu(1) band individualities are maintained with, however, added satellite companions that come from the far IR (FIR) absorption. These added to the fundamental bands are responsible for the band broadness and almost featureless shape of the massive OH stretch absorption of liquid water. Comparison of light and heavy water mixture spectra indicates that the OH and OD stretch regions show five different configurations: OH(4); OH(3)D; OH(2)D(2); OHD(3); and OD(4) [J. Chem. Phys. 116, 4626 (2002)]. The comparison of the OH bands of OH(4) with that of OHD(3) indicates that the main component in OHD(3) is nu(OH), whereas in OH(4) two main components are present: nu(3) and nu(1). Similar results are obtained for the OD bands of OD(4) and ODH(3). These results indicate that the C(2) (v) symmetry of H(2)O and D(2)O is preserved in the liquid and aqueous solutions whereas C(s) is that of HDO. PMID- 21528969 TI - Molecular dynamics simulations of D2O ice photodesorption. AB - Molecular dynamics (MD) calculations have been performed to study the ultraviolet (UV) photodissociation of D(2)O in an amorphous D(2)O ice surface at 10, 20, 60, and 90 K, in order to investigate the influence of isotope effects on the photodesorption processes. As for H(2)O, the main processes after UV photodissociation are trapping and desorption of either fragments or D(2)O molecules. Trapping mainly takes place in the deeper monolayers of the ice, whereas desorption occurs in the uppermost layers. There are three desorption processes: D atom, OD radical, and D(2)O molecule photodesorption. D(2)O desorption takes places either by direct desorption of a recombined D(2)O molecule, or when an energetic D atom produced by photodissociation kicks a surrounding D(2)O molecule out of the surface by transferring part of its momentum. Desorption probabilities are calculated for photoexcitation of D(2)O in the top four monolayers and are compared quantitatively with those for H(2)O obtained from previous MD simulations of UV photodissociation of amorphous water ice at different ice temperatures [Arasa et al., J. Chem. Phys. 132, 184510 (2010)]. The main conclusions are the same, but the average D atom photodesorption probability is smaller than that of the H atom (by about a factor of 0.9) because D has lower kinetic energy than H, whereas the average OD radical photodesorption probability is larger than that of OH (by about a factor of 2.5 2.9 depending on ice temperature) because OD has higher translational energy than OH for every ice temperature studied. The average D(2)O photodesorption probability is larger than that of H(2)O (by about a factor of 1.4-2.3 depending on ice temperature), and this is entirely due to a larger contribution of the D(2)O kick-out mechanism. This is an isotope effect: the kick-out mechanism is more efficient for D(2)O ice, because the D atom formed after D(2)O photodissociation has a larger momentum than photogenerated H atoms from H(2)O, and D transfers momentum more easily to D(2)O than H to H(2)O. The total (OD + D(2)O) yield has been compared with experiments and the total (OH + H(2)O) yield from previous simulations. We find better agreement when we compare experimental yields with calculated yields for D(2)O ice than when we compare with calculated yields for H(2)O ice. PMID- 21528970 TI - Intermolecular vibrational modes and orientational dynamics of cooperative hydrogen-bonding dimer of 7-azaindole in solution. AB - We observed the low-frequency Raman-active intermolecular vibrational modes of 7 azaindole in CCl(4) by femtosecond Raman-induced Kerr effect spectroscopy. To understand the dynamical aspects and vibrational modes of 7-azaindole in the solution, the ultrafast dynamics of 1-benzofuran in CCl(4) was also examined as a reference and ab initio quantum chemistry calculations were performed for 7 azaindole and 1-benzofuran. The cooperative hydrogen-bonding vibrational bands of 7-azaindole dimer in CCl(4) appeared at 89 cm(-1) and 105 cm(-1) represent the overlap of stagger and wheeling modes and the intermolecular stretching mode, respectively. They are almost independent of the concentration in the solution. We further found from the low-frequency differential Kerr spectra of the solutions with neat CCl(4) that the intermolecular motion in the low frequency region below 20 cm(-1) was less active in the case of 7-azaindole/CCl(4) than in the case of 1-benzofuran/CCl(4). The slow orientational relaxation time in 7 azaindole/CCl(4) is ~3.5 times that in 1-benzofuran/CCl(4) because of the nature of the dimerization of 7-azaindole. PMID- 21528971 TI - Pressure-energy correlations in liquids. V. Isomorphs in generalized Lennard Jones systems. AB - This series of papers is devoted to identifying and explaining the properties of strongly correlating liquids, i.e., liquids with more than 90% correlation between their virial W and potential energy U fluctuations in the NVT ensemble. Paper IV [N. Gnan et al., J. Chem. Phys. 131, 234504 (2009)] showed that strongly correlating liquids have "isomorphs," which are curves in the phase diagram along which structure, dynamics, and some thermodynamic properties are invariant in reduced units. In the present paper, using the fact that reduced-unit radial distribution functions are isomorph invariant, we derive an expression for the shapes of isomorphs in the WU phase diagram of generalized Lennard-Jones systems of one or more types of particles. The isomorph shape depends only on the Lennard Jones exponents; thus all isomorphs of standard Lennard-Jones systems (with exponents 12 and 6) can be scaled onto a single curve. Two applications are given. One tests the prediction that the solid-liquid coexistence curve follows an isomorph by comparing to recent simulations by Ahmed and Sadus [J. Chem. Phys. 131, 174504 (2009)]. Excellent agreement is found on the liquid side of the coexistence curve, whereas the agreement is less convincing on the solid side. A second application is the derivation of an approximate equation of state for generalized Lennard-Jones systems by combining the isomorph theory with the Rosenfeld-Tarazona expression for the temperature dependence of the potential energy on isochores. It is shown that the new equation of state agrees well with simulations. PMID- 21528972 TI - Computer simulation study of the phase behavior and structural relaxation in a gel-former modeled by three-body interactions. AB - We report a computer simulation study of a model gel-former obtained by modifying the three-body interactions of the Stillinger-Weber potential for silicon. This modification reduces the average coordination number and consequently shifts the liquid-gas phase coexistence curve to low densities, thus facilitating the formation of gels without phase separation. At low temperatures and densities, the structure of the system is characterized by the presence of long linear chains interconnected by a small number of three coordinated junctions at random locations. At small wave vectors the static structure factor shows a nonmonotonic dependence on temperature, a behavior which is due to the competition between the percolation transition of the particles and the stiffening of the formed chains. We compare in detail the relaxation dynamics of the system as obtained from molecular dynamics with the one obtained from Monte Carlo dynamics. We find that the bond correlation function displays stretched exponential behavior at moderately low temperatures and densities, but exponential relaxation at low temperatures. The bond lifetime shows an Arrhenius behavior, independent of the microscopic dynamics. For the molecular dynamics at low temperatures, the mean squared displacement and the (coherent and incoherent) intermediate scattering function display at intermediate times a dynamics with ballistic character and we show that this leads to compressed exponential relaxation. For the Monte Carlo dynamics we always find an exponential or stretched exponential relaxation. Thus we conclude that the compressed exponential relaxation observed in experiments is due to the out-of-equilibrium dynamics. PMID- 21528973 TI - Positron annihilation and relaxation dynamics from dielectric spectroscopy and nuclear magnetic resonance: cis-trans-1,4-poly(butadiene). AB - We report a joint analysis of positron annihilation lifetime spectroscopy (PALS), dielectric spectroscopy (BDS), and nuclear magnetic resonance (NMR) on cis-trans 1,4-poly(butadiene) (c-t-1,4-PBD). Phenomenological analysis of the orthopositronium lifetime tau(3)-T dependence by linear fitting reveals four characteristic PALS temperatures: T(b1)(G)=0.63T(g)(PALS), T(g)(PALS), T(b1)(L)=1.22T(g)(PALS), and T(b2)(L)=1.52T(g)(PALS). Slight bend effects in the glassy and supercooled liquid states are related to the fast or slow secondary beta process, from neutron scattering, respectively, the latter being connected with the trans-isomers. In addition, the first bend effect in the supercooled liquid coincides with a deviation of the slow effective secondary beta(eff) relaxation related to the cis-isomers from low-T Arrhenius behavior to non Arrhenius one and correlates with the onset of the primary alpha process from BDS. The second plateau effect in the liquid state occurs when tau(3) becomes commensurable with the structural relaxation time tau(alpha)(T(b2)). It is also approximately related to its crossover from non-Arrhenius to Arrhenius regime in the combined BDS and NMR data. Finally, the combined BDS and NMR structural relaxation data, when analyzed in terms of the two-order parameter (TOP) model, suggest the influence of solidlike domains on both the annihilation behavior and the local and segmental chain mobility in the supercooled liquid. All these findings indicate the influence of the dynamic heterogeneity in both the primary and secondary relaxations due to the cis-trans isomerism in c-t-1,4-PBD and their impact into the PALS response. PMID- 21528974 TI - Free-energy landscape of nucleation with an intermediate metastable phase studied using capillarity approximation. AB - Capillarity approximation is used to study the free-energy landscape of nucleation when an intermediate metastable phase exists. The critical nucleus that corresponds to the saddle point of the free-energy landscape as well as the whole free-energy landscape can be studied using this capillarity approximation, and various scenarios of nucleation and growth can be elucidated. In this study, we consider a model in which a stable solid phase nucleates within a metastable vapor phase when an intermediate metastable liquid phase exists. We predict that a composite critical nucleus that consists of a solid core and a liquid wetting layer as well as pure liquid and pure solid critical nuclei can exist depending not only on the supersaturation of the liquid phase relative to that of the vapor phase but also on the wetting behavior of the liquid surrounding the solid. The existence of liquid critical nucleus indicates that the phase transformation from metastable vapor to stable solid occurs via the intermediate metastable liquid phase, which is quite similar to the scenario of nucleation observed in proteins and colloidal systems. By studying the minimum-free-energy path on the free energy landscape, we can study the evolution of the composition of solid and liquid within nuclei which is not limited to the critical nucleus. PMID- 21528975 TI - Structure and phase behavior of a confined nanodroplet composed of the flexible chain molecules. AB - A polymer density functional theory has been employed for investigating the structure and phase behaviors of the chain polymer, which is modelled as the tangentially connected sphere chain with an attractive interaction, inside the nanosized pores. The excess free energy of the chain polymer has been approximated as the modified fundamental measure-theory for the hard spheres, the Wertheim's first-order perturbation for the chain connectivity, and the mean field approximation for the van der Waals contribution. For the value of the chemical potential corresponding to a stable liquid phase in the bulk system and a metastable vapor phase, the flexible chain molecules undergo the liquid-vapor transition as the pore size is reduced; the vapor is the stable phase at small volume, whereas the liquid is the stable phase at large volume. The wide liquid vapor coexistence curve, which explains the wide range of metastable liquid-vapor states, is observed at low temperature. The increase of temperature and decrease of pore size result in a narrowing of liquid-vapor coexistence curves. The increase of chain length leads to a shift of the liquid-vapor coexistence curve towards lower values of chemical potential. The coexistence curves for the confined phase diagram are contained within the corresponding bulk liquid-vapor coexistence curve. The equilibrium capillary phase transition occurs at a higher chemical potential than in the bulk phase. PMID- 21528976 TI - State-resolved investigation of the photodesorption dynamics of NO from (NO)2 on Ag nanoparticles of various sizes in comparison with Ag(111). AB - The translational and internal state energy distributions of NO desorbed by laser light (2.3, 3.5, and 4.7 eV) from adsorbed (NO)(2) on Ag nanoparticles (NPs) (mean diameters, D = 4, 8, and 11 nm) have been investigated by the (1 + 1) resonance enhanced multiphoton ionization technique. For comparison, the same experiments have also been carried out on Ag(111). Detected NO molecules are hyperthermally fast and both rotationally and vibrationally hot, with temperatures well above the sample temperature. The translational and rotational excitations are positively correlated, while the vibrational excitation is decoupled from the other two degrees of freedom. Most of the energy content of the desorbing NO is contained in its translation. The translational and internal energy distributions of NO molecules photodesorbed by 2.3, 3.5, and in part also 4.7 eV light are approximately constant as a function of Ag NPs sizes, and they are the same on Ag(111). This suggests that for these excitations a common mechanism is operative on the bulk single crystal and on NPs, independent of the size regime. Notably, despite the strongly enhanced cross section seen on NP at 3.5 eV excitation energy in p-polarization, i.e., in resonance with the plasmon excitation, the mechanism is also unchanged. At 4.7 eV and for small particles, however, an additional desorption channel is observed which results in desorbates with higher energies in all degrees of freedom. The results are well compatible with our earlier measurements of size-dependent translational energy distributions. We suggest that the broadly constant mechanism over most of the investigated range runs via a transient negative ion state, while at high excitation energy and for small particles the transient state is suggested to be a positive ion. PMID- 21528977 TI - Pyrene: hydrogenation, hydrogen evolution, and pi-band model. AB - We present a theoretical investigation of the hydrogenation of pyrene and of the subsequent molecular hydrogen evolution. Using density functional theory (DFT) at the GGA-PBE level, the chemical binding of atomic hydrogen to pyrene is found to be exothermic by up to 1.6 eV with a strong site dependence. The edge C atoms are found most reactive. The barrier for the formation of the hydrogen-pyrene bond is small, down to 0.06 eV. A second hydrogen binds barrierless at many sites. The most stable structure of dihydrogenpyrene is more stable by 0.64 eV than pyrene plus a molecular hydrogen molecule and a large barrier of 3.7 eV for the molecular hydrogen evolution is found. Using a simple tight-binding model we demonstrate that the projected density of pi-states can be used to predict the most stable binding sites for hydrogen atoms and the model is used to investigate the most favorable binding sites on more hydrogenated pyrene molecules and on coronene. Some of the DFT calculations were complemented with hybrid-DFT (PBE0) showing a general agreement between the DFT and hybrid-DFT results. PMID- 21528978 TI - A fast algorithm for simulating flow-induced nucleation in polymers. AB - We present a fast computer simulation algorithm for high dimensional barrier crossing simulations. The algorithm is described with reference to the Graham and Olmsted (GO) model of flow-induced nucleation in polymers [R. S. Graham and P. D. Olmsted, Phys. Rev Lett. 103, 115702 (2009)]. Inspired by Chandler's barrier crossing algorithm [D. Chandler, J. Chem. Phys 68, 2959 (1978)], our algorithm simulates only the region around the top of the nucleation barrier, where the system deviates most strongly from equilibrium. When applied to the kinetic Monte Carlo (kMC) routine used in the GO model, our algorithm has two advantages: it requires very little additional coding; and it is simple enough to be applied to any barrier crossing problem that can be written in terms of a kMC simulation. Our fast nucleation algorithm is shown to vastly decrease the computer time required to perform the kMC simulations of high barrier crossing. PMID- 21528979 TI - A comparison of implicit- and explicit-solvent simulations of self-assembly in block copolymer and solute systems. AB - We have developed explicit- and implicit-solvent models for the flash nanoprecipitation process, which involves rapid coprecipitation of block copolymers and solutes by changing solvent quality. The explicit-solvent model uses the dissipative particle dynamics (DPD) method and the implicit-solvent model uses the Brownian dynamics (BD) method. Each of the two models was parameterized to match key properties of the diblock copolymer (specifically, critical micelle concentration, diffusion coefficient, polystyrene melt density, and polyethylene glycol radius of gyration) and the hydrophobic solute (aqueous solubility, diffusion coefficient, and solid density). The models were simulated in the limit of instantaneous mixing of solvent with antisolvent. Despite the significant differences in the potentials employed in the implicit- and explicit solvent models, the polymer-stabilized nanoparticles formed in both sets of simulations are similar in size and structure; however, the dynamic evolution of the two simulations is quite different. Nanoparticles in the BD simulations have diffusion coefficients that follow Rouse behavior (D ? M(-1)), whereas those in the DPD simulations have diffusion coefficients that are close to the values predicted by the Stokes-Einstein relation (D ? R(-1)). As the nanoparticles become larger, the discrepancy between diffusion coefficients grows. As a consequence, BD simulations produce increasingly slower aggregation dynamics with respect to real time and result in an unphysical evolution of the nanoparticle size distribution. Surface area per polymer of the stable explicit-solvent nanoparticles agrees well with experimental values, whereas the implicit-solvent nanoparticles are stable when the surface area per particle is roughly two to four times larger. We conclude that implicit-solvent models may produce questionable results when simulating nonequilibrium processes in which hydrodynamics play a critical role. PMID- 21528980 TI - Anomalous diffusion of oligomerized transmembrane proteins. AB - Transmembrane proteins frequently form (transient) oligomers on biomembranes, e.g., while participating in protein sorting and signaling events. Using coarse grained membrane simulations we show here that transmembrane proteins show a subdiffusive motion on short time scales when being part of a linear oligomer, i.e., a flexible polymer, embedded in a two-dimensional membrane. Our results are in agreement with previous experimental observations. They further indicate that polymers of transmembrane proteins are well described by predictions from Rouse theory in two dimensions even in the presence of hydrodynamic interactions. PMID- 21528982 TI - Lattice model of oligonucleotide hybridization in solution. I. Model and thermodynamics. AB - A coarse-grained lattice model of DNA oligonucleotides is proposed to investigate the general mechanisms by which single-stranded oligonucleotides hybridize to their complementary strands in solution. The model, based on a high-coordination cubic lattice, is simple enough to allow the direct simulation of DNA solutions, yet capturing how the fundamental thermodynamic processes are microscopically encoded in the nucleobase sequences. Physically relevant interactions are considered explicitly, such as interchain excluded volume, anisotropic base pairing and base-stacking, and single-stranded bending rigidity. The model is studied in detail by a specially adapted Monte Carlo simulation method, based on parallel tempering and biased trials, which is designed to overcome the entropic and enthalpic barriers associated with the sampling of hybridization events of multiple single-stranded chains in solution. This methodology addresses both the configurational complexity of bringing together two complementary strands in a favorable orientation (entropic barrier) and the energetic penalty of breaking apart multiple associated bases in a double-stranded state (enthalpic barrier). For strands with sequences restricted to nonstaggering association and homogeneous pairing and stacking energies, base-pairing is found to dominate the hybridization over the translational and conformational entropy. For strands with sequence-dependent pairing corresponding to that of DNA, the complex dependence of the model's thermal stability on concentration, sequence, and degree of complementarity is shown to be qualitatively and quantitatively consistent both with experiment and with the predictions of statistical mechanical models. PMID- 21528981 TI - A permeation theory for single-file ion channels: one- and two-step models. AB - How many steps are required to model permeation through ion channels? This question is investigated by comparing one- and two-step models of permeation with experiment and MD simulation for the first time. In recent MD simulations, the observed permeation mechanism was identified as resembling a Hodgkin and Keynes knock-on mechanism with one voltage-dependent rate-determining step [Jensen et al., PNAS 107, 5833 (2010)]. These previously published simulation data are fitted to a one-step knock-on model that successfully explains the highly non Ohmic current-voltage curve observed in the simulation. However, these predictions (and the simulations upon which they are based) are not representative of real channel behavior, which is typically Ohmic at low voltages. A two-step association/dissociation (A/D) model is then compared with experiment for the first time. This two-parameter model is shown to be remarkably consistent with previously published permeation experiments through the MaxiK potassium channel over a wide range of concentrations and positive voltages. The A/D model also provides a first-order explanation of permeation through the Shaker potassium channel, but it does not explain the asymmetry observed experimentally. To address this, a new asymmetric variant of the A/D model is developed using the present theoretical framework. It includes a third parameter that represents the value of the "permeation coordinate" (fractional electric potential energy) corresponding to the triply occupied state n of the channel. This asymmetric A/D model is fitted to published permeation data through the Shaker potassium channel at physiological concentrations, and it successfully predicts qualitative changes in the negative current-voltage data (including a transition to super-Ohmic behavior) based solely on a fit to positive-voltage data (that appear linear). The A/D model appears to be qualitatively consistent with a large group of published MD simulations, but no quantitative comparison has yet been made. The A/D model makes a network of predictions for how the elementary steps and the channel occupancy vary with both concentration and voltage. In addition, the proposed theoretical framework suggests a new way of plotting the energetics of the simulated system using a one-dimensional permeation coordinate that uses electric potential energy as a metric for the net fractional progress through the permeation mechanism. This approach has the potential to provide a quantitative connection between atomistic simulations and permeation experiments for the first time. PMID- 21528983 TI - The stretching of single poly-ubiquitin molecules: static versus dynamic disorder in the non-exponential kinetics of chain unfolding. AB - Static disorder has recently been implicated in the non-exponential kinetics of the unfolding of single molecules of poly-ubiquitin under a constant force [Kuo, Garcia-Manyes, Li, Barel, Lu, Berne, Urbakh, Klafter, and Fernandez, Proc. Natl. Acad. Sci. U.S.A. 107, 11336 (2010)]. In the present paper, it is suggested that dynamic disorder may provide a plausible, alternative description of the experimental observations. This suggestion is made on the basis of a model in which the barrier to chain unfolding is assumed to be modulated by a control parameter r that evolves in a parabolic potential under the action of fractional Gaussian noise according to a generalized Langevin equation. The treatment of dynamic disorder within this model is pursued using Zwanzig's indirect approach to noise averaging [Acc. Chem. Res. 23, 148 (1990)]. In conjunction with a self consistent closure scheme developed by Wilemski and Fixman [J. Chem. Phys. 58, 4009 (1973); ibid. 60, 866 (1974)], this approach eventually leads to an expression for the chain unfolding probability that can be made to fit the corresponding experimental data very closely. PMID- 21528984 TI - Comment on "Uncertainties in scaling factors for ab initio vibrational zero-point energies" [J. Chem. Phys. 130, 114102 (2009)] and "Calibration sets and the accuracy of vibrational scaling factors: a case study with the X3LYP hybrid functional" [J. Chem. Phys. 133, 114109 (2010)]. PMID- 21528989 TI - Application of a scattered-light radiometric power meter. AB - The power measurement of high-power continuous-wave laser beams typically calls for the use of water-cooled thermopile power meters. Large thermopile meters have slow response times that can prove insufficient to conduct certain tests, such as determining the influence of atmospheric turbulence on transmitted beam power. To achieve faster response times, we calibrated a digital camera to measure the power level as the optical beam is projected onto a white surface. This scattered light radiometric power meter saves the expense of purchasing a large area power meter and the required water cooling. In addition, the system can report the power distribution, changes in the position, and the spot size of the beam. This paper presents the theory of the scattered-light radiometric power meter and demonstrates its use during a field test at a 2.2 km optical range. PMID- 21528990 TI - A system and methodologies for absolute quantum efficiency measurements from the vacuum ultraviolet through the near infrared. AB - In this paper we present our system design and methodology for making absolute quantum efficiency (QE) measurements through the vacuum ultraviolet (VUV) and verify the system with delta-doped silicon CCDs. Delta-doped detectors provide an excellent platform to validate measurements through the VUV due to their enhanced UV response. The requirements for measuring QE through the VUV are more strenuous than measurements in the near UV and necessitate, among other things, the use of a vacuum monochromator, good dewar chamber vacuum to prevent on-chip condensation, and more stringent handling requirements. PMID- 21528991 TI - A comb-sampling method for enhanced mass analysis in linear electrostatic ion traps. AB - In this paper an algorithm for extracting spectral information from signals containing a series of narrow periodic impulses is presented. Such signals can typically be acquired by pickup detectors from the image-charge of ion bunches oscillating in a linear electrostatic ion trap, where frequency analysis provides a scheme for high-resolution mass spectrometry. To provide an improved technique for such frequency analysis, we introduce the CHIMERA algorithm (Comb-sampling for High-resolution IMpulse-train frequency ExtRAaction). This algorithm utilizes a comb function to generate frequency coefficients, rather than using sinusoids via a Fourier transform, since the comb provides a superior match to the data. This new technique is developed theoretically, applied to synthetic data, and then used to perform high resolution mass spectrometry on real data from an ion trap. If the ions are generated at a localized point in time and space, and the data is simultaneously acquired with multiple pickup rings, the method is shown to be a significant improvement on Fourier analysis. The mass spectra generated typically have an order of magnitude higher resolution compared with that obtained from fundamental Fourier frequencies, and are absent of large contributions from harmonic frequency components. PMID- 21528992 TI - Self-eliminating instrumental frequency response from free carrier absorption signals for silicon wafer characterization. AB - Accurate determination of electronic transport properties of semiconductor wafers with modulated free carrier absorption (MFCA) and multiparameter fitting requires the total elimination of instrumental response from the MFCA signals. In this paper, an approach to eliminate the effect of instrumental response on the frequency dependence of MFCA amplitude and phase is developed both theoretically and experimentally to simultaneously determine the transport properties (minority carrier lifetime, carrier diffusion coefficient, and front surface recombination velocity) of silicon wafers. Experimental results showed that with the proposed method the instrumental frequency response was fully eliminated from the experimental MFCA data and had no impact on the multiparameter fitting, while with conventional methods the accuracy of the fitted transport parameters was influenced detrimentally by the errors of the measured instrumental frequency responses, in particular for the minority-carrier lifetime and the front surface recombination velocity. PMID- 21528993 TI - Polarization-preserving confocal microscope for optical experiments in a dilution refrigerator with high magnetic field. AB - We present the design and operation of a fiber-based cryogenic confocal microscope. It is designed as a compact cold-finger that fits inside the bore of a superconducting magnet, and which is a modular unit that can be easily swapped between use in a dilution refrigerator and other cryostats. We aimed at application in quantum optical experiments with electron spins in semiconductors and the design has been optimized for driving with and detection of optical fields with well-defined polarizations. This was implemented with optical access via a polarization maintaining fiber together with Voigt geometry at the cold finger, which circumvents Faraday rotations in the optical components in high magnetic fields. Our unit is versatile for use in experiments that measure photoluminescence, reflection, or transmission, as we demonstrate with a quantum optical experiment with an ensemble of donor-bound electrons in a thin GaAs film. PMID- 21528994 TI - The hyperspectral irradiometer, a new instrument for long-term and unattended field spectroscopy measurements. AB - Reliable time series of vegetation optical properties are needed to improve the modeling of the terrestrial carbon budget with remote sensing data. This paper describes the development of an automatic spectral system able to collect continuous long-term in-field spectral measurements of spectral down-welling and surface reflected irradiance. The paper addresses the development of the system, named hyperspectral irradiometer (HSI), describes its optical design, the acquisition, and processing operations. Measurements gathered on a vegetated surface by the HSI are shown, discussed and compared with experimental outcomes with independent instruments. PMID- 21528995 TI - Small-sized dichroic atomic vapor laser lock. AB - Two, lightweight diode laser frequency stabilization systems designed for experiments in the field are described. A significant reduction in size and weight in both models supports the further miniaturization of measurement devices in the field. Similar to a previous design, magnetic field lines are contained within a magnetic shield enclosing permanent magnets and a Rb cell, so that these dichroic atomic vapor laser lock (DAVLL) systems may be used for magnetically sensitive instruments. The mini-DAVLL system (49 mm long) uses a vapor cell (20 mm long) and does not require cell heaters. An even smaller micro-DAVLL system (9 mm long) uses a microfabricated cell (3 mm square) and requires heaters. These new systems show no degradation in performance with regard to previous designs while considerably reducing dimensions. PMID- 21528996 TI - An integrated laser Raman optical sensor for fast detection of nitrogen and oxygen in a cryogenic mixture. AB - An integrated fiber optic Raman sensor was designed for real-time, nonintrusive detection of liquid nitrogen (LN(2)) in liquid oxygen (LO(2)) at high pressures and high flow rates. This was intended to monitor the quality of LO(2) in oxidizer feed lines during the ground testing of rocket engines. Various issues related to optical diagnosis of cryogenic fluids (LN(2)/LO(2)) in supercritical environment of rocket engine test facility, such as fluorescence from impurity in optical window of feed line, signal-noise ratio, and fast data acquisition time, etc., are well addressed. The integrated sensor employed a frequency doubled 532 nm continuous wave Nd:YAG laser as an excitation light source. The other optical components included were InPhotonics Raman probes, spectrometers, and photomultiplier tubes (PMTs). The spectrometer was used to collect the Raman spectrum of LN(2) and LO(2). The PMT detection unit was integrated with home built LABVIEW software for fast monitoring of concentration ratios LN(2) and LO(2). Prior to designing an integrated sensor system, its optical components were also tested with gaseous nitrogen (GN(2)) and oxygen (GO(2)). PMID- 21528997 TI - One-dimensional space resolving flat-field holographic grating soft x-ray framing camera spectrograph for laser plasma diagnostics. AB - A 1D space resolving x-ray spectrum diagnostic system has been developed to study the radiation opacity of hot plasma on SG-II laser facility. The diagnostic system consists of a 2400 lines/mm flat-field holographic grating and a gated microchannel plate coupled with an optical CCD and covers the wavelength range of 5-50 A. The holographic grating was compared with a ruled one by measuring the emission spectra from a laser-produced molybdenum plasma. The results indicate that the holographic grating possesses better sensitivity than the ruled grating having nearly similar spectral resolution. The spectrograph has been used in radiative opacity measurement of Fe plasma. Simultaneous measurements of the backlight source and the transmission spectrum in appointed time range in one shot have been accomplished successfully with the holographic grating spectrometer. The 2p-3d transition absorption of Fe plasma near 15.5 A in has been observed clearly. PMID- 21528998 TI - Characteristics of stand-alone microlenses in fiber-based fluorescence imaging applications. AB - Microlens-ended fibers, which have found tremendous interest in the recent past, find potential biomedical applications, in particular, in endoscopic imaging. The work presented in this paper focuses on the stand-alone microlenses along with custom-fabricated specialty optical fiber, such as imaging fiber, for probe imaging applications. Stand-alone self-aligned microlenses have been fabricated employing microcompression molding and then attached at the end facet of imaging fiber. A detailed characterization of the fabricated microlens is carried and it demonstrates appropriate focusing ability, high fluorescence collection efficiency and imaging ability for biomedical applications. The surface roughness of the microlens is found to be 25 nm with a minimum spot size of 38 MUm. The probe imaging system is found to be able to image the fluorescence microspheres of 10 MUm size. The collection efficiency of the fiber probe with lens found to be enhanced by three times approximately. PMID- 21528999 TI - A novel high resolution ion wide angle spectrometer. AB - A novel ion wide angle spectrometer (iWASP) has been developed, which is capable of measuring angularly resolved energy distributions of protons and a second ion species, such as carbon C(6 +), simultaneously. The energy resolution for protons and carbon ions is better than 10% at ~50 MeV/nucleon and thus suitable for the study of novel laser-ion acceleration schemes aiming for ultrahigh particle energies. A wedged magnet design enables an acceptance angle of 30 degrees (~524 mrad) and high angular accuracy in the MUrad range. First, results obtained at the LANL Trident laser facility are presented demonstrating high energy and angular resolution of this novel iWASP. PMID- 21529000 TI - Design and characterization of optical heads for interferometric ballistic velocity measurements. AB - The design of optical fiber based heads offering high accuracy and bandwidth for use in VISAR (velocity interferometer system for any reflector) experiments measuring ballistic velocities is described. A new, expanded, model for predicting the distance-dependent collection efficiency of the heads is presented. The model is shown to agree very well with experimental results, both within and outside the "depth of field". Various optical heads are demonstrated, to suit different experimental setups and conditions. Designs offering options for high bandwidths, accurate prealignment, and large stand-off distances are discussed. Results from a typical VISAR experiment are presented, verifying that our designs yield high-quality data. PMID- 21529001 TI - A novel compact design of calibration equipment for gas and thermal sensors. AB - A novel design of calibration equipment has been developed for static and dynamic calibrations of gas and thermal sensors. This system is cheap, compact, and easily adjustable, which is also combined with a plasma surface modification source for tailoring the surface of sensors to ensure the sensitivity and selectivity. The main advantage of this equipment is that the operating temperature, bias voltage, types of plasma source (for surface modification), types of feeding gases, and gas flow rate (for calibrations), etc., can be independently controlled. This novel system provides a highly reliable, reproducible, and economical method of calibrations for various gas and thermal sensors. PMID- 21529002 TI - Two-screen single-shot electron spectrometer for laser wakefield accelerated electron beams. AB - The laser wakefield acceleration electron beams can essentially deviate from the axis of the system, which distinguishes them greatly from beams of conventional accelerators. In case of energy measurements by means of a permanent-magnet electron spectrometer, the deviation angle can affect accuracy, especially for high energies. A two-screen single-shot electron spectrometer that correctly allows for variations of the angle of entry is considered. The spectrometer design enables enhancing accuracy of measuring narrow electron beams significantly as compared to a one-screen spectrometer with analogous magnetic field, size, and angular acceptance. PMID- 21529003 TI - Double-sensor method for detection of oscillating electric field. AB - An electric-field sensor consisting of thin copper plates is designed to measure an oscillating electric field produced by charge separations on a plasma column. The sensor installed in a vacuum region around plasma detects charges induced by the electric field on the copper plates. The value of the induced charges depends not only on the strength of the electric field, but also on the design of the sensor. To obtain the correct strength of the electric field, a correction factor arising from the design of the sensor must be known. The factor is calculated numerically using Laplace's equation and compared with a value measured using a uniform electric field in the frequency range of 10-500 kHz. When an external circuit is connected to the sensor to measure the induced charges, the electric field around the sensor is disturbed. Therefore, a double-sensor method for excluding a disturbed component in the measured electric field is proposed. The reliability of the double-sensor method is confirmed by measuring dipole-like and quadrupole-like electric fields. PMID- 21529004 TI - A novel algorithm for quick and continuous tracing the change of radon concentration in environment. AB - Several measurements of the radon concentration are performed by RAD7 in the University of South China. We find that 30-40 min is needed for RAD7 for tracing the concentration of the standard radon chamber. There are two reasons. The first is that the sufficient time of air cycle is needed for the radon concentration in internal cell of RAD7 equal to that of the environment; and the second is that the sufficient decay time is needed for the (218)Po concentration in internal cell of RAD7 equal to that of the radon. We used a zeroth order approximation to describe the evolution of the environment radon concentration, and obtained a novel algorithm for quick and continuous tracing the change of radon concentration. The corrected radon concentration obtained through this method is in good agreement with the reference value. This method can be applied to develop and improve the instruments for tracing the change of radon concentration quickly. PMID- 21529005 TI - A compact repetitive high-voltage nanosecond pulse generator for the application of gas discharge. AB - Uniform and stable discharge plasma requires very short duration pulses with fast rise times. A repetitive high-voltage nanosecond pulse generator for the application of gas discharge is presented in this paper. It is constructed with all solid-state components. Two-stage magnetic compression is used to generate a short duration pulse. Unlike in some reported studies, common commercial fast recovery diodes instead of a semiconductor opening switch (SOS) are used in our experiment that plays the role of SOS. The SOS-like effects of four different kinds of diodes are studied experimentally to optimize the output performance. It is found that the output pulse voltage is higher with a shorter reverse recovery time, and the rise time of pulse becomes faster when the falling time of reverse recovery current is shorter. The SOS-like effect of the diodes can be adjusted by changing the external circuit parameters. Through optimization the pulse generator can provide a pulsed voltage of 40 kV with a 40 ns duration, 10 ns rise time, and pulse repetition frequency of up to 5 kHz. Diffuse plasma can be formed in air at standard atmospheric pressure using the developed pulse generator. With a light weight and small packaging the pulse generator is suitable for gas discharge application. PMID- 21529006 TI - Ion temperature fluctuation measurements using a retarding field analyzer. AB - The retarding field analyzer (RFA) is a widely used diagnostic tool for the ion temperature measurement in the scrape-off-layer (SOL) of the thermonuclear plasma devices. However, the temporal resolution in the standard RFA application is restricted to the ms timescale. In this paper, a dc operation of the RFA is considered, which allows for the measurement of the plasma ion temperature fluctuations. The method is based on the relation for the RFA current-voltage (I V) characteristic resulted from a common RFA model of shifted Maxwellian distribution of the analyzed ions, and the measurements of two points on the exponentially decaying region of the I-V characteristic with two differently dc biased RFA electrodes. The method has been tested and compared with conventional RFA measurements of the ion temperature in the tokamak ISTTOK SOL plasma. An ion temperature of T(i) = 17 eV is obtained near the limiter position. The agreement between the results of the two methods is within ~25%. The amplitude of the ion temperature fluctuations is found to be around 5 eV at this location. The method has been validated by taking into account the effect of fluctuations in the plasma potential and the noise contamination, proving the reliability of the results obtained. Finally, constrains to the method application are discussed that include a negligible electron emission from the RFA grids and the restriction to operate in the exponentially decaying region of the I-V characteristic. PMID- 21529007 TI - Angled long tip to tuning fork probes for atomic force microscopy in various environments. AB - We expand the range of applications of a tuning fork probe (TFP) in frequency modulation atomic force microscopy (FM-AFM) by attaching a long metal tip at a certain angle. By the combined flexure of the metal tip and the tuning fork prong, this TFP can change the direction of the detectable force by switching the resonance frequency, which has not been realized with conventional TFPs with short tips. The oscillatory behavior of the tip apex of the TFP is predicted by computer simulations and is experimentally confirmed with scanning electron microscope. FM-AFM operations using this TFP are performed in various environments, i.e., in ultrahigh vacuum, air, and water. FM-AFM images obtained at an atomic step of highly oriented pyrolytic graphite in air show a clear difference depending on the excitation frequency. It is also revealed that the higher order flexural modes of this TFP are advantageous for FM-AFM in water due to the reduction in the degree of hydrodynamic damping. PMID- 21529008 TI - Optical sectioning microscope with a binary hologram based beam scanning. AB - We describe the development of a beam scanning microscope that can perform optical sectioning based on the principle of confocal microscopy. The scanning is performed by a laser beam diffracted from a dynamic binary hologram implemented using a liquid crystal spatial light modulator. Using the proposed scanning mechanism, unlike the conventional confocal microscopes, scanning over a two dimensional area of the sample can be obtained without the use of a pair of galvo mirror scanners. The proposed microscope has a number of advantages, such as superior frame to frame repeatability, simpler optical arrangement, increased pixel dwell time relative to the time between two pixels, illumination of only the sample points without pulsing the laser, and absolute control over the amplitude and phase of the illumination beam on a pixel to pixel basis. The proposed microscope can be particularly useful for applications requiring very long exposure time or very large working distance objective lenses. In this paper we present experimental implementation of the setup using a nematic liquid crystal spatial light modulator and proof-of-concept experimental results. PMID- 21529009 TI - Piezoresistive cantilever force-clamp system. AB - We present a microelectromechanical device-based tool, namely, a force-clamp system that sets or "clamps" the scaled force and can apply designed loading profiles (e.g., constant, sinusoidal) of a desired magnitude. The system implements a piezoresistive cantilever as a force sensor and the built-in capacitive sensor of a piezoelectric actuator as a displacement sensor, such that sample indentation depth can be directly calculated from the force and displacement signals. A programmable real-time controller operating at 100 kHz feedback calculates the driving voltage of the actuator. The system has two distinct modes: a force-clamp mode that controls the force applied to a sample and a displacement-clamp mode that controls the moving distance of the actuator. We demonstrate that the system has a large dynamic range (sub-nN up to tens of MUN force and nm up to tens of MUm displacement) in both air and water, and excellent dynamic response (fast response time, <2 ms and large bandwidth, 1 Hz up to 1 kHz). In addition, the system has been specifically designed to be integrated with other instruments such as a microscope with patch-clamp electronics. We demonstrate the capabilities of the system by using it to calibrate the stiffness and sensitivity of an electrostatic actuator and to measure the mechanics of a living, freely moving Caenorhabditis elegans nematode. PMID- 21529010 TI - Experimental observation of contact mode cantilever dynamics with nanosecond resolution. AB - We report the use of a laser Doppler vibrometer to measure the motion of an atomic force microscope contact mode cantilever during continuous line scans of a mica surface. With a sufficiently high density of measurement points the dynamics of the entire cantilever beam, from the apex to the base, can be reconstructed. We demonstrate nanosecond resolution of both rectangular and triangular cantilevers. This technique permits visualization and quantitative measurements of both the normal and lateral tip sample interactions for the first and higher order eigenmodes. The ability to derive quantitative lateral force measurements is of interest to the field of microtribology/nanotribology while the comprehensive understanding of the cantilever's dynamics also aids new cantilever designs and simulations. PMID- 21529011 TI - A high frequency sensor for optical beam deflection atomic force microscopy. AB - We demonstrate a novel electronic readout for quadrant photodiode based optical beam deflection setups. In our readout, the signals used to calculate the deflections remain as currents, instead of undergoing an immediate conversion to voltages. Bipolar current mirrors are used to perform all mathematical operations at the transistor level, including the signal normalizing division. This method has numerous advantages, leading to significantly simpler designs that avoid large voltage swings and parasitic capacitances. The bandwidth of our readout is solely limited by the capacitance of the quadrant photodiode junctions, making the effective bandwidth a function of the intensity of photocurrents and thus the applied power of the beam deflection laser. Using commercially available components and laser intensities of 1-4 mW we achieved a 3 dB bandwidth of 20 MHz with deflection sensitivities of up to 0.5-1 V/nm and deflection noise levels below 4.5 fm/Hz. Atomic resolution imaging of muscovite mica using FM-AFM in water demonstrates the sensitivity of this novel readout. PMID- 21529013 TI - Topography and near-field image measurement of soft biological samples in liquid by using a tuning fork based bent optical-fiber sensor. AB - The fabrication of a tuning fork based bent optical-fiber sensor and its application for topography and near-field image measurement of soft biological samples in physiological solution are reported. By adopting the bent optical fiber and tuning fork feedback scheme, the possibility of signal interference with stray light is minimized, which is especially important for near-field applications. From the measured tuning fork amplitude and its calibration with the preamplifier output voltage, it was determined that the interaction force between the fiber tip and a soft sample in liquid needs to be controlled within approximately 10 nN level and that the image quality depends sensitively to the interaction force. The results of topography measurements of fixed COS-7 and MCF 7 cells in phosphate buffered saline and of the near-field imaging of red blood cell also in phosphate buffered saline with a resolution of about 100 nm are presented. PMID- 21529012 TI - Image reconstruction from sparse data in synchrotron-radiation-based microtomography. AB - Synchrotron-radiation-based microcomputed-tomography (SR-MUCT) is a powerful tool for yielding 3D structural information of high spatial and contrast resolution about a specimen preserved in its natural state. A large number of projection views are required currently for yielding SR-MUCT images by use of existing algorithms without significant artifacts. When a wet biological specimen is imaged, synchrotron x-ray radiation from a large number of projection views can result in significant structural deformation within the specimen. A possible approach to reducing imaging time and specimen deformation is to decrease the number of projection views. In the work, using reconstruction algorithms developed recently for medical computed tomography (CT), we investigate and demonstrate image reconstruction from sparse-view data acquired in SR-MUCT. Numerical results of our study suggest that images of practical value can be obtained from data acquired at a number of projection views significantly lower than those used currently in a typical SR-MUCT imaging experiment. PMID- 21529014 TI - High-sensitivity Q-band electron spin resonance imaging system with submicron resolution. AB - A pulsed electron spin resonance (ESR) microimaging system operating at the Q band frequency range is presented. The system includes a pulsed ESR spectrometer, gradient drivers, and a unique high-sensitivity imaging probe. The pulsed gradient drivers are capable of producing peak currents ranging from ~9 A for short 150 ns pulses up to more than 94 A for long 1400 ns gradient pulses. Under optimal conditions, the imaging probe provides spin sensitivity of ~1.6 * 10(8) spins/?Hz or ~2.7 * 10(6) spins for 1 h of acquisition. This combination of high gradients and high spin sensitivity enables the acquisition of ESR images with a resolution down to ~440 nm for a high spin concentration solid sample (~10(8) spins/MUm(3)) and ~6.7 MUm for a low spin concentration liquid sample (~6 * 10(5) spins/MUm(3)). Potential applications of this system range from the imaging of point defects in crystals and semiconductors to measurements of oxygen concentration in biological samples. PMID- 21529015 TI - A high-pressure atomic force microscope for imaging in supercritical carbon dioxide. AB - A high-pressure atomic force microscope (AFM) that enables in situ, atomic scale measurements of topography of solid surfaces in contact with supercritical CO(2) (scCO(2)) fluids has been developed. This apparatus overcomes the pressure limitations of the hydrothermal AFM and is designed to handle pressures up to 100 atm at temperatures up to ~350 K. A standard optically-based cantilever deflection detection system was chosen. When imaging in compressible supercritical fluids such as scCO(2), precise control of pressure and temperature in the fluid cell is the primary technical challenge. Noise levels and imaging resolution depend on minimization of fluid density fluctuations that change the fluid refractive index and hence the laser path. We demonstrate with our apparatus in situ atomic scale imaging of a calcite (CaCO(3)) mineral surface in scCO(2); both single, monatomic steps and dynamic processes occurring on the (1014) surface are presented. This new AFM provides unprecedented in situ access to interfacial phenomena at solid-fluid interfaces under pressure. PMID- 21529016 TI - High speed nano-metrology. AB - For manufacturing at the nanometre scale a method for rapid and accurate measurement of the resultant functional devices is required. Although atomic force microscopy (AFM) has the requisite spatial resolution, it is severely limited in scan speed, the resolution and repeatability of vertical and lateral measurements being degraded when speed is increased. Here we present a new approach to AFM that makes a direct and feedback-independent measurement of surface height using a laser interferometer focused onto the back of the AFM tip. Combining this direct height measurement with a passive, feedback-free method for maintaining tip-sample contact removes the constraint on scan speed that comes from the bandwidth of the z-feedback loop. Conventional laser reflection detection is used for feedback control, which now plays the role of minimising tip-sample forces, rather than producing the sample topography. Using the system in conjunction with a rapid scanner, true height images are obtained with areas up to (36 * 36) MUm(2) at 1 image/second, suitable for in-line applications. PMID- 21529017 TI - Multipurpose modular experimental station for the DiProI beamline of Fermi@Elettra free electron laser. AB - We present a compact modular apparatus with a flexible design that will be operated at the DiProI beamline of the Fermi@Elettra free electron laser (FEL) for performing static and time-resolved coherent diffraction imaging experiments, taking advantage of the full coherence and variable polarization of the short seeded FEL pulses. The apparatus has been assembled and the potential of the experimental setup is demonstrated by commissioning tests with coherent synchrotron radiation. This multipurpose experimental station will be open to general users after installation at the Fermi@Elettra free electron laser in 2011. PMID- 21529018 TI - A precise method for visualizing dispersive features in image plots. AB - In order to improve the advantages and the reliability of the second derivative method in tracking the position of extrema from experimental curves, we develop a novel analysis method based on the mathematical concept of curvature. We derive the formulas for the curvature in one and two dimensions and demonstrate their applicability to simulated and experimental angle-resolved photoemission spectroscopy data. As compared to the second derivative, our new method improves the localization of the extrema and reduces the peak broadness for a better visualization on intensity image plots. PMID- 21529019 TI - A micro-optical modulation spectroscopy technique for local strain measurement. AB - We provide a high throughput method of performing optical modulation spectroscopy, such as photoreflectance or other spectroscopy techniques which include photoluminescence on a micrometric resolution scale of the order of 10 MUm. The spectroscopic technique is designed for strain induced by process in silicon wafers. The optical system is optimized using a polarizing beamsplitter in conjunction with a single Fresnel rhomb for the provision of an optimum separation of the reflected probe beam with minimal optical losses. In addition, a rapid detection system is used that allows the spectrum to be acquired within few seconds. PMID- 21529020 TI - Versatile, high sensitivity, and automatized angular dependent vectorial Kerr magnetometer for the analysis of nanostructured materials. AB - Magneto-optical Kerr effect (MOKE) magnetometry is an indispensable, reliable, and one of the most widely used techniques for the characterization of nanostructured magnetic materials. Information, such as the magnitude of coercive fields or anisotropy strengths, can be readily obtained from MOKE measurements. We present a description of our state-of-the-art vectorial MOKE magnetometer, being an extremely versatile, accurate, and sensitivity unit with a low cost and comparatively simple setup. The unit includes focusing lenses and an automatized stepper motor stage for angular dependent measurements. The performance of the magnetometer is demonstrated by hysteresis loops of Co thin films displaying uniaxial anisotropy induced on growth, MnIr/CoFe structures exhibiting the so called exchange bias effect, spin valves, and microfabricated flux guides produced by optical lithography. PMID- 21529021 TI - Studying single nanocrystals under high pressure using an x-ray nanoprobe. AB - In this report, we demonstrate the feasibility of applying a 250-nm focused x-ray beam to study a single crystalline NbSe(3) nanobelt under high-pressure conditions in a diamond anvil cell. With such a small probe, we not only resolved the distribution and morphology of each individual nanobelt in the x-ray fluorescence maps but also obtained the diffraction patterns from individual crystalline nanobelts with thicknesses of less than 50 nm. Single crystalline diffraction measurements on NbSe(3) nanobelts were performed at pressures up to 20 GPa. PMID- 21529022 TI - Fiber-coupled laser-driven flyer plates system. AB - A system for the launch of hypervelocity flyer plates has been developed and characterized. Laser-driven flyers were launched from the substrate backed aluminum-alumina-aluminum sandwiched films. A laser-induced plasma is used to drive flyers with typical thickness of 5.5 MUm and diameters of less than 1 mm, to achieve velocities of a few km/s. These flyer plates have many applications, from micrometeorite simulation to laser ignition. The flyer plates considered here have up to three layers: an ablation layer, to form plasma; an insulating layer; and a final, thicker layer that forms the final flyer plates. This technique was developed aiming at improving the energy efficiency of the system. The kinetic energy of flyers launched with the additional layer was found to be enhanced by a factor of near 2 (up to 30%). The optical fiber delivery system governs the output spatial profile of the laser spot and power capacity. Moreover, a technique for coupling high-power laser pulses into an optical fiber has been developed. This fiber optic system has been successfully used to launch flyer plates, and the surface finishing quality of the fiber was found to be an important factor. Importantly, measurements of the flyer performance including the mean velocities and planarity were made by an optical time-of-arrival technique using an optical fiber array probe, demonstrating the good planarity of the flyer and the achievable average velocity of 1.7 km/s with approaching 1 mm diameter. Finally, the relationship between flyer velocities and incident laser pulses energy was also investigated. PMID- 21529023 TI - A spectroscopic proton-exchange membrane fuel cell test setup allowing fluorescence x-ray absorption spectroscopy measurements during state-of-the-art cell tests. AB - A test setup for membrane-electrode-assemblies (MEAs) of proton exchange membrane fuel cells which allows in situ fluorescence x-ray absorption spectroscopy studies of one electrode with safe exclusion of contributions from the counter electrode is described. Interference by the counter electrode is excluded by a geometry including a small angle of incidence (< 6 degrees ) between primary beam and electrode layer. The cell has been constructed by introducing just minor modifications to an electrochemical state-of-the-art MEA test setup, which ensures realistic electrochemical test conditions. This is at the expense of significant intensity losses in the path of the incident beam, which calls for the brilliance of third-generation synchrotrons to provide meaningful data. In measurements on Pt/C and Pt-Co/C cathodes combined with Pt-C anodes (H(2)/O(2) feed), good data quality was demonstrated both for the majority element Pt as well as for Co despite of a low areal Co density in the order of 0.02 mg/cm(2). PMID- 21529024 TI - An effusive molecular beam technique for studies of polyatomic gas-surface reactivity and energy transfer. AB - An effusive molecular beam technique is described to measure alkane dissociative sticking coefficients, S(T(g), T(s); theta), on metal surfaces for which the impinging gas temperature, T(g), and surface temperature, T(s), can be independently varied, along with the angle of incidence, theta, of the impinging gas. Effusive beam experiments with T(g) = T(s) = T allow for determination of angle-resolved dissociative sticking coefficients, S(T; theta), which when averaged over the cos (theta)/pi angular distribution appropriate to the impinging flux from a thermal ambient gas yield the thermal dissociative sticking coefficient, S(T). Nonequilibrium S(T(g), T(s); theta) measurements for which T(g) ? T(s) provide additional opportunities to characterize the transition state and gas-surface energy transfer at reactive energies. A resistively heated effusive molecular beam doser controls the T(g) of the impinging gas striking the surface. The flux of molecules striking the surface from the effusive beam is determined from knowledge of the dosing geometry, chamber pressure, and pumping speed. Separate experiments with a calibrated leak serve to fix the chamber pumping speed. Postdosing Auger electron spectroscopy is used to measure the carbon of the alkyl radical reaction product that is deposited on the surface as a result of alkane dissociative sticking. As implemented in a typical ultrahigh vacuum chamber for surface analysis, the technique has provided access to a dynamic range of roughly 6 orders of magnitude in the initial dissociative sticking coefficient for small alkanes on Pt(111). PMID- 21529025 TI - Intersatellite laser ranging with homodyne optical phase locking for Space Advanced Gravity Measurements mission. AB - In this paper, we present the scheme and the preliminary results of an intersatellite laser ranging system that is designed for the Earth's gravity recovery mission proposed in China, called Space Advanced Gravity Measurements (SAGM). The proposed intersatellite distance is about 100 km and the precision of inter-satellite range monitoring is 10 nm/Hz(1/2) at 0.1 Hz. To meet the needs, we designed a transponder-type intersatellite laser ranging system by using a homodyne optical phase locking technique, which is different from the heterodyne optical phase-locked loop used in GRACE follow-on mission. Since an ultrastable oscillator is unnecessary in the homodyne phase-locked loop, the measurement error caused by the frequency instability of the ultrastable oscillator need not be taken into account. In the preliminary study, a heterodyne interferometer with 10-m baseline (measurement arm-length) was built up to demonstrate the validity of the measurement scheme. The measurement results show that a resolution of displacement measurement of about 3.2 nm had been achieved. PMID- 21529026 TI - Apparatus for dimensional characterization of fused silica fibers for the suspensions of advanced gravitational wave detectors. AB - Detection of gravitational waves from astrophysical sources remains one of the most challenging problems faced by experimental physicists. A significant limit to the sensitivity of future long-baseline interferometric gravitational wave detectors is thermal displacement noise of the test mass mirrors and their suspensions. Suspension thermal noise results from mechanical dissipation in the fused silica suspension fibers suspending the test mass mirrors and is therefore an important noise source at operating frequencies between ~10 and 30 Hz. This dissipation occurs due to a combination of thermoelastic damping, surface and bulk losses. Its effects can be reduced by optimizing the thermoelastic and surface loss, and these parameters are a function of the cross sectional dimensions of the fiber along its length. This paper presents a new apparatus capable of high resolution measurements of the cross sectional dimensions of suspension fibers of both rectangular and circular cross section, suitable for use in advanced detector mirror suspensions. PMID- 21529027 TI - A layered microchip conductance detector with through-layer access to detection fields and high sensitivity to dielectric constant. AB - The present study explores a novel apertured microchip conductance detector (AMCD) that is sensitive to dielectric constant. Fashioned on silicon oxide/silicon using optical microlithography, the detector has novel parallel plate geometry with a top mesh electrode, a middle apertured insulator, and a bottom conducting electrode. This monolithic apertured architecture is planar and may be provided with a thin insulator layer enabling large capacitances, while the top mesh electrode and middle apertured-insulator enable access to regions of the capacitor where electric fields are strong. Hence, the detector is sensitive yet mechanically robust. To test its response, the AMCD was immersed in various solvents, namely water, methanol, acetonitrile, and hexanes. Its response was found to vary in proportion to the solvents' respective dielectric constants. The AMCD was also able to distinguish quantitatively the presence of various molecules in solution, including molecules with chromophores [such as acetylsalicylic acid (ASA)] in methanol and those without chrompohores [such as polyethylene glycol 200 Daltons (PEG200)] in methanol or water. The universal nature of dielectric constant and the microchip detector's sensitivity point to a wide range of potential applications. PMID- 21529028 TI - Characterization of a high mechanical-Q fiber laser Lorentz force dc magnetometer. AB - A magnetic field sensor is described based on coupling the field into a time varying strain in a fiber laser strain sensor, through the Lorentzian force. A conducting bridge carries an ac current and oscillates at resonance in the presence of a magnetic field. A fiber laser strain sensor attached to the ribbon measures the deflections. The quality factor is shown to be limited by air damping resulting in a measurement resolution of 704 pT/Hz(1/2)+/-10% at ambient pressure and 360 pT/Hz(1/2)+/-10% at a reduced pressure of 1700 Pa at 1 Hz and 75 mA (rms). PMID- 21529029 TI - Split Hopkinson resonant bar test for sonic-frequency acoustic velocity and attenuation measurements of small, isotropic geological samples. AB - Mechanical properties (seismic velocities and attenuation) of geological materials are often frequency dependent, which necessitates measurements of the properties at frequencies relevant to a problem at hand. Conventional acoustic resonant bar tests allow measuring seismic properties of rocks and sediments at sonic frequencies (several kilohertz) that are close to the frequencies employed for geophysical exploration of oil and gas resources. However, the tests require a long, slender sample, which is often difficult to obtain from the deep subsurface or from weak and fractured geological formations. In this paper, an alternative measurement technique to conventional resonant bar tests is presented. This technique uses only a small, jacketed rock or sediment core sample mediating a pair of long, metal extension bars with attached seismic source and receiver-the same geometry as the split Hopkinson pressure bar test for large-strain, dynamic impact experiments. Because of the length and mass added to the sample, the resonance frequency of the entire system can be lowered significantly, compared to the sample alone. The experiment can be conducted under elevated confining pressures up to tens of MPa and temperatures above 100 [ordinal indicator, masculine]C, and concurrently with x-ray CT imaging. The described split Hopkinson resonant bar test is applied in two steps. First, extension and torsion-mode resonance frequencies and attenuation of the entire system are measured. Next, numerical inversions for the complex Young's and shear moduli of the sample are performed. One particularly important step is the correction of the inverted Young's moduli for the effect of sample-rod interfaces. Examples of the application are given for homogeneous, isotropic polymer samples, and a natural rock sample. PMID- 21529030 TI - Laser-nucleated acoustic cavitation in focused ultrasound. AB - Acoustic cavitation can occur in therapeutic applications of high-amplitude focused ultrasound. Studying acoustic cavitation has been challenging, because the onset of nucleation is unpredictable. We hypothesized that acoustic cavitation can be forced to occur at a specific location using a laser to nucleate a microcavity in a pre-established ultrasound field. In this paper we describe a scientific instrument that is dedicated to this outcome, combining a focused ultrasound transducer with a pulsed laser. We present high-speed photographic observations of laser-induced cavitation and laser-nucleated acoustic cavitation, at frame rates of 0.5*10(6) frames per second, from laser pulses of energy above and below the optical breakdown threshold, respectively. Acoustic recordings demonstrated inertial cavitation can be controllably introduced to the ultrasound focus. This technique will contribute to the understanding of cavitation evolution in focused ultrasound including for potential therapeutic applications. PMID- 21529031 TI - Reduction of temperature fluctuation within low temperature region using a cryocooler. AB - Modeling and experiments are performed to decrease temperature fluctuation generated by the periodic motion of the displacer in a Gifford-McMahon (GM) type cryocooler within the low-temperature region. The one-dimensional heat equation allows us to show that thermal diffusivity is an essential factor to achieve much smaller temperature fluctuation, and fiber-reinforced plastic (FRP) with low thermal diffusivity makes it possible to reduce the temperature fluctuation dramatically. Based on the model, experiments are performed to vary the thickness of two FRP dampers, on the cryohead of the cryocooler and on the sample stage. As a result, the FRP dampers enable us to achieve the temperature fluctuations of only 0.7 mK, corresponding to a standard deviation of 0.25 mK, when the sample stage is maintained at 4.2000 K, even if a GM cryocooler is utilized for cooling the temperature, which introduces an initial temperature fluctuation of 282 mK at the cryohead. PMID- 21529032 TI - Photoacoustic detection of CO2 based on LABVIEW at 10.303 MUm. AB - A detailed study on a photoacoustic carbon dioxide detection system, through sound card based on virtual instrument, is presented in this paper. In this system, the CO(2) concentration was measured with the non-resonant photoacoustic cell technique through measuring the photoacoustic signal caused by the CO(2). In order to obtain small photoacoustic signals buried in noise, a measurement software was designed with LABVIEW. It has functions of Lock-in Amplifier, digital filter, and signal generator; can also be used to achieve spectrum analysis and signal recovery; has been provided with powerful function for data processing and communication with other measuring instrument. The test results show that the entire system has an outstanding measuring performance with the sensitivity of 10 MUv between 10-44 KHz. The non-resonance test of the trace gas analyte CO(2) conducted at 100 Hz demonstrated large signals (15.89 mV) for CO(2) concentrations at 600 ppm and high signal-to-noise values (~85:1). PMID- 21529033 TI - Detection of high frequency intensity oscillations at RESEDA using the CASCADE detector. AB - We have explored the technological potential of combining neutron resonance spin echo (NRSE) with the time-of-flight method in quasielastic neutron scattering (QENS) experiments. For these test measurements at the new NRSE instrument RESEDA (FRM II, Munich), we have employed CASCADE, one of the fastest neutron detectors in the world, developed at the University of Heidelberg. Conventionally, scintillation detectors are used, in order to detect neutron intensities with high time resolution. In contrast, we used the new CASCADE detector converting neutrons in thin (10)B layers being capable of resolving neutron intensity modulations up to the megahertz regime. This fast detector allows us to abandon the last resonance flip coil of a standard NRSE setup. The classical spin echo signal is replaced by a time-modulated signal. In this setup, fast intensity modulations are present at the detector position. In order to demonstrate, that NRSE-CASCADE operates well up to detector frequencies of 10 MHz, we performed elastic polarization test measurements on a standard sample. The CASCADE detector is a multidetector accumulating counts in 128 * 128 pixels on a surface of 200 mm * 200 mm. We have analyzed the signal in 600 pixels, providing information about the spin phase reaching the detector and about the resolution function of this new variant tested at RESEDA. PMID- 21529034 TI - High voltage pulser with a fast fall-time for plasma immersion ion implantation. AB - A novel high voltage (HV) modulator that offers a short fall time to minimize sputtering effects and allow more precise control of the incident ion fluence in plasma immersion ion implantation is described. The use of 36 insulated-gate bipolar transistors in the 30 kV hard-tube pulser reduces the HV fall time to 3.5 MUs, compared to a fall time of 80 MUs if a pull-down resister is used. The voltage balance is achieved by a voltage-balancing resistor, clamped capacitance, and the synchronization of drive signals. Compared to the traditional method employing a pull-down resister or an additional hard tube, our design consumes less power and is more economical and reliable. PMID- 21529035 TI - An apparatus for in situ spectroscopy of radiation damage of polymers by bombardment with high-energy heavy ions. AB - A new target station providing Fourier transform infrared (FT-IR) spectroscopy and residual gas analysis (RGA) for in situ observation of ion-induced changes in polymers has been installed at the GSI Helmholtz Centre for Heavy Ion Research. The installations as well as first in situ measurements at room temperature are presented here. A foil of polyimide Kapton HN((r)) was irradiated with 1.1 GeV Au ions. During irradiation several in situ FT-IR spectra were recorded. Simultaneously outgassing degradation products were detected with the RGA. In the IR spectra nearly all bands decrease due to the degradation of the molecular structure. In the region from 3000 to 2700 cm(-1) vibration bands of saturated hydrocarbons not reported in literature so far became visible. The outgassing experiments show a mixture of C(2)H(4), CO, and N(2) as the main outgassing components of polyimide. The ability to combine both analytical methods and the opportunity to measure a whole fluence series within a single experiment show the efficiency of the new setup. PMID- 21529036 TI - Extensional rheometer for in situ x-ray scattering study on flow-induced crystallization of polymer. AB - We designed and constructed an extensional rheometer for in situ small and wide angle x-ray study on flow-induced crystallization of polymer. Two rotating drums with an axis distance of 20 mm are employed to impose extensional deformation on the samples. With a constant angular velocity, the two drums generate a constant Henkcy strain rate as sample length for testing keeps constant during deformation. An ionic liquid is used as heating medium to prevent polymer melt from bending downward due to gravity, which is excellent in terms of high thermal stability, low viscosity, and relative low adsorption on x-ray. Flow-induced crystallization experiments are conducted with this apparatus on x-ray scattering station in Shanghai Synchrotron Radiation Facility (SSRF), which allows us to collect rheological and structural data simultaneously and may lead to a better understanding on flow-induced crystallization of polymer. PMID- 21529037 TI - Omnifocus video camera. AB - The omnifocus video camera takes videos, in which objects at different distances are all in focus in a single video display. The omnifocus video camera consists of an array of color video cameras combined with a unique distance mapping camera called the Divcam. The color video cameras are all aimed at the same scene, but each is focused at a different distance. The Divcam provides real-time distance information for every pixel in the scene. A pixel selection utility uses the distance information to select individual pixels from the multiple video outputs focused at different distances, in order to generate the final single video display that is everywhere in focus. This paper presents principle of operation, design consideration, detailed construction, and over all performance of the omnifocus video camera. The major emphasis of the paper is the proof of concept, but the prototype has been developed enough to demonstrate the superiority of this video camera over a conventional video camera. The resolution of the prototype is high, capturing even fine details such as fingerprints in the image. Just as the movie camera was a significant advance over the still camera, the omnifocus video camera represents a significant advance over all-focus cameras for still images. PMID- 21529038 TI - The freestanding sensor-based 3omega technique for measuring thermal conductivity of solids: principle and examination. AB - In recent two decades, the 3omega technique has been proven to be valuable for characterizing thermophysical properties of materials from nanoscale to bulk, but some inherent deficiencies in this technique such as laborious and repeated four pad micro strip heater/sensor deposition process and flimsiness of the micro heater/sensor limit its practical applications. Here, the authors report a novel 3omega technique, based on a freestanding sensor replacing the conventional 3omega heater/sensor adjacent to the specimen surface. A zigzag temperature response curve of the new sensor instead of the classical straight line was observed and used to extract the specimen thermal conductivity. Experimental results which excellently agree with calculation values show that the new technique is of great application value to thermal properties characterization of amorphous bulks and hundreds of microns thick wafers. PMID- 21529039 TI - Testing facility for hydrogen storage materials designed to simulate application based conditions. AB - For the daily use of hydrogen storage materials, not only their intrinsic storage properties are important, but also equally important is the performance under practical conditions. Besides the techniques already available for the fundamental characterization of storage materials, there is a growing need to test storage materials under conditions resembling day-to-day use. For that we developed and tested a downscaled hydrogen storage reactor with which it is possible to monitor the hydrogenation behavior under nonideal conditions. Here we present a characterization of the developed reactor setup which enables a fast screening of storage materials. For characterization and calibration purposes, we use the rather well-documented LaNi(5)-Al alloy as reference. The found experimental results agree well with the properties of LaNi(5)-Al as reported in literature. Our results show that this reactor setup enables an efficient screening of new developed storage alloys under realistic conditions and is therefore complementary to the already existing characterization setups. PMID- 21529040 TI - Preparation of W-Ta thin-film thermocouple on diamond anvil cell for in-situ temperature measurement under high pressure. AB - In this paper, a W-Ta thin-film thermocouple has been integrated on a diamond anvil cell by thin-film deposition and photolithography methods. The thermocouple was calibrated and its thermal electromotive force was studied under high pressure. The results indicate that the thermal electromotive force of the thermocouple exhibits a linear relationship with temperature and is not associated with pressure. The resistivity measurement of ZnS powders under high pressure at different temperatures shows that the phase transition pressure decreases as the temperature increases. PMID- 21529041 TI - In situ, noninvasive characterization of superhydrophobic coatings. AB - Light scattering was used to measure the time-dependent loss of air entrapped within a submerged microporous hydrophobic surface subjected to different environmental conditions. The loss of trapped air resulted in a measurable decrease in surface reflectivity and the kinetics of the process was determined in real time and compared to surface properties, such as porosity and morphology. The light-scattering results were compared with measurements of skin-friction drag, static contact angle, and contact-angle hysteresis. The in situ, noninvasive optical technique was shown to correlate well with the more conventional methods for quantifying surface hydrophobicity, such as flow slip and contact angle. PMID- 21529042 TI - Single-mode fiber, velocity interferometry. AB - In this paper, we describe a velocity interferometer system based entirely on single-mode fiber optics. This paper includes a description of principles used in developing the single-mode velocity interferometry system (SMV). The SMV design is based on polarization-insensitive components. Polarization adjusters are included to eliminate the effects of residual birefringence and polarization dependent losses in the interferometers. Characterization measurements and calibration methods needed for data analysis and a method of data analysis are described. Calibration is performed directly using tunable lasers. During development, we demonstrated its operation using exploding-foil bridge-wire fliers up to 200 m/s. In a final test, we demonstrated the SMV in a gas gun experiment up to 1.2 km/sec. As a basis for comparison in the gas gun experiment, we used another velocimetry technique that is also based on single-mode fiber optics: photonic Doppler velocimetry (PDV). For the gas gun experiment, we split the light returned from a single target spot and performed a direct comparison of the homodyne (SMV) and heterodyne (PDV) techniques concurrently. The two techniques had a negligible mean difference and a 1.5% standard deviation in the one-dimensional shock zone. Within one interferometer delay time after a sudden Doppler shift, a SMV unencumbered by multimode-fiber dispersion exhibits two color beats. These beats have the same period as PDV beats-this interference occurs between the "recently" shifted and "formerly unshifted" paths within the interferometer. We believe that recognizing this identity between homodyne and heterodyne beats is novel in the shock-physics field. SMV includes the conveniences of optical fiber, while removing the time resolution limitations associated with the multimode delivery fiber. PMID- 21529043 TI - Design and development of repetitive capacitor charging power supply based on series-parallel resonant converter topology. AB - LCL resonant converter based repetitive capacitor charging power supply (CCPS) is designed and developed in the division. The LCL converter acts as a constant current source when switching frequency is equal to the resonant frequency. When both resonant inductors' values of LCL converter are same, it results in inherent zero current switching (ZCS) in switches. In this paper, ac analysis with fundamental frequency approximation of LCL resonant tank circuit, frequency dependent of current gain converter followed by design, development, simulation, and practical result is described. Effect of change in switching frequency and resonant frequency and change in resonant inductors ratio on CCPS will be discussed. An efficient CCPS of average output power of 1.2 kJ/s, output voltage 3 kV, and 300 Hz repetition rate is developed in the division. The performance of this CCPS has been evaluated in the laboratory by charging several values of load capacitance at various repetition rates. These results indicate that this design is very feasible for use in capacitor-charging applications. PMID- 21529044 TI - Calibration of ac and dc magnetometers with a Dy2O3 standard. AB - The ac susceptibility and magnetization curves of a glued Dy(2)O(3) powder sample are measured by an ac susceptometer and a dc superconducting quantum interference device magnetometer, both of which have been calibrated previously. It is shown that the magnetic moment of the paramagnetic sample as a function of field and temperature may be accurately expressed by a combination of the Curie-Weiss law and the Langevin function at T > 45 K with three adjusting parameters, so that the dc magnetization curves and the magnitude and phase of ac susceptibility at different values of dc bias field measured by any magnetometer can be calibrated by using Dy(2)O(3) as a standard. The expressions are empirical and cannot be justified in the entire field and temperature range by existing theories of paramagnetism. Below 10 K, indication of approaching a possible phase transition is found. It is shown that pure Dy(2)O(3) powder may be used as a primary standard, with susceptibility [13.28(T + 17)](-1) emu/Oe/g at T > 50 K and H < 10 kOe, in consistency with the Curie-Weiss law and the quantum mechanical theory of paramagnetism. PMID- 21529045 TI - Note: analysis of the efficiency of a dielectric elastomer generator for energy harvesting. AB - In this study, a dielectric elastomer (DE) generator is developed for micropower generation, and its efficiency is derived. It is shown explicitly that power generation efficiency depends on the thickness of the DE generator, the charging voltage, the effective stiffness of the DE generator, the dielectric constant, and the relative deformation. Through experiments with VHBTM 4905 film, the proposed analysis is verified. In particular, the effective stiffness of a DE generator inversely improves the power generation efficiency. PMID- 21529046 TI - Note: fast, small, and low vibration mechanical laser shutters. AB - We present three novel mechanical laser shutter designs based, respectively, on a stepper motor, a relay, and a piezoelectric actuator. Each shutter type is ideally suited to a specific shuttering application. The stepper motor is well suited for applications requiring low vibrations, the relay is compact and capable of rapid bursts, and the piezoelectric is 2 orders of magnitude faster than other available mechanical shutters. PMID- 21529047 TI - Note: a high performance pulse energy detector for Q-switched laser based on photoacoustic effect. AB - A high performance pulse energy detector is developed based on photoacoustic effect. Different from the detectors reported before which also utilized photoacoustic effect, our detector can measure the energy of each pulse output from a Q-switched laser and monitor the pulse energy fluctuation in real time owing to the signal processing circuit designed. By comparing with a commercial laser energy meter, our detector is proved to be of high sensitivity and accuracy. We test the detector under illumination of different pulse energy at varied wavelengths, and the results demonstrate that the detector has a broad spectral response and a dynamical energy range. Besides, the measurements of this detector will not be affected by the background light according to the principle of photoacoustic effect. PMID- 21529048 TI - Note: resonant microwave compressor with two output ports for synchronous energy extraction. AB - The brief theoretical analysis shows the resonant microwave compressor provides the output pulse power higher than the traveling wave power in the storage cavity. The experimental study was made with the model of the S-band microwave compressor. The power of pulses generated by the device reached the value three times as much as the value of the traveling wave power in the storage cavity at the maximum amplification 23 dB, peak power 400 MW, and pulse width 4-5 ns. PMID- 21529049 TI - Note: a portable, light-emitting diode-based ruby fluorescence spectrometer for high-pressure calibration. AB - Ruby (Al(2)O(3), with ~0.5 wt. % Cr doping) is one of the most widely used manometers at the giga-Pascal scale. Traditionally, its fluorescence is excited with intense laser sources. Here, I present a simple, robust, and portable design that employs light-emitting diodes (LEDs) instead. This LED-based system is safer in comparison with laser-based ones. PMID- 21529050 TI - Note: creep character of piezoelectric actuator under switched capacitor charge pump control. AB - A major deficiency in piezoelectric actuator performance is caused by hysteresis and creep effects. Switched capacitor charge pump control was previously proved to be an effective way to reduce hysteresis. In this work, creep character of a piezoelectric stack under charge pump control is investigated and modeled. Experiments show that the creep can be reduced by about 77% compared with the one under voltage control. The creep factor denoting the degree of creep shows hysteresis loops similar to displacement outputs under voltage control. PMID- 21529051 TI - Note: ferrule-top atomic force microscope. II. Imaging in tapping mode and at low temperature. AB - In a recent paper [D.Chavan et al., Rev. Sci. Instrum. 81, 123702 (2010)] we have demonstrated that ferrule-top cantilevers, obtained by carving the end of a ferruled fiber, can be used for contact mode atomic force microscopy in ambient conditions. Here we show that those probes can provide tapping mode images at both room and cryogenic temperatures (12 K). PMID- 21529052 TI - Note: discharging fused silica test masses with ionized nitrogen. AB - We have developed a technique for discharging fused silica test masses in a gravitational-wave interferometer with nitrogen ionized by an electron beam. The electrons are produced from a heated filament by thermionic emission in a low pressure region to avoid contamination and burnout. Some electrons then pass through a small aperture and ionize nitrogen in a higher-pressure region, and this ionized gas is pumped across the test mass surface, neutralizing both polarities of charge. The discharge rate varies exponentially with charge density and filament current, quadratically with filament potential, and has an optimal working pressure of ~8 mT. Adapting the technique to larger test mass chambers is also discussed. PMID- 21529053 TI - Note: ultrasonic gas flowmeter based on optimized time-of-flight algorithms. AB - A new digital signal processor based single path ultrasonic gas flowmeter is designed, constructed, and experimentally tested. To achieve high accuracy measurements, an optimized ultrasound driven method of incorporation of the amplitude modulation and the phase modulation of the transmit-receive technique is used to stimulate the transmitter. Based on the regularities among the received envelope zero-crossings, different received signal's signal-to-noise ratio situations are discriminated and optional time-of-flight algorithms are applied to take flow rate calculations. Experimental results from the dry calibration indicate that the designed flowmeter prototype can meet the zero-flow verification test requirements of the American Gas Association Report No. 9. Furthermore, the results derived from the flow calibration prove that the proposed flowmeter prototype can measure flow rate accurately in the practical experiments, and the nominal accuracies after FWME adjustment are lower than 0.8% throughout the calibration range. PMID- 21529054 TI - Note: electrode polarization of Galinstan electrodes for liquid impedance spectroscopy. AB - Electrode polarization is a significant obstacle in the impedance measurements of ionic liquids. An atomically smooth electrode surface could potentially reduce unwanted impedance contributions from electrode polarization. Liquid metal electrodes were formed by adhering Galinstan to acrylic plates in a parallel plate capacitor arrangement. Electrode polarization was compared to a similar cell with stainless steel electrodes. The impedance of salt and protein solutions (beta-lactoglobulin) was measured from 40 Hz to 110 MHz. Because of oxide layer formation, the performance of the Galinstan electrode is significantly different than the theoretical ideal. PMID- 21529055 TI - Note: design and characterization of an optical light source based on mixture of white and near-ultraviolet light emitting diode spectra. AB - An optical light source based on a solid-state lighting technology is designed. Main components of the light source are a phosphor-converted white and a near ultraviolet (near-UV) light emitting diodes (LEDs), the spectral power distributions (SPDs) of which are mixed using a fiber optic combiner. The near-UV LED is used for improving insufficient SPDs of the white LED at shorter wavelengths of the visible radiation. Stable direct current power supplies are also designed and used to operate each of the LED separately. Three steps of the driving current can be selected by means of serial resistors altered with a commutator at nominal current values of ~40%, ~50%, and ~69%. The light source can be used for many characteristic measurements within the scope of photometry and colorimetry. PMID- 21529056 TI - Note: flowing ion population from a resonance cavity source. AB - The experimental low energy plasma for hemispherical analyzers nominal testing thermal plasma facility of Dartmouth College uses a microwave plasma source which generates an ionosphere-like plasma through a two-step process. The plasma is initially generated inside a cylindrical, insulated, resonance cavity. This initial plasma must pass through a sheath in order to enter the main experimental region. This process imparts a significant flow velocity to the ions which has been neglected in previous analysis of this plasma source. We predict the flow energy of the ions to be between 12-15 eV depending on conservation laws and show agreement with experimental results. PMID- 21529057 TI - Note: a simple technique for reduction of the fall time and enhancement of the peak power of diode side-pumped intracavity frequency doubled repetitively Q switched green laser pulse. AB - A simple method to reduce the fall time and enhancement of peak power of intracavity generated Q-switched green pulses is demonstrated. In this method, a mirror with partial transmission at the fundamental lasing wavelength is inserted in front of the nonlinear crystal inside a conventional linear intracavity frequency doubled configuration to form two coupled sub-cavities. The coupled cavity configuration exhibits considerable improvement in the pulse quality. The fall time and timing jitter of the green pulses are reduced by a factor of 2.5 and 4.5, respectively, in comparison to an intracavity frequency doubled system with nearly identical cavity parameters and the peak power of the green pulses is considerably increased. The pulse shape from the Q-switched coupled cavity green laser system is analyzed using the rate equation model. The simulation results are in good agreement with the experiment. PMID- 21529063 TI - Assessment of the role of circulating breast cancer cells in tumor formation and metastatic potential using in vivo flow cytometry. AB - The identification of breast cancer patients who will ultimately progress to metastatic disease is of significant clinical importance. The quantification and assessment of circulating tumor cells (CTCs) has been proposed as one strategy to monitor treatment effectiveness and disease prognosis. However, CTCs have been an elusive population of cells to study because of their small number and difficulties associated with isolation protocols. In vivo flow cytometry (IVFC) can overcome these limitations and provide insights in the role these cells play during primary and metastatic tumor growth. In this study, we used two-color IVFC to examine, for up to ten weeks following orthotopic implantation, changes in the number of circulating human breast cells expressing GFP and a population of circulating hematopoietic cells with strong autofluorescence. We found that the number of detected CTCs in combination with the number of red autofluorescent cells (650 to 690 nm) during the first seven days following implantation was predictive in development of tumor formation and metastasis eight weeks later. These results suggest that the combined detection of these two cell populations could offer a novel approach in the monitoring and prognosis of breast cancer progression, which in turn could aid significantly in their effective treatment. PMID- 21529064 TI - Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy. AB - Multiphoton microscopy was employed for monitoring the structure changes of mouse dermis collagen in the intrinsic- or the extrinsic-age-related processes in vivo. The characteristics of textures in different aging skins were uncovered by fast Fourier transform in which the orientation index and bundle packing of collagen were quantitatively analyzed. Some significant differences in collagen-related changes are found in different aging skins, which can be good indicators for the statuses of aging skins. The results are valuable to the study of aging skin and also of interest to biomedical photonics. PMID- 21529065 TI - Dermal reflectivity determined by optical coherence tomography is an indicator of epidermal hyperplasia and dermal edema within inflamed skin. AB - Psoriasis is a common inflammatory skin disease resulting from genetic and environmental alterations of cutaneous immune responses. While numerous therapeutic targets involved in the immunopathogenesis of psoriasis have been identified, the in vivo dynamics of inflammation in psoriasis remain unclear. We undertook in vivo time course focus-tracked optical coherence tomography (OCT) imaging to noninvasively document cutaneous alterations in mouse skin treated topically with Imiquimod (IMQ), an established model of a psoriasis-like disease. Quantitative appraisal of dermal architectural changes was achieved through a two parameter fit of OCT axial scans in the dermis of the form A(x, y, z) = rho(x, y)exp [-MU(x, y)z]. Ensemble averaging over 2000 axial scans per mouse in each treatment arm revealed no significant changes in the average dermal attenuation rate, , however the average local dermal reflectivity , decreased significantly following 1, 3, and 6 days of IMQ treatment (p < 0.001) in comparison to vehicle-treated control mice. In contrast, epidermal and dermal thickness changes were only significant when comparing controls and 6-day IMQ treated mice. This suggests that dermal alterations, attributed to collagen fiber bundle enlargement, occur prior to epidermal thickness changes due to hyperplasia and dermal thickness changes due to edema. Dermal reflectivity positively correlated with epidermal hyperplasia (r(epi)(2) = 0.78) and dermal edema (r(derm)(2) = 0.86). Our results suggest that dermal reflectivity as measured by OCT can be utilized to quantify a psoriasis-like disease in mice, and thus has the potential to aid in the quantitative assessment of psoriasis in humans. PMID- 21529066 TI - Contact and contactless diffuse reflectance spectroscopy: potential for recovery monitoring of vascular lesions after intense pulsed light treatment. AB - Optical fiber contact probe diffuse reflectance spectroscopy and remote multispectral imaging methods in the spectral range of 400 to 1100 nm were used for skin vascular malformation assessment and recovery tracing after treatment by intense pulsed light. The results confirmed that oxy-hemoglobin relative changes and the optical density difference between lesion and healthy skin in the spectral region 500 to 600 nm may be successfully used for objective appraisal of the therapy effect. Color redness parameter a* = 2 is suggested as a diagnostic border to distinguish healthy skin and vascular lesions, and as the indicator of phototreatment efficiency. Valuable diagnostic information on large area (>5 mm) lesions and lesions with uncertain borders can be proved by the multispectral imaging method. PMID- 21529067 TI - Optical coherence elastography: current status and future applications. AB - Optical coherence tomography (OCT) has several advantages over other imaging modalities, such as angiography and ultrasound, due to its inherently high in vivo resolution, which allows for the identification of morphological tissue structures. Optical coherence elastography (OCE) benefits from the superior spatial resolution of OCT and has promising applications, including cancer diagnosis and the detailed characterization of arterial wall biomechanics, both of which are based on the elastic properties of the tissue under investigation. We present OCE principles based on techniques associated with static and dynamic tissue excitation, and their corresponding elastogram image-reconstruction algorithms are reviewed. OCE techniques, including the development of intravascular- or catheter-based OCE, are in their early stages of development but show great promise for surgical oncology or intravascular cardiology applications. PMID- 21529068 TI - Visualization of light propagation in visible Chinese human head for functional near-infrared spectroscopy. AB - Using the visible Chinese human data set, which faithfully represents human anatomy, we visualize the light propagation in the head in detail based on Monte Carlo simulation. The simulation is verified to agree with published experimental results in terms of a differential path-length factor. The spatial sensitivity profile turns out to seem like a fat tropical fish with strong distortion along the folding cerebral surface. The sensitive brain region covers the gray matter and extends to the superficial white matter, leading to a large penetration depth (>3 cm). Finally, the optimal source-detector separation is suggested to be narrowed down to 3-3.5 cm, while the sensitivity of the detected signal to brain activation reaches the peak of 8%. These results indicate that the cerebral cortex folding geometry actually has substantial effects on light propagation, which should be necessarily considered for applications of functional near infrared spectroscopy. PMID- 21529069 TI - Toward label-free Raman-activated cell sorting of cardiomyocytes derived from human embryonic stem cells. AB - Raman micro-spectroscopy (RMS) has been recently proposed for label-free phenotypic identification of human embryonic stem cells (hESC)-derived cardiomyocytes. However, the methods used for measuring the Raman spectra led to acquisition times of minutes per cell, which is prohibitive for rapid cell sorting applications. In this study we evaluated two measurement strategies that could reduce the measurement time by a factor of more than 100. We show that sampling individual cells with a laser beam focused to a line could eliminate the need of cell raster scanning and achieve high prediction accuracies (>95% specificity and >96% sensitivity) with acquisition times ~ 5 seconds per cell. However, the use of commercially-available higher power lasers could potentially lead to sorting speeds of ~ 10 cells per s. This would start to progress RMS to the field of cell sorting for applications such as enrichment and purification of hESC-derived cardiomyocytes. PMID- 21529070 TI - Monitoring of drug and stimulation induced cerebral blood flow velocity changes in rat sensory cortex using spectral domain Doppler optical coherence tomography. AB - Doppler optical coherence tomography (DOCT) provides a novel method to measure blood flow velocity in vessels with diameter at micrometer scale. In this study, a developed spectral domain DOCT system is applied to monitor cerebral blood flow velocity changes in a rat. An animal model with a cranial window is used, and by application of a drug, light, and electric stimulations, changes in blood flow velocity of the pial artery in sensory cortex are measured in real time. The results show significant differences in blood flow velocity before and after drug administration or light and electric stimulations, demonstrating the feasibility of DOCT in cerebral microcirculation study. Given its noninvasive nature, high spatial resolution, high velocity sensitivity, and high imaging speed, DOCT shows great promise in brain research by imaging blood flow changes at micrometer scale vessels, which helps to understand the pathogenesis of cerebral diseases and neurodegenerative diseases. PMID- 21529071 TI - Intravital microscopy of subpleural alveoli via transthoracic endoscopy. AB - Transfer of too high mechanical energy from the ventilator to the lung's alveolar tissue is the main cause for ventilator-induced lung injury (VILI). To investigate the effects of cyclic energy transfer to the alveoli, we introduce a new method of transthoracic endoscopy that provides morphological as well as functional information about alveolar geometry and mechanics. We evaluate the new endoscopic method to continuously record images of focused subpleural alveoli. The method is evaluated by using finite element modeling techniques and by direct observation of subpleural alveoli both in isolated rat lungs as well as in intact animals (rats). The results confirm the overall low invasiveness of the endoscopic method insofar as the mechanical influences on the recorded alveoli are only marginal. It is, hence, a suited method for intravital microscopy in the rat model as well as in larger animals. PMID- 21529072 TI - Dark-field illuminated reflectance fiber bundle endoscopic microscope. AB - We propose a reflectance fiber bundle microscope using a dark-field illumination configuration for applications in endoscopic medical imaging and diagnostics. Our experiment results show that dark-field illumination can effectively suppress strong specular reflection from the proximal end of the fiber bundle. We realized a lateral resolution of 4.4 MUm using the dark-field illuminated fiber bundle configuration. To demonstrate the feasibility of using the system to study cell morphology, we obtained still and video images of two thyroid cancer cell lines. Our results clearly allow differentiation of different cancer cell types. PMID- 21529073 TI - Optical coherence tomography for high-resolution imaging of mouse development in utero. AB - Although the mouse is a superior model to study mammalian embryonic development, high-resolution live dynamic visualization of mouse embryos remain a technical challenge. We present optical coherence tomography as a novel methodology for live imaging of mouse embryos through the uterine wall thereby allowing for time lapse analysis of developmental processes and direct phenotypic analysis of developing embryos. We assessed the capability of the proposed methodology to visualize structures of the living embryo from embryonic stages 12.5 to 18.5 days postcoitus. Repetitive in utero embryonic imaging is demonstrated. Our work opens the door for a wide range of live, in utero embryonic studies to screen for mutations and understand the effects of pharmacological and toxicological agents leading to birth defects. PMID- 21529074 TI - Reconstruction of fluorescence distribution hidden in biological tissue using mesoscopic epifluorescence tomography. AB - Mesoscopic epifluorescence tomography is a novel technique that discovers fluorescence bio-distribution in small animals by tomographic means in reflectance geometry. A collimated laser beam is scanned over the skin surface to excite fluorophores hidden within the tissue while a CCD camera acquires an image of the fluorescence emission for each source position. This configuration is highly efficient in the visible spectrum range where trans-illumination imaging of small animals is not feasible due to the high tissue absorption and scattering in biological organisms. The reconstruction algorithm is similar to the one used in fluorescence molecular tomography. However, diffusion theory cannot be employed since the source-detector separation for most image pixels is comparable to or below the scattering length of the tissue. Instead Monte Carlo simulations are utilized to predict the sensitivity functions. In a phantom study we show the effect of using enhanced source grid arrangements during the data acquisition and the reconstruction process to minimize boundary artefacts. Furthermore, we present ex vivo data that show high spatial resolution and quantitative accuracy in heterogeneous tissues using GFP-like fluorescence in B6-albino mice up to a depth of 1100 MUm. PMID- 21529075 TI - Resting-state functional connectivity assessed with two diffuse optical tomographic systems. AB - Functional near-infrared spectroscopy (fNIRS) is recently utilized as a new approach to assess resting-state functional connectivity (RSFC) in the human brain. For any new technique or new methodology, it is necessary to be able to replicate similar experiments using different instruments in order to establish its liability and reproducibility. We apply two different diffuse optical tomographic (DOT) systems (i.e., DYNOT and CW5), with various probe arrangements to evaluate RSFC in the sensorimotor cortex by utilizing a previously published experimental protocol and seed-based correlation analysis. Our results exhibit similar spatial patterns and strengths in RSFC between the bilateral motor cortexes. The consistent observations are obtained from both DYNOT and CW5 systems, and are also in good agreement with the previous fNIRS study. Overall, we demonstrate that the fNIRS-based RSFC is reproducible by various DOT imaging systems among different research groups, enhancing the confidence of neuroscience researchers and clinicians to utilize fNIRS for future applications. PMID- 21529076 TI - Development of a stigmatic mass microscope using laser desorption/ionization and a multi-turn time-of-flight mass spectrometer. AB - A novel stigmatic mass microscope using laser desorption/ionization and a multi turn time-of-flight mass spectrometer, MULTUM-IMG, has been developed. Stigmatic ion images of crystal violet masked by a fine square mesh grid with a 12.7 MUm pitch as well as microdot patterns with a 5 MUm dot diameter and a 10 MUm pitch made with rhodamine B were clearly observed. The estimated spatial resolution was about 3 MUm in the linear mode with a 20-fold ion optical magnification. Separating stigmatic ion images according to the time-of-flight, i.e., the mass to-charge ratio of the ions was successfully demonstrated by a microdot pattern made with two different dyes, crystal violet and methylene blue. Stigmatic ion images of a microdot pattern made with crystal violet were observed after circulation in MULTUM-IMG, and the pattern of the ion image was maintained after ten cycles in MULTUM-IMG. A section of a mouse brain stained with crystal violet and methylene blue was observed in the linear mode, and the stigmatic total ion image of crystal violet and methylene blue agreed well with the optical microphotograph of the hippocampus for the same section. PMID- 21529077 TI - Dynamic fluorescence imaging for multiparametric measurement of tumor vasculature. AB - Angiogenesis is essential for tumor growth and a promising target for cancer therapy. Blood vessel monitoring is an indispensable tool for evaluation and development of anti-angiogenic drugs. Here, we report a new noninvasive in vivo imaging tool, named dynamic fluorescence imaging (DyFI), for the simultaneous measurement of multiple vascular parameters including vascular density, perfusion rate, and permeability using spatiotemporal profiles of indocyanine green. Using DyFI in a tumor xenograft model, we quantitatively measured multiple vascular parameters in tumors and normal tissues with high spatial resolution. The multimodality of this method allowed us to find negative spatial correlations between perfusion and permeability. Moreover, DyFI was effective for revealing the early effects of an anti-angiogenic drug. We suggest that DyFI could be a useful tool for the preclinical development of anti-angiogenic drugs. PMID- 21529078 TI - Noncontact detection of dry eye using a custom designed infrared thermal image system. AB - Dry eye syndrome is a common irritating eye disease. Current clinical diagnostic methods are invasive and uncomfortable for patients. This study developed a custom designed noncontact infrared (IR) thermal image system to measure the spatial and temporal variation of the ocular surface temperature over a 6-second eye-open period. This research defined two parameters: the temperature difference value and the compactness value to represent the temperature change and the irregularity of the temperature distribution on the tear film. Using these two parameters, this study achieved discrimination results for the dry eye and the normal eye groups; the sensitivity is 0.84, the specificity is 0.83, and the receiver operating characteristic area is 0.87. The results suggest that the custom designed IR thermal image system may be used as an effective tool for noncontact detection of dry eye. PMID- 21529080 TI - Assessment of inflow and washout of indocyanine green in the adult human brain by monitoring of diffuse reflectance at large source-detector separation. AB - Recently, it was shown in measurements carried out on humans that time-resolved near-infrared reflectometry and fluorescence spectroscopy may allow for discrimination of information originating directly from the brain avoiding influence of contaminating signals related to the perfusion of extracerebral tissues. We report on continuation of these studies, showing that the near infrared light can be detected noninvasively on the surface of the tissue at large interoptode distance. A multichannel time-resolved optical monitoring system was constructed for measurements of diffuse reflectance in optically turbid medium at very large source-detector separation up to 9 cm. The instrument was applied during intravenous injection of indocyanine green and the distributions of times of flight of photons were successfully acquired showing inflow and washout of the dye in the tissue. Time courses of the statistical moments of distributions of times of flight of photons are presented and compared to the results obtained simultaneously at shorter source-detector separations (3, 4, and 5 cm). We show in a series of experiments carried out on physical phantom and healthy volunteers that the time-resolved data acquisition in combination with very large source-detector separation may allow one to improve depth selectivity of perfusion assessment in the brain. PMID- 21529079 TI - Target detection and quantification using a hybrid hand-held diffuse optical tomography and photoacoustic tomography system. AB - We present a photoacoustic tomography-guided diffuse optical tomography approach using a hand-held probe for detection and characterization of deeply-seated targets embedded in a turbid medium. Diffuse optical tomography guided by coregistered ultrasound, MRI, and x ray has demonstrated a great clinical potential to overcome lesion location uncertainty and to improve light quantification accuracy. However, due to the different contrast mechanisms, some lesions may not be detectable by a nonoptical modality but yet have high optical contrast. Photoacoustic tomography utilizes a short-pulsed laser beam to diffusively penetrate into tissue. Upon absorption of the light by the target, photoacoustic waves are generated and used to reconstruct, at ultrasound resolution, the optical absorption distribution that reveals optical contrast. However, the robustness of optical property quantification of targets by photoacoustic tomography is complicated because of the wide range of ultrasound transducer sensitivity, the orientation and shape of the targets relative to the ultrasound array, and the uniformity of the laser beam. We show in this paper that the relative optical absorption map provided by photoacoustic tomography can potentially guide the diffuse optical tomography to accurately reconstruct target absorption maps. PMID- 21529081 TI - New closed-form approximation for skin chromophore mapping. AB - The concentrations of blood and melanin in skin can be estimated based on the reflectance of light. Many models for this estimation have been built, such as Monte Carlo simulation, diffusion models, and the differential modified Beer Lambert law. The optimization-based methods are too slow for chromophore mapping of high-resolution spectral images, and the differential modified Beer-Lambert is not often accurate enough. Optimal coefficients for the differential Beer-Lambert model are calculated by differentiating the diffusion model, optimized to the normal skin spectrum. The derivatives are then used in predicting the difference in chromophore concentrations from the difference in absorption spectra. The accuracy of the method is tested both computationally and experimentally using a Monte Carlo multilayer simulation model, and the data are measured from the palm of a hand during an Allen's test, which modulates the blood content of skin. The correlations of the given and predicted blood, melanin, and oxygen saturation levels are correspondingly r = 0.94, r = 0.99, and r = 0.73. The prediction of the concentrations for all pixels in a 1-megapixel image would take ~ 20 min, which is orders of magnitude faster than the methods based on optimization during the prediction. PMID- 21529082 TI - Application of optical methods to characterize textile materials and their influence on the human skin. AB - The skin is not only the largest organ of the human body, but it is also a barrier to the environment. The major part of the human skin is in constant contact with textile materials. The objective of this study was to characterize textile materials and to investigate their influence on the skin properties. For this purpose, two different textile materials (polyamide and polyester) were objectively characterized by optical coherence tomography and surface structure 3D-profilometry. In addition, subjective textile properties like haptic sensation and stiffness, as tactile characteristics felt by volunteers, were analyzed. The objective textile characteristics and subjective parameters were compared to the barrier properties measured by in vivo laser scanning microscopy . Comparable results were achieved between barrier properties and subjective assessment in relation to the textile characteristics in favor of the polyester fabric. Consequently, the optical method used in dermatology for the analysis of the skin can be applied to characterize and evaluate textile fabrics and their interaction with human skin in vivo. PMID- 21529083 TI - Endomicroscopy imaging of epithelial structures using tissue autofluorescence. AB - We explore autofluorescence endomicroscopy as a potential tool for real-time visualization of epithelial tissue microstructure and organization in a clinical setting. The design parameters are explored using two experimental systems--an Olympus Medical Systems Corp. stand-alone clinical prototype probe, and a custom built bench-top rigid fiber conduit prototype. Both systems entail ultraviolet excitation at 266 nm and/or 325 nm using compact laser sources. Preliminary results using ex vivo animal and human tissue specimens suggest that this technology can be translated toward in vivo application to address the need for real-time histology. PMID- 21529084 TI - Artifact reduction method in ultrasound-guided diffuse optical tomography using exogenous contrast agents. AB - In diffuse optical tomography (DOT), a typical perturbation approach requires two sets of measurements obtained at the lesion breast (lesion or target site) and a contra-lateral location of the normal breast (reference site) for image reconstruction. For patients who have a small amount of breast tissue, the chest wall underneath the breast tissue at both sites affects the imaging results. In this group of patients, the perturbation, which is the difference between measurements obtained at the lesion and reference sites, may include the information of background mismatch which can generate artifacts or affect the reconstructed quantitative absorption coefficient of the lesion. Also, for patients who have a single breast due to prior surgery, the contra-lateral reference is not available. To improve the DOT performance or overcome its limitation, we introduced a new method based on an exogenous contrast agent and demonstrate its performance using animal models. Co-registered ultrasound was used to guide the lesion localization. The results have shown that artifacts caused by background mismatch can be reduced significantly by using this new method. PMID- 21529085 TI - Tomographic bioluminescence imaging reconstruction via a dynamically sparse regularized global method in mouse models. AB - Generally, the performance of tomographic bioluminescence imaging is dependent on several factors, such as regularization parameters and initial guess of source distribution. In this paper, a global-inexact-Newton based reconstruction method, which is regularized by a dynamic sparse term, is presented for tomographic reconstruction. The proposed method can enhance higher imaging reliability and efficiency. In vivo mouse experimental reconstructions were performed to validate the proposed method. Reconstruction comparisons of the proposed method with other methods demonstrate the applicability on an entire region. Moreover, the reliable performance on a wide range of regularization parameters and initial unknown values were also investigated. Based on the in vivo experiment and a mouse atlas, the tolerance for optical property mismatch was evaluated with optical overestimation and underestimation. Additionally, the reconstruction efficiency was also investigated with different sizes of mouse grids. We showed that this method was reliable for tomographic bioluminescence imaging in practical mouse experimental applications. PMID- 21529086 TI - Photoacoustic tomography of foreign bodies in soft biological tissue. AB - In detecting small foreign bodies in soft biological tissue, ultrasound imaging suffers from poor sensitivity (52.6%) and specificity (47.2%). Hence, alternative imaging methods are needed. Photoacoustic (PA) imaging takes advantage of strong optical absorption contrast and high ultrasonic resolution. A PA imaging system is employed to detect foreign bodies in biological tissues. To achieve deep penetration, we use near-infrared light ranging from 750 to 800 nm and a 5-MHz spherically focused ultrasonic transducer. PA images were obtained from various targets including glass, wood, cloth, plastic, and metal embedded more than 1 cm deep in chicken tissue. The locations and sizes of the targets from the PA images agreed well with those of the actual samples. Spectroscopic PA imaging was also performed on the objects. These results suggest that PA imaging can potentially be a useful intraoperative imaging tool to identify foreign bodies. PMID- 21529087 TI - Long-term imaging of mouse embryos using adaptive harmonic generation microscopy. AB - We present a detailed description of an adaptive harmonic generation (HG) microscope and culture techniques that permit long-term, three-dimensional imaging of mouse embryos. HG signal from both pre- and postimplantation stage (0.5-5.5 day-old) mouse embryos are fully characterized. The second HG images reveal central spindles during cytokinesis whereas third HG images show several features, such as lipid droplets, nucleoli, and plasma membranes. The embryos are found to develop normally during one-day-long discontinuous HG imaging, permitting the observation of several dynamic events, such as morula compaction and blastocyst formation. PMID- 21529088 TI - Cell tracking in live Caenorhabditis elegans embryos via third harmonic generation imaging microscopy measurements. AB - In this study, we demonstrate the potential of employing third harmonic generation (THG) imaging microscopy measurements for cell tracking studies in live Caenorhabditis elegans (C. elegans) embryos. A 1028-nm femtosecond laser was used for the excitation of unstained C. elegans samples. Different C. elegans embryonic stages (from two-cell to threefold) were imaged. Live biological specimens were irradiated for prolonged periods of time (up to 7 h), testifying to the nondestructive nature of this nonlinear imaging technique. Thus, THG image contrast modality is a powerful diagnostic tool for probing in vivo cell division during early embryogenesis. PMID- 21529089 TI - Fluorescence recovery after photobleaching on the confocal laser-scanning microscope: generalized model without restriction on the size of the photobleached disk. AB - Fluorescence recovery after photobleaching (FRAP) carried out on a confocal laser scanning microscope (CLSM) performs well for photobleached disks that are large compared to the resolution of the bleaching beam. For smaller disks approaching this resolution, current FRAP models providing a closed-form solution do not allow one to extract the diffusion coefficient accurately. The new generalized disk model we present addresses this shortcoming by bringing into account the bleaching resolution and the total confocal imaging resolution. A closed-form solution is obtained under the assumption of linear photobleaching. Furthermore, simultaneous analysis of FRAP data collected at various disk sizes allows for the intrinsic determination of the instrumental resolution parameters, thereby obviating the need for an extrinsic calibration. A new method to estimate the variance of FRAP data is introduced to allow for proper weighting in this global analysis approach by nonlinear least squares. Experiments are performed on two independent CLSMs on homogeneous samples providing validation over a large range of diffusion coefficients. PMID- 21529090 TI - Waveguide evanescent field fluorescence microscopy: high contrast imaging of a domain forming mixed lipid Langmuir-Blodgett monolayer mimicking lung surfactant. AB - Waveguide evanescent field fluorescence (WEFF) microscopy is a new development that allows the imaging of contact regions between biological cells and their substratum, as well as imaging of ultrathin films such as monomolecular Langmuir Blodgett (LB) films. Mixed-lipid monolayer systems mimicking lung surfactant were fabricated on waveguides using the LB technique and imaged by both WEFF and standard wide field epi-fluorescence microscopy. These two technologies were compared with respect to contrast, photobleaching, and sensitivity. It was found that WEFF microscopy produced images with a much higher contrast, lower photobleaching, and higher sensitivity. In addition, fine structures in the lipidic domains were observed for the first time. PMID- 21529091 TI - Spectroscopic sensitive polarimeter for biomedical applications. AB - We present the design and calibration of a spectroscopic sensitive polarimeter. The polarimeter can measure the full Stokes vector in the wavelength range 550 to 750 nm with 1-nm resolution and consists of a fiber-based spectrophotometer, a white light emitting diode light source, two liquid crystal retarders, and one polarizer. Calibration of the system is achieved with a scheme that does not require knowledge of the polarizing elements' orientation or retardation. Six intensity spectra are required to calculate the full spectrum Stokes vector. Error in the polarimeter is less than 5%. We report the Stokes vectors for light transmitted through nonscattering polarizing elements as well as a measurement of the depolarizing properties of chicken muscle at several wavelengths. PMID- 21529092 TI - Application of near-infrared spectroscopy to measurement of hemodynamic signals accompanying stimulated saliva secretion. AB - We aim to test the feasibility of using near-infrared spectroscopy (NIRS) for indirect measurement of human saliva secretion in response to taste stimuli for potential application to organoleptic testing. We use an NIRS system to measure extracranial hemodynamics (Hb-signals around the temples) of healthy participants when taste stimuli are taken in their mouths. First, the Hb-signals and volume of expelled saliva (stimulated by distilled-water or sucrose-solution intake) are simultaneously measured and large Hb-signal changes in response to the taste stimuli (Hb-responses) are found. Statistical analysis show that both the Hb response and saliva volume are larger for the sucrose solution than for the distilled water with a significant correlation between them (r = 0.81). The effects of swallowing on the Hb-signals are investigated. Similar Hb responses, differing from the sucrose solution and distilled water, are obtained even though the participants swallow the mouth contents. Finally, functional magnetic resonance imaging is used to identify possible sources of the Hb signals corresponding to salivation. Statistical analysis indicates similar responses in the extracranial regions, mainly around the middle meningeal artery. In conclusion, the identified correlation between extracranial hemodynamics and the saliva volume suggests that NIRS is applicable to the measurement of hemodynamic signals accompanying stimulated saliva secretion. PMID- 21529093 TI - Comparison of human optimized bacterial luciferase, firefly luciferase, and green fluorescent protein for continuous imaging of cell culture and animal models. AB - Bioluminescent and fluorescent reporter systems have enabled the rapid and continued growth of the optical imaging field over the last two decades. Of particular interest has been noninvasive signal detection from mammalian tissues under both cell culture and whole animal settings. Here we report on the advantages and limitations of imaging using a recently introduced bacterial luciferase (lux) reporter system engineered for increased bioluminescent expression in the mammalian cellular environment. Comparison with the bioluminescent firefly luciferase (Luc) system and green fluorescent protein system under cell culture conditions demonstrated a reduced average radiance, but maintained a more constant level of bioluminescent output without the need for substrate addition or exogenous excitation to elicit the production of signal. Comparison with the Luc system following subcutaneous and intraperitoneal injection into nude mice hosts demonstrated the ability to obtain similar detection patterns with in vitro experiments at cell population sizes above 2.5 * 10(4) cells but at the cost of increasing overall image integration time. PMID- 21529094 TI - Choroidal laser Doppler flowmeter with enhanced sensitivity based on a scattering plate. AB - A portable choroidal laser Doppler flowmeter (LDF) with enhanced sensitivity based on a scattering plate is developed. The portable LDF is weighted 2 kg operated at center wavelength of 780 nm, leading to a better penetration into the eye fundus in contrast to the previous LDF operated at center wavelength of 670 nm. Enhancement of number of detected photons that undergo Doppler scattering and improved measured speed of choroidal blood flow are achieved with the use of a scattering plate positioned in front of the eye. The mechanism of detection and sensitivity enhancement is theoretically analyzed. Evaluation of system performance is done by in vivo measurements on ten volunteers. The results demonstrate that an increased percentage of backscattering light at high Doppler shift frequency is collected due to utilization of the scattering plate. However, this kind of light detection influences spatial resolution of the system and decreases the total signal measured. The proposed method for detection and sensitivity enhancement might be useful in a case where the perception of very slight alternation of blood flow is pursued and the spatial resolution is not as critical as that in a choroidal vascular bed. PMID- 21529095 TI - Precision of cerebral oxygenation and hemoglobin concentration measurements in neonates measured by near-infrared spectroscopy. AB - BACKGROUND AND AIM: One source of error with near-infrared spectroscopy (NIRS) is the assumption that the measured tissue is optically homogeneous. This is not always the case. Our aim is to assess the impact of tissue homogeneity (TH) on the precision of NIRS measurements in neonates. METHODS: On 36 term and 27 preterm neonates at least five 1-min measurements are performed on each subject using the OxiplexTS. The sensor position is slightly changed before each measurement while assessing TH. The precision for cerebral tissue oxygenation saturation (StO(2)) and total hemoglobin concentration (tHb) are calculated by repeated measures analysis of variance. RESULTS: The mean StO(2) is not significantly different between term and preterm infants. The mean tHb is significantly lower in preterm infants (p < 0.01). With increasing TH, the precision of StO(2) increase from 5.6 to 4.6% for preterm and from 11.0 to 2.0% for term infants; the precision of tHb increases from 10.1 to 7.5MUM for preterm and from 16.4 to 3.5 MUM for term infants. The precision for StO(2) is higher in term than in preterm infants. The precision for tHb shows no significant difference between the two groups. CONCLUSIONS: The precision of NIRS measurements correlates with tissue homogeneity. PMID- 21529096 TI - Development of a compact terahertz time-domain spectrometer for the measurement of the optical properties of biological tissues. AB - Terahertz spectrometers and imaging systems are currently being evaluated as biomedical tools for skin burn assessment. These systems show promise, but due to their size and weight, they have restricted portability, and are impractical for military and battlefield settings where space is limited. In this study, we developed and tested the performance of a compact, light, and portable THz time domain spectroscopy (THz-TDS) device. Optical properties were collected with this system from 0.1 to 1.6 THz for water, ethanol, and several ex vivo porcine tissues (muscle, adipose, skin). For all samples tested, we found that the index of refraction (n) decreases with frequency, while the absorption coefficient (MU(a)) increases with frequency. Muscle, adipose, and frozen/thawed skin samples exhibited comparable n values ranging between 2.5 and 2.0, whereas the n values for freshly harvested skin were roughly 40% lower. Additionally, we found that the freshly harvested samples exhibited higher MU(a) values than the frozen/thawed skin samples. Overall, for all liquids and tissues tested, we found that our system measured optical property values that were consistent with those reported in the literature. These results suggest that our compact THz spectrometer performed comparable to its larger counterparts, and therefore may be a useful and practical tool for skin health assessment. PMID- 21529097 TI - Monte Carlo modeling of in vivo protoporphyrin IX fluorescence and singlet oxygen production during photodynamic therapy for patients presenting with superficial basal cell carcinomas. AB - We present protoporphyrin IX (PpIX) fluorescence measurements acquired from patients presenting with superficial basal cell carcinoma during photodynamic therapy (PDT) treatment, facilitating in vivo photobleaching to be monitored. Monte Carlo (MC) simulations, taking into account photobleaching, are performed on a three-dimensional cube grid, which represents the treatment geometry. Consequently, it is possible to determine the spatial and temporal changes to the origin of collected fluorescence and generated singlet oxygen. From our clinical results, an in vivo photobleaching dose constant, beta of 5-aminolaevulinic acid induced PpIX fluorescence is found to be 14 +/- 1 J/cm(2). Results from our MC simulations suggest that an increase from our typical administered treatment light dose of 75-150 J/cm(2) could increase the effective PDT treatment initially achieved at a depth of 2.7-3.3 mm in the tumor, respectively. Moreover, this increase reduces the surface PpIX fluorescence from 0.00012 to 0.000003 of the maximum value recorded before treatment. The recommendation of administrating a larger light dose, which advocates an increase in the treatment time after surface PpIX fluorescence has diminished, remains valid for different sets of optical properties and therefore should have a beneficial outcome on the total treatment effect. PMID- 21529098 TI - Effect of 405-nm high-intensity narrow-spectrum light on fibroblast-populated collagen lattices: an in vitro model of wound healing. AB - High-intensity narrow-spectrum (HINS) 405-nm light is a novel technology developed to address the significant problem of health-care associated infection. Its potential for wound-decontamination applications is assessed on mammalian cells and bacteria. The fibroblast-populated collagen lattice (FPCL) is used as an in vitro model of wound healing, and the effect of HINS light on contraction is examined. Effects on cell proliferation, morphological changes, and alpha smooth muscle actin (alpha-SMA) expression are investigated. Bactericidal effects are assessed using the bacterium Staphylococcus epidermidis. Low doses of HINS light were found to have no significant inhibitory effects on FPCL contraction, cell proliferation, or alpha-SMA expression. Doses of up to 18 Jcm(-2) had no significant inhibitory effects on FPCL cell numbers, and this dose was shown to cause almost complete inactivation of bacteria. These results show that HINS light has potential for disinfection applications without adversely influencing wound healing. PMID- 21529099 TI - Performance assessment of novel side firing safe tips for endodontic applications. AB - During root canal or periodontal treatment, directing laser energy onto the walls of the root canal is essential for effective disinfection. This study assessed the performance of four different fiber modifications that have increased lateral emission, including three designs with safe tips to reduce irradiation directed toward the root apex. Free-running pulsed infrared lasers (Nd:YAG, Er:YAG, and Er,Cr:YSGG) and a diode laser (980 nm) were used in combination with plain ended (forward emitting) laser fibers; conical laser fibers, side firing honeycomb pattern fibers without a safe end; honeycomb fibers with silver coated ends, conical fibers with selectively abraded tips, and selectively abraded honeycomb fibers with silver coated tips (20 fibers for each laser type). Laser emissions forward and laterally were measured, and digital photographs and thermally sensitive paper used to record the emission profiles. Thermochromic dyes painted onto the root surface of an extracted tooth were used to explore the distribution of laser energy with different tips designs. All three safe tipped ends gave reduced emissions in the forward direction (range 17-59%), but had similar lateral emission characteristics. Fiber designs with reduced forward emission may be useful for various dental laser procedures. PMID- 21529102 TI - Thyroid autoimmunity role in the evolution of endemic goiter in rural area, Fars, Iran. AB - BACKGROUND: WHO reports indicate no iodine insufficiency in Iran, however, goiter is still endemic in Fars Province. This study evaluates the role of thyroid autoimmunity in the evolution of endemic goiter. METHODS: A total of 516 permanent residents of Akbarabad County of the Kavar area in Fars Province, Iran were selected by simple random sampling. Patients with thyroid malignancy and dysfunction, and those who consumed drugs affecting thyroid function were excluded. After signing a written consent form and undergoing a thyroid examination, 5 cc of blood were drawn to measure free T3 and T4 (RIA), TSH (IRMA), and anti-thyroid peroxidase (competitive RIA) levels. Moreover, samples of 50 cc morning urine were collected for the measurement of urinary iodine excretion (UIE; chloridric acid digestion). Data were analyzed by SPSS (version 13). P<0.05 was significant. RESULTS: The prevalence of goiter was 38.4% by WHO classification. The prevalence of children with UIE 2-4.9 ug/dL was 5.8%, which indicated sufficient iodine intake. Goiter was more prevalent in females, as well as in patients with positive anti-TPO or higher TSH titers (P<0.01). The prevalence of positive anti-TPO was higher in goiterous patients than healthy persons (P=0.002), which increased with an increase in age, grade of thyromegaly or TSH (P<0.02). Regression analysis showed the odds ratio for diagnosing goiter in females was 2.4 (P<0.001), in those with positive anti-TPO it was 1.87 (P=0.03) and in those with TSH>5.2 mIU/mL the odds ratio was 2.74 (P=0.01). In adolescents compared to children the odds ratio was 0.36 (P=0.01) and the odds ratio in adults to children was 0.33 (P=0.001). CONCLUSION: This study indicates that despite normal UIE, goiter is endemic in Akbarabad County. Some degree of goiter endemicity may be due to thyroid autoimmunity. PMID- 21529103 TI - Treatment of relapsed acute promyelocytic leukemia by arsenic trioxide in Iran. AB - BACKGROUND: Although standard first line treatment of acute promyelocytic leukemia is All trans retinoic acid (ATRA) and chemotherapy, some patients relapse and need a second line of treatment. Relapsed cases of promyelocytic leukemia can be salvaged with arsenic trioxide. METHODS: Between May 1999 and Jan. 2010, we treated 31 relapsed cases of promyelocytic leukemia with arsenic trioxide. These cases relapsed after previous treatment with ATRA and chemotherapy. We applied arsenic trioxide as 0.15 mg/kg iv infusion until complete remission. After achieving complete remission patients received 2-4 consolidation therapy in the same schedule as remission induction. RESULTS: The median age of patients was 27 years. Complete remission rate was 77.4%. We observed four mortalities during remission induction. With a median follow up of 32 months, ten more relapses occurred. Two year disease-free survival and overall survival for the entire cohort was 54.6% and 81.1%, respectively. CONCLUSION: Our result is the same as other studies. Thus, we suggest that arsenic trioxide can be used as salvage therapy in patients who relapsed. Despite a good complete remission rate, the relapse rate during the first two years of treatment is high and hematopoietic stem cell transplantation should be considered after achieving complete remission. PMID- 21529104 TI - The influence of Bcl-2 and myeloid antigen expression on response to therapy in childhood acute lymphoblastic leukemia. AB - BACKGROUND: The possible prognostic significance of the expression of a variety of markers has been investigated in acute lymphoblastic leukemia (ALL). METHODS: In the present study we investigated the prognostic significance of CD13 and CD33 myeloid antigens (MY) aberrantly expressed on the blasts of ALL patients and Bcl 2 anti- apoptotic molecule expression in childhood ALL. RESULTS: Aberrant expression of MY occurred in 8.8% of cases. Variant levels of Bcl-2 were expressed in patients (44.2+/-25.5%), with more than 20% positivity for Bcl-2 in 64.7% of patients. Bcl-2+ patients survived 959+/-242 days compared to 1059+230 days for Bcl-2- patients (P=0.2). Corresponding data for complete remission duration was 682+/-170 and 716+/-173 days (P=0.3), respectively, indicating no significant association between survival and complete remission duration of patients with expression of the Bcl-2 molecule. Analysis of clinical response according to MY expression, however, showed significant association with survival and complete remission duration. MY+ patients had shorter complete remission duration (383+/-58 days) and survival (473+/-68 days) than MY- patients (complete remission duration, 724+/-144 days; survival, 1045+/-186 days; P<0.001). Expression of Bcl-2 along with MY was not associated with a significant decrease in survival or complete remission duration. CONCLUSION: Results of this study indicated that expression of MY was a poor prognostic factor in childhood ALL. Bcl-2 expression in MY+ patients could not influence the response to therapy. PMID- 21529105 TI - Familial aspects of colorectal cancers in southern littoral of Caspian Sea. AB - BACKGROUND: About 50,000 new cancer cases occur annually in Iran, of which gastrointestinal (GI) cancers are the most common. Colorectal cancers (CRC) account for the third and fourth most prevalent cancers amongst Iranian men and women, respectively. Since CRC has some well-known hereditary forms with differences in their prevalence according to regional heterogeneity, we designed a study to assess familial aspects of this cancer in subjects who reside in Mazandaran Province, Iran. METHODS: We interviewed all CRC patients who attended a private GI clinic during 1999-2007, with histologically confirmed diagnoses of colorectal adenocarcinoma, about their family histories of CRC and age at diagnosis. Pedigrees were drawn up to second-degree relatives. RESULTS: A total of 293 CRC cases enrolled in the study, of which 152 were male and 141 were female. The mean age of patients was 52.6+/-15.2 years. Of these, 98 patients (33.5%) were under the age of 45. A total of 66 cases (22.5%) had familial histories of CRC, being significantly more prevalent in younger subjects (11.2% vs. 44.9%, P<0.0001). Thirty-two patients (10.9%) fulfilled the criteria for hereditary non-polyposis colon cancer. In addition, right-sided colon cancers were more prevalent in those with positive familial histories (P<0.05). CONCLUSION: Due to the frequency of early-onset CRC and familial syndromes, a more intense screening protocol for early detection of CRC should be developed for this population. PMID- 21529106 TI - Overlap of ADHD and oppositional defiant disorder DSM-IV derived criteria. AB - OBJECTIVE: One possible reason for being controversies regarding ADHD may be related to the validity and reliability of diagnostic criteria of attention deficit hyperactivity disorder and oppositional defiant disorder. Diagnostic criteria of oppositional defiant disorder include eight symptoms. This study examines the factor structure of oppositional defiant disorder symptoms, its discriminant validity from attention deficit hyperactivity disorder, its convergent validity and internal reliability. METHODS: Parents of 111 referral children and adolescents with attention deficit hyperactivity disorder completed DSM-IV referenced based attention deficit hyperactivity disorder and oppositional defiant disorder checklists. RESULTS: Factor analysis indicated that the attention deficit hyperactivity disorder symptom of: "often has trouble organizing activities" and "often runs about or climbs when and where it is not appropriate" were a part of the oppositional defiant disorder component. These symptoms less often than other symptoms differentiate attention deficit hyperactivity disorder from oppositional defiant disorder. The convergent validity for oppositional defiant disorder symptoms ranged from 0.64 to 0.79. CONCLUSION: The parent-rating checklist of oppositional defiant disorder symptoms properly differentiates oppositional defiant disorder from attention deficit hyperactivity disorder. However, two items of the attention deficit hyperactivity disorder were listed as symptoms of oppositional defiant disorder. If the factor loading of the items is to be confirmed in further studies, it might be necessary to revise these symptoms criterion in future editions of DSM-IV diagnostic criteria. PMID- 21529107 TI - The effects of demographic factors and cigarette smoking status on drug treatment success rate in outpatient treatment and rehabilitation centers. AB - BACKGROUND: This was an analytical historical cohort study based on an existing data base study conducted in different areas of Tehran. The present study determined the effect of demographic factors and cigarette smoking status on success rate of addiction treatment in outpatient treatment and rehabilitation clinics for substance abusers. METHODS: We accomplished our study in outpatient clinics authorized by the "welfare organization," which included three governmental treatment centers and private centers among those located in 22 regions of Tehran. Data were collected using a checklist, which contained demographic characteristics, personal information and information about prevention, treatment and follow-up records of 1372 patients. Factors associated with addiction treatment success rate were reviewed using multiple logistic regression tests. RESULTS: Our study showed that addiction treatment was successful in only 258 cases (18.8%). The final multiple regression model showed that single and married patients were 2.18 times (P=0.033) and 2.70 times more successful in quitting than divorced, or separated cases (P=0.005). In addition, patients who lived in rental or mortgaged houses were 1.43 times more successful than homeowners (P=0.036). More than 90% of participants in this study were daily smokers at the time of the study. Patients who did not have a history of smoking were 1.69 times more successful than ex-smokers (P=0.007). CONCLUSION: Based on our study results only a few people were successful in addiction treatment; marital status, type of housing, residential status and smoking status were the most important factors associated with the outcome of addiction treatment. PMID- 21529108 TI - Gene dosage analysis of proximal spinal muscular atrophy carriers using real-time PCR. AB - BACKGROUND: Autosomal recessive spinal muscular atrophy is a disease resulting from homozygous absence of SMN1 gene in approximately 94% of SMA patients. To identify patients who retained a single SMN1 copy, SMN1 dosage analysis was performed by quantitative Real-time PCR using SYBR green dye. SMN1 dosage analysis results were utilized to identify carriers before offering prenatal diagnosis. METHOD: Carrier testing was performed for 150 individuals. Copy number of the SMN1 gene was determined by the comparative threshold cycle (Ct) method and human serum albumin gene was used as a reference. RESULT: Analysis of 150 DNA samples with quantitative PCR determined the number of SMN1 gene copies. Of these, 50 (33.33%) cases had one SMN1 gene copy, 87 (58%) had two copies and 13 (8.66%) did not have any copies of SMN1. The homozygous SMN1 deletion ratio was 0.00 and deletion of one copy of SMN1 gene ratio ranged from 0.3 to 0.58. CONCLUSION: This report demonstrates modification of risk estimation for the diagnosis and detection of SMA carriers by accurate determination of SMN1 copy number. SMN1 copy number analysis is an important parameter for identification of couples at risk of having children affected with SMA. It also reduces unwarranted prenatal diagnosis for SMA. Furthermore, the dosage analysis might be useful for the counseling of clinically suspected SMA patients with negative diagnostic SMA tests. PMID- 21529109 TI - Helicobacter pylori and its effects on human health and disease. AB - H. pylori is now a known cause of gastric and duodenal ulcers, noncardia gastric cancer and gastric MALT lymphoma. In addition, the role of this microorganism in causing or preventing a large number of other diseases has been investigated, some of which include esophageal cancer, functional dyspepsia, gastroesophageal reflux disease, asthma, cardiovascular diseases, iron deficiency anemia and idiopathic thrombotic purpura. This article reviews the evidence for these associations and provides suggestions for further research. PMID- 21529110 TI - Soluble Fas in pemphigus vulgaris. AB - BACKGROUND: The Fas/Fas ligand (FasL) system has been recognized as an important pathway for apoptosis induction in cells and tissues. It has recently been shown that skin lesions of pemphigus vulgaris are associated with Fas mediated apoptosis. The aim of this study was to evaluate the level of serum soluble Fas of ten newly diagnosed patients with pemphigus vulgaris. METHODS: Sera were collected from ten patients with pemphigus vulgaris. Commercial sandwich enzyme linked immunosorbent assay (ELISA) for quantitative detection of soluble Fas was applied. RESULTS: Patients with mucosal skin involvement had higher median values in contrast to patients with cutaneous involvement. CONCLUSION: Elevation of soluble Fas in our study may give insights for the pathogenesis of pemphigus vulgaris. Suppression of this underlying mechanism may be an important target for novel therapies and relapse prevention. PMID- 21529111 TI - Theoretical shortcomings of Institutional Review Boards and possible solutions. PMID- 21529112 TI - Bell's palsy associated with chronic HCV infection before and during peginterferon alfa and ribavirin therapy. AB - Neuropsychiatric side effects of peg interferon-alpha (PEG-IFN-alpha) therapy consist of a large spectrum of symptoms. Organic personality syndrome, organic affective syndrome, psychotic manifestations and seizures are more common side effects of PEG-IFN-alpha whereas cranial neuropathy and movement disorders are less common. Bell's palsy is often idiopathic, but has been linked to some viral infections, particularly with herpes viruses. Other infections, such as human immunodeficiency virus infection and Lyme disease, may also lead to idiopathic facial paralysis. Neither acute nor chronic Hepatitis C infection has been implicated previously in Bell's palsy, but PEG-IFN-alpha may play a role. Two patients with CHC who developed Bell's palsy before and during treatment with PEG IFN-alpha and Ribavirin are presented here. PMID- 21529113 TI - Isaac's syndrome associated with CIDP and pregnancy. AB - Neuromyotonia with all its synonyms is a disorder of peripheral nerve hyperexcitability characterized by regular or irregular myokymia, muscle cramps and stiffness, delayed muscle relaxation after contraction, and hyperhidrosis associated with well-described spontaneous electromyographic features. Herein, we report clinical and electrodiagnostic findings of a pregnant woman with neuromyotonia who also suffered from chronic inflammatory demyelinating polyneuropathy. We treated the patient with plasma exchange, 50 mL/kg (twice weekly, for six weeks). After two weeks of treatment, cramps and stiffness were substantially reduced. After four weeks, she looked normal with a relatively smooth gait. After eight weeks, the patient was entirely well with no cramps or stiffness. Repeat EMG showed no myokymic discharges. After four months she was in good health and the plasma exchanges continued every other week without the use of corticosteroids or cytotoxic agents. Afterwards, we discontinued the plasma exchange and only visited the patient regularly. One year later, we repeated a five-day course of plasma exchange to overcome mild recurrence of myokymia in her thighs. Now, after four years, she is healthy without any disability or problem. The patient's child has been healthy throughout without any evidence of neuromyotonia. PMID- 21529114 TI - Congenital tuberculosis presenting as ascites. AB - Congenital tuberculosis is a rare disease of which the most common presentations include respiratory distress, fever, and organomegaly. We report a case of congenital tuberculosis presenting with ascites. PMID- 21529115 TI - Photoclinic. Alveolar hydatid cyst of the liver. PMID- 21529116 TI - Photoclinic. Metastatic prostate adenocarcinoma to the mandible. PMID- 21529117 TI - A brief history of tuberculosis in Iran during the 19th and 20th centuries. AB - The history of tuberculosis as a worldwide fatal illness traces back to antiquity, a well-known disease in ancient civilizations. However, its causative agent remained unidentified until the last decades of the 19th century, when discovered by Robert Koch. In due course, preparation of the BCG vaccine, application of the Mantoux intradermal diagnostic tuberculosis test and administration of proper antituberculosis medications eventually controlled tuberculosis. However, despite these significant advancements tuberculosis remained uneradicated, particularly in developing countries after the emergence of both multidrug-resistant tuberculosis and HIV co-infection. Presented here, is a brief review of the history of tuberculosis in the world as well as its historical background in Iran, mainly during the 19th and 20th centuries. PMID- 21529118 TI - "Scientometric analysis of the major Iranain medical universities". PMID- 21529119 TI - Application of stem cells in Gastroenterology and Hepatology, 6th January 2011; In Memory of Dr. Saeid Kazemi Ashtiani, A Great Scientist Who Passed Away Too Soon But Left A Legacy. PMID- 21529120 TI - Occurrence of both subspecies of Photobacterium damselae in mullets collected in the river Magra (Italy). AB - The natural reservoirs and biological characteristics of pathogenic populations of both subspecies of Photobacterium damselae in aquatic habitants remain unclear because of difficulties in obtaining pathogenic strains from the environment. In the present study, we assessed the occurrence of Photobacterium damselae subsp. piscicida and Photobacterium damselae subsp. damselae , considered to be the causative agent of past epizootic outbreaks in mullets collected in the river Magra, Italy. Two hundred and seventy-eight mullets were collected during a period of two years (2008-2009) and analyzed using multiplex PCR. During this period, 57% of fishes were positive for Photobacterium damselae subsp. piscicida and 37% for Photobacterium damselae subsp. damselae, with an higher presence in summer months although none of PCR-positive mullets showed clinical signs of disease. Our results indicate that the two micro-organisms are widespread in the population of mullets studied, and this could be a possible cause for outbreaks in favourable environmental conditions. PMID- 21529121 TI - Construction and characterization of Lactobacillus pentosus expressing the D antigenic site of the spike protein of Transmissible gastroenteritis virus. AB - This study explored the feasibility of Lactobacillus pentosus as a live vehicle to deliver and express antigen. First of all, L. pentosus transformed by electroporation with the plasmids pg611-6D (anchored) and pg612-6D (secretory) based on the xylose operon generated the recombinant strains rLppg611-6D and rLppg612-6D, respectively, expressing the D antigenic site of the spike (S) protein of Transmissible gastroenteritis virus (TGEV), for intragastric administration in mice. Secondly, we collected serum, fecal, nasal, ophthalmic, and vaginal samples from pre-immune mice and after the first immunization (on days 7, 14, 21, 28, 35, and 42) that were used to analyze the levels of immunoglobulins G and A against TGEV by using ELISA. In addition, a plaque reduction assay was performed using sera from groups pg611, pg612-6D, pg11-6D, and phosphate-buffered saline (blank control) to analyze TGEV-neutralizing antibody activity in vitro. A statistically significant difference in serum tests between groups demonstrated that rLppg612-6D induced better immunogenicity than rLppg611-6D, making rLppg612-6D the better candidate for oral vaccine. Taken together, L. pentosus possessed the potential to become a novel vector for mucosal vaccine in the future. PMID- 21529122 TI - Rhizosphere soil microorganism populations and community structures of different watermelon cultivars with differing resistance to Fusarium oxysporum f. sp. niveum. AB - Fusarium wilt is an increasingly serious disease of watermelon that reduces crop productivity. Changes in microorganism populations and bacterial and fungal community structures in rhizosphere soil of watermelon cultivars resistant or susceptible to Fusarium oxysporum f. sp. niveum were investigated using a plate culture method and PCR-DGGE analysis. Plate culture showed that populations of culturable bacteria and actinomycetes were more abundant in the rhizosphere of the resistant watermelon cultivar than the susceptible cultivar, but the fungi population had the opposite pattern. Populations of Penicillium , Fusarium , and Aspergillus were significantly lower in the resistant cultivar than the susceptible cultivar at the fruiting and uprooting stages (p < 0.05). Pattern matching analysis generated the dendrogram of the DGGE results indicating the relatedness of the different resistant watermelon cultivars and their corresponding rhizosphere microbial communities. Further sequencing analysis of specific bands from DGGE profiles indicated that different groups of bacteria and fungi occurred in the rhizosphere of different watermelon cultivars. Our results demonstrated that plant genotype had a significant impact on soil microbial community structure, and the differences in the rhizosphere microbial community may contribute to the differences in resistance to F. oxysporum f. sp. niveum. PMID- 21529123 TI - Measuring impairment and functional limitations in children with cerebral palsy. AB - OBJECTIVE: The disablement model provides a theoretical framework for the assessments of individuals with cerebral palsy (CP). The purpose of this study was to evaluate the relative validity of multiple measures for impairment and functional limitations and to estimate the relationship between the two global factors using confirmatory factor analysis. METHODS: Over 50 measures of impairment and functional limitations were collected for 57 children with spastic CP. There were 12, 10, 5, 7 and 23 children who were classified in Gross Motor Function Classification System (GMFCS) Levels I to V, respectively. RESULTS: The measures of impairment with the highest factor loadings were several single-item ratings of spasticity; the Modified Ashworth hamstring and biceps ratings, and goniometric measures. All of the functional limitation measures had high factor loadings, including the gross motor function measure, GMFCS, the Paediatric Evaluation of Disability Inventory and WeeFIM self care and mobility scales. The correlation between the global factors of impairment and functional limitations was 0.96, indicating that the two factors are highly correlated in spastic CP. CONCLUSION: The disablement model is a valuable theoretical tool that can be used to organise assessments in CP and to explain how they are related. PMID- 21529124 TI - Psychometric properties of a Chinese version of the Home Environment Measure for Motor Development. AB - PURPOSE: This study examined the psychometric properties of the Chinese version of the Affordance in the Home Environment for Motor Development - Toddler version (AHEMD-Toddler-C) for children developing typically (DT) or having motor delays (MD). METHODS: This was a methodology study. Parent-child dyads with DT (n = 106, mean age of 27.9 months) and with MD (n = 45, 23.6 months) were enrolled. For test-retest reliability, parents completed AHEMD-Toddler-C twice within 2 weeks. For convergent validity, correlations were analysed between AHEMD-Toddler-C and Home Observation for Measurement of the Environment Inventory (HOME), and between AHEMD-Toddler-C and family variables. RESULTS: Test-retest reliabilities for AHEMD-Toddler-C were adequate except for Variety of Stimulation (VS) subscale. For convergent validity, the correlation coefficients between AHEMD and HOME were 0.44 (p <0.05). Two subscales of motor toys of AHEMD demonstrated convergent validity with Learning Material subscale of HOME and some family variables in children with MD. Inside Space subscale of AHEMD correlated with family variables. Outside Space (OS) subscale of AHEMD was not significantly correlated with HOME or family variables. CONCLUSION: AHEMD-Toddler-C is a new measure option to explore the relationships between home environment and motor development in Chinese-speaking countries. Nevertheless, VS and OS subscales should be used cautiously. PMID- 21529125 TI - Active immunization against Pneumocystis carinii with p55-v3 DNA vaccine in rats. AB - Pneumocystis pneumonia (PCP) occurs predominately in patients with impaired immunity. Because standard PCP chemoprophylaxis and chemotherapies have limitations, immunotherapy, particularly vaccination, offers an attractive alternative approach for PCP prevention and treatment. The goal of this study was to evaluate the potential of DNA vaccines targeting two closely related antigens, p55-v0 and p55-v3, in an immunosuppressed rat PCP model. We found that immunization with p55-v0 and p55-v3 DNA vaccines afforded a similar level of protection to rats against PCP, as evidenced by significant reductions in organism burdens, improved histological scores, and lower lung weight to body weight ratios. Additionally, vaccination elicited both cellular and humoral immunity in immunosuppressed rats. Our data suggest the potential of p55 DNA vaccines to protect against PCP in rats. Future work should focus on epitope mapping and identifying protective moieties in each gene. PMID- 21529126 TI - Ability of electromyographic monitoring to determine the presence of malpositioned pedicle screws in the lumbosacral spine: analysis of 2450 consecutively placed screws. AB - OBJECT: Pedicle screws provide efficient stabilization along all 3 columns of the spine, but they can be technically demanding to place, with malposition rates ranging from 5% to 10%. Intraoperative electromyographic (EMG) monitoring has the capacity to objectively identify a screw breaching the medial pedicle cortex that is in proximity to a nerve root. The purpose of this study is to describe and evaluate the authors' 7-year institutional experience with intraoperative EMG monitoring during placement of lumbar pedicle screws and to determine the clinical utility of intraoperative EMG monitoring. METHODS: The authors retrospectively studied 2450 consecutive lumbar pedicle screws placed in 418 patients from June 2002 through June 2009. All screws were inserted using a free hand technique and anatomical landmarks, stimulated at 10.0 mA, and evaluated with CT scanning within 48 hours postoperatively. Medial pedicle screw breach was defined as having greater than 25% of the screw diameter extend outside of the pedicle, as confirmed on CT scanning or intraoperatively by a positive EMG response indicating a medial breach. The sensitivity and specificity of intraoperative EMG monitoring in detecting the presence of a medial screw breach was evaluated based on the following definitions: 1) true positive (a positive response to EMG stimulation confirmed as a breach intraoperatively or on postoperative CT scans); 2) false positive (positive response to EMG stimulation confirmed as a correctly positioned screw on postoperative CT scans); 3) true negative (no response to EMG stimulation confirmed as a correctly positioned screw on postoperative CT scans); or 4) false negative (no response to EMG stimulation but confirmed as a breach on postoperative CT scans). RESULTS: One hundred fifteen pedicle screws (4.7%) showed positive stimulation during intraoperative EMG monitoring. At stimulation thresholds less than 5.0, 5.0-8.0, and > 8.0 mA, the specificity of a positive response was 99.9%, 97.9%, and 95.9%, respectively. The sensitivity of a positive response at these thresholds was only 43.4%, 69.6%, and 69.6%, respectively. At a threshold less than 5.0 mA, 91% of screws with a positive EMG response were confirmed as true medial breaches. However, at thresholds of 5.0-8.0 mA or greater than 8.0 mA, a positive EMG response was associated with 89% and 100% false positives (no breaches), respectively. CONCLUSIONS: When using intraoperative EMG monitoring, a positive response at screw stimulation thresholds less than 5.0 mA was highly specific for a medial pedicle screw breach but was poorly sensitive. A positive response to stimulation thresholds greater 5.0 mA was associated with a very high rate of false positives. The authors' experience suggests that pedicle screws showing positive stimulation below 5.0 mA warrants intraoperative investigation for malpositioning while responses at higher thresholds are less reliable at accurately representing a medial breach. PMID- 21529127 TI - A very rare cause of low-back pain and sciatica: deep vein thrombosis due to absence of the inferior vena cava mimicking the clinical and radiological signs of lumbar disc herniation. AB - The authors report a very rare cause of low-back pain and sciatica in a patient with iliac vein thrombosis attributed to absence of the infrarenal segment of the inferior vena cava (IVC) with massively dilated venous collaterals draining via a paraspinal plexus into the azygous system. This 21-year-old man presented with acute low-back pain radiating to the left ventral thigh. The initial CT scan revealed an intraspinal lesion that mimicked lumbar disc herniation. Further clarification revealed an iliac vein thrombosis, which was triggered by the absence of the infrarenal segment of the IVC, a very rare vascular anomaly. Collateral venous return was developed and led to lumbar varicosities and epidural vein engorgements. Laboratory examinations revealed factor V mutation as a predisposing factor for thrombosis. The patient's symptoms were relieved with anticoagulation and antiinflammatory therapy. Absence of the infrarenal IVC associated with iliac vein thrombosis should be regarded as a very rare cause of radicular and low-back pain, and this condition can mimic the clinical and radiological signs of lumbar disc herniation. Sciatica might be the first clinical manifestation of this rare venous anomaly. PMID- 21529128 TI - Technique of cervicothoracic junction pedicle subtraction osteotomy for cervical sagittal imbalance: report of 11 cases. AB - OBJECT: Sagittal imbalance of the cervicothoracic spine often causes severe pain and loss of horizontal gaze. Historically, the Smith-Peterson osteotomy has been used to restore sagittal balance. Cervicothoracic junction pedicle subtraction osteotomy (PSO) offers more controlled closure and greater biomechanical stability but has been infrequently reported in the literature. This study details the cervicothoracic PSO technique in 11 cases and correlates clinical kyphosis (chin-brow to vertical angle [CBVA]) with radiographic measurements. METHODS: Between February 2008 and September 2010, 11 patients (mean age 70 years) underwent a modified PSO (10 at C-7, 1 at T-1) for treatment of sagittal imbalance. Preoperative and postoperative sagittal plane radiographic measurements were made. The CBVA was measured on clinical photographs. Operative technique and perioperative correction were reported for all 11 patients and long term follow-up data was reported for 9 patients, in whom the mean duration of follow-up was 23 months. Outcome measures used for these 9 patients were the Neck Disability Index, the 36-Item Short Form Health Survey (SF-36), and a visual analog scale for neck pain. RESULTS: The mean values for estimated blood loss, surgical time, and hospital stay in the 11 patients were 1100 ml, 4.3 hours, and 9.9 days, respectively. The mean preoperative and immediate postoperative values (+/- SD) for cervical sagittal imbalance were 7.9 +/- 1.4 cm and 3.4 +/- 1.7 cm. The mean overall correction was 4.5 +/- 1.5 cm (42.8%), the mean PSO correction 19.0 degrees , and the mean CBVA correction 36.7 degrees . There was essentially no correlation between preoperative C2-T1 radiographic kyphosis and preoperative CBVA (R(2) = 0.0165). There was a moderate correlation with PSO correction angle and postoperative CBVA (R(2) = 0.38). There was a significant decrease in both the Neck Disability Index (51.1 to 38.6, p = 0.03) and visual analog scale scores for neck pain (8.1 to 3.9, p = 0.0021). The SF-36 physical component summary scores increased by 18.4% (30.2 to 35.8) with no neurological complications. CONCLUSIONS: The cervicothoracic junction PSO is a safe and effective procedure for the management of cervicothoracic kyphotic deformity. It results in excellent correction of cervical kyphosis and CBVA with a controlled closure and improvement in health-related quality-of-life measures even at early time points. PMID- 21529129 TI - Horizontal C-1 fractures in association with unstable distraction injuries of the craniocervical junction. AB - OBJECT: Horizontal fractures of the anterior arch of the atlas not associated with odontoid fractures have been regarded as stable fractures that can be simply treated with a cervical collar. The authors report that C-1 horizontal fractures also occur in association with severe distraction injuries of the craniocervical junction. METHODS: The authors retrospectively reviewed imaging studies obtained in all surviving patients in whom unstable distraction injuries of the craniocervical junction were diagnosed and in whom surgery was performed at their institution between 1995 and 2009. All patients who also had a C-1 horizontal fracture as a component of their spinal injury were included in the study. RESULTS: Of 47 patients with unstable craniocervical distraction injuries, 5 patients had a horizontal fracture through the anterior ring of C-1: 1 patient had a primarily C1-2 distractive injury whereas 4 others had a grossly unstable injury across the occipitoatlantal junction (occipitoatlantal dissociation). CONCLUSIONS: The finding of a C-1 horizontal fracture does not always reflect a benign injury and its presence should heighten the concern of a more severe and unstable injury at the craniocervical junction. PMID- 21529130 TI - Monitoring. PMID- 21529131 TI - Noninvasive assessment of intracranial pressure with venous ophthalmodynamometry. Clinical article. AB - OBJECT: Venous ophthalmodynamometry is a technique used to register the pressure within the central retinal vein. Because the outflow of the central retinal vein is exposed to the intracranial pressure (ICP), the pressure of the central retinal vein may be correlated with the ICP. In the absence of adequate statistical evidence, the authors compared the pressure of the central retinal vein with results of simultaneous invasive monitoring of ICP in neurosurgical patients. METHODS: The pressure within the central retinal vein was recorded in 102 patients, in whom invasive continuous monitoring of ICP had become necessary for various reasons, mostly because of suspected hydrocephalus and intracranial hemorrhage. RESULTS: A highly significant correlation of the pressure in the central retinal vein and the intracranial cavity was confirmed statistically. An increased pressure of the central retinal vein indicated an elevated ICP, with a probability of 84.2%, whereas a normal pressure of the central retinal vein indicated a normal ICP in 92.8% of patients. Conclusions Venous ophthalmodynamometry is a valuable technique for the noninvasive assessment of ICP. PMID- 21529133 TI - Epidemiology. PMID- 21529132 TI - Treatment and survival of patients with nonmalignant intracranial meningioma: results from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Clinical article. AB - OBJECT: The authors conducted a study to determine population-based estimates of survival following the diagnosis and treatment of nonmalignant intracranial meningioma in the US in the modern era. METHODS: Patients with nonmalignant intracranial meningioma were identified through the Surveillance, Epidemiology, and End Results (SEER) database for the years 2004-2007. Predictors of undergoing resection were identified and odds ratios calculated. Estimates of survival were calculated using Kaplan-Meier estimation method and Cox proportional hazards model. RESULTS: There were 12,284 patients with a diagnosis of nonmalignant intracranial meningioma included in the analysis. Only 55% had histological confirmation of the diagnosis of nonmalignant meningioma. Resection was used as an initial treatment in 43% of cases. Patients treated with surgery were more likely to be younger (OR 9.3, 95% CI 8.1-10.7, for resection in patients age 40 59 years compared with age > 80 years), male (OR 1.4, 95% CI 1.3-1.5, for males compared with females), white (OR 0.8, 95% CI 0.7-0.9, for black patients compared with white patients), and have larger tumors (OR 11.8, 95% CI 10.3-13.6, for tumors of the largest quartile compared with the smallest quartile). Patients treated with resection had a 3-year postdiagnosis survival estimate of 93.4% (95% CI 92.5%-94.3%) compared with 88.3% (95% CI 85.5%-90.6%) in patients not treated with resection (p < 0.01). Younger patient age, female sex, unilateral tumors, and resection were predictors of improved postdiagnosis survival after multivariate adjustment in patients with histologically confirmed meningiomas. conclusions: This analysis represents the first modern population-based analysis of treatment patterns and outcomes in US patients with nonmalignant intracranial meningioma. Over 85% of patients survive 3 years after diagnosis, and resection is associated with improved survival. PMID- 21529134 TI - Predictors of seizure freedom after resection of supratentorial low-grade gliomas. A review. AB - OBJECT: Seizures are the most frequent presenting symptom in patients with low grade gliomas (LGGs), and significantly influence quality of life if they are uncontrolled. Achieving freedom from seizures is of utmost importance in surgical planning, but the factors associated with seizure control remain incompletely understood. METHODS: The authors performed a systematic literature review of seizure outcomes after resection of LGGs causing seizures, examining 773 patients across 20 published series. Rates of seizure freedom were stratified across 7 variables: patient age, tumor location, preoperative seizure control with medication, seizure semiology, epilepsy duration, extent of resection, and the use of intraoperative electrocorticography (ECoG). RESULTS: Gross-total resection was most predictive of complete seizure freedom, when compared with subtotal resection (OR 3.41, 95% CI 2.36-4.93). Other predictors of seizure freedom included preoperative seizure control on antiepileptic medication (OR 2.12, 95% CI 1.33-3.38) and duration of seizures of <= 1 year (OR 1.85, 95% CI 1.22-2.79). Patients with simple partial seizure semiology achieved seizure freedom less often than those with complex partial, generalized, or mixed seizure types (OR 0.46, 95% CI 0.26-0.80). No significant differences in seizure outcome were observed between adults versus children, patients with temporal lobe versus extratemporal tumors, or with the use of intraoperative ECoG. CONCLUSIONS: Seizure control is one of the most important considerations in planning surgery for low-grade brain tumors. Gross-total resection is a critical factor in achieving seizure freedom. PMID- 21529135 TI - Improvement in cognitive function and cerebral perfusion after bur hole surgery in an adult with moyamoya disease. Case report. AB - Recent studies have suggested that cognitive impairment may be a common complication in adults with moyamoya disease (MMD). However, the mechanisms of cognitive dysfunction have not been clarified. Whether cognitive impairment may occur as a consequence of cerebral hypoperfusion and may improve after revascularization surgery has not been determined. A 39-year-old West Indian woman with subacute dysexecutive cognitive syndrome and no history of stroke was diagnosed with MMD. Magnetic resonance imaging showed an old, small cerebral infarction in the left frontal white matter and no evidence of recent cerebral ischemia. Perfusion MR imaging with acetazolamide challenge demonstrated a reduced cerebrovascular reserve in both frontal lobes. Revascularization with bur hole surgery was performed, which resulted in complete regression of initial cognitive impairment. Improvement in cognitive function correlated with the development of transdural collaterals on angiography and improvement in cerebral perfusion on MR imaging. This case suggests a relationship between cognitive dysfunction and cerebral hypoperfusion in MMD. Cognitive impairment may be potentially reversible after bur hole surgery and cerebral perfusion improvement. PMID- 21529136 TI - Resolution of syringohydromyelia with targeted CT-guided epidural blood patching. AB - In the scientific literature, syringohydromyelia has only rarely been reported in association with spontaneous intracranial hypotension. Management of the syringohydromyelia in these patients has heretofore involved relatively invasive surgical procedures. The authors report the first case of syringohydromyelia in the setting of intracranial hypotension successfully treated with CT-guided epidural blood patches. This case is important in that it represents a potential minimally invasive treatment strategy. Furthermore, the case also highlights the need to consider spontaneous intracranial hypotension when clinically appropriate as a cause of syrinx in patients with cerebellar tonsillar ectopia, in whom the lesion might otherwise be misclassified as a Chiari I malformation. Finally, the responses to the various attempted treatments offer insight into the pathophysiology of this syringohydromyelia, which may differ from classical models of syrinx formation. PMID- 21529137 TI - Right-left discrimination. PMID- 21529138 TI - Outcome of repeat revascularization surgery for moyamoya disease after an unsuccessful indirect revascularization. Clinical article. AB - OBJECT: Revascularization for moyamoya disease, either by direct anastomosis or indirect procedures, is an accepted and effective form of treatment for prevention of future ischemic events. Indirect procedures do not provide sufficient collateral vessels in a subset of patients, who then have persistent or new symptoms. Repeat revascularization procedures may be recommended for these patients. METHODS: Sixteen patients underwent repeat revascularization after undergoing an indirect procedure in the same hemisphere. These patients were included in the study, and a retrospective review of their clinical details, neuroimaging results, surgical details, and outcome was performed. Direct revascularization was the procedure of choice; however, in patients with no acceptable recipient vessel (> 0.6 mm) the authors added a second indirect procedure for further revascularization. RESULTS: Over the last 19 years, 16 patients (8 male and 8 female patients, age range 5-48 years, mean 16.7 years, 10 pediatric and 6 adult patients) underwent repeat revascularization for moyamoya disease. Initially all patients presented with ischemic symptoms (4 transient ischemic attacks [TIAs] and 12 strokes; 2 patients had bilateral symptoms). Angiography revealed that 13 patients had bilateral disease, and 3 had unilateral disease. Initial surgery was bilateral encephaloduroarteriosynangiosis (EDAS) in 9, unilateral EDAS alone in 3, unilateral EDAS with contralateral superficial temporal artery-middle cerebral artery (STA-MCA) bypass in 2, bilateral encephalomyosynangiosis (EMS) in 1, and unilateral EMS in 1. Thirteen of the 16 patients continued to have TIAs in the hemisphere ipsilateral to surgery, whereas 1 patient had seizures and cognitive deficit, 1 had asymptomatic infarct on MR imaging, and 1 had visual symptoms. Poor revascularization was seen on angiography studies in all patients. The median duration between the surgeries was 24 months (3 months-10 years). Repeat revascularization was performed in 23 hemispheres (16 patients). Direct revascularization was performed in 14 hemispheres (60.9%): STA-MCA bypass in 10, external carotid artery-MCA vein bypass in 2, occipital artery (OA)-MCA in 1, and OA-posterior cerebral artery in 1 hemisphere. Indirect revascularization was performed for patients without an acceptable recipient vessel, and was done in 9 hemispheres. The procedures included EMS (4 hemispheres), repeat EDAS (2), and omental transposition (3). There was 1 postoperative death in a patient undergoing a high-flow vein graft implantation. None of the other patients experienced any neurological worsening after surgery. Follow-up was available in all patients, ranging from 3 to 144 months (mean 34 months, median 12 months). Of the 15 patients who survived repeat revascularization surgery, 12 (80%) were free from any TIA, stroke, or any other neurological symptoms. Two patients had occasional TIAs, less frequent than before, whereas 1 patient had frequent TIAs and underwent revision of the revascularization. Angiographic studies were available in 11 patients, and showed improved flow in the hemispheres in 10 patients. Follow-up MR imaging performed at 6 months did not reveal a new infarct in any patient. CONCLUSIONS: Repeat revascularization procedures are effective for patients who are clinically symptomatic and have inadequate collateral vessels following indirect procedures. Although direct procedures are preferred, the choice of procedure depends on the operative findings and the status of donor and recipient vessels. PMID- 21529139 TI - Simple assay based on restriction fragment length polymorphism associated with IL28B in chronic hepatitis C patients. AB - OBJECTIVE: Several studies recently revealed that single nucleotide polymorphisms (SNPs) in the interleukin28B (IL28B) region are associated with the response to pegylated interferon-alfa (PEG-IFN-alfa) and ribavirin (RBV) treatment among hepatitis C virus (HCV)-infected individuals of European, African and Asian ancestry. The purpose of the study was to establish methods for determining the SNP rs8099917 associated with IL28B, which might be useful for further research of the treatment of HCV. MATERIAL AND METHODS: Blood samples obtained from 93 consecutive patients with chronic hepatitis C were examined. On the basis of the sequence data, a new simple genotyping assay based on a PCR-restriction fragment length polymorphism (RFLP) with two enzymes, BsrDI and Tsp45I, was developed. RESULTS: The proportion of null virological responders in the combined TG/GG group was higher than that in the TT group (p = 0.015), suggesting that minor allele is one of the important factors playing crucial roles in IFN-resistance. Genotyping of rs8099917 by our new method showed results identical to PCR and sequence in 98.9% and 98.9% by BsrDI and Tsp45I, respectively. Using two enzymes, BsrDI and Tsp45I, it was possible to distinguish IL28B SNP rs8099917. CONCLUSION: This simple method using RFLP will provide the framework for further studies of HCV. PMID- 21529140 TI - Development of soybean aphid genomic SSR markers using next generation sequencing. AB - Simple sequence repeats (SSRs) or microsatellites are very useful molecular markers, owing to their locus-specific codominant and multiallelic nature, high abundance in the genome, and high rates of transferability across species. The soybean aphid (Aphis glycines Matsumura) has become the most damaging insect pest of soybean (Glycine max (L.) Merr.) in North America, since it was first found in the Midwest of the United States in 2000. Biotypes of the soybean aphid capable of colonizing newly developed aphid-resistant soybean cultivars have been recently discovered. Genetic resources, including molecular markers, to study soybean aphids are severely lacking. Recently developed next generation sequencing platforms offer opportunities for high-throughput and inexpensive genome sequencing and rapid marker development. The objectives of this study were (i) to develop and characterize genomic SSR markers from soybean aphid genomic sequences generated by next generation sequencing technology and (ii) to evaluate the utility of the SSRs for genetic diversity or relationship analyses. In total 128 SSR primer pairs were designed from sequences generated by Illumina GAII from a reduced representation library of A. glycines. Nearly 94% (120) of the primer pairs amplified SSR alleles of expected size and 24 SSR loci were polymorphic among three aphid samples from three populations. The polymorphic SSRs were successfully used to differentiate among 24 soybean aphids from Ohio and South Dakota. Sequencing of PCR products of two SSR markers from four aphid samples revealed that the allelic polymorphism was due to variation in the SSR repeats among the aphids. These markers should be particularly useful for genetic differentiation among aphids collected from soybean fields at different localities and regions. These SSR markers provide the soybean aphid research community with the first set of PCR-based codominant markers developed from the genomic sequences of A. glycines. PMID- 21529141 TI - Mitochondrial genome sequences of representatives of three families of scorpionflies (Order Mecoptera) and evolution in a major duplication of coding sequence. AB - The complete mitochondrial DNA sequences of a hangingfly, Bittacus pilicornis (Mecoptera: Bittacidae), a snow scorpion fly, Boreus elegans (Mecoptera: Boreidae), and a nearly complete sequence from another scorpionfly species, Microchorista philpotti (Mecoptera: Nannochoristidae) were determined. The coding sequence of all three genomes includes the 37 genes normally found in insect mtDNAs, in the same gene order as first described in Drosophila. In addition to the standard set of genes, the Microchorista sequence includes a large duplication of the coding region. The duplication is at least 4 kb (and may be much larger) and includes the remnants of three protein-coding genes and seven tRNA genes. The duplication evidently arose as a single event, and the duplicated region can be aligned in its entirety with the corresponding region of the functional genome. Although most of the genes contain defects that render them nonfunctional, analysis shows that the protein-coding genes in the duplicated region evolved for a considerable period under constraints expected of functional protein-coding genes. It is evident, therefore, that for a period two copies of some of the mitochondrial genes were functional in this species, including genes coding for proteins. PMID- 21529143 TI - Defective leptin-AMP-dependent kinase pathway induces nitric oxide release and contributes to mitochondrial dysfunction and obesity in ob/ob mice. AB - AIMS: Obesity arises on defective neuroendocrine pathways that increase energy intake and reduce mitochondrial metabolism. In the metabolic syndrome, mitochondrial dysfunction accomplishes defects in fatty acid oxidation and reciprocal increase in triglyceride content with insulin resistance and hyperglycemia. Mitochondrial inhibition is attributed to reduced biogenesis, excessive fission, and low adipokine-AMP-activated protein kinase (AMPK) level, but lateness of the respiratory chain contributes to perturbations. Considering that nitric oxide (NO) binds cytochrome oxidase and inhibits respiration, we explored NO as a direct effector of mitochondrial dysfunction in the leptin deficient ob/ob mice. RESULTS: A remarkable three- to fourfold increase in neuronal nitric oxide synthase (nNOS) expression and activity was detected by western blot, citrulline assay, electronic and confocal microscopy, flow cytometry, and NO electrode sensor in mitochondria from ob/ob mice. High NO reduced oxygen uptake in ob/ob mitochondria by inhibition of complex IV and nitration of complex I. Low metabolic status restricted beta-oxidation in obese mitochondria and displaced acetyl-CoA to fat synthesis; instead, small interference RNA nNOS caused a phenotype change with fat reduction in ob/ob adipocytes. INNOVATION: We evidenced that leptin increases mitochondrial respiration and fat utilization by potentially inhibiting NO release. Accordingly, leptin administration to ob/ob mice prevented nNOS overexpression and mitochondrial dysfunction in vivo and rescued leptin-dependent effects by matrix NO reduction, whereas leptin-Ob-Rb disruption increased the formation of mitochondrial NO in control adipocytes. We demonstrated that in ob/ob, hypoleptinemia is associated with critically low mitochondrial p-AMPK and that, oppositely to p-Akt2, p-AMPK is a negative modulator of nNOS. CONCLUSION: Thereby, defective leptin-AMPK pathway links mitochondrial NO to obesity with complex I syndrome and dysfunctional mitochondria. PMID- 21529144 TI - Short-term in vivo inhibition of nitric oxide synthase with L-NAME influences the contractile function of single left ventricular myocytes in rats. AB - The main purpose of this study was to investigate the effects of short-term L NAME treatment on the contractile function of left ventricle (LV) myocytes and the expression of proteins related to Ca(2+) homeostasis. Data from Wistar rats treated with L-NAME (L group, n = 20; 0.7 g/L in drinking water; 7 days) were compared with results from untreated controls (C group, n = 20). Cardiomyocytes from the L group showed increased (p < 0.05) fractional shortening (23%) and maximum rate of shortening (20%) compared with the C group. LV from the L group also showed increased (p < 0.05) expression of the ryanodine receptor 2 and Na(+)/Ca(2+) exchanger proteins (76% and 83%, respectively; p < 0.05). However, the L and C groups showed similar in vivo hemodynamic parameters of cardiac function. In conclusion, short-term NOS inhibition determines an increased expression of Ca(2+) regulatory proteins, which contributes to improving cardiomyocyte contractile function, preserving left ventricular function. PMID- 21529145 TI - Preclinical evaluation of Som230 as a radiation mitigator in a mouse model: postexposure time window and mechanisms of action. AB - The somatostatin analog SOM230 has potent radioprophylactic and radiation mitigating properties that are unrelated to cytoprotection but appear to be due to suppression of secretion of pancreatic enzymes into the intestinal lumen. To determine the maximal postirradiation time window for administration, male CD2F1 mice were exposed to 8.5-11 Gy total-body radiation; SOM230 (0.5, 2 or 5 mg/kg) or vehicle was given by twice daily subcutaneous injections for 14 days, beginning 24-72 h after irradiation, and 30-day animal survival was recorded. The contribution of the gut to systemic cytokine levels was estimated by analyzing plasma samples obtained simultaneously from the portal vein and carotid artery. The effect of SOM230 on cell trypsin secretion was assessed in vitro and intestinal proteolytic activity was measured in vivo. SOM230 was associated with a 40-60% absolute improvement in overall postirradiation survival when treatment was started 48 h after irradiation and even exhibited a statistically significant survival benefit when started at 72 h. SOM230 ameliorated the radiation-induced decrease in chemokine (C-X-C motif) ligand 9 (CXCL9). SOM230 inhibited pancreatic acinar cell trypsin secretion in vitro in a dose-dependent fashion and reduced intraluminal and intestinal tissue proteolytic activity in vivo. SOM230 is an excellent radiation mitigator with a postirradiation time window in excess of 48 h. The mechanism likely involves preservation of intestinal barrier function due to decreased secretion of pancreatic enzymes into the bowel lumen. PMID- 21529146 TI - Terminal maturation of megakaryocytes and platelet production by hematopoietic stem cells irradiated with heavy-ion beams. AB - Hematopoietic processes, especially megakaryocytopoiesis and thrombopoiesis, are highly sensitive to high-linear energy transfer (LET) radiations such as heavy ion beams that have greater biological effects than low-LET radiation. This study examined the terminal maturation of megakaryocytes and platelet production derived from hematopoietic stem cells irradiated with heavy-ion beams. CD34(+) cells derived from human placental/umbilical cord blood were exposed to monoenergetic carbon-ion beams (LET = 50 keV/um) and then cultured in a serum free medium supplemented with thrombopoietin and interleukin-3. There was no significant difference in megakaryocyte-specific markers between nonirradiated control and irradiated cells. Expression of Tie-2, a receptor that acts in early hematopoiesis, showed a significant 1.31-fold increase after 2 Gy irradiation compared to control cells on day 7. There was a significant increase in Tie-2 mRNA expression. In addition, the expression of other mRNAs, such as PECAM1, SELP and CD44, was also significantly increased in cells irradiated with heavy-ion beams. However, the adherent function of platelets derived from the irradiated cells showed no difference from that in the controls. These results clarify that the functions of megakaryocytopoiesis and thrombopoiesis derived from hematopoietic stem/progenitor cells irradiated with heavy-ion beams are similar to those in the unirradiated cells, although heavy-ion beams affect the expression of genes associated with cellular adhesion. PMID- 21529147 TI - Growth inhibition of Beauveria bassiana by bacteria isolated from the cuticular surface of the corn leafhopper, Dalbulus maidis and the planthopper, Delphacodes kuscheli, two important vectors of maize pathogens. AB - The phytosanitary importance of the corn leafhopper, Dalbulus maidis (De Long and Wolcott) (Hemiptera: Cicadellidae) and the planthopper, Delphacodes kuscheli Fennah (Hemiptera: Delphacidae) lies in their ability to transmit phloem associated plant pathogens, mainly viruses and mollicutes, and to cause considerable mechanical damage to corn plants during feeding and oviposition. Fungi, particularly some members of the Ascomycota, are likely candidates for biocontrol agents against these insect pests, but several studies revealed their failure to invade the insect cuticle possibly because of the presence of inhibitory compounds such as phenols, quinones, and lipids and also by the antibiosis effect of the microbiota living on the cuticular surface of the host. The present work aims to understand interactions between the entomopathogenic fungus Beauveria bassiana (Balsamao-Crivelli) Vuillemin (Hypocreales: Cordycipitaceae) and bacterial antagonists isolated from the cuticular surface of D. maidis and D. kuscheli. A total of 155 bacterial isolates were recovered from the insect's cuticle and tested against B. bassiana. Ninety-one out of 155 strains inhibited the growth of B. bassiana. Bacterial strains isolated from D. maidis were significantly more antagonistic against B. bassiana than those isolates from D. kuscheli. Among the most effective antagonistic strains, six isolates of Bacillus thuringiensis Berliner (Bacillales: Bacillaeae (after B. subtilis)), one isolate of B. mycoides Flugge, eight isolates of B. megaterium de Bary, five isolates of B.pumilus Meyer and Gottheil, one isolate of B. licheniformis (Weigmann) Chester, and four isolates of B. subtilis (Ehrenberg) Cohn were identified. PMID- 21529148 TI - A comparison of the pitfall trap, Winkler extractor and Berlese funnel for sampling ground-dwelling arthropods in tropical montane cloud forests. AB - Little is known about the ground-dwelling arthropod diversity in tropical montane cloud forests (TMCF). Due to unique habitat conditions in TMCFs with continuously wet substrates and a waterlogged forest floor along with the innate biases of the pitfall trap, Berlese funnel and Winkler extractor are certain to make it difficult to choose the most appropriate method to sample the ground-dwelling arthropods in TMCFs. Among the three methods, the Winkler extractor was the most efficient method for quantitative data and pitfall trapping for qualitative data for most groups. Inclusion of floatation method as a complementary method along with the Winkler extractor would enable a comprehensive quantitative survey of ground-dwelling arthropods. Pitfall trapping is essential for both quantitative and qualitative sampling of Diplopoda, Opiliones, Orthoptera, and Diptera. The Winkler extractor was the best quantitative method for Psocoptera, Araneae, Isopoda, and Formicidae; and the Berlese funnel was best for Collembola and Chilopoda. For larval forms of different insect orders and the Acari, all the three methods were equally effective. PMID- 21529149 TI - A new genus and species of Brachyscleromatinae (Hymenoptera: Ichneumonidae) from China, Laxiareola ochracea. AB - Laxiareola Sheng and Sun, gen.nov. and Laxiareola ochracea Sheng and Sun, sp.nov. belong to Brachyscleromatinae of the family Ichneumonidae, from the Jiangxi Province in China, are described in the present study. A key to the genera of Brachyscleromatinae is given. PMID- 21529150 TI - The organization of foraging in the fire ant, Solenopsis invicta. AB - Although natural selection in ants acts most strongly at the colony, or superorganismal level, foraging patterns have rarely been studied at that level, focusing instead on the behavior of individual foragers or groups of foragers. The experiments and observations in this paper reveal in broad strokes how colonies of the fire ant, Solenopsis invicta Buren (Hymenoptera: Formicidae), allocate their available labor to foraging, how they disperse that force within their territory, and how this force changes with colony size, season and worker age. Territory area is positively related to colony size and the number of foragers, more so during the spring than fall. Changes of colony size and territory area are driven by seasonal variation of sexual and worker production, which in turn drive seasonal variation of worker age-distribution. During spring sexual production, colonies shrink because worker production falls below replacement. This loss is proportional to colony size, causing forager density in the spring to be negatively related to colony and territory size. In the fall, colonies emphasize worker production, bringing colony size back up. However, because smaller colonies curtailed spring worker production less than larger ones, their fall forager populations are proportionally greater, causing them to gain territory at the expense of large colonies. Much variation of territory area remains unexplained and can probably be attributed to pressure from neighboring colonies. Boundaries between territories are characterized by "no ants' zones" mostly devoid of fire ants. The forager population can be divided into a younger group of recruitable workers that wait for scouts to activate them to help retrieve large food finds. About one-third of the recruits wait near openings in the foraging tunnels that underlie the entire territory, while two-thirds wait in the nest. Recruitment to food is initially very rapid and local from the foraging tunnels, while sustained recruitment gradually involves the recruits waiting in the nest. As recruits age, they become scouts searching for food on the surface, and die about two weeks later. Foraging tunnels decrease in cross-sectional area with distance from the nest, in keeping with the gradual bleeding off of workers to the surface with distance. Foragers lack route-faithfulness, and having been marked and released at one point within the territory, they can be recaptured at any other point a day later. The size of the territory actually occupied may be limited during dry weather, resulting in very large no-ants' zones. PMID- 21529151 TI - Pollen preference for Psychotria sp. is not learned in the passion flower butterfly, Heliconius erato. AB - Heliconius butterflies are known to maximize fitness by feeding on pollen from Gurania sp. and Psiguria sp. (Cucurbitales: Curcurbitaceae), and Psychotria sp. (Gentianales: Rubiaceae). This specialization involves specific physical, physiological, and behavioral adaptations including efficient search strategies in the forest to locate pollen host plants, pollen removal, and pollen external digestion. Reducing pollen host plant search time is crucial to out-compete other flower visitors and to reduce exposure to predators. One way in which this can be achieved is by using chemical cues to learn from experienced foragers in roosting aggregations. Similar strategies have been documented in bumblebees, where inexperienced individuals learn floral odors from experienced foragers. Behavioral experiments using plants preferred by Heliconius erato suggest that pollen preference in H. erato is an innate trait and consequently learning of chemical cues at roosting aggregations is unlikely. PMID- 21529152 TI - Description of the immatures of the ant, Myrmelachista catharinae. AB - The Neotropical ant genus Myrmelachista Roger comprises 69 described species and subspecies, and still is a poorly studied group. Larvae play a paramount role in colony nutrition in social hymenopterans and bear considerable value in the reconstruction of group phylogenies, however, they are generally neglected. Larvae of different instars of Myrmelachista catharinae Mayr (Hymenoptera: Formicidae) are herein described in detail by light and scanning electron microscopy. The number of larval instars was estimated as three based on the frequency distribution of maximum head capsule widths. The described larvae confirmed some traits typical of the genus: general shape of body and mandibles, general aspect and distribution of body hairs, and the number of sensilla on the palps and galea. Differently from other Myrmelachista larvae previously described, M. catharinae presented two distinct kinds of second instars, some additional types of body hairs, different number of antennal sensilla, and a distinct labrum shape. M. catharinae presented ten pairs of spiracles, which is the first record for this genus. PMID- 21529153 TI - First record of the scarab beetle, Phyllophaga lissopyge from South America, with descriptions of adult seasonal activity and male response to sex attractants. AB - Phyllophaga lissopyge (Bates) (Coleoptera: Scarabaeidae: Melolonthinae) is reported for the first time from South America. Male sex pheromone response is described for P. lissopyge and two other co-occurring Phyllophaga species. Adults of P. lissopyge and P. menetriesi (Blanchard) flew to traps baited with methyl 2 (methylthio) benzoate whereas adults of P. obsoleta (Blanchard) flew irregularly to four different pheromone compounds. Adult seasonal activity is described from males captures in Rionegro, Antioquia, Colombia. PMID- 21529154 TI - Mechanics and energetics of excavation by burrowing wolf spiders, Geolycosa spp. AB - Burrowing wolf spiders, Geolycosa sp. (Araneae:Lycosidae), excavate vertical burrows and inhabit them throughout their lives or, in the case of males, until they mature and wander in search of mates. Three species: G. fatifera Kurata, G. missouriensis Banks, and G. rogersi Wallace were studied to understand how and at what expense the burrowing is accomplished. Normal and high-speed videography coupled with scanning electron microscopy revealed (a) that the convex surfaces of the two fangs, together, constitute the digging tool, (b) that boluses of soil are transported to the burrow entrance on the anterior surfaces of the chelicerae held there by the pedipalps, and (c) that each bolus is either incorporated into the growing turret or flung away, propelled by the forelegs. To elucidate the energetics of burrow construction, burrow volumes were calculated and then the costs associated with dislodging, elevating, and throwing the known volumes of soil were measured. A typical Geolycosa burrow, at a volume of 23.6 +/- 2.0 ml and a depth of 13.2 +/- 0.7 cm, required the removal of 918 boluses each weighing about 34 mg. The aggregate dislodging cost was close to 1.9 Joules in sand/sandy loam and 5.6 J in clayey subsoil, the work against gravity necessary to raise all of the boluses to the surface was about 0.13 J, and the aggregate cost of flinging the boluses was close to 0.014 J. Assuming that the ratio of external work to metabolic cost of external work is between 0.20 and 0.25 in spiders, the real cost of burrow construction would be between 8 J and 29 J, depending primarily on soil type. This is a small but not negligible cost when placed in the context of reproductive effort: a single Geolycosa egg, dozens to hundreds of which are produced in a clutch, contains about 10 J. PMID- 21529155 TI - The parasitoid, Verticia fasciventris causes morphological and behavioral changes in infected soldiers of the fungus-growing termite, Macrotermes carbonarius. AB - The larval parasitoid Verticia fasciventris Malloch (Diptera: Calliphoridae) develops in the head of soldiers of the fungus-growing termite Macrotermes carbonarius (Hagen) (Isoptera: Termitidae). Morphological and behavioral changes in the host were evaluated and the termite castes and stages that were parasitized were identified. The larval emergence process is also described and possible mechanisms for the parasitoid fly's entry into the host body are discussed based on qualitative observations. Only a single larva per host was found. The mature larva pupated outside the host's body by exiting between the abdominal cerci. Parasitized soldiers possess a short and square-shaped head capsule, a pair of notably short mandibles, and a pair of 18-segmented antennae. Although parasitized soldiers were statistically less aggressive than healthy soldiers (P < 0.05), they expressed varying levels of aggression. Both minor and major soldiers can be parasitized and based on evidence from presoldiers, parasitization may begin during the precursor stages of soldiers. However, the stage at which parasitism first occurs has not been determined. PMID- 21529156 TI - Molecular phylogenetic analysis of the Stegana ornatipes species group (Diptera: Drosophilidae) in China, with description of a new species. AB - A new species of the Stegana (Steganina) ornatipes species group (Diptera: Drosophilidae) is described from Hainan, China, S. (S.) xipengi sp. nov. Based on the mitochondrial ND2 and COI gene sequences, the relationships among eight species from mainland China of the ornatipes group, and their relationships to the undulata, nigrolimbata and shirozui species groups of the same subgenus, are investigated, using two species of the subgenus Stegana, S. emeiensis and S. quadrata, as outgroups. The result shows that S. (S.) mengla is debarred from the ornatipes group. PMID- 21529157 TI - RNA-RNA recombination in plant virus replication and evolution. AB - RNA-RNA recombination is one of the strongest forces shaping the genomes of plant RNA viruses. The detection of recombination is a challenging task that prompted the development of both in vitro and in vivo experimental systems. In the divided genome of Brome mosaic virus system, both inter- and intrasegmental crossovers are described. Other systems utilize satellite or defective interfering RNAs (DI RNAs) of Turnip crinkle virus, Tomato bushy stunt virus, Cucumber necrosis virus, and Potato virus X. These assays identified the mechanistic details of the recombination process, revealing the role of RNA structure and proteins in the replicase-mediated copy-choice mechanism. In copy choice, the polymerase and the nascent RNA chain from which it is synthesized switch from one RNA template to another. RNA recombination was found to mediate the rearrangement of viral genes, the repair of deleterious mutations, and the acquisition of nonself sequences influencing the phylogenetics of viral taxa. The evidence for recombination, not only between related viruses but also among distantly related viruses, and even with host RNAs, suggests that plant viruses unabashedly test recombination with any genetic material at hand. PMID- 21529159 TI - Development of probes for cellular functions using fluorescent proteins and fluorescence resonance energy transfer. AB - Many genetically encoded probes that employ fluorescent proteins and fluorescence resonance energy transfer (FRET) have been developed to better understand the spatiotemporal regulation of various cellular processes. The different types of FRET and measurement techniques necessitate characterization of their specific features. Here I provide theoretical and practical comparisons of bimolecular and unimolecular FRET constructs, intensity-based and lifetime-based FRET measurements, FRET imaging using live- and fixed-cell samples, green fluorescent protein-based and chemical fluorophore-based FRET, and FRET efficiency and indices. The potential benefits and limitations of a variety of features in the technologies using fluorescent proteins and FRET are discussed. PMID- 21529158 TI - Cytochrome P450s in the regulation of cellular retinoic acid metabolism. AB - The active metabolite of vitamin A, retinoic acid (RA), is a powerful regulator of gene transcription. RA is also a therapeutic drug. The oxidative metabolism of RA by certain members of the cytochrome P450 (CYP) superfamily helps to maintain tissue RA concentrations within appropriate bounds. The CYP26 family--CYP26A1, CYP26B1, and CYP26C1--is distinguished by being both regulated by and active toward all-trans-RA (at-RA) while being expressed in different tissue-specific patterns. The CYP26A1 gene is regulated by multiple RA response elements. CYP26A1 is essential for embryonic development, whereas CYP26B1 is essential for postnatal survival as well as germ cell development. Enzyme kinetic studies have demonstrated that several CYP proteins are capable of metabolizing at-RA; however, it is likely that CYP26A1 plays a major role in RA clearance. Thus, pharmacological approaches to limiting the activity of CYP26 enzymes may extend the half-life of RA and could be useful clinically in the future. PMID- 21529160 TI - Signals and combinatorial functions of histone modifications. AB - Alterations of chromatin structure have been shown to be crucial for response to cell signaling and for programmed gene expression in development. Posttranslational histone modifications influence changes in chromatin structure both directly and by targeting or activating chromatin-remodeling complexes. Histone modifications intersect with cell signaling pathways to control gene expression and can act combinatorially to enforce or reverse epigenetic marks in chromatin. Through their recognition by protein complexes with enzymatic activities cross talk is established between different modifications and with other epigenetic pathways, including noncoding RNAs (ncRNAs) and DNA methylation. Here, we review the functions of histone modifications and their exploitation in the programming of gene expression during several events in development. PMID- 21529161 TI - Assembly of bacterial ribosomes. AB - The assembly of ribosomes from a discrete set of components is a key aspect of the highly coordinated process of ribosome biogenesis. In this review, we present a brief history of the early work on ribosome assembly in Escherichia coli, including a description of in vivo and in vitro intermediates. The assembly process is believed to progress through an alternating series of RNA conformational changes and protein-binding events; we explore the effects of ribosomal proteins in driving these events. Ribosome assembly in vivo proceeds much faster than in vitro, and we outline the contributions of several of the assembly cofactors involved, including Era, RbfA, RimJ, RimM, RimP, and RsgA, which associate with the 30S subunit, and CsdA, DbpA, Der, and SrmB, which associate with the 50S subunit. PMID- 21529162 TI - MRI-guided nanorobotic systems for therapeutic and diagnostic applications. AB - This review presents the state of the art of magnetic resonance imaging (MRI) guided nanorobotic systems that can perform diagnostic, curative, and reconstructive treatments in the human body at the cellular and subcellular levels in a controllable manner. The concept of an MRI-guided nanorobotic system is based on the use of an MRI scanner to induce the required external driving forces to propel magnetic nanocapsules to a specific target. It is an active targeting mechanism that provides simultaneous propulsion and imaging capabilities, which allow the implementation of real-time feedback control of the targeting process. The architecture of the system comprises four main modules: (a) the nanocapsules, (b) the MRI propulsion module, (c) the MRI tracking module (for image processing), and (d) the controller module. A key concept is the nanocapsule technology, which is based on carriers such as liposomes, polymer micelles, gold nanoparticles, quantum dots, metallic nanoshells, and carbon nanotubes. Descriptions of the significant challenges faced by the MRI-guided nanorobotic system are presented, and promising solutions proposed by the involved research community are discussed. Emphasis is placed on reviewing the limitations imposed by the scaling effects that dominate within the blood vessels and also on reviewing the control algorithms and computational tools that have been developed for real-time propulsion and tracking of the nanocapsules. PMID- 21529164 TI - In vitro models of traumatic brain injury. AB - In vitro models of traumatic brain injury (TBI) are helping elucidate the pathobiological mechanisms responsible for dysfunction and delayed cell death after mechanical stimulation of the brain. Researchers have identified compounds that have the potential to break the chain of molecular events set in motion by traumatic injury. Ultimately, the utility of in vitro models in identifying novel therapeutics will be determined by how closely the in vitro cascades recapitulate the sequence of cellular events that play out in vivo after TBI. Herein, the major in vitro models are reviewed, and a discussion of the physical injury mechanisms and culture preparations is employed. A comparison between the efficacy of compounds tested in vitro and in vivo is presented as a critical evaluation of the fidelity of in vitro models to the complex pathobiology that is TBI. We conclude that in vitro models were greater than 88% predictive of in vivo results. PMID- 21529163 TI - Multiscale cancer modeling. AB - Simulating cancer behavior across multiple biological scales in space and time, i.e., multiscale cancer modeling, is increasingly being recognized as a powerful tool to refine hypotheses, focus experiments, and enable more accurate predictions. A growing number of examples illustrate the value of this approach in providing quantitative insights in the initiation, progression, and treatment of cancer. In this review, we introduce the most recent and important multiscale cancer modeling works that have successfully established a mechanistic link between different biological scales. Biophysical, biochemical, and biomechanical factors are considered in these models. We also discuss innovative, cutting-edge modeling methods that are moving predictive multiscale cancer modeling toward clinical application. Furthermore, because the development of multiscale cancer models requires a new level of collaboration among scientists from a variety of fields such as biology, medicine, physics, mathematics, engineering, and computer science, an innovative Web-based infrastructure is needed to support this growing community. PMID- 21529165 TI - Surgical decision-making strategies in tuberculum sellae meningioma resection. AB - OBJECT: Although the transcranial route (TCR) has been the traditional approach for removing tuberculum sellae meningiomas (TSMs), the use of the microscopic and/or more recently the endoscopic transsphenoidal approach (ETSA) has gained acceptance for selected cases. In this study, the authors present their experience with the ETSA and the TCR and examine the criteria most important for deciding the optimal approach in a particular case. METHODS: The authors retrospectively reviewed recent cases of TSMs treated surgically by the senior author via either the TCR or the ETSA or both. Demographic information, clinical presentation, and clinical and radiological outcomes of the patients were evaluated. RESULTS: Twenty-seven patients underwent removal of a TSM during a recent period. Gross-total or near-total resection was achieved in 20 (91%) of 22 patients who underwent resection via the TCR and in 3 (60%) of 5 patients who underwent the ETSA. Among the patients in whom gross- or near-total resection was achieved, recurrence was observed in only 1 patient, whose tumor was removed via the ETSA. CONCLUSIONS: In the majority of patients, the TCR provided complete resection of the tumor without compromising the safety of the procedure. In select cases of tumors with a reasonable size and location (midline and/or extending into the sphenoid sinus) as well as no involvement of inaccessible neurovascular and bony elements via this approach, the ETSA could also be a viable option. PMID- 21529166 TI - Hemangiopericytomas of the skull base. AB - OBJECT: Intracranial hemangiopericytomas are frequently located along the dural sinuses along the skull base and represent rare, aggressive CNS neoplasms that are difficult to distinguish from meningiomas based on both imaging and gross characteristics. The authors of this study describe 3 patients with these lesions and review the pertinent literature. METHODS: Two men and 1 woman, whose median age at the time of the initial presentation was 37 years (range 20-53 years), constitute this series. They underwent multimodal treatment consisting of resection, embolization, radiation therapy, and in 1 case chemotherapy. RESULTS: Two of the 3 patients treated were alive after a mean follow-up of 93 months (range 4-217 months). One patient died 217 months after the initial diagnosis. The longest tumor progression-free interval after the initial or secondary resection was 43 months (range 4-84 months). CONCLUSIONS: Hemangiopericytomas have been reclassified as mesenchymal non-meningothelial tumors. They have an inevitable tendency to recur locally and metastasize distally. The mainstay of therapy remains an aggressive attempt to achieve gross-total resection at the initial surgery. Postoperative adjuvant radiotherapy should be offered to all patients, regardless of the degree of resection achieved. Diligent long-term follow-up is paramount as local recurrences and distal metastases can develop sometimes years after the initial treatment. PMID- 21529167 TI - Treatment of unresectable skull base meningiomas with somatostatin analogs. AB - OBJECT: The standard surgical treatment for meningiomas is total resection, but the complete removal of skull base meningiomas can be difficult for several reasons. Thus, the management of certain meningiomas of the skull base--for example, those involving basal vessels and cranial nerves--remains a challenge. In recent reports it has been suggested that somatostatin (SST) administration can cause growth inhibition of unresectable and recurrent meningiomas. The application of SST and its analogs is not routinely integrated into standard treatment strategies for meningiomas, and clinical studies proving growth inhibiting effects do not exist. The authors report on their experience using octreotide in patients with recurrent or unresectable meningiomas of the skull base. METHODS: Between January 1996 and December 2010, 13 patients harboring a progressive residual meningioma (as indicated by MR imaging criteria) following operative therapy were treated with a monthly injection of the SST analog octreotide (Sandostatin LAR [long-acting repeatable] 30 mg, Novartis). Eight of 13 patients had a meningioma of the skull base and were analyzed in the present study. Postoperative tumor enlargement was documented in all patients on MR images obtained before the initiation of SST therapy. All tumors were benign. No patient received radiation or chemotherapy before treatment with SST. The growth of residual tumor was monitored by MR imaging every 12 months. RESULTS: Three of the 8 patients had undergone surgical treatment once; 3, 2 times; and 2, 3 times. The mean time after the last meningioma operation (before starting SST treatment) and tumor enlargement as indicated by MR imaging criteria was 24 months. A total of 643 monthly cycles of Sandostatin LAR were administered. Five of the 8 patients were on SST continuously and stabilized disease was documented on MR images obtained in these patients during treatment (median 115 months, range 48 180 months). Three of the 8 patients interrupted treatment: after 60 months in 1 case because of tumor progression, after 36 months in 1 case because of side effects, and after 36 months in 1 case because the health insurance company denied cost absorption. CONCLUSIONS: Although no case of tumor regression was detected on MR imaging, the study results indicated that SST analogs can arrest the progression of unresectable or recurrent benign meningiomas of the skull base in some patients. It remains to be determined whether a controlled prospective clinical trial would be useful. PMID- 21529168 TI - Meningiomas involving the optic canal: pattern of involvement and implications for surgical technique. AB - OBJECT: Juxtasellar meningiomas frequently extend into the optic canal. Removing these meningiomas from the optic canal is crucial for favorable visual outcome. METHODS: The authors performed a retrospective analysis of 45 patients with anterior and middle fossa meningiomas with involvement of the optic pathway in whom surgery was performed by the senior author (O.A.M.) during the period from 1993 to 2007. Extent of resection and recurrence rates were determined by pre- and postoperative MR imaging studies. Visual outcomes were evaluated with full ophthalmological examinations performed before and after surgery. RESULTS: Forty five patients (31 women and 14 men) were involved in this study; their mean age was 51.6 years. Patients were followed for a mean of 29.8 months (range 6-108 months). No surgery-related death occurred. The average tumor size was 3.1 cm. Total resection of the tumor (Simpson Grade I) was achieved in 32 patients (71.1%). Gross-total resection (Simpson Grades II and III) was achieved in 13 patients (28.9%). Only 1 patient harboring a left cavernous sinus meningioma had tumor recurrence and underwent repeat resection. Meningiomas extended into 58 optic canals in these cases; 13 patients showed extension into both optic canals. Visual disturbance was the main presenting symptom in 37 patients (82.2%); 8 patients had normal vision initially. Visual improvement after surgery was seen in 21 (57%) of 37 patients and in 27 (34.6%) of 78 affected eyes. Vision remained unchanged in 48 (61.5%) of 78 eyes. Transient postoperative visual deterioration occurred in 2 eyes (2.6%), with recovery to baseline over time. Only 1 (1.3%) of 78 eyes had permanent visual deterioration after surgery. The visual outcome was affected mainly by the tumor size, the preoperative visual status, and the duration of symptoms. CONCLUSIONS: Involvement of the optic canal in meningiomas is frequent. It occurs in a wide variety of anterior skull base meningiomas and it can be bilateral. It is a prominent factor that affects the preoperative visual status and postoperative recovery. Decompression of the optic canal and removal of the tumor inside is a crucial step in the surgical management of these tumors to optimize visual recovery and prevent tumor recurrence. PMID- 21529169 TI - Pneumosinus dilitans and meningioma: a case series and review of the literature. AB - Pneumosinus dilitans (PSD) is enlargement of the sinuses of the skull base and is frequently seen with meningiomas. Identifying PSD on imaging can assist with operative planning and preparation. Meningiomas associated with PSD are not more commonly high grade, and complete resection is frequently possible. PMID- 21529170 TI - Decision making for the surgical approach of posterior petrous bone meningiomas. AB - OBJECT: The authors undertook this study to examine the surgical approaches used to treat posterior petrous bone meningiomas at a single institution and retrospectively evaluate their surgical strategy based on a previously published classification. METHODS: Cases in which craniotomies were performed to treat posterior petrous bone meningiomas between 2002 and 2010 were retrospectively reviewed. Data were examined from 57 patients who were treated for 59 tumors. The tumors were classified into 3 types according to the location of their primary dural attachment: Type A, located around the porus trigeminus (33 tumors); Type M, located at the level of the porus of the internal auditory canal (IAC) (12 tumors); and Type P, located laterally to the IAC (14 tumors). The median tumor diameter was 34 mm (range 20-67 mm). RESULTS: The choice of the approach was based on tumor location, as the displacement of vascular structures and cranial nerves was primarily determined by the site of dural attachment on the posterior petrous bone. An anterior petrosectomy was performed in 82% of Type A meningiomas, and a retrosigmoid approach was used in 86% of Type P meningiomas. The spectrum of approaches was less uniform for Type M meningiomas. Overall, total resection was obtained in 39% of all cases, and in 18%, 50%, and 86% of Type A, Type M, and Type P tumors, respectively. The postoperative mortality rate was 8.8% (5 deaths among 57 patients), and all 5 patients who died during the early postoperative period had large Type A tumors. At last follow-up, the functional preservation of the facial nerve was excellent in 49 (94%) of the 52 surviving patients. CONCLUSIONS: The authors believe that proper selection of the approach favorably impacts functional outcome in patients undergoing surgery for the treatment of skull base tumors. In the authors' case series of posterior petrous bone meningiomas, Type P and most Type M tumors were safely managed through a regular retrosigmoid approach, whereas Type A tumors were optimally treated via an epidural anterior petrosectomy. PMID- 21529171 TI - Expanded endonasal endoscopic resection of anterior fossa meningiomas: report of 13 cases and meta-analysis of the literature. AB - OBJECT: Transnasal endoscopic (TNE) approaches have been proposed for the resection of anterior cranial base meningiomas. The purpose of this article was to evaluate the results of endoscopic resection of anterior cranial fossa meningiomas by reviewing available published data in addition to the authors' experience with 13 cases. METHODS: The literature was searched via OVID to identify all available disaggregate data pertaining to anterior fossa meningiomas treated primarily by TNE. In addition, the authors reviewed the records of a personal series of 13 patients who underwent TNE removal of parasellar meningiomas through a pure TNE approach. RESULTS: Meta-analysis from studies included a total of 69 patients with adequate disaggregated data to summarize. Mean age (+/- SD) at surgery was 53.3 +/- 13.0 years (range 27-80 years); 78% of the patients were women. Tumor size was skewed toward smaller lesions, with a mean volume of 24.4 +/- 2.9 cm(3). Intraoperative impressions were of gross-total resection in 76% of cases. The most common complication reported was CSF leakage, occurring in 32% of the cases (22 of 69). The rate of CSF leakage was not affected by size (p = 0.52), location of tumor (p = 0.9), or age (p = 0.56). There was 1 death overall. The mean duration of follow-up was 21 +/- 18 months. CONCLUSIONS: Transnasal endoscopic resection of anterior cranial base meningiomas is feasible in selected cases. Reported resection rates are adequate, although the follow-up in the reported series is too short (mean 21 months) to make definitive conclusions regarding the long-term effectiveness. Cerebrospinal fluid leakage is a common complication, although it appears not to be associated with additional morbidity except for the need for reoperation. Long-term results are necessary before considering TNE resection as a valid alternative, in selected cases, to the more established transcranial techniques. PMID- 21529172 TI - Endonasal versus transcranial resection. PMID- 21529173 TI - Surgical nuances for removal of tuberculum sellae meningiomas with optic canal involvement using the endoscopic endonasal extended transsphenoidal transplanum transtuberculum approach. AB - Tuberculum sellae meningiomas frequently extend into the optic canals. Radical tumor resection including the involved dural attachment, underlying hyperostotic bone, and intracanalicular tumor in the optic canal offers the best chance of a Simpson Grade I resection to minimize recurrence. Decompression of the optic canal with removal of the intracanalicular tumor also improves visual outcome since this portion of the tumor is usually the cause of asymmetrical visual loss. The purely endoscopic endonasal extended transsphenoidal approach offers a direct midline trajectory and immediate access to tuberculum sellae meningiomas without brain retraction and manipulation of neurovascular structures. Although the endoscopic approach has been previously criticized for its inability to remove tumor within the optic canals, complete Simpson Grade I tumor removal including intracanalicular tumor, dural attachment, and involved hyperostotic bone can be achieved in properly selected patients. Excellent visualization of the suprasellar region and the inferomedial aspects of both optic canals allows for extracapsular, extraarachnoid dissection of the tumor from the critical structures using bimanual microsurgical dissection. In this report, the authors describe the operative nuances for removal of tuberculum sellae meningiomas with optic canal involvement using a purely endoscopic endonasal extended transsphenoidal (transplanum transtuberculum) approach. They specifically highlight the technique for endonasal bilateral optic nerve decompression and removal of intracanalicular tumor to improve postoperative visual function, as demonstrated in 2 illustrative cases. Special attention is also given to cranial base reconstruction to prevent CSF leakage using the vascularized pedicled nasoseptal flap. PMID- 21529175 TI - Endoscopic endonasal approach to anterior skull base meningiomas. PMID- 21529174 TI - Surgical nuances for removal of olfactory groove meningiomas using the endoscopic endonasal transcribriform approach. AB - Olfactory groove meningiomas represent 10% of intracranial meningiomas and arise in the midline of the anterior cranial fossa along the dura of the cribriform plate and planum sphenoidale. Hyperostosis of the adjacent underlying bone is common, and further extension into ethmoid sinuses and nasal cavity can occur in 15%-25% of cases. Radical tumor resection including the involved dural attachment and underlying hyperostotic bone offers the best chance of a Simpson Grade I resection to minimize recurrence. Incomplete removal of involved hyperostotic bone can result in tumor recurrence at the cribriform plate with extension into the paranasal sinuses. Resection has traditionally been performed using a bifrontal or pterional approach, both of which require some degree of brain retraction or manipulation to expose the tumor. The endoscopic endonasal transcribriform approach offers the most direct and immediate exposure to the tumor without brain retraction and manipulation of neurovascular structures. An endonasal "keyhole craniectomy" is performed in the ventral skull base directly over the basal dural attachment, extending from the posterior wall of the frontal sinus to the planum sphenoidale and tuberculum sellae in the anteroposterior plane, and from one medial orbit to the other in the coronal plane. Excellent panoramic visualization of the keyhole skull base defect can be obtained with a 30 degrees endoscope after performing a modified Lothrop procedure. Because the dural attachment is adjacent to the paranasal sinuses, early devascularization and total Simpson Grade I removal of the tumor including the dural attachment and underlying hyperostotic bone can be achieved in properly selected patients. This approach is also very suitable for meningiomas that have recurred or extended into the paranasal sinuses. Extracapsular, extraarachnoid dissection of the tumor from the frontal lobes and neurovascular structures can be performed using conventional bimanual microsurgical techniques. In this report, we review the surgical technique and describe our operative nuances for removal of olfactory groove meningiomas, including recurrent tumors with extension into the nasal cavity, using a purely endoscopic endonasal transcribriform approach. In addition, we discuss the advantages, limitations, patient selection, and complications of this approach. We specifically highlight our technique for multilayer reconstruction of large anterior skull base dural defects using fascia lata and acellular dermal allograft supplemented by bilateral vascularized pedicled nasoseptal flaps. Three new cases of endoscopically resected olfactory groove meningiomas are also presented. PMID- 21529176 TI - Level I to III craniofacial approaches based on Barrow classification for treatment of skull base meningiomas: surgical technique, microsurgical anatomy, and case illustrations. AB - OBJECT: Although craniofacial approaches to the midline skull base have been defined and surgical results have been published, clear descriptions of these complex approaches in a step-wise manner are lacking. The objective of this study is to demonstrate the surgical technique of craniofacial approaches based on Barrow classification (Levels I-III) and to study the microsurgical anatomy pertinent to these complex craniofacial approaches. METHODS: Ten adult cadaveric heads perfused with colored silicone and 24 dry human skulls were used to study the microsurgical anatomy and to demonstrate craniofacial approaches in a step wise manner. In addition to cadaveric studies, case illustrations of anterior skull base meningiomas were presented to demonstrate the clinical application of the first 3 (Levels I-III) approaches. RESULTS: Cadaveric head dissection was performed in 10 heads using craniofacial approaches. Ethmoid and sphenoid sinuses, cribriform plate, orbit, planum sphenoidale, clivus, sellar, and parasellar regions were shown at Levels I, II, and III. In 24 human dry skulls (48 sides), a supraorbital notch (85.4%) was observed more frequently than the supraorbital foramen (14.6%). The mean distance between the supraorbital foramen notch to the midline was 21.9 mm on the right side and 21.8 mm on the left. By accepting the middle point of the nasofrontal suture as a landmark, the mean distances to the anterior ethmoidal foramen from the middle point of this suture were 32 mm on the right side and 34 mm on the left. The mean distance between the anterior and posterior ethmoidal foramina was 12.3 mm on both sides; the mean distance between the posterior ethmoidal foramen and distal opening of the optic canal was 7.1 mm on the right side and 7.3 mm on the left. CONCLUSIONS: Barrow classification is a simple and stepwise system to better understand the surgical anatomy and refine the techniques in performing these complex craniofacial approaches. On the other hand, thorough anatomical knowledge of the midline skull base and variations of the neurovascular structures is crucial to perform successful craniofacial approaches. PMID- 21529177 TI - The molecular genetics and tumor pathogenesis of meningiomas and the future directions of meningioma treatments. AB - Meningiomas are mostly benign, slow-growing tumors of the CNS that originate from arachnoidal cap cells. While monosomy 22 is the most frequent genetic abnormality found in meningiomas, a multitude of other aberrant chromosomal alterations, signaling pathways, and growth factors have been implicated in its pathogenesis. Losses on 22q12.2, a region encoding the tumor suppressor gene merlin, represent the most common genetic alterations in early meningioma formation. Malignant meningioma progression, however, is associated with more complex karyotypes and greater genetic instability. Cytogenetic studies of atypical and anaplastic meningiomas revealed gains and losses on chromosomes 9, 10, 14, and 18, with amplifications on chromosome 17. However, the specific gene targets in a majority of these chromosomal abnormalities remain elusive. Studies have also implicated a myriad of aberrant signaling pathways involved with meningioma tumorigenesis, including those involved with proliferation, angiogenesis, and autocrine loops. Understanding these disrupted pathways will aid in deciphering the relationship between various genetic changes and their downstream effects on meningioma pathogenesis. Despite advancements in our understanding of meningioma pathogenesis, the conventional treatments, including surgery, radiotherapy, and stereotactic radiosurgery, have remained largely stagnant. Surgery and radiation therapy are curative in the majority of lesions, yet treatment remains challenging for meningiomas that are recurrent, aggressive, or refractory to conventional treatments. Future therapies will include combinations of targeted molecular agents as a result of continued progress in the understanding of genetic and biological changes associated with meningiomas. PMID- 21529178 TI - Molecular genetics of meningiomas: a systematic review of the current literature and potential basis for future treatment paradigms. AB - Although a majority of meningiomas are benign neoplasms, those occurring at the cranial base may be challenging tumors to treat because of extensive tissue invasion, an inability to achieve gross-total microscopic resection, and local tumor recurrence and/or progression. A more comprehensive understanding of the genetic abnormalities associated with meningioma tumorigenesis, growth, and invasion may provide novel targets for grading assessments and individualizing molecular therapies for skull base meningiomas. The authors performed a review of the current literature to identify genes that have been associated with the formation and/or progression of meningiomas. Mutations in the NF2 gene have been most commonly implicated in the formation of the majority of meningiomas. Inactivation of other tumor suppressor genes, including DAL-1 and various tissue inhibitors of matrix metalloproteinases, upregulation of several oncogenes including c-sis and STAT3, and signaling dysregulation of pathways such as the Wnt pathway, have each been found to play important, and perhaps, complementary roles in meningioma development, progression, and recurrence. Identification of these genetic factors using genome-wide association studies and high-throughput genomics may provide data for future individualized treatment strategies. PMID- 21529179 TI - Quantitative and qualitative 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in skull base meningiomas. AB - OBJECT: Complete resection of skull base meningiomas provides patients with the best chance for a cure; however, surgery is frequently difficult given the proximity of lesions to vital structures, such as cranial nerves, major vessels, and venous sinuses. Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative assessment of protoporphyrin IX (PpIX) fluorescence following the exogenous administration of 5-aminolevulinic acid (ALA) has demonstrated utility in malignant glioma resection but limited use in meningiomas. Here the authors demonstrate the use of ALA-induced PpIX fluorescence guidance in resecting a skull base meningioma and elaborate on the advantages and disadvantages provided by both quantitative and qualitative fluorescence methodologies in skull base meningioma resection. METHODS: A 52-year old patient with a sphenoid wing WHO Grade I meningioma underwent tumor resection as part of an institutional review board-approved prospective study of fluorescence-guided resection. A surgical microscope modified for fluorescence imaging was used for the qualitative assessment of visible fluorescence, and an intraoperative probe for in situ fluorescence detection was utilized for quantitative measurements of PpIX. The authors assessed the detection capabilities of both the qualitative and quantitative fluorescence approaches. RESULTS: The patient harboring a sphenoid wing meningioma with intraorbital extension underwent radical resection of the tumor with both visibly and nonvisibly fluorescent regions. The patient underwent a complete resection without any complications. Some areas of the tumor demonstrated visible fluorescence. The quantitative probe detected neoplastic tissue better than the qualitative modified surgical microscope. The intraoperative probe was particularly useful in areas that did not reveal visible fluorescence, and tissue from these areas was confirmed as tumor following histopathological analysis. CONCLUSIONS: Fluorescence-guided resection may be a useful adjunct in the resection of skull base meningiomas. The use of a quantitative intraoperative probe to detect PpIX concentration allows more accurate determination of neoplastic tissue in meningiomas than visible fluorescence and is readily applicable in areas, such as the skull base, where complete resection is critical but difficult because of the vital structures surrounding the pathology. PMID- 21529180 TI - Predicting postoperative hydrocephalus in 227 patients with skull base meningioma. AB - OBJECT: Some patients develop communicating hydrocephalus after meningioma surgery, and this can develop into a serious clinical condition. However, this has rarely been addressed in the literature. Therefore, the authors sought to determine predictive patient variables for the occurrence of postoperative hydrocephalus following skull base meningioma surgery. METHODS: For this purpose, the authors retrospectively analyzed all patients who underwent resection of intracranial meningiomas between 1998 and 2009 at the Department of Neurosurgery, University Hospital Zurich, Switzerland. Of 594 patients with meningioma, 227 (38%) had a lesion located at the skull base, and thus were included for analysis. The following patient variables were examined: demographic data (age and sex); tumor number (solitary vs multiple); tumor side and localization within the skull base region (anterior, medial, posterior); infiltration of the cavernous sinus; compression of the optic channel/optic nerve; tumor volume; preoperative embolization (yes/no); duration of surgery; Simpson grade of resection; histopathological features (WHO grade); number of surgeries (single vs multiple); preoperative embolization; duration of hospital stay; tumor recurrence; use of an artificial dural substitute; postoperative infection rate; and clinical outcome (Glasgow Outcome Scale score at discharge and at 3 months, and vital status at last follow-up). Hierarchical clustering, factor analysis, and stepwise regression models revealed a ranking list for the top predictive variables for the occurrence of postoperative hydrocephalus. RESULTS: A total of 35 patients (5.9%) of the cohort of 594 developed communicating postoperative hydrocephalus, with no patient manifesting obstructive hydrocephalus. Of these 35 patients, 18 had a meningioma located at the skull base (18 [7.9%] of 227), in contrast to 17 patients with meningiomas in other locations (17 [4.6%] of 367). The following patient variables correlated with the occurrence of hydrocephalus, as defined by factor analysis: age, duration of surgery, duration of hospital stay, tumor volume, postoperative infection, and preoperative embolization. A stepwise regression analysis of the latter variables identified 2 variables as significantly predictive: age (p = 0.0012) and duration of surgery (p = 0.0013). CONCLUSIONS: In this study, the incidence of communicating postoperative hydrocephalus was almost twice as high in patients with skull base lesions as in patients with meningiomas in other locations. Patient age, duration of surgery, duration of hospital stay, tumor volume, postoperative infection, and preoperative embolization were associated with the occurrence of hydrocephalus. In the statistical prediction model, patient age and duration of surgery were the most significant predictors of postoperative hydrocephalus after skull base meningioma surgery. PMID- 21529181 TI - Skull base meningiomas. PMID- 21529182 TI - The microvascular corticocancellous femur flap for reconstruction of the anterior maxilla in adult cleft lip, palate, and alveolus patients. AB - OBJECTIVE: Free nonvascularized alveolar bone grafting in severe defects of the cleft region often results in poor implant bed conditions. Here an alternative augmentation technique using a new technique of vascularized bone transfer is described. DESIGN: In five patients with clefts of the lip, palate, and alveolus (four unilateral, one bilateral) there was a severe defect of the anterior maxillary alveolar ridge after tooth loss. The patients previously had augmentative surgery one to three times without success. The defect was covered using a microvascular corticocancellous transplant from the medial distal femur. The defects to be corrected measured 2.5 to 4.0 cm long, 1.0 to 1.5 cm wide, and 1 to 1.5 cm high. The microvascular pedicle of the femur bone flap was 3 to 7 cm long. The descending genicular artery was anastomosed to the facial or labial superior artery and the accompanying veins accordingly. In every case, the anastomoses were performed via an intraoral transmucosal approach. RESULTS: There were no serious complications and no flap loss. In all patients the defect was covered by a flap of the correct size and design. All patients were treated with dental implants (13 total) 6 months after successful reconstruction of the ridge. The implants were loaded 4 to 6 months after placement with fixed superstructures. There were good peri-implant conditions and no implant loss. CONCLUSION: The microvascular osteoperiosteal femur flap can be used successfully in individual reconstruction of segmental defects of the alveolar ridge in adult cleft patients. PMID- 21529184 TI - Multidisciplinary approach to cerebrospinal fluid shunt infection with an appeal for attention to details in assessment and standardization in reporting. AB - OBJECT: The goal of this study was to evaluate the problems encountered in monitoring CSF shunt infection, including the collection, analysis, and reporting of data. The authors propose a system that would produce more accurate, and hence more meaningful, information on shunt infection than do the methodologies and customs now in common use. METHODS: The authors reviewed and analyzed 19 years of quarterly records of a committee that has addressed CSF shunt infection in an ongoing manner. RESULTS: There are strong incentives, political and otherwise, to identify low rates of CSF shunt infection. Details of the composition and operation of a multidisciplinary approach to CSF shunt infection are summarized. Many factors affect the occurrence of shunt infection and its accurate assessment and reporting. Easily accessible sources for the identification of cases of shunt infections and for the assessment of an at-risk population often contain discrepancies in significant numbers. CONCLUSIONS: Multidisciplinary oversight of the entire matter of CSF shunt infection enhances the chances for collecting accurate data, identifying causes of infection, and developing effective preventative strategies. Valid data require a mechanism for finding all individuals within the at-risk pool; the accurate identification of patients who had shunt infections; standard, pragmatic, and robust criteria for diagnosis of shunt infection; and multidisciplinary oversight of the entire process. PMID- 21529183 TI - Neurosurgical management of extraaxial central nervous system infections in children. AB - OBJECT: Extraaxial infections of the CNS, including subdural empyema and epidural abscess, are rare but potentially life-threatening conditions. Symptoms are usually progressive, and early diagnosis is therefore important. Early intervention with appropriate treatment offers the best opportunity for eradicating the infection and promoting maximal neurological recovery. METHODS: The medical records of children with extraaxial CNS infection over the last 24 years at the Hospital for Sick Children were analyzed. Only those patients with radiological and/or operative confirmation of the diagnosis of subdural empyema or epidural abscess were included in the study. Demographic and clinical data were collected to determine the outcomes after such infections and factors that predict for such outcomes. RESULTS: The authors identified 70 children who fulfilled the inclusion criteria. Sinusitis was the most common etiology and was seen in 38 patients. All of these patients were older than 7 years of age at diagnosis. Subdural empyemas were diagnosed in 13 patients following bacterial meningitis, and they were found primarily in infants within the 1st year of life. Other etiological factors included otogenic infection (4 cases), postneurosurgical infection (7 cases), and hematogenous spread of infection (7 cases including 6 cases of spinal epidural abscess). Streptococcus anginosus and Staphylococcus aureus were the most common pathogens identified. Sixty-four patients (91.4%) underwent at least 1 neurosurgical procedure. Seizures and cerebral edema from cortical vein thrombosis were the most common complications. CONCLUSIONS: Due to variable etiology, identification of the responsible microorganism through neurosurgical drainage followed by long-term intravenous antibiotics remains the mainstay in treating extraaxial CNS infections. Optimal outcome is achieved with early diagnosis and therapy. PMID- 21529185 TI - Pediatric patients with poor neurological status and arteriovenous malformation hemorrhage: an outcome analysis. AB - OBJECT: In general, patients who present with low Glasgow Coma Scale (GCS) scores and/or fixed and dilated pupils are not expected to do well following arteriovenous malformation (AVM) hemorrhage. However, there is a sense among neurosurgeons that pediatric patients may make a better recovery than adults following such an event. There have been few studies focusing on the outcome of pediatric patients with poor neurological status following AVM hemorrhage. The purpose of this study was to characterize functional outcome in pediatric patients with severe disability after AVM hemorrhage. METHODS: This was a retrospective analysis of clinical presentation and outcome in 15 patients seen at the authors' pediatric hospital presenting with low GCS scores (defined as GCS <= 8) following AVM hemorrhage. RESULTS: Initial GCS scores ranged from 3 to 6, and 11 of 14 patients had fixed pupils on clinical examination (data were not available in 1 patient). Eight of 15 patients suffered primarily a lobar hemorrhage, 3 suffered primarily infratentorial bleeding, 2 suffered primarily hemorrhages of the basal ganglia, and 2 suffered intraventricular hemorrhage. The overall mortality rate was 20% (3 of 15 patients). The clinical outcome of survivors was defined by the Pediatric Cerebral Performance Category (PCPC) and Pediatric Overall Performance Category (POPC) scores at follow-up. One year after AVM hemorrhage, 7 (58%) of the 12 surviving patients showed normal or mild disability (PCPC Score 1 or 2), whereas 5 (42%) of 12 patients had moderate or severe disability (PCPC Score 3 or 4). No patients were in a coma or vegetative state, and 11 (92%) of the 12 patients were functioning independently (POPC Score 1, 2, or 3) 1 year after AVM hemorrhage. All patients were functionally independent by last follow-up, with 8 patients (67%) in the normal or mild disability PCPC category, and 4 in the moderate category (PCPC Score 3). All 12 survivors made a meaningful recovery and went on to live independent lives. CONCLUSIONS: Pediatric patients suffering AVM hemorrhage have a good outcome and are able to function independently, despite a poor neurological state initially. PMID- 21529186 TI - Complications associated with recombinant human bone morphogenetic protein use in pediatric craniocervical arthrodesis. AB - OBJECT: Management of pediatric occipitocervical instability remains especially challenging. The off-label use of recombinant human bone morphogenetic protein (rhBMP)-2 for spinal fusion has increased with a well-documented increase in fusion rate in many case series. Unfortunately, recent reports have documented complications associated with rhBMP use in adult spinal fusions. Complications associated with the use of rhBMP in pediatric spinal surgery is less well understood. In this study the authors report on the fusion rate and complications associated with rhBMP in pediatric occipitocervical arthrodesis. METHODS: The authors reviewed the medical records of those patients 18 years old and younger who underwent dorsal occipitocervical fusion from January 2004 to December 2007 at the University of Iowa Hospitals and Clinics. Forty-eight patients were identified who received rhBMP-augmented fusion. The clinical outcome and complications of these fusions were analyzed. RESULTS: All 48 patients had fusion confirmed on lateral radiographs within 4-14 months with an average fusion time of 6.7 months. There were 6 complications, 5 of which included seroma formation. Two of 5 patients who developed postoperative seroma presented with symptoms suggesting brainstem compression and obstructive hydrocephalus requiring emergency reoperation. One patient developed heterotopic bone formation causing cervicomedullary compression requiring reoperation. CONCLUSIONS: The use of rhBMP to augment autograft in occipitocervical fusion allows for a high rate of successful arthrodesis, but is associated with potentially life-threatening complications in pediatric patients. PMID- 21529187 TI - Use of occipital bone graft in pediatric posterior cervical fusion: an alternative paramedian technique and review of the literature. AB - An alternative method of bone grafting for pediatric posterior cervical and occipitocervical fixation is presented in detail. Full-thickness autografts from small craniectomies of the occipital bone are used to augment posterior segmental fusion in pediatric patients. Twelve patients have been treated successfully without bone graft donor site complications. The technical differences from previously reported uses of calvarial autograft in spine fusion are reviewed. PMID- 21529189 TI - Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases. AB - OBJECT: The authors undertook this study to analyze the efficacy of vagus nerve stimulation (VNS) in a large consecutive series of children 18 years of age and younger with treatment-resistant epilepsy and compare the safety and efficacy in children under 12 years of age with the outcomes in older children. METHODS: The authors retrospectively reviewed 141 consecutive cases involving children (75 girls and 66 boys) with treatment-resistant epilepsy in whom primary VNS implantation was performed by the senior author between November 1997 and April 2008 and who had at least 1 year of follow-up since implantation. The patients' mean age at vagus nerve stimulator insertion was 11.1 years (range 1-18 years). Eighty-six children (61.0%) were younger than 12 years at time of VNS insertion (which constitutes off-label usage of this device). RESULTS: Follow-up was complete for 91.8% of patients and the mean duration of VNS therapy in these patients was 5.2 years (range 25 days-11.4 years). Seizure frequency significantly improved with VNS therapy (mean reduction 58.9%, p < 0.0001) without a significant reduction in antiepileptic medication burden (median number of antiepileptic drugs taken 3, unchanged). Reduction in seizure frequency of at least 50% occurred in 64.8% of patients and 41.4% of patients experienced at least a 75% reduction. Major (3) and minor (6) complications occurred in 9 patients (6.4%) and included 1 deep infection requiring device removal, 1 pneumothorax, 2 superficial infections treated with antibiotics, 1 seroma/hematoma treated with aspiration, persistent cough in 1 patient, severe but transient neck pain in 1 patient, and hoarseness in 2 patients. There was no difference in efficacy or complications between children 12 years of age and older (FDA-approved indication) and those younger than 12 years of age (off-label usage). Linear regression analyses did not identify any demographic and clinical variables that predicted response to VNS. CONCLUSIONS: Vagus nerve stimulation is a safe and effective treatment for treatment-resistant epilepsy in young adults and children. Over 50% of patients experienced at least 50% reduction in seizure burden. Children younger than 12 years had a response similar to that of older children with no increase in complications. Given the efficacy of this device and the devastating effects of persistent epilepsy during critical developmental epochs, randomized trials are needed to potentially expand the indications for VNS to include younger children. PMID- 21529188 TI - Rapid online language mapping with electrocorticography. AB - OBJECT: Emerging research in evoked broadband electrocorticographic (ECoG) measurement from the cortical surface suggests that it might cleanly delineate the functional organization of cortex. The authors sought to demonstrate whether this could be done in a same-session, online manner to identify receptive and expressive language areas. METHODS: The authors assessed the efficacy of simple integration of "chi-band" (76-200 Hz) change in the ECoG signal by implementing a simple band-pass filter to estimate broadband spectral change. Following a brief (less than 10-second) period to characterize baseline activity, chi-band activity was integrated while 7 epileptic patients with implanted ECoG electrodes performed a verb-generation task. RESULTS: While the patients were performing verb-generation or noun-reading tasks, cortical activation was consistently identified in primary mouth motor area, superior temporal gyrus, and Broca and Wernicke association areas. Maps were robust after a mean time of 47 seconds (using an "activation overlap" measure). Correlation with electrocortical stimulation was not complete and was stronger for noun reading than verb generation. CONCLUSIONS: Broadband ECoG changes can be captured online to identify eloquent cortex. This demonstrates the existence of a powerful new tool for functional mapping in the operative and chronic implant setting. PMID- 21529190 TI - Microscopic endonasal transsphenoidal pituitary adenomectomy in the pediatric population. AB - OBJECT: Pituitary adenomas are uncommon in childhood. Although medical treatment can be effective in treating prolactinomas and some growth hormone (GH)-secreting tumors, resection is indicated when visual function is affected or the side effects of medical therapy are intolerable. The authors of this report describe their 10-year experience in managing pituitary adenomas via the microscopic endonasal transsphenoidal approach in a pediatric population. METHODS: They performed a retrospective review of a surgical case series based at a single institution and consisting of 34 consecutive pediatric patients with endocrine active (32 patients) and endocrine-inactive (2 patients) adenomas. These patients were surgically treated via an endonasal transsphenoidal approach between 1999 and 2008. Patient charts were reviewed, and clinical data were compiled and analyzed using the chi-square and Kaplan-Meier tests. RESULTS: The patient cohort consisted of 20 girls and 14 boys, with ages ranging from 9 to 18 years and a median age of 16 years. Thirty-two patients (94%) underwent surgery for endocrine active tumors, including 10 (29%) with Cushing disease, 21 (62%) with prolactinomas, and 1 (3%) with GH-secreting tumors. Two patients with nonsecreting adenomas underwent surgery for apoplexy. The mean tumor volume was 5.4 cm(3), and 13 patients (38%) had suprasellar extension and 7 (21%) had cavernous sinus invasion. Gross-total resection was achieved in 26 patients (76%), although it was significantly less likely to be achieved in the setting of cavernous sinus invasion (p < 0.001) but was unaffected by suprasellar extension. Residual tumor was treated with radiation therapy in 6 patients (18%). The average duration of hospital stay was 1.6 days. The median follow-up time was 18 months. After surgery, 19 patients (56%) had normal hormone function without adjuvant therapy, 8 (24%) had normal function with adjuvant therapy, and 5 (15%) had persistently elevated hormone levels. Patients with a macroprolactinoma were significantly more likely to require postoperative adjuvant therapy than were those with a microprolactinoma (p < 0.03). CONCLUSIONS: Endonasal transsphenoidal resection is a safe, well-tolerated, and potentially curative treatment option for pituitary adenomas in children. Despite the technical challenges associated with this approach in the pediatric population, these tumors can be effectively managed with minimal morbidity. Endocrine function is usually preserved, and the majority of patients will not require lifelong medical therapy. PMID- 21529191 TI - Nonneoplastic enlargement of the pituitary gland in children. AB - Primary neoplasms of the pituitary gland are uncommon in children. Physiological enlargement of the gland, however, is universal and can sometimes be confused with a tumor. Due to widespread availability of MR imaging, the number of children referred to pediatric neurosurgeons with an enlarged pituitary associated with nonspecific symptoms, most commonly headache, is increasing. In this review, the authors illustrate two common causes of pituitary enlargement in children, namely physiological hypertrophy of puberty, more commonly seen in females, and secondary hyperplasia caused by hypothyroidism. The importance of early and accurate diagnosis, without recourse to extensive endocrine investigations or inappropriate surgery, is underscored. PMID- 21529192 TI - Use of a minimally invasive tubular retraction system for deep-seated tumors in pediatric patients. AB - OBJECT: Microsurgical removal is the preferred treatment for most deep-seated, intraaxial tumors in the pediatric population. The feasibility of surgery as an option has improved with advances in surgical technology and technique. Tubular retractors disperse retraction forces over a greater surface area than do conventional retractors, which can lower the risk of ischemic complications. The authors describe their experience utilizing a new tubular retractor system specifically designed for cranial applications in conjunction with frameless neuronavigation. METHODS: The Vycor ViewSite retractor was used in 4 pediatric patients (ages 15 months and 9, 10, and 16 years) with deep-seated intraaxial tumors. The lesions included a papillary tumor of the pineal region, a low-grade astrocytoma in the occipital lobe, a dysembryoplastic neuroepithelial tumor arising from the basal ganglia, and an intraventricular low-grade glioma. The extent of white matter damage along the surgical trajectory (based on T2 or FLAIR and diffusion restriction/apparent diffusion coefficient signals) and the extent of resection were assessed on postoperative imaging. RESULTS: Satisfactory resection or biopsy was achieved in all patients. A comparison of pre- and postoperative MR imaging studies revealed evidence of white matter damage along the surgical trajectory in 1 patient. None of the patients demonstrated new neurological deficits postoperatively. CONCLUSIONS: Obtaining surgical access to deep-seated, intraaxial tumors is challenging. In this small series of pediatric patients, the combination of the ViewSite tubular retractor and frameless neuronavigation facilitated the surgical approach. The combination of these technologies adds to the armamentarium to safely approach tumors in deep locations. PMID- 21529193 TI - Regression of recurrent glioblastoma infiltrating the brainstem after convection enhanced delivery of nimustine hydrochloride. AB - This 13-year-old boy with a history of cranial irradiation for the CNS recurrence of acute lymphocytic leukemia developed a glioblastoma in the right cerebellum. Resection and chemo- and radiotherapy induced remission of the disease. However, recurrence was noted in the brainstem region 8 months later. Because no effective treatment was available for this recurrent lesion, the authors decided to use convection-enhanced delivery (CED) to infuse nimustine hydrochloride. On stereotactic insertion of the infusion cannula into the brainstem lesion, CED of nimustine hydrochloride was performed with real-time MR imaging to monitor the co infused chelated gadolinium. The patient's preinfusion symptom of diplopia disappeared after treatment. Follow-up MR imaging revealed the response of the tumor. The authors report on a case of recurrent glioblastoma infiltrating the brainstem that regressed after CED of nimustine hydrochloride. PMID- 21529194 TI - Posterior interhemispheric retrocallosal approach to pineal region and posterior fossa lesions in a pediatric population. AB - OBJECT: The purpose of this study was to evaluate the posterior interhemispheric retrocallosal approach (PIRA) for its safety and efficacy in the resection of pineal region and posterior fossa lesions in children. METHODS: Twenty-nine PIRAs were performed in 26 children between March 1997 and March 2009, and these cases were retrospectively reviewed. There were 15 girls and 11 boys in the series. The median age at the time of surgery was 7 years (range 7 months-17 years). Twenty seven cases were treated for tumor, 1 for loculated hydrocephalus, and 1 for an aneurysm. RESULTS: Of the 27 cases treated for tumor, there were 20 (74%) gross total resections, 5 (19%) subtotal resections, and 2 (7%) biopsies. One bridging vein was sacrificed in 6 cases and 2 bridging veins were divided in 1 case, whereas in 3 cases there was sacrifice of a single deep cerebral vein. No patient developed radiographic evidence of venous infarction. Approach-related complications were low, and included 2 cases of transient homonymous hemianopia. There were no surgery-related deaths. CONCLUSIONS: This approach allows for ample access to pineal region and posterior fossa lesions, with low postoperative morbidity. PMID- 21529195 TI - Papillary tumor of the pineal region in a 15-month-old boy. AB - The papillary tumor of the pineal region (PTPR) is a distinct entity that is particularly rare in the pediatric population. The authors document the youngest reported patient with this clinicopathological entity to date. A case of PTPR in a 15-month-old boy is described. Initially thought to be a tectal glioma, the tumor was later identified as a pineal region tumor after demonstrating growth on routine imaging. Diagnosis of PTPR was established by histopathological evaluation of biopsy samples, which revealed papillary, cystic, and solid tumor components. The patient's postoperative course was complicated by tumor growth despite several debulking procedures and chemotherapy, as well as persistent hydrocephalus requiring 2 endoscopic third ventriculostomies and eventual ventriculoperitoneal shunt placement. After a 15-month follow-up period, the patient has received proton-beam therapy and has a stable tumor size. The PTPR is a recently described tumor of the CNS that must be included in the differential diagnosis of pineal region masses. The biological behavior, prognosis, and appropriate treatment of PTPR have yet to be fully defined. PMID- 21529196 TI - Pilomyxoid astrocytoma of the cerebellum. AB - Pilomyxoid astrocytomas (PMAs) are low-grade (WHO Grade II) tumors for which the imaging features are similar to pilocytic astrocytomas (PAs), but for which histological features and the clinical course differ. They are classified as a variant of PA. They have only been recently recognized, and they behave more aggressively than PAs. Most cases occur in the hypothalamic-chiasmatic area, although they may be located in any part of the neuraxis. Posterior fossa PMAs are very rare. The authors report a case of a 2-year-old girl with cerebellar PMA. PMID- 21529197 TI - Treatment of a malignant peripheral nerve sheath tumor and its complications through a multidisciplinary approach. AB - The authors report the case of a 14-year-old girl with a residual malignant peripheral nerve sheath tumor after thoracotomy, chemotherapy, and radiation therapy. The residual tumor, which involved the intercostal muscles, aorta, and neural foramina of T4-10, was completely resected through a costotransversectomy and multiple hemilaminotomies with the patient in the prone position and was stabilized using a T1-12 pedicle screw fusion. Postoperatively, the patient developed several infections requiring multiple washouts and prolonged antibiotics. Thirty months after surgery, she developed a bronchocutaneous fistula. The hardware was removed, and a vascularized latissimus dorsi free flap was placed over the lung. She continued to have an air leak and presented 3 weeks later with a 40 degrees left thoracic curve. She returned to the operating room for a T2-L2 fusion with a vascularized fibular graft. On postoperative Day 1, she underwent a bronchoscopy and had her left lower lobe airways occluded with multiple novel one-way endobronchial valves. She is now 5 years out from her tumor resection and 3 years out from her definitive fusion. She has no evidence of residual tumor, infection, or pseudarthrosis and continues to remain asymptomatic. PMID- 21529198 TI - Cyst-ventricle stent as primary or salvage treatment for posterior fossa arachnoid cysts. AB - OBJECT: The optimal treatment of symptomatic posterior fossa arachnoid cysts is controversial. Current options include open or endoscopic resection, fenestration, or cyst-peritoneal shunt placement. There are potential drawbacks with all options. Previous authors have described stenting a cyst into the ventricular system for supratentorial lesions. The current authors have used a similar strategy for posterior fossa cysts. METHODS: The authors performed a retrospective review of 79 consecutive patients (1993-2010) with surgically treated intracranial arachnoid cysts. RESULTS: The authors identified 3 patients who underwent placement of a stent from a posterior fossa arachnoid cyst to a supratentorial ventricle. In 2 patients the stent construct consisted of a catheter placed into a posterior fossa arachnoid cyst and connecting to a lateral ventricle catheter. Both patients underwent stent placement as a salvage procedure after failure of open surgical fenestration. In the third patient a single-catheter cyst-ventricle stent was stereotactically placed. All 3 patients improved clinically. Two patients remained asymptomatic, with radiographic stability in a follow-up period of 1 and 5 years, respectively. The third patient experienced initial symptom resolution with a demonstrable reduction of intracystic pressure. However, he developed recurrent headaches after 2 years. CONCLUSIONS: Posterior fossa cyst-ventricle stenting offers the benefits of ease of surgical technique and a low morbidity rate. It may also potentially reduce the incidence of shunt-related headaches by equalizing the pressure between the posterior fossa and the supratentorial compartments. While fenestration is considered the first-line therapy for most symptomatic arachnoid cysts, the authors consider cyst-ventricle stenting to be a valuable additional strategy in treating these rare and often difficult lesions. PMID- 21529199 TI - Short- and long-term effects of selective dorsal rhizotomy on gross motor function in ambulatory children with spastic diplegia. AB - OBJECT: The primary aim of this prospective cohort study was to evaluate the short-term (1 year) and long-term (mean 6 years) effects of selective dorsal rhizotomy (SDR) on gross motor function and spasticity in ambulatory children with spastic diplegia. Secondary aims were to investigate side effects, additional treatment during follow-up (botulinum toxin type A injections or orthopedic surgery), and parental satisfaction. METHODS: Thirty-three children who had undergone SDR at a mean age of 6 years and 7 months (+/- 2 years) were included. There were 7 children at Gross Motor Function Classification System (GMFCS) Level I, 7 at Level II, and 19 at Level III. Gross motor function was assessed with the Gross Motor Function Measure-66 (GMFM-66). Spasticity was measured according to a modified Tardieu scale. Side effects, additional treatment, and parental satisfaction were recorded using a parental questionnaire and medical records. RESULTS: At 1-year follow-up, mean GMFM-66 scores improved significantly by 4.3 +/- 4.1 points. Children at GMFCS Levels I and II showed significantly more improvement (7.2 points) on the GMFM-66 compared with children at GMFCS Level III (2.9 points). On long-term follow-up (mean 6 years +/- 22 months), mean GMFM-66 scores improved significantly by 6.5 +/- 5.9 points, without a difference between children at GMFCS Levels I and II and Level III. No relapse of spasticity was noted. Ten children (30%) needed orthopedic surgery and 13 children (39%) received botulinum toxin type A treatment after SDR. Twenty (91%) of the 22 parents who answered the questionnaire at long-term follow-up believed that their child's functioning had improved after SDR. CONCLUSIONS: Selective dorsal rhizotomy resulted in short- and long-term improvements in gross motor function, without relapse of spasticity. However, the majority of the children still needed additional surgery or botulinum toxin A treatment. PMID- 21529201 TI - Functional restoration of the paralyzed diaphragm in high cervical quadriplegia via phrenic nerve neurotization utilizing the functional spinal accessory nerve. AB - The authors report a case of functional improvement of the paralyzed diaphragm in high cervical quadriplegia via phrenic nerve neurotization using a functional spinal accessory nerve. Complete spinal cord injury at the C-2 level was diagnosed in a 44-year-old man. Left diaphragm activity was decreased, and the right diaphragm was completely paralyzed. When the level of metabolism or activity (for example, fever, sitting, or speech) slightly increased, dyspnea occurred. The patient underwent neurotization of the right phrenic nerve with the trapezius branch of the right spinal accessory nerve at 11 months postinjury. Four weeks after surgery, training of the synchronous activities of the trapezius muscle and inspiration was conducted. Six months after surgery, motion was observed in the previously paralyzed right diaphragm. The lung function evaluation indicated improvements in vital capacity and tidal volume. This patient was able to sit in a wheelchair and conduct outdoor activities without assisted ventilation 12 months after surgery. PMID- 21529202 TI - Motion segment-sparing repair of symptomatic chronic pars defects. AB - OBJECT: The current standard of care for symptomatic chronic spondylolysis (SP) is a one-level posterior spinal fusion for defects at L-5 or direct pars repair (motion segment sparing) for more rostral SP in younger patients and if no disc degeneration or listhesis is present. Since many patients with SP undergoing operative repair are young, a procedure with the lowest biomechanical profile is desirable, and direct pars repair is recommended. The authors here explore the limits of direct pars repair. METHODS: A retrospective review of all patients who underwent direct repair of SP between 2002 and 2009 was performed. Data were analyzed for predictors of symptom relief and radiographic fusion failure. RESULTS: Of 49 patients, only 7 required a reoperation to treat clinical symptoms, and 6 of them were female (p = 0.049). In all cases of treatment failure, the patient had bilateral L-5 SP. Patients with a slip percentage as high as 30% experienced radiographic fusion and symptom relief. Disc degeneration (measured using the Modified Pfirrmann Scale) did not predict symptom persistence or radiographic fusion failure. Patients with high-grade disc disease experienced symptom relief. The authors found no predictors of treatment failure. CONCLUSIONS: The number of patients undergoing motion segment-sparing fusions of symptomatic chronic SP can be safely increased to include patients with Grade I spondylolisthesis as well as high-grade disc disease. Female patients with bilateral L-5 SP and low lordotic angles may be better served by a posterior spinal fusion from L-5 to S-1. PMID- 21529203 TI - Cost-effectiveness of transforaminal lumbar interbody fusion for Grade I degenerative spondylolisthesis. AB - OBJECT: Transforaminal lumbar interbody fusion (TLIF) for spondylolisthesis associated back and leg pain is associated with improvement in pain, disability, and quality of life. However, given the rising health care costs associated with spinal fusion procedures and varying results of recent cost-utility studies, the cost-effectiveness of TLIF remains unclear. The authors set out to assess the comprehensive costs of TLIF at their institution and to determine its cost effectiveness in the treatment of degenerative spondylolisthesis. METHODS: Forty five patients undergoing TLIF for Grade I degenerative spondylolisthesis associated back and leg pain after 6-12 months of conservative therapy were included. The authors assessed the 2-year back pain visual analog scale (VAS) score, leg pain VAS score, Oswestry Disability Index, and total back-related medical resource utilization, missed work, and health-state values (quality adjusted life years [QALYs], calculated from EQ-5D with US valuation). Two-year resource use was multiplied by unit costs based on Medicare national allowable payment amounts (direct cost), and patient and caregiver workday losses were multiplied by the self-reported gross-of-tax wage rate (indirect cost). The mean total 2-year cost per QALY gained after TLIF was assessed. RESULTS: Compared with preoperative health states reported after at least 6 months of medical management, a significant improvement in back pain VAS score, leg pain VAS score, and Oswestry Disability Index was observed 2 years after TLIF, with a mean 2-year gain of 0.86 QALYs. The mean +/- SD total 2-year cost of TLIF was $36,836 +/- $11,800 (surgery cost, $21,311 +/- $2800; outpatient resource utilization cost, $3940 +/- $2720; indirect cost, $11,584 +/- $11,363). Transforaminal lumbar interbody fusion was associated with a mean 2-year cost per QALY gained of $42,854. CONCLUSIONS: Transforaminal lumbar interbody fusion improved pain, disability, and quality of life in patients with degenerative spondylolisthesis associated back and leg pain. The total cost per QALY gained for TLIF was $42,854 when evaluated 2 years after surgery with Medicare fees, suggesting that TLIF is a cost-effective treatment of lumbar spondylolisthesis. PMID- 21529204 TI - Incidence of postoperative symptomatic epidural hematoma in spinal decompression surgery. AB - OBJECT: Neurological deterioration due to spinal epidural hematoma (SEH) is a rare but significant complication of spinal surgery. The frequency of hematoma evacuation after spinal surgery is reportedly 0.1%-3%. The objective of this study was to investigate the symptomatology of SEH and the frequency of evacuation for each surgical procedure after spinal decompression surgery. METHODS: This is a retrospective study of 26 patients who underwent SEH evacuation after spinal decompression surgery between 1986 and 2005. During this period, 6356 spinal decompression surgeries were performed. The factors studied were the frequency of SEH evacuation for each surgical procedure, symptoms, time to SEH evacuation, comorbidities, and neurological recovery. RESULTS: The frequency of SEH evacuation was 0.41% (26 of 6356) for all operations. The frequency for each surgical procedure was 0% (0 of 1568) in standard lumbar discectomy, 0.50% (8 of 1614) in lumbar laminectomy, 0.67% (8 of 1191) in posterior lumbar interbody fusion, 4.46% (5 of 112) in thoracic laminectomy, 0.44% (4 of 910) in cervical laminoplasty, and 0.21% (1 of 466) in cervical anterior spinal fusion. Nine patients had comorbidities involving hemorrhage. Spinal epidural hematoma evacuation was performed between 4 hours and 8 days after the initial operation. Whereas severe paralysis was observed within 24 hours in most patients undergoing cervical and/or thoracic surgery, half of the patients undergoing lumbar surgery had symptoms of SEH such as leg pain or bladder dysfunction after suction drain removal. The shorter the period to evacuation, the better were the results of neurological recovery. CONCLUSIONS: Postoperative SEH was most frequent after thoracic laminectomy. In cervical and thoracic surgeries, symptoms of SEH were noted within 24 hours, mostly severe paralysis, and almost half of the lumbar surgery patients had symptoms after suction drain removal. PMID- 21529205 TI - Cost-effectiveness of transforaminal lumbar interbody fusion. PMID- 21529206 TI - Letter to the Editor. PMID- 21529207 TI - Letter to the Editor. PMID- 21529209 TI - Effects of syringomyelia on electrodiagnostic test results in Cavalier King Charles Spaniels. AB - OBJECTIVE: To determine the effects of syringomyelia on electromyography (EMG) findings, somatosensory-evoked potentials (SEPs), and transcranial magnetic motor evoked potentials (TMMEPs) in Cavalier King Charles Spaniels (CKCSs). ANIMALS: 27 client-owned CKCSs that underwent prebreeding magnetic resonance imaging screening or investigation of clinical signs consistent with syringomyelia. PROCEDURES: In dogs with (n = 11) and without (16) magnetic resonance imaging confirmed syringomyelia, the median nerve in each thoracic limb was stimulated and SEPs were recorded over the C1 vertebra; onset latency and latency and amplitude of the largest negative (N1) and positive (P1) peaks were measured. The TMMEPs were recorded bilaterally from the extensor carpi radialis and tibialis cranialis muscles; onset latencies in all 4 limbs were measured. Bilateral systematic needle EMG examination was performed on the cervical epaxial musculature, and the number of sites with spontaneous activity was recorded. RESULTS: In dogs with syringomyelia, amplitudes of N1 and P1 and the amplitude difference between P1 and N1 were significantly smaller than those recorded for dogs without syringomyelia (approx 2-fold difference). No difference in SEP latencies, TMMEP latencies, or the proportion of dogs with > 2 sites of spontaneous activity detected during EMG examination was detected between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that SEP amplitude at the C1 vertebra was a more sensitive measure of spinal cord function in CKCSs with syringomyelia, compared with results of EMG or TMMEP assessment. Measurement of SEP amplitude may have use as an objective assessment of the evolution and treatment of this disease. PMID- 21529210 TI - Reliability and validity of a visual analogue scale used by owners to measure chronic pain attributable to osteoarthritis in their dogs. AB - OBJECTIVE: To assess validity and reliability for a visual analogue scale (VAS) used by owners to measure chronic pain in their osteoarthritic dogs. SAMPLE: 68, 61, and 34 owners who completed a questionnaire. PROCEDURES: Owners answered questionnaires at 5 time points. Criterion validity of the VAS was evaluated for all dogs in the intended-to-treat population by correlating scores for the VAS with scores for the validated Helsinki Chronic Pain Index (HCPI) and a relative quality-of-life scale. Intraclass correlation was used to assess repeatability of the pain VAS at 2 baseline evaluations. To determine sensitivity to change and face validity of the VAS, 2 blinded, randomized control groups (17 dogs receiving carprofen and 17 receiving a placebo) were analyzed over time. RESULTS: Significant correlations existed between the VAS score and the quality-of-life scale and HCPI scores. Intraclass coefficient (r = 0.72; 95% confidence interval, 0.57 to 0.82) for the VAS indicated good repeatability. In the carprofen and placebo groups, there was poor correlation between the 2 pain evaluation methods (VAS and HCPI items) at the baseline evaluation, but the correlation improved in the carprofen group over time. No correlation was detected for the placebo group over time. CONCLUSIONS AND CLINICAL RELEVANCE: Although valid and reliable, the pain VAS was a poor tool for untrained owners because of poor face validity (ie, owners could not recognize their dogs' behavior as signs of pain). Only after owners had seen pain diminish and then return (after starting and discontinuing NSAID use) did the VAS have face validity. PMID- 21529211 TI - Effect of duration and type of anesthetic on tear production in dogs. AB - OBJECTIVE: To determine effects of duration and type of anesthetic on tear production in dogs. ANIMALS: 8 female Beagles. PROCEDURES: Each dog was randomly allocated into 1 of 4 groups according to a Latin square design to receive anesthesia as follows: 1 hour with isoflurane, 1 hour with desflurane, 4 hours with isoflurane, and 4 hours with desflurane. Each dog was anesthetized with the selected inhalant 4 times during a 4-week period, with at least 5 days separating anesthetic episodes. Aqueous tear production was measured via the Schirmer I tear test at baseline and 10 minutes, 30 minutes, and 1 hour after induction of anesthesia as well as 2, 3, and 4 hours after induction for the 4-hour groups. Tear production was also measured after the dogs were standing after recovery from anesthesia and 2, 10, and 22 hours after recovery from anesthesia. RESULTS: Aqueous tear production was significantly reduced in dogs during anesthesia and returned to baseline values immediately after recovery and until 10 hours after anesthesia in all treatment groups. Inhalant type and duration had no significant effect. Neither lateral recumbency nor left versus right eyes had a significant effect. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that inhalant anesthetics did not reduce tear production after anesthesia and that longer duration anesthesia did not cause decreased tear production, compared with shorter-duration anesthesia. PMID- 21529212 TI - Comparison of two tourniquets and determination of amikacin sulfate concentrations after metacarpophalangeal joint lavage performed simultaneously with intravenous regional limb perfusion in horses. AB - OBJECTIVE: To determine whether joint lavage performed simultaneously with IV regional limb perfusion (IVRLP) reduces the effectiveness of IVRLP and to compare 2 types of tourniquets used for this procedure in horses. ANIMALS: 11 adult horses. PROCEDURES: 2 groups of 6 horses were tested by use of a pneumatic or an Esmarch tourniquet (1 horse was tested twice [once in each group]). Standing IVRLP with amikacin (500 mg) was performed for 30 minutes. Simultaneously, the metacarpophalangeal joint was lavaged with 2 L of lactated Ringer's solution and the egress fluids were collected. Samples of the distal interphalangeal joint synovial fluid and blood from the digital and jugular veins were collected at set time intervals. Amikacin concentrations in all fluids were determined via fluorescence polarization immunoassay. RESULTS: Less amikacin was measured in the systemic circulation with the Esmarch tourniquet than with the pneumatic tourniquet. Amikacin concentrations in the synovial fluid from the distal interphalangeal joints of the Esmarch tourniquet group ranged from 45.1 to 1,968 MUg/mL and in the pneumatic tourniquet group ranged from 1.7 to 92.3 MUg/mL after 30 minutes of IVRLP. Total loss of amikacin in the egress fluids from the joint lavage ranged from < 1.36 to 7.72 mg for the Esmarch tourniquet group and from < 1.20 to 1.75 mg for the pneumatic tourniquet group. CONCLUSIONS AND CLINICAL RELEVANCE: On standing horses, IVRLP performed simultaneously with joint lavage resulted in negligible loss of amikacin in the egress lavage fluids. The Esmarch tourniquet was more effective in preventing loss of amikacin from the distal portion of the limb, easier to use, and less expensive than the pneumatic tourniquet. PMID- 21529214 TI - Effects of industrial polystyrene foam insulation pads on the center of pressure and load distribution in the forefeet of clinically normal horses. AB - OBJECTIVE: To evaluate the ability of industrial polystyrene foam insulation pads to redistribute loads placed on clinically normal weight-bearing structures of the foot and shift the location of the center of pressure palmarly in horses. ANIMALS: 25 nonlame mature horses. PROCEDURES: Both forefeet from each horse were evaluated. Center of pressure data and solar load distribution patterns were recorded during a 5-second trial by use of a commercial pressure measurement system prior to placement of foam sole support and at 0, 6, 12, 24, and 48 hours after placement. Total contact surface area, contact pressure, peak contact pressure, and center of pressure positions were compared by use of a linear mixed model with repeated measurements. RESULTS: Total contact surface area was increased significantly at all time points, whereas contact pressure and peak contact pressure were significantly decreased at all time points following application of foam sole supports. Immediately following application of sole support, the position of the center of pressure was significantly moved cranially. However, by 48 hours, the center of pressure was significantly positioned more palmarly than prior to application of the foam supports. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the use of foam sole supports may be an effective, economical, and immediate treatment for acute laminitis. PMID- 21529213 TI - Associations among behavioral and acute physiologic responses to lipopolysaccharide-induced clinical mastitis in lactating dairy cows. AB - OBJECTIVE: To examine behavioral and physiologic effects of lipopolysaccharide (LPS)-induced mastitis in lactating dairy cows. ANIMALS: 20 Holstein cows. PROCEDURES: Cows were assigned to 5 blocks (4 cows/block) on the basis of parity and number of days in lactation. Intramammary infusion and IV treatments were assigned in a 2 * 2 factorial arrangement. Cows within each block were assigned to receive intramammary infusion with 25 MUg of LPS or sterile PBS solution 3 hours after milking, and treatment with flunixin meglumine or sterile PBS solution was administered IV 4 hours after intramammary infusion. Video monitoring was continuously performed during the study. RESULTS: LPS-infused cows spent less time during the first 12 hours after infusion lying, eating, and chewing cud, compared with results for PBS solution-infused cows. Behavioral responses were correlated with physiologic responses for the first 12 hours after intramammary infusion. Flunixin meglumine administration after intramammary infusion mitigated some behavioral and clinical systemic responses. CONCLUSIONS AND CLINICAL RELEVANCE: Intramammary infusion of LPS caused changes in both behavioral and physiologic variables in lactating dairy cows. Time spent lying, eating, and chewing cud were negatively correlated with physiologic responses in cows. Evaluation of behavior patterns may provide an ancillary measure, along with evaluation of physiologic variables, for monitoring well-being, clinical responses, and recovery from acute clinical mastitis. PMID- 21529215 TI - Effects of long-term administration of carprofen on healing of a tibial osteotomy in dogs. AB - OBJECTIVE: To evaluate effects of long-term administration of carprofen on healing of a tibial osteotomy in dogs. ANIMALS: 12 healthy female Beagles. PROCEDURES: A mid-diaphyseal transverse osteotomy (stabilized with an intramedullary pin) of the right tibia was performed in each dog. The carprofen group (n = 6 dogs) received carprofen (2.2 mg/kg, PO, q 12 h) for 120 days; the control group (6) received no treatment. Bone healing and change in callus area were assessed radiographically over time. Dogs were euthanized 120 days after surgery, and tibiae were evaluated biomechanically and histologically. RESULTS: The osteotomy line was not evident in the control group on radiographs obtained 120 days after surgery. In contrast, the osteotomy line was still evident in the carprofen group. Callus area was significantly less in the carprofen group, compared with the area in the control group, at 20, 30, and 60 days after surgery. At 120 days after surgery, stiffness, elastic modulus, and flexural rigidity in the carprofen group were significantly lower than corresponding values in the control group. Furthermore, histologic evaluation revealed that the cartilage area within the callus in the carprofen group was significantly greater than that in the control group. CONCLUSIONS AND CLINICAL RELEVANCE: Long-term administration of carprofen appeared to inhibit bone healing in dogs that underwent tibial osteotomy. We recommend caution for carprofen administration when treating fractures that have delays in healing associated with a reduction in osteogenesis as well as fractures associated with diseases that predispose animals to delays of osseous repair. PMID- 21529216 TI - Evaluation of N-terminal pro-B-type natriuretic peptide as a diagnostic marker of various stages of cardiomyopathy in Doberman Pinschers. AB - OBJECTIVE: To evaluate the diagnostic value of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations in Doberman Pinschers in various stages of dilated cardiomyopathy (DCM). ANIMALS: 328 Doberman Pinschers. PROCEDURES: Staging of DCM was determined via analysis of results of physical examinations, 24-hour ambulatory ECG (Holter) recordings, and echocardiographic evaluations. Plasma samples for NT-proBNP assays were obtained at each examination. Concentrations of NT-proBNP were measured in 337 samples obtained from 196 healthy Doberman Pinschers (control dogs) and in 195 samples obtained from 132 Doberman Pinschers in various stages of DCM. These included dogs that had ventricular premature contractions (VPCs; 79 samples), echocardiographic changes (23 samples), or both (51 samples); 16 samples were from dogs with overt DCM, and 26 were from dogs that were considered normal during initial examination but developed DCM within 1.5 years after this assessment. Receiver operating characteristic curves were analyzed to determine sensitivity and specificity of NT-proBNP concentrations for detection of DCM. RESULTS: NT-proBNP concentrations in dogs that had or developed DCM were significantly higher than those of control dogs. Sensitivity and specificity of NT-proBNP concentrations (cutoff value, > 400 pmol/L) to detect all stages of DCM were 81.1 % and 75.0%, respectively; sensitivity was 90.0% and specificity was 75.0% to predict echocardiographic changes. Specificity to detect echocardiographic changes was 90.4% at a cutoff value of 550 pmol/L. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma concentrations of NT-proBNP were increased in dogs with DCM and in apparently healthy dogs that developed DCM within 1.5 years after samples were obtained, compared with concentrations in control dogs. PMID- 21529217 TI - Comparison of echocardiographic indices of myocardial strain with invasive measurements of left ventricular systolic function in anesthetized healthy dogs. AB - OBJECTIVE: To compare echocardiographic indices of myocardial strain with invasive measurements of left ventricular (LV) systolic function in anesthetized healthy dogs. ANIMALS: 7 healthy dogs. PROCEDURES: In each anesthetized dog, preload and inotropic conditions were manipulated sequentially to induce 6 hemodynamic states; in each state, longitudinal, radial, and global strains and strain rate (SR), derived via 2-D speckle-tracking echocardiography, were evaluated along with conventional echocardiographic indices of LV function and maximum rate of rise (first derivative) of LV systolic pressure (LV+dp/dt(max)). Catheter-derived and echocardiographic data were acquired simultaneously. Partial and semipartial correlation coefficients were calculated to determine the correlation between LV+dp/dt(max) and each echocardiographic variable. Global longitudinal strain was compared with conventional echocardiographic indices via partial correlation analysis. RESULTS: All myocardial segments could be analyzed in all dogs. Significant semipartial correlations were identified between conventional echocardiographic strain indices and LV+dp/dt(max). Correlation coefficients for longitudinal deformation and global strain, segmental longitudinal strain, and segmental SR were -0.773, -0.562 to -0.786, and -0.777 to -0.875, respectively. Correlation coefficients for radial segments and strain or SR were 0.654 to 0.811 and 0.748 to 0.775, respectively. Correlation coefficients for traditional echocardiographic indices and LV+dp/dt(max) (-0.586 to 0.821) and semipartial correlation coefficients for global strain and echocardiographic indices of LV systolic function (-0.656 [shortening fraction], 0.726 [shortening area], and -0.744 [ejection fraction]) were also significant. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that LV systolic function can be predicted by myocardial strain and SR derived via 2-D speckle-tracking echocardiographic analysis in anesthetized healthy dogs. PMID- 21529218 TI - Determination of the concentrations of trilostane and ketotrilostane that inhibit ex vivo canine adrenal gland synthesis of cortisol, corticosterone, and aldosterone. AB - OBJECTIVE: To determine whether trilostane or ketotrilostane is more potent in dogs and determine the trilostane and ketotrilostane concentrations that inhibit adrenal gland cortisol, corticosterone, and aldosterone secretion by 50%. SAMPLE: 24 adrenal glands from 18 mixed-breed dogs. PROCEDURES: Adrenal gland tissues were sliced, placed in tissue culture, and stimulated with 100 pg of ACTH/mL alone or with 5 concentrations of trilostane or ketotrilostane. Trials were performed independently 4 times. In each trial, 6 samples (1 for each time point) were collected for each of the 5 concentrations of trilostane and ketotrilostane tested as well as a single negative control samples. At the end of 0, 1, 2, 3, 5, and 7 hours, tubes were harvested and media and tissue slices were assayed for cortisol, corticosterone, aldosterone, and potassium concentrations. Data were analyzed via pharmacodynamic modeling. One adrenal slice exposed to each concentration of trilostane or ketotrilostane was submitted for histologic examination to assess tissue viability. RESULTS: Ketotrilostane was 4.9 and 2.4 times as potent in inhibiting cortisol and corticosterone secretion, respectively, as its parent compound trilostane. For trilostane and ketotrilostane, the concentrations that inhibited secretion of cortisol or corticosterone secretion by 50% were 480 and 98.4 ng/mL, respectively, and 95.0 and 39.6 ng/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Ketotrilostane was more potent than trilostane with respect to inhibition of cortisol and corticosterone secretion. The data should be useful in developing future studies to evaluate in vivo serum concentrations of trilostane and ketotrilostane for efficacy in the treatment of hyperadrenocorticism. PMID- 21529219 TI - Evaluation of the effects of pregnancy on insulin sensitivity, insulin secretion, and glucose dynamics in Thoroughbred mares. AB - OBJECTIVE: To characterize the effects of pregnancy on insulin sensitivity (SI) and glucose dynamics in pasture-maintained mares fed supplemental feeds of differing energy composition. ANIMALS: Pregnant (n = 22) and nonpregnant (10) healthy Thoroughbred mares. PROCEDURES: Pregnant and nonpregnant mares underwent frequently sampled intravenous glucose tolerance tests at 2 times (period 1, 25 to 31 weeks of gestation; period 2, 47 weeks of gestation). Following period 1 measurements, mares were provided a high-starch (HS; 39% starch) or high-fat and fiber (14% fat and 70% fiber) supplemental feed. From a subset of mares (n = 12), blood samples were collected hourly for 24 hours to assess glycemic and insulinemic response to feeding while pastured. The minimal model of glucose and insulin dynamics was used to estimate SI, glucose effectiveness, and acute insulin response to glucose from tolerance testing data. RESULTS: Pregnant mares during period 1 had a lower SI and glucose effectiveness and higher acute insulin response to glucose than did nonpregnant mares. The SI value decreased in nonpregnant but not pregnant mares from periods 1 to 2. Pregnant mares fed HS feed had a greater glycemic and insulinemic response to feeding than did any other group. CONCLUSIONS AND CLINICAL RELEVANCE: Pregnant mares had slower glucose clearance and greater insulin secretion at 28 weeks of gestation than did nonpregnant mares. Glucose and insulin responses to meal feeding, particularly with HS feed, were greater in pregnant mares, indicating that pregnancy enhanced the postprandial glycemic and insulinemic effects of starch-rich feed supplements. PMID- 21529220 TI - Effect of combined lignan phytoestrogen and melatonin treatment on secretion of steroid hormones by adrenal carcinoma cells. AB - OBJECTIVE: To investigate the in vitro effect of the combination of lignan enterolactone (ENL) or lignan enterodiol (END) with melatonin on steroid hormone secretion and cellular aromatase content in human adrenal carcinoma cells. SAMPLE: Human adrenocortical carcinoma cells. PROCEDURES: Melatonin plus ENL or END was added to cell culture medium along with cAMP (100MUM); control cells received cAMP alone. Medium and cell lysates were collected after 24 and 48 hours of cultivation. Samples of medium were analyzed for progesterone, 17 hydroxyprogesterone, androstenedione, aldosterone, estradiol, and cortisol concentration by use of radioimmunoassays. Cell lysates were used for western blot analysis of aromatase content. RESULTS: The addition of ENL or END with melatonin to cAMP-stimulated cells (treated cells) resulted in significant decreases in estradiol, androstenedione, and cortisol concentrations at 24 and 48 hours, compared with concentrations in cells stimulated with cAMP alone (cAMP control cells). The addition of these compounds to cAMP-stimulated cells also resulted in higher progesterone and 17-hydroxyprogesterone concentrations than in cAMP control cells; aldosterone concentration was not affected by treatments. Compared with the content in cAMP control cells, aromatase content in treated cells was significantly lower. CONCLUSIONS AND CLINICAL RELEVANCE: The combination of lignan and melatonin affected steroid hormone secretion by acting directly on adrenal tumor cells. Results supported the concept that this combination may yield similar effects on steroid hormone secretion by the adrenal glands in dogs with typical and atypical hyperadrenocorticism. PMID- 21529221 TI - Expression of cyclooxygenase genes in the jejunum of horses during low-flow ischemia and reperfusion. AB - OBJECTIVE: To determine expression of cyclooxygenase (COX) genes 1 and 2 (also called prostaglandin-endoperoxide synthases 1 and 2) and stability of housekeeping gene expression during low-flow ischemia and reperfusion in the jejunum of horses. ANIMALS: 5 healthy adult horses. PROCEDURES: Horses were anesthetized, and two 30-cm segments of jejunum were surgically exteriorized. Blood flow was maintained at baseline (untreated) values in 1 (control) segment and was decreased to 20% of baseline (low-flow ischemia) for 75 minutes, followed by 75 minutes of reperfusion, in the other (experimental) segment. Biopsy samples were collected from experimental segments at baseline (T0), after 75 minutes of ischemia (T1), and after 75 minutes of reperfusion (T2); samples were collected from control segments at T0 and T2. Horses were euthanized 24 hours after induction of ischemia (T3), and additional samples were collected. Samples were evaluated histologically. Total RNA was extracted; expression of COX genes and stability of 8 housekeeping genes were determined via quantitative real-time PCR assays. RESULTS: COX-1 and COX-2 genes were constitutively expressed in baseline samples. Low-flow ischemia resulted in significant upregulation of COX-2 gene expression at each subsequent time point, compared with baseline values. The most stably expressed reference genes were beta-actin and hypoxanthine phosphoribosyltransferase, whereas glyceraldehyde 3-phosphate dehydrogenase and beta-2 microglobulin were the least stably expressed. CONCLUSIONS AND CLINICAL RELEVANCE: Low-flow ischemia resulted in upregulation of COX-2 gene expression in the jejunum of horses. Housekeeping genes traditionally used as internal standards may not be stable in this tissue during arterial low-flow ischemia and reperfusion. PMID- 21529222 TI - Effects of powdered whole grapefruit and metoclopramide on the pharmacokinetics of cyclosporine in dogs. AB - OBJECTIVE: To determine whether oral administration of metoclopramide or a commercially available powdered whole grapefruit (PWG) nutraceutical in combination with cyclosporine enhances systemic availability of cyclosporine in dogs. SAMPLE: 8 healthy mixed-breed dogs in part 1 and 6 of these 8 dogs in part 2. PROCEDURES: Cyclosporine pharmacokinetics were determined over the course of 24 hours after oral administration of cyclosporine (5 mg/kg) alone, cyclosporine with metoclopramide (0.3 to 0.5 mg/kg), cyclosporine with 2 g of PWG, or cyclosporine combined with both metoclopramide and 2 g of PWG by use of a Latin square crossover study with a 14-day washout period between treatments. Sixty days later, 6 of the 8 dogs were given 10 g of PWG followed by cyclosporine, and pharmacokinetic parameters were compared with those previously obtained after administration of cyclosporine alone. RESULTS: Although metoclopramide or coadministration of metoclopramide and 2 g of PWG had no effect on the pharmacokinetic parameters of cyclosporine, compared with results for cyclosporine alone, the higher (10-g) dose of PWG resulted in 29% faster mean time to maximal plasma cyclosporine concentration, 54% larger area under the curve, and 38% lower apparent oral clearance. CONCLUSIONS AND CLINICAL RELEVANCE: Adjustment of the cyclosporine dose may not be needed when metoclopramide is coadministered orally to prevent common adverse effects of cyclosporine. Powdered whole grapefruit has the potential to reduce the required orally administered dose of cyclosporine but only when PWG is used in an amount (at least 10 g) that is currently not cost-effective. PMID- 21529223 TI - Comparison of results for weight-adjusted and fixed-amount bronchoalveolar lavage techniques in healthy Beagles. AB - OBJECTIVE: To compare recovery of epithelial lining fluid (ELF) in bronchoalveolar lavage fluid (BALF) by use of weight-adjusted or fixed-amount volumes of lavage fluid in dogs. ANIMALS: 13 healthy Beagles. PROCEDURES: Dogs were allocated to 2 groups. In 1 group, the right caudal lung lobe was lavaged on the basis of each dog's weight (2 mL/kg, divided into 2 aliquots) and the left caudal lung lobe was lavaged with a fixed amount of fluid (50 mL/dog, divided into 2 aliquots). In the second group, the right and left caudal lung lobes were lavaged by use of the fixed-amount and weight-adjusted techniques, respectively. The BALF was collected by use of bronchoscopy. A recovery percentage >= 40% was required. The proportion of ELF was calculated by use of the following equation: (concentration of urea in BALF/concentration of urea in serum) * 100. RESULTS: Mean +/- SD proportion of ELF in BALF was 2.28 +/- 0.39% for the weight-adjusted technique and 2.89 +/- 0.89% for the fixed-amount technique. The SDs between these 2 techniques differed significantly (calculated by comparing 2 covariance structures [unstructured and compound symmetry] in a repeated-measures mixed ANOVA). CONCLUSIONS AND CLINICAL RELEVANCE: The findings strongly suggested that use of a weight-adjusted bronchoalveolar lavage technique provided a more uniform ELF recovery, compared with that for a fixed-amount bronchoalveolar lavage technique, when urea was used as a marker of dilution. A constant ELF fraction can facilitate more accurate comparisons of cellular and noncellular constituents in BALF among patients of various sizes. PMID- 21529224 TI - Evaluation of the use of an autologous platelet-rich fibrin membrane to enhance tendon healing in dogs. AB - OBJECTIVE: To examine effects of an autologous platelet-rich fibrin (PRF) membrane for enhancing healing of a defect of the patellar tendon (PT) in dogs. ANIMALS: 8 adult dogs. PROCEDURES: Defects were created in the central third of the PT in both hind limbs of each dog. An autologous PRF membrane was implanted in 1 defect/dog, and the contralateral defect was left empty. Dogs (n = 4/time period) were euthanized at 4 and 8 weeks after surgery, and tendon healing was assessed grossly and histologically via a semiquantitative scoring system. Cross sectional area of the PTs was also compared. RESULTS: Both treated and control defects were filled with repair tissue by 4 weeks. There was no significant difference in the histologic quality of the repair tissue between control and PRF membrane-treated defects at either time point. At both time points, the cross sectional area of PRF membrane-treated tendons was significantly greater (at least 2.5-fold as great), compared with that of sham-treated tendons. At 4 weeks, the repair tissue consisted of disorganized proliferative fibrovascular tissue originating predominantly from the fat pad. By 8 weeks, the tissue was less cellular and slightly more organized in both groups. CONCLUSIONS AND CLINICAL RELEVANCE: A PRF membrane did not enhance the rate or quality of tendon healing in PT defects. However, it did increase the amount of repair tissue within and surrounding the defect. These results suggested that a PRF membrane may not be indicated for augmenting the repair of acutely injured tendons that are otherwise healthy. PMID- 21529225 TI - Comparison of the toxic effects of two duncecap larkspur (Delphinium occidentale) chemotypes in mice and cattle. AB - OBJECTIVE: To compare the toxic effects of a Delphinium occidentale chemotype containing N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type alkaloids and a D occidentale chemotype lacking MSAL-type alkaloids in mice and cattle. ANIMALS: 225 male Swiss Webster mice and 11 Black Angus steers. PROCEDURES: 4 collections of larkspur containing MSAL-type alkaloids and 4 collections of larkspur lacking MSAL-type alkaloids were used. From each collection, total alkaloid extracts (0.05 to 0.20 mL) were administered via tail-vein injection in 27 to 29 mice. Dried, finely ground plant material from 1 collection with and 1 collection without MSAL-type alkaloids (doses equivalent to 37.6 mg of total alkaloids/kg) were each administered to 8 cattle via oral gavage in a crossover experiment; 3 cattle received a single dose equivalent to 150.4 mg of total alkaloids/kg (no MSAL-type alkaloids). In mice, clinical effects were monitored; in cattle, heart rate was monitored before (baseline) and 24 hours after treatment. At the 24-hour time point, cattle were exercised as a measure of muscle weakness. RESULTS: In mice, mean LD(50) associated with alkaloid extracts prepared from plants that did or did not contain MSAL-type alkaloids was 2.3 and 54.2 mg/kg, respectively. In cattle at 24 hours after treatment, plant material containing MSAL-type alkaloids significantly increased heart rate from baseline and was associated with exercise-induced collapse; plant material lacking MSAL type alkaloids had no similar effects. CONCLUSIONS AND CLINICAL RELEVANCE: Taxonomic classification of D occidentale alone was not a good indicator of the toxic risk to grazing cattle. PMID- 21529227 TI - Research in motion. Tropical location provides unique opportunities. PMID- 21529228 TI - A business case for diversity and inclusion: why it is important for veterinarians to embrace our changing communities. PMID- 21529229 TI - What is your diagnosis? Thymoma, thymic lymphoma, or possible hemorrhage in the cranial mediastinal reflection. PMID- 21529230 TI - What is the evidence? Inflammatory bowel disease in a dog. PMID- 21529231 TI - Pathology in practice. Lymphoplasmacytic panniculitis. PMID- 21529232 TI - Pathology in practice. Myocarditis and epicarditis. PMID- 21529233 TI - Comparing percentages. PMID- 21529234 TI - Representations of the veterinary profession in nonfiction children's books. AB - OBJECTIVE: To evaluate how the veterinary profession is represented in nonfiction children's books and determine whether representations reflect the current veterinary profession or the demographics of the United States. DESIGN: Survey. SAMPLE: Covers of 46 nonfiction children's books and contents of 45 nonfiction children's books. PROCEDURES: Book covers and book contents (images and text) were evaluated for representations of veterinarians and to identify settings, clients, technology and equipment, and animals portrayed. Book contents were additionally evaluated to identify specialties and career opportunities specifically mentioned in the text. RESULTS: Book covers predominantly portrayed veterinarians as Caucasian women who wore examination coats, worked alone in veterinary clinics, and cared for dogs without a client present. Book contents predominantly portrayed veterinarians as a Caucasian man or woman who wore an examination coat, worked as part of a team in a veterinary clinic, and helped clients care for dogs, cats, and exotic animals. Specialties and career opportunities in the veterinary profession were mentioned in the text of 29 of 45 (64.4%) books. CONCLUSIONS AND CLINICAL RELEVANCE: Nonfiction children's book covers that focused on the veterinary profession portrayed a greater percentage of women than is currently found in the profession. Similarly, books portrayed a greater percentage of Caucasians than in the current or predicted US population. With the exception of Asians, books collectively represented lower or similar percentages of underrepresented minorities, compared with the US population. Veterinarians are encouraged to select books for individual children that portray veterinarians with whom the children can identify. PMID- 21529235 TI - Demographic differences between urban feeding groups of neutered and sexually intact free-roaming cats following a trap-neuter-return procedure. AB - OBJECTIVE: To examine demographic differences during a 1-year observational period between urban feeding groups of neutered and unneutered free-roaming cats following a trap-neuter-return procedure. DESIGN: Natural-setting trial. Animals Free-roaming adult cats (n = 184) and kittens (76) living in 4 feeding groups in an urban region of Israel. PROCEDURES: Cats in 2 feeding groups were subjected to a trap-neuter-return (TNR) procedure. Cats in 2 other feeding groups were untreated. Data were collected on a weekly basis before and during feeding time over a 1-year period. Following individual cat identification, presence of adults and kittens was recorded throughout the year. Rates of immigration, emigration, and kitten survival were compared between neutered and unneutered groups. RESULTS: The number of adult cats in the 2 neutered groups increased significantly during the study period because of higher immigration and lower emigration rates than in the unneutered groups, in which the number decreased. In the neutered groups, annual presence of neutered cats was significantly higher than that of sexually intact cats. Kitten survival in the neutered groups was significantly higher than in the unneutered groups. CONCLUSIONS AND CLINICAL RELEVANCE: Targeting the TNR method mainly at feeding groups in urban residential neighbourhoods may result in increased group size, as a consequence of 2 major changes in group dynamics: sexually intact cats immigrate into the neutered groups more readily and neutered cats reduce their emigration rates, possibly because of a reduction in reproductive and competitive pressures. To maintain a high proportion of neutered cats in such cat groups, persistent TNR campaigns are therefore necessary. PMID- 21529236 TI - Behavioral differences between urban feeding groups of neutered and sexually intact free-roaming cats following a trap-neuter-return procedure. AB - OBJECTIVE: To examine behavioral differences during a 1-year observational period between urban feeding groups of neutered and sexually intact free-roaming cats following a trap-neuter-return procedure. DESIGN: Natural-setting trial. Animals Free-roaming cats (n = 184) living in 4 feeding groups in an urban region of Israel. PROCEDURES: Trap-neuter-return procedures were applied to 2 cat feeding groups (A and B). Their social and feeding behaviors and frequency of appearance at feeding time were compared with those of 2 unneutered cat groups (C and D). Behavioral data were obtained from weekly observations before and during feeding over a 1-year period. Results-A lower rate of agonistic interactions was observed in the neutered groups than in the unneutered groups. Sexually intact male cats participated in more agonistic male-male encounters than did neutered male cats. Of 199 such encounters in the feeding groups, only 1 occurred between 2 neutered males. Neutered cats in group A appeared earlier and had higher frequencies of feeding and appearance at the feeding site, compared with unneutered cats. CONCLUSIONS AND CLINICAL RELEVANCE: Less aggression was observed in the neutered groups, specifically, fewer agonistic neutered-neutered male encounters occurred. This reduced agonistic behavior of neutered males resulted in reduced fighting and vocalizations, potentially leading to fewer injuries and reduced transmission of fight-related infectious diseases and reduced noise disturbance from a human perspective. Regarding food delivery, the feeding groups were time-and-place dependent, exhibiting context-related social interactions. When competing for food resources, as neutered cats time their arrival in accordance with food delivery, they thereby gain access to the choicest items. PMID- 21529237 TI - Risk factors associated with failure of heartworm prophylaxis among members of a national hunting dog club. AB - OBJECTIVE: To identify practices associated with failure of heartworm prophylaxis among dog and kennel owners and dog trainers. DESIGN: Online survey and mail-in questionnaire. Sample-708 members of a national hunting dog club. PROCEDURES: Heartworm prevention practices used by respondents that reported failure of prophylaxis were compared with practices used by respondents that reported success. RESULTS: Univariate analyses indicated failure of heartworm prophylaxis was inversely related to the number of dogs under a respondent's care. Year-round prophylactic practice was not significantly associated with reduced odds of failure, and efforts to control exposure to mosquitoes were similar among the comparison groups. Respondents reporting prophylaxis failure were more likely to test for heartworm infection >= 1 time/y, compared with those reporting success. In a multivariable analysis, residence south of the Virginia-North Carolina state line (ie, the 37th geographic parallel), testing for heartworm infection < once a year when the test was administered prior to April 1, and keeping dogs outdoors for longer periods at dusk, at dawn, or after dark were associated with increased odds of prophylaxis failure. CONCLUSIONS AND CLINICAL RELEVANCE: Veterinarians should stress the importance of annual heartworm testing 6 to 7 months after the last possible date of exposure to heartworm, regardless of whether a dog receives prophylactic treatment year-round. Reducing the number of hours dogs spend outdoors at dusk, at dawn, or after dark may reduce the odds of heartworm disease even when dogs are given preventive treatment. PMID- 21529238 TI - Evaluation of dexmedetomidine and ketamine in combination with opioids as injectable anesthesia for castration in dogs. AB - OBJECTIVE: To compare efficacy and cardiorespiratory effects of dexmedetomidine and ketamine in combination with butorphanol, hydromorphone, or buprenorphine (with or without reversal by atipamezole) in dogs undergoing castration. DESIGN: Prospective, randomized, split-plot, blinded study. ANIMALS: 30 healthy client owned sexually intact male dogs. PROCEDURES: Dogs (n = 10 dogs/group) were assigned to receive dexmedetomidine (15 MUg/kg [6.82 MUg/lb]) and ketamine (3 mg/kg [1.36 mg/lb]) with butorphanol (0.2 mg/kg [0.09 mg/lb]; DKBut), the same dosages of dexmedetomidine and ketamine with hydromorphone (0.05 mg/kg [0.023 mg/lb]; DKH), or the same dosages of dexmedetomidine and ketamine with buprenorphine (40 MUg/kg [18.18 MUg/lb]; DKBup). All drugs were administered as a single IM injection for induction and maintenance of anesthesia for castration. At conclusion of the surgery, 5 dogs in each treatment group received atipamezole (150 MUg/kg [68.18 MUg/lb], IM), and the remainder received saline (0.9% NaCl) solution IM. Cardiorespiratory variables and quality of anesthesia were assessed. Supplemental isoflurane was administered to the dogs when anesthesia was considered inadequate during surgery. RESULTS: All drug combinations rapidly induced anesthesia. Dogs were intubated within 10 minutes after injection. Supplemental isoflurane was needed during surgery in 1, 3, and 4 dogs in the DKBup, DKBut, and DKH groups, respectively. Dogs that received atipamezole had a significantly shorter recovery time. Some dogs in each group had bradycardia and hypoxemia with hypertension. CONCLUSIONS AND CLINICAL RELEVANCE: DKBup was the most suitable injectable anesthetic combination used. Recovery was shortened by IM administration of atipamezole. There were minimal adverse effects in all groups. PMID- 21529239 TI - Surgical treatment of medial patellar luxation without femoral trochlear groove deepening procedures in dogs: 91 cases (1998-2009). AB - OBJECTIVE: To assess signalment, outcomes, and complications for dogs surgically treated for medial patellar luxation (MPL) with a combination of lateral retinacular imbrication and tibial crest transposition procedures without femoral trochlear groove deepening techniques, and to determine whether osteoarthritis progressed in these patients during the 8-week period following surgery. DESIGN: Retrospective case series. Animals-91 dogs. PROCEDURES: Medical records were reviewed for information on signalment, clinical history, unilateral versus bilateral disease, preoperative and postoperative MPL grades, duration of follow up, and perioperative and postoperative complications. Radiographs obtained preoperatively and during 8-week follow-up examinations were reviewed and assigned degenerative joint disease (DJD) scores (range, 0 to 3). Data were analyzed to determine factors influencing outcomes. Kaplan-Meier curves were constructed for recurrence of MPL. RESULTS: Minor postoperative complications were reported for 31 of 91 (34.1%) dogs. Patellar reluxation occurred in 18 of 91 (19.8%) dogs. Reluxation or complications for which additional surgery was recommended developed in 6 of 91 (6.6%) dogs. At last clinical follow-up, 10 of 91 (11.0%) dogs had at least occasional lameness. No difference was revealed between preoperative and postoperative (8-week follow-up) radiographic DJD scores. CONCLUSIONS AND CLINICAL RELEVANCE: Results of surgical treatment of MPL without femoral trochlear groove deepening procedures were comparable to those in studies of surgical treatment that included groove deepening procedures. Radiographic indices of DJD did not increase during the 8 weeks following surgery. These results suggest that trochlear groove deepening procedures are not always necessary, and patients that undergo these techniques should be carefully selected. PMID- 21529240 TI - Successful replacement of an obstructed ureter with an ileal graft in a cat. AB - CASE DESCRIPTION: A 10-year-old spayed female domestic shorthair cat with a 1 week history of vomiting, lethargy, and anorexia was examined. CLINICAL FINDINGS: Abdominal radiography and ultrasonography revealed that calculi and a nonpatent stricture obstructed the right ureter, which resulted in secondary dilatation of the ureter proximal to the obstruction and severe hydronephrosis. The left kidney was small and suspected to be failing. Concentrations of BUN and creatinine were elevated. Despite administration of fluids, azotemia persisted. TREATMENT AND OUTCOME: Surgery was performed. The obstructed right ureter was replaced with a vascularized segment of ileum. Azotemia resolved, and the cat improved with regard to clinical signs. The cat was clinically normal for > 36 months after the surgery. CLINICAL RELEVANCE: An ileal graft can successfully be used as a surgical option for ureteral obstruction in cats. PMID- 21529241 TI - Successful outcome of hepatectomy as treatment for liver lobe torsion in four domestic rabbits. AB - CASE DESCRIPTION: 4 rabbits (1.5 to 6 years old) were evaluated at the Angell Animal Medical Center from June 2007 to March 2009 because of nonspecific clinical signs including anorexia, lethargy, and decreased fecal output. CLINICAL FINDINGS: Physical examination revealed signs of pain in the cranial portion of the abdomen, gas distention of the gastrointestinal tract, and diminished borborygmi. Serum biochemical analyses and CBCs revealed moderately to markedly high alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activities and mild to moderate anemia with polychromasia. Abdominal radiographic findings were nonspecific. Three of the 4 rabbits underwent abdominal ultrasonography; abnormalities in shape, size, echogenicity, and blood flow of the liver, indicative of liver lobe torsion, were detected. TREATMENT AND OUTCOME: All 4 rabbits underwent surgery, during which liver lobe torsion was confirmed and the affected liver lobe was resected. Histologic examination of sections of the excised lobe obtained from 3 of the 4 rabbits revealed severe, diffuse, acute to sub-acute hepatic ischemic necrosis. All rabbits recovered from surgery; owners reported that the rabbits were doing well 22 to 43 months after surgery. CLINICAL RELEVANCE: Liver lobe torsions in any species are rarely reported, yet 4 cases of liver lobe torsion in domestic rabbits were treated at 1 referral center in a 2-year period. In rabbits, clinical signs of this condition are nonspecific and results of additional tests, including abdominal ultrasonography and serum biochemical analysis, are necessary for diagnosis. Prompt diagnosis and hepatectomy of the affected lobe are recommended and appear to be associated with an excellent prognosis. PMID- 21529242 TI - Efficacy of oral administration of a modified-live Salmonella Dublin vaccine in calves. AB - OBJECTIVE: To determine the efficacy a modified-live Salmonella Dublin vaccine administered PO in an extralabel manner in the prevention of diseases associated with Salmonella Dublin infection. DESIGN: Randomized clinical trial. ANIMALS: 288 preweaned Holstein dairy calves on a commercial dairy farm. PROCEDURES: Calves were orally administered either 2 mL of a commercially available, modified-live Salmonella Dublin vaccine (n = 140) or a placebo (148) at 3 and 10 days of age. Signs of diarrhea and depression were recorded daily. Weight gain between 3 days of age and time of weaning was measured. Fecal samples from clinically depressed or diarrheic calves and fresh tissues samples from calves that died were submitted for bacterial culture of Salmonella organisms. RESULTS: Salmonella organisms were isolated from samples of 1.4% (2/140) and 3.4% (5/148) of calves receiving the vaccine and placebo, respectively. Additionally, 57.1% (80/140) and 60.1 % (89/148) of the vaccinated and control calves, respectively, had at least 1 day with an abnormal fecal score. Calves receiving the vaccine and placebo were not significantly different in terms of overall morbidity rate, Salmonella specific morbidity rate, or average daily gain. Adverse reactions related to administration of the vaccine were not seen. The attenuated vaccine strain was not isolated from any fecal or tissue samples. CONCLUSIONS AND CLINICAL RELEVANCE: This method of vaccination was safe in young Holstein calves, although it was not effective in reducing the incidence of disease or improving weight gain on this farm. However, the power of this study was limited by a low incidence of clinical salmonellosis. PMID- 21529243 TI - The cystine/cysteine cycle and GSH are independent and crucial antioxidant systems in malignant melanoma cells and represent druggable targets. AB - AIMS: Cancer chemoresistance is often due to upregulation of antioxidant systems. Therapeutic targeting of these systems is however hampered by their redundancy. Here, we have performed a functional dissection of the antioxidant systems in different melanoma cases aimed at the identification of the most effective redox active drug. RESULTS: We have identified two crucial antioxidant mechanisms: glutathione (GSH), the major intracellular redox buffer, and the cystine/cysteine cycle, which switches the extracellular redox state from an oxidized to a reduced state. The two mechanisms are independent in melanoma cells and may be substitutes for each other, but targeting both of them is lethal. Exposure to the pro-oxidant compound As(2)O(3) induces an antioxidant response. However, while in these cells the intracellular redox balance remains almost unaffected, a reduced environment is generated extracellularly. GSH depletion by buthioninesulfoximine (BSO), or cystine/cysteine cycle inhibition by (S)-4-carboxyphenylglycine (sCPG), enhanced the sensitivity to As(2)O(3). Remarkably, sCPG also prevented the remodeling of the microenvironment redox state. INNOVATION: We propose that the definition of the prevalent antioxidant system(s) in tumors is crucial for the design of tailored therapies involving redox-directed drugs in association with pro-oxidant drugs. CONCLUSION: In melanoma cells, BSO is the best enhancer of As(2)O(3) sensitivity. However, since the strong remodeling of the microenvironmental redox state caused by As(2)O(3) may promote tumor progression, the concomitant use of cystine/cysteine cycle blockers is recommended. PMID- 21529245 TI - Small-area variations in sales of TNF inhibitors in Sweden between 2000 and 2009: comments on the article by M Neovius et al. PMID- 21529244 TI - Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease. AB - AIMS: Mitochondrial damage due to Ca(2+) overload-induced opening of permeability transition pores (PTP) is believed to play a role in selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Genetic ablation of mitochondrial matrix protein cyclophilin D (CYPD) has been shown to increase Ca(2+) threshold of PTP in vitro and to prevent cell death in several in vivo disease models. We investigated the role of CYPD in a mouse model of MPTP (1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. RESULTS: We demonstrate that in vitro, brain mitochondria isolated from CYPD knockout mice were less sensitive to MPP+ (1-methyl-4-phenyl-pyridinium ion)-induced membrane depolarization, and free radical generation compared to wild-type mice. CYPD knockout mitochondria isolated from ventral midbrain of mice treated with MPTP in vivo exhibited less damage as judged from respiratory chain Complex I activity, State 3 respiration rate, and respiratory control index than wild-type mice, whereas assessment of apoptotic markers showed no differences between the two genotypes. However, CYPD knockout mice were significantly resistant only to an acute regimen of MPTP neurotoxicity in contrast to the subacute and chronic MPTP paradigms. INNOVATION: Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity. CONCLUSION: Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity. PMID- 21529247 TI - Bone marrow concentrate and bovine bone mineral for sinus floor augmentation: a controlled, randomized, single-blinded clinical and histological trial--per protocol analysis. AB - PURPOSE: The purpose of this work was to evaluate the potential of substituting autogenous bone (AB) by bone marrow aspirate concentrate (BMAC). Both AB and BMAC were tested in combination with a bovine bone mineral (BBM) for their ability of new bone formation (NBF) in a multicentric, randomized, controlled, clinical and histological noninferiority trial. MATERIALS AND METHODS: Forty-five severely atrophied maxillary sinus from 26 patients were evaluated in a partial cross-over design. As test arm, 34 sinus of 25 patients were augmented with BBM and BMAC containing mesenchymal stem cells. Eleven control sinus from 11 patients were augmented with a mixture of 70% BBM and 30% AB. Biopsies were obtained after a 3 4-month healing period at time of implant placement and histomorphometrically analyzed for NBF. RESULTS: NBF was 14.3%+/-1.8% for the control and nonsignificantly lower (12.6%+/-1.7%) for the test (90% confidence interval: -4.6 to 1.2). Values for BBM (31.3%+/-2.7%) were significantly higher for the test compared with control (19.3%+/-2.5%) (p<0.0001). Nonmineralized tissue was lower by 3.3% in the test compared with control (57.6%; p=0.137). CONCLUSIONS: NBF after 3-4 months is equivalent in sinus, augmented with BMAC and BBM or a mixture of AB and BBM. This technique could be an alternative for using autografts to stimulate bone formation. PMID- 21529248 TI - Paracrine effects influenced by cell culture medium and consequences on microvessel-like structures in cocultures of mesenchymal stem cells and outgrowth endothelial cells. AB - Mesenchymal stem cells (MSC) from bone marrow and outgrowth endothelial cells (OEC) from peripheral blood are considered as attractive cell types for applications in regenerative medicine aiming to build up complex vascularized tissue-engineered constructs. MSC provide several advantages such as the potential to differentiate to osteoblasts and to support the neovascularization process by release of proangiogenic factors. On the other hand, the neovascularization process can be actively supported by OEC forming perfused vascular structures after co-implantation with other cell types. In this study the formation of angiogenic structures in vitro was investigated in cocultures of MSC and OEC, cultured either in the medium for osteogenic differentiation of MSC (ODM) or in the medium for OEC cultivation endothelial cell growth medium-2 (EGM2 Bullet Kit). After 2 weeks, cocultures in EGM2 formed more microvessel-like structures compared to cocultures in ODM as demonstrated by immunofluorescence staining for the endothelial marker CD31. Increased expression of CD31 and CD146 in quantitative real-time polymerase chain reaction as well as a higher percentage of CD31- and CD146-positive cells in flow cytometry indicated a beneficial influence of EGM2 on endothelial cell growth and function. In addition, the improved formation of vascular structures in EGM2 correlates with higher levels of the proangiogenic factor vascular endothelial growth factor and platelet-derived growth factor in the supernatant of cocultures as well as in monocultures of MSC when cultivated in EGM-2. Nevertheless, ODM was more suitable for the differentiation of MSC to osteoblastic lineages in the cocultures, whereas EGM2 favored factors involved in vessel stabilization by pericytes. In conclusion, this study highlights the importance of medium components for cell interaction triggering the formation of angiogenic structures. PMID- 21529249 TI - Incidence of celiac disease among second-generation immigrants and adoptees from abroad in Sweden: evidence for ethnic differences in susceptibility. AB - BACKGROUND AND AIMS: The incidence of celiac disease (CD) shows large, worldwide variation. However, whether its causes are environmental (gluten-containing diet) or genetic (specific haplotype) have not been established. The aim of the present study is to examine the incidence of CD among second-generation immigrants and adoptees from abroad to disentangle genetic/ethnic versus environmental influences (assuming that immigrants have similar gluten exposures to native Swedes, and thus differ from them only in terms of their genetic background). METHODS: Second-generation immigrants and adoptees from abroad were identified in the MigMed 2 Database and were followed until diagnosis of CD, death, or the end of study. Standardized incidence ratios (SIRs) were calculated among these immigrants with native Swedes as the reference group. RESULTS: A total of 1,050,569 children were defined as second-generation immigrants and the overall SIR of CD (SIR = 0.89, 95% confidence interval 0.84-0.94) was significantly lower than that of native Swedes. The incidence of CD among children with parents from Western, Eastern, and Northern European countries was similar to that in native Swedes, but was lower for those with parents from low-prevalence countries, especially Eastern and Southeast Asian countries. A total of 51,557 children born in foreign countries were adopted by Swedes. Adoptees from Eastern Asia had a significantly decreased SIR of CD. CONCLUSIONS: The decreased incidence of CD in second-generation immigrants and some groups of adoptees from abroad strongly suggests that ethnic genetic heterogeneity may contribute to the worldwide variation in CD incidence. PMID- 21529250 TI - The rearing and biology of the desert beetle, Microdera punctipennis, under laboratory conditions. AB - Microdera punctipennis Kasz (Coleoptera: Tenebrionidae) is a unique species that lives in the desert region of Central Asia and has adopted a nocturnal habit to survive the desert environment. Female adults are larger in size than male adults. The female/male ratio was 1.04:1. A rearing method using reused plastic bottles was used. The rearing conditions were 30 +/- 0.5 degrees C, 30 +/- 6% relative humidity (RH), and 16:8 L:D photoperiod. Cabbage was provided as food. Cannibalism was avoided by rearing one larva in a bottle. A complete life cycle was obtained under these conditions. The viability of eggs, larvae, prepupae, pupae, and teneral adults was 93.54%, 83.71%, 84.76%, 87.64%, and 93.59%, respectively. Embryogenesis took 7.35 days on average. The larval duration in each instar was 2.25 days. The mean duration of the larvae, prepupae, pupae, and teneral adult was 49.27, 7.05, 9.95, and 10.12 days, respectively. The coloration of each developmental stage gradually changed from creamy white to light brownish or black. Females commenced oviposition when their body color became black. On average, each female produced 568 eggs. PMID- 21529251 TI - Local abundance patterns of noctuid moths in olive orchards: life-history traits, distribution type and habitat interactions. AB - Local species abundance is related to range size, habitat characteristics, distribution type, body size, and life-history variables. In general, habitat generalists and polyphagous species are more abundant in broad geographical areas. Underlying this, local abundance may be explained from the interactions between life-history traits, chorological pattern, and the local habitat characteristics. The relationship within taxa between life-history traits, distribution area, habitat characteristics, and local abundance of the noctuid moth (Lepidoptera: Noctuidae) assemblage in an olive orchard, one of the most important agro-ecosystems in the Mediterranean basin, was analyzed. A total of 66 species were detected over three years of year-round weekly samplings using the light-trap method. The life-history traits examined and the distribution type were found to be related to the habitat-species association, but none of the biological strategies defined from the association to the different habitats were linked with abundance. In contrast to general patterns, dispersal ability and number of generations per year explained differences in abundance. The relationships were positive, with opportunistic taxa that have high mobility and several generations being locally more abundant. In addition, when the effect of migrant species was removed, the distribution type explained abundance differences, with Mediterranean taxa (whose baricenter is closer to the studied area) being more abundant. PMID- 21529252 TI - The semiaquatic nematoceran fly assemblages of three wetland habitats and concordance with plant species composition, a case study from subalpine Fennoscandia. AB - Semiaquatic flies (Diptera, Nematocera) are an ecologically important and species rich group of insects within the boreal and arctic biomes. Community structure, species richness and abundance of semiaquatic flies were studied in three habitat types (aapa mires, springs and headwater streams), totaling 19 study sites, within the subalpine ecoregion of northern boreal Finland. Concordance of semiaquatic fly species composition with plant assemblages (higher plants and mosses), and geographical and environmental distance matrices were also studied. The collected insect material consisted of 94 species and 9038 specimens. According to non-metric multidimensional scaling ordination (visual inspection), multi-response permutation procedure and analysis of similarity tests, fly assemblages of aapa mires were clearly different from those of springs and headwater streams, but no differences were found between spring and headwater stream assemblages. The cumulative number of species was highest in headwater streams. Alpha diversity varied within the habitat types but was generally highest among headwater streams. Semiaquatic fly communities of headwater streams were the most abundant (number of specimens) and their rank-abundance distributions were relatively skewed; assemblages of aapa mires were less abundant and rather even. Community composition of combined plant material (219 taxa), higher plants (116 taxa) and mosses (103 taxa) were all in concordance with the flies; the strongest matrix correlation was found between higher plants and flies (Mantel test). The influence of geographical distance of the study sites to species composition was statistically significant but rather weak; instead, much stronger concordance was noted with environmental variables (Mantel test). Plants, especially higher plants, may be potential surrogates for semiaquatic fly assemblage composition. However, more studies of community concordance in a larger geographic area and within one habitat type are needed. PMID- 21529253 TI - The trail pheromone of the venomous samsum ant, Pachycondyla sennaarensis. AB - Ant species use branching networks of pheromone trails for orientation between nest and resources. The current study demonstrated that workers of the venomous samsum ant, Pachycondyla sennaarensis (Mayr) (Hymenoptera: Formicidae: Ponerinae), employ recruitment trail pheromones discharged from the Dufour's gland. Secretions of other abdomen complex glands, as well as hindgut gland secretions, did not evoke trail following. The optimum concentration of trail pheromone was found to be 0.1 gland equivalent/40 cm trail. This concentration demonstrated effective longevity for about one hour. This study also showed that P. sennaarensis and Tapinoma simrothi each respond to the trail pheromones of the other species as well as their own. PMID- 21529254 TI - A review of the genus Miresa Walker in China (Lepidoptera: Limacodidae). AB - Eight species of the genus Miresa Walker are recognized in China including two new species, M. fangae Wu & Solovyev and M. polargenta Wu & Solovyev, described herein. M. burmensis Hering species is reported for the first time in China. The M. argentifera kwangtungensis Hering, 1931 taxon is raised to full specific status. The lectotypes are designated for the following 5 taxa: M. bracteata Butler, 1880 (?, Natural History Museum, London); M. fulgida Wileman, 1910 (?, Natural History Museum, London); M. bracteata var. orientis Strand, 1915 (?, Rijksmuseum van Natuurlijke Historie, Leiden); M. argentifera kwangtungensis Hering, 1931 (?, Zoologisches Museum der Humboldt Universitat zu Berlin) and M. urga Hering, 1933 (?, Zoologisches Museum der Humboldt Universitat zu Berlin). The photographs of moths and their genitalia are given, a key to the Chinese species of the genus is provided, and the distributional maps are also given. PMID- 21529255 TI - The putative AKH receptor of the tobacco hornworm, Manduca sexta, and its expression. AB - Adipokinetic hormones are peptide hormones that mobilize lipids and/or carbohydrates for flight in adult insects and activate glycogen Phosphorylase in larvae during starvation and during molt. We previously examined the functional roles of adipokinetic hormone in Manduca sexta L. (Lepidoptera: Sphingidae). Here we report the cloning of the full-length cDNA encoding the putative adipokinetic hormone receptor from the fat body of M. sexta. The sequence analysis shows that the deduced amino acid sequence shares common motifs of G protein-coupled receptors, by having seven hydrophobic transmembrane segments. We examined the mRNA expression pattern of the adipokinetic hormone receptor by quantitative Real Time PCR in fat body during development and in different tissues and found the strongest expression in fat body of larvae two days after molt to the fifth instar. We discuss these results in relation to some of our earlier results. We also compare the M. sexta adipokinetic hormone receptor with the known adipokinetic hormone receptors of other insects and with gonadotropin releasing hormone-like receptors of invertebrates. PMID- 21529256 TI - Cloning and expression analysis of the Bombyx mori alpha-amylase gene (Amy) from the indigenous Thai silkworm strain, Nanglai. AB - alpha-Amylase is a common enzyme for hydrolyzing starch. In the silkworm, Bombyx mori L. (Lepidoptera: Bombycidae), alpha-amylase is found in both digestive fluid and hemolymph. Here, the complete genomic sequence of the Amy gene encoding alpha amylase from a local Thai silkworm, the Nanglai strain, was obtained. This gene was 7981 bp long with 9 exons. The full length Amy cDNA sequence was 1749 bp containing a 1503 bp open reading frame. The ORF encoded 500 amino acid residues. The deduced protein showed 81-54% identity to other insect alpha-amylases and more than 50% identity to mammalian enzymes. Southern blot analysis revealed that in the Nanglai strain Amy is a single-copy gene. RT- PCR showed that Amy was transcribed only in the foregut. Transgenic B. mori also showed that the Amy promoter activates expression of the transgene only in the foregut. PMID- 21529257 TI - Identification, characterization, and expression of a novel P450 gene encoding CYP6AE25 from the Asian corn borer, Ostrinia furnacalis. AB - An allele of the cytochrome P450 gene, CYP6AE14, named CYP6AE25 (GenBank accession no. EU807990) was isolated from the Asian com borer, Ostrinia fumacalis (Guenee) (Lepidoptera: Pyralidae) by RT-PCR. The cDNA sequence of CYP6AE25 is 2315 bp in length and contains a 1569 nucleotides open reading frame encoding a putative protein with 523 amino acid residues and a predicted molecular weight of 59.95 kDa and a theoretical pI of 8.31. The putative protein contains the classic heme-binding sequence motif F**G***C*G (residues 451-460) conserved among all P450 enzymes as well as other characteristic motifs of all cytochrome P450s. It shares 52% identity with the previously published sequence of CYP6AE14 (GenBank accession no. DQ986461) from Helicoverpa armigera. Phylogenetic analysis of amino acid sequences from members of various P450 families indicated that CYP6AE25 has a closer phylogenetic relationship with CYP6AE14 and CYP6B1 that are related to metabolism of plant allelochemicals, CYP6D1 which is related to pyrethroid resistance and has a more distant relationship to CYP302A1 and CYP307A1 which are related to synthesis of the insect molting hormones. The expression level of the gene in the adults and immature stages of O. furnacalis by quantitative real-time PCR revealed that CYP6AE25 was expressed in all life stages investigated. The mRNA expression level in 3(rd) instar larvae was 12.8- and 2.97-fold higher than those in pupae and adults, respectively. The tissue specific expression level of CYP6AE25 was in the order of midgut, malpighian tube and fatty body from high to low but was absent in ovary and brain. The analysis of the CYP6AB25 gene using bioinformatic software is discussed. PMID- 21529258 TI - Structure and spatial distribution of the Chironomidae community in mesohabitats in a first order stream at the Poco D'Anta Municipal Biological Reserve in Brazil. AB - The Chironomidae occupy different habitats along the lotic system with their distribution determined by different factors such as the substrate characteristics and water speed. The input of vegetable material from the riparian forest allows a higher habitat diversity and food to the benthic fauna. The main aim of this paper is to verify the structure and spatial distribution of the Chironomidae fauna in different mesohabitats in a first order stream located at a Biological Reserve in the southeast of Brazil. In the months of July, August, and September 2007, and in January, February, and March 2008, samples were collected with a hand net (250 um) in the following mesohabitats: litter from riffles, litter from pools, and sediment from pools. The community structure of each mesohabitat was analyzed through the abundance of organisms, taxa richness, Pielou's evenness, Shannon's diversity, and taxa dominance. Similarity among the mesohabitats was obtained by Cluster analysis, and Chironomidae larvae distribution through the Correspondence analysis. Indicator species analysis was used to identify possible taxa preference for a determined mesohabitat. The analyzed mesohabitats showed high species richness and diversity favored by the large environmental heterogeneity. Some taxa were indicators of the type of mesohabitat. The substrate was the main factor that determined taxa distribution in relation to water flow differences (riffle and pool). Stream characteristics such as low water speed and the presence of natural mechanisms of retention may have provided a higher faunistic similarity between the areas with different flows. The results showed that the physical characteristics of each environment presented a close relationship with the structure and spatial distribution of the Chironomidae fauna in lotic systems. PMID- 21529259 TI - Potential use of the bushmint, Hyptis suaveolens, for the control of infestation by the pink stalk borer, Sesamia calamistis on maize in southern Benin, West Africa. AB - Maize production in Benin, especially in resource-poor farmers' fields, is constrained by stemborers among other factors. One of the major stemborers in southern Benin is Sesamia calamistis Hampson (Lepidoptera: Noctuidae). African farmers cannot afford to use commercial insecticides for controlling stemborers - they are expensive and unsuitable for durable pest management systems due to eco toxicity. There is therefore a need for cheaper and environmentally friendly methods and botanicals offer an attractive alternative. The bushmint, Hyptis suaveolens (L.) Poit. (Lamiales: Lamiaceae), was compared with the commercial insecticide Furadan (carbofuran) for the control of S. calamistis on maize Zea mays L. (Poales: Poaceae). Trials were conducted in the screenhouse and in the field during the minor cropping season in 2004 at the International Institute of Tropical Agriculture (IITA)-Benin station. The variables measured included numbers of egg masses per plant, eggs per egg mass (in the screenhouse study), population density of S. calamistis, percentage of infested plants and/or ears, and deadhearts in the field. Irrespective of the variable considered, the aqueous extract of H. suaveolens compared favorably with Furadan while maize surrounded by live H. suaveolens plants had lower S. calamistis densities. PMID- 21529260 TI - Non-esophageal symptoms cannot differentiate between erosive reflux esophagitis and non-erosive reflux disease in a referred population. AB - BACKGROUND: Non-esophageal symptoms are highly prevalent in non-erosive reflux disease (NERD). However, their prevalence in erosive esophagitis (ErE) is unclear. The aims of this study were to compare patients with pH-positive NERD and ErE in terms of non-esophageal symptoms and to investigate whether such symptoms can differentiate between these two conditions. MATERIAL AND METHODS: A prospective observational study of ErE and pH-positive NERD patients matched for age and gender with a nested case-control analysis. Symptoms were scored on validated scales. The association between the scale scores and diagnosis was evaluated in a random group comprising 67% of the total (group A) and was validated on the rest (group B). RESULTS: 124 ErE and 248 pH-positive NERD patients were studied. In group A, pH-positive NERD patients scored higher than ErE patients on all symptom scales. Scores on chest, constipation, sleep and urinary symptoms scales were significantly associated with diagnosis. A composite weighted score on these scales was 41.5% sensitive and 86.0% specificity in the differentiation of ErE from pH-positive NERD patients. When applied to group B, the sensitivity and specificity of this score were 48.8% and 70.3%, respectively. CONCLUSIONS: Digestive and non-digestive symptoms occurred with a significant higher prevalence in pH-positive NERD compared with ErE patients. However a composite score on scales of constipation, chest, sleep and urinary symptoms was not enough sensitive and specific to differentiate these two conditions. PMID- 21529261 TI - Three-dimensional fibroblast cultures stimulate improved ventricular performance in chronically ischemic canine hearts. AB - The current study's purpose was to evaluate the safety and biological effect of a scaffold-based three-dimensional human dermal fibroblast culture (3DFC, also known as AngineraTM) to treat chronically ischemic canine hearts. It was hypothesized that treatment with 3DFC would be safe and significantly improve ventricular performance and wall motion. In this study, chronic myocardial ischemia was induced in 40 animals through the surgical placement of an ameroid constrictor. Approximately 30 days after ameroid placement, animals were randomized into four test groups: (1) sham treatment, (2) one unit of acellular 3DFC, (3) one unit of viable 3DFC, and (4) three units of viable 3DFC. Animals were necropsied 30 or 90 days after treatment. Evaluation of the safety endpoint demonstrated the safety of 3DFC at all dosing levels and at both time points. Additionally, parameters of cardiac output, left ventricular ejection fraction, left ventricular end systolic volume index, and systolic wall thickening support the conclusions that 3DFC stimulates a positive biologic effect on ischemic canine hearts. Further, these data support the conclusion that treatment with viable 3DFC improves ventricular performance and ventricular wall motion in chronically ischemic canine hearts 30 days after treatment. PMID- 21529262 TI - Mesenchymal progenitor cells from canine fetal tissues: yolk sac, liver, and bone marrow. AB - During fetal development, mesenchymal progenitor (MP) cells are co-localized in major hematopoietic territories, such as yolk sac (YS), bone marrow (BM), liver (LV), and others. Studies using mouse and human MP cells isolated from fetus have shown that these cells are very similar but not identical to adult mesenchymal stem cells (MSC). Their differentiation potential is usually restricted to production of highly committed osteogenic and chondrogenic precursors. Such properties of fetal MP cells can be very useful for tissue regeneration, when a great number of committed precursors are required. The objectives of this study were to isolate and characterize MP cells from canine YS, BM, and LV in early and late stages of fetal development. Gestational stage was identified, and cell culture conditions were evaluated for efficient isolation of canine MP cells. All canine fetal MP cells expressed vimentin, nestin, and CD44 proteins. Cytokeratin 18 expression was observed in BM- and LV-MP cells, and vascular endothelial (VE) cadherin expression was observed only in YS-MP cells. A small number of MP cells (5%) from LV and YS expressed Oct3/4 protein. The differentiation potential of canine fetal MP cells varied significantly: YS- and BM-MP cells differentiated into bone and cartilage, whereas LV-MP cells differentiation was limited to osteogenic fate. None of the canine fetal MP cells were able to differentiate into adipose cells. Our data suggest that canine fetal MP cells are an appropriate in vitro model to study MP biology from hematopoietic territories and they are a source of committed osteogenic and chondrogenic precursors for regenerative medicine. PMID- 21529263 TI - Apatite-coated collagen scaffold for bone morphogenetic protein-2 delivery. AB - Bone morphogenetic proteins (BMPs) are the most potent osteoinductive growth factors. BMP-2 is clinically used for spine fusion and bone fracture healing. Commercially available BMP-2 uses a type I collagen scaffold as a carrier, but it only releases BMP-2 for a short period of time, which may release the bone formation efficacy. In the present study, we hypothesize that apatite coating of a collagen scaffold increases the release period as well as the osteogenic efficacy of BMP-2. Apatite coating was achieved by incubating collagen scaffolds in simulated body fluids (SBFs). Apatite coating on collagen scaffolds was confirmed by X-ray diffraction, electron spectroscopy for chemical analysis, attenuated total reflectance-Fourier transform infrared spectroscopy, and scanning electron microscopy. The rate and period of BMP-2 release from apatite coated collagen scaffolds varied depending on the concentration of SBFs used. The 5* and 10* SBF apatite-coated collagen scaffolds released 91.8%+/-11.5% and 82.2%+/-13.1% of their loaded BMP-2 over 13 days in vitro, respectively, whereas noncoated collagen scaffold released 98.3%+/-2.2% over the initial one day. BMP-2 released from apatite-coated collagen scaffold significantly increased the alkaline phosphatase activity of cultured osteoblasts, compared with BMP-2 released from noncoated collagen scaffold. Computed tomography and histomorphometry showed that BMP-2 delivery using apatite-coated collagen scaffolds resulted in 2.5-fold higher bone formation volume and 4.0-fold higher bone formation area than BMP-2 delivery using noncoated collagen scaffolds. This study shows that simple apatite coating of a collagen scaffold results in a BMP-2 carrier that renders long-term release of BMP-2 and dramatically enhances osteogenic efficacy. PMID- 21529264 TI - Chronic care treatment of obese children and adolescents. AB - OBJECTIVES: Clinically-relevant protocols for the treatment of childhood obesity are lacking. This study report results for a clinic-based structured treatment program for chronic childhood obesity. METHODS: Patients were measured at baseline and for up to 24 months; there were no prior eligibility criteria. At baseline, height, weight, Tanner stages, testicular size, time of menarche, and social class of the parents were registered. A structured, tailored treatment plan including best-practice-based interventions was initiated. Height, weight, and pubertal development were measured at subsequent visits. RESULTS: A total of 617 children or youths were included; 325 were girls and 292 were boys. At entry, the mean age was 11.6 years and the mean body mass index (BMI) standard deviation score (SDS) was 3.0. Seventy stopped treatment, 547 were in treatment, 125 had 1 examination, and 492 had two or more examinations, with a mean visit interval of six weeks. After 12 months, the mean BMI SDS decreased by 0.23 (P < 0.0001) in girls and by 0.32 (P < 0.0001) in boys. After one year, the retention rate was 90.2%, and 68.7% had reduced BMI SDS. After two years, the retention rate was 75.0%, of which 62.5% had reduced BMI SDS. The reductions in BMI SDS were independent of baseline adiposity, age (in boys), puberty stage, and social class, but were dependent on sex, age (girls), and place of referral. CONCLUSIONS: This clinical obesity treatment was safe and effective in reducing BMI SDS independent of baseline adiposity, age (boys), or social class in these young people. PMID- 21529265 TI - Impact of volume status on blood pressure and left ventricle structure in patients undergoing chronic hemodialysis. AB - In this study, we aimed to examine the impact of volume status on blood pressure (BP) and on left ventricular mass index (LVMI) in chronic hemodialysis (HD) patients. This study enrolled 74 patients (F/M: 36/38, mean age 53.5 +/- 15.3 years, mean HD time 41.5 +/- 41 months) that were on HD treatment for at least 3 months. Demographics, biochemical tests, hemogram and C-reactive protein levels, mean interdialytic weight gain (IDWG), mean percentage of ultrafiltration (UF), and intradialytic complications such as hypotension and cramps were determined. Mean values of predialysis and postdialysis BP measurements were recorded a month before echocardiographic examination. On the day after a midweek dialysis session, 24 h ambulatory BP monitoring (ABPM) and echocardiographic examination were made concurrently. The patients were classified into two groups according to volume status: normovolemic (group 1; 14F/24M, mean age 50 +/- 16.7 years, mean dialysis time 47.7 +/- 47.7 months) and hypervolemic (group 2; 15F/21M, mean age 57.3 +/- 12.7 years, mean dialysis time 34.9 +/- 32 months). HD duration, IDWG, UF, and interdialytic complication rates were similar between the two groups (p < 0.05). Eleven patients (28.9%) of group 1 and 8 patients (22.2%) of group 2 showed dipper (p = 0.50). Valvular damage was more common in group 2 (p = 0.002). Whereas 33 patients (91.7%) had left ventricular hypertrophy (LVH) in group 2, 21 patients of the group 1 (55.3%) had LVH (p < 0.001). Although LVMI showed a significant positive correlation with cardiothoracic index, predialysis and postdialysis BP, IDWG, UF, daytime and nighttime BP measurements of 24 h ABPM, a significant negative correlation was seen with Kt/V urea and serum albumin levels. In conclusion, increased IDWG and UF and elevated BP are independent predictors of LVH for HD patients. Increased volume status leads to IDWG and elevated BP and eventually causes severe LVMI increases. PMID- 21529266 TI - Ethylene-vinyl alcohol copolymer dialyzer membrane reduces protein oxidation in hemodialysis patients. AB - BACKGROUND: Oxidative stress has been implicated in the cardiovascular complications that affect hemodialysis (HD) patients. Ethylene-vinyl alcohol copolymer (EVAL) dialyzer membrane induces less production of reactive oxygen species as compared to conventional dialyzers. We evaluated the impact of EVAL membrane on plasma protein oxidation in HD patients. METHODS: HD patients treated with cellulose triacetate (CTA) dialyzers were selected. In the first study performed in a 2-month crossover design alternating between CTA and EVAL, nonmercaptalbumin and advanced oxidation protein products levels were measured in the predialysis blood from 10 subjects. In the second study, predialysis plasma myeloperoxidase levels were measured before and after a 2-week EVAL treatment on 12 patients. RESULTS: Plasma advanced oxidation protein products levels were reduced after a 2-month EVAL treatment and increased again after CTA treatment, although the nonmercaptalbumin proportions were not affected significantly by the change in dialyzer membranes. The following study, a 2-week EVAL treatment, showed the decrease in myeloperoxidase levels immediately before HD. CONCLUSION: The frequent use of EVAL dialyzers has been shown to reduce protein oxidation, possibly through the suppression of circulating phagocytes. This novel biocompatible dialyzer is expected to protect cardiovascular mortality in HD patients. PMID- 21529267 TI - Prevalence of chronic kidney disease in hypertensive patients in Ghana. AB - Chronic kidney disease (CKD) is common in tropical Africa although there are few data on the prevalence of this disorder. Therefore we initiated a multicenter screening study to identify the prevalence and staging of CKD in 712 patients with known hypertension in four polyclinics in Accra, Ghana. We measured estimated glomerular filtration rate by the six-variable modification of diet in renal disease equation and proteinuria by the protein/creatinine ratio. All the subjects studied were Ghanaian. Of the 712 patients studied, the median age was 59 years (range 19-90 years) and 560 (78.7%) of the patients were female. The mean duration of hypertension was 4 years (range 0.1-50). The overall prevalence of CKD was 46.9% (95% CI: 43.2-50.7%); 19.1% had CKD stages 1-2 and 27.8% had CKD stages 3-5. There was no difference in age between patients with or without CKD (p = 0.12). The overall prevalence of proteinuria was 28.9% (95% CI: 25.6-32.4%); 14.7% of subjects had preexisting diabetes mellitus and their prevalence of CKD (55%; 95% CI: 42.4-62.2) did not differ from those without diabetes (46%; 95% CI: 41.9-50.0, p = 0.133). CKD is common in hypertensive patients in Ghana, with a prevalence of 46.9%. This provides justification for the inclusion of this group in CKD screening programs in Ghana. PMID- 21529268 TI - Associations of plasma pentraxin 3 and monocyte chemoattractant protein-1 concentrations with cardiovascular disease in patients with chronic kidney disease. AB - Both pentraxin 3 (PTX3) and monocyte chemoattractant protein-1 (MCP-1) are mediators of inflammation. They also appear to play critical roles in vascular endothelial dysfunction but their associations with cardiorenal syndrome remain largely unknown. The objective of this study was to examine their associations with cardiorenal syndrome. Circulating levels of PTX3, MCP-1, and some other biomarkers were evaluated in 134 patients with chronic kidney disease (CKD) and/or cardiovascular disease (CVD) and 55 age- and gender-matched subjects without CKD or CVD. Levels of PTX3, high-sensitivity C-reactive protein (hsCRP), and tumor necrosis factor alpha (TNFalpha) were significantly higher in CKD patients with CVD than in those without CVD. In advanced CKD patients (estimated glomerular filtration rate < 30 mL/min/1.73 m2), the values of area under the curve of PTX3, TNFalpha, and hsCRP for the detection of the association of CVD were 0.664, 0.507, and 0.318, respectively. In contrast, serum levels of MCP-1 were significantly higher in CKD patients than in control subjects independently of association with CVD. PTX3, hsCRP, and TNFalpha, but not MCP-1 could predict the presence of CVD as a complication associated with CKD. Additionally, PTX3 might be a more sensitive marker for the association of CVD than hsCRP and TNFalpha in patients with advanced CKD. PMID- 21529269 TI - Predisposing factors to the development of urinary tract infections in renal transplant recipients and the impact on the long-term graft function. AB - Urinary tract infections (UTIs) represent the most common cause of bacterial infection in renal allograft recipients. The purpose of this study was to estimate the predisposing factors and the impact of UTIs in the long-term graft function. We studied 122 patients (75 males and 47 females), aged 44 +/- 12 years. UTIs occurring during the first month, during the first year, and through the entire follow-up period were analyzed. Diabetes mellitus (DM), delayed graft function, acute rejection episodes, and urinary tract obstruction were evaluated as potential predisposing factors. UTI episodes (n = 316) were recorded in 74 of 122 patients (60.7%). The most common pathogen was Escherichia coli. Most patients (81%) who developed infection during the first month had a new episode in the first year. Hospitalization was necessary in 141 of the 316 UTI episodes whereas 87 were hospital acquired. A strong correlation between female gender and UTI occurrence was found (p = 0.01). Urinary tract obstruction was also related to the UTI occurrence during the first year after transplantation (p = 0.001). Patients' age, DM, delayed graft function, and acute rejection episodes did not correlate with UTI. Long-term renal graft function was not found to be affected by UTI occurrence. UTIs are common infectious complications in renal transplant recipients and often relapse and require hospitalization. The long-term graft function is not affected by the occurrence of UTIs. PMID- 21529270 TI - Endothelial function and oxidative stress in chronic kidney disease of varying severity and the effect of acute hemodialysis. AB - AIM: Oxidative stress (OS) and endothelial dysfunction are implicated in accelerated atherosclerosis in chronic kidney disease (CKD). We assessed endothelial function, OS, and carotid intimal medial thickness (CIMT) and their correlates in 44 CKD stage 5 patients (group III) before and after hemodialysis (HD), 40 patients of CKD stages 3 and 4 (group II), and 25 matched controls (group I). METHODS: OS was measured by serum concentration of antioxidants; vitamin C and fractional reducing ability of plasma (FRAP) and pro-oxidant; thiobarbituric acid reactive substances (TBARS). Ultrasonography of carotid artery for CIMT and of brachial artery for flow-mediated dilatation (endothelium dependent dilatation, EDD) was done. RESULTS: TBARS increased significantly with severity of CKD. Antioxidants FRAP and vitamin C were significantly lower in CKD patients as compared with controls, but there was no significant difference between groups II and III. EDD decreased significantly with severity of CKD, whereas CIMT though higher in CKD patients as compared with controls was not significantly different between groups II and III. After a session of HD as compared with predialysis, levels of TBARS decreased, whereas those of FRAP, vitamin C, and EDD increased. On multivariate analysis, there was negative correlation of TBARS with glomerular filtration rate (GFR), serum albumin, hemoglobin, and EDD. Vitamin C had positive correlations with GFR, serum albumin, hemoglobin, and EDD. EDD had direct correlation with GFR, whereas CIMT correlated negatively with EDD. CONCLUSIONS: Endothelial dysfunction and OS occur early in CKD, are closely related to each other and structural atherosclerosis, and are proportional to decline in GFR. PMID- 21529271 TI - The mechanism of spleen injury in rabbits with acute renal failure. AB - Immune function disorders are common during acute renal failure (ARF), but the mechanisms are unknown. As the spleen is the largest organ of the immune system, we aimed to observe if there are morphological changes in the spleen in rabbits with ARF. In addition, we tried to explore its mechanism from the perspective of oxygen free radicals, nitric oxide (NO), myeloperoxidase (MPO), and membrane pump activities. ARF animal models were established by either hypodermic injection of 1.3 mL/kg bw 1% HgCl2 or intramuscular injection of 10 mL/kg bw 50% glycerin. Animals were divided into 12 h, 24 h, and 48 h treatment groups with six rabbits in each group. Compared with control animals, congestion was found in the spleen and splenic trabeculae were increased in the two ARF model groups at multiple time points. The malonaldehyde, NO, nitric oxide synthase, and MPO levels in the ARF models were increased compared with the control group at 24 h or 48 h, and the superoxide dismutase and adenosine triphosphatase activities were significantly lower than the levels in the control group at multiple time points. These indices of free radical damage were induced gradually with ARF development, and there were statistically significant differences at different time points. These data suggested that histological damage of spleen during ARF may lead to immune disorders, which might be related to free radical injury, NO excessive release, polymorphonuclear neutrophils (PMN) sequestration, and membrane pump dysfunction. PMID- 21529272 TI - The effects of the iodinated X-ray contrast media iodixanol, iohexol, iopromide, and ioversol on the rat kidney epithelial cell line NRK 52-E. AB - Nephrotoxicity, associated with the administration of iodinated X-ray contrast media (ICM), continues to be a major side effect in a significant number of vulnerable patients undergoing diagnostic X-ray imaging procedures. The molecular mechanisms underlying these adverse effects on the kidneys are unclear despite several decades of investigation. Side effects are more common after exposure to high-osmolar compared with low-osmolar ICM, suggesting that osmolality may be an important physical-chemical property related to nephrotoxicity. This investigation in cultured NRK 52-E cells, a cell line of renal origin, compares the in vitro toxicity of the iso-osmolal ICM iodixanol with the low-osmolal ICM iohexol, iopromide, and ioversol. The cellular toxicity was evaluated with the trypan blue exclusion assay, the MTT assay, and incidences of cell death. A qualitative assessment of vacuolation of the cultured NRK 52-E cells was taken as a measure of intracellular uptake of ICM. A difference in cell death incidence was observed between the iso-osmolal iodixanol and the low-osmolal iohexol, iopromide, and ioversol contrast media, with the iso-osmolal iodixanol having the least effect in each of the in vitro systems tested. The osmolality of the contrast media appeared to be the major cause for the observed in vitro toxicity. PMID- 21529273 TI - The effects of Syzygium aromaticum-derived oleanolic acid on glycogenic enzymes in streptozotocin-induced diabetic rats. AB - Studies indicate that the antihyperglycemic effects of Syzygium aromaticum derived oleanolic acid (OA) are mediated in part through increased hepatic glycogen synthesis. Accordingly, this study assessed the influence of OA on the activity of glucokinase (GK) and hexokinase (HK) of skeletal muscle and liver tissues in streptozotocin (STZ)-induced diabetic rats. After 5 weeks of OA treatment, hepatic and gastrocnemius muscle glycogen concentrations and activities of GK and HK were measured spectrophotometrically in reactions where the oxidation of glucose-6-phosphate (G-6-PDH) formed was coupled to nicotinamide adenine dinucleotide phosphate (NADP+) reduction catalyzed by G-6-PDH dehydrogenase. Rats treated with deionized water or standard hypoglycemic drugs acted as untreated and treated positive controls, respectively. STZ-induced diabetic rats exhibited depleted glycogen levels and low activities of glycogenic enzymes in muscle and hepatic tissues. OA administration restored these biochemical alterations to near normalcy. The combination of OA and insulin did not significantly alter the activities of HK and GK of STZ-induced diabetic rats, suggesting that glycogen synthesis can also occur from precursors such as amino acids or fructose and lactate. The attenuation of the activities of glycogenic enzymes with concomitant increases of hepatic and muscle glycogen concentrations of STZ-induced diabetic rats provides a therapeutic strategy for diabetes treatment. PMID- 21529274 TI - The role of carnitine in preventing renal damage developed as a result of infrarenal aortic ischemia-reperfusion. AB - BACKGROUND: This study was designed to use carnitine for preventing deposition of end products of lipid peroxidation in rat models in the prevention of ischemia reperfusion (IR) damage frequently seen following operations of infrarenal abdominal aorta (AA). METHODS: Forty male rats of Sprague-Dawley type were evenly (n = 8) randomized to five groups: sham laparotomy (SHAM), carnitine control (CC), aortic IR (AIR), AIR + low-dose carnitine (AIR+LDC), and AIR + high-dose carnitine (AIR+HDC). RESULTS: Compared to other groups, serum creatinine levels of AIR group were significantly higher. Also tissue malondialdehyde (MDA) levels of AIR group were significantly higher compared to SHAM, CC, and AIR+HDC groups. In histopathological examination, although tubular necrosis atrophy and tubular degeneration observed in AIR group showed regression with low-dose carnitine, tubular necrosis atrophy, tubular degeneration, glomerular damage, and vascular congestion thrombosis decreased with high-dose carnitine. Total score of histological damage was significantly higher in AIR, AIR+LDC, and AIR+HDC groups compared to SHAM and CC groups. Moreover, total score of histological damage was significantly lower in AIR+HDC group than AIR+LDC group. CONCLUSIONS: In this study, we showed carnitine can partially prevent renal damage in infrarenal AIR models of rats. This result may open new prospects to us in the prevention of renal IR damage during surgery of aorta. PMID- 21529275 TI - Extrarenal pseudoaneurysm of the arterial anastomosis in a renal transplant: endovascular coil embolization with balloon remodeling technique. AB - Anastomotic pseudoaneurysms of transplanted kidneys are a very rare complication and encountered in less than 1% of such operations. They may be devastating and cause functional impairment and even loss of the graft. In this report, we present the first case of treatment of extrarenal pseudoaneurysm of arterial anastomosis in a renal transplant patient with endovascular coil embolization with the balloon remodeling technique. This method is mostly used in the treatment of wide-neck intracranial aneurysms. PMID- 21529276 TI - Prolonged hemodialysis for severe metformin intoxication. AB - Lactic acidosis is a rare and often lethal complication of metformin therapy. We describe a patient who ingested at least 52 g, and possibly more, of metformin and presented with severe lactic acidosis and acute renal failure. He was treated with prolonged hemodialysis: a 3.5 h treatment that did not result in significant clinical improvement, followed by an additional 31 h treatment. With this treatment regimen, his lactate levels gradually decreased and his clinical status improved. A metformin level drawn approximately 25 h after the initiation of the second hemodialysis treatment was still elevated at about five times the upper therapeutic limit. It is suggested that prolonged dialysis is indicated in patients with severe metformin overdose, particularly those with renal failure. In patients whose cardiovascular status permits, prolonged hemodialysis should be strongly considered. PMID- 21529277 TI - Comment on: hemodialysis and immunization against swine flu. PMID- 21529278 TI - Comment on: low-dose quetiapine-induced severe rhabdomyolysis. PMID- 21529279 TI - Is there any protective effect on organs upon higher uric acid level in tumor lysis syndrome? PMID- 21529280 TI - Comment on: does zinc supplementation affect inflammatory markers in hemodialysis patients? PMID- 21529281 TI - Regeneration of completely transected spinal cord using scaffold of poly(D,L lactide-co-glycolide)/small intestinal submucosa seeded with rat bone marrow stem cells. AB - Using a complete spinal cord transection model, the present study employed a combinatorial strategy comprising rat bone marrow stem cells (rBMSCs) and polymer scaffolds to regenerate neurological function after spinal cord injury (SCI) of different lengths. SCI models with completely transected lesions were prepared by surgical removal of 1 mm (SC1) or 3 mm (SC3) lengths of spinal cord in the eighth to-ninth spinal vertebrae, a procedure that resulted in bilateral hindlimb paralysis. A cylindrical poly(D,L-lactide-co-glycolide)/small intestinal submucosa scaffold 1 or 3 mm in length with or without rBMSCs was fitted into the completely transected lesion. Rats in SC1 and SC3 groups implanted with rBMSC containing scaffolds received Basso-Beattie-Bresnahan scores for hindlimb locomotion of 15 and 8, respectively, compared with ~3 for control rats in SC1-C and SC3-C groups implanted with scaffolds lacking rBMSCs. The amplitude of motor evoked potentials recorded in the hindlimb area of the sensorimotor cortex after stimulation of the injured spinal cord averaged ~100 MUV in SC1-C and 10-50 MUV in SC3-C groups at 4 weeks, and then declined to nearly zero at 8 weeks. In contrast, the amplitude of motor-evoked potentials increased from ~300 to 350 MUV between 4 and 8 weeks in SC1 rats and from ~200 to ~250 MUV in SC3 rats. These results demonstrate functional recovery in rBMSC-transplanted rats, especially those with smaller defects. Immunohistochemically stained sections of the injury site showed clear evidence for axonal regeneration only in rBMSC-transplanted SC1 and SC3 models. In addition, rBMSCs were detected at the implanted site 4 and 8 weeks after transplantation, indicating cell survival in SCI. Collectively, our results indicate that therapeutic rBMSCs in a poly(D,L-lactide-co glycolide)/small intestinal submucosa scaffold induced nerve regeneration in a complete spinal cord transection model and showed that functional recovery further depended on defect length. PMID- 21529282 TI - Enhanced immune response of T-cell independent or dependent antigens in SIGN-R1 knock-out mice. AB - Dextran was used to explore a novel method of enhancing an immune response against T-cell independent type 2 (TI-2) polysaccharide antigens, because of its suitability as a model for the immunogenecity of many TI-2 polysaccharide antigens and its high affinity to SIGN-R1. Here we showed that the primary immune response of IgM, IgG3, and IgG2b was enhanced by dextran in SIGN-R1 knock-out (KO) mice, further evoking the induction of a secondary immune response to IgG2b in parallel. On the other hand, an immune response of IgG1 and IgG2b against T cell dependent (TD) antigen was strongly enhanced by the administration of ovalbumin (OVA) in SIGN-R1 KO mice. These results indicate that SIGN-R1 is critical in the regulation of immune responses. Therefore, our study suggests that inhibition of TI-2 polysaccharide antigen uptake in SIGN-R1(+) macrophages contributes to the development of novel vaccination strategies against TI-2 polysaccharide antigens. PMID- 21529283 TI - Development of a colloidal gold-based immunochromatographic test strip for screening of microalbuminuria. AB - A rapid immunochromatography (ICG) assay based on antibody colloidal gold nanoparticles specific to human serum albumin (HSA) was developed, and its applications for primary screening of HSA in the urine were evaluated. A monoclonal antibody (MAb) specific to HSA was produced from cloned hybridoma cells (EMRC1) and used to develop an ICG strip. The nanocolloidal gold, with an average particle diameter of 20 nm, was synthesized and labeled MAb as the detection reagent. An antibody colloidal gold probe was applied on the conjugate pad, and HSA antigen was immobilized to a nitrocellulose membrane as the capture reagent to prepare the ICG strip test. This test required only 10 min to accomplish a semiquantitative detection of albumin. The sensitivity to urinary albumin was found to be approximately 20 MUg/mL, and the analytical range was 20 25 MUg/mL. The reliability of the testing procedures was examined by carrying out the ICG strip test with 40 urine samples and comparing the results of these tests with those obtained via immunoturbidimetry. The ICG strip was adequately sensitive and accurate for a rapid screening of HSA in the urine. PMID- 21529284 TI - Immunodetection of human double homeobox 4. AB - Double homeobox 4 (DUX4) is a candidate disease gene for facioscapulohumeral dystrophy (FSHD), one of the most common muscular dystrophies characterized by progressive skeletal muscle degeneration. Despite great strides in understanding precise genetics of FSHD, the molecular pathophysiology of the disease remains unclear. One of the major limitations has been the availability of appropriate molecular tools to study DUX4 protein. In the present study, we report the development of five new monoclonal antibodies targeted against the N- and C termini of human DUX4, and characterize their reactivity using Western blot and immunofluorescence staining. Additionally, we show that expression of the canonical full coding DUX4 induces cell death in human primary muscle cells, whereas the expression of a shorter splice form of DUX4 results in no such toxicity. Immunostaining with these new antibodies reveals a differential effect of two DUX4 isoforms on human muscle cells. These antibodies will provide an excellent tool for investigating the role of DUX4 in FSHD pathogenesis. PMID- 21529285 TI - Monoclonal antibodies against lipopolysaccharide of Chlamydia trachomatis with cross reactivity to human ApoB. AB - Splenocytes obtained from mice immunized with whole purified elementary bodies of Chlamydia trachomatis were used for hybridoma construction. The resulting clones were screened with ELISA using chlamydial lipopolysaccharide (LPS) and full length human apolipoprotein B (ApoB). One analyzed clone producing IgG1 (MAb 7B5) showed simultaneous recognition of chlamydial LPS and human ApoB, suggesting the presence of common antigenic epitopes in their structures. MAb 7B5 exhibited agreeable activity in immunoblot analysis conducted using chlamydial extracts or full-length human ApoB as well as in immunofluorescence (IF) detecting typical inclusion bodies of C. trachomatis and C. pneumoniae in the infected eukaryotic host cells. The removal of LPS from chlamydial suspensions with lauroyl sarcosyl led to a complete disappearance of IF associated with the elementary bodies of C. trachomatis. Therefore, immunologic response to chlamydial antigen may be associated with the generation of ApoB-specific antibody. Molecular mimicry and subsequent formation of cross-reactive antibodies might be an essential mechanism explaining the appearance of circulating auto-antibodies against low density lipoproteins (LDL) in patients with atherosclerosis. Moreover, newly generated MAb 7B5 can be a useful tool in the laboratory diagnosis of chlamydial infections. PMID- 21529286 TI - Generation and characterization of a high-affinity monoclonal antibody for MUC1 measurement in breast cancer. AB - Breast mucin is secreted by breast tumor cells and serves as a marker for breast cancer. Thus, antibodies against breast mucin will be valuable in the development of immunotherapy and laboratory diagnostic tests. Monoclonal antibodies (MAbs) against breast cancer-associated antigen were generated and characterized. Balb/c mice were immunized with breast cancer-associated antigen CA15-3, and subsequently splenocytes from immunized mice were fused with myeloma cells. After fusion, culture supernatants from hybridomas surviving HAT medium were screened by enzyme-linked immunosorbent assay (ELISA). A total of eight hybridomas producing MAbs against breast cancer showed significant levels of antibody activity against CA15-3. Two selected stable hybridomas were adapted into CELLine CL 350 bioreactors, and the MAbs produced were characterized for their subclass, specificity, and affinity. The MAbs were of high specificity and affinity as shown by ELISA. The MAbs produced may represent a powerful tool and are considered promising reagents for use in diagnosis and detection of early stage of the disease. PMID- 21529287 TI - Generation and characterization of anti-chitinase monoclonal antibodies. AB - Class IV chitinase, an allergenic protein of Vitis vinifera (grape), was purified by anion exchange chromatography and used for immunization of Balb/c mice. Monoclonal antibodies (MAbs) were raised by hybridoma technology using Sp2/0 myeloma cells. Finally after three limiting dilutions, six stable clones were generated. Antibody isotyping showed that IgG(2a), IgG(2b), and IgM were produced by one, two, and three of the clones, respectively. All of the MAbs had kappa light chain. The affinities were in the range of 3 * 10(8) to 1.2 * 10(9) M(-1). The MAbs were specific for grape chitinase as confirmed by Western blotting. In conclusion, we successfully produced several MAbs against grape class IV chitinase, which could be used for assessment of this allergen in different grape cultivars. PMID- 21529288 TI - Generation and characterization of rat anti-mouse ST2L monoclonal antibodies. AB - ST2L is a transmembrane receptor that belongs to the IL-1 receptor family. The receptor is expressed on various cell types including Th2 cells, mast cells, basophils, growth-activated fibroblasts, and vascular endothelial cells. ST2L activation by its ligand IL-33 has been implicated in Th2-mediated immunity, inflammation, and allergic responses in vivo. Inhibition of ST2L activity can attenuate Th2-dominated immune responses such as lung eosinophilia, airway hyper responsiveness, and arthritis in animal models. Here we report the generation and in vitro characterization of a panel of rat anti-mouse ST2L monoclonal antibodies. We demonstrate that the antibodies specifically bind to recombinant receptor protein and that a subset of the binders inhibits mouse ST2L activity in multiple in vitro assays. Four of the identified anti-mouse ST2L antibodies were shown to prevent IL-33 from binding to ST2L, down-regulate IL-33-induced NF kappaB signaling, and neutralize the ability of IL-33 to stimulate mouse Th2 cell proliferation. The characterized monoclonal antibodies are important tools that will be used to study mouse ST2L receptor functionality in vivo. PMID- 21529290 TI - Generation and characterization of antibody against porcine interleukin-18. AB - The gene-encoding mature porcine interleukin-18 (pIL-18) was amplified by PCR and cloned into a prokaryotic expression vector pET-30a(+). The resulting recombinant plasmid pET-30a-pIL-18 was transformed into Escherichia coli. Expression of recombinant pIL-18 protein was induced by 1 mM isopropyl beta-D-thiogalactoside at 37 degrees C. The purified recombinant protein was used to generate a hyperimmune antiserum in a rabbit. The anti-pIL-18 serum was evaluated for its specificity and titer through indirect enzyme-linked immunosorbent assay. The specific reactivity of the anti-pIL-18 antibody was further confirmed by Western blot and immunofluorescence assays. Moreover, the pIL-18 was able to stimulate the proliferation of pig peripheral blood mononuclear cells in vitro, indicating it may have certain biological activity. PMID- 21529289 TI - Generation and characterization of monoclonal antibodies against human Chibby protein. AB - Chibby (Cby) was originally identified as an antagonist of the Wnt/beta-catenin signaling pathway. It physically interacts with the key co-activator beta-catenin and inhibits beta-catenin-mediated transcriptional activation. More recently, we demonstrated that Cby protein localizes to the base of motile cilia and is required for ciliogenesis in the respiratory epithelium of mice. To gain further insight into the physiological function of Cby, we developed mouse monoclonal antibodies (MAbs) against human Cby protein and characterized two Cby MAbs, designated 8-2 and 27-11, in depth. Western blot analysis revealed that 8-2 reacts with both human and mouse Cby proteins, whereas 27-11 is specific to human Cby. The epitopes of 8-2 and 27-11 were narrowed down to the middle portion (aa 49-63) and N-terminal region (aa 1-31) of the protein, respectively. We also determined their isotypes and found that 8-2 and 27-11 belong to IgG2a and IgG1 with kappa light chains, respectively. Both MAbs can be employed for immunoprecipitation assays. Moreover, 8-2 detects endogenous Cby protein on Western blots, and marks the ciliary base of motile cilia in the murine lung and trachea as shown by immunofluorescence staining. These Cby MAbs therefore hold promise as useful tools for the investigation of Wnt signaling and ciliogenesis. PMID- 21529291 TI - Characterization of a monoclonal antibody to erythroid related factor. AB - We describe here a novel IgG monoclonal antibody to erythroid-related factor (ERAF), also known as alpha hemoglobin stabilizing protein (AHSP) and eryththroid differentiation related factor (EDRF). Our antibody named PCE 5 is an IgG(1) kappa chain and is to the peptide sequence MVTVVE ranked highly in our active site analysis and binds with high affinity to ERAF. PMID- 21529292 TI - Monoclonal antibodies against Muscleblind-like 3, a protein with punctate nuclear localization. AB - Muscleblind-like 3 (MBNL3) belongs to a family of RNA binding proteins that regulate alternative splicing. We have generated a set of monoclonal antibodies (MAbs) against mouse MBNL3, three of which do not cross-react with the other muscleblind-like (MBNL) proteins, MBNL1 and MBNL2. Epitope mapping revealed that MAbs P1C7, P1E7, SP1C2, and P2E6 recognize distinct, non-overlapping segments of the MBNL3 polypeptide sequence. Immunohistochemical staining of proliferating muscle precursor cells localized MBNL3 to the nucleus in a punctate pattern, characteristic of subcellular structures in the nucleus enriched in pre-messenger RNA splicing factors. Although MBNL3 did not co-localize with SC35 and PSP1 (widely used markers of splicing speckles and paraspeckles), the punctate localization pattern of MBNL3 within interchromatin regions of the nucleus is highly predictive of proteins involved in pre-mRNA processing. Monoclonal antibodies specific for mouse MBNL3 will facilitate further investigation of the expression pattern and unique functions of this splicing factor during development and in different adult mouse tissues. PMID- 21529293 TI - Metabolic activity and monoclonal antibody production of Salmonella enteritidis O and H antigen specific hybridoma cells in static culture. AB - The aim of the present work was to study the kinetics of two hybridomas that produce monoclonal antibody against Salmonella Enteritidis O (5A8) and H (D7) antigen. The hybridomas originated from the Ag8x653 (5A8) and Sp2/O (D7) myeloma cell lines. The relationship between the uptake of glucose and glutamine and the release of the lactate and ammonia and monoclonal antibody production into hybridoma growth were investigated in static culture with serum-containing DMEM/F:12 medium for the determination of pilot-production strategies of the hybridomas. Results showed that glucose and glutamine concentrations were reduced, with an increase in ammonia and lactate concentration in the culture medium. The hybridoma cell line 5A8 has shown lower metabolic activities compared with D7, whereas its monoclonal antibody productivity was found to be two-fold higher than the D7. MAb production by the hybridoma cell line 5A8 seems promising, considering the moderate level of productivity compared to that found in the literature. PMID- 21529294 TI - Differentiation of porcine reproductive and respiratory syndrome virus N protein using a virus-based ELISA. AB - The bacterially expressed nucleocapsid (N) protein of porcine respiratory and reproductive syndrome virus (PRRSV) was used as immunogen to generate a rabbit derived polyclonal antibody. The immunoreactivity of the protein to the antibody was confirmed by Western blot analysis. Using PRRSV, transmissible gastroenteritis virus, porcine epidemic diarrhea virus, pseudorabies virus, and avian infectious bronchitis virus as coating antigens, a virus-based ELISA was established. The polyclonal antibody against PRRSV N protein used as a diagnostic agent was capable of differentiating PRRSV from the other viruses. PMID- 21529295 TI - Generation of chicken monoclonal antibodies against the a1, a2, and a3 subunit isoforms of vacuolar-type proton ATPase. AB - The vacuolar-type proton pump ATPase (V-ATPase) plays several pivotal roles in the acidification of diverse intracellular compartments and the extracellular environment. The a subunit isoforms a1, a2, and a3, constituting the membrane embedded section, are expressed in various tissues, and they are involved in the regulation of subcellular localization and activity of the holocomplex. Therefore, the characterization of their properties is indispensable for dissection of the physiological roles of the V-ATPase in highly differentiated cells. In this study, we report the production and characterization of chicken monoclonal antibodies (MAbs) against these mouse a1, a2 and a3 subunit isoforms. These MAbs are shown to be suitable for both immunoblotting and immunofluorescence analysis. The MAbs obtained in this study are useful in understanding the pathological basis of V-ATPase dysfunction. PMID- 21529300 TI - Emerging drugs to treat juvenile idiopathic arthritis. AB - INTRODUCTION: Juvenile idiopathic arthritis (JIA) differs markedly from adult rheumatoid arthritis (RA). It is not a single disease, but an exclusion diagnosis that gathers together all forms of arthritis that begin before the age of 16 years, persist for > 6 weeks and are of unknown origin. This heterogeneous group of disorders has been classified on clinical and laboratory features to try to identify homogeneous, mutually exclusives categories. While some of them appear to represent rather homogenous entities others still seem to include heterogeneous conditions. AREAS COVERED: The advent of new biological treatments has dramatically changed both the observed responses to treatment and the expectations of therapies. The implementation of an adequate legislation as well as the presence of international research networks of pediatric rheumatology have contributed to foster the conduct of controlled clinical trials and the development of validated outcome measures. EXPERT OPINION: Despite these progresses, there are still many problems to be solved to provide a better treatment for those patients who fail to adequately respond to current therapies. Some of the new drugs that are under investigation for RA could also be suitable in the future for improving the treatment of JIA. PMID- 21529301 TI - Bevacizumab in combination with cetuximab and irinotecan after failure of cetuximab and irinotecan in patients with metastatic colorectal cancer. AB - BACKGROUND: The efficacy and safety of concurrent administration of irinotecan with the two monoclonal antibodies cetuximab and bevacizumab as fourth line therapy in heavily pretreated patients with metastatic colorectal cancer were evaluated. PATIENTS AND METHODS: Patients with metastatic colorectal cancer who had progressed on therapy with 5-FU, oxaliplatin and irinotecan in the first and second line setting and on the combination of irinotecan and cetuximab in third line setting independent of their KRAS mutation status, were treated with irinotecan and cetuximab combined with bevacizumab in a dosage of 5 mg/kg. All drugs were administered every second week. RESULTS: From January 2007 to November 2008 27 patients were treated with cetuximab, irinotecan and bevacizumab. The triple-combination was well tolerated. Progression free survival (PFS) was 8.3 months and median overall survival (mOS) was 12.0 months. Two patients without KRAS mutation (7%) obtained a partial response and 17 (63%) had stable disease for at least two months. A retrospective KRAS mutation analysis revealed that there was a trend toward longer PFS and mOS in patients without KRAS mutations compared to patients with KRAS mutations with a PFS of 8.9 vs. 5.1 months and a mOS of 12.7 vs. 9.0 months. CONCLUSION: Bevacizumab is safe to add to irinotecan and cetuximab with a toxicity profile that seems to be similar to what would be expected from the agents alone. The results indicate that adding bevacizumab to irinotecan and cetuximab in a fourth line setting may induce a high rate of disease control in heavily pretreated patients with metastatic colorectal cancer. PMID- 21529302 TI - Increase of IL-17, IL-22 and IL-23 serum levels induced by immunoglobulin infusion for Parvovirus-B associated Pure Red Cell Aplasia in a renal transplant recipient. PMID- 21529303 TI - Morning symptoms in rheumatoid arthritis: a defining characteristic and marker of active disease. AB - Many human biological processes are regulated by circadian rhythms, which follow 24-h cycles and involve the neuroendocrine and immune systems. Pathological manifestations of this system may also follow circadian rhythms. In rheumatoid arthritis (RA), clinical symptoms of joint stiffness, pain, and functional disability are commonly most severe in the early morning. These symptoms closely follow the circadian rhythm of the pro-inflammatory cytokine, interleukin (IL)-6. In RA, the increase in nocturnal anti-inflammatory cortisol secretion is insufficient to suppress ongoing inflammation, resulting in the morning symptoms characteristic of RA. Established diagnostic criteria for RA include morning stiffness, although it is not part of the more recent classification criteria developed to guide early treatment decisions. Measures that are widely used to monitor disease control also omit morning stiffness. However, such measures may not capture all disease activity, and one in six patients in remission or with low disease activity still experiences prolonged morning stiffness. Such findings suggest that morning symptoms in RA remain an important marker of active disease that should continue to be monitored. PMID- 21529304 TI - Impact of impaired morning function on the lives and well-being of patients with rheumatoid arthritis. AB - Morning joint stiffness and pain are prominent features in patients suffering from rheumatoid arthritis (RA) and contribute to impaired function. A survey was conducted across 11 European countries to assess the impact of impaired morning function on patients' quality of life. A total of 518 rheumatologists, and 750 patients aged 18-75 years with RA for >= 6 months and impaired morning function at least three times a week, completed the structured questionnaires. Impaired morning function was defined as 'stiffness and pain in the joints first thing in the morning that results in difficulty to function or perform tasks'. The mean duration of morning stiffness and pain was 83 min according to patients, slightly longer than that estimated by rheumatologists (70 min). Impaired morning function lasting more than 30 min/day was reported by 75% of patients, with 76% of rheumatologists estimating this duration for their patients. Most respondents (82% of patients and 96% of rheumatologists) considered that impaired morning function had a significant effect on patient quality of life. Around two-thirds of patients reported changes in how they carry out usual morning activities. Patients who were unable to function normally in the morning reported feeling frustrated (58%) and angry (32%). Almost one in five patients in the survey (18%) was unable to work as a direct result of their RA. Of the 274 patients included in the survey who were in paid work, 73% reported that impaired morning function had a significant impact on their job; 40% missed time from work in the past 6 months due to impairment in morning function, resulting in a mean of 4.5 days lost from work/employed person. In conclusion, the survey shows that impaired morning function has a considerable impact on the lives and well-being of patients with RA. PMID- 21529305 TI - How much is a reduction in morning stiffness worth to patients with rheumatoid arthritis? AB - OBJECTIVE: The aim of this study was to determine the monetary equivalent of the emotional and functional impact of morning stiffness (MS) in patients with rheumatoid arthritis (RA), using alternative valuing methods. METHODS: Telephone interviews were conducted among 166 patients with RA to assess utility and clinical symptoms, including MS. Three standard economic methods were used: the human capital approach (HCA), marginal value of time (MVT), and willingness-to pay (WTP). RESULTS: The monetary equivalent of the impact of MS varied with the method used (from EUR 5.74 to EUR 17.87 per patient per day) and severity of MS (5-8-fold higher in patients with severe MS compared with mild MS). Patients placed considerable value on a reduction in duration and severity of MS. Patients with MS lasting an hour or more were willing to pay EUR 21.74/day to stop the symptom and EUR 10.63/day to halve the duration. Patients with severe MS were willing to pay EUR 47.86/day to stop the symptom and EUR 21.68/day to halve the severity. CONCLUSIONS: The observed variation in the monetary equivalent of the impact of MS obtained with the three estimation methods indicates that the findings of studies using different valuing methods should not be compared directly. The study demonstrates that a reduction in MS is worth a considerable amount to patients with RA, particularly those with severe or prolonged MS. These findings suggest that clinical treatment decisions to improve patients' quality of life should also incorporate therapy that reduces MS. PMID- 21529306 TI - How should morning function in rheumatoid arthritis be assessed? Bibliographic study of current assessment. AB - In patients with rheumatoid arthritis (RA), symptoms of joint stiffness and pain may be most severe in the morning, resulting in impaired ability to carry out normal morning functions. Although morning stiffness was included in the criteria for classification and remission of RA, defined by the American College of Rheumatology (ACR) in 1987, the approach to assessment of this circadian symptom has not been standardized, and other circadian aspects of the disease (i.e. pain, functional ability) were not included. A bibliographic study of papers published in English in the period January 2007 to January 2010 and reporting morning stiffness, pain or function was undertaken to investigate methods of assessing circadian aspects of RA. A total of 73 studies were identified using Medline, including 62 clinical trials. Full papers were obtained for 52 reports of clinical studies (84%), most of which (44/52, 85%) assessed duration of morning stiffness. Only two studies (4%) specified that severity of morning stiffness was assessed, only three (6%) assessed pain in the morning, and none assessed morning functional ability. These findings suggest the need for consistent reporting of a measure to reflect the impaired morning function, arising from joint stiffness and pain that is commonly experienced by patients. PMID- 21529307 TI - Morning stiffness and other patient-reported outcomes of rheumatoid arthritis in clinical practice. AB - Morning stiffness has been recognized in traditional approaches to assessment of disease activity in rheumatoid arthritis (RA). Although morning stiffness is not specific to RA, changes in morning stiffness for an individual patient are helpful when monitoring health status. Health professionals can ask about morning stiffness but the most accurate and consistent approach to assessment from one visit to the next appears to be a patient self-report questionnaire. However, quantitative measures of patient-reported data are not an integral part of clinical monitoring in most clinics. No single measure is adequate for all individual patients, so quantitative measurement of patient-reported data should include many elements such as pain, functional status, fatigue, sleep, morning stiffness, work capacity, and physical and emotional well-being. In daily clinical practice, patient-reported outcomes can be collected easily using a standard questionnaire that patients can complete with pencil and paper or electronically on a touch screen in the waiting room. The results are then immediately available to the rheumatologists, to facilitate doctor-patient communication to improve the quality of patient care, leading to better patient outcomes. PMID- 21529308 TI - How should impaired morning function in rheumatoid arthritis be treated? AB - Patients with rheumatoid arthritis (RA) commonly experience morning symptoms of joint stiffness and pain that result in impaired function. However, current treatment options are limited. The management of impaired morning function is based primarily on non-pharmacological approaches, including simple or short exercises, application of heat or a hot shower or bath, and delaying activities until later in the day. Although it seems that the majority of patients follow the management advice they are given by rheumatologists, symptoms persist. In recent years, only a minority of clinical studies have assessed the impact on morning symptoms of pharmacological treatments for RA. The paucity of data makes it difficult to evaluate systematically the ability of current treatments to improve morning function. However, treatment seems to be suboptimal; in a pan European survey of 518 rheumatologists, 61% considered that current treatment options do not address impaired morning function specifically, and 68% considered there is a need for new treatment options. Understanding the pathophysiology of circadian symptoms may provide the key to improving treatment of impaired morning function. In patients with morning symptoms of RA, there may be insufficient endogenous cortisol released during the night to counter elevated levels of the pro-inflammatory cytokine, interleukin (IL)-6. Delivering exogenous glucocorticoid during the night was found to reduce IL-6 levels and reduce morning stiffness, but was inconvenient for patients. However, this chronotherapeutic approach has now been facilitated by the development of modified-release prednisone tablets. Taken at bedtime (approximately 10:00 pm), these tablets give programmed delivery of prednisone around 4 h later, at the optimal time to suppress IL-6. Clinical studies suggest that morning stiffness in patients with RA could be treated successfully with the use of low-dose modified release prednisone. PMID- 21529309 TI - Radioprotective gene therapy. AB - INTRODUCTION: Radiation-induced myelosuppression or mucositis can limit the effectiveness of radiotherapy by requiring dose reduction or delaying treatment of tumour patients. The transfer of a radioprotective gene into normal tissue cells would provide the opportunity to reduce the risks associated with haematopoietic or intestinal toxicity after irradiation. AREAS COVERED: Several potentially radioprotective genes like multidrug resistance 1 (MDR1), snail homolog 2 (SNAI2), and superoxide dismutases have been evaluated in preclinical models for their radioprotective potential in the last years. For gene transfer and ectopic expression, adenoviral, adeno-associated virus (AAV) or retroviral vectors were used. The feasibility of radioprotective gene therapy is discussed in consideration of the application of cytoprotective agents and small-molecule protectors. EXPERT OPINION: Further vector optimization for targeted cell specific transduction and for more stable or regulated transgene expression is still required. However, radioprotective gene therapy represents a very promising method for reducing radiotherapy-related cytotoxicity of normal tissue cells and thus may improve therapy success and the patient's quality of life. PMID- 21529310 TI - Combining temozolomide with other antitumor drugs and target-based agents in the treatment of brain metastases: an unending quest or chasing a chimera? AB - INTRODUCTION: Medical treatment of brain metastases (BM) is still a controversial issue in cancer therapy being mainly limited by the existence of the BBB. Temozolomide (TMZ) can cross BBB and several clinical trials have been performed attempting to demonstrate the activity of TMZ in combination with whole brain radiotherapy (WBRT) in the treatment of BM. AREAS COVERED: This review summarizes TMZ-WBRT combination trials highlighting the confounding factors that limit the interpretation of the achieved results and describes the main clinical trials using TMZ in combination with other cytotoxic or biological agents. The main limitations of these trials are: i) patient selection for heterogenous primitive neoplasms and for heterogeneous neuro-functional score; ii) poor penetration across BBB of the other drugs; iii) cumulative toxicity and iv) poor control of extracranial tumor sites. EXPERT OPINION: Biotechnological, biological and biochemical advances in the management of BM could allow in short time the definition of new schedules based on the rational use of new anticancer weapons. The latter could be cytotoxic agents encapsulated in nanotechnological tools able to cross BBB, lipophilic small kinase inhibitors (lapatinib, sunitinib), mTOR inhibitors and PARP inhibitors combined with old drugs such as TMZ. PMID- 21529311 TI - Are aromatase inhibitors effective in endometriosis treatment? AB - INTRODUCTION: Current therapies for endometriosis cannot completely cure the disease, and patients present with high recurrence rates. Novel medical approaches are, therefore, needed. AREAS COVERED: In endometriosis, aromatase was long thought to be involved in the in situ formation of estrogens, leading to a positive feedback loop favoring estrogens, themselves inducing prostaglandin production and inflammation. This hypothesis led to aromatase inhibitors (AIs) being proposed as the new medical therapy for endometriosis, as reported in all the studies reviewed here. Recent findings nevertheless indicate that aromatase may be less implicated in endometriosis than previously postulated. More than 10 years after the first successful treatment of a rare and severe case of postmenopausal endometriosis with an AI, there are only three small randomized controlled trials in the literature. EXPERT OPINION: Until recently, AIs were thought to be an alternative to current medical therapies for endometriosis. However, recent findings question their real utility in clinical practice in the context of this disease. Because there is no strong evidence of their efficacy or benefit compared to other molecules in existing clinical trials, AIs need to be investigated further in well-designed studies to confirm/disprove their hypothetical impact on endometriotic lesions. PMID- 21529312 TI - Association of serum high molecular weight adiponectin and blood pressure among non-diabetic community-dwelling men. AB - Adiponectin is one of the important molecules in the development of metabolic syndrome, and its concentration is decreased in obesity, type-2 diabetes, and cardiovascular disease. We aim to determine whether serum high-molecular weight (HMW) adiponectin, which is thought to represent the biological active form, was associated with a risk for the prevalence of prehypertension and hypertension. The cross-sectional study was carried out in 2002. A total of 614 men, aged 58 +/ 14 (range, 20-89) years, and 779 women, aged 62 +/- 12 (range, 21-88) years without medications for hypertension, diabetes, or dyslipidemia were recruited from a single community at the time of their annual health examination. In men, nonadjusted and age-adjusted mean serum HMW adiponectin were significantly lower in subjects with prehypertension and hypertension than those with normotension. In women, only nonadjusted values were higher in subjects with hypertension than those with normotension. Multiple linear regression analysis using systolic blood pressure (SBP) and diastolic blood pressure (DBP) as an objective variable, adjusted for risk factors as explanatory variables, showed that only in men, log serum HMW adiponectin were significantly and independently associated with SBP and DBP. In men, lower serum HMW adiponectin categories were positively associated with prehypertension and hypertension in an age-adjusted model, and hypertension in an age- and BMI-adjusted model. Serum HMW adiponectin concentrations were inversely associated with blood pressure (BP) in the general male population. PMID- 21529313 TI - Blood pressure and circulatory relationships with physical activity level in young normotensive individuals: IPAQ validity and reliability considerations. AB - Physical activity (PA) reduces risk of cardiovascular diseases, including hypertension. However, the international physical activity questionnaire (IPAQ) relationships with blood pressure (BP) and flow (BF) and vascular resistance (VR) in healthy young individuals have not been studied. Therefore, BP, BF, and VR relationships with the IPAQ were evaluated in college normotensive students (18 23 yrs). Additionally, the IPAQ relationships with body fat (%BF), muscle mass (MM), body mass index (BMI), waist/hip (W/H) ratio, maximum walking distance in 6 min (6MWD), and handgrip strength (MHG) were examined to evaluate the questionnaire validity against fitness. Subsequently, the IPAQ was administered three times to examine its reliability. Walking, moderate, and total PAs correlated negatively with sysbolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) (range: r = -3 to -0.5, p < 0.05). Additionally, all BP measures were greater in least physically active individuals. In a subgroup of 42 students, IPAQ sitting time correlated with BF (r = -0.3) and VR (r = 0.4). The intraclass correlation coefficient (ICC) for walking, moderate, vigorous, and total PAs and sitting time/week were, 0.97, 0.96, 0.97, 0.97, and 0.96, respectively. The males scored greater vigorous PA (p = 0.001) than the females, while moderate, walking, and total PAs were the same (p > 0.05). Additionally, vigorous PA correlated with %BF (r = -0.2), MM (r = 0.3), MHG (r = 0.3), and 6MWD (r = 0.3) and total PA correlated with MM (r = 0.2), MHG (r =0.2), and 6MWD (r = 0.3). The IPAQ association with the circulatory measures demonstrates PA importance for controlling BP and adds clinical value to the IPAQ. Additionally, the IPAQ is reliable, can discriminate between populations, and reasonably valid against health-related fitness. PMID- 21529314 TI - Blood pressure changes after automatic and fixed CPAP in obstructive sleep apnea: relationship with nocturnal sympathetic activity. AB - Treatment of obstructive sleep apnea (OSA) by continuous positive airway pressure (CPAP) usually causes a reduction in blood pressure (BP), but several factors may interfere with its effects. In addition, although a high sympathetic activity is considered a major contributor to increased BP in OSA, a relationship between changes in BP and in sympathetic nervous system activity after OSA treatment is uncertain. This study was undertaken to assess if, in OSA subjects under no pharmacologic treatment, treatment by CPAP applied at variable levels by an automatic device (APAP) may be followed by a BP reduction, and if that treatment is associated with parallel changes in BP and catecholamine excretion during the sleep hours. Nine subjects underwent 24-h ambulatory BP monitoring and nocturnal urinary catecholamine determinations before OSA treatment and 2 months following OSA treatment by APAP (Somnosmart2, Weinmann, Hamburg, Germany). Eight control subjects were treated by CPAP at a fixed level. After APAP treatment, systolic blood pressure (SBP) decreased during sleep (p < 0.05), while diastolic blood pressure (DBP) decreased both during wakefulness (p < 0.05) and sleep (p < 0.02). Similar changes were observed in subjects receiving fixed CPAP. Nocturnal DBP changes were correlated with norepinephrine (in the whole sample: r = .61, p < 0.02) and normetanephrine (r = .71, p < 0.01) changes. In OSA subjects under no pharmacologic treatment, APAP reduces BP during wakefulness and sleep, similarly to CPAP. A reduction in nocturnal sympathetic activity could contribute to the reduction in DBP during sleep following OSA treatment. PMID- 21529315 TI - Gender disparities in the awareness and control of hypertension. AB - Hypertension is an important risk factor for the commonest cause of death among men, namely, cardiovascular diseases. The purpose of this study was to provide data concerning gender difference in the awareness, treatment, and control of hypertension in adults. We conducted a cross-sectional study in Riyadh, the capital city of Saudi Arabia. Subjects were asked if they had been told by a physician that they had hypertension or were on blood pressure (BP) medication. Blood pressure was measured using standardized Joint National Committee (JNC) protocol. The study sample consisted of 814 adults who were at least 18 years old. Of the estimated 27.6% people with hypertension, 38.6% were unaware of their hypertension, 29.8% were aware of their condition but were not being treated, and among those who had been treated 40.8% remained uncontrolled. Independent predictors of a lack of awareness of hypertension were an age of at least 45 years, male gender, and BMI greater than 30. The extent of awareness and control of hypertension did not differ significantly by monthly income, educational level, physical activities, or smoking status. Awareness and control of hypertension is low in men, making them public health priorities. Achieving more stringent BP control will require increased attention by physicians and public education to improve the awareness and control of hypertension. PMID- 21529316 TI - High salt intake accelerated cardiac remodeling in spontaneously hypertensive rats: time window of left ventricular functional transition and its relation to salt-loading doses. AB - Salt-loading is an accelerator of hypertensive left ventricular (LV) remodeling. The relationship between salt-loading doses and the time window in which a transition from compensated to decompensated LV hypertrophy occurs in spontaneously hypertensive rats (SHR) is unclear. Eight-week-old male SHR and Wistar Kyoto rats (WKY) were randomized to receive normal (0.5% NaCl) and high salt diets (4% or 8% NaCl) for 12 weeks. Left ventricular remodeling was dynamically determined by echocardiography. LV invasive hemodynamics and morphologic staining [collagen deposition, cardiomyocte hypertrophy, DNA damage (8-hydroxy-2-deoxyguanosine, 8-OHdG) and apoptosis] were performed at time of sacrifice. Cardiac malonyldialdehyde (MDA) level was measured by ELISA. No differences between 4% and 8% salt diets, in terms of blood pressure (BP) levels, heart mass index, and myocardial fibrosis were observed either in SHR or in WKY. In high salt-loaded SHR, the LV ejection fraction and wall thickness peaked at 8 weeks after salt-loading, parallel with a progressive enlargement of the LV chamber size. Furthermore, when compared to 4% salt SHR, LV functions were significantly compromised in 8% salt SHR, accompanied by more prominent cardiomyoctye hypertrophy, oxidative stress (and related DNA damage), and apoptosis. Salt-loading for 12 weeks with 8% NaCl diet is more efficient to induce LV dysfunction than 4% NaCl diet does in SHR, possibly by initiating increased oxidative stress and resultant cardiac damage. Moreover, 8 to 12 weeks after 8% salt-loading is the key time window in which a transition from compensated to decompensated LV hypertrophy occurs. PMID- 21529317 TI - Curcumin attenuates the expression and secretion of RANTES after spinal cord injury in vivo and lipopolysaccharide-induced astrocyte reactivation in vitro. AB - Curcumin has been proposed for treatment of various neuroinflammatory and neurodegenerative conditions, including post-traumatic inflammation during acute spinal cord injury (SCI). In this study, we examined whether curcumin anti inflammation involves regulation of astrocyte reactivation, with special focus on the injury-induced RANTES (regulated on expression normal T-cell expressed and secreted) from astrocytes in acute SCI. Male Sprague-Dawley (SD) rats were subjected to impact injury of the spinal cord followed by treatment with curcumin (40 mg/kg i.p.). RANTES and inducible nitric oxide synthase expression as well as RANTES-positive astrocytes were all induced by injury accompanied by the elevation of lipid peroxidation, and attenuated by the curcumin treatment. In primary cultured rat astrocytes challenged with lipopolysaccharide (LPS) to mimic astrocyte reactivation following SCI, LPS induces robust increase of RANTES expression and the effect was also reduced by 1 MUM curcumin treatment. Furthermore, cortical neurons cultured with astrocyte conditioned medium (ACM) conditioned with both LPS and curcumin (LPS-curcumin/ACM), which characteristically exhibited decreased RANTES expression when compared with ACM from astrocytes treated with LPS alone (LPS/ACM), showed higher level of cell viability and lower level of cell death as assessed by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) reduction activity assay and lactate dehydrogenase release assay, respectively. Knockdown of RANTES expression by siRNA (siRANTES) shows reduced RANTES expression and release from LPS-reactivated astrocytes, and ACM obtained from this condition (LPS-siRANTES/ACM) becomes less cytotoxic as compared with the LPS-ACM. Therefore, curcumin reduction of robust RANTES production in reactivated astrocytes both in vitro and in vivo may contribute to its neuroprotection and potential application in SCI. PMID- 21529318 TI - Novel model to investigate blast injury in the central nervous system. AB - Blast-induced neurotrauma (BINT) is a common injury modality associated with the current war efforts and increasing levels of terrorist activity. Exposure to the primary blast wave generated by explosive devices causes significant neurological deficits and is responsible for many of the war-related pathologies. Despite research efforts, the mechanism of injury is still poorly understood. To this end, we have established a novel ex vivo model for the direct observation and quantification of BINT at the tissue level. The model provides a quantifiable and reproducible method to illustrate the mechanism of BINT. Isolated sections of guinea pig spinal cord white matter were exposed to a supersonic shockwave using a blast generator with small-scaled explosives. The blast wave impact with isolated tissue was observed using focused shadowgraphy with a high-speed camera recording at 90,000 fps. Concurrently, functional deficits were measured by monitoring the production of compound action potentials using a double sucrose gap-recording chamber. Additionally, anatomical deficits were measured after blast exposure with a dye exclusion assay to visualize axonal membrane permeability. Our findings demonstrate that direct exposure to the blast wave compressed nervous tissue at a rate of 60 m/sec and led to significant functional deficits. Damage to the isolated spinal cord was marked by increased axonal permeability, suggesting rapid compression from the shockwave-generated high strain rates that resulted in membrane disruption. The model provides new insight into the mechanism of BINT and permits direct observation that may contribute to the development of appropriate treatment regimens. PMID- 21529319 TI - The impact of old age on skeletal muscle energetics: supply and demand. AB - Properly functioning skeletal muscle is critical for locomotion and performance of many activities of daily living. Muscle wasting and decreased function of skeletal muscle are important factors in many age-related morbidities. There are several pathways for generating ATP in skeletal muscle that allow adequate ATP supply to meet increased demand during muscle activity. A growing body of literature provides evidence that the aging process may be accompanied by changes in metabolic supply and demand during muscle contractions. Herein, we review a body of evidence that several pathways of ATP synthesis (anaerobic glycolysis, oxidative phosphorylation) may be impaired in aging skeletal muscle as well as several underlying molecular and cellular mechanisms. However, detrimental effects of aging on muscle energy metabolism are not universally accepted, particularly when physical inactivity is accounted for. We discuss this important concept as well as several potential countermeasures that may compress the period of morbidity in old age. In the second half of this review, we discuss how energetic demand of skeletal muscle is affected by aging, with specific focus on basal and contractile ATPase activity. PMID- 21529320 TI - Expression and regulation of excitation-contraction coupling proteins in aging skeletal muscle. AB - Functional and structural decline of the neuromuscular system is a recognized cause of decreased strength, impaired performance of daily living activities, and loss of independence in the elderly. However, in mammals, including humans, age related loss of strength is greater than loss of muscle mass, so the underlying mechanisms remain only partially understood. This review focuses on the mechanisms underlying impaired skeletal muscle function with aging, including external calcium-dependent skeletal muscle contraction; increased voltage sensitive calcium channel Cav1.1 beta1asubunit and junctional face protein JP-45 and decreased Cav1.1 (alpha1) expression, and the potential role of these and other recently discovered molecules of the muscle T-tubule/sarcoplasmic reticulum junction in excitation-contraction uncoupling. We also examined neural influences and trophic factors, particularly insulin-like growth factor-I (IGF-1). Better insight into the triad proteins' involvement in muscle ECC and nerve/muscle interactions and regulation will lead to more rational interventions to delay or prevent muscle weakness with aging. The focus of this review is on the proteins mediating excitation-contraction coupling (ECC) and their expression and regulation in humans and rodent models of skeletal muscle functional decline with aging. Age-dependent changes in proteins other than those related to ECC, muscle composition, clinical assessment and interventions, have been extensively reviewed recently [1-3]. PMID- 21529322 TI - The endocrine system and sarcopenia: potential therapeutic benefits. AB - Age related muscle loss, known as sarcopenia, is a major factor in disability, loss of mobility and quality of life in the elderly. There are many proposed mechanisms of age-related muscle loss that include the endocrine system. A variety of hormones regulate growth, development and metabolism throughout the lifespan. Hormone activity may change with age as a result of reduced hormone secretion or decreased tissue responsiveness. This review will focus on the complex interplay between the endocrine system, aging and skeletal muscle and will present possible benefits of therapeutic interventions for sarcopenia. PMID- 21529321 TI - Development of physical disability in older adults. AB - Demographers expect the number of older persons to double to 86.7 million - or to 20.6% of the US population - by the year 2050. As has occurred over the past decade, the health care costs associated with older age are expected to steadily increase approximately 2% per year causing both a public health and personal burden. A key component to reducing health care costs and maintaining well-being in older persons is preserving physical function throughout the lifespan. The challenge to this objective is to combat the origin of the loss of physical function through treatment of chronic disease conditions. Another approach is to enhance physical function despite the occurrence of comorbid conditions through enhancement of the neuromuscular system. The neuromuscular system provides the necessary components for all locomotion, and is thus a logical choice for preventative therapies to target. This article will give a general overview of the models and risk factors that explain the development of physical disability. PMID- 21529323 TI - Cellular and molecular mechanisms of apoptosis in age-related muscle atrophy. AB - Age-related muscle atrophy is due to loss of muscle fibers as well as atrophy of the remaining fibers. Evidence shows that loss of myofibers may be, in part, due to apoptosis. Two major apoptotic pathways have been extensively studied which are the mitochondrion-mediated and receptor-mediated pathways. However, other pathways exist, such as the p53 pathway. To date, it is not completely clear what pathways are responsible for loss of fibers in age-related muscle atrophy. Evidence suggests that multiple pathways may play a role. In this review article the effects of aging on the mitochondrion-, receptor-, and p53-mediated apoptotic pathways in skeletal muscle are discussed. PMID- 21529324 TI - Aging changes in satellite cells and their functions. AB - Vertebrate skeletal muscle fibers have two traits that make them unique: the fibers are multinucleated and their nuclei are post-mitotic. The activity and mass of the muscles in the body make them susceptible to constant injury. When this occurs, myonuclei can be increased or replaced by the adult stem cells of muscle, satellite cells (SCs). These SCs are vital for normal growth, repair and regeneration. This review collates recent studies to determine the size of the nuclear domains and its change with activity. The relationship between the percent change in myonuclear number, cross-sectional area, and myonuclear domain indicates that the nucleus generally maintains a highly regulated domain size in spite of large variations in fiber size. The SC divides to add nuclei for growth and repair, and the SC identification and number are discussed. It is concluded that SC number does not reflect a change in regenerative ability by the muscle. However, the SC number increases with changes in muscular activity, and any reduced number of satellite cells in the elderly does not appear to reflect a decline in reparative or regenerative ability. The effects of aging on SC function are reviewed, and the significance of the SC's connective tissue environment is emphasized as being a major factor in the decrement of the SC's ability to repair and regenerate the aging muscle. Therefore growth factors and cytokines in the connective tissue around the SC are major influences in the decline of SC function with age. PMID- 21529325 TI - Age-related changes in adult muscle morphology. AB - Skeletal muscle undergoes numerous morphological changes from early adulthood to old age including muscle size, configuration, and structure. This review discusses these changes, considers the limitations in interpreting studies, addresses the potential health implications, and describes some mechanisms and interventions to ameliorate aging-related changes in skeletal muscle. Discussion in each section focuses on measurement and analysis techniques of muscle morphology, limitations of human research, and the discussion uses animal work to support findings in humans. We examine the discrepancies in the study of fiber type distribution with age, and special emphasis is given to two topics: fiber type distribution and intra- and intercellular fat. Finally, training adaptations and health implications are briefly discussed. The focus of the current review is the morphological changes that occur in skeletal muscle during the normal aging process, with emphasis on human studies. PMID- 21529327 TI - Adaptations in motor unit behavior in elderly adults. AB - Alterations in motor unit behavior associated with aging deteriorate fine or gross motor performance. In human aging, the alterations depend on muscles and the habitual activity of each muscle. This paper will discuss the current knowledge on the adaptations in major aspects of motor unit behavior including recruitment order, mean and maximal discharge rate, synchronized discharges, oscillatory discharges, and discharge variability in elderly adults to identify unresolved problems. By considering studies on disuse in young adults and training in elderly adults, future research directions are proposed to help resolve the problems. PMID- 21529326 TI - Skeletal muscle protein balance and metabolism in the elderly. AB - The loss of lean muscle mass occurring with advancing age is termed sarcopenia. This condition often leads to a concomitant loss of strength, increased frailty and risk of falls and an overall loss of functional independence in the elderly. Muscle protein metabolism is a dynamic process characterized by the balance between the synthesis and breakdown of muscle proteins. A disturbance of this equilibrium can lead to the loss of muscle mass, and a perturbation of muscle protein turnover with aging has been proposed to play a role in the development of sarcopenia. However, basal muscle protein synthesis and breakdown rates do not differ between young and old adults, which has led to the hypothesis that older adults are resistant to anabolic stimuli. In support of this hypothesis, older adults have either no response or a blunted response to nutrients, insulin and resistance exercise, and this anabolic resistance is likely a key factor in the loss of skeletal muscle mass with aging. Recent studies have investigated potential interventions to overcome this anabolic resistance. In particular, combining resistance exercise with essential amino acid supplementation restores the muscle protein anabolic response in older men. The novel rehabilitation technique of performing light resistance exercise during blood flow restriction was also successful in overcoming the anabolic resistance to exercise. Future research is needed to determine whether these novel interventions will be successful in preventing sarcopenia and improving muscle strength and function in older adults. PMID- 21529328 TI - Motor unit and neuromuscular junction remodeling with aging. AB - The neuromuscular system is one of the largest and most vital organ systems of the body. The function and mass of the neuromuscular system gradually deteriorate during the natural process of aging. The neuromuscular system is comprised of individual motor units, each of which features a single motor neuron and all the muscle fibers it innervates. Motor units also demonstrate age-related remodeling such as reduced number, muscle fiber atrophy, but an increased number of fibers per motor unit. Enabling communication between motor neurons and the muscle fibers they innervate is a specialized synapse known as the neuromuscular junction. Aging, too, elicits remodeling of this synapse joining motor nerve terminal endings with a small ( < 0.1%) area of the muscle fiber's surface called the endplate. Aged neuromuscular junctions exhibit elevations in pre-synaptic nerve terminal branching, and in the post-synaptic distribution of receptor sites for neurotransmitter. This anatomical remodeling is coupled with age-related neurophysiological alterations including increased quantal content, with a more rapid rundown of endplate potential strength during continuous stimulation of the pre-synaptic neuron. Moreover, there is a growing body of evidence indicating that aging impacts the capacity of the NMJ to adapt to increased, as well as decreased physical activity. Because of the marked increase in the number of people considered to be aged in industrialized countries, it is essential to expand our understanding of the influence of aging on the neuromuscular system, its constituent motor units, and the neuromuscular junctions which allow neural cells and muscle fibers to effectively work together. PMID- 21529330 TI - Aldosterone, from (patho)physiology to treatment in cardiovascular and renal damage. AB - Aldosterone, a steroid hormone with mineralocorticoid activity, is far more than merely a salt-and-water hormone. Aldosterone has a number of non-classical, mineralocorticoid receptor (MR)-mediated actions, including tissue remodeling, modulation of vascular tone and stimulating inflammation and fibrosis, which may fuel progression of end organ damage. Aldosterone breakthrough during blockade of the renin-angiotensin aldosterone system (RAAS) may explain why this treatment regimen only confers partial cardiovascular and renal protection. Of major interest, aldosterone is deleterious only if inappropriately high for its sodium status i.e. high aldosterone and high sodium. The mechanism of sodium dependence of aldosterone-induced renal and cardiovascular damage continues to fascinate. Aldosterone excess increases sodium and fluid retention and consequently increases blood pressure, which, in turn, mediates target organ damage. Moreover, blood pressure independent effects play a role with dissociation of low circulating and high tissue aldosterone levels during high sodium intake and possibly enhanced MR signaling. MR blockade is a valuable strategy, which has potency to halt the progressive end organ damage as observed during current treatments. In heart failure, MR blockade on top of RAAS blockade reduces hard clinical endpoints. Despite encouraging results on the intermediate endpoint proteinuria, long-term data on the efficacy and safety of MR blockade in preventing dialysis and/or cardiovascular endpoints in chronic kidney disease are still lacking. It is obligatory that future clinical studies on the effects of MR blockade on end-organ damage take into account the sodium status. PMID- 21529329 TI - Age-related changes in motor cortical properties and voluntary activation of skeletal muscle. AB - Aging is associated with dramatic reductions in muscle strength and motor control, and many of these agerelated changes in muscle function result from adaptations in the central nervous system. Aging is associated with widespread qualitative and quantitative changes of the motor cortex. For example, advancing age has been suggested to result in cortical atrophy, reduced cortical excitability, reduced cortical plasticity, as well as neurochemical abnormalities.The associated functional effects of these changes likely influence numerous aspects of muscle performance such as muscle strength and motor control. For example, there is evidence to suggest that the muscle weakness associated with aging is partially due to impairments in the nervous system's ability to fully activate motor neurons- particularly in the larger proximal muscle groups. In this review article we discuss age-related changes in the motor cortex, as well as the abilityor lack thereof- of older adults to voluntarily activate skeletal muscle. We also provide perspectives on scientific and clinical questions that need to be addressed in the near future. PMID- 21529331 TI - Lipoprotein(a): current perspectives. AB - Recent data from genetic and epidemiological studies strongly support a causal relationship between elevated lipoprotein(a) [Lp(a)] concentrations and the development of atherosclerosis and cardiovascular disease. This relationship is continuous, without an Lp(a) threshold, and it is independent of low density lipoprotein and high density lipoprotein cholesterol (LDL-C and HDL-C, respectively) levels. Although the mechanism(s) through which Lp(a) promotes atherosclerosis are not clearly understood, proposed mechanisms include an increased Lp(a)-associated cholesterol entrapment in the arterial intima, inflammatory cell recruitment, carrying of proinflammatory oxidized phospholipids, impairing fibrinolysis by inhibition of plasminogen activation and enhancing coagulation by inhibition of the tissue factor pathway inhibitor. Phenotypically there are two forms, isolated hyperlipoproteinemia(a) in the presence of normal LDL-C, and combined elevations of Lp(a) and LDL-C. There are no drugs or other therapeutic options available that selectively decrease Lp(a). Those that can lower Lp(a) levels only have a moderate effect and their actions include decreasing LDL-C levels. The strongest effects are seen with niacin at high doses. Nevertheless, there is no convincing evidence that decreasing isolated elevations of Lp(a) offers cardiovascular benefit. This review considers the evidence supporting the association between Lp(a) and atherosclerotic disease, discusses the potential mechanisms involved in the pro-atherosclerotic potential of Lp(a), and evaluates the therapeutic options that decrease elevated Lp(a) levels. PMID- 21529332 TI - Green nanotechnology of trends in future energy. AB - It is well known that current fossil fuel usage is unsustainable and associated with greenhouse gas production. The amount of the world's primary energy supply provided by renewable energy technologies is required urgently. Therefore, the relevant technologies such as hydrogen fuel, solar cell, biotechnology based on nanotechnology and the relevant patents for exploiting the future energy for the friendly environment are reviewed. At the same time, it is pointed out that the significantly feasible world's eco-energy for the foreseeable future should not only be realized, but also methods for using the current energy and their by products more efficiently should be found correspondingly to ensure the minimal environmental impact. PMID- 21529333 TI - Development of natural zeolites for their use in water-treatment systems. AB - This paper gives an overview of research and patents concerning the use of natural zeolites in water-treatment systems in the last ten years. Furthermore, nanocomposite materials made of natural zeolites and organic and polymeric materials are also mentioned as an effective solution in water treatment. An additional emphasis is put on a variety of possibilities for further application of natural zeolite materials for environment protection and preservation. PMID- 21529334 TI - Copper metallization for current very large scale integration. AB - As silicon technology scaling progresses to the 32 nm node or even further, the design on the propagation of electromagnetic signals becomes increasingly appealing due to their unyielding constraints on interconnect delay. Because of its high conductivity and electromigration resistance, Cu is now the interconnect materials in current VLSI. To ensure the signal propagation via the Cu interconnects upon the increasingly reduction in the interconnect width, related issues on Cu interconnects, such as electron scattering at surfaces and grain boundaries, electromigration failure and surface oxidation, still need to be further understood and addressed. Besides this, the performance of low-k dielectrics and reliable barrier structures, which are also much important among the device parts, are required to be further improved to minimize the signal delay and to prevent penetration of different materials, respectively. On the basis of the paper published at Recent Patent on Nanotechnology 2007; 1: 193-209, this review will focus on recent patents and some studies on Cu metallization including Cu interconnect wires, low-k dielectrics and related barrier materials as well as manufacturing techniques in VLSI, which are one of the most essential concerns in microelectronic industry and decide further development of VLSI. This review will benefit for the design of the Cu metallization in the current VLSI. PMID- 21529335 TI - Tumor necrosis factor inhibitors from poxviruses with an emphasis on tanapoxvirus 2L protein. AB - Viruses have evolved strategies to counteract host defenses. Some tactics employ viral proteins to neutralize host immune effector proteins such as cytokines, chemokines and their receptors, which help coordinate the host responses against the virus. Tumor necrosis factor (TNF) is one of the crucial pro inflammatory/anti-viral cytokines involved in inflammatory and autoimmune diseases. Poxvirus anti-immune proteins represent some of the most complex and efficient mechanisms of regulating TNF and its pathological effects. These proteins have considerable potential for treating TNF-related diseases. Here we discuss two major classes of poxvirus-TNF inhibitors focusing on the tanapoxvirus (TPV)-2L protein, previously called TPV-gp38. TPV-2L has been shown to interact and biologically neutralize human (h)TNF, and has been indirectly associated with the inhibition of other cytokines (hIFN-gamma, hIL-2 and hIL-5). The TPV-2L protein alone has been expressed, purified and shown to bind with high affinity to hTNF, but lacked binding to the other cytokines. Further studies identified sequential binding of hbeta2-microglobulin and halpha2-macroglobulin to TPV-2L. The ability of a single viral protein to form multi-protein complexes suggests that TPV might also possess other novel strategies of evading the immune system. Reviewed here are patented poxvirus TNF-binding proteins and their genes to evaluate their potential therapeutic value. PMID- 21529336 TI - MicroRNAs patents: the road from bench to bedsides for cancer treatment. AB - MicroRNAs are a class of non-coding small RNAs, which posttranscriptionally regulate gene expression through mainly binding to 3' untranslated region of mRNA. Most microRNAs are evolutionally conserved cross species; whereas, novel microRNAs expressed in different organisms are also identified with next generation sequencing technology. MicroRNAs play crucial roles in development, stem cells self-renewal, apoptosis and cell cycle. Aberrant microRNA expression in cancer and other diseases has been extensively investigated; the specific microRNAs have been developed for cancer diagnosis, prediction of drug-response and therapeutic outcome. Given the roles of microRNAs in pathophysiological conditions, it is conceivable that development of "miR-drugs" with different strategies (miR mimics, anti-miR, small molecule inhibitors of specific miRs) provides great hope to fight against cancer in combination of conventional treatment. In this review, the course of microRNA research to understand cancer biology is briefly introduced, the translation of miRNA studies from bench to bedside, particularly, microRNA implication in cancer with patents for diagnosis, prognosis will be described; the current status and challenges of "miR-drugs" development will be discussed. PMID- 21529337 TI - Recent patents on biclustering algorithms for gene expression data analysis. AB - In DNA microarray experiments, discovering groups of genes that share similar transcriptional characteristics is instrumental in functional annotation, tissue classification and motif identification. However, in many situations a subset of genes only exhibits a consistent pattern over a subset of conditions. Although used extensively in gene expression data analysis, conventional clustering algorithms that consider the entire row or column in an expression matrix can therefore fail to detect useful patterns in the data. Recently, biclustering has been proposed as a powerful computational tool to detect subsets of genes that exhibit consistent pattern over subsets of conditions. In this article, we review several recent patents in bicluster analysis, and in particular, highlight a recent patent from our group about a novel geometric-based biclustering method that handles the class of bicluster patterns with linear coherent variation across the row and/or column dimension. This class of bicluster patterns is of particular importance since it subsumes all constant, additive, and multiplicative bicluster patterns normally used in gene expression data analysis. PMID- 21529338 TI - A reporter platform for the monitoring of in vivo conformational changes in AcrB. AB - AcrB is an inner membrane protein in Escherichia coli that is a component of a triplex AcrA-AcrB-TolC (AcrAB-TolC) multidrug efflux pump. The AcrAB-TolC complex and its homologues are highly conserved among Gram-negative bacteria and are major players in conferring multidrug resistance (MDR) in many pathogens. In this study we developed a disulfide trapping method that may reveal AcrB conformational changes under the native condition in the cell membrane. Specifically, we created seven disulfide bond pairs in the periplasmic domain of AcrB, which can be used as probes to determine local conformational changes. We have developed a rigorous protocol to measure the extent of disulfide bond formation in membrane proteins under the native condition. The rigorousness of the method was verified through examining the extent of disulfide bond formation in Cys pairs separated by different distances. The blocking-reducing-labeling scheme combined with fluorescence labeling made the current method convenient, reliable, and quantitative. PMID- 21529339 TI - Investigation by fluorescence spectroscopy, resonance rayleigh scattering and zeta potential approaches of the separate and simultaneous binding effect of Paclitaxel and estradiol with human serum albumin. AB - Separate and simultaneous binding effects of paclitaxel (a drug with anti-tumor activity) and estradiol (used for treating multiple maladies) with human serum albumin (HSA) were investigated by fluorescence quenching, UV absorption, circular dichroism, zeta potential and molecular dynamic techniques. An extensive fluorescence quenching was observed during the reaction of drugs and HSA and was rationalized in terms of a static quenching mechanism. The molecular distances between the donor (HSA) and acceptors (paclitaxel or estradiol) in binary and ternary systems were estimated according to Forster's theory of dipole-dipole non radiation energy transfer. The features of drug-induced structural disturbances of HSA have been studied in detail by synchronous fluorescence and circular dichroism (CD) analysis. The resonance Rayleigh scattering (RRS) intensities were proportional to the paclitaxel and estradiol concentrations in the range of respectively (0-8)*10(-6) and (0-1)*10(-4) mM in binary systems. The critical induced aggregation concentrations (C(CIAC)) of paclitaxel and estradiol for binary and ternary systems were determined by nonlinear relationships between the enhancement of the RRS intensities and the drug concentrations. A comparison between binary and ternary systems for two drugs allowed us to estimate the effect of a drug on the initial formation aggregation of the second drug. The zeta potential results were used to verify the existence of complexation and confirmed the C(CIAC) values obtained by the RRS technique. This phenomenon was supported by a progressive rise of the protein charge to a reversal point as a consequence of drug binding. The quantitative analysis data of circular dichroism (CD) spectra demonstrated that the binding of paclitaxel and/or estradiol to HSA induced conformational changes in HSA. Moreover, the alpha-helix content in HSA greatly decreased in the presence of paclitaxel as opposed when estradiol was present. Protein-ligand docking suggested that estradiol bound to residues situated in subdomain IIA of HSA. On the other hand, in the ternary system, the presence of the first drug decreased the binding affinity of the second drug to HSA. Therefore binding effects of paclitaxel and estradiol with HSA alone have different behavior than simultaneous interaction. PMID- 21529340 TI - The water effect on the kinetic of the bovine liver catalase. AB - Catalase is an enzyme that occurs in almost all aerobic organisms. Its main metabolic function is to prevent oxidative damage to tissues induced by hydrogen peroxide which is a strong oxidizing agent. Catalase is very effective in performing this task, since it has the highest turnover rate among all the enzymes. The properties of catalase have been investigated extensively for many years; however, the role of the solvent molecules in the catalytic reaction of this enzyme has not yet been investigated. Therefore, the objective of this work was to investigate the contribution of the solvent molecules on the catalytic reaction of bovine liver catalase with its substrate H2O2 by the osmotic stress method. As a probe for protein structural changes in solution, the differential number of water molecules released during the transition from free to bound form of the enzyme was measured. These assays were correlated with protein structural data provided by the SAXS technique and crystallographic structures of free and CN(-) bonded enzymes. The results showed that the difference in surface accessible area of the crystal structures does not reflect the variation that is observed in solution. Moreover, catalase is not influenced by the solvent during the catalytic reaction, which represents a lower energy barrier to be crossed in the overall energetics of the reaction, a fact that contributes to the high turnover rate of catalase. PMID- 21529341 TI - SemiHS: an iterative semi-supervised approach for predicting protein-protein interaction hot spots. AB - Protein-protein interaction hot spots, as revealed by alanine scanning mutagenesis, make dominant contributions to the free energy of binding. Since mutagenesis experiments are expensive and time-consuming, the development of computational methods to identify hot spots is becoming increasingly important. In this study, by using a new combination of sequence, structure and energy features, we propose an iterative semi-supervised algorithm, SemiHS, to incorporate unlabeled data to improve the accuracy of hot spots prediction when sufficient training data is un-available and to overcome the imbalanced data problem. We evaluate the predictive power of SemiHS on a labeled set of 265 alanine-mutated interface residues in 17 complexes and a large unlabeled set of 2465 interface residues with 10-fold cross validation, and get an AUC score of 0.85, with a sensitivity of 0.70 and a specificity of 0.87, which are better than those of the existing methods. Moreover, we validate the proposed method by an independent test and obtain encouraging results. PMID- 21529342 TI - QSAR study on MHC class I a alleles based on the novel parameters of amino acids. AB - MHC-epitope binding plays a key role in the cellular immune response. Accurate prediction of MHC-epitope binding affinity can greatly expedite epitope screening by reducing costs and experimental effort. In this paper, 13 T descriptors, which derived from 544 physicochemical properties of the natural amino acids, were used to characterize 4 MHC class I alleles epitope peptide sequences, the optimal QSAR models were constructed by using stepwise regression combines with multiple linear regression (STR-MLR). For HLA-A*0201, HLA-A*0203, HLA-A*0206 and HLA A*1101 alleles, the leave one out cross validation values (Q(2)(train)) were 0.581, 0.553, 0.525 and 0.588, the correlation coefficients (R(2)(train)) of training datasets were 0.607, 0.582, 0.556 and 0.606, the correlation coefficients (R(2)(test)) of test datasets were 0.533, 0.506, 0.501 and 0.502, respectively. The results showed that all models can obtain good performance for prediction and explain the mechanism of interaction between MHC and epitope. The descriptors will be useful in structure characterization and activity prediction of peptide sequences. PMID- 21529343 TI - A novel method to predict protein-protein interactions based on the information of protein-protein interaction networks and protein sequence. AB - Protein-protein interactions (PPIs) are crucial to most biochemical processes in human beings. Although many human PPIs have been identified by experiments, the number is still limited compared to the available protein sequences of human organisms. Recently, many computational methods have been proposed to facilitate the recognition of novel human PPIs. However the existing methods only concentrated on the information of individual PPI, while the systematic characteristic of protein-protein interaction networks (PINs) was ignored. In this study, a new method was proposed by combining the global information of PINs and protein sequence information. Random forest (RF) algorithm was implemented to develop the prediction model, and a high accuracy of 91.88% was obtained. Furthermore, the RF model was tested using three independent datasets with good performances, suggesting that our method is a useful tool for identification of PPIs and investigation into PINs as well. PMID- 21529344 TI - Coverage of intermittent prevention treatment with sulphadoxine-pyrimethamine among pregnant women and congenital malaria in Cote d'Ivoire. AB - BACKGROUND: The World Health Organization (WHO) recommends using insecticide treated mosquito nets (ITNs) and intermittent preventive treatment with sulphadoxine-pyrimethamine (IPT-SP) to prevent malaria in sub-Saharan Africa. Data on IPT-SP coverage and factors associated with placental malaria parasitaemia and low birth weight (LBW) are scarce in Cote d'Ivoire. METHODS: A multicentre, cross-sectional survey was conducted in Cote d'Ivoire from March to September 2008 at six urban and semi-urban antenatal clinics. Standardized forms were used to collect the demographic information and medical histories of women and their offspring. IPT-SP coverage (>=2 doses) as well as placental and congenital malaria prevalence parasitaemia were estimated. Regression logistics were used to study factors associated with placental malaria and LBW (birth weight of alive babies < 2,500 grams). RESULTS: Overall, 2,044 women with a median age of 24 years were included in this study. Among them 1017 (49.8%) received >=2 doses of IPT-SP and 694 (34.0%) received one dose. A total of 99 mothers (4.8%) had placental malaria, and of them, four cases of congenital malaria were diagnosed. Factors that protected from maternal placental malaria parasitaemia were the use of one dose (adjusted odds ratio (aOR), 0.32; 95%CI: 0.19-0.55) or >=2 doses IPT-SP (aOR: 0.18; 95%CI: 0.10-0.32); the use of ITNs (aOR: 0.47; 95%CI: 0.27-0.82). LBW was associated with primigravidity and placental malaria parasitaemia. CONCLUSION: IPT-SP decreases the rate of placental malaria parasitaemia and has a strong dose effect. Despite relatively successful IPT-SP coverage in Cote d'Ivoire, substantial commitments from national authorities are urgently required for such public health campaigns. Strategies, such as providing IPT-SP free of charge and directly observing treatment, should be implemented to increase the use of IPT-SP as well as other prophylactic methods. PMID- 21529345 TI - Persistent work-life conflict and health satisfaction - a representative longitudinal study in Switzerland. AB - BACKGROUND: The objectives of the present study were (1) to track work-life conflict in Switzerland during the years 2002 to 2008 and (2) to analyse the relationship between work-life conflict and health satisfaction, examining whether long-term work-life conflict leads to poor health satisfaction. METHODS: The study is based on a representative longitudinal database (Swiss Household Panel), covering a six-year period containing seven waves of data collection. The sample includes 1261 persons, with 636 men and 625 women. Data was analysed by multi-level mixed models and analysis of variance with repeated measures. RESULTS: In the overall sample, there was no linear increase or decrease of work life conflict detected, in either its time-based or strain-based form. People with higher education were more often found to have a strong work-life conflict (time- and strain-based), and more men demonstrated a strong time-based work-life conflict than women (12.2% vs. 5%). A negative relationship between work-life conflict and health satisfaction over time was found. People reporting strong work-life conflict at every wave reported lower health satisfaction than people with consistently weak work-life conflict. However, the health satisfaction of those with a continuously strong work-life conflict did not decrease during the study period. CONCLUSIONS: Both time-based and strain-based work-life conflict are strongly correlated to health satisfaction. However, no evidence was found for a persistent work-life conflict leading to poor health satisfaction. PMID- 21529346 TI - Murine immune responses to a Plasmodium vivax-derived chimeric recombinant protein expressed in Brassica napus. AB - BACKGROUND: To develop a plant-based vaccine against Plasmodium vivax, two P. vivax candidate proteins were chosen. First, the merozoite surface protein-1 (MSP 1), a major asexual blood stage antigen that is currently considered a strong vaccine candidate. Second, the circumsporozoite protein (CSP), a component of sporozoites that contains a B-cell epitope. METHODS: A synthetic chimeric recombinant 516 bp gene encoding containing PvMSP-1, a Pro-Gly linker motif, and PvCSP was synthesized; the gene, named MLC, encoded a total of 172 amino acids. The recombinant gene was modified with regard to codon usage to optimize gene expression in Brassica napus. The Ti plasmid inducible gene transfer system was used for MLC chimeric recombinant gene expression in B. napus. Gene expression was confirmed by polymerase chain reaction (PCR), beta-glucuronidase reporter gene (GUS) assay, and Western blot. RESULTS: The MLC chimeric recombinant protein expressed in B. napus had a molecular weight of approximately 25 kDa. It exhibited a clinical sensitivity of 84.21% (n=38) and a clinical specificity of 100% (n=24) as assessed by enzyme-linked immunosorbent assay (ELISA). Oral immunization of BALB/c mice with MLC chimeric recombinant protein successfully induced antigen-specific IgG1 production. Additionally, the Th1-related cytokines IL-12 (p40), TNF, and IFN-gamma were significantly increased in the spleens of the BALB/c mice. CONCLUSIONS: The chimeric MLC recombinant protein produced in B. napus has potential as both as an antigen for diagnosis and as a valuable vaccine candidate for oral immunization against vivax malaria. PMID- 21529347 TI - DX5+NKT cells display phenotypical and functional differences between spleen and liver as well as NK1.1-Balb/c and NK1.1+ C57Bl/6 mice. AB - BACKGROUND: Natural killer T cells represent a linkage between innate and adaptive immunity. They are a heterogeneous population of specialized T lymphocytes composed of different subsets. DX5+NKT cells are characterized by expression of the NK cell marker DX5 in the context of CD3. However, little is known about the phenotype and functional capacity of this unique cell population. Therefore, we investigated the expression of several T cell and NK cell markers, as well as functional parameters in spleen and liver subsets of DX5+NKT cells in NK1.1- Balb/c mice and compared our findings to NK1.1+ C57Bl/6 mice. RESULTS: In the spleen 34% of DX5+NKT cells expressed CD62L and they up-regulated the functional receptors CD154 as well as CD178 upon activation. In contrast, only a few liver DX5+NKT cells expressed CD62L, and they did not up-regulate CD154 upon activation. A further difference between spleen and liver subsets was observed in cytokine production. Spleen DX5+NKT cells produced more Th1 cytokines including IL-2, IFN-gamma and TNF-alpha, while liver DX5+NKT cells secreted more Th2 cytokines (e.g. IL-4) and even the Th17 cytokine, IL-17a. Furthermore, we found inter-strain differences. In NK1.1+ C57Bl/6 mice DX5+NKT cells represented a distinct T cell population expressing less CD4 and more CD8. Accordingly, these cells showed a CD178 and Th2-type functional capacity upon activation. CONCLUSION: These results show that DX5+NKT cells are a heterogeneous population, depending on the dedicated organ and mouse strain, that has diverse functional capacity. PMID- 21529348 TI - Cellular transcripts regulated during infections with Highly Pathogenic H5N1 Avian Influenza virus in 3 host systems. AB - BACKGROUND: Highly pathogenic Avian Influenza (HPAI) virus is able to infect many hosts and the virus replicates in high levels in the respiratory tract inducing severe lung lesions. The pathogenesis of the disease is actually the outcome of the infection as determined by complex host-virus interactions involving the functional kinetics of large numbers of participating genes. Understanding the genes and proteins involved in host cellular responses are therefore, critical for the elucidation of the mechanisms of infection. METHODS: Differentially expressed transcripts regulated in a H5N1 infections of whole lung organ of chicken, in-vitro chick embryo lung primary cell culture (CeLu) and a continuous Madin Darby Canine Kidney cell line was undertaken. An improved mRNA differential display technique (Gene FishingTM) using annealing control primers that generates reproducible, authentic and long PCR products that are detectable on agarose gels was used for the identification of differentially expressed genes (DEGs). Seven of the genes have been selected for validation using a TaqMan(r) based real time quantitative PCR assay. RESULTS: Thirty seven known and unique differentially expressed genes from lungs of chickens, CeLu and MDCK cells were isolated. Among the genes isolated and identified include heat shock proteins, Cyclin D2, Prenyl (decaprenyl) diphosphate synthase, IL-8 and many other unknown genes. The quantitative real time RT-PCR assay data showed that the transcription kinetics of the selected genes were clearly altered during infection by the Highly Pathogenic Avian Influenza virus. CONCLUSION: The Gene FishingTM technique has allowed for the first time, the isolation and identification of sequences of host cellular genes regulated during H5N1 virus infection. In this limited study, the differentially expressed genes in the three host systems were not identical, thus suggesting that their responses to the H5N1 infection may not share similar mechanisms and pathways. PMID- 21529350 TI - KBWS: an EMBOSS associated package for accessing bioinformatics web services. AB - The availability of bioinformatics web-based services is rapidly proliferating, for their interoperability and ease of use. The next challenge is in the integration of these services in the form of workflows, and several projects are already underway, standardizing the syntax, semantics, and user interfaces. In order to deploy the advantages of web services with locally installed tools, here we describe a collection of proxy client tools for 42 major bioinformatics web services in the form of European Molecular Biology Open Software Suite (EMBOSS) UNIX command-line tools. EMBOSS provides sophisticated means for discoverability and interoperability for hundreds of tools, and our package, named the Keio Bioinformatics Web Service (KBWS), adds functionalities of local and multiple alignment of sequences, phylogenetic analyses, and prediction of cellular localization of proteins and RNA secondary structures. This software implemented in C is available under GPL from http://www.g-language.org/kbws/ and GitHub repository http://github.com/cory-ko/KBWS. Users can utilize the SOAP services implemented in Perl directly via WSDL file at http://soap.g language.org/kbws.wsdl (RPC Encoded) and http://soap.g-language.org/kbws_dl.wsdl (Document/literal). PMID- 21529349 TI - Detection and differentiation of Borrelia burgdorferi sensu lato in ticks collected from sheep and cattle in China. AB - BACKGROUND: Lyme disease caused by Borrelia burgdorferi sensu lato complex is an important endemic zoonosis whose distribution is closely related to the main ixodid tick vectors. In China, isolated cases of Lyme disease infection of humans have been reported in 29 provinces. Ticks, especially ixodid ticks are abundant and a wide arrange of Borrelia natural reservoirs are present. In this study, we developed a reverse line blot (RLB) to identify Borrelia spp. in ticks collected from sheep and cattle in 7 Provinces covering the main extensive livestock regions in China. RESULTS: Four species-specific RLB oligonucleotide probes were deduced from the spacer region between the 5S-23S rRNA gene, along with an oligonucleotide probe which was common to all. The species specific probes were shown to discriminate between four genomic groups of B. burgdorferi sensu lato i.e. B. burgdorferi sensu stricto, B. garinii, B. afzelii, and B. valaisiana, and to bind only to their respective target sequences, with no cross reaction to non target DNA. Furthermore, the RLB could detect between 0.1 pg and 1 pg of Borrelia DNA.A total of 723 tick samples (Haemaphysalis, Boophilus, Rhipicephalus and Dermacentor) from sheep and cattle were examined with RLB, and a subset of 667 corresponding samples were examined with PCR as a comparison. The overall infection rate detected with RLB was higher than that of the PCR test.The infection rate of B. burgdoreri sensu stricto was 40% in south areas; while the B. garinii infection rate was 40% in north areas. The highest detection rates of B. afzelii and B. valaisiana were 28% and 22%, respectively. Mixed infections were also found in 7% of the ticks analyzed, mainly in the North. The proportion of B. garinii genotype in ticks was overall highest at 34% in the whole investigation area. CONCLUSION: In this study, the RLB assay was used to detect B. burgdorferi sensu lato in ticks collected from sheep and cattle in China. The results showed that B. burdorferi senso stricto and B. afzelii were mainly distributed in the South; while B. garinii and B. valaisiana were dominant in the North. Borrelia spirochaetes were detected in Rhipicephalus spp for the first time. It is suggested that the Rhipicephalus spps might play a role in transmitting Borrelia spirochaetes. PMID- 21529351 TI - Inhibin secretion in women with the polycystic ovary syndrome before and after treatment with progesterone. AB - OBJECTIVES: It has been suggested that inhibin secretion is altered in women with the polycystic ovary syndrome (PCOS). However, the contribution of a preceding luteal phase has not been taken into account. The aim of the present study was to investigate whether progesterone in the context of a simulated luteal phase affects basal and FSH-induced inhibin secretion in women with PCOS and elevated LH. METHODS: Ten women with PCOS and 8 normally cycling women participated in an experimental procedure (Exp) involving the administration of a single injection of recombinant FSH (450 IU sc). In the women with PCOS, the procedure was performed before (Exp 1) and after a 20-day treatment with progesterone (Exp 2), while in the normal women on day 2 of the cycle (Exp 3). Inhibin A and B levels were measured in blood samples taken before and 24 hours after the FSH injection. RESULTS: Basal LH levels were significantly higher and inhibin A levels were significantly lower in the PCOS group compared to the control group, while inhibin B levels were comparable in the two groups. In the PCOS group, after treatment with progesterone inhibin A and LH but not inhibin B levels decreased significantly (p < 0.05). After the FSH injection, inhibin A and B levels increased significantly in the women with PCOS (Exp 1 and Exp 2) but not in the control women (Exp 3). CONCLUSIONS: In women with PCOS, as compared to control women, the dissimilar pattern of inhibin A and inhibin B secretion in response to FSH appears to be independent of a preceding simulated luteal phase. It is possible that compared to normal ovaries, the PCOS ovaries are less sensitive to endogenous LH regarding inhibin A secretion and more sensitive to exogenous FSH stimulation in terms of inhibin A and inhibin B secretion. PMID- 21529352 TI - WEE1 inhibition sensitizes osteosarcoma to radiotherapy. AB - BACKGROUND: The use of radiotherapy in osteosarcoma (OS) is controversial due to its radioresistance. OS patients currently treated with radiotherapy generally are inoperable, have painful skeletal metastases, refuse surgery or have undergone an intralesional resection of the primary tumor. After irradiation induced DNA damage, OS cells sustain a prolonged G(2) cell cycle checkpoint arrest allowing DNA repair and evasion of cell death. Inhibition of WEE1 kinase leads to abrogation of the G(2) arrest and could sensitize OS cells to irradiation induced cell death. METHODS: WEE1 expression in OS was investigated by gene-expression data analysis and immunohistochemistry of tumor samples. WEE1 expression in OS cell lines and human osteoblasts was investigated by Western blot. The effect of WEE1 inhibition on the radiosensitivity of OS cells was assessed by cell viability and caspase activation analyses after combination treatment. The presence of DNA damage was visualized using immunofluorescence microscopy. Cell cycle effects were investigated by flow cytometry and WEE1 kinase regulation was analyzed by Western blot. RESULTS: WEE1 expression is found in the majority of tested OS tissue samples. Small molecule drug PD0166285 inhibits WEE1 kinase activity. In the presence of WEE1-inhibitor, irradiated cells fail to repair their damaged DNA, and show higher levels of caspase activation. The inhibition of WEE1 effectively abrogates the irradiation-induced G(2) arrest in OS cells, forcing the cells into premature, catastrophic mitosis, thus enhancing cell death after irradiation treatment. CONCLUSION: We show that PD0166285, a small molecule WEE1 kinase inhibitor, can abrogate the G(2) checkpoint in OS cells, pushing them into mitotic catastrophe and thus sensitizing OS cells to irradiation-induced cell death. This suggests that WEE1 inhibition may be a promising strategy to enhance the radiotherapy effect in patients with OS. PMID- 21529353 TI - Parallel evolution controlled by adaptation and covariation in ammonoid cephalopods. AB - BACKGROUND: A major goal in evolutionary biology is to understand the processes that shape the evolutionary trajectory of clades. The repeated and similar large scale morphological evolutionary trends of distinct lineages suggest that adaptation by means of natural selection (functional constraints) is the major cause of parallel evolution, a very common phenomenon in extinct and extant lineages. However, parallel evolution can result from other processes, which are usually ignored or difficult to identify, such as developmental constraints. Hence, understanding the underlying processes of parallel evolution still requires further research. RESULTS: Herein, we present a possible case of parallel evolution between two ammonoid lineages (Auguritidae and Pinacitidae) of Early-Middle Devonian age (405-395 Ma), which are extinct cephalopods with an external, chambered shell. In time and through phylogenetic order of appearance, both lineages display a morphological shift toward more involute coiling (i.e. more tightly coiled whorls), larger adult body size, more complex suture line (the folded walls separating the gas-filled buoyancy-chambers), and the development of an umbilical lid (a very peculiar extension of the lateral shell wall covering the umbilicus) in the most derived taxa. Increased involution toward shells with closed umbilicus has been demonstrated to reflect improved hydrodynamic properties of the shell and thus likely results from similar natural selection pressures. The peculiar umbilical lid might have also added to the improvement of the hydrodynamic properties of the shell. Finally, increasing complexity of suture lines likely results from covariation induced by trends of increasing adult size and whorl overlap given the morphogenetic properties of the suture. CONCLUSIONS: The morphological evolution of these two Devonian ammonoid lineages follows a near parallel evolutionary path for some important shell characters during several million years and through their phylogeny. Evolution of some traits (involution, umbilical lid) appears to be mainly driven by adaptation to improve the hydrodynamic properties of the shell, whereas other characters (sutural complexity) evolved due to covariation with features that play a central role in the morphogenesis of mollusc shells. This example provides evidence that parallel evolution can be driven simultaneously by different factors such as covariation (constructional constraints) and adaptation (natural selection). PMID- 21529354 TI - Viscoat versus Visthesia during phacoemulsification cataract surgery: corneal and foveal changes. AB - BACKGROUND: Ophthalmic viscosurgical devices (OVDs) are widely used in phacoemulsification cataract surgery to maintain adequate intraocular space, stabilize ocular tissue during the operation and decrease the possible damage of the corneal endothelium. Our study has the purpose to compare the corneal and foveal changes of Viscoat and Visthesia in patients undergoing uneventful phacoemulsification cataract surgery. METHODS: Participants in our study were 77 consecutive patients, who were randomized into two groups based on type of OVD used during phacoemulsification: Viscoat or Visthesia. All patients underwent a complete ophthalmological examination i.e., measurement of best corrected visual acuity (BCVA) by means of Snellen charts, intraocular pressure examination by Goldmann tonometry, slit lamp examination, fundus examination, optical coherence tomography, specular microscopy and ultrasound pachymetry preoperatively and at three time points postoperatively (day 3, 15, 28 postoperatively). The differences in baseline characteristics, as well as in outcomes between the two groups were compared by Mann-Whitney-Wilcoxon test and Student's t-test, as appropriate. RESULTS: Intraoperatively, there was no statistically significant difference in the duration of the ultrasound application between the two groups, while Viscoat group needed more time for the operation performance. It is also worthy to mention that Visthesia group exhibited less intense pain than patients in Viscoat group. Postoperatively, there was a statistically significant difference in central corneal thickness, endothelial cell count and macular thickness between the two groups, but BCVA (logMAR) did not differ between the two groups. CONCLUSIONS: Our study suggests that Viscoat is more safe and protective for the corneal endothelium during uneventful phacoemulsification cataract surgery, while Visthesia is in superior position regarding intraoperative pain. Patients of both groups acquired excellent visual acuity postoperative. Finally, this is the first study comparing OVDs in terms of macular thickness, finding that Visthesia cause a greater increase in macular thickness postoperatively than Viscoat, although it reaches normal ranges in both groups. PMID- 21529355 TI - Prevalence of antibody to Trypanosoma cruzi in Hispanic-surnamed patients seen at Parkland Health & Hospital System, Dallas, Texas. AB - BACKGROUND: Chagas disease constitutes an important public health threat in terms of morbidity and mortality in the areas in the United States where immigrant populations from Latin America are conspicuous. We conducted a survey to assess the prevalence of anti-T. cruzi antibody in Hispanic-surnamed patients seen at Parkland Memorial Hospital in Dallas, Texas. FINDINGS: Five hundred serum specimens from Hispanic-surnamed patients were tested by a preliminary ELISA method. On a subset of 50 sera confirmatory testing was also performed using an alternative ELISA, indirect immunofluorescence, and TESA immunoblot. For 274 of 500 Hispanic-surnamed patients, we were able to ascertain immigration status upon medical chart review. Of the 274 sera analyzed, one sample tested as positive for anti-T. cruzi antibody by the preliminary ELISA, and by the three confirmatory methods. CONCLUSIONS: The goal of this study is to increase the awareness of T. cruzi infection and Chagas disease in areas where the Latin American immigrant communities are growing. Our study highlights the importance of testing for Chagas disease in the populations most at risk, and the need for current data on the actual seroprevalence in areas where such immigrant populations are conspicuous. Larger-scale epidemiologic surveys on Chagas disease in the immigrant communities from Latin America are warranted. PMID- 21529356 TI - A pilot histomorphology and hemodynamic of vasculogenic mimicry in gallbladder carcinomas in vivo and in vitro. AB - BACKGROUND: Vasculogenic mimicry (VM), as a new blood supply for tumor growth and hematogenous metastases, has been recently described in highly aggressive human melanoma cells, etc. We previously reported VM in human gallbladder carcinomas and its clinical significance. In this study, we further studied histomorphology and hemodynamic of VM in gallbladder carcinomas in vivo and in vitro. METHODS: The invasive potential of human gallbladder carcinoma cell lines GBC-SD and SGC 996 were identified by Transwell membrane. The vasculogenic-like network structures and the signal intensities i.e. hemodynamic in gallbladder carcinomas stimulated via the three-dimensional matrix of GBC-SD or SGC-996 cells in vitro, the nude mouse xenografts of GBC-SD or SGC-996 cells in vivo were observed by immunohistochemistry (H&E staining and CD31-PAS double staining), electron microscopy and micro-MRA with HAS-Gd-DTPA, respectively. RESULTS: Highly aggressive GBC-SD or poorly aggressive SGC-996 cells preconditioned by highly aggressive GBC-SD cells could form patterned networks containing hollow matrix channels. 85.7% (6/7) of GBC-SD nude mouse xenografts existed the evidence of VM, 5.7% (17/300) channels contained red blood cells among these tumor cell-lined vasculatures. GBC-SD xenografts showed multiple high-intensity spots similar with the intensity observed at tumor marginal, a result consistent with pathological VM. CONCLUSIONS: VM existed in gallbladder carcinomas by both three-dimensional matrix of highly aggressive GBC-SD or poorly aggressive SGC-996 cells preconditioned by highly aggressive GBC-SD cells in vitro and GBC-SD nude mouse xenografts in vivo. PMID- 21529358 TI - Trust and the regulation of pharmaceuticals: South Asia in a globalised world. AB - BACKGROUND: Building appropriate levels of trust in pharmaceuticals is a painstaking and challenging task, involving participants from different spheres of life, including producers, distributors, retailers, prescribers, patients and the mass media. Increasingly, however, trust is not just a national matter, but involves cross-border flows of knowledge, threats and promises. METHODS: Data for this paper comes from the project 'Tracing Pharmaceuticals in South Asia', which used ethnographic fieldwork and qualitative interviews to compared the trajectories of three pharmaceuticals (Rifampicin, Oxytocin and Fluoxetine) from producer to patient in three sites (north India, West Bengal and Nepal) between 2005-08. RESULTS: We argue that issues of trust are crucial in reducing the likelihood of appropriate use of medicines. Unlike earlier discussions of trust, we suggest that trust contexts beyond the patient-practitioner relationship are important. We illustrate these arguments through three case studies: (i) a conflict over ethics in Nepal, involving a suggested revised ethical code for retailers, medical representatives, producers and prescribers; (ii) disputes over counterfeit, fake, substandard and spurious medicines, and quality standards in Indian generic companies, looking particularly at the role played by the US FDA; and (iii) the implications of lack of trust in the DOTS programmes in India and Nepal for the relationships among patients, government and the private sector. CONCLUSIONS: We conclude that the building of trust is a necessary but always vulnerable and contingent process. While it might be desirable to outline steps that can be taken to build trust, the range of conflicting interests in the pharmaceutical field make feasible solutions hard to implement. PMID- 21529357 TI - Sternal plate fixation for sternal wound reconstruction: initial experience (retrospective study). AB - BACKGROUND: Median sternotomy infection and bony nonunion are two commonly described complications which occur in 0.4-5.1% of cardiac procedures. Although relatively infrequent, these complications can lead to significant morbidity and mortality. The aim of this retrospective study is to evaluate the initial experience of a transverse plate fixation system following wound complications associated with sternal dehiscence with or without infection following cardiac surgery. METHODS: A retrospective chart review of 40 consecutive patients who required sternal wound reconstruction post sternotomy was performed. Soft tissue debridement with removal of all compromised tissue was performed. Sternal debridement was carried using ronguers to healthy bleeding bone. All patients underwent sternal fixation using three rib plates combined with a single manubrial plate (Titanium Sternal Fixation System(r), Synthes). Incisions were closed in a layered fashion with the pectoral muscles being advanced to the midline. Data were expressed as mean+/-SD, Median (range) or number (%). Statistical analyses were made by using Excel 2003 for Windows (Microsoft, Redmond, WA, USA). RESULTS: There were 40 consecutive patients, 31 males and 9 females. Twenty two patients (55%) were diagnosed with sternal dehiscence alone and 18 patients (45%) with associated wound discharge. Thirty eight patients went on to heal their wounds. Two patients developed recurrent wound infection and required VAC therapy. Both were immunocompromised. Median post-op ICU stay was one day with the median hospital stay of 18 days after plating. CONCLUSION: Sternal plating appears to be an effective option for the treatment of sternal wound dehiscence associated with sternal instability. Long-term follow-up and further larger studies are needed to address the indications, benefits and complications of sternal plating. PMID- 21529359 TI - A novel AMPK activator, WS070117, improves lipid metabolism discords in hamsters and HepG2 cells. AB - BACKGROUND: WS070117 is a novel small molecule compound that significantly improves lipid metabolism disorders in high-fat-diet (HFD) induced hyperlipidemia in hamsters. METHODS AND RESULTS: We evaluated liver/body weight ratio, liver histology, serum and hepatic lipid content in HFD-fed hamsters treated with WS070117 for 8 weeks. Comparing with HFD fed hamsters, WS070117 (2 mg/kg per day and above) reduced serum triglyceride (TAG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and hepatic cholesterol and triglyceride contents. Oil Red O staining of liver tissue also showed that WS070117 improved lipid accumulation. We then carried out an experiment in the oleic acid (OLA) induced steatosis model in HepG2 cell to investigate the lipid-lowering effect of WS070117. Oleic acid (0.25 mM) markedly induced lipid accumulation in HepG2 cells, but WS070117 (10 MUM) inhibited cellular lipid accumulation. In OLA treated HepG2 cells, WS070117 (above 1 MUM) treatment reduced lipid contents which synthesized from [1-(14)C] labeled acetic acid. Because WS070117 is an analog of adenosine, we evaluated the effect of WS070117 on AMP-activated protein kinase (AMPK) signaling. The results showed that the activation of AMPK in OLA induced steatosis in HepG2 cells was up-regulated by treatment with 0.1, 1 and 10 MUM WS070117. The hepatic cellular AMPK phosphorylation is also up regulated by WS070117 (6 and 18 mg/kg) treatment in HFD fed hamsters. CONCLUSION: These new findings identify WS070117 as a novel molecule that regulates lipid metabolism in the hyperlipidemia hamster model. In vitro and in vivo studies suggested that WS070117 may regulate lipid metabolism through stimulating the activation of AMPK and its downstream pathways. PMID- 21529360 TI - Cross-cultural adaptation of the Neck Disability Index and Copenhagen Neck Functional Disability Scale for patients with neck pain due to degenerative and discopathic disorders. Psychometric properties of the Polish versions. AB - BACKGROUND: Even though there are several region-specific functional outcome questionnaires measuring neck disorders that have been developed in English speaking countries, no Polish version has ever been validated. The purpose of our study was to translate, culturally adapt and validate the Neck Disability Index (NDI) and Copenhagen Neck Functional Disability Scale (CDS) for Polish-speaking patients with neck pain. METHODS: The translation was carried out according to the International Quality of Life Association (IQOLA) Project. Sixty patients were treated due to degenerative and discopathic disorders in the cervical spine filled out the NDI-PL and the CDS-PL. The pain level was evaluated using the Visual Analog Scale. The mean age of the assessed group was 47.1 years (SD 8.9). We used Cronbach's alpha to assess internal consistency. We assessed the test retest reliability using the Intraclass Correlation Coefficients (ICCs). The Spearman's rank correlation coefficient (rS) was used to determine dependency between quantitative characteristics. The Mann-Whitney test was applied to determine dependency between quantitative and qualitative characteristics. RESULTS: The Cronbach's alpha values were excellent for the NDI-PL in the test and in the retest (0.84, 0.85, respectively), and for the CDS-PL (0.90 in the test and in the retest). Intraclass Correlation Coefficients were excellent for the CDS-PL and NDI-PL and equalled 0.93 (95% CI from 0.89 to 0.95) and 0.87 (95% CI from 0.80 to 0.92), respectively The concurrent validity was good in the test and in the retest (rs = 0.42 p < 0.001; rs = 0.40 p = 0.002, respectively) for NDI-PL and for CDS-PL (rs = 0.42 p < 0.001; rs = 0.40 p = 0.001, respectively). The adapted questionnaires showed a strong inter-correlation both in the test (0.87 p < 0.001) and in the retest (0.79 p < 0.001). CONCLUSIONS: The present versions of the NDI-PL and CDS-PL, the first to be published in Polish, have proven to be reliable and valid for patients with degenerative changes in the cervical spine. The NDI-PL and CDS-PL have excellent internal consistency and test-retest reliability, and good concurrent validity. The adapted questionnaires showed a strong inter-correlation both in the test and in the retest. No ceiling or floor effects were detected in the NDI-PL and CDS-PL. The NDI-PL and CDS-PL are comparable with other versions and can be recommended and used in international comparative studies. PMID- 21529362 TI - Macroscopic changes during negative pressure wound therapy of the open abdomen using conventional negative pressure wound therapy and NPWT with a protective disc over the intestines. AB - BACKGROUND: Higher closure rates of the open abdomen have been reported with negative pressure wound therapy (NPWT) than with other wound management techniques. However, the method has occasionally been associated with increased development of fistulae. We have previously shown that NPWT induces ischemia in the underlying small intestines close to the vacuum source, and that a protective disc placed between the intestines and the vacuum source prevents the induction of ischemia. In the present study we compare macroscopic changes after 12, 24, and 48 hours, using conventional NPWT and NPWT with a protective disc between the intestines and the vacuum source. METHODS: Twelve pigs underwent midline incision. Six animals underwent conventional NPWT, while the other six pigs underwent NPWT with a protective disc inserted between the intestines and the vacuum source. Macroscopic changes were photographed and quantified after 12, 24, and 48 hours of NPWT. RESULTS: The surface of the small intestines was red and mottled as a result of petechial bleeding in the intestinal wall in all cases. After 12, 24 and 48 hours of NPWT, the area of petechial bleeding was significantly larger when using conventional NPWT than when using NPWT with the protective disc (9.7 +/- 1.0 cm(2) vs. 1.8 +/- 0.2 cm(2), p < 0.001, 12 hours), (14.5 +/- 0.9 cm(2) vs. 2.0 +/- 0.2 cm(2), 24 hours) (17.0 +/- 0.7 cm(2) vs. 2.5 +/- 0.2 cm(2) with the disc, p < 0.001, 48 hours) CONCLUSIONS: The areas of petechial bleeding in the small intestinal wall were significantly larger following conventional NPWT after 12, 24 and 48 hours, than using NPWT with a protective disc between the intestines and the vacuum source. The protective disc protects the intestines, reducing the amount of petechial bleeding. PMID- 21529361 TI - Gene expression analysis of flax seed development. AB - BACKGROUND: Flax, Linum usitatissimum L., is an important crop whose seed oil and stem fiber have multiple industrial applications. Flax seeds are also well-known for their nutritional attributes, viz., omega-3 fatty acids in the oil and lignans and mucilage from the seed coat. In spite of the importance of this crop, there are few molecular resources that can be utilized toward improving seed traits. Here, we describe flax embryo and seed development and generation of comprehensive genomic resources for the flax seed. RESULTS: We describe a large scale generation and analysis of expressed sequences in various tissues. Collectively, the 13 libraries we have used provide a broad representation of genes active in developing embryos (globular, heart, torpedo, cotyledon and mature stages) seed coats (globular and torpedo stages) and endosperm (pooled globular to torpedo stages) and genes expressed in flowers, etiolated seedlings, leaves, and stem tissue. A total of 261,272 expressed sequence tags (EST) (GenBank accessions LIBEST_026995 to LIBEST_027011) were generated. These EST libraries included transcription factor genes that are typically expressed at low levels, indicating that the depth is adequate for in silico expression analysis. Assembly of the ESTs resulted in 30,640 unigenes and 82% of these could be identified on the basis of homology to known and hypothetical genes from other plants. When compared with fully sequenced plant genomes, the flax unigenes resembled poplar and castor bean more than grape, sorghum, rice or Arabidopsis. Nearly one-fifth of these (5,152) had no homologs in sequences reported for any organism, suggesting that this category represents genes that are likely unique to flax. Digital analyses revealed gene expression dynamics for the biosynthesis of a number of important seed constituents during seed development. CONCLUSIONS: We have developed a foundational database of expressed sequences and collection of plasmid clones that comprise even low-expressed genes such as those encoding transcription factors. This has allowed us to delineate the spatio-temporal aspects of gene expression underlying the biosynthesis of a number of important seed constituents in flax. Flax belongs to a taxonomic group of diverse plants and the large sequence database will allow for evolutionary studies as well. PMID- 21529363 TI - Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years. AB - BACKGROUND: The once-weekly (QW) formulation of the glucagon-like peptide-1 receptor agonist exenatide has been demonstrated to improve A1C, fasting plasma glucose (FPG), body weight, serum lipid profiles, and blood pressure in patients with type 2 diabetes through 52 weeks of treatment. In this report, we describe the 2-year results of the open-label, open-ended extension to the DURATION-1 trial of exenatide QW for type 2 diabetes. METHODS: A 2-stage protocol was used: patients received either exenatide QW (2 mg) or exenatide twice daily for 30 weeks (5 MUg for the first 4 weeks and 10 MUg thereafter), followed by 1.5 years of treatment with exenatide QW (2 mg), for a total of 2 years (104 weeks) of exenatide treatment. Of the 295 (intent-to-treat [ITT]) patients who entered the trial, 73% (n = 216) completed 2 years of treatment (completer population). Baseline characteristics (mean +/- SE) for these patients were: A1C, 8.2 +/- 0.1%; FPG, 168.4 +/- 43.0 mg/dL; body weight, 101.1 +/- 18.7 kg; and diabetes duration, 7 +/- 5 years. RESULTS: In the completer population, significant improvements (LS mean +/- SE [95% CI]) were maintained after 2 years of treatment in A1C (-1.71 +/- 0.08% [-1.86 to -1.55%]), FPG (-40.1 +/- 2.9 mg/dL [-45.7 to 34.5 mg/dL]), and body weight (-2.61 +/- 0.52 kg [-3.64 to -1.58 kg]) compared with baseline. The percentages of patients who achieved an A1C of <7.0% and <=6.5% at 2 years were 60% and 39%, respectively. A significant reduction in systolic blood pressure (SBP; -3.0 +/- 1.0 mmHg [-4.9 to -1.1 mmHg]) was maintained through 2 years of treatment. Serum lipid profiles were also significantly improved, including triglycerides (geometric LS mean change from baseline, -15 +/- 2.7% [-21% to -10%]), total cholesterol (-8.6 +/- 2.8 mg/dL [ 14.0 to -3.1 mg/dL]), and low-density lipoproteins (-4.5 +/- 2.2 mg/dL [-8.9 to 0.01 mg/dL]). Changes in A1C, body weight, FPG, SBP, and lipids in the ITT population were similar to those seen in the completer population. Nausea (predominantly mild in intensity) was the most common adverse event, although the frequency and intensity of nausea decreased over time. No severe hypoglycemia was observed. CONCLUSIONS: Exenatide QW was well tolerated during the 2-year treatment period. This study demonstrated sustained glucose control and weight loss throughout 2 years of treatment with exenatide QW. TRIAL REGISTRATION: ClinicalTrials.gov NCT00308139. PMID- 21529364 TI - Clarifying mammalian RISC assembly in vitro. AB - BACKGROUND: Argonaute, the core component of the RNA induced silencing complex (RISC), binds to mature miRNAs and regulates gene expression at transcriptional or post-transcriptional level. We recently reported that Argonaute 2 (Ago2) also assembles into complexes with miRNA precursors (pre-miRNAs). These Ago2:pre-miRNA complexes are catalytically active in vitro and constitute non-canonical RISCs. RESULTS: The use of pre-miRNAs as guides by Ago2 bypasses Dicer activity and complicates in vitro RISC reconstitution. In this work, we characterized Ago2:pre miRNA complexes and identified RNAs that are targeted by miRNAs but not their corresponding pre-miRNAs. Using these target RNAs we were able to recapitulate in vitro pre-miRNA processing and canonical RISC loading, and define the minimal factors required for these processes. CONCLUSIONS: Our results indicate that Ago2 and Dicer are sufficient for processing and loading of miRNAs into RISC. Furthermore, our studies suggest that Ago2 binds primarily to the 5'- and alternatively, to the 3'-end of select pre-miRNAs. PMID- 21529365 TI - Reduction of anti-malarial consumption after rapid diagnostic tests implementation in Dar es Salaam: a before-after and cluster randomized controlled study. AB - BACKGROUND: Presumptive treatment of all febrile patients with anti-malarials leads to massive over-treatment. The aim was to assess the effect of implementing malaria rapid diagnostic tests (mRDTs) on prescription of anti-malarials in urban Tanzania. METHODS: The design was a prospective collection of routine statistics from ledger books and cross-sectional surveys before and after intervention in randomly selected health facilities (HF) in Dar es Salaam, Tanzania. The participants were all clinicians and their patients in the above health facilities. The intervention consisted of training and introduction of mRDTs in all three hospitals and in six HF. Three HF without mRDTs were selected as matched controls. The use of routine mRDT and treatment upon result was advised for all patients complaining of fever, including children under five years of age. The main outcome measures were: (1) anti-malarial consumption recorded from routine statistics in ledger books of all HF before and after intervention; (2) anti-malarial prescription recorded during observed consultations in cross sectional surveys conducted in all HF before and 18 months after mRDT implementation. RESULTS: Based on routine statistics, the amount of artemether lumefantrine blisters used post-intervention was reduced by 68% (95%CI 57-80) in intervention and 32% (9-54) in control HF. For quinine vials, the reduction was 63% (54-72) in intervention and an increase of 2.49 times (1.62-3.35) in control HF. Before-and-after cross-sectional surveys showed a similar decrease from 75% to 20% in the proportion of patients receiving anti-malarial treatment (Risk ratio 0.23, 95%CI 0.20-0.26). The cluster randomized analysis showed a considerable difference of anti-malarial prescription between intervention HF (22%) and control HF (60%) (Risk ratio 0.30, 95%CI 0.14-0.70). Adherence to test result was excellent since only 7% of negative patients received an anti malarial. However, antibiotic prescription increased from 49% before to 72% after intervention (Risk ratio 1.47, 95%CI 1.37-1.59). CONCLUSIONS: Programmatic implementation of mRDTs in a moderately endemic area reduced drastically over treatment with anti-malarials. Properly trained clinicians with adequate support complied with the recommendation of not treating patients with negative results. Implementation of mRDT should be integrated hand-in-hand with training on the management of other causes of fever to prevent irrational use of antibiotics. PMID- 21529366 TI - Role of adhesion molecules and inflammation in Venezuelan equine encephalitis virus infected mouse brain. AB - BACKGROUND: Neuroinvasion of Venezuelan equine encephalitis virus (VEEV) and subsequent initiation of inflammation in the brain plays a crucial role in the outcome of VEEV infection in mice. Adhesion molecules expressed on microvascular endothelial cells in the brain have been implicated in the modulation of the blood brain barrier (BBB) and inflammation in brain but their role in VEEV pathogenesis is not very well understood. In this study, we evaluated the expression of extracellular matrix and adhesion molecules genes in the brain of VEEV infected mice. FINDINGS: Several cell to cell adhesion molecules and extracellular matrix protein genes such as ICAM-1, VCAM-1, CD44, Cadherins, integrins, MMPs and Timp1 were differentially regulated post-VEEV infection. ICAM 1 knock-out (IKO) mice infected with VEEV had markedly reduced inflammation in the brain and demonstrated a delay in the onset of clinical symptoms of disease. A differential regulation of inflammatory genes was observed in the IKO mice brain compared to their WT counterparts. CONCLUSIONS: These results improve our present understanding of VEEV induced inflammation in mouse brain. PMID- 21529367 TI - Adaptive phenotypic plasticity in the Midas cichlid fish pharyngeal jaw and its relevance in adaptive radiation. AB - BACKGROUND: Phenotypic evolution and its role in the diversification of organisms is a central topic in evolutionary biology. A neglected factor during the modern evolutionary synthesis, adaptive phenotypic plasticity, more recently attracted the attention of many evolutionary biologists and is now recognized as an important ingredient in both population persistence and diversification. The traits and directions in which an ancestral source population displays phenotypic plasticity might partly determine the trajectories in morphospace, which are accessible for an adaptive radiation, starting from the colonization of a novel environment. In the case of repeated colonizations of similar environments from the same source population this "flexible stem" hypothesis predicts similar phenotypes to arise in repeated subsequent radiations. The Midas Cichlid (Amphilophus spp.) in Nicaragua has radiated in parallel in several crater-lakes seeded by populations originating from the Nicaraguan Great Lakes. Here, we tested phenotypic plasticity in the pharyngeal jaw of Midas Cichlids. The pharyngeal jaw apparatus of cichlids, a second set of jaws functionally decoupled from the oral ones, is known to mediate ecological specialization and often differs strongly between sister-species. RESULTS: We performed a common garden experiment raising three groups of Midas cichlids on food differing in hardness and calcium content. Analyzing the lower pharyngeal jaw-bones we find significant differences between diet groups qualitatively resembling the differences found between specialized species. Observed differences in pharyngeal jaw expression between groups were attributable to the diet's mechanical resistance, whereas surplus calcium in the diet was not found to be of importance. CONCLUSIONS: The pharyngeal jaw apparatus of Midas Cichlids can be expressed plastically if stimulated mechanically during feeding. Since this trait is commonly differentiated--among other traits--between Midas Cichlid species, its plasticity might be an important factor in Midas Cichlid speciation. The prevalence of pharyngeal jaw differentiation across the Cichlidae further suggests that adaptive phenotypic plasticity in this trait could play an important role in cichlid speciation in general. We discuss several possibilities how the adaptive radiation of Midas Cichlids might have been influenced in this respect. PMID- 21529368 TI - Prevalence of SOS-mediated control of integron integrase expression as an adaptive trait of chromosomal and mobile integrons. AB - BACKGROUND: Integrons are found in hundreds of environmental bacterial species, but are mainly known as the agents responsible for the capture and spread of antibiotic-resistance determinants between Gram-negative pathogens. The SOS response is a regulatory network under control of the repressor protein LexA targeted at addressing DNA damage, thus promoting genetic variation in times of stress. We recently reported a direct link between the SOS response and the expression of integron integrases in Vibrio cholerae and a plasmid-borne class 1 mobile integron. SOS regulation enhances cassette swapping and capture in stressful conditions, while freezing the integron in steady environments. We conducted a systematic study of available integron integrase promoter sequences to analyze the extent of this relationship across the Bacteria domain. RESULTS: Our results showed that LexA controls the expression of a large fraction of integron integrases by binding to Escherichia coli-like LexA binding sites. In addition, the results provide experimental validation of LexA control of the integrase gene for another Vibrio chromosomal integron and for a multiresistance plasmid harboring two integrons. There was a significant correlation between lack of LexA control and predicted inactivation of integrase genes, even though experimental evidence also indicates that LexA regulation may be lost to enhance expression of integron cassettes. CONCLUSIONS: Ancestral-state reconstruction on an integron integrase phylogeny led us to conclude that the ancestral integron was already regulated by LexA. The data also indicated that SOS regulation has been actively preserved in mobile integrons and large chromosomal integrons, suggesting that unregulated integrase activity is selected against. Nonetheless, additional adaptations have probably arisen to cope with unregulated integrase activity. Identifying them may be fundamental in deciphering the uneven distribution of integrons in the Bacteria domain. PMID- 21529369 TI - Selective regulation of nerve growth factor expression in developing cutaneous tissue by early sensory innervation. AB - BACKGROUND: In the developing vertebrate peripheral nervous system, the survival of sympathetic neurons and the majority of sensory neurons depends on a supply of nerve growth factor (NGF) from tissues they innervate. Although neurotrophic theory presupposes, and the available evidence suggests, that the level of NGF expression is completely independent of innervation, the possibility that innervation may regulate the timing or level of NGF expression has not been rigorously investigated in a sufficiently well-characterized developing system. RESULTS: To address this important question, we studied the influence of innervation on the regulation of NGF mRNA expression in the embryonic mouse maxillary process in vitro and in vivo. The maxillary process receives its innervation from predominantly NGF-dependent sensory neurons of the trigeminal ganglion and is the most densely innervated cutaneous territory with the highest levels of NGF in the embryo. When early, uninnervated maxillary processes were cultured alone, the level of NGF mRNA rose more slowly than in maxillary processes cultured with attached trigeminal ganglia. In contrast to the positive influence of early innervation on NGF mRNA expression, the levels of brain derived neurotrophic factor (BDNF) mRNA and neurotrophin-3 (NT3) mRNA rose to the same extent in early maxillary processes grown with and without trigeminal ganglia. The level of NGF mRNA, but not BDNF mRNA or NT3 mRNA, was also significantly lower in the maxillary processes of erbB3-/- mice, which have substantially fewer trigeminal neurons than wild-type mice. CONCLUSIONS: This selective effect of initial innervation on target field NGF mRNA expression provokes a re-evaluation of a key assertion of neurotrophic theory that the level of NGF expression is independent of innervation. PMID- 21529370 TI - A Depression Recognition and Treatment package for families living with Stroke (DepReT-Stroke): study protocol for a randomised controlled trial. AB - BACKGROUND: Depression occurs in up to 50% of patients after stroke and limits rehabilitation and recovery. Mood disorders are also highly prevalent in carers; their mental health intertwined with the physical and mental wellbeing of the person they are caring for. We argue that working with families, rather than patients alone may improve the treatment of depression in both patients and their carers enhancing the mental wellbeing and quality of life of both. METHODS: A single blind cluster randomised controlled trial to evaluate whether families after stroke who are treated with the Depression Recognition and Treatment package (DepReT-Stroke) in addition to treatment as usual (TAU) show improved mental well being compared to those families who receive only TAU. We aim to recruit one hundred and twenty-six families (63 in each group). The DepReT-Stroke intervention will help families to consider the various treatment options for depression, make choices about which are likely to fit best with their lives and support them in the use of self-help therapies (e.g. computerised Cognitive Behavioural Therapy or exercise). An essential component of the DepReT-Stroke package will be to help people adhere to their chosen treatment(s). The primary outcome will be the Mental Component Subscale of the SF-36 assessed at baseline and again six months post intervention. Effectiveness of the intervention will be determined using analysis of co-variance; comparing the mean change in MCS scores from baseline to six months follow-up adjusting for the clustering effects of baseline scores and family. An economic evaluation of the intervention will help us determine whether the intervention represents a cost-effective use of resources. DISCUSSION: Depression both for patients and their carers is common after stroke. Our Depression Recognition and Treatment package (DepReT-stroke) may help clinicians be more effective at detecting and managing a common co morbidity that limits rehabilitation and recovery. TRIAL REGISTRATION: ISRCTN: ISRCTN32451749 Research Ethics Committee Reference Number: 10/H0310/23 Grant Reference Number: (NIHR) PB-PG-0808-17056. PMID- 21529372 TI - Phenotype recognition with combined features and random subspace classifier ensemble. AB - BACKGROUND: Automated, image based high-content screening is a fundamental tool for discovery in biological science. Modern robotic fluorescence microscopes are able to capture thousands of images from massively parallel experiments such as RNA interference (RNAi) or small-molecule screens. As such, efficient computational methods are required for automatic cellular phenotype identification capable of dealing with large image data sets. In this paper we investigated an efficient method for the extraction of quantitative features from images by combining second order statistics, or Haralick features, with curvelet transform. A random subspace based classifier ensemble with multiple layer perceptron (MLP) as the base classifier was then exploited for classification. Haralick features estimate image properties related to second-order statistics based on the grey level co-occurrence matrix (GLCM), which has been extensively used for various image processing applications. The curvelet transform has a more sparse representation of the image than wavelet, thus offering a description with higher time frequency resolution and high degree of directionality and anisotropy, which is particularly appropriate for many images rich with edges and curves. A combined feature description from Haralick feature and curvelet transform can further increase the accuracy of classification by taking their complementary information. We then investigate the applicability of the random subspace (RS) ensemble method for phenotype classification based on microscopy images. A base classifier is trained with a RS sampled subset of the original feature set and the ensemble assigns a class label by majority voting. RESULTS: Experimental results on the phenotype recognition from three benchmarking image sets including HeLa, CHO and RNAi show the effectiveness of the proposed approach. The combined feature is better than any individual one in the classification accuracy. The ensemble model produces better classification performance compared to the component neural networks trained. For the three images sets HeLa, CHO and RNAi, the Random Subspace Ensembles offers the classification rates 91.20%, 98.86% and 91.03% respectively, which compares sharply with the published result 84%, 93% and 82% from a multi-purpose image classifier WND-CHARM which applied wavelet transforms and other feature extraction methods. We investigated the problem of estimation of ensemble parameters and found that satisfactory performance improvement could be brought by a relative medium dimensionality of feature subsets and small ensemble size. CONCLUSIONS: The characteristics of curvelet transform of being multiscale and multidirectional suit the description of microscopy images very well. It is empirically demonstrated that the curvelet-based feature is clearly preferred to wavelet-based feature for bioimage descriptions. The random subspace ensemble of MLPs is much better than a number of commonly applied multi-class classifiers in the investigated application of phenotype recognition. PMID- 21529371 TI - EBF factors drive expression of multiple classes of target genes governing neuronal development. AB - BACKGROUND: Early B cell factor (EBF) family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. RESULTS: We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. CONCLUSIONS: The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate. PMID- 21529373 TI - A parametric study delineating irreversible electroporation from thermal damage based on a minimally invasive intracranial procedure. AB - BACKGROUND: Irreversible electroporation (IRE) is a new minimally invasive technique to kill undesirable tissue in a non-thermal manner. In order to maximize the benefits from an IRE procedure, the pulse parameters and electrode configuration must be optimized to achieve complete coverage of the targeted tissue while preventing thermal damage due to excessive Joule heating. METHODS: We developed numerical simulations of typical protocols based on a previously published computed tomographic (CT) guided in vivo procedure. These models were adapted to assess the effects of temperature, electroporation, pulse duration, and repetition rate on the volumes of tissue undergoing IRE alone or in superposition with thermal damage. RESULTS: Nine different combinations of voltage and pulse frequency were investigated, five of which resulted in IRE alone while four produced IRE in superposition with thermal damage. CONCLUSIONS: The parametric study evaluated the influence of pulse frequency and applied voltage on treatment volumes, and refined a proposed method to delineate IRE from thermal damage. We confirm that determining an IRE treatment protocol requires incorporating all the physical effects of electroporation, and that these effects may have significant implications in treatment planning and outcome assessment. The goal of the manuscript is to provide the reader with the numerical methods to assess multiple-pulse electroporation treatment protocols in order to isolate IRE from thermal damage and capitalize on the benefits of a non-thermal mode of tissue ablation. PMID- 21529375 TI - Virtual reality exposure therapy as treatment for pain catastrophizing in fibromyalgia patients: proof-of-concept study (Study Protocol). AB - BACKGROUND: Albeit exercise is currently advocated as one of the most effective management strategies for fibromyalgia syndrome (FMS); the implementation of exercise as a FMS treatment in reality is significantly hampered by patients' poor compliance. The inference that pain catastrophizing is a key predictor of poor compliance in FMS patients, justifies considering the alteration of pain catastrophizing in improving compliance towards exercises in FMS patients. The aim of this study is to provide proof-of-concept for the development and testing of a novel virtual reality exposure therapy (VRET) program as treatment for exercise-related pain catastrophizing in FMS patients. METHODS: Two interlinked experimental studies will be conducted. Study 1 aims to objectively ascertain if neurophysiological changes occur in the functional brain areas associated with pain catastrophizing, when catastrophizing FMS subjects are exposed to visuals of exercise activities. Study 2 aims to ascertain the preliminary efficacy and feasibility of exposure to visuals of exercise activities as a treatment for exercise-related pain catastrophizing in FMS subjects. Twenty subjects will be selected from a group of FMS patients attending the Tygerberg Hospital in Cape Town, South Africa and randomly allocated to either the VRET (intervention) group or waiting list (control) group. Baseline neurophysiological activity for subjects will be collected in study 1 using functional magnetic resonance imaging (fMRI). In study 2, clinical improvement in pain catastrophizing will be measured using fMRI (objective) and the pain catastrophizing scale (subjective). DISCUSSION: The premise is if exposing FMS patients to visuals of various exercise activities trigger the functional brain areas associated with pain catastrophizing; then as a treatment, repeated exposure to visuals of the exercise activities using a VRET program could possibly decrease exercise-related pain catastrophizing in FMS patients. Proof-of-concept will either be established or negated. The results of this project are envisaged to revolutionize FMS and pain catastrophizing research and in the future, assist health professionals and FMS patients in reducing despondency regarding FMS management. TRIAL REGISTRATION: PACTR201011000264179. PMID- 21529376 TI - Antibody levels to multiple malaria vaccine candidate antigens in relation to clinical malaria episodes in children in the Kasena-Nankana district of Northern Ghana. AB - BACKGROUND: Considering the natural history of malaria of continued susceptibility to infection and episodes of illness that decline in frequency and severity over time, studies which attempt to relate immune response to protection must be longitudinal and have clearly specified definitions of immune status. Putative vaccines are expected to protect against infection, mild or severe disease or reduce transmission, but so far it has not been easy to clearly establish what constitutes protective immunity or how this develops naturally, especially among the affected target groups. The present study was done in under six year old children to identify malaria antigens which induce antibodies that correlate with protection from Plasmodium falciparum malaria. METHODS: In this longitudinal study, the multiplex assay was used to measure IgG antibody levels to 10 malaria antigens (GLURP R0, GLURP R2, MSP3 FVO, AMA1 FVO, AMA1 LR32, AMA1 3D7, MSP1 3D7, MSP1 FVO, LSA-1and EBA175RII) in 325 children aged 1 to 6 years in the Kassena Nankana district of northern Ghana. The antigen specific antibody levels were then related to the risk of clinical malaria over the ensuing year using a negative binomial regression model. RESULTS: IgG levels generally increased with age. The risk of clinical malaria decreased with increasing antibody levels. Except for FMPOII-LSA, (p = 0.05), higher IgG levels were associated with reduced risk of clinical malaria (defined as axillary temperature >=37.5 degrees C and parasitaemia of >=5000 parasites/ul blood) in a univariate analysis, upon correcting for the confounding effect of age. However, in a combined multiple regression analysis, only IgG levels to MSP1-3D7 (Incidence rate ratio = 0.84, [95% C.I.= 0.73, 0.97, P = 0.02]) and AMA1 3D7 (IRR = 0.84 [95% C.I.= 0.74, 0.96, P = 0.01]) were associated with a reduced risk of clinical malaria over one year of morbidity surveillance. CONCLUSION: The data from this study support the view that a multivalent vaccine involving different antigens is most likely to be more effective than a monovalent one. Functional assays, like the parasite growth inhibition assay will be necessary to confirm if these associations reflect functional roles of antibodies to MSP1-3D7 and AMA1-3D7 in this population. PMID- 21529377 TI - [18F]fluoroethylcholine-PET/CT imaging for radiation treatment planning of recurrent and primary prostate cancer with dose escalation to PET/CT-positive lymph nodes. AB - BACKGROUND: At present there is no consensus on irradiation treatment volumes for intermediate to high-risk primary cancers or recurrent disease. Conventional imaging modalities, such as CT, MRI and transrectal ultrasound, are considered suboptimal for treatment decisions. Choline-PET/CT might be considered as the imaging modality in radiooncology to select and delineate clinical target volumes extending the prostate gland or prostate fossa. In conjunction with intensity modulated radiotherapy (IMRT) and imaged guided radiotherapy (IGRT), it might offer the opportunity of dose escalation to selected sites while avoiding unnecessary irradiation of healthy tissues. METHODS: Twenty-six patients with primary (n = 7) or recurrent (n = 19) prostate cancer received Choline-PET/CT planned 3D conformal or intensity modulated radiotherapy. The median age of the patients was 65 yrs (range 45 to 78 yrs). PET/CT-scans with F18 fluoroethylcholine (FEC) were performed on a combined PET/CT-scanner equipped for radiation therapy planning. The majority of patients had intermediate to high risk prostate cancer. All patients received 3D conformal or intensity modulated and imaged guided radiotherapy with megavoltage cone beam CT. The median dose to primary tumours was 75.6 Gy and to FEC-positive recurrent lymph nodal sites 66,6 Gy. The median follow-up time was 28.8 months. RESULTS: The mean SUV(max) in primary cancer was 5,97 in the prostate gland and 3,2 in pelvic lymph nodes. Patients with recurrent cancer had a mean SUV(max) of 4,38. Two patients had negative PET/CT scans. At 28 months the overall survival rate is 94%. Biochemical relapse free survival is 83% for primary cancer and 49% for recurrent tumours. Distant disease free survival is 100% and 75% for primary and recurrent cancer, respectively. Acute normal tissue toxicity was mild in 85% and moderate (grade 2) in 15%. No or mild late side effects were observed in the majority of patients (84%). One patient had a severe bladder shrinkage (grade 4) after a previous treatment with TUR of the prostate and seed implantation. CONCLUSIONS: FEC-PET/CT planning could be helpful in dose escalation to lymph nodal sites of prostate cancer. PMID- 21529374 TI - Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill's epidemiologic criteria for causality. AB - BACKGROUND: Modern diets have been suggested to increase systemic acid load and net acid excretion. In response, alkaline diets and products are marketed to avoid or counteract this acid, help the body regulate its pH to prevent and cure disease. The objective of this systematic review was to evaluate causal relationships between dietary acid load and osteoporosis using Hill's criteria. METHODS: Systematic review and meta-analysis. We systematically searched published literature for randomized intervention trials, prospective cohort studies, and meta-analyses of the acid-ash or acid-base diet hypothesis with bone related outcomes, in which the diet acid load was altered, or an alkaline diet or alkaline salts were provided, to healthy human adults. Cellular mechanism studies were also systematically examined. RESULTS: Fifty-five of 238 studies met the inclusion criteria: 22 randomized interventions, 2 meta-analyses, and 11 prospective observational studies of bone health outcomes including: urine calcium excretion, calcium balance or retention, changes of bone mineral density, or fractures, among healthy adults in which acid and/or alkaline intakes were manipulated or observed through foods or supplements; and 19 in vitro cell studies which examined the hypothesized mechanism. Urine calcium excretion rates were consistent with osteoporosis development; however calcium balance studies did not demonstrate loss of whole body calcium with higher net acid excretion. Several weaknesses regarding the acid-ash hypothesis were uncovered: No intervention studies provided direct evidence of osteoporosis progression (fragility fractures, or bone strength as measured using biopsy). The supporting prospective cohort studies were not controlled regarding important osteoporosis risk factors including: weight loss during follow-up, family history of osteoporosis, baseline bone mineral density, and estrogen status. No study revealed a biologic mechanism functioning at physiological pH. Finally, randomized studies did not provide evidence for an adverse role of phosphate, milk, and grain foods in osteoporosis. CONCLUSIONS: A causal association between dietary acid load and osteoporotic bone disease is not supported by evidence and there is no evidence that an alkaline diet is protective of bone health. PMID- 21529378 TI - Tetherin inhibits prototypic foamy virus release. AB - BACKGROUND: Tetherin (also known as BST-2, CD317, and HM1.24) is an interferon- induced protein that blocks the release of a variety of enveloped viruses, such as retroviruses, filoviruses and herpesviruses. However, the relationship between tetherin and foamy viruses has not been clearly demonstrated. RESULTS: In this study, we found that tetherin of human, simian, bovine or canine origin inhibits the production of infectious prototypic foamy virus (PFV). The inhibition of PFV by human tetherin is counteracted by human immunodeficiency virus type 1 (HIV-1) Vpu. Furthermore, we generated human tetherin transmembrane domain deletion mutant (delTM), glycosyl phosphatidylinositol (GPI) anchor deletion mutant (delGPI), and dimerization and glycosylation deficient mutants. Compared with wild type tetherin, the delTM and delGPI mutants only moderately inhibited PFV production. In contrast, the dimerization and glycosylation deficient mutants inhibit PFV production as efficiently as the wild type tetherin. CONCLUSIONS: These results demonstrate that tetherin inhibits the release and infectivity of PFV, and this inhibition is antagonized by HIV-1 Vpu. Both the transmembrane domain and the GPI anchor of tetherin are important for the inhibition of PFV, whereas the dimerization and the glycosylation of tetherin are dispensable. PMID- 21529379 TI - A study of toxicity and differential gene expression in murine liver following exposure to anti-malarial drugs: amodiaquine and sulphadoxine-pyrimethamine. AB - BACKGROUND: Amodiaquine (AQ) along with sulphadoxine-pyrimethamine (SP) offers effective and cheaper treatment against chloroquine-resistant falciparum malaria in many parts of sub-Saharan Africa. Considering the previous history of hepatitis, agranulocytosis and neutrocytopenia associated with AQ monotherapy, it becomes imperative to study the toxicity of co-administration of AQ and SP. In this study, toxicity and resulting global differential gene expression was analyzed following exposure to these drugs in experimental Swiss mice. METHODS: The conventional markers of toxicity in serum, oxidative stress parameters in tissue homogenates, histology of liver and alterations in global transcriptomic expression were evaluated to study the toxic effects of AQ and SP in isolation and in combination. RESULTS: The combination therapy of AQ and SP results in more pronounced hepatotoxicity as revealed by elevated level of serum ALT, AST with respect to their individual drug exposure regimen. Furthermore, alterations in the activity of major antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase), indicating the development of oxidative stress, was more significant in AQ+SP combination therapy. cDNA microarray results too showed considerably more perturbed gene expression following combination therapy of AQ and SP as compared to their individual drug treatment. Moreover, a set of genes were identified whose expression pattern can be further investigated for identifying a good biomarker for potential anti malarial hepatotoxicity. CONCLUSION: These observations clearly indicate AQ+SP combination therapy is hepatotoxic in experimental Swiss mice. Microarray results provide a considerable number of potential biomarkers of anti-malarial drug toxicity. These findings hence will be useful for future drug toxicity studies, albeit implications of this study in clinical conditions need to be monitored with cautions. PMID- 21529380 TI - IL-4 and IL-13 exposure during mucociliary differentiation of bronchial epithelial cells increases antimicrobial activity and expression of antimicrobial peptides. AB - The airway epithelium forms a barrier against infection but also produces antimicrobial peptides (AMPs) and other inflammatory mediators to activate the immune system. It has been shown that in allergic disorders, Th2 cytokines may hamper the antimicrobial activity of the epithelium. However, the presence of Th2 cytokines also affects the composition of the epithelial layer which may alter its function. Therefore, we investigated whether exposure of human primary bronchial epithelial cells (PBEC) to Th2 cytokines during mucociliary differentiation affects expression of the human cathelicidin antimicrobial protein (hCAP18)/LL-37 and human beta defensins (hBD), and antimicrobial activity.PBEC were cultured at an air-liquid interface (ALI) for two weeks in the presence of various concentrations of IL-4 or IL-13. Changes in differentiation and in expression of various AMPs and the antimicrobial proteinase inhibitors secretory leukocyte protease inhibitor (SLPI) and elafin were investigated as well as antimicrobial activity.IL-4 and IL-13 increased mRNA expression of hCAP18/LL-37 and hBD-2. Dot blot analysis also showed an increase in hCAP18/LL-37 protein in apical washes of IL-4-treated ALI cultures, whereas Western Blot analysis showed expression of a protein of approximately 4.5 kDa in basal medium of IL-4-treated cultures. Using sandwich ELISA we found that also hBD-2 in apical washes was increased by both IL-4 and IL-13. SLPI and elafin levels were not affected by IL-4 or IL-13 at the mRNA or protein level. Apical wash obtained from IL-4- and IL-13-treated cultures displayed increased antimicrobial activity against Pseudomonas aeruginosa compared to medium-treated cultures. In addition, differentiation in the presence of Th2 cytokines resulted in increased MUC5AC production as has been shown previously.These data suggest that prolonged exposure to Th2 cytokines during mucociliary differentiation contributes to antimicrobial defence by increasing the expression and release of selected antimicrobial peptides and mucus. PMID- 21529381 TI - Sentinel lymph node biopsy as guidance for radical trachelectomy in young patients with early stage cervical cancer. AB - BACKGROUND: The purpose of this study was to assess the feasibility and accuracy of sentinel lymph nodes (SLNs) detection using 99mTc phytate in predicting pelvic lymph nodes status for radical abdominal trachelectomy (RAT) in patients with early stage cervical cancer. METHODS: Sixty-eight women with stage IA2-IB1 cervical cancer and scheduled to undergo fertility-sparing surgery enrolled in this study. 99mTc-labeled phytate was injected before surgery. Intraoperatively, SLNs were identified, excised, and submitted to fast frozen section. Systematic bilateral pelvic lymphadenectomy and/or para-aortic lymph node dissection was performed. Then RAT was performed in patients with negative SLNs. All nodes were sent for routine pathological examination and immunostained with anti-cytokeratin antibody to detect micrometastases. Outcomes of follow up and fertility were observed. RESULTS: SLNs were identified in 64 of 68 patients (94.1%). Of these, SLNs of 8 patients (11.8%) were positive on frozen sections and proved to be metastasis by final pathologic examination. The sensitivity, accuracy, and false negative rates were 100%, 100%, and 0%, respectively. All 60 patients with negative SLN underwent RAT successfully. Two relapses occurred and no one died of tumor progression during follow-up. Five of the 15 patients with procreative desire conceived 8 pregnancies (3 term delivery, 2 premature birth, 1 spontaneous abortion, and 2 were still in the duration of pregnancy) after surgery. CONCLUSIONS: The identification of SLN using 99mTc-labeled phytate is accurate and safe to assess pelvic nodes status in patients with early cervical cancer. SLNs biopsy guided RAT is feasible for patients who desire to have fertility preservation. PMID- 21529382 TI - Vector-borne infections. AB - Infections with vector-borne pathogens are a major source of emerging diseases. The ability of vectors to bridge spatial and ecologic gaps between animals and humans increases opportunities for emergence. Small adaptations of a pathogen to a vector can have profound effects on the rate of transmission to humans. PMID- 21529383 TI - Intravenous artesunate for severe malaria in travelers, Europe. AB - Multicenter trials in Southeast Asia have shown better survival rates among patients with severe malaria, particularly those with high parasitemia levels, treated with intravenous (IV) artesunate than among those treated with quinine. In Europe, quinine is still the primary treatment for severe malaria. We conducted a retrospective analysis for 25 travelers with severe malaria who returned from malaria-endemic regions and were treated at 7 centers in Europe. All patients survived. Treatment with IV artesunate rapidly reduced parasitemia levels. In 6 patients at 5 treatment centers, a self-limiting episode of unexplained hemolysis occurred after reduction of parasitemia levels. Five patients required a blood transfusion. Patients with posttreatment hemolysis had received higher doses of IV artesunate than patients without hemolysis. IV artesunate was an effective alternative to quinine for treatment of malaria patients in Europe. Patients should be monitored for signs of hemolysis, especially after parasitologic cure. PMID- 21529384 TI - Lessons learned about pneumonic plague diagnosis from two outbreaks, Democratic Republic of the Congo. AB - Pneumonic plague is a highly transmissible infectious disease for which fatality rates can be high if untreated; it is considered extremely lethal. Without prompt diagnosis and treatment, disease management can be problematic. In the Democratic Republic of the Congo, 2 outbreaks of pneumonic plague occurred during 2005 and 2006. In 2005, because of limitations in laboratory capabilities, etiology was confirmed only through retrospective serologic studies. This prompted modifications in diagnostic strategies, resulting in isolation of Yersinia pestis during the second outbreak. Results from these outbreaks demonstrate the utility of a rapid diagnostic test detecting F1 antigen for initial diagnosis and public health management, as well as the need for specialized sampling kits and trained personnel for quality specimen collection and appropriate specimen handling and preservation for plague confirmation and Y. pestis isolation. Efficient frontline management and a streamlined diagnostic strategy are essential for confirming plague, especially in remote areas. PMID- 21529385 TI - Evolution of new genotype of West Nile virus in North America. AB - Previous studies of North American isolates of West Nile virus (WNV) during 1999 2005 suggested that the virus had reached genetic homeostasis in North America. However, genomic sequencing of WNV isolates from Harris County, Texas, during 2002-2009 suggests that this is not the case. Three new genetic groups have been identified in Texas since 2005. Spread of the southwestern US genotype (SW/WN03) from the Arizona/Colorado/northern Mexico region to California, Illinois, New Mexico, New York, North Dakota, and the Texas Gulf Coast demonstrates continued evolution of WNV. Thus, WNV continues to evolve in North America, as demonstrated by selection of this new genotype. Continued surveillance of the virus is essential as it continues to evolve in the New World. PMID- 21529386 TI - Transstadial transmission of Francisella tularensis holarctica in mosquitoes, Sweden. AB - In Sweden, human cases of tularemia caused by Francisella tularensis holarctica are assumed to be transmitted by mosquitoes, but how mosquito vectors acquire and transmit the bacterium is not clear. To determine how transmission of this bacterium occurs, mosquito larvae were collected in an area where tularemia is endemic, brought to the laboratory, and reared to adults in their original pond water. Screening of adult mosquitoes by real-time PCR demonstrated F. tularensis lpnA sequences in 14 of the 48 mosquito pools tested; lpnA sequences were demonstrated in 6 of 9 identified mosquito species. Further analysis confirmed the presence of F. tularensis holarctica-specific 30-bp deletion region sequences (FtM19inDel) in water from breeding containers and in 3 mosquito species (Aedes sticticus, Ae. vexans, and Ae. punctor) known to take blood from humans. Our results suggest that the mosquitoes that transmit F. tularensis holarctica during tularemia outbreaks acquire the bacterium already as larvae. PMID- 21529387 TI - Molecular epidemiology of Oropouche virus, Brazil. AB - Oropouche virus (OROV) is the causative agent of Oropouche fever, an urban febrile arboviral disease widespread in South America, with >30 epidemics reported in Brazil and other Latin American countries during 1960-2009. To describe the molecular epidemiology of OROV, we analyzed the entire N gene sequences (small RNA) of 66 strains and 35 partial Gn (medium RNA) and large RNA gene sequences. Distinct patterns of OROV strain clustered according to N, Gn, and large gene sequences, which suggests that each RNA segment had a different evolutionary history and that the classification in genotypes must consider the genetic information for all genetic segments. Finally, time-scale analysis based on the N gene showed that OROV emerged in Brazil ~223 years ago and that genotype I (based on N gene data) was responsible for the emergence of all other genotypes and for virus dispersal. PMID- 21529388 TI - Severe imported Plasmodium falciparum malaria, France, 1996-2003. AB - Little is known about severe imported Plasmodium falciparum malaria in industrialized countries where the disease is not endemic because most studies have been case reports or have included <200 patients. To identify factors independently associated with the severity of P. falciparum, we conducted a retrospective study using surveillance data obtained from 21,888 P. falciparum patients in France during 1996-2003; 832 were classified as having severe malaria. The global case-fatality rate was 0.4% and the rate of severe malaria was ~3.8%. Factors independently associated with severe imported P. falciparum malaria were older age, European origin, travel to eastern Africa, absence of chemoprophylaxis, initial visit to a general practitioner, time to diagnosis of 4 to 12 days, and diagnosis during the fall-winter season. Pretravel advice should take into account these factors and promote the use of antimalarial chemoprophylaxis for every traveler, with a particular focus on nonimmune travelers and elderly persons. PMID- 21529389 TI - Plasmodium knowlesi malaria in children. AB - Plasmodium knowlesi can cause severe malaria in adults; however, descriptions of clinical disease in children are lacking. We reviewed case records of children (age <15 years) with a malaria diagnosis at Kudat District Hospital, serving a largely deforested area of Sabah, Malaysia, during January-November 2009. Sixteen children with PCR-confirmed P. knowlesi monoinfection were compared with 14 children with P. falciparum monoinfection diagnosed by microscopy or PCR. Four children with knowlesi malaria had a hemoglobin level at admission of <10.0 g/dL (minimum lowest level 6.4 g/dL). Minimum level platelet counts were lower in knowlesi than in falciparum malaria (median 76,500/MUL vs. 156,000/mL; p = 0.01). Most (81%) children with P. knowlesi malaria received chloroquine and primaquine; median parasite clearance time was 2 days (range 1-5 days). P. knowlesi is the most common cause of childhood malaria in Kudat. Although infection is generally uncomplicated, anemia is common and thrombocytopenia universal. Transmission dynamics in this region require additional investigation. PMID- 21529390 TI - Travel-related dengue virus infection, The Netherlands, 2006-2007. AB - To assess the incidence of and risk factors for clinical and subclinical dengue virus (DENV) infection, we prospectively studied 1,207 adult short-term travelers from the Netherlands to dengue-endemic areas. Participants donated blood samples for serologic testing before and after travel. Blood samples were tested for antibodies against DENV. Seroconversion occurred in 14 (1.2%) travelers at risk. The incidence rate was 14.6 per 1,000 person-months. The incidence rate was significantly higher for travel during the rainy months. Dengue-like illness occurred in 5 of the 14 travelers who seroconverted. Seroconversion was significantly related to fever, retro-orbital pain, myalgia, arthralgia, and skin rash. The risk for DENV infection for short-term travelers to dengue-endemic areas is substantial. The incidence rate for this study is comparable with that in 2 other serology-based prospective studies conducted in the 1990s. PMID- 21529391 TI - Experimental infection of Amblyomma aureolatum ticks with Rickettsia rickettsii. AB - We experimentally infected Amblyomma aureolatum ticks with the bacterium Rickettsia rickettsii, the etiologic agent of Rocky Mountain spotted fever (RMSF). These ticks are a vector for RMSF in Brazil. R. rickettsii was efficiently conserved by both transstadial maintenance and vertical (transovarial) transmission to 100% of the ticks through 4 laboratory generations. However, lower reproductive performance and survival of infected females was attributed to R. rickettsii infection. Therefore, because of the high susceptibility of A. aureolatum ticks to R. rickettsii infection, the deleterious effect that the bacterium causes in these ticks may contribute to the low infection rates (<1%) usually reported among field populations of A. aureolatum ticks in RMSF-endemic areas of Brazil. Because the number of infected ticks would gradually decrease after each generation, it seems unlikely that A. aureolatum ticks could sustain R. rickettsii infection over multiple successive generations solely by vertical transmission. PMID- 21529392 TI - Genotypic profile of Streptococcus suis serotype 2 and clinical features of infection in humans, Thailand. AB - To examine associations between clinical features of Streptococcus suis serotype 2 infections in humans in Thailand and genotypic profiles of isolates, we conducted a retrospective study during 2006-2008. Of 165 patients for whom bacterial cultures of blood, cerebrospinal fluid, or both were positive for S. suis serotype 2, the major multilocus sequence types (STs) found were ST1 (62.4%) and ST104 (25.5%); the latter is unique to Thailand. Clinical features were examined for 158 patients. Infections were sporadic; case-fatality rate for adults was 9.5%, primarily in northern Thailand. Disease incidence peaked during the rainy season. Disease was classified as meningitis (58.9%) or nonmeningitis (41.1%, and included sepsis [35.4%] and others [5.7%]). Although ST1 strains were significantly associated with the meningitis category (p<0.0001), ST104 strains were significantly associated with the nonmeningitis category (p<0.0001). The ST1 and ST104 strains are capable of causing sepsis, but only the ST1 strains commonly cause meningitis. PMID- 21529393 TI - Babesiosis in Lower Hudson Valley, New York, USA. AB - Although Lyme disease has been endemic to parts of the Lower Hudson Valley of New York, United States, for >2 decades, babesiosis has emerged there only since 2001. The number of Lower Hudson Valley residents in whom babesiosis was diagnosed increased 20-fold, from 6 to 119 cases per year during 2001-2008, compared with an ~1.6-fold increase for the rest of New York. During 2002-2009, a total of 19 patients with babesiosis were hospitalized on 22 occasions at the regional tertiary care center. Concurrent conditions included advanced age, malignancies, splenectomy, and AIDS. Two patients acquired the infection from blood transfusions and 1 from perinatal exposure, rather than from a tick bite. One patient died. Clinicians should consider babesiosis in persons with fever and hemolytic anemia who have had tick exposure or have received blood products. PMID- 21529394 TI - Experimental oral transmission of atypical scrapie to sheep. AB - To investigate the possibility of oral transmission of atypical scrapie in sheep and determine the distribution of infectivity in the animals' peripheral tissues, we challenged neonatal lambs orally with atypical scrapie; they were then killed at 12 or 24 months. Screening test results were negative for disease-specific prion protein in all but 2 recipients; they had positive results for examination of brain, but negative for peripheral tissues. Infectivity of brain, distal ileum, and spleen from all animals was assessed in mouse bioassays; positive results were obtained from tissues that had negative results on screening. These findings demonstrate that atypical scrapie can be transmitted orally and indicate that it has the potential for natural transmission and iatrogenic spread through animal feed. Detection of infectivity in tissues negative by current surveillance methods indicates that diagnostic sensitivity is suboptimal for atypical scrapie, and potentially infectious material may be able to pass into the human food chain. PMID- 21529395 TI - Evidence of tungiasis in pre-Hispanic America. AB - Ancient parasites of the genus Tunga originated in America and, during the first half of the 19th century, were transported to the Eastern Hemisphere on transatlantic voyages. Although they were first documented by Spanish chroniclers after the arrival of Columbus, little is known about their presence in pre Hispanic America. To evaluate the antiquity of tungiasis in America, we assessed several kinds of early documentation, including written evidence and pre-Incan earthenware reproductions. We identified 17 written documents and 4 anthropomorphic figures, of which 3 originated from the Chimu culture and 1 from the Maranga culture. Tungiasis has been endemic to Peru for at least 14 centuries. We also identified a pottery fragment during this study. This fragment is the fourth representation of tungiasis in pre-Hispanic America identified and provides explicit evidence of disease endemicity in ancient Peru. PMID- 21529396 TI - Human intraocular filariasis caused by Dirofilaria sp. nematode, Brazil. AB - A case of human intraocular dirofilariasis is reported from northern Brazil. The nematode was morphologically and phylogenetically related to Dirofilaria immitis but distinct from reference sequences, including those of D. immitis infesting dogs in the same area. A zoonotic Dirofilaria species infesting wild mammals in Brazil and its implications are discussed. PMID- 21529397 TI - Human intraocular filariasis caused by Pelecitus sp. nematode, Brazil. AB - A male nematode was extracted from iris fibers of a man from the Brazilian Amazon region. This nematode belonged to the genus Pelecitus but was distinct from the 16 known species in this genus. Similarities with Pelecitus spp. from neotropical birds suggested an avian origin for this species. PMID- 21529398 TI - Linguatula serrata tongue worm in human eye, Austria. AB - Linguatula serrata, the so-called tongue worm, is a worm-like, bloodsucking parasite belonging to the Pentastomida group. Infections with L. serrata tongue worms are rare in Europe. We describe a case of ocular linguatulosis in central Europe and provide molecular data on L. serrata tongue worms. PMID- 21529399 TI - Rickettsia rickettsii transmission by a lone star tick, North Carolina. AB - Only indirect or circumstantial evidence has been published to support transmission of Rickettsia rickettsii by Amblyomma americanum (lone star) ticks in North America. This study provides molecular evidence that A. americanum ticks can function, although most likely infrequently, as vectors of Rocky Mountain spotted fever for humans. PMID- 21529400 TI - Tick-borne encephalitis virus, Kyrgyzstan. AB - Tick-borne encephalitis virus (TBEV) is an emerging pathogen in Europe and Asia. We investigated TBEV in Kyrgyzstan by collecting small mammals and ticks from diverse localities and analyzing them for evidence of TBEV infection. We found TBEV circulating in Kyrgyzstan much farther south and at higher altitudes than previously reported. PMID- 21529401 TI - Probable non-vector-borne transmission of Zika virus, Colorado, USA. AB - Clinical and serologic evidence indicate that 2 American scientists contracted Zika virus infections while working in Senegal in 2008. One of the scientists transmitted this arbovirus to his wife after his return home. Direct contact is implicated as the transmission route, most likely as a sexually transmitted infection. PMID- 21529402 TI - Tick-borne relapsing fever borreliosis, rural senegal. AB - Detecting spirochetes remains challenging in cases of African tick-borne relapsing fever. Using real-time PCR specific for the 16S rRNA Borrelia gene, we found 27 (13%) of 206 samples from febrile patients in rural Senegal to be positive, whereas thick blood smear examinations conducted at dispensaries identified only 4 (2%) as positive. PMID- 21529403 TI - Novel bluetongue virus serotype from Kuwait. AB - Sheep and goats sampled in Kuwait during February 2010 were seropositive for bluetongue virus (BTV). BTV isolate KUW2010/02, from 1 of only 2 sheep that also tested positive for BTV by real-time reverse transcription-PCR, caused mild clinical signs in sheep. Nucleotide sequencing identified KUW2010/02 as a novel BTV serotype. PMID- 21529404 TI - Spotted fever group rickettsiae in ticks, Germany. AB - To explore increased risk for human Rickettsia spp. infection in Germany, we investigated recreational areas and renatured brown coal surface-mining sites (also used for recreation) for the presence of spotted fever group rickettsiae in ticks. R. raoultii (56.7%), R. slovaca (13.3%), and R. helvetica (>13.4%) were detected in the respective tick species. PMID- 21529405 TI - Bartonella spp. in feral pigs, southeastern United States. AB - In conjunction with efforts to assess pathogen exposure in feral pigs from the southeastern United States, we amplified Bartonella henselae, B. koehlerae, and B. vinsonii subsp. berkhoffii from blood samples. Feral pigs may represent a zoonotic risk for hunters or butchers and pose a potential threat to domesticated livestock. PMID- 21529406 TI - Rickettsia parkeri in gulf coast ticks, southeastern Virginia, USA. AB - We report evidence that Amblyomma maculatum tick populations are well established in southeastern Virginia. We found that 43.1% of the adult Gulf Coast ticks collected in the summer of 2010 carried Rickettsia parkeri, suggesting that persons living in or visiting southeastern Virginia are at risk for infection with this pathogen. PMID- 21529407 TI - Multitarget test for emerging Lyme disease and anaplasmosis in a serosurvey of dogs, Maine, USA. AB - To determine if the range of deer ticks in Maine had expanded, we conducted a multitarget serosurvey of domestic dogs (Canis lupus familiaris) in 2007. An extension of exposure to Borrelia burgdorferi to the northern border and local transmission of Anaplasma phagocytophilum throughout southern areas was found. PMID- 21529408 TI - Phylogenetic analysis of West Nile virus isolates, Italy, 2008-2009. AB - To determine the lineage of West Nile virus that caused outbreaks in Italy in 2008 and 2009, several West Nile virus strains were isolated from human specimens and sequenced. On the basis of phylogenetic analyses, the strains isolated constitute a distinct group within the western Mediterranean cluster. PMID- 21529409 TI - Genomic characterization of Nipah virus, West Bengal, India. AB - An intrafamilial outbreak in West Bengal, India, involving 5 deaths and person-to person transmission was attributed to Nipah virus. Full-genome sequence of Nipah virus (18,252 nt) amplified from lung tissue showed 99.2% nt and 99.8% aa identity with the Bangladesh-2004 isolate, suggesting a common source of the virus. PMID- 21529410 TI - Chikungunya virus, southeastern France. AB - In September 2010, autochthonous transmission of chikungunya virus was recorded in southeastern France, where the Aedes albopictus mosquito vector is present. Sequence analysis of the viral genomes of imported and autochthonous isolates indicated new features for the potential emergence and spread of the virus in Europe. PMID- 21529411 TI - Upward trend in dengue incidence among hospitalized patients, United States. AB - International travel and a global expansion of dengue fever have the potential to increase the incidence of dengue in the United States. We conducted a retrospective cohort analysis of trends in dengue among hospitalized patients by using the National Inpatient Sample (2000-2007); the number of cases more than tripled (p<0.0001). PMID- 21529412 TI - Detection and phylogenetic characterization of human hepatitis E virus strains, Czech Republic. AB - To determine the origin of hepatitis E virus in the Czech Republic, we analyzed patient clinical samples. Five isolates of genotypes 3e, 3f, and 3g were obtained. Their genetic relatedness with Czech strains from domestic pigs and wild boars and patient recollections suggest an autochthonous source likely linked to consumption of contaminated pork. PMID- 21529413 TI - Genetic characterization of West Nile virus lineage 2, Greece, 2010. AB - We conducted a complete genome analysis of a West Nile virus detected in Culex pipiens mosquitoes during a severe outbreak of human West Nile disease in Greece 2010. The virus showed closest genetic relationship to the lineage 2 strain that emerged in Hungary in 2004; increased virulence may be associated with amino acid substitution H249P. PMID- 21529414 TI - The crab hole mosquito blues. AB - Venezuelan equine encephalomyelitis (VEE) epizoodemics were reported at 6-10-year intervals in northern South America beginning in the 1920s. In 1937, epizootic VEE virus was isolated from infected horse brain and shown as distinct from the North American equine encephalomyelitis viruses. Subsequently, epizootic and sylvatic strains were isolated in distinct ecosystems; isolates were characterized serologically as epizootic subtype I, variants A/B and C; or sylvatic (enzootic) subtype I, variants D, E, and F, and subtypes II, III, and IV. In 1969, variant I-A/B virus was transported from a major outbreak in northern South America to the borders of El Salvador, Guatemala, and Honduras. This musical poem describes the history and ecology of VEE viruses and the epidemiology of an unprecedented 1969 movement of VEE viruses from South America to equids and humans in Central America from Costa Rica to Guatemala and Belize and in Mexico and the United States that continued until 1972. PMID- 21529415 TI - Plasmodium vivax seroprevalence in bred cynomolgus monkeys, China. PMID- 21529417 TI - Strongyloidiasis in man 75 years after initial exposure. PMID- 21529416 TI - Imported dengue virus serotype 3, Yemen to Italy, 2010. PMID- 21529418 TI - Anaplasma phagocytophilum infection in ticks, China-Russia border. PMID- 21529419 TI - Japanese encephalitis, Tibet, China. PMID- 21529420 TI - Babesia sp. EU1 infection in a forest reindeer, The Netherlands. PMID- 21529421 TI - Dengue virus serotype 4, Roraima State, Brazil. PMID- 21529422 TI - Novel phlebovirus in febrile child, Greece. PMID- 21529423 TI - Seroprevalence of Toscana virus in blood donors, France, 2007. PMID- 21529424 TI - Quinine-resistant malaria in traveler returning from French Guiana, 2010. PMID- 21529425 TI - Kyasanur Forest Disease virus Alkhurma subtype in ticks, Najran Province, Saudi Arabia. PMID- 21529426 TI - West Nile virus infection, Assam, India. PMID- 21529427 TI - Rare rotavirus strains in children with severe diarrhea, Malaysia. PMID- 21529428 TI - Avian malaria deaths in parrots, Europe. PMID- 21529429 TI - Fatal human case of Western equine encephalitis, Uruguay. PMID- 21529430 TI - Widespread availability of artemisinin monotherapy in the United States. PMID- 21529431 TI - Yersinia pestis DNA sequences in late medieval skeletal finds, Bavaria. PMID- 21529432 TI - And therefore i have sailed the seas and come to the holy city of Byzantium. PMID- 21529433 TI - Value of [18F] fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in diagnosis and localization of Cushing's disease. AB - OBJECTIVE: To explore the value of [18F]fluoro-2-deoxy-D-glucose(18 FDG) positron emission tomography and computer tomography (PET/CT) in the qualitative diagnosis and localization of Cushing's disease. METHODS: Totally 12 patients underwent transsphenoidal adenomectomy and were histopathologically proven to be with Cushing's disease. 18FDG PET/CT whole-body and brain scannings were performed preoperatively; meanwhile, magnetic resonance imaging (MRI) and 99mTc-octreotide examination were done in all 12 cases, and inferior petrosal sinus sampling (IPSS) were done in 6 patients. RESULTS: The sensitivity of 18FDG in diagnosing Cushing's disease was 91.6% (11/12), but MRI was 66.7%(8/12). For the 6 patients who performed IPSS, 5 of them was diagnosed to be with Cushing's disease, and only 50% (3/6) were localized correctly in the pituitary gland. CONCLUSIONS: 18FDG PET/CT whole-body scan can exclude ectopic adrenocorticotropin-secreting tumors and localize the pituitary lesions with higher accuracy than MRI. Therefore, it is useful for suspected Cushing's disease, especially for patients their MRI and IPSS have negative or paradoxical results. PMID- 21529434 TI - Value of brain magnetic resonance imaging and tumor markers in the diagnosis and treatment of intracranial germinoma in children. AB - OBJECTIVE: To evaluate the role of brain magnetic resonance imaging (MRI) and tumor markers in the cerebral spinal fluid (CSF) and serum in the diagnosis and treatment of intracranial germinoma in children. METHODS: Totally 5 children (3 girls and 2 boys) who were treated in our hospital between January 2009 and December 2010 due to central diabetes insipidus. All patients received contrast enhanced brain MRI at presentation and during each follow-up: meanwhile, their anterior pituitary hormones and tumor markers including human chorionic gonadotropin (hCG) and alpha fetoprotein (AFP) were also determined. RESULTS: Three patients presented without prior evaluation, and two patients were referred to our hospital due to exaggerated disease of unknown cause. Their ages at presentation ranged from 8 years to 12 years 1 month, and the duration of symptoms at presentation was between 1 month to 78 months. All of them had polyuria and polydipsia at presentation. Except one child, the other 4 patients had growth retardation and failure in initiation of puberty. Although the growth rate and puberty development were normal during the 2-year follow-up for the excepted child, all child experienced anterior pituitary hypofunction and an increased concentration of plasma prolactin after the lesion became enlarged. Three patients had cerebral hernia, which presented in 18, 24, and 78 months, respectively. In three patients, brain MRI at presentation showed isolated pituitary stalk thickening, which further developed into massive tumor in the hypothalamus pituitary region 18-22 months later; in the remaining two patients, large brain tumor was found via MRI at their first presentations. In all five patients, the posterior pituitary gland (bright spot) disappeared on T1-weighted MRI images. CSF hCG elevated in all five patients, and serum hCG increased in four patients; the level of hCG varied with the mass size of tumor. Serum and CSF AFP increased in only one patient. CONCLUSIONS: Patients with idiopathic central diabetes insipidus must be closely followed to identify the etiology, especially when anterior pituitary hormone deficiencies are detected. For patients with normal brain MRI results or simply isolated pituitary stalk thickening at presentation, the changes of serial contrast-enhanced brain MRI should be observed during follow-up to ensure the early detection of an evolving occult hypothalamic-stalk lesion. Determination of CSF hCG at the first presentation may be useful, because an increased CSF level of hCG precedes MRI abnormalities. PMID- 21529435 TI - Long-term follow-up and humanistic care for patients with hypophyseal tumor. AB - The number of new cases of hypophyseal tumor increases along with the advances in neuroimaging technology in recent years. The common treatment models include surgical treatment, radiotherapy, and medical therapies. This article discusses the application of long-term follow-up in non-operative hypophyseal tumor patients and its influence on the prognosis. Meanwhile, since the medical mode has switched from biomedical model to biopsychosocial medical model, management of hypophyseal tumor should not be limited in its biological aspect, but also from the perspective of psychology by providing more humanistic care to meet the patients'psychological needs. PMID- 21529436 TI - Application of positron emission tomography in the clinical evaluation and treatment of hypothalamic-pituitary diseases. AB - Positron emission tomography (PET) and PET/CT are playing increasingly important roles in the clinical evaluation and treatment of tumors. As neuroendocrine tissues, the hypothalamus and pituitary gland have their unique features, and PET can be valuable in evaluating hypothalamic-pituitary diseases lesions. This article reviews the application of PET in the clinical evaluation and treatment of hypothalamic-pituitary diseases. PMID- 21529437 TI - Safety of recombinant human growth hormone in treating children with growth hormone deficiency and idiopathic short stature. AB - Recombinant human growth hormone is generally safe in treating children with growth hormone deficiency and idiopathic short stature. However, side effects such as sodium and water retention, benign intracranial hypertension, insulin insensitivity, increasing risk of secondary neoplasm, scoliosis, and slipped capital femoral epiphysis may occur occasionally, although the overall incidence remains low. PMID- 21529438 TI - Advances in pathogenesis of pituitary adenomas. AB - Along with the rapid development of molecular biology, cell biology, genetics, and immunology, there is a new understanding on the pathogenesis of pituitary adenomas. The pathogenesis of pituitary adenomas is considered to be related with gene mutation, growth factors, cell receptors, transcription factors, and cellular signaling pathways. PMID- 21529439 TI - Impact of lesion size on the detection rate of non-palpable breast malignant lesions. AB - OBJECTIVE: To evaluate the impact of lesion size on the detection rate of non palpable breast malignant lesions and determine whether lesion size should prompt biopsy of non-palpable breast lesions. METHODS: The study included 816 ultrasonographically detected non-palpable breast lesions. We divided the lesions into five groups based on their largest diameters: <=0.5cm, 0.6-1.0cm, 1.1-1.5cm, 1.6-2.0 cm, and >2.0 cm. The detection rate of malignancies of different sizes were compared among these lesions, Breast Imaging Reporting and Data System (BI RADS) category 2-3 lesions, and BI-RADS grades 4-5 lesions. The feasibility of using lesion size as biopsy indicator for BI-RADS category 2-3 non-palpable breast lesion was analyzed using ROC curve. RESULTS: Of these 816 lesions, 100 (12.3%) were found to be malignant lesions. The detection rate of malignancy significantly increased along with the increase of lesion size (P<0.05). When the BI-RADS category was not considered, the frequency of malignancy in the >2.0 cm group was significantly higher than in other groups (P<0.05) The frequencies of malignancy in the 0.6-1.0 cm group, 1.1-1.5 cm group, and 1.6-2.0 cm group were higher than that in <=0.5 cm group, but the difference was not significant (P>0.05) For BI RADS category 4 and 5 lesions, the frequency of malignancy in >2.0 cm group was higher than in other groups, but significant difference was only seen between >2.0 cm group and <=0.5 cm group (P<0.05). CONCLUSIONS: Lesion size may influence the detection rate of malignancy of non palpable breast lesions, and can be used as biopsy indicator of non palpable breast lesions in BI RADS 2,3 category When we use 1.25cm as threshold,the sensitivity and specificity may be satisfying. PMID- 21529440 TI - Diagnosis of popliteal artery entrapment syndrome with multidetector row spiral computed tomography. AB - OBJECTIVE: To evaluate the role of multidetector row spiral computed tomography in the diagnosis of popliteal artery entrapment syndrome (PAES). METHOD: Ten patients (13 limbs) were diagnosed as PAES through open surgery in Peking Union Medical College Hospital from January 2006 to December 2009, among whom three (30.0%) had both limbs involved. RESULTS: Eleven limbs (84.6%) had occlusions in popliteal artery at admission. While only 15.4% of the patients were diagnosed as PAES by positional stress test, Doppler ultrasound, and arterial angiography, the disease was confirmed in all 10 patients by spiral computed tomography. As shown by inter-operative exploration, the PAES types included type 1 (n=2, 15.4%), 2(n=5, 38.5%),3 (n=4, 30.8%), and 5 (n=2, 15.4%). Two limbs underwent popliteal artery release only, 8 limbs underwent politeal artery release, thromboendarterectomy, and angioplasty with a venous or prosthetic patch, and 3 patients underwent catheter-based thrombolysis and popliteal artery release subsequently. During the follow-up (mean: 22 months; range: 4-33 months), the primary patency rate was 92.3% (12/13), the total patency rate was 100% (13/13), and the limb salvage rate was 100%. CONCLUSION: Positional stress test, Doppler ultrasound, and arterial angiography play limited roles in the diagnosis of PAES with popliteal artery occlusion, while multidetector row spiral computed tomography is much helpful in diagnosing and typing PAES. PMID- 21529441 TI - Expression of proteasome immunosubunit in labial glands of patients with primary Sjogren's syndrome. AB - OBJECTIVE: To investigate the expression of proteasome immunosubunit low molecular weight polypeptide (LMP)2 and LMP7 in labial glands of patients with primary Sjogren's syndrome patients, and thus explore their role in the diagnosis, differential diagnosis and pathogenesis of primary Sjogren's syndrome (pSS). METHODS: Labial specimens were collected from 40 patients with pSS, 15 patients with connective tissue diseases other than pSS, and 9 healthy controls. The expressions of LMP2 and LMP7 in labial specimens were determined using immunohistochemical approaches and analyzed using semi-quantitative methods. The positive rate of acinar was calculated. After the square arcsine transformation of data, the differences of the positive rate in acinar between LMP2 and LMP7 were compared among three groups. Spearman's rank correlation coefficient was used for analyzing the correlation of clinical manifestations with LMP2 and LMP7 expressions. RESULTS: The expressions of LMP2 and LMP7 within the acinar and ductal epithelial cells were confirmed. Although the LMP2 expression in labial specimens was not significantly different among three groups(P=0.369), the expression of LMP7 was significantly higher in pSS patients compared with patients with connective tissue disease and healthy controls (P<0.01). Only in pSS group, LMP7 was found to be with higher positive rate in acinar than LMP2 (P<0.01). No significant correlation was found between LMP2/LMP7 and clinical manifestations (P>0.05). CONCLUSION: In patients with pSS, the expression of LMP7 (but not LMP2) is up-regulated in labial gland, indicating these two proteins have different genetic regulation mechanisms. PMID- 21529442 TI - Therapeutic effect of anti-amyloid beta peptide single-chain antibody gene mediated by adeno-associated virus on animal Alzheimer's disease. AB - OBJECTIVE: To investigate the therapeutic effect of recombinant adeno-associated virus carrying anti-amyloid beta peptide single-chain antibody gene on Alzheimer's disease (AD) in animal models. METHODS: The recombinant adeno associated viruses were injected to the leg muscle of mutant amyloid precursor protein transgenic AD mice. The latency of the mice in Morris water maze was tested before and 3, 7, 10 months after drug administration. The animal brains were harvested 10 months after drug administration and sectioned for amyloid plaques staining. RESULTS: The learning and memory abilities of AD model mice were improved significantly 3 months after gene drug administration. Ten months after gene therapy, the numbers of amyloid plaque in hippocampus of model mice decreased. CONCLUSION: The adeno-associated virus carrying anti-amyloid beta peptide single-chain antibody gene has therapeutic effect on AD in model mice. PMID- 21529443 TI - Insulin-like growth factor binding protein-3 interacts with the thyroid hormone receptor alpha1 and modulates transcription of thyroid hormone responsive gene. AB - OBJECTIVE: To study the interaction between insulin-like growth factor binding protein-3 (IGFBP-3) and thyroid hormone receptor alpha1 (TRalpha1) and the modulatory effect of IGFBP-3 on transcription of the thyroid hormone responsive gene. METHODS: The interaction between IGFBP-3 and TRalpha1 was detected with glutathione-S-transferase pull-down method, co-immunoprecipitation, fluorescence resonance energy transfer test. The cellular distribution of these two proteins was observed by confocal laser scanning microscopy. The effect of IGFBP-3 on the growth hormone promoter activity stimulated by triiodothyronine (T3) was determined by dual-luciferase reporter assay. RESULTS: IGFBP-3 interacted with TRalpha1 both in vivo and in vitro. IGFBP-3 and TRalpha1 were shown to co localize in the nucleus of HEK-293 cells. The overexpressed IGFBP-3 inhibited the growth hormone promoter activity stimulated by T3 (P<0.01). CONCLUSIONS: IGFBP-3 interacts with TRalpha1 and inhibits T3 responsive gene transcription. This finding further confirms the insulin-like growth factor-independent role of IGFBP 3 in the nucleus. PMID- 21529444 TI - Prevalence and risk factors of peripheral arterial diseases in male Chinese octogenarians and nonagenarians with hypertension. AB - OBJECTIVE: To investigate the prevalence and risk factors of peripheral arterial disease (PAD) in male Chinese octogenarians and nonagenarians with hypertension. METHODS: Ankle-brachial index (ABI) was measured in the noninvasive vascular laboratory for hypertensive male octogenarians and nonagenarians enrolled from outpatient and inpatient departments. The baseline conditions were investigated using standard questionnaire and by routine physical examinations. PAD was diagnosed when an ABI<=0.9 in either lower extremity. RESULTS: Totally 290 male Chinese octogenarians and nonagenarians [age: (84.61+/-4.20) years] with hypertension who were receiving antihypertensive therapy were enrolled in this study, among whom 9 men with missing data except age and ABI measurements. The ABI was 0.948+/-0.258, with the range of highest frequency of 0.91-1.30, and 106 patients were diagnosed as PAD, 182 as non-PAD, and 2 had ABI>1.3. ABI in hypertensive men with PAD were significantly lower than in those without PAD (P<0.05). On the contrary, age, blood urea nitrogen, white blood cell counts, platelets and aspartic transaminase were significantly higher in PAD patients than in non-PAD patients (all P<0.05). The prevalence of PAD in this study population were 36.5%; more specifically, it significantly differed between different subgroups when stratified by age (28.6% vs. 46.3%, below and above 85 years), with and without hypertension (27.5% vs. 40.1%), stroke (44.7% vs. 27.5%), dyslipidemia (41.4% vs. 33.3%), coronary artery disease (44.1% vs. 13.9%), and diabetes mellitus (53.7% vs. 21.8%) (all P<0.05). The prevalences of PAD in hypertensive patients treated with diuretics, calcium antagonists, beta blocker, or angiotensin receptor antagonist were 41.4%, 36.1%, 22.4%, and 26.8%, respectively. No association was observed between the prevalence of PAD and smoking/alcohol drinking in these subjects. Multivariate analysis showed that age (OR 1.12, 95%CI 1.014-1.238), blood urea nitrogen (OR 1.15, 95%CI 1.025-1.301), aspartic transaminase (OR 1.05, 95%CI 1.005-1.089), diabetes mellitus (OR 4.02, 95%CI 1.797-9.009), coronary artery disease (OR 6.34, 95%CI 1.734-23.214) were strong risk factors of PAD. CONCLUSION: PAD is highly prevalent among aged Chinese hypertensive men, in which age, blood urea nitrogen, aspartic transaminase, diabetes mellitus, coronary artery disease may be involved in the development of this condition. PMID- 21529445 TI - T2 mapping of articular cartilage in knee osteoarthritis using a magnetic resonance staging. AB - OBJECTIVE: To evaluate T2 mapping of articular cartilage in knee osteoarthritis (OA). METHODS: Totally 38 healthy subjects (group H) and 53 OA patients received scoring with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)and underwent T2 mapping of tibiofemoral articular cartilages. The T2 values in 10 subregions of the cartilages were measured. Patients in the OA group were further divided into OA1 group and OA2 group using the modified Magnetic Resonance Recht Grading System. In OA group, the fat-suppressed three-dimensional fast spoiled gradient echo MRI was performed to obtain the modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). The differences of T2 values among group H, group OA1, and group OA2 were compared. The correlation between T2 value and WORMS/WOMAC scores was analyzed. The intra- and inter-observer reproducibility of measurement was calculated. RESULTS: The T2 values in all the subregions ranged 43.9-53.6ms in group H, 41.1-55.0 ms in group OA1, and 45.6 56.1ms in group OA2. T2 values in group OA2 were significantly higher in central medial femoral subregion, central medial, and lateral tibial subregions compared with group H, also significantly higher in central medial femoral subregion, anterior and central medial tibial subregions compared with group OA1 (P<0.05). T2 values were significantly correlated with WORMS scores (R=0.307-0.811, P<0.01) except in posterior lateral femoral subregion, but not with WOMAC scores. The correlation coefficients for intra- and inter-observer measurement showed good reproducibility (R>0.740, P<0.05) except in anterior lateral tibial subregion for inter-observer of measurement. CONCLUSION: T2 mapping can differentiate the OA severity of knee cartilage using a magnetic resonance staging, and therefore can be a sensitive technique for monitoring the severity of OA. PMID- 21529446 TI - Role of transrectal real-time tissue elastography in the diagnosis of prostate cancer. AB - OBJECTIVE: To investigate the role of transrectal real-time tissue elastography (TRTE) in the diagnosis of prostate cancer (PCa). METHODS: Eighty-four patients with suspected PCa and scheduled for prostate biopsies underwent TRTE, digital rectal examination (DRE), transrectal ultrasonography (TRUS), and magnetic resonance imaging (MRI). The findings of TRTE were compared with those of other examinations and pathological findings. RESULTS: Of these 84 patients, 36 had benign lesions and 48 had PCa. The diagnostic sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 91.7%, 72.2%, 83.3%, 81.5%, and 86.7% for TRTE and 85.4%i63.9%i76.2%, 75.9%, and 76.7% for TRUS (P>0.05), while its specificity (72.2%) was significantly higher than that of MRI (44.4%) (P=0.03). The TRTE findings were not significantly correlated with the pathological findings and serum total prostate specific antigen (P>0.05), and the diagnostic sensitivity of TRTE decreased along with the enlargement of prostate. However, the diagnostic specificity of TRTE was higher than MRI for nodules with soft to medium texture (P=0.04).For PCa, the diagnostic sensitivity of TRTE increased when the Gleanson scores of tumors increased (P<0.05). CONCLUSION: TRTE can be used as a diagnostic test to supplement clinical diagnosis of PCa. PMID- 21529447 TI - Total pelvic floor reconstruction surgery for repair of severe pelvic organ prolapse. AB - OBJECTIVE: To evaluate clinical effectiveness of total pelvic floor reconstruction surgery for repair of severe pelvic organ prolapse. METHODS: We retrospectively analyzed the clinical data of 21 patients with severe pelvic organ prolapse. The anatomical outcomes were evaluated by Pelvic Organ Prolapse Quantitation, functional effectiveness by Prolapse Quality of Life method, and sexual function and operation-related complications were also analyzed. RESULTS: All surgical operations were accomplished successfully by the same surgeon. No impairment of bladder, urethra, rectum, or great vessels was noted, and no patient required blood transfusion. The mean operation duration was (63+/-19) minutes, and the mean intra-operative blood loss was (143+/-72) ml. One patients experienced post-operative urinary retention for 7 days, and the remaining 20 patients were able to micturate spontaneously 1-2 day after surgery. The post operative morbidity rate was 14.3%. Three patients (14.3%) experienced mesh erosion. Of 12 patients who were sexually active, two patients suffered from algopareunia from dyspareunia, one from de novo overactive bladder, and one from stress urinary incontinence Questionnaire scores showed that the overall post operative quality of life was improved significantly (P=0.000), while quality of sexual life significantly degraded (P=0.044) The anatomic cure rate was 95.2% (20/21), and the patient subjective satisfaction rate was 85.7% (18/21) CONCLUSIONS: The total pelvic floor reconstruction is a safe and effective approach for the repair of severe pelvic organ prolapse, although its functional effectiveness is not as notable as anatomical outcomes However, the complications such as mesh erosion, low urinary tract symptoms, algopareunia, and dyspareunia should be carefully managed. PMID- 21529448 TI - Expression of MicroRNA-146a in peripheral blood mononuclear cells in patients with systemic lupus erythematosus. AB - OBJECTIVE: To explore the expression pattern of microRNAs in the peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE), with an attempt to identify the role of microRNA in the pathogenesis of SLE. METHODS: SLE-related genes were searched from the published literatures. Using the microRNA target gene prediction databases, we predicted the putative microRNA targets in these SLE-related genes. For some of the corresponding microRNAs (hsa miR-146a), quantitative real-time polymerase chain reaction was performed to determine the expression levels of these microRNAs in PBMCs of SLE patients (SLE group) and healthy controls (control group). RESULT: The discrepancy of cycle threshold of hsa-miR-146a in PBMCs was significantly higher in SLE group (4.52+/ 1.18) than in control group (2.76+/-1.38) (P=0.02), and the expression level of hsa-miR-146a was significantly lower in SLE group. CONCLUSION: The expression of hsa-miR-146a decreases in SLE patients, indicating that hsa-miR-146a may play a role in the pathogenesis of SLE. PMID- 21529449 TI - Effects of drag-reducing polymers on microcirculation of normal rat hindlimb skeletal muscle. AB - OBJECTIVE: To observe the effects of polyethylene oxide (PEO) on microcirculation of normal rat hindlimb skeletal muscle. METHODS: Sixteen male Wistar rats were anesthetized and equally and randomly divided into PEO group (administered with 10 ppm PEO solution) and control group (administered with equal volume of normal saline). The PEO solution or saline was separately injected through the caudal vein at a constant rate of 5 ml/h for 20 minutes. Using short axis view at right mid thigh region, contrast-enhanced ultrasonography was performed before and after the administration of solution. Electrocardiogram, blood pressure, and central venous pressure were also monitored. RESULTS: In the PEO group, after the administration of PEO, microcirculation capillary volume increased from (20.78+/ 2.63) dB to (22.40+/-1.94) dB (P=0.023), red blood cell velocity from (0.27+/ 0.08) s-1 to (0.35+/-0.13) s-1(P=0.010), and capillary blood flow from (5.65+/ 1.81) dB/s to (7.91+/-3.28) dB/s (P=0.013). In the control group, there were no significant changes in microcirculation capillary volume, red blood cell velocity, and capillary blood flow (all Pp0.05) after the injection of normal saline. The changes of heart rates, blood pressures and central venous pressure were not significant after the administration of either PEO or saline (all Pp0.05). CONCLUSION: PEO can remarkably increase capillary volume, red blood cell velocity, and capillary blood flow in normal rat hindlimb skeletal muscle. PMID- 21529450 TI - Spinal factors affecting pulmonary function in patients with scoliosis. AB - OBJECTIVE: To investigate pulmonary function impairment and the spinal factors that may determine pulmonary function in patients with scoliosis. METHODS: Seventy-eight patients with idiopathic scoliosis or congenital scoliosis and 78 age- and gender-matched healthy subjects were enrolled in this study. The radiographic parameters of spinal deformity were obtained from patients with scoliosis. Both two groups received pulmonary function tests. RESULTS: Patients with scoliosis demonstrated a restrictive pattern of pulmonary function impairment with a proportional decrease in both forced expiratory volume in one second and forced vital capacity. Total lung capacity and functional residual capacity were reduced. Carbon monoxide diffusion capacity was decreased, while diffusion coefficient remained normal or slightly higher. Airway resistance and conductance were not affected. In addition, airway resistance and residual volume were found abnormal in patients with congenital scoliosis. Multiple linear regression analysis showed that three spinal factors including involved thoracic vertebrae, vertical height from C7 to S1, and Cobb angle were independently responsible for 40%-51% of total variances of forced vital capacity, forced expiratory volume in one second, total lung capacity, and functional residual capacity. CONCLUSIONS: Patients with scoliosis have restrictive ventilation defects. More thoracic vertebrae involvement, lower vertical height, and larger Cobb angle are associated with severer impairment of lung volume. PMID- 21529451 TI - Detection of genetic variations of regulator of G-protein signaling 2 in hypertensives by sequencing. AB - OBJECTIVE: To investigate the new genetic variations of regulator of G-protein signalling 2 (RGS2) gene in Kazakh hypertensives. METHODS: Totally 94 Kazakh patients with essential hypertension were enrolled and genomic DNA was extracted from their peripheral blood leukocytes. All the exon regions and their flanking sequences of RGS2 were directly sequenced. RESULTS: We identified 13 variants including 5 common- single nucleotide polymorphisms with a minor allele frequency over 5%single nucleotide polymorphisms and 8 novel variations in 94 Kazakh hypertensives. Among these variations, 2 were in the introns and 7 in the promoter region. One subject had a G-to-C substitution at nucleotide 54 in exon 1, which lead to an amino acid substitution from K-to-N at position 18; another individual had an A-to-G substitution at nucleotide 2422 in exon 5, resulting in an amino acid from Y-to-C at position 178. Among eight common single nucleotide polymorphisms, -638A>G, -395G>C, 1891-1892TC I/D, and 2971G>C,and -43A>T and 2297A>G were in tight linkage disequilibrium with an r-square of more than 0.8, respectively. CONCLUSIONS: The variants and their frequencies in RGS2 gene in Kazakh hypertensives may have ethnic differences when compared with other populations. The frequencies of the mutations are low in this population, and whether they influence blood pressure regulation requires further functional experiments. PMID- 21529452 TI - Significance of trypsinogen activation peptides and interleukin-6 in experimental acute pancreatitis. AB - OBJECTIVE: To explore the feasibility of using plasma trypsinogen activation peptides (TAP) and serum interleukin-6(IL-6) as early markers for predicting the severity of experimental acute pancreatitis. METHODS: Ninety male adult Sprague Dawley rats were equally randomized into five groups: edema pancreatitis group, treated with retrograde ductal infusion of 3% sodium taurocholate solution; necrosis pancreatitis group, treated with retrograde ductal infusion of 5% sodium taurocholate solution; treatment pancreatitis group, treated with retrograde ductal infusion of 3% sodium taurocholate solution and ulinastatin intravenous infusion half an hour later; control pancreatitis group, treated with 0.9% normal saline retrograde ductal infusion; and sham operation group, treated with sham operation. Rats in each group were equally randomized into three subgroups, which were killed by exsanguination 3, 6, or 24 hours after infusion, and blood specimens were obtained. Serum amylase, plasma TAP, and serum IL-6 were determined. The severity of pancreatitis was scored by two blinded pathologists under microscope. RESULTS: At 3 and 6 hours after infusion, plasma TAP concentration of necrosis pancreatitis group [(4.798+/-0.169) and (3.999+/ 0.299)nmol/L, respectively]were significantly higher than those of edema pancreatitis group [(2.416+/-0.148) and (3.356+/-0.211)nmol/L, respectively] (P<0.01); at 6 hours after infusion, serum IL-6 level of necrosis pancreatitis group [(1339.51+/-56.43)pg/ml]was significantly higher than that of edema pancreatitis group [(619.07+/-42.25)pg/ml] (P<0.01). CONCLUSIONS: In this acute pancreatitis model, the peak levels of plasma TAP and serum IL-6 may appear earlier in rats with severer disease. Serum TAP level may be used as a marker for the accurate early prediction of the severity of acute pancreatitis. PMID- 21529453 TI - Application of trichloroacetic acid-acetone precipitation method for protein extraction in bone tissue. AB - OBJECTIVE: To explore the feasibility and efficiency of extracting protein from bone tissue using trichloroacetic acid (TCA)-acetone precipitation method. METHODS: Hydrochloric acid (HCL) decalcification method and TCA-acetone precipitation method were separately used for bone protein extraction. The efficiencies of these two methods were compared. RESULTS: TCA-acetone precipitation method had significantly higher extraction efficiency. Compared with HCL decalcification method, it had less pollution from bone marrow hematopoietic tissue. Protein band distribution was similar between these two methods. CONCLUSION: TCA-acetone precipitation method is useful for bone proteomics research. PMID- 21529576 TI - Sustained delivery of oncolytic adenovirus in alginate gel for local tumor virotheraphy. PMID- 21529577 TI - Improved drug loading/release capacities of commercial contact lenses obtained by supercritical fluid assisted molecular imprinting methods. PMID- 21529578 TI - Cationic solid lipid nanoparticles loaded by cystein proteinase genes as a novel anti-leishmaniasis DNA vaccine delivery system: characterization and in vitro evaluations. PMID- 21529579 TI - Functionalized poly(l-lactide) single crystals coated with antigens in development of vaccines. PMID- 21529580 TI - Development of liposome-based freeze-dried rods for vaginal vaccine delivery against HIV-1. PMID- 21529581 TI - Supercritical fluids strategies to produce hybrid structures for drug delivery. PMID- 21529582 TI - Supramolecular triblock copolymers controlled by the coiled-coil motif: a new tool for drug delivery. PMID- 21529583 TI - Nanoparticles against Alzheimer's disease: PEG-PACA nanoparticles are able to link the abeta-peptide and influence its aggregation kinetic. PMID- 21529584 TI - Tumor cell killing efficiency of doxorubicin loaded microbubbles after ultrasound exposure. PMID- 21529585 TI - Inhibition of influenza virus activity by newly designed multivalent glycoarchitectures. PMID- 21529586 TI - Folate PEGylated archaeal lipids: cell targeting and drug delivery. PMID- 21529587 TI - Targeting tumor stromal cells through a PDGF-beta receptor binding carrier. PMID- 21529588 TI - Comprehensive in vitro investigations on biodegradable photosensitizer nanoparticle delivery systems. PMID- 21529589 TI - A preliminary study of chitosan-pentosan polysulfate sodium complex as vaginal sustained drug delivery system in a rare disease treatment. PMID- 21529590 TI - Novel paclitaxel nanoparticles: development, in vitro anti-tumor activity in BT 549 cells and in vivo evaluation. PMID- 21529591 TI - Crosslinkable polymers for nanocrystal stabilization. PMID- 21529592 TI - Targeted core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin. PMID- 21529593 TI - Nanosuspensions of chemically modified saponins: reduction of hemolytic side effects and potential tool in drug targeting strategy. PMID- 21529594 TI - Tumor targeted adenovirus nanocomplex ionically crosslinked by chitosan. PMID- 21529595 TI - Unbreakable codes in electrospun fibers to stop medicine counterfeiting. PMID- 21529596 TI - Biodegradable polymersomes as efficient nanocarriers for controlled paclitaxel delivery. PMID- 21529597 TI - Development of controlled release formulations by means of ALRISE's ImSus((r)) platform technology. PMID- 21529598 TI - Protein macromonomers for covalent immobilization and subsequent triggered release from hydrogels. PMID- 21529599 TI - Polymeric nanoreactors for enzyme replacement therapy of MNGIE. PMID- 21529600 TI - Development of polymeric and cyclodextrin nanoparticles for camptothecin delivery. PMID- 21529601 TI - Stereocomplexed & photocrosslinked poly(ethylene glycol)-poly(lactide) star block copolymer hydrogels. PMID- 21529602 TI - Development of efficient macromolecular prodrugs derived from dendritic polyglycerol. PMID- 21529603 TI - Microfluidic reactors for controlled synthesis of polymeric micelles. PMID- 21529604 TI - Production of low cost microfluidic chips by a "shrinking" approach: applications to emulsion and microparticle production. PMID- 21529605 TI - In-situ forming hydrogels by simultaneous thermal gelling and Michael addition reaction between methacrylate bearing thermosensitive triblock copolymers and thiolated hyaluronan. PMID- 21529606 TI - Increment in molecular weight of poly (dimethylamino-ethylmethacrylate) based polymers cause strong red blood cell aggregation but not hemolytic response. PMID- 21529607 TI - Exploring the binding of Pt drugs to gold nanoparticles for controlled passive release of cisplatin. PMID- 21529608 TI - Interaction of liposomes with proteins measured by surface plasmon resonance correlates with their in vivo circulation time. PMID- 21529609 TI - Supercritical solvent impregnation of natural bioactive compounds in N carboxybutyl chitosan membranes for the development of topical wound healing applications. PMID- 21529610 TI - Transport and delivery of antimicrobial agents in Burkholderia biofilms. PMID- 21529611 TI - Monitoring of surface interactions as a tool for nanoparticle design. PMID- 21529612 TI - In vitro evaluation of the stability of proline-specific endopeptidases under simulated gastrointestinal conditions. PMID- 21529613 TI - Microspheres of hydrophilic PLGA highly attractive for protein delivery. PMID- 21529614 TI - The effect of HPbetaCD on Cyclosporine A in-vitro release from PLGA nanoparticles. PMID- 21529615 TI - Rapid gelation of injectable hydrogels based on hyaluronic acid and poly(ethylene glycol) via Michael-type addition. PMID- 21529616 TI - Mesoporous silicon microparticles as carriers for peptides. PMID- 21529617 TI - Morphology of new zwitterionic copolymer matrices for sustained drug release. PMID- 21529618 TI - Lysozyme uptake and release by oxidized starch polymer microgels. PMID- 21529619 TI - Degradable polyesteramides: a novel platform for sustained drug delivery. PMID- 21529620 TI - Investigation of sterically stabilized liposomes by diffusion ordered NMR spectroscopy. PMID- 21529621 TI - Photocrosslinked poly(ester anhydride) for surface erosion controlled drug release. PMID- 21529622 TI - Drug loading in Pluronic(r) micelles made by solvent casting and equilibrium methods using resveratrol as a model drug. PMID- 21529623 TI - Aerosol-processed polymeric drug nanoparticles for sustained and triggered drug release. PMID- 21529624 TI - Temperature controlled release from polystyrene-block-poly(N-isopropylacrylamide block-polystyrene block copolymer hydrogel. PMID- 21529625 TI - Protein encapsulation in polyelectrolyte microcapsules for antigen delivery. PMID- 21529626 TI - Novel manganese-ferrite nanocomposites for targeted delivery of anticancer drugs. PMID- 21529627 TI - Ultrasound responsive doxorubicin-loaded microbubbles; towards an easy applicable drug delivery platform. PMID- 21529628 TI - Adeno-associated virus loaded microbubbles as a tool for targeted gene delivery. PMID- 21529629 TI - Thermoresponsive micelles for radionuclide delivery. PMID- 21529630 TI - Ultrasound-mediated targeted microbubble sonoporation of endothelial cells. PMID- 21529631 TI - Engineering magnetic nanoparticles and formulations for gene delivery. PMID- 21529632 TI - Targeted delivery of gold nanorods modified with thermo-sensitive polymer. PMID- 21529633 TI - Investigation of dye glycopolymer and glycopolymer hydrogel interactions for development of multi-release system. PMID- 21529634 TI - MRI contrast enhancement potential of different superparamagnetic iron oxide nanoparticle (SPION) formulations. PMID- 21529635 TI - Magnetic particles and sensing methods for medical applications. PMID- 21529636 TI - Lyophilisomes: Potential carriers for tumor targeting. PMID- 21529637 TI - IR-light triggered drug delivery from micron-sized polymer biocoatings. PMID- 21529638 TI - Using controlled laser-microporation to increase transdermal delivery of prednisone. PMID- 21529639 TI - Flexible scaffolds based on poly(trimethylene carbonate) networks for cardiac tissue engineering. PMID- 21529640 TI - Process optimization for the production of alginate microparticles containing wjmscs by a design of experiments (doe) approach. PMID- 21529641 TI - Preparation and characterization of cationic nanoparticles loaded with Mitomycin C by double emulsion and ionotropic gelation techniques. PMID- 21529642 TI - Photo-crosslinked poly(trimethylene carbonate)-fumarate/n-vinyl pyrrolidone networks for the controlled release of proteins. PMID- 21529643 TI - Novel encapsulation technology for the preparation of core-shell microparticles. PMID- 21529644 TI - Super-macroporous poly(ethoxytriethyleneglycol acrylate) hydrogels for sustained delivery of hydrophilic drugs. PMID- 21529645 TI - Charged dextran hydrogels for post-loading and release of proteins. PMID- 21529646 TI - An alternative cyclodextrin based formulation for oral anticancer drug exemestane: In vitro and cell culture studies. PMID- 21529647 TI - Poly(amido amine) copolymers derived from aminobutanol and ethylene diamine are excellent carriers for siRNA delivery. PMID- 21529648 TI - siRNA versus pharmacological inhibition of endocytic pathways for studying cellular uptake of cell penetrating peptides. PMID- 21529649 TI - Programmed packaging of multicomponent envelope-type nanoparticle system (MENS). PMID- 21529650 TI - Design of solid lipid nanoparticles for gene delivery into prostate cancer. PMID- 21529651 TI - siRNA transfection by dendritic core-shell nanocarriers. PMID- 21529652 TI - Bioreducible poly(amidoamine)s with charge-reversal properties for intracellular protein delivery. PMID- 21529653 TI - Interactions of siRNA loaded dextran nanogel with blood cells. PMID- 21529654 TI - Monoolein as helper lipid for non-viral transfection in mammals. PMID- 21529655 TI - Effects of charge density and hydrophobicity: acetylation versus benzoylation of amino butyl SS-PAAS for gene delivery. PMID- 21529656 TI - Surface adsorption of protein corona controls the cell uptake mechanism in efficient cationic liposome/DNA complexes in serum. PMID- 21529657 TI - Biodegradable dextran nanogels as functional carriers for the intracellular delivery of small interfering RNA. PMID- 21529658 TI - Nuclear inclusion of inert and chromatin-targeted polystyrene spheres and plasmid DNA containing nanoparticles. PMID- 21529659 TI - Photochemical internalization (PCI)-mediated enhancement of gene silencing efficiency of polymethacrylates and N,N,N-trimethylated chitosan (TMC) based siRNA polyplexes. PMID- 21529660 TI - Unraveling the cellular uptake of bioreducible poly(amido amine)--gene complexes in cells of the retinal pigment epithelium. PMID- 21529701 TI - Whether, how, and when social anxiety shapes positive experiences and events: a self-regulatory framework and treatment implications. AB - Although neglected in diagnostic criteria lists, theoretical models, and treatment approaches, attenuated positive emotions and cognitions distinguish social anxiety and social anxiety disorder from other anxiety conditions (and cannot be accounted for by comorbidity with depression). We present a self control resource depletion model to explain how the intense self-regulatory efforts of high socially anxious individuals dampen positive experiences and events. We review existing research on individuals with social anxiety difficulties, focusing on impoverished positive experiences and quality of life, atypical reactions to overtly positive social outcomes, the absence of a normative bias toward the positive in social situations, and a meaningful subset of individuals who show signs of impulsive, short-lived positive events. We also discuss findings from the social psychology literature for how to enhance positive experiences, positive events, and self-regulatory capacity in individuals with social anxiety difficulties. The aim of the review is to broaden theory, research, and treatment efforts to the positive spectrum of human functioning. PMID- 21529702 TI - Cognition and beta-amyloid in preclinical Alzheimer's disease: data from the AIBL study. AB - The 'preclinical' phase of Alzheimer's disease is a future target for treatment, but additional research is essential to understand the relationship between beta amyloid burden and cognition during this time. We investigated this relationship using a large sample of apparently healthy older adults (N=177), which also enabled examination of whether the relationship differed according to age, gender, years of education, apolipoprotein E status, and the presence of subjective memory complaints. In addition to episodic memory, a range of cognitive measures (global cognition, semantic memory, visuospatial performance, and executive function) were examined. Participants were aged over 60 years with no objective cognitive impairment and came from the imaging arm of the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study of ageing. (11)C-PiB PET was used to measure beta-amyloid burden and a PiB 'cut-off' level of 1.5 was used to separate participants with low PiB retention from those with high PiB retention. Thirty-three percent of participants had a PiB positive scan. PiB positive participants were 5 years older, twice as likely to carry an apolipoprotein E E4 allele, and their composite episodic memory was 0.26 SD worse than PiB negative volunteers. Linear regressions with beta-amyloid burden as a dichotomous predictor, revealed an interaction between beta-amyloid burden and gender, as well as age and education effects, in predicting episodic memory and visuospatial performance. In females, but not in males, increased beta-amyloid was related to worse episodic memory and visuospatial performance. Furthermore, an interaction between beta-amyloid burden and APOE status was found in predicting visuospatial performance, whereby there was a trend for increased beta-amyloid to relate to worse visuospatial performance for those without an APOE E4 allele. There were no other main or interaction effects of beta-amyloid on any of the other composite cognitive measures. These cross-sectional findings suggest that beta-amyloid burden does not have a large effect on cognition in this subset of apparently healthy older people. The finding of gender differences deserves further research to answer definitively the important question of gender susceptibility to adverse cognitive effects from beta-amyloid. PMID- 21529703 TI - Serious methodological issues with the study by Gwini et al. PMID- 21529704 TI - Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells. AB - During brain development, cAMP induces morphological changes and inhibits growth effects in several cell types. However, the molecular mechanisms underlying the growth inhibition remain unknown. Tumor suppressor protein phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid phosphatase that inhibits the phosphoinositide 3-kinase (PI3K) pathway. The phosphorylation of Akt, which is one of the key molecules downstream of PI3K, inhibits apoptosis. In this study, we investigated the role of PTEN in cAMP-mediated growth inhibition. B92 rat glial cells were treated with 2 different cAMP stimulatory agents, a phosphodiesterase (PDE) inhibitor and a beta-adrenoceptor agonist. Both cAMP stimulatory agents induced marked morphological changes in the cells, decreased cell number, decreased Akt phosphorylation, activated PTEN, cleaved caspase-3, and induced the condensation and fragmentation of nuclei. These results indicate that the cAMP stimulatory agents induced apoptosis. Protein phosphatase inhibitor prevented cAMP-induced dephosphorylation of PTEN and Akt. In addition, cAMP analogs and Epac-selective agonists affected PTEN and Akt activities. These results suggested that cAMP-induced apoptosis may be mediated by PTEN activation and Akt inhibition through protein phosphatase in B92 cells. Our results provide new insight into the role of PTEN in cAMP-induced apoptosis in glial cells. PMID- 21529706 TI - Translational control by the eukaryotic ribosome. AB - The ribosome plays a universally conserved role in catalyzing protein synthesis. Kondrashov et al. (2011) now provide evidence that the loss of function of ribosomal protein L38 in mice leads to a selective reduction in the translation of Hox mRNAs, thus suggesting that ribosomal proteins play a critical role during embryonic development. PMID- 21529705 TI - Association of polymorphisms in HCN4 with mood disorders and obsessive compulsive disorder. AB - Hyperpolarization activated cyclic nucleotide-gated (HCN) potassium channels are implicated in the control of neuronal excitability and are expressed widely in the brain. HCN4 is expressed in brain regions relevant to mood and anxiety disorders including specific thalamic nuclei, the basolateral amygdala, and the midbrain dopamine system. We therefore examined the association of HCN4 with a group of mood and anxiety disorders. We genotyped nine tag SNPs in the HCN4 gene using Sequenom iPLEX Gold technology in 285 Caucasian patients with DSM-IV mood disorders and/or obsessive compulsive disorder and 384 Caucasian controls. HCN4 polymorphisms were analyzed using single marker and haplotype-based association methods. Three SNPs showed nominal association in our population (rs12905211, rs3859014, rs498005). SNP rs12905211 maintained significance after Bonferroni correction, with allele T and haplotype CTC overrepresented in cases. These findings suggest HCN4 as a genetic susceptibility factor for mood and anxiety disorders; however, these results will require replication using a larger sample. PMID- 21529707 TI - An antioxidant link between sickle cell disease and severe malaria. AB - Although a link between sickle cell disease and resistance to severe malaria is well established, the biochemical relationship between the two is unknown. Ferreira et al. (2011) show that carriers of the sickle cell mutation increase expression of the heme oxygenase-1 enzyme, which produces antioxidant molecules that may prevent severe disease symptoms. PMID- 21529708 TI - Does metabolite deficiency mark oncogenic cell cycles? AB - Genome instability occurs early in the development of most cancers. Bester et al. now provide evidence that oncogenic signals trigger cell division without coordinate nucleotide synthesis, engendering aberrant DNA replication and damage that could promote carcinogenesis. A mismatch between proliferation and metabolite production may characterize oncogenic cell cycles. PMID- 21529709 TI - Protease power strokes force proteins to unfold. AB - ATP-dependent proteases degrade proteins in the cytosol of cells. Two recent articles, by Aubin-Tam et al. (2011) and Maillard et al. (2011 [this issue]), use single-molecule optical tweezers to show directly that these molecular machines use the energy derived from ATP hydrolysis to mechanically unfold and translocate its substrates into the proteolytic chamber. PMID- 21529710 TI - Macrophages in the pathogenesis of atherosclerosis. AB - In atherosclerosis, the accumulation of apolipoprotein B-lipoproteins in the matrix beneath the endothelial cell layer of blood vessels leads to the recruitment of monocytes, the cells of the immune system that give rise to macrophages and dendritic cells. Macrophages derived from these recruited monocytes participate in a maladaptive, nonresolving inflammatory response that expands the subendothelial layer due to the accumulation of cells, lipid, and matrix. Some lesions subsequently form a necrotic core, triggering acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death. This Review discusses the central roles of macrophages in each of these stages of disease pathogenesis. PMID- 21529711 TI - A conserved F box regulatory complex controls proteasome activity in Drosophila. AB - The ubiquitin-proteasome system catalyzes the degradation of intracellular proteins. Although ubiquitination of proteins determines their stabilities, there is growing evidence that proteasome function is also regulated. We report the functional characterization of a conserved proteasomal regulatory complex. We identified DmPI31 as a binding partner of the F box protein Nutcracker, a component of an SCF ubiquitin ligase (E3) required for caspase activation during sperm differentiation in Drosophila. DmPI31 binds Nutcracker via a conserved mechanism that is also used by mammalian FBXO7 and PI31. Nutcracker promotes DmPI31 stability, which is necessary for caspase activation, proteasome function, and sperm differentiation. DmPI31 can activate 26S proteasomes in vitro, and increasing DmPI31 levels suppresses defects caused by diminished proteasome activity in vivo. Furthermore, loss of DmPI31 function causes lethality, cell cycle abnormalities, and defects in protein degradation, demonstrating that DmPI31 is physiologically required for normal proteasome activity. PMID- 21529712 TI - Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning. AB - Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than regulatory capacity in mRNA translation. Here we identify mutations of the Ribosomal Protein L38 (Rpl38) gene in mice exhibiting surprising tissue-specific patterning defects, including pronounced homeotic transformations of the axial skeleton. In Rpl38 mutant embryos, global protein synthesis is unchanged; however the translation of a select subset of Homeobox mRNAs is perturbed. Our data reveal that RPL38 facilitates 80S complex formation on these mRNAs as a regulatory component of the ribosome to confer transcript specific translational control. We further show that Rpl38 expression is markedly enriched in regions of the embryo where loss-of-function phenotypes occur. Unexpectedly, a ribosomal protein (RP) expression screen reveals dynamic regulation of individual RPs within the vertebrate embryo. Collectively, these findings suggest that RP activity may be highly regulated to impart a new layer of specificity in the control of gene expression and mammalian development. PMID- 21529713 TI - Sickle hemoglobin confers tolerance to Plasmodium infection. AB - Sickle human hemoglobin (Hb) confers a survival advantage to individuals living in endemic areas of malaria, the disease caused by Plasmodium infection. As demonstrated hereby, mice expressing sickle Hb do not succumb to experimental cerebral malaria (ECM). This protective effect is exerted irrespectively of parasite load, revealing that sickle Hb confers host tolerance to Plasmodium infection. Sickle Hb induces the expression of heme oxygenase-1 (HO-1) in hematopoietic cells, via a mechanism involving the transcription factor NF-E2 related factor 2 (Nrf2). Carbon monoxide (CO), a byproduct of heme catabolism by HO-1, prevents further accumulation of circulating free heme after Plasmodium infection, suppressing the pathogenesis of ECM. Moreover, sickle Hb inhibits activation and/or expansion of pathogenic CD8(+) T cells recognizing antigens expressed by Plasmodium, an immunoregulatory effect that does not involve Nrf2 and/or HO-1. Our findings provide insight into molecular mechanisms via which sickle Hb confers host tolerance to severe forms of malaria. PMID- 21529714 TI - Induced ectopic kinetochore assembly bypasses the requirement for CENP-A nucleosomes. AB - Accurate chromosome segregation requires assembly of the multiprotein kinetochore complex at centromeres. Although prior work identified the centromeric histone H3 variant CENP-A as the important upstream factor necessary for centromere specification, in human cells CENP-A is not sufficient for kinetochore assembly. Here, we demonstrate that two constitutive DNA-binding kinetochore components, CENP-C and CENP-T, function to direct kinetochore formation. Replacing the DNA binding regions of CENP-C and CENP-T with alternate chromosome-targeting domains recruits these proteins to ectopic loci, resulting in CENP-A-independent kinetochore assembly. These ectopic kinetochore-like foci are functional based on the stoichiometric assembly of multiple kinetochore components, including the microtubule-binding KMN network, the presence of microtubule attachments, the microtubule-sensitive recruitment of the spindle checkpoint protein Mad2, and the segregation behavior of foci-containing chromosomes. We additionally find that CENP-T phosphorylation regulates the mitotic assembly of both endogenous and ectopic kinetochores. Thus, CENP-C and CENP-T form a critical regulated platform for vertebrate kinetochore assembly. PMID- 21529715 TI - Nucleotide deficiency promotes genomic instability in early stages of cancer development. AB - Chromosomal instability in early cancer stages is caused by stress on DNA replication. The molecular basis for replication perturbation in this context is currently unknown. We studied the replication dynamics in cells in which a regulator of S phase entry and cell proliferation, the Rb-E2F pathway, is aberrantly activated. Aberrant activation of this pathway by HPV-16 E6/E7 or cyclin E oncogenes significantly decreased the cellular nucleotide levels in the newly transformed cells. Exogenously supplied nucleosides rescued the replication stress and DNA damage and dramatically decreased oncogene-induced transformation. Increased transcription of nucleotide biosynthesis genes, mediated by expressing the transcription factor c-myc, increased the nucleotide pool and also rescued the replication-induced DNA damage. Our results suggest a model for early oncogenesis in which uncoordinated activation of factors regulating cell proliferation leads to insufficient nucleotides that fail to support normal replication and genome stability. PMID- 21529716 TI - Live-cell chromosome dynamics and outcome of X chromosome pairing events during ES cell differentiation. AB - Random X inactivation represents a paradigm for monoallelic gene regulation during early ES cell differentiation. In mice, the choice of X chromosome to inactivate in XX cells is ensured by monoallelic regulation of Xist RNA via its antisense transcription unit Tsix/Xite. Homologous pairing events have been proposed to underlie asymmetric Tsix expression, but direct evidence has been lacking owing to their dynamic and transient nature. Here we investigate the live cell dynamics and outcome of Tsix pairing in differentiating mouse ES cells. We find an overall increase in genome dynamics including the Xics during early differentiation. During pairing, however, Xic loci show markedly reduced movements. Upon separation, Tsix expression becomes transiently monoallelic, providing a window of opportunity for monoallelic Xist upregulation. Our findings reveal the spatiotemporal choreography of the X chromosomes during early differentiation and indicate a direct role for pairing in facilitating symmetry breaking and monoallelic regulation of Xist during random X inactivation. PMID- 21529717 TI - ClpX(P) generates mechanical force to unfold and translocate its protein substrates. AB - AAA(+) unfoldases denature and translocate polypeptides into associated peptidases. We report direct observations of mechanical, force-induced protein unfolding by the ClpX unfoldase from E. coli, alone, and in complex with the ClpP peptidase. ClpX hydrolyzes ATP to generate mechanical force and translocate polypeptides through its central pore. Threading is interrupted by pauses that are found to be off the main translocation pathway. ClpX's translocation velocity is force dependent, reaching a maximum of 80 aa/s near-zero force and vanishing at around 20 pN. ClpX takes 1, 2, or 3 nm steps, suggesting a fundamental step size of 1 nm and a certain degree of intersubunit coordination. When ClpX encounters a folded protein, it either overcomes this mechanical barrier or slips on the polypeptide before making another unfolding attempt. Binding of ClpP decreases the slip probability and enhances the unfolding efficiency of ClpX. Under the action of ClpXP, GFP unravels cooperatively via a transient intermediate. PMID- 21529719 TI - SnapShot: The hippo signaling pathway. PMID- 21529718 TI - A high-resolution C. elegans essential gene network based on phenotypic profiling of a complex tissue. AB - High-content screening for gene profiling has generally been limited to single cells. Here, we explore an alternative approach-profiling gene function by analyzing effects of gene knockdowns on the architecture of a complex tissue in a multicellular organism. We profile 554 essential C. elegans genes by imaging gonad architecture and scoring 94 phenotypic features. To generate a reference for evaluating methods for network construction, genes were manually partitioned into 102 phenotypic classes, predicting functions for uncharacterized genes across diverse cellular processes. Using this classification as a benchmark, we developed a robust computational method for constructing gene networks from high content profiles based on a network context-dependent measure that ranks the significance of links between genes. Our analysis reveals that multi-parametric profiling in a complex tissue yields functional maps with a resolution similar to genetic interaction-based profiling in unicellular eukaryotes-pinpointing subunits of macromolecular complexes and components functioning in common cellular processes. PMID- 21529720 TI - Mondini deformity in a case of Turner syndrome. A radiological finding. AB - Turner syndrome (TS) is the human being's most frequent sex chromosome abnormality. Progressive sensorineural hearing loss is documented in more than 50% of the women affected by this syndrome. Although Mondini defect is the cochlear congenital malformation most frequently identified in other polymalformative syndromes, it has rarely been reported in TS. We describe the case of a 32-year-old woman with TS who presented progressive sensorineural hearing loss. The computed tomography of the ears showed bilateral Mondini deformity. PMID- 21529721 TI - [Hemostatic systems in thyroid surgery and complications]. AB - INTRODUCTION: There have been significant technological advances for hemostasis in thyroid surgery, which allow more precise and safer vascular sealing than the traditional bond associated with mono- or bipolar electrocoagulation. OBJECTIVE: To compare the complications in total thyroidectomy using traditional techniques (ligation and electrocoagulation, including LigaSure) compared to the exclusive use of the Ultracision Harmonic scalpel, performing dissection, cutting and hemostasis simultaneously. METHODS: Retrospective descriptive non-randomized comparative study with 887 patients who underwent total thyroidectomy by the same surgeon. They were distributed into Group A (traditional techniques in 468 patients, January 1997 to September 2006) and Group B (Harmonic Ultracision in 419 patients, October 2006 to May 2010). RESULTS: There was a statistically significant lower incidence of complications in Group B (0.95% versus 4.06% in group A): bleeding (0.24% versus 1.92% in group A), tracheostomy (0% versus 1.28%) and intensive care unit stay (0% versus 4.06%). Improvement of surgical activity parameters was also significant for Group B: shorter operation time (60 minutes versus 180 minutes), fewer hospital stays (4.62 versus 8.5 stays) and increase in operations per month (9.63 versus 4 interventions). Persistent sequelae (recurrent paralysis [0.48%] and hypoparathyroidism [0.47%]) decreased in the second group but the difference was not statistically significant compared to Group A. The cost per patient was lower in Group B CONCLUSIONS: The Ultracision Harmonic scalpel system is the technique of choice for thyroid surgery. PMID- 21529722 TI - [Ossiculoplasty with titanium prosthesis]. AB - OBJECTIVES: The goal of this study was to make a review of the patients who underwent ossicular chain reconstruction with titanium prosthesis during an eight year period in our Department. METHODS: A retrospective study was made on the ossiculoplasty cases over a period of eight years in a Public Hospital District. The information was extracted by clinical process consultation. Between 1999 and 2008, 124 ossiculoplasties using Kurz((r)) titanium prosthesis for chronic otitis media were performed (78 partial ossicular chain reconstructions and 46 total ossicular chain reconstructions). The single stage, staged and revision ossicular chain reconstruction were included in the analysis. All patients had a minimum of 6 month postoperative follow up (mean 3 years and 4 months). Comparisons of preoperative and postoperative pure tone averages were performed. Air-bone gap and implant extrusion rates were measured. The success of the reconstruction was defined as a postoperative air-bone gap (ABG) of 20 dB or better. RESULTS: Successful ossiculoplasty was obtained in 73,1% of partial ossicular reconstruction reconstructions and 30,4% of total ossicular chain reconstructions (P<.05). The postoperative pure-tone average air-bone gaps was 16 dB in partial reconstructions and 26,7 dB in total reconstructions (P<.05). There were five cases of prosthesis extrusion. CONCLUSIONS: The majority of the ossiculoplasties improved satisfactorily the hearing status. There was no difference in hearing results in one-stage and two-stage partial ossicular chain reconstruction, but there were better hearing results in the cases of two-stage total ossicular chain reconstruction. PMID- 21529723 TI - [Indications for referral to a skin allergy unit]. AB - Contact dermatitis is one of the most common reasons for consultation in dermatology. However, general dermatologists do not always appreciate the importance of patch testing. These tests should ideally be performed in specialist skin allergy units, most importantly in cases suggestive of contact dermatitis, severe acute dermatitis, chronic persistent dermatitis, and dermatitis affecting the eyelids, genital region or adjacent to venous ulcers. Eczematous changes in pre-existing skin lesions or lesions at atypical sites in patients diagnosed with atopic eczema should also be investigated. Finally, cases diagnosed as occupational dermatitis can be best managed by the workers' health insurance scheme. PMID- 21529724 TI - Usefulness of satisfactory control of low-density lipoprotein cholesterol to predict left ventricular remodeling after a first ST-elevation myocardial infarction successfully reperfused. AB - Left ventricular (LV) remodeling represents an important determinant in the progression to heart failure in patients after myocardial infarction. The aim of the present study was to evaluate in patients with first ST-segment elevation acute myocardial infarction who were successfully and completely reperfused whether the control of cholesterol is predictive of LV remodeling. A total of 109 patients referred to a coronary care unit for first ST-segment elevation myocardial infarction were analyzed. According to the change in indexed LV end diastolic volume detected at follow-up visits, patients were divided into nonremodeling (n = 79) and remodeling (n = 30) groups. At coronary care unit admission, the prevalence of cardiovascular risk factors was similar in the 2 groups. Low-density lipoprotein (LDL) cholesterol values were used as criteria for cholesterol control. At follow-up visits, the prevalence of patients with target levels of plasma LDL cholesterol was lower in the remodeling compared to the nonremodeling group (67% and 91%, respectively, p <0.01). After adjusting for age, gender, baseline LV ejection fraction, baseline indexed LV end-diastolic volume, hypertension, diabetes, obesity, smoking status, time from acute event, drugs (beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and statins), wall motion score index, and troponin levels, logistic regression analysis showed that patients with nontarget LDL cholesterol values at follow-up were significantly more likely to show cardiac remodeling (odds ratio 22.3, 95% confidence interval 2.91 to 171.9, p = 0.003). In conclusion, the present study shows that unsatisfactory control of LDL cholesterol independently predicts LV remodeling in patients with first ST-segment elevation myocardial infarction. PMID- 21529725 TI - Transmission of hepatitis C virus during myocardial perfusion imaging in an outpatient clinic. AB - Reports of health care--associated viral hepatitis transmission have been increasing in the United States. Transmission due to poor infection control practices during myocardial perfusion imaging (MPI) has not previously been reported. The aim of this study was to identify the source of incident hepatitis C virus (HCV) infection in a patient without identified risk factors who had undergone MPI 6 weeks before diagnosis. Practices at the cardiology clinic and nuclear pharmacy were evaluated, and HCV testing was performed in patients with shared potential exposures. Clinical and epidemiologic information was obtained for patients with HCV infection, and molecular testing was performed to assess viral relatedness. Evidence of HCV transmission among patients who had undergone MPI at the cardiology clinic on 2 separate dates was found, involving 2 potential source patients and a total of 5 newly infected patients. Molecular testing identified a high degree of genetic homology among viruses from patients with common procedure dates. The nuclear medicine technologist routinely drew up flush from multidose vials of saline solution using the same needle and syringe that had been used to administer radiopharmaceutical doses. Multipatient use of vials was not observed, but a review of purchasing invoices and interviews with staff members suggested that this had occurred. No evidence of transmission via contamination of radiopharmaceuticals at the nuclear pharmacy was found. In conclusion, transmission of HCV occurred because of unsafe injection practices during MPI. Cardiologists should carefully review their infection control practices and the practices of other staff members involved with these procedures. PMID- 21529726 TI - Elastic properties of aortic wall in patients with bicuspid aortic valve by magnetic resonance imaging. AB - Bicuspid aortic valve (BAV) is frequently associated with aortic wall abnormalities, including dilation of the ascending aorta and even dissection. We propose 2 new indexes of aortic wall biophysical properties, the maximum rates of systolic distension and diastolic recoil (MRSD and MRDR, respectively), in patients with BAV and matched control subjects. We evaluated 53 consecutive young patients with BAV (36 males, mean age 16 +/- 4 years) with mild aortic valve disease and a control group of 22 age- and gender-matched healthy volunteers. All subjects underwent a cardiac magnetic resonance imaging study that included phase velocity mapping and cine acquisition at several aortic levels. The MRSD and MRDR were measured in the ascending aorta in both patients with BAV and controls. Of the 53 patients with BAV, 26 had enlarged ascending aortas (dilated BAV), and 27 had a normal aortic diameter (nondilated BAV). Compared to controls, the MRSD was significantly lower in the whole BAV group (4.37 +/- 1.1 vs 9.1 +/- 2.1), in patients with dilated BAV (4.5 +/- 1.1 p <0.0001), and in those with nondilated BAV (4.3 +/- 1.0, p <0.0001). The MRDR was greater in the whole BAV group (-4 +/- 1.2 vs -7.6 +/- 2.7, p <0.0001), in the dilated BAV group (-3.9 +/- 1.3, p <0.0001), and in the nondilated BAV group (-4.1 +/- 1.2, p <0.0001). A receiver operating characteristic curve analysis of MRSD distinguished BAV from controls with 100% sensitivity and 95% specificity. In conclusion, MRSD and MRDR were slower in the patients with BAV than in the controls, regardless of the dimensions of the ascending aorta. PMID- 21529727 TI - Relation of body mass index to urinary creatinine excretion rate in patients with coronary heart disease. AB - In patients with prevalent coronary heart disease (CHD), studies have found a paradoxical relation in that patients with higher body mass indexes (BMIs) have lower mortality. One possibility is that patients with higher BMIs have greater muscle mass, and higher BMI may be a marker of better overall health status. The aim of this study was to evaluate whether the paradoxical association of BMI with mortality in patients with CHD is attenuated when accounting for urinary creatinine excretion, a marker of muscle mass. The Heart and Soul Study is an observational study of outpatients with stable CHD. Outpatient 24-hour timed urine collections were obtained. Participants were followed up for death for 5.9 +/- 1.9 years. Cox proportional-hazards models were used to evaluate the association between gender-specific BMI quintiles and mortality. There were 886 participants in the study population. Participants in higher quintiles of BMI were younger, were more likely to have diabetes mellitus and hypertension, and had higher urinary creatinine excretion rate. Compared to the lowest BMI quintile, subjects in higher BMI quintiles were less likely to die during follow up. Adjustment for major demographic variables, traditional cardiovascular risk factors, and kidney function did not attenuate the relation. Additional adjustment for urinary creatinine excretion rate did not materially change the association between BMI and all-cause mortality. In conclusion, low muscle mass and low BMI are each associated with greater all-cause mortality, but low muscle mass does not appear to explain why CHD patients with low BMIs have worse prognosis. PMID- 21529729 TI - Comparison of magnetic resonance imaging of aortic valve stenosis and aortic root to multimodality imaging for selection of transcatheter aortic valve implantation candidates. AB - The purpose of the present study was to compare the aortic valve area, aortic valve annulus, and aortic root dimensions measured using magnetic resonance imaging (MRI) with catheterization, transthoracic echocardiography (TTE), and transesophageal echocardiography (TEE). An optimal prosthesis--aortic root match is an essential goal when evaluating patients for transcatheter aortic valve implantation. Comparisons between MRI and the other imaging techniques are rare and need validation. In 24 consecutive, high-risk, symptomatic patients with severe aortic stenosis, aortic valve area was prospectively determined using MRI and direct planimetry using three-dimensional TTE and calculated by catheterization using the Gorlin equation and by Doppler echocardiography using the continuity equation. Aortic valve annulus and the aortic root dimensions were prospectively measured using MRI, 2-dimensional TTE, and invasive aortography. In addition, aortic valve annulus was measured using TEE. No differences in aortic valve area were found among MRI, Doppler echocardiography, and 3-dimensional TTE compared with catheterization (p = NS). Invasive angiography underestimated aortic valve annulus compared with MRI (p <0.001), TEE (p <0.001), and 2 dimensional TTE (p <0.001). Two-dimensional TTE tended to underestimate the aortic valve annulus diameters compared to TEE and MRI. In contrast to 2 dimensional TTE, 3 patients had aortic valve annulus beyond the transcatheter aortic valve implantation range using TEE and MRI. In conclusion, MRI planimetry, Doppler, and 3-dimensional TTE provided an accurate estimate of the aortic valve area compared to catheterization. MRI and TEE provided similar and essential assessment of the aortic valve annulus dimensions, especially at the limits of the transcatheter aortic valve implantation range. PMID- 21529728 TI - Short- and long-term prognostic significance of ST-segment elevation in lead aVR in patients with non-ST-segment elevation acute coronary syndrome. AB - We sought to evaluate the prognostic significance of ST-segment elevation (STE) in lead aVR in unselected patients with non-STE acute coronary syndrome (NSTE ACS). We enrolled 1,042 consecutive patients with NSTE-ACS. Patients were divided into 5 groups according to the following electrocardiographic (ECG) patterns on admission: (1) normal electrocardiogram or no significant ST-T changes, (2) inverted T waves, (3) isolated ST deviation (ST depression [STD] without STE in lead aVR or transient STE), (4) STD plus STE in lead aVR, and (5) ECG confounders (pacing, right or left bundle branch block). The main angiographic end point was left main coronary artery (LM) disease as the culprit artery. Clinical end points were in-hospital and 1-year cardiovascular death defined as the composite of cardiac death, fatal stroke, and fatal bleeding. Prevalence of STD plus STE in lead aVR was 13.4%. Rates of culprit LM disease and in-hospital cardiovascular death were 8.1% and 3.8%, respectively. On multivariable analysis, patients with STD plus STE in lead aVR (group 4) showed an increased risk of culprit LM disease (odds ratio 4.72, 95% confidence interval [CI] 2.31 to 9.64, p <0.001) and in hospital cardiovascular mortality (odds ratio 5.58, 95% CI 2.35 to 13.24, p <0.001) compared to patients without any ST deviation (pooled groups 1, 2, and 5), whereas patients with isolated ST deviation (group 3) did not. At 1-year follow-up 127 patients (12.2%) died from cardiovascular causes. On multivariable analysis, STD plus STE in lead aVR was a stronger independent predictor of cardiovascular death (hazard ratio 2.29, 95% CI 1.44 to 3.64, p <0.001) than isolated ST deviation (hazard ratio 1.52, 95% CI 0.98 to 2.36, p = 0.06). In conclusion, STD plus STE in lead aVR is associated with high-risk coronary lesions and predicts in-hospital and 1-year cardiovascular deaths in patients with NSTE-ACS. Therefore, this promptly available ECG pattern could be useful to improve risk stratification and management of patients with NSTE-ACS. PMID- 21529730 TI - Usefulness of combined assessment with computed tomographic signs of right ventricular dysfunction and cardiac troponin T for risk stratification of acute pulmonary embolism. AB - The aim of this study was to evaluate the incremental value of combined assessment with computed tomographic (CT) signs of right ventricular (RV) dysfunction and cardiac troponin T level for predicting early death or adverse outcomes due to acute pulmonary embolism (PE). One hundred seventy-three non-high risk patients with acute PE, confirmed by CT pulmonary angiography, were retrospectively evaluated. The area under the curve and hazard ratio of CT signs and troponin T levels were compared for predicting early death or adverse outcomes. Patients were classified into intermediate- and low-risk groups on the basis of CT signs and troponin T levels, and mortality was compared. Seventeen patients (9.8%) died within 3 months. Early mortality of intermediate-risk patients (14% to 19%) was higher than that of low-risk patents (2% to 6%). A ratio of RV volume to left ventricular volume > 1.5 had the highest area under the curve (0.709) and hazard ratio (5.402) for predicting early death. The combination of CT signs and elevated troponin T level had an increased area under the curve and hazard ratio for predicting early death and adverse outcomes compared to those of CT signs or elevated troponin T level alone. In conclusion, the combined assessment of the ratio of RV volume to left ventricular volume and an elevated troponin T level provided incrementally more prognostic information in non-high-risk patients with acute PE compared to the single predictor of CT signs or troponin T level. PMID- 21529731 TI - Prognostic usefulness of circulating high-sensitivity troponin T in aortic stenosis and relation to echocardiographic indexes of cardiac function and anatomy. AB - The new high-sensitivity cardiac troponin T (hs-cTnT) assay seems to provide important prognostic information in patients with stable cardiovascular disease. To understand the merit of hs-cTnT more closely in stable cardiovascular disease, we performed extensive echocardiographic characterization of 57 patients with aortic stenosis and myocardial hypertrophy and related hs-cTnT levels to prognosis and echocardiographic indexes of myocardial structure and function. The hs-cTnT levels were above the assay's detection limit in all patients, correlated with echocardiographic indexes of structure and function, most notably with left ventricular mass, and demonstrated prognostic utility of similar strength as N terminal pro-B-type natriuretic peptide. In conclusion, these findings indicate that hs-cTnT may provide prognostic information in patients with aortic stenosis, and that left ventricular mass is an important determinant of TnT levels in stable patients as measured by the new highly sensitive assay. PMID- 21529732 TI - Comparison of outcomes of unprotected left main versus multivessel coronary artery interventions. AB - Left main coronary artery (LMCA) percutaneous coronary intervention (PCI) has emerged as an appealing alternative to bypass surgery for significant LMCA disease, especially in high-risk candidates. PCI for unprotected LMCA stenosis is currently designated a class IIb indication. Direct comparisons between unprotected LMCA PCI and multivessel PCI are lacking. We aimed to determine the incremental risk associated with unprotected LMCA PCI compared to multivessel PCI. We queried the Cleveland Clinic PCI database to identify patients who underwent unprotected LMCA PCI from 2003 through 2009 and compared these to patients undergoing multivessel PCI in the same period. Patients undergoing PCI for acute myocardial infarction were excluded. Mortality was derived using the Social Security Death Index. Short-term (<=30-day) mortality rates in the LMCA PCI group (n = 468, 1.9%) were similar to the death rate in the multivessel PCI group (n = 1,973, 1.3%, p = 0.3). There was no significant difference in adjusted mortality between the 2 study groups. Stratifying LMCA PCI by the number of concomitant vessel territories treated, there was no significant difference in mortality in any LMCA PCI category (LMCA only, LMCA + 1-vessel PCI, LMCA + multivessel PCI) compared to multivessel PCI. In conclusion, there was comparable short-term and long-term mortality in the LMCA PCI and multivessel PCI groups. LMCA stenting did not appear to incur incremental risk compared to multivessel PCI. PMID- 21529733 TI - Comparison of long-term survival of men versus women with heart failure treated with cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is an established treatment of patients with heart failure. Several baseline characteristics can influence the CRT outcomes, and little is known about the effect of gender. The aim of the present study was to elucidate the gender-related differences in long-term survival after CRT. A total of 578 consecutive patients with heart failure underwent CRT. At baseline and 6 months after CRT, the clinical and echocardiographic parameters were obtained. All-cause mortality was compared between the men and women. The study population included 431 men (67 +/- 9 years) and 147 women (65 +/- 11 years). No differences in the clinical and echocardiographic characteristics were observed between the men and women, except for left bundle branch block and a nonischemic etiology of heart failure, which were more frequent in women (81% vs 68% and 63% vs 33%, respectively; p <0.01), and atrial fibrillation, which was more prevalent in men (20% vs 10%, respectively; p = 0.01). During a mean follow up of 34 +/- 25 months, 197 patients died (158 men and 39 women). Kaplan-Meier analysis showed a significant difference in long-term survival between the women and men (p = 0.007). The 2-year all-cause mortality rate was 15% in men and 8% in women (p = 0.025). Cox proportional hazard analysis revealed female gender is an independent predictor of long-term survival, together with heart failure etiology and renal function. In particular, women with heart failure due to a nonischemic etiology showed the best long-term survival rate. In conclusion, female gender and nonischemic etiology were independently associated with better long-term survival after CRT. PMID- 21529734 TI - Meta-analysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation. AB - The association between obstructive sleep apnea (OSA) and atrial fibrillation (AF) is strong and is now well established. However, studies on the role of OSA on AF recurrence after catheter ablation have yielded conflicting results. The aim of the present study was to investigate the role of OSA on AF recurrence after catheter-based pulmonary vein isolation. We performed a data search on the PubMed, Web of Science, and the Cochrane databases for studies published by August 2010. In addition, we manually searched the conference proceedings of the European Society of Cardiology, American College of Cardiology, and American Heart Association for related abstracts. After the initial search returned 402 reports, we identified 6 studies with a total of 3,995 patients that met our inclusion criteria. Overall, patients with OSA have a 25% greater risk of AF recurrence after catheter ablation than those without OSA (risk ratio 1.25, 95% confidence interval 1.08 to 1.45, p = 0.003). Subgroup analysis showed that OSA diagnosed using polysomnography is a strong predictor of AF recurrence (risk ratio 1.40, 95% confidence interval 1.16 to 1.68, p = 0.0004) but not when OSA was diagnosed using the Berlin questionnaire (risk ratio 1.07, 95% confidence interval 0.91 to 1.27, p = 0.39). In conclusion, patients with OSA have significantly greater AF recurrence rates after pulmonary vein isolation. In addition to other factors, a diagnosis of OSA merits special consideration when evaluating patients for catheter-based AF ablation. PMID- 21529736 TI - Relation of symptomatic heart failure and psychological status to persistent depression in patients with implantable cardioverter-defibrillator. AB - Studies on psychological morbidity in patients with an implantable cardioverter defibrillator (ICD) have focused on mean differences rather than intraindividual differences. Such an approach masks the chronicity of symptoms in individual patients and the potential differences in cardiac outcomes. We examined the prevalence and correlates of persistent depression using an intraindividual approach. Consecutive patients who had undergone ICD implantation (n = 386; 79.3% men) completed a set of validated questionnaires, including the Hospital Anxiety and Depression Scale (HADS), at baseline and 3 months after implantation. Information on ICD therapies was obtained by device interrogation. At 3 months after implantation, 52 (14%) of the 386 patients had persistent depression (HADS cutoff >=8 before and 3 months after implantation). Heart failure (odds ratio [OR] 2.29; 95% confidence interval [CI] 1.26 to 4.15), cardiac resynchronization therapy (OR 1.92; 95% CI 1.05 to 3.52), New York Heart Association class III-IV (OR 2.47; 95% CI 1.36 to 4.48), diabetes (OR 2.09; 95% CI 1.01 to 4.29), Type D personality (OR 8.30; 95% CI 4.42 to 15.58), high levels of ICD concerns (OR 2.60; 95% CI 1.44 to 1.71), diuretics (OR 2.41; 95% CI 1.26 to 4.61), and psychotropic medication (OR 3.58; 95% CI 1.86 to 6.90) were all significant univariate correlates of persistent depression at 3 months. No effect was found for ICD shock during follow-up (OR 1.59; 95% CI 0.57 to 4.41). In adjusted analysis, New York Heart Association class III-IV (OR 2.95; 95% CI 1.47 to 5.89), Type D personality (OR 7.98; 95% CI 3.98 to 16.04), and the use of psychotropic medication (OR 2.73; 95% CI 1.27 to 5.84) were independent correlates of persistent depression. In conclusion, symptomatic heart failure, psychological status, and psychotropic medication use predicted persistent depression after ICD implantation. PMID- 21529735 TI - Role of intravascular ultrasound in patients with acute myocardial infarction undergoing percutaneous coronary intervention. AB - Stent thrombosis and restenosis remain drawbacks of drug-eluting stents in patients with acute myocardial infarction (AMI). Intravascular ultrasound (IVUS) guidance for stent deployment helps optimize its results in stable patients. The aim of this study was to examine the utility of routine IVUS guidance in patients with AMI undergoing percutaneous coronary intervention (PCI). Employing data from Korea Acute Myocardial Infarction Registry (KAMIR), we analyzed 14,329 patients with AMI from April 2006 through September 2010. Patients with cardiogenic shock and rescue PCI after thrombolysis were excluded. Clinical outcomes of 2,127 patients who underwent IVUS-guided PCI were compared to those of 8,235 patients who did not. Mean age was 63.6 +/- 13.5 years and 72.3% were men. Patients undergoing IVUS-guided PCI were younger, more often men, more hyperlipemic, and had increased body mass index and left ventricular ejection fraction. Number of treated vessels and stents used, stent length, and stent diameter were increased in the IVUS-guided group. Multivessel involvement was less frequent and American College of Cardiology/American Heart Association type C lesion was more frequent in the IVUS-guided group. Drug-eluting stents were more frequently used compared to bare-metal stents in the IVUS group. There was no significant relation of stent thrombosis between the 2 groups. Twelve-month all-cause death was lower in the IVUS group. After multivariate analysis and propensity score adjustment, IVUS guidance was not an independent predictor for 12-month all-cause death (hazard ratio 0.212, 0.026 to 1.73, p = 0.148). In conclusion, this study does not support routine use of IVUS guidance for stent deployment in patients who present with AMI and undergo PCI. PMID- 21529737 TI - Implications of progressive aberrancy versus true fusion for diagnosis of wide complex tachycardia. AB - At the onset of wide complex tachycardia, beats with intermediate morphologies sometimes occur between the normally conducted beats and the wide complex tachycardia QRS. Intermediate beats could be true fusion; however, progressive aberrancy has been reported to mimic true fusion. To evaluate the incidence of progressive aberrancy, wide complex tachycardia tracings were collected in which an intermediate beat was noted at the onset. When the associated electrocardiographic findings were diagnosed as supraventricular tachycardia, the beat was identified as progressive aberrancy. When diagnosed as ventricular tachycardia, the intermediate beat was identified as true fusion. Electrocardiographic criteria were then identified from this cohort to identify the distinguishing features between progressive aberrancy and true fusion. Of 24 episodes of wide complex tachycardia, 17 (71%) were identified as true fusion and 7 (29%) as progressive aberrancy. The QRS duration of the intermediate and wide complex tachycardia beats were shorter with progressive aberrancy than with true fusion (109 +/- 23 ms vs 131 +/- 20 ms, p <0.023; and 139 +/- 21 ms vs 177 +/- 24 ms, p <0.001, respectively). In progressive aberrancy (n = 3), the PR interval of the intermediate beat was always greater than the PR interval of the normally conducted beat. In contrast, in true fusion (n = 11), the PR interval of the intermediate beat was always less than the PR interval of the normally conducted beat. Multiple intermediate beats were present in 4 of 7 cases of progressive aberrancy and in 0 of 17 cases of true fusion. In conclusion, true fusion is the most common explanation for intermediate beats, but progressive aberrancy occurs a significant proportion of the time (29%). The identified criteria will be helpful in differentiating ventricular tachycardia from supraventricular tachycardia with aberrancy as a cause of wide complex tachycardia. PMID- 21529738 TI - Impact of body mass index, physical activity, and other clinical factors on cardiorespiratory fitness (from the Cooper Center longitudinal study). AB - Cardiorespiratory fitness (CRF) is widely accepted as an important reversible cardiovascular risk factor. In the present study, we examined the nonmodifiable and modifiable determinants of CRF within a large healthy Caucasian population of men and women. The study included 20,239 patients presenting to Cooper Clinic (Dallas, Texas) for a comprehensive medical examination from 2000 through 2010. CRF was determined by maximal treadmill exercise testing. Physical activity categories were 0 metabolic equivalent tasks (METs)/min/week (no self-reported moderate or vigorous intensity physical activity), 1 to 449 METs/min/week (not meeting physical activity guideline), 450 to 749 METs/min/week (meeting guideline), and >=750 METs/min/week (exceeding guideline). Linear regression modeling was used to determine the most robust clinical factors associated with achieved treadmill time. Age, gender, body mass index (BMI), and physical activity were the most important factors associated with CRF, explaining 56% of the variance (R(2) = 0.56). The addition of all other factors combined (current smoking, systolic blood pressure, blood glucose, high-density and low-density lipoprotein cholesterol, health status) were associated with CRF (p <0.05) but additively only improved R(2) by 2%. There was a significant interaction between BMI and physical activity on CRF, such that normal-weight (BMI <25 kg/m(2)) subjects achieved higher CRF for a given level of physical activity compared to obese subjects (BMI >=30 kg/m(2)). Percent body fat, not lean body mass, was the key factor driving this interaction. In conclusion, BMI was the most important clinical risk factor associated with CRF other than nonmodifiable risk factors age and gender. For a similar amount of physical activity, normal-weight subjects achieved a higher CRF level compared to obese subjects. These data suggest that obesity may offset the benefits of physical activity on achieved CRF, even in a healthy population of men and women. PMID- 21529739 TI - Meta-analysis of cohort and case-control studies of type 2 diabetes mellitus and risk of atrial fibrillation. AB - Atrial fibrillation (AF) is 1 of the most clinically diagnosed cardiac disturbances but little is known about its risk factors. Previous epidemiologic studies have reported on the association between diabetes mellitus (DM) and subsequent risk of AF, with inconsistent results. The aim of this study was to conduct a meta-analysis of published studies to reliably determine the direction and magnitude of any association between DM and AF. A systematic review and meta analysis was conducted. PubMed and EMBASE were searched to identify prospective cohort and case-control studies that had reported on the association between DM and other measurements of glucose homeostasis with incident AF by April 2010. Studies conducted in primarily high-risk populations and participants in randomized controlled trials were excluded. Seven prospective cohort studies and 4 case-control studies with information on 108,703 cases of AF in 1,686,097 subjects contributed to this analysis. The summary estimate indicated that patients with DM had an approximate 40% greater risk of AF compared to unaffected patients (relative risk [RR] 1.39, 95% confidence interval [CI] 1.10 to 1.75, p for heterogeneity <0.001). After correcting for publication bias, the RR was 1.34 (1.07 to 1.68). Studies that had adjusted for multiple risk factors reported a smaller effect estimate compared to age-adjusted studies (RR 1.24, 95% CI 1.06 to 1.44, vs 1.70, 1.29 to 2.22, p for heterogeneity = 0.053). The population attributable fraction of AF owing to DM was 2.5% (95% CI 0.1 to 3.9). In conclusion, DM is associated with an increased risk of subsequent AF but the mechanisms that may underpin the relation between DM and AF remain speculative. PMID- 21529740 TI - Short-term, high-dose Atorvastatin pretreatment to prevent contrast-induced nephropathy in patients with acute coronary syndromes undergoing percutaneous coronary intervention (from the ARMYDA-CIN [atorvastatin for reduction of myocardial damage during angioplasty--contrast-induced nephropathy] trial. AB - Contrast-induced nephropathy (CIN) impairs clinical outcome in patients undergoing angiographic procedures. The aim of this study was to investigate whether short-term high-dose atorvastatin load decreases the incidence of CIN after percutaneous coronary intervention (PCI). Statin-naive patients with acute coronary syndrome undergoing PCI (n = 241) randomly received atorvastatin (80 mg 12 hours before intervention with another 40-mg preprocedure dose, n = 120) or placebo (n = 121). All patients had long-term atorvastatin treatment thereafter (40 mg/day). Primary end point was incidence of CIN defined as postintervention increase in serum creatinine >=0.5 mg/dl or >25% from baseline. Five percent of patients in the atorvastatin arm developed CIN versus 13.2% of those in the placebo arm (p = 0.046). In the atorvastatin group, postprocedure serum creatinine was significantly lower (1.06 +/- 0.35 vs 1.12 +/- 0.27 mg/dl in placebo, p = 0.01), creatinine clearance was decreased (80.1 +/- 32.2 vs 72.0 +/- 26.6 ml/min, p = 0.034), and C-reactive protein peak levels after intervention were decreased (8.4 +/- 10.5 vs 13.1 +/- 20.8 mg/l, p = 0.01). Multivariable analysis showed that atorvastatin pretreatment was independently associated with a decreased risk of CIN (odds ratios 0.34, 95% confidence interval 0.12 to 0.97, p = 0.043). Prevention of CIN with atorvastatin was paralleled by a shorter hospital stay (p = 0.007). In conclusion, short-term pretreatment with high-dose atorvastatin load prevents CIN and shortens hospital stay in patients with acute coronary syndrome undergoing PCI; anti-inflammatory effects may be involved in this renal protection. These results lend further support to early use of high dose statins as adjuvant pharmacologic therapy before percutaneous coronary revascularization. PMID- 21529741 TI - Impact of body mass index on the five-year outcome of patients having percutaneous coronary interventions with drug-eluting stents. AB - The purpose of this study was to assess the impact of body mass index (BMI) on clinical outcome of patients treated by percutaneous coronary intervention (PCI) using drug-eluting stents. Patients were stratified according to BMI as normal (<25 kg/m(2)), overweight (25 to 30 kg/m(2)), or obese (>30 kg/m(2)). At 5-year follow-up all-cause death, myocardial infarction, clinically justified target vessel revascularization (TVR), and definite stent thrombosis were assessed. A complete dataset was available in 7,427 patients, of which 45%, 22%, and 33% were classified according to BMI as overweight, obese, and normal, respectively. Mean age of patients was significantly older in those with a normal BMI (p <0.05). Incidence of diabetes mellitus, hypertension, and dyslipidemia increased as BMI increased (p <0.05). Significantly higher rates of TVR (15.3% vs 12.8%, p = 0.02) and early stent thrombosis (1.5% vs 0.9%, p = 0.04) were observed in the obese compared to the normal BMI group. No significant difference among the 3 BMI groups was observed for the composite of death/myocardial infarction/TVR or for definite stent thrombosis at 5 years, whereas the normal BMI group was at higher risk for all-cause death at 5 years (obese vs normal BMI, hazard ratio 0.74, confidence interval 0.53 to 0.99, p = 0.05; overweight vs normal BMI, hazard ratio 0.73, confidence interval 0.59 to 0.94, p = 0.01) in the multivariate Cox proportional hazard model. Age resulted in a linearly dependent covariate with BMI in the all-cause 5-year mortality multivariate model (p = 0.001). In conclusion, the "obesity paradox" observed in 5-year all-cause mortality could be explained by the higher rate of elderly patients in the normal BMI group and the existence of colinearity between BMI and age. However, obese patients had a higher rate of TVR and early stent thrombosis and a higher rate of other risk factors such as diabetes mellitus, hypertension, and hypercholesterolemia. PMID- 21529742 TI - Catheter ablation of electrical storm in a collaborative hospital network. AB - An electrical storm (ES) is defined as multiple ventricular arrhythmia episodes leading to implantable cardioverter defibrillator interventions. Although conventional rhythm stabilization might be of help acutely, ES involves high mortality and morbidity. We evaluated the effect of catheter ablation strategies in the setting of an interhospital collaborative network on the recurrence of ventricular arrhythmia episodes and mortality in patients with ES. Consecutive patients presenting for invasive treatment of ES from December 2007 to December 2009 were included. All patients underwent catheter ablation of ventricular arrhythmia. The strategies were adapted to the individual cardiac pathologic features. The follow-up examination constituted periodic implantable cardioverter defibrillator interrogation. A total of 32 patients were included. Of the 32 patients, 29 (91%) had monomorphic ventricular tachycardia and 3 ventricular fibrillation. The mean number of implantable cardioverter defibrillator-treated episodes within 7 days before ablation was 16 +/- 11. Of the 32 patients, 27 underwent ablation within 24 hours after admission, and 5 underwent acute ablation within 8 hours. In 3 patients, epicardial ablation was performed. In all but 2 patients (6%), the clinical arrhythmia was successfully ablated. During a median follow-up of 15 months, 10 patients (31%) had recurrences of sustained ventricular arrhythmia, including 2 patients (6%) with recurrent ES. Three patients (9%) died during the follow-up period. In conclusion, catheter ablation effectively suppressed ventricular arrhythmia midterm recurrences in patients presenting with ES. Catheter ablation is complex in these severely sick patients. The recurrence rate of ventricular arrhythmia appears to be 31% and the mortality rate to be 9%. Collaborative hospital networks to increase the prompt availability of ES ablation might help to optimize the ES outcome. PMID- 21529743 TI - Comparison of everolimus-eluting stent with paclitaxel-eluting stent in long chronic total occlusions. AB - The aim of the present study was the comparison of the everolimus-eluting stent (EES) with the paclitaxel-eluting stent (PES) in patients treated for long chronic total occlusions (CTOs). Previous randomized trials have shown the superiority of EESs over PESs. No data exist about the efficacy and safety of EESs in patients treated for complex CTOs requiring multiple stent implantation. We identified 258 patients treated for CTOs who received multiple EESs (n = 112) or PESs (n = 146), with a total stent length of >=40 mm. The primary end point was in-segment restenosis, defined as >50% luminal narrowing at the segment site, including the stent and 5 mm proximal and distal to the stent edges of the target vessel, on the follow-up angiogram. The secondary end point was the 9-month composite of major adverse cardiovascular events. The 2 patient groups were similar in all baseline characteristics. The median lesion length was 48 mm in the EES group and 46 mm in the PES group (p = 0.793). The incidence of the primary end point of the study was 11.8% in the EES group and 31.4% in the PES group (p = 0.001). The major adverse cardiovascular event rate was lower in the EES group than in the PES group (8.9% and 22.6%, respectively, p = 0.003). Definite or probable stent thrombosis occurred in 5 patients in the PES group (3.4%), with no stent thrombosis occurring in the EES group (p = 0.048). On multivariate analysis, EES was the only variable independently related to the risk of binary angiographic restenosis with an odds ratio of 0.29 (95% confidence interval 0.14 to 0.62; p = 0.002). In conclusion, in patients treated for long CTOs and requiring multiple stent implantation, EESs performed better than PESs, with a >50% reduction in the risk of restenosis and major adverse cardiovascular events. PMID- 21529744 TI - Effectiveness and safety of the genous endothelial progenitor cell-capture stent in acute ST-elevation myocardial infarction. AB - The endothelial progenitor cell (EPC)-capture stent promotes endothelialization and preliminary studies have suggested its safety and feasibility in ST-elevation myocardial infarction (STEMI). Detailed late clinical follow-up and angiographic analyses are, however, limited. We sought to determine late angiographic and clinical outcomes of the Genous EPC-capture stent in primary angioplasty. EPC capture stents were implanted during primary angioplasty in 489 consecutive patients presenting with STEMI from 2004 through 2008. The first 100 consenting patients undergoing successful stent implantation scheduled to undergo relook coronary angiography at 6 to 12 months were enrolled. Ninety-five patients with 96 lesions were analyzed independently. Mean duration of follow-up coronary angiography was 245 days. In-stent late luminal loss measured 0.87 +/- 0.67 mm. Binary restenosis (defined as >50% diameter stenosis) was 28%, with diffuse in stent restenosis (Mehran class II) as the predominant pattern. Of 27 patients with binary restenosis, 14 (52%) were symptomatic, with 10 patients undergoing target lesion revascularization. Asymptomatic patients had significantly larger reference vessel and in-stent minimal luminal diameters (2.77 +/- 0.39 vs 2.54 +/ 0.44 mm, p = 0.040; 2.74 +/- 0.34 vs 2.31 +/- 0.72 mm, p = 0.004, respectively). Follow-up late loss and diameter stenoses were also in favor of the asymptomatic group. Major adverse cardiac event rate was 16% at a mean follow-up of 34 months. There were no cases of Academic Research Consortium-defined stent thrombosis. In conclusion, implantation of the EPC-capture stent during primary angioplasty is associated with a favorable late clinical outcome but with higher than anticipated angiographic late loss. PMID- 21529745 TI - Best clinical trials reported in 2010. AB - Each year, a number of clinical trials emerge with data sufficient to change clinical practice. Determining which findings will result in practice change and which will provide only incremental benefit can be a dilemma for clinicians. The authors review selected clinical trials reported in 2010 in journals, at society meetings, and at conferences, focusing on those studies that have the potential to change clinical practice. This review offers 3 separate means of analysis: an abbreviated text summary, organized by subject area; a comprehensive table of relevant clinical trials that provides a schematic review of the hypotheses, interventions, methods, primary end points, results, and implications; and a complete bibliography for further reading as warranted. It is hoped that this compilation of relevant clinical trials and their important findings released in 2010 will be of benefit in the everyday practice of cardiovascular medicine. PMID- 21529746 TI - Predictors for restoration of normal left ventricular function in response to cardiac resynchronization therapy measured at time of implantation. AB - There are no parameters predicting the individual probability of "full response" to cardiac resynchronization therapy (CRT). The aim of this work was to find prognostic factors of full clinical and echocardiographic responses (i.e., >=50% left ventricular ejection fraction [LVEF] and New York Heart Association class I) after 1 year of CRT. This was a prospective follow-up study that involved 2 hospitals. Patients (n = 75) with advanced heart failure (64 +/- 9 years of age, 87% men, LVEF 24 +/- 7%) who received CRT were followed for 17 +/- 9 months. Univariate and multivariate regression analyses were used to identify predictors of full CRT response. A nomogram predicting the individual probability of full CRT response during follow-up was calculated. There were 13 patients with restoration of normal LVEF versus 62 without (mean LVEF 56% +/- 5% vs 31% +/- 8%, respectively, p <0.001). Predictors of full response included cause of heart disease, baseline QRS width, and degree of QRS shortening in response to CRT. Patients with nonischemic heart disease, baseline QRS width <=150 ms, and QRS shortening >=40 ms in response to CRT had a >75% probability of restoration of normal LVEF. In conclusion, our nomogram using a combination of cause, baseline QRS width, and degree of QRS shortening in response to CRT allows assessment of individual probability of full response. This observation awaits further confirmation from larger series. PMID- 21529747 TI - A LEOPARD mimicking ST-elevation myocardial infarction. AB - A 47-year-old man was referred because of an acute anterolateral ST-segment elevation myocardial infarction. Coronary angiography showed marked ectasia of the coronary arteries, with no obstructive lesions. Ventriculography strongly suggested severe left ventricular hypertrophy, later confirmed by cardiovascular magnetic resonance imaging. Complete clinical investigation showed that the patient also had multiple lentigines, ocular hypertelorism, and deafness. These associations led to the diagnosis of LEOPARD (Lentigines, Electrocardiographic anomalies, Ocular hypertelorism, Pulmonary stenosis, Anomalies of the genitalia, Retarded growth, and Deafness [sensorineural]) syndrome. Although uncommon, LEOPARD syndrome is important to recognize because it can be associated with serious adverse cardiac events, particularly in patients with severe left ventricular hypertrophy. PMID- 21529748 TI - Longitudinal exercise capacity of patients with repaired tetralogy of fallot. AB - Patients with repaired tetralogy of Fallot have a reduced percentage of predicted peak oxygen consumption (VO(2)) and percentage of oxygen pulse (O(2)P%) compared to healthy controls. Because data regarding the progression of exercise intolerance in these patients is limited, we sought to analyze the serial exercise data from patients with Tetralogy of Fallot to quantify the changes in their exercise capacity over time and to identify associations with clinical and cardiac magnetic resonance imaging variables. The data from cardiopulmonary exercise tests (CPXs) from 2002 to 2010 for patients with repaired tetralogy of Fallot with >=2 CPXs separated by >=12 months were analyzed. Tests occurring after interventional catheterization or surgery were excluded. A total of 70 patients had 179 CPXs. They had a median age at the initial study of 23.6 years and an interval between the first and last CPX of 2.8 years. At the initial CPX, the peak VO(2) was 27.6 +/- 8.8 ml/kg/min (78 +/- 19% of predicted), and the peak O(2)P% was 89 +/- 22% of predicted. At the most recent study, the peak VO(2) averaged 25.0 +/- 7.4 ml/kg/min (73 +/- 16% of predicted), and the peak O(2)P% averaged 83 +/- 20% (p <0.01) for each versus the initial CPX. The decrease in the peak VO(2) was strongly associated with a decrease in O(2)P% and an increase (worsening) in the slope of the minute ventilation-versus-carbon dioxide production relation. Changes in the peak VO(2) did not correlate with concomitant changes in any other CPX variable. The rate of decrease was not related to a history of shunt palliation, age at CPX, or any other baseline clinical parameter, including cardiac magnetic resonance measurements. In conclusion, the exercise capacity of patients with repaired tetralogy of Fallot tends to decrease over time. This deterioration is variable and unpredictable and is primarily related to a decrease in the forward stroke volume at peak exercise. PMID- 21529749 TI - Prevalence and determinants of incomplete right atrial reverse remodeling after device closure of atrial septal defects. AB - Whether the relief of chronic right atrial (RA) volume load by device closure of an atrial septal defect (ASD) normalizes RA size is unknown. The present study evaluated the prevalence and determinants of incomplete RA reverse remodeling (RAR) after ASD closure in adults. Transthoracic echocardiography was performed in 44 consecutive patients with secundum ASD (age 43 +/- 17 years, 10 men) without a history of atrial arrhythmia shortly before and at 3 months after device closure of ASD. The pulmonary/systemic flow ratio was derived using invasive oximetry. The RA size had significantly decreased at 3 months of follow up (RA volume index [RAVI] 52 +/- 29 to 27 +/- 17 ml/m(2), p <0.001). Incomplete RAR (defined as a RAVI of >=21 ml/m(2)) was detected in 25 patients (57%) after closure. They were older, had a larger pulmonary/systemic flow ratio, a higher pulmonary arterial systolic pressure, more tricuspid regurgitation, and larger RA, left atrial, and right ventricular sizes before closure than those with a normalized right atrium. Before closure, RAVI was the only independent determinant for incomplete RAR (odds ratio 1.115, 95% confidence interval 1.019 to 1.220; p = 0.018). A cutoff value of RAVI of >=40 ml/m(2) has a sensitivity of 84% and specificity of 72% in the receiver operating characteristic curve. The preclosure RAVI correlated moderately with the shunt-duration index, calculated by multiplying the age to pulmonary/systemic flow ratio (r = 0.64, p <0.01). In conclusion, incomplete RAR occurred in >1/2 of the adult patients at 3 months after ASD device closure and was related to excessive preclosure RA dilation. PMID- 21529750 TI - Risk prediction of complex diseases from family history and known susceptibility loci, with applications for cancer screening. AB - Risk prediction based on genomic profiles has raised a lot of attention recently. However, family history is usually ignored in genetic risk prediction. In this study we proposed a statistical framework for risk prediction given an individual's genotype profile and family history. Genotype information about the relatives can also be incorporated. We allow risk prediction given the current age and follow-up period and consider competing risks of mortality. The framework allows easy extension to any family size and structure. In addition, the predicted risk at any percentile and the risk distribution graphs can be computed analytically. We applied the method to risk prediction for breast and prostate cancers by using known susceptibility loci from genome-wide association studies. For breast cancer, in the population the 10-year risk at age 50 ranged from 1.1% at the 5th percentile to 4.7% at the 95th percentile. If we consider the average 10-year risk at age 50 (2.39%) as the threshold for screening, the screening age ranged from 62 at the 20th percentile to 38 at the 95th percentile (and some never reach the threshold). For women with one affected first-degree relative, the 10-year risks ranged from 2.6% (at the 5th percentile) to 8.1% (at the 95th percentile). For prostate cancer, the corresponding 10-year risks at age 60 varied from 1.8% to 14.9% in the population and from 4.2% to 23.2% in those with an affected first-degree relative. We suggest that for some diseases genetic testing that incorporates family history can stratify people into diverse risk categories and might be useful in targeted prevention and screening. PMID- 21529751 TI - Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]. AB - Genes disrupted in human microcephaly (meaning "small brain") define key regulators of neural progenitor proliferation and cell-fate specification. In comparison, genes mutated in human lissencephaly (lissos means smooth and cephalos means brain) highlight critical regulators of neuronal migration. Here, we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly, and show that they carry homozygous frameshift mutations in NDE1, which encodes a multidomain protein that localizes to the centrosome and mitotic spindle poles. Both human mutations in NDE1 truncate the C-terminal NDE1domains, which are essential for interactions with cytoplasmic dynein and thus for regulation of cytoskeletal dynamics in mitosis and for cell-cycle-dependent phosphorylation of NDE1 by Cdk1. We show that the patient NDE1 proteins are unstable, cannot bind cytoplasmic dynein, and do not localize properly to the centrosome. Additionally, we show that CDK1 phosphorylation at T246, which is within the C-terminal region disrupted by the mutations, is required for cell-cycle progression from the G2 to the M phase. The role of NDE1 in cell-cycle progression probably contributes to the profound neuronal proliferation defects evident in Nde1-null mice and patients with NDE1 mutations, demonstrating the essential role of NDE1 in human cerebral cortical neurogenesis. PMID- 21529752 TI - The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. AB - We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10% of expected size (<=10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination (microlissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment. PMID- 21529753 TI - Repeated course antenatal steroids, inflammation gene polymorphisms, and neurodevelopmental outcomes at age 2. AB - OBJECTIVE: We sought to evaluate the interaction between repeated-course antenatal corticosteroids and inflammation gene polymorphisms with neurodevelopmental outcomes at age 2 years. STUDY DESIGN: We conducted nested case-control analysis of a randomized controlled trial of single- vs repeated course antenatal corticosteroids. Cases had mental and/or psychomotor delay at age 2 years. Controls had normal neurodevelopment. Previous analyses of 125 cases and 147 controls identified 4 inflammation gene polymorphisms associated with neurodevelopmental delay at age 2 years. RESULTS: The interaction between repeated-course corticosteroids and the interleukin (IL)-6 -174 genotype with neurodevelopmental delay was significant (P = .046). The IL-6 -174 GG genotype was associated with neurodevelopmental delay at age 2 years in the single-course corticosteroid group (odds ratio, 6.47; 95% confidence interval, 1.86-22.50). Exposure to repeated-course antenatal corticosteroids abrogated this genotype effect (odds ratio, 1.30; 95% confidence interval, 0.48-3.54). Results were unchanged after controlling for potential confounders. CONCLUSION: Repeated course antenatal steroids may reduce the increased risk of neurodevelopmental delay at age 2 years associated with IL-6 -174 GG genotype. PMID- 21529754 TI - Contribution of different local vascular responses to mid-gestational vasodilation. AB - OBJECTIVE: At-term pregnancy-induced vasodilation is the resultant of endothelium dependent vasodilation, decreased myogenic reactivity, increased compliance, and reduced sensitivity to vasoconstrictor agents. We hypothesized that these vascular changes are already present at mid-gestation. STUDY DESIGN: In 20 mid pregnant and 20 nonpregnant Wistar Hannover rats, we measured vascular responses of isolated mesenteric arteries and kidney. RESULTS: In the pregnant rats compared with the nonpregnant rats, mesenteric flow-mediated vasodilation and renal perfusion flow increased 1.52-fold (from 47+/-5 to 31+/-4 MUL/min) and 1.13 fold (from 12.8+/-0.1 to 14.4+/-0.1 mL/min), respectively. Nitric oxide inhibition reduced mesenteric flow-mediated vasodilation to a similar extent in the pregnant and nonpregnant rats; it completely blocked the pregnancy-induced increase in renal perfusion flow. Pregnancy did not change mesenteric artery sensitivity to phenylephrine, myogenic reactivity, nor vascular compliance. CONCLUSION: At mid-gestation, alterations in rat mesenteric vascular tone depend primarily on flow-mediated endothelium-dependent changes and not on changes in alpha-adrenergic vasoconstrictor sensitivity, myogenic reactivity, or vascular compliance. PMID- 21529756 TI - Preparing a research presentation: a guide for investigators. AB - Many obstetrics and gynecology residencies require trainees to complete a research project as a graduation requirement. These projects may be submitted for publication in a peer-review journal or presentation at a professional meeting. Although written instructions are available for novice authors, few references target research abstract submission and presentation. This paper provides investigators with the advice to successfully negotiate this process. PMID- 21529755 TI - Placental endothelial nitric oxide synthase in multiple and single dose betamethasone exposed pregnancies. AB - OBJECTIVE: To compare endothelial nitric oxide synthase expression and capillary density (CDS) in placentas exposed to single or multiple courses of betamethasone. STUDY DESIGN: Placental specimens exposed to single vs repeat courses of betamethasone were analyzed through immunohistochemistry and digital image quantification for endothelial nitric oxide synthase and CD34. Quantified endothelial nitric oxide synthase staining, calculated capillary density, ratio of endothelial nitric oxide synthase to capillary density, and clinical characteristics were compared. Linear regression was performed with these as dependent variables. RESULTS: Mean and maximum capillary density were increased (P = .013 and .005) and the ratio of endothelial nitric oxide synthase to capillary density decreased (P = .016) in specimens exposed to 4 courses of betamethasone compared with 1 to 3 courses. Exposure to 4 courses of betamethasone was associated with increased capillary density, but not with endothelial nitric oxide synthase expression. CONCLUSION: Exposure to 4 courses of betamethasone is associated with increased placental capillary density. The placental effects of multiple courses of betamethasone are unrelated to endothelial nitric oxide synthase expression. PMID- 21529757 TI - Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes: a systematic review and metaanalysis. AB - OBJECTIVE: To determine whether supplementation with vitamins C and E during pregnancy reduces the risk of preeclampsia and other adverse maternal and perinatal outcomes. STUDY DESIGN: Systematic review and metaanalysis of randomized controlled trials. RESULTS: Nine trials involving a total of 19,810 women were included. Overall, there were no significant differences between the vitamin and placebo groups in the risk of preeclampsia (9.6% vs 9.6%; relative risk, 1.00, 95% confidence interval, 0.92-1.09). Similar results were obtained when subgroup analyses were restricted to women at high risk or low/moderate risk for preeclampsia. Women supplemented with vitamins C and E were at increased risk of developing gestational hypertension and premature rupture of membranes, and decreased risk of abruptio placentae. There were no significant differences between the vitamin and placebo groups in the risk of other adverse maternal or fetal/perinatal outcomes. CONCLUSION: Supplementation with vitamins C and E during pregnancy does not prevent preeclampsia. PMID- 21529758 TI - Congenital diaphragmatic hernia: lung-to-head ratio and lung volume for prediction of outcome. AB - OBJECTIVE: The purpose of this study was to evaluate observed/expected (O/E) lung to-head ratio (LHR) by ultrasound (US) and total fetal lung volume (TFLV) by magnetic resonance imaging as neonatal outcome predictors in isolated fetal congenital diaphragmatic hernia (CDH). STUDY DESIGN: We conducted a retrospective study of 72 fetuses with isolated CDH, in whom O/E LHR and TFLV were evaluated as survival predictors. RESULTS: O/E LHR on US and O/E TFLV by magnetic resonance imaging were significantly lower in newborn infants with isolated CDH who died compared with survivors (30.3 +/- 8.3 vs 44.2 +/- 14.2; P < .0001 for O/E LHR; 21.9 +/- 6.3 vs 41.5 +/- 17.6; P = .001 for O/E TFLV). Area under receiver operator characteristics curve for survival for O/E LHR was 0.80 (95% confidence interval, 0.70-0.90). On multivariate analysis, O/E LHR predicted survival, whereas hernia side and first neonatal pH did not. For each unit increase in O/E LHR, mortality odds decreased by 11% (95% confidence interval, 4-17%). CONCLUSION: In fetuses with isolated CDH, O/E LHR (US) independently predicts survival and may predict severity, allowing management to be optimized. PMID- 21529759 TI - The relationship between the Trp 64 Arg polymorphism of the beta 3-adrenoceptor gene and idiopathic overactive bladder. AB - OBJECTIVE: The purpose of this study was to verify the association between the Trp 64 Arg polymorphism and idiopathic overactive bladder (OAB) syndrome. STUDY DESIGN: A case-control study was conducted with 218 women. The case group consisted of 49 patients with OAB symptoms; the control group included 169 women without urinary symptoms. The studied polymorphism was detected by restriction fragment length polymorphism analysis. The chi(2) test was used to compare categoric data, with a significance level of 5%. Numeric data were compared with the use of the parametric t test or nonparametric Mann-Whitney U test. RESULTS: The distribution of the polymorphism in the investigated women was digested homozygous T allele 69.75%, heterozygotes 29.8%, and homozygous A allele 0.45%. A comparison between the groups showed higher prevalence of the digested homozygous T allele genotype in women with OAB syndrome (P = .001). Multiple logistic regression analysis identified that a family history of OAB syndrome was an independent risk factor for OAB syndrome. CONCLUSION: The Trp 64 Arg polymorphism was associated with OAB syndrome in the Brazilian population. PMID- 21529761 TI - Duplicity: Sonography suggested a twin gestation was dichorionic-and monochorionic. PMID- 21529762 TI - Intraocular foreign bodies in china: clinical characteristics, prognostic factors, and visual outcomes in 1,421 eyes. AB - PURPOSE: To investigate epidemiologic and clinical characteristics, prognostic factors, and visual outcomes of posttraumatic intraocular foreign body (IOFB). DESIGN: Retrospective, consecutive case series. METHODS: Information from 1,421 eyes (1299 inpatients) with IOFB selected from all open-globe injury cases (4,968 eyes of 4,865 inpatients) in 15 tertiary hospitals in China over a 5-year period were collected from a standardized preformulated database of eye injuries. Factors affecting retinal lesions or detachment, development of endophthalmitis, and visual outcome were analyzed statistically. RESULTS: IOFBs represented 28.60% of all open-globe injuries. Of the 1,421 eyes, endophthalmitis developed in 232 (16.76%), and independent protective factors included primary repair within 24 hours (odds ratio [OR], 0.59; P = .006) and self-sealing wounds (OR, 0.69; P = .013). At discharge or follow-up, the enucleation rate was 7.53%, best-corrected visual acuity (VA) improved in 54.33%, and 4.85% had no light perception. Wound length of at least 3 mm and IOFB located in the posterior segment increased the risk of retinal lesion or detachment, and both (OR, 1.66; P < .001; OR, 4.04; P < .001) were significant negative predictors for visual outcome, along with wound larger than IOFB in largest length (OR, 2.38; P = .002) and endophthalmitis (OR, 2.01; P = .0003). Better initial VA (OR, 0.76; P < .001) was a protective factor for final VA. CONCLUSIONS: For IOFBs, primary wound closure by repair within 24 hours or self-sealing independently reduces the risk of endophthalmitis. Worse presenting VA, larger wounds, IOFB in posterior segment, wound larger than IOFB in largest length, and endophthalmitis predict worse visual outcome. PMID- 21529760 TI - SOD1 overexpression in vivo blocks hyperglycemia-induced specific PKC isoforms: substrate activation and consequent lipid peroxidation in diabetic embryopathy. AB - OBJECTIVE: Oxidative stress plays a causative role in diabetic embryopathy. We tested whether mitigating oxidative stress, using superoxide dismutase 1 (SOD1) transgenic (Tg) mice, would block hyperglycemia-induced specific protein kinase C (PKC) isoform activation and its downstream cascade. STUDY DESIGN: Day 8.5 embryos from nondiabetic wild-type control (NC), diabetic mellitus wild-type (DM), and diabetic SOD1-Tg mice (DM-SOD1-Tg) were used for detection of phosphorylated (p-) PKCalpha/betaII and p-PKCdelta, and levels of 2 prominent PKC substrates, phosphorylated myristoylated alanine-rich protein kinase C substrate (MARCKS) and receptor for activated C kinase 1 (RACK1), and lipid peroxidation markers, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). RESULTS: Levels of p PKCalpha/betaII, p-PKCdelta, p-MARCKS, 4-HNE, and MDA were significantly elevated in the DM group compared with those in the NC group and the DM-SOD1-Tg group. The NC and DM-SOD1-Tg groups had comparable levels of these protein and lipid peroxidation markers. RACK1 levels did not differ among the 3 groups. CONCLUSION: Mitigating oxidative stress by SOD1 overexpression blocks maternal hyperglycemia induced activation of specific PKC isoforms and downstream cascades. PMID- 21529763 TI - Corneal cross-linking with hypo-osmolar riboflavin solution in thin keratoconic corneas. AB - PURPOSE: To evaluate the 1-year results of keratoconic eyes with thin corneas that were treated by a hypo-osmolar riboflavin solution and ultraviolet A collagen cross-linking (CXL). DESIGN: Retrospective, nonrandomized study. METHODS: setting: Department of Ophthalmology, Carl Gustav Carus University Hospital, Dresden, Germany. study population: Thirty-two eyes of 29 patients with progressive keratoconus and a corneal thickness of less than 400 MUm (without the epithelium). intervention: Application of a hypo-osmolar riboflavin solution to the cornea after its de-epithelization followed by ultraviolet A collagen cross linking. main outcome measures: Thirty-two eyes with a follow-up within 1 year were evaluated before and after the procedure. Examinations comprised an evaluation of visual acuity, corneal topography, slit-lamp microscopy, and corneal thickness measurements. RESULTS: Before surgery, the mean corneal thickness (with the epithelium) was 382.3 +/- 41.9 MUm, and after the removal of epithelium, the thickness of the cornea was reduced to 337.0 +/- 51.9 MUm. After the application of the hypo-osmolar riboflavin solution, this value increased to 451.8 +/- 46.7 MUm. Before surgery, the mean K-value of the apex of the keratoconus was 65.6 +/- 11.2 diopters, and 1 year after treatment, this value remained unchanged at 64.9 +/- 11.0 diopters (P = .839). Mean best-corrected visual acuity at the time of the treatment was 0.63 +/- 0.37 logarithm of the minimal angle of resolution, and 1 year after the treatment, this value was not statistically different (0.59 +/- 0.42 logarithm of the minimal angle of resolution; P = .662). At the last follow-up examination, which was 1 year after the procedure, all corneas were transparent, without any scarring lesions in the stroma. CONCLUSIONS: The results of our study, using hypo-osmolar riboflavin solution in a cross-linking procedure of thin corneas, show a stability of keratoconus one year after cross-linking. Application of the hypo-osmolar riboflavin solution preserved cross-linked corneas from developing stromal scars. PMID- 21529764 TI - 23- and 20-gauge vitrectomy with air tamponade with combined phacoemulsification for idiopathic macular hole: a single-surgeon study. AB - PURPOSE: To compare the results of 23- and 20-gauge vitrectomies combined with phacoemulsification and aspiration and intraocular lens implantation (phacoemulsification surgery) 1 year after repair of idiopathic macular holes. DESIGN: Retrospective, consecutive, comparative case series. METHODS: The medical charts of 100 consecutive eyes were reviewed that had undergone either 23- or 20 gauge vitrectomy combined with phacoemulsification surgery to treat an idiopathic macular hole performed by 1 surgeon. The rate of improvement of the logarithm of the minimal angle of resolution visual acuity (VA) was calculated using the formula: (postoperative value - preoperative value) * 100/(1-year postoperative value - preoperative value). RESULTS: The macular holes closed successfully after the primary vitrectomy in all eyes in both groups. Although the VAs did not differ significantly before surgery or 1 year after surgery between the 2 groups, the VA improvement was significantly greater 1 and 3 months after surgery (P = .02, for both) in the 23-gauge group compared with the 20-gauge group. The induced corneal astigmatism levels 1 week and 1 and 3 months after surgery were significantly lower (P = .01, P = .01, and P = .03, respectively) and the surgical time was significantly shorter (P = .01) in the 23-gauge group than in the 20-gauge group. No apparent complications developed in either group. CONCLUSIONS: Since 23-gauge vitrectomy combined with phacoemulsification surgery is advantageous because the VA improved rapidly after treating the macular holes with an acceptable safety profile, idiopathic macular holes are a good indication for 23-gauge vitrectomy combined with phacoemulsification surgery. PMID- 21529765 TI - Traumatic optic neuropathy: an evolving understanding. AB - PURPOSE: To critically review the treatment of traumatic optic neuropathy. DESIGN: A perspective of clinical and basic science studies related to traumatic optic neuropathy and its treatment. METHODS: Published clinical and basic science studies on traumatic optic neuropathy were critically reviewed and interpreted. RESULTS: Clinical progress in the treatment of traumatic optic neuropathy is limited by small clinical studies lacking appropriate control groups. The Corticosteroid Randomization for Acute Head Trauma (CRASH) trial found an increased rate of death among patients with acute head trauma treated with high dose corticosteroids compared to placebo-treated patients (21% vs 18%, P = .0001). Recent animal studies also suggest that high-dose corticosteroids are toxic to the injured optic nerve. CONCLUSIONS: The Corticosteroid Randomization for Acute Head Trauma study is immediately relevant to the treatment of traumatic optic neuropathy as individuals with traumatic optic neuropathy often have concomitant head trauma. High-dose corticosteroids for traumatic optic neuropathy will result in a measurable loss of life in patients who also have a brain injury. Death has never been an endpoint for traumatic optic neuropathy studies. Given human and animal data suggesting that treatment is harmful and the lack of demonstrated clinical efficacy, corticosteroids should not be used to treat traumatic optic neuropathy. The benefit of optic canal decompression is also unclear. There is a need to identify traumatic optic neuropathy soon after injury to further define the natural history of this injury. This information will provide a basis for assessing potential future treatments for traumatic optic neuropathy. PMID- 21529766 TI - Acquired sessile hemangioma of the conjunctiva: a report of 10 cases. AB - PURPOSE: To report 10 cases of an unusual conjunctival lesion that has been termed acquired sessile hemangioma. DESIGN: Retrospective, interventional case series. METHODS: A chart review was conducted on patients coded as having a conjunctival vascular tumor at the Ocular Oncology Service at Wills Eye Institute, Thomas Jefferson University. A cohort of these patients was identified as having a lesion comprising a complex sessile arrangement of conjunctival blood vessels that were remarkably similar to one another, but were distinctly different from other known conjunctival vascular tumors and malformations. These lesions were called acquired sessile hemangioma of the conjunctiva. Each case was evaluated for patient age, gender, race, laterality, and follow-up. Each tumor was assessed for anatomic location in the conjunctiva, quadrant of involvement, diameter, thickness, margin (sharp or ill-defined), and presence of feeder blood vessels. RESULTS: Ten cases were identified. The median age at the time of diagnosis was 58 years (mean, 58 years; range, 31-83 years). There were 8 women and 3 men, and all patients were white. Only 1 patient was referred specifically for the vascular lesion. In the other 9 cases, it was a coincidental finding by the authors on referral for unrelated problems. There were no related systemic or ocular findings that seemed to be related to acquired sessile hemangioma. In each case, acquired sessile hemangioma was characterized by a flat array of intertwining, mildly dilated blood vessels, usually on the bulbar conjunctiva. Fluorescein angiography, performed in 1 case, demonstrated a feeding artery, draining vein, and leakage of dye from the deeper blood vessels in the lesion and minimal or no leakage of dye from the more superficial blood vessels. Histopathologic analysis, obtained in 1 case, disclosed that the lesion comprised 2 to 3 layers of dilated congested blood vessels that were otherwise of normal appearance. A literature review failed to detect any previous reports on this lesion. CONCLUSIONS: Acquired sessile hemangioma is an unusual conjunctival vascular lesion of adults that has characteristic clinical features. It should be differentiated from other conjunctival vascular lesions. There are no systemic associations. The best management is observation only, since most remain stable and have no known complications. PMID- 21529767 TI - The Ross operation in children and young adults: a fifteen-year, single institution experience. AB - BACKGROUND: The optimal operation for aortic valve disease in children and young adults remains controversial. The Ross operation offers avoidance of anticoagulation and the potential for growth but is technically demanding and creates double-valve disease. The goal of this study is to report our experience with the Ross operation and the need for reintervention at intermediate follow up. METHODS: A retrospective review of Ross operations in a single surgeon experience from 1992 to 2007 was conducted. All echocardiograms were reevaluated by a single cardiologist. RESULTS: The cohort included 54 patients with a mean age of 13.5 years (range 0.5 to 35 years). Pulmonary autograft implantation was accomplished using root replacement (n=43), root inclusion (n=9), and Dacron tube root replacement (n=2). Follow-up was available for 47 patients (87%) at a mean length of 6.4 years. There were no deaths. Kaplan-Meier estimates of freedom from explantation at 10 years were 100% for the autograft and 71% for the homograft. Autograft insufficiency at latest follow-up was trivial in 37 patients (82%), mild in 6 patients (13%), and moderate in 2 patients (4%). Reintervention for the homograft included balloon dilation in 3 children and conduit change in 5 children (all<=2 years old at initial operation). CONCLUSIONS: The Ross operation can be performed in children and adults with low mortality and can provide a durable result for the aortic valve with a low incidence of aortic insufficiency. The need for homograft replacement during follow-up in our series was primarily limited to children who were age 2 years or younger at initial operation. PMID- 21529768 TI - Starting a robotic program in general thoracic surgery: why, how, and lessons learned. AB - BACKGROUND: We report our experience in starting a robotic program in thoracic surgery. METHODS: We retrospectively reviewed our experience in starting a robotic program in general thoracic surgery on a consecutive series of patients. RESULTS: Between February 2009 and September 2010, 150 patients underwent robotic operations. Types of procedures were lobectomy in 62, thymectomy in 30, and benign esophageal procedures in 6. No thymectomy or esophageal procedures required conversion. One conversion was needed for suspected bleeding for a mediastinal mass. Twelve patients were converted for lobectomy (none for bleeding, 1 in the last 24). Median operative time for robotic thymectomy was 119 minutes, and median length of stay was 1 day. The median time for robotic lobectomy was 185 minutes, and median length of stay was 2 days. There were no operative deaths. Morbidity occurred in 23 patients (15%). All patients with cancer had R0 resections and resection of all visible mediastinal and hilar lymph nodes. CONCLUSIONS: Robotic surgery is safe and oncologically sound. It requires training of the entire operating room team. The learning curve is steep, involving port placement, availability of the proper instrumentation, use of the correct robotic arms, and proper patient positioning. The robot provides an ideal surgical approach for thymectomy and other mediastinal tumors. Its advantage over thoracoscopy for pulmonary resection is unproven; however, we believe complete thoracic lymph node dissection and teaching is easier. Importantly, defined credentialing for surgeons and cost analysis studies are needed. PMID- 21529769 TI - Thoracic aortic mobile thrombus: is there a role for early surgical intervention? AB - BACKGROUND: The diagnosis of thoracic aortic mobile thrombus (TAMT) is rare and is usually made after debilitating embolic events. The optimal treatment strategy is unknown. We report 14 patients with TAMT and aim to better define the role of early (less than 2 weeks) surgical thrombectomy. METHODS: Between February 1996 and February 2010, we treated 14 patients (9 women; aged 32 to 84 years, mean age 51 years) with TAMT. Hypercoagulable disorders or a strong family history of vascular thrombosis, or both, occurred in 9 patients. Diagnosis was made by transesophageal echocardiogram in 6, computed tomography angiography in 7, and digital subtraction angiography in 1. Embolic locations were extremities (n=9), cerebral (n=6), and abdominal (n=6). Aortic thrombi (n=17) locations were ascending/arch (n=7), descending (n=8), and thoracoabdominal (n=2). RESULTS: All patients were initially treated with heparin and aspirin. Thoracic aortic thrombectomies were performed in 8 patients within 2 weeks of diagnosis: left thoracotomy (n=5), thoracoabdominal (n=1), and median sternotomy (n=2). Left atrial-femoral bypass was used in 5 patients, cardiopulmonary bypass in 2, and no support in 1. Additional procedures were celiac artery (n=1) and left subclavian artery (n=2) thrombectomies. Procedures for embolic complications were performed in 7 patients before aortic thrombectomy. Operative mortality was 0%, with no recurrent embolic events after 24+/-16 months. One patient had thrombectomy of the ascending aorta and medical therapy with warfarin and aspirin for a second concurrent small thrombus in the descending aorta. One patient presented with multiorgan failure and died shortly after admission. Six patients treated medically were discharged on a regimen of oral warfarin and aspirin (14+/-11 months follow-up), with 2 fatal recurrent embolic events within 6 weeks (p=0.09). CONCLUSIONS: Thoracic aortic mobile thrombus is rare and is commonly associated with morbid thromboembolic events. In our experience, early surgical aortic thrombectomy had a low operative risk and may prevent fatal recurrent embolic events. PMID- 21529770 TI - Computed tomographic modeling before and after treatment for posttraumatic empyema: early decortication is superior to catheter drainage. AB - BACKGROUND: Posttraumatic empyema is relatively unusual. There are little data comparing the results of various interventions, and no data that have documented the restoration of lung volumes. METHODS: We compared patients with posttraumatic empyema who were treated with catheter drainage or decortication. Computed tomographic scans of the chest were obtained before and after treatment, and computed tomographic modeling was used to determine the change in lung volumes after each intervention. RESULTS: From 2006 to 2010 there were 478 patients admitted after sustaining chest trauma and 25 (5%) developed an empyema. The definitive treatment was decortication in 15 patients (60%) and chest tube or catheter drainage in 10 (40%). Four patients (16%) initially treated with chest tubes later required decortication. The overall complication rate was 33% for decortication and 100% for catheters. There was no significant difference in days of mechanical ventilation (catheter-median 0, SD+/-13 days; decortication-median 10, SD+/-12 days; p=0.6), total length of stay (catheter-median 15, SD+/-36 days; decortication-median 27, SD+/-17 days; p=0.9), and intensive care unit days (catheter-median 6, SD+/-19 days; decortication-median 15, SD+/-17 days; p=0.5). After chest tube drainage, the lung volume increased on average by 751 cubic centimeters (range, 99 to 1,982 cc). After decortication, the lung volume increased on average by 1,519 cc (range, 616 to 2,916, p=0.02). CONCLUSIONS: Decortication for posttraumatic empyema results in higher postoperative lung volumes than catheter drainage and has a lower complication rate. Decortication is more effective in restoring full pulmonary capacity in the treatment of posttraumatic empyema. PMID- 21529771 TI - Preferred viewing distance of liquid crystal high-definition television. AB - This study explored the effect of TV size, illumination, and viewing angle on preferred viewing distance in high-definition liquid crystal display televisions (HDTV). Results showed that the mean preferred viewing distance was 2856 mm. TV size and illumination significantly affected preferred viewing distance. The larger the screen size, the greater the preferred viewing distance, at around 3-4 times the width of the screen (W). The greater the illumination, the greater the preferred viewing distance. Viewing angle also correlated significantly with preferred viewing distance. The more deflected from direct frontal view, the shorter the preferred viewing distance seemed to be. PMID- 21529772 TI - Development and evaluation of an office ergonomic risk checklist: ROSA--rapid office strain assessment. AB - The Rapid Office Strain Assessment (ROSA) was designed to quickly quantify risks associated with computer work and to establish an action level for change based on reports of worker discomfort. Computer use risk factors were identified in previous research and standards on office design for the chair, monitor, telephone, keyboard and mouse. The risk factors were diagrammed and coded as increasing scores from 1 to 3. ROSA final scores ranged in magnitude from 1 to 10, with each successive score representing an increased presence of risk factors. Total body discomfort and ROSA final scores for 72 office workstations were significantly correlated (R = 0.384). ROSA final scores exhibited high inter and intra-observer reliability (ICCs of 0.88 and 0.91, respectively). Mean discomfort increased with increasing ROSA scores, with a significant difference occurring between scores of 3 and 5 (out of 10). A ROSA final score of 5 might therefore be useful as an action level indicating when immediate change is necessary. ROSA proved to be an effective and reliable method for identifying computer use risk factors related to discomfort. PMID- 21529773 TI - Real-time biomechanical biofeedback effects on top-level rifle shooters. AB - The aim was to examine the effects of training with real-time biomechanical biofeedback on technique and performance of rifle shooters. Top-level shooters were randomly assigned to biofeedback- (n = 5) and control- (n = 4) groups. Bi weekly training of 20 shots air-rifle for 4 weeks, with pre- and post-tests of 20 shots air-rifle and smallbore, were performed. The biofeedback group received individualized real-time auditory biofeedback on postural- and barrel stabilities. Results revealed a technique of reducing postural- and barrel stabilities towards triggering (e.g. barrel speed 8.0 +/- 1.2 mm/s at 3.0-1.0 s reducing to 5.4 +/- 0.8 mm/s at 0.3-0.1 s). There were no changes pre- to post tests and no differences between groups in these measures of stability. The biofeedback group showed meaningful improvements in performance measures, whereas the control group showed no improvement (e.g. smallbore shot group diameter change: biofeedback group -2.6 mm; control group 0.1 mm). Biomechanical biofeedback is proposed to have improved performance, possibly through training better decision making, but the actual cause requires further research. PMID- 21529774 TI - Estimation of 3-D peak L5/S1 joint moment during asymmetric lifting tasks with cubic spline interpolation of segment Euler angles. AB - Previous research proposed a method using interpolation of the joint angles in key frames extracted from a field-survey video to estimate the dynamic L5/S1 joint loading for symmetric lifting tasks. The advantage of this method is that there is no need to use unwieldy equipment for capturing full body movement for the lifting tasks. The current research extends this method to asymmetric lifting tasks. The results indicate that 4-point cubic spline interpolation of segment Euler angles combined with a biomechanical model can provide a good estimation of 3-D peak L5/S1 joint moments for asymmetric lifting tasks. The average absolute error in the coronal, sagittal, and transverse planes with respect to the local pelvis axes was 16Nm, 22Nm, and 11Nm, respectively. It was also found that the dynamic component of the peak L5/S1 joint moment was not monotonously convergent when the number of interpolation points was increased. These results can be helpful for developing applied ergonomic field-survey tools such as video bases systems for estimating L5/S1 moments of manual materials handling tasks. PMID- 21529775 TI - Clarithromycin, as an adjunct to non surgical periodontal therapy for chronic periodontitis: a double blinded, placebo controlled, randomized clinical trial. AB - OBJECTIVE: Along with conventional non-surgical periodontal therapy (NSPT) systemic antimicrobials may provide more effective treatment for chronic periodontitis by targeting tissue-invasive bacteria. The aim of this randomized, placebo-controlled, double-masked clinical trial was to evaluate the adjunctive effects of oral clarithromycin (CLM) to non-surgical periodontal therapy for chronic periodontitis. METHODS: 40 patients were categorized into two groups: test group - scaling and root planing (SRP) plus CLM (500 mg b.i.d. for 3 days) and control group - SRP plus placebo. Clinical parameters were recorded at baseline and at 1, 3, 6, and 9 months. They included gingival index (GI), probing depth (PD), and clinical attachment level (CAL). Also microbial analysis of dental plaque was done at baseline, 3 and 9 months to estimate the levels of periodontopathic organisms using polymerase chain reaction. ANOVA, Chi-square and Bonferroni tests were used for statistical analysis. RESULTS: Thirty-seven subjects completed the study and the results demonstrated that both groups displayed clinical improvements. Using a subject-based analysis, patients treated with SRP+CLM showed enhanced reductions in PD and gains in CAL (p<0.001) over time, as compared to control group. Also significant reductions in periodontopathic organisms were noticed in the test group compared to control group. However, no statistically significant differences were noted for Tannerella forsythia levels between the groups during the course of the study. CONCLUSIONS: The utilisation of CLM in combination with SRP improves the efficacy of NSPT in reducing PD, improving CAL and in lessening microbial loads. Hence, CLM may be beneficial in the non-surgical treatment regimen of chronic periodontitis. PMID- 21529776 TI - Association of masticatory performance with age, gender, number of teeth, occlusal force and salivary flow in Japanese older adults: is ageing a risk factor for masticatory dysfunction? AB - OBJECTIVE: In general, ageing is a risk factor for sensory and motor deterioration, with the rate of decline varying amongst individuals. Concerning masticatory function, missing teeth along with oral disease seem to accelerate the dysfunction. Here, we aimed to confirm whether masticatory dysfunction by ageing is inevitable. This study investigated the effect of age, gender, number of natural teeth, occlusal force and salivary flow on the masticatory performance in a large sample of elderly adults. DESIGN: The study sample consisted of 1288 independently living people aged 60-84 years. Masticatory performance was determined by the comminuted particles of test food. Bilateral maximal occlusal force in the intercuspal position was measured with pressure sensitive sheets. Stimulated whole saliva was collected. RESULTS: Masticatory performance was significantly correlated to age, number of residual teeth, occlusal force and stimulated salivary flow rate by Pearson's correlation test. The multiple linear regression analysis showed that, with other variables controlled, masticatory performance was significantly associated with the number of residual teeth (beta=0.456, P<0.001), occlusal force (beta=0.244, P<0.001) and stimulated salivary flow rate (beta=0.069, P=0.003). Age was not related to masticatory performance (beta=-0.007, P=0.753). CONCLUSIONS: Declines in the number of residual teeth, occlusal force and salivary flow were associated with a reduction of masticatory performance in older adults. If tooth loss is not considered as an attribute of physiological ageing, then ageing by itself may not be a risk factor for masticatory dysfunction. PMID- 21529777 TI - Periodontal conditions and prevalence of putative periodontopathogens and Candida spp. in insulin-dependent type 2 diabetic and non-diabetic patients with chronic periodontitis--a pilot study. AB - OBJECTIVES: The aims of this study were to evaluate periodontal conditions and identify the presence of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Tannerella forsythia, and four different species of Candida (C. albicans, C. dubliniensis, C. glabrata and C. tropicalis) in periodontal pockets and furcation sites of insulin-dependent type 2 diabetic and non-diabetic patients with generalised chronic periodontitis. DESIGN: Clinical parameters, including oral status assessed using plaque index, gingival index, probing depth, gingival recession and clinical attachment level and systemic conditions with fasting glucose level or glycosylated haemoglobin were measured in diabetic and non-diabetic patients with chronic periodontitis. Samples of subgingival biofilm were obtained from the periodontal pockets and furcation sites and submitted to phenol-chloroform DNA extraction and PCR analysis using specific primers. RESULTS: Clinical conditions of diabetic and non-diabetic patients were similar, without statistical differences in both periodontal indexes and glucose levels (p>0.05). Diabetics had a higher prevalence of Candida spp., mainly C. albicans and C. dubliniensis, and a lower frequency of T. forsythia, when compared to non diabetic patients, for both periodontal sites. C. glabrata and C. tropicalis were not found in periodontal pockets and furcation sites of non-diabetic patients. CONCLUSION: The results demonstrated a strong colonisation of Candida spp. in the periodontal sites of diabetic patients that have generalised chronic periodontitis with a higher prevalence of C. dubliniensis followed by C. albicans. PMID- 21529778 TI - Spinal cord mechanism involving the remote effects of dry needling on the irritability of myofascial trigger spots in rabbit skeletal muscle. AB - OBJECTIVE: To elucidate the neural mechanisms underlying the remote effects produced by dry needling rabbit skeletal muscle myofascial trigger spots (MTrSs) via analyses of their endplate noise (EPN) recordings. DESIGN: Experimental animal controlled trial. SETTING: An animal laboratory of a university. ANIMALS: Male New Zealand rabbits (N=96) (body weight, 2.5-3.0kg; age, 16-20wk). INTERVENTION: Animals received no intervention for neural interruption in group I, transection of the tibial nerve in group II, transection of L5 and L6 spinal cord in group III, and transection of the T1 and T2 spinal cord in group IV. Each group was further divided into 4 subgroups: animals received ipsilateral dry needling, contralateral dry needling, ipsilateral sham needling, or contralateral sham needling of gastrocnemius MTrSs. MAIN OUTCOME MEASURES: EPN amplitudes of biceps femoris (BF) MTrSs. RESULTS: BF MTrS mean EPN amplitudes significantly increased (P<.05) initially after gastrocnemius verum needling but reduced to a level significantly lower (P<.05) than the preneedling level in groups I and IV with ipsilateral dry needling or contralateral dry needling, and in group II with contralateral dry needling (but not ipsilateral dry needling). No significant EPN amplitude changes were observed in BF MTrS in group III or in the control animals receiving superficial needling (sham). CONCLUSION: This remote effect of dry needling depends on an intact afferent pathway from the stimulating site to the spinal cord and a normal spinal cord function at the levels corresponding to the innervation of the proximally affected muscle. PMID- 21529779 TI - Is there altered activity of the extensor muscles in chronic mechanical neck pain? A functional magnetic resonance imaging study. AB - OBJECTIVE: To compare the pattern of neck extensor muscle use in participants with chronic mechanical neck pain to that of healthy controls during 2 different extension exercises by use of muscle functional magnetic resonance imaging (mfMRI). DESIGN: Cross-sectional. SETTING: University laboratory. PARTICIPANTS: Data recorded from subjects with chronic mechanical neck pain (n=12; 10 women, 2 men) were compared with previously recorded data from healthy subjects (n=11; 7 men, 4 women). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: mfMRI measures of shifts in T2 relaxation were made for the multifidus, semispinalis cervicis, semispinalis capitis, and splenius capitis muscles, at C2-3, C5-6, and C7-T1 levels, prior and immediately after 2 different exercises: cervical extension in craniocervical neutral (CCN) and cervical extension in craniocervical extension. T2 shift values (difference between pre- and postexercise T2 relaxation values) for each muscle and exercise condition were used for analysis. RESULTS: While there were observed differences in differential activation of the extensor muscles in participants with mechanical neck pain compared with controls, these differences were only evident for the CCN exercise condition and were only observed for 3 out of the 7 muscle regions of interest during this exercise. CONCLUSIONS: Results of this study suggest some alteration in the differential activation of the cervical extensors in patients with mechanical neck pain and indicate that further investigation of this muscle group in mechanical neck pain disorders is warranted. PMID- 21529780 TI - Induction of prolonged mania during ketamine therapy for reflex sympathetic dystrophy. PMID- 21529781 TI - Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia II: developing imaging biomarkers to enhance treatment development for schizophrenia and related disorders. AB - The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative, funded by an R13 from the National Institute of Mental Health, seeks to enhance translational research in treatment development for impaired cognition in schizophrenia by developing tools from cognitive neuroscience into useful measures of treatment effects on behavior and brain function. An initial series of meetings focused on the selection of a new set of tasks from cognitive neuroscience for the measurement of treatment effects on specific cognitive and neural systems. Subsequent validation and optimization studies are underway and a subset of validated measures with well-characterized psychometric properties will be generally available in 2011. This article describes results of the first meeting of the second phase of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia, which seeks to develop imaging biomarkers and improved animal models to enhance translational research. In this meeting, we considered issues related to the use of methods such as functional magnetic resonance imaging, electroencephalography, magnetoencephalography, and transcranial magnetic simulation as biomarkers for treatment development. We explored the biological nature of the signals measured by each method, their validity and reliability as measures of cognition-related neural activity, potential confounds related to drug effects on the signal of interest, and conceptual, methodological, and pragmatic issues related to their use in preclinical, first into human, and multicenter phase II and III studies. This overview article describes the background and goals of the meeting together with a summary of the major issues discussed in more detail in the accompanying articles appearing in this issue of Biological Psychiatry. PMID- 21529782 TI - Spatial attention, feature-based attention, and saccades: three sides of one coin? AB - The last three decades has seen a steady growth of neuroscience research aimed at understanding the functions and sources of top-down attentional modulation in the brain. This correlates with recognition that attention may be a necessary component of sensory systems to support natural behaviors in natural environments. Complexity and clutter are two of the most recognizable hallmarks of natural environments, which can simultaneously contain vitally important and completely irrelevant stimuli. Attention serves as an adaptive filter providing each sensory modality preferential processing routes for important stimuli while suppressing responses to distracters, thus optimizing use of limited neural resources. In other words, attention is the family of mechanisms by which organisms are able to effectively and selectively allocate limited neural resources to achieve specific behavioral goals. This review provides some historical context for considering attentional frameworks and modern neurophysiological attention research, focusing on visual attention. A taxonomy of common attentional effects and neural mechanisms is provided, along with consideration of the specific relationship between attention and saccade planning. We examine the validity of premotor theories of attention, which posit that attention and saccade planning are one and the same. While there is strong evidence that attention and oculomotor planning are similar, with shared neural substrates, there is also evidence that these two functions are not synonymous. Finally, we examine neurophysiological explanations for dysfunction in attention deficit/hyperactivity disorder and the hypothesis that social impairment in autism spectrum disorders is partially attributable to perturbations of attentional control circuitry. PMID- 21529783 TI - A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. AB - BACKGROUND: Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted a quantitative trait genome wide association study (GWAS) for phenotypes related to alcohol use and dependence. METHODS: Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed with 8754 individuals (2062 alcohol-dependent cases) selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score, and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genome-wide SNP data. RESULTS: No findings reached genome-wide significance (p = 8.4 * 10(-8) for this study), with lowest p value for primary phenotypes of 1.2 * 10(-7). Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk. CONCLUSIONS: We conclude that 1) meta-analyses of consumption data may contribute usefully to gene discovery; 2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; and 3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g., prospective high-risk or resilience studies). PMID- 21529785 TI - Tight junction proteins vary in the choroid plexus of ewes according to photoperiod. AB - Sheep from temperate latitudes exhibit seasonal variations in many physiological functions such as reproduction, food intake, body weight, and pelage growth. Majority of seasonal changes are controlled by the annual photoperiodic cycle and melatonin secretion. For reproduction, the resulting key event is a modulation of the negative feedback of steroids on gonadotropin secretion. However, this seasonal effect could also depend on variable uptake of steroids by the brain. Seasonal regulation of food intake also involves numerous peripheral hormones, among which the protein hormone leptin informs the brain on the metabolic status of the animal. It has been shown previously that access of progesterone, estradiol and leptin to the cerebrospinal fluid (CSF) increases under long days. This physiological modulation of the passage of hormones to the brain could depend on regulation of the permeability of the blood-CSF barrier. This study therefore compared the tight junction proteins in the choroid plexus of ewes exposed to short days or long days. Levels of occludin, zonula occludens proteins (ZO) ZO-1 and ZO-2, afadin and cadherin were significantly higher during short days, but no statistical difference was observed for junctional adhesion molecule 1 (JAM-1), ZO-3 or claudins 1 and 5. These results are consistent with an increase in the blood-CSF barrier permeability during long days through a regulation of tight junctions and show that the permeability could depend upon physiological conditions such as photoperiodic status. PMID- 21529784 TI - Behavioral effects of clozapine: involvement of trace amine pathways in C. elegans and M. musculus. AB - Clozapine is an antipsychotic medication with superior efficacy in treatment refractory schizophrenia. The molecular basis of clozapine's therapeutic profile is not well understood. We studied behavioral effects of clozapine in Caenorhabditis elegans to identify novel pathways that modulate clozapine's biological effects. Clozapine stimulated egg laying in C. elegans in a dose dependent manner. This effect was clozapine-specific, as it was not observed with exposure to a typical antipsychotic, haloperidol or an atypical antipsychotic, olanzapine. A candidate gene screen of biogenic amine neurotransmitter systems identified signaling pathways that mediate this clozapine-specific effect on egg laying. Specifically, we found that clozapine-induced increase in egg laying requires tyramine biosynthesis. To test the implications of this finding across species, we explored whether trace amine systems modulate clozapine's behavioral effects in mammals by studying trace amine-associated receptor 1 (TAAR1) knockout mice. Clozapine increased prepulse inhibition (PPI) in wild-type mice. This increase in PPI was abrogated in TAAR1 knockout mice, implicating TAAR1 in clozapine-induced PPI enhancement. In transfected mammalian cell lines, we found no TAAR activation by antipsychotics, suggesting that modulation of trace amine signaling in mice does not occur directly at the receptor itself. In summary, we report a heretofore-unknown role for trace amine systems in clozapine-mediated effects across two species: C. elegans and mice. PMID- 21529786 TI - The nucleus locus coeruleus/subcoeruleus contributes to antinociception during freezing behavior following the air-puff startle in rats. AB - An air puff elicits a startle response in mammals. Following the startle response, rats react with a defensive-like, immobile posture (DIP) of approximately 2-5s in length. We have previously reported that air-puff stimulation (APS) activates the nucleus locus coeruleus/subcoeruleus (LC/SC) so that the DIP is induced. The LC/SC is one of the structures that plays an important role in endogenous pain control. Our particular interest is whether APS induces nociceptive modulation. Rats were tested for behavioral nociception with heating of the tail. Rats whisked their tail following heating and then bit the heat source when the tail could not escape heating by tail flick. The tail flick latency (TFL) and the bite latency (BL) were measured as an indicator of nociception. Compressed house air (14.4 psi in strength, 0.1s in duration) was presented for APS. Two weeks before the experiment, the rats received bilateral injections of 6 MUg of the neurotoxin 6-hydroxydopamine to specifically lesion noradrenaline-containing neurons of the LC/SC. APS produced prolongation of the TFL and the BL. In both the TFL and the BL, APS-induced prolongation was not observed in rats with the LC/SC lesions. When BLs were plotted against DIP periods, the BL was almost constant regardless of the change in the DIP period. These results suggest that (1) APS produces nociceptive modulation, (2) the LC/SC is involved in APS-induced nociceptive modulation, and (3) two APS-induced events, the DIP and nociceptive modulation, are a parallel phenomenon. PMID- 21529787 TI - Thyroid hormone deficiency disrupts rat eye neurodevelopment. AB - Clinical and experimental studies have highlighted the role played by thyroid hormones (TH) in neural and neuro-sensorial development. However, knowledge on TH mechanisms on the developing visual system is still incomplete. To uncover TH actions on the eyes and vision we carried out a microscopical study on the role of TH in the developing retina and optic nerve, in a rat model of controlled TH deficiency (THD). Morphometric and stereological analyses of the retina and optic nerve showed a reduction in the volume of the eye (p<0.001) and optic nerve cross sectional area (p<0.001), and thinning of the retinal layers (p<0.001). Glial development and myelination was significantly delayed in the THD optic nerves (p<0.001), as compared to controls. The data indicate that TH play an essential role in neuro-retinogenesis. Substitutive TH therapy in critical periods, should be considered in hypothyroidism-related eye disorders as well as neurodegenerative retinal processes. PMID- 21529788 TI - ASICs mediate the modulatory effect by paeoniflorin on alpha-synuclein autophagic degradation. AB - Acid-sensing ion channels (ASICs) are ligand-gated cation channels that respond to acidic stimuli. They are expressed throughout the mammalian nervous system. Complex subunit combinations and lack of specific blockers of native receptors result in the difficulty of resolving the functions of ASICs. In this study, we showed that rat pheochromocytoma cells (PC12 cells) functionally express ASICs with the activity of endogenous proton-gated conductance. PF is the principal active ingredient extracted from the root of Paeoniae alba, a Chinese herb commonly used to treat neurodegenerative disorders, especially PD. It was found that PF significantly up regulated the expression of LC3-II, which is specifically associated with autophagic vacuole membranes. PF also reduced the MPP(+) and acidosis-induced accumulation of alpha-synuclein, the major component of Lewy bodies. Moreover, PF was highly efficacious in modulating ASICs activity and protein expression. In addition, the data showed that PF was able to protect PC12 cells against MPP(+) and acidosis-induced cytotoxicity. In summary, these findings demonstrate for the first time that PF could enhance the autophagic degradation of alpha-synuclein by regulating the expression and activity of ASICs and thus produces protective effects against cytotoxicity. It also offers the experimental evidence for the potential role of ASICs in the pathogenesis of PD. PMID- 21529789 TI - Comparative study of the efficacies of nine assay methods for the dextransucrase synthesis of dextran. AB - A comparative study of nine assay methods for dextransucrase and related enzymes has been made. A relatively widespread method for the reaction of dextransucrase with sucrose is the measurement of the reducing value of D-fructose by alkaline 3,5-dinitrosalicylate (DNS) and thereby the amount of D-glucose incorporated into dextran. Another method is the reaction with (14)C-sucrose with the addition of an aliquot to Whatman 3MM paper squares that are washed three times with methanol to remove (14)C-D-fructose and unreacted (14)C-sucrose, followed by counting of (14)C-dextran on the paper by liquid scintillation counting (LSC). It is shown that both methods give erroneous results. The DNS reducing value method gives extremely high values due to over-oxidation of both D-fructose and dextran, and the (14)C-paper square method gives significantly low values due to the removal of some of the (14)C-dextran from the paper by methanol washes. In the present study, we have examined nine methods and find two that give values that are identical and are an accurate measurement of the dextransucrase reaction. They are (1) a (14)C-sucrose/dextransucrase digest in which dextran is precipitated three times with three volumes of ethanol, dissolved in water, and added to paper and counted in a toluene cocktail by LSC; and (2) precipitation of dextran three times with three volumes of ethanol from a sucrose/dextransucrase digest, dried, and weighed. Four reducing value methods were examined to measure the amount of D fructose. Three of the four (two DNS methods, one with both dextran and D fructose and the other with only D-fructose, and the ferricyanide/arsenomolybdate method with D-fructose) gave extremely high values due to over-oxidation of D fructose, D-glucose, leucrose, and dextran. PMID- 21529790 TI - [Malignant skin melanoma intestinal metastasis as a cause of recurrent jejunal intussuseption]. PMID- 21529791 TI - [Axillary Schwannoma: an unusual location]. PMID- 21529792 TI - Transarterial embolization in the management of persistent post-traumatic urinary extravasation from a horseshoe kidney. PMID- 21529793 TI - Evaluation of human muscle hardness after dynamic exercise with ultrasound real time tissue elastography: a feasibility study. AB - AIM: To assess the feasibility of ultrasound real-time tissue elastography (RTE) for measuring exercise-induced changes in muscle hardness and to compare the findings of RTE with those of a tissue hardness meter for semi-quantitative assessment of the hardness of exercised muscles. MATERIALS AND METHODS: Nine male participants performed an arm-curl exercise. RTE measurements were performed by manually applying repetitive compression with the transducer on the scan position before exercise, immediately after exercise, and at 30 min after exercise; strain ratios between muscle and a reference material (hydrogel) were calculated (muscle strain/material strain). A tissue hardness meter was also used to evaluate muscle hardness. The intraclass correlation coefficients (ICCs) for the three repeated measurements at each measurement time were calculated to evaluate the intra observer reproducibility of each technique. RESULTS: Immediately after exercise, the strain ratio and the value obtained using the tissue hardness meter significantly decreased (from 1.65 to 1.35) and increased (from 51.8 to 54.3), respectively. Both parameters returned to their pre-exercise value 30 min after exercise. The ICCs of the RTE (and the ICCs of the muscle hardness meter) were 0.971 (0.816) before exercise, 0.939 (0.776) immediately after exercise, and 0.959 (0.882) at 30 min after exercise. CONCLUSION: Similar to the muscle hardness meter, RTE revealed the exercise-induced changes of muscle hardness semi quantitatively. The intra-observer reproducibility of RTE was very high at each measurement time. These findings suggest that RTE is a clinically useful technique for assessing hardness of specific exercised muscles. PMID- 21529794 TI - False-positive diagnosis of cerebral aneurysms using MR angiography: location, anatomic cause, and added value of source image data. AB - PURPOSE: To investigate the anatomic causes of false-positive unruptured aneurysms (FPUIAs) and the added value of source images (SIs) in magnetic resonance angiography (MRA)-based UIA diagnosis. METHODS: The MRA images of 59 patients with 63 FPUIAs and 113 patients with 127 aneurysms were retrospectively reviewed. Two neurointerventionists reviewed MRA- maximum intensity projection (MIP) and conventional angiographic images of patients with FPUIAs, and determined the anatomical causes of FPUIAs by location. They also reviewed both MIP images alone (MIP mode) and additional SI together with MIP (MIP+SI mode) and rated aneurysm probability separately. Receiver operating characteristic (ROC) analysis was performed to compare diagnostic performance of both image modes. RESULTS: FPUIAs were most commonly found at the internal carotid artery (ICA) posterior communicating artery (Pcom) (36%). False-positive results at the ICA Pcom and ICA-anterior choroidal artery resulted from the presence of infundibuli in 28 (97%) and six (100%), respectively. An arterial loop was the leading cause of FPUIAs throughout all locations of the anterior cerebral artery and middle cerebral artery except the anterior communicating artery, where fenestration was found in six (60%) cases. The areas under the ROC curves of the two image modes were not significantly different (0.887 versus 0.925; p=0.103). Addition of the SIs did not cause a significant change in sensitivity (88.2 versus 83.5%; p=0.21), whereas it led to a significant increase in specificity (74.6 versus 95.2%; p=0.0002). CONCLUSIONS: MRA-based FPUIAs are mostly attributable to infundibuli and arterial loops. Although the addition of the SIs appears not to significantly increase the sensitivity of UIA diagnosis, it may significantly improve the specificity. PMID- 21529795 TI - Sixteen cases of pulmonary sclerosing haemangioma: CT findings are not definitive for preoperative diagnosis. AB - AIM: To describe and assess computed tomography (CT) imaging findings of pathologically confirmed pulmonary sclerosing haemangioma (PSH), a rare benign tumour, in 16 patients. MATERIALS AND METHODS: This study was approved by the human investigation committees of the two participating institutions, and the requirement of informed consent was waived. Findings from CT examinations in 16 patients with pathologically confirmed PSH were retrospectively reviewed. Two radiologists in consensus assessed the location, size, contour, and border of nodules, as well as the enhancement patterns. RESULTS: The study comprised 16 patients (two male and 14 female) aged 30-70 years. PSHs appeared as well defined, round or ovoid masses with a diameter of 2.2+/-0.3cm, and were generally demonstrated as juxtapleural masses (94%) on CT. Calcification (13%), the air crescent sign (13%), and a prominent pulmonary artery (25%) in the tumours were also demonstrated in the cohort. The mean tumour attenuation value at CT was 30+/ 3HU before intravenous administration of contrast media, and was significantly lower than that of the enhanced phase (79+/-3HU, p<0.05). Twelve tumours (75%) enhanced homogeneously compared with four tumours (25%) which enhanced heterogeneously. The diameters of the heterogeneously enhanced tumours were larger than those of the homogeneously enhanced tumours (p<0.05). CONCLUSION: The relatively characteristic CT findings include a markedly contrast-enhanced juxtapleural mass with homogeneous enhancement for the smaller tumours (<3cm in diameter) or heterogeneous enhancement for the larger tumours (>3cm). However, CT findings are not definitive for preoperative diagnosis of PSH. PMID- 21529796 TI - Hand preferences in human adults: non-communicative actions versus communicative gestures. AB - Hand preferences for pointing gestures and bimanual manipulative activities were investigated in 127 adult participants. Pointing gestures were produced in two different conditions: a speech condition, in which the gestures were accompanied by speech, and a silent condition. Although the classification of participants as left- or right-handers, or ambidextrous, was consistent across the manipulation and pointing tasks for 85% of participants, results showed only moderate correlations between handedness scores for bimanual manipulation and pointing gestures. Moreover, results did not reveal any difference in the degree of hand preference between pointing gestures produced along with speech and gestures produced on their own. The implications of these findings are discussed in relation to the lateralization of non-communicative manual actions, communicative gestures and speech. PMID- 21529797 TI - Hypercalcemia: an unusual etiology of a common menopausal symptom. AB - OBJECTIVE: To describe atypical vasomotor symptoms that were secondary to primary hyperparathyroidism. DESIGN: Case report. SETTING: University medical center. PATIENT(S): A 57-year-old, postmenopausal woman with recalcitrant hot flushes. INTERVENTION(S): Parathyroid adenomectomy. MAIN OUTCOME MEASURE(S): Vasomotor symptom relief. RESULT(S): Postoperative relief of atypical vasomotor symptoms. CONCLUSION(S): A patient 17 years postmenopause presented with atypical vasomotor symptoms that did not respond to hormone therapy and proved to be due to hypercalcemia secondary to primary hyperparathyroidism. An atypical manifestation of a common condition or an uncharacteristic therapeutic response should alert health care providers to the possibility of a different diagnosis. PMID- 21529798 TI - Elevated body mass index is associated with lower serum anti-mullerian hormone levels in infertile women with diminished ovarian reserve but not with normal ovarian reserve. AB - OBJECTIVE: To investigate the association between elevated body mass index (BMI) and ovarian reserve. DESIGN: Cross-sectional study. SETTING: Academic institutions. PATIENT(S): Two hundred ninety women with infertility. Diminished ovarian reserve (DOR) was defined as day 3 FSH>10 IU/L. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Random serum antimullerian hormone (AMH) levels and number of oocytes retrieved during assisted reproductive technology cycle. RESULT(S): Increasing BMI was associated with lower random serum AMH levels in infertile women with DOR but not in women with normal ovarian reserve (NOR). Among women with DOR, mean random serum AMH levels were 33% lower in overweight and obese women compared with women with normal weight. The same association was not true for women with NOR. Out of 290 women evaluated for infertility, 109 women underwent a controlled ovarian hyperstimulation (COH)-IVF cycle. Women with elevated BMI and DOR had lower number of oocytes retrieved compared with women with normal BMI and DOR (6.4+/-4.3 vs. 9.4+/-6), an association that was not observed among women with NOR. CONCLUSION(S): Overweight and obese women with DOR as defined by high day 3 serum FSH levels have lower serum AMH levels and number of oocytes retrieved compared with nonobese women with DOR. PMID- 21529800 TI - Phylogeny of the southern Plateau: an osteometric evaluation of inter-tribal relations. AB - This project focuses on whether determination of physical differences among closely affiliated Native American populations inhabiting the southern Plateau is possible. The study includes 318 individuals and approximately 100 recorded measurements of the cranium, humerus, femur, and tibia of each individual. The compiled measurements were evaluated in terms of their implied genetic affiliation, environmental location, and cultural identity. Along with metric measurements, pathological conditions were also compared to provide a control experiment to confirm or reject the findings. The results indicate that there are slight differences detectable among the populations as a result of environmental and European contact factors. The most apparent disparities are seen in relation to the size and shape of the lower extremities, which are highly associated with environmental and dietary stress. Pathological analysis supports the findings of the osteological analysis, suggesting that if the location of the burial and a general time period for interment are known, cultural identification is possible. PMID- 21529801 TI - Selective non-operative management of penetrating abdominal injury in Great Britain and Ireland: survey of practice. AB - BACKGROUND: The selective non-operative management of penetrating abdominal injury is gaining increasing acceptance. In Great Britain and Ireland, the management of trauma remains the responsibility of general surgeons. This study appraises the acceptance and utilisation of selective non-operative management strategies by British and Irish general surgeons, compared with trauma surgeons in the United States of America. METHODS: Electronic questionnaire survey of British and Irish consultant general surgeons and trauma surgeons in the United States of America. RESULTS: 139 British and Irish general surgeons and 75 US trauma surgeons completed the survey. 84.3% of British and Irish general surgeons and 94.4% of US trauma surgeons practise selective non-operative management of abdominal stab wounds, and 14.0% and 74.3% practise selective non-operative management of abdominal gunshot wounds. The management of those British and Irish surgeons who do practise selective non-operative management is broadly similar to that of US trauma surgeons, with the exception of the use of laparoscopy to examine the left hemidiaphragm following thoracoabdominal injuries, which is employed by fewer British and Irish general surgeons than US trauma surgeons. CONCLUSIONS: The selective non-operative management of abdominal stab wounds is generally accepted by British and Irish general surgeons. In contrast, few British and Irish surgeons are comfortable with non-operatively managing patients with abdominal gunshot wounds, reflecting both the rarity of this type of injury, and surgeons' training and experience. This proportion is unlikely to change until the management of torso trauma is recognised as a specialty, and services are concentrated in regional centres. PMID- 21529802 TI - Posterior screw fixation in rotationally unstable pelvic ring injuries. AB - OBJECTIVE: Although the stability of the pelvic ring primarily depends on the integrity of the posterior sacroiliac arch, lateral compression fractures with rotational instability are commonly treated by anterior fixation alone. The objective of the present study was to assess the outcome of patients with these fractures treated by posterior iliosacral screw fixation alone. METHODS: Patients with rotationally unstable lateral compression fractures of the pelvic ring (Young and Burgess LC I and LC II or AO/Tile B2) treated by percutaneous iliosacral fixation alone were included. Postoperative complications, need for secondary surgery, malunion, secondary fracture displacement and the time to full weight bearing were documented. RESULTS: Twenty-five patients (13 female, 26 male; age: 56+/-20 years) were treated by percutaneous screw fixation (14 bilaterally, 11 unilaterally). Mean follow-up was 6+/-4 months, mean time to full weight bearing 9+/-3 weeks. Revision surgery was necessary in two patients (8%) due to nerve irritation; an additional anterior stabilisation was needed in two other patients (8%) due to secondary dislocation. Wound infection or motor weakness were not encountered, non-union of the posterior arch did not occur. Non union of the pubic rami, however, occurred in two patients. The presence of malunion of the pubic rami did not affect the time to full weight bearing. CONCLUSIONS: Percutanous iliosacral screw fixation alone is a sufficient technique for the stabilisation of rotationally unstable pelvic fractures with low rates of complications or non-unions. It allows for a minimally invasive treatment thus being a useful option in patients who do not qualify for open anterior fixation. PMID- 21529803 TI - Mental disorder as a risk factor for dog bites and post-bite cellulitis. AB - OBJECTIVES: Patients with mental disorders are at an increased risk for sustaining traumatic injury. No study has evaluated the association between mental disorders and the injury of dog bite. We conducted case-control studies to investigate whether people with mental disorders are at elevated risks of dog bite and post-bite cellulitis. METHODS: Using insurance data of 2000-2007, we compared 4660 patients with dog bites and 18,640 controls without the events for the association with mental disorders and other covariates. Amongst those with dog bites, a nested case-control study was performed to compare 286 patients with post-bite cellulites and rest of 4374 patients for factors associated with the infection. RESULTS: Young children, the older adults, and people with low socioeconomic status were at an elevated risk of sustaining the dog bite. In separate logistic regression models adjusting for socio-demographic variables, the results showed that patients with concomitant psychotic and non-psychotic mental disorders were associated with increased risks of dog bites (adjusted odds ratio [OR]=1.51, 95% confidence interval [CI]: 1.32-1.74) and of post-bite cellulitis (OR=2.13, 95% CI 1.46-3.10). CONCLUSIONS: Individuals with mental disorders are likely at an elevated risk for serious dog bites and post-bite cellulitis. PMID- 21529804 TI - Elevated transforming growth factor-beta 1 (TGF-beta1) levels in human fracture healing. AB - INTRODUCTION: Transforming growth factor-beta 1(TGF-beta1) is a regulatory protein, involved in bone fracture healing. Circulating TGF-beta1 levels have been reported to be a predictor of delayed bone healing and non-union, suggesting active relationship between tissue and circulating TGF-beta1 in fracture healing. The purpose of this study was to analyse TGF-beta1 local and serum concentrations in fracture healing to further contribute to the understanding of molecular regulation of fracture healing. PATIENTS AND METHODS: Serum samples of 113 patients with long bone fractures were collected over a period of 6 months following a standardised time schedule. TGF-beta1 serum concentrations were measured using ELISA. Patients were assigned to 2 groups: Group 1 contained 103 patients with physiological healing. Group 2 contained 10 patients with impaired healing. Patients in both groups were matched. One patient of the group 2 had to be excluded because of missing match partner. In addition, fracture haematoma from 11 patients of group 1 was obtained to analyse local TGF-beta1 concentrations. 33 volunteers donated serum which served as control. RESULTS: TGF beta1 serum concentrations increased during the early healing period and were significantly higher in patients with physiological healing compared to controls (P=0.04). Thereafter, it decreased continuously between weeks 2 and 8 and fell again after week 8. TGF-beta1 serum concentrations in patients with physiological healing were significantly higher at week 24 compared to controls (P=0.05). In non-unions, serum concentrations differed significantly from those of controls at week 6 (P=0.01). No significant difference in between patients with physiological and impaired fracture healing was observed. Fracture haematoma contained significantly higher TGF-beta1 concentrations than peripheral serum of the patients (P=0.017). CONCLUSION: Elevated levels of TGF-beta1 in haematoma and in serum after bone fracture especially during the entire healing process indicate its importance for fracture healing. PMID- 21529805 TI - Transvaginal repair of complex and complicated vesicovaginal fistulae. AB - OBJECTIVE: To document the experience at a tertiary referral hospital in India with managing complex and complicated vesicovaginal fistulae (VVF) by the transvaginal route, and to document the complications and the long-term outcome of the patients. METHODS: The medical records of 102 patients with complex or complicated VVF who underwent transvaginal surgical repair during 2000-2009 were reviewed retrospectively. RESULTS: The mean age of the patients was 24 years and the mean duration of urinary incontinence was 3 years (range 6 months to 12 years). The patients were followed up for a median of 48 months. In total, 78 patients had obstetric fistulae, 20 patients had surgical (gynecologic) fistulae, and 4 patients had postradiation fistulae. The overall success rate for the transvaginal approach was 86.3%. Fourteen patients remained incontinent despite the surgical repair. Early failure of the repair was observed in 11.8% of the patients and delayed failure in 2.0%. Postoperative complications included stress urinary incontinence (9.8%), urge urinary incontinence (7.8%), dyspareunia (5.9%), and chronic labial pain (2.0%). CONCLUSION: The transvaginal approach to the repair of complex and complicated VVF gives good long-term results with low complication rates. PMID- 21529806 TI - Cysticercosis of the temporalis muscle causing temporal headache in a pregnant woman. PMID- 21529807 TI - Self-reported oral health and hygiene habits, dental decay, and periodontal condition among pregnant European women. AB - OBJECTIVE: To investigate the relationship among self-reported oral hygiene habits, dental decay, and periodontal condition among pregnant women. METHOD: In a cross-sectional study, a structured questionnaire and dental examination were used to assess pregnant women's knowledge of oral health and attitudes to oral hygiene, in addition to their dental and periodontal condition. Data were collected from 337 pregnant women living in Murcia in southeast Spain. RESULTS: The questionnaire was completed by 337 women, 282 of whom also had an oral examination. More than 57% were in their first pregnancy, their mean age was 30 years, and most (80.1%) were Spanish with a medium-high educational level. Most of the pregnant woman (84%) brushed their teeth 2 or 3 times a day, and a third (30.9%) used a mouthwash daily. The pregnant women who self-reported having good or very good dental health had a lower level of active decay (P < 0.001) and a lower periodontal index (P < 0.001). CONCLUSION: In the present study, there was a significant correlation between a high level of self-reported oral health in pregnant women and low levels of dental decay and low periodontal indexes. PMID- 21529808 TI - Cesarean delivery-related fistulae in the Democratic Republic of Congo. AB - OBJECTIVE: To compare the characteristics of urogenital fistulae after cesarean delivery with those after spontaneous vaginal delivery. METHODS: A retrospective analysis of hospital records of 597 consecutive patients with a urogenital fistula who received treatment at Panzi Hospital, Bukavu, Democratic Republic of Congo, during 2005-2007. RESULTS: Of 576 women with an obstetric fistula, 229 (40%) had had a cesarean delivery; 55 (24%) of the 229 fistulae were considered to be iatrogenic. The distribution of risk factors (age, stature, parity, and labor duration) was similar to that among 226 women with a spontaneous vaginal delivery, but the odds ratios for having a ureterovaginal or a vesicouterine fistula were 11.9 (95% confidence interval [CI] 2.8-51.2) and 9.5 (95% CI 2.8 31.9), respectively. Vesicovaginal fistulae with cervical involvement were also significantly more frequent in the cesarean delivery group. The fistulae in this group had less surrounding fibrosis and there was less treatment delay. Stillbirth rates were 87% (cesarean delivery) and 95% (spontaneous vaginal delivery). CONCLUSION: The data indicate that cesarean delivery-related fistulae are a separate clinical entity. Focus on this condition is important for fistula prevention and provision of adequate obstetric care, particularly for training in surgery and alternative delivery methods. PMID- 21529809 TI - Male infertility management in a Nigerian tertiary hospital. PMID- 21529810 TI - PPARalpha activation differently affects microparticle content in atherosclerotic lesions and liver of a mouse model of atherosclerosis and NASH. AB - BACKGROUND: Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are complex pathologies characterized by lipid accumulation, chronic inflammation and extensive tissue remodelling. Microparticles (MPs), small membrane vesicles produced by activated and apoptotic cells, might not only be biomarkers, but also functional actors in these pathologies. The apoE2-KI mouse is a model of atherosclerosis and NAFLD. Activation of the nuclear receptor PPARalpha decreases atherosclerosis and components of non-alcoholic steatohepatitis (NASH) in the apoE2-KI mouse. OBJECTIVES: (1) To determine whether MPs are present in atherosclerotic lesions, liver and plasma during atherosclerosis and NASH progression in apoE2-KI mice, and (2) to study whether PPARalpha activation modulates MP concentrations. METHODS: ApoE2-KI mice were fed a Western diet to induce atherosclerosis and NASH. MPs were isolated from atherosclerotic lesions, liver and blood and quantified by flow cytometry. RESULTS: An increase of MPs was observed in the atherosclerotic lesions and in the liver of apoE2-KI mice upon Western diet feeding. PPARalpha activation with fenofibrate decreased MP levels in the atherosclerotic lesions in a PPARalpha-dependent manner, but did not influence MP concentrations in the liver. CONCLUSION: Here we report that MPs are present in atherosclerotic lesions and in the liver of apoE2-KI mice. Their concentration increased during atherosclerosis and NASH development. PPARalpha activation differentially modulates MP levels in a tissue-specific manner. PMID- 21529811 TI - Effect of acetabular component anteversion on dislocation mechanisms in total hip arthroplasty. AB - Quantifying soft-tissue tension around the hip joint during total hip arthroplasty remains difficult. In this study, a three-dimensional computer-aided design model was developed to clarify how component position in total hip arthroplasty contributes to the primary cause of posterior dislocation in cases of flexion, adduction and internal rotation. To better understand the influences of anteversion angle of the acetabular component, its effects on the primary causes of dislocations and the range of motion were investigated. Three different primary dislocation mechanisms were noted: impingement of the prosthetic femoral neck on the cup liner; impingement of the osseous femur on the osseous pelvis; and spontaneous dislocation caused by soft-tissue traction without impingement. Spontaneous dislocation could be detected by calculating hip forces at any thigh position using the computer-aided design model developed. In computer analysis, a transition from prosthetic impingement rate to osseous impingement rate occurred with increasing anteversion angle of the acetabular component. Spontaneous dislocation was detected at angles > 10 degrees of anteversion of the acetabular component when flexion occurred with extreme adduction and internal rotation. This study demonstrated the possibility of spontaneous dislocation that results not from prosthetic or bony impingement but from muscle traction with increased range of motion. PMID- 21529812 TI - Letter to the Editor referring to the article "Mineral heterogeneity affects predictions of intratrabecular stress and strain" published in Journal of Biomechanics (volume 44, Issue 3, Pages 402-407). PMID- 21529813 TI - Aggregation and dispersion of silver nanoparticles in exposure media for aquatic toxicity tests. AB - Silver nanoparticles (AgNPs) are currently being very widely used in industry, mainly because of their anti-bacterial properties, with applications in many areas. Once released into the environment, the mobility, bioavailability, and toxicity of AgNPs in any ecosystem are dominated by colloidal stability. There have been studies on the stability or the aggregation of various nanoparticles (NPs) under a range of environmental conditions, but there is little information on fully characterised AgNPs in media used in (eco)toxicity studies. In this study, monodisperse 7, 10 and 20 nm citrate-stabilised AgNPs were synthesised, characterised and then fractionated and sized by flow field-flow fractionation (FFF) and measured with dynamic light scattering (DLS) in different dilutions of the media recommended by OECD for Daphnia magna (water flea) toxicity testing. Stability of NPs was assessed over 24 h, and less so over 21 days, similar time periods to the OECD acute and chronic toxicity tests for D. magna. All particles aggregated quickly in the media with high ionic strength (media1), resulting in a loss of colour from the solution. The size of particles could be measured by DLS in most cases after 24h, although a fractogram by FFF could not be obtained due to aggregation and polydispersity of the sample. After diluting the media by a factor of 2, 5 or 10, aggregation was reduced, although the smallest NPs were unstable under all media conditions. Media diluted up to 10-fold in the absence of AgNPs did not induce any loss of mobility or fecundity in D. magna. These results confirm that standard OECD media causes aggregation of AgNPs, which result in changes in organism exposure levels and the nature of the exposed particles compared to exposure to fully dispersed particles. Setting aside questions of dose metrics, significant and substantial reduction in concentration over exposure period suggests that literature data are in the main improperly interpreted and nanoparticles are likely to have far greater biological effects than suggested thus far by poorly controlled exposures. We recommend that the standard OECD media is diluted by a factor of ca. 10 for use with these NPs and this test media, which reduces AgNP aggregation without affecting the viability of the text organism. PMID- 21529815 TI - Separation of 9,10-anthraquinone derivatives: evaluation of functionalised stationary phases in reversed phase mode. AB - A series of reversed phases bonded with several functional groups was investigated for separation of anthraquinone derivatives, following the previous work, dedicated to the selectivity of octadecyl silica bonded phases. Considering wide diversity of substitutions in hydrophobic anthraquinone skeleton, interactions like dipole-dipole, pi-pi or H-bond acceptor/donor, as well as inclusion complexes formation can be employed to improve separation. In this study, several phases with grafts like cyano, nitro, aromatic, PEG, diol, calixarene and cyclodextrin were used with water-acetonitrile gradient for separation of thirty anthraquinoids' standards. The evaluation of performances was measured using the symmetry parameter and the number of critical pairs of peaks formed. The results point out the aromatic and calixarene bonded silica as the most interesting in terms of symmetry and critical pairs number. Finally we tested the performance of Caltrex Resorcinaren, Pursuit XRs DP and Luna Phenyl Hexyl on real samples of anthraquinone natural dye extracted from a red thread taken from a 15th C. tapestry. We observed and compared the retention behaviour of some new anthraquinoids additional to our standards set and showing behaviour particular to substituted anthraquinone carboxylic acids. PMID- 21529814 TI - Modeling of flow in a polymeric chromatographic monolith. AB - The flow behavior of a commercial polymeric monolith was investigated by direct numerical simulations employing the lattice-Boltzmann (LB) methodology. An explicit structural representation of the monolith was obtained by serial sectioning of a portion of the monolith and imaging by scanning electron microscopy. After image processing, the three-dimensional structure of a sample block with dimensions of 17.8 MUm * 17.8 MUm * 14.1 MUm was obtained, with uniform 18.5 nm voxel size. Flow was simulated on this reconstructed block using the LB method to obtain the velocity distribution, and in turn macroscopic flow properties such as the permeability and the average velocity. The computed axial velocity distribution exhibits a sharp peak with an exponentially decaying tail. Analysis of the local components of the flow field suggests that flow is not evenly distributed throughout the sample geometry, as is also seen in geometries that exhibit preferential flow paths, such as sphere pack arrays with defects. A significant fraction of negative axial velocities are observed; the largest of these are due to flow along horizontal pores that are also slightly oriented in the negative axial direction. Possible implications for mass transfer are discussed. PMID- 21529816 TI - Chromatographic studies of unusual on-column degradations of aniline compounds on XBridge Shield RP18 column in high pH aqueous mobile phase. AB - This paper reports unusual on-column degradations of aniline compounds on Waters XBridge Shield RP18 column when ammonium hydroxide in water and acetonitrile were used as mobile phases in liquid chromatography. The change of the level of on column degradation of a model compound (Compound 1) with time was observed in the first fifteen injections when started at 60 degrees C. During a subsequent cooling program from 60 degrees C to 10 degrees C with a 10 degrees C interval, the levels of the degradation products of Compound 1 changed with the change of temperature and reached a maximum at 40 degrees C. The on-column degradation of Compound 1 was observed when started at 10 degrees C in the first injection, however, the magnitude of the change of the level of on-column degradation of Compound 1 with time in the first fifteen injections was much smaller than that at 60 degrees C. During a subsequent heating program from 10 to 60 degrees C with a 10 degrees C interval, the levels of the degradation products of Compound 1 increased with the increase in temperature but without a maximum. The change of the degradation product levels of this model compound in the heating process is not super-imposable with that in the cooling process, which demonstrates the degree of the degradation also depends on the heating or cooling process. Column history studies demonstrated that the on-column degradation of Compound 1 changed dramatically on the used columns at both starting temperatures while the dependency of heating and cooling processes on on column degradation still existed. The unusual on-column degradation of Compound 1 on the used columns can be regenerated in a very similar fashion with an acetic acid column-wash procedure, but is not identical to that on the new column. Similar degradations of other commercially available aniline compounds were also observed with this high pH aqueous mobile phase system. PMID- 21529817 TI - Nanoparticle-wall collision in a laminar cylindrical liquid jet. AB - Although nanoparticle impacts on a solid surface always occur in natural or engineering processes and cause extensive investigations, less works have been reported on the nanoparticle-wall collisions in a liquid. In present paper, by considering the inertial effect and the Brownian motion of nanoparticles, a theoretical model was established for calculating the collision frequency between the nanoparticles and the solid surface in a laminar cylindrical liquid jet impacting normally on the solid surface. The analysis showed that the collision frequency grows as the square root of the impacting speed for low impacting speed regime in which the Brownian motion is predominant, whereas increases as the second power of the impacting speed for high impacting speed regime in which the inertial effect is predominant. Meanwhile, an observation system for nanoparticle wall collisions in a laminar cylindrical liquid jet has been developed. The adsorption of the nanoparticles on the solid surface after collision has also been observed. Because of their lower attractive energy with the solid surface, these adsorbed nanoparticles are easier to be removed by the hydrodynamic force of the impacting liquid than that deposited on a dry surface. PMID- 21529818 TI - Controlling photochromism between fluoroalkyl end-capped oligomer/polyaniline and N,N'-diphenyl-1,4-phenylenediamine nanocomposites induced by UV-light-responsive titanium oxide nanoparticles. AB - Colloidal stable fluoroalkyl end-capped 2-(methacryloyloxy)ethanesulfonic acid oligomer [R(F)-(MES)(n)-R(F)]/polyaniline[PAn]/TiO(2) nanocomposites and R(F) (MES)(n)-R(F)/An-dimer (An-dimer: N,N'-diphenyl-1,4-phenylenediamine)/TiO(2) nanocomposites were prepared by the interactions of TiO(2) nanoparticles with R(F)-(MES)(n)-R(F)/PAn nanocomposites or R(F)-(MES)(n)-R(F)/An-dimer nanocomposites, which were prepared by the composite reaction of R(F)-(MES)(n) R(F) oligomer with PAn or An-dimer. These two types of fluorinated TiO(2) nanocomposites can exhibit quite different photochromic behaviors: R(F)-(MES)(n) R(F)/PAn/TiO(2) nanocomposites can exhibit a reversible wavelength change for polaron absorptions around 760-820 nm by alternation of UV irradiation and storage in the dark; in contrast, R(F)-(MES)(n)-R(F)/An-dimer/TiO(2) nanocomposites can exhibit a reversible color change from blue to colorless (a reversible absorbance change) by the similar treatment. PMID- 21529819 TI - Mixed matrix membrane incorporated with large pore size halloysite nanotubes (HNT) as filler for gas separation: experimental. AB - This study investigated the gas separation and transport properties of asymmetric mixed matrix membranes (MMM) fabricated from polyetherimide (PEI); Ultem 1000 incorporated with raw and modified halloysite nanotubes (HNT) as filler. The modified HNTs; S-HNTs were prepared by treating HNTs with N-beta-(aminoethyl) gamma-aminopropyltrimethoxy silane (AEAPTMS). FESEM, XRD, FTIR, TGA, DSC and pure gas permeation testing were used to characterise the S-HNTs and the fabricated MMMs. In the first part of the experiments, the effect of dope preparation factors such as: ultrasonic sonication period, filler wetting period and priming period were investigated. In the second part, the influence of silane concentration on the fabricated MMMs was studied. Results showed that, increasing the silane concentration, led to higher tendency in HNT agglomeration which resulted in poor separation properties but permeability enhancement. In the last part, the effect of S-HNTs loading was experienced. Our observations showed that the dispersion of nanoparticles decreased with an increase in the S-HNTs loading. Accordingly, 0.5% loading of silylated-HNT yielded the optimum MMMs in terms of permeability (27% increase) and selectivity (8% increase). PMID- 21529820 TI - The use of a modified semantic features analysis approach in aphasia. AB - Several studies have reported improved naming using the semantic feature analysis (SFA) approach in individuals with aphasia. Whether the SFA can be modified and still produce naming improvements in aphasia is unknown. The present study was designed to address this question by using a modified version of the SFA approach. Three, rather than the typical six, features were used, and written along with verbal responses were allowed in an individual with both aphasia and apraxia of speech. A single-subject multiple-baseline design across behaviors was used to treat naming of single objects across three different semantic categories in a 72-year-old individual with aphasia and apraxia of speech. Stimulus generalization of training was measured by using photographs of trained items presented in natural contexts. Training of the three different categories resulted in improved naming. At a 6-week follow-up session, naming remained above pre-treatment levels but declines were noted compared to treatment levels. Generalization to the same trained items presented in different contexts was also demonstrated although declines in performance were also noted over time. Results of the study provide qualified support for the use of three features in promoting long-term improvement of naming in an individual with both aphasia and apraxia of speech. Future SFA studies should focus on whether it is the number or types of features used, aphasia severity, or length of treatment that are critical factors in rehabilitating naming deficits in aphasia. PMID- 21529821 TI - Heart fatty acid-binding protein in combination with the 80-lead body surface potential map improves early detection of acute myocardial infarction in patients who are cardiac troponin T-negative at presentation. AB - Of patients who present with ischemic-type chest pain and a negative cardiac troponin T (cTnT) at first medical contact, there are patients at a very early stage of infarction. The aim of this research was to assess heart fatty acid binding protein (H-FABP), a novel marker of myocyte necrosis, in combination with the 80-lead body surface potential map (BSPM) in the early diagnosis of acute myocardial infarction (AMI). METHODS: In this prospective study, consecutive patients presenting with acute ischemic-type chest pain between 2003 and 2006 were enrolled. At first medical contact, blood was sampled for cTnT and H-FABP; in addition, a 12-lead electrocardiogram (ECG) and BSPM were recorded. A second cTnT was sampled 12 hours or more after presentation. Peak cTnT 0.03 MUg/L or higher diagnosed AMI. Elevated H-FABP was 5 ng/mL or higher. A cardiologist blinded to both the clinical details and 12-lead ECG interpreted the BSPM. RESULTS: Enrolled were 407 patients (age 62 +/- 13 years; 70% men). Of these 407, 180 had cTnT less than 0.03 MUg/L at presentation. Acute myocardial infarction occurred in 52 (29%) of 180 patients. Of these 180 patients, 27 had ST-segment elevation (STE) on ECG, 104 had STE on BSPM (sensitivity, 88%; specificity, 55%), and 95 (53%) had H-FABP elevation. The proportion with elevated H-FABP was higher in the AMI group compared with non-AMI group (P < .001). Body surface potential map STE was significantly associated with H-FABP elevation (P < .001). Of those with initial cTnT less than 0.03 MUg/L, the c-statistic for the receiver operating characteristic curve distinguishing AMI from non-AMI using H-FABP alone was 0.644 (95% confidence interval [CI], 0.521-0.771), using BSPM alone was 0.716 (95% CI, 0.638-0.793), and using the combination of BSPM and H-FABP was 0.812 (95% CI, 0.747-0.876; P < .001). CONCLUSION: In patients with acute ischemic-type chest pain who have a normal cTnT at presentation, the combination of H-FABP and BSPM at first assessment identifies those with early AMI (c-statistic, 0.812; P < .001), thus allowing earlier triage to reperfusion therapy and secondary prevention. PMID- 21529822 TI - Herpes simplex virus hepatitis in infants: clinical outcomes and correlates of disease severity. AB - OBJECTIVE: To better characterize the clinical outcomes of infants with herpes simplex virus (HSV) infection and identify useful correlates of disease severity. STUDY DESIGN: Infants aged <=6 months with HSV infection treated between 1999 and 2009 were identified. In patients with concurrent hepatitis, laboratory and clinical variables were examined to identify predictors of specific outcomes, including death or the need for liver transplantation and the need for intensive care. RESULTS: Of the 15 patients enrolled, 4 (27%) had fatal disease and 2 (13%) required liver transplantation. Infants who lacked skin lesions (P = .04), had a positive HSV polymerase chain reaction result (P = .01), had more severe thrombocytopenia (P = .001), or had other organ system dysfunction (P = .002) were more likely to require intensive care. A higher International Normalized Ratio value (P = .001) and peak total bilirubin level (P = .0002) were predictive of death or the need for liver transplantation. Peak direct bilirubin level was predictive of the need for intensive care and of death or the need for liver transplantation (P = .04 and .009, respectively). CONCLUSIONS: HSV hepatitis represents a broad spectrum of disease from mild aminotransferase elevation to fulminant liver failure and death. HSV DNA detected by polymerase chain reaction, a lack of skin lesions, and the degree of coagulopathy, thrombocytopenia, and cholestasis portend unfavorable outcomes. PMID- 21529823 TI - Prevalence and characterization of cardiac involvement in Hunter syndrome. AB - OBJECTIVES: To assess the prevalence of cardiovascular signs and symptoms in a large group of patients with Hunter syndrome, an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. STUDY DESIGN: The Hunter Outcome Survey was established to characterize the natural history of Hunter syndrome and to assess the response to enzyme replacement therapy. Echocardiographic and electrocardiographic examination results were available for 102 patients who were enzyme replacement therapy-naive in the Hunter Outcome Survey (median age at examination, approximately 8 years) as of Jan 23, 2009. RESULTS: The most common cardiovascular finding was valve disease, which was present in 63% of patients. Left ventricular hypertrophy (defined as left ventricular mass indexed to height(2.7) >=50 g/m(2.7)) was found in 48% of patients <18 years old. Elevated blood pressure (defined as a Z score >=2 for systolic blood pressure or diastolic blood pressure) was present in 25% of patients <18 years old. Other findings included abnormal heart frequency (7%), arrhythmia (5%), and congestive heart failure (6%). CONCLUSIONS: Treating physicians should be aware of the early emergence of cardiovascular manifestations in patients with Hunter syndrome so that appropriate treatment can be initiated. PMID- 21529824 TI - Successful transfection of genes using AAV-2/9 vector in swine coronary and peripheral arteries. AB - BACKGROUND: Gene therapy has attracted attention for its potential to treat several cardiovascular diseases. The use of adeno-associated viral (AAV) vectors to facilitate therapeutic gene transfer to suppress intimal hyperplasia is a promising concept. The objective of this study was to analyze the in vivo transduction of a novel recombinant AAV-2/9 vector with SM22alpha promoter, containing beta-galactosidase gene (LacZ) or green fluorescent protein (GFP) as reporter genes, to the medial layer smooth muscle cells (SMCs) of swine coronary and peripheral arteries. METHODS: The AAV-2/9 vector containing SM22alpha (1 * 10(13) pfu) were administered into carotid/femoral/coronary arteries of domestic swine using irrigating balloon catheter-based gene delivery. Following gene transfer, cryosections of arteries were processed for X-Gal and GFP analysis. Fluorescence microscopy and Western blotting were done to analyze the GFP expression in the SMCs. RESULTS: LacZ mRNA expression was visualized in the medial layer 7 d after vector administration. The GFP expression was detected at day 7 and lasted for at least 2 mo showing the longer-lasting expression of the AAV-2/9 vector. Control arteries did not show any expression of GFP or LacZ. There was no significant effect of AAV-2/9 viral transduction on serum amylase, fibrinogen, and serum CRP levels. CONCLUSION: These finding support the use of AAV-2/9 as a vector to effectively transduce a gene in SMCs of coronary and peripheral arteries without causing inflammation. PMID- 21529825 TI - IL6 deficiency affects function after traumatic brain injury. AB - OBJECTIVE: Interleukin-6 (IL6) is a major inflammatory mediator and one of the first cytokines produced after traumatic brain injury (TBI). This study evaluates early behavioral changes and acute inflammation after TBI in IL6 knock-out mice using electromagnetic controlled cortical impact. METHODS: IL6 knock-out (KO) and C57BL/6 (WT) male mice were subjected to TBI or sham injury (n = 6 mice per group) using electromagnetic controlled cortical impact. Behavioral deficits were tested by standard performance tests. Brain IL1beta expression was measured by ELISA and HSP70 expression was measured by Western blot. RESULTS: After TBI, KO showed reduced performance on the neuroscreen compared with wild type (KO 3.2 +/- 0.7 versus WT 4.7 +/- 0.2 points, P = 0.007), less exploratory activity in the open field test (KO 1090.2 +/- 1799.2 versus WT 5636.8 +/- 1291.8 regions explored per hour, P = 0.003) less rearing behavior in the open field test (KO 36.4 +/- 79.2 versus WT 346.5 +/- 18.5 rearing per hour, P = 0.0006), reduced travel on the rotarod (KO 3.5 +/- 4.0 versus WT 13.0 +/- 4.0 cm, P = 0.0109), and reduced time balanced on the rotarod (KO 15.0 +/- 11.5 versus WT 36.2 +/- 5.9 s, P = 0.0109). After TBI, IL6 knock-out mice had significantly elevated IL1beta (KO 58.16 +/- 17.54 versus WT 14.98 +/- 8.33 pg/mL, P = 0.003 and nonsignificantly increased HSP70 levels (KO 0.93 +/- 0.96 versus WT 0.68 +/- 0.97, P = 0.77). CONCLUSION: IL6 deficiency after TBI is associated with poor behavior performance, and appears to affect expression of IL1beta and, possibly, HSP70. PMID- 21529826 TI - Involvement of oxidative stress in age-related bone loss. AB - BACKGROUND: Age-related bone loss is a primary factor in osteoporosis and osteoporotic fractures in the elderly. Although oxidative stress was reported to play an important role in aging and postmenopausal bone loss, data on relating oxidative stress to age-related bone loss were scanty. This study aimed to investigate whether oxidative stress is involved in age-related bone loss. MATERIALS AND METHODS: Young, adult, and old male Wistar rats were used in this study. Each group consisted of 26 animals. Oxidative stress parameters, such as advanced oxidation protein products (AOPP), malondialdehyde (MDA), and superoxide dismutase (SOD), were measured in the plasma and right femur homogenates. Bone mineral density (BMD) of left femurs and histomorphometry of tibias were investigated. RESULTS: In the plasma and femurs, the levels of AOPP and MDA were increased and the SOD activity was decreased with aging. Femur BMD decreased significantly in old rats. Bone histomorphometry indicated decreases in cancellous bone volume, trabecular thickness, percent labeled perimeter, mineral apposition rate, and bone formation rate with aging. The AOPP levels in plasma and femur, and MDA levels in the plasma were negatively correlated with the femur BMD. The SOD activity in plasma and femur was positively correlated with the femur BMD. CONCLUSIONS: Increase of oxidative stress and bone loss appear with aging. Oxidative stress is involved in age-related bone loss and might play an important role in the pathology of age-related bone loss. PMID- 21529827 TI - Diagnostic values of a single serum biomarker at different time points compared with Alvarado score and imaging examinations in pediatric appendicitis. AB - BACKGROUND: A large number of children with right lower quadrant pain are evaluated on a daily basis by primary care clinicians in order to rule out acute appendicitis. The aim of this study was to determine the cutoff values of serum biomarkers, including white blood cell (WBC) count and C-reactive protein (CRP) in predicting pediatric appendicitis based on how long the patients' symptoms were present. We further compared the diagnostic values of these serum biomarkers with the Alvarado score and imaging examinations. MATERIALS AND METHODS: This prospective study comprised of 594 pediatric patients with suspected appendicitis was conducted at a medical center in Taiwan from 2004 to 2006. Receiver operating characteristic (ROC) curves were used to establish the best cutoff values of serum biomarkers for discriminating pediatric appendicitis. We further analyzed the diagnostic values of the Alvarado score, abdominopelvic computerized tomography (CT), and ultrasonography in predicting appendicitis, and then compared them with our selected serum biomarkers. RESULTS: ROC analysis showed that the best cutoff value of WBC count was 11,000/mm on the first day after onset of symptoms (d 1), and the best cutoff values of CRP concentration were 25 mg/L (d 2) and 89 mg/L (d 3) in diagnosing acute appendicitis. The cutoff values of CRP concentration to indicate perforated appendicitis were 24 mg/L (d 1), 50 mg/L (d 2), and 119 mg/L (d 3). A single serum biomarker at different time points has a diagnostic value, which is as favorable as that of Alvarado score and CT imaging and better than that of ultrasonography in predicting pediatric acute or perforated appendicitis. CONCLUSION: A single serum biomarker at different time points has a favorable diagnostic value, which is inexpensive, objective, and readily available without the risk of radiation or the need of sedation and is useful for primary caregiver. PMID- 21529828 TI - Hispanic ethnicity and fatal fall risk: do age, gender, and community modify the relationship? AB - BACKGROUND: Hispanic ethnicity is associated with a reduced risk of fatal falls in the elderly despite lower socioeconomic standing. The factors responsible for this "Hispanic paradox" are unknown. We hypothesized that age and gender would modify this relationship and that the association would be accentuated in a community with prominent Hispanic culture. MATERIALS AND METHODS: The number of fatal falls in a 3-year period in the United States (US) and in Miami-Dade County, Florida (MDC) were obtained through the CDC's WISQARS database and the Florida Office of Vital Statistics. US Census Bureau data were used to define the total at-risk populations by age group and gender. Age group- and gender-specific ratios of the risk of fatal fall in Hispanic to white non-Hispanic individuals were calculated. RESULTS: In the US and MDC, Hispanic ethnicity was associated with a reduced risk of fatal fall across all age and gender subgroups. In the US, the risk reduction associated with Hispanic ethnicity grew from 11% and 23% in 65 to 74-year-old men and women, respectively, to 43% for both men and women over 84-years-old. This relationship was stronger in MDC than nationally in five of the six age and gender subgroups examined. CONCLUSIONS: Older individuals, women, and residents of communities with prominent Hispanic culture have the greatest reduction in fatal fall risk associated with Hispanic ethnicity. PMID- 21529829 TI - Fine needle aspiration of the thyroid: a contemporary experience of 3981 cases. AB - BACKGROUND: Fine needle aspiration (FNA) is an essential tool for the management of thyroid nodules. Recently, several national organizations have recommended FNA of all thyroid nodules >1 cm. With the increase use of imaging in the practice of medicine over the last decade, the number of incidentally discovered thyroid nodules is rising. Therefore, we analyzed our experience to determine if these changes in practice led to alterations in the population of patients undergoing FNA at our institution. MATERIALS AND METHODS: Data were collected from 981 consecutive patients who underwent thyroid FNA at our institution between 2002 and 2009. Patients were divided in two groups: the early time period 2002-2005 (group 1) and later time period 2006-2009 (group 2). Data from the two groups were analyzed with t-test and chi(2) tests (SPSS, Inc., Chicago, IL). RESULTS: Comparing the groups, the number of FNAs performed in the later time period increased significantly by 250%. Patients in the later time period (group 2) were more likely to be female and were significantly older. With regard to FNA diagnoses, the number of benign FNAs increased, while the percentage of FNAs diagnosed as malignant and as follicular neoplasm decreased. There also appears to be an increase in the incidence of thyroiditis. CONCLUSIONS: The use of thyroid FNA has markedly increased during this contemporary series. This rise in thyroid FNA appears to be due to biopsy of benign thyroid nodules. With time, more females and older patients have undergone FNA, possibly reflecting the increased use of imaging studies in this patient population. PMID- 21529831 TI - Another use of the mobile device: warm-up for laparoscopic surgery. AB - BACKGROUND: An important facet of laparoscopic surgery is its psychomotor component. As this aspect of surgery gains attention, lessons from other psychomotor-intense fields such as athletics have led to an investigation of the benefits of "warming up" prior to entering the operating room. Practical implementation of established methods of warm-up is hampered by a reliance on special equipment and instrumentations that are not readily available. In light of emerging evidence of translatability between video-game play and operative performance, we sought to find if laparoscopic task performance improved after warming up on a mobile device balance game. MATERIALS AND METHODS: Laparoscopic novices were randomized into either the intervention group (n = 20) or the control group (n = 20). The intervention group played a mobile device balance game for 10 min while the control group did no warm-up whatsoever. Assessment was performed using two tasks on the ProMIS laparoscopic simulation system: "object positioning" (where small beads are transferred between four cups) and "tissue manipulation" (where pieces of plastic are stretched over pegs). Metrics measured were time to task completion, path length, smoothness, hand dominance, and errors. RESULTS: The intervention group made fewer errors: object positioning task 0.20 versus 0.70, P = 0.01, tissue manipulation task 0.15 versus 0.55, P = 0.05, total errors 0.35 versus 1.25, P = 0.002. The two groups performed similarly on the other metrics. CONCLUSIONS: Warm-up using a mobile device balance game decreases errors on basic tasks performed on a laparoscopic surgery simulator, suggesting a practical way to warm-up prior to cases in the operating room. PMID- 21529830 TI - Differentiating passive from transporter-mediated uptake by PepT1: a comparison and evaluation of four methods. AB - BACKGROUND: To quantify transmembrane transport of dipeptides by PepT1, passive uptake (non-PepT1 mediated) must be subtracted from total (measured) uptake. Three methods have been described to estimate passive uptake: perform experiments at cold temperatures, inhibit target dipeptide uptake with a greater concentration of a second dipeptide, or use modified Michaelis-Menten kinetics. We hypothesized that performing uptake experiments at pH 8.0 would estimate passive uptake accurately, because PepT1 requires a proton gradient. Our aim was to determine the most accurate method to estimate passive uptake. METHODS: Caco-2 cells were incubated with various concentrations of glycyl-sarcosine (gly-sar) at pH 6.0 and at 37 degrees C to measure total uptake. Passive uptake was estimated: (1) by incubating Caco-2 cells with varying concentrations of gly-sar at 4 degrees C, (2) in the presence of 50 mM glycyl-leucine, (3) in solution at pH 8.0, or (4) using modified Michaelis-Menten kinetics. PepT1-mediated uptake was calculated by subtracting passive uptake from total uptake. K(m), V(max), and % gly-sar transported by PepT1 were calculated and compared. RESULTS: K(m), V(max), and % gly-sar transported by PepT1 varied from 0.7 to 2.4 mM, 8.4 to 21.0 nmol/mg protein/10 min, and 69% to 87%, respectively. Uptakes calculated with cold, 50 mM gly-leu and using modified Michaelis-Menten kinetics were similar but differed significantly from uptake at pH 8.0 (P < 0.001). CONCLUSIONS: Estimating passive uptake at pH 8.0 does not appear to be accurate. Measuring uptake at cold temperatures or in the presence of a greater concentration of a second dipeptide, and confirming results with modified Michaelis-Menten kinetics is recommended. PMID- 21529832 TI - Superior mesenteric vein-caval-right atrium Y shunt for treatment of Budd-Chiari syndrome with obstruction to the inferior vena cava and the hepatic veins--a study of 62 patients. AB - OBJECTIVE: To explore the use of superior mesenteric vein-caval-right atrium Y shunt (SMV-CV-RA Y shunt) as a treatment for Budd-Chiari syndrome (B-CS) with a long stenotic segment of IVC >= 2 cm and complete obstruction of all major hepatic veins with no compensating hypertrophy of the small hepatic veins that drain from the liver into the inferior vena cava (IVC) (type IIIB mixed pattern of B-CS). METHODS: The clinical data of 101 consecutive patients with this mixed pattern of B-CS treated by surgery using artificial vascular grafts were retrospectively studied: 62 patients were treated with SMV-CV-RA Y shunt compared with historical groups of 26 patients treated with splenic vein-caval shunt and 13 patients with superior mesenteric vein-caval shunt. RESULTS: On follow-up, the clinical results assessed to be good/improved for the groups of patients who received SMV-CV-RA Y shunt, splenic vein-caval shunt, and superior mesenteric vein-caval shunt were 57/62 (91.9%), 11/26 (42.3%), and 5/13 (38.5%), respectively (P < 0.05). The patency rates of the artificial vascular grafts were 95.2% (59/62), 69.2% (18/26), and 38.4% (5/13), respectively (P > 0.05). Compared with patients who received splenic vein-caval shunt and superior mesenteric vein caval shunt, the platelet count of the 62 patients who received SMV-CV-RA Y shunt increased significantly 1 mo after surgery (P < 0.05). The portal venous pressure of the patients with SMV-CV-RA Y shunt decreased significantly than before shunting (P < 0.05), although this pressure decrease in patients who received splenic vein-caval shunt and superior mesenteric vein-caval shunt were insignificant (P > 0.05). CONCLUSION: Compared with the historical splenic vein caval shunt and superior mesenteric vein-caval shunt, SMV-CV-RA Y shunt more satisfactorily improved clinical results of patients with a special mixed pattern of B-CS, and in reducing the portal and inferior vena venous pressures. The shunt could reverse hypersplenism. The splenic vein-caval shunt and superior mesenteric vein-caval shunt were not useful for this type of patients. PMID- 21529833 TI - Rhabdomyosarcoma in children: a SEER population based study. AB - OBJECTIVE: To examine incidence and outcomes for pediatric rhabdomyosarcoma (RMS). METHODS: The SEER registry was examined for patients with RMS < 20 y old. RESULTS: Overall, 1544 patients were identified for an incidence of 0.4414/100,000 per year. Males outnumbered females 3:2. Tumors were classified as embryonal (67%), alveolar (32%), and pleomorphic (1%). Alveolar and pleomorphic RMS were more common in adolescents, whereas embryonal type was more common in younger children (P = 0.0001). Pleomorphic (47%) and alveolar (39%) RMS commonly presented with distant disease, in contrast to embryonal (25%). Most patients had surgical resection (81%) and radiotherapy (63%). Overall, 5- and 10-y survival was 60% and 57%, respectively. Univariate analysis identified higher survival for age < 10 y, local stage, favorable site, embryonal type, <5 cm tumor size, and surgical resection. Multivariate analysis identified non-embryonal type (HR 1.451), non-favorable site (HR 1.570), no surgery (HR 1.726), age >= 10 y (HR 1.734), 1973-1978 diagnosis year (HR 1.730), and distant disease (HR 3.456) as independent predictors of mortality. CONCLUSIONS: Embryonal histology, the most common type of pediatric RMS, presents in young children and has better prognosis than alveolar or pleomorphic types. Patients with embryonal tumors, favorable tumor location, age < 10 y, localized disease, and surgical resection have improved survival. PMID- 21529834 TI - Histerocystoplasty: a novel surgical procedure in the rat. AB - BACKGROUND: Enterocystoplasties are associated to complications. To avoid them, different types of tissue templates have been used to augment the bladder and induce native bladder regeneration. MATERIALS AND METHODS: A novel surgical technique for bladder reconstruction using autologous uterine tissue was evaluated in a rat model. Forty-two female Wistar rats were randomly allocated into three groups: sham-operation hysterocystorrhaphy (n = 12), hysterocystoplasty (n = 18), and control (n = 12). Two weeks after surgery, ultrasound examination of the bladder was performed. At 2, 4, or 6 mo after surgery, the rats were anesthetized and blood and urine samples were taken. They were then euthanized and post-mortem and histologic examination were performed. Ultrasound examination, analytical parameters and weight control, as well as gross and histologic examination were performed in all the operated animals. The statistical analysis was performed using Kruskal-Wallis and the extension of Fisher's exact tests. Significance was set at 5% (P < 0.05). RESULTS: Serum chemistry, blood count and peripheral blood smears, electrolytes, and urinary parameters were all within the normal range for the rat. Histologic sections of the surgically augmented zone between the bladder and uterine horn demonstrated urothelial epithelization, providing adequate coverage of the transition area in 72.22% of the rats that underwent hysterocystoplasty. CONCLUSIONS: The hysterocystoplasty was technically viable in all the cases and proved to be an easy and safe surgical model for bladder reconstruction. All animals were healthy after surgery and all systemic parameters analyzed were within normal physiologic range for the rat. PMID- 21529835 TI - Race disparities in Wilms tumor incidence and biology. AB - BACKGROUND: Wilms tumor (WT) is thought to arise in children of Black African ancestry with greater frequency than in Whites. To clarify the biological basis for race disparities in WT, we first verified that Black children residing in Tennessee have an increased incidence of WT, and second, established molecular profiles in WT that are specific to race. MATERIALS AND METHODS: To assess race disparities in WT epidemiology, the Tennessee Cancer Registry (TCR) was queried for all in-state patients less than 20 y of age and registered between 1999 and 2008. To explore race disparities in WT biology, six Black and four White WT specimens acquired in Tennessee were analyzed using imaging mass spectrometry (IMS). RESULTS: TCR data show that Black children are over-represented among WT patients (29%) relative to all other childhood cancers (18.5%; P = 0.01). WT ranked the fifth most common cancer diagnosis among Blacks, but ninth among Whites. The diagnosis of WT occurred 79% more frequently among Blacks (n = 28) than Whites (n = 69; P = 0.01), and proportionally more Blacks tended to present with distant disease. Although overall survival from WT was not statistically different between Blacks (92.9%) and Whites (94.0%), Black males showed the lowest survival (85%; P = 0.21). IMS analysis identified peptide spectra from both WT blastema and stroma that independently classify specimens according to race with greater than 80% accuracy. CONCLUSIONS: In Tennessee, Black children appear more susceptible than Whites to develop WT. Race-specific molecular profiles can be determined that may help to clarify pathways of Wilms tumorigenesis and the biological basis for race disparities in WT incidence and biology. PMID- 21529837 TI - Demographic and laboratory data may predict positive temporal artery biopsy. AB - BACKGROUND: Temporal artery biopsy is performed in patients suspected of having giant cell arteritis. This study was conducted to evaluate clinical and laboratory criteria correlating with positive biopsy results in an effort to limit the number of negative biopsies performed. METHODS: A retrospective review was performed of patients who underwent temporal artery biopsy at two urban medical centers from 2002 to 2009. A multivariate analysis of patient demographics, clinically relevant signs and symptoms, laboratory data, and pathologic outcomes was performed. RESULTS: Temporal artery biopsy histologically confirmed giant cell arteritis in 24% of cases. The mean age of those with disease was 77.8 y and those without were 73.1 y; age was found to be statically significant (P = 0.0227); 76% were female and 24% were male; gender was not significant (P = 0.9594); 42% were Caucasian (39% had a positive temporal artery biopsy), 27% were Hispanic (17% positive), and 31% of the patients were African American (3% positive); ethnicity was significant (P = 0.0005). The PPV of elevated ESR was 27%; sensitivity was 100%; specificity was 16%. A history of headache or visual disturbance was not predictive of a positive biopsy CONCLUSION: Fewer negative biopsy results may be achieved by screening patients with normal ESR or lower risk patients with other modalities. PMID- 21529836 TI - Hemorrhagic shock induces a proinflammatory milieu in the gut lumen. AB - BACKGROUND: Intestinal injury is a consequence of hemorrhagic shock and resuscitation. The intestinal mucosa has been shown to respond to ischemia/reperfusion injury with production of inflammatory mediators. Previous work in our laboratory indicates that intestinal epithelial cells secrete proinflammatory cytokines in the direction of both the lamina propria and intestinal lumen. The ability of the intestinal mucosa to transmit inflammatory signals into the gut lumen after hemorrhagic shock is unknown. We hypothesized that hemorrhagic shock results in secretion of proinflammatory cytokines into the gut lumen. METHODS: Male C57/Bl6 mice underwent femoral artery cannulation and hemorrhage to a systolic blood pressure of 20 mmHg for 1 h, then resuscitation with lactated Ringer's (LR) solution. Sham animals were cannulated only. Mice were decannulated and sacrificed at intervals. Stool and succus were removed from intestinal segments, weighed, and placed into buffer solution. Specimens were analyzed via enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with sham-injured mice, hemorrhagic shock resulted in increased intestinal luminal cytokines. At 3 h after injury, elevated levels of IL-6 were found in the cecal stool. At 6 h after injury, TNFalpha, IL-6, and MIP-2 were significantly elevated in the cecal stool, and IL-6 and MIP-2 were significantly elevated in the distal colonic stool. CONCLUSIONS: Hemorrhagic shock results in secretion of proinflammatory cytokines into the intestinal lumen. These findings suggest that the intestinal mucosa may transmit and receive signals in a paracrine fashion via the gut lumen. PMID- 21529838 TI - A low mortality model of chronic pulmonary hypertension in sheep. AB - BACKGROUND: Pulmonary hypertension and right ventricular failure are major contributors to morbidity and mortality in chronic lung disease. Therefore, large animal models of pulmonary hypertension and right ventricular hypertrophy are needed to study underlying disease mechanisms and test new treatment modalities. The objective of this study was to create a low-mortality model of chronic pulmonary hypertension and right ventricular hypertrophy in sheep. METHODS: The vena cavae of nine sheep weighing 62 +/- 2 (SEM) kg were injected with 0.375 g of dextran beads (sephadex) every day for 60 d. Pulmonary hemodynamics were assessed via pulmonary artery catheterization prior to the first injection and again on d 14, 28, 35, 42, 49, and 56. At the end of the experiment, the heart was removed, dissected, and weighed to determine the ratio of right ventricular mass to left ventricle plus septal mass (RV:LV+S). RESULTS: All sheep survived to 60 d. The average pulmonary artery pressure rose from 17 +/- 1 mmHg at baseline to 35 +/- 3 mmHg on d 56 with no significant change in cardiac output (8.7 +/- 0.7 to 9.8 +/- 0.7 L/min, P = 0.89). The RV:LV+S was significantly higher (0.42 +/- 0.01, P < 0.001) than a historic group of untreated normal animals (0.35 +/- 0.01, n = 13). CONCLUSION: This study provides a low-mortality large animal model of moderate chronic pulmonary hypertension and right ventricular hypertrophy. PMID- 21529839 TI - Vitamin E derivative ETS-GS reduces liver ischemia-reperfusion injury in rats. AB - BACKGROUND: Ischemic liver injury is often the result of surgical procedures such as liver transplantation and hepatic resection. Liver damage occurs after reperfusion, leading to increased systemic inflammation. Recent studies have reported that vitamin E and glutathione can ameliorate ischemia-reperfusion (I/R) injury. In the present study, we evaluated the ability of a new vitamin E derivative, ETS-GS, to improve liver I/R injury. MATERIALS AND METHODS: Male Wistar received a subcutaneous injection of ETS-GS (10 mg/kg) or saline before experimentally-induced liver I/R injury or sham treatment. The rats were sacrificed after the 60-min ischemia and 24-h reperfusion. Histology and serum levels of cytokines [tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and high-mobility group box 1 (HMGB1) protein] and liver enzymes were determined to evaluate the protective effects of ETS-GS. RESULTS: We found that ETS-GS treatment attenuated I/R-induced histologic alterations, reduced levels of liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH). In addition, ETS-GS treatment decreased serum cytokine levels. CONCLUSIONS: Taken together, our results demonstrate that ETS-GS attenuates I/R injury in a rat model and suggests that ETS-GS may exert anti inflammatory effects. Accordingly, ETS-GS may have therapeutic potential to treat various clinical conditions involving I/R injury. PMID- 21529840 TI - Infrared thermographic profiles of vessel sealing devices on thyroid parenchyma. AB - BACKGROUND: During thyroid lobectomy, division of the thyroid parenchyma has traditionally been accomplished using suture ligation. Development of hemostatic techniques in the forms of ultrasonic dissection (UD) and electronic vessel sealing (EVS) have increased the usage of these devices during thyroid operations. We sought to characterize the thermal profile of each of these devices when used to divide the parenchyma of the thyroid gland. METHODS: Using a porcine model, the parenchyma of the gland was sealed by alternating application of the UD and EVS devices. In each case, the thermal activity was recorded using infrared thermal imaging. We performed multiple seals with each instrument and then compared the thermal profiles. RESULTS: There was no significant difference in lateral thermal spread of EVS and UD above 39, 40 or 60 degrees C (2.30 +/- 0.31 mm versus 2.53 +/- 0.47 mm, P = 0.26; 2.22 +/- 0.27 mm versus 2.47 +/- 0.47 mm, P = 0.22, and 1.37 +/- 0.27 mm versus 1.54 +/- 0.26 mm, P = 0.22). There was no significant difference in mean time above 39 or 40 degrees C (35.1 +/- 8.7 s versus 31.7 +/- 9.3 s, P = 0.47 and 29.9 +/- 8.1 s versus 27.3 +/- 6.7 s, P = 0.50). UD reached a greater maximum temperature (179.12 +/- 0.0008C versus 96.52 +/- 5.6C, P <= 0.001) and stayed over 60 degrees C for longer than EVS (9.5 +/- 1.8 s versus 5.3 +/- 0.97 , P <= 0.001). CONCLUSIONS: The amount of lateral spread of thermal energy was not significantly different between the UD and EVS devices. However, the use of UD produced a higher maximum temperature during thyroid parenchyma sealing and remained above 60 degrees C longer than EVS. This may translate into greater thermal injury to thyroid and surrounding tissues during division. PMID- 21529842 TI - Prognosis of non-small-cell lung cancer with unexpected pleural spread at thoracotomy. AB - BACKGROUND: The aim of the study is to investigate the prognosis of non-small cell lung cancer (NSCLC) with unexpected pleural spread at thoracotomy. MATERIALS AND METHODS: We conducted a retrospective review of the clinicopathologic characteristics of NSCLC patients with unexpected pleural spread at thoracotomy in Taipei Veterans General Hospital between January 1990 and December 2008. Inclusion criteria were patients with frozen section of pleural nodules identified as metastatic carcinoma during operation. A survival analysis was done. RESULTS: There were 138 patients included in this study. The median follow up time was 19.9 mo. The overall 1, 3, and 5-year survival rates were 72.9%, 26.8%, and 16.6%, respectively. Multivariate analysis showed that main tumor resection and mediastinal lymph nodal involvement (P < 0.001 and 0.002, respectively) were significant predictors for overall survival rate. Patients who underwent main tumor resection and those without mediastinal lymph node metastasis had better outcomes. CONCLUSIONS: Among the unexpected pleural spread detected at thoracotomy, limited pulmonary resection was an alternative surgical procedure for these patients without mediastinal nodal metastasis. PMID- 21529841 TI - The NFKB1 (g.-24519delATTG) variant is associated with necrotizing enterocolitis (NEC) in premature infants. AB - OBJECTIVE: While it is known that gene-environment interactions contribute to necrotizing enterocolitis (NEC) pathogenesis, characterization of genetic risk factors that can predict NEC in preterm infants remains nascent. We hypothesized that altered intestinal immune responses arising from sequence variation in the toll-like receptor (TLR) pathway genes contribute to NEC susceptibility. MATERIALS AND METHODS: Very low birth weight (VLBW) infants were recruited prospectively in a multi-center, cohort study involving collection of blood samples along with collation of clinical information. DNA obtained from blood samples was used to genotype nine single nucleotide polymorphisms (SNPs) in eight TLR pathway genes by single-base extension. Prevalence of the variant allele was compared between cases and controls using Fisher's exact test. RESULTS: In our cohort of 271 infants, 15 infants (5.6%) developed NEC, and five died from it. Infants with NEC were less mature (P < 0.001), and were more likely to be African American (P = 0.007). SNPs in the TLR2, TLR4, TLR5, TLR9, IRAK1, and TIRAP genes were not associated with NEC. The NFKB1 (g.-24519delATTG) variant was present in all infants with NEC but only in 65% of infants without NEC (P = 0.003), while the NFKBIA (g.-1004A>G) variant was present in 13.3% of infants with NEC but in 49% of infants without NEC (P = 0.007). After correcting for multiple comparisons, the NFKB1 and NFKBIA variants remained associated with NEC (P < 0.05). CONCLUSIONS: These data suggest that TLR genetic variants can alter susceptibility to NEC in VLBW infants and support the hypothesis that genetically programmed differences in the innate immune response contribute to NEC pathogenesis. PMID- 21529843 TI - Accelerated central nervous system autoimmunity in BAFF-receptor-deficient mice. AB - B cell activating factor (BAFF) is critical for B cell survival, a function that is mediated by BAFF receptor, (BAFF-R). The role of BAFF (or BAFF-R) in the multiple sclerosis model, experimental autoimmune encephalomyelitis (EAE), was examined using BAFF-R-deficient mice. BAFF-R deficiency resulted in paradoxically increased severity of EAE induced by myelin-oligodendrocyte glycoprotein (MOG) peptide 35-55. Inflammatory foci in BAFF-R-deficient mice comprised increased numbers of activated macrophages expressing BAFF and correlated with increased BAFF secretion. Thus, BAFF-R may be important in EAE pathogenesis, possibly by influencing macrophage function through a mechanism that involves modulation of BAFF expression. PMID- 21529844 TI - Autonomic dysfunction in PD: a window to early detection? AB - It has been suggested that autonomic dysfunction constitutes a biomarker for early detection of the disease process in Parkinson disease (PD). Recent findings based on cardiac sympathetic and striatal dopaminergic imaging in the same patients indicate that this view is overly simple. Although evidence of cardiac sympathetic denervation is associated with other non-motor manifestations such as anosmia, REM behavior disorder, dementia, baroreflex failure, and orthostatic hypotension (OH), across individual patients the severities of OH and of the cardiac sympathetic lesion (indicated by thoracic 6-[(18)F]fluorodopamine PET scanning) are unrelated to the severity of the putamen dopaminergic lesion (indicated by brain 6-[(18)F]fluorodopa PET scanning). Moreover, whereas cases have been reported with neuroimaging evidence of cardiac sympathetic denervation several years before motor onset of PD, in other cases loss of cardiac sympathetic innervation progresses approximately concurrently with the movement disorder or can even occur as a late finding. Bases for independent sympathetic noradrenergic and striatal dopaminergic lesions in Lewy body diseases remain poorly understood. In elderly patients with unexplained OH or other evidence of autonomic failure, it is reasonable for clinicians to look for subtle signs of parkinsonism, such as masked facies, cogwheel rigidity, and shuffling gate. PMID- 21529845 TI - Respiratory pattern in an adult population of dystrophic patients. AB - We studied respiratory function and Chest Wall kinematics in a large population of adult patients affected by slow course muscular dystrophies such as Limb Girdle Muscular Dystrophy (LGMD, n=38), Becker Muscular Dystrophy (BMD, n=20) and Facio-Scapulo Humeral Dystrophy (FSHD, n=30), through standard spirometry and through the Optoelectronic Plethysmography, to measure the thoraco-abdominal motion during Quiet Breathing and Slow Vital Capacity maneuvers. Within the restrictive pulmonary syndrome characterizing LGMD and FSHD, several different thoraco-abdominal patterns compared to those of healthy subjects were present in the more advanced stages of the disease. These differences were present in the seated position, during the execution of a maximal maneuver such as Slow Vital Capacity. A global respiratory (both inspiratory and expiratory) muscle involvement was more pronounced in the LGMD and FSHD than in the BMD patients, and a significant reduction of abdominal contribution in wheelchair bound patients was observed. In conclusion, OEP technique is able to reveal mild initial modifications in the respiratory muscles in FSHD and LGMD patients, which could be helpful for functional and new therapeutic strategy evaluation. PMID- 21529846 TI - Assessment of long-term anticoagulation in patients with a continuous-flow left ventricular assist device: a pilot study. PMID- 21529847 TI - Percutaneous radiofrequency ablation of clinical stage I non-small cell lung cancer. AB - OBJECTIVE: This study aimed at retrospectively evaluating the outcomes of radiofrequency ablation of clinical stage I non-small cell lung cancer. METHODS: This study was carried out on 50 nonsurgical candidates (29 men and 21 women; mean age, 74.7 years) with clinical stage I (IA, n = 38; IB, n = 12) histologically proven non-small cell lung cancer. A total of 52 tumors were treated with 52 ablation sessions. Radiofrequency ablation was performed percutaneously under computed tomography fluoroscopic guidance. The outcomes of radiofrequency ablation were evaluated, including toxicity, local efficacy, and patient survival. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Local efficacy was evaluated by using computed tomography scan with a contrast medium. The overall, cancer-specific, and disease-free survivals were estimated with Kaplan-Meier analysis. RESULTS: Grade 2 and 3 adverse events occurred after 6 (12%) and 3 (6%) of the 52 sessions, respectively. The median follow-up period was 37 months. Local progression was observed in 16 (31%) of the 52 tumors. The median survival time was 67 months. The overall, cancer-specific, and disease-free survivals were 94%, 100%, and 82% at 1 year, 86%, 93%, and 64% at 2 years, and 74%, 80%, and 53% at 3 years, respectively. CONCLUSIONS: Radiofrequency ablation of clinical stage I non-small cell lung cancer was minimally invasive and provided promising patient survival, although the local efficacy needs to be improved. PMID- 21529848 TI - On-pump versus off-pump surgical revascularization in patients with acute coronary syndromes: analysis from the Acute Catheterization and Urgent Intervention Triage Strategy trial. AB - OBJECTIVE: Early invasive strategy, defined as early coronary angiography and subsequent revascularization, when appropriate, is recommended by current guidelines for the management of patients with moderate- to high-risk acute coronary syndromes. We sought to compare the outcomes of patients with acute coronary syndromes undergoing surgical revascularization with an on-pump versus off-pump approach. METHODS: Among a total of 13,819 patients with moderate- to high-risk acute coronary syndromes enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy trial, 1375 patients were triaged to isolated coronary artery bypass grafting. One thousand one hundred fifty-four patients underwent operations with cardiopulmonary bypass (the coronary artery bypass grafting group), and 221 patients underwent off-pump coronary artery bypass grafting (the off-pump coronary artery bypass grafting group). Propensity score matching (1:3) was applied to adjust for differences in baseline clinical and angiographic characteristics, yielding a total of 880 matched patients with acute coronary syndromes (220 managed with off-pump coronary artery bypass grafting and 660 managed with coronary artery bypass grafting). RESULTS: At 30 days, patients undergoing off-pump coronary artery bypass grafting had fewer events of bleeding (43.7% vs 56.3%, P = .0005) and myocardial infarction (7.3% vs 12.1%, P = .055) but higher rates of reintervention (3.7% vs 1.2%, P = .02). At 1 year, there was no difference between groups in death, total myocardial infarctions, reinterventions, strokes, or major adverse cardiac events, but there was a lower rate of non-Q-wave myocardial infarctions in the off-pump coronary artery bypass grafting group (4.6% vs 9.2%, P = .03). CONCLUSIONS: In this large-scale study evaluating the outcomes of patients with acute coronary syndromes, off-pump coronary artery bypass grafting was associated with lower rates of bleeding and non-Q-wave myocardial infarction but more reinterventions early after the procedure. At 1 year, there was no major outcome difference between the 2 surgical strategies. PMID- 21529849 TI - The first successful use of the Levitronix PediMag ventricular support device as a biventricular bridge to transplant in an infant. PMID- 21529850 TI - Papillary muscle-to-anterior annulus stitches: another technique to prevent systolic anterior motion after mitral valve repair. PMID- 21529851 TI - Sedimentation on the cold-water coral Lophelia pertusa: cleaning efficiency from natural sediments and drill cuttings. AB - Anthropogenic threats to cold-water coral reefs are trawling and hydrocarbon drilling, with both activities causing increased levels of suspended particles. The efficiency of Lophelia pertusa in rejecting local sediments and drill cuttings from the coral surface was evaluated and found not to differ between sediment types. Further results showed that the coral efficiently removed deposited material even after repeated exposures, indicating an efficient cleaning mechanism. In an experiment focusing on burial, fine-fraction drill cuttings were deposited on corals over time. Drill cutting covered coral area increased with repeated depositions, with accumulation mainly occurring on and adjacent to regions of the coral skeleton lacking tissue cover. Tissue was smothered and polyp mortality occurred where polyps became wholly covered by material. Burial of coral by drill cuttings to the current threshold level used in environmental risk assessment models by the offshore industry (6.3mm) may result in damage to L. pertusa colonies. PMID- 21529852 TI - Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in harbor sediments from Sea Lots, Port-of-Spain, Trinidad and Tobago. AB - Concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were determined in nearshore marine surficial sediments from three locations in Trinidad. Sediments were sampled at Sea Lots on the west coast, in south Port-of-Spain Harbor, south of Sea Lots at Caroni Lagoon National Park, and on Trinidad's east coast at Manzanilla. Total PCB concentrations in Sea Lots sediments ranged from 62 to 601ng/g (dry weight {dw}), which was higher than at Caroni and Manzanilla, 13 and 8ng/g dw, respectively. Total OCP concentrations at Sea Lots were ranged from 44.5 to 145ng/g dw, compared with 13.1 and 23.8n/g (dw), for Caroni and Manzanilla respectively. The concentrations of PCBs and of some OCPs in sediments from Sea Lots were above the Canadian interim sediment quality guidelines. To date, this data is the first report on the levels of PCBs and other organochlorine compounds from Trinidad and Tobago. PMID- 21529853 TI - Mercury in blood and eggs of the sea turtle Lepidochelys olivacea from a nesting colony in Oaxaca, Mexico. AB - Mercury concentrations were assessed in the sea turtle Lepidochelys olivacea from a nesting colony of Oaxaca, Mexico; 25 female turtles were sampled, a total of 250 eggs were collected during the season 2005-2006. Higher concentrations were found in yolk fraction, while in blood and albumen mean levels were below of 0.0010MUg g(-1) dry wt. On the basis of one nesting season, the maternal transfer of Hg via eggs-laying was estimated in 2.0+/-1.1%. According to international norms, the health of this population and its habitats is acceptable for Hg and corresponds to baseline levels of a nearly pristine environment. PMID- 21529854 TI - Uranium pollution in an estuary affected by pyrite acid mine drainage and releases of naturally occurring radioactive materials. AB - After the termination of phosphogypsum discharges to the Huelva estuary (SW Spain), a unique opportunity was presented to study the response of a contaminated environmental compartment after the cessation of its main source of pollution. The evolution over time of uranium concentrations in the estuary is presented to supply new insights into the decontamination of a scenario affected by Naturally Occurring Radioactive Material (NORM) discharges. The cleaning of uranium isotopes from the area has not taken place as rapidly as expected due to leaching from phosphogypsum stacks. An in-depth study using various techniques of analysis, including (234)U/(238)U and (230)Th/(232)Th ratios and the decreasing rates of the uranium concentration, enabled a second source of uranium contamination to be discovered. Increased uranium levels due to acid mine drainage from pyrite mines located in the Iberian Pyrite Belt (SW Spain) prevent complete uranium decontamination and, therefore, result in levels nearly twice those of natural background levels. PMID- 21529855 TI - [Consensus for the study and treatment of Fabry disease. GETER Foundation]. PMID- 21529856 TI - [Bilateral failure of fusion between pedicles and body of C7]. AB - We expose the case of a 48-year-old woman suffering of a chronic bilateral C7 radiculalgy and bilateral C7 failure of fusion between pedicles and body. According to spine embryogenesis we bring three hypothesis to explain this failure of fusion. Then we show that bilateral C6-C7 foraminal compression can arise from local cervical spine instability due to C7 and disk development abnormalities. The treatment proposed is dissectomy bone graft and anterior osteosynthesis leading to clinical and radiological good results. The patient went back to work after three months. PMID- 21529857 TI - Non-protein amino acids in plant defense against insect herbivores: representative cases and opportunities for further functional analysis. AB - Chemical defense against herbivores is of utmost importance for plants. Primary and secondary metabolites, including non-protein amino acids, have been implicated in plant defense against insect pests. High levels of non-protein amino acids have been identified in certain plant families, including legumes and grasses, where they have been associated with resistance to insect herbivory. Non protein amino acids can have direct toxic effects via several mechanisms, including misincorporation into proteins, obstruction of primary metabolism, and mimicking and interfering with insect neurological processes. Additionally, certain non-protein amino acids allow nitrogen to be stored in a form that is metabolically inaccessible to herbivores and, in some cases, may act as signals for further plant defense responses. Specialized insect herbivores often possess specific mechanisms to avoid or detoxify non-protein amino acids from their host plants. Although hundreds of non-protein amino acids have been found in nature, biosynthetic pathways and defensive functions have been elucidated in only a few cases. Next-generation sequencing technologies and the development of additional plant and insect model species will facilitate further research on the production of non-protein amino acids, a widespread but relatively uninvestigated plant defense mechanism. PMID- 21529858 TI - Motherhood, migration and mortality in Dikgale: modelling life events among women in a rural South African community. AB - OBJECTIVES: Although particular types of life events in populations are often studied separately, this study investigated the joint effects of three major event types in South African women's lives: motherhood, migration and mortality. STUDY DESIGN: Data were taken from a health and demographic surveillance site (HDSS) over an 11-year period, reflecting the entire population of a defined geographic area as an open cohort, in which individuals participated in regular longitudinal surveillance for health and demographic events. This HDSS is a member of the Indepth Network. METHODS: Multivariate Poisson regression models were built for each of the three life event types, in which individual person time observed out of the total possible 11-year period was used as a rate multiplier. These models were used to calculate adjusted incidence rate ratios for each factor. RESULTS: In the 21,587 person-years observed for women aged 15 49 years, from 1996 to 2006, adjusted rate ratios for mortality and migration increased substantially over time, while motherhood remained fairly constant. Women who migrated were less likely to bear children; temporary migrants were at greater risk of dying, while permanent in-migrants had higher survival rates. Women who subsequently died were much less likely to bear children or migrate. CONCLUSIONS: The associations between motherhood, migration and mortality among these rural South African women were complex and dynamic. Extremely rapid increases in mortality over the period studied are presumed to reflect the effects of the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic. Understanding these complex interactions between various life events at population level is crucial for effective public health planning and service delivery. PMID- 21529859 TI - Quality of life among Chinese college teachers: a cross-sectional survey. PMID- 21529860 TI - [Pulmonary mycosis caused by Paracoccidioides brasiliensis: dangerous confusion with sarcoidosis]. AB - We present the case of a patient from South America with a lung disease that was initially diagnosed as sarcoidosis and treated with corticoids. Despite an initial improvement, the patient worsened gradually until his condition was finally attributed to paracoccidioidomycosis. This systemic mycosis has features in common with sarcoidosis, but the treatment differs drastically because corticoids can place the patient's life at risk. PMID- 21529861 TI - [Calcifying tendinosis of the pectoralis major muscle with intraosseous migration]. AB - Calcifying tendinosis is characterized by macroscopic deposits of hydroxyapatite within the tendon. Most cases involve the tendons of the rotator cuff, fundamentally the supraspinous tendon, and less frequently other tendons in practically any location. Cortical erosion with intraosseous migration of calcium deposits is rare. An atypical location combined with bone involvement can often lead to confusion with other processes like an infection or malignant tumor resulting in unnecessary biopsies or interventions. We present the case of a man who presented with pain and loss of function of the shoulder. Plain-film X-rays showed an erosion of the anteromedial cortex of the proximal diaphysis of the humerus with extra- and intra-osseous calcifications that made us suspect an infectious or malignant process. The findings at computed tomography, together with the clinical and radiological course, were key in enabling us to recognize this atypical presentation of calcifying tendinosis of the pectoralis major muscle. PMID- 21529862 TI - [Capillary telangiectasia and developmental venous anomaly: a rare association]. AB - We review the relevant literature for a case of capillary telangiectasia associated with a developmental venous anomaly in the pons discovered incidentally. The most common established associations among vascular malformations are capillary telangiectasias with cavernous malformations and developmental venous anomalies with cavernous malformations. The association of a capillary telangiectasia with a developmental venous anomaly is very rare and only two cases affecting the posterior fossa have been reported. An analysis of the associations among vascular malformations leads to a discussion of the role of obstructed flow in their pathogenesis and whether these malformations can be considered a spectrum of manifestations of a single disease. PMID- 21529863 TI - Cloning and sequence analysis of IL-2, IL-4 and IFN-gamma from Indian Dromedary camels (Camelus dromedarius). AB - The cDNAs of three cytokines, viz., IL-2, IL-4 and IFN-gamma from Dromedary camels were amplified by PCR using Bactrian camel sequences and subsequently cloned for sequence analysis. Relationship based on amino acid sequences revealed that Dromedary camel IL-2 shared 99.5% and 99.3% identity at the nucleotide and amino acid levels with Bactrian camel IL-2. In the case of IL-4, the identity of Dromedary camel was 99.7% and 99.2% at the nucleotide and amino acid levels, respectively with that of Bactrian camel. The Dromedary camel IFN-gamma shared 100% identity both at nucleotide and amino acid levels with Bactrian camel IFN gamma. Phylogenetic analysis based on amino acid sequences indicated the close relationship in these cytokine genes between the Dromedary camel and other camelids. PMID- 21529864 TI - Characterization of Haemophilus parasuis isolated from Brazilian swine through serotyping, AFLP and PFGE. AB - Haemophilus parasuis infection in pigs is characterized by fibrinous polyserositis, arthritis and meningitis. Despite the fact that traditional diagnosis is based on herd history, clinical signs, bacterial isolation and serotyping, molecular-based methods are alternatives for species-specific tests and epidemiological studies. The aim of this study was to characterize H. parasuis field strains from different states of Brazil, employing serotyping and genotyping methods. Serotyping revealed that serovar 4 was the most prevalent (26.1%), followed by serovars 5 (17.4%), 14 (8.7%), 13 (4.4%) and 2 (4.4%), whereas 39% of the strains were considered as untypeable. AFLP with a single enzyme and PFGE were able to type all isolates tested, generating 34 and 20 different profiles, respectively, including untypeable strains. Besides the slightly higher discrimination index presented by AFLP, PFGE with Not I restriction enzyme showed a better correlation with epidemiological data, grouping strains of the same serovar, animal or farm origin. The results indicated AFLP and PFGE as valuable tools for typing H. parasuis isolates collected in Brazil. PMID- 21529865 TI - Natural co-infection of torque teno virus and porcine circovirus 2 in the reproductive apparatus of swine. AB - This work aimed to detect and study natural co-infection of Circoviridae torque teno virus (TTV) and porcine circovirus 2 (PCV2) in the swine reproductive apparatus. Semen and organs from 17 boars were tested by nested and real-time PCR. PCV2 was amplified from semen (47%), lymph nodes (84.6%) and testicles (35.3%). TTV2 was amplified from 16/17 testis and 13/13 lymph nodes. TTV1 DNA was detected in fewer testicle samples (2/17), which were also TTV2 positive. Analyzed ovaries, follicular fluid and uteri of 83 culled sows showed TTV2, TTV1 and PCV2 from 49.3%, 30.1% and 6.0% of the sows, respectively. Sperm analysis indicated insignificant differences between PCV2 and TTVs positive and negative boars. The most frequent pathologic lesion in sows was endometritis (28.9%), but this was unassociated with PCV2 or TTVs detection. These findings question the importance of PCV2 and TTV2 natural co-infection in the pathology of porcine reproductive failures. PMID- 21529866 TI - Craniocervical junction in dogs revisited--new ligaments and confirmed presence of enthesis fibrocartilage. AB - The study was performed to investigate and to describe features of gross and microscopic morphology of craniocervical junction (CCJ) in dogs. Seventy mature dogs (38 females, 32 males) of different body weight, representing small, medium and large breeds of dolicho-, mesati-, and brachycephalic morphotype were dissected. Morphological details were localised using an operating microscope with integrated video channel. Occurrence and distribution of fibrocartilage in the ligaments from 10 dogs was analysed histologically. Three new pairs of ligaments were described and named: dorsal ligaments of atlas, cranial internal collateral ligaments of atlas, and caudal internal collateral ligaments of atlas. Several new findings in the course of the known ligaments were found relating to breed and body weight. For the first time enthesis fibrocartilage was identified in ligaments of CCJ in dogs. Sesamoidal fibrocartilage was identified in the transversal ligament of atlas in large dogs. The findings are discussed for clinical importance. PMID- 21529867 TI - [Facial wounds: an epidemiological review of 850 cases]. AB - BACKGROUND: Facial wound are among the most frequent emergencies. They often affect a young population. We studied the epidemiological profile of facial wounds admitted in our hospital. PATIENTS AND METHODS: This prospective study was carried out in the Emergency Unit from June 2008 to June 2009. It included all patients having presented with at least one facial wound. The analysed parameters were patient, trauma, and wound characteristics. RESULTS: Eight hundred and fifty patients were included, 20% of whom were female patients. The most frequent etiologies were traffic accidents for men, assault for women, and domestic accidents for children. Alcohol abuse was involved in 12.4% of the cases. The most frequent wound localization was frontal (35.4%). A craniofacial organ (eye, brain...) was affected in 6.1% of the cases; the wound was associated to a craniofacial fracture in 9.6% of the cases, and to an extrafacial lesion in 22% of the cases. DISCUSSION: Facial wounds are a frequent emergency. They are predominant in young male patients. The high frequency of traffic accident and alcohol abuse requires an adequate prevention policy. PMID- 21529868 TI - [Distal hereditary motor neuropathy]. AB - INTRODUCTION: Distal hereditary motor neuropathy (dHMN), also known as spinal muscular atrophy, represents a group of clinically and genetically heterogeneous diseases caused by degenerations of spinal motor neurons and leading to distal muscle weakness and wasting. Nerve conduction studies reveal a pure motor axonopathy and needle examination shows chronic denervation. STATE OF ART: dHMN were initially subdivided into seven subtypes according to mode of inheritance, age at onset, and clinical evolution. Recent studies have shown that these subtypes are still heterogeneous at the molecular genetic level and novel clinical and genetic entities have been characterized. To date, mutations in 11 different genes have been identified for autosomal-dominant, autosomal-recessive, and X-linked recessive dHMN. Most of the genes encode protein involved in housekeeping functions, endosomal trafficking, axonal transport, translation synthesis, RNA processing, oxidative stress response and apoptosis. PERSPECTIVES: The pathophysiological mechanisms underlying dHMN seem to be related to the "length-dependent" death of motor neurons of the anterior horn of the spinal cord, likely because their large axons have higher metabolic requirements for maintenance. CONCLUSION: dHMN remain heterogeneous at the clinical and molecular genetic level. The molecular pathomechanisms explaining why mutations in these ubiquitously expressed housekeeping genes result in the selective involvement of spinal motor neurons remain to be unravelled. PMID- 21529870 TI - [Cerebellar infarction]. AB - Cerebellar infarction can be difficult to diagnose because the clinical picture is often dominated by fairly non-specific symptoms, which are more indicative of a benign condition. When cerebellar infarction affects the brainstem, the semiology is richer, and pure cerebellar signs are rendered less important. A perfect knowledge of the organisation of the cerebellar artery territories is required, regardless of the infarct topography. This knowledge is essential for making an accurate diagnosis, understanding the mechanisms and organising a treatment plan. Clinical algorithms for the treatment of dizziness, headaches and vomiting would improve the selection of candidates for brain imaging. Thus, the early identification of patients with a high risk of subsequent deterioration would lead to a better prognosis in cases of cerebellar artery territory infarction. PMID- 21529869 TI - [Medulloblastomas: review]. AB - INTRODUCTION: The term of "medulloblastoma" refers to cerebellar tumors belonging to the family of primitive neuro-ectodermic tumors (PNET). Medulloblastomas represent 40% of cerebellar tumors, 15 to 20% of brain tumors and the first cause of malignant brain tumors in childhood. Seventy to 80% of cases are diagnosed in children versus 20 to 30% in adults. UPDATED KNOWLEDGE: Diagnosis is based on clinical and radiological exams, and proved on pathological analysis in association with molecular biology. Treatment comprises surgery, craniospinal radiotherapy except for children under five years of age and chemotherapy according to age and high-risk criteria. Medulloblastoma is a rare case of a central nervous system tumor which is radio- and chemo-sensitive. Treatment goals are, on one hand, to improve the survival rates and, on the other hand, to avoid late neurocognitive, neuroendocrine and orthopedic side effects related to radiation therapy, notably in children. The prognosis is relatively good, with a five year survival rate over 75% after complete resection of a localized tumor although sequelae may still compromise outcome. PERSPECTIVES AND CONCLUSION: Management of patients with medulloblastoma implies a multidisciplinary approach combining the contributions of neurosurgery, neuroradiology, pediatric oncology, neuro-oncology and radiotherapy teams. PMID- 21529871 TI - [Functional organisation of the cerebellum: a neuroanatomical approach]. AB - Knowledge of the functional organisation of the cerebellum has progressed. The phylogenetic and anatomical divisions within the cerebellum, which have long been used to describe cerebellar functions, are now too simplistic. The understanding of cerebellar motor functions requires knowledge of a neuroanatomical division based on the afferents and the corticonuclear organisation of the cerebellum. Non motor cerebellar functions are even more poorly systematised, but the rapid progress being made in neuroscience and neuroimaging techniques should enable them to be better understood. PMID- 21529872 TI - [Spinal cord infarction due to compression of a lumbar artery by the right diaphragmatic crus]. PMID- 21529873 TI - Optimization design of high power ultrasonic circular ring radiator in coupled vibration. AB - This paper presents a new high power ultrasonic (HPU) radiator, which consists of a transducer, an ultrasonic horn, and a metal circular ring. Both the transducer and horn in longitudinal vibrations are used to drive a metal circular ring in a radial-axial coupled vibration. This coupled vibration cannot only generate ultrasound in both the radial and axial directions, but also focus the ultrasound inside the circular ring. Except for the radial-axial coupled vibration mode, the third longitudinal harmonic vibration mode with relative large vibration amplitude is also detected, which can be used as another operation mode. Overall, the HPU with these two vibration modes should have good potential to be applied in liquid processing, such as sonochemistry, ultrasonic cleaning, and Chinese herbal medicine extraction. PMID- 21529874 TI - Targeting the HIV entry, assembly and release pathways for anti-HIV gene therapy. AB - Targeting the HIV entry and assembly pathways holds promise for development of novel anti-HIV gene therapy vectors. We characterized discrete dominant negative (DN) Gag and Envelope mutants for their anti-HIV-1 activity. We show here that capsid mutants (Q155N and Y164A) are more potent inhibitors of WT HIV than the matrix mutant 1GA. Both the Envelope mutants tested, V513E and R515A, were equally effective and a combination of Gag and Envelope DN genes significantly enhanced potency. Interestingly, the DN mutants acted at multiple steps in the virus life cycle rather than solely disrupting virus release or infection. Inhibition mediated by R515A could be partially attributed to the Envelope cytoplasmic tail, as deletion of R515A tail partially abrogated its DN effect. Finally, the Y164A/R515A double mutant expressed in a lentiviral vector was effective at inhibiting HIV replication in CD34+ hematopoietic stem cell-derived macrophages, demonstrating the therapeutic potential of our approach. PMID- 21529876 TI - Sorption and biodegradation of sulfonamide antibiotics by activated sludge: experimental assessment using batch data obtained under aerobic conditions. AB - This study investigated the adsorption, desorption, and biodegradation characteristics of sulfonamide antibiotics in the presence of activated sludge with and without being subjected to NaN(3) biocide. Batch experiments were conducted and the relative contributions of adsorption and biodegradation to the observed removal of sulfonamide antibiotics were determined. Three sulfonamide antibiotics including sulfamethoxazole (SMX), sulfadimethoxine (SDM), and sulfamonomethoxine (SMM), which had been detected in the influent and the activated sludge of wastewater treatment plants (WWTP) in Taiwan, were selected for this study. Experimental results showed that the antibiotic compounds were removed via sorption and biodegradation by the activated sludge, though biodegradation was inhibited in the first 12 h possibly due to competitive inhibition of xenobiotic oxidation by readily biodegradable substances. The affinity of sulfonamides to sterilized sludge was in the order of SDM > SMM > SMX. The sulfonamides existed predominantly as anions at the study pH of 6.8, which resulted in a low level of adsorption to the activated sludge. The adsorption/desorption isotherms were of a linear form, as well described by the Freundlich isotherm with the n value approximating unity. The linear distribution coefficients (K(d)) were determined from batch equilibrium experiments with values of 28.6 +/- 1.9, 55.7 +/- 2.2, and 110.0 +/- 4.6 mL/g for SMX, SMM, and SDM, respectively. SMX, SMM, and SDM desorb reversibly from the activated sludge leaving behind on the solids 0.9%, 1.6%, and 5.2% of the original sorption dose of 100 MUg/L. The sorbed antibiotics can be introduced into the environment if no further treatments were employed to remove them from the biomass. PMID- 21529875 TI - Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein. AB - In a bioinformatics-based screen for cellular genes that enhance Zaire ebolavirus (ZEBOV) transduction, AXL mRNA expression strongly correlated with ZEBOV infection. A series of cell lines and primary cells were identified that require Axl for optimal ZEBOV entry. Using one of these cell lines, we identified ZEBOV entry events that are Axl-dependent. Interactions between ZEBOV-GP and the Axl ectodomain were not detected in immunoprecipitations and reduction of surface expressed Axl by RNAi did not alter ZEBOV-GP binding, providing evidence that Axl does not serve as a receptor for the virus. However, RNAi knock down of Axl reduced ZEBOV pseudovirion internalization and alpha-Axl antisera inhibited pseudovirion fusion with cellular membranes. Consistent with the importance of Axl for ZEBOV transduction, Axl transiently co-localized on the surface of cells with ZEBOV virus particles and was internalized during virion transduction. In total, these findings indicate that endosomal uptake of filoviruses is facilitated by Axl. PMID- 21529877 TI - Study on two operating conditions of a full-scale oxidation ditch for optimization of energy consumption and effluent quality by using CFD model. AB - The operating condition of an oxidation ditch (OD) has significant impact on energy consumption and effluent quality of wastewater treatment plants (WWTPs). An experimentally validated numerical tool, based on computational fluid dynamics (CFD) model, was proposed to optimize the operating condition by considering two important factors: flow field and dissolved oxygen (DO) concentration profiles. The model is capable of predicting flow pattern and oxygen mass transfer characteristics in ODs equipped with surface aerators and submerged impellers. Performance demonstration and comparison of two operating conditions (existing and improved) were carried out in two full-scale Carrousel ODs at the Ping Dingshan WWTP in Henan, China. A moving wall model and a fan model were designed to simulate surface aerators and submerged impellers, respectively. Oxygen mass transfer in the ditch was predicted by using a unit analysis method. In aeration zones, the mass inlets representing the surface aerators were set as one source of DO. In the whole straight channel, the oxygen consumption was modeled by using modified BOD-DO model. The following results were obtained: (1) the CFD model characterized flow pattern and DO concentration profiles in the full-scale OD. The predicted flow field values were within 1.98 +/- 4.28% difference from the actual measured values while the predicted DO concentration values were within 4.71 +/- 4.15% of the measured ones, (2) a surface aerator should be relocated to around 15m from the curve bend entrance to reduce energy loss caused by fierce collisions at the wall of the curve bend, and (3) DO concentration gradients in the OD under the improved operating condition were more favorable for occurrence of simultaneous nitrification and denitrification (SND). PMID- 21529878 TI - Kaolinite-supported nanoscale zero-valent iron for removal of Pb2+ from aqueous solution: reactivity, characterization and mechanism. AB - The use of nanoscale zero-valent iron (nZVI) to remediate contaminated groundwater is limited due to its lack of durability and mechanical strength. To address this issue, 20% (w/w) nZVI was loaded onto kaolinite as a support material (K-nZVI). More than 96% of Pb(2+) was removed from aqueous solution using K-nZVI at an initial condition of 500 mg/L Pb(2+) within 30 min under the conditions of 10 g/L of K-nZVI, pH 5.10 and a temperature of 30 degrees C. To understand the mechanism of removal of Pb(2+), various techniques were implemented to characterize K-nZVI. Scanning electron microscopy (SEM) indicated that K-nZVI had a suitable dispersive state with a lower aggregation, where the mean specific surface area and average particle size as determined by the BET N(2) method and X-ray diffraction (XRD), were 26.11 m(2)/g and 44.3 nm, respectively. The results obtained from XRD, X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) indicated that a small number of iron oxides formed on the surface of K-nZVI, suggesting that free Pb(2+) was adsorbed onto K-nZVI and subsequently reduced to Pb(0). PMID- 21529879 TI - Adsorption mechanism-based screening of cyclodextrin polymers for adsorption and separation of pesticides from water. AB - A rational screening of cyclodextrin-based polymer (CDP), in terms of the relationship between adsorption potential and adsorbent-adsorbate, was investigated to adsorb and separate pesticides from water. Seven spherical porous CDPs were prepared with onefold or composite cyclodextrin(s) as complex and epichlorohydrin as cross-linking reagent. The adsorption kinetics and isotherms of the polymers toward a mixture of ten distinct pesticides clearly demonstrate that the adsorbents with a homogeneous open network structure can absorb pesticides via multiple adsorption interactions such as CD inclusion, loading into swelling water and physical adsorption on network. The multivariate regression analysis distinguishes the quantitative contributions of polymer properties to its adsorption potential, among which CD content, swelling capacity and pore size appear to be major influencing factors. Consequently, a facile mixture of three CDPs (i.e., beta-CDP, RM-CDP and HP-CDP) was screened to obtain above prerequisite properties. The multiplex polymer could superiorly separate the pesticides at environmentally relevant levels from water. PMID- 21529880 TI - Examining the link between terrestrial and aquatic phosphorus speciation in a subtropical catchment: the role of selective erosion and transport of fine sediments during storm events. AB - This study examined the link between terrestrial and aquatic phosphorus (P) speciation in the soils and sediments of a subtropical catchment. Specifically, the study aimed to identify the relative importance of P speciation in source soils, erosion and transport processes upstream, and aquatic transformation processes as determinants of P speciation in lake sediments (Lake Wivenhoe). Using a sequential extraction technique, NH(4)Cl extractable P (NH(4)Cl-P; exchangeable P), bicarbonate-dithionite extractable P (BD-P; reductant soluble P), NaOH extractable P (NaOH-rP; Al/Fe oxide P), HCl extractable P (HCl-P; apatite-P), and residual-P (Res-P; organic and residual inorganic P) fractions were compared in different soil/sediment compartments of the upper Brisbane River (UBR) catchment, Queensland, Australia. Multidimensional scaling identified two distinct groups of samples, one consisting of lake sediments and suspended sediments, and another consisting of riverbed sediments and soils. The riverbed sediments and soils had significantly higher HCl-P and lower NaOH-rP and Res-P relative to the lake and suspended sediments (P < 0.05). Analysis of the enrichment factors (EFs) of soils and riverbed sediments showed that fine grained particles (<63 MUm) were enriched in all but the HCl-P fraction. This indicated that as finer particles are eroded from the soil surface and transported downstream there is a preferential export of non-apatite P (NaOH-rP, NaOH-nrP, BD P and Res-P). Therefore, due to the preferential erosion and transport of fine sediments, the lake sediments contained a higher proportion of more labile forms of inorganic-P relative to the broader soil/sediment system. Our results suggest that a greater focus on the effect of selective erosion and transport on sediment P speciation in lakes and reservoirs is needed to better target management strategies aimed at reducing P availability, particularly in P-limited water bodies impacted by soil erosion. PMID- 21529881 TI - Modelling biocide leaching from facades. AB - Biocides leach from facades during rain events and subsequently enter the aquatic environment with storm water. Little is known about the losses of an entire settlement, since most studies referred to wash-off experiments conducted under laboratory conditions. Their results show a fast decrease of concentrations in the beginning, which subsequently slows down. The aim of this study is to develop a simple model to understand the mechanisms leading to these losses as well as to simulate losses under various rainfall and application conditions. We developed a four-box model based on the knowledge gained from fits of an exponential function to an existing experimental data set of a wash-off experiment. The model consists of two mobile stocks from which biocides are washed off during a rain event. These mobile stocks are supplied with biocides from storage stocks by diffusion type processes. The model accurately reproduced the measured data of wash-off during single cycles as well as peak wash-offs over all cycles. Our model results for diuron losses showed that a large proportion (~ 70%) of the applied biocides are still in the stocks even after a rain volume corresponding to several years (1100 mm y(-1), Swiss Plateau). Applications to realistic outdoor conditions showed that losses can not be neglected for urban environments and that knowledge about the amount of rainfall turned into runoff and the decay constants of the biocides in the facades are crucial. The model increased our understanding of the processes leading to the observed dynamic in laboratory experiments and was used to simulate losses for various rainfall and application conditions. PMID- 21529882 TI - Assessing granular media filtration for the removal of chemical contaminants from wastewater. AB - Granular media filtration was evaluated for the removal of a suite of chemical contaminants that can be found in wastewater. Laboratory- and pilot-scale sand and granular activated carbon (GAC) filters were trialled for their ability to remove atrazine, estrone (E1), 17alpha-ethynylestradiol (EE2), N nitrosodimethylamine (NDMA), N-nitrosomorpholine (NMOR) and N-nitrosodiethylamine (NDEA). In general, sand filtration was ineffective in removing the contaminants from a tertiary treated wastewater, with the exception of E1 and EE2, where efficient removals were observed after approximately 150 d. Batch degradation experiments confirmed that the removal of E1 was through biological activity, with a pseudo-first-order degradation rate constant of 7.4 * 10(-3) h(-1). GAC filtration was initially able to effectively remove all contaminants; although removals decreased over time due to competition with other organics present in the water. The only exception was atrazine where removal remained consistently high throughout the experiment. Previously unreported differences were observed in the adsorption of the three nitrosamines, with the ease of removal following the trend, NDEA > NMOR > NDMA, consistent with their hydrophobic character. In most instances the removals from the pilot-scale filters were generally in agreement with the laboratory-scale filter, suggesting that there is potential in using laboratory-scale filters as monitoring tools to evaluate the performance of pilot- and possibly full-scale sand and GAC filters at wastewater treatment plants. PMID- 21529883 TI - Effects of primary sludge particulate (PSP) entrapment on ultrasonic (20 kHz) disinfection of Escherichia coli. AB - The role of primary sludge particulates (PSPs) in ultrasonic disinfection of Escherichia coli (E. coli) was investigated. Entrapment of E. coli by PSP was directly observed through scanning electron microscope (SEM) after E. coli and PSP were incubated together in water for 24 h at 35 degrees C. Entrapment coefficient was proposed for the first time to reflect the ability of PSP to entrap E. coli and was estimated as 1.4 * 10(3) CFU/mg PSP under our experimental conditions. Ultrasonication (20 kHz) of different E. coli-PSPs solutions showed that the entrapped E. coli cells were protected by PSP from ultrasonication and the unentrapped cells were not. However, the protection of entrapped E. coli cells gradually decreased as ultrasonication proceeded, suggesting the ability of power ultrasonication to deprotect the entrapped E. coli cells. SEM studies suggested a two-step mechanism for ultrasonic (20 kHz) disinfection of entrapped E. coli: breakdown of the protective PSP refugia and disinfection of the exposed E. coli cells. This research will enable more informed decisions about disinfection of aqueous samples where porous PSP are present. PMID- 21529884 TI - Performance of granular zirconium-iron oxide in the removal of fluoride from drinking water. AB - In this study, a granular zirconium-iron oxide (GZI) was successfully prepared using the extrusion method, and its defluoridation performance was systematically evaluated. The GZI was composed of amorphous and nano-scale oxide particles. The Zr and Fe were evenly distributed on its surface, with a Zr/Fe molar ratio of ~2.3. The granular adsorbent was porous with high permeability potential. Moreover, it had excellent mechanical stability and high crushing strength, which ensured less material breakage and mass loss in practical use. In batch tests, the GZI showed a high adsorption capacity of 9.80 mg/g under an equilibrium concentration of 10 mg/L at pH 7.0, which outperformed many other reported granular adsorbents. The GZI performed well over a wide pH range, of 3.5-8.0, and especially well at pH 6.0-8.0, which was the preferred range for actual application. Fluoride adsorption on GZI followed pseudo-second-order kinetics and could be well described by the Freundlich equilibrium model. With the exception of HCO(3)(-), other co-existing anions and HA did not evidently inhibit fluoride removal by GZI when considering their real concentrations in natural groundwater, which showed that GZI had a high selectivity for fluoride. In column tests using real groundwater as influent, about 370, 239 and 128 bed volumes (BVs) of groundwater were treated before breakthrough was reached under space velocities (SVs) of 0.5, 1 and 3 h(-1), respectively. Additionally, the toxicity characteristic leaching procedure (TCLP) results suggested that the spent GZI was inert and could be safely disposed of in landfill. In conclusion, this granular adsorbent showed high potential for fluoride removal from real groundwater, due to its high performance and physical-chemical properties. PMID- 21529885 TI - Effects of selected pharmaceutically active compounds on treatment performance in sequencing batch reactors mimicking wastewater treatment plants operations. AB - The impact of four pharmaceutically active compounds (PhACs) introduced both individually and in mixtures was ascertained on the performance of laboratory scale wastewater treatment sequencing batch reactors (SBRs). When introduced individually at concentrations of 0.1, 1 and 10 MUM, no significant differences were observed with respect to chemical oxygen demand (COD) and ammonia removal. Microbial community analyses reveal that although similarity index values generally decreased over time with an increase in PhAC concentrations as compared to the controls, no major microbial community shifts were observed for total bacteria and ammonia-oxidizing bacteria (AOB) communities. However, when some PhACs were introduced in mixtures, they were found to both inhibit nitrification and alter AOB community structure. Ammonia removal decreased by up to 45% in the presence of 0.25 MUM gemfibrozil and 0.75 MUM naproxen. PhAC mixtures did not however affect COD removal performance suggesting that heterotrophic bacteria are more robust to PhACs than AOB. These results highlight that the joint action of PhACs in mixtures may have significantly different effects on nitrification than the individual PhACs. This phenomenon should be further investigated with a wider range of PhACs so that toxicity effects can more accurately be predicted. PMID- 21529886 TI - Occurrence of Mycobacterium avium subsp. paratuberculosis in raw water and water treatment operations for the production of potable water. AB - Mycobacterium avium subsp. paratuberculosis (Map) causes Johne's disease of cattle and is implicated as a cause of Crohn's disease in humans. The organism is excreted in animal faeces and can contaminate water catchment areas. This coupled with Map's survival in the environment means that water destined for domestic use may be a source of exposure. This work was designed to determine the occurrence of Map in Lough Neagh (the largest freshwater lake in the British Isles), used as a reservoir, and in two water treatment works (WTW1 and WTW2) which abstract from the lough and which have slow sand filtration (SSF) and dissolved air flotation respectively as their principal treatment regimes. The organism was not detected in lough water samples by culture (n=70) but 29% (20/70) were positive by PCR. In the raw water to WTW1 and WTW2 no culture positives were detected but 54% (13/24) and 58% (14/24) respectively were PCR positive. In WTW1 there were no culture positives at the SSF or final water but 31% (8/26) and 45% (9/20) respectively were PCR positive. In WTW2 similar results were obtained with 26% (6/23) and 48% (11/23) in the floccules and final water respectively. At WTW2 however one culture positive was detected in the final water. This latter finding is of concern. The inability to reach definitive conclusions indicates the need for further research, particularly in the detection methods for viable Map. PMID- 21529887 TI - Removal and biosorption of C60 from water by an aquatic plant, Ceratophyllum sp. AB - The fate of fullerene water suspension (FWS) in an aquatic system of Ceratophyllum sp., a rootless submerged plant, under non-sterile sediment-free conditions was investigated. Fast removal of FWS from water by the plants was observed and irreversible adsorption of C(60) onto plants and increasing C(60) mass on the plant surface with prolonged exposure durations were confirmed. An intact plant extraction procedure was developed and the majority (>80%) of C(60) removed from water was extracted from the plants. C(60) remained aggregated after being associated with the plants, which was verified by (13)C NMR spectroscopy. Light micrographs showed association of FWS on and in the cuticle layers. PMID- 21529888 TI - Amendment of arsenic and chromium polluted soil from wood preservation by iron residues from water treatment. AB - An iron-rich water treatment residue (WTR) consisting mainly of ferrihydrite was used for immobilization of arsenic and chromium in a soil contaminated by wood preservatives. A leaching batch experiment was conducted using two soils, a highly contaminated soil (1033 mg kg(-1) As and 371 mg kg(-1) Cr) and slightly contaminated soil (22 5mg kg(-1) As and 27 mg kg(-1) Cr). Compared to an untreated reference soil, amendment with 5% WTR reduced leaching in the highly contaminated soil by 91% for Cr and 98% for As. No aging effect was observed after 103 d. In a small field experiment, soil was mixed with 2.5% WTR in situ. Pore water was extracted during 3 years from the amended soil and a control site. Pore water arsenic concentrations in the amended soil were more than two orders of magnitude lower than in the control for the upper samplers. An increased release of arsenic was observed during winter in both fields, mostly in the deepest samplers. This is likely due to the formation of a pseudo-gley because of precipitation surplus. Stabilization of arsenic and chromium contaminated soil using WTR is a promising method but the transformation of ferrihydrite in soil proves a concern in case of waterlogged soils. Still the amendment minimized the leaching of arsenic, even in cases of seasonal releases. PMID- 21529889 TI - Histopathological and biochemical alternations of the heart induced by acute cadmium exposure in the freshwater crab Sinopotamon yangtsekiense. AB - Cadmium (Cd) is a highly toxic element in water. Its toxicity has been attributed to oxidative stress mediated by free radicals. Here we investigated the effects of Cd on the histopathology, antioxidant enzymes and lipid peroxidation of crustacean heart. The freshwater crabs Sinopotamon yangtsekiense were exposed to different concentrations of Cd for 1, 3, 5 and 7d. After exposure, histological abnormalities were discovered, including myocardial edema, vacuolar and vitreous degeneration, and infiltration of inflammatory cells. Additionally, alterations in nuclei, mitochondria, rough endoplasmic reticulum as well as myofibrils were observed. Meanwhile, superoxide dismutase (SOD) activity was significantly increased after Cd exposure. Catalase (CAT) activity was only increased in the group exposed to 14.50 mg L(-1) Cd on day 5 and decreased with increasing Cd concentration and exposure time. Glutathione peroxidase (GPx) activity was increased in groups treated with 29.00, 58.00 and 116.00 mg L(-1) on days 1 and 3, and decreased thereafter. Besides, malondialdehyde (MDA) levels were significantly increased after 3d of Cd exposure at all the indicated concentrations. These results showed that acute Cd exposure led to harmful effects on the histology of crab heart, which are most likely linked to Cd induced oxidative stress. PMID- 21529890 TI - Bioaccumulation and depuration of anthracene in Penaeus monodon (Fibricius) through food ingestion. AB - Understanding on the bioaccumulation and depuration of PAHs (polycyclic aromatic hydrocarbons) in Penaeus monodon is important in seafood safety because it is one of the most popular seafood consumed worldwide. In this study, we used anthracene as the precursor compound for PAHs accumulation and depuration in the shrimp. Commercial feed pellets spiked with anthracene were fed to P. monodon. At 20 mg kg(-1) anthracene, P. monodon accumulated 0.1% of the anthracene from the feed. P. monodon deputed the PAH two times faster than its accumulation. The shrimp reduced its feed consumption when anthracene content in the feed exceeded 20 mg kg(-1). At 100 mg kg(-1) anthracene, P. monodon started to have necrosis tissues on the posterior end of their thorax. The bioaccumulation factor (BAF), uptake rate constant (k(1)) and depuration rate constant (k(2)) of anthracene in P. monodon were 1.15*10(-3), 6.80*10(-4) d(-1) and 6.28*10(-1) d(-1), respectively. The depuration rate constant is about thousand times higher than the uptake rate constant and this indicated that this crustacean is efficient in depurating hydrocarbons from their tissue. PMID- 21529891 TI - Temporal variability in dynamic and colloidal metal fractions determined by high resolution in situ measurements in a UK estuary. AB - In recent environmental legislation, such as the Water Framework Directive in the European Union (WFD, 2000/60/EC), the importance of metal speciation and biological availability is acknowledged, although analytical challenges remain. In this study, the Voltammetric In situ Profiler (VIP) was used for high temporal resolution in situ metal speciation measurements in estuarine waters. This instrument simultaneously determines Cd, Cu and Pb species within a size range (ca. <4 nm) that is highly relevant for uptake by organisms. The colloidal metal fraction can be quantified through a combination of VIP measurements and analyses of total dissolved metal concentrations. VIP systems were deployed over tidal cycles in a seasonal study of metal speciation in the Fal Estuary, southwest England. Total dissolved concentrations were 4.97-315 nM Cu, 0.13-8.53 nM Cd and 0.35-5.75 nM Pb. High proportions of Pb (77+/-17%) and Cu (60+/-25%) were present as colloids, which constituted a less important fraction for Cd (37+/-30%). The study elucidated variations in the potentially toxic metal fraction related to river flow, complexation by organic ligands and exchanges between dissolved and colloidal phases and the sediment. Based on published toxicity data, the bioavailable Cu concentrations (1.7-190 nM) in this estuary are likely to severely compromise the ecosystem structure and functioning with respect to species diversity and recruitment of juveniles. The study illustrates the importance of in situ speciation studies at high resolution in pursuit of a better understanding of metal (bio)geochemistry in dynamic coastal systems. PMID- 21529892 TI - A dynamic model to calculate cadmium concentrations in bovine tissues from basic soil characteristics. AB - A chain model was developed to calculate the flow of cadmium from soil, drinking water and feed towards bovine tissues. The data used for model development were tissue Cd concentrations of 57 bovines and Cd concentrations in soil, feed and drinking water, sampled at the farms were the bovines were reared. Validation of the model occurred with a second set of measured tissue Cd concentrations of 93 bovines of which age and farm location were known. The exposure part of the chain model consists of two parts: (1) a soil-plant transfer model, deriving cadmium concentrations in feed from basic soil characteristics (pH and organic matter content) and soil Cd concentrations, and (2) bovine intake calculations, based on typical feed and water consumption patterns for cattle and Cd concentrations in feed and drinking water. The output of the exposure model is an animal-specific average daily Cd intake, which is then taken forward to a kinetic uptake model in which time-dependent Cd concentrations in bovine tissues are calculated. The chain model was able to account for 65%, 42% and 32% of the variation in observed kidney, liver and meat Cd concentrations in the validation study. PMID- 21529893 TI - Organohalogenated contaminants in eggs of rockhopper penguins (Eudyptes chrysocome) and imperial shags (Phalacrocorax atriceps) from the Falkland Islands. AB - In this study, we evaluated the use of seabird eggs of two common bird species from the Falkland Islands as bioindicators of contamination with organohalogenated contaminants (OHCs). We compared contamination levels and profiles of different OHCs between eggs of the rockhopper penguin (Eudyptes chrysocome) and the imperial shag (Phalacrocorax atriceps). In addition, laying order effects on OHC concentrations and profiles were also investigated in both species. For polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) as well as polybrominated diphenyl ethers (PBDEs), concentrations were significantly lower in eggs of rockhopper penguins (27.6+/-0.70 ng/g lw, 56.5+/ 1.33 ng/g lw and 0.98+/-0.04 ng/g lw, respectively) compared to the imperial shags (140+/-5.54 ng/g lw, 316+/-11.53 ng/g lw, 1.92+/-0.15 ng/g lw, respectively). On the other hand, 2'MeO-BDE 68 and 6MeO-BDE 47, two brominated compounds of reported natural origin, were significantly higher in the penguin eggs (0.55+/-0.05 ng/g lw and 7.01+/-0.64 ng/g lw, respectively) compared to the shag eggs (0.17+/-0.03 ng/g lw and 0.50+/-0.06 ng/g lw, respectively). In addition, PCB, OCP and PBDE contamination profiles differed markedly between the two species. Various factors, such as diet, feeding behaviour, migratory behaviour and species-specific metabolism, may be responsible for the observed results. For both rockhopper penguins and imperial shags, PCB, OCP and PBDE concentrations and profiles did not significantly change in relation to the laying order. This suggests that, for both species, any egg of a clutch is useful as a biomonitoring tool for OHCs. Although our results showed that OHCs have also reached the Falkland Islands, concentrations were relatively low compared to other studies. However, future monitoring may be warranted to assess temporal trends of different OHCs. PMID- 21529894 TI - Effect of ZnO particles on activated sludge: role of particle dissolution. AB - The release of nanoparticles (NPs) into the environment, including wastewater treatment plants, is expected to increase in the future. Therefore, it is important to understand the potential effects of these NPs on activated sludge treatment processes. A pulse-flow respirometer was used to study the toxicity of nano-ZnO on activated sludge endogenous respiration, BOD biodegradation, and nitrification. In addition, toxicities of bulk ZnO particles and Zn ion (e.g. soluble Zn) were also studied. All three Zn forms were found to adversely impact the activity of activated sludge, with soluble Zn exhibited the greatest toxicity. The effects of nano-ZnO and bulk ZnO on activated sludge were caused by soluble Zn resulting from ZnO particle dissolution. The IC(50) values of soluble Zn on activated sludge endogenous respiration, BOD biodegradation, ammonia oxidation, and nitrite oxidation were 2.2, 1.3, 0.8, and 7.3 mg-Zn/L, respectively. Therefore, the first step of nitrification was most sensitive to Zn. PMID- 21529895 TI - Soil management systems and short term CO2 emissions in a clayey soil in southern Spain. AB - The soil in general and that destined for agricultural use, more specifically, can act as a source or sink of carbon, hence its direct involvement in strategies for mitigating climate change. A large proportion of this mitigation potential is produced by the sequestration of carbon by soils and, to a lesser extent, by a reduction in emissions from the soil. The most effective practices for increasing the organic carbon in the soils are generally those linked to conservation agriculture, which includes practices of no tillage or minimum tillage and the use of cover crops. During the farming seasons of 2006/07, 2007/08, 2008/09 and 2009/10, a trial was conducted in which the carbon dioxide emissions in soil with a high percentage of clay in the Vega de Carmona (Seville) were estimated, and it was determined how climate conditions and the adoption of conservation agriculture practices vs. the use of traditional tillage influenced the flux of gas into the atmosphere. PMID- 21529896 TI - Evaluation of a new set of automated chemiluminescense assays for anticardiolipin and anti-beta2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. AB - INTRODUCTION: The laboratory diagnosis of antiphospholipid syndrome (APS) requires the demonstration of antiphospholipid antibodies (aPL): lupus anticoagulant (LAC) measured through coagulation assays, anticardiolipin IgG or IgM antibodies (aCL) and/or anti-beta2glycoprotein I IgG or IgM antibodies (abeta2GPI), usually detected by ELISA. MATERIALS AND METHODS: We evaluated the diagnostic value of aCL and abeta2GPI measured by a new automated system using the chemiluminescence principle, the immunoanalyzer Zenit RA (Menarini). RESULTS: Results of aCL and abeta2GPI were correlated with the clinical background of the patients and with results of ELISA (n=314). Correlated to the clinical background sensitivity/specificity ranged for aCL IgG between 7.5-45.2% / 54.2-98.8%, for aCL IgM 3.4-5.5% / 89.9-94%, for abeta2GPI IgG 5.5-25.3% / 75.6-100% and abeta2GPI IgM 3.4-4.8% / 89.9-92.3%, depending on the cut-off used. Sensitivity with manufacturer's cut-offs was comparable to ELISA, except for abeta2GPI IgG with a significantly lower sensitivity compared to ELISA (5.5% vs 11.6%). In the APS patient population (n=30) sensitivity of aCL IgG and abeta2GPI IgG was higher measured by ELISA compared to Zenit RA (46.7% vs 30.0%, and 46.7% vs 26.7%, respectively). Agreement between Zenit RA results and ELISA results for the four parameters was moderate (Kappa-values ranging 0.509-0.565). Sensitivity was 38.5%, 53.3%, 40% and 69.2% for aCL IgG, aCL IgM, abeta2GPI IgG and abeta2GPI IgM, respectively, applying the highest cut-off value for Zenit RA, raising towards 64.3%, 100%, 57.1%, for aCL IgG, aCL IgM, abeta2GPI IgG, respectively, in a APS patient population. CONCLUSIONS: The new technology of chemiluminescense for measuring aPL showed good performance characteristics. Interpretation of results with a cut-off value associated with a good discrimination for disease, resulted in a lower sensitivity for the diagnosis of APS for abeta2GPI IgG measured by Zenit RA assays compared to ELISA; sensitivity for aCL IgG was comparable to ELISA. Specificity for all parameters was high and comparable for aCL and abeta2GPI. PMID- 21529897 TI - New antithrombotics: the impact on global health care. AB - New and generic forms of widely used medications introduced in the antiplatelet, anticoagulant and fibrinolytic therapeutic classes will have a world-wide impact on prescribing, practice guidelines, and routine patient care. However, several uncertainties regarding these agents will remain even after the publication of their respective pivotal trials or regulatory approval. These questions include dosing in the frail, the elderly, and in those with renal and/or hepatic dysfunction, timing of administration in the peri-operative period, efficacy and safety in subgroup populations such as patients with cancer, the interchangeability of biosimilar products, and outcome differences between new agents in the absence of head-to-head clinical trials. Additionally, new generic forms of widely used agents have recently impacted the United States (US) and Canadian market place and more are under development. Clinicians should be vigilant concerning these agents and be prepared to inform patients and make decisions with their use. PMID- 21529898 TI - Quantification of collagen organization using fractal dimensions and Fourier transforms. AB - Collagen fibers and fibrils that comprise tendons and ligaments are disrupted or damaged during injury. Fibrillogenesis during healing produces a matrix that is initially quite disorganized, but remodels over time to resemble, but not replicate, the original roughly parallel microstructure. Quantification of these changes is traditionally a laborious and subjective task. In this work we applied two automated techniques, fast Fourier transformation (FFT) and fractal dimension analysis (FA) to quantify the organization of collagen fibers or fibrils. Using multi-photon images of collagen fibers obtained from rat ligament we showed that for healing ligaments, FA differentiates more clearly between the different time points during healing. Using scanning electron microscopy images of overstretched porcine flexor tendon, we showed that combining FFT and FA measures distinguishes the damaged and undamaged groups more clearly than either method separately. PMID- 21529899 TI - Cytokine responses to E. coli-induced epididymitis in the rat: blockade by vasectomy. AB - OBJECTIVES: To determine cytokine responses in rat epididymal tissues after retrograde Escherichia coli inoculation of the cauda epididymidis via the intact and obstructed vas deferens. METHODS: Adult male Sprague-Dawley rats were divided into 3 groups: bilateral sham vasectomy followed by unilateral sham retrograde inoculation in the vas deferens (group A), bilateral sham vasectomy followed by unilateral retrograde inoculation of E. coli (group B), and bilateral vasectomy followed by left-sided inoculation of E. coli (group C). Three days later, the cauda epididymides and proximal vasa were subjected to histologic examination and assay for 9 cytokines. RESULTS: Groups A and C showed no histologic evidence of epididymal inflammation. Group B had leukocyte infiltrates in the inoculated tissue. Cytokine levels in the injected cauda epididymides were low in groups A and C; however, interleukin (IL)-1alpha, IL-1beta, and IL-4 were significantly increased in group B. The 6 other cytokines showed no significant change after E. coli infection though tumor necrosis factor-alpha, and IL-6 did show strong trends for increase. Contralateral epididymides never showed an inflammatory response. CONCLUSIONS: Experimental epididymitis induced by retrograde movement of bacteria in the vas deferens results in different responses by different cytokines. The cytokine responses and the histologically evident inflammation are prevented by vasectomy. PMID- 21529900 TI - Pazopanib synergizes with docetaxel in the treatment of bladder cancer cells. AB - OBJECTIVES: To investigate the efficacy of pazopanib, both alone and in combination with docetaxel, in bladder cancer cells. Bladder cancer expresses many potential therapeutic targets of biological agents, including the vascular endothelial growth factor receptor (VEGFR). Pazopanib is a small molecule inhibitor of VEGFR-1, -2-3, platelet-derived growth factor receptor (PDGFR), and c-Kit. MATERIALS AND METHODS: Using human bladder cancer cells HTB3, HT1376, J82, RT4, CRL1749, T24, Sup, and HTB9, the treatment effect of pazopanib and cytotoxic chemotherapy was assessed using a tetrazolium-based assay. The combinatorial effect of these agents on clonogenic growth was further examined. Western blotting was used to assess changes in relevant downstream targets, including phospho-AKT, phospho-FAK, total AKT, and total FAK. RESULTS: Single-agent pazopanib had modest activity. However, synergy was seen with the combination of docetaxel and pazopanib in these multiple cells lines. J82 and T24 cells were selected for additional clonogenic testing because of their resistance to single agent docetaxel chemotherapy. 1.25 nM of docetaxel had little effect on clonogenic formation; however, in combination with pazopanib, significant inhibition of colony formation was observed. This combination treatment additionally decreased phospho-AKT, an important mediator of cell survival in all cell lines, whereas phospho-FAK expression was variably affected. CONCLUSIONS: The present study demonstrates synergistic efficacy of pazopanib with docetaxel in docetaxel-resistant bladder cancer cells. This work supports future evaluation of pazopanib with docetaxel for the treatment of bladder cancer with the potential of improved efficacy and toxicity. PMID- 21529901 TI - Initial clinical experience with use of ureteral access sheaths in the diagnosis and treatment of upper tract urothelial carcinoma. AB - OBJECTIVE: To describe our experience with ureteral access sheaths in the diagnosis and treatment of upper tract urothelial carcinoma. METHODS: We retrospectively identified a patient cohort who underwent ureteroscopy for suspicion of upper tract urothelial carcinoma and identified those with placement of a ureteral access sheath. Records were reviewed for demographic information, comorbidity data, operative complications, and pathology results. The histologic grade of ureteroscopic biopsies and nephroureterectomy specimens were evaluated for concordance. RESULTS: A total of 125 patients underwent 235 procedures for known or suspected upper tract urothelial carcinoma. Access sheaths were used in patients in whom significant urothelial lesions were noted in the proximal upper urinary tract. A total of 64 patients underwent 85 sheath-inclusive procedures. Sheath deployment was successful in 83 (97.6%) of the 85 procedures. Biopsies yielded specimen adequate for histopathologic diagnosis in 75 (90.4%) of 83 cases. No ureteral access sheath-related complications were noted. Of the 125 patients, 34 underwent removal of 35 renal units. The concordance of tumor grade between biopsy and nephroureterectomy specimens was 88.6% (P=.0002). CONCLUSION: Ureteral access sheaths are safe for use in the diagnosis and treatment of upper tract urothelial carcinoma. Sheath placement facilitated the acquisition of multiple biopsy specimens adequate for histopathologic evaluation. Our technique precluded the need for repeat ureteroscopy to establish a diagnosis. Biopsies obtained through an access sheath were highly predictive of tumor grade in nephroureterectomy specimens. PMID- 21529902 TI - Oxalobacter colonization in the morbidly obese and correlation with urinary stone risk. AB - OBJECTIVE: To establish the baseline preoperative prevalence of Oxalobacter formigenes (OF) colonization in a cohort of obese patients scheduled for Roux-en Y gastric bypass (RYGB) and determine the effect of OF colonization on urinary oxalate excretion. It has been proposed that loss of OF colonization after RYGB may contribute to the development of hyperoxaluria. METHODS: Adult patients scheduled to undergo RYGB were requested to provide a stool specimen and 24-hour urine collection before surgery. OF colonization status was determined by the calcium precipitation test. The 24-hour urine specimens were analyzed by the Litholink Corporation (Chicago, IL). RESULTS: Of the 51 patients submitting initial stool specimens, only 8 (16%) tested positive for OF, whereas 43 (84%) were negative. Patients colonized with OF were older than uncolonized subjects (52.9+/-6.8 vs 46.0+/-10.4 years, P=.03). Urinary oxalate was not significantly different between these groups (P=.14). CONCLUSION: OF colonization is uncommon in morbidly obese patients (16%) before surgery. Because hyperoxaluria develops in more than 50% of patients after RYGB, it is unlikely that loss of OF colonization is the primary cause. PMID- 21529903 TI - What can we learn from pediatric urology certification logs? AB - OBJECTIVES: To use the billing logs submitted to obtain insight into the operative practice of pediatric urology. The American Board of Urology recently offered a certificate of special qualification in pediatric urology. As a part of the application process, the candidates for this certificate submitted billing logs. METHODS: We reviewed the practice logs of practitioners applying for a certificate of added competence in pediatric urology in 2007 and 2008. The de identified logs were grouped by case severity and type. In addition, the numbers of cases by a given practitioner were grouped by percentiles. We also analyzed the data for differences in experience, geography, and practice type. RESULTS: A total of 230 logs from the first 2 years of applications were analyzed. The median number of cases was 505 annually, with the most common procedure being circumcision (55 annually), followed by orchiopexy (40 annually) and hernia repair (40 annually). Major procedures were rarer (eg, proximal hypospadias, 2 annually; pyeloplasty, 8 annually; nephrectomy/partial nephrectomy, 4 annually; and genital reconstruction, 1 annually). CONCLUSIONS: In 2006 and 2007, the typical applicant for a subspeciality certificate in pediatric urology had a surgical practice that was primarily of penile and groin cases, with few major cases. PMID- 21529904 TI - A randomized phase III trial of IV carboplatin and paclitaxel * 3 courses followed by observation versus weekly maintenance low-dose paclitaxel in patients with early-stage ovarian carcinoma: a Gynecologic Oncology Group Study. AB - OBJECTIVE: To compare the recurrence-free interval (RFI) and safety profile in patients with completely resected high-risk early-stage ovarian cancer treated with intravenous (IV) carboplatin and paclitaxel with or without maintenance low dose paclitaxel for 24 weeks. METHODS: Eligibility was limited to patients with stage IA/B (grade 3 or clear cell), all IC or II epithelial ovarian cancer. All patients were to receive carboplatin AUC 6 and paclitaxel 175 mg/m2 q3 weeks * 3 courses with random assignment to either observation or maintenance paclitaxel 40 mg/m2/week * 24 weeks. Recurrence required clinical or radiological evidence of new tumor. RESULTS: There were 571 patients enrolled onto this study, of whom 29 were deemed ineligible due to inappropriate stage or pathology, leaving 542 patients. At least 3 cycles of treatment were administered to 524/542 (97%) of patients, and among those assigned to maintenance paclitaxel, 80% completed the regimen. The incidence of grade 2 or worse peripheral neuropathy (15.5% vs. 6%), infection/fever (19.9% vs. 8.7%), and dermatologic events (70.8% vs. 52.1%) was higher on the maintenance regimen (p<0.001). The cumulative probability of recurring within 5 years for the maintenance paclitaxel regimen is 20% vs. 23% for surveillance (hazard ratio 0.807; 95% CI: 0.565-1.15). The probability of surviving 5 years was 85.4% and 86.2%, respectively. CONCLUSION: Maintenance paclitaxel at 40 mg/m2/week * 24 weeks added to standard dose AUC6 and paclitaxel 175 mg/m2 * 3 doses provides no significant increase in RFI. PMID- 21529905 TI - MicroRNA-200a inhibits CD133/1+ ovarian cancer stem cells migration and invasion by targeting E-cadherin repressor ZEB2. AB - OBJECTIVES: MicroRNA-200a (miR-200a) has been reported to be a prognostic marker and to play an important role in ovarian cancer progression. The aim of the study was to elucidate the mechanism of miR-200a involved in migration and invasion in CD133/1+ ovarian cancer stem cells (OCSCs). METHODS: The expression of miR-200a between CD133/1+ and CD133/1- cells was performed using real-time PCR, and wound healing assay and matrigel invasion assay were used to detect migration and invasion of CD133/1+ cells, respectively, target gene regulated by miR-200a was detected using Dual Luciferase Reporter system, The expression levels of target gene were confirmed using real-time PCR and western blot. RESULTS: miR-200a was downregulated in CD133/1+ cells compared with CD133/1- cells, and overexpression of miR-200a significantly reduced CD133/1+ cells migration and invasion compare with negative control (NC) (p<0.05). The 3'-UTR of ZEB2 mRNA, a transcriptional repressor of E-cadherin, was found to be regulated directly by miR-200a. In addition, when miR-200a was overexpressed in CD133/1+ cells, the mRNA and protein levels of ZEB2 were both suppressed, which resulted in an increase in the E cadherin expression level, suggesting that ZEB2 was a functionally important target of miR-200a in CD133/1+ cells. CONCLUSIONS: Our results suggest that loss of expression of miR-200a may play a critical role in the repression of E cadherin by ZEB2, thereby enhancing migration and invasion in CD133/1+ cells. PMID- 21529906 TI - Tetrathiomolybdate induces doxorubicin sensitivity in resistant tumor cell lines. AB - OBJECTIVE: Doxorubicin is a potent anti-cancer agent with efficacy against a broad range of tumors, including endometrial cancer. Doxorubicin produces reactive oxygen species (ROS) resulting in cytotoxicity. Tetrathiomolybdate (TM), a copper-chelating agent, is known to target a cellular antioxidant enzyme copper/zinc-superoxide dismutase. This study tests the hypothesis that TM can modulate antioxidants in tumor cells and render doxorubicin resistant tumor cells sensitive to doxorubicin. METHODS: The anti-cancer activities of doxorubicin and TM, as single agents and in combination, were assessed. Flow cytometric and immunoblot analysis were conducted to investigate the induction of apoptosis and changes in apoptotic signaling pathways. RESULTS: Doxorubicin-induced growth inhibition was observed in each endometrial cancer cell line (ECC-1, AN3CA, and KLE) tested with cell specificity. ECC-1 and KLE cells were found to have increased resistance to doxorubicin than AN3CA cells. Moreover, doxorubicin mediated apoptosis was greater in the AN3CA cell line than ECC-1 and KLE. The combination of doxorubicin with a sub-cytotoxic level of TM was significantly more effective at inducing apoptosis in doxorubicin resistant cell lines. CONCLUSION: Our results highlight the therapeutic potential of TM to sensitize tumor cells to doxorubicin for endometrial cancer treatment. PMID- 21529907 TI - Polymorphism of the pre-miR-146a is associated with risk of cervical cancer in a Chinese population. AB - OBJECTIVE: MicroRNAs are tiny non-coding RNAs that reportedly play an important role in numerous physiological processes. A G>C polymorphism (rs2910164) is located on the passenger strand of the precursor of miR-146a, which could alter mature miR-146a expression. We hypothesized that a possible association exists between miR-146a gene polymorphisms and cervical cancer risk in a population based control study of female residents in Jiangsu Province. METHODS: The subjects included 447 cervical cancer cases and 443 cancer-free controls with frequency matched by age. We genotyped the functional polymorphism of miR-146a (rs2910164) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and used a sample of 24 cervical cancer tissue to test the expression of miR-146a by real-time quantitative reverse transcription. RESULTS: Our study indicated that the subjects carrying GG homozygote had a 1.496-fold increased risk than those carrying CG/CC genotypes (95% CI=1.068-2.095). Moreover, miR-146a quantification showed that the carriers of GG genotype had obviously more reduced miR-146a expression level compared with the carriers of CC genotype. CONCLUSION: Our study suggests that the risk of cervical cancer in a Chinese population partly results from miRNA-146a expression deviation in vivo, being caused by common polymorphism in miR-146a. This is an initial study to indicate that miR-146a (rs2910164) might contribute to cervical cancer susceptibility. PMID- 21529908 TI - Value of sentinel node mapping in cancer of the cervix. AB - OBJECTIVES: To compare the relative value of two methods of detection for the sentinel lymphatic nodes (SLNs): colorimetric with Isosulfan blue (ISB) and radio isotopic with Technetium-99 (Tc99), and to evaluate the concept of the SLN mapping applied to cervical cancer. METHODS: From October 2000 to December 2006, radical surgery was planned in 211 patients who presented early-stage cancer of the cervix. Both ISB and Tc99 were used to detect the SLNs. In all cases, we proceeded with laparoscopy for the identification and removal of the SLNs, followed by a complete pelvic lymphadenectomy with or without para-aortic node sampling. The SLNs were sent for frozen section (1 level) and were ultra-staged (6 levels) for final pathology. Detection rate, sensitivity and negative predictive value (NPV) were calculated. RESULTS: Among the 211 patients, ISB (n=152) identified at least 1 SLN in 92.8% of the cases. With Tc99 (n=166), the detection rate of SLN increased to 96.9%. When both techniques were used together (n=107), Tc99 was significantly better than ISB by 7.8% (p=0.0094) and at least 1 SLN (hot and/or blue) was found in 99.1% of the cases. In 16.7% of patients, a SLN was located in aberrant sites, including 3.8% in the para-aortic area. Thirty three out of the 211 patients (15.6%) had lymph node metastases. When considering only the 181 patients with bilateral SLNs identified, the NPV of SLN is 100% after ultra staging on final pathology and 94.2% on frozen section (FS). CONCLUSION: Sentinel node mapping is feasible using laparoscopy. The radio isotopic technique adds significantly to the rate of detection. The main benefits of SLN mapping in cervical cancer are the detection of micro-metastases on ultra staging which might be missed on routine pathological evaluation, and identification of aberrant drainage sites. However, the current frozen section techniques lack sensitivity to identify very small metastases and need refinement. SLN mapping should become the standard of care in the modern management of cervical cancer and complete pelvic lymphadenectomy could be avoided when bilateral SLNs are detected in patients with lesions less than 2 cm. PMID- 21529909 TI - An epigenetic signature for monoallelic olfactory receptor expression. AB - Constitutive heterochromatin is traditionally viewed as the static form of heterochromatin that silences pericentromeric and telomeric repeats in a cell cycle- and differentiation-independent manner. Here, we show that, in the mouse olfactory epithelium, olfactory receptor (OR) genes are marked in a highly dynamic fashion with the molecular hallmarks of constitutive heterochromatin, H3K9me3 and H4K20me3. The cell type and developmentally dependent deposition of these marks along the OR clusters are, most likely, reversed during the process of OR choice to allow for monogenic and monoallelic OR expression. In contrast to the current view of OR choice, our data suggest that OR silencing takes place before OR expression, indicating that it is not the product of an OR-elicited feedback signal. Our findings suggest that chromatin-mediated silencing lays a molecular foundation upon which singular and stochastic selection for gene expression can be applied. PMID- 21529910 TI - Arbutin's suppression of cryodamage in goat sperm and its mechanism of cryoprotection. AB - Arbutin (4-hydroxyphenyl-glucopyranoside) is a glycosylated hydroquinone present in high concentrations in the leaves of several plants capable of surviving prolonged, extreme dehydration. Two experiments were conducted to determine the effects of arbutin on cryopreservation of goat sperm. In Experiment 1, goat sperm were frozen in extenders with various ratios of Tris-citric acid-glucose (TCG) and arbutin; concentrations of the latter were 0.0 (only TCG), 0.1, 0.2, 0.3, and 0.4 M (only arbutin)]. All extenders had 20% (v/v) egg yolk (EY) and 4% (v/v) glycerol (osmolality = 370 mOsm, pH = 7.0). Sperm motility and acrosome integrity were assessed using CASA, and fluorescein isothiocyanate-labeled peanut agglutinin (FITC-PNA), respectively. Percentages of motile and progressively motile sperm improved with the addition of arbutin; results were optimal (89.0 and 70.0%, respectively; P < 0.05), with 0.4 M arbutin. Furthermore, arbutin improved (P < 0.05) post-thaw recovery rates for both motility and progressive motility. After incubation for 3 h, motility of frozen-thawed washed sperm improved (70%, P < 0.05) with arbutin in the extender. The percentage of sperm with an intact acrosome peaked (77.2%, P < 0.05) with 0.4 M arbutin in the extender. In Experiment 2, the percentage of cells with merocyanine 540/Yo-Pro staining was higher in sperm treated with arbutin than with TCG (P < 0.05), with the best result (58.0%) with 0.4 M arbutin; therefore, arbutin increased membrane fluidity. In conclusion, substitution of a TCG-EY diluent composition with arbutin improved freezability of goat sperm (apparently due to increased membrane fluidity). Furthermore removal of arbutin by centrifugation after freezing and thawing increased sperm longevity. PMID- 21529911 TI - Neither duration of progesterone insert nor initial GnRH treatment affected pregnancy per timed-insemination in dairy heifers subjected to a Co-synch protocol. AB - Our objectives were to: 1) compare response to cloprostenol, synchrony of ovulation, and pregnancy per timed-AI (P/TAI) in a 5 d versus a 7 d Co-synch + PRID protocol (Experiment 1); and 2) investigate whether the initial GnRH is necessary to achieve acceptable P/TAI in a 5 d Co-synch + PRID protocol (Experiment 2) in dairy heifers. In Experiment 1, 64 Holstein heifers, 15 to 17 mo, were assigned by age to receive 100 MUg of GnRH and a PRID for 5 or 7 d (PRID5 and PRID7, respectively). At PRID removal 500 MUg of cloprostenol (PGF) was given i.m. Heifers received the second GnRH treatment concurrently with TAI at 72 (PRID5) or 56 (PRID7) h after PRID removal. Transrectal ultrasonography monitored ovarian dynamics, ovulation synchrony, and pregnancy status (28 and 45 d after TAI). Plasma progesterone concentrations were determined at PRID removal and TAI. Five of seven heifers that ovulated before TAI became pregnant, and only two heifers did not respond to PGF treatment in the PRID5 group. Five PRID5 and 2 PRID7 heifers failed to ovulate after the second GnRH. However, P/TAI did not differ between PRID5 (59.4%) and PRID7 (58.1%). Overall ovulation response to first GnRH treatment was only 31.7%, and a larger proportion of heifers that did not ovulate became pregnant (65.1 versus 45.0%). In Experiment 2, 56 Holstein heifers, assigned as in Experiment 1, were subjected to a PRID5 protocol with (PRID5G) or without (PRID5NoG) GnRH at PRID insertion; all heifers were TAI 72 h after PRID removal. Transrectal ultrasonography and progesterone determinations were performed as in Experiment 1. Pregnancy per TAI did not differ whether or not heifers received GnRH at PRID insertion (67.9 versus 71.4%). Consistent with our previous findings, seven of nine heifers that ovulated before TAI became pregnant, and only two heifers did not respond to PGF treatment. Combining both experiments, length of proestrus but not ovulatory follicle diameter was identified as a significant predictor of probability of pregnancy 28 d after TAI, with a maximum predicted probability of 80.1% when the length of proestrus was 3 d. In summary, a PRID5 protocol resulted in comparable P/TAI to a PRID7 protocol. Most of the heifers that ovulated before TAI in the PRID5, PRID5G, and PRID5NoG protocols became pregnant. More than one PGF or a GnRH treatment at PRID insertion in a 5 d Co-synch + PRID protocol was not required to achieve acceptable P/TAI in dairy heifers. PMID- 21529912 TI - Xenografting of testis tissue from bison calf donors into recipient mice as a strategy for salvaging genetic material. AB - The objective was to evaluate the long-term outcome of testis tissue xenografting from neonatal bison calves as a model for closely related rare or endangered ungulates. Testis tissue was collected postmortem from two newborn bison calves (Bison bison bison) and small fragments of the tissue were grafted under the back skin of immunodeficient recipient mice (n = 15 mice; eight fragments/mouse). Single xenograft samples were removed from representative recipient mice every 2 mo after grafting (for up to 16 mo). The retrieved xenografts were evaluated for seminiferous tubular density, tubular diameter, seminiferous tubular morphology, and identification of the most advanced germ cell type. Overall, 69% of the grafted testis fragments were recovered as xenografts. Xenografts weight increased (P < 0.02) approximately four-fold by 2 mo and 10-fold by 16 mo post grafting. In testis xenografts, gradual maturational changes were evident, manifested as the first detection of the following at the times specified: seminiferous tubule expansion, 2 mo; spermatocytes, 6 mo; round spermatids, 12 mo; and elongated spermatids, 16 mo. Furthermore, there were differences between the two donor calves regarding the efficiency of spermatogenesis in xenografts. The timing of complete spermatogenesis approximately corresponded to the reported timing of sexual maturation in bison. This study demonstrated, apparently for the first time, that testis tissue xenografting from neonatal bison donors into recipient mice resulted in testicular maturation and complete development of spermatogenesis in the grafts. PMID- 21529913 TI - Clinical implications of induced twin reduction in dairy cattle. AB - Embryo reduction may prevent the negative effects of twinning in dairy cattle; however, the technique may carry an additional risk of pregnancy loss. The aim of this study was to evaluate the effect on pregnancy maintenance of embryo reduction by manual amnion rupture in unilateral and bilateral twin pregnant cows. A secondary objective was to examine the dynamics of endocrine factors following the treatment. On Day 35-41 of gestation 55 cows bearing two live twin embryos (28 bilateral, 27 unilateral) were randomly assigned to a twin reduction group (n = 27; cows fitted with a progesterone releasing intra-vaginal device for 21 days after manual amnion rupture) or control group (n = 28; untreated cows). Pregnancy loss before Day 90 was recorded in nine control and eleven twin reduction cows (32.1% vs 40.7%, respectively, p = 0.508). Logistic regression models indicated that laterality was the only variable significantly affecting pregnancy loss. The pregnancy loss risk was 8.7 times higher for unilateral than for bilateral twin pregnancies (59.3% vs 14.3%, respectively, P < 0.001) yet was similar in the unilateral control and unilateral twin reduction cows (62.3% vs 53.8%, respectively, P = 0.581). In contrast, four of 14 cows with bilateral twin pregnancies undergoing twin reduction lost their pregnancies while no losses were recorded in control cows with bilateral pregnancies (P = 0.049). A rise in plasma progesterone concentration was detected on the day following treatment in the twin reduction group and concentrations remained high within the first week of treatment. Plasma pregnancy-associated glycoprotein-1 (PAG-1) concentrations fell between Day 35-41 and Day 42-48, regardless of treatment. Our findings indicate that embryo reduction by manual amnion rupture did not carry an additional risk of pregnancy loss for unilateral twin pregnancies, whereas it increased the risk of pregnancy failure in bilateral twin pregnancies. However, benefits of preventing cows from delivering twins might also be considered when assessing the success of embryo reduction in bilateral twin pregnancies. PMID- 21529914 TI - Presence and distribution of fungi and bacteria in the reproductive tract of healthy stallions. AB - A saprophytic bacterial flora is present on the penis and the distal part of the urethra of stallions. Little is known about the fungal flora of their reproductive tract. As micro organisms play an important role in mares fertility, the aim of the study was to describe the distribution of fungi and bacteria in the normal genital apparatus of stallions. The microbic flora of the reproductive tract of 11 healthy, fertile stallions was evaluated, collecting samples from 5 different locations: urethral fossa, penis/internal lamina of the prepuce, urethra pre- and post-ejaculation, and semen. For fungal examination samples were taken on 3 different occasions (N = 165), while for bacteriologic examination samples were taken on one occasion only (N = 55). There was a statistical difference in the presence of filamentous fungi between urethral fossa or penis/prepuce (45.4%) and urethra pre- or postejaculation or semen (15.1%, 6.0%, and 0.0%, respectively). Yeasts were isolated in 9.1% of the samples, never in semen. The most represented mycelial fungi were Penicillium spp., Aspergillus spp., Scopulariopsis spp., Trichosporon spp. and Mucoracee. The proportion of samples showing a total bacterial count >= 10,000 colony forming units (CFU) was higher for urethral fossa than for urethra pre- or postejaculation or for semen. Some bacterial growth was always observed in all locations, including the ejaculate. Differences between sampling locations were observed also for Staphylococci, both coagulase positive and negative. Salmonella enterica Abortus equi and sulphite reducing clostridia and other pathogens (including Klebsiella spp. and Pseudomonas spp.) were never isolated. Escherichia coli and coliforms always showed a low or absent flora. These data add information to the literature. PMID- 21529915 TI - Incidence of X-Y aneuploidy in sperm of two indigenous cattle breeds by using dual color fluorescent in situ hybridization (FISH). AB - The present study reports on the incidence of X-Y aneuploidy in the sperm population of two indigenous cattle breeds reared in Italy for beef purposes, the Podolian and Maremmana. Totally, more than 50 000 sperm nuclei from 10 subjects (5 from each breed) have been fluorescent in situ hybridization (FISH) analyzed by using Xcen- and Y-chromosome-specific painting probes. In both breeds, the fraction of Y-bearing sperm was significantly higher (P < 0.01) compared with the X-counterpart. The rates of X-Y aneuploidy were 0.180% and 0.200%, respectively, in the Podolian and Maremmana. No significant interindividual differences were found. Average frequencies of disomic and diploid sperm were 0.149% and 0.031% in the former and 0.098% and 0.102% in the latter. Significant differences (P < 0.05) were found among the XX-XY and YY-disomy classes in both breeds, while diploidy classes were uniformly represented. In the Podolian breed, disomies were more frequent than diploidies (P < 0.05), whereas in the Maremmana they showed similar frequencies. In both breeds disomies arising from errors in meiosis I (X Y disomies) were more represented than those arising in meiosis II (XX and YY), while this difference was not detected for diploidies. The present study provides specific information on the incidence of X-Y sperm aneuploidy in two indigenous breeds of cattle, in order to establish a breed-specific 'aneuploidy data-base' that could be used as reference for genetic improvement and future monitoring of the reproductive health of the breed. PMID- 21529916 TI - Association of CRISP2, CCT8, PEBP1 mRNA abundance in sperm and sire conception rate in Holstein bulls. AB - The objective was to determine the association of mRNA expression of cystine rich secretary protein 2 (CRISP2), chaperonin containing T-complex protein 1, subunit 8 (CCT8), and phosphatidylethanolamine-binding protein 1 (PEBP1), in sperm of Holstein bulls with Sire Conception Rate (SCR) scores between -4 and +4. These proteins were involved in sperm capacitation and sperm-egg fusion. Samples of sperm obtained on a single day from Holstein bulls (N = 34) in a commercial AI centre were used to evaluate relative mRNA expression of CRISP2, CCT8, and PEBP1. The mRNA abundance of CRISP2 was positively correlated (r = 0.88; P < 0.002), CCT8 was negatively correlated (r = -0.87; P < 0.002), and PEBP1 was positively correlated (r = 0.83; P < 0.006) with SCR-scores. The means of CRISP2 mRNA abundance was greater among positive SCR-score bulls (2.5 to 8 fold), the means of CCT8 mRNA abundance was greater among the negative SCR-score bulls (9.5 to 3.5 fold), and the means of PEBP1 mRNA abundance was greater for the positive SCR score bulls (5.4 to 7.7 fold). In multivariate regression models predicting SCR scores, mRNA abundance of CCT8 was significantly associated with SCR-score in all models. In the presence of CRISP2 mRNA abundance in the model, the SCR score's predictability of PEBP1 was insignificant. However, in the absence of CRISP2 mRNA abundance in the model, the SCR-score's predictability of PEBP1 was significant. In multivariate regression models, CRISP2 and CCT8 mRNA expression in sperm accounted for 95% of the variance in Holstein bull's SCR-scores. In conclusion, Holstein bulls with greater CRISP2 and lower CCT8 mRNA expression in sperm had higher probabilities of siring calves. PMID- 21529917 TI - Effects of antioxidants and duration of pre-freezing equilibration on frozen thawed ram semen. AB - The objective was to evaluate the effects of various antioxidants and duration of pre-freezing equilibration on cryopreservation of ram semen. Semen samples from four rams were pooled, diluted with Tris-egg yolk extender without antioxidants (control), or supplemented with reduced glutathione (GSH: 0.5, 1.0, and 2.0 mM), superoxide dismutase (SOD: 5, 10, and 20 U/mL), or catalase (CAT: 5, 10, and 20 U/mL), and cryopreserved, immediately after thermal equilibrium was reached at 5 degrees C (0 h), or 12 or 24 h after equilibration. Total antioxidant capacity was determined in the in natura extenders and after addition of semen samples for various durations of processing (fresh/dilute, throughout refrigeration, and post thaw). Plasma membrane (PI-CFDA), acrosome integrity (FITC-PNA), and mitochondrial membrane potential (JC-1) were determined in fresh/diluted, refrigerated, and post-thaw samples. Post-thaw sperm motility was assessed with a computerized analysis system (CASA). There were no significant differences in acrosome damage or mitochondrial membrane potential after refrigeration and freeze-thaw, regardless of antioxidant addition. Sperm plasma membrane integrity was worse (P < 0.05) with cryopreservation immediately after equilibration (average 20.1 +/- 8.3; mean +/- SD) than after 12 h of equilibration (average 42.5 +/- 10.9); however, the addition of SOD and CAT (10 and 20 U/mL) resulted in no significant difference between post-equilibration intervals of 0 and 12 h. Total antioxidant activity was not different (P > 0.05) among treatments after sperm addition or throughout the refrigeration and post-thaw. In conclusion, adding GSH, SOD or CAT did not increase the total antioxidant capacity of semen, nor did it enhance the quality of the post-thaw sperm. However, maintenance of ram semen at 5 degrees C for 12 h prior to cryopreservation reduced membrane damage of frozen-thawed sperm. PMID- 21529918 TI - Low plasma progesterone concentrations are accompanied by reduced luteal blood flow and increased size of the dominant follicle in dairy cows. AB - To investigate the influence of low plasma progesterone (P(4)) concentrations on luteal and ovarian follicular development as well as endometrial gene expression in the concomitant and subsequent estrous cycle, 20 lactating dairy (Holstein Friesian and Brown Swiss x Holstein Friesian) cows received either a single treatment with 25 mg prostaglandin F(2alpha) (PGF(2alpha)) on Day 4 Hour 12 (PG1; n = 8), or two treatments (25 mg PGF(2alpha) each) on Day 4 Hours 0 and 12 (PG2; n = 12) of the estrous cycle (Day 1, Hour 0 = ovulation). In four cows, ovulation occurred between 4 and 6 d after the second PGF(2alpha) treatment; these cows and one lame cow were excluded. In the 15 remaining cows with physiological interovulatory intervals (18 to 24 d), P(4), luteal size (LS) and blood flow (LBF), as well as follicular size (FS) and blood flow (FBF), were determined daily until Day 4, immediately prior to (0 h) and 12 h after each PGF(2alpha) treatment, and then every 2 d, from Day 5 to 8 d after the subsequent ovulation. Because P(4) did not differ (P > 0.05) between PG1 and PG2, cows were regrouped according to their mean P(4) concentration from Days 7 to 15, either P(4) <2 ng/mL (P(4)L; n = 7) or P(4) >2 ng/mL (P(4)H; n = 8). In the treatment cycle, LS was smaller in P(4)L than P(4)H on Days 13 (P = 0.01) and 15 (P = 0.03), and LBF was lower in P(4)L than P(4)H on Day 15 (P = 0.02). The dominant follicle of the first follicular wave was larger in P(4)L than P(4)H on Days 13 (P = 0.03), 15 (P = 0.03), and 17 (P = 0.01). In the subsequent cycle, there were no significant differences between P(4)L and P(4)H for P(4), FS, LS, and LBF; however, FBF was lower (P = 0.01) in P(4)L than P(4)H on Day 7. In Group P(4)L, endometrial expressions of estrogen receptor alpha and oxytocin receptor were lower (P = 0.05 and P = 0.03, respectively) at the estrus that preceded treatment compared to the post-treatment estrus. In summary, low P(4) during diestrus was associated with smaller LS, reduced LBF, and larger FS in the treatment cycle, but not in the subsequent cycle. PMID- 21529919 TI - Standardization of computer-assisted semen analysis using an e-learning application. AB - Computer-assisted semen analysis (CASA) is primarily used to obtain accurate and objective kinetic sperm measurements. Additionally, AI centers use computer assessed sperm concentration in the sample as a basis for calculating the number of insemination doses available from a given ejaculate. The reliability of data is often limited and results can vary even when the same CASA systems with identical settings are used. The objective of the present study was to develop a computer-based training module for standardized measurements with a CASA system and to evaluate its training effect on the quality of the assessment of sperm motility and concentration. A digital versatile disc (DVD) has been produced showing the standardization of sample preparation and analysis with the CASA system SpermVisionTM version 3.0 (Minitube, Verona, WI, USA) in words, pictures, and videos, as well as the most probable sources of error. Eight test persons educated in spermatology, but with different levels of experience with the CASA system, prepared and assessed 10 aliquots from one prediluted bull ejaculate using the same CASA system and laboratory equipment before and after electronic learning (e-learning). After using the e-learning application, the coefficient of variation was reduced on average for the sperm concentration from 26.1% to 11.3% (P <= 0.01), and for motility from 5.8% to 3.1% (P <= 0.05). For five test persons, the difference in the coefficient of variation before and after use of the e-learning application was significant (P <= 0.05). Individual deviations of means from the group mean before e-learning were reduced compared with individual deviations from the group mean after e-learning. According to a survey, the e learning application was highly accepted by users. In conclusion, e-learning presents an effective, efficient, and accepted tool for improvement of the precision of CASA measurements. This study provides a model for the standardization of other laboratory procedures using e-learning. PMID- 21529920 TI - Vitrification and transfer of cynomolgus monkey (Macaca fascicularis) embryos fertilized by intracytoplasmic sperm injection. AB - Protocols for cryopreservation of monkey embryos are not well established. The objective of the current study was to determine the efficacy of the polypropylene strip method for cryopreserving cynomolgus monkey embryos. Cynomolgus monkey embryos, 63 and 56 at the 4- to 8-cell and 56 blastocyst stages, respectively, were produced by intracytoplasmic sperm injection and in vitro culture, and vitrified using a polypropylene strip. For these two stages, 95 and 86% survived after thawing and pregnancy rates were 29.2% (7 pregnant females/24 recipients, with three live births) and 0% (n = 16 recipients). These were apparently the first live births obtained from embryos fertilized by ICSI. In conclusion, 4- to 8-cell preimplantation cynomolgus monkey embryos were successfully cryopreserved using a polypropylene strip. PMID- 21529921 TI - Major morphological sperm abnormalities in the bull are related to sperm DNA damage. AB - The influence of sperm morphology and chromatin integrity on bull fertility suggests a strong but undefined biological relationship between these two parameters. In this study we explore this relationship, making use of the Sperm Chromatin Dispersion test, which allows simultaneous observation of sperm abnormalities and DNA fragmentation. Based on spermatozoa from 17 Holstein Friesian bulls, we determined a relationship between DNA fragmentation and the presence of the "so called" major-type sperm defects. Values for DNA fragmentation index (mean +/- SEM) calculated from cells with major-type abnormalities were significantly (P < 0.05) higher (85.05 +/- 5.00%) than those from abnormal forms classified as minor-type (17.89 +/- 5.55%). Some of the sperm abnormalities, such as double forms, narrow base heads, small heads, shortened tails and proximal cytoplasmic droplets, were only associated with sperm showing fragmented DNA. The simultaneous assessment of sperm morphology and DNA fragmentation has the potential to improve the efficacy of sperm quality assessment in this species. PMID- 21529922 TI - Development of the foremost light-curable calcium-silicate MTA cement as root-end in oral surgery. Chemical-physical properties, bioactivity and biological behavior. AB - AIM: An innovative light-curable calcium-silicate cement containing a HEMA-TEGDMA based resin (lc-MTA) was designed to obtain a bioactive fast setting root-end filling and root repair material. METHODS: lc-MTA was tested for setting time, solubility, water absorption, calcium release, alkalinizing activity (pH of soaking water), bioactivity (apatite-forming ability) and cell growth proliferation. The apatite-forming ability was investigated by micro-Raman, ATR FTIR and ESEM/EDX after immersion at 37 degrees C for 1-28 days in DPBS or DMEM+FBS. The marginal adaptation of cement in root-end cavities of extracted teeth was assessed by ESEM/EDX, and the viability of Saos-2 cell on cements was evaluated. RESULTS: lc-MTA demonstrated a rapid setting time (2min), low solubility, high calcium release (150-200ppm) and alkalinizing power (pH 10-12). lc-MTA proved the formation of bone-like apatite spherulites just after 1 day. Apatite precipitates completely filled the interface porosities and created a perfect marginal adaptation. lc-MTA allowed Saos-2 cell viability and growth and no compromising toxicity was exerted. SIGNIFICANCE: HEMA-TEGDMA creates a polymeric network able to stabilize the outer surface of the cement and a hydrophilic matrix permeable enough to allow water absorption. SiO(-)/Si-OH groups from the mineral particles induce heterogeneous nucleation of apatite by sorption of calcium and phosphate ions. Oxygen-containing groups from poly-HEMA TEGDMA provide additional apatite nucleating sites through the formation of calcium chelates. The strong novelty was that the combination of a hydraulic calcium-silicate powder and a poly-HEMA-TEGDMA hydrophilic resin creates the conditions (calcium release and functional groups able to chelate Ca ions) for a bioactive fast setting light-curable material for clinical applications in dental and maxillofacial surgery. The first and unique/exclusive light-curable calcium silicate MTA cement for endodontics and root-end application was created, with a potential strong impact on surgical procedures. PMID- 21529923 TI - Nanofilled and microhybrid composite restorations: Five-year clinical wear performances. AB - OBJECTIVES: To compare the clinical wear performance of nanofilled restorations (Filtek Supreme) against microhybrid restorations (Z100) in a 5-year randomized clinical trial to evaluate the wear rate and the influence of subject-, operator- and restoration-related variables on wear rate. MATERIALS AND METHODS: 18 Filtek Supreme and 17 Z100 restorations were placed in human molars (split-mouth-model) and bonded with Single Bond/Scotch Bond Adhesive. Restorations were recalled at baseline, 6-, 12-months and at annual intervals until 5-years of clinical service. The gypsum replicas at each recall were used for 3D-Pro-laser scanning to quantify wear and the epoxy resin replicas were observed under SEM for microwear patterns. Linear-mixed-models were used to study the influence of the different variables on the vertical and volume loss. RESULTS: Volume wear, but not the vertical wear rate of the two restorative materials were significantly influenced (p<0.05) by the factors such as operator, cavity type, as well as combination of operator-cavity type and quadrant type. The variations in the occlusal surface microwear patterns over time reflect the effect of biomechanics of mastication on the restorative composite. CONCLUSIONS: The rate of vertical and volume loss of both the restoratives appear, on average, not to be constant even after the early stage wear, under the influence of certain clinical variables. PMID- 21529924 TI - Mechanical properties of denture base resin cross-linked with methacrylated dendrimer. AB - OBJECTIVES: The aim of this study was to investigate the mechanical properties of denture base resin cross-linked with methacrylated dendrimer. METHODS: The test specimens (3 mm * 10 mm * 65 mm) were fabricated from autopolymerizing resin with the powder/liquid ratio of 10 g/7 ml. The monomer liquid of resin was applied with the mixture of methylmethacrylate and crosslinker dendrimer (DD1) or crosslinker ethyleneglycol dimethacrylate (EGDMA) with five different volume percentages (vol%). The dendrimer crosslinker in this study is a methacrylated molecule (MW=3617 g/mol) with 12 methacrylate groups. Quantity of crosslinkers varied from 1.1 to 9.1 vol%. The specimens (n=8/group) were polymerized in distilled water maintained at 55 degrees C under pressure of 0.4 MPa for 20 min. Test specimens were stored dry at room temperature before testing. The flexural strength (MPa) and flexural modulus (GPa) was measured with three-point bending test at a crosshead speed of 5mm/min. Surface microhardness (MHN) of matrix area of polymer (n=8/group) was measured with a load of 245.3 mN by 10s. Data were analyzed with two-way ANOVA. RESULTS: ANOVA showed that the addition of DD1 had a significantly higher effect (p<0.05) on flexural modulus and hardness of matrix area than EGDMA but on flexural strength (p>0.05). The effect of quantity differences of crosslinker was statistically significant only on flexural strength (p<0.05). SIGNIFICANCE: The results of this study suggest that dendrimer crosslinked resin gives better stiffness than that of EGDMA. PMID- 21529925 TI - "We don't need no education": Video game preferences, video game motivations, and aggressiveness among adolescent boys of different educational ability levels. AB - This research focuses on low educational ability as a risk factor for aggression and violent game play. We propose that boys of lower educational ability are more attracted to violent video games than other boys are, and that they are also higher in trait aggressiveness and sensation seeking. Participants were Dutch boys in public schools (N = 830, age-range 11-17). In the Netherlands, standardized tests are used to place students into lower, medium, and higher educational ability groups. Results showed that boys in the lower educational ability group preferred to play violent, stand-alone games, identified more with video game characters, and perceived video games to be more realistic than other boys did. Lower levels of education were also related to higher levels of aggressiveness and sensation seeking. Higher educational ability boys preferred social, multiplayer games. Within a risk and resilience model, boys with lower educational ability are at greater risk for aggression. PMID- 21529926 TI - Primary biliary cirrhosis. AB - Primary biliary cirrhosis is a chronic liver disease characterised by intrahepatic bile-duct destruction, cholestasis, and, in some cases, cirrhosis. Evidence supporting the autoimmune nature of this disorder includes the appearance of highly specific antimitochondrial antibodies (AMAs) and autoreactive T cells. Concordance rates in monozygotic twins, familial prevalence, and genetic associations underscore the importance of genetic factors, whereas findings of epidemiological studies and murine models suggest a possible role for exogenous chemicals and infectious agents through molecular mimicry. The incidence of primary biliary cirrhosis has increased over recent decades, possibly attributable to augmented testing of liver biochemistry rather than a rise in disease incidence. AMAs remain the hallmark of diagnosis in most cases and allow detection of asymptomatic patients. Symptomatic individuals usually present with either pruritus or fatigue and, more rarely, with either jaundice or complications of cirrhosis. The prognosis of primary biliary cirrhosis has improved because of early diagnosis and use of ursodeoxycholic acid, the only established medical treatment for this disorder. Although not a cure, treatment can slow disease progression and delay the need for liver transplantation. However, some patients do not respond adequately to ursodeoxycholic acid and might need alternative therapeutic approaches. PMID- 21529927 TI - Efficacy of stapler versus hand-sewn closure after distal pancreatectomy (DISPACT): a randomised, controlled multicentre trial. AB - BACKGROUND: The ideal closure technique of the pancreas after distal pancreatectomy is unknown. We postulated that standardised closure with a stapler device would prevent pancreatic fistula more effectively than would a hand-sewn closure of the remnant. METHODS: This multicentre, randomised, controlled, parallel group-sequential superiority trial was done in 21 European hospitals. Patients with diseases of the pancreatic body and tail undergoing distal pancreatectomy were eligible and were randomly assigned by central randomisation before operation to either stapler or hand-sewn closure of the pancreatic remnant. Surgical performance was assessed with intraoperative photo documentation. The primary endpoint was the combination of pancreatic fistula and death until postoperative day 7. Patients and outcome assessors were masked to group assignment. Interim and final analysis were by intention to treat in all patients in whom a left resection was done. This trial is registered, ISRCTN18452029. FINDINGS: Between Nov 16, 2006, and July 3, 2009, 450 patients were randomly assigned to treatment groups (221 stapler; 229 hand-sewn closure), of whom 352 patients (177 stapler, 175 hand-sewn closure) were analysed. Pancreatic fistula rate or mortality did not differ between stapler (56 [32%] of 177) and hand-sewn closure (49 [28%] of 175; OR 0.84, 95% CI 0.53-1.33; p=0.56). One patient died within the fi rst 7 days after surgery in the hand-sewn group; no deaths occurred in the stapler group. Serious adverse events did not differ between groups. INTERPRETATION: Stapler closure did not reduce the rate of pancreatic fistula compared with hand-sewn closure for distal pancreatectomy. New strategies, including innovative surgical techniques, need to be identified to reduce this adverse outcome. FUNDING: German Federal Ministry of Education and Research. PMID- 21529928 TI - Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. AB - BACKGROUND: Opioid dependence is associated with low rates of treatment-seeking, poor adherence to treatment, frequent relapse, and major societal consequences. We aimed to assess the efficacy, safety, and patient-reported outcomes of an injectable, once monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) for treatment of patients with opioid dependence after detoxification. METHODS: We did a double-blind, placebo-controlled, randomised, 24-week trial of patients with opioid dependence disorder. Patients aged 18 years or over who had 30 days or less of inpatient detoxification and 7 days or more off all opioids were enrolled at 13 clinical sites in Russia. We randomly assigned patients (1:1) to either 380 mg XR-NTX or placebo by an interactive voice response system, stratified by site and gender in a centralised, permuted block method. Participants also received 12 biweekly counselling sessions. Participants, investigators, staff , and the sponsor were masked to treatment allocation. The primary endpoint was the response profile for confirmed abstinence during weeks 5-24, assessed by urine drug tests and self report of non use. Secondary endpoints were self-reported opioid-free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00678418. FINDINGS: Between July 3, 2008, and Oct 5, 2009, 250 patients were randomly assigned to XR-NTX (n=126) or placebo (n=124). The median proportion of weeks of confirmed abstinence was 90.0% (95% CI 69.9-92.4) in the XR-NTX group compared with 35.0% (11.4-63.8) in the placebo group (p=0.0002). Patients in the XR-NTX group self-reported a median of 99.2% (range 89.1-99.4) opioid-free days compared with 60.4% (46.2-94.0) for the placebo group (p=0.0004). The mean change in craving was -10.1 (95% CI -12.3 to -7.8) in the XR NTX group compared with 0.7 (-3.1 to 4.4) in the placebo group (p<0.0001). Median retention was over 168 days in the XR-NTX group compared with 96 days (95% CI 63 165) in the placebo group (p=0.0042). Naloxone challenge confirmed relapse to physiological opioid dependence in 17 patients in the placebo group compared with one in the XR-NTX group (p<0.0001). XR-NTX was well tolerated. Two patients in each group discontinued owing to adverse events. No XR-NTX-treated patients died, overdosed, or discontinued owing to severe adverse events. INTERPRETATION: XR-NTX represents a new treatment option that is distinct from opioid agonist maintenance treatment. XR-NTX in conjunction with psychosocial treatment might improve acceptance of opioid dependence pharmacotherapy and provide a useful treatment option for many patients. FUNDING: Alkermes. PMID- 21529929 TI - DISPACT trial: what do we learn from equivalency? PMID- 21529930 TI - Concerns about injectable naltrexone for opioid dependence. PMID- 21529931 TI - An injectable calcium phosphate cement for the local delivery of paclitaxel to bone. AB - Bone metastases are usually treated by surgical removal, fixation and chemotherapeutic treatment. Bone cement is used to fill the resection voids. The aim of this study was to develop a local drug delivery system using a calcium phosphate cement (CPC) as carrier for chemotherapeutic agents. CPC consisted of alpha-tricalcium phosphate, calcium phosphate dibasic and precipitated hydroxyapatite powders and a 2% Na(2)HPO(4) hardening solution. Scanning electron microscopy (SEM) was used to observe CPC morphology. X-ray diffraction (XRD) was used to follow CPC transformation. The loading/release capacity of the CPC was studied by a bovine serum albumin-loading model. Release/retention was measured by high performance liquid chromatography and X-ray photoelectron spectrometry. For chemotherapeutic loading, paclitaxel (PX) was loaded onto the CPC discs by absorption. Viability of osteosarcoma U2OS and metastatic breast cancer MDA-MB 231 cells was measured by an AlamarBlue assay. Results of SEM and XRD showed changes in CPC due to its transformation. The loading model indicated a high retention behavior by the CPC composition. Cell viability tests indicated a PX minimal lethal dose of 90 MUg/ml. PX released from CPC remained active to influence cell viability. In conclusion, this study demonstrated that CPC is a feasible delivery vector for chemotherapeutic agents. PMID- 21529932 TI - The binding affinity of anti-Abeta1-42 MAb-decorated nanoliposomes to Abeta1-42 peptides in vitro and to amyloid deposits in post-mortem tissue. AB - Amyloid beta (Abeta) aggregates are considered as possible targets for therapy and/or diagnosis of Alzheimer disease (AD), and nanoparticles functionalized with Abeta-specific ligands are considered promising vehicles for imaging probes and therapeutic agents. Herein, we characterized the binding properties of nanoliposomes decorated with an anti-Abeta monoclonal antibody (Abeta-MAb). The Abeta-MAb was obtained in mice by immunization with Abeta antigen followed by hybridoma fusion. Surface Plasmon Resonance (SPR) studies confirmed the very high affinity of purified Abeta-MAb for both Abeta monomers and fibrils (K(D) = 0.08 and 0.13 nm, respectively). The affinity of the biotinylated Abeta-MAb, used thereafter for liposome decoration, was lower although still in the low nanomolar range (K(D) = 2.1 and 1.6 nm, respectively). Biotin-streptavidin ligation method was used to decorate nanoliposomes with Abeta-MAb, at different densities. IgG decorated liposomes were generated by the same methodology, as control. Vesicles were monodisperse with mean diameters 124-134 nm and demonstrated good colloidal stability and integrity when incubated with serum proteins. When studied by SPR, Abeta-MAb-liposomes, but not IgG-liposomes, markedly bound to Abeta monomers and fibrils, immobilized on the chip. K(D) values (calculated on Abeta-MAb content) were about 0.5 and 2 nm with liposomes at high and low Abeta-MAb density, respectively. Abeta-MAb-liposome binding to Abeta fibrils was additionally confirmed by ultracentrifugation technique, in which interactions occur in solution under physiological conditions. Moreover, Abeta-MAb-liposomes bound amyloid deposits in post-mortem AD brain samples, confirming the potential of these nanoparticles for the diagnosis and therapy of AD. PMID- 21529933 TI - Microstructure design of biodegradable scaffold and its effect on tissue regeneration. AB - Biodegradable scaffolds play a critical role in therapeutic tissue engineering, in which the matrix degradation and tissue ingrowth are of particular importance for determining the ongoing performance of tissue-scaffold system during regenerative process. This paper aims to explore the mechanobiological process within biodegradable scaffolds, where the representative volume element (RVE) is extracted from periodic scaffold micro-architectures as a base-cell design model. The degradation of scaffold matrix is modeled in terms of a stochastic hydrolysis process enhanced by diffusion-controlled autocatalysis; and the tissue ingrowth is modeled through the mechano-regulatory theory. By using the finite element based homogenization technique and topology optimization approach, the effective properties of various periodic scaffold structures are obtained. To explore the effect of scaffold design on the mechanobiological evolutions of tissue-scaffold systems, different scaffold architectures are considered for polymer degradation and tissue regeneration. It is found that the different tissues can grow into the degraded voids inside the polymer matrix. It is demonstrated that the design of scaffold architecture has a considerable impact on the tissue regeneration outcome, which exhibits the importance of implementing different criteria in scaffold micro-structural design, before being fabricated via rapid prototyping technique, e.g. solid free-form fabrication (SFF). This study models such an interactive process of scaffold degradation and tissue growth, thereby providing some new insights into design of biodegradable scaffold micro-architecture for tissue engineering. PMID- 21529935 TI - Thermoresponsive nanostructured polycarbonate block copolymers as biodegradable therapeutic delivery carriers. AB - Water-soluble, thermoresponsive block copolymers based on a biodegradable platform were synthesized by the ring opening polymerization of cyclic carbonate monomers functionalized with hydrophilic and hydrophobic groups for application as nanocarriers in medicine. The approach based on cyclic carbonate monomers derived from 2,2-bis(methylol)propionic acid (bis-MPA) allowed a simple and versatile route to functional monomers capable of undergoing ring opening polymerization (ROP). The resulting polymers possessed the predicted molecular weights based on the molar ratio between monomers to initiators and the narrow molecular weight distributions. Transmittance measurement for aqueous polymer solutions provided an evidence for temperature-responsiveness with lower critical solution temperature (LCST) in the range of 36 degrees C-60 degrees C, depending on the molecular weight of hydrophilic poly(ethylene glycol) (PEG) chains, compositions of copolymers, molar ratios of hydrophilic to hydrophobic monomers in the corona, and the hydrophobic core. This study showed synthetic advancement toward the design and preparation of biodegradable thermoresponsive polymers with extremely low CMC values for injectable drug delivery systems. TRC350-10,30,60, which possessed an LCST of 36 degrees C in PBS, was identified as a useful model polymer. Paclitaxel, an anti-cancer drug, was loaded into the micelles efficiently, giving rise to nano-sized particles with a narrow size distribution. Paclitaxel release from the micelles was faster, and cellular uptake of the micelles was higher at the body temperature (i.e. 37 degrees C) as compared to a temperature below the LCST. While the polymer was not cytotoxic, paclitaxel-loaded micelles killed HepG2 human liver carcinoma cells more efficiently at the body temperature as compared to free paclitaxel and paclitaxel loaded micelles at the temperature below the LCST. These micelles are ideally suited to deliver anti-cancer drugs to tumor tissues through local injection. PMID- 21529934 TI - Delineating the roles of the GPIIb/IIIa and GP-Ib-IX-V platelet receptors in mediating platelet adhesion to adsorbed fibrinogen and albumin. AB - Platelet adhesion to adsorbed plasma proteins, such as fibrinogen (Fg), has been conventionally thought to be mediated by the GPIIb/IIIa receptor binding to Arg Gly-Asp (RGD)-like motifs in the adsorbed protein. In previous studies, we showed that platelet adhesion response to adsorbed Fg and Alb was strongly influenced by the degree of adsorption-induced protein unfolding and that platelet adhesion was only partially blocked by soluble RGD, with RGD-blocked platelets adhering without activation. Based on these results, we hypothesized that in addition to the RGD-specific GPIIb/IIIa receptor, which mediates both adhesion and activation, a non-RGD-specific receptor set likely also plays a role in platelet adhesion (but not activation) to both Fg and albumin (Alb). To identify and elucidate the role of these receptors, in addition to GPIIb/IIIa, we also examined the GPIb-IX-V receptor complex, which has been shown to mediate platelet adhesion (but not activation) in studies by other groups. The platelet suspension was pretreated with either a GPIIb/IIIa-antagonist drug Aggrastat((r)) or monoclonal antibodies 6B4 or 24G10 against GPIb-IX-V prior to adhesion on Fg- and Alb-coated OH- and CH(3)-functionalized alkanethiol self-assembled monolayer surfaces. The results revealed that GPIIb/IIIa is the primary receptor set involved in platelet adhesion to adsorbed Fg and Alb irrespective of their degree of adsorption-induced unfolding, while the GPIb-IX-V receptor complex plays an insignificant role. Overall, these studies provide novel insights into the molecular-level mechanisms mediating platelet interactions with adsorbed plasma proteins, thereby assisting the biomaterials field develop potent strategies for inhibiting platelet-protein interactions in the design of more hemocompatible cardiovascular biomaterials and effective anti-thrombotic therapies. PMID- 21529936 TI - The effect of polymer architecture, composition, and molecular weight on the properties of glycopolymer-based non-viral gene delivery systems. AB - Although a variety of non-viral gene delivery vectors has been synthesized and used for gene delivery purposes, well-defined glycopolymer-based gene delivery carriers is not well explored. Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization technique allows successful and facile synthesis of cationic glycopolymers containing pendant sugar moieties in the absence of protecting group chemistry. A library of cationic glycopolymers of pre-determined molar masses and narrow polydispersities ranging from 3 to 30 kDa has been synthesized using RAFT polymerization technique. These polymers differ from each other in their architectures (block versus random), molecular weights, and monomer ratios (carbohydrate to cationic segment). It is shown that the above mentioned parameters can largely affect the toxicity, DNA condensation ability and gene delivery efficacy of these polymers. Statistical copolymers of high degree of polymerization are found to be the ideal vector for gene delivery purposes. These statistical copolymers show lower toxicity and higher gene expression in the presence and absence of serum, as compared to the corresponding diblock copolymers. This is the first example of well-defined synthetic glycopolymers as DNA carriers that works both in the presence and absence of serum proteins. The critical composition of carbohydrate segment in copolymers for enhanced gene delivery and low toxicity was determined and an increase in carbohydrate residues in copolymers resulted in a decrease in transfection efficiencies of these polymers. The effect of serum proteins on statistical and diblock copolymer based polyplexes and hence gene delivery efficacy was studied. The results showed that the diblock copolymer-based polyplexes showed lower interactions with serum proteins, lower cellular uptake and very low gene expression in both Hep G2 and Hela cells in comparison to statistical copolymers. PMID- 21529937 TI - The promotion of cerebral ischemia recovery in rats by laminin-binding BDNF. AB - Brain-derived neurotrophic factor (BDNF) has been shown to have therapeutic effects on cerebral ischemia. However, the delivery approach limits its application. Laminin is a rich extra cellular matrix in the central nervous system, and is highly expressed in the ischemic region after cerebral ischemia. We reported here by fusing with laminin-binding domain (LBD) to BDNF to construct laminin-binding BDNF (LBD-BDNF). LBD-BDNF could target accumulated laminin in the ischemic region and exert targeting therapy of injured neurons after ischemia. We examined the laminin-binding ability and neurotrophic bioactivity of LBD-BDNF in vitro, and assessed its targeting therapy using a rat permanent middle cerebral artery occlusion (MCAO) model in vivo. It was found that LBD-BDNF could specifically bind to laminin and maintain BDNF activity both in vitro and in vivo. LBD-BDNF treatment attenuated neural-degeneration after MCAO, and also resulted in a reduction of infarct volume that is associated with a parallel improvement in neurological functional outcome and neurogenesis in the dentate gyrus of hippocamp. PMID- 21529938 TI - Analysis of CaM-kinase signaling in cells. AB - A change in intracellular free calcium is a common signaling mechanism that modulates a wide array of physiological processes in most cells. Responses to increased intracellular Ca(2+) are often mediated by the ubiquitous protein calmodulin (CaM) that upon binding Ca(2+) can interact with and alter the functionality of numerous proteins including a family of protein kinases referred to as CaM-kinases (CaMKs). Of particular interest are multifunctional CaMKs, such as CaMKI, CaMKII, CaMKIV and CaMKK, that can phosphorylate multiple downstream targets. This review will outline several protocols we have used to identify which members and/or isoforms of this CaMK family mediate specific cellular responses with a focus on studies in neurons. Many previous studies have relied on a single approach such as pharmacological inhibitors or transfected dominant negative kinase constructs. Since each of these protocols has its limitations, that will be discussed, we emphasize the necessity to use multiple, independent approaches in mapping out cellular signaling pathways. PMID- 21529940 TI - Flow cytometry in myelodysplastic syndromes: ready for translation into clinical practice. PMID- 21529939 TI - The endo-lysosomal system as an NAADP-sensitive acidic Ca(2+) store: role for the two-pore channels. AB - Accumulating evidence suggests that the endo-lysosomal system provides a substantial store of Ca(2+) that is tapped by the Ca(2+)-mobilizing messenger, NAADP. In this article, we review evidence that NAADP-mediated Ca(2+) release from this acidic Ca(2+) store proceeds through activation of the newly described two-pore channels (TPCs). We discuss recent advances in defining the sub-cellular targeting, topology and biophysics of TPCs. We also discuss physiological roles and the evolution of this ubiquitous ion channel family. PMID- 21529941 TI - A novel PML-ADAMTS17-RARA gene rearrangement in a patient with pregnancy-related acute promyelocytic leukemia. PMID- 21529942 TI - Effects of heavy metals on production of thiol compounds and antioxidant enzymes in Agaricus bisporus. AB - In a pre-experiment, Agaricus bisporus mycelia grown in PDL medium were found to have a substantial ability to tolerate and accumulate heavy metals. In the study, we investigated changes in the contents of soluble protein and thiol compounds as well as the activities of antioxidant enzymes caused by copper, zinc, lead, and cadmium (nitrate salts) in mycelia of A. bisporus during short-and long-term exposure. Results showed that high-level metal concentrations significantly decrease the contents of soluble protein after long-term exposure, Cu and Zn concentrations significantly increase the thiol compounds levels after long-term exposure, while high-level Cd significantly decrease thiol compounds after long term exposure. Additionally, SOD activities were significantly increased after long-term exposure to metals, especially to Cd. The CAT activities were enhanced after long-term exposure to low-level Cu and high-level Zn, and enhanced after short-and long-term exposure to high-level Pb. The POD activities were significantly increased after long-term exposure to metals, and increased after short-term exposure to Cd and high-level Pb. PMID- 21529943 TI - Toxicity of uranium, molybdenum, nickel, and arsenic to Hyalella azteca and Chironomus dilutus in water-only and spiked-sediment toxicity tests. AB - A series of laboratory spiked-sediment toxicity tests with the amphipod Hyalella azteca and the midge Chironomus dilutus were undertaken to determine acute and chronic toxicity thresholds for uranium (U), molybdenum (Mo), nickel (Ni), and arsenic (As) based on both whole-sediment (total) and pore water exposure concentrations. Water-only toxicity data were also generated from separate experiments to determine the toxicities of these metals/metalloids under our test conditions and to help evaluate the hypothesis that pore water metal concentrations are better correlated with sediment toxicity to benthic organisms than whole-sediment metal concentrations. The relative toxicity of the four elements tested differed depending on which test species was used and whether whole-sediment or pore water metal concentrations were correlated with effects. Based on measured whole-sediment concentrations, Ni and As were the two most acutely toxic elements to H. azteca with 10-d LC50s of 521 and 532 mg/kg d.w., respectively. Measured pore water concentrations indicated that U and Ni were the two most acutely toxic elements, with 10-d LC50s to H. azteca of 2.15 and 2.05 mg/L, respectively. Based on pore water metal concentrations, the no-observed effect concentrations (NOECs) for growth were (H. azteca and C. dilutus, respectively) 0.67 and 0.21 mg/L for U, <0.37 and 0.60 mg/L for Ni, and 16.43 and <0.42 mg/L for As. Pore-water lowest-observed-effect concentrations (LOECs) for growth were (H. azteca and C. dilutus, respectively) 2.99 and 0.48 mg/L for U, 0.37 and 2.33 mg/L for Ni, and 58.99 and 0.42 mg/L for As. For U and Ni, results from 96-h water-only acute toxicity tests correlated well with pore water metal concentrations in acutely toxic metal-spiked sediment. This was not true for As where metalloid concentrations in overlying water (diffusion from sediment) may have contributed to toxicity. The lowest whole-sediment LOEC reported here for As was 6.6- and 4-fold higher than the Canadian Council of Ministers of the Environment interim sediment quality guideline and the Canadian Nuclear Safety Commission (CNSC) lowest effect level (LEL), respectively. The lowest whole sediment LOECs reported here for Ni, U and Mo were 4-, 17.5-, and >260-fold higher, respectively, than the CNSC LELs for these metals/metalloids. Data on pore water metal concentrations in toxic sediment would be a useful addition to future Guidelines documents. PMID- 21529944 TI - From offender to situation: the 'cold' approach to sexual violence prevention? AB - Many commentators have pointed to the monstrous nature of sexual violence, with its related sense of pollution and disgust. In response, post-release regulation has a 'hot' quality: in the USA, sexually violent predator statutes, residency requirements, GPS satellite monitoring, and variations on the theme of community notification all speak of the expressiveness of the response. 'Hot' signifies and has embedded within it an 'individualist' rather than 'structural' account of action, emphasises a dramaturgical reading of the social world, and privileges the political rather than the problem-solving sphere. What has been far less explored, until recently, is research and prevention policy related specifically to the sexual violence itself, or the situation in which the offense occurs. By contrast to the 'hot' response, elision from offender to situation appears to betoken a 'cold' quality. This paper analyses the conceptual and empirical underpinnings of such a 'cold' situational approach, evaluates existing studies across settings, and assesses the implications of this problem-solving process for prevention policy and practice. It concludes by embedding the analysis within a broader precautionary politics of 'hot' and 'cold' control. PMID- 21529945 TI - Who are the people in your neighborhood? A descriptive analysis of individuals on public sex offender registries. AB - Despite growing focus on registration and notification systems as central elements of national sex offender management practice, there has been remarkably little systematic analysis of the content of these registries and the diversity of individuals contained within them. Specifically, little research attention has been paid to examining the heterogeneity of the population of registered sex offenders - a circumstance that may obscure important distinctions within the population and, in turn, may undermine the ostensible purpose of SORN to prevent sexual victimization. Addressing this significant gap in our current knowledge, this article sets forth a national profile of the registered sex offender (RSO) population, drawn from an analysis of data on 445,127 RSOs obtained from the public registries of 49 states, Washington, DC, Puerto Rico and Guam. In contrast with the homogenized perception about registered sex offenders that permeates much public discourse, the analysis illuminates the wide diversity of registrants across a range of demographic, offense-related, registry status, and risk oriented variables. Policy and practice implications concerning risk, prevention, and the public safety utility of sex offender registries are discussed. PMID- 21529946 TI - Quantifying summed fullerene nC60 and related transformation products in water using LC LTQ Orbitrap MS and application to environmental samples. AB - The application of engineered nanomaterials increases strongly. Development of analytical techniques and their application to environmental samples is essential for human and environmental risk assessment of the nanoparticles. The objective of this study was to develop a sensitive analytical method to quantify nC(60) in water, using accurate mass screening liquid chromatography-hybrid linear ion trap Orbitrap mass spectrometry. nC(60) can be transformed by oxidation, reduction and photochemical reaction. Therefore, the formation of some transformation products of nC(60) was studied as well. Finally, the developed analytical method was applied to surface water samples from several locations in the Netherlands. The developed method enabled to detect and quantify aqueous concentrations of the summed nC(60) and its transformation products as low as 5 ng/L. It was observed that nC(60) transformation products exceed quantities of the parent C(60). Despite the high sensitivity of the developed method, no nC(60) or transformation products were detected in an array of Dutch surface waters. This might be due to low emissions, losses in the aqueous phase by sedimentation, sorption or further transformation processes. PMID- 21529947 TI - Dechlorane plus and possible degradation products in white stork eggs from Spain. AB - The occurrence of the emerging chlorinated flame retardant Dechlorane Plus (DP) and three of its possible degradation products was investigated in white stork eggs from two colonies in Spain. The average DP concentrations were 401 pg/g wet weight (w.w.) for the urban/industrial colony and 105 pg/g w.w. for the rural colony. One possible degradation product, anti-[DP-1Cl], was found in approximately 10% of the samples. No significant stereoisomer enrichments were detected in any colony based on the average anti-DP fractional abundances found which agrees with previous studies in herring gulls. The relationship between DP and PBDE contents in both colonies was explored leading to different scenarios, i.e. no correlation was found in the urban colony but they were statistically correlated in the rural colony. To the best of our knowledge, this is the first study to report DP in a species from a terrestrial food web, and also to report a DP degradation product in biota. PMID- 21529948 TI - Perfluoroalkyl carboxylates and sulfonates and precursors in relation to dietary source tracers in the eggs of four species of gulls (Larids) from breeding sites spanning Atlantic to Pacific Canada. AB - In the present study, we identified and examined the spatial trends, sources and dietary relationships of bioaccumulative perfluorinated sulfonate (PFSA; C(6), C(8), and C(10) chain lengths) and carboxylate (PFCA; C(6) to C(15) chain lengths) contaminants, as well as precursor compounds including several perfluorinated sulfonamides, and fluorotelomer acids and alcohols, in individual eggs (collected in 2008) from four gull species [glaucous-winged (Larus glaucescens), California (Larus californicus), ring-billed (Larus delawarensis) and herring (Larus argentatus) gulls] from 15 marine and freshwater colony sites in provinces across Canada. The pattern of PFSAs was dominated by perfluorooctane sulfonate (PFOS; >89% of SigmaPFSA concentration) regardless of egg collection location. The highest SigmaPFSA concentrations were found in the eggs collected in the urbanized areas in the Great Lakes and the St. Lawrence River area [Big Chicken Island 308 ng/g ww, Toronto Harbour 486 ng/g ww, and Ile Deslauriers (HG) 299 ng/g ww]. Also, eggs from all freshwater colony sites had higher SigmaPFSA concentrations, which were significant (p<0.05) in many cases, compared to the marine sites with the exception of the Sable Island colony in Atlantic Canada off the coast of Nova Scotia. C(6) to C(15) chain length PFCAs were detected in the eggs, although the pattern was variable among the 15 sites, where PFUnA and PFTrA dominated the pattern for most colonies. Like the SigmaPFSA, the highest concentrations of SigmaPFCA were found in the eggs from Big Chicken Island, Toronto Harbour, Ile Deslauriers (HG), and Sable Island, although not all freshwater sites had higher concentrations compared to marine sites. Dietary tracers [delta(15)N and delta(13)C stable isotopes (SIs)] revealed that PFSA and PFCA exposure is colony dependent. SI signatures suggested that gulls from most marine colony sites were exposed to PFCs via marine prey. The exception was the Mandarte Island colony in Pacific British Columbia, where PFSA and PFCA exposure appeared to be via terrestrial and/or freshwater prey consumption. The same was true for the freshwater sites where egg SIs suggested both aquatic and terrestrial prey consumption as the source for PFC exposure depending on the colony. Both aquatic (marine and freshwater) and terrestrial prey are likely sources of PFC exposure to gulls but exposure scenarios are colony-specific. PMID- 21529949 TI - Novel immunostimulatory phosphodiester oligodeoxynucleotides with CpT sequences instead of CpG motifs. AB - The innate immune system recognizes bacterial DNA as a nonself to induce rapid immune activation. TLR9 recognizes synthetic oligodeoxynucleotides (ODNs) and bacterial DNA containing unmethylated CpG dinucleotides in the context of specific base sequences (CpG-DNA). Here, we demonstrate that phosphorothioate backbone CT-ODN (PS-CT-ODN), a derivative of phosphorothioate backbone CpG-DNA (PS-ODN) with CT sequences substituted for the CG sequences, stimulates IL-8 promoter activation and gene expression. Furthermore, we identified an immunostimulatory phosphodiester bond CT-ODN (PO-CT-ODN) from Staphylococcus aureus chromosomal DNA and found that the PO-CT-ODN induces cytokine production in a TLR9-dependent manner when encapsulated with a proper liposome. Our experimental analyses also demonstrate that the immunostimulatory PO-CT-ODN can act as an adjuvant for the induction of Ag-driven IgG production. Further investigation of the functional role of PO-CT-ODN may support the future application of PO-CT-ODN in immunotherapeutics. PMID- 21529951 TI - Complement factor I in health and disease. AB - Factor I (FI) is a crucial inhibitor controlling all complement pathways due to its ability to degrade activated complement proteins C3b and C4b in the presence of cofactors such as factor H, C4b-binding protein, complement receptor 1 or CD46. Complete deficiency of FI, which is synthesized mainly in the liver is rare and leads to complement consumption resulting in recurrent severe infections, glomerulonephritis or autoimmune diseases. Incomplete FI deficiency is in turn associated with atypical haemolytic uremic syndrome, a severe disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and acute renal failure. Structurally, FI is a 88kDa heterodimer of a heavy chain consisting of one FI-membrane attack complex (FIMAC) domain, one CD5 domain and two low-density lipoprotein receptor domains (LDLr), and a light chain which is a serine protease domain (SP), linked to the heavy chain by a disulfide bond. FI cleaves its in vivo substrates C3b and C4b only in the presence of cofactors, it shows poor enzymatic activity towards synthetic substrates tested so far and it has no natural inhibitor. PMID- 21529950 TI - Identification of conformational core epitope Lys68 in C5a based on the 3-D modeling complex C5a and its functional antibody F20. AB - Inhibition of C5a by antibodies has been demonstrated to dramatically improve survival in various sepsis models in mice and rats. The structural basis of C5a mediated bioactivity and C5a antibody mediated neutralization are of interesting to be investigated. In the previous study, we obtained a novel functional mouse antibody named as F20. With computer-guided modeling method, the 3-D theoretical structure of F20 Fv fragment was constructed. Using the crystal structure of C5a, the 3-D complex structure of C5a and F20 Fv fragment was modeled with molecular docking method. Based on distance geometry method and intermolecular interaction theory, the key residue Lys(68) in C5a identified by F20 was predicted. The mutant experimental results showed that the residue Lys(68) was the critical residue of C5a for it's bioactivity and F20 binding activity. The present study shed new light on the structural basis of C5a mediated bioactivity. The identification of the critical residue will provide useful information for human complement C5a targeted therapeutic intervention. PMID- 21529952 TI - Endogenous MCP-1 promotes lung inflammation induced by LPS and LTA. AB - Monocyte chemoattractant protein 1 (MCP-1) plays an important role in leukocyte recruitment to sites of infection and inflammation. In addition, MCP-1 may attenuate inflammation by virtue of its capacity to inhibit the production of proinflammatory cytokines. We here investigated the role of MCP-1 in lung inflammation induced by lipopolysaccharide (LPS) or lipoteichoic acid (LTA), constituents of the gram-negative and gram-positive bacterial cell wall, respectively. Healthy humans demonstrated elevated MCP-1 concentrations in their bronchoalveolar lavage fluid (BALF) 6h after inhalation of LPS. Similarly, intranasal administration of LPS or LTA to mice resulted in a rise in BALF MCP-1 levels. Murine alveolar macrophage-like cells released significant amounts of MCP 1 upon stimulation with LPS or LTA in vitro. Compared to Wt mice, MCP-1(-/-) mice demonstrated lower TNF-alpha levels and a diminished neutrophil influx into their bronchoalveolar space after either LPS or LTA instillation. After intrapulmonary delivery of LPS MCP-1(-/-) mice had decreased interleukin-6 and KC concentrations and less severe lung inflammation upon histopathological examination. Remarkably, MCP-1 deficiency was associated with an early enhancement of interleukin-10 release in BALF after both LPS and LTA instillation. These data suggest that MCP 1 is a proinflammatory mediator during pulmonary inflammation induced by either LPS or LTA. PMID- 21529953 TI - Ten-year longitudinal changes in retinal microvascular lesions: the atherosclerosis risk in communities study. AB - OBJECTIVE: There are limited data on the natural history and longitudinal changes of retinal microvascular lesions. We examined 10-year changes in retinal microvascular lesions, focusing on those related to hypertension and shown to predict development of cardiovascular disease. DESIGN: Prospective cohort. PARTICIPANTS: We included 1120 middle-aged participants without diabetes of the Atherosclerosis Risk in Communities (ARIC) Study in 1993 to 1995 and again 10 years later in 2003 to 2005. METHODS: Retinal microvascular lesions were graded from retinal photographs using the same protocol at both examinations, with changes (incidence or disappearance) adjudicated by a side-by-side comparison of photographs. The study sample was stratified by carotid intima media thickness (IMT) and ARIC field center; thus, all analyses were weighted by these factors. Persons with diabetes were excluded because the frequency and pathophysiology of diabetic retinal lesions is different. MAIN OUTCOME MEASURES: Incidence and disappearance rates of lesions. RESULTS: The 10-year incidence of focal arteriolar narrowing, arteriovenous (AV) nicking, and retinopathy in persons without diabetes was 3.4% (95% confidence interval [CI], 2.3-4.9), 2.5% (95% CI, 1.6-3.9), and 2.2% (95% CI, 1.3-3.5) respectively. Over the 10-year period, of 32, 219, and 24 eyes with focal arteriolar narrowing, AV nicking and retinopathy at baseline, 50.3% (95% CI, 28.6-71.9), 40.7% (95% CI, 32.7-49.4), and 65.9% (95% CI, 42.4-83.5), respectively, disappeared. Higher baseline plasma fibrinogen and white cell counts were associated with incident focal arteriolar narrowing; antihypertensive medication use was associated with incident AV nicking, and higher diastolic blood pressure, carotid IMT, and white cell counts were associated with incident retinopathy. Higher fasting serum glucose was not significantly associated with incident retinopathy, although this may be related to the small number of lesions (odds ratio, 5.88; 95% CI, 0.74-46.64 per standard deviation difference). CONCLUSIONS: In this sample of middle-aged adults, new retinal microvascular lesions appeared at a rate between 2% and 4% over 10 years. A high percentage of lesions (>=40%) disappeared over the same period, suggesting considerable remodeling in the retinal microvasculature. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 21529954 TI - Evaluation of retinal nerve fiber layer progression in glaucoma: a comparison between spectral-domain and time-domain optical coherence tomography. AB - OBJECTIVE: To compare the performance of a spectral-domain optical coherence tomography (OCT) device and a time-domain OCT device to detect retinal nerve fiber layer (RNFL) progression in glaucoma patients. DESIGN: Prospective study. PARTICIPANTS: One hundred twenty-eight eyes of 81 glaucoma patients. METHODS: Patients were followed up at 4-month intervals for at least 24 months for RNFL imaging and visual field examination. Both eyes were imaged by the Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin, CA) and the Stratus OCT (Carl Zeiss Meditec, Inc.) and underwent visual field testing at the same visit. Linear regression analyses between circumpapillary RNFL measurements (average, superior, and inferior RNFL thicknesses), visual field index (VFI), and follow-up time were performed. RNFL progression and RNFL improvement were identified when a significant negative or positive trend was detected, respectively. The agreement between the OCT instruments for progression detection was analyzed with kappa statistics. MAIN OUTCOME MEASURES: Number of eyes with RNFL progression and improvement, agreement of progression detection between RNFL measurements and VFI, and rate of change of average RNFL thickness. RESULTS: Twenty-two eyes (19 patients) and 4 eyes (4 patients) had progression, and 0 and 5 eyes (5 patients) had improvement detected by the Cirrus HD-OCT and the Stratus OCT average RNFL measurements, respectively. The agreement for detection of RNFL progression was poor between the 2 OCT instruments (kappa = 0.188, 0.027, and 0.267 for average, superior, and inferior RNFL thicknesses, respectively). The respective agreement between VFI and average RNFL thickness progression determined by the Cirrus HD OCT and the Stratus OCT was 0.125 and 0.047. The rate of average RNFL thickness progression ranged between -1.52 MUm/year and -5.03 MUm/year for the Cirrus HD OCT and between -2.22 MUm/year and -7.60 MUm/year for the Stratus OCT. CONCLUSIONS: The Cirrus HD-OCT outperformed the Stratus OCT in detecting more eyes with RNFL progression and fewer eyes with RNFL improvement. Because of reduced measurement variability, the Cirrus HD-OCT could detect changes in RNFL thickness sooner than the Stratus OCT. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21529955 TI - Prevalence and risk factors for visual impairment in preschool children the sydney paediatric eye disease study. AB - PURPOSE: To assess the prevalence and associations of visual impairment (VI) in preschool children. DESIGN: Cross-sectional, population-based study. PARTICIPANTS: A total of 2461 children (73.8% participation rate), aged 6 to 72 months, were examined in the Sydney Paediatric Eye Disease Study during 2007 2009; of whom 1188, aged 30 to 72 months, with complete visual acuity (VA) data in both eyes, were included in this report. METHODS: Measurement of VA was attempted on all children using the Electronic Visual Acuity (EVA) system or a logarithm of the minimum angle of resolution (logMAR) chart. Visual impairment was defined as presenting VA <20/40 in children aged >=48 months and <20/50 in those aged <48 months. Post-cycloplegic refraction was measured, and myopia was defined as spherical equivalent (SE) <=-0.50 diopters (D), hyperopia was defined as SE >=2.00 D, astigmatism was defined as cylinder >=1.00 D, and anisometropia was defined as SE difference >=1.00 D between 2 eyes. Ethnicity, birth parameters, and sociodemographic information were collected in questionnaires completed by parents. MAIN OUTCOME MEASURES: Visual impairment prevalence and its associations with child demographic factors and birth parameters. RESULTS: Visual impairment was found in 6.4% of the worse eye and 2.7% of the better eye in our sample. Refractive errors (69.7%) and amblyopia (26.3%) were the principal causes of VI in the worse eye. Astigmatism (51.3%) and hyperopia (28.9%) were the main refractive errors causing VI. In regression analysis controlling for other factors, VI was independently associated with low birthweight of <2500 g (odds ratio 2.4, 95% confidence interval, 1.1-5.3), but not with age, gender, ethnicity, or measures of socioeconomic status (P > 0.05). CONCLUSIONS: Visual impairment in at least 1 eye was found in 6.4% of Australian preschool children, with bilateral VI found in 2.7%. Uncorrected refractive errors and amblyopia were the principal ocular conditions associated with VI. Low birthweight was a significant risk factor independent of age, gender, and ethnicity. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21529956 TI - Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography a predictor of visual acuity? AB - PURPOSE: To characterize and grade the spectrum of foveal hypoplasia based on different stages of arrested development of the fovea. Grading was performed using morphologic findings obtained by ultra high-resolution spectral-domain optical coherence tomography. Best-corrected visual acuity (BCVA) was calculated for different grades. DESIGN: Observational case series. PARTICIPANTS AND CONTROLS: Sixty-nine patients with foveal hypoplasia (albinism, n = 34; PAX6 mutations, n = 10; isolated cases, n = 14; achromatopsia, n = 11) and 65 control subjects were examined. METHODS: A 7*7-mm retinal area was sampled using a 3 dimensional scanning protocol (743*75, A scans*B scans) with ultra high resolution spectral-domain optical coherence tomography (SOCT Copernicus HR; 3 MUm axial resolution). Gross morphologic abnormalities were documented. B-scans at the fovea were segmented using a longitudinal reflectivity profile. Logarithm of the minimum angle of resolution BCVA was obtained. MAIN OUTCOME MEASURES: Grading was based on presence or absence of foveal pit and widening of the outer nuclear layer (ONL) and outer segment (OS) at the fovea. Quantitative measurements were obtained for comparing atypical foveal hypoplasia in achromatopsia. Best-corrected visual acuity was compared with the grade of foveal hypoplasia. RESULTS: Four grades of foveal hypoplasia were distinguished: grade 1, shallow foveal pit, presence of ONL widening, presence of OS lengthening; grade 2, grade 1 but absence of foveal pit; grade 3, grade 2 but absence of OS lengthening; grade 4, grade 3 but absence of ONL widening. There was significant difference in visual acuity (VA) associated with each grade (P<0.0001). Grade 1 was associated with the best VA (median VA, 0.2), whereas grades 2, 3, and 4 were associated with progressively poorer VA with a median VA of 0.44, 0.60, and 0.78, respectively. The atypical features seen with foveal hypoplasia associated with achromatopsia were characterized by decreased retinal and ONL thickness and deeper foveal depth. CONCLUSIONS: A structural grading system for foveal hypoplasia was developed based on the stage at which foveal development was arrested, which helps to provide a prognostic indicator for VA and is applicable in a range of disorders associated with foveal hypoplasia. Atypical foveal hypoplasia in achromatopsia shows different characteristics. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21529958 TI - Evaluation of retinal nerve fiber layer progression in glaucoma a prospective analysis with neuroretinal rim and visual field progression. AB - OBJECTIVE: To evaluate the performance of progression detection and the rate of change of retinal nerve fiber layer (RNFL), neuroretinal rim, and visual field measurements in glaucoma. DESIGN: Prospective study. PARTICIPANTS: One hundred eight eyes of 70 glaucoma patients. METHODS: Patients were followed up every 4 months for at least 2.9 years (median, 3.2 years) for measurement of RNFL thickness with the Stratus optical coherence tomograph (OCT) (Carl Zeiss Meditec, Dublin, CA), neuroretinal rim area with the Heidelberg Retinal Tomograph (HRT 3; Heidelberg Engineering, GmbH, Dossenheim, Germany), and visual field with the Humphrey Field Analyzer II (Carl Zeiss Meditec). Linear regression analyses were performed between visual field index (VFI), RNFL, and neuroretinal rim measurements and age, with progression defined when a significant negative trend was detected. The agreement among structural and functional measurements was evaluated with kappa statistics. The mean rate of change was estimated with linear mixed modeling. MAIN OUTCOME MEASURES: The agreement on progression detection and the rate of change of RNFL, neuroretinal rim, and VFI measurements. RESULTS: A total of 1105 OCT, 1062 HRT, and 1099 visual field measurements were analyzed. The agreement of progression detection among the 3 investigations was poor (kappa<=0.09). Ten eyes (9.3%; 9 patients) showed progression by average RNFL thickness, 16 (14.8%; 14 patients) by global neuroretinal rim area, and 35 (32.4%; 31 patients) by VFI. Only 1 eye (0.9%) had progression detected by all 3 methods. There were large variations in the rate of change of VFI, average RNFL thickness, and global neuroretinal rim area, with a range between -0.63% and 4.97% per year, -2.32% and -10.12% per year, and -0.61% and -8.48% per year, respectively. The respective mean rate estimates were -1.15% per year (95% confidence interval [CI], -1.56% to -0.73%), -0.70% per year (95% CI, -1.19% to 0.21%), and -1.06% per year (95% CI, -1.56% to -0.55%). CONCLUSIONS: The agreement of progression detection among RNFL, neuroretinal rim, and visual field measurements was poor, and the rate of RNFL, neuroretinal rim, and visual field progression varied considerably within and between subjects. Given this variability, interpretation of RNFL, neuroretinal rim, and VFI progression always should be evaluated on an individual basis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21529959 TI - Phenotypic variability in RDH5 retinopathy (Fundus Albipunctatus). AB - PURPOSE: To describe phenotypic variability and report novel mutational data in patients with mutation in RDH5 (fundus albipunctatus). DESIGN: Retrospective case series. PARTICIPANTS: Nine patients from 8 families (aged 7-55 years) with night blindness and electrophysiologic or fundoscopic findings in keeping with RDH5 mutation were ascertained. METHODS: Detailed ophthalmologic examination, fundus photography, fundus autofluorescence imaging, spectral domain optical coherence tomography (SD-OCT), and electrophysiologic assessment were performed. The coding region and intron-exon boundaries of RDH5 were analyzed. MAIN OUTCOME MEASURES: RDH5 mutation status and resultant clinical and functional characteristics. RESULTS: Eleven mutations in RDH5 were detected in the 8 families in the study, with 9 of these changes being novel. Visual acuity was normal in all but 1 eye of a patient with adult-onset central visual loss. Most patients had white dots extending into the mid-periphery on fundus examination, consistent with fundus albipunctatus, but 1 patient had normal fundi. Autofluorescence imaging revealed an association between the white dots and the hyperautofluorescent foci in younger subjects. The overall autofluorescence signal appeared low in all patients. The SD-OCT changes included deposits associated with the white dots that extended from Bruch's membrane to the external limiting membrane and focal loss of outer segments. Full-field electroretinogram (ERG) performed after standard dark adaptation showed moderate to severe generalized rod system dysfunction. Dim flash rod system ERGs were undetectable (N = 3) or subnormal (N = 6), but normalized after prolonged dark adaptation in 7 cases. Scotopic bright flash ERGs contained a reduced b:a ratio ("negative" ERG) in most cases; the use of a red stimulus under dark adaptation and extended recordings in the dark adapted state in 1 patient identified dark-adapted cones as the probable source of the ERG signals. Photopic responses were abnormal in 6 of 9 cases. CONCLUSIONS: The clinical and electrophysiologic phenotype of patients with RDH5 retinopathy is variable. Mutations in RDH5 lead to reduced autofluorescence signal possibly because of absence of retinoid-derived fluorophores. The dark adapted bright flash ERG is often electronegative and likely a manifestation of the dark-adapted cone system exposed in the absence of normal rod function. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21529960 TI - Topographic analyses of shape of eyes with pathologic myopia by high-resolution three-dimensional magnetic resonance imaging. AB - OBJECTIVE: To analyze the topography of human eyes with pathologic myopia by high resolution magnetic resonance imaging (MRI) with volume rendering of the acquired images. DESIGN: Observational case series. PARTICIPANTS: Eighty-six eyes of 44 patients with high myopia (refractive error >=-8.00 diopters [D] or axial length >26.5 mm) were studied. Forty emmetropic eyes were examined as controls. METHODS: The participants were examined with an MRI scanner (Signa HDxt 1.5T, GE Healthcare, Waukesha, WI), and T(2)-weighted cubes were obtained. Volume renderings of the images from high-resolution 3-dimensional (3D) data were done by computer workstation. The margins of globes were then identified semiautomatically by the signal intensity, and the tissues outside the globes were removed. MAIN OUTCOME MEASURES: The 3D topographic characteristic of the globes and the distribution of the 4 distinct shapes of globes according to the symmetry and the radius of curvature of the contour of the posterior segment: the barrel, cylindric, nasally distorted, and temporally distorted types. RESULTS: In 69.8% of the patients with bilateral high myopia, both eyes had the same ocular shape. The most protruded part of the globe existed along the central sagittal axis in 78.3% of eyes and was slightly inferior to the central axis in the remaining eyes. In 38 of 68 eyes (55.9%) with bilateral pathologic myopia, multiple protrusions were observed. The eyes with 2 protrusions were subdivided into those with nasal protrusions and those with temporal protrusions. The eyes with 3 protrusions were subdivided into nasal, temporal superior, and temporal inferior protrusions. The eyes with visual field defects that could not be explained by myopic fundus lesions significantly more frequently had a temporally distorted shape. Eyes with >=2 protrusions had myopic chorioretinal atrophy significantly more frequently than eyes with <=1 protrusion. CONCLUSIONS: Our results demonstrate that it is possible to obtain a complete topographic image of human eyes by high-resolution MRI with volume-rendering techniques. The results showed that there are different ocular shapes in eyes with pathologic myopia, and that the difference in the ocular shape is correlated with the development of vision-threatening conditions in eyes with pathologic myopia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21529961 TI - Acute hepatitis B infection following a community-acquired needlestick injury. AB - We report a case of acute Hepatitis B infection occurring 2 months after a community-acquired needlestick injury. The patient had a history of incomplete vaccination and Hepatitis B vaccine booster was delayed. He did not receive immunoglobulin. This is only the second report of Hepatitis B transmission in this setting. PMID- 21529962 TI - The gender paradox in suicidal behavior and its impact on the suicidal process. AB - BACKGROUND: An important gender difference has been reported regarding suicidal behavior with an overrepresentation of females in nonfatal suicidal behavior and a preponderance of males in completed suicide, also known as the 'gender paradox of suicidal behavior'. The concept of a 'suicidal process' classifies suicidal behavior chronologically; this process starts with suicidal ideation and then implies a progression of suicidality ranging from suicidal ideation over plans to suicide attempts and finally fatal suicide. AIMS/METHODS: The current paper aims to deepen the knowledge on the gender paradox by collecting and discussing the recent literature on this topic: the most relevant, impacting gender-related factors will be discussed within the suicidal process concept. RESULTS: Several factors had a gender-dependent impact on suicidal behavior: psychosocial life stressors such as stressful life events but also sociodemographical or socio economical factors, and sexual abuse. The gender differences in psychiatric (co)morbidity and in response to or attitude towards antidepressant treatment also appear to have an impact. Furthermore, not only suicide methods but also the gender-dependent variation in reporting suicide has an influence. Finally, the gender differences in help seeking behavior as well as region-dependent cultural beliefs and societal attitudes are discussed. CONCLUSIONS: Especially life-events seem to exert an important influence at the beginning of a suicidal process, whereas the other factors occur at a further stage in the process, however without a fixed chronology. Also, the duration of the suicidal process is much shorter in male than in females. Finally, some implications with regard to clinical practice and suicide prevention are suggested. PMID- 21529957 TI - A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. AB - PURPOSE: To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula associated with vision loss not due to ischemia. DESIGN: Randomized (1:1), sham-controlled, multicenter, parallel group trial. PARTICIPANTS: Subjects with DME. INTERVENTION: Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the proportion gaining >= 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout. RESULTS: In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of >= 10 letters at week 54 compared with baseline (odds ratio [OR], 2.38; 95% confidence interval, 1.32 4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P<0.05) to sham at weeks 6, 24, 30, 36, 42, 54, 78, 84, 90, 96, and 102. At week 102, pegaptanib-treated subjects gained, on average, 6.1 letters versus 1.3 letters for sham (P<0.01). Fewer pegaptanib- than sham-treated subjects received focal/grid laser treatment (week 54, 31/133 [23.3%] vs 53/127 [41.7%], respectively, P = 0.002; week 102, 27/107 [25.2%] vs 45/100 [45.0%], respectively, P = 0.003). The pegaptanib treatment group showed significantly better results on the National Eye Institute-Visual Functioning Questionnaire than sham for subscales important in this population. Pegaptanib was well tolerated; the frequencies of discontinuations, adverse events, treatment-related adverse events, and serious adverse events were comparable in the pegaptanib and sham groups. CONCLUSIONS: Patients with DME derive clinical benefit from treatment with the selective vascular endothelial growth factor antagonist pegaptanib 0.3 mg. These findings indicate that intravitreal pegaptanib is effective in the treatment of DME and, taken together with prior study data, support a positive safety profile in this population. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21529963 TI - Screening for perinatal common mental disorders in women in the north of Vietnam: a comparison of three psychometric instruments. AB - BACKGROUND: There is increasing recognition that Perinatal Common Mental Disorders (CMDs) are a major public health problem for women in resource constrained countries. There is an urgent need for screening tools suitable for use by community based health workers to assist in the identification of people with compromised mental health. The aim of this study was to establish the validity of three widely used psychometric screening instruments in detecting CMDs in women in northern Viet Nam. METHODS: Translated and culturally verified versions of the Edinburgh Postnatal Depression Scale (EPDS), General Health Questionnaire 12 items (GHQ-12), Zung's Self-rated Anxiety Scale (Zung SAS) and a gold-standard diagnostic tool, the Structured Clinical Interview for DSM IV, were administered to a community-based representative cohort of 364 Vietnamese women in the perinatal period. Post-hoc analyses, Cronbach's alpha, and Receiver Operating Characteristic (ROC) analyses were performed to identify the optimal cut-off points and to compare the validity of three scales. RESULTS: The Areas under the ROC Curve were: EPDS 0.77 (95%CI 0.72-0.82); Zung SAS 0.79 (95%CI 0.74 0.84) and GHQ-12 0.72 (95%CI 0.67-0.78). The optimal cut-off point for the EPDS was 3/4 (Se 69.7%; Sp 72.9%). The corresponding value for Zung SAS was 37/38 (Se 67.9%; Sp 75.3%) and for GHQ-12 was 0/1 (Se 77.1%; Sp 56.6%). The internal reliability Cronbach's alpha for EPDS was 0.75, for Zung SAS was 0.76, and for GHQ-12 was 0.64. CONCLUSIONS: These instruments are suitable for use as screening tools for CMDs in women in northern Viet Nam, but probably because of differences in emotional literacy, familiarity with test-taking and the effects of chronic social adversity require much lower cut off scores to detect clinically significant symptoms than in other settings. PMID- 21529964 TI - Stress increases VCAM-1 expression at the fetomaternal interface in an abortion prone mouse model. AB - Sound stress exposure increases fetal loss via inflammatory pathways. Inflammation is known to up-regulate cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), which mediates the adhesion of leukocytes to the vascular endothelium. In this work, we studied the frequency of VCAM-1(+) vessels at the fetomaternal interface in stressed and non-stressed pregnant CBA/J female mice mated with DBA/2J (high fetal loss model) or BALB/c (low fetal loss model) males. The high fetal loss model had fewer large vessels on gestation day 6.5, and stress reduced the frequency of large vessels to a similar number in both high and low fetal loss models. In the high fetal loss model, however, the frequency of VCAM-1+ vessels was dramatically increased. This study shows that VCAM-1 expression is modulated by stress at the fetomaternal interface in abortion-prone cross-breeding. PMID- 21529965 TI - Granulocyte superoxide anion production and regulation by plasma factors in normal and preeclamptic pregnancy. AB - Data on the respiratory burst activity of granulocytes from healthy and preeclamptic women have remained contradictory. To investigate the role of reactive oxygen species in the etiology of preeclampsia we measured superoxide anion generation by granulocytes from non-pregnant, healthy, and preeclamptic women. We also examined the reciprocal effects of heat-inactivated and non inactivated plasma on superoxide production. Superoxide generation was measured by ferricytochrome-c reduction. Superoxide production induced by either phorbol 12,13-dibutirate or N-formyl-methionyl-leucyl-phenylalanine was significantly decreased in granulocytes from normal pregnant women compared with non-pregnant and preeclamptic women. The phorbol-12,13-dibutirate-induced superoxide generation by granulocytes from non-pregnant and preeclamptic women was significantly inhibited by plasma from healthy pregnant women. The N-formyl methionyl-leucyl-phenylalanine-stimulated superoxide production by granulocytes from non-pregnant and preeclamptic women was suppressed only by non-inactivated plasma, not heat-inactivated plasma from healthy pregnant women. Plasma from preeclamptic women did not influence the phorbol-12,13-dibutirate- and N-formyl methionyl-leucyl-phenylalanine-induced superoxide production by control granulocytes. The phorbol-12,13-dibutirate-induced superoxide generation by granulocytes from healthy pregnant women was significantly increased by the effect of plasma from non-pregnant and preeclamptic women, but when stimulating with N-formyl-methionyl-leucyl-phenylalanine only non-inactivated plasma caused the same enhancement. These data indicate that reduced superoxide generation in normal pregnancy may be caused by maternal immunosuppressive factors present in plasma. The failure to reduce superoxide production in preeclampsia may be partly responsible for the endothelial dysfunction characteristic of that condition. PMID- 21529966 TI - The etiology of preeclampsia: the role of the father. AB - Preeclampsia is often considered as simply a maternal disease with variable degrees of fetal involvement. More and more the unique immunogenetic maternal paternal relationship is appreciated, and also the specific 'genetic conflict' that is characteristic of haemochorial placentation. From that perspective, pre eclampsia can be seen as a disease of an individual couple with primarily maternal and fetal manifestations. The maternal and fetal genomes perform different roles during development. Heritable paternal, rather than maternal, imprinting of the genome is necessary for normal trophoblast development. Large population studies have estimated that 35% of the variance in susceptibility to preeclampsia is attributable to maternal genetic effects; 20% to fetal genetic effects (with similar contributions of both parents), 13% to the couple effect, less than 1% to the shared sibling environment and 32% to unmeasured factors. Not one of these large population studies focussed on the paternal contribution to preeclampsia, which is demonstrated by (1) the effect of the length of the sexual relationship; (2) the concept of primipaternity versus primigravidity; and (3) the existence of the so-called 'dangerous' father, as demonstrated in various large population studies. It is currently unknown how the father exerts this effect. Possible mechanisms include seminal cytokine levels and their effect on maternal immune deviation, specific paternal HLA characteristics and specific paternal single nucleotide polymorphisms (SNPs), in particular in the paternally expressed genes affecting placentation. Several large cohort studies, including the large international SCOPE consortium, have identified paternal SNPs with strong associations with preeclampsia. PMID- 21529967 TI - Association of FCRL3 C-169T promoter single-nucleotide polymorphism with idiopathic infertility and infertility-related endometriosis. AB - An aberrant immunological mechanism is thought to be involved in the pathogenesis of endometriosis. The present study aimed to determine whether there is a relationship between endometriosis and/or infertility and the FCRL3 C-169T polymorphism. This case-control study included 167 infertile women with endometriosis, 60 women with idiopathic infertility and 167 fertile women. Detection of the FCRL3 C-169T polymorphism was performed using TaqMan PCR. A significant difference in the genotype and allele frequencies of the FCRL3 C-169T polymorphism between endometriosis-related infertility (p=0.003 and p=0.001) and idiopathic infertility (p=0.027 and p=0.0185) versus controls was demonstrated. In conclusion, the results suggest that the FCRL3 C-169T polymorphism may play an important role in the pathogenesis of endometriosis and/or infertility. PMID- 21529968 TI - Associations among perceptual anomalies, social anxiety, and paranoia in a college student sample. AB - Recent evidence suggests that normal-range paranoid ideation may be particularly likely to develop in individuals disposed to both social anxiety and perceptual anomalies. This study was designed to test the hypothesis that among college students in an unselected sample, social anxiety and experience of perceptual anomalies would not only each independently predict the experience of self reported paranoid ideation, but would also interact to predict paranoid patterns of thought. A diverse sample of 644 students completed a large battery of self report measures, as well as the five-factor Paranoia/Suspiciousness Questionnaire (PSQ). We conducted hierarchical multiple regression analyses predicting scores on each PSQ factor from responses on measures of social anxiety, perceptual aberration, and the interaction between the two constructs. Current general negative affect was covaried in all analyses. We found that both social anxiety and perceptual aberrations, along with negative affect, predicted multiple dimensions of paranoia as measured by the PSQ; the two constructs did not, however, interact significantly to predict any dimensions. Our findings suggest that perceptual aberration and anxiety may contribute to normal-range paranoid ideation in an additive rather than an interactive manner. PMID- 21529969 TI - Expressed emotion in first-episode schizophrenia and in ultra high-risk patients: results from the Programma2000 (Milan, Italy). AB - Expressed emotion (EE) was examined in a large sample of families of patients with either first-episode psychosis (FEP) within the schizophrenia spectrum, or who met the criteria for ultra high-risk (UHR) of psychosis. The aim of our study was to determine the patterns and relationship of EE with the duration of untreated illness (DUI) or of untreated psychosis (DUP), as well as with illness severity. The sample used in our study included 77 FEP and 66 UHR families. The Camberwell Family Interview was used to assess EE. In both samples, about one third of patients' families were classified as high EE, with emotional over involvement (EOI) being the most frequent reason for a family to be classified as high EE. In FEP, higher EE correlated with longer DUI, and higher paternal EOI with longer DUP. DUI, however, was not found to correlate to EE in UHR patients. Severity of illness at the initial assessment did not relate to EE in either FEP or UHR families. Families of FEP and UHR patients were not found to differ in terms of the prevalence of a high EE rating, or of any of its subcomponents. The results of this study only partially support the hypothesis that high EE develops as a reaction to patient status. Patients from families with high EE could possibly benefit from interventions that are targeted at improving their resilience when dealing with problematic family environments. PMID- 21529970 TI - A virtual reality application in role-plays of social skills training for schizophrenia: a randomized, controlled trial. AB - Although social skills training (SST) is an effective approach for improving social skills for schizophrenia, the motivational deficit attenuates its efficacy. Virtual reality (VR) applications have allowed individuals with mental disabilities to enhance their motivation for rehabilitation. We compared SST using VR role-playing (SST-VR) to SST using traditional role-playing (SST-TR). This randomized, controlled trial included 91 inpatients with schizophrenia who were assigned to either SST-VR (n=46) or SST-TR (n=45). Both groups were administered over 10 semiweekly group sessions. An experienced, blinded rater assessed vocal, nonverbal and conversational skills. We also obtained data on motivation for SST and various social abilities. Throughout the 10 sessions, the SST-VR group (n=33) showed greater interest in SST and generalization of the skills than the SST-TR group (n=31). After SST, the SST-VR group improved more in conversational skills and assertiveness than the SST-TR group, but less in nonverbal skills. The VR application in role-plays of SST for schizophrenia may be particularly beneficial in terms of improving the conversational skills and assertiveness, possibly through its advantages in enhancing motivation for SST and generalization of the skills, and thus it may be a useful supplement to traditional SST. PMID- 21529971 TI - Hearing aid functioning in the preschool setting: stepping back in time? AB - PURPOSE: In order for children with hearing impairment to receive maximum benefit from preschool programs, their amplification devices must be functioning appropriately. The purpose of this study, therefore, was to investigate the functionality of hearing aids in a preschool setting. METHODS: Forty-four hearing aids worn by 24 preschool children, whose ages ranged from three to five years, (mean age=45.2 months, median age=48 months) from four state funded aural/oral habilitation preschools were evaluated using listening checks and visual examinations. Hearing aids passing both evaluations were given a pass rating and those failing one or more of the evaluations were given a fail rating. Causes of fail rates were documented. RESULTS: Over half of the hearing aids tested were determined to have at least one or more problems (n=27). These problems were detected using listening and visual checks. CONCLUSIONS: Failure rates based on basic listening and visual checks among the hearing aids examined in this study demonstrated no improvement over those reported in the 1970's. The results re emphasize the need for a national dialogue on this topic. PMID- 21529972 TI - Toll-like receptors as targets for immune disorders. AB - Since the identification of the first Toll-like receptor (TLR) in humans in 1997, understanding of the molecular basis for innate immunity has increased significantly. The TLR family and downstream signalling pathways have been extensively characterised, There is now significant evidence suggesting a role for TLRs in human inflammatory and immune diseases such as rheumatoid arthritis, diabetes, allergy/asthma and atherosclerosis. Various approaches have been taken to identify novel therapeutic agents targeting TLRs including biologics, small molecules and nucleic acid-based drugs. Several are now being evaluated in the clinic and showing promise against various diseases. This review paper outlines the recent advances in the understanding of TLR biology and highlights novel TLR agonists and antagonists in development for the treatment of immune diseases. PMID- 21529974 TI - Hospital acquired infections (HAI) in the elderly: comparison with the younger patients. AB - The aim of this retrospective study is to determine the frequency, type, microbiological characteristics and outcome of HAIs in the elderly (age >= 65) and to compare the data with younger patients in a Turkish Training and Research Hospital. From January 2008 to December 2009, the infection control team analyzed HAIs among 60,585 hospitalized patients (20,109 aged >= 65 and 40,747 aged between 18 and 64 years) with a total number of 419,017 patient days. A total of 825 HAIs episodes were detected in 607 patients, of which 395 episodes were in 301 elderly patients. The incidence of HAIs per 1000 patient days was 2.49 in the elderly and 1.64 in the younger patients' group (p<0.001). The most common site of infection in the elderly patients was the urinary tract, whereas in non elderly group this was the lower respiratory tract. The incidence density of urinary tract infections, respiratory tract infections, surgical site, skin and soft tissue infections, primary bacteremia, and prosthesis infections were significantly higher in the elderly group (p<0.05). Gram-negative species were the most frequently isolated agents in both groups. There were no significant differences between the groups in the frequency of isolated pathogens or antibiotic susceptibility patterns. Overall, the fatality rate was found 16.8%. The elderly patients were more likely to have crude mortality rates (22% vs. 12%; p<0.01). The death was most often related to pneumonia, primary bacteremia or intravascular catheter infections in both groups. PMID- 21529973 TI - Pharmacogenomics and cancer stem cells: a changing landscape? AB - Pharmacogenomics in oncology holds the promise to personalize cancer therapy. However, its clinical application is still limited to a few genes, and, in the large majority of cancers, the correlation between genotype and clinical outcome has been disappointing. One possible explanation is that current pharmacogenomic studies do not take into account the emerging role of cancer stem cells (CSCs) in drug sensitivity and resistance. CSCs are a subpopulation of cells driven by specific signal-transduction pathways, but genetic variants affecting their activity are generally neglected in current pharmacogenomic studies. Moreover, in several malignancies, CSCs represent a rare sub-population; therefore, whole tumor profiling might mask CSC gene expression patterns. This article reviews current evidence on CSC chemoresistance and shows how common genetic variations in CSC-related genes may predict individual response to anti-cancer agents. Furthermore, we provide insights into the design of pharmacogenomic studies to address the clinical usefulness of CSC genetic profiling. PMID- 21529975 TI - Detecting RNA viruses in living mammalian cells by fluorescence microscopy. AB - Traditional methods that rely on viral isolation and culture techniques continue to be the gold standards used for detection of infectious viral particles. However, new techniques that rely on visualization of live cells can shed light on understanding virus-host interaction for early stage detection and potential drug discovery. Live-cell imaging techniques that incorporate fluorescent probes into viral components provide opportunities for understanding mRNA expression, interaction, and virus movement and localization. Other viral replication events inside a host cell can be exploited for non-invasive detection, such as single virus tracking, which does not inhibit viral infectivity or cellular function. This review highlights some of the recent advances made using these novel approaches for visualization of viral entry and replication in live cells. PMID- 21529976 TI - Efficacy of adding detergents to sanitizer solutions for inactivation of Escherichia coli O157:H7 on Romaine lettuce. AB - Numerous Escherichia coli O157:H7 outbreaks have been linked to consumption of fresh lettuce. The development of effective and easily implemented wash treatment could reduce such incidents. The purpose of this study was to evaluate the addition of food-grade detergents to sanitizer solutions for inactivation of E. coli O157:H7 on Romaine lettuce. Freshly-cut leaves of Romaine lettuce were dip inoculated to achieve a final cell concentration of 7.8+/-0.2 log CFU/g, air dried for 2h, and stored overnight at 4 degrees C. Leaves were then washed for 2 min in an experimental short chain fatty acid formulation (SCFA) or in one of the following solutions with or without 0.2% dodecylbenzenesulfonic acid or 0.2% sodium 2-ethyl hexyl sulfate: 1) deionized water; 2) 100 ppm chlorine dioxide; 3) 100 ppm chlorine; and 4) 200 ppm chlorine. Following wash treatment, samples were blended in neutralizing buffer (1:3) and surface plated on the selective media CT SMAC. The efficacy of wash treatments, with or without the detergents, in inactivating E. coli O157:H7 cells on lettuce leaves were not significantly different. The most effective wash solution was SCFA, which was capable of reducing E. coli O157:H7 populations by more than 5 log CFU/g. The rest of the wash treatments resulted in a population reduction of less than 1 log CFU/g. The effectiveness of SCFA surpasses that of other sanitizer treatments tested in this study and requires further research to optimize treatments to preserve lettuce quality. Conventional detergents did not enhance the efficacy of any of the wash treatments tested during this study. PMID- 21529977 TI - Isolation and selection of yeasts from wine grape ecosystem secreting cold-active pectinolytic activity. AB - The present study was undertaken with the purpose of selecting yeasts from wine grapes that are able to produce extracellular cold-active pectinases. After two consecutive selections yeast isolates were identified by pheno- and genotyping, and pectinolytic activity was preliminarily characterised at proximate winemaking conditions. Out of 1023 indigenous microorganisms isolated from grape skins of D.O. San Rafael (Mendoza, Argentina) viticulture region, 565 (55%) showed pectinolytic activity on plates and, among them, 96 (17%) were chosen in a primary selection. Ten isolates were finally selected for exhibiting the greatest activity at low temperature (12 degrees C) and identified as Aureobasidium pullulans. GM-R-22 strain demonstrated the highest pectinolytic activity (0.751 U/mL) at pH 3.5 and 12 degrees C. Yeast pectinases were constitutively produced. This study is the first report about strains of A. pullulans producing pectinases which are able to show good activity at low temperature. These pectinolytic strains could be of interest in wine production. PMID- 21529978 TI - Low HDL-cholesterol: a strong predictor of glycemic response to glitazone treatment in patients with type 2 diabetes. AB - We performed a study in 102 people with type 2 diabetes aiming to determine "easy to-use" predictive factors for glycemic response to glitazones. We found that low baseline HDL-cholesterol (<40 mg/L [1.04 mmol/L] in males, <50 mg/L [1.30 mmol/L] in females) was a strong independent predictor of glycemic response to glitazones (OR=2.67 [2.02-3.52], p=0.0004). PMID- 21529979 TI - Experience of the introduction of routine antibody testing in primary care and of running a trial for latent autoimmune diabetes in adults (LADA). AB - This brief report discusses the introduction of routine Glutamic Acid Decarboxylase Antibody (GADA) testing in primary care for newly diagnosed diabetes. GADA testing is well used and the majority of people found to be positive are initiated on insulin rapidly and progress to require a basal bolus regime. PMID- 21529980 TI - A structured tool to analyse coverage decisions: development and feasibility test in the field of cancer screening and prevention. AB - OBJECTIVES: The comparison of fourth hurdle processes is challenging because they are heterogeneous and decision practice may deviate from formal process rules. This study applies a published framework consisting of key steps of coverage decision processes to the area of cancer prevention. METHODS: A research design was developed for analysis of case studies on past decision processes. Decisions were identified and information on the process steps was elicited by semi structured telephone interviews with decision-makers and experts. The scheme was validated with experts from the areas of screening and prevention and fourth hurdle decision making. RESULTS: Indicators for a structured empirical comparison of coverage decisions were derived. Corresponding ordinal rankings were proposed. Details on six decisions about cancer screening (colorectal and prostate cancer) and vaccination against human papillomavirus in Sweden, Austria and Lithuania are presented. CONCLUSIONS: The development of the structured scheme for analysis of coverage decisions allows validation of official statements on decision processes and collection of larger data sets for empirical analysis. However, the semi structured phone interviews were time-consuming for collecting information on a larger number of decisions. Further validation of the structured scheme and development of a research tool for large-scale empirical studies is still needed. PMID- 21529981 TI - Analysis of normal and epileptic seizure EEG signals using empirical mode decomposition. AB - Epilepsy is one of the most common neurological disorders characterized by transient and unexpected electrical disturbance of the brain. The electroencephalogram (EEG) is an invaluable measurement for the purpose of assessing brain activities, containing information relating to the different physiological states of the brain. It is a very effective tool for understanding the complex dynamical behavior of the brain. This paper presents the application of empirical mode decomposition (EMD) for analysis of EEG signals. The EMD decomposes a EEG signal into a finite set of bandlimited signals termed intrinsic mode functions (IMFs). The Hilbert transformation of IMFs provides analytic signal representation of IMFs. The area measured from the trace of the analytic IMFs, which have circular form in the complex plane, has been used as a feature in order to discriminate normal EEG signals from the epileptic seizure EEG signals. It has been shown that the area measure of the IMFs has given good discrimination performance. Simulation results illustrate the effectiveness of the proposed method. PMID- 21529982 TI - Application of clustering analyses to the diagnosis of Huntington disease in mice and other diseases with well-defined group boundaries. AB - Nuclear magnetic resonance (NMR) spectroscopy has emerged as a technology that can provide metabolite information within organ systems in vivo. In this study, we introduced a new method of employing a clustering algorithm to develop a diagnostic model that can differentially diagnose a single unknown subject in a disease with well-defined group boundaries. We used three tests to assess the suitability and the accuracy required for diagnostic purposes of the four clustering algorithms we investigated (K-means, Fuzzy, Hierarchical, and Medoid Partitioning). To accomplish this goal, we studied the striatal metabolomic profile of R6/2 Huntington disease (HD) transgenic mice and that of wild type (WT) mice using high field in vivo proton NMR spectroscopy (9.4T). We tested all four clustering algorithms (1) with the original R6/2 HD mice and WT mice, (2) with unknown mice, whose status had been determined via genotyping, and (3) with the ability to separate the original R6/2 mice into the two age subgroups (8 and 12 weeks old). Only our diagnostic models that employed ROC-supervised Fuzzy, unsupervised Fuzzy, and ROC-supervised K-means Clustering passed all three stringent tests with 100% accuracy, indicating that they may be used for diagnostic purposes. PMID- 21529983 TI - Lung cancer in lung transplant recipients: experience of a tertiary hospital and literature review. AB - BACKGROUND: Lung transplantation is a viable therapy for patients with end-stage lung disease and is being increasingly performed worldwide. The incidence of lung cancer after lung transplantation has increased concomitantly, although data are still sparse. METHODS: The computerized medical records of the Pulmonary Institute of a tertiary care medical center were searched for patients who underwent lung transplantation from 1997 to 2009 and acquired lung cancer postoperatively. The prevalence, potential contributing factors, and outcome of bronchogenic cancer were determined, and the medical literature was reviewed. RESULTS: Bronchogenic cancer developed in 7 of the 290 lung transplant recipients (2.4%). All had received a single lung transplant and in most cases, the cancer developed in the native lung. These findings were similar to reports in the literature. The indication for transplantation was chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis/interstitial lung disease. All had a history of smoking. The average interval from transplantation to development of lung cancer was 5 years (range 1-9). Five patients had stage 4 cancer at diagnosis and 2 had stage 1. Six patients died from 10 days to 1 year after diagnosis. CONCLUSION: Lung transplantation is associated with a relatively high prevalence of bronchogenic cancer, particularly in the native lung, in patients with primary chronic obstructive pulmonary disease/idiopathic pulmonary fibrosis, and a history of smoking. The cancer is usually diagnosed at an advanced stage with poor outcome. Efforts to improve screening are recommended, as aggressive management and treatment may be beneficial for earlier stage disease. PMID- 21529984 TI - Klotho predicts good clinical outcome in patients with limited-disease small cell lung cancer who received surgery. AB - BACKGROUND: The important role of surgery in early-stage small cell lung cancer (SCLC) has been recognized, and curative surgical resection is recommended. However, the role of adjuvant chemotherapy for stage I SCLC has not yet been evaluated, and novel approaches focusing on the specific genomic characteristics of SCLC may be invaluable for customized therapy. In this study, we focused on the Klotho gene, which is an anti-aging gene known to be a potential tumor suppressor. We investigated whether the expression of Klotho, assessed by immunohistochemistry, can predict survival in patients with resected SCLC. METHODS: The medical records of patients diagnosed as having limited-disease (LD) SCLC and treated by surgical resection (n=30) at Tokyo Medical University Hospital were retrospectively reviewed. The expression status of Klotho, and of the ATP-binding cassette (ABC) transporters MRP1, MDR and breast cancer resistant protein (BCRP), which can cause resistance to anticancer drugs, including irinotecan, was assessed by immunohistochemical analysis in resected surgical specimens of patients with early-stage SCLC. RESULTS: Of the 30 patients, Klotho expression was seen in the specimens from 18 patients (60.0%), but not in those of the remaining 12 patients (40.0%). The immunostaining for Klotho was mostly localized in the cytoplasm. The expression of Klotho was significantly associated with the overall survival (OS) (ratio 0.088; 95% confidence interval 0.019-0.409; P=0.002). The administration of perioperative chemotherapy had no significant effect in improving the survival, as assessed by the Kaplan-Meier method. However, the patients showing Klotho expression in the resected specimens in p stage I and II, may have benefited from perioperative chemotherapy. A multivariate analysis revealed no significant association between the expression status of MRP1, MDR or BCRP and the OS. CONCLUSION: Expression of Klotho was predictive of a favorable outcome following resection in limited-disease SCLC patients, and the Klotho expression status may serve as a new biomarker for the need of additional therapies to be developed in the future. PMID- 21529985 TI - Serum discrimination of early-stage lung cancer patients using electrospray ionization mass spectrometry. AB - The goal of this study was to evaluate the usefulness of electrospray ionization mass spectrometry (ESI-MS) technology to distinguish sera of early-stage lung cancer patients from control individuals. ESI-MS m/z (mass divided by charge) data were generated from sera of 43 non-small cell lung cancer patients (pathological stages I and II) and 21 control individuals. Identifications of m/z peak area significances between cancer and control ESI-MS sera spectra were performed using t-tests. A "leave one out" cross validation procedure, which mimics blinded sera analysis and corrects for "over-fitting" of data, yielded discriminatory cancer versus control distribution p value and ROC curve area value of <0.001 and 0.87, respectively. Analysis without the "leave one out" cross validation procedure yielded a ROC curve area of 0.99 for discrimination of sera from lung cancer patients versus control individuals. Predictive value measurements revealed overall test efficiency and sensitivity for distinguishing sera from lung cancer patients from controls (using "leave one out" cross validation) of 80% and 84%, respectively. ESI-MS serum analysis between control individuals and lung cancer patients who smoked or did not smoke had p values in ranges indicating that smoking effects are not pronounced in our analysis. These studies indicate that ESI-MS analyses of sera from early stage non-small cell lung cancer patients were helpful in distinguishing these patients from control individuals. PMID- 21529986 TI - Tubulin, BRCA1, ERCC1, Abraxas, RAP80 mRNA expression, p53/p21 immunohistochemistry and clinical outcome in patients with advanced non small cell lung cancer receiving first-line platinum-gemcitabine chemotherapy. AB - BACKGROUND: The aim of this study was to assess the predictive value of tumor expression of nine genes on clinical outcome in patients with advanced NSCLC receiving platinum-gemcitabine chemotherapy. METHODS: Quantitative PCR or immunohistochemistry were used to analyze the expression of beta-tubuline IIA (TUBB2A), beta-tubuline III (TUBB3), BRCA1, ERCC1, Abraxas (ABRX) and RAP80 in mRNA isolated from paraffin-embedded tumor biopsies of 45 NSCLC patients treated as part of a larger observational trial. All patients received first-line platinum-gemcitabine chemotherapy for stage IIIB or IV NSCLC. RESULTS: Median progression-free survival (PFS) was 7 months, overall survival (OS) 12 months. A partial treatment response was found in 14 patients (33%). Patients with low ERCC1 or ABRX expression had a significantly better response to chemotherapy (R= 0.45, p<0.01 for ERCC1; R=-0.40, p=0.016 for ABRX). A significant correlation was found between the individual time for PFS and the expression of both ERCC1 (R= 0.36, p=0.015) and ABRX (R=-0.46, p=0.001). Patients with low ERCC1 expression had a longer OS as compared to patients with high ERCC1 expression (HR=0.26, log rank p=0.02). CONCLUSIONS: The study confirms tumor expression of ERCC1 as a predictor for clinical outcome in patients with advanced NSCLC receiving platinum based chemotherapy, and found ABRX expression to be similarly predictive of clinical outcome. Prospective validation is warranted and - if confirmed - non platinum-containing chemotherapy should be explored as the preferred treatment in patients with high ERCC1 or ABRX expression and no activating mutations of EGFR. PMID- 21529987 TI - Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: clinical benefit with optimal patient selection. AB - BACKGROUND: Recent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy. METHODS: One hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009. RESULTS: The response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5-15%), 44% (95% CI, 35-53%), and 2.0 months (95% CI, 1.4-2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4-16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12-43%); DCR, 72% (95% CI, 53-86%); and median PFS, 3.4 months (95% CI, 2.4-4.9 months). CONCLUSIONS: Higher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies. PMID- 21529988 TI - Clinicopathological findings of non-small-cell lung cancer with high serum progastrin-releasing peptide concentrations. AB - Although progastrin-releasing peptide (proGRP) is used as a serum tumor marker for small cell lung cancer (SCLC), high serum pro-GRP concentrations are observed in some non-small-cell lung cancers (NSCLCs). The characteristics of these NSCLCs are not well known. To determine the clinicopathological features of NSCLC in patients with elevated serum proGRP concentrations, serum proGRP values were assessed in 654 advanced lung cancer patients, and positive (>46pg/mL) NSCLC specimens were subjected to cytological and histopathological reevaluation. Serum proGRP concentrations were positive in 34 of 421 NSCLC patients (8.1%) and 186 of 233 SCLC patients (80%). Histological subtypes of the 34 NSCLC patients at diagnosis were 20 adenocarcinomas, 5 squamous cell carcinomas, 4 large cell carcinomas, and 5 large cell neuroendocrine carcinomas. Six of 27 cytology specimens contained characteristic neuroendocrine morphology. Immunohistochemical analysis showed that 11 of 17 tumors were positive for neuroendocrine markers (64.7%). Twenty of 34 serum proGRP-positive NSCLC patients received platinum based chemotherapy, and the response rate was 55.0%. These results suggest that serum proGRP-positive NSCLCs may have neuroendocrine differentiation. In addition, serum proGRP-positive NSCLCs may have clinical characteristics that are different from other NSCLCs. PMID- 21529989 TI - A phase II trial of high dose carboplatin and paclitaxel with G-CSF and peripheral blood stem cell support followed by surgery and/or chest radiation in patients with stage III non-small cell lung cancer: CALGB 9531. AB - PURPOSE: We designed a phase II trial to evaluate the efficacy and tolerability of high dose induction chemotherapy with carboplatin and paclitaxel with G-CSF and stem cell support followed by surgical resection and/or chest radiotherapy in patients with stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients had pathologically confirmed stage IIIA-IIIB NSCLC, adequate end-organ function, no prior chemotherapy or radiation, and performance status 0-1. Peripheral stem cells were mobilized with G-CSF stimulation on days 1-5 and collected prior to chemotherapy. Chemotherapy consisted of 2 cycles of paclitaxel 250 mg/m(2) over 3h and carboplatin at an AUC 18 on days 11 and 32, each followed by stem cell reinfusion. Stable and responding patients went on to surgical resection (in patients deemed resectable) followed by post-operative radiation, or to conventional chest radiotherapy to 66 Gy in unresectable patients. RESULTS: Twelve patients (11 eligible) were accrued from 1996 to 1999. The 11 patients were predominately male (64%), white (82%), of performance status 0 (64%), and with weight loss less than 5% (55%). The median age was 51 (range 31-63). Ten (10) patients (91%) experienced grade 4 toxicity. There were no lethal toxicities. Grade 3-4 toxicities most commonly reported included: platelets (100%), lymphocytopenia (91%), leukopenia (91%), neutropenia (73%), anemia (55%), pain (45%), and nausea (27%). Three patients (27%) had a partial response to induction chemotherapy. Of the 11 patients, 7 underwent surgical exploration, and 10 received radiation. Two patients were completely resected, 3 patients had incomplete resections, and 2 patients had no resection. There were 4 complete responses and 3 partial responses following surgery and/or radiation. The median overall survival time was 17.8 months. The median failure-free survival time was 8.3 months. One-year and 2-year overall survival are estimated at 64% and 27%, respectively. CONCLUSIONS: High dose induction chemotherapy with carboplatin and paclitaxel and stem cell support in patients with stage IIIA-IIIB NSCLC produced response rates and survival similar to standard therapy. Excessive toxicity (and cost) suggests that this approach does not merit further investigation. PMID- 21529990 TI - Re-appraisal of N2 disease by lymphatic drainage pattern for non-small-cell lung cancers: by terms of nodal stations, zones, chains, and a composite. AB - PURPOSE: N2 non-small-cell lung cancer (NSCLC) is a heterogeneous disease with an extremely wide range of 5-year survival rates. A composite method of sub classification for N2 is likely to provide a more accurate method to more finely differentiate prognosis of N2 disease. METHODS: A total of 720 pN2 (T1-4N2M0) NSCLC cases were enrolled in our retrospective analysis of the proposed composite method. Survival rates were respectively calculated according to the N2 stratification methods: singly by "nodal stations", "nodal zones", or "nodal chains", or by combination of all three. Statistical analysis was carried out by Kaplan-Meier and Cox regression models. RESULTS: A total of 10,199 lymph nodes (8059 mediastinal; 2140 hilar and intra-lobar) were removed. By nodal station, there were 173 cases of single-station involvement and 547 multi-stations. By nodal zone, there were 413 single-zone involvement and 307 with multiple zones. By nodal chain, there were 311 cases with single-chain and 409 multi-chain involvements. The overall 5-year survival was 20% and median survival time was 27.52 months. The 5-year survival was significantly better for cases of single zone involvement, as compared to multi-zones (29% vs. 6%, p<0.0001). The 5-year survival rates of single- and multi-chains involvement were 36% and 8%, respectively (p<0.0001). When taking all of the above grouping methods into consideration, the N2 disease state could be further sub-classified into two subgroups with respective survival rates of 36% and 7% (p<0.0001). Subgroup I was composed of individuals with single-chain involvement and having either one or two station metastasis; individuals with any other metastasis combinations formed Subgroup II. Multivariate analysis revealed that the composite sub-classification method, number of positive lymph nodes, ratio of nodal metastasis, and pT information were the most important risk factors of 5-year survival. CONCLUSIONS: By combining the three N2 stratification methods based on "stations", "zones", and "chains" into one composite method, prognosis prediction was more accurate for N2 NSCLC disease. Single nodal chain involvement, which may be either one or two nodal stations metastasis, is associated with best outcome for pN2 patients. PMID- 21529991 TI - Synergistic cytotoxicity, inhibition of signal transduction pathways and pharmacogenetics of sorafenib and gemcitabine in human NSCLC cell lines. AB - INTRODUCTION: Lung cancer is one of the most lethal tumors and, although standard chemotherapy produces clinical response, there has been little improvement in prognosis. Therefore, research effort has focused on target-specific agents, such as sorafenib, which blocks both the RAF/MEK/ERK signalling pathways and receptors involved in neovascularization and tumor progression, including VEGFR-2 and c Kit. We investigated whether sorafenib would be synergistic with gemcitabine against NSCLC cell lines. MATERIALS AND METHODS: Human lung cancer cells A549, CALU-1, CALU-6, H23 and HCC 827 were treated with sorafenib and gemcitabine, alone or in combination, and the cytotoxicity was assessed with CellTiter 96 Non radioactive cell proliferation kit. Cell cycle and apoptosis were investigated with flow cytometry and fluorescence microscopy, respectively. Moreover, the effects of drugs on Akt (S473), c-Kit (Y823) and ERK (pTpY185/187) phosphorylation were studied with ELISA. Finally, quantitative PCR analysis was performed to assess whether sorafenib and gemcitabine modulated the expression of genes related to drug activity. RESULTS: Gemcitabine and sorafenib synergistically interacted on the inhibition of cell proliferation, and assessment of apoptosis demonstrated that drug associations increased the apoptotic index. Sorafenib reduced c-Kit and ERK activation and gemcitabine inhibited Akt phosphorylation. Moreover quantitative PCR showed that sorafenib modulated the expression of targets related to gemcitabine activity, while gemcitabine induced the expression of RKIP. CONCLUSIONS: These data demonstrate that sorafenib and gemcitabine synergistically interact against NSCLC cells, through suppression of Akt, c-Kit and ERK phosphorylation, induction of apoptosis and modulation of dCK, RRM1, RRM2 and RKIP gene expression. The association between traditional cytotoxic agents with new target-specific agents, such as sorafenib, is a challenge for both clinical and preclinical future investigations in lung cancer treatments. PMID- 21529992 TI - Faunal histories from Holocene ancient DNA. AB - Recent studies using ancient DNA have been instrumental in advancing understanding of the impact of Holocene climate change on biodiversity. Ancient DNA has been used to track demography, migration and diversity, and is providing new insights into the long-term dynamics of species and population distributions. The Holocene is key to understanding how the past has impacted on the present, as it bridges the gap between contemporary phylogeographic studies and those with inference on Pleistocene patterns, based on ancient DNA studies. Here, we examine the major patterns of Holocene faunal population dynamics and connectivity; highlighting the dynamic nature of species and population responses to Holocene climatic change, thereby providing an 'analogue' for understanding potential impacts of future change. PMID- 21529993 TI - CD40 ligand: a neo-inflammatory molecule in vascular diseases. AB - CD40 Ligand (CD40L), a member of the TNF family, was initially thought to be solely implicated in thymus-dependent humoral responses. However, work by several groups showed that CD40L plays a more global role in various systems. Recent evidence has outlined an important role for CD40L in the physiopathology of the vascular system. Indeed, by interacting with its principal receptor, CD40, or with the recently identified receptors, namely alphaIIbbeta3, alpha5beta1, and Mac-1 integrins, CD40L displayed many biological functions in different types of vascular cells. In addition, the CD40L system was demonstrated a major player in the pathology of vascular diseases, such as atherosclerosis and restenosis. This review outlines the expression pattern and the functional properties of CD40L and its receptors at different cellular levels in the vascular system. In addition, we thoroughly describe evidence showing the implication of CD40L interactions in atherosclerosis, restenosis, and their associated clinical complications. PMID- 21529994 TI - Influence of 1,25-dihydroxy vitamin D3 on TLR4-induced activation of antigen presenting cells is dependent on the order of receptor engagement. AB - The vitamin D metabolite, 1,25-(OH)2D3, binds the vitamin D receptor (VDR) to exert its regulatory effects at the transcription level. VDR is expressed in professional antigen-presenting cells (pAPCs), such as macrophages (Mo) and dendritic cells (DCs). We show for the first time that the 24-hydroxylase enzyme is activated in bone marrow-derived dendritic cell (BMDC), due to 1,25(OH)2D3 stimulation which resulted in the induction of its gene, CYP24A1. Furthermore, we provide evidence that the influence of 1,25-(OH)2D3 on TLR-4-L-induced activation of pAPC is dependent on the order of VDR and TLR-4 engagement. Thus, pre treatment of pAPC with 1,25-(OH)2D3 partially inhibited LPS-induced nitric oxide (NO) production. However, these inhibitory effects were not observed when LPS and 1,25-(OH)2D3 were added simultaneously or when LPS preceded 1,25-(OH)2D3. Moreover, we found that 1,25-(OH)2D3 pre-treatment of pAPCs did not cause general suppression since it interfered with NO levels but not with the cytokines IL-6 or TNF-alpha. Consequently, engagement of VDR by 1,25-(OH)2D3 can partially interfere with TLR-4-L-induced activation of pAPCs only when it occurs before TLR 4 stimulation. PMID- 21529995 TI - Unraveling the role of fermentation in the mode of action of acetolactate synthase inhibitors by metabolic profiling. AB - Herbicides that inhibit branched chain amino acid biosynthesis induce aerobic fermentation. The role of fermentation in the mode of action of these herbicides is not known, nor is the importance of this physiological response in the growth inhibition and the lethality caused by them. Metabolic profiling was used to compare the effects of the herbicide imazethapyr (IM) on pea plants with two other treatments that also induce fermentation: hypoxia and the exogenous supply pyruvate for seven days. While hypoxic roots did not show internal anoxia, feeding pyruvate or applying IM to the roots led to internal anoxia, probably related to the respiratory burst detected. The three treatments induced ethanol fermentation, but fermentation induced following herbicide treatment was earlier than that following pyruvate supply and was not associated with a decrease in the energy status. No striking changes were detected in the metabolic profiling of hypoxic roots, indicating that metabolism was only slightly impaired. Feeding pyruvate resulted in marked succinate accumulation and a general amino acid accumulation. IM-treated roots showed a general accumulation of glycolytic metabolites upstream of pyruvate, a decrease in some TCA intermediates and an increase in the free amino acid pool sizes. All treatments caused GABA and putrescine accumulation. Our results indicate that IM supply impairs carbon/nitrogen metabolism and this impaired metabolism is likely to be related to the growth arrest detected. As growth is arrested, carbohydrates and glycolytic intermediates accumulate and energy becomes more available. PMID- 21529997 TI - Statin use and risk of first-time psoriasis diagnosis. AB - BACKGROUND: Statins have been suggested as a potential treatment for psoriasis because of their anti-inflammatory properties. However, evidence on the benefits of statins is scarce. OBJECTIVE: We sought to study the association between use of statins or other lipid-lowering agents and the risk of developing psoriasis. METHODS: We conducted a case-control analysis using the United Kingdom-based General Practice Research Database. We identified patients with an incident psoriasis diagnosis between 1994 and 2005 and matched one control subject to each patient on age, sex, general practice, calendar time, and years of history in the database. We estimated odds ratios (ORs) with 95% confidence intervals (CIs), stratified exposure by timing and duration, and adjusted the ORs for potential confounders. RESULTS: We identified 36,702 incident psoriasis cases and the same number of matched controls. Adjusted ORs for current use (last prescription <30 days before index date) of 1 to 4, 5 to 19, or greater than or equal to 20 prescriptions for statins, as compared with nonuse, were 0.60 (95% CI 0.45-0.80), 1.00 (95% CI 0.84-1.18), and 1.08 (95% CI 0.92-1.28), respectively. The ORs for recent and past use (last prescription 30-89 days and >=90 days ago, respectively) were around 1, except for past use of 1 to 4 prescriptions (OR 1.39; 95% CI 1.09-1.78). LIMITATIONS: Potential of residual confounding as a result of retrospective study design is a limitation. CONCLUSIONS: This large case-control study does not provide evidence for an altered risk of developing psoriasis in association with long-term use of statins. The reduced psoriasis risk for current short-term statin users is interesting, but whether the association is indeed causal needs further investigation. PMID- 21529996 TI - Analgesic and nonsteroidal anti-inflammatory use in relation to nonmelanoma skin cancer: a population-based case-control study. AB - BACKGROUND: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are potentially chemopreventive. OBJECTIVE: We examined the relation between NSAID use and nonmelanoma skin cancer in a population-based case-control study. METHODS: NSAID and analgesic use was analyzed in 1484 participants: 535 with squamous cell carcinoma (SCC), 487 with basal cell carcinoma (BCC), and 462 control subjects. RESULTS: Use of NSAIDs, particularly aspirin, was associated with a reduced odds ratio (OR) of SCC, especially tumors positive for p53 (OR 0.29; 95% confidence interval 0.11-0.79) or with PTCH loss of heterozygosity (OR 0.35; 95% confidence interval 0.13-0.96). Although not considered a NSAID, decreased ORs of both basal cell carcinoma and SCC were observed in relation to use of paracetamol (acetaminophen). Risk of BCC was unrelated to NSAID use. LIMITATIONS: Self-reported drug use was a limitation. CONCLUSIONS: This study supports the hypothesis that NSAIDs, aspirin in particular, may reduce risk of SCC and may affect specific molecular subtypes of SCC. PMID- 21529998 TI - Poikilodermatous mycosis fungoides: a study of its clinicopathological, immunophenotypic, and prognostic features. AB - BACKGROUND: Poikilodermatous mycosis fungoides (MF) is a variant of MF, and its clinicopathological, immunophenotypic, molecular, and prognostic features have not previously been defined in the literature. OBJECTIVE: The purpose of this study was to improve the data available for this variant of MF thus enabling clinicians to apply the appropriate treatment and follow-up. METHODS: In a retrospective single center study we evaluated the clinical, histopathological, immunohistochemical, and molecular characteristics of patients with predominant (>50%) poikilodermatous lesions of MF. RESULTS: In all, 49 patients were identified. The median age at diagnosis was 44 years (15-81 years). Of 49 patients, 43 (88%) had early stage disease (<=IIA) at diagnosis. No patients had stage IV disease at presentation. A frequent association was coexistence of lymphomatoid papulosis (9/49; 18%). Histopathology review showed a high number of cases with CD8(+) CD4(-) atypical lymphocytes (38%). After diagnosis most patients were treated with expectant or skin-directed therapy. Psoralen plus ultraviolet A therapy was most frequently used and had high response rates (83%). Five (10%) of 49 received systemic therapy. The mean follow-up was 11 years, 10 months (1->40 years). In all, 47 (96%) of 49 patients had stable disease and two (4%) of 49 had progressive disease. No patients died during follow-up. LIMITATIONS: As a tertiary center our patient cohort may be expected to have more advanced and aggressive disease. CONCLUSION: Poikilodermatous MF represents a distinct clinicopathological entity from classic patch/plaque MF. It presents at a younger age and is more frequently associated with lymphomatoid papulosis. There is an increased number of cases with predominantly CD8(+) CD4(-) atypical lymphocytes. Overall there is a good response to phototherapy and the overall prognosis appears favorable. PMID- 21529999 TI - Topical nitroglycerin: a promising treatment option for chondrodermatitis nodularis helicis. AB - BACKGROUND: Chondrodermatitis nodularis helicis (CNH) is a painful nodule that often interferes with sleep and occurs on the helix or antihelix of the ear in older patients. Although several case reports describe a variety of seemingly effective surgical and conservative treatment options, well-studied treatment modalities have varying efficacy rates and can often demonstrate disappointing results. OBJECTIVES: The purpose of this study was to evaluate the efficacy of 2% topical nitroglycerin for the treatment of CNH. METHODS: A retrospective chart review was performed in 12 patients given the diagnosis of CNH who received 2% topical nitroglycerin twice daily for therapy. Therapeutic efficacy was determined by identifying improvement in the appearance and symptomatology of the lesion. RESULTS: A total of 13 lesions in 12 patients were treated, with 12 (92%) lesions demonstrating improvement with the use of topical nitroglycerin. Eight of 13 (61.5%) CNH lesions developed complete clearance and resolution of symptoms, requiring no further treatment. Four of 13 (30.8%) lesions were found to have only symptomatic improvement, and these patients continued to use the ointment as needed. One of 12 (8.3%) patients found no benefit with the treatment but had also failed multiple other treatments modalities. LIMITATIONS: Limitations include the small number of patients treated and the retrospective nature of the study. CONCLUSIONS: Topical nitroglycerin demonstrated efficacy in treating both the symptoms and lesional appearance of CNH in a noninvasive manner, with an overall success rate that is comparable with other published methods. PMID- 21530000 TI - Nosocomial outbreak of hepatitis B virus infection involving two hospitals in the Republic of Ireland. AB - The routes of nosocomial hepatitis B virus (HBV) transmission have changed over the years. Initiatives to prevent transfusion-associated HBV and healthcare worker-to-patient transmission have had a positive impact on these transmission routes. Recent reports of outbreaks of nosocomial HBV have implicated breaches in standard precautions as important causes of HBV transmission. This report describes a nosocomial outbreak of HBV infection in the Republic of Ireland, which occurred between January 2005 and March 2006. The outbreak was detected following identification of a case of acute HBV infection in a patient whose only risk factor was a recent surgical procedure. The extensive multi-agency investigation that followed revealed that the patient was one of five cases of acute HBV infection and that four separate transmission events between infectious cases had occurred in two different hospitals over a 15-month period. A definitive cause for each transmission event was not identified, although lapses in adherence to standard precautions, safe injection and phlebotomy practices could not be ruled out. Two secondary cases of acute HBV infection in community contacts of two of the nosocomial cases were identified. Phylogenetic analysis proved a useful tool in confirming infection with a pre-core HBV mutant and viral transmission between the seven patients. A patient notification exercise involving 1028 potentially exposed patients found no evidence of additional cases of nosocomial HBV infection. These findings highlight the importance of consistent application of standard precautions. PMID- 21530001 TI - Altered expression of brain acetylcholinesterase in FTDP-17 human tau transgenic mice. AB - Pathological hyperphosphorylation and aggregation of the tau protein is associated with dementia and can be the central cause of neurodegeneration. Here, we examined potential alterations in the level of the cholinergic enzyme acetylcholinesterase (AChE) in the brain of transgenic mice (Tg-VLW) expressing human tau mutations. Overexpression of mutant hyperphosphorylated tau (P-tau) led to an increase in the activity of AChE in the brain of Tg-VLW mice, paralleled by an increase in AChE protein and transcripts; whereas the levels of the enzyme choline acetyltransferase remained unaffected. VLW tau overexpression in SH-SY5Y cells also increased AChE activity levels. All major molecular forms of AChE were increased in the Tg-VLW mice, including tetrameric AChE, which is the major species involved in hydrolysis of acetylcholine in the brain. Colocalization of human P-tau and AChE supports the conclusion that P-tau can act to increase AChE. This study is the first direct evidence of a modulatory effect of P-tau on brain AChE expression. PMID- 21530002 TI - Sensory memory during physiological aging indexed by mismatch negativity (MMN). AB - Physiological aging affects early sensory-perceptual processes. The aim of this experiment was to evaluate changes in auditory sensory memory in physiological aging using the Mismatch Negativity (MMN) paradigm as index. The MMN is a marker recorded through the electroencephalogram and is used to evaluate the integrity of the memory system. We adopted a new, faster paradigm to look for differences between 3 groups of subjects of different ages (young, middle age and older adults) as a function of short or long intervals between stimuli. We found that older adults did not show MMN at long interval condition and that the duration of MMN varied according to the participants' age. The current study provides electrophysiological evidence supporting the theory that the encoding of stimuli is preserved during normal aging, whereas the maintenance of sensory memory is impaired. Considering the advantage offered by the MMN paradigm used here, these data might be a useful reference point for the assessment of auditory sensory memory in pathological aging (e.g., in neurodegenerative diseases). PMID- 21530004 TI - [Obstructive jaundice secondary to the presence of liver fluke: a case report]. PMID- 21530003 TI - Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly. AB - It is not well known whether Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers are associated with brain damage in cognitively normal elderly. The combined influence of CSF biomarkers and hypertension (HTN) on the gray matter (GM) is also not well described. One hundred fifteen cognitively healthy subjects (mean age 62.6 +/- 9.5%, 62% women) received clinical assessment, a high resolution magnetic resonance imaging (MRI), and a lumbar puncture. The CSF levels of total tau (t-tau), hyperphosphorylated tau (p-tau(231)), amyloid beta (Abeta42/Abeta40), p-tau(231)/Abeta42, and t-tau/Abeta42 were dichotomized as "high" and "low" based on accepted cut off values. Statistical parametric mapping was used to examine MRI scans for regional GM density, studied as a function of the CSF markers, HTN, and combination of both. Global and medial temporal lobe (MTL) GM was also assessed. Voxel based morphometry revealed that higher t-tau was associated with lower GM density in the precunei. Subjects with higher p tau(231) and p-tau(231)/Abeta42 had less GM in temporal lobes. Low Abeta42/Abeta40 was related to less GM in the thalami, caudate, and midbrain. Subjects with hypertension showed more GM atrophy in the cerebellum, occipital, and frontal regions. Simultaneous presence of elevated CSF AD biomarkers and HTN was associated with more GM atrophy than either marker individually, but no interaction effects were identified. In conclusion, in normal elderly CSF tau markers were associated predominantly with lower GM estimates in structures typically affected early in the AD process. In this presymptomatic stage when no cognitive impairment is present, AD biomarkers and HTN have additive effects on gray matter damage. PMID- 21530005 TI - [Descriptive study of hepatocellular carcinoma in noncirrhotic liver]. AB - INTRODUCTION AND OBJECTIVE: Hepatocellular carcinoma (HCC) is the sixth leading cause of cancer. In western countries its impact is steadily growing and most of these tumors arise in cirrhotic liver. The aim of this study was to evaluate the incidence and characteristics of HCC developing in noncirrhotic patients. METHODS: We conducted a retrospective review of 469 patients diagnosed with HCC between January 2003 and December 2007. Patients who met the histological criteria, or a combination of clinical, laboratory, imaging and hemodynamic criteria for the absence of cirrhosis were included. RESULTS: We identified 29 patients with a diagnosis of HCC in non-cirrhotic liver (6.2%). Most (86.2%) were men and the median age was 61.6 (23 - 82) years. The most frequent histology of the liver was mild-moderate liver fibrosis (68.9%) and 62.1% of the patients were asymptomatic at diagnosis. HCC was a solitary nodule in 86.2%, and the median size of the main nodule was 46 (20 - 150) mm. Macroscopic vascular invasion was demonstrated in two patients and bone metastases in a further two patients. Active treatment was provided in 25 patients, consisting of tumoral resection in 15, radiofrequency ablation in six and transarterial chemoembolization in four. The overall cumulative survival at 1, 2 and 3 years was 84.3%, 67.2% and 50.1%, respectively. CONCLUSION: HCC arising in non-cirrhotic liver is uncommon and there is wide tumor extension at diagnosis. Nevertheless, in most patients, treatment with curative intent can be applied, achieving better survival than that expected patients with cirrhosis. PMID- 21530006 TI - [Optimization of ascitic fluid culture in spontaneous bacterial peritonitis]. AB - INTRODUCTION AND AIMS: Spontaneous bacterial peritonitis (SBP) is ascitic fluid (AF) infection in the absence of an intraperitoneal source of infection in patients with liver disease and portal hypertension. The aim of this study was to evaluate the yield of microbiological cultures to optimize their collection and systematic implementation in routine clinical practice. METHODS: We analyzed two cohorts: the first consisted of retrospective data from the clinical records of 156 consecutive episodes of SBP from January 2003 to December 2005 (group R), and the second was composed of data collected prospectively from October 2007 to October 2008, consisting of 79 episodes (group P), with systematic inoculation of 10 cc of AF in each blood culture bottle. RESULTS: No significant differences were demonstrated in baseline epidemiological or clinical characteristics among episodes, except the more frequent presence of alcoholic liver disease and the incidence of tense ascites, paralytic ileus and kidney failure at diagnosis in group P. Microbiological isolation in AF was achieved in 12.2% of the episodes in group R compared with 53.2% in group P (p = 0.001) and 8.5 and 26.6% (p = 0.001) in blood culture, respectively. Microbiological isolation was achieved in 65.8% of episodes in group P versus 19.2% in group R (OR 8; 95% CI: 4.4-14.9; p = 0.001). The most frequently isolated organism in AF in group P was Escherichia coli (42.9%). CONCLUSIONS: Optimizing the diagnostic procedure in cirrhotic patients with ascites significantly increases diagnostic microbiologic performance. PMID- 21530007 TI - [Informing of the diagnosis in dementia]. AB - Dementia is a syndrome characterized by a progressive deterioration of cognitive functions, accompanied by psychiatric symptoms and behavioral disturbances that produce a progressive and irreversible disability. The way it should communicate the diagnosis of dementia is a key discussion point on which there is no unanimous agreement so far. The communicating of the diagnosis of dementia is a complex issue that affects not only, the patient but also to caregivers and health professionals who care and must conform to the ethical principles governing medical practice (autonomy, nonmaleficence, beneficence, and justice). Therefore, from the Dementia Working Group of the Catalan Geriatric Society (Grupo de Trabajo de Demencia de la Sociedad Catalana de Geriatria) arises the need to review the issue and propose a course of action for the disclosure of diagnosis. PMID- 21530008 TI - [Identification and selection of diseases of possible occupational origin managed through the National Health System]. AB - OBJECTIVE: To identify and select common diseases of possible occupational origin, managed through the Spanish National Health System. DESIGN: Cross sectional study. SETTING: Catalonia (Spain). PARTICIPANTS: Data were collected on people over 15 years of age who were seen for the first time in a primary care clinic or were admitted to a hospital or had an episode of non-occupational sickness absence in catalonia in 2008 or died in this region in 2007. MAIN MEASUREMENTS: A total of 407 diagnostic codes for possible occupationally-related diseases were selected from a modified version of the european union ICD-10 list of diagnostic codes, from which 34 were selected and assessed by an expert panel. RESULTS: The initial 34 diagnoses represented 6.7% of all new outpatient visits, 13.8% of the sickness absence episodes, 13.6% of acute admissions and 15.8% of all annual deaths. Asthma appeared prominently in all four databases. The list was pared down to a final list of 26 four-digit icd-10 codes, that accounted for 3.3% of the first visits, 8.9% of lost work time episodes and 2.7% of acute admissions. CONCLUSIONS: The implementation of a "red flag" into the electronic medical record each time one of these 26 diagnostic codes is entered, could help to improve the reporting of occupational diseases. PMID- 21530009 TI - [Hematoma versus urinoma: a diagnostic dilemma of 99mTc-MAG3 renal scan in the evaluation of renal transplantation]. PMID- 21530010 TI - [Sentinel node biopsy in patients with breast cancer and previous breast surgery]. AB - AIM: The aim of this study was to establish the efficacy and safety of sentinel lymph node biopsy for lymph node staging in patients with breast cancer and prior breast surgery, considering its extension, localization and time since the previous surgical procedure. MATERIAL AND METHODS: A sentinel lymph node biopsy was performed in 38 patients with early breast cancer and previous breast surgery: recent excisional biopsy in 22 patients (Group I), previous lumpectomy or mammoplasty in 16, including one case of cancer treated with breast-conserving surgery (tumor recurrence). Lymphoscintigraphy was performed after periareolar injection, also sometimes adding an injection near to the surgical scar. After removing the sentinel node, axillary lymph node dissection was performed when the lymph node was positive (and not localized). RESULTS: The efficacy of the scintigraphic localization of the sentinel node was 92.1% of the patients, with 15.8% of extra-axillary drainages. Axillary intraoperative detection was 81.6%. The identification rate after recent excisional biopsy or previous surgery was similar (81.8 vs 81.2%). However, extra-axillary sentinel nodes were more frequent in Group II (9.1 vs 25%). Having a localization of previous surgical procedures in upper outer quadrant caused drainages outside of the axilla more frequently (27.2 vs 11.1%). Axillary detection rate was similar to other quadrants (81.8 vs 81.5%). The rate of breast cancer-related events was 5.2% (2/38), without axillary recurrences (mean follow-up: 3 years). CONCLUSION: Sentinel lymph node biopsy in patients with previous but not extensive breast surgery is safe. Extra-axillary drainages are more common when the previous surgical area was wide, especially in the upper-outer quadrant. PMID- 21530011 TI - [Myocardial metastasis from carcinoid tumor in absence of liver involvement]. PMID- 21530012 TI - Acalculous cholecystitis during infectious mononucleosis in a young male patient. PMID- 21530013 TI - Synthesis, antiproliferative activity, and mechanism of action of a series of 2 {[(2E)-3-phenylprop-2-enoyl]amino}benzamides. AB - Several new 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides 12a-s and 17t-v were synthesized by stirring in pyridine the (E)-3-(2-R1-3-R2-4-R3-phenyl)acrylic acid chlorides 11c-k and 11t-v with the appropriate anthranilamide derivatives 10a-c or the 5-iodoanthranilic acid 13. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). COMPARE analysis, effects on tubulin polymerization in cells and with purified tubulin, and effects on cell cycle distribution for 17t, the most active of the series, indicate that these new antiproliferative compounds act as antitubulin agents. PMID- 21530014 TI - 3-(1,3,4-Thiadiazole-2-yl)quinoline derivatives: synthesis, characterization and anti-microbial activity. AB - A new series of thiadiazoles and intermediate thiosemicarbazones were synthesized from the chloroquinone molecule, with an aim to explore their effect on in vitro growth of microorganisms causing microbial infection. The chemical structures of the compound were elucidated by elemental analysis, FTIR, 1H and 13C NMR and ESI MS spectral data. In vitro anti-microbial activity was performed against Staphylococcusaureus, Streptococcuspyogenes, Salmonellatyphimurium, and Escherichiacoli. The MIC was detected using the double dilution method. The results were compared by calculating percent inhibit area/MUg of the compounds and the standard "amoxicillin". The selected compounds were tested for cytotoxic results using MTT assay H9c2 cardiac myoblasts cell line and the results showed that all the compounds offered remarkable >80% viability to a concentration of 200 MUg/mL. PMID- 21530015 TI - Cyathane diterpenes from Chinese mushroom Sarcodon scabrosus and their neurite outgrowth-promoting activity. AB - Two novel cyathane diterpenoids, designated scabronines K (1) and L (2), were isolated from the fruiting bodies of the basidiomycete Sarcodon scabrosus together with four known analogues, sarcodonins G (3), A (5), M (6), and scabronine H (4). Their structures were elucidated on the basis of extensive spectroscopic analysis including 2D-NMR (HMBC, HSQC, ROESY, (1)H,(1)H-COSY) and MS experiments. The isolated compounds were evaluated for nerve growth factor (NGF)-mediated neurite outgrowth using rat pheochromocytoma (PC12) cells as a model system of neuronal differentiation. Among these compounds, only sarcodonins G and A (3 and 5) at 25 MUM showed significant neurite outgrowth (neuritegenesis) promoting activity in the presence of 20 ng/mL NGF after 24h treatment. Their structure-neurite inducing activity relationship was also discussed. PMID- 21530016 TI - Design, synthesis and in vitro drug release investigation of new potential 5-FU prodrugs. AB - In order to identify new efficient prodrugs of 5-fluorouracil (5-FU) and to develop an original targeting approach using 2-fluoro-2-deoxyglucose (FDG) as a potential drug carrier, eight original 5-FU derivatives were synthesized: 5-FU was attached by the N1 position of the pyrimidinic ring to the C1 position of the FDG structure either by direct coupling (2a) or via various spacers (3, 6a-c, 10b and 19). A new sensitive high-performance liquid chromatography method was developed to simultaneously quantify 5-FU and its derivatives in human plasma and other relevant media at physiological temperatures. Half-lives were determined from the degradation profiles of these conjugates. Slow degradation of compounds 2a, 3, 10b and 19 was observed in vitro at 37 degrees C, but no 5-FU release was noticed. By contrast, the in vitro drug release profiles of compounds 6a-c followed pseudo-first-order kinetics, and 5-FU was found in all the media. The antiproliferative activity of the eight compounds was assessed in vitro by a fluorometric assay against two human solid cancer cell lines and one healthy cell line. A correlation was found between the activities of the compounds and their ability to release 5-FU efficiently. PMID- 21530018 TI - Synthesis and in vitro antimalarial activity of tetraoxane-amine/amide conjugates. AB - A series of tetraoxanes, tetraoxane-amine and tetraoxane-amide conjugates have been synthesized and screened for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Most of the conjugates showed slightly better antimalarial activity than the parent tetraoxanes. Three of the conjugate compounds were potentially active with IC(50) values in the range of 0.38-0.80MUM. Cytotoxicity of four selected compounds was also evaluated in a panel of four cancer (SK-MEL, KB, BT-549, SK-OV 3) and two non-cancer (Vero and LLC-PK(11)) cell lines up to a concentration of 25MUM and none of the compounds was found toxic to any of the cells. PMID- 21530017 TI - Effects of external phase on D-cycloserine loaded W/O nanocapsules prepared by the interfacial polymerization method. AB - Water in oil (W/O) polybutylcyanoacrylate nanocapsules containing D-cycloserine (D-CS) for intranasal delivery were prepared by the interfacial polymerization method. Different oils, as external phase, for the preparation of the initial W/O miniemulsions were used and their effect on mean size and other physico-chemical properties were evaluated by photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM) analysis. Two probes at different hydrophilicity were used to verify the internal aqueous nature of the core. Both miniemulsions and nanocapsules mean size and polydispersity index were influenced by the used external phase. Different entrapment efficiency were obtained for D-cycloserine loaded nanocapsules correlated to the used oil [ranging from 39 to 51% encapsulation efficiency (E.E.)]. In vitro drug release showed an initial burst effect (ranging from 20 to 40%) followed by a slow release of D-CS for all preparations. This study demonstrated that many relevant physico-chemical and technological properties of polybutylcyanoacrylate nanocapsules prepared by interfacial polymerization of miniemulsions are significantly influenced by the external oil phase used. PMID- 21530019 TI - Combining molecular docking and QSAR studies for modelling the antigyrase activity of cyclothialidine derivatives. AB - DNA gyrase is a well-established antibacterial target consisting of two subunits, GyrA and GyrB, in a heterodimer A(2)B(2), where GyrB catalyzes the hydrolysis of ATP. Cyclothialidine (Ro 09-1437) has been considered as a promising inhibitor whose modifications might lead to more potent compounds against the enzyme. We report here for the first time, QSAR studies regarding to ATPase inhibitors of DNA Gyrase. 1D, 2D and 3D descriptors from DRAGON software were used on a set of 42 cyclothialidine derivatives. Based on the core of the cyclothialidine GR122222X, different conformations were created by using OMEGA. FRED was used to dock these conformers in the cavity of the GyrB subunit to select the best conformations, paying special attention to the 12-membered ring. Three QSAR models were developed considering the dimension of the descriptors. The models were robust, predictive and good in statistical significance, over 70% of the experimental variance was explained. Interpretability of the models was possible by extracting the SAR(s) encoded by these predictive models. Analyzing the compound-enzyme interactions of the complexes obtained by docking allowed us to increase the reliability of the information obtained for the QSAR models. PMID- 21530020 TI - Preeclampsia: a multi-stress disorder. PMID- 21530021 TI - [Poitiers: 732, Charles Martel and...2011, the SNFMI!]. PMID- 21530022 TI - Application of radiochemical determination methods in cleanability research of building materials. AB - During recent years increasing effort has been made to modify surface properties with easy-to-clean or self-cleaning characteristics, and concomitantly there is a need to be able to quantify cleanability. Methodology is a complex issue, including aspects of selection and characterization of the surface materials, the soiling materials (contaminants), soiling and cleaning methods, and the detection methods. Different biological, chemical, physical and visual methods have been included in studies of surface cleanability. One challenge has been to obtain quantitative information about soiling. The radiochemical methods, gamma spectrometry (NaI(Tl)-crystal) and liquid scintillation counting, have been shown to be suitable for evaluating cleanability of different surface materials and different soiling material types, providing quantitative information about the amount of soiling material both on and beneath the surface. Due to the different labelled soiling components, the interaction of the surface with different soiling material types can be evaluated. Radiochemical methods have unique benefits particularly for examining porous materials and surfaces. However, they are suitable only for highly controlled studies because of the hazards. Different features and details of radiochemical methods are discussed with the view to aid planning of future cleanability studies. PMID- 21530023 TI - A follow up of the decrease of non exchangeable organically bound tritium levels in the surroundings of a nuclear research center. AB - In the past decades limited amounts of tritium were handled on the CEA site of Bruyeres le Chatel with authorised atmospheric releases. A small fraction of the tritium released entered into environmental samples under three forms: (i) as part of free water (TFWT - Tissue Free Water Tritium), or associated with organic matter in two ways; either (ii) bound to the oxygen and nitrogen atoms of the material as exchangeable organically bound tritium (E-OBT), or (iii) bound to carbon atoms as non exchangeable organically bound tritium (NE-OBT). The first two components provide only a picture of atmospheric tritium concentrations at the sampling time as they are in equilibrium with atmospheric moisture and soil humidity. Unlike these exchangeable forms, however, NE-OBT is tightly bound to the organic matter and provides an integrated record of atmospheric tritium during the growing phase of the vegetation. We mapped NE-OBT in tree leaf samples in an area of about 25*30km(2) around the centre of the CEA site and compared the results with those obtained during a previous sampling exercise in 1989. At this time, the activity levels were almost ten times higher than those observed presently in a similar area almost 20 years later which is consistent with the decrease of atmospheric releases issued from the centre. As the activity levels are now close to environmental background specific attention was also paid to the analytical procedure to ensure reliable low level NE-OBT detection. PMID- 21530024 TI - Tissue radionuclide concentrations in water birds and upland birds on the Hanford Site (USA) from 1971-2009. AB - Historical operations at the Hanford Site (Washington State, USA) have released a wide array of non-radionuclide and radionuclide contaminants into the environment. As a result, there is a need to characterize contaminant effects on site biota. Within this framework, the main purpose of our study was to evaluate radionuclide concentrations in bird tissue, obtained from the Hanford Environmental Information System (HEIS). The database was sorted by avian group (water bird vs. upland bird), radionuclide (over 20 analytes), tissue (muscle, bone, liver), location (onsite vs. offsite), and time period (1971-1990 vs. 1991 2009). Onsite median concentrations in water birds were significantly higher (Bonferroni P < 0.05) than those in onsite upland birds for Cs-137 in muscle (1971-1990) and Sr-90 in bone (1991-2009), perhaps due to behavioral, habitat, or trophic species differences. Onsite median concentrations in water birds were higher (borderline significance with Bonferroni P = 0.05) than those in offsite birds for Cs-137 in muscle (1971-1990). Onsite median concentrations in the earlier time period were significantly higher (Bonferroni P < 0.05) than those in the later time period for Co-60, Cs-137, Eu-152, and Sr-90 in water bird muscle and for Cs-137 in upland bird muscle tissue. Median concentrations of Sr-90 in bone were significantly higher (Bonferroni P < 0.05) than those in muscle for both avian groups and both locations. Over the time period, 1971-2009, onsite median internal dose was estimated for each radionuclide in water bird and upland bird tissues. However, a meaningful dose comparison between bird groups was not possible, due to a dissimilar radionuclide inventory, mismatch of time periods for input radionuclides, and lack of an external dose estimate. Despite these limitations, our results contribute toward ongoing efforts to characterize ecological risk at the Hanford Site. PMID- 21530025 TI - Abundance and diversity of aquatic macroinvertebrate communities in lakes exposed to Chernobyl-derived ionising radiation. AB - Littoral (lake shore) macroinvertebrate communities were studied in eight natural lakes affected by fallout from the Chernobyl accident. The lakes spanned a range in (137)Cs contamination from 100 to 15500 kBq m(-2) and estimated external dose rates ranged from 0.13 to 30.7 MUGy h(-1). General linear models were used to assess whether abundance of individuals, taxon richness, Berger-Parker dominance and Shannon-Wiener diversity varied across the lakes. Step-wise multiple regressions were used to relate variation in total abundance, taxon richness, Berger-Parker dominance, Shannon-Wiener diversity, taxon richness within major groups of macroinvertebrates and abundance of the more common individual taxa to the measured environmental characteristics (conductivity, pH, total hardness and phosphate; lake area, lake maximum depth and total external dose) of the lakes. No evidence was found in this study that the ecological status of lake communities has been influenced by radioactive contamination from the Chernobyl accident. Indeed, the most contaminated lake, Glubokoye, contained the highest richness of aquatic invertebrates. Taxon richness in the eight study lakes varied from 22 (Svyatskoe #7) to 42 (Glubokoye) which spans a range typical for uncontaminated lakes in the region. Since (90)Sr is readily-absorbed by Mollusca, estimated dose rates to this group exceeded those for other invertebrate groups in two lakes (Perstok and Glubokoye). However this study found no association between mollusc diversity or abundance of individual snail species and variation between lakes in the external radiation dose. Indeed Glubokoye, the lake most contaminated by (90)Sr, had the highest richness of freshwater snails per sample (an average of 8.9 taxa per sample). PMID- 21530026 TI - Elevated radioxenon detected remotely following the Fukushima nuclear accident. AB - We report on the first measurements of short-lived gaseous fission products detected outside of Japan following the Fukushima nuclear releases, which occurred after a 9.0 magnitude earthquake and tsunami on March 11, 2011. The measurements were conducted at the Pacific Northwest National Laboratory (PNNL), (46 degrees 16'47"N, 119 degrees 16'53"W) located more than 7000 km from the emission point in Fukushima Japan (37 degrees 25'17"N, 141 degrees 1'57"E). First detections of (133)Xe were made starting early March 16, only four days following the earthquake. Maximum concentrations of (133)Xe were in excess of 40 Bq/m(3), which is more than *40,000 the average concentration of this isotope is this part of the United States. PMID- 21530027 TI - Duane retraction syndrome mimicking orbital fracture. AB - We describe the case of a 20-year-old patient who presented at the accident and emergency department with symptoms and signs of fractures of the zygomatic complex and orbit following an assault. He was later discovered to have Duane retraction syndrome, a rare congenital disorder of eye movement that has some of the clinical characteristics of fractures of the zygomatic complex and orbit. The fracture was not displaced, and without knowledge of the syndrome a surgeon might have been forced to investigate further. PMID- 21530028 TI - Traumatic brain injury: review of current management strategies. AB - Head injury is a common condition with a high morbidity and mortality. Serious intracranial haematomas require early recognition and evacuation to maximise chances of independent outcomes. Recent organisational changes have promoted the development of trauma units and major trauma centres where patients can go through triage and be managed in an appropriate environment, and the development of management pathways in intensive treatment units has resulted in improvements in the outcome of traumatic brain injuries. Evidence for the treatment of cerebral perfusion pressure, and management of hyperventilation, osmotherapy, tracheostomy, and leakage of cerebrospinal fluid (CSF) has accumulated during the last decade and is important in the management of patients in all clinical settings. Since head injury is commonly associated with maxillofacial injuries, this review will be relevant to all who deal with this aspect of trauma. PMID- 21530029 TI - Closure of oroantral fistula using auricular cartilage: a new method to repair an oroantral fistula. PMID- 21530030 TI - Seasonal variation and source estimation of organic compounds in urban aerosol of Augsburg, Germany. AB - This study reports a general assessment of the organic composition of the PM(2.5) samples collected in the city of Augsburg, Germany in a summer (August-September 2007) and a winter (February-March 2008) campaign of 36 and 30 days, respectively. The samples were directly submitted to in-situ derivatisation thermal desorption gas chromatography coupled with time of flight mass spectrometry (IDTD-GC-TOFMS) to simultaneously determine the concentrations of many classes of molecular markers, such as n-alkanes, iso- and anteiso-alkanes, polycyclic aromatic hydrocarbons (PAHs), oxidized PAHs, n-alkanoic acids, alcohols, saccharides and others. The PCA analysis of the data identified the contributions of three emission sources, i.e., combustion sources, including fossil fuel emissions and biomass burning, vegetative detritus, and oxidized PAHs. The PM chemical composition shows seasonal trend: winter is characterized by high contribution of petroleum/wood combustion while the vegetative component and atmospheric photochemical reactions are predominant in the hot season. PMID- 21530031 TI - Urban environment: defining its nature and problems and developing strategies to overcome obstacles to sustainability and quality of life. PMID- 21530032 TI - Evidence of lead biomagnification in invertebrate predators from laboratory and field experiments. AB - This report includes atomic absorption data from water column, elutriates and zooplankton that demonstrate that lead biomagnifies at El Niagara reservoir, Mexico. Results include field data (bioaccumulation factors) (BAFs) and laboratory data (bioconcentration factors) (BCFs). Two findings: high BAFs for invertebrate predator like Acanthocyclops robustus, Asplanchna brightwellii, Culex sp. larvae, and Hyalella azteca, compared to grazer species Moina micrura and Simocephalus vetulus; low BCF's found for some predators, suggested that lead biomagnifications were taking place. The presence of Moina micrura in the gut of Asplanchna allowed us to design experiments where A. brightwellii was fed lead exposed M. micrura neonates. The BAF of Asplanchna was 123,684, BCF was 490. Asplanchna individuals fed exposed Moina had 13.31 times more lead than Asplanchna individuals just exposed 48-h to lead, confirming that lead biomagnification occurs. Results of two fish species showed no lead biomagnification, suggesting that lead biomagnification might be restricted to invertebrate predators. PMID- 21530033 TI - The effect of nitrogen deposition on the species richness of acid grasslands in Denmark: a comparison with a study performed on a European scale. AB - The effect of atmospheric nitrogen deposition on the species richness of acid grasslands was investigated by combining data from a large Danish monitoring program with a large European data set, where a significant non-linear negative effect of nitrogen deposition had been demonstrated (Stevens et al., 2010). The nitrogen deposition range in Denmark is relatively small and when only considering the Danish data a non-significant decrease in the species richness with nitrogen deposition was observed. However, when both data sets were combined, then the conclusion of the European survey was further corroborated by the results of the Danish monitoring. Furthermore, by combining the two data sets a more comprehensive picture of the threats to the biodiversity of acid grasslands emerge; i.e., species richness in remnant patches of acid grassland in intensively cultivated agricultural landscapes is under influence not only from nitrogen deposition, but also from current and historical land use. PMID- 21530034 TI - Kidney transplantation in HIV-infected patients. PMID- 21530036 TI - The Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor: rationale and methods for an initiative to monitor the new US bundled dialysis payment system. AB - A new initiative of the US Dialysis Outcomes and Practice Patterns Study (DOPPS), the DOPPS Practice Monitor (DPM), provides up-to-date data and analyses to monitor trends in dialysis practice during implementation of the new Centers for Medicare & Medicaid Services (CMS) end-stage renal disease Prospective Payment System (PPS; 2011-2014). We review DPM rationale, design, sampling approach, analytic methods, and facility sample characteristics. Using stratified random sampling, the sample of ~145 US facilities provides results representative nationally and by facility type (dialysis organization size, rural/urban, free standing/hospital based), achieving coverage similar to the CMS sample frame at average values and tails of the distributions for key measures and patient characteristics. A publicly available web report (www.dopps.org/DPM) provides detailed trends, including demographic, comorbidity, and dialysis data; medications; vascular access; and quality of life. Findings are updated every 4 months with a lag of only 3-4 months. Baseline data are from mid-2010, before the new PPS. In sum, the DPM provides timely representative data to monitor effects of the expanded PPS on dialysis practice. Findings can serve as an early warning system for possible adverse effects on clinical care and as a basis for community outreach, editorial comment, and informed advocacy. PMID- 21530037 TI - No strings attached: good intentions and unintended consequences in promoting kidney donation. PMID- 21530035 TI - Pathogenesis of acute kidney injury: foundation for clinical practice. AB - The pathogenesis of acute kidney injury (AKI) is complex, involving such factors as vasoconstriction, leukostasis, vascular congestion, cell death, and abnormal immune modulators and growth factors. Many targeted clinical therapies have failed, are inconclusive, or have yet to be tested. Given the complexity of the pathogenesis of AKI, it may be naive to expect that one therapeutic intervention would have success. Some examples of detrimental processes that can be blocked in preclinical models to improve kidney function and survival are apoptotic cell death in tubular epithelial cells, complement-mediated immune system activation, and impairment of cellular homeostasis and metabolism. Modalities with the potential to decrease morbidity and mortality in patients with AKI include vasodilators, growth factors, anti-inflammatory agents, and cell-based therapies. Pharmacologic agents that target these diverse pathways are being used clinically for other indications. Using combinatorial approaches in future clinical trials may improve our ability to prevent and treat AKI. PMID- 21530038 TI - Prenatal care among immigrant and racial-ethnic minority women in a new immigrant destination: exploring the impact of immigrant legal status. AB - Despite the rising share of undocumented immigrants in the US population, research has been quite limited regarding immigrant legal status and how it may limit healthcare access, especially research involving direct identification of undocumented populations. Drawing upon the Utah Population Database, a unique, comprehensive linked system of vital, medical, and administrative records, we analyze the prenatal care utilization in a large and recent cohort of births to mothers residing in the pre-emerging immigrant gateway state of Utah. Our analyses focus on the racial-ethnic, nativity and legal status of mothers as factors that influence prenatal care utilization. State administrative records are used to assess legal status among foreign-born mothers, specifically driver privilege cards made available to undocumented migrants. Our results indicate the importance of disaggregating the expansive categories of Hispanics and the foreign born to better understand health outcomes and healthcare utilization among immigrants. In particular, we find that the legal status of immigrant mothers is one of several important factors influencing prenatal care utilization. Undocumented women are among the least likely to obtain adequate levels of prenatal care. However, undocumented women's prenatal care utilization is enhanced among those using the state's integrative driver privilege program, and among those residing in neighborhoods with high concentrations of immigrants. Results are discussed in light of theory on immigrant integration and healthcare access, and in terms of public policies, such as those extending driver privileges to unauthorized immigrants, which aim to facilitate immigrants' access to institutions within destination communities. PMID- 21530039 TI - Obesity disparities among disadvantaged men: national adult male inmate prevalence pooled with non-incarcerated estimates, United States, 2002-2004. AB - Obesity prevalence among inmates in the United States is unknown. Since incarceration disproportionately affects minorities, excluding inmates from surveys may bias national obesity estimates. Including inmates may also help explain racial obesity disparities among men. This descriptive study summarizes obesity prevalence among US male inmates and analyzes the effect of incarceration on national prevalence estimates. Data for male inmates came from the 2002 Survey of Inmates in Local Jails and the 2004 Survey of Inmates in State and Federal Correctional Facilities. Data for the non-incarcerated US adult male population came from the 2004 National Health Interview Survey. Self-reported weight and height data were analyzed from men aged 25-59 years for all surveys (obesity equaled BMI >= 30.0 kg/m(2)). Pooled inmate obesity prevalence was less than non incarcerated estimates across all race/ethnic-education subgroups. However, unlike non-incarcerated estimates, inmates had obesity disparities between Hispanics and non-Hispanic Whites. Merging inmate and non-incarcerated estimates lowered obesity prevalence among men aged 25-39 with lower education levels. Merged estimates showed a positive obesity gradient within Whites by education. This study indicates that the exclusion of inmates from national obesity estimates leads to overestimates in obesity prevalence, particularly for low SES White and Black men. PMID- 21530040 TI - Best-worst scaling vs. discrete choice experiments: an empirical comparison using social care data. AB - This paper presents empirical findings from the comparison between two principal preference elicitation techniques: discrete choice experiments and profile-based best-worst scaling. Best-worst scaling involves less cognitive burden for respondents and provides more information than traditional "pick-one" tasks asked in discrete choice experiments. However, there is lack of empirical evidence on how best-worst scaling compares to discrete choice experiments. This empirical comparison between discrete choice experiments and best-worst scaling was undertaken as part of the Outcomes of Social Care for Adults project, England, which aims to develop a weighted measure of social care outcomes. The findings show that preference weights from best-worst scaling and discrete choice experiments do reveal similar patterns in preferences and in the majority of cases preference weights--when normalised/rescaled--are not significantly different. PMID- 21530041 TI - Massive craniofacial teratoma: a case report. PMID- 21530042 TI - The effect of crown/implant ratio and crown height space on stress distribution in unsplinted implant supporting restorations. AB - PURPOSE: To measure the transfer of axial and nonaxial load in unsplinted fixed implant supported restoration with varying crown to implant (C/I) ratios and crown height space (CHS). MATERIALS AND METHODS: A photoelastic block model was constructed. Three holes were drilled vertically in a straight line in the mid axis of the photoelastic model at predetermined locations to lengths of 12 mm. Three implants were inserted into the model. Two strain gauges were cemented onto the neck of each implant on the buccal and lingual aspects, which provided a simultaneous direct reading of strain. Four groups of cement retained restorations with C/I ratios of 1:1; 1:1.5; 1:1.75, and 1:2 were used. CHS were 10, 15, 17.5, and 20 mm, respectively. Fifteen static loadings were carried out simultaneously with 20 kg weights via a custom-built loading apparatus at 0 and 30 degrees to the vertical axis. Descriptive analysis consisted of mean and standard deviation of microstrain values for each group. Groups were compared by the use of the 1-way parametric analysis of variance. A P value of less than .05 was considered statistically significant. RESULTS: Occlusal force application at 30 degrees showed a statistically significant increase in both buccal (1,588 +/- 150 vs 2,610.59 +/- 150) and palatal (64.92 +/- 7 vs 146.59 +/- 15) microstrain values as C/I ratio increased from 1:1 to 1:1.5 (P < .001). Force application at 30 degrees in cases with C/I ratio of 1:1.75 and 1:2 resulted in fracture of the abutment screw followed by dislodgment of the crowns. Failures were noted at CHS >15 mm. CONCLUSIONS: CHS is more significant than the C/I ratio in assessing biomechanical-related detrimental effects. Prosthetic failure occurred at CHS >= 15 mm. PMID- 21530043 TI - Attitudes and opinions of residency directors and residents about the importance of research in oral and maxillofacial surgery residencies. AB - PURPOSE: The purpose of this study was to determine the current status of research done by residents in oral and maxillofacial surgery training programs and the attitudes and opinions of the program directors and residents regarding the need and benefits of such activity. MATERIALS AND METHODS: Separate questionnaires were developed for program directors and residents. These were sent through the Inquisite System to the 101 program directors in the United States and they were requested to fill them out and to ask their residents to do the same. Forty-four of the program directors (43%) and 277 of the 951 residents responded (29%). RESULTS: Only 75% of the program directors indicated that their residents participated in research. The projects generally could be selected by the program director or the resident. Only 36% of the programs provided scheduled research time, and in these programs it was usually 3 months or less. Residents generally believed the scheduled research time was inadequate. Most program directors and residents believed that research experience was important for those considering an academic career but that it was not important for those entering private practice. CONCLUSIONS: The failure of all residency programs to provide actual research experience for their trainees has resulted in a decrease in the contributions that such programs have traditionally made to the literature and the advancement of the speciality. It is important that steps be taken to reverse this trend. PMID- 21530044 TI - Subsequent publication of oral and maxillofacial surgery meeting abstracts. AB - PURPOSE: Previous studies in various medical specialties have shown that fewer than 50% of abstracts presented at meetings are subsequently published. The purpose of the present study was to determine the publication rate of abstracts presented at the annual meetings of the American Association of Oral and Maxillofacial Surgeons. MATERIALS AND METHODS: The titles and authors of the abstracts from all oral abstract session presentations and posters by American contributors were collected from the Final Programs of the American Association of Oral and Maxillofacial Surgeons annual meetings for 2006 to 2009. A PubMed search for published articles through December 2010 was then performed using the authors' names, abstract titles, and key words. RESULTS: A total of 311 abstract presentations were done at the 4 annual meetings. Of these, only 85 (24%) were subsequently published. No difference was found between abstracts from oral or poster presentations. Most of the articles were published in the Journal of Oral and Maxillofacial Surgery. CONCLUSION: Because of deficiencies that can occur in abstracts and the need to disseminate the information they contain, it is important to take the appropriate measures to ensure that full articles are subsequently published. PMID- 21530045 TI - WITHDRAWN: Comparison of Enucleation With and Without Carnoy Solution for the Treatment of Odontogenic Keratocyst: A Prospective, Randomized Clinical Trial. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.joms.2011.01.034. The duplicate article has therefore been withdrawn. PMID- 21530047 TI - A 3-dimensional airway analysis of an obstructive sleep apnea surgical correction with cone beam computed tomography. AB - PURPOSE: The purpose of this case report is to present cephalometric changes in the craniofacial region and volumetric changes in the oropharyngeal region of a patient diagnosed with obstructive sleep apnea syndrome after maxillomandibular advancement and genial tubercle advancement surgeries. MATERIALS AND METHODS: Cone beam computed tomographic images were used to evaluate cephalometric changes in the craniofacial region and linear changes in the oropharyngeal region of the patient. RESULTS: A patient with obstructive sleep apnea was treated successfully with maxillomandibular advancement and genial tubercle advancement surgery. Airway analysis showed a significant increase in the volume of the patient's oropharynx after surgery. CONCLUSION: Cone beam computed tomographic images are recommended for 3-dimensional airway evaluation in the treatment of obstructive sleep apnea syndrome. PMID- 21530046 TI - Influence of estrogen deficiency on bone around osseointegrated dental implants: an experimental study in the rat jaw model. AB - PURPOSE: The aim of this study was to evaluate the influence of estrogen deficiency on bone around osseointegrated dental implants in a rat jaw model. MATERIALS AND METHODS: This study used 16 female rats that had the first molars bilaterally extracted and were allowed to heal for 30 days before implant placement. Sixty days after implant placement, the animals were randomly subjected to sham surgery or ovariectomy (OVX). The animals were euthanized 90 days after OVX. Bone-to-implant contact, bone area fraction occupancy between implant threads, mineral density, turnover markers, and cells positive for tartrate-resistant acid phosphatase were assessed for the 2 groups. RESULTS: The results showed that OVX group presented a decrease of systemic bone density, alterations in bone turnover markers, and an increase of cells positive for tartrate-resistant acid phosphatase compared with the sham-surgery group. However, no difference relative to bone-to-implant contact and bone area fraction occupancy was observed between groups. CONCLUSIONS: The findings of this study demonstrate that estrogen deficiency may not be considered a risk factor for osseointegrated implant failure in jaw bone. PMID- 21530048 TI - Effect of drilling technique on the early integration of plateau root form endosteal implants: an experimental study in dogs. AB - PURPOSE: This study tested the hypothesis that early integration of plateau root form endosseous implants is significantly affected by surgical drilling technique. MATERIALS AND METHODS: Sixty-four implants were bilaterally placed in the diaphysial radius of 8 beagles and remained 2 and 4 weeks in vivo. Half the implants had an alumina-blasted/acid-etched surface and the other half a surface coated with calcium phosphate. Half the implants with the 2 surface types were drilled at 50 rpm without saline irrigation and the other half were drilled at 900 rpm under abundant irrigation. After euthanasia, the implants in bone were nondecalcified and referred for histologic analysis. Bone-to-implant contact, bone area fraction occupancy, and the distance from the tip of the plateau to pristine cortical bone were measured. Statistical analyses were performed by analysis of variance at a 95% level of significance considering implant surface, time in vivo, and drilling speed as independent variables and bone-to-implant contact, bone area fraction occupancy, and distance from the tip of the plateau to pristine cortical bone as dependent variables. RESULTS: The results showed that both techniques led to implant integration and intimate contact between bone and the 2 implant surfaces. A significant increase in bone-to-implant contact and bone area fraction occupancy was observed as time elapsed at 2 and 4 weeks and for the calcium phosphate-coated implant surface compared with the alumina blasted/acid-etched surface. CONCLUSIONS: Because the surgical drilling technique did not affect the early integration of plateau root form implants, the hypothesis was refuted. PMID- 21530049 TI - University of Michigan Oral and Maxillofacial Surgery Training Program. PMID- 21530050 TI - From the teaching centers: University of Illinois Oral and Maxillofacial Surgery. PMID- 21530051 TI - Dichotic listening in children: age-related changes in direction and magnitude of ear advantage. AB - Children between the ages of 5 and 12 years were tested with dichotic listening tests utilizing single syllable words and random presentations of digits. They produced a higher prevalence of left ear dominance than expected, especially among right-handed children when tested with words. Whether more children demonstrate the LEA because of right hemisphere dominance for language or because there is less stability in ear advantage direction at younger ages cannot be fully resolved by this study. When ear advantages were measured by subtracting each child's lower score from the higher score without regard to right or left direction, an age-related trend toward lower measures of ear advantage was evident. This trend was greater for dichotic words than for dichotic digits. Structural factors that may be related to these results and possible influences of attention and verbal workload on the two kinds of dichotic stimuli are discussed. PMID- 21530052 TI - [Exposure to secondhand smoke and dental caries in children]. PMID- 21530053 TI - [The European Resuscitation Council's Guidelines for Resuscitation 2010 in Perspective: we need to do better]. PMID- 21530054 TI - [Retinal vascular signs: a window to the heart?]. AB - There is increasing recognition that coronary microvascular dysfunction also plays an important role in coronary heart disease. Little is known about this aspect of coronary heart disease due to difficulties in studying the coronary microcirculation directly. The retina is a unique site where the microcirculation can be imaged directly, providing an opportunity to study in vivo the structure and pathology of the human circulation and the possibility of detecting changes in microvasculature relating to the development of cardiovascular disease. This review covers the recent progress in research linking retinal vascular signs to coronary heart disease, and finds accumulating evidence that retinal vascular signs may provide a window into the health of the coronary microvasculature. The most widely studied signs, arteriolar narrowing, and more recently, venular dilation, are likely associated with increased risk of coronary heart disease in women, independent of traditional risk factors. Attempts to improve coronary heart disease risk prediction by incorporating retinal vessel calibre size into risk prediction scores complementing traditional algorithms such as the Framingham risk scores have so far been disappointing. Research is ongoing into the predictive utility of other retinal vascular signs. Retinal photography provides long-lasting records that enable monitoring of longitudinal changes in these retinal signs and vascular health. Full English text available fromwww.revespcardiol.org. PMID- 21530055 TI - Effectiveness of thrombolysis for massive pulmonary embolism with an atrial septal defect. PMID- 21530056 TI - Simple linear and multivariate regression models. AB - In biomedical research it is common to find problems in which we wish to relate a response variable to one or more variables capable of describing the behaviour of the former variable by means of mathematical models. Regression techniques are used to this effect, in which an equation is determined relating the two variables. While such equations can have different forms, linear equations are the most widely used form and are easy to interpret. The present article describes simple and multiple linear regression models, how they are calculated, and how their applicability assumptions are checked. Illustrative examples are provided, based on the use of the freely accessible R program. PMID- 21530057 TI - Elevated C-reactive protein and monocyte chemoattractant protein-1 in patients with polycystic ovary syndrome. AB - OBJECTIVES: C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP 1) are inflammatory factors involved in the pathogenesis of atherosclerosis. This study aimed to analyse serum concentrations of CRP and MCP-1 in patients with polycystic ovary syndrome (PCOS), and to test the effect of these factors on human THP-1 cells to determine the inflammatory state of these patients. STUDY DESIGN: Eighty-five women with PCOS and 65 healthy women with regular menstrual cycles, matched for age and body mass index (BMI), were included in the study. Serum total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL C), low-density lipoprotein-cholesterol, fasting glucose and fasting insulin were monitored. Serum CRP and MCP-1 were compared between patients with PCOS and controls. Phorbol 12-myristate 13-acetate was used to induce the differentiation of human THP-1 monocytes into THP-1 macrophages. THP-1 macrophages were incubated with serum from patients with PCOS or controls for 24h, and MCP-1 mRNA expression was determined using real-time reverse transcriptase polymerase chain reaction. RESULTS: Serum CRP and MCP-1 levels were significantly higher in women with PCOS compared with controls (CRP 1.9+/-2.0 mg/l vs. 0.9+/-0.8 mg/l; MCP-1 125.7+/-68.0 ng/ml vs. 89.8+/-68.3 ng/ml, respectively). Serum CRP level was positively correlated with BMI (r=0.494, p=0.000), waist:hip ratio (r=0.451, p=0.000), testosterone (r=0.214, p=0.032), homeostasis model assessment of insulin resistance (HOMA-IR; r=0.617, p=0.000) and MCP-1 (r=0.219, p=0.027), and negatively correlated with HDL-C (r=-0.209, p=0.035). MCP-1 level was positively correlated with BMI (r=0.381, p=0.000), waist:hip ratio (r=0.421, p=0.000), HOMA IR (r=0.265, p=0.007) and triglycerides (r=0.439, p=0.000). MCP-1 mRNA expression in THP-1 cells incubated with serum from patients with PCOS was significantly higher than that in THP-1 cells incubated with serum from controls (p<0.05). CONCLUSION: Patients with PCOS suffer low-grade chronic inflammation indicated by higher levels of CRP and MCP-1, which could lead to increased risk of atherogenesis. PMID- 21530058 TI - The administration of metformin during pregnancy reduces polycystic ovary syndrome related gestational complications. AB - OBJECTIVES: To prospectively evaluate the safety of metformin administration during pregnancy in a group of PCOS patients by assessing its effect on the prevalence of gestational complications and neonatal outcome. STUDY DESIGN: Our prospective, single centre study included 98 pregnant women with PCOS treated with metformin throughout pregnancy and 110 normal pregnant controls. All PCOS patients were hyperinsulinemic and received metformin (1700-3000 mg/day) before conception and until 37 weeks' gestation. RESULTS: Metformin treatment in the pregnant PCOS patients resulted in significant decrease in miscarriage rate (9.1% vs 20%; p<0.05), gestational diabetes (0 vs 13%; p<0.005), and gestational hypertension (0 vs 11%; p<0.005) and a non-significant decrease in pre-eclampsia (0 vs 3%; p=.24), compared to the control group. Mean neonatal Apgar score, weight and length were comparable between the two groups. CONCLUSIONS: Continuing metformin therapy throughout pregnancy resulted in significant reduction in pregnancy complications with concomitant improved neonatal outcome, with no serious deleterious side effects. PMID- 21530059 TI - Association of genetic variants in the two isoforms of 5alpha-reductase, SRD5A1 and SRD5A2, in lean patients with polycystic ovary syndrome. AB - OBJECTIVE: Given its role in converting testosterone to dihydrotestosterone and cortisol to dihydrocortisol, 5alpha-reductase may be important in the pathophysiology of the polycystic ovary syndrome (PCOS). Increased activity of this enzyme has already been demonstrated in ovaries of affected women, and might be caused by genetic alterations. The aim of this study was to analyze representative genetic variants of both isoforms of 5alpha-reductase with regard to PCOS parameters in lean and obese women. STUDY DESIGN: We analyzed one single nucleotide polymorphism (SNP) (rs523349) of the isoform 2 (SRD5A2) and one haplotype of the isoform 1 (SRD5A1), consisting of the two SNPs rs39848 and rs3797179, in 249 women with PCOS and 226 healthy women using a 5'-exonuclease assay. The genotypes were associated with anthropometric, metabolic and hormonal as well as functional tests in these women. RESULTS: In the investigated haplotype of SRD5A1, the TA variant was associated with an increased frequency of PCOS (P=0.022) and an increased Ferriman-Gallwey Score (hirsutism) (P=0.016) in women with normal weight. The G allele at the examined position of the SRD5A2 showed a decreased frequency of PCOS (P=0.03) in women with normal weight. CONCLUSION: One of the keys in the development of the PCOS is hyperandrogenism, which might be caused by an increased 5alpha-reductase activity, as it is often seen in obesity. This mechanism might therefore be of importance in lean PCOS patients and contribute to the clinical findings. PMID- 21530060 TI - Influence of LH and high-density lipoprotein cholesterol (HDL-C) on metformin response in women with polycystic ovary syndrome. AB - OBJECTIVE: To search for predictors of metformin response in women with polycystic ovary syndrome (PCOS) through a detailed analysis of clinical and laboratory parameters. STUDY DESIGN: We designed a prospective study to investigate clinical and laboratory parameters to search for predictors of metformin response in women with PCOS. A total of 53 PCOS patients were given metformin 850 mg twice a day for 6 months, after which patients were classified as responders or non-responders. Parameters analyzed for comparison between the two groups were: plasma fasting insulin glucose/insulin ratio; oral glucose tolerance test (OGTT) with insulin (120 min); HOMA and QUICKI tests; total cholesterol and fractions, triglycerides; LH, FSH, estradiol, progesterone, testosterone, androstenedione, 17-OH progesterone, and DHEAS. RESULTS: From all patients, 30 (56.6%) were responders and 23 (43.3%) were non-responders. Multinomial analysis showed that the positive response to metformin was associated with higher levels of basal LH (p=0.038) and lower levels of high density lipoprotein cholesterol (HDL-C) (p=0.015). CONCLUSION: In weight-matched PCOS subjects, laboratory markers might predict the metformin response. Higher levels of basal LH and lower levels of HDL-C are correlated with a positive response to metformin treatment in PCOS subjects. PMID- 21530061 TI - Assessing the contribution of heterogeneous distributions of oligomers to aggregation mechanisms of polyglutamine peptides. AB - Polyglutamine aggregation is associated with neurodegeneration in nine different disorders. The effects of polyglutamine length and peptide concentration on the kinetics of aggregation were previously analyzed using a homogeneous nucleation model that assumes the presence of a single bottleneck along the free energy profile G(n), where n denotes the number of polyglutamine molecules. The observation of stable, soluble oligomers as intermediates along aggregation pathways is refractory to the assumptions of homogeneous nucleation. Furthermore, the analysis of in vitro kinetic data using a specific variant of homogeneous nucleation leads to confounding observations such as fractional and/or negative values for estimates of the critical nucleus size. Here, we show that the homogeneous nucleation model is inherently robust and is unlikely to yield fractional values if the underlying process is strictly homogeneous with a free energy profile G(n) that displays a sharp maximum at n=n*, where n* corresponds to the critical nucleus. Conversely, a model that includes oligomers of different size and different potentials for supporting turnover into fibrils yields estimates of fractional and/or negative nucleus sizes when the kinetic data are analyzed using the assumption of a homogeneous process. This model provides a route to reconcile independent observations of heterogeneous distributions of oligomers and other non-fibrillar aggregates with results obtained from analysis of aggregation kinetics using the assumption of a homogeneous nucleation model. In the new model, the mechanisms of fibril assembly are governed by the relative stabilities of two types of oligomers viz., fibril-competent and fibril incompetent oligomers, the size of the smallest fibril competent oligomer, and rates for conformational conversion within different oligomers. PMID- 21530062 TI - Energetics of ligand binding to human glutathione transferase A1-1: Tyr-9 associated localisation of the C-terminal helix is ligand-dependent. AB - A C-terminal helix (alpha9) adjacent to the active site on each subunit is a structural feature unique to the alpha isoform of glutathione transferases which contributes to the catalytic and ligandin functions of the enzyme. The ionisation state of Tyr-9, a residue critical to catalysis, influences alpha9 dynamics, although the mechanism is poorly understood. In this study, isothermal titration calorimetry was used to probe the binding energetics of G-site (glutathione and glutathione sulfonate) and H-site (ethacrynic acid) ligands to wild-type and a Y9F mutant of human glutathione transferase A1-1. Although previous studies have reported a favourable entropic component to the binding of conjugates occupying both sites, our data reveal that ligand binding is enthalpically driven when either the G- or H-site is occupied independently. Also, heat capacity changes demonstrate that alpha9 is fully localised by H-site but not G-site occupation. The Tyr-9 hydroxyl group contributes significantly to ligand binding energetics, although the effect differs between the two binding sites. G-site binding is made slightly enthalpically more favourable and entropically less favourable by the Y9F mutation. Binding to the H-site is more dramatically affected, with the K(d) for ethacrynic acid increasing 5 fold despite a more favourable DeltaS. The heat capacity change is more negative for G-site binding in the absence of the Tyr-9 hydroxyl (DeltaDeltaC(p)=-0.73 kJ mol(-1) K(-1)), but less negative for H-site binding to the Y9F mutant (DeltaDeltaC(p)=0.63 kJ mol(-1) K(-1)). This suggests that the relationship between Tyr-9 and alpha9 is not independent of the ligand. Rather, Tyr-9 appears to function in orienting the ligand optimally for alpha9 closure. PMID- 21530063 TI - The role of fibroblast growth factors on the differentiation of vaginal epithelium of neonatal mice. AB - The uterus and upper 3/5 of the vagina originate from the Mullerian duct; however, these organs show quite distinct characteristics in morphology and function. To investigate factors controlling vaginal epithelial cell differentiation from a single layer of pseudostratified epithelium to a multi layered stratified epithelium with keratin, we focused on fibroblast growth factors (Fgfs). Transformation related protein 63 (Trp63) expression, a marker of stratified epithelium, increased in the Mullerian vaginal epithelial cells from days 0 to 5, and keratin 14 (Krt14) was expressed from day 5, suggesting that Trp63-negative vaginal epithelial cells can differentiate into Trp63-positive cells after birth. Fgf7 and Fgf10 were localized in the vaginal stroma but their receptor, Fgf receptor 2IIIb (Fgfr2IIIb), was localized in the vaginal epithelium. Both Fgf9 and its receptor, Fgfr2IIIc, were localized in the vaginal epithelium. Vaginae cultured with FGF10 or anti-FGF9 antibody showed stratified epithelium with an intense Krt14 expression; however, an inhibitor of phosphorylation of mitogen-activated protein kinase 1/3 (MAPK1/3) canceled the effect of FGF10 and anti-FGF9 antibody. Thus, Fgf10 stimulates the differentiation of pseudostratified epithelial cells into stratified cells via MAPK1/3 pathway, and Fgf9 inhibits this differentiation in the neonatal mouse vagina. PMID- 21530064 TI - Radiological impacts of phosphogypsum. AB - This study was carried out to assess the radiological impact of Syrian phosphogypsum (PG) piles in the compartments of the surrounding ecosystem. Estimating the distribution of naturally occurring radionuclides (i.e. (226)Ra, (238)U, (232)Th, (210)Po and (210)Pb) in the raw materials, product and by product of the Syrian phosphate fertilizer industry was essential. The data revealed that the concentrations of the radionuclides were enhanced in the treated phosphate ore. In PG, (226)Ra content had a mean activity of 318 Bq kg( 1). The uranium content in PG was low, ca. 33 Bq kg(-1), because uranium remained in the phosphoric acid produced. Over 80% of (232)Th, (210)Po and (210)Pb present partitioned in PG. The presence of PG piles did not increase significantly the concentration of (222)Rn or gamma rays exposure dose in the area studied. The annual effective dose was only 0.082 mSv y(-1). The geometric mean of total suspended air particulates (TSP) ca. 85 MUg m(-3). The activity concentration of the radionuclides in filtrates and runoff waters were below the detection limits (ca. 0.15 mBq L(-1) for (238)U, 0.1 mBq L(-1) for (232)Th and 0.18 mBq L(-1) for both of (210)Po and (210)Pb); the concentration of the radionuclides in ground water samples and Qattina Lake were less than the permissible limits set for drinking water by the World Health Organisation, WHO, (10, 1 and 0.1 Bq L(-1) for (238)U, (232)Th and both of (210)Po and (210)Pb, respectively). Eastern sites soil samples of PG piles recorded the highest activity concentrations, i.e. 26, 33, 28, 61 and 40 Bq kg(-1) for (226)Ra, (238)U, (232)Th, (210)Po and (210)Pb, respectively, due to the prevailing western and north-western wind in the area, but remained within the natural levels reported in Syrian soil (13-32 Bq kg(-1) for (226)Ra, 24.9-62.2 Bq kg(-1) for (238)U and 10-32 Bq kg(-1) for (232)Th). The impact of PG piles on plants varied upon the plant species. Higher concentrations of the radionuclides were recorded for grass in comparison to broad-leaved plants. Among the species that grow naturally on PG piles, Inula, Ecballium and Polygonium may be radionuclides accumulators. A determined effort is needed at a national level to achieve a common and coherent approach to regulate PG piles or to consider it a resource material rather than waste or residue. PMID- 21530065 TI - Risk factors for elevated Enterococcus concentrations in a rural tropical island watershed. AB - Associations were examined between riparian canopy cover, presence of cattle near streams, and month of year with the concentration of Enterococcus (Most Probable Number (MPN)/100 ml) in surface water at Waipa watershed on the North Side of the Hawaiian island Kaua'i. Each one percent decrease in riparian canopy cover was associated with a 3.6 MPN/100 ml increase of waterborne Enterococcus. Presence of cattle near monitoring sites was associated with an increase of 99.3 MPN/100 ml of Enterococcus in individual grab samples. Lastly, summer samples (July) were substantially higher in concentration of Enterococcus than winter collected samples (February) in Enterococcus in sampled streams. These results suggest that reducing canopy cover and introduction of cattle into riparian zones may contribute to increases of Enterococcus concentrations in stream water. PMID- 21530066 TI - Reconstructing historical trends of Berre lagoon contamination from surface sediment datasets: influences of industrial regulations and anthropogenic silt inputs. AB - These last decades, the Berre lagoon (in southeastern France) has been deeply affected since the 1930s by strong inputs of contaminants associated with industrial development and since 1966 by huge inputs of freshwater and silts due to the installation of a hydroelectric power plant. Surveys of the surface sediment contamination have been sparsely performed since 1964 for management and research purposes. These surveys were performed by various laboratories that investigated different chemicals and sampling areas using different analysis protocols. Therefore, the available data are disconnected in time and space and differ in quality. In order to reconstruct coherent time series of sediment contamination from this heterogeneous datasets and to discuss the influences of industrial and hydroelectric discharges we used a statistical approach. This approach is based on Principal Component Analysis (PCA) and Fuzzy clustering analysis on data from one extensive survey realized on surface sediments in 1976. The PCA allowed identifying two geochemical indexes describing the main surface sediment geochemical characteristics. The fuzzy clustering analysis on these indexes allowed identifying sub-areas under the specific influence of industrial or hydroelectric discharges. This allowed us to reconstruct, for each sub-area, a coherent and interpretable long-term time series of sediment contamination from the available database. Reconstructed temporal trends allowed us to estimate: (i) the overall decrease of sediment contamination since the mid-1970 attributed to industrial discharge regulations enacted at this period and (ii) the dilution of the concentrations of sediment bound contaminants induced by the hydroelectric power plant and its associated particulate matter inputs. PMID- 21530067 TI - Passive monitoring of nitrogen dioxide in urban air: a case study of Durban metropolis, South Africa. AB - To devise and implement strategies to manage the quality of urban air, a metropolis needs air pollution data on which an air quality management plan can be formulated. Although air pollutants can come from several sources, many reports suggest that nitrogen dioxide from motor vehicle emissions is the major contributor to air pollution in cities. Since vehicles stop or move slowly through traffic intersections, concentrations of nitrogen dioxide (NO(2)) are expected to be relatively high at these sites. Inexpensive Ogawa passive samplers were placed at selected traffic intersections in the Durban Metropolis to trap the NO(2) which was then analysed by a sensitive laboratory-based method. The data obtained by this method was compared with data from sophisticated system comprising an active sampler cum on-line chemiluminescence detector. The sampling was done over a twelve month period to cover all seasons. Statistical analysis of the data showed that there was no significant difference between the means for the two methods. This study has established that an Ogawa passive sampler may be used as an economical and reliable collector for NO(2) in ambient air under varying climatic conditions. Further, the analysis method using a UV-Visible spectrophotometer was sensitive enough to detect NO(2) at the 10-20 ppb level. The cost of the method should be well within the budgets of most municipalities and it would motivate them to develop policies to alleviate traffic congestion. PMID- 21530068 TI - Seasonal variation of atmospheric polycyclic aromatic hydrocarbons along the Kaohsiung coast. AB - Thirty-three air samples were collected by high-volume samplers from May 2007 to June 2008 in the coastal area of southwest Taiwan and analyzed for total suspended particulates (TSP) and polycyclic aromatic hydrocarbons (PAHs). Concentrations of TSP and total PAHs ranged from 40.4 to 251 MUg m(-3) and 1.86 56.4 ng m(-3), respectively. Except for joss paper burning during the religious celebration of Ghost Month, which resulted in the highest concentration of PAHs in the summer of 2007, a seasonal variation in total PAH concentration was observed over this study period, with the highest concentrations in winter and the lowest in summer. Because of the geographical and climatic characteristics of the sampling site, monsoon activities modulate the seasonal variations of PAHs. Diagnostic ratios showed that PAHs in the atmosphere of the Kaohsiung coastal area arose predominantly from vehicle emissions (mainly from diesel exhaust), joss paper burning, and coal/wood combustion. The results of hierarchical cluster analysis (HCA) and principal component analysis (PCA) indicated that the sampling days could be divided into three groups and that the major source identification of PAHs was the same as the identification by diagnostic ratios. In addition, the results of HCA and PCA suggest that the samples collected with a prevailing northerly or northeasterly wind direction contain both local emissions and those from neighboring sources. On the other hand, the cases related to westerly or northwesterly winds indicated that local emission was the major source for the sampling site. PMID- 21530069 TI - Intensification of degradation of aqueous solutions of rhodamine B using sonochemical reactors at operating capacity of 7 L. AB - In the present work, degradation of rhodamine B, a typical dye effluent commonly observed in chemical processing wastewaters has been investigated using a sonochemical reactor with capacity of 7 L. The reactor consists of an ultrasonic bath equipped with a single large transducer having longitudinal vibrations with operating frequency of 25 kHz and rated power output of 1 kW. The effect of operational conditions such as the rhodamine B initial concentration, operating pH and use of additives such as H(2)O(2), CCl(4) and TiO(2) has been investigated initially. A mathematical model has also been fitted to estimate the rate constant for rhodamine B removal under different operating conditions. Intensification studies have been carried by combining sonochemical oxidation with photocatalytic oxidation under optimized conditions. In all the investigated systems, complete removal of rhodamine B (10 ppm initial concentration) was obtained using a combination of sonochemical reactor and CCl(4). Sonocatalysis (in the presence of TiO(2)) of rhodamine B showed 92% degradation, while sonophotocatalysis gave degradation of 93%. TOC analysis at various optimum conditions was also performed to quantify the extent of mineralization and it was observed that the extent of mineralization is always lower than the extent of removal of parent compound. PMID- 21530070 TI - Cognitive and functional impairments in ischemic stroke patients with concurrent small vessel and large artery disease. AB - BACKGROUND AND PURPOSE: Concurrent small vessel, intracranial and extracranial large artery disease (SLAD) is common in Asian but its impact on cognitive and functional outcomes is unclear. We aimed to evaluate the clinical, cognitive and functional outcomes in ischemic stroke patients with SLAD. METHODS: Chinese ischemic stroke patients with diffuse white matter lesions (WMLs) were recruited as part of the VITATOPS Trial. They were studied with MRI and MRA of brain. Various neuropsychiatric batteries were used to assess the cognitive functions. RESULTS: Totally 97 patients with acute ischemic stroke and diffuse WMLs were included, of whom 44 (45%) had SLAD. Patients with SLAD had lower Mini Mental State Examination (MMSE) when compared with the patients without SLAD. They had more behavioral symptoms and caused more stress in caregivers as assessed by the Neuropsychiatric Inventory (NPI). Multivariate regression analysis showed SLAD contributed significantly to MMSE, NPI Patient (NPI P) and NPI Care Giver (NPI CG). Among 44 patients with SLAD, 30 (68%) had severe cognitive impairment. They were older and less educated. They had more diabetes and poorer performance in neuropsychiatric tests including Mattis Dementia Rating Scale Initiation/Perseveration subset (MDRS I/P) and Clinical Dementia Rating (CDR). They also had poorer functional outcomes as assessed by Barthel Index (BI) and Instrumental activities of daily living (IADL). CONCLUSIONS: This was the first MRA-based study to take into consideration the clinical, cognitive and functional outcomes in ischemic stroke patients with SLAD. Patients with SLAD had poorer cognitive and functional outcomes when compared to patients without SLAD. PMID- 21530071 TI - Hospitalizations due to spontaneous intracerebral hemorrhage in the region of Nis (Serbia): 11-year time-series analysis. AB - BACKGROUND: The study of seasonal variability of intracerebral hemorrhage (ICH) occurrence may contribute to a better understanding of the nature of this disease and open up new perspectives in its prevention. The aim of this study was to test seasonal patterns in the number of admissions of ICH patients and determine which months have maximal and minimal number of admissions. METHODS: The main data source for this study was a hospital-based registry at the Clinic of Neurology in Nis, Serbia. During the studied period (1997-2007) a total of 1569 ICH patients were registered. Time series, consisting of the monthly number of hospitalized patients, for the 128 months of the study duration, has been successfully modeled using the multiplicative Auto Regressive Integrated Moving Average (ARIMA) model. RESULTS: Using the maximum likelihood method, utilizing Melrad's algorithm, the parameters of this ARIMA model have been calculated: constant (estimate 12.068, p<0.001), auto regressive-AR(1) (estimate 0.866, p<0.001), moving average-MA(1) (estimate 0.775, p<0.001), seasonal moving average-SMA(12) (estimate -0.198, p=0.036). ARIMA modeling has been successful and showed that there is a clear seasonal pattern in the data analyzed. CONCLUSION: Based on the seasonal multiplicative ARIMA model and the seasonal time series decomposition, we showed that, in the period covered by the study, the peak of admissions occurred in March, and the trough of admissions was found in August. PMID- 21530072 TI - A case of solitary Blastomyces dermatitidis meningitis. AB - We present a case of a 35 year-old male with Blastomyces dermatitidis meningitis as the primary presentation of blastomycosis infection, without evidence of involvement outside the CNS at time of discharge. We focus on the magnetic resonance imaging findings, with histopathologic correlation. PMID- 21530073 TI - Neuroimaging and functional navigation as potential tools to reduce the incidence of surgical complications of lateral ventricular meningiomas. AB - OBJECTIVE: Post-operative complications are common following treatment for meningiomas in the lateral ventricles because it is unavoidable to disrupt the integrity of the brain during surgery. This study discusses our experience with strategies for reducing these complications. METHOD: Twenty-seven cases of lateral ventricular meningiomas treated surgically were summarized. The surgical corridors of 11 patients were selected according to the traditional anatomical markers. Navigation technologies including neuronavigation, ultrasonography, neuro-endoscopy, fMRI and intraoperative brain mapping were used in the other 16 patients. The post-operative Karnofsky Performance Status (KPS) of patients with or without navigation were compared at 1 week and 3, 6 and 12 months. RESULTS: Except for one patient who died from postoperative intracerebral hemorrhage, most of the preoperative disorders improved after surgery. Although only 4 out of 27 cases suffered from permanent complications of visual field defect or epilepsy, novel postoperative complications were found in 8 of 11 patients without navigation but in only 5 of 16 patients with navigation. The post-operative KPS of patients with navigation were better than those without navigation at 1 week and 3 months after surgery. CONCLUSION: The use of neuroimaging and functional navigation technologies may effectively lower the incidence of postoperative complications. PMID- 21530074 TI - Frequency of CD45RO+ subset in CD4+CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma. AB - The purpose of this study was to assess the properties of CD4+CD25(high/low/negative) T cell subsets and analyze their relation with dendritic cells (DCs) in patients with hepatocellular carcinoma (HCC). In HCC patients, the prevalence of CD45RO+ cells in CD4+CD25(high) T cells was increased and associated with higher frequencies of plasmacytoid DCs. Larger proportions of this T cell subset were detected in the patients with larger tumor burdens. These results suggest that increased frequencies of the CD45RO+ subset in CD4+CD25(high) Tregs in HCC patients may establish the immunosuppressive environment cooperatively with tolerogenic plasmacytoid DCs to promote disease progression of liver cancer. PMID- 21530075 TI - Chemokine receptor CXCR4-mediated transformation of mammary epithelial cells by enhancing multiple RTKs expression and deregulation of the p53/MDM2 axis. AB - Recent studies have shown that CXCR4 is associated with tumor metastasis. Elevated levels of CXCR4 are also detected in a high percentage of DCIS cases. The high frequency of CXCR4 expression in DCIS suggests that many DCIS cases are "primed" for invasiveness. In this study, we demonstrated that expression of CXCR4 reveals morphological alterations in cells, from normal acinar morphological epithelial cells to a more invasive morphology in a 3D-culture system. Ectopic expression of CXCR4 induces invasion of MCF-10A cells. Interestingly, CXCR4 is capable of orchestrating a complex alteration in signaling networks, which include upregulation of multiple receptor tyrosine kinases (RTKs), deregulation of p53/MDM2 axis, upregulation of E-cadherin and c myc, as well as modulation of cell cycle molecules to facilitate mammary epithelia cell transformation. These findings reveal that CXCR4 expression exerts a critical role in early stages of breast lesions, which may explain the high frequency of CXCR4 expression detected in DCIS. We believe that these studies will lead to new, biologically-based therapeutic strategies for clinical intervention, prevention and treatments of breast cancer. PMID- 21530076 TI - Investigation on the solubilization of polycyclic aromatic hydrocarbons in the presence of single and mixed Gemini surfactants. AB - Water solubility enhancements of naphthalene (Naph), phenanthrene (Phen) and pyrene (Py) by a series of single cationic Gemini surfactants (CG(s), s=4, 8, 12 and 16) as well as their equimolar binary combinations (CG(12-m), m=4, 8 and 16) have been investigated. The relationships between their surface properties and solubilizing capacities toward three polycyclic aromatic hydrocarbons (PAHs) have been quantified and discussed. The selected single Gemini surfactants observably enhance the water solubility of PAHs following the order of Phen>Py>Naph except for CG(8) which has a superior solubilizing ability for Py. For the same organic compound, the solubilizing abilities of single Gemini surfactants are in tune with the order of variation tendencies of CMC values. However, the different mixed Gemini surfactant systems have shown selective solubilization on various PAHs which is not simply related to their mixed molar properties. Particularly, the CG(12-16) surfactant has relatively comparable solubilization on Py and inferior solubilization on Phen compared to all other investigated solubilizing systems. It is presumably attributed to the relationships between the structure of surfactants and the chemical nature of both solutes and surfactants. The analysis studied herein has provided valuable information for the selection of mixed Gemini surfactants for solubilizing water-insoluble compounds. PMID- 21530077 TI - Comparison of sorption behavior of Th(IV) and U(VI) on modified impregnated resin containing quinizarin with that conventional prepared impregnated resin. AB - This paper reports the results obtained by studying the ion-exchange properties of a new solvent impregnated resin (SIR), which was prepared by impregnation of quinizarin (1,4-dihydroxyanthraquinone, QNZ) on Amberlite XAD-16 after nitration of the benzene rings present in its structure. The sorption behavior of Th(IV) and U(VI) on/in the modified SIR was compared with that of the SIR prepared via the conventional method. It was observed that sorption capacity and sorption rate of the modified SIR are significantly greater than the conventional one. The modified SIR was then applied to the extraction of Th(IV) and U(VI) ions at the presence of many co-existence metal ions. The results obtained denote on successful application of this new SIR to analysis of natural water samples spiked to Th(IV) and U(VI) ions. PMID- 21530078 TI - Synergistic effect of thermophilic temperature and biosurfactant produced by Acinetobacter calcoaceticus BU03 on the biodegradation of phenanthrene in bioslurry system. AB - This study aimed at investigating the synergistic effect of temperature and biosurfactant on the biodegradation of phenanthrene in bioslurry. Bench-scale bioslurry experiments were conducted at 25 and 55 degrees C. The desorption rate coefficients of phenanthrene (K(des)) obtained using the pseudo-first order model were 0.0026 and 0.0035 kg mg(-1)h(-1) at 25 and 55 degrees C, respectively. Addition of 1500 mg L(-1) biosurfactant, produced by Acinetobacter calcoaceticus BU03, marginally increased the K(des) at 25 degrees C since most of biosurfactant was sorbed onto soil; however, significantly increased the K(des) to 0.0087 kg mg(-1)h(-1) at 55 degrees C as the thermophilic temperature reduced the adsorption of the biosurfactant onto soil and subsequently enhanced the desorption of phenanthrene. The biodegradation of phenanthrene well fitted pseudo first order kinetics based on the assumption that biodegradation was limited by the desorption. About 78.7% of phenanthrene was degraded in 30 days at 25 degrees C; and addition of biosurfactant did not affect the biodegradation. However, addition of the biosurfactant or inoculation of A. calcoaceticus BU03 at 55 degrees C significantly enhanced the biodegradation by increasing the K(des). Results indicate that synergistic application of thermophilic temperature and biosurfactant or inoculation of biosurfactant producing microorganisms is an effective and innovative method to enhance the efficiency of PAH degradation in bioslurry system. PMID- 21530079 TI - Removal of phosphate from water by activated carbon fiber loaded with lanthanum oxide. AB - Phosphate removal from wastewater is very important for the prevention of eutrophication. Adsorption of phosphate from water was investigated using activated carbon fiber loaded with lanthanum oxide (ACF-La) as a novel adsorbent. The effects of variables (La/ACF mass ratio, impregnation time, activation time, and activation temperature) have been studied by the single-factor method. Response surface methodology (RSM), based on three-variable-three-level Box Behnken design (BBD), was employed to assess the individual and collective effects of the main independent parameters on the phosphate removal. The optimal conditions within the range studied for preparing ACF-La were found as follows: La/ACF mass ratio of 11.78%, activation time of 2.5h and activation temperature at 650 degrees C, respectively. The phosphate removal using the ACF-La prepared under the optimal conditions was up to 97.6% even when the phosphate concentration in water was 30 mgP/L, indicating that ACF-La may be an effective adsorbent. The results from Fourier transform infrared (FT-IR) spectroscopy and change of pH values associated with the adsorption process revealed that the probable mechanism of phosphate ions onto ACF-La was not only ion exchange and coulomb interaction, but also a result of Lewis acid-base interaction due to La-O coordination bonding. PMID- 21530080 TI - Production of poly-beta-hydroxybutyrate (PHB) by Methylobacterium organophilum isolated from a methanotrophic consortium in a two-phase partition bioreactor. AB - The biodegradation of methane, a greenhouse gas, and the accumulation of poly beta-hydroxybutyrate (PHB) were studied using a methanotrophic consortium and an isolated strain thereof. The specific rates for methane consumption were 100 and [Formula: see text] for the isolate and the consortium, respectively. Also the effect of including 10% (vv(-1)) of silicone oil in a two-phase partitioning bioreactor (TPPB) was assayed for the elimination of 1% methane in air stream. TPPB allowed a 33-45% increase of methane elimination under growing conditions. Nitrogen limitation was assayed in bioreactors to promote PHB production. Under this condition, the specific methane degradation rate remained unchanged for the consortium and decreased to [Formula: see text] for the isolated strain. The accumulated PHB in the reactor was 34% and 38% (ww(-1)) for the consortium and the isolate, respectively. The highest productivity was obtained in the TPPB and was 1.61 mg(PHB)g(x)(-1) h(-1). The CZ-2 isolate was identified as Methylobacterium organophilum, this is the first study that reports this species as being able to grow on methane and accumulate up to 57% (ww(-1)) of PHB under nitrogen limitation in microcosm experiments. PMID- 21530081 TI - Anodic oxidation of textile dyehouse effluents on boron-doped diamond electrode. AB - The electrochemical oxidation of textile effluents over a boron-doped diamond anode was investigated in the present study. Experiments were conducted with a multi-component synthetic solution containing seventeen dyes and other auxiliary inorganics, as well as an actual effluent from a textile dyeing process. The effect of varying operating parameters, such as current density (4-50 mA/cm2), electrolyte concentration (0.1-0.5 M HClO4), initial solution pH (1-12.3) and temperature (22-43 degrees C), on process efficiency was investigated following changes in total organic carbon (TOC), chemical oxygen demand (COD) and color. Complete decolorization accompanied by significant mineralization (up to 85% depending on the conditions) could be achieved after 180 min of treatment. Performance was improved at higher electrolyte concentrations and lower pH values, while the effect of temperature was marginal. Energy consumption per unit mass of COD removed was favored at lower current densities, since energy was unnecessarily wasted to side reactions at higher densities. PMID- 21530082 TI - Comparing the sensitivity of two in vitro assays to evaluate the anthelmintic activity of tropical tannin rich plant extracts against Haemonchus contortus. AB - The present trial aimed at comparing the sensitivity of two in vitro methods, i.e. the larval migration inhibition assay (LMIA) and the larval exsheathment inhibition assay (LEIA), to evaluate the anthelmintic (AH) properties of tannin rich plant extracts against Haemonchus contortus infective larvae. The two assays were applied on the same batch of H. contortus infective larvae exposed to water/acetonic extracts obtained from four tropical plants with different tannin contents: Acacia gaumeri, Brosimum alicastrum, Havardia albicans and Leucaena leucocephala. Increasing concentrations (0, 75, 150, 300, 600, 1200 MUg/ml PBS) of lyophilized extracts were used in both in vitro assays. A general lineal model test was used to determine the dose-effect in the LMIA or the difference in the percentage of exsheathed larvae between the respective control and treated groups. The LMIA showed a dose-dependent AH effect for H. albicans (P<0.001) and A. gaumeri (P<0.05), but not for L. leucocephala and B. alicastrum. In contrast, the exsheathment process was significantly affected by all doses of H. albicans and A. gaumeri extracts and a significant dose-dependent effect was found for B. alicastrum and L. leucocephala. Calculation of lethal dose (LD) was possible with LEIA using B. alicastrum and L. leucocephala but not with H. albicans and A. gaumeri as the lowest tested concentration was achieving more than 50% inhibition. Calculation of LD with the LMIA results was not feasible. These results suggest that tannin-rich plant extracts are more potent inhibitors of the exsheathment of H. contortus L(3) larvae than their motility. This information underlines the difference of sensitivity between methodological procedures to evaluate the AH properties of plant extracts on the same nematode stage. PMID- 21530083 TI - Temporal IgG subclasses response in dogs following vaccination against Leishmania with Leishmune(r). AB - Canine Visceral Leishmaniasis (CVL) is a widespread zoonotic disease with mandatory euthanasia of infected dogs determined by the Brazilian Ministry of Health. Development of vaccines against CVL may provide a prophylactic barrier, but transitory peak of antibody response detected by standard diagnostic techniques in vaccinated dogs may be interpreted as natural infection. Accordingly, the aim of the present study was to sequentially evaluate total and IgG subclasses response between naturally Leishmania-infected and dogs vaccinated with Leishmune((r)). A total of 172 mongrel dogs were divided in four groups: Group 1 (G1) with 45 clinically healthy dogs, Group 2 (G2) and Group 3 (G3) with 45 dogs naturally infected by Leishmania sp. each, symptomatic and asymptomatic respectively, and G4 (G4) with 37 healthy dogs submitted to a complete protocol of a commercially available vaccine against CVL, monitored and evaluated in 5 different chronological moments (M0-M4) up to 180 days after M0. Total IgG, IgG1 and IgG2 were unable to differentiate between infected (G2 and G3) and vaccinated (G4) dogs, demonstrating that polyclonal commercial antibodies do not distinguish these groups apart. Total and IgG subclasses antibodies were not detected until 21 days of the second vaccination dose; however, seroconversion was observed on 21 days and sustained positivity up to 6 months after the vaccination start. A peak of antibodies response was observed on 90 days (M3), when results for total IgG, IgG1, IgG2, IgG3 and IgG4 where highly significant when compared to M0 (P<0.0001). Neither total IgG nor IgG1 effectively differentiated between infected (G2 and G3) and vaccinated (G4) dogs. In conclusion, despite dogs may test serologically negative immediately after vaccination against CVL with Leishmune((r)), subsequent seroconversion, antibody peak and positivity up to six months may lead vaccinated dogs to be mistakenly identified as naturally infected dogs during this period. PMID- 21530084 TI - Genotyping of potentially zoonotic Giardia duodenalis from exotic and wild animals kept in captivity in Brazil. AB - We have studied the variability of glutamate dehydrogenase (gdh) and small subunit ribosomal (SSU) rRNA coding genes of Giardia species in fecal samples isolated from wild and exotic animals in Brazil, and compared with homologous sequences of isolates from human and domestic animals characterized in previous studies. Cysts of Giardia duodenalis were obtained from feces of naturally infected monkeys (Alouatta fusca) (n=20), chinchillas (Chinchilla lanigera) (n=3), ostriches (Struthio camelus) (n=2) and jaguar (Panthera onca) (n=1). Assemblage AI was assigned to the unique isolate of jaguar. All the samples from monkeys, chinchillas, and ostriches were assigned to Assemblage B. There was little evolutionary divergence between the referred isolates and isolates described elsewhere. The Assemblage B isolates identified in this study were closely related to Assemblage BIV isolated from humans. The molecular identification of Assemblages A and B of G. duodenalis isolates from exotic and wild animals demonstrates that such hosts may be a potential reservoir for zoonotic transmission of G. duodenalis. PMID- 21530085 TI - Assessment of the effectiveness of a combination product of spinosad and milbemycin oxime on the prophylaxis of canine heartworm infection. AB - Three separate randomized, blinded, vehicle-controlled studies were conducted to determine the effectiveness of a single treatment and consecutive monthly treatments of a combination flavored tablet product containing spinosad and milbemycin oxime (MBO) in the prevention of the establishment of heartworm infections in dogs challenged with recent field isolates of the heartworm (HW), Dirofilaria immitis. For each study, dogs were allocated randomly based on pre treatment body weights to treated or control groups of 10 animals each. Dogs were infected once with infective HW larvae, on Day-30, using either a Michigan isolate or a Georgia (MP3) isolate of D. immitis. Treatments of beef-flavored chewable tablets were administered in two studies one time either on Day 0 or Day 15, and in one study twice (Days 0 and 30, or Days 15 and 45) or 3 times (Days 0, 30 and 60). For the combination product groups, dosages were in the range of 30 45 mg/kg (13.6-20.5mg/lb) for spinosad and 0.5-0.75 mg/kg (0.2-0.34 mg/lb) for MBO. Necropsies for heartworm counts were completed following euthanasia on Day 120 or Day 123. A single treatment with the combination product of spinosad and MBO 30 or 45 days post-inoculation with infective HW larvae was completely effective (100%) in preventing establishment of the Michigan D. immitis isolate, but efficacy against the Georgia MP3 isolate was incomplete, with geometric mean reductions in HW counts relative to vehicle treated controls of 99% reduction of the 30 day infection and a 98.9% reduction of the 45 day old infection. Against this same MP3 isolate, 3 consecutive monthly treatments provided complete prevention (100%) against establishment of D. immitis infections. The combination product of spinosad and MBO provides effective control of canine heartworms. A single treatment at 30 days post infection showed high but incomplete effectiveness against a heartworm isolate that had been shown to be partially refractory to treatment with marketed monthly heartworm preventives. Three consecutive monthly treatments provided complete control, providing support to the recommendation that heartworm prophylaxis should be maintained year round for optimal effectiveness. PMID- 21530086 TI - Pulmonary function, exercise capacity and physical activity participation in adults following burn. AB - PURPOSE: To determine the relationship between pulmonary function, aerobic exercise capacity and physical activity participation in adults following burn. METHODS: Eight burn injured males aged 20-55 years (%TBSA 33.3+/-18.7, 5.1 years+/-1.8 post injury), and 30 healthy adult controls participated. Pulmonary function was assessed during rest via spirometry. A graded exercise test measuring peak oxygen consumption (VO(2peak)) and oxygen saturation (S(p)O(2)) was conducted, and physical activity was assessed via the Older Adult Exercise Status Inventory (OA-EI). RESULTS: No significant correlation was observed between resting pulmonary function, aerobic capacity and physical activity participation for burn injured patients or controls. Two burn injured patients presented with obstructive ventilatory defects, and one displayed a restrictive ventilatory defect. Burn injured patients had a significantly lower VO(2peak) (p<0.001) and time to fatigue (p=0.026), and a greater degree of oxygen desaturation (p=0.063, Effect Size=1.02) during a graded exercise test. Burn injured patients reported significantly less participation in leisure-related activity>9 METs (p=0.01), and significantly greater participation in work-related activity (p=0.038), than healthy controls. CONCLUSION: Compromised lung function, decreased aerobic capacity and reduced participation in leisure-related physical activity may still exist in some adults, even up to 5 years post injury. Limitations and long term outcomes of cardiopulmonary function and physical fitness need to be considered in the prescription of exercise rehabilitation programmes following burn. PMID- 21530087 TI - Measuring common outcome measures and their concepts using the International Classification of Functioning, Disability and Health (ICF) in adults with burn injury: a systematic review. AB - PURPOSE: To identify and quantify the health related concepts contained in the most common outcome instruments used in adult burn care, and to compare the content of these instruments based on their linkage to the International Classification of Functioning, Disability and Health (ICF). The ICF has been validated as a reference tool by the World Health Organization and is a framework that incorporates physical, emotional, environmental and social aspects of daily functioning. METHODS: Electronic searches of MEDLINE, EMBASE CINAHL, PsychINFO and the Cochrane Library from 2003 onwards were carried out using a predetermined search strategy. Specific characteristics of the included studies and data pertaining to the outcome instruments were extracted. Two reviewers independently categorised the underlying concepts contained in the most commonly used outcome measures and linked them to ICF categories using standardised linkage rules. RESULTS: Out of a total 132 included studies, 151 outcome instruments were identified. Of these, 14 frequently used generic and burn-specific instruments were selected for linkage to the ICF. From the 381 items contained in the 14 instruments, 356 concepts were extracted and subsequently linked to 99 ICF categories. Nearly 46% of the concepts were linked to body function and 20% to activities and participation, whereas only a few concepts were formally linked to health condition, body structures and personal or environmental factors. CONCLUSION: The ICF proved highly useful for the content comparison of frequently used generic and burn-specific instruments. The results may provide clinicians and researchers with new insights when selecting health-status measures for clinical studies in those with burn injury. PMID- 21530088 TI - Solitary sleeping in young infants is associated with heightened cortisol reactivity to a bathing session but not to a vaccination. AB - BACKGROUND: In this prospective longitudinal study, we investigated the relation between sleeping arrangements and infant cortisol reactivity to stressors in the first two post-natal months. Co-sleeping, as compared to solitary sleeping, is hypothesized to provide more parental external stress regulation by night, thus reducing general stress sensitivity. We therefore expected lower cortisol reactivity to stress in infants who co-slept more regularly. METHODS: Participants were 163 mothers and infants from uncomplicated, singleton pregnancies. Mothers completed daily diaries on sleeping arrangements in the first 7 weeks of life. Co-sleeping was defined as sleeping in the parents' bedroom (i.e. own or parents' bed). Cortisol reactivity was measured twice: to a mild physical stressor (bathing session) at 5 weeks of age and to a mild pain stressor (vaccination) at 2 months of age. RESULTS: Infants with a solitary sleeping arrangement in their first month of life showed a heightened cortisol response to the bathing session at 5 weeks compared to infants that co-slept regularly. This effect was not explained by breastfeeding practices, maternal caregiving behavior, or infants' night waking and sleep duration. No effects were found of co-sleeping on the cortisol response to the vaccination at 2 months. CONCLUSIONS: The results suggest that solitary sleeping in the first month of life is associated with heightened sensitivity of the HPA-axis to a mild stressor, possibly due to less nocturnal parental availability as external stress regulator. Whether this effect continues in later life, remains to be investigated. PMID- 21530089 TI - Stress resilience and vulnerability: the association with rearing conditions, endocrine function, immunology, and anxious behavior. AB - BACKGROUND: The current study explored the underlying behavioral, endocrine, and immune markers of vulnerability to stress-induced depression, and the impact of rearing environments on adult functioning. METHOD: Adult Sprague-Dawley rats (n=195) were reared in either Maternal Separation (MS), Early Weaning and Isolation (EWI), or Non-Handled (NH) conditions. Anxiety behavior was assessed using the emergence test at mean postnatal day (PND) 60. Stress-induced depressive behavior was measured at mean PND 86 using an intermittent cold water swim stress and swim escape test (SET) paradigm. Immediately following the SET, and in a sample of naive controls (N=31), trunk blood was collected to assay for serum corticosterone (CORT) and spleens were removed for determination of Concanavalin A (Con-A) stimulated T-cell proliferation. RESULTS: Stress vulnerable rats (top tertile of SET swim time) were characterised by increased anxiety-like behavior, greater post-stress CORT concentrations, and a significantly higher Con-A induced T-cell proliferative response compared to stress resilient rats (bottom tertile of SET swim time). The EWI rearing condition was a contributing factor in predicting total swim escape time, however MS was not. MS offspring did have double the basal level of CORT than NH offspring, suggestive of a hyperfunctioning HPA axis. CONCLUSION: The swim stress animal model enabled observation of stress vulnerability and resilience; results point towards the existence of distinct behavioral, endocrine, and immunological profiles of the vulnerable and resilient animal, which may have important implications for mental health and stress research. PMID- 21530091 TI - Re: "The effect of cortisol on emotional responses depends on order of cortisol and placebo administration in a within-subject design" by Wirth et al. PMID- 21530093 TI - The complete control of glucose level utilizing the composition of ketogenic diet with the gluconeogenesis inhibitor, the anti-diabetic drug metformin, as a potential anti-cancer therapy. AB - In the animal models of glucose dependent cancer growth, the growth is decreased 15-30% through the use of low-carbohydrate, calorically restricted and/or ketogenic diet. The remaining growth depends on glucose formed by the liver kidney gluconeogenesis as is the case in the cancer cachexia. It is hypothesized that a new treatment for cancer diseases should be explored which includes the ketogenic diet combined with the inhibition of gluconeogenesis by the anti diabetic drug metformin. PMID- 21530094 TI - The role of COX-2 and Nrf2/ARE in anti-inflammation and antioxidative stress: Aging and anti-aging. AB - Oxidative stress and inflammation are constant features of many chronic diseases and complications, and have been linked to carcinogenesis. Cyclooxygenase 2 (COX 2), a rate-limiting enzyme for the synthesis of prostaglandins, plays important roles in physiology and pathology, but has been a source of controversy within the scientific and clinical community. However, recent work has shown that nuclear factor erythroid-2-related factor-2 (Nrf2) confers protection against oxidative stress. Furthermore, COX-2-dependent electrophile oxo-derivative (EFOX) molecules have been shown to act as anti-inflammatory mediators via activation of the Nrf2-dependent antioxidant response element (ARE). These studies have provided more insight into COX-2-mediated events. The function of all tissues, especially epithelial and endothelial tissues, declines with age, leading to the production of reactive oxygen species (ROS). COX-2 expression increases with aging in most tissues, due in part to ROS, chemical reactions, physical shearing, and dietary molecules. Here we discuss new findings related to COX-2 inflammatory and anti-inflammatory responses. Taken together, we hypothesize that COX-2 levels increase during the aging process because increasing levels of ROSs necessitate the involvement of COX-2-dependent EFOXs for anti-inflammation and Nrf2/ARE signaling for antioxidation. We also propose that COX-2 may act as an intrinsic biological aging clock due to its role in balancing inflammatory and anti inflammatory responses. PMID- 21530092 TI - Evaluation of cognitive behavioral therapy/motivational enhancement therapy (CBT/MET) in a treatment trial of comorbid MDD/AUD adolescents. AB - OBJECTIVE: Behavioral therapies developed specifically for co-occurring disorders remain sparse, and such therapies for comorbid adolescents are particularly rare. This was an evaluation of the long-term (2-year) efficacy of an acute phase trial of manualized cognitive behavioral therapy/motivation enhancement therapy (CBT/MET) vs. naturalistic treatment among adolescents who had signed consent for a treatment study involving the SSRI antidepressant medication fluoxetine and CBT/MET therapy for comorbid major depressive disorder (MDD) and an alcohol use disorder (AUD). We hypothesized that improvements in depressive symptoms and alcohol-related symptoms noted among the subjects who had received CBT/MET would exceed that of those in the naturalistic comparison group that had not received CBT/MET therapy. METHODS: We evaluated levels of depressive symptoms and alcohol related symptoms at a two-year follow-up evaluation among comorbid MDD/AUD adolescents who had received an acute phase trial of manual-based CBT/MET (in addition to the SSRI medication fluoxetine or placebo) compared to those who had received naturalistic care. RESULTS: In repeated measures ANOVA, a significant time by enrollment status difference was noted for both depressive symptoms and alcohol-related symptoms across the two-year time period of this study, with those receiving CBT/MET demonstrating superior outcomes compared to those who had not received protocol CBT/MET therapy. No significant difference was noted between those receiving fluoxetine vs. those receiving placebo on any outcome at any time point. CONCLUSIONS: These findings suggest long-term efficacy for an acute phase trial of manualized CBT/MET for treating comorbid MDD/AUD adolescents. Large multi-site studies are warranted to further clarify the efficacy of CBT/MET therapy among various adolescent and young adult comorbid populations. PMID- 21530095 TI - A new horizon into the pathobiology, etiology and treatment of migraine. AB - Sexual dimorphism in the prevalence of migraine (70% women 30% men) suggests the involvement of reproductive hormones in a women's life. Excessive estrogen during menstruation directly stimulate estrogen receptor alpha thickly populated in trigeminal ganglia and periaqueductal gray which manifest as menstrual migraine. In contrast increased progesterone during pregnancy evokes progesterone receptors A/B, which coexist with ERs, providing complete remission from migraine episodes. Moreover, estrogen also increases nociception through extracellularly signal regulated kinase (ERK) stimulation and down-regulating antinociceptive GABA, IL R1 and Zn-fingers. Hormones may provoke migraine indirectly by disrupting mineral homeostasis. Estrogen enhances the absorption and half-life of copper which in turn inhibits the absorption of zinc. Zinc is required for the synthesis of melatonin and CoQ10 essential for growing women. Excess of copper exacerbates the deficiency of zinc, melatonin and CoQ10 typically low in migraineurs. Melatonin is an antioxidant, free radical scavenger and activates antioxidant enzymes like CuZn-superoxide dismutase, catalase, glutathione peroxidase (a Se-enzyme) and glutathione reductase. Zinc deficiency reduces activity of CuZn-SOD. Magnesium and vitamin B6 modulates the level of NO in the cell, both of which are deficient in migraineurs. Magnesium is essential for the removal of trapped NO from within the cell which does not occur under low magnesium levels, which reacts with superoxide generating dangerous peroxynitrite. Iron stimulates nitric oxide synthase producing more NO which is inhibited by zinc, thus, antagonizing peroxynitrite generation. Female hormones lowers magnesium but increase calcium levels which enhance migraine ubiquitousness. Accumulation of copper and iron in deep areas of brain and peripheral nerves typically catalyses the oxidation of catecholamines and generate free radicals involved in lipid-peroxidation, demyelination, denudation of axons and neurodegeneration in specific areas exposing hyperalgesic axons provoking Classical migraine. Furthermore, zinc is an essential component of Zn-fingers (Krox20 and Krox24) which play a pivotal role in the differentiation of Schwann cells-the mainstay for the myelination/remyelination of peripheral nerves. Taken together, conceptually and logically, 30 migraineurs were administered 75 mg of zinc sulfate orally in water daily for 6 weeks+one capsule of vitamin B-complex+one capsule of vitamin A or E (first 10 days) which almost cured all of them. Placebo controlled trials with incremental doses of zinc sulfate along with magnesium and selenium are proposed to augment recovery involving large population of migraineurs. Monitoring of hair and blood mineral analysis for rational therapy is recommended. PMID- 21530096 TI - Polymorphism and expression of the porcine Tenascin C gene associated with meat and carcass quality. AB - The research aimed to screen for polymorphism, expression of Tenascin C (TNC) and association with meat and carcass quality traits. Three single nucleotide polymorphisms were detected. In a Duroc*Pietrain F2 cross (DuPi) population, g.44488C>T was associated with meat color and ham weight; g.68794A>G was associated with pH at 24h post mortem in ham (pH24(H)) and muscle area but g.68841C>T was not statistically associated. Genotyping in a commercial Pietrain (Pi) population showed that g.44488C>T was associated with pH24(H), whereas g.68794A>G was associated with conductivity at 45 min post mortem in loin and backfat thickness. Diplotypes showed significant effects on pH24(H) in both populations. The expression was associated with pH at 45 min post mortem in loin and cooking loss. TNC was significantly higher in animals with higher muscle pH. Linkage analysis revealed four trans-regulated eQTL on four autosomes. These results suggest that TNC could be a potential candidate gene for meat quality traits in pigs. PMID- 21530097 TI - Exogenous surfactant protects against endotoxin induced acute respiratory distress syndrome in rodents via vascular endothelial growth factor. AB - Vascular endothelial growth factor (VEGF) is a potent angiogenic factor which is abundantly expressed in the normal lung and is released by numerous cell types. Using a bacteria-induced lung injury model and surfactant therapy in rats, VEGF expression in lung was investigated. Sprague Dawley male rats were divided into four groups: buffer controls; rats challenged with LPS (055:B5 E. coli); challenged with LPS and treated with porcine surfactant (P-SF); and challenged with LPS and treated with synthetic surfactant (S-SF). The expressions of VEGF, PCNA, and BrdU were studied. VEGF protein expression was decreased in comparison to the control rats, as seen by both Western immunoblot and immunohistochemistry. Protein expression of PCNA and proliferation index as determined by both PCNA and BrdU immunostaining were also seen to be decreased in the LPS-treated animals, and with the surfactant treatment the expression was increased. The downregulation of VEGF in the alveolar space may reflect the recovery from acute lung injury, which leads to the limited endothelial permeability, and may participate in the decrease in capillary number, as observed during acute respiratory distress syndrome with potentially significant clinical consequences. PMID- 21530098 TI - Gamma knife radiosurgery for treatment of cerebral metastases from non-small-cell lung cancer. AB - PURPOSE: To evaluate clinical and physico-dosimetric variables affecting clinical outcome of patients treated with Gamma Knife radiosurgery (GKRS) for brain metastases from non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Between 2001 and 2006, 373 patients (298 men and 75 women, median age 65 years) with brain metastases from NSCLC underwent GKRS. All of them had KPS >= 60%, eight or fewer brain metastases, confirmed histopathological diagnosis and recent work-up (<3 months). Thirty-five patients belonged to recursive partitioning analysis (RPA) Class I, 307 patients were in RPA Class II, 7 patients were in RPA Class III. Median tumor volume was 3.6 cm(3). Median marginal dose was 22.5 Gy at 50% isodose.; median 10 Gy and 12 Gy isodose volumes were 30.8 cm(3) and 15.8 cm(3), respectively. Follow-up with MRI was performed every 3 months. Overall survival data were collected from internal database, telephone interviews, and identifying registries. RESULTS: Mean follow-up after GKRS was 51 months (range, 6 to 96 months); mean overall survival was 14.2 months. Of 373 patients, 29 were alive at time of writing, 104 had died of cerebral progression, and 176 had died of systemic progression. In 64 cases it was not possible to ascertain the cause. Univariate and multivariate analysis were adjusted for the following: RPA class, surgery, WBRT, age, gender, number of lesions, median tumor volume, median peripheral dose, and 10 Gy and 12 Gy volumes. Identified RPA class and overall tumor volume >5 cc were the only two covariates independently predictive of overall survival in patients who died of cerebral progression. CONCLUSIONS: Global volume of brain disease should be the main parameter to consider for performing GKRS, which is a first-line therapy for patient in good general condition and controlled systemic disease. PMID- 21530099 TI - Tumor shrinkage assessed by volumetric MRI in long-term follow-up after fractionated stereotactic radiotherapy of nonfunctioning pituitary adenoma. AB - PURPOSE: To evaluate tumor control and side effects associated with fractionated stereotactic radiotherapy (FSRT) in the management of residual or recurrent nonfunctioning pituitary adenomas (NFPAs). METHODS AND MATERIALS: We assessed exact tumor volume shrinkage in 16 patients with NFPA after FSRT. All patients had previously undergone surgery. Gross tumor volume (GTV) was outlined on contrast-enhanced magnetic resonance imaging (MRI) before and median 63 months (range, 28-100 months) after FSRT. MRI was performed as an axial three dimensional gradient echo T1-weighted sequence at 1.6-mm slice thickness without gap (3D MRI). RESULTS: Mean tumor size of all 16 pituitary adenomas before treatment was 7.4 mL (3.3-18.9 mL). We found shrinkage of the treated pituitary adenoma in all patients. Within a median follow-up of 63 months (28-100 months) an absolute mean volume reduction of 3.8 mL (0.9-12.4 mL) was seen. The mean relative size reduction compared with the volume before radiotherapy was 51% (22% 95%). Shrinkage measured by 3D MRI was greater at longer time intervals after radiotherapy. A strong negative correlation between the initial tumor volume and the absolute volume reduction after FSRT was found. There was no correlation between tumor size reduction and patient age, sex, or number of previous surgeries. CONCLUSIONS: By using 3D MRI in all patients undergoing FSRT of an NFPA, tumor shrinkage is detected. Our data demonstrate that volumetric assessment based on 3D MRI adds additional information to routinely used radiological response measurements. After FSRT a mean relative size reduction of 51% can be expected within 5 years. PMID- 21530100 TI - ACR appropriateness criteria retreatment of recurrent head and neck cancer after prior definitive radiation expert panel on radiation oncology-head and neck cancer. AB - Recurrent and second primary head-and-neck squamous cell carcinomas arising within or in close proximity to previously irradiated fields are a common clinical challenge. Whereas surgical salvage therapy is recommended for resectable disease, randomized data support the role of postoperative reirradiation in high-risk patients. Definitive reirradiation is an established approach for patients with recurrent disease who are medically or technically inoperable or decline radical surgery. The American College of Radiology Expert Panel on Head and Neck Cancer reviewed the relevant literature addressing re treatment after prior definitive radiation and developed appropriateness criteria for representative clinical scenarios. Examples of unresectable recurrent disease and microscopic residual disease after salvage surgery were addressed. The panel evaluated the appropriateness of reirradiation, the integration of concurrent chemotherapy, radiation technique, treatment volume, dose, and fractionation. The panel emphasized the importance of patient selection and recommended evaluation and treatment at tertiary-care centers with a head-and-neck oncology team equipped with the resources and experience to manage the complexities and toxicities of re-treatment. PMID- 21530101 TI - Risk factors for regional nodal relapse in breast cancer patients with one to three positive axillary nodes. AB - PURPOSE: In many centers, supraclavicular fossa radiotherapy (SCF RT) is not routinely offered to breast cancer patients with one to three positive lymph nodes. We aimed to identify a subgroup of these patients who are at high risk of supra or infraclavicular fossa relapse (SCFR) such that they can be offered SCFRT at the time of diagnosis to improve long term locoregional control. METHODS AND MATERIALS: We performed a retrospective analysis of the pathological features of 1,065 cases of invasive breast cancer with one to three positive axillary lymph nodes. Patients underwent radical breast conserving surgery or mastectomy. A total of 45% of patients received adjuvant chest wall/breast RT. No patients received adjuvant SCFRT. The primary outcome was SCFR. Secondary outcomes were chest wall/breast recurrence, distant metastasis, all death, and breast-cancer specific death. Kaplan-Meier estimates were used to calculate actuarial event rates and survival functions compared using log-rank tests. Multivariate analyses (MVA) of factors associated with outcome were conducted using Cox proportional hazards models. RESULTS: Median follow-up was 9.7 years. SCFR rate was 9.2%. Median time from primary diagnosis to SCFR was 3.4 years (range, 0.7-14.4 years). SCFR was associated with significantly lower 10-year survival (18% vs. 65%; p < 0.001). Higher grade and number of positive lymph nodes were the most significant predictors of SCFR on MVA (p < 0.001). 10 year SCFR rates were less than 1% in all patients with Grade 1 cancers compared with 30% in those having Grade 3 cancers with three positive lymph nodes. Additional factors associated with SCFR on univariate analysis but not on MVA included larger nodal deposits (p = 0.002) and proportion of positive nodes (p = 0.003). CONCLUSIONS: Breast cancer patients with one to three positive lymph nodes have a heterogenous risk of SCFR. Patients with two to three positive axillary nodes and/or high-grade disease may warrant consideration of SCFRT. PMID- 21530102 TI - Dorsal approach in transfer of the distal spinal accessory nerve into the suprascapular nerve: histomorphometric analysis and clinical results in 14 cases of upper brachial plexus injuries. AB - PURPOSE: The spinal accessory nerve (SAN) is conventionally transferred to the suprascapular nerve (SSN) through an incision in the supraclavicular region (the anterior approach) to improve shoulder function in brachial plexus injuries. This approach carries a risk of partial denervation of upper trapezius muscle. Here we describe how dorsal nerve transfer through an incision placed directly over the scapular spine preserves the proximal branches to the upper trapezius muscle and allows nerve transfer close to target muscles. METHODS: We report our experience with the dorsal approach in 14 cases managed between February 2007 and January 2008. Results were compared with 21 control cases treated by the anterior approach. In addition, we submitted proximal cut ends of the SAN in 10 cases from the experimental group for histomorphometry. RESULTS: A total of 11 patients had C5 and C6 injuries, whereas 3 had associated C7 injuries. The denervation period ranged between 3 and 10 months. In all cases, the distal SAN could be transferred to the SSN without a graft. Histomorphometry revealed an average of 1,671 myelinated axons. Shoulder abduction and external rotation were restored in 13 and 9 cases, respectively, compared with 16 and 12, respectively, in the control group. Electromyography revealed the first sign of reinnervation of infraspinatus muscle at 23 +/- 4 weeks, compared with 30 +/- 4 weeks in the control group. Initial evidence of shoulder abduction appeared earlier in the study population (28 +/- 4 vs 34 +/- 4 weeks). Shoulder abduction and external rotation in the study group ranged between 70 degrees and 170 degrees and 30 degrees and 80 degrees , compared with 65 degrees and 160 degrees and 22 degrees and 55 degrees in the control group. Using the Medical Research Council (MRC) grading system, at 6 months postreconstruction, 13 patients had M4 power in the trapezius muscle, whereas 1 had M3, compared with 5 in the control group who displayed grade 3 weakness. CONCLUSIONS: A dorsal approach for transfer of the distal SAN into the SSN is an alternative and effective technique in restoring shoulder function in upper brachial plexus injuries. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 21530103 TI - Hand appearance as a patient motivation for surgery and a determinant of satisfaction with metacarpophalangeal joint arthroplasty for rheumatoid arthritis. AB - PURPOSE: To determine patient motivations for surgery and satisfaction with outcomes for metacarpophalangeal (MCP) joint arthroplasty in 3 domains (appearance, function, and pain) and whether patient-reported satisfaction correlates with standard outcome measures. METHODS: In a randomized controlled trial of MCP joint implants, 33 patients with rheumatoid arthritis had primary MCP joint arthroplasty: 15 hands received Swanson implants, and 18 received NeuFlex implants. Range of motion, ulnar drift, grip strength, Sollerman hand function test, and the Michigan Hand Questionnaire were collected before surgery and 1 year after surgery. Preoperative patient motivations for and expectations of MCP joint arthroplasty were assessed for function, pain, and appearance. Patient-perceived improvement and satisfaction within the 3 domains and global satisfaction were assessed after surgery. RESULTS: Function was rated the most important motivator for surgery by 31 patients, pain by 22, and appearance by 15. Twenty-six patients rated 2 or more motivators equally high. Michigan Hand Questionnaire subscores were moderately correlated or weakly correlated with patient-reported satisfaction. The Sollerman score was weakly correlated with patient-reported satisfaction. Range of motion, ulnar drift, and grip strength were not correlated with patient-reported satisfaction. More patients stated that a much better improvement was obtained for appearance than for function or pain relief. CONCLUSIONS: Patient expectations of MCP joint arthroplasty were uniformly high. The greatest motivation for surgery was functional improvement. Pain was highly ranked, and 25 patients rated hand appearance as the first or second motivator. Patient satisfaction correlated poorly with traditional outcome measures and moderately with patient-reported outcomes. We conclude that appearance should be considered an important motivator for surgery and determinant of satisfaction. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I. PMID- 21530104 TI - [Perineal morbidity of operative vaginal delivery using spatulas and vacuum: what's the truth?]. AB - OBJECTIVES: To evaluate the perineal morbidity of operative vaginal delivery using spatulas and vacuum. METHODS: From December 2008 to May 2010, 419 single pregnancies after 37 weeks of gestation in cephalic position were prospectively included: 226 spontaneous vaginal deliveries and 193 operative vaginal deliveries (126 spatulas and 67 vacuum). Each patient had rigorous clinical examination of the perineum. Perineal tears were classified in four different degrees depending on their severity: injury to skin only or episiotomy, injury to the perineum involving perineal muscles, anal sphincter rupture without and with anal epithelium tear, respectively. RESULTS: The rate of second degree or more perineal tear among patients who had spontaneous vaginal delivery, operative vaginal delivery using spatulas and vacuum was: 5.9%, 27% and 28.6%, respectively (p<0.001). If no significant difference was observed between the rate of perineal damages after spatulas and vacuum, compared to spontaneous vaginal delivery, only spatulas were significantly associated to the risk of third degree or more perineal damage: 2 (0.9%) vs. 6 (5.2%), respectively (p=0.022). Only operative vaginal delivery was identified as an independent risk factor for second degree or more perineal tear (AOR: 4.589; 95%CI: 2.012-10.467; p<0.001). Episiotomy had no independent significant impact on that risk (AOR: 0.690; 95%CI: 0.350-1.359; p=0.283). CONCLUSION: Operative vaginal delivery using spatulas and vacuum does significantly increase perineal morbidity. This risk appears to be independent of the practice of episiotomy. PMID- 21530105 TI - Understanding subtypes of inner-city drug users with a latent class approach. AB - AIMS: We empirically identified subtypes of inner-city users of heroin and cocaine based on type of drug used and route of administration. METHOD: The sample was recruited from the communities in Baltimore, MD (SHIELD study) and consisted of 1061 participants who used heroin and or cocaine in the past 6 months on a weekly basis or more. Latent class analysis (LCA) was used to identify subtypes of drug users based on type of drug and route of administration. Logistic regression was used to compare the subtypes on depressive symptoms, injection risk and drug network compositions. FINDINGS: Inner-city drug users were classified into five subtypes: three subtypes of injection drug users (IDUs) [heroin injecting (n=134; 13%), polydrug and polyroute (n=88, 8%), and heroin and cocaine injecting (n=404, 38%)], and two subtypes with low proportions of IDUs (LIDUs) [heroin snorting (n=275, 26%) and crack smoking (n=160; 14%)]. The polydrug and polyroute subtype had the highest depressive symptoms risk among all subtypes. Injection risk was lowest in the heroin injecting subtype and significantly differed from heroin and cocaine injecting subtype. The IDU subtypes also varied in the drug network compositions. The LIDU subtypes had similar depressive symptoms risk but vastly differed in the drug network compositions. CONCLUSIONS: Subgroups of inner-city cocaine and heroin users based on type and route of administration differed in their depressive symptoms, injection risk and drug network compositions. Future studies should longitudinally examine factors associated with transitioning across these subtypes to better inform prevention and treatment efforts. PMID- 21530106 TI - Nicotine behavioral pharmacology: clues from planarians. AB - BACKGROUND: Nicotine is one of the world's most addictive substances and the primary reason that humans inhale tobacco smoke. The pharmacological effects of nicotine can be investigated in planarians, aquatic flatworms that possess an integrated neural network including cephalic ganglia that some consider the earliest 'brain' and spinal cord. Here, we tested the hypothesis that nicotine exposure elicits mammalian-like behaviors in planarians. METHODS: Planarian motility and stereotypy (C-shape hyperkinesias) were quantified following acute nicotine exposure. During repeated nicotine exposure, we investigated the presence of withdrawal, tolerance, behavioral sensitization, and environmental place conditioning. RESULTS: Acute nicotine exposure increased stereotypical activity and elicited biphasic effects on motility. A low concentration (0.01 mM) increased motility whereas higher concentrations (0.3-10mM) elicited the opposite effect. Planarians exposed to nicotine (0.03 mM) for 60 min and then tested in water displayed reduced motility that was not observed during exposure to water, acute nicotine, or continuous nicotine. Nicotine-treated planarians withdrawn from the drug for 3 days before being challenged with nicotine displayed behavioral sensitization at low concentrations (0.1, 0.3mM) but tolerance at higher concentrations (1, 3mM). Planarians conditioned with nicotine in the ambient light (non-preferred environment) displayed a reduction in their natural preference for a dark environment. CONCLUSIONS: The present results suggest nicotine elicits mammalian-like effects in planarians, including decreased motility and increased stereotypy following acute administration and abstinence induced withdrawal, behavioral sensitization, tolerance, and place conditioning during repeated exposure. PMID- 21530107 TI - Avian cathelicidins: paradigms for the development of anti-infectives. AB - The broad-spectrum defense system based on host defense peptides (HDPs) is evolutionary very old and many invertebrates rely on this system for protection from bacterial infections. However, in vertebrates the system remained important in spite of the superposition of a very sophisticated adaptive immune system. The cathelicidins comprise a major group of HDPs in mammals. About six years ago it was first described that cathelicidins are also present in birds. Here we review the properties and biological activities of the recently discovered avian cathelicidins and their potential to be used as a paradigm for the development of anti-infectives. Like the mammalian cathelicidins, avian cathelicidins exert direct antimicrobial activities but can also selectively boost host immune responses by regulation of cytokine production and recruitment of immune cells. In addition, it was found that chicken cathelicidins bind endotoxins and dampen the endotoxin-mediated inflammatory response. Molecular dissection has allowed identification of different structural elements involved in bacterial killing and immunomodulation. These studies have enabled the design of small HDP-based antibiotics with specific functions, i.e. having primarily immunomodulatory or antimicrobial activities. Since the immunomodulatory effects may, to a certain degree, be species-specific, we hypothesize that poultry-specific antibiotics can be developed based on avian cathelicidins. PMID- 21530108 TI - The use of quantitative PCR for identification and quantification of Brachyspira pilosicoli, Lawsonia intracellularis and Escherichia coli fimbrial types F4 and F18 in pig feces. AB - Four quantitative PCR (qPCR) assays were evaluated for quantitative detection of Brachyspira pilosicoli, Lawsonia intracellularis, and E. coli fimbrial types F4 and F18 in pig feces. Standard curves were based on feces spiked with the respective reference strains. The detection limits from the spiking experiments were 10(2) bacteria/g feces for Bpilo-qPCR and Laws-qPCR, 10(3)CFU/g feces for F4 qPCR and F18-qPCR. The PCR efficiency for all four qPCR assays was between 0.91 and 1.01 with R(2) above 0.993. Standard curves, slopes and elevation, varied between assays and between measurements from pure DNA from reference strains and feces spiked with the respective strains. The linear ranges found for spiked fecal samples differed both from the linear ranges from pure culture of the reference strains and between the qPCR tests. The linear ranges were five log units for F4-qPCR, and Laws-qPCR, six log units for F18-qPCR and three log units for Bpilo-qPCR in spiked feces. When measured on pure DNA from the reference strains used in spiking experiments, the respective log ranges were: seven units for Bpilo-qPCR, Laws-qPCR and F18-qPCR and six log units for F4-qPCR. This shows the importance of using specific standard curves, where each pathogen is analysed in the same matrix as sample DNA. The qPCRs were compared to traditional bacteriological diagnostic methods and found to be more sensitive than cultivation for E. coli and B. pilosicoli. The qPCR assay for Lawsonia was also more sensitive than the earlier used method due to improvements in DNA extraction. In addition, as samples were not analysed for all four pathogen agents by traditional diagnostic methods, many samples were found positive for agents that were not expected on the basis of age and case history. The use of quantitative PCR tests for diagnosis of enteric diseases provides new possibilities for veterinary diagnostics. The parallel simultaneous analysis for several bacteria in multi-qPCR and the determination of the quantities of the infectious agents increases the information obtained from the samples and the chance for obtaining a relevant diagnosis. PMID- 21530109 TI - Proteomic analysis of multidrug resistant Escherichia coli strains from scouring calves. AB - A number of researchers have used chemical inhibitors that target membrane efflux pumps as an experimental treatment strategy for multidrug resistant (MDR) bacterial infections. However, most of these compounds are toxic in vertebrate animals. The present research was therefore done to describe expression dynamics of drug resistance-associated Escherichia coli proteins that could serve as novel drug targets. Proteomes of MDR and antimicrobial susceptible (AS) E. coli were studied in two dimensional (2-D) polyacrylamide gels and liquid chromatography mass spectrometry (LC-MS) was performed on proteins of interest. The number of recovered peptides per protein was used to elucidate the amounts of target proteins expressed in MDR and AS E. coli strains. Eight proteins that may be potentially involved in mechanisms of drug resistance were analyzed and identified by LC-MS. These were grouped into membrane porins (TolC, OmpA, OmpC, Nmpc Precursor), proteins involved in microbial protein synthesis (EF-Ts, EF-Tu, RpsA) and Dps, a protein of unknown location and function. Experimental data demonstrated variability in the expression patterns and quantities of the four porins (TolC, OmpA, OmpC, Nmpc precursor), the three microbial protein synthesis associated proteins (EF-Ts, EF-Tu and RpsA), and Dps which has been previously associated with drug resistance. While variability was seen in quantities and expression patterns of some of the proteins of interest, the present data falls short of determining the suitability of these proteins as novel drug targets. Further studies are required to explore how these proteins could be targeted for drug development. PMID- 21530110 TI - Clostridium difficile infection in humans and animals, differences and similarities. AB - Clostridium difficile is well known as the most common cause of nosocomial infections in human patients. In recent years a change in epidemiology towards an increase in incidence and severity of disease, not only inside the hospital, but also in the community, is reported. C. difficile is increasingly recognized in veterinary medicine as well and is now considered the most important cause of neonatal diarrhea in swine in North America. Research on the presence of C. difficile in production and companion animals revealed a huge overlap with strains implicated in human C. difficile infection (CDI). This has lead to the concern that interspecies transmission of this bacterium occurs. In this review C. difficile infections in humans and animals are compared. The pathogenesis, clinical signs, diagnosis and prevalence of CDI are described and similarities and differences of CDI between humans and animals are discussed. PMID- 21530111 TI - The 16MDeltavjbR as an ideal live attenuated vaccine candidate for differentiation between Brucella vaccination and infection. AB - Brucellosis brings great economic burdens for developing countries. Live attenuated vaccines are the most efficient means for prevention and control of animal Brucellosis. However, the difficulties of differentiating of infection from vaccine immunization, which is essential for eradication programs, limit their applications. Therefore, the development of a vaccine that could differentiate infection from immunization will overcome the limitations and get extensive application. VjbR is a quorum sensing regulator involving in Brucella's intracellular survival. The vjbR?Tn5 mutants have been proven effective against wild type strain challenge, implying its possibility of use in vaccine candidate development. To further evaluate this candidate gene, in the present study, the antigenicity of purified recombinant VjbR protein was analyzed. Antibodies to Brucella melitensis VjbR could be detected in sera from patients and animals with brucellosis but not in control ones, implying the potential use of this protein as a diagnostic antigen. Then a vjbR mutant of B. melitensis 16M was constructed by replacing the vjbR with kanamycin gene. The mutant showed reduced survival in macrophage and mice. Vaccination of BALB/c mice with 16MDeltavjbR conferred significant protective immunity against B. melitensis strain 16M challenges, being equivalent to which induced by the license vaccine Rev.1. The vjbR deletion mutant elicited an anti-Brucella-specific immunoglobulin G response and induced the secretion of gamma interferon and interleukin-10. The most importance is that, the use of vjbR mutants as vaccines in association with diagnostic tests based on the VjbR antigen would allow the serological differentiation between infected and vaccinated animals. These results suggest that 16MDeltavjbR is an ideal live attenuated vaccine candidate against B. melitensis and deserves further evaluation for vaccine development. PMID- 21530112 TI - Novel genes associated with biofilm formation of Actinobacillus pleuropneumoniae. AB - Actinobacillus pleuropneumoniae is a gram-negative bacterium and is the causative agent of swine pleuropneumonia, a highly contagious respiratory disease. Biofilm formation is an important ability possessed by numerous bacterial pathogens. The purpose of this study was to identify and characterize biofilm mutants of A. pleuropneumoniae serotype 1 strain S4074 created using a mini Tn-10 transposon. The transposon library was screened to identify mutants with a modified ability to form biofilms in polystyrene microtiter plates. A total of 1200 mutants were screened and the analysis identified 24 mutants that exhibited abnormal biofilm formation, at least 16 unique genes were identified. Most genes identified in the enhanced-biofilm mutants encoded proteins with unknown functions, whereas most genes identified in the biofilm-reduced mutants encoded proteins related to transport, protein synthesis and nucleic acid synthesis. Approximately 50% of genes, including hns, potD2, ptsI, tig and rpmF, identified in our screen have been previously associated with biofilm formation in A. pleuropneumoniae and other bacterial species, and thus validated the screening method. The rest of genes identified, such as APL_0049, APL_0637 and APL_1572, have not been previously associated with biofilm formation. Interestingly, gene APL_0049 was previously seen among the genes differentially expressed during a natural infection of pig lungs. Preliminary characterization of the mutants was also initiated by assessing their hydrophobicity, their biofilm matrix composition and their ability to adhere to a polystyrene surface or NPTr cells. Based on the preliminary characterization, some of the mutants identified appear to have deficiencies during the initial attachment or growth of the biofilm. In conclusion, transposon mutagenesis analysis allowed the identification of new genes associated with biofilm formation in A. pleuropneumoniae. PMID- 21530113 TI - Changes in the structures of motile sperm subpopulations in dog spermatozoa after both cryopreservation and centrifugation on PureSperm((r)) gradient. AB - The aims of the present study were to: (1) determine if discrete motile sperm subpopulations exist and their incidence in fresh dog ejaculates, (2) evaluate the effects of cryopreservation on the distribution of spermatozoa within the different subpopulations, and (3) determine the effect of the discontinuous PureSperm((r)) gradient on the sperm subpopulation structure of frozen-thawed dog spermatozoa. Semen from 5 dogs were collected and cryopreserved following a standard protocol. After thawing, semen samples were selected by centrifugation on PureSperm((r)). Sperm motility (assessed by computerized-assisted semen analysis, CASA) was assessed before freezing, just after thawing and after preparation on the PureSperm((r)) gradients. Cryopreservation had a significant (P<0.001) effect on CASA-derived parameters. PureSperm((r)) centrifugation yielded sperm suspensions with improved motility (P<0.01). A multivariate clustering procedure separated 19414 motile spermatozoa into four subpopulations: Subpopulation 1 consisting of poorly active and non-progressive spermatozoa (20.97%), Subpopulation 2 consisting of slow and low-linear spermatozoa (18.24%), Subpopulation 3 consisting of highly active but non-progressive spermatozoa (20.75%), and Subpopulation 4 consisting of high speed and progressive spermatozoa (40.03%). Although, cryopreservation had a significant (P<0.001) effect on both the frequency distribution of spermatozoa within subpopulations and the motion characteristics of each subpopulation, the sperm subpopulation structure was perfectly maintained after freezing and thawing. The selected sperm samples was enrich in Subpopulation 4, reaching a proportion of 31.9% of the present spermatozoa, in contrast with the unselected sperm samples, where this sperm subpopulation accounted for 24.9% of the total. From these results, we concluded that four well-defined motile sperm subpopulations were present either in fresh semen, in unselected sperm samples or in selected preparations from dogs. The discontinuous PureSperm((r)) gradient is a simple method to improve the quality of canine frozen-thawed semen samples, since Subpopulation 4 (high-speed and progressive spermatozoa) was more frequently observed after preparation on the gradient. Finally, this study also demonstrated that the general motile sperm structure present in dog remains constant despite the effect caused by either cryopreservation or separation on PureSperm((r)) gradient. PMID- 21530114 TI - Glutamate supply positively affects serum release of triiodothyronine and insulin across time without increases of glucose during the onset of puberty in female goats. AB - The current study evaluated the effect of glutamate supply on the onset of puberty and possible links to changes in serum concentrations of insulin [INS], glucose [GLU] and triiodothyronine [T(3)]. The study was conducted from June to November in prepuberal female goats (n=18; 3 mo. old, 7/8 Saanen-Alpine, 1/8 Criollo, 26 degrees north) randomly assigned to two experimental groups: (i) excitatory amino acids group (group AA, n=10; 16.52+/-1.04 kg LW, 3.4+/-0.12 body condition score [BCS], receiving an intravenous infusion of 7 mg kg(-1) live weight [LW] of l-glutamate, twice a week, and (ii) control group (group CC, n=8; 16.1+/-1.04 kg LW, 3.1+/-0.12 BCS) receiving saline. Blood samples were obtained twice a week, for assessing progesterone [P(4)], as well as in a monthly basis to evaluate INS and T(3) by RIA. Mean final LW and BCS were 23.2+/-0.72 kg, 3.53+/ 0.10 units, without differences between groups. The AA group depicted an earlier onset of puberty (6.9+/-0.3 compared to 7.5+/-0.4 mo.; P<0.05) and an increased ovarian activity (70+/-0.28% compared to 25+/-0.26%; P<0.05). Neither serum INS concentrations nor serum glucose concentrations differed between treatments (1.2+/-0.06 ng mL(-1) and 89.6+/-1.8 mg 100 mL(-1); P>0.05, respectively). Serum T(3) concentrations, however, were greater in AA goats (1.55+/-0.03 compared to 1.39+/-0.04 ng mL(-1)). In addition, a treatment x time interaction occurred (P<0.05) across the experimental period for both T(3) and INS, with increases by the last third of the experimental period, time at which the onset of puberty occurred in both experimental groups. No differences (P>0.05) for glucose concentrations across time occurred between treatments. Results indicate that, in prepuberal goats, glutamate acts as a cue for sexual maturation in a glucose independent pathway, while both T(3) and INS seem to act as metabolic modulators for the establishment of puberty in goats. Actions of INS and T(3) are mediated directly on hypothalamic centers regulating the pulsatile release of GnRH or indirectly by peripheral cues reflecting INS-T(3) actions on somatic development remains to be determined. PMID- 21530115 TI - Endothelial biology in the post-menopausal obese woman. AB - Women generally have a reduced risk of cardiovascular disease (CVD). However, this protection of gender diminishes rapidly after menopause and with advancing age, particularly in obese women. Alterations in vascular function are thought to a key early step in the development of atherosclerosis. In this review, we will describe the features of endothelial dysfunction in the post-menopausal obese female and discuss the interplay of aging, estrogen withdrawal, and obesity. The objectives include (1) a review of endothelial biology and endothelial dysfunction, and (2) a discussion how the endothelial function is altered in the context of aging, hormonal changes and insulin resistance. The clinical consequences of endothelial dysfunction and CVD will also be reviewed. PMID- 21530116 TI - Is urinary continence considered in the assessment of older people after a fall in England and Wales? Cross-sectional clinical audit results. AB - OBJECTIVES: To investigate adherence to the urinary function assessments of the national falls guidelines for England and Wales. STUDY DESIGN: Secondary data analysis of the 2006 National Clinical Audit of Falls and Bone Health. SETTING: Acute hospitals in the UK. PARTICIPANTS: Patients aged 65 years and older with a fragility fracture as a result of a fall. MAIN OUTCOME MEASURES: Data were analysed to determine whether patients with fragility fractures received an assessment of urinary function including continence status; whether impairment was detected and if action was taken to prevent continence related falls. RESULTS: 63% (2009) of 3184 patients were assessed for urinary continence following a hip fracture and 41% (817) of these identified a problem. 21% (1187) of 5642 patients with nonhip fragility fractures were assessed and a problem was found in 27% (316). Hip fracture patients were more likely (p<0.0001) to receive a continence assessment and have problems detected. Only about half of those with problems had any intervention or a referral to a continence service. Admission to hospital for nonhip fracture patients was a strong predictor of being assessed (p<0.0001). CONCLUSION: Rates of assessment and action for those with who fall and have continence problems are low despite current national guidelines. PMID- 21530117 TI - Evaluation of human brain damage in fire fatality by quantification of basic fibroblast growth factor (bFGF), glial fibrillary acidic protein (GFAP) and single-stranded DNA (ssDNA) immunoreactivities. AB - Burns and inhalation of toxic gases, including carbon monoxide (CO) and cyanide, which are produced by combustion, are major factors involved in fire death. The present study immunohistochemically investigated basic fibroblast growth factor (bFGF), glial fibrillary acidic protein (GFAP) and single-stranded DNA (ssDNA) in the brains of fire fatalities (n=49) to examine the differences between fatal burns and CO intoxication, compared with those in cardiac deaths (n=24) and mechanical asphyxiation cases (n=23). In acute fire fatality, neuronal ssDNA immunopositivity in the cerebral cortex of the parietal lobe was high in both fatal burns and fatal CO intoxication, but that of the pallidum was higher for CO intoxication than for burns. The number of neurons was decreased in prolonged fire deaths, irrespective of the severity of burns or CO intoxication, but glias were increased in cases of fatal burns. Prolonged deaths due to burns had a higher glial bFGF immunopositivity in the cortex and white matter, higher and lower glial GFAP immunopositivity in the cortex and white matter, respectively, and a low neuronal ssDNA immunopositivity in the cerebral cortex and hippocampus. In prolonged deaths due to CO intoxication, however, glial bFGF and GFAP immunopositivities were low at each site, but neuronal ssDNA immunopositivity showed a higher value. These observations suggest increased cerebral neuronal ssDNA immunopositivity to be a finding of vitality in acute fire death, and a neuronal loss accompanied by active glial responses after severe burns, and a neuronal loss and progressive apoptosis without glial responses after CO intoxication to be characteristic in prolonged death. PMID- 21530118 TI - An evaluation of non-metric cranial traits used to estimate ancestry in a South African sample. AB - Establishing ancestry from a skeleton for forensic purposes has been shown to be difficult. The purpose of this paper is to address the application of thirteen non-metric traits to estimate ancestry in three South African groups, namely White, Black and "Coloured". In doing so, the frequency distribution of thirteen non-metric traits among South Africans are presented; the relationship of these non-metric traits with ancestry, sex, age at death are evaluated; and Kappa statistics are utilized to assess the inter and intra-rater reliability. Crania of 520 known individuals were obtained from four skeletal samples in South Africa: the Pretoria Bone Collection, the Raymond A. Dart Collection, the Kirsten Collection and the Student Bone Collection from the University of the Free State. Average age at death was 51, with an age range between 18 and 90. Thirteen commonly used non-metric traits from the face and jaw were scored; definition and illustrations were taken from Hefner, Bass and Hauser and De Stephano. Frequency distributions, ordinal regression and Cohen's Kappa statistics were performed as a means to assess population variation and repeatability. Frequency distributions were highly variable among South Africans. Twelve of the 13 variables had a statistically significant relationship with ancestry. Sex significantly affected only one variable, inter-orbital breadth, and age at death affected two (anterior nasal spine and alveolar prognathism). The interaction of ancestry and sex independently affected three variables (nasal bone contour, nasal breadth, and interorbital breadth). Seven traits had moderate to excellent repeatability, while poor scoring consistency was noted for six variables. Difficulties in repeating several of the trait scores may require either a need for refinement of the definitions, or these character states may not adequately describe the observable morphology in the population. The application of the traditional experience-based approach for estimating ancestry in forensic case work is problematic. PMID- 21530119 TI - Cognitive dysfunction and mental fatigue in childhood chronic fatigue syndrome--a 6-month follow-up study. AB - OBJECTIVES: Cognitive function was investigated in patients with childhood type chronic fatigue syndrome (CCFS) using the modified advanced trail making test (mATMT). METHODS: mATMT was performed on 19 patients with CCFS and 25 healthy controls of comparable age and sex. The effectiveness of combined treatment with cognitive behavioral therapy (CBT) and pharmacotherapy and its relationship to cognitive function was investigated by evaluation of Chalder's fatigue scale and behavior state before and after treatment for 6 consecutive months. RESULTS: All three tasks (motor skill, selective and alternative attention, and spatial working memory) of the mATMT, especially the difference in reaction time of the alternative attention task, could discriminate CCFS patients from control subjects with 70.5% accuracy (P=0.007). CCFS patients showed significantly lower alternative attention and Chalder's fatigue score before treatment (P=0.037 and 0.002, respectively). A significant improvement in performance status scores was found during the 6 months follow-up period with combined treatment with CBT and medication (P<0.001). Improvement of their cognitive symptoms was significantly correlated with improvement of alternative attention (r=0.653, P=0.002). CONCLUSIONS: Higher-order level cognitive dysfunction affects CCFS pathogenesis. Alternative attention performance evaluated by the mATMT may be used to monitor improvement in patients with CCFS. Combined treatment with CBT and medication may be effective to improve poor attention characteristics associated with CCFS. PMID- 21530120 TI - [Do smokers and potential smokers have to be offended in order to be dissuaded from smoking? The effectiveness of anti-smoking pictograms]. AB - BACKGROUND: As recommended by WHO in the fight against smoking, the French authorities have decided to implement the display of 14 "shock pictures" on cigarette packages in 2011. This study examines the effectiveness of this policy. METHODS: The present study is based on a self-reported questionnaire administered to a sample of 418 first-year medical students from a private faculty in January 2010. We consider a set of 12 European visual warnings that address different smoking problems. Econometric modeling is used to study the determinants of answers. RESULTS: Our results were twofold. Firstly, the most effective symbols concern the smoker himself/herself, they are explicit and related to an advanced stage of disease. Secondly, the warnings seem to be more effective to confirm the non-smokers in their choice than to deter smokers to smoke. CONCLUSION: This tobacco control policy seems to be effective. Therefore, visual warnings have to be carefully chosen before implementation. PMID- 21530121 TI - Imaging of hip arthroplasty. AB - The imaging evaluation of the prosthetic hip begins with radiography, but arthrography, aspiration, scintigraphy, sonography, CT and MR imaging all have roles in the evaluation of the painful prosthesis. This article will review the appearance of normal hip arthroplasty including hemiarthroplasty, total arthroplasty, and hip resurfacing, as well as the appearances of potential complications such as aseptic loosening and osteolysis, dislocation, infection, periprosthetic fracture, hardware failure, and soft tissue abnormalities. PMID- 21530122 TI - The run-off resistance (ROR) assessed on MR angiograms may serve as a valid scoring system in patients with symptomatic peripheral arterial disease (PAD) and correlates with the ankle-brachial pressure index (ABI). AB - OBJECTIVE: To investigate the correlation between the hemodynamic parameter ankle brachial pressure index (ABI) and the run-off resistance (ROR) assessed on MR angiograms (MRA) in patients with peripheral arterial disease (PAD) Fontaine Stage I and II and its potential as reliable reporting system in clinical routine. METHODS: Contrast-enhanced MRA was performed in 321 PAD patients using a 1.5T MR scanner with moving bed technique. The ROR and resting ABI were determined in each patient's leg and correlation analysis was performed using the Pearson test. RESULTS: A significant negative correlation (r = -.513; p<.001) between ROR (mean 11.03+/-5.42) and resting ABI (mean .81+/-.26) was identified. An even more pronounced correlation was found in patients younger than median age who had higher ABI values (r = -.608; p<.001). CONCLUSION: The ROR scoring system evaluated in this series correlates better with the ABI than previously published scoring systems and could be suggested as reporting system for routine MRA evaluation. PMID- 21530123 TI - Quantitative analysis of elastography images in the detection of breast cancer. AB - PURPOSE: The aim of this study was to develop a quantitative method for breast cancer diagnosis based on elastosonography images in order to reduce whenever possible unnecessary biopsies. The proposed method was validated by correlating the results of quantitative analysis with the diagnosis assessed by histopathologic exam. MATERIAL AND METHODS: 109 images of breast lesions (50 benign and 59 malignant) were acquired with the traditional B-mode technique and with elastographic modality. Images in Digital Imaging and COmmunications in Medicine format (DICOM) were exported into a software, written in Visual Basic, especially developed to perform this study. The lesion was contoured and the mean grey value and softness inside the region of interest (ROI) were calculated. The correlations between variables were investigated and receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic accuracy of the proposed method. Pathologic results were used as standard reference. RESULTS: Both the mean grey value and the softness inside the ROI resulted statistically different at the t test for the two populations of lesions (i.e., benign versus malignant): p<0.0001. The area under the curve (AUC) was 0.924 (0.834-0.973) and 0.917 (0.826-0.970) for the mean grey value and for the softness respectively. CONCLUSIONS: Quantitative elastosonography is a promising ultrasound technique in the detection of breast cancer but large prospective trials are necessary to determine whether quantitative analysis of images can help to overcome some pitfalls of the methodic. PMID- 21530124 TI - Using Onyx in endovascular embolization of internal carotid artery large or giant aneurysms. AB - BACKGROUND AND PURPOSE: Internal carotid artery (ICA) large or giant saccular aneurysms is challenging for endovascular coil embolization and surgical clipping with a high recanalization and rebleeding rate. We report our results using Onyx in the endovascular treatment of ICA large or giant saccular aneurysms. METHODS: During 2008-2010, 5 patients with 5 large or giant saccular aneurysms in ICA were treated with a liquid embolic agent (Onyx; Micro Therapeutics, Irvine, CA). One aneurysm was small (<10mm), 2 were large (>=10mm, <25mm) and 2 were giant saccular aneurysms (>=25mm). Of 3 female and 2 male patients, 3 were incidental and 2 had bleeding. Selective embolization was performed with Onyx alone or a combination with coils. Clinical and anatomic outcomes were assessed with the Modified Glasgow Outcome Scale and follow-up angiography was performed at 4-21 months (mean 12.2 months). RESULTS: Complete aneurysm occlusion was obtained in all of the aneurysms on immediate control angiogram. There was not any procedure related complication. No recanalization was observed at the follow- up periods. There were 2 ICA occlusions in giant ICA aneurysms. The 5 patients were all clinically asymptomatic at follow-up. CONCLUSION: Endovascular embolization with Onyx is a useful treatment for ICA large or giant aneurysms, which is unsuitable for coiling or surgical treatment. PMID- 21530125 TI - Denitrification is a common feature among members of the genus Bacillus. AB - Although several Gram-positive denitrifiers have been characterized in the past, there is still uncertainty about the occurrence of the denitrification trait among these bacteria. In an isolation campaign on luvisol soil, Bacillus spp. were among the most abundant retrieved cultured denitrifiers next to members of Rhizobiaceae family and genus Cupriavidus. Subsequent screening of 180 representatives of the genus Bacillus (encompassing more than half of the current validly described species diversity in Bacillus) was performed and demonstrated the potential for dissimilatory reduction of nitrogen compounds in 45 of the 87 investigated species, with 19 species containing denitrifying members. The influence of several electron donors and acceptors was tested. The use of more than one electron acceptor, e.g. both nitrate and nitrite, was crucial to detect the denitrification potential of reference strains. Complex electron donors, most suitable for aerobic growth, were ideal for denitrification testing, while retrieval of denitrifiers from the environment was facilitated by the use of defined electron donors, due to less interference of other anaerobic growers. The outcome of the isolation campaign and screening of reference strain set suggest that bacilli may be potential contributors to denitrification in terrestrial and possibly other ecosystems. PMID- 21530126 TI - Metabolite profiling of hemodialysate using gas chromatography time-of-flight mass spectrometry. AB - Hemodialysis is an important alternative for renal replacement therapy to remove uremic retention solutes (URS) for the uremic syndrome. The metabolites in the hemodialysate directly reflect the efficiency of URS clearance. Here we report a highly sensitive and reliable metabolomic procedure for the measurement of small molecule metabolites in hemodialysate using gas chromatography coupled with time of-flight mass spectrometry (GC/TOF/MS). The method was developed and evaluated through orthogonal experimental design using multivariate statistical analysis. The optimized method involves the use of methanol and water in the ratio of 3:1 (v/v) for dissolving the lyophilized solid of the hemodialysate after degradation of urea with urease (no less than 50U) for 10min. Validation of the method demonstrated a good linearity with regression coefficients greater than 0.99. Relative standard deviations of precision and stability of proposed method were less than 15%, and recoveries ranged from 71.8 to 115.8%. This method was successfully applied in the metabolite profiling of human hemodialysate samples which was able to differentiate the patients treated with high-flux hemodialysis from those with low-flux hemodialysis. The metabolomic results reveal a higher concentration of URS, and thus, better URS removal, from the patients under high flux dialysis than those under low-flux dialysis. PMID- 21530127 TI - Quantification of sofalcone in human plasma and urine by high performance liquid chromatography-mass spectrometry. AB - Sofalcone, isolated from the root of the Chinese medicinal plant Sophora subprostrata, is well known to be a mucosal protective agent for gastritis and peptic ulcer treatment. Although the LC-MS/MS and HPLC-DAD methods for assay of plasma concentration of sofalcone were reported before for the pharmacokinetic study, they were either too complicated or not sensitive enough for current pharmacokinetic study. In addition, no urinary assay method or pharmacokinetic information was available. Thus an improved high performance liquid chromatography-mass spectrometric method employing negative electrospray ionization was developed for the determination of sofalcone concentration in human plasma and urine sample. A liquid-liquid extraction method was utilized to extract sofalcone together with the indometacin (internal standards) from 0.5ml of human plasma or urine samples. Multiple reaction monitoring was used for quantification by monitoring the transition of m/z from 449.5 to 313.1 for sofalcone and 356.9 to 313.0 for IS. The validation of the method regarding to specificity, sensitivity, linearity, reproducibility, accuracy and stability was evaluated. The lower limit of quantification (LLOQ) of the developed assay method for sofalcone was 0.5ng/ml and the linear calibration curve was acquired with R(2)>0.99 between 0.5 and 500ng/ml for both plasma and urine samples. The intra- and inter-day variations of the current assay were evaluated with the relative standard deviation (RSD) within 13.77% at low concentration of quality control samples (QCs) and 8.71% for other QCs, whereas the mean accuracy ranged from 96.21 to 107.33%. The samples were found to be stable under the storage conditions at least for a month and other experimental conditions. This validated method was then utilized to test sofalcone concentration in clinical samples. Based on these data, the pharmacokinetic behavior of sofalcone in plasma as well as urine was described. As a conclusion, the present method proved to be a rapid and sensitive analytical tool for sofalcone in human plasma or urine samples and has been successfully applied to a clinical pharmacokinetic study of in healthy Chinese subjects. PMID- 21530128 TI - Simultaneous characterization of bile acids and their sulfate metabolites in mouse liver, plasma, bile, and urine using LC-MS/MS. AB - Sulfation is a major metabolic pathway involved in the elimination and detoxification of bile acids (BAs). Several lines of evidence are available to support the role of sulfation as a defensive mechanism to attenuate the toxicity of accumulated BAs during hepatobiliary diseases. Individual BAs and their sulfate metabolites vary markedly in their physiological roles as well as their toxicities. Therefore, analytical techniques are required for the quantification of individual BAs and BA-sulfates in biological fluids and tissues. Here we report a simple, sensitive, and validated LC-MS/MS method for the simultaneous quantification of major BAs and BA-sulfates in mouse liver, plasma, bile, and urine. One-step sample preparation using solid-phase extraction (for bile and urine) or protein precipitation (for liver and plasma) was used to extract BAs and BA-sulfates. Base-line separation of all analytes (unsulfated- and sulfated BAs) was achieved in 25min with a limit of quantification of 1ng/ml. This LC MS/MS method was applied to simultaneously quantify BAs and BA-sulfates in both male and female mouse tissues and fluids. Less than 3% of total BAs are present in the sulfate form in the mouse liver, plasma, and bile, which provides strong evidence that sulfation is a minor metabolic pathway of BA elimination and detoxification in mice. Furthermore, we report that the marked female-predominant expression of Sult2a1 is not reflected into a female-predominant pattern of BA sulfation. PMID- 21530129 TI - Comparison of polysaccharides from different Dendrobium using saccharide mapping. AB - Multiple species of Dendrobium are widely used as Shihu, a well known Chinese herb, for medicinal purpose in China. Small molecules such as phenols, alkaloids and coumarins are obviously varied in different species of Dendrobium. But there are few reports on polysaccharides, one of major active components, from Dendrobium. In this study, polysaccharides from different species or locations of Dendrobium were compared using saccharide mapping. The results showed that polysaccharides of Dendrobium from different species or locations were obviously varied in spite of they had some similar characters, which is helpful to control the quality of Dendrobium. PMID- 21530130 TI - Validation of immunoassay for protein biomarkers: bioanalytical study plan implementation to support pre-clinical and clinical studies. AB - Biomarkers have emerged as an important tool to optimize the benefit/risk ratio of therapeutics. The scientific impact of biomarker studies is directly related to the quality of the underlying data. It is therefore important that guidance be established for validation of assays used to support drug development. This paper specifically focuses on validation of immunoassay for protein biomarker to support pre-clinical and clinical studies. Therapeutics (small- and macro molecules) and their respective target/ligand are out of scope. This paper describes the implementation of a bioanalytical study plan for the validation of immunoassays to support decision-making biomarkers and biomarker selection during preclinical and clinical studies. It establishes the complete operating procedure as well as the parameters and their respective acceptance criteria and defines milestones and decision points to be followed during the assay validation that should result in high quality bioanalytical data in a limited timeframe and with reduced costs. The bioanalytical study plan can be applied to the validation of a wild range of immunoassay technology such as monoplex ELISA, automated analyzer, multiplex assays or cutting edge technology. Before any validation, a feasibility study is performed to assess the performance of the immunoassay using biological samples which should mimic the clinical population. The feasibility study addresses the likelihood that an assay will be able to achieve its intended purpose with parallelism being the most critical element (milestone 1). At the end of the feasibility study, a decision is taken to either continue with the validation or change the assay (milestone 2). The milestone 3 consists of the establishment of the nominal value of quality control to be used during the validation. The quality controls used to validate an assay should preferentially be prepared using neat (non-spiked) biological matrix (ideally derived from the specific trial population). The last milestone (milestone 4), the formal validation, includes demonstration of the assay performance meeting accuracy and precision acceptance criteria within (intra-run) and between (inter-run) validation runs for each QC sample. Validation also includes the assessment of stability of the protein biomarker in the biological matrix. It is recognized that the extent of the validation should be correlated to the intended use of the data and the assay acceptance criteria should take into consideration the study objective(s), nature of the methodology and the biological variability of the biomarker. PMID- 21530131 TI - High-throughput analysis of standardized pharmacokinetic studies in the rat using sample pooling and UPLC-MS/MS. AB - As a consequence of a continuous demand for increased throughput of pharmacokinetic (PK) studies, industries have introduced strategies to reduce the number of samples such as cassette analysis (pooling of samples after the in-life phase). Here, we have investigated whether relevant PK parameters change as a consequence of cassette analysis, and whether there are circumstances that disqualify this technique from being used. 22 compounds were intravenously and orally administered to parallel groups of 3 rats. Each compound was administered discretely. Equal volumes of three plasma samples corresponding to each time point of three discretely dosed rats with different compounds were pooled (cassette analysis). Samples were prepared by protein precipitation followed by UPLC-MS/MS analysis using pos/neg switching when required. With cassette analysis, 4 compounds, morphine, phenytoin, rofecoxib and diclofenac, showed high limit of quantification (LOQ) values after pooling, which led to less reliable PK analyses. Of all samples with contents above LOQ, about 5% could not be detected in pool samples compared to single samples. However, an excellent correlation was seen for all PK parameters when comparing the parameters obtained from discrete analysis versus those obtained from cassette analysis, although half life showed somewhat more scatter than the others. When PK parameters were grouped as low medium-high, clearance, volume of distribution, half life and bioavailability were similar between discrete and cassette analysis for 90%, 86%, 95% and 90% of the total number of compounds tested, respectively. Some additional improvement was achieved if compounds with a low MS response were excluded. In summary, cassette analysis is an effective strategy to reduce samples without affecting the estimated PK parameters that are important for decision-making. PMID- 21530132 TI - Isolation and characterization of process-related impurities and degradation products in larotaxel. AB - The isolation and characterization of the process related impurities and degradation products of larotaxel drug substance were described. Forced degradation of larotaxel was carried out under acidic, basic, oxidation, light and thermal conditions to assess the nature of the impurities. The pure impurities were obtained by semi-preparative LC isolation and analyzed by NMR and MS. The structures of impurities were confirmed as 7,8-cyclopropyl baccatin III, 10-deacetyl larotaxel, 10-deacetyl-7, 8-cyclopropyl baccatin III, 7-acetyl-8 methyl larotaxel and 2',13-bissidechain larotaxel. PMID- 21530133 TI - Rapid profiling and identification of triterpenoid saponins in crude extracts from Albizia julibrissin Durazz. by ultra high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. AB - Ultra high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC/ESI-Q-TOF-MS/MS) was applied to separate and identify triterpenoid saponins in crude extract from the stem bark of Albizia julibrissin Durazz. The molecular weights were determined by comparing quasi-molecular ions [M+NH(4)](+) in positive mode and [M-H](-) and [M 2H](2-) ions in negative mode. The MS/MS spectra of the [M-H](-) ions for saponins provided a wealth of structural information related to aglycone skeletons, sugar types and linked sequence. On the basis of the fragmentation behavior of known saponins isolated before, saponins from this plant were identified, even though references were not available. As a result, a total of twenty-eight saponins in the crude extract were identified, which all had a common basic skeleton of the triterpene oleanolic acid and eight of them were new compounds. PMID- 21530134 TI - Stress testing in young low-risk patients with potential acute coronary syndromes. AB - OBJECTIVE: Young patients are at low risk for an acute coronary syndrome (ACS); however, many of these patients still enter a "rule-out ACS" pathway and receive stress testing. We hypothesized that stress testing in patients younger than 40 years without known coronary disease will not identify patients at high risk for 30-day adverse cardiovascular events. METHODS: We conducted a cohort study of patients younger than 40 years evaluated in the emergency department for potential ACS. Patients were excluded if they used cocaine, had known cardiac disease, or had an abnormal electrocardiogram. Patients were followed up in house; follow-up was performed by direct telephone contact and medical record review. The main outcome was a composite of death, acute myocardial infarction (AMI), and revascularization at 30 days. Comparisons between patients with and without stress testing were done using chi2 or t test, as appropriate; 95% confidence intervals were reported for the main outcomes. RESULTS: Of 8816 patient visits, 1144 patients met inclusion criteria. Within 30 days, 82 patients (7.2%) received stress testing, 2 of whom led to cardiac catheterization. Death (n=2), AMI (n=3), and revascularization (n=1) were not different between patients who did and did not receive stress testing (2.4% [0.2%-8.5%] vs 0.4% [0.1% 1.0%]). CONCLUSION: The 30-day cardiovascular complication rate is not different between young patients without known heart disease who do and do not receive stress testing when they present with symptoms of a potential ACS. Testing of young patients at low risk for disease should be reconsidered. PMID- 21530135 TI - Spontaneous resolution of a large traumatic pneumothorax. AB - The aim of this study was to describe a case of a large traumatic pneumothorax (>55%) that resolved completely without intervention. A pneumothorax is the accumulation of air between the visceral and parietal pleura. It can occur spontaneously or be traumatic. Spontaneous pneumothoraces can occur with no underlying lung disease or secondary in nature. The emergency department (ED) treatment of pneumothoraces depends on their size, their etiology, and clinical stability of the patient. The current recommendation is observation in stable patients with <15% pneumothorax and tube thoracostomy in patients with >15% pneumothorax. A 33-year-old woman presented to our ED complaining of right knee and right lateral chest wall pain after falling. Her breath sounds were reported as normal. A chest radiograph was ordered, which showed a large right-sided pneumothorax with tracheal deviation suggestive of a tension pneumothorax. The provider did not appreciate the pneumothorax at the time, and she was subsequently discharged home. The radiograph was over-read in the morning, and several attempts were made to recall the patient but were unsuccessful. Fortunately, the patient returned to the ED for an unrelated complaint approximately 1 month later, and the radiograph was repeated, confirming full resolution of the pneumothorax. She was not treated at another facility during that time. This is a typical manifestation of a traumatic pneumothorax but with an atypical course and outcome. It raises the question of whether, even in the case of traumatic pneumothorax, the threshold for placement of chest tubes could be reconsidered in stable patients. PMID- 21530136 TI - Sepsis-associated takotsubo cardiomyopathy can be reversed with levosimendan. AB - Sepsis is a stressful physical condition, and at the acute phase, overstimulation of the sympathetic nervous system may occur; these events have the potential to induce cardiomyopathy. Takotsubo cardiomyopathy (TTC) is a form of catecholamine induced cardiomyopathy, which occurs very rarely in sepsis. However, TTC management in critically ill patients with sepsis may be challenging because the use of exogenous catecholamines for circulatory support might augment further TTC. Herein, we report a rare case of TTC after urosepsis; and we point out that cardiac function may improve after catecholamine withdrawal and the application of calcium channel sensitizer levosimendan. PMID- 21530137 TI - Woman with red urine: hydroxocobalamin-induced chromaturia. PMID- 21530138 TI - Recurrent respiratory depression associated with fentanyl transdermal patch gel reservoir ingestion. AB - BACKGROUND: Opioid abuse is common in the United States and is currently on the rise. Fentanyl transdermal patches (FTPs) have been on the market since 1991, and have recently become a popular source of opioids for abusers. There are currently two distinct FTP designs available on the market today; a gel reservoir system and a matrix construct. The gel reservoirs of FTPs contain massive amounts of fentanyl and are easily extractable for abuse. Ingesting the gel reservoir of an FTP is potentially lethal. CASE SERIES: In this case series, 4 patients ingested the gel reservoir of an FTP and experienced severe and recurrent respiratory depression necessitating continuous naloxone infusions. All patients responded adequately to initial prehospital doses of naloxone (0.8-2 mg intravenous) but developed recurrent respiratory depression within 2 h of presentation to the hospital. CONCLUSION: The gel reservoir of an FTP contains massive amounts of fentanyl. Ingestion of the gel may cause severe and recurrent respiratory depression necessitating repeated naloxone boluses, continuous naloxone infusion, and a prolonged observation period. PMID- 21530139 TI - Pulmonary embolism in pediatrics. AB - BACKGROUND: Pulmonary embolism (PE), an uncommon diagnosis in pediatric patients, is a potentially life-threatening condition with significant morbidity and mortality. Improvements in pediatric care have resulted in survival of more chronically and critically ill children and thus, an increased number of pediatric patients at risk for this disease. OBJECTIVES: We review the pathophysiology, risk factors, presentation, diagnosis, and initial management of PE in pediatric patients presenting to the Emergency Department. DISCUSSION: Although there is a significant lack of pediatric-specific literature pertaining to the diagnosis and management of PE, there are clear differences in the emergency approach to these patients, including specific risk factors and the inutility of clinical decision rules and D-dimer. CONCLUSION/SUMMARY: We outline these differences and present rational diagnostic and treatment algorithms. PMID- 21530140 TI - "User-testing" as a method for testing the fitness-for-purpose of written medicine information. AB - OBJECTIVE: Written medicine information is essential to support spoken information from pharmacists, but must be fit-for-purpose. This study applied "user testing" to the booklet supplied to UK patients taking anticoagulant medicines. METHODS: "User testing" uses mixed-methods, applied iteratively, to assess document performance - can people find and understand key points of information through a questionnaire and short semi-structured interview. The booklet was tested in 3 rounds of 10 people. After each round it was revised according to participants' responses, and re-tested. RESULTS: The first round questionnaire identified problems with 6/18 information points (booklet purpose; other information; what affected daily doses; effect of ibuprofen; tablet colour; drinking alcohol); interviews raised further issues. The booklet was revised and, in the second testing round, one problem identified (changing doses of other medicines); the interviews raised fewer issues. After further re-wording and re design, a third round showed all questions found and understood by at least 8/10 participants. CONCLUSION: User testing assesses whether people can find and understand key information and can be applied using small numbers of participants. Application to medicine information can markedly improve performance. PRACTICE IMPLICATIONS: Information producers should consider user testing to ensure documents are 'fit for purpose' in informing patients. PMID- 21530141 TI - Marrying contradictions: healthcare professionals perceptions of empowerment in the care of people with Type 2 Diabetes. AB - OBJECTIVE: The aim of the study was to establish how healthcare professionals (HCPs) involved in Type 2 Diabetes (T2D) perceive patient-empowerment. We aimed to identify their understanding of empowerment, and how these inform their day-to day practice. METHODS: Employing a qualitative approach, ten interviews with diabetes HCPs in two local Health Trusts were conducted. Data were transcribed verbatim and analysed using framework analysis. RESULTS: HCPs viewed empowerment as a rejection of the paternalistic approach. Emphasis was given to ways of balancing clinical aims against patients' concerns. Some saw the approach as improving service quality, whereas others saw empowerment as a process of social justice. These were related variably to the expedient use of resources. CONCLUSION: Models of empowerment, which promote that HCPs bring clinical expertise and patients 'lay' expertise of illness to the medical encounter, are inadequately descriptive of how empowerment approaches are actually engaged with, by HCPs. PRACTICE IMPLICATIONS: The empowerment approach is construed and utilised in different ways. Clarification of what empowerment entails in practice for HCPs, as well as what HCPs perceive are its multiple aims, is required. PMID- 21530142 TI - Emergency stent graft implantation for ruptured visceral artery pseudoaneurysm. AB - BACKGROUND: Literature series that include visceral artery pseudoaneurysms rarely separate them from true aneurysms, although they address different issues. Guidelines for optimal management of these lesions are lacking. We report our experience of stent graft treatment of these lesions with midterm results. METHODS: We retrospectively reviewed all patients with a visceral pseudoaneurysm who were treated with a stent graft in our institution. Patient history, clinical characteristics, procedure details, and outcome were recorded and analyzed. RESULTS: From March 2004 to June 2009, 10 consecutive patients (9 men), who were a mean age of 59 years, were treated for symptomatic visceral artery pseudoaneurysm, with hemorrhagic shock in 8 patients (80%), after pancreaticoduodenectomy in 8, gastrectomy in 1, and abdominal trauma in 1. A mean of 24 days (range, 7-60 days) passed between the initial surgery or trauma and pseudoaneurysm diagnosis. Septic complications were associated in six patients (60%). The pseudoaneurysm was in the hepatic artery in 8 patients, the splenic artery in 1, and the superior mesenteric artery in 1. Technical and clinical success was achieved in 80% of patients. Two failures of catheterization were followed by redo surgery and death (20%). No patients died postoperatively, and no complications among the patients who were treated successfully. Mean follow-up was 37 months (range, 10-63 months). All stent grafts were patent, with no signs of infection. Two patients died secondary to neoplasm. No rebleeding or recurrent aneurysms were noted. CONCLUSION: Stent graft exclusion of visceral artery pseudoaneurysm seems to be a valid therapeutic approach regardless of the patient's septic or hemodynamic status. PMID- 21530143 TI - [GlideScope(r) Cobalt with disposable blades: series of 121 intubations in young children]. PMID- 21530144 TI - [Oropharyngeal submucosal post-traumatic emphysema]. PMID- 21530145 TI - [Anaesthesia and Parkinson's disease]. AB - OBJECTIVE: The purpose of this review is to draw up a statement on current knowledge available on perioperative management of Parkinson's disease patients. STUDY DESIGN: Review. DATA SYNTHESIS: In France, approximately 150,000 persons suffer from Parkinson's disease, a neurodegenerative disorder of central nervous system. Parkinson's disease results in selective and irreversible loss of dopaminergic neurons in the substantia nigra pars compacta. Medications based on dopaminergic drugs are used to control motor symptoms and improve motor function. Development of surgical approach, especially deep brain stimulation, has revolutionized the medical management of many patients with Parkinson's disease. Anesthesia of these patients remains a challenge for the clinician. The aim of this review is to describe anaesthetic considerations of patients with Parkinson's disease and to discuss management of antiparkinsonians medications during the perioperative period. PMID- 21530146 TI - [The uncanny]. PMID- 21530147 TI - Re: Hip and knee arthroplasty in hypophosphatemic rickets. PMID- 21530148 TI - Bipolar hip arthroplasty. AB - Our aim was to compare hip arthroplasty with internal screw fixation in the repair of intertrochanteric fractures in elderly patients with osteoporosis. Of 112 included patient, 70 (81.81 +/- 4.88 years) received hip arthroplasty with a prosthesis specially designed for intertrochanteric fractures, and 42 (83.46 +/- 5.11 years) underwent plate-screw fixation. The hip arthroplasty group had significantly longer operation time, intraoperative blood loss, and total volume of blood transfused but had shorter time to beginning weight-bearing (5.94 +/- 2.76 vs 23.68 +/- 22.01 days) and higher postoperative Harris hip score (91.37 +/ 4.80 vs 86.14 +/- 5.46). In the arthroplasty group, there were 2 dislocations; and in the plate-screw fixation group, there were 5 internal fixation failures. Hip arthroplasty is preferable to internal fixation in elderly patients (age >80 years) with osteoporosis. PMID- 21530149 TI - Rotating platform spinouts with cruciate-retaining mobile-bearing knees. AB - Spinout or dislocation is a complication of mobile-bearing total knee arthroplasty. We have observed this complication in 7 of 1255 cruciate-retaining mobile-bearing total knees (0.56%). Patient factors associated with a spinout included female sex, obesity, and preoperative valgus deformity. Operative treatment was generally successful, but significant complications occurred in 3 of the 7 patients. PMID- 21530150 TI - Comment on "Swallowing dysfunction after mechanical ventilation in trauma patients". PMID- 21530151 TI - Dynamic changes of matrix metalloproteinases and their tissue inhibitors in severe sepsis. AB - PURPOSE: Little is known about the dynamic changes of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in sepsis. Our aim was therefore to investigate the time course of MMPs and their inhibitors in patients experiencing severe sepsis. METHODS: Our prospective controlled analysis included 38 patients with severe sepsis. Plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured daily at a 5-day-long period with enzyme-linked immunosorbent assay. Seventeen healthy volunteers were invited as controls. RESULTS: MMP-2 showed no difference compared to controls, whereas significantly elevated MMP-9 levels were detected on admission (P < .005). Significantly elevated but declining TIMP-1 levels were measured during the whole trial (P < .002-.004). Except for the second day, TIMP-2 levels were significantly lower than controls (P < .05-.009). MMP2/TIMP-1 ratios were significantly lower in septic patients (P < .03-.006), whereas MMP-2/TIMP-2 ratios were elevated throughout our study (P < .03-.006). MMP-9/TIMP-1 ratios were significantly lower at the first 3 days (P < .05-.008). MMP-9/TIMP-2 was significantly elevated on admission (P < .006). CONCLUSIONS: Our research is the first follow-up study dealing with MMPs, TIMPs, and their ratios in severe sepsis. Our results indicate that MMPs and TIMPs may play a crucial role in severe sepsis, especially TIMP-1, MMP-9, and possibly TIMP-2, after an extensive study. PMID- 21530152 TI - Advance care planning in Belgium and The Netherlands: a nationwide retrospective study via sentinel networks of general practitioners. AB - CONTEXT: Advance care planning (ACP) is an important part of patient-centered palliative care. There have been few nationwide studies of ACP, especially in Europe. OBJECTIVES: To investigate the prevalence and characteristics of ACP in two European countries and identify the associated factors. METHODS: A mortality follow-back study was undertaken in 2007 via representative nationwide Sentinel Networks of general practitioners (GPs) in Belgium and The Netherlands using similar standardized procedures. All GPs reported on each non-suddenly deceased patient in their practice. Our main outcome measure was whether or not ACP, that is, an agreement for medical treatment and/or medical decisions in the last phase of life in the case of the patient losing competence, was present. RESULTS: Among 1072 non-sudden deaths, ACP was done with 34% of patients and most often related to the forgoing of potential life-prolonging treatments in general (24%). In 8% of cases, ACP was made in consultation with the patient and in writing. In 23% of cases, care was planned with the patient's family only. Multivariate analysis revealed that ACP was more often made with patients if they were capable of decision making during the last three days of life (odds ratio [OR] 3.86; 95% confidence interval [CI] 2.4-6.1), received treatment aimed at palliation in the last week (OR 2.57; 95% CI 1.6-4.2), had contact with a GP in the last week (OR 2.71; 95% CI 1.7-4.1), died of cancer (OR 1.46; 95% CI 1.1-2.0), or died at home (OR 2.16; 95% CI 1.5-3.0). CONCLUSION: In these countries, ACP is done with approximately one-third of the studied terminally ill patient population. Most agreements are made only verbally, and care also is often planned with family only. ACP relates strongly both to patient factors and to health care measures performed at the very end of life. PMID- 21530153 TI - Development and validation of the general module of the system of quality of life instruments for chronic diseases and its comparison with SF-36. AB - CONTEXT: Quality of life (QOL) for patients is now a worldwide concern, but there are few specific instruments developed by modular approach to measure outcomes in chronic diseases. OBJECTIVES: This study aimed to develop and validate the System of Quality of Life Instruments for Chronic Diseases--General Module (QLICD-GM). METHODS: Based on the World Health Organization's definition of QOL and programmed decision procedures, the QLICD-GM was developed using focus group discussions, pilot tests of 201 cases, and field tests of 620 cases representing seven different chronic diseases. The number of items in the final version was reduced to 30 from a 73-item pool, and the psychometric properties of the scale were evaluated by indicators, such as validity and reliability coefficients, standardized response mean, and statistical methods of correlational analysis, t tests, and structural equation modeling. RESULTS: Correlational and structural equation model analyses confirmed good construct validity with root mean square error of approximation of 0.0606, nonnormed fit index of 0.941, and comparative fit index of 0.947. Test-retest reliability coefficients for all domains and facets were higher than 0.70, with a range of 0.71-0.92, and the internal consistency alphas for most domains and facets were higher than 0.65 (ranging from 0.52 to 0.89). All domains and overall scores of the QLICD-GM had a statistically significant change after treatment, with moderate effect size. CONCLUSION: The QLICD-GM has good validity, reliability, and better responsiveness compared with the SF-36(r) Health Survey and can be used as the general module for chronic diseases. PMID- 21530154 TI - Validity of the memorial symptom assessment scale-short form psychological subscales in advanced cancer patients. AB - CONTEXT: The Memorial Symptom Assessment Scale-Short Form (MSAS-SF) is designed to evaluate physical and psychological symptom burden in advanced cancer patients. There are no current data assessing the validity of the MSAS-SF psychological symptom scores when compared with anxiety and depression. OBJECTIVES: This observational cross-sectional study was designed to determine the relationship between the MSAS-SF subscales and the presence of anxiety and depression. METHODS: Advanced cancer patients attending a U.K. oncology center completed the MSAS-SF and the Hospital Anxiety and Depression Scale. RESULTS: One hundred twenty patients participated in the study. There was an association between the presence of anxiety and depression and the MSAS-SF global distress index. There was no association between the presence of anxiety and depression and the MSAS-SF physical symptom subscale. The MSAS-SF psychological symptom subscale was more closely correlated with anxiety than depression. CONCLUSION: These results support the validity of the MSAS-SF global distress index and psychological subscales in the assessment of patients with anxiety and depressive disorders. PMID- 21530155 TI - Carotid artery revascularization in patients with concomitant carotid artery stenosis and asymptomatic unruptured intracranial artery aneurysm. AB - BACKGROUND: The incidence of concomitant carotid artery stenosis and unruptured intracranial aneurysm (UIA) has been reported to be between 3% and 5%. The rupture risk of UIA measuring <7 mm is very low according to International Study of Unruptured Intracranial Aneurysm data. However, there may be a potential risk of aneurysm rupture after carotid artery revascularization because of increased cerebral blood flow. The aims of this study were to investigate the incidence of concomitant UIA in patients who needed carotid artery intervention and to survey the incidence of aneurysm rupture after treatment. METHODS: Between October 2004 and December 2009, 114 patients with severe carotid artery stenosis were treated in our hospital (69 carotid endarterectomies and 45 carotid artery stentings). Cerebral angiography and medical records were reviewed retrospectively. RESULTS: Cerebral angiography revealed seven asymptomatic UIAs in six patients (5%, 6/114). Of them, four patients underwent carotid endarterectomy and two underwent carotid artery stenting. All patients were male, and the mean age of the patients was 72 years (range, 67-79 years). Aneurysm size ranged between 2.3 and 4.0 mm. Two patients had UIAs on the same side of the treated carotid artery, whereas others developed UIAs on the contralateral side. There was no periprocedural aneurysm rupture. During follow-up (mean: 18 months, 5-31 months), two patients died from other causes, and no rupture of aneurysm occurred in any of the patients. CONCLUSION: In our series, the carotid artery revascularization did not have an effect on the natural course of small-sized asymptomatic UIA. PMID- 21530156 TI - Effects of lower extremity revascularization on the endothelial functions measured with noninvasive brachial artery flow-mediated dilatation. AB - BACKGROUND: Endothelial function is best measured with the noninvasive brachial artery flow-mediated dilatation (FMD) method. Peripheral arterial diseases and systemic cardiovascular diseases have FMD-lowering effect. The effects of lower extremity ischemia are associated with muscle inflammation and claudication, which may further lead to arterial stress. Our aim in this study was to investigate the effects of peripheral arterial revascularization on the endothelial functions through noninvasive brachial artery FMD. METHODS: Between January 2007 and February 2008, 54 patients diagnosed with lower extremity arterial disease undergoing revascularization were included in the study. Endothelial function is measured preoperatively and at the fourth week postoperatively using the brachial artery FMD method. Blood samples were collected at the same intervals for the measurement of interleukin-6, leukocyte count, tumor necrosis factor-alpha, and nitric oxide values. RESULTS: Femoropopliteal bypass grafting was performed in all patients with a synthetic graft. The mean ankle-brachial index in the preoperative period was 0.29 +/- 0.083, and after the operation, dorsalis pedis and/or posterior tibial artery became palpable in all patients. The nitric oxide, interleukin-6, high sensitivity C-reactive protein, and tumor necrosis factor-alpha levels decreased significantly after 4 weeks postoperatively as compared with the preoperative levels (p < 0.05). Postoperative Doppler ultrasonography FMD of brachial artery increased from preoperative value of 9.2 +/- 2.1 to 16.2 +/- 4.5 (p < 0.01) at postoperative week 4. CONCLUSIONS: Systemic inflammation and muscle ischemia lead to reduced endothelial functions. After successful lower extremity revascularization, endothelial functions improve dramatically, which may be easily detected with the noninvasive brachial artery FMD method. PMID- 21530157 TI - Comparison of carotid artery stenting in patients with single versus bilateral carotid artery disease and factors affecting midterm outcome. AB - BACKGROUND: Carotid artery stenting (CAS) is the method of choice for carotid artery revascularization of patients at high risk for carotid endarterectomy. In this study, we compared the midterm results of CAS in patients with unilateral versus bilateral carotid artery disease. METHODS AND RESULTS: This is a retrospective analysis of 1-year outcome of 273 consecutive patients in whom 342 CAS procedures were performed. The incidence of periprocedural transient ischemic attacks (TIAs) differed significantly (8% vs. 1%; p = 0.01) among patients with and without bilateral internal carotid disease, and a tendency to a lower occurrence of early adverse events (death, stroke, periprocedural TIA, periprocedural myocardial infarction) was subsequently shown (11% vs. 5%; p = 0.12). At 1-year follow-up, there was a high incidence of adverse events (death, stroke, periprocedural TIA, periprocedural myocardial infarction, restenosis) in patients with bilateral carotid artery disease (40% vs. 14%; p < 0.01), which was mainly driven by a higher incidence of death, periprocedural TIA, and restenosis (p <= 0.02 for all). According to multivariate analysis, the independent predictors of midterm adverse events were left ventricular dysfunction, male gender, bilateral carotid artery disease, renal insufficiency, cerebral symptoms within the last 6 months before the intervention, and low-density lipoprotein cholesterol level. CONCLUSIONS: At midterm follow-up, patients with bilateral carotid artery disease treated by CAS have significantly more adverse events than those with unilateral disease. PMID- 21530158 TI - Axillary artery dissection after scapular fracture. AB - Blunt shoulder trauma rarely causes damage to either arteries or nerves. Neurovascular structures are covered by muscles and protected by the surrounding bones deep in the axilla. We report a case of a 34-year-old male motorbike driver referred to us 5 hours after injury. Standard X-ray of the left shoulder revealed multipart fracture of the left scapula, and angiography showed that the first segment of the left axillary artery was dissected proximal to the minor pectoral muscle. Urgent diagnosis using imaging techniques and restoration of blood flow using open or endovascular repair are crucial for optimal outcome. Damage to the nerves predicts the final functional outcome regardless of prompt revascularization. PMID- 21530159 TI - Visuospatial support for verbal short-term memory in individuals with Down syndrome. AB - Individuals with Down syndrome (DS) tend to have impaired verbal short-term memory (STM), which persists even when visual support is provided for carrying out verbal tasks. OBJECTIVE: The current study aims to investigate whether visuospatial support, rather than just visual, can compensate for verbal STM deficits in these individuals. The performance of 25 children and adolescents with DS (mean age=12.5, SD=3.8) on five word span tasks was compared with that of two groups of typically developing children, matched for mental age (N=25; mean age=6.0, SD=.2) and for receptive vocabulary (N=25; mean age=4.0, SD=.8). Four of the five tasks varied in terms of input and output--verbal and/or visual--and the fifth task included a spatial component in addition to visual input and output. DS individuals performed equally bad in the pure verbal task and in those with visual components; however, there was a significant improvement when the spatial component was included in the task. The mental age matched group outperformed DS individuals in all tasks except for that with the spatial component; the receptive vocabulary matched group, outperformed DS individuals only in the pure verbal task. We found that visuospatial support improves verbal STM in individuals with DS. This result may have implications for intervention purposes. PMID- 21530160 TI - Unstable longitudinal motor performance in preterm infants from 6 to 24 months on the Bayley Scales of Infant Development--Second edition. AB - Preterm birth increases the risk for neurologic and developmental disabilities and therefore long-term follow-up is important. This prospective follow-up study aims to describe longitudinal motor performance in preterm infants from 6 to 24 months and to detect the influence of risk factors on motor performance trajectories. We included preterm infants (n=348) with a gestational age of <=32 weeks. The Bayley Scales of Infant Development, 2nd edition (BSID-II) Motor Scale and the Behaviour Rating Scale were recorded at the corrected ages of 6, 12 and 24 months. The Motor Scale raw score was the dependent variable in random coefficient analysis for risk factors in the cohort if infants with cerebral damage were in- and excluded. The raw score increased, showed the highest correlation (rp=0.48-0.67) and was more stable than the PDI and its classification. Fifteen percent of the infants had a stable classification, while 45% changed one class. Male sex and intra-ventricular haemorrhage (IVH) lowered the raw scores. Higher motor quality scores and height increased the raw scores, while the influence of maternal education varied at different time points. Removal of infants with cerebral damage from the cohort did not change the risk factors. The results showed that the raw score trajectories were more stable, but after corrections for norm data, the measurements became highly unstable. This is clinically important when reporting results to parents, guiding intervention and in randomised trials. The risk factors predominantly influenced the level of motor performance raw scores. Maternal education additionally influenced the trajectory and should be included in randomisation procedures. PMID- 21530161 TI - The Center for Epidemiologic Studies Depression Scale: factor validity and reliability in a French sample of adolescents with Intellectual Disability. AB - The purpose of this study was to test the factor validity and reliability of the Center for Epidemiologic Studies Depression Scale (CES-D) within a sample of adolescents with mild to moderate Intellectual Disability (ID). A total sample of 189 adolescents (121 boys and 68 girls), aged between 12 and 18 years old, with mild to moderate ID were involved in two studies. In study 1, the content, phrasing and answering format of the CES-D were adapted for adolescents with ID. This instrument was renamed CES-D for ID (CES-D-ID) and two different versions based on two alternative answer scales (Likert and Likert-graphical) were developed and their psychometric properties were verified in study 2. The results provided support for the factor validity, reliability and invariance across gender and age of a 14-item version of the CES-D-ID based on a Likert-graphical answer scale. PMID- 21530162 TI - A study of behaviour profiles among intellectually disabled people in residential care in Hungary. AB - The authors investigated the behavioural dimensions of 269 intellectually disabled (ID) people in residential care in specialized institutions in Tolna county (South-West Hungary) with the aim of screening the frequency and severity of the relevant behavioural symptoms associated with intellectual disability and depending on the level of intellectual impairment. Only 120 residents had an International Classification of Disease (ICD) diagnosis of "mental retardation (MR)" and a valid IQ grading either by means of the Hungarian standard version of the HAWIK or by the coloured Raven test. 4 IQ groups were created: borderline (B), mild (MID), moderate (MOD) and profound (PID) intellectual disability subgroups. The Hungarian pilot version of the Behaviour Problem Inventory (BPI) was used. seventy-two percent of the residents displayed behavioural problems. All scale score means exhibited an enhancing tendency with IQ loss, as both frequency and Seventy increased linearly towards the more severe groups, but significantly only in the category of stereotyped behaviour. The authors focussed on problems of patient recruitment and discussed the measurement of behavioural and other psychiatric symptoms when researchers reported on the increased occurrence of behaviour and psychiatric symptoms in ID populations. PMID- 21530163 TI - Voice disorders in the elderly. AB - OBJECTIVES: Despite the prevalence of voice disorders, as well as the physiological and functional changes of the aging larynx, there is a lack of data analyzing dysphonia in the geriatric population. The goal of this study was to investigate dysphonia in this cohort. STUDY DESIGN: Retrospective chart review. METHODS: This study analyzes the histories, demographics, Voice Handicap Index (VHI) questionnaires, and objective voice measures (OVMs) for 175 patients with voice complaints, age ranging from 65 to 89 years. Diagnoses of any vocal fold pathology were made via strobovideolaryngoscopy and laryngeal electromyography (LEMG) at the time of presentation. RESULTS: Strobovideolaryngoscopy revealed that laryngeal laryngopharyngeal reflux in 91% (N=159) was the most common diagnosis associated with the voice complaints, followed by muscle tension dysphonia in 73% (N=127) and paresis in 72% (N=126). Of the 175 patients in this study, 27% (N=48) of patients had a history of antecedent event, which might have contributed to their current dysphonia, most commonly upper respiratory tract infection in 27% (N=13) and endotracheal intubation in 21% (N=10). Ninety-three percent (N=153) of patients who underwent LEMG had weakness in the distribution of at least one nerve. VHI scores varied greatly, ranging from 4 to 104, with an average score of 43.9. When VHI scores were correlated with OVMs, correlations were found with mean jitter (%), jitter (abs.), maximum phonation time (s), and shimmer (%). When OVM scores were compared with KayPENTAX normative thresholds, 69.7% of subjects were found to be above the threshold for soft phonation index. CONCLUSION: Our studies identified at least one pathologic factor contributing to dysphonia in all elderly patients presenting with voice complaints. The high average VHI score indicated that these geriatric patients experienced significant dissatisfaction because of their dysphonia. The problem was of sufficient magnitude to result in a high percentage of patients proceeding with treatment. Additional research is needed to determine normative values for OVMs and other assessments in the elderly population and establish whether normative values in common use are appropriate for this population. PMID- 21530164 TI - A voice acoustic analysis of thyroid adenoma patients after a unilateral thyroid lobectomy. AB - OBJECTIVE: The objective of this study was to investigate the features of voice changes in thyroid adenoma patients secondary to a unilateral thyroid lobectomy that did not result in laryngeal nerve injury. STUDY DESIGN: Prospective study. METHODS: Pre- and postoperative fiberlaryngoscopic and voice acoustic analyses were performed on 32 adult patients (eight males and 24 females) with unilateral thyroid adenoma. Forty adults (20 women and 20 men) with normal voice function were grouped as controls. RESULTS: The vocal folds before and after surgery in all patients appeared to be normal under the fiberlaryngoscope. The preoperative voice was slightly abnormal in female patients and normal in male patients. One week after surgery, the F0 levels of both male and female patients decreased significantly from the values recorded before surgery (P<0.05). One month after the surgery, the F0 standard deviation, fundamental frequency perturbation, amplitude perturbation, noise/harmonic ratio, voice turbulence index, and degree of subharmonics in female patients decreased significantly from the values observed before surgery (P<0.05). Three months after surgery, the values of these indicators returned to normal. CONCLUSIONS: The preoperative voice was slightly abnormal in female patients and normal in male patients. After a unilateral thyroid lobectomy, which did not result in injury of the laryngeal nerve, the acoustic measures of male patients consequently became slightly abnormal and returned to normal within 1 month. The indicators of female patients improved from that demonstrated before surgery and returned to normal within 3 months. PMID- 21530165 TI - WITHDRAWN: Very Early Improvement in Valvuloarterial Impedance Induced by Transcatheter Aortic Valve Implantation (CoreValve) in Symptomatic Aortic Stenosis. AB - The editors have requested that the article be withdrawn because of concern that some of its contents appear quite similar to portions of another publication from the same group of investigators. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21530166 TI - Left atrial volume by real-time three-dimensional echocardiography: validation by 64-slice multidetector computed tomography. AB - BACKGROUND: Left atrial (LA) enlargement has been acknowledged as a significant predictor of cardiovascular morbidity and mortality. METHODS: To evaluate the accuracy of two-dimensional and three-dimensional echocardiography for determining LA volume, LA volume measurements by echocardiography were compared with those measured by 64-slice multidetector computed tomography (MDCT) as a reference standard. RESULTS: Fifty-seven consecutive patients (mean age, 66 +/- 11 years; 59% men) referred to echocardiography and MDCT on the same day were prospectively evaluated. LA volume by three-dimensional echocardiography was correlated closely with that by MDCT (r = 0.95, P < .0001), with 8% underestimation. LA volume by two-dimensional echocardiography was correlated less well with that measured by MDCT (r = 0.86, P < .0001) and consistently underestimated LA volume by 19%, particularly as the left atrium enlarged. CONCLUSIONS: LA volume assessment by three-dimensional echocardiography was correlated closely with that measured by MDCT, albeit with an 8% underestimation. Three-dimensional echocardiography is a feasible noninvasive method to evaluate LA volume. PMID- 21530167 TI - Coronary artery plaque burden does not affect left ventricular diastolic function in asymptomatic adults with normal ejection fraction. AB - BACKGROUND: Coronary artery disease (CAD) is commonly cited as a mechanism underlying diastolic dysfunction. However, the association of CAD without ischemia and left ventricular (LV) diastolic dysfunction has not been convincingly demonstrated in asymptomatic patients. The objective of this study was to determine if such a relation exists using coronary artery calcium score (CACS) as a surrogate for coronary atherosclerosis burden. METHODS: Consecutive eligible patients with normal ejection fraction who underwent CACS assessment, echocardiography, and stress testing with negative results for obstructive CAD between August 2006 and September 2007 were included in this retrospective study. Clinical variables were collected from the medical record. Diastolic function classification was based on established echocardiographic guidelines recommended by the American Society of Echocardiography. Statistical analysis was used to identify predictors of CACS. RESULTS: A total of 349 subjects (302 men) aged 58 +/- 6 years were studied. Risk factors included hyperlipidemia (n = 202 [58%]), hypertension (n = 127 [36%]), impaired fasting glucose (n = 78 [22%]), and diabetes (n = 21 [6%]). Left atrial volume index was weakly correlated with CACS (r = 0.26, P < .001). There was no significant relationship between CACS and LV diastolic function grade in the entire group (P = .14) or in a subgroup of younger patients (n = 140) who matched the ages qualifying for premature CAD (P = .17). After stepwise elimination multivariate analysis, five variables independently predicted CACS: age (P < .001), hyperlipidemia (P < .001), LA volume index (P < .001), male gender (P = .01), and LV posterior wall thickness (P = .03). CONCLUSIONS: In asymptomatic patients with normal LV ejection fraction and negative cardiac stress test results, CACS does not correlate with LV diastolic function as defined by established Doppler echocardiographic criteria. In the absence of ischemia, postinfarction LV remodeling, or previous coronary artery bypass surgery, CAD does not appear be a cause of LV diastolic dysfunction in asymptomatic patients. PMID- 21530168 TI - Echocardiographic marker for bland-white-garland syndrome in adult. AB - Bland-White-Garland syndrome, also known anomalous origin of the left main coronary artery, is a rare congenital malformation. The authors report the case of a 51-year-old woman with anomalous origin of the left main coronary artery from the pulmonary artery. A prominent large ostium of the right coronary artery and intercoronary "steal" collaterals should raise suspicion for this pathology and subsequently guide a step-by-step echocardiographic approach to identify the left main coronary artery from the pulmonary artery. PMID- 21530169 TI - Adjusting for publication biases across similar interventions performed well when compared with gold standard data. AB - OBJECTIVE: To extend, apply, and evaluate a regression-based approach to adjusting meta-analysis for publication and related biases. The approach uses related meta-analyses to improve estimation by borrowing strength on the degree of bias. STUDY DESIGN AND SETTING: The proposed adjustment approach is described. Adjustments are applied both independently and by borrowing strength across journal-extracted data on the effectiveness of 12 antidepressant drugs from placebo-controlled trials. The methods are also applied to Food and Drug Administration (FDA) data obtained on the same 12 drugs. Results are compared, viewing the FDA observed data as gold standard. RESULTS: Estimates adjusted for publication biases made independently for each drug were very uncertain using both the journal and FDA data. Adjusted estimates were much more precise when borrowing strength across meta-analyses. Reassuringly, adjustments in this way made to the journal data agreed closely with the observed estimates from the FDA data, while the adjusted FDA results changed only minimally from those observed from the FDA data. CONCLUSION: The method worked well in the case study considered and therefore further evaluation is encouraged. It is suggested that this approach may be especially useful when adjusting several meta-analyses on similar interventions and outcomes, particularly when there are small numbers of studies. PMID- 21530170 TI - Rasch analysis informed modifications to the Work Instability Scale for Rheumatoid Arthritis for use in work-related upper limb disorders. AB - OBJECTIVE: The Work Instability Scale for Rheumatoid Arthritis (RA-WIS) is a promising prognostic tool for future work disability outcomes. Rasch analysis was conducted to examine the psychometric performance of the RA-WIS in work-related upper limb disorders. STUDY DESIGN AND SETTING: Eligible injured workers (n=396) attending a Shoulder and Elbow Specialty clinic participated in a 1-year study with surveys fielded at four time points. Fit of RA-WIS data (range, 0-23 with 23=highest work instability) to the Guttman structure was evaluated by item-fit, person-fit, item-trait interaction statistics, and the person separation index (PSI). Differential item functioning (DIF) was evaluated by two-way analyses of variance of the residuals across age, sex, location of injury, perceived exertion at work, and repeated testing over time. Unidimensionality was evaluated by principal component analysis of residuals and tests of local independence. RESULTS: RA-WIS data showed significant deviations from the Guttman structure (item-trait interaction chi(2)=181.6, P<0.0001, PSI=0.86). A sequential removal of the six most misfitting items was performed, resulting in a 17-item scale that met all Rasch model expectations (chi(2)=57.5, P=0.007, PSI=0.83), including unidimensionality, local independence of items, and the absence of DIF across all tested factors. CONCLUSION: A new 17-item Upper Limb Work Instability Scale that satisfied assumptions for interval-level scaling was derived. PMID- 21530171 TI - A framework for applying unfamiliar trial designs in studies of rare diseases. AB - OBJECTIVE: Rare diseases may be difficult to study through conventional research methods, but are amenable to study through certain uncommonly used designs. We sought to explain these designs and to provide a framework to assist researchers in identifying the most appropriate design for a given research question. STUDY DESIGN AND SETTING: We systematically searched for literature describing rare disease research frameworks, trial designs, and trials that applied them. We present the advantages and disadvantages of each approach using these published examples, and a practical framework to help researchers in selecting between design choices. RESULTS: When research participants are limited, researchers should consider using: 1) a crossover design; 2) n-of-1 trials; or 3) one of the following adaptive designs: a) a response-adaptive randomization design, b) a ranking and selection design, c) an internal pilot design,or d) a sequential design. Bayesian analysis may be applied to conventional designs, or to any of these uncommon designs. Several of these approaches may also be used in combination. The choice between methods should be guided by factors related to the intervention, disease,anticipated recruitment duration and success, and current state of knowledge about the treatment. CONCLUSION: These techniques may facilitate research in rare diseases. PMID- 21530172 TI - Total cardiovascular risk approach to improve efficiency of cardiovascular prevention in resource constrain settings. AB - OBJECTIVES: To determine the population distribution of cardiovascular risk in eight low- and middle-income countries and compare the cost of drug treatment based on cardiovascular risk (cardiovascular risk thresholds >= 30%/>= 40%) with single risk factor cutoff levels. STUDY DESIGN AND SETTING: Using World Health Organization (WHO) and the International Society of Hypertension risk prediction charts, cardiovascular risk was categorized in a cross-sectional study of 8,625 randomly selected people aged 40-80 years (mean age, 54.6 years) from defined geographic regions of Nigeria, Iran, China, Pakistan, Georgia, Nepal, Cuba, and Sri Lanka. Cost estimates for drug therapy were calculated for three countries. RESULTS: A large fraction (90.0-98.9%) of the study population has a 10-year cardiovascular risk <20%. Only 0.2-4.8% are in the high-risk categories (>= 30%). Adopting a total risk approach and WHO guidelines recommendations would restrict unnecessary drug treatment and reduce the drug costs significantly. CONCLUSION: Adopting a total cardiovascular risk approach instead of a single risk factor approach reduces health care expenditure by reducing drug costs. Therefore, limited resources can be more efficiently used to target high-risk people who will benefit the most. This strategy needs to be complemented with population wide measures to shift the cardiovascular risk distribution of the whole population. PMID- 21530173 TI - Serum antioxidant levels and nutritional status in early and advanced stage lung cancer patients. AB - OBJECTIVE: Malnutrition frequently occurs in lung cancer patients. We aimed to determine nutritional status and antioxidant and mineral levels in Thai patients with lung cancer. METHODS: A prospective study with matched case-control was conducted. Nutritional status was assessed by body mass index (BMI) and subjective global assessment (SGA). Eastern Cooperative Oncology Group (ECOG) performance status was used to assess the performance. The serum antioxidant and mineral levels were determined. RESULTS: Forty-nine patients with a mean age of 58.8 (range, 35-82) who were first diagnosed with lung cancer were enrolled. They were compared with 60 healthy controls, and levels of retinol, alpha-tocopherol, beta-carotene, lycopene, beta-cryptoxanthin, selenium, and zinc were lower (P < 0.05). However, peroxidase activity was higher (P = 0.002) in patients. Selenium levels were higher in early stage compared to advanced stage patients (P = 0.041). Overweight patients had higher selenium levels (0.04 mg/L) than normal BMI patients (beta = 0.04, P = 0.035). Patients with SGA class C had lower selenium levels (0.03 mg/L) than those with class A (beta = -0.03, P = 0.035). The poorer ECOG performance patients had significantly lower beta-carotene (beta = -0.192, P = 0.003) and selenium (beta = -0.031, P = 0.011) levels compared with those with good ECOG performance status. CONCLUSIONS: Significantly lower levels of antioxidants and selenium were found in lung cancer patients compared to healthy controls. Levels of some antioxidants and minerals differed among categories of BMI, SGA categories, or ECOG performance status. These findings may be helpful for further studies, such as the effect of nutritional supplementation on clinical outcomes. PMID- 21530174 TI - Current status and prospects of antiplatelet therapy in percutaneous coronary intervention in Japan: focus on adenosine diphosphate receptor inhibitors. AB - Dual antiplatelet therapy with aspirin and clopidogrel is routinely used to prevent thrombotic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI) in Japan. However, these agents have various limitations and some patients will experience further cardiovascular events. The purpose of this article is to review the antiplatelet agents currently used in patients undergoing PCI in Japan, to discuss the issues and limitations associated with these antiplatelet agents, and to characterize new antiplatelet agents currently under investigation in Japan. Particular emphasis is placed on the novel thienopyridine prasugrel, and the potential this drug has for overcoming the issues associated with other antiplatelet agents. PMID- 21530175 TI - The serum level of interleukin-6 in patients with intellectual disability and refractory epilepsy. AB - We aimed to study the influences of active epilepsy and intellectual disability (ID) on the serum interleukin-6 (IL-6) by determining levels in 74 patients with developmental disorder with epilepsy and 63 healthy controls. The patients showed significantly higher IL-6 levels than the controls (4.1+/-4.5pg/ml vs. 2.1+/ 1.0pg/ml; p<0.001). High seizure frequency and severe intellectual disability emerged as predictors for elevated serum levels of IL-6. PMID- 21530176 TI - The impact of marital status on epilepsy-related health concerns. AB - Social support from marriage has been linked with better health outcomes. Persons with epilepsy (PWE) are significantly less likely to be married than persons without epilepsy. No previous studies have examined the impact of marriage on epilepsy-related health concerns. Outpatient PWE (n=267) were asked to identify their top five concerns on the Epilepsy Foundation Concerns Index. After controlling for clinical factors (seizure frequency, age of epilepsy diagnosis and disability status) PWE who were married were significantly less likely to report "Fear of being injured during a seizure" Odds Ratio (OR) 0.33, "Holding down a job" OR 0.29, "Getting the work or education you want" OR 0.29, "Medical costs of your epilepsy" OR 0.21 and "Lack of people's understanding of epilepsy" OR 0.27. Once we controlled for both clinical factors and demographic factors only one concern "Medical costs of your epilepsy" OR 0.24 remained significant. Our findings support several theories examining the health benefits of marriage related to selection, protection and economic resources. PWE are particularly prone to economic disparities due to lower educational attainment and unemployment. Earlier intervention especially for those with childhood onset epilepsy may help mitigate these disparities and their impact on social relationships and marriage. PMID- 21530177 TI - Factors associated with poor seizure control and increased side effects after switching to generic antiepileptic drugs. AB - OBJECTIVE: To determine those factors associated with increased seizures and side effects after switching from brand name to generic antiepileptic drugs (AEDs). METHODS: We surveyed adult epilepsy patients and obtained demographic, clinical, and psychosocial data. We inquired whether they switched from brand name to generic AEDs, and whether they experienced poorer seizure control and increased side effects. Using univariate analysis, we determined those variables significantly associated with increased seizures and side effects. We applied binary logistic regression to determine those independently associated with these target variables. RESULTS: One hundred and twenty-one subjects completed the questionnaire. Seventy-one switched to generic AEDs. Of these, 18 subjects (25.7%) reported increased seizure frequency. This was associated with high seizure count (p=0.03) and scores on the Beliefs About Medicines-General (BMQ-G) questionnaire (p=0.04). On multivariate analysis, these variables were not independently significant. Fourteen subjects (20.6%) reported increased side effects. This was associated with being African-American (p=0.04), and high scores on the BMQ-G (p=0.01). On multivariate analysis, BMQ-G scores were independently associated with increased adverse effects. INTERPRETATION: High baseline seizure count is associated with increased seizure frequency while high BMQ-G scores are associated with increased seizure frequency and adverse effects when patients switch from brand name to generic AEDs. PMID- 21530178 TI - A meta-analysis of diffusion tensor imaging studies of the corpus callosum in schizophrenia. AB - BACKGROUND: The corpus callosum has been hypothesized to play an important role in neurobiological models of schizophrenia. Diffusion tensor imaging studies have provided evidence for a disruption in corpus callosum morphology in schizophrenia, but the regional distribution of abnormalities is not well known. METHODS: We conducted 2 meta-analyses investigating the genu and splenium of the corpus callosum in schizophrenia, respectively, based on published diffusion tensor imaging studies that employed a region-of-interest approach. Seven studies investigating the genu and splenium involving a total of 202 patients with schizophrenia and 213 healthy volunteers were included. RESULTS: The meta analysis of the genu yielded an effect size of 0.223 and was not statistically significant. The second meta-analysis investigating the splenium yielded a modest effect size of 0.527 (p=0.001), indicating that patients had lower fractional anisotropy in this region compared to healthy volunteers. Studies that included fewer men had a larger effect size for the splenium. DISCUSSION: These findings implicate an abnormality involving the splenium of the corpus callosum in the neurobiology of schizophrenia as inferred by diffusion tensor imaging. A defect in the splenium could contribute to abnormalities in posterior interhemispheric connectivity in patients, including regions of the heteromodal association cortex. PMID- 21530179 TI - Suicide risk in first episode psychosis: a selective review of the current literature. AB - Many studies have confirmed that the risk of suicide in patients with first episode psychosis (FEP) is high, and high rates of premature mortality, particularly from suicide, may occur in the early phases of schizophrenia. However, suicide rates are difficult to measure in FEP patients, even in carefully defined samples, and there is relatively little specific information about the risk of suicide at illness onset or retrospectively concerning the untreated psychotic period. This selected review of the literature investigates suicidal behaviour with particular regard to severe suicidality (plans and attempts) and risk factors associated with suicide in FEP patients. A search was performed to identify all papers and book chapters during the period 1965-2010, and approximately 100 studies met the inclusion criteria. Most of evidence suggests that risk of suicidal behaviour is relatively high in FEP patients. The research reports highlight the need for universal, comprehensive, public mental health interventions aimed, not only toward early detection, but also toward the rapid engagement in treatment of people with psychoses. These interventions should include an adequate assessment of suicidal behaviour in patients with FEP, and an examination of the efficacy of specific components of the interventions. PMID- 21530180 TI - Novel point mutation in the STS gene in a patient with X-linked recessive ichthyosis. PMID- 21530181 TI - Comparison of the antimelanogenic effects of p-coumaric acid and its methyl ester and their skin permeabilities. AB - BACKGROUND: p-Coumaric acid (PCA) inhibits human tyrosinase (TYR) activity and melanin synthesis in human epidermal melanocytes. OBJECTIVE: The purpose of the current study was to examine the potential of PCA and its hydrophobic derivative, methyl p-coumarate (MPC), as hypopigmenting agents for topical use. METHODS: PCA and MPC were comparatively tested against in vitro human TYR enzyme activity and cellular melanin synthesis in human epidermal melanocytes. Permeation studies were undertaken using an artificial lipophilic membrane and an excised porcine skin. In vivo hypopigmenting efficacy was assessed on the skin of melanin possessing hairless mice exposed to UVB. RESULTS: Although PCA was a stronger inhibitor than MPC against TYR activity in vitro, the former inhibited cellular melanin synthesis less effectively than the latter. A non-cell based permeability assay indicated that PCA was practically impermeable through the lipophilic barrier while MPC was highly permeable. In contrast, an ex vivo skin permeation study demonstrated that topically applied PCA in the form of a cream can diffuse into the aqueous medium underneath the skin. No MPC was released from a MPC cream but PCA was released instead as a bio-converted product. Topical application of PCA cream attenuated the UVB-induced erythema formation and pigmentation in mice models, more effectively compared with MPC cream. CONCLUSION: PCA may be useful as an active ingredient for topical applications for a hypopigmenting effect. MPC has potential as a hypopigmenting agent but requires rather invasive methods for its delivery to the target cells. PMID- 21530182 TI - Nitroxides and a nitroxide-based UV filter have the potential to photoprotect UVA irradiated human skin fibroblasts against oxidative damage. AB - BACKGROUND: Antioxidants are now being incorporated into sunscreens as additional topical measure for delaying the aging process and reducing photo-damage to skin induced by excessive UVA exposure. UVA radiation reaching the skin leads to the generation of ROS (reactive oxygen species) implicated in DNA damage and activation of matrix metalloproteinase-1 (MMP-1) responsible for collagen damage and photo-aging. Nitroxides are a class of compounds endowed with versatile antioxidant activity and recently, nitroxide-based UV filters in which a nitroxide moiety has been attached to the most popular UV filter present in sunscreens have been developed. OBJECTIVE: This study explores the potential photo-protective effects of these compounds on ROS production and induction of MMP-1 in cultured human dermal fibroblasts exposed to UVA. For comparison, vitamin E was also tested. METHODS: The effects were assessed by measuring intracellular ROS production using a ROS-index probe and MMP-1 mRNA expression levels using quantitative real-time PCR (qPCR). RESULTS: Exposure of fibroblasts to 18J/cm(2) UVA lead to a two-fold increase in ROS production which was reduced to non-irradiated control levels in the presence of 50MUM nitroxide compounds and vitamin E. Under the same conditions, a ten-fold increase in MMP-1 mRNA expression levels was observed 24h post-UVA treatment which was significantly reduced by all nitroxide compounds but not vitamin E. CONCLUSION: The results of this study support the potential use of nitroxide compounds, including novel nitroxide-based UV filters, as a useful and alternative strategy for improving the efficacy of topical formulations against photo-aging and possibly photo carcinogenesis. PMID- 21530183 TI - BMP-4 down-regulates the expression of Ret in murine melanocyte precursors. PMID- 21530184 TI - Post-exposure therapy of inhalational anthrax in the common marmoset. AB - The aim of this study was to compare the pharmacokinetics and efficacy of ciprofloxacin as post-exposure therapy against inhalational anthrax in the common marmoset (Callithrix jacchus) with other non-human primate models in order to determine whether the marmoset is a suitable model to test post-exposure therapies for anthrax. Pharmacokinetic (PK) and efficacy studies with ciprofloxacin were performed in the marmoset. Ciprofloxacin plasma pharmacokinetics were determined in six animals in separate single-dose and multiple-dose studies and were analysed by high-performance liquid chromatography (HPLC). A separate group of marmosets was exposed to ca. 100* the 50% lethal dose (LD(50)) of Bacillus anthracis Ames strain by the airborne route. On Day 5 of a twice-daily dosing regimen of 17.5 mg/kg, the ciprofloxacin half-life (t(1/2)), maximum drug concentration (C(max)) and area under the concentration-time curve (AUC) in marmoset plasma were 1.9 h, 2.1 MUg/mL and 7.9 MUg/mL/h, respectively. Naive untreated control animals succumbed to infection by Day 9. All animals treated with ciprofloxacin, started on the day of exposure and continued for 10 days, remained healthy during the treatment period. Two antibiotic-treated animals (33%) died after withdrawal of antibiotic therapy, attributed to the germination of residual spores. In conclusion, in many respects the marmoset appears to respond to B. anthracis in a similar way to the macaque, suggesting that this small non-human primate is an acceptable, practical alternative model for the evaluation of medical countermeasures against respiratory anthrax infection. PMID- 21530185 TI - To stop or not to stop? How long should medication treatment of attention-deficit hyperactivity disorder be extended? AB - ADHD is a common neuropsychiatric disorder with a strong persistence over time. Medication is frequently used in the clinical management of ADHD. After response, medication is typically prescribed for months to years. It is unclear whether extended medication treatment provides long-term benefits and how long it should be continued. Furthermore, there is concern about the long-term safety of ADHD medication. The aim of this systematic review is to address these issues and provide recommendations about the decision to stop or not to stop ADHD medication. We performed a search in PubMed and focused on medication studies with a treatment longer than 12weeks in subjects 6-18years old. Extended placebo controlled double-blind parallel studies are not available. Placebo-controlled discontinuation studies and prospective long-term observational treatment studies provide evidence that medication management leads to a substantial reduction of ADHD symptoms and less impairment of functioning for a period of about 2years. There is limited and inconsistent evidence for long-term advantage of medication treatment beyond symptom control, such as improved social functioning, academic achievement, employment status and less adverse psychiatric outcome. In terms of safety, long-term effects of medication on growth, blood pressure and heart rate are limited and the occurrence of suicidal, psychotic and manic symptoms is rare. Animal data about neurotoxic effects of psycho stimulants cannot be directly extrapolated to humans. Therefore, clinical decisions about starting, continuing, and stopping of ADHD medication should be made on an individual basis. Medication free periods should be implemented at regular times to investigate the need for an ongoing benefit of medication. Unfounded assumptions about continuing benefit of medication use should be abandoned. Careful monitoring of side effects is necessary and must be able to detect early alarming signals. PMID- 21530186 TI - Electrochemical behaviour of carbon paste electrodes enriched with tin oxide nanoparticles using voltammetry and electrochemical impedance spectroscopy. AB - The effect of the SnO(2) nanoparticles (SNPs) on the behaviour of voltammetric carbon paste electrodes were studied for possible use of this material in biosensor development. The electrochemical behaviour of SNP modified carbon paste electrodes (CPE) was first investigated by using cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) techniques. The performance of the SNP modified electrodes were compared to those of unmodified ones and the parameters affecting the response of the modified electrode were optimized. The SNP modified electrodes were then tested for the electrochemical sensing of DNA purine base adenine to explore their further development in biosensor applications. PMID- 21530187 TI - Preparation, characterization and biocompatibility studies on risperidone-loaded solid lipid nanoparticles (SLN): high pressure homogenization versus ultrasound. AB - The suitability of solid lipid nanoparticles (SLN) for the encapsulation of risperidone (RISP), an antipsychotic lipophilic drug, was assessed for oral administration. The hot high pressure homogenization (HPH) and the ultrasound (US) technique were used as production methods for SLN. All the studies on the SLN formulations were done in parallel, in order to compare the results and conclude about the advantages and limitations of both techniques. The particle sizes were in the nanometer range for all prepared SLN formulations and the zeta potential absolute values were high, predicting good long-term stability. Optical analyses demonstrated the achievement of stable colloidal dispersions. Physicochemical characterization of dispersions and bulk lipids, performed by differential scanning calorimetry (DSC) and X-ray assays, support prediction of occurrence of drug incorporation in the SLN and good long term stability of the systems. The toxicity of SLN with Caco-2 cells and the existence of contaminations derived from the production equipments were assessed by the (4,5 dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) assay. The results showed 90% of cell viability after SLN exposure, with no significant differences within all prepared formulations (p > 0.05). From this study, we conclude that SLN can be considered as efficient carriers for RISP encapsulation. Moreover, HPH and US revealed to be both effective methods for SLN production. PMID- 21530188 TI - Wet-grinding assisted ultrasonic dispersion of pristine multi-walled carbon nanotubes (MWCNTs) in chitosan solution. AB - Ultrasonication is often used to disperse nano-particles in aqueous solution. However, a good dispersion of nano-particles in aqueous solution is not always achieved, due to the fact that incoming ultrasonicwaves in liquid are usually reflected and damped at the gas/liquid interface. In this work, we report a so called wet-grinding assisted ultrasonication (GU) method, in which wet-grinding of multi-walled carbon nanotubes (MWCNTs) in chitosan solution is carried out before ultrasonication. The dispersions of MWCNTs were characterized by visual comparison, UV/vis spectroscopy, and scanning electron microscopy (SEM). The results demonstrate that the dispersion quality of chitosan/MWCNT suspension prepared by wet-grinding assisted ultrasonication is much better than that by ultrasonication or wet-grinding alone. It was found that wet-grinding could improve the water wettability of MWCNTs and eliminate the barrier of air layer around MWCNTs to ultrasonicwaves. Meanwhile, the composite from the chitosan/MWCNTs suspension prepared by GU method has an obvious improvement in mechanical property compared to pure chitosan. This simple method for integrating MWCNTs and biocompatible chitosan into a homogeneous dispersion may have great potential application in biotechnology, such as preparing composite materials for medicine, bio-fiber, biosensor, antibacterial coating, and cell cultivation. PMID- 21530189 TI - A novel amperometric hydrogen peroxide biosensor based on electrospun Hb-collagen composite. AB - In this paper, the hemoglobin (Hb)-collagen microbelt modified electrode with three-dimensional configuration was fabricated via the electrospinning method. Direct electron transfer of the Hb immobilized into the electrospun collagen microbelts was greatly facilitated. The apparent heterogeneous electron transfer rate constant (k(s)) was calculated to be 270.6s-1. The electrospun Hb-collagen microbelt modified electrode showed an excellent bioelectrocatalytic activity toward the reduction of H2O2. The amperometric response of the biosensor varied linearly with the H2O2 concentration ranging from 5 * 10-6molL-1 to 30*10-6molL 1, with a detection limit of 0.37 * 10-6molL-1 (signal-to-noise ratio of 3). The apparent Michaelis-Menten constant (K(m)(app)) was 77.7 MUmolL-1. The established biosensor exhibited fast amperometric response, high sensitivity, good reproducibility and stability. PMID- 21530190 TI - Introducing surface-tethered poly(acrylic acid) brushes as 3D functional thin film for biosensing applications. AB - Carboxyl groups of surface-tethered poly(acrylic acid) (PAA) brushes should be able to serve as versatile moieties for a wide range of chemical modifications, including an attachment of bioactive species that can act as sensing probes for biosensors. In this research, poly(tert-butyl acrylate) (Pt-BA) brushes were prepared by surface-initiated atom transfer radical polymerization of tert-butyl acrylate. PAA brushes were then obtained after removal of the tert-butyl groups from the Pt-BA brushes by acid hydrolysis. The carboxyl group density of the PAA brushes can be varied as a function of chain length or molecular weight. The reactivity of the carboxyl groups of PAA brushes towards the immobilization of biotin, a frequently used model bioactive probe in biosensing applications, was evaluated. Qualitative determination of streptavidin (SA) binding to the biotin attached PAA brushes was verified by fluorescence microscopy. The efficiency of the PAA brushes to act as a three dimensional (3D) precursor layer for biosensing applications was further demonstrated using surface plasmon resonance (SPR), where the biotin-attached PAA brushes showed an enhanced signal for the biospecific binding of SA in comparison with a self-assembled monolayer (SAM) of a carboxyl-terminated alkanethiol, used as a model two-dimensional (2D) conventional precursor layer. The PAA brushes showed very low non-specific interactions with two other tested proteins of a similar pI but different sizes. This desirable feature should be highly beneficial for the development of biosensors. PMID- 21530191 TI - [Cleidocranial dysplasia: report of 2 cases and literature review]. AB - Cleidocranial dysplasia or dysostosis involves dental anomalies, bone abnormalities with membranous ossification (clavicles, cranium, face, pelvis), rarely of the spine and the remainder of the skeleton. We report 2 new cases and describe the different clinical aspects of this disorder and the orthopedic problems that it can pose. The clinical demonstrations of this disease are highly variable and inconsistent, which explains the diversity of circumstances of discovery. Abnormalities of the face and clavicles, as well as of pelvic ossification are most frequent and can be regarded as major signs. These clinical demonstrations do not require treatment in the majority of the cases. Dental anomalies, coxa vara and scoliosis require regular monitoring and treatment in the event of progressive aggravation. The incomplete penetrance of this autosomal dominant disease and its good tolerance explain the frequency of undiagnosed forms, whose clinical expression is discrete. PMID- 21530192 TI - [Pertussis in adults in the maternity ward: management and prevention for protecting newborns and infants]. AB - Pertussis is a potentially serious illness in very young infants. The growing number of cases encountered in the past few years is partly explained by the loss of immunity, either natural or post vaccinal. To prevent the occurrence of pertussis in newborns and very young infants, it is mandatory to ensure compliance with vaccination recommendations regarding the general population (vaccination of young adults likely to have a child, of fathers and siblings during pregnancies, of mothers soon after birth), as well as professionals in contact with infants too young to have received their three doses of primary vaccination (diphtheria-tetanus-polio-pertussis booster may be performed as soon as the latest is more than two years). Obstetricians, midwives and pediatricians are directly concerned by this vaccinal strategy, owing to their prominent place in both informing couples during pregnancy and after delivery, and performing maternal vaccines soon after birth. PMID- 21530193 TI - Bone metastases: assessment of therapeutic response through radiological and nuclear medicine imaging modalities. AB - Radiological and nuclear medicine imaging modalities used for assessing bone metastases treatment response include plain and digitalised radiography (XR), skeletal scintigraphy (SS), dual-energy X-ray absorptiometry (DEXA), computed tomography (CT), magnetic resonance imaging (MRI), [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) and PET/CT. Here we discuss the advantages and disadvantages of these assessment modalities as evident through different clinical trials. Additionally, we present the more established response criteria of the International Union Against Cancer and the World Health Organization and compare them with newer MD Anderson criteria. Even though serial XR and SS have been used to assess the therapeutic response for decades, several months are required before changes are evident. Newer techniques, such as MRI or PET, may allow an earlier evaluation of response that may be quantified through monitoring changes in signal intensity and standard uptake value, respectively. Moreover, the application of PET/CT, which can follow both morphological and metabolic changes, has yielded interesting and promising results that give a new insight into the natural history of metastatic bone disease. However, only a few studies have investigated the application of these newer techniques and further clinical trials are needed to corroborate their promising results and establish the most suitable imaging parameters and evaluation time points. Last, but not least, there is an absolute need to adopt uniform response criteria for bone metastases through an international consensus in order to better assess treatment response in terms of accuracy and objectivity. PMID- 21530195 TI - Thyroxine dosing after I131Radioiodine ablation for differentiated thyroid cancer. PMID- 21530194 TI - Can nurses manage gastrointestinal symptoms arising from pelvic radiation disease? AB - AIMS: About 17,000 patients receive radiotherapy for pelvic cancer in the UK annually. Up to 50% are left with altered bowel function affecting quality of life. The UK National Cancer Survivorship Initiative Vision acknowledges that the needs of cancer survivors are not being met and challenges professionals to develop new models of care. MATERIALS AND METHODS: A prospective, observational qualitative study was carried out to assess whether nurse-delivered care is feasible for patients with radiotherapy-induced bowel dysfunction. The experience of a senior nurse, directed by an algorithm of investigation with a comprehensive treatment pathway, is reported. RESULTS: Over 12 months, 59 new and 103 follow-up appointments were managed by the nurse. In total, 37 women and 73 men, with a median age of 69 years, were seen; 9 had been treated for gastrointestinal, 33 for gynaecological and 68 for urological cancers, 26 months (median) previously. Sixty minutes (new consultations) (median, range 35-80) and 40 minutes (follow-up consultations) (range 20-85) were required. Ordering investigations, treatment initiation, long-term care planning and discharge seemed to be manageable in 83% of patients. CONCLUSION: An experienced nurse, working within a defined scope of practice, with medical support can manage care in patients with mild or moderate symptoms arising after pelvic radiotherapy. An ongoing randomised controlled trial is assessing patient outcomes. PMID- 21530196 TI - Dependence of the anti-CD66 antibody biodistribution on the dissociation constant: a simulation study. AB - In radioimmunotherapy (RIT) with radiolabelled anti-CD66 antibody, the red bone marrow is selectively irradiated. A preceding study, employing a physiologically based pharmacokinetic model, has shown that currently about 50% of the anti-CD66 antibody is accumulated in the red marrow. In this work, the potential improvement of the biodistribution is quantified for other anti-CD66 antibodies with lower dissociation constants K(D). Biodistribution simulations were performed based on a recently published mathematical model for a 10- and 100-fold lower monovalent K(D). The therapeutic index was compared to the therapeutic index which is achieved using the actual antibody. The simulations indicate that a considerably increased therapeutic index can be obtained by decreasing the dissociation constant.A reduction of the K(D) to 10-fold or 100-fold lower values would lead to an improvement of the therapeutic index, by a factor of 2.4-5 and 2.4-6.5 respectively. To investigate the predicted improvement of the radioimmunotherapy, new anti-CD66 antibodies with lower dissociation constants should be developed. PMID- 21530197 TI - Does IMRT increase the peripheral radiation dose? A comparison of treatment plans 2000 and 2010. AB - It has been reported in several papers and textbooks that IMRT treatments increase the peripheral dose in comparison with non-IMRT fields. But in clinical practice not only open fields have been used in the pre-IMRT era, but also fields with physical wedges or composed fields. The aim of this work is to test the hypothesis of increased peripheral dose when IMRT is used compared to standard conformal radiotherapy. Furthermore, the importance of the measured dose differences in clinical practice is discussed and compared with other new technologies for the cases where an increase of the peripheral dose was observed. For cancers of the head and neck, the cervix, the rectum and for the brain irradiation due to acute leukaemia, one to four plans have been calculated with IMRT or conformal standard technique (non-IMRT). In an anthropomorphic phantom the dose at a distance of 30cm in cranio-caudal direction from the target edge was measured with TLDs using a linear accelerator Oncor ((r)) (Siemens) for both techniques. IMRT was performed using step-and-shoot technique (7 to 11 beams), non-IMRT plans with different techniques. The results depended on the site of irradiation. For head and neck cancers IMRT resulted in an increase of 0.05 - 0.09% of the prescribed total dose (Dptv) or 40 - 70 mGy (Dptv=65Gy), compared to non-IMRT technique without wedges or a decrease of 0.16% (approx. 100 mGy) of the prescribed total dose compared to non-IMRT techniques with wedges. For the cervical cancer IMRT resulted in an increased dose in the periphery (+ 0.07% - 0.15% of Dptv or 30 - 70 mGy at Dptv=45Gy), for the rectal cancer in a dose reduction (0.21 - 0.26% of Dptv or 100 - 130 mGy at Dptv=50Gy) and for the brain irradiation in an increase dose (+ 0.05% of Dptv=18Gy or 9 mSv). In summary IMRT does not uniformly cause increased radiation dose in the periphery in the model used. It can be stated that these dose values are smaller than reported in earlier papers. Slightly increased additional radiation dose in the periphery is likely to be counterbalanced by the much higher conformity and the often better homogeneity. PMID- 21530198 TI - Low-energy photons in high-energy photon fields--Monte Carlo generated spectra and a new descriptive parameter. AB - The varying low-energy contribution to the photon spectra at points within and around radiotherapy photon fields is associated with variations in the responses of non-water equivalent dosimeters and in the water-to-material dose conversion factors for tissues such as the red bone marrow. In addition, the presence of low energy photons in the photon spectrum enhances the RBE in general and in particular for the induction of second malignancies. The present study discusses the general rules valid for the low-energy spectral component of radiotherapeutic photon beams at points within and in the periphery of the treatment field, taking as an example the Siemens Primus linear accelerator at 6 MV and 15 MV. The photon spectra at these points and their typical variations due to the target system, attenuation, single and multiple Compton scattering, are described by the Monte Carlo method, using the code BEAMnrc/EGSnrc. A survey of the role of low energy photons in the spectra within and around radiotherapy fields is presented. In addition to the spectra, some data compression has proven useful to support the overview of the behaviour of the low-energy component. A characteristic indicator of the presence of low-energy photons is the dose fraction attributable to photons with energies not exceeding 200 keV, termed P(D)(200 keV). Its values are calculated for different depths and lateral positions within a water phantom. For a pencil beam of 6 or 15 MV primary photons in water, the radial distribution of P(D)(200 keV) is bellshaped, with a wide-ranging exponential tail of half value 6 to 7 cm. The P(D)(200 keV) value obtained on the central axis of a photon field shows an approximately proportional increase with field size. Out-of-field P(D)(200 keV) values are up to an order of magnitude higher than on the central axis for the same irradiation depth. The 2D pattern of P(D)(200 keV) for a radiotherapy field visualizes the regions, e.g. at the field margin, where changes of detector responses and dose conversion factors, as well as increases of the RBE have to be anticipated. Parameter P(D)(200 keV) can also be used as a guidance supporting the selection of a calibration geometry suitable for radiation dosimeters to be used in small radiation fields. PMID- 21530199 TI - [Relaxation times T1, T2, and T2* of apples, pears, citrus fruits, and potatoes with a comparison to human tissues]. AB - The aim of the project was a systematic assessment of relaxation times of different fruits and vegetables and a comparison to values of human tissues. Results provide an improved basis for selection of plant phantoms for development of new MR techniques and sequences. Vessels filled with agar gel are mostly used for this purpose, preparation of which is effortful and time-consuming. In the presented study apples, (malus, 8 species), pears, (pyrus, 2 species), citrus fruits (citrus, 5 species) and uncooked potatoes (solanum tuberosum, 8 species) from the supermarket were examined which are easily available nearly all-the year. T1, T2 and T2* relaxation times of these nature products were measured on a 1.5 Tesla MR system with adapted examination protocols and mono-exponential fitting, and compared to literature data of human parenchyma tissues, fatty tissue and body fluid (cerebrospinal fluid). Resulting values were as follows: apples: T1: 1486-1874 ms, T2: 163-281 ms, T2*: 2.3-3.2 ms; pears: T1: 1631-1969 ms, T2: 119-133 ms, T2* : 10.1-10.6 ms, citrus fruits (pulp) T1: 2055-2632 ms, T2: 497-998 ms, T2* : 151-182 ms; citrus fruits (skin) T1: 561-1669 ms, T2: 93 119 ms; potatoes: T1: 1011-1459 ms, T2: 166 - 210 ms, T2* : 20 - 30 ms. All T1 values of the examined objects (except for potatoes and skins of citrus fruits) were longer than T1 values of human tissues. Also T2 values (except for pears and skins of citrus fruits) of the fruits and the potatoes tended to be longer. T2* values of apples, pears and potatoes were shorter than in healthy human tissue. Results show relaxation values of many fruits to be not exactly fitting to human tissue, but with suitable selection of the fruits and optionally with an adaption of measurement parameters one can achieve suitable contrast and signal characteristics for some purposes. PMID- 21530200 TI - Metal artifact reduction in cone beam computed tomography using forward projected reconstruction information. AB - In this work we present a new method to reduce artifacts, produced by high density objects, especially metal implants, in X-ray cone beam computed tomography (CBCT). These artifacts influence clinical diagnostics and treatments using CT data, if metal objects are located in the field of view (FOV). Our novel method reduces metal artifacts by virtually replacing the metal objects with tissue objects of the same shape. First, the considered objects must be segmented in the original 2D projection data as well as in a reconstructed 3D volume. The attenuation coefficients of the segmented voxels are replaced with adequate attenuation coefficients of tissue (or water), then the required parts of the volume are projected onto the segmented 2D pixels, to replace the original information. This corrected 2D data can then be reconstructed with reduced artifacts, i. e. all metal objects virtually vanished. After the reconstruction, the segmented 3D metal objects were re-inserted into the corrected 3D volume. Our method was developed for mobile C-arm CBCTs; as it is necessary that they are of low weight, the C-arm results in unpredictable distortion. This misalignment between the original 2D data and the forward projection of the reconstructed 3D volume must be adjusted before the correction of the segmented 2D pixels. We applied this technique to clinical data and will now present the results. PMID- 21530201 TI - Advantage of biological over physical optimization in prostate cancer? AB - The biological effects of an applied dose can be accounted for by using biological objective functions with IMRT. A commonly used concept is the generalized equivalent uniform dose (gEUD), developed by Niemierko. Unlike the equivalent uniform dose (EUD) which is defined for tumor only, the gEUD can be used for both target volume and organs-at-risk (OAR). In this study, the gEUD has been integrated in our in-house inverse treatment planning system DMCO. DMCO is based on an inverse kernel concept and maintains full Monte-Carlo precision. The system applies direct aperture optimization by means of simulated annealing. Thereby DMCO is per se predestined for the optimization of non-quadratic biological objective functions. In this work, the feasibility of gEUD-based optimization with DMCO is investigated and compared to modified physical optimization. A 'pseudo' Pareto study is performed in order to derive the gEUD parameters 'a' for the volumes-of-interest of a prostate case. The best biological plan is compared to a physically optimized plan, based on dose-volume objectives (DVO). Furthermore, a hybrid objective function (OF) was developed. It consists of both a biological OF for the OARs and a physical OF for the PTV. The plans are compared to another physically optimized plan, which includes additional zero-DVOs in order to further improve OAR-sparing. As a result of the comparisons it turns out, that the biological OF may improve plan quality with regard to the OARs, but at the price of a degradation of the PTV. This disadvantage can be overcome by a hybrid OF, by which the advantages of both biological and physical OF can be combined. With the application of the physical OF with properly set zero-DVOs, a similar or even superior plan quality may be achieved. The physical OFs do not need the time consuming stochastic optimization, which is mandatory in biological optimization and which is included in DMCO. Furthermore, biological evaluation leaves plan quality rather similar compared to physical optimization, but it cares automatically for the target and the OARs. PMID- 21530202 TI - Elution characteristics of residual monomers in different light- and auto-curing resins. AB - The aim of this in vitro study was to assess different auto-curing resins based on methylmethacrylate (MMA) and new light-curing resins based on urethane dimethacrylate (UDMA) regarding the residual monomers remaining in the resin and their elution over time. Specimens from three auto-curing and three light-curing resins were produced following the manufacturer's instructions. The concentration of residual MMA and UDMA monomers present in the resins as well as the quantity of the residual monomers released into artificial saliva solution after immersion times of 1, 3, and 7 days were analyzed by high-performance liquid chromatography (HPLC). Data were statistically analyzed using ANOVA and the post hoc Student Newman-Keuls test. The highest and lowest amounts of residual monomers were found in the group of light-curing resins (p<0.05). The light-curing resins Triad Trans Sheet (0.06 wt%) and Primosplint (0.06 wt%) released over the entire immersion time of 7 days the smallest (p<0.05) quantity of UDMA. These two light-curing resins based on UDMA exhibited lower elution of residual monomers than auto curing resins (MMA). The elution characteristics of the residual monomers do not seem to correlate with the residual monomer concentration in resins. These observations demonstrate that the quantitative determination of residual monomers alone - as required by the ISO specification 20795-1 - does not seem to be sufficient for an assessment of the biological properties of different resins. Instead, the evaluation of elution characteristics appears to be of higher clinical relevance. PMID- 21530203 TI - Involvement of oxidative stress in the mechanism of triptolide-induced acute nephrotoxicity in rats. AB - Triptolide is one of the most widely used and one of the most potent Chinese traditional herbal medicines. However, side effects, especially nephrotoxicity, limit the use of triptolide. It has been reported that oxidative stress is involved in drug-induced nephrotoxicity. In the present study, we focused on observing triptolide-induced acute nephrotoxicity in rats and investigating whether or not oxidative stress is involved in the pathogenesis of this process. The results showed that a single large dose peritoneal injection of triptolide caused severe oxidative stress characterized by significant decreases of renal SOD and GSH-Px activities, as well as significant increase of renal MDA content and also led to severe impairment of renal structure and function characterized by injury of renal tubules observed in HE-stained and TUNEL-stained slides and increases of Cre and BUN concentrations in a short time. However, pretreatment with the antioxidant vitamin C significantly ameliorated triptolide-induced depletion in renal SOD and GSH-Px activities, caused marked normalization of renal MDA content and also blunt the impairment of renal tubules and renal function. These results suggest that triptolide induces oxidative stress via impairing the antioxidant system, and oxidative stress contributes, at least in part, to the mechanism of triptolide-induced acute nephrotoxicity. PMID- 21530204 TI - Preventive effect of a galactoglucomannan (GGM) from Dendrobium huoshanense on selenium-induced liver injury and fibrosis in rats. AB - This study was carried out to investigate the preventive effects of galactoglucomannan (GGM), a homogeneous polysaccharide from Dendrobium huoshanense, on liver injury and fibrosis induced by sodium selenite. Sprague Dawley rats injected subcutaneously with sodium selenite at the dosage of 3.28 mgkg(-1) b.wt. were set as the model groups. Rats treated with sodium selenite at the dosage of 3.28 mgkg(-1) b.wt. and GGM at 50-200 mgkg(-1) b.wt. were set as the prevention groups. Biochemical and histological analysis showed that GGM significantly ameliorated selenite-induced liver injury and fibrosis in rats. Oral administration of GGM effectively attenuated the toxicity of selenite to liver tissue, which was judged both by the decreased activities of serum hepatic enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and by liver histopathological examination. Meanwhile, GGM also reduced the levels of H(2)O(2) and malondialdehyde (MDA), elevated the levels of GSH, restored the fluidity of hepatic plasma membrane, and retained the activities of endogenous enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione S transferase (GST). The prevention of selenite-induced liver injury and fibrosis by GGM was further supported by the reduced expression of transforming growth factor-beta1 (TGF-beta1) and type I collagen. These results suggested that GGM may be developed into a novel antifibrotic agent for the prevention of liver injury and fibrosis. PMID- 21530205 TI - DNA from keratinous tissue. Part I: hair and nail. AB - Keratinous tissues such as nail, hair, horn, scales and feather have been used as a source of DNA for over 20 years. Particular benefits of such tissues include the ease with which they can be sampled, the relative stability of DNA in such tissues once sampled, and, in the context of ancient genetic analyses, the fact that sampling generally causes minimal visual damage to valuable specimens. Even when freshly sampled, however, the DNA quantity and quality in the fully keratinized parts of such tissues is extremely poor in comparison to other tissues such as blood and muscle - although little systematic research has been undertaken to characterize how such degradation may relate to sample source. In this review paper we present the current understanding of the quality and limitations of DNA in two key keratinous tissues, nail and hair. The findings indicate that although some fragments of nuclear and mitochondrial DNA appear to be present in almost all hair and nail samples, the quality of DNA, both in quantity and length of amplifiable DNA fragments, vary considerably not just by species, but by individual, and even within individual between hair types. PMID- 21530206 TI - Morphologic features of the fetal mandibular condyle: layers, canals and microvascular pattern. AB - During organogenesis the mandibular condyle is divided by a fibrovascular septum, the persistence of which in the growing cartilage can lead to a bifid condyle. In this study we have evaluated the morphology of 3rd trimester human fetal temporomandibular (TMJ) specimens in order to determine the pattern of the vascular morphology associated with the layers and vascular canals (VCs) of the developing condyle (covering layers and condyle proper). Eleven human fetuses of 27-38cm crown-rump length were used for histological (hematoxylin-eosin, Van Gieson stain) and immunohistochemical evaluation (antibodies for bcl2 and CD34) and another two of 24 and 31cm, for TMJ microvasculature studies after black ink injections. With increasing fetal age, the intermediate loose lamina (LL) of the condylar proliferative layer evolves from a vascular-mesenchymal to a fibrillar pattern, via a transitory stage of a clear space that may be misdiagnosed as lower joint cavity (LJC). Within the condyle proper VCs may be present on its entire sagittal length, deepening variably towards the erosive zone and opened superiorly in the LL loose layer. Vessels of the evolving LL enter the condyle, directly or through the VCs; these vessels retract peripherally with increasing age and the intrinsic vessels of the condyle supplied from the erosive zone become prevalent. Vascular morphogenesis at the level of the LL seems comparable to that at the level of the LJC where characteristic glomeruli regress with increasing age. Lack of vascular regression and closure of central V-shaped defects of the condyle, as observed in 2/22 condyles, may represent a developmental substrate for condylar bifidism or a predisposing condition weakening the condyle, and making it more sensitive to trauma in childhood. PMID- 21530207 TI - New developments in the field of peripheral nerve regeneration. PMID- 21530208 TI - Short-term effects of zoledronate on the histomorphology of osteoclast in young albino rats. AB - The present study was conducted to histomorphometrically evaluate the effects of short-term administration of zoledronate, a third generation bisphosphonate, on the metaphysis of the proximal end of tibia in twenty day old male albino rats. Zoledronate (2.8 MUg/kg body weight), was daily given subcutaneously for eleven days. The animals were sacrificed; tibiae were dissected out and decalcified in EDTA. Seven micron thick, serial longitudinal paraffin sections were stained with haematoxylin and eosin and examined under a Zeiss light microscope and Image Pro Express Analyzer. In zoledronate treated rats, a significant increase (p<0.05) in the number of osteoclasts was observed both in the regions of primary spongiosa (zoledronate treated: 6.41 +/- 0.30/mm(2), control: 2.90 +/- 0.28/mm(2)) and secondary spongiosa (zoledronate treated: 49.58 +/- 0.84/mm(2), control: 31.81 +/ 2.02/mm(2)) along with a significant increase (p<0.05) in the length of the metaphyseal region as compared to the control group. The number of nuclei per osteoclast and area of the osteoclast also showed a significant increase (p<0.001; p<0.05 respectively) following the uptake of zoledronate. The findings in the present study, suggest that the osteoclasts are the primary sites of action of zoledronate resulting in decreased osteoclastic activity, which would account for the great increase in the number and size of inactive osteoclasts resulting in marked cancellous bone formation. PMID- 21530209 TI - Polyphenols from Parabarium huaitingii and their positive inotropic and anti myocardial infarction effects in rats. AB - Eight phenolic compounds, including (-)-epicatechin (1) and seven proanthocyanidins (2-8), were obtained from the butanol extract of Parabarium huaitingii (PHB). Their chemical structures were identified based on analyses of mass spectra (MS), NMR, CD spectra, and partial acid catalyzed thiolytic degradation. The observation made by laser scanning confocal microscope found a significant increase of the concentration of intracellular Ca2+ ([Ca2+](i)) in single myocytes when the PHB was added, while compounds 1 and 3 had the same physiological effect. Further investigations showed PHB had a dose-dependent positive inotropic effect on isolated right atria and papillary muscle of left ventricle of the rat, while having no significant influence on the spontaneous beating rate of the isolated right atria. The inotropic effect of PHB could be greatly abolished by pretreating the myocardium in Ca2+-free solution. These findings indicated that PHB could significantly increase [Ca2+](i) in myocytes, which was greatly dependent on the influx of extracellular Ca2+. Compounds 1 and 3 might be the effective ingredients of the inotropic effect of PHB. In addition, PHB could also significantly decrease the infarct size of the heart on acute myocardial infarction (AMI) model rats, which suggested its myocardial protective effect on ischemic myocardium. The positive inotropic effect of PHB, together with its myocardial protective effect on AMI, suggested that PHB had a promising potential for the prevention and treatment of heart failure, especially the one that was caused by AMI. PMID- 21530210 TI - Time-dependent changes in the brain arachidonic acid cascade during cuprizone induced demyelination and remyelination. AB - Phospholipases A(2) (PLA(2)) are the enzymatic keys for the activation of the arachidonic acid (AA) cascade and the subsequent synthesis of pro-inflammatory prostanoids (prostaglandins and tromboxanes). Prostanoids play critical roles in the initiation and modulation of inflammation and their levels have been reported increased in several neurological and neurodegenerative disorders, including multiple sclerosis (MS). Here, we aimed to determine whether brain expression PLA(2) enzymes and the terminal prostagland in levels are changed during cuprizone-induced demyelination and in the subsequent remyelination phase. Mice were given the neurotoxicant cuprizone through the diet for six weeks to induce brain demyelination. Then, cuprizone was withdrawn and mice were returned to a normal diet for 6 weeks to allow spontaneous remyelination. We found that after 4 6 weeks of cuprizone, sPLA(2)(V) and cPLA(2), but not iPLA(2)(VI), gene expression was upregulated in the cortex, concomitant with an increase in the expression of astrocyte and microglia markers. Cyclooxygenase (COX)-2 gene expression was consistently upregulated during all the demyelination period, whereas COX-1 sporadically increased only at week 5 of cuprizone exposure. However, we found that at the protein level only sPLA(2)(V) and COX-1 were elevated during demyelination, with COX-1 selectively expressed by activated and infiltrated microglia/macrophages and astrocytes. Levels of PGE(2), PGD(2), PGI(2) and TXB(2) were also increased during demyelination. During remyelination, none of the PLA(2) isoforms was significantly changed, whereas COX-1 and -2 were sporadically upregulated only at the gene expression level. PGE(2), PGI(2) and PGD(2) levels returned to normal, whereas TXB(2) was still upregulated after 3 weeks of cuprizone withdrawal. Our study characterizes for the first time time dependent changes in the AA metabolic pathway during cuprizone-induced demyelination and the subsequent remyelination and suggests that sPLA(2)(V) is the major isoform contributing to AA release. PMID- 21530211 TI - The effect of n-3 polyunsaturated fatty acids on leukotriene B4 and leukotriene B5 production from stimulated neutrophil granulocytes in patients with chronic kidney disease. AB - The proinflammatory leukotriene B4 (LTB4) may be of importance in the progression of chronic kidney disease (CKD). We investigated whether n-3 polyunsaturated fatty acids (PUFA) decrease LTB4 and increase the formation of the less inflammatory leukotriene B5 (LTB5) in patients with CKD. Fifty-six patients with CKD stage 2-5 were randomised to 2.4 g n-3 PUFA or olive oil for 8 weeks. Compared to controls, n-3 PUFA significantly decreased release of LTB4 (p<0.001) and 5-hydroxyeicosatetraenoic acid (5-HETE) (p<0.01) and significantly increased release of LTB5 (p<0.001) and 5-hydroxyeicosapentaenoic acid (5-HEPE) (p<0.001) from stimulated neutrophil granulocytes. Kidney function evaluated by creatinine clearance and proteinuria did not improve. In conclusion, n-3 PUFA supplementation for 8 weeks in patients with CKD stage 2-5 significantly decreased LTB4 and 5-HETE and significantly increased LTB5 and 5-HEPE. No effect was seen on kidney function. PMID- 21530213 TI - Premature discontinuation during the UPLIFT study. AB - RATIONALE: Placebo-controlled clinical trials on COPD are characterized by premature discontinuation. At present, no clear insight into this phenomenon is available. OBJECTIVE: To obtain better insight into the phenomenon of premature discontinuation. METHODS: We analyzed the pattern of discontinuation in the UPLIFT-trial. MEASUREMENTS AND MAIN RESULTS: Premature discontinuation was substantial and greater in the placebo than in the tiotropium group (45 vs. 37%, p < 0.001). Patients discontinuing were characterized by more severe COPD (p < 0.0001), greater number of pack years (p < 0.002), smaller pre-bronchodilator and post-bronchodilator FEV(1) (p < 0.0001 for both), and worse SGRQ scores (p < 0.0001). Rates of decline of FEV(1) and SGRQ were greater in non-completers (p < 0.0001 for both). The latter differences increased over time indicating that the evolution of variables in time was related to trial completion. The risks of exacerbations and hospitalizations were greater in non-completers. In logistic regression analysis BMI, post-bronchodilator FEV(1), male gender and treatment with tiotropium were positively related to trial completion, whereas age, worse SGRQ, female gender, current smoking and assignment to the placebo group were negatively related. CONCLUSION: Assignment to the control group is related to premature discontinuation. Discontinuation was important and selective in this large trial. Pulmonary function, health-related quality of life and smoking are the most important other variables related to discontinuation. The evolution of variables during the trial is also related to discontinuation. Complete follow-up of discontinued patients may provide better insight into the efficacy of medication in future trials. PMID- 21530212 TI - Electroporation delivery of DNA vaccines: prospects for success. AB - A number of noteworthy technology advances in DNA vaccines research and development over the past few years have led to the resurgence of this field as a viable vaccine modality. Notably, these include--optimization of DNA constructs; development of new DNA manufacturing processes and formulations; augmentation of immune responses with novel encoded molecular adjuvants; and the improvement in new in vivo delivery strategies including electroporation (EP). Of these, EP mediated delivery has generated considerable enthusiasm and appears to have had a great impact in vaccine immunogenicity and efficacy by increasing antigen delivery upto a 1000 fold over naked DNA delivery alone. This increased delivery has resulted in an improved in vivo immune response magnitude as well as response rates relative to DNA delivery by direct injection alone. Indeed the immune responses and protection from pathogen challenge observed following DNA administration via EP in many cases are comparable or superior to other well studied vaccine platforms including viral vectors and live/attenuated/inactivated virus vaccines. Significantly, the early promise of EP delivery shown in numerous pre-clinical animal models of many different infectious diseases and cancer are now translating into equally enhanced immune responses in human clinical trials making the prospects for this vaccine approach to impact diverse disease targets tangible. PMID- 21530214 TI - Exhaled nitric oxide measure using multiple flows in clinically relevant subgroups of COPD. AB - Although there is widespread interest in fractional exhaled nitric oxide (FeNO) as a non-invasive, time and cost effective biomarker for assessing airway inflammation in chronic obstructive pulmonary disease (COPD), its usefulness is still controversial. We examined the FeNO levels in clinically meaningful subgroups of COPD in a group of 91 COPD patients with FEV(1) 17-77% of predicted. Multiple flow rates FeNO at 10, 30, 50, 100 and 200 mL/s were measured and a two compartment model was used to estimate the diffusion Capacity (D), alveolar NO concentration (Calv) and airway wall NO concentration (Caw). All patients had spirometry, assessment of symptoms with questionnaires and low-dose CT scan as well as assessment of weight and body composition. We examined the following subgroups of COPD: Patients with 1) Severe emphysema, 2) Chronic bronchitis, 3) Frequent exacerbations, 4) Loss of lean body mass and 5) Low fat-free mass index. We used advanced non-linear mixed model adjusted for age and gender. The modelled differences in D, Calv or Caw among COPD subgroups were small and not statistically significant. The analysis showed significant effects of current smoking on Caw and of gender on D and Calv. The results were the same if the advanced non-linear mixed model was substituted by more standard analysis techniques. This study questions the relevance of using FeNO as a biomarker to evaluate local inflammation in COPD and points to a need for developing novel non invasive biomarkers for research laboratory work and daily clinical practice. PMID- 21530215 TI - Association of MAOA and COMT gene polymorphisms with palatable food intake in children. AB - Several studies have implicated dopamine (DA) in appetite regulation. The enzymes catechol-o-methyltransferase (COMT) and monoamine oxidase A (MAOA) control DA availability and their genes have well-characterized functional variants. In this study, we examined three polymorphisms in these genes, T941G and MAOAu-VNTR in the MAOA gene and Val158Met in the COMT gene, to investigate how heritable variations in enzymes that determine DA levels might influence food intake and nutritional status. This investigation was a cross-sectional examination of 354 Brazilian children of three to four years old. Polymorphisms were analyzed by PCR based methods. Means of dietary and anthropometric data were compared among genotypes by one-way analyses of variance or Kruskal Wallis tests. The MAOAu-VNTR and COMT Val158Met polymorphisms were associated with the amount of palatable food intake in boys. Presence of the MAOAu-VNTR*long allele was associated with higher intake of lipid-dense foods (LDF) when compared with the *short allele (P=.009); the amount of sugar-dense foods (SDF) intake was also higher in males carriers of the MAOAu-VNTR *long allele than in carriers of the *short allele (P=.034). In the girls' sample, MAOAu-VNTR polymorphism was not associated with food intake and nutritional status. Carriers of the COMT Val158Met*Val allele presented higher intake of LDF when compared with Met/Met homozygotes (P=.008). This study provides the first indication that genetic variants of enzymes that control DA availability might be involved in determination of the amount of palatable food intake in children. PMID- 21530216 TI - Performance and coverage of HIV interventions for injection drug users: Insights from triangulation of programme, field and surveillance data from Pakistan. AB - INTRODUCTION: Nearly 20% of the estimated 84,000 injecting drug users in Pakistan are HIV infected. Non-governmental organisations have implemented HIV interventions for IDUs in 7 cities in Pakistan. Here we report on the performance, coverage and costs of these interventions. METHODS: National HIV bio behavioural surveillance data were used to measure effectiveness of interventions by comparing HIV prevalence and behavioural trends in intervention and non intervention cities. Coverage was measured by comparing the supply of syringes with the total syringe need and intervention cost per IDU served per year was calculated. RESULTS: The NGOs registered 20,640 IDUs (original targets: <10,000); provided 66% of new syringes for all registered IDUs and 75% for all estimated street-based IDUs. This compared to a national coverage of about 13%. Intervention cities had higher baseline HIV prevalence, reflecting their choice as intervention sites. More IDUs from intervention cities (59% vs. 27%) reported always using a clean syringe. Condom use with last sexual partner (24% vs. 11%) and HIV prevention knowledge were also higher amongst this group (all at p<0.001). HIV prevalence in intervention cities remained unchanged in Faisalabad (13%) and Quetta (10%) but increased in Karachi (26-30%) and Lahore (4-7%). Coverage of sterile syringes for intervention cities was 30% compared to 13% nationwide. However within city, coverage varied from 30 to 99%. The costs of services varied widely by NGOs from USD 146 to 403. CONCLUSIONS: IDUs interventions are performing well in some Pakistani cities. However, considerable expansion is needed to increase nationwide coverage. PMID- 21530217 TI - Mycophenolic acid in kidney transplant patients with diabetes mellitus: does the formulation matter? AB - Diabetes mellitus is frequent in kidney transplant recipients and is commonly associated with gastrointestinal (GI) complications. Delayed gastric emptying affects 30% to 50% of patients with type 1 or 2 diabetes and can influence oral drug absorption. Time-to-peak concentration of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) is longer in diabetic kidney transplant patients than patients without diabetes. By retaining gut contents in the stomach for longer, this could increase local GI toxicity in diabetic recipients due to an extended duration of exposure to MPA in the stomach. The enteric-coated mycophenolate sodium (EC-MPS) formulation delays the release of MPA until pH is higher than 5.5, such that absorption takes place more distally compared with MMF. Patient reported outcomes data have been used to assess the effect of conversion to EC MPS in maintenance kidney transplant patients with diabetes who were experiencing MMF-related GI symptoms. Results indicated that conversion leads to improved GI symptom burden despite higher MPA exposure under the EC-MPS regimen. Improved GI tolerance using EC-MPS has permitted maintenance of optimal MPA exposure in nondiabetic populations. Comparative trials to evaluate the GI symptom burden and maximum achieved MPA dosing using the EC-MPS and MMF formulations in de novo and maintenance diabetic kidney transplant recipients are merited. PMID- 21530218 TI - Hepatitis B virus and renal transplantation. AB - Hepatitis B virus (HBV) infection remains an important cause of liver disease in the renal transplant (RT) population, potentially diminishing survival. Consequences of HBV infection after RT include progression to decompensated cirrhosis and an increased risk of hepatocellular carcinoma. Although precautions initially recommended by the Centers for Diseases Control and Prevention 30 years ago have substantially reduced HBV transmission within hemodialysis units, acute HBV outbreaks continue to be reported in patients with chronic kidney disease on maintenance hemodialysis. In addition, immigration from areas of high HBV prevalence implies that HBV-infected organs with chronic kidney disease will continue to enter the RT pool. Fortunately, the advent of oral therapy for HBV infection now reduces the risk of HBV progression post-RT. PMID- 21530219 TI - Recommendations for management of Chagas disease in organ and hematopoietic tissue transplantation programs in nonendemic areas. AB - The substantial immigration into Spain from endemic areas of Chagas disease such as Latin America has increased the number of potential donors of organs and tissues. In addition, an increasing number of patients with advanced Chagas heart disease may eventually be eligible to receive a heart transplant, a universally accepted therapeutic strategy for the advanced stages of this disease. Therefore, it is necessary to establish protocols for disease management. This document is intended to establish the guidelines to be followed when a potential donor or a tissue or organ recipient is potentially affected by Chagas disease and summarizes the action criteria against the possibility of Chagas disease transmission through the donation of organs, tissues, or hematopoietic stem cells and aims to help professionals working in this field. A single registry of transplants in Trypanosoma cruzi infected donors and/or recipients will provide and disseminate experience in this area, which has shown a low recorded incidence to date. PMID- 21530220 TI - Treatment of municipal landfill leachate by catalytic wet air oxidation: Assessment of the role of operating parameters by factorial design. AB - The wet air oxidation (WAO) of municipal landfill leachate catalyzed by cupric ions and promoted by hydrogen peroxide was investigated. The effect of operating conditions such as WAO treatment time (15-30min), temperature (160-200 degrees C), Cu(2+) concentration (250-750mgL(-1)) and H(2)O(2) concentration (0-1500mgL( 1)) on chemical oxygen demand (COD) removal was investigated by factorial design considering a two-stage, sequential process comprising the heating-up of the reactor and the actual WAO. The leachate, at an initial COD of 4920mgL(-1), was acidified to pH 3 leading to 31% COD decrease presumably due to the coagulation/precipitation of colloidal and other organic matter. During the 45min long heating-up period of the WAO reactor under an inert atmosphere, COD removal values up to 35% (based on the initial COD value) were recorded as a result of the catalytic decomposition of H(2)O(2) to reactive hydroxyl radicals. WAO at 2.5MPa oxygen partial pressure advanced treatment further; for example, 22min of oxidation at 200 degrees C, 250mgL(-1) Cu(2+) and 0-1500mgL(-1) H(2)O(2) resulted in an overall (i.e. including acidification and heating-up) COD reduction of 78%. Amongst the operating variables in question, temperature had the strongest influence on both the heating-up and WAO stages, while H(2)O(2) concentration strongly affected the former and reaction time the latter. Nonetheless, the effects of temperature and H(2)O(2) concentration were found to depend on the concentration levels of catalyst as suggested by the significance of their 3rd order interaction term. PMID- 21530221 TI - Deactivation and regeneration of ZSM-5 zeolite in catalytic pyrolysis of plastic wastes. AB - In this work, a study of the regeneration and reuse of ZSM-5 zeolite in the pyrolysis of a plastic mixture has been carried out in a semi-batch reactor at 440 degrees C. The results have been compared with those obtained with fresh catalyst and in non-catalytic experiments with the same conditions. The use of fresh catalyst produces a significant change in both the pyrolysis yields and the properties of the liquids and gases obtained. Gases more rich in C3-C4 and H(2) are produced, as well as lower quantities of aromatic liquids if compared with those obtained in thermal decomposition. The authors have proved that after one pyrolysis experiment the zeolite loses quite a lot of its activity, which is reflected in both the yields and the products quality; however, this deactivation was found to be reversible since after regeneration heating at 550 degrees C in oxygen atmosphere, this catalyst recovered its initial activity, generating similar products and in equivalent proportions as those obtained with fresh catalyst. PMID- 21530222 TI - Recovery of polypropylene and polyethylene from packaging plastic wastes without contamination of chlorinated plastic films by the combination process of wet gravity separation and ozonation. AB - Wet gravity separation technique has been regularly practiced to separate the polypropylene (PP) and polyethylene (PE) (light plastic films) from chlorinated plastic films (CP films) (heavy plastic films). The CP films including poly vinyl chloride (PVC) and poly vinylidene chloride (PVDC) would float in water even though its density is more than 1.0g/cm(3). This is because films are twisted in which air is sometimes entrapped inside the twisted CP films in real existing recycling plant. The present research improves the current process in separating the PP and PE from plastic packaging waste (PPW), by reducing entrapped air and by increasing the hydrophilicity of the CP films surface with ozonation. The present research also measures the hydrophilicity of the CP films. In ozonation process mixing of artificial films up to 10min reduces the contact angle from 78 degrees to 62 degrees , and also increases the hydrophilicity of CP films. The previous studies also performed show that the artificial PVDC films easily settle down by the same. The effect of ozonation after the wet gravity separation on light PPW films obtained from an actual PPW recycling plant was also evaluated. Although actual light PPW films contained 1.3% of CP films however in present case all the CP films were removed from the PPW films as a settled fraction in the combination process of ozonation and wet gravity separation. The combination process of ozonation and wet gravity separation is the more beneficial process in recovering of high purity PP and PE films from the PPW films. PMID- 21530223 TI - The use of commercial and industrial waste in energy recovery systems - A UK preliminary study. AB - With 2020 energy targets set out by the EU fast approaching, the UK is trying to source a higher proportion of its energy from renewable resources. Coupled with this, a growing population and increasing trends in consumer demand have resulted in national waste loads increasing. A possible solution to both issues is energy from-waste (EfW) technologies. Many studies have focused on municipal solid waste (MSW) as a potential feedstock, but appear to overlook the potential benefits of commercial and industrial waste (C&IW). In this study, samples of C&IW were collected from three North West waste management companies and Lancaster University campus. The samples were tested for their gross and net calorific value, moisture content, ash content, volatile matter, and also elemental composition to determine their suitability in EfW systems. Intra-sample analysis showed there to be little variation between samples with the exception two samples, from waste management site 3, which showed extensive variation with regards to net calorific value, ash content, and elemental analysis. Comparisons with known fuel types revealed similarities between the sampled C&IW, MSW, and refuse derived fuel (RDF) thereby justifying its potential for use in EfW systems. Mean net calorific value (NCV) was calculated as 9.47MJ/kg and concentrations of sulphur, nitrogen, and chlorine were found to be below 2%. Potential electrical output was calculated using the NCV of the sampled C&IW coupled with four differing energy generation technologies. Using a conventional incinerator with steam cycle, total electrical output was calculated as 24.9GWh, based on a plant operating at 100,000tpa. This value rose to 27.0GWh when using an integrated gasification combined cycle. A final aspect of this study was to deduce the potential total national electrical output if all suitable C&IW were to be used in EfW systems. Using incineration coupled with a steam turbine, this was determined to be 6TWh, 1.9% of the national demand thereby contributing 6.5% towards the UK's 2020 renewable electricity target. PMID- 21530224 TI - The anaerobic digestion of solid organic waste. AB - The accumulation of solid organic waste is thought to be reaching critical levels in almost all regions of the world. These organic wastes require to be managed in a sustainable way to avoid depletion of natural resources, minimize risk to human health, reduce environmental burdens and maintain an overall balance in the ecosystem. A number of methods are currently applied to the treatment and management of solid organic waste. This review focuses on the process of anaerobic digestion which is considered to be one of the most viable options for recycling the organic fraction of solid waste. This manuscript provides a broad overview of the digestibility and energy production (biogas) yield of a range of substrates and the digester configurations that achieve these yields. The involvement of a diverse array of microorganisms and effects of co-substrates and environmental factors on the efficiency of the process has been comprehensively addressed. The recent literature indicates that anaerobic digestion could be an appealing option for converting raw solid organic wastes into useful products such as biogas and other energy-rich compounds, which may play a critical role in meeting the world's ever-increasing energy requirements in the future. PMID- 21530225 TI - Correlation between physicochemical and ecotoxicological approaches to estimate landfill leachates toxicity. AB - Leachates from municipal solid waste (MSW) landfills may contain a huge diversity of contaminants; these wastewaters should be considered as potentially hazardous complex mixtures, representing a potential environmental risk for surface and groundwater. Current MSW landfill wastes regulatory approaches deem exclusively on the physicochemical characterization and does not contemplate the ecotoxicological assessment of landfill leachates. However, the presence of highly toxic substances in consumer products requires reconsideration on the need of more specific ecotoxicological assessments. The main aim of this study was to evaluate the toxicity of different MSW landfill leachates using a battery of toxicity tests including acute toxicity tests with Daphnia magna and the anuran Xenopus laevis and the in vitro toxicity test with the fish cell line RTG-2. The additional objective was to study the possible correlation between physicochemical properties and the toxicity results obtained for untreated landfill leachates. The results showed that the proposed test battery was effective for the ecotoxicological characterization of MSW landfill leachates. A moderate to strong correlation between the measured physicochemical parameters and the calculated toxicity units was detected for all toxicity assays. Correlation factors of 0.85, 0.86 and 0.55 for Daphnia, Xenopus and RTG-2 tests, respectively, were found. The discriminant analysis showed that certain physicochemical parameters could be used for an initial categorization of the potential aquatic acute toxicity of leachates; this finding may facilitate leachates management as the physicochemical characterization is currently the most common or even only monitoring method employed in a large majority of landfills. Ammonia, alkalinity and chemical oxygen demand (COD), together with chloride, allowed a proper categorization of leachates toxicity for up to 75% of tested samples, with a small percentage of false negatives. PMID- 21530226 TI - Effect of fresh green waste and green waste compost on mineral nitrogen, nitrous oxide and carbon dioxide from a Vertisol. AB - Incorporation of organic waste amendments to a horticultural soil, prior to expected risk periods, could immobilise mineral N, ultimately reducing nitrogen (N) losses as nitrous oxide (N(2)O) and leaching. Two organic waste amendments were selected, a fresh green waste (FGW) and green waste compost (GWC) as they had suitable biochemical attributes to initiate N immobilisation into the microbial biomass and organic N forms. These characteristics include a high C:N ratio (FGW 44:1, GWC 35:1), low total N (<1%), and high lignin content (>14%). Both products were applied at 3t C/ha to a high N (plus N fertiliser) or low N (no fertiliser addition) Vertisol soil in PVC columns. Cumulative N(2)O production over the 28 day incubation from the control soil was 1.5mg/N(2)O/m(2), and 11mg/N(2)O/m(2) from the control+N. The N(2)O emission decreased with GWC addition (P<0.05) for the high N soil, reducing cumulative N(2)O emissions by 38% by the conclusion of the incubation. Analysis of mineral N concentrations at 7, 14 and 28 days identified that both FGW and GWC induced microbial immobilisation of N in the first 7 days of incubation regardless of whether the soil environment was initially high or low in N; with the FGW immobilising up to 30% of available N. It is likely that the reduced mineral N due to N immobilisation led to a reduced substrate for N(2)O production during the first week of the trial, when soil N(2)O emissions peaked. An additional finding was that FGW+N did not decrease cumulative N(2)O emissions compared to the control+N, potentially due to the fact that it stimulated microbial respiration resulting in anaerobic micro sites in the soil and ultimately N(2)O production via denitrification. Therefore, both materials could be used as post harvest amendments in horticulture to minimise N loss through nitrate-N leaching in the risk periods between crop rotations. The mature GWC has potential to reduce N(2)O, an important greenhouse gas. PMID- 21530227 TI - A novel disposable electrochemical immunosensor for phenyl urea herbicide diuron. AB - A disposable electrochemical immunosensor has been developed for the determination of phenyl urea herbicide-diuron using a low cost laser ablated gold electrodes (LC-LAGE) fabricated on polystyrene substrate. The electrodes were electrochemically deposited with prussian blue-gold nanoparticle (PB-GNP) film, and a competitive inhibition immunoassay was performed on LC-LAGE by using a specific hapten-protein conjugate. The binding of available diuron specific antibody on conjugate coated electrode was detected using alkaline phosphatase rabbit anti-IgG antibody. The addition of 1-naphthyl phosphate substrate resulted in the production of electrochemically active product, 1-naphthol, which was monitored using square wave voltammetry technique. The assay exhibited an excellent sensitivity and specificity showing the dynamic response range between 1 ppt and 10 ppm for diuron with detection limit around 1 ppt. This study provides insight into development of a rapid and high-throughput screening of pesticides in environmental samples at a very low cost. PMID- 21530228 TI - Engineered cardiac tissues. AB - Cardiac tissue engineering offers the promise of creating functional tissue replacements for use in the failing heart or for in vitro drug screening. The last decade has seen a great deal of progress in this field with new advances in interdisciplinary areas such as developmental biology, genetic engineering, biomaterials, polymer science, bioreactor engineering, and stem cell biology. We review here a selection of the most recent advances in cardiac tissue engineering, including the classical cell-scaffold approaches, advanced bioreactor designs, cell sheet engineering, whole organ decellularization, stem cell-based approaches, and topographical control of tissue organization and function. We also discuss current challenges in the field, such as maturation of stem cell-derived cardiac patches and vascularization. PMID- 21530229 TI - MicroRNAs and developmental timing. AB - MicroRNAs regulate temporal transitions in gene expression associated with cell fate progression and differentiation throughout animal development. Genetic analysis of developmental timing in the nematode Caenorhabditis elegans identified two evolutionarily conserved microRNAs, lin-4/mir-125 and let-7, that regulate cell fate progression and differentiation in C. elegans cell lineages. MicroRNAs perform analogous developmental timing functions in other animals, including mammals. By regulating cell fate choices and transitions between pluripotency and differentiation, microRNAs help to orchestrate developmental events throughout the developing animal, and to play tissue homeostasis roles important for disease, including cancer. PMID- 21530230 TI - Translational regulation in growth cones. AB - Axonal growth cones (GCs) steer in response to extrinsic cues using mechanisms that include local protein synthesis. This adaptive form of gene regulation occurs with spatial precision and depends on subcellular mRNA localisation. Recent genome-wide studies have shown unexpectedly complex and dynamically changing mRNA repertoires in growing axons and GCs. Axonal targeting of some transcripts seems to be highly selective and involves sequence diversity in non coding regions generated by transcriptional and/or post-transcriptional mechanisms. New evidence reports direct coupling of a guidance receptor to the protein synthesis machinery and other findings demonstrate that some guidance cues can repress translation. The recent findings shed further light on the exquisitely regulated process that enables distant cellular compartments to respond to local stimuli. PMID- 21530231 TI - Making and breaking synapses through local mRNA regulation. AB - Neurons are exquisitely polarized cells that extend intricate axonal and dendritic arbors. Developmental cues guide axons and dendrites into circuits by inducing rapid changes in local protein expression and cytoskeletal structure. Neurons can transduce these signals through local mRNA regulation. Here, we review the latest insights regarding post-transcriptional control of gene expression through mRNA transport and local protein synthesis in developing neurons. We focus on local mRNA regulation during axon growth and guidance, dendrite morphogenesis, and synapse formation and refinement. Dysregulated mRNA transport and translation in neurological disorders are also discussed. The collection of molecules and mechanisms reviewed includes sequence-specific RNA binding proteins, microtubule motors and adaptors, microRNAs, translation initiation factors, and the receptor-mediated signaling that modulates these molecules. PMID- 21530232 TI - RNA structure and the mechanisms of alternative splicing. AB - Alternative splicing is a widespread means of increasing protein diversity and regulating gene expression in eukaryotes. Much progress has been made in understanding the proteins involved in regulating alternative splicing, the sequences they bind to, and how these interactions lead to changes in splicing patterns. However, several recent studies have identified other players involved in regulating alternative splicing. A major theme emerging from these studies is that RNA secondary structures play an under appreciated role in the regulation of alternative splicing. This review provides an overview of the basic aspects of splicing regulation and highlights recent progress in understanding the role of RNA secondary structure in this process. PMID- 21530233 TI - New views on antidepressant action. AB - The increasing incidence of depressive spectrum disorders worldwide, together with the failure of current medication to effectively treat a significant proportion of cases, calls for a better knowledge of the physiopathology of depression and of the therapeutic action of antidepressants. Recent research has unveiled an array of new mechanisms through which antidepressant drugs help restore neuronal plasticity and neurotransmission. In this review, we summarize the latest advances in the field, focusing on the effectors and molecular pathways that sustain the action of antidepressants. Grasping the overall brain response to antidepressants, with an integrated overview of the neurotransmitter systems, signaling cascades and neural circuits at play, should help to design more potent and selective therapies. PMID- 21530234 TI - Constructing ensembles for intrinsically disordered proteins. AB - The relatively flat energy landscapes associated with intrinsically disordered proteins makes modeling these systems especially problematic. A comprehensive model for these proteins requires one to build an ensemble consisting of a finite collection of structures, and their corresponding relative stabilities, which adequately capture the range of accessible states of the protein. In this regard, methods that use computational techniques to interpret experimental data in terms of such ensembles are an essential part of the modeling process. In this review, we critically assess the advantages and limitations of current techniques and discuss new methods for the validation of these ensembles. PMID- 21530236 TI - Sequences and topology: intrinsic disorder in the evolving universe of protein structure. PMID- 21530235 TI - Base ionization and ligand binding: how small ribozymes and riboswitches gain a foothold in a protein world. AB - Genome sequencing has produced thousands of nonprotein coding (nc)RNA sequences including new ribozymes and riboswitches. Such RNAs are notable for their extraordinary functionality, which entails exquisite folding that culminates in biocatalytic or ligand-binding capabilities. Here we discuss advances in relating ncRNA form to function with an emphasis on base pK(a) shifting by the hairpin and hepatitis delta virus ribozymes. We then describe ligand binding by the two smallest riboswitches, which target preQ(1) and S-adenosyl-(l)-homocysteine, followed by an analysis of a second-messenger riboswitch that binds cyclic-di GMP. Each riboswitch is then compared to a protein that binds the same ligand to contrast binding properties. The results showcase the breadth of functionality attainable from ncRNAs, as well as molecular features notable for antibacterial design. PMID- 21530237 TI - Childhood cancer survival in Ireland: temporal, regional and deprivation-related patterns. AB - Survival after childhood cancer varies across Europe, but national or regional studies have so far shown no survival differences related to socio-economic disparity. The relationship of childhood cancer survival to disparity has not been studied in Ireland. We assessed observed survival for Irish children (ages 0 14 years) diagnosed with cancer during the period 1994-2005, overall (for all cancers included in the 3rd edition of the International Classification of Childhood Cancer) and for three main diagnostic groups - leukaemias, lymphomas, and central nervous system tumours. Comparisons were made between two diagnosis periods (1994-1999 and 2000-2005), between four regions of residence, and between five area-based deprivation categories. Regional patterns of treatment were examined to help assess the impact of centralisation of services. There was only limited evidence of improvements in survival over time. No clear evidence was found of deprivation-related influences on childhood cancer survival in Ireland, overall or for the three main diagnostic groups examined, although a weak trend was apparent for lymphoid leukaemias. Regional variation in survival was likewise not clear-cut, with the possible exception of CNS tumours (significantly higher survival amongst patients resident in the Western region). The absence of clear trends or patterns for regional or deprivation-related variation in survival may reflect a high degree of coordination and uniformity of treatment (and perhaps diagnostic) services, and application of standard treatment protocols nationally. PMID- 21530238 TI - Adherence to national guidelines for treatment and outcome of endometrial cancer stage I in relation to co-morbidity in southern Netherlands 1995-2008. AB - BACKGROUND: Endometrial cancer (EC) occurs more frequently amongst women over 60years old, who often also suffer from co-morbidity. Since treatment guidelines are derived from clinical trials that usually exclude such patients, nevertheless these guidelines are also applied for older EC patients. We assessed the independent influence of age and co-morbidity on treatment modalities and survival of patients with stage I EC in everyday clinical practice, thereby also examining the implementation of Dutch guidelines on treatment, since 2000. METHODS: All 2099 stage I EC patients diagnosed between 1995 and 2008 in the southern Netherlands were registered in the ECR (Eindhoven Cancer Registry) were included for analysis of the influence of age and co-morbidity on treatment and survival. For co-morbidity we used a modified version of Charlson's list, uniquely recorded in the ECR since 1993. A subgroup analysis was performed of patients who should have received adjuvant radiotherapy based on the risk factors advised in the Dutch guidelines of 2000. We considered five periods (1995-97; 1989-2000; 2001-03; 2004-06; 2007-08). RESULTS: Having two or more co-morbid conditions resulted in a significant reduction of receiving adjuvant radiotherapy (Odds Ratio: 0.6, 95% Confidence Interval (95% CI): 0.3-1.0)) but receiving adjuvant radiotherapy did not appear to improve survival. After adjustment for age, tumour stage, tumour grade, period of diagnosis and treatment, co-morbidity increased the risk of death, especially diabetes (Hazard Ratio (HR) for mortality: 2.9,95% CI: 2.2-4.0), a previous cancer (HR: 2.6, 95%CI: 1.9-3.7) and cardiovascular disease (HR: 2.3, 95%CI: 1.7-3.2). The combination of two or more co-morbid conditions resulted in a HR of 3.0 (95%CI: 2.2-3.9). CONCLUSION: Co morbidity decreased the likelihood of receiving adjuvant radiotherapy in patients with stage I EC qualifying to undergo this according to the Dutch guidelines of 2000. Whereas adjuvant radiotherapy did not seem to affect survival in those patients, co-morbidity significantly did. PMID- 21530239 TI - Effects of key operational parameters on biohydrogen production via anaerobic fermentation in a sequencing batch reactor. AB - In this study, a series of tests were conducted in a 6L anaerobic sequencing batch reactor (ASBR) to investigate the effect of pH, hydraulic retention time (HRT) and organic loading rate on biohydrogen production at 28 degrees C. Sucrose was used as the main substrate to mimic carbohydrate-rich wastewater and inoculum was prepared from anaerobic digested sludge without pretreatment. The reactor was operated initially with nitrogen sparging to form anaerobic condition. Results showed that methanogens were effectively suppressed. The optimum pH value would vary depending on the HRT. Maximum hydrogen production rate and yield of 3.04 L H(2)/L reactor d and 2.16 mol H(2)/mol hexose respectively were achieved at pH 4.5, HRT 30 h, and OLR 11.0 kg/m(3)d. Two relationships involving the propionic acid/acetic acid ratio and ethanol/acetic acid ratio were derived from the analysis of the metabolites of fermentation. Ethanol/acetic acid ratio of 1.25 was found to be a threshold value for higher hydrogen production. PMID- 21530240 TI - Production of hydrocarbon fuels from biomass using catalytic pyrolysis under helium and hydrogen environments. AB - This study is focused on hydrocarbon production through changing carrier gas and using zeolite catalysts during pyrolysis. A large reduction in high molecular weight, oxygenated compounds was noticed when the carrier gas was changed from helium to hydrogen during pyrolysis. A catalytic pyrolysis was conducted using two different methods based on how the biomass and catalysts were contacted together. For both methods, there was no significant change in the carbon yield with the change in pyrolysis environment. However, the mixing-method produced higher aromatic hydrocarbons than the bed-method. In addition, two methods were also tested using two ratios of biomass to catalyst. Nonetheless, there was no significant increase in hydrocarbon yield as the catalyst loading was increased from two to five times of biomass in the catalyst-bed method. In contrast to this, a significant increase was noticed for the catalytic-mixing method when the biomass to catalyst loading was increased from 1:4 to 1:9. PMID- 21530241 TI - Electrocatalytic activity of anodic biofilm responses to pH changes in microbial fuel cells. AB - This study investigates the effects of anodic pH on electricity generation in microbial fuel cells (MFCs) and the intrinsic reasons behind them. In a two chamber MFC, the maximum power density is 1170 +/- 58 mW m(-2) at pH 9.0, which is 29% and 89% higher than those working at pH 7.0 and 5.0, respectively. Electrochemical measurements reveal that pH affects the electron transfer kinetics of anodic biofilms. The apparent electron transfer rate constant (k(app)) and exchange current density (i(0)) are greater whereas the charge transfer resistance (R(ct)) is smaller at pH 9.0 than at other conditions. Scanning electron microscopy verifies that alkaline conditions benefit biofilm formation in MFCs. These results demonstrate that electrochemical interactions between bacteria and electrodes in MFCs are greatly enhanced under alkaline conditions, which can be one of the important reasons for the improved MFC output. PMID- 21530242 TI - Biohydrogen from thermophilic co-fermentation of swine manure with fruit and vegetable waste: maximizing stable production without pH control. AB - Hydrogen production by dark fermentation may suffer of inhibition or instability due to pH deviations from optimality. The co-fermentation of promptly degradable feedstock with alkali-rich materials, such as livestock wastes, may represent a feasible and easy to implement approach to avoid external adjustments of pH. Experiments were designed to investigate the effect of the mixing ratio of fruit vegetable waste with swine manure with the aim of maximizing biohydrogen production while obtaining process stability through the endogenous alkalinity of manure. Fruit-vegetable/swine manure ratio of 35/65 and HRT of 2d resulted to give the highest production rate of 3.27 +/- 0.51 L(H2)L(-1)d(-1), with a corresponding hydrogen yield of 126 +/- 22 mL(H2)g(-1)(VS-added) and H2 content in the biogas of 42 +/- 5%. At these operating conditions the process exhibited also one of the highest measured stability, with daily productions deviating for less than 14% from the average. PMID- 21530243 TI - Development of long-term stable partial nitrification and subsequent anammox process. AB - The partial nitrification reactor was successfully started up and operated stably for more than 250 days with a maximum nitrite production rate of 1.12 kg-Nm( 3)day(-1). The important factors for successful partial nitrification were high ammonium loading rate (>1.0 kg-Nm(-3)day(-1)) and relatively high pH (ca. 8.0), giving high free ammonia concentrations (>10mg NH(3)-NL(-1)). In addition, the air flow rate must be controlled at the ratio of air flow rate to ammonium loading rate below 0.1 (m(air)(3)day(-1))/(kg-Nm(-3)day(-1)). After the establishment of stable partial nitrification, the effluent NO(2)(-)-N/NH(4)(+)-N ratio and effluent NO(3)(-)-N concentration were 1.20 +/- 0.33 and 1.2 +/- 1.0mg NL(-1), respectively, which was then fed into an granular-sludge anammox reactor. Consistent nitrogen removal was achieved for more than 250 days with a maximum nitrogen removal rate of 15.0 kg-TNm(-3)day(-1). PMID- 21530244 TI - Photofermentative hydrogen production from wastes. AB - In many respects, hydrogen is an ideal biofuel. However, practical, sustainable means of its production are presently lacking. Here we review recent efforts to apply the capacity of photosynthetic bacteria to capture solar energy and use it to drive the nearly complete conversion of substrates to hydrogen and carbon dioxide. This process, called photofermentation, has the potential capacity to use a variety of feedstocks, including the effluents of dark fermentations, leading to the development of various configurations of two-stage systems, or various industrial and agricultural waste streams rich in sugars or organic acids. The metabolic and enzymatic properties of this system are presented and the possible waste streams that might be successfully used are discussed. Recently, various immobilized systems have been developed and their advantages and disadvantages are examined. PMID- 21530245 TI - Production of biodiesel and lactic acid from rapeseed oil using sodium silicate as catalyst. AB - Biodiesel and lactic acid from rapeseed oil was produced using sodium silicate as catalyst. The transesterification in the presence of the catalyst proceeded with a maximum yield of 99.6% under optimized conditions [3% (w/w) sodium silicate, methanol/oil molar ratio 9/1, reaction time 60 min, reaction temperature 60 degrees C, and stirring rate 250 rpm]. After six consecutive transesterification reactions, the catalyst was collected and used for catalysis of the conversion of glycerol to lactic acid. A maximum yield of 80.5% was achieved when the reaction was carried out at a temperature of 300 degrees C for 90 min. Thus, sodium silicate is an effective catalyst for transesterification and lactic acid production from the biodiesel by-product, glycerol. PMID- 21530246 TI - NMR evaluation of interactions between substituted-indole and PDZ1 domain of PSD 95. AB - We synthesized small organic molecules designed as PDZ ligands. These indole based compounds were evaluated for their interaction with the PDZ1 domain of the post-synaptic density 95 (PSD-95) protein. Three molecules were found to interact with the targeted PDZ protein by NMR. One of them showed chemical shift perturbations closely related to the natural ligands. PMID- 21530247 TI - Synthesis and in vitro antimicrobial activities of new (cyano-NNO-azoxy)pyrazole derivatives. AB - The antibacterial and antifungal activity of a series of products, in which the 1,5-dimethyl-4-(cyano-NNO-azoxy)pyrazol-3-yl and 1,3-dimethyl-4-(cyano-NNO azoxy)pyrazol-5-yl moieties were linked to pyridine, pyrazole, isoxazole, thiophene and the furan ring, were examined. No molecule displayed activity against the gram-negative bacteria tested. Conversely, some compounds displayed activity against two Staphylococcus aureus strains, including the methicillin resistant strain. All compounds displayed interesting antifungal activity, the most active compound of the series being the thiophene derivative 7a. This compound's activity against Candida krusei and Candida glabrata (MIC=0.25 and 0.5 MUg/mL, respectively), two fungal species resistant to azoles, is noteworthy. The presence of the cyano function appeared essential for activity. PMID- 21530248 TI - Anti-inflammatory activity of constituents from Glechoma hederacea var. longituba. AB - Rosmarinic acid, its analogues, and a phenolic compound were obtained from G. hederacea var. longituba. There were two new compounds, methyl isoferuloyl-7-(3,4 dihydroxyphenyl) lactate (1) and benzyl-4'-hydroxy-benzoyl-3'-O-beta-D glucopyranoside (4), and four known compounds (2, 3, 5 and 6). The structures of these compounds were determined on the basis of spectroscopic methods. Each compound was tested by NF-kappaB luciferase assay and three rosmarinic acid analogues inhibited NF-kappaB production and the induction of COX-2 and iNOS mRNA in HepG2 cells. PMID- 21530249 TI - Synthesis of biotinylated muramyl tripeptides with NOD2-stimulating activity. AB - Muramyl di- and tri-peptides are putative activators of the innate immune system through stimulation of the NOD2 receptor. To provide tools for the clarification of the mechanism of this activation we isolated different UDP-muramyl tripeptides (Lys- and DAP-type) from bacteria and used them to synthesize biotinylated derivatives. All biotinylated compounds retained their ability to activate NOD2 in a cell-based test system and are therefore suitable for binding studies aimed at identifying the appropriate pattern recognition receptor(s). PMID- 21530250 TI - Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast. AB - Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3 yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C 7' in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3'-centre to C-4' strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast. PMID- 21530251 TI - Synthesis of cholestane saponins as mimics of OSW-1 and their cytotoxic activities. AB - To fulfill the structure-activity relationship (SAR) of OSW-1, and aim at finding the simplest structural part while maintaining most of the biological activities, six cholestane saponins were synthesized by introducing OSW-1 disaccharide (2-O-4 methoxybenzoyl-beta-D-xylopyranosyl-(1->3)-2-O-acetyl-alpha-L-arabinopyranosyl) and its 1->4-linked analogue to the 7-hydroxy or 16-hydroxy of steroidal sapogenins. Cytotoxic activities of the products were tested. Compounds 1 and 3 exhibited potent cytotoxicities against five types of human tumor cells, with minimum IC(50) of 2.0 and 75 nM, respectively. And due to its high activity and easy accessibility compound 1 could be a potential candidate for new anti-tumor agents. PMID- 21530252 TI - Telethonin-deficiency initially presenting as a congenital muscular dystrophy. AB - Congenital muscular dystrophies are defined by congenital or infantile onset of muscle weakness; while 12 culprit genes have been identified, many cases remain molecularly uncharacterized. On the other hand, mutations in the telethonin gene (TCAP) have been associated with a rare form of recessive limb girdle muscular dystrophy, usually presenting in the second decade. So far, three different mutations in telethonin have been reported in patients suffering from limb muscular dystrophy type 2G. We have identified a novel telethonin mutation in a child presenting with mildly delayed motor development and muscle weakness from infancy, clinically improving over the first decade, indicative of a CMD. Muscle biopsy showed a dystrophic process, with preserved laminin alpha2, collagen VI, and alpha-dystroglycan, but absent telethonin immunolabeling. Sequence analysis of TCAP showed a novel non-sense p.Gln58X (c.172C>T) homozygous mutation. Our observation indicates that telethonin deficiency may present in infancy with clinical features overlapping with mild forms of alpha-dystroglycanopathy. Therefore telethonin analysis should be performed in patients suffering from congenital muscular dystrophy of unknown cause. PMID- 21530253 TI - Evaluations of aesthetic outcomes of oncoplastic surgery by surgeons of different gender and specialty: a prospective controlled study. AB - This prospective trial was designed to assess aesthetic outcomes of oncoplastic surgery. Standardized photographs were taken of 45 breast cancer patients undergoing oncoplastic surgery, preoperatively and 6 and 12 months postoperatively (oncoplastic group), and of 45 patients treated by conservative surgery without breast reconstruction (control group). Photographs were assessed by senior male and female physicians, 2 breast surgeons and 2 plastic surgeons. Aesthetic outcomes were evaluated using patients' own assessments (rated 0 to 10) and scoring by panelists (using 0 to 10 global rating scales and a subscales system). Patients in both groups scored the aesthetic outcomes better than physicians did. Panelists and patients considered aesthetic outcomes of oncoplastic group better than control group outcomes. Patients and plastic surgeons attributed progressively higher grades to outcomes of oncoplastic group at 6 and 12 months postoperatively; breast surgeons did not. Overall, female physicians and breast surgeons scored better the aesthetic outcomes of both groups. PMID- 21530254 TI - How not to neglect the care of elderly breast cancer patients? AB - Breast cancer is one of the leading causes of cancer mortality in women. Its incidence increases with increasing age; those over 70 years constitute more than one-third of the current breast cancer population. Despite significant advances in the field of breast cancer treatment, elderly patients have seen neither a meaningful improvement in treatment strategies, nor a decline in breast cancer specific mortality. Studies have shown that a high percentage of elderly breast cancer patients do not receive standard treatment because of their age, co morbidities, and sometimes due to their personal choice. However, in routine clinical practice there is no comprehensive assessment in place, on which to base treatment decisions, to ensure that elderly patients receive clinically appropriate treatment. We have reviewed the current literature and discuss differences in treatment of breast cancer between young and older patients. We also discuss different ways to optimise the treatment of breast cancer in elderly patients and the need for further research in this area. PMID- 21530255 TI - Leiomyosarcoma of the breast: a case report and review of the literature about therapeutic management. AB - We experienced a leiomyosarcoma of the breast in an 18-year-old female. No specific treatment has been established. In order to clarify appropriate therapeutic management methods, the limited data available from our and previous case reports were assessed. A leiomyosarcoma of the breast must be excised with a negative margin. If the tumor size is large and an adequate margin, greater than 3-cm margin around the excised tumor, is not achieved due to anatomical constraints, radiotherapy may be indicated. PMID- 21530256 TI - Heterotypic gap junctions between two neurons in the drosophila brain are critical for memory. AB - Gap junctions play an important role in the regulation of neuronal metabolism and homeostasis by serving as connections that enable small molecules to pass between cells and synchronize activity between cells. Although recent studies have linked gap junctions to memory formation, it remains unclear how they contribute to this process. Gap junctions are hexameric hemichannels formed from the connexin and pannexin gene families in chordates and the innexin (inx) gene family in invertebrates. Here we show that two modulatory neurons, the anterior paired lateral (APL) neuron and the dorsal paired medial (DPM) neuron, form heterotypic gap junctions within the mushroom body (MB), a learning and memory center in the Drosophila brain. Using RNA interference-mediated knockdowns of inx7 and inx6 in the APL and DPM neurons, respectively, we found that flies showed normal olfactory associative learning and intact anesthesia-resistant memory (ARM) but failed to form anesthesia-sensitive memory (ASM). Our results reveal that the heterotypic gap junctions between the APL and DPM neurons are an essential part of the MB circuitry for memory formation, potentially constituting a recurrent neural network to stabilize ASM. PMID- 21530257 TI - Monkeys recall and reproduce simple shapes from memory. AB - If you draw from memory a picture of the front of your childhood home, you will have demonstrated recall. You could also recognize this house upon seeing it. Unlike recognition, recall demonstrates memory for things that are not present. Recall is necessary for planning and imagining, and it can increase the flexibility of navigation, social behavior, and other cognitive skills. Without recall, memory is more limited to recognition of the immediate environment. Amnesic patients are impaired on recall tests [1, 2], and recall performance often declines with aging [3]. Despite its importance, we know relatively little about nonhuman animals' ability to recall information; we lack suitable recall tests for them and depend instead on recognition tests to measure nonhuman memory. Here we report that rhesus monkeys can recall simple shapes from memory and reproduce them on a touchscreen. As in humans [4, 5], monkeys remembered less in recall than recognition tests, and their recall performance deteriorated more slowly. Transfer tests showed that monkeys used a flexible memory mechanism rather than memorizing specific actions for each shape. Observation of recall in Old World monkeys suggests that it has been adaptive for over 30 million years [6] and does not depend on language. PMID- 21530258 TI - A pair of inhibitory neurons are required to sustain labile memory in the Drosophila mushroom body. AB - Labile memory is thought to be held in the brain as persistent neural network activity. However, it is not known how biologically relevant memory circuits are organized and operate. Labile and persistent appetitive memory in Drosophila requires output after training from the alpha'beta' subset of mushroom body (MB) neurons and from a pair of modulatory dorsal paired medial (DPM) neurons. DPM neurons innervate the entire MB lobe region and appear to be pre- and postsynaptic to the MB, consistent with a recurrent network model. Here we identify a role after training for synaptic output from the GABAergic anterior paired lateral (APL) neurons. Blocking synaptic output from APL neurons after training disrupts labile memory but does not affect long-term memory. APL neurons contact DPM neurons most densely in the alpha'beta' lobes, although their processes are intertwined and contact throughout all of the lobes. Furthermore, APL contacts MB neurons in the alpha' lobe but makes little direct contact with those in the distal alpha lobe. We propose that APL neurons provide widespread inhibition to stabilize and maintain synaptic specificity of a labile memory trace in a recurrent DPM and MB alpha'beta' neuron circuit. PMID- 21530259 TI - The Y-encoded gene zfy2 acts to remove cells with unpaired chromosomes at the first meiotic metaphase in male mice. AB - During male but not female mammalian meiosis, there is efficient apoptotic elimination of cells with unpaired (univalent) chromosomes at the first meiotic metaphase (MI) [1]. Apoptotic elimination of MI spermatocytes is seen in response to the univalent X chromosome of XSxr(a)O male mice [2], in which the X chromosome carries Sxr(a) [3, 4], the Y-chromosome-derived sex-reversal factor that includes the testis determinant Sry. Sxr(b) is an Sxr(a)-derived variant in which a deletion has removed six Y short-arm genes and created a Zfy2/Zfy1 fusion gene spanning the deletion breakpoint [4, 5]. XSxr(b)O males have spermatogonial arrest that can be overcome by the re-addition of Eif2s3y from the deletion as a transgene; however, XSxr(b)OEif2s3y transgenic males do not show the expected elimination of MI spermatocytes in response to the univalent [6]. Here we show that these XSxr(b)OEif2s3y males have an impaired apoptotic response with completion of the first meiotic division, but there is no second meiotic division. We then show that Zfy2 (but not the closely related Zfy1) is sufficient to reinstate the apoptotic response to the X univalent. These findings provide further insight into the basis for the much lower transmission of chromosomal errors originating at the first meiotic division in men than in women [7]. PMID- 21530260 TI - Cofilin tunes the nucleotide state of actin filaments and severs at bare and decorated segment boundaries. AB - Actin-based motility demands the spatial and temporal coordination of numerous regulatory actin-binding proteins (ABPs), many of which bind with affinities that depend on the nucleotide state of actin filament. Cofilin, one of three ABPs that precisely choreograph actin assembly and organization into comet tails that drive motility in vitro, binds and stochastically severs aged ADP actin filament segments of de novo growing actin filaments. Deficiencies in methodologies to track in real time the nucleotide state of actin filaments, as well as cofilin severing, limit the molecular understanding of coupling between actin filament chemical and mechanical states and severing. We engineered a fluorescently labeled cofilin that retains actin filament binding and severing activities. Because cofilin binding depends strongly on the actin-bound nucleotide, direct visualization of fluorescent cofilin binding serves as a marker of the actin filament nucleotide state during assembly. Bound cofilin allosterically accelerates P(i) release from unoccupied filament subunits, which shortens the filament ATP/ADP-P(i) cap length by nearly an order of magnitude. Real-time visualization of filament severing indicates that fragmentation scales with and occurs preferentially at boundaries between bare and cofilin-decorated filament segments, thereby controlling the overall filament length, depending on cofilin binding density. PMID- 21530261 TI - QUASIMODO, a Novel GPI-anchored zona pellucida protein involved in light input to the Drosophila circadian clock. AB - BACKGROUND: Circadian clocks are synchronized to the solar day via visual and specialized photoreceptors. In Drosophila, CRYPTOCHROME (CRY) is a major photoreceptor that mediates resetting of the circadian clock via light-dependent degradation of the clock protein TIMELESS (TIM). However, in the absence of CRY, this TIM-mediated resetting still occurs in some pacemaker neurons, resulting in synchronized behavioral rhythms when flies are exposed to light-dark cycles. Even in the additional absence of visual photoreception, partial molecular and behavioral light synchronization persists. Therefore, other important clock related photoreceptive and synchronization mechanisms must exist. RESULTS: We identified a novel clock-controlled gene (quasimodo) that encodes a light responsive and membrane-anchored Zona Pellucida domain protein that supports light-dependent TIM degradation. Whereas wild-type flies become arrhythmic in constant light (LL), quasimodo mutants elicit rhythmic expression of clock proteins and behavior in LL. QUASIMODO (QSM) can function independently of CRY and is predominantly expressed within CRY-negative clock neurons. Interestingly, downregulation of qsm in the clock circuit restores LL clock protein rhythms in qsm-negative neurons, indicating that qsm-mediated light input is not entirely cell autonomous and can be accessed by the clock circuit. CONCLUSIONS: Our findings indicate that QSM constitutes part of a novel and CRY-independent light input to the circadian clock. Like CRY, this pathway targets the clock protein TIM. QSM's light-responsive character in conjunction with the predicted localization at the outer neuronal membrane suggests that its function is linked to a yet unidentified membrane-bound photoreceptor. PMID- 21530262 TI - Box jellyfish use terrestrial visual cues for navigation. AB - Box jellyfish have an impressive set of 24 eyes of four different types, including eyes structurally similar to those of vertebrates and cephalopods [1, 2]. However, the known visual responses are restricted to simple phototaxis, shadow responses, and object avoidance responses [3-8], and it has been a puzzle why they need such a complex set of eyes. Here we report that medusae of the box jellyfish Tripedalia cystophora are capable of visually guided navigation in mangrove swamps using terrestrial structures seen through the water surface. They detect the mangrove canopy by an eye type that is specialized to peer up through the water surface and that is suspended such that it is constantly looking straight up, irrespective of the orientation of the jellyfish. The visual information is used to navigate to the preferred habitat at the edge of mangrove lagoons. PMID- 21530263 TI - Proteasome function is required for biological timing throughout the twenty-four hour cycle. AB - Circadian clocks were, until recently, seen as a consequence of rhythmic transcription of clock components, directed by transcriptional/translational feedback loops (TTFLs). Oscillations of protein modification were then discovered in cyanobacteria. Canonical posttranslational signaling processes have known importance for clocks across taxa. More recently, evidence from the unicellular eukaryote Ostreococcus tauri revealed a transcription-independent, rhythmic protein modification shared in anucleate human cells. In this study, the Ostreococcus system reveals a central role for targeted protein degradation in the mechanism of circadian timing. The Ostreococcus clockwork contains a TTFL involving the morning-expressed CCA1 and evening-expressed TOC1 proteins. Cellular CCA1 and TOC1 protein content and degradation rates are analyzed qualitatively and quantitatively using luciferase reporter fusion proteins. CCA1 protein degradation rates, measured in high time resolution, feature a sharp clock-regulated peak under constant conditions. TOC1 degradation peaks in response to darkness. Targeted protein degradation, unlike transcription and translation, is shown to be essential to sustain TTFL rhythmicity throughout the circadian cycle. Although proteasomal degradation is not necessary for sustained posttranslational oscillations in transcriptionally inactive cells, TTFL and posttranslational oscillators are normally coupled, and proteasome function is crucial to sustain both. PMID- 21530264 TI - Subjective socioeconomic status predicts human ventral striatal responses to social status information. AB - The enormous influence of hierarchical rank on social interactions [1] suggests that neural mechanisms exist to process status-related information [2] and ascribe value to it. The ventral striatum is prominently implicated in processing value and salience, independent of hedonic properties [3, 4], and a functional magnetic resonance imaging (fMRI) study of social status perception in humans demonstrated that viewing higher-ranked compared to lower-ranked individuals evokes a ventral striatal response [5], indicative of a greater assignment of value/salience to higher status. Consistent with this interpretation, nonhuman primates value information associated with higher-ranked conspecifics more than lower-ranked, as illustrated using a choice paradigm in which monkeys preferentially take the opportunity to view high-status monkeys [6]. Interestingly, this status-related value assignment in nonhuman primates is influenced by one's own hierarchical rank: high-status monkeys preferentially attend to conspecifics of high status, whereas low-status monkeys will also attend to other low-status monkeys [7]. Complementary to these findings, using fMRI and a social status judgment task in humans, we suggest a neurobiological mechanism by which one's own relative hierarchical rank influences the value attributed to particular social status information by demonstrating that one's subjective socioeconomic status differentially influences ventral striatal activity during processing of status-related information. PMID- 21530265 TI - Novel insights into epithelial polarity proteins in Drosophila. AB - Apical-basal polarity is a basic organizing principle of epithelial cells. Consequently, defects in polarity are associated with numerous human pathologies, including many forms of cancer. Recent work in Drosophila has identified novel roles for, or has greatly enhanced our understanding of, functional modules within the epithelial polarity network. A series of recent papers have highlighted the key function of the scaffolding protein Bazooka/Par3 as an early polarity landmark, and its crucial role in dynamic segregation of the apical membrane from the adherens junction. Moreover, novel polarity modules have recently been discovered; the Yurt/Coracle group supports the basolateral membrane during a defined time window of development, while a second module, including the kinases LKB1 and AMP-activated protein kinase, is required for polarity when epithelial cells experience metabolic stress. These new findings emphasize unforeseen complexities in the regulation of epithelial polarity, and raise new questions about the mechanisms of epithelial tissue organization and function. PMID- 21530266 TI - Pause locally, splice globally. AB - Most eukaryotic protein-coding transcripts contain introns, which vary in number and position along the transcript body. Intron removal through pre-mRNA splicing is tightly linked to transcription by RNA polymerase II as it translocates along each gene. Here, we review recent evidence that transcription and splicing are functionally coupled. We focus on how RNA polymerase II elongation rates impact splicing through local regulation and transcriptional pausing within genes. Emerging concepts of how splicing-related changes in elongation might be achieved are highlighted. We place the interplay between transcription and splicing in the context of chromatin where nucleosome positioning influences elongation, and histone modifications participate directly in the recruitment of splicing regulators to nascent transcripts. PMID- 21530267 TI - Multi-segmental postural coordination in professional ballet dancers. AB - Ballet dancers have heightened balance skills, but previous studies that compared dancers to non-dancers have not quantified patterns of multi-joint postural coordination. This study utilized a visual tracking task that required professional ballet dancers and untrained control participants to sway with the fore-aft motion of a target while standing on one leg, at target frequencies of 0.2 and 0.6Hz. The mean and variability of relative phase between the ankle and hip, and measures from cross-recurrence quantification analysis (i.e., percent cross-recurrence, percent cross-determinism, and cross-maxline), indexed the coordination patterns and their stability. Dancers exhibited less variable ankle hip coordination and a less deterministic ankle-hip coupling, compared to controls. The results indicate that ballet dancers have increased coordination stability, potentially achieved through enhanced neuromuscular control and/or perceptual sensitivity, and indicate proficiency at optimizing the constraints that enable dancers to perform complex balance tasks. PMID- 21530268 TI - Postural recovery following voluntary arm movement is impaired in people with chronic low back pain. AB - STUDY DESIGN: Recovery of postural equilibrium following bilateral voluntary arm movement was evaluated using a case-control study, with 13 subjects with chronic LBP and 13 age- and gendermatched control subjects. OBJECTIVES: To evaluate control of the centre-of-pressure (COP), as a marker of the quality of control of postural equilibrium associated with voluntary arm movements, in people with and without LBP. Summary of background data. When healthy individuals perform rapid voluntary arm movements, small spinal movements (preparatory movement) opposite to the direction of the reactive moments precede voluntary arm movements. Evaluation of trunk movement in people with LBP suggests that this strategy is used infrequently in this population and is associated with an increased spinal displacement following arm flexion. As the preparatory spinal movement was also thought to be an anticipatory mechanism limiting postural perturbation caused by arm movements, we hypothesized that LBP subjects would have compromised control of postural equilibrium following arm flexion. METHODS: Subjects performed bilateral voluntary rapid arm flexion while standing on support surface of different dimensions with eyes opened or closed. RESULTS: Results indicated that people with LBP consistently took longer to recover postural equilibrium and made more postural adjustments in different stance conditions. However, there was no increase in the excursion of the COP during the recovery period in the LBP group. CONCLUSION: These data suggest that while COP is tightly controlled during postural recovery, the finetuning of the control of postural equilibrium is compromised in people with LBP. Postural control dysfunctions should be considered in the management of chronic low back pain. PMID- 21530269 TI - The effect of choice reaction task on impact of single-leg landing. AB - This study aimed to investigate attentional demand during single-leg landing after a jump. The experiment was set up as dual-task test. Twelve healthy male participants were instructed to make a two-leg jump with right-leg landing as softly as possible. The flight time of the jump was set to 300ms through sufficient practice. As a cognitive task, the participants were asked to push the right or left custom-made button as soon as a go-signal was presented. The timing when the go-signal presented varied from 0 to 300ms from the take-off. Catch trials in which the go-signal was not presented were randomly inserted. The results showed that the maximum vertical ground reaction force after touchdown was greater under the dual-task condition than in the single-task condition. Increase in the maximum vertical ground reaction force was consistent regardless of the timing of presenting the go-signal, and the same effect was observed in the catch trials. These results indicate that the effect of dual tasking was caused by attentional allocation to the choice reaction time task. Athletes may be exposed a large ground reaction forces during landing while performing cognitive tasks. PMID- 21530271 TI - Osteoporosis affects component positioning in computer navigation-assisted total knee arthroplasty. AB - Although computer-assisted navigation in total knee arthroplasty (TKA) has many advantages, undetected tracker pin movement can result in poor lower limb alignment and component position. Osteoporosis may be an underlying cause of tracker pin movement. The present prospective case-control study compared 6-month radiographic outcomes in 44 osteoporotic and 56 non-osteoporotic knees undergoing navigation TKAs. Osteoporotic knees were defined as those having a T-score of 2.5 or less either in the femoral neck or lumbar spine or both. At postoperative 6 months' follow-up, the average coronal tibial component position was greater valgus in osteoporotic group than in nonosteoporotic group (non osteoporotic=varus 0.7 degrees +/-1.8 degrees ; osteoporotic=valgus 1.2 degrees +/-3.4 degrees ; p=0.041). Multiple linear regression analysis showed that being in the osteoporotic group was a predictor of tibial coronal component position (beta=0.321, p=0.039). In addition, preoperative lumbar spine bone mineral density was found to be a predictor of coronal and sagittal alignments of the tibial component (beta=0.406, p=0.015, beta=-0.463, p=0.007). The present study found that osteoporosis affected tibial component position in computer-assisted navigation TKA. Clinicians should be particularly aware of the possibility of undetectable tracker pin movement during navigation TKA in osteoporotic knees. PMID- 21530270 TI - Multifaceted roles for lipids in viral infection. AB - Viruses have evolved complex and dynamic interactions with their host cell. In recent years we have gained insight into the expanding roles for host lipids in the virus life cycle. In particular, viruses target lipid signaling, synthesis, and metabolism to remodel their host cells into an optimal environment for their replication. This review highlights examples from different viruses that illustrate the importance of these diverse virus-lipid interactions. PMID- 21530272 TI - Preparation of allosamidin and demethylallosamidin photoaffinity probes and analysis of allosamidin-binding proteins in asthmatic mice. AB - Allosamidins, metabolites of Streptomyces with strong inhibitory activities toward family 18 chitinases, show a variety of biological activities in various organisms. We prepared photoaffinity and biotinylated probes of allosamidin and demethylallosamidin, the N-demethyl derivative that shows much stronger anti asthmatic activity than allosamidin. Mild acid hydrolysis of allosamidins afforded mono-amine derivatives, which were amidated to prepare probes with a photoactivatable aryl azide and/or biotin moieties. The derivatives with an N acyl group at C-2 of the D-allosamine residue at the non-reducing end of allosamidins inhibited Trichoderma chitinase as strongly as the original compounds. Since the target of allosamidins in asthma is unclear, photoaffinity probes were used to analyze allosamidin-binding proteins in bronchoalveolar lavage (BAL) fluid in IL-13-induced asthmatic mice. Ym1, a chitinase-like protein, was identified as the main allosamidin-binding protein among proteins whose expression was upregulated by IL-13 in BAL fluid. Binding of allosamidins with Ym1 was confirmed by the experiments with photoaffinity probes and recombinant Ym1. PMID- 21530273 TI - Synthesis and antifungal activities of natural and synthetic biflavonoids. AB - The synthesis of some natural and synthetic biflavonoids was performed in good overall yields starting from readily available materials via high yielding aldol and Ullmann condensations. Some of these compounds, especially bichalcones, display an interesting activity against fungi, higher than that of the corresponding monomers. PMID- 21530274 TI - New 3-, 8-disubstituted pyrazolo[5,1-c][1,2,4]benzotriazines useful for studying the interaction with the HBp-3 area (hydrogen bond point area) in the benzodiazepine site on the gamma-aminobutyric acid type A (GABAA) receptor. AB - The pharmacophoric model using ADLR procedure, based on pyrazolo[5,1 c][1,2,4]benzotriazine system, studied in our laboratory, allowed us to identify the essential interaction points (HBp-1, HBp-2, and Lp-1) and the important areas for affinity modulation (HBp-3 and Lp-2) for binding recognition at benzodiazepine (Bzs) site of GABA(A) receptors (GABA(A)-Rs). In this work ADLR method is used to rationalize the affinity data of 23 new compounds and to improve the knowledge on HBp-3 area, hydrogen bond area. Among these new compounds emerge the pyrrolo derivatives (18, 25, 28, 34, and 37) for their good affinity value (14.9>K(i)(nM)>63.0). In the orientations proposed by ADLR, the NH moiety of the pyrrole ring, independently of the position in the pyrazolobenzotriazine core, fits in HBp-3 area and points out the acceptor feature of this hydrogen bond area, already known as donor area. Unexpectedly, the oxygen atom of the furane ring does not form efficient hydrogen bond with the same area, probably for an imperfect distance. The size of substituent at position 8 is important but not necessary for the receptor recognition, in fact the interdependence between the features of the 3- and 8-substituent's is again verified, (i.e., compound 20 vs 32). PMID- 21530275 TI - Structure-based design, synthesis, and nonalcoholic steatohepatitis (NASH) preventive effect of phenylpropanoic acid peroxisome proliferator-activated receptor (PPAR) alpha-selective agonists. AB - A series of alpha-ethylphenylpropanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) alpha-selective agonists, based on our PPARalpha/delta dual agonist 3 as a lead compound. Structure-activity relationship studies clearly indicated that the steric bulkiness and position of the distal hydrophobic tail part are critical for PPARalpha agonistic activity and PPARalpha selectivity, as had been predicted from a molecular-modeling study. A representative compound blocked the progression of nonalcoholic steatohepatitis (NASH) in an animal model. PMID- 21530276 TI - Synthesis and biological evaluation of unique stereodimers of sinomenine analogues as potential inhibitors of NO production. AB - Inhibition of the excessive NO production has been recognized as a potential means for the treatment of rheumatoid arthritis (RA). In order to discover more potent inhibitors and explore the preliminary structure activity relationship, a series of unique stereodimers of sinomenine analogues were designed and synthesized. Their inhibitory activity on NO production and cytotoxicity were evaluated using LPS-activated murine macrophages RAW264.7 assay and MTT method, respectively. Among these compounds, 1a, 2, 2a, 2b, and 4 showed potent inhibitory activity on NO production without obvious cytotoxicity. Furthermore, 2, 2a, and 2b significantly suppressed mRNA expression of iNOS. Interestingly, (S)-dimers displayed a better bioactivity than (R)-dimers. These compounds may sever as lead candidates in the development of novel therapeutic drugs for RA treatment. PMID- 21530277 TI - Molecular docking studies and in vitro screening of new dihydropyridine derivatives as human MRP1 inhibitors. AB - The overexpression of multidrug resistance protein 1 (MRP1) by tumor cells results in multidrug resistance (MDR) to structurally unrelated anticancer drugs. Circumvention of MDR by combination of chemosensitizers with antitumor compounds is a new field of investigation in cancer chemotherapy. Much effort has been put in recently to identify the modulators/inhibitors of MRP1 to overcome the MDR. 1,4-Dihydropyridine (DHP) derivatives are indicated to be a new class of MRP1 inhibitors in cancer treatment. Molecular docking studies were carried out on 48 newly synthesized DHP derivatives with the crystal structure of MRP1 to gain some structural insights on the binding mode and possible interactions with the active site of MRP1 (NBD1). The 10 top-ranked molecules were selectively evaluated, experimentally for their MRP1 inhibitory effect using the insect cell membrane MRP1 ATPase assay. The inhibitory capacity (IC(50) concentrations) of the test compounds was compared with the reported IC(50)- or the K(i)-concentrations for benzbromarone, a standard MRP1 inhibitor. Amongst the compounds tested, compounds IA(1) and IIA(5) were found to exhibit a potent MRP1 inhibitory action with IC(50) values of 20+/-4 and 14+/-2 MUM (mean+/-SD), respectively as compared to benzbromarone (IC(50)=4 MUM). The compound IIA(5), in particular was found to be more potent than IA(1) in accordance with the docking results. These new DHP derivatives possess promising characteristics for their development as MDR reversal agents. PMID- 21530278 TI - Design, synthesis and inhibition activity of a novel cyclic enediyne amino acid conjugates against MPtpA. AB - In course of studies towards the discovery of selective inhibitors of MPtpA, a novel cyclic endiyne malonamic acid has been designed and synthesized. The synthesis involves a crucial intramolecular Knoevenagel reaction. The compound displayed a reversible non-competitive inhibition against MPtpA with inhibition constant K(i) of 22.5 MUM. The enediyne acts as a recognition framework in inducing the inhibition and not as a reactive functional moiety. This was confirmed by comparing the inhibiting activity with that of the corresponding saturated cyclic non-enediyne analogue. PMID- 21530279 TI - A new structural model of bivalve ligament from Solen grandis. AB - It is widely accepted that the structure of bivalve ligament contains two layers: outer organic lamellar and inner aragonite fibrous layer. However, by using scanning electron microscopy (SEM), X-ray diffraction (XRD), and infrared spectroscopy (FTIR), we found an additional protein fibrous layer in the Solen grandis ligament. The ligament consists of three layers: an outer layer (OL), middle layer (ML), and inner layer (IL). OL consists of lamellar protein, oriented normal to dorsal edge. ML has unique spring-like protein fibers (ca. 120 nm in diameter) structure, stretching continuously from the left to right valve. Interestingly, IL comprises of aragonite fibers (ca. 100 nm in diameter) oriented posteriorly and inclined at an angle about 26 degrees to dorsal edge at dorsal part; then they turn gradually to ventral part, showing striking zigzag structure vertical to ventral surface (VS). The ligament presents a new three-layered structural model different from previous reports; it may inspire not only in materials synthesis and mechanical design, but also in bivalve classification and evolution. PMID- 21530280 TI - Automatic white blood cell segmentation using stepwise merging rules and gradient vector flow snake. AB - This study aims at proposing a new stained WBC (white blood cell) image segmentation method using stepwise merging rules based on mean-shift clustering and boundary removal rules with a GVF (gradient vector flow) snake. This paper proposes two different schemes for segmenting the nuclei and cytoplasm of WBCs, respectively. For nuclei segmentation, a probability map is created using a probability density function estimated from samples of WBC's nuclei and sub images cropped to include a nucleus based on the fact that nuclei have a salient color against the background and red blood cells. Mean-shift clustering is then performed for region segmentation, and a stepwise merging scheme applied to merge particle clusters with a nucleus. Meanwhile, for cytoplasm segmentation, morphological opening is applied to a green image to boost the intensity of the granules and canny edges detected within the sub-image. The boundary edges and noise edges are then removed using removal rules, while a GVF snake is forced to deform to the cytoplasm boundary edges. When evaluated using five different types of stained WBC, the proposed algorithm produced accurate segmentation results for most WBC types. PMID- 21530281 TI - Effective dose evaluation for BNCT treatment in the epithermal neutron beam at THOR. AB - This paper aims to evaluate the effective dose as well as equivalent doses of several organs of an adult hermaphrodite mathematical phantom according to the definition of ICRP Publication 60 for BNCT treatments of brain tumors in the epithermal neutron beam at THOR. The MCNP5 Monte Carlo code was used for the calculation of the average absorbed dose of each organ. The effective doses for a typical brain tumor treatment with a tumor treatment dose of 20 Gy-eq were evaluated to be 0.59 and 0.35 Sv for the LLAT and TOP irradiation geometries, respectively. In addition to the stochastic effect, it was found that it is also likely to produce deterministic effects, such as cataracts and depression of haematopoiesis. PMID- 21530282 TI - On the geochemistry of the Kyra eruption sequence of Nisyros volcano on Nisyros and Tilos, Greece. AB - The Kyra sequence is a volcanic eruption sequence originating from the eastern flank of Nisyros volcano, Greece. Its eruptions products can be found not only on Nisyros itself but also on the nearby non-volcanic island of Tilos. In an extensive sampling campaign, outcrops of the Kyra eruption products on Nisyros were sampled and corresponding samples on Tilos were taken. The clear stratigraphical relationship between the different units within in the individual outcrops, combined with the chemical information gained by the application of instrumental neutron activation analysis (INAA) to the samples, made a detailed chemo-stratigraphy of the complete eruption sequence possible. It can be shown that the sequence is separated into eight distinguishable eruptions. Furthermore, no eruption products of the caldera-forming eruptions from Nisyros (Lower- and Upper Caldera Pumice) or from Santorin were found on Tilos. PMID- 21530283 TI - In vitro studies of cellular response to DNA damage induced by boron neutron capture therapy. AB - The aim of these studies was to evaluate the mechanisms of cellular response to DNA damage induced by BNCT. Thyroid carcinoma cells were incubated with (10)BPA or (10)BOPP and irradiated with thermal neutrons. The surviving fraction, the cell cycle distribution and the expression of p53 and Ku70 were analyzed. Different cellular responses were observed for each irradiated group. The decrease of Ku70 in the neutrons +BOPP group could play a role in the increase of sensitization to radiation. PMID- 21530284 TI - Coincidence summing between X-rays and conversion electrons in 137Cs. AB - The probability of coincidence summing between the conversion electrons and the X rays emitted in the decay of the first excited state of (137)Ba was measured in close geometry. It was shown that the probability of the registration of electrons decreases exponentially with the amount of material between the source and the detector. The probability of the registration of a conversion electron emitted in the solid angle subtended by the detector crystal amounts, in the absence of any material between the source and detector, to about 0.6. PMID- 21530285 TI - Cytosolic calcium rises and related events in ergosterol-treated Nicotiana cells. AB - The typical fungal membrane component ergosterol was previously shown to trigger defence responses and protect plants against pathogens. Most of the elicitors mobilize the second messenger calcium, to trigger plant defences. We checked the involvement of calcium in response to ergosterol using Nicotiana plumbaginifolia and Nicotiana tabacum cv Xanthi cells expressing apoaequorin in the cytosol. First, it was verified if ergosterol was efficient in these cells inducing modifications of proton fluxes and increased expression of defence-related genes. Then, it was shown that ergosterol induced a rapid and transient biphasic increase of free [Ca2+](cyt) which intensity depends on ergosterol concentration in the range 0.002-10 MUM. Among sterols, this calcium mobilization was specific for ergosterol and, ergosterol-induced pH and [Ca2+](cyt) changes were specifically desensitized after two subsequent applications of ergosterol. Specific modulators allowed elucidating some events in the signalling pathway triggered by ergosterol. The action of BAPTA, LaCl3, nifedipine, verapamil, neomycin, U73122 and ruthenium red suggested that the first phase was linked to calcium influx from external medium which subsequently triggered the second phase linked to calcium release from internal stores. The calcium influx and the [Ca2+](cyt) increase depended on upstream protein phosphorylation. The extracellular alkalinization and ROS production depended on calcium influx but, the ergosterol-induced MAPK activation was calcium-independent. ROS were not involved in cytosolic calcium rise as described in other models, indicating that ROS do not systematically participate in the amplification of calcium signalling. Interestingly, ergosterol-induced ROS production is not linked to cell death and ergosterol does not induce any calcium elevation in the nucleus. PMID- 21530286 TI - Antisense-mediated depletion of tomato chloroplast glutathione reductase enhances susceptibility to chilling stress. AB - A tomato (Lycopersicon esculentum Mill.) chloroplast glutathione reductase gene (LeGR) was isolated and antisense transgenic tomato lines were obtained. Under chilling stress, transgenic plants accumulated more H(2)O(2), leaked more electrolyte and showed lower net photosynthetic rate (Pn), maximal photochemical efficiency of PSII (Fv/Fm) and oxidizable P700 compared with wild-type (WT) plants. Transgenic seedlings were more suppressed in fresh-weight growth and lost more cotyledon chlorophyll. The decrease in the activity of ascorbate peroxidase (APX) was implied to be potentially relevant to the greater accumulation of H(2)O(2) in transgenic plants. Chilling treatment induced more decrease in the level of reducted glutathione (GSH) and redox ratio of glutathione in transgenic plants than in WT plants, but aroused more increase in GSSG in transgenic plants than in WT plants. Total glutathione displayed no change. Besides, chilling stress resulted in greater decreases in the level of reducted ascorbate (AsA), total ascorbate and redox ratio of ascorbate in transgenic plants than in WT plants, but led to equivalent degree of dehydroascorbate (DHA) increase in WT and transgenic plants. These assessments of glutathione-ascorbate cycle revealed that the decrease of glutathione reductase activity in transgenic plants affected glutathione regeneration, and consequently affected ascorbate regeneration and total ascorbate content. This resulted in a greater accumulation of H(2)O(2) and an enhanced sensitivity to chilling stress in transgenic plants. Moreover, a putative concept model of ecophysiological reaction was discussed. PMID- 21530287 TI - Molecular characterization and expression analysis of cDNAs encoding four Rab and two Arf GTPases in the latex of Hevea brasiliensis. AB - In plants, Rab and Arf GTPases are key regulators of vesicle trafficking. To investigate whether these small GTPases (SG) play a role in the regulation of the regeneration of latex (the cytoplasm of the rubber-producing laticifer cell) in Hevea brasiliensis (Hevea hereafter), full-length cDNAs that encode four HbRab and two HbArf GTPases were cloned. The four HbRab proteins showed specific GTP binding activity when expressed in Escherichia coli. Transcript expression of the six SG genes was investigated by real-time RT-PCR. All genes revealed to be expressed in each of the six Hevea tissues examined, but the expression patterns were different. Four genes, HbArf1, HbRab2, HbRab3 and HbRab4, displayed a preferential expression in latex. The expression of all genes was upregulated by the act of latex exploitation (tapping), and HbRab1 had the highest level of upregulation. Wounding markedly upregulated the expression of two SG genes (HbRab1 and HbArf2), and exogenous methyl jasmonate upregulated all six SG genes. Wounding might upregulate the expression of HbRab1 and HbArf2 through a jasmonic acid-mediated signaling pathway. None of the genes were markedly upregulated by Ethrel (an ethylene releaser and latex stimulator); instead, HbArf2 and HbRab4 were downregulated significantly after a 24 h treatment with Ethrel. This paper gives the first description of Rab and Arf GTPases in Hevea and provides clues for their involvement, HbRab1 in particular, in latex regeneration. PMID- 21530288 TI - Changes in 1-aminocyclopropane-1-carboxlate (ACC) oxidase expression and enzyme activity in response to excess manganese in white clover (Trifolium repens L.). AB - To examine the effect on Mn treatment on the ACO gene family of white clover [Trifolium repens (L.) cv. Grasslands Challenge], rooted stolon cuttings were maintained in modified Hoaglands medium, at pH 5.4, containing either 5.2 MUM Mn or 100 MUM Mn over a 9-day time course. A significant uptake of Mn was observed in leaf tissue of plants grown in the 100 MUM Mn treatment after 24 h and the content increased in these plants to reach 334 mg/kg DW at the conclusion of the time course. The growth of plants, measured as the petiole extension rate (PER), was significantly less in the 100 MUM Mn treatment by day 9, while significantly less accumulation of leaf biomass was observed by day 7. The activity of a cell wall-associated H(2)O(2)-generating NADH peroxidase was shown to be higher in the 100 MUM Mn treatment after day 5 of the time course while no significant difference in a H(2)O(2)-consuming guaiacol peroxidase activity was observed between the two Mn treatments. The expression of two leaf-associated ACC oxidase (ACO) genes, TR-ACO2 and TR-ACO3 was examined over the 9-day course but no difference between the two treatments was observed. In contrast, TR-ACO2 enzyme activity was measured and shown to decrease in the 100 MUM Mn treatment after day 5 of the time course, with a concomitant decrease in TR-ACO2 accumulation, as determined by western analysis. Using 2DE and western analysis, evidence for post translational modification of TR-ACO2 was observed. PMID- 21530289 TI - Enzyme characterisation, isolation and cDNA cloning of polyphenol oxidase in the hearts of palm of three commercially important species. AB - Heart of palm (palmito) is the edible part of the apical meristem of palms and is considered a gourmet vegetable. Palmitos from the palms Euterpe edulis (Jucara) and Euterpe oleracea (Acai) oxidise after harvesting, whereas almost no oxidation is observed in palmitos from Bactris gasipaes (Pupunha). Previous investigations showed that oxidation in Jucara and Acai was mainly attributable to polyphenol oxidase (PPO; EC 1.14.18.1) activity. In this study, we partially purified PPOs from these three palmitos and analysed them for SDS activation, substrate specificity, inhibition by specific inhibitors, thermal stability, optimum pH and temperature conditions, Km and Ki. In addition, the total phenolic content and chlorogenic acid content were determined. Two partial cDNA sequences were isolated and sequenced from Acai (EoPPO1) and Jucara (EePPO1). Semi-quantitative RT-PCR expression assays showed that Acai and Jucara PPOs were strongly expressed in palmitos and weakly expressed in leaves. No amplification was observed for Pupunha samples. The lack of oxidation in the palmito Pupunha might be explained by the low PPO expression, low enzyme activity or the phenolic profile, particularly the low content of chlorogenic acid. PMID- 21530290 TI - Abscisic acid enhances resistance to Alternaria solani in tomato seedlings. AB - The plant hormone abscisic acid (ABA) is an important regulator in many aspects of plant growth and development, as well as stress resistance. Here, we investigated the effects of exogenous ABA application on the interaction between tomato (Solanum lycopersicon L.) and Alternaria solani (early blight). Foliar spraying of 7.58 MUM ABA was effective in reducing disease severity in tomato plants. Previously, increased activities of phenylalanine ammonia-lyase (PAL), polyphenol oxidase (PPO) and peroxidase (POD) were observed in exogenous ABA treated tomato leaves. Moreover, these enzyme activities were maintained at higher levels in ABA-pretreated and A. solani challenged tomato plants. Tomato defense genes, such as PR1, beta-1, 3-glucanase (GLU), PPO, POD, and superoxide dismutase (SOD), were rapidly and significantly up-regulated by exogenous ABA treatment. Furthermore, a subsequent challenge of ABA-pretreated plants with the pathogen A. solani resulted in higher expression of defense genes, compared to water-treated or A. solani inoculated plants. Therefore, our results suggest that exogenous ABA could enhance disease resistance against A. solani infection in tomato through the activation of defense genes and via the enhancement of defense related enzymatic activities. PMID- 21530291 TI - Tissue-engineered vascular graft remodeling in a growing lamb model: expression of matrix metalloproteinases. AB - OBJECTIVES: We have previously demonstrated the functionality and growth of autologous, living, tissue-engineered vascular grafts (TEVGs) in long-term animal studies. These grafts showed substantial in vivo tissue remodeling and approximation to native arterial wall characteristics. Based on this, in vitro and in vivo matrix metalloproteinase (MMP) activity of TEVGs is investigated as a key marker of matrix remodeling. METHODS: TEVGs fabricated from biodegradable scaffolds (polyglycolic-acid/poly-4-hydroxybutyrate, PGA/P4HB) seeded with autologous vascular cells were cultured in static and dynamic in vitro conditions. Thereafter, TEVGs were implanted as pulmonary artery replacements in lambs and followed up for 2 years. Gelatin gel zymography to detect MMP-2 and -9 was performed and collagen content quantified (n=5). Latent (pro) and active MMP 2 and -9 were detected. RESULTS: Comparable levels of active MMP-9 and pro-MMP-2 were detected in static and dynamic culture. Higher levels of active MMP-2 were detected in dynamic cultures. Expression of MMP-2 and -9 was minimal in native grafts but was increased in implanted TEVG. Pro-MMP-9 was expressed 20 weeks post implantation and persisted up to 80 weeks post implantation. Collagen content in vitro was increased in dynamically conditioned TEVG as compared with static constructs and was increased in vivo compared with the corresponding native pulmonary artery. CONCLUSIONS: MMPs are up-regulated in vitro by dynamic culture conditions and could contribute to increased matrix remodeling, native analogous tissue formation and functional growth of TEVGs in vivo. Monitoring of MMP activity, for example, by molecular imaging techniques, may enable the non invasive assessment of functional tissue quality in future clinical tissue engineering applications. PMID- 21530292 TI - Interrupted nitinol U-Clips versus standard running suture for the central arterial T-graft anastomosis: a prospective randomized study. AB - OBJECTIVES: Studies carried out to date suggest that the interrupted suture technique using U-Clips for anastomoses in coronary surgery may be superior to the standard running polypropylene suture. The purpose of this study was to compare safety and effectiveness of a central T-graft anastomosis constructed with the left internal thoracic artery (LITA) in situ (to the left anterior descending (LAD)) in which the free right internal thoracic artery (to the circumflex branch of the right coronary artery (RCX)) was implanted (RITA-to LITA) using either self-closing nitinol U-Clips or simple continuous suture. We hypothesized that internal thoracic arteries could adapt their diameter to the blood flow. METHODS: Thirty patients underwent total arterial revascularization using a T-graft constructed with free LITA in situ to LAD in which the free RITA to the circumflex artery was implanted (central T-graft anastomosis). In all cases, free RITA was used as a sequential graft with two peripheral anastomoses. Patients were randomly assigned to two groups: in group A (n=15), central T-graft anastomosis was performed using a standard 8/0 polypropylene running suture. In group B (n=15), central T-graft anastomosis was performed using U-Clips. Intra operative transit time flow measurements were recorded. Patency control was performed in 30 patients 2 weeks and 6 months postoperatively, using 64-slice computed tomography (CT) angiography. The diameter of the LITA was measured proximal and distal and the diameter of the RITA distal to the central T-graft anastomosis. RESULTS: Perioperative results were similar in the two groups (P=ns). Intra-operative transit time flow measurement showed patent grafts in all patients. There were no hospital deaths. Two weeks postoperatively, all grafts were patent. At 6-month follow-up, one RITA and one LITA (both in group B) were closed distal to the central T-graft anastomosis. There was no death and no re intervention during follow-up. Statistical analysis showed no significant changes in graft diameters after 2 weeks and 6 months in both groups. CONCLUSIONS: The U Clip anastomosis technique is in our experience safe but not superior to the standard running suture using polypropylene material. Remodeling of the ITA grafts close to the central T-graft anastomosis was neither observed for the standard running suture nor for the U-Clip anastomoses. PMID- 21530293 TI - Long-term patency of the stapled bovine pericardial conduit for replacement of the superior vena cava. AB - OBJECTIVE: Artificial prosthesis of the superior vena cava (SVC) may occlude with time. For this reason, we proposed in 2003 the use of a biological material (bovine pericardium) and devised an original technique to construct the prosthetic conduit. We hereby report the long-term results in 15 patients. METHODS: The SVC prosthetic conduit is realized by wrapping a bovine pericardial leaflet around a 5 or 10 cm(3) syringe and stapling it on the side by a 60-80 linear stapler. This procedure is carried out intra-operatively after the size of the patient's SVC has been ascertained; the conduit is then cut to the appropriate length. We have employed this technique in 15 patients with lung (eight) or mediastinal (seven) tumors; after a minimum follow-up of 1 year, all patients underwent computed tomographic-volume rendering (CT-VR) studies of the SVC. RESULTS: Technically, the stapled pericardial conduit has several advantages: (1) it is simple and expeditious; (2) it allows an even and regular suture line, which cannot be achieved by hand suturing; (3)'one size fits all': with one single pericardial leaflet, conduits of all sizes can be realized; this is important for an operation which is performed only few times per year; (4) patency is granted by the intrinsic rigidity of the pericardium and staple line, without the need for any reinforcement; (5) different calibers at the two extremities can be obtained by simply placing the stapler obliquely; and (6) the staple line is excellent for the orientation of the conduit while suturing. In our patients, SVC clamping time ranged between 18 and 50 min (mean 29 min); one patient needed cardiopulmonary bypass. Intra-operative anticoagulation (1.500 2.500 units of heparin) was continued postoperatively subcutaneously for 7 days and then shifted to oral anticoagulation for 6 months. One patient died postoperatively of heart failure (mortality 6%). One to 5 years after surgery, CT VR showed full patency of the pericardial conduit, no clots or thrombus formation, and absence of collateral venous circulation in all 14 patients. One- and 5-year survival was 93% and 73%, respectively (Kaplan-Meier). CONCLUSIONS: The stapled bovine pericardial conduit is a simple, expeditious, and economic solution to SVC replacement, and offers reliable long-term patency without permanent anticoagulation. PMID- 21530294 TI - Editorial comment: Does the time of onset of postoperative stroke determine outcome? PMID- 21530295 TI - Fluid and electrolyte balance after major thoracic surgery by bioimpedance and endocrine evaluation. AB - OBJECTIVE: Weight gain with oedema development is a complication of major surgical procedures with an incidence as high as 40%. Fluid retention is not always clinically evident and it is reported despite fluid-restriction regime. The causes are several and not totally clear. We performed a prospective study to assess the amount of fluid accumulation and redistribution observed after major thoracic surgery. METHODS: In 49 patients submitted to lobectomy with systematic lymph node dissection for lung cancer, we measured preoperatively and on the postoperative days 1, 2, 4 and 7, body weight, fluid balance, brain natriuretic peptide (BNP) and bioimpedance analysis (BIA)-derived parameters resistance (R) and reactance (X(c)). RESULTS: The postoperative course was characterised by significant changes. Mean increase in body weight was 2.7 kg ((1.9-3.4); p<0.001) on postoperative day 2. Most of the patients had a negative basal fluid balance ( 244 ml (-520 to -50)), whereas, on postoperative day 2, we observed a positive and significant change (+968 ml (646-1456), p<0.001)). Total body R and X(c) fell on the first day (p<0.001), anticipating the changes in weight and fluid balance. BNP increased on day 1, immediately after surgery, and remained significantly above basal values for the entire observation period (p<0.001), in the absence of clinical signs of heart failure. CONCLUSION: The three methods used consistently showed a significant fluid retention over the course of the study. BIA was an easy, reproducible and non-invasive method for the estimation and early detection of fluid retention. Increase in BNP may be related to the systemic reaction to stress and to the decreased pulmonary vascular bed. We found no correlation between fluid retention and length of anaesthesia, sex, age, blood loss and body mass index. The clinical and prognostic implication of weight gain may be relevant to patient's health. PMID- 21530297 TI - Current evidence on transcervical mediastinal lymph nodes dissection. AB - In the last decade, we witnessed the development of two new, fascinating techniques of mediastinal exploration: the video-assisted mediastinoscopic lymphadenectomy (VAMLA) and the transcervical extended mediastinal lymphadenectomy (TEMLA). During this time, several articles were published, providing a substantial body of evidence regarding different aspects of these techniques. Based on this evidence, we discuss the operative technique, its applications and results as well as questions to be answered and possible future development. The aim of this review is to provide the readers who have no personal experience with these techniques, with the key information regarding the usefulness, advantages and drawbacks of VAMLA and TEMLA. PMID- 21530296 TI - Clinical features of lung cancer in smokers with light and mild chronic obstructive pulmonary disease: a retrospective analysis of Japanese surgical cases. AB - OBJECTIVES: We estimated the influence of chronic obstructive pulmonary disease (COPD) upon the clinicopathological characteristics of lung cancer (LC) in Japanese surgical cases by comparing LC cases in non-COPD smokers. METHOD: A consecutive cohort comprising 157 COPD patients (78 in Global Initiative for Obstructive Lung Disease-1 (GOLD-1) and 79 in GOLD-2) and 374 non-COPD smoker-LC patients were enrolled in this study. Comparative analyses of the clinicopathological features of these two groups, including clinical outcomes, were performed. RESULTS: By analyzing all cases, we found that LC patients with COPD were older on average, more likely to be male, and heavier smokers than LC patients without COPD. In sub-analysis involving matched patient backgrounds, histological differentiation grade of LC in smokers with COPD was lower than in LC smokers without COPD, although distribution of clinical stages and histological types of LCs did not differ between smokers with and without COPD. The 5-year-survival rate in COPD patients was poorer than in non-COPD smokers in terms of both overall (38% vs 54%) and cancer-related mortality (45% vs 63%). By single-variant risk analysis, COPD became a prognostic factor. CONCLUSION: We concluded from our analysis that COPD-related LC may have a higher malignant potential than LC in non-COPD smokers, as the histological differentiation grade and clinical outcomes were poorer. PMID- 21530298 TI - Constitution and energetics of photosystem I and photosystem II in the chlorophyll d-dominated cyanobacterium Acaryochloris marina. AB - This mini review presents current topics of discussion about photosystem (PS) I and PS II of photosynthesis in the Acaryochloris marina. A. marina is a photosynthetic cyanobacterium in which chlorophyll (Chl) d is the major antenna pigment (>95%). However, Chl a is always present in a few percent. Chl d absorbs light with a wavelength up to 30 nm red-shifted from Chl a. Therefore, the chlorophyll species of the special pair in PS II has been a matter of debate because if Chl d was the special pair component, the overall energetics must be different in A. marina. The history of this field indicates that a purified sample is necessary for the reliable identification and characterization of the special pair. In view of the spectroscopic data and the redox potential of pheophytin, we discuss the nature of special pair constituents and the localization of the enigmatic Chl a. PMID- 21530299 TI - Interspecies variation in survival and growth of filamentous heterotrophic bacteria in response to UVC radiation. AB - Ultraviolet radiation is an important environmental constraint on the evolution of life. In addition to its harmful effects, ultraviolet radiation plays an important role in generating genetic polymorphisms and acting as a selective agent. Understanding how prokaryotes cope with high radiation can give insights on the evolution of life on Earth. Four representative filamentous bacteria from the family Cytophagaceae with different pigmentation were selected and exposed to different doses of UVC radiation (15-32,400Jm(-2)). The effect of UVC radiation on bacterial survival, growth and morphology were investigated. Results showed high survival in response to UVC for Rudanella lutea and Fibrisoma limi, whereas low survival was observed for Fibrella aestuarina and Spirosoma linguale. S. linguale showed slow growth recovery after ultraviolet exposure, R. lutea and F. limi showed intermediate growth recovery, while F. aestuarina had the fastest recovery among the four tested bacteria. In terms of survival, S. linguale was the most sensitive bacterium whereas R. lutea and F. limi were better at coping with UVC stress. The latter two resumed growth even after 2h exposure (~10,800Jm( 2)). Additionally, the ability to form multicellular filaments after exposure was tested using two bacteria: one representative of the high (R. lutea) and one of the low (F. aestuarina) survival rates. The ability to elongate filaments due to cell division was preserved but modified. In R. lutea 10min exposure reduced the average filament length. The opposite was observed in F. aestuarina, where the 5 and 10min exposures increased the average filament length. R. lutea and F. limi are potential candidates for further research into survival and resistance to ultraviolet radiation stress. PMID- 21530300 TI - Listening to PS II: enthalpy, entropy, and volume changes. AB - Photosystem II, located in the thylakoid membranes of green plants, algae, and cyanobacteria, uses sunlight to split water into protons, electrons, and a dioxygen molecule. The mechanism of its electron transfers and oxygen evolution including the structure of the protein and rates of the S-state cycle has been extensively investigated. Substantial progress has been made; however, the thermodynamics of PS II electron transfer and of the oxygen cycle are poorly understood. Recent progress in thermodynamic measurements in photosynthesis provides novel insights on the enthalpic and entropic contribution to electron transfer in proteins. In this review the thermodynamic parameters including quantum yield, enthalpy, entropy, and volume changes of PS II photochemistry determined by photoacoustics and other laser techniques are summarized and evaluated. Light-driven volume changes via electrostriction are directly related to the photoreaction in PS II and thus can be a useful measurement of PS II activity and function. The enthalpy changes of the reactions observed can be directly measured by photoacoustics. The apparent reaction entropy can also be estimated when the free energy is known. Dissecting the free energy of a photoreaction into enthalpic and entropic components provides critical information about mechanisms of PS II function. Potential limitations and future direction of the study of the thermodynamics of PS II electron transfer and oxygen evolution are presented. PMID- 21530301 TI - Photosystem II fluorescence: slow changes--scaling from the past. AB - With the advent of photoelectric devices (photocells, photomultipliers) in the 1930s, fluorometry of chlorophyll (Chl) a in vivo emerged as a major method in the science of photosynthesis. Early researchers employed fluorometry primarily for two tasks: to elucidate the role in photosynthesis, if any, of other plant pigments, such as Chl b, Chl c, carotenoids and phycobilins; and to use it as a convenient inverse measure of photosynthetic activity. In pursuing the latter task, it became apparent that Chl a fluorescence emission is influenced (i) by redox active Chl a molecules in the reaction center of photosystem (PS) II (photochemical quenching); (ii) by an electrochemical imbalance across the thylakoid membrane (high energy quenching); and (iii) by the size of the peripheral antennae of weakly fluorescent PSI and strongly fluorescent PSII in response to changes in the ambient light (state transitions). In this perspective we trace the historical evolution of our awareness of these concepts, particularly of the so-called 'State Transitions'. PMID- 21530302 TI - A carbonic anhydrase inhibitor induces bicarbonate-reversible suppression of electron transfer in pea photosystem 2 membrane fragments. AB - The effects of suppression of the carbonic anhydrase (CA) activity by a CA inhibitor, acetazolamide (AA), on the photosynthetic activities of photosystem II (PS II) particles from higher plants were investigated. AA along with CA-activity inhibits the PS II photosynthetic electron transfer and the AA-induced suppression is totally reversed by the addition of bicarbonate (3-5 mM). Similar effect of recovery in the PS II photosynthetic activity was also revealed upon the addition of known artificial electron donors (potassium ferrocyanide and TMPD). Significance and possible functions of CA for the PS II donor side are discussed. PMID- 21530303 TI - Re: Explicit declaration of ethical approval for clinical research. PMID- 21530304 TI - Growth hormone-releasing hormone: not only a neurohormone. AB - Growth hormone-releasing hormone (GHRH) is mostly thought to act by stimulating the production and release of growth hormone from the pituitary. However, this neuropeptide emerges as a rather pleiotropic hormone in view of the identification of various extrapituitary sources for GHRH production, as well as the demonstration of a direct action of GHRH on several tissues other than the pituitary. Non-pituitary GHRH has a wide spectrum of activity, exemplified by its ability to modulate cell proliferation, especially in malignant tissues, to regulate differentiation of some cell types, and to promote healing of skin wounds. These findings extend the role of GHRH and its analogs beyond its accepted regulation of somatotropic activity and indicate new possibilities for therapeutic intervention. PMID- 21530305 TI - Baseline variation and associations between subject characteristics and five cytokine biomarkers of vaginal safety among healthy non-pregnant women in microbicide trials. AB - Interleukins (IL)-8, IL-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1RA) have emerged as indicators of vaginal inflammation and HIV-1 transmission risk. We provide values and factors of normal variation of these immune mediators in premenopausal women to allow their wider clinical application as biomarkers of vaginal health. Cross-sectional analyzes (Kruskal-Wallis and Wilcoxon exact tests) of cytokine concentrations in relation to sociodemographic variables and Nugent score were performed on baseline (prior to product) cervicovaginal lavage from two Phase I randomized microbicide trials. All women in the analysis had regular menstrual cycles, 72 h abstinence, normal blood and Pap tests, and absence of genitourinary infections, study-relevant allergies, antibiotics use and history of substance abuse. Cytokine norms were defined as the values among those with Nugent score <4. Among women with normal Nugent score (n=92), IL-8 and IL-1beta were lowest in those using abstinence as compared to hormonal contraceptives or male/female sterilization as their primary method for birth control. No difference was found by age, prior pregnancy, or education, and also by race after controlling for contraceptive method. Women with abnormal (>7) and borderline (4-6) Nugent scores had elevated IL-1alpha and/or IL-1beta although their IL-1RA-to-IL(alpha+beta) ratio remained within the normal range due to higher IL-1RA. Women with borderline Nugent scores had IL-8 levels above the normal range. IL-8 and the IL-1RA-to-IL-1 ratio can be used as independent biomarkers of vaginal immune balance. More studies must determine the role of sexual activity, contraceptive method, and borderline Nugent scores, which normally are not exclusion criteria for enrollment in microbicide trials but may affect product tolerability and HIV-1 risk due to the aberrant cytokine levels. PMID- 21530306 TI - Joint angle affects volitional and magnetically-evoked neuromuscular performance differentially. AB - This study examined the volitional and magnetically-evoked neuromuscular performance of the quadriceps femoris at functional knee joint angles adjacent to full extension. Indices of volitional and magnetically-evoked neuromuscular performance (N=15 healthy males, 23.5 +/- 2.9 years, 71.5 +/- 5.4 kg, 176.5 +/- 5.5 cm) were obtained at 25 degrees , 35 degrees and 45 degrees of knee flexion. Results showed that volitional and magnetically-evoked peak force (PF(V) and P(T)F(E), respectively) and electromechanical delay (EMD(V) and EMD(E), respectively) were enhanced by increased knee flexion. However, greater relative improvements in volitional compared to evoked indices of neuromuscular performance were observed with increasing flexion from 25 degrees to 45 degrees (e.g. EMD(V), EMD(E): 36% vs. 11% improvement, respectively; F([2,14])=6.8, p<0.05). There were no significant correlations between EMD(V) and EMD(E) or PF(V) and P(T)F(E), at analogous joint positions. These findings suggest that the extent of the relative differential between volitional and evoked neuromuscular performance capabilities is joint angle-specific and not correlated with performance capabilities at adjacent angles, but tends to be smaller with increased flexion. As such, effective prediction of volitional from evoked performance capabilities at both analogous and adjacent knee joint positions would lack robustness. PMID- 21530307 TI - A radiofrequency electrode catheter-guide wire system for arterial occlusion. AB - PURPOSE: To describe the design of a radiofrequency (RF) electrode catheter/guide wire system to allow endovascular coagulation of vessels. MATERIALS AND METHODS: A circuit was created by modifying an ordinary microcatheter. An electrically conductive ring was placed at a microcatheter tip, and an extension lead at the hub site. They were each connected to an inherent coil mesh. The rings (ie, cathodes) were 1, 3, 5, 10, and 20 mm in length. In egg white, a coagulation study was performed by changing the length of the guide wire (ie, anode; 1, 3, 5, 10, 20, and 40 mm) in each cathode at 20 W. The coagulation time and site were analyzed. In rabbits, the renal artery was ablated with the use of a 20-mm cathode and 10-mm anode. RESULTS: In the egg white study, the coagulation time was proportionally increased and was dependent on the lengths of the cathode and anode (P < .05). Coagula developed at the anode to the 3-mm protrusion for the 1 mm cathode, to the 5-mm protrusion for the 3-mm cathode, to the 5-mm protrusion for the 5-mm cathode, to the 10-mm protrusion for the 10-mm cathode, and to the 20-mm protrusion for the 20-mm cathode. In rabbits, the renal artery was successfully occluded. Pathologic examination showed occlusion of the renal artery with organization, and the presence of a necrotic arterial wall with fibrosis, inflammation, and intact internal elastic lamina. CONCLUSIONS: The RF electrode catheter/guide wire system successfully coagulated egg white and occluded the rabbit renal artery. PMID- 21530308 TI - Optional vena cava filter use in the elderly population. AB - PURPOSE: To review utility, safety, and efficacy of optional inferior vena cava (IVC) filters in patients 65 years or older at a single institution over a 6-year period. MATERIALS AND METHODS: Retrospective review of permanent and optional IVC filters placed in elderly patients was performed. Older and younger groups were compared based on technical success of filter placement and clinical success measured by recurrent pulmonary embolism (PE) or thrombotic complications. The rate of successful filter removal was compared with that in the cohort of patients of all ages who received optional filters. RESULTS: Fifty-three patients received an optional filter and 445 received a permanent filter. Technical success rates for filter placement in the permanent and optional filter groups were 99.8% (447 of 448) and 98.1% (53 of 54), respectively (P = .51). Rates of PE after filter placement were 0% and 1.4% (five of 359) in the optional and permanent filter groups, respectively (P = .87). Incidences of deep vein thrombosis were 12% (six of 50) and 4.5% (16 of 359) in optional and permanent filter recipients, respectively (P = .06). Filter retrieval was attempted in 55.6% of optional filter recipients (30 of 54), similar to that seen in patients of any age with optional filters. Retrieval was unsuccessful in one patient in whom a suprarenal IVC filter was placed. CONCLUSIONS: Optional filters are safe and effective in patients aged 65 years or older. Age alone is a poor predictor of a clinical opportunity to remove a filter. With appropriate patient selection and aggressive follow-up, retrieval rates comparable with those in younger populations can be achieved. PMID- 21530309 TI - Photothermal ablation with the excimer laser sheath technique for embedded inferior vena cava filter removal: initial results from a prospective study. AB - PURPOSE: To evaluate the safety and effectiveness of the excimer laser sheath technique for removing embedded inferior vena cava (IVC) filters. MATERIALS AND METHODS: Over 12 months, 25 consecutive patients undergoing attempted IVC filter retrieval with a laser-assisted sheath technique were prospectively enrolled into an institutional review board-approved study registry. There were 10 men and 15 women (mean age 50 years, range 20-76 years); 18 (72%) of 25 patients were referred from an outside hospital. Indications for retrieval included symptomatic filter-related acute caval thrombosis (with or without acute pulmonary embolism), chronic IVC occlusion, and bowel penetration. Retrieval was also performed to remove risks from prolonged implantation and potentially to eliminate need for lifelong anticoagulation. After failure of standard methods, controlled photothermal ablation of filter-adherent tissue with a Spectranetics laser sheath and CVX-300 laser system was performed. All patients were evaluated with cavography, and specimens were sent for histologic analysis. RESULTS: Laser assisted retrieval was successful in 24 (96%) of 25 patients as follows: 11 Gunther Tulip (mean 375 days, range 127-882 days), 4 Celect (mean 387 days, range 332-440 days), 2 Option (mean 215 days, range 100-330 days), 4 OPTEASE (mean 387 days, range 71-749 days; 1 failed 188 days), 2 TRAPEASE (mean 871 days, range 187 1,555 days), and 2 Greenfield (mean 12.8 years, range 7.2-18.3 years). There was one (4%) major complication (acute thrombus, treated with thrombolysis), three (12%) minor complications (small extravasation, self-limited), and one adverse event (coagulopathic retroperitoneal hemorrhage) at follow-up (mean 126 days, range 13-302 days). Photothermal ablation of filter-adherent tissue was histologically confirmed in 23 (92%) of 25 patients. CONCLUSIONS: The laser assisted sheath technique appears to be a safe and effective tool for retrieving embedded IVC filters, including permanent types, with implantation ranging from months to > 18 years. PMID- 21530310 TI - Unidirectional ablation electrode to minimize thermal injury during radiofrequency ablation: an experimental study in an ex vivo bovine liver model. AB - PURPOSE: To modify the direction of radiofrequency (RF) ablation and to find optimal technical parameters using a partially insulated electrode. MATERIALS AND METHODS: The authors developed a unidirectional ablation electrode (UAE) by partial insulation of a 1-cm active electrode tip. Each electrode produced 60 ablation zones using insulation of the active tip (270 degrees , group A; 180 degrees , group B; and noninsulated, group C). In each group, six subgroups were created by combining the RF powers (5 W, 10 W, and 20 W) and ablation duration (6 minutes and 12 minutes). Technical success was determined when a half-moon-shaped ablation zone was achieved. The volumes of the technical success zone (Vs) and the technical failure zone (Vf) were measured. RESULTS: Technical success was achieved in all 10 cases using a 270 degrees insulated electrode with a 5-W/6 minute parameter. The mean Vs of group A was significantly smaller than the mean Vs of either group B or group C (P = .003 and P < .001). The mean Vf of group A was significantly smaller than the mean Vf of group B, which was smaller than that of group C (P < .001). CONCLUSIONS: A UAE with a partially insulated tip can modify the ablation zone, especially when using 270 degrees insulation with a 5 W/6-minute parameter. PMID- 21530311 TI - MR-guided radiofrequency ablation of hepatocellular carcinoma: long-term effectiveness. AB - PURPOSE: To evaluate long-term effectiveness of magnetic resonance (MR)-guided radiofrequency (RF) ablation of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This prospective study was approved by the institutional review board. In 20 patients, 28 HCCs (mean diameter, 28.0 mm; range, 6-58 mm) were treated with 25 sessions of MR-guided RF ablation. Previous chemoembolization had been performed in nine HCCs with diameters greater than 3 cm. The entire RF ablation procedures were carried out on a 0.2-T open MR system. Placement of MR-compatible internally cooled electrodes was performed under MR fluoroscopic imaging with fast gradient-echo sequences. Therapeutic assessment was based on dynamic MR imaging (1.5 T) at a mean follow-up of 24.2 months (range, 6-52 mo). RESULTS: MR guided RF ablation was technically successful in all 25 sessions (100%), as assessed at the end of each session. T2-weighted sequences were accurate to monitor the ablation zone and supported guidance of overlapping ablations if necessary. Technique effectiveness, defined as complete ablation confirmed at MR imaging 4 months after RF ablation, was achieved in 27 of 28 HCCs (96.4%). To achieve complete ablation, 25 of 27 tumors (92.6%) were treated in a single session and two tumors were treated twice. In one tumor initially defined as having been treated with technically effective RF ablation, local tumor progression was detected more than 4 months after ablation. Consequently, the available follow-up indicated complete ablation in 26 of 28 HCCs (92.9%). There was one major complication (4.0%) and one minor complication (4.0%). CONCLUSIONS: On a long-term basis, MR-guided RF ablation is an effective therapy option in the treatment of HCC. PMID- 21530312 TI - A new self-convertible inferior vena cava filter: experimental in-vitro and in vivo evaluation. AB - PURPOSE: To evaluate using in-vitro and in-vivo models the feasibility and capture efficiency of a new self-convertible inferior vena cava filter (SCF), equipped with a biodegradable self-converting switch. MATERIALS AND METHODS: Capture rates were tested in an in-vitro flow model for simulated supine and upright positions with clot diameters of 3 mm and 5 mm and tube diameters of 22 mm, 25 mm, and 28 mm. In the in-vivo study, five filters were implanted in five adult dogs. Venography was performed after the procedure every 2 weeks until filter conversion. RESULTS: All filters were successfully implanted and completely converted with a mean trapping efficiency of 75.5% in the in-vivo study. The SCF was most efficient at 92% in the upright orientation with 5-mm clots and a 22-mm caval diameter. All five filters exhibited successful delivery and conversion in vitro. The SCFs were manually manufactured without barbs or hooks, and because of this feature, migration occurred. CONCLUSIONS: The SCF is feasible and highly efficient and converts itself successfully. Evaluation is planned of future prototypes with appropriate modifications for risk of migration of the filter. PMID- 21530313 TI - Proposed angiographic criteria for measurement of vertebral artery origin stenosis: the vertebral origin treatment with endovascular therapy (VOTE) method. AB - Standard measurement criteria for vertebral artery origin (VAO) stenosis have not yet been established. We propose such criteria and report on interrater agreement using two measurement methods in a series of patients referred for endovascular therapy. Three experienced angiography raters independently reviewed magnified cerebral angiograms. The formula [1 - (Ds/Dn)] * 100 was used, where Ds is the diameter of the most stenotic portion of the lesion and Dn is normal vessel diameter. The first measurement method allows unrestricted use of the V1 segment for measurement of normal diameter. In the second method, normal diameter is measured in the first portion of the V2 segment with exclusion of any region of poststenotic dilatation. Ten consecutive patients with VAO stenosis were reviewed. The mean degree of stenosis was 71.9% (standard deviation, +/- 10.7%) with the first method and 66.9% +/- 10.6% with the second method. Average interrater agreement was 80% with the first method and 87% with the second method. The intraclass correlation coefficient (ICC) demonstrated greater interrater agreement when the tortuous proximal V1 segment was excluded in normal diameter measurement (ICC = 0.7750) compared with the unrestricted use of the V1 segment for normal diameter (ICC = 0.7256). The kappa statistic was the best among the 3 raters with 10% variance when the tortuous V1 segment was excluded, at 0.73 (overall agreement, 87%). Our findings indicate that excluding the tortuous V1 portion when measuring normal diameter improves interrater agreement and simplifies the measurement of high-grade VAO stenosis. PMID- 21530314 TI - Right heart failure and "failure to thrive" after left ventricular assist device: clinical predictors and outcomes. AB - BACKGROUND: This study determined predictors of early post-operative right heart failure (RHF) and its consequences, as well as predictors of those who clinically thrive longer term after insertion of a continuous-flow left ventricular assist device (LVAD). METHODS: Pre-operative and latest follow-up data were analyzed for 40 consecutive patients who received third-generation centrifugal-flow LVADs. RHF was defined using previously described criteria, including post-operative inotropes, pulmonary vasodilator use, or right-sided mechanical support. Patients were also categorized according to clinical outcomes after LVAD insertion. RESULTS: LVADs were implanted as a bridge to transplantation (BTT) in 33 patients and as destination therapy in 7. Before LVAD implant, 22 patients were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level 1, and 17 were at level 2. Temporary mechanical assistance was present in 50% of the cohort at LVAD implantation. The 6-month survival/progression to transplant was 92.5%. Average LVAD support time was 385 days (range, 21-1,011 days). RHF developed postoperatively in 13 of 40 patients (32.5%). RHF patients had more severe pre-operative tricuspid incompetence than non-RHF patients. The BTT patients with evidence of RHF had poorer survival to transplant (6 of 11 [54.5%]) than those without RHF (20 of 22 [90.9%]), p = 0.027). There were no other hemodynamic or echocardiographic predictors of short-term RHF. After LVAD, 22 of the 40 patients (55%) thrived clinically. For BTT patients, 20 of 21 (95%) of those who thrived progressed to transplant or were alive at latest follow-up vs 6 of 12 (50%) of those who failed to thrive (FTT; p < 0.005). The thrivers had lower New York Heart Association class (1.5 vs 2.9, p < 0.001), spent less time in the hospital, and had less ventricular tachycardia than the FTT patients. However, no differences were noted in pre-operative INTERMACS level, echocardiographic, hemodynamic, and biochemical indices, or in early post operative RHF. Age was the only significant predictor: the thrivers were significantly younger (43.7 +/- 15.9 vs 60.3 +/- 12.6 years; p < 0.001). This age difference was unchanged after exclusion of destination strategy patients. RV function deteriorated in the FTT patients and remained stable in those who thrived. CONCLUSIONS: Early post-operative RHF results in poorer survival/progression to transplantation for BTT patients and is predicted by greater pre-operative tricuspid incompetence. The most important predictor for those who will clinically thrive longer-term after LVAD insertion is younger age. PMID- 21530315 TI - Less invasive off-pump implantation of axial flow pumps in chronic ischemic heart failure: survival effects. AB - BACKGROUND: Off-pump implantation of left ventricular assist device (LVAD) axial or centrifugal flow pumps in patients with low ejection fraction (EF) is of major clinical relevance. In addition, all pre-clinical, long-term implantations performed so far have been carried out in healthy animals, but this does not reflect the eventual clinical setting. In this study we established a new technique using a miniaturized axial flow pump in sheep with chronically ischemic myocardium. METHODS: Sheep (n = 15) underwent intracoronary sphere injection to create chronic ischemic heart failure. Reduced EF was assessed using transesophageal echocardiography. All animals underwent implantation of a new miniaturized axial flow pump via an extraperitoneal, subcostal surgical approach. RESULTS: Our technique allows easy exposure of the diaphragmatic surface of the heart and the descending aorta. Ten animals (range 65 to 78 kg) underwent off pump implantation 30 (range 25 to 33) days after intracoronary sphere injection. All animals had significantly reduced EF (25 +/- 4.8%) and were receiving high doses of inotropic agents to maintain cardiac function. Nine animals survived the surgical procedure. The average 12-hour blood loss was 435 ml. Cardiac index improved significantly in all animals. The procedure time was not extended by any adverse events (60 to 145 minutes). CONCLUSIONS: The extraperitoneal, subcostal surgical approach is less invasive than a median sternotomy and allows centrifugal or axial to be implanted quickly and without cardiopulmonary bypass (CPB). Avoiding CPB and an extensive mediastinal dissection can help to decrease significantly the number of complications in patients with end-stage organ failure. PMID- 21530316 TI - The SynCardia freedom driver: a portable driver for discharge home with the total artificial heart. PMID- 21530317 TI - Inhaled nitric oxide after left ventricular assist device implantation: a prospective, randomized, double-blind, multicenter, placebo-controlled trial. AB - BACKGROUND: Used frequently for right ventricular dysfunction (RVD), the clinical benefit of inhaled nitric oxide (iNO) is still unclear. We conducted a randomized, double-blind, controlled trial to determine the effect of iNO on post operative outcomes in the setting of left ventricular assist device (LVAD) placement. METHODS: Included were 150 patients undergoing LVAD placement with pulmonary vascular resistance >= 200 dyne/sec/cm(-5). Patients received iNO (40 ppm) or placebo (an equivalent concentration of nitrogen) until 48 hours after separation from cardiopulmonary bypass, extubation, or upon meeting study-defined RVD. For ethical reasons, crossover to open-label iNO was allowed during the 48 hour treatment period if RVD criteria were met. RESULTS: RVD criteria were met by 7 of 73 patients (9.6%; 95% confidence interval, 2.8-16.3) in the iNO group compared with 12 of 77 (15.6%; 95% confidence interval, 7.5-23.7) who received placebo (p = 0.330). Time on mechanical ventilation decreased in the iNO group (median days, 2.0 vs 3.0; p = 0.077), and fewer patients in the iNO group required an RVAD (5.6% vs 10%; p = 0.468); however, these trends did not meet statistical boundaries of significance. Hospital stay, intensive care unit stay, and 28-day mortality rates were similar between groups, as were adverse events. Thirty-five patients crossed over to open-label iNO (iNO, n = 15; placebo, n = 20). Eighteen patients (iNO, n = 9; placebo, n = 9) crossed over before RVD criteria were met. CONCLUSIONS: Use of iNO at 40 ppm in the perioperative phase of LVAD implantation did not achieve significance for the primary end point of reduction in RVD. Similarly, secondary end points of time on mechanical ventilation, hospital or intensive care unit stay, and the need for RVAD support after LVAD placement were not significantly improved. PMID- 21530318 TI - Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. AB - BACKGROUND: In this study we investigated gastrointestinal (GI) bleeding and its relationship to arteriovenous malformations (AVMs) in patients with the continuous-flow HeartMate II (HMII) left ventricular assist device (LVAD). METHODS: The records of 172 patients who received HMII support between November 2003 and June 2010 were reviewed. Patients were considered to have GI bleeding if they had 1 or more of the following symptoms: guaiac-positive stool; hematemesis; melena; active bleeding at the time of endoscopy or colonoscopy; and blood within the stomach at endoscopy or colonoscopy. The symptom(s) had to be accompanied by a decrease of >1 g/dl in the patient's hemoglobin level. The location of the bleeding was identified as upper GI tract, lower GI tract or both according to esophagogastroduodenoscopy, colonoscopy, small-bowel enteroscopy or mesenteric angiography. Post-LVAD implantation anti-coagulation therapy consisted of warfarin, aspirin and dipyridamole. RESULTS: Thirty-two of the 172 patients (19%) had GI bleeding after 63 +/- 62 (range 8 to 241) days of HMII support. Ten patients had GI bleeding from an AVM; these included 3 patients who had 2 bleeding episodes and 2 patients who had 5 episodes each. Sixteen patients had upper GI bleeding (10 hemorrhagic gastritis, 4 gastric AVM, 2 Mallory-Weiss syndrome), 15 had lower GI bleeding (6 diverticulosis, 6 jejunal AVM, 1 drive line erosion of the colon, 1 sigmoid polyp, 1 ischemic colitis) and 1 had upper and lower GI bleeding (1 colocutaneous and gastrocutaneous fistula). All GI bleeding episodes were successfully managed medically. CONCLUSIONS: Arteriovenous malformations can cause GI bleeding in patients with continuous-flow LVADs. In all cases in this series, GI bleeding was successfully managed without the need for surgical intervention. PMID- 21530319 TI - Evaluation of right ventricular function and post-operative findings using cardiac computed tomography in patients with left ventricular assist devices. AB - BACKGROUND: Right ventricular (RV) failure is a major contributor to morbidity and mortality after left ventricular assist device (LVAD) implantation. Accurate evaluation of RV function in patients with LVAD remains challenging. We hypothesized that, after LVAD implantation, electrocardiographic-gated cardiac computed tomography (CCT) allows RV evaluation with higher feasibility and reproducibility compared with echocardiography. METHODS: Thirty-six patients with an implanted LVAD who had 2-dimensional echocardiography and CCT evaluation were studied. RV end-diastolic and end-systolic volumes and ejection fraction were quantified using CCT. RV fractional area change, tricuspid annular plane systolic excursion and RV end-diastolic short-to-long axis ratio were calculated by echocardiography. Intraclass correlation coefficients (ICCs) and Bland-Altman analysis were used to assess intra- and interobserver reproducibility for all measurements. RESULTS: The quality of CCT studies was good in all cases except for one. Intra- and interobserver reproducibility for all CCT measurements was high (interobserver ICC for RV ejection fraction = 0.89, 95% confidence interval 0.74 to 0.95). Echocardiographic indices of RV function and geometry had lower reproducibility. The echocardiographic index that best correlated with the CCT determined RV ejection fraction was RV fractional area change (r = 0.80, p < 0.001). In addition, CCT detected relevant post-operative findings in 50% of the patients. CONCLUSIONS: CCT is highly effective and reproducible compared with echocardiography for the evaluation of RV function in patients with LVAD support and provides relevant information on post-operative findings. Our results suggest that CCT should be considered as a useful imaging modality in this clinical setting. PMID- 21530320 TI - The prevalence of shoulder osteoarthritis in the elderly Korean population: association with risk factors and function. AB - BACKGROUND: The purpose of this study was to document the prevalence of shoulder osteoarthritis (OA) in the elderly population in South Korea, to determine the risk factors for shoulder OA, and to evaluate the relationship with function. MATERIALS AND METHODS: This project was part of a population-based prospective cohort study of health, aging, and common geriatric diseases in the elderly population of the authors' area of Seongnam. A total of 1118 residents were randomly invited, and 679 participated. The mean age of respondents was 71.8 +/- 5.7 years (range, 65-97 years), and 396 (58.3%) were women. Bilateral shoulder radiographs were taken, and the grade of OA was evaluated using the Samilson Prieto method. Functional status was evaluated using the Disabilities of Arm, Shoulder and Hand (DASH) instrument. RESULTS: Radiographic primary shoulder OA was detected in 109 people (16.1%), and secondary OA in 9 (1.3%). There were 77 shoulders of grade 1 (11.3%), 23 of grade 2 (3.4%), and 9 of grade 3 (1.3%). The risk of shoulder OA increased according to age, with odds ratio (OR) of 2.20 in patients aged 70 to 74 years (P = .004) and 3.42 in patients aged 75 years and older (P < .001). Knee OA was also a significant risk factor for shoulder OA (OR, 1.96; P = .002). The DASH score was significantly higher in the OA group and increased according to the grade of shoulder OA (P < .001). CONCLUSION: Primary shoulder OA is not as rare as previously reported. Our data also demonstrated that older age and knee OA were determining risk factors for shoulder OA, and shoulder OA was related to poor function. PMID- 21530321 TI - Operative versus nonoperative treatment after primary traumatic anterior glenohumeral dislocation: expected-value decision analysis. AB - BACKGROUND: The optimal management strategy for primary traumatic anterior glenohumeral dislocation remains controversial. Patients have traditionally been managed nonoperatively, but high recurrence rates in certain populations have led to increased interest in early operative stabilization. The purpose of this study was to use expected-value decision analysis to determine the optimal management strategy--nonoperative treatment or arthroscopic stabilization--for a first-time traumatic anterior shoulder dislocation. MATERIALS AND METHODS: Probabilities for the occurrences of the potential outcomes after nonoperative and arthroscopic treatment of a first-time traumatic anterior glenohumeral dislocation were determined from a systematic review of the literature. Utilities for these outcomes were obtained from a questionnaire on patient preferences completed by 42 subjects without a history of shoulder injury. A decision tree was constructed, fold-back analysis was performed to determine optimal management, and sensitivity analyses were used to determine the effect on decision making of varying outcome probabilities and utilities. RESULTS: Nonoperative treatment was associated with a utility value of 5.9 and early arthroscopic surgery with a value of 7.6. On sensitivity analysis, it was found that when the rate of recurrence after nonoperative treatment falls below 32% or when the utility value for successful arthroscopic stabilization falls below 6.6, nonoperative treatment is the preferred management strategy. CONCLUSIONS: Arthroscopic stabilization was the preferred strategy after a primary anterior glenohumeral dislocation. In clinical settings where the likelihood of recurrent instability is low after nonoperative care or when an informed patient has an aversion to surgery, nonoperative treatment may be the preferred treatment strategy. PMID- 21530322 TI - Effect of deltoid tension and humeral version in reverse total shoulder arthroplasty: a biomechanical study. AB - BACKGROUND: No clear recommendations exist regarding optimal humeral component version and deltoid tension in reverse total shoulder arthroplasty (TSA). MATERIALS AND METHODS: A biomechanical shoulder simulator tested humeral versions (0 degrees , 10 degrees , 20 degrees retroversion) and implant thicknesses (-3, 0, +3 mm from baseline) after reverse TSA in human cadavers. Abduction and external rotation ranges of motion as well as abduction and dislocation forces were quantified for native arms and arms implanted with 9 combinations of humeral version and implant thickness. RESULTS: Resting abduction angles increased significantly (up to 30 degrees ) after reverse TSA compared with native shoulders. With constant posterior cuff loads, native arms externally rotated 20 degrees , whereas no external rotation occurred in implanted arms (20 degrees net internal rotation). Humeral version did not affect rotational range of motion but did alter resting abduction. Abduction forces decreased 30% vs native shoulders but did not change when version or implant thickness was altered. Humeral center of rotation was shifted 17 mm medially and 12 mm inferiorly after implantation. The force required for lateral dislocation was 60% less than anterior and was not affected by implant thickness or version. CONCLUSION: Reverse TSA reduced abduction forces compared with native shoulders and resulted in limited external rotation and abduction ranges of motion. Because abduction force was reduced for all implants, the choice of humeral version and implant thickness should focus on range of motion. Lateral dislocation forces were less than anterior forces; thus, levering and inferior/posterior impingement may be a more probable basis for dislocation (laterally) than anteriorly directed forces. PMID- 21530323 TI - Proximal humeral malunion treated with reverse shoulder arthroplasty. AB - BACKGROUND: The purpose of this study was to determine the outcomes of patients with proximal humeral malunions treated with reverse shoulder arthroplasty (RSA). MATERIALS AND METHODS: Sixteen patients were treated with RSA for sequelae of a proximal humeral fracture with a malunion. Clinical outcomes (American Shoulder and Elbow Surgeons [ASES] score, Simple Shoulder Test, visual analog scale [VAS] score for pain and function, range of motion, and patient satisfaction) and radiographs were evaluated at a minimum follow-up of 2 years. Wilcoxon signed rank tests were used to analyze preoperative and postoperative data. RESULTS: All patients required alteration of humeral preparation with increased retroversion of greater than 30 degrees . The total ASES score improved from 28 to 63 (P = .001), ASES pain score from 15 to 35 (P = .003), ASES functional score from 15 to 27 (P = .015), VAS pain score from 7 to 3 (P = .003), VAS function score from 0 to 5 (P = .001), and Simple Shoulder Test score from 1 to 4 (P = .0015). Forward flexion improved from 53 degrees to 105 degrees (P = .002), abduction from 48 degrees to 105 degrees (P = .002), external rotation from 5 degrees to 30 degrees (P = .015), and internal rotation from S1 to L3 (P = .005). There were no major complications reported. Postoperative radiographic evaluation showed 2 patients with evidence of notching and 1 patient with proximal humeral bone resorption. CONCLUSION: RSA is indicated for treating the most severe types of proximal humeral fracture sequelae. The results of RSA for proximal humeral malunions with altered surgical technique yield satisfactory outcomes in this difficult patient population. PMID- 21530324 TI - Lack of association of ABCB1 haplotypes on five loci with response to treatment in epilepsy. AB - Approximately one third of newly treated epilepsy patients do not respond to antiepileptic drugs (AEDs). Overexpression of P-glycoprotein (P-gp) efflux transporter has been proposed to have a critical role in causing resistance to AEDs. P-gp is a product of the ATP-binding cassette subfamily B member 1 (ABCB1) gene. The purpose of this study was to investigate a possible link between ABCB1 rs3789243 C>T, C1236T, G2677T/A, rs6949448 C>T, and C3435T haplotypes with response to carbamazepine (CBZ) or sodium valproate (VPA) monotherapy in Malaysian epilepsy patients. No ABCB1 haplotype association was found with response to either CBZ or VPA monotherapy in the Chinese, Indian, and Malay patients. C3435 allele carriers of the Indian males with cryptogenic epilepsy were more prone to resistance to either CBZ or VPA than carriers of T allele. Moreover, rs3789243T allele carriers of Malay females with symptomatic epilepsy were more resistant to either CBZ or VPA than C allele carriers. Our findings suggest that the ABCB1 rs3789243 C>T, C1236T, G2677T/A, rs6949448 C>T, and C3435T haplotypes do not contribute to response to AED treatment in epilepsy. PMID- 21530325 TI - Validation of the American College of Foot and Ankle Surgeons Scoring Scales. AB - The American College of Foot and Ankle Surgeons (ACFAS) assembled a task force to develop a scoring scale that could be used by the membership and practitioners-at large. The original publication that introduced the scale focused primarily on use of the scale and provided only brief background on the development of the health measurement instrument. Concerns regarding the validity and reliability of the scale were raised within the professional community, and ACFAS assembled a task force to address these concerns. The purpose of this article is to address the issues raised by reporting the detailed methods used in the development of the ACFAS Scoring Scales. The authors who constitute this task force reviewed the body of work previously conducted and applied standards that serve to evaluate the scoring scale for: 1) validity, 2) reliability, and 3) sensitivity to change. The results showed that a systematic and comprehensive approach was used in the development of the scoring scales, and the task force concluded that the statistical methods and instrument development process for all 4 modules of the scoring scales were conducted in an appropriate manner. Furthermore, modules 1 and 2 have been rigorously assessed and the elements of these modules have been shown to meet standards for validity, reliability, and sensitivity to change. PMID- 21530326 TI - Sentinel node biopsy alone for node-positive breast cancer: 12-year experience at a single institution. AB - BACKGROUND: Complete node dissection for a tumor-positive sentinel node (SN) is becoming more controversial. We report our institution's 12-year experience with sentinel node biopsy (SNB) alone for a tumor-positive SN. STUDY DESIGN: This was a retrospective review from 1998 to 2009. Of 3,806 patients who underwent SNB, 2,139 underwent SNB alone, of which 1,997 were tumor-negative and 123 were tumor positive. SNs were staged node-positive (N1mic or N1) according to American Joint Committee on Cancer criteria. RESULTS: One hundred and twenty-three node-positive patients underwent SNB alone with no completion axillary dissection for invasive breast cancer. Mean age was 57 years (range 32 to 92 years) and stage distribution was as follows: stage IIA: 76 (62%) patients; stage IIB: 40 (33%) patients; and stage III: 4 patients (3%). Mean size of the tumors was 1.9 cm (range 0.1 to 9 cm). Eighty-nine (72%) underwent lumpectomy and 34 (28%) underwent mastectomy. Ninety-three percent of patients underwent some form of adjuvant therapy. Forty-two patients (34%) did not undergo radiation and there were no axillary recurrences in this group. At median follow-up of 95 months, there has been 1 axillary recurrence (0.8%) and 13 deaths, 4 of which were attributed to metastatic breast cancer and the rest to non-breast-related causes. CONCLUSIONS: Axillary recurrence is rare after SN biopsy alone. This might be related to favorable tumor and patient characteristics and frequent use of adjuvant therapy. PMID- 21530327 TI - B7-h2 is a costimulatory ligand for CD28 in human. AB - CD28 and CTLA-4 are cell surface cosignaling molecules essential for the control of T cell activation upon the engagement of their ligands B7-1 and B7-2 from antigen-presenting cells. By employing a receptor array assay, we have demonstrated that B7-H2, best known as the ligand of inducible costimulator, was a ligand for CD28 and CTLA-4 in human, whereas these interactions were not conserved in mouse. B7-H2 and B7-1 or B7-2 interacted with CD28 through distinctive domains. B7-H2-CD28 interaction was essential for the costimulation of human T cells' primary responses to allogeneic antigens and memory recall responses. Similar to B7-1 and B7-2, B7-H2 costimulation via CD28 induced survival factor Bcl-xL, downregulated cell cycle inhibitor p27(kip1), and triggered signaling cascade of ERK and AKT kinase-dependent pathways. Our findings warrant re-evaluation of CD28 and CTLA-4's functions previously attributed exclusively to B7-1 and B7-2 and have important implications in therapeutic interventions against human diseases. PMID- 21530328 TI - The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. AB - A chief Ca(2+) entry pathway in immune cells is store-operated Ca(2+) (SOC) influx, which is triggered by depletion of Ca(2+) from the endoplasmic reticulum (ER). However, its physiological role in B cells remains elusive. Here, we show that ER calcium sensors STIM1- and STIM2-induced SOC influx is critical for B cell regulatory function. B cell-specific deletion of STIM1 and STIM2 in mice caused a profound defect in B cell receptor (BCR)-induced SOC influx and proliferation. However, B cell development and antibody responses were unaffected. Remarkably, B cells lacking both STIM proteins failed to produce the anti-inflammatory cytokine IL-10 because of defective activation of nuclear factor of activated T cells (NFAT) after BCR stimulation. This resulted in exacerbation of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our data establish STIM-dependent SOC influx as a key signal for B cell regulatory function required to limit autoimmunity. PMID- 21530329 TI - Smoking inhibits the frequency of bronchovascular bundle thickening in sarcoidosis. AB - RATIONALE/OBJECTIVES: Smoking has been associated with decreased incidence and prevalence of sarcoidosis, but few studies have evaluated effects of smoking on clinical parameters of the disease. The objectives were to determine the association of smoking with radiographic patterns and to evaluate the associations of these smoking-related radiographic patterns on airflow obstruction in sarcoidosis. MATERIALS AND METHODS: Clinical data and computed tomography (CT) scans of 124 patients with sarcoidosis were reviewed. CT scans were assessed for lymph nodes, nodules, bronchiectasis, bronchovascular bundle thickening, displaced hilum, fibrosis, ground glass, emphysema, pleural changes, and alveolar opacities. CT patterns were compared between patients with and without a history of smoking. The effect of smoking on the associations between radiographic patterns and airflow obstruction was assessed with multivariable analysis. RESULTS: Smokers had less frequency of bronchovascular bundle thickening than nonsmokers (11/38 subjects [29%] vs 50/86 subjects [58%], P = .003) and more emphysema (7/38 subjects [18%] vs 1/86 subjects [1%], P = .001). Patients who had bronchovascular bundle thickening were less likely to have ever smoked (11/61 subjects [18%] vs 27/63 subjects [43%], P = .003) or be current smokers (4/61 subjects [7%] vs 15/63 subjects [24%], P = .008). Age (P = .003) and bronchovascular bundle thickening (P = .02) were independent predictors of airflow obstruction. There were no differences in smoking history between patients with airflow obstruction versus those without (10/37 subjects [27%] vs 28/87 subjects [32%], P = .63). CONCLUSIONS: In patients with sarcoidosis, smoking is associated with decreased frequency of bronchovascular bundle thickening, an important clinical manifestation of the lung disease. Further, bronchovascular bundle thickening and age are the only independent predictors of airflow obstruction, and smoking does not confound these associations. PMID- 21530330 TI - Low-dose unenhanced CT for IV contrast bolus timing: is it reliable to assess hepatic steatosis? AB - RATIONALE AND OBJECTIVES: To determine whether an unenhanced low-dose image acquired during automated contrast bolus timing can be used to assess hepatic steatosis. MATERIALS AND METHODS: Fifty subjects (29 male, 21 female; 26-92 years; mean body mass index (BMI; 26.9) with abdominal multiphasic computed tomography were included. Abdominal diameters and circumferences were derived from anteroposterior and lateral scout radiographs. Hepatic attenuation (HA) was measured on unenhanced low-dose images (120 kV; 40 mA; 0.5 seconds' rotation time) and corresponding unenhanced standard-dose images (120 kV, z-axis automatic tube current modulation, noise index 11.5). Noise estimates were measured in surrounding air. Pearson correlation was calculated between abdominal circumference and BMI. Mean HA assessed on low-dose images and standard-dose images was compared using a paired Student's t-test and Bland Altman plots. RESULTS: Abdominal circumference (mean, 142.8cm) correlated well with BMI (r = 0.83). No significant difference was found for HA on low-dose images (mean +57.7 HU) compared to HA on standard-dose images (+56.0 HU) (P = .077). Image noise (+11.5 HU) was significantly higher on low-dose images compared to image noise (+8.1 HU) on standard-dose images (P < .05). For HA mean difference comparing low and standard-dose images was -1.7 HU (limits of agreement: -14.6, 11.2). CONCLUSION: In all subjects, hepatic attenuation can be correctly assessed on unenhanced low-dose images. PMID- 21530331 TI - Duplex ultrasound investigation of the veins of the lower limbs after treatment for varicose veins - UIP consensus document. AB - OBJECTIVES: Duplex ultrasound has become the reference standard in assessing the morphology and haemodynamics of the lower limb veins. The project described in this article was an initiative of the Union Internationale de Phlebologie (UIP). The aim was to obtain a consensus of international experts on the methodology and terminology to be used for assessment after treatment of incompetent superficial and perforating veins in the lower limb by ultrasound imaging. DESIGN: The study design was consensus meetings leading to a consensus document. METHODS: The UIP invited group submitted relevant literature references and written contributions concerning the methodology, terminology and value of duplex imaging after treatment. The authors prepared a draft document that was circulated to a larger group of experts and revised according to the comments received. Eventually, all participants agreed upon the final version of the article. RESULTS: Formal analysis of the results of interventions for varicose veins relies on adequate preoperative assessment and a careful description of the procedure employed. The timing of investigations of outcome should be classified as immediate (1-4 weeks), short-term (1 year), midterm (2-3 years) and long-term (5 years or more). The examination should employ standard methodology and formally described variables, which can be tailored to the intervention that was undertaken. The experts have made detailed recommendations concerning the methods to be used for duplex ultrasound examination and reporting after various treatments for varicose veins, including novel treatments under scientific study. CONCLUSIONS: Duplex ultrasonography is a fundamental component of the investigation of the lower limb venous system after treatment for varicose veins. PMID- 21530332 TI - The association of clinical variables and filter design with carotid artery stenting thirty-day outcome. AB - OBJECTIVE: Patient and device selection are important for the success of carotid artery stenting (CAS). We hypothesize that distal protection filter (DPF) design characteristics that minimize blood flow resistance and maximize capture efficiency are associated with the absence of transient ischemic attack (TIA), stroke and neurologic-related death after 30 days. METHODS: Records from 208 patients were reviewed retrospectively. Filter design characteristics were quantified previously in our laboratory. The association between risk factors and design characteristics with 30-day outcome was quantified using univariate analysis. RESULTS: The 30-day all-cause stroke and death rate was 8.7% (asymptomatic: 7.7%, symptomatic: 10.6%). Five DPFs were used in the study: Accunet (41.3%), Angioguard (33.2%), FilterWire (24%), Emboshield (1%), and Spider (.5%). Diabetes (P = .04) and prior carotid endarterectomy (CEA, P = .03) were associated with adverse outcome. Prior stroke (P = .01) and prior CEA (P = .04) were significant for peri-procedural stroke. Design characteristics such as capture efficiency were associated with favorable outcomes. CONCLUSIONS: Patients with prior CEA or stroke are more likely to have unfavorable CAS outcomes after 30 days. Filters with high capture efficiency may yield the best clinical results. Analysis of the effect of design characteristics on CAS outcome should aid the design of future devices. PMID- 21530333 TI - Perforating veins: an anatomical approach to arteriovenous fistula performance in the forearm. AB - OBJECTIVES: Arteriovenous fistulae (AVFs) play a key role for people who rely on chronic haemodialysis. Stenosis in the venous outflow of the AVF will cause an alternative route of the subcutaneous blood flow via the deeper venous pathways by means of side branches and the perforating veins (PVs). The purpose for the present study was to define the number and anatomical localisation of the perforating veins in the forearm. METHODS: Twenty forearms were dissected to study the venous anatomy. The localisation, size and connections of the perforators were recorded and stored digitally. RESULTS: In total, 189 PVs were defined (mean, 9.5 per arm; range, 6-19), with 60 (32%) PVs connected to the cephalic vein, 97 (51%) connections to the basilic vein and 32 (17%) PVs to the median vein of the forearm. Most PVs originate from the basilic vein and connect with the ulnar venae comitans. The cephalic vein connects equally to the radial venae comitans, interossea veins and the muscles. CONCLUSION: The cephalic vein has the fewest PVs and almost a third of them connect to the muscles. This is probably important for the maturation of the AVF, the superficial flow volume and the accessibility for puncture. PMID- 21530334 TI - The influence of cone-beam computed tomography and periapical radiographic evaluation on the assessment of periapical bone destruction in dog's teeth. AB - OBJECTIVE: The aim of this study was to determine the influence of periapical radiographs, cone beam computed tomography (CBCT) sections, and cone beam volumetric data on the determination of periapical bone destruction in endodontically treated distal root canals of premolar canine teeth. Nontreated mesial roots were used as controls. STUDY DESIGN: Enterococcus faecalis strain (ATCC 29212) was inoculated into 30 root canals of 2 mongrel dogs to induce apical periodontitis. After 60 days, the root canals of the distal roots of the 11 mandibular and 4 maxillary premolars were endodontically treated (n = 15). The mesial root canals were used as controls (no treatment). The bone destruction was evaluated after 6 months by 5 evaluators using periapical radiographs and by CBCT (coronal and sagittal sections). After the experimental period, the area of the lesions in periapical radiographs and CBCT sections were measured in mm(2) using the ImageTool software. A single evaluator measured the volumetric data using the OsiriX software. The comparison between the diagnosis methods in treated root canals and controls was performed using parametric and nonparametric criteria. The Pearson correlation coefficient was computed between radiographic values and CBCT volumetric data in treated root canals and controls. RESULTS: The results showed the presence of chronic apical periodontitis in every inoculated tooth. After 6 months, periapical radiographs, coronal CBCT sections, and volumetric data showed lower bone destruction in endodontically treated teeth in comparison with the control group (P < .05). The 5 evaluators found no differences between the apical periodontitis area of treated teeth and controls when CBCT sagittal sections were used (P > .05). No correlation was found between x-ray and CBCT volumetric values in treated root canals. CONCLUSIONS: Although selected CBCT sagittal sections showed similar values of bone destruction in endodontically and nontreated root canals, volumetric CBCT data showed that periapical lesions of endodontically treated root canals had half of the volume of periapical lesions in nontreated root canals. No relationship could be found between the periapical values of bone destruction and volumetric data found in CBCT of treated rood canals. PMID- 21530335 TI - Evaluation of decalcifying effect of maleic acid and EDTA on root canal dentin using energy dispersive spectrometer. AB - OBJECTIVE: The aim of this study was to evaluate mineral contents of root canal dentin after treatment with 7% maleic acid (MA) or 17% EDTA. STUDY DESIGN: Thirty pieces of teeth were divided into 3 groups: 1) 17% EDTA; 2) 7% MA; and 3) saline. All specimens were treated for 0, 1, 5, 10, 15 minutes. Levels of calcium, phosphorus, magnesium, sodium, sulfur, and oxygen were measured using energy dispersive spectrometer. Data were analyzed using 1-way analysis of variance. Tukey honest significant difference and Bonferroni test were used for comparison between the groups and time periods. RESULTS: MA reduced maximum amount of calcium and phosphorus at all time intervals, but was significant only up to 5 minutes (P < .001). Oxygen, sulfur, and magnesium were decreased more with saline and least with MA (P < .001). Sodium was decreased more with MA and least with EDTA (P < .001). CONCLUSIONS: MA decalcifies the root dentin, with most calcium and phosphorus extracted during the first 5 minutes, compared with EDTA. PMID- 21530337 TI - On the contextual nature of sex-related biases in pain judgments: the effects of pain duration, patient's distress and judge's sex. AB - Although women report feeling more pain than men their pain is often under-valued as compared to men's pain. We argue that such biases are not universal, being either enhanced or suppressed by context-related variables pertaining to the situation, the patient and the perceiver. Consequently, we aimed at understanding the effects of pain duration, patient's distress and the judge's sex on sex related biases in pain judgements. Two-hundred and five nursing students (44.9% male) participated in a between-subjects design, 2 (pain duration)*2 (patient's distress)*2 (patient's sex)*2 (participant's sex). Participants read a vignette depicting a man/woman going into an Emergency Room complaining of low-back pain, that he/she had had for 3days/years, with/without signs of distress. Afterwards, participants judged the: (1) clinical severity/urgency; (2) pain credibility; and (3) pain disability. Findings showed that sex-related biases were only evident when pain was acute or expressed without distress. In these cases, the woman's clinical situation was perceived as less severe/urgent and her pain as less credible as compared to the man's. Moreover, only the judgments on the woman's pain were moderated by such contextual variables. Finally, male students were more biased than females. Implications for gender equality in pain treatments are drawn. PMID- 21530336 TI - Kruppel-like factor 2 regulated gene expression in mouse embryonic yolk sac erythroid cells. AB - KLF2 is a Kruppel-like zinc-finger transcription factor required for blood vessel, lung, T-cell and erythroid development. KLF2-/- mice die by embryonic day 14.5 (E14.5), due to hemorrhaging and heart failure. In KLF2-/- embryos, beta like globin gene expression is reduced, and E10.5 erythroid cells exhibit abnormal morphology. In this study, other genes regulated by KLF2 were identified by comparing E9.5 KLF2-/- and wild-type (WT) yolk sac erythroid precursor cells, using laser capture microdissection and microarray assays. One hundred and ninety six genes exhibited significant differences in expression between KLF2-/- and WT; eighty-nine of these are downregulated in KLF2-/-. Genes involved in cell migration, differentiation and development are over-represented in the KLF2 regulated gene list. The SOX2 gene, encoding a pluripotency factor, is regulated by KLF2 in both ES and embryonic erythroid cells. Previous work had identified genes with erythroid-enriched expression in the yolk sac. The erythroid-enriched genes reelin, adenylate cyclase 7, cytotoxic T lymphocyte-associated protein 2 alpha, and CD24a antigen are downregulated in KLF2-/- compared to WT and are therefore candidates for controlling primitive erythropoiesis. Each of these genes contains a putative KLF2 binding site(s) in its promoter and/or an intron. Reelin has an established role in neuronal development. Luciferase reporter assays demonstrated that KLF2 directly transactivates the reelin promoter in erythroid cells, validating this approach to identify KLF2 target genes. PMID- 21530338 TI - Abnormal facilitatory mechanisms in motor cortex of migraine with aura. AB - Experimental evidence suggests impairment of inhibitory intracortical circuits in migraine, while not much is known about activity of facilitatory intracortical circuits. In the present work we evaluated the effects of high frequency repetitive transcranial magnetic stimulation (hf-rTMS) on the activity of facilitatory circuits of motor cortex in 18 patients affected by migraine with aura and 18 healthy subjects. Trains of 10 stimuli were applied to the motor cortex at 5-Hz frequency with recording of the EMG traces from the contralateral abductor pollicis brevis muscle (APB). Two intensities of stimulation (110% and 130% of resting motor threshold) were used in order to explore whether motor cortex excitability was differently modulated. Twelve patients underwent hf-rTMS both before and during prophylactic treatment with levetiracetam. Results showed that rTMS delivered at 110% intensity of stimulation at rest had a facilitatory effect on MEP size in untreated patients, while left MEP unchanged in controls. Conversely, when rTMS was applied at 130%, we observed MEP potentiation in healthy subjects and paradoxical MEP inhibition in migraineurs. In treated patients, levetiracetam inhibited MEP size at both 110% and 130% intensity of stimulation. Our findings reveal an opposite response of migraine motor cortex to 5-Hz rTMS when it is delivered at different stimulation intensities, providing evidence of both hyper-responsivity and self-limiting hyperexcitability capacity, in line with studies supporting the concept that under conditions of cortical hyperexcitability inhibitory mechanisms of homeostatic plasticity could be activated. PMID- 21530339 TI - Differential effects on sensory functions and measures of epidermal nerve fiber density after application of a lidocaine patch (5%) on healthy human skin. AB - Topical application of lidocaine is an effective approach for treatment of post herpetic neuralgia and other painful neuropathies. Lidocaine inhibits voltage gated Na(+) channels and it most likely reduces excitability of cutaneous sensory neurons which can be hyperexcitable or spontaneously active in states of neuropathic pain. However, lidocaine and other local anesthetics also exert a pronounced neurotoxicity and they activate the irritant receptors TRPV1 and TRPA1. In this randomized and double-blinded study, we explored the ability of lidocaine patches (5%) to alter sensory function and epidermal nerve fiber density in skin of healthy volunteers. As assessed by quantitative sensory testing, significantly elevated thresholds for touch, pin prick pain and mechanically induced wind-up were observed in skin treated with lidocaine patches. These effects reversed to baseline values within 2days after termination of the treatment. Pressure pain and thresholds for heat and cold-induced pain were not affected by the lidocaine patch. A moderate but significant decrease in epidermal nerve fiber density was observed in skin blister roofs obtained after 42days of treatment with lidocaine patches. The placebo patch did not induce any changes in sensory thresholds or nerve fiber density. In conclusion, lidocaine patches seem to have differential effects on sensory modalities in healthy skin. A degeneration of epidermal nerve fibers has previously been demonstrated for patches containing the TRPV1-agonist capsaicin and our findings suggest that this effect might also be relevant for lidocaine patches. These data warrant further studies on molecular mechanisms mediating a relief of neuropathic pain by topical lidocaine. PMID- 21530340 TI - Malacoplakia of the tongue complicating the site of irradiation for squamous cell carcinoma with review of the literature. AB - Malacoplakia is a benign and uncommon inflammatory response that develops most frequently in the genitourinary tract but has been reported at other sites. We report the case of 67-year-old man who presented with a lesion at the base of the tongue 7 months after chemoradiation for biopsy-proven invasive squamous cell carcinoma of the tongue. The lesion showed intense avidity by positron emission tomography and was biopsied with the putative clinical diagnosis of recurrent malignancy. Histologically, the lesion showed the characteristics of malacoplakia as well as abundant intracellular gram-negative bacilli. Ultrastructural analysis revealed giant lysosomes, intracytoplasmic calcific concretions (Michaelis-Gutman bodies), and partially digested gram-negative bacilli within vacuolated lysosomes of macrophages. To our knowledge, this is the seventh reported case of malacoplakia of the tongue and the first to develop at the site of prior radiation treatment of a carcinoma. The clinical features of this case, a review of previously reported cases, and a consideration of pathogenesis are presented. PMID- 21530341 TI - Iso-energetic multiple conformations of hypermodified nucleic acid base wybutine (yW) which occur at 37(th) position in anticodon loop of tRNA(Phe). AB - Conformational preferences of wybutine (yW) have been studied by quantum chemical semi-empirical Perturbative Configuration Interaction with Localized Orbitals (PCILO) and PM3 methods. Automated full geometry optimization by using RM1 along with ab-initio Hartree-Fock (HF-SCF) and Density Functional Theory (B3LYP/6 31G**) calculations have also been made to compare the salient features. Molecular dynamics (MD) simulation has been performed to see the solvation effect on wybutine side chain. The preferred conformations of wybutine side chain spreads away 'distal' from five membered imidazole moiety of tricyclic base. The intramolecular interactions provide stability to the preferred wybutine structure. The most stable and alternative stable structures obtained by PCILO and PM3 methods reveal that wybutine side chain may have multiple iso-energetic conformations. Molecular dynamics (MD) simulation study also confirms multiple conformations of wybutine side chain by showing regular periodical fluctuations over the 2 ns time period. These fluctuations occur when torsion angle alpha takes value +/-90 degrees and +/-120 degrees as observed in the most stable and alternative stable structures resulted by PCILO and PM3 methods. Such conformational behavior of wybutine may have certain implications on frameshifting to prevent extended Watson-Crick base pairing by maintaining proper codon-anticodon interactions during protein biosynthesis process. PMID- 21530343 TI - Orthopedic implant of a polyhydroxybutyrate (PHB) and hydroxyapatite composite in cats. AB - The purpose of this study was to evaluate the tissue response to a 70% polyhydroxybutyrate and 30% hydroxyapatite composite in the form of a bone implant, placed intracortically in the distal metaphyseal of the right femur, and subcutaneous implants in cats. Samples of the composite were implanted subcutaneously in the dorsolumbar region and the distal metaphyseal region of the right femur of the animals. The study used 12 neutered adult mixed breed cats, weighing an average of 3.5kg. The cats were randomly divided into three groups: GI, GII and GIII, according to the length of the assessment period. The assessments of their subcutaneous and bone tissues were performed at 15, 30 and 45 days and at 30, 60 and 90 days, respectively. The subcutaneous and bone reactions to the composites were characterized by granulomatous inflammation with a predominance of macrophages and giant cells. The results showed that the composites triggered a chronic local inflammatory response, despite their clinical acceptance. PMID- 21530342 TI - Molecular modelling and competition binding study of Br-noscapine and colchicine provide insight into noscapinoid-tubulin binding site. AB - We have previously discovered the tubulin-binding anti-cancer properties of noscapine and its derivatives (noscapinoids). Here, we present three lines of evidence that noscapinoids bind at or near the well studied colchicine binding site of tubulin: (1) in silico molecular docking studies of Br-noscapine and noscapine yield highest docking score with the well characterised colchicine binding site from the co-crystal structure; (2) the molecular mechanics generalized Born/surface area (MM-GB/SA) scoring results DeltaDeltaG(bind-cald) for both noscapine and Br-noscapine (3.915 and 3.025 kcal/mol) are in reasonably good agreement with our experimentally determined binding affinity (DeltaDeltaG(bind-Expt) of 3.570 and 2.988 kcal/mol, derived from K(d) values); and (3) Br-noscapine competes with colchicine binding to tubulin. The simplest interpretation of these collective data is that Br-noscapine binds tubulin at a site overlapping with, or very close to colchicine-binding site of tubulin. Although we cannot rule out a formal possibility that Br-noscapine might bind to a site distinct and distant from the colchicine-binding site that might negatively influence the colchicine binding to tubulin. PMID- 21530344 TI - Use of a self-expanding metallic stent for the treatment of a urethral stricture in a young cat. AB - A 4-month-old intact male domestic shorthair cat was evaluated for urinary outflow obstruction after several weeks of medical management for traumatic urethral rupture. Positive-contrast retrograde urethrography and anterograde cystoscopy performed 4 weeks after the initial urethral injury confirmed a stricture approximately 1cm distal to the bladder trigone at the site of the initial urethral tear. A self-expanding metallic urethral stent (SEMS) was placed under fluoroscopic guidance to relieve the urethral stricture and re-establish luminal patency. After stent placement, the cat was able to void urine normally with minimal urinary incontinence noted. This resolved several months post-stent placement. No known clinical complications persisted other than mild intermittent hematuria. PMID- 21530345 TI - [Possible rosuvastatin-induced fatal rhabdomyolysis]. PMID- 21530346 TI - [Tools for assessing the quality of cross-sectional epidemiological studies]. PMID- 21530347 TI - [Endoscopic percutaneous gastrostomy: an update on the indications, technique and nursing care]. AB - There are numerous conditions and pathologies in which the patient's swallowing ability is diminished or prevented despite having working digestive system. These are the fundamental requirements for the placement of a percutaneous gastrostomy tube (PEG) as a method of choice to provide safe, effective, and prolonged enteral nutrition for the patient at home or when admitted to hospital. Due to its simplicity, safety and low cost, PEG offers several advantages over other feeding techniques, particularly nasogastric tube and parenteral feeding, although it does require simple and accurate knowledge and application of care that ensures low incidence of complications. The placement of a PEG tube should be contemplated in several clinical situations: a) for temporal use in those patients with potentially reversible diseases; b) in non-reversible diseases in which a long survival (of more than 6 months) is foreseeable, and c) in patients affected of terminal and debilitating illnesses in whom a relatively long survival is probable. In these last cases the indication and implementation for PEG should be individualized and agreed jointly. The appropriate training of care professionals and familiar supporters in charge of the patients carrying a PEG tube ensures its continuous functioning and reduces the risk of complications. This paper aims to review the indications and appropriate care for patients carrying a PEG tube and presents the most accurate care that should be provided by both the professional health carers and caregivers. PMID- 21530348 TI - Effect of a single dose of methyl prednisolone as rescue medication for patients who develop hypotensive dengue shock syndrome during the febrile phase: a retrospective observational study. PMID- 21530349 TI - Meningococcal septic shock: is insulin lifesaving in children? PMID- 21530350 TI - Candidemic complications in patients with intravascular catheters colonized with Candida species: an indication for preemptive antifungal therapy? AB - BACKGROUND: The impact of Candida-colonized catheter tips in patients without candidemia is unclear. METHODS: A retrospective study of patients with tip cultures positive for Candida was conducted over an 8-year period, to determine the outcomes in patients with Candida cultured from an intravascular catheter tip in the absence of preceding Candida-positive blood cultures. The primary outcome measure was definite candidemia. Secondary outcomes included possible candidemia and in-hospital mortality. A possible candidemia was defined as clinical signs and symptoms of invasive candidiasis without explanation other than a candidemia, but with negative blood cultures. RESULTS: Sixty-eight cultures from 64 patients were included in the study. Definite candidemia developed in three cases (4%) and possible candidemia developed in five cases (7%). In-hospital mortality was significantly increased in patients with definite or possible candidemia (63% vs. 22%, p=0.028). Risk factors for the development of definite or possible candidemia were catheter time in situ >8 days (odds ratio (OR) 6.0, 95% confidence interval (CI) 1.1-32.9) and abdominal surgery (OR 6.0, 95% CI 1.1 32.4). CONCLUSIONS: Intravascular catheter tip colonization in patients without preceding blood cultures with Candida is associated with candidemia in from 4% of patients (definite candidemia) up to 12% of patients (definite and possible candidemia combined). Considering the adverse prognosis associated with delayed treatment of candidemia, preemptive treatment based on catheter tip cultures might outweigh the disadvantages of costs and side effects of antifungal therapy. PMID- 21530351 TI - Locked metacarpophalangeal joint of long fingers: classification, definition and treatment based on 15 cases and literature review. AB - OBJECTIVES: The purpose of this study was to clarify the definition, classification and treatment of the disorder known as the locked metacarpophalangeal (MCP) joint of long fingers, through the analysis of 15 cases and a literature review. PATIENTS AND METHODS: We carried out a retrospective study of 15 patients with locked MCP joint of long fingers, all treated between 1997 and 2007. All patients underwent some imaging investigations including lateral, anteroposterior and Brewerton X-ray examinations. All these patients had been treated by surgery, which allowed us to describe the concerned lesions. RESULTS: The patients were 47 years old on average, 70% of the locks involved the index and the middle finger. Twelve fingers were locked in flexion. In nine of these cases, the cause was a blocking due to a clinging of the radial or ulnar accessory collateral ligament that overlapped a prominent metacarpal condyle or an osteophyte of the metacarpal head. Three fingers were locked in extension due to an imprisonment of a strap of the palmar plate. One patient was lost to follow up. The remaining 14 patients had an average follow-up of 12.6 months. All recovered normal mobility without any recurrence. CONCLUSION: This study and the literature review show that there are in fact two clinical presentations depending on the etiologies. We suggest a modification of both Posner's definition and Harvey's classification; a new classification should focus on the causes depending on the clinical presentation of the locking, so as to improve the correlation between clinical presentation, etiology and treatment. PMID- 21530352 TI - [The big step of settlement (of the private consultant)]. PMID- 21530353 TI - [Residency in obstetrics and gynaecology in Poitou-Charentes]. PMID- 21530354 TI - [Evidence for universal GBS screening in pregnancy]. PMID- 21530355 TI - Medical Engineering & Physics. Editorial. PMID- 21530356 TI - The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. AB - The antiparkinsonian response to levodopa is characterized by an immediate motor improvement lasting hours and a more sustained response lasting days. These two responses have been referred to as the short-duration response (SDR) and the long duration response (LDR). The LDR represents a substantial component of the clinical effect of levodopa and has been clinically recognized for several decades, but it remains poorly understood. This review will focus on the LDR phenomenology and theories about its origin, with the goal of promoting inquiry into this important but as yet poorly understood aspect of levodopa therapy for PD. PMID- 21530357 TI - Paroxysmal exercise-induced dyskinesia with self-limiting partial epilepsy: a novel GLUT-1 mutation with benign phenotype. AB - Paroxysmal exercise-induced dyskinesia (PED) is a rare form of dystonia induced by prolonged exercise, usually involving lower limbs. PED has been recently described as a possible clinical manifestation of mutations of SLC2A1 gene, encoding for the glucose transport GLUT-1. We report a case of a young woman with a mild form of PED associated with self-limiting partial epilepsy. She carries a novel sporadic heterozygous mutation of the SLC2A1 gene. Diagnostic difficulties and possible treatment with carbamazepine are discussed. PMID- 21530358 TI - Parkinson's disease and hospitalization: the need for guidelines. PMID- 21530359 TI - Migration does not enlarge inequalities in health between rich and poor neighbourhoods in The Netherlands. AB - We estimate to what extent migration contributes to inequalities in health between rich and poor neighbourhoods in The Netherlands. We used a sample from the survey WoonOnderzoek Nederland 2006. Using multilevel logistic regression analyses, we assessed the magnitude of health differences between poor vs. rich areas for the migrant and total population. Next, we compared the health of migrants to non-migrant populations and we assessed the role of sociodemographic characteristics. For most health indicators, area inequalities in health were much smaller in the migrant population than in the total population. The health of migrants was generally in-between the health of non-migrants who lived in areas of origin and destination. The differences in health with the population in the areas of origin were almost completely explained by sociodemographic characteristics. Health is related to risk of migration between poor and rich areas, mostly through sociodemographic selection instead of a direct effect of health. Despite the relationship with health, migration does not enlarge inequalities in health between poor and rich neighbourhoods but possibly attenuates the health differences. PMID- 21530360 TI - A comprehensive study of stent visualization enhancement in X-ray images by image processing means. AB - In this work we propose a comprehensive study of Digital Stent Enhancement (DSE), from the analysis of the requirements to the validation of the proposed solution. First, we derive the stent visualization requirements in the context of the clinical application and workflow. Then, we propose a DSE algorithm combining automatic detection, tracking, registration and contrast enhancement. The most original parts of our solution: landmark segmentation and non-linear image registration are detailed. Finally, we validate the algorithm on a large number of synthetic and clinical cases. Performance is characterized in terms of automation, image quality and execution time. This work is, to the best of our knowledge, the first comprehensive article on DSE, covering problem statement, proposed solution, and validation strategies. PMID- 21530361 TI - Evaluation of visualization of the prostate gland in vibro-elastography images. AB - In this paper, vibro-elastography (VE), an ultrasound-based method that creates images of tissue viscoelasticity contrast, is evaluated as an imaging modality to visualize and segment the prostate. We report a clinical study to characterize the visibility of the prostate in VE images and the ability to detect the boundary of the gland. Measures for contrast, edge strength characterized by gradient and statistical intensity change at the edge, and the continuity of the edges are proposed and computed for VE and B-mode ultrasound images. Furthermore, using MRI as the gold standard, we compare the error in the computation of the volume of the gland from VE and B-mode images. The results demonstrate that VE images are superior to B-mode images in terms of contrast, with an approximately six fold improvement in contrast-to-noise ratio, and in terms of edge strength, with an approximately two fold improvement in the gradient in the direction normal to the edge. The computed volumes show that the VE images provide an accurate 3D visualization of the prostate with volume errors that are slightly lower than errors computed based on B-mode images. The total gland volume error is 8.8+/-2.5% for VE vs. MRI and 10.3+/-4.6% for B-mode vs. MRI, and the total gland volume difference is -4.6+/-11.1% for VE vs. MRI and -4.1+/-17.1% for B mode vs. MRI, averaged over nine patients and three observers. Our results show that viscoelastic mapping of the prostate region using VE images can play an important role in improving the anatomic visualization of the prostate and has the potential of becoming an integral component of interventional procedures such as brachytherapy. PMID- 21530362 TI - Role of contact lenses in relieving ocular allergy. AB - PURPOSE: To examine the potential barrier and lubricating effects of modern daily disposable contact lenses (DD) against airborne antigens. METHODS: Ten patients with skin prick and ocular conjunctival provocation confirmed allergic sensitivity to grass pollen were recruited (average age 27.4 +/- 7.7 years). Each had their ocular symptoms (on a 0 none to 5 extreme scale) and appearance of bulbar and limbal conjunctival redness, palpebral conjunctival redness and roughness, and corneal and conjunctival fluorescein staining (CCLRU scale) graded before and five minutes after exposure to 400 grains grass pollen/m(3) for 2 min in a purpose-designed exposure chamber to simulate the conditions of a 'very high' pollen-count day. This was repeated on three occasions separated by >72 h wearing etafilcon A (sDD), nelfilcon A with enhanced lubricating agents (ELDD) and no contact lenses in random order out of the pollen season. Each sign and symptom was compared to baseline for each condition. The duration of the symptoms was also recorded (http://www.clinicaltrials.govNCT01125540). RESULTS: Only symptoms of burning and stinging were significantly reduced in severity by ELDD (Chi-Sq = 7.6, p = 0.02), but overall symptoms were significantly reduced in duration (F = 3.60, p = 0.05). Bulbar hyperaemia, corneal and conjunctival staining, and palpebral conjunctival roughness were significantly reduced by DD wear (p < 0.01), with limbal and palpebral conjunctival redness further reduced in ELDD (p < 0.05). CONCLUSION: Daily disposable contact lenses offer a barrier to airborne antigen which is enhanced by modern lenses with enhanced lubricating agents. PMID- 21530363 TI - The status of EGFR CA SSR1 is a potential prognostic factor for patients with oral squamous cell carcinoma. AB - The EGFR is an oncogene known to be involved in the development and progression of many cancers. It has been reported that the expression of EGFR and EGFR CA simple sequence repeat 1 (CA SSR1) repeat numbers in tumors can be useful prognostic factors in several cancer types. The objective of the present study was to analyze whether the EGFR polymorphism can be a useful prognostic factor in OSCC in the Taiwanese population. OSCC tissues were collected from 47 patients by surgical excision. The genotyping of EGFR were performed with the ABI Prism 3100 Genetic Analyzer. OSCC patients had a tendency toward an allelic imbalance of CA SSR1. The results also suggested that OSCC patients who were homozygous for CA SSR1 had a poorer prognosis than those who were heterozygous (P<0.001). Besides, patients with an allelic imbalance of CA SSR1 had significantly lower overall and disease free survival rates than those without, using the Kaplan-Meier method (P<0.001). This suggests that the status of CA SSR1 has the potential to be a useful prognosis factor in OSCC. PMID- 21530365 TI - Back to the past for pollination biology. AB - Manipulations of the interactions between plants and their floral visitors remain the most successful path to an understanding of floral traits, which may have been shaped by both herbivores and pollinators. By using genetic tools in combination with old-fashioned field work the dual protective/advertisement functions of floral traits are being realized. The distinction between wanted and unwanted floral visitors is blurring, and plants with specialized pollination systems are being found capable of using alternative pollinators if the specialized pollinators fail to perform. PMID- 21530364 TI - Bevacizumab enhances the therapeutic efficacy of Irinotecan against human head and neck squamous cell carcinoma xenografts. AB - Combining antiangiogenic agents with traditional cytotoxic chemotherapy offers the potential to target both vascular and cellular components of a growing tumor mass. Here, we examined the antitumor activity of the vascular endothelial growth factor antibody, Bevacizumab (Avastin(r)) in combination with the topoisomerase I inhibitor, Irinotecan (CPT-11) against human head and neck squamous cell carcinoma (HNSCC) xenografts. Bevacizumab was administered daily (at 5 or 20mg/kg) to nude mice bearing FaDu HNSCC xenografts for 28days with the first dose beginning seven days prior to Irinotecan (100mg/kg, weekly * 4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and immunohistochemical (IHC) methods were employed to study the antiangiogenic effects of Bevacizumab in vivo. Kinetics of tumor response to treatment was studied by monitoring tumor volume over a 60-day period. DCE-MRI detected a significant reduction in vascular permeability following treatment with Bevacizumab (5mg/kg) while high dose Bevacizumab (20mg/kg) induced significant microvascular damage and tumor necrosis, confirmed by immunohistochemistry (IHC). Irinotecan alone resulted in complete tumor regression (cures) in ~40% of animals while Bevacizumab alone did not result in any cures. Treatment with Bevacizumab (5mg/kg/day*28days) in combination with Irinotecan (100mg/kg, weekly * 4) was highly effective in inhibiting FaDu tumor growth and resulted in complete tumor regression in 80% of animals. These results demonstrate that long term administration of Bevacizumab effectively modulates chemotherapeutic efficacy against HNSCC xenografts. Further investigation into the therapeutic potential of this combination strategy against HNSCC is warranted. PMID- 21530367 TI - From lab to field, new approaches to phenotyping root system architecture. AB - Plant root system architecture (RSA) is plastic and dynamic, allowing plants to respond to their environment in order to optimize acquisition of important soil resources. A number of RSA traits are known to be correlated with improved crop performance. There is increasing recognition that future gains in productivity, especially under low input conditions, can be achieved through optimization of RSA. However, realization of this goal has been hampered by low resolution and low throughput approaches for characterizing RSA. To overcome these limitations, new methods are being developed to facilitate high throughput and high content RSA phenotyping. Here we summarize laboratory and field approaches for phenotyping RSA, drawing particular attention to recent advances in plant imaging and analysis. Improvements in phenotyping will facilitate the genetic analysis of RSA and aid in the identification of the genetic loci underlying useful agronomic traits. PMID- 21530366 TI - Mutualistic interactions on a knife-edge between saprotrophy and pathogenesis. AB - Saprophytic, ectomycorrhizal (ECM) and pathogenic fungi play a key role in carbon and nutrient cycling in forest ecosystems. Whereas more than 50 genomes of saprotrophic and pathogenic fungi have been published, only two genomes of ECM fungi, Laccaria bicolor and Tuber melanosporum, have been released. Comparative analysis of the genomes of biotrophic species highlighted convergent evolution. Mutualistic and pathogenic biotrophic fungi share expansion of genome size through transposon proliferation and common strategies to avoid plant detection. Differences mainly rely on nutritional strategies. Such analyses also pinpointed how blurred the molecular boundaries are between saprotrophism, symbiosis and pathogenesis. Sequencing of additional ECM species, as well as soil saprotrophic fungi, will facilitate the identification of conserved traits for ECM symbiosis and those leading to the transition from white-rotting and brown-rotting to the ECM lifestyle. PMID- 21530368 TI - The role of transition metal homeostasis in plant seed development. AB - For human health, transition metal accumulation in edible seeds like cereal grains is of worldwide importance, since Fe and Zn deficiencies are among the most prevalent human nutritional disorders in the world. There have been many recent developments in our understanding of the patterns in which transition metals accumulate in the seeds, the identity of some specific transporters that are required for efficient seed metal accumulation, and the central role played by the ubiquitous plant metal chelator nicotianamine (NA). These and other recent discoveries will be reviewed here. PMID- 21530369 TI - Preparation of 4,4'-bis-(carboxyl phenylazo)-dibenzo-18-crown-6 dye and its application on ratiometric colorimetric recognition to Hg2+. AB - A multifunctional dye, 4,4'-bis-(carboxyl phenylazo)-dibenzo-18-crown-6 dye (BCADC) was designed and prepared via diazotization and coupling reaction of dibenzo-18-crown-6 with p-amino benzoic acid. The dye, combining crown ether ring, azo and carboxyl group, exhibits well-defined Hg(2+)-selective ratiometric colorimetric behavior, with the maximum absorbance peak changing from 354 nm to 408 nm exclusively. Under the optimum conditions, the recognition to Hg(2+) has a linear range of 2.5-58*10(-7) mol L(-1) with a 0.9978 correlation coefficient. The method was applied to analyse 3 environmental water samples with a detection limit of 2.9*10(-8) mol L(-1) and a relative standard deviation (R.S.D.) lower than 3.7% (n=5). The action mechanism between BCADC and metal ions was discussed by means of Job's plots and theoretical calculations. PMID- 21530370 TI - The use of a multi-method approach to identify the pigments in the 12th century manuscript Liber Floridus. AB - A selection of illuminations of the 12th century manuscript Liber Floridus was analysed with Raman spectroscopy (in situ and laboratory measurements), X-ray fluorescence spectroscopy, UV-fluorescence photography and infrared reflectography (IRR). The aim of this study is to determine the pigments used, in order to search for anachronisms. Using a combination of Raman spectroscopy (molecular information) and X-ray fluorescence spectroscopy (elemental information) following pigments could be identified: ultramarine (Na(8 10)Al(6)Si(6)O(24)S(2-4)), azurite (2CuCO(3).Cu(OH)(2)), caput mortuum (Fe(2)O(3)), vermilion (HgS), orpiment (As(2)S(3)) and lead white (2PbCO(3).Pb(OH)(2)). Moreover, two synthetic red pigments, PR4 and PR176, and a degradation product, gypsum (CaSO(4).2H(2)O), were present in the manuscript. To establish the origin of the modern materials UV-fluorescence photography was used. Infrared reflectography (IRR) was applied to visualise the underdrawing of the investigated folios. PMID- 21530371 TI - Absorption spectrophotometric, fluorescence and theoretical investigations on supramolecular interaction of a designed bisporphyrin with C60 and C70. AB - The present article reports the spectroscopic and theoretical investigations on supramolecular interaction between fullerenes (C(60) and C(70)) and a designed bisporphyrin, namely 1, in toluene. Job's method of continuous variation establishes 1:1 stoichiometry of the fullerene/1 complexes. Both absorption spectrophotometric and steady-state fluorescence studies reveal effective and selective interaction between fullerenes and 1 as average binding constants (K) for the C(60)/1 and C(70)/1 complexes are enumerated to be 34,700 and 359,925 dm(3) mol(-1), respectively. Large selectivity ratio in K, i.e., K(C(70))/K(C(60)), indicates that 1 acts as an effective molecular tweezers for C(70) in solution. Time-resolved fluorescence study evokes that the quenching of fluorescence of 1 by fullerenes is of static type in nature. Molecular mechanics calculations in vacuo determine the energies and single projection structures of the supramolecular systems, which provide very good support in favor of strong binding between C(70) and 1. PMID- 21530372 TI - Use of the Raman spectrometer in gemmological laboratories: review. AB - The current paper gives an overview of the development of Raman spectrometry in gemmological laboratories. While before 1990s, no commercial gemmological laboratory possessed such an instrument, all larger international labs have acquired these instruments by now. The Raman spectrometer is routinely used for the detection of emerald fillers, HPHT treatment of diamonds, analysis of the nature of a gemstone, analysis of gemstone inclusions and treatments, and the characterisation of natural or colour enhanced pearls and corals. Future developments in gemstone research lie in the closer analysis of the features of Raman and PL spectra and in the combination of several instruments. PMID- 21530373 TI - A novel acetate selective chromogenic chemosensor based on phenanthroline. AB - A novel colorimetric anion-chemosensor based on 1,10-phenanthroline-2,9 dicarbonyl-p-nitro-phenylhydrazine has been synthesized. Among the different anions tested, it shows the best selectivity towards AcO(-). The addition of acetate causes the color to change from yellow to red, which could be detected with naked eyes. The binding ability of chemosensor 1 with anions has been investigated through UV-vis spectral titrations. In addition, (1)H NMR experiment was carried out to explore the nature of interaction between chemosensor 1 and acetate. PMID- 21530374 TI - Synthesis, crystal structure and luminescence properties of one inorganic-organic hybrid compound [FTMA]2[Co(NCS)4] (FTMA = ferrocenylmethyltrimethylammonium cation). AB - A new inorganic-organic hybrid compound [FTMA](2)[Co(NCS)(4)] (FTMA = ferrocenylmethyltrimethylammonium cation) has been synthesized and characterized by IR, UV, elemental analysis and X-ray crystallography. Co(II) atom has a distorted tetrahedral environment with four N atoms of four NCS(-) anions. In the solid state there are C-H?pi interactions between adjacent ferrocenyl cations, which generate one-dimensional (1-D) supramolecular chain, and C-H?S hydrogen bonds between [FTMA](+) cations and cobalt thiocyanate anions. The title compound shows strong purple fluorescence emission in the solid state at room temperature. PMID- 21530375 TI - Ultra-sensitive determination of cadmium in rice and water by UV-vis spectrophotometry after single drop microextraction. AB - In this work, a new method based on single drop microextraction (SDME) preconcentration using tetrachloromethane (CCl(4)) as extraction solvent was proposed for the spectrophotometric determination of cadmium in rice and water samples. The influence factors relevant to SDME, such as type and volume of extractant, stirring rate and time, dithizone concentration, pH, drop volume and instrumental conditions were studied systematically. Under the optimal conditions, the limit of detection (LOD) was 0.5 ng L(-1), with sensitivity enhancement factor (EF) of 128. The different maximum absorption wavelength caused by the different extraction acidity compared with some conventional works and the enhancement effect of acetone (dilution solvent) for the spectrophotometric determination were the two key factors of the high EF and sensitivity. The proposed method was applied to the determination of rice and water samples with satisfactory analytical results. The proposed method was simple, rapid, cost-efficient and sensitive. PMID- 21530376 TI - Solvatochromaticity and pH dependence of the electronic absorption spectra of some purines and pyrimidines and their metal complexes. AB - The solvatochromic responses of uric acid (Ua), 6-amino-2-thiouracil (ATU) and a series of their complexes dissolved in ten solvents of different polarity have been measured. The solvent-dependent UV/Vis spectroscopic absorption maxima, lambda(max), are assigned to the corresponding electronic transitions and analyzed using SPSS program, regression analysis and Kamlet and Taft methods. The observed solvatochromism is discussed using various solute-solvent interaction mechanisms. The electronic absorption spectra of ATU were investigated in aqueous buffer solutions of varying pH and utilized for the determination of dissociation constants. The ranges of pH, where individual ionic species are predominant have been determined. PMID- 21530377 TI - Spectrophotometric determination of boron based on charge transfer reaction. AB - Boron determination by a charge transfer spectrophotometric method is described. Accompanied the reaction, a charge transfer complex can be formed by lysine with sodium 1, 2-naphthoquinone-4-sulfonate and boron in alkaline solution (pH 12.00). Subsequently, a new reaction mechanism has been proposed and discussed. The absorbance at the maximal absorption wavelength is 574 nm and boron concentration agrees well with Beer's law in a range of 2.16-43.24 MUg mL(-1). The linear regression equation is A=-0.01867+0.01326C (MUg mL(-1)), with a linearly correlation coefficient of 0.9935. The relative standard deviation (R.S.D.) of eleven parallel determinations is 2.1% with a detection limit (3sigma/k) of 2.00 MUg mL(-1). The recovery ranges from 96.4% to 104.5% with the satisfactory results. This method has been successfully applied to determine boron in pharmaceutical samples directly. PMID- 21530378 TI - Experimental (FT-IR and FT-Raman), electronic structure and DFT studies on 1 methoxynaphthalene. AB - In this work, FT-IR and FT-Raman spectra of 1-methoxynapthalene (C(11)H(10)O) have been reported in the regions 4000-400 cm(-1) and 3500-100 cm(-1), respectively. Density functional method (DFT) has been used to calculate the optimized geometrical parameters, atomic charges, vibrational wavenumbers and intensity of the vibrational bands. The vibrational frequencies have been calculated and scaled values are compared with experimental FT-IR and FT-Raman spectra. The structure optimizations and normal coordinate force field calculations are based on density functional theory (DFT) method with B3LYP/3 21G, B3LYP/6-31G, B3LYP/6-31G(d,p) and B3LYP/6-311++G(d,p) basis sets. The complete vibrational assignments of wavenumbers are made on the basis of potential energy distribution (PED). The optimized geometric parameters are compared with experimental values of naphthoic acid. The results of the calculation shows excellent agreement between experimental and calculated frequencies in B3LYP/6-311++G(d,p) basis set. The effects due to the substitutions of methyl group and carbon-oxygen bond are also investigated. A study on the electronic properties, such as excitation energies and wavelengths, were performed by time-dependent DFT (TD-DFT) approach. HOMO and LUMO energies are calculated that these energies show charge transfer occurs within the molecule. PMID- 21530379 TI - Vibrational spectra and non linear optical proprieties of L-histidine oxalate: DFT studies. AB - This paper presents the results of our calculations on the geometric parameters, vibrational spectra and hyperpolarizability of a nonlinear optical material L histidine oxalate. Due to the lack of sufficiently precise information on geometric structure in literature, theoretical calculations were preceded by re determination of the crystal X-ray structure. Single crystal of L-histidine oxalate has been growing by slow evaporation of an aqueous solution at room temperature. The compound crystallizes in the non-Centro symmetric space group P2(1)2(1)2(1) of orthorhombic system. The FT-IR and Raman spectra of L-histidine oxalate were recorded and analyzed. The vibrational wave numbers were examined theoretical with the aid of Gaussian98 package of programs using the DFT//B3LYP/6 31G(d) level of theory. The data obtained from vibrational wave number calculations are used to assign vibrational bands obtained in IR and Raman spectroscopy of the studied compound. The geometrical parameters of the title compound are in agreement with the values of similar structures. To investigate microscopic second order non-linear optical NLO behaviour of the examined complex, the electric dipole MU(tot), the polarizability alpha(tot) and the hyperpolarizability beta(tot) were computed using DFT//B3LYP/6-31G(d) method. According to our calculation, the title compound exhibits non-zero beta(tot) value revealing microscopic second order NLO behaviour. PMID- 21530380 TI - Experimental and theoretical study on the structure and vibrational spectra of beta-2-aminopyridinium dihydrogenphosphate. AB - Experimental and theoretical vibrational spectra of beta-2-aminopyridinium dihydrogenphosphate (beta-2APDP) have been investigated. The FT-IR spectrum of beta-2APDP was recorded in the region 4000-400 cm(-1). The optimized molecular structure and theoretical vibrational frequencies of beta-2APDP have been investigated using ab initio Hartree-Fock (HF) and density functional B3LYP method with 6-311++G(d,p) basis set. The optimized geometric parameters (bond lengths and bond angles) and theoretical frequencies have been compared with the corresponding experimental data and it is found that they agree well with each other. All the assignments of the theoretical frequencies were performed by potential energy distributions using VEDA 4 program. Furthermore, the used scale factors were obtained from the ratio of the frequency values of the strongest peaks in the experimental and theoretical IR spectra. From the results it was concluded that the B3LYP method is superior to the HF method for the vibrational frequencies. PMID- 21530381 TI - Online health consultation: examining uses of an interactive cancer communication tool by low-income women with breast cancer. AB - PURPOSE: To examine how psychosocial variables predicted use of an online health consultation service among low-income breast cancer patients and in turn how using this service affected these same psychosocial outcomes. METHOD: This retrospective study included 231 recently diagnosed, low-income (at or below 250% of the federal poverty level) breast cancer patients provided a free computer with 16 weeks of access to the Internet-based 'Ask an Expert' service offered as part of the Comprehensive Health Enhancement Support System (CHESS) "Living with Breast Cancer" program. The use activity included a total of 502 messages submitted to the online health consultation service. The data included five psychosocial variables: information seeking, social support, health self efficacy, participation in health care, and doctor-patient relationship, were collected at both the pre-test and 16-week post-test after using the service. Correlation tests were conducted to examine the relationship between pre- and post-test, and use activity. A multiple regression model was formed for each of five psychosocial variables to examine how use activity of the consultation service was associated with various psychosocial measurements. RESULTS: In total, 865 distinct consulting queries from 502 messages were identified as measurement of patients' use activities (3.74 consulting queries per participant). Use activity had significant negative relationships with pre-test scores across all five psychosocial variables. The regression models found significant positive main effects (use activity) associated with three of these psychosocial variables: health self efficacy, participation in health care and doctor-patient relationship. Use activity of the online consultation service did not have significant relationships with the dependent variables of information seeking and perceived social support. CONCLUSION: Low-income breast cancer patients sought out information from an online cancer information expert. Patients with more negative perceptions at pre-test tended to use the service more. Greater use of the service was associated with improvement in patients' perception of health self-efficacy, participation in health care and doctor-patient relationship. Moreover, use of online health consultation appears to level the differences, narrowing the gaps between those who were worse and better off at pre-test. These findings suggest that online health consultation can serve as an effective complement to other resources, which help low-income, breast cancer patients feel more confident to participate more actively in their health care, become more actively involved in making decisions about their treatments and enhance the relationship with their doctors. PMID- 21530382 TI - Review of "pull" point-of-care services. PMID- 21530383 TI - Paper persistence, workarounds, and communication breakdowns in computerized consultation management. AB - OBJECTIVE: The consultation request process between primary care and specialty services often contains paper-based components that may be inefficient and difficult to track. Other barriers may include workarounds and communication breakdowns with the potential to adversely impact delivery of quality medical care. We investigated current challenges to the electronic outpatient consult management process in the United States Veterans Health Administration (VHA). DESIGN: We conducted ethnographic observation and semi-structured interviews in nine different specialty clinics and three primary care clinics in a large, tertiary Veterans Affairs Medical Center (VAMC). We also performed a national level query of 'electronic error and enhancement requests' (E3Rs) related to the consult package in the VA's electronic health record (EHR) submitted over a 5 year period (2005-2009). MEASUREMENTS: Two researchers recorded the observable interactions and interview responses of 16 healthcare workers related to their work with consultations. Two separate coding schemes were applied to both the observational and the interview data. E3Rs from the national query were reviewed and categorized based on the nature of the enhancement requests. RESULTS: We identified several examples of paper persistence, as well as workarounds, communication breakdowns, and redundancies in computerized consult management. An analysis of enhancement requests for the consults also revealed three broad needs related to reporting, configuration or customization, and user interface enhancements. CONCLUSION: Understanding these challenges to the current consult management process is important to help design enhanced informatics tools integrated into workflow to support coordination of care and tracking of consults requests. PMID- 21530385 TI - Efficacy of Abbott RealTime High Risk HPV test in evaluation of atypical squamous cells of undetermined significance from an Asian screening population. AB - BACKGROUND: Abbott RealTime High Risk HPV test is a new qualitative real-time PCR assay for the detection of 14 high risk HPV (HR-HPV) types and specific identification of HPV16 and HPV18. For each new HPV DNA test, it is important to validate its clinical performance using established tests as benchmarks. Hybrid Capture 2 (HC2) is the first USA FDA-approved HR-HPV DNA test. OBJECTIVES: To compare the performance of Abbott RealTime High Risk HPV test with that of Hybrid Capture 2 in detecting cytology samples with varying prognosis. STUDY DESIGN: 250 liquid-based cervical cytology samples diagnosed of Atypical Squamous cells of Undetermined Significance (ASC-US) collected from an Asian Screening Population were independently tested with both Abbott RealTime High Risk HPV test and HC2. Their utility in predicting disease progression was evaluated in 82 of the samples for which follow up cytology or colposcropic histology data was available. RESULTS: Good to excellent agreement between the two tests was demonstrated (Kappa=0.800, 95% CI: 0.726-0.874). The sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the two tests in detecting cases with underlying HSIL/CIN2+ were evaluated (Abbott: 100%, 20.83%, 14.93% and 100% respectively; HC2: 100%, 12.50%, 13.70% and 100% respectively). HPV16/18 genotyping provided by the Abbott test enhanced specific identification of cases with LSIL/CIN1+ (specificity 91.30%, PPV 84.62%) and HSIL/CIN2+ (specificity 86.11%, PPV 23.08%) at follow-up. CONCLUSIONS: The Abbott test performed similarly to HC2 and is unlikely to be affected by ethnicity. Abbott combined HPV detection and HPV 16/18 genotyping is found to provide enhanced sensitivity and specificity for triage of ASC-US. PMID- 21530384 TI - A national study of US bird banders for evidence of avian influenza virus infections. AB - BACKGROUND: Previously we have found that Midwestern US wildlife biologists, poultry farmers, veterinarians, and duck hunters have had evidence of avian influenza virus infections (AIVs). OBJECTIVES: We sought to evaluate a national sample of US bird banders for previous evidence of AIV infection. STUDY DESIGN: Controlled, cross-sectional serological survey. RESULTS: In 2009 and 2010 we enrolled 157 registered bird banders from 40 US states and compared their enrollment data and serological results with 78 adult age-group matched controls from Iowa. On average, the bird banders had 15 years of wild bird exposure, banded 20 days per year, worked chiefly in 1 of the 4 North American flyways, and banded 300 individual birds of 5 different species per season. While handling birds, only 15% of banders reported wearing gloves. Three bird banders and 1 control had evidence of previous infection (1 AIV each) with A/BWTE/Ohio/07/495762-6(H7N3), A/Ty/MN/38391-6/95(H9N2) or A/CK/NJ/7290 2/95(H11N3) by microneutralization assay. There was no evidence of previous infection with a representative sample of H4, H5, H6, H8, or H10 AIVs. Participants were followed for influenza-like-illness for a median of 7 months and 4 (3 bird banders) submitted self-collected eye, nasal, and throat influenza like-illness swab specimens, 1 of which collected in November of 2009, yielded a pandemic H1N1 influenza A virus. CONCLUSION: Despite reports of conjunctivitis and upper respiratory symptoms while bird banding, we found sparse evidence that US bird banders had infections with AIVs. PMID- 21530386 TI - False-negative serology in patients with acute parvovirus B19 infection. AB - BACKGROUND: Acute parvovirus B19 (B19V) infection is characterized by high-level viremia. Antibodies against the capsid proteins VP1 and VP2 may complex with B19V particles thereby becoming undetectable in diagnostic tests. OBJECTIVES: We intended to obtain data on the frequency of false-negative serology in acute B19V infection. STUDY DESIGN: 129 plasma or serum samples of healthy blood donors and of patients with suspected B19V-infection were analyzed for B19V-DNA by qPCR and VP1/VP2-specific IgG and IgM by ELISA. Eleven of these samples were derived from four pregnant women with previous contact to B19V-infected individuals. Using acidic conditions virus/antibody-complexes were disrupted and detected by WesternLine and ELISA. RESULTS: 83/118 samples were derived from acutely infected individuals displaying viremia (10(3)-10(12)geq/mL). In 24/83 viremic samples (28.9%) VP1/VP2-specific IgM and IgG were undetectable in ELISA, but could be demonstrated to be complexed with B19V-particles. Each 7/83 (8.4%) was IgM positive/IgG-negative and IgM-negative/IgG-positive, in 45/83 samples (54.2%) IgG and IgM could be detected. 35 samples did not contain B19V-DNA; five of these were from seronegative persons. Analyzing consecutive sera derived from four pregnant women, B19V-DNA was demonstrated in 10/11 samples, B19V-specific IgG- and IgM-antibodies were detectable in 10/11 and 4/11 samples, respectively. In 2/4 women seroconversion was observed, but IgM was not detected in 50% of the samples. B19V-specific IgG but not IgM was detectable in 2/4 women. CONCLUSION: Acute B19V-infection cannot be diagnosed by exclusive analysis of B19V-specific antibodies. Only the combination of assays for detection of B19V-DNA and antibodies enables correct serodiagnosis. PMID- 21530387 TI - F wave to height or limb length ratios as rational alternatives for F wave latency in clinical electrodiagnostic medicine. AB - OBJECTIVE: To delineate the F wave latency/height (F min/He) or F wave latency/limb length (F min/L) ratio as a more useful alternative for the currently reported shortest latency in milliseconds. METHODS: One hundred and sixty-six healthy volunteers, 85 upper limbs and 84 lower limbs entered the study. Minimum F wave latencies were determined in median, ulnar, tibial and peroneal nerves. The F min/He and F min/L ratios of each nerve were calculated. RESULTS: F latencies of all nerves had significant correlation with height and limb length but there was no correlation between either F min/He or F min/L and height in any nerve except for peroneal F min/He (p = 0.04, r = 0.23). CONCLUSIONS: Using the F min/He or F min/L ratios are more accurate than reporting only the F wave minimum latency, since these ratios incorporate corrections for height and/or limb length. This method also eliminates the false positive and negative reports caused by using a single reference table for all heights. SIGNIFICANCE: A unique reference table can be produced using the F min/He or F min/L for all populations and races, so that the comparison between different population samples can be done easily. Also data of different investigations can be pooled together for meta-analysis purposes when a single reference table is used for different samples. PMID- 21530388 TI - EEG monitoring in the neonatal intensive care unit: a critical juncture. PMID- 21530390 TI - Enzymatic assay method for measuring mizoribine levels in serum. AB - A sensitive and specific method for assaying serum mizoribine levels that can be applied to general automatic clinical analyzers was developed. Regression analysis of the enzymatic assay (y) vs. the HPLC method (x) produced the following relation: y=0.964x+0.090 (n=262, Sy, x=6.37 ng/mL). PMID- 21530389 TI - Measuring interconnection of the residual cortical functional islands in persistent vegetative state and minimal conscious state with EEG nonlinear analysis. AB - OBJECTIVES: The aim of the study is to investigate the cortical response to painful and auditory stimuli for subjects in persistent vegetative state (PVS) and minimal conscious state (MCS), and measure the interconnection of the residual cortical functional islands with electroencephalographic (EEG) nonlinear dynamic analysis (NDA). METHODS: Thirty PVS subjects, 20 MCS subjects and 30 subjects in normal conscious state (NCS) were involved in the study. EEG was recorded under three conditions: eyes closed, auditory stimuli and painful stimuli. EEG nonlinear index of cross-approximate entropy (C-ApEn) was calculated for all subjects. RESULTS: Interconnection of local and distant cortical networks of patients in PVS was generally suppressed, and painful or auditory stimulation could hardly cause any activation of associative cortices. Instead, interconnection of local cortical networks of patients in MCS improved significantly. The only significant difference with the NCS existed in the unaffected distant cortical networks. CONCLUSIONS: Interconnection of local and distant cortical networks in MCS is superior to that of PVS. NDA could measure interconnection of the residual cortical functional islands with associative cortices in the unconscious patients. SIGNIFICANCE: NDA can characterise the interconnection of cortical networks for the unconscious state and provide some information of unconsciousness at the awareness level. PMID- 21530391 TI - Acute effects of air pollution on peak expiratory flow rates and symptoms among asthmatic patients in Chiang Mai, Thailand. AB - The open burnings and forest fires have been recognized as the major sources of severe air pollution in the upper north of Thailand; however, there have been no clear evidences to show the associations between the air pollution and health effects in the area. We assessed the effects of air pollutants on the peak expiratory flow rates (PEFR) and symptoms in asthmatics. A cohort of 121 asthmatics was followed daily, for 306 days, for their PEFR and asthma symptoms. The daily air pollutants, including particulate matter with aerodynamic diameter <2.5 MUm, particulate matter with aerodynamic diameter <10 MUm (PM(10)), carbon monoxide, ozone, nitrogen dioxide (NO(2)), and sulfur dioxide (SO(2)), and the meteorological parameters, including pressure, temperature, relative humidity, rain quantity, and sunshine duration, were monitored. The PEFRs were fitted with general linear mixed models. The asthma symptoms were analyzed with the generalized estimating equations. There were positive associations of NO(2) with morning PEFR, with a coefficient of 0.06 [95% confidence interval (CI), 0.00 0.12]; of SO(2) with evening PEFR [with a range of coefficients of 0.88-1.00 (95% CI, 0.31-1.54)] and daily average PEFR [with a coefficient of 0.47 (95% CI, 0.00 0.94)]; of PM(10) with evening PEFR, with a coefficient of 0.02 (95% CI, 0.00 0.04). There was also negative association of PM(10) with DeltaPEFR, with a coefficient of -0.01 (95% CI, -0.01 to -0.00). No pollutants were related to asthma symptoms. More studies are needed, particularly at low dose in adult asthmatics, to validate our findings. PMID- 21530392 TI - The relationship between physical capacity and match performance in elite Australian football: a mediation approach. AB - The aim of this study was to verify if yo-yo intermittent recovery test (level 2) (yo-yo IR2) score is linked to Australian football (AF) performance through match exercise intensity. Six week prospective study design. Twenty-one data sets were recorded from nine individual players that completed the yo-yo IR2, and played an Australian Football League match in the first five rounds of the 2010 season wearing a global positioning system (GPS) unit. Simple mediation modelling was used to analyse the inter-relationship between yo-yo IR2 score, match exercise intensity and AF performance. Playing position and experience were also incorporated into the model to identify conditional affects. A significant direct relationship was observed between yo-yo IR2 and number of ball disposals (p<0.1) and a significant indirect relationship was observed between yo-yo IR2 and number of ball disposals through distance travelled at high intensity (HIR m min(-1)) (p<0.1). Moderation analysis showed that playing position affected the relationship between of yo-yo IR2 and HIR m min(-1) (p<0.1) and HIR m min(-1) and total ball disposals (p<0.1). Playing experience also significantly affected the relationship between HIR m min(-1) and total ball disposals. This study is the first to identify the effects of yo-yo IR2 on total ball disposals through HIR m min(-1) performed during AF matches, and that playing position and playing experience affect these interactions. PMID- 21530393 TI - Noninvasive coronary artery imaging: current clinical applications: Cardiac Society of Australia and New Zealand guidelines. PMID- 21530394 TI - Aortic valve replacement using a stentless bioprosthesis through right minithoracotomy: an initial experience. AB - OBJECTIVE: Aortic valve replacement (AVR) is nowadays a safe procedure with low rates of mortality and morbidity, but the necessity for a less invasive approach is going to increase. The use of a stentless prosthesis through right mini thoracotomy has not yet been described and our experience could be useful for other surgeons. METHODS: From June 2009 until March 2010, seven female patients (mean age 79.9 +/- 5.7 years) underwent stentless-AVR for aortic stenosis through a right mini-thoracotomy (RM). The logistic Euroscore was 11.3 +/- 6.1, and left ventricular ejection fraction was 60.7 +/- 4.5%. In five cases RM was performed through the second intercostal space (ICS); in two cases through the third ICS. The cannulation was in most cases between ascending aorta and femoral vein (5/7). When transverse sternotomy was required (two patients), the right mammary artery was clipped and cut. RESULTS: Extracorporeal circulation time (ECC) was 110 +/- 41min and aortic cross clamp was 80 +/- 35min. Two patients required transverse sternotomy. The mean bleeding was 484 +/- 469ml and the duration of mechanical ventilation was 22.0 +/- 12.5h. The ICU stay was 3.3 +/- 2.2 days. No in-hospital death was observed. The mean hospital stay was 11.6 +/- 5.4 days. CONCLUSION: Right mini-thoracotomy is a safe and applicable approach even in case of AVR using stentless prosthesis. The risk of insufficient surgical exposure or complication may be safely managed, by enlarging the thoracotomy through transverse sternotomy. However, valve implantation could be more difficult than the standard approach and it requires an expert and confident surgeon with a large experience in standard stentless implantation. PMID- 21530395 TI - Surviving cancer treatment: an investigation of the experience of fear about, and monitoring for, recurrence in patients following treatment for colorectal cancer. AB - BACKGROUND: It is known that many individuals worry about their cancer recurring after colorectal cancer treatment but the significance and specific manifestations of this problem require exploration. PURPOSE: This paper reports upon the research findings of a qualitative study to explain how fears of recurrence can affect individuals recovering from curative colorectal cancer surgery. METHODS: A longitudinal, grounded theory study was conducted. Sixteen participants who had received curative treatment for colorectal cancer were interviewed on up to four occasions during the 12 months following their surgery, 62 interviews were conducted in total. RESULTS: Many participants expressed anxiety about if and when their cancer might return, despite the knowledge that they had had successful treatment for early-stage colorectal cancer. This fear led some to adopt new behaviours in a desire to achieve a more dependable and controllable body. Heightened monitoring and management of the body characterised a state of 'guarding' - a concept developed from the data. By contrast, other participants did not perceive the risk of cancer recurrence to be as personally threatening or were able to assume strategies to manage any such concerns and find a sense of resolution to their recovery. CONCLUSION: The nature of an individual's response to fears of recurrence and consequent impact on their recovery warrants greater clinical consideration. Providing opportunities to openly discuss the possibility of cancer recurrence, assessing individual fears and offering suggestions on possible coping strategies to lessen the associated distress, are essential supportive activities enabling transition to life beyond cancer. PMID- 21530396 TI - Elderly cancer survivorship: an integrative review and conceptual framework. AB - The intersection of ageing and cancer in the phase of post-treatment survivorship represents a large and growing population with unique needs. PURPOSE: The goal of this work is to review and integrate the current gerontology and oncology literature relevant to elderly cancer survivorship, to identify knowledge gaps and research opportunities and to propose a conceptual model to guide future research. The long-term, global goal is the prevention of morbidity and mortality in elderly cancer survivors by identification of vulnerable elders, maintenance of independence, tailoring of treatment, establishing intervention guidelines and planning for necessary resources within the entire trajectory of cancer survival for older survivors. METHODS: Targeted and integrative review of selected literature from multiple disciplines. Search engines included PubMed, article reference lists and internet searches for epidemiological data (US Census, World Health Organization, American Cancer Society, Canadian Cancer Cancer Society, etc). RESULTS: A conceptual model that incorporates the gerontologic, oncologic and personal characteristics of older cancer survivors is proposed that may provide a comprehensive approach by which to frame elderly survivorship research. CONCLUSION: Cancer survivorship among the elderly is quantitatively and qualitatively different from cancer survivorship among other age groups. The current large numbers and predicted increase in elderly cancer survivors in the near future mandate attention to this population. Future research must consider the complexity of intersecting needs in the gero-oncology population. PMID- 21530397 TI - The effect of web-assisted education and reminders on health belief, level of knowledge and early diagnosis behaviors regarding prostate cancer screening. AB - PURPOSE OF THE RESEARCH: The aim of this study was to investigate the effect of web-assisted education and reminders on health belief, level of knowledge and early diagnosis behaviors regarding prostate cancer screening. METHODS AND SAMPLE: In this pretest-posttest longitudinal study, Turkish men over 40 years of age were given an interactive educational session on prostate cancer and prostate cancer screening, and were then given related web-assisted education and consultation for a period of 6 months. As well as the Internet, reminders such as desk calendar, booklets, e-mails and cell phone messages were used in the study. Changes in the screening behaviors, the health belief and knowledge level of patients were examined 3 and 6 months after the interventions. KEY RESULTS: During the study, participants' prostate examination rate increased from 9.3% to 19.1% and PSA measurement rate increased from 6.7% to 31.4%. The interventions raised the susceptibility perception on prostate cancer and prostate cancer screening while decreasing the barrier perception (p < 0.05). No change was observed in other health belief components and the level of knowledge. CONCLUSION: Web-assisted education and reminders provided positive changes in the barrier and susceptibility perceptions of individuals. Participation in the screening also increased. PMID- 21530398 TI - Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. AB - BACKGROUND: 15% of women treated for high-grade cervical intraepithelial neoplasia (CIN grade 2 or 3) develop residual or recurrent CIN grade 2 or 3 or cervical cancer, most of which are diagnosed within 2 years of treatment. To gain more insight into the long-term predictive value of different post-treatment strategies, we assessed the long-term cumulative risk of post-treatment CIN grade 2 or 3 or cancer and different follow-up algorithms to identify women at risk of residual or recurrent disease. METHODS: Women who were included in three studies in the Netherlands and who were treated for CIN grade 2 or 3 between July, 1988, and November, 2004, were followed up by cytology and testing for high-risk human papillomavirus (hrHPV) at 6, 12, and 24 months after treatment, and subsequently received cytological screening every 5 years. The primary endpoint was the cumulative risk of post-treatment CIN grade 2 or higher by December, 2009. We also assessed the cumulative risk of CIN grade 2 or higher in women with three consecutive negative cytological smears and women with negative co-testing with cytology and hrHPV at months 6 and 24. This study is registered in the Dutch trial register, NTR1468. FINDINGS: 435 women were included, 76 (17%) of whom developed post-treatment CIN grade 2 or higher, of which 39 were CIN grade 3 or higher. The 5-year risk of developing post-treatment CIN grade 2 or higher was 16.5% (95% CI 13.0-20.7) and the 10-year risk was 18.3% (13.8-24.0). The 5-year risk of developing post-treatment CIN grade 3 or higher was 8.6% (95% CI 6.0 12.1) and the 10-year risk was 9.2% (5.8-14.2). Women with three consecutive negative cytological smears had a CIN grade 2 or higher risk of 2.9% (95% CI 1.2 7.1) in the next 5 years and of 5.2% (2.1-12.4) in the next 10 years. The 5-year risk of CIN grade 3 or higher was 0.7% (95% CI 0.0-3.9) and the 10-year risk was 0.7% (0.0-6.3). Women with negative results for co-testing had a 5-year risk of CIN grade 2 or higher of 1.0% (95% CI 0.2-4.6) and a 10-year risk of 3.6% (1.1 10.7). The 5-year risk of CIN grade 3 or higher was 0.0% (95% CI 0.0-3.0) and the 10-year risk was 0.0% (0.0-5.3). INTERPRETATION: The 5-year risk of post treatment CIN grade 2 or higher in women with three consecutive negative cytological smears or negative co-testing for cytology and hrHPV at 6 and 24 months was similar to that of women with normal cytology in population-based screening and therefore justifies their return to regular screening. FUNDING: VU University Medical Center, Erasmus University Medical Center, Netherlands. PMID- 21530399 TI - Immunohistochemical analysis of FKBP51 in human cancers. AB - FKBP51 is a FK506-binding immunophilin involved in the regulation of several fundamental biological processes. A growing body of data indicates that this protein has also a role in the abnormal cell growth of cancers, and could be considered as a promising new marker of tumor progression and response to radio/chemotherapy. However, the data concerning the expression of FKBP51 in cancer are not conclusive, and partially contradictory. They delineate a very complex scenario, in which many molecular FKBP51-related pathways are variously intersected among different tumors. This review reports the available data concerning FKBP51 expression in normal tissues and human malignancies, outlining the role of the immunohistochemical analysis as a fundamental tool for better understanding the role of this immunophilin in cancer biology. PMID- 21530400 TI - Pulmonary neuroepithelial bodies as airway sensors: putative role in the generation of dyspnea. AB - The neuroepithelial bodies (NEB) of the intrapulmonary airways (AW) are multimodal AW sensors responding to a variety of stimuli including hypoxia, hypercarbia, and mechanical stretch. NEBs are richly innervated by a diverse population of mostly vagal afferent nerve fibers and owing to their early developmental maturation may be especially important during the perinatal period. This article reviews recent findings of NEB functional morphology and innervation, and postulates a role in the generation of dyspnea. This is based on their potential for transduction of dyspneic stimuli and findings of NEB cell abnormalities in a number of pulmonary disorders presenting with this symptom. PMID- 21530401 TI - Exercise and its impact on dyspnea. AB - Dyspnea is a subjective experience of breathing discomfort that can limit the ability and motivation to perform exercise or exertion. It is a common problem that affects specific groups of patients, such as, those suffering from chronic obstructive pulmonary disease, congestive heart failure, and interstitial lung disease, and in healthy humans during aging, pregnancy, and obesity. In this review, the current mechanistic model of exertional dyspnea is summarized and new research demonstrating how treatment strategies improve dyspnea by reducing central ventilatory drive, improving dynamic ventilatory mechanics, and improving respiratory muscle function is highlighted. Lastly, we review the effects of healthy aging and recent evidence for a male-female difference with respect to exertional-related dyspnea. PMID- 21530403 TI - Inbred laboratory cultures and natural trematode transmission under climate change. PMID- 21530404 TI - Finding and using evidence in academic assignments: the bane of student life. AB - Within schools of nursing, students are expected to produce academic assignments which demonstrate their abilities, to find, appraise and apply research findings in clinical practice. The main objective of academic education is to develop lifelong learning skills in the student (Jerlock et al., 2003) with lecturers being expected to educate students who are competent, knowledgeable, and able to successfully complete both academic and clinical assignments and assessments. However, little is known about how student nurses acquire such skills or whether they perceive such skills to be valuable to their future role as qualified nurses. AIMS: To explore student nurses' experiences of learning to search for and use evidence in order to support their academic assignments, and unearth their perceptions of the value of such skills to their future role as qualified nurses. METHODS: An exploratory pilot study at two schools of nursing in the United Kingdom, using questionnaires, with a sample size of 110, Year 3 nursing students from adult and children's nursing fields of practice. FINDINGS: The findings indicate that students value specific teaching sessions (taught by members of library staff) delivered at the beginning of the programme. Students make good use of in-house search engines where these are provided and are mainly searching for nursing literature with a small minority appearing to have no clear search strategy. Students appear to associate literature searching skills as potentially valuable in their future role as a qualified nurse, however, consider that such skills are more closely associated with further academic study rather than with clinical practice. CONCLUSION: It seems that more work is required by educators in order to help students to associate literature searching skills with nursing practice. PMID- 21530402 TI - Interferon-beta exacerbates Th17-mediated inflammatory disease. AB - Interferon (IFN)-beta is the treatment most often prescribed for relapsing remitting multiple sclerosis (RRMS). 30-50% of MS patients, however, do not respond to IFN-beta. In some cases, IFN-beta exacerbates MS, and it consistently worsens neuromyelitis optica (NMO). To eliminate unnecessary treatment for patients who are non-responsive to IFN-beta, and to avoid possible harm, researchers are identifying biomarkers that predict treatment outcome before treatment is initiated. These biomarkers reveal insights into the mechanisms of disease. Recent discoveries on human samples from patients with RRMS, NMO, psoriasis, rheumatoid arthritis, systemic lupus erythematosus and ulcerative colitis, indicate that IFN-beta is ineffective and might worsen clinical status in diverse diseases when a Th17 immune response is prominent. PMID- 21530405 TI - Increased incidence of mosaicism detected by FISH in murine blastocyst cultured in vitro. AB - The majority of in-vitro-derived human preimplantation embryos are chromosomally abnormal but whether the same pattern exists in vivo is unknown. This would be impossible to demonstrate in humans. Hence we chose murine embryos to study this difference owing to their ease of manipulation and compared the incidence of mosaicism between in-vivo- and in-vitro-cultured embryos. Two groups of embryos were analysed. Group A (in vitro) were obtained 48h following superovulation and cultured in vitro until the blastocyst stage. Fluorescent in-situ hybridization (FISH) was performed at different stages that included the cleavage, morula and blastocyst stage. Group B (in vivo) were obtained on day 2 or day 5 and FISH was performed immediately without culture. There was an increase in chromosomal mosaicism seen from the cleavage stage up to the blastocyst stage in the in-vitro culture group. Overall chromosomal abnormality from day 3 to day 5 was found to be 30% (28/94) in group A. The incidence of chromosomal abnormalities in blastocysts from group B was significantly lower than group A blastocysts (8% (3/40) and 31% (20/64) respectively; P<0.05). These data show that in-vitro cultured embryos had a significantly higher incidence of mosaicisim in comparison with the in-vivo group. Cultured human embryos show high levels of chromosomal abnormalities but whether this is a pattern seen in all embryos or is the result of culture is unknown. To study this pattern we used mouse embryos and carried out chromosome analysis by fluorescent in-situ hybridization. We compared embryos that were cultured (in vitro) with those that were not (in vivo, i.e. grown exclusively in the mouse). We found that cultured embryos showed significantly higher chromosomal abnormalities as compared with in vivo embryos. This suggests that certain culture conditions are responsible for the high level of chromosomal abnormalities seen in these embryos, which should be investigated further. PMID- 21530406 TI - T lymphocyte surface expression of exhaustion markers as biomarkers of the efficacy of chemotherapy for tuberculosis. AB - Predictive biomarkers illustrating the effectiveness of chemotherapeutic regimens for tuberculosis still remain elusive. To date, most are predicated on assays using sputum or serum; as a result, if not predictive, treatment failure in patients may not be evident for some time. We report here the results of a simple screening study in which T cell surface markers were examined in mice infected with Mycobacterium tuberculosis and then treated with drugs. These studies identified certain markers, the exhaustion markers PD-1 and TIM-3, as well as the marker KLRG-1, particularly on CD8 T cells, that changed in concert with reduction of the bacterial load in the lungs. While there is no guarantee these changes would also be seen on T cells in the blood, this approach should be further investigated. PMID- 21530409 TI - Pacemaker failure caused by traveller's diarrhoea. AB - A female patient with a VVI pacemaker suffered from traveller's diarrhoea which she treated with tea and water. After the onset of arrhythmia a pacemaker failure and a sodium concentration of 117 mmol/l was found. After substitution of sodium chloride, there was a remission of symptoms, the pacemaker ECG was normal. PMID- 21530408 TI - Dietary energy density: a mediator of depressive symptoms and abdominal obesity or independent predictor of abdominal obesity? AB - BACKGROUND: In the U.S., Europe, and throughout the world, abdominal obesity prevalence is increasing. Depressive symptoms may contribute to abdominal obesity through the consumption of diets high in energy density. PURPOSE: To test dietary energy density ([DED]; kilocalories/gram of food and beverages consumed) for an independent relationship with abdominal obesity or as a mediator between depressive symptoms and abdominal obesity. METHODS: This cross-sectional study included 87 mid-life, overweight adults; 73.6% women; 50.6% African-American. Variables and measures: Beck depression inventory-II (BDI-II) to measure depressive symptoms; 3-day weighed food records to calculate DED; and waist circumference, an indicator of abdominal obesity. Hierarchical regression tested if DED explained waist circumference variance while controlling for depressive symptoms and consumed food and beverage weight. Three approaches tested DED as a mediator. RESULTS: Nearly three-quarters of participants had abdominal obesity, and the mean waist circumference was 103.2 (SD 14.3) cm. Mean values: BDI-II was 8.67 (SD 8.34) which indicates that most participants experienced minimal depressive symptoms, and 21.8% reported mild to severe depressive symptoms (BDI II >= 14); DED was 0.75 (SD 0.22) kilocalories/gram. Hierarchical regression showed an independent association between DED and waist circumference with DED explaining 7.0% of variance above that accounted for by BDI-II and food and beverage weight. DED did not mediate between depressive symptoms and abdominal obesity. CONCLUSIONS: Depressive symptoms and DED were associated with elevated waist circumference, thus a comprehensive intervention aimed at improving depressive symptoms and decreasing DED to reduce waist circumference is warranted. PMID- 21530410 TI - Four imported cases of tungiasis in Mallorca. AB - Tungiasis is an endemic disease in many resource-poor communities some of which are in South America, which are visited frequently by Spanish travelers. Its diagnosis can be improved with the knowledge of the typical presentation and the correct management of its injuries. We report the first four cases identified of imported tungiasis in Mallorca. All four patients visited beaches in Brazil and presented the classical black lesions after their return. Two of the patients were diagnosed at primary care level and all were treated by dermatologists with surgical techniques. Dermoscopy was used for the initial approach to the injuries. Tungiasis can be suspected easily by examining carefully the black lesions and asking about previous travel. It can be treated readily by minor surgical techniques. PMID- 21530411 TI - Dietary intakes of urban, high body mass index, African American children: family and child dietary attributes predict child intakes. AB - OBJECTIVE: To identify family and child nutrition and dietary attributes related to children's dietary intakes. DESIGN: African American children (ages 8-11 years, n = 156), body mass index > 85th percentile, from urban, low-income neighborhoods. Baseline, cross-sectional data collected as part of an ongoing diabetes prevention intervention. Dietary intakes were collected by 3-day food diary to assess total energy, percent fat, discretionary fat, added sugar, whole grains, vegetables, fruit, meat, and dairy. Questionnaires on nutrition and dietary attributes administered to children and parents were used to develop 5 diet-related indices: child knowledge, child preferences, child snack habits, child beverage habits, and family food habits. RESULTS: A higher child nutrition knowledge score was significantly related to a lower starchy vegetable intake. Higher scores on the child snack habits index were significantly related to higher intakes of fruit, total fruits and vegetables, total fruits and nonstarchy vegetables, and to lower intakes of added sugars. A higher score on the family food habits index was significantly related to lower intakes of total energy and discretionary fat. CONCLUSIONS AND IMPLICATIONS: Targeting both child and family food and nutrition attributes may be used to promote more healthful eating among urban, low-income, overweight African American children. PMID- 21530412 TI - gamma-Hydroxybutyric acid-induced psychosis and seizures. AB - Disulfiram and gamma-hydroxybutyric acid (GHB) are used to treat alcohol dependence and may both increase dopamine brain levels and modulate GABAergic transmission. We describe a patient affected by bipolar disorder (on valproate as mood-stabilizing treatment) and alcohol dependence who developed a disulfiram induced hypomanic episode and in whom the switch from disulfiram to GHB induced recurrent convulsive seizures, not responsive to treatment with diazepam, and psychosis. Seizures and psychiatric symptoms ceased after GHB discontinuation. We outline the deregulation of the neurotransmitter systems (GABAergic and dopaminergic networks) that are involved in these drug-drug interactions and that might be responsible for both psychosis and generalized tonic-clonic seizures resistant to standard treatments. PMID- 21530413 TI - Pediatric epileptology. AB - Challenges facing children with epilepsy are understanding the neurobiology of pharmacoresistance of epileptic encephalopathies and the development of effective surgical treatment options for those with "non-lesional" epilepsy. Although, understanding the genetics of childhood epilepsy has advanced, an effective treatment intervention has not occurred. Recently, understanding the neurobiology of hamartin and tuberin in the development of epilepsy and cognitive impairment associated with tuberous sclerosis complex allowed the development of sirolimus and everolimus to be used in human clinical trials. In spite of these breakthroughs a large number of children are likely to be outside the scope of interventional therapies. For such patients the burden of seizures is onerous and psycho-social consequences debilitating. Surgical resective options are often limited by the lack of a well defined epileptic lesion. Co-registered synthesis of advanced functional, structural and electrographic seizure onset allows identification of a focus in patients thought to have "non-lesional" epilepsy. Developments of a Pipeline for prospective data sharing are likely to increase understanding and validation of the epileptogenic zone and offer the hope of seizure freedom. Two outstanding young investigators provide a review of their exciting research and its implications in pediatric epilepsy. PMID- 21530414 TI - Effects of psychiatric comorbidity on costs in patients undergoing disc surgery: a cross-sectional study. AB - BACKGROUND CONTEXT: Back pain presents a significant cause of health care costs and lost productivity. In most cases, conservative treatment will be sufficient, but in the most severe cases, disc surgery is indicated. PURPOSE: To analyze the effect of psychiatric comorbidity on health care costs and lost productivity in patients with back pain undergoing disc surgery. STUDY DESIGN: A cross-sectional study design was used. PATIENT SAMPLE: A sample of 305 disc surgery patients (lumbar, 239; cervical, 66). OUTCOME MEASURES: Patients were interviewed using the German version of the Composite International Diagnostic Interview to assess psychiatric comorbidity and a questionnaire to assess resource utilization and lost productivity for a 3-month period prior disc surgery. Health care resources were monetarily valued by unit costs, whereas productivity was valuated by labor costs. METHODS: Cost differences between patients with and without psychiatric comorbidity were analyzed using bootstrap regression techniques. RESULTS: Back pain was associated with mean 3-month direct health care costs ranging from ?5,534 (lumbar disc herniation without psychiatric comorbidity) to ?8,507 (cervical disc herniation with psychiatric comorbidity), of which between 51% and 79% were caused by disc surgery. Mean indirect costs ranged from ?7,589 to ?8,492. Psychiatric comorbidity was significantly associated with increased direct costs in lumbar disc herniation (?7,042 vs. ?5,534). Regression analysis showed increments of ?851 (p=.043) in direct costs and ?1,636 (p=.058) in total costs for psychiatric comorbidity, which predominantly resulted from nonpsychiatric health care utilization. CONCLUSIONS: Severe back pain is associated with high direct and indirect costs, which are influenced by the presence of psychiatric comorbidity. We found a lack of treatment for psychiatric comorbidity indicated by low mental health care utilization in affected individuals. More attention should be given to psychiatric comorbidity in the treatment of patients undergoing disc surgery. Clinicians should be aware of the high prevalence rates of psychiatric comorbidity in this patient group. They should consider the assessment of psychiatric distress and support of mental health professionals if applicable. PMID- 21530415 TI - Lumbar intraspinal arachnoid cyst superimposed by hyperacute spinal subdural hematoma: an unusual case. AB - BACKGROUND CONTEXT: Lumbar intradural arachnoid cyst (AC) concomitant with hyperacute spinal subdural hematoma (SSDH) has never been reported in the literature. PURPOSE: To report a case of lumbar AC superimposed by hyperacute SSDH, which was difficult to diagnose preoperatively using magnetic resonance imaging. Herein, we describe diagrams showing the proposed mechanisms underlying the formation of a symptomatic AC. STUDY DESIGN/SETTING: The study was designed to be a case report and literature review. METHODS: A 65-year-old man presented with acute onset of low back pain, followed by 5-day history of numbness and weakness in both legs before admission. Magnetic resonance imaging of the lumbosacral spine revealed an intradural extramedullary biconvex lesion at the L3 L4 level; the lesion compressed the cauda equina posteriorly. The lesion mainly appeared as hyperintense on T2-weighted images and hypointense on T1-weighted images. On the basis of these findings, the lesion was preoperatively diagnosed as a symptomatic lumbar subdural AC that compressed the cauda equina. RESULTS: The patient underwent laminectomy from L2 to L4. After a dura incision, a partially organized subdural hematoma was noted. Beneath the subdural hematoma was an AC compressing the underlying nerve roots. The patient's back pain and muscle strength markedly improved after the operation. CONCLUSIONS: Preoperative diagnosis of concomitant hyperacute SSDH and AC is difficult. In cases of patients who present with intraspinal AC accompanied by an acute onset of clinical presentation, an associated etiology should be considered until proven otherwise. PMID- 21530417 TI - Pharmacists' awareness of clinical decision support in pharmacy information systems: an exploratory evaluation. AB - BACKGROUND: Clinical decision support (CDS), such as drug-drug interaction (DDI) and drug-allergy checking, has been used in pharmacy information systems for several decades; however, there has been limited research on CDS use by practicing pharmacists. OBJECTIVE: The purpose of this study was to document pharmacists' awareness of DDI and other medication-related CDS features available within pharmacy information systems. METHODS: Researchers conducted on-site interviews with pharmacists throughout the state of Arizona from December 2008 to November 2009 regarding their pharmacy information systems features. Pharmacists were asked to provide information about DDI and other medication-related decision support features of the pharmacy software at their practice site. Descriptive statistics were used to summarize interview responses. RESULTS: Sixty-one pharmacists from a variety of practice settings completed the interview. All respondents indicated that their pharmacy system provided drug-allergy and DDI alerts. Approximately 60% of the pharmacists reported that their DDI decision support systems included recommendations for managing drug interactions. Two thirds of respondents reported that their pharmacy's computer system permitted the addition of medications from other pharmacies and/or over-the-counter products to a patient's profile. Approximately 40% of the pharmacists reported that some drugs entered into the pharmacy computer system were not included in (or linked to) the electronic DDI checking. Most pharmacists indicated the presence of other medication-related decision support features, such as drug disease (78%), drug-age precautions (67%), and inappropriate dosage alerts (79%). However, fewer pharmacists reported more advanced functionality, such as laboratory recommendations (34%) and pediatric dosing (39%). CONCLUSION: Overall, pharmacists' awareness regarding the many decision support functionalities of their systems was limited. Based on the study findings, it appears that there are a number of limitations associated with currently available pharmacy decision support software. Further research is needed to formally evaluate pharmacist knowledge of pharmacy decision support software functionality. More formal training about software capabilities coupled with the addition of more advanced decision support features has the potential to improve pharmacists' use of these systems to make better clinical decisions and avoid preventable errors. PMID- 21530418 TI - Dealing with illegal pharmaceutical sales over the Internet; can we benefit from lessons learned from informal drug sellers in Africa? PMID- 21530420 TI - Kinetic analysis of DNA double-strand break repair pathways in Arabidopsis. AB - Double-strand breaks in genomic DNA (DSB) are potentially lethal lesions which separate parts of chromosome arms from their centromeres. Repair of DSB by recombination can generate mutations and further chromosomal rearrangements, making the regulation of recombination and the choice of recombination pathways of the highest importance. Although knowledge of recombination mechanisms has considerably advanced, the complex interrelationships and regulation of pathways are far from being fully understood. We analyse the different pathways of DSB repair acting in G2/M phase nuclei of irradiated plants, through quantitation of the kinetics of appearance and loss of gamma-H2AX foci in Arabidopsis mutants. These analyses show the roles for the four major recombination pathways in post-S phase DSB repair and that non-homologous recombination pathways constitute the major response. The data suggest a hierarchical organisation of DSB repair in these cells: C-NHEJ acts prior to B-NHEJ which can also inhibit MMEJ. Surprisingly the quadruple ku80 xrcc1 xrcc2 xpf mutant can repair DSB, although with severely altered kinetics. This repair leads to massive genetic instability with more than 50% of mitoses showing anaphase bridges following irradiation. This study thus clarifies the relationships between the different pathways of DSB repair in the living plant and points to the existence of novel DSB repair processes. PMID- 21530421 TI - Gas chromatographic enantioseparation of derivatized alpha-amino acids on chiral stationary phases--past and present. AB - The historical development of the enantioseparation of derivatized alpha-amino acids by high-resolution capillary gas chromatography on chiral stationary phases derived from alpha-amino acid-derivatives and modified cyclodextrins is described. The pioneering work emerging from Emanuel Gil-Av and his associates at the Weizmann Institute of Science is reviewed. A bridge to more recent developments is spanned aimed at helping to select appropriate tools for contemporary chiral alpha-amino acid analysis by gas chromatography in different research areas. PMID- 21530422 TI - [Phenotype of the C634Y mutation in the RET proto-oncogene in MEN2A: report of a family]. AB - BACKGROUND AND OBJECTIVES: Genetic testing of RET proto-oncogen allows an early diagnosis of Multiple Endocrine Neoplasia syndrome type 2 and establish a correlation between genotype and clinical manifestations. The purpose of this study was to demonstrate the benefits of an early diagnosis with genetic testing followed by prompt surgery on the cure of MTC versus a later diagnosis with serum calcitonin. PATIENTS AND METHOD: Retrospective descriptive study of 8 members of a MEN 2A family by C634Y mutation. We performed serum calcitonin screening until 1999 and subsequently RET genetic testing was obtained. Carriers underwent total thyroidectomy and periodic determination of calcitonin, urinary metanephrines, calcium, phosphorus and neck and abdominal imaging techniques. RESULTS: Five patients were diagnosed by calcitonin familial screening and all of them have high calcitonin by now. Three patients were diagnosed by genetic testing (an adult and two children) and they are free of disease. Calcitonin was closely monitored in children and they underwent surgery when it started to raise, at 6 and 10 years old respectively, finding nodular C-cell hyperplasia in both. Of 8 carriers 3 developed pheochromocytomas, bilateral and asynchronous, one-half had normal urinary metanephrines and two of them were simultaneous with MTC. No patient had biochemical data suggesting hyperparathyroidism although in one patient multiple parathyroid adenomas were found at thyroidectomy. CONCLUSIONS: RET genetic analysis has achieved an early diagnosis and treatment with no development of MTC in our patients, adjusting the time and type of surgery and allowing a genotype-phenotype correlation. It demonstrates how a genetic alteration is associated with a pathology that we can prevent and manage improving the prognosis of our patients. PMID- 21530423 TI - Neurodegeneration as an early event in diabetic retinopathy. PMID- 21530424 TI - [Efficacy of oral supplementation during dialysis in patients with chronic renal failure]. AB - Protein-calorie malnutrition is common in hemodialysis patients and is a powerful predictor of morbidity and mortality. Nutritional supplementation, administered orally or parenterally, especially during dialysis, may compensate for the relatively inadequate protein and energy intake and improves net protein anabolism in chronic hemodialysis patients. Intradialytic oral nutrition seems preferable to intradialytic parenteral nutrition (IDPN) due to its lower cost and persistence of its anabolic effects after infusion is stopped, and because IDPN induces a higher increase in serum glucose and insulin levels and a greater reduction in serum ghrelin concentrations. Further larger scale randomized, controlled trials of nutritional interventions should be performed in maintenance dialysis patients to assess their efficacy regarding quality of life, morbidity, and mortality. PMID- 21530425 TI - [Age of onset of puberty and menarche in type 1 diabetic girls]. AB - INTRODUCTION: Delayed pubertal maturation has been reported in girls with type 1 diabetes. OBJECTIVES: To report the age of onset of puberty and menarche in girls with type 1 diabetes diagnosed before puberty. To investigate clinical factors affecting the occurrence of puberty and menarche in this population. PATIENTS AND METHODS: A retrospective study of 38 girls with type 1 diabetes, all of them on intensive insulin therapy since diagnosis and followed up at our hospital until menarche. Age of onset of puberty and age of menarche were collected as dependent variables, and time since onset of diabetes, glycosylated hemoglobin levels, daily insulin requirements, and body mass index standard deviation score were collected as independent variables. Variables are expressed as mean +/- standard deviation. Multivariate linear regression models tested the associations between dependent and independent variables. Statistical analysis was performed using SPSS software. RESULTS: Thirty-eight girls were enrolled. Age of onset of puberty was 10.4 +/- 1.1 years and age of menarche, 12.6 +/- 1.0 years. Time since diabetes onset influenced age at onset of puberty (beta = +0.12; p=0.047). A negative association was found between body mass index standard deviation score and age at menarche (beta=-0.39; p=0.014). CONCLUSION: Diabetes duration and body mass index were correlated with age of onset of puberty and age of menarche in girls with type 1 diabetes. PMID- 21530426 TI - Differences in diet between the 19th and 21st centuries: could they lead to insulin and leptin resistance and inflammation? PMID- 21530427 TI - Beclomethasone dipropionate: a second chance for topical steroids as maintenance therapy in ileal Crohn's disease. PMID- 21530428 TI - The epidemiological pattern of chronic liver diseases in a community undergoing voluntary screening for hepatitis B and C. AB - BACKGROUND: Vallecamonica-Sebino is a community in Northern Italy (99,776 inhabitants) with one of the highest mortality rates for primary liver cancer and cirrhosis in Italy, and voluntary screening for HCV and HBV is widespread. The aim of this study was to estimate the prevalence of chronic liver diseases and their aetiology in the area. METHODS: We used the following sources of data, linked at an individual level: (1) hospital discharge data; (2) local Viral Hepatitis Services; (3) tests for anti-HCV antibodies and HBsAg from local laboratories; (4) Local Health Authority registry of chronic liver disease patients; (5) drug prescriptions for HBV and HCV treatment; (6) archives of Alcohol Units. RESULTS: 3.5% of the residents had chronic liver disease, mainly chronic hepatitis (61.6%), followed by cirrhosis (14.0%) and alcoholic liver disease (11.2%). HCV was the main cause of chronic liver disease in females (46.3%) and males (29.8%), followed by alcohol abuse in males (22.9%) and HBV (10.9% males and 9.2% females). Prevalence of anti-HCV positivity was 3.2%, and increased with age to 8.8% in subjects aged 65 years and over. CONCLUSION: This study shows that an epidemiologic pattern of the prevalence of chronic liver diseases and their aetiology can be obtained using routinely collected data. PMID- 21530429 TI - Socio-geographical determinants of colonoscopy uptake after faecal occult blood test. AB - BACKGROUND: Survival from colorectal cancer is poorer in patients of lower socioeconomic level, or living far from the cancer reference centre. AIMS: To evaluate the impact of material deprivation and geographical remoteness on the uptake of colonoscopy after a positive screening faecal occult blood test. METHODS: Data from two large French average-risk population-based trials comparing two faecal occult blood tests were used. Compliance with colonoscopy after a positive faecal occult blood test was analysed using a logistic model and a Cox model considering time between faecal occult blood test and colonoscopy. Covariates studied were sex, age, distance to nearest gastroenterologist, distance to regional capital, and Townsend's deprivation score. RESULTS: Amongst 4320 eligible subjects, 4131 were included. The rate of colonoscopy was 83.8%, within a median time of 66.0 days after faecal occult blood test. Distance to regional capital (p-trend=0.02) and study centre (p<0.0001) were independently associated with colonoscopy uptake. Time from positive faecal occult blood test to colonoscopy, was associated only with distance to the regional capital (p<0.0001, multivariate model stratified on study centre). CONCLUSION: Geographical remoteness but not material deprivation was responsible for lower uptake of colonoscopy. Healthcare decision-makers should focus on geographical remoteness to promote equal access to diagnostic procedures in faecal occult blood test colorectal cancer screening programmes. PMID- 21530430 TI - Minimally invasive surgery in the neonate. AB - The advent of minimally invasive surgical techniques in the neonate has been delayed due to the limited working space and the unique physiology of the newborn. In the last decade, with the introduction of new instruments and techniques, many of the initial problems have been solved making minimally invasive surgery feasible for a variety of indications in the neonate and a favored approach in specialized centers around the world. Although an increasing number of reports document the feasibility of this exciting technique, data demonstrating its benefit compared to conventional surgery is limited. This review focuses on recent developments in minimally invasive surgery in neonates and the evidence for its use. PMID- 21530431 TI - Impact of prenatal diagnosis and therapy on neonatal surgery. AB - The field of neonatal surgery is now inextricably linked to the field of obstetrics. Neonatologists and surgical specialists experienced with the postnatal management and outcomes of infants with various disorders now look in utero along with obstetricians and fetal medicine specialists to characterize the development and well-being of fetuses with congenital anomalies with a goal to optimize fetal, perinatal and postnatal management. The purpose of this article is to examine how prenatal diagnosis and therapy has influenced neonatal surgery. An overview of prenatal diagnosis and the evolution of fetal therapy are provided. In addition, we review the impact of prenatal diagnosis and therapy on the management and outcomes of infants with specific anomalies, including congenital lung malformations, sacrococcygeal teratoma, myelomeningocele, giant fetal neck masses, diaphragmatic hernia and congenital heart defects. PMID- 21530432 TI - Postoperative leucocytoclastic vasculitis in free flap mimicking venous insufficiency. AB - A 29-year-old man, who had been diagnosed with myelodysplastic syndrome 1 year before, developed a wound on his thigh and knee due to necrotising fasciitis. Forty h after a free thoracodorsal artery perforator flap transfer, the colour of the flap changed from pink to purple, starting from the peripheral margin and epitheliolysis proceeded. Within a week, the colour returned to normal spontaneously and the flap survived completely. On punch biopsy, the lesion was confirmed as leucocytoclastic vasculitis, necrotising inflammatory disease of the small vessels in the dermis. This case demonstrates that leucocytoclastic vasculitis mimics postoperative venous insufficiency of a free flap; hence, differential diagnosis by careful judgement of vascular status is required. This rare occurrence needs to be considered in free-flap monitoring, especially in immunosuppressed patients. PMID- 21530433 TI - Morbidly obese patients undergoing bariatric and body contouring surgery: psychological evaluation after treatments. PMID- 21530435 TI - Upper incisor intrusion: an anatomical analysis via CBCT. AB - OBJECTIVE: To verify, via CBCT, the existence of a definable distance for bodily intrusion of maxillary incisors, and its correlation to age, sex and/or facial biotype. MATERIALS AND METHODS: The sample consisted of sagittal sections obtained from 79 CBCTs of 220 maxillary incisors correctly aligned on their osseous base (maxillary plane/long axis between 105 degrees and 115 degrees ). The same sagittal sections were then used to measure the distance between the root apex and upper internal cortical bone of the jaw at each incisor, along the extension of the long axis. The patient sample was divided into three distinct subgroups based on the degree of divergence; it was also subdivided by gender and by age. RESULTS: The mean distances between the apex and upper internal cortical bone were higher than 5mm for the four maxillary incisors. Statistically significant differences were evidenced between the two age groups in the means measured for the right lateral incisor, left central and lateral incisor. The mean of the distance measured for the right lateral incisor in the hyperdivergent patients was significantly greater with respect to that of the hypodivergent patients. CONCLUSION: The CBCT data obtained permitted identification of the alveolar anatomy and quantification of the intrusion possible. In the older age group, potential intrusion was significantly greater for teeth 12, 21 and 22. Furthermore, a directly proportional relationship between the measurements pertaining to each tooth in a single patient was noted. PMID- 21530436 TI - A protocol for direct and rapid multiplex PCR amplification on forensically relevant samples. AB - Forensic DNA typing involves a multi-step workflow. Steps include DNA isolation, quantification, amplification of a set of short tandem repeat (STR) markers, separation of polymerase chain reaction (PCR) products by capillary electrophoresis (CE) and DNA profile analysis and interpretation. With that, the process takes around 10-12h. For several scenarios it may be very valuable to speed up this process and obtain an interpretable DNA profile, suited to search a DNA database, within a few hours. For instance in cases of national security, abduction with danger of life, risk of repetition by a serial perpetrator or when custody time of suspects is limited. By a direct and rapid PCR approach we reduced the total DNA profiling time to 2-3h after which genotyping information for the 10 STR markers plus the amelogenin (AMEL) marker present in the commercially available AmpFlSTR((r)) SGM PlusTM (SGM+) profiling kit is obtained. This reduction in time is achieved by using the following elements: (1) the inhibitor tolerant, highly processive Phusion((r)) Flash DNA polymerase; (2) a modified, non-adenylated allelic ladder; (3) the quick PIKO((r)) thermal cycler system with ultra-thin walled reaction tubes; (4) profile interpretation guidelines with an increased allele calling threshold, modified stutter ratios and marked low-level artefact peaks and (5) regulation of sample input by the use of mini-tapes that lift a limited amount of cell material from swabs or fabrics. The procedure is specifically effective for high level DNA, single source samples such as samples containing saliva, blood, semen and hair roots. Success rates, defined as a complete DNA profile, depend on stain type and surface. Due to the use of tape lifting as the sampling technique, the swab or fabric remains dry and intact and can be analyzed at a later stage using regular procedures. Validation experiments were performed which showed that the protocol effectively instructs researchers unfamiliar with the procedure. We have incorporated direct and rapid PCR in a "DNA-6h" service that can assist police investigations by rapidly deriving DNA information from trace evidence left by a perpetrator, searching the STR profile against a DNA database and reporting the outcomes to police or prosecution. PMID- 21530437 TI - Roles of activated astrocyte in neural stem cell proliferation and differentiation. AB - Recent studies demonstrated that the molecules secreted from astrocytes play important roles in the cell fate determination of neural stem cells (NSCs). However, the exact molecules involved and its possible mechanisms in the process remain largely unknown. In this study, astrocyte-conditioned medium (ACM) obtained from astrocytes unstimulated or stimulated by lipopolysaccharide was prepared to treat NSCs. The results showed that both the proliferation and differentiation of NSCs treated with stimulated ACMs were significantly increased compared with those treated with unstimulated ACM. Interleukin-6 (IL-6) antibody neutralization of the ACMs decreased NSC proliferation and astrogliogenesis, while NSC neurogenesis was increased. In contrast, recombinant IL-6 cytokine increased NSC proliferation and astrogliogenesis, but decreased neurogenesis. Furthermore, the expression of phosphorylated signal transducer and activator of transcription 3 (p-stat3) protein as well as serial of basic helix-loop-helix transcription factors (bHLH) mRNA in NSCs exposed to stimulated ACMs significantly increased, respectively. The expression levels of p-stat3 protein and bHLH mRNA of NSCs were significantly altered after adding anti-IL-6 antibody or recombinant IL-6, respectively. The data suggest that IL-6 secreted from activated astrocytes participates in ACM-induced proliferation and differentiation of NSCs via the phosphorylation of stat3 signals and the expression of bHLH transcription factors. PMID- 21530438 TI - Association of Rex-1 to target genes supports its interaction with Polycomb function. AB - Rex-1/Zfp42 displays a remarkably restricted pattern of expression in preimplantation embryos, primary spermatocytes, and undifferentiated mouse embryonic stem (ES) cells and is frequently used as a marker gene for pluripotent stem cells. To understand the role of Rex-1 in selfrenewal and pluripotency, we used Rex-1 association as a measure to identify potential target genes, and carried out chromatin-immunoprecipitation assays in combination with gene specific primers to identify genomic targets Rex-1 associates with. We find association of Rex-1 to several genes described previously as bivalently marked regulators of differentiation and development, whose repression in mouse embryonic stem (ES) cells is Polycomb Group-mediated, and controlled directly by Ring1A/B. To substantiate the hypothesis that Rex-1 contributes to gene regulation by PcG, we demonstrate interactions of Rex-1 and YY2 (a close relative of YY1) with Ring1 proteins and the PcG-associated proteins RYBP and YAF2, in line with interactions reported previously for YY1. We also demonstrate the presence of Rex-1 protein in both trophectoderm and Inner Cell Mass of the mouse blastocyst and in both ES and in trophectoderm stem (TS) cells. In TS cells, we were unable to demonstrate association of Rex-1 to the genes it associates with in ES cells, suggesting that association may be cell-type specific. Rex-1 might fine-tune pluripotency in ES cells by modulating Polycomb-mediated gene regulation. PMID- 21530439 TI - Radius graft pedicled on the anterior interosseous artery for recurrent ulnar nonunion. AB - Recurrent ulnar nonunion challenges the functional prognosis and raises major problems concerning the best therapeutic strategy to follow. The case of a female patient presenting recurrent nonunion of the ulnar diaphysis despite successive treatments is reported. The radius graft pedicled on the anterior interosseous artery from a retrograde approach obtained bone union in 3 months with no functional sequelae. For the first time, we propose a therapeutic alternative calling on a proximally pedicled anterior interosseous flap. This technique can be performed under locoregional anesthesia and does not sacrifice the main artery of the forearm. However, the size of the graft does not entirely compensate for segmentary bone loss. The radius graft pedicled on the anterior interosseus artery is an inventive technique that can solve the problem of difficult ulna nonunions without the disadvantages of vascularized fibula harvesting. PMID- 21530440 TI - Is a hip distractor useful in the arthroscopic treatment of femoroacetabular impingement? AB - INTRODUCTION: There is increasing interest in using hip arthroscopy for the treatment of femoroacetabular impingement (FAI). However, the distraction is typically done with a traction table, which can lead to complications. Our working hypothesis was that a hip-specific distractor could be used to perform arthroscopic treatment of FAI without the complications associated with traction. MATERIAL AND METHODS: Twenty-three patients were included in this prospective study with an average follow-up of 21 months (range 12-28 months). The average age was 34 +/- 4 years. The technical feasibility, complications, quality of the distraction and early clinical results were evaluated. RESULTS: None of the arthroscopy procedures had to be converted to an arthrotomy. In all cases, the procedures planned for the central and peripheral compartments were fully executed. One patient (4%) had a grade 1 cartilage iatrogenic injury of the femoral head. The distraction was determined to be effective in all the patients, with an average of 15 mm of distraction achieved (range 12-21 mm). The average Merle d'Aubigne score went from 11 (range 9-18) preoperatively to 16 (range 14 18) postoperatively; the average Harris score went from 76 (range 46-80) to 91 (range 87-100); the average Christensen score went from 64 (range 48-88) to 84 (range 72-100); the average Womac score went from 58 (range 42-96) to 84 (range 74-100). No neurological, infectious or bone complications were recorded. DISCUSSION: The use of a distractor during hip arthroscopy appears to be a reliable and reproducible technique that allows FAI to be treated. Early results are consistent with those reported in the literature, and the risks associated with the use of a traction table are reduced. This technique makes hip arthroscopy safer and contributes to advances in labrum and cartilage repair, without additional complications. LEVEL OF EVIDENCE: Level III prospective study. PMID- 21530441 TI - Gracilis tendon transfer associated with distal alignment for patella alta with recurrent dislocations: an original surgical technique. AB - Many surgical techniques for the medial patellofemoral ligament have recently been suggested, all of which included problems identifying the femoral anchorage point and determining the proper extent of knee flexion for the transplant. P. Burdin proposed a different and original approach consisting in performing a gracilis muscle transfer to the medial edge of the patella, thus obtaining progressive tension of the transfer during knee flexion by means of the myotatic reflex. We report the results herein. We retrospectively assessed 17 knees treated for patellofemoral instability using this technique. Two cases presented subjective patellofemoral instability and 15 presented objective patellofemoral instability. The patients' mean age was 17.4 years (range, 8-47 years) during the first episode of dislocation. Two cases of instability were secondary to advanced neuromuscular disease. Two knees had already undergone two stabilization attempts. Fifteen knees presented trochlear dysplasia (four stage A, eight stage B, and three stage C). The mean age at surgery was 28.2 years (range, 16-47 years). In 15 cases, the gracilis transfer was associated with lowering the anterior tibial tuberosity (mean, 10mm). No patellar fracture occurred. A persistent sensory deficit of the anterior branch of the internal saphenous nerve was observed in 15 cases. One knee remained painful and retained subjective instability; total knee arthroplasty was performed 3 years after the intervention. The mean follow-up at revision was 5.5 years (range, 1.5-16.5 years). No recurrence of dislocation was reported. Eight cases retained subjective instability. The SF-36 and IKDC scores were good or excellent in 12 cases and the KOOS was good or excellent in 13 cases. Radiologically, patellar tilt persisted in six cases out of 14, translation persisted in two cases out of 14, and secondary patella baja was observed in one. Medial patellofemoral osteoarthritis was observed in five cases: one case IWANO stage I and four cases IWANO stage II. These satisfactory results seem stable over time and were acquired using a simple procedure with reduced morbidity, making it possible to avoid significant displacement of the anterior tibial tuberosity and stabilize the extensor apparatus. It can also be hoped that the onset of secondary patellofemoral osteoarthritis, undoubtedly inevitable, has been delayed. PMID- 21530442 TI - Fascial flap protecting the fibular nerve: a rare childhood case. AB - Compression of the peripheral nerves (PNs) induces intraneural lesions, which, once surgical decompression has been achieved, requires that the peripheral scar tissue be as non-adherent as possible. This allows optimal nerve tissue regeneration and the flexibility necessary for longitudinal movements of the PNs. In cases showing a risk for adherence, tissue interposition (with fat, muscle, fascia, etc.) can be proposed. The authors describe the use of a fascial flap of the fibular muscles used to protect the fibular nerve (FN) and the fibula head. This flap procedure was performed in a case of PN compression due to exostosis of the fibular nerve in a child. PMID- 21530443 TI - Therapeutic education in persons with spinal cord injury: a review of the literature. AB - INTRODUCTION: Therapeutic education is an integrant part of the physical medicine and rehabilitation care of persons with spinal cord injury. It is often conducted in an empirical manner. The objective of this literature review was to evaluate the state of the art regarding the evaluations and therapeutic education programs for persons with spinal cord injury. MATERIAL AND METHOD: Systematic review of the literature with Medline and Cochrane Library databases from 1966 to 2009. RESULTS: The main areas of interest, for the evaluations found in the literature, focused on clinical variables, patients' knowledge, health behaviors, functional independence and quality of life but also psychological dimensions such as health locus of control, representations, abilities to resolve problems and self perceived efficacy. Ten clinical studies were retained for analysis. These clinical studies were built around various health and educational models. An impact was highlighted on clinical variables (pressure ulcer, urinary tract infection), knowledge, quality of life and psychological criteria (depression, self-perceived efficacy, coping and problem solving strategies). DISCUSSION AND CONCLUSION: The global level of evidence on the effects of therapeutic education in persons with spinal cord injury is low because of the number of studies and their low statistical power and requires additional studies. However, the analysis of the literature allows for discussing the organization of therapeutic education in clinical practice. PMID- 21530444 TI - Impression tray designs and techniques for complete dentures in cases of microstomia--a review. AB - OBJECTIVES: The present paper aims to review the literature on various approaches in the tray designs and different techniques used to overcome difficulties in making impressions of patients with severely limited mouth opening published from 1984 to 2009. STUDY DESIGN: A search in the National Library of Medicine's Pub Med database, Google search and Science Direct was performed to include all case reports and reviews on prosthodontic rehabilitation of patients with microstomia. A total of 17 articles were included for discussion in the review out of the 22 articles found to be giving new tray designs. CONCLUSIONS: Different tray designs and impression techniques which can be useful in management of difficult cases causing little discomfort to the patient and help in getting back such patients to a comfortable social living. PMID- 21530445 TI - Regression of new-onset diabetes mellitus after conversion from tacrolimus to cyclosporine in liver transplant patients: results of a pilot study. AB - INTRODUCTION: New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation. AIM: To evaluate the impact of conversion from tacrolimus to cyclosporine in liver transplant patients presenting NODM. METHOD: In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study. RESULTS: At month 12, NODM had significantly resolved (FBG<7 mmol/L without treatment) in 36% of patients (95% CI 20.8-51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L (P=0.008) and mean HbA(1c) decreased from 6.4 to 6.0% (P=0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L (P<0.001). CONCLUSIONS: These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required. PMID- 21530473 TI - Judging a book by its cover and its contents: the representation of polysemous and homophonous meanings in four-year-old children. AB - Unlike homophonous meanings, which are semantically unrelated (e.g., the use of bat to refer to a baseball bat and a flying rodent), polysemous meanings are systematically related to one another (e.g., the use of book, CD, and video to refer to physical objects, as in 'the leather book', or to the intellectual content they contain, as in 'the profound book'). But do perceived relations among polysemous meanings reflect the presence of generative lexical or conceptual structures that permit the meanings of these words to shift? If so, these structures may also support children's early representations of polysemous meanings. In four studies, we demonstrate (1) that four-year-old children can understand both the concrete and abstract meanings of words like book, (2) that when taught a novel label for one of these meanings, children can readily understand an extension of that label to the other meaning, and (3) that extension does not occur between two homophonous meanings, which share a common phonological form but are otherwise unrelated. We conclude that the polysemous meanings of words like book rely on a common representational base early in development, and suggest that this may be the result of foundational, generative properties of the lexicon or conceptual system. PMID- 21530474 TI - Tungsten-dependent formaldehyde ferredoxin oxidoreductase: reaction mechanism from quantum chemical calculations. AB - Formaldehyde ferredoxin oxidoreductase from Pyrococcus furiosus is a tungsten dependent enzyme that catalyzes the oxidation of formaldehyde to formic acid. In the present study, quantum chemical calculations are used to elucidate the reaction mechanism of this enzyme. Several possible mechanistic scenarios are investigated with a large model of the active site designed on the basis of the X ray crystal structure of the native enzyme. Based on the calculations, we propose a new mechanism in which the formaldehyde substrate binds directly to the tungsten ion. W(VI)=O then performs a nucleophilic attack on the formaldehyde carbon to form a tetrahedral intermediate. In the second step, which is calculated to be rate limiting, a proton is transferred to the second-shell Glu308 residue, coupled with a two-electron reduction of the tungsten ion. The calculated barriers for the mechanism are energetically very feasible and in relatively good agreement with experimental rate constants. Three other second shell mechanisms, including one previously proposed based on experimental findings, are considered but ruled out because of their high barriers. PMID- 21530475 TI - A proteomic analysis of the effects of metal contamination on Sydney Rock Oyster (Saccostrea glomerata) haemolymph. AB - The current study uses proteomics to assess the effects of metal contamination on Sydney Rock oyster haemolymph. Saccostrea glomerata were exposed in aquaria for four days to three environmentally relevant metals (copper, lead or zinc). Oyster haemolymph proteins from metal-exposed oysters were then compared to haemolymph from non-exposed controls using 2-dimensional electrophoresis to identify proteins that differed significantly in intensity. These proteins were then subjected to tandem mass spectrometry so that putative protein identities could be assigned. The data suggest that there are unique protein expression profiles for each metal. Exposure to 100 MUg/l of copper, lead or zinc yielded a total of 25 differentially expressed proteins. However, only one of these protein spots exhibited altered intensities in response to all three metals. Eighteen of the 25 spots were significantly affected by just one of the three metals. Differentially expressed proteins were assigned to five different categories of biological function. Proteins affecting shell properties were the most common functional group accounting for 34% of the identified proteins. Cytoskeletal activities and metabolism/stress responses each accounted for a further 25% of the proteins. PMID- 21530477 TI - Studies on the protective efficacy and immunogenicity of Hsp70 and Hsp83 based vaccine formulations in Leishmania donovani infected BALB/c mice. AB - Visceral leishmaniasis, a chronic systemic infection, is the major cause of morbidity and mortality in many parts of world. The current drugs for the treatment of leishmaniasis are toxic, expensive, difficult to administer and becoming ineffective due to the emergence of drug resistance. In the absence of effective treatment, vaccination remains the only hope for control of the disease. We have evaluated the protective efficacy of two heat shock proteins (Hsp70 and Hsp83) in combination with two different adjuvants (MPLA and ALD) in Leishmania donovani infected inbred BALB/c mice. The proteins were isolated by SDS-PAGE and the mice were immunized subcutaneously with Hsp70+Hsp83, Hsp70+Hsp83+ALD and Hsp70+Hsp83+MPLA. These were challenged with 10(7) promastigotes of L. donovani. The animals were sacrificed on 30, 60 and 90 days post challenge for the assessment of parasite load and generation of cellular and humoral immune responses. The vaccines induced a strong protective response against experimental visceral leishmaniasis as shown by reduced parasite load in liver of all immunized groups as compared to the infected controls. The vaccines also led to the augmentation of DTH responses, increased levels of IgG2a, IFN gamma and IL-2. Both the adjuvants raised significantly the level of protection imparted by the proteins but MPLA was more effective in comparison to ALD. PMID- 21530476 TI - The influence of gene-environment interactions on alcohol consumption and alcohol use disorders: a comprehensive review. AB - Since 2005, a rapidly expanding literature has evaluated whether environmental factors such as socio-cultural context and adversity interact with genetic influences on drinking behaviors. This article critically reviews empirical research on alcohol-related genotype-environment interactions (GxE) and provides a contextual framework for understanding how genetic factors combine with (or are shaped by) environmental factors to influence the development of drinking behaviors and alcohol use disorders. Collectively, evidence from twin, adoption, and molecular genetic studies indicates that the degree of importance of genetic influences on risk for drinking outcomes can vary in different populations and under different environmental circumstances. However, methodological limitations and lack of consistent replications in this literature make it difficult to draw firm conclusions regarding the nature and effect size of alcohol-related GxE. On the basis of this review, we describe several methodological challenges as they relate to current research on GxE in drinking behaviors and provide recommendations to aid future research. PMID- 21530478 TI - Directional, seamless, and restriction enzyme-free construction of random-primed complementary DNA libraries using phosphorothioate-modified primers. AB - Directional cloning of complementary DNA (cDNA) primed by oligo(dT) is commonly achieved by appending a restriction site to the primer, whereas the second strand is synthesized through the combined action of RNase H and Escherichia coli DNA polymerase I (PolI). Although random primers provide more uniform and complete coverage, directional cloning with the same strategy is highly inefficient. We report that phosphorothioate linkages protect the tail sequence appended to random primers from the 5'->3' exonuclease activity of PolI. We present a simple strategy for constructing a random-primed cDNA library using the efficient, size independent, and seamless In-Fusion cloning method instead of restriction enzymes. PMID- 21530479 TI - Gold nanoparticle-based colorimetric detection of kanamycin using a DNA aptamer. AB - A selective kanamycin-binding single-strand DNA (ssDNA) aptamer (TGGGGGTTGAGGCTAAGCCGA) was discovered through in vitro selection using affinity chromatography with kanamycin-immobilized sepharose beads. The selected aptamer has a high affinity for kanamycin and also for kanamycin derivatives such as kanamycin B and tobramycin. The dissociation constants (K(d) [kanamycin]=78.8 nM, K(d) [kanamycin B]=84.5 nM, and K(d) [tobramycin]=103 nM) of the new aptamer were determined by fluorescence intensity analysis using 5'-fluorescein amidite (FAM) modification. Using this aptamer, kanamycin was detected down to 25 nM by the gold nanoparticle-based colorimetric method. Because the designed colorimetric method is simple, easy, and visible to the naked eye, it has advantages that make it useful for the detection of kanamycin. Furthermore, the selected new aptamer has many potential applications as a bioprobe for the detection of kanamycin, kanamycin B, and tobramycin in pharmaceutical preparations and food products. PMID- 21530480 TI - Pitfalls of reverse transcription quantitative polymerase chain reaction standardization: Volume-related inhibitors of reverse transcription. AB - A large part of the reliability of reverse transcription quantitative polymerase chain reaction (RT-qPCR) data depends on technical variations. Such variations are mainly attributable to the reverse transcription step. Standardization is a key factor in decreasing the intersample variability. However, an ideal standardization is not always possible, and compromises must be found. Due to technical requirements, the current consensus is that a constant amount of total RNA should be used for the RT step (CA-RT). Because RNA isolation yields are variable, such a practice requires the use of variable volumes of nucleic acid extracts in RT reaction. We demonstrate that some RNA extracts contain both exogenous and endogenous inhibitors. These inhibitors induce a decrease in RT efficiency that significantly impairs the reliability of RT-qPCR data. Conversely, these inhibitors have a slight effect on the qPCR step. To overcome such drawbacks, we proposed to carry out the RT reaction with a constant volume of RNA extract by preserving a constant RNA amount through the supplementation of yeast transfer RNA (CV-RT). We show that CV-RT, compared with the usual CA-RT, allows us to decrease the RT-qPCR variability induced by intersample differences. Such a decrease is a prerequisite for the reliability of messenger RNA quantification. PMID- 21530481 TI - Quikgene: a gene synthesis method integrated with ligation-free cloning. AB - Gene synthesis is a convenient tool that is widely used to make genes for a variety of purposes. All current protocols essentially take inside-out approaches to assemble complete genes using DNA oligonucleotides or intermediate fragments. Here we present an efficient method that integrates gene synthesis and cloning into one step. Our method, which is evolved from QuikChange mutagenesis, can modify, extend, or even de novo synthesize relatively large genes. The genes are inserted directly into vectors without ligations or subcloning. We de novo synthesized a 600-bp gene through multiple steps of polymerase chain reaction (PCR) directly into a bacterial expression vector. This outside-in gene synthesis method is called Quikgene. Furthermore, we have defined an overlap region of a minimum of nine nucleotides in insertion primers that is sufficient enough to circularize PCR products for efficient transformation, allowing one to significantly reduce the lengths of primers. Taken together, our protocol greatly extends the current length limit for QuikChange insertion. More importantly, it combines gene synthesis and cloning into one step. It has potential applications for high-throughput structural genomics. PMID- 21530482 TI - Ultra-performance ion-pairing liquid chromatography with on-line electrospray ion trap mass spectrometry for heparin disaccharide analysis. AB - A high-resolution method for the separation and analysis of disaccharides prepared from heparin and heparan sulfate (HS) using heparin lyases is described. Ultra-performance liquid chromatography in a reverse-phase ion-pairing mode efficiently separates eight heparin/HS disaccharides. The disaccharides can then be detected and quantified using electrospray ionization mass spectrometry. This method is particularly useful in the analysis of small amounts of biological samples, including cells, tissues, and biological fluids, because it provides high sensitivity without being subject to interference from proteins, peptides, and other sample impurities. PMID- 21530483 TI - AMPK activation enhances PPARalpha activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway. AB - Activation of adenosine monophosphate-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy through peroxisome proliferators-activated receptor-alpha (PPARalpha) signaling pathway, but the detailed mechanism remains unclear. A rat model of cardiac hypertrophy created by transaortic constriction (TAC) was used to investigate the mechanism involved in regulation of PPARalpha activity by AMPK. It was observed that treatment with AICAR (5-aminoimidazole 1 carboxamide ribonucleoside), an AMPK activator, significantly inhibited cardiac hypertrophy in vivo and in vitro. Phosphorylated extracellular signal regulated protein kinase (phospho-ERK1/2) and phospho-p38 mitogen-activated protein kinase (MAPK) protein levels were significantly up-regulated, while PPARalpha protein level was down-regulated in TAC rats. AICAR treatment reversed the changes of PPARalpha and phospho-ERK1/2, but increased phospho-p38 MAPK protein level in TAC rats. Similar changes of PPARalpha and phospho-ERK1/2 protein levels were observed in the hypertrophied cardiomyocytes induced by phenylephrine treatment. Epidermal growth factor (EGF, ERK1/2 activator), but not SB203580 (p38 inhibitor) blocked the up-regulation of PPARalpha protein level induced by AICAR. Luciferase assay showed that AICAR increased PPARalpha transcriptional activity which was abrogated by EGF, but not by SB203580. These results demonstrate that AMPK activation enhances the activity of PPARalpha to inhibit cardiac hypertrophy through ERK1/2, but not p38 MAPK, signaling pathway. PMID- 21530484 TI - The kinetic mechanism for cytochrome P450 metabolism of type II binding compounds: evidence supporting direct reduction. AB - The metabolic stability of a drug is an important property that should be optimized during drug design and development. Nitrogen incorporation is hypothesized to increase the stability by coordination of nitrogen to the heme iron of cytochrome P450, a binding mode that is referred to as type II binding. However, we noticed that the type II binding compound 1 has less metabolic stability at sub-saturating conditions than a closely related type I binding compound 3. Three kinetic models will be presented for type II binder metabolism; (1) Dead-end type II binding, (2) a rapid equilibrium between type I and II binding modes before reduction, and (3) a direct reduction of the type II coordinated heme. Data will be presented on reduction rates of iron, the off rates of substrate (using surface plasmon resonance) and the catalytic rate constants. These data argue against the dead-end, and rapid equilibrium models, leaving the direct reduction kinetic mechanism for metabolism of the type II binding compound 1. PMID- 21530485 TI - AP-1 binding transcriptionally regulates human neutral ceramidase. AB - Many forms of cellular stress cause an elevation of endogenous ceramide levels leading to growth arrest or apoptosis. Ceramidases (CDase) play a critical role in regulating apoptosis by hydrolyzing ceramide into sphingosine, a precursor for promitogenic sphingosine-1-phosphate. Growth factor induction of neutral CDase (nCDase) has been shown to have a cytoprotective effect against cytokine-induced increases in ceramide levels. To further define the physiological regulation of nCDase, we identified a 200 bp promoter region and demonstrated that serum activated this proximal promoter, which correlated with a serum-induced increase in human nCDase mRNA expression. Computational analysis revealed a putative cis element for AP-1, a transcription factor activated by serum. Electrophoretic mobility shift assays demonstrated that the identified transcriptional response element binds to AP-1 transcription factors. RNA interference-mediated knockdown of the AP-1 subunit, c-Jun, inhibited the activity of the human nCDase proximal promoter, whereas, c-Jun overexpression increased promoter activity, which directly correlated with human nCDase mRNA transcription, decreased ceramide mass, and protection against caspase 3/7-dependent apoptosis. Taken together, our findings suggest that c-Jun/AP-1 signaling may, in part, regulate serum-induced human nCDase gene transcription. PMID- 21530486 TI - The role of Phe329 in binding of cationic triarylmethane dyes to human butyrylcholinesterase. AB - Cationic triarylmethane dyes (TAM(+))s which are used as colorants in industry and as frequent tools and reagents in analytical, cell biological and biomedical research have been recently characterized as reversible inhibitors of human butyrylcholinesterase. In this study, the inhibitory effects of two TAM(+)s, malachite green (MG) and methyl green (MeG) on five human BChE mutants (A277V, P285L, H77L, A328F and F329A) were studied spectrophotometrically at 25 degrees C in 50mM MOPS buffer pH 8, using butyrylthiocholine as substrate. The kinetic results obtained with mutant enzymes were compared to those obtained with recombinant wild type BChE. MG and MeG were found to act as competitive/linear mixed inhibitors of recombinant wild type BChE and all BChE mutants except the F329A mutant. Both dyes caused complex nonlinear inhibition of F329A mutant, pointing to multisite binding. K(i) values for MG and MeG, estimated by nonlinear regression analysis, were 3.8 and 27 MUM, respectively, as compared to the 50- to 150-fold lower values observed with recombinant wild type BChE. The observed significant differences in kinetic pattern and K(i) values between recombinant wild type BChE and F329A mutant suggest that phenylalanine at position 329 in human BChE is a critical residue in MG and MeG binding to enzyme. PMID- 21530487 TI - IL-17A increases ADP-induced platelet aggregation. AB - The increased risk of thromboembolism and higher incidence of cardiovascular disorders are among the most common causes of morbidity in patients suffering from autoimmune diseases. In this study we tested the hypothesis that IL-17A, a key pro-inflammatory cytokine involved in the development of autoimmune diseases, exerts pro-aggregant effects on both human and mouse platelets. Human or murine platelets were incubated with IL-17A for 2 min at 37 degrees C prior the addition of the stimuli. Aggregation was monitored in a light transmission aggregometer measuring changes in turbidity with continuous observation over a 5-min interval after the addition of the stimuli. IL-17RA, CD42b and CD62P expression as well as fibrinogen bindings were measured by FACS while Erk-2 phosphorylation was analyzed by western blot using phospho-specific antibodies. Pre-incubation with IL-17A increased ADP-, but not collagen-induced platelet aggregation and accelerated CD62P expression and exposure of fibrinogen binding sites. These effects were associated with a faster kinetic of ADP-induced Erk-2 phosphorylation and were lost in platelets deficient in the IL-17 receptor. Together these results unveil a novel aspect of the inflammatory nature of IL-17A suggesting, at the same time, that therapeutic strategies targeting this cytokine might provide further benefit for the treatment of autoimmune diseases by reducing the risk of cardiovascular-related pathologies. PMID- 21530488 TI - Crystal structure of PHYHD1A, a 2OG oxygenase related to phytanoyl-CoA hydroxylase. AB - Phytanoyl-CoA hydroxylase (PAHX) catalyzes an important step in the metabolism of the fatty acid side chain of chlorophyll. PHYHD1 exists in three isoforms and is the closest human homologue of PAHX. We show that like PAHX, the PHYHD1A but likely not the PHYHD1B/C isoforms, is a functional Fe(II) and 2-oxoglutarate (2OG) dependent oxygenase. Crystallographic and biochemical analyses reveal that PHYHD1A has the double-stranded beta-helix fold and Fe(II) and cosubstrate binding residues characteristic of the 2-oxoglutarate dependent oxygenases and catalyzes the conversion of 2-oxoglutarate to succinate and CO(2) in an iron dependent manner. However, PHYHD1A did not couple 2OG turnover to the hydroxylation of acyl-coenzyme A derivatives that are substrates for PAHX, implying that it is not directly involved in phytanoyl coenzyme-A metabolism. PMID- 21530489 TI - A let-7/Fas double-negative feedback loop regulates human colon carcinoma cells sensitivity to Fas-related apoptosis. AB - Interferon-gamma (IFN-gamma) is considered essential for the regulation of anti tumor reactions as it sensitizes Fas-related apoptosis in HT29 cells, but the mechanism is unclear. In the current study, our data demonstrated that IFN-gamma stimulation and Fas activation suppressed Dicer processing and let-7 microRNA biogenesis, while let-7 microRNA strongly inhibited Fas expression by directly targeting Fas mRNA. Accordingly, our results indicate that Fas and let-7 microRNAs form a double-negative feedback loop in IFN-gamma and Fas induced apoptosis in colon carcinoma cell line HT29, which may be an important synergistic mechanism in anti-tumor immune response. We also found that a let-7 microRNA inhibitor increased Fas expression and sensitized cells to Fas-related apoptosis, which may have future implications in colon carcinoma therapy. PMID- 21530490 TI - Structural analysis of ConBr reveals molecular correlation between the carbohydrate recognition domain and endothelial NO synthase activation. AB - Diocleinae lectins are highly homologous in their primary structure which features metal binding sites and a carbohydrate recognition domain (CRD). Differences in the biological activity of legume lectins have been widely investigated using hemagglutination inhibition assays, isothermal titration microcalorimetry and co-crystallization with mono- and oligosaccharides. Here we report a new lectin crystal structure (ConBr) extracted from seeds of Canavalia brasiliensis, predict dimannoside binding by docking, identify the alpha aminobutyric acid (Abu) binding pocket and compare the CRD of ConBr to that of homologous lectins. Based on the hypothesis that the carbohydrate affinity of lectins depends on CRD configuration, the relationship between tridimensional structure and endothelial NO synthase activation was used to clarify differences in biological activity. Our study established a correlation between the position of CRD amino acid side chains and the stimulation of NO release from endothelium. PMID- 21530491 TI - PARP-1 regulates the expression of caspase-11. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is a multifunctional enzyme that regulates DNA repair, cell death and transcription of inflammatory proteins. In the present study, we present evidence that PARP-1 regulates the expression of caspase-11 following lipopolysaccharide (LPS) stimulation. Knockdown of PARP-1 suppressed the LPS-induced expression of caspase-11 at both mRNA and protein levels as well as caspase-11 promoter activity. Importantly, PARP-1 was recruited to the caspase 11 promoter region containing predicted nuclear factor (NF)-kappaB-binding sites when examined by chromatin immunoprecipitation assay. However, knockdown of PARP 1 did not suppress the expression of caspase-11 induced by interferon-gamma that activates signal transducer and activator of transcription 1 but not NF-kappaB. PARP-1 enzymatic activity was not required for the caspase-11 upregulation since pharmacological inhibitors of PARP-1 did not suppress the induction of caspase 11. Our results suggest that PARP-1, as a transcriptional cofactor for NF-kappaB, regulates the induction of caspase-11 at a transcriptional level. PMID- 21530492 TI - Protective effect of the phosphodiesterase III inhibitor cilostazol on amyloid beta-induced cognitive deficits associated with decreased amyloid beta accumulation. AB - Alzheimer's disease (AD), which is characterized by progressive cognitive impairment, is the most common neurodegenerative disease. Here, we investigated the preventive effect of a phosphodiesterase III inhibitor, cilostazol against cognitive decline in AD mouse model. In vitro studies using N2a cells stably expressing human amyloid precursor protein Swedish mutation (N2aSwe) showed that cilostazol decreased the amyloid beta (Abeta) levels in the conditioned medium and cell lysates. Cilostazol attenuated the expression of ApoE, which is responsible for Abeta aggregation, in N2aSwe. Intracerebroventricular injection of Abeta(25-35) in C57BL/6J mice resulted in increased immunoreactivity of Abeta and p-Tau, and microglia activation in the brain. Oral administration of cilostazol for 2 weeks before Abeta administration and once a day for 4 weeks post-surgery almost completely prevented the Abeta-induced increases of Abeta and p-Tau immunoreactivity, as well as CD11b immunoreactivity. However, post treatment with cilostazol 4 weeks after Abeta administration, when Abeta was already accumulated, did not prevent the Abeta-induced neuropathological responses. Furthermore, cilostazol did not affect the neprilysin and insulin degrading enzymes involved in the degradation of the Abeta peptide, but decreased ApoE levels in Abeta-injected brain. In addition, cilostazol significantly improved spatial learning and memory in Abeta-injected mice. The findings suggest that a phosphodiesterase III inhibitor, cilostazol significantly decreased Abeta accumulation and improved memory impairment induced by Abeta(25-35). The beneficial effects of cilostazol might be explained by the reduction of Abeta accumulation and tau phosphorylation, not through an increase in Abeta degradation but via a significant decrease in ApoE-mediated Abeta aggregation. Cilostazol may be the basis of a novel strategy for the therapy of AD. PMID- 21530493 TI - Intersectin 2 nucleotide exchange factor regulates Cdc42 activity during Xenopus early development. AB - Intersectin 2 (ITSN2) is an evolutionarily conserved scaffold protein involved in endocytic internalization, regulation of actin cytoskeleton and epithelial morphogenesis. Recent studies of different Itsn-deficient organisms revealed that this gene is essential for the functioning of the nervous system and for organism viability. Here we report investigations on a possible role of the ITSN2 long isoform in the early embryonic development of Xenopus laevis. In vertebrates, alternative splicing generates several alternatively spliced isoforms of ITSN2. To date the long splice variant of ITSN2 (ITSN2-L) has been reported only for mammals. We show that transcripts of ITSN2-L can be detected in Xenopus embryos from the first cleavage onwards. Overexpression of functional domains of ITSN2-L in embryos resulted in aberrant phenotypes. The strongest phenotype was produced by the C-terminal extension of ITSN2-L. Embryos displayed hyperpigmentation and gastrulation failure that were incompatible with survival. The C-terminus of ITSN2-L includes the DH-PH tandem, a nucleotide exchange factor for the small GTPase Cdc42 and the C2 domain. Further investigations revealed that the DH-PH tandem was responsible for the development of the phenotype affecting the actin cytoskeleton in embryos. Observed developmental defects depended on Cdc42. The effect of expression of the constitutively active GTPase strongly resembled that of the DH-PH tandem. The dominant negative Cdc42 partially rescued developmental defects induced by the expression of the DH-PH tandem. Thus, our data indicate that the ITSN2 exchange factor regulates the activity of Cdc42 during embryo development affecting actin cytoskeleton in Xenopus embryos. PMID- 21530495 TI - A conserved histidine in human DNLZ/HEP is required for stimulation of HSPA9 ATPase activity. AB - The DNL-type zinc-finger protein DNLZ regulates the activity and solubility of the human mitochondrial chaperone HSPA9. To identify DNLZ residues that are critical for chaperone regulation, we carried out an alanine mutagenesis scan of charged residues in a W115I mutant of human DNLZ and assessed the effect of each mutation on interactions with HSPA9. All mutants analyzed promote the solubility of HSPA9 upon expression in Escherichia coli. However, binding studies examining the effect of DNLZ mutants on chaperone tryptophan fluorescence identified three mutations (R81A, H107A, and D111A) that decrease DNLZ binding affinity for nucleotide-free chaperone. In addition, ATPase measurements revealed that DNLZ R81A and DNLZ-D111A both stimulate the catalytic activity HSPA9, whereas DNLZ H107A does not elicit an increase in activity even when present at a concentration that is 10-fold higher than the level required for half-maximal stimulation by DNLZ. These findings implicate a conserved histidine as critical for DNLZ regulation of mitochondrial HSPA9 catalytic activity. PMID- 21530494 TI - Molecular analysis of DNA repair gene methylation and protein expression during chemical-induced rat lung carcinogenesis. AB - A defective ratio between DNA damage and repair may result in the occurrence of a malignant phenotype. Previous studies have found that many genetic alterations in DNA repair genes occur frequently in lung cancer. However, the epigenetic mechanisms underlying this tumorigenesis are not clear. Herein, we have used a chemical-induced rat lung carcinogenesis model to study the evolution of methylation alterations of DNA repair genes BRCA1, ERCC1, XRCC1, and MLH1. Methylation-specific PCR and immunohistochemistry were used to analyze gene methylation status and protein expression during the progression of lung carcinogenesis. Promoter hypermethylation of BRCA1 was only detected in three samples of infiltrating carcinoma. CpG island hypermethylation of ERCC1, XRCC1, and MLH1 was found to increase gradually throughout lung carcinogenesis progression. Both the prevalence of at least one methylated gene and the average number of methylated genes were heightened in squamous metaplasia and dysplasia compared with normal tissue and hyperplasia, and was further increased in carcinoma in situ (CIS) and infiltrating carcinoma. Immunohistochemical analysis showed that BRCA1 and MLH1 protein expression decreased progressively during the stages of lung carcinogenesis, whereas ERCC1 and XRCC1 expression were only found in later stages. Although methylation levels were elevated for ERCC1 and XRCC1 during carcinogenesis, an inverse correlation with protein expression was found only for BRCA1 and MLH1. These results suggest that a continuous accumulation of DNA repair gene hypermethylation and the consequent protein alterations might be a vital molecular mechanism during the process of multistep chemical-induced rat lung carcinogenesis. PMID- 21530496 TI - Inhibition of TNF-alpha-mediated inflammatory responses by a benzodioxolylacetylamino-linked benzothiazole analog in human fibroblast-like synoviocytes. AB - The pathologic processes of rheumatoid arthritis are mediated by a number of cytokines, chemokines, and matrix metalloproteinases, the expressions of which are controlled by NF-kappaB. This study was performed to explore the effects of a benzothiazole analog, SPA0537, on the control of the NF-kappaB activation pathway. We also investigated whether SPA0537 had any anti-inflammatory effects in human rheumatoid fibroblast-like synoviocytes (FLS). SPA0537 inhibited the nuclear translocation and the DNA binding of NF-kappaB subunits, which correlated with the inhibitory effects on IKK phosphorylation and IkappaBalpha degradation in TNF-alpha-stimulated rheumatoid FLS. These events further suppressed chemokine production, matrix metalloproteinase secretion, and TNF-alpha-induced cell proliferation. In addition, SPA0537 inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor (MCSF) and receptor activator of the NF-kappaB ligand (RANKL) in bone marrow macrophages. These findings suggest that SPA0537 exerts anti-inflammatory effects in rheumatoid FLS through the inhibition of the NF-kappaB pathway. Therefore, it may have therapeutic value for the treatment of rheumatoid arthritis. PMID- 21530497 TI - Inhibition of DNA binding activity of cAMP response element-binding protein by 1,2-naphthoquinone through chemical modification of Cys-286. AB - 1,2-Naphthoquinone (1,2-NQ) is an atmospheric electrophile that reacts covalently with protein thiols. Our previous study revealed that exposure of bovine aortic endothelial cells to 1,2-NQ causes covalent modification of cAMP response element binding protein (CREB), thereby inhibiting its DNA binding activity and substantial gene expression of B-cell lymphoma-2 (Bcl-2) that is regulated by this transcription factor. In this study, we identified the modification sites of CREB that are associated with the decreased transcriptional activity. Matrix assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI TOF/MS) analysis indicated that three amino acids (Cys-286, Lys-290, and Lys-319) were irreversibly modified by 1,2-NQ. Mutational analysis revealed that electrophilic modification of Cys-286, but not the other two amino acids, at the DNA binding domain is essential for the reduced CREB activity. Substitution of Cys-286 with tryptophan (C286W), which mimics CREB modification by 1,2-NQ, supported this notion. These results suggest that the covalent interaction of CREB with 1,2-NQ through Cys-286 blocks the DNA binding activity of CREB, resulting in the repression of CREB-regulated genes. PMID- 21530498 TI - F4-neuroprostanes mediate neurological severity in Rett syndrome. AB - BACKGROUND: Rett syndrome (RTT) is a pervasive development disorder, mainly caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene. No reliable biochemical markers of the disease are available. Here we assess F4 neuroprostanes (F4-NeuroPs), lipid peroxidation products of the docosahexaenoic acid, as a novel disease marker in RTT and correlate it with clinical presentation, MeCP2 mutation type, and disease progression. In addition, we investigate on the impact of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) supplementation on F4-NeuroPs levels. METHODS: A case-control study design was used. A cohort of RTT patients (n=144) exhibiting different clinical presentations, disease stages, and MeCP2 gene mutations were evaluated. F4 NeuroPs were measured in free form using a GC/NICI-MS/MS technique. Plasma F4 NeuroPs levels in patients were compared to healthy controls and related to RTT forms, disease progression, and response to omega-3 PUFAs supplementation. RESULTS: Plasma F4-NeuroPs levels were i) higher in RTT than in controls; ii) increased with the severity of neurological symptoms; iii) significantly elevated during the typical disease progression; iv) higher in MeCP2-nonsense as compared to missense mutation carriers; v) higher in typical RTT as compared to RTT variants; and vi) decreased in response to 12 months omega-3 PUFAs oral supplementation. CONCLUSIONS: Quantification of plasma F4-NeuroPs provides a novel RTT marker, related to neurological symptoms severity, mutation type and clinical presentation. PMID- 21530500 TI - Small dense LDL cholesterol is a robust therapeutic marker of statin treatment in patients with acute coronary syndrome and metabolic syndrome. AB - BACKGROUND: Small dense low-density lipoprotein (sd-LDL) is an atherogenic LDL subfraction and often increased in metabolic syndrome (MetS). This study aimed to determine whether sd-LDL cholesterol (sd-LDL-C) is a therapeutic marker of statin treatment in patients with acute coronary syndrome (ACS) and MetS. METHODS: We examined 71 patients with ACS and 50 non-ACS subjects with normal coronary arteries (controls). The patients with ACS were treated with life-style modifications (n=36) or those plus 20mg atorvastatin daily (n=35) for 6 months. We measured sd-LDL-C by a novel detergent-based homogenous assay and calculated buoyant LDL-C (b-LDL-C). RESULTS: The patients with ACS had higher sd-LDL-C than did the controls (30+/-14 vs. 22+/-8 mg/dl, p<0.001). Furthermore, sd-LDL-C was higher in the patients with ACS and MetS (n=31) than in those without MetS (n=40) (35+/-17 vs. 27+/-11 mg/dl, p<0.05). Atorvastatin reduced LDL-C and sd-LDL-C by 31% (102+/-23 to 70+/-28 mg/dl, p<0.0001) and 24% (29+/-15 to 22+/-13 mg/dl, p<0.01). The reduction in sd-LDL-C by atorvastatin was 5.5-fold greater in the patients with ACS and MetS than in those without MetS (p<0.001). Contrary, that in b-LDL-C was similar between the groups. CONCLUSIONS: sd-LDL-C is a superior therapeutic marker of statin treatment in patients with ACS and MetS. PMID- 21530499 TI - Analysis of human glutathione S-transferase alpha 1 (hGSTA1) gene promoter polymorphism using denaturing high performance liquid chromatography (DHPLC). AB - AIM: The GST enzyme, encoded by hGSTA1 gene, catalyses the GSH dependant detoxification of a variety of carcinogenic metabolites and alkylating chemotherapeutic agents. Two genetic variants of hGSTA1, namely hGSTA1*A and hGSTA1*B, are characterized by three linked SNPs, of which -52 G>A variation being solely responsible for the differential promoter activity of hGSTA1. Individuals homozygous for hGSTA1*B have low hepatic expression of hGSTA1. Given the time and labor consuming PCR-RFLP method and the direct prediction of -52 G>A variation, we opted to establish a high throughput DHPLC procedure for the characterization of hGSTA1 variants. METHODS: 117 DNA samples from South India were included in the study. Control samples were generated for DHPLC using conventional PCR-RFLP technique. Heteroduplexes were produced by in vitro mixing of control DNA samples (hGSTA1*A) to all the samples which are subsequently subjected to DHPLC analysis. The samples were analyzed for the presence of heteroduplexes from the chromatographic profiles. RESULTS AND CONCLUSION: From the total of 117 samples, 43.5% are homozygous for hGSTA1*A allele, 13% are homozygous for hGSTA1*B allele and 43.5% are hGSTA1*A/B heterozygotes. This is, to our knowledge, the first report on the use of DHPLC for the evaluation of hGSTA1 gene promoter polymorphism. PMID- 21530501 TI - Immunosensors for quantifying cyclooxygenase 2 pain biomarkers. AB - BACKGROUND: Cyclooxygenase 2 (COX-2) is a key enzyme in pain biomarkers, inflammation and cancer cell proliferation. Thus biosensors that can quantify pain mediators based on biochemical mechanism are imperative. METHODS: Biomolecular recognition and affinity of antigenic COX-2 with the antibody were investigated using surface plasmon resonance (SPR) and ultra-sensitive portable capillary (UPAC) fluorescence sensors. Polyclonal goat anti-COX-2 (human) antibodies were covalently immobilized on gold SPR surface and direct recognition for the COX-2 antigen assessed. The UPAC sensor utilized an indirect sandwich design involving covalently attached goat anti-COX-2 as the capture antibody and rabbit anti-COX-2 (human) antibody as the secondary antibody. RESULTS: UPAC fluorescence signals were directly proportional to COX-2 at a linear range of 7.46*10-4-7.46*101 ng/ml with detection limit of 1.02*10-4 ng/ml. With SPR a linear range was 3.64*10-4-3.64*102 ng/ml was recorded and a detection limit of 1.35*10-4 ng/ml. Validation was achieved in simulated blood samples with percent recoveries of 81.39% and 87.23% for SPR and UPAC respectively. CONCLUSION: The developed sensors have the potential to provide objective characterization of pain biomarkers for clinical diagnoses. PMID- 21530502 TI - Influence of intracellular trehalose concentration and pre-freeze cell volume on the cryosurvival of rapidly frozen human erythrocytes. AB - Significant interest exists in the application of trehalose, which has low permeability to the phospholipid bilayer, as a non-toxic intracellular cryopreservative for mammalian cells. Introduction of between 8 +/- 3mM and 266 +/- 22 mM trehalose into human erythrocytes using the membrane permeabilizing polymer PP-50 allowed investigation of the relationship between intracellular trehalose concentration, pre-freeze cell volume, and cryosurvival. Cellular cryosurvival increased approximately linearly with pre-freeze cell volume up to the normal volume of fresh cells; diminished cell survival correlated with subnormal pre-freeze cell volume in some cases even at >100mM intracellular trehalose concentration. Uptake of >200 mM trehalose in cells with near-normal cell volume facilitated enhancement of cellular cryosurvival by up to 15 +/- 5%. PMID- 21530503 TI - Fibroblast expression of alpha-smooth muscle actin, alpha2beta1 integrin and alphavbeta3 integrin: influence of surface rigidity. AB - Open wound contraction necessitates cell and connective tissue interactions, that produce tension. Investigating fibroblast responses to tension utilizes collagen coated polyacrylamide gels with differences in stiffness. Human foreskin fibroblasts were plated on native type I collagen-coated polyacrylamide gel cover slips with different rigidities, which were controlled by bis-acrylamide concentrations. Changes in alpha smooth muscle actin (alphaSMA), alpha2beta1 integrin (CD49B) and alphavbeta3 integrin (CD-51) were documented by immuno histology and Western blot analysis. Cells plated on rigid gels were longer, and expressed alphavbeta3 integrin and alphaSMA within cytoplasmic stress fibers. In contrast, cells on flexible gels were shorter, expressed alpha2beta1 integrin and had fine cytoskeletal microfilaments without alphaSMA. Increased tension changed the actin makeup of the cytoskeleton and the integrin expressed on the cell's surface. These in vitro findings are in agreement with the tension buildup as an open wound closes by wound contraction. It supports the notion that cells under minimal tension in early granulation tissue express alpha2beta1 integrin, required for organizing fine collagen fibrils into thick collagen fibers. Thicker fibers create a rigid matrix, generating more tension. With increased tension cytoskeletal stress fibers develop that contain alphaSMA and alphavbeta3 integrin that replaces alpha2beta1 integrin, consistent with cell switching from collagen to non-collagen proteins interactions. PMID- 21530504 TI - Lentivirus mediated IL-17R blockade improves diastolic cardiac function in spontaneously hypertensive rats. AB - BACKGROUND: Hypertension causes cardiac fibrosis characterized by low-grade inflammation. We hypothesized that proinflammatory cytokine, interleukin-17 (IL 17) is important in hypertensive cardiac fibrosis. The pre-ligand assembly domain (PLAD) of IL-17 receptor A (IL-17RA) mediates receptor-chain associations essential for signaling. This study was designed to explore the role of IL-17 RA PLAD in hypertension-induced cardiac fibrosis. METHODS: Eight-week-old male spontaneously hypertensive rats (SHRs) were divided into 2 groups, depending on receiving IL-17RA PLAD-Ig or green fluorescent protein (GFP) lentivirus. Age matched Wistar Kyoto rats served as controls. Cardiac function was determined by echocardiography. Cardiac hypertrophy and fibrosis were histopathologically examined. Matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) expression were quantified by immunoblotting. Collagen content was quantified. RESULTS: Both cardiac systolic and diastolic function and myocardial fibrosis in SHRs was improved significantly by the IL-17RA PLAD. Expression of MMP-2 and MMP-9, TIMP-1 and -2, type I and type III collagen were statistically decreased by IL-17RA PLAD-Ig treatment. Collagen quantitation, as well as collagen concentration and collagen cross-linking, were reduced by IL 17/IL-17R signal blockade. CONCLUSIONS: IL-17/IL-17RA signaling plays an important role in myocardial collagen metabolism in hypertension-induced diastolic dysfunction. PMID- 21530505 TI - The response of HMGA1 to changes in oxygen availability is evolutionarily conserved. AB - Zebrafish embryos have evolved to cope with hypoxia during development. This includes the ability to completely suspend embryo development for extended periods until normoxia is restored. However, only a limited number of studies have examined the gene regulatory responses of zebrafish embryos to hypoxia. The High Mobility Group A1 protein encoded by the mammalian gene HMGA1 is widely expressed during embryo development but not in adults. Its expression can be induced in adult neurons by hypoxia/oxidative stress and it is commonly reactivated in many types of cancer. We report the identification by phylogenetic and conserved synteny analyses of an HMGA1 orthologue in zebrafish, hmga1 (hmg i/y) and analysis of sodium azide as a chemical agent for inducing hypoxia-like responses in zebrafish embryos including temporary suspension of development ("suspended animation"). Evidence was only found for the existence of the "a" isoform of HMGA1 in fish. The "b" and "c" isoforms were not detected. We show that zebrafish hmga1 is expressed in a manner similar to in mammals including its induction by hypoxia during hatching stage and in adult zebrafish brain. However, earlier during development, hypoxia causes a decrease in hmga1 transcript levels. By analysis of conservation of the HMGA1a isoform binding site in zebrafish psen2 gene transcripts, we predict that a zebrafish equivalent of the PS2V isoform of human PSEN2 is not formed and we support this by RT-PCR analyses. Thus, analysis of hmga1 function in zebrafish embryogenesis may be valuable for understanding its wider role in vertebrate development, cancer and cellular responses to hypoxia but not for analysis of the action of HMGA1 in PS2V formation. PMID- 21530507 TI - Neuronal plasticity after a human spinal cord injury: positive and negative effects. AB - In patients suffering an incomplete spinal cord injury (SCI) an improvement in walking function can be achieved by providing a functional training with an appropriate afferent input. In contrast, in immobilized incomplete and complete subjects a negative neuroplasticity leads to a neuronal dysfunction. After an SCI, neuronal centers below the level of lesion exhibit plasticity that either can be exploited by specific training paradigms or undergo a degradation of function due to the loss of appropriate input. Load- and hip-joint-related afferent inputs seem to be of crucial importance for the generation of a locomotor pattern and, consequently, the effectiveness of the locomotor training. In severely affected SCI subjects rehabilitation robots allow for a longer and more intensive training and can provide feedback information. Conversely, in severely affected chronic SCI individuals without functional training the locomotor activity in the leg muscles exhausts rapidly during assisted locomotion. This is accompanied by a shift from early to dominant late spinal reflex components. The exhaustion of locomotor activity is also observed in non ambulatory patients with an incomplete SCI. It is assumed that in chronic SCI the patient's immobility results in a reduced input from supraspinal and peripheral sources and leads to a dominance of inhibitory drive within spinal neuronal circuitries underlying locomotor pattern and spinal reflex generation. A training with an enhancement of an appropriate proprioceptive input early after an SCI might serve as an intervention to prevent neuronal dysfunction. PMID- 21530506 TI - Retinal proteomic changes following unilateral optic nerve transection and early experimental glaucoma in non-human primate eyes. AB - In this work we compared proteomic changes in non-human primate (NHP) retinas at the onset of early experimental glaucoma (EEG) and 3 weeks after optic nerve transection (ONT), as a means to identify regulators in the retina's response to EEG and ONT. Both eyes of 7 NHPs with either unilateral EEG (n = 4) or ONT (n = 3) were enucleated. Proteins were analyzed by a label-free quantitative mass spectrometry system and the abundance of identified retinal proteins was compared between the treated eye and its contralateral control for each NHP. Cellular processes associated with regulated proteins were identified using the MetaCore program. As a result, a total of 209 and 200 proteins were identified in EEG and ONT retinas, respectively. The EEG eyes exhibited two distinguishable levels of maximum IOP: the highest IOP <27 mmHg (n = 2) and >45 mmHg (n = 2), termed mild IOP EEG and high IOP EEG eyes, respectively. A limited overlap of proteins regulated in the same direction was seen between the high IOP EEG and either the mild IOP EEG eyes or ONT eyes. Most of the proteins that were up regulated in the high IOP EEG eyes were down regulated in the mild IOP EEG eyes; the latter showed an overall down regulation that was not seen in the other two conditions. An association with cytoskeleton regulation was recognized for up-regulated proteins in the high IOP EEG eyes. We conclude that mild IOP EEG, high IOP EEG and ONT retinas exhibited condition-specific proteomic changes with little overlap between conditions. Cytoarchitecture regulation appears to be a component of the early retinal response to chronic experimental IOP elevation. PMID- 21530508 TI - Anti-Nogo-A and training: can one plus one equal three? AB - Following spinal cord injury (SCI) the adult central nervous system (CNS) has a limited but substantial capacity for repair and plastic reorganisation. The degree of reorganisation is determined by a number of factors such as the extent and location of the lesion, the remaining circuit activity within the CNS and the age at injury. However, even in the best cases this spontaneous reorganisation does not lead to full recovery of the affected behaviour but instead often results in a functionally successful but compensatory strategy. Current SCI research focuses on enhancing fibre tract (re-)growth and recovery processes. Two currently promising approaches are the neutralisation of CNS growth inhibitory factors, and rehabilitative training of remaining networks. Independently, both approaches can lead to substantial functional recovery and anatomical reorganisation. In this review we focus on Nogo-A, a neurite growth inhibitory protein present in the adult CNS, and its role in regenerative and plastic growth following SCI. We then discuss the efforts of rehabilitative training and the potential combination of the two therapies. PMID- 21530509 TI - Ghrelin protects spinal cord motoneurons against chronic glutamate-induced excitotoxicity via ERK1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3beta pathways. AB - Excitotoxic degeneration of spinal cord motoneurons has been proposed as a pathogenic mechanism in amyotrophic lateral sclerosis (ALS). Recently, we have reported that ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R) 1a, functions as a neuroprotective factor in various animal models of neurodegenerative diseases. In this study, the potential neuroprotective effects of ghrelin against chronic glutamate-induced cell death were studied by exposing organotypic spinal cord cultures (OSCC) to threohydroxyaspartate (THA), as a model of excitotoxic motoneuron degeneration. Ghrelin receptor was expressed on spinal cord motoneurons. Exposure of OSCC to THA for 3 weeks resulted in a significant loss of motoneurons. However, THA induced loss of motoneurons was significantly reduced by treatment of ghrelin. Exposure of OSCC to the receptor-specific antagonist D-Lys-3-GHRP-6 abolished the protective effect of ghrelin against THA. Treatment of spinal cord cultures with ghrelin caused rapid phosphorylation of extracellular signal-regulated kinase 1/2, Akt, and glycogen synthase kinase-3beta (GSK-3beta). The effect of ghrelin on motoneuron survival was blocked by the MEK inhibitor PD98059 and the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002. Taken together, these findings indicate that ghrelin has neuroprotective effects against chronic glutamate toxicity by activating the MAPK and PI3K/Akt signaling pathways and suggest that administration of ghrelin may have the potential therapeutic value for the prevention of motoneuron degeneration in human ALS. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3beta in motoneurons contributes to the protective effect of ghrelin. PMID- 21530510 TI - Drug-resistant malaria: molecular mechanisms and implications for public health. AB - Resistance to antimalarial drugs has often threatened malaria elimination efforts and historically has led to the short-term resurgence of malaria incidences and deaths. With concentrated malaria eradication efforts currently underway, monitoring drug resistance in clinical settings complemented by in vitro drug susceptibility assays and analysis of resistance markers, becomes critical to the implementation of an effective antimalarial drug policy. Understanding of the factors, which lead to the development and spread of drug resistance, is necessary to design optimal prevention and treatment strategies. This review attempts to summarize the unique factors presented by malarial parasites that lead to the emergence and spread of drug resistance, and gives an overview of known resistance mechanisms to currently used antimalarial drugs. PMID- 21530511 TI - Salicylic acid and its location in response to biotic and abiotic stress. AB - Salicylic acid (SA) is an important signal involved in the activation of plant defence responses against abiotic and biotic stress. SA may derive from the phenylpropanoid pathway or via isochorismate synthase as demonstrated in Nicotiana benthamiana, tomato and Arabidopsis thaliana. The phenylpropanoid pathway as well as isochorismate synthase are localized in the chloroplasts but it remains unknown if the end product SA is in the same organelle. We have studied the localization of SA in A. thaliana using the salicylate hydroxylase (NahG) gene expressed with a chloroplast targeting sequence. Plants expressing NahG in the chloroplasts are unable to accumulate SA induced after pathogen or UV exposure. Our data infer that SA is initially located in the chloroplasts. PMID- 21530512 TI - microRNA-1274a, a modulator of sorafenib induced a disintegrin and metalloproteinase 9 (ADAM9) down-regulation in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with poor prognosis. Sorafenib, a multikinase inhibitor, has been widely used to treat patients with advanced HCC in clinic. We postulated that microRNAs (miRNA) might be involved in HCC target-chemotherapy with sorafenib. MiRNA profile of HepG2 was evaluated after cells were treated with vehicle or sorafenib and alterations in miRNA expression occurred with 14 miRNAs. MiR-1274a, which is up-regulated by sorafenib, could significantly repress expression of ADAM9, a protease that is involved in sorafenib target-therapy of HCC, in HCC cells. Taken together, our data emphasizes a new miRNA-based mechanism of sorafenib antitumor therapy. PMID- 21530513 TI - Small bowel perforation in a patient with AIDS. Diagnosis: Small bowel infection with Cryptococcus neoformans. PMID- 21530514 TI - EUS treatment of pancreatic cysts: let's keep the alcohol (and the chemotherapy) locked in the cupboard. PMID- 21530515 TI - A man with dysphagia, aspiration, and hematemesis. Diagnosis: Hematemesis from a bleeding vessel in a large Zenker's diverticulum. PMID- 21530517 TI - Presentation of the Julius M. Friedenwald Medal to David A. Peura, MD, AGAF. PMID- 21530518 TI - Abdominal pain after consuming a chestnut. Diagnosis: Chestnut bezoar in the jejunum. PMID- 21530519 TI - Endoscopic management of large sessile colonic polyps: getting the low down from down under. PMID- 21530522 TI - Programmable matter: applications for gastrointestinal endoscopy and surgery. PMID- 21530527 TI - Unusual submucosal tumor in the stomach. Diagnosis: Endometriosis. PMID- 21530520 TI - Functions of autophagy in hepatic and pancreatic physiology and disease. AB - Autophagy is a lysosomal pathway that degrades and recycles intracellular organelles and proteins to maintain energy homeostasis during times of nutrient deprivation and to remove damaged cell components. Recent studies have identified new functions for autophagy under basal and stressed conditions. In the liver and pancreas, autophagy performs the standard functions of degrading mitochondria and aggregated proteins and regulating cell death. In addition, autophagy functions in these organs to regulate lipid accumulation in hepatic steatosis, trypsinogen activation in pancreatitis, and hepatitis virus replication. This review discusses the effects of autophagy on hepatic and pancreatic physiology and the contribution of this degradative process to diseases of these organs. The discovery of novel functions for this lysosomal pathway has increased our understanding of the pathophysiology of diseases in the liver and pancreas and suggested new possibilities for their treatment. PMID- 21530528 TI - Idiopathic gastroparesis or functional dyspepsia with delayed gastric emptying: where is the difference? PMID- 21530529 TI - Adiponectin profiles are affected by chronic and acute changes in carbohydrate intake in healthy cats. AB - Adiponectin is a key adipokine that regulates carbohydrate and lipid metabolism. It circulates in stable low (LMW) and high molecular weight (HMW) forms. The aims of this study were to characterize baseline adiponectin profiles (total, LMW and HMW multimers) in healthy cats and to assess the effects of varying dietary carbohydrate content on adiponectin profiles. Cats were maintained on a diet with moderate carbohydrate content (37% metabolisable energy [ME]) for 4 weeks and then randomly allocated to either a low carbohydrate (19% ME) or high carbohydrate (52% ME) diet for 4 weeks. Fasting and postprandial plasma adiponectin profiles were measured by ELISA and sucrose gradient/Western blot. After consuming the moderate carbohydrate diet for 4 weeks, fasting total, HMW and LMW plasma adiponectin concentrations were 5.0+/-0.6, 2.5+/-0.5 and 2.6+/-0.2 MUg/mL, respectively. After changing to the low carbohydrate diet, fasting total adiponectin was unchanged but HMW adiponectin increased and LMW adiponectin decreased. No significant postprandial changes were observed. Cats consuming the high carbohydrate diet had increased fasting total and LMW adiponectin with no change in HMW adiponectin. In the postprandial state total adiponectin was reduced and there was a trend towards a decrease in HMW (p=0.086) but not LMW multimers. These data indicate that feline adiponectin multimer profiles are similar to those reported in other species and demonstrate that changes in plasma adiponectin occur in response to chronic and acute carbohydrate intake and these reflect differential changes in adiponectin multimers. PMID- 21530530 TI - Localization of diversified relaxin gene transcripts in the brain of eels. AB - Relaxin 3 (RLN3) is a newly-discovered member of the insulin superfamily. We isolated three RLN3-like cDNAs from the brain of the Japanese eel (Anguilla japonica). The deduced amino acid sequences of the RLN3-like cDNAs contained the two-chain structure common to relaxin including a RXXXRXXI/V motif in the B chain. Phylogenetic analysis assigned the two prepropeptides into teleost/mammalian RLN3 group, which are a pair of duplicates generated by the teleost-specific third-round whole genome duplication, and the other one into teleost RLN group. Therefore, they have been named eel rln3a, rln3b and rln. rln3a transcripts were abundant in the middle-posterior region of the brain and detected at lower levels in the gills, head kidney and kidney. rln3b transcripts were also detected in the middle-posterior region of the brain, but the expression levels were lower than those of rln3a. Low levels of rln transcripts were detected in all brain areas, pituitary, digestive tract and gonad. Quantitative PCR analysis did not detect differences in expression of any rln3 or rln gene between freshwater- and seawater-acclimated eels. In situ hybridization showed that rln3a was expressed in neurons of the lateral lemniscus of the midbrain and of the griseum centrale (GC) of the hindbrain, while low amounts of rln transcripts were found in neurons of the periventricular nucleus of the posterior tuberculum of the diencephalon and the GC. These results suggest that the multiple RLN3-like peptides may play regulatory roles in the brain of euryhaline fish. PMID- 21530531 TI - Histocompatibility testing after fifty years of transplantation. AB - Histocompatibility testing has been used in support of solid organ and hematopoietic stem cell transplantation for over fifty years and transplantation has clearly served as a major stimulus for interest in the human major histocompatibility complex, the HLA system. Until the 1990s, typing and definition of antibodies to HLA antigens was performed primarily by serologic techniques using cell-based assays. Two major technological advances have greatly increased knowledge of HLA alleles and HLA-specific antibodies, namely the introduction of DNA based molecular typing and solid phase immunoassays using purified HLA antigens as targets. By virtue of these advances, the number of recognized HLA alleles has increased from a few hundred to greater than 6000 and definition of the specificities of antibodies to HLA antigens is now possible at the level of individual epitopes. The technological advancements have also raised new challenges. The vast and ever increasing number of HLA alleles has resulted in ambiguities in allele assignments which confound matching for hematopoietic stem cell transplants. Similarly, the ability to detect extremely low levels of HLA-specific antibodies has raised questions about whether such low levels are clinically relevant. Next generation DNA sequencing methods likely will offer the solution to many of the HLA typing ambiguities and future studies on the nature of both HLA and non-HLA-specific antibodies will clarify their impact on transplant outcomes. PMID- 21530532 TI - Losing the battle against fungal infection: suppression of termite immune defenses during mycosis. AB - The dampwood termite, Zootermopsis angusticollis is known to generate humoral immune responses to the entomopathogenic fungus Metarhizium anisopliae. However, little is known about how the termite's cellular immune system reacts to fungal infection. To test the effect of conidia exposure on cellular immunity, we quantified the number and types of hemocytes in the hemolymph of naive nymphs and compared their circulating counts with those of nestmates exposed to 0, 2*10(3), 2*10(6) or 2*10(8) conidia/ml doses. These termites were then bled and their hemocytes counted on days 1, 2, 3, 4, 7 post-exposure. Our results show, first, that naive Z. angusticollis nymphs have three different blood cell types tentatively identified as granular hemocytes, prohemocytes and plasmatocytes. In these individuals, plasmatocytes were on average 13.5 and 3.3 times more numerous than granular hemocytes and prohemocytes, respectively. Second, a full factorial general linear analysis indicated that hemocyte type, time elapsed since conidia exposure and conidia dosage as well as all their interactions explained 43% of the variability in hemocyte density. The numbers of prohemocytes and particularly plasmatocytes, but not granular hemocytes, appear to be affected by the progression of disease. The decline in hemocyte numbers coincided with the appearance of hyphal bodies and the onset of "sluggish" termite behavior that culminated in the insect's death. Hemocyte counts of infected males and females were affected to the same extent. Hence, M. anisopliae overtakes the cellular immune responses of Z. angusticollis mainly by destroying the host's most abundant hemocyte types. PMID- 21530533 TI - Comparative growth kinetics and virulence of four different isolates of entomopathogenic fungi in the house fly (Muscadomestica L.). AB - Virulence (speed of kill) of a fungal entomopathogen against a particular host insect depends on biological properties of the specific isolate-host combination, together with factors such as fungal dose. How these intrinsic and extrinsic factors affect the actual pattern and extent of fungal growth invivo is poorly understood. In this study we exposed adult house flies (Muscadomestica L.) to surfaces treated with high and low doses of Beauveriabassiana (isolates BbGHA and Bb5344), Metarhiziumanisopliae (strain MaF52) and M.anisopliae var. acridum (isolate Ma189) and used quantitative real-time PCR with species-specific primers to examine the relationship between fungal growth kinetics and virulence. At the highest dose, all fungal isolates killed flies significantly faster than controls, with BbGHA, Bb5344 and MaF52 roughly equivalent in virulence (median survival time (+/-SE)=5.0+/-0.10, 5.0+/-0.08 and 5.0+/-0.12days, respectively) and Ma189 killing more slowly (MST=8.0+/-0.20days). At the lower dose, effective virulence was reduced and only flies exposed to isolates BbGHA and Bb5344 died significantly faster than controls (MST=12+/-1.36, 15+/-0.64, 18+/-0.86 and 21.0+/-0.0days for BbGHA, Bb5344, MaF52 and Ma189, respectively). Real-time PCR assays revealed that flies exposed to surfaces treated with the high dose of spores had greater spore pickup than flies exposed to the low dose for each isolate. After pickup, a general pattern emerged for all isolates in which there was a significant reduction of recovered fungal DNA 48h after exposure followed by a brief recovery phase, a stable period of little net change in fungal sequence counts, and then a dramatic increase in sequence counts of up to three orders of magnitude around the time of host death. However, while the patterns of growth were similar, there were quantitative differences such that higher final sequence counts were recovered in insects infected with the most lethal isolates and with the higher dose. These results suggest that variation in virulence between isolates, species and doses is determined more by quantitative rather than qualitative differences in fungal growth kinetics. PMID- 21530534 TI - Naloxone-precipitated morphine withdrawal evokes phosphorylation of heat shock protein 27 in rat heart through extracellular signal-regulated kinase. AB - Heat shock protein 27 (Hsp27) is a well-known stress response protein that becomes phosphorylated through extracellular signal-regulated kinase (ERK). Different drugs of abuse, such as morphine and/or its withdrawal, induce severe stress situations. In this study, we investigated Hsp27 and phospho-Hsp27 expression during morphine dependence and withdrawal and evaluated the involvement of ERK in the phosphorylation of Hsp27 in the rat right ventricle. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by injection of naloxone (2 mg/kg, s.c.). ERK1/2, Hsp27 and phospho-Hsp27 at Ser15 were determined by quantitative blot immunolabeling using specific antibodies. Hsp27 expression was increased 30, 60, 90 and 120 min (144.5+/-14.2%, P<0.0001; 128.9+/-4.6%, P=0.04; 177.4+/-12.7, P<0.0001; and 136.2+/-11.0%, P=0.042, respectively) after saline injection to rats dependent on morphine. Naloxone-precipitated morphine withdrawal also increased the phosphorylation of Hsp27 at Ser15 at those time points (146.8+/-19.8%, P=0.034; 143.9+/-17.9%, P=0.032; 161.2+/-33.3%, P=0.029; and 152.2+/-25.5%, P=0.008, respectively). However, there were no changes in Hsp27 phosphorylation in the morphine dependent group injected with saline. In addition, there was an increase in the phosphorylation of ERK 60 min after naloxone injection in morphine dependent rats (pERK1: 116.3+/-4.2%, P=0.015 and pERK2: 117.2+/-1.5%, P=0.05). Pretreatment with SL327, an inhibitor of ERK phosphorylation, decreased activation (phosphorylation) of both ERK and Hsp27 (pERK1: 4.5+/-3.6%, P<0.0001; pERK2: 42.3+/-3.3%, P<0.0001; and pHsp27: 97.6+/ 1.5%, P=0.008), suggesting that ERK activation triggers Hsp27 phosphorylation. The present findings demonstrate that morphine withdrawal is capable of inducing the activation of Hsp27 in the heart and suggest that phosphorylation of Hsp27 is closely linked to and also dependent on the ERK pathway. PMID- 21530535 TI - X-ray-radiation-induced changes in bacteriorhodopsin structure. AB - Bacteriorhodopsin (bR) provides light-driven vectorial proton transport across a cell membrane. Creation of electrochemical potential at the membrane is a universal step in energy transformation in a cell. Published atomic crystallographic models of early intermediate states of bR show a significant difference between them, and conclusions about pumping mechanisms have been contradictory. Here, we present a quantitative high-resolution crystallographic study of conformational changes in bR induced by X-ray absorption. It is shown that X-ray doses that are usually accumulated during data collection for intermediate-state studies are sufficient to significantly alter the structure of the protein. X-ray-induced changes occur primarily in the active site of bR. Structural modeling showed that X-ray absorption triggers retinal isomerization accompanied by the disappearance of electron densities corresponding to the water molecule W402 bound to the Schiff base. It is demonstrated that these and other X ray-induced changes may mimic functional conformational changes of bR leading to misinterpretation of the earlier obtained X-ray crystallographic structures of photointermediates. PMID- 21530536 TI - Light-induced conformational change and transient dissociation reaction of the BLUF photoreceptor Synechocystis PixD (Slr1694). AB - The light-induced reaction of the BLUF (blue light photoreceptor using flavin adenine dinucleotide) photoreceptor PixD from Synechocystis sp. PCC6803 (Slr1694) was investigated using the time-resolved transient grating method. A conformational change coupled with a volume contraction of 13 mL mol(-1) was observed with a time constant of 45 ms following photoexcitation. At a weak excitation light intensity, there were no further changes in volume and diffusion coefficient (D). The determined D-value (3.7*10(-11) m(2) s(-1)) suggests that PixD exists as a decamer in solution, and this oligomeric state was confirmed by size-exclusion chromatography and blue native polyacrylamide gel electrophoresis. Surprisingly, by increasing the excitation laser power, we observed a large increase in D with a time constant of 350 ms following the volume contraction reaction. The D-value of this photoproduct species (7.5*10(-11) m(2) s(-1)) is close to that of the PixD dimer. Combined with transient grating and size exclusion chromatography measurements under light-illuminated conditions, the light-induced increase in D was attributed to a transient dissociation reaction of the PixD decamer to a dimer. For the M93A-mutated PixD, no volume or D-change was observed. Furthermore, we showed that the M93A mutant did not form the decamer but only the dimer in the dark state. These results indicate that the formation of the decamer and the conformational change around the Met residue are important factors that control the regulation of the downstream signal transduction by the PixD photoreceptor. PMID- 21530537 TI - Post-transcriptional fine-tuning of COP9 signalosome subunit biosynthesis is regulated by the c-Myc/Lin28B/let-7 pathway. AB - The COP9 signalosome (CSN) complex controls protein degradation via the ubiquitin (Ub) proteasome system (UPS) in eukaryotes. In mammalian cells, the multimeric CSN is composed of eight subunits (CSN1 - CSN8). It regulates cullin-RING Ub ligases (CRLs), which target essential regulatory proteins for ubiquitination and subsequent degradation. Thereby, the CSN cooperates with the UPS in a variety of essential cellular functions, including DNA repair, cell cycle and differentiation. Although functions of the CSN have been elucidated, mechanisms and regulatory principles of its de novo formation are completely unknown. Here, we show that there is a fundamental mechanism that allows a coordinated expression of all CSN subunits, a prerequisite for CSN assembly. CSN subunit mRNAs are targets of miRNAs of the let-7 family suppressing CSN subunit expression in human cells. Factors that reduce or block let-7 miRNAs induce the coordinated expression of CSN subunits. For instance, over-expression of CSN1 specifically traps let-7a-1 miRNA and elevates CSN subunit levels by two- to fourfold in a coordinated manner. CSN subunit expression is also increased by specific miRNA inhibitors or by interferon (IFN)-mediated induction of STAT1 and c-Myc reducing levels of let-7 miRNAs. Activation of STAT1 by IFNalpha or IFNgamma induces c-Myc, which increases CSN subunit expression via the Lin28B/let 7 regulatory pathway. By contrast, a let-7a-1 mimic reduces CSN subunit expression. Our data show that let-7 miRNAs control the fine-tuning and coordinated expression of subunits for CSN de novo formation, presumably a general regulatory principle for other Zomes complexes as well. PMID- 21530538 TI - An alternative mechanism for the catalysis of peptide bond formation by L/F transferase: substrate binding and orientation. AB - Eubacterial leucyl/phenylalanyl tRNA protein transferase (L/F transferase) catalyzes the transfer of a leucine or a phenylalanine from an aminoacyl-tRNA to the N-terminus of a protein substrate. This N-terminal addition of an amino acid is analogous to that of peptide synthesis by ribosomes. A previously proposed catalytic mechanism for Escherichia coli L/F transferase identified the conserved aspartate 186 (D186) and glutamine 188 (Q188) as key catalytic residues. We have reassessed the role of D186 and Q188 by investigating the enzymatic reactions and kinetics of enzymes possessing mutations to these active-site residues. Additionally three other amino acids proposed to be involved in aminoacyl-tRNA substrate binding are investigated for comparison. By quantitatively measuring product formation using a quantitative matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-based assay, our results clearly demonstrate that, despite significant reduction in enzymatic activity as a result of different point mutations introduced into the active site of L/F transferase, the formation of product is still observed upon extended incubations. Our kinetic data and existing X-ray crystal structures result in a proposal that the critical roles of D186 and Q188, like the other amino acids in the active site, are for substrate binding and orientation and do not directly participate in the chemistry of peptide bond formation. Overall, we propose that L/F transferase does not directly participate in the chemistry of peptide bond formation but catalyzes the reaction by binding and orientating the substrates for reaction in an analogous mechanism that has been described for ribosomes. PMID- 21530539 TI - The extra-membranous domains of the competence protein HofQ show DNA binding, flexibility and a shared fold with type I KH domains. AB - Secretins form large oligomeric assemblies in the membrane that control both macromolecular secretion and uptake. Several Pasteurellaceae are naturally competent for transformation, but the mechanism for DNA assimilation is largely unknown. In Haemophilus influenzae, the secretin ComE has been demonstrated to be essential for DNA uptake. In closely related Aggregatibacter actinomycetemcomitans, an opportunistic pathogen in periodontitis, the ComE homolog HofQ is believed to be the outer membrane DNA translocase. Here, we report the structure of the extra-membranous domains of HofQ at 2.3 A resolution by X-ray crystallography. We also show that the extra-membranous domains of HofQ are capable of DNA binding. The structure reveals two secretin-like folds, the first of which is formed by means of a domain swap. The second domain displays extensive structural similarity to K homology (KH) domains, including the presence of a GxxG motif, which is essential for the nucleotide-binding function of KH domains, suggesting a possible mechanism for DNA binding by HofQ. The data indicate a direct involvement in DNA acquisition and provide insight into the molecular basis for natural competence. PMID- 21530540 TI - Probing dimerization and structural flexibility of mammalian lipoxygenases by small-angle X-ray scattering. AB - Human lipoxygenases (LOXs) and their metabolites have a great impact on human homeostasis and are of interest for targeted drug design. This goal requires detailed knowledge of their structures and an understanding of structure-function relationship. At the moment, there are two complete crystal structures for mammalian LOX [rabbit 12/15LOX (r-12/15LOX) and human 5LOX (h-5LOX)] and a fragment of human 12LOX. The low-resolution structures in solution for various LOX isoforms have brought about controversial results. Here we explored the behavior of r-12/15LOX in aqueous solution under different conditions (salt and pH) by small-angle X-ray scattering (SAXS) and compared it with human platelet type 12S-LOX (hp-12LOX) and h-5LOX. Thermodynamic calculations concerning the stability of molecular assemblies, thermal motion analysis [TLSMD (translation, libration, and screw rotation motion detection based on crystallographic temperature factor B(j))], and results of SAXS analyses brought about the following conclusions: (i) in contrast to its crystal structure, r-12/15LOX functions as a monomer that dominates in solution; (ii) it dimerizes at higher protein concentrations in the presence of salt and with increasing degree of motional freedom of the N-terminal PLAT domain, as suggested by the Y98,614->R double mutant; (iii) in aqueous solutions, hp-12LOX is stable as a dimer, in contrast to h-5LOX and r-12/15LOX, which are monomeric; and (iv) all three mammalian isozymes show a high level of flexibility not only for the PLAT domain but also for other subdomains of the catalytic part in TLS (translation, libration, and screw rotation) analysis and hp-12LOX in SAXS. PMID- 21530542 TI - Helix 12 dynamics and thyroid hormone receptor activity: experimental and molecular dynamics studies of Ile280 mutants. AB - Nuclear hormone receptors (NRs) form a family of transcription factors that mediate cellular responses initiated by hormone binding. It is generally recognized that the structure and dynamics of the C-terminal helix 12 (H12) of NRs' ligand binding domain (LBD) are fundamental to the recognition of coactivators and corepressors that modulate receptor function. Here we study the role of three mutations in the I280 residue of H12 of thyroid hormone receptors using site-directed mutagenesis, functional assays, and molecular dynamics simulations. Although residues at position 280 do not interact with coactivators or with the ligand, we show that its mutations can selectively block coactivator and corepressor binding, and affect hormone binding affinity differently. Molecular dynamics simulations suggest that ligand affinity is reduced by indirectly displacing the ligand in the binding pocket, facilitating water penetration and ligand destabilization. Mutations I280R and I280K link H12 to the LBD by forming salt bridges with E457 in H12, stabilizing H12 in a conformation that blocks both corepressor and coactivator recruitment. The I280M mutation, in turn, blocks corepressor binding, but appears to enhance coactivator affinity, suggesting stabilization of H12 in agonist conformation. PMID- 21530543 TI - The X-ray structure of the zinc transporter ZnuA from Salmonella enterica discloses a unique triad of zinc-coordinating histidines. AB - ZnuA is the soluble component of the high-affinity ZnuABC zinc transporter belonging to the cluster 9 group of ATP-binding cassette-type periplasmic Zn- and Mn-binding proteins. In Gram-negative bacteria, the ZnuABC system is essential for zinc uptake and homeostasis and is an important determinant of bacterial resistance to the host defense mechanisms. The cluster 9 members share a two (alpha/beta)(4) domain architecture with a long alpha-helix connecting the two domains. In the Zn-specific proteins, the so-called alpha3c and the alpha4 helices are separated by an insert of variable length, rich in histidine and negatively charged residues. This distinctive His-rich loop is proposed to play a role in the management of zinc also due to its location at the entrance of the metal binding site located at the domain interface. The known Synechocystis 6803 and Escherichia coli ZnuA structures show the same metal coordination involving three conserved histidines and a glutamic acid or a water molecule as fourth ligand. The structures of Salmonella enterica ZnuA, with a partially or fully occupied zinc binding site, and of a deletion mutant missing a large part of the His-rich loop revealed unexpected differences in the metal-coordinating ligands, as histidine 140 from the mobile (at the C-terminal) part of the loop substitutes the conserved histidine 60. This unforeseen coordination is rendered possible by the "open conformation" of the two domains. The possible structural determinants of these peculiarities and their functional relevance are discussed. PMID- 21530541 TI - Structural features and chaperone activity of the NudC protein family. AB - The NudC family consists of four conserved proteins with representatives in all eukaryotes. The archetypal nudC gene from Aspergillus nidulans is a member of the nud gene family that is involved in the maintenance of nuclear migration. This family also includes nudF, whose human orthologue, Lis1, codes for a protein essential for brain cortex development. Three paralogues of NudC are known in vertebrates: NudC, NudC-like (NudCL), and NudC-like 2 (NudCL2). The fourth distantly related member of the family, CML66, contains a NudC-like domain. The three principal NudC proteins have no catalytic activity but appear to play as yet poorly defined roles in proliferating and dividing cells. We present crystallographic and NMR studies of the human NudC protein and discuss the results in the context of structures recently deposited by structural genomics centers (i.e., NudCL and mouse NudCL2). All proteins share the same core CS domain characteristic of proteins acting either as cochaperones of Hsp90 or as independent small heat shock proteins. However, while NudC and NudCL dimerize via an N-terminally located coiled coil, the smaller NudCL2 lacks this motif and instead dimerizes as a result of unique domain swapping. We show that NudC and NudCL, but not NudCL2, inhibit the aggregation of several target proteins, consistent with an Hsp90-independent heat shock protein function. Importantly, and in contrast to several previous reports, none of the three proteins is able to form binary complexes with Lis1. The availability of structural information will be of help in further studies on the cellular functions of the NudC family. PMID- 21530544 TI - Knowledge-based virtual screening of HLA-A*0201-restricted CD8+ T-cell epitope peptides from herpes simplex virus genome. AB - A novel knowledge-based method is developed to virtually screen potential HLA A*0201 binders from large-scale peptide candidates. This method utilizes the information from both the crystal structures and experimental affinities of various peptides bound with HLA-A*0201 to construct a single-position mutation free energy profile for accurately characterizing HLA-A*0201-peptide interaction and for effectively predicting the binding affinities of peptides to HLA-A*0201. We employ this method to analyze physicochemical properties and structural implication underlying the specific recognition and association between the HLA A*0201 and a large panel of peptide segments generated from the herpes simplex virus type 1 (HSV-1) genome, and to evaluate the binding potencies of these peptide candidates to HLA-A*0201. As a result, 288 out of 38,020 candidates are predicted as the potential high-affinity binders of HLA-A*0201, from which three most promising peptides are picked out for further development of potent vaccines against HSV-1. In addition, we also demonstrate that this newly proposed method can successfully identify 8 known binders and 3 known nonbinders from the glycoproteins D and K of HSV-1. PMID- 21530545 TI - Effects of stochastic channel gating and distribution on the cardiac action potential. AB - Ion channels exhibit stochastic conformational changes determining their gating behavior. In addition, the process of protein turnover leads to a natural variability of the number of membrane and gap junctional channels. Nevertheless, in computational models, these two aspects are scarcely considered and their impacts are largely unknown. We investigated the effects of stochastic current fluctuations and channel distributions on action potential duration (APD), intercellular conduction delays (ICDs) and conduction blocks using a modified ventricular cell model (Rudy et al.) with Markovian formulations of the principal ion currents (to simulate their stochastic open-close gating behavior) and with channel counts drawn from Poisson distributions (to simulate their natural variability). In single cells, APD variability (coefficient of variation: 1.6% at BCL=1000ms) was essentially caused by stochastic channel gating of I(Ks), persistent I(Na) and I(Ca,L). In cell strands, ICD variability induced by stochastic channel gating and Poissonian channel distributions was low under normal conditions. Nonetheless, at low intercellular coupling levels, Poissonian gap junctional channel distribution resulted in a large ICD variability (coefficient of variation >20%), highly heterogeneous conduction patterns and conduction blocks. Therefore, the stochastic behavior of current fluctuations and channel distributions can contribute to the heterogeneity of conduction patterns and to conduction block, as observed previously in experiments in cardiac tissue with altered intercellular coupling. PMID- 21530546 TI - A biomechanical model of swallowing for understanding the influence of saliva and food bolus viscosity on flavor release. AB - After swallowing a liquid or a semi-liquid food product, a thin film responsible for the dynamic profile of aroma release coats the pharyngeal mucosa. The objective of the present article was to understand and quantify physical mechanisms explaining pharyngeal mucosa coating. An elastohydrodynamic model of swallowing was developed for Newtonian liquids that focused on the most occluded region of the pharyngeal peristaltic wave. The model took lubrication by saliva film and mucosa deformability into account. Food bolus flow rate and generated load were predicted as functions of three dimensionless variables: the dimensionless saliva flow rate, the viscosity ratio between saliva and the food bolus, and the elasticity number. Considering physiological conditions, the results were applied to predict aroma release kinetics. Two sets of conditions were distinguished. The first one was obtained when the saliva film is thin, in which case food bolus viscosity has a strong impact on mucosa coating and on flavor release. More importantly, we demonstrated the existence of a second set of conditions. It was obtained when the saliva film is thick and the food bolus coating the mucosa is very diluted by saliva during the swallowing process and the impact of its viscosity on flavor release is weak. This last phenomenon explains physically in vivo observations for Newtonian food products found in the literature. Moreover, in this case, the predicted thickness of the mix of food bolus with saliva coating the mucosa is approximately of 20 MUm; value in agreement with orders of magnitude found in the literature. PMID- 21530547 TI - A numerical model for durotaxis. AB - Cell migration is a phenomenon that is involved in several physiological processes. In the absence of external guiding factors it shares analogies with Brownian motion. The presence of biochemical or biophysical cues, on the other hand, can influence cell migration transforming it in a biased random movement. Recent studies have shown that different cell types are able to recognise the mechanical properties of the substratum over which they move and that these properties direct the motion through a process called durotaxis. In this work a 2D mathematical model for the description of this phenomenon is presented. The model is based on the Langevin equation that has been modified to take into account the local mechanical properties of the substratum perceived by the cells. Numerical simulations of the model provide individual cell tracks, whose characteristics can be compared with experimental observations directly. The present model is solved for two important cases: an isotropic substratum, to check that random motility is recovered as a subcase, and a biphasic substratum, to investigate durotaxis. The degree of agreement is satisfactory in both cases. The model can be a useful tool for quantifying relevant parameters of cell migration as a function of the substratum mechanical properties. PMID- 21530548 TI - The information encoded by the sex steroid hormones testosterone and estrogen: a hypothesis. AB - It is suggested that the sex steroid hormones testosterone and estrogen (SSH) provide receptor cells with reliable information on protein synthesis and on the level of oxidative metabolism in the cells of the gonads. The SSH are derived from the oxidation of cholesterol. This oxidation is a side reaction of the oxidative processes in the mitochondria that generate most of the energy to the organism. The amount of SSH that is synthesized is correlated to the partial pressure of oxygen at the synthesizing cells. The amount of free SSH that a cell can hold is checked by the damage that free steroids may cause. This damage is prevented by proteins that bind with SSH. As a result, SSH levels are correlated also with the ability of the SSH synthesizing cell to produce proteins that bind with them. A cell can only synthesize SSH in relation to the oxidative processes within it and to its ability to produce the binding proteins necessary to prevent the damage caused by SSH. As a result, the information conveyed by SSH is reliable. We examine the specific damage caused by testosterone and estrogen, and suggest why each of them is best suited for its function. Although both SSH can provide similar information on the metabolism in the cells that synthesize them, there are secondary reasons why testosterone and estrogen were selected to serve particular functions. Testosterone improves the efficiency of the proton pump at the mitochondria in producing ATP, but increases oxidative damage. Estrogen on the other hand decreases oxygen damage but also decreases the efficiency of the proton pump. These differences between the two SSH may explain why females use estrogen to inform the body about the activity of the cells in their gonads while males do it by testosterone. The increased oxidative damage may also explain why in males the testosterone that reaches the brain is turned into estrogen. We also suggest why fish use 11-keto testosterone and why insects do not use these two steroids. PMID- 21530549 TI - Timing as a window on cognition in schizophrenia. AB - Distorted interval timing is a common feature of the cognitive impairment observed in patients with schizophrenia. The neural circuits which are required for interval timing and those thought to be compromised in schizophrenia overlap and include the cortico-striatal pathways. Here, we suggest that a focus on temporal information processing offers a window into understanding the cognitive deficits of schizophrenia and how deficits might contribute to a variety of symptoms. A disruption in the functioning of the cortico-striatal pathways may lead to cognitive deficits which in turn lead to impaired processing of temporal information. Disrupted temporal processing may also contribute to a variety of other symptoms associated with the disorder. Because interval timing is a cognitive/behavioral phenotype that can easily be assessed in animals it can be used as a sensitive screen for deficits in animal models. Using a recently developed transgenic mouse that models increased D2 receptor upregulation in the striatum similar to that observed in patients with schizophrenia we illustrate the utility of an interval timing approach in assessing cognitive impairment. We further discuss how variants of timing procedures can be used to assess attention and working memory performance as well as other necessary components of adaptive cognitive function. PMID- 21530551 TI - Activation of orexin neurons in dorsomedial/perifornical hypothalamus and antidepressant reversal in a rodent model of depression. AB - Chronic stressful life events are risk factors for depression often accompanied by homeostatic disturbances. Hypothalamic neuropeptides, such as orexins (OXs) and melanin-concentrating hormone (MCH), are involved in regulation of several autonomic functions that are altered in depression. However, little is known about the link between orexinergic or MCH-ergic systems and depression. Using double immunohistochemical labeling for OX- or MCH-containing neurons and Fos protein, we studied the effects of a chronic selective serotonin reuptake inhibitor antidepressant treatment (fluoxetine) on the OX and MCH neuronal activation in mice exposed to unpredictable chronic mild stress (UCMS), a rodent model of depression. Western blot was also performed to assess OX and MCH receptor expression in various brain areas. Finally, almorexant, a dual OX receptor antagonist, was assessed in the tail suspension test. UCMS induced physical and behavioral disturbances in mice reversed by 6-week fluoxetine treatment. Orexinergic neurons were more activated in the dorsomedial and perifornical hypothalamic area (DMH-PFA) of UCMS-subjected mice compared to the lateral hypothalamus (LH), and this increase was reversed by 6-week fluoxetine treatment. UCMS also reduced expression of OX-receptor 2 in the thalamus and hypothalamus, but not in animals chronically treated with fluoxetine. MCH neurons were neither affected by UCMS nor by antidepressant treatment, while UCMS modulated MCH receptor 1 expression in thalamus and hippocampus. Finally, chronic but not acute administration of almorexant, induced antidepressant-like effect in the tail suspension test. These data suggest that OX neurons in the DMH-PFA and MCH-ergic system may contribute to the pathophysiology of depressive disorders. PMID- 21530550 TI - New translational assays for preclinical modelling of cognition in schizophrenia: the touchscreen testing method for mice and rats. AB - We describe a touchscreen method that satisfies a proposed 'wish-list' of desirables for a cognitive testing method for assessing rodent models of schizophrenia. A number of tests relevant to schizophrenia research are described which are currently being developed and validated using this method. These tests can be used to study reward learning, memory, perceptual discrimination, object place associative learning, attention, impulsivity, compulsivity, extinction, simple Pavlovian conditioning, and other constructs. The tests can be deployed using a 'flexible battery' approach to establish a cognitive profile for a particular mouse or rat model. We have found these tests to be capable of detecting not just impairments in function, but enhancements as well, which is essential for testing putative cognitive therapies. New tests are being continuously developed, many of which may prove particularly valuable for schizophrenia research. PMID- 21530554 TI - Mecamylamine attenuates dexamethasone-induced anxiety-like behavior in association with brain derived neurotrophic factor upregulation in rat brains. AB - Mecamylamine (MEC), which was initially developed as a ganglionic blocker for the treatment of hypertension has been investigated as a potent antagonist for most types of nicotinic acetylcholine receptors (nAChRs). Most studies of MEC have focused on its inhibitory effects for nAChRs; however its biological uses have recently been expanded to the treatment of psychological disorders accompanying anxiety-related symptoms. Although MEC shows obvious anxiolytic action, there is no clear evidence on its function. In this study, we investigated whether MEC affects brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. MEC increased BDNF expression in differentiated SH-SY5Y cells and the cerebral cortex region of rat brains. To determine if the anxiolytic effect of MEC is associated with BDNF upregulation, the elevated plus maze (EPM) task was conducted in a dexamethasone (DEX)-induced anxiety model. MEC reduced DEX-induced anxiety-like behavior, and increased BDNF expression in the cerebral cortex of rats. These results suggest that the anxiolytic effect of MEC in EPM might be associated with BDNF upregulation in the cerebral cortex region of rats. The therapeutic efficacy of MEC for anxiety might be partly dependent on BDNF modulation. PMID- 21530552 TI - Raphe serotonin neurons are not homogenous: electrophysiological, morphological and neurochemical evidence. AB - The median (MR) and dorsal raphe (DR) nuclei contain the majority of the 5 hydroxytryptamine (5-HT, serotonin) neurons that project to limbic forebrain regions, are important in regulating homeostatic functions and are implicated in the etiology and treatment of mood disorders and schizophrenia. The primary synaptic inputs within and to the raphe are glutamatergic and GABAergic. The DR is divided into three subfields, i.e., ventromedial (vmDR), lateral wings (lwDR) and dorsomedial (dmDR). Our previous work shows that cell characteristics of 5-HT neurons and the magnitude of the 5-HT(1A) and 5-HT(1B) receptor-mediated responses in the vmDR and MR are not the same. We extend these observations to examine the electrophysiological properties across all four raphe subfields in both 5-HT and non-5-HT neurons. The neurochemical topography of glutamatergic and GABAergic cell bodies and nerve terminals were identified using immunohistochemistry and the morphology of the 5-HT neurons was measured. Although 5-HT neurons possessed similar physiological properties, important differences existed between subfields. Non-5-HT neurons were indistinguishable from 5-HT neurons. GABA neurons were distributed throughout the raphe, usually in areas devoid of 5-HT neurons. Although GABAergic synaptic innervation was dense throughout the raphe (immunohistochemical analysis of the GABA transporters GAT1 and GAT3), their distributions differed. Glutamate neurons, as defined by vGlut3 anti-bodies, were intermixed and co-localized with 5-HT neurons within all raphe subfields. Finally, the dendritic arbor of the 5-HT neurons was distinct between subfields. Previous studies regard 5-HT neurons as a homogenous population. Our data support a model of the raphe as an area composed of functionally distinct subpopulations of 5-HT and non-5-HT neurons, in part delineated by subfield. Understanding the interaction of the cell properties of the neurons in concert with their morphology, local distribution of GABA and glutamate neurons and their synaptic input, reveals a more complicated and heterogeneous raphe. These results provide an important foundation for understanding how specific subfields modulate behavior and for defining which aspects of the circuitry are altered during the etiology of psychological disorders. PMID- 21530553 TI - Positive affective vocalizations during cocaine and sucrose self-administration: a model for spontaneous drug desire in rats. AB - Ultrasonic vocalizations in the 50 kHz range (50 kHz USVs) are emitted by rodents upon activation of positive affective states and appear to be a direct measure of internal emotional and motivational urges to seek rewarding stimuli such as drugs of abuse. Since these behavioral responses do not rely on training for expression, they can be viewed as a "spontaneous" measure of affective state. The goal of the present study was to monitor spontaneous USVs throughout a widely used cocaine self-administration and reinstatement model of addiction and relapse. To gain insight into the changes in affective state across the different phases of a standard self-administration experiment, we measured 50 kHz USVs in rats during cocaine self-administration and reinstatement, and compared these to sucrose self-administration and reinstatement. During cocaine self administration, the number of 50 kHz USVs increased over acquisition of self administration and decreased during extinction. Furthermore, the number of USVs on the first day of acquisition in the cocaine experiment was positively correlated with how rapidly cocaine self-administration was acquired. These findings suggest that the initial affective response to cocaine may be a sensitive predictor of the motivational efficacy of rewarding stimuli and therefore the susceptibility to acquire self-administration of cocaine. Cue- and cocaine-induced reinstatement elevated 50 kHz USVs above extinction levels. Rats trained for sucrose self-administration showed no elevation in USVs during acquisition when USVs were considered over the entire 2 h session, but they did show an elevation in USVs during acquisition when considered over only the first 5 min of the session. As with cocaine-induced reinstatement, sucrose-induced reinstatement produced significantly more USVs compared to the prior extinction day. Taken together, USVs may serve as a sensitive and dynamic non-invasive measure that spontaneously (i.e. without any formal reinforcement contingencies) quantifies the extent to which positive affect is elicited by rewards such as drugs of abuse. PMID- 21530555 TI - Blockade of glycine transporter 1 by SSR-504734 promotes cognitive flexibility in glycine/NMDA receptor-dependent manner. AB - Accumulating evidence suggests that cognitive processes may be regulated by glycine concentration in the local environment of glutamate N-methyl-d-aspartate receptor (NMDAR). The concentration of glycine is controlled, among other factors, by the glycine transporter 1 (GlyT1). While GlyT1 inhibitors are developed for a number of indications including cognitive improvement, little is known about their effects in tasks depending on prefrontal cortical function. We examined the effect of GlyT1 inhibitor SSR-504734 on cognitive flexibility assessed in the attentional set-shifting task in rats (ASST). The second goal was to elucidate whether SSR-504734 effect has been due to the compound's action at glycine/NMDAR site. Rats treated with SSR-504734 (3 and 10 mg/kg, IP) required significantly less trials to criteria during extra-dimensional shift (EDs) phase of the ASST. The effect of SSR-504734 (3 mg/kg) was completely prevented by the glycine/NMDAR site antagonist, L-687,414 (30 mg/kg, IP) that by itself exerted no effect on cognitive flexibility. Present study demonstrates that the elevation of glycine concentration through the blockade of its reuptake facilitates cognitive flexibility. As this effect was fully blocked by glycine/NMDAR antagonist, SSR 504734-induced cognitive improvement is likely mediated through glycine action at NMDAR. It is suggested that GlyT1 inhibitors like SSR-504734 may represent a useful pharmacological approach for cognitive enhancement, especially in domains critically affected in schizophrenia. PMID- 21530556 TI - Where did I put that? Patients with amnestic mild cognitive impairment demonstrate widespread reductions in activity during the encoding of ecologically relevant object-location associations. AB - Remembering the location of objects in the environment is both important in everyday life and difficult for patients with amnestic mild cognitive impairment (aMCI), a clinical precursor to Alzheimer's disease. To test the hypothesis that memory impairment for object location in aMCI reflects hippocampal dysfunction, we used an event-related functional magnetic resonance imaging paradigm to compare patients with aMCI and healthy elderly controls (HEC) as they encoded 90 ecologically relevant object-location associations (OLAs). Two additional OLAs, repeated a total of 45 times, served as control stimuli. Memory for these OLAs was assessed following a 1-h delay. The groups were well matched on demographics and brain volumetrics. Behaviorally, HEC remembered significantly more OLAs than did aMCI patients. Activity differences were assessed by contrasting activation for successfully encoded Novel stimuli vs. Repeated stimuli. The HEC demonstrated activity within object-related (ventral visual stream), spatial location-related (dorsal visual stream), and feature binding-related cortical regions (hippocampus and other memory-related regions) as well as in frontal cortex and associated subcortical structures. Activity in most of these regions correlated with memory test performance. Although the aMCI patients demonstrated a similar activation pattern, the HEC showed significantly greater activity within each of these regions. Memory test performance in aMCI patients, in contrast to the HEC, was correlated with activity in regions involved in sensorimotor processing. We conclude that aMCI patients demonstrate widespread cerebral dysfunction, not limited to the hippocampus, and rely on encoding-related mechanisms that differ substantially from healthy individuals. PMID- 21530558 TI - Vertical bias in neglect: a question of time? AB - Neglect is defined as the failure to attend and to orient to the contralesional side of space. A horizontal bias towards the right visual field is a classical finding in patients who suffered from a right-hemispheric stroke. The vertical dimension of spatial attention orienting has only sparsely been investigated so far. The aim of this study was to investigate the specificity of this vertical bias by means of a search task, which taps a more pronounced top-down attentional component. Eye movements and behavioural search performance were measured in thirteen patients with left-sided neglect after right hemispheric stroke and in thirteen age-matched controls. Concerning behavioural performance, patients found significantly less targets than healthy controls in both the upper and lower left quadrant. However, when targets were located in the lower left quadrant, patients needed more visual fixations (and therefore longer search time) to find them, suggesting a time-dependent vertical bias. PMID- 21530557 TI - Acute effects of nicotine administration during prospective memory, an event related fMRI study. AB - We previously demonstrated that stimulating neuronal nicotinic acetylcholine receptors modulates prospective memory (PM), the ability to remember and implement a prior intention. Here we used fMRI to explore the neuronal correlates of acute nicotinic (1mg) modulation during PM, employing a double blind, valence matched placebo-controlled design, and a solely event-related analysis. Eight healthy adults completed on two occasions (1 week washout) a simple attentional task containing infrequent PM trials. PM activated bilateral parietal, prefrontal (BA10) and anterior cingulate, and deactivated genual cingulate and medial prefrontal regions. Further, acute nicotine administration decreased activity within a largely overlapping right parietal region. This data validates a purely event-related approach to exploring PM, and suggests procholinergic modulation of PM by parietal rather than BA10/frontal regions. PMID- 21530559 TI - Spared structural knowledge in a case of semantic dementia: implications for models of object recognition, semantic memory and structural description. AB - Most models of visual object recognition assume that items belonging to known categories are represented in long-term memory in terms of both structural descriptions and semantic representations. The former specify the visual appearance of category members and the latter allow recognising them as meaningful objects. Nevertheless, the format of these two kinds of representations and their relationships are still a matter of debate. Recently, the independence of structural and semantic representations has been questioned on the basis of the finding of an impaired performance of subjects suffering from semantic dementia on the object decision task, which was originally devised to tap the structural description system. In the present case study of a patient with semantic dementia, we provide data supporting the independence of these two systems. Our results allowed us to better qualify the content and format of structural descriptions in terms of purely geometric non-verbalizable information, specifying the appearance of exemplars at a rather coarse level of categorisation. PMID- 21530560 TI - Taste as a basis for body wisdom. AB - The sense of taste uses a variety of discrete receptor mechanisms to identify nutrients and toxins. Information from receptors is arrayed along a dimension of physiological welfare, which serves as the organizing principle of the taste system. This, in turn, drives central physiological and neurochemical processes that underlie hedonics: nutrients elicit reward; toxins, aversion. The sensitivity of the taste system, and so the placement of chemical stimuli along the welfare dimension, is modifiable based on level of satiety, experience, or physiological need. These modifications may be sufficient to guide the animal's food choices according to those that satisfy its needs at the moment. Thus, judicious changes in taste sensitivity of the rodent may underlie the demonstrated behavior of body wisdom. PMID- 21530563 TI - From bedside to bench and back again: a 30-year saga. AB - My work (Mark S. Gold) began in the 70s looking for the mechanisms of drug reinforcement and withdrawal. Through observation and experience, drugs of abuse and the drive for food appeared to be quite related. As pioneered by Bart Hoebel, food can become an object of desire and act in most respects as a drug of abuse. The Gold lab is investigating working models for pathological attachment to eating and food addiction. New pharmacological treatments which interfere with food reinforcement may be the next step. PMID- 21530561 TI - The ovarian hormone estradiol plays a crucial role in the control of food intake in females. AB - Despite a strong male bias in both basic and clinical research, it is becoming increasingly accepted that the ovarian hormone estradiol plays an important role in the control of food intake in females. Estradiol's feeding inhibitory effect occurs in a variety of species, including women, but the underlying mechanism has been studied most extensively in rats and mice. Accordingly, much of the data reviewed here is derived from the rodent literature. Adult female rats display a robust decrease in food intake during estrus and ovariectomy promotes hyperphagia and weight gain, both of which can be prevented by a physiological regimen of estradiol treatment. Behavioral analyses have demonstrated that the feeding inhibitory effect of estradiol is mediated entirely by a decrease in meal size. In rats, estradiol appears to exert this action indirectly via interactions with peptide and neurotransmitter systems implicated in the direct control of meal size. Here, I summarize research examining the neurobiological mechanism underlying estradiol's anorexigenic effect. Central estrogen receptors (ERs) have been implicated and activation of one ER subtype in particular, ERalpha, appears both sufficient and necessary for the estrogenic control of food intake. Future studies are necessary to identify the critical brain areas and intracellular signaling pathways responsible for estradiol's anorexigenic effect. A clearer understanding of the estrogenic control of food intake is prerequisite to elucidating the biological factors that contribute to obesity and eating disorders, both of which are more prevalent in women, compared to men. PMID- 21530562 TI - Food scarcity, neuroadaptations, and the pathogenic potential of dieting in an unnatural ecology: binge eating and drug abuse. AB - In the laboratory, food restriction has been shown to induce neuroadaptations in brain reward circuitry which are likely to be among those that facilitate survival during periods of food scarcity in the wild. However, the upregulation of mechanisms that promote foraging and reward-related learning may pose a hazard when food restriction is self-imposed in an ecology of abundant appetitive rewards. For example, episodes of loss of control during weight-loss dieting, use of drugs with addictive potential as diet aids, and alternating fasting with alcohol consumption in order to avoid weight gain, may induce synaptic plasticity that increases the risk of enduring maladaptive reward-directed behavior. In the present mini-review, representative basic research findings are outlined which indicate that food restriction alters the function of mesoaccumbens dopamine neurons, potentiates cellular and behavioral responses to D-1 and D-2 dopamine receptor stimulation, and increases stimulus-induced synaptic insertion of AMPA receptors in nucleus accumbens. Possible mechanistic underpinnings of increased drug reward magnitude, drug-seeking, and binge intake of sucrose in food restricted animal subjects are discussed and possible implications for human weight-loss dieting are considered. PMID- 21530564 TI - Food intake, metabolism and homeostasis. AB - This tribute to Bart Hoebel briefly reviews the following topics. Metabolic processes are intimately intertwined with food intake as well as drug taking. Changes in any of these processes can be adequately adjusted to the environment to preclude major perturbations in homeostatically-regulated systems, but only if the environment is predictable. Learning plays a critical role in adapting these processes to specific situations. The regulatory context plays a critical role in how metabolism and food intake interact. PMID- 21530565 TI - Detection of new urinary exemestane metabolites by gas chromatography coupled to mass spectrometry. AB - Exemestane is an aromatase enzyme complex inhibitor. Its metabolism in humans is not fully described and there is only one known metabolite: 17beta hydroxyexemestane. In this work, excretion studies were performed with four volunteers aiming at the detection of new exemestane metabolites in human urine by gas chromatography coupled to mass spectrometry (GC-MS) after enzymatic hydrolysis and liquid-liquid extraction. Urine samples collected from four volunteers were analyzed separately. The targets of the study were mainly the 6 exomethylene oxidized metabolites. Two unreported metabolites were identified in both free and glucuconjugated urine fractions from all four volunteers, both of them were the result of the 6-exomethylene moiety oxidation: 6xi-hydroxy-6xi hydroxymethylandrosta-1,4-diene-3,17-dione (metabolite 1) and 6xi-hydroxyandrosta 1,4-diene-3,17-dione (metabolite 2). Furthermore, only in glucoconjugated fractions from all volunteers, one metabolite arising from the A-ring reduction was identified as well, 3xi-hydroxy-5xi-androst-1-ene-6-methylene-17-one (metabolite 3). The molecular formulae of all these metabolites were ascertained by the determination of exact masses using gas chromatography coupled to high resolution mass spectrometry (GC-HRMS). Moreover, all metabolites were confirmed using an alternative derivatization with methoxyamine and MSTFA/TMS-imidazole. PMID- 21530566 TI - Desulfohaplosamate, a new phosphate-containing steroid from Dasychalina sp., is a selective cannabinoid CB2 receptor ligand. AB - From the polar organic extract of the Indonesian sponge Dasychalina sp. we have isolated haplosamate A (1), a unique C(28) sterol containing a sulfate group at C 3 and a methyl phosphate at C-15, along with its new desulfo analogue 2, whose structure has been secured by detailed NMR investigation. Compounds 1 and 2, as well as their semi-synthetic analogues 3-5, have been evaluated for interaction with CB(1) and CB(2) receptors through a binding test. Desulfohaplosamate (2) showed a selective affinity for CB(2) receptors in the low MUM range, while a semi-synthetic derivative with cleaved ring B showed a complete loss of affinity for both receptors, highlighting the importance of an intact steroid nucleus. To our knowledge, haplosamate derivatives represent the first CB receptor ligands belonging to the class of steroids. PMID- 21530567 TI - E6-AP facilitates efficient transcription at estrogen responsive promoters through recruitment of chromatin modifiers. AB - E6-AP is a known coactivator of the estrogen receptor alpha (ERalpha), however the coactivation mechanism of E6-AP is not clear. This work was undertaken to elucidate the coactivation mechanism of E6-AP. In order to examine the role of E6 AP in ERalpha signaling, we knocked-down the expression of E6-AP and examined the transactivation functions of ERalpha. Knockdown of E6-AP showed reduced mRNA production of the ERalpha target genes pS2 and GREB1 suggesting that E6-AP is required for their proper transcription facilitated by ERalpha. In order to study the mechanism(s) by which E6-AP regulates the transcriptional functions of ERalpha, we performed chromatin immunoprecipitation (ChIP) assays under E6-AP knockdown conditions. Our ChIP data suggest that knockdown of E6-AP leads to decreased recruitment of the histone acetylase p300 to the ERalpha target gene pS2 promoter as well as reduced histone modifications at the promoter. Although there was reduced p300 recruitment to the pS2 promoter, loss of p300 did not account fully for the loss of histone acetylation. Taken together our data suggest that E6-AP regulates the transactivation functions of ERalpha in part by complexing with p300 and other chromatin modifying enzymes at target gene promoters to create a transcriptionally active promoter environment. PMID- 21530568 TI - Cytotoxic and antioxidant property of a purified fraction (NN-32) of Indian Naja naja venom on Ehrlich ascites carcinoma in BALB/c mice. AB - A cytotoxic and antioxidant protein (NN-32) from the Indian spectacled cobra Naja naja venom was identified and its probable mode of action on murine Ehrlich ascites carcinoma (EAC) was established. The venom purified through ion exchange chromatography produced several peaks, among which fraction 32 produced cytotoxic cardiotoxic properties. This fraction (NN-32) showed a single peak (retention time 38.3 min) by HPLC using C4 column. The molecular mass determined by MALDI MS, found to be 6.7 kDa and the first ten N-terminal sequence was determined (LKCNKLVPLF) by Edmann degradation method using applied Biosystem procise sequencer. It was observed that the sequence shared 100% homology with other cytotoxin cardiotoxin identified from the venom of Naja species. NN-32 showed cytotoxicity on EAC cells, increased survival time of inoculated EAC mice, reduced solid tumor volume and weight. NN-32 increased proapoptotic protein caspase 3 and 9 activity and Bax-Bcl2 ratio. It also increased the antioxidant markers glutathione, glutathione peroxidase, glutathione transferase, superoxide dismutase and catalase activity. NN-32 increased serum IL-10 level and decreased murine keratinocyte-derived chemokine level. The cardiotoxicity of NN-32 was established on isolated guinea pig auricle, where 100% irreversible blockade of auricular contraction was observed. Thus, it may be concluded that, NN-32 induced anticancer activity in EAC mice was partly mediated through its apoptogenic - antioxidant property. PMID- 21530569 TI - Neutralization of Vipera and Macrovipera venoms by two experimental polyvalent antisera: a study of paraspecificity. AB - We conducted an extensive study of neutralization of lethality of 11 species and one subspecies of snakes of the genus Vipera, and of five species of Macrovipera, by two experimental equine antisera. One antiserum was a trivalent preparation raised against the venoms of Vipera aspis aspis, Vipera berus berus and Vipera ammodytes ammodytes; the other was a pentavalent preparation that also included venoms of Vipera (now Montivipera) xanthina and Macrovipera lebetina obtusa. We measured specific neutralization of lethality against all venoms included in the immunization schemes, and paraspecific neutralization against the venoms of Vipera ammodytes montandoni, Vipera (Montivipera) bornmuelleri, Vipera latastei, Vipera (Mo.) latifii, Vipera (Mo.) lotievi, Vipera (Daboia) palaestinae, Vipera (Mo.) raddei and Vipera seoanei, as well as against Macrovipera (D.) deserti, Macrovipera lebetina cernovi, Macrovipera lebetina turanica and Macrovipera schweitzeri. We found an important degree of paraspecific protection within each genera (omitting recent reclassification) that was quite independent of both the lethal potency of the venoms and their geographic origin. This information may be of use to clinicians charged with the treatment of Vipera or Macrovipera envenomations with non-specific antivenoms. PMID- 21530570 TI - Cytotoxicity of monocrotaline in isolated rat hepatocytes: effects of dithiothreitol and fructose. AB - Monocrotaline (MCT) is a pyrrolizidine alkaloid present in plants of the Crotalaria species that causes cytotoxicity and genotoxicity, including hepatotoxicity in animals and humans. It is metabolized by cytochrome P-450 in the liver to the alkylating agent dehydromonocrotaline (DHM). In previous studies using isolated rat liver mitochondria, we observed that DHM, but not MCT, inhibited the activity of respiratory chain complex I and stimulated the mitochondrial permeability transition with the consequent release of cytochrome c. In this study, we evaluated the effects of MCT and DHM on isolated rat hepatocytes. DHM, but not MCT, caused inhibition of the NADH-linked mitochondrial respiration. When hepatocytes of rats pre-treated with dexamethasone were incubated with MCT (5 mM), they showed ALT leakage, impaired ATP production and decreased levels of intracellular reduced glutathione and protein thiols. In addition, MCT caused cellular death by apoptosis. The addition of fructose or dithiotreitol to the isolated rat hepatocyte suspension containing MCT prevented the ATP depletion and/or glutathione or thiol oxidation and decreased the ALT leakage and apoptosis. These results suggest that the toxic effect of MCT on hepatocytes may be caused by metabolite-induced mitochondrial energetic impairment, together with a decrease of cellular glutathione and protein thiols. PMID- 21530571 TI - Continuous enriched environment improves learning and memory in adult NMRI mice through theta burst-related-LTP independent mechanisms but is not efficient in advanced aged animals. AB - INTRODUCTION: Effects of 3-month continuous environmental enrichment (EE) on cognitive abilities and on theta burst-related synaptic plasticity of CA1 hippocampal neuronal networks have been assessed in 6- and 20-month old NMRI female mice. RESULTS: EE decreased anxiety-like behavior and improved learning and memory performances in adult but not in aged mice. Electrophysiological results in CA1 hippocampal slices showed that basal synaptic transmission was not affected by EE in adult mice whereas it was partially improved in aged animals, even though not sufficient to rescue the decrease related to aging. Besides, no effect of EE on N-methyl-d-aspartate receptor activation and theta-burst-induced long-term potentiation was found in adult or aged animals. DISCUSSION: These results indicate that continuous EE is able to improve cognitive abilities in adult NMRI female mice, that does not correlate with changes in theta burst related synaptic plasticity within neuronal networks. In addition, the lack of effects in aged animals suggests the existence of a critical delay for the beneficial effects of EE on cognitive aging. PMID- 21530573 TI - Attenuation of apomorphine-induced sensitization by buspirone. AB - Apomorphine, a dopamine D1/D2 agonist is effective in the treatment of Parkinson's disease; but its long term use is often associated with the dependence and addiction. The development of locomotor sensitization to psychostimulants including apomorphine is considered to be an important contributor to psychostimulant drug abuse. Previous studies have shown that long term administration of drugs of abuse increases the effectiveness of somatodendritic 5-hydroxytryptamine (5-HT)-1A receptors. Repeated administration of buspirone attenuates the effectiveness of somatodendritic 5-HT(1A) receptors. The present study was designed to test the hypothesis that coadministration of buspirone may attenuate apomorphine induced sensitization. Administration of apomorphine at a dose of 1.0, 2.0 & 4.0mg/kg increased motor activity in an activity box in a dose dependent manner. Locomotor enhancing effects of a low dose of apomorphine were augmented upon repeated administration suggesting drug induced sensitization. The sensitization effects were significant in an activity box as well as in an open field. Coadministration of buspirone at a dose of 1.0mg/kg reversed apomorphine-induced sensitization. Repeated administration of buspirone at a dose of 2.0 mg/kg but not 1.0 mg/kg also elicited sensitization in motor behavior. It is suggested that buspirone may oppose the development of sensitization to apomorphine by decreasing the sensitivity of somatodendritic 5 HT(1A) receptors. Findings may help in extending therapeutics in Parkinson's disease. PMID- 21530572 TI - The RFamide neuropeptide 26RFa and its role in the control of neuroendocrine functions. AB - Identification of novel neuropeptides and their cognate G protein-coupled receptors is essential for a better understanding of neuroendocrine regulations. The RFamide peptides represent a family of regulatory peptides that all possess the Arg-Phe-NH2 motif at their C-terminus. In mammals, seven RFamide peptides encoded by five distinct genes have been characterized. The present review focuses on 26RFa (or QRFP) which is the latest member identified in this family. 26RFa is present in all vertebrate phyla and its C-terminal domain (KGGFXFRF NH2), which is responsible for its biological activity, has been fully conserved during evolution. 26RFa is the cognate ligand of the orphan G protein-coupled receptor GPR103 that is also present from fish to human. In all vertebrate species studied so far, 26RFa-expressing neurons show a discrete localization in the hypothalamus, suggesting important neuroendocrine activities for this RFamide peptide. Indeed, 26RFa plays a crucial role in the control of feeding behavior in mammals, birds and fish. In addition, 26RFa up-regulates the gonadotropic axis in mammals and fish. Finally, evidence that the 26RFa/GPR103 system regulates steroidogenesis, bone formation, nociceptive transmission and arterial blood pressure has also been reported. Thus, 26RFa appears to act as a key neuropeptide in vertebrates controlling vital neuroendocrine functions. The pathophysiological implication of the 26RFa/GPR103 system in human is totally unknown and some fields of investigation are proposed. PMID- 21530575 TI - How many deaths are attributable to smoking in the United States? Comparison of methods for estimating smoking-attributable mortality when smoking prevalence changes. AB - BACKGROUND: The number of smoking-attributable deaths is commonly estimated using current and former smoking prevalences or lung cancer mortality as an indirect metric of cumulative population smoking. Neither method accounts for differences in the timing with which relative risks (RRs) for different diseases change following smoking initiation and cessation. We aimed to develop a method to account for time-dependent RRs. METHODS: We used birth cohort lung cancer mortality and its change over time to characterize time-varying cumulative smoking exposure. We analyzed data from the American Cancer Society Cancer Prevention Study II to estimate RRs for disease-specific mortality associated with current and former smoking, and change in RRs over time after cessation. RESULTS: When lung cancer was used to measure cumulative smoking exposure, 254,700 male and 227,000 female deaths were attributed to smoking in the US in 2005. A modified method in which RRs for different diseases decreased at different rates after cessation yielded similar but slightly lower estimates [251,900 (male) and 221,100 (female)]. The lowest estimates resulted from the method based on smoking prevalence [225,800 (male) and 163,700 (female)]. CONCLUSIONS: Although all methods estimated a large number of smoking attributable deaths, future efforts should account for temporal changes in smoking prevalence and in accumulation/reversibility of disease-specific risks. PMID- 21530574 TI - Increased pain perception and attenuated opioid antinociception in paradoxical sleep-deprived rats are associated with reduced tyrosine hydroxylase staining in the periaqueductal gray matter and are reversed by L-dopa. AB - Paradoxical sleep deprivation (PSD) increases pain sensitivity and reduces morphine antinociception. Because dopaminergic neurons in the periaqueductal gray matter (PAG) participate in pain modulation and opioid-induced antinociception, we evaluated the effects of PSD on thermal pain sensitivity, morphine- and L-DOPA induced antinociception and dopaminergic functionality in the PAG by assessing tyrosine hydroxylase (TH) immunoreactivity. Rats that were subjected to 96h of PSD received vehicle, morphine (2.5, 5 or 10mg/kg), L-DOPA (50 or 100mg/kg) or L DOPA (50mg/kg)+morphine (2.5 and 5mg/kg) and were tested with a 46 degrees C hot plate 1h after. The paw withdrawal latency responses to the hot plate were decreased in PSD rats and were modified by the highest dose of morphine, L-DOPA and L-DOPA+morphine. Analgesic effects were observed in control groups for all of the morphine doses as well as 100mg/kg of L-DOPA and L-DOPA (50mg/kg)+morphine (5mg/kg). The number of cell bodies that were immunopositive for TH in the PAG was reduced in PSD rats. In conclusion, increased thermal sensitivity was reversed by L-DOPA and could be caused by a reduction TH levels in the PAG. Our data also suggest a relationship between central dopaminergic networks and opiate induced analgesia in rats. PMID- 21530576 TI - Porcine regulatory T cells: mechanisms and T-cell targets of suppression. AB - Tregs are known for their suppressive capacity on various immune reactions. In swine, existence as well as suppressive activity of Foxp3(+) Tregs could be demonstrated but detailed functional investigations are lacking. Therefore, we analysed the functional properties of porcine Tregs. We observed that besides TCR stimulation Tregs require IL-2 for activation. Furthermore, we investigated the following mechanisms of suppression: (i) cell-cell contact dependency, (ii) production of soluble suppressive factors and (iii) competition for growth factors. Our experiments revealed that suppression by porcine Tregs is abrogated by blocking cell-cell contact or by supplementing excessive amounts of IL-2. Additionally it could be shown that porcine Tregs produce immunosuppressive IL 10. Thereby, we demonstrated that porcine Tregs can use all main mechanisms of suppression mentioned above. Further investigations on the suppressive activity of Tregs using CFSE proliferation assays demonstrated that suppression affects T helper cells as well as cytotoxic T lymphocytes and TCR-gammadelta T cells. PMID- 21530577 TI - Haemocyte protein expression profiling of scallop Chlamys farreri response to acute viral necrosis virus (AVNV) infection. AB - Acute viral necrosis virus (AVNV) was newly reported as one causative agent responsible for mass mortality of adult Chinese scallop Chlamys farreri, which is widely cultured on northern China coast. Unfortunately, the interaction between virus and host is largely unknown. According to these, this study was undertaken to deeply explore the immune response of haemocyte against AVNV. Two-dimensional gel electrophoresis (2-DE) was introduced to produce protein expression profiles from samples taken at 24h post-infection (hpi) from the haemocytes of C. farreri that were either specific pathogen free or else infected with AVNV. Forty-eight protein spots, which consistently showed either a marked change (>=1.5-fold difference) in accumulated levels or else were highly expressed in haemocytes, were selected for further investigation. In-gel trypsin digestion was conducted followed by matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF-MS). Matching search was subsequently performed throughout bioinformatics databases. A total of 42 proteins were identified, all of which were classified into eight categories according to their Gene Ontology annotations of biological processes and molecular functions, i.e. cytoskeleton proteins, proteins involved in metabolism, proteins related to calcium homeostasis, chaperone, proteins involved in immunity, proteins involved in transcriptional regulation, proteins related to signal transduction, and ungrouped proteins. The possible biological significance of some observed proteins in the host response to AVNV was discussed. These studies could be served as the first global analysis of differentially expressed proteins in haemocytes from AVNV-infected C. farreri, and in addition to increasing our understanding of the pathogenesis of this virus-associated scallop disease, the results presented here should be useful both for potential biomarkers identification and anti-virus approaches development as well. PMID- 21530578 TI - Cytotoxic T cells in teleost fish. AB - The presence of antigen-specific cytotoxic T cells has been suggested in a number of in vivo and in vitro studies in fish. Acute allograft rejection with an accelerated response on second-set grafts and the presence of graft-versus-host reaction (GVHR) has been reported in teleost. Alloantigen- and virus-specific cytotoxicity has also been demonstrated in ex vivo studies in ginbuna and rainbow trout. In addition, alloantigen-specific cytotoxic T cell clones have been produced in cultures initiated with peripheral blood leukocytes (PBL) from an alloantigen-immunized channel catfish. Over the last decade several fish genomes have been sequenced and genetic information is rapidly accumulating. Thanks to these genome data bases and EST analysis, mRNA expression of T cell surface marker genes in alloantigen- or virus-specific effector cells has been reported in some fish species, e.g. TCR alpha or beta and CD8alpha in ginbuna and rainbow trout, and TCR alpha, beta or gamma in channel catfish. These findings suggest the presence of CD8(+) cytotoxic T lymphocyte (CTL) in fish similar to those of higher vertebrates. Recently, monoclonal antibodies against CD8alpha and CD4 antigens have been produced in some fish species. Investigation on the characteristics of CTL and cell-mediated immune mechanisms is now possible at defined T cell subsets, although identification of T cell subset is limited in a few fish species at present. In this review, we describe the recent progress in this field focusing on cells involved in antigen specific cytotoxicity. PMID- 21530579 TI - CXCL8 of Scophthalmus maximus: expression, biological activity and immunoregulatory effect. AB - CXCL8, or interleukin-8, is a CXC chemokine that promotes neutrophil migration in response to inflammatory stimuli. In this study, we identified and analyzed a CXCL8 orthologue, SmCXCL8, from turbot (Scophthalmus maximus). The deduced amino acid sequence of SmCXCL8 is 99-residue in length and shares 52-83% overall identities with the lineage 1 CXCL8 of a number of teleost. SmCXCL8 possesses a CXC chemokine domain that contains the conserved CXC motif preceded by the tripeptide sequence EMH. Purified recombinant SmCXCL8 (rSmCXCL8) induced chemotaxis in peripheral blood neutrophils and, to lesser extents, head kidney (HK) lymphocytes and macrophages in a dose-dependent manner. Mutation of the EMH motif by alanine substitution reduced the chemoattractive effect of rSmCXCL8. Expression of SmCXCL8 as determined by quantitative real time RT-PCR (qRT-PCR) was detected mainly in immune organs under normal physiological conditions and was upregulated by experiment challenges with bacterial pathogen and poly(I:C). In addition, SmCXCL8 expression was also induced to significant extents following vaccination of turbot with a subunit vaccine. When rSmCXCL8 was added to the cell cultures of peripheral blood leukocytes and HK lymphocytes and macrophages, it stimulated the proliferation of these cells and enhanced cellular resistance against intracellular bacterial survival. qRT-PCR analysis showed that rSmCXCL8 induced the expression of TNF-alpha and suppressor of cytokine signaling 3 in HK lymphocytes in different time frames. On the other hand, SmCXCL8 expression was also upregulated by TNF-alpha. Taken together, these results indicate that SmCXCL8 is a functional CXC chemokine with immunomodulatory effect and plays a role in inflammatory response induced by bacterial infection. PMID- 21530580 TI - Molecular cloning, expression and functional analysis of interleukin-8 (IL-8) in South African clawed frog (Xenopus laevis). AB - In this study, an IL-8 homologue has been cloned and identified from South African clawed frog Xenopus laevis (designated XlIL-8). The open reading frame (ORF) of XlIL-8 consists of 312 bases encoding a protein of 103 amino acids. The chemokine CXC domain, which contained Glu-Leu-Arg (ELR) motif and four cysteine residues, was well conserved in South African clawed frog IL-8. By quantitative real-time PCR, mRNA transcript of XlIL-8 was detectable in all the examined tissues with higher level in spleen and kidney. The temporal expression of XlIL-8 mRNA in the monocytes was up-regulated by lipopolysaccharide (LPS) stimulation and reached the maximum level at about 6h post-stimulation. Recombinant soluble XlIL-8 (XlsIL-8) was fused with a small ubiquitin-related modifier gene (SUMO) to enhance the soluble expression level in Escherichia coli BL21 (DE3). The fusing protein SUMO-XlsIL-8 was purified using metal chellate affinity chromatography (Ni-NTA) and cleaved by a SUMO-specific protease, then confirmed by SDS-PAGE and Western blotting analysis. Chemotaxis assays showed that lymphocytes but not monocytes could be recruited toward SUMO-XlsIL-8 or XlsIL-8 protein in a dose dependent manner in vitro. The present study may be useful for understanding the anti-bacteria immunity in amphibian and gives the potential to use the recombinant proteins to manipulate the immune response. PMID- 21530581 TI - Effect of crude lipopolysaccharide from Escherichia coli O127:B8 on the amebocyte producing organ of Biomphalaria glabrata (Mollusca). AB - Lipopolysaccharide (LPS) is a pathogen associated molecular pattern (PAMP) to which the internal defense system (IDS) of both vertebrates and invertebrates responds. We measured the mitotic response of the hematopoietic tissue of the schistosome-transmitting snail, Biomphalaria glabrata, to crude LPS from Escherichia coli 0127:B8. In a dose-response study, snails were injected with a range of concentrations of crude LPS, and mitotic figures were enumerated in histological sections of amebocyte-producing organ (APO) fixed at 24h post injection (PI) following a 6h treatment with 0.1% colchicine. In APOs from Salvador strain snails, which are genetically resistant to infection with Schistosoma mansoni, LPS concentrations of 0.01 mg/ml and above triggered a large increase in mitotic activity, whereas in APOs from schistosome-susceptible NIH albino snails, concentrations of 0.1mg/ml elicited a much smaller, but statistically significant increase. A time course study, without colchicine treatment, revealed that in Salvador APOs the mitotic response to 0.1mg/ml occurred by 18 h PI, peaked at 24h, and returned to control levels by 72 h; NIH albino APOs showed no detectible response. When Salvador APOs were exposed to crude LPS in vitro, no increase in mitotic activity occurred, a result suggesting the possible requirement for a peripheral tissue or hemolymph factor. The increased cell proliferation induced by crude LPS represents a novel systemic response of an invertebrate IDS to one or more PAMPs from a Gram-negative bacterium. PMID- 21530582 TI - Analysis of the antimicrobial responses of primary phagocytes of the goldfish (Carassius auratus L.) against Mycobacterium marinum. AB - The slow growth rate of Mycobacterium spp. that infect humans coupled with a lack of reliable in vitro infection model systems has hindered the progress of research in host cell-mycobacteria interactions. Recent studies have utilized the relatively fast growing Mycobacterium marinum to examine the host-pathogen interface in natural fish hosts. Here we describe the use of primary goldfish monocyte and mature macrophage cultures to investigate the immune cell-M. marinum interactions. Live and heat-killed M. marinum abrogated the recombinant goldfish (rg)TNFalpha2 and rgIFNgamma-induced monocyte reactive oxygen production. Live but not heat-killed M. marinum also ablated rgIFNgammarel and rg-TNFalpha2 induced macrophage nitric oxide production. M. marinum induced significant changes in gene expression of select NADPH oxidase components and inflammatory cytokine receptors and up-regulated the expression of immunosuppressive genes IL 10, TGFbeta1 and SOCS-3. The exposure of monocytes and mature macrophages to M. marinum caused an increase in the mRNA levels of several pro-inflammatory genes. Stimulation of monocytes and macrophages with rgTNFalpha2, rgIFNgamma, or rgIFNgammarel reduced the survival of intracellular mycobacteria. The characterization of the interaction between M. marinum and natural host-derived primary phagocyte cultures will enable future studies on the host-pathogen interactions in mycobacterial infections. PMID- 21530583 TI - Involvement of pore-forming molecules in immune defense and development of the Mediterranean mussel (Mytilus galloprovincialis). AB - The membrane attack complex and perforin (MACPF) superfamily is one of the largest families of pore-forming molecules. Although MACPF proteins are able to destruct invading microbes, several MACPF proteins play roles in embryonic development, neural migration or tumor suppression. We describe two apextrin-like proteins (ApelB and ApelP) and one MACPF-domain-containing protein (Macp) in Mytilus galloprovincialis. The two apextrin-like proteins did not present any conserved domain. The Macp protein contained the membrane/attack complex domain and its signature motif. Gene expression during larval development was analyzed by RT-PCR. There was a stage-specific up-regulation of the three proteins, suggesting that they play a role in development. Apextrin-like proteins were highly expressed at blastula and trochophore stage, whereas Macp was expressed at veliger stage. RT-PCR revealed up-regulation of the three genes in tissues and hemocytes from adults treated with bacteria and pathogen-associated molecular patterns, suggesting that they may be involved in the immune response. PMID- 21530584 TI - Cannabis use in young people: the risk for schizophrenia. AB - Cannabis is one of the most commonly used illicit drugs, and despite the widely held belief that it is a safe drug, its long-term use has potentially harmful consequences. To date, the research on the impact of its use has largely been epidemiological in nature and has consistently found that cannabis use is associated with schizophrenia outcomes later in life, even after controlling for several confounding factors. While the majority of users can continue their use without adverse effects, it is clear from studies of psychosis that some individuals are more vulnerable to its effects than others. In addiction, evidence from both epidemiological and animal studies indicates that cannabis use during adolescence carries particular risk. Further studies are warranted given the increase in the concentration of the main active ingredient (Delta(9) tetrahydrocannabinol) in street preparations of cannabis and a decreasing age of first-time exposure to cannabis. PMID- 21530585 TI - The auditory dorsal pathway: orienting vision. AB - A particularly prominent model of auditory cortical function proposes that a dorsal brain pathway, emanating from the posterior auditory cortex, is primarily concerned with processing the spatial features of sounds. In the present paper, we outline some difficulties with a strict functional interpretation of this pathway, and highlight the recent trend to understand this pathway in terms of one that uses acoustic information to guide motor output towards objects of interest. In this spirit, we consider the possibility that some of the auditory spatial processing activity that has been observed in the dorsal pathway may actually be understood as a form of action processing in which the visual system may be guided to a particular location of interest. In this regard, attentional orientation may be considered a low-level form of action planning. Incorporating an auditory-guided motor aspect to the dorsal pathway not only offers a more holistic account of auditory processing, but also provides a more ecologically valid perspective on auditory processing in dorsal brain regions. PMID- 21530586 TI - A neurocognitive theory of higher mental emergence: from anoetic affective experiences to noetic knowledge and autonoetic awareness. AB - This essay provides an overview of evolutionary levels of consciousness, with a focus on a continuum of consciousness: from primarily affective to more advanced cognitive forms of neural processing-from anoetic (without knowledge) consciousness based on affective feelings, elaborated by brain networks that are subcortical- and can function without neocortical involvement, to noetic (knowledge based) and autonoetic (higher reflective mental) processes that permits conscious awareness. An abundance of such mind-brain linkages have been established using standard neuropsychological and brain-imaging procedures. Much of the characterization of human mental landscapes has been achieved with long accepted psychometric procedures that often do not adequately tap the lived anoetic experiential phenomenological aspects of mind. Without an understanding of affective based anoetic forms of consciousness, an adequate characterization of the human mind may never be achieved. A full synthesis will require us to view mental-experiential processes concurrently at several distinct neurophysiological levels, including foundational affective-emotional issues that are best probed with cross-species affective neuroscience strategies. This essay attempts to relate these levels of analysis to the neural systems that constitute lived experience in the human mind. PMID- 21530587 TI - Functional imaging within individual pain fibres ex vivo with optical microscopy. AB - Here we introduce a simple experimental approach for studying afferent pain fibre physiology. We have developed a mouse en bloc dural-skull preparation for optical microfluorometric imaging to directly study the physiological functioning in selectively identified, individual nociceptive fibre free nerve endings. Functional optical imaging using widefield epifluorescence microscopy was combined with electrophysiological stimulations, pharmacological manipulations, and the UV photolysis of caged compounds. For the first time, we show high resolution functional imaging of single action potential-evoked fluorescent transients, as well as sub- and supra-threshold calcium signaling events within individual nociceptive fibre terminations. This novel experimental approach opens up a new window for studying nociceptive fibre physiology and pathophysiology. PMID- 21530588 TI - Circulating levels of chromatin fragments are inversely correlated with anti dsDNA antibody levels in human and murine systemic lupus erythematosus. AB - Anti-dsDNA antibodies represent a central pathogenic factor in Lupus nephritis. Together with nucleosomes they deposit as immune complexes in the mesangial matrix and along basement membranes within the glomeruli. The origin of the nucleosomes and when they appear e.g. in circulation is not known. Serum samples from autoimmune (NZBxNZW)F1 mice, healthy BALB/c mice, patients with SLE, RA and normal healthy individuals were analyzed for presence and amount of circulating anti-dsDNA antibodies and nucleosomal DNA. Here we use a quantitative PCR to measure circulating DNA in sera. We demonstrate an inverse correlation between anti-dsDNA antibodies and the DNA concentration in the circulation in both murine and human serum samples. High titer of anti-DNA antibodies in human sera correlated with reduced levels of circulating chromatin, and in lupus prone mice with deposition within glomeruli. The inverse correlation between DNA concentration and anti-dsDNA antibodies may reflect antibody-dependent deposition of immune complexes during the development of lupus nephritis in autoimmune lupus prone mice. The measurement of circulating DNA in SLE sera by using qPCR may indicate and detect the development of lupus nephritis at an early stage. PMID- 21530590 TI - How does the corpus callosum mediate interhemispheric transfer? A review. AB - The corpus callosum is the largest white matter structure in the human brain, connecting cortical regions of both hemispheres. Complete and partial callosotomies or callosal lesion studies have granted more insight into the function of the corpus callosum, namely the facilitation of communication between the cerebral hemispheres. How the corpus callosum mediates this information transfer is still a topic of debate. Some pose that the corpus callosum maintains independent processing between the two hemispheres, whereas others say that the corpus callosum shares information between hemispheres. These theories of inhibition and excitation are further explored by reviewing recent behavioural studies and morphological findings to gain more information about callosal function. Additional information regarding callosal function in relation to altered morphology and dysfunction in disorders is reviewed to add to the discussion of callosal involvement in interhemispheric transfer. Both the excitatory and inhibitory theories seem likely candidates to describe callosal function, however evidence also exists for both functions within the same corpus callosum. For future research it would be beneficial to investigate the functional role of the callosal sub regions to get a better understanding of function and use more appropriate experimental methods to determine functional connectivity when looking at interhemispheric transfer. PMID- 21530589 TI - Oral immunization with live Lactococcus lactis expressing rotavirus VP8 subunit induces specific immune response in mice. AB - Rotaviruses are the major cause of worldwide infectious diarrhea in children and vaccination is considered to be the most effective way to control these infections. The development of a mucosal live vaccine using the food-grade lactic acid bacteria Lactococcus lactis as antigen vehicle is an attractive and safe vaccination strategy against rotavirus. In this study, the construction of recombinant L. lactis strains able to produce the rotavirus spike-protein subunit VP8 in cytoplasmic, secreted and cell wall-anchored forms is reported. Evaluation of the immune response generated after immunization was conducted in a mouse model. The present study shows that animals inoculated orally with the L. lactis strain producing the cytoplasmic form of VP8 (LL1) developed significant levels of intestinal IgA antibodies while animals receiving L. lactis producing the cell wall-anchored VP8 form (LL3) exhibited anti-VP8 antibodies at both intestinal and systemic levels. Furthermore, it was observed that intestinal antibodies of the LL1-treated group and serum antibodies of the LL3-treated group were able to block rotavirus infection by 50% and 100%, respectively. These encouraging results represent a step towards the development of a new and safe mucosal vaccine against rotavirus. PMID- 21530591 TI - A densely overlapping gene fragmentation approach improves yeast two-hybrid screens for Plasmodium falciparum proteins. AB - Use of the yeast two-hybrid assay to study Plasmodium falciparum protein-protein interactions is limited by poor expression of P. falciparum genes in yeast and lack of easily implemented assays to confirm the results. We report here two methods to create gene fragments - random fragmentation by partial DNAse I digestion and generation of densely overlapping fragments by PCR - that enable most portions of P. falciparum genes to be expressed and screened in the yeast two-hybrid assay. The PCR-based method is less technically challenging and facilitates fine-scale mapping of protein interaction domains. Both approaches revealed a putative interaction between PfMyb2 (PF10_0327) and PFC0365w. We developed new plasmids to express the proteins in wheat germ extracts and confirmed the interaction in both the split-luciferase assay and in co purification experiments with glutathione-S-transferase and HA-tagged proteins. The combination of improved yeast two-hybrid screening approaches and convenient systems to validate interactions enhances the utility of yeast two-hybrid assays for P. falciparum. PMID- 21530592 TI - Apoptosis signal-regulating kinase 1 is an intracellular inducer of p38 MAPK mediated myogenic signalling in cardiac myoblasts. AB - Myogenic differentiation is an essential process for the myogenesis in response to various extracellular stimuli. p38 MAPK is a core signalling molecule in myogenic differentiation. The activation of p38 MAPK is required for myogenic differentiation; however, the mechanism for this activation remains undefined. ASK1 is a member of the MAP3K family that activates both JNK and p38 MAPK pathways in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. Here, we reported that TNFalpha was significantly released from H9c2 cardiac myoblast in differentiation medium. Furthermore, the oxidant H(2)O(2) acted as a messenger in the TNFalpha signalling pathway to disrupt the complex of ASK1-Trx, which was followed by the activation of ASK1 in cardiac myogenic differentiation. Subsequently, the activated ASK1 stimulated MKK3/6-p38MAPK signalling cascade to induce specific myogenic differentiation. In addition, exogenous TNFalpha added to the medium at physiological levels enhanced the ASK1-p38 MAPK signalling pathway through the increased generation of H(2)O(2). Interestingly, inhibition of p38 MAPK abrogated the production of H(2)O(2), suggesting that there might be a positive feedback loop in the myogenic-redox signalling pathway. These results indicate that ASK1 is a new intracellular regulator of activation of the p38 MAPK in cardiac myogenic differentiation. PMID- 21530593 TI - Regulation of nucleocytoplasmic trafficking of viral proteins: an integral role in pathogenesis? AB - Signal-dependent targeting of proteins into and out of the nucleus is mediated by members of the importin (IMP) family of transport receptors, which recognise targeting signals within a cargo protein and mediate passage through the nuclear envelope-embedded nuclear pore complexes. Regulation of this process is paramount to processes such as cell division and differentiation, but is also critically important for viral replication and pathogenesis; phosphorylation appears to play a major role in regulating viral protein nucleocytoplasmic trafficking, along with other posttranslational modifications. This review focuses on viral proteins that utilise the host cell IMP machinery in order to traffic into/out of the nucleus, and in particular those where trafficking is critical to viral replication and/or pathogenesis, such as simian virus SV40 large tumour antigen (T-ag), human papilloma virus E1 protein, human cytomegalovirus processivity factor ppUL44, and various gene products from RNA viruses such as Rabies. Understanding of the mechanisms regulating viral protein nucleocytoplasmic trafficking is paramount to the future development of urgently needed specific and effective anti-viral therapeutics. This article was originally intended for the special issue "Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import". The Publisher apologizes for any inconvenience caused. PMID- 21530594 TI - Evaluation of an automated system for the detection of carbapenem resistant Acinetobacter baumannii and assessment of metallo-beta-lactamase production using two different phenotyping methods. AB - We tested 200 clinical Acinetobacter baumannii isolates against imipenem and meropenem using the methods of broth microdilution, disk diffusion, agar dilution, MicroScan/WalkAway automated system. Very major errors were mostly obtained between MicroScan/WA system and disk diffusion test. MicroScan/WA system generated unacceptable errors. Combined disk and modified Hodge tests used for detection of metallo-beta-lactamase production were practical and useful. PMID- 21530595 TI - The mood stabilizer valproic acid induces proliferation and myelination of rat Schwann cells. AB - Schwann cells (SCs) within peripheral nerve respond robustly after exposure to neurotrophic factors. Recent results have revealed that valproic acid (VPA), at a clinically relevant therapeutic concentration, produces effects similar to neurotrophic factors, and promotes neurite growth and cell survival. We hypothesized that VPA could also induce Schwann cell response. In this study, we sought to determine how pure Schwann cells responded to VPA by evaluating for proliferation, expression of S-100, growth cone-associated protein 43 (GAP-43), myelin-associated glycoprotein (MAG), and myelin basic protein (MBP). Immunohistochemistry demonstrated that the Schwann cells were positive for S-100, GAP-43, MAG, and MBP greater than 99% of the experimental cells. The rate of proliferation was increased in experimental cells from MTT assay and Bromodeoxyuridine/DAPI double staining. Furthermore, Western blot showed an up regulation in GAP-43, MAG and MBP protein expression in experimental cells, respectively. We also found that mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) 1/2 pathway was involved in the enhanced cell proliferation of Schwann cells evoked by VPA. This study provides novel information regarding Schwann cell response to VPA, which might help the understanding of VPA-based treatment for peripheral nerve injury. PMID- 21530596 TI - Comparison of polysialic acid production in Escherichia coli K1 during batch cultivation and fed-batch cultivation applying two different control strategies. AB - The polysialic acid (PSA) production in Escherichia coli (E. coli) K1 was studied using three different cultivation strategies. A batch cultivation, a fed-batch cultivation at a constant specific growth rate of 0.25 h(-1) and a fed-batch cultivation at a constant glucose concentration of 50 mg l(-1) was performed. PSA formation kinetics under different cultivation strategies were analyzed based on the Monod growth model and the Luedeking-Piret equation. The results revealed that PSA formation in E. coli K1 was completely growth associated, the highest specific PSA formation rate (0.0489 g g(-1)h(-1)) was obtained in the batch cultivation. However, comparing biomass and PSA yields on the glucose consumed, both fed-batch cultivations provided higher yields than that of the batch cultivation and acetate formation was prevented. Moreover, PSA yield on glucose was also correlated to the specific growth rate of the cells. The optimal specific growth rate for PSA production was 0.32 h(-1) obtained in the fed-batch cultivation at a constant glucose concentration of 50 mg l(-1), with highest conversion efficiency of 43 mg g(-1). PMID- 21530597 TI - Delivery of a cocktail DNA vaccine encoding cysteine proteinases type I, II and III with solid lipid nanoparticles potentiate protective immunity against Leishmania major infection. AB - Earlier generations of Leishmania vaccines have reached the third-phase of clinical trials, however none of them have shown adequate efficacy due to lack of an appropriate adjuvant. In this study, cationic solid lipid nanoparticles (cSLNs) were used to formulate three pDNAs encoding L. major cysteine proteinase type I (cpa), II (cpb) and III (cpc). BALB/c mice were immunized twice with a 3 week interval, with SLN-pcDNA-cpa/b/c, pcDNA-cpa/b/c, SLN, SLN-pcDNA and PBS. Footpad assessments, parasite burden, cytokine and antibody responses were evaluated. Mice vaccinated with SLN-pcDNA-cpa/b/c significantly (p<0.05) showed higher protection levels with specific Th1 immune response development compared to other groups. This is the first report demonstrating cSLNs as a nanoscale vehicle boosting immune response quality and quantity; in a designable trend. The nanomedical feature of this novel formulation can be applied for wide-spread use in genetic vaccination against leishmaniasis, which is currently managed only through relatively ineffectual therapeutic regimens. PMID- 21530598 TI - Physiological roles of preproghrelin-derived peptides in GH secretion and feeding. AB - Among the factors playing a crucial role in the regulation of energy metabolism, gastro-intestinal peptides are essential signals to maintain energy homeostasis as they relay to the central nervous system the informations about the nutritional status of the body. Among these factors, preproghrelin is a unique prohormone as it encodes ghrelin, a powerful GH secretagogue and the only orexigenic signal from the gastrointestinal tract and obestatin, a proposed functional ghrelin antagonist. These preproghrelin-derived peptides may contribute to balance energy intake, metabolism and body composition by regulating the activity of the GH/IGF-1 axis and appetite. Whereas the contribution of ghrelin has been well characterized, the role of the more recently identified obestatin, in this regulatory process is still controversial. In this chapter, we describe the contribution of these different preproghrelin derived peptides and their receptors in the regulation of GH secretion and feeding. Data obtained from pharmacological approaches, mutant models and evaluation of the hormones in animal and human models are discussed. PMID- 21530599 TI - Hypo- and hyperthyroidism affect NEI concentration in discrete brain areas of adult male rats. AB - To date, there has been only one in vitro study of the relationship between neuropeptide EI (NEI) and the hypothalamic-pituitary-thyroid (HPT) axis. To investigate the possible relationship between NEI and the HPT axis, we developed a rat model of hypothyroidism and hyperthyroidism that allows us to determine whether NEI content is altered in selected brain areas after treatment, as well as whether such alterations are related to the time of day. Hypothyroidism and hyperthyroidism, induced in male rats, with 6-propyl-1-thiouracil and l thyroxine, respectively, were confirmed by determination of triiodothyronine, total thyroxine, and thyrotropin levels. All groups were studied at the morning and the afternoon. In rats with hypothyroidism, NEI concentration, evaluated on postinduction days 7 and 24, was unchanged or slightly elevated on day 7 but was decreased on day 24. In rats with hyperthyroidism, NEI content, which was evaluated after 4 days of l-thyroxine administration, was slightly elevated, principally in the preoptic area in the morning and in the median eminence arcuate nucleus and pineal gland in the afternoon, the morning and afternoon NEI contents being similar in the controls. These results provide the bases to pursue the study of the interaction between NEI and the HPT axis. PMID- 21530600 TI - CD4(+)CD25(high)CD127(low) regulatory T cells in patients with stable angina and their dynamics after intracoronary sirolimus-eluting stent implantation. AB - Rapamycin contributes to the expansion of regulatory T cells (Tregs) in vitro. We investigated CD4(+)CD25(high)CD127(low) Treg level dynamics as well as the major parameters of cell immunity and sCD25 and highly sensitive C-reactive protein (hsCRP) concentrations in the blood of patients after coronary stenting (CS) with sirolimus (rapamycin)-eluting stents (SES; n = 43). The relation between initial Treg values and the severity of coronary atherosclerosis was observed. Treg and sCD25 levels were increased 1 month after CS versus baseline values and versus data in the control group (coronary angiography [CA], n = 20). A positive correlation between Treg and sCD25 levels was reported, whereas no relation was observed with the length of SES implanted. HsCRP level was increased during the first 7 days and returned to baseline values 1 month after CS/CA. Treg content is lower in patients with multivessel CAD. Elevated levels of Tregs and sCD25 after SES implantation might occur because of the immunomodulating effect of rapamycin. PMID- 21530601 TI - Performance of broiler chickens fed event DAS-40278-9 maize containing the aryloxyalkanoate dioxygenase-1 protein. AB - Event DAS-40278-9 maize grain (containing the aryloxyalkanoate dioxygenase-1 protein), a non-transgenic near-isogenic maize grain, or one of three commercial maize grains were included in the diets of broiler chickens for six weeks. Growth, feed conversion, and carcass measurements indicated no significant difference between the groups fed the diets containing the DAS-40278-9 maize grain and those fed diets containing the matched control grain. The absence of adverse effects in this study supports the dietary safety of the AAD-1 protein expressed in event DAS-40278-9 maize. PMID- 21530602 TI - Speciation of Cr(III) and Cr(VI) in geological and water samples by ytterbium(III) hydroxide coprecipitation system and atomic absorption spectrometry. AB - A novel coprecipitation method with ytterbium(III) hydroxide has been established for speciation of Cr(III) and Cr(VI) in geological and water samples. At pH 10, while Cr(III) was quantitatively recovered, Cr(VI) was recovered under 10% levels. Total chromium was determined reducing of Cr(VI) to Cr(III) in acidic media with KI reagent. The concentration of Cr(VI) was calculated by the concentration difference between the total chromium and Cr(III). For the quantitative recovery of Cr(III), parameters such as pH, amount of ytterbium, centrifugation time and speed, matrix effect, KI amount, and sample volume were investigated. The preconcentration factor was 30. The limit of detection was obtained as 1.1 MUg/L for Cr(III). The accuracy was checked by analyte addition and analyses of standard reference materials (TMDA-54.4 Certified Reference Water, NIST 2710 Montana Soil). Method has been successfully applied to the chromium speciation for industrial waste water of leather factories located in Bor-Nigde, and also for mine and soil samples. PMID- 21530603 TI - Pressurized liquid extraction of phenolic compounds from Anatolia propolis and their radical scavenging capacities. AB - Propolis samples from important honey producing locations of Anatolia namely; Bingol (BG), Rize (RZ), Tekirdag (TK) and Van (VN), were evaluated for their antiradical capacities, total phenolic contents and individual phenolic compounds which was recovered by means of pressurized liquid extraction (PLE). Several extraction parameters of PLE such as; temperature, pressure, solvent type, extraction time and cell size were investigated for their effects on the extraction performances. The results showed that, 40 degrees C, 1500 psi, Ethanol:water:HCl; (70:25:5, v/v/v) containing 0.1% tert-butylhydroquinone (tBHQ) as solvent, three extraction cycles within 15 min, and a cell size of 11 mL was the most favorable PLE operating conditions. Results of the tests performed to designate the success of the polyphenol analysis showed that the recovery was in the range of 97.2% and 99.7%. Major phenolic compounds in all samples were found to be gallocatechin (GCT), catechin (CT), epicatechin gallate (ECTG), caffeic acid (CA), chlorogenic acid (ChA), and myricetin (Myr). ChA level of BG propolis was 4.5, 3 and 23 times higher than that of RZ, TK and VN region, respectively. Antiradical tests showed that all propolis samples have superior antiradical capacities up to 500 mg Trolox equivalent activity per gram of extract. PMID- 21530604 TI - 16-Hydroxycleroda-3,13-dien-15,16-olide deregulates PI3K and Aurora B activities that involve in cancer cell apoptosis. AB - The PI3K-AKT pathway and Aurora kinase play essential roles in such cellular processes as cell survival, angiogenesis, and differentiation, and are usually expressed at maximum levels during cancer cell proliferation. The present study investigated the effect of the natural compound, 16-hydroxycleroda-3,13-dien 15,16-olide (PL3), on regulating the PI3K-AKT pathway and Aurora B, which led to cancer cell apoptosis. PL3 acts as a PI3K inhibitor by influencing cell survival, signaling transduction, and cell cycle progression. It was observed that PL3 targeted and induced dephosphorylation of the PI3K pathway, degradation of Aurora B and mitotic-related gene expressions, and sequentially shut down the cell cycle. This eventually resulted in cell death. As Aurora B was downregulated, spindle dysfunction and destruction of the G2/M phase checkpoint resulted in DNA damaged cells undergoing apoptosis. Moreover, PL3 also resensitized T315I-mutated Bcr-ABL+ BA/F3 cells to improve the cytotoxicity of Imatinib in Imatinib resistant cell line. Taken together, PL3 can perturb the PI3K-AKT pathway and Aurora B resulting in gene silencing and cell cycle disturbance. It was demonstrated that PL3 acted like a novel small-molecule PI3K modulator, thereby potentially contributing to cancer chemotherapy and combination medication. PMID- 21530605 TI - Short- and long-term regulation of 3-hydroxy 3-methylglutaryl coenzyme A reductase by a 4-methylcoumarin. AB - Dyslipidemia is one of the most significant risk factors for cardiovascular diseases. Cholesterol homeostasis is regulated by both the receptor-mediated endocytosis of Low Density Lipoproteins by LDL receptors and de novo cholesterol synthesis via the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase. Although statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase substrate competitors, have revolutionized the management of cardiovascular diseases by lowering serum LDL, their side effects range from myalgia to rhabdomyolysis. Treatment with antioxidant compounds could represent an efficient alternative in the modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Indeed it has already been demonstrated that the rise in reactive oxygen species levels causes the complete dephosphorylation and, in turn activation of the enzyme. Many coumarins and their derivatives have the special ability to scavenge reactive oxygen species or show a lipid lowering potential. Here we evaluated whether the coumarin, 4-methylesculetin could exert both the ability to scavenge ROS and to modulate 3-hydroxy-3-methylglutaryl coenzyme A reductase in HepG2 cell line where the enzyme activity dysregulation induced by reactive oxygen species has already been reported. The antioxidant property of 4 methylesculetin led to the reduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activation state through the increase of the enzyme phosphorylation. In addition, this coumarin showed the ability to modulate 3-hydroxy-3-methylglutaryl coenzyme A reductase protein levels both by transcriptional and degradational events independent of its antioxidant activity. PMID- 21530606 TI - Multi-site TBT binding skews the inhibition of oligomycin on the mitochondrial Mg ATPase in Mytilus galloprovincialis. AB - Tributyltin (TBT), a persistent lipophilic contaminant found especially in the aquatic environment, is known to be toxic to mitochondria with the F(1)F(0) ATPase as main target. Recently our research group pointed out that in mussel digestive gland mitochondria TBT, apart from decreasing the catalytic efficiency of Mg-ATPase activity, at concentrations >=1.0 MUM in the ATPase reaction medium lessens the enzyme inhibition promoted by the specific inhibitor oligomycin. The present work aims at casting light on the mechanisms involved in the TBT-driven enzyme desensitization to inhibitors, a poorly explored field. The mitochondrial Mg-ATPase desensitization is shown to be confined to inhibitors of transmembrane domain F(0), namely oligomycin and N,N'-dicyclohexylcarbodiimide (DCCD). Accordingly, quercetin, which binds to catalytic portion F(1), maintains its inhibitory efficiency in the presence of TBT. Among the possible mechanisms involved in the Mg-ATPase desensitization to oligomycin by >=1.0 MUM TBT concentrations, a structural detachment of the two F(1) and F(0) domains does not occur according to experimental data. On the other hand TBT covalently binds to thiol groups on the enzyme structure, which are apparently only available at TBT concentrations approaching 20 MUM. TBT is able to interact with multiple sites on the enzyme structure by bonds of different nature. While electrostatic interactions with F(0) proton channel are likely to be responsible for the ATPase activity inhibition, possible changes in the redox state of thiol groups on the protein structure due to TBT binding may promote structural changes in the enzyme structure leading to the observed F(1)F(0)-ATPase oligomycin sensitivity loss. PMID- 21530609 TI - Liposomal encapsulation of a synergistic molar ratio of cytarabine and daunorubicin enhances selective toxicity for acute myeloid leukemia progenitors as compared to analogous normal hematopoietic cells. AB - OBJECTIVE: To evaluate the possibility of improved selective killing of acute myeloid leukemia (AML) cells with CPX-351 (a liposomal formulation of cytarabine and daunorubicin). CPX-351 and the same molar ratio of free drugs were compared for cytotoxicity against colony-forming cells (CFCs) and subpopulations of cells enriched for primitive progenitors from AML patients and normal granulocyte colony-stimulating factor-mobilized peripheral blood (PB) and bone marrow (BM) donors. MATERIALS AND METHODS: AML blasts (n = 13) and normal PB and BM cells (n = 7) were incubated for 24 hours in various concentrations of CPX-351 or free drugs before plating in CFC assay or staining with anti-CD34 and anti-CD38 antibodies, Annexin-V, and propidium iodide followed by fluorescence-activated cell sorting analysis. High performance liquid chromatography was used to measure intracellular daunorubicin accumulation. RESULTS: AML blasts and progenitors from patients who achieved complete remission were more sensitive to both CPX-351 and free drugs than the same cells from patients with chemotherapy refractory leukemia. However, AML CFCs and CD34(+)CD38(-) AML blasts (enriched for candidate leukemia stem cells) from the same patient showed similar sensitivity to the liposomal or free drug formulations. In contrast, CFCs and CD34(+)CD38(-) cells from normal PB and BM were fivefold more sensitive to the free drugs than to CPX 351. Consistent with these observations, preferential intracellular accumulation of CPX-351 in AML over normal cells was observed, while there was little difference in drug uptake between AML and normal cells with the free drug cocktail. CONCLUSIONS: CPX-351, as compared to free cytarabine:daunorubicin, shows enhanced selective in vitro cytotoxicity for AML rather than normal progenitors. PMID- 21530610 TI - Rebuilding Iberian motorways with slime mould. AB - Plasmodium of a cellular slime mould Physarum polycephalum is a unique living substrate proved to be efficient in solving many computational problems with natural spatial parallelism. The plasmodium solves a problem represented by a configuration of source of nutrients by building an efficient foraging and intra cellular transportation network. The transportation networks developed by the plasmodium are similar to transport networks built by social insects and simulated trails in multi-agent societies. In the paper we are attempting to answer the question "How close plasmodium of P. polycephalum approximates man made motorway networks in Spain and Portugal, and what are the differences between existing motorway structure and plasmodium network of protoplasmic tubes?". We cut agar plates in a shape of Iberian peninsula, place oat flakes at the sites of major urban areas and analyse the foraging network developed. We compare the plasmodium network with principle motorways and also analyse man-made and plasmodium networks in a framework of planar proximity graphs. PMID- 21530607 TI - Function and mechanism of axonal targeting of voltage-sensitive potassium channels. AB - Precise localization of various ion channels into proper subcellular compartments is crucial for neuronal excitability and synaptic transmission. Axonal K(+) channels that are activated by depolarization of the membrane potential participate in the repolarizing phase of the action potential, and hence regulate action potential firing patterns, which encode output signals. Moreover, some of these channels can directly control neurotransmitter release at axonal terminals by constraining local membrane excitability and limiting Ca(2+) influx. K(+) channels differ not only in biophysical and pharmacological properties, but in expression and subcellular distribution as well. Importantly, proper targeting of channel proteins is a prerequisite for electrical and chemical functions of axons. In this review, we first highlight recent studies that demonstrate different roles of axonal K(+) channels in the local regulation of axonal excitability. Next, we focus on research progress in identifying axonal targeting motifs and machinery of several different types of K(+) channels present in axons. Regulation of K(+) channel targeting and activity may underlie a novel form of neuronal plasticity. This research field can contribute to generating novel therapeutic strategies through manipulating neuronal excitability in treating neurological diseases, such as multiple sclerosis, neuropathic pain, and Alzheimer's disease. PMID- 21530611 TI - Involvement of protein kinase C in the galanin-induced antinociception in the brain of rats. AB - Previous study in our laboratory demonstrates that microinjection of galanin into the arcuate nucleus of hypothalamus produced antinociceptive effects in rats. In the present study we investigated the involvement of protein kinase C (PKC) and PKC signaling pathways in the galanin-induced antinociception in the brain of rats. Intracerebroventricular injection of galanin produced antinociceptive effects in rats tested by hot-plate and Randall Selitto test. Interestingly, the galanin-induced antinociception was significantly attenuated by intracerebroventricular injection of the PKC inhibitor chelerythrine, indicating an involvement of PKC in the galanin-induced antinociception in rats. Taken together, the results demonstrate that galanin induces antinociceptive effects in the rat brain, and PKC is involved in the galanin-induced antinociception in the brain of rats. PMID- 21530608 TI - Control of synapse development and plasticity by Rho GTPase regulatory proteins. AB - Synapses are specialized cell-cell contacts that mediate communication between neurons. Most excitatory synapses in the brain are housed on dendritic spines, small actin-rich protrusions extending from dendrites. During development and in response to environmental stimuli, spines undergo marked changes in shape and number thought to underlie processes like learning and memory. Improper spine development, in contrast, likely impedes information processing in the brain, since spine abnormalities are associated with numerous brain disorders. Elucidating the mechanisms that regulate the formation and plasticity of spines and their resident synapses is therefore crucial to our understanding of cognition and disease. Rho-family GTPases, key regulators of the actin cytoskeleton, play essential roles in orchestrating the development and remodeling of spines and synapses. Precise spatio-temporal regulation of Rho GTPase activity is critical for their function, since aberrant Rho GTPase signaling can cause spine and synapse defects as well as cognitive impairments. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). We propose that Rho-family GEFs and GAPs provide the spatiotemporal regulation and signaling specificity necessary for proper Rho GTPase function based on the following features they possess: (i) existence of multiple GEFs and GAPs per Rho GTPase, (ii) developmentally regulated expression, (iii) discrete localization, (iv) ability to bind to and organize specific signaling networks, and (v) tightly regulated activity, perhaps involving GEF/GAP interactions. Recent studies describe several Rho-family GEFs and GAPs that uniquely contribute to spinogenesis and synaptogenesis. Here, we highlight several of these proteins and discuss how they occupy distinct biochemical niches critical for synaptic development. PMID- 21530612 TI - Knockdown of TFPI-2 promotes migration and invasion of glioma cells. AB - Glioblastoma is the most malignant primary brain tumor. Due to its highly promigratory and proinvasive properties, standard therapy including surgery, chemotherapy and radiation fails in eradicating this highly aggressive type of cancer. Here, we evaluated the role of TFPI-2, a Kunitz-type serine protease inhibitor, which has been previously described as a tumor suppressor gene in several types of cancer, including glioma. TFPI-2 expression was absent in five of nine investigated high-grade glioma cell lines. Lentiviral knockdown of TFPI-2 in two of the TFPI-2-expressing cell lines (MZ-18 and Hs 638) was associated with pronounced changes in the cellular behavior: glioma cell proliferation, migration and invasion were significantly increased in TFPI-2 knockdown cells in comparison to empty vector-transfected control cells. Since TFPI-2 might exert its tumor suppressor function by inhibiting MMPs, we subsequently analyzed the effects of specific MMP inhibitors on cell invasion of TFPI-2 KD cells vs. control cells. The data obtained from these experiments suggest that the anti-invasive properties of TFPI-2 are associated with inhibition of MMP-1 and MMP-2, while inhibition of MMP-9 seems to play a minor role in this context. Our findings underscore the important role of TFPI-2 as a tumor suppressor gene and indicate that TFPI-2 may be a useful diagnostic marker for the aggressive phenotype of glial tumors. PMID- 21530613 TI - State-dependent functional connectivity of rat olfactory system assessed by fMRI. AB - Functional connectivity between the piriform cortex and limbic and neocortical areas was assessed using functional magnetic resonance imaging (fMRI) of urethane anesthetized rats that spontaneously cycled between slow-wave and fast-wave states. Slow-wave and fast-wave states were determined indirectly through monitoring of respiration rate, which was confirmed to co-vary with state as determined by electrophysiological recordings. Previous electrophysiological data have suggested that the piriform cortex shifts between responsiveness to afferent odor input during fast-wave states and enhanced functional connectivity with limbic areas during slow-wave state. The present results demonstrate that fMRI based resting state functional connectivity between the piriform cortex and both limbic and neocortical areas is enhanced during slow-wave state compared to fast wave state using respiration as an indirect measure of state in urethane anesthetized rats. This state-dependent shift in functional connectivity may be important for sleep-dependent odor memory consolidation. PMID- 21530614 TI - Role of endothelial dysfunction in modulating the plasma redox homeostasis in visceral leishmaniasis. AB - BACKGROUND: Evidence in the literature suggests that down-regulation of nitric oxide (NO) is associated with the pathophysiological conditions during visceral leishmaniasis (VL). Here we have investigated the mechanism that leads to the down regulation of systemic NO in the infected condition. Moreover, we have determined whether down regulation of NO is associated with increased generation of reactive oxygen species (ROS) during this disease. Therapeutic strategy targeting signaling molecules of these events was evaluated. METHODS: Plasma protein-nitrotyrosine was examined by ELISA kit. Generation of superoxides and peroxynitrites was investigated by flow cytometry. NO bioavailability in endothelial cells was evaluated using DAF-2DA fluorescence. Ceramide contents were evaluated using FACS analysis, HPTLC and HPLC. RESULTS: L. donovani infected reticulo-endothelial cells regulated the activity of eNOS and NAD(P)H oxidase in the endothelial cells through the generation of intercellular messenger, ceramide. Activation of SMases played an important role in the generation of ceramide in animals during chronic infection. These events led to generation of ROS within endothelial cells. Modulation of redox status of plasma and accumulation of ROS in endothelial cells were critically involved in the regulation of NO bioavailability in plasma of the infected animal. Endothelial dysfunction and decline of NO were resulted from an increased production of superoxide where upregulation of eNOS expression appeared as an ineffective compensatory event. Inhibition of ceramide generation increased NO bioavailability, prevented endothelial dysfunction and concomitant oxidative stress. CONCLUSION AND GENERAL SIGNIFICANCE: Decreased NO bioavailability and endothelial dysfunction were the downstream of ceramide signaling cascade. ROS accumulation promoted peroxynitrite generation and reduced NO bioavailability. Inhibition of ceramide generation may be a potential therapeutic option in preventing the co-morbidity associated with VL. PMID- 21530615 TI - Novel microdialysis method to assess neuropeptides and large molecules in free moving mouse. AB - Microdialysis is a powerful in vivo technique for the continuous sampling of small molecules within the extracellular fluid space. However, efforts to collect larger molecules have met with little success. To identify biologically active larger molecules in free-moving animals would be of great benefit. For this purpose, we have developed a novel microdialysis method that allows consistent recovery of large molecules from the brain interstitial space in the awake, free moving mouse. Using a new "vent" probe with a push-pull perfusion system, the present study successfully demonstrated in vivo sampling of pathophysiologically important macromolecules in free-moving mouse brain. This sampling system allowed monitoring of the dynamic changes in their concentrations. Overall, this novel microdialysis system would provide the opportunity to identify the expression patterns of pathophysiologically important proteins in a variety of physiological and pathological processes for a better understanding of various diseases. PMID- 21530616 TI - Up-regulation of tetrodotoxin-sensitive sodium currents by prostaglandin E2 in type-4 rat dorsal root ganglion cells. AB - Mechanisms were studied by which prostaglandin E(2) (PGE(2)) up-regulates Na(+) currents (INa) in medium diameter dorsal root ganglion (DRG) cells that express large T-type Ca(2+) currents (type-4 DRG cells). PGE(2) or the adenylyl cyclase (AC) activator forskolin (10 MUM) up-regulated peak INa evoked by test potentials (TP) to -10 mV by an average of 13.5% and 21.8%, respectively. The PGE(2) and forskolin induced up-regulation of INa, evoked with TPs to -10 mV, began approximately 15-20 s after initiation of drug exposure and continued gradually over the course of 2-3 min. Both PGE(2) and forskolin significantly increased peak conductance without significantly shifting the voltage at which INa was 1/2 activated (V(a)) or 1/2 steady state inactivated. However, although V(a) was not significantly shifted, both PGE(2) and forskolin induced a proportionally greater percent increase in conductance at weak TPs to around -30 mV compared to stronger TPs to around 10 mV. The PGE(2)-induced up-regulation of INa was occluded by prior up-regulation with forskolin, and the up-regulation of INa by both PGE(2) and forskolin was blocked by Rp-cAMPs and 50 nM tetrodotoxin (TTX). In the presence of Rp-cAMPs, both PGE(2) and forskolin induced decreases in INa that peaked around 25 s following initiation of PGE(2)/forskolin application. The decrease induced by PGE(2) averaged 8.5%, which was significantly greater than the average 3.5% decrease induced by forskolin. Estimation of kinetic rate constants by fitting INa with a Markov channel state model, suggested that both PGE(2) and forskolin up-regulated INa by changing channel gating rather than by increasing channel number or unitary conductance. The data suggest that application of PGE(2) may initially induce a relatively rapid down-regulation of TTX-sensitive INa (signaling pathway uncharacterized), followed by a gradual up regulation of INa via activation of an AC/PKA-dependent signaling pathway. The up regulation of INa in sensory neurons with type-4 cell bodies may increase excitability and strengthen signaling, and may play some role in the allodynia and hyperalgesia associated with injury to nerves and peripheral tissues. PMID- 21530618 TI - Expression, phosphorylation, and glycosylation of CNS proteins in aversive operant conditioning associated memory in Lymnaea stagnalis. AB - Long-term memory formation requires "de novo" expression and post-translational modification of many proteins. Understanding the temporal and spatial regulatory pattern of these proteins is fundamental to decoding the molecular basis of learning and memory. We characterized changes in expression, phosphorylation, and glycosylation of CNS proteins after operant conditioning in pond snail Lymnaea stagnalis. The phosphorylation and the glycosylation levels of proteins, measured by the ratio of Pro-Q Diamond (phosphoproteins) or Pro-Q Emerald (glycoproteins) vs. SYPRO-Ruby (total proteins) signals, increased during memory formation. Proteins whose modulation of phosphorylation might be involved in learning and memory were identified by mass spectrometry (MS) and are associated with cytoskeleton, glutamine cycle, energy metabolism, G-protein signaling, neurotransmitter release regulation, iron transport, protein synthesis, and cell division. Phosphorylation of actin increased during memory formation. To identify proteins whose expression levels changed in long-term memory formation we used two-dimensional difference gel electrophoresis followed by MS. The up-regulated proteins are mostly associated with lipoprotein and cholesterol metabolism, protein synthesis and degradation, cytoskeleton, nucleic acid synthesis, and energy supply. The down-regulated proteins are enzymes of aspartic acid metabolism involved in regulation of protein synthesis. Our proteomic analyses have revealed a number of candidate proteins associated with memory formation. These findings provide new directions for further investigation into the signaling networks required for memory formation and consolidation. PMID- 21530617 TI - Vagal intramuscular array afferents form complexes with interstitial cells of Cajal in gastrointestinal smooth muscle: analogues of muscle spindle organs? AB - Intramuscular arrays (IMAs), vagal mechanoreceptors that innervate gastrointestinal smooth muscle, have not been completely described structurally or functionally. To delineate more fully the architecture of IMAs and to consider the structure-function implications of the observations, the present experiment examined the organization of the IMA terminal arbors and the accessory tissue elements of those arbors. IMA terminal fields, labeled by injection of biotinylated dextran into the nodose ganglia, were examined in whole mounts of rat gastric smooth muscle double-labeled with immunohistochemistry for interstitial cells of Cajal (ICCs; c-Kit) and/or inputs of different neuronal efferent transmitter (markers: tyrosine hydroxylase (TH), vesicular acetylcholine transporter (VAChT), and nitric oxide synthase (NOS)) or afferent neuropeptidergic (calcitonin gene-related peptide (CGRP)) phenotypes. IMAs make extensive varicose and lamellar contacts with ICCs. In addition, axons of the multiple efferent and afferent phenotypes examined converge and articulate with IMA terminal arbors innervating ICCs. This architecture is consistent with the hypothesis that IMAs, or the multiply innervated IMA-ICC complexes they form, can function as stretch receptors. The tissue organization is also consonant with the proposal that those units can operate as functional analogues of muscle spindle organs. For electrophysiological assessments of IMA functions, experiments will need protocols that preserve both the complex architecture and the dynamic operations of IMA-ICC complexes. PMID- 21530619 TI - Zinc modulation of glycine receptors. AB - Glycine receptors are widely expressed in the mammalian central nervous system, and previous studies have demonstrated that glycine receptors are modulated by endogenous zinc. Zinc is concentrated in synaptic vesicles in several brain regions but is particularly abundant in the hippocampus and olfactory bulb. In the present study, we used patch-clamp electrophysiology of rat hippocampal and olfactory bulb neurons in primary culture to examine the effects of zinc on glycine receptors. Although glycine has been reported to reach millimolar concentrations during synaptic transmission, most previous studies on the effects of zinc on glycine receptors have used relatively low concentrations of glycine. High concentrations of glycine cause receptor desensitization. Our current results extend our previous demonstration that the modulatory actions of zinc are largely prevented when co-applied with desensitizing concentrations of glycine (300 MUM), suggesting that the effects of zinc are dependent on the state of the receptor. In contrast, pre-application of 300 MUM zinc, prior to glycine (300 MUM) application, causes a slowly developing inhibition with a slow rate of recovery, suggesting that the timing of zinc and glycine release also influences the effects of zinc. Furthermore, previous evidence suggests that synaptically released zinc can gain intracellular access, and we provide the first demonstration that low concentrations of intracellular zinc can potentiate glycine receptors. These results support the notion that zinc has complex effects on glycine receptors and multiple factors may interact to influence the efficacy of glycinergic transmission. PMID- 21530620 TI - Long-term evaluation of organophosphate toxicity and antidotal therapy in co cultures of spinal cord and muscle tissue. AB - Victims of nerve agents basically require antidotal treatment. There is need for novel antidotes and for therapeutic procedures that are specifically adapted to these patients. To cope with this challenge, in vitro test systems which are easy to handle and allow for conducting long-term studies would be of great benefit. The present work introduces co-cultures of spinal cord and muscle tissue as ex vivo testing systems meeting these criteria. Cell cultures in which functional neuromuscular synapses formed ex vivo were prepared from embryonic mice. Spontaneous muscle activity was recorded by video microscopy. Muscle contractions involved intact neuromuscular transmission as indicated by the effect of succinylcholine, a muscle relaxant that completely abolished muscle activity. At a concentration of 0.75 MUM the nerve agent VX reduced the frequency of spontaneous muscle contractions by about 75%. Subsequent application of obidoxime re-established muscle movements. After 24 h of antidotal treatment, muscle activity approached the level of sham-treated cultures and remained stable over the following week. In summary, co-cultures of spinal cord and muscle tissue are promising tools for evaluating the success of antidotal treatment following organophosphate intoxication over a period of at least seven days. PMID- 21530621 TI - The therapeutic use of localized cooling in the treatment of VX poisoning. AB - The organophosphate (OP) nerve agent VX is a weaponized chemical warfare agent that has also been used by terrorists against civilians. This contact poison produces characteristic signs of OP poisoning, including miosis, salivation, mastication, dysrhythmias and respiratory distress prior to death. Although successful treatment of OP poisoning can be obtained through decontamination and/or oxime reactivation of agent-inhibited cholinesterase, medical countermeasures that increase the therapeutic window for these measures would be of benefit. An anaesthetized swine model was utilized to examine the effects of lethal VX exposure to the skin, followed by cooling the exposure site prior to decontamination or treatment. The cooling was simply accomplished by using crushed ice in grip-seal plastic bags applied to the exposure sites. Cooling of skin exposed to lethal doses of VX significantly increased the window of opportunity for successful decontamination using the Reactive Skin Decontaminant Lotion((r)) (RSDL((r))) or treatment with the oxime antidotes HI-6 and 2PAM. Analyses of blood VX levels showed that cooling acted to slow or prevent the entry of VX into the bloodstream from the skin. If the exposure site is known, the simple and non-invasive application of cooling provides a safe means with which to dramatically increase the therapeutic window in which decontamination and/or antidote treatment against VX are life-saving. PMID- 21530623 TI - Influence of PEI as a core modifying agent on PLGA microspheres of PGE1, a pulmonary selective vasodilator. AB - This study tests the hypothesis that large porous poly (lactic-co-glycolic acid) (PLGA) microparticles modified with polyethyleneimine (PEI) are viable carriers for pulmonary delivery of prostaglandin E(1) (PGE(1)) used in the treatment of pulmonary arterial hypertension (PAH), a pulmonary vascular disorder. The particles were prepared by a double-emulsion solvent evaporation method with PEI 25 kDa in the internal aqueous phase to produce an osmotic pressure gradient. Polyvinyl alcohol (PVA) was used for external coating of the particles. The particles were examined for morphology, size, aerodynamic diameter, surface area, pore volume and in-vitro release profiles. Particles with optimal properties for inhalation were tested for in-vivo pulmonary absorption, metabolic stability in rat lung homogenates, and acute toxicity in rat bronchoalveolar lavage fluid and respiratory epithelial cells, Calu-3. The micromeritic data indicated that the PEI-modified particles of PGE(1) are optimal for inhalation. Incorporation of PEI in the formulations resulted in an increased entrapment efficiency - 83.26 +/- 3.04% for particles with 1% PVA and 95.48 +/- 0.46% for particles with 2% PVA. The amount of cumulative drug released into the simulated interstitial lung fluid was between 50.8 +/- 0.76% and 55.36 +/- 0.06%. A remarkable extension of the circulation half-life up to 6.0-6.5h was observed when the formulations were administered via the lungs. The metabolic stability and toxicity studies showed that the optimized formulations were stable at physiological conditions and relatively safe to the lungs and respiratory epithelium. Overall, this study demonstrates that large porous inhalable polymeric microparticles can be a feasible option for non-invasive and controlled release of PGE(1) for treatment of PAH. PMID- 21530624 TI - Mechanistic studies on the uptake and intracellular trafficking of novel cyclodextrin transfection complexes by intestinal epithelial cells. AB - Oral delivery of gene therapeutics would facilitate treatment of local intestinal disease, including colon cancer and inflammatory bowel disease, thus avoiding invasive surgery. The aims of this study were to investigate; if the orientation of the lipid tail on the cyclodextrin (CD) influenced the efficacy of a novel poly-6-cationic amphiphilic CD to transfect intestinal enterocytes; the endocytotic uptake pathway(s), and, the intracellular trafficking of the CD.DNA complexes. Inhibitors of clathrin- and caveolae-mediated endocytosis and macropinocytosis were used to determine the mechanism(s) of CD.DNA uptake by both undifferentiated and differentiated Caco-2 cells. Cell surface heparan sulphate proteoglycans were involved in the association of CD.DNA complexes with undifferentiated Caco-2 cells. Complexation of pDNA with CD facilitated significant levels of pDNA uptake and gene expression (comparable to PEI) in both undifferentiated and differentiated Caco-2 cells. Disruption of intracellular vesicular trafficking reduced transfection activity. CD was also capable of transfecting the more physiologically relevant differentiated Caco-2 model. Macropinocytosis was responsible for the uptake of CD.DNA transfection complexes by both undifferentiated and differentiated Caco-2 cells. The ability of this novel CD to transfect differentiated intestinal cells indicates the potential of this vector for oral gene delivery. PMID- 21530622 TI - Airborne polychlorinated biphenyls (PCBs) reduce telomerase activity and shorten telomere length in immortal human skin keratinocytes (HaCat). AB - PCBs, a group of 209 individual congeners, are ubiquitous environmental pollutants and classified as probable human carcinogens. One major route of exposure is by inhalation of these industrial compounds, possibly daily from inner city air and/or indoor air in contaminated buildings. Hallmarks of aging and carcinogenesis are changes in telomere length and telomerase activity. We hypothesize that semi-volatile PCBs, like those found in inner city air, are capable of disrupting telomerase activity and altering telomere length. To explore this possibility, we exposed human skin keratinocytes to a synthetic Chicago Airborne Mixture (CAM) of PCBs, or the prominent airborne PCB congeners, PCB28 or PCB52 for up to 48 days and determined telomerase activity, telomere length, cell proliferation, and cell cycle distribution. PCBs 28, 52 and CAM significantly reduced telomerase activity from days 18-48. Telomere length was shortened by PCB 52 from day 18 and PCB 28 and CAM from days 30 on. All PCBs decreased cell proliferation from day 18; only PCB 52 produced a small increase of cells in G0/G1 of the cell cycle. This significant inhibition of telomerase activity and reduction of telomere length by PCB congeners suggest a potential mechanism by which these compounds could lead to accelerated aging and cancer. PMID- 21530625 TI - A priori performance prediction in pharmaceutical wet granulation: testing the applicability of the nucleation regime map to a formulation with a broad size distribution and dry binder addition. AB - In this study, Hapgood's nucleation regime map (Hapgood et al., 2003) was tested for a formulation that consists of an active pharmaceutical ingredient (API) of broad size distribution and a fine dry binder. Gabapentin was used as the API and hydroxypropyl cellulose (HPC) as the dry binder with deionized water as the liquid binder. The formulation was granulated in a 6l Diosna high shear granulator. The effect of liquid addition method (spray, dripping), liquid addition rate (29-245 g/min), total liquid content (2, 4 and 10%), and impeller speed (250 and 500 rpm) on the granule size distribution and lump formation were investigated. Standard methods were successfully used to characterize the process parameters (spray drop size, spray geometry and powder surface velocity) for calculating the dimensionless spray flux. However, the addition of dry binder had a very strong effect on drop penetration time that could not be predicted from simple capillary flow considerations. This is most likely due to preferential liquid penetration into the fine pores related to the dry binder particles and subsequent partial softening and dissolution of the binder. For systems containing a dry binder or other amorphous powders, it is recommended that drop penetration time be measured directly for the blended formulation and then scaled to the drop size during spraying. Using these approaches to characterize the key dimensionless groups (dimensionless spray flux and drop penetration time), Hapgood's nucleation regime map was successfully used to predict a priori the effect of process conditions on the quality of the granule size distribution as measured by lump formation and the span of the size distribution, both before and after wet massing for range of conditions studied. Wider granule size distributions and higher amount of lumps were obtained moving from intermediate to mechanical dispersion regime. Addition of the liquid in the dripping mode gave the broadest size distribution with ungranulated fines and highest percentage of lumps compared to spraying mode. Addition of the liquid by spraying in the intermediate regime gave the narrowest size distribution with the lowest amount of lumps. The effects of impeller speed and wet massing time on granule size distribution were complex. At 2% liquid content, increasing the impeller speed and adding wet massing time caused some breakage of lumps and the production of fines. At higher liquid contents, the effects were less clear, likely due to a balance between increased breakage and increased granule consolidation and growth. Nevertheless, this work has demonstrated that for complex formulations with dry binder addition, the final granule size distribution still depends strongly on the homogeneity of the initial liquid distribution which is well predicted by the nucleation regime map analysis. PMID- 21530626 TI - Penetration enhancer containing vesicles as carriers for dermal delivery of tretinoin. AB - The ability of a recently developed novel class of liposomes to promote dermal delivery of tretinoin (TRA) was evaluated. New penetration enhancer-containing vesicles (PEVs) were prepared adding to conventional phosphatidylcholine vesicles (control liposomes) different hydrophilic penetration enhancers: Oramix NS10 (OrNS10), Labrasol (Lab), Transcutol P (Trc), and propylene glycol (PG). Vesicles were characterized by morphology, size distribution, zeta potential, incorporation efficiency, stability, rheological behaviour, and deformability. Small, negatively charged, non-deformable, multilamellar vesicles were obtained. Rheological studies showed that PEVs had fluidity higher than conventional liposomes. The influence of the obtained PEVs on (trans)dermal delivery of tretinoin was studied by ex vivo diffusion experiments through new born pig skin using formulations having the drug both inside and outside the vesicles, having TRA only inside, in comparison with non-incorporated drug dispersions of the same composition used to produce the studied vesicles. Main result of these experiments was an improved cutaneous drug accumulation and a reduced transdermal TRA delivery (except for PG-PEVs). TRA deposition provided by PEVs was higher for dialysed than for non-dialysed vesicles. Further, the accumulation increased in the order: control liposomes=25% MCT, the lymphatic transport of sirolimus was a major contributor to oral bioavailability. The formulation including more content of oil presented higher lymphatic transport of drug and further exhibited the increased oral bioavailability. Besides, distal ileum presented much more lymphatic transport of drug compared to proximal jejunum. Furthermore, even though the smaller droplet size of resultant microemulsions and more surfactant content also can positively influence the intestinal absorption of drug, their influences on the drug intestinal lymphatic transport were relatively weaker than that of more oil content. In addition, there was a high linear correlation between the AUC values and the mean of P(eff) values in jejunum and ileum. PMID- 21530656 TI - Solubilization of the novel anionic amphiphilic photosensitizer TPCS 2a by nonionic Pluronic block copolymers. AB - The influence of four nonionic Pluronic block copolymers (L44, F68, P123 and F127) on the solubilization and aggregation of the novel anionic amphiphilic photosensitizer TPCS(2a), intended for use in the technology of photochemical internalization (PCI), was evaluated in aqueous media as part of pharmaceutical preformulation studies. The evaluation was performed by use of UV-Vis spectroscopy for diluted samples of TPCS(2a) (3*10(-6)M), and capillary viscosimetry, freezing point depression measurements and atomic force microscopy (AFM) at pharmaceutical relevant concentrations (2; 10 or 30 mg/ml TPCS(2a)). The critical micelle concentration (CMC) of the Pluronics in presence of TPCS(2a) was determined spectrophotometrically. The Pluronic block copolymers solubilized the photosensitizer above CMC at ambient temperature by formation of vehicle-drug complexes apparently organized in networks of varying viscosity and morphology, which were sensitive towards the addition of neutral and charged excipients. PMID- 21530657 TI - The characterization of Lucilia cuprina acetylcholinesterase as a drug target, and the identification of novel inhibitors by high throughput screening. AB - Acetylcholinesterase (AChE, EC3.1.1.7.) is the molecular target for the carbamate and organophosphate pesticides that are used to combat parasitic arthropods. In this paper we report the functional heterologous expression of AChE from Lucilia cuprina (the sheep blowfly) in HEK293 cells. We show that the expressed enzyme is cell-surface-exposed and possesses a glycosyl-phosphatidylinositol membrane anchor. The substrates acetyl-, propionyl- and butyrylthiocholine (AcTC, PropTC, ButTC), and also 11 further thiocholine and homo-thiocholine derivatives were chemically synthesized to evaluate and compare their substrate properties in L. cuprina AChE and recombinant human AChE. The Michaelis-Menten constants K(M) for AcTC, PropTC and ButTC were found to be 3-7-fold lower for the L. cuprina AChE than for the human AChE. Additionally, 2-methoxyacetyl-thiocholine and isobutyryl thiocholine were better substrates for the insect enzyme than for the human AChE. The AcTC, PropTC and ButTC specificities and the Michaelis-Menten constants for recombinant L. cuprina AChE were similar to those determined for AChE extracted from L. cuprina heads, which are a particularly rich source of this enzyme. The median inhibition concentrations (IC(50) values) were determined for 21 organophosphates, 23 carbamates and also 9 known non-covalent AChE inhibitors. Interestingly, 11 compounds were 100- to >4000-fold more active on the insect enzyme than on the human enzyme. The substrate and inhibitor selectivity data collectively indicate that there are structural differences between L. cuprina and human AChE in or near the active sites, suggesting that it may be possible to identify novel, specific L. cuprina AChE inhibitors. To this end, a high throughput screen with 107,893 compounds was performed on the L. cuprina head AChE. This led to the identification of 195 non-carbamate, non-organophosphate inhibitors with IC(50) values below 10MUM. Analysis of the most potent hit compounds identified 19 previously unknown inhibitors with IC(50) values below 200nM, which were up to 335-fold more potent on the L. cuprina enzyme than on the human AChE. Some of these compounds may serve as leads for lead optimization programs to generate fly-specific pesticides. PMID- 21530658 TI - Adenovirus-mediated anti-sense ERK2 gene therapy inhibits tubular epithelial mesenchymal transition and ameliorates renal allograft fibrosis. AB - PURPOSE: Epithelial-mesenchymal transition (EMT) plays an important role in progress of renal allograft fibrosis. The adenovirus-mediated anti-sense extracellular signal-regulated kinase 2 (Adanti-ERK2) gene therapy was used to block ERK signaling pathway, and its effect on EMT and renal allograft fibrosis both in vivo and in vitro was explored. METHODS: We first generated an in vitro EMT model by connective tissue growth factor (CTGF) stimulation in a HK-2 cell culture system, and then applied Adanti-ERK2 gene therapy on it. The transition of epithelial marker (E-cadherin) to mesenchymal markers (alpha-SMA, Vimentin) and the cell mobility function alteration were monitored for the observation of EMT progress. In vivo, a rat renal transplant model with Fisher-Lewis combination was employed and the Adanti-ERK2 gene therapy was given. The tubular EMT changes and pathology of allograft fibrosis were examined. RESULTS: In vitro, Adanti-ERK2 gene therapy inhibited CTGF-induced tubular EMT and attenuated the cell motility function induced by CTGF. In vivo, Adanti-ERK2 gene therapy attenuated tubular EMT, modulated the infiltration of macrophages and CD8(+), CD4(+)T lymphocytes, and ameliorated fibrosis effectively in the renal allografts 24weeks after transplantation. CONCLUSIONS: Adanti-ERK2 gene therapy inhibits tubular EMT and attenuates renal allograft fibrosis. It is possible to develop promising molecular drug(s) in the future based on ERK signaling pathway. PMID- 21530659 TI - Glutamate and glutathione interplay in a motor neuronal model of amyotrophic lateral sclerosis reveals altered energy metabolism. AB - Impairment of mitochondrial function might contribute to oxidative stress associated with neurodegeneration in amyotrophic lateral sclerosis (ALS). Glutamate levels in tissues of ALS patients are sometimes altered. In neurons, mitochondrial metabolism of exogenous glutamine is mainly responsible for the net synthesis of glutamate, which is a neurotransmitter, but it is also necessary for the synthesis of glutathione, the main endogenous antioxidant. We investigated glutathione synthesis and glutamine/glutamate metabolism in a motor neuronal model of familial ALS. In standard culture conditions (with glutamine) or restricting glutamine or cystine, the level of glutathione was always lower in the cell line expressing the mutant (G93A) human Cu, Zn superoxide dismutase (G93ASOD1) than in the line expressing wild-type SOD1. With glutamine the difference in glutathione was associated with a lower glutamate and impairment of the glutamine/glutamate metabolism as evidenced by lower glutaminase and cytosolic malate dehydrogenase activity. d-beta-hydroxybutyrate, as an alternative to glutamine as energy substrate in addition to glucose, reversed the decreases of cytosolic malate dehydrogenase activity and glutamate and glutathione. However, in the G93ASOD1 cell line, in all culture conditions the expression of pyruvate dehydrogenase kinase l protein, which down-regulates pyruvate dehydrogenase activity, was induced, together with an increase in lactate release in the medium. These findings suggest that the glutathione decrease associated with mutant SOD1 expression is due to mitochondrial dysfunction caused by the reduction of the flow of glucose-derived pyruvate through the TCA cycle; it implies altered glutamate metabolism and depends on the different mitochondrial energy substrates. PMID- 21530660 TI - Local insulin and the rapid regrowth of diabetic epidermal axons. AB - Insulin deficiency may contribute toward the neurological deficits of diabetic polyneuropathy (DPN). In particular, the unique trophic properties of insulin, acting on sensory neuron and axon receptors offer an approach toward reversing loss of skin axons that develops during diabetes. Here we examined how local cutaneous insulin, acting on axon receptors, influences innervation of the epidermis. That cutaneous axons might be amenable to regrowth was suggested by confirming that a high proportion of epidermal axons expressed GAP43/B50, a growth associated protein. Also, IRbeta (insulin receptor subunit beta) mRNA was expressed and upregulated in the footpads of diabetic mice and protein expression was upregulated in their sensory dorsal root ganglia. Moreover, footpads expressed mRNAs of the downstream insulin transduction molecules, IRS-1 and IRS 2. IRbeta protein was identified in dermal axons, some epidermal sensory axons, and in keratinocytes. In separate models of experimental diabetes, we identified a surprising and rapid local response of this axon population to insulin. C57BL/6J streptozotocin (STZ) injected mice, as a model of type 1 diabetes and dbdb mice, as a model of type 2 diabetes were both evaluated after 3 months of diabetes duration. Local hindpaw plantar injections of low dose subhypoglycemic insulin (that did not alter diabetic hyperglycemia) and carrier (into the opposite paw) were given over two days and innervation studied at 5 days. Insulin injections in both models were associated with an ipsilateral rise in the density of PGP 9.5 labeled diabetic epidermal axons at 5 days, compared to that of their contralateral carrier injected hindpaw. Nondiabetic controls did not have changes in innervation following insulin. In a separate cohort of STZ diabetic mice and controls evaluated for paw sensation, there was mild improvement in mechanical, but not thermal sensation at 2 weeks after insulin injection in diabetics but not controls. Fine unmyelinated epidermal axons have considerable plasticity. Here we identify a rapid improvement of skin innervation by doses of insulin insufficient to alter glycemia or innervation of the opposite paw. Local direct insulin signaling of receptors expressed on diabetic cutaneous axons may reverse retraction of their branches during experimental DPN. PMID- 21530661 TI - Glucocorticoid receptor stimulation and the regulation of neonatal cerebellar neural progenitor cell apoptosis. AB - Glucocorticoids are used to treat respiratory dysfunction associated with premature birth but have been shown to cause neurodevelopmental deficits when used therapeutically. Recently, we established that acute glucocorticoid exposure at clinically relevant doses produces neural progenitor cell apoptosis in the external granule layer of the developing mouse cerebellum and permanent decreases in the number of cerebellar neurons. As the cerebellum naturally matures and neurogenesis is no longer needed, the external granule layer decreases proliferation and permanently disappears during the second week of life. At this same time, corticosterone (the endogenous rodent glucocorticoid) release increases and a glucocorticoid-metabolizing enzyme that protects the external granule layer against glucocorticoid receptor stimulation (11beta-Hydroxysteroid Dehydrogenase-Type 2; HSD2) naturally disappears. Here we show that HSD2 inhibition and raising corticosterone to adult physiological levels both can independently increase neural progenitor cell apoptosis in the neonatal mouse. Conversely, glucocorticoid receptor antagonism decreases natural physiological apoptosis in this same progenitor cell population suggesting that endogenous glucocorticoid stimulation may regulate apoptosis in the external granule layer. We also found that glucocorticoids which HSD2 can effectively metabolize generate less external granule layer apoptosis than glucocorticoids this enzyme is ineffective at breaking down. This finding may explain why glucocorticoids that this enzyme can metabolize are clinically effective at treating respiratory dysfunction yet seem to produce no neurodevelopmental deficits. Finally, we demonstrate that both acute and chronic glucocorticoid exposures produce external granule layer apoptosis but without appropriate control groups this effect becomes masked. These results are discussed in terms of their implications for glucocorticoid therapy and neurodevelopment during the perinatal period. PMID- 21530662 TI - Errors of interpretation and modeling: a reply to Grinband et al. AB - Grinband et al., 2011 compare evidence that they have collected from a neuroimaging study of the Stroop task with a simulation model of performance and conflict in that task, and interpret the results as providing evidence against the theory that activity in dorsal medial frontal cortex (dMFC) reflects monitoring for conflict. Here, we discuss several errors in their methods and conclusions and show, contrary to their claims, that their findings are entirely consistent with previously published predictions of the conflict monitoring theory. Specifically, we point out that their argument rests on the assumption that conflict must be greater on all incongruent trials than on all congruent trials-an assumption that is theoretically and demonstrably incorrect. We also point out that their simulations are flawed and diverge substantially from previously published implementations of the conflict monitoring theory. When simulated appropriately, the conflict monitoring theory predicts precisely the patterns of results that Grinband et al. take to present serious challenges to the theory. Finally, we note that their proposal that dMFC activity reflects time on task is theoretically weak, pointing to a direct relationship between behavior (RT) and neural activity but failing to identify any intervening psychological construct to relate the two. The conflict monitoring theory provides such a construct, and a mechanistic implementation that continues to receive strong support from the neuroimaging literature, including the results reported by Grinband et al. PMID- 21530663 TI - The possible impact of noise-induced Ca2+-dependent activity in the central auditory pathway: a manganese-enhanced MRI study. AB - Noise exposure at high intensities leads to a temporary shift of hearing thresholds (TTS) and is followed by a permanent threshold shift (PTS). Permanent threshold shift is not only associated with cochlear damage as the primary site of-lesion, but also with subsequent structural and functional changes within the central auditory pathway. The aim of the present study was to monitor neuronal activity within central auditory structures in mice after noise exposure at different time intervals using manganese-enhanced magnetic resonance imaging (MEMRI). The results demonstrate for the first time that calcium-dependent activity patterns are modified in several structures of the central auditory system as the result of a noise-induced hearing loss (NIHL). The MEMRI data demonstrate that temporary threshold shift is correlated with an activity increase in hierarchically lower structures of the auditory pathway. This seems to be indicative of a direct noise impact at the first stage of central auditory processing. However, noise-dependent changes of higher auditory structures were found as well in the phase of PTS. Repeated noise exposure was found to induce an additional elevation of calcium-dependent activity in all investigated auditory structures - without a significant shift in auditory thresholds. Sustained manganese accumulation was present in the auditory brainstem after moderate acoustic stimulation as well without PTS induction. The long-lasting enhancement of MEMRI signals suggests a noise-induced activity increase of various calcium dependent processes of different origin (such as neuroprotective mechanisms). The present findings could be helpful to better understand the time-course of different symptoms in NIHL and the individual susceptibility to noise. PMID- 21530664 TI - Evolutionary history of Lissotriton helveticus: multilocus assessment of ancestral vs. recent colonization of the Iberian Peninsula. AB - The Pleistocene was characterized by climatic changes that greatly altered the distribution of organisms. Population extinctions, bottlenecks, isolation, range expansions and contractions were often associated with glaciations, leaving signatures in the spatial patterns of genetic diversity across species. Lissotriton helveticus belongs to a Pan-European lineage of newts that were strongly affected by glaciations and represent an excellent model to analyse the effect of generalized climatic changes in phylogeographic patterns. We studied the genetic diversity of the species using data from two mitochondrial and three nuclear genes analyzed in a Bayesian phylogenetic framework to investigate the historical processes shaping spatial patterns of genetic diversity. Mitochondrial haplotypes cluster in four different groups present in the Iberian Peninsula and of Pleistocene origin, probably by allopatric fragmentation. Nuclear genes present no obvious geographic structure patterns, suggesting gene flow and generalized incomplete lineage sorting. Populations north of the Pyrenees are closely related to those from northeastern Iberia, suggesting recent range expansion from this region. Historical demographic analyses indicate a demographic expansion starting about 100,000years ago and more recent population declines. Compared to other Lissotriton species, L. helveticus includes only relatively young genetic lineages, suggesting a Central European pre-Pleistocene distribution followed by complete extirpation of the species during glaciations in that area. Historical demographic trends in the Iberian Peninsula are reversed with respect to the more Mediterranean species Lissotriton boscai, indicating different responses of both species to climate changes. Diversity patterns among Lissotriton species seem to be defined by four main factors: ancestral distributions, colonization capabilities, interactions with other species and effective population sizes. Differences in these factors define two types of species, referred to as "R" (refugia) and "S" (sanctuaries) that explain part of the diversity in patterns of genetic diversity created by glaciations in Western Europe. PMID- 21530665 TI - A deviant genetic code in the green alga-derived plastid in the dinoflagellate Lepidodinium chlorophorum. AB - We here report a deviant genetic code, in which AUA is read as methionine (Met) instead of isoleucine (Ile), in the green alga-derived plastid in the dinoflagellate Lepidodinium chlorophorum. Although L. chlorophorum cDNA sequences of 11 plastid-encoded genes were deposited in the GenBank database, the non canonical usage of AUA in this dinoflagellate plastid has been overlooked prior to this study. We compared 11 plastid-encoded genes of L. chlorophorum with the corresponding genes of 17 green algal plastids. Intriguingly, AUA often occurred in the L. chlorophorum sequences at codon positions that are predominantly occupied by Met amongst the green algal sequences. Coincidentally, the L. chlorophorum sequences utilized few AUA codons at the positions predominantly occupied by Ile amongst the green algal sequences. These observations clearly indicated that both AUA and AUG encode Met, while AUU and AUC encode Ile, in the L. chlorophorum plastid. Despite the rapidly-evolving nature of L. chlorophorum plastid-encoded genes, our statistical tests incorporating the deviant code suggest no significant difference in amino acid composition among the L. chlorophorum plastid and the green algal plastids considered in this study. Finally, the possible evolutionary events required for the reassignment of AUA from Ile to Met in Lepitodinium plastids were discussed. PMID- 21530667 TI - Antibiotic resistance and adhesion potential of Bacteroides fragilis clinical isolates from Cape Town, South Africa. AB - The minimum inhibitory concentrations of 23 Bacteroides fragilis clinical isolates from Cape Town, South Africa, were established using the E-test method. Eight percent of the strains were found to be highly resistant to metronidazole (>=256 mg/L) imipenem and cefoxitin. This is an 8% increase in resistance compared to the previous metronidazole susceptibility screening performed in South Africa in 1998. Clindamycin was the most effective antibiotic with all strains showing sensitivity. Most of the strains (65%) were tetracycline resistant, while one strain, B. fragilis GSH15, showed multidrug resistance to metronidazole, imipenem, cefoxitin and tetracycline. PCR screening revealed that none of the strains contained any of the published nim genes. The particle agglutination assay was employed to determine the ability of the isolates to bind the ECM components fibronectin, laminin, mucin and collagen. This revealed that 78% of the clinical isolates adhered to all four ECM components to varying extents, with the strongest being to laminin and weakest to mucin and collagen Type I. PMID- 21530666 TI - Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems. AB - Repeated cycles of ethanol intoxication and withdrawal associated with dependence induce neuroadaptations in a variety of brain systems. Withdrawal-induced negative emotional states can be ameliorated by ethanol consumption; a learned process termed negative reinforcement. Accordingly, a dependence-induced phenotype is escalated ethanol self-administration. Matrix metalloproteinases (MMPs) are proteolytic enzymes which degrade the extracellular matrix to allow for synaptic reorganization and plasticity. To test the hypothesis that an intact MMP system is required for animals to learn about the negative reinforcing effects of ethanol and display escalated self-administration during acute withdrawal when ethanol-dependent, male Wistar rats were trained to self administer ethanol and then assigned to either acute or chronic MMP inhibition treatment groups. The chronic treatment group received intracerebroventricular (ICV) infusions of the broad spectrum MMP inhibitor FN-439 or artificial cerebrospinal fluid (aCSF) via osmotic minipumps during a 1 month ethanol dependence induction period and subsequent post-dependence induction self administration sessions that occurred during acute withdrawal. The acute treatment group only received ICV FN-439 or aCSF on the day of self administration sessions following dependence induction during acute withdrawal. The results showed that inhibition of MMPs attenuated escalated ethanol self administration following chronic and acute exposure conditions. Furthermore, once learning (i.e., plasticity) had occurred, MMP inhibition had no impact on escalated response patterns and animals previously subjected to MMP inhibition that did not escalate evidenced normal escalations in operant ethanol self administration once FN-439 treatments were terminated. Thus, the present data identified that an intact MMP system is required for the escalated responding that occurs during acute withdrawal in dependent animals and implicate such escalation as a learned response. PMID- 21530668 TI - Diversity of gut Bifidobacterium species is not altered between allergic and non allergic French infants. AB - Some clinical studies have suggested a relationship between allergic diseases and gut microbiota. We aimed to study bifidobacterial colonization at species and strain levels in ten allergic French infants included at their first clinical consultation and 20 controls matching for age at sampling, mode of delivery, per partum antibiotics, type of feeding and antibiotics in the first weeks of life. The faecal microbiota was analyzed by culture methods and TTGE. Bifidobacterial species and strains were identified using multiplex PCR and Box-PCR fingerprinting. No differences were observed between groups in the number of colonized infants or in the levels of colonization by the main aerobic and anaerobic genera. All infants were colonized with high levels of Bifidobacterium except for one in each group. One to 5 Bifidobacterium species and 1 to 7 strains were observed per subject independently of allergic status and age at sampling. Our study showed the infants to be colonized by several species and strains, including several strains from the same species. This diversity in Bifidobacterium colonization was not related with the allergic status and showed that the link between Bifidobacterium colonization and allergic diseases is complex and cannot be restricted to the role attributed to Bifidobacterium species. PMID- 21530669 TI - Use of ultra pure nitric oxide generated by the reduction of nitrogen dioxide to reverse pulmonary hypertension in hypoxemic swine. AB - Inhaled nitric oxide (NO) has the capacity to selectively dilate pulmonary blood vessels, and thus enhance the matching of ventilation and perfusion, improve oxygenation and decrease pulmonary hypertension. However, existing approaches for the administration of inhaled NO are associated with the co-delivery of potentially toxic concentrations of nitrogen dioxide (NO2) due to the oxidation of NO in oxygen rich environments. We tested the ability of a novel methodology for generating highly purified NO through the reduction of NO2 by ascorbic acid to reverse pulmonary hypertension. In vitro testing demonstrated that the NO output of the novel device is ultrapure and free of NO2. An in vivo hypoxemic swine model of pulmonary hypertension was used to examine the dose response to NO in terms of pulmonary pressures and pulmonary vascular resistance. Pulmonary hypertension was induced by lowering inspired oxygen to 15% prior to treatment with inhaled ultra purified NO (1, 5, 20, and 80PPM). Hypoxemia increased mean pulmonary artery pressures and pulmonary vascular resistance. Inhaled ultra purified NO doses (down to 1PPM) show a marked reduction of hypoxemia-induced pulmonary vascular resistance. These experiments demonstrate a simple and robust method to generate purified inhaled NO that is devoid of NO2 and capable of reversing hypoxemia induced pulmonary hypertension. PMID- 21530670 TI - Penile erectile activity of dinitrosyl iron complexes with thiol-containing ligands. AB - It has been established that intracavernous injections of water-soluble dinitrosyl iron complexes (DNIC) with glutathione or cysteine (0.4-6.0MUmoles/kg) to male rats induce short-term (2-3 min) penile erection along with a short-term drop of arterial pressure and appearance of protein-bound DNIC in cavernous tissue and circulating blood. The duration of erection and the hypotensive activity of DNIC increase dramatically after simultaneous intracavernous injection of DNIC and the phosphodiesterase-5 inhibitor papaverine. Surgical denervation of cavernous bodies does not influence the erectile activity of DNIC. No penile erection takes place after intravenous (instead of intracavernous) injection of the same dose of DNIC; in this case, protein-bound DNIC are detected only in the blood. These findings suggest that water-soluble DNIC with thiol containing ligands (cysteine or glutathione) can be used as a basis in the design of a novel class of drugs for treating erectile dysfunctions. PMID- 21530671 TI - Measurement of luminal nitric oxide in the uterine cavity using a silicon balloon catheter. AB - The aim of this pilot case-control study was to measure nitric oxide (NO) gas in air incubated in a catheter balloon in the uterus of healthy women and patients with pelvic inflammatory disease, to determine the optimal time of incubation and to find whether NO level rises after manipulation in the uterine cavity. We measured nitric oxide levels in air incubated for 2-10 min in a catheter balloon in the uterine cavity in 6 non pregnant women from 22 to 50 years of age with lower abdominal pain and 10 healthy women with regular menstrual cycles. After an incubation time of just 2 min, intrauterine nitric oxide levels were significantly increased in patients with diagnosed pelvic inflammatory disease compared to healthy women. Uterine nitric oxide levels did not rise after manipulation in the uterine cavity. In conclusion, NO gas can be measured directly in the uterine cavity with a fast, simple, well-tolerated and safe method. The levels of nitric oxide are increased in women diagnosed with pelvic inflammatory disease already after an incubation time of 2 min. PMID- 21530672 TI - Conjugated linoleic acid (CLA): is it time to supplement asthma therapy? AB - The limitations and side effects of existing asthma therapies prompt interest in complementary and alternative therapies. Conjugated linoleic acids (CLA) are a family of natural fatty acids found primarily in beef and dairy products. These molecules have a variety of biological properties which suggest potential benefit in asthma, including effects on energy regulation, lipid metabolism, inflammation and immune function. Here we review the evidence for these effects from pre clinical and clinical studies, their significance in the context of human asthma, and discuss the potential role for CLA supplementation in asthma management. PMID- 21530673 TI - AICAR and Compound C regulate food intake independently of AMP-activated protein kinase in lines of chickens selected for high or low body weight. AB - AMP-activated protein kinase (AMPK) functions to maintain cellular and body energy balance. Our aim was to investigate the effect of intracerebroventricular (ICV) administration of AMPK stimulator AICAR and AMPK inhibitor Compound C on food intake in lines of chickens that had undergone long-term selection from a common founder population for high (HWS) or low (LWS) body weight. AICAR caused a quadratic dose-dependent decrease in food intake in LWS but not HWS chicks. Compound C caused a quadratic dose-dependent increase in food intake in HWS but not in LWS chicks. Key aspects of the AMPK pathway, including upstream kinases mRNA expression, AMPK subunit alpha mRNA expression and phosphorylation, and a downstream target acetyl CoA carboxylase (ACC) phosphorylation were not affected by either AICAR or Compound C in either line. The exception was a significant inhibitory effect of AICAR on ACC phosphorylation ratio due to increased total ACC protein content without changing phosphorylated ACC protein levels. Thus, the anorexigenic effect of AICAR in LWS chicks and orexigenic effect of Compound C in HWS chicks resulted from activation or inhibition of other kinase pathways separate from AMPK. These results suggest genetic variation in feeding response for central AICAR and Compound C in chickens, which may contribute to the different body weights between the HWS and LWS lines. PMID- 21530674 TI - Characterization of sarcoplasmic calcium binding protein (SCP) variants from freshwater crayfish Procambarus clarkii. AB - Sarcoplasmic calcium binding protein (SCP) is an invertebrate EF-hand calcium buffering protein that has been proposed to fulfill a similar function in muscle relaxation as vertebrate parvalbumin. We have identified three SCP variants in the freshwater crayfish Procambarus clarkii. The variants (pcSCP1a, pcSCP1b, and pcSCP1c) differ across a 37 amino acid region that lies mainly between the second and third EF-hand calcium binding domains. We evaluated tissue distribution and response of the variants to cold exposure, a stress known to affect expression of parvalbumin. Expression patterns of the variants were not different and therefore do not provide a functional rationale for the polymorphism of pcSCP1. Compared to hepatopancreas, expression of pcSCP1 variants was 100,000-fold greater in axial abdominal muscle and 10-fold greater in cardiac muscle. Expression was 10-100 greater in fast-twitch deep flexor and extensor muscles compared to slow-twitch superficial flexor and extensors. In axial muscle, no significant changes of pcSCP1, calmodulin (CaM), or sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA) expression were measured after one week of 4 degrees C exposure. In contrast, large decreases of pcSCP1 were measured in cardiac muscle, with no changes in CaM or SERCA. Knockdown of pcSCP1 by dsRNA led to reduced muscle activity and decreased expression of SERCA. In summary, the pattern of pcSCP1 tissue expression is similar to parvalbumin, supporting a role in muscle contraction. However, the response of pcSCP1 to cold exposure differs from parvalbumin, suggesting possible functional divergence between the two proteins. PMID- 21530675 TI - Metabolic engineering of Clostridium tyrobutyricum for n-butanol production. AB - Clostridium tyrobutyricum ATCC 25755, a butyric acid producing bacterium, has been engineered to overexpress aldehyde/alcohol dehydrogenase 2 (adhE2, Genebank no. AF321779) from Clostridium acetobutylicum ATCC 824, which converts butyryl CoA to butanol, under the control of native thiolase (thl) promoter. Butanol titer of 1.1g/L was obtained in C. tyrobutyricum overexpressing adhE2. The effects of inactivating acetate kinase (ack) and phosphotransbutyrylase (ptb) genes in the host on butanol production were then studied. A high C4/C2 product ratio of 10.6 (mol/mol) was obtained in ack knockout mutant, whereas a low C4/C2 product ratio of 1.4 (mol/mol) was obtained in ptb knockout mutant, confirming that ack and ptb genes play important roles in controlling metabolic flux distribution in C. tyrobutyricum. The highest butanol titer of 10.0g/L and butanol yield of 27.0% (w/w, 66% of theoretical yield) were achieved from glucose in the ack knockout mutant overexpressing adhE2. When a more reduced substrate mannitol was used, the butanol titer reached 16.0 g/L with 30.6% (w/w) yield (75% theoretical yield). Moreover, C. tyrobutyricum showed good butanol tolerance, with >80% and ~60% relative growth rate at 1.0% and 1.5% (v/v) butanol. These results suggest that C. tyrobutyricum is a promising heterologous host for n butanol production from renewable biomass. PMID- 21530676 TI - Distinctive and critical roles for cellular immunity and immune-inflammatory response in the immunopathology of Sendai virus infection in mice. AB - Respiratory viral infections result in severe pulmonary injury, to which host immune response may be a significant contributor. At present, it is not entirely clear the extent to which lung injury is a necessary consequence of host defense. In this report, we use functional genomics approach to characterize the key roles of cellular immunity and immune-inflammatory response in the immunopathology of Sendai virus infection in resistant C57BL/6J and susceptible DBA/2J mice. Infected mice manifested an immune-inflammatory response characterized by the pulmonary influx of neutrophils and mononuclear cells. DBA/2J mice mounted a vigorous immune response, with significant up-regulation of cytokine/chemokine genes in two successive waves through the course of infection. Whereas, C57BL/6J mice displayed an efficient immune response with less severe pathology and clusters of immune-inflammatory responsive genes were exclusively up-regulated on day 4 in this strain. Overall, DBA/2J mice exhibited a dysregulated hyper inflammatory cytokine/chemokine cascades that does not limit viral spread resulting in a predisposition to severe lung pathology. This response is similar to severe human respiratory paramyxovirus infections, which will serve as a model for the elucidation of hyper-immune inflammatory response that result to severe immunopathology in respiratory viral infections. PMID- 21530677 TI - Microtubule and kinesin/dynein-dependent, bi-directional transport of autolysosomes in neurites of PC12 cells. AB - Autophagy, a major degradative pathway of the lysosomal system, has been implicated in various neurodegenerative diseases. During autophagic process, organelles and proteins are encapsulated in double-membrane vacuoles called autophagosomes, which finally fuse with lysosomes to form autolysosomes where incorporated materials are degraded. Despite extensive investigations in identifying the molecular components that participate in autophagy, little is known about routes and dynamics of autophagosomes/autolysosomes in the neurites of live cells. Hence, in the present study, we aim to investigate the biophysical characteristics of neuritic transport of autolysosomes in PC12 cells. Our study demonstrated that monomeric red fluorescence protein-light chain 3 (mRFP-LC3) labeled autolysosomes were motile and moved along PC12 neurites in both anterograde and retrograde directions with a bias towards the nucleus during starvation. By using image processing, quantitative analysis was made to show the dynamic biophysical characteristics of these vesicles. The average velocity of anterograde and retrograde transport was 0.33+/-0.04MUm/s and 0.39+/-0.05MUm/s, respectively. Disruption of microtubules by nocodazole completely abolished their movements, suggesting the neuritic transport of autolysosomes depends on microtubules. The directional transport of autolysosomes was also affected by blockage of motor protein activity. Altogether, our study documents many aspects of the highly dynamic movement of autolysosome in PC12 neurites. Autolysosomes transported in a bi-directional manner along microtubules by dynein and kinesin motor proteins. These findings provide valuable insight into understanding the mechanism and control of autophagy in neurites under physiological and pathological conditions. PMID- 21530678 TI - High MR sensitive fluorescent magnetite nanocluster for stem cell tracking in ischemic mouse brain. AB - Stem cells have shown a great potential to treat diseases and injuries, including ischemic brain injury. However, developing agents for the long-term tracking of stem cells with few side effects is still challenging. Our aim is to develop a novel fluorescent-magnetite-nanocluster (FMNC) with high MRI sensitivity and to examine its application in the labeling and tracking of mesenchymal stem cells (MSC). For this purpose, we developed FMNC by embedding individual magnetite nanoparticles (NPs) into a polystyrene scaffold coated with two layers of silica and a sandwiched layer of rhodamine. We examined the efficacy of FMNC in MSC labeling and the feasibility of tracking FMNC-labeled MSCs in the ischemic mouse brain. We found that FMNC has high cell-labeling efficiency with no adverse effects on MSCs. In a mouse middle cerebral artery occlusion model, FMNC-labeled MSCs migrated to and accumulated in the ischemic region after FMNC-labeled MSC transplantation. MRI findings highly correlated to immunohistochemistry results. FROM THE CLINICAL EDITOR: In this study, the authors report a novel fluorescent magnetite-nanocluster with high MRI sensitivity and to labeling and tracking of mesenchymal stem cells, and provide in vivo data utilizing a murine stroke model. PMID- 21530679 TI - Economic benefits of sponsored clinical trials on pharmaceutical expenditures at a medical center in Taiwan. AB - Concerns exist regarding the additional cost of patient care when patients are enrolled in clinical trials at hospitals. To assess the avoidance of drug costs by conducting sponsored clinical trials, a retrospective analysis evaluating drug cost avoidance in all sponsored clinical trials was conducted in 2008 at the most prominent medical center in Taiwan. The National Health Insurance (NHI) reimbursement prices of either the investigated drugs or the standardized drug therapy for each specific disease were used to calculate the cost avoidance. Drug cost avoidance from sponsored clinical trials per year, per trial, per patient, in different therapeutic areas, and in different phases was analyzed. Three quarters of the cost avoidance in drug expenditures from 194 sponsored clinical trials were estimated. All cost values are in US Dollars. Around $11.2 million was avoided at the center in 2008. The average value of cost avoidance was $58,000/trial-year or $3,900/participant-year. The early-phase trials and phase III trials accounted for 25% and 56% of all trials, respectively, while they constituted 32% and 49% of the total costs avoided, respectively. The most frequently conducted and highest cost-avoiding trials were those for antineoplastic agents, especially targeted therapy which accounted for 85% of the total cost avoidance of anti-cancer trials. This study demonstrates the profoundly positive economic impact on the healthcare system in Taiwan by sponsored clinical trials. To understand the trend of economic benefits of the trials on pharmaceutical expenditure, it would be important to analyze the cost avoidance of trials regularly in an institution. PMID- 21530680 TI - Use of a precious resource: parental decision making about using autologous umbilical cord blood in studies involving young children with type 1 diabetes. AB - OBJECTIVE: To assess parental decision making and experiences in an autologous umbilical cord blood infusion study in young children with type 1 diabetes (T1D). METHODS: Surveys were completed with 22 parents of children with T1D who received infusion and 22 parents who declined infusion. RESULTS: Parents who stored umbilical cord blood were middle-aged, highly-educated, Caucasian, married, and privately insured. Parents of children who did not receive infusion declined because they did not want to deplete their cord blood supply. Parents of children who decided to have their children participate in the infusion study were similar on approaches to storing cord blood and attitudes about research as compared to parents who declined to have their children participate in the infusion. Parents of children who received infusion were positive about their experiences and held expectations that infusion would lead to a T1D cure. CONCLUSIONS: The manner in which cord blood is stored needs to be considered so that participation in future studies does not risk depletion of the cord blood supply. In addition, it appears that the process of storing umbilical cord blood leads to restricted demographic characteristics of eligible participants, which may impact recruitment in clinical trials. These results are relevant to designing future cord blood studies in T1D and other non-malignant diseases. PMID- 21530682 TI - Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb/c mice. AB - There has been lack of the uniform standard for establishment of animal immunodepressive models induced by cyclophosphamide (CTX), and the information about the immunosuppressive effect of CTX on peripheral blood lymphocyte subsets in rodents. Here we describe a CTX-induced mouse model and try to establish a feasible immunosuppressive model for studying the fungal pathogenicity. Balb/c mice received two intraperitoneal injections of different CTX doses (50-200 mg/kg) at 2-day intervals. Peripheral whole blood collected at different time points before and after CTX injection was used to detect white blood cells (WBCs), lymphocytes and their subsets by automated hematology analyzer and flow cytometry, respectively. WBCs and lymphocytes in all groups except CTX50 (50 mg/kg CTX) group commenced to decrease in a dose-dependent manner on day 1, reached the nadir on day 4, rebounded on day 10, and declined again on day 17 after CTX treatment. Low dose (50 mg/kg) CTX produced no obvious change of percentage of CD3(+), CD4(+) and CD8(+) T cells and CD19(+) cells, but high doses (100 or 150 mg/kg) yielded a significant decrease of CD3(+) and CD4(+) cells on day 4 and CD19(+) cells on day 10, and increase of CD8(+) cells on day 4. The CD4(+)/CD8(+) ratio decreased on day 4, followed by a rebound thereafter when treated with 3 different doses of CTX. The results indicate that two intraperitoneal injections of CTX at 150 mg/kg at 2-day intervals may establish good immunosuppressive models of Balb/c mice for studying the fungal pathogenicity. PMID- 21530681 TI - First evidence that parasite infecting apparent aparasitemic serological suspects in human African trypanosomiasis are Trypanosoma brucei gambiense and are similar to those found in patients. AB - Thanks to its sensitivity and its ease of use in the field, the card agglutination test for trypanosomiasis (CATT) is widely used for serological screening of Trypanosoma brucei gambiense human African trypanosomiasis (HAT). Positive subjects are then examined by microscopy to confirm the disease. However, the CATT exhibits false-positive results raising the question of whether CATT-positive subjects who are not confirmed by microscopic detection of trypanosomes (SERO) are truly exposed to T.b. gambiense infection. For this purpose, we applied microsatellite genotyping on DNA extracted from blood of both HAT confirmed patients and SERO subjects in Guinea and Cote d'Ivoire since microsatellite genotyping has proved useful for the study of T.b. gambiense genetic diversity. Problems of amplification failures raise the question of the sensitivity of microsatellite markers when applied on biological samples especially from SERO subjects for who low blood parasitaemia are suspected. Nevertheless, we have shown that the trypanosomes from SERO individuals that have been genotyped belong to T.b. gambiense group 1 and were identical to those found in HAT patients. These results constitute the first evidences that at least some SERO are indeed infected by T.b. gambiense group 1 and that they may constitute a human reservoir of parasite in HAT foci. Whether these individuals should undergo treatment remains an open question as long as their role in HAT transmission is unknown. Our results strongly recommend the follow-up of such subjects to improve control strategies. PMID- 21530683 TI - CD4+ T cell depletion changes the cytokine environment from a TH1/TH2 response to a TC17-like response in a murine model of atopic dermatitis. AB - Atopic dermatitis (AD) is a common inflammatory skin disease often associated with co-morbidities including allergic hypersensitivity. We have studied induced AD-like disease in NC/Nga mice using the hapten FITC. Following FITC-treatment the NC/Nga mice develop AD-like skin lesions in regard to the histopathological and immunological changes. Consistent with AD in humans the number of CD4(+) T cells within the blood and draining lymph nodes increases considerably. To evaluate the contribution of T(H) cells on disease development we examined the effect of CD4 depletion. Following CD4 depletion the mice still develop AD-like skin lesions characterized by e.g. increased epidermal proliferation, hyperkeratosis and cellular infiltrate, however, the underlying immunological mechanisms change. CD4 depletion results in increased IL-17A and IL-22 production, which traditionally are associated with T(H)17 cells. Using confocal microscopy, we demonstrate that epidermal CD8(+) cells are positive for IL-17A, indicating that these cells are T(C)17 cells, the cytotoxic T cell counterpart to T(H)17 cells. In conclusion, we show that NC/Nga mice develop AD-like disease following CD4 depletion. This is mirrored by an increased production of IL-17A, which we suggest are produced by T(C)17 cells. These findings support that CD8(+) T cells can play a role in AD. PMID- 21530684 TI - CM-DiI labeled mesenchymal stem cells homed to thymus inducing immune recovery of mice after haploidentical bone marrow transplantation. AB - The results of haploidentical hematopoietic stem cell transplantation (HSCT) have been disappointing due to the high incidence of severe graft-versus-host disease (GVHD) and infectious complications. It is well known that mesenchymal stem cells (MSCs) can prevent severe acute GVHD in HSCT. However, there is a controversy concerning whether MSC-mediated suppression of T cell functions is accompanied by inducing T cells maturation effects after HSCT. The CB6F1((H-2bd)) female mice irradiated with 8 Gy (60)Co gamma-rays were divided into two groups: mice in the MSCs group were infused with MSCs labeled with cm-DiI and mononuclear cells from the bone marrow and spleen of BALB/c((H-2d)) mice; the control group was infused with only the mononuclear cells of BALB/c((H-2d)) mice. After transplantation, chimerisms of donor MSCs were observed in the recipients. The recovery of the T lymphocyte subpopulation, the proliferative activity of T-cells after stimulation with ConA, the mixed lymphocytes' reaction between donor and recipient and three parts, and the number of apoptosis thymus cells were compared in two groups. The results showed that MSCs preferentially homed to the thymus and grew there, a more rapid recovery of T-cells in the peripheral blood, and decreased the apoptosis of the thymocytes. Thus MSCs may affect the thymus in order to improve T-cells maturation and immune system recovery. PMID- 21530685 TI - Vaccination of non-obese diabetic mice with a fragment of peptide P277 attenuates insulin-dependent diabetes mellitus. AB - P277 is a peptide derived from the HSP60 regions, have potent immunological effect on insulin-dependent diabetes mellitus (IDDM) and its phase III clinical trials are currently under investigation. However, we recently discovered a positive correlation between anti-P277 autoantibodies and the presence of endothelial cells damage in inducing vascular leak syndrome. Therefore, the aim of our study was to demonstrate the critical peptide epitope of P277 to IDDM and to highlight the effects of this peptide therapy on inflammation of the islets. Groups of 4-week old female non-obese diabetic (NOD) mice were immunized one time every three weeks for three times with a residue of P277, showing a significant effect of down-regulating immunity to P277 protein and preventing the development of IDDM. Immunologic results including the suppression of T-cell proliferation, the increase of interleukin-10 (IL-10) production and reduction of interferon gamma (IFN-gamma) production caused immune tolerance to P277. Hence, a functional role of the key epitope in P277 peptide capable of preventing IDDM is suggested, which could be modified to develop a novel safe and effective peptide vaccine against IDDM by reconstructing P277 in the further studies. PMID- 21530686 TI - VDAC, a multi-functional mitochondrial protein as a pharmacological target. AB - Regulation of mitochondrial physiology requires an efficient exchange of molecules between mitochondria and the cytoplasm via the outer mitochondrial membrane (OMM). The voltage-dependent anion channel (VDAC) lies in the OMM and forms a common pathway for the exchange of metabolites between the mitochondria and the cytosol, thus playing a crucial role in the regulation of metabolic and energetic functions of mitochondria. VDAC is also recognized to function in mitochondria-mediated apoptosis and in apoptosis regulation via interaction with anti-apoptotic proteins, namely members of Bcl-2 family, and the pro-survival protein, hexokinase, overexpressed in many cancer types. Thus, VDAC appears to be a convergence point for a variety of cell survival and cell death signals, mediated by its association with various ligands and proteins. In this article, we review mammalian VDAC, specifically focusing on VDAC1, addressing its functions in cell life and the regulation of apoptosis and its involvement in several diseases. Additionally, we provide insight into the potential of VDAC1 as a rational target for novel therapeutics. PMID- 21530687 TI - Mitochondrial dysfunction in epilepsy. AB - Mitochondrial dysfunction has been identified as one potential cause of epileptic seizures. Impaired mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and Ammon's horn sclerosis and of adult and immature animal models of epilepsy. Since mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca(2+) homeostasis and generation of reactive oxygen species, their dysfunction strongly affects neuronal excitability and synaptic transmission. Therefore, mitochondrial dysfunction is proposed to be highly relevant for seizure generation. Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a prominent feature of therapy-resistant epilepsy. For this reason mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy. PMID- 21530688 TI - Changes in oxygen sensitivity of TASK in carotid body glomus cells during early postnatal development. AB - A post-natal increase in carotid body (CB) hypoxia responsiveness occurs at the level of carotid sinus nerve activity, intracellular calcium, cell membrane depolarization and hypoxic inhibition of O(2)-sensitive background K(+) conductance. TASK-1, TASK-1/3 and TASK-3 are functionally expressed in CB glomus cells, with TASK-1/3 providing the major part of the O(2)-sensitive TASK-like background K(+) conductance. Here we report the effects of graded hypoxia on TASK like channel activity in CB glomus cells from rats aged 0 to 1, 6 to 7 and 16 to 18 days; the time frame of postnatal CB functional maturation. TASK was active in nearly all cell-attached patches and TASK activity during normoxia did not differ across ages. Hypoxia produced a progressive decrease in channel opening frequency with graded decreases in O(2) level and also produced glomus cell depolarization, as assessed by the shift in reversal potential of TASK single channel current. Hypoxic inhibition of TASK activity was least at P0-P1 and increased with age mainly between 6-7 and 16-18 days. The O(2)-sensitive TASK activity was significantly greater in glomus cells from P16 to P18 when compared to cells from P0 to P1 day old rats. These results support the hypothesis that postnatal carotid body functional maturation is due, at least in part, to changes in the sensitivity of TASK to the hypoxic signals generated in glomus cells. PMID- 21530689 TI - Embryonic control of heart rate: examining developmental patterns and temperature and oxygenation influences using embryonic avian models. AB - Long-term measurements (days and weeks) of heart rate (HR) have elucidated infradian rhythms in chicken embryos and circadian rhythms in chicken hatchlings. However, such rhythms are lacking in emu embryos and only rarely observed in emu hatchlings. Parasympathetic control of HR (instantaneous heart rate (IHR) decelerations) occurs at ~60% of incubation in both precocial and altricial avian embryos, with sympathetic control (IHR accelerations) becoming more prevalent close to hatching. A large increase in avian embryonic HR occurs during hatching (presumably an energetically expensive process, i.e. increased oxygen consumption M(O) 2), beginning during pipping when a physical barrier to O(2) conductance is removed. Alterations in ambient O(2) have little effect on early embryonic HR, likely due to the low rate of M(O)2 of early embryos and the fact that adequate O(2) delivery can occur via diffusion. As M(O)2 increases in advanced embryos and circulatory convection becomes important for O(2) delivery, alterations in ambient O(2) have more profound effects on embryonic HR. Early embryos demonstrate a wide ambient temperature (T(a)) tolerance range compared with older embryos. In response to a rapid decrease in T(a), embryonic HR decreases (stroke volume and blood flow are preserved) in an exponential fashion to a steady state (from which it can potentially recover if re-warmed). A more severe decrease in T(a) results in complete cessation of HR; however, depending on developmental age, embryos are able to survive severe cold exposure and cessation of HR for up to 24h in some instances. The development of endothermy can be tracked by measuring baseline HR during T(a) changes. HR patterns change from thermo conformity to thermoregulation (reverse to T(a) changes). Further, IHR low frequency oscillations mediated by the autonomic nervous system are augmented at low T(a)s in hatchlings. Transitions of baseline HR during endothermic development are unique to individual avian species (e.g. chickens, ducks and emu), reflecting differences in life history. PMID- 21530690 TI - Snake venom metalloproteinases: structure, function and relevance to the mammalian ADAM/ADAMTS family proteins. AB - Metalloproteinases are among the most abundant toxins in many Viperidae venoms. Snake venom metalloproteinases (SVMPs) are the primary factors responsible for hemorrhage and may also interfere with the hemostatic system, thus facilitating loss of blood from the vasculature of the prey. SVMPs are phylogenetically most closely related to mammalian ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin type-1 motif) family of proteins and, together with them, constitute the M12B clan of metalloendopeptidases. Large SVMPs, referred to as the P-III class of SVMPs, have a modular architecture with multiple non-catalytic domains. The P-III SVMPs are characterized by higher hemorrhagic and more diverse biological activities than the P-I class of SVMPs, which only have a catalytic domain. Recent crystallographic studies of P-III SVMPs and their mammalian counterparts shed new light on structure-function properties of this class of enzymes. The present review will highlight these structures, particularly the non-catalytic ancillary domains of P-III SVMPs and ADAMs that may target the enzymes to specific substrates. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome. PMID- 21530691 TI - Aminopropyl-functionalized cubic Ia3d mesoporous silica nanoparticle as an efficient support for immobilization of superoxide dismutase. AB - In this research, the immobilization of superoxide dismutase (SOD) onto aminopropyl-functionalized KIT-6 [n-PrNH(2)-KIT-6] was investigated. This organo functionalized mesoporous silica nanoparticle was prepared using a non-ionic surfactant and was fully characterized by XRD, nitrogen adsorption-desorption isotherm assay, IR and TGA techniques. An activity assay demonstrated that the immobilized SOD had a higher activity than the free enzyme. Further investigations using FT-IR, circular dichroism (CD), and probe 1-anilino-8 naphthalene sulfonate (ANS) fluorescence intensity measurements indicated that the structure of the enzyme did not change upon binding to the mesoporous silica, and that immobilized SOD was also less affected by higher temperatures. The melting temperatures of the free and immobilized enzymes were measured by differential scanning calorimetry (DSC), which showed that a fraction of immobilized enzyme was more stable and revealed that immobilized enzyme was partly reversible. PMID- 21530692 TI - Nano-osteoimmunology as an important consideration in the design of future implants. AB - The size of wear particles emanating from a prosthesis at interfaces is critical to the interfacial properties of the joint replacement and responses from the biological environment. Nanoscale particles in particular require investigation. This project aimed to evaluate the osteoimmunological response to nanoscale ultrahigh molecular weight polyethylene (UHMWPE) wear particles in vitro, including dendritic cells (DCs), macrophages, osteoclasts (OCs), cytokine secretion, and co-cultured OCs and osteoblasts (OBs). The wear particles generated from a constant-load knee prosthesis actuator were profiled using atomic force microscopy and fractionated into sizes of 0.05-0.2, 0.2-0.8, 0.8-1, 1-5 and 5-10 MUm. The fractions were exposed to DCs isolated from mice spleen, human OCs, and co-cultured human OBs and OCs, and the effects of the particles on the cells were determined. Results revealed that exposure to nanoscale UHMWPE wear particles induced significant DC activation (p<0.05) and consequently increased cytokine interleukin (IL)-6 and IL-1beta secretion (p<0.05). Exposure to nanoscale particles promoted OC maturation, resulting in the suppression of OB proliferation in OB and OC co-cultures. Therefore, the results of this study could contribute to a more mechanistic understanding of wear-debris-associated prosthesis failure. Furthermore, nanoscale UHMWPE wear particles should be considered as mediators of periprosthetic inflammation in the future development of biomaterials for joint replacement bearing surfaces. PMID- 21530693 TI - Electroconductive polymeric nanowire templates facilitates in vitro C17.2 neural stem cell line adhesion, proliferation and differentiation. AB - Stem cells still remain one of the most exciting and lucrative options for treatment of a variety of nervous system disorders and diseases. Although there are neural stem cells present in adults, the ability of both the peripheral and central nervous system for self-repair is limited at best. As such, there is a great need for a tissue engineering approach to solve nervous system disorders and diseases. In this study, we have developed electrically conductive surfaces with controlled arrays of high aspect ratio nanowires for the growth and maintenance of neural stem cells. The nanowire surfaces were fabricated from polycaprolactone using a novel nanotemplating technique, and were coated with an electrically conductive polymer, polypyrrole. The polypyrrole-coated nanowire surfaces were characterized using scanning electron microscopy and X-ray photoelectron spectroscopy. Additionally, the surface resistance of polypyrrole coated nanowire surfaces was measured. C17.2 neural stem cells were used to evaluate the efficacy of the polypyrrole-coated nanowire surfaces to promote cell adhesion, proliferation and differentiation. The results presented here indicate significantly higher cellular adhesion and proliferation on polypyrrole-coated nanowire surfaces as compared to control surfaces. The differentiation potential of polypyrrole nanowire surfaces was also evaluated by immunostaining key neuronal markers that are expressed when NSCs differentiate into their respective neural lineages. PMID- 21530694 TI - Synthesis of a novel photopolymerized nanocomposite hydrogel for treatment of acute mechanical damage to cartilage. AB - Intra-articular fractures initiate a cascade of pathobiological and pathomechanical events that culminate in post-traumatic osteoarthritis (PTOA). Hallmark features of PTOA include destruction of the cartilage matrix in combination with loss of chondrocytes and acute mechanical damage (AMD). Currently, treatment of intra-articular fractures essentially focuses completely on restoration of the macroanatomy of the joint. However, current treatment ignores AMD sustained by cartilage at the time of injury. We are exploring aggressive biomaterial-based interventions designed to treat the primary pathological components of AMD. This study describes the development of a novel injectable co-polymer solution that forms a gel at physiological temperatures that can be photocrosslinked, and can form a nanocomposite gel in situ through mineralization. The injectable co-polymer solution will allow the material to fill cracks in the cartilage after trauma. The mechanical properties of the nanocomposite are similar to those of native cartilage, as measured by compressive and shear testing. It thereby has the potential to mechanically stabilize and restore local structural integrity to acutely injured cartilage. Additionally, in situ mineralization ensures good adhesion between the biomaterial and cartilage at the interface, as measured through tensile and shear testing. Thus we have successfully developed a new injectable co-polymer which forms a nanocomposite in situ with mechanical properties similar to those of native cartilage, and which can bond well to native cartilage. This material has the potential to stabilize injured cartilage and prevent PTOA. PMID- 21530695 TI - d-lactate as a marker of venous-induced intestinal ischemia: an experimental study in pigs. AB - BACKGROUND: Intestinal ischemia is difficult to diagnose. The search for biomarkers has led to an increased interest in d-lactate. d-lactate measured in higher concentrations arises from bacterial fermentation in the gastrointestinal tract. Permeable intestinal wall is an early consequence of intestinal ischemia, which allows d-lactate to enter the portal circulation. METHODS: The superior mesenteric vein was clamped in eight pigs for two hours to induce ischemia of the intestine. Eight sham-operated pigs served as controls. Systemic and portal plasma d- and l-lactate, l-LDH and leukocytes were measured. RESULTS: Plasma d lactate increased significantly and nearly simultaneously in the systemic and portal circulation. After 75 min, samples from the jugular vein showed concentrations of .019 +/- .008 mmol/L in the sham group and .042 +/- .022 mmol/L in the intervention group (P = .023). A similar significant effect was seen in the portal circulation after 90 min. l-lactate increased five minutes after clamping in the portal circulation, with values of 3.396 +/- 1.119 mmol/L in the intervention group compared to 1.696 +/- .483 mmol/L in the control group (P = .006). l-LDH increased significantly in the intervention group, while leukocytes were unaffected. l-LDH and l-lactate in plasma led to an overestimation of d lactate if not handled. CONCLUSION: Both systemic d- and l-lactate were markers of venous-induced intestinal ischemia. We speculate that d-lactate may be a valuable aid to the clinician in search of the anaerobic focus, because it may be more specific for mesenteric ischemia than l-lactate, in the sense that it is of bacterial origin. PMID- 21530696 TI - A history of Guy's, King's and St. Thomas' hospitals from 1649 to 2009: 360 years of innovation in science and surgery. AB - Much has been achieved in the scientific and surgical fields over the last 360 years. Some institutions have contributed disproportionately to these advances. The medical schools and hospitals of Guy's (est. 1721), King's (est. 1840) and St. Thomas' (est. 1173) seem to provide a focus and a catalyst for much innovation and creativity dating back to 1608. This review sets to provide an overview of the major contributors to surgical advances at these institutions over the last 360 years and what factors affected unique to these institutions contributed to the climate of discovery. It is based on a lecture given to the Osler Club of London (est. 1928) at the Royal College of Physicians in London on 4 November 2010. It is the author's premise that the people and the discoveries they made within these institutions within three square miles of London changed the practice and understanding of science and healthcare as we know it today. PMID- 21530697 TI - Induced malignant genome reprogramming in somatic cells by testis-specific factors. AB - Germline cell differentiation is controlled by a specific set of genes whose expression is tightly locked into the repressed state in somatic cells. Large scale epigenome alterations, now evidenced in nearly all cancers, lead to aberrant activation of these normally silenced genes, as attested by the many reports describing the expression of testis-specific factors, known as cancer testis genes, in various cancer cells. Here, based on the literature, we argue that off-context activity of some of the testis-specific epigenome regulators can reprogram the somatic cell epigenome toward a malignant state by favoring self renewal and sustaining cell proliferation under stressful conditions, thereby constituting a major oncogenic mechanism. PMID- 21530698 TI - In situ accumulation of advanced glycation endproducts (AGEs) in bone matrix and its correlation with osteoclastic bone resorption. AB - Advanced glycation end products (AGEs) have been observed to accumulate in bone with increasing age and may impose effects on bone resorption activities. However, the underlying mechanism of AGEs accumulation in bone is still poorly understood. In this study, human cortical bone specimens from young (31+/-6years old), middle-aged (51+/-3years old) and elderly (76+/-4years old) groups were examined to determine the spatial-temporal distribution of AGEs in bone matrix and its effect on bone resorption activities by directly culturing osteoclastic cells on bone slices. The results of this study indicated that the fluorescence intensity (excitation wave length 360nm and emission wave length 470+/-40nm) could be used to estimate the relative distribution of AGEs in bone (pentosidine as its marker) under an epifluorescence microscope. Using the fluorescence intensity as the relative measure of AGEs concentration, it was found that the concentration of AGEs varied with biological tissue ages, showing the greatest amount in the interstitial tissue, followed by the old osteons, and the least amount in newly formed osteons. In addition, AGEs accumulation was found to be dependent on donor ages, suggesting that the younger the donor the less AGEs were accumulated in the tissue. Most interestingly, AGEs accumulation appeared to initiate from the region of cement lines, and spread diffusively to the other parts as the tissue aged. Finally, it was observed that the bone resorption activities of osteoclasts were positively correlated with the in situ concentration of AGEs and such an effect was enhanced with increasing donor age. These findings may help elucidate the mechanism of AGEs accumulation in bone and its association with bone remodeling process. PMID- 21530700 TI - Nursing's role in the transformation of health care. PMID- 21530699 TI - Alcohol intake and bone status in elderly Japanese men: baseline data from the Fujiwara-kyo osteoporosis risk in men (FORMEN) study. AB - There are no data concerning a relationship between alcohol and bone status from a large-scale community-based study of elderly Japanese men. The baseline survey for the Fujiwara-kyo Osteoporosis Risk in Men Study was performed in 2174 male participants during the period from 2007 to 2008 in Nara Prefecture, Japan. Among them 1665 fitted the following inclusion criteria: (a) age >=65years, (b) no diseases or drug therapy that could affect bone mineral density (BMD). We analyzed 1421 men with complete information about alcohol intake. We found that alcohol intake and BMD were positively correlated after adjustment for age, body mass index, natto intake, milk intake, smoking, physical activity, education, marital status, and hypertension. Adjusted total hip BMD of men with alcohol intake >39g/day was 0.90g/cm(2) and that of abstainers was 0.85g/cm(2). With regard to bone turnover markers, alcohol intake was inversely associated with serum levels of osteocalcin and tartrate-resistant acid phosphatase isoenzyme 5b. A two-piece linear regression model revealed a positive relationship between alcohol intake and crude mean BMD for the total hip in those with alcohol intake of less than 55g/day. In contrast, alcohol intake and BMD in those with an alcohol intake of 55g/day or more was inversely correlated. The present large scale study of elderly Japanese men revealed that although an alcohol intake of <55g/day was positively correlated to BMD, alcohol intake of >=55g/day was inversely correlated to BMD. PMID- 21530701 TI - Patients' trust in nurses' care. PMID- 21530702 TI - A few minutes with George D. Allen. PMID- 21530703 TI - Defining competency in high-performance teams. PMID- 21530704 TI - Causes of near misses: perceptions of perioperative nurses. AB - The purpose of this study was to examine the near-miss experiences of RNs working in perioperative services to understand their perception of the causes of near misses. The setting was a multi-facility health care system in the mid-Atlantic region of the United States. The study design was descriptive, using a survey of perioperative nurses that was developed for the study. Study participants could complete up to four surveys for near misses that they personally experienced in the perioperative setting. Participants ranked six causal factors (ie, team, workload, task, staff, patient characteristics, hospital characteristics) according to the extent of that factor's contribution to the near miss. The team factor was the most frequently identified cause of near misses, with the top ranked cause as "communication between team." Two causal factor subcategories, "inconsistent information" and "incorrect monitoring," were predominant in the near misses reported. The findings from the study provide an understanding of perioperative nurses' near-miss experiences and detail the frequency of near misses as well as identify types of near-miss causes. PMID- 21530705 TI - Endoscopically assisted correction of sagittal craniosynostosis. AB - Craniosynostosis is premature fusion of one or more of the cranial sutures of an infant's skull. Several sutures may be fused, alone or in combination. The endoscopically assisted approach to correcting craniosynostosis is an alternative to more traditional techniques, such as open-strip craniectomy and the Pi procedure for infants younger than four months of age and the cranial vault remodeling procedure for older children. The endoscopic procedure is less invasive and decreases the time patients spend under anesthesia, the need for transfusions, and lengths of hospital stay. The endoscopic approach relies on early diagnosis and surgery because the bones of very young infants are thin and pliable, which makes it easier to cut and remove the fused suture via a minimally invasive approach. After surgery, a cranial remolding helmet is used to direct skull growth. PMID- 21530706 TI - Eliminating lateral violence in the ambulatory setting: one center's strategies. AB - Lateral violence (eg, disruptive, disparaging, or uncivil behavior inflicted by one peer on another) creates an unpleasant work environment that can have harmful effects on individual nurses, team members, patients, and the bottom line of the health care organization. Educating nurses about the most common forms of lateral violence and strategies for handling inappropriate behavior can be the first step toward eliminating this behavior. Effective nursing leaders develop and maintain a "zero-tolerance" culture that includes clear and concise behavioral expectations and consequences for employees who exhibit unprofessional behavior. Use of a code of conduct, open communication, and quick resolution of issues that arise are strategies that one ambulatory surgery center has used to successfully combat lateral violence in the workplace. PMID- 21530707 TI - AORN Ergonomic Tool 3: lifting and holding the patient's legs, arms, and head while prepping. AB - Lifting the arms, legs, or head of a patient while prepping these areas for surgery can exert strong forces on the muscles and joints of the shoulders and backs of perioperative team members who perform this task, which may lead to work related musculoskeletal disorders. AORN Ergonomic Tool 3: Lifting and Holding the Patient's Legs, Arms, and Head While Prepping provides scientifically based determinations of the amount of weight perioperative personnel can safely lift and hold manually for up to one, two, and three minutes using one hand or both. If these weight limits are exceeded, additional staff members or assistive devices are needed to help with the task. PMID- 21530708 TI - Perioperative pharmacology: a focus on vancomycin. AB - Given the increase in various drug-resistant organisms and in patients who are allergic to penicillin, perioperative nurses are likely to encounter patients who are receiving IV vancomycin, a tricyclic glycopeptide antibiotic. In general, vancomycin is not considered a first-line agent because of its possible adverse effects (e.g., hypotension, phlebitis, nephrotoxicity, ototoxicity); therefore, it is reserved for treating serious or severe infections caused by organisms that are unresponsive to other antimicrobial agents. Vancomycin is administered intravenously over a minimum of 60 minutes to avoid infusion-related reactions. Some considerations for nurses administering vancomycin include ensuring a patent IV line, planning for administration of the preoperative dose as much as two hours before the initial incision is made, and including information about the dose and timing of preoperative vancomycin administration in the surgical time out. PMID- 21530709 TI - Using an alternative site marking form to comply with the Universal Protocol. PMID- 21530710 TI - Managing waiting lists: an Australian case study. PMID- 21530711 TI - The future of nursing and patient safety: the nurse's role. PMID- 21530714 TI - Who "nose" where the airway is? PMID- 21530715 TI - Association of antidepressant medication therapy with inpatient rehabilitation outcomes for stroke, traumatic brain injury, or traumatic spinal cord injury. AB - OBJECTIVE: To study whether outcomes in patients who have undergone inpatient rehabilitation for stroke, traumatic brain injury (TBI), or traumatic spinal cord injury (TSCI) differ based on antidepressant medication (ADM) use. DESIGN: Retrospective cohort study of 867 electronic medical records of patients receiving inpatient rehabilitation for stroke, TBI, or TSCI. Four cohorts were formed within each rehabilitation condition: patients with no history of ADM use and no indication of history of depression; patients with no history of ADM use but with a secondary diagnostic code for a depressive illness; patients with a history of ADM use prior to and during inpatient rehabilitation; and patients who began ADM therapy in inpatient rehabilitation. SETTING: Freestanding inpatient rehabilitation facility (IRF). PARTICIPANTS: Patients diagnosed with stroke (n=625), TBI (n=175), and TSCI (n=67). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FIM, rehabilitation length of stay (LOS), deviation between actual LOS and expected LOS, and functional gain per day. RESULTS: In each impairment condition, patients initiating ADM therapy in inpatient rehabilitation had longer LOS than patients in the same impairment condition on ADM at IRF admission, and had significantly longer LOS than patients with no history of ADM use and no diagnosis of depression (P<.05). LOS for patients initiating ADM therapy as inpatients even exceeded LOS for patients without ADM history, but who had a diagnosis for a depressive disorder. Deviation in LOS was significantly larger in the stroke and TBI groups initiating ADM in IRF than their counterparts with no history of ADM use, illustrating that the group initiating ADM therapy in rehabilitation significantly exceeded expected LOS. Increased LOS did not translate into functional gains, and in fact, functional gain per day was lower in the group initiating ADM therapy in IRF. CONCLUSIONS: Explanations for unexpectedly long LOS in patients initiating ADM in inpatient rehabilitation focus on the potential for ADM to inhibit therapy-driven remodeling of the nervous system when initiated close in time to nervous system injury, or the possibility that untreated sequelae (eg, depressive symptoms or fatigue) were limiting progress in therapy, which triggered ADM treatment. PMID- 21530716 TI - A prospective study to evaluate a residential community reintegration program for patients with chronic acquired brain injury. AB - OBJECTIVE: To examine the effects of a residential community reintegration program on independent living, societal participation, emotional well-being, and quality of life in patients with chronic acquired brain injury and psychosocial problems hampering societal participation. DESIGN: A prospective cohort study with a 3-month waiting list control period and 1-year follow up. SETTING: A tertiary rehabilitation center for acquired brain injury. PARTICIPANTS: Patients (N=70) with acquired brain injury (46 men; mean age, 25.1y; mean time post-onset, 5.2y; at follow up n=67). INTERVENTION: A structured residential treatment program was offered directed at improving independence in domestic life, work, leisure time, and social interactions. MAIN OUTCOME MEASURES: Community Integration Questionnaire (CIQ), Employability Rating Scale, living situation, school, work situation, work hours, Center for Epidemiological Studies Depression Scale, EuroQOL quality of life scale (2 scales), World Health Organization Quality of Life Scale Abbreviated (WHOQOL-BREF; 5 scales), and the Global Assessment of Functioning (GAF) scale. RESULTS: There was an overall significant time effect for all outcome measures (multiple analysis of variance T(2)=26.16; F(36,557) 134.9; P=.000). There was no spontaneous recovery during the waiting list period. The effect sizes for the CIQ, Employability Rating Scale, work hours, and GAF were large (partial eta(2)=0.25, 0.35, 0.22, and 0.72, respectively). The effect sizes were moderate for 7 of the 8 emotional well-being and quality of life (sub)scales (partial eta(2)=0.11-0.20). The WHOQOL-BREF environment subscale showed a small effect size (partial eta(2)=0.05). Living independently rose from 25.4% before treatment to 72.4% after treatment and was still 65.7% at follow up. CONCLUSIONS: This study shows that a residential community reintegration program leads to significant and relevant improvements of independent living, societal participation, emotional well-being, and quality of life in patients with chronic acquired brain injury and psychosocial problems hampering societal participation. PMID- 21530717 TI - Prevalence of 25-hydroxyvitamin D deficiency in the acute inpatient rehabilitation population and its effect on function. AB - OBJECTIVES: To assess the prevalence of 25-hydroxyvitamin D (25[OH]D) insufficiency and deficiency in the acute inpatient rehabilitation setting, identify risk factors associated with low serum 25(OH)D levels, and assess whether hypovitaminosis D affects the function of rehabilitation patients. DESIGN: Retrospective cohort study. SETTING: Academic acute rehabilitation facility. PARTICIPANTS: Patients (N=101) admitted for acute inpatient rehabilitation between September 2008 and December 2008. INTERVENTIONS: Serum 25(OH)D levels drawn within 24 hours of admission. MAIN OUTCOME MEASURES: 25(OH)D level, total/motor/cognitive FIM efficiency. RESULTS: Considering patients not receiving 25(OH)D supplementation at the time of admission, 23.0% were 25(OH)D sufficient, 68.9% were insufficient, and 8.1% were deficient. Patients receiving 25(OH)D supplementation at the time of admission had significantly higher 25(OH)D levels than patients not receiving 25(OH)D supplementation (33.4+/-12.8 vs 23.7+/ 11.4ng/mL; P=.001). A total of 72.2% of patients with any fracture and 80.0% of patients with fracture due to fall were not receiving supplementation at the time of admission; 72.2% of patients with any fracture and 73.3% of patients with fracture due to fall were 25(OH)D insufficient. Unadjusted total FIM efficiency scores were statistically significantly different by 25(OH)D status (2.96+/-1.42 vs 2.29+/-1.41ng/mL; P=.039). However, 25(OH)D level was not a significant predictor of total FIM efficiency score after controlling for demographic and clinical factors. CONCLUSIONS: Of acute rehabilitation patients, 77% are 25(OH)D insufficient or deficient at admission. 25(OH)D supplementation is associated with a greater 25(OH)D level in these patients; however, almost half those supplemented had 25(OH)D levels less than the reference range. Most inpatients with fracture due to fall were transferred to acute inpatient rehabilitation without 25(OH)D supplementation despite clear guidelines indicating its use in this situation. PMID- 21530718 TI - A comparison of discharge functional status after rehabilitation in skilled nursing, home health, and medical rehabilitation settings for patients after lower-extremity joint replacement surgery. AB - OBJECTIVE: To examine differences in outcomes of patients after lower-extremity joint replacement across 3 post-acute care (PAC) rehabilitation settings. DESIGN: Prospective observational cohort study. SETTING: Skilled nursing facilities (SNFs; n=5), inpatient rehabilitation facilities (IRFs; n=4), and home health agencies (HHAs; n=6) from 11 states. PARTICIPANTS: Patients with total knee (n=146) or total hip replacement (n=84) not related to traumatic injury. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Self-care and mobility status at PAC discharge measured by using the Inpatient Rehabilitation Facility Patient Assessment Instrument. RESULTS: Based on our study sample, HHA patients were significantly less dependent than SNF and IRF patients at admission and discharge in self-care and mobility. IRF and SNF patients had similar mobility levels at admission and discharge and similar self-care at admission, but SNF patients were more independent in self-care at discharge. After controlling for differences in patient severity and length of stay in multivariate analyses, HHA setting was not a significant predictor of self-care discharge status, suggesting that HHA patients were less medically complex than SNF and IRF patients. IRF patients were more dependent in discharge self-care even after controlling for severity. For the full discharge mobility regression model, urinary incontinence was the only significant covariate. CONCLUSIONS: For the patients in our U.S.-based study, direct discharge to home with home care was the optimal strategy for patients after total joint replacement surgery who were healthy and had social support. For sicker patients, availability of 24-hour medical and nursing care may be needed, but intensive therapy services did not seem to provide additional improvement in functional recovery in these patients. PMID- 21530719 TI - Factors that predict acute hospitalization discharge disposition for adults with moderate to severe traumatic brain injury. AB - OBJECTIVE: To identify factors predicting acute hospital discharge disposition after moderate to severe traumatic brain injury (TBI). DESIGN: Secondary analysis of existing datasets. SETTING: Acute care hospitals. PARTICIPANTS: Adults hospitalized with moderate to severe TBI included in 3 large sets of archival data: (1) Centers for Disease Control and Prevention Central Nervous System Injury Surveillance database (n=15,646); (2) the National Trauma Data Bank (n=52,012); and (3) the National Study on the Costs and Outcomes of Trauma (n=1286). INTERVENTIONS: None. MAIN OUTCOME MEASURE: Discharge disposition from acute hospitalization to 1 of 3 postacute settings: (1) home, (2) inpatient rehabilitation, or (3) subacute settings, including nursing homes and similar facilities. RESULTS: The Glasgow Coma Scale (GCS) score and length of acute hospital length of stay (LOS) accounted for 35% to 44% of the variance in discharges to home versus not home, while age and sex added from 5% to 8%, and race/ethnicity and hospitalization payment source added another 2% to 5%. When predicting discharge to rehabilitation versus subacute care for those not going home, GCS and LOS accounted for 2% to 4% of the variance, while age and sex added 7% to 31%, and race/ethnicity and payment source added 4% to 5%. Across the datasets, longer LOS, older age, and white race increased the likelihood of not being discharged home; the most consistent predictor of discharge to rehabilitation was younger age. CONCLUSIONS: The decision to discharge to home a person with moderate to severe TBI appears to be based primarily on severity related factors. In contrast, the decision to discharge to rehabilitation rather than to subacute care appears to reflect sociobiologic and socioeconomic factors; however, generalizability of these results is limited by the restricted range of potentially important variables available for analysis. PMID- 21530720 TI - Reliability and validity of ultrasonographic measurements of acromion-greater tuberosity distance in poststroke hemiplegia. AB - OBJECTIVES: The primary aim of this study was to assess the intrarater reliability of ultrasonographic measurements of acromion-greater tuberosity (AGT) distance in patients with stroke using portable ultrasound. A secondary aim was to determine the discriminant validity of the ultrasonographic technique by comparison of AGT distance measurements of stroke-affected and unaffected shoulders. DESIGN: Test-retest design. SETTING: Two local National Health Service hospitals in the South West of England. PARTICIPANTS: Patients with first-time stroke (N=26; 16 men, 10 women; mean age +/- SD, 71+/-10y) with 1-sided weakness who gave informed consent were recruited. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Portable diagnostic ultrasound was used to record measurements on day 1 and again within a fortnight. Bedside measurements were undertaken by a single physical therapist with patients seated upright in a standard hospital chair. Intraclass correlation coefficients (ICCs) and standard errors of measurement were used to assess reliability. Minimum detectable change (MDC90) scores were used to estimate the magnitude of change that is likely to exceed measurement error. Repeated-measures analysis of variance (ANOVA) was used to assess discriminant validity. RESULTS: Mean +/- SD AGT distances on the stroke affected side and unaffected side were 2.3+/-0.6cm and 1.9+/-0.3cm, respectively. ICC for within-day reliability was .98 for the affected shoulder and .95 for the unaffected shoulder. Corresponding values for between-day reliability were .94 and .76. The standard error of measurement for both affected and unaffected shoulders was less than 0.2cm. Within-day MDC90 for the affected shoulder and the unaffected shoulder was +/-0.2cm and +/-0.1cm, respectively. Repeated-measures ANOVA showed a significant difference between mean AGT distance for the affected and unaffected shoulders. CONCLUSIONS: Ultrasonographic measurement of AGT distance demonstrates both intrarater reliability and discriminant validity and has the potential to assess shoulder subluxation in patients with stroke. Research into interrater reliability and concurrent validity of ultrasonographic measurements of AGT distance in patients with stroke is required. PMID- 21530721 TI - Functional and occupational characteristics associated with very early return to work after stroke in Japan. AB - OBJECTIVES: To examine clinical, functional, and occupational factors associated with very early return to work after stroke, and to identify factors manageable through occupational arrangements, patient education, and other welfare programs. DESIGN: Prospective cohort study. SETTING: Acute care of the first stroke event in 21 acute care hospitals specializing in clinical and occupational health. PARTICIPANTS: Consecutive patients with stroke in working age (N=335). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Data pertaining to demographic, clinical, functional, and occupational factors were collected from hospital records. Multiple logistic regression analysis with backward stepwise selection was used to obtain a final model to predict the likelihood of patients returning very early to work. RESULTS: The sample was predominantly men (80%) with a mean age +/- SD of 55.2+/-7.2 years; 30% succeeded in very early return to work. After adjusting for age, sex, and modified Rankin scale at discharge, white collar versus blue-collar occupation (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.00-4.21), Barthel Index at onset (OR, 1.02; 95% CI, 1.01-1.03), and employment status at discharge (OR, 17.36; 95% CI, 3.15-95.72) were selected in the final model as significant predictors of very early return to work. Patients with mild physical disability and higher cortical dysfunction found it more difficult to return to work very early compared with those without these conditions. CONCLUSIONS: We found that patients with stroke who had mild disability at onset, were in a white collar occupation, and were employed at discharge were more likely to return to work very early, even after adjusting for functional levels at discharge. Cognitive rehabilitation is needed for those with mild physical disability and higher cortical dysfunction. PMID- 21530722 TI - Pragmatic lifestyle intervention in patients recovering from colon cancer: a randomized controlled pilot study. AB - OBJECTIVE: To investigate the feasibility of a pragmatic lifestyle intervention in patients who had recently completed surgery and chemotherapy for colon cancer and to obtain preliminary data of its impact on important health outcomes. DESIGN: A prospective, randomized, controlled pilot trial. SETTING: University rehabilitation facility. PARTICIPANTS: Eighteen (N=18) colon cancer survivors (mean age=69y; range, 52-80y), Dukes stage A to C. INTERVENTIONS: Participants were randomized 6 to 24 months postoperatively to either a 12-week program of combined exercise and dietary advice or standard treatment. MAIN OUTCOME MEASURES: Exercise and dietary behavior, fatigue, health-related quality of life (QOL), aerobic exercise tolerance, functional capacity, muscle strength, and anthropometery were assessed at baseline and immediately after the intervention. RESULTS: Adherences to supervised and independent exercise during the intervention were 90% and 94%, respectively, and there was low attrition (6%). The lifestyle intervention elicited improvements in exercise behavior (P=.068), fatigue (P=.005), aerobic exercise tolerance (P=.010), chair sit-to-stand performance (P=.003), and waist-to-hip ratio (P=.002). A positive change in dietary fiber intake (P=.044) was also observed in the intervention group. No change in QOL was observed (P=.795). CONCLUSIONS: These preliminary results suggest that a pragmatic lifestyle intervention implemented 6 to 24 months after primary treatment for colon cancer was feasible. We observed a significant impact on dietary behavior, fatigue, aerobic exercise tolerance, functional capacity, and waist-to-hip ratio. These findings need to be confirmed with a larger-scale definitive randomized controlled trial. PMID- 21530723 TI - Assessment of lymphatic contractile function after manual lymphatic drainage using near-infrared fluorescence imaging. AB - OBJECTIVE: To investigate the feasibility of assessing the efficacy of manual lymphatic drainage (MLD), a method for lymphedema (LE) management, by using near infrared (NIR) fluorescence imaging. DESIGN: Exploratory pilot study. SETTING: Primary care unit. PARTICIPANTS: Subjects (N=10; age, 18-68y) with a diagnosis of grade I or II LE and 12 healthy control subjects (age, 22-59y). INTERVENTION: Indocyanine green (25 MUg in 0.1 mL each) was injected intradermally in bilateral arms or legs of subjects. Diffused excitation light illuminated the limbs, and NIR fluorescence images were collected by using custom-built imaging systems. Subjects received MLD therapy, and imaging was performed pre- and posttherapy. MAIN OUTCOME MEASURES: Apparent lymph velocities and periods between lymphatic propulsion events were computed from fluorescence images. Data collected pre- and post-MLD were compared and evaluated for differences. RESULTS: By comparing pre MLD lymphatic contractile function against post-MLD lymphatic function, results showed that average apparent lymph velocity increased in both the symptomatic (+23%) and asymptomatic (+25%) limbs of subjects with LE and control limbs (+28%) of healthy subjects. The average lymphatic propulsion period decreased in symptomatic (-9%) and asymptomatic (-20%) limbs of subjects with LE, as well as in control limbs (-23%). CONCLUSIONS: We showed that NIR fluorescence imaging could be used to quantify immediate improvement of lymphatic contractile function after MLD. PMID- 21530724 TI - Parent perspectives to inform development of measures of children's participation and environment. AB - OBJECTIVE: To obtain parents' perspectives on children's participation and environment to inform the development of new measures. DESIGN: Descriptive design using qualitative methods with focus groups and semistructured interviews. SETTING: Focus groups and interviews with parents of children with disabilities were held on campus, in the home, and at community agencies; interviews with parents of children without disabilities were conducted in their homes. PARTICIPANTS: Parents (N=42): parents of children with disabilities (n=25) from the United States (n=14) and Canada (n=11) and parents of children without disabilities (n=17) from the United States. Most children (93%) were aged 5 to 16 years. Children with disabilities had diagnoses characterized by psychosocial, learning, attention, and sensory-processing difficulties. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Not applicable. RESULTS: Parents described common life activities and environmental factors that were similar to and expanded on categories currently reported in the literature. Differences identified among parents mainly focused on impairments and challenges of children with disabilities and concerns related to activities and programs designed for them. Parents spontaneously talked about participation and environmental factors together. Their descriptions consistently included information about features of the physical and social environment and other factors that influenced their child's participation, such as demands of the activity, parent strategies, and the child's age, preferences, and abilities. Parents' standards and expectations for their child's participation often varied depending on the specific setting, activity, and situation. CONCLUSIONS: Findings have informed the development of a parent-report measure that explicitly links participation and environmental factors specific to home, school, and community settings. Having 1 measure to assess participation and environment rather than using distinct tools to assess each construct separately should situate the child's participation in real-life contexts. PMID- 21530725 TI - Effects of hippotherapy on gait parameters in children with bilateral spastic cerebral palsy. AB - OBJECTIVES: To evaluate the effects of hippotherapy on temporospatial parameters and pelvic and hip kinematics of gait in children with bilateral spastic cerebral palsy. DESIGN: Nonrandomized prospective controlled trial. SETTING: Outpatient therapy center. PARTICIPANTS: Children (N=32) with bilateral spastic cerebral palsy, Gross Motor Function Classification System level 1 or 2. INTERVENTION: Hippotherapy (30 min twice weekly for 8 consecutive weeks). MAIN OUTCOME MEASURES: Temporospatial parameters and pelvic and hip kinematic parameters in 3 dimensional motion analysis, Gross Motor Function Measure (GMFM)-88, and score for dimensions D (standing) and E (walking, running, jumping) of the GMFM, GMFM 66, and Pediatric Balance Scale (PBS). RESULTS: Hippotherapy significantly improved walking speed, stride length, and pelvic kinematics (average pelvic anterior tilt, pelvic anterior tilt at initial contact, pelvic anterior tilt at terminal stance). Scores for dimension E of the GMFM, GMFM-66 and PBS also increased. CONCLUSIONS: Hippotherapy provided by licensed health professionals using the multidimensional movement of the horse may be used in conjunction with standard physical therapy for improvement of gait and balance in children with bilateral spastic cerebral palsy. PMID- 21530726 TI - Correlation of electromyogram and muscle biopsy in myopathy of young age. AB - OBJECTIVE: To investigate the accuracy of electromyogram (EMG) compared to muscle biopsy in young myopathic patients. DESIGN: Observational study. SETTING: A university rehabilitation hospital. PARTICIPANTS: Cases (N=62) were included if the patient was 18 years or younger, and if data were available from muscle biopsy, EMG, and final clinical diagnosis. INTERVENTION: No intervention. MAIN OUTCOME MEASURE: Sensitivity of EMG. RESULTS: EMG showed myopathic findings in 55 patients, and microscopy revealed myopathy in 50 patients and nonspecific findings in 5 patients. Twenty-eight out of 33 patients showed myogenic EMG findings with a conventional EMG, and histology revealed myopathy in 24 patients. In comparison, turns/amplitude analysis (TAA) with a conventional EMG detected myogenic findings in 27 of 29 patients. Twenty-six of these 27 patients showed myogenic findings in the biopsy. CONCLUSIONS: We concluded that EMG is useful for the detection of myopathy in young patients. In addition, TAA may be helpful in cases of no definite conventional EMG findings and less cooperative patients. PMID- 21530727 TI - The Mini-Mental State Examination and Montreal Cognitive Assessment in persons with mild subacute stroke: relationship to functional outcome. AB - OBJECTIVES: To compare Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) global and subscores in classifying cognitive impairment in persons with mild stroke and to explore the relationship between admission and discharge functional status and improvement. DESIGN: Retrospective analysis of data. SETTING: Acute rehabilitation unit of a large urban university-affiliated hospital. PARTICIPANTS: Inpatients with stroke (N=72; mean age, 70y; median time poststroke, 8.5d) and mild neurologic (median National Institutes of Health Stroke Scale score, 4) and cognitive deficits (median MMSE score, 25). INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Admission cognitive status was assessed by using the MMSE and MoCA. The motor subscale of the FIM instrument (mFIM) and motor relative functional efficiency was used to assess discharge functional status and improvement. RESULTS: The MoCA classified more persons as cognitively impaired than the MMSE (89% vs 63%, respectively; using a cutoff score of 27 on the MMSE and 26 on the MoCA). The MoCA also showed less of a ceiling effect than the MMSE, higher internal reliability (Cronbach alpha=.78 compared with alpha=.60), and marginally stronger associations with discharge functional status (r=.40; P<.001) than the MMSE (r=0.30; P<.05). The MoCA visuoexecutive subscore was the strongest predictor of functional status (P=.01) and improvement (P=.02) in global and subscores for both tests. CONCLUSIONS: The MoCA may be an important cognitive screening tool for persons with stroke and mild cognitive dysfunction on an acute rehabilitation unit. Lower visuoexecutive subscores may assist in identifying persons at risk for decreased functional gains in self-care and mobility (mFIM) during inpatient rehabilitation. The findings justify further validation studies of the MoCA in persons with subacute stroke. PMID- 21530728 TI - Dynamic gait stability, clinical correlates, and prognosis of falls among community-dwelling older adults. AB - OBJECTIVE: To establish an accurate measure for prognostic assessment of fall risk in community-dwelling older adults, this study examined the prediction accuracy of a dynamic gait stability measure and common clinical tests for slip related falls among these adults. DESIGN: Participants were tested for their fall risk likelihood on a slip-test. SETTING: Biomechanics research laboratory. PARTICIPANTS: Community-dwelling older adults (N=119; >=65y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants performed a battery of clinical tests, including Berg Balance Scale, Timed Up & Go (TUG) test, static posturography, isometric muscle strength, and bone density. They were then exposed to an unannounced slip during gait. The dynamic stability during unperturbed gait was measured based on the center of mass position and velocity relative to the limits of stability against backward falling. Accuracy of each measure was examined for prediction of slip outcome (fall or recovery). RESULTS: On the slip, 59 participants fell, 56 recovered their balance, and 4 were harness assisted. Dynamic stability predicted fall outcome with 69% accuracy. Except for TUG and bone density, no other measure could differentiate fallers from nonfallers; TUG predicted 56% of fall outcomes. CONCLUSIONS: Reproduction of actual falls provides a new benchmark for evaluating the prognostic power of different performance-based assessment tools. The TUG was able to better predict fall outcome than other clinical measures; however, the new dynamic gait stability measure was more sensitive than TUG in its prediction of falls. Ultrasound bone scan could be used to screen older adults for fall risk. PMID- 21530729 TI - Walkway length, but not turning direction, determines the six-minute walk test distance in individuals with stroke. AB - OBJECTIVES: To examine (1) the effect of different walkway distances, and (2) turning directions on the six-minute walk test (6MWT) in subjects with stroke. DESIGN: A cross-sectional study. SETTING: University-based rehabilitation center. PARTICIPANTS: Subjects (N=26) with chronic stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Total distance covered and number of turns in the 6MWT with different walkway lengths (10-, 20-, and 30-m walkway distances) and turning directions (turning to affected side and unaffected side); rate of perceived exertion (RPE) using Borg Scale, and heart rate (HR) using handheld pulse oximeter recorded before and immediately after the test. RESULTS: The distance covered and the number of turns in the 6MWT were significantly different between different walkway lengths (P<.05), with the longest distance covered and lowest number of turns in the 30-m walkway distance. For all walkway lengths, turning to the affected or unaffected side did not result in significant differences in the distance covered and the number of turns in the 6MWT. Significant increases were found between the pretest and posttest for the HR and RPE (P<.05) in all testing conditions. There was no significant effect of walkway distance and turning direction on the change in HR and RPE between the 6 conditions of the 6MWT. CONCLUSIONS: Different walkway distances have a significant effect on the distance covered in the 6MWT, whereas turning direction did not significantly affect the distance covered in the 6MWT. PMID- 21530730 TI - Reliability of the parallel walk test for the elderly. AB - OBJECTIVE: To determine interrater agreement and test-retest reliability of the parallel walk test (PWT), a simple method of measuring dynamic balance in the elderly during gait. DESIGN: Cohort study. SETTING: Outpatient clinic. PARTICIPANTS: Elderly fallers (N=34; mean +/- SD age, 81.3+/-5.4y) registered at a falls clinic participated in this study based on Mini-Mental State Examination and Barthel Index scores. INTERVENTIONS: Subjects were timed as they walked 6m between 2 parallel lines on the floor at 3 different widths (20, 30.5, 38cm) wearing their own footwear. They were scored for foot placement on (1 point) or outside the lines (2 points) by 2 separate raters. Fifteen subjects were retested 1 week later. MAIN OUTCOME MEASURES: Footfall score and time to complete the PWT. Intraclass correlation coefficients (ICCs) and 95% limits of agreement were calculated for interrater and test-retest reliability. RESULTS: For widths of 20, 30.5, and 38cm, interrater reliability ICC range was .93 to .99 and test-retest ICC range was .63 to .90. CONCLUSIONS: The PWT was implemented easily by 2 raters with a high degree of interrater reliability. Test-retest reliability was not as high, possibly because of the high susceptibility of variation from 1 week to the next for frail elderly subjects. The 20- and 30.5-cm widths are recommended for future use of the PWT. PMID- 21530731 TI - Do somatic and cognitive symptoms of traumatic brain injury confound depression screening? AB - OBJECTIVE: To evaluate whether items of the Patient Health Questionnaire 9 (PHQ 9) function differently in persons with traumatic brain injury (TBI) than in persons from a primary care sample. DESIGN: This study was a retrospective analysis of responses to the PHQ-9 collected in 2 previous studies. Responses to the PHQ-9 were modeled using item response theory, and the presence of DIF was evaluated using ordinal logistic regression. SETTING: Eight primary care sites and a single trauma center in Washington state. PARTICIPANTS: Participants (N=3365) were persons from 8 primary care sites (n=3000) and a consecutive sample of persons with complicated mild to severe TBI from a trauma center who were 1 year postinjury (n=365). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: PHQ 9. RESULTS: No PHQ-9 item demonstrated statistically significant or meaningful DIF attributable to TBI. A sensitivity analysis failed to show that the cumulative effects of nonsignificant DIF resulted in a systematic inflation of PHQ-9 total scores. Therefore, the results also do not support the hypothesis that cumulative DIF for PHQ-9 items spuriously inflates the numbers of persons with TBI screened as potentially having major depressive disorder. CONCLUSIONS: The PHQ-9 is a valid screener of major depressive disorder in people with complicated mild to severe TBI, and all symptoms can be counted toward the diagnosis of major depressive disorder without special concern about overdiagnosis or unnecessary treatment. PMID- 21530732 TI - Single-lead percutaneous peripheral nerve stimulation for the treatment of hemiplegic shoulder pain: a case report. AB - Previous studies demonstrated the efficacy of 6 weeks of a 4-lead percutaneous, peripheral nerve stimulation system in reducing hemiplegic shoulder pain. This case report describes the first stroke survivor treated for 3 weeks with a less complex, single-lead approach. The participant was a 59-year-old male who developed hemiplegic shoulder pain shortly after his stroke 7.5 years prior to study enrollment and was treated with multiple modalities without sustained pain relief. After study enrollment, a single intramuscular lead was placed percutaneously into the deltoid muscle. He was treated 6 hours per day for 3 weeks and the lead was removed. The primary outcome measure was the Brief Pain Inventory (Short-Form) Question 3 (BPI-3), which queries the worst pain in the last week on a 0 to 10 numeric rating scale. At baseline, BPI 3 was an 8. At the end of treatment and at 1 and 4 weeks after treatment was completed, BPI 3 scores were 3, 2, and 2, respectively. Substantial improvements in quality of life measures were also observed. The participant remained infection-free and the lead was removed fully intact. After completing the study protocol, the participant was followed clinically for 13 months posttreatment with complete resolution of hemiplegic shoulder pain. This case report demonstrates the feasibility of a single-lead peripheral nerve stimulation for the treatment of chronic hemiplegic shoulder pain. Additional studies are needed to further demonstrate safety and efficacy, determine optimal dose, define optimal prescriptive parameters, expand clinical indications, and demonstrate long-term effect. PMID- 21530733 TI - Proof of concept for perturbation-based balance training in older adults at a high risk for falls. AB - OBJECTIVE: To investigate the efficacy of perturbation-based balance training (PBBT) on time to stabilization (TTS) after a nonstepping response to a postural perturbation in older adults at a high risk for falls. DESIGN: Single-subject design. Participants completed 4 baseline tests, 1 month of PBBT, and posttraining tests both 1 week and 1 month after training. SETTING: Assisted living facility. PARTICIPANTS: Older adults (N=5; mean +/- SD age, 85+/-6.5y; residents of assisted-living facility) at a high risk for falls. INTERVENTION: PBBT involved 3 sessions a week for 4 weeks. Each session involved standing for 50 trials on a pneumatic instrumented moving platform that translated 0 to 0.08m forward or 0 to 0.13m backward in approximately 390ms (average velocity, 0.25m/s). MAIN OUTCOME MEASURES: Time to stabilization of center of pressure (COP) after a perturbation on the moving platform. RESULTS: TTS of COP was 41.6% shorter than baseline tests (P<.001) 1 week after completing PBBT and 46.3% shorter than baseline tests (P<.001) 1 month after completing PBBT. CONCLUSIONS: PBBT improved TTS after a postural perturbation in older adults at a high risk for falls, and these improvements were retained for 1 month. PMID- 21530734 TI - Relationship of clinic-based gait speed measurement to limitations in community based activities in older adults. AB - OBJECTIVE: To examine the ability of clinic-based assessments of gait speed to capture limitations in a broad range of home- and community-based activities. DESIGN: Cross-sectional study. SETTING: Community-based aging cohort study. PARTICIPANTS: Community-residing subjects (N=655; 61% women; age >=70y; mean, 80.4y). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Limitations on 3 gait-related activities of daily living (walking inside home, climbing up and down stairs) and 6 motor-based but gait-independent activities (bathing, dressing, getting up from a chair, toileting, shopping, using public transportation). RESULTS: Gait speed was associated with the presence of self-reported difficulty for all 3 home-based activities that were directly gait related and 5 of 6 motor-based activities. Gait speed of 1m/s or less was associated with increased risk for limitations on at least 1 of the 9 selected activities (odds ratio, 3.21; 95% confidence interval, 2.24-4.58; P<.001). CONCLUSIONS: Gait speed measured in clinical settings has ecologic validity as a clinical marker of functional status in older adults for use in clinical and research settings. PMID- 21530735 TI - Inflammatory bowel disease: an update on the fundamental biology and clinical management. PMID- 21530736 TI - Recent insights into the genetics of inflammatory bowel disease. AB - Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemiologic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL. Although CD and UC are both associated with genomic regions that implicate products of genes involved in leukocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-predominant associations include NOD2 and genes that regulate autophagy. In UC, the predominant association signal is on chromosome 6p21, in the major histocompatibility complex region, near HLA class II genes. UC-predominant loci have also implicated genes mediating epithelial defense function. There is a striking overlap of loci between diseases, which could provide comparative insight into mechanisms of disease pathogenesis. Genes that encode factors that function in the interleukin-23 pathway have been associated with a number of chronic inflammatory diseases, notably psoriasis and ankylosing spondylitis. Distinct genetic associations indicate that the colitis associated with primary sclerosing cholangitis is pathophysiologically distinct from UC that is not associated with primary sclerosing cholangitis. As many as 14 susceptibility loci are shared between IBD and celiac disease, indicating significant overlap in pathophysiology. Future genetic studies will be directed toward identifying uncommon variations with potentially greater statistical effects, defining population differences, and more completely accounting for familial transmission of disease. PMID- 21530737 TI - Development of the human gastrointestinal microbiota and insights from high throughput sequencing. AB - Little was known about the development of the gastrointestinal (GI) tract microbiota, until recently, because of difficulties in obtaining sufficient sequence information from enough people or time points. Now, with decreased costs of DNA sequencing and improved bioinformatic tools, we can compare GI tract bacterial communities among individuals, of all ages from infancy to adulthood. Some key recent findings are that the initial bacterial community, even in the GI tract, depends strongly on delivery mode; that the process of early development of the microbiota is highly unstable and idiosyncratic; that the microbiota differs considerably among children from different countries; and that older adults have substantially different GI tract communities than younger adults, indicating that the GI tract microbiota can change throughout life. We relate these observations to different models of evolution including the evolution of senescence and suggest that probiotics be selected based on patient age. Studies of the microbiota in older people might tell us which probiotics could increase longevity. Drug metabolism varies among individuals with different microbial communities, so age- and region-specific clinical trials are required to ensure safety and efficacy. PMID- 21530738 TI - The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases. AB - Intestinal inflammation arises from abnormal host-microbe interactions. The perturbations of homeostatic coexistence involve host genetic factors, barrier function, innate and adaptive immunity, as well as qualitative and quantitative changes in the composition of the microbiota. Dysbiosis toward selected micro organisms and decreased complexity of commensal bacteria have been observed in patients with Crohn's disease and ulcerative colitis, but it is not clear whether the dysbiosis contributes to development of inflammatory bowel disease or is instead a consequence of the disease. Pathogens with virulence factors that allow them to breach the intestinal barrier and induce chronic inflammation might mediate the pathogenesis of these diseases. To identify new therapeutic approaches for inflammatory bowel disease, it is important to identify host susceptibility factors involved in the control of microbial infection, characterize potential pathogens, and eliminate them or block the expression of their virulence factors. PMID- 21530739 TI - Interactions between the host innate immune system and microbes in inflammatory bowel disease. AB - The intestinal immune system defends against pathogens and entry of excessive intestinal microbes; simultaneously, a state of immune tolerance to resident intestinal microbes must be maintained. Perturbation of this balance is associated with intestinal inflammation in various mouse models and is thought to predispose humans to inflammatory bowel disease (IBD). The innate immune system senses microbes; dendritic cells, macrophages, and epithelial cells produce an initial, rapid response. The immune system continuously monitors resident microbiota and utilizes constitutive antimicrobial mechanisms to maintain immune homeostasis. associations between IBD and genes that regulate microbial recognition and innate immune pathways, such as nucleotide oligomerization domain 2 (Nod2), genes that control autophagy (eg, ATG16L1, IRGM), and genes in the interleukin-23-T helper cell 17 pathway indicate the important roles of host microbe interactions in regulating intestinal immune homeostasis. There is increasing evidence that intestinal microbes influence host immune development, immune responses, and susceptibility to human diseases such as IBD, diabetes mellitus, and obesity. Conversely, host factors can affect microbes, which in turn modulate disease susceptibility. We review the cell populations and mechanisms that mediate interactions between host defense and tolerance and how the dysregulation of host-microbe interactions leads to intestinal inflammation and IBD. PMID- 21530740 TI - Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial function in inflammatory bowel disease. AB - Increasing evidence has emerged that supports an important intersection between 3 fundamental cell biologic pathways in the pathogenesis of inflammatory bowel disease. These include the intersection between autophagy, as revealed by the original identification of ATG16L1 and IRGM as major genetic risk factors for Crohn's disease, and intracellular bacterial sensing, as shown by the importance of NOD2 in autophagy induction upon bacterial entry into the cell. A pathway closely linked to autophagy and innate immunity is the unfolded protein response, initiated by endoplasmic reticulum stress due to the accumulation of misfolded proteins, which is genetically related to ulcerative colitis and Crohn's disease (XBP1 and ORMDL3). Hypomorphic ATG16L1, NOD2, and X box binding protein-1 possess the common attribute of profoundly affecting Paneth cells, specialized epithelial cells at the bottom of intestinal crypts involved in antimicrobial function. Together with their functional juxtaposition in the environmentally exposed intestinal epithelial cell, their remarkable functional convergence on Paneth cells and their behavior in response to environmental factors, including microbes, these 3 pathways are of increasing importance to understanding the pathogenesis of inflammatory bowel disease. Moreover, in conjunction with studies that model deficient nuclear factor-kappaB function, these studies suggest a central role for altered intestinal epithelial cell function as one of the earliest events in the development of inflammatory bowel disease. PMID- 21530741 TI - Hypoxia and metabolic factors that influence inflammatory bowel disease pathogenesis. AB - The gastrointestinal epithelium is anatomically positioned to provide a selective barrier between the anaerobic lumen and lamina propria, which has a high rate of metabolism. Supported by a complex vasculature, this important barrier is affected by reduced blood flow and resultant tissue hypoxia, particularly during the severe metabolic shifts associated with active inflammation in individuals with inflammatory bowel disease. Activation of hypoxia-inducible factor (HIF) under these conditions promotes resolution of inflammation in mouse models of disease. Protective influences of HIF are attributed, in part, to the complex regulation of barrier protection with the intestinal mucosa. Reagents that activate HIF, via inhibition of the prolyl hydroxylase enzymes, might be developed to induce hypoxia-mediated resolution in patients with intestinal mucosal inflammatory disease. PMID- 21530743 TI - Regulation of homeostasis and inflammation in the intestine. AB - The gastrointestinal tract is the largest immune interface with the environment. Exposure to large numbers of dietary and microbial antigens requires complex and highly regulated immune responses by different mucosal cell types, which result in the induction and maintenance of intestinal homeostasis. Defects in this equilibrium can disrupt the homeostatic mechanisms and lead to chronic intestinal inflammation. We review the cell populations and mechanisms involved in the control of intestinal homeostasis and inflammation, focusing on inflammatory bowel diseases. We describe some aspects of gut immunity that could alter the delicate balance between inflammatory and tolerogenic responses and result in chronic gastrointestinal tract inflammation in patients. PMID- 21530742 TI - Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. AB - The cytokine responses characterizing the inflammatory bowel diseases are the key pathophysiologic elements that govern the initiation, evolution, and, ultimately, the resolution of these forms of inflammation. Studies during the last 2 decades now provide a detailed (but not yet complete) picture of the nature of these responses. The first tier of cytokine responses are governed by the T-cell differentiation patterns dominating the disease. In Crohn's disease, the major cytokines arise from T-helper cell (Th) 1 and Th17 CD4(+) T-cell differentiation and consist of interferon-gamma and interleukin (IL)-17/IL-22 generated by these types of differentiation. The relative importance of these cytokines to Crohn's inflammation is still unclear, although evidence is mounting that interferon gamma is primus inter pare (first among equals). In contrast, in ulcerative colitis, a Th2-like differentiation process is paramount, which results in expansion of natural killer T cells producing IL-13 (and perhaps IL-5). These disease-specific cytokine patterns give rise to a second tier of cytokines that span the Th1/Th17-Th2 divide and act as upstream facilitators and downstream mediators of inflammation. These cytokines include the well-known tumor necrosis factor-alpha, IL-1beta, IL-6 triumphirate, as well as a more recently studied cytokine known as TL1A (tumor necrosis factor-like ligand). In this review, we will explore this cytokine landscape with the view of providing an understanding of how recent and future anticytokine therapies actually function. PMID- 21530745 TI - Epidemiology and natural history of inflammatory bowel diseases. AB - In the West, the incidence and prevalence of inflammatory bowel diseases has increased in the past 50 years, up to 8-14/100,000 and 120-200/100,000 persons, respectively, for ulcerative colitis (UC) and 6-15/100,000 and 50-200/100,000 persons, respectively, for Crohn's disease (CD). Studies of migrant populations and populations of developing countries demonstrated a recent, slow increase in the incidence of UC, whereas that of CD remained low, but CD incidence eventually increased to the level of UC. CD and UC are incurable; they begin in young adulthood and continue throughout life. The anatomic evolution of CD has been determined from studies of postoperative recurrence; CD begins with aphthous ulcers that develop into strictures or fistulas. Lesions usually arise in a single digestive segment; this site tends to be stable over time. Strictures and fistulas are more frequent in patients with ileal disease, whereas Crohn's colitis remains uncomplicated for many years. Among patients with CD, intestinal surgery is required for as many as 80% and a permanent stoma required in more than 10%. In patients with UC, the lesions usually remain superficial and extend proximally; colectomy is required for 10%-30% of patients. Prognosis is difficult to determine. The mortality of patients with UC is not greater than that of the population, but patients with CD have greater mortality than the population. It has been proposed that only aggressive therapeutic approaches, based on treatment of early recurrent lesions in asymptomatic individuals, have a significant impact on progression of these chronic diseases. PMID- 21530744 TI - Blocking lymphocyte localization to the gastrointestinal mucosa as a therapeutic strategy for inflammatory bowel diseases. AB - Lymphocyte migration (homing) to specific tissues has an important role during protective and pathological immune responses, including inflammatory bowel diseases. Lymphocytes use integrin alpha4beta7 and the chemokine receptor CCR9 to localize to the gastrointestinal mucosa; their respective ligands, mucosal addressin cell adhesion molecule-1 and CCL25, are displayed on endothelial cells in intestinal postcapillary venules. Although gastrointestinal-homing receptors are required for lymphocyte migration to the intestine in the noninflamed steady state, their role during inflammation is a matter of debate. Reagents designed to block interactions between these receptors and their ligands have had variable degrees of success in animal models of inflammatory bowel diseases and patients. We discuss the mechanisms involved in lymphocyte localization to the intestinal mucosa and how they can be applied to therapy for inflammatory bowel diseases. PMID- 21530746 TI - New concepts in intestinal imaging for inflammatory bowel diseases. AB - In the last decade, multiple imaging technologies have been developed that improve visualization of the mucosal, mural, and perienteric inflammation associated with inflammatory bowel diseases. Whereas these technologies have traditionally been used to detect and stage suspected enteric inflammation, we review new, emerging roles in detecting clinically occult inflammation (in asymptomatic patients) and inflammatory complications, predicting response prior to therapy, assessing response after therapy, and enteric healing. We compare the relative performance of these technologies in detecting inflammation, focusing on their advantages and disadvantages and how they might complement each other. We also discuss their potential benefits for patients and clinical trials, reviewing technologic developments and areas of research that could provide important insights into the pathophysiology of inflammatory bowel diseases-related enteric inflammation. PMID- 21530747 TI - Intestinal inflammation and cancer. AB - Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer (CRC). Chronic inflammation is believed to promote carcinogenesis. The risk for colon cancer increases with the duration and anatomic extent of colitis and presence of other inflammatory disorders (such as primary sclerosing cholangitis), whereas it decreases when patients take drugs to reduce inflammation (such as mesalamine and steroids). The genetic features that lead to sporadic CRC-chromosome instability, microsatellite instability, and DNA hypermethylation-also occur in colitis-associated CRC. Unlike the normal colonic mucosa, cells of the inflamed colonic mucosa have these genetic alterations before there is any histologic evidence of dysplasia or cancer. The reasons for these differences are not known, but oxidative stress is likely to be involved. Reactive oxygen and nitrogen species produced by inflammatory cells can affect regulation of genes that encode factors that prevent carcinogenesis (such as p53, DNA mismatch repair proteins, and DNA base excision-repair proteins), transcription factors (such as nuclear factor-kappaB), or signaling proteins (such as cyclooxygenases). Administration of agents that cause colitis in healthy rodents or genetically engineered, cancer-prone mice accelerates development of colorectal tumors. Mice genetically prone to inflammatory bowel disease also develop CRC, especially in the presence of bacterial colonization. Individual components of the innate and adaptive immune response have also been implicated in carcinogenesis. These observations offer compelling support for the role of inflammation in colon carcinogenesis. PMID- 21530749 TI - Conventional medical management of inflammatory bowel disease. AB - Conventional therapies for ulcerative colitis and Crohn's disease (CD) include aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti-tumor necrosis factor agents. A time-structured approach is required for appropriate management. Traditional step-up therapy has been partly replaced during the last decade by potent drugs and top-down therapies, with an accelerated step-up approach being the most appropriate in the majority of patients. When patients are diagnosed with CD or ulcerative colitis, physicians should consider the probable pattern of disease progression so that effective therapy is not delayed. This can be achieved by setting arbitrary time limits for administration of biological therapies, changing therapy from mesalamine in patients with active ulcerative colitis, or using rescue therapy for acute severe colitis. In this review, we provide algorithms with a time-structured approach for guidance of therapy. Common mistakes in conventional therapy include overprescription of mesalamine for CD; inappropriate use of steroids (for perianal CD, when there is sepsis, or for maintenance); delayed introduction or underdosing with azathioprine, 6-mercaptopurine, or methotrexate; and failure to consider timely surgery. The paradox of anti-tumor necrosis factor therapy is that although it too is used inappropriately (when patients have sepsis or fibrostenotic strictures) or too frequently (for diseases that would respond to less-potent therapy), it is also often introduced too late in disease progression. Conventional drugs are the mainstay of current therapy for inflammatory bowel diseases, but drug type, timing, and context must be optimized to manage individual patients effectively. PMID- 21530751 TI - The use of a coded healing abutment as an impression coping to design and mill an individualized anatomic abutment: a clinical report. AB - A coded implant healing abutment makes an impression at the implant level no longer necessary. An impression is made of the healing abutment, which is placed onto the implant directly after implant placement. The codes embedded in the occlusal surface of the healing abutment provide essential information for the computer software to place the implant analog in the definitive cast and to design and mill the definitive abutment. PMID- 21530748 TI - The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease. AB - Fecal and serologic biomarkers can be used in the diagnosis and management of inflammatory bowel disease (IBD). Fecal markers such as calprotectin and lactoferrin have been studied for their ability to identify patients with IBD, assess disease activity, and predict relapse. Antibodies against Saccharomyces cerevisiae and perinuclear antineutrophil cytoplasmic proteins have been used in diagnosis of IBD, to distinguish Crohn's disease (CD) from ulcerative colitis, and to predict the risk of complications of CD. Tests for C-reactive protein and erythrocyte sedimentation rate have been used to assess inflammatory processes and predict the course of IBD progression. Levels of drug metabolites and antibodies against therapeutic agents might be measured to determine why patients do not respond to therapy and to select alternative treatments. This review addresses the potential for biomarker assays to improve treatment strategies and challenges to their use and development. PMID- 21530750 TI - Future therapeutic approaches for inflammatory bowel diseases. AB - In this review, we speculate about future therapeutic approaches for inflammatory bowel diseases (IBDs), focusing on the need for better preclinical and clinical models and approaches beyond small molecules and systemically administered biologics. We offer ideas to change clinical trial programs and to use immunologic and genetic biomarkers to personalize medicine. We attempt to reconcile past therapeutic successes and failures to improve future approaches. Some of our ideas might be provocative, but we hope that the examples we provide will stimulate discussion about what will advance the field of IBD therapy. PMID- 21530752 TI - Consequences of insufficient treatment planning for flapless implant surgery for a mandibular overdenture: a clinical report. AB - Flapless implant surgery is an emerging modality of treatment in implant dentistry that is known to offer several advantages. However, this procedure is inadvisable for situations where there is an absence of labial/buccal bone, reduced width of alveolar ridge, or a need for alveoloplasty to create prosthetic space. This clinical report describes the biologic and prosthodontic consequences of placing implants through flapless surgery and without preoperative treatment planning. Importance of proper treatment planning and a detailed discussion of prosthetic/restorative space analysis are discussed. PMID- 21530753 TI - Reconstruction of a maxillectomy patient with an osteocutaneous flap and implant retained fixed dental prosthesis: a clinical report. AB - This clinical report describes a multidisciplinary approach in the implant rehabilitation of a 53-year-old white male diagnosed with chondrosarcoma. Following a maxillectomy and insertion of a surgical obturator, the patient was unable to adapt physically and psychologically to the removable prosthesis. The patient underwent a microvascular free tissue transfer using an osteocutaneous free fibula flap to reconstruct a right/left infrastructure maxillectomy defect, a soft tissue modification of the skin component using an implant retained stent, and placement of maxillary dental implants to retain a fixed prosthesis. Prosthodontic planning and treatment considerations are discussed. PMID- 21530754 TI - Effect of metal primers on microtensile bond strength between zirconia and resin cements. AB - STATEMENT OF PROBLEM: There are no established clinical procedures for bonding zirconia to tooth structure using resin cements. PURPOSE: The purpose of this study was to evaluate the influence of metal primers, resin cements, and aging on bonding to zirconia. MATERIAL AND METHODS: Zirconia was treated with commercial primers developed for bonding to metal alloys (Metaltite, Metal Primer II, Alloy Primer or Totalbond). Non-primed specimens were considered as controls. One hundred disk-shaped specimens (19 * 4 mm) were cemented to composite resin substrates using Panavia or RelyX Unicem (n=5). Microtensile bond strength specimens were tested after 48 hours and 5 months (150 days), and failure modes were classified as type 1 (between ceramic/cement), 2 (between composite resin/cement) or 3 (mixed). Data were analyzed by 3-way ANOVA and Multiple Comparison Tukey test (alpha=.05). RESULTS: The interactions primer/luting system (P=.016) and luting system/storage time (P=.004) were statistically significant. The use of Alloy Primer significantly improved the bond strength of RelyX Unicem (P<.001), while for Panavia, none of the primers increased the bond strength compared to the control group. At 48 hours, Panavia had statistically higher bond strength (P=.004) than Unicem (13.9 +/- 4.4 MPa and 10.2 +/- 6.6 MPa, respectively). However, both luting systems presented decreasing, statistically similar, values after aging (Panavia: 3.6 +/- 2.2 MPa; Unicem: 6.1 +/- 5.3 MPa). At 48 hours, Alloy Primer/Unicem had the lowest incidence of type 1 failure (8%). After aging, all the groups showed a predominance of type 1 failures. CONCLUSIONS: The use of Alloy Primer improved bond strength between RelyX Unicem and zirconia. Though the initial values obtained with Panavia were significantly higher than RelyX Unicem, after aging, both luting agents presented statistically similar performances. PMID- 21530755 TI - Translucency of shaded zirconia core material. AB - STATEMENT OF PROBLEM: With the development of various zirconia core shades, questions arise regarding the effect of the shaded zirconia on the translucency of ceramic crowns. PURPOSE: The purpose of this study was to investigate the translucency of the 3 Procera Zirconia shaded core materials. The hypothesis was that differences exist in the translucency of various shaded zirconia cores. MATERIAL AND METHODS: Disk-shaped (0.6 +/- 0.01 * 12 mm) zirconia core (Procera Zirconia) specimens (n=90) were fabricated by the manufacturer using a CAD/CAM process. The disks were fabricated in 3 groups according to shade (light, medium, intense) (n=30). A spectrophotometer was used to measure contrast ratio (CR) which is indicative of translucency. One-way ANOVA was conducted to determine significant differences among the shades (alpha=.05). RESULTS: A significant difference in translucency between the light and intense shades (P=.030) and the medium and intense shades (P<.001) was observed. There was no significant difference between the light and medium shades (P=.15). CONCLUSIONS: Shaded zirconia is partially translucent. In addition, significant differences in translucency measurements were identified between specific shades. PMID- 21530756 TI - The effect of slurry preparation methods on biaxial flexural strength of dental porcelain. AB - STATEMENT OF PROBLEM: One-step and incremental mixing procedures are currently used to produce dental ceramic pastes. In the ceramic industry, high quality is obtained using one-step mixing, but in dentistry, the best method has not been yet determined. PURPOSE: The purpose of this study is to evaluate the effects of 2 mixing techniques on the biaxial flexural strength and microstructure of dental porcelain. MATERIAL AND METHODS: Feldspathic porcelain discs (2 * 15 mm in diameter) were produced and divided according to the ceramic paste preparation method, powder-liquid incremental mixing group (n=50) or one-step mixing, as a control group (n=50). Specimens were tested for biaxial flexural strength and characterized using porosimetry, relative humidity, SEM/EDS, XRD, and FT-IR analyses. Statistical analysis was conducted using Weibull statistics. The Weibull modulus, characteristic strength and relative humidity were compared between groups, using Student's t-test and Mann-Whitney U test (alpha=.05). RESULTS: The powder-liquid incremental mixing group showed significantly higher values (SD) of Weibull modulus (6.74 (0.70), P<.001) and characteristic strength (79.87 (2.01) MPa, P<.001) when compared to the one-step mixing group (4.94 (0.94) and 75.95 (2.61) MPa). Significantly lower mean (SD) relative humidity values (P=.009) were found for powder-liquid incremental mixing group (20% (0.5%)) compared to one-step mixing group (22% (1%)). XRD spectra showed that the one-step mixing group produced higher amounts of the amorphous phase. CONCLUSIONS: Specimens produced by the incremental mixing technique showed higher biaxial flexural strength than one-step mixing. PMID- 21530757 TI - Effect of zirconia surface treatments on the shear bond strength of veneering ceramic. AB - STATEMENT OF PROBLEM: Various surface treatments of zirconia have been recommended for veneering ceramics. However, it has not been determined which of these treatments produces the highest bond strength. PURPOSE: This study examined the effects of various surface treatments on the shear bond strength of zirconia and veneering ceramic. MATERIAL AND METHODS: Square-shaped (5 * 10 * 10 mm) zirconia (Everest) specimens were divided into 4 groups (n=8) according to surface treatment as follows: group C, grinding with #320 diamond disc (control); group A, airborne-particle abrasion with 110 MUm Al(2)O(3); group L, application of liner (Cerabien); and group AL, airborne-particle abrasion with 110 MUm Al(2)O(3) and application of liner. A cylinder of veneering ceramic (2.4 mm in diameter and 3 mm in height) (Cerabien) was fabricated and fired on the zirconia specimens. The shear bond strength was tested using a universal testing machine. The data were analyzed statistically using a 1-way ANOVA and Tukey's multiple comparisons test (alpha=.05). The interface and fractured surfaces of the specimens were also evaluated by field emission scanning electron microscopy (FE SEM). RESULTS: The mean and SD values for the shear bond strength of the groups ranged from 27.87 +/- 3.59 MPa (for group L) to 36.63 +/- 2.96 MPa (for group A). The 1-way ANOVA revealed a significant difference between groups (P=.001). The airborne-particle abrasion group showed significantly higher bond strength than liner applied groups (L, AL) (P<.05). The SEM revealed that liner-applied groups (L, AL) showed primarily adhesive failure. Complete delamination and microspaces were also observed in the liner-applied groups. CONCLUSIONS: The mean in vitro shear bond strength of veneering ceramic on zirconia treated with airborne particle abrasion was significantly higher than that subjected to liner-applied treatments. PMID- 21530758 TI - Effects of N-vinylcaprolactam containing polyelectrolytes on hardness, fluoride release and water sorption of conventional glass ionomers. AB - STATEMENT OF PROBLEM: N-vinylcaprolactam (NVC) containing glass ionomers are promising dental restorative materials with improved mechanical properties; however, little information is available on other physical properties of this type of modified glass ionomer, especially their water sorption, fluoride releasing properties and microhardness. PURPOSE: The purpose of this study was to investigate the effects of NVC-containing polyelectrolytes on microhardness, fluoride release and water sorption of conventional glass ionomer cements (GIC). MATERIAL AND METHODS: The terpolymer of acrylic acid (AA), itaconic acid (IA) and N-vinylcaprolactam (NVC) with 8:1:1 and 7:1:2 (AA: IA: NVC) molar ratios was synthesized by free radical polymerization and characterized using 1H-NMR and FTIR. Experimental GIC specimens were made from a 50% solution of the synthesized terpolymer with Fuji IX powder in a 3.6:1 P/L ratio. Specimens were mixed and fabricated at room temperature. Vickers hardness was determined using a microhardness tester. Water sorption and fluoride releasing properties were also investigated. Commercial Fuji IX was used as the control group. All specimens were first conditioned in distilled water at 37 degrees C for 1 day up to 1 month. Results for the experimental GIC were compared with the control group, using 1-way and 2-way ANOVA and the Tukey multiple range test (alpha=.05). RESULTS: The NVC-modified GIC exhibited higher mean values of Vickers hardness numbers (VHN). However, the data exhibited no statistically significant differences between the experimental and control groups. The experimental cement (TP2) absorbed significantly more water than the control group (P<.034). Additionally, NVC-containing specimens showed comparable fluoride releasing properties with almost the same fluoride burst and continued fluoride release from the bulk of the material. CONCLUSIONS: It was concluded that a hydrophilic monomer such as NVC might be able to increase the water sorption and decrease the amount of initial fluoride release of the glass ionomers. Hydrophilic monomer such as NVC might be able to increase the water sorption and decrease the amount of initial fluoride release of the glass ionomers. PMID- 21530759 TI - Classification and management of restorative space in edentulous implant overdenture patients. AB - A classification system of available vertical restorative space (from the crest of the soft tissue edentulous ridge to the proposed occlusal plane) is introduced for edentulous arches to be restored with implant overdentures. The Class I arch has available vertical restorative space equal to or greater than 15 mm. An arch with 12 to 14 mm of available vertical restorative space is categorized as Class II. Class III represents an arch with 9 to 11 mm of available space, while an arch with less than 9 mm of vertical restorative space is categorized as Class IV. A review of clinical procedures designed to improve vertical space availability is provided, including alveoloplasty, intentional increase of occlusal vertical dimension, occlusal plane repositioning and management of overdenture attachment selection. The authors stress the importance of considering vertical restorative space and its management for implant overdenture patients during treatment planning prior to implant placement. PMID- 21530760 TI - Effects of rigid and nonrigid extracoronal attachments on supporting tissues in extension base partial removable dental prostheses: a nonlinear finite element study. AB - STATEMENT OF PROBLEM: Resilient (nonrigid) and non-resilient (rigid) attachments are used in extension base partial removable dental prostheses for retention. However, the biomechanical effects of these 2 types of retainers on the terminal abutment and supporting tissues, which may influence clinical treatment planning, have not been compared. PURPOSE: The purpose of this study was to compare the mechanical effects of 2 types of extracoronal attachments (rigid and nonrigid) in distal extension removable partial prostheses on the alveolar ridge and abutment tooth periodontal ligament. MATERIAL AND METHODS: A finite element model of a human left mandible edentulous arch distal to the second premolar was fabricated. The second premolar was the terminal abutment for an attachment-retained denture. Two types of attachments (rigid and nonrigid) were modeled in the study. For the nonrigid attachment, there was movement between the patrix and matrix component of the attachment, but there was no movement between the 2 component parts for the rigid attachment. Six levels of loading (100, 150, 200, 250, 300, and 350 N) were applied from 3 directions (axial, buccolingual, and mesiodistal) on the central fossa of the first and second molars. Denture motion and stress distributions of denture supporting tissues were observed. Maximum equivalent stress values (SEQV) were recorded for 6 regions (cervical bone, cervical and apical periodontal ligaments, mesial and distal ridges, and mucosa). The data were divided into 2 groups according to the attachment type. Paired t tests were used to compare the values of the 2 groups. Factorial ANOVA was used to test the difference between the loading directions (alpha=.05). Multiple linear regression was used to analyze the interactions among the factors of region, direction, and level (alpha=.05). RESULTS: Stress distributions in the rigid and nonrigid attachment models were similar but the magnitudes were different. For all 3 loading directions, significantly different stresses in the alveolar ridge and periodontal tissue of the terminal abutment were found between the rigid and nonrigid groups (P<.05). There were significant differences among the 3 loading directions (P<.05). In the nonrigid group, the stress ratio of the mesial to the distal area was higher than that of the rigid group from axial and mesiodistal loading (P<.05). Linear interactions were found between the direction and level and region and level combinations (P<.05). Movement between the patrix and matrix components increased as loading increased. The most obvious movement of attachment occurred when loading was in the buccolingual direction. CONCLUSIONS: Stress on the terminal abutment can be reduced by the use of an extracoronal resilient attachment that allocates more loads onto the distal edentulous ridge. The level of loading influenced the extent of reduction. A resilient attachment with a universal hinge had the most movement when loading was in the buccolingual direction. Interactions were found between direction and level, as well as region and level combinations (P<.05). PMID- 21530761 TI - A technique for effective shade modification of a provisional restoration. PMID- 21530762 TI - Delaware School Climate Survey-Student: its factor structure, concurrent validity, and reliability. AB - The Delaware School Climate Survey-Student (DSCS-S) was developed to provide schools with a brief and psychometrically sound student survey for assessing school climate, particularly the dimensions of social support and structure. Confirmatory factor analyses, conducted on a sample of 11,780 students in 85 schools, showed that a bifactor model consisting of five specific factors and one general factor (School Climate) best represented the data. Those five factors are represented in five subscales of the DSCS-S: Teacher-Student Relations, Student Student Relations, Fairness of Rules, Liking of School, and School Safety. The factor structure was shown to be stable across grade levels (i.e., elementary, middle, and high school), racial-ethnic groups (i.e., Caucasian, African American, and Hispanic), and gender. As evidence of the survey's concurrent validity, scores for each of the five subscales and the total scale correlated moderately, across groups and at the school level, with academic achievement and suspensions and expulsions. PMID- 21530763 TI - The role of context in preschool learning: a multilevel examination of the contribution of context-specific problem behaviors and classroom process quality to low-income children's approaches to learning. AB - Research suggests that promoting adaptive approaches to learning early in childhood may help close the gap between advantaged and disadvantaged children. Recent research has identified specific child-level and classroom-level variables that are significantly associated with preschoolers' approaches to learning. However, further research is needed to understand the interactive effects of these variables and determine whether classroom-level variables buffer the detrimental effects of child-level risk variables. Using a largely urban and minority sample (N=275) of preschool children, the present study examined the additive and interactive effects of children's context-specific problem behaviors and classroom process quality dimensions on children's approaches to learning. Teachers rated children's problem behavior and approaches to learning and independent assessors conducted classroom observations to assess process quality. Problem behaviors in structured learning situations and in peer and teacher interactions were found to negatively predict variance in approaches to learning. Classroom process quality domains did not independently predict variance in approaches to learning. Nonetheless, classroom process quality played an important role in these associations; high emotional support buffered the detrimental effects of problem behavior, whereas high instructional support exacerbated them. The findings of this study have important implications for classroom practices aimed at helping children who exhibit problem behaviors. PMID- 21530764 TI - Identification of preschool children at risk for emotional and behavioral disorders: development and validation of a universal screening system. AB - Three studies were designed to measure various indicators of the reliability and validity of the Preschool Behavior Screening System (PBSS) as a screening instrument for emotional and behavioral disorder risk status of children of preschool age. Study 1 and Study 2 served to establish evidence for content validity. Study 3 investigated one type of reliability evidence (i.e., internal consistency) and four types of validity evidence (i.e., internal structure validity, validity evidence based on external relations, concurrent validity, and cross-informant agreement).Teachers and parents of children (N=113) enrolled in preschool and childcare programs completed Phase 1 and Phase 2 of the PBSS and the Behavior Assessment System for Children (BASC-2). Cross-informant agreement between parent and teacher ratings on the PBSS was generally moderate, and internal consistency was high. PBSS Phase 1 and PBSS Phase 2 were correlated in the expected directions, and sensitivity and negative predictive value were high. Results suggest that the PBSS may yield psychometrically sound scores for helping states meet child-find requirements. Directions for future development of the PBSS are provided. PMID- 21530765 TI - Personality as a moderator of context effects on academic achievement. AB - We investigated whether personality moderates group influence of classmates on academic achievement and whether these so-called context effects can be attributed to peer pressure. The sample consisted of 2498 students in their first year of Dutch secondary education. The data were analyzed by a two-level (students within classes) analysis, separately for boys (n=1033, in 92 classes) and girls (n=1465, in 119 classes). For both sexes, we found a context effect on Dutch language achievement but not on mathematics achievement. Emotional Stability appeared a moderator of this context effect but for girls only. The results suggest further that peer pressure is not a likely mechanism of group influence of classmates on academic achievement. PMID- 21530766 TI - Adolescents' deliberate self-harm, interpersonal stress, and the moderating effects of self-regulation: a two-wave longitudinal analysis. AB - The predictive effects of peer victimization and harsh parenting on deliberate self-harm were examined. As derived from the experiential avoidance model, the study also tested whether these links were moderated by individual self regulation approaches. Data were collected at two points in time from 880 junior high school students (mean age=13.72) in Sweden. Analyses using structural equation modeling revealed that Peer Victimization was predictive of self-harm. Although Harsh Parenting was not predictive of self-harm, this link was moderated by adolescents' gender. No moderating effect of self-regulation was revealed. The study concludes that the high prevalence of deliberate self-harm recently found in community samples of adolescents cannot be prevented without attending to environmental psychosocial factors. PMID- 21530767 TI - The evolving role of bendamustine in lymphoid malignancy: understanding the drug and its mechanism of action--introduction. PMID- 21530768 TI - Mechanism of action: the unique pattern of bendamustine-induced cytotoxicity. AB - Bendamustine has demonstrated substantial efficacy in the treatment of hematologic malignancies and continues to distinguish itself from other alkylating agents with regard to its activity in tumor cells. The mechanistic and clinical differences associated with bendamustine may be directly related to its unique structural features. Although the precise mechanisms of action are still poorly understood, bendamustine is associated with extensive and durable DNA damage. The increased potency of bendamustine may be due to secondary mechanisms such as inhibition of mitotic checkpoints, inefficient DNA repair, and initiation of p53-dependent DNA-damage stress response, all of which lead to mitotic catastrophe and apoptosis. It has also been hypothesized that the presence of a benzimidazole ring in addition to the nitrogen mustard group may influence the way bendamustine interacts with DNA and/or confer antimetabolite properties. Further elucidation of the mechanisms of action for bendamustine and the signaling pathways involved in the response to bendamustine-induced DNA damage is essential to maximize its therapeutic potential, identify biomarkers for response, and understand the potential for synergy with other agents involved in DNA damage and inhibition of DNA repair. This review will discuss the current understanding and hypotheses regarding bendamustine mechanisms of action and suggest future investigations that would shed light on the many unanswered questions. PMID- 21530769 TI - Bendamustine's emerging role in the management of lymphoid malignancies. AB - The potent alkylating agent bendamustine has demonstrated substantial efficacy in patients with non-Hodgkin lymphomas (NHLs), including chronic lymphocytic leukemia (CLL), follicular lymphoma, and mantle cell lymphoma. Due to incomplete cross-reactivity between bendamustine and other chemotherapeutic agents, bendamustine has been extensively tested in the relapsed/refractory setting. Bendamustine is highly effective in rituximab-refractory NHL and in patients whose disease is refractory to chemotherapy, including other alkylating agents. It has also demonstrated considerable efficacy in previously untreated NHLs, both alone and in combination with rituximab or other chemotherapeutic agents. Studies suggest complete responses and durability of remission achieved with bendamustine are superior to those achieved with standard regimens. However, longer follow-up is needed to fully establish long-term response duration. Additionally, bendamustine is associated with hematologic toxicity and risk of infection, which must be carefully monitored and managed. This is particularly important in elderly patients with advanced disease. Increased understanding of the mechanisms of action of bendamustine and the efficacy of bendamustine in combination with rituximab in newly diagnosed or relapsed/refractory CLL and indolent lymphomas led to investigation of other combinations. Ongoing studies are examining bendamustine with bortezomib, lenalidomide, temsirolimus, ofatumumab, alemtuzumab, and other novel agents. Bendamustine is also undergoing clinical investigation in patients with relapsed/refractory diffuse large B-cell lymphomas, a patient population with limited therapeutic options currently. This review will summarize current clinical data regarding the efficacy and safety of bendamustine in patients with lymphoma and highlight ongoing clinical trials expanding the role of this alkylating agent in the treatment of hematologic malignancies. PMID- 21530770 TI - Conclusion and future directions. AB - Bendamustine is a bifunctional mechlorethamine derivative that shares similarities to other alkylators; however, the presence of a benzimidazole ring may confer "nucleoside-like" properties and may allow the stabilization of the molecule leading to longer lasting DNA damage. Though bendamustine has demonstrated promising response rates in preclinical and clinical studies, particularly in follicular lymphoma, chronic lymphocytic leukemia, diffuse B-cell lymphoma, and mantle cell lymphoma, the unique and exact mechanism of action of this agent remains unclear. Several studies have been initiated to address this question, and it is hoped that emerging data will provide the basis for more effective utilization of this interesting drug. Several recent clinical trials have reported impressive results with bendamustine in lymphoid malignancies, and appropriate clinical use of this agent and the rationale behind its use are of growing importance. This review discussed emerging data and aimed to provide clinical updates and scientific rationales that are relevant to practicing clinicians who provide care to patients with lymphoid malignancies, and/or who are interested in understanding the evolving role of bendamustine in this setting. PMID- 21530771 TI - Bendamustine: rescue of an effective antineoplastic agent from the mid-twentieth century. AB - Although the alkylating agent bendamustine was developed in Germany in the mid twentieth century, it has only recently come to the forefront in the rest of the world as an effective chemotherapeutic agent for the treatment of several hematologic malignancies. Based on the activity demonstrated in single-arm and randomized trials, this nitrogen mustard is approved by the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia and rituximab-refractory indolent non-Hodgkin lymphoma. The unique structural and mechanistic features of bendamustine differentiate it from other alkylating agents, providing increased stability and potency in DNA cross linking and subsequent cytotoxicity. Due to its unusual development, few studies have closely examined the mechanisms of action for this nitrogen mustard and many unanswered questions remain. Additionally, phase I and pharmacokinetic studies are limited, although increased understanding of the clinical pharmacology of bendamustine led to development of dosing recommendations by international experts based on the available data. The clinical activity of bendamustine as a single agent and in combination with other chemotherapeutic and immunotherapeutic drugs, coupled with its potential lack of cross-resistance with many other chemotherapy agents, make bendamustine an attractive therapy for patients with newly diagnosed and refractory hematologic malignancies. This review will discuss the development of bendamustine, its structural and pharmacologic characteristics, and current data regarding the optimal dosing of this agent in specific clinical settings. PMID- 21530772 TI - Special susceptive aqueous ammonia chemi-sensor: extended applications of novel UV-curable polyurethane-clay nanohybrid. AB - In this contribution, chemical sensor for the detection of aqueous ammonia has been fabricated using UV-curable polyurethane acrylate (PU) and nanohybrids (NH 1, NH-3 and NH-5). PU has been prepared by reacting polycaprolactone triol (PCLT) and isophorone diisocyanate (IPDI) while the nanohybrids, NH-1, NH-3, and NH-5 have been synthesized by solution blending method using PU with 1, 3, and 5 wt% loading levels of C-20B. PU and their nanohybrids showed higher sensitivity investigated by I-V technique using aqueous ammonia as a target chemical. All the nanohybrids showed higher sensitivity as compared to neat PU. The sensitivity increased with increase in clay content and the nanohybrid containing 5 wt% of clay showed the highest sensitivity (8.5254 MUA cm(-2) mM(-1)) with the limit of detection (LOD) of 0.0175 +/- 0.001 MUM, being 7.8 times higher than pure PU. The calibration plot for all the sensors was linear over the large range of 0.05 MUM to 0.05 M. The response time of the fabricated sensor was <10.0 s. Therefore, one can fabricate efficient aqueous ammonia sensor by utilization of nanohybrid as an efficient electron mediator. PMID- 21530773 TI - Biospeciation of tungsten in the serum of diabetic and healthy rats treated with the antidiabetic agent sodium tungstate. AB - It is known that oral administration of sodium tungstate preserves the pancreatic beta cell function in diabetic rats. Healthy and streptozotocin-induced diabetic rats were treated with sodium tungstate for one, three or six weeks, after which the species of W in serum, were analysed. An increase in serum W with treatment time was observed. After six weeks, the serum W concentration in diabetic rats (70 mg L(-1)) was about 4.6 times higher than in healthy specimens. This different behaviour was also observed for Cu accumulation, while the Zn pattern follows the contrary. The patterns observed in the retention of Cu and Zn may be attributable to a normalization of glycaemia. The speciation analysis of W was performed using 2D separations, including an immunoaffinity packing and a SEC (Size Exclusion Chromatography) column coupled to an ICP-MS (Inductively Coupled Plasma Mass Spectrometry) for elemental detection. Ultrafiltration data together with SEC-ICP-MS results proved that around 80% of serum W was bound to proteins, the diabetic rats registering a higher W content than their healthy counterparts. Most of the protein-bound W was due to a complex with albumin. An unknown protein with a molecular weight higher than 100 kDa was also found to bind a small amount of W (about 2%). MALDI-TOF (Matrix-Assisted Laser Desorption Ionization Time-of Flight) analysis of the desalted and concentrated chromatographic fractions confirmed albumin as the main protein bound to tungstate in rat serum, while no binding to transferrin (Tf) was detected. The interaction between glutathione and W was also evaluated using standard solutions; however, the formation of complexes was not observed. The stability of the complexes between W and proteins when subjected to more stringent procedures, like those used in proteomic methodologies (denaturing with urea or SDS, boiling, sonication, acid media, reduction with beta-mercaptoethanol (BME) or DTT (dithiotreitol) and alkylation with iodoacetamide (IAA), was also evaluated. Our results indicate that the stability of the complexes between W and proteins is not too high enough to remain unaltered during protein separation by SDS-PAGE in denaturing and reducing conditions. However, the procedures for in-solution tryptic digestion and for ESI MS analysis in MeOH/H(2)O/with 0.1% formic acid could be used for protein identification without large loss of binding between W and proteins. PMID- 21530774 TI - Temperature-response polymer coating for in-tube solid-phase microextraction coupled to high-performance liquid chromatography. AB - The silica nanoparticle (SiO(2) NP)-deposited capillary fabricated by liquid phase deposition (LPD) was bonded by 3-(triethoxysilyl) propyl methacrylate and then modified with poly(N-isopropylacrylamide) (PNIPAAm) by polymerization. The resulting PNIPAAm modified SiO(2) NP-deposited capillary was applied to in-tube solid-phase microextraction coupled to high-performance liquid chromatography (in tube SPME-HPLC). To investigate the extraction performance of the prepared capillary, diethylstilbestrol (DES) with moderate polarity was selected as the model analyte. Results demonstrate that PNIPAAm modified SiO(2) NP-deposited capillary exhibited obvious temperature responsive character. Finally, the PNIPAAm modified SiO(2) NP-deposited capillary was applied to the analysis of three synthetical estrogens from milk samples. The detection limit of the method was found to be in the range 1.2-2.2 ng/g, and recovery was 71.7-98.9% with relative standard deviations in the range of 2.8-12.6%. PMID- 21530775 TI - Rapid quantification of four major bioactive alkaloids in Corydalis decumbens (Thunb.) Pers. by pressurised liquid extraction combined with liquid chromatography-triple quadrupole linear ion trap mass spectrometry. AB - A new method based on pressurised liquid extraction (PLE) followed by liquid chromatography-triple quadrupole linear ion trap mass spectrometry (LC-QTrap-MS) analysis has been developed for the identification and quantification of four major alkaloids in extracts of Corydalis decumbens (Thunb.) Pers. PLE extractions were performed using 90% ethanol; temperature was set at 100 degrees C and pressure at 1500 psi. HPLC analysis was performed on a Waters XBridgeTM C(18) column (150 mm * 2.1mm i.d., 3.5 MUm) eluted by a mobile phase of acetonitrile and 0.2% acetic acid. Data acquisition was carried out in multiple reaction monitoring transitions (MRMs) mode, monitoring two MRM transitions to ensure an accurate identification of target compounds in the samples. Additional identification and confirmation of target compounds were performed using the enhanced product ion modus (EPI) of the linear ion trap. The novel LC-QTrap-MS platform offers the best sensitivity and specificity for characterization and quantitative determination of the four alkaloids in C. decumbens (Thunb.) Pers. and fulfils the quality criteria for routine laboratory application. PMID- 21530776 TI - Application of renewable silver amalgam annular band electrode to voltammetric determination of vitamins C, B1 and B2. AB - In this work, the design and results of applying silver liquid amalgam film modified silver solid amalgam annular band electrode (AgLAF-AgSAE), refreshed before each measurement, to voltammetric determination of vitamins C (VC), B(1) (VB1) and B(2) (VB2) are presented. The method is based on adsorptive accumulation of analytes at the AgLAF-AgSAE in a phosphate buffer (VB1), phosphate buffer with Triton X-100 (VB2) and an alkaline borate buffer with Triton X-100 (VC). The analytical parameters and procedure of electrode activation were optimized. The calibration graphs obtained for vitamins C, B(1) and B(2) are linear, respectively, for concentration range 0.05-12, 0.01-0.1 and 0.05-3 mg L(-1). The detection limits were calculated and equaled 0.02, 0.003 and 0.009 mg L(-1), while repeatability of the peak current was 2%, 1% and 3%, respectively. These results are comparable with results obtained for polarographic determination of the same vitamins using mercury electrodes. Finally, the AgLAF-AgSAE was applied to the determination of vitamins in pharmaceutical samples and fruit juices with satisfactory results. PMID- 21530778 TI - Effect of substituent of beta-diketones on the synergistic extraction of lanthanoids with linear polyether. AB - The synergistic extraction of 14 trivalent lanthanoids (Ln(3+)) into 1,2 dichloroethane with a linear polyether (DEO6), HO(C(2)H(4)O)(6)C(12)H(25), and beta-diketones (HA) having different substituents was investigated at 25.0 degrees C. The HAs used were trifluoroacetylacetone (Htfa), thenoyltrifluoroacetone (Htta), benzoyltrifluoroacetone (Hbta), naphthoyltrifluoroacetone (Hnta), and pivaloyltrifluoroacetone (Hpta). By the extraction of Ln(3+) with beta-diketone alone, the extraction constants of the neutral LnA(3) complex, [Formula: see text] , were determined. The intrinsic extraction constants, [Formula: see text] , were evaluated by employing the regular solution theory. Results indicate that the extractability of LnA(3) is dependent on the lipophilicity of the ligand, and the planar aromatic rings do not cause steric hindrance in the formation of the binary complex. Addition of DEO6 significantly enhanced the extraction of Ln(3+) by the formation of LnA(3)(DEO6). The ternary complex formation constants, beta(add), were determined for all the Ln(3+) and HA. The beta(add) of bta(-) and nta(-) complexes is similar with those of tfa(-) complexes, indicating that planar aromatic rings do not sterically hinder even the formation of the ternary complex. The higher values of beta(add) for the complexes of tta(-), which has a slightly dipolar thenoyl moiety, can be accounted for the presence of ligand-ligand interaction. The formation constants of the ternary complexes of pta(-) were lower compared to complexes of other beta-diketones because of steric hindrance due to the bulky t butyl moiety. The detailed structures of the ternary complexes in solution were elucidated by NMR spectroscopy. Estimated structures sufficiently explain the variation in stability constants of LnA(3)(DEO6) among HAs and across the series of Ln(3+). The structures thus obtained were ascertained by the molecular models created by MM2 calculation. PMID- 21530777 TI - Recognition of molecularly imprinted polymers for a quaternary alkaloid of berberine. AB - Selective and affinitive imprinted polymers incorporating a quaternary alkaloid of berberine (BER) were prepared using a non-covalent imprinting method. The results showed that, compared to other imprinted polymers, the polymer AD-10 had not only a higher of the ratio of Q(MIP)/Q(BP) for BER adsorption, and but also a larger of the ratio of Q(MIP,B)/Q(MIP,P) for BER and palmatine (PAL) adsorptions. Spectrophotometric analysis demonstrated that a 1:1 cooperative hydrogen-bonding complex might be predominating in the pre-polymerization between the BER template and AA monomer. Adsorption experiments of BER on the polymer AD-10 were in accordance with the second-order and Langmuir adsorption models. The E value (5.70 kJ/mol) calculated from the Dubinin-Radushkevich model indicated that the adsorption followed a physisorption process. In addition, a Scatchard plot showed a single straight line with an equilibrium dissociation constant (K(D)) of 65.80 MUmol/L. SPE analyses of a mixture of BER and PAL and the methanol extract from the cortices of Phellodendron wilsonii showed that AD-10 had more efficiency, and higher specificity and selectivity for SPE in the concentration and determination of BER and its extraction from natural products. PMID- 21530779 TI - Simultaneous determination of oxygen, nitrogen and hydrogen in metals by pulse heating and time of flight mass spectrometric method. AB - The inert gas fusion and infrared absorption and thermal conductivity methods are widely used for quantitative determination of oxygen(O), nitrogen(N) and hydrogen(H) in metals. However, O, N and H cannot be determined simultaneously with this method in most cases and the sensitivity cannot meet the requirement of some new metal materials. Furthermore, there is no equipment or method reported for determination of Argon(Ar) or Helium(He) in metals till now. In this paper, a new method for simultaneous quantitative determination of O, N, H and Ar(or He) in metals has been described in detail, which combined the pulse heating inert gas fusion with time of flight mass spectrometric detection. The whole analyzing process was introduced, including sample retreatment, inert gas fusion, mass spectral line selection, signal acquisition, data processing and calibration. The detection limit, lower quantitative limit and linear range of each element were determined. The accuracy and precision of the new method have also been verified by measurements of several kinds of samples. The results were consistent with that obtained by the traditional method. It has shown that the new method is more sensitive and efficient than the existing method. PMID- 21530780 TI - An ultrasensitive post chemiluminescence reaction of ammonium in NBS dichlorofluorescein system and its application. AB - A strong post chemiluminescence (PCL) phenomenon was observed when ammonium was injected into the reaction mixture after the finish of CL reaction of N bromosuccinimide (NBS) and dichlorofluorescein. Based on this, a sensitive flow injection PCL method was established for the determination of ammonium. The possible CL mechanism of the reaction was proposed based on a series of experiments. The PCL intensity responded linearly to the concentration of ammonium in the range 3.0 * 10(-11) -1.0 * 10(-7) g mL(-1) with a detection limit of 1 * 10(-11) g mL(-1). The relative standard deviation (R.S.D.) was 1.4% for 1.0 * 10(-9) g mL(-1) ammonium (n=11). This method had been applied to the determination of ammonium in samples of mineral water, tap water and river water. PMID- 21530781 TI - Fesoterodine stress degradation behavior by liquid chromatography coupled to ultraviolet detection and electrospray ionization mass spectrometry. AB - In the present study, a rapid validated stability-indicating LC method was established and comprehensive stress testing of fesoterodine was carried out according to ICH guidelines. Fesoterodine was subjected to stress conditions of acid and basic hydrolysis, oxidation, photolysis and thermal decomposition. The degradation products formed under stress conditions were investigated by LC-UV and LC-ESI-MS. Successful separation of the drug from its degradation products was achieved on a monolithic C(18) column (100 mm * 4.6mm i.d.) maintained at 45 degrees C using acetonitrile-methanol-0.03 mol L(-1) ammonium acetate (pH 3.8) (30:15:55, v/v/v) as the mobile phase. The flow rate was 2.4 mL min(-1) and the detection wavelength was 208 nm. Validation parameters such as specificity, linearity, precision, accuracy, and robustness were evaluated. Chromatographic separation was obtained within 2.5 min and it was suitable for high-throughput analysis. Fragmentation patterns of degradation products formed under different stress conditions were studied and characterized through LC-ESI-MS fragmentation. Based on the results, a drug degradation pathway was proposed, and the validated LC method was successfully applied to the quantitative analysis of fesoterodine in tablet dosage forms, helping to improve quality control and to assure therapeutic efficacy. PMID- 21530782 TI - Enantiomeric separation in high-performance liquid chromatography using novel beta-cyclodextrin derivatives modified by R-configuration groups as chiral stationary phases. AB - Two new chiral stationary phases (CSP) were successfully prepared through bonding beta-cyclodextrin (CD) derivatives modified by R-configuration groups (R-CPGCD, R HMPGCD) to silica gel. Nineteen chiral nitro aromatic alcohol derivatives were separated under the polar organic and the reversed phase modes. Better enantioseparation was obtained in the reversed phase mode. The resolution values of the analytes ranged from 1.98 to 7.57 and from 2.19 to 8.14 on R-CPGCD and R HMPGCD CSPs, respectively, using a mobile phase composed of methanol/water (v/v, 40/60). Better enantioseparation was obtained on R-HMPGCD CSP than on R-CPGCD CSP because of stronger hydrogen bonding and pi-pi interactions between the substituents on the cyclodextrin derivatives and the analytes. For different analytes, the increasing electronic density of the benzene ring was found to be favorable to the enantioseparation of the test analytes. The thermodynamic parameters showed that the enantioseparation of analytes was enthalpy-controlled and a lower temperature aided the enantiomeric separation of the solutes on the two CSPs. MD simulations were used to investigate the recognition mechanism between the chiral selectors and the analyte using R-, S-2-naphthalenemethanol and R-CPGCD and R-HMPGCD complexes as examples. S-2-naphthalenemethanol had the stronger interactions with R-CPGCD and R-HMPGCD than the R-isomer. The substituent derivatized on R-CPGCD and the cyclodextrin cavity contributed to the discrimination of the S-isomer, but only the derivatized group on R-HMPGCD was found to play a major role in separating prosess. In addition, the larger free energy deviation of the R- and S-isomers in the R-HMPGCD system brought about a higher resolution value (R(s)=8.14). PMID- 21530783 TI - Determination of primary and secondary aliphatic amines with high performance liquid chromatography based on the derivatization using 1,3,5,7-tetramethyl-8-(N hydroxysuccinimidyl butyric ester)-difluoroboradiaza-s-indacene. AB - In this article, the simultaneous determination of primary and secondary aliphatic amines including dimethylamine (DMA), diethylamine and eleven primary aliphatic amines by high performance liquid chromatography (HPLC) with fluorescence detection has been achieved using a BODIPY-based fluorescent derivatization reagent, 1,3,5,7-tetramethyl-8-(N-hydroxysuccinimidyl butyric ester)-difluoroboradiaza-s-indacene (TMBB-Su). The derivatization reaction of TMBB-Su with aliphatic amines was optimized with orthogonal design experiment and the derivatization reaction proceeded at 15 degrees C for 25 min. The baseline separation of these derivatives was carried out on a C(8) column with methanol tetrahydrofuran-50mM pH 6.50 HAc-NaAc buffer (55/5/40, v/v/v) as a mobile phase. Detected at the excitation and emission of 490 and 510 nm, respectively, the detection limits were obtained in the range of 0.01-0.04 nM (signal-to-noise ratio=3). The proposed method has been applied to the determination of trace aliphatic amines in viscera samples from mice without complex pretreatment or enrichment method. The recoveries ranged from 95.1% to 106.8%, depending on the samples investigated. PMID- 21530784 TI - A facile light-emitting-diode induced fluorescence detector coupled to an integrated microfluidic device for microchip electrophoresis. AB - In this paper, a compact and inexpensive light emitting diode induced fluorescence (LED-IF) detector with simplified optical configuration was developed and assembled in an integrated microfluidic device for microscale electrophoresis. The facile detector mainly consisted of an LED, a focusing pinhole, an emission filter and a photodiode, and was encapsulated in the upper layer of an aluminum alloy device with two layers. At the bottom layer, integrated circuit (IC) was assembled to manipulate the voltage for sample injection and separation, LED emission and signal amplifying. A high-power LED with fan-shaped heat sink was used as excitation source. The excitation light was focused by a 1.1mm diameter pinhole fabricated in a thin piece of silver foil, and the obtained sensitivity was about 3 times as high as that using electrode plate. Other important parameters including LED driven current, fluorescence collection angle and detection distance have also been investigated. Under optimal conditions, considerable high-response of 0.09 fmol and 0.18 fmol mass detection limits at 0.37 nL injection volume for sodium fluorescein (SF) and FITC was achieved, respectively. This device has been successfully employed to separate penicillamine (PA) enantiomers. Due to such significant features as low cost, integration, miniaturization, and ease of commercialization, the presented microfluidic device may hold great promise for clinical diagnostics and bioanalytical applications. PMID- 21530785 TI - Analytical evaluation of enzyme-linked immunosorbent assay for neonicotinoid dinotefuran for potential application to quick and simple screening method in rice samples. AB - The analytical performance of a kit-based enzyme-linked immunosorbent assay (ELISA) for the determination of a neonicotinoid insecticide dinotefuran residue in rice samples is addressed. The sensitivity (I(50) value) was 5.4 ng/mL, with the limit of detection, 0.6 ng/mL and the dynamic range from 1.0 to 30 ng/mL. The ELISA showed substantially high specificity toward dinotefuran besides clothianidin (184%). For rice samples, dinotefuran was extracted with methanol and the extracts were directly determined with the ELISA because of no significant matrix interference. Good recoveries were observed and ranged from 92.5% to 113.2% with coefficients of variation below 10%. The results obtained with the ELISA correlated well with those by the HPLC method for rice samples (r>0.98). These findings strongly indicate that the evaluated and validated ELISA has a potential utility in a quick, simple, and reliable residue analysis, especially a screening method before shipment contributing to food safety. PMID- 21530787 TI - Colorimetric analysis of water and sand samples performed on a mobile phone. AB - Analysis of water and sand samples was done by reflectance measurements using a mobile phone. The phone's screen served as light source and front view camera as detector. Reflected intensities for white, red, green and blue colors were used to do principal component analysis for classification of several compounds and their concentrations in water. Analyses of colored solutions and colorimetric reactions based on widely available chemicals were performed. Classification of iron(III), chromium(VI) and sodium salt of humic acid was observed using reflected intensities from blue and green light for concentrations 2-10mg/l. Addition of complex forming sodium salt of ethylenediaminetetraacidic acid enabled the discrimination of Cu(II) ions in the 2-10mg/l concentration range based on reflection of red light. An alternate method using test strips for copper solutions with the phone as reader also demonstrated a detection limit of 2mg/l. Analysis of As(III) from 25 to 400 MUg/l based on reflection of red light was performed utilizing the bleaching reaction of tincture of iodine containing starch. Enhanced sensitivity to low concentrations of arsenic was obtained by including reflected intensities from white light in the analysis. Model colored sand samples representing discoloration caused by the presence of arsenic in groundwater were analyzed as a complementary method for arsenic detection. PMID- 21530786 TI - Determination of type A and type B trichothecenes in paprika and chili pepper using LC-triple quadrupole-MS and GC-ECD. AB - There is a need to develop sensitive and accurate analytical methods for determining deoxynivalenol (DON), HT-2 toxin and T-2 toxin in paprika to properly assess the relevant risk of human exposure. An optimized analytical method for determination of HT-2 toxin and T-2 toxin using capillary gas chromatography with electron capture detection and another method for determination of DON by liquid chromatography-mass spectrometry in paprika was developed. The method for determination of HT-2 toxin and T-2 toxin that gave the best recoveries involved extraction of the sample with acetonitrile-water (84:16, v/v), clean-up by solid phase extraction on a cartridge made of different sorbent materials followed by a further clean-up in immunoaffinity column that was specific for the two toxins. The solvent was changed and the eluate was derivatized with pentafluoropropionic anhydride and injected into the GC system. The limits of detection (LOD) for T-2 and HT-2 toxins were 7 and 3 MUg/kg, respectively, and the recovery rates for paprika spiked with 1000 MUg toxin/kg were 71.1% and 80.1% for HT-2 and T-2 toxins, respectively. For DON determination, the optimized method consisted of extraction with acetonitrile-water (84:16, v/v) solution followed by a solid phase extraction clean-up process in a cartridge made of different sorbent compounds. After solvent evaporation in N(2) stream, the residue was dissolved and DON was separated and determined by LC-MS/MS. The LOD for this method was 14 MUg DON/kg paprika sample and the DON recovery rate was 86.8%. PMID- 21530789 TI - New developments in the analysis of fragrances and earthy-musty compounds in water by solid-phase microextraction (metal alloy fibre) coupled with gas chromatography-(tandem) mass spectrometry. AB - Fragrances are widespread aquatic contaminants due to their presence in many personal care products used daily in developed countries. Levels of galaxolide and tonalide are commonly found in surface waters, urban wastewaters and river sediments. On the other hand, earthy-musty compounds confer bad odour to drinking water at levels that challenge the analytical capabilities. The combined determination of earthy-musty compounds and fragrances in water would be a breakthrough to make the traditional organoleptic evaluation of the water quality stricter and safer for the analyst. Two approaches were attempted to improve the analytical capabilities: analyte pre-concentration with a newly developed PDMS DVB solid-phase microextraction fibre on metal alloy core and sensitive detection by tandem mass spectrometry (MS/MS). The optimization of SPME parameters was carried out using a central composite design and desirability functions. The final optimum extraction conditions were: headspace extraction at 70 degrees C during 40 min adding 200 g L(-1) of NaCl. The detection limits in tandem MS (0.02 20 ng L(-1)) were marginally lower compared to full scan except for geosmin and trichloroanisol which go down to 0.1 and 0.02 ng L(-1), respectively. The analysis of different water matrices revealed that fragrances and earthy-musty compounds were absent from ground- and drinking waters. Surface waters of river Leca contained levels of galaxolide around 250 ng L(-1) in the 4 terminal sampling stations, which are downstream of WWTPs and polluted tributaries. Geosmine was ubiquitously distributed in natural waters similarly in rivers Leca and Douro at concentrations <7 ng L(-1). PMID- 21530788 TI - Synthesis of surface molecularly imprinted polymer and the selective solid phase extraction of imidazole from its structural analogs. AB - A surface molecularly imprinted polymer (MIP) was synthesized by using imidazole as the template and modified silica particles as the support material. The static adsorption, solid phase extraction (SPE) and high-performance liquid chromatography (HPLC) experiments were performed to investigate the adsorption properties and selective recognition characteristics of the polymer for imidazole and its structural analogs. It was shown that the maximum binding capacities of imidazole on the MIP and the non-imprinted polymer (NIP) were 312 and 169 MUmol g(-1), respectively. The adsorption was fast and the adsorption equilibrium was achieved in 30 min. The binding process could be described by pseudo-second order kinetics. Compared with the corresponding non-imprinted polymer, the molecularly imprinted polymer exhibited much higher adsorption performance and selectivity for imidazole. The selective separation of imidazole from a mixture of 1-hexyl-3 methylimidazolium bromide ([C(6)mim][Br]) and 2,4-dichlorophenol could be achieved on the MIP-SPE column. The recoveries of imidazole and [C(6)mim][Br] were 97.6-102.7% and 12.2-17.3%, respectively, but 2,4-dichlorophenol could not be retained on the column. The surface molecularly imprinted polymer presented here may find useful application as a solid phase absorbent to separate trace imidazole in environmental water samples. This may also form the basis for our research program on the preparation and application of alkyl-imidazolium imprinted polymers. PMID- 21530790 TI - Determination of 15 isomers of chlorobenzoic acid in soil samples using accelerated sample extraction followed by liquid chromatography. AB - A study was conducted to elaborate a fast, simple and efficient method for determination of 15 isomers chlorobenzoic acids (CBAs) in soil using HPLC-UV. Artificially contaminated soil samples were extracted using accelerated solvent extraction (ASE) with 1% acetic acid in a mixture of hexane and acetone (1:1, V/V) under a pressure of 10.34 MPa and temperature of 150 degrees C. The recovery of the ASE method was above 82%. The extracts were concentrated; dimethyl sulfoxide was used to prevent CBA volatilization and the final analysis was performed with a C18 XBridge HPLC column employing a mobile phase consisting of acetonitrile and 0.1% trifluoracetic acid in water. A HPLC procedure with gradient elution and UV detection was developed and validated. The method exhibited a linear range for 2-CBA; 2,6-CBA; 3-CBA; 4-CBA; 2,3-CBA; 2,3,6-CBA; 2,5-CBA; and 2,4-CBA from 5 to 120 MUg/mL with a limit of quantification (LOQ) of 5 MUg/mL, RSD from 2.42 to 9.42% and accuracy from 82 +/- 2 to 103 +/- 3%. The linear range of determination of 2,4,6-CBA, 3,4-CBA, 2,3,5,6-CBA, 3,5-CBA, 2,3,5 CBA, 2,3,4,5,6-CBA and 2,3,4,5-CBA was 10-120 MUg/mL with LOQ 10 MUg/mL, RSD from 0.74 to 5.84% and accuracy from 94 +/- 1 to 114 +/- 1%. The optimized analytical procedure was finally applied on two historically PCB contaminated soils and 9 CBAs were quantified in the samples. PMID- 21530791 TI - Study of the GC-MS determination of the palmitic-stearic acid ratio for the characterisation of drying oil in painting: La Encarnacion by Alonso Cano as a case study. AB - The correct identification of drying oils plays an essential role in providing an understanding of the conservation and deterioration of artistic materials in works of art. To this end, this work proposes the use of peak area ratios from fatty acids after ensuring that the linear responses of the detector are tested. A GC-MS method, previously reported in the literature, was revisited to its developed and validated in order to identify and quantify of eight fatty acids that are widely used as markers for drying oils in paintings, namely myristic acid (C(14:0)), palmitic acid (C(16:0)), stearic acid (C(18:0)), oleic acid (C(18:1)), linoleic acid (C(18:2)), suberic acid (2C(8)), azelaic acid, (2C(9)) and sebacic acid (2C(10)). The quaternary ammonium reagent m (trifluoromethyl)phenyltrimethylammonium hydroxide (TMTFAH) was used for derivatization prior to GC-MS analysis of the oils. MS spectra were obtained for each methyl ester derivative of the fatty acids and the characteristic fragments were identified. The method was validated in terms of calibration functions, detection and quantification limits and reproducibility using the signal recorded in SIR mode, since two of the methyl derivatives were not totally separated in the chromatographic run. The proposed method was successfully applied to identify and characterise the most widely used drying oils (linseed oil, poppy seed oil and walnut oil) in the painting La Encarnacion. This 17th century easel painting is located in the main chapel of the cathedral in Granada (Spain) and was painted by the well-known artist of the Spanish Golden Age, Alonso Cano (1601-1667). PMID- 21530792 TI - Simultaneous pressurized liquid extraction and clean-up for the analysis of polybrominated biphenyls by gas chromatography-tandem mass spectrometry. AB - This paper describes a fast and simple pressurized liquid extraction (PLE) method combined with gas chromatography coupled to ion trap tandem mass spectrometry (GC ITMS-MS) for the determination of polybrominated biphenyls (PBBs) in fish samples. The method is based on a simultaneous extraction/clean-up step to reduce analysis time and solvent consumption. The effect of several PLE operating conditions, such as solvent type, extraction temperature and time, number of cycles, and lipid retainer, was optimized to obtain maximum recovery of the analytes with the minimum presence of matrix-interfering compounds. The best conditions were obtained at 100 degrees C with n-hexane using 15 g of silica modified with sulphuric acid (44%, w/w) as sorbent for lipid removal. Quality parameters of the GC-ITMS-MS method were established, achieving good linearity (r>0.998), between 1 and 500 ng ml(-1), and low instrumental limits of detection (0.14-0.76 pg injected). For the whole method, limits of detection ranging from 0.03 to 0.16 ng g(-1) wet weight and good precision (RSD<16%) were obtained. PMID- 21530794 TI - Potentiometric detection of citrate in beverages using a graphite carbon electrode. AB - The development, evaluation and application of a simple and low-cost graphite carbon electrode for the direct determination of citrate in food samples are described here. The electrode exhibits a linear response with a slope of -29.0 +/ 1.0 mV decade(-1) in a concentration range of 0.07-7.0 mmol L(-1) in 0.1 mol L( 1) KCl/1.0 mmol L(-1) phosphate buffer solution with a limit of detection of 3.0 MUmol L(-1). The electrode is easily constructed at a relatively low cost and has a fast time response (within 120 s) with no significant changes in its performance characteristics. The performance of the graphite sensor was tested to determine citrate in beverage samples (juices and an isotonic drink), and the results were validated against a reference procedure. The proposed method is quick, inexpensive, selective and sensitive, and is based entirely on conventional instrumentation. PMID- 21530793 TI - Determination of pharmaceutical and personal care products in wastewater by capillary electrophoresis with UV detection. AB - Capillary electrophoresis (CE) offers a fast and cost-effective alternative analytical technique to LC-MS/MS for separation and quantitation of many PPCP compounds in wastewater. In this study, we have developed a method that can simultaneously analyze eight different PPCP compounds in untreated wastewater (ibuprofen, triclosan, carbamazepine, caffeine, acetaminophen, sulfamethoxazole, trimethoprim, and lincomycin), using capillary electrophoresis with UV detection (CE-UV). The method detection limit (MDL) ranged from 1.6 to 68.7 ppb through solid phase extraction. The standard limit of quantification (LOQ) ranged from 0.63 to 7.72 ppm. Factors affecting separation and quantification of PPCPs, such as pH, electrophoretic potential, buffer strength, buffer type, and additives, were investigated and optimized. Water samples from two different wastewater treatment plants were collected and analyzed. The results obtained were comparable with those of LC-MS/MS. The technique developed in this study provides a low cost, simple, fast, and relatively sensitive method for determination of various PPCPs in wastewater samples for PPCP screening. PMID- 21530796 TI - A discriminant based charge deconvolution analysis pipeline for protein profiling of whole cell extracts using liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry. AB - A discriminant based charge deconvolution analysis pipeline is proposed. The molecular weight determination (MoWeD) charge deconvolution method was applied directly to the discrimination rules obtained by the fuzzy rule-building expert system (FuRES) pattern classifier. This approach was demonstrated with synthetic electrospray ionization-mass spectra. Identification of the tentative protein biomarkers by bacterial cell extracts of Salmonella enterica serovar typhimurium strains A1 and A19 by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) was also demonstrated. The data analysis time was reduced by applying this approach. In addition, this method was less affected by noise and baseline drift. PMID- 21530795 TI - Anion separations for liquid chromatography using propylpyridinium silica as the stationary phase. AB - This work describes the characterization and potential applications of a silica based anion-exchange phase prepared by a two-step modification process that incorporates a propylpyridinium group. The effects of pH and eluent concentration on anion separation were examined using 150 mm * 3.9 mm HPLC columns packed with the new phase. The mobile phase pH values ranged from 3.8 to 6.6 using phthalic acid/Tris solutions. The best separation was achieved using 2.5 mmol L(-1) phthalate/2.4 mmol L(-1) Tris solution at pH 4.2 as mobile phase with non suppressed conductivity detection. The new stationary phase was used for the separation of some inorganic and organic anions showing good resolution. The stability of the silica-based anion exchange phase was also evaluated. Analytical curves, for concentrations ranging from 0.25 to 10 mg L(-1) for the inorganic anions chloride, nitrite, bromide and nitrate, showed good linear correlations (r>0.998). The method was tested with certified rainwater samples. The measured and certified values were in good agreement, indicating that the new phase holds significant promise for the analysis of these anions in environmental samples. PMID- 21530797 TI - Silver nanoparticles fluorescence enhancement effect for determination of nucleic acids with kaempferol-Al(III). AB - Nucleic acids can greatly enhance fluorescence intensity of the kaempferol (Km) Al(III) system in the presence of silver nanoparticles (AgNPs). Based on this, a novel method for the determination of nucleic acids is proposed. Under studied conditions, there are linear relationships between the extent of fluorescence enhancement and the concentration of nucleic acids in the range of 5.0 * 10(-9) to 2.0 * 10(-6) g mL(-1) for fish sperm DNA (fsDNA), 7.0 * 10(-9) to 2.0 * 10(-6) gm L(-1) for salmon sperm DNA (smDNA) and 2.0 * 10(-8) to 3.0 * 10(-6) gm L(-1) for yeast RNA (yRNA), and their detection limits are 2.5 * 10(-9) gm L(-1), 3.2 * 10(-9) gm L(-1) and 7.3 * 10(-9) gm L(-1), respectively. Samples were satisfactorily determined. And the system of Km-Al(III)-AgNPs was used as a fluorescence staining reagent for sensitive DNA detection by DNA pattern of agarose gel electrophoresis analysis. The results indicate that the fluorescence enhancement should be attributed to the formation of Km-Al(III)-AgNPs-nucleic acids aggregations through electrostatic attraction and adsorption bridging action of Al(III) and the surface-enhanced fluorescence effect of AgNPs. PMID- 21530798 TI - Uncoupling protein 1 gene -3826 A/G polymorphism is associated with weight loss on a short-term, controlled-energy diet in young women. AB - Uncoupling protein 1 (UCP1) plays an important role in thermogenesis in brown adipose tissue. Previously, we reported an association between -3826 A/G single nucleotide polymorphism (SNP) in the promoter of UCP1 gene and lower thermogenesis in young women, suggesting this SNP has an adverse effect on the regulation of energy balance. Based on the hypothesis that this SNP (G allele) may have resistance against diet-induced weight loss, we examined its effects on anthropometric and metabolic responses to short-term, controlled-energy diet in young women. Seventeen lean women (20.9 +/- 0.2 years; body mass index, 22.1 +/- 0.5 kg/m(2)) were fed a controlled-energy diet (5.0 MJ/d, 62% carbohydrate, 19% protein, and 19% fat) administered by dietitians for 2 weeks. Clinical measurements were determined at baseline and after the dietary intervention. The subjects' physical activity was obtained using pedometers and self-reporting. The thermoregulatory sympathetic nervous system was evaluated using heart rate variability power spectral analysis. Upon the completion of the intervention, subjects were genotyped using an allele-specific DNA primer assay and results compared with their clinical measurements focusing on with or without the G allele. After dietary intervention, G allele subjects (A/G + G/G, n = 10) showed significantly smaller changes in body weight, body mass index, and waist circumference compared with A/A genotype subjects (n = 7). Similar changes were observed in parameters regarding glucose or lipid metabolism in both groups. These results suggest that the UCP1 gene -3826 G allele may result in smaller weight loss after a short-term, controlled-energy diet in young, lean women. PMID- 21530799 TI - All-natural nitrite and nitrate containing dietary supplement promotes nitric oxide production and reduces triglycerides in humans. AB - There is an emerging paradigm that certain foods promote nitric oxide (NO) production from the stepwise reduction of nitrate to nitrite to NO, providing an endothelium independent source of bioactive NO. We hypothesize that a unique formulation containing nitrate-rich beetroot along with Hawthorn berry shown to have a robust nitrite reductase activity would improve NO status in humans and modify cardiovascular risk factors. The trial was conducted at the Houston Institute for Clinical Research in Houston, Texas. Inclusion criteria for this double-blinded, placebo-controlled study were patients older than 40 years with 3 or more of the following cardiovascular risk factors: hypertension, obesity, hyperlipidemia, smoking, sedentary, family history of cardiovascular disease, and diabetes. Subjects were instructed to take either the NO dietary supplement called Neo40 Daily(r) or placebo twice daily on an empty stomach for 30 days. Patients taking the NO dietary supplement twice a day for 30 days led to a significant increase in both plasma nitrite (P < .01) and nitrate (P < .0001), indicating an increase in systemic NO availability. There was a statistically significant reduction in 72% of patients with elevated triglycerides (>150 mg/dL) after 30 days compared with their starting levels before taking the NO dietary supplement (168 +/- 17 mg/dL vs 232 +/- 19 mg/dL, P = .02). The strategy of formulating a combination of natural products and botanicals chosen specifically for their NO activity shows promise in restoring NO homeostasis in human subjects at risk for cardiovascular disease for use as a dietary supplement. PMID- 21530800 TI - White potatoes, including french fries, contribute shortfall nutrients to children's and adolescents' diets. AB - To test the hypothesis that white potatoes (WP), oven-baked fries (OBF), and french fries (FF) contribute important nutrients within energy needs to children's and adolescents' diets, secondary analysis of 24-hour dietary recall data from the National Health and Nutrition Examination Survey 2003-2006 was conducted. Potato content of survey foods was determined using US Department of Agriculture recipe databases (Standard Reference (SR)-Link files). Nutrient content of potatoes was determined by linking SR codes to US Department of Agriculture food composition data. Daily nutrient intakes from potatoes were determined by applying the composition database to respondent's recall data. Sample-weighted data were analyzed; t tests assessed differences between age and sex groups. Results indicated that approximately 35% of children and adolescents consumed WP + FF + OBF; 18% consumed FF. Intakes were lower in children compared with adolescents (P < .01). Among adolescents, more boys than girls consumed FF (P < .05); boys ate larger amounts of WP + FF + OBF (134 g/d) and FF (100 g/d) (P < .01). Both WP + FF + OBF and FF provided 9% to 12% of total daily energy (but was within energy requirements in the highest consumers); 8% to 15% of daily fat (>75% monounsaturated fatty acids + polyunsaturated fatty acids); >= 10% dietary fiber, vitamin B(6), and potassium; 5% or greater thiamin, niacin, vitamin K, phosphorus, magnesium, and copper; and less than 5% sodium intake, for all sex age groups. The combination WP + FF + OBF provided 5% or greater vitamin C for all sex-age groups and 5% or greater vitamin E and iron for most groups; FF provided 5% or greater vitamin E intakes for all. These cross-sectional data show that WP, including FF, provided shortfall nutrients within energy requirements to children and adolescents and, when consumed in moderate amounts, can be part of healthful diets. PMID- 21530801 TI - Unsaturated fatty acids repress the expression of ATP-binding cassette transporter A1 in HepG2 and FHs 74 Int cells. AB - Adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays a critical role in the formation and metabolism of high-density lipoproteins (HDLs). Adenosine triphosphate-binding cassette transporter A1 in the liver and small intestine, in particular, accounts for approximately 90% of plasma HDL cholesterol. Therefore, any alterations in the hepatic and intestinal expression of ABCA1 could have a large impact on HDL biogenesis. We tested the hypothesis that ABCA1 expression is regulated differentially by different types of fatty acids in the liver and small intestine. Human hepatoma HepG2 and human small intestine epithelial FHs 74 Int cells were used as an in vitro model. Cells were incubated with saturated and unsaturated fatty acids in the presence or absence of T0901317, a synthetic agonist of liver X receptor. Unsaturated fatty acids decreased ABCA1 protein levels at 100 MUmol/L of concentration regardless of the agonist with a minimal effect on messenger RNA abundance. Incubation of HepG2 and FHs 74 Int cells with rottlerin, a protein kinase C delta (PKCdelta) inhibitor, increased ABCA1 protein but did not abolish linoleic acid-induced decrease in ABCA1 protein levels. Depletion of PKCdelta using small interfering RNA showed decreased ABCA1 protein levels in control, palmitic acid-, and linoleic acid treated cells; but the repressive effect of linoleic acid was sustained. In conclusion, our results indicate that unsaturated fatty acids regulate ABCA1 expression in HepG2 and FHs 74 Int cells at the posttranscriptional level and PKCdelta is likely to be involved in maintaining ABCA1 protein levels. PMID- 21530803 TI - The soluble fiber complex PolyGlycopleX lowers serum triglycerides and reduces hepatic steatosis in high-sucrose-fed rats. AB - Viscous soluble fibers have been shown to reduce risk factors associated with type 2 diabetes and cardiovascular disease. The novel functional fiber, PolyGlycopleX (PGX) (InovoBiologic Inc, Calgary, Alberta, Canada) displays greater viscosity than other currently identified soluble fibers. The objective of this study was to determine if PGX lowers serum and hepatic triglycerides (TGs) in a high-sucrose-fed rat model. In this rodent model, feeding a high sucrose diet consistently increases serum TGs. We hypothesized that consumption of PGX would attenuate hypertriglyceridemia and reduce hepatic steatosis compared with cellulose in rats fed a high-sucrose background diet. Male Sprague-Dawley rats were fed diets containing 65% sucrose and supplemented with either 5% cellulose (control) or 5% PGX (wt/wt) for 43 weeks. At study termination, serum insulin and TGs, hepatic steatosis, and hepatocellular injury were assessed. Body weight increased over time in both groups, but weight gain was attenuated in rats fed PGX vs cellulose in weeks 2 through 22 (P < .05). Serum TGs did not differ from baseline for the first half of the study but consistently increased in the cellulose group thereafter. PolyGlycopleX significantly reduced serum TG to near baseline levels. At study termination, rats fed PGX had significantly lower hepatic steatosis scores (measured by Sudan black staining) compared with rats fed cellulose. Hepatocellular injury scores did not differ between the groups. In conclusion, PGX reduced serum TG and lipid accumulation in the liver of sucrose fed rats. Further examination of its potential as a fiber supplement aimed at lessening the burden of hepatic steatosis is warranted. PMID- 21530802 TI - Dietary polyunsaturated fatty acids reduce retinal stress induced by an elevation of intraocular pressure in rats. AB - N-6 and n-3 polyunsaturated fatty acids (PUFAs) have been shown to prevent tissue release of inflammatory molecules. We have shown that a combination of n-6 and n 3 PUFAs is more efficient than single supplementations on the long-term consequences of intraocular pressure elevation. We hypothesized that such an association is also more effective during early retinal stress by modifying retinal proinflammatory prostaglandin and cytokine productions. Rats were supplemented for 3 months with n-6 PUFAs, n-3 PUFAs, or both n-6 and n-3 PUFAs. After 3 months, a surgical elevation of intraocular pressure was induced. Retinal morphometry and glial cell activation were evaluated 24 hours after laser treatment. The retinal levels of prostaglandin E(1) (PGE(1)) and prostaglandin E(2) (PGE(2)) and the messenger RNA levels of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha were measured. Retinal glial cell activation after laser treatment was partly prevented by dietary n-6, n-3, and n-6 and n-3 PUFAs. Retinal PGE(1) was unaffected by the laser treatment or by the diet. Dietary n-6 and/or n-3 PUFAs prevented the increase in PGE(2) levels observed in laser-treated retinas without affecting the induction of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha messenger RNAs. This study shows that not only a combination of n-6 and n-3 PUFAs but also single supplementations can preserve the retina from early glial cell activation and PGE(2) release. The protective effect is not mediated by changes in cytokine expression but may be related to modifications in retinal prostaglandin metabolism. PMID- 21530804 TI - Maize and resistant starch enriched breads reduce postprandial glycemic responses in rats. AB - White wheat bread is a poor source of dietary fiber, typically containing less than 2%. A demand exists for the development of breads with starch that is slowly digestible or partially resistant to the digestive process. The utilization of maize flour and resistant starch is expected to reduce the release and absorption of glucose and, hence, lower the glycemic index of bread. This study was undertaken to investigate the hypothesis that a diet of maize bread, as produced and consumed in Portugal, would have beneficial metabolic effects on rats compared to white wheat bread. We also hypothesized that the effect of resistant starch on glycemic response could be altered by the use of different formulations and breadmaking processes for wheat and maize breads. Resistant starch (RS) was incorporated into formulations of breads at 20% of the inclusion rate of wheat and maize flours. Assays were conducted with male Wistar rats (n = 36), divided into four groups and fed either wheat bread, RS-wheat bread, maize bread, and RS maize bread to evaluate feed intake, body weight gain, fecal pH, and postprandial blood glucose response (glycemic response). Blood triglycerides, total cholesterol concentrations, and liver weights were also determined. The maize bread group presented higher body weight gain and cholesterol level, lower fecal pH, and postprandial blood glucose response than the wheat bread group. The RS wheat bread group showed significant reductions in feed intake, fecal pH, postprandial blood glucose response, and total cholesterol. The RS-maize group displayed significant reductions of body weight gain, fecal pH, and total cholesterol levels; however, for the glycemic response, only a reduction in fasting level was observed. These results suggest that maize bread has a lower glycemic index than wheat bread, and the magnitude of the effect of RS on glycemic response depends of type of bread. PMID- 21530805 TI - Lipoic acid increases the expression of genes involved in bone formation in mice fed a high-fat diet. AB - Antioxidant lipoic acid (LA) has been reported to have a potential prophylactic effect on bone loss induced by high-fat diet (HFD). The aim of this work was to examine the hypothesis that LA decreases bone resorption-related gene expression and increases bone formation-related gene expression in HFD-fed mice, preventing a shift in the bone metabolism balance toward resorption. Male C57BL/6 mice were fed a normal diet, HFD, or HFD plus 0.1% LA for 12 weeks. The bone metabolism related genes differentially expressed between mice fed HFD and those fed HFD supplemented with LA were identified through complementary DNA microarray. The supplemental LA significantly increased bone mineral density and bone antioxidant capacity in mice fed HFD (P < .05). Compared with the HFD-fed mice, LA induced the decreased expression of genes associated with bone resorption, such as Mmp9 (1.9-fold) and Ctsk (2.3-fold), and increased those genes associated with bone formation, such as Col1a1 (1.3-fold) and Alp1 (1.5-fold). Furthermore, LA upregulated many genes involved in the Igf signaling pathway, such as Igf-1 (increased 1.7-fold), and downregulated genes involved in the p53 apoptotic pathway, such as p53 (decreased 2.3-fold), thus attenuating the HFD-induced inhibition of bone formation. Lipoic acid induced upregulation of Il12a (2.1 fold) and downregulation of Tgfbr1 (4.3-fold) and Il17a (11.3-fold), which may reduce bone resorption. In summary, LA supplementation during HFD could affect bone density, altering gene expression. PMID- 21530806 TI - Vitamin supplementation reduces the level of homocysteine in the urine of autistic children. AB - Significant differences in homocysteine levels in the urine of autistic children are observed. We hypothesized that vitamin supplementation might reduce the level of urinary homocysteine. To rationalize such a hypothesis, analyses were performed using the gas chromatography/mass spectrometry method. The homocysteine level in the urine of autistic children was measured twice: (1) before vitamin supplementation (group C, 30 autistic children) and (2) after supplementation, with either folic acid and vitamins B(6) and B(12) (group A1, 24 autistic children) or vitamins B(6) and B(12) alone (group A2, 6 autistic children). The homocysteine level in the urine of autistic children before vitamin supplementation was 2.41 +/- 1.10 mmol/mol creatinine (mean +/- SD difference). After treatment, the homocysteine level was reduced to 1.13 +/- 0.44 and 1.33 +/- 0.39 mmol/mol creatinine for A1 and A2 groups, respectively. The intake of vitamins B(6) and B(12), together with folic acid, was found to be more effective in lowering the levels of urinary homocysteine than the intake of vitamins B(6) and B(12) alone. Our findings may lead to the recommendation of including vitamins B(6) and B(12) together with folic acid supplementation in the diets of children with autism. PMID- 21530809 TI - Foreword: allergen immunotherapy. PMID- 21530807 TI - Tualang honey has higher phenolic content and greater radical scavenging activity compared with other honey sources. AB - Many chronic diseases are associated with increased oxidative stress caused by an imbalance between free-radical production and the antioxidant level. Antioxidants, which are abundant in natural honey, are free-radical scavengers that either reduce the formation of or neutralize free radicals. The composition and source of honey greatly dictates its biochemical properties. We performed a comparative analysis of the total phenolic content and antioxidant potential of common commercially available honeys along with Malaysian tualang honey. In vitro biochemical analysis of the phenolic content by the Folin-Ciocalteau method revealed a significantly elevated phenolic content (83.96 +/- 4.53 mg gallic acid equivalents per 100 g) in tualang honey. In addition, the antioxidant capacity (53.06 +/- 0.41 mg ascorbic acid equivalents per gram) of tualang honey was greater, as assessed by the phosphomolybdenum method, 2,2-diphenyl-1-picryl hydrazyl assay, and ferric reducing/antioxidant power assay. Peroxynitrite and superoxide radical scavenging activity was determined by spectrophotometric analysis in different honey types. Our data suggest that the elevated free radical scavenging and antioxidant activity observed in tualang honey is due to the increased level of phenolic compounds. In addition to its antibacterial, anticarcinogenic, and anti-inflammatory properties, our study highlights the favorable antioxidant properties of tualang honey, which may be important to human nutrition and health. PMID- 21530810 TI - Preface allergen immunotherapy: the first centenary and beyond. PMID- 21530811 TI - History of immunotherapy: the first 100 years. AB - Allergen-specific immunotherapy (SIT) defines and distinguishes the modern practice of clinical allergy and immunology as the 100th anniversary of this pioneering technique is celebrated. Despite the tremendous advancements made in therapeutics, pharmacology, and the basic science of allergy, SIT remains the only treatment modality that offers a potential cure for atopic diseases rather than simply an amelioration of symptoms. A historical perspective not only offers an opportunity to tell some of the fascinating stories that led to the conception of SIT but also gives an occasion to recognize, remember, and honor those individuals who have contributed to its development. PMID- 21530812 TI - Immunotherapy: The meta-analyses. What have we Learned? AB - Meta-analysis is a powerful tool for evaluating the efficacy of a therapeutic intervention, and has clearly demonstrated that specific allergen immunotherapy (SIT) is effective for treating allergic rhinitis and asthma. Future research needs to focus on specifying the most effective forms of SIT for specific populations and allergens, using validated clinical outcomes, studying long-term outcomes (particularly the potential disease-modifying effect of immunotherapy), and assessing outcomes regarding health economics. The safety profile of SIT should be evaluated using international guidelines and terminology, and needs to include high-quality surveillance data. PMID- 21530813 TI - Mechanisms of subcutaneous allergen immunotherapy. AB - Allergen-specific immunotherapy (SIT) is the only curative approach in the treatment of allergic diseases defined up-to-date. Peripheral T-cell tolerance to allergens, the goal of successful allergen-SIT, is the primary mechanism in healthy immune responses to allergens. By repeated administration of increased doses of the causative allergen, allergen-SIT induces a state of immune tolerance to allergens through the constitution of T regulatory (Treg) cells, including allergen-specific interleukin (IL)-10-secreting Treg type 1 cells and CD4(+)CD25(+)Treg cells; induction of suppressive cytokines, such as IL-10 and transforming growth factor beta; suppression of allergen-specific IgE and induction of IgG4 and IgA; and suppression of mast cells, basophils, eosinophils, and inflammatory dendritic cells. This review summarizes the current knowledge on the mechanisms of allergen-SIT with emphasis on the roles of Treg cells in allergen-SIT. PMID- 21530814 TI - Mechanisms of sublingual immunotherapy. AB - Sublingual immunotherapy (SLIT) has been shown to be effective in the treatment of seasonal allergic rhinoconjunctivitis. Despite comparable clinical efficacy to traditional subcutaneous immunotherapy, the mechanisms of SLIT have yet to be fully established. This article considers the role of the local oral mucosa and regional lymphoid tissues in the processing of allergen during SLIT and the subsequent effects on T-cell and B-cell immune compartments and at mucosal sites. The likely time course of events and the evidence for long-lasting tolerance following SLIT are discussed. PMID- 21530815 TI - Subcutaneous injection immunotherapy for optimal effectiveness. AB - Immunotherapy by the subcutaneous injection of increasing doses and then maintenance doses of extracts of inhalant allergens has been practiced for 100 years. Controlled clinical trials have established its efficacy in treating allergic rhinitis, asthma, and stinging insect sensitivity, and there are preliminary data to suggest a favorable response in some patients with atopic dermatitis. The response to subcutaneous injection immunotherapy is dose dependent. Disease-modifying actions include blocking development of new sensitivities in monosensitized patients, blocking progression to asthma in patients with allergic rhinitis, and persistence of treatment effects for up to 7 to 10 years after an initial course. PMID- 21530816 TI - Allergen compatibilities in extract mixtures. AB - Stability studies with a few well-characterized allergen extracts have yielded useful information about the shelf-life of these products stored under various conditions. The development of validated stability-indicating tests and their clinical verification remains a fundamental challenge for extending this information to cover more products. This challenge becomes even greater for evaluations of more complex, multiextract mixtures that are used in clinical practice. Thus, the current approach for developing guidelines for extract expiration dating practices must rely on extrapolations of data obtained from a few well-controlled studies. PMID- 21530817 TI - Systemic reactions to subcutaneous allergen immunotherapy. AB - Subcutaneous allergen immunotherapy (SCIT) has been practiced for 100 years. Many trials have established the efficacy of SCIT in reducing symptoms of both seasonal allergic rhinitis and asthma due to aeroallergens. However, clinical benefits of SCIT are tempered by risks of injection-related systemic reactions and life-threatening anaphylaxis. This article reviews data derived from retrospective surveys conducted to define the incidence, prevalence, and factors contributing to injection-related fatal anaphylactic and near-fatal systemic reactions, as well as recently initiated longitudinal surveillance studies of SCIT reactions. PMID- 21530818 TI - Accelerated immunotherapy schedules and premedication. AB - Subcutaneous immunotherapy is divided into a buildup and a maintenance phase. Accelerated immunotherapy has the advantage of a reduced number of office visits. Rush and cluster immunotherapy schedules are the most common accelerated schedules used in the United States. A cluster immunotherapy schedule involves the patient receiving several allergen injections sequentially in a single day of treatment on nonconsecutive days. The maintenance dose is reached in 4 to 8 weeks. In rush immunotherapy protocols, higher doses are administered at intervals of 15 to 60 minutes in a period of 1 to 3 days until the maintenance dose is achieved. PMID- 21530819 TI - Sublingual immunotherapy for allergic respiratory diseases: efficacy and safety. AB - Subcutaneous immunotherapy (SCIT) is effective and safe when properly prescribed and administered. However, a certain risk of severe side effects exists, even when the reaction is managed correctly. These potential adverse effects stimulated the search for new administration routes (nasal, bronchial, oral, sublingual), which were expected to be safer. Not all of these alternative routes provided an improved benefit-safety profile compared with SCIT. The sublingual route (SLIT) seemed to be a good candidate for the clinical practice because of its satisfactory safety profile and is now considered an acceptable alternative to SCIT in adults and children. PMID- 21530820 TI - Sublingual immunotherapy: other indications. AB - Sublingual immunotherapy (SLIT) represents a significant advance and it seems particularly suitable in pediatric patients. There are favorable results for food allergy in controlled trials. For latex allergy, the results of several trials are encouraging. For atopic dermatitis, previous experience with subcutaneous immunotherapy and some earlier trials suggest the possible application of SLIT in children with mild to moderate dermatitis and sensitization to dust mite, but this recommendation is considered insufficiently evidence based. In hymenoptera allergy, the only trial available is a proof-of-concept study in large local reactions that needs to be confirmed in well-controlled studies. PMID- 21530821 TI - Allergen-specific immunotherapy: which outcome measures are useful in monitoring clinical trials? AB - Various clinical outcome measures are commonly applied in clinical trials on specific immunotherapy for allergic rhinoconjunctivitis with or without asthma to provide evidence of its clinical efficacy. These "primary endpoints" measure clinical symptoms as well as the use for concomitant medication. "Secondary outcome endpoints" are represented by health-related quality of life (HRQoL), "well-days," provocation-tests, in vitro tests and others. This article reviews different methods assessing the clinical outcome of trials on both subcutaneous and sublingual immunotherapy, and highlights potential advantages and drawbacks of each method. PMID- 21530822 TI - Serum immunologic markers for monitoring allergen-specific immunotherapy. AB - Allergen immunotherapy is an effective treatment option in patients with IgE mediated allergy, particularly in those who do not respond to usual antiallergic drugs. Successful immunotherapy has been associated with the suppression of allergic inflammation in target organs and increases in allergen-specific IgG antibodies, particularly the IgG(4) subclass. To date there are no biomarkers that are predictive of the clinical response to immunotherapy. This article explores the possibility that functional assays based on the ability of IgG to compete with IgE and inhibit IgE-allergen complex formation may be surrogate or predictive of the clinical response to immunotherapy. PMID- 21530823 TI - The health economics of allergen immunotherapy. AB - In contrast to symptomatic drug treatment, which only temporarily relieves allergy symptoms, allergen-specific immunotherapy (SIT) has the potential to alter the course of allergic disease, thereby reducing the need for long-term treatment, the progression of allergic rhinitis (AR) to asthma, and the development of new allergies. The clinical benefits of SIT have been shown to persist for an additional 3 to 12 years after discontinuation of a 2.5- to 5.0 year treatment. It therefore stands to reason that the clinical benefits of SIT also extend to economic benefits. A growing number of studies have evaluated the economic benefits of SIT in patients with AR and/or asthma. The authors critically examine each of these studies published from 1995 to present. PMID- 21530824 TI - Future forms of immunotherapy and immunomodulators in allergic disease. AB - Future forms of immunotherapy, particularly toll-like receptor agonists, have shown promising results in animal models of allergic disease although most have failed to translate into successful human clinical trials. These results have helped to elucidate the pleotropic roles of cytokines as well as the diverse phenotypes of allergic diseases, particularly asthma. The goals of these therapies are to improve patient symptoms and quality of life, to prevent and favorably alter disease course, and to maintain a good risk/benefit ratio along with a cost-effective profile. PMID- 21530825 TI - Oral desensitization for food hypersensitivity. AB - Food allergy has become an increasingly prevalent international health problem. Allergic reactions can result in life-threatening anaphylaxis in a short period of time, so the current standard of care dictates strict avoidance of suspected trigger foods and accessibility to injectable epinephrine. Intervention at the time of exposure is considered a rescue therapy rather than a disease-modifying treatment. Investigators have been studying allergen immunotherapy to promote induction of oral tolerance. This article examines the mechanisms of oral tolerance and the breakdown that leads to food allergy, as well as the history and current state of oral and sublingual immunotherapy development. PMID- 21530826 TI - Peptide and recombinant immunotherapy. AB - Because of the need to standardize allergen immunotherapy and the desire to reduce allergic adverse events during therapy, a transition to recombinant/synthetic hypoallergenic approaches is inevitable. Evidence supports the notion that effective therapy can be delivered using a limited panel of allergens or even epitopes, weakening the argument that all allergens must be present for optimal efficacy. Moreover, standardized products will allow direct comparisons between studies and, for the first time, immunotherapy studies will be truly blinded, allowing an accurate assessment of the actual treatment effect that can be achieved with this form of intervention. PMID- 21530827 TI - Novel administration routes for allergen-specific immunotherapy: a review of intralymphatic and epicutaneous allergen-specific immunotherapy. AB - For the past century, subcutaneous allergen-specific immunotherapy has been the state-of-the-art treatment for IgE-mediated allergic disease. Current research on allergen-specific immunotherapy is focused on enhancing its efficacy, safety, and patient convenience with the goal of offering a broadly accepted treatment option. There is a growing interest in intralymphatic allergen-specific immunotherapy because it is a highly efficacious and safe treatment route that requires only 3 injections. Concurrently, epicutaneous allergen-specific immunotherapy is attracting increasing attention because of its capacity to offer a safe, needle-free, and potentially self-administrable treatment option for IgE mediated allergic diseases. In this article, we discuss the principles and immunologic rationale of these unconventional routes of allergen-specific immunotherapy while highlighting their developmental process and clinical relevance. PMID- 21530828 TI - Adjuvants and vector systems for allergy vaccines. AB - Allergen-specific immunotherapy represents a curative treatment of type I allergies. Subcutaneous immunotherapy is conducted with allergens adsorbed on aluminum hydroxide or calcium phosphate particles, whereas sublingual immunotherapy relies on high doses of soluble allergen without any immunopotentiator. There is a potential benefit of adjuvants enhancing regulatory and Th1 CD4+T cell responses during specific immunotherapy. Molecules affecting dendritic cells favor the induction of T regulatory cell and Th1 responses and represent valid candidate adjuvants for allergy vaccines. Furthermore, the interest in viruslike particles and mucoadhesive particulate vector systems, which may better address the allergen(s) to tolerogenic antigen-presenting cells, is documented. PMID- 21530829 TI - Coffee and muscle cramps. PMID- 21530831 TI - Abortion access for imprisoned women: marginalized medical care for a marginalized group. PMID- 21530832 TI - Sociodemographic factors associated with obstacles to abortion care: findings from a survey of abortion patients in Mexico City. AB - BACKGROUND: First-trimester abortion was legalized in Mexico City in 2007, and services are now provided at public and private sites throughout the city. However, little is known about the obstacles women face when seeking abortion care. METHODS: We surveyed women who obtained abortion services (n = 398) at three public sector facilities in Mexico City to identify the obstacles women faced when obtaining abortions. We used logistic regression to test whether obstacles varied by sociodemographic characteristics. RESULTS: Women with low education were more likely than high school-educated women to report difficulty getting appointments. Unmarried women and women with low education were more likely than married women or high school educated women to report difficulty getting time off work for appointments and arranging for transportation to the facility. Separated or divorced women were more likely than married women to report partner or other family member opposition to the abortion. Women who lived outside of Mexico City were more likely than Mexico City residents to report difficulty with transportation. CONCLUSION: Education, marital status, and place of residence were associated with the obstacles women reported. Strategies to improve access to care should be targeted to the groups at highest risk of experiencing obstacles: Women with primary education or lower, single women, separated/divorced women, and those residing outside of Mexico City. PMID- 21530833 TI - The Ellertson Fellowship: advancing reproductive health through social science and public health research. PMID- 21530834 TI - Out of time and out of pocket: experiences of women seeking state-subsidized insurance for abortion care in Massachusetts. AB - BACKGROUND: Massachusetts has implemented reforms aimed at providing universal health care coverage and covers abortion through subsidized state insurance programs. Three Massachusetts abortion funds evaluated their referral processes for low-income women from April to October 2010 to learn about women's experiences applying for subsidized insurance and to identify barriers to obtaining insurance or its use for abortion services. METHODS: Follow-up interviews were conducted with 39 low-income women thought eligible for subsidized insurance at least 1 month after their initial contact with the funds. RESULTS: Health insurance literacy was low, and participants reported confusion distinguishing between levels of subsidized insurance. The process of applying for subsidized insurance delayed a substantial proportion of procedures. More than two thirds of the women who applied for state coverage had become insured or expected to become insured shortly, but only one third of respondents who applied were able to secure insurance in time for their abortion care. Two women were unable to obtain abortions as a result of delays. Delays also limited low-income women's ability to obtain medication abortion. CONCLUSION: This analysis suggests that the process for enrolling in subsidized insurance does not currently meet the goal of providing women with coverage for abortion care (and other health needs) in a timely way. Systemic improvements are needed to ensure that enrollments are processed quickly and disruptions in coverage are minimized. Information resources should be developed to help women and their families understand health insurance and coverage of services. PMID- 21530835 TI - Perceived and insurance-related barriers to the provision of contraceptive services in U.S. abortion care settings. AB - BACKGROUND: Abortion facilities represent a potentially convenient setting for providing contraception to women experiencing unintended pregnancies. This analysis examines a range of factors that may act as barriers to integrating contraceptive and abortion services and documents abortion providers' perspectives on their role in their patients' contraceptive care. METHODS: Administrators from 173 large, nonhospital facilities that provide abortions in the United States responded to a structured survey between May and September 2009. We used chi-square tests to assess differences in categorical outcomes. RESULTS: Although the majority of U.S. abortion facilities offer a range of contraceptive methods on site, facility staff identified multiple barriers to full integration of the two services, in particular, insurance, patient, and cost barriers. Few of these perceived barriers, however, were associated with differences in the actual provision of most contraceptive methods. Specialized abortion clinics that do not accept health insurance were less likely to have highly effective methods, such as intrauterine devices and implants, on site. Facilities located in Medicaid states were more likely to accept both public and private health insurance for contraceptive services. CONCLUSION: Increased access to contraceptive services during abortion care is one strategy for reducing repeat unintended pregnancy, and stakeholders at all levels--including abortion providers, insurance companies, and policy makers--have a role to play in achieving this goal. PMID- 21530836 TI - Physicians and abortion: provision, political participation and conflicts on the ground--the cases of Brazil and Poland. AB - BACKGROUND: Two qualitative studies have been conducted between 2002 and 2009 in Poland and Brazil, two different geopolitical settings in which the Catholic Church has had a significant political influence and where abortion is highly restricted. In both countries, struggles for abortion rights have played an important role in challenging the current restrictive policies and bringing attention to the plight of women unable to obtain abortions. This article examines the political role that physicians play in these contestations, drawing on some findings of two larger qualitative studies. METHODS: In Poland semi structured interviews were conducted with 26 physicians in Warsaw and Krakow and with 55 women aged 18 to 45 in Gdansk. In Brazil questionnaires were administered and semi-structured interviews conducted with 22 obstetrician-gynecologists and 23 health professionals in two public maternity hospitals in Salvador da Bahia. FINDINGS: This article argues that gynecologists' perspectives and practices not only reflect or heed religious precepts on reproductive rights, but are also deeply influenced by inadequate medical training and by the fear of being prosecuted or stigmatized, especially in Brazil. The political non-engagement of physicians in Poland is driven by the lack of abortion rights discourse in the public arena, poor links with women's rights groups, and the lack of political unity within the medical community. CONCLUSIONS: Comparisons between Brazil and Poland ultimately suggest that strong liaisons between physicians and the feminist movement influence physicians' attitudes and political engagement and are most promising in abortion rights advocacy efforts. PMID- 21530837 TI - Sex-selective abortion in Nepal: a qualitative study of health workers' perspectives. AB - BACKGROUND: Sex-selective abortion is expressly prohibited in Nepal, but limited evidence suggests that it occurs nevertheless. Providers' perspectives on sex selective abortion were examined as part of a larger study on legal abortion in the public sector in Nepal. METHODS: In-depth interviews were conducted with health care providers and administrators providing abortion services at four major hospitals (n = 35), two in the Kathmandu Valley and two in outlying rural areas. A grounded theory approach was used to code interview transcripts and to identify themes in the data. RESULTS: Most providers were aware of the ban on sex selective abortion and, despite overall positive views of abortion legalization, saw sex selection as an increasing problem. Greater availability of abortion and ultrasonography, along with the high value placed on sons, were seen as contributing factors. Providers wanted to perform abortions for legal indications, but described challenges identifying sex-selection cases. Providers also believed that illegal sex-selective procedures contribute to serious abortion complications. CONCLUSION: Sex-selective abortion complicates the provision of legal abortion services. In addition to the difficulty of determining which patients are seeking abortion for sex selection, health workers are aware of the pressures women face to bear sons and know they may seek unsafe services elsewhere when unable to obtain abortions in public hospitals. Legislative, advocacy, and social efforts aimed at promoting gender equality and women's human rights are needed to reduce the cultural and economic pressures for sex-selective abortion, because providers alone cannot prevent the practice. PMID- 21530838 TI - Expanding the pool of abortion providers: nurse-midwives, nurse practitioners, and physician assistants. PMID- 21530839 TI - Later abortions and mental health: psychological experiences of women having later abortions--a critical review of research. AB - BACKGROUND: Some abortion policies in the U.S. are based on the notion that abortion harms women's mental health. The American Psychological Association (APA) Task Force on Abortion and Mental Health concluded that first-trimester abortions do not harm women's mental health. However, the APA task force does not make conclusions regarding later abortions (second trimester or beyond) and mental health. This paper critically evaluates studies on later abortion and mental health in order to inform both policy and practice. METHOD: Using guidelines outlined by Steinberg and Russo (2009), post 1989 quantitative studies on later abortion and mental health were evaluated on the following qualities: 1) composition of comparison groups, 2) how prior mental health was assessed, and 3) whether common risk factors were controlled for in analyses if a significant relationship between abortion and mental health was found. Studies were evaluated with respect to the claim that later abortions harm women's mental health. RESULTS: Eleven quantitative studies that compared the mental health of women having later abortions (for reasons of fetal anomaly) with other groups were evaluated. Findings differed depending on the comparison group. No studies considered the role of prepregnancy mental health, and one study considered whether factors common among women having later abortions and mental health problems drove the association between later abortion and mental health. CONCLUSION: Policies based on the notion that later abortions (because of fetal anomaly) harm women's mental health are unwarranted. Because research suggests that most women who have later abortions do so for reasons other than fetal anomaly, future investigations should examine women's psychological experiences around later abortions. PMID- 21530840 TI - Abortion stigma: a reconceptualization of constituents, causes, and consequences. AB - Stigmatization is a deeply contextual, dynamic social process; stigma from abortion is the discrediting of individuals as a result of their association with abortion. Abortion stigma is under-researched and under-theorized, and the few existing studies focus only on women who have had abortions. We build on this work, drawing from the social science literature to describe three groups whom we posit are affected by abortion stigma: Women who have had abortions, individuals who work in facilities that provide abortion, and supporters of women who have had abortions, including partners, family, and friends, as well as abortion researchers and advocates. Although these groups are not homogeneous, some common experiences within the groups--and differences between the groups--help to illuminate how people manage abortion stigma and begin to reveal the roots of this stigma itself. We discuss five reasons why abortion is stigmatized, beginning with the rationale identified by Kumar, Hessini, and Mitchell: The violation of female ideals of sexuality and motherhood. We then suggest additional causes of abortion stigma, including attributing personhood to the fetus, legal restrictions, the idea that abortion is dirty or unhealthy, and the use of stigma as a tool for anti-abortion efforts. Although not exhaustive, these causes of abortion stigma illustrate how it is made manifest for affected groups. Understanding abortion stigma will inform strategies to reduce it, which has direct implications for improving access to care and better health for those whom stigma affects. PMID- 21530841 TI - Beyond abstinence and risk: a new paradigm for adolescent sexual health. PMID- 21530842 TI - It's not just about abortion: incorporating intersectionality in research about women of color and reproduction. AB - Intersectionality was first articulated in the 1970s and 1980s by women of color scholars, such as Deborah King, Patricia Hill Collins, Kimberle Crenshaw, Cherrie Moraga, Gloria Anzualdua, and Nira Yuval-Davis, and has now become a core concept in women's and gender studies. It is generally understood within feminist circles that researchers must address the interlocking effects of identities, oppressions, and privileges to fully understand the range and complexity of women's experiences. Women (and men) not only experience the effects of gender in their lives, but they are also affected by their race, ethnicity, class, sexual orientation, and (dis)ability, among other aspects of their identities. These identities do not operate separately from one another, but work in tandem to shape the social, cultural, economic, and political conditions of individuals and social groups. In sum, intersectionality is not about identity politics, but is about the social, cultural, political, and economic processes that affect our lives. PMID- 21530843 TI - Conducting collaborative abortion research in international settings. AB - Nearly 20% of the 208 million pregnancies that occur annually are aborted. More than half of these (21.6 million) are unsafe, resulting in 47,000 abortion related deaths each year. Accurate reports on the prevalence of abortion, the conditions under which it occurs, and the experiences women have in obtaining abortions are essential to addressing unsafe abortion globally. It is difficult, however, to obtain accurate and reliable reports of attitudes and practices given that abortion is often controversial and stigmatized, even in settings where it is legal. To improve the understanding and measurement of abortion, specific considerations are needed throughout all stages of the planning, design, and implementation of research on abortion: Establishment of strong local partnerships, knowledge of local culture, integration of innovative methodologies, and approaches that may facilitate better reporting. This paper draws on the authors' collaborative research experiences conducting abortion related studies using clinic- and community-based samples in five diverse settings (Poland, Zanzibar, Mexico City, the Philippines, and Bangladesh). The purpose of this paper is to share insights and lessons learned with new and established researchers to inform the development and implementation of abortion related research. The paper discusses the unique challenges of conducting abortion-related research and key considerations for the design and implementation of abortion research, both to maximize data quality and to frame inferences from this research appropriately. PMID- 21530844 TI - Associations between perceived partner support and relationship dynamics with timing of pregnancy termination. AB - BACKGROUND: Little is known about partner- and relationship-level characteristics that may affect the timing of pregnancy termination. The present study sought to address this issue by examining women's perceptions of social support and relationship-level dynamics for their association with timing of pregnancy termination. METHODS: Data on partner characteristics and relationship dynamics were collected from 373 women receiving abortions at clinics in two large East Coast cities via a brief, self-administered survey. These surveys collected information on individual and partner characteristics as well as perceived emotional, financial, and material support and relationship dynamics. RESULTS: Forty-six percent of women (mean age, 25 years; 52% African American, 27% Latina, 9% White; 34% currently in school; 37% employed full time) in this study were terminating a pregnancy at more than 9 weeks' gestation (mean, 9.6; median, 8; interquartile range, 6-12). On bivariate analysis, we found that women terminating early (<9 weeks) were more likely to report perceptions of supportive partner interactions and joint decision making compared with those terminating later. Perceived negative interactions with partners were associated with later termination. In multivariate analysis, controlling for sociodemographic characteristics, women who reported delays in pregnancy termination were also more likely to report a greater degree of perceived negative interactions in their relationships (adjusted odds ratio, 1.95; 95% confidence interval, 1.19 3.20). DISCUSSION: These findings suggest that factors influencing a woman's decision to terminate a pregnancy are not limited to her own professional or personal goals, but also include the social and relationship context within which the pregnancy occurs. PMID- 21530845 TI - Treatment strategy for hepatocellular carcinoma with major portal vein or inferior vena cava invasion: a single institution experience. AB - BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) invading the main trunk of the portal vein and the inferior vena cava is dismal. The best strategy for treatment is not well known. STUDY DESIGN: We retrospectively reviewed the medical records of 641 patients treated for HCC between 1990 and June 2009. Eighty-four (13%) of these patients had HCC, with a tumor thrombus invading the main trunk or the first-order branch of the portal vein, or the inferior vena cava. Thirty-four patients underwent hepatectomy and 50 patients underwent transcatheter arterial chemoembolization (TACE). We specifically focused on these 34 patients to describe our results of surgical treatment for advanced HCC. RESULTS: Among the 34 patients who underwent hepatectomy, preoperative TACE was performed in 15 patients. Six patients were identified as having a tumor size reduction or necrosis of 50% or higher (TE3) by TACE. The median operative duration was 355 minutes. Postoperative morbidity and mortality rates were 44% and 2.9%, respectively. The 5-year survival rate after hepatectomy was 20%, which was better than that of patients after TACE alone. The response after preoperative TACE (hazard ratio 4.65; 95% CI, 1.39 to 15.5) and tumor diameter (hazard ratio 2.78; 95% CI, 1.16 to 6.64) were identified as significant favorable preoperative prognostic factors for survival using the multivariable Cox model. Patients with tumors smaller than 10 cm and TE3 effect had a more favorable survival than patients with tumors 10 cm or larger and who did not have a good TACE outcome. CONCLUSIONS: A combination of aggressive surgical treatment and effective preoperative TACE treatment for HCC with major vascular invasion may be beneficial for selected patients. PMID- 21530846 TI - Is malignant dedifferentiation for mucinous appendiceal neoplasms a valid phenomenon or merely histopathologic ambiguity? PMID- 21530848 TI - Comparing the quality of surgical care: a reason for caution. PMID- 21530851 TI - Meta-analysis of hyperoxia to prevent surgical site infection. PMID- 21530852 TI - Surgical site infection in colorectal surgery: a review of the nonpharmacologic tools of prevention. PMID- 21530854 TI - Improving performance in single-incision laparoscopy. PMID- 21530856 TI - The impact of select chronic disease on outcomes after trauma. PMID- 21530857 TI - The diverse surgeons initiative and increasing underrepresented minorities in academic surgery. PMID- 21530859 TI - What is the best way to guarantee postoperative glycemic control? PMID- 21530860 TI - Business course for residents. PMID- 21530861 TI - Oncologically safe suture retraction in single-incision laparoscopic surgery. PMID- 21530863 TI - On the cover - buffalo grass. PMID- 21530864 TI - Potency variability in diagnostic allergen extracts: is there an optimal strength? PMID- 21530865 TI - The role of epigenetics in the developmental origins of allergic disease. AB - OBJECTIVE: To review current research findings in the field of epigenetics pertaining to the developmental origins of allergic disease. DATA SOURCES: We examined original research and review articles identified from MEDLINE, OVID, and PubMed that addressed the topic of interest, using the search terms atopy, allergy, asthma, development, IgE, origins, and cord blood paired with epigenetic(s). Relevant references from each article were also procured for review. STUDY SELECTION: Articles were selected based on their relevance to the contributory role of epigenetic modifications in asthma and other atopic diseases. RESULTS: There is increasing evidence pointing to the influence of prenatal and early life exposures on the development of allergic disease. A growing body of literature supports the theory that transient environmental pressures can have permanent effects on gene regulation and expression through epigenetic mechanisms. Histone modifications have been associated with degree of bronchial hyperresponsiveness and corticosteroid resistance in asthma. Epigenetic mechanisms can operate independently in various cell types; recent studies have suggested a role in the differentiation of human T cells. Murine studies have revealed that a maternal diet rich in methyl donors can enhance susceptibility to allergic inflammation in the offspring, mediated through increased DNA methylation. Murine studies have also implicated epigenetically modified dendritic cells in the transmission of allergic risk from mothers to offspring. CONCLUSION: The current literature offers exciting data to support a role for epigenetics in the development and persistence of asthma and allergic rhinitis. However, further human studies are necessary to explore these mechanisms and assess future clinical applicability. PMID- 21530866 TI - Predictive factors for airway hyperresponsiveness in children with respiratory symptoms. AB - BACKGROUND: Asthma diagnosis is a challenging condition, particularly in patients without obstructive pattern and reversibility on spirometry. Determination of airway hyperresponsiveness (AHR) may be helpful, but the procedure is time consuming and not always practical. OBJECTIVE: To determine the potential factors that may predict the presence of AHR in children with asthmalike symptoms but without obstructive pattern and reversibility on spirometry. METHODS: All patients with asthmalike symptoms but without obstructive pattern and reversibility on spirometry were analyzed retrospectively between January 9, 2007, and December 30, 2009. The features of clinical history and laboratory results were analyzed with univariate and multivariate regression analysis. RESULTS: A total of 111 children between 6 and 18 years of age, with a median age of 10.2 years, were analyzed, and AHR was detected in 67 patients (60.3%). Multivariate logistic regression analysis revealed coexistence of nocturnal cough and exercise-induced cough (odds ratio [OR], 22.1; 95% confidence interval [CI], 3.1-159.2; P = .004), eosinophilia (OR, 18.7; 95% CI, 1.9-178.7; P = .01), and borderline bronchodilator response in forced expiratory volume in 1 second (between 7% and 11%) (OR, 10.1; 95% CI, 2.1-49.1; P = .004) as significant risk factors for the presence of AHR, whereas exercise-induced dyspnea was found to be related to the absence of AHR (OR, 0.2; 95% CI, 0.1-0.8; P = .02). CONCLUSION: In children with asthmalike symptoms but with normal spirometry, certain features of clinical history and laboratory results can strongly predict the presence of AHR and may help less frequent use of challenge tests. PMID- 21530868 TI - Stability of sealed-bag samples for off-line measurement of fractional exhaled nitric oxide. AB - BACKGROUND: Fractional exhaled nitric oxide (FeNO) measurement is an index of airway eosinophilic inflammation and is primarily employed to diagnose bronchial asthma and assess airway inflammation. It can be measured with on- and off-line methods. In the latter, sample storage is possible; this is useful in Japan, because the number of facilities in which this instrument has been installed is limited. OBJECTIVE: We investigated the maximum period in which the samples continued to show stable values, as well as the influences of the storage environment. METHODS: Exhaled air samples were collected from 19 bronchial asthma patients (male/female: 8/11; mean age: 54.9 +/- 15.6 years), and divided into 2 groups: a group with an FeNO level of less than 30 ppb and that with a level of 30 ppb or more. They were stored at 4 and 25 degrees C to examine serial changes. RESULTS: The off-line-measured FeNO value was 33.7 +/- 17.1 ppb, significantly lower than the on-line measured value (71.4 +/- 47.7 ppb) (P < .01). In a group with an FeNO level of less than 30 ppb, temperature had no influence. However, in the other group, the period was prolonged to 72 hours when the samples were stored at 4 degrees C. The samples were stable at 4 degrees C for 24 hours, regardless of the initial measurements. CONCLUSION: The duration of sample storage can be prolonged at 4 degrees C. The standard FeNO measurement method is the on-line method, but the alternative use of the off-line method may contribute to the diagnosis and treatment of the patients. PMID- 21530867 TI - Association of elevated plasminogen activator inhibitor 1 levels with diminished lung function in patients with asthma. AB - BACKGROUND: We previously reported that plasminogen activator inhibitor 1 (PAI-1) was upregulated in human asthmatic airways and promotes airway fibrosis in an allergen-challenged murine model of asthma. OBJECTIVES: To examine whether elevated plasma levels of PAI-1 are associated with poor lung function in asthmatic patients. METHODS: Five hundred nineteen adults were eligible for the study, and ultimately 353 adults were enrolled and completed the baseline protocol between January 24, 2004, and July 30, 2005. Of these, 231 adults with asthma from the Chicago Initiative to Raise Asthma Health Equity study were randomly selected and the plasma levels of PAI-1 were measured by enzyme-linked immunosorbent assay. Asthma burden, medication, smoking status, and body mass index (BMI) were obtained by history and spirometry was performed. A multivariate regression analysis was performed to evaluate the association of PAI-1 levels and lung function and the potential determinant variables that were associated with PAI-1. RESULTS: We found associations between PAI-1 and BMI (beta = 0.606, P = .002), smoking (beta = 7.526, P = .001), and African American race (beta = 9.061, P = .01). Obese patients showed a significant increase in PAI-1, and current smokers demonstrated higher levels of PAI-1 compared with nonsmokers. When we evaluated the associations between lung function parameters and PAI-1, we found that PAI-1 was negatively associated with forced vital capacity (FVC) (beta = -0.098, P = .011) but not with forced expiratory volume in 1 second (FEV(1)) or the FEV(1)/FVC ratio. There was a negative association between BMI and FVC, and PAI-1 may mediate some of this association. CONCLUSIONS: This study suggests a significant association between PAI-1 and lung function in patients with asthma. The effect of obesity on FVC may in part be mediated by PAI-1. PMID- 21530869 TI - The CHI3L1 rs4950928 polymorphism is associated with asthma-related hospital admissions in children and young adults. AB - BACKGROUND: Asthma exacerbations are the commonest cause of medical admissions in childhood. These have a significant effect on quality of life and are a major financial burden on worldwide healthcare services. A range of gene-environment interactions may influence the course and severity of asthma in children and their response to medication. The Chitinase 3-like 1 (CHI3L1)-131C>G genotype (rs4950928) is associated with increased asthma susceptibility and severity in adults. OBJECTIVES: To study the interactions of the Chitinase 3-Like-1 functional promoter SNP rs4950928 and its role on asthma exacerbations in a population of children and young adults with asthma. METHODS: A cross-sectional survey was undertaken using medical records and direct interviews of 1,071 children and young adults with asthma, aged 3 to 22 years, from Scotland. Saliva samples were collected for genotyping. Binary logistic regression was used to calculate odds ratios (ORs) and P-values for measures of asthma exacerbations. RESULTS: The minor -131G allele confers protection against asthma-related hospital admissions (OR = 0.62; 95% CI 0.41-0.92; P = .018) in children and young adults with asthma. CONCLUSIONS: Our study shows that rs4950928 is significantly associated with hospital admissions in children and young adults; screening for rs4950928 may predict asthma-related hospital admissions, and through individually defined treatment management plans, potentially reduce health care costs. PMID- 21530870 TI - The diagnostic value of basophil activation test in patients with an immediate hypersensitivity reaction to radiocontrast media. AB - BACKGROUND: No available test diagnoses allergic reactions to radiocontrast media (RCM). The basophil activation test (BAT) has been introduced for the diagnosis of both immunoglobulin (Ig) E and non-IgE-dependent mast cell degranulation, but its value to diagnose immediate RCM reactions is still unknown. OBJECTIVE: This study aims to evaluate the diagnostic value of BAT in immediate RCM hypersensitivity. METHODS: The BATs were performed in 26 patients with immediate RCM reactions and in 43 specimens from healthy volunteers. The sample's whole blood was incubated with the responsible RCM and % activated (CD63+/CCR3+) basophils were analyzed by flow cytometry. Receiver operating characteristics (ROC) curve analysis was performed to calculate the optimal cutoff value of activated basophils to diagnose patients with RCM hypersensitivity. RESULTS: The incubation of blood with RCM yielded significantly higher activated basophil percentages in patients with a history of immediate RCM reactions than in normal controls with both 1:100 and 1:10 dilutions (13.11% vs. 2.71%, P value = .01; and 19.23% vs. 3.73%, P = .001, respectively). Both % activated basophils and stimulation index (SI) had acceptable discrimination powers to diagnose RCM hypersensitivity. The area under the curve was 0.79 (95% CI 0.67-0.91, P = .000) by using SI as the diagnostic criteria with 1:100 dilution of RCM. The specificity of the test ranged from 88.4% to 100%. CONCLUSION: Our study demonstrated the potential of BAT as a diagnostic tool for an immediate RCM hypersensitivity, particularly as a confirmation test. Further studies are required to confirm the test accuracy and identify a patient's predisposing factors. PMID- 21530871 TI - Identification of nasal eosinophils using two-photon excited fluorescence. AB - BACKGROUND: Eosinophils trigger symptoms in allergic rhinitis. New diagnostic methods for identifying nasal eosinophils based on autofluorescence of flavin adenine dinucleotide in eosinophil granules could offer rapid monitoring without fixation or staining. Two-photon excitation is a powerful method for detecting this intrinsic fluorescence. OBJECTIVES: To demonstrate the use of 2-photon excited fluorescence (TPEF) to detect eosinophils from nasal mucosa in a proof-of concept study for a future miniature in vivo imaging instrument. METHODS: Thirty subjects with rhinitis were recruited. Results of our standard environmental panel were recorded. Fluorescence images were collected from nasal cytology smears with a 2-photon microscope. Cells were evaluated for intensity and size, and compared with Hansel stains. Correlation of cell count was made by linear regression, diagnostic performance was evaluated at various intensity thresholds, and correlation of nasal eosinophil count to allergic status was done through the Wilcoxon rank-sum test. RESULTS: The fluorescence intensity of eosinophils compared with epithelial cells was 13.8 +/- 4.3 versus 3.7 +/- 1.8 (P < .01), and the size was 27.0 +/- 10.2 versus 392.0 +/- 214.6 MUm2 (P < .01), respectively. Using both fluorescence intensity and size, a total accuracy of 100% is achieved. Eosinophil count on TPEF correlates with Hansel stain, R(2) = 0.91. Nasal eosinophil count correlates with allergic status on both TPEF (P = .008) and Hansel stain images (P = .027). CONCLUSIONS: TPEF is a promising novel technique for identifying and quantifying nasal eosinophils on nasal cytology specimens without the need for fixation or staining. Future development of a rhinoscope compatible 2-photon microscope could be used as a clinical adjunct for the diagnosis and management of rhinitis patients in vivo. PMID- 21530872 TI - Anaphylaxis in emergency department patients 50 or 65 years or older. AB - BACKGROUND: Anaphylaxis is a potentially life-threatening allergic reaction commonly managed in the emergency department (ED). Data describing patients 50 or 65 years or older with anaphylaxis are limited. OBJECTIVE: To describe the presentation and management of patients with anaphylaxis who were 50 or 65 years or older and to compare these findings with those of younger patients. METHODS: A consecutive cohort study of patients presenting to an ED with approximately 80,000 visits per year was conducted. Patients who met diagnostic criteria for anaphylaxis from April 2008 to June 2010 were included. Data were collected on suspected causes, signs and symptoms, management, ED disposition, and follow-up. RESULTS: The study included 220 patients. Food was the most common suspected cause of anaphylaxis for patients younger than 50 (42.2%) or 65 years (38.5%) but was much less common in patients 50 (14.8%, P < .001) or 65 years or older (14.3%, P = .01). Cardiovascular symptoms were more likely to occur in older patients (>=50 years old, 55.6% vs 30.1%, P < .001; >=65 years old, 64.3% vs 32.3%, P = .002). Patients 50 or 65 years or older were less likely to be dismissed home directly from the ED (>=50 years old, 35.2% vs 56.6%, P = .006; >=65 years old, 32.1% vs 54.2%, P = .03) and were less likely to be prescribed self-injectable epinephrine (>=50 years old, 40.7% vs 63.3%, P = .004; >=65 years old, 32.1% vs 61.5%, P = .003). CONCLUSIONS: In ED patients presenting with anaphylaxis, age of 50 or 65 years or older is associated with a decreased likelihood of food-induced anaphylaxis, increased likelihood of experiencing cardiovascular symptoms, decreased dismissal to home directly from the ED, and decreased prescriptions for self-injectable epinephrine. PMID- 21530873 TI - The possible influence of the environment on respiratory allergy: a survey on immigrants to Italy. AB - BACKGROUND: Respiratory allergy is influenced and determined by genetic and environmental factors. Migration is a good model to indirectly evaluate the possible influence of environment. OBJECTIVE: To assess the clinical characteristics of respiratory allergy in immigrants to Italy, in comparison with the Italian population. METHODS: The clinical/demographic data of those immigrants stably living in Italy and referred for the first time to allergy services for respiratory allergy were collected in a multicenter survey. All the patients underwent a standard diagnostic workup. A matched Italian population was also examined. RESULTS: Six hundred ninety-eight immigrants and 859 Italians had at least one positive skin test and were analyzed. Most of the patients were referred to the allergy units by their general practitioners. In those patients, the demographic characteristics were not different, except for family size. Immigrants had less family history of atopy. Only 16% had a clinical history of allergy before migration. The time elapsed between migration and onset of symptoms was 5.3 +/- 3.1 years, with a minimum of 0.5 and a maximum of 7 years. A higher rate of monosensitization was seen among immigrants, and the severity of their asthma/rhinitis was greater than in Italians. No difference was seen in the pattern of sensitizations. CONCLUSION: In this population of immigrants, environmental factors play a relevant role in the onset of respiratory allergies. PMID- 21530875 TI - European and Mexican vs US diagnostic extracts of Bermuda grass and cat in skin testing. AB - BACKGROUND: Laboratory testing of various diagnostic extracts has shown lower potencies for several European and Mexican extracts relative to the US Food and Drug Administration (FDA) reference (10,000 BAU/mL). Quantitative skin prick testing (QSPT) with Dermatophagoides pteronyssinus extracts have previously shown a similar picture. OBJECTIVE: To compare European and Mexican Bermuda grass (BG) and cat diagnostic extracts against an FDA-validated extract using QSPT. METHODS: Six diagnostic BG and cat extracts (1 reference FDA extract, 3 European extracts, 1 imported nonstandardized extract from the United States, and 1 Mexican extract) were tested with quadruplicate QSPT, as a concentrate and as 2 serial 2-fold dilutions, in cat and BG allergic individuals. RESULTS: BG showed good dose response in wheal size for the concentrate (1:2-1:4 dilutions; steep part of the curve). Cat showed poorer dose response. The Wilcoxon test for linked random samples was used to investigate whether the distribution of the reference differed from each of the test extracts to a statistically significant degree (2 sided asymptotic significance, alpha = .05). All BG and 2 cat extracts were statistically less potent than the 10,000 BAU/mL US reference. European BG extracts were 7,700, 4,100, and 1,600 BAU/mL, and cat extracts were 12,500, 4,400, and 5,100 BAU/mL. CONCLUSIONS: The potency of some diagnostic extracts of BG and cat used in Europe, Mexico, and the United States differs, with the US extracts being generally more potent. On the basis of provocation tests, optimal diagnostic concentrations should be determined. Similar comparisons using other manufacturers and therapeutic extracts might be interesting. PMID- 21530874 TI - Clinical and immunobiochemical characterization of airborne Peltophorum pterocarpum (yellow gulmohar tree) pollen: a dominant avenue tree of India. AB - BACKGROUND: Peltophorum pterocarpum (yellow gulmohar, PP) pollen is an important aeroallergen for type I hypersensitivity in the tropics. OBJECTIVE: To isolate and characterize the IgE-binding proteins of PP pollen for the first time. METHODS: Pollen extract was fractionated by a combination of Sephacryl S-200 column and diethylaminoethyl-Sephadex column. Allergen characterization was done by sodium dodecyl sulphate polyacrylamide gel electrophoresis, periodic acid Schiff staining, enzyme-linked immunosorbent assay, and western blotting. Allergenic activities were determined by in vivo (skin prick test) and in vitro (enzyme-linked immunosorbent assay and histamine release) analyses. To determine whether the carbohydrate chains are involved in immunoreactivity, deglycosylation of PP pollen proteins was performed. RESULTS: SPT results on the respiratory allergic patients of Calcutta showed that 32.77% showed positivity with PP pollen. Eight IgE-reactive protein components were found in crude extract. Optimum IgE-reactive fraction 1 was resolved into five subfractions. The subfraction 1a showed maximum IgE reactivity containing the 28 kDa IgE-reactive component. Periodate oxidation showed that protein component was involved in its IgE binding. Twenty-eight kilodalton IgE reactive protein component was recognized by 75% of PP-sensitive patients in Western blotting. It also induced significant histamine release in sensitive patient sera. CONCLUSIONS: The purified 28 kDa protein is a clinically relevant allergen with a potential for diagnosis and therapy of patients susceptible to PP pollen. PMID- 21530876 TI - Pollen and plant food profilin allergens show equivalent IgE reactivity. AB - BACKGROUND: Profilins are commonly involved in polysensitization of allergic patients; therefore, appropriate markers should be used in component-resolved diagnosis. OBJECTIVE: To evaluate the immunological equivalence between profilins from pollens and plant-derived foods, to be used in component-resolved diagnosis. METHODS: Specific immunoglobulin (Ig) G antibodies against pollen and fruit profilins, as well as sera from patients allergic to mustard, melon, or olive pollen, were used. Purified profilins from mustard seeds, fruit melon, and chenopod and birch pollen were assayed in immunoblotting, enzyme-linked immunosorbent assay (ELISA), and ELISA inhibition assays. RESULTS: Significant correlation was found in the response of purified profilins by ELISA and immunoblotting for both specific IgG and IgE. The highest levels of IgE binding were obtained for olive pollen-allergic patients, which could be related to the route of sensitization. The responses of individual patients to profilins were also similar and independent of the sensitizing source. The inhibition between pairs of allergens was generally higher than 70%, indicating that profilins share most of the IgE epitopes. Modeling of mimotopes in the conformational structure of the implicated profilins supports their strong cross-reactivity obtained experimentally. CONCLUSIONS: No correlation exists between the level of IgE response of individual patients to specific profilins and the corresponding theoretical sensitizing source, suggesting that the sensitization could be attributable to any profilin present in the environment of the patients. This would bear out the use of most profilins as a common marker for polysensitization in component-resolved diagnosis and for therapeutic approaches. PMID- 21530877 TI - DPP-4 inhibitors and angioedema: a cause for concern? PMID- 21530878 TI - Association of dermographic urticaria with the use of progesterone in cottonseed oil. PMID- 21530879 TI - Analysis of anaphylaxis cases after vaccination: 10-year review from the National Vaccine Injury Compensation Program. PMID- 21530880 TI - Resolution of bronchomalacia presenting as severe asthma by endoscopic intervention. PMID- 21530881 TI - Eosinophilic fasciitis mimicking angioedema and treatment response to infliximab in a pediatric patient. PMID- 21530882 TI - Safe administration of seasonal influenza vaccine to children with egg allergy of all severities. PMID- 21530883 TI - Contact urticaria to raw arugula and parsley. PMID- 21530884 TI - Seasonal eosinophilic bronchitis due to allergy to Cupressus arizonica pollen. PMID- 21530885 TI - The worldwide epidemic of multidrug-resistant tuberculosis. PMID- 21530886 TI - Transmitted antiretroviral-resistant HIV: a coming anarchy? PMID- 21530887 TI - Campaigns and continuity. PMID- 21530888 TI - Jeddah declaration on mass gatherings health. PMID- 21530889 TI - Clinical impact of antimicrobial resistance: design matters. PMID- 21530891 TI - Schistosomiasis elimination. PMID- 21530892 TI - Schistosomiasis elimination. PMID- 21530894 TI - Metallo-beta-lactamases: a last frontier for beta-lactams? AB - Metallo-beta-lactamases are resistance determinants of increasing clinical relevance in Gram-negative bacteria. Because of their broad range, potent carbapenemase activity and resistance to inhibitors, these enzymes can confer resistance to almost all beta-lactams. Since the 1990s, several metallo-beta lactamases encoded by mobile DNA have emerged in important Gram-negative pathogens (ie, in Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii). Some of these enzymes (eg, VIM-1 and NDM-1) have been involved in the recent crisis resulting from the international dissemination of carbapenem resistant Klebsiella pneumoniae and other enterobacteria. Although substantial knowledge about the molecular biology and genetics of metallo-beta-lactamases is available, epidemiological data are inconsistent and clinical experience is still lacking; therefore, several unsolved or debatable issues remain about the management of infections caused by producers of metallo-beta-lactamase. The spread of metallo-beta-lactamases presents a major challenge both for treatment of individual patients and for policies of infection control, exposing the substantial unpreparedness of public health structures in facing up to this emergency. PMID- 21530895 TI - Professional challenges and opportunities in clinical microbiology and infectious diseases in Europe. AB - The two closely linked specialties of clinical microbiology and infectious diseases face important challenges. We report the consensus of clinical microbiologists and infectious disease physicians assembled by the European Society for Clinical Microbiology and Infectious Diseases. Both specialties have different training requirements in different European countries and are not universally recognised as professions. The specialties are rapidly evolving as they adapt to the changing demands within hospital practice, including the need to deal with emerging infections, rapidly increasing internationalisation, and immigration. Clinical microbiology needs to develop and master technological advances such as laboratory automation and an avalanche of new methods for rapid diagnostics. Simultaneously, the pressure for concentration, amalgamation, and out-sourcing of laboratory services is ever-increasing. Infectious disease physicians have to meet the professional challenge of subspecialisation and the continual need to find new niches for their skills. Despite these challenges, each of these specialties continues to thrive in Europe and will enjoy important opportunities over the next few years. The recently formed European Centre for Disease Prevention and Control in Stockholm, Sweden, will increase demands in areas of surveillance of infectious diseases and antimicrobial resistance on both specialties. PMID- 21530896 TI - Scopulariopsis brevicaulis abscess in a child treated for myeloblastic leukaemia. PMID- 21530897 TI - Suppression of edr2-mediated powdery mildew resistance, cell death and ethylene induced senescence by mutations in ALD1 in Arabidopsis. AB - EDR2 is a negative regulator of the defense response and cell death in Arabidopsis. Loss-of-function of EDR2 leads to enhanced resistance to powdery mildew. To identify new components in the EDR2 signal transduction pathway, mutations that suppress edr2 resistant phenotypes were screened. Three mutants, edts5-1, edts5-2 and edts5-3 (edrtwo suppressor 5), were identified. The EDTS5 gene was identified by map-based cloning and previously was shown to encode an aminotransferase (ALD1). Therefore we renamed these three alleles ald1-10, ald1 11 and ald1-12, respectively. Mutations in ALD1 suppressed all edr2-mediated phenotypes, including powdery mildew resistance, programmed cell death and ethylene-induced senescence. Accumulation of hydrogen peroxide in edr2 was also suppressed by ald1 mutation. The expression of defense-related genes was up regulated in the edr2 mutant, and the up-regulation of those genes in edr2 was suppressed in the edr2/ald1 double mutant. The ald1 single mutant displayed delayed ethylene-induced senescence. In addition, ald1 mutation suppressed edr1 mediated powdery mildew resistance, but could not suppress the edr1/edr2 double mutant phenotype. These data demonstrate that ALD1 plays important roles in edr2 mediated defense responses, and senescence and revealed a crosstalk between ethylene and salicylic acid signaling mediated by ALD1 and EDR2. PMID- 21530898 TI - Identification and molecular characterization of two novel mutations in COL1A2 in two Chinese families with osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI, also known as brittle bone disease) is caused mostly by mutations in two type I collagen genes, COL1A1 and COL1A2 encoding the pro alpha1 (I) and pro-alpha2 (I) chains of type I collagen, respectively. Two Chinese families with autosomal dominant OI were identified and characterized. Linkage analysis revealed linkage of both families to COL1A2 on chromosome 7q21.3 q22.1. Mutational analysis was carried out using direct DNA sequence analysis. Two novel missense mutations, c.3350A>G and c.3305G>C, were identified in exon 49 of COL1A2 in the two families, respectively. The c.3305G>C mutation resulted in substitution of a glycine residue (G) by an alanine residue (A) at codon 1102 (p.G1102A), which was found to be mutated into serine (S), argine (R), aspartic acid (D), or valine (V) in other families. The c.3350A>G variant may be a de novo mutation resulting in p.Y1117C. Both mutations co-segregated with OI in respective families, and were not found in 100 normal controls. The G1102 and Y1117 residues were evolutionarily highly conserved from zebrafish to humans. Mutational analysis did not identify any mutation in the COX-2 gene (a modifier gene of OI). This study identifies two novel mutations p.G1102A and p.Y1117C that cause OI, significantly expands the spectrum of COL1A2 mutations causing OI, and has a significant implication in prenatal diagnosis of OI. PMID- 21530899 TI - Human transcription factor genes involved in neuronal development tend to have high GC content and CpG elements in the proximal promoter region. AB - Transcription factors (TFs) play critical roles in the development of the nervous system, but the transcriptional regulatory mechanisms of these genes are poorly understood. Here we analyzed 5-kb of the 5' flanking genomic DNA sequences of 41 TF genes involved in neuronal development. The results showed that the TF genes tend to have higher GC contents in the proximal region and most of the TF genes have at least one proximal GC-rich (GC content > 60%) promoter with a CpG island. The promoter distribution analysis showed that the GC-poor promoters were sporadically distributed within the 5-kb flanking genomic sequence (FGS); however, more than half (37 of 70) of the GC-rich promoters were located in the proximal region between nucleotides -1 and -500. Luciferase assays showed that partial GC-rich promoters increased gene expression in SH-SY5Y cells and that CpG methylation repressed the promoter activity. This study suggests a potential general mechanism for regulation of TF expression. PMID- 21530900 TI - Association of WNK1 exon 1 polymorphisms with essential hypertension in Hani and Yi minorities of China. AB - The association of polymorphisms in exon 1 of the WNK1 gene with essential hypertension in the minority groups of Hani and Yi of China was investigated in the case-control study. The sequence of 1257bp containing the WNK1 gene exon 1 was determined in 1307 individuals (649 essential hypertension subjects and 658 controls) to identify SNPs in Hani and Yi minority groups. Four of eleven previously known SNPs (rs3168640, rs11885, rs11554421 and rs34880640) were identified. The SNP analysis indicated that SNPs rs11885 and rs11554421 were significantly associated with hypertension in both Hani and Yi populations, and rs34880640 was significantly associated with hypertension in Hani but not in Yi population, adjusted for covariates. Haplotype analysis indicated that the haplotype H1 significantly decreased the risk of hypertension in both populations. These results suggested that WNK1 polymorphisms were involved in the predisposition of essential hypertension in Hani and Yi populations and its effects showed a clear population specificity. This finding supported the importance of population specificity in determining the genetic factors associated with diseases and thus disease treatment. PMID- 21530901 TI - Toward genetic transformation of mitochondria in mammalian cells using a recoded drug-resistant selection marker. AB - Due to technical difficulties, the genetic transformation of mitochondria in mammalian cells is still a challenge. In this report, we described our attempts to transform mammalian mitochondria with an engineered mitochondrial genome based on selection using a drug resistance gene. Because the standard drug-resistant neomycin phosphotransferase confers resistance to high concentrations of G418 when targeted to the mitochondria, we generated a recoded neomycin resistance gene that uses the mammalian mitochondrial genetic code to direct the synthesis of this protein in the mitochondria, but not in the nucleus (mitochondrial version). We also generated a universal version of the recoded neomycin resistance gene that allows synthesis of the drug-resistant proteins both in the mitochondria and nucleus. When we transfected these recoded neomycin resistance genes that were incorporated into the mouse mitochondrial genome clones into mouse tissue culture cells by electroporation, no DNA constructs were delivered into the mitochondria. We found that the universal version of the recoded neomycin resistance gene was expressed in the nucleus and thus conferred drug resistance to G418 selection, while the synthetic mitochondrial version of the gene produced no background drug-resistant cells from nuclear transformation. These recoded synthetic drug-resistant genes could be a useful tool for selecting mitochondrial genetic transformants as a precise technology for mitochondrial transformation is developed. PMID- 21530903 TI - [Quality of life measurement: a suitable method for benefit-risk assessment?]. AB - Measurement of health-related quality of life can play a major role in benefit risk assessment. Preference-based methods for measuring quality of life where data are aggregated into a single quality of life index are particularly well suited for use in quantitative analysis. Using two examples from research on cancer and multiple sclerosis, this paper compares approaches in which quality of life data from genuine studies or from external sources is used. It will be demonstrated that quality of life data can provide relevant information for quantitative benefit-risk assessment in applied research. In addition, quality of life data may be included in more complex approaches of multi-criteria decision analysis. PMID- 21530904 TI - [Benefits and harms - two sides of the same medal?]. AB - Efficacy, efficiency, value, and harm constitute the terminology that is used to decide about drug licensing and reimbursement. This article discusses to what extent legal requirements dictate the way clinical trials are planned and assessed. Cardiovascular disease is the best example of indications where efficacy and safety are described with the same set of endpoints. It is explained that the assessment of clinical trials must not be restricted to the assessment of primary endpoints. Instead components of a composite endpoint, secondary endpoints, and relevant subgroups of the patient population all require careful inspection. In cases where efficacy and safety are not two sides of the same medal, assessment is either trivial, or extremely difficult, and eventually benefit and risk can be balanced only for individual cases. PMID- 21530905 TI - [Balancing benefit and harm in palliative care: the difficult position of palliative medicine in view of the promises of curative medicine]. AB - The significance of palliative care as an interdisciplinary and multi professional approach to treating patients with extremely severe medical conditions should be investigated using the same methodological standards as for clinical medicine in general. Clinical studies in palliative medicine show that certain standards, e.g. in pain therapy, have still not been sufficiently implemented. There is also a lack of methodologically appropriate studies to investigate palliative medicine as a complex intervention. This research deficit is all the more regrettable as - specifically in the field of oncology - it can be demonstrated that the benefit provided by the services of palliative care teams is very large, especially for patients with a particularly unfavorable course of the disease. PMID- 21530906 TI - [Balancing benefits and harms of population-based interventions, using the example of cancer screening]. AB - The assessment of the balance between benefits and harms of population-based interventions faces both methodological and practical difficulties. This paper uses the example of cancer screening to outline existing challenges such as the consideration of outcomes that occur at substantially different times, or the lack of direct evidence which can lead to false conclusions and adverse health effects for healthy individuals undergoing screening. Sometimes not even sound evidence provides clear answers about the benefits and harms of preventive interventions. This is why informed decision-making is a particularly important step for individuals taking preventive interventions into consideration. Due to the lack of a clear answer to the question of benefits and harms from scientific evidence, individuals' attitudes and values may become a decisive factor. Studies, however, indicate that the prerequisite for informed decision making, namely objective and balanced information about benefits and harms, is often missing. PMID- 21530907 TI - [Regulations concerning data transparency- a comparison between the USA and Europe]. AB - Since 2007 a far-reaching obligation to register and publish clinical trials of pharmaceuticals on the generally accessible website www.clinicaltrials.gov has applied under the US Food and Drug Administration Amendment Act ("FDAAA") section 801. This obligation also comprises clinical trials results. In the EU clinical trials are registered with the EudraCT data base. The published data are strictly confidential and only accessible to public authorities. The publicly accessible data base Eudrapharm does not generate information on trials; there have been vague extension plans. Since 2011, S 42b of the German Drugs Act provides that the results of clinical trials need to be reported (on the "PharmNet.Bund" website) in order to improve information for doctors and patients. The US regulations serve as a role model for an approach to keeping the general public fully informed about the start and the results of clinical drug trials and to avoiding publication bias. PMID- 21530908 TI - [Data transparency regarding medical devices - the position of the medical device industry]. AB - The medical device industry, strongly dominated by medium-sized firms, has significant growth potential and a high number of job opportunities with 170,000 employees in more than 11,000 companies. Approximately one third of the business volume is achieved with innovative products that are less than three years old. The safety, quality and efficiency of the products is tested and approved by CE certification. Due to the heterogeneous field of devices, however, evidence requirements must be differentiated according to the type of device in question. Transparency is as important as the type of evidence, and industry is well aware of the significance of transparency for credibility in the market. Industry believes that all the stakeholders affected must collaborate to define the evidence requirements and decide which data are necessary to assess the benefits of a technology. Before a consistent level of transparency can be achieved, however, it is crucial to jointly develop a framework of requirements including invasiveness, risk potential, patient-relevant endpoints and intended use of the technology, as well as the data source. Transparency is a process that can only be achieved if all stakeholders cooperate successfully. Also, it is important to keep in mind that the development of study designs and reliable evidence needs time. In the interest of all patients it is essential to maintain an innovation friendly climate in Germany. PMID- 21530909 TI - [Publication bias in trials other than RCTs]. AB - Publication bias arises from the preferential publication of studies with positive, statistically significant, or particularly strong effects. In meta analysis on the effectiveness of interventions this may, for example, lead to an overestimation of an effect. In studies on harm, though, wish bias and publication bias frequently take opposing directions. In consequence the overall effect is more difficult to interpret. Generally, non randomized studies might be expected to have a higher potential for publication bias as they have lower publication rates. Specifically, adverse effects are often not reported in a standardized way and tend to be secondary outcomes. Related biases such as positive outcome bias and location bias (problems in locating studies, retrieval bias) are therefore also more likely. As yet, however, there is no empirical proof to support this since research activities on the subject of publication bias is almost exclusively focused on randomized controlled trials. PMID- 21530910 TI - [Implications of publication bias on guideline development and appraisal]. AB - The issue of selective publishing of research results is gaining more and more scientific, public and political awareness. For guideline authors, in particular, it leads to uncertainty about the interpretability of the methodological quality and clinical relevance of the available evidence and the risk of bias where their conclusions and thus guideline recommendations are concerned. The actual impact of publication bias on guideline contents appears to be low if a systematic and methodically sound approach is followed in the process of guideline development. However, the quality of the evidence on this topic is poor. Different strategies to deal with publication bias have been proposed for authors of systematic reviews but they are of limited use for guideline authors. The goal must therefore be to implement appropriate measures in order to avoid the problem ex ante. The first step would be the systematic registration of study results in publicly accessible registers. PMID- 21530911 TI - [Data transparency - an ethical imperative? Approaching the issues]. AB - Several studies show that the findings of clinical trials are often not published in full, resulting in a biased presentation of results (publication bias). First, this paper discusses the ethical arguments in favour of complete transparency of biomedical research data. There are relevant deontological (like obligations towards study participants and research sponsors) and consequentialist (harm for patients and misallocation of scarce resources) ethical reasons for the full publication of all trial results, which cannot be overridden by counter arguments like freedom of research, data protection or the individual interests of researchers and manufacturers. The article therefore discusses (1) which strategies are appropriate to guarantee data transparency and (2) who bears responsibility for the implementation of these strategies. Finally, open questions and the need for further action will be discussed. PMID- 21530913 TI - Comparison of real-time PCR and microscopy to evaluate sclerotial colonisation by a biocontrol fungus. AB - The biocontrol agent Trichoderma harzianum colonises sclerotia of the plant pathogenic fungus Sclerotinia sclerotiorum. Plating of sclerotia typically has been used to determine the incidence of mycoparasitism, but does not quantify the extent to which individual sclerotia are colonised. We developed a specific PCR primer/probe set for the green fluorescent protein (GFP)-transformant T. harzianum ThzID1-M3, which exhibited high precision and reproducibility. Quantitative real-time PCR was evaluated along with epifluorescence microscopy and image analysis to investigate dynamics of colonisation of sclerotia in non sterile soil. Amounts of ThzID1-M3 DNA and S. sclerotiorum DNA from entire individual sclerotia were quantified using real-time PCR. Epifluorescence micrographs were captured from sclerotial thin-section samples, and GFP fluorescence from these was quantified using computer image analysis in order to estimate colonisation on a per-sclerotium basis. As determined by either method, ThzID1-M3 colonised sclerotia in soil, and both methods quantified colonisation dynamics over time. In a separate experiment, colonisation of sclerotia on agar plates was observed using confocal laser scanning microscopy to view the GFP fluorescing hyphae of ThzID1-M3. This method, while highly labour-intensive, provided high spatial resolution of colonisation dynamics. Thus, each method has advantages: microscopy combined with image analysis can provide useful information on the spatial and temporal dynamics of colonisation, while real-time PCR can provide a more precise assessment of the extent of sclerotial colonisation over time and can more easily be used to sample entire sclerotia. PMID- 21530914 TI - Application of fluorescent indicators to analyse intracellular calcium and morphology in filamentous fungi. AB - A novel staining and quantification method to investigate changes in intracellular calcium levels [Ca(2+)](i) and morphology in filamentous fungus is presented. Using a simple protocol, two fluorescent dyes, Fluo-4-AM and Cell trace calcein red-orange-AM were loaded into the filamentous fungus Penicillium chrysogenum. The present study investigates the applicability of using Ca(2+) sensitive dye to quantify and image [Ca(2+)](i) in P. chrysogenum cultures chosen for its potential as an experimental system to study Ca(2+) signalling in elicited cultures. The dye loading was optimised and investigated at different pH loading conditions. It was observed that the fluorophore was taken up throughout the hyphae, retaining cell membrane integrity and no dye compartmentalisation within organelles was observed. From the fluorescent plate-reader studies a significant rise (p<0.001) in the relative fluorescence levels corresponding to [Ca(2+)](i) levels in the hyphae was observed when challenged with an elicitor (mannan oligosaccharide, 150mgL(-1)) which was dependent upon extracellular calcium. Concurrently a novel application of dye-loaded hyphae for morphological analysis was also examined using the imaging software Filament Tracer (Bitplane). Essential quantitative mycelial information including the length and diameter of the segments and number of branch points was obtained using this application based on the three-dimensional data. PMID- 21530915 TI - Genetic analysis of Phytophthora infestans populations in the Nordic European countries reveals high genetic variability. AB - Late blight, caused by the oomycete Phytophthora infestans, is the most important disease of potato (Solanum tuberosum). The pathogen is highly adaptable and to get an overview of the genetic variation in the Nordic countries, Denmark, Finland, Norway and Sweden we have analyzed 200 isolates from different fields using nine simple-sequence repeat (SSR) markers. Forty-nine alleles were detected among the nine SSR loci and isolates from all four Nordic countries shared the most common alleles across the loci. In total 169 multilocus genotypes (based on seven loci) were identified among 191 isolates. The genotypic diversities, quantified by a normalized Shannon's diversity index (H(s)), were 0.95 for the four Nordic countries. The low F(ST) value of 0.04 indicates that the majority of variation is found within the four Nordic countries. The large number of genotypes and the frequency distribution of mating types (60% A1) support the hypothesis that sexual reproduction is contributing notably to the genetic variation of P. infestans in the Nordic countries. PMID- 21530916 TI - Mites are the most common vectors of the fungus Gondwanamyces proteae in Protea infructescences. AB - Entomochoric spore dispersal is well-documented for most ophiostomatoid fungal genera, most of which are associated with bark or ambrosia beetles. Gondwanamyces spp. are unusual members of this group that were first discovered in the flower heads of the primitive angiosperm genus Protea, that is mostly restricted to the Cape Floristic region of Africa. In this study, we present the discovery of the vectors of Gondwanamyces proteae in Protea repens infructescences, which were identified using PCR, direct isolation, and light microscopy. Gondwanamyces proteae DNA and ascospores were identified on diverse lineages of arthropods including beetles (Euderes lineicolis and Genuchus hottentottus), bugs (Oxycarenus maculates), a psocopteran species and five mite (Acari) species. Based on isolation frequency, however, a mite species in the genus Trichouropoda appears to be the most common vector of G. proteae. Gondwanamyces spores were frequently observed within pit mycangia at the base of the legs of these mites. Manipulative experiments demonstrated the ability of mites to carry viable G. proteae spores whilst in transit on the beetle G. hottentottus and that these mites are able to transfer G. proteae spores to uncolonised substrates in vitro. Interestingly, this same mite species has also been implicated as vector of Ophiostoma spores on P. repens and belongs to the same genus of mites that vector Ophiostoma spp. associated with pine-infesting bark beetles in the Northern Hemisphere. PMID- 21530917 TI - The effects of hydroxy fatty acids on the hyphal branching of germinated spores of AM fungi. AB - Two hydroxy fatty acids, tentatively identified previously in carrot root exudates, were tested for their effects on hyphal growth of the arbuscular mycorrhizal (AM) fungus, Gigaspora gigantea (Nicol. and Gerd.) Gerdemann and Trappe. Best results were achieved with a long-term bioassay (7-8d) with nanomolar concentrations throughout the Petri dish in contrast to the rapid microinjection bioassay (16-24h) in which nanogram quantities were injected near growing hyphal tips. When 5nM 2-hydroxy fatty acids of various chain length were tested, the length of the hydroxyl fatty acid was significant since only 2 hydroxytetradecanoic acid (2OH-TDA) and to a slightly lesser degree, 2 hydroxydodecanoic acid (2OH-DDA) induced a hyphal growth response while 2 hydroxydecanoic acid (2OH-DA) and 2-hydroxyhexadecanoic (2OH-HDA) acid did not. The position of the hydroxyl group was critical since 5nM 3-hydroxytetradecanoic acid (3OH-TDA) had no effect on hyphal growth. The length of the non-hydroxy containing straight chain fatty acid, per se, did not appear significant since none of these fatty acids had an effect on hyphal growth. The morphological growth response promoted by 2OH-TDA consisted of multiple lateral branches, spaced fairly regularly apart, along the primary germ tubes as well as some lateral branch formation off the major secondary hyphae. This growth response was identical to that observed when germinated spores were allowed to grow towards cultured carrot roots in vitro. This response to 2OH-TDA also was observed with an unidentified Gigaspora species but no morphological response was observed with Glomus intraradices Schenck and Smith. The results indicate that 2-hydroxy fatty acids are another putative category of root exudate signals perceived by Gigaspora species, stimulating an increase in elongated lateral branches. PMID- 21530919 TI - Exploring the life cycles of three South American rusts that have potential as biocontrol agents of the stipoid grass Nassella neesiana in Australasia. AB - Three rusts, Puccinia nassellae, Uromyces pencanus, and Puccinia graminella, are being studied as potential biological control agents for Nassella neesiana (Chilean needle grass) in Australia and New Zealand. An understanding of the life cycle of a pathogen is desirable before its release as a biocontrol agent is considered, to enable the assessment of the risks involved in such a release. Field observations and experiments have been carried out to elucidate the life cycles of these three pathogens. Puccinia nassellae cycles as urediniospores and produces dormant teliospores. Dormancy of teliospores has been broken through manipulation in the laboratory, but resulting basidiospores have failed to infect N. neesiana plants under the conditions tested. Uromyces pencanus cycles as urediniospores and its telia appear to have lost the capacity to produce basidiospores. Aecia have been reported for this rust in the literature. However, evidence is provided that these aecia in fact belong to the life cycle of P. graminella. Puccinia graminella produces only aecia and telia. The aeciospores have been shown to be repetitive (aecidioid urediniospores). Teliospores germinate directly without a dormant phase, but resulting basidiospores failed to infect N. neesiana plants under the conditions tested. The role of teliospores in the life cycle of all three rusts remains unknown. Although the autoecious nature of their life cycles has not been proven experimentally, neither is there any evidence that they are heteroecious. Practical and theoretical implications of these findings are discussed. PMID- 21530918 TI - The roles of the alternative NADH dehydrogenases during oxidative stress in cultures of the filamentous fungus Aspergillus niger. AB - Despite the importance of filamentous fungi in the biotechnology industry, little is known about their metabolism under the stressful conditions experienced in typical production fermenters. In the present study, oxygen enrichment was used to recreate an industrial batch process, and the effects of the increasing dissolved oxygen tension were studied as regards the cellular metabolism. It was found that elevated dissolved oxygen tension led to an oxidatively stressful environment, as detailed by rapid initial increases in reactive oxygen species (ROS) concentrations and antioxidant enzyme activities. Intracellular protein concentrations also decreased in oxygenated cultures; this appeared to be concomitant with a decrease in the adenosine-5'-triphosphate (ATP) pool in these cultures. Oxygenated cultures showed early senescence and death compared to aerated control cultures. Despite earlier studies proposing various mechanisms for such findings in fungal cultures subjected to oxidative stress, these findings can best be explained by the fact that in such cultures the activity of alternative NADH dehydrogenases was significantly increased, which served to maintain lower ROS concentrations throughout the duration of the process but in doing so also reduced the ability of the organism to create a proton motive force by which to drive ATP synthesis. The findings of the present study help further our understanding of the central roles of these highly conserved enzymes within fungal metabolism under oxidative stress. PMID- 21530921 TI - 8-Carbon oxylipins inhibit germination and growth, and stimulate aerial conidiation in Aspergillus nidulans. AB - Germination of Aspergillus nidulans conidia in liquid cultures was progressively inhibited at inoculum loads above 1*10(5)conidiamL(-1). High conidial densities also inhibited growth of neighbouring mycelia. The eight-carbon oxylipin 1-octen 3-ol was identified as the main inhibitor in a fraction also containing 3 octanone and 3-octanol. These three oxylipins also increased the conidiation rate of dark-grown surface cultures, but had no effect on liquid cultures. 3-octanone was the most conidiogenic compound. The action of 3-octanone required functional forms of developmental activators fluG, flbB-D and brlA, and was not additive to the conidiogenic effect of stress stimuli such as osmotic stress or carbon starvation. Oxylipins were produced shortly after hyphae made contact with the atmosphere and were most effective on aerial mycelia, indicating that they perform their signalling function in the gas phase. PMID- 21530920 TI - Molecular phylogeny of the Blastocladiomycota (Fungi) based on nuclear ribosomal DNA. AB - The Blastocladiomycota is a recently described phylum of ecologically diverse zoosporic fungi whose species have not been thoroughly sampled and placed within a molecular phylogeny. In this study, we investigated the phylogeny of the Blastocladiomycota based on ribosomal DNA sequences from strains identified by traditional morphological and ultrastructural characters. Our results support the monophyly of the Coelomomycetaceae and Physodermataceae but the Blastocladiaceae and Catenariaceae are paraphyletic or polyphyletic. The data support two clades within Allomyces with strains identified as Allomyces arbusculus in both clades, suggesting that species concepts in Allomyces are in need of revision. A clade of Catenaria species isolated from midge larvae group separately from other Catenaria species, suggesting that this genus may need revision. In the Physodermataceae, Urophlyctis species cluster with a clade of Physoderma species. The algal parasite Paraphysoderma sedebokerensis nom. prov. clusters sister to other taxa in the Physodermataceae. Catenomyces persicinus, which has been classified in the Catenariaceae, groups with the Chytridiomycota rather than Blastocladiomycota. The rDNA operon seems to be suitable for classification within the Blastocladiomycota and distinguishes among genera; however, this region alone is not suitable to determine the position of the Blastocladiomycota among other basal fungal phyla with statistical support. A focused effort to find and isolate, or directly amplify DNA from additional taxa will be necessary to evaluate diversity in this phylum. We provide this rDNA phylogeny as a preliminary framework to guide further taxon and gene sampling and to facilitate future ecological, morphological, and systematic studies. PMID- 21530922 TI - Chemical taxonomy of Torrubiella s. lat.: zeorin as a marker of Conoideocrella. AB - The insect pathogens in the genus Torrubiella s. lat. were recently divided into new genera based on molecular phylogenetic characters. Isolates collected at various locations in Thailand, were tested for their productivity of a hopane type triterpene, zeorin (6alpha,22-dihydroxyhopane), when cultured in potato dextrose broth under static conditions. Among the 49 strains of Torrubiella s. lat. species, Conoideocrella luteorostrata (ten strains) and C. tenuis (seven strains), all collected on scale insects (Hemiptera), produced zeorin, whereas another six strains of Orbiocrella petchii (which was recently removed from Torrubiella) failed in the detection of this secondary metabolite. All other Torrubiella s. lat. (26 strains), collected on other insect hosts including leafhoppers (eight strains), Lepidoptera (one strain), and spiders (17 strains), produced no detectable zeorin. Paecilomyces cinnamomeus (nine strains), the anamorph of C. luteorostrata, also produced zeorin. These results correspond with the recent taxonomic reclassification based on multigene phylogeny. PMID- 21530923 TI - Distribution of sterigmatocystin in filamentous fungi. AB - During the last 50y, the carcinogenic mycotoxin sterigmatocystin (ST) has been reported in several phylogenetically and phenotypically different genera: Aschersonia, Aspergillus, Bipolaris, Botryotrichum, Chaetomium, Emericella, Eurotium, Farrowia, Fusarium, Humicola, Moelleriella, Monocillium and Podospora. We have reexamined all available strains of the original producers, in addition to ex type and further strains of each species reported to produce ST and the biosynthetically derived aflatoxins. We also screened strains of all available species in Penicillium and Aspergillus for ST and aflatoxin. Six new ST producing fungi were discovered: Aspergillus asperescens, Aspergillus aureolatus, Aspergillus eburneocremeus, Aspergillus protuberus, Aspergillus tardus, and Penicillium inflatum and one new aflatoxin producer: Aspergillus togoensis (=Stilbothamnium togoense). ST was confirmed in 23 Emericella, four Aspergillus, five Chaetomium, one Botryotrichum and one Humicola species grown on a selection of secondary metabolite inducing media, and using multiple detection methods: HPLC-UV/Vis DAD, - HRMS and - MS/MS. The immediate precursor for aflatoxin, O methylsterigmatocystin was found in Chaetomium cellulolyticum, Chaetomium longicolleum, Chaetomium malaysiense and Chaetomium virescens, but aflatoxin was not detected from any Chaetomium species. In all 55 species, representing more than 11 clades throughout the Pezizomycotina, can be reliably claimed to be ST producers and 13 of these can also produce aflatoxins. It is not known yet whether the ST/aflatoxin pathway has been developed independently 11 times, or is the result of partial horizontal gene transfer. PMID- 21530924 TI - Quantitative genetics to dissect the fungal-fungal interaction between Lecanicillium verticillium and the white button mushroom Agaricus bisporus. AB - Lecanicillium fungicola (formerly Verticillium fungicola) is responsible for dry bubble disease in the white button mushroom Agaricus bisporus. Selection for resistance to this pathogen raises an important challenge for mushroom breeders. We have investigated the inheritance of resistance to dry bubble under artificial inoculation in three independent experiments, using a progeny of 89 hybrids derived from an intervarietal A. bisporus var. bisporus*A. bisporus var. burnettii cross. Overall, phenotypic correlations were highly significant between the different experiments. Principal component analysis, together with analysis of variance results stated that the disease reactions were accurately assessed using the percentage of bubbles (PB) and the percentage of spotty cap mushrooms (PS) separately rather than with the combination of both. An original contribution of this study lies in the effective use of area under the disease progress curve (AUDPC) to describe the dry bubble resistance. The continuous phenotypic distribution observed for the resistance traits suggested that tolerance to dry bubble was under polygenic control. Heritability estimates for either PB or AUDPC were high (0.67-0.86) while it was inconsistent for PS (0.33 0.68) suggesting a strong impact of the environment on this latter trait. Earliness and latent period were found highly correlated with disease incidence. The earliest strains appeared to be the most resistant ones. These results contribute to disentangle the complex fungal-fungal A. bisporus / L. fungicola interaction and to provide genetic basis as a prerequisite for mushroom breeding program. PMID- 21530925 TI - Genetic characterization of Phytophthora nicotianae by the analysis of polymorphic regions of the mitochondrial DNA. AB - A new method based on the analysis of mitochondrial intergenic regions characterized by intraspecific variation in DNA sequences was developed and applied to the study of the plant pathogen Phytophthora nicotianae. Two regions flanked by genes trnY and rns and trnW and cox2 were identified by comparing the whole mitochondrial genomes of Phytophthora infestans, Phytophthora ramorum, and Phytophthora sojae and amplified using primers designed from the flanking conserved genes. These regions were sequenced from 51 isolates of P. nicotianae of both A1 and A2 mating type recovered from different hosts and geographic regions. Amplicon length varied from 429bp to 443bp (trnY/rns) and 322bp to 373bp (trnW/cox2) with intraspecific variation due to single nucleotide polymorphisms and indels. Seventeen, seven and 20 different haplotypes were detected by individually analyzing regions trnY-rns, trnW-cox2 and the combined data set of sequences from both regions, respectively. Phylogenetic analysis inferred with three different methods enabled the grouping of isolates in five clades, each containing different mitochondrial haplotypes and revealed diversity in the mitochondrial genome of P. nicotianae. The majority of isolates from citrus grouped in a single clade indicating either movement of isolates on planting stock or an association of particular isolates with this host. Phylogenetic groups were not correlated with the radial growth rate of the isolates or the rapidity of apple flesh colonization. The method developed in the present study represents an innovative molecular tool for the characterization of natural populations of P. nicotianae and should be easily expanded to other species of Phytophthora as well as other plant pathogens. It can be used to track specific haplotypes and, thanks to its high genetic resolution, it could be standardized and applied in a DNA barcoding like strategy for the precise identification of sub-specific taxa. Compared to alternative molecular methods, a major advantage is that results are unbiased (a list of nucleotides) and highly reproducible, thus enabling the comparison of data from different laboratories and time periods. Furthermore, the method could be further enhanced by the identification of additional variable mitochondrial and/or nuclear genomic regions. PMID- 21530926 TI - [Melanocytic nevi, melanoma, and pregnancy]. AB - Malignant melanoma is among the malignant tumors whose incidence has risen markedly in recent decades. For many years the medical community debated the potential adverse effects of female hormones (whether of exogenous or pregnancy related endogenous origin), on melanocytic nevi and malignant melanoma. Given that women have been delaying pregnancy until their thirties or forties and that the incidence of malignant melanoma increases in those decades, the likelihood of this tumor developing during pregnancy has increased. Recent clinical and experimental evidence has suggested that pregnancy does not affect prognosis in malignant melanoma and that it does not seem to lead to significant changes in nevi. This review examines the relationship between malignant melanoma and hormonal and reproductive factors. Evidence was located by MEDLINE search (in PubMed and Ovid) for articles in English and Spanish for the period from 1966 to March 2010; additional sources were found through the reference lists of the identified articles. PMID- 21530927 TI - [Extramammary Paget disease treated with 5% imiquimod cream]. PMID- 21530928 TI - [Clinical characteristics and disease course in patients treated with efalizumab following suspension of marketing authorization by the European medicines agency: a multicenter observational study]. AB - BACKGROUND AND OBJECTIVES: The withdrawal of marketing authorization for efalizumab by the European Medicines Agency in February, 2009 provided a unique opportunity to assess the course of disease in patients who were not subject to the selection criteria and biases that were common in the pivotal trials. The aim of this study was to evaluate the course of psoriasis following forced suspension of efalizumab in a group of patients treated in normal clinical practice. As secondary objectives, we sought to assess the relationships between clinical characteristics, treatment response, and disease course during efalizumab treatment and 12 and 24 weeks after suspension. PATIENTS AND METHODS: Information on the epidemiological profile and disease course during treatment and following suspension of the drug was collected from a group of patients treated with efalizumab. Statistical analyses were performed to identify predictive factors. RESULTS: One hundred forty-seven patients from 12 Spanish hospitals were included in the study. During treatment, 4% of patients were diagnosed with generalized inflammatory flares. Most patients could be classified as having a good (55%) or moderate (18%) response to treatment. Rebound following withdrawal of efalizumab was observed in 30% of patients. The likelihood of rebound was independent of clinical characteristics, treatment response, or therapeutic approach used by the dermatologist following suspension. CONCLUSIONS: There was a high frequency of rebound following suspension of efalizumab, exceeding the rate reported in pivotal trials. This is particularly noteworthy given the large proportion of patients with a good response to treatment and therefore believed to have a better prognosis. Other significant findings were the higher frequency of positive treatment response than observed in previous studies (possibly influenced by the mean treatment duration) and the high frequency of generalized inflammatory flares. PMID- 21530929 TI - [Skin involvement as the presenting feature of primary systemic anaplastic lymphoma kinase-negative CD30+ anaplastic lymphoma]. PMID- 21530930 TI - [Widespread nodules in an immunosuppressed adult]. PMID- 21530931 TI - [Descriptive dermoscopic study of depigmentation in melanocytic nevi without a visible halo]. AB - BACKGROUND AND OBJECTIVES: There are few cases described in the literature in which depigmentation of melanocytic nevi occurs without the appearance of halos. The aim of this study was to analyze the correlation between clinical and dermoscopic findings and to assess the usefulness of dermoscopy to identify possible markers of complete regression in melanocytic lesions. MATERIALS AND METHODS: A prospective, observational, descriptive study of 77 melanocytic lesions in 52 patients was undertaken over a 5-year period. Melanocytic lesions from patients who underwent periodic follow-up in the digital dermoscopy unit were analyzed if they had exhibited partial or total, permanent depigmentation without a clinically apparent halo. RESULTS: We observed substantial variation in the time taken for pigmentation to disappear and the morphological characteristics of the nevi during the depigmentation process. Female sex and dermoscopic evidence of melanophage activity or of a halo were all associated with more rapid involution of pigmented lesions. The only variable which displayed a statistically significant association with complete depigmentation of melanocytic nevi was the presence of vascular proliferation. Fibrosis was the only variable that displayed a statistically significant association with heterogeneous depigmentation of melanocytic nevi. CONCLUSIONS: In this study, we have identified patterns of depigmentation in melanocytic lesions that differ from the classic halo nevus. PMID- 21530932 TI - [Papules and pustules on the knee of a young woman]. PMID- 21530933 TI - [Usefulness of dermoscopy in plantar pilonidal sinus]. PMID- 21530934 TI - [Climate change and the thinning of the ozone layer: implications for dermatology]. PMID- 21530935 TI - Association of the metabolic syndrome with atrial fibrillation among United States adults (from the REasons for Geographic and Racial Differences in Stroke [REGARDS] Study). AB - Metabolic syndrome (MS) and atrial fibrillation (AF) are associated with increased cardiovascular disease morbidity and mortality. This analysis evaluated the association between MS and AF in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. MS was defined using criteria recommended in the joint interim statement from several international societies. AF was defined by electrocardiogram (ECG) and/or self-report and by ECG alone. In patients with 0, 1, 2, 3, 4, and 5 MS components, prevalences of AF by ECG and/or self-report were 5.5%, 7.7%, 8.2%, 9.2%, 9.6%, and 11.5%, respectively (p for trend <0.001). After multivariable adjustment, each MS component except serum triglycerides was significantly associated with AF. The multivariable-adjusted odds ratio for AF, defined by ECG and/or or self-reported history, comparing those with to those without MS was 1.20 (95% confidence interval 1.10 to 1.29). Results were consistent when AF was defined by ECG alone (odds ratio 1.15, 95% confidence interval 0.92 to 1.39). In conclusion, MS is associated with an increased prevalence of AF. Further studies investigating a potential mechanism for this excess risk are warranted. PMID- 21530936 TI - Post-traumatic stress disorder, coronary atherosclerosis, and mortality. AB - Post-traumatic stress disorder (PTSD) is associated with increased risk of multiple medical problems including myocardial infarction. However, a direct link between PTSD and atherosclerotic coronary artery disease (CAD) has not been made. Coronary artery calcium (CAC) score is an excellent method to detect atherosclerosis. This study investigated the association of PTSD to atherosclerotic CAD and mortality. Six hundred thirty-seven veterans without known CAD (61 +/- 9 years of age, 12.2% women) underwent CAC scanning for clinical indications and their psychological health status (PTSD vs non-PTSD) was evaluated. In subjects with PTSD, CAC was more prevalent than in the non-PTSD cohort (76.1% vs 59%, p = 0.001) and their CAC scores were significantly higher in each Framingham risk score category compared to the non-PTSD group. Multivariable generalized linear regression analysis identified PTSD as an independent predictor of presence and extent of atherosclerotic CAD (p <0.01). During a mean follow-up of 42 months, the death rate was higher in the PTSD compared to the non-PTSD group (15, 17.1%, vs 57, 10.4%, p = 0.003). Multivariable survival regression analyses revealed a significant linkage between PTSD and mortality and between CAC and mortality. After adjustment for risk factors, relative risk (RR) of death was 1.48 (95% confidence interval [CI] 1.03 to 2.91, p = 0.01) in subjects with PTSD and CAC score >0 compared to subjects without PTSD and CAC score equal to 0. With a CAC score equal to 0, risk of death was not different between subjects with and without PTSD (RR 1.04, 95% CI 0.67 to 6.82, p = 0.4). Risk of death in each CAC category was higher in subjects with PTSD compared to matched subjects without PTSD (RRs 1.23 for CAC scores 1 to 100, 1.51 for CAC scores 101 to 400, and 1.81 for CAC scores >=400, p <0.05 for all comparisons). In conclusion, PTSD is associated with presence and severity of coronary atherosclerosis and predicts mortality independent of age, gender, and conventional risk factors. PMID- 21530937 TI - Evaluation of the "learning curve" for left and right radial approach during percutaneous coronary procedures. AB - The transradial approach for percutaneous coronary procedures may be effectively performed through the right radial approach (RRA) or left radial approach (LRA) after an appropriate "learning curve." However, studies evaluating the "learning curve" for RRA and LRA are lacking. In the Transradial Approach (Left vs Right) and Procedural Times During Percutaneous Coronary Procedures (TALENT) study, which randomized 1,540 patients to the RRA or LRA, transradial procedures were performed by either seniors or fellows. Diagnostic procedures performed by fellows were divided into 3 stages: 0 to 100 procedures (stage 1), 101 to 200 procedures (stage 2), and >200 procedures (sage 3). The primary end point of the study was fluoroscopy time during the 3 stages. Six fellows performed 532 procedures, 260 through the RRA and 272 through the LRA. During the training period, fellows showed a progressive significant reduction in fluoroscopy time for the LRA over the 3 stages (stage 1: 258 seconds, interquartile range [IQR] 138 to 377; stage 2: 198 seconds, IQR 126.5 to 375; stage 3: 142 seconds, IQR 95 to 325; p = 0.003), whereas for the RRA, only a slight and nonsignificant reduction in fluoroscopy time was observed (stage 1: 271 seconds, IQR 186 to 364; stage 2: 240 seconds, IQR 156 to 395; stage 3: 218.5 seconds, IQR 145.5 to 300.5; p = 0.20). Cannulation time was progressively reduced over the time for the 2 radial approaches: during stage 1, <40% of procedures required <=3 minutes for radial cannulation, whereas at stage 3, radial cannulation time was <=3 minutes in >60% of procedures (p <0.0001). In conclusion, the LRA is associated with a shorter learning curve compared to the RRA. PMID- 21530938 TI - Early reintervention on the pulmonary arteries and right ventricular outflow tract after neonatal or early infant repair of truncus arteriosus using homograft conduits. AB - Patients with truncus arteriosus often require pulmonary arterial (PA) and/or right ventricular outflow tract (RVOT) reintervention within the first year of repair. However, little is known about the risk factors for early reintervention on the PAs or RVOT in this population. The objective of the present retrospective cohort study was to determine the risk factors for early PA or RVOT reintervention after repair of truncus arteriosus in neonates and young infants. Of 156 patients ascertained (median age at repair 14 days; 143 early survivors), reinterventions on the RVOT and/or PAs were performed in 109. The first reintervention was catheter therapy in 73 patients (conduit dilation/stenting in 29, PA dilation/stenting in 31, both in 13) and conduit reoperation in 36 patients. The freedom from any RVOT or PA reintervention was 68 +/- 4% at 1 year and 48 +/- 5% at 2 years. The factors associated with early reintervention (shorter 1-year freedom from reintervention) on univariate analysis were repair quartile, neonatal repair, smaller weight at repair, and smaller implanted conduit size. On multivariable analysis, only smaller conduit size remained significant (multivariable hazard ratio 0.66/mm, range 0.53 to 0.83; p <0.001). The freedom from conduit reoperation was 92 +/- 3% at 1 year and 76 +/- 4% at 2 years. Overall, the left and right PA sizes were modestly larger than normal by the 1-sample t test, and PA Z scores and the PA area index were not associated with the risk of reintervention. Early reintervention for PA and/or RVOT conduit obstruction is common after neonatal and early infant repair of truncus arteriosus using homograft conduits. A smaller conduit size was associated with early RVOT/PA reintervention. The branch PA size was normal before surgery, suggesting that the PA stenosis in these patients resulted from factors other than intrinsic stenosis or hypoplasia. PMID- 21530939 TI - Myasis in uterine prolapse, successful treatment. AB - We describe the case of an elderly female with total genital prolapse and superinfected uterine myasis. The successful treatment included mechanical extraction of the larvae, antibiotics, and ivermectin (this last one reported for the first time); along with the surgical correction of the prolapse. PMID- 21530940 TI - Human reliability assessment of a critical nursing task in a radiotherapy treatment process. AB - Radiotherapy treatment, like many other fields of medicine, has changed significantly in the last decade with the introduction of more advanced technology and automation. This change has often resulted in aspects of the system which cannot be automated due to technological feasibility and local implementation constraints. This has resulted in a requirement for significant human interaction. This combination of human operations and automation has introduced new error pathways. Traditionally, recommendations to improve the safety of such systems are typically made after the analysis of an adverse event or a significant series of incidents. In contrast, adopting a proactive approach to safety would enable prior identification of potential errors and the specification of appropriate defences against them, thus avoiding costs associated with adverse outcomes. In this paper, a modified version of the proactive Human Reliability Assessment (HRA) method Human Error Assessment and Reduction Technique (HEART) was used to analyse a critical nursing task within a modern radiotherapy system. The modified technique used a participative team approach to complete the assessment in contrast to the normal approach, which uses a single expert assessor. The HEART technique quantifies the likelihood of unreliability of a task and ranks the conditions which most affect the successful completion of that task. HEART has been proposed as a potentially useful HRA tool for applications in healthcare, but such applications have not previously been formally documented. As a result of the modified HEART analysis reported in this paper, remedial measures were identified which were both cost effective and easy to implement. PMID- 21530941 TI - The rating consistency of aesthetic preferences for icon-background color combinations. AB - This study explored the degree of rating consistency for different icon background color combinations, and identified the color combinations with the highest rating for consistency. Rating consistency is the degree of agreement among subjective aesthetic preferences for a specific color combination. In total, 3306 color combinations were rated in this study. The standard deviation of each color combination was calculated as the performance measure for assessing rating consistency among subjects for each color combination. Analysis of variance (ANOVA) results demonstrated that the gender effect was insignificant and rating consistency was very low for both males and females. Furthermore, the experimental results showed that the color combinations affected rating consistency. Hence, cluster analysis with non-hierarchical procedures was then used to categorize color combinations via the clustering variable, the standard deviation of aesthetic preference ratings. Few color combinations in clusters had an extremely high rating consistency. The results indicated that the degree of rating consistency among subjects varied with color combinations. Therefore, using a single average of user aesthetic preference scores may not be appropriate for application to color combinations. Finally, the 30 color combinations determined experimentally can be used as default color combinations as the color scheme for an interface that can be changed because they have consistently high preference scores. PMID- 21530942 TI - Sequence analysis of PAX9, MSX1 and AXIN2 genes in a Chinese oligodontia family. AB - OBJECTIVES: The goal of our research was to look into the clinical traits and genetic mutations in nonsyndromic oligodontia in a Chinese family and to gain insight into the role of mutations of PAX9, MSX1 and AXIN2 in oligodontia phenotypes. MATERIALS AND METHODS: 6 subjects from a family underwent complete oral examination, including panoramic radiographs. Retrospective data were reviewed and blood samples were collected. PCR primers for PAX9, MSX1, and AXIN2 were designed through the Oligo Primer Analysis Software. PCR products were purified and sequenced using the BigDye Terminator Kit and analysed by the 3730 DNA Analyzer. RESULTS: The proband missed 4 permanent canines, 2 permanent maxillary lateral incisors, 2 permanent mandibular lateral incisors, and 2 permanent mandibular central incisors, whilst his maternal grandfather lacked only 2 permanent mandibular central incisors. Moreover, the size of some permanent teeth appeared smaller than normal values of crown width of Chinese people. Oligodontia and abnormalities of teeth were not present in other family members. Radiographic examination showed that the proband and the rest of family members retained all germs of the third molars. There was one known mutation A240P (rs4904210) of PAX9 in the coding region in the proband and the maternal family members (II-2, II-3, and II-4), which possibly contributed to structural and functional changes of proteins. No mutations were identified in MSX1 and AXIN2. CONCLUSIONS: Our findings may imply that the PAX9 A240P mutation is a risk factor for oligodontia in the Chinese population. A240P is likely to be a genetic cause of oligodontia though previous literature suggested it as a polymorphism only. PMID- 21530944 TI - Effects of nitric oxide synthase blockade on dorsal vagal stimulation-induced pancreatic insulin secretion. AB - We and others have previously shown that the dorsal motor nucleus of the vagus (DMV) is involved in regulation of pancreatic exocrine secretion. Many pancreatic preganglionic neurons within the DMV are inhibited by pancreatic secretagogues suggesting that an inhibitory pathway may participate in the control of pancreatic exocrine secretion. Accordingly, the present study examined whether chemical stimulation of the DMV activates the endocrine pancreas and whether an inhibitory pathway is involved in this response. All experiments were conducted in overnight fasted isoflurane/urethane-anesthetized Sprague Dawley rats. Activation of the DMV by bilateral microinjection of bicuculline methiodide (BIM, GABA(A) receptor antagonist, 100 pmol/25 nl; 4 mM) resulted in a significant and rapid increase in glucose-induced insulin secretion (9.2+/-0.1 ng/ml peak response) compared to control microinjection (4.0+/-0.6 ng/ml). Activation of glucose-induced insulin secretion by chemical stimulation of the DMV was inhibited (2.1+/-1.1 ng/ml and 1.6+/-0.1 ng/ml 5 min later) in the presence of the muscarinic receptor antagonist atropine methonitrate (100 MUg/kg/min, i.v.). On the other hand, the nitric oxide (NO) synthesis inhibitor l-nitroarginine methyl ester (30 mg/kg, i.v.) significantly increased the excitatory effect of DMV stimulation on glucose-induced insulin secretion to 15.3+/-3.0 ng/ml and 16.1+/-3.1 ng/ml 5 min later. These findings suggest that NO may play an inhibitory role in the central regulation of insulin secretion. PMID- 21530945 TI - Expression of myeloid differentiation primary response protein 88 (Myd88) in the cerebral cortex after experimental traumatic brain injury in rats. AB - A growing body of evidence indicates that Toll-like receptors (TLRs) and Interleukin-1 (IL-1) family have been shown to be involved in the damaging inflammatory processes associated with stroke, infection, neoplasia, and other diseases in the central nervous system. Myeloid differentiation primary response protein 88 (Myd88) is a critical adaptor protein that transmits signals for TLRs and IL-1 family. Therefore, this study aimed to detect the expression of Myd88 protein and mRNA in a rat weight-dropping trauma model and to clarify the role of Myd88 after traumatic brain injury (TBI). A total of fifty-four Sprague Dawley (SD) rats were randomly divided into control group and TBI groups at hours 6, 12 and on day 1, day 2, day 3, and day 7. The TBI groups suffered experimental TBI by improved Feeney model. Myd88 expression is measured by Reverse Transcription PCR (RT-PCR), Western blot analysis and immunohistochemistry; and nuclear factor kappaB (NF-kappaB) binding activity by electrophoretic mobility shift assay (EMSA); The levels of tumor necrosis factor-alpha (TNF-alpha) and Interleukin 1beta (IL-1beta) were measured by enzyme linked immunosorbent assay (ELISA) and the intercellular adhesion molecule-1 (ICAM-1) expression by immunohistochemistry. The expression of Myd88 in the injured brain was dramatically increased through 6 h and 7 days postinjury, and peaked on 3days. NF kappaB, TNF-alpha, IL-1beta and ICAM-1 also ascended significantly after TBI. Our data demonstrated that Myd88 was increasingly expressed in a parallel time course to the up-regulation of NF-kappaB, proinflammatory cytokines and ICAM-1 and there was a highly positive relationship among them. These findings might have important implications during the administration of specific Myd88 antagonists in order to prevent or reduce inflammatory response after TBI. PMID- 21530943 TI - Pain coping skills training for patients with elevated pain catastrophizing who are scheduled for knee arthroplasty: a quasi-experimental study. AB - OBJECTIVES: To (1) describe a behavioral intervention designed for patients with elevated pain catastrophizing who are scheduled for knee arthroplasty, and (2) use a quasi-experimental design to evaluate the potential efficacy of the intervention on pain severity, catastrophizing cognitions, and disability. DESIGN: Quasi-experimental nonequivalent control group design with a 2-month follow-up. SETTING: Two university-based orthopedic surgery departments. PARTICIPANTS: Adults (N=63) scheduled for knee replacement surgery who reported elevated levels of pain catastrophizing. Patients were recruited from 2 clinics and were assessed prior to surgery and 2 months after surgery. INTERVENTIONS: A group of 18 patients received a psychologist-directed pain coping skills training intervention comprising 8 sessions. The other group, a historical cohort of 45 patients, received usual care. MAIN OUTCOME MEASURES: Western Ontario and McMaster Universities Arthritis Index Pain and Disability scores, as well as scores on the Pain Catastrophizing Scale. RESULTS: Two months after surgery, the patients who received pain coping skills training reported significantly greater reductions in pain severity and catastrophizing, and greater improvements in function as compared to the usual care cohort. CONCLUSIONS: Pain catastrophizing is known to increase risk of poor outcome after knee arthroplasty. The findings provide preliminary evidence that the treatment may be highly efficacious for reducing pain, catastrophizing, and disability, in patients reporting elevated catastrophizing prior to knee arthroplasty. A randomized controlled trial is warranted to confirm these effects. PMID- 21530946 TI - Age-related differences during simple working memory decisions: ERP indices of early recognition and compensation failure. AB - Imaging data has identified frontal cortical activation in older adults during simple recognition tasks that relates positively with performance and could, therefore, be considered compensatory. However, in a previous electrophysiological study involving a Sternberg task with proactive interference manipulations, we observed a frontal positive scalp potential between 400 and 500 ms that was unique to older adults and predictive of poorer performance. These results led us to ask whether unique frontal activation in older adults serves a compensatory role only during relatively simple tasks when stimulus familiarity provides an unambiguous basis for response selection. In the current study, we tested this hypothesis by having younger and older adults complete a verbal Sternberg task without interference manipulations. In younger adults, we observed an early posterior negativity (90-120 ms) that predicted performance accuracy. Older adults failed to show this early negativity but did produce the expected frontal positivity. However, the frontal positivity was again associated with poorer performance. These data support the view that younger adults are able to bias early target discrimination to benefit response selection whereas older adults rely on later controlled processes that are not always effective in buffering against normative age-related decline. PMID- 21530947 TI - Synthesis of fluorescently labelled rhamnosides: probes for the evaluation of rhamnogalacturonan II biosynthetic enzymes. AB - Three fluorescently labelled saccharides 10-12, representing structures found in pectic glycan rhamnogalacturonan II (RG-II), were synthesised by chemical glycosylation of O-6 of diacetone-d-galactose followed by deprotection and reductive amination with amino-substituted fluorophore APTS. This convenient method installs a common aminogalactitol-based tether in order to preserve the integrity of the reducing end of specific carbohydrates of interest. APTS labelled glycans prepared in this manner were purified by carbohydrate gel electrophoresis and subjected to capillary electrophoresis analysis, as a basis for the subsequent development of high sensitivity assays for RG-II-active enzymes. PMID- 21530948 TI - [Prospective randomised study: robotic-assisted versus conventional laparoscopic surgery in colorectal cancer resection]. AB - INTRODUCTION: Robotic-assisted surgery is playing an increasingly important role in the last few years in the treatment of colorectal oncological disease. However, there are still no studies that objectively demonstrate the advantages of this type of surgery. We present a prospective randomised study in order to compare the short-term results between colorectal robotic surgery and laparoscopic surgery. MATERIAL AND METHOD: A total of 56 patients diagnosed with colorectal cancer between January 2008 and January 2009, were randomised and assigned to the robotic or laparoscopic group. Age, body mass index, tumour location, conversions in each group, complications during and after surgery, and histological characteristics of the specimens obtained, were all compared. RESULTS: There were no significant differences between age (P=.055), body mass index (P=.12), or tumour location (P=.91). Only one patient in the robotic group required a transfusion and none in the laparoscopic group. The percentage of conversions was the same in both groups, however, the preparation times and operating times were significantly longer in patients intervened using the robotic device (P=.0001 and P=.017, respectively). There were no differences as regards the rate of complications or in the percentage of re-interventions (14.2% and 7.1%). The mean hospital stay of the patients was 9.3 (8.1) days in the robotic group and 9.2 (6.8) days in the laparoscopic (P=.79). The distal resection margin was greater in the specimen obtained using robotic surgery (P =.003) as well as the number of lymph nodes obtained in the specimen (P =.23). CONCLUSION: Robotic colorectal was performed safely and effectively, and with similar clinical results. International Trial Number for this study is: ISRCTN60866560. PMID- 21530950 TI - [Atypical location of the right hepatic artery]. PMID- 21530949 TI - [Pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy: critical analysis of prospective randomised trials]. AB - This is a critical analysis of prospective randomised trials that compare pancreatic reconstruction techniques with the stomach and the intestine, after pancreaticoduodenectomy. A questionnaire with questions from the Evidence Based Medicine Centre of Oxford University (PICO analysis) was used, following the criteria for the evaluation of randomised prospective studies for surgical interventions of the McMaster University in Ontario. It was found that the studies differed in methodological aspects, the most important being the lack of a uniform definition of a pancreatic fistula. The techniques for performing pancreaticogastrostomy and pancreaticojejunostomy were not homogeneous. There were no differences in the percentage of pancreatic fistula in three of these studies; one which modified the pancreaticogastrostomy technique had more favourable results. New comparative studies should use new definitions of the complications of pancreaticoduodenectomy and standardise the pancreatic reconstruction technique. PMID- 21530951 TI - [Hereditary angioedema: a rare cause of abdominal pain]. PMID- 21530952 TI - [Use of biological markers in the differential diagnosis of sepsis after liver transplant]. AB - The use of biological markers is developing in the field of liver transplant. Biomarkers are being studied in different contexts: 1) detection of tolerant patient; 2) recurrence of hepatitis C virus; 3) diagnosis and prognosis of liver cancers, and 4) diagnosis of infection. The immunological changes occurring in the transplant patient given their previous cirrhotic condition, the immunosuppression received, and possible intercurrent diagnoses (rejection, recurrence of hepatitis C virus...) highlight the importance of finding useful biomarkers in clinical practice to diagnose infection. After a review of the usefulness of biomarkers, we should perhaps add the serial determination of C reactive protein in the immediate post-operative period, and later on procalcitonin, in the infection diagnosis algorithm. Although the determination of procalcitonin appears to be the most reliable biomarker in the differential diagnosis of sepsis and rejection, the studies carried out make it difficult to establish conclusions on its real clinical usefulness. PMID- 21530953 TI - [Emergency thoracotomy. Indications, surgical technique and results]. AB - Emergency thoracotomy is a surgical technique that has been extended in the last few years, and is currently included in advanced cardiopulmonary resuscitation protocols. Despite its proven use in patients with penetrating heart wounds, it is often not used due to lack of knowledge of the technique. Currently, the increase in chest wounds due to violence, traffic accidents, crashes or suicides, and advances in extra-hospital medical care systems, has currently awakened new interest in this technique. A review of emergency thoracotomy is presented in this article: indications, surgical technique, results, and its usefulness in the extra-hospital setting. PMID- 21530954 TI - Systemic arterial air embolism after percutaneous lung biopsy. AB - Systemic arterial air embolism is a rarely encountered but much feared complication of percutaneous lung biopsy. We present a comprehensive review of iatrogenic air embolism post-lung biopsy, a complication that is often suboptimally managed. This review was inspired by our own institutional experience and we use this to demonstrate that excellent outcomes from this complication can be seen with prompt treatment using hyperbaric oxygen chamber therapy, after initial patient stabilization has been achieved. Pathophysiology, clinical features, and risk factors are reviewed and misconceptions regards venous versus arterial air embolism are examined. An algorithm is provided for radiologists to ensure suspected patients are appropriately managed with more favourable outcomes. PMID- 21530955 TI - Cystic change in thyroid nodules: a confounding factor for real-time qualitative thyroid ultrasound elastography. AB - OBJECTIVE: To evaluate real-time qualitative ultrasound elastography for focal thyroid masses undergoing fine-needle aspiration in a routine thyroid ultrasound clinic. MATERIALS AND METHODS: Ninety-four thyroid nodules scheduled for fine needle aspiration cytology in a thyroid ultrasound clinic also underwent real time freehand elastography. Colour-scaled elastograms were graded visually on the stiffness of the solid component of nodules relative to thyroid parenchyma using an elastography score (ES) scale from 1 (soft) to 4 (stiff). The ES for benign and malignant nodules and the influence of cystic change on ES were analysed using Chi-square with trend and Fishers exact tests, with a p<0.05 used to indicate statistical significance. RESULTS: There were 19 papillary carcinomas, five metastases, 57 hyperplastic nodules, and four follicular adenomas based on definitive cytology (n=54) or histology (n=31). Nine nodules were excluded due to indeterminate cytology and no histology. Of malignancies (all solid), two were ES=1, four were ES=2, eight were ES=3, and 10 were ES=4. Of benign nodules, 17 were ES=1, 17 were ES=2, 16 were ES=3, and 11 were ES=4. An ES>2 was more common in benign nodules with predominant cystic components (17/18) than mildly cystic (3/12) or completely solid (7/31) benign nodules (p=0.0004, p<0.0001). The ES was not significantly different between benign and malignant nodules (p=0.09) unless partially cystic nodules were excluded (p=0.005). For solid nodules, an ES>2 optimally predicted malignancy, achieving 74% sensitivity, 77% specificity, and 76% accuracy. CONCLUSION: Qualitative real-time thyroid elastography predicts malignancy only if predominantly cystic nodules are excluded, which may limit its utility in routine clinical practice. PMID- 21530956 TI - Multiscale entropy and detrended fluctuation analysis of QT interval and heart rate variability during normal pregnancy. AB - Pregnancy leads to physiological changes in various parameters of the cardiovascular system. The aim of this study was to investigate longitudinal changes in the structure and complexity of heart rate variability (HRV) and QT interval variability during the second half of normal gestation. We analysed 30 min high-resolution ECGs recorded monthly in 32 pregnant women, starting from the 20th week of gestation. Heart rate and QT variability were quantified using multiscale entropy (MSE) and detrended fluctuation analyses (DFA). DFA of HRV showed significantly higher scaling exponents towards the end of gestation (p<0.0001). MSE analysis showed a significant decrease in sample entropy of HRV with progressing gestation on scales 1-4 (p<0.05). MSE analysis and DFA of QT interval time series revealed structures significantly different from those of HRV with no significant alteration during the second half of gestation. In conclusion, pregnancy is associated with increases in long-term correlations and regularity of HRV, but it does not affect QT variability. The structure of QT time series is significantly different from that of RR time series, despite its close physiological dependence. PMID- 21530959 TI - [An internist in the Prado Museum. The challenge of "the naked eye" diagnosis]. AB - Painting and medicine include the humans. They describe, investigate, diagnose and magnify them, with the idea of being able to offer them a cure. The aim of this paper is to describe the disease through the eyes of the painting. To do so, we have selected the pictures exhibited in the Prado Museum and have described the diseases that they express and that may attract the attention of a good physician. All of this has then been contrasted with the opinion of experts in medicine and painting. PMID- 21530960 TI - [Diagnosis of Takayasu arteritis diagnosis at 64 years of age: is it worth considering in the physical examination?]. PMID- 21530957 TI - Urban land-use and respiratory symptoms in infants. AB - BACKGROUND: Children's respiratory health has been linked to many factors, including air pollution. The impacts of urban land-use on health are not fully understood, although these relationships are of key importance given the growing populations living in urban environments. OBJECTIVES: We investigated whether the degree of urban land-use near a family's residence is associated with severity of respiratory symptoms like wheeze among infants. METHODS: Wheeze occurrence was recorded for the first year of life for 680 infants in Connecticut for 1996-1998 from a cohort at risk for asthma development. Land-use categories were obtained from the National Land Cover Database. The fraction of urban land-use near each subject's home was related to severity of wheeze symptoms using ordered logistic regression, adjusting for individual-level data including smoking in the household, race, gender, and socio-economic status. Nitrogen dioxide (NO(2)) exposure was estimated using integrated traffic exposure modeling. Different levels of urban land-use intensity were included in separate models to explore intensity-response relationships. A buffer distance was selected based on the log likelihood value of models with buffers of 100-2000 m by 10 m increments. RESULTS: A 10% increase in urban land-use within the selected 1540 m buffer of each infant's residence was associated with 1.09-fold increased risk of wheeze severity (95% confidence interval, 1.02-1.16). Results were robust to alternate buffer sizes. When NO(2), representing traffic pollution, was added to the model, results for urban land-use were no longer statistically significant, but had similar central estimates. Higher urban intensity showed higher risk of prevalence and severity of wheeze symptoms. CONCLUSIONS: Urban land-use was associated with severity of wheeze symptoms in infants. Findings indicate that health effect estimates for urbanicity incorporate some effects of traffic related emissions, but also involve other factors. These may include differences in housing characteristics or baseline healthcare status. PMID- 21530962 TI - Prevention of ovarian hyperstimulation syndrome. PMID- 21530963 TI - Complete hysteroscopic resection of a large atypical polypoid adenomyoma, followed by a successful pregnancy. AB - OBJECTIVE: To describe the hysteroscopic resection of a large atypical polypoid adenomyoma (APA) in a young patient followed by a successful pregnancy. DESIGN: Case report. SETTING: Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan. PATIENT(S): A 29-year-old female who had an endocervical tumor 4 cm in size and a diagnosis of APA. INTERVENTION(S): Conservative hysteroscopic resection of the lesion. MAIN OUTCOME MEASURE(S): Disease and pregnancy outcome. RESULT(S): The lesion was completely resected by a pathologically guided, hysteroscopic surgery. The patient spontaneously became pregnant and gave birth by vaginal delivery and is free from disease 3 years after the surgery. CONCLUSION(S): Conservative hysteroscopic surgery may be a good treatment option for APA in patients who wish to preserve their fertility, even for patients with a large lesion. PMID- 21530964 TI - Complex X chromosome rearrangement delineated by array comparative genome hybridization in a woman with premature ovarian insufficiency. AB - OBJECTIVE: To investigate candidate genes affected by a complex X chromosome rearrangement that may play a role in the diagnosis of spontaneous premature ovarian insufficiency (POI). DESIGN: Prospective cytogenetic analysis, fluorescence in situ hybridization (FISH) analysis and oligonucleotide array comparative genome hybridization (CGH). SETTING: University medical center. PATIENT(S): A 36-year-old woman with POI found to have a highly rearrangement X chromosome. INTERVENTION(S): FISH analysis and oligonucleotide array CGH. MAIN OUTCOME MEASURE(S): Oligonucleotide microarray analysis to detect duplicated, deleted, or translocated regions of the X chromosome. RESULT(S): Complex rearrangement of the X chromosome involving >=12 breakpoints resulting in two deletions, four duplications, and several intrachromosomal translocations. At least 13 genes with possible relevance to POI may be affected by the rearrangement. CONCLUSION(S): Array CGH can reveal candidate genes that may have essential roles in fertility and POI. PMID- 21530965 TI - New skeletal tuberculosis cases in past populations from Western Hungary (Transdanubia). AB - The distribution, antiquity and epidemiology of tuberculosis (TB) have previously been studied in osteoarchaeological material in the eastern part of Hungary, mainly on the Great Plain. The purpose of this study is to map the occurrence of skeletal TB in different centuries in the western part of Hungary, Transdanubia, and to present new cases we have found. Palaeopathological analysis was carried out using macroscopic observation supported by radiographic and molecular methods. A large human osteoarchaeological sample (n=5684) from Transdanubian archaeological sites ranging from the 2nd to the 18th centuries served as a source of material. Spinal TB was observed in seven individuals (in three specimens with Pott's disease two of which also had cold abscess) and hip TB was assumed in one case. The results of DNA for Mycobacterium tuberculosis were positive in seven of the eight cases identified by paleopathology, and negative in the assumed case of hip TB. However, the molecular results are consistent with highly fragmented DNA, which limited further analysis. Based on the present study and previously published cases, osteotuberculosis was found in Transdanubia mainly during the 9th-13th centuries. However, there are no signs of TB in many other 9th-13th century sites, even in those that lie geographically close to those where osteotuberculous cases were found. This may be due to a true absence of TB caused by the different living conditions, way of life, or origin of these populations. An alternative explanation is that TB was present in some individuals with no typical paleopathology, but that death occurred before skeletal morphological features could develop. PMID- 21530966 TI - Distraction osteogenesis for bone repair in the 21st century: lessons learned. AB - Bone regeneration obtained by distraction osteogenesis is influenced by a series of factors. These include factors that are related to the mechanical stability of the system of distraction (internal or external devices), and to factors directly depending on the biology of the bone tissue, such as the method of bone interruption (osteotomy), the delay and rhythm of distraction, the anatomical site of the osteotomy, and the histological characteristics of the bone requiring reconstruction. The stability of the system of bone fixation depends on the rigidity of the frame, the connexion of the apparatus to the bone (wires, pins) and the intrinsic stability of the segment (length and level of maturation of bone regenerate). The radiological characteristics of bone regeneration (hypo- or hypertrophy) lead to the adaptation of the rhythm of distraction. Following more than 28 years of experience of application of the Ilizarov method for bone reconstruction, the authors describe the technique of frame assembly and the methods of evaluation and treatment of the complications of new bone formation. PMID- 21530967 TI - Exacerbation of thrombocytopenia in a pregnant woman with thrombocytopenia-absent radius syndrome. PMID- 21530968 TI - Resveratrol prevents the development of abdominal aortic aneurysm through attenuation of inflammation, oxidative stress, and neovascularization. AB - OBJECTIVE: We sought to examine the effect of resveratrol (3,4',5-trihydroxy trans-stilbene), a plant-derived polyphenolic compound, on the development of abdominal aortic aneurysm (AAA). METHODS: AAA was induced in mice by periaortic application of CaCl(2). NaCl (0.9%)-applied mice were used as a sham group. Mice were treated with intraperitoneal injection of PBS (Sham/CON, AAA/CON, n=30 for each) or resveratrol (100 mg/kg/day) (AAA/RSVT, n=30). Six weeks after the operation, aortic tissue was excised for further examinations. RESULTS: Aortic diameter was enlarged in AAA/CON compared with Sham/CON. Resveratrol treatment reduced the aneurysm size and inflammatory cell infiltration in the aortic wall compared with AAA/CON. Elastica Van Gieson staining showed destruction of the wavy morphology of the elastic lamellae in AAA/CON, while it was preserved in AAA/RSVT. The increased mRNA expression of monocyte chemotactic protein-1, tumor necrosis factor-alpha, intercellular adhesion molecule-1, CD68, vascular endothelial growth factor-A, p47, glutathione peroxidase (GPX)1 and GPX3 were attenuated by resveratrol treatment (all p<0.05). Administration of resveratrol decreased protein expression of phospho-p65 in AAA. The increased 8-hydroxy-2' deoxyguanosine-positive cell count and 4-hydroxy-2-nonenal-positive cell count in AAA were also reduced by resveratrol treatment. Zymographic activity of matrix metalloproteinase (MMP)-9 and MMP-2 was lower in AAA/RSVT compared with AAA/CON (both p<0.05). Compared with AAA/CON, Mac-2(+) macrophages and CD31(+) vessels in the aortic wall were decreased in AAA/RSVT (both p<0.05). CONCLUSION: Treatment with resveratrol in mice prevented the development of CaCl(2)-induced AAA, in association with reduced inflammation, oxidative stress, neoangiogenesis, and extracellular matrix disruption. These findings suggest therapeutic potential of resveratrol for AAA. PMID- 21530970 TI - Kinematic performance of a six degree-of-freedom hand model (6DHand) for use in occupational biomechanics. AB - Upper extremity musculoskeletal disorders represent an important health issue across all industry sectors; as such, the need exists to develop models of the hand that provide comprehensive biomechanics during occupational tasks. Previous optical motion capture studies used a single marker on the dorsal aspect of finger joints, allowing calculation of one and two degree-of-freedom (DOF) joint angles; additional algorithms were needed to define joint centers and the palmar surface of fingers. We developed a 6DOF model (6DHand) to obtain unconstrained kinematics of finger segments, modeled as frusta of right circular cones that approximate the palmar surface. To evaluate kinematic performance, twenty subjects gripped a cylindrical handle as a surrogate for a powered hand tool. We hypothesized that accessory motions (metacarpophalangeal pronation/supination; proximal and distal interphalangeal radial/ulnar deviation and pronation/supination; all joint translations) would be small (less than 5 degrees rotations, less than 2mm translations) if segment anatomical reference frames were aligned correctly, and skin movement artifacts were negligible. For the gripping task, 93 of 112 accessory motions were small by our definition, suggesting this 6DOF approach appropriately models joints of the fingers. Metacarpophalangeal supination was larger than expected (approximately 10 degrees ), and may be adjusted through local reference frame optimization procedures previously developed for knee kinematics in gait analysis. Proximal translations at the metacarpophalangeal joints (approximately 10mm) were explained by skin movement across the metacarpals, but would not corrupt inverse dynamics calculated for the phalanges. We assessed performance in this study; a more rigorous validation would likely require medical imaging. PMID- 21530971 TI - Synthesis of (S)-naproxen-benzotriazole and its application as chiral derivatizing reagent for microwave-assisted synthesis and indirect high performance liquid chromatographic separation of diastereomers of penicillamine, cysteine and homocysteine. AB - (S)-Naproxen-benzotriazole was synthesized by the reaction of (S)-naproxen with 1H-benzotriazole using coupling reagent dicyclohexyl carbodiimide and 4 dimethylamino pyridine (DCC/DMAP). It was used as chiral derivatizing reagent for microwave irradiated synthesis of diastereomers of penicillamine, cysteine and homocysteine. The diastereomers were separated by reversed phase high performance liquid chromatography using gradient elution of triethylammonium phosphate (pH 3.5)-acetonitrile (30-65% within 30 min). The method was validated for accuracy, precision, and limit of detection. PMID- 21530969 TI - Long-term nano-mechanical properties of biomodified dentin-resin interface components. AB - Failures of dental composite restorative procedures are largely attributed to the degradation of dentin-resin interface components. Biomodification of dentin using bioactive agents may improve the quality and durability of the dentin-resin bonds. The aim of this study was to nanomechanically assess the reduced modulus of elasticity (Er) and nano-hardness (H) of major components of the dentin-resin interface (hybrid layer, adhesive layer and underlying dentin) biomodified by collagen cross-linkers at 24h, 3 and 6 months following restorative procedure. Demineralized dentin surfaces were biomodified with 5% glutaraldehyde (GD) or 6.5% grape seed extract (GSE) prior to placement of adhesive systems and composite resin. Nano-measurements of the interface components in a fluid cell showed that both agents increased the Er and H of underlying dentin after 3 and 6 months when compared to a control. The mechanical properties of the adhesive and hybrid layers decreased over time. Biomodification of the dentin-resin interface structures using GD and GSE can increase the mechanical properties of the interface over time and may contribute to the long-term quality of adhesive restorations. PMID- 21530972 TI - Impact of solvent conditions on separation and detection of basic drugs by micro liquid chromatography-mass spectrometry under overloading conditions. AB - In this study the impact of solvent conditions on the performance of MULC/MS for the analysis of basic drugs was investigated. Our aim was to find experimental conditions that enable high-performance chromatographic separation particularly at overloading conditions paired with a minimal loss of mass spectrometric detection sensitivity. A focus was put on the evaluation of the usability of different kinds of acidic modifiers (acetic acid (HOAc), formic acid (FA), methansulfonic acid (CH3SO3H), trifluoroacetic acid (TFA), pentafluoropropionic acid (PFPA), and heptafluorobutyric acid (HFBA)). The test mixture consisted of eleven compounds (bunitrolol, caffeine, cocaine, codeine, diazepam, doxepin, haloperidol, 3,4-methylendioxyamphetamine, morphine, nicotine, and zolpidem). Best chromatographic performance was obtained with the perfluorinated acids. Particularly, 0.010-0.050% HFBA (v/v) was found to represent a good compromise in terms of chromatographic performance and mass spectrometric detection sensitivity. Compared to HOAc, on average a 50% reduction of the peak widths was observed. The use of HFBA was particularly advantageous for polar compounds such as nicotine; only with such a hydrophobic ion-pairing reagent chromatographic retention of nicotine was observed. Best mass spectrometric performance was obtained with HOAc and FA. Loss of detection sensitivity induced by HFBA, however, was moderate and ranged from 0 to 40%, which clearly demonstrates that improved chromatographic performance is able to compensate to a large extent the negative effect of reduced ionization efficiency on detection sensitivity. Applications of MULC/MS for the qualitative and quantitative analysis of clinical and forensic toxicological samples are presented. PMID- 21530973 TI - Rapid determination of glyphosate, glufosinate, bialaphos, and their major metabolites in serum by liquid chromatography-tandem mass spectrometry using hydrophilic interaction chromatography. AB - We developed a simple and rapid method for the simultaneous determination of phosphorus-containing amino acid herbicides (glyphosate, glufosinate, bialaphos) and their major metabolites, aminomethylphosphonic acid (AMPA) and 3 methylphosphinicopropionic acid (MPPA), in human serum. Serum samples were filtrated through an ultrafiltration membrane to remove proteins. The filtrate was then washed with chloroform, and injected into a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. Chromatographic separation was achieved on a hydrophilic interaction chromatography (HILIC) column. Determination of the target herbicides and metabolites was successfully carried out without derivatization or solid phase extraction (SPE) cartridge clean-up. The recoveries of these compounds, added to human serum at 0.2MUg/mL, ranged from 94% to 108%, and the relative standard deviations (RSDs) were within 5.9%. The limits of detection (LODs) were 0.01MUg/mL for MPPA, 0.02MUg/mL for AMPA, 0.03MUg/mL for both glyphosate and glufosinate, and 0.07MUg/mL for bialaphos, respectively. PMID- 21530975 TI - Possible factors influencing the separation mechanism of diastereomeric amino acid derivatives obtained from s-triazine type reagents. AB - Diastereomeric derivatives prepared from an amino acid and an amino amide using trichloro s-triazine as a coupling platform are known to produce good chromatographic diastereoselectivity for many amino acid analytes. The chromatographic diastereoselectivity of these derivatives is difficult to rationalize based on the possibility of four possible conformational isomers, which can interconvert by rotation about the C-N bonds between the amino substituents and the triazine ring. The observed diastereoselectivity implicates an unobvious but significant driving force which causes one of several conformations to be favored over the others. Several possibilities are discussed. Intramolecular hydrogen bonding between acid and amide substituents was explored using computer aided molecular modeling. While such hydrogen bonding may be geometrically possible between the amino acid and the amide substituents, it does not explain why derivatives produced from other chiral compounds which are not capable of the same hydrogen bonding interaction nevertheless exhibit substantial diastereoselectivity. Two other more general effects, steric hindrance to solvation and ion pairing, are therefore suggested as possible contributing factors to the chromatographic diastereoselectivity. Based on the conformational equilibrium behavior of related triazine compounds as reported in the literature, either one of these effects could influence the conformation of the diastereomeric derivatives even in the absence of intramolecular hydrogen bonding interactions between the two chiral substituents, and these effects may therefore be a contributing factor for the observed elution order of the diastereomers. PMID- 21530974 TI - Chromatographic evaluation of reversed-phase/anion-exchange/cation-exchange trimodal stationary phases prepared by electrostatically driven self-assembly process. AB - This work describes chromatographic properties of reversed-phase/cation exchange/anion-exchange trimodal stationary phases. These stationary phases were based on high-purity porous spherical silica particles coated with nano-polymer beads using an electrostatically driven self-assembly process. The inner-pore area of the material was modified covalently with an organic layer that provided both reversed-phase and anion-exchange properties while the outer surface was coated with nano-sized polymer beads with strong cation-exchange characteristics. This design ensured spatial separation of the anion-exchange and the cation exchange regions, and allowed reversed-phase, anion-exchange and cation-exchange retention mechanisms to function simultaneously. Chromatographic evaluation of ions and small molecules suggested that retention of ionic analytes was influenced by the ionic strength, pH, and mobile phase organic solvent content, and governed by both ion-exchange and hydrophobic interactions. Meanwhile, neutral analytes were retained by hydrophobic interaction and was mainly affected by mobile phase organic solvent content. Depending on the specific application, selectivity could be optimized by adjusting the anion-exchange/cation-exchange capacity ratio (selectivity), which was achieved experimentally by using porous silica particles with different surface areas. PMID- 21530976 TI - Retention behavior of peptides in hydrophilic-interaction chromatography. AB - Selected hydrophilic interaction chromatography (HILIC) columns packed with bare silica, bridge-ethyl hybrid silica, or an amide sorbent chemistry were utilized for an investigation of chromatographic behavior and separation selectivity of tryptic peptides. Retention model was proposed allowing for retention prediction of peptides with correlation coefficient R(2)~0.92-0.97 for various columns. The values of optimized amino acid retention coefficients were compared to those obtained for reversed-phase liquid chromatography (Gilar et al., Anal. Chem. 2010, 82, 265-275) and used to elucidate the impact of different amino acid on peptide HILIC retention. In contrast to reversed-phase chromatography, where presence of Phe, Trp, Ile, and Leu amino acid residues in sequence strongly promoted, and presence of hydrophilic His, Lys and Arg residues strongly reduced peptide retention, the effects of these amino acid residues in HILIC were opposite (His, Lys and Arg promote, Phe, Trp, Ile and Leu demote peptide retention in HILIC). Retention coefficient optimized for pH experiments illustrated the impact of silanols on HILIC retention. PMID- 21530977 TI - A chromatography-focused bioprocess that eliminates soluble aggregation for bioactive production of a new antimicrobial peptide candidate. AB - Human beta defensins (hBDs) are an important class of antimicrobial peptides (AMPs), which provide the host with innate protection from bacteria, fungi and viruses. Human beta-defensin-25 (hBD25) is a new hBD variant which has been recently discovered in the male genital tract. Since its discovery, hBD25 was hypothesized to play a key role in protection against genital tract infection, which has significantly increased mortality rates in the last decade. However, further studies to confirm the role of hBD25 are hindered by the lack of sufficient amounts of pure hBD25 for clinical studies. This study reports the first successful development of an efficient and low cost chromatography-oriented bioprocess for production of hBD25. hBD25 was expressed predominantly as soluble aggregates although the peptide was co-expressed with a Maltose Binding Protein (MBP) fusion tag in E. coli. The soluble aggregates were disrupted by denaturation-reduction of the hBD25, followed by an in vitro size exclusion chromatography refolding step which readily yielded bioactive and purified hBD25 peptides at 90% purity. The refolded hBD25 showed antimicrobial activity against E. coli K12 at a minimal inhibitory concentration of 60 MUg/mL. With an overall hBD25 bioprocess yield of 48% obtained, this bioprocess will open the way for detailed clinical studies of hBD25, and serve as a generic platform for efficient recovery of other 'fusion protein'-derived peptides that inevitably exist as soluble aggregates. PMID- 21530978 TI - Effective indirect enrichment and determination of nitrite ion in water and biological samples using ionic liquid-dispersive liquid-liquid microextraction combined with high-performance liquid chromatography. AB - An ionic liquid dispersive liquid-liquid microextraction high-performance liquid chromatography (IL-DLLME-HPLC) method for effective enrichment and determination of nitrite ion in water and biological samples was developed. The method was based on the reaction of nitrite ion with p-nitroaniline in the presence of diphenylamine in acid media and IL-DLLME of azo product. The optimization of reaction and extraction conditions, such as kind and concentration of acid, reaction time, volume of reaction solvent, temperature, kind of extraction and dispersive solvent, volume of extraction and dispersive solvent, addition of salt, extraction and centrifugal time were studied. Under the optimal conditions, 1-octyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide IL-DLLME procedure provided high enrichment factor of 430 and good extraction recovery of 91.7% for nitrite ion. The linearity was observed in the range of 0.4-500.0 MUg L 1 with good correlation coefficient (r2=0.9996). The relative standard deviations (RSDs) for five replicate measurements varied between 1.5% and 4.8%. The limit of detection of the method (S/N=3) was 0.05 MUg L-1. The interference effect of some anions and cations was also tested. The developed method allowed achieving an excellent enrichment factor, yielding a lower LOD in comparison with other methods. Moreover, the proposed method was able to analyze nitrite ion in water and biological samples with satisfactory recovery ranged from 96.5% to 107.3%. PMID- 21530980 TI - Liking and identifying emotionally expressive music: age and gender differences. AB - Adults and children 5, 8, and 11 years of age listened to short excerpts of unfamiliar music that sounded happy, scary, peaceful, or sad. Listeners initially rated how much they liked each excerpt. They subsequently made a forced-choice judgment about the emotion that each excerpt conveyed. Identification accuracy was higher for young girls than for young boys, but both genders reached adult like levels by age 11. High-arousal emotions (happiness and fear) were better identified than low-arousal emotions (peacefulness and sadness), and this advantage was exaggerated among younger children. Whereas children of all ages preferred excerpts depicting high-arousal emotions, adults favored excerpts depicting positive emotions (happiness and peacefulness). A preference for positive emotions over negative emotions was also evident among females of all ages. As identification accuracy improved, liking for positively valenced music increased among 5- and 8-year-olds but decreased among 11-year-olds. PMID- 21530981 TI - Early clinical markers of central nervous system involvement in mucopolysaccharidosis type II. AB - OBJECTIVE: To identify early clinical markers of neurologic involvement in mucopolysaccharidosis type II. STUDY DESIGN: A retrospective review of neurobehavioral standardized assessments of patients with mucopolysaccharidosis type II evaluated at the Program for Neurodevelopmental Function in Rare Disorders was completed. Patients were grouped based on the presence or absence of central nervous system (CNS) involvement at the most recent evaluation. Differences in early signs and symptoms between resulting cohorts were tested for significance, and an index severity score was developed. RESULTS: Between December 2002 and November 2010, clinical evaluations of 49 patients and 151 patient encounters were reviewed. Thirty-seven patients exhibited neurologic deterioration. Of the 25 signs evaluated, 7 early clinical markers were strongly correlated with subsequent cognitive dysfunction: sleep disturbance, increased activity, behavior difficulties, seizure-like behavior, perseverative chewing behavior, and inability to achieve bowel training and bladder training. A new severity score index was developed, with a score >=3 indicating a high likelihood of developing CNS disease. CONCLUSION: Seven early clinical markers and a severity score index of CNS involvement can be used for initial screening of children who might benefit from CNS-directed therapies. PMID- 21530979 TI - The association between valuing popularity and relational aggression: the moderating effects of actual popularity and physiological reactivity to exclusion. AB - The association between having a reputation for valuing popularity and relational aggression was assessed in a sample of 126 female children and adolescents (mean age = 12.43 years) at a 54-day residential summer camp for girls. Having a reputation for valuing popularity was positively related to relational aggression. This association was moderated by both popularity and physiological reactivity to social exclusion (i.e., respiratory sinus arrhythmia reactivity [RSAR] and heart rate reactivity [HRR]). Popular girls with a reputation for valuing popularity were at greater risk for engaging in relational aggression when they also exhibited blunted reactivity to social exclusion. Conversely, girls who had a reputation for valuing popularity but were not popular (i.e., the "wannabes") were at risk for engaging in relational aggression when they exhibited heightened reactivity to exclusion. PMID- 21530982 TI - Robotic transthoracic esophagectomy in the prone position: experience with 32 patients with esophageal cancer. PMID- 21530983 TI - Validation of Arenicola marina in field toxicity bioassays using benthic cages: biomarkers as tools for assessing sediment quality. AB - Sediment toxicity assessments using caged organisms present advantages over using laboratory and native community studies. The use of caged Arenicola marina in sediment toxicity assessments was evaluated. Lugworms were exposed in situ to sediments from coastal and port areas in Spain for seven days, and the activities of the biotransformation enzymes ethoxyresorufin O-deethylase, dibenzylfluorescein dealkylase and glutathione S-transferase, the activities of the antioxidant enzymes glutathione reductase and glutathione peroxidase and lipid peroxidation were then analyzed as biomarkers. Biomarker results and sediment physicochemical data were integrated. Cadiz Bay (SW Spain) sediments presented metal contamination that was not linked to a biochemical response. In LPGC Port (SW Spain), Pb contamination exhibited a moderate toxic potential, while PAHs, and presumably pharmaceuticals, provoked biochemical responses that efficiently prevented lipid peroxidation. In Santander Bay (N Spain), exposure to PAHs and, presumably, pharmaceuticals induced biomarker responses, but lipid peroxidation occurred nevertheless. These results indicated that caged A. marina were effective for the assessment of sediment quality and that the selected biomarkers were sufficiently sensitive to identify chemical exposure and toxicity. PMID- 21530984 TI - Estrogen pollution in a highly productive ecosystem off central-south Chile. AB - While the presence of steroid estrogens in the environment has become a major environmental and health concern, their occurrence in coastal sediments remains poorly characterized. In this study, we measured the levels of three natural (estrone, 17beta-estradiol, estriol) and one synthetic (17alpha-ethinylestradiol) estrogens in 54 coastal sediment samples collected from nine locations off central-southern Chile. Steroid estrogens were found in every sample. Remarkably high levels of 17alpha-ethinylestradiol were detected, reaching up to 48.14 ng/g dry weight. As a result, the global estrogenic loads were estimated to be high at all sites. Interestingly, they were found to correlate with the size of human populations served by sewage plants. Our study indicates that 17alpha ethinylestradiol may accumulate in coastal sediments. The possible impact of this highly potent synthetic estrogen on the biota of the marine ecosystem off central south Chile and on human health remains an open question. PMID- 21530985 TI - White matter anatomy of the human deep brain revisited with high resolution DTI fibre tracking. AB - BACKGROUND AND PURPOSE: Deep white matter (WM) fascicles play a major, yet poorly understood, role in the overall connectivity of human brain. Better knowledge of their anatomy is requisite to understand the clinical correlates of their lesions and develop targeted treatments. We investigated whether MR-based diffusion tensor imaging (DTI) and fibre tracking could reveal in vivo, in explicit details, the 3D WM architecture within the subthalamic region and the internal capsule. METHODS: High-resolution DTI images were acquired on six healthy volunteers on a three Tesla MR scanner. We studied using single-subject analysis WM fascicles within the subthalamic region and the internal capsule, as follows: DTI deterministic fibre tracking (FT) of fascicles; embedding fascicles in the volume-rendered brain coupled with a triplanar view; rigorous anatomic labelling of each fascicle according to classical knowledge as described by pioneer neuroanatomists. Deterministic FT effects were taken into account. RESULTS: We charted most of WM fascicles of the deep brain, in particular large and complex fascicles such as the basal forebrain bundle and the ansa lenticularis. A topographic classification of subthalamic fascicles was proposed into three groups: the cerebellorubral, the reticulo-dorsal and the tegmento-peripheral one. CONCLUSIONS: Beyond to demonstrate the feasibility of imaging the deepest WM fascicles in vivo, our results pave the way for a better understanding of the brain connectivity and for developing targeted neuromodulation. PMID- 21530986 TI - [Endoscopic decompression of the ulnar nerve in the cubital tunnel syndrome: about 55 patients]. AB - INTRODUCTION: Sulcus ulnaris syndrome is the second most common neurocompression syndrome in the upper limb after carpal tunnel syndrome. Its severity can be appreciated by the Dellon Classification. We present our experience and results after endoscopic decompression. PATIENTS AND METHODS: A retrospective chart review of 55 patients operated over a 3-year period was performed. The patients, 37 men and 18 women, had an average age of 54 years (range: 27-82 years) at the time of surgery. The clinical diagnostic was always confirmed by a neurophysiological examination of the nerve conduction. According to the Dellon Classification, 11 patients had mild sulcus ulnaris syndrome, 31 had moderate and 13 had severe. The mean follow-up time was 21 months (range: 6-42 months). RESULTS: The sensibility was normalised in 85% of the patients. Compared to the contralateral non-operated side, the mean grip strength improved from 68 to 94% and the mean pinch grip from 72 to 95%. The rate of nerve luxation did not change (5.5%). According to the modified Bishop rating system, 38 patients (69%) had excellent, 13 patients (23.5%) good and four patients (7.5%) fair results. One haematoma necessitating a revision, a minimal lesion of the ulnar nerve with restitution ad integrum and a hypoesthesia of the elbow, occurred after surgery resulting in a complication rate of 5.5%. Ninety-eight percent of the patients responded that they would undergo the endoscopic procedure again if needed. CONCLUSION: Endoscopic decompression of the ulnar nerve in sulcus ulnaris syndrome is very well appreciated by patients and also provides promising clinical results. PMID- 21530987 TI - [Adjunctive use of endoscopy during microvascular decompression in the cerebellopontine angle: 27 case reports]. AB - Microvascular decompression is an important procedure for the management of microvascular compression syndromes in the cerebellopontine angle (CPA) like trigeminal neuralgia or hemifacial spasm. The ability to identify the offending vessel is the key to success. Can the endoscope help surgeons to identify and understand the responsible conflict in order to treat them? Our series concerns 27 consecutive patients who underwent microvascular decompression systematically using an endoscope with an angulation of 30 degrees at the beginning and the end of the intervention. The decompression procedure was done under microscope. Endoscopic exploration was successful for all patients. Endoscopy improved visualization of the cranial nerves and allowed to see and understand the neurovascular conflicts, which were not able to be observed using the microscope alone for two of the 27 patients. The endoscope is a useful adjunct to microscopic exploration of the cranial nerves in the CPA avoiding significant cerebellar or brainstem retraction. PMID- 21530988 TI - [Magnetic resonance imaging of infratentorial anaplastic ependymoma in children]. AB - OBJECTIVE: To show the main findings for anaplastic ependymoma on MRI. MATERIAL AND METHODS: We reviewed all patients diagnosed with anaplastic ependymoma at our tertiary hospital during a six-year period. We recorded the MRI findings for this type of tumor (on conventional sequences following the protocol for the study of CNS tumors, diffusion-weighted imaging, contrast-enhanced sequences, and MR spectroscopy). RESULTS: Our series comprises seven children with infratentorial anaplastic ependymoma. We found no definitive characteristics to distinguish between grade II and grade III tumors before histology, as none of the lesions had spread to the cerebrospinal fluid at diagnosis or showed increased restriction in the diffusion-weighted sequence. CONCLUSIONS: The MRI characteristics cannot definitively distinguish between grade II ependymomas and anaplastic grade III ependymomas. Only a few details about diffusion and dissemination to the cerebrospinal fluid, if present, can distinguish between these types at imaging. PMID- 21530989 TI - [Diabetic mastopathy: clinical presentation, imaging and histologic findings, and treatment]. AB - OBJECTIVE: Diabetic mastopathy is an uncommon complication of longstanding diabetes mellitus that must be considered in the differential diagnosis with breast cancer. We report the clinical presentation and course, the imaging and histologic findings, and the treatment of the patients diagnosed with diabetic mastopathy at our hospital. MATERIAL AND METHODS: In an 11-year period, we studied six insulin-dependent diabetic patients (five women and one man) with diabetic mastopathy. Imaging studies included mammography, ultrasonography, and magnetic resonance imaging. A definitive histologic diagnosis was reached after core needle or surgical biopsy in all cases. Fine-needle aspiration cytology was not used in any of the cases. The mean follow-up period was 7 years. RESULTS: The most common clinical presentation was a palpable nodule (67%). The imaging findings were a) at mammography: asymmetrical density (50%), b) at ultrasonography: a solid, hypoechoic nodule measuring between 1cm and 5cm in diameter, with ill-defined margins, acoustic shadowing, and no Doppler signal (50%), and c) at MRI: enhancement after the administration of contrast media (66%). The most common histologic finding was lymphocytic mastitis in the initial stages (83%). All patients underwent surgical treatment (100%). CONCLUSIONS: Diabetic mastopathy is an uncommon disease that should be included in the differential diagnosis with breast cancer in diabetic patients. The diagnosis is complex because it requires knowledge of the patient's history, clinical presentation, and the imaging and histologic findings, Conservative surgery is the treatment of choice because the condition does not respond to medical treatment. PMID- 21530990 TI - [Arteriovenous fistula and popliteal pseudoaneurysm after arthroscopic meniscectomy: endovascular treatment with a Viabahn((r)) stent]. PMID- 21530991 TI - [Filter content after carotid angioplasty and stenting: relation to ischemic lesions in diffusion-weighted imaging]. AB - OBJECTIVES: To evaluate the relation between the material retrieved from distal filters after carotid angioplasty and stenting and the development of ischemic brain lesions in diffusion-weighted imaging (DWI). To determine the influence of demographic, clinical, and procedural variables in the pathogenesis of emboli and in ischemia after carotid angioplasty and stenting. MATERIAL AND METHODS: We submitted the contents of the filters of 76 patients (60 men; mean age, 68.39 years; range, 46-82) who had undergone angioplasty and stenting for severe stenosis of the internal carotid artery for histologic analysis evaluating volume (< 1 lambda = 0.001 ml = 1 MUl; 1-10 lambda; and > 10 lambda) and the composition of the particles. All patients underwent DWI before and 24 hours after the procedure; we recorded whether lesions appeared and their number, size, and distribution. We correlated the findings with demographic, clinical, and procedural variables. RESULTS: Symptoms were present before the procedure in 58 (76.3%) patients. Particles were present in 49 (64.5%) of the filters; most particles (77.5%) were 1 lambda with a predominance of fibrin-platelet aggregates, cell remnants, and cholesterol crystals. DWI after the procedure detected lesions in 12 (15.8%) patients. We found no statistically significant correlation between filter contents and lesion detection after the procedure or between filter contents and other variables. CONCLUSIONS: Ischemia after carotid angioplasty and stenting does not depend solely on the embolic load and its nature. We consider that the lower prevalence of postprocedural lesions in our series compared to others suggests that appropriate patient selection and experience minimize the negative influence of some variables like age in their development. PMID- 21530992 TI - [Myocardial clefts: a report of four cases]. AB - Current cardiac magnetic resonance imaging (cMRI) techniques enable many heart defects, like myocardial clefts, to be detected. We present four clinical cases of myocardial clefts. Myocardial clefts are uncommon abnormalities that are found in both healthy individuals and patients with different heart problems. The etiopathogenesis is unknown, although several hypotheses have been proposed. Although myocardial clefts are usually discovered incidentally, it is important to be aware of their existence because they can cause systemic embolisms. PMID- 21530993 TI - Photodegradation of estrone enhanced by dissolved organic matter under simulated sunlight. AB - In the present work the degradation of estrone (E1) a natural estrogenic hormone has been studied under simulated solar irradiation. The photodegradation of E1 has been investigated in the absence and in the presence of 7.7-8.9 mg L(-1) of dissolved organic carbon (DOC), under solar light simulation with irradiance approximating that of the sun. DOC extracts from different origins have been used. Half-lives ranging between 3.9 h and 7.9 h were observed. Results indicated that E1 was photodegraded even in the absence of DOC. The presence of DOC was found to enhance the degradation of E1. Experiments performed with the addition of reactive species scavengers (azide ions and 2-propanol) have shown that these two species play a significant role in the photodegradation. Some experiments have been performed with a DOC previously submitted to solar irradiation. Changes in optical and physico-chemical properties of DOC strongly affect its photoinductive properties, and hence its efficiency on E1 degradation. A part of the study consisted in the investigation of photoproducts structures. Five photoproducts were shown by chromatographic analysis: one arising from direct photolysis and the four others from DOC photoinduced degradation. PMID- 21530994 TI - Anaerobic co-digestion of by-products from sugar production with cow manure. AB - Sugar beet leaves (SBL), sugar beet top (SBT), sugar beet pulp (SBP) and desugared molasses (DM) are by-products from the sugar production. In the present study we investigated the potential of SBL, SBT and SBP as feedstock for biogas production. The maximum methane potential of SBL, SBT and SBP determined by batch assays was found to be 490, 500 and 240 mL-CH(4)/gVS-added respectively. Three reactor experiments were carried out to investigate the effect of co-digestion of SBP, DM and manure at different ratios, on biogas process efficiency and stability. The results showed that DM was potentially inhibiting the biogas process and the co-digestion of SBP and DM was only successful at high dilution with manure or water. In contrast, SBP was shown to be a good substrate for biogas production and the methane yield of 280 mL-CH(4)/gVS-added was obtained in a thermophilic continuously operated reactor, co-digesting 50% of SBP with cow manure. PMID- 21530995 TI - Occurrence of multiclass UV filters in treated sewage sludge from wastewater treatment plants. AB - Many substances related to human activities end up in wastewater and accumulate in sewage sludge. So far, there is only one extensive survey on the occurrence of UV filter residues in sewage sludge. However, more data are required to draw a reliable picture of the fate and effects of these compounds in the environment. This study attempts to fill this gap through the determination of selected UV filters and derivatives namely 4-methylbenzylidenecamphor, benzophenone-3, octocrylene, ethylhexylmethoxycinnamate, ethylhexyldimethyl PABA, 4 hydroxybenzophenone, 2,4-dihydroxybenzophenone, and 4,4'-dihydroxybenzophenone in treated sewage sludge. The target compounds were extracted using pressurized liquid extraction and after this, determined by ultra high resolution liquid chromatography-tandem mass spectrometry. The determination was fast and sensitive, affording limits of detection lower than 19 ng g(-1) dry weight (dw) except for 2,4-dihydroxybenzophenone (60 ng g(-1) dw). Good recovery rates, especially given the high complexity of sludge matrix (between 70% and 102% except for 2,4-dihydroxybenzophenone (30%)) were achieved. The application of developed method allowed reporting for the first time the occurrence of two major degradation products of benzophenone-3 that have estrogenic activity in sewage sludge: 4,4'-dihydroxybenzophenone (in 5/15 WWTPs) and 4-hydroxybenzophenone (in 1/15 WWTPs). Results revealed the presence of UV filters in 15 wastewater treatment plants in Catalonia (Spain) at concentrations ranging from 0.04 to 9.17 MUg g(-1) dw. PMID- 21530996 TI - Mechanochemical degradation of chlorinated contaminants in fly ash with a calcium based degradation reagent. AB - This report presents our results in a low-temperature mechanochemical hydrodechlorination process applied to fly ash coming from a municipal waste incinerator in order to efficiently remove all traces of PCDDs, PCDFs and PCBs. We found that the most suitable degradation agent is a mixture of metallic calcium and calcium oxide. A sample of fly ash presenting a TEQ of 5200 pg g(-1) was completely detoxified (no traces of PCDDs, PCDFs and PCBs detected) after ball-milling at 400 rpm over night. PMID- 21530998 TI - Ganglioneuroma of the uterine cervix--a case report. AB - Ganglioneuroma is a rare, benign tumor usually found in the mediastinum, retroperitoneum, or adrenal glands. We present a case of ganglioneuroma arising in the uterine cervix. A 65-year-old woman (gravida 3, para 3, abortus 0) showed vaginal spotting. The clinician observed a mild erosive lesion of her cervix and performed a biopsy and then conization. Histopathology revealed ganglioneuroma arising in the cervix. To our knowledge, this is the first report of a ganglioneuroma in the uterine cervix. Although ganglioneuroma is normally benign, a few malignant changes have been reported. Regular follow-up is necessary. PMID- 21530997 TI - Influences of redox transformation, metal complexation and aggregation of fulvic acid and humic acid on Cr(VI) and As(V) removal by zero-valent iron. AB - This study investigated the removal kinetics and mechanisms of Cr(VI) and As(V) by Fe(0) in the presence of fulvic acid (FA) and humic acid (HA) by means of batch experiments. The focus was on the involvements of FA and HA in redox reactions, metal complexation, and iron corrosion product aggregation in the removal of Cr(VI) and As(V) removal by Fe(0). Synthetic groundwater was used as the background electrolyte to simulate typical groundwater. The results showed faster Cr(VI) removal in the presence of HA compared to FA. Fluorescence spectroscopy revealed that no redox reaction occurred in the FA and HA. The results of the speciation modeling indicate that the free Fe(II) concentration was higher in the presence of HA, resulting in a higher removal rate of Cr(VI). However, the removal of As(V) was inhibited in the HA solution. Speciation modeling showed that the concentration of dissolved metal-natural organic matter (metal-NOM) complexes significantly affected the aggregation of the iron corrosion products which in turn affected the removal of As(V). The aggregation was found to be induced by gel-bridging of metal-NOM with the iron corrosion products. The effects of metal-NOM on the aggregation of the iron corrosion products were further confirmed by TEM studies. Larger sizes of iron corrosion products were formed in the FA solution compared to HA solution. This study can shed light on understanding the relationships between the properties of NOM (especially the content of metal-binding sites) and the removal of Cr(VI) and As(V) by Fe(0). PMID- 21530999 TI - Divergent expression of L-type amino acid transporter 1 during uterine cervical carcinogenesis. AB - L-type amino acid transporter 1 (LAT1) is a Na+-independent neutral amino acid transporter that has an essential role in cell proliferation. Although LAT1 expression is observed in various tumor cell lines and immunohistochemical expression of LAT1 has been investigated in carcinomas of various organs, LAT1 expression in uterine cervical neoplasm has not been reported. Therefore, in the present study, we immunohistochemically analyzed LAT1 expression along with the well-known markers of cervical carcinogenesis Ki-67 and p16 in normal uterine cervical mucosa (49 specimens) as well as cervical intraepithelial neoplasia (17 mild or moderate dysplasias and 19 severe dysplasias or carcinomas in situ) and invasive carcinomas (17 squamous cell carcinomas and 9 adenocarcinomas). LAT1 expression was limited to the basal layer of normal squamous epithelium, and it was significantly decreased in cervical intraepithelial neoplasia (P < .001), generally paralleled by increased expression of Ki-67 and p16. Interestingly, in invasive squamous cell carcinoma, LAT1 expression again increased especially at the invasive fronts (P < .001), whereas Ki-67 and p16 expressions were almost unchanged relative to noninvasive neoplasia. Although virtually no LAT1 expression was demonstrated in normal uterine cervical glands, LAT1 expression was observed in some adenocarcinomas (P < .001). The present study suggests that LAT1 expression decreases because of human papillomavirus infection as reflected by p16 overexpression in cervical intraepithelial neoplasia, whereas LAT1 expression in invasive carcinoma is associated with acquired malignant potential. PMID- 21531001 TI - PIK3CA mutations and amplification in endometrioid endometrial carcinomas: relation to other genetic defects and clinicopathologic status of the tumors. AB - Alterations of the PIK3CA gene occur in endometrial carcinomas, but their role in the carcinogenesis of those malignancies is still poorly understood. In this study, PIK3CA mutations and amplification in 196 endometrioid endometrial carcinomas and 20 endometrial hyperplasias were assessed by single-strand conformation polymorphism (PCR-SSCP), sequencing, and quantitative polymerase chain reaction. Results were correlated with mutations in the PTEN, KRAS, and CTNNB1 genes and with the clinicopathologic parameters of the tumors. PIK3CA mutations were found in 39 (20%) carcinomas. Six new mutations were identified. No PIK3CA mutations were found in endometrial hyperplasias. PIK3CA amplification was observed in 24 (12.2%) carcinomas and in 2 (10%) hyperplasias. The PIK3CA mutations and amplifications (with the exception of 6 cases) occurred independently. PIK3CA mutations were significantly associated with PTEN mutations (P = .0414) and tended to be associated with CTNNB1 (P = .0833), but not with KRAS mutations. Conversely, the PIK3CA amplifications significantly negatively correlated with PTEN mutations (P = .0038) and did not coexist with CTNNB1 and KRAS mutations. The PIK3CA mutations were significantly associated with poorly differentiated tumors (P = .0423). Interestingly, PIK3CA amplifications, but not mutations, were strongly associated with older age (>=63 years, P = .0018). Our data show that mutations and amplification of PIK3CA are significant genetic alterations in endometrioid endometrial carcinomas associated with adverse clinicopathologic parameters (grade and stage). These data also demonstrate that PIK3CA mutations cooperate with PTEN mutations, suggesting an additive effect to PTEN, whereas PIK3CA amplification can, as an isolated event, enable the development of those tumors. Moreover, for the first time, a possible role of PIK3CA amplification in initiation and progression of endometrial carcinomas in older women is suggested, but this preliminary suggestion requires further research. PMID- 21531000 TI - Intratumoral c-Met expression is associated with vascular endothelial growth factor C expression, lymphangiogenesis, and lymph node metastasis in oral squamous cell carcinoma: implications for use as a prognostic marker. AB - Hepatocyte growth factor has been identified as a lymphangiogenic factor in experimental animal models. However, the correlation between hepatocyte growth factor or c-Met expression and lymphangiogenesis in human spontaneous tumors has been rarely reported, and the distribution pattern of c-Met on tumor-related lymphatic vessels remains to be further investigated. Lymphatic vessel density, lymphatic invasion, the expression of hepatocyte growth factor, c-Met, and vascular endothelial growth factor C proteins were evaluated by immunohistochemistry in 76 cases of oral squamous cell carcinoma. The distribution of c-Met on lymphatic endothelium was examined. High expression of c Met in tumor cells was significantly associated with advanced clinical stage (P = .045), high expression of vascular endothelial growth factor-C (P < .001), higher peritumoral lymphatic vessel density (P = .003), higher incidence of peritumoral lymphatic invasion (P = .032), and positive lymph node status (P = .005), in spite of its negative expression on most lymphatic vessels. Patients with high-c Met expression tumors exhibited shorter overall survival and disease-free survival (P < .001 and P = .010, respectively). Taken together, our results provide indirect evidence for an association and possible regulatory link of c Met with the lymphangiogenic factor, vascular endothelial growth factor C, and, by extension, with lymphangiogenesis and lymph node metastasis, suggesting important prognostic significance of c-Met for patients with oral squamous cell carcinoma. PMID- 21531002 TI - Chromosome aberrations associated with centrosome defects: a study of comparative genomic hybridization in breast cancer. AB - Centrosome abnormalities occur frequently in various tumors and can cause chromosomal instability and eventually promote cancer development. We investigated the chromosome aberrations associated with centrosome abnormalities in 30 cases of breast cancer, combining immunohistochemical staining and comparative genomic hybridization. Except for some common chromosome alterations (including gains of 1q, 8q, 17q, 20q, and Xq and losses of 8p, 11q, 13q, 14q, 16q, 17p, 22q, and Xp) that have also been seen more frequently in other studies, we discovered some new changes that have rarely been reported, including gains at 2p, 5p, 10p, 15q, 16p, 18q, 21q, and 22q and losses at 6p, 8p23, 11p13-pter, 13q34, and 14q32-qter. We also identified some changes (such as gains of 17q, 20q, and Xq and losses of 17p, 13q, and 14q) harboring candidate genes. We also explored the expression of centrosome protein in different molecular subtypes of breast cancer. Our findings provide a new way to explore the molecular mechanisms of breast tumorigenesis and accordingly potential new targets for therapy for this disease. PMID- 21531003 TI - Predictors of tumor response after preoperative chemoradiotherapy for rectal adenocarcinomas. AB - The ability to predict response after chemoradiotherapy in rectal adenocarcinoma may allow selecting patients to whom less invasive surgical treatment could be proposed. Tumor hypoxia has been implicated in the mechanisms of resistance to chemoradiotherapy in several malignancies. The aim was to identify morphological criteria and molecular markers of hypoxia associated with chemoradiotherapy response. Clinicopathologic data from 61 patients (35 male, 60.5 +/- 10 years) undergoing rectal cancer resection after neoadjuvant chemoradiotherapy were collected. Pretreatment biopsies, available for 40 patients, were immunostained for hypoxia markers (carbonic anhydrase 9, glucose transporter 1, chemokine receptor 4) and microvascular density determination. Mean tumor size was 2.7 +/- 1.6 cm. Twenty-one patients (34%) were considered as responders, that is, having significant or complete primary tumor regression without lymph node metastasis. Compared to other patients, responders had significantly more often flat tumors with or without ulceration (57% versus 18%, P = .01) and less vascular and/or neural invasions (9% versus 65%, P < .0001) or tumor necrosis (9% versus 41%, P < .01), respectively. Regarding pretreatment biopsies, carbonic anhydrase 9 expression was significantly lower in responders (7% versus 46%, P = .012). This study showed that tumor necrosis as an overexpression of carbonic anhydrase 9 was an effective molecular marker of postchemoradiotherapy response. This might suggest a key role of hypoxia in resistance mechanisms of chemoradiotherapy in rectal adenocarcinoma. This study highlighted the importance of predictive criteria to chemoradiotherapy response in proposing to selected patients an alternative treatment (eg, local resection) to more radical surgery. PMID- 21531004 TI - Expression of the glucocorticoid receptor in renal cell neoplasms: an immunohistochemical and quantitative reverse transcriptase polymerase chain reaction study. AB - Glucocorticoid receptors mediate the action of steroid hormones in a variety of tissues, including the kidney. Our goal was to determine the expression pattern and prognostic significance of glucocorticoid receptor in renal cell neoplasms. Paraffin-embedded microarrays from 200 patients with RCNs including 147 clear cell renal cell carcinomas, 23 papillary, 16 chromophobe renal cell carcinoma, and 14 oncocytomas were analyzed for glucocorticoid receptor expression by immunohistochemistry. Glucocorticoid receptor expression was also quantitated by real-time reverse transcriptase polymerase chain reaction in 45 cases (33 clear cell renal cell carcinomas, 5 chromophobe renal cell carcinomas, and 3 oncocytomas). Strong nuclear glucocorticoid receptor expression was present in normal glomeruli and in the proximal convoluted tubules. Nuclear glucocorticoid receptor expression was found in most clear cell renal cell carcinomas (66%), in 26% of papillary renal cell carcinomas, and in only 6% of chromophobe renal cell carcinomas and 14% of oncocytoma (P < .005). Within the clear cell renal cell carcinoma group, most positive cases (87%) demonstrated strong immunoreactivity (2+ and 3+), whereas only 1 papillary renal cell carcinoma, 1 chromophobe renal cell carcinoma, and none of the oncocytomas showed strong expression. Glucocorticoid receptor alpha messenger RNA expression was significantly higher in clear cell renal cell carcinoma than in chromophobe renal cell carcinoma, oncocytoma, or in the normal kidney. Significantly more frequent glucocorticoid receptor expression was associated with tumors of low nuclear grade (Fuhrman grade 1 and 2) and low stage (stages 1 and 2; P = .0068 and P = .0002). Survival analysis revealed a significant direct correlation between glucocorticoid receptor expression and overall survival in clear cell renal cell carcinoma (P = .01). In summary, strong glucocorticoid receptor expression was most commonly seen in clear cell renal cell carcinoma and only rarely seen in other subtypes. The glucocorticoid receptor expression pattern in RCNs seems to reflect the histogenetic origin of clear cell renal cell carcinoma from the proximal nephron. Finally, glucocorticoid receptor expression proved to be a marker of less aggressive behavior in clear cell renal cell carcinoma. PMID- 21531005 TI - Lysine-specific demethylase 1 is highly expressed in solitary fibrous tumors, synovial sarcomas, rhabdomyosarcomas, desmoplastic small round cell tumors, and malignant peripheral nerve sheath tumors. AB - Epigenetic changes including histone methylation, histone acetylation, and DNA methylation are thought to play important roles in the onset and progression of cancer in numerous tumor types. Recent evidence shows that dysregulated epigenetic modifications are as significant as genetic mutations and can act as oncogenic driver lesions causing autonomous growth of cancer cells. Here, we investigated the role of lysine-specific demethylase 1 in mesenchymal tumors. Lysine-specific demethylase 1 is the first discovered histone lysine demethylase and can demethylate both H3K4me2/1 and H3K9me2/1. By analyzing a total of 468 tumors, we describe for the first time high lysine-specific demethylase 1 expression in several highly malignant sarcomas, including synovial sarcomas, rhabdomyosarcomas, desmoplastic small round cell tumors and malignant peripheral nerve sheath tumors. Among the intermediate tumors only solitary fibrous tumors were found to be highly lysine-specific demethylase 1 positive, whereas lysine specific demethylase 1 expression was low or absent in benign tumors. Lysine specific demethylase 1 inhibition with small molecule inhibitors resulted in growth inhibition of synovial sarcoma cells in vitro and an increase in global H3K4me2 methylation. Sarcomas continue to remain a clinical challenge and therefore the identification of both diagnostic markers and novel drug targets for the development of new therapeutic options are needed. Our results suggest that dysregulation of lysine-specific demethylase 1 is associated with highly malignant sarcomas proposing them as molecular tumor markers as well as targets for the treatment of these tumor types. PMID- 21531007 TI - Flat urothelial carcinoma in situ of the bladder with glandular differentiation. AB - We present the clinicopathologic and immunonohistochemical features of 25 cases of flat urothelial carcinoma in situ with glandular differentiation. Previously, cases on this category have been reported as in situ adenocarcinoma (a term not currently preferred). Fourteen of 25 cases had concurrent conventional urothelial carcinoma in situ. Five of the cases were primary carcinoma in situ with glandular differentiation; twenty cases of secondary carcinoma in situ with glandular differentiation were associated with urothelial carcinoma alone (n = 11) or with glandular differentiation (n = 7), discohesive (n = 1) or micropapillary carcinoma (n = 1). The individual tumor cells were columnar. The architectural pattern of the carcinoma in situ with glandular differentiation consisted of 1 or more papillary, flat or cribriform glandular patterns. Univariate statistical analysis showed no survival differences between urothelial carcinoma in situ with glandular differentiation and conventional urothelial carcinoma in situ (log-rank 0.810; P = .368). Carcinoma in situ with glandular differentiation showed high ki-67 index and p53 accumulation, high nuclear and cytoplasmic p16 expression and diffuse PTEN expression, a phenotype that also characterized concurrent conventional carcinoma in situ. MUC5A, MUC2, CK20, and c erbB2 were positive in all 25 cases of urothelial carcinoma in situ with glandular differentiation, and CDX-2 was present in 19 cases; MUC1, CK7, or 34betaE12 was focally present in 21, 19, and 18 cases, respectively. MUC1core was negative in all cases. We concluded that urothelial carcinoma in situ with glandular differentiation is a variant of carcinoma in situ that follows the natural history of conventional urothelial carcinoma in situ. The immunophenotype suggests urothelial origin with the expression of MUC5A and CDX2 as signature for glandular differentiation. PMID- 21531006 TI - Glioma-associated oncogene homologue 3, a hedgehog transcription factor, is highly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma. AB - The hedgehog signaling pathway has been shown to play a pathogenic role in diffuse large B-cell lymphoma and anaplastic large cell lymphoma, but has not been assessed in classical Hodgkin lymphoma. Glioma-associated oncogene homologues 1, 2, and 3 are transcriptional effectors of the hedgehog pathway. In this study, we first used real-time quantitative polymerase chain reaction to investigate the expressions of GLI1, GLI2, and GLI3 in 3 classical Hodgkin lymphoma cell lines. GLI1 and GLI2 were variably expressed, but GLI3 was highly expressed in all cell lines. We then used immunohistochemistry to assess glioma associated oncogene homologues 1, 2, and 3 in 39 classical Hodgkin lymphoma patient samples. Glioma-associated oncogene homologues 1 and 2 were weakly to variably expressed in a subset of classical Hodgkin lymphoma patient samples. In contrast, glioma-associated oncogene homologue 3 showed strong, uniform nuclear expression in virtually all Hodgkin/Reed-Stenberg cells. We then performed an immunohistochemical survey of glioma-associated oncogene homologue 3 expression in 13 cases of nodular lymphocyte predominant Hodgkin lymphoma and 218 non Hodgkin lymphomas. Most other lymphoma types showed variable or no expression of glioma-associated oncogene homologue 3, with a minor subset of cases of nodular lymphocyte predominant Hodgkin lymphoma, ALK-positive and ALK-negative anaplastic large cell lymphoma, and B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma showing a glioma-associated oncogene homologue 3 staining pattern indistinguishable from classical Hodgkin lymphoma. Our data provide a rationale to further investigate the biologic significance of glioma-associated oncogene homologue 3 in classical Hodgkin lymphoma biology. PMID- 21531008 TI - In vitro estimates of bioaccessible nickel in field-contaminated soils, and comparison with in vivo measurement of bioavailability and identification of mineralogy. AB - This study determined nickel (Ni) bioaccessibility in weathered smelter contaminated soils, separately for particle-sized fractions using two in vitro methods: simulated gastrointestinal digestion (PBET) and PBET followed by absorption by Caco-2 cells. Relative bioavailability of Ni in soils was determined in vivo using rats, validating in vitro estimates; a mineralogical basis of variation in bioavailability/bioaccessibility among soils was explored. In vitro assays identified the same difference in bioaccessibility for Ni among particle size fractions. PBET estimates were more precise, thus likely to be more useful in discerning differences among soils. In vivo bioavailability for Ni was below limit of detection for the small soil particles, and 31% and 56% for the larger particles. The relative bioavailability calculated from this work suggests that risk from ingesting Ni-contaminated soils could be overestimated by between 2- and 50-fold if the estimates of exposure are not adjusted for the lower bioavailability of weathered Ni originating from smelter emissions. The overestimation that would occur by using total Ni is greatest for the particle size that is most likely to adhere to the hands of children, demonstrating the importance of particle-size separation of soils for bioavailability determination and risk assessment. PMID- 21531009 TI - Tissue factor as a target for the treatment of disseminated intravascular coagulation. PMID- 21531010 TI - Spectrin labeling during oogenesis in zebrafish (Danio rerio). AB - Progression through mitosis and meiosis during early zebrafish ovarian development is accompanied by highly regulated series of transformations in the architecture of oocytes. These cytoskeletal-dependent membrane events may be assumed to be brought about by deployment of proteins. While the cytoskeleton and its associated proteins play a pivotal role in each of these developmental transitions, it remains unclear how specific cytoskeletal proteins participate in regulating diverse processes of oocyte development in zebrafish. Results from this study show that a pool of spectrin accumulates during oogenesis and parallels an increase in volume of oocytes at pre-vitellogenic stages of development. Spectrin labeling is restricted to the surface of oogonia, the cortex of post-pachytene oocytes and later accumulates on the cytoplasm of pre vitellogenic and vitellogenic oocytes. Results here suggest a correlation between spectrin labeling, increased cytoplasm volume of oocytes, an increase in the number of nucleoli and accumulation of cytoplasmic organelles. Overall, these results suggest that synthesis and storage of spectrin during pre-vitellogenic stages of oogenesis primes the egg with a pre-established pool of membrane cytoskeletal precursors for use during embryogenesis, and that the presence of spectrin at the oocyte sub-cortex is essential for maintaining oocyte structure. PMID- 21531011 TI - Use of estradiol-progestin therapy associates with increased risk for uterine sarcomas. AB - OBJECTIVE: Insufficient data exist on the effect of postmenopausal hormone therapy as the risk factor for uterine sarcomas. We therefore evaluated the association of estradiol-progestin therapy (EPT) with the risk of uterine sarcoma in nation-wide cohort study. METHODS: All Finnish women (>50 years of age) who had used EPT during the years 1994-2008 for at least 6 months (n=243,857) were identified from the national Medical Reimbursement Registry. Their incidence of uterine stromal and leiomyosarcoma among the EPT users was compared to that in the background population with the aid of the Finnish Cancer Registry. RESULTS: A total of 76 uterine sarcomas were encountered in the EPT cohort; 45 (59%) were leiomyosarcomas, 24 (32%) stromal sarcomas and 7 (9%) other sarcomas. The exposure to EPT for less than 5 years did not associate with significant rises in the sarcoma risk but longer exposure was accompanied with significant risk elevations for all uterine sarcomas: the standardized incidence ratio (SIR) for 5 10 years of use was 2.0, 95% confidence interval (CI) 1.4-2.9 and for >=10 years of use 3.0 (1.3-5.9): the SIRs were highest for leiomyosarcoma. The sequential and continuous uses of progestin were associated with similar increased SIRs for uterine sarcoma. CONCLUSIONS: The use of EPT for 5 years or more is associated with an increased risk for uterine sarcomas. This turns to an absolute excess risk of 2-3 extra uterine sarcoma cases per 10,000 long-time EPT users followed for 10 years. PMID- 21531012 TI - Surgical staging of early stage epithelial ovarian cancer. PMID- 21531013 TI - Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome. AB - BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency characterized by thrombocytopenia, eczema, infections, autoimmunity, and lymphomas. Transplantation of hematopoietic stem cells from HLA identical donors is curative, but it is not available to all patients. We have developed a gene therapy (GT) approach for WAS by using a lentiviral vector encoding for human WAS promoter/cDNA (w1.6W) and demonstrated its preclinical efficacy and safety. OBJECTIVE: To evaluate B-cell reconstitution and correction of B-cell phenotype in GT-treated mice. METHODS: We transplanted Was(-/-) mice sublethally irradiated (700 rads) with lineage marker-depleted bone marrow wild type cells, Was(-/-) cells untransduced or transduced with the w1.6W lentiviral vector and analyzed B-cell reconstitution in bone marrow, spleen, and peritoneum. RESULTS: Here we show that WAS protein(+) B cells were present in central and peripheral B-cell compartments from GT-treated mice and displayed the strongest selective advantage in the splenic marginal zone and peritoneal B1 cell subsets. After GT, splenic architecture was improved and B-cell functions were restored, as demonstrated by the improved antibody response to pneumococcal antigens and the reduction of serum IgG autoantibodies. CONCLUSION: WAS GT leads to improvement of B-cell functions, even in the presence of a mixed chimerism, further validating the clinical application of the w1.6W lentiviral vector. PMID- 21531014 TI - American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology Omalizumab-Associated Anaphylaxis Joint Task Force follow-up report. PMID- 21531015 TI - Therapeutic strategies to reduce asthma exacerbations. AB - Asthma exacerbations can occur in patients with all degrees of asthma severity. They generally develop over 5 to 7 days and are most often initiated by an upper respiratory tract infection (usually with human rhinovirus) or by environmental allergen exposure in atopic subjects. Inhaled corticosteroids (ICSs) taken on a regular basis are very effective in reducing the risk of asthma exacerbations, and the combination of ICSs and long-acting inhaled beta2-agonists further reduces this risk. In addition, use of the combination of the ICS budesonide and the long-acting inhaled beta2-agonist formoterol, both as maintenance asthma treatment and also as rescue treatment (instead of a short-acting inhaled beta2 agonist), has a significant further beneficial effect on asthma exacerbation risk. Other therapies that have been demonstrated to reduce severe asthma exacerbations are leukotriene receptor antagonists, which have been demonstrated to be effective most consistently in this regard in children, and anti-IgE mAbs, which are effective in subjects with difficult-to-treat allergic asthma. Approximately 50% of severe asthma exacerbations are eosinophilic in nature, whereas many of the remaining are neutrophilic. Several studies have demonstrated that making asthma treatment decisions based on minimizing airway eosinophil numbers (measured in induced sputum) can reduce the risks of severe exacerbations. In addition, treatment of patients with severe asthma with an anti IL-5 mAb also reduces the number of severe asthma exacerbations, demonstrating a central role of eosinophils in many exacerbations. PMID- 21531017 TI - The many routes of dendritic cells to ensure immune regulation. PMID- 21531016 TI - Purine metabolism, immune reconstitution, and abdominal adipose tumor after gene therapy for adenosine deaminase deficiency. PMID- 21531018 TI - The effect of preparation order on the crystal structure of yttria-stabilized tetragonal zirconia polycrystal and the shear bond strength of dental resin cements. AB - OBJECTIVES: The purpose of this study was to evaluate the effect of preparation order on the crystal structure of yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) and the shear bond strength of dental resin cements. METHODS: One-hundred fifty pre-sintered Y-TZP cylinders (O 9mm*13.5mm) were prepared and divided into three groups (control group, SBS group and SAS group). Specimens in control group were not treated. Specimens in SBS group were sandblasted and then densely sintered, and specimens in SAS group were sintered in advance, and then sandblasted. The specimens were analyzed by X-ray diffractometry, confocal laser scanning microscopy and Energy dispersive X-ray spectroscopy before and after sandblasting. All specimens were embedded in polytetrafluoroethylene (PTFE) molds using PMMA and each group was divided into five subgroups. The mixed resin cements (Clearfil SA luting cement, Zirconite, Superbond C&B, Rely-X Unicem, and Multilink) were placed onto the Y-TZP surfaces using PTFE molds with O 3mm*3mm, followed by storage in distilled water at 37 degrees C for 24h, and thermocycling (5000 cycles at 5 degrees C and 55 degrees C with a 30s dwelling time). All specimens were tested for the shear bond strengths with a universal testing machine, and fractured surfaces were evaluated by SEM. Statistical analysis was performed using one-way ANOVA and Scheffe comparison with alpha=.05. RESULTS: Sandblasting of the zirconia significantly increased shear bond strength of resin cements, but the preparation order had no significant influence on the shear bond strength in both test groups. In SEM observation, the natures of the surface faceting of the zirconia grains were totally different between SBS and SAS groups. SBS group exhibited less monoclinic structures than SAS group. SIGNIFICANCE: Sandblasting of pre-sintered Y-TZP and then sintering may induce favorable proportion of tetragonal structures. This might have positive effect on the clinical performance of zirconia restorations. PMID- 21531019 TI - An equivalent strain/Coffin-Manson approach to multiaxial fatigue and life prediction in superelastic Nitinol medical devices. AB - Medical devices, particularly endovascular stents, manufactured from superelastic Nitinol, a near-equiatomic alloy of Ni and Ti, are subjected to complex mixed mode loading conditions in vivo, including axial tension and compression, radial compression, pulsatile, bending and torsion. Fatigue lifetime prediction methodologies for Nitinol, however, are invariably based on uniaxial loading and thus fall short of accurately predicting the safe lifetime of stents under the complex multiaxial loading conditions experienced physiologically. While there is a considerable body of research documented on the cyclic fatigue of Nitinol in uniaxial tension or bending, there remains an almost total lack of comprehensive fatigue lifetime data for other loading conditions, such as torsion and tension/torsion. In this work, thin-walled Nitinol tubes were cycled in torsion at various mean and alternating strains to investigate the fatigue life behavior of Nitinol and results compared to equivalent fatigue data collected under uniaxial tensile/bending loads. Using these strain-life results for various loading modes and an equivalent referential (Lagrangian) strain approach, a strategy for normalizing these data is presented. Based on this strategy, a fatigue lifetime prediction model for the multiaxial loading of Nitinol is presented utilizing a modified Coffin-Manson approach where the number of cycles to failure is related to the equivalent alternating transformation strain. PMID- 21531020 TI - The use of Eugenol and electro-narcosis as anaesthetics: transcriptional impacts on the European eel (Anguilla anguilla L.). AB - Ecotoxicological studies aim to assess the potential environmental risks of various products. This implies the use of various biological models and tests on live animals. In case of handling fish and mammals, ethical rules have to be respected. The use of anaesthesia is considered to be the best way to ensure animal welfare. Eugenol and electro-narcosis are among the most popular chemical and physical anaesthetics used in fisheries and by field biologists. In this study, the genetic and endocrine impacts of these anaesthetics were assessed in order to establish whether the use of such methods could skew the results of ecotoxicological studies. Twenty yellow European eels (Anguilla anguilla) were submitted to Eugenol (50mg/L) and electro-narcosis until they reached a level of deep anaesthesia, while 20 other eels were kept aware. Five anaesthetized and five unanaesthetized eels were sacrificed and analysed directly after treatment and after 1, 7 and 21 days of recovery. At the brain level, Eugenol triggered an increase in the transcription level of genes encoding proteins involved in oxidative stress responses (catalase expression 2.5-fold, mitochondrial superoxide dismutase expression 3-fold), probably due to a hypoxic event during anaesthesia. Later impacts were detected in muscles 21 days after anaesthesia (ATP synthase subunit 6 3-fold, NADH deshydrogenase subunit 5 4-fold and mitochondrial superoxide dismutase 3-fold increased) revealing oxidative stress from an accrued mitochondrial respiratory metabolism. Hormone dosages showed that the use of Eugenol reduced the release of plasma cortisol during anaesthesia. However, this impact seemed to be reversible within one day. In case of electro narcosis, no significant variation in transcriptional levels could be detected between anaesthetized and unanaesthetized eels. Our results suggest that the use of Eugenol as an aesthetic in ecotoxicological studies measuring gene expression or plasma cortisol concentration is not appropriate, while electro-narcosis does not seem to have any impact, at least on the parameters taken into consideration in this study. PMID- 21531021 TI - Environmental safety to decomposer invertebrates of azadirachtin (neem) as a systemic insecticide in trees to control emerald ash borer. AB - The non-target effects of an azadirachtin-based systemic insecticide used for control of wood-boring insect pests in trees were assessed on litter-dwelling earthworms, leaf-shredding aquatic insects, and microbial communities in terrestrial and aquatic microcosms. The insecticide was injected into the trunks of ash trees at a rate of 0.2 gazadirachtin cm(-1) tree diameter in early summer. At the time of senescence, foliar concentrations in most (65%) leaves where at or below detection (<0.01 mg kg(-1) total azadirachtin) and the average concentration among leaves overall at senescence was 0.19 mg kg(-1). Leaves from the azadirachtin-treated trees at senescence were added to microcosms and responses by test organisms were compared to those in microcosms containing leaves from non-treated ash trees (controls). No significant reductions were detected among earthworm survival, leaf consumption rates, growth rates, or cocoon production, aquatic insect survival and leaf consumption rates, and among terrestrial and aquatic microbial decomposition of leaf material in comparison to controls. In a further set of microcosm tests containing leaves from intentional high-dose trees, the only significant, adverse effect detected was a reduction in microbial decomposition of leaf material, and only at the highest test concentration (~6 mg kg(-1)). Results indicated no significant adverse effects on litter-dwelling earthworms or leaf-shredding aquatic insects at concentrations up to at least 30 * the expected field concentrations at operational rates, and at 6 * expected field concentrations for adverse effects on microbial decomposition. We conclude that when azadirachtin is used as a systemic insecticide in trees for control of insect pests such as the invasive wood-boring beetle, emerald ash borer, resultant foliar concentrations in senescent leaf material are likely to pose little risk of harm to decomposer invertebrates. PMID- 21531022 TI - Toxic effects of nine polycyclic aromatic compounds on Enchytraeus crypticus in artificial soil in relation to their properties. AB - The aim of this study was to compare the toxic effects of selected two- and three ringed PAHs (naphthalene, phenanthrene, and anthracene) and their N-heterocyclic analogs with one (quinoline, acridine, and phenanthridine) or two (quinoxaline, phenazine, and 1,10-phenanthroline) nitrogen atoms on the survival and reproduction of Enchytraeus crypticus in artificial soil. Toxicity of compounds was recalculated to soil pore-water concentrations using the data of chemical analyses of 0.01 M CaCl(2) extracts of spiked soils. When toxicity was based on molar concentrations in pore water (MUmol/L), it significantly increased with increasing K(ow) value. This relationship indicates nonpolar narcosis as the general toxicity mechanism of the tested compounds. In addition, significant correlation between the toxicity of PACs and their ionization potential has been identified by multidimensional QSAR models. PMID- 21531024 TI - Preventing sexual violence: can examination of offense location inform sex crime policy? AB - Recently, legislative initiatives to prevent sex crime recidivism include the passage of child safety zones (also called loitering zones) that prohibit sex offenders from lingering near places where children congregate. The ability of policies such as these or residence restrictions to curb sexual recidivism depends on the empirical reality of sex offender perpetration patterns. As such, the current study sought to examine locations where sex offenders first come into contact with their victims and whether sex crime locations differ among those who perpetrate offenses against children as compared to those who perpetrate offenses against adults. Further, this study examined actuarial risk scores and recidivism rates among offenders who met victims in child-dense public locations to determine if these offenders are more at risk of re-offense. Descriptive analyses, based on archival sex offender file review (N=1557), revealed that offenders primarily cultivated their offenses in private residential locations (67.0%); relatively few offenders (4.4%) met their victims in child-dense public locations. Further, offenders who perpetrated crimes against children were more likely to meet victims within a residence, while those who perpetrate crimes against adults were more likely to encounter victims in a more public type of location (e.g., bar, workplace). Though only 3.7% of all offenders in this sample sexually recidivated, those who recidivated were more likely to have met their victim in a child-dense public location than those who did not recidivate. Current sex crime policies that focus only on where offenders live may fail to focus on where offenders go and, further, may misdirect efforts away from the place where sex crimes most often occur, namely, in the home. PMID- 21531023 TI - Oxidative stress and anxiety-like symptoms related to withdrawal of passive cigarette smoke in mice: beneficial effects of pecan nut shells extract, a by product of the nut industry. AB - The present study evaluated the role of pecan nut (Carya illinoensis) shells aqueous extract (AE) against oxidative damage induced by cigarette smoke exposure (CSE) and behavioral parameters of smoking withdrawal. Mice were passively exposed to cigarette smoke for 3 weeks (6, 10, and 14 cigarettes/day) and orally treated with AE (25 g/L). CSE induced lipid peroxidation in brain and red blood cells (RBC), increased catalase (CAT) activity in RBC, and decreased plasma ascorbic acid levels. AE prevented oxidative damage and increased antioxidant defenses of mice exposed to cigarette smoke. In addition, AE reduced the locomotor activity and anxiety symptoms induced by smoking withdrawal, and these behavioral parameters showed a positive correlation with RBC lipid peroxidation. Our results showed the beneficial effects of this by-product of the pecan industry, indicating its usefulness in smoking cessation. PMID- 21531025 TI - Levels and profiles of PCDD/Fs, PCBs in mothers' milk in Shenzhen of China: estimation of breast-fed infants' intakes. AB - Sixty breast milk samples were collected in Shenzhen, China from July to November in 2007. The samples were analyzed of the concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs). The range of upper-bound for ?TEQ (PCDD/Fs+PCBs) in the samples was 4.10-35.3 pg TEQ g(-1) lipid (median: 10.6 pg TEQ g(-1) lipid; mean: 11.9 pg TEQ g(-1) lipid). The levels of the measured contaminants in the breast milk had significant correlations with the length of inhabitation period in Shenzhen (r=0.487, p<0.05 for PCDD/Fs, r=0.431, p<0.05 for PCBs and r=0.478, p<0.05 for ?TEQ-(PCDD/Fs+PCBs)), and the consumption rate of fish (r=0.366, p<0.05 for PCDD/Fs, r=0.486, p<0.05 for PCBs and r=0.416, p<0.05 for ?TEQ-(PCDD/Fs+PCBs)), respectively. Moreover, significant positive correlations were also detected between the participant's age (r=0.305, p<0.05 for ?TEQ-PCBs and r=0.275, p<0.05 for ?TEQ-(PCDD/Fs+PCBs)) and the body burdens of these contaminants respectively. It is estimated that the daily intake (EDI) of the sum of PCDD/Fs and DL-PCBs by the breast-fed infants was 5.60-161 pg TEQ kg(-1) bw per day (mean: 48.2 pg TEQ kg(-1) bw per day; median: 42.2 pg TEQ kg( 1) bw per day). The result showed that both the body burdens of PCDD/Fs and PCBs of the recruit population and the calculated EDI of the breast-fed infants were higher than those in the non-exposed areas in mainland China. This suggests that continuous surveillance on PCDD/Fs and PCBs levels in human milk is critical to more precisely evaluate the human health risk posed by the negative environmental impact in Shenzhen in the future. PMID- 21531026 TI - Pesticide burial grounds in Poland: a review. AB - Obsolete pesticides were stored in Poland from the middle sixties until the late eighties of the 20th century mostly in underground disposal sites, called "pesticide burial grounds" or "pesticide tombs". The total amount of pesticide waste and packaging materials disposed of in these landfills exceeded 20000 Mg. Typically, the content of a pesticide tomb was dominated by organochlorine pesticides (comprising 10-100% of the total waste volume) with DDT as the prevailing compound. Other pesticide types, such as phosphoroorganic, carbamate insecticides, dinitrophenols, phenoxyacids, and inorganic compounds were stored in smaller quantities, usually not exceeding 10-20% of the total waste volume. With the growing awareness of the threats that these landfills posed to the environment, the first inventory for the whole country was made in 1993 and remediation was initiated in 1999. The total amount of waste, which had to be removed from the known pesticide tombs (hazardous substances, contaminated soils, construction materials etc.) was about 100000 Mg. According to the National Waste Management Plan, the reclamation of pesticide tombs was assumed to have been finished by the end of 2010, however, this goal has not been achieved. The aim of this review is to present a historical perspective of pesticide burial grounds in Poland with an emphasis on their creation, function, inventory, and remediation. Based on unpublished reports, and other published materials of limited availability written in Polish, this review may serve as a source of information for representatives of other countries, where remediation of pesticide burial grounds is still in progress. The experience gained over a ten-year period, when restoration of pesticide tombs was implemented in Poland, reveals that there are many obstacles to this action arising not only from technical, but also from economic and social issues. PMID- 21531027 TI - The insular cortex and the neuroanatomy of major depression. AB - BACKGROUND: The neuroanatomical substrate underlying Major Depressive Disorder (MDD) is incompletely understood. Recent reports have implicated the insular cortex. METHODS: Two cohorts of participants with MDD were tested. In the first MDD cohort, we used standardised facial expression recognition tasks. In the second cohort, we focused on facial disgust recognition, a function associated with the insular cortex. T1 weighted MR imaging was used in the second cohort to test the hypothesis of abnormal insular volume being associated with impaired disgust recognition. RESULTS: Disgust recognition was particularly impaired in both cohorts. In the second cohort, the magnitude of the disgust recognition deficit correlated with reduced insula grey matter volume. Exploring the idea of insula involvement in MDD further, we identified the insular cortex and the anterior cingulate cortex as key neural correlates of core symptoms, in that scores of 3 clinical scales (the Beck Depression Inventory, the Hamilton Depression Rating Scale, and the Snaith-Hamilton Pleasure Scale) correlated with grey matter volume in these structures. LIMITATIONS: MDD participants were clinically representative of specialist and academic psychiatric practice in the UK and presented with robust primary diagnoses; we did not exclude common co morbidities such as anxiety and personality disorders. CONCLUSIONS: We propose that cognitive and emotional functions assumed to be associated with the insula are adversely affected in patients with MDD and that this may, therefore, represent the substrate for some core clinical features of MDD. Further exploration of the involvement of the insular cortex in MDD is warranted. PMID- 21531028 TI - Endometrial secretions: creating a stimulatory microenvironment within the human early placenta and implications for the aetiopathogenesis of preeclampsia. AB - Endometrial glands represent an important source of nutrients for the conceptus during the first trimester. Their secretions are enriched with carbohydrates, and glycogen accumulates within the syncytiotrophoblast of the placenta. It has been assumed that fetal and placental metabolism follow adult pathways, although it is now appreciated that early development occurs in a low-oxygen environment. In past decades, a novel family of putative insulin mediators, inositol phosphoglycans (IPGs), was discovered. These molecules act as allosteric activators and/or inhibitors of enzymes and transduction proteins involved in the control of cell signalling and metabolic pathways, and determine the specificity of responses after activation of the insulin receptor. One member, IPG P-type, activates pyruvate dehydrogenase phosphatase (PDH-Pase), glycogen synthase phosphatase, and glycerol-3-phosphate acyltransferase. Activation of key phosphatases play a major role in the regulation of glucose disposal by oxidative metabolism via PDH, and the non-oxidative storage by glycogen synthesis, both pathways classically known to be regulated by insulin. High concentrations of IPG P-type in amniotic fluid suggest a role in the regulation of carbohydrate metabolism in the fetal-placental unit. Glycogen accumulation in the syncytiotrophoblast also occurs in preeclamptic pregnancies, and is consistently associated with higher placental levels of IPG P-type. Here, we explore the relationship between nutrients provided by the endometrial glands during early pregnancy, IPG P-type and fetal metabolic requirements. We also discuss whether a disconnect between the placental/fetal metabolic state and oxygen tension could lead to a preeclamptic-type syndrome via leakage of Warburg/IPG mediators into the maternal circulation. PMID- 21531029 TI - Diagnosis and treatment of pediatric vallecular cysts and pseudocysts. AB - OBJECTIVE: To review the experience at a children's hospital diagnosing and treating vallecular cysts. SECONDARY OBJECTIVES: To determine if cyst type, operative mode, or ages are risk factor(s) for recurrence. METHODS: Chart review of eleven children with vallecular cysts and pseudocysts from 1997 to 2009. RESULTS: The most common presenting symptoms were stridor (8/12, 67%), respiratory distress (7/12, 58%), and feeding difficulties (4/12, 33%). Symptoms of gastroesophageal reflux disease were present in 67% of patients and 17% carried a concurrent diagnosis of laryngomalacia. Eleven of twelve patients required operative intervention, the majority of which were transoral endoscopic procedures. Three patients (3/11, 27%) had recurrences. Two of these patients required only a second procedure, but one patient required multiple procedures. Fifty percent (2/4) of the patients 2 years or older experienced a recurrence, whereas only 14% (1/7) of the patients less than 2 years old had a recurrence, a difference which was not statistically significant (p=0.49). Pseudocysts tended to recur more frequently than vallecular cysts. (p=0.13). Surgical approach (marsupialization versus total excision) did not affect recurrence rate. One patient with a small, asymptomatic cyst was observed and continues to be symptom free. There were no surgical complications. CONCLUSIONS: Vallecular cysts and pseudocysts are rare congenital lesions of the upper aerodigestive tract. Vallecular pseudocysts tended to recur more than vallecular cysts in our series. Surgery is the treatment of choice for symptomatic patients; smaller cysts may be followed closely. PMID- 21531030 TI - Use of chloral hydrate as a sedative for auditory brainstem response testing in a pediatric population. AB - OBJECTIVE: Chloral hydrate (CH) is an oral sedative widely used to sedate infants and young children during auditory brainstem response (ABR) testing. The aim of this study was to record effectiveness, complications and safety of CH as a sedative for ABR. METHODS: From January of 2003 until December of 2007, 1903 children were tested for ABR, 568 of them being under the age of 6 months. CH (8%) was used for sedation at a dose of 40 mg/kg with a repeat dose, if necessary, for an adequate sedation, in 20-30 min. We recorded the effectiveness of CH as a sedative for ABR examination, as well as all complications related to the use of CH such as vomiting, rash, hyperactivity, respiratory distress and apnea. The statistical method used was the absolute and percentage frequency distribution of the occurrences. RESULTS: Sedation with CH was necessary to perform testing in 1591 (83.6%) of the examined children. However, in the population of the examined infants, only 341 (60%) were sedated with CH, because the remaining 227 (40%) fell asleep by themselves. Complications included hyperactivity in 152 children (8%), minor respiratory distress in 10 children (0.4%), vomiting in 217 children (11.4%), apnea in 4 children (0.2%) and rash in 10 children (0.4%). The complications of hyperactivity, vomiting and rash resolved without any medical treatment. The apnea cases were managed effectively by supplying ventilation to the children via a mask in the presence of an anesthesiologist. CONCLUSIONS: The use of CH at a dose of 40 mg/kg up to 80 mg/kg is safe and effective when administered in a setting with adequate equipment and the presence of well trained personnel. PMID- 21531031 TI - Artificial neural networks for analyzing inter-limb coordination: the golf chip shot. AB - Motor control research relies on theories, such as coordination dynamics, adapted from physical sciences to explain the emergence of coordinated movement in biological systems. Historically, many studies of coordination have involved inter-limb coordination of relatively few degrees of freedom. This study looked at the high-dimensional inter-limb coordination used to perform the golf chip shot toward six different target distances. This study also introduces a visualization of high-dimensional coordination relevant within the coordination dynamics theoretical framework. A specific type of Artificial Neural Network (ANN), the Self-Organizing Map (SOM), was used for the analysis. In this study, the trajectory of consecutive best-matching nodes on the output map was used as a collective variable and subsequently fed into a second SOM which was used to create visualization of coordination stability. The SOM trajectories showed changes in coordination between movement patterns used for short chip shots and movement patterns used for long chip shots. The attractor diagrams showed non linear phase transitions for three out of four players. The methods used in this study may offer a solution for researchers from a coordination dynamics perspective who intend to use data obtained from discrete high-dimensional movements. PMID- 21531032 TI - Assessment of Escherichia coli O157:H7-specific bacteriophages e11/2 and e4/1c in model broth and hide environments. AB - The efficacy of bacteriophages e11/2 and e4/1c as potential biocontrol agents for Escherichia coli O157:H7 in food applications was assessed under conditions relevant to the food chain environment. The stability of each phage was determined following exposure to varying environmental conditions (pH, temperature, water activity, and sodium chloride) and the ability of each phage to infect and reduce E. coli O157:H7 numbers under selected conditions was also examined. Both e11/2 and e4/1c significantly (p<0.05) reduced numbers of E. coli O157:H7 when exposed to pH values ranging from pH>4 to pH 9, temperatures from 4 degrees C to 37 degrees C, water activity values of 0.87 or 0.91 to 1.00 and NaCl concentrations of 1% to 2.5%. Subsequently, a cocktail of both phages was used (e11/2 and e4/1c) to assess reduction of E. coli O157:H7 on cattle hide pieces. This involved inoculating pieces of hide (20*20 cm) with E. coli O157:H7 (approximately 106cfu/cm2) which were subsequently treated with either a suspension of a phage cocktail, consisting of e11/2 and e4/1c (multiplicity of infection of 1000 and 10,000, respectively) or water or not treated. Two different investigations were carried out; immediately or 1h after treatment application was performed in different experiments. Swab samples taken immediately after phage treatment showed no significant (p>0.05) reduction of E. coli O157:H7 numbers compared to the water treated or untreated samples. However, an extended exposure time of 1h following phage application revealed a significant reduction (p<0.05) (1.5 log10 cfu/cm2 reduction) in E. coli O157:H7 numbers compared to the numbers recovered on samples treated with water only. These findings demonstrate the potential use of e11/2 and e4/1c phages as a biocontrol agent for E. coli O157:H7 within various stages of the food chain, including on cattle hide. PMID- 21531034 TI - Proteome analysis of the fungus Aspergillus carbonarius under ochratoxin A producing conditions. AB - Aspergillus carbonarius is an important ochratoxin A producing fungus that is responsible for mycotoxin contamination of grapes and wine. In this study, the proteomes of highly (W04-40) and weakly (W04-46) OTA-producing A. carbonarius strains were compared to identify proteins that may be involved in OTA biosynthesis. Protein samples were extracted from two biological replicates and subjected to two dimensional gel electrophoresis analysis and mass spectrometry. Expression profile comparison (PDQuest software), revealed 21 differential spots that were statistically significant and showed a two-fold change in expression, or greater. Among these, nine protein spots were identified by MALDI-MS/MS and MASCOT database and twelve remain unidentified. Of the identified proteins, seven showed a higher expression in strain W04-40 (high OTA producer) and two in strain W04-46 (low OTA producer). Some of the identified amino acid sequences shared homology with proteins involved in regulation, amino acid metabolism, oxidative stress and sporulation. It is worth noting the presence of a protein with 126.5 fold higher abundance in strain W04-40 showing homology with protein CipC, a protein with unknown function related with pathogenesis and mycotoxin production by some authors. Variations in protein expression were also further investigated at the mRNA level by real-time PCR analysis. The mRNA expression levels from three identified proteins including CipC showed correlation with protein expression levels. This study represents the first proteomic analysis for a comparison of two A. carbonarius strains with different OTA production and will contribute to a better understanding of the molecular events involved in OTA biosynthesis. PMID- 21531033 TI - Outlining a future for non-Saccharomyces yeasts: selection of putative spoilage wine strains to be used in association with Saccharomyces cerevisiae for grape juice fermentation. AB - The use of non-Saccharomyces yeasts that are generally considered as spoilage yeasts, in association with Saccharomyces cerevisiae for grape must fermentation was here evaluated. Analysis of the main oenological characteristics of pure cultures of 55 yeasts belonging to the genera Hanseniaspora, Pichia, Saccharomycodes and Zygosaccharomyces revealed wide biodiversity within each genus. Moreover, many of these non-Saccharomyces strains had interesting oenological properties in terms of fermentation purity, and ethanol and secondary metabolite production. The use of four non-Saccharomyces yeasts (one per genus) in mixed cultures with a commercial S. cerevisiae strain at different S. cerevisiae/non-Saccharomyces inoculum ratios was investigated. This revealed that most of the compounds normally produced at high concentrations by pure cultures of non-Saccharomyces, and which are considered detrimental to wine quality, do not reach threshold taste levels in these mixed fermentations. On the other hand, the analytical profiles of the wines produced by these mixed cultures indicated that depending on the yeast species and the S. cerevisiae/non-Saccharomyces inoculum ratio, these non-Saccharomyces yeasts can be used to increase production of polysaccharides and to modulate the final concentrations of acetic acid and volatile compounds, such as ethyl acetate, phenyl-ethyl acetate, 2-phenyl ethanol, and 2-methyl 1-butanol. PMID- 21531035 TI - A wavelet-based Markov random field segmentation model in segmenting microarray experiments. AB - In the present study, an adaptation of the Markov Random Field (MRF) segmentation model, by means of the stationary wavelet transform (SWT), applied to complementary DNA (cDNA) microarray images is proposed (WMRF). A 3-level decomposition scheme of the initial microarray image was performed, followed by a soft thresholding filtering technique. With the inverse process, a Denoised image was created. In addition, by using the Amplitudes of the filtered wavelet Horizontal and Vertical images at each level, three different Magnitudes were formed. These images were combined with the Denoised one to create the proposed SMRF segmentation model. For numerical evaluation of the segmentation accuracy, the segmentation matching factor (SMF), the Coefficient of Determination (r(2)), and the concordance correlation (p(c)) were calculated on the simulated images. In addition, the SMRF performance was contrasted to the Fuzzy C Means (FCM), Gaussian Mixture Models (GMM), Fuzzy GMM (FGMM), and the conventional MRF techniques. Indirect accuracy performances were also tested on the experimental images by means of the Mean Absolute Error (MAE) and the Coefficient of Variation (CV). In the latter case, SPOT and SCANALYZE software results were also tested. In the former case, SMRF attained the best SMF, r(2), and p(c) (92.66%, 0.923, and 0.88, respectively) scores, whereas, in the latter case scored MAE and CV, 497 and 0.88, respectively. The results and support the performance superiority of the SMRF algorithm in segmenting cDNA images. PMID- 21531036 TI - Active scepticism must drive biodiversity conservation science. PMID- 21531037 TI - Integrated planning and spatial evaluation of megasite remediation and reuse options. AB - Redevelopment of large contaminated brownfields (megasites) is often hampered by a lack of communication and harmonization among diverse stakeholders with potentially conflicting interests. Decision support is required to provide integrative yet transparent evaluation of often complex spatial information to stakeholders with different areas of expertise. It is considered crucial for successful redevelopment to identify a shared vision of how the respective contaminated site could be remediated and redeveloped. We describe a framework of assessment methods and models that analyzes and visualizes site- and land use specific spatial information at the screening level, with the aim to support the derivation of recommendable land use layouts and to initiate further and more detailed planning. The framework integrates a GIS-based identification of areas to be remediated, an estimation of associated clean-up costs, a spatially explicit market value appraisal, and an assessment of the planned future land use's contribution to sustainable urban and regional development. Case study results show that derived options are potentially favorable in both a sustainability and an economic sense and that iterative re-planning is facilitated by the evaluation and visualization of economic, ecological and socio economic aspects. The framework supports an efficient early judgment about whether and how abandoned land may be assigned a sustainable and marketable land use. PMID- 21531038 TI - CXC chemokine expression profiles in aqueous humor of patients with different clinical entities of endogenous uveitis. AB - Aqueous humor (AH) samples from patients with Behcet's disease (BD) (n=29), Vogt Koyanagi-Harada (VKH) disease (n=21), and HLA-B27-associated uveitis (n=8), and 42 control patients were assayed for the neutrophil chemoattractants CXCL1/GRO alpha and CXCL8/IL-8 and the lymphocyte chemoattractants CXCL9/MIG, CXCL10/IP-10 and CXCL12/SDF-1 with the use of a multiplex chemokine assay. Chemokine levels except SDF-1 were significantly higher in the 3 disease groups than in normal controls. Considering all patients, mean GRO-alpha levels were 15-fold higher than IL-8 levels and mean IP-10 levels were 22-fold higher than MIG levels. In patients with the same disease activity, AH levels of GRO-alpha and IP-10 were significantly higher in patients with BD than in patients with VKH disease and HLA-B27-associated uveitis (p=0.0474; p<0.001, respectively). These data suggest that GRO-alpha and IP-10 are the predominant CXC chemokines involved in neutrophil and activated T lymphocyte chemoattraction in endogenous uveitis, particularly in BD. PMID- 21531039 TI - Patterns of nail matrix and bed of longitudinal melanonychia by intraoperative dermatoscopy. AB - BACKGROUND: The dermatoscopic examination of the nail plate has been recently introduced for the evaluation of pigmented nail lesions. There is, however, no evidence that this technique improves diagnostic accuracy of in situ melanoma. OBJECTIVE: To establish and validate patterns for intraoperative dermatoscopy of the nail matrix. METHODS: Intraoperative nail matrix dermatoscopy was performed in 100 consecutive bands of longitudinal melanonychia that were excised and submitted to histopathologic examination. RESULTS: We identified 4 dermatoscopic patterns: regular gray pattern (hypermelanosis), regular brown pattern (benign melanocytic hyperplasia), regular brown pattern with globules or blotch (melanocytic nevi), and irregular pattern (melanoma). LIMITATIONS: Nail matrix dermatoscopy is an invasive procedure that can not routinely be performed in all cases of melanonychia. CONCLUSION: The patterns described present high sensitivity and specificity for intraoperative differential diagnosis of pigmented nail lesions. PMID- 21531041 TI - Skin blood flow abnormalities in diabetic dermopathy. AB - BACKGROUND: Diabetic dermopathy is the most common specific cutaneous finding in diabetes. OBJECTIVE: Using laser Doppler technology, we tested the hypothesis that diabetic dermopathy arises from abnormal local skin blood flow. METHODS: We measured cutaneous blood flow in patients with type 1 diabetes without dermopathy and compared values with those in a control group of patients with type 1 diabetes without diabetic dermopathy and in a nondiabetic group. We measured at 3 separate sites on the pretibial area on the legs of each participant, at dermopathy lesions, and at a number of standard sites on the upper and lower extremities. RESULTS: We studied 25 patients with diabetes and diabetic dermopathy, average age 51 +/- 2 years, mean duration of diabetes 28 +/- 3 years. In all, 58 patients with type 1 diabetes without diabetic dermopathy served as control patients, average age 41 +/- 2 years, mean duration of diabetes 23 +/- 2 years. There were 67 nondiabetic control subjects, average age 47 +/- 3 years. The patients with diabetic dermopathy showed a marked reduction in skin blood flow at 35 degrees C at normal-appearing skin areas on the pretibial surface of the legs (1.1 +/- 0.1 mL/min/100 g) compared with 1.7 +/- 0.1 mL/min/100 g (P = .01) in the type 1 diabetic control group and 2.1 +/- 0.3 mL/min/100 g (P < .01) in the nondiabetic group. The dermopathy lesions themselves showed markedly higher blood flow: 2.5 +/- 0.3 mL/min/100 g. LIMITATIONS: Our diabetic dermopathy patients were somewhat older than the control type 1 diabetes subjects, but were of comparable age to the nondiabetic subjects. CONCLUSIONS: These results suggest that patients susceptible to diabetic dermopathy have a functional abnormality in blood flow leading to this scarring process. PMID- 21531042 TI - Activity of a dry mist-generated hydrogen peroxide disinfection system against methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii. AB - BACKGROUND: The aim of this study was to evaluate the activity of a dry mist generated hydrogen peroxide (DMHP) system (Sterinis; Gloster Sante Europe, Labege cedex, France) against methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii. METHODS: McFarland 0.5 suspensions of 2 test bacteria, either pure or containing 5% sterile serum, were prepared and inoculated onto sterile stainless steel disks. Each disk in a Petri dish-with the Petri dish cover either closed or open-was placed in different locations in an intensive care unit room. Quantitative cultures were performed after the cycle. RESULTS: No growth occurred on the disks in the absence of a barrier, except 1 disk containing serum. Existence of a barrier, as a drawer or a covered Petri dish, caused failure in the disinfection activity. The mean reduction in initial log(10) bacterial count was lower for both of the test bacteria in presence of a barrier: 4.44- to 4.70-log(10) colony-forming units (cfu) decrease was observed in absence of a barrier, whereas 1.49- to 3.79-log(10) cfu decrease was observed in presence of a barrier. When the culture results were compared according to organic load content, the mean (+/-standard deviation) reduction of initial contamination in pure and in serum containing MRSA suspensions was 4.25 +/- 1.20- and 3.34 +/- 1.89-log(10) cfu, respectively. The mean (+/-standard deviation) reduction in pure and in serum containing A baumannii suspensions was 4.34 +/- 0.89- and 3.87 +/- 1.26-log(10) cfu, respectively. The differences were statistically significant (P < .001). CONCLUSION: Sterinis was capable of killing MRSA and A baumannii on open surfaces; however, it was not effective in closed or semiclosed areas. Presence of serum also caused failure in the disinfection activity of the system. PMID- 21531040 TI - The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. AB - BACKGROUND: Dermatomyositis (DM) is a multisystem autoimmune disease, in which serologic evidence of immune responses to disease-specific antigenic targets is found in approximately 50% to 70% of patients. Recently, melanoma differentiation associated gene 5 (MDA5) has been identified as a DM-specific autoantigen that appears to be targeted in patients with DM and mild or absent muscle inflammation and with an increased risk of interstitial lung disease. OBJECTIVE: We wished to understand the role of MDA5 in DM skin inflammation by testing it to determine if a specific cutaneous phenotype is associated with MDA5 reactivity. METHODS: We retrospectively screened plasma from 77 patients with DM in the outpatient clinics at the Stanford University Department of Dermatology in California. RESULTS: We found that 10 (13%) patients had circulating anti-MDA5 antibodies, and had a characteristic cutaneous phenotype consisting of skin ulceration, tender palmar papules, or both. Typical areas of skin ulceration included the lateral nailfolds, Gottron papules, and elbows. Biopsy specimens of the palmar papules showed a vasculopathy characterized by vascular fibrin deposition with variable perivascular inflammation. Patients with anti-MDA5 antibodies also had an increased risk of oral pain and/or ulceration, hand swelling, arthritis/arthralgia, and diffuse hair loss. Consistent with previous reports, these patients had little or no myositis and had increased risk of interstitial lung disease. LIMITATIONS: This study was conducted at a tertiary referral center. Multiple associations with MDA5 antibodies were tested retrospectively on a relatively small cohort of 10 anti-MDA5-positive patients. CONCLUSION: We suggest that MDA5 reactivity in DM characterizes a patient population with severe vasculopathy. PMID- 21531043 TI - Altered ryanodine receptor expression in mild cognitive impairment and Alzheimer's disease. AB - Intracellular Ca(2+) dysregulation is an underlying component of Alzheimer's disease (AD) pathophysiology, and recent evidence implicates the ryanodine receptor (RyR) in the disease pathway. Three genes code for different RyR isoforms and each gene transcript gives rise to several alternatively spliced messenger RNAs (mRNAs). These variants confer distinct functionality to the RyR channel, such as altering Ca(2+) release properties or subcellular localization. Changes in RyR isoform expression and alternative splicing have not been examined for potential roles in AD pathogenesis. Here, we compare mRNA levels of the RyR2 and RyR3 isoforms as well as specific alternatively spliced variants across vulnerable brain regions from postmortem samples of individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. We find an increase in RyR2 transcripts in MCI brains compared with no cognitive impairment. In addition, there is a reduction in a RyR2 splice variant, associated with an antiapoptotic function, in MCI and AD brains. These alterations in RyR expression at early disease stages may reflect the onset of pathologic mechanisms leading to later neurodegeneration. PMID- 21531044 TI - Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson's disease. AB - The nuclear receptor related 1 (Nurr1) transcription factor contributes to the development and maintenance of dopamine (DA) neurons in the brain. We found that heterozygous Nurr1 knockout (Nurr1 +/-) influenced the age-dependent decline in the number of DA neurons and influenced DA signaling. We examined the DA marker, tyrosine hydroxylase, using immunohistochemistry, and we measured DA signaling using fast-scan cyclic voltammetry in 3 age groups of wild-type (Nurr1 +/+) and mutant (Nurr1 +/-) mice: 3-6, 9-12, and 15-23 mo old. Prior to significant loss of DA neurons and to the onset of parkinsonian symptoms, young Nurr1 +/- mice (3 6 mo) exhibited a decrease in peak evoked DA release that was partially countered by a decrease in the rate of DA reuptake. As peak evoked DA release declined with age for both the wild-type and Nurr1 +/- mice, both genotypes manifested decreased DA reuptake. As the DA release fell further with age, decreased DA reuptake eventually could not adequately compensate the Nurr1 +/- mice. The results indicated that Nurr1 deficiency led to impaired DA release even before significant DA neuron loss. PMID- 21531045 TI - Gadolinium-staining reveals amyloid plaques in the brain of Alzheimer's transgenic mice. AB - Detection of amyloid plaques in the brain by in vivo neuroimaging is a very promising biomarker approach for early diagnosis of Alzheimer's disease (AD) and evaluation of therapeutic efficacy. Here we describe a new method to detect amyloid plaques by in vivo magnetic resonance imaging (MRI) based on the intracerebroventricular injection of a nontargeted gadolinium (Gd)-based contrast agent, which rapidly diffuses throughout the brain and increases the signal and contrast of magnetic resonance (MR) images by shortening the T1 relaxation time. This gain in image sensitivity after in vitro and in vivo Gd staining significantly improves the detection and resolution of individual amyloid plaques in the cortex and hippocampus of AD transgenic mice. The improved image resolution is sensitive enough to demonstrate an age-dependent increase of amyloid plaque load and a good correlation between the amyloid load measured by MUMRI and histology. These results provide the first demonstration that nontargeted Gd staining can enhance the detection of amyloid plaques to follow the progression of AD and to evaluate the activity of amyloid-lowering therapeutic strategies in longitudinal studies. PMID- 21531046 TI - Aging redistributes medial prefrontal neuronal excitability and impedes extinction of trace fear conditioning. AB - Cognitive flexibility is critical for survival and reflects the malleability of the central nervous system (CNS) in response to changing environmental demands. Normal aging results in difficulties modifying established behaviors, which may involve medial prefrontal cortex (mPFC) dysfunction. Using extinction of conditioned fear in rats to assay cognitive flexibility, we demonstrate that extinction deficits reminiscent of mPFC dysfunction first appear during middle age, in the absence of hippocampus-dependent context deficits. Emergence of aging related extinction deficits paralleled a redistribution of neuronal excitability across two critical mPFC regions via two distinct mechanisms. First, excitability decreased in regular spiking neurons of infralimbic-mPFC (IL), a region whose activity is required for extinction. Second, excitability increased in burst spiking neurons of prelimbic-mPFC (PL), a region whose activity hinders extinction. Experiments using synaptic blockers revealed that these aging-related differences were intrinsic. Thus, changes in IL and PL intrinsic excitability may contribute to cognitive flexibility impairments observed during normal aging. PMID- 21531047 TI - [Epiploic appendagitis: an underdiagnosed cause of acute abdominal pain]. PMID- 21531048 TI - [Characteristics of antiretroviral drugs]. AB - As of November 2010, a total of 22 antiretroviral agents are marketed in Spain. These agents are divided into 6 classes according to their mechanism of action: 1) nucleos(t)ide reverse transcriptase inhibitors (NRTI) (abacavir, didanosine, emtricitabine, stavudine, lamivudine, zidovudine, and tenofovir), 2) non nucleoside reverse transcriptase inhibitors (NNRTI) (efavirenz, etravirine, and nevirapine), 3) protease inhibitors (PI) (atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir), 4) entry inhibitors (enfuvirtide), 5) coreceptor CCR5 inhibitors (maraviroc), and 6) integrase inhibitors (raltegravir). All 22 agents are indicated for the treatment of HIV-1 infection in combination with other antiretroviral drugs. Most have also proven to be active against HIV-2 (except the NNRTIs, enfuvirtide, and maraviroc) and some are active against hepatitis B virus (lamivudine, emtricitabine, and tenofovir). The present article reviews the main characteristics of the different antiretroviral agents and classes, namely, commercial presentations, paediatric and adult dosages, dose adjustments in renal and hepatic insufficiency, pharmacokinetics and interactions, mechanism of action, treatment indications, resistance, adverse effects, and safety during pregnancy and breastfeeding. Some of the characteristics of antiretrovirals are class-specific and common to other agents of the same class, and others are individual and different from those of other drugs in the same class. Knowledge of these characteristics enables us to prepare efficacious therapeutic regimens according to the specific requirements of the patient (tolerability, simplicity, adaptability to lifestyle) and clinical setting (naive, simplification, rescue, resistance). PMID- 21531049 TI - Synthesis, antitumor and antimicrobial activities of 4-(4-chlorophenyl)-3-cyano-2 (beta-O-glycosyloxy)-6-(thien-2-yl)-nicotinonitrile. AB - 4-(4-Chlorophenyl)-3-cyano-6-(thien-2-yl)-1H-pyridin-2-one (2) was obtained by reaction of 2-acetyl thiophene with 4-chlorobenzaldehyde and ethyl cyanoacetate in presence of ammonium acetate or by the reaction of alpha,beta-unsaturated compound 1 with ethyl cyanoacetate in the presence of ammonium acetate. 4-(4 Chlorophenyl)-2-(2',3',4',6'-tetra-O-acetyl-beta-d-gluco/galactopyranosyloxy)-6 (thien-2-yl)nicotinonitrile (5a and 5b), riboside 11, xyloside 12 and lactoside 16 were prepared by the reaction of 2 with glycosyl/galactosyl/xylosyl/lactosyl bromide and peracetylated xylose/ribose under the conventional and microwave irradiation methods. The reaction has regioselectively gave the O-glycosides and not the N-glycosides. The glycosides 5a,b, riboside 11, xyloside 12 and lactoside 16 were deacetylated in the presence of Et(3)N/MeOH and few drops of water to give 7a,b, 13, 14 and 17. The structure of the new synthesized compounds was confirmed by using IR, (1)H, (13)C NMR spectra and microanalysis. Selected members of these compounds were screened for antitumor and antibacterial activity. PMID- 21531050 TI - Novel (E)-5-styryl-2,2'-bithiophene derivatives as ligands for beta-amyloid plaques. AB - In continuation of our investigation on the bithiophene structure as potential beta-amyloid probes, a series of (E)-5-styryl-2,2'-bithiophene (SBTP) derivatives was designed and synthesized. In vitro binding showed that all of them displayed high binding affinities to Abeta(1-42) aggregates (K(i)=0.10-41.05nM). Moreover, two radio-iodinated probes, [(125)I]-(E)-5-(4-iodostyryl)-2,2'-bithiophene ([(125)I]8) and [(125)I]-(E)-5-iodo-5'-(4-methoxystyryl)-2,2'-bithiophene ([(125)I]31) were prepared. Both of them displayed specific labeling of Abeta plaques in the brain sections of AD model mice with low background. In vivo biodistribution in normal mice indicated that [(125)I]8 exhibited high initial brain uptake (2.11% ID/g at 2 min) and rapid clearance (0.41% ID/g at 30 min). These preliminary results suggest that SBTP derivatives may be served as novel beta-amyloid imaging probes. PMID- 21531051 TI - Pharmacophore based virtual screening, molecular docking studies to design potent heat shock protein 90 inhibitors. AB - The identification of important chemical features of Heat Shock Protein 90 (HSP90) inhibitors will be helpful to discover the potent candidate to inhibit the HSP90 activity. The best hypothesis from Hip-Hop, Hypo1, one hydrogen bond donor (HBD), two hydrogen bond acceptors (HBA), and two hydrophobic (H) and structure-based hypothesis, SB_Hypo1, one HBA, one HBD and four H features, were generated using Discovery Studio and LigandScout, respectively. Test and decoy sets were used to corroborate the best hypotheses and the validated hypotheses were used to screen the chemical databases. Subsequently, the screened compounds were filtered by applying the rule of five, ADMET and molecular docking. Finally, four compounds were obtained as novel leads to inhibit the HSP90 activity. PMID- 21531052 TI - DNA-binding study of anthraquinone derivatives using chemometrics methods. AB - This work presents the interaction of two anthraquinones including quinizarin (1, 4-dihydroxyanthraquinone) and danthron (1, 8-dihydroxyanthraquinone) with CT-DNA in a mixture of Brittone-Robinson buffer (pH=7) with 50% of ethanol by UV-vis absorption, circular dichroism spectroscopic methods and viscosity measurements. The PCA and INDICES methods were used for predicting the number of light absorbing components. Partially intercalative and hydrogen binding were found to be the dominant binding modes between anthraquinones and CT-DNA. The effect of ionic strength and pH on the behavior of the above system and also the interaction of anthraquinones with ds and ss-DNA were used to confirm the mentioned binding modes. The EQUISPEC software and nonlinear least-squares analysis were applied for binding constant determination. PMID- 21531053 TI - Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf. AB - STAT3 is a transcription factor that modulates survival-directed transcription. It is persistently activated in many human cancers. Literature has shown that sorafenib, Raf kinase inhibitor, reduces Phospho-STAT3 and induces cell death. A series of sorafenib derivatives were synthesized as new inhibitors for STAT3. Urea, sulfonamide, and carboxamide linkers brought out different SARs from the end of sorafenib. Urea and carboxamide linked derivatives showed greater inhibition against STAT3 activity than sulfonamide linked derivatives. In particular, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(4 cyanophenoxy)phenyl)urea (1), a urea linker, was as potent as sorafenib in reducing P-STAT3 level and cell death but no inhibition for Raf activity. Such result provides a new lead for the design of STAT3 inhibitors. PMID- 21531054 TI - Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position. AB - In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different prion-infected murine cell models. They also exhibited greater binding affinities for a human prion protein fragment (hPrP(121-231)) than quinacrine, and had permeabilities on the PAMPA-BBB assay that fall within the range of CNS permeant candidates. When evaluated on bidirectional assays on a Pgp overexpressing cell line, one analog was less susceptible to Pgp efflux activity compared to quinacrine. Taken together, the results point to an important role for the substituted 9-amino side chain attached to the acridine, tetrahydroacridine and quinoline scaffolds. The nature of this side chain influenced cell-based potency, PAMPA permeability and binding affinity to hPrP(121-231). PMID- 21531055 TI - Identification of 5-arylidene-4-thiazolidinone derivatives endowed with dual activity as aldose reductase inhibitors and antioxidant agents for the treatment of diabetic complications. AB - In continuing the search for more effective 5-arylidene-4-thiazolidinones as aldose reductase inhibitors, a new set of suitably substituted compounds (4, 5 and 8) was explored. Acetic acids 5, particularly 5a and 5h, proved to be interesting inhibitors of the enzyme as well as excellent antioxidant agents that are potentially able to counteract the oxidative stress associated with both diabetic complications as well as other pathologies. Molecular docking experiments supported SAR studies. PMID- 21531056 TI - Dynamics, deterministic nature and correlations of outdoor (222)Rn and (220)Rn progeny concentrations measured at Bacau, Romania. AB - The long-term variation, nature and correlations of outdoor (222)Rn and (220)Rn progeny concentrations measured during the period 1994-2009 were investigated. The time series of data were obtained within the framework of the monitoring program performed by the Environmental Radioactivity Monitoring Station (ERMS) Bacau, a component part of the National Environmental Radioactivity Survey Network (NERSN), coordinated by National Environmental Protection Agency (NEPA). The measuring method is based on the total beta measurements of atmospheric aerosol filters, using a low background total beta counter and ((90)Sr/Y) reference standard. Analysis of the time series of progeny concentrations in the low atmosphere makes evident different patterns of variation of these concentrations: diurnal, seasonal and annual. A possible relationship of progeny concentration increase with global warming is emphasized. In order to find the dominant frequency of the physical processes determining progeny concentration variability the power spectrum has been used. The deterministic nature of the time series of concentrations has been studied making use of the autocorrelation function and stationarity of the original data and of their phase randomized time series. Also, the correlations with meteorological parameters have been investigated using Pearson's correlation coefficient with corresponding level of significance. PMID- 21531057 TI - Effect of topography on nitrous oxide emissions from winter wheat fields in Central France. AB - We assessed nitrous oxide (N(2)O) emissions at shoulder and foot-slope positions along three sloping sites (1.6-2.1%) to identify the factors controlling the spatial variations in emissions. The three sites received same amounts of total nitrogen (N) input at 170kgNha(-1). Results showed that landscape positions had a significant, but not consistent effect on N(2)O fluxes with larger emission in the foot-slope at only one of the three sites. The effect of soil inorganic N (NH(4)(+)+NO(3)(-)) contents on N(2)O fluxes (r(2)=0.55, p<0.001) was influenced by water-filled pore space (WFPS). Soil N(2)O fluxes were related to inorganic N at WFPS>60% (r(2)=0.81, p<0.001), and NH(4)(+) contents at WFPS<60% (r(2)=0.40, p<0.01), respectively. Differences in WFPS between shoulder and foot-slope correlated linearly with differences in N(2)O fluxes (r(2)=0.45, p<0.001). We conclude that spatial variations in N(2)O emission were regulated by the influence of hydrological processes on soil aeration intensity. PMID- 21531058 TI - Differentiation of nitrous oxide emission factors for agricultural soils. AB - Nitrous oxide (N(2)O) direct soil emissions from agriculture are often estimated using the default IPCC emission factor (EF) of 1%. However, a large variation in EFs exists due to differences in environment, crops and management. We developed an approach to determine N(2)O EFs that depend on N-input sources and environmental factors. The starting point of the method was a monitoring study in which an EF of 1% was found. The conditions of this experiment were set as the reference from which the effects of 16 sources of N input, three soil types, two land-use types and annual precipitation on the N(2)O EF were estimated. The derived EF inference scheme performed on average better than the default IPCC EF. The use of differentiated EFs, including different regional conditions, allows accounting for the effects of more mitigation measures and offers European countries a possibility to use a Tier 2 approach. PMID- 21531059 TI - A novel method dependent only on the mixture information (MIM) for evaluating the toxicity of mixture. AB - Compound contamination and toxicity interaction necessitate the development of models that have an insight into the combined toxicity of chemicals. In this paper, a novel and simple model dependent only on the mixture information (MIM), was developed. Firstly, the concentration-response data of seven groups of binary and multi-component (pseudo-binary) mixtures with different mixture ratios to Vibrio qinghaiensis sp.-Q67 were determined using the microplate toxicity analysis. Then, a desirable non-linear function was selected to fit the data. It was found that there are good linear correlations between the location parameter (alpha) and mixture ratio (p) of a component and between the steepness (beta) and p. Based on the correlations, a mixture toxicity model independent of pure component toxicity profiles was built. The model can be used to accurately estimate the toxicities of the seven groups of mixtures, which greatly simplified the predictive procedure of the combined toxicity. PMID- 21531060 TI - Effect of Ecuador's cash transfer program (Bono de Desarrollo Humano) on child development in infants and toddlers: a randomized effectiveness trial. AB - We examined the effects of Ecuador's Bono de Desarrollo Humano (BDH)--an unconditional cash transfer program that was rolled-out using a randomized design -on health and development outcomes in very young children. Communities that were randomly assigned to the treatment group began receiving the BDH in 2004 and those randomly assigned to the comparison group began receiving benefits two years later. Families enrolled in the BDH received a monthly cash stipend ($15USD) representing an approximate 6-10% increase in household income. Participants analyzed in this study are children aged 12-35 months from treatment (n = 797) and comparison (n = 399) communities in rural and urban Ecuador. Main outcomes measured were language skills (the Fundacion MacArthur Inventorio del Desarollo de Habilidades Comunicativas-Breve), height-for-age z-score, and hemoglobin concentration. Results indicate that in rural areas, being randomized to receive the BDH in very early childhood led to significantly better performance on the number of words a child was saying, and on the probability that the child was combining two or more words. There were no significant effects on language development for children in urban areas and there were no effects on height-for-age z-score or hemoglobin concentration in rural or urban areas. A limited number of potential pathways with respect to cognitive/language stimulation, health behaviors, and parenting quality were also explored. Findings indicate that compared to children in comparison areas, rural children in treatment areas were more likely to have received vitamin A or iron supplementation and have been bought a toy in the past six months. This study provides evidence for significant benefits of an unconditional cash transfer program for language development in very young children in rural areas. PMID- 21531061 TI - Caught in the crosshairs: identity and cultural authority within chiropractic. AB - In this paper the discourse over identity and cultural authority within the profession of chiropractic in the United States has been analyzed using critical discourse analysis. As the profession struggles to construct one singular image, versions of self must be internally debated and also shaped in consideration of larger, external forces. The dilemma of remaining tied to a marginal professional status must be balanced against considerations of integration. Written texts from chiropractic journals and newspapers are analyzed in a multidimensional approach that considers the rhetorical devices and thematic issues of identity construction; the representation of various voices within the discourse (both heard and unheard); and the extent to which external pressures affect the projection of cultural authority for the profession. A heterogeneous discourse characterized by conflict was found, with discrepancies between everyday chiropractors in actual practice versus academic chiropractors and leaders particularly over the idea, practice and significance of science for the profession. PMID- 21531062 TI - Medical returns: seeking health care in Mexico. AB - Despite the growing prevalence of transnational medical travel among immigrant groups in industrialized nations, relatively little scholarship has explored the diverse reasons immigrants return home for care. To date, most research suggests that cost, lack of insurance and convenience propel US Latinos to seek health care along the Mexican border. Yet medical returns are common even among Latinos who do have health insurance and even among those not residing close to the border. This suggests that the distinct culture of medicine as practiced in the border clinics Latinos visit may be as important a factor in influencing medical returns as convenience and cost. Drawing upon qualitative interviews, this article presents an emic account of Latinos' perceptions of the features of medical practice in Mexico that make medical returns attractive. Between November 15, 2009 and January 15, 2010, we conducted qualitative interviews with 15 Mexican immigrants and nine Mexican Americans who sought care at Border Hospital, a private clinic in Tijuana. Sixteen were uninsured and eight had insurance. Yet of the 16 uninsured, six had purposefully dropped their insurance to make this clinic their permanent "medical home." Moreover, those who substituted receiving care at Border Hospital for their US health insurance plan did so not only because of cost, but also because of what they perceived as the distinctive style of medical practice at Border Hospital. Interviewees mentioned the rapidity of services, personal attention, effective medications, and emphasis on clinical discretion as features distinguishing "Mexican medical practice," opposing these features to the frequent referrals and tests, impersonal doctor-patient relationships, uniform treatment protocols and reliance on surgeries they experienced in the US health care system. While interviewees portrayed these features as characterizing a uniform "Mexican medical culture," we suggest that they are best described as unique to the private clinics and hospitals returning migrants visit. In short, we suggest that the perceived contrast in cultures of medicine derives from the difference in organization of health care services on each side of the border. PMID- 21531063 TI - Perspectives on dichotic listening and the corpus callosum. AB - The present review summarizes historic and recent research which has investigated the role of the corpus callosum in dichotic processing within the context of audiology. Examination of performance by certain clinical groups, including split brain patients, multiple sclerosis cases, and other types of neurological lesions is included. Maturational, age related, and genetic factors are also discussed. Finally, some attention is given to recent trends in audiology research to develop improved diagnostic and rehabilitation tools for individuals with dichotic deficits potentially related to callosal dysfunction. PMID- 21531064 TI - [Childhood and adolescent obesity. A matter of confusion]. PMID- 21531065 TI - [Regression modeling strategies]. AB - Multivariable regression models are widely used in health science research, mainly for two purposes: prediction and effect estimation. Various strategies have been recommended when building a regression model: a) use the right statistical method that matches the structure of the data; b) ensure an appropriate sample size by limiting the number of variables according to the number of events; c) prevent or correct for model overfitting; d) be aware of the problems associated with automatic variable selection procedures (such as stepwise), and e) always assess the performance of the final model in regard to calibration and discrimination measures. If resources allow, validate the prediction model on external data. PMID- 21531067 TI - CPR knowledge and attitude to performing bystander CPR among secondary school students in Norway. AB - BACKGROUND: Early bystander cardiopulmonary resuscitation (CPR) is essential for survival from out-of-hospital cardiac arrest (OHCA). Young people are potentially important bystander CPR providers, as basic life support (BLS) training can be distributed widely as part of the school curriculum. METHODS: Questionnaires were distributed to nine secondary schools in North Norway, and 376 respondents (age 16-19 years) were included. The completed questionnaires were statistically analysed to assess CPR knowledge and attitude to performing bystander CPR. RESULTS: Theoretical knowledge of handling an apparently unresponsive adult person was high, and 90% knew the national medical emergency telephone number (113). The majority (83%) was willing to perform bystander CPR in a given situation with cardiac arrest. However, when presented with realistic hypothetical cardiac arrest scenarios, the option to provide full BLS was less frequently chosen, to e.g. a family member (74%), a child (67%) or an intravenous drug user (18%). Students with BLS training in school and self-reported confidence in their own BLS skills reported stronger willingness to perform BLS. 8% had personally witnessed a cardiac arrest, and among these 16% had performed full BLS. Most students (86%) supported mandatory BLS training in school, and three out of four wanted to receive additional training. CONCLUSION: Young Norwegians are motivated to perform bystander CPR, but barriers are still seen when more detailed cardiac arrest scenarios are presented. By providing students with good quality BLS training in school, the upcoming generation in Norway may strengthen the first part of the chain of survival in OHCA. PMID- 21531066 TI - PEP-1-SOD1 protects brain from ischemic insult following asphyxial cardiac arrest in rats. AB - AIM OF THE STUDY: Reperfusion following cerebral ischemia leads to excessive production of reactive oxygen species (ROS) and consumption of endogenous antioxidants. Antioxidant enzymes are considered to have beneficial effects against various diseases mediated by ROS. Copper, zinc-superoxide dismutase (SOD1) is one of the major defensive mechanisms by which cells counteract the deleterious effects of ROS after ischemia. However, exogenous SOD1 can not be delivered into living cells because of the poor permeability and selectivity of the cell membrane, thus its application for protecting cells/tissues from oxidative stress damage is greatly limited. METHODS: The purified SOD1 or PEP-1 SOD1 fusion proteins were injected into rats via their tail veins, the transduction ability of PEP-1-SOD1 was examined with immunofluorescent staining and SOD1 activity was measured. Moreover, we determined whether or not PEP-1-SOD1 can protect brain from ischemic injury in an experimental asphyxial cardiac arrest rat model through histopathologic analysis, evaluating the levels of malondialdehyde (MDA), S100beta and neuron specific enolase (NSE). RESULTS: SOD1 protein was observed in PEP-1-SOD1-treated animals and SOD1 activity was significantly increased. However, SOD1 protein was not detected in SOD1-treated animals. The transduced PEP-1-SOD1 significantly attenuated cerebral ischemia reperfusion damage, inhibited ischemia-induced lipid peroxidation, and protected neurons in hippocampus from the damage induced by transient global ischemic insults. CONCLUSIONS: PEP-1-SOD1 fusion protein can be transduced into the neurons in vivo and protect the neurons from the transient global ischemia induced damage, suggesting PEP-1-SOD1 may be used for the treatment of oxidative stress-associated disorders such as transient global cerebral ischemia. PMID- 21531068 TI - Assessing the impact of fisheries co-management interventions in developing countries: a meta-analysis. AB - Co-management is now established as a mainstream approach to small-scale fisheries management across the developing world. A comprehensive review of 204 potential cases reveals a lack of impact assessments of fisheries co-management. This study reports on a meta-analysis of the impact of fisheries co-management in developing countries in 90 sites across 29 case-studies. The top five most frequently measured process indicators are participation, influence, rule compliance, control over resources, and conflict. The top five most frequently measured outcome indicators are access to resources, resource well-being, fishery yield, household well-being, and household income. To deal with the diversity of the 52 indicators measured and the different ways these data are collected and analysed, we apply a coding system to capture change over time. The results of the meta-analysis suggest that, overall fisheries co-management delivers benefits to end-users through improvements in key process and outcome indicators. However, the dataset as a whole is constituted primarily of data from the Philippines. When we exclude this body of work, few generalisations can be made about the impact of fisheries co-management. The lack of comparative data suitable for impact assessment and the difficulties in comparing data and generalising across countries and regions reiterates calls in other fields for more systematic approaches to understanding and evaluating governance frameworks. PMID- 21531069 TI - Influence of ground tire rubber on the transient loading response of a peat biofilter. AB - The effect of using ground tire rubber (GTR) as an adsorptive material in the removal of a 2:1:1 weight mixture of n-butyl acetate, toluene and m-xylene by using a peat biofilter under different intermittent conditions was investigated. The performance of two identical size biofilters, one packed with fibrous peat alone and the other with a 3:1 (vol) fibrous peat and GTR mixture, was examined for a period of four months. Partition coefficients of both materials were measured. Values of 53, 118 and 402 L kg(-1) were determined for n-butyl acetate, toluene and m-xylene in peat, respectively; and values of 40, 609 and 3035 L kg( 1) were measured for the same compounds in GTR. Intermittent load feeding of 16 h per day, 5 days per week working at an EBRT of 60 s and an inlet VOC concentration of 0.3 g C m(-1), resulted in removal efficiencies higher than 90% for both biofilters, indicating that the addition of GTR did not adversely affect the behavior of the bioreactor. Full removal of n-butyl acetate was obtained for both biofilters. GTR improved the removal of the aromatics in the first part of the biofilter, facilitating lower penetration of the toluene and m-xylene into the bed. A 31-day starvation period was applied and intermittent operation subsequently restarted. In both biofilters, high removal efficiencies after a re acclimation period of two days were achieved. A shock loading test related to 1-h peaks of three- and four-fold increases in its baseline concentration (0.30 g C m(-3)) was applied in both biofilters. For the biofilter packed with the peat and GTR mixture, attenuation greater than 60% was observed in the maximum outlet concentration when compared to the biofilter packed with peat alone. PMID- 21531070 TI - Natural attenuation of residual heavy metal contamination in soils affected by the Aznalcollar mine spill, SW Spain. AB - Non-amended soils affected by pyritic sludge residues were monitored for 7 years to assess the long-term natural attenuation ability of these soils. The decrease in both the total concentration of elements (particularly As) and (NH(4))(2)SO(4) extractable fractions of Mn, and Zn, below the maximum permissible levels indicate a successful natural ability to attenuate soil pollution. Soil acidification by pyrite oxidation and rainfall-enhanced leaching were the largest contributors to the reduction of metals of high (Mn, Cu, Zn and Cd) and low (Fe, Al, and As) availability. Periodic use of correlation and spatial distribution analysis was useful in monitoring elemental dispersion and soil property/element relationships. PMID- 21531071 TI - Re: Willem Oosterlinck,Richard Sylvester, Marco Babjuk, et al. Should all patients receive an immediate chemotherapeutic drug instillation after resection of papillary bladder tumors? Eur Urol 2011;59:374-6. PMID- 21531073 TI - Re: Amit R. Patel, Edmund S. Sabanegh, J. Stephen Jones, et al. Bacillus Calmette Guerin osteomyelitis mimicking spinal metastasis from urothelial cell carcinoma of the bladder. Eur Urol 2010;58:934-7. PMID- 21531074 TI - An investigation on the new operational parameter effective in Cr(VI) removal efficiency: a study on electrocoagulation by alternating pulse current. AB - The performance of an electrocoagulation (EC) process with aluminum/iron electrodes for removal of chromium on laboratory scale was studied. The effect of operational parameters such as initial pH, current density (CD), reaction time, initial concentrations (50, 100, 500, 1000 mg/L), solution conductivity, electrical energy consumption (EEC) and type of circuit were studied in an attempt to reach higher Cr(VI) removal efficiency. Alternating pulse current (APC) was used to prevent the passivity or polarization of electrodes. Important operating parameters were optimized to access higher (99%) Cr(VI) removal efficiency as follows: EEC range: 4-58 kW h/m(3) wastewater, CD: 56-222 A/m(2), operating time: 20-110 min, pH 3-9 (pH(optimum) 5), voltage: 15-25 V. NaCl, KCl, PAC (poly aluminum chloride), NaNO(3) were used as supporting electrolytes. NaCl as well as KCl handled the EC with the best performance in every aspect; however, PAC and NaNO(3) did not have the same results (Applied conductivity is better than literature). The results of this work are comparable with those of recent studies. Equal removal efficiency was obtained in "direct current" (DC) and (APC); however, when "APC" was used, water recovery (0.92 m(3)/m(3) wastewater) was significant and the turbidity was 1 NTU. "APC" amazed our experimental team. PMID- 21531075 TI - Modeling uranium transport in acidic contaminated groundwater with base addition. AB - This study investigates reactive transport modeling in a column of uranium(VI) contaminated sediments with base additions in the circulating influent. The groundwater and sediment exhibit oxic conditions with low pH, high concentrations of NO(3)(-), SO(4)(2-), U and various metal cations. Preliminary batch experiments indicate that additions of strong base induce rapid immobilization of U for this material. In the column experiment that is the focus of the present study, effluent groundwater was titrated with NaOH solution in an inflow reservoir before reinjection to gradually increase the solution pH in the column. An equilibrium hydrolysis, precipitation and ion exchange reaction model developed through simulation of the preliminary batch titration experiments predicted faster reduction of aqueous Al than observed in the column experiment. The model was therefore modified to consider reaction kinetics for the precipitation and dissolution processes which are the major mechanism for Al immobilization. The combined kinetic and equilibrium reaction model adequately described variations in pH, aqueous concentrations of metal cations (Al, Ca, Mg, Sr, Mn, Ni, Co), sulfate and U(VI). The experimental and modeling results indicate that U(VI) can be effectively sequestered with controlled base addition due to sorption by slowly precipitated Al with pH-dependent surface charge. The model may prove useful to predict field-scale U(VI) sequestration and remediation effectiveness. PMID- 21531076 TI - Occurrence and removal of NDMA and NDMA formation potential in wastewater treatment plants. AB - N-Nitrosodimethylamine (NDMA) is a potent carcinogen that is formed during disinfection by chlorination or ozonation in wastewater treatment plants (WWTPs). At present, little is known about the occurrence and fate of NDMA and its formation potential (FP) during wastewater treatment. We investigated the fate of NDMA and NDMA FP in 12 WWTPs. NDMA occurred in the influents at a concentration ranging from below the limit of quantification (LOQ <10 ng/L) to 80 ng/L, and in the final discharges from below the LOQ to 73 ng/L. In three WWTPs located in industrial areas, the influent had a high NDMA FP (up to 8230 ng/L). The rate of NDMA FP reduction from influent to secondary effluent varied between 85 and 98%, regardless of treatment process. The rate of NDMA removal is due more to the influent properties than to the type of biological treatment process. PMID- 21531078 TI - TRPs along the alimentary canal. PMID- 21531077 TI - Prescription opioid analgesics rapidly change the human brain. AB - Chronic opioid exposure is known to produce neuroplastic changes in animals; however, it is not known if opioids used over short periods of time and at analgesic dosages can similarly change brain structure in humans. In this longitudinal, magnetic resonance imaging study, 10 individuals with chronic low back pain were administered oral morphine daily for 1 month. High-resolution anatomical images of the brain were acquired immediately before and after the morphine administration period. Regional changes in gray matter volume were assessed on the whole brain using tensor-based morphometry, and those significant regional changes were then independently tested for correlation with morphine dosage. Thirteen regions evidenced significant volumetric change, and degree of change in several of the regions was correlated with morphine dosage. Dosage correlated volumetric decrease was observed primarily in the right amygdala. Dosage-correlated volumetric increase was seen in the right hypothalamus, left inferior frontal gyrus, right ventral posterior cingulate, and right caudal pons. Follow-up scans that were conducted an average of 4.7 months after cessation of opioids demonstrated many of the morphine-induced changes to be persistent. In a separate study, 9 individuals consuming blinded placebo capsules for 6 weeks evidenced no significant morphologic changes over time. The results add to a growing body of literature showing that opioid exposure causes structural and functional changes in reward- and affect-processing circuitry. Morphologic changes occur rapidly in humans during new exposure to prescription opioid analgesics. Further research is needed to determine the clinical impact of those opioid-induced gray matter changes. PMID- 21531079 TI - Clinical study of cultured epithelial autografts in liquid suspension in severe burn patients. AB - We address the clinical application of the suspension type cultured epithelial autografts (CEAs), KerahealTM (MCTT, Seoul, Korea), along with the effects, application method, merits and demerits thereof. From February 2007 to June 2010, 29 burn patients with extensive burns, participated in the suspension type of CEA clinical test. A widely meshed autograft (1:4-6 ratio) was applied to the wound bed and the suspension type CEA was sprayed with a Tissomat cell sprayer, followed by a Tissucol spray, a fibrin sealant. The patients' (men/women=26/3) median (interquartile ranges) age was 42 (30-49) years old, the burned TBSA was 55 (44-60) %, and the full thickness burn area was 40 (30-46.5) %. The area of KerahealTM applied was 800 (400-1200) cm(2). The take rate was 96 (90.5-99) % and 100 (98.5-100) % at 2 and 4 weeks after treatment with KerahealTM, respectively. The Vancouver burn scar scale was 5 (4-6.5), 4 (3-6), and 3 (2-4) at 8, 12 and 24 weeks after the KerahealTM application. Widely meshed autograft must be applied in massive burns but it's take rate is greatly reduced. The CEAs enhance the take rate of a wide meshed autograft in massive burns and allow for grafting wide meshed autograft together with acellular dermal matrix in some cases. PMID- 21531080 TI - Microskin autografting in the treatment of burns over 70% of total body surface area: 14 years of clinical experience. AB - Despite the fact that early excision and grafting have significantly improved burn outcomes, the management of severely burned patients whose burn size exceeds 70% total body surface area (TBSA) still represents a big challenge for burn surgeons all over the world. During the period of 1997-2010 at our centre, aggressive excision and microskin autografting were performed in 63 severely burned patients. Their burn sizes ranged from 70% to 98% TBSA with a mean of 84.9%. The average full-thickness burn was 66.3% (range, 29-94%). Thirty patients had concomitant inhalation injury. Two to 7 days after burn, these patients underwent aggressive excisions ranging from 25% to 60% TBSA and transplantation of microskin autograft overlaid with allograft. The ratios of donor-site to recipient-site surface area were between 1:6 and 1:18. Signs of epithelialization were shown within 35-55 days. The wound healing rate was 74.9% (176/235), with 51.1% of cases (120/235) healing completely and 23.8% (56/235) improving. Microskin autografting yielded an overall survival rate of 63.5%; only 23 patients died. Our clinical experience in using the microskin autografting for burn coverage suggests that the technique is very effective in covering extensive burns, and that it is particularly useful when graft donor sites are very limited due to its high utilization rate of donor site. The factors affecting the outcome of microskin autografting are discussed herein. PMID- 21531081 TI - Glucocorticoid and mineralocorticoid receptor polymorphisms and clinical characteristics in bipolar disorder patients. AB - INTRODUCTION: The hypothalamus-pituitary-adrenal (HPA)-axis is often found to be dysregulated in bipolar disorder (BD) while stress and changes in day-night rhythms can trigger a new mood episode. Genetic variants of the glucocorticoid receptor (GR)- and mineralocorticoid receptor (MR)-gene influence both the reactivity of the stress-response and associate with changes in mood. In this study we tested the hypothesis that these polymorphisms associate with different clinical characteristics of BD. METHODS: We studied 326 outpatients with BD and performed GR genotyping of the TthIIII, ER22/23EK, N363S, BclI, and 9beta polymorphisms, as well as MR genotyping of the 2G/C and I180V variants. All patients were interviewed for clinical characteristics. RESULTS: Seasonal patterns of hypomania are related to the BclI haplotype and the TthIIII+9beta haplotype of the GR gene (respectively, crude p=.007 and crude p=.005). Carriers of the ER22/23EK polymorphism had an almost 8 years earlier onset of their first (hypo)manic episode than non-carriers (crude p=.004, after adjustment p=.016). No evidence for a role of the MR in modifying clinical manifestations was found. CONCLUSION: Polymorphisms of the GR-gene are factors which influence some clinical manifestations of BD, with respect to seasonal pattern of (hypo)mania and age of onset. PMID- 21531082 TI - Cognitive flexibility and Agouti-related protein in adolescent patients with anorexia nervosa. AB - INTRODUCTION: Cognitive flexibility and the flexible learning and relearning of stimulus-reward-associations are important for decision-making and goal-directed behavior. Studies on patients with anorexia nervosa (AN) have shown difficulties in cognitive functions associated with malnutrition and extreme underweight. However, to date we find a lack of neuropsychological studies on cognitive flexibility among adolescent patients with AN. Furthermore, the underlying biological mechanisms remain unclear. Therefore, we aim to examine cognitive functions, especially reward association learning, as a measure of cognitive flexibility in adolescent patients with AN and investigate the relationship between Agouti-related protein (AGRP) and cognitive functions. METHODS: The study population consists of 30 patients with AN (M(age)=16.2 +/- 1.2) and a healthy control group (CG) of 28 female adolescents (M(age)=16.3 +/- 1.3). All subjects completed a neuropsychological test battery including the probabilistic Object Reversal Task, the Digit Symbol Test and the Trail Making Test. Patients with AN were explored before and after weight gain, the CG initially and after 3 months. RESULTS: Subtle deficits in cognitive flexibility were found in patients with AN compared to the CG. After weight gain, the AN group improved relative to their baseline values in most of the variables but did not reach CG values. They still showed slight impairments. Moreover the study revealed a clear association between AGRP levels and cognitive flexibility. DISCUSSION: Cognitive flexibility plays an important role in AN and may be modulated by abnormal levels of the appetite-regulating peptide AGRP. Even subtle impairments in cognitive flexibility can be relevant for the ability to fully engage in therapy and therefore may hinder a prosperous treatment. PMID- 21531083 TI - Hepatic granulomas: a clinicopathologic analysis of 86 cases. AB - The aim of this study was to determine the prevalence and histopathological characteristics of hepatic granulomas. All records of liver biopsies/resections evaluated in our pathology department between 2002 and 2009 were retrospectively reviewed. Specimens with hepatic granulomas were reexamined by a designated pathologist. Type and localization of granulomas, size of granulomas and epithelioid histiocytes, and the morphological findings of surrounding liver tissue were recorded in an attempt to establish a correlation with relevant clinical, laboratory and radiological findings. Out of 1420 liver biopsy/resected specimens evaluated at our institution during the study period, 86 cases of epithelioid cell granulomas (6.05%) were observed. Of the 86 cases, 23 were men and 63 were women. The most common underlying etiology was PBC in 38 patients, infections in 34, malignancies in five, sarcoidosis in four, and foreign bodies in three patients. One case (1.2%) of a drug-induced hepatic granuloma was encountered, while another case was deemed idiopathic (of unknown etiology). Contrary to common belief, granulomas were observed not only in early stage PBC but also in cases with stage 3 disease. Out of all the PBC cases with granulomas, 55.6% had stage 3 disease, and besides periductal granulomas, intraacinar granulomas were also seen. For sarcoidosis, intra- and peri-granulomatous fibrosis was observed in as many as 75% of cases. A large majority of granulomas (82.4%) associated with infections were of the necrotizing type. Extensive evaluation of the morphological characteristics of hepatic granulomas and surrounding liver tissue along with clinical, radiological, and other laboratory findings may help arrive at an accurate diagnosis in a majority of cases. Rather than being a final diagnosis, the presence of hepatic granulomas entails the need for further investigations towards identifying the underlying etiology, with a pathologist being at the center of the diagnostic process. PMID- 21531084 TI - Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: molecular bases for EGFR-targeted therapy. AB - Cutaneous squamous cell carcinoma (SCC) ranks second in the frequency of all skin tumors. Its incidence has risen significantly due to an increased sun exposure and the number of immunocompromised patients. It has a well-defined progression with known precursor lesions called actinic keratosis. The degree of cellular differentiation, tumor thickness, location, and other features has prognostic value. It has a better prognosis than mucosal SCC of the head and neck, also called head and neck squamous cell carcinoma (HNSCC). Ultraviolet light plays a fundamental role as an initiator and promoter of carcinogenesis of SCC, allowing the accumulation of genetic alterations that allows a selective growth advantage. The TP53 (p53) gene often mutates and Ras is frequently activated, but with low frequency of mutations. Normally, the extracellular signals determine whether the cells move from a quiescent state into an active proliferative state. In tumor cells an increase in the production of growth factors and its receptors can be often seen that gives rise to such an autocrine circuit facilitating cellular division. Recently, frequent mutations in the epidermal growth factor receptor (EGFR) have been detected in lung cancer, mainly deletions in exon 19 and L858R mutation in exon 21. These are located at the EGFR tyrosine kinase domain (TK). EGFR TK mutations produce activation of the signaling pathways downstream and preferentially activated antiapoptotic pathways (PI3K/AKT, JAK-STAT and ERK/MAPK). These mutations are correlated with the clinical response of patients to tyrosine kinase inhibitors (gefinitib and erlotinib), because the tumor cells are addicted to the constant activation of specific signaling pathways. Glioblastoma shows another EGFR mutation (EGFRvIII), corresponding to a deletion of the extracellular domain, and it is present in 24-67% of these tumors. This variant has been found in 42% of HNSCC, related to the poor response to monoclonal antibody cetuximab. Many observations show that there are abnormalities in the expression of epidermal growth factor receptor (EGFR) and/or its ligands in HNSCC with frequent activation of multiple pathways downstream EGFR, and unrelated to RAS mutation. This suggests the possibility of activation by mutation or overexpression of a component of the pathway located upstream-Ras. While in other tumors, especially lung cancer and glioblastoma, the EGFR mutations are frequent genetic events, it is unknown whether EGFR is mutated or amplified in SCC of the skin and what would be its pathogenic role in this malignancy and its precursors. PMID- 21531085 TI - What is the best way to contour lung tumors on PET scans? Multiobserver validation of a gradient-based method using a NSCLC digital PET phantom. AB - PURPOSE: To evaluate the accuracy and consistency of a gradient-based positron emission tomography (PET) segmentation method, GRADIENT, compared with manual (MANUAL) and constant threshold (THRESHOLD) methods. METHODS AND MATERIALS: Contouring accuracy was evaluated with sphere phantoms and clinically realistic Monte Carlo PET phantoms of the thorax. The sphere phantoms were 10-37 mm in diameter and were acquired at five institutions emulating clinical conditions. One institution also acquired a sphere phantom with multiple source-to-background ratios of 2:1, 5:1, 10:1, 20:1, and 70:1. One observer segmented (contoured) each sphere with GRADIENT and THRESHOLD from 25% to 50% at 5% increments. Subsequently, seven physicians segmented 31 lesions (7-264 mL) from 25 digital thorax phantoms using GRADIENT, THRESHOLD, and MANUAL. RESULTS: For spheres <20 mm in diameter, GRADIENT was the most accurate with a mean absolute % error in diameter of 8.15% (10.2% SD) compared with 49.2% (51.1% SD) for 45% THRESHOLD (p < 0.005). For larger spheres, the methods were statistically equivalent. For varying source-to-background ratios, GRADIENT was the most accurate for spheres >20 mm (p < 0.065) and <20 mm (p < 0.015). For digital thorax phantoms, GRADIENT was the most accurate (p < 0.01), with a mean absolute % error in volume of 10.99% (11.9% SD), followed by 25% THRESHOLD at 17.5% (29.4% SD), and MANUAL at 19.5% (17.2% SD). GRADIENT had the least systematic bias, with a mean % error in volume of -0.05% (16.2% SD) compared with 25% THRESHOLD at -2.1% (34.2% SD) and MANUAL at -16.3% (20.2% SD; p value <0.01). Interobserver variability was reduced using GRADIENT compared with both 25% THRESHOLD and MANUAL (p value <0.01, Levene's test). CONCLUSION: GRADIENT was the most accurate and consistent technique for target volume contouring. GRADIENT was also the most robust for varying imaging conditions. GRADIENT has the potential to play an important role for tumor delineation in radiation therapy planning and response assessment. PMID- 21531086 TI - Predicting nonauditory adverse radiation effects following radiosurgery for vestibular schwannoma: a volume and dosimetric analysis. AB - PURPOSE: To define clinical and dosimetric predictors of nonauditory adverse radiation effects after radiosurgery for vestibular schwannoma treated with a 12 Gy prescription dose. METHODS: We retrospectively reviewed our experience of vestibular schwannoma patients treated between September 2005 and December 2009. Two hundred patients were treated at a 12 Gy prescription dose; 80 had complete clinical and radiological follow-up for at least 24 months (median, 28.5 months). All treatment plans were reviewed for target volume and dosimetry characteristics; gradient index; homogeneity index, defined as the maximum dose in the treatment volume divided by the prescription dose; conformity index; brainstem; and trigeminal nerve dose. All adverse radiation effects (ARE) were recorded. Because the intent of our study was to focus on the nonauditory adverse effects, hearing outcome was not evaluated in this study. RESULTS: Twenty-seven (33.8%) patients developed ARE, 5 (6%) developed hydrocephalus, 10 (12.5%) reported new ataxia, 17 (21%) developed trigeminal dysfunction, 3 (3.75%) had facial weakness, and 1 patient developed hemifacial spasm. The development of edema within the pons was significantly associated with ARE (p = 0.001). On multivariate analysis, only target volume is a significant predictor of ARE (p = 0.001). There is a target volume threshold of 5 cm3, above which ARE are more likely. The treatment plan dosimetric characteristics are not associated with ARE, although the maximum dose to the 5th nerve is a significant predictor of trigeminal dysfunction, with a threshold of 9 Gy. The overall 2-year tumor control rate was 96%. CONCLUSIONS: Target volume is the most important predictor of adverse radiation effects, and we identified the significant treatment volume threshold to be 5 cm3. We also established through our series that the maximum tolerable dose to the 5th nerve is 9 Gy. PMID- 21531087 TI - Quantifying the reproducibility of heart position during treatment and corresponding delivered heart dose in voluntary deep inhalation breath hold for left breast cancer patients treated with external beam radiotherapy. AB - PURPOSE: Voluntary deep inhalation breath hold (VDIBH) reduces heart dose during left breast irradiation. We present results of the first study performed to quantify reproducibility of breath hold using bony anatomy, heart position, and heart dose for VDIBH patients at treatment table. METHODS AND MATERIALS: Data from 10 left breast cancer patients undergoing VDIBH whole-breast irradiation were analyzed. Two computed tomography (CT) scans, free breathing (FB) and VDIBH, were acquired to compare dose to critical structures. Pretreatment weekly kV orthogonal images and tangential ports were acquired. The displacement difference from spinal cord to sternum across the isocenter between coregistered planning Digitally Reconstructed Radiographs (DRRs) and kV imaging of bony thorax is a measure of breath hold reproducibility. The difference between bony coregistration and heart coregistration was the measured heart shift if the patient is aligned to bony anatomy. RESULTS: Percentage of dose reductions from FB to VDIBH: mean heart dose (48%, SD 19%, p = 0.002), mean LAD dose (43%, SD 19%, p = 0.008), and maximum left anterior descending (LAD) dose (60%, SD 22%, p = 0.008). Average breath hold reproducibility using bony anatomy across the isocenter along the anteroposterior (AP) plane from planning to treatment is 1 (range, 0-3; SD, 1) mm. Average heart shifts with respect to bony anatomy between different breath holds are 2 +/- 3 mm inferior, 1 +/- 2 mm right, and 1 +/- 3 mm posterior. Percentage dose changes from planning to delivery: mean heart dose (7%, SD 6%); mean LAD dose, ((9%, SD 7%)S, and maximum LAD dose, (11%, SD 11%) SD 11%, p = 0.008). CONCLUSION: We observed excellent three-dimensional bony registration between planning and pretreatment imaging. Reduced delivered dose to heart and LAD is maintained throughout VDIBH treatment. PMID- 21531088 TI - [An ovarian mucinous borderline tumour with mixed mural nodules]. AB - The occurrence of mural nodules in serous or mucinous ovarian tumours is not frequent. Mural nodule can be developed in benign, borderline or malignant tumours. They can be benign, malignant or mixed type. Thus the prognosis of the ovarian tumour can be dramatically modified by the presence if these nodules. Eighty-two cases of mural nodules were reported in the literature, among which we account four cases of mixed nodules type. We report an additional case of mixed type mural nodules of anaplastic carcinoma and sarcoma-like developed in an ovarian mucinous borderline tumour at a 60-year-old woman.We give details about the classification, the differential diagnosis and prognosis of theses nodules. PMID- 21531089 TI - Motivational interviewing to reduce substance-related consequences: effects for incarcerated adolescents with depressed mood. AB - BACKGROUND: The impact of depressed mood on Motivational Interviewing (MI) to reduce risky behaviors and consequences in incarcerated adolescents was examined in this brief report. METHODS: Adolescents (N=189) were randomly assigned to receive MI or Relaxation Training (RT). RESULTS: At 3-month follow-up assessment, MI significantly reduced risks associated with marijuana use, with a trend towards reducing risks associated with alcohol use. There was also a trend for depressive symptoms to be associated with reduced risks after release. Interaction effects were non-significant, indicating no moderating effects for depressed mood on treatment outcome. CONCLUSIONS: MI may be a useful treatment for incarcerated adolescents in order to reduce risks and consequences associated with substance use after release. PMID- 21531091 TI - Effects of beta-adrenergic receptor blockade on drug-related memory reconsolidation in abstinent heroin addicts. AB - RATIONALE AND OBJECTIVE: The reactivation of a consolidated memory can return it to a labile state, a process referred to as reconsolidation. A previous study showed that oral administration of the beta-adrenergic receptor antagonist propranolol before memory reactivation in humans erased the behavioral expression of the fear memory 24h later. In this study, we investigated whether propranolol impairs the drug-related memory by disrupting the reconsolidation process in heroin addicts. METHODS: Seventy abstinent heroin addicts learned a word list (including 10 heroin-related positive words, 10 heroin-related negative words, and 10 neutral words) on day 1. Participants orally administered the beta adrenergic receptor antagonist propranolol or placebo before retrieval of the word list on day 2. Free recall of the word list and other psychological and physical responses were assessed on day 3. RESULTS: Oral administration of propranolol before reactivation of the word list impaired reconsolidation of drug related positive and negative but not neutral words in abstinent heroin addicts, and these impairments critically depended on reactivation of the word list. CONCLUSIONS: This study extends earlier reports that a beta-adrenergic receptor antagonist affects the drug-related memory reconsolidation process. Our findings may have important implications for the understanding and treatment of persistent and abnormal drug-related memories in abstinent heroin addicts. PMID- 21531090 TI - Availability of nicotine replacement therapy in substance use disorder treatment: longitudinal patterns of adoption, sustainability, and discontinuation. AB - BACKGROUND: There is growing recognition regarding the clinical importance of integrating smoking cessation services, such as nicotine replacement therapy (NRT), within programs that treat substance use disorders (SUDs) since the majority of individuals receiving treatment also smoke. Previous research has not examined the organizational characteristics associated with NRT availability over time in SUD treatment programs. METHOD: Using longitudinal data collected from administrators of 868 SUD treatment programs over a four-year period, the availability of NRT in the forms of the nicotine patch or nicotine gum was measured. Associations between organizational covariates and NRT adoption were estimated using multinomial logistic regression. RESULTS: The rate of NRT availability significantly decreased over time from 38.0% of SUD programs at baseline to 33.8% at follow-up. The multinomial logistic regression model indicated programs that sustained adoption of NRT over time were more medically oriented, as measured by location in a hospital setting and access to physicians, and were less likely to offer outpatient services. Sustained and recent adopters of NRT were more likely to offer other smoking cessation interventions at follow- up than NRT discontinuers or NRT non-adopters. CONCLUSIONS: These findings suggest that patients' access to NRT varies across different types of treatment organizations. Future research should continue to measure the availability of NRT and other smoking cessation interventions in SUD treatment since these services may help patients to quit smoking and reduce the likelihood of SUD relapse. PMID- 21531092 TI - In vitro inhibition of Citrobacter freundii, a red-leg syndrome associated pathogen in raniculture, by indigenous Lactococcus lactis CRL 1584. AB - Red-leg syndrome (RLS) is one of the main infectious diseases that cause economic losses in Lithobates catesbeianus hatcheries, Citrobacter freundii being an etiological agent. Treatment or prevention with therapeutics or chemicals results in modifications of the indigenous microbiota, development of antibiotic resistance, presence of their residues in food and enhancement of production costs. Thus, probiotics could be used as an alternative therapy. Lactic acid bacteria are part of the indigenous microbiota of healthy frogs and can prevent pathogen colonization by different mechanisms, including the production of antagonistic substances. In this work, the evaluation and characterization of the inhibition of C. freundii CFb by Lactococcus lactis subsp. lactis CRL 1584, a potentially probiotic candidate, were carried out. This strain produced lactic acid, H(2)O(2) and bacteriocin in static and shaken conditions and inhibited pathogen growth in associative cultures, with an earlier inhibition under agitated conditions. The elimination of each of the antimicrobial metabolites partially abolished the inhibition of the pathogen, suggesting that the inhibitory effect could be attributed to a combined action of the three antagonistic molecules. Electron microphotographs revealed the damage caused by L. lactis CRL 1584 supernatants to C. freundii cells. The addition of pure lactic acid, H(2)O(2) and bacteriocin to the culture media showed that each metabolite caused different morphological modifications in C. freundii, in agreement with the effect on viable cell counts. The results support the possibility that L. lactis CRL 1584 might be considered as a probiotic to be used in the prevention of RLS in raniculture. PMID- 21531093 TI - Presence of ISS1-like insertion sequence in wild type Streptococcus uberis strains isolated from cases of bovine mastitis. AB - Streptococcus uberis is a major cause of environmental mastitis worldwide. In spite of significant economic losses caused by S. uberis in many well-managed dairy herds, virulence factors and mechanisms associated with the pathogenesis of S. uberis mastitis are not well known. The ability of S. uberis to attach to and internalize into mammary epithelial cells and subsequent intracellular survival enables it to avoid host defense mechanisms. Research to determine virulence factors responsible for these pathogenic strategies involved creating a random chromosomal mutant library of S. uberis strain UT888 using the thermosensitive plasmid pGh9:ISS1 mutagenesis system. During Southern blot analysis of the mutant library, an endogenous element similar to ISS1 insertion sequence of Lactococcus lactis was found. ISS1 is a transposable bacterial insertion sequence isolated originally from L. lactis and are small phenotypically cryptic sequences of DNA with a simple genetic organization and capable of inserting at multiple sites in a target molecule. They are flanked by inverted repeats; generally encode their own transposition functions. A total of 29 of 34 wild type strains of S. uberis evaluated were positive for ISS1 by Southern blot. Insertion of ISS1 might have a significant phenotypic and genotypic role in the S. uberis genome because of its ability to transpose within the genome. PMID- 21531094 TI - Very long-chain acyl CoA dehydrogenase deficiency which was accepted as infanticide. AB - Very-long-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (VLCADD) (OMIM #201475) is an autosomal recessive disorder of fatty acid oxidation. Major phenotypic expressions are hypoketotic hypoglycemia, hepatomegaly, cardiomyopathy, myopathy, rhabdomyolysis, elevated creatinine kinase, and lipid infiltration of liver and muscle. At the same time, it is a rare cause of Sudden Infant Death Syndrome (SIDS) or unexplained death in the neonatal period [1-4]. We report a patient with VLCADD whose parents were investigated for infanticide because her three previous siblings had suddenly died after normal deliveries. PMID- 21531095 TI - Maybe a new killer in illicit cocaine. AB - This is the study of the author that refers about a case of a 46 years old man found dead inside his house, the death was related to cocaine intake. The police found the corpse laying in his bed with a sheet of newspaper rolled up and a few plastic coverings containing trace of cocaine on the desk. Toxicological analysis was performed and drug levels measured by means of gas chromatography/mass spectrometry technology. Based on the autopsy findings and toxicological results the cause of death was related to an acute intoxication due to cocaine "overdose". In addition to the presence of cocaine and smaller alkaloids, in the sheet made of newspaper rolled up and eluted of the nasal mucosas has been highlighted the presence of 2,6-disopropylnaphtalene (2,6-DIPN), a fungicidal pesticide very health hazard for human. A very easy, simple and selective gas chromatography mass spectrometry method was employed for the detection of 2,6 DIPN in the cocaine powder. PMID- 21531096 TI - Another promising treatment option for neuroblastoma-associated opsoclonus myoclonus syndrome by oral high-dose dexamethasone pulse: lymphocyte markers as disease activity. AB - A one-year-old boy with neuroblastoma (NBoma)-associated opsoclonus-myoclonus syndrome (OMS) was treated by oral high-dose dexamethasone (DEX) pulses (20 mg/m(2)/day of DEX for three consecutive days) every 28 days for 6 months after resection of the tumor. All OMS symptoms improved after the first course of DEX pulse therapy and disappeared after the last course. No adverse effects were observed. Minor deterioration of his developmental quotient was noted 33 months after the onset of the disease. NBoma remission has been maintained since treatment. Before DEX pulse therapy, frequency of T lymphocyte, in particular CD4 positive cell decreased markedly resulted in low CD4/8 ratio in the peripheral blood (PB). The frequency of B lymphocyte increased, especially in cerebrospinal fluid. These aberrant values in PB were reversed by DEX pulse therapy and correlated well with the neurological symptoms. A prospective study that assesses the efficacy of this promising and inexpensive treatment for OMS is warranted. PMID- 21531097 TI - [Thoraco-abdominal aortitis in ankylosing spondylitis: a case report and review of literature]. AB - We report a case of aortitis in a patient with ankylosing spondylitis revealed by an unexplained persistent inflammation. CASE STUDY: The diagnosis of ankylosing spondylitis was retained in a 64-year-old woman suffering from inflammatory back and neck pain combined with buttock pain relieved by anti-inflammatory drugs (NSAIDs) since 2004 and more recent bilateral heel pain in the morning since 2006; sacroiliitis was grade 3 on the right and grade 2 on the left (modified New York criteria). The patient had remained asymptomatic from April 2006 to 2007 with NSAID as needed. Nevertheless, biological inflammation persisted: erythrocyte sedimentation rate 44 to 55 mm/h, activated protein C 34 to 90 mg/L. Complementary examinations are negative: bilateral temporal artery biopsy, endoscopy with duodenal biopsy looking for Tropheryma whipplei. The thoraco abdominal and pelvic CT scan revealed aortitis extending from the abdominal aorta to the iliac axis. Treatment with prednisone 0.5 mg/kg was started to decrease the inflammatory aortitis. DISCUSSION: The most "classical" cardiovascular damage observed in spondylitis is aortic insufficiency and conduction disturbances. The first cases of aortitis were reported in 1958. CONCLUSION: Inflammatory vascular disease should be evoked as a possible diagnosis in patients with ankylosing spondylitis the presenting an unexplained biological inflammation (ESR and CRP). PMID- 21531098 TI - [Empirical check of the quality of the plans of LQAS sampling in the surveillance of the endemic schistosomiasis in North-Cameroon]. PMID- 21531099 TI - Role of MRI in hip fractures, including stress fractures, occult fractures, avulsion fractures. AB - MR imaging plays a vital role in the diagnosis and management of hip fractures in all age groups, in a large spectrum of patient groups spanning the elderly and sporting population. It allows a confident exclusion of fracture, differentiation of bony from soft tissue injury and an early confident detection of fractures. There is a spectrum of MR findings which in part is dictated by the type and cause of the fracture which the radiologist needs to be familiar with. Judicious but prompt utilisation of MR in patients with suspected hip fractures has a positive therapeutic impact with healthcare cost benefits as well as social care benefits. PMID- 21531100 TI - Disrupted functional connectivity in social anxiety disorder: a resting-state fMRI study. AB - Dysfunction of the corticolimbic circuitry has been highlighted in social anxiety disorder (SAD) during social stimuli. However, few studies have investigated functional connectivity in SAD during the resting state, which may improve our understanding of SAD pathophysiology. The aim of this study was to investigate whether whole-brain functional connectivity might be aberrant in SAD patients, and if so, whether these changes are related to the measured clinical severity. Seventeen SAD patients and 19 healthy controls participated in resting-state functional magnetic resonance imaging. The brain was first divided into 90 paired brain regions and functional connectivity was then estimated by temporal correlation between each of these regions. Furthermore, connections that were significantly disrupted in SAD patients were correlated with clinical severity measured using the Liebowitz Social Anxiety Scale. Compared with healthy controls, SAD patients showed decreased positive connections within the frontal lobe and decreased negative connections between the frontal and occipital lobes. In particular, the weaker negative connections between the frontal lobe, which mainly involved the right median prefrontal cortex, and the occipital lobe had a significant positive correlation with the severity of SAD symptoms. The results support the hypothesis that some abnormalities of functional connectivity exist in SAD patients, which relate to the frontal cortex and occipital cortex. In addition, decreased functional connectivity between the frontal and occipital lobes and within the frontal lobe might be related to abnormal information processing and reflect disturbed neural organization resulting in defective social cognition, which could represent an early imaging biomarker for SAD. PMID- 21531101 TI - High-resolution MR spectroscopy via intermolecular double-quantum coherences in inhomogeneous B0 and B1 fields. AB - Inhomogeneity in static field B0 and/or RF field B1 is inevitable under some circumstances. In this work, a method based on intermolecular double-quantum coherences is employed for high-resolution 1D MR spectroscopy via 2D acquisition under such a condition. High-resolution information on chemical shifts, multiplet patterns, J coupling constants and relative peak areas can be retained in the resulting 1D projected spectra, as shown with results from a narrow-bore NMR spectrometer and a whole-body clinical scanner. PMID- 21531102 TI - Simple mobile single-sided NMR apparatus with a relatively homogeneous B0 distribution. AB - This work presents a simple design for a mobile single-sided nuclear magnetic resonance (NMR) apparatus with a relatively homogeneous static magnetic field (B(0)) distribution. In the proposed design, the B(0) magnetic field of the apparatus is synthesized using only two permanent magnet blocks, i.e., a cube (main) magnet and a small shim magnet placed above the main magnet. The magnetic flux of the shim magnet partially cancels out that of the main magnet, subsequently creating a smooth B(0) profile above the shim magnet where low resolution NMR experiments are performed. Compared with many previously published designs, this straightforward design simplifies the construction of the apparatus and simultaneously generates a B(0) field parallel to the apparatus surface, allowing the use of a simple loop-type radiofrequency (RF) coil. Additionally, an apparatus prototype is constructed according to the proposed design. Weighing only 1.8 kg, the constructed apparatus has a compact structure and can be held in the palm of a hand. The apparatus generates a B(0) strength of about 0.0746 T. Within a B(0) field deviation of 3 mT, the region with a relatively homogeneous B(0) distribution extends to about 11 mm above the shim magnet. The proposed apparatus can detect a clear Hahn echo or Carr-Purcell-Meiboom-Gill (CPMG) echoes of a pencil eraser block or a bottle of oil placed on the apparatus in 5 s with signal averaging using an RF transmitter power of only 19 W; the detection range of the apparatus exceeds 6 mm. The strength of the residual static magnetic field gradient of the apparatus is roughly estimated at 0.58 T/m. Applying different CPMG echo spacings in this residual static gradient leads to various transverse relaxation time (T(2)) contrasts for liquids with distinct viscosities such as water and oil. Two nondestructive inspection applications of the apparatus, including correlating the concentrations of magnetic nanoparticle solutions with their measured transverse relaxation rates (R(2)) and monitoring the outgassing from an opened bottle of oxygen-supersaturated water by measuring its longitudinal relaxation rate (R(1)), are also demonstrated. PMID- 21531103 TI - Accelerating image registration of MRI by GPU-based parallel computation. AB - Automatic image registration for MRI applications generally requires many iteration loops and is, therefore, a time-consuming task. This drawback prolongs data analysis and delays the workflow of clinical routines. Recent advances in the massively parallel computation of graphic processing units (GPUs) may be a solution to this problem. This study proposes a method to accelerate registration calculations, especially for the popular statistical parametric mapping (SPM) system. This study reimplemented the image registration of SPM system to achieve an approximately 14-fold increase in speed in registering single-modality intrasubject data sets. The proposed program is fully compatible with SPM, allowing the user to simply replace the original image registration library of SPM to gain the benefit of the computation power provided by commodity graphic processors. In conclusion, the GPU computation method is a practical way to accelerate automatic image registration. This technology promises a broader scope of application in the field of image registration. PMID- 21531104 TI - PDE-based spatial smoothing: a practical demonstration of impacts on MRI brain extraction, tissue segmentation and registration. AB - Spatial smoothing is typically used to denoise magnetic resonance imaging (MRI) data. Gaussian smoothing kernels, associated with heat equations or isotropic diffusion (ISD), are widely adopted for this purpose because of their easy implementation and efficient computation, but despite these advantages, Gaussian smoothing kernels blur the edges, curvature and texture of images. To overcome these issues, researchers have proposed anisotropic diffusion (ASD) and non-local means [i.e., diffusion (NLD)] kernels. However, these new filtering paradigms are rarely applied to MRI analyses. In the current study, using real degraded MRI data, we demonstrated the effect of denoising using ISD, ASD and NLD kernels. Furthermore, we evaluated their impact on three common preprocessing steps of MRI data analysis: brain extraction, segmentation and registration. Results suggest that NLD-based spatial smoothing is most effective at improving the quality of MRI data preprocessing and thus should become the new standard method of smoothing in MRI data processing. PMID- 21531105 TI - Fractional Brownian motion analysis does not provide evidence for neurophysiologic feedback mechanisms: a comment on "White matter hyperintensities and dynamics of postural control". PMID- 21531107 TI - Performance of single spin-echo and doubly refocused diffusion-weighted sequences in the presence of eddy current fields with multiple components. AB - Echo-planar diffusion-weighted images can display significant geometric distortions due to eddy current fields. Several preparation schemes have been proposed, which can null eddy currents with a single time constant. The aim of this work was to compare the performance of three such pulse sequences in the presence of multiple components and investigate whether affine registration is capable of correcting for the resulting distortions. A magnetic resonance imaging simulator was used to eliminate potential confounding factors. The doubly refocused sequences showed substantially reduced effects. Applying affine registration to the single spin-echo images leads to reduced residuals, but not to the level observed for the doubly refocused sequences. Modified versions of the standard single spin-echo and doubly refocused sequences performed better than their original counterparts. Affine registration is not sufficient to correct for strong eddy current effects, which should therefore be minimized at source. When the use of a doubly refocused sequence is not possible, a modified single spin-echo sequence should be considered. PMID- 21531106 TI - On the relationship between the apparent diffusion coefficient and extravascular extracellular volume fraction in human breast cancer. AB - MRI techniques have been developed that can noninvasively probe the apparent diffusion coefficient (ADC) of water via diffusion-weighted MRI (DW-MRI). These methods have found much application in cancer where it is often found that the ADC within tumors is inversely correlated with tumor cell density, so that an increase in ADC in response to therapy can be interpreted as an imaging biomarker of positive treatment response. Dynamic contrast enhanced MRI (DCE-MRI) methods have also been developed and can noninvasively report on the extravascular extracellular volume fraction of tissues (denoted by v(e)). By conventional reasoning, the ADC should therefore also be directly proportional to v(e). Here we report measurements of both ADC and v(e) obtained from breast cancer patients at both 1.5 and 3.0 T. The 1.5-T data were acquired as part of normal standard of care, while the 3.0-T data were obtained from a dedicated research protocol. We found no statistically significant correlation between ADC and v(e) for the 1.5- or 3.0-T patient sets on either a voxel-by-voxel or a region-of-interest (ROI) basis. These data, combined with similar results from other disease sites in the literature, may indicate that the conventional interpretation of either ADC, v(e) or their relationship is not sufficient to explain experimental findings. PMID- 21531108 TI - Automated registration of sequential breath-hold dynamic contrast-enhanced MR images: a comparison of three techniques. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is increasingly in use as an investigational biomarker of response in cancer clinical studies. Proper registration of images acquired at different time points is essential for deriving diagnostic information from quantitative pharmacokinetic analysis of these data. Motion artifacts in the presence of time-varying intensity due to contrast enhancement make this registration problem challenging. DCE-MRI of chest and abdominal lesions is typically performed during sequential breath-holds, which introduces misregistration due to inconsistent diaphragm positions and also places constraints on temporal resolution vis-a-vis free-breathing. In this work, we have employed a computer-generated DCE-MRI phantom to compare the performance of two published methods, Progressive Principal Component Registration and Pharmacokinetic Model-Driven Registration, with Sequential Elastic Registration (SER) to register adjacent time-sample images using a published general-purpose elastic registration algorithm. In all three methods, a 3D rigid-body registration scheme with a mutual information similarity measure was used as a preprocessing step. The DCE-MRI phantom images were mathematically deformed to simulate misregistration, which was corrected using the three schemes. All three schemes were comparably successful in registering large regions of interest (ROIs) such as muscle, liver, and spleen. SER was superior in retaining tumor volume and shape, and in registering smaller but important ROIs such as tumor core and tumor rim. The performance of SER on clinical DCE-MRI data sets is also presented. PMID- 21531109 TI - Neural specificity of acupuncture stimulation from support vector machine classification analysis. AB - Acupoint specificity, as a crucial issue in acupuncture neuroimaging studies, is still a controversial topic. Previous studies have generally adopted a block based general linear model (GLM) approach, which predicts the temporal changes in the blood oxygenation level-dependent signal conforming to the "on-off" specifications. However, this method might become impractical since the precise timing and duration of acupuncture actions cannot be specified a priori. In the current study, we applied a data-driven multivariate classification approach, namely, support vector machine (SVM), to explore the neural specificity of acupuncture at gall bladder 40 (GB40) using kidney 3 (KI3) as a control condition (belonging to different meridians but the same nerve segment). In addition, to verify whether the typical GLM approach is sensitive enough in exploring the neural response patterns evoked by acupuncture, we also employed the GLM method to the same data sets. The SVM analysis detected distinct neural response patterns between GB40 and KI3--positive predominantly for the GB40, while negative following the KI3. By contrast, group analysis from the GLM showed that acupuncture at these different acupoints can both evoke similar widespread signal decreases in multiple brain regions, and most of these regions were spatially overlapped, mainly distributing in the limbic and subcortical structures. Our findings may provide additional evidence to support the specificity of acupuncture, relevant to its clinical efficacy. Moreover, we also proved that GLM analysis is prone to be susceptible to errors and is not appropriate for detecting neural response patterns evoked by acupuncture stimulation. PMID- 21531111 TI - Prognostic factors of solitary large hepatocellular carcinoma: the importance of differentiation grade. AB - AIMS: Solitary large hepatocellular carcinoma (SL-HCC), a novel subtype with relative good prognosis, has recently been defined. However, the concept has not been validated. Besides, prognostic factors of SL-HCC remain unknown. The present study is designed to address the issues. MATERIALS AND METHODS: Clinicopathological variables and survival of consecutive 85 patients with SL-HCC after curative resection are compared with those of 48 patients with small HCC (SHCC). The prognosticators of SL-HCC are also evaluated. RESULTS: Disease-free survival of SL-HCC is similar with that of SHCC, whereas significant poorer overall survival is observed in SL-HCC than that in SHCC, accompanied by more frequent vascular invasion, later TNM stage and potentially higher Edmondson Steiner grade. Vascular invasion, Edmondson-Steiner grade, TNM stage and preoperative AFP level impact overall and/or disease-free survival of SL-HCC, but only Edmondson-Steiner grade is independent. Additionally, differences in both overall and disease-free survival between SL-HCC with Edmondson-Steiner grade I II and SHCC are all not significant. CONCLUSIONS: Factors predictive for prognosis of SL-HCC are all tumor-related. The involvement of differentiation grade might be helpful for further distinguishing a particularly good outcome in SL-HCC. PMID- 21531110 TI - Determination of steroids adulterated in liquid herbal medicines using QuEChERS sample preparation and high-performance liquid chromatography. AB - QuEChERS sample preparation was optimized using solvent extraction with acetonitrile and dispersive-solid phase extraction with primary and secondary amine sorbents, and validated for high-performance liquid chromatographic determination of nine steroids commonly used to adulterate herbal medicines: such as triamcinolone, prednisolone, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, beclomethasone, fludrocortsone acetate and cortisone acetate. Satisfactory extraction recoveries of 91-113% for all nine steroids were obtained, along with an acceptable precision in extraction recoveries shown by R.S.D. of <=4.6 and 3.2% for intraday and interday, respectively. The QuEChERS sample preparation developed here allows the reliable detection of adulterated steroids with the limits of detection in the range of 0.06-0.17ppm. Adulterated steroids in three out of six real commercial liquid herbal medicines were found, such as 1.6 and 8.8ppm dexamethasone and 0.43ppm prednisolone. PMID- 21531112 TI - [1/1 plasma to red blood cell ratio: an evidence-based practice?]. AB - Coagulopathy during massive haemorrhage increases morbidity and mortality rates. The modalities of treatment by transfusion of fresh frozen plasma (FFP) are a matter of debate. According to most clinical practice guidelines, FFP administration is driven by coagulation tests but, in cases of massive transfusion, patient management may be delayed whilst awaiting results and thawing FFP. Several retrospective cohort studies of military or civilian multiple trauma casualties requiring massive transfusion (>10 red blood cells (RBC) within 24h) have suggested that early use of FFP and high FFP:RBC ratios (approaching 1) might improve survival and lessen morbidity. However, the methodology of these studies is suboptimal. They are subject, in particular, to survival bias. Massive FFP transfusions can also lead to an enhanced incidence of transfusion-related acute lung injury (TRALI), acute respiratory distress syndrome (ARDS), and multi-organ failure. At the present time, it is clear that FFP transfusion should be initiated early with a high FFP:RBC ratio in massive bleeding associated with haemostatic abnormalities such as multiple trauma. This does not imply that such a recommendation can be extended to the correction of high blood loss in other situations such as scheduled surgery. Actually, very few patients are likely to derive benefit from a 1/1 FFP:RBC transfusion strategy. They are chiefly multiple trauma victims with haemorrhagic shock and cases of ruptured abdominal aortic aneurysm. In other patients, in order to minimize risks and costs, a more parsimonious FFP use policy remains the best option until evidence for the benefit of 1/1 FFP:RBC is demonstrated. PMID- 21531113 TI - [Impact of anaesthesia management on post-surgical ventilation in post anaesthesia care unit]. AB - INTRODUCTION: Control of residual muscle paralysis and hypothermia reduce postoperative complications rate. Short context sensitive half life anaesthetic agents allow a better adjustment of anaesthesia depth according to surgical requirement and a safe early extubation. Using a large clinical database, impact of these three strategies was assessed on clinical criteria such as use of neostigmine in postanaesthesia care unit (PACU), temperature, sedation score at the arrival into PACU and mechanical ventilation weaning. METHODS: This is a retrospective study on two separated periods. Since 2001, clinical events are entered into the database during and after anaesthesia in the same file. Agreement of anaesthesia staff to these strategies was assessed by the proportion of patients receiving modern anaesthetic agents (desflurane, sevoflurane and remifentanil) and the use of warming devices. Clinical impact was assessed by the number of patients receiving neostigmine in PACU, sedation score and temperature at the arrival in PACU and number of patients with mechanical ventilation in PACU. RESULTS: Between the two periods (12,033 and 11,805 patients, respectively), use of sevoflurane, desflurane and remifentanil markedly increased, as well as the use of warming devices. Number of patients with neuromuscular reversal in PACU decreased from 73 to 11 and sedation score improved dramatically. Incidence of postoperative ventilation in PACU decreased from 1.1% (n=132) to 0.2% (n=30). Incidence of postoperative hypothermia was not changed during the two periods but incidence of hypothermia in the mechanically ventilated patient increased from 34.1 to 46.6%. Length of stay in PACU decreased from 122 to 114 minutes (p<0.05). DISCUSSION: Implementation of new intraoperative protocols induced major effects on postoperative clinical parameters and especially postoperative mechanical ventilation. Failure of our hypothermia prevention associated with a fast return of consciousness lead to wean from mechanical ventilation hypothermic patients. Risks of this strategy were not estimated. PMID- 21531114 TI - A comparison of wound closure techniques for total knee arthroplasty. AB - Four wound closure techniques for total knee arthroplasty were compared in a prospective, randomized, controlled, institutional review board-approved study with 75 subjects. The study compared tissue adhesives, stapling, and suturing with respect to procedure time and cost, together with functional and clinical outcome. Total knee arthroplasty closure time (capsule to cutaneous) favored staples at 26 s/cm, followed by adhesives (45 and 37 s/cm for 2-octyl and n-butyl 2, respectively) and, finally, subcuticular suturing at 54 s/cm (P < .0007). Reduced procedure time translated into intraoperative cost reduction where closure cost per centimeter was $70, $62, $57, and $75 for 2-octyl, n-butyl-2, staples, and sutures, respectively. No significant differences in infection, dehiscence, cosmesis, general health (SF-12v2 (QualityMetric Inc., Lincoln, RI)), and functional and clinical assessments (range of motion, Knee Society knee score, and pain) were observed. PMID- 21531115 TI - Self reported attentional control with the Attentional Control Scale: factor structure and relationship with symptoms of anxiety and depression. AB - The Attentional Control Scale (ACS) is a self-report questionnaire that has been developed to measure individual differences in attentional control. Despite its fairly widespread use, little is known about the psychometric properties of the scale in adult samples. In the present study, factor structure of the ACS and its relationship with symptoms of anxiety and depression was investigated in a total sample of 728 Icelandic university students. Exploratory factor analysis in sample 1 (n=361), yielded two factors, labeled focusing and shifting. Confirmatory factor analysis in sample 2 (n=367) showed a reasonable fit of this two factor model. The two factors correlated strongly (0.73). The two subscales showed different predictive validity in a set of hierarchical regression analyses where the focusing subscale made a significant prediction of anxiety scores when depression scores were controlled for, and the shifting subscale significant prediction of depression scores when anxiety scores were controlled for. These findings are discussed in relation to previous studies on attentional and executive control in anxiety and depression. PMID- 21531116 TI - Specificity and generalization of attentional bias in sexual trauma victims suffering from posttraumatic stress disorder. AB - The present study investigated specificity of attentional biases for trauma related stimuli using an Emotional Stroop Task. Participants were 14 women suffering from posttraumatic stress disorder (PTSD) who had experienced a sexual trauma and 24 healthy non-traumatized women. They were asked to name print colors of 4 different word types: threatening sexual violence words and non-threatening sexual words, threatening accident trauma words, and positive words. Compared to control participants, PTSD patients displayed increased interference by threatening trauma-related, but not by accident trauma and positive words. Interference by non-threatening sexual words occurred as well, but only in those patients who suffered from more severe PTSD arousal symptoms. These findings suggest graded generalization of the attentional bias across stimuli of varying emotional valence, but specificity regarding the trauma topic. Results are discussed in light of current cognitive models of PTSD, and clinical implications are suggested. PMID- 21531117 TI - Basilic vein transposition fistulas versus prosthetic bridge grafts in patients with end-stage renal failure. AB - BACKGROUND: Basilic vein transposition fistulas (BVTFs) and prosthetic bridge grafts (PBGs) provide good vascular access for hemodialysis. To evaluate the patency and complication rates after arteriovenous fistula formation, a concurrent series of patients was reviewed. METHODS: Between September 2003 and September 2009, 147 hemodialysis access procedures were performed in 147 consecutive patients at Van Research and Training Hospital and Yuzuncu Yil University Hospital, Van, Turkey. All access procedures were planned on the basis of preoperative duplex scans of arm and forearm veins. Functional patency was defined as the ability to cannulate hemodialysis patients successfully. Primary and secondary cumulative functional patency rates of BVTFs and PBGs were determined with life-table analysis and differences were analyzed with retrospective study. Differences in revision rates, including thrombolysis thrombectomies and operative revisions, were analyzed with the Fisher exact t test. RESULTS: Mean follow-up was 15 months (range, 3-24 months). Risk factors were similar between the two groups. BVTFs had better patency at 15 months. The dialysis access complications were higher in the PBG group versus BVTF group, and the PBG group had a higher infection rate than the BVTF group. CONCLUSION: The primary and secondary patency rates were superior in the BVTF group. Our data strongly support the contention that as long as the patient is a candidate for an upper arm BVTF based on anatomical criteria, BVTF always be considered before a PBG. PMID- 21531118 TI - Effect of translucency on transparency and symbol learning for children with and without cerebral palsy. AB - Based on the concept of iconicity, the iconicity hypothesis was emphasized for decades. The aims of this study were to explore the effect of translucency on transparency and symbol learning for children with and without cerebral palsy. Twenty children with cerebral palsy and forty typical peers participated in the study. Ten symbols with high translucency and ten with low translucency were used as experimental material. The results of transparency testing demonstrated the positive relationship between translucency and transparency. The effect of translucency on symbol learning was supported partially, all children with and without CP could learn the low translucent symbols only after two teaching sessions, or three sessions at most. The authors also provided some suggestions for further study based the results of this study. PMID- 21531120 TI - Altered lipid profiles in the stratum corneum of Sjogren-Larsson syndrome. PMID- 21531119 TI - Child's positive and negative impacts on parents--a person-oriented approach to understanding temperament in preschool children with intellectual disabilities. AB - BACKGROUND: Despite previous efforts to understand temperament in children with intellectual disability (ID), and how child temperament may affect parents, the approach has so far been unidimensional. Child temperament has been considered in relation to diagnosis, with the inherent risk of overlooking individual variation of children's temperament profiles within diagnostic groups. The aim of the present study was to identify temperamental profiles of children with ID, and investigate how these may affect parents in terms of positive and negative impacts. METHOD: Parent-rated temperament in children with ID was explored through a person-oriented approach (cluster analysis). Children with ID (N=49) and typically developing (TD) children (N=82) aged between 4 and 6 years were clustered separately. RESULTS: Variation in temperament profiles was more prominent among children with ID than in TD children. Out of the three clusters found in the ID group, the disruptive, and passive/withdrawn clusters were distinctly different from clusters found in the TD group in terms of temperament, while the cluster active and outgoing was similar in shape and level of temperament ratings of TD children. Children within the disruptive cluster were described to have more negative and less positive impacts on mothers compared to children within the other clusters in the ID group. CONCLUSIONS: Mothers who describe their children as having disruptive temperament may be at particular risk for experiencing higher parenting stress as they report that the child has higher negative and lower positive impacts than other parents describe. The absence of a relationship between child temperament profile and positive or negative impact on fathers may indicate that fathers are less affected by child temperament. However, this relationship needs to be further explored. PMID- 21531121 TI - Curvature effect on nanometer-scale surface properties of phospholipid layers. AB - Phospholipid bilayers were formed through liposome fusion on surfaces with different curvatures that were defined with silica spheres deposited on silicon water. Prior to the fusion, the surfaces became hydrophobic with octadecyltrimethoxysilane solution. Using atomic force microscope, surface forces were measured on dipalmitoylphosphatidylcholine (DPPC) layers and dioleoylphosphatidylcholine (DOPC) layers upon the curvature at 25 degrees C. The short-range repulsions were higher at 20 and 100 nm curvatures than other curvatures for the DPPC layer, while they were lower for the DOPC layer. Since it was known that the forces are related to its low mechanical stability of the lipid layer, this opposite behavior was analyzed in terms of stability upon the curvature, which appears to be eventually determined by the correlation between the lipid molecule geometry and the surface curvature. PMID- 21531123 TI - The blossoming of plant archaeogenetics. AB - Recent years have seen a broadening range of studies undertaken in the field of plant archaeogenetics as the field has entered a new stage of maturity. There has been a movement towards a more functional understanding of plant evolution that has been facilitated by sequencing technologies and increasingly powerful genomic annotation. Studies have progressed to consideration of genes of pertinent function, metagenomics and investigation of the genetic basis of domestication traits coupled with human agricultural selection. Recent applications of high throughput sequencing have facilitated archaeogenomic investigations and allowed increasingly fragmented DNA to be retrieved and characterised. While these developments are leading to the selective resequencing of targeted genomic regions in archaeobotanical samples, they have also opened up new avenues of opportunity in terms of the accessibility of biomolecules. Material once thought to be void of useful quantities of ancient DNA is now being accessed in the light of diagenetic information thrown up by HTS. The amount of archaeobotanical material that can be utilised and the work that is possible with that material are both increasing making it likely that a fertile period of plant archaeogenetics is underway. PMID- 21531122 TI - Dosimetry prior to I-131-therapy of benign thyroid disease. AB - The activity to be administered in I-131 therapy of benign thyroid disease is determined by the radiation absorbed dose necessary to cure the disease, the target mass, and the residence time of the I-131 in the target volume. Data from 73 patients with complete sets of uptake measurements 2, 6, 24, 48, and 96 (n=53) or 120 (n=20) hours after oral administration of 1 MBq I-131 were used to deduce residence times from subsets of 3, 2, or only 1 measurement for each individual. The values were compared to those obtained with the reference method, i.e. a fit of an uptake function based on a 2-compartment model to all 5 measurements, to quantify the errors introduced by the less demanding assessments. Deviations are less than 10% if the 2- compartment uptake function is fitted to only 3 values measured after 6, 24, and 96-120h. Use of 2, 24, and 96-120h data results in errors >20% in individual patients. The effective half-lives as determined from 2 measurements after 24 and 96-120h correlate well with those deduced from the reference method with larger deviations in individuals with slow iodine kinetics and late maximal uptake. Residence times determined from the 24h uptake, assuming linear increase during the first day, and the effective half-life limited to maximum 8days underestimate the actual values systematically in patients with long and short half-lives. These errors can be eliminated by a modification of the calculation method resulting in deviations less than 14% in all but one individual for this procedure. The accuracy of methods based on only one retention value increases with the time of measurement after the administration of I-131. While systematic errors up to a factor of two occur if the 24h uptake is used for the estimate, deviations are less than 18% for measurements after 120h. The results suggest that only one late uptake assessment warrants residence time estimates with an acceptable error. Given the high inherent uncertainties in the complete dosimetry procedure, additional measurements must be considered only if a high precision of the absorbed dose assessment is required e.g. for clinical trials. PMID- 21531124 TI - Bronchodilator responsiveness and onset of effect with budesonide/formoterol pMDI in COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are thought to have limited bronchodilator response, determined by changes in forced expiratory volume in 1s (FEV(1)). In this study, we assessed bronchodilator response in patients with COPD using not only FEV(1) but also changes in lung volume expressed as forced vital capacity (FVC) and inspiratory capacity (IC). We also evaluated the speed of onset of bronchodilation. METHODS: Data were from 2 randomized, double-blind, placebo-controlled studies (6-months [NCT00206154]; 12 months [NCT00206167]) in patients with moderate to very severe COPD. TREATMENTS: twice daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9MUg, budesonide/formoterol pMDI 160/9MUg, formoterol dry powder inhaler (DPI) 9MUg, placebo. RESULTS: The percentage of patients with FEV(1) improvement (>=12% and >=200mL; American Thoracic Society [ATS] criterion) was 34-39% post albuterol (screening). On day of randomization (DOR), a larger proportion receiving formoterol-containing treatment exhibited reversibility within 60min: FEV(1) (57-59%). Similar results were seen for IC (50-61%) and FVC (57-67%) using the same improvement criteria. The time to >=15% FEV(1) improvement on DOR was 5.0, 4.8, and 7.3min for budesonide/formoterol 320/9, budesonide/formoterol 160/9, and formoterol, respectively. Time to >=15% FEV(1) improvement was better maintained with budesonide/formoterol than formoterol at treatment end (6 and 12 months). CONCLUSIONS: Most patients with moderate to very severe COPD exhibit ATS defined bronchodilator reversibility based on flow and lung volume measures after budesonide/formoterol pMDI or formoterol treatment. Budesonide/formoterol pMDI also has a rapid (within 5min) onset of bronchodilation that is maintained over time compared with formoterol alone. PMID- 21531125 TI - Development of a lab-on-a-chip device for diagnosis of plant pathogens. AB - A lab-on-a-chip system for rapid nucleic acid-based analysis was developed that can be applied for diagnosis of selected Phytophthora species as a first example for use in plant pathology. All necessary polymerase chain reaction process (PCR) and hybridization steps can be performed consecutively within a single chip consisting of two components, an inflexible and a flexible one, with integrated microchannels and microchambers. Data from the microarray is collected from a simple electrical measurement that is based on elementary silver deposition by enzymatical catalyzation. Temperatures in the PCR and in the hybridization zone are managed by two independent Peltier elements. The chip will be integrated in a compact portable system with a pump and power supply for use on site. The specificity of the lab-on-a-chip system could be demonstrated for the tested five Phytophthora species. The two Pythium species gave signals below the threshold. The results of the electrical detection of the microarray correspond to the values obtained with the control method (optical grey scale analysis). PMID- 21531126 TI - Recent progress in cartilage tissue engineering. AB - Despite over two decades of research on cartilage tissue engineering, very few products have moved from bench to bedside and effective therapy remains lacking. This review discusses recent progress in developing novel strategies for engineering cartilage tissues with long-term functionality. Specifically we focus on the following aspects including identifying promising cell sources, designing 3D scaffolds with dynamic and spatially patterned cues to guide desired cellular processes, mimicking zonal organization, integrating with host tissue, and monitoring cell fate and tissue regeneration in situ. PMID- 21531127 TI - Signaling cue presentation and cell delivery to promote nerve regeneration. AB - Limitations in current nerve regeneration techniques have stimulated the development of various approaches to mimic the extrinsic cues available in the natural nerve regeneration environment. Biomaterials approaches modulate the microenvironment of a regenerating nerve through tailored presentation of signaling molecules, creating physical and biochemical guidance cues to direct axonal regrowth across nerve lesion sites. Cell-based approaches center on increasing the neurotrophic support, adhesion guidance and myelination capacity of Schwann cells and other alternative cell types to enhance nerve regrowth and functional recovery. Recent advances in presenting directional guidance cues in nerve guidance conduits and improving the regenerative outcomes of cell delivery provide inspirations to engineering the next generation of nerve repair solutions. PMID- 21531128 TI - Place of death and hospital care for children who died of cancer in England, 1999 2006. AB - AIM: To describe patterns of hospital care and to evaluate factors influencing place of death for children who died after a diagnosis of cancer in England during 1999-2006. MATERIALS AND METHODS: Registrations of children on the National Registry of Childhood Tumours (NRCT) who were diagnosed with cancer and died during 1999-2006 in England were linked to the Hospital Episode Statistics (HES) and to death certificates. Multivariable logistic modelling was used to assess factors that influence dying at home or in hospital. RESULTS: 1864 (96%) of children with cancer registrations were linked to HES records. The validation of hospital as a place of death and ethnicity between data sources was good, although anomalies within HES data exist. Similar proportions of children are dying at home (45%) and in hospital (47%), and the percentage dying in a hospice or care home increased from 2% to 10%. Of the children who died in hospital, 74% were admitted as emergencies or as a transfer from another hospital. Greater proportions of children were diagnosed with a leukaemia or lymphoma, those dying within six months of diagnosis, Asian and Black children, those from a deprived background and those not treated in a CCLG centre died in a hospital. CONCLUSIONS: Patterns of hospital care varied considerably by type of cancer, death within six months of diagnosis, ethnicity and deprivation. Further research is required to elucidate explanations for these patterns and to evaluate methods to increase the proportion of children dying at home who wish to do so. PMID- 21531129 TI - Prognostic value of the multidrug resistance transporter ABCG2 gene polymorphisms in Chinese patients with de novo acute leukaemia. AB - BACKGROUND: Functional polymorphisms of the ABCG2 gene may contribute to individual variability in drug response and the prognosis of patients. METHODS: In the present study, the genetic polymorphisms and expression of ABCG2 were analysed in blasts cells obtained from 184 Chinese patients with de novo acute leukaemia to investigate their possible association with clinical outcomes. RESULTS: A novel synonymous ABCG2-single nucleotide polymorphism (SNP) at exon 16 (13561218 C/T) and five known SNPs at exon 2 (13608835 G/A), exon 5 (13600044 C/A), intron 10 (13576005 C/T), intron 13 (13564503 C/T) and intron 14 (13563578 A/G) were identified with occurrence rates of 1.1%, 64.1%, 30.4%, 21.2%, 39.7% and 28.8%, respectively. We found that patients with the ABCG2 34GG genotype displayed longer disease free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001) than those with the 34GA/AA genotypes. Furthermore, the DFS and OS were significantly diminished in bone marrow transplantation (BMT) patients with the 34GA/AA genotypes relative to those with the 34GG genotype. CONCLUSIONS: These results suggest that these highly prevalent ABCG2 34GA/AA genotypes are associated with poor prognosis of Chinese patients with acute leukaemia and BMT patients. PMID- 21531130 TI - Differential gene expression signatures between colorectal cancers with and without KRAS mutations: crosstalk between the KRAS pathway and other signalling pathways. AB - PURPOSE: KRAS mutation is an important predictive marker in determining resistance to anti-Epidermal Growth Factor Receptor (EGFR) antibody therapies. In order to clarify whether not only KRAS related signalling pathways but also other signalling pathways are altered in patients with colorectal cancers (CRCs) with KRAS mutations, we examined the differences in the gene expression signatures between CRCs with and without KRAS mutation. PATIENTS AND METHODS: One-hundred and thirteen patients who underwent a surgical resection of a primary CRC were examined. KRAS mutational status was determined using the Peptide Nucleic Acid (PNA)-clamp real-time polymerase chain reaction (PCR) TaqMan assay. Gene expression profiles were compared between CRCs with and without KRAS mutation using the Human Genome GeneChip array U133. RESULTS: Among 113 CRCs, KRAS mutations were present in 35 tumours (31%). We identified 30 genes (probes) that were differentially expressed between CRCs with and without KRAS mutation (False Discovery Rate (FDR), p<0.01), by which we were able to predict the KRAS status with an accuracy of 90.3%. Thirty discriminating genes included TC21, paired-like homeodomain 1 (PITX1), Sprouty-2, dickkopf homologue 4 (DKK-4), SET and MYND domain containing 3 (SMYD3), mitogen-activated protein kinase kinase kinase 14 (MAP3K14) and c-mer Proto-oncogene tyrosine kinase (MerTK). These genes were related to not only KRAS related signalling pathway but also to other signalling pathways, such as the Wnt-signalling pathway, the NF-kappa B activation pathway and the TGF-beta signalling pathway. CONCLUSIONS: KRAS mutant CRCs exhibited a distinct gene expression signature different from wild-type KRAS CRCs. Using human CRC samples, we were able to show that there is crosstalk between the KRAS mediated pathway and other signalling pathways. These results are necessary to be taken into account in establishing chemotherapeutic strategies for patients with anti-EGFR-refractory KRAS mutant CRCs. PMID- 21531131 TI - Amine functional monodisperse microbeads via precipitation polymerization of N vinyl formamide: immobilized laccase for benzidine based dyes degradation. AB - Densely cross-linked poly(vinylamine) microbeads (~ 2 MUm) were prepared by precipitation copolymerization of N-vinyl formamide and ethylene glycoldimethacrylate in acetonitrile. The formamido groups of the microbeads were hydrolyzed into amino groups. Then, amino-functionalized microbeads were used for covalent immobilization of laccase via glutaraldehyde coupling. The average amount of immobilized enzyme was 18.7 mg/g microbeads. Kinetic parameters, V(max) and K(m) values were determined as 20.7 U/mg protein and 2.76 * 10(-2)mmol/L for free enzyme and 15.8 U/mg protein and 4.65 mmol/L for the immobilized laccase, respectively. The immobilized laccase was operated in a batch reactor for the degradation of two different benzidine based dyes (i.e., Direct Blue 1 and Direct Red 128). The laccase immobilized on the microbeads was very effective for removal of these dyes which interfere with the hormonal system. PMID- 21531132 TI - Modeling and optimization of fermentative hydrogen production. AB - Biohydrogen is a sustainable energy resource due to its potentially higher efficiency of conversion to usable power, non-polluting nature and high energy density. The purpose of modeling and optimization is to improve, analyze and predict biohydrogen production. Biohydrogen production depends on a number of variables, including pH, temperature, substrate concentration and nutrient availability, among others. Mathematical modeling of several distinct processes such as kinetics of microbial growth and products formation, steady state behavior of organic substrate along with its utilization and inhibition have been presented. Present paper summarizes the experimental design methods used to investigate effects of various factors on fermentative hydrogen production, including one-factor-at-a-time design, full factorial and fractional factorial designs. Each design method is briefly outlined, followed by the introduction of its analysis. In addition, the applications of artificial neural network, genetic algorithm, principal component analysis and optimization process using desirability function have also been highlighted. PMID- 21531133 TI - Influence of physico-chemical changes on enzymatic digestibility of ionic liquid and AFEX pretreated corn stover. AB - Ionic liquid (IL) and ammonia fiber expansion (AFEX) pretreatments were studied to develop the first direct side-by-side comparative assessment on their respective impacts on biomass structure, composition, process mass balance, and enzymatic saccharification efficiency. AFEX pretreatment completely preserves plant carbohydrates, whereas IL pretreatment extracts 76% of hemicellulose. In contrast to AFEX, the native crystal structure of the recovered corn stover from IL pretreatment was significantly disrupted. For both techniques, more than 70% of the theoretical sugar yield was attained after 48 h of hydrolysis using commercial enzyme cocktails. IL pretreatment requires less enzyme loading and a shorter hydrolysis time to reach 90% yields. Hemicellulase addition led to significant improvements in the yields of glucose and xylose for AFEX pretreated corn stover, but not for IL pretreated stover. These results provide new insights into the mechanisms of IL and AFEX pretreatment, as well as the advantages and disadvantages of each. PMID- 21531134 TI - Multi-objective optimization of glycopeptide antibiotic production in batch and fed batch processes. AB - Fermentation optimization involves potentially conflicting multiple objectives such as product concentration and production media cost. Simultaneous optimization of these objectives would result in a multiobjective optimization problem, which is characterized by a set of multiple solutions, knows as pareto optimal solutions. These solutions gives flexibility in evaluating the trade-offs and selecting the most suitable operating policy. Here, epsilon-constraint approach was used to generate the pareto solutions for two objectives: product concentration and product per unit cost of media, for batch and fed batch operations using process model for Amycolatopsis balhimycina, a glycopeptide antibiotic producer. This resulted in a set of several pareto optimal solutions with the two objectives ranging from (0.75 g l(-1), 3.97 g $(-1)) to (0.44 g l( 1), 5.19 g $(-1)) for batch and from (1.5 g l(-1), 5.46 g $(-1)) to (1.1 g l(-1), 6.34 g $(-1)) for fed batch operations. One pareto solution each for batch and for fed batch mode was experimentally validated. PMID- 21531135 TI - Discovery of novel HCV polymerase inhibitors using pharmacophore-based virtual screening. AB - We report the use of pharmacophore-based virtual screening as an efficient tool for the discovery of novel HCV polymerase inhibitors. A three-dimensional pharmacophore model for the HCV-796 binding site, NNI site IV inhibitor, to the enzyme was built by means of the structure-based focusing module in Cerius2 program. Using these models as a query for virtual screening, we produced a successful example of using pharmacophore-based virtual screening to identify novel compounds with HCV replicon assay through inhibition of HCV polymerization. Among the hit compounds, compounds 1 and 2 showed 56% and 48% inhibition of NS5B polymerization activity at 20 MUM, respectively. In addition, compound 1 also exhibited replicon activity with EC(50) value of 2.16 MUM. Following up the initial hit, we obtained derivatives of compound 1 and evaluated polymerization inhibition activity and HCV replicon assay. These results provide information necessary for the development of more potent NS5B inhibitors. PMID- 21531136 TI - Naphthol derivatives as TRPV1 inhibitors for the treatment of urinary incontinence. AB - We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystometry models of urinary incontinence after intravenous administration. PMID- 21531137 TI - Efficacy switching SAR of mGluR5 allosteric modulators: highly potent positive and negative modulators from one chemotype. AB - A series of metabotropic glutamate 5 receptor (mGluR5) allosteric ligands with positive, negative or no modulatory efficacy is described. The ability of this series to yield both mGluR5 PAMs and NAMs with single-digit nanomolar potency is unusual, and the underlying SAR is detailed. PMID- 21531138 TI - Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot Marie-Tooth type 2. AB - Mutations of the mitofusin 2 (MFN2) gene have been reported to be the most common cause of the axonal form of Charcot-Marie-Tooth disease (CMT). The aim of this study was to describe a de novo MFN2 p.R104W mutation and characterize the associated phenotype. We screened the entire coding region of MFN2 gene and characterized its clinical phenotype, nerve conduction studies and sural nerve biopsy. Neuropsychological tests and brain MRI were also performed. A de novo mutation was found in exon 4 (c.310C>T; p.R104W). In addition to a severe and early onset axonal neuropathy, the patient presented learning problems, obesity, glucose intolerance, leukoencephalopathy, brain atrophy and evidence of myelin involvement and mitochondrial structural changes on sural nerve biopsy. These results suggest that MFN2 p.R104W mutation is as a hot-spot for MFN2 gene associated to a large and complex range of phenotypes. PMID- 21531139 TI - Normative spatiotemporal gait parameters in older adults. AB - While factor analyses have characterized pace, rhythm and variability as factors that explain variance in gait performance in older adults, comprehensive analyses incorporating many gait parameters have not been undertaken and normative data for many of those parameters are lacking. The purposes of this study were to conduct a factor analysis on nearly two dozen spatiotemporal gait parameters and to contribute to the normative database of gait parameters from healthy, able bodied men and women over the age of 70. Data were extracted from 294 participants enrolled in the Mayo Clinic Study of Aging. Spatiotemporal gait data were obtained as participants completed two walks across a 5.6-m electronic walkway (GAITRite((r))). Five primary domains of spatiotemporal gait performance were identified: a "rhythm" domain was characterized by cadence and temporal parameters such as stride time; a "phase" domain was characterized by temporophasic parameters that constitute distinct divisions of the gait cycle; a "variability" domain encompassed gait cycle and step variability parameters; a "pace" domain was characterized by parameters that included gait speed, step length and stride length; and a "base of support" domain was characterized by step width and step width variability. Several domains differed between men and women and differed across age groups. Reference values of 23 gait parameters are presented which researchers or clinicians can use for assessing and interpreting gait dysfunction in aging persons. PMID- 21531140 TI - Revision of medial Oxford unicompartmental knee replacement to a total knee replacement: similar to a primary? AB - Unicompartmental knee replacement (UKR) is an option for the treatment of isolated medial compartment osteoarthritis. A commonly perceived potential advantage is that revision of a UKR is straightforward. The purpose of this study was to determine the early outcomes and the level of complexity of revisions of Oxford UKRs performed at our hospital. A retrospective review of a prospective database of all phase III Oxford UKRs was undertaken. This identified 89 Oxford UKRs which were revised at our institution between 2002 and 2008. The median time from the primary procedure to revision was 19 months (interquartile range 2-73 months). Nine were revised to another UKR. Eighty were revised to a total knee replacement (TKR). Fifty-three were revised with primary TKR components. Twenty seven were revised using stems and/or augments. The median overall tibial component thickness (including augments) was 15 mm. Forty-five knees had an overall tibial component thickness greater than 15 mm. A primary Oxford UKR bearing thickness of greater than 6mm was associated with an increased likelihood of requiring revision components. On the basis of this review, tibial bone defects were commonly encountered when revising UKRs. Reconstruction with either an augment and a stem, or thick polyethylene component was often required. We recommend that the potential complexity of revision for UKR failure should be borne in mind when considering a primary Oxford UKR. PMID- 21531141 TI - Design, synthesis and pharmacological evaluation of spirocyclic sigma(1) receptor ligands with exocyclic amino moiety (increased distance 1). AB - Various pharmacophore models for potent sigma(1) ligands specify a basic amino group flanked by two different hydrophobic regions in defined distances to the basic amine (distance 1 and distance 2, respectively). According to these models distance 1 of the potent spirocyclic sigma(1) ligand 1 is too short. In order to find a new class of more potent sigma(1) ligands and to verify the distance hypothesis of the pharmacophore models spirocyclic compounds 2 with an exocyclic amino group were designed and synthesized. The secondary amines 8 and 9 with N benzyl residues are >100-fold less potent than the spirocyclic piperidine 1. However, the tertiary methylamines trans-11 and cis-11 represent potent sigma(1) ligands with K(i)-values of 43 and 24 nM, respectively. Whereas one large benzyl moiety is required for high sigma(1) receptor binding, a second large N substituent is not tolerated by the sigma(1) receptor protein. As a rule, cis configured diastereomers with a longer distance 1 (predominantly 7.16-7.23 A) show higher sigma(1) affinities than their trans-configured counterparts (distance 1 is predominantly 5.88-6.26 A). PMID- 21531142 TI - Microscopic evaluation of proliferative disorders in the gerbil female prostate: evidence of aging and the influence of multiple pregnancies. AB - The gerbil female prostate is located paraurethrally and has all the histological components of the male prostate, like secretor epithelium and fibromuscular stroma. This gland, like the prostate in males, is targeted by testosterone action, which promotes morphofunctional development. Furthermore, estrogens are required to maintain the male and female prostate and this gland presents both estrogen receptors (ER-alpha and ER-beta). In the present work the structural and morphometric-stereological and serological aspects, as well as the quantification of the incidence, multiplicity and percentage of acini affected by different lesions were analyzed. Animals were divided into four groups: five adult nuliparous (AN) gerbils; five adult multiparous (AM) gerbils; five senescent nulliparous (SN) gerbils; five senescent multiparous (SM) gerbils, and were weighed and sacrificed by CO(2) inhalation. The ventral prostate was dissected out, weighed and fixed to perform histological and morphometric-stereological analysis and quantification of prostate disorders. A high rate of lesions, mainly dysplasia, was identified in tissue from senescent multiparous and adult multiparous animals. Prostatitis was found mainly in SN animals, while dysplasia, hyperplasia, neoplasia, PIA and adenocarcinoma were common in SM ones. Although the proliferative lesion incidence was high in AN group, it was highest in the SM group. The hormonal events which occur due to the estrous cycle in female gerbils (after and before each pregnancy) may be responsible for the high number of lesions observed in our study and all the data presented herein lead us to assume that pregnancy promotes augmentations in both the incidence and the multiplicity of proliferative disorders in the gerbil female prostate since progesterone levels remain high during pregnancy. PMID- 21531143 TI - Synthesis of conjugates of polyhedral boron compounds with tumor-seeking molecules for neutron capture therapy. AB - Recent achievements in design and synthesis of boronated acids, amino acids, glycerols as well as conjugates of polyhedral boron hydrides (ortho-carborane, closo-dodecaborate and cobalt bis(dicarbollide)) with natural porphyrins, carbohydrates and nucleosides are described. PMID- 21531144 TI - Biochemical and spectroscopic characterization of a novel metalloprotease, cotinifolin from an antiviral plant shrub: Euphorbia cotinifolia. AB - A high molecular mass novel metalloprotease, cotinifolin is purified from the latex of Euphorbia cotinifolia by a combination of anion exchange and hydrophobic interaction chromatography. The nonglycosylated enzyme has a molecular mass of 79.76 kDa (ESI-MS) and the isoelectric point of the enzyme is pH 7.7. Cotinifolin hydrolyzes denatured natural substrates such as casein, azoalbumin, and hemoglobin with high specific activity. The K(m) value of the enzyme was found to be 20 MUM with azocasein. The enzyme is not prone to autolysis even at very low concentrations. Polyclonal antibodies specific to enzyme was raised and immunodiffusion reveals that the enzyme has unique antigenic determinants. Maximum caseinolytic activity of cotinifolin is observed in the range of pH 7.0 8.0 and temperature of 50 degrees C. Using 0.2 mL of 1 mM solution of each metal ion, the purified protease was inhibited slightly by Ba2+ and Mn2+, moderately by Mg2+, Ca2+ and Cs2+ and significantly by Zn2+, Cu2+ and Co2+. On the other hand, substantial activation in caseinolytic activity was achieved by Ni2+. The enzyme activity was also inhibited by EDTA and o-phenanthroline but not by any other protease inhibitors. Perturbation studies by temperature, pH, and chaotrophs of the enzyme also reveal its high stability as seen by CD, fluorescence and proteolytic activity. Spectroscopic studies reveal that cotinifolin has secondary structural features with alpha/beta type with approximately 9% of alpha-helicity. Easy availability and simple purification procedure makes the enzyme a good system for biophysical study, biotechnological and industrial applications. PMID- 21531145 TI - In vitro investigation of aortic valve annuloplasty using prosthetic ring devices. AB - OBJECTIVES: The remodeling of the dilatated valve annulus with a prosthetic ring for the repair of valve insufficiency is a well-established concept in mitral valve surgery, and may also be suitable for aortic valve reconstruction. In this study, two models of prosthetic aortic annuloplasty devices were investigated. METHODS: Fresh porcine aortic roots (n=16) were investigated in a pulsatile flow simulator after patch dilatation of the annulus and subsequent reconstruction using both an external and an internal prosthetic ring. For each configuration, leakage was determined by ultrasonic flow measurements and leaflet co-aptation by transesophageal echocardiography. In addition, valves' motions were recorded by high-speed video. RESULTS: By the use of the prosthetic annuloplasty rings, leakage volumes decreased significantly compared with the dilatated root, more pronounced with the intra-annular ring. Similarly, the co-aptation height of the leaflets increased. Pressure gradients were not significantly influenced by the ring application, but leaflet motion patterns changed from the usual trapezoid to a more rectangular opening characteristic, visible at both echocardiographic and high-speed video analysis. CONCLUSIONS: The reconstruction of a dilatated aortic valve annulus using external and internal ring devices is feasible and effective for reduction of regurgitation at which the internal ring provides a greater potential to decrease valve insufficiency. PMID- 21531146 TI - Role of endoplasmic reticulum neutral lipid hydrolases. AB - Lipid droplets are universal intracellular organelles composed of a triglyceride, cholesteryl ester and retinyl ester core, surrounded by a monolayer of phospholipids and free (unesterified) cholesterol and lipid droplet-associated proteins. Core lipids are hydrolyzed by lipases to provide fatty acids, cholesterol and retinol for various cellular functions. In addition to cytosolic adipose triglyceride lipase and hormone-sensitive lipase, recent studies show the existence of other neutral lipid hydrolases that reside in the endoplasmic reticulum. In this review we highlight the role of these novel lipases including several members of the carboxylesterase family and enzymes termed arylacetamide deacetylase and KIAA1363/neutral cholesteryl ester hydrolase1/arylacetamide deacetylase-like 1. Some of these enzymes might be attractive targets for the treatment of dyslipidemias, viral infection and atherosclerosis. PMID- 21531147 TI - Differential effects of proinflammatory cytokines on cell death and ER stress in insulin-secreting INS1E cells and the involvement of nitric oxide. AB - Proinflammatory cytokines produced by immune cells destroy pancreatic beta cells in type 1 diabetes. The aim of this study was to investigate the cytokine network and its effects in insulin-secreting cells. INS1E cells were exposed to different combinations of proinflammatory cytokines. Cytokine toxicity was estimated by MTT assay and caspase activation measurements. The NFkappaB-iNOS pathway was analyzed by a SEAP reporter gene assay, Western-blotting and nitrite measurements. Gene expression analyses of ER stress markers, Chop and Bip, were performed by real time RT-PCR. Cytokines tested in this study, namely IL-1beta, TNFalpha and IFNgamma, had deleterious effects on beta cell viability. The most potent toxicity exhibited IL-1beta and its combinations with other cytokines. The toxic effects of IL-1beta towards cell viability, caspase activation and iNOS activity were dependent on nitric oxide and abolished by an iNOS blocker. IL-1beta was the strongest inducer of the NFkappaB activation. An iNOS blocker inhibited IL-1beta mediated NFkappaB activation in the first, initial phase of cytokine action, but did not affect significantly NFkappaB activation after prolonged incubation. Interestingly iNOS protein expression was induced predominantly by IL-1beta and decreased in the presence of an iNOS blocker in the case of a short time exposure. The changes in the expression of ER stress markers were also almost exclusively dependent on the IL-1beta presence and counteracted by iNOS blockade. Thus cytokine-induced beta cell death is primarily IL-1beta mediated with a NO independent enhancement by TNFalpha and IFNgamma. The deleterious effects on cell viability and function are crucially dependent on IL-1beta-induced nitric oxide formation. PMID- 21531148 TI - Alternative methods of normalising EMG during running. AB - We evaluated possible methods of normalising EMG measured during running. MVC, Sprint and 70% Peak Running Speed methods were evaluated and their repeatability, reliability and sensitivity to incremental running speed were compared. Twelve runners performed the same experimental protocol on three separate occasions. Each day, subjects firstly performed MVCs, followed by a 20 m maximal sprint (with a 20-30 m run-up). Following this, they performed the peak running speed (PRS) test until exhaustion. After which they ran at 70% of PRS for 5 laps. Results indicated that normalising EMG data to MVC and Sprint methods are more repeatable for VM, BF, MG and RF, VL, LG, respectively, with the average ICC>0.80. The 70% PRS demonstrated poor to fair levels of repeatability ranging between ICC 0.27 and 0.70. Whereas the 70% PRS method had the least intra-subject variability and the greatest sensitivity to increasing running speeds. More specifically, demonstrating significant changes in muscle activity in VM with increasing running speed while MVC and Sprint methods were unable to detect these changes. The dynamic methods were the most appropriate for EMG normalisation showing repeatability, better intra-subject reliability and better sensitivity during running over different days and for once-off measurements. PMID- 21531149 TI - Dreaming and hallucinations - continuity or discontinuity? Perspectives from dementia with Lewy bodies. AB - Comparing the phenomenology, neurochemical pathology, and psychopharmacology of hallucinations and dreaming is limited by the available data. Evidence to date reveals no simple correspondence between the two states. Differences in the phenomenology of visual hallucinations and the visual component of dreams may reflect variations in visual context acting on the same underlying mechanism - the minimal visual input during dreaming contrasts with the more substantial perceived context in hallucinations. Variations in cholinergic, dopaminergic and serotonergic neurotransmitter function during sleep and during hallucinations in Lewy body dementias, together with relevant drug effects suggest that, on the whole, different, potentially opposite, changes characterise the two states. A similar analysis of other psychotic features in Lewy body dementia and other disorders suggests that, in contrast to hallucinations, there may be more convincing parallels between dreaming and delusional states. PMID- 21531151 TI - Regarding "Correlation of psychomotor findings and the outcome of a physical therapy program to treat scapular dyskinesis". PMID- 21531150 TI - Result of a pyrocarbon prosthesis after comminuted and unreconstructable radial head fractures. AB - BACKGROUND: The purpose of this study is to analyze the results of treating unreconstructable acute radial head fractures associated with other elbow fractures and soft-tissue injuries with a pyrocarbon radial head prosthesis replacement, as well as repair of the associated injuries. MATERIALS AND METHODS: Twenty-eight patients with Mason type III unreconstructable and unstable radial head fractures and with associated injuries (according to Hotchkiss classification modified by van Riet) were treated with a pyrocarbon radial head prosthesis replacement; repair of collateral ligaments and associated elbow fractures was also carried out. Patients were evaluated in accordance with the Mayo Elbow Performance Score, measuring pain, grip strength, range of motion, and stability, as well as radiographic images. RESULTS: After a mean of 32 months postoperatively (range, 12-62 months), the mean Mayo Elbow Performance Score was 92 points. The result was considered excellent or good in 25 patients, with a high degree of satisfaction and functional restoration. CONCLUSION: The results of treating Mason type III radial head fractures with additional elbow fractures and soft-tissue injuries with pyrocarbon radial head prostheses are satisfactory; nevertheless, long-term follow-up is still necessary. PMID- 21531152 TI - Endoscopic plantar fasciotomy: preliminary study with cadaveric specimens. 1991. AB - The authors have developed an endoscopic approach to a plantar fasciotomy. This technique would minimize the surgical trauma that is normally induced with a conventional type of heel spur surgery. The authors believe that this new technique will provide an earlier return to normal ambulation, less loss of work, and earlier, overall increased patient comfort. PMID- 21531153 TI - Cytokines and culture medium have a major impact on human in vitro T-cell differentiation. AB - An important proof of principle has been achieved with the development of an in vitro T-cell differentiation assay based on the coculture of hematopoietic progenitors with the OP9-Delta1 stromal cell line. The original murine T cell differentiation assay has since been adapted for human T-cell differentiation, however with lower efficiency. The choice of both medium and cytokines is crucial in this assay, therefore our work has been focused on these two factors. The use of freshly reconstituted medium, the optimization of interleukine-7 (IL-7) concentration, and the addition of stem cell factor (SCF) have allowed to improve the proliferation of progenitors and T-cell precursors as well as the yield of double positive CD4+CD8+ T cells, and mature gammadelta and alphabeta T cells. These optimizations make the OP9-Delta1 system sensitive enough to perform both quantitative and qualitative assays with various type of progenitors, including those transduced by a retroviral vector. The improved OP9-Delta1 assay therefore constitutes an extremely useful test for basic research purposes and for translational medicine. PMID- 21531154 TI - Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications. AB - Combined chelation treatment may be a better approach for transfusion-dependent thalassemia major patients with iron overload complications because of increased efficacy. Combination therapy with desferrioxamine and deferiprone has already been reported to improve survival dramatically by reversing cardiac dysfunction and other endocrine complications. Some patients have intolerance or inconvenience to parenteral desferrioxamine. The hypothesis of this study was that combining two oral chelators, deferiprone and deferasirox, might lead to similar results. Following approval by the hospital ethical committee and a written informed consent from each patient, 16 patients who fulfilled the criteria participated in a study protocol for a period of up to 2 years. Efficacy measures analysis demonstrated a statistically significant decrease of total body iron load as estimated by serum ferritin, LIC and MRI T2* indices. Regarding the safety assessment, the incidence of adverse events was minor compared to the associated toxicity of monotherapy of each drug. No new onset of iron overload related complications was demonstrated. A reversal of cardiac dysfunction was observed in 2/4 patients, while the mean LVEF increased significantly. Regarding endocrine assessment, in 2/8 patients with impaired glucose tolerance, we noted a significant decrease in the mean 2h glucose in OGTT. Additionally an improvement in gonadal function was observed and one male and one female gave birth to two healthy children without hormonal stimulation. Combined oral chelation in thalassemia offers the promise of easier administration, better compliance and may lead to an improvement of patient quality of life by preventing or even reversing iron overload complications. PMID- 21531155 TI - End-of-life opioid administration on neonatal and pediatric intensive care units: nurses' attitudes and practice. AB - OBJECTIVES: (1) To compare caregivers attitudes on the use of end-of-life opioid analgesia in neonatal (NICU) and pediatric (PICU) intensive care units. (2) To investigate actual opioid administration to DR (delivery room), NICU and PICU patients in various end-of-life situations. METHODS: (1) Administration of an anonymous self-report questionnaire survey to nurses of 2 level III NICUs and 3 PICUs, presenting 5 hypothetical NICU and PICU patients in end-of-life situations. (2) Retrospective chart review of all deaths at the above mentioned DRs (served by NICU staff), NICUs and PICUs during the years 2008-2009. RESULTS: There was no difference between NICU and PICU nurses in self-proclaimed opioid administration in dying NICU or PICU patients with signs of pain (about 80%) or distress (about 65%). 35.0% of NICU and 44.5% of PICU nurses favoured opioid administration with the implicit aim of active intentional ending of life. Shortening of life as an adverse effect of end-of-life opioid analgesia was acceptable for the majority of PICU (94.5%) and NICU (87.0%) nurses. The rate of dying infants who actually had received opioids was similar in NICUs (41/74, 55.4%) and PICUs (40/68, 58.8%). In contrast, none of the neonates (n=24) who died under primary comfort care in the DR received opioids. CONCLUSIONS: End-of life opioid administration to primary comfort care patients in the DR differs fundamentally from NICU or PICU handling of dying patients. Once patients are admitted to an intensive care unit, practice and attitudes towards end-of-life opioid administration are similar in NICUs and PICUs. PMID- 21531156 TI - Dissolution DNP NMR with solvent mixtures: substrate concentration and radical extraction. AB - Dynamic nuclear polarization (DNP) followed by sudden sample dissolution, is a topic of active investigation owing to the method's unique prospects for the delivery of NMR spectra and images with unprecedented sensitivity. This experiment achieves hyperpolarization by the combined effects of electron-nuclear irradiation and cryogenic operation; the exploitation of these states occurs following a sudden melting and flushing of the resulting pellet from its original environment into a conventional, liquid-state setting. This melting and flushing usually demands using the equivalent of a few milliliters of hot solvent, a procedure which although well suited for in vivo studies leads to an excessive sample volume when considering typical analytical settings. The present study explores a way of reducing the ensuing dilution of the hyperpolarized analytes, by employing a combination of immiscible liquids for performing the melting and flushing. It is shown that suitable combinations of immiscible solvents - both in terms of their heat capacities and densities - allow one to melt the targeted cryogenic pellet and dissolve the hyperpolarized analytes in a fraction of the solvent hitherto required. By tailoring the resulting volume to the needs of a conventional 5mm NMR probe, a substantial sensitivity enhancement can be added to the hyperpolarization process. An extra benefit may arise from using radicals that preferentially dissolve in the immiscible organic phase, by way of a lengthening of the relaxation time of the investigated analytes. Examples of these principles are given, and further potential extensions of this approach are discussed. PMID- 21531157 TI - Plasmablastic lymphoma clinically presenting in the urinary tract. AB - Plasmablastic lymphoma is a high-grade B-cell lymphoma that poses major diagnostic problems and carries an extremely poor prognosis. This tumor was first described in the oral cavity of HIV+ patients but has since been identified in other sites and in seronegative patients. We describe 2 cases of plasmablastic lymphoma of the urinary tract that both presented with hydronephrosis. One occurred in an HIV+ patient and harbored a MYC translocation; the other, in an HIV- patient with no translocation detected. PMID- 21531158 TI - Binding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study. AB - HIV-1 integrase (IN) has become an attractive target since drug resistance against HIV-1 reverse transcriptase (RT) and protease (PR) has appeared. Diketo acid (DKA) inhibitors are potent and selective inhibitors of HIV-1 IN: however the action mechanism is not well understood. Here, to study the inhibition mechanism of DKAs we performed 10 ns comparative molecular dynamics simulations on HIV-1 IN bound with three most representative DKA inhibitors: Shionogi inhibitor, S-1360 and two Merck inhibitors L-731,988 and L-708,906. Our simulations show that the acidic part of S-1360 formed salt bridge and cation-pi interactions with Lys159. In addition, the catalytic Glu152 in S-1360 was pushed away from the active site to form an ion-pair interaction with Arg199. The Merck inhibitors can maintain either one or both of these ion-pair interaction features. The difference in potencies of the DKA inhibitors is thus attributed to the different binding modes at the catalytic site. Such structural information at atomic level, not only demonstrates the action modes of DKA inhibitors but also provides a novel starting point for structural-based design of HIV-1 IN inhibitors. PMID- 21531160 TI - [Assessment of effectiveness of a plan against tobacco in a universitary hospital]. AB - AIMS: Assessment of effectiveness of a plan entitled "Smoke-free hospitals", specifically the reduction in the number of smoking staff and an increase in smoke-free areas. METHOD: Interventional, non-controlled, populational study. A baseline study was conducted in 2004 to find out the situation as regards the prevalence of smokers in our hospital and the support of health workers for the smoke-free hospital plan. We used the questionnaire validated for the European smoke free hospital network in a sample of 483 workers randomly selected and stratified by gender, age and establishment. In 2007 we repeated the study with the same methodology to ascertain the progress of the project, in this case a sample of 425 workers was collected. RESULTS: The number of smoking workers had decreased from 35.2% to 27.4 (P<.05). This reduction was seen in virtually all sectors, but was less so in nursing staff. In 2007 we had achieved that people only smoke in smoking areas (P<.0001). The plan was supported by smokers and non smokers. CONCLUSIONS: The "Smoke-free hospital" plan has achieved the objectives proposed. The actions carried out helped to enforce the law and respect that hospital areas should not be for smoking, together with strong support to help workers who want to quit smoking are shown to be effective. PMID- 21531159 TI - Novel ligands that target the mitochondrial membrane protein mitoNEET. AB - Ligands of the thiazolidinedione (TZD) class of compounds, pioglitazone (ActosTM) and rosiglitazone (AvandiaTM) are currently approved for treatment of type 2 diabetes and are known to bind to the PPAR-gamma nuclear receptor subtype. Recent evidence suggesting PPAR-gamma independent action of the TZDs led to the discovery of a novel integral outer mitochondrial membrane protein, mitoNEET. In spite of the several reported X-ray crystal structures of the unbound form of mitoNEET, the location and nature of the mitoNEET ligand binding sites (LBS) remain unknown. In this study, a molecular blind docking (BD) method was used to discover potential mitoNEET LBS and novel ligands, utilizing the program AutoDock Vina (v 1.0.2). Validation of BD was performed on the PPAR-gamma receptor (PDB ID: 1ZGY) with the test compound rosiglitazone, demonstrating that the binding conformation of rosiglitazone determined by AutoDock Vina matches well with that of the cocrystallized ligand (root mean square deviation of the heavy atoms 1.45A). The locations and a general ligand binding interaction model for the LBS were determined, leading to the discovery of novel mitoNEET ligands. An in vitro fluorescence binding assay utilizing purified recombinant mitoNEET protein was used to determine the binding affinity of a predicted mitoNEET ligand, and the data obtained is in good agreement with AutoDock Vina results. The discovery of potential mitoNEET ligand binding sites and novel ligands, opens up the possibility for detailed structural studies of mitoNEET-ligand complexes, as well as rational design of novel ligands specifically targeted for mitoNEET. PMID- 21531161 TI - Botulinum toxin-responsive oromandibular dystonia in cerebrotendinous xanthomatosis. PMID- 21531162 TI - How effective is GPi-DBS in the treatment of Meige's syndrome? PMID- 21531163 TI - Spinocerebellar ataxia type 10 - A review. AB - Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant inherited ataxia caused by an expanded ATTCT pentanucleotide repeat in intron 9 of the ATXN10 gene, on chromosome 22q13.3. SCA10 represents a rare form of SCA, until now only described in Latin America, particularly in Mexico, Brazil, Argentina and Venezuela. In Mexico and Brazil SCA10 represents the second most common type of autosomal dominant cerebellar ataxia. The phenotype described in Mexico, is characterized by the association of cerebellar ataxia with epilepsy, while in Brazil the SCA10 phenotype is that of a pure cerebellar ataxia. As yet unidentified genotypic variables may account for this phenotypic difference. PMID- 21531164 TI - Interleukin 15 as a promising candidate for tumor immunotherapy. AB - Interleukin 15 participates in the development of important immune antitumor mechanisms. It activates CD8(+) T cells, natural killer (NK) cells, NK T cells, and can promote the formation of antitumor antibodies. IL-15 can also protect T effector cells from the action of T regulatory cells and reverse tolerance to tumor-associated antigens. In pre-clinical studies IL-15 has been found to demonstrate potentiated antitumor effects following pre-association with IL 15Ralpha, or when used in combination with chemotherapy, adoptive therapy, monoclonal antibodies, and tumor vaccines. Although a clinical trial based on application of IL-15 in tumor patients has already begun, it is important to be aware of its potential side effects, including induction of autoimmunity and promotion of proliferation, survival, and dissemination of some tumor cells. PMID- 21531165 TI - The implication of adiponectin and resistin in gastrointestinal diseases. AB - Adiponectin and resistin, members of the adipokine family, are multi-task hormones involved in several disorders, including those of the alimentary tract. In the present review, eligible studies focusing on the role of adiponectin and resistin in gastrointestinal diseases are manifested together and classified according to anatomic criteria. In addition, similarities and common patterns have been recognized, ultimately revealing an inverse association: the down regulation of adiponectin and up-regulation of resistin - both in vitro and in vivo - in gastrointestinal disorders, irrespective of their diverse nature - inflammatory, autoimmune or malignant - or anatomic position - esophageal, gastric, of the small intestine, colonic. Finally, a potential role for both adipokines in alimentary tract-related carcinogenesis has been identified, possibly representing a missing link between obesity and cancer. PMID- 21531166 TI - Metal hyperaccumulation and hypertolerance: a model for plant evolutionary genomics. AB - In the course of evolution, plants adapted to widely differing metal availabilities in soils and therefore represent an important source of natural variation of metal homeostasis networks. Research on plant metal homeostasis can thus provide insights into the functioning, regulation and adaptation of biological networks. Here, we describe major recent breakthroughs in the understanding of the genetic and molecular basis of metal hyperaccumulation and associated hypertolerance, a naturally selected complex trait which represents an extreme adaptation of the metal homeostasis network. Investigations in this field reveal further the molecular alterations underlying the evolution of natural phenotypic diversity and provide a highly relevant framework for comparative genomics. PMID- 21531167 TI - Improving immunity in crops: new tactics in an old game. AB - Crop disease remains a major cause of yield loss and emerging diseases pose new threats to global food security. Despite the dearth of commercial development to date, progress in using our rapidly expanding knowledge of plant-pathogen interactions to invent new ways of controlling diseases in crops has been good. Many major resistance genes have now been shown to retain function when transferred between species, and evidence indicates that resistance genes are more effective when deployed in a background containing quantitative resistance traits. The EFR pattern-recognition receptor, present in only the Brassicaceae, functions to provide bacterial disease control in the Solanaceae. Knowledge of how transcription activator-like effectors bind DNA is leading to new methods for triggering disease resistance and broader applications in genome engineering. PMID- 21531168 TI - Determination of brilliant green from fish pond water using carbon nanotube assisted pseudo-stir bar solid/liquid microextraction combined with UV-vis spectroscopy-diode array detection. AB - This paper describes the development of a new design of hollow fiber solid/liquid phase microextraction (HF-SLPME) for determination of brilliant green (BG) residues in water fish ponds. This method consists of an aqueous donor phase and carbon nanotube reinforced organic solvent (acceptor phase) operated in direct immersion sampling mode. The multi-walled carbon nanotube dispersed in the organic solvent is held in the pores and lumen of a porous polypropylene hollow fiber. It is in contact directly with the aqueous donor phase. In this method the solid/liquid extractor phase is supported using a polypropylene hollow fiber membrane. Both ends of the hollow fiber segment are sealed with magnetic stoppers. This device is placed inside the donor solution and plays the rule of a pseudo-stir bar. It is disposable, so single use of the fiber reduces the risk of carry-over problems. Brilliant green (BG) after extraction from the aqueous samples with mentioned HF-SLPME device was determined by ultraviolet-visible spectroscopy with diode array detection (UV-vis/DAD). The absorption wavelength was set to 625 nm (lambda(max)). The effect of different variables on the extraction was evaluated and optimized to enhance the sensitivity and extraction efficiency of the proposed method. The calibration curve was linear in the range of 1.00-10,000 MUg L(-1) of BG in the initial solution with R(2)=0.979. Detection limit, based on three times the standard deviation of the blank, was 0.55 MUg L( 1). All experiments were carried out at room temperature (25+/-0.5 degrees C). PMID- 21531169 TI - Charge-transfer complexes of pyrimidine Schiff bases with aromatic nitro compounds. AB - Charge-transfer (CT) complexes of pyrimidine Schiff bases, derived from condensation of 2-aminopyrimidine and substituted benzaldehydes, with some aromatic polynitro compounds were prepared and investigated using IR, UV, visible and (1)H NMR spectroscopy. For all solid complexes, the main interaction between the donor and acceptor molecules takes place through the pi-pi* interaction. Strong and some weak acidic acceptors, in addition interact through proton transfer from the acceptor molecule to the basic centre of the electron donor. Also, an n-pi* transition was detected in some complexes. PMID- 21531170 TI - Characterization of the interaction between farrerol and bovine serum albumin by fluorescence and circular dichroism. AB - The binding of farrerol to bovine serum albumin (BSA) in aqueous solution was investigated by fluorescence quenching spectra, synchronous fluorescence spectra, circular dichroism (CD) and the three-dimensional (3D) fluorescence spectra at pH 7.40. The results of fluorescence titration indicated that farrerol could quench the intrinsic fluorescence of BSA in a static quenching way. The cause of showing upward curvy patterns in Stern-Volmer plots was analyzed. The binding sites number n and binding constant K using fluorescence quenching equation at 310 K were calculated. The binding distance and the energy transfer efficiency between farrerol and BSA were also obtained according to the theory of Forster's non radiation energy transfer. The effect of some metal ions on the binding constant of farrerol with BSA was also studied. The effect of farrerol on the conformation of BSA was analyzed using CD, synchronous fluorescence spectra and three dimensional (3D) fluorescence spectra under experimental conditions. Furthermore, the fluorescence displacement experiments indicated that farrerol could bind to the site I of BSA. PMID- 21531171 TI - Synthesis, FTIR, FT-Raman, UV-visible, ab initio and DFT studies on benzohydrazide. AB - A systematic vibrational spectroscopic assignment and analysis of benzohydrazide (BH) has been carried out by using FTIR and FT-Raman spectral data. The vibrational analysis were aided by electronic structure calculations--ab initio (RHF) and hybrid density functional methods (B3LYP and B3PW91) performed with 6 31G(d,p) and 6-311++G(d,p) basis sets. Molecular equilibrium geometries, electronic energies, IR intensities, harmonic vibrational frequencies, depolarization ratios and Raman activities have been computed. Potential energy distribution (PED) and normal mode analysis have also been performed. The assignments proposed based on the experimental IR and Raman spectra have been reviewed and complete assignment of the observed spectra have been proposed. UV visible spectrum of the compound was also recorded and the electronic properties, such as HOMO and LUMO energies and lambda(max) were determined by time-dependent DFT (TD-DFT) method. The geometrical, thermodynamical parameters and absorption wavelengths were compared with the experimental data. The interactions of carbonyl and hydrazide groups on the benzene ring skeletal modes were investigated. PMID- 21531172 TI - Steroid up-regulation of FKBP51 and its role in hormone signaling. AB - FK506 binding protein 51 (FKBP51, FKBP5) functions as a co-chaperone for androgen, glucocorticoid, mineralocorticoid and progesterone receptors. The FKBP51 can act as an important determinant of the responses to steroids, especially to glucocorticoids in stress and mood disorders and androgens in prostate cancer, raising medical and pharmacological interests in the protein and its gene. Recent studies have revealed the molecular mechanisms by which the androgens and the glucocorticoids via their nuclear receptors elicit the robust up-regulation of the FKBP51 gene. Several polymorphisms in the FKBP51 gene have been associated with the mood disorders and differences in glucocorticoid sensitivity. The polymorphisms may contribute to the steroid up-regulation of the FKBP51 and thus influence the regulatory loops in steroid signaling. PMID- 21531173 TI - Outpatient treatment of patients with enteric fever. PMID- 21531175 TI - Statistical analysis and exposure status classification of transmembrane beta barrel residues. AB - Several computational methods exist for the identification of transmembrane beta barrel proteins (TMBs) from sequence. Some of these methods also provide the transmembrane (TM) boundaries of the putative TMBs. The aim of this study is to (1) derive the propensities of the TM residues to be exposed to the lipid bilayer and (2) to predict the exposure status (i.e. exposed to the bilayer or hidden in protein structure) of TMB residues. Three novel propensity scales namely, BTMC, BTMI and HTMI were derived for the TMB residues at the hydrophobic core region of the outer membrane (OM), the lipid-water interface regions of the OM, and for the helical membrane proteins (HMPs) residues at the lipid-water interface regions of the inner membrane (IM), respectively. Separate propensity scales were derived for monomeric and functionally oligomeric TMBs. The derived propensities reflect differing physico-chemical properties of the respective membrane bilayer regions and were employed in a computational method for the prediction of the exposure status of TMB residues. Based on the these propensities, the conservation indices and the frequency profile of the residues, the transmembrane residues were classified into buried/exposed with an accuracy of 77.91% and 80.42% for the residues at the membrane core and the interface regions, respectively. The correlation of the derived scales with different physico-chemical properties obtained from the AAIndex database are also discussed. Knowledge about the residue propensities and burial status will be useful in annotating putative TMBs with unknown structure. PMID- 21531174 TI - Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open label, randomised, controlled trial. AB - BACKGROUND: We aimed to investigate whether gatifloxacin, a new generation and affordable fluoroquinolone, is better than chloramphenicol for the treatment of uncomplicated enteric fever in children and adults. METHODS: We did an open-label randomised superiority trial at Patan Hospital, Kathmandu, Nepal, to investigate whether gatifloxacin is more effective than chloramphenicol for treating uncomplicated enteric fever. Children and adults clinically diagnosed with enteric fever received either gatifloxacin (10 mg/kg) once a day for 7 days, or chloramphenicol (75 mg/kg per day) in four divided doses for 14 days. Patients were randomly allocated treatment (1:1) in blocks of 50, without stratification. Allocations were placed in sealed envelopes opened by the study physician once a patient was enrolled into the trial. Masking was not possible because of the different formulations and ways of giving the two drugs. The primary outcome measure was treatment failure, which consisted of at least one of the following: persistent fever at day 10, need for rescue treatment, microbiological failure, relapse until day 31, and enteric-fever-related complications. The primary outcome was assessed in all patients randomly allocated treatment and reported separately for culture-positive patients and for all patients. Secondary outcome measures were fever clearance time, late relapse, and faecal carriage. The trial is registered on controlled-trials.com, number ISRCTN 53258327. FINDINGS: 844 patients with a median age of 16 (IQR 9-22) years were enrolled in the trial and randomly allocated a treatment. 352 patients had blood-culture-confirmed enteric fever: 175 were treated with chloramphenicol and 177 with gatifloxacin. 14 patients had treatment failure in the chloramphenicol group, compared with 12 in the gatifloxacin group (hazard ratio [HR] of time to failure 0.86, 95% CI 0.40 1.86, p=0.70). The median time to fever clearance was 3.95 days (95% CI 3.68 4.68) in the chloramphenicol group and 3.90 days (3.58-4.27) in the gatifloxacin group (HR 1.06, 0.86-1.32, p=0.59). At 1 month only, three of 148 patients were stool-culture positive in the chloramphenicol group and none in the gatifloxacin group. At the end of 3 months only one person had a positive stool culture in the chloramphenicol group. There were no other positive stool cultures even at the end of 6 months. Late relapses were noted in three of 175 patients in the culture confirmed chloramphenicol group and two of 177 in the gatifloxacin group. There were no culture-positive relapses after day 62. 99 patients (24%) experienced 168 adverse events in the chloramphenicol group and 59 (14%) experienced 73 events in the gatifloxacin group. INTERPRETATION: Although no more efficacious than chloramphenicol, gatifloxacin should be the preferred treatment for enteric fever in developing countries because of its shorter treatment duration and fewer adverse events. FUNDING: Wellcome Trust. PMID- 21531176 TI - Does compliance status predict clinical status in patients undergoing endoscopic management of vesico-ureteral reflux? AB - OBJECTIVE: Previous studies of endoscopic management of vesico-ureteral reflux (VUR) have had non-compliance rates around 50%. We examined success rates of patients non-compliant with a delayed follow up protocol after endoscopic injection for VUR. MATERIALS AND METHODS: Patients undergoing Double HIT, dextranomer/hyaluronic acid copolymer endoscopic injection for VUR were enrolled in a 1-year, delayed voiding cysto-urethrogram (VCUG) study. All patients non compliant with the VCUG were contacted and information on their clinical status was collected. Non-compliant patients were re-scheduled for a VCUG. RESULTS: 49/54 (91%) patients underwent endoscopic injection for VUR and completed the 6 week ultrasound. At 1-year 49% (24/49) were non-compliant with a VCUG; 75% (18/24) were contacted and provided clinical information. All but one patient agreed to the VCUG. Patients compliant with the 1-year VCUG showed 96% (24/25) clinical and 92% (23/25) radiologic success rates. Non-compliant patients had an 89% (16/18) clinical success rate; 5 (21%) non-compliant patients underwent VCUGs with a 100% success rate. CONCLUSIONS: Long-term compliance remains an issue for patients treated endoscopically for VUR, but compliance does not predict clinical status as both groups have favorable clinical outcomes. The repeat VCUG is a barrier to long-term follow up as only 21% of patients underwent the study. PMID- 21531177 TI - Community food environment, home food environment, and fruit and vegetable intake of children and adolescents. AB - OBJECTIVES: To determine (1) reliability of new food environment measures; (2) association between home food environment and fruit and vegetable (FV) intake; and (3) association between community and home food environment. METHODS: In 2005, a cross-sectional survey was conducted with readministration to assess test retest reliability. Adolescents, parents of adolescents, and parents of children (n = 458) were surveyed in San Diego, Boston, and Cincinnati. RESULTS: Most subscales had acceptable reliability. Fruit and vegetable intake was positively associated with availability of healthful food (r = 0.15-0.27), FV (r = 0.22 0.34), and ratio of more-healthful/less-healthful food in the home (r = 0.23 0.31) and was negatively associated with less-healthful food in the home (r = 0.17 to -0.18). Home food environment was associated with household income but not with community food environment. CONCLUSIONS AND IMPLICATIONS: A more healthful home food environment was related to youth FV intake. Higher income households had more healthful food in the home. The potential influence of neighborhood food outlets warrants further study. PMID- 21531178 TI - Theory-driven intervention improves calcium intake, osteoporosis knowledge, and self-efficacy in community-dwelling older Black adults. AB - OBJECTIVE: To assess the effectiveness of an osteoporosis education program to improve calcium intake, knowledge, and self-efficacy in community-dwelling older Black adults. DESIGN: Randomized repeated measures experimental design. SETTING: Churches and community-based organizations. PARTICIPANTS: Men and women (n = 110) 50 years old and older from 3 south Florida counties. INTERVENTION: Participants randomly assigned to either of 2 groups: Group 1 (experimental group) or Group 2 (wait-list control group). Group 1 participated in 6 weekly education program sessions immediately following baseline assessment, and Group 2 started the program following Group 1's program completion. A tested curriculum was adapted to meet the needs of the target population. MAIN OUTCOME MEASURES: Dietary calcium intake, osteoporosis knowledge, health beliefs, and self-efficacy. ANALYSIS: Descriptive and summary statistics, repeated measures analysis of variance, and regression analysis. RESULTS: Of the total participants, 84.6% completed the study (mean age = 70.2 years). Overall, an educational program developed with a theoretical background was associated with improvement in calcium intake, knowledge, and self-efficacy, with no effect on most health belief subscales. Assigned group was the major predictor of change in calcium intake. CONCLUSIONS AND IMPLICATIONS: A theory-driven approach is valuable in improving behavior to promote bone health in this population. Health professionals should consider using more theory-driven approaches in intervention studies. PMID- 21531179 TI - AMDA--a leader in developing international long-term care. PMID- 21531180 TI - Influence of different spacer arms on Mimetic LigandTM A2P and B14 membranes for human IgG purification. AB - Microporous membranes are an attractive alternative to circumvent the typical drawbacks associated to bead-based chromatography. In particular, the present work intends to evaluate different affinity membranes for antibody capture, to be used as an alternative to Protein A resins. To this aim, two Mimetic LigandsTM A2P and B14, were coupled onto different epoxide and azide group activated membrane supports using different spacer arms and immobilization chemistries. The spacer chemistries investigated were 1,2-diaminoethane (2LP), 3,6-dioxa-1,8 octanedithiol (DES) and [1,2,3] triazole (TRZ). These new mimetic membrane materials were investigated by static and by dynamic binding capacity studies, using pure polyclonal human immunoglobulin G (IgG) solutions as well as a real cell culture supernatant containing monoclonal IgG(1). The best results were obtained by combining the new B14 ligand with a TRZ-spacer and an improved Epoxy 2 membrane support material. The new B14-TRZ-Epoxy 2 membrane adsorbent provided binding capacities of approximately 3.1mg/mL, besides (i) a good selectivity towards IgG, (ii) high IgG recoveries of above 90%, (iii) a high Pluronic-F68 tolerance and (iv) no B14-ligand leakage under harsh cleaning-in-place conditions (0.6M sodium hydroxide). Furthermore, foreseeable improvements in binding capacity will promote the implementation of membrane adsorbers in antibody manufacturing. PMID- 21531181 TI - Dried blood spot assay for estimation of metronidazole concentrations in rats and its application in single animal drug pharmacokinetic study. AB - An HPLC-UV-dried blood spot (DBS) method for the estimation of metronidazole (MTZ) in rat whole blood is reported. Method employs Ahlstrom 226 sample collection paper and DBS samples were prepared by spotting with 30 MUl of whole blood (spiked calibration standards/quality control samples/in vivo study samples). A 6mm disc was punched from each DBS and extraction was carried out using water containing the internal standard (tinidazole). The calibration for MTZ was linear over 2.5-50 MUg/ml concentration range. Accuracy (% bias) and precision (expressed as % Coefficient of variation) values for within and between day were <20% at the lower level quality control sample (LQC) and <15% at all other concentrations tested. The limit of quantification (LOQ) of the method was 2.5 MUg/ml. The validated method was applied for the analysis of in vivo pharmacokinetic (PK) study samples after intravenous administration of MTZ to a rat. Whole blood PK parameters observed in this study were in compliance with literature based PK parameters. The DBS sampling approach was found to be useful in a single animal pharmacokinetic study. PMID- 21531182 TI - Determination of midazolam and 1-hydroxymidazolam from plasma by gas chromatography coupled to methane negative chemical ionization mass spectrometry after sublingual administration of midazolam. AB - A sensitive and selective gas chromatographic mass spectrometric method for the determination of midazolam and its biologically active metabolite, 1 hydroxymidazolam, in rabbit plasma has been developed and validated. Sample preparation includes mixed-mode solid-phase extraction and derivatization with silylating reagents. Midazolam-d4 was used as an internal standard for the determination of parent drug and its active metabolite. The instrumentation consisted of a capillary column gas chromatography and a single quadrupole mass spectrometer with a negative chemical ionization. The method was found to be valid in terms of selectivity, linearity, precision, accuracy, and recovery over the concentration range of 2-200 ng/ml and 1-100 ng/ml for midazolam and 1 hydroxymidazolam, respectively. For both analytes, the lower limit of quantification was 2 ng/ml. Midazolam was stable in stock solutions stored three months at -20 degrees C and in human plasma stored for three months at -80 degrees C. In addition, no degradation of midazolam was found after three freeze thaw cycles, in short-term stability at room temperature for 24h, or in post preparative stability in the autosampler. The validity of the method was further tested by performing a pharmacokinetic study of sublingual administration of midazolam in rabbits. The method will be used in studies related to a formulation development of novel midazolam formulations for use in paediatric anaesthesia. PMID- 21531183 TI - [Retropharyngeal and parapharyngeal abscess: experience in a tertiary-care center in Seville during the last decade]. AB - INTRODUCTION: Retropharyngeal and parapharyngeal abscesses are rare but associated with significant morbidity and potential mortality. This study reviews our experience in the diagnosis and management of retro- and parapharyngeal abscesses and compares children treated conservatively with those undergoing surgical intervention. MATERIAL AND METHODS: A retrospective analysis of children diagnosed with retro- and parapharyngeal abscess from 2000 to 2009 in our tertiary-care centre. RESULTS: Thirty-one children were identified. There were 17 retropharyngeal abscesses and 11 parapharyngeal abscesses; 3 children suffered from both conditions. The mean annual frequency increased significantly from 1.4 cases/year during 2000-2004 to 4.8 cases/year during 2005-2009 (P=.006). Median age was 3 years (range 1-10). A total of 18 (58%) children had received pre admission oral antibiotics (beta-lactams in 84%). Clinical findings at presentation were: fever (93%), cervical lymphadenopathy (93%), neck pain (90%), torticollis (74%), odynophagia (64%), trismus (32%), drooling (22%) and stridor (6%). Thirteen (42%) children underwent surgical intervention, of those, microbiological culture was positive in 8 children; S. pyogenes being the most commonly isolated organism (n=4). All the patients received parenteral antibiotic therapy. There were no significant differences in the length of hospital stay, complication or recurrence rates between children treated conservatively compared to those undergoing surgical intervention. CONCLUSIONS: Retro- and parapharyngeal abscesses were increasingly observed during the 2(nd) part of the study period. The majority of children (58%) were treated conservatively with excellent clinical response. Indication for surgical intervention should be made based on the clinical presentation and response to antibiotic therapy. PMID- 21531184 TI - Benefits of immediate dermoglandular preserving reconstruction following giant fibroadenoma excision in two patients. AB - Giant fibroadenoma is a rare, benign stromal tumor that typically occurs in adolescent women. This rapidly-growing tumor can result in a significant aesthetic and psychosocial morbidity due to gross asymmetry changes in the overlying skin envelope and concerns about malignancy. On initial work-up this lesion must be differentiated from other rare primary breast tumors, including phyllodes tumor, or metastatic disease. Appropriate treatment of giant fibroadenoma requires surgical excision; however, many surgeons are reluctant to perform a concomitant mastopexy or reconstruction at the time of tumor extirpation. This conservative approach results in a loose, ptotic, aesthetically displeasing breast postoperatively. While some degree of skin retraction is expected, patients may have to wait for up to a year to see final results, and further surgical correction may still be required. It is unknown whether these surgeons are not familiar with these techniques or hesitate to increase the amount of scarring on the breast mound of a young female. Using an immediate dermoglandular preserving mastopexy after giant fibroadenoma excision, we have decreased postoperative breast ptosis, removed much of the lax, poor-quality skin and achieved stable, long-term results in two patients. This technique improves the immediate aesthetic outcome, reduces the psychosocial comorbidity associated with waiting for skin retraction and decreases the likelihood of a second surgery. PMID- 21531185 TI - [Hematologic malignant complications after transplantation]. AB - Post-transplant hemopathies are a serious complication of organ transplantation. They include several entities: non-hodgkin lymphoma, Hodgkin disease and myeloma. The pathophysiology, clinical and histological features, treatment and evolution of these diseases are different, but share some similarities. Among factors involved in lymphomagenesis, the role of Epstein Barr virus and immunosuppression are central. EBV primo-infection or reactivation together with a deep depression of T-cell immunity is at particular risk of lymphoma development. The clinical expression and outcome of lymphomas are varied. Assays for EBV replication quantification have been developed leading to immunosuppression decreasing and antiviral therapy when the replication increases. Treatment of post-transplant lymphoproliferations consists mainly in immunotherapy and chemotherapy. Hodgkin disease and myeloma are rare after transplantation; their management is close to the one of immunocompetent patients. The recurrence of myeloma, amyloidosis or light chain deposition disease seems frequent after transplantation and only patients with disappearance of monoclonal component should be proposed for transplantation. On the opposite, the risk of recurrence appears lower for Hodgkin disease; therefore the transplantation of patients with a history of Hodgkin disease looks possible. PMID- 21531186 TI - Allele frequencies and concordance study of 16 STR loci--including the new European Standard Set (ESS) loci--in an Austrian population sample. PMID- 21531187 TI - Automated DNA extraction of single dog hairs without roots for mitochondrial DNA analysis. AB - Dogs are intensely integrated in human social life and their shed hairs can play a major role in forensic investigations. The overall aim of this study was to validate a semi-automated extraction method for mitochondrial DNA analysis of telogenic dog hairs. Extracted DNA was amplified with a 95% success rate from 43 samples using two new experimental designs in which the mitochondrial control region was amplified as a single large (+/- 1260 bp) amplicon or as two individual amplicons (HV1 and HV2; +/- 650 and 350 bp) with tailed-primers. The results prove that the extraction of dog hair mitochondrial DNA can easily be automated to provide sufficient DNA yield for the amplification of a forensically useful long mitochondrial DNA fragment or alternatively two short fragments with minimal loss of sequence in case of degraded samples. PMID- 21531188 TI - The arthritic wrist. I--the degenerative wrist: surgical treatment approaches. AB - The primary goal in treating a degenerative wrist is to provide pain relief, while maintaining strength and mobility if possible. After failure of the recommended conservative treatment, the choice of approaches can be made from a large collection of techniques, some which are well validated. Partial wrist fusion, particularly the Watson procedure, results in a pain-free wrist in 80% of cases, with 50% of the mobility preserved, good grasping strength and stable results for at least 10 years. Proximal row carpectomy provides similar results if the cartilage on the head of the capitate is preserved and the patient is not involved in heavy manual labour. Complete denervation provides pain relief in almost 80% of cases while preserving motion and strength. This is a safe and effective option, with no age limit, that still allows other procedures to be performed in the future. Total wrist fusion also has its place in revision, and even as first-line treatment, because of the reliable outcome in terms of pain and strength, high satisfaction rates, little to no repercussions linked to the loss of mobility and fewer complications. Other techniques are now available. The partial or complete resection of a carpal bone and placement of an implant is back in vogue because of the availability of pyrocarbon. Such implants are an option in the future for localized osteoarthritis or even diffuse affections, and a useful alternative to more invasive procedures. The use of a rib cartilage graft to partially or completely replace a carpal bone or resurface the radius has promising results in terms of pain reduction and fusion. The role of total joint replacement must be defined relative to the classic, reliable techniques that have long-term outcome data. LEVEL OF PROOF: IV. PMID- 21531189 TI - Vein conduit associated with microsurgical suture for complete collateral digital nerve severance. AB - The aim of this study is to present the long term results of a series of 53 vein conduit grafts as first line therapy to repair complete severance of one or more collateral digital nerves. The surgical technique included an epi-perineural suture of the nerve under minimal tension, associated with a vein graft harvested from the back of the hand to cover the nerve. None of the patients presented with a neuroma, spontaneous pain or had stopped using the injured finger. Sensibility results were good or very good in 67% of cases. The scar at the donor site was very light or invisible. A total of 96% of patients were satisfied or very satisfied. This simple technique, by protecting the injured nerve, results in a rate of sensory nerve recovery that is comparable or better than that of other series in the literature, without neuroma and with minimal scarring at the donor site. PMID- 21531190 TI - Occlusal contacting condition and masticatory function of 2 types of pattern that differ in the closing path of the mandibular incisal point during chewing. AB - PURPOSE: To clarify the difference in the state of occlusal contact and masticatory function between two patterns of masticatory movement path that differed in the closing path. METHODS: Fifteen healthy subjects with Pattern I (a linear or concave opening path and a convex closing path) and Pattern II (similar opening path to that in Pattern I and a concave closing path) were selected. The state of occlusal contact on the working and balancing sides and the masticatory function (integral value of the masseter muscular activity, gape, masticatory width, cycle time, indicators representing the stability of the path and rhythm, and glucose extraction) were compared between the two patterns. RESULTS: The occlusal contact on the working side was about the same. For the balancing side, occlusal contact at the molar region was observed for Pattern II in most cases, whereas no occlusal contact was observed for Pattern I. The integral value of the masseter muscular activity and the glucose extraction were greater for Pattern I. The gape was not different between the two patterns. Pattern I had a wide masticatory width and a short cycle time. The values of the indicators representing the stability of the path and rhythm were smaller for Pattern I. CONCLUSION: It was suggested that Pattern I with a convex closing path had a functional difference and a superior masticatory function from Pattern II with a concave closing path, and the difference in the occlusal contact on the balancing side was related. PMID- 21531191 TI - Acute liver failure in children. AB - The management of children with acute liver failure mandates a multidisciplinary approach and intense monitoring. In recent years, considerable progress has been made in developing specific and supportive medical measures, but clinical studies have mainly concerned adult patients. There are no specific medical therapies, except for a few metabolic diseases presenting with acute liver failure. Liver transplantation still remains the only definitive therapy in most instances. Recent clinical studies suggest that hepatocyte transplantation may be useful for bridging patients to liver transplantation, for providing metabolic support during liver failure and for replacing liver transplantation in certain metabolic liver diseases. PMID- 21531192 TI - Words of wisdom. Re: Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Sylvester RJ, Brausi MA, Kirkels WJ, et al. PMID- 21531193 TI - Words of wisdom. Re: Acceptance and durability of surveillance as a management choice in men with screen-detected, low-risk prostate cancer: improved outcomes with stringent enrollment criteria. Miocinovic R, Jones JS, Pujara AC, Klein EA, Stephenson AJ. PMID- 21531194 TI - Words of wisdom. Re: Salvage therapy with bicalutamide 150 mg in nonmetastatic castration-resistant prostate cancer. Lodde M, Lacombe L, Fradet Y. PMID- 21531195 TI - Words of wisdom. Re: An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint terminology and classification of the complications related directly to the insertion of prostheses (meshes, implants, tapes) and grafts in female pelvic floor surgery. Haylen BT, Freeman RM, Swift SE, et al. PMID- 21531196 TI - Words of wisdom. Re: Revision of current American Association for the Surgery of Trauma renal injury grading system. Buckley JC, McAninch JW. PMID- 21531197 TI - Words of wisdom. Re: A randomized comparison of totally tubeless and standard percutaneous nephrolithotomy in elderly patients. Kara C, Resorlu B, Bayindir M, Unsal A. PMID- 21531198 TI - Analytical platform for verification and quantitation of target peptides in human serum: application to cathelicidin. AB - A selective and sensitive, fully automated platform for verification and quantitative determination of target peptides in biofluids is proposed and then validated by development of a method for analysis of cathelicidin in human serum. The method is based on the on-line coupling of solid-phase extraction (SPE) and tandem mass spectrometry with direct infusion. Mass spectrometry analysis was carried out by multiple reaction monitoring using three transitions (one for quantitative analysis and two for qualitative analysis), all them confirmed by in silico fragmentation of the target peptide. Samples were prepared in the SPE workstation on a polymeric divinylbenzene resin by preconcentration, deproteinization, and cleanup, removing salts and interferences after direct injection of human serum. The analytical process required 12 min. The limits of detection and quantitation were 2.5 and 8.25 MUg/L, respectively (0.20 and 0.66 pg on column). Repeatability and within-laboratory reproducibility were 2.4% and 2.7%, respectively. A dual-cartridge configuration was used to test recovery of cathelicidin in serum, resulting in 80%. Because quantitative retention in the cartridge was assessed, determination of cathelicidin was validated without using synthetic peptides labeled with stable isotopes. The hyphenated system allows full automation, thereby improving reproducibility and accuracy, as demanded by clinical analysis. PMID- 21531199 TI - Modulation of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase activity and oxidative modification during the development of adjuvant arthritis. AB - Adjuvant arthritis (AA) was induced by intradermal administration of Mycobacterium butyricum to the tail of Lewis rats. In sarcoplasmic reticulum (SR) of skeletal muscles, we investigated the development of AA. SR Ca(2+)-ATPase (SERCA) activity decreased on day 21, suggesting possible conformational changes in the transmembrane part of the enzyme, especially at the site of the calcium binding transmembrane part. These events were associated with an increased level of protein carbonyls, a decrease in cysteine SH groups, and alterations in SR membrane fluidity. There was no alteration in the nucleotide binding site at any time point of AA, as detected by a FITC fluorescence marker. Some changes observed on day 21 appeared to be reversible, as indicated by SERCA activity, cysteine SH groups, SR membrane fluidity, protein carbonyl content and fluorescence of an NCD-4 marker specific for the calcium binding site. The reversibility may represent adaptive mechanisms of AA, induced by higher relative expression of SERCA, oxidation of cysteine, nitration of tyrosine and presence of acidic phospholipids such as phosphatidic acid. Nitric oxide may regulate cytoplasmic Ca(2+) level through conformational alterations of SERCA, and decreasing levels of calsequestrin in SR may also play regulatory role in SERCA activity and expression. PMID- 21531200 TI - Transcriptional regulation of the human neutral ceramidase gene. AB - Ceramidases play a critical role in generating sphingosine-1-phosphate by hydrolyzing ceramide into sphingosine, a substrate for sphingosine kinase. In order to elucidate its transcriptional regulation, we identify here a putative promoter region in the 5'-UTR of the human neutral CDase (nCDase) gene. Using human genomic DNA, we cloned a 3000 bp region upstream of the translational start site of the nCDase gene. Luciferase reporter analyses demonstrated that this 3000 bp region had promoter activity, with the strongest induction occurring within the first 200 bp. Computational analysis revealed the 200 bp essential promoter region contained several well-characterized promoter elements, lacked a conical TATA box, but did contain a reverse oriented CCAAT box, a feature common to housekeeping genes. Electrophoretic mobility shift assays demonstrated that the identified candidate transcriptional response elements (TRE) bind their respective transcription factors, including NF-Y, AP-2, Oct-1, and GATA. Mutagenic analyses of the TRE revealed that these sites regulated promoter activity and mutating an individual site decreased promoter reporter activity by up to 50%. Together, our findings suggest that regulation of nCDase expression involves coordinated TATA-less transcriptional activity. PMID- 21531201 TI - Co(II)-substituted Haemophilus influenzae beta-carbonic anhydrase: spectral evidence for allosteric regulation by pH and bicarbonate ion. AB - Cobalt(II)-substituted Haemophilus influenzae beta-carbonic anhydrase (HICA) has been produced by overexpression in minimal media supplemented with CoCl(2), enabling kinetic, structural, and spectroscopic characterization. Co(II) substituted HICA (Co-HICA) has comparable catalytic activity to that of wild-type enzyme with k(cat)=82+/-19 ms(-1) (120% of wild-type). The X-ray crystal structure of Co-HICA was determined to 2.5A resolution, and is similar to the zinc enzyme. The absorption spectrum of Co-HICA is consistent with four coordinate geometry. pH-dependent changes in the absorption spectrum of Co-HICA, including an increase in molar absorptivity and a red shift of a 580 nm peak with decreasing pH, correlate with the pH dependence of k(cat)/K(m). The absence of isosbestic points in the pH-dependent absorption spectra suggest that more than two absorbing species are present. The addition of bicarbonate ion at pH 8.0 triggers spectral changes in the metal coordination sphere that mimic that of lowering pH, supporting its hypothesized role as an allosteric inhibitor of HICA. Homogeneously (99+/-1% Co) and heterogeneously (52+/-5% Co) substituted Co-HICA have distinctly different colors and absorption spectra, suggesting that the metal ions in the active sites in the allosteric dimer of Co-HICA engage in intersubunit communication. PMID- 21531202 TI - Novel mutations in the SOX10 gene in the first two Chinese cases of type IV Waardenburg syndrome. AB - OBJECTIVE: We analyzed the clinical features and family-related gene mutations for the first two Chinese cases of type IV Waardenburg syndrome (WS4). METHODS: Two families were analyzed in this study. The analysis included a medical history, clinical analysis, a hearing test and a physical examination. In addition, the EDNRB, EDN3 and SOX10 genes were sequenced in order to identify the pathogenic mutation responsible for the WS4 observed in these patients. RESULTS: The two WS4 cases presented with high phenotypic variability. Two novel heterozygous mutations (c.254G>A and c.698-2A>T) in the SOX10 gene were detected. The mutations identified in the patients were not found in unaffected family members or in 200 unrelated control subjects. CONCLUSIONS: This is the first report of WS4 in Chinese patients. In addition, two novel mutations in SOX10 gene have been identified. PMID- 21531203 TI - Circadian rhythm of cholesterol synthesis in mouse liver: a statistical analysis of the post-squalene metabolites in wild-type and Crem-knock-out mice. AB - Circadian rhythms affect the total cholesterol levels in humans and animals, although their effect on cholesterol synthesis remain poorly understood. Here, we show for the first time that intermediates of the post-squalene portion of cholesterol synthesis also follow a circadian rhythm in the mouse liver. We used Crem-knock-out mice to investigate the effects of cAMP response element modulator (CREM) isoforms on cholesterol synthesis over time, as compared to wild-type mice. Multiple linear regression and cosinor statistical analysis were carried out on data obtained from 166 liver samples of mice, and the 24-h profiles were modelled across genotype, gender and zeitgeber time for lanosterol, 24,25 dihydrolanosterol, testis meiosis-activating sterol, and 7-dehydrocholesterol, along with cholesterol. The levels of these sterols were higher in female mice compared to males, although the genotype/gender factors showed no effects on the circadian oscillation of these sterols, except for 24,25-dihydrolanosterol. This study also highlights the importance of the statistical methods, where time, genotype and gender are the studied variables. PMID- 21531205 TI - Multi-domain CGFS-type glutaredoxin Grx4 regulates iron homeostasis via direct interaction with a repressor Fep1 in fission yeast. AB - The fission yeast Schizosaccharomyces pombe contains two CGFS-type monothiol glutaredoxins, Grx4 and Grx5, which are localized primarily in the nucleus and mitochondria, respectively. We observed involvement of Grx4 in regulating iron responsive gene expression, which is modulated by a repressor Fep1. Lack of Grx4 caused defects not only in growth but also in the expression of both iron-uptake and iron-utilizing genes regardless of iron availability. In order to unravel how Grx4 is involved in Fep1-mediated regulation, interaction between them was investigated. Co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) revealed that Grx4 physically interacts with Fep1 in vivo. BiFC revealed localized nuclear dots produced by interaction of Grx4 with Fep1. Mutation of cysteine-172 in the CGFS motif to serine (C172S) produced effects similarly observed under Grx4 depletion, such as the loss of iron-dependent gene regulation and the absence of nuclear dots in BiFC analysis. These results suggest that the ability of Grx4 to bind iron, most likely Fe-S cofactor, could be critical in interacting with and modulating the activity of Fep1. PMID- 21531204 TI - A putative disease-associated haplotype within the SCN1A gene in Dravet syndrome. AB - Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is one of the most severe forms of childhood epilepsy. DS is caused by a mutation in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A). However, 25-30% of patients with DS are negative for the SCN1A mutation screening, suggesting that other molecular mechanisms may account for these disorders. Recently, the first case of DS caused by a mutation in the neuronal voltage-gated sodium-channel beta-subunit gene (SCN1B) was also reported. In this report we aim to make the molecular analysis of the SCN1A and SCN1B genes in two Tunisian patients affected with DS. The SCN1A and SCN1B genes were tested for mutations by direct sequencing. No mutation was revealed in the SCN1A and SCN1B genes by sequencing analyses. On the other hand, 11 known single nucleotide polymorphisms were identified in the SCN1A gene and composed a putative disease-associated haplotype in patients with DS phenotype. One of the two patients with putative disease-associated haplotype in SCN1A had also one known single nucleotide polymorphism in the SCN1B gene. The sequencing analyses of the SCN1A gene revealed the presence of a putative disease-associated haplotype in two patients affected with Dravet syndrome. PMID- 21531206 TI - AMSH is required to degrade ubiquitinated proteins in the central nervous system. AB - Deubiquitination is a biochemical process that mediates the removal of ubiquitin moieties from ubiquitin-conjugated substrates. AMSH (associated molecule with the SH3 domain of STAM) is a deubiquitination enzyme that participates in the endosomal sorting of several cell-surface molecules. AMSH impairment results in missorted ubiquitinated cargoes in vitro and severe neurodegeneration in vivo, but it is not known how AMSH deficiency causes neuronal damage in the brain. Here, we demonstrate that AMSH(-/-) mice developed ubiquitinated protein accumulations as early as embryonic day 10 (E10), and that severe deposits were present in the brain at postnatal day 8 (P8) and P18. Interestingly, TDP-43 was found to accumulate and colocalize with glial marker-positive cells in the brain. Glutamate receptor and p62 accumulations were also found; these molecules colocalized with ubiquitinated aggregates in the brain. These data suggest that AMSH plays an important role in degrading ubiquitinated proteins and glutamate receptors in vivo. AMSH(-/-) mice provide an animal model for neurodegenerative diseases, which are commonly characterized by the generation of proteinaceous aggregates. PMID- 21531207 TI - Pharmacological inhibition of HDAC6 attenuates endothelial barrier dysfunction induced by thrombin. AB - BACKGROUND: Endothelial barrier dysfunction (EBD) involves microtubule disassembly and enhanced cell contractility. Histone deacetylase 6 (HDAC6) deacetylates alpha-tubulin, and thereby destabilizes microtubules. This study investigates a role for HDAC6 in EBD. METHODS: EBD was induced with thrombin+/ HDAC6 inhibitors (tubacin and MC1575), and assessed by transendothelial electrical resistance (TEER). Markers for microtubule disassembly (alpha-tubulin and acetylated alpha-tubulin) and contraction (phosphorylated myosin light chain 2, P-MLC2) were measured using immunoblots and immunofluorescence. RESULTS AND CONCLUSION: Thrombin induced a ~50% decrease in TEER that was abrogated by the HDAC6 inhibitors. Moreover, inhibition of HDAC6 diminished edema in the lung injured by lipopolysaccharide. Lastly, inhibition of HDAC6 attenuated thrombin induced microtubule disassembly and P-MLC2. Our results suggest that HDAC6 can be targeted to limit EBD. PMID- 21531208 TI - Tau regulates the subcellular localization of calmodulin. AB - Lack of tau expression in neuronal cells results in a change in the expression of few genes. However, little is known about how tau regulates gene expression. Here we show that the presence of tau could alter the subcellular localization of calmodulin, a protein that could be located at the cytoplasm or in the nucleus. Nuclear calmodulin binds to co-transcription factors, regulating the expression of genes like calbindin. In this work, we have found that in neurons containing tau, a higher proportion of calmodulin is present in the cytoplasm compared with neurons lacking tau and that an increase in cytoplasmic calmodulin correlates with a higher expression of calbindin. PMID- 21531209 TI - The cytoplasmic domain is not involved in directing Class 5 mutant LDL receptors to lysosomal degradation. AB - The low density lipoprotein receptor (LDLR) binds and internalizes low density lipoprotein (LDL). At the mildly acidic pH of the sorting endosomes, LDL is released from the receptor and the receptor recycles back to the cell membrane. Mutations in the LDLR gene may disrupt the normal function of the LDLR in different ways. Class 5 mutations result in receptors that are able to bind and internalize LDL, but they fail to release LDL in the sorting endosomes and fail to recycle. Instead they are rerouted to the lysosomes for degradation. However, the underlying mechanism remains to be determined. To study the role of the cytoplasmic domain of the LDLR for rerouting Class 5 mutants to the lysosomes, we have performed studies to determine whether Class 5 mutants caused by mutations E387K or V408M are degraded when the cytoplasmic domain has been altered or deleted. As determined by confocal laser-scanning microscopy, these mutant LDLR were inserted into the cell membrane and were able to internalize LDL. As determined by Western blot analysis, Class 5 mutants without a cytoplasmic domain still were degraded after binding LDL. Thus, the cytoplasmic domain does not play a role in rerouting Class 5 mutant LDLR to the lysosomes. Rather, one may speculate that sterical hindrance may prevent Class 5 mutants with bound LDL from entering the narrow recycling tubules of the sorting endosome. PMID- 21531210 TI - Aurora-C interacts with and phosphorylates the transforming acidic coiled-coil 1 protein. AB - Aurora-C, a member of the Aurora kinase family, is implicated in the regulation of mitosis. In contrast to Aurora-A and Aurora-B its cellular localization and functions are poorly characterized. TACC1 protein belongs to the transforming acidic coiled-coil family shown to interact with the Aurora kinases. In the present study we analyzed the interaction between Aurora-C and TACC1 by means of immunofluorescence (IF), co-immunoprecipitation (IP) and in vitro phosphorylation experiments. We demonstrated that Aurora-C and TACC1 proteins co-localize to the midbody of HeLa cells during cytokinesis. Immunoprecipitated TACC1 from HeLa cell extracts was associated with Aurora-C. In addition, the interaction of the two proteins was tested by analyzing the phosphorylation of TACC1 in vitro. The results demonstrated that TACC1 is phosphorylated by Aurora-C on a serine at position 228. In conclusion, the study demonstrated that TACC1 localizes at the midbody during cytokinesis and interacts with and is a substrate of Aurora-C, which warrant further investigation in order to elucidate the functional significance of this interaction. PMID- 21531211 TI - Dominant induction of vaccine antigen-specific cytotoxic T lymphocyte responses after simian immunodeficiency virus challenge. AB - Cytotoxic T lymphocyte (CTL) responses are crucial for the control of human and simian immunodeficiency virus (HIV and SIV) replication. A promising AIDS vaccine strategy is to induce CTL memory resulting in more effective CTL responses post viral exposure compared to those in natural HIV infections. We previously developed a CTL-inducing vaccine and showed SIV control in some vaccinated rhesus macaques. These vaccine-based SIV controllers elicited vaccine antigen-specific CTL responses dominantly in the acute phase post-challenge. Here, we examined CTL responses post-challenge in those vaccinated animals that failed to control SIV replication. Unvaccinated rhesus macaques possessing the major histocompatibility complex class I haplotype 90-088-Ij dominantly elicited SIV non-Gag antigen specific CTL responses after SIV challenge, while those induced with Gag-specific CTL memory by prophylactic vaccination failed to control SIV replication with dominant Gag-specific CTL responses in the acute phase, indicating dominant induction of vaccine antigen-specific CTL responses post-challenge even in non controllers. Further analysis suggested that prophylactic vaccination results in dominant induction of vaccine antigen-specific CTL responses post-viral exposure but delays SIV non-vaccine antigen-specific CTL responses. These results imply a significant influence of prophylactic vaccination on CTL immunodominance post viral exposure, providing insights into antigen design in development of a CTL inducing AIDS vaccine. PMID- 21531212 TI - Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment. AB - Primary cultures of patient tumor cells (PCPTC) have been used for prediction of diagnosis-specific activity and individual patient response to anticancer drugs, but have not been utilized as a model for identification of novel drugs in high throughput screening. In the present study, ovarian carcinoma cells from three patients were tested in response to a library of 3000 chemically diverse compounds. Eight hits were retrieved after counter screening using normal epithelial cells, and one of the two structurally related hit compounds was selected for further preclinical evaluation. This compound, designated VLX 50, demonstrated a broad spectrum of activity when tested in a panel of PCPTCs representing different forms of leukemia and solid tumors and displayed a high tumor to normal cell activity. VLX 50 induced delayed cell death with some features of classical apoptosis. Significant in vivo activity was confirmed on primary cultures of human ovarian carcinoma cells in mice using the hollow fiber model. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. This query signature was analyzed using the Gene Set Enrichment Analysis and the Connectivity Map database. Strong connections to hypoxia inducible factor 1 and iron chelators were retrieved. The mechanistic hypothesis of intracellular iron depletion leading to hypoxia signaling was confirmed by a series of experiments. The results indicate the feasibility of using PCPTC for cancer drug screening and that intracellular iron depletion could be a potentially important strategy for cancer therapy. PMID- 21531213 TI - 24S-hydroxycholesterol and cholesterol-24S-hydroxylase (CYP46A1) in the retina: from cholesterol homeostasis to pathophysiology of glaucoma. AB - Free cholesterol is the predominant form of cholesterol in the neural retina. The vertebrate neural retina exhibits its own capacity to synthesize cholesterol and meets its demand also by taking it from the circulation. Defects in cholesterol synthesis and trafficking in the neural retina has detrimental consequences on its structure and function, highlighting the crucial importance of maintaining cholesterol homeostasis in the retina. Our purpose was to give a review on the functioning of the retina, the role of cholesterol and cholesterol metabolism therein, with special emphasis on cholesterol-24S-hydroxylase (CYP46A1). Similar to the brain, the retina expresses cholesterol-24S-hydroxylase (CYP46A1) and is enriched in its metabolic product, 24S-hydroxycholesterol. We recently published that one single nucleotide polymorphism in CYP46A1 gene, designated as rs754203, was a risk factor for glaucoma. Glaucoma is the second leading cause of blindness worldwide, affecting more than 60 million people. Glaucoma is characterized by the loss of retinal ganglion cells, which show high CYP46A1 expression. These data suggest the potential involvement of CYP46A1 and 24S-hydroxycholesterol in the pathophysiology of glaucoma. PMID- 21531215 TI - Method development for routine liquid chromatography-mass spectrometry measurement of the alcohol biomarker phosphatidylethanol (PEth) in blood. AB - BACKGROUND: Phosphatidylethanol (PEth) is a group of phospholipids formed from ethanol and phosphatidylcholine by action of phospholipase D. Measurement of PEth in whole blood samples is employed as an alcohol biomarker. This work aimed to further develop an LC-MS method for PEth to make it practical for routine laboratory use. METHODS: Blood samples were obtained from blood donors and from the clinical samples pool. A whole blood total lipid extract was separated on a C4 column, followed by ESI-MS detection of the deprotonated molecules in SIM mode or ESI-MS/MS detection of the major product ions (fatty acid fragments) by SRM. RESULTS: Initial results indicated that individual calibration curves are required for MS quantitation of some PEth forms, and that deuterated analogs are preferable over phosphatidylpropanol as the internal standard. PEth-16:0/18:1 was the single most sensitive molecular form as alcohol biomarker, being detected in every of 211 blood specimens containing 0.1-20 MUmol/L total PEth at reporting limits in the range 0.1-1.0 MUmol/L. PEth-16:0/18:1 and 16:0/18:2, accounting for about 36% and 26%, respectively, of the total amount, correlated well with total PEth (R(2)=0.922-0.940), but the correlation was better for the sum of both forms (R(2)=0.994). Based on analysis of specimens from 200 blood donors, 95% reference intervals (CLSI C28-A3) were estimated to be <0.70 MUmol/L for total PEth, <0.20 MUmol/L for PEth-16:0/18:1, and <0.18 MUmol/L for PEth-16:0/18:2. CONCLUSIONS: The LC-ESI-MS(/MS) method allowed for simultaneous qualitative and quantitative measurements of PEth forms in whole blood samples. Related to the routine application of blood PEth as alcohol biomarker, reference intervals were suggested for total PEth and the major molecular forms PEth-16:0/18:1 and 16:0/18:2. PMID- 21531214 TI - Postprandial lipoprotein metabolism: VLDL vs chylomicrons. AB - Since Zilversmit first proposed postprandial lipemia as the most common risk of cardiovascular disease, chylomicrons (CM) and CM remnants have been thought to be the major lipoproteins which are increased in the postprandial hyperlipidemia. However, it has been shown over the last two decades that the major increase in the postprandial lipoproteins after food intake occurs in the very low density lipoprotein (VLDL) remnants (apoB-100 particles), not CM or CM remnants (apoB-48 particles). This finding was obtained using the following three analytical methods; isolation of remnant-like lipoprotein particles (RLP) with specific antibodies, separation and detection of lipoprotein subclasses by gel permeation HPLC and determination of apoB-48 in fractionated lipoproteins by a specific ELISA. The amount of the apoB-48 particles in the postprandial RLP is significantly less than the apoB-100 particles, and the particle sizes of apoB-48 and apoB-100 in RLP are very similar when analyzed by HPLC. Moreover, CM or CM remnants having a large amount of TG were not found in the postprandial RLP. Therefore, the major portion of the TG which is increased in the postprandial state is composed of VLDL remnants, which have been recognized as a significant risk for cardiovascular disease. PMID- 21531216 TI - Establishment of reference intervals for bone markers in children and adolescents. AB - OBJECTIVES: To determine age and gender specific reference intervals for bone markers. DESIGN AND METHODS: Morning blood samples were collected after overnight fast from 356 healthy children (6 to 18 year-old) for the determination of bone marker levels, PTH and vitamin D(3). Multiple regression analysis was done to assess the effect of factors that could influence the bone marker levels; the central 95% reference interval and their 90% CI were calculated. RESULTS: After excluding samples when BMI-z -scores were <-2 or >+2, both vitamin D(3) and PTH levels were abnormal and from children who used steroids the remainder were partitioned using Tanner stage based chronological age. As expected the reference intervals show a significant variation with age and gender. All the bone marker levels, except total alkaline phosphatase, were significantly higher in puberty with vitamin D(3) >75nmol/L. CONCLUSION: Vitamin D status, age and gender are important for establishing reference intervals of bone markers in healthy children. PMID- 21531217 TI - Aberrant methylation of the CpG island of HLTF gene in gastric cardia adenocarcinoma and dysplasia. AB - OBJECTIVES: To investigate the promoter methylation of HLTF in the tissues and plasma of patients with gastric cardia adenocarcinoma (GCA) and dysplasia. DESIGN AND METHODS: Nested MSP approach was used to detect HLTF methylation status. RESULTS: The frequency of HLTF methylation in high grade dysplasia and GCA tumor tissues was significantly higher than that in chronic inflammation tissues and was significantly associated with upper gastrointestinal cancers (UGIC) family history and protein and mRNA expression of the gene. HLTF methylation was not found in the plasma of patients with chronic inflammation and low grade dysplasia, while 4.0% (1/25) of patients with high grade dysplasia and 20.8% of (20/96) GCA patients were detected with hypermethylation of HLTF in the plasma. CONCLUSIONS: In all, HLTF methylation may exist in gastric cardia dysplasia stages and may play important role in the development of GCA especially in individuals with UGIC family history. PMID- 21531218 TI - Influence of pre-analytical factors on alpha-galactosidase A, arylsulfatase B and alpha-glucosidase activities measured on dried blood spots on filter paper. AB - OBJECTIVES: To analyze the effect of blood collection and storage conditions on activity of alpha-galactosidase A, arylsulfatase B and alpha-glucosidase. DESIGN AND METHODS: Blood was collected in EDTA, heparin, or direct spotting on filter paper and stored at different temperatures (-20, 4, 25 and 37 degrees C) and storage times (3, 10, 17 and 180 days). The influence of filter paper size was also assessed (3.0 and 1.2mm). RESULTS: No statistically significant difference was observed between the three collection methods. alpha-Glucosidase A activity significantly decreased after the 10th day, while arylsulfatase B activity only differed significantly after the 180th day, and alpha-galactosidase A activity remained constant throughout this storage time. Excellent correlation coefficients were observed for the two filter paper sizes used. CONCLUSIONS: Both paper sizes may be employed. Filter paper specimens should be transported under refrigeration as soon as possible after blood collection. PMID- 21531219 TI - Cholangiocarcinoma presenting as metastases to the cervical spine. PMID- 21531220 TI - Methylene chloride intoxication treated with hyperbaric oxygen therapy. PMID- 21531221 TI - A more complete picture of higher cardiovascular disease prevalence among blacks compared to whites. PMID- 21531223 TI - Some simple rules for effective communication in clinical teaching and practice environments. PMID- 21531224 TI - Compression-only cardiopulmonary resuscitation improves survival. PMID- 21531225 TI - Pulmonary disorders induced by monoclonal antibodies in patients with rheumatologic autoimmune diseases. AB - Monoclonal antibodies have emerged as a new class of agents causing drug-related pulmonary involvement in patients with systemic rheumatologic autoimmune diseases. The most frequently associated noninfectious pulmonary diseases are interstitial pneumonia (118 cases reported by August 2010), sarcoid-like disease and vasculitis (40 cases), and 97% of cases are associated with agents blocking tumor necrosis factor (TNF), a cytokine implicated in pulmonary fibrosis, granuloma formation, and maintenance. Drug-induced interstitial pneumonia has a poor prognosis, with an overall mortality rate of around one-third, rising to two thirds in patients with pre-existing interstitial disease. Sarcoid-like disease has a better prognosis, with resolution or improvement in 90% of cases. Although the evidence comes overwhelmingly from case reports and case series, suggested recommendations for patient management include a detailed pre-therapeutic evaluation, early identification of symptoms suggestive of pulmonary disease, and tailored therapy. Mycobacterial infection should be exhaustively investigated, especially after anti-TNF administration. Large, prospective, postmarketing studies including nonbiological agents as controls may help elucidate the real risk of pulmonary disease in patients with rheumatologic autoimmune diseases receiving monoclonal antibodies. PMID- 21531227 TI - Upper-extremity deep venous thrombosis: a review. AB - Upper-extremity deep venous thrombosis is less common than lower-extremity deep venous thrombosis. However, upper-extremity deep venous thrombosis is associated with similar adverse consequences and is becoming more common in patients with complex medical conditions requiring central venous catheters or wires. Although guidelines suggest that this disorder be managed using approaches similar to those for lower-extremity deep venous thrombosis, studies are refining the prognosis and management of upper-extremity deep venous thrombosis. Physicians should be familiar with the diagnostic and treatment considerations for this disease. This review will differentiate between primary and secondary upper extremity deep venous thromboses; assess the risk factors and clinical sequelae associated with upper-extremity deep venous thrombosis, comparing these with lower-extremity deep venous thrombosis; and describe an approach to treatment and prevention of secondary upper-extremity deep venous thrombosis based on clinical evidence. PMID- 21531226 TI - Implications of using hemoglobin A1C for diagnosing diabetes mellitus. AB - Until 2010, the diagnosis of diabetes mellitus was based solely on glucose concentration, but the American Diabetes Association (ADA) recommendations now include a new criterion: hemoglobin A1C >=6.5%. Because this change may have significant implications for diabetes diagnosis, we conducted a comprehensive literature review including peer-reviewed articles not referenced in the ADA report. We conclude that A1C and plasma glucose tests are frequently discordant for diagnosing diabetes. A1C >=6.5% identifies fewer individuals as having diabetes than glucose-based criteria. Convenience of A1C test might increase the number of patients diagnosed, but this is unproven. Diagnostic cut-points for both glucose and A1C are based on consensus judgments regarding optimal sensitivity and specificity for the complications of hyperglycemia. A1C may not accurately reflect levels of glycemia in some situations, but in comparison with glucose measurements, it has greater analytic stability and less temporal variability. When choosing a diagnostic test for diabetes, the limitations of each choice must be understood. Clinical judgment and consideration of patient preference are required to appropriately select among the diagnostic alternatives. PMID- 21531228 TI - Outpatient management of the elderly patient following fragility hip fracture. AB - Hip fractures associated with underlying osteoporosis result in significant morbidity and mortality in elderly patients and increase the risk for future fractures. Several underlying modifiable contributors may be identified, while osteoporosis itself is amenable to a number of effective treatments. Other interventions can further reduce the risk of falls and second fractures. This paper reviews evaluation and management options after fragility (low trauma) hip fractures in the geriatric population. PMID- 21531229 TI - The green cerebrospinal fluid. PMID- 21531230 TI - A tale of two rashes. PMID- 21531231 TI - Osteoporotic fractures and heart failure in the community. AB - PURPOSE: Recent findings suggest a role for heart failure in the etiology of osteoporotic fractures, yet the temporal sequence of occurrence of the 2 conditions needs clarification. METHODS: Using the Rochester Epidemiology Project, the authors conducted a 2-phase study: a case-control study compared osteoporotic fracture history among Olmsted County, Minnesota, residents newly diagnosed with heart failure in 1979-2002 with age- and sex-matched community controls without heart failure (961 pairs; mean age 76 years; 54% women). Both groups were then followed to July 2009 to evaluate their subsequent fracture risk in a cohort study. RESULTS: Prior fractures were more frequent in heart failure cases than controls (23.1% vs. 18.8%, P=.02). The adjusted odds ratio (OR) for heart failure associated with prior fracture was 1.39 (95% confidence interval [CI], 1.07-1.81), mainly driven by hip fractures (OR 1.82; 95% CI, 1.25-2.66) with little or no association with other fractures. Over a mean follow-up of 7.5 years, 444 individuals developed subsequent osteoporotic fractures. The adjusted fracture risk was marginally elevated in heart failure patients compared with controls (hazard ratio [HR] 1.32; 95% CI, 0.98-1.79), again largely attributable to hip fractures (HR 1.58; 95% CI, 1.03-2.41). CONCLUSIONS: In this community, the association with fracture risk was about as strong before as after the diagnosis of heart failure and was nearly entirely attributable to hip fractures. Additional work is needed to identify common underlying mechanisms for heart failure and hip fracture, which may define prevention opportunities. PMID- 21531232 TI - Long-term use of aspirin and the risk of gastrointestinal bleeding. AB - BACKGROUND: In short-term trials, aspirin is associated with gastrointestinal bleeding. However, the effect of dose and duration of aspirin use on risk remains unclear. METHODS: We conducted a prospective study of 87,680 women enrolled in the Nurses' Health Study in 1990 who provided biennial data on aspirin use. We examined the relative risk (RR) of major gastrointestinal bleeding requiring hospitalization or blood transfusion. RESULTS: During a 24-year follow-up, 1537 women reported a major gastrointestinal bleeding. Among women who used aspirin regularly (>=2 standard [325 mg] tablets/week), the multivariate RR of gastrointestinal bleeding was 1.43 (95% confidence interval [CI], 1.29-1.59) when compared with nonregular users. Compared with women who denied any aspirin use, the multivariate RRs of gastrointestinal bleeding were 1.03 (95% CI, 0.85-1.24) for women who used 0.5 to 1.5 standard aspirin tablets/week, 1.30 (95% CI, 1.07 1.58) for women who used 2 to 5 tablets/week, 1.77 (95% CI, 1.44-2.18) for women who used 6 to 14 tablets/week, and 2.24 (95% CI, 1.66-3.03) for women who used more than 14 tablets/week (P(trend)<.001). Similar dose-response relationships were observed among short-term users (<=5 years; P(trend)<.001) and long-term users (>5 years; P(trend)<.001). In contrast, after adjustments were made for dose, increasing duration of use did not confer a greater risk of bleeding (P(trend) = .28). CONCLUSION: Regular aspirin use is associated with gastrointestinal bleeding. Risk seems more strongly related to dose than duration of aspirin use. Efforts to minimize adverse effects of aspirin therapy should emphasize using the lowest effective dose among both short- and long-term users. PMID- 21531234 TI - B-type natriuretic peptide in the early diagnosis and risk stratification of acute chest pain. AB - BACKGROUND: Myocardial ischemia is a strong trigger of B-type natriuretic peptide (BNP) release. As ischemia precedes necrosis in acute myocardial infarction, we hypothesized that BNP might be useful in the early diagnosis and risk stratification of patients with acute chest pain. METHODS: In a prospective, international multicenter study, BNP was measured in 1075 unselected patients with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long term regarding mortality. RESULTS: Acute myocardial infarction was the adjudicated final diagnosis in 168 patients (16%). BNP levels at presentation were significantly higher in acute myocardial infarction as compared with patients with other diagnoses (median 224 pg/mL vs. 56 pg/mL, P <.001). The diagnostic accuracy of BNP for the diagnosis of acute myocardial infarction as quantified by the area under the receiver operating characteristic curve (AUC) (0.74; 95% confidence interval [CI], 0.70-0.78) was lower compared with cardiac troponin T at presentation (AUC 0.88; 95% CI, 0.84 0.92; P <.001). Cumulative 24-month mortality rates were 0.5% in the first, 2.1% in the second, 7.0% in the third, and 22.9% in the fourth quartile of BNP (P <.001). BNP predicted all-cause mortality independently of and more accurately than cardiac troponin T: AUC 0.81 (95% CI, 0.76-0.86) versus AUC 0.70 (95% CI, 0.62-0.77; P <.001). Net reclassification improvement for BNP was 0.10 (P=.04), and integrated discrimination improvement 0.068 (P=.01). CONCLUSIONS: BNP accurately predicts mortality in unselected patients with acute chest pain independently of and more accurately than cardiac troponin T, but does not seem to help in the early diagnosis of acute myocardial infarction. PMID- 21531233 TI - Immunosuppressive therapy with oral prednisone to prevent restenosis after PCI. A multicenter randomized trial. AB - BACKGROUND: Prednisone at immunosuppressive doses after stenting has shown remarkable efficacy in reducing ischemic recurrences in nondiabetic patients with high post-procedural levels of C-reactive protein; the study aim was to compare the clinical outcome obtained in a control group of patients treated with bare metal stents versus 2 other study groups--bare metal stent plus oral prednisone or drug eluting stents--assuming similar optimal adjunctive medical treatment. METHODS: Five tertiary Italian hospitals enrolled 375 nondiabetic patients with coronary artery disease and no contraindications to dual antiplatelet treatment or corticosteroid therapy in a randomized, controlled study performed between 2007 and 2009. Patients were allocated into 3 study groups: bare metal stents (controls), bare metal stents followed by a 40-day prednisone treatment, or drug eluting stents. The primary endpoint was the event-free survival of cardiovascular death, myocardial infarction, and recurrence of ischemia needing repeated target vessel revascularization at 1 year as adjudicated by an independent clinical events committee. RESULTS: One-year follow-up was obtained in all patients. Patients receiving bare metal stents alone as compared to those treated with prednisone or drug-eluting stents had lower event-free survival; the primary endpoint was 80.8% in controls compared to 88.0% in the prednisone and 88.8% in the drug-eluting stent groups, respectively (P=.04 and .006). CONCLUSION: Compared with bare metal stents alone, prednisone treatment after bare metal stents or drug-eluting stent implantation result in a better event free survival at 1 year. PMID- 21531235 TI - Defining the ideal qualities of mentorship: a qualitative analysis of the characteristics of outstanding mentors. AB - OBJECTIVE: The study's objective was to identify the important qualities of outstanding mentors as described by their mentees' letters of nomination for a prestigious lifetime achievement award in mentorship. METHODS: The Lifetime Achievement in Mentorship Award at the University of California, San Francisco, recognizes a faculty member who has demonstrated sustained mentoring excellence in the academic health sciences. Recommendation letters in support of the top 10 nominees in 2008 (n=53 letters) were analyzed using grounded theory and constant comparative technique until thematic saturation was achieved. RESULTS: In 2008, 29 faculty members (of>1000 eligible senior faculty) were nominated. Nominees were 53 to 78 years old, and 30% were women. The nominees represented 4 schools (Medicine, Nursing, Pharmacy and Dentistry) and 22 departments/divisions. Five themes emerged from the analysis. Outstanding mentors: 1) exhibit admirable personal qualitites, including enthusiasm, compassion, and selflessness; 2) act as a career guide, offering a vision but purposefully tailoring support to each mentee; 3) make strong time commitments with regular, frequent, and high-quality meetings; 4) support personal/professional balance; and 5) leave a legacy of how to be a good mentor through role modeling and instituting policies that set global expectations and standards for mentorship. CONCLUSION: This is the first study to describe the qualities of admired mentors by analyzing nomination letters for a prestigious mentoring award. Our results give new insight into how mentors foster the careers of junior faculty in the academic health sciences. The results can guide academic leaders on how to train and evaluate mentors. PMID- 21531236 TI - Adverse events during the Scleroderma Lung Study. AB - BACKGROUND: The Scleroderma Lung Study (SLS) was a 1-year, randomized, controlled trial of oral cyclophosphamide for scleroderma-related pulmonary alveolitis. It concluded that oral cyclophosphamide slowed the decline in the forced vital capacity (% predicted) and had a beneficial effect on dyspnea, skin changes, and several quality of life measures of systemic sclerosis. We now report an in-depth assessment of the toxicity of cyclophosphamide during the year of therapy and the year after therapy was completed, during which time the investigators were still masked to the treatment assignment. METHODS: One-year, double-blind, randomized controlled trial of oral cyclophosphamide versus placebo with 1-year masked follow-up. Adverse events (AEs) were tabulated, described, and compared using descriptive statistics (eg, mean and median) and t, Wilcoxon rank sum, chi squared, or Fisher's exact tests as appropriate. RESULTS: During year 1, treatment-related overall AEs occurred more frequently in cyclophosphamide (CYC) treated patients (overall AEs for CYC=154 events vs placebo=60 events; P=0.002), and especially for mild to moderate leukopenia (CYC=19 subjects vs placebo=0 subjects; P < .0001). For cancer, we followed patients beyond 2 years. There were no differences in the occurrence of cancer (CYC=4 subjects vs placebo=2 subjects), serious related AEs (CYC=8 events vs placebo=13 events), or deaths (CYC=6 subjects vs placebo=6 subjects). CONCLUSION: Over 2 years, cyclophosphamide was associated with more AEs than placebo, including overall AEs and relative leukopenia. There were no differences in other AEs, including serious AEs, cancers, or deaths. PMID- 21531238 TI - A comprehensive 3-year internal medicine residency research curriculum. PMID- 21531237 TI - Racial differences in two self-management hypertension interventions. AB - BACKGROUND: Only one half of Americans have their blood pressure controlled, and there are significant racial differences in blood pressure control. The goal of this study was to examine the effectiveness of 2 patient-directed interventions designed to improve blood pressure control within white and non-white subgroups (African Americans, 49%). METHODS: Post hoc analysis of a 2 by 2 randomized trial with 2-year follow-up in 2 university-affiliated primary care clinics was performed. Within white and non-white patients (n=634), 4 groups were examined: 1) usual care; 2) home blood pressure monitoring (3 times per week); 3) tailored behavioral self-management intervention administered via telephone by a nurse every other month; and 4) a combination of the 2 interventions. RESULTS: The overall race by time by treatment group effect suggested differential intervention effects on blood pressure over time for whites and non-whites (systolic blood pressure, P=. 08; diastolic blood pressure, P=.01). Estimated trajectories indicated that among the 308 whites, there was no significant effect on blood pressure at 12 or 24 months for any intervention compared with the control group. At 12 months, the non-whites (n=328) in all 3 intervention groups had systolic blood pressure decreases of 5.3 to 5.7 mm Hg compared with usual care (P <.05). At 24 months, in the combined intervention, non-whites had sustained lower systolic blood pressure compared with usual care (7.5 mm Hg; P <.02). A similar pattern was observed for diastolic blood pressure. CONCLUSION: Combined home blood pressure monitoring and a tailored behavioral phone intervention seem to be particularly effective for improving blood pressure in non-white patients. PMID- 21531239 TI - Mastectomy without anesthesia: the cases of Abigail Adams Smith and Fanny Burney. PMID- 21531240 TI - Shared experiences and best practices in the management of rheumatoid arthritis and Crohn's disease. PMID- 21531241 TI - Human sleep and cognition part II--clinical and applied research. Preface. PMID- 21531242 TI - Cognition in circadian rhythm sleep disorders. AB - Circadian rhythms in physiology and behavior exist in all living organisms, from cells to humans. The most evident rhythms are the recurrent cycles of sleep and wake as well as changes in alertness and cognitive performance across the 24h. Clearly, sleep pressure can exert a strong influence on cognitive performance, but the influence of circadian modulation of alertness and cognitive function is evident even when the pressure for sleep is high. Circadian rhythms also influence more complex cognitive tasks, such as selective attention and executive function, which are important for work performance and safety. The circadian timekeeping system also ensures that circadian rhythms are appropriately synchronized to the external physical environment and work and social schedules. Circadian misalignment is the basis for all circadian rhythm sleep disorders. These disorders are often associated with impairments of cognitive performance that can have adverse effects on school and work performance, overall quality of life, and safety. PMID- 21531243 TI - Sleep-wake changes and cognition in neurodegenerative disease. AB - With the increasing aging population, neurodegenerative disorders will become more common in clinical practice. These disorders involve multiple pathophysiological mechanisms that differentially affect cognition, mood, and physical functions. Possibly due to the involvement of common underlying neurobiological circuits, sleep and/or circadian (sleep-wake) changes are also common in this disease group. Of significance, sleep-wake changes are often a prodromal feature and are predictive of cognitive decline, psychiatric symptoms, quality of life, need for institutional care, and caregiver burden. Unfortunately, in neurodegenerative disease, few studies have included detailed polysomnography or neuropsychological assessments although some data indicate that sleep and neurocognitive features are related. Further studies are also required to address the effects of pharmacological and nonpharmacological treatments on cognitive functioning. Such research will hopefully lead to targeted early intervention approaches for cognitive decline in older people. PMID- 21531244 TI - Cognition and daytime functioning in sleep-related breathing disorders. AB - Sleep-related breathing disorders encompass a range of disorders in which abnormal ventilation occurs during sleep as a result of partial or complete obstruction of the upper airway, altered respiratory drive, abnormal chest wall movement, or respiratory muscle function. The most common of these is obstructive sleep apnea (OSA), occurring in both adults and children, and causing significant cognitive and daytime dysfunction and reduced quality of life. OSA patients experience repetitive brief cessation of breathing throughout the night, which causes intermittent hypoxemia (reductions in hemoglobin oxygen levels) and fragmented sleep patterns. These nocturnal events result in excessive daytime sleepiness, and changes in mood and cognition. Chronic excessive sleepiness during the day is a common symptom of sleep-related breathing disorders, which is assessed in sleep clinics both subjectively (questionnaire) and objectively (sleep latency tests). Mood changes are often reported by patients, including irritability, fatigue, depression, and anxiety. A wide range of cognitive deficits have been identified in untreated OSA patients, from attentional and vigilance, to memory and executive functions, and more complex tasks such as simulated driving. These changes are reflected in patient reports of difficulty in concentrating, increased forgetfulness, an inability to make decisions, and falling asleep at the wheel of a motor vehicle. These cognitive changes can also have significant downstream effects on daily functioning. Moderate to severe cases of the disorder are at a higher risk of having a motor vehicle accident, and may also have difficulties at work or school. A number of comorbidities may also influence the cognitive changes in OSA patients, including hypertension, diabetes, and stroke. These diseases can cause changes to neural vasculature and result in neural damage, leading to cognitive impairments. Examination of OSA patients using neuroimaging techniques such as structural magnetic resonance imaging and proton magnetic resonance spectroscopy has observed significant changes to brain structure and metabolism. The downstream effects of neural, cognitive, and daytime functional impairments can be significant if left untreated. A better understanding of the cognitive effects of these disorders, and development of more effective assessment tools for diagnosis, will aid early intervention and improve quality of life of the patient. PMID- 21531245 TI - Cognitive recovery following positive airway pressure (PAP) in sleep apnea. AB - Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common sleep disorder that is characterized by repeated episodes of complete or partial cessation of breathing while sleeping. These recurrent breathing events result in fragmented sleep and recurrent hypoxemia. Distressing daytime sequelae reported by OSAHS patients include excessive daytime sleepiness, self-reported changes in mood, and cognitive problems. It has been well established that OSAHS can negatively impact functioning in multiple cognitive domains, such as attention and memory. In this chapter, neurobehavioral deficits in OSAHS are discussed, and proposed models of cognitive dysfunction are summarized. Current studies examining cognitive recovery with positive airway pressure treatment are presented. It appears that the cognitive dysfunction of OSAHS is not likely to be due to a single mediating mechanism, nor is it pervasive across all patients. Future research should attempt to identify these moderators for cognitive dysfunction in OSAHS and to highlight the mechanisms of dysfunction by cognitive domain. PMID- 21531246 TI - Effects of the use of hypnotics on cognition. AB - Hypnotic drugs are intended to induce sedation and promote sleep. As a result, they have deteriorating effects on cognitive performance following intake. Most hypnotics are benzodiazepine receptor agonists which can have effects on memory in addition to their sedative effects. Other sedating drugs, such as histamine H1 antagonists or melatonin agonists, may have less effect on memory and learning. Hypnotics with other mechanisms of action are currently being investigated for efficacy and safety. For patients using hypnotic drugs, the effects on cognition are relevant to the extent that a drug dose affects daytime performance. Use of benzodiazepine hypnotics is associated with increased risk of car accidents and falling. Therefore, most hypnotics are studied to determine whether they produce residual sedation and impairing effects on performance the morning after bedtime use. Experimental studies using a standardized driving test clearly show that some drugs and doses produce severe residual effects, whereas others seem to have no or only minor impairing effects on next-day performance. No hypnotic has been found yet to improve daytime performance. Studies on long-term use of benzodiazepine hypnotics suggest that effects on daytime performance may diminish over time due to tolerance. However, there are also studies showing that performance may improve after discontinuation of chronic benzodiazepine use, which suggests that tolerance may not be complete. PMID- 21531247 TI - Effects of caffeine on sleep and cognition. AB - Caffeine can be used effectively to manipulate our mental state. It is beneficial in restoring low levels of wakefulness and in counteracting degraded cognitive task performance due to sleep deprivation. However, caffeine may produce detrimental effects on subsequent sleep, resulting in daytime sleepiness. This justifies a careful consideration of risks related to sleep deprivation in combination with caffeine consumption, especially in adolescents. The efficacy of caffeine to restore detrimental effects of sleep deprivation seems to be partly due to caffeine expectancy and to placebo effects. The claim that stimulant effects of caffeine are related to withdrawal or withdrawal reversal seems to be untenable. PMID- 21531248 TI - Can light make us bright? Effects of light on cognition and sleep. AB - Light elicits robust nonvisual effects on numerous physiological and behavioral variables, such as the human sleep-wake cycle and cognitive performance. Light effects crucially rely on properties such as dose, duration, timing, and wavelength. Recently, the use of methods such as fMRI to assess light effects on nonvisual brain responses has revealed how light can optimize brain function during specific cognitive tasks, especially in tasks of sustained attention. In this chapter, we address two main issues: how light impinges on cognition via consolidation of human sleep-wake cycles; and how light directly impacts on sleep and cognition, in particular in tasks of sustained attention. A thorough understanding of how light affects sleep and cognitive performance may help to improve light settings at home and at the workplace in order to improve well being. PMID- 21531249 TI - Sleep's effects on cognition and learning in adolescence. AB - Adolescence is accompanied by striking changes in sleep behavior and in the phenomenology of sleep. Maturational changes in the central nervous system underlie changes in adolescent sleep structure. Sleep behaviors change during adolescence in response to maturational changes in sleep regulatory processes and competing behaviors. This pattern leads to insufficient sleep for many teens on school nights. Associations of reduced sleep with poorer school performance beg the question of how prelearning and posttraining sleep affect the learning process. Thus, insufficient sleep can impair acquisition and retrieval when sleep reduction results in sleepiness, irritability, distractibility, inattention, and lack of motivation. Strong evidence indicates that adequate sleep enhances memory consolidation and resistance to interference. Hence, insufficient sleep can also threaten learning by jeopardizing this part of the memory formation process. PMID- 21531250 TI - Individual differences in cognitive vulnerability to fatigue in the laboratory and in the workplace. AB - Individual differences in cognitive functioning during extended work hours and shift work are of considerable magnitude, and observed both in the laboratory and in the workplace. These individual differences have a biological basis in trait like, differential vulnerability to fatigue from sleep loss and circadian misalignment. Trait-like vulnerability is predicted in part by gene polymorphisms and other biological or psychological characteristics, but for the larger part it remains unexplained. A complicating factor is that whether individuals are vulnerable or resilient to sleep deprivation depends on the fatigue measure considered--subjective versus objective assessment, or one cognitive task versus another. Such dissociation has been observed in laboratory data published previously, and in data from a simulated operational setting first presented here. Discordance between subjective and objective measures of fatigue has been documented in various contexts, and may be one of the reasons why vulnerable individuals do not systematically opt out of professions involving high cognitive demands and exposure to fatigue. Discordance in vulnerability to fatigue among different measures of cognitive performance may be related to the "task impurity problem," which implies that interrelated cognitive processes involved in task performance must be distinguished before overall performance outcomes can be fully understood. Experimental studies and cognitive and computational modeling approaches are currently being employed to address the task impurity problem and gain new insights into individual vulnerability to fatigue across a wide range of cognitive tasks. This ongoing research is driving progress in the management of risks to safety and productivity associated with vulnerability to cognitive impairment from fatigue in the workplace. PMID- 21531251 TI - Predicting cognitive impairment and accident risk. AB - Sleep and cognition are temporally regulated by a homeostatic process generating pressure for sleep as a function of sleep/wake history, and a circadian process generating pressure for wakefulness as a function of time of day. Under normal nocturnal sleep conditions, these two processes are aligned in such a manner as to provide optimal daytime performance and consolidated nighttime sleep. Under conditions of sleep deprivation, shift work or transmeridian travel, the two processes are misaligned, resulting in fatigue and cognitive deficits. Mathematical models of fatigue and performance have been developed to predict these cognitive deficits. Recent studies showing long-term effects on performance of chronic sleep restriction suggest that the homeostatic process undergoes gradual changes that are slow to recover. New developments in mathematical modeling of performance are focused on capturing these gradual changes and their effects on fatigue. Accident risk increases as a function of fatigue severity as well as the duration of exposure to fatigue. Work schedule and accident rate information from an operational setting can thus be used to calibrate a mathematical model of fatigue and performance to predict accident risk. This provides a fatigue risk management tool that helps to direct mitigation resources to where they would have the greatest mitigating effect. PMID- 21531252 TI - Sleep loss and accidents--work hours, life style, and sleep pathology. AB - A very important outcome of reduced sleep is accidents. The present chapter will attempt to bring together some of the present knowledge in this area. We will focus on the driving situation, for which the evidence of the link between sleep loss and accidents is quite well established, but we will also bring up working life in general where evidence is more sparse. It should be emphasized that reduced sleep as a cause of accidents implies that the mediating factor is sleepiness (or fatigue). This link is discussed elsewhere in this volume, but here we will bring in sleepiness (subjective or physiological) as an explanatory factor of accidents. Another central observation is that many real life accident studies do not link accidents to reduced sleep, but infer reduced sleep and/or sleepiness from the context, like, for example, from work schedules, life styles, or sleep pathology. Reduced sleep is mainly due to suboptimal work schedules (or to a suboptimal life style) or to sleep pathology. We have divided the present chapter into two areas. PMID- 21531253 TI - Occupational sleep medicine: practice and promise. AB - Occupational sleep medicine is a new field within sleep medicine. Occupational sleep medicine applies (1) the science of sleep, frequently as instantiated into mathematical modeling; (2) the tactics, techniques, and procedures of sleep and performance measurement in the operational environment; and (3) the clinical practice of sleep medicine to reduce the risks of poor performance, lost productivity, and error, incident, and accident in the workplace. As envisioned here, occupational sleep medicine will play a crucial role in fatigue risk management to, in the short term, improve performance, productivity, and safety and in the longer term improve worker health and well-being. PMID- 21531254 TI - Can oral pathogens influence allergic disease? AB - The hygiene hypothesis contends that fewer opportunities for infections and microbial exposures have resulted in more widespread asthma and atopic disease. Consistent with that hypothesis, decreases in infectious oral diseases over the past half century have coincided with increases in the prevalence of asthma and other allergic diseases. This observation has led some researchers to speculate that exposures to oral bacteria, including pathogens associated with periodontal diseases, such as gingivitis and periodontitis, might play a protective role in the development of asthma and allergy. Colonization of the oral cavity with bacteria, including some species of periodontal pathogens, begins shortly after birth, and the detection of serum antibodies to oral pathogens in early childhood provides evidence of an early immune response to these bacteria. Current knowledge of the immune response to oral bacteria and the immunologic pathogenesis of periodontal diseases suggests biologically plausible mechanisms by which oral pathogens could influence the risk of allergic disease. However, studies investigating the association between oral pathogen exposures and allergic disease are few in number and limited by cross-sectional or case-control design, exclusion of young children, and use of surrogate measures of oral bacterial colonization. Additional studies, particularly well-designed case control studies among very young children and prospective birth cohort studies, are needed. PMID- 21531256 TI - The three stages of Alzheimer's disease. PMID- 21531257 TI - Artesunate for severe malaria. PMID- 21531258 TI - Strengthening the regulation of herbal medicines in Europe. PMID- 21531260 TI - Colin Sullivan: inventive pioneer of sleep medicine. PMID- 21531261 TI - Initial combination therapy for treatment of hypertension. PMID- 21531262 TI - Initial combination therapy for treatment of hypertension. PMID- 21531263 TI - Initial combination therapy for treatment of hypertension. PMID- 21531265 TI - The complexity of ABO in coronary heart disease. PMID- 21531266 TI - The complexity of ABO in coronary heart disease. PMID- 21531268 TI - Live case demonstrations: patient safety, ethics, consent, and conflicts. PMID- 21531269 TI - A deadly aversion to pork. PMID- 21531270 TI - Isolation of Burkholderia cenocepacia J 2315 from non-cystic fibrosis pediatric patients in India. AB - We report for the first time 2 cases of multidrug-resistant Burkholderia cenocepacia J2315 isolated from blood samples of patients without cystic fibrosis from a pediatric unit in a hospital in India. The first patient presented with community-acquired bacteremia, and the second patient was immunocompromised and developed hospital-acquired infection approximately 17 days after admission. The isolates from both patients were multidrug-resistant and strong biofilm producers. Surveillance cultures identified the secondary sources of the infections, but not the primary sources. PMID- 21531271 TI - Nursing home deficiency citations for infection control. AB - BACKGROUND: This study examined the deficiency citation for infection control (ie, F-Tag 441). This information represents potential problems in infection control as identified in the yearly certification process of almost all US nursing homes. METHODS: The data used came primarily from the Online Survey, Certification, and Reporting data base, which contains information on both deficiency citations and characteristics of nursing homes. The data for each nursing home from 2000 through 2007 were combined, providing a panel of 100,000 observations. Multivariate analyses and generalized estimating equations with a logit link were used. RESULTS: An average of 15% of all nursing homes received a deficiency citation for infection control each year from 2000 to 2007. In the multivariate analyses, several staffing levels were robust in their significance. For all 3 types of caregiver examined (ie, nurse aides, Licensed Practical Nurses, and Registered Nurses), low staffing levels were associated with receipt of a deficiency citation for infection control. CONCLUSION: The high number of deficiency citations for infection control problems identified in this study suggests the need for increased emphasis on these programs in nursing homes to protect vulnerable elders. PMID- 21531272 TI - Hospital adoption of automated surveillance technology and the implementation of infection prevention and control programs. AB - BACKGROUND: This research analyzes the relationship between hospital use of automated surveillance technology (AST) for identification and control of hospital-acquired infections (HAI) and implementation of evidence-based infection control practices. Our hypothesis is that hospitals that use AST have made more progress implementing infection control practices than hospitals that rely on manual surveillance. METHODS: A survey of all acute general care hospitals in California was conducted from October 2008 through January 2009. A structured computer-assisted telephone interview was conducted with the quality director of each hospital. The final sample includes 241 general acute care hospitals (response rate, 83%). RESULTS: Approximately one third (32.4%) of California's hospitals use AST for monitoring HAI. Adoption of AST is statistically significant and positively associated with the depth of implementation of evidence-based practices for methicillin-resistant Staphylococcus aureus and ventilator-associated pneumonia and adoption of contact precautions and surgical care infection practices. Use of AST is also statistically significantly associated with the breadth of hospital implementation of evidence-based practices across all 5 targeted HAI. CONCLUSION: Our findings suggest that hospitals using AST can achieve greater depth and breadth in implementing evidenced-based infection control practices. PMID- 21531273 TI - A realistic approach towards hand hygiene for long-term care residents and health care personnel. AB - The Centers for Disease Control and Prevention and The World Health Organization's hand hygiene recommendations focus on health care personnel in all health care settings. In the long-term care facility (LTCF) environment, where, for many residents, the LTCF is also their home, the recommendations may not be applicable to commonly encountered LTCF situations. The recommendations also do not address the importance of resident hand hygiene program to promote health and prevent infection. PMID- 21531274 TI - Measurement of hand hygiene compliance and gloving practices in different settings for the elderly considering the location of hand hygiene opportunities during patient care. AB - We monitored hand hygiene and gloving practices by direct observation in 8 health care settings for elderly persons in western France. Compliance with hand hygiene was better than that reported by previous studies, was better for single contacts and before or after a series of successive contacts than inside series, and was closely related to gloving practices. Practices differed among the settings. PMID- 21531275 TI - Evaluation of a geriatric inpatient influenza immunization program. AB - This study evaluated a hospital influenza immunization program for inpatients aged >=65 years during the 2008-2009 influenza season. Of the 520 inpatients in this age group, 45.0% had documented eligibility screening and 23.1% received vaccination in the hospital. Staff and physicians participating in interviews felt that standardizing processes and improving documentation could help enhance the existing program. PMID- 21531276 TI - "Comment, culture, and research"!? PMID- 21531277 TI - Implementation of chlorhexidine gluconate in the prevention of line-related infection. PMID- 21531278 TI - Only automated surveillance with 100% sensitivity can save ICPs' time. PMID- 21531279 TI - Prevention of needlestick injuries among health care workers. PMID- 21531280 TI - [Specialists in emergency family medicine]. PMID- 21531281 TI - What Kraepelin might say about schizophrenia: just the facts. PMID- 21531282 TI - Validation of an amino-acid-based radionuclide therapy plus external beam radiotherapy in heterotopic glioblastoma models. AB - BACKGROUND AND PURPOSE: Malignant gliomas represent a major therapeutic challenge because no efficient treatment is currently available. p-[(131)I]iodo-L phenylalanine ([(131)I]IPA) is a glioma avid radiopharmaceutical that demonstrated antiproliferative and tumoricidal effects in gliomas. The present study validated the therapeutic efficiency of [(131)I]IPA combined with external beam radiotherapy in experimental gliomas. MATERIALS AND METHODS: Glioma cells derived from the primary human A1207, T5135, Tx3868 and M059K glioblastoma cell lines or rat F98 glioma cell line were treated with various doses of [(131)I]IPA, external photon irradiation (RT) or combined [(131)I]IPA/RT treatment. Responsiveness of glioma cells to the different therapy modalities was investigated at 24, 48 and 72 h after treatments by trypan blue, WST-1 assay, propidium iodide and bisbenzimide staining as well as by clonogenic assay. In addition, the therapy-induced DNA damage and repair were evaluated using phosphorylated histone H2AX (gamma-H2AX). In vivo, the effectiveness of the combination treatment was validated in human Tx3868 and A1207 glioblastoma xenografts in CD1 nu/nu mice and RNU rats. RESULTS: In vitro, the combination treatment resulted in a greater than additive increase in cytotoxic effect in glioma cell lines. Cell survival rate following a treatment with 1.0 MUCi (37 kBq) of [(131)I]IPA amounted to 70%+/-15% and 60%+/-10% after 48 and 72 h, respectively, and decreased under 20% after additional RT with 5 Gy. At higher RT doses, cell survival rate decreased below 5%. As a measure of DNA double-strand break, nuclear gamma-H2AX foci were determined as a function of time. Within 24 h, the number of gamma-H2AX foci per cell was significantly greater after combined modality compared with the individual treatments. In vivo, when combined with RT, the radionuclide therapy with [(131)I]IPA resulted in an extended tumor growth delay, a reduction of the initial tumor volume and an enhanced radiosensitivity in Tx3868 and A1207 glioblastoma xenografts in CD1 nu/nu mice and RNU rats. On day 90 after monotherapy with [(131)I]IPA (20 MBq) or RT (20 Gy), 35%-50% of the treated rats were still alive. In comparison, up to 70%-80% survival rates were registered after combined [(131)I]IPA/RT treatment on day 100 for all animal models. CONCLUSIONS: These preclinical data convincingly demonstrated that [(131)I]IPA plus external beam photon radiotherapy is a safe and highly effective treatment for experimental gliomas, which may merit a clinical trial to ascertain its potential as a therapeutic approach in patients. As only a low [(131)I]IPA activity and a low RT dose were applied, further optimization strategies should be pursued experimentally, including application of higher radiation doses and conventional fractionated regimens or use of methods aiming to increase target doses and maximize dose effects. PMID- 21531283 TI - Radiopharmacological evaluation of 6-deoxy-6-[18F]fluoro-D-fructose as a radiotracer for PET imaging of GLUT5 in breast cancer. AB - INTRODUCTION: Several clinical studies have shown low or no expression of GLUT1 in breast cancer patients, which may account for the low clinical specificity and sensitivity of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) used in positron emission tomography (PET). Therefore, it has been proposed that other tumor characteristics such as the high expression of GLUT2 and GLUT5 in many breast tumors could be used to develop alternative strategies to detect breast cancer. Here we have studied the in vitro and in vivo radiopharmacological profile of 6 deoxy-6-[(18)F]fluoro-D-fructose (6-[(18)F]FDF) as a potential PET radiotracer to image GLUT5 expression in breast cancers. METHODS: Uptake of 6-[(18)F]FDF was studied in murine EMT-6 and human MCF-7 breast cancer cells over 60 min and compared to [(18)F]FDG. Biodistribution of 6-[(18)F]FDF was determined in BALB/c mice. Tumor uptake was studied with dynamic small animal PET in EMT-6 tumor bearing BALB/c mice and human xenograft MCF-7 tumor-bearing NIH-III mice in comparison to [(18)F]FDG. 6-[(18)F]FDF metabolism was investigated in mouse blood and urine. RESULTS: 6-[(18)F]FDF is taken up by EMT-6 and MCF-7 breast tumor cells independent of extracellular glucose levels but dependent on the extracellular concentration of fructose. After 60 min, 30+/-4% (n=9) and 12+/-1% (n=7) ID/mg protein 6-[(18)F]FDF was found in EMT-6 and MCF-7 cells, respectively. 6-deoxy-6-fluoro-d-fructose had a 10-fold higher potency than fructose to inhibit 6-[(18)F]FDF uptake into EMT-6 cells. Biodistribution in normal mice revealed radioactivity uptake in bone and brain. Radioactivity was accumulated in EMT-6 tumors reaching 3.65+/-0.30% ID/g (n=3) at 5 min post injection and decreasing to 1.75+/-0.03% ID/g (n=3) at 120 min post injection. Dynamic small animal PET showed significantly lower radioactivity uptake after 15 min post injection in MCF-7 tumors [standard uptake value (SUV)=0.76+/-0.05; n=3] compared to EMT-6 tumors (SUV=1.23+/-0.09; n=3). Interestingly, [(18)F]FDG uptake was significantly different in MCF-7 tumors (SUV(15 min) 0.74+/-0.12 to SUV(120 min) 0.80+/-0.15; n=3) versus EMT-6 tumors (SUV(15 min) 1.01+/-0.33 to SUV(120 min) 1.80+/-0.25; n=3). 6-[(18)F]FDF was shown to be a substrate for recombinant human ketohexokinase, and it was metabolized rapidly in vivo. CONCLUSION: Based on the GLUT5 specific transport and phosphorylation by ketohexokinase, 6 [(18)F]FDF may represent a novel radiotracer for PET imaging of GLUT5 and ketohexokinase-expressing tumors. PMID- 21531284 TI - Nucleophilic radiosynthesis of 2-[18F]fluoro-2-deoxy-D-galactose from Talose triflate and biodistribution in a porcine model. AB - INTRODUCTION: The galactose analogue 2-[(18)F]fluoro-2-deoxy-D-galactose (FDGal) is a promising positron emission tomography (PET) tracer for studies of regional differences in liver metabolic function and for clinical evaluation of patients with liver cirrhosis and patients undergoing treatment of liver diseases. However, there is an unmet need for routine production of FDGal from readily available starting material. In this study, we present the preparation of FDGal with high radiochemical purity and in amounts sufficient for clinical investigations from commercially available Talose triflate (1,3,4,6-tetra-O acetyl-2-O-trifluoromethanesulfonyl-beta-D-talopyranose). In addition, the biodistribution of FDGal in the pig is presented. METHODS: FDGal was prepared by nucleophilic fluorination of Talose triflate followed by basic hydrolysis. The entire synthesis was performed using the GE TRACERlab MX 2-[(18)F]fluoro-2-deoxy D-glucose (FDG) synthesizer and existing methods for quality control of FDG were applied. Biodistribution of FDGal was studied by successive whole-body PET recordings of two anaesthetized 37-kg pigs. RESULTS: Up to 3.7 GBq sterile, pyrogen-free and no-carrier-added FDGal was produced with a radiochemical yield of 3.8+/-1.2% and a radiochemical purity of 98+/-1% (42 productions; yield is decay corrected). The adopted quality control methods for FDG were directly applicable for FDGal. Biodistribution studies in the pig revealed the liver and the urinary bladder as critical organs in terms of radiation dose. CONCLUSION: Commercially available Talose triflate is a suitable starting material for routine productions of FDGal. The presented radiosynthesis and quality control methods allow for the production of pure, no-carrier-added FDGal in sufficient amounts for clinical PET-investigations of the liver. PMID- 21531285 TI - Noninvasive assessment of cell proliferation in ovarian cancer using [18F] 3'deoxy-3-fluorothymidine positron emission tomography/computed tomography imaging. AB - INTRODUCTION: Positron emission tomography (PET)/computed tomography (CT) imaging of suspected new and recurrent ovarian carcinoma was performed to assess the relationship between [(18)F] 3'deoxy-3'fluorothymidine ((18)FLT) uptake and histopathological tissue markers of cellular proliferation (Ki67) and thymidine kinase-1 (TK-1) expression. METHODS: Six subjects were included in this pilot study. Subjects were injected with 5 mCi of (18)FLT prior to a planned surgery and then scanned on a GE Discovery-ST PET/CT scanner within an hour of injection. Regions of interest in tumor and control tissue were identified on the diagnostic CT scans and marked for later surgical biopsy. Surgery was performed within 2 days after the scan. At the time of surgery, the regions of interest identified on PET/CT were available to guide the surgeon to the tumor biopsy sites. Tissue from normal ovarian tissue control regions was also sampled. (18)FLT uptake in tumor and control tissue regions was calculated by measuring the maximum standardized uptake values (SUV(max)). The excised tumor and normal ovarian tissue control tissues were analyzed by immunohistochemical staining for Ki67 and CD34. TK-1 messenger RNA expression was measured by real-time polymerase chain reaction. RESULTS: (18)FLT uptake (SUV(max)) was higher in malignant (mean 4.85/range 1.7-8.8) compared to benign (1.65/range 1.4-1.9) and normal ovarian control tissue (1.12/range 0.6-1.5). Mitotic index, as determined by Ki67 staining, was higher in malignant (18.89/range 11.97-27.19) compared to benign (0.59/range 0.23-0.95) and control tissue (0.45/range 0.06-1.20). TK-1 expression was also higher in malignant (35.52/range 5.21-106.62) compared to benign (8.71/range 4.74-12.67) and control tissue (9.79/range 0.85-39.46). An increasing trend between (18)FLT uptake and Ki67 mitotic index is seen in malignant tissue CD 34 staining between malignant, benign and control tissues was not qualitatively different. CONCLUSION: An increasing trend between (18)FLT uptake and Ki67 mitotic index is seen in malignant tissue. Additional studies will determine whether (18)FLT PET/CT is specific enough to distinguish between cancerous and noncancerous cells and to assess its role in ovarian carcinoma patient management. PMID- 21531286 TI - Development of the radiosynthesis of high-specific-activity 123I-NKJ64. AB - INTRODUCTION: (123)I-NKJ64, a reboxetine analogue, is currently under development as a potential novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain. This study describes the development of the radiosynthesis of (123)I-NKJ64, highlighting the advantages and disadvantages, pitfalls and solutions encountered while developing the final radiolabelling methodology. METHODS: The synthesis of (123)I-NKJ64 was evaluated using an electrophilic iododestannylation method, where a Boc-protected trimethylstannyl precursor was radioiodinated using peracetic acid as an oxidant and deprotection was investigated using either trifluoroacetic acid (TFA) or 2 M hydrochloric acid (HCl). RESULTS: Radioiodination of the Boc-protected trimethylstannyl precursor was achieved with an incorporation yield of 92+/-6%. Deprotection with 2 M HCl produced (123)I-NKJ64 with the highest radiochemical yield of 98.05+/-1.63% compared with 83.95+/-13.24% with TFA. However, the specific activity of the obtained (123)I-NKJ64 was lower when measured after using 2 M HCl (0.15+/-0.23 Ci/MUmol) as the deprotecting agent in comparison to TFA (1.76+/-0.60 Ci/MUmol). Further investigation of the 2 M HCl methodology found a by-product, identified as the deprotected proto-destannylated precursor, which co-eluted with (123)I-NKJ64 during the high-performance liquid chromatography (HPLC) purification. CONCLUSIONS: The radiosynthesis of (123)I NKJ64 was achieved with good isolated radiochemical yield of 68% and a high specific activity of 1.8 Ci/MUmol. TFA was found to be the most suitable deprotecting agent, since 2 M HCl generated a by-product that could not be fully separated from (123)I-NKJ64 using the HPLC methodology investigated. This study highlights the importance of HPLC purification and accurate measurement of specific activity while developing new radiosynthesis methodologies. PMID- 21531288 TI - Evaluation of 4-[18F]fluorobenzoyl-FALGEA-NH2 as a positron emission tomography tracer for epidermal growth factor receptor mutation variant III imaging in cancer. AB - INTRODUCTION: This study describes the radiosynthesis, in vitro and in vivo evaluation of the novel small peptide radioligand, 4-[(18)F]fluorobenzoyl-Phe-Ala Leu-Gly-Glu-Ala-NH(2,) ([(18)F]FBA-FALGEA-NH(2)) as a positron emission tomography (PET) tracer for imaging of the cancer specific epidermal growth factor receptor (EGFR) variant III mutation, EGFRvIII. METHODS: For affinity, stability and PET measurements, H-FALGEA-NH(2) was radiolabelled using 4 [(18)F]fluorobenzoic acid ([(18)F]FBA). The binding affinity of ([(18)F]FBA) FALGEA-NH(2) was measured on EGFRvIII expressing cells, NR6M. Stability studies in vitro and in vivo were carried out in blood plasma from nude mice. PET investigations of [(18)F]FBA-FALGEA-NH(2) were performed on a MicroPET scanner, using seven nude mice xenografted subcutaneously with human glioblastoma multiforme (GBM) tumours, expressing the EGFRvIII in its native form, and five nude mice xenografted subcutaneously with GBM tumours lacking EGFRvIII expression. Images of [(18)F]FDG were also obtained for comparison. The mice were injected with 5-10 MBq of the radiolabelled peptide or [(18)F]FDG. Furthermore, the gene expression of EGFRvIII in the tumours was determined using quantitative real-time PCR. RESULTS: Radiolabelling and purification was achieved within 180 min, with overall radiochemical yields of 2.6-9.8% (decay-corrected) and an average specific radioactivity of 6.4 GBq/MUmol. The binding affinity (K(d)) of [(18)F]FBA-FALGEA-NH(2) to EGFRvIII expressing cells was determined to be 23 nM. The radiolabelled peptide was moderately stable in the plasma from nude mice where 53% of the peptide was intact after 60 min of incubation in plasma but rapidly degraded in vivo, where no intact peptide was observed in plasma 5 min post-injection. The PET imaging showed that [(18)F]FBA-FALGEA-NH(2) accumulated preferentially in the human GBM xenografts which expressed high amounts of the mutated receptor. The average tumour-to-muscle ratio (T/M) in the EGFRvIII tumours was 7.8 at 60 min post-injection, compared with 4.6 in the wild-type EGFR tumours. Furthermore, there was a strong correlation (R=0.86, P=.007) between the expression of EGFRvIII in the tumours and the tracer uptake expressed as T/M. CONCLUSION: Our results indicate that, despite its rapid metabolism, [(18)F]FBA FALGEA-NH(2) binds preferentially to EGFRvIII in the tumours in vivo and is a promising lead for further development of EGFRvIII specific peptide radiopharmaceuticals. PMID- 21531287 TI - Synthesis and evaluation of two novel 2-nitroimidazole derivatives as potential PET radioligands for tumor imaging. AB - INTRODUCTION: Nitroimidazole (azomycin) derivatives labeled with radioisotopes have been developed as cancer imaging and radiotherapeutic agents based on the oncological hypoxic mechanism. By attaching nitroimidazole core with different functional groups, we synthesized new nitroimidazole derivatives and evaluated their potentiality as tumor imaging agents. METHODS: Starting with commercially available 2-nitroimidazole, 2-fluoro-N-(2-(2-nitro-1H-imidazol-1 yl)ethyl)acetamide (NEFA, [(19)F]7) and 2-(2-methyl-5-nitro-1H-imidazol-1 yl)ethyl 2-fluoroacetate (NEFT, [(19)F]8), as well as radiolabeling precursors, the bromo-substituted analogs were quickly synthesized through a three-step synthetic pathway. The precursors were radiolabeled with [(18)F]F(-)/18-crown 6/KHCO(3) in dimethyl sulfoxide at 90 degrees C for 10 min followed by purification with an Oasis HLB cartridge. Biodistribution studies were carried out in EMT-6 tumor-bearing mice. The uptake (%ID/g) in tumors and normal tissues were measured at 30 min postinjection. Liquid chromatography-electrospray ionization mass spectrometry (LC/MS) was used to distinguish metabolites from parent drugs in urine and plasma of rat injected with "cold" NEFA ([(19)F]7) and NEFT ([(19)F]8). RESULTS: Two radiotracers, [(18)F]NEFA ([(18)F]7) and [(18)F]NEFT ([(18)F]8), were prepared with average yields of 6%-7% and 9%-10% (not decay corrected). Radiochemical purity for both tracers was >95% as determined by HPLC. Biodistribution studies in EMT-6 tumor-bearing mice indicated that the tumor to blood and tumor to liver ratios of both [(18)F]7 (0.96, 0.61) and [(18)F]8 (0.98, 1.10) at 30 min were higher than those observed for [(18)F]FMISO (1) (0.91, 0.59), a well-investigated azomycin-type hypoxia radiotracer. Liquid chromatography-electrospray ionization mass spectrometry analysis demonstrated that fluoroacetate was the main in vivo metabolite for both NEFA ([(19)F]7) and NEFT ([(19)F]8). CONCLUSIONS: In this research, two new fluorine-18 labeled 2-nitroimidazole derivatives, [(18)F]7 and [(18)F]8, both of which containing in vivo hydrolyzable group, were successfully prepared. Further biological evaluations are warranted to investigate their potential as PET radioligands for imaging tumor. PMID- 21531289 TI - In vivo evaluation of carbon-11-labelled non-sarcosine-based glycine transporter 1 inhibitors in mice and conscious monkeys. AB - INTRODUCTION: Glycine transporter 1 (GlyT-1) is an attractive target in positron emission tomography (PET) studies. Here, we report the in vivo evaluation of three carbon-11-labelled non-sarcosine-type GlyT-1 inhibitors--[(11)C]SA1, [(11)C]SA2 and [(11)C]SA3--as novel PET tracers for GlyT-1. METHODS: The regional brain distributions of the three compounds in mice were studied at baseline and under receptor-blockade conditions with co-injection of carrier loading or pretreatment with an excess of selective GlyT-1 inhibitors (ALX-5407 and SSR504734). Metabolic stability was investigated by radio high-performance liquid chromatography. Dynamic PET scans in conscious monkeys were performed with/without selective GlyT-1 inhibitors. RESULTS: The IC(50) values of SA1, SA2 and SA3 were 9.0, 6400 and 39.7 nM, respectively. The regional brain uptakes of [(11)C]SA1 and [(11)C]SA3 in mice were heterogeneous and consistent with the known distribution of GlyT-1. [(11)C]SA2 showed low and homogeneous uptake in the brain. Most radioactivity in the brain was detected in unchanged form, although peripherally these compounds were degraded. Carrier loading decreased the uptake of [(11)C]SA1 in GlyT-1-rich regions. However, similar reductions were not observed with [(11)C]SA3. Pretreatment with ALX-5407 decreased the uptake of [(11)C]SA1 in GlyT-1-rich regions. In the monkey at baseline, regional brain uptake of [(11)C]SA1 was heterogeneous and consistent with the known GlyT-1 distribution. Pretreatment with selective GlyT-1 inhibitors significantly decreased the distribution volume ratio of [(11)C] SA1 in GlyT-1-rich regions. CONCLUSIONS: [(11)C]SA1 has the most suitable profile among the three carbon-11 labelled GlyT-1 inhibitors. Lead optimization of [(11)C]SA1 structure will be required to achieve in vivo selective GlyT-1 imaging. PMID- 21531290 TI - Noninvasive visualization and quantification of tumor alphaVbeta3 integrin expression using a novel positron emission tomography probe, 64Cu-cyclam-RAFT-c( RGDfK-)4. AB - INTRODUCTION: The alpha(V)beta(3) integrin is a well-known transmembrane receptor involved in tumor invasion, angiogenesis and metastasis. Our aim was to evaluate a novel positron emission tomography (PET) probe, (64)Cu-cyclam-RAFT-c(-RGDfK )(4), for noninvasive visualization and quantification of alpha(V)beta(3) integrin expression. METHODS: RAFT-c(-RGDfK-)(4), a tetrameric cyclic Arg-Gly-Asp (RGD)-based peptide, was conjugated with a bifunctional chelator, 1,4,8,11 tetraazacyclotetradecane (cyclam), radiolabeled with the positron emitter (64)Cu and evaluated in vitro by cell binding and competitive inhibition assays and in vivo by biodistribution and receptor blocking studies, and PET imaging. The following cell lines, human embryonic kidney HEK293(beta(1)) [alpha(V)beta(3) negative] and HEK293(beta(3)) [alpha(V)beta(3)-overexpressing] and human glioblastoma U87MG [naturally expressing alpha(V)beta(3)], together with their subcutaneous xenografts in athymic nude mice, were used for the present study. The expression levels of alpha(V)beta(3) on these cell lines and tumor xenografts were analyzed by flow cytometry and sodium dodecyl sulfate-polyacrylamide gel electrophoresis/autoradiography, respectively. RESULTS: (64)Cu-cyclam-RAFT-c( RGDfK-)(4) demonstrated the in vitro and in vivo specificity for the alpha(V)beta(3) integrin and displayed rapid blood clearance, predominantly renal excretion and low uptake in nontumor tissues. Tumor uptake of (64)Cu-cyclam-RAFT c(-RGDfK-)(4) (3 h postinjection) in HEK293(beta(3)) (high levels of alpha(V)beta(3)), U87MG (moderate levels of alpha(V)beta(3)) and HEK293(beta(1)) (undetectable levels of alpha(V)beta(3)) tumors was 9.35%+/-1.19%, 3.46%+/-0.45% and 1.18%+/-0.30% injected dose per gram, respectively, with a strong and positive correlation with the tumor alpha(V)beta(3) expression levels (correlation coefficient=0.967; P<.0001). Positron emission tomographic images showed that alpha(V)beta(3)-positive tumors were clearly visualized with high tumor-to-background contrast, and agreed well with the biodistribution results. CONCLUSION: (64)Cu-cyclam-RAFT-c(-RGDfK-)(4) exhibits potential for noninvasively quantifying alpha(V)beta(3) expression. PMID- 21531291 TI - Binding of 2-[18F]fluoro-CP-118,954 to mouse acetylcholinesterase: microPET and ex vivo Cerenkov luminescence imaging studies. AB - Acetylcholinesterase (AChE) has been an important cholinergic factor for the diagnosis of Alzheimer's disease (AD), because of reduced AChE activity in the postmortem brains of AD patients. We previously developed 5,7-dihydro-3-(2-(1-(2 [(18)F]fluorobenzyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2,f)-1,2-benzisoxazol-6 one (2-[(18)F]fluoro-CP-118,954) for in vivo studies of AChE in mice. In the present study, we automated the synthesis of 2-[(18)F]fluoro-CP-118,954 for the routine use and evaluated the radioligand by microPET and ex vivo Cerenkov luminescence imaging of mouse AChE. 4-[(18)F]Fluoro-donepezil, another AChE inhibitor, was used for comparison. Automated syntheses of 2-[(18)F]fluoro-CP 118,954 and 4-[(18)F]fluoro-donepezil resulted in high radiochemical yields (25 33% and 30-40%) and high specific activity (27.1-35.4 and 29.7-37.3 GBq/MUmol). Brain microPET images of two ICR mice injected with 2-[(18)F]fluoro-CP-118,954 demonstrated high uptake in the striatum (ROI analysis: 5.1 %ID/g for the first 30 min and 4.1 %ID/g for another 30 min), and a blocking study with injection of CP-118,954 into one of the mice at 30 min after radioligand injection led to complete blocking of radioligand uptake in the striatum (ROI analysis: 1.9 %ID/g), whereas (18)F-labeled donepezil did not show specific uptake in the striatum. In another set of experiments, the brain tissues (striatum, parietal cortex, frontal cortex and cerebellum) were excised after brain microPET/CT imaging of mouse injected with 2-[(18)F]fluoro-CP-118,954, and a high striatal uptake was also detected in ex vivo optical and microPET images (ROI analysis: 1.4 %ID/g) and in gamma-counting data (2.1 %ID/g at 50 min post-injection) of the brain tissues. Taken together, these results demonstrated that 2-[(18)F]fluoro-CP 118,954 specifically binds to AChE in mouse brains. PMID- 21531292 TI - Labeling, stability and biodistribution studies of 99mTc-cyclized Tyr3-octreotate derivatives. AB - INTRODUCTION: To probe the interplay between radiotracer stability and somatostatin receptor affinity, Tyr(3)-octreotate and six variations of its peptide sequence, for which the Re-cyclized products were previously reported, were radiolabeled with (99m)Tc and investigated for their in vitro stability. METHODS: Radiolabeling of the peptides was effected by ligand exchange from (99m)Tc-glucoheptonate, and the desired products were purified by radio-RP-HPLC. The in vitro stability in phosphate buffered saline, mouse serum and cysteine solutions at physiological temperature and pH for all seven (99m)Tc-cyclized peptides was determined by radio-RP-HPLC and radio-TLC. Normal CF-1 mouse biodistribution studies were performed for three of the (99m)Tc-cyclized peptides. RESULTS: Based on the fully characterized Re-cyclized peptide analogues, four (99m)Tc-coordination motifs were proposed for the (99m)Tc cyclized peptides. Technetium-99m-cyclized Tyr(3)-octreotate derivatives with N(2)S(2) metal coordination modes and large metal ring sizes were susceptible to oxidation and loss of (99m)Tc in the form of (99m)TcO(4)(-), as evidenced by their instability in the various solutions under physiological conditions (15-58% intact at 24 h). As anticipated, the addition of a third cysteine to the sequence stabilized the (99m)Tc metal coordination, and peptides with NS(3) coordination modes remained >85% intact out to 24 h. No significant differences were observed in the biodistribution studies performed with three peptides of varying stabilities. CONCLUSIONS: Improvements in stability were not sufficient to outweigh the low somatostatin receptor affinity for the peptides in this study. Further improvements in the peptide sequence and/or metal coordination are needed to result in a radiodiagnostic/radiotherapeutic pair for targeting the somatostatin receptor. PMID- 21531293 TI - Synthesis and in vitro/in vivo evaluation of 99mTc-labeled folate conjugates for folate receptor imaging. AB - INTRODUCTION: Folate receptor (FR) is a potential molecular target for radionuclide imaging since it is overexpressed in many human epithelial tumor cells. In this study, a novel folate conjugate was synthesized and labeled with (99m)Tc using different coligands. In vitro and in vivo evaluations of these complexes have been done to explore the effect of coligands on the stable, affinity and pharmacokinetic properties. METHODS: A novel folate conjugate, HYNIC NHHN-FA, was synthesized and characterized. This conjugate was radiolabeled with (99m)Tc using tricine, tricine/diphenylphosphinobenzene-3-sulfonic acid sodium (TPPMS) and tricine/trisodium triphenylphosphine-3,3',3''-trisulfonate (TPPTS) as coligands, respectively. The complexes were purified by high-pressure liquid chromatography (HPLC). In vitro and in vivo evaluations were performed with FR positive KB cells, normal Kunming mice and athymic nude mice bearing KB tumors. RESULTS: Labeling with (99m)Tc using different coligands resulted in three complexes, (99m)Tc (HYNIC-NHHN-FA)(tricine), 5, (99m)Tc (HYNIC-NHHN FA)(tricine/TPPMS), 6 and (99m)Tc (HYNIC-NHHN-FA)(tricine/TPPTS), 7. Complex 5 showed at least two isomers and was unstable after being purified by HPLC. Complexes 6 and 7 displayed high stability and similar affinity to FR in vitro. Biodistribution results in athymic nude mice bearing KB tumor showed that complex 7 had a high uptake in FR-positive tumor (9.79+/-1.66%ID/g at 4 h postinjection), and the results of blockade studies confirmed the specific accumulation of the radiotracer in vivo. However, complex 6 showed a low tumor uptake due to its fast excretion via the gastrointestinal tract. CONCLUSION: The modification of the coligands can significantly alter the pharmacokinetic properties of the corresponding (99m)Tc-HYNIC complexes. (99m)Tc (HYNIC-NHHN-FA)(tricine/TPPTS), 7 could be a promising radiotracer for FR imaging. PMID- 21531294 TI - Evaluation of adenosine preconditioning with 99mTc-His10-annexin V in a porcine model of myocardium ischemia and reperfusion injury: preliminary study. AB - PURPOSE: The goal of this study was to evaluate the feasibility of (99m)Tc His(10)-annexin V for the detection of acute myocardial cell death and to assess the effect of adenosine preconditioning in a porcine model of myocardium ischemia and reperfusion injury (RI). MATERIALS AND METHODS: (99m)Tc-His(10)-annexin V was prepared by one-step direct labeling, and RCP and radiostability were tested. The binding of (99m)Tc-His(10)-annexin V to apoptosis was validated in vitro using camptothecin-induced Jurkat cells. In vivo biodistribution was determined in mice by the dissection method. Ischemia of 20-30 min was induced by balloon occlusion of the epicardial coronary artery of the porcine model (n=14). Adenosine was infused intravenously in six pigs before coronary occlusion. (99m)Tc-His(10) annexin V (n=12) was injected intravenously at 1 h after reperfusion. SPECT/CT was acquired at 3 h postinjection. Myocardial perfusion imaging (MPI) with (99m)Tc-MIBI was also performed 1 day after His(10)-annexin V imaging. Cardiac tissues were analyzed postmortem using hematoxylin-and-eosin and TUNEL staining. Caspase-3 activity was measured to confirm the presence of apoptosis. RESULTS: (99m)Tc-His(10)-annexin V had a RCP >98% and high stability 2 h after radiolabeling; it could bind to apoptotic cells with high affinity. Biodistribution of (99m)Tc-His(10)-annexin V showed a predominant uptake in the kidney and relatively low uptake in the myocardium, liver and gastrointestinal tract; rapid clearance from blood and kidney was observed. In the untreated group, intense uptake of His(10)-annexin V was visualized in the defect which was shown in MPI, whereas in the adenosine group a mild uptake of (99m)Tc-His(10) annexin was found in the risk area which showed no defects in the (99m)Tc-MIBI image. TUNEL staining and activated caspase-3 confirmed the ongoing apoptosis in RI. Adenosine preconditioning significantly diminished the level of apoptosis. Uptake of His(10)-annexin V in RI correlated with TUNEL-positive nuclei. CONCLUSION: This study addresses the feasibility of imaging of myocardial cell death in acute ischemia and RI in pigs with (99m)Tc-His(10)-annexin V; it holds prospect for the detection of myocardial cell death in clinical practice. Adenosine preconditioning could attenuate the myocardial apoptosis; its cardioprotective effect might partially be fulfilled by suppressing the ongoing apoptosis in ischemia and reperfusion. Further study is warranted. PMID- 21531295 TI - Development of a nano-zirconia based 68Ge/68Ga generator for biomedical applications. AB - INTRODUCTION: Most of the commercially available (68)Ge/(68)Ga generator systems are not optimally designed for direct applications in a clinical context. We have developed a nano-zirconia based (68)Ge/(68)Ga generator system for accessing (68)Ga amenable for the preparation of radiopharmaceuticals. METHODS: Nano zirconia was synthesized by the in situ reaction of zirconyl chloride with ammonium hydroxide in alkaline medium. The physical characteristics of the material were studied by various analytical techniques. A 740 MBq (20 mCi) (68)Ge/(68)Ga generator was developed using this sorbent and its performance was evaluated for a period of 1 year. The suitability of (68)Ga for labeling biomolecules was ascertained by labeling DOTA-TATE with (68)Ga. RESULTS: The material synthesized was nanocrystalline with average particle size of ~7 nm, pore-size of ~4 A and a high surface area of 340+/-10 m(2) g(-1). (68)Ga could be regularly eluted from this generator in 0.01N HCl medium with an overall radiochemical yield >80% and with high radionuclidic (<10(-5)% of (68)Ge impurity) and chemical purity (<0.1 ppm of Zr, Fe and Mn ions). The compatibility of the product for preparation of (68)Ga-labeled DOTA-TATE under the optimized reaction conditions was found to be satisfactory in terms of high labeling yields (>99%). The generator gave a consistent performance with respect to the elution yield and purity of (68)Ga over a period of 1 year. CONCLUSIONS: The feasibility of preparing an efficient (68)Ge/(68)Ga generator which can directly be used for biomedical applications has been demonstrated. PMID- 21531296 TI - Synthesis and in vivo evaluation of 201Tl(III)-DOTA complexes for applications in SPECT imaging. AB - INTRODUCTION: The aim of this study was to assess the use of (201)thallium(3+) ((201)Tl(3+)) as a radiolabel for nuclear imaging tracers. Methods for labeling of 1,4,7,10-tetraazacyclododecane-N,N',N",N'" tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA) chelators with (201)Tl(3+) were investigated, and the levels of stability of these chelates were tested in vitro and in vivo. METHODS: (201)Tl(I)Cl was treated with hydrochloric acid and ozone to form (201)Tl(III)Cl(3). The procedure for labeling of DOTA and DTPA was optimized, testing different buffer solutions and pH values. The stability levels of (201)Tl(III)-DOTA and (201)Tl(III)-DTPA were assessed in buffer, mouse serum and human serum (1:1, v/v) at a temperature of 310 K for 48 h. Subsequently, in vivo stability studies with (201)Tl(III)-DOTA were performed, comparing the biodistribution of (201)Tl(III)-DOTA with that of (201)Tl(I)Cl in a single isotope study and with that of (177)Lu(III)-DOTA in a dual-isotope single photon emission computed tomography study. RESULTS: (201)Tl(III)-DTPA, (201)Tl(III)-DOTA and (177)Lu(III)-DOTA were prepared with >95% radiochemical purity. While (201)Tl(III)-DOTA showed a prolonged level of stability in buffer and serum, (201)Tl was quickly released from DTPA in serum. Apart from some urinary excretion, the biodistribution of DOTA-chelated (201)Tl(3+) was similar to that of free (ionic) (201)Tl(+) and did not match the biodistribution of (177)Lu(III) DOTA. This indicated a limited stability of (201)Tl(III)-DOTA complexes in vivo. CONCLUSION: Despite promising results on the labeling and in vitro stability of (201)Tl(III)-DOTA, our in vivo results indicate that the integrity of (201)Tl(III)-DOTA decreases to <20% during the time required for urinary excretion, thereby limiting the use of (201)Tl(3+) as a radiolabel for tracer imaging. PMID- 21531297 TI - New automated synthesis of [18F]FP-CIT with base amount control affording high and stable radiochemical yield: a 1.5-year production report. AB - We describe new [(18)F]Fluoropropylcarbomethoxyiodophenyl-nor-tropane ([(18)F]FP CIT) automatic preparation method by (1) using 2-methyl-2-butanol as [(18)F]fluorination solvent, (2) base amount control to minimize side reaction and (3) salt elution method to elute trapped [(18)F]fluoride. We developed manual synthesis procedures for automatic synthesis application. In this manual synthesis, we trapped [(18)F]F(-) on ion exchange cartridge and eluted with 0.2 M potassium methanesulfonate solution. We have [(18)F]fluorination at 100 degrees C with 2-methyl-2-butanol as protic solvent for [(18)F]fluorination. After high performance liquid chromatography analysis, we have 69.3+/-3.2% of [(18)F]F(-) incorporation ratio on the manual synthesis and applied these conditions to automatic preparation with GE TracerLab FX module. After setting-up of automatic synthesis and quality control procedures for clinical procedures, we have routine production of [(18)F]FP-CIT with 86.9+/-9.5 GBq/2.5 ml of [(18)F]F(-) as initial radioactivity and have 192 productions for 1.5 year. We have 42.5+/-10.9% of decay corrected radiochemical yields and they were satisfied all quality control procedures and stability to 6 h. New [(18)F]FP-CIT automatic preparation method showed high and reliable radiochemical yield and we could have enough >35 patient doses of [(18)F]FP-CIT from one production. PMID- 21531298 TI - Feasibility of a novel positive feedback effect of 131I-promoted Bac-Egr1-hNIS expression in malignant glioma via baculovirus. AB - PURPOSE: As intracellular iodine is released rapidly, increased expression of sodium/iodide symporter (NIS) is required for effective radioiodine treatment of tumor. As Egr1 promoter is activated by 131I and may promote human NIS (hNIS) expression, hNIS also induces 131I uptake and activates Egr1, so the existence of a positive feedback effect of 131I-promoted Egr1-hNIS expression is possible. Our purpose was to investigate the possible existence of this positive feedback effect through a series of in vitro pioneer studies. METHOD: Recombinant baculovirus (Bac-Egr1-hNIS) encoding the hNIS gene under the control of a radiation-inducible Egrl promoter was constructed. To test 131I-promoted hNIS expression, human malignant glioma U87 cells were transfected with Bac-Egr1-hNIS, stimulated with or without 131I; the expression of hNIS protein was detected by immunofluorescence and flow cytometry test. In addition, the uptake and efflux of 131I were determined after the incubation of Bac-Egr1-hNIS-transfected U87 cells with or without 131I. RESULTS: Immunocytochemical staining and flow cytometry test showed a higher hNIS protein expression in Bac-Egr1-hNIS-transfected U87 cells with 131I stimulation than in cells without stimulation. Bac-Egr1-hNIS transfected U87 cells accumulated up to about 4.05 times of 131I after 131I stimulation. The amount of 131I uptake in both groups showed a baculovirus dose dependent manner. However, rapid efflux of radioactivity was observed in both groups, with 50% lost during the first 2 min after the 131I-containing medium had been replaced by a nonradioactive medium. CONCLUSION: Our results indicated that an improved transgene expression of 131I-stimulated hNIS in U87 cells using a baculovirus vector containing the Egr1 promoter is possible, and the increased expression of hNIS is responsible for a higher 131I uptake. It might provide a reference for the existence of a positive feedback effect in 131I-promoted Bac Egr1-hNIS expression in malignant glioma and is an interesting aspect of NIS related studies. PMID- 21531299 TI - Development and validation of an anion-exchange HPLC method for the determination of fluoride content and radiochemical purity in [18F]NaF. AB - (18)F-labeled sodium fluoride ([(18)F]NaF) is a useful bone imaging agent that has been demonstrated to be significantly more accurate than (99m)Tc-labeled methylene diphosphonate for the detection of both sclerotic and lytic lesions in various malignancies. A reliable anion-exchange HPLC method equipped with suppressed conductivity and radioactive detectors has been developed in order to analyze the content of NaF and radiochemical purity in [(18)F]NaF radiopharmaceuticals. The method described for fluoride analysis uses an isocratic elution of NaF in a Hamilton anion-exchange column using a mobile phase that consists of 7.5 mM sodium carbonate and 0.018 mM potassium thiocyanate. The flow rate was 1.0 ml/min. The method was validated in accordance with several parameters, including system suitability, specificity, precision, accuracy, linearity, robustness, limit of detection and limit of quantification. The results are described as follows: (1) The system suitability includes the tailing factor, theoretical plate number and resolution, which are 1.192534, 2729.6594 and 16.7415, respectively. (2) For specificity, the solvent peak and chloride ion did not interfere with the retention time of the fluoride. (3) The percentage coefficient of variation for analysis of precision, including repeatability and intermediate precision, is less than 2.0%. (4) Accuracy of method is within the range of 98%-102%. (5) The range of linearity is from 10 to 400 MUg/ml, with the correlation coefficient (R(2)) always being above 0.9985. (6) The data of method robustness are within acceptance criteria. (7) The limit of detection and limit of quantification are 0.0678 and 0.20 MUg/ml, respectively. All of the analysis results demonstrate that this method is highly sensitive, convenient, specific and suitable for quantification of NaF over a wide linear range. Therefore, the method can be successfully performed for routine analysis of fluoride content in [(18)F]NaF radiopharmaceuticals and reduce the time required for analysis. PMID- 21531300 TI - Health care reform and radiology education. PMID- 21531301 TI - Complications. PMID- 21531302 TI - The new ABR examination schedule and how it affects resident call: one community program's approach. PMID- 21531303 TI - Emotional intelligence. PMID- 21531304 TI - CT abdomen and pelvis: a case study in devaluation. PMID- 21531305 TI - ACR Appropriateness Criteria(r) on Hodgkin's lymphoma-unfavorable clinical stage I and II. AB - Combined-modality therapy, consisting of chemotherapy followed by radiation therapy (RT), represents the standard of care for most patients with unfavorable prognosis early-stage Hodgkin's lymphoma. The most widely accepted chemotherapy regimen is ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine); however, recent trials have evaluated other regimens such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and Stanford V. After chemotherapy, the standard radiation field is involved-field RT, although there is increasing interest now in involved-node RT. The authors review recent trials on chemotherapy and RT for unfavorable-prognosis early-stage Hodgkin's lymphoma. This article presents illustrative clinical cases, with treatment recommendations from an expert panel of radiation oncologists and medical oncologists. PMID- 21531307 TI - The value of clinical interventional radiology. AB - Interventional radiology (IR) is a vital component of diagnostic imaging (DI). The Society of Interventional Radiology has long held that the practice of IR should be clinical in nature, with dedicated clinical time, space, and infrastructure. The ACR has recognized the necessity of the clinical practice of IR. The cost to DI groups and hospitals of providing clinical IR is substantial. A willingness to invest in the creation or maintenance of a clinical IR service should be based on the value such an investment may provide. The author presents a 2-fold assessment of the value of IR. A review of the intangible value of IR to DI groups and facilities follows the presentation of an algorithm that ascribes a tangible, financial value to the provision of clinical IR services. The author provides an example of this algorithm applied to a mature, clinical IR practice. The author's assertion is that this value is compelling justification to warrant support of clinical IR. Additionally, the author's hope is that the utilization of this algorithm may allow DI groups to determine the financial value of clinical IR in their own settings. PMID- 21531306 TI - ACR white paper: Strategies for radiologists in the era of health care reform and accountable care organizations: a report from the ACR Future Trends Committee. AB - Accountable care organizations have received considerable attention as a component of health care reform and have been specifically addressed in recent national legislation and demonstration projects by CMS. The role or roles of radiologists in such organizations are currently unclear, as are changes to the ways in which imaging services will be delivered. The authors review concepts fundamental to accountable care organizations and describe roles for radiologists that may facilitate their success in such health care delivery systems. PMID- 21531308 TI - Summary of workshop on CT in emergency medicine: ensuring appropriate use. AB - This paper addresses the increasing use of CT in medical radiologic imaging, with a focus on applications in emergency medicine. The rapidly increasing use of CT in medical imaging over the past 3 decades has been a major subject in many recent publications, including a discussion of concerns about patient radiation doses, unnecessary CT examinations, and the costs of CT examinations. One area of these concerns has been the use of CT examinations for triage, selection of treatment options, and release of patients from emergency medical settings. On September 23 and 24, 2009, the National Council on Radiation Protection and Measurements held a workshop on appropriate uses of CT imaging with emergency patients. The workshop was cosponsored by 8 private and government organizations: the American Association of Physicists in Medicine, the American College of Emergency Physicians, the ACR, the American Society of Emergency Radiology, the Centers for Disease Control and Prevention, Landauer, Inc, the Society for Academic Emergency Medicine, and the US Environmental Protection Agency. This paper presents a summary of discussions at the workshop and recommendations for important areas of consideration in a subsequent consensus paper to be prepared on clinical guidance for applications of CT in emergency medicine procedures. PMID- 21531309 TI - Global quality imaging: improvement actions. AB - Workforce shortage, workload increase, workplace changes, and budget challenges are emerging issues around the world, which could place quality imaging at risk. It is important for imaging stakeholders to collaborate, ensure patient safety, improve the quality of care, and address these issues. There is no single panacea. A range of improvement measures, strategies, and actions are required. Examples of improvement actions supporting the 3 quality measures are described under 5 strategies: conducting research, promoting awareness, providing education and training, strengthening infrastructure, and implementing policies. The challenge is to develop long-term, cost-effective, system-based improvement actions that will bring better outcomes and underpin a sustainable future for quality imaging. In an imaging practice, these actions will result in selecting the right procedure (justification), using the right dose (optimization), and preventing errors along the patient journey. To realize this vision and implement these improvement actions, a range of expertise and adequate resources are required. Stakeholders should collaborate and work together. In today's globalized environment, collaboration is strength and provides synergy to achieve better outcomes and greater success. PMID- 21531310 TI - Incorporating gross anatomy education into radiation oncology residency: a 2-year curriculum with evaluation of resident satisfaction. AB - PURPOSE: Radiation oncologists require a thorough understanding of anatomy, but gross anatomy is not part of the standard residency curriculum. "Oncoanatomy" is an educational program for radiation oncology residents at Duke University that integrates cadaver dissection into the instruction of oncologic anatomy, imaging, and treatment planning. In this report, the authors document their experience with a 2-year curriculum. METHODS: Nineteen radiation oncology residents from Duke University and the University of North Carolina participated during academic years 2008-2009 and 2009-2010. Monthly modules, based on anatomic site, consisted of one or two clinically oriented hour-long lectures, followed by a 1-hour gross anatomy session. Clinical lectures were case based and focused on radiographic anatomy, image segmentation, and field design. Gross anatomy sessions centered on cadaver prosections, with small groups rotating through stations at which anatomists led cadaver exploration. Adjacent monitors featured radiologic imaging to facilitate synthesis of gross anatomy with imaging anatomy. Satisfaction was assessed on a 10-point scale via anonymous survey. RESULTS: Twenty modules were held over the 2-year period. Participants gave the course a median rating of 8 (interquartile range, 7-9), with 1 signifying "as effective as the worst educational activities" and 10 "as effective as the best educational activities." High resident satisfaction was seen with all module components. CONCLUSIONS: Incorporating a structured, 2-year gross anatomy-based curriculum into radiation oncology residency is feasible and associated with high resident satisfaction. PMID- 21531311 TI - Rewards. AB - For much of the 20th century, psychologists and economists operated on the assumption that work is devoid of intrinsic rewards, and the only way to get people to work harder is through the use of rewards and punishments. This so called carrot-and-stick model of workplace motivation, when applied to medical practice, emphasizes the use of financial incentives and disincentives to manipulate behavior. More recently, however, it has become apparent that, particularly when applied to certain kinds of work, such approaches can be ineffective or even frankly counterproductive. Instead of focusing on extrinsic rewards such as compensation, organizations and their leaders need to devote more attention to the intrinsic rewards of work itself. This article reviews this new understanding of rewards and traces out its practical implications for radiology today. PMID- 21531312 TI - A survey on the use of premedication prior to iodinated and gadolinium-based contrast material administration. AB - PURPOSE: The aim of this study was to assess Society of Uroradiology member use of premedication before the intravenous administration of low-osmolality iodinated contrast materials (LOCM) and gadolinium-based contrast materials (GBCM). METHODS: Society of Uroradiology members were invited to complete a Web based survey concerning the use of premedication. The survey included scenarios concerning intravenous LOCM or GBCM injection in which respondents were asked whether they would recommend premedication or withhold contrast material injection. Results for LOCM questions were compared with those for GBCM questions. Question responses for LOCM were also compared with those from a similar Society of Uroradiology survey published in 1995. RESULTS: Sixty-two of 72 respondents (86%) used standardized premedication regimens. Fifty-nine of 61 described regimens (97%) included oral corticosteroids and 48 (79%) antihistamines. Twenty of 69 respondents (29%) had separate urgent premedication regimens. There was general agreement concerning premedication use; however, responses were inconsistent in patients with severe food or medication allergies, severe symptomatic asthma, or prior mild urticarial reactions. More respondents recommended premedication before LOCM than GBCM administration. More respondents recommended premedication or avoidance of contrast material injection in patients with prior contrast reactions in the current study compared with the 1995 study. CONCLUSIONS: There is frequent agreement among uroradiologists concerning the use of corticosteroid prophylaxis, but there is inconsistency in some clinical situations. The threshold for premedication is often lower for LOCM than GBCM. Since 1995, recommendations for use of premedication have become more widespread. PMID- 21531313 TI - Impact of a quality assessment program on radiologist performance in ultrasound guided renal transplant biopsy. AB - PURPOSE: The purpose of this study was to analyze the impact of a quality assessment (QA) program on radiologist performance in ultrasound-guided renal transplant biopsy. METHODS: The numbers of glomeruli and small arteries obtained during ultrasound-guided renal transplant biopsy of all consecutive patients performed by any of 8 radiologists in an ultrasound section between September 1, 2007, and May 31, 2010, were recorded. Procedural success was assessed using Banff 97 criteria. Two subgroups were defined on the basis of each radiologist's approximate fractional full-time equivalent effort in the section, with 2 radiologists who were engaged 100% of their clinical noncall time in the ultrasound section constituting the primary ultrasound subgroup and 6 radiologists who were engaged <25% of their clinical noncall time in the ultrasound section constituting the secondary ultrasound subgroup. The biopsy success rate for individuals, subgroups, and the entire section for 9 months before (pre-QA) and 24 months after (post-QA) the onset of quarterly dissemination of the QA data was analyzed. RESULTS: Of 339 biopsies in the pre-QA period, 90.5% were successful. Of 1,063 biopsies in the post-QA period, 96.0% were successful (P < .001). The pre-QA individual radiologist success rates ranged between 71.4% and 96.7% (mean, 86.2 +/- 10.3%). The post-QA individual radiologist success rates ranged between 80.0% and 97.9% (mean, 92.5 +/- 6.6%). The primary ultrasound subgroup success rate increased from 93.4% to 97.5% (P = .005). The secondary ultrasound subgroup success rate increased from 85.7% to 93.8% (P = .004). CONCLUSIONS: A renal transplant biopsy QA program improves operator performance. PMID- 21531314 TI - Staff meetings/choosing the chief resident. PMID- 21531315 TI - Implementation of a 24-hour radiation safety call center: one institution's initial experience. PMID- 21531316 TI - Social media: a brave new world for doctors. PMID- 21531317 TI - CT radiation dose reduction by modifying primary factors. PMID- 21531318 TI - Russell H. Morgan. PMID- 21531319 TI - The player and his equipment. PMID- 21531320 TI - The hemodialysis machine: where the nephrologists and toxicologists meet. PMID- 21531322 TI - Intoxications amenable to extracorporeal removal. AB - Extracorporeal removal of drugs was first attempted in 1913, by John Jacob Abel. Previously known to be a rarity, dialysis and to a lesser extent hemoperfusion have now become obvious tools for nephrologists in treating life-threatening cases of poisoning. Moreover, for dialysis patients, dialysis along with chelation therapy for removal of aluminum, once known to be common in the United States, is resurging in some countries. This article will discuss the principles of drug removal, the indications for dialysis, and give a brief outline of poisons amenable to dialysis. PMID- 21531321 TI - Blood purification in toxicology: nephrology's ugly duckling. AB - Contrary to popular opinion, application of extracorporeal therapies for poisonings predates their use for ESRD. Despite this observation, the science of blood purification in toxicology remains desperately stagnant today. In fact, much of our current knowledge is derived from George Schreiner's 1958 review. Original publications are almost exclusively composed of case reports and case series, from which good inference is impossible. Until randomized controlled trials become available, the medical community would be well served by a group mandated to systematically review available literature, extract relevant information, provide recommendations based on current evidence, and propose research initiatives. The EXtracorporeal TReatments In Poisoning workgroup, formed by several international experts in different medical fields and represented by over 20 societies, now has this mission. PMID- 21531323 TI - Have advances in extracorporeal removal techniques changed the indications for their use in poisonings? AB - During the past 25 years, numerous changes have taken place in the use of hemodialysis as a therapeutic modality. Advances in technologies and a progression in our collective understanding of the pharmacokinetics of certain xenobiotics have resulted in alterations in the indications, effectiveness, and safety of hemodialysis. However, these changes have not necessarily been reflected in the current published data regarding treatment of intoxications. Reported clearance rates often reflect what was achievable in the 1970s and 1980s, and more recent reports are frequently lacking. Our goal in this review is to summarize the changes in hemodialysis and in other extracorporeal removal technologies and highlight the effects of these changes on the current indications for hemodialysis of the poisoned patient. Changes in dialysis performance that are reviewed in this article include the use of high-efficiency and high-flux dialysis membranes, improved hemodynamic stability because of ultrafiltration control, and the use of bicarbonate as a source of base. We review the indications for hemodialysis for removal of specific toxins, including vancomycin, methotrexate, carbamazepine, and valproic acid. PMID- 21531324 TI - High cut-off dialysis membranes: current uses and future potential. AB - The removal of larger uremic toxins by conventional dialysis membranes is restricted by their molecular weight cut-offs. The recent availability of a new generation of hemodialysis membranes with molecular weight cut-offs closer to that of the native kidney (65 kDa) has led to work assessing their potential utility across several different clinical scenarios. Initially designed to remove proinflammatory cytokines in patients with severe sepsis syndrome, clinicians are now using these membranes for the treatment of myeloma kidney and rhabdomyolysis. Further early pilot studies have demonstrated a potential utility for the removal of larger middle molecules in the population with end-stage renal failure. The purpose of this review was to summarize the current evidence base for the use of high cut-off hemodialysis membranes and discuss their future clinical relevance. PMID- 21531325 TI - Nephrogenic systemic fibrosis and gadolinium-based contrast agents. AB - The strong association between nephrogenic systemic fibrosis (NSF) and exposure to gadolinium-based contrast agents (GBCAs) has greatly affected the care of patients with kidney disease. NSF has been reported in patients with ESRD, CKD, and acute kidney injury (AKI). The majority of cases have occurred in patients with ESRD, but about 20% have been reported in patients with AKI or CKD stages 4 and 5. There is also a risk difference among GBCAs, with the Food and Drug Administration contraindicating 3 linear agents in patients at risk. Given the significant morbidity and mortality of NSF, it is imperative to identify individuals at risk. Although there are no data to support a role for hemodialysis (HD) in reducing the risk for NSF after administration of GBCAs, immediate HD is still recommended within 2 hours. Patients maintained on peritoneal dialysis seem to be at high risk and immediate HD is also recommended. However, this is not the current recommendation for CKD stages 4 and 5, especially with suspected lower risk of noncontraindicated agents. Individualized assessment is important and especially in those patients close to dialysis initiation. Instituting policies is important to address the imaging needs of patients with CKD and AKI while ensuring a balance between benefits and risks. PMID- 21531326 TI - Iodinated contrast media and the role of renal replacement therapy. AB - Iodinated contrast media are among the most commonly used pharmacologic agents in medicine. Although generally highly safe, iodinated contrast media are associated with several adverse effects, most significantly the risk of acute kidney injury, particularly in patients with underlying renal dysfunction. By virtue of their pharmacokinetic characteristics, these contrast agents are efficiently cleared by hemodialysis and to a lesser extent, hemofiltration. This has led to research into the capacity for renal replacement therapies to prevent certain adverse effects of iodinated contrast. This review examines the molecular and pharmacokinetic characteristics of iodinated contrast media and critically analyzes data from past studies on the role of renal replacement therapy to prevent adverse effects of these diagnostic agents. PMID- 21531327 TI - Avoiding toxicity from water-borne contaminants in hemodialysis: new challenges in an era of increased demand for water. AB - Water is necessary for all hemodialysis treatments. However, drinking water contains a range of substances that are toxic to patients on hemodialysis. Thus, all dialysis facilities are equipped with a water treatment system that removes those substances from the water before it is used to prepare dialysate. Increased demand for water and ever-evolving drinking water regulations are leading to changes in drinking water quality that may compromise the ability of typical dialysis water treatment systems to adequately remove substances that are known to be toxic or to deal with unexpected increases in other substances of unknown toxicity. In addition to these external challenges to dialysis water quality, the growing recognition that microbial contaminants in dialysate contribute to long term morbidity has led to more stringent microbiological quality standards for dialysate and a consequent need to control biofilm formation in the fluid pathways involved in dialysate preparation. Avoiding toxicity from water contaminants in this dynamic environment requires a comprehensive approach to water treatment, including flexibility regarding the choice of water treatment processes, close communication with the suppliers of drinking water, and an emphasis on training technicians responsible for monitoring and maintaining all aspects of the fluid handling systems. PMID- 21531328 TI - Novel nephrotoxins. AB - Drug and xenobiotic toxicity is an important cause of kidney injury, especially in vulnerable patients. Nephrotoxic syndromes include functional disorders; vascular injury, such as thrombotic microangiopathy; glomerular injury resulting in nephrotic syndrome or glomerulonephritis; acute tubular necrosis; acute interstitial nephritis; and crystalopathy/nephrolithiasis. Recently reported nephrotoxins are reviewed in the context of these syndromes of kidney injury. PMID- 21531329 TI - The microbial-mammalian metabolic axis: beyond simple metabolism. AB - The microbiome heavily influences the metabolism of its host. In this issue of Cell Metabolism, Donohoe and colleagues demonstrate that microbial butyrate, used as a fuel metabolite, prevents autophagy in colonocytes, showing that the microbial-mammalian metabolic axis goes beyond simple metabolism. PMID- 21531330 TI - Branching out for detection of type 2 diabetes. AB - Type 2 diabetes is an epidemic disease worldwide, but it is difficult to predict its appearance in the general population. A recent study demonstrates that circulating concentrations of a small group of essential amino acids predict risk for diabetes, contributing to a recent resurgence of interest in these common analytes. PMID- 21531331 TI - A potential link between dorsomedial hypothalamic nucleus NPY and energy balance. AB - The function of dorsomedial hypothalamic neuropeptide Y (NPY) in energy balance has largely been restricted to lactation-induced hyperphagia. In this issue, Chao et al. (2011) expand this role to include inhibition of both brown fat thermogenesis and conversion of white-to-brown adipocytes in a white fat depot, resulting in reduced energy expenditure. PMID- 21531332 TI - Autophagy in the cellular energetic balance. AB - Autophagy mediates the degradation of cellular components in lysosomes, assuring removal of altered or dysfunctional proteins and organelles. Autophagy is not only activated in response to cellular damage; in fact, one of its strongest and better-characterized stimuli is starvation. Activation of autophagy when nutrients are scarce allows cells to reutilize their own constituents for energy. Besides protein breakdown, autophagy also contributes to the mobilization of diverse cellular energy stores. This recently discovered interplay between autophagy and lipid and carbohydrate metabolism reveals the existence of a dynamic feedback between autophagy and cellular energy balance. PMID- 21531333 TI - Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16. AB - Arginine methylation is a widespread posttranslational modification of proteins catalyzed by a family of protein arginine methyltransferases (PRMTs). It is well established that PRMTs are implicated in various cellular processes, but their physiological roles remain unclear. Using nematodes with a loss-of-function mutation, we show that prmt-1, the major asymmetric arginine methyltransferase, is a positive regulator of longevity in C. elegans. This regulation is dependent on both its enzymatic activity and DAF-16/FoxO transcription factor, which is negatively regulated by AKT-mediated phosphorylation downstream of the DAF 2/insulin signaling. prmt-1 is also required for stress tolerance and fat storage but not dauer formation in daf-2 mutants. Biochemical analyses indicate that PRMT 1 methylates DAF-16, thereby blocking its phosphorylation by AKT. Disruption of PRMT-1 induces phosphorylation of DAF-16 with a concomitant reduction in the expression of longevity-related genes. Thus, we provide a mechanism by which asymmetric arginine dimethylation acts as an antiaging modification in C. elegans. PMID- 21531334 TI - The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. AB - The microbiome is being characterized by large-scale sequencing efforts, yet it is not known whether it regulates host metabolism in a general versus tissue specific manner or which bacterial metabolites are important. Here, we demonstrate that microbiota have a strong effect on energy homeostasis in the colon compared to other tissues. This tissue specificity is due to colonocytes utilizing bacterially produced butyrate as their primary energy source. Colonocytes from germfree mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the TCA cycle. Consequently, there is a marked decrease in NADH/NAD(+), oxidative phosphorylation, and ATP levels, which results in AMPK activation, p27(kip1) phosphorylation, and autophagy. When butyrate is added to germfree colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy. The mechanism is due to butyrate acting as an energy source rather than as an HDAC inhibitor. PMID- 21531335 TI - MTERF4 regulates translation by targeting the methyltransferase NSUN4 to the mammalian mitochondrial ribosome. AB - Precise control of mitochondrial DNA gene expression is critical for regulation of oxidative phosphorylation capacity in mammals. The MTERF protein family plays a key role in this process, and its members have been implicated in regulation of transcription initiation and site-specific transcription termination. We now demonstrate that a member of this family, MTERF4, directly controls mitochondrial ribosomal biogenesis and translation. MTERF4 forms a stoichiometric complex with the ribosomal RNA methyltransferase NSUN4 and is necessary for recruitment of this factor to the large ribosomal subunit. Loss of MTERF4 leads to defective ribosomal assembly and a drastic reduction in translation. Our results thus show that MTERF4 is an important regulator of translation in mammalian mitochondria. PMID- 21531336 TI - Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. AB - We show that mice with a targeted deficiency in the gene encoding the lipogenic transcription factor SREBP-1a are resistant to endotoxic shock and systemic inflammatory response syndrome induced by cecal ligation and puncture (CLP). When macrophages from the mutant mice were challenged with bacterial lipopolysaccharide, they failed to activate lipogenesis as well as two hallmark inflammasome functions, activation of caspase-1 and secretion of IL-1beta. We show that SREBP-1a activates not only genes required for lipogenesis in macrophages but also the gene encoding Nlrp1a, which is a core inflammasome component. Thus, SREBP-1a links lipid metabolism to the innate immune response, which supports our hypothesis that SREBPs evolved to regulate cellular reactions to external challenges that range from nutrient limitation and hypoxia to toxins and pathogens. PMID- 21531337 TI - Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARgamma-dependent nongenomic signaling. AB - Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma). However, the use of TZDs is associated with plasma volume expansion through a mechanism that remains to be clarified. Here we showed that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from the renal proximal tubule in vitro and in vivo. TZD-induced transport stimulation is dependent on PPARgamma Src-EGFR-ERK and observed in rat, rabbit and human, but not in mouse proximal tubules where Src-EGFR is constitutively activated. The existence of PPARgamma Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPARgamma, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPARgamma and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPARgamma-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion. PMID- 21531338 TI - Protein tyrosine phosphatase epsilon affects body weight by downregulating leptin signaling in a phosphorylation-dependent manner. AB - Molecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation. PMID- 21531339 TI - Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. AB - Hypothalamic neuropeptide Y (NPY) has been implicated in control of energy balance, but the physiological importance of NPY in the dorsomedial hypothalamus (DMH) remains unclear. Here we report that knockdown of NPY expression in the DMH by adeno-associated virus-mediated RNAi reduced fat depots in rats fed regular chow and ameliorated high-fat diet-induced hyperphagia and obesity. DMH NPY knockdown resulted in development of brown adipocytes in inguinal white adipose tissue through the sympathetic nervous system. This knockdown increased uncoupling protein 1 expression in both inguinal fat and interscapular brown adipose tissue (BAT). Consistent with the activation of BAT, DMH NPY knockdown increased energy expenditure and enhanced the thermogenic response to a cold environment. This knockdown also increased locomotor activity, improved glucose homeostasis, and enhanced insulin sensitivity. Together, these results demonstrate critical roles of DMH NPY in body weight regulation through affecting food intake, body adiposity, thermogenesis, energy expenditure, and physical activity. PMID- 21531340 TI - Leptin does not directly affect CNS serotonin neurons to influence appetite. AB - Serotonin (5-HT) and leptin play important roles in the modulation of energy balance. Here we investigated mechanisms by which leptin might interact with CNS 5-HT pathways to influence appetite. Although some leptin receptor (LepRb) neurons lie close to 5-HT neurons in the dorsal raphe (DR), 5-HT neurons do not express LepRb. Indeed, while leptin hyperpolarizes some non-5-HT DR neurons, leptin does not alter the activity of DR 5-HT neurons. Furthermore, 5-HT depletion does not impair the anorectic effects of leptin. The serotonin transporter-cre allele (Sert(cre)) is expressed in 5-HT (and developmentally in some non-5-HT) neurons. While Sert(cre) promotes LepRb excision in a few LepRb neurons in the hypothalamus, it is not active in DR LepRb neurons, and neuron specific Sert(cre)-mediated LepRb inactivation in mice does not alter body weight or adiposity. Thus, leptin does not directly influence 5-HT neurons and does not meaningfully modulate important appetite-related determinants via 5-HT neuron function. PMID- 21531341 TI - Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium. AB - Oxidatively modified low-density lipoprotein (oxLDL) plays a key role in the initiation of atherosclerosis by increasing monocyte adhesion. The mechanism that is responsible for the oxLDL-induced atherogenic monocyte recruitment in vivo, however, still remains unknown. Oxidation of LDL generates lysophosphatidylcholine, which is the main substrate for the lysophosphatidic acid (LPA) generating enzyme autotaxin. We show that oxLDL requires endothelial LPA receptors and autotaxin to elicit CXCL1-dependent arterial monocyte adhesion. Unsaturated LPA releases endothelial CXCL1, which is subsequently immobilized on the cell surface and mediates LPA-induced monocyte adhesion. Local and systemic application of LPA accelerates the progression of atherosclerosis in mice. Blocking the LPA receptors LPA(1) and LPA(3) reduced hyperlipidemia-induced arterial leukocyte arrest and atherosclerosis in the presence of functional CXCL1. Thus, atherogenic monocyte recruitment mediated by hyperlipidemia and modified LDL crucially depends on LPA, which triggers endothelial deposition of CXCL1, revealing LPA signaling as a target for cardiovascular disease treatments. PMID- 21531342 TI - Mitochondrial matrix calcium is an activating signal for hormone secretion. AB - Mitochondrial Ca(2+) signals have been proposed to accelerate oxidative metabolism and ATP production to match Ca(2+)-activated energy-consuming processes. Efforts to understand the signaling role of mitochondrial Ca(2+) have been hampered by the inability to manipulate matrix Ca(2+) without directly altering cytosolic Ca(2+). We were able to selectively buffer mitochondrial Ca(2+) rises by targeting the Ca(2+)-binding protein S100G to the matrix. We find that matrix Ca(2+) controls signal-dependent NAD(P)H formation, respiration, and ATP changes in intact cells. Furthermore, we demonstrate that matrix Ca(2+) increases are necessary for the amplification of sustained glucose-dependent insulin secretion in beta cells. Through the regulation of NAD(P)H in adrenal glomerulosa cells, matrix Ca(2+) also acts as a positive signal in reductive biosynthesis, which stimulates aldosterone secretion. Our dissection of cytosolic and mitochondrial Ca(2+) signals reveals the physiological importance of matrix Ca(2+) in energy metabolism required for signal-dependent hormone secretion. PMID- 21531343 TI - From the editor. PMID- 21531344 TI - Visit-to-visit blood pressure variations: new independent determinants for carotid artery measures in the elderly at high risk of cardiovascular disease. AB - Recently, visit-to-visit variability in systolic blood pressure (SBP) has been shown to be a predictor of stroke. In this study, we investigated the relationship of visit-to-visit blood pressure (BP) variations (based on 12 visits once a month) with intima-media thickness (IMT) and stiffness in common carotid artery among the 201 high-risk elderly (female 75%) at cardiovascular disease. Max-IMT was significantly positively correlated with age, smoking, renin angiotensin system inhibitor use, coefficient of variation (CV), and delta (maximum-minimum) in SBP, and CV in diastolic BP (DBP) but was significantly negatively correlated with female, high-density lipoprotein (HDL), and minimum in SBP. Stiffness parameter beta was significantly positively correlated with age, standard deviation (SD), CV, maximum, and delta in SBP, and SD, CV, and delta in DBP but was significantly negatively correlated with smoking, HDL, average, and minimum in DBP. In a multiple regression analysis, delta SBP (P < .001) was associated with max-IMT independently of average SBP. CV (P < .05) and delta (P < .05) in SBP, and CV (P < .001) and delta (P < .01) in DBP were associated with stiffness parameter beta independently of average BP. In the high-risk elderly, exaggerated visit-to-visit BP fluctuations were significant indicators for carotid artery atherosclerosis and stiffness independently of average BP. PMID- 21531345 TI - Human colostral phagocytes eliminate enterotoxigenic Escherichia coli opsonized by colostrum supernatant. AB - BACKGROUND: Several elements in colostrum and human milk, including antibodies and nonspecific factors with bactericidal and antiviral activity, may play an important anti-infectious and protective role. In developing countries, enterotoxigenic Escherichia coli (ETEC) is the main etiological agent of diarrhea in low-socioeconomic level children. In the present work, we studied the functional activity of mononuclear (MN) and polymorphonuclear (PMN) phagocytes of human colostrum against ETEC, as well as the interactions between these cells and colostral or serum opsonins. METHODS: Colostrum samples were collected from 33 clinically healthy women between 48 and 72 hours postpartum. We verified superoxide release in colostral MN and PMN using cytochrome C reduction methods, phagocytosis, and bactericidal activity using acridine orange methods and superoxide dismutase (SOD) in the colostrum supernatants. RESULTS: Colostral MN and PMN phagocytes exposed to ETEC opsonized with colostrum supernatants caused a significant increase (p<0.05) in superoxide release. Phagocytosis by colostral PMN cells increased significantly (p<0.5) when the phagocytes were incubated with both sources of opsonins (sera and colostrum). Increases in superoxide release in the presence of opsonized bacteria triggered the bactericidal activity of the phagocytes. Phagocyte treatment with SOD decreased their ability to eliminate ETEC. Colostrum supernatant had higher SOD concentrations (p<0.05) compared with normal human sera. CONCLUSIONS: These results suggest that the ability of phagocytes to eliminate ETEC depends on the activation of cellular oxidative metabolism; moreover, activation of colostral phagocytes is likely an additional breast-feeding protection mechanism against intestinal infections in infants. PMID- 21531346 TI - Serotypes, surface proteins, and clinical syndromes of invasive Group B streptococcal infections in northern Taiwan, 1998-2009. AB - BACKGROUND: The incidence of invasive Group B streptococcal (GBS) infections is increasing in the elderly and immunocompromised adults in many countries worldwide. There are, however, few reports regarding the current status of the infection in northern Taiwan. This study investigated retrospectively the molecular epidemiology and clinical syndromes of the invasive GBS diseases in a tertiary care hospital in northern Taiwan over the past decade. METHODS: One hundred twenty episodes of invasive GBS disease were recorded at Cathay General Hospital, a tertiary care, teaching hospital in northern Taiwan, from January 1998 to June 2009. Clinical information was acquired from medical records. Capsular serotypes and alpha family of surface proteins were genotyped with multiplex and specific polymerase chain reaction. RESULTS: Of all episodes, 58.3% was found in the elderly (age >= 65), 36.1% in nonpregnant women and young adults (age 18-64), and 5.9% in the neonates (0-90 days). Case-fatality rate was 6.7%. Eighty-three (69%) of the invasive isolates were available for genotyping. In sharp contrast to the studies in southern Taiwan (1991-2004), Type Ib (26.5%) was the most frequent invasive isolate, followed by V (22.9%), III (18.1%), VI (12%), Ia (10.8%), II (6%), VIII (2.4%), and nontypable strain (1.2%). In particular, Serotype VI, which had been rarely implicated in invasive infection, emerged as a significant pathogen. A significant trend of increase in incidence was observed for the infection (p<0.0001), with concurrent increase of cases in the elderly and of Serotype Ib and VI. There was significant association with young adults of Type II and III and chronic skin conditions and older adults with Type Ia and V and chronic cardiovascular diseases. Type V was closely associated with skin and soft tissue infection. Recurrent episodes (10%) occurred most often in patients with concomitant malignancy, with an average of 314 days for recurrence. CONCLUSIONS: The incidence of GBS invasive infection among nonpregnant women and adults is rising in northern Taiwan, particularly in the elderly caused by Serotype Ib and VI. Population-based surveillance program should be implanted for assessment of the disease burden to the susceptible adult population. PMID- 21531347 TI - Isolation of Campylobacter sp in surface waters of Taiwan. AB - BACKGROUND: Campylobacter sp is one of the main causes of human acute enteritis and diarrhea. It is commonly found in bird intestinal canal and pollutes water bodies through bird droppings. Clinically, detection of Campylobacter sp is by culture method and most are fecal samples. The objective of this study is to investigate the distribution of Campylobacter sp in river water of Taiwan. METHODS: The detection of campylobacters in water by the United Kingdom Health Protection Agency was adopted and simplified. Water samples (1L) were enriched through membrane filters and selective enrichment Bolton broth. The mCCDA medium was used for culturing Campylobacter sp. In addition to using the selective media, DNA sequencing for species' identification was also included in this study. RESULTS: Campylobacter sp was detected in only 2 of 75 water samples, and 72 suspected strains were isolated from the selective mCCDA medium, in which several pathogenic bacteria included Escherichia coli O157. CONCLUSIONS: Not only there was pollution of Campylobacter sp in water environment but also other antibiotics-resistant pathogenic bacteria, which may cause public health risk. PMID- 21531348 TI - Detection of immunoglobulin G antibodies to Toxoplasma gondii: Evaluation of two commercial immunoassay systems. AB - BACKGROUND: Toxoplasmosis is a disease, which can cause severe congenital infection and is normally diagnosed by the detection of Toxoplasma gondii (T gondii)-specific antibodies in the serum of infected patients. Several different tests allow to distinguish recent from past infections and to quantify anti-T gondii-specific IgG, and the results can be used as markers for a chronic or recently seroconverted toxoplasma. METHODS: In the present study, the recent Cobas 6000 Toxo IgG assay (Roche Diagnostics, Indianapolis, IN, USA) for the serological diagnosis of toxoplasmosis was compared with the Axsym Toxo IgG assay (Abbott Laboratories, Diagnostics Division, Abbott Park, IL, USA) employing a panel of negative, low- or high-reactive serum samples that were selected after routine screening in a laboratory of clinical analyses. RESULTS: The overall agreement between two methods was 99% (r=0.99, p<0.001). Of 91 analyzed samples, only one presented discrepant result, being positive in the Cobas 6000 Toxo IgG assay and negative in the Axsym Toxo IgG assay. By using an immunofluorescent assay as a confirmation test, this positive result was assayed to be negative. CONCLUSIONS: Both assays performed in each analyzer were proven to be fast and fully automated procedures for reproducible measurement of IgG antibodies to T gondii. The new method, used for the determination of anti-T gondii IgG antibodies, should be evaluated with a further analysis with increased number of serum samples to get a broad performance of this newer test. PMID- 21531349 TI - Molecular and phenotypic characterization of atypical enteropathogenic Escherichia coli serotypes isolated from children with and without diarrhea. AB - BACKGROUND: We characterized 36 atypical enteropathogenic Escherichia coli (EPEC) serotypes isolated from children with and without diarrhea in Iran. Because the identification of atypical EPEC based on biochemical features is rather difficult and time consuming, we used a combination of three approaches, including a polymerase chain reaction-based method, culture adherence assay, and the restriction analysis of fliC gene (fliC-restriction fragment length polymorphism), to identify E coli serotypes. METHODS: To distinguish typical and atypical EPEC strains, the presence of EPEC attaching effacing A gene (eaeA) gene and EPEC-attaching factor (EAF) plasmid were analyzed. All E coli strains were identified based on the detection of the eaeA(+), bundle-forming pili A gene (bfpA(-)), EAF(-) or eaeA(-), bfpA(+), EAF(-) profiles and the absence of stx (encoded for shiga toxin) gene as atypical EPEC. RESULTS: All strains studied belonged to 5 atypical EPEC serogroups and 15 serotypes based on the virulence profiles. Of 36 atypical EPEC serotypes, 22 (61.2%) and 14 (38.8%) strains isolated from diarrheal and healthy cases, respectively. O142:H48 (19.5%) and O111:H21 (11.1%) serotypes were the most prevalent isolates, followed by serotypes O111: H(-) and O86:H48 (5.6% each). CONCLUSIONS: The characteristics of the atypical EPEC serotypes from children with diarrhea were significantly different from those without diarrhea. The compilation of data on atypical EPEC strains presented here indicates the importance of a combined approach of conventional and molecular tests to study the virulence and epidemiology of EPEC serotypes in human subjects. PMID- 21531350 TI - Intravenous minocycline versus oral doxycycline for the treatment of noncomplicated scrub typhus. AB - BACKGROUND: Scrub typhus is an acute febrile disease for which synthetic tetracycline antibiotics are efficacious. However, no clinical studies have compared oral doxycycline with intravenous minocycline for treatment of scrub typhus. METHODS: We conducted a retrospective analysis in patients diagnosed with noncomplicated scrub typhus by serologic or molecular methods from August 2001 to July 2007. We compared the efficacy of intravenous minocycline with oral doxycycline for treatment of noncomplicated scrub typhus in these patients. RESULTS: Forty seven cases receiving tetracycline antibiotics for the treatment of noncomplicated scrub typhus were included. There was no statistically significant difference for the response rate between the 25 cases receiving intravenous minocycline (96%) and the 22 cases receiving oral doxycycline (91%) (p=0.909). Kaplan-Meier curve with a long-rank test for the time to defervescence showed no statistically significant difference between minocycline therapy (mean 30 hours; range 4-124 hours) and doxycycline therapy (mean 32.4 hours; range 4 144 hours) (p=0.860). After multivariate Cox regression models, the time to defervescence was only affected by Acute Physiology and Chronic Health Evaluation II score (hazard ratio 0.868; p=0.016). Nearly all patients (93.6%) became afebrile within 72 hours after use of tetracycline antibiotics. Prolonged hospitalization (> 7 days) was correlated with the timing to start tetracycline antibiotics after admission. CONCLUSION: Both antibiotics have similar efficacy for the treatment of noncomplicated scrub typhus. Nearly all cases responding to both antibiotics became afebrile within 3 days. PMID- 21531351 TI - Emergence and dissemination of blaOXA-23-carrying imipenem-resistant Acinetobacter sp in a regional hospital in Taiwan. AB - BACKGROUND: The distribution and characterization of OXA-type carbapenemases in Acinetobacter sp in Taiwan has less been reported. The aim of the study was to investigate the molecular epidemiology and OXA-type carbapenemase genes in a regional hospital in Taiwan. METHODS: Imipenem-resistant Acinetobacter sp were collected between 2005 and 2007 in a regional hospital. Genotyping was performed by pulsed-field gel electrophoresis. OXA-type carbapenemase genes were determined by multiplex polymerase chain reaction (PCR) and gene sequencing. RESULTS: A total of 136 isolates were collected. Fifty-six pulsotypes were identified. None of the pulsotypes established predominance throughout the 3-year period. Multiplex PCR of blaOXA genes showed that 99% (135/136) of the Acinetobacter sp possessed blaOXA51-like genes. The coexistences of blaOXA51-like/blaOXA-23-like and blaOXA51-like/blaOXA-24-like were detected in 19% (26/136) and 1% (2/136) of the isolates, respectively. Among blaOXA-23-like gene-carrying isolates, two isolates (Pulsotypes 18 and 20) were found in 2006 and the remainder (n=24), including Pulsotypes 27 (n=18), 29 (n=1), 52 (n=3), and 53 (n=2), were found in 2007. Sequencing performed on the 26 representative isolates confirmed the presence of the blaOXA-23 carbapenemase gene. Analysis of the genetic content of blaOXA-23 showed that these genes were presumably chromosomal and associated with the upstream-located insertion sequence ISAba1. CONCLUSIONS: The emergence and imminent widespread of blaOXA-23-carrying imipenem-resistant Acinetobacter sp appeared in Taiwan during the period from 2006 to 2007. PMID- 21531352 TI - Clinical experience with tigecycline as treatment for serious infections in elderly and critically ill patients. AB - BACKGROUND: Tigecycline was approved for the treatment of complicated intra abdominal and complicated skin/skin structure infections. Because of its in vitro effectiveness for multidrug-resistant (MDR) isolates, tigecycline has been prescribed more broadly. This study evaluated tigecycline use after its first introduction in Taiwan and experience with tigecycline for the treatment of MDR Acinetobacter baumannii (MDRAB) infection, especially for ventilator-associated pneumonia. METHODS: Patients treated with tigecycline were collected retrospectively from February 2008 to July 2008 in Taipei Veterans General Hospital, a 2,900-bed tertiary care medical center in Taiwan. Patients were divided into three groups according to the indications: Group 1, Food and Drug Administration-approved indications; Group 2, health care-associated pneumonia (HAP); and Group 3, urinary tract infection, osteomyelitis, bacteremia, etc. Cases of MDRAB were also identified. RESULTS: Among 66 cases, indications for the administration of tigecycline included Food and Drug Administration-approved indications (12, 18.2%), HAP (38, 57.6%), bacteremia (3, 4.5%), catheter-related infections (3, 4.5%), urinary tract infection (4, 6.1%), osteomyelitis (4, 6.1%), and others (2, 3%). Clinical outcome was positive in 20 cases, with higher clinical success rate for Group 1 than Group 2, which may correlate with higher Sequential Organ Failure Assessment score, older age, and more frequent intensive care admission in Group 2. Of the microbiologically evaluable cases, MDRAB predominated (33/51, 64.7%). Among infections with MDRAB (excluding pneumonia without ventilator), the clinical success rate was 12% (3/25). CONCLUSIONS: The most common indication for the prescription of tigecycline was HAP. Success rate for MDRAB infection was lower than that previously reported, possibly because of serious underlying conditions and comorbidities in our patients. Because of limited choices, physicians should weigh the risk and benefit for prescribing tigecycline. PMID- 21531353 TI - Etanercept treatment for children with refractory juvenile idiopathic arthritis. AB - BACKGROUND: Etanercept has been shown to be an effective treatment for juvenile idiopathic arthritis (JIA). In this study, we evaluated the effectiveness of etanercept therapy in the treatment of refractory JIA. METHODS: This was a retrospective analysis of 11 patients with refractory JIA (polyarticular type n=7; pauciarticular type, n=2; systemic type, n=2) who received treatment with etanercept during the period 2005-2009 in a medical center. The indications for etanercept treatment included persistent fever, arthritis/arthralgia, or elevated levels of inflammatory mediators after treatment with methotrexate and/or prednisolone for more than 6 months. The patients were treated with etanercept (0.4 mg/kg, with maximal 25mg, subcutaneously, twice a week) for a total of 12 months. RESULTS: The degree of arthritis/arthralgia improved (range of motion and painful sensation of involved joints), and the levels of inflammatory markers (C reactive protein and erythrocyte sedimentation rate) decreased progressively in 10 of the 11 patients (p<0.05) at 1-, 3-, 5-, and 12-month follow-up after treatment with etanercept. Mean hemoglobin levels significantly increased, whereas mean platelet counts decreased after etanercept treatment (p<0.05). Only one patient with systemic type of JIA failed to respond to the treatment after 6 weeks of etanercept therapy. Methotrexate, prednisolone, and other immunosuppressive drugs were successfully discontinued after a mean of 2.5 months (range, 1-5 months) of etanercept therapy in the 10 patients who responded to etanercept treatment. CONCLUSION: Etanercept is beneficial for patients with polyarticular and pauciarticular type of JIA that is refractory to conventional treatment but less beneficial for systemic type of JIA. PMID- 21531354 TI - Determination of antimicrobial susceptibility patterns and inducible clindamycin resistance in Staphylococcus aureus strains recovered from southeastern Turkey. AB - BACKGROUND: In this study, we determined the susceptibility patterns of Staphylococcus aureus strains to various antimicrobials and prevalence of inducible clindamycin resistance (ICR) in these isolates. METHODS: Two hundred and one S aureus strains, isolated from various clinical samples, were included in the study. Antibiotic susceptibilities were studied by disc diffusion method on the basis of the guidelines by the Clinical and Laboratory Standards Institute. The disc diffusion induction test (D test) was applied to determine ICR resistance among erythromycin-resistant S aureus isolates. RESULTS: Of the 201 S aureus strains, 101 (50.2%) were resistant to methicillin. All strains were susceptible to vancomycin, teicoplanin, quinupristin/dalfopristin, and linezolid. It was found that 54 (53.4%) methicillin-resistant S aureus (MRSA) strains were erythromycin resistant, and 40 (39.6%) of them showed constitutive clindamycin resistance. ICR was detected in seven (6.9%) MRSA strains. It was found that 13 (13.0%) methicillin-susceptible S aureus (MSSA) strains were erythromycin resistant. Constitutive clindamycin resistance was seen in one (1.0%) MSSA strain, and ICR was detected in 10 (10.0%) cases. CONCLUSION: There was a high rate of methicillin resistance among S aureus strains in our hospital. However, no statistically significant difference of ICR was observed between MRSA and MSSA strains (p=0.434) or between inpatients and outpatients (p=0.804). It was concluded that ICR should be routinely evaluated in each S aureus case to avoid therapy failure among patients. PMID- 21531355 TI - Clinical significance of erythromycin-resistant Campylobacter jejuni in children. AB - Campylobacter has been recognized as the common cause of bacterial gastroenteritis in many countries. Increasing erythromycin resistance in Campylobacter jejuni infection is noted recently, but severe case was rarely reported. In this study, we aimed to clarify the clinical significance of the resistant strain of C jejuni in children. We reviewed the charts of children who were diagnosed with C jejuni enteritis in our hospital from January 2000 to December 2005, including 326 patients (117 males and 209 females). All the cases had positive stool culture. We divided them into two groups, the sensitive group (a total of 306 cases) and resistant group (a total of 20 cases), according to the drug sensitivity. We analyzed the clinical manifestations and laboratory data between the two groups. The mean age was 3.79 +/- 3.24 years in the sensitive group and 3.03 +/- 2.84 years in the resistant group. There was no significant difference between the two groups in clinical presentations and laboratory examinations. No mortality was found, and one case was initially presented with colonic perforation. This report demonstrates that infection by erythromycin resistant strains of C jejuni has no clinical significance in children, despite the probably increased emergence of erythromycin resistance. PMID- 21531356 TI - Comamonas testosteroni infection in Taiwan: Reported two cases and literature review. AB - Comamonas testosteroni is a widely distributed aerobic gram-negative bacillus. Infection by C testosteroni is infrequent, and no such cases have been reported in Taiwan. Here, we would like to present a 54-year-old alcoholic patient from Taiwan, and his left leg was injured during a fishing trip, resulting in left leg cellulitis and C testosteroni bacteremia. The patient's fever subsided after initial treatment with extended-spectrum cephalosporin, whereas his erythematous swelling did not resolve until switched to ciprofloxacin. The second patient is a 73-year-old Taiwanese male with chronic hepatitis B infection, liver cirrhosis, and hepatocellular carcinoma. Comamonas testosteroni bacteremia was found after transarterial embolization. Further studies are necessary to determine the best antibiotic(s) for patients infected with C testosteroni. PMID- 21531357 TI - Visceral leishmaniasis (kala-azar) and malaria coinfection in an immigrant in the state of Terengganu, Malaysia: A case report. AB - Malaria is endemic in Malaysia. Leishmaniasis is a protozoan infection rarely reported in Malaysia. Here, a 24-year-old Nepalese man who presented with prolonged fever and hepatosplenomegaly is reported. Blood film examination confirmed a Plasmodium vivax malaria infection. Despite being adequately treated for malaria, his fever persisted. Bone marrow examination showed presence of Leishman-Donovan complex. He was successfully treated with prolonged course of amphotericin B. The case highlights the importance of awareness among the treating physicians of this disease occurring in a foreign national from an endemic region when he presents with fever and hepatosplenomegaly. Coinfection with malaria can occur although it is rare. It can cause significant delay of the diagnosis of leishmaniasis. PMID- 21531358 TI - [Influence of gender on the sensory organisation test and the limits of stability in healthy subjects]. AB - INTRODUCTION: The sensory organization test and the limits of stability are the gold standard for dynamic posturography. It is postulated that these measurements vary depending on age, activity of the subject and musculoskeletal system, emotional condition or other factors. The aim of this study was to determine the influence of gender on the above-mentioned analyses. MATERIAL AND METHODS: 70 healthy subjects (35 males and 35 females); mean age: 44.9 years. A clinical history was taken and a physical and otoneurological exploration was performed for each subject, along with a posturography study using the Neurocom SMART Balance Master platform model. The statistical study was carried out with the ANOVA test (p<0.05). RESULTS: Condition 5 presented the lowest percentage of balance in both sexes (64.36%). The highest percentage of balance in males was in Condition 1 (p<0.001) and the lowest in 3 (p=0.030). There were no differences in the sensory analysis. The lowest employment of ankle strategy was in Condition 5 for both sexes (88.61%); women used the ankle strategy in Condition 4 more efficiently (p=0.0129). There were also differences in the time of reaction towards the right (p=0.022) and the mean (p=0.011) (higher in females), and in the speed of movement backwards (p=0.001) and towards the right (p=0.04) (higher in males). In path length and directional control, there were no differences. CONCLUSIONS: Gender differences should be taken into consideration for vestibular rehabilitation. Greater speed in conducting the tests does not lead to better balance control. PMID- 21531359 TI - [Radiofrequency treatment in simple snoring: tolerance, safety and results]. AB - OBJECTIVE: Snoring is a non-pathologic social problem. In the search for non aggressive efficacious treatment, we introduce our experience in using temperature-controlled radiofrequency treatment for snoring. METHODS: A 6-month follow-up revision of thirty-seven patients that received a mean of 1.1 radiofrequency treatment sessions at turbinates, soft palate, tonsils and/or tongue-base. RESULTS: Mean sample age was 39.6+-9 years; mean BMI was 29.5+/-4. Good tolerance was presented by 78% of our patients, 78% had no postoperative pain complaints and 68.3% no postoperative symptoms a week after procedure. Minor complications (mainly mucosal breakdown) were presented by 14.6% of the patients. The snoring score went from a mean of 8.6 to 5.6 on the visual analogue scale; 86.5% of the patients improved their clinical snoring and 37.8% were cured of it. Epworth daytime somnolence test results went from mean 9.3 to 6.1. CONCLUSIONS: Radiofrequency is a procedure that is safe, well-tolerated and fairly painless postoperatively, effective in improving clinical snoring in simple snorers. Radiofrequency is an effective primary treatment for snoring whose cause is accessible to radiofrequency. PMID- 21531360 TI - [Portfolios: a tool for the training and assessment of residents in dermatology, part 2]. AB - A portfolio is a collection of material documenting reflection about practice. It contains documents (eg, case histories and questionnaires the resident has used), images, and video recordings that reveal that an individual has acquired the competencies needed for professional practice. This assessment tool simultaneously supports learning and provides evidence for certifying competence. The adoption of portfolio use by a dermatology department requires the support of both the training supervisor and the chief of department. The learning objectives defined by the National Board for Medical-Surgical Dermatology and Venereology must be taken into consideration so that ways to assess each objective can be included; this approach supports holistic ongoing education as well as the certification of competencies the resident finally achieves. Use of portfolios in medical residency training can improve on current assessment methods, which we believe lack precision. We propose that portfolios gradually begin to replace the resident's training log. We are currently developing an online software application that will facilitate the use of portfolios. PMID- 21531361 TI - [Pemphigoid gestationis: therapeutic response to pre- and postpartum immunoglobulin therapy]. PMID- 21531362 TI - [Role of chemokines in melanoma progression]. AB - Metastasis is the main cause of death from melanoma. Chemokines are low molecular weight chemotactic cytokines that facilitate cellular migration. Thus, cells that express receptors for a given chemokine are attracted to the site of its production. As certain chemokines are found in abundance in organs that are common targets of metastasis and receptors for these chemokines are expressed by tumor cells, it was hypothesized that chemokine gradients might selectively facilitate metastasis to these organs. A later finding that these chemokines were produced by tumor cells, with evidence of autocrine effects, obliged the modification of that hypothesis. Many chemokines are also known to have opposing effects according to the type of cell they are acting on (tumor, inflammatory/immune, or endothelial cells), their functional status, or interactions with other molecules. The expression of chemokines and their receptors by melanoma cells enhances tumor progression by altering their microenvironment, stimulating angiogenesis, and inhibiting the immune response. PMID- 21531363 TI - [Submammary perifollicular papules in a young woman]. PMID- 21531364 TI - [Malignant transformation of a nevus of Ito: description of a rare case]. AB - Dermal melanocytosis refers to congenital or acquired lesions characterized by the presence of dendritic cells derived from melanocytes that migrate from the neural crest to the epidermis. The nevus of Ito develops in the territory supplied by the acromioclavicular nerve. Malignant transformation in dermal melanocytosis is extremely rare, with only isolated case reports; only 2 cases of malignant transformation of a nevus of Ito have been reported. We report a very rare case that is the third to be described in the literature. The patient was a 24-year-old man who presented with a subcutaneous nodule that had developed in the anterolateral region of the thorax over the previous 8 months. The nodule was located beneath a faint blue-gray macule with poorly defined borders. Biopsy of the nodule revealed malignant melanoma; biopsies of the adjacent skin lesion showed a diffuse proliferation of scattered melanocytes in a collagen stroma in the reticular dermis. A diagnosis of malignant transformation of a nevus of Ito was made after other possibilities were ruled out. PMID- 21531365 TI - Accidental polydipsia and hyponatremia from diphenhydramine urinary retention. PMID- 21531366 TI - The 10 things I like best about my job. PMID- 21531367 TI - There is nothing prosaic about the PROSE competition. PMID- 21531368 TI - Illicit drug, ischemic bowel. PMID- 21531369 TI - Hydroxycitric acid dietary supplement-related herbal nephropathy. PMID- 21531370 TI - A true MI? PMID- 21531371 TI - Patient safety series: obstetric safety improvement and its reflection in reserved claims. AB - In reviewing outcomes that are associated with the implementation of a series of labor and delivery patient safety efforts from 2004-2009, we requested data on the number of related professional liability claims that were reserved by our insurance companies that are established with the specific objective of financing risks that emanate from their parent group or groups. While we restructured the manner in which we give care, required training modules, and provided simulations to our providers, our legal risk continued to be monitored independently and in parallel. Retrospective review of the number of cases for which money was held in reserve for claims demonstrated a 20% decrease per year, which was adjusted for delivery volume, over this time period. We believe that the improved care that resulted from our safety projects has led to this decreased legal risk. PMID- 21531372 TI - The role of oxidative stress in the developmental origin of adult hypertension. AB - OBJECTIVE: To determine whether oxidative stress plays a role in the development of hypertension using a mouse model of fetal programming induced by endothelial nitric oxide synthase deficiency. STUDY DESIGN: Homozygous nitric oxide synthase knockout and wild type mice were cross-bred producing maternal (endothelial nitric oxide synthase+pat/-mat) and paternal (endothelial nitric oxide synthase+mat/-pat) heterozygous offspring. RNA from liver and kidney tissues of female pups were obtained at 14 weeks of age. Relative expression of the heat shock protein-B6, peroxiredoxin-3, superoxide dismutase-1, peroxisome proliferator-activated receptor gamma, nitric oxide synthase-1 and -2 were determined. RESULTS: In the kidneys, expression of nitric oxide synthase-2, peroxiredoxin-3, heat shock protein-B6, and superoxide dismutase-1 was up regulated in endothelial nitric oxide synthase+pat/-mat but not in endothelial nitric oxide synthase+mat/-pat compared with wild type offspring. In the liver, there were no significant differences in the expression of nitric oxide synthase 1, nitric oxide synthase-2, peroxiredoxin, superoxide dismutase-1, or peroxisome proliferator-activated receptor gamma; however, heat shock protein-B6 was down regulated in both heterozygotes offspring compared with wild type. CONCLUSION: The intrauterine environment alters oxidative pathways gene expression in the kidneys of offspring, which may be a mechanism in the development of adult hypertension. PMID- 21531373 TI - Fetal cardiac ventricular volume, cardiac output, and ejection fraction determined with 4-dimensional ultrasound using spatiotemporal image correlation and virtual organ computer-aided analysis. AB - OBJECTIVE: The objective of this study was to quantify fetal cardiovascular parameters using spatiotemporal image correlation (STIC) and virtual organ computer-aided analysis (VOCAL). STUDY DESIGN: A cross-sectional study was performed in normal pregnancies (19-42 weeks) to evaluate ventricular volume, stroke volume (SV), cardiac output (CO), and ejection fraction (EF). The CO was also expressed as a function of estimated fetal weight and biometric parameters. RESULTS: The following results were found: (1) 184 STIC datasets; (2) with advancing gestation, ventricular volume, SV, CO, and adjusted CO increased, whereas EF decreased; (3) right ventricular (RV) volume was larger than the left ventricular (LV) volume in systole (0.50 vs 0.27 mL; P < .001) and diastole (1.20 vs 1.03 mL; P < .001); (4) there were no differences between the LV and RV in SV, CO, or adjusted CO; and (5) LV EF was greater than the RV EF (72.2 vs 62.4%; P < .001). CONCLUSION: Normal fetal cardiovascular physiology is characterized by a larger RV volume and a greater LV EF, resulting in similar LV and RV SV and CO. PMID- 21531374 TI - Severe early-onset preeclampsia is not associated with a change in placental catechol O-methyltransferase (COMT) expression. AB - The genetic deletion of catechol O-methyltransferase (COMT) in mice produces a preeclampsia-like phenotype, with mice exhibiting hypertension, proteinuria, and histological changes, consistent with human pathological features. 2 Methoxyoestradiol, a metabolite of COMT, increases human trophoblast invasiveness in vitro under hypoxic conditions, providing further support that decreased COMT expression may have a role in preeclampsia. However, evidence confirming decreased COMT expression in human disease has been limited to small studies of placentas obtained from cases of term preeclampsia. We examined COMT expression in placentas obtained from healthy term pregnancies (n = 14), preterm normotensive pregnancies (n = 8), and pregnancies complicated by severe preterm preeclampsia (delivery at < 34 weeks' gestation; n = 22). Among our preeclamptic cohort were 10 pregnancies further complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets); and one pregnancy complicated by an eclamptic seizure. COMT expression was analyzed by RT-PCR, Western analysis, and IHC. COMT was mainly expressed in the syncytiotrophoblast. We did not find a significant difference in placental COMT expression in severe preeclampsia compared with either term or preterm normotensive cohorts. Our results suggest that severe preeclampsia may not be associated with a decrease in placental COMT expression. PMID- 21531375 TI - Inflammation induced by infection potentiates tau pathological features in transgenic mice. AB - Comorbidities that promote the progression of Alzheimer's disease (AD) remain to be uncovered and evaluated in animal models. Because elderly individuals are vulnerable to viral and bacterial infections, these microbial agents may be considered important comorbidities that could potentiate an already existing and tenuous inflammatory condition in the brain, accelerating cognitive decline, particularly if the cellular and molecular mechanisms can be defined. Researchers have recently demonstrated that triggering inflammation in the brain exacerbates tau pathological characteristics in animal models. Herein, we explore whether inflammation induced via viral infection, compared with inflammation induced via bacterial lipopolysaccharide, modulates AD-like pathological features in the 3xTg AD mouse model and provide evidence to support the hypothesis that infectious agents may act as a comorbidity for AD. Our study shows that infection-induced acute or chronic inflammation significantly exacerbates tau pathological characteristics, with chronic inflammation leading to impairments in spatial memory. Tau phosphorylation was increased via a glycogen synthase kinase-3beta dependent mechanism, and there was a prominent shift of tau from the detergent soluble to the detergent-insoluble fraction. During chronic inflammation, we found that inhibiting glycogen synthase kinase-3beta activity with lithium reduced tau phosphorylation and the accumulation of insoluble tau and reversed memory impairments. Taken together, infectious agents that trigger central nervous system inflammation may serve as a comorbidity for AD, leading to cognitive impairments by a mechanism that involves exacerbation of tau pathological characteristics. PMID- 21531377 TI - Safety of magnetic resonance imaging in patients with implanted cardiac prostheses and metallic cardiovascular electronic devices. AB - Magnetic resonance imaging (MRI) in patients with implanted cardiac prostheses and metallic cardiovascular electronic devices is sometimes a risky procedure. Thus MRI in these patients should be performed when it is the only examination able to help with the diagnosis. Moreover the diagnostic benefit must outweigh the risks. Coronary artery stents, prosthetic cardiac valves, metal sternal sutures, mediastinal vascular clips, and epicardial pacing wires are not contraindications for MRI, in contrast to pacemakers and implantable cardioverter defibrillators. Appropriate patient selection and precautions ensure MRI safety. However it is commonly accepted that although hundreds of patients with pacemakers or implantable cardioverter-defibrillators have undergone safe MRI scanning, it is not a safe procedure. Currently, heating of the pacemaker lead is the major problem undermining MRI safety. According to the US Food and Drug Administration (FDA), there are currently neither "MRI-safe" nor "MRI-compatible" pacemakers and implantable cardioverter-defibrillators. In this article we review the international literature in regard to safety during MRI of patients with implanted cardiac prostheses and metallic cardiovascular electronic devices. PMID- 21531376 TI - Microcalcifications in early intimal lesions of atherosclerotic human coronary arteries. AB - Although calcium (Ca) precipitation may play a pathogenic role in atherosclerosis, information on temporal patterns of microcalcifications in human coronary arteries, their relation to expression of calcification-regulating proteins, and colocalization with iron (Fe) and zinc (Zn) is scarce. Human coronary arteries were analyzed post mortem with a proton microprobe for element concentrations and stained (immuno)histochemically for morphological and calcification-regulating proteins. Microcalcifications were occasionally observed in preatheroma type I atherosclerotic intimal lesions. Their abundance increased in type II, III, and IV lesions. Moreover, their appearance preceded increased expression of calcification-regulating proteins, such as osteocalcin and bone morphogenetic protein-2. In contrast, their presence coincided with increased expression of uncarboxylated matrix Gla protein (MGP), whereas the content of carboxylated MGP was increased in type III and IV lesions, indicating delayed posttranslational conversion of biologically inactive into active MGP. Ca/phosphorus ratios of the microcalcifications varied from 1.6 to 3.0, including amorphous Ca phosphates. Approximately 75% of microcalcifications colocalized with the accumulation of Fe and Zn. We conclude that Ca microprecipitation occurs in the early stages of atherosclerosis, inferring a pathogenic role in the sequel of events, resulting in overt atherosclerotic lesions. Microcalcifications may be caused by local events triggering the precipitation of Ca rather than by increased expression of calcification-regulating proteins. The high degree of colocalization with Fe and Zn suggests a mutual relationship between these trace elements and early deposition of Ca salts. PMID- 21531379 TI - Wang-Zwische double-lumen cannula leads to total cavopulmonary support in a failing Fontan sheep model. AB - BACKGROUND: We are developing a total cavopulmonary support system for failing Fontan physiology using the percutaneous Wang-Zwische double-lumen cannula (DLC). METHODS: We developed a sheep model of failing Fontan physiology through a right thoracotomy in 5 sheep. An extracardiac conduit was anastomosed to the inferior vena cava and superior vena cava, and a graft was applied to connect the conduit and the right pulmonary artery (PA) to create total vena cava-to-PA diversion, excluding the right heart. The DLC (commercialized as AvalonElite, Avalon Laboratories LLC, Rancho Dominguez, CA) was coupled with a CentriMag pump (Levitronix Waltham, MA) to form a cavopulmonary support system. The DLC was inserted through the right jugular vein and the superior vena cava into the extracardiac conduit with the infusion lumen opening aligned with the right PA bridge. Blood was withdrawn from the superior vena cava and the inferior vena cava through the drainage lumen and pumped into the right PA through the infusion lumen, with flow adjusted to 4.0+/-0.5 L/min. RESULTS: A successful Fontan model was created without cardiopulmonary bypass. After total venous blood diversion from the vena cava to the right PA artery, failing Fontan physiology developed, evidenced by elevated central venous pressure and dropping mean PA pressure and systolic arterial pressure. The DLC was successfully inserted, and hemodynamics were normalized in all 5 sheep for the duration of the 2-hour study. CONCLUSIONS: We created a model of failing Fontan circulation in sheep without cardiopulmonary bypass. The DLC system achieved total cavopulmonary support for 2 hours in our failing Fontan sheep model. PMID- 21531378 TI - Serum C-reactive protein as a predictor of morbidity and mortality in intensive care unit patients after esophagectomy. AB - BACKGROUND: Serum C-reactive protein (CRP) is an acute-phase protein, synthesized during any proinflammatory response in the body. Preoperative elevation of serum CRP has been reported to be a prognostic indicator in oncologic surgery. The aim of this study was to investigate the value of postoperative serum CRP elevation as a prognostic parameter in patients undergoing elective esophagectomy followed by routine admission to the intensive care unit (ICU). METHODS: In a prospective follow-up cohort study, data were collected of 63 patients admitted to the ICU after elective esophagectomy surgery from October 2007 to December 2008. Postoperative serum CRP levels were determined at the moment of admission to the ICU, 24, 48, and 72 hours postoperatively, and the relation with the development of complications and the 1-year survival status was investigated. RESULTS: In postoperative esophagectomy patients admitted to the ICU, CRP levels at T24 and T48 were significantly higher in the patients who developed postoperative complications, which in itself was associated with lower 1-year survival. CONCLUSIONS: In patients undergoing esophagectomy with gastric tube reconstruction, increased CRP levels were associated with the occurrence of postoperative complications and higher 1-year mortality. Postoperative serum CRP levels can easily be monitored in the ICU in order to identify patients at risk for the development of postoperative complications; future research is needed to determine whether these complications can be prevented and improve outcome. PMID- 21531380 TI - Titanium plates and Dualmesh: a modern combination for reconstructing very large chest wall defects. AB - BACKGROUND: The reconstruction of large full-thickness chest wall defects after resection of T3/T4 non-small cell lung carcinomas or primary chest wall tumors presents a technical challenge for thoracic surgeons and plays a central role in determining postoperative morbidity. The objective is to evaluate our results in chest wall reconstruction using a combination of expanded polytetrafluoroethylene (ePTFE) mesh and titanium plates. METHODS: Since 2006, 19 patients underwent reconstruction for wide chest wall defects using a combination of ePTFE mesh and titanium plates. The chest wall reconstruction was achieved by using a layer of 2 mm thickness ePTFE shaped to match the chest wall defect and sewed under maximum tension. The ePTFE is placed close to the lung and fixed onto the bony framework and onto the titanium plate, which is inserted on the ribs. RESULTS: Seventeen patients underwent a complete R0 resection with the removal of 3 to 9 ribs (mean, 4.8 ribs), including the sternum in 7 cases. Reconstruction required 1 to 4 horizontal titanium bars (mean, 1.7 bars). In 1 patient, a vertical titanium device was implanted for a large posterolateral defect. There were 2 cases of infection, which required explantation of the osteosynthesis system in 1 patient. One patient had partial skin necrosis that required prompt debridement. One patient had a major complication in the form of respiratory failure. CONCLUSIONS: Our experience and initial results show that titanium rib osteosynthesis in combination with Dualmesh can easily and safely be used in a one-stage procedure for major chest wall defects. PMID- 21531381 TI - Movement compatibility for configurations of displays located in three cardinal orientations and ipsilateral, contralateral and overhead controls. AB - Stereotype strength and reversibility were determined for displays that were in the Front, Right and Left orientations relative to the operator, along with rotary, horizontally and vertically-moving controls located in the overhead, left sagittal and right-sagittal planes. In each case, responses were made using the left and right hands. The arrangements used were (i) rotary control with a circular display (ii) horizontal/transverse control moving forward/rearward in the left and right-sagittal planes or transversely in the overhead plane and (iii) vertical/longitudinal control moving vertically in the left and right sagittal planes and longitudinally in the overhead plane. These are all combinations not previously researched. Stereotype strength varied with display plane, type of control and plane of control. Models for the stereotype strength are developed, showing the contribution of various components to the overall stereotype strength. The major component for horizontally-moving controls comes from the "visual field" model of Worringham and Beringer (1998); for the rotary control important factors are "clockwise-for-clockwise" and the hand/control location effect (Hoffmann, 2009a). Vertically-moving controls are governed by a simple 'up-for-up' relationship between displays and controls. Overall stereotype strength is a maximum when all components add positively. PMID- 21531382 TI - Mood-linked responses in medial prefrontal cortex predict relapse in patients with recurrent unipolar depression. AB - BACKGROUND: Altered cognitive processing following mood challenge is associated with elevated relapse risk in remitted unipolar depressed patients, but little is known about the neural basis of this reactivity and its link to depressive relapse and prophylaxis. METHODS: Remitted unipolar depressed participants (n = 16) and healthy control subjects (n = 16) underwent functional magnetic resonance imaging (fMRI) while viewing sad and neutral film clips. Correlations were determined between emotional reactivity (neural responses to sad vs. neutral films) in remitted patients and subsequent relapse status over an 18 month follow up period. A receiver operating characteristic analysis was used to determine signal cutoffs for predicting relapse. Emotional reactivity in relapse prognostic areas was compared between groups. RESULTS: Within the remitted group, relapse was predicted by medial prefrontal cortical (mPFC; Brodmann's area 32) activity and contraindicated by visual cortical activity (Brodmann's area 17). mPFC reactivity predicted rumination, whereas visual cortical reactivity predicted distress tolerance (acceptance). Compared with control participants, remitted depressed patients demonstrated a more pronounced tradeoff between mPFC and visual cortex reactivity. The difference score between mPFC and visual reactivity yielded excellent prediction of depressive relapse. CONCLUSIONS: Medial prefrontal cortical reactivity to mood provocation in remitted unipolar depressed patients serves as a marker of relapse risk rather than successful emotion regulation. Enduring remission is characterized by normalization of the mPFC to that of healthy control subjects. Furthermore, visual cortex reactivity predicts resilience against depressive relapse, indicating a prophylactic role for sensory rather than ruminative cognitive reactivity in the processing of negative emotion. PMID- 21531383 TI - Suicidal behavior is associated with reduced corpus callosum area. AB - BACKGROUND: Corpus callosum (CC) size has been associated with cognitive and emotional deficits in a range of neuropsychiatric and mood disorders. As such deficits are also found in suicidal behavior, we investigated specifically the association between CC atrophy and suicidal behavior. METHODS: We studied 435 right-handed individuals without dementia from a cohort of community-dwelling persons aged 65 years and over (the ESPRIT study). They were divided in three groups: suicide attempters (n = 21), affective control subjects (AC) (n = 180) without history of suicide attempt but with a history of depression, and healthy control subjects (HC) (n = 234). T1-weighted magnetic resonance images were traced to measure the midsagittal areas of the anterior, mid, and posterior CC. Multivariate analysis of covariance was used to compare CC areas in the three groups. RESULTS: Multivariate analyses adjusted for age, gender, childhood trauma, head trauma, and total brain volume showed that the area of the posterior third of CC was significantly smaller in suicide attempters than in AC (p = .020) and HC (p = .010) individuals. No significant differences were found between AC and HC. No differences were found for the anterior and mid thirds of the CC. CONCLUSIONS: Our findings emphasize a reduced size of the posterior third of the CC in subjects with a history of suicide, suggesting a diminished interhemispheric connectivity and a possible role of CC in the pathophysiology of suicidal behavior. Further studies are needed to strengthen these results and clarify the underlying cellular changes leading to these morphometric differences. PMID- 21531384 TI - Exaggerated brain activation during emotion processing in unaffected siblings of patients with schizophrenia. AB - BACKGROUND: Schizophrenia is characterized by impaired social cognition, including emotion processing. Behavioral studies have reported impaired performance on various emotion processing tasks, and imaging studies in patients have observed aberrant activity within the underlying neural circuitry. Also, subjects at increased genetic risk of developing schizophrenia, including unaffected siblings of patients, show behavioral impairments in emotion processing. It is unclear, however, whether and how the underlying neural system is disrupted in these subjects. In this study, we investigated whether siblings of patients with schizophrenia show abnormal brain activation during basic emotion processing. METHODS: Brain activity was measured using functional magnetic resonance imaging in 24 unaffected siblings of patients with schizophrenia and 25 healthy control subjects while they viewed and rated neutral, positive, and negative pictures. None of the subjects had a psychiatric disorder, and the two groups did not differ in age, gender, or level of own, paternal, or maternal education. RESULTS: Compared with control subjects, siblings showed increased activity within the amygdala, hippocampus, medial prefrontal cortex, posterior and anterior cingulate cortex, and middle temporal gyrus in response to emotionally arousing pictures relative to neutral pictures. No activation differences between the groups were found during the neutral stimuli, indicating that the observed hyperactivity is likely caused by abnormal emotion processing rather than impaired visuoattentional processing. CONCLUSIONS: Our findings of hyperactivity in siblings during emotion processing suggest that functional abnormalities within the neural circuitry of emotion processing are related to the genetic risk for developing schizophrenia. PMID- 21531385 TI - ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22 associated with the subgroup of schizophrenia with deficits in attention and executive function. AB - BACKGROUND: A genome scan of Taiwanese schizophrenia families suggested linkage to chromosome 10q22.3. We aimed to find the candidate genes in this region. METHODS: A total of 476 schizophrenia families were included. Hierarchical clustering method was used for clustering families to homogeneous subgroups according to their performances of sustained attention and executive function. Association analysis was performed using family-based association testing and TRANSMIT. Candidate associated regions were identified using the longest significance run method. The relative messenger RNA expression level was determined using real-time reverse transcriptase polymerase chain reaction. RESULTS: First, we genotyped 18 microsatellite markers between D10S1432 and D10S1239. The maximum nonparametric linkage score was 2.79 on D10S195. Through family clustering, we found the maximum nonparametric linkage score was 3.70 on D10S195 in the family cluster with deficits in attention and executive function. Second, we genotyped 79 single nucleotide polymorphisms between D10S1432 and D10S580 in 90 attention deficit and execution deficit families. Association analysis indicated significant transmission distortion for nine single nucleotide polymorphisms. Using the longest significance run method, we identified a 427 kilobase region as a significant candidate region, which encompasses nine genes. Third, we studied messenger RNA expression of these nine genes in Epstein-Barr virus-transformed lymphoblastic cells. In schizophrenic patients, there was significantly lower expression of ANXA7, PPP3CB, and DNAJC9 and significantly higher expression of ZMYND17. CONCLUSIONS: ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes are potential candidate genes for schizophrenia, especially in patients with deficits in sustained attention and executive function. The responsible functional variants remained to be clarified. PMID- 21531386 TI - May posterror performance be a critical factor for behavioral deficits in attention-deficit/hyperactivity disorder? AB - BACKGROUND: Although the performance of children with attention deficit/hyperactivity disorder (ADHD) is impaired in a variety of cognitive tasks, the specific capacity of strategic readaptation after errors as a source of behavioral deficits is not sufficiently understood. This study used an extended and refined behavioral parameterization to assess performance monitoring and posterror adaptation in children with ADHD. METHODS: Twenty-eight healthy control subjects and 47 ADHD patients (7-16 years of age, all males, matched for age and IQ) performed a visual flanker task in which targets were congruent or incongruent with preceding flankers. Posterror adaptation was measured for response speed (posterror slowing), accuracy, and variability by using normalized individual rates of change. Markers of error detection and general performance were also analyzed. RESULTS: Postcorrect response speed and accuracy did not differ between the groups, in contrast to posterror behaviors. Whereas posterror slowing was not evident in any of the groups, the error rate and performance instability (reaction time variance) substantially increased after errors only in ADHD patients, not in control subjects. No reliable between-group differences were found for error detection and global performance. CONCLUSIONS: In healthy children, posterror adaptation preserves performance at its ongoing level. No such adaptation was evident in ADHD, leading to consecutive errors and increased behavioral instability. Performance deficits in ADHD were only present after error but not after correct behaviors, which shapes the general profile of performance impairment in ADHD. The findings have practical implications for strategic designs of behavioral therapy in ADHD. PMID- 21531387 TI - Corticolimbic function in impulsive aggressive behavior. AB - Building on animal and human lesion evidence, neuroimaging studies are increasingly identifying abnormalities in corticolimbic circuits mediating aggressive behavior. This review focuses on three neural systems involved in impulsive/reactive aggression: 1) subcortical neural systems that support the production of aggressive impulses; 2) decision-making circuits and social emotional information processing circuits that evaluate the consequences of aggressing or not aggressing; and 3) frontoparietal regions that are involved in regulating emotions and impulsive motivational urges. We review psychiatric disorders, including borderline personality disorder and antisocial personality disorder, characterized by elevated reactive aggression, focusing on abnormalities in these three neural systems. PMID- 21531389 TI - Convergence of two independent mental disease genes on the protein level: recruitment of dysbindin to cell-invasive disrupted-in-schizophrenia 1 aggresomes. AB - BACKGROUND: Both disrupted-in-schizophrenia 1 (DISC1) and dysbindin have been identified as schizophrenia candidate genes in independent genetic linkage studies. The proteins have been assigned distinct subcellular locations and functions. We investigated whether both proteins converge into a common pathway specific for schizophrenia or mental diseases. METHODS: DISC1 and dysbindin were expressed as recombinant proteins with or without a fluorescent protein-tag in human or mouse neuroblastoma cells and as recombinant proteins in E. coli. Postmortem brains of patients with mental diseases from the Stanley Research Medical Institute's Consortium Collection were used to demonstrate molecular interactions in biochemically purified protein fractions. RESULTS: First, upon overexpression in neuroblastoma cells, DISC1 formed aggresomes that recruited homologous soluble C-terminal DISC1 fragment or heterologous dysbindin. Domains involved in binding could be mapped to DISC1 (316-597) and dysbindin (82-173), indicating a specific interaction. In addition, recruitment was demonstrated when externally added, purified DISC1 aggresomes penetrated recipient cells after coincubation. Second, a direct interaction between soluble DISC1 protein and dysbindin was demonstrated in a cell free system using E. coli-expressed proteins. Third, co-aggregation of DISC1 and dysbindin was demonstrated in postmortem brains for a subgroup of cases with chronic mental disease but not healthy control subjects. CONCLUSIONS: A direct interaction of soluble and insoluble DISC1 protein with dysbindin protein demonstrates convergence of so far considered independent mental disease genes by direct molecular interaction. Our findings highlight protein aggregation and recruitment as a biological mechanism in mental disease. PMID- 21531390 TI - Diminished gray matter within the hypothalamus in autism disorder: a potential link to hormonal effects? AB - BACKGROUND: Subjects with autism suffer from impairments of social interaction, deviations in language usage, as well as restricted and stereotyped patterns of behavior. These characteristics are found irrespective of age, IQ, and gender of affected subjects. However, brain changes due to age, IQ, and gender might pose potential confounds in autism neuroimaging analyses. METHODS: To investigate gray matter differences in autism that are not related to these potential confounds, we performed a voxel-based morphometry analysis in 52 affected children and adolescents and 52 matched control subjects. RESULTS: We observed diminished gray matter in a region of the hypothalamus, which synthesizes the behaviorally relevant hormones oxytocin and arginine vasopressin. CONCLUSIONS: This finding provides support for further investigations of the theory of abnormal functioning of this hormonal system in autism and potentially for experimental therapeutic approaches with oxytocin and related neuropeptides. PMID- 21531388 TI - Inverted-U-shaped dopamine actions on human working memory and cognitive control. AB - Brain dopamine (DA) has long been implicated in cognitive control processes, including working memory. However, the precise role of DA in cognition is not well-understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans, and patients with Parkinson's disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum DA level for cognitive function implicates the need to take into account baseline levels of DA when isolating the effects of DA. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum, respectively. Manipulating DA will thus have paradoxical consequences for distinct cognitive control processes, depending on distinct basal or optimal levels of DA in different brain regions. PMID- 21531392 TI - Voltage-gated potassium channel antibody associated mood disorder without paraneoplastic disease. PMID- 21531394 TI - Modelling of physical ageing in starch using the TNM equation. AB - Gelatinised wheat starch, freeze dried and equilibrated at different RH, was aged at different temperatures and for different times. The Tool-Narayanaswamy Moynihan (TNM) model was used to describe the ageing for all samples under all conditions. Three TNM parameters: x, Deltah* and A were determined experimentally using, respectively, the peak shift method (x) and the dependency of T'(f) (the limiting value of T(f)) on the cooling rate (Deltah* and A). The non-linearity parameter x and the non exponential parameter beta were also estimated by optimising a fit of the experimental normalised specific heat at different ageing times and temperatures to curves generated using the TNM model. The TNM model successfully described the normalised experimental data. It was found that the intermolecular forces were strong and the relaxation times depended more strongly on the glass structure than the glass temperature. The hydration level of the starch had a direct impact of the breadth of the relaxation time distribution. A dependency of the non-linearity parameter x on ageing temperature (peak shift method) was observed. This suggests that physical ageing is more complex than is described by TNM formalism. PMID- 21531395 TI - Microwave-assisted methylation of cassava starch with dimethyl carbonate. AB - A novel and environmentally friendly process for the methylation of cassava starch with dimethyl carbonate (DMC) could be accelerated by employing a combined strategy: using disodium hydrogen phosphate (Na(2)HPO(4)) as the catalyst (chemical means) and microwave irradiation as the energy source (physical means). By varying the volume of 5% sodium chloride aqueous solution between 50 and 150 mL, the amount of Na(2)HPO(4) between 0 and 1.25 g, the volume of DMC between 75 and 200 mL, and the microwave time from 5 to 20 min, methyl cassava starch with degree of substitution (DS) values in the range of 0.033 and 1.087 was prepared. The chemical structure of methyl cassava starch was analyzed by (1)H NMR spectroscopy. PMID- 21531396 TI - Regioselective reductive openings of 4,6-benzylidene acetals: synthetic and mechanistic aspects. AB - The use of benzylidene acetals as protecting groups in carbohydrate chemistry is utterly important. The main advantage of benzylidene acetal is the ability for regioselective openings. 4,6-benzylidene acetal can be opened selectively under reductive conditions to yield either free 4-OH or 6-OH. There are a plethora of methods available for regioselective openings, but only a few of these are widely used. In recent years, the mechanism has been investigated for borane mediated openings and it seems likely that the regioselectivity is determined by borane, rather than Lewis acid. When borane is activated by Lewis acids, borane is the most electrophilic species that consequently coordinates to the most nucleophilic oxygen of the acetals, usually O-6. This results in the formation of 6-O-benzyl ethers. If borane is not activated, Lewis acid is the most electrophilic species that thus adds to O-6 and hence generates the 4-O-benzyl ether. PMID- 21531397 TI - Synthesis and NMR studies on the ABO histo-blood group antigens: synthesis of type III and IV structures and NMR characterization of type I-VI antigens. AB - The ABO histo-blood group antigens are best known for their important roles in solid organ and bone marrow transplantation as well as transfusion medicine. Here we report the synthesis of the ABO type III and IV antigens with a 7-octen-1-yl aglycone. Also described is an NMR study of the ABO type I to VI antigens, which were carried out to probe differences in overall conformation of the molecules. These NMR investigations showed very little difference in the (1)H chemical shifts, as well as (1)H-(1)H coupling constants, across all compounds, suggesting that these ABO subtypes adopt nearly identical conformations in solution. PMID- 21531391 TI - Right anterior cingulate cortical thickness and bilateral striatal volume correlate with child behavior checklist aggressive behavior scores in healthy children. AB - BACKGROUND: The anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and basal ganglia have been implicated in pathological aggression. This study aimed at identifying neuroanatomical correlates of impulsive aggression in healthy children. METHODS: Data from 193 representative 6- to 18-year-old healthy children were obtained from the National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development after a blinded quality control. Cortical thickness and subcortical volumes were obtained with automated software. Aggression levels were measured with the Aggressive Behavior scale (AGG) of the Child Behavior Checklist. AGG scores were regressed against cortical thickness and basal ganglia volumes using first- and second-order linear models while controlling for age, gender, scanner site, and total brain volume. Gender by AGG interactions were analyzed. RESULTS: There were positive associations between bilateral striatal volumes and AGG scores (right: r = .238, p = .001; left: r = .188, p = .01). A significant association was found with right ACC and subgenual ACC cortical thickness in a second-order linear model (p < .05, corrected). High AGG scores were associated with a relatively thin right ACC cortex. An AGG by gender interaction trend was found in bilateral OFC and ACC associations with AGG scores. CONCLUSIONS: This study shows the existence of relationships between impulsive aggression in healthy children and the structure of the striatum and right ACC. It also suggests the existence of gender-specific patterns of association in OFC/ACC gray matter. These results may guide research on oppositional-defiant and conduct disorders. PMID- 21531393 TI - Kappa opioid receptor signaling in the basolateral amygdala regulates conditioned fear and anxiety in rats. AB - BACKGROUND: The kappa opioid receptor (KOR) system contributes to the prodepressive and aversive consequences of stress and is implicated in the facilitation of conditioned fear and anxiety in rodents. Here, we sought to identify neural circuits that mediate KOR system effects on fear and anxiety in rats. METHODS: We assessed whether fear conditioning induces plasticity in KOR or dynorphin (the endogenous KOR ligand) messenger RNA (mRNA) expression in the basolateral (BLA) and central (CeA) nuclei of the amygdala, hippocampus, or striatum. We then assessed whether microinfusions of the KOR antagonist JDTic (0 10 MUg/side) into the BLA or CeA affect the expression of conditioned fear or anxiety. Finally, we examined whether fear extinction induces plasticity in KOR mRNA expression that relates to the quality of fear extinction. RESULTS: Fear conditioning upregulated KOR mRNA in the BLA by 65% and downregulated it in the striatum by 22%, without affecting KOR levels in the CeA or hippocampus, or dynorphin levels in any region. KOR antagonism in either the BLA or CeA decreased conditioned fear in the fear-potentiated startle paradigm, whereas KOR antagonism in the BLA, but not the CeA, produced anxiolytic-like effects in the elevated plus maze. Effective fear extinction was associated with a 67% reduction in KOR mRNA in the BLA. CONCLUSIONS: These findings suggest that fear conditioning and extinction dynamically regulate KOR expression in the BLA and provide evidence that the BLA and CeA are important neural substrates mediating the anxiolytic like effects of KOR antagonists in models of fear and anxiety. PMID- 21531398 TI - The conformation of tetrafluorinated methyl galactoside anomers: crystallographic and NMR studies. AB - The first single-crystal X-ray diffraction study of tetrafluorinated monosaccharide derivatives is presented. Both alpha- and beta-methyl 2,3-dideoxy 2,2,3,3-tetrafluoro-d-galactopyranoside anomers adopt the (4)C(1) conformation. The values for the C1-O1 and C1-O5 bond lengths and the O5-C1-O1-CH(3) dihedral angles are in line with what can be expected from the anomeric and exo-anomeric effects. The chair conformations are slightly distorted, presumably due to repulsion between 1,3-diaxial C-O and C-F bonds. The asymmetric unit of both compounds contains up to three independent molecules, which differ in the conformation of the hydroxymethyl group (including in one case a 'forbidden'gg rotamer). The molecular packing of the beta-anomer shows a clear segregation between fluorinated and hydrophilic domains, while for the alpha-anomer the regions of fluorine segregation are broken by interleafing of OMe groups. There is one close OH?F contact, which is likely to arise from the crystal packing. NMR studies show that the two anomers also adopt a (4)C(1) conformation in solution (D(2)O, CDCl(3)). PMID- 21531399 TI - [Robotic surgery. A present and future technological advance]. PMID- 21531400 TI - [Amyand's hernia]. PMID- 21531401 TI - [What is the surgical technique of choice in the obese patient with paraesophageal hiatal hernia?]. PMID- 21531402 TI - A system for detecting and describing pathological changes using dynamic perfusion computer tomography brain maps. AB - This paper presents a novel method of detecting and describing pathological changes that can be visualized on dynamic computer tomography brain maps (perfusion CT). The system was tested on a set of dynamic perfusion computer tomography maps. Each set consisted of two perfusion maps (CBF, CBV and TTP for testing the irregularity detection algorithm) and one CT brain scan (for the registration algorithm) from 8 different patients with suspected strokes. In 36 of the 84 brain maps, abnormal perfusion was diagnosed. The results of the algorithm were compared with the findings of a team of two radiologists. All of the CBF and CBV maps that did not show a diagnosed asymmetry were classified correctly (i.e. no asymmetry was detected). In four of the TTP maps the algorithm found asymmetries, which were not classified as irregularities in the medical diagnosis; 84.5% of the maps were diagnosed correctly (85.7% for the CBF, 85.7% for the CBV and 82.1% for the TTP); 75% of the errors in the CBF maps and 100% of the errors in the CBV and the TTP maps were caused by the excessive detection of asymmetry regions. Errors in the CBFs and the CBVs were eliminated in cases in which the symmetry axis was selected manually. Subsequently, 96.4% of the CBF maps and 100% of the CBV maps were diagnosed correctly. PMID- 21531403 TI - From symmetry to asymmetry? The development of smile. AB - The left side of the face has been reported to be more expressive than the right side in human adults. The developmental origin of this lateralization, however, is unknown. Chimeric still composite photos of smiling faces of 0-5 months (n=61), 6-12 months (n=67) old infants, 3-8 years old children (n=78), and 32 adults (>18 years) were rated for intensity by 90 judges. The results showed left hemiface dominance in adults only, and not in infants or children. It can be speculated that this early functional symmetry may evolutionarily increase attractiveness and elicits secure bonding and care. PMID- 21531404 TI - Human exposure to allergenic pollens: a comparison between urban and rural areas. AB - BACKGROUND: Pollinosis is found more frequently in urban areas than in rural environments. This could be partly related to the different types of pollen exposure in these dissimilar areas. The objective of this study was to compare the distribution of pollen in these environments across an urbanization gradient. METHODS: Daily pollen abundances were obtained in France using Hirst-type sensors. Sampling was conducted from January to June in 2003 and 2006 in a rural area, a semi-rural area and in two urban areas, which were characterized by several urbanization criteria. RESULTS: Total allergenic pollen abundance was higher in rural and semi-rural areas than in urban areas irrespective of the sampling year. Multivariate analyses showed that pollen exposures differed according to the type of area and were strongly explained by the urbanization gradient. Grass, ash, birch, alder, hornbeam, hazel and plantain pollen quantities exceeded the allergy threshold more often in rural settings than in urban areas. In urban areas, only plane pollen quantities exceeded the allergy threshold more often than in rural areas. CONCLUSIONS: Allergenic pollen exposure is higher in rural areas than in urban areas, and the most abundant pollen in each area did not originated from the same taxa. This result should be taken into account in epidemiological studies comparing allergies in rural and urban areas to adapt the panel of pollen extracts for human environmental exposure. In addition, this study highlights that some ornamental trees produce a large number of allergenic pollens and provide new sources of aeroallergens. PMID- 21531405 TI - [Core competencies in internal medicine]. AB - The working group of the Spanish Society of Internal Medicine (SEMI) on "Competencies of the Internist" has defined the basic medical knowledge, skills and attitudes that all internists in Spain should have. This list of competencies represents the Internal Medicine core curriculum within the context of the future educational framework of medical specialties in Health Sciences. PMID- 21531406 TI - [Tolvaptan in antidiuretic hormone secretion syndrome secondary to treatment with citalopram]. PMID- 21531407 TI - [Diarrhea as first manifestation of the autoimmune pluriglandular syndrome type II (Schmidt Syndrome)]. PMID- 21531408 TI - Aberrant right hepatic duct with patent ducts of Luschka. PMID- 21531409 TI - Patients often hold the clue for diagnosis-even if they do not know it. PMID- 21531410 TI - Quality of colonoscopy withdrawal technique and variability in adenoma detection rates (with videos). AB - BACKGROUND: Studies suggest that endoscopist-related factors such as colonoscopy withdrawal time are important in determining the adenoma detection rate (ADR). OBJECTIVE: To determine the importance of withdrawal technique in differentiating among endoscopists with varying ADRs. DESIGN: Prospective, multicenter study. SETTING: Five academic tertiary-care medical centers. PARTICIPANTS: This study involved 11 gastroenterology faculty endoscopists. INTERVENTION: A retrospective review of screening colonoscopies was performed to categorize endoscopists into low, moderate, and high ADR groups. Video recordings were randomly obtained for each endoscopist on 20 (10 real, 10 sham) withdrawals during colonoscopies performed for average-risk colorectal cancer screening. Three blinded reviewers assigned withdrawal technique scores (total of 75 points) on 110 video recordings. A separate reviewer recorded withdrawal times. MAIN OUTCOME MEASUREMENTS: Withdrawal technique scores and withdrawal times. RESULTS: Mean (+/ standard deviation [SD]) withdrawal technique scores were higher in the moderate (62 +/- 2.5) and high (59.5 +/- 3) ADR groups compared with the low (40.8+/-3) ADR group (P = .002). Mean (+/- SD) withdrawal times were 6.3 +/- 1.8 minutes (low ADR), 10.2 +/- 1.5 minutes (moderate ADR), and 8.2 +/- 1.8 minutes (high ADR) (P = .29). A comparison of the withdrawal times and technique scores of the two individual endoscopists with the lowest and highest ADRs did not find a significant difference in withdrawal times (6.6 +/- 1.7 vs 7.4 +/- 1.7 minutes) (P = .36) but did find a nearly 2-fold difference in technique scores (36.2 +/- 9 vs 62.8 +/- 9.9) (P = .0001). LIMITATIONS: Not adequately powered to detect small differences in withdrawal times. CONCLUSION: Withdrawal technique is an important indicator that differentiates between endoscopists with varying ADRs. It is possible that withdrawal technique is equal to, if not more important than, withdrawal time in determining ADRs. PMID- 21531411 TI - A novel device for ablation of abnormal esophageal mucosa (with video). AB - BACKGROUND: Current ablation devices for Barrett's esophagus are effective but have significant limitations. OBJECTIVE: To evaluate a new ablation device. DESIGN AND SETTING: Laboratory and animal model evaluation of the CryoBalloon, a compliant balloon that is simultaneously inflated and cooled by liquid nitrous oxide delivered by using a small, disposable, handheld unit. INTERVENTION: Cryoablation of esophageal mucosa was performed in 11 swine. Multiple ablations were created in each animal at various ablation times. MAIN OUTCOME MEASUREMENTS: Animals were euthanized at 4 days (n = 6) or 28 days (n = 5), and histological assessments were performed. At 4 days, the percentage of esophageal mucosa successfully ablated was measured. At 28 days, the circumference of the esophagus at the center of the ablation zone was measured to assess for stricture formation. RESULTS: The CryoBalloon was simple to operate, and balloon contact with tissue was easily maintained. As the ablation time was increased from 6 to 12 seconds, the percentage of mucosa ablated increased from below 60% to above 90%. Maximal effect on the mucosa was reached at 12 seconds. Ablation of up to 14 seconds resulted in minimal luminal narrowing. As the ablation duration increased from 14 to 22 seconds, there was progressive stricture formation evident at 28 days. All of the animals tolerated the treatments without difficulty and, regardless of ablation duration, were able to continue oral intake and gain weight after the procedure. LIMITATIONS: Ablation of normal porcine squamous mucosa may differ from that of human Barrett's esophagus. CONCLUSION: The CryoBalloon device enables circumferential mucosal ablation in a 1-step process by using a novel, through-the-scope balloon. The maximal effect on the mucosa is achieved with a 12-second application time. Because of its ease of use, this new device merits further study so that we can find its possible role in the treatment of Barrett's esophagus. PMID- 21531412 TI - Is the addition of choleretic agents in multiple double-pigtail biliary stents effective for difficult common bile duct stones in elderly patients? A prospective, multicenter study. AB - BACKGROUND: Temporary biliary stenting is both technically easy and feasible, and choleretic agents such as ursodeoxycholic acid (UDCA) and a terpene preparation may promote a reduction in stone size. However, there are few comparative data on the effectiveness of choleretic agents available. OBJECTIVE: To investigate the efficacy of multiple double-pigtail stents with or without UDCA and terpene on difficult common bile duct (CBD) stones. DESIGN: A prospective, multicenter study. SETTING: Four tertiary-care referral centers. PATIENTS: This study involved 51 patients. INTERVENTION: In total, 51 elderly patients with comorbidities who had difficult CBD stones refractory to conventional methods were randomized to receive either multiple 7F double-pigtail stents (group A) or stents in combination with UDCA and terpene (group B) for a period of 6 months. MAIN OUTCOME MEASUREMENTS: Stone size reduction, successful duct clearance, and complications. RESULTS: Complete endoscopic duct clearance was achieved in 14 patients (73.7%) in group A and 19 patients (86.4%) in group B (P = .826). The mean size of CBD stones (transverse/longitudinal diameter, mean +/- SD) was 19.12 +/- 4.48 mm/20.47 +/- 3.86 mm in group A and 21.30 +/- 7.08 mm/22.58 +/- 7.61 mm in group B. Stone size decreased significantly to 12.04 +/- 3.26 mm/13.31 +/- 5.12 mm and 13.67 +/- 5.40 mm/14.04 +/- 6.12 mm, respectively (P < .01). However, there was no statistical difference in stone size reduction between the two groups (P = .685, P = .289). No serious complications related to the stent or endoscopic procedures were observed, except for cholangitis (n = 1, group A) and distal stent migration (n = 2, group B). LIMITATIONS: Small number of patients in East Asia. CONCLUSION: Temporary multiple double-pigtail biliary stenting was a safe and feasible method of treating difficult and large CBD stones in elderly patients and contributed to a reduction in stone size and successful duct clearance. However, the addition of choleretic agents did not result in a statistical difference in stone size or rate of successful duct clearance. PMID- 21531413 TI - Operative strategy in postero-medial fracture-dislocation of the proximal tibia. AB - OBJECTIVE: In 1981, Moore introduced a new classification for dislocation-type fractures caused by high-energy mechanisms. The most common medial Moore-type fractures are entire condyle fractures with the avulsion of the median eminence (tibial anterior cruciate ligament (ACL) insertion). They are usually associated with a posterolateral depression of the tibial plateau and an injury of the lateral menisco-tibial capsule. This uniform injury of the knee is increasingly observed in the recent years after skiing injuries due to the high-speed carving technique. This uprising technique uses shorter skis with more sidecut allowing much higher curve speeds and increases the forces on the knee joint. The aim of this study was to describe the injury pattern, our developed operative approach for reconstruction and outcome. METHODS: A total of 28 patients with 29 postero medial fracture dislocation of the proximal tibia from 2001 until 2009 were analysed. Clinical and radiological follow-up was performed after 4 years on average (1 year in minimum). Evaluation criteria included the Lysholm score for everyday knee function and the Tegner score evaluating the activity level. All fractures were stabilised post primarily. The surgical main approach was medial. First, the exposure of the entire medial condyle fracture was performed following the fracture line to the articular border. The posterolateral impaction was addressed directly through the main fracture gap from anteromedial to posterolateral. Small plateau fragments were removed, larger fragments reduced and preliminarily fixed with separate K-wire(s). The postero-medial part of the condyle was then prepared for main reduction and application of a buttress T plate in a postero-medial position, preserving the pes anserinus and medial collateral ligament. In addition, a parapatellar medial mini-arthrotomy through the same main medial approach was performed. Through this mini-arthrotomy, the avulsed anterior eminence with attached distal ACL is retained by a transosseous suture back to the tibia. RESULTS: We could evaluate 26 patients (93%); two patients were lost to follow-up due to foreign residence. Median age was 51 years (20-77 years). The fractures were treated post primarily at an average of 4 days; in 18 cases a two-staged procedure with initial knee-spanning external fixator was used. All fractures healed without secondary displacement or infection. As many as 25 patients showed none to moderate osteoarthritis after a median of 4 years. One patient showed a severe osteoarthritis after 8 years. All patients judge the clinical result as good to excellent. The Lysholm score reached 95 (75 100) of maximal 100 points and the Tegner activity score 5 (3-7) of maximal 10 points (competitive sports). The patients achieved a median flexion of 135 degrees (100-145 degrees ). CONCLUSION: In our view, it is crucial to recognise the different components of the injury in the typical postero-medial fracture dislocation of the proximal tibia. The described larger medial approach for this type of medial fracture dislocation allows repairing most of the injured aspects of the tibial head, namely the medial condyle with postero-medial buttressing, the distal insertion of the ACL and the posterolateral impaction of the plateau. PMID- 21531414 TI - Patterns of cytokine release and evolution of remote organs from proximal femur fracture in COPD rats. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is at increased risk for developing osteoporosis (OP) with subsequent proximal femur fracture. The presence of COPD is suggested to be a strong risk factor for proximal femur fracture or hip fracture. However, what happen behind it is not clearly understood. OBJECTIVE: To investigate the pattern of cytokine (TNF-a, IL-6, and IL-10) releases in pulmonary and hepatic in rats with COPD suffering from proximal femur fracture, and its possible adverse effect on pulmonary and hepatic. METHODS AND SUBJECTIVE: This paper has two parts. In the first part, we describe the procedure of COPD model in detail. In the second part, we study the influences of fracture on the COPD rats. 5 months WISTAR rats with 37 weeks cigarette smoking exposure (CS group) were dynamically determined for pulmonary function, inflammatory response in bronchoalveolar lavage fluid (BALF), histological changes in pulmonary in the first part. When the COPD model is proved to be successful, we begin the second part. COPD rats were euthanized at 2, 24, 48, 72, and 96h after proximal femur fracture (fracture group) or anaesthesia (control group). Cytokines (TNF-a, IL-6, and IL-10) and myeloperoxidase activity of pulmonary and hepatic (MPO) were measured with enzyme liked immunosorbent assay technique. Permeability changes of the lung were assessed via bronchoalveolar lavage, and those of the liver via assessment of oedema formation. Tissues were further examined microscopically. RESULTS: The current sidestream cigarette smoke induced rat COPD model has been proved an adequate animal model with several advantages as assessed by dynamically monitored lung mechanics and pathological changes for 37 weeks. In the second part, TNF-a, IL-6, and IL-10 levels of pulmonary tissue were significantly increased after proximal femur fracture compared to control rats. TNF-a, and IL-6 levels in pulmonary peaked at 2h, 24h in fracture group, whereas IL-10 level peaked at 24h and 96h. Pulmonary myeloperoxidase activity, permeability and histological score in fracture group were remarkably elevated, and peaked at 24h. In addition to TNF-a, all above parameters did not return to normal through our study. Hepatic in COPD rats showed notable increase of cytokines (TNF-a, IL-6, and IL-10), myeloperoxidase activity, histological score, and permeability in fracture group compared to control rats, and severity of these changes were much lower than in pulmonary. Apart from TNF-a, the peak of these parameters was at 24h after fracture. Changes of cytokines, MPO activity, permeability and histological score in pulmonary and hepatic in control rat were little changed. CONCLUSION: COPD rats produced a remarkably increase of inflammatory response (TNF-a, IL-6, IL-10) in lung (liver) after proximal femur fracture, which lead to lung (liver) injury, as evidence by changes of MPO, permeability, and histological scores in local organs. PMID- 21531415 TI - Premature closure of the ductus arteriosus. PMID- 21531416 TI - Influence of material coupling and assembly condition on the magnitude of micromotion at the stem-neck interface of a modular hip endoprosthesis. AB - Hip prostheses with a modular neck exhibit, compared to monobloc prostheses, an additional interface which bears the risk of fretting as well as corrosion. Failures at the neck adapter of modular prostheses have been observed for a number of different designs. It has been speculated that micromotions at the stem neck interface were responsible for these implant failures. The purpose of this study was to investigate the influence of material combinations and assembly conditions on the magnitude of micromotions at the stem-neck interface during cyclic loading. Modular (n = 24) and monobloc (n = 3) hip prostheses of a similar design (Metha, Aesculap AG, Tuttlingen, Germany) were subjected to mechanical testing according to ISO 7206-4 (F(min) = 230N, F(max) = 2300N, f = 1Hz, n = 10,000 cycles). The neck adapters (Ti-6Al-4V or Co-Cr29-Mo alloy) were assembled with a clean or contaminated interface. The micromotion between stem and neck adapter was calculated at five reference points based on the measurements of the three eddy current sensors. The largest micromotions were observed at the lateral edge of the stem-neck taper connection, which is in accordance with the crack location of clinically failed prostheses. Titanium neck adapters showed significantly larger micromotions than cobalt-chromium neck adapters (p = 0.005). Contaminated interfaces also exhibited significantly larger micromotions (p < 0.001). Since excessive micromotions at the stem-neck interface might be involved in the process of implant failure, special care should be taken to clean the interface prior to assembly and titanium neck adapters with titanium stems should generally be used with caution. PMID- 21531417 TI - Absorbance detector for high-performance liquid chromatography based on light emitting diodes for the deep-ultraviolet range. AB - A HPLC-detector has been designed which employs light-emitting diodes in the deep UV-range below 300 nm as wavelength specific radiation sources and special UV photodiodes for measuring the signal. A monochromator is therefore not needed. The design features a beam splitter and a reference photodiode, precision mechanics for adjustment of the light beams and electronics for stabilization of the LED-current. The processing of the photodiode currents is carried out with a high performance log-ratio amplifier which allows direct absorbance measurements. The optical and electronic performance of the detector was characterised and high precision over several absorbance units was obtained. Testing of analytical separation methods in isocratic as well as gradient modes employing UV-detection at 255 and 280 nm showed a very similar performance to a commercial photodiode array detector used in the fixed wavelength mode in terms of linearity, precision and detection limits. The chief advantages of the new device are small size, low power consumption, and low cost. PMID- 21531418 TI - Study of polyethylene glycol as a green solvent in the microwave-assisted extraction of flavone and coumarin compounds from medicinal plants. AB - In this paper, the application of polyethylene glycol (PEG) aqueous solution as a green solvent in microwave-assisted extraction (MAE) was firstly developed for the extraction of flavone and coumarin compounds from medicinal plants. The PEG solutions were optimized by a mono-factor test, and the other conditions of MAE including the size of sample, liquid/solid ratio, extraction temperature and extraction time were optimized by means of an orthogonal design L(9) (3(4)). Subsequently, PEG-MAE, organic solvent-MAE, and conventional heating reflux extraction (HRE) were evaluated with nevadensin extraction from Lysionotus pauciflorus, aesculin and aesculetin extraction from Cortex fraxini. Furthermore, the mechanism of PEG-MAE was investigated, including microwave-absorptive property and viscosity of PEG solutions, the kinetic mechanism of PEG-MAE and different microstructures of those samples before and after extraction. Under optimized conditions, the extraction yields of nevadensin from L. pauciflorus, aesculin and aesculetin from C. fraxini were 98.7%, 97.7% and 95.9% in a one-step extraction, respectively. The recoveries of nevadensin, aesculin and aesculetin were in the range of 92.0-103% with relative standard derivation lower than 3.6% by the proposed procedure. Compared with organic solvent-MAE and conventional extraction procedures, the proposed methods were effective and alternative for the extraction of flavone and coumarin compounds from medicinal plants. On the basis of the results, PEG solution as a green solvent in the MAE of active compounds from medicinal plants showed a great promising prospect. PMID- 21531419 TI - Preparation and characterization of novel crown ether functionalized ionic liquid based solid-phase microextraction coatings by sol-gel technology. AB - A novel crown ether functionalized ionic liquid (IL), 1-allyl-3-(6'-oxo-benzo-15 crown-5 hexyl) imidazolium hexafluorophosphate was synthesized and used as selective stationary phase to prepare task-specific IL-based solid phase microextraction (SPME) fibers by sol-gel method and free radical cross-linking technology. The underlying mechanism of the sol-gel reaction was proposed and the successful chemical bonding of the crown ether functionalized IL to the formed hybrid organic-inorganic copolymer coating was confirmed by FT-IR spectroscopy. The performance of this in situ created crown ether functionalized IL-based SPME fibers, was investigated in detail. The coating has porous surface structure, stable performance in high temperature (to 340 degrees C) and in different solutions (water, organic solvent, acid and alkali), and good coating preparation reproducibility. In contrast to the sol-gel derived 1-allyl-3-methyl imidazolium hexafluorophosphate-based coating prepared in our previous work with the identical procedure, the extraction performance of this newly developed sol-gel crown ether functionalized IL-based coating was superior for alcohols, phthalate esters, phenolic environmental estrogens, fatty acids and aromatic amines due to the introduction of benzo-15-crown-5 functional group in IL structure. Moreover, it was shown to provide higher or comparable extraction efficiencies for most analytes studied than did the commercial PDMS, PDMS/DVB and PA fibers. PMID- 21531420 TI - Ultra-high capacity liquid chromatography chip/quadrupole time-of-flight mass spectrometry for pharmaceutical analysis. AB - Nanoflow liquid chromatography/mass spectrometry (nano-LC/MS) has attracted increasing interest in virtue of high sensitivity, low sample consumption, and minimal matrix effect. In this work a HPLC-Chip/quadrupole time-of-flight (Q-TOF) MS device with a new ultra-high capacity small molecule chip (UHC-Chip) which features a 500 nL enrichment column and a 150 mm * 75 MUm analytical column, was evaluated with a drug mixture covering a wide range of polarities. Excellent chromatographic precision with 0.1-0.5% RSD for retention time and 1.7-9.0% RSD for peak area, low limit of detection, good chip-to-chip reproducibility and linearity were obtained by using this UHC-Chip. Compared with the standard HPLC Chip with 40 nL trapping column, the UHC-Chip showed higher enrichment capability and hence gave a higher response in signal detection. Additionally, 4-30 times increase in sensitivity was obtained compared with conventional LC/MS, which indicated that UHC-Chip/MS was a valuable tool for the quantitative analysis of low level impurities and degradation products in pharmaceuticals. Moreover, satisfactory results obtained from trace drug analysis of serum samples further proved its practicality and potential for use in drug testing and development. PMID- 21531421 TI - Synthesis and evaluation of a chiral stationary phase based on quinine: enantioresolution of dinitrophenyl derivatives of alpha-amino acids. AB - The natural alkaloid quinine (QN) was immobilized on porous silica particles, and part of the material was subsequently endcapped with n-hexyl hydrocarbon chains. Two synthetic strategies for silanization of the support were first compared. These columns were thoroughly evaluated in order to study the influence of endcapping in the enantiorecognition features. Enantioseparations of twenty N derivatized 2,4-dinitrophenyl alpha-amino acids (DNP-amino acids) were studied by changing mobile phase pH, buffer concentration, type of organic solvent in the mobile phase, and column temperature. Maximum retention factors were observed at pH ~6, at this intermediate pH the tertiary amine of the quinine is protonated to a high degree and therefore available for strong electrostatic interactions with unprotonated anionic DNP-amino acids. The enantioselectivity factors, however, increased as the pH did in the range between 5 and 7. The increase in ionic strength had influence on retention, but not on enantioselectivity, allowing the use of this variable for optimization of retention factors. Finally, the thermodynamic transfer parameters of the enantiomers from the mobile to both CSPs (with and without endcapping, QN-CSP(EC) and QN-CSP, respectively) were estimated from van't Hoff plots within the range of 10-40 degrees C. Thus, the differences in the transfer enthalpy, Delta(DeltaH degrees ), and transfer entropy, Delta(DeltaS degrees ), enabled an investigation of the origin of the differences in interaction energies. PMID- 21531422 TI - Polydopamine supported preparation method for solid-phase microextraction coatings on stainless steel wire. AB - In this paper, we introduced a novel and versatile route to prepare solid-phase microextraction coatings on the chemically inert stainless steel wire. Polydopamine films can be created on metallic substrates by an oxidant-induced polymerization and subsequently support various secondary reactions to prepare functional surfaces. In the present work, polydopamine-bioactivated stainless steel wire was successfully modified by nanostructured hydroxyapatite. Extraction performance of the fiber was assessed on several polycyclic aromatic hydrocarbons in water solutions. Extraction mechanism was suggested based on the correlation of partition coefficients and LogPs. Both aqueous and solid real life samples were used to test the reliability of the solid-phase microextraction-gas chromatography method; some analytes were detected and quantified. PMID- 21531423 TI - Multiresidue analytical method for the determination of antimicrobials, preservatives, benzotriazole UV stabilizers, flame retardants and plasticizers in fish using ultra high performance liquid chromatography coupled with tandem mass spectrometry. AB - A multiresidue analytical method for the determination of emerging pollutants belonging to personal care products (PCPs) (antimicrobials, preservatives), benzotriazole UV stabilizers (BUVSs) and organophosphorus compounds (OPCs) in fish has been developed using high speed solvent extraction (HSSE) followed by silica gel clean up and ultra fast liquid chromatography coupled with tandem mass spectrometry (UFLC-MS/MS) analysis. Developed extraction and clean up method yielded good recovery (> 70%) for all the four groups of emerging pollutants, i.e. antimicrobials (78.5-85.6%), preservatives (85.0-89.4%), BUVSs (70.9-112%) and OPCs (81.6-114%; except for TEP - 68.9% and TPeP - 58.1%) with RSDs ranging from 0.7 to 15.4%. Intra- and inter-day repeatabilities were less than 19.8% and 19.0%, respectively at three spiked levels. The concentrations were given in lipid weight (lw) basis, and the method detection limits were achieved in the lowest range of 0.001-0.006 ng g-1 for two antimicrobials, 0.001-0.015 ng g-1 for four preservatives, 0.0002-0.009 ng g-1 for eight BUVSs and 0.001-0.014 ng g-1 for nine OPCs. Finally, the method was successfully validated as a simple and fast extraction method for the determination of 23 compounds belonging to PCPs, BUVSs and OPCs and applied to the analysis of three species of fish from Manila Bay, the Philippines. Concentrations ranged from 27 to 278 ng g-1 for antimicrobials, 6.61 to 1580 ng g-1 for paraben preservatives, 1 mg kg(-1)) and Pb (up to 40 mg kg(-1)). The vertical profiles of these metals suggested that elevated concentrations of Cd were of natural origin, derived from the erosion of the Jurassic dolomite bedrock, while Pb was predominately of recent anthropogenic origin. A similar distribution pattern, suggesting the same prevailing mechanism of input, was observed for pyrolytic PAHs. The characteristic diagnostic PAH ratios revealed that higher PAHs prevailingly originated from the combustion of biomass and fossil fuels. LAS, which represent highly specific indicators of untreated wastewaters, were found in rather high concentrations in the recent sediment layers (up to 4.7 mg kg(-1)), suggesting that contaminated household and hotel wastewaters reach the Lakes, very probably by leaking through the porous karst rocks. PMID- 21531437 TI - Effect of fluctuating soil humidity on in situ bioavailability and degradation of atrazine. AB - This study elucidates the effect of fluctuating soil moisture on the co-metabolic degradation of atrazine (6-chloro-N(2)-ethyl-N(4)-isopropyl-1,3,5-triazine-2,4 diamine) in soil. Degradation experiments with (14)C-ring-labelled atrazine were carried out at (i) constant (CH) and (ii) fluctuating soil humidity (FH). Temperature was kept constant in all experiments. Experiments under constant soil moisture conditions were conducted at a water potential of -15 kPa and the sets which were run under fluctuating soil moisture conditions were subjected to eight drying-rewetting cycles where they were dried to a water potential of around -200 kPa and rewetted to -15 kPa. Mineralization was monitored continuously over a period of 56d. Every two weeks the pesticide residues in soil pore water (PW), the methanol-extractable pesticide residues, the non-extractable residues (NER), and the total cell counts were determined. In the soil with FH conditions, mineralization of atrazine as well as the formation of the intermediate product deisopropyl-2-hydroxyatrazine was increased compared to the soil with constant humidity. In general, we found a significant correlation between the formation of this metabolite and atrazine mineralization. The cell counts were not different in the two experimental variants. These results indicate that the microbial activity was not a limiting factor but the mineralization of atrazine was essentially controlled by the bioavailability of the parent compound and the degradation product deisopropyl-2-hydroxyatrazine. PMID- 21531438 TI - Aerobic cometabolism of trichloroethene and cis-dichloroethene with benzene and chlorinated benzenes as growth substrates. AB - Using inoculum from a microcosm study that exhibited aerobic transformation of cis-1,2-dichloroethene (cDCE) and trichloroethene (TCE) commensurate with biodegradation of monoaromatic compounds, enrichment cultures were developed by providing benzene, chlorobenzene (CB), dichlorobenzene (DCB) isomers and 1,2,4 trichlorobenzene as carbon and energy sources. Isolates that grow on benzene, CB, 1,2-DCB and 1,3-DCB were identified as Rhodococcus, Ralstonia, Variovorax and Ralstonia spp., respectively. Cometabolic transformation of cDCE and TCE by resting cells was demonstrated. Transformation capacities (T(c)=0.47-1.0 MUg TCE mg(-1)biomass; 1.3-5.3 MUg cDCE mg(-1)biomass), transformation yields (T(y)=0.18 0.27 MUg TCE mg(-1)substrate; 0.46-2.1 MUg cDCE mg(-1)substrate), and pseudo first-order cometabolic degradation rate constants (0.00081-0.0031 L mg TCE(-1)d( 1); 0.0012-0.030 L mg cDCE(-1)d(-1)) for resting cells grown on benzene, CB, 1,2 DCB and 1,3-DCB were generally lower in comparison to phenol and toluene-grown isolates. Cometabolic transformation of cDCE and TCE also occurred while the cultures concurrently consumed their growth substrate (T(c)(')=0.15-0.33 MUg TCE mg(-1)biomass; 4.9-11 MUg cDCE mg(-1)biomass; T(y)(')=0.06-0.11 MUg TCE mg( 1)substrate; 1.7-4.6 MUg cDCE mg(-1)substrate), a condition that is more likely to be encountered in situ compared to cometabolic transformations by resting cells. This study is the first to report transformation rates, capacities, and yields for cometabolism of cDCE and TCE during aerobic growth on benzene, CB, 1,2 DCB and 1,3-DCB. This type of information is needed to predict the potential for natural attenuation when these compounds occur as co-contaminants. PMID- 21531439 TI - Phosphorus recovery from fosfomycin pharmaceutical wastewater by wet air oxidation and phosphate crystallization. AB - Fosfomycin pharmaceutical wastewater contains highly concentrated and refractory antibiotic organic phosphorus (OP) compounds. Wet air oxidation (WAO)-phosphate crystallization process was developed and applied to fosfomycin pharmaceutical wastewater pretreatment and phosphorus recovery. Firstly, WAO was used to transform concentrated and refractory OP substances into inorganic phosphate (IP). At 200 degrees C, 1.0MPa and pH 11.2, 99% total OP (TOP) was transformed into IP and 58% COD was reduced. Subsequently, the WAO effluent was subjected to phosphate crystallization process for phosphorus recovery. At Ca/P molar ratio 2.0:1.0 or Mg/N/P molar ratio 1.1:1.0:1.0, 99.9% phosphate removal and recovery were obtained and the recovered products were proven to be hydroxyapatite and struvite, respectively. After WAO-phosphate crystallization, the BOD/COD ratio of the wastewater increased from 0 to more than 0.5, which was suitable for biological treatment. The WAO-phosphate crystallization process was proven to be an effective method for phosphorus recovery and for fosfomycin pharmaceutical wastewater pretreatment. PMID- 21531440 TI - A comparative study on sorption of perfluorooctane sulfonate (PFOS) by chars, ash and carbon nanotubes. AB - Perfluorooctane sulfonate (PFOS), as one of emerging contaminants, has been attracting increasing concerns in recent years. Sorption of PFOS by maize straw- and willow-derived chars (M400 and W400), maize straw-origin ash (MA) as well as three carbon nanotubes (CNTs) was studied in this work. The sorption kinetics of PFOS by the six adsorbents was well fitted by the pseudo-second-order model. CNTs reached equilibrium in 2h, much faster than those by chars (384 h) and ash (48 h). According to the sorption isotherms, both single-walled carbon nanotubes (SWCNT) and MA had high sorption capacities (over 700 mg g(-1)), while the two chars had low sorption capacities (below 170 mg g(-1)) caused by their small BET surface area. In the case of MA, due to its positively charged surface, both hydrophobic interaction and electrostatic attraction involved in the sorption, and the formation of hemi-micelles further favored the sorption. This study suggested that SWCNT and MA were effective adsorbents for PFOS removal from water. Compared to SWCNT, MA is low cost and easy to obtain, so it could be a preferred adsorbent for PFOS removal. PMID- 21531441 TI - Concentrations of PFOS, PFOA and other perfluorinated alkyl acids in Australian drinking water. AB - Perfluorinated alkyl acids (PFAAs) are persistent environmental pollutants, found in the serum of human populations internationally. Due to concerns regarding their bioaccumulation, and possible health effects, an understanding of routes of human exposure is necessary. PFAAs are recalcitrant in many water treatment processes, making drinking water a potential source of human exposure. This study was conducted with the aim of assessing the exposure to PFAAs via potable water in Australia. Sixty-two samples of potable water, collected from 34 locations across Australia, including capital cities and regional centers. The samples were extracted by solid phase extraction and analyzed via liquid chromatography/tandem mass spectrometry for a range of perfluoroalkyl carboxylates and sulfonates. PFOS and PFOA were the most commonly detected PFAAs, quantifiable in 49% and 44% of all samples respectively. The maximum concentration in any sample was seen for PFOS with a concentration of 16 ng L(-1), second highest maximums were for PFHxS and PFOA at 13 and 9.7 ng L(-1). The contribution of drinking water to daily PFOS and PFOA intakes in Australia was estimated. Assuming a daily intake of 1.4 and 0.8 ng kg(-1) bw for PFOS and PFOA the average contribution from drinking water was 2-3% with a maximum of 22% and 24% respectively. PMID- 21531442 TI - Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms. AB - Gastric neuroendocrine neoplasms differ considerably in histology, clinicopathologic background, stage, and patient outcome, implying a wide spectrum of therapeutic options, hence the need for improved diagnostic and prognostic criteria to select appropriate therapy. Here, we tested the European NeuroEndocrine Tumor Society and the novel World Health Organization 2010 grade and stage classifications together with additional clinicopathologic and histologic parameters in a series of 209 gastric neuroendocrine neoplasms with a median follow-up of 89 months. Fifty-one grade 3 neuroendocrine carcinomas and 15 mixed endocrine-exocrine carcinomas of poor outcome were separated from 143 neuroendocrine tumors, including 132 G1 or G2 enterochromaffin-like (ECL) cell neoplasms and 11 G1 gastrin-cell, somatostatin-cell, or serotonin-cell tumors. Most G1 cases had excellent prognosis, even when metastatic, whereas G2 and G3 neoplasms had worse or very severe prognosis, respectively. The European NeuroEndocrine Tumor Society-World Health Organization 2010 proliferative grading system well correlated with patient survival. Structural histologic parameters were equally predictive and when combined with the European NeuroEndocrine Tumor Society-World Health Organization 2010 grading system in a "global grade" improved tumor prognostic stratification. The European NeuroEndocrine Tumor Society-World Health Organization 2010 staging system proved effective. Introduction of novel T (T(1a) and T(1b) or deep submucosal) and N categories (N(1), <3 nodes metastases; N(2), >=3) allowed a simplified, equally informative 3-stage TNM system. Such improved diagnostic and prognostic criteria for gastric neuroendocrine neoplasms are proposed and discussed. PMID- 21531443 TI - Early Pleistocene human mandible from Sima del Elefante (TE) cave site in Sierra de Atapuerca (Spain): a comparative morphological study. AB - We present a detailed morphological comparative study of the hominin mandible ATE9-1 recovered in 2007 from the Sima del Elefante cave site in Sierra de Atapuerca, Burgos, northern Spain. Paleomagnetic analyses, biostratigraphical studies, and quantitative data obtained through nuclide cosmogenic methods, place this specimen in the Early Pleistocene (1.2-1.3 Ma). This finding, together with archaeological evidence from different European sites, suggests that Western Europe was colonised shortly after the first hominin expansion out of Africa around the Olduvai subchron. Our analysis of the ATE9-1 mandible includes a geometric morphometric analysis of the lower second premolar (LP(4)), a combined and detailed external and internal assessment of ATE9-1 roots through CT and microCT techniques, as well as a comparative study of mandibular and other dental features. This analysis reveals some primitive Homo traits on the external aspect of the symphysis and the dentition shared with early African Homo and the Dmanisi hominins. In contrast, other mandibular traits on the internal aspect of the symphysis are derived with regard to African early Homo, indicating unexpectedly large departures from patterns observed in Africa. Reaching the most occidental part of the Eurasian continent implies that the first African emigrants had to cross narrow corridors and to overcome geographic barriers favouring genetic drift, long isolation periods, and adaptation to new climatic and seasonal conditions. Given these conditions and that we are dealing with a long time period, it is possible that one or more speciation events could have occurred in this extreme part of Eurasia during the Early Pleistocene, originating in the lineages represented by the Sima del Elefante-TE9 hominins and possibly by the Gran Dolina-TD6 hominins. In the absence of any additional evidence, we prefer not include the specimen ATE9-1 in any named taxon and refer to it as Homo sp. PMID- 21531444 TI - Changes in land cover and vegetation carbon stocks in Andalusia, Southern Spain (1956-2007). AB - Land use has significantly changed during the recent decades at global and local scale, while the importance of ecosystems as sources/sinks of C has been highlighted, emphasizing the global impact of land use changes. Land use changes can increase C loss rates which are extremely difficult to reverse, in the short term, opposite to organic carbon (OC) which accumulates in soil in the long-term. The aim of this research is to improve and test methodologies to assess land cover change (LCC) dynamics and temporal and spatial variability in C stored in vegetation at a wide scale. LCCs between 1956 and 2007 in Andalusia (Southern Spain) were selected for this pilot study, assessed by comparison of spatial data from 1956 to 2007 and were reclassified following land cover flows (LCFs) reported in major areas in Europe. Carbon vegetation densities were related to land cover, and C vegetation stocks for 1956 and 2007 were calculated by multiplying C density for each land cover class with land cover areas. The study area has supported important changes during the studied period with significant consequences for vegetation C stocks, mainly due to afforestation and intensification of agriculture, resulting in a total vegetation C stock of 156.08Tg in 2007, with an increase of 17.24Tg since 1956. This study demonstrates the importance of LCC for C sequestration in vegetation from Mediterranean areas, highlighting possible directions for management policies in order to mitigate climate change as well as promoting land conservation. The methodologies and information generated in this project will be a useful basis for designing land management strategies helpful for decision makers. PMID- 21531445 TI - Ecotoxicity of chlorophenolic compounds depending on soil characteristics. AB - Three chlorophenolic compounds (2-chlorophenol, 2,4,6-trichlorophenol, and pentachlorophenol) were tested to assess their effects on two soils with different properties: a granitic soil (Haplic Arenosol) and a calcareous one (Calcaric Regosol). Different concentrations of the pollutants (ranging from 0.001 to 10,000 mg kg(-1) soil, d.w.) were assayed for their effects on soil microbial activity and composition, using manometric respirometry and PCR-DGGE analysis, respectively. Other ecotoxicity tests such as Lactuca sativa seedling growth in the contaminated soils and algal growth inhibition (Pseudokirschneriella subcapitata) in their water extracts were done. The behaviour of the pollutants in the soils with respect to biodegradability and volatilization was also investigated. In the Haplic Arenosol, volatilization is the main process affecting 2-chlorophenol. Degradation and fixation of this compound in the soil matrix are favored in the Calcaric Regosol. This is the least toxic pollutant assayed. For 2,4,6-trichlorophenol, the soil pH is a critical parameter in the toxicity assays due to the neutral pKa of the compound. It is toxic in the soil microbial activity assay, but some recovery of the biotic processes can be observed, particularly in the Calcaric Regosol. This compound is more toxic in the Haplic Arenosol than in the Calcaric Regosol. Pentachlorophenol is ionized in both soils due to its low pKa, increasing its water solubility. It is highly toxic to the soil microbiota, thus inhibiting respiration, biodegradation and other biotic dissipation processes. Plant and alga tests, were more sensitive than soil microbial tests, except for PCP. The microbial populations tend to show changes at lower concentrations than the microbial activity. Some soil types (abundant in the Mediterranean area), with alkaline pH and fine textures could show higher level of ecotoxicity for ionizable organic pollutants than the soil type recommended by the OECD in ecotoxicity testing. PMID- 21531446 TI - Thrombogenic potential of whole blood is higher in patients with acute coronary syndrome than in patients with stable coronary diseases. AB - INTRODUCTION: Although thrombogenic potential of blood may play an important role for the onset of acute coronary syndrome (ACS), there is no established way to evaluate it by single parameter. We compared the thrombogenic potential of whole blood between patients with ACS and those with stable coronary diseases using single comprehensive parameter. MATERIALS AND METHODS: Consecutive patients with ACS (n=146) and those with stable coronary heart diseases (control, n=92) were prospectively examined. Thrombogenic potential of whole blood was evaluated by blood vulnerability index measured by Micro-Channel Array Flow Analyzer (MC-FAN). RESULTS: Blood vulnerability index was higher in ACS than in control patients (5099+/-2278 vs. 2071+/-389, p<0.0001), higher in acute MI than in unstable angina patients (5693+/-2146 vs. 3524+/-1841, p<0.0001), and higher in ACS patients with initial TIMI 0/1 flow grade than in those with TIMI 2/3 flow grade (6061+/-1936 vs. 2560+/-1301, p<0.0001). Furthermore, blood vulnerability index decreased from acute to chronic stage in acute MI patients. Multivariate logistic regression analysis revealed that high blood vulnerability index, high LDL cholesterol, high CRP, no use of aspirin, and no use of beta-blocker were the independent contributors for the onset of ACS. CONCLUSION: High thrombogenic potential of whole blood evaluated by blood vulnerability index was significantly associated with ACS and was reduced from acute to chronic stage in acute MI. CONDENSED ABSTRACT: Thrombogenic potential of whole blood was evaluated by blood vulnerability index measured comprehensively by Micro-Channel Array Flow Analyzer (MC-FAN) in consecutive patients with ACS (n=146) or stable coronary diseases (control, n=92) prospectively. Blood vulnerability index was significantly higher in ACS patients, especially in acute MI and poor initial TIMI flow grade patients, compared with control patients; and blood vulnerability index was reduced from acute to chronic stage in acute MI patients. PMID- 21531447 TI - Problems with measuring compression device performance in preventing deep vein thrombosis. AB - The purpose of this article is to discuss issues related to the use and performance of mechanical compression devices in preventing deep vein thrombosis (DVT), such as graduated compression stockings (GCSs) and pneumatic compression devices (PCDs). While various studies have shown mechanical compression to be effective against DVT, the adequacy of the performance of these devices has not been conclusively determined. One reason for this inconclusiveness is small sample bias in which the results of many studies are open to a considerable chance of error. Another problem is that the studies may not be appropriate designed to measure device effectiveness and be free of bias. In addition, new methods of DVT prophylaxis are forcing a reexamination of what it means for a device to be "effective." Finally, the prevention of DVT is not likely to occur if the patient declines to comply with a prescribed treatment. Compliance is particularly bad with GCSs and some compliance comparisons on PCDs have suffered from failing to control for potentially confounding factors. As such, more and better studies need to be performed on these devices. PMID- 21531448 TI - The impact of pretreatment thrombocytosis and persistent thrombocytosis after adjuvant chemotherapy in patients with advanced epithelial ovarian cancer. AB - OBJECTIVE: To evaluate the impact of both pretreatment thrombocytosis, and platelet count reduction post-adjuvant chemotherapy, on survival in patients with advanced epithelial ovarian cancer. METHODS: Records of 179 women who underwent cytoreductive surgery for FIGO stage III or IV epithelial ovarian cancer and received six cycles of platinum/paclitaxel-based chemotherapy between July 1998 and March 2009 were retrospectively reviewed. Platelet ratio was defined as the preoperative platelet count divided by the platelet count after chemotherapy. The prognostic significance of thrombocytosis and platelet ratio, together with various clinicopathological factors, were evaluated by multivariate analysis. RESULTS: Sixty-two of 179 (34.6%) patients had thrombocytosis at primary diagnosis. Patients with preoperative thrombocytosis had greater elevations of CA 125 (p<0.0001) and a greater volume of ascites (p=0.007). On multivariate analysis, thrombocytosis and CA-125 elevation retained significance as indicators of poor prognosis in patients with stage III or IV disease. In patients with normal CA-125 after chemotherapy, a high platelet ratio was an independent risk factor for reduced survival (p=0.05). CONCLUSIONS: Preoperative thrombocytosis and a high platelet ratio appear to be poor prognostic factors of survival in patients with advanced epithelial ovarian cancer who were treated with cytoreductive surgery and adjuvant platinum/paclitaxel-based chemotherapy. PMID- 21531449 TI - Surveillance of survivors: follow-up after risk-reducing salpingo-oophorectomy in BRCA 1/2 mutation carriers. AB - OBJECTIVES: To characterize the post-operative care of BRCA1 and BRCA2 mutation carriers who undergo risk-reducing salpingo-oophorectomy (RRSO). METHODS: BRCA1 and BRCA2 mutation carriers from our Cancer Risk Program who elected RRSO were sent questionnaires regarding their post-surgical surveillance and treatment for menopause symptoms, primary peritoneal cancer and bone loss. RESULTS: In 51 mutation carriers who were surveyed a median of 6 years after RRSO, 24 (47%) received dual-energy X-ray absorptiometry (DXA) testing, yearly CA-125 serum testing and yearly pelvic examination. Three women received none of these examinations in follow-up. Respondents reported an average of 3.5 menopausal symptoms (range 0-9). The mean number of menopausal symptoms reported by respondents using HRT was 2.8, compared to 3.9 symptoms reported by women not using HRT (p=0.06). Six of 10 (60%) subjects who reported no history of DXA bone scan, and 10 of 15 (67%) subjects who reported no post-surgical CA-125 serum monitoring noted that their physicians "did not recommend" testing. Two out of six symptomatic women who were younger than 50 (33%) who had no other contraindication to the use of HRT reported their non-use was because their care providers "advised against" HRT use. CONCLUSION: We believe that the lack of post RRSO health care guidelines has resulted in inconsistent care for this cohort of patients. We proposed that national guidelines be developed to standardize care with the goal of optimizing long term survival in this unique cohort of young cancer previvors. PMID- 21531450 TI - The opioid growth factor (OGF) and low dose naltrexone (LDN) suppress human ovarian cancer progression in mice. AB - OBJECTIVE: The opioid growth factor (OGF) and its receptor, OGFr, serve as a tonically active inhibitory axis regulating cell proliferation in normal cells and a variety of cancers, including human ovarian cancer. Blockade of OGF and OGFr with the nonselective opioid receptor antagonist naltrexone (NTX) upregulates expression of OGF and OGFr. Administration of a low dosage of NTX (LDN) blocks endogenous opioids from opioid receptors for a short period of time (4-6 h) each day, providing a window of 18-20 h for the upregulated opioids and receptors to interact. The present study investigated the repercussions of upregulating the OGF-OGFr axis by treatment with OGF or LDN on human ovarian tumorigenesis in vivo. METHODS: Female nude mice were transplanted intraperitoneally with SKOV-3 human ovarian cancer cells and treated on a daily basis with OGF (10 mg/kg), LDN (0.1 mg/kg), or an equivalent volume of vehicle (saline). Tumor burden, as well as DNA synthesis, apoptosis, and angiogenesis was assessed in tumor tissue following 40 days of treatment. RESULTS: OGF and LDN markedly reduced ovarian tumor burden (tumor nodule number and weight). The mechanism of action was targeted to an inhibition of tumor cell proliferation and angiogenesis; no changes in cell survival were noted. CONCLUSIONS: This study shows that a native opioid pathway can suppress human ovarian cancer in a xenograft model, and provides novel non-toxic therapies for the treatment of this lethal neoplasia. PMID- 21531451 TI - Achieving and maintaining asthma control in inner-city children. AB - BACKGROUND: Despite guidelines-defined care, inner-city children of low socioeconomic status have poor asthma control. OBJECTIVE: This study evaluated time to achieve control, maintenance of control, and factors associated with well controlled asthma for pediatric patients receiving specialty-based asthma care in mobile asthma clinics designed to reduce barriers to delivering effective asthma care (the Breathmobile Program). METHODS: Existing clinical data collected from January 1998 to June 2008 for 7822 pediatric patients with asthma (34,339 visits) enrolled in similarly structured mobile asthma programs across the United States evaluated the effect of asthma control on the reduction of asthma-related morbidity, time to achieve asthma control, maintenance of asthma control, and factors associated with well controlled asthma. RESULTS: Comparison of pre and post year data for subjects enrolled in the program for at least 1 year revealed reductions in the percentage of patients reporting emergency department visits (mean, 66%), hospitalizations (mean, 84%), and missed school days >=5/year (mean, 78%). Well controlled asthma was achieved by visit 3 for an estimated 80% of patients. Factors contributing to well controlled asthma include non-African American race, visit interval <90 days, and adherence to prescribed therapy. CONCLUSION: This study demonstrates the ability to achieve and maintain asthma control in high-risk populations in association with intensive, accessible, guidelines-defined care with close follow-up. PMID- 21531452 TI - Opposing effects of nasal epithelial NAD(P)H dehydrogenase quinine 1 and heme oxygenase 1 expression on upper and lower airway symptoms in adolescents with asthma. PMID- 21531453 TI - Long-term microtensile bond strength of surface modified zirconia. AB - OBJECTIVE: To compare long-term microtensile bond strength of zirconia, surface modified via a novel treatment, to current surface conditioning methods for zirconia, when resin bonded to dental composite. METHODS: Two ProCAD (porcelain) and 10 sintered ZirCAD (ZrO(2)) blocks (18 mm * 14 mm * 12 mm) were obtained from manufacturers. Twelve Herculite XRV composite blocks were fabricated (18 mm * 14 mm * 12 mm). Bonding surface of blocks was polished through 1200-grit SiC and air abraded (50 MUm alumina, 0.28MPa, 20s). Blocks were then separated into six groups: (1) porcelain (control), HF-etched/silane-treated, (2) ZrO(2), tribochemical-coated/silane-treated, (3) ZrO(2), primer-treated, (4) ZrO(2), modified via novel 3.2 nm silica layer/silane-treated, (5) ZrO(2), modified via novel 5.8nm silica layer/silane-treated, and (6) ZrO(2), modified via novel 30.4 nm silica layer/silane-treated. Blocks were bonded to composite using Clearfil Esthetic cement. Blocks were stored in distilled water (37 degrees C, 24h), then cut into microtensile bars (n=8/gp), then bond strengths were measured using a universal testing machine at 0, 1, 3, and 6 months. All groups were statistically analyzed (ANOVA, Tukey's, p<0.05). RESULTS: At 6 months (aging), all silica seed layer specimens displayed microtensile bond strength similar to CoJet specimens but less than that of silane-modified dental porcelain. CONCLUSION: The deposition of a silica layer on zirconia resulted in similar or superior long term resin bond strength when compared to traditional silanation and bonding techniques for zirconia but lower than that for silane-treated dental porcelain. PMID- 21531454 TI - Comparison of methods used for computing the impact of sound on the marine environment. AB - Concern about the impact of sound on marine mammals has increased over the last decade, causing governments to take a more rigorous look at the potential impact of activities that introduce sound into the ocean. Environmental Impact Statements (EIS's) can be prepared using differing analysis methods to estimate the impact on marine mammals. To assess consistency in assessment methods, differences in the base assumptions were investigated; in particular, differences that arise between assumptions of dynamic marine mammals (animat method) and static distributions of marine mammals (static distribution method). Using several ocean environment scenarios and species, it is demonstrated that differences consistently arise between the two methods. The static distribution method underestimates the number of behavioral harassments compared with the animat method. Repeating many simulations with the animat method provides a robust risk assessment, provides a measure of variability, and allows the probability of "spurious events" to be estimated. PMID- 21531455 TI - Chlorotoxin-modified macromolecular contrast agent for MRI tumor diagnosis. AB - Clinical diagnosis of cancers using magnetic resonance imaging (MRI) is highly dependent on contrast agents, especially for brain tumors which contain blood brain barrier (BBB) at the early stage. However, currently mostly used low molecular weight contrast agents such as Gd-DTPA suffer from rapid renal clearance, non-specificity, and low contrast efficiency. The aim of this paper is to investigate the potential of a macromolecular MRI contrast agent based on dendrigraft poly-l-lysines (DGLs), using chlorotoxin (CTX) as a tumor-specific ligand. The contrast agent using CTX-modified conjugate as the main scaffold and Gd-DTPA as the payload was successfully synthesized. The results of fluorescent microscopy showed that the modification of CTX could markedly enhance the cellular uptake in C6 glioma and liver tumor cell lines, but not in normal cell line. Significantly increased accumulation of CTX-modified conjugate within glioma and liver tumor was further demonstrated in tumor-bearing nude mice using in vivo imaging system. The MRI results showed that the signal enhancement of mice treated with CTX-modified contrast reached peak level at 5 min for both glioma and liver tumor, 144.97% +/- 19.54% and 158.69% +/- 12.41%, respectively, significantly higher than that of unmodified counterpart and commercial control. And most importantly, the signal enhancement of CTX-modified contrast agent maintained much longer compared to that of controls, which might be useful for more exact diagnosis for tumors. CTX-modified dendrimer-based conjugate might be applied as an efficient MRI contrast agent for targeted and accurate tumor diagnosis. This finding is especially important for tumors such as brain glioma which is known hard to be diagnosed due to the presence of BBB. PMID- 21531456 TI - Active targeting of RGD-conjugated bioreducible polymer for delivery of oncolytic adenovirus expressing shRNA against IL-8 mRNA. AB - Even though oncolytic adenovirus (Ad) has been highlighted in the field of cancer gene therapy, transductional targeting and immune privilege still remain difficult challenges. The recent reports have noted the increasing tendency of adenoviral surface shielding with polymer to overcome the limits of its practical application. We previously reported the potential of the biodegradable polymer, poly(CBA-DAH) (CD) as a promising candidate for efficient gene delivery. To endow the selective-targeting moiety of tumor vasculature to CD, cRGDfC well-known as a ligand for cell-surface integrins on tumor endothelium was conjugated to CD using hetero-bifunctional cross-linker SM (PEG)(n). The cytopathic effects of oncolytic Ad coated with the polymers were much more enhanced dose-dependently when compared with that of naked Ad in cancer cells selectively. Above all, the most potent oncolytic effect was assessed with the treatment of Ad/CD-PEG(500)-RGD in all cancer cells. The enhanced cytopathic effect of Ad/RGD-conjugated polymer was specifically inhibited by blocking antibodies to integrins, but not by blocking antibody to CAR. HT1080 cells treated with Ad/CD-PEG(500)-RGD showed strong induction of apoptosis and suppression of IL-8 and VEGF expression as well. These results suggest that RGD-conjugated bioreducible polymer might be used to deliver oncolytic Ad safely and efficiently for tumor therapy. PMID- 21531457 TI - The in vivo performance of an enzyme-assisted self-assembled peptide/protein hydrogel. AB - We demonstrate the distribution of the important extracellular matrix protein laminin in a novel biomaterial consisting of a hydrogel underpinned by nanofibrillar networks. These are formed by the immobilised enzyme mediated self assembly of fmoc-L(3) (9-fluorenylmethoxycarbonyl-tri-leucine). The peptide assembly yields nanofibrils formed of beta-sheets that are locked together via pi stacking interactions. This ordering allows the localisation of the peptide sidechains on the surface, creating a hydrophobic environment. This induces the formation of bundles of these nanofibrils producing a clear hydrogel. This mechanism enables the three dimensional distribution of laminin throughout the network via supramolecular interactions. These forces favour the formation and improve the order of the network itself, as observed by spectroscopic and mechanical testing. In order to test the stability and suitability of this class of material for in vivo applications, we utilise microinjection to deliver the biomaterial under fine spatial control into a dystrophic zebrafish model organism, which lacks laminin as a result of a genetic mutation. Using confocal and transmission electron microscopy, we confirm that the biomaterial remains stable structurally, and is confined spatially to the site of injection. PMID- 21531458 TI - Uterine artery blood flow volume in pregnant women with an abnormal pulsatility index of the uterine arteries delivering normal or intrauterine growth restricted newborns. AB - The aim of this study was to assess and compare uterine artery (UtA) blood flow volume in pregnant patients with an abnormal uterine Doppler pulsatility index (PI) who delivered fetuses with an appropriate weight for gestational age (AGA) or with intrauterine growth restricted (IUGR). We prospectively recruited singleton pregnancies with abnormal uterine arteries P.I. between 18 and 38 weeks of gestation regardless of estimated fetal weight (EFW). Vessel diameter and blood flow velocity were measured along the UtA upstream to the vessel bifurcation in both the right and left UtAs. Uterine blood flow volumes measured in these pregnancies were compared to historical Control-pregnancies. Forty-three patients delivered at term a normal weight newborn (AGA-pregnancies). Thirty patients delivered growth restricted newborns at 32 weeks (i.r. 29-36w) with a median weight of 1160 gr (i.r. 1000-2065 gr) (IUGR-pregnancies). At mid-gestation (18 + 0 - 25 + 6 weeks + days of gestation) a significantly lower uterine blood flow volume per unit weight was observed between the two study groups and compared to controls: 142 ml/min/kg in IUGR-pregnancies, 217 ml/min/kg in AGA pregnancies and 538 ml/min/kg in Control-pregnancies. These striking differences in blood flow volume were already present at mid-gestation, at a time when EFW was still normal. In late gestation (27 + 0 - 37 + 6 weeks + days of gestation), pregnancies with an abnormal uterine P.I. showed persistently low UtA flow (<50% of controls) even when corrected for fetal weight: 81 ml/min/kg in IUGR pregnancies, 105 ml/min/kg in AGA-pregnancies, and 193 ml/min/kg in Control pregnancies; p < 0.0001. Our findings are consistent with other recent studies regarding the association between reduced uterine blood flow volume and fetal growth restriction. However, the study brings new insight into the finding of abnormal uterine P.I. in normally grown fetuses typically dismissed as "falsely abnormal" or "false positive" findings. Our study suggests that blood flow volume measurement may serve as a new tool to assess this group of patients and possibly those with ischemic placental diseases that may provide some basis for therapeutic interventions. PMID- 21531459 TI - Funisitis and risk for the development of neonatal respiratory distress syndrome. PMID- 21531461 TI - Development of an enzyme-linked immunosorbent assay for determination of pretilachlor in water and soil. AB - An indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) has been developed for detection of pretilachlor in water and soil. An immunogen was prepared from haptens of pretilachlor conjugated to bovine serum albumin(BSA). The specific polyclonal antibodies were obtained by immunizing New Zealand white rabbits. The influence of parameters including concentrations of methanol, ionic strength and pH values were optimized to improve the sensitivity of the assay. The optimized ELISA was shown to have a high sensitivity and specificity for pretilachlor. Under optimal conditions, the ELISA has demonstrated an 50% inhibitory concentration (IC(50)) value of 0.0359 mg/L with a limit of detection (LOD, IC(10)) of 6.9 ng/L. The cross-reactivities to some analogs of pretilachlor (acetochlor, butachlor, metazachlor and metalaxyl) were below 1.5%. The average recoveries of pretilachlor from distilled water, tap water, paddy water and soil were in the range of 77.0-115.2% between 0.005 and 5.0mg/L. The results of ELISA for spiked samples were confirmed by GC-ECD with a high correlation coefficient of 0.9950(n=11). Thus, the ELISA proven to be a sensitive, specific, inexpensive and quantitative tool for detection of pretilachlor from four kinds of spiked samples. PMID- 21531460 TI - Use of the receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a diagnostic tool in chronic lymphocytic leukemia (CLL). AB - Flow cytometry is commonly used to establish the diagnosis of chronic lymphocytic leukemia (CLL). A defined combination of antibodies discriminates between normal B cells and CLL cells (coexpression of CD5, CD19, and CD23). The receptor tyrosine-like orphan receptor one (ROR1) is an embryonic glycoprotein involved in several developmental processes. It was shown to be highly and specifically expressed on circulating B lymphoma cells, but not on normal B cells. Here, we examined the potential of ROR1 as a diagnostic marker in initial and follow-up diagnostics of patients with CLL. 105 untreated and 72 treated patients, as well as healthy volunteers were examined using flow cytometry assays. Furthermore, we examined 10 patients with various B cell non-Hodgkin lymphomas (B-NHL). ROR1 was detected using a directly labeled antibody. We detected uniformly high ROR1 expression levels in all CLL samples. In marked contrast, only low or absent ROR1 expression levels were found on B cells from healthy donors. ROR1 expression in CLL patients was not influenced by various treatments. Taken together, ROR1 may be used as a diagnostic marker for CLL. As it is the only antigen which can exclusively be detected on neoplastic B cells it may greatly increase both, specificity as well as sensitivity, in lymphoma diagnostics. PMID- 21531462 TI - Degradation of polychlorinated biphenyls in aqueous solutions after UV-peroxide treatment: focus on toxicity of effluent to primary producers. AB - The combination of UV irradiation and hydrogen peroxide (UV-H(2)O(2)) was shown to be effective in treating water spiked with 2,2',4,4',5,5'-hexachlorobipheny (PCB 153), reducing its concentration by as much as 98%. To test the toxicity of the effluent, bioassays involving three species of primary producers were performed. Results showed the effluent exerting an adverse effect on the algae Scenedesmus bijugatus and the duckweed Lemna paucicostata. On the other hand, exposure of the mungbean Vigna radiata to the effluent revealed mostly no statistically significant adverse effect or growth stimulation. This suggested that on an exposure period of 96 h, higher forms of chlorophyll-bearing species such as plants are relatively unaffected by trace concentrations of PCBs and degradation products, while less differentiated species like algae and duckweeds are vulnerable. PMID- 21531463 TI - DSM-5 proposed diagnostic criteria for sexual paraphilias: tensions between diagnostic validity and forensic utility. AB - In order to prevent sexual crimes, "sexual predator" laws now allow indefinite preventive civil commitment of criminals who have completed their prison sentences but are judged to have a paraphilic mental disorder that makes them likely to commit another crime. Such proceedings can bypass the usual protections of criminal law as long as the basis for incarceration is the attribution of a mental disorder. Thus, the difficult conceptual distinction between deviant sexual desires that are mental disorders versus those that are normal variations in sexual preference (even if they are eccentric, repugnant, or illegal if acted upon) has attained critical forensic significance. Yet, the concept of paraphilic disorders - called "perversions" in earlier times - is inherently fuzzy and controversial and thus open to conceptual abuse for social control purposes. Consequently, the criteria used in diagnosing paraphilic disorders deserve careful scrutiny. The DSM-5 sexual disorders work group is proposing substantial revisions to the paraphilia diagnostic criteria in the DSM-5 nosology. It is claimed that the new criteria provide a reconceptualization that clarifies the distinction between normal variation and paraphilic disorder in a way relevant to forensic settings. In this article, after considering the logic of the concept of a paraphilic disorder, I examine each of the proposed changes to the DSM-5 paraphilia criteria and assess their conceptual validity. I argue that the DSM-5 proposals, while containing a kernel of an advance in distinguishing paraphilias from paraphilic disorders, nonetheless would yield criteria for paraphilic disorders that are conceptually invalid in ways open to serious forensic abuse. PMID- 21531465 TI - Biometric analysis of pigment dispersion syndrome using anterior segment optical coherence tomography. AB - PURPOSE: To compare anterior chamber volume (ACV), iris volume, and iridolenticular contact (ILC) area before and after laser peripheral iridotomy (LPI) in eyes with pigment dispersion syndrome (PDS) using anterior segment optical coherence tomography (AS OCT) and image processing software. DESIGN: Cross-sectional study. PARTICIPANTS: Eighteen eyes of 18 patients with PDS; 30 eyes of 30 controls matched for age, gender, and refraction. METHODS: Anterior segment OCT imaging was performed in all eyes before LPI and 1, 4, and 12 weeks after LPI. At each visit, 12 cross-sectional images of the AS were taken: 4 in bright conditions with accommodation (accommodation), 4 in bright conditions without accommodation (physiological miosis), and 4 under dark conditions (physiologic mydriasis). Biometric parameters were estimated using AS OCT radial sections and customized image-processing software. MAIN OUTCOME MEASURES: Anterior chamber volume, iris volume-to-length ratio, ILC area, AS OCT anterior chamber depth, and A-scan ultrasonography axial length. RESULTS: Before LPI, PDS eyes had a significantly greater ACV and ILC area than control eyes (P<0.01) and a significantly smaller iris volume-to-length ratio than the controls (P<0.05). After LPI, ACV and ILC area decreased significantly in PDS eyes, but iris volume to-length ratio increased significantly (P<0.02) and was not significantly different from that of controls. These biometric changes were stable over time. Iris volume-to-length ratio decreased significantly from accommodation to mydriasis and from miosis to mydriasis, both in PDS and control eyes (P<0.01). In PDS eyes, ILC area decreased significantly from accommodation to mydriasis, both before and after LPI (P<0.01). On multivariate analysis, greater anterior chamber (AC) volume (P<0.02) and larger AC depth (P<0.05) before LPI were significant predictors of a larger ILC area. CONCLUSIONS: Pigment dispersion syndrome eyes do not have an iris that is abnormally large, relative to the AS size, but have a weakly resistant iris that is stretched and pushed against the lens when there is a pressure difference across the iris. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21531464 TI - The response to TLR ligation of human CD16+CD14- monocytes is weakly modulated as a consequence of persistent infection with the hepatitis C virus. AB - Little is known about the frequency and function of CD16(+)CD14(-) monocytes from chronic HCV patients. We observed that the absolute numbers and ratio of CD16(+)CD14(-) to CD14(+)CD16(-) monocytes were similar between chronic HCV patients and healthy individuals. Functionally, we found that CD16(+)CD14(-) monocytes are more responsive to TLR8-ligation and only weakly responsive to LPS stimulation in producing TNF as compared to CD14(+)CD16(-) monocytes. We found no overt impairment of the function of CD16(+)CD14(-) monocytes from patients, except for an augmented induction of MIP-1beta-producing CD16(+)CD14(-) monocytes upon TLR4-ligation. However, the increased frequency of MIP-1beta-producing CD16(+)CD14(-) monocytes was not associated with viral load, ALT or fibrosis level. Our findings indicate that, different from other infectious diseases, the frequency and function of CD16(+)CD14(-) monocytes are only minimally altered as a consequence of the persistent state of HCV infections, and our findings therefore do not suggest a role for CD16(+)CD14(-) monocytes in HCV pathogenesis. PMID- 21531466 TI - Variation in immunophenotype of lactating mice. AB - Immunological factors have been shown to play a crucial role in mammary remodelling in rodent models of lactation, particularly at the stage of mammary involution. However, the relationship between immunological factors and the ability of normal mammary gland to produce milk, as well as the genetic components contributing to lactation performance remain largely unknown. In this study, we assessed the lactation and immunological phenotypes of 11 inbred mouse strains, namely 129X1/SvJ (129), A/J, AKR, C3H/HeJ (C3H), CBA/CaH (CBA), C57BL/6J (C57), DBA/1J, DBA/2J, FVB/N (FVB), QSi5 and SJL/J (SJL) to identify potential links. Leukocyte analyses showed no direct link between the fraction of splenic leukocytes and lactation performance. However, significant strain differences were discovered in the fraction of CD8+ T lymphocytes (P=0.016) and CD11b+Gr-1 mid-low monocytes (P<0.001). Cytokine profiles in plasma were examined and a subset of plasma cytokines, namely CCL2, CCL3, CCL5, CSF2, CSF3, IL10, IL15, IL1B, IL4, IL5, IL7 and TNF, were fitted to a linear regression model for prediction of lactation performance (R-sq=62%, S=0.309). Significant strain differences in the plasma cytokine levels were also discovered amongst these inbred strains. Analysis of immunological phenotypes showed strong correlations between splenic immune cell subsets and their regulating cytokine levels in plasma. The results demonstrate the extent of genetic variability in the immunological phenotypes of lactating mice, and provide a basis for understanding the role of cytokines in milk production, and identifying potential biomarkers of lactation performance. PMID- 21531467 TI - Serotonin-related gene pathways associated with undifferentiated somatoform disorder. AB - It has been suggested that serotonergic hypofunction and serotonergic pathway genes underlie the somatic symptoms of somatoform disorders. We examined a variety of serotonin-related gene polymorphisms to determine whether undifferentiated somatoform disorder is associated with specific serotonin related gene pathways. Serotonin-related polymorphic markers were assessed using single nucleotide polymorphism (SNP) genotyping. One hundred and two patients with undifferentiated somatoform disorder and 133 healthy subjects were enrolled. The genotype and allele frequencies of tryptophan hydroxylase (TPH)1 A218C, TPH2 rs1386494, serotonin receptor 2A-T102C (5-HTR 2A-T102C), 5-HTR 2A-G1438A and serotonin transporter (5HTTLPR) gene were compared between the groups. The Hamilton Rating Scale for Depression and the somatization subscale of the Symptom Checklist-90-Revised (SCL-90-R) were used for psychological assessment. Patients with undifferentiated somatoform disorder had higher frequencies of the TPH1 C allele than healthy controls (p=0.02) but the difference was not significant after Bonferroni correction. The frequency of TPH1 genotype also did not differ significantly between the patients and the healthy controls, nor did TPH2 rs1386494, 5-HTR 2A-T102C, 5-HTR 2A-G1438A or 5HTTLPR allele and genotype frequencies differ significantly between the two groups. These findings suggest that a variety of serotonin-related gene pathways are unlikely to be definite genetic risk factors for undifferentiated somatoform disorder. Therefore, the pathogenesis of the disorder may be related to epigenetic factors, including psychosocial and cultural factors. Nonetheless, future studies need to include a larger sample of subjects and polymorphisms of more serotonin-related gene variants. PMID- 21531468 TI - The translational value of rodent gastrointestinal functions: a cautionary tale. AB - Understanding relationships between gene complements and physiology is important, especially where major species-dependent differences are apparent. Molecular and functional differences between rodents (rats, mice, guinea pigs) and humans are increasingly reported. Recently, the motilin gene, which encodes a gastrointestinal hormone widely detected in mammals, was found to be absent in rodents where the receptors are pseudogenes; however, actions of motilin in rodents are sometimes observed. Although ghrelin shares common ancestry with motilin, major species-dependent abberations are not reported. The apparently specific absence of functional motilin in rodents is associated with specialised digestive physiology, including loss of ability to vomit; motilin is functional in mammals capable of vomiting. The exception is rabbit, the only other mammal unable to vomit, in which motilin might be conserved to regulate caecotrophy, another specialised digestive process. Motilin illustrates a need for caution when translating animal functions to humans. Nevertheless, motilin receptor agonists are under development as gastroprokinetic drugs. PMID- 21531470 TI - Nesting of asymmetric functions in skilled bimanual action: dynamics of hammering behavior of bead craftsmen. AB - In human manual activities, the two hands are often engaged in differentiated roles while cooperating with each other to produce an integrated outcome. Using recurrence methods, we studied the asymmetric bimanual action involved in stone bead production by craftsmen of different skill levels, and examined (a) how the control of unilateral movement is embedded in that of a bimanual system, and (b) how the behavior of a bimanual system is embedded in the context of the function performed in the world. Evidence was found that the movements of the two hands of experts were functionally linked, reflecting the roles assumed by each hand. We further found that only the dynamics of bimanual coordination of experts differentiated the functional requirements of different sub-goals. These results suggest that expertise in this skilled bimanual action lies in the nesting of functionally specific adjustments at different levels of a control hierarchy. PMID- 21531469 TI - Gender differences in cardiac rehabilitation programs from the Italian survey on cardiac rehabilitation (ISYDE-2008). AB - PURPOSE: In recent years epidemiological and clinical evidence has shown gender disparities in several aspects of cardiovascular disease. Aim of this study was to identify gender differences in the clinical profile and management of patients admitted to cardiac rehabilitation (CR) programs. POPULATION: Patients enrolled in the ISYDE-2008 survey were considered. RESULTS: The ISYDE-2008 survey enrolled 2281 patients; 604 (26.5%) were women. Compared to men, women were older (mean age 70.8 +/- 11.5 versus men's 65.6 +/- 11.5 years), had less traditional risk factors (low cardiovascular risk profile in 45.3% of women and 38.0% of men, p=0.003), were more frequently admitted after valvular surgery and heart failure, but less for post-acute myocardial infarction and post-by-pass procedure. Women were more frequently admitted to an in-hospital rehabilitation program. Women showed a more complicated acute and rehabilitative course, with 63.2% of them having at least one complication during acute-phase, compared to 52.5% of men, and 48.3% during rehabilitation, compared to 35.0% of men (p<0.0001). During rehabilitation, women underwent exercise tests less frequently, except for the 6 minute walking test. At discharge, women received ACE-inhibitors/ARBs, beta blockers, statins, omega-3 fatty acids, antiplatelet agents less frequently, but more frequently digoxin, amiodarone, diuretics, oral anticoagulants, insulin and anti-depressive drugs. The duration of the rehabilitation program was longer for women. Mortality was very low in the entire population. CONCLUSIONS: Women are less frequently admitted to CR than men. They are older and show a greater cardiovascular burden. Women are more likely to be enrolled in CR after valvular surgery and heart failure than men. PMID- 21531471 TI - Sensory characteristics of spoilage and volatile compounds associated with bacteria isolated from cooked and peeled tropical shrimps using SPME-GC-MS analysis. AB - The spoilage potential of six bacterial species isolated from cooked and peeled tropical shrimps (Brochothrix thermosphacta, Serratia liquefaciens-like, Carnobacterium maltaromaticum, Carnobacterium divergens, Carnobacterium alterfunditum-like and Vagococcus penaei sp. nov.) was evaluated. The bacteria were inoculated into shrimps, packaged in a modified atmosphere and stored for 27 days at 8 degrees C. Twice a week, microbial growth, as well as chemical and sensory changes, were monitored during the storage period. The bacteria mainly involved in shrimp spoilage were B. thermosphacta, S. liquefaciens-like and C. maltaromaticum whose main characteristic odours were cheese-sour, cabbage-amine and cheese-sour-butter, respectively. The volatile fraction of the inoculated shrimp samples was analysed by solid-phase microextraction (SPME) and gas chromatography coupled to mass spectrometry (GC-MS). This method showed that the characteristic odours were most likely induced by the production of volatile compounds such as 3-methyl-1-butanal, 2,3-butanedione, 2-methyl-1-butanal, 2,3 heptanedione and trimethylamine. PMID- 21531472 TI - Constitutive modeling of the non-linear visco-elasticity of the periodontal ligament. AB - A non-linear visco-elastic constitutive model is adopted to describe the relaxation phenomena of the periodontal ligament (PDL). The introduction of a non linear formulation of visco-elasticity is necessary because experimental data from the literature referring to animal models show that the relaxation rate depends on the level of strain applied. In particular, the percentage of relaxation increases with decrease of the applied strain. The constitutive model is consistent with the non-linear elastic behavior of the PDL in the case of high rate loading and large strains attained by the tissue. A hyperelastic formulation is adopted for the elastic behavior of the PDL and this formulation is developed adopting suitable measures of stress and strain. The anisotropy of the tissue induced by specific spatial orientation of collagen fibers is included in the model. With respect to recent numerical formulation proposed to describe the non linear visco-elasticity of the PDL, the proposed model has the advantage of being more consistent with the micro-structural configuration of the tissue and the large strains it can undergo. The results obtained show that a reasonable description of the PDL relaxation phenomena can be obtained by assuming that relaxation times are independent of strain, whereas the relative stiffness results are dependent on strain applied through an exponential function. PMID- 21531473 TI - 2D and 3D finite element analysis of central incisor generated by computerized tomography. AB - The purpose of this study was to compare the results of different hierarchical models in engineering analysis applied to dentistry with 2D and 3D models of a tooth and its supporting structures under 100 N occlusal loading at 45 degrees and examine the reliability of simplified 2D models in dental research. Five models were built from computed-tomography scans: four 2D models with Plane Strain and Plane Stress State with linear triangular and quadratic quadrilateral elements and one 3D model. The finite element results indicated that the stress distribution was similar qualitatively in all models but the stress magnitude was quite different. It was concluded that 2D models are acceptable when investigating the biomechanical behavior of upper central incisor qualitatively. However, quantitative stress analysis is less reliable in 2D-finite element analysis, because 2D models overestimate the results and do not represent the complex anatomical configuration of dental structures. Therefore 3D finite element analyses of dental biomechanics cannot be simplified. PMID- 21531474 TI - TC-VGC: a tumor classification system using variations in genes' correlation. AB - Classification analysis of microarray data is widely used to reveal biological features and to diagnose various diseases, including cancers. Most existing approaches improve the performance of learning models by removing most irrelevant and redundant genes from the data. They select the marker genes which are expressed differently in normal and tumor tissues. These techniques ignore the importance of the complex functional-dependencies between genes. In this paper, we propose a new method for cancer classification which uses distinguished variations of gene-gene correlation in two sample groups. The cancer specific genetic network composed of these gene pairs contains many literature-curated prostate cancer genes, and we were successful in identifying new candidate prostate cancer genes inferred by them. Furthermore, this method achieved a high accuracy with a small number of genes in cancer classification. PMID- 21531475 TI - Classifier ensemble construction with rotation forest to improve medical diagnosis performance of machine learning algorithms. AB - Improving accuracies of machine learning algorithms is vital in designing high performance computer-aided diagnosis (CADx) systems. Researches have shown that a base classifier performance might be enhanced by ensemble classification strategies. In this study, we construct rotation forest (RF) ensemble classifiers of 30 machine learning algorithms to evaluate their classification performances using Parkinson's, diabetes and heart diseases from literature. While making experiments, first the feature dimension of three datasets is reduced using correlation based feature selection (CFS) algorithm. Second, classification performances of 30 machine learning algorithms are calculated for three datasets. Third, 30 classifier ensembles are constructed based on RF algorithm to assess performances of respective classifiers with the same disease data. All the experiments are carried out with leave-one-out validation strategy and the performances of the 60 algorithms are evaluated using three metrics; classification accuracy (ACC), kappa error (KE) and area under the receiver operating characteristic (ROC) curve (AUC). Base classifiers succeeded 72.15%, 77.52% and 84.43% average accuracies for diabetes, heart and Parkinson's datasets, respectively. As for RF classifier ensembles, they produced average accuracies of 74.47%, 80.49% and 87.13% for respective diseases. RF, a newly proposed classifier ensemble algorithm, might be used to improve accuracy of miscellaneous machine learning algorithms to design advanced CADx systems. PMID- 21531476 TI - CD8alpha+ dendritic cells improve collagen-induced arthritis in CC chemokine receptor (CCR)-2 deficient mice. AB - OBJECTIVE: Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3+ regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGFbeta-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC chemokine receptor-2 deficient (Ccr2-/-) mice had impaired DCs migration and reduced CD8alpha+ DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2-/- mice, we tested the hypothesis that CD8alpha+ DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8alpha+ DCs in Ccr2-/- and SKG mice. METHODS: To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8alpha+ DCs. RESULTS: Flt3L mediated expansion of endogenous CD8alpha+ DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8alpha+ DCs ameliorated arthritis in Ccr2-/- mice and enhanced TGFbeta1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype. CONCLUSION: CD8alpha+ DCs were tolerogenic to the development of arthritis. CD8alpha+ DCs deficiency heightened the sensitivity to arthritis in Ccr2-/- mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2-/- mice was T cell-independent. PMID- 21531477 TI - [Bilateral acute depigmentation of the iris syndrome]. AB - Bilateral acute depigmentation of the iris syndrome (BADI syndrome) is a new clinical entity. Young females from 20 to 45 years of age are most commonly affected. It is characterized by bilateral nontransilluminating depigmentation of the iris stroma. During the acute phase, this clinical entity also combines with red painful eye, pigmentation of the trabecular meshwork, anterior chamber flare, circulating pigment, and pigmented deposit on the endothelium cornea. At the acute stage, the symptoms are controlled with topical corticosteroid treatment. The prognosis is good. We report a 41-year-old woman presenting with BADI syndrome. PMID- 21531478 TI - [Corneal tumor secondary to trichiasis]. AB - A rare lesion of secondary amyloidosis of the cornea caused by trichiasis is reported. A 33-year-old Asian woman presented with progressive decrease of visual acuity of the right eye evolving over several years, combined with the growth of a lower budding, gelatinous, pink corneal mass located next to an inferior lid trichiasis. The treatment consisted of eyelid surgery for trichiasis, followed by ablation of the corneal lesion by anterior keratectomy. After 14 months of follow up, no recurrence was observed. Visual acuity is 9/10 P3 without correction. Pathological examination of the mass revealed secondary corneal amyloidosis, AL type (light chains), rarely reported in the literature (18 cases). No other organ involvement by amyloidosis was identified. Corneal amyloidosis is a rare complication of trichiasis. To avoid recurrence, this anomaly should be recognized as the cause and should be treated prior to removal of the corneal lesion. PMID- 21531479 TI - [Underlying conditions associated with the occurrence of retinal vein occlusion]. AB - BACKGROUND: Conventional risk factors for retinal vein occlusion (RVO) are well established through large epidemiological studies, but triggering factors remain poorly known. PATIENTS AND METHODS: A prospective observational study through a questionnaire was completed between January and October 2009 by patients with RVO and controls. RESULTS: Sixty-one patients, including 42 central retinal vein occlusions (CRVO) and 19 branch vein occlusions (BRVO) as well as 118 controls were included. Of the CRVO patients, 77% discovered visual loss upon awakening in contrast to only 33% of BRVO patients. The comparison between RVO and controls showed a higher proportion in the RVO group for (in order of the highest risk): migraine headache (CRVO, 21 %; BRVO, 47 %; controls, 13 %; p=0.008), hypertension (CRVO, 52%; BRVO, 63%; controls, 37%; p=0.012), glaucoma (CRVO, 33%; BRVO, 22%; controls, 16%; p=0.034), antiplatelet or anticoagulant medication (CRVO, 42%; BRVO, 33%; controls, 26%; p=0.074), hyperlipidemia, ocular trauma, sudden deafness, or vertigo. The prevalence was similar in both groups for body mass index, history of phlebitis or peptic ulcer, smoking habits, stress, fasting, dehydration, vasodilator intake, and altitude stay. CONCLUSION: In addition to the already known risk factors, this study underlines certain underlying conditions or circumstances related to the onset of RVO, such as migraine. In CRVO, three-quarters of the patients on average discovered visual loss upon awakening, which may indicate that nocturnal events may play a significant role in the pathogenesis of the occlusion. PMID- 21531481 TI - The effects of 90-day supplementation with the omega-3 essential fatty acid docosahexaenoic acid (DHA) on cognitive function and visual acuity in a healthy aging population. AB - The omega-3 fatty acid docosahexaenoic acid (DHA) is essential for nervous system and retinal development and there is evidence to suggest that DHA deficiencies increase with normal aging. A triple-blind placebo-controlled randomized repeated measures trial was conducted with 74 healthy participants, aged 45-77 years. Cognitive and visual acuity measures and plasma levels of DHA were determined at baseline and after 90 days of administration of either HiDHA((r)) (Clover Corp., Sydney, NSW, Australia: 1000 mg of tuna oil; comprising 252 mg DHA, 60 mg EPA and 10 mg vitamin E) or placebo (1000 mg soybean oil). Ninety days of DHA supplementation was found to significantly raise both plasma DHA and total omega 3 plasma levels in the treatment group, as well as significantly lower total omega-6 levels. However, no significant effects of DHA supplementation on cognitive functioning were found. For participants with corrected vision, the group receiving DHA were found to have significantly better right eye visual acuity posttreatment in comparison with the placebo group (F(1,22) = 7.651; p = 0.011; partial eta(2) = 0.258). PMID- 21531480 TI - Cardiorespiratory fitness is associated with atrophy in Alzheimer's and aging over 2 years. AB - We sought to describe change in cardiorespiratory (CR) fitness over 2 years in those with early-stage Alzheimer's disease (AD) and nondemented aging and assess the relationship of CR fitness with cognitive decline, brain atrophy, and dementia progression. Individuals with early-stage AD (n = 37) and without dementia (n = 53) attended clinical evaluations, cognitive and exercise tests, and magnetic resonance imaging (MRI) at baseline and 2 years later. CR fitness was lower in those with AD over the study period. Lower baseline CR fitness was associated with progression of dementia severity in AD. Declining CR fitness over 2 years was associated with brain atrophy in AD, especially in the parahippocampus. In nondemented participants, there was a trend for lower baseline fitness to be related to cognitive decline. Both lower baseline CR fitness and declining CR fitness over 2 years were associated with regional brain atrophy. We conclude that CR fitness is chronically reduced in those with AD. Further, in those with AD, CR fitness is associated with progression of dementia severity and brain atrophy in AD, suggesting a link between progression of dementia severity and cardiorespiratory health. PMID- 21531483 TI - [The access to health services and their use by immigrant patients: the voice of the professionals]. AB - OBJECTIVE: To find out, from the health professionals' point of view, how different immigrant groups access and use the health services. DESIGN: Qualitative, descriptive and phenomenological study carried out in Barcelona between September and December of 2007. SETTING: The study was carried out in the 6 Basic Health Areas of Barcelona, where there is a higher percentage of immigrant population, and in 3 public hospitals. PARTICIPANTS: A total of 73 hospital and primary health care professionals. Theoretical sampling was carried out on respondents who defined 4 professional profiles: directors or coordinators, physicians, nurses, and cultural mediators. METHODS: There were 7 debate groups and 12 partly-structured interviews. Both the interviews and groups were analysed by a narrative analysis of the content. RESULTS: The outcomes indicate that, according to the professionals, the immigrant patients do not find barriers that can make their access to health services more difficult. The perception that the emergency service is their main access gate for them is unanimous, as well as that most of the immigrant patients have less continuity of care. Finally, professionals detect differences in the access and use of health services depending on their origin and the level of social integration of the immigrant group. CONCLUSIONS: Professionals attribute a higher use of emergencies, late access to the health services, and less continuity of care, to a series of factors related to economic precariousness and to aspects related to the social inclusion. There is the room for social inclusion policies to reduce these inequalities. PMID- 21531482 TI - Maximal brain size remains an important predictor of cognition in old age, independent of current brain pathology. AB - There is growing interest in the influence of early-life development on clinical manifestations of late-life diseases. Latent variable modeling was used to investigate how maximal brain volume (measured by intracranial volume [ICV]) and current brain volumes uniquely contribute to domain-specific cognitive performance in a group of 401 cognitively and ethnically diverse older adults. Individual effects of volumetric magnetic resonance imaging (MRI) measures including ICV were examined as predictors of episodic memory, semantic memory, spatial ability, and executive function. Total brain matter volume related to all cognitive domains; hippocampal volume was associated primarily with episodic memory; white matter hyperintensity volume was related to executive function and episodic memory. Maximal brain size as measured by ICV was related to semantic memory, executive function, and spatial ability independent of current brain volumes (ps < 0.01). Relationships between magnetic resonance imaging (MRI) variables and cognition did not differ substantially across groups defined by ethnicity, gender, and with minor exceptions, clinical diagnosis. Results suggest maximal brain development and measures of brain injury/atrophy jointly contribute to cognitive function in older people. PMID- 21531484 TI - [Effective doses associated to the usual multimodal examinations in nuclear medicine]. AB - OBJECTIVE: To know the effective doses (E) that can be given in the common multimodal procedures in nuclear medicine, Single Photon Emission Tomography and Positron Emission Tomography, combined with Computed Tomography, SPECT/CT and PET/CT. Effective dose will be expressed according to Background Equivalent Radiation Time (BERT) and the contribution of the CT scan to the total dose will also be studied. MATERIAL AND METHODS: The effective dose of each procedure has been calculated as the sum of the external radiation dose (CT part) and internal one (radiopharmaceutical administration). Data from each side were collected through extensive literature search. RESULTS: A range of minimum and maximum effective dose [E(min), E(max)] associated with each procedure is shown. These doses range from 0.5 to 49.1 mSv. BERT ranges from 2.6 months to 20.4 years. The CT contribution to the total effective dose varies from 2.1% to 93%, according to the image acquisition protocol and its purpose. Performing a diagnostic CT scan increases the dose up to a factor of 4.3 times compared to the dose used for CT acquisition for attenuation correction and anatomic localization. CONCLUSIONS: This article focus on the effective dose level that can be given in multimodal procedures, bearing in mind that the data are subject to constant changes and should be updated periodically. It is important to know the dosimetric impact when the CT scan is added. The application of optimized protocols according to the indication of the study reduces the patient's exposure without the loss of significant information. PMID- 21531485 TI - Design, synthesis and molecular docking studies of novel triazole as antifungal agent. AB - In order to meet the urgent need for novel antifungal agents with improved activity and broader spectrum, a series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorophenyl)-3-[(4-substituted trifluoromethyl phenyl)-piperazin-1-yl]-propan 2-ols were designed, synthesized and evaluated as antifungal agents. The MIC(80) values indicate that the compounds 7a-7q, 8a-8d showed higher antifungal activities against Candida albicans than 5a-5i, 6a-6j. Moreover, the molecular model for the binding between compound 5a, 7a and the active site of CACYP51 was provided based on the computational docking results, and the structure-activity relationship was analyzed. PMID- 21531486 TI - Synthesis and biological evaluation of a novel human stem/progenitor cells proliferation activator: 4-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl) thiosemicarbazide (Stemazole). AB - Stem/progenitor cells are crucial for cell-based therapy and regenerative medicine, and their application in clinical and basic research requires a large supply of cells. To identify effective stem/progenitor cell proliferation activators, we synthesised a series of new 4-(4-(5-mercapto-1,3,4-oxadiazol-2 yl)phenyl) thiosemicarbazide (named Stemazole) derivatives. Preliminary evaluation of the structure-activity relationship (SAR) and the biological activities of the compounds were determined with a luminescent cell viability assay. The identified leading compound, Stemazole, exhibited remarkable proliferation-promoting activity in human hippocampal stem/progenitor cells (HSCs) in a time-dependent and concentration-dependent manner. The proliferation promoting activity of Stemazole was further confirmed against a panel of human stem/progenitor cells derived from each of the three blastoderm layers. In conclusion, Stemazole is a novel activator of stem cells proliferation. PMID- 21531487 TI - Interprofessional learning in acute care: developing a theoretical framework. AB - There are a number of adult learning theories that have been used to inform IPE delivery (e.g. Kolb's theory of experiential learning), and one of the most important to emerge in recent times has been the contact theory or contact hypothesis, which looks at the outcomes when two differing groups of health care professionals are brought together. The team responsible for the development of an acute care IPE programme called Student Management of Acute illness Recognition and Treatment (SMART(TM)) set out to incorporate the most up to date educational theory into the programme. Following an extensive review of the literature, it was decided to adopt a blended theoretical approach, involving a combination of 'contact theory' and 'scaffolding', supported by interprofessional facilitation. It was clear that there were a number of enabling factors that could be incorporated into any IPE programme. These were the educational setting, group characteristics (group size, balance and stability), quality of IPE facilitation and opportunities for informal learning. Although the contact theory provides us with a better understanding of interprofessional groups, an understanding of how the organised contact of different professional groups of students helps to reduce intergroup prejudice and improve intergroup relations is still required. PMID- 21531488 TI - Infant's bed climate and bedding in the Japanese home. AB - OBJECTIVE: to assess the bed climate of infants in their homes in Japan. DESIGN: descriptive, exploratory, non-experimental research design. SETTING: the data were collected at the participants' homes under normal circumstances. PARTICIPANTS: nineteen healthy infants between the ages of two and five months. Their mothers, who joined a parenting class organised by a maternity clinic in Okayama, Japan, consented to participate in this study. MEASUREMENTS AND FINDINGS: we visited the infants' homes and interviewed their mothers concerning the types and use of bedding. The temperature and relative humidity of the bed climate at the back and foot of the bedding, and in the room were measured every minute for four consecutive days. Differences among the bed climates measured during three seasons (spring, summer, and autumn) were assessed by one-way analysis of variance. The bed temperature was higher for infants than for adults. No significant difference in temperature was noted among the three seasons. The bed temperature was about 36.0 degrees C when waterproof sheets and futon mattresses for children or adult were used. The average relative humidity of the bed climate at the back was highest in summer, followed by that in spring and autumn; the differences were significant. The use of waterproof sheets and futon mattresses for children in summer increased the relative humidity to 80% or more. The use of infant beds, sunoko drainboards, and cotton futon mattresses in summer was effective in reducing the bed humidity. CONCLUSIONS: these results suggest that nurse-midwives should advise the parents on comfortable bed climates for their infants, as well as how to select and use bedding for them. PMID- 21531489 TI - Biomarker responsiveness in different tissues of caged Ruditapes philippinarum and its use within an integrated sediment quality assessment. AB - Biomarkers comprising activities of biotransformation enzymes (ethoxyresorufin-O deethylase -EROD-, dibenzylfluorescein dealkylase -DBF-, glutathione S transferase -GST), antioxidant enzymes (glutathione reductase -GR- and glutathione peroxidase -GPX), lipid peroxidation -LPO- and DNA strand breaks were analyzed in the clam Ruditapes philippinarum caged at Cadiz Bay, Santander Bay and Las Palmas de Gran Canaria (LPGC) Port (Spain). Sediments were characterized. Digestive gland was the most sensitive tissue to sediment contamination. In Cadiz Bay, changes in LPO regarding day 0 were related with metals. In LPGC Port, DBF, EROD, and GST activity responses suggested the presence of undetermined contaminants which might have led to DNA damage. In Santander Bay, PAHs were related with EROD activity, organic and metal contamination was found to be associated with GR and GST activities and DNA damage presented significant (p < 0.05) induction. R. philippinarum was sensitive to sediment contamination at biochemical level. Biomarkers allowed chemical exposure and sediment quality assessment. PMID- 21531490 TI - Contrasting effects of black carbon amendments on PAH bioaccumulation by Chironomus plumosus larvae in two distinct sediments: role of water absorption and particle ingestion. AB - Two sediment matrices with different characteristics were amended with chars from different sources for bioaccumulation assay with filter-feeding Chironomus plumosus larvae. Chars greatly decreased porewater concentrations of PAHs (C(iw)) measured using polyethylene devices in sediments. In organic rich sediment matrix based systems where suspended char particles were absent, PAH concentrations in larvae (C(iB)) were significantly correlated with C(iw), and there was no difference in water-based bioaccumulation factors (BAFs) between different treatments, suggesting that water absorption was the main contaminant uptake route for larvae. In organic poor sediment matrix-based systems where suspended char particles were present, poor Pearson correlation between C(iB) and C(iw) was found, but there was a significant linear increase of BAF values with char contents, which indicated that ingestion of suspended char particles could also be important for PAH bioaccumulation. Therefore, we need to rethink of the effectiveness and risks for the application of black carbon to sediment/soil remediation. PMID- 21531491 TI - Understanding the effect of disease adaptation information on general population values for hypothetical health states. AB - It has been recommended that economic evaluation of healthcare technologies should use values for hypothetical health states elicited from the general population rather than patients. The drawback is the general population may not consider the possibility of adapting to the impaired state. This study explored the extent to which the general population changes their initial values, and the factors that influenced this change, after being informed with different disease adaptation techniques. Three rheumatoid arthritis states were used for illustration. General population respondents from the United Kingdom initially valued the states. An adaptation exercise followed, where they listened to recordings of patients discussing how they adapted; they then valued the same states again. The differences between the valuations were examined using t-tests. A multivariate regression model was developed to assess the factors that impacted individuals to change their initial values. After undergoing the adaptation exercise, the respondents increased their values for the rheumatoid arthritis states. Younger and healthier individuals were more likely to increase their initial values after being informed. PMID- 21531492 TI - Incorporating concerns for equal lifetime health in evaluations of public health programs. AB - Economic evaluations are increasingly common as evidence in priority setting decisions, but lack of quantification of equity impact represents a situation of asymmetric information that easily lead to discrepancies between stated preferences for distribution of health care and the preferences revealed in actual priority setting. We suggest Gini impact and Achievement Index methodology as tools that can be used to incorporate concerns for equal lifetime health in numerical evaluation of public health programs. In a case study from Tanzania we explore how these techniques may diminish this information asymmetry. By comparing a childhood vaccine with treatment of hypertension in adults, we show that concerns for equity in the distribution of healthy years can be captured with standard measures of inequality and combined with a maximization concern. This illustrative case from a low-income setting, where resources are insufficient to meet the needs of both patient groups, illustrates how quantification of equity impact may change priorities. PMID- 21531494 TI - More evidence is required before we alter guidance on prognostication following cardiac arrest. PMID- 21531493 TI - The intersection of school racial composition and student race/ethnicity on adolescent depressive and somatic symptoms. AB - Schools are one of the strongest socializing forces in the U.S. and wield considerable influence over individuals' social and economic trajectories. Our study investigates how school-level racial composition, measured by the percentage non-Hispanic white students in a school, affects depressive and somatic symptoms among a representative sample of U.S. adolescents, and whether the association differs by race/ethnicity. We analyzed Wave I data from the US National Longitudinal Study of Adolescent Health, resulting in a sample size of 18,419 students attending 132 junior and senior high schools in 1994/5. After controlling for individual and school characteristics, our multilevel analyses indicated that with increasing percentages of white students at their school, black students experienced more depressive symptoms and a higher risk of reporting high levels of somatic symptoms. After including students' perceptions of discrimination and school attachment, the interaction between black student race and school-level racial composition was no longer significant for either outcome. Our findings suggest that attending predominantly-minority schools may buffer black students from discrimination and increase their school attachment, which may reduce their risk of experiencing depressive and somatic symptoms. PMID- 21531495 TI - Effect of the point mutation H148G on GFPmut2 unfolding kinetics by fluorescence spectroscopy. AB - We have used fluorescence spectroscopy techniques such as fluorescence correlation spectroscopy and fluorescence anisotropy decay on a wide time range, from nanoseconds to seconds, to investigate the unfolding kinetics induced by guanidinium chloride of GFPMut2 and its point mutation H148G, which has proved to be relevant for GFP photochemistry and photophysics. The mutation affects the unfolding kinetics of GFP leading to a much faster process at alkaline pH values, where protonation dynamics is negligible, that can be ascribed to a twofold role of His148, either as a proton shutter towards the chromophore and as a conformation stabiliser. For both mutants a soft region located near beta-strand 3 is found that starts to gain flexibility in the ns range at denaturant concentrations far lower than those required to turn off the chromophore fluorescence, as derived from the anisotropy decay of an extrinsic probe covalently bound to the proteins. PMID- 21531496 TI - Minimum recovery time between reactive hyperemia stimulus in the repeated measurement of brachial flow-mediated dilatation. AB - The ability to undertake repeat measurements of flow-mediated dilatation (FMD) within a short time of a previous measurement would be useful to improve accuracy or to repeat a failed initial procedure. Although standard methods report that a minimum of 10 min is required between measurements, there is no published data to support this. Thirty healthy volunteers had five FMD measurements performed within a 2-h period, separated by various time intervals (5, 15 and 30 min). In 19 volunteers, FMD was also performed as soon as the vessel had returned to its baseline diameter. There was no significant difference between any of the FMD measurements or parameters across the visits indicating that repeat measurements may be taken after a minimum of 5 min or as soon as the vessel has returned to its baseline diameter, which in some subjects may be less than 5 min. PMID- 21531497 TI - Detecting angiogenesis in breast tumors: comparison of color Doppler flow imaging with ultrasound-guided diffuse optical tomography. AB - We investigated the correlation between color Doppler flow imaging (CDFI) and ultrasound (US)-guided diffuse optical tomography (DOT) for detection of breast tumor angiogenesis. Both CDFI and DOT were performed in 214 breast lesions scheduled for biopsy. The lesions were classified as vascular or nonvascular on CDFI and total hemoglobin concentration (THC) was measured by DOT. Sonographic results were correlated with the THC measurements. Pathologic examination showed 118 breast cancers and 96 benign breast masses. When vascularization on CDFI as a sign of malignancy and a cutoff of 140 MUmol/L was used, the sensitivity, specificity and accuracy were 83.9, 50.0 and 68.7% for CDFI and 83.9, 66.7 and 76.2% for DOT, respectively. Thirteen (11.0%) nonvascular breast cancers presented high THC levels. Twenty-five (52.1%) vascular benign tumors demonstrated low THC levels. Mean THC did not differ significantly in malignancies with vascular or without vascular (228.14 +/- 85.37 MUmol/L vs. 191.42 +/- 92.59 MUmol/L; p > 0.05). Likewise, for benign lesions, the difference between THC values in vascular lesions and nonvascular lesions was not statistically significant (140.86 +/- 79.63 MUmol/L vs. 110.13 +/- 85.05 MUmol/L; p > 0.05). Our results suggest that the addition of DOT to CDFI could be helpful for characterizing CDFI nonvascular lesions that are suspicious for malignancy or vascular lesions that are probably benign. PMID- 21531498 TI - Characterizing the subharmonic response of phospholipid-coated microbubbles for carotid imaging. AB - The subharmonic vibration of BR14 (Bracco Research S.A., Geneva, Switzerland) contrast agent microbubbles is investigated within the preferable frequency range for carotid ultrasound imaging (8-12 MHz). The response of the bubbles was recorded optically with an ultra-fast recording camera (Brandaris 128) at three acoustic pressures (50, 100 and 120 kPa). The vibration of the microbubbles was measured as a function of the excitation frequency and its frequency content was determined. Among 390 recordings, 40% showed subharmonic oscillations. It was observed that for smaller microbubbles (diameter < 3 MUm) the frequency of the maximum subharmonic response increases for increasing pressures (shell hardening) opposite to what has been reported for larger microbubbles (3 MUm < diameter < 15 MUm). These findings are well predicted by the model proposed by Marmottant et al. (2005) after including the dilatational shell viscosity of the microbubbles measured by Van der Meer et al. (2007), which indicates a marked shear-thinning behavior of the phospholipid shell. PMID- 21531500 TI - Diagnostic value of contrast-enhanced ultrasound, computed tomography and magnetic resonance imaging for focal liver lesions: a meta-analysis. AB - The diagnostic performance of contrast-enhanced ultrasound (CEUS), contrast enhanced computed tomography (CECT) and contrast-enhanced magnetic resonance imaging (CEMRI) was determined in patients with focal liver lesions (FLLs) in a meta-analysis. Meta-Disc version 1.4 was used to describe and calculate sensitivity, specificity, summary receiver operating characteristic (SROC) curves and area under the curve (AUC). In the 25 included studies, the pooled estimate of CEUS studies for sensitivity, specificity and diagnostic odds ratio (DOR) was 87% (95% CI 85-88), 89% (95% CI 87-91) and 78.84 (95% CI 29.40-211.40), respectively. Sensitivity, specificity and DOR were 86% (95% CI 84-88), 82% (95% CI 77-86) and 26.34 (95% CI 8.32-83.39), respectively, for the CECT studies. Sensitivity, specificity and DOR were 85% (95% CI 82-88), 87% (95% CI 83-91) and 48.37 (95% CI 15.87-147.45), respectively, for the CEMRI studies. SROC analysis indicated that the diagnostic value of CEUS for FLLs is not significantly different from that of CECT and CEMRI. PMID- 21531499 TI - Novel ultrasound and DCE-MRI analyses after antiangiogenic treatment with a selective VEGF receptor inhibitor. AB - We report a comparison between tumor perfusion estimates acquired using contrast enhanced MRI and motion-corrected contrast-enhanced ultrasound before and after treatment with AG-028262, a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor. Antiangiogenic activity was determined by assessing weekly ultrasound and MRI images of rats with bilateral hind flank mammary adenocarcinomas before and after treatment with AG-028262. Images were acquired with a spoiled gradient, 1.5 T magnetic resonance sequence and a destruction replenishment ultrasound protocol. For ultrasound, a time to 80% contrast replenishment was calculated for each tumor voxel; for MR imaging, a measure of local flow rate was estimated from a linear fit of minimum to maximum intensities. AG-028262 significantly decreased tumor growth and increased the time required to replenish tumor voxels with an ultrasound contrast agent from 2.66 to 4.54 s and to fill with an MR contrast agent from 29.5 to 50.8 s. Measures of flow rate derived from MRI and ultrasound demonstrated a positive linear correlation of r2 = 0.86. PMID- 21531501 TI - Laparoscopic microwave ablation and enucleation of small renal masses: preliminary experience. AB - Advancements in imaging and laparoscopy have led to the expansion of minimally invasive techniques in the ablation of small renal masses (SRMs). We report the results of a study aimed at assessing the efficacy of thermoablative microwave (MW) effects on SRMs and the haemostatic as well as necrotic MW effects on the parenchyma surrounding the neoplasm. From November 2008 to October 2010, 10 patients with SRMs underwent laparoscopy-guided Tru-Cut biopsy, MW tumour ablation, and enucleation. Mean age was 66 yr (range: 46-84 yr). Mean renal tumour diameter was 2.75 cm (range: 1.3-4.2 cm). MW antennas were applied one to three times depending on tumour volume, location, and shape. After MW thermoablation, laparoscopic enucleation was performed to evaluate the histopathologic and haemostatic effects of MW. The mean MW antenna application time was 14.1 min (range: 4-30 min). Enucleation did not require renal pedicle clamping in any of the cases because no significant bleeding took place. Preablation pathology revealed clear cell renal carcinoma of Fuhrman grade I-II in all cases. Postablation pathology showed extensive coagulative necrosis without skipped tumour areas. No intra- or postoperative complications were reported. Histopathologic effects on SRMs provide consistent proof of principle for future studies. PMID- 21531502 TI - The role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle-invasive bladder cancer: a systematic review. AB - CONTEXT: Due to the suboptimal clinical outcomes of current therapies for non muscle-invasive bladder cancer (NMIBC), the search for better therapeutic options continues. One option is chemohyperthermia (C-HT): microwave-induced hyperthermia (HT) with intravesical chemotherapy, typically mitomycin C (MMC). During the last 15 yr, the combined regimen has been tested in different clinical settings. OBJECTIVE: To perform a systematic review to evaluate the efficacy of C-HT as a treatment for NMIBC. EVIDENCE ACQUISITION: The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken. Relevant conference abstracts and urology journals were also searched manually. Two reviewers independently reviewed candidate studies for eligibility and abstracted data from studies that met inclusion criteria. The primary end point was time to recurrence. Secondary end points included time to progression, bladder preservation rate, and adverse event (AE) rate. EVIDENCE SYNTHESIS: A total of 22 studies met inclusion criteria and underwent data extraction. When possible, data were combined using random effects meta-analytic techniques. Recurrence was seen 59% less after C-HT than after MMC alone. Due to short follow-up, no conclusions can be drawn about time to recurrence and progression. The overall bladder preservation rate after C-HT was 87.6%. This rate appeared higher than after MMC alone, but valid comparison studies were lacking. AEs were higher with C-HT than with MMC alone, but this difference was not statistically significant. CONCLUSIONS: Published data suggest a 59% relative reduction in NMIBC recurrence when C-HT is compared with MMC alone. C-HT also appears to improve bladder preservation rate. However, due to a limited number of randomized trials and to heterogeneity in study design, definitive conclusions cannot be drawn. In the future, C-HT may become standard therapy for high-risk patients with recurrent tumors, for patients who are unsuitable for radical cystectomy, and in cases for which bacillus Calmette-Guerin treatment is contraindicated. PMID- 21531503 TI - Kinetic study of trichloroethylene combustion on exchanged zeolites catalysts. AB - In this paper is presented a kinetic study of the catalytic combustion of trichloroethylene (TCE) over Y-zeolites exchanged with several cations. The catalysts, based on zeolite, were prepared by ion exchange and characterized by means of physico-chemical techniques and then tested under kinetic conditions. The kinetic results obtained were interpreted using kinetic models of power-law type and Eley-Rideal. The results obtained indicate that catalyst Y-Cr is more active than Y-Co catalyst. The greater activity of catalyst exchanged with Cr can be attributed to the higher acidity that presented these catalysts. PMID- 21531504 TI - Use of characterisation leaching tests and associated modelling tools in assessing the hazardous nature of wastes. AB - The evaluation of the hazardous nature of a waste is frequently based on total composition in many jurisdictions, while for most cases the chemical form of the constituents and the release pathways that may result in exposure of man and organisms under conditions of handling, transport, disposal or beneficial use are the most important factors controlling potential environmental impact. Thus, leaching assessment related to possible management scenarios rather than total content can provide a much more robust basis for evaluating health risks and environmental risks for waterborne pathways. Standardized characterisation leaching tests based on intrinsic characteristics of a material provide a new foundation for needed decisions. Chemical speciation modelling using characterisation testing results provides a means to identify mechanisms controlling constituent release, including mineral or sorptive phases, and thus insights into the long-term release behaviour of the material and approaches to reducing potential impacts. PMID- 21531505 TI - Identification and characterization of Leucobacter sp. N-4 for Ni (II) biosorption by response surface methodology. AB - In the present study, batch experiments were carried out to characterize and optimize the removal process of Ni (II) by a nickel tolerant strain Leucobacter sp. N-4, which was isolated from the soil samples. The effects of operating parameters with respect to initial solution pH (3.0-6.5), initial nickel concentration (50-100mg/L) and biomass dosage (1-10 g/L) on Ni (II) biosorption were investigated by response surface methodology (RSM). The maximal Ni (II) removal efficiency (nearly 99%) was achieved under the following conditions: pH 4.75, biomass dosage 5.38 g/L and initial Ni (II) concentration 53.6 mg/L. The adsorption-equilibrium data fitted well with both Langmuir and Freundlich isotherms. The monolayer adsorption capacity of biomass obtained from Langmuir isotherm was about 19.6 mg/g. Infrared spectrometer (IR) results showed that chemical functional groups (e.g. -NH(2), -OH and COO-M) of the biomass should be the active binding sites for Ni (II) biosorption from aqueous solutions. PMID- 21531506 TI - Removal of chloride from electric arc furnace dust. AB - Electric arc furnace (EAF) dust with high chloride content increases the threat of dioxin emissions and the high chloride content reduces the value of recycled zinc oxide produced by EAF dust recycling plants. This study conducts a number of laboratory experiments to determine the technical feasibility of a new dechlorination method. These methods consist of a series of roasting processes and water washing processes. In the roasting process, EAF dust was heated in a tube furnace to evaluate the parameters of atmospheric conditions, roasting temperature, and roasting time. Results indicate that sulfation roasting is more efficient in reducing chloride content than other roasting processes. The water washing process can totally remove water-soluble chloride at a solid to liquid ratio of 1:10. However, the remaining water-insoluble substance is difficult to dechlorinate. For example, lead chloride forms a hydroxyl-halide (PbOHCl) and lead chloride carbonate (Pb(2)CO(3)Cl(2)) agglutinative matrix that is hard to wash away. PMID- 21531507 TI - New photocatalysts based on MIL-53 metal-organic frameworks for the decolorization of methylene blue dye. AB - The photocatalytic decolorization of methylene blue dye in aqueous solution using a novel photocatalyst MIL-53(Fe) metal-organic frameworks was investigated under UV-vis light and visible light irradiation. The effect of electron acceptor H(2)O(2), KBrO(3) and (NH(4))(2)S(2)O(8) addition on the photocatalytic performance of MIL-53(Fe) was also evaluated. The results show that MIL-53(Fe) photocatalyst exhibited photocatalytic activity for MB decolorization both under UV-vis light and visible light irradiation, and the MB decolorization over MIL 53(Fe) photocatalyst followed the first-order kinetics. The addition of different electron acceptors all enhances the photocatalytic performance of MIL-53(Fe) photocatalyst, and the enhanced rate follows the order of H(2)O(2)>(NH(4))(2)S(2)O(8)>KBrO(3) under UV-vis light irradiation, while in the order of (NH(4))(2)S(2)O(8)>H(2)O(2)>KBrO(3) under visible light irradiation. Moreover, MIL-53(Fe) did not exhibit any obvious loss of the activity for MB decolorization during five repeated usages. The photocatalytic activities over MIL-53(M) (M=Al, Fe), the isostructure to MIL-53(Fe), indicate that the metal centers show nil effect on the photocatalytic activity of MIL-53(M) photocatalysts. PMID- 21531508 TI - Effect of ignition condition on typical polymer's melt flow flammability. AB - Polymer's melt flow behavior has triggered great interest due to the mutual enhancing loop effect between vertical polymer fire and the induced flowing pool fire. The aim of the study was to quantitatively investigate the effect of ignition conditions on the polymer's melt flow flammability. Polypropylene (PP) sheets with a thickness of 4mm were selected as the test samples. An experimental rig was designed to study the interaction between the vertical PP sheet fire and the corresponding pool fire. Ignition was achieved at three locations, i.e. the lower right corner, the lower middle edge, and the whole lower edge of the PP sheets. All tests were conducted in an ISO9705 fire test room. Heat release rate, smoke temperature and other common parameters in fire hazard analysis were measured with the help of the fire room facilities. Results indicated that ignition conditions evidently impact on heat release rate development, peak heat release rate, smoke temperature, smoke generation and smoke toxicity. Furthermore, these experimental results preliminarily demonstrated the feasibility of the designed setup in studying interaction between vertical polymer sheet fire and the induced pool fire, although further modification may be needed. PMID- 21531509 TI - Combined mild soil washing and compost-assisted phytoremediation in treatment of silt loams contaminated with copper, nickel, and chromium. AB - A new soil remediation option, combining the soil washing process using pure water followed by the compost-assisted phytoextraction, is evaluated using silt loams contaminated with plating wastewater containing Cu, Ni, and Cr. Plants utilized in this study are the rapeseeds, sunflowers, tomatoes, and soapworts. Phytoextraction operation was carried out in pot experiments over a period of 4 months. Metal concentrations in roots and shoots of plants were analyzed upon completion of each pot experiment. Hypothesis testing was employed in assessing the significance of difference in the experimental data. Results indicated that the rapeseed, a hyperaccumulator, is most effective in extracting metals from the compost-amended silt loams. The fast-growing sunflowers and tomatoes are comparable to rapeseeds in accumulating metals despite their relatively low metal concentrations in tissues. Bioaccumulation coefficients obtained for all plants are less than one, indicating that phytostabilization rather than phytoextraction is the dominant mechanism at this simulated final-phase condition. PMID- 21531510 TI - Trichinella spiralis infection induces angiogenic factor thymosin beta4 expression. AB - Trichinella spiralis (T. spiralis) has been reported to up-regulate the expression of the angiogenic molecule vascular endothelial cell growth factor (VEGF) during nurse cell formation. In order to analyze the induction of angiogenesis by T. spiralis, the expression patterns of angiogenesis-related proteins were investigated by immunohistochemical analysis. VEGF expression was induced in the infected muscles at an early stage of infection (10 days after infection) and diminished after 3 weeks. Thymosin beta4, a major factor which induces VEGF, showed increased expression in muscle fibers 10 days after infection, and the expression remained high in the nurse cells for 6 weeks, when the formation of the nurse cell complex was completed. The hypoxia inducible factor (HIF)-1alpha showed a diffuse expression pattern around the infected muscle fibers and was strongly expressed in inflammatory cells but was not related to the hypoxic condition caused by nurse cell formation. Localization of the hypoxic regions by the hypoxia marker, pimonidazole showed T. spiralis infection does not induce a hypoxic condition in nurse cells. These results suggest that the expression of VEGF and thymosin beta4 induce angiogenesis and the expression of thymosin beta4 remained elevated to potentially regulate nurse cell formation and maintenance. PMID- 21531511 TI - Presence of Porocephalus clavatus (Arthropoda: Porocephalidae) in Peruvian Boidae snakes. AB - The pentastome species, Porocephalus clavatus, has been found to infect the lungs of two species of snakes in the family Boidae family (Boa constrictor and Epicrates cenchria). The individual of B. constrictor was collected in the Amazonian rainforest of Departamento Loreto, Peru. The E. cenchria was recovered from the pet trade in Lima, Peru's capital city. A total of 22 P. clavatus were collected and examined from these two snakes. This is the first report of P. clavatus in Peru. The morphology of the parasites and the possible importance in public and animal health are discussed. PMID- 21531512 TI - Questioning the rationale and conduct of the management of myelomeningocele study. AB - Surgical intervention in fetal spina bifida developed from the belief that amniotic fluid damages the spinal cord in utero and low spinal pressure from failure of neural tube closure causes hindbrain herniation leading to hydrocephalus after birth for many infants with open spinal lesions. Intrauterine intervention is undergoing a randomised human trial known by the acronym MOMS. It is hoped that randomisation and long-term follow up will demonstrate whether benefits to the infant may result from closure of the vertebral defect before birth. It is argued here that the premise upon which the pathogenesis of neural injury in human spina bifida used to launch this study is mistaken. This has implications for the conduct and conclusions of the trial. It is proposed that fetal surgery improves central nervous system outcome by improving cerebrospinal fluid flow at the foramen magnum. Successful intervention results in a more normal development of both neural and skeletal components of the neuraxis. Closure of the defect is required before signs of hindbrain herniation and ventriculomegaly are evident on ultrasound imaging as these are indicators of the presence of fetal hydrocephalus. PMID- 21531513 TI - Influence of partial replacement of NaCl with KCl, CaCl2 and MgCl2 on lipolysis and lipid oxidation in dry-cured ham. AB - Sodium intake above nutritional recommendations may involve harmful consequences to health such as the increased risk of cardiovascular diseases. Dry-cured ham constitutes a product with a relatively large amount of sodium. Thus, to obtain a healthier product for consumers with reduced sodium content, two formulations containing KCl alone (formulation II) or mixed with CaCl2 and MgCl2 (formulation III) have been proposed to partially replace NaCl. Lipolysis and lipid oxidation occurring in hams processed with these formulations have been studied since they have direct influence on the final flavor. No significant differences in acid lipase activity or lipid oxidation were found at the end of the process between the alternative formulations and formulation I (control with 100% NaCl). Differences in some free fatty acids, generated along the processing, were detected among treatments and at the end of dry-curing. Data suggests a slight trend towards a major lipolysis during treatment III. PMID- 21531514 TI - High-dose spatially fractionated GRID radiation therapy (SFGRT): a comparison of treatment outcomes with Cerrobend vs. MLC SFGRT. AB - PURPOSE: Spatially fractionated GRID radiotherapy (SFGRT) using a customized Cerrobend block has been used to improve response rates in patients with bulky tumors. The clinical efficacy of our own multileaf collimator (MLC) technique is unknown. We undertook a retrospective analysis to compare clinical response rates attained using these two techniques. METHODS AND MATERIALS: Seventy-nine patients with bulky tumors (median diameter, 7.6 cm; range, 4-30 cm) treated with SFGRT were reviewed. Between 2003 and late 2005, the Cerrobend block technique (n = 39) was used. Between late 2005 and 2008, SFGRT was delivered using MLC-shaped fields (n = 40). Dose was prescribed to dmax (depth of maximum dose) and was typically 15 Gy. Eighty percent of patients in both groups received external beam radiotherapy in addition to SFGRT. The two-sided Fisher-Freeman-Halton test was used to compare pain and mass effect response rates between the two groups. RESULTS: Sixty-one patients (77%) were treated for palliative intent and 18 (23%) for curative intent. The majority of patients had either lung or head-and-neck primaries in both groups; the most frequent site of SFGRT application was the neck. The majority of patients complained of either pain (65%) or mass effect (58%) at intake. Overall response rates for pain and mass response were no different between the Cerrobend and MLC groups: pain, 75% and 74%, respectively (p = 0.50), and mass effect, 67% and 73%, respectively (p = 0.85). The majority of toxicities were Grade 1 or 2, and only 3 patients had late Grade 3-4 toxicities. CONCLUSIONS: MLC-based and Cerrobend-based SFGRT have comparable and encouraging response rates when used either in the palliative or curative setting. MLC-based SGFRT should allow clinics to more easily adopt this novel treatment approach for the treatment of bulky tumors. PMID- 21531515 TI - Treatment of oral cavity squamous cell carcinoma with adjuvant or definitive intensity-modulated radiation therapy. AB - PURPOSE: The optimal management of oral cavity squamous cell carcinoma (OCSCC) typically involves surgical resection followed by adjuvant radiotherapy or chemoradiotherapy (CRT) in the setting of adverse pathologic features. Intensity modulated radiation therapy (IMRT) is frequently used to treat oral cavity cancers, but published IMRT outcomes specific to this disease site are sparse. We report the Dana-Farber Cancer Institute experience with IMRT-based treatment for OCSCC. METHODS AND MATERIALS: Retrospective study of all patients treated at Dana Farber Cancer Institute for OCSCC with adjuvant or definitive IMRT between August 2004 and December 2009. The American Joint Committee on Cancer disease stage criteria distribution of this cohort included 5 patients (12%) with stage I; 10 patients (24%) with stage II (n = 10, 24%); 14 patients (33%) with stage III (n = 14, 33%); and 13 patients (31%) with stage IV. The primary endpoint was overall survival (OS); secondary endpoints were locoregional control (LRC) and acute and chronic toxicity. RESULTS: Forty-two patients with OCSCC were included, 30 of whom were initially treated with surgical resection. Twenty-three (77%) of 30 surgical patients treated with adjuvant IMRT also received concurrent chemotherapy, and 9 of 12 (75%) patients treated definitively without surgery were treated with CRT or induction chemotherapy and CRT. With a median follow-up of 2.1 years (interquartile range, 1.1-3.1 years) for all patients, the 2-year actuarial rates of OS and LRC following adjuvant IMRT were 85% and 91%, respectively, and the comparable results for definitive IMRT were 63% and 64% for OS and LRC, respectively. Only 1 patient developed symptomatic osteoradionecrosis, and among patients without evidence of disease, 35% experienced grade 2 to 3 late dysphagia, with only 1 patient who was continuously gastrostomy-dependent. CONCLUSIONS: In this single-institution series, postoperative IMRT was associated with promising LRC, OS, and lower late toxicity rates, and chemoradiotherapy was a successful treatment for patients with high risk disease. In contrast, outcomes of radiation-based treatment for patients with inoperable locally advanced disease were markedly less successful. PMID- 21531516 TI - Normal tissue complication probability estimation by the Lyman-Kutcher-Burman method does not accurately predict spinal cord tolerance to stereotactic radiosurgery. AB - PURPOSE: To determine whether normal tissue complication probability (NTCP) analyses of the human spinal cord by use of the Lyman-Kutcher-Burman (LKB) model, supplemented by linear-quadratic modeling to account for the effect of fractionation, predict the risk of myelopathy from stereotactic radiosurgery (SRS). METHODS AND MATERIALS: From November 2001 to July 2008, 24 spinal hemangioblastomas in 17 patients were treated with SRS. Of the tumors, 17 received 1 fraction with a median dose of 20 Gy (range, 18-30 Gy) and 7 received 20 to 25 Gy in 2 or 3 sessions, with cord maximum doses of 22.7 Gy (range, 17.8 30.9 Gy) and 22.0 Gy (range, 20.2-26.6 Gy), respectively. By use of conventional values for alpha/beta, volume parameter n, 50% complication probability dose TD(50), and inverse slope parameter m, a computationally simplified implementation of the LKB model was used to calculate the biologically equivalent uniform dose and NTCP for each treatment. Exploratory calculations were performed with alternate values of alpha/beta and n. RESULTS: In this study 1 case (4%) of myelopathy occurred. The LKB model using radiobiological parameters from Emami and the logistic model with parameters from Schultheiss overestimated complication rates, predicting 13 complications (54%) and 18 complications (75%), respectively. An increase in the volume parameter (n), to assume greater parallel organization, improved the predictive value of the models. Maximum-likelihood LKB fitting of alpha/beta and n yielded better predictions (0.7 complications), with n = 0.023 and alpha/beta = 17.8 Gy. CONCLUSIONS: The spinal cord tolerance to the dosimetry of SRS is higher than predicted by the LKB model using any set of accepted parameters. Only a high alpha/beta value in the LKB model and only a large volume effect in the logistic model with Schultheiss data could explain the low number of complications observed. This finding emphasizes that radiobiological models traditionally used to estimate spinal cord NTCP may not apply to the dosimetry of SRS. Further research with additional NTCP models is needed. PMID- 21531517 TI - Sensor technology for smart homes. AB - A smart home is a residence equipped with technology that observes the residents and provides proactive services. Most recently, it has been introduced as a potential solution to support independent living of people with disabilities and older adults, as well as to relieve the workload from family caregivers and health providers. One of the key supporting features of a smart home is its ability to monitor the activities of daily living and safety of residents, and in detecting changes in their daily routines. With the availability of inexpensive low-power sensors, radios, and embedded processors, current smart homes are typically equipped with a large amount of networked sensors which collaboratively process and make deductions from the acquired data on the state of the home as well as the activities and behaviors of its residents. This article reviews sensor technology used in smart homes with a focus on direct environment sensing and infrastructure mediated sensing. The article also points out the strengths and limitations of different sensor technologies, as well as discusses challenges and opportunities from clinical, technical, and ethical perspectives. It is recommended that sensor technologies for smart homes address actual needs of all stake holders including end users, their family members and caregivers, and their doctors and therapists. More evidence on the appropriateness, usefulness, and cost benefits analysis of sensor technologies for smart homes is necessary before these sensors should be widely deployed into real-world residential settings and successfully integrated into everyday life and health care services. PMID- 21531518 TI - [Organ donation: point of view of private practice physicians in the region Nord Pas de Calais in France]. AB - BACKGROUND: In 2008, in France, 222 patients died because they did not receive the graft they expected. The main objective of this study was to determine the attitude of private practice physicians concerning organ donation. METHODS: A postal questionnaire was sent to all private practice office-based physicians in the Nord-Pas de Calais region. This questionnaire was elaborated with a panel of physicians and sociologists. It was sent with the monthly journal of the regional union of private physicians of June 2008. RESULTS: Two hundred and seventy eight questionnaires were returned. One hundred and thirty four (48.2%) respondents declared they knew what the regulations about organ donation were. The majority of respondents approved organ donation. Information to patients was provided during visits by 34.53% (96) of practitioners. For those who were knowledgeable about regulations, 50.75% of them talked about organ donation. Physicians who had already had experience with organ donation were more inclined to talk about it with other patients. The practitioners described three actions they felt could have a positive influence on family acceptance: providing information before death, talking about organ donation in an appropriate sensitive way, and relying on the confidence established by a solid patient-physician relationship. CONCLUSION: Almost 90% of private physicians who responded to the survey were in favor of organ donation but only 34.5% delivered information and discussed the issue with their patients. The physicians coped with the topics more easily when they had experienced cases and when they were informed about existing regulations. A specific educational program on the current regulations and how to interact with patients on this subject during a visit could be a first answer to the problem and would be welcomed by practitioners. PMID- 21531520 TI - Genetic diversity of symbiotic Bradyrhizobium elkanii populations recovered from inoculated and non-inoculated Acacia mangium field trials in Brazil. AB - Acacia mangium is a legume tree native to Australasia. Since the eighties, it has been introduced into many tropical countries, especially in a context of industrial plantations. Many field trials have been set up to test the effects of controlled inoculation with selected symbiotic bacteria versus natural colonization with indigenous strains. In the introduction areas, A. mangium trees spontaneously nodulate with local and often ineffective bacteria. When inoculated, the persistence of inoculants and possible genetic recombination with local strains remain to be explored. The aim of this study was to describe the genetic diversity of bacteria spontaneously nodulating A. mangium in Brazil and to evaluate the persistence of selected strains used as inoculants. Three different sites, several hundred kilometers apart, were studied, with inoculated and non-inoculated plots in two of them. Seventy-nine strains were isolated from nodules and sequenced on three housekeeping genes (glnII, dnaK and recA) and one symbiotic gene (nodA). All but one of the strains belonged to the Bradyrhizobium elkanii species. A single case of housekeeping gene transfer was detected among the 79 strains, suggesting an extremely low rate of recombination within B. elkanii, whereas the nodulation gene nodA was found to be frequently transferred. The fate of the inoculant strains varied depending on the site, with a complete disappearance in one case, and persistence in another. We compared our results with the sister species Bradyrhizobium japonicum, both in terms of population genetics and inoculant strain destiny. PMID- 21531519 TI - Investigation of the role of computed tomography as an adjunct to autopsy in the evaluation of stillbirth. AB - INTRODUCTION: The number of parents agreeing to autopsy following stillbirth is declining, which has undermined clinicians' ability to assess causes of intrauterine death and can impact counselling regarding recurrence. Post-mortem radiological imaging is a potential alternative method of investigating perinatal loss. The aim of this study was to assess the role of multi-detector computed tomography (MDCT) in the investigation of stillbirth. STUDY DESIGN: Following ethical approval and written consent, parents were offered MDCT of the stillborn infant. MDCT was performed with 3D reconstruction, and images were analysed for image quality, anthropomorphic measurements and pathologic findings. Body part and organ-specific measurements were performed; including head, chest and abdominal circumferences, and muscle and liver mass was also measured. Findings were correlated with obstetric history, post-mortem skeletal survey (plain radiography), and formal autopsy. RESULTS: Fourteen third-trimester stillborn infants were scanned. Image quality was moderate to excellent for most body structures. CT was better than plain radiography for imaging skeletal structures and large solid organs and demonstrated a range of pathologies including renal vein thrombosis, mesenteric calcification and skeletal hyperostosis that were not seen on plain radiographs. MDCT did not overlook autopsy findings and provided some additional information. CONCLUSION: This study confirms the feasibility of MDCT in the investigation of third trimester stillbirth. MDCT image quality is acceptable and the examination can demonstrate a range of anatomic and pathologic findings. Initially, its value may be as an important adjunct to conventional autopsy. PMID- 21531521 TI - Determination of aminorex in human urine samples by GC-MS after use of levamisole. AB - The Drug Enforcement Administration (DEA) reports that as of October 2010, 79% of all cocaine seized in the United States contained levamisole. The equine conversion of levamisole to aminorex has been demonstrated. However, the metabolic fate of levamisole in humans is unknown. Nevertheless, as aminorex is amphetamine-like and hallucinogenic, it may be used as an adulterant to increase the effects of cocaine. We report here the results of in vivo studies demonstrating for the first time that not only equine, but also canine and human metabolism all result in aminorex formation. Levamisole and aminorex were extracted from real urine samples by liquid-liquid extraction and identified and quantified by GC-MS (identification by 3 ions per substance, LLOQ at 0.15ng/ml for both). PMID- 21531522 TI - Recommendations for the validation of cell-based assays used for the detection of neutralizing antibody immune responses elicited against biological therapeutics. AB - The administration of biological therapeutics may result in the development of anti-drug antibodies (ADAs) in treated subjects. In some cases, ADA responses may result in the loss of therapeutic efficacy due to the formation of neutralizing ADAs (NAbs). An important characteristic of anti-drug NAbs is their direct inhibitory effect on the pharmacological activity of the therapeutic. Neutralizing antibody responses are of particular concern for biologic products with an endogenous homolog whose activity can be potentially dampened or completely inhibited by the NAbs leading to an autoimmune-type deficiency syndrome. Therefore, it is important that ADAs are detected and characterized appropriately using sensitive and reliable methods. The design, development and optimization of cell-based assays used for detection of NAbs have been published previously by Gupta et al. 2007 [1]. This paper provides recommendations on best practices for the validation of cell-based NAb assay and suggested validation parameters based on the experience of the authors. PMID- 21531523 TI - The cardiac literature 2010. PMID- 21531524 TI - Therapeutic management of superior mesenteric artery aneurysms. AB - OBJECTIVE: Superior mesenteric artery (SMA) aneurysms are rare but life threatening entities. This study summarizes our experience in providing therapeutic management for true aneurysms of the SMA. METHODS: Between February 1998 and March 2010, 10 patients were diagnosed with true SMA aneurysms in our hospital. Medical data for demographics, clinical presentation, diagnosis, aneurysm characteristics, treatment modalities, outcomes, and follow-up were retrospectively analyzed. RESULTS: Ten patients (six women, four men) were enrolled with a mean age of 56.7 years (range, 42-69 years). One patient (10%) had aneurysm rupture and presented with abdominal pain, and seven (70%) were asymptomatic. The size of nonruptured aneurysms ranged from 1.2 to 8.0 cm (mean, 3.5 cm). Of 10 patients, five received endovascular stent graft repair, two were treated surgically, two were observed, and one with aneurysm rupture died of hemorrhagic shock before surgery. The two surgical patients underwent SMA reconstruction after aneurysmectomy, and segmental bowel resection was performed in one patient after reconstruction. The overall mortality rate was 10%. Postoperative gastroparesis was identified in one patient (14.3%). Mean operation time was 3.6 hours in the surgical group and 1.3 hours in the endovascular group. Mean postoperative hospital stay for the two groups was 20.0 days and 2.2 days, respectively. Mean follow-up was 30.9 months (range, 3-72 months). Endoleak was found in one patient 3 months after endovascular repair. CONCLUSION: True SMA aneurysms are uncommon entities with definite rupture risk and mortality. Compared with surgical intervention, endovascular stent graft placement is associated with less trauma and rapid recovery. It may be a promising alternative to surgical intervention. The most appropriate treatment depends on the characteristics of the lesion and the condition of the patient. PMID- 21531525 TI - Tongue necrosis as an unusual presentation of carotid artery stenosis. AB - A 57-year-old man with premature coronary artery disease presented to the emergency department with left facial pain, numbness, and tongue swelling. The patient was found to have significant tongue necrosis, and subsequent arteriography demonstrated carotid bifurcation stenosis with embolization to the left lingual artery. The patient was successfully treated with debridement of his tongue and left carotid endarterectomy. PMID- 21531528 TI - Defining successful mobility after lower extremity amputation for complications of peripheral vascular disease and diabetes. AB - BACKGROUND: Information about longer-term functional outcomes following lower extremity amputation for peripheral vascular disease and diabetes remains limited. This study examined factors associated with mobility success during the first year following amputation. METHODS: Prospective cohort study of 87 amputees experiencing a first major unilateral amputation surgery. Seventy-five (86%) participants completed 12-month follow-up interview. RESULTS: Twenty-eight subjects (37%) achieved mobility success, defined as returning to or exceeding a baseline level of mobility on the locomotor capability index (LCI-5). Forty-three subjects (57%) were satisfied with their mobility. Individuals who were 65 years of age and older (risk difference [RD] = -0.52; 95% confidence interval [CI]: 0.75, -0.29), reported a current alcohol use disorder (RD = -0.37; 95% CI: -0.48, -0.26), had a history of hypertension (RD = -0.23; 95% CI: -0.43, -0.03) or treatment for anxiety or depression (RD = -0.39; 95% CI: -0.50, -0.28) were less likely to achieve mobility success. Mobility success was associated with mobility satisfaction (RD = 0.36; 95% CI: 0.20, 0.53) and satisfaction with life (RD = 0.28; 95% CI: 0.06, 0.50). Although higher absolute mobility at 12 months was also associated with mobility satisfaction and overall life satisfaction, 50% of individuals who achieved success with low to moderate 12-month mobility function reported they were satisfied with their mobility. CONCLUSION: Defining success after amputation in relation to an individual's specific mobility prior to the development of limb impairment which led to amputation provides a useful, patient centered measure that takes other aspects of health, function, and impairment into account. PMID- 21531527 TI - Iliac artery stenting combined with open femoral endarterectomy is as effective as open surgical reconstruction for severe iliac and common femoral occlusive disease. AB - PURPOSE: To compare outcomes of hybrid repair (HR) combining iliac artery stenting and open common femoral endarterectomy (CFE) with open aortoiliac and femoral reconstruction (OR) in patients with extensive iliac and common femoral occlusive disease (IFOD). METHODS: Between 1998 and 2008, 92 patients (164 limbs) underwent OR and 70 (84 limbs) underwent HR. All patients underwent concomitant CFE. Thirty-day mortality and morbidity, long-term patency, procedurally related limb salvage, and overall survival were analyzed after stratification by iliac TransAtlantic InterSociety Consensus (TASC) classification into TASC A/B and TASC C/D. RESULTS: HR patients were older for both TASC groups (A/B, P = .02; C/D, P = .01) and had higher Society for Vascular Surgery (SVS) cardiac comorbidity scores (A/B, P = .01; C/D, P < .001) compared with OR. Technical success was >=99% in both groups. An increase in the ankle-brachial index after the procedure was significantly higher in OR patients (0.49 +/- 0.28) with TASC A/B lesions than HR (0.22 +/- 0.18, P = .031). Hospital and intensive care unit (ICU) lengths of stay were 3.9 days for HR patients in TASC C/D vs 9.4 days for OR patients (P = .005). Comparing HR and OR, 30-day morbidity (3% vs 5%, P = .55) and mortality (1.1% vs 1.4%, P = .85) were equivalent. Primary patency of HR vs OR at 3 years was similar (91% vs 97%, P = .29) and was maintained after stratification by TASC A/B (89% vs 100%, P = .38) and TASC C/D (95% vs 97%, P = .54). Multivariate analysis for patency indicated that major tissue loss (Rutherford class 6) at presentation in the HR group was predictive of decreased long-term patency (P = .02). Limb salvage at 3 years was 100% in both groups. Overall survival was 74% for OR vs 40% for HR (P = .007). CONCLUSION: IFOD can be treated using HR with similar early and long-term efficacy vs OR. HR patients with TASC C/D lesions experienced a shorter ICU and hospital stay than OR patients. HR should be considered for all patients with IFOD regardless the severity of TASC classification, particularly in those with high surgical risk. When deciding between HR and OR, one must consider that major tissue loss at presentation is a negative predictor of long term patency in patients undergoing HR. PMID- 21531529 TI - Impact of renal insufficiency on clinical outcomes in patients with critical limb ischemia undergoing endovascular revascularization. AB - BACKGROUND: Patients with renal insufficiency (RI) are frequently excluded from trials assessing various endovascular revascularization concepts in critical limb ischemia (CLI) although information on clinical outcomes is scarce. METHODS: Consecutive patients with CLI undergoing endovascular lower limb revascularization during a 4.5-year time interval at a tertiary referral center were prospectively followed over a 12-month period. Patients were grouped according to renal function defined as normal (estimated glomerular filtration rate [eGFR] >= 60 mL/min/1.73 m(2); n = 108, 49.5%), moderate RI (eGFR >= 30-59 mL/min/1.73 m(2); n = 86, 39.5%) and severe RI, including dialysis (eGFR < 30 mL/min/1.73 m(2); n = 24, 11%). Clinical endpoints assessed were sustained clinical success, peri- and postprocedural mortality and major, above-the-ankle amputation. Sustained clinical improvement was defined as an upward shift of at least one category on the Rutherford classification compared with baseline to a level of claudication without repeated revascularization or unplanned amputation in surviving patients. Survival analysis was performed using the Kaplan-Meier method. Multivariate regression analysis was conducted in separate models for all above-mentioned clinical endpoints. RESULTS: A total of 208 patients (218 limbs, mean age 77.1 +/- 9.5, 131 men) underwent endovascular revascularization. Technical success rate was 95.2%, 92.5%, and 100% in patients without, moderate or severe RI. Sustained clinical success was 81.7%, 74.1%, and 51.5% in patients with normal renal function, 87.8%, 67.0%, and 63.3% with moderate, and 81.0%, 64.6%, and 50.2% with severe RI (P = .87 by log-rank) at 2, 6, and 12 months. Accordingly, major amputation rates were 9.9%, 18.2%, and 20.8% vs 9.9%, 22.6%, and 24% vs 12.5%, 16.7%, and 21.1% (P = .83, by log-rank). Mortality rates were 8.4%, 17.6%, and 26.5% in patients with normal renal function, 9.6%, 17.6%, and 30.1% with moderate and 17.5%, 26.6%, and 31.9% in patients with severe RI (P = .77, by log-rank) at corresponding intervals. Multivariate analysis revealed eGFR (hazard ratio [HR], 1.016; 95% confidence interval [CI], 1.001-1.031; P = .036), age (HR, 1.12; 95% CI, 1.061-1.189; P < .0001) and cigarette smoking (HR, 3.14; 95% CI, 1.153-8.55; P = .026) to be predictors for increased mortality within 1 year of follow-up. CONCLUSION: While functional lower limb outcomes were not influenced by renal function in this study, presence of RI was an independent predictor for higher mortality in CLI patients undergoing endovascular revascularization. PMID- 21531530 TI - A comparison between one- and two-stage brachiobasilic arteriovenous fistulas. AB - OBJECTIVES: Brachiobasilic arteriovenous fistulas (BBAVF) can be performed in one or two stages. We compared primary failure rates, as well as primary and secondary patency rates of one- and two-stage BBAVF at two institutions. METHODS: Patients undergoing one- and two-stage BBAVF at two institutions were compared retrospectively with respect to age, sex, body mass index, use of preoperative venous duplex ultrasound, diabetes, hypertension, and cause of end-stage renal disease. Categorical variables were compared using chi-square and Fisher's exact test, whereas the Wilcoxon rank-sum test was used to compare continuous variables. Patency rates were assessed using the Kaplan-Meier survival analysis and the Cox proportional hazards model with propensity analysis to determine hazard ratios. RESULTS: Ninety patients (60 one-stage and 30 two-stage) were identified. Mean follow-up was 14.2 months and the mean time interval between the first and second stage was 11.2 weeks. Although no significant difference in early failure existed (one-stage, 22.9% vs two-stage, 9.1%; P = .20), the two stage BBAVF showed significantly improved primary functional patency at 1 year at 88% vs 61% (P = .047) (hazard ratio, 0.2 (95% confidence interval [CI], .04-.80; P = .03). Patency for one-stage BBAVF markedly decreased to 34% at 2 years compared with 88% for the two-stage procedure (P = .047). Median primary functional patency for one-stage BBAVF was 31 weeks (interquartile range [IQR], 11-54) vs 79 weeks (IQR, 29-131 weeks) for the two-stage procedure, respectively (P = .0015). Two-year secondary functional patency for one- and two-stage procedures were 41% and 94%, respectively (P = .015). CONCLUSIONS: Primary and secondary patency at 1 and 2 years as well as functional patency is improved with the two-stage BBAVF when compared with the one-stage procedure. Lower primary failure rates prior to dialysis with the two-stage procedure approached, but did not reach statistical significance. While reasons for these finding are unclear, certain technical aspects of the procedure may play a role. PMID- 21531531 TI - Differences in anatomy and outcomes in patients treated with open mesenteric revascularization before and after the endovascular era. AB - OBJECTIVE: To compare the clinical characteristics, anatomy, and outcomes of patients treated with open mesenteric revascularization (OR) for chronic mesenteric ischemia (CMI) before and after the preferential use of endovascular revascularization (ER). METHODS: We reviewed a prospective database of 257 patients treated for CMI with OR or ER from 1998 to 2009. Treatment trends were analyzed to identify changes in practice paradigm. Prior to 2002, OR was used in 58 of 81 patients (72%). Since 2002, ER surpassed OR as the most common treatment option; OR was indicated in 58 of 176 patients (33%) who either failed ER or had unfavorable lesions for stent placement. We analyzed differences in clinical data, anatomical characteristics, and outcomes in 116 patients treated with OR before (Pre-Endo, n = 58) and after 2002 (Post-Endo, n = 58). Anatomical characteristics were determined by a blinded investigator using conventional angiography, magnetic resonance angiography, and computed tomography angiography with centerline of flow measurements. RESULTS: Both groups had similar demographics, risk factors, and clinical presentation, with the exception of higher (P < .05) rates of hypertension, hyperlipidemia, cardiac interventions, dysrhythmias, and higher comorbidity scores in the Post-Endo group. This group also had more extensive mesenteric artery disease, including higher incidence of three-vessel involvement (76% vs 57%; P = .048) and superior mesenteric artery (SMA) occlusion (67% vs 41%;P = .005). There were no differences (P > .05) in the number of vessels revascularized (1.8 +/- 0.4 vs 1.7 +/- 0.5) and in graft configuration (antegrade, 91% vs 78%; retrograde, 9% vs 22%; two-vessel, 69% vs 81%) in the Pre- and Post-Endo groups, respectively. There were no differences in operative mortality (1.7% vs 3.4%), morbidity (43% vs 53%), length of stay (12 +/ 1 vs 12 +/- 1 days), and immediate symptom improvement (88% vs 86%) in the Pre- and Post-Endo groups, respectively. Mean follow-up was 57 +/- 6 months for patients treated before 2002 and 29 +/- 6 months for those treated after 2002 (P = .0001). At 5 years, primary and secondary patency rates and recurrence-free survival were 82%, 86%, and 84% in the Pre-Endo and 81%, 82%, and 76% in the Post Endo groups (P > .05). CONCLUSION: OR has been used in approximately one-third of patients treated for CMI since 2002. Despite more comorbidities and more extensive mesenteric artery disease in patients now treated with OR, outcomes have not changed compared with those operated prior to the preferential use of mesenteric stents before 2002. PMID- 21531532 TI - Time of year does not influence mortality for vascular operations at academic centers. AB - OBJECTIVE: Studies in general surgery have suggested worse outcomes due to the presence of new trainees. We hypothesized that outcomes for vascular operations would be equal regardless of teaching hospital status or academic quarter within the United States. METHODS: From 2003 to 2007, 264,374 vascular operations were evaluated using the Nationwide Inpatient Sample database. Patients were stratified according to Non-Teaching (non-Teaching Hospital [NTH], n = 137,406), Teaching (Teaching Hospital [TH], n = 126,968), and Teaching with Vascular Surgery Training Program (VSH, n = 28,730) hospital status. Multivariate analyses were used to examine the effect of academic quarter (AQ) on mortality. RESULTS: Unadjusted mortality was higher at TH compared with NTH (2.5% vs 2.0%; P < .001). Aortic and peripheral vascular operations were more common at TH, while carotid endarterectomy (P < .001) was more frequent at NTH (P < .001). After risk adjustment, the odds of death were significantly (P < .001) increased for aortic and peripheral vascular operations but were similar at both TH (1.11 [0.98-1.25]; P = .10) and VSH (1.16 [0.98-1.37]; P = .08) compared with NTH. Importantly, AQ was not associated with increased risk of mortality at either TH (AQ1 odds ratios [OR] = 0.95 [080-1.13], AQ2 OR = 1.08 [0.91-1.28], AQ3 OR = 1.13 [0.96-1.34], AQ4 = Reference; P = .19) or VSH (AQ1 OR = 1.02 [0.81-1.29], AQ2 OR = 0.99 [0.79 1.25], AQ3 OR = 1.02 [0.81-1.28], AQ4 = Reference; P = .99). CONCLUSIONS: Mortality is not significantly influenced by operative time of year following vascular operations at academic centers. TH perform more high-risk operations compared with NTH with similar risk adjusted mortality. PMID- 21531533 TI - The efficacy of acupressure for symptom management: a systematic review. AB - CONTEXT: Acupressure is a noninvasive strategy used to manage various symptoms. OBJECTIVES: The purpose of this article was to review randomized controlled trials that investigated the efficacy of acupressure for the management of symptoms. METHODS: A literature search was conducted in the Cumulative Index to Nursing and Allied Health Literature, Medline, and PubMed using the key words acupressure, clinical trial, human, and/or randomized. Randomized clinical trials published between January 1, 2000 and January 31, 2010, which used acupressure as the sole intervention for one group, were included when they were written in English and when there were four or more studies of the efficacy of acupressure for that particular symptom. RESULTS: Forty-three studies were included in this review. Investigators in 16 of 23 studies concluded acupressure was effective, primarily for the management of nausea and vomiting in patients during pregnancy and during chemotherapy. Investigators in nine of 10 studies concluded that acupressure was effective for pain in patients with dysmenorrhea, during labor and after trauma. Investigators of four studies concluded that acupressure was effective in the management of dyspnea and investigators in six studies concluded that acupressure was effective in improving fatigue and reducing insomnia in a variety of populations. However, evaluation of the randomized controlled trial reports indicated a significant likelihood of bias. CONCLUSION: Acupressure may be a useful strategy for the management of multiple symptoms in a variety of patient populations, but rigorous trials are needed. Inclusion of acupressure as an intervention may improve patient outcomes. PMID- 21531534 TI - Arm swing during walking at different speeds in children with Cerebral Palsy and typically developing children. AB - Children with Cerebral Palsy (CP) have difficulties walking at a normal or high speed. It is known that arm movements play an important role to achieve higher walking speeds in healthy subjects. However, the role played by arm movements while walking at different speeds has received no attention in children with CP. Therefore we investigated the use of arm movements at two walking speeds for children with diplegia (DI) and hemiplegia (HE) as compared to typically developing (TD) children. Arm and leg swing lengths were determined in 11 HE children and 15 DI children and compared to 24 TD children using 3D gait analysis at their preferred and "as fast as possible" walking speeds. We found that TD children increased walking speed more than both CP groups. HE children showed larger arm swings on the non-hemiplegic compared to the hemiplegic side for both walking speeds. In contrast to TD or DI children, the HE group did not show an increase in arm swing length with increasing walking speed. Their leg swing length was larger on the non-hemiplegic than on the hemiplegic side but only at the preferred walking speed. The DI children exhibited smaller leg swings at both walking speeds. Since arm swing is used both by DI (to increase speed) and by HE children (to compensate for the reduced movement on the affected side) it is argued that these movements are important and should be allowed (or even encouraged) in gait training procedures (such as treadmill training). PMID- 21531535 TI - The effect of vision on postural strategies in Prader-Willi patients. AB - The aim of this study was to quantify the role of visual contribution in patients with Prader-Willi syndrome (PWS) on balance maintenance using a force platform. We enrolled 14 individuals with PWS free from conditions associated with impaired balance, 44 obese (OG) and 20 healthy controls (CG). Postural sway was measured for 60s while standing on a force platform (Kistler, CH; acquisition frequency: 500 Hz) integrated with a video system. Patients maintained an upright standing position with Open Eyes (OE) and then with Closed Eyes (CE). The ratio between the value of the parameter under OE and CE conditions was measured. Under OE condition PWS and OG were characterized by higher postural instability than CG, with the PWS group showing poorer balance capacity than OG. The Romberg ratio showed that while OG and CG had lower balance without vision, PWS maintained the same performance changing from OE to CE. The integration of different sensory inputs appears similar in OG and CG with higher postural stability under OE than CE. Balance in PWS is not influenced by the elimination of visual input. PMID- 21531536 TI - Improvement of fine motor skills in children with visual impairment: an explorative study. AB - In this study we analysed the potential spin-off of magnifier training on the fine-motor skills of visually impaired children. The fine-motor skills of 4- and 5-year-old visually impaired children were assessed using the manual skills test for children (6-12 years) with a visual impairment (ManuVis) and movement assessment for children (Movement ABC), before and after receiving a 12-sessions training within a 6-weeks period. The training was designed to practice the use of a stand magnifier, as part of a larger research project on low-vision aids. In this study, fifteen children trained with a magnifier; seven without. Sixteen children had nystagmus. In this group head orientation (ocular torticollis) was monitored. Results showed an age-related progress in children's fine-motor skills after the training, irrespective of magnifier condition: performance speed of the ManuVis items went from 333.4s to 273.6s on average. Accuracy in the writing tasks also increased. Finally, for the children with nystagmus, an increase of ocular torticollis was found. These results suggest a careful reconsideration of which intervention is most effective for enhancing perceptuomotor performance in visually impaired children: specific 'fine-motor' training or 'non-specific' visual-attention training with a magnifier. PMID- 21531537 TI - Testing a tool for the classification of study designs in systematic reviews of interventions and exposures showed moderate reliability and low accuracy. AB - OBJECTIVES: To develop and test a study design classification tool. STUDY DESIGN: We contacted relevant organizations and individuals to identify tools used to classify study designs and ranked these using predefined criteria. The highest ranked tool was a design algorithm developed, but no longer advocated, by the Cochrane Non-Randomized Studies Methods Group; this was modified to include additional study designs and decision points. We developed a reference classification for 30 studies; 6 testers applied the tool to these studies. Interrater reliability (Fleiss' kappa) and accuracy against the reference classification were assessed. The tool was further revised and retested. RESULTS: Initial reliability was fair among the testers (kappa=0.26) and the reference standard raters kappa=0.33). Testing after revisions showed improved reliability (kappa=0.45, moderate agreement) with improved, but still low, accuracy. The most common disagreements were whether the study design was experimental (5 of 15 studies), and whether there was a comparison of any kind (4 of 15 studies). Agreement was higher among testers who had completed graduate level training versus those who had not. CONCLUSION: The moderate reliability and low accuracy may be because of lack of clarity and comprehensiveness of the tool, inadequate reporting of the studies, and variability in tester characteristics. The results may not be generalizable to all published studies, as the test studies were selected because they had posed challenges for previous reviewers with respect to their design classification. Application of such a tool should be accompanied by training, pilot testing, and context-specific decision rules. PMID- 21531538 TI - Biopsy needle detection in transrectal ultrasound. AB - Using the fusion of pre-operative MRI and real time intra-procedural transrectal ultrasound (TRUS) to guide prostate biopsy has been shown as a very promising approach to yield better clinical outcome than the routinely performed TRUS only guided biopsy. In several situations of the MRI/TRUS fusion guided biopsy, it is important to know the exact location of the deployed biopsy needle, which is imaged in the TRUS video. In this paper, we present a method to automatically detect and segment the biopsy needle in TRUS. To achieve this goal, we propose to combine information from multiple resources, including ultrasound probe stability, TRUS video background model, and the prior knowledge of needle orientation and position. The proposed algorithm was tested on TRUS video sequences which have in total more than 25,000 frames. The needle deployments were successfully detected and segmented in the sequences with high accuracy and low false-positive detection rate. PMID- 21531539 TI - A novel method for color correction in epiluminescence microscopy. AB - This paper proposes a new color correction pipeline to improve the dermoscopy image quality. Images acquired with different cameras or different dermoscopes often present problems of faithful color reproduction. The colors of these images are often far different the ones observed with the naked eye, and usually vary from one camera to another. Nowadays digital cameras perform "black-box" color corrections taking into account the color temperature of the imaged scene, which may result in some cases in unrealistic color rendering. For this reason, it is necessary to calibrate the imaging system (the camera and a specific dermoscope). The calibration process requires finding a relationship between a device dependent color space and a standard color space depending only on the human eye. This relation is obtained acquiring known color patches of a color checker and relating them with the pixel values obtained by the camera. In our approach we model the color calibration problem using a new formulation that takes into account the spectral distribution of the dermoscope lighting system and conveys a solution for both RAW and JPEG images. When comparing images captured with different cameras, this new method improves the results between 0.1 and 0.9 DeltaE with respect to previous approaches. PMID- 21531540 TI - [Acute otitis media in ambulatory practice: epidemiological and clinical characteristics after 7 valent pneumococcal conjugate vaccine (PCV7) implementation]. AB - BACKGROUND: In US, pneumococcal conjugate vaccine (PCV7) had reduced the burden of AOM and changed the profile of the disease. Prior to PCV7 implementation in France, AOM represented 8% of pediatricians visits and failure rate was 12%. The aim of this study is to describe the epidemiologic characteristics of AOM after PCV7 implementation. METHODS: From 2007 to 2008, 30 pediatricians enrolled 3141 patients 3 to 36 months old with AOM. Standardized history and physical examination findings were recorded. Factors related to AOM failures were identified by multivariate logistic regression. RESULTS: AOM accounted for 5.8% of the 43 433 visits or 6.2 cases/week per pediatrician. Among 3141 evaluable AOM cases (mean age 16.7+/-8 months, peak incidence at 10 months), 99% had been vaccinated with PCV7 and 42.1% attended day care (DCC). Recurrent AOM comprised 24.5% of cases and 51% of children had received ATB in the last 3 months. At the time of diagnosis, 47.1% had fever>=38,5 degrees C, 74.5% otalgia and 4.7% otorrhea. Febrile and painful AOM accounted for 29.5% of cases and cunjunctivitis otitis syndrome for 18.2%. ATB was prescribed in 98.7% of cases (cefpodoxime proxetil, 59% and amoxicillin/clavulanate, 37%). The failure rate was 6.4% and failure risk was greater in children in DCC (OR=1.50, [1.10;2.05]), young age<18 months (OR=1.47, [1.06;2.04]) and history of recurrent AOM (OR=1.45, [1.02;2.06]). CONCLUSION: Despite PCV7 implementation, AOM remains a very frequent childhood infection and a major reason for ATB prescriptions. PMID- 21531541 TI - [Intrapancreatic duodenal duplication causing acute abdominal symptoms]. PMID- 21531542 TI - Direct electrochemistry and electrocatalysis of hemoglobin in composite film based on ionic liquid and NiO microspheres with different morphologies. AB - Flowerlike, spherical, and walnutlike NiO microspheres were respectively mixed with ionic liquid (IL) to form three stable composite films, which were used to immobilize hemoglobin (Hb) on carbon paste electrodes. Spectroscopic and electrochemical examinations revealed that the three NiO/IL composites were biocompatible matrix for immobilizing Hb, which showed good stability and bioactivity. However, electrochemical studies demonstrated that flowerlike NiO microspheres were far more effective than the other two in adsorbing Hb and facilitating the electron transfer between Hb and underlying electrode, which resulted from its unique flower architecture and large surface area. With advantages of flowerlike NiO and ionic liquid, a pair of stable and well-defined quasi-reversible redox peaks of Hb were obtained with a formal potential of 0.275 V (vs. Ag/AgCl) in pH 7.0 buffer. Meantime, flowerlike NiO modified electrode showed better electrocatalytic activity toward hydrogen peroxide reduction with a high sensitivity (15.7MUAmM(-1)), low detection limit (0.68 MUM) and small apparent Michaelis-Menten constant K(M) (0.18 mM). Flowerlike NiO could be a promising matrix for the fabrication of direct electrochemical biosensors in biomedical analysis. PMID- 21531543 TI - Dopaminergic control of the striatum for high-level cognition. AB - Dopamine has long been implicated in a wide variety of high-level cognitive processes, ranging from working memory to rule learning and attention switching. Notable progress has been made in the past decades, but the mechanisms underlying effects of dopamine on high-level cognition remain unclear. This article reviews evidence for an important role of the striatum and its interaction with the prefrontal cortex and suggests a variety of ways by which changes in dopamine transmission can bias high-level cognition. PMID- 21531544 TI - Multiple representations and algorithms for reinforcement learning in the cortico basal ganglia circuit. AB - Accumulating evidence shows that the neural network of the cerebral cortex and the basal ganglia is critically involved in reinforcement learning. Recent studies found functional heterogeneity within the cortico-basal ganglia circuit, especially in its ventromedial to dorsolateral axis. Here we review computational issues in reinforcement learning and propose a working hypothesis on how multiple reinforcement learning algorithms are implemented in the cortico-basal ganglia circuit using different representations of states, values, and actions. PMID- 21531545 TI - Phenol and phenolics from lignocellulosic biomass by catalytic microwave pyrolysis. AB - Catalytic microwave pyrolysis of biomass using activated carbon was investigated to determine the effects of pyrolytic conditions on the yields of phenol and phenolics. The high concentrations of phenol (38.9%) and phenolics (66.9%) were obtained at the temperature of 589 K, catalyst-to-biomass ratio of 3:1 and retention time of 8 min. The increase of phenol and its derivatives compared to pyrolysis without catalysts has a close relationship with the decomposition of lignin under the performance of activated carbon. The concentration of esters was also increased using activated carbon as a catalyst. The high content of phenols obtained in this study can be used either directly as fuel after upgrading or as feedstock of bio-based phenols for chemical industry. PMID- 21531546 TI - Evaluation of value-added components of dried distiller's grain with solubles from triticale and wheat. AB - This study focused on the detection of value-added co-products in dried distiller's grain plus soluble (DDGS), a possibility that could open new avenues for further processing and marketing of DDGS and improving economic sustainability of ethanol industry. Varieties of triticale, wheat and two benchmarks, CPS wheat and Pioneer Hi-Bred corn, were fermented using two very high gravity (VHG) fermentation approaches: jet-cooking and raw starch processing (STARGEN fermentation). DDGS from STARGEN fermentation could be promising sources of value-added co-products. Pronghorn triticale DDGS (STARGEN fermentation) had the highest concentration of sterols (3.7 mg/g), phenolic compounds (13.61 mg GAE/g), and beta-glucan (2.07%). CDC Ptarmigan DDGS (STARGEN fermentation) had the highest concentration of tocopherols and tocotrienols (107.0 MUg/g), 1.93% of beta-glucan, and 53.0mg/g of fatty acids. AC Reed DDGS (STARGEN method) showed 1.97% of beta-glucan. This study shows that proper choice of fermentation approach and feedstock for ethanol production could improve commercial quality of DDGS. PMID- 21531547 TI - Injection of air into the headspace improves fermentation of phosphoric acid pretreated sugarcane bagasse by Escherichia coli MM170. AB - Microaeration (injecting air into the headspace) improved the fermentation of hemicellulose hydrolysates obtained from the phosphoric acid pretreatment of sugarcane bagasse at 170 degrees C for 10 min. In addition, with 10% slurries of phosphoric acid pretreated bagasse (180 degrees C, 10 min), air injection into the headspace promoted xylose utilization and increased ethanol yields from 0.16 to 0.20 g ethanol/g bagasse dry weight using a liquefaction plus simultaneous saccharification and co-fermentation process (L+SScF). This process was scaled up to 80 L using slurries of acid pretreated bagasse (96 h incubation; 0.6L of air/min into the headspace) with ethanol yields of 312-347 L (82-92 gal) per tone (dry matter), corresponding to 0.25 and 0.27 g/g bagasse (dry weight). Injection of small amounts of air into the headspace may provide a convenient alternative to subsurface sparging that avoids problems of foaming, sparger hygiene, flotation of particulates, and phase separation. PMID- 21531548 TI - Microbial community developments and biomass characteristics in membrane bioreactors under different organic loadings. AB - Microbial community developments and biomass characteristics (concentration, particle size, extracellular polymeric substances (EPS), and membrane fouling propensity) were compared when three MBRs were fed with the synthetic wastewater at different organic loadings. Results showed that the bacterial communities dynamically shifted in different ways and the EPS displayed dissimilar profiles under various organic loadings, which were associated with the ratios of food to microorganism and dissolved oxygen levels in the MBRs. The membrane fouling tendency of biomass in the low-loading MBR (0.57 g COD/L day) was insignificantly different from that in the medium-loading MBR (1.14 g COD/L day), which was apparently lower than that in the high-loading MBR (2.28 g COD/L day). The membrane fouling propensity of biomass was strongly correlated with their bound EPS contents, indicating cake layer fouling (i.e., deposition of microbial flocs) was predominant in membrane fouling at a high flux of 30 L/m(2)h. PMID- 21531549 TI - Biomass adaptation over anaerobic co-digestion of sewage sludge and trapped grease waste. AB - The feasibility of sewage sludge co-digestion using intermediate waste generated inside a wastewater treatment plant, i.e. trapped grease waste from the dissolved air flotation unit, has been assessed in a continuous stirred lab reactor operating at 35 degrees C with a hydraulic retention time of 20 days. Three different periods of co-digestion were carried out as the grease waste dose was increased. When the grease waste addition was 23% of the volatile solids fed (organic loading rate 3.0 kg(COD)m(-3)d(-1)), an increase in methane yield of 138% was reported. Specific activity tests suggested that anaerobic biomass had adapted to the co-substrate. The adapted inoculum showed higher acetoclastic methanogenic and beta-oxidation synthrophic acetogenic activities but lower hydrogenotrophic methanogenic activity. The results indicate that a slow increase in the grease waste dose could be a strategy that favours biomass acclimation to fat-rich co-substrate, increases long chain fatty acid degradation and reduces the latter's inhibitory effect. PMID- 21531551 TI - Effects of flow rate and substrate concentration on the formation and H2 production of photosynthetic bacterial biofilms. AB - Photosynthetic bacteria (PSB), Rhodopseudomonas palustris CQK 01, were immobilized on the surface of a thin glass slide in a lab-scale flat panel photobioreactor under different flow rates and substrate concentrations. The morphology, dry weight and thickness of the mature PSB biofilms were determined to reveal the relationship between biofilm formation and hydrogen production performance. The mature biofilm formed at a low flow rate and a high substrate concentration showed a looser structure, these structures of the mature biofilm then affected the H(2) production performance of the bioreactor during mature stage. The biofilm formed at a flow rate of 228 ml/h and a substrate concentration of 60 mmol/l exhibited the highest dry weight and optimally porous structure, which is beneficial not only for hydrogen removal from the biofilm but also glucose diffusion into the biofilm, thus significantly boosting the photo hydrogen production performance. PMID- 21531550 TI - High level expression and characterization of a novel thermostable, organic solvent tolerant, 1,3-regioselective lipase from Geobacillus sp. strain ARM. AB - The mature ARM lipase gene was cloned into the pTrcHis expression vector and over expressed in Escherichia coli TOP10 host. The optimum lipase expression was obtained after 18 h post induction incubation with 1.0mM IPTG, where the lipase activity was approximately 1623-fold higher than wild type. A rapid, high efficient, one-step purification of the His-tagged recombinant lipase was achieved using immobilized metal affinity chromatography with 63.2% recovery and purification factor of 14.6. The purified lipase was characterized as a high active (7092 U mg(-1)), serine-hydrolase, thermostable, organic solvent tolerant, 1,3-specific lipase with a molecular weight of about 44 kDa. The enzyme was a monomer with disulfide bond(s) in its structure, but was not a metalloenzyme. ARM lipase was active in a broad range of temperature and pH with optimum lipolytic activity at pH 8.0 and 65 degrees C. The enzyme retained 50% residual activity at pH 6.0-7.0, 50 degrees C for more than 150 min. PMID- 21531552 TI - Reduction in time required for synthesis of high specific surface area silica from pyrolyzed rice husk by precipitation at low pH. AB - Porous silica with a high specific surface area (SSA) was prepared from pyrolyzed rice husk (PRH) by adding H(3)PO(4) to sodium silicate solution (SSS) until the pH values of 5.7, 5.0, 4.1 and 3.2 were achieved. The preparation process involved producing SSS from PRH, forming silica-polyethylene glycol (PEG) composites using SSS, H(3)PO(4) and PEG, and calcinating the composites. The required preparation time was below 10h, and the SSA of the sample prepared at pH 3.2 reached 1018 m(2)/g. Decreasing pH significantly increased the amount of PEG incorporated into the silica-PEG composites, and hence more pores were generated in the lower pH sample when the PEG was destroyed by calcination at 500 degrees C. The process developed in this study could lead to more efficient conversion of rice husk into high value-added porous materials that might be used for the adsorption of gas and heavy metal ions. PMID- 21531553 TI - Styrene removal from polluted air in one and two-liquid phase biotrickling filter: steady and transient-state performance and pressure drop control. AB - A Sporothrix variecibatus-inoculated biotrickling filter (BTF) was examined for styrene removal, without and with the addition of silicone oil, at different empty bed residence times. The highest elimination capacities (ECs) were 172.8 (without silicone oil) and 670 g m(-3)h(-1) (with silicone oil), respectively, corresponding to a 4-fold improvement in presence of oil. The addition of silicone oil formed a well-coalesced emulsion of fungi and silicone oil, resulting in filter-bed clogging. Clogging prevention strategies adopted were; (i) lowering the volume ratio of silicone oil from 10% to 2% (v/v), and (ii) periodic increase in trickling rate of the medium from 50 to 190 mL min(-1). During shock-load experiments, the BTF with silicone oil (2% v/v) could withstand high styrene loads, of up to 1900 g m(-3)h(-1), when compared to the BTF without silicone oil (400 g m(-3)h(-1)). PMID- 21531554 TI - Robust in-gel fluorescence detection of mucin-type O-linked glycosylation. AB - Mucin-type O-linked glycosylation is a common post translational modification of cell-surface and secretory pathway proteins and is implicated in vital biological processes as well as human disease. We report here the use of the metabolic chemical reporter GalNAz along with Cu(I)-catalyzed [3+2] azide-alkyne cycloaddition conditions for the robust, in-gel fluorescent visualization of mucin-type O-linked glycoproteins. PMID- 21531555 TI - Rational design of SAM analogues targeting SAM-II riboswitch aptamer. AB - Riboswitches are noncoding RNA elements embedded in 5'-untranslated region of many bacterial mRNAs regulating gene expression in response to essential metabolites. They are unique from other RNA targets because they have evolved to form specific structural receptors for the purpose of binding small molecular metabolites suggesting that structure-based rational drug design approach may be used in designing metabolite mimics targeting riboswitches. We have developed a fluorescence binding assay for SAM-II riboswitch aptamer and identified an S adenosylmethionine (SAM) analogue that selectively binds to SAM-II riboswitch aptamer with comparable binding affinity to its native metabolite using structure based design approach. PMID- 21531556 TI - Synthesis and biological evaluation of 3-alkyl-dihydrotetrabenazine derivatives as vesicular monoamine transporter-2 (VMAT2) ligands. AB - In the search of new probes for in vivo brain imaging of vesicular monoamine transporter type 2 (VMAT2), we have developed an efficient synthesis of a novel series of 3-alkyl-dihydrotetrabenazine (DTBZ) derivatives. The affinity of VMAT2 was evaluated by an in vitro inhibitory binding assay using [(125)I]-iodovinyl TBZ or [(18)F](+)-FP-DTBZ as radioligands in rat striatal tissue homogenates. New DTBZ derivatives exhibited moderate to good binding affinity to VMAT2. Among these new ligands, compound 4b showed the best affinity for VMAT2 (K(i)=5.98 nM) and may be a useful lead compound for future structure-activity studies. PMID- 21531557 TI - Identification of plasmepsin inhibitors as selective anti-malarial agents using ligand based drug design. AB - We describe the application of ligand based virtual screening technologies towards the discovery of novel plasmepsin (PM) inhibitors, a family of malarial parasitic aspartyl proteases. Pharmacophore queries were used to screen vendor libraries in search of active and selective compounds. The virtual hits were biologically assessed for activity and selectivity using whole cell Plasmodium falciparum parasites and on target in PM II, PM IV and the closely related human homologue, Cathepsin D assays. Here we report the virtual screening highlights, structures of the hits and their demonstrated biological activity. PMID- 21531558 TI - Phenolic compounds with NF-kappaB inhibitory effects from the fungus Phellinus baumii. AB - Chemical investigation of the fungus Phellinus baumii has resulted in characterization of five previously undescribed hispidin derivatives, phellibaumins A-E (1-5), as well as two pairs of new non-equivalent epimeric benzyl dihydroflavones, methylphelligrin A (9), epi-methylphelligrin A (10), methylphelligrin B (11), and epi-methylphelligrin B (12), together with five known compounds, interfungin B (6), phelligridin H (7), phelligridimer A (8), phelligrin A (13), and epi-phelligrin A (14). Phellibaumin A (1) was a novel hispidin derivative with a unique 3,4-dihydroxybenzofuran unit. These compounds exhibited NF-kappaB inhibitory activity with IC(50) values of 52.96 MUM (1), 41.40 MUM (2), 52.92 MUM (5), 36.44 MUM (9 and 10), and 22.46 MUM (11 and 12), respectively. PMID- 21531559 TI - Quinazolinedione sulfonamides: a novel class of competitive AMPA receptor antagonists with oral activity. AB - Quinazoline-2,4-diones with a sulfonamide group attached to the N(3) ring atom constitute a novel class of competitive AMPA receptor antagonists. One of the synthesized compounds, 28, shows nanomolar receptor affinity, whereas other examples of the series display oral anticonvulsant activity in animal models. PMID- 21531560 TI - Calpastatin is associated with lymphovascular invasion in breast cancer. AB - Metastasis of breast cancer is a major contributor to mortality. Histological assessment of vascular invasion (VI) provides important prognostic information and demonstrates that VI occurs predominantly via lymphatics in breast cancer. We sought to examine genes and proteins involved in lymphovascular invasion (LVI) to understand the mechanisms of this key disease process. A gene expression array of 91 breast cancer patients was analysed by an Artificial Neural Network (ANN) approach using LVI to supervise the analysis. 89 transcripts were significantly associated (p<0.001) with the presence of LVI. Calpastatin, a specific calpain inhibitor, had the second lowest selection error and was investigated in breast cancer specimens using real-time PCR (n=56) and immunohistochemistry (n=53). Both calpastatin mRNA and protein levels were significantly associated with the presence of LVI (p=0.014 and p=0.025 respectively). The data supports the hypothesis that calpastatin may play a role in regulating the initial metastatic dissemination of breast cancer. PMID- 21531561 TI - Checkpoint mechanisms: the puppet masters of meiotic prophase. AB - The coordinated execution of cell cycle processes during meiosis is essential for the production of viable gametes and fertility. Coordination is particularly important during meiotic prophase, when nuclei undergo a dramatic reorganization that requires the precise choreography of chromosome movements, pairing interactions and DNA double-strand break (DSB) repair. Analysis of the underlying regulatory mechanisms has revealed crucial and widespread roles for DNA-damage checkpoint proteins, not only in cell cycle surveillance, but also in controlling many processes uniquely characteristic of meiosis. The resulting regulatory network uses checkpoint machinery to provide an integral coordinating mechanism during every meiotic division and enables cells to safely maintain an error-prone event such as DSB formation as an essential part of the meiotic program. PMID- 21531562 TI - Quantifying gait impairment in multiple sclerosis using GAITRite technology. AB - This pilot study investigated the validity of the functional ambulatory profile (FAP) score from the GAITRite electronic pathway in persons with multiple sclerosis (PwMS) who had onset of walking impairment. Thirteen PwMS who had Expanded Disability Status Scale (EDSS) scores of 4.0-6.0 performed four trials on GAITRiteTM pathway, and completed a multidimensional walking assessment including performance tests (timed 25 foot walk; T25FW, timed up and go; TUG), self reports of walking ability (Multiple Sclerosis Walking Scale-12; MSWS-12) and function (Late Life Function and Disability Inventory; LL-FDI), and free living walking behavior (accelerometry). The FAP score correlated strongly with neurological disability (EDSS, rho=-0.81), walking performance (T25FW, rho=-0.82; TUG, rho=-0.88) and self-reported walking function (LL-FDI, rho=0.81), and moderately with self-reported walking impairment (MSWS-12, rho=0.49) and free living walking behavior (accelerometry, rho=0.52). This suggests that the FAP score is a valid marker of gait impairment in PwMS who have onset of walking impairment. PMID- 21531563 TI - Age- and sex-related differences for electromyography gaps during daily activity and a discrete task. AB - Temporal patterns of quiescent electromyography termed 'gaps' were investigated in young and old men and women for a discrete task and daily activity. Gaps in women (1.3+/-3.2) and old adults (1.5+/-3.4) were fewer compared with men (4.7+/ 6.7) and young adults (4.6+/-6.9) for the discrete task (p<0.001). Gap duration was shorter for women (0.1+/-0.2s) and old adults (0.1+/-0.3s) compared with men (0.2+/-0.3s) and young adults (0.2+/-0.2s) (p<0.01). For daily activity, gap number was similar with age, but gap duration and percentage of total time occupied by gaps were less in old compared with young adults (50%), and in women compared with men (43%) (p<0.001). Results suggest gap activity is sensitive to type and duration of activity and that old adults and women demonstrate less quiescent electromyography than young adults and men. PMID- 21531564 TI - Two-stepping through time: mammals and viruses. AB - Recent studies have identified ancient virus genomes preserved as fossils within diverse animal genomes. These fossils have led to the revelation that a broad range of mammalian virus families are older and more ubiquitous than previously appreciated. Long-term interactions between viruses and their hosts often develop into genetic arms races where both parties continually jockey for evolutionary dominance. It is difficult to imagine how mammalian hosts have kept pace in the evolutionary race against rapidly evolving viruses over large expanses of time, given their much slower evolutionary rates. However, recent data has begun to reveal the evolutionary strategy of slowly-evolving hosts. We review these data and suggest a modified arms race model where the evolutionary possibilities of viruses are relatively constrained. Such a model could allow more accurate forecasting of virus evolution. PMID- 21531565 TI - The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. AB - The Ras-extracellular signal-regulated kinase (Ras-ERK) and phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) signaling pathways are the chief mechanisms for controlling cell survival, differentiation, proliferation, metabolism, and motility in response to extracellular cues. Components of these pathways were among the first to be discovered when scientists began cloning proto-oncogenes and purifying cellular kinase activities in the 1980s. Ras-ERK and PI3K-mTOR were originally modeled as linear signaling conduits activated by different stimuli, yet even early experiments hinted that they might intersect to regulate each other and co-regulate downstream functions. The extent of this cross-talk and its significance in cancer therapeutics are now becoming clear. PMID- 21531566 TI - Policing starter unit selection of the enterocin type II polyketide synthase by the type II thioesterase EncL. AB - Enterocin is an atypical type II polyketide synthase (PKS) product from the marine actinomycete 'Streptomyces maritimus'. The enterocin biosynthesis gene cluster (enc) codes for proteins involved in the assembly and attachment of the rare benzoate primer that initiates polyketide assembly with the addition of seven malonate molecules and culminates in a Favorskii-like rearrangement of the linear poly-beta-ketone to give its distinctive non-aromatic, caged core structure. Fundamental to enterocin biosynthesis, which utilizes a single acyl carrier protein (ACP), EncC, for both priming with benzoate and elongating with malonate, involves maintaining the correct balance of acyl-EncC substrates for efficient polyketide assembly. Here, we report the characterization of EncL as a type II thioesterase that functions to edit starter unit (mis)priming of EncC. We performed a series of in vivo mutational studies, heterologous expression experiments, in vitro reconstitution studies, and Fourier-transform mass spectrometry-monitored competitive enzyme assays that together support the proposed selective hydrolase activity of EncL toward misprimed acetyl-ACP over benzoyl-ACP to facilitate benzoyl priming of the enterocin PKS complex. While this system resembles the R1128 PKS that also utilizes an editing thioesterase (ZhuC) to purge acetate molecules from its initiation module ACP in favor of alkylacyl groups, the enterocin system is distinct in its usage of a single ACP for both priming and elongating reactions with different substrates. PMID- 21531567 TI - Radiosynthesis of antitumor spliceosome modulators. AB - A set of novel antitumor agents (the sudemycins) has recently been described that are analogs of the natural product FR901464. We report the radiosynthesis of two of these antitumor drug lead compounds, using a three step procedure: (1) ester hydrolysis, (2) Lindlar's catalyst/tritium gas to give a (S,Z)-4-acetoxypent-2 enoic acid derivative, and finally (3) amide bond formation. These labeled analogs are useful in developing a better understanding of the pharmacological properties of this new class of therapeutic lead compounds. PMID- 21531568 TI - Effect of drought and re-watering on fructan metabolism in Vernonia herbacea (Vell.) Rusby. AB - Vernonia herbacea (Vell.) Rusby, a native species from the Brazilian Cerrado, accumulates about 80% of fructans in the rhizophores, the underground reserve organs. Besides their role as reserve, fructans have been recognized as protective compounds against drought. This physiological function attributed to fructans seems consistent with the wide occurrence of these carbohydrates in the cerrado, a biome that undergoes seasonal drought. The aim of this work was to analyze fructan composition and the activities of the enzymes involved in fructan synthesis, sucrose:sucrose 1-frutosyltransferase (1-SST) and fructan:fructan 1 frutosyltransferase (1-FFT), and depolymerization, fructan 1-exohydrolase (1-FEH) in plants submitted to water suppression. The plants were divided into 3 groups receiving 3 treatments: daily watering (control), water suppression for 23 days (WS) and re-watering after 15 days (RW). Samples were taken at the beginning of the experiment (Time 0) and after 3, 7, 11, 15, 17 and 23 days of water suppression. 1-SST and 1-FFT activities increased at the beginning of the water restriction period, coinciding with a decrease in 1-FEH activity, the onset of the reduction in soil water potential and in leaf water potential. Increases in 1 FEH and invertase activities led to a high yield of reducing sugars at the 23rd day after water suppression, and together with 1-FFT, 1-FEH also seemed to act in the redistribution of fructan molecules after re-watering. The increase in reducing sugars and in the fructo-oligo:fructo-polysaccharide ratio were associated to the maintenance of rhizophore turgor. Considering that WS plants showed changes in fructan metabolism that favored water retention and absorption after re-watering, the occurrence of osmotic adjustment mechanisms is suggested, reinforcing the hypothesis of fructans as protective agents against abiotic stresses, such as drought. PMID- 21531569 TI - The impact of deep and moderate body temperatures on end-organ function during hypothermic circulatory arrest. AB - OBJECTIVE: Hypothermic circulatory arrest (HCA) at different temperatures is a protection technique for operations involving the aortic arch. In combination with selective cerebral perfusion, higher arrest temperatures for the remaining body may be permitted. However, the ischaemic/reperfusion injury (I/R) in various organ systems, other than the brain, related to the specific HCA temperature has so far not been evaluated. METHODS: Fourteen pigs were randomly assigned to 60 min of sole HCA at 20 or 30 degrees C temperature, weaned from cardiopulmonary bypass (CPB) and followed 4h after HCA. Besides complex haemodynamic monitoring, laser-Doppler spectrophotometry for measuring capillary blood flow, tissue oxygen saturation and post-capillary venous filling pressures of the bowel was installed. At the end of experiment, organs were perfusion fixated and harvested. RESULTS: During the entire experiment, haemodynamics revealed no differences between the groups. CPB bypass times were 177 +/- 12 min in the 20 degrees C and 158 +/- 11 min in the 30 degrees C group, respectively (p = 0.02). During reperfusion, lactate levels were initially significantly higher in the 30 degrees C animals (p = 0.001) but subsequently declined. Microcirculatory blood flow and velocity in the bowel were significantly reduced during cooling and reperfusion (p < 0.05), but were independent of final HCA temperature. Histological evaluation revealed significantly more oedema formation in the bowel wall of the 30 degrees C animals (p = 0.05). CONCLUSIONS: Higher levels of circulating lactate levels during reperfusion indicate less effective organ protection at 30 than at 20 degrees C after 60 min of HCA. This is further substantiated by histological evidence for a more pronounced oedema inflammatory response within the bowel wall. PMID- 21531570 TI - Photocleavage of avidin by a new pyrenyl probe. AB - In this study, a new small-molecule-based reagent was designed to recognize and bind to specific site in protein. A new pyrenyl probe, d-biotinyl-1(1 pyrene)methylamide (Py-biotin) was designed and synthesized by coupling of d biotin to 1(1-pyrene)methylamine hydrochloride. Binding studies and site-specific photocleavage of avidin by Py-biotin were demonstrated. Binding of Py-biotin to avidin was studied using absorbance and fluorescence spectroscopic techniques. Red shifts of the absorption peak positions of the pyrenyl chromophore followed by hyperchromism were observed upon binding to avidin. The photocleavage of avidin was achieved when a mixture of the protein, Py-biotin, and an electron acceptor, cobalt(III) hexammine trichloride (CoHA), was irradiated at 342nm. No reaction occurred in the absence of the probe, CoHA, or light. N-terminal sequencing of the peptide fragments indicated a cleavage site of avidin between Thr 77 and Val 78. The high specificity of photocleavage may be valuable in targeting specific sites of proteins with small molecules. PMID- 21531571 TI - Sensitivity of Xanthoria parietina to UV-A: role of metabolic modulators. AB - Effects of methyl jasmonate (MeJA), salicylic acid (SA) or 2-aminoindane-2 phosphonic acid (AIP) pre-treatments on the sensitivity of Xanthoria parietina exposed to UV-A were studied. UV decreased chlorophylls and stimulated increase in hydrogen peroxide and superoxide level. Accumulation of soluble phenols and flavonoids increased in response to UV treatment. Metabolic modulators had negligible impact on these UV-induced changes. Within free amino acids, AIP (-UV variant) and SA and MeJA (+UV variants) altered their accumulation. AIP had no effect on the amount of phenylalanine. Benzoic and cinnamic acids were elevated by UV and mainly MeJA influenced their accumulations. Among lichen specific metabolites, vulpinic acid and ergosterol increased while usnic acid and atranorin decreased after exposure to UV; accumulation of parietin was not affected. Applied modulators showed a different effect on these lichen metabolites but biosynthetic pathway-specific trend of alteration was visible. Overall, MeJA showed the most pronounced effect among studied parameters. Accumulation of selected phenolics in response to UV-A seems to be an important feature of Xanthoria tolerance. Present finding in the context of phenolic metabolism in non-vascular plants and with respect to limited data about effect of studied modulators on non-vascular plants are discussed. PMID- 21531572 TI - Optical properties, excitation energy and primary charge transfer in photosystem II: theory meets experiment. AB - In this review we discuss structure-function relationships of the core complex of photosystem II, as uncovered from analysis of optical spectra of the complex and its subunits. Based on descriptions of optical difference spectra including site directed mutagenesis we propose a revision of the multimer model of the symmetrically arranged reaction center pigments, described by an asymmetric exciton Hamiltonian. Evidence is provided for the location of the triplet state, the identity of the primary electron donor, the localization of the cation and the secondary electron transfer pathway in the reaction center. We also discuss the stationary and time-dependent optical properties of the CP43 and CP47 subunits and the excitation energy transfer and trapping-by-charge-transfer kinetics in the core complex. PMID- 21531573 TI - Expanding roles for lipid droplets. PMID- 21531574 TI - Acute administration of recombinant Angiopoietin-1 ameliorates multiple-organ dysfunction syndrome and improves survival in murine sepsis. AB - INTRODUCTION: Endothelial activation leading to vascular barrier breakdown plays an essential role in the pathophysiology of multiple-organ dysfunction syndrome (MODS) in sepsis. Increasing evidence suggests that the function of the vessel protective factor Angiopoietin-1 (Ang-1), a ligand of the endothelial-specific Tie2 receptor, is inhibited by its antagonist Angiopoietin-2 (Ang-2) during sepsis. In order to reverse the effects of the sepsis-induced suppression of Ang 1 and elevation of Ang-2 we aimed to investigate whether an intravenous injection of recombinant human (rh) Ang-1 protects against MODS in murine sepsis. METHODS: Polymicrobiological abdominal sepsis was induced by cecal ligation and puncture (CLP). Mice were treated with either 1 MUg of intravenous rhAng-1 or control buffer immediately after CLP induction and every 8h thereafter. Sham-operated animals served as time-matched controls. RESULTS: Compared to buffer-treated controls, rhAng-1 treated septic mice showed significant improvements in several hematologic and biochemical indicators of MODS. Moreover, rhAng-1 stabilized endothelial barrier function, as evidenced by inhibition of protein leakage from lung capillaries into the alveolar compartment. Histological analysis revealed that rhAng-1 treatment attenuated leukocyte infiltration in lungs and kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression in rhAng-1 treated mice. Finally, the protective effects of rhAng-1 treatment were reflected by an improved survival time in a lethal CLP model. CONCLUSIONS: In a clinically relevant murine sepsis model, intravenous rhAng-1 treatment alone is sufficient to significantly improve a variety of sepsis-associated organ dysfunctions and survival time, most likely by preserving endothelial barrier function. Further studies are needed to pave the road for clinical application of this therapy concept. PMID- 21531575 TI - Percutaneous radiofrequency ablation for pulmonary metastases from hepatocellular carcinoma: results of a multicenter study in Japan. AB - PURPOSE: To retrospectively evaluate technical success, effectiveness, complications, patient survival, and prognostic factors with percutaneous radiofrequency (RF) ablation for pulmonary metastases resulting from hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Thirty-two patients from six institutions were included, with a total of 83 pulmonary metastases treated in 65 sessions. RF ablation was always performed percutaneously with computed tomography (CT) guidance. Primary endpoints were technical success and technique effectiveness. Technique effectiveness was evaluated based on sequential follow up CT images. Secondary study endpoints were complications, patient survival, and determination of prognostic factors. Complications were classified as major or minor. Prognostic factors were determined by analyzing multiple variables with the log-rank test. RESULTS: Technical success rate was 100%. Primary technique effectiveness rates were 92% each at 1, 2, and 3 years. Major and minor complications occurred after 16 (25%) and 23 (35%) of the 65 sessions, respectively. The median follow-up period was 20.5 months. Overall survival rates were 87% at 1 year and 57% each at 2 and 3 years (median and mean survival times, 37.7 mo and 43.2 mo, respectively). Significantly better survival rates were obtained in cases of (i) no viable intrahepatic recurrence (P < .001), (ii) Child Pugh class A disease (P < .001), (iii) absence of liver cirrhosis (P < .001), (iv) absence of hepatitis C virus infection (P = .006), and (v) alpha-fetoprotein level of 10 ng/mL or lower (P = .007) at the time of RF ablation. CONCLUSIONS: RF ablation appears effective, with an acceptable safety profile, in selected patients with pulmonary metastases resulting from HCC. PMID- 21531576 TI - Intravenous tissue plasminogen activator for patients with minor ischemic stroke. AB - BACKGROUND: Patients with minor ischemic stroke (MIS) are frequently excluded from thrombolytic therapy. Denial of therapy to these patients, however, remains controversial. We compared outcomes in patients with MIS who received intravenous (IV) tissue plasminogen activator (t-PA) with those who were not treated. METHODS: We selected adult patients with stroke onset within 3 hours from a prospectively collected stroke registry. MIS was defined as an admission National Institutes of Health Stroke Scale (NIHSS) score <= 5. The primary outcome was a 90-day modified Rankin scale (mRS) score of 0 to 1. Secondary outcomes were a Barthel index (BI) score >= 95 at 90 days, symptomatic intracranial hemorrhage (SICH), and death. Multivariable logistic regression was performed to determine the association between outcomes adjusting for age, history of diabetes, and NIHSS score at admission. Reasons for t-PA exclusion were obtained. RESULTS: We identified 133 patients with MIS; 59 patients received IV t-PA. The NIHSS score (mean +/- SD) at admission was higher in the t-PA treated group (3.4 +/- 1.4 v 1.9 +/- 1.3 in the untreated group; P < .0001). Other baseline characteristics were not significantly different between the 2 groups. At 90 days, 57.6% of patients in the t-PA group and 68.9% of patients in the untreated group had a mRS score of 0 to 1 (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.39-2.2; P = .87). A BI score of 95 to 100 was achieved in 75% of patients in the IV t-PA group versus 78.9% in the untreated group (OR 1.18, 95% CI 0.43-3.23; P = .74). There were 3 deaths (5.1%) in the IV t-PA group and 3 deaths (4.1%) in the control group. CONCLUSIONS: In our sample, patients with MIS treated with IV t-PA have similar outcomes as patients not receiving thrombolysis. A randomized trial or larger observational study is needed confirm or reject these findings. PMID- 21531577 TI - Prognostic factors associated with increased survival in patients with pulmonary arterial hypertension treated with subcutaneous treprostinil in randomized, placebo-controlled trials. AB - BACKGROUND: Because of the challenges associated with conducting large survival studies of patients with pulmonary arterial hypertension (PAH), we analyzed the surrogate markers predictive of long-term survival in a large cohort of patients treated with subcutaneous treprostinil. METHODS: A retrospective review was conducted using data from a total of 811 patients with New York Heart Association Functional Class (NYHA FC) II to IV PAH, who were treated with subcutaneous treprostinil. Patient baseline disease and on-treatment parameters were analyzed by uni- and multivariate analyses for predictive value of 3-year survival with PAH. RESULTS: Among the baseline disease-related factors analyzed, there was a significantly higher risk of death (p < 0.001) associated with connective tissue disease-associated PAH relative to idiopathic PAH (hazard ratio for death [HR] 1.93), NYHA FC IV vs III (HR 2.31), pulmonary vascular resistance index (PVRI) >30 vs <=16 mm Hg/liter/min/m(2) (HR 2.44) and mixed venous oxygen saturation (SVO(2)) <=55% vs >55%. The 6-minute walk distance (6MWD) of <=295 m after 12 weeks of treprostinil treatment was associated with reduced survival at 3 years (58%). A >=20-m increase from baseline in 6MWD was associated with greater survival (80%) vs smaller walk increments (69%; p = 0.039). Treprostinil dose of >=40 ng/kg/min (p < 0.001) and every 10-ng/kg/min dose increase (p = 0.009) resulted in improved long-term survival. In a multivariate analysis, only SVO(2), 6MWD and treprostinil dose were significant on-treatment predictors (p < 0.02) of survival. CONCLUSIONS: Disease etiology, baseline factors (NYHA FC, PVRI and SVO(2)) and on-treatment factors (6MWD, SVO(2) and treprostinil dose) were predictors of survival in this study and may be used to aid in treatment optimization. PMID- 21531578 TI - High-urgency priority heart transplantation in HIV-positive patients on life support: breaking barriers? PMID- 21531579 TI - Osteopontin: a potential biomarker for heart failure and reverse remodeling after left ventricular assist device support. AB - BACKGROUND: Left ventricular assist device (LVAD) support in end-stage heart failure (HF) leads to recovery of the patient's condition, size reduction of cardiomyocytes, and also volume reduction and change in the composition of the extracellular matrix (ECM). Myocardial expression of ECM osteopontin (OPN) protein increases with the severity of HF. We analyzed whether OPN messenger RNA expression in heart tissue and/or OPN protein in plasma are associated with reverse remodeling during LVAD support. METHODS: Plasma and heart tissue specimens of 22 end-stage HF patients before and after LVAD implantation and subsequent heart transplantation (HTx) were used to determine the concentrations of OPN protein (EIA) and OPN messenger RNA (mRNA) by quantitative polymerase chain reaction. Immunohistochemistry (IHC) and in situ hybridization (ISH) were performed to locate OPN protein and mRNA. RESULTS: The high OPN protein levels in plasma of HF patients did not differ significantly before and after LVAD support in ischemic heart disease (IHD) (pre-LVAD 167 +/- 32 ng/ml; post-LVAD 165 +/- 28 ng/ml) and in dilated cardiomyopathy (DCM) (pre-LVAD 99 +/- 12 ng/ml; post-LVAD (142 +/- 6 ng/ml). The OPN plasma levels after HTx decreased to control levels (IHD, 48 +/- 6; DCM, 40 +/- 5; control, 31 +/- 3 ng/ml). In contrast, expression of OPN mRNA in heart biopsy specimens decreased significantly after LVAD support (the relative quantity decreased > 90% in IHD and 50% in DCM). ISH and IHC revealed that OPN was present in cardiomyocytes and in the ECM. CONCLUSIONS: Levels of OPN mRNA in the myocardium of HF patients showed a significant decrease after LVAD support but OPN protein expression did not. LVAD support only induced a decrease of OPN plasma levels in individual patients, whereas OPN plasma levels reduced significantly in all patients after HTx. PMID- 21531580 TI - Qualitative interviews vs standardized self-report questionnaires in assessing quality of life in heart transplant recipients. AB - Quality of life (QoL) studies in heart transplant recipients (HTRs) using validated, quantitative, self-report questionnaires have reported poor QoL in approximately 20% of patients. This consecutive mixed methods study compared self report questionnaires, the Medical Outcomes Study 36-item Short Form Health Survey (MOS SF-36) and the Atkinson Life Satisfaction Scale, with phenomenologically informed audiovisual (AV) qualitative interview data in 27 medically stable HTRs (70% male; age 53 +/- 13.77 years; time since transplant 4.06 +/- 2.42 years). Self-report questionnaire data reported poor QoL and more distress compared with previous studies and normative population samples; in contrast, 52% of HTRs displayed pervasive distress according to visual methodology. Using qualitative methods to assess QoL yields information that would otherwise remain unobserved by the exclusive use of quantitative QOL questionnaires. PMID- 21531581 TI - The influence of synesthesia on eye movements: no synesthetic pop-out in an oculomotor target selection task. AB - Recent research on grapheme-colour synesthesia has focused on whether visual attention is necessary to induce a synesthetic percept. The current study investigated the influence of synesthesia on overt visual attention during an oculomotor target selection task. Chromatic and achromatic stimuli were presented with one target among distractors (e.g. a '2' (target) among multiple '5's (distractors)). Participants executed an eye movement to the target. Synesthetes and controls showed a comparable target selection performance across conditions and a 'pop-out effect' was only seen in the chromatic condition. As a pop-out effect was absent for the synesthetes in the achromatic condition, a synesthetic element appears not to elicit a synesthetic colour, even when it is the target. The synesthetic percepts are not pre-attentively available to distinguish the synesthetic target from synesthetic distractors when elements are presented in the periphery. Synesthesia appears to require full recognition to bind form and colour. PMID- 21531582 TI - Do we conceptualize every color we consciously discriminate? AB - Mandik understands color-consciousness conceptualism to be the view that one deploys in a conscious qualitative state concepts for every color consciously discriminated by that state. Some argue that the experimental evidence that we can consciously discriminate barely distinct hues that are presented together but cannot do so when those hues are presented in short succession suggests that we can consciously discriminate colors that we do not conceptualize. Mandik maintains, however, that this evidence is consistent with our deploying a variety of nondemonstrative concepts for those colors and so does not pose a threat to conceptualism. But even if Mandik has shown that we deploy such concepts in these experimental conditions, there are cases of conscious states that discriminate colors but do not involve concepts of those colors. Mandik's arguments sustain only a theory in the vicinity of conceptualism: The view that we possess concepts for every color we can discriminate consciously, but need not deploy those concepts in every conscious act of color discrimination. PMID- 21531583 TI - Levetiracetam monotherapy--outcomes from an epilepsy clinic. AB - INTRODUCTION: Levetiracetam (LEV) is a broad spectrum antiepileptic drug (AED) with a unique mechanism of action. This retrospective audit explores outcomes in patients commenced on LEV monotherapy at the Epilepsy Unit at the Western Infirmary, Glasgow, Scotland from 1st January 2001 until 30th June 2009. METHODS: LEV monotherapy was started in 228 patients (89 men, 139 women, aged 12-81 years [median 28 years]). Of these, 161 (70.6%) had partial-onset seizures, 59 (25.9%) had idiopathic generalized epilepsies (35 primary generalized tonic-clonic seizures [PGTCS], 20 juvenile myoclonic epilepsy, 4 juvenile absence epilepsy), and 8 (3.5%) had unclassified GTCS. Initial dosing was 250 mg twice daily for 2 weeks, followed by 500 mg twice daily. Patients were reviewed every 6-8 weeks. If required, the LEV dose was titrated in 500 mg increments to a maximum tolerated or effective dose. RESULTS: In total, 112 (49.1%) patients remained seizure-free for >=1 year on a median LEV dose of 1000 mg/day (range 500-3000 mg/day). Patients were more likely to achieve seizure freedom with LEV as a first monotherapy (81 of 149 [54.4%]), as opposed to switching from another AED (31 of 79 [39.2%]; p=0.03). In this latter group, seizure freedom was more likely in those who switched after failing their 1st or 2nd AED (n=39 of 64 [60.9%]), compared to later in the treatment schedule (n=2 of 15 [13.3%]; p=0.029). Patients reporting <5 seizures (70 of 118) prior to starting LEV were more likely to become seizure-free than those with >=5 seizures (42 of 110; p=0.001). Thirty six (15.8%) patients had a >=50% seizure reduction over 1 year; 43 (18.9%) were classified as having a <50% improvement, but elected to continue on LEV. The drug was withdrawn in 37 (16.2%) patients (30 side effects, 7 lack of efficacy). Eighteen (7.9%) patients reported intolerable neuropsychiatric symptoms (7 aggression, 7 mood swings, 2 irritability, 2 depression). Other side effects leading to drug withdrawal included sedation (n=5) and lethargy (n=4). CONCLUSION: Seizure freedom was achieved in around half the patients on a median LEV dose of 1000 mg/day. This was more likely to occur in those taking the drug as first monotherapy, and in those with <5 pre-treatment seizures. Around 50% of those who discontinued LEV due to side effects developed neuropsychiatric symptoms. PMID- 21531584 TI - Overdiagnosis of heparin-induced thrombocytopenia in surgical ICU patients. AB - BACKGROUND: Heparin use in surgical patients places them at increased risk for developing heparin-induced thrombocytopenia (HIT). The false positive rate of HIT using the current standard criteria is unknown in surgical ICU patients, who often have confounding factors that cause thrombocytopenia. STUDY DESIGN: Surgical ICU patients, admitted over a 2-year period with a positive screening test for HIT (platelet factor [PF] 4 >= 0.4 optical density [OD]), were reviewed retrospectively at a single institution. Correlation of the Warkentin 4-T score and commercial heparin PF4 ELISA with serotonin releasing assay (SRA) was performed. Logistic regression was used to determine independent risk factors associated with the development of HIT. RESULTS: PF4 tests were requested in 643 patients based on a clinical suspicion of HIT. Of these, 104 patients had a PF4 result, an SRA value (%), and a 4-T score available. Twenty patients (19%) had true positive HIT, defined as a positive PF4 and positive SRA (SRA >= 20%). Eighty-four patients (81%) were false positive, defined as a positive PF4 and negative SRA. Five of 58 patients with Warkentin score of 0 to 3, and 6 of 14 patients with Warkentin score of 6 to 8 were HIT positive by SRA. CONCLUSIONS: In surgical ICU patients, clinical suspicion for HIT necessitates PF4 and SRA analysis. Testing for HIT or treatment with a direct thrombin inhibitor should not depend on the Warkentin 4-T score alone. Although a PF4 >= 0.4 OD is considered a positive screening test for HIT, a PF4 >= 2.0 OD is preferable in surgical ICU patients. PMID- 21531585 TI - Duplex guided dialysis access interventions can be performed safely in the office setting: techniques and early results. AB - OBJECTIVE: To determine the utility of duplex guided angioplasty for hemodialysis access maturation and maintenance. DESIGN/MATERIALS/METHODS: Between January 2008 and June 2009, 223 office-based duplex-guided hemodialysis access angioplasty procedures were performed in 125 patients. Two hundred eight of the accesses were autogenous. The most common indication for intervention was maturation failure (104 cases). Other indications included pulsatility, low access flow, decreased flow and infiltration. Procedures were performed in the office using topical and local anesthesia. Volume flow (VF) was recorded prior to introducer insertion (baseline) and post intervention. RESULTS: Technical success was achieved in 219 cases (98.2%). Minor complications occurred in 21 cases (9.4%). Immature autogenous AV accesses had a median baseline VF of 210 mL/min. Median final VF for these autogenous AV accesses was 485 mL/min. The VF increased by 131%. Dysfunctional autogenous AV accesses and nonautogenous AV accesses had a median baseline VF of 472 mL/min. Median final VF was 950 mL/min. The VF increased by 101%. CONCLUSIONS: Duplex guided dialysis access angioplasty can be performed safely and effectively in the office setting. It offers the advantage of treating the patient without radiation or contrast as well as the assessment of the hemodynamic effects of intervention. PMID- 21531586 TI - Prevalence and clinical consequences of carotid artery residual defects following endarterectomy: a prospective CT angiography evaluation study. AB - OBJECTIVES: It is still unclear whether residual defects seen after carotid endarterectomy (CEA) have clinical consequences. We investigated prevalence of residual defects in the carotid artery and their possible impact on clinical and Duplex ultrasound (DUS) follow-up. MATERIALS AND METHODS: Sixty-five patients who had undergone CEA were prospectively examined with 1-3 month postoperative computed tomographic angiography (CTA), clinical and DUS follow-up. Defects in common (CCA), external (ECA) and internal carotid artery (ICA) were scored as clamp marks, intimal step or flap, mural thrombus, kink, microdehiscence suture or residual stenosis. RESULTS: Fifty-eight patients (89.2%) had residual defects in CCA, ECA or ICA (143 defects). Intimal steps (n = 39) and residual stenosis (n = 17) were most noted defects. Only residual defects in ECA were significantly associated with significant higher PSV values both at short-term and long-term follow-up (1990 vs. 1400 mm s(-1) at 1 year and 2000 vs. 1230 mm s(-1) at 2 years, P-values 0.031 and 0.016). CONCLUSION: Carotid artery residual defects on CTA after CEA are very common, simple fingerprints of the operative procedure, have no clear consequence. When CTA is performed clinically after CEA, knowledge of high prevalence and type of defects detected on CTA may be of importance for radiologists and clinicians. PMID- 21531587 TI - In vivo biological effects of foam sclerotherapy. AB - OBJECTIVES: This study aims to assess by biological markers the in vivo consequences of foam sclerotherapy (FS) of saphenous veins. The secondary objective of this randomised controlled trial (RCT) is to compare results of two randomised groups: with or without post-treatment compression. PATIENTS AND METHODS: Forty patients with incompetent great or small saphenous veins underwent ultrasound-guided FS. Randomisation was conducted immediately after sclerotherapy to two parallel groups, one (CG) with compression stockings and the other (WCG) without compression. A laboratory work-up was done on days 0 (before sclerotherapy), 1, 7, 14 and 28. The studied markers were: fibrinogen, factor VIII, thrombomodulin, thrombin-antithrombin complex, D-dimers, platelet factor 4 and troponin. RESULTS: General data repartition was homogenous for CG and WCG. Twenty patients were included in each group (females 90%; mean age 58 years). On day 28 (D28), the occlusion rate of the veins was 100% in both groups. In all the samples (D0-D28), apart from a moderate D-dimers' increase at D1-D14, no significant biological change was observed in either the WCG or the CG groups. CONCLUSION: In terms of inflammation and coagulation, FS seems to have a minimal effect on peripheral blood, either with or without post-treatment compression and does not appear to have an effect on the myocardial risk. PMID- 21531588 TI - Air versus physiological gas for ultrasound guided foam sclerotherapy treatment of varicose veins. AB - OBJECTIVES: We have used ultrasound guided foam sclerotherapy (UGFS) to treat varicose veins in 2029 limbs since 2006. In 2009 we introduced physiological gas (30% O2 and 70% CO2) for making foam with sodium tetradecyl sulphate (Fibrovein, STD Pharmaceutical Products Ltd, Hereford UK) instead of air. The aim of this study was to compare our early experience of UFGS using CO2/O2 with our prior experience using air. METHODS: Data were collected in a prospectively maintained database. In this series 470 limbs were treated with UGFS and followed up at 6 weeks with clinical and duplex ultrasound assessment. The 235 consecutive limbs undergoing UGFS immediately before and the 235 after the introduction of CO2/O2 were selected for comparison. RESULTS: The age, gender and CEAP classifications for the two groups were not significantly different. 73% were primary veins and 70% great saphenous, with no differences between the groups. Transient neurological events are rare in our experience (0.7%) with only one visual disturbance occurring in this series. There was a significant reduction in the incidence of skin staining in the CO2/O2 (7.2% vs 3.3%, p = 0.02, chi2 test) as compared to the air treated group, but no difference in the incidence of thrombophlebitis. The total volume of foam injected was similar in both groups but use of CO2/O2 foam was associated with a significant improvement in the truncal occlusion rate, from 86% to 91% (p < 0.05, chi2 test). CONCLUSION: UGFS with CO2/O2 instead of air was associated with a slightly increased saphenous truncal occlusion rate and reduced the incidence of skin staining without increasing thrombophlebitis in this clinical series. We observed only one transient neurological event in this series so could not evaluate the effect of CO2/O2 foam in reducing these events. PMID- 21531589 TI - Validation of the chronic venous insufficiency quality of life questionnaire in Dutch patients treated for varicose veins. AB - BACKGROUND: The Chronic Venous Insufficiency Quality of Life Questionnaire (CIVIQ) is a disease-specific instrument to measure the impact of chronic venous insufficiency (CVI) on patients' lives. The objective of this study is to test the psychometric properties of the CIVIQ, and to validate the use of the questionnaire translated into the Dutch language. METHODS: A standardised questionnaire, including CIVIQ and Short Form (36) Health Survey (SF-36), was obtained before and 1 month after treatment to all new patients with varicose veins. The feasibility was tested by missing responses and response distribution. CIVIQ scores were compared to the SF-36 scores and between different levels of severity of varicose veins. The CIVIQ's reliability was assessed using Cronbach's alpha and test-retest reliability. The structure was studied using factor analysis. The scores before and after therapy were compared to assess responsiveness. RESULTS: There was a response rate of 93.5%. None of 20 items missed < 10% of responses, but three showed ceiling effect. The CIVIQ correlated well with the physical and moderately with the mental MCS of the SF-36, suggesting a good construct validity of the CIVIQ. The median CIVIQ scores increased significantly with the severity of varicose veins. The CIVIQ showed an excellent internal consistency and an excellent test-retest reliability. The CIVIQ score decreased in 76% of patients after treatment. The results were in accordance with the Norman's rule and showed a median effect size. CONCLUSION: This study confirms the feasibility, validity, reliability and responsiveness of the CIVIQ in patients with varicose veins. The psychometric properties of the Dutch CIVIQ were comparable to the original French version. PMID- 21531590 TI - Comments regarding 'Surgical treatment of patients with congenital vascular malformation-associated aneurysms'. PMID- 21531591 TI - Simplifying post-EVAR surveillance. PMID- 21531592 TI - Comments regarding 'Walking performance and health-related quality of life after surgical or endovascular invasive versus non-invasive treatment for intermittent claudication--a prospective randomised trial'. PMID- 21531593 TI - Patency of direct revascularisation of the hypogastric arteries in patients with aortoiliac occlusive disease. AB - OBJECTIVES: Various indications for internal iliac artery (IIA) revascularisation have been reported. Revascularisations for gluteal ischaemia and buttock claudication remain controversial and uncommon. The objective of the study was to assess the patency of direct conventional revascularisations (CRs) of the IIA in patients with aortoiliac occlusive disease because few studies have focussed on this specific topic. MATERIALS AND METHODS: The charts of all patients who underwent CR of the IIA, between August 2000 and January 2009, were retrospectively reviewed. We recorded for each patient preoperative vascular work up. All patients were tested for patency on January 2009. A computed tomography (CT) scan was requested if the duplex scan casts any doubt with regard to patency. If non-patent, the last date for confirmed patency was kept for the analysis. Functional outcomes at the proximal level were also collected. RESULTS: We studied 40 patients with occlusive disease. Buttock claudication was observed in 27 patients (66%), including eight (20%) in whom these symptoms were isolated. The 13 other patients had distal claudication or rest pain and documented proximal ischaemia, justifying the IIA revascularisations. We performed 44 conventional direct revascularisations of the IIA concomitant to aorto- or iliofemoral bypasses in these patients. The overall postoperative patency rate was 89%. Five early occlusions of the IIA remained asymptomatic. The median duration of follow-up was 39 months (3-86 months). The survival rate was 95% at 1 year and 86% at 5 years. The primary patency rate of the IIA was 89% at 1 year and 72.5% at 5 years. Buttock claudication disappeared in 23 of the 27 patients (85%), who were symptomatic at the proximal level prior to surgery. CONCLUSION: Direct IIA concomitant revascularisation has an acceptable patency rate in patients undergoing aorto- or iliofemoral bypasses for occlusive disease. When feasible, this technique appears to be safe for the treatment and prevention of buttock claudication. PMID- 21531595 TI - The effects of dentin debris on the cyclic fatigue resistance of several nickel titanium rotary systems. AB - OBJECTIVE: The aim of this study was to compare the effects of impacted dentin debris on the cyclic fatigue resistance of a traditional ground file, an electropolished file, and a thermally treated twisted file. STUDY DESIGN: One hundred thirty-five files were rotated against bovine dentin or a highly polished surface at the manufacturers' recommended rotation speed with a continuous 5-mm axial movement of 1 cycle per second. The files were equally divided into 3 groups: group 1, contacting dentin for 500 cycles and then metal to failure; group 2, contacting metal only to failure; group 3, contacting dentin only to failure. Cycles to failure were analyzed using analysis of variance (P < .05). RESULTS: K3 and Twisted Files outperformed EndoSequence files in the dentin-only group. No difference was found between the metal and dentin-metal groups. CONCLUSIONS: In the presence of dentin, the electropolished surface of the EndoSequence NiTi rotary files did not increase the files' cyclic fatigue resistance compared with K3 or Twisted Files of the same tip size and taper. PMID- 21531596 TI - A case of synovial chondromatosis of the temporomandibular joint followed for 17 years. AB - The patient was a 52-year-old woman who visited our hospital for the chief complaint of a strange sensation in the left temporomandibular joint region on February 22, 1992. On the first examination, crepitus was heard, but no disturbance of mouth opening was noted. On panoramic radiography, radiopaque bodies were present in the left temporomandibular joint region, diagnosed as synovial chondromatosis. Course observation without active treatment was selected. Calcified bodies were noted on the lateral side directly below the left temporomandibular articular tubercle on the first computed tomography image performed in December 1998. Reportedly, this lesion grows slowly, but the lesions started to enlarge at a specific time point during the 17-year follow-up in this patient, showing the necessity of long-term follow-up by imaging even though no quality-of-life reduction or subjective symptom is observed. PMID- 21531597 TI - ERBB2 gene amplification in oral squamous cell malignancies: a correlation with tumor progression and gene expression. AB - OBJECTIVES: Chromosomal instability is hallmark of carcinoma. Amplification of chromosome 17q11-q12 is present in some oral squamous cell cancer (OSCC) cases. In this study, we investigated the copy number variations of ERBB2 gene, which is located at this locus in collected OSCC samples and their correlation with tumor progression and gene expression. STUDY DESIGN: Quantitative real-time polymerase chain reaction was performed to detect the copy number of ERBB2 gene and the mRNA expression in 92 OSCC samples with matched adjacent normal tissues (ANTs). Proportional odds regression and 2-way repeated measurement analysis of variance were used to analyze the association between copy number variations and mRNA expression of the targeted gene. RESULTS: Copy number gains of ERBB2 were detected in some of the OSCCs (19.6%, 18/92) and correlated with tumor stage (P < .001). Copy number gains of ERBB2 also showed a positive correlation with mRNA overexpression in OSCCs (P < .001). However, enhanced ERBB2 mRNA expression was also detected in a group of OSCC samples with unaltered copy number of ERBB2 gene (P < .05). CONCLUSIONS: Copy number increase of ERBB2 is observed in OSCCs and correlates with gene overexpression in these tumors. In addition, overexpression of ERBB2 is also observed in some OSCCs that lack copy number changes, indicating involvement of another mechanism. PMID- 21531598 TI - Antibacterial efficacy of endodontic irrigating solutions and their combinations in root canals contaminated with Enterococcus faecalis. AB - OBJECTIVE: The objective of this study was to evaluate the antibacterial efficacy of irrigating solutions and their combinations against Enterococcus faecalis. STUDY DESIGN: One hundred ten single-rooted human teeth were inoculated with E. faecalis and incubated for 21 days. Teeth were divided according to the irrigant: Group I (GI), 2.5% sodium hypochlorite solution (NaOCl); GII, 2.5% NaOCl + 10% citric acid; GIII, 2.5% NaOCl + apple cider vinegar; GIV, apple cider vinegar; GV, 2% chlorhexidine solution; GVI, 1% peracetic acid; GVII, saline solution. Microbiological samples were taken after root canal preparation and 7 days later. Data were submitted to ANOVA (5%). RESULTS: All solutions promoted reduction of E. faecalis after instrumentation, but bacterial counts were higher in the final sample. GI, GV, and GVI had lower bacterial counts than the other groups. CONCLUSIONS: The irrigating solutions may present activity but do not eradicate E. faecalis in the root canal system. PMID- 21531599 TI - Micrometer scale resolution of materials by stray-field Magnetic Resonance Imaging. AB - As Magnetic Resonance Imaging devices are becoming more and more powerful, resolutions as small as 10 MUm can now be obtained. But, this is only possible when systems with slow transverse relaxation rates, like living tissues, are investigated. In this case, the time available for gradients space-encoding is long, and high k values can be reached in the Fourier domain. However, numerous materials have fast relaxation rates, thus limiting the spatial resolution to a few hundreds of microns. The Stray Field Imaging technique has solved this problem by using a very high (typically 5000 G/cm) static gradient. Consequently, the trajectory in k space is accelerated and it is possible, in principle, to reach a micrometer resolution in a few hundreds of microseconds. Most of the time, however, only resolutions in the millimeter range can be achieved due to mispositioning of the sample within the static magnetic field. Here, we show that by finely mapping the magnetic field and precisely positioning the sample, it is possible with a standard spectrometer to reach a micrometer resolution even on very fast relaxing materials. PMID- 21531600 TI - Relationship of adiponectin to endogenous GH pulse secretion parameters in response to stimulation with a growth hormone releasing factor. AB - OBJECTIVE: Obesity is associated with both reduced growth hormone (GH) and adiponectin. However, the relationship between adiponectin and parameters of endogenous GH secretion remains unknown. The aim of this study was to determine the relationship between total and high molecular weight (HMW) adiponectin and parameters of endogenous pulsatile GH secretion and the effects of tesamorelin, a synthetic GH releasing hormone (GHRH(1-44)), on total and HMW adiponectin. DESIGN: A 2-week interventional study with tesamorelin was conducted at an academic medical center in 13 men with BMI 20-35 kg/m(2). Overnight frequent blood sampling and measurement of total and HMW adiponectin at baseline and after treatment were performed to assess the effects of augmenting endogenous pulsatile GH secretion. RESULTS: Total, but not HMW, adiponectin was positively associated with log(10)Peak GH area (r=+0.73; P=0.005), basal GH secretion (r=+0.67; P=0.01), and total GH production (r=+0.57; P=0.04), but was not associated with the number of secretion events (P=0.85). Two-week treatment with tesamorelin increased endogenous GH release and IGF-1, but neither total (change -0.16+/ 0.64; P=0.40), nor HMW (change +0.03+/-0.70; P=0.87) adiponectin changed significantly with treatment. Sub-analyses in overweight and obese men yielded similar results. CONCLUSIONS: Our study demonstrates a strong relationship between specific parameters of endogenous GH pulsatility and adiponectin. However, short-term augmentation of GH pulsatility over 2-weeks does not change adiponectin. Therefore, the relationship between GH and adiponectin is most likely mediated by specific covariates related to adiposity or other factors. PMID- 21531602 TI - [Reflexivity: a critical issue in qualitative research]. AB - Reflexivity is an English term that Spanish speaking people have to assign a technical meaning. Reflexivity expresses the conscience of researchers conscience and refers to their connection with the study's situation. It is a process by which researchers step back to critically exam the effect they have on the study and the impact of their interactions with participants. The reflexive process is embedded in all research levels and is present in all the research phases, from the research question to fieldwork, from data analysis to writing the final report. Nevertheless, the question is not so much to engage in reflective activities but to be a reflexive researcher. Reflexivity is a human ability that is present during social interactions. For this reason it is present in qualitative research. A self inquirer can be addressed as it is constructed by the relationships and interactions that are established with study participants. Reflexivity has an educational character that continues after the study is completed. PMID- 21531601 TI - Clotrimazole disrupts glycolysis in human breast cancer without affecting non tumoral tissues. AB - Human breast cancer tissues, as well as normal tissues from the same patients, were treated with clotrimazole (CTZ) and have their capacities for glucose consumption and lactate production evaluated. This treatment strongly decreased the lactate production rate by tumor tissues (85% inhibition) without affecting the other measurements made, i.e. lactate production by control tissues or glucose consumption by both, control and tumor tissues. This result directly correlates with the inhibition promoted by CTZ on the activity of the major regulatory glycolytic enzyme 6-phosphofructo-1-kinase (PFK) that was observed in tumor tissues (84% inhibition) but not in control tissues. Fractionation of the tissues revealed that this inhibition does not occur in the soluble fraction of the enzyme, but is exclusive of a particulate fraction. It has been previously shown that the particulate fraction of PFK activity in tumors is associated to actin filaments (f-actin). Thus, we investigated whether CTZ would affect the association between PFK and f-actin and we found that the drug directly induces the dissociation of the two proteins in the same extent that it inhibits lactate production, total PFK activity and the particulate PFK activity. We concluded that CTZ disrupts glycolysis on human breast tumor tissues, inhibiting PFK activity by dissociating the enzyme from f-actin. PMID- 21531603 TI - [Fear of death among nursing students]. AB - OBJECTIVE: To assess, using a sample of nursing students, the fear of their own death and that of others and its relationship with several sociodemographic variables: gender, age, academic year, geographical origin, marital status and previous experiences with death. METHODS: An observational, descriptive and cross sectional study including 243 nursing students who completed a questionnaire containing the sociodemographic variables and the Spanish version of the Collet Lester's Fear of Death Scale (CLFDS). Means and standard deviations, Student t test, ANOVA and Pearson and Spearman correlation coefficients, were calculated in the statistical analysis. RESULTS: A negative correlation was obtained between the CLFDS and age. Women scored higher on the four subscales of the CLFDS. Religious belief and practice were negatively correlated with fear of own death. Previous experiences with death are negatively correlated with three subscales of the CLFDS. Single nursing students scored higher on two subscales of the CLFDS. Statistical significance with the academic year was observed in the subscale of fear of others' death. CONCLUSIONS: To plan the training of nursing students based on specific competences on caring at the end of life, it is very important to understand the students' attitudes toward death. It is also important to understand the related variables, as well as the elements that trigger more fear or anxiety in the students, which can affect the quality of care they provide in their future professional practice. PMID- 21531604 TI - Using distraction forces to drive an autodistractor during limb lengthening. AB - Distraction osteogenesis can result in high forces developing in the limb. To determine and control the distraction forces (DF), a motorized distractor driven by feedback from DF was developed and used to lengthen the tibiae of 6 sheep undergoing distraction osteogenesis. The forces were measured continually, and, in 4 of the sheep, a force threshold was set, above which an increase in rate was initiated. The rate kept increasing to a set limit if forces remained above the threshold; otherwise, the rate was decreased. Radiographs were acquired biweekly, and muscle samples were analyzed from both the operated and contralateral limbs upon termination of the experiment. Results demonstrated a drop in DF associated with increased lengthening rate, attributed to separation of the callus as indicated by radiography. Histological evidence of muscle damage generally correlated with higher DF levels. There was a significant decrease in muscle fiber diameter in lengthened relative to contralateral limbs. Collectively, the results demonstrated the use of a force-driven distraction system and support the need for considering force data in regulating distraction rates to achieve optimal clinical outcomes. PMID- 21531605 TI - A new device and method for measuring the elastic modulus of single trabeculae. AB - The smallest functional unit of cancellous bone is the single trabecula. To investigate its influence at the macroscopic level, a mechanical characterization is required. The aim of this work is to present a new procedure for measuring the elastic behavior of a single trabecula, assumed as an isotropic material, by means of a bending protocol. Our experimental setup permits the measurement of the bending force and deflection of a single trabecula within the natural network. The exact geometry of the trabecula is attained by using a laser scanning microscopy of the labeled sample and subsequently using it as the input for FE simulation. The results between the FE analysis and experimental data are compared in order to determine an isotropic elastic modulus of the trabecula. The system uncertainty has been estimated using the propagation of uncertainty method based on the analytical bending function for a fixed beam. Variables are force, deflection, radius and length and their relative uncertainties. It results in a total uncertainty of 13%, dominated by the influence of radius uncertainty, which is related to the exact determination of the real geometry of the trabecula. The system has been subsequently validated using samples with known geometry and elastic modulus. Finally, the proposed new method consists of sample preparation, a newly designed sample positioning system, an experimental bending test on a single trabecula within the trabecular network, labeling of the bone with a fluorescent marker, 3D imaging of the trabecula and FE analysis of the bending test. PMID- 21531606 TI - Ongoing challenges to finding people with Parkinson's disease for epidemiological studies: a comparison of population-level case ascertainment methods. AB - BACKGROUND: Locating Parkinson's disease cases for epidemiological studies has long been challenging. Self reports, secondary records of physician diagnosis and drug tracer methods each exhibit known disadvantages but have rarely been compared directly. Prescriptions of levodopa have in some studies been considered to comprise a reasonable proxy for Parkinson's disease diagnosis. We tested this assumption by comparing three methods of population-level case ascertainment. DESIGN: We compared the number of Parkinson's disease cases in British Columbia derived from self-reports in the 2001 Canadian Community Health Survey to those obtained from administrative records of filled levodopa prescriptions and to Parkinson's disease diagnoses from physician visit billing and hospital discharge records in 1996 and 2005. We directly compared a case definition based on levodopa prescriptions with a definition based on records of physician diagnosis by calculating positive predictive value and sensitivity. RESULTS: Crude prevalence estimates ranged from approximately 100 to 200 per 100,000. Levodopa based case definitions overestimated prevalence, while physician- and hospital record-based case definitions provided lower prevalence estimates compared to survey derived estimates. The proportion of levodopa users with a diagnosis of Parkinson's disease declined from 62% to 52% between 1996 and 2005. This decrease was most dramatic among women (64%-44%) and those under age 65 (54%-39%). CONCLUSIONS: Sex and age trends suggest increasing use of levodopa among patients with conditions other than Parkinson's disease, such as restless legs syndrome. Increased non-Parkinson's levodopa use decreases the efficiency of levodopa as a Parkinson's disease case tracer. PMID- 21531608 TI - Exceptional virion release mechanism: one more surprise from archaeal viruses. AB - Virion release from the host cell is the final and essential step for completion of the viral life cycle and spread of virions in the environment. Although for eukaryotic and bacterial viruses the egress mechanisms are reasonably well understood, this subject has not been studied in detail for archaeal viruses until recently. Here we summarize available data on the extraordinary egress mechanism exploited by the Sulfolobus islandicus rod-shaped virus SIRV2 and the Sulfolobus turreted icosahedral virus STIV. In addition, we describe features of the virus-induced pyramidal formation, VAP, involved in this process. Being an autonomous structure different from the capsid, the VAP can be considered as a representative of a specific class of virus-coded structures which we suggest to name 'virodomes'. PMID- 21531607 TI - CRISPR-based adaptive immune systems. AB - CRISPR-Cas systems are recently discovered, RNA-based immune systems that control invasions of viruses and plasmids in archaea and bacteria. Prokaryotes with CRISPR-Cas immune systems capture short invader sequences within the CRISPR loci in their genomes, and small RNAs produced from the CRISPR loci (CRISPR (cr)RNAs) guide Cas proteins to recognize and degrade (or otherwise silence) the invading nucleic acids. There are multiple variations of the pathway found among prokaryotes, each mediated by largely distinct components and mechanisms that we are only beginning to delineate. Here we will review our current understanding of the remarkable CRISPR-Cas pathways with particular attention to studies relevant to systems found in the archaea. PMID- 21531609 TI - Microbial diversity of cellulose hydrolysis. AB - Enzymatic hydrolysis of cellulose by microorganisms is a key step in the global carbon cycle. Despite its abundance only a small percentage of microorganisms can degrade cellulose, probably because it is present in recalcitrant cell walls. There are at least five distinct mechanisms used by different microorganisms to degrade cellulose all of which involve cellulases. Cellulolytic organisms and cellulases are extremely diverse possibly because their natural substrates, plant cell walls, are very diverse. At this time the microbial ecology of cellulose degradation in any environment is still not clearly understood even though there is a great deal of information available about the bovine rumen. Two major problems that limit our understanding of this area are the vast diversity of organisms present in most cellulose degrading environments and the inability to culture most of them. PMID- 21531610 TI - Vibrationally selective radiative and non-radiative transitions in gaseous hydrogen molecules. AB - An efficient vibrationally selective technique to build-up the v"=1 vibrational levels in gaseous hydrogen is demonstrated using stimulated Raman pumping (SRP). Both photo-acoustic Raman spectroscopy (PARS) and coherent anti-Stokes Raman spectroscopy (CARS) are used to study non-radiative and radiative (v"=0 and v"=1) transitions in gaseous H(2) molecules. The population fraction in the v"=1 vibrational level has been estimated using combined photo-acoustic and coherent anti-Stokes Raman spectroscopy with stimulated Raman pumping. PMID- 21531611 TI - Raman spectroscopic analysis of real samples: Brazilian bauxite mineralogy. AB - In this investigation, Raman spectroscopy with 1064 and 632.8 nm excitation was used to investigate real mineral samples of bauxite ore from mines of Northern Brazil, together with Raman mapping and X-rays diffraction. The obtained results show clearly that the use of microRaman spectroscopy is a powerful tool for the identification of all the minerals usually found in bauxites: gibbsite, kaolinite, goethite, hematite, anatase and quartz. Bulk samples can also be analysed, and FT-Raman is more adequate due to better signal-to-noise ratio and representativity, although not efficient for kaolinite. The identification of fingerprinting vibrations for all the minerals allows the acquisition of Raman based chemical maps, potentially powerful tools for process mineralogy applied to bauxite ores. PMID- 21531612 TI - Investigation of chemically modified barium titanate beads as surface-enhanced Raman scattering (SERS) active substrates for the detection of benzene thiol, 1,2 benzene dithiol, and rhodamine 6G. AB - SERS active surfaces were prepared by depositing silver films using Tollen's reaction on to barium titanate beads. The SERS activity of the resulting surfaces was probed using two thiols (benzene thiol and 1,2-benzene dithiol) and rhodamine 6G. The intensity of the SERS signal for the three analytes was investigated as a function of silver deposition time. The results indicate that the SERS intensity increased with increasing thickness of the silver film until a maximum signal intensity was achieved; additional silver deposition resulted in a decrease in the SERS intensity for all of the studied molecules. SEM measurement of the Ag coated barium titanate beads, as a function of silver deposition time, indicate that maximum SERS intensity corresponded with the formation of atomic scale islands of silver nanoparticles. Complete silver coverage of the beads resulted in a decreased SERS signal and the most intense SERS signals were observed at deposition times of 30 min for the thiols and 20 min for rhodamine 6G. PMID- 21531613 TI - In situ synthesis, photometric and spectroscopic studies of chelating system during the 1,4,7,10,13,16-hexaoxacyclooctadecane charge transfer reaction with different acceptors. AB - Electron donor acceptor complexes (EDA) of the 1,4,7,10,13,16 hexaoxacyclooctadecane (18-crown-6) as a rich donor were spectrophotometrically discussed and synthesized in solid form according the interactions with different nine of usual pi-acceptors like 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (p-chloranil; p-CHL), tetrachloro-1,2-benzoquinone (o-chloranil; o-CHL), 2,3 dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), tetracyanoquinodimethane (TCNQ), 2,6 dichloroquinone-4-chloroimide (DCQ), 2,6-dibromoquinone-4-chloroimide (DBQ), 2,5 dichloro-3,6-dihydroxy-1,4-benzoquinone (chloranilic acid; CLA), N bromosuccinimide (NBS), 2,4,6-trinitrophenol (picric acid; PA). Spectroscopic and physical data such as formation constant (K(CT)), molar extinction coefficient (E(CT)), standard free energy (DeltaG degrees ), oscillator strength (f), transition dipole moment (MU), resonance energy (R(N)) and ionization potential (I(p)) were estimated in chloroform or methanol at 25 degrees C. Based on the elemental analysis and photometric titrations the CT-complexes were formed indicated the formation of 1:1 charge-transfer complexes for the o-CHL, TCNQ, DCQ, DBQ and NBS acceptors but 1:3 ratio for p-CHL, DDQ, CLA and PA, respectively. The charge-transfer interactions were interpretative according to the formation of dative ion pairs [18C6(*+), A(*-)], where A is acceptor. All of the resulting charge transfer complexes were isolated in amorphous form and the complexes formations on IR and (1)H NMR spectra were discussed. PMID- 21531614 TI - Quantitative surface enhanced Raman scattering detection based on the "sandwich" structure substrate. AB - A sandwich structured substrate was designed for quantitative molecular detection using surface enhanced Raman scattering (SERS), in which the probe molecule was sandwiched between silver nanoparticles (SNPs) and silver nanoarrays. The SNPs was prepared using Lee-Meisel method, and the silver nanoarrays was fabricated on porous anodic aluminum oxide (AAO) using electrodepositing method. The SERS studies show that the sandwich structured substrate exhibits good stability and reproducibility, and the detection sensitivity of Rhodamine 6G (R6G) and Melamine can respectively reach up to 10(-19) M and 10(-9) M, which is improved greatly as compared to other SERS substrates. The improved SERS sensitivity is closely associated with the stronger electromagnetic field enhancement, which stems from localized surface plasmon (LSP) coupling between the two silver nanostructures. Furthermore, the SERS intensity increased almost linearly as the mother concentration increased, which indicates that such a sandwich structure may be used as a good SERS substrate for quantitative analysis. PMID- 21531615 TI - Near-infrared and mid-infrared investigations of Na-dodecylbenzenesulfate intercalated into hydrocalumite chloride (CaAl-LDH-Cl). AB - Hydrocalumite (CaAl-LDH-Cl) belongs to layered double hydroxides (LDHs). The intercalation of Na-dodecylbenzenesulfate (SDBS) into CaAl-LDH-Cl has been investigated by X-ray diffraction (XRD), mid-infrared (MIR) spectroscopy and near infrared (NIR) spectroscopy. The mid-infrared spectra indicated that SDBS could be intercalated into CaAl-LDH-Cl, with the same lattice structure to that of CaAl LDH-Cl, and the interlayer distance of resultant product was expanded to 2.78 nm as confirmed by XRD. The near-infrared spectra (9200-4000 cm(-1)) showed that a special spectral range from 6200 to 5600 cm(-1) and prominent bands of CaAl-LDH Cl intercalated with SDBS around 8300 cm(-1). This band was assigned to the second overtone of the first fundamental of C-H stretching vibrations of SDBS, and can be used to determinate the result of CaAl-LDH-Cl modified by anionic surfactants. The bands of water stretching vibrations and -OH groups shifted to higher wavenumbers when CaAl-LDH-Cl was intercalated by SDBS, and their intensity of MIR and NIR spectra became lower in intensity. PMID- 21531616 TI - EPR and photoluminescence studies of ZnO:Mn nanophosphors prepared by solution combustion route. AB - Nanocrystalline ZnO:Mn (0.1 mol%) phosphors have been successfully prepared by self propagating, gas producing solution combustion method. The powder X-ray diffraction of as-formed ZnO:Mn sample shows, hexagonal wurtzite phase with particle size of ~40 nm. For Mn doped ZnO, the lattice parameters and volume of unit cell (a=3.23065 A, c=5.27563 A and V=47.684 (A)(3)) are found to be greater than that of undoped ZnO (a=3.19993 A, c=5.22546 A and V=46.336 (A)(3)). The SEM micrographs reveal that besides the spherical crystals, the powders also contained several voids and pores. The TEM photograph also shows the particles are approximately spherical in nature. The FTIR spectrum shows two peaks at ~3428 and 1598 cm(-1) which are attributed to O-H stretching and H-O-H bending vibration. The PL spectra of ZnO:Mn indicate a strong green emission peak at 526 nm and a weak red emission at 636 nm corresponding to (4)T(1)->(6)A(1) transition of Mn(2+) ions. The EPR spectrum exhibits fine structure transition which will be split into six hyperfine components due to (55)Mn hyperfine coupling giving rise to all 30 allowed transitions. From EPR spectra the spin-Hamiltonian parameters have been evaluated and discussed. The magnitude of the hyperfine splitting (A) constant indicates that there exists a moderately covalent bonding between the Mn(2+) ions and the surrounding ligands. The number of spins participating in resonance (N), its paramagnetic susceptibility (chi) have been evaluated. PMID- 21531617 TI - Vibrational spectra study of fluorescent dendrimers built from the cyclotriphosphazene core with terminal dansyl and carbamate groups. AB - The FTIR and FT Raman spectra of the "Janus"-type dendrimers, possessing five carbamate groups on one side and five fluorescent dansyl derivatives on the other side, with amide G(1) and hydrazone G(2) central linkages were studied. These surface-block dendrimers are obtained by the coupling of two different dendrons. The FTIR and FT-Raman spectra of the zero generation dendrons, built from the hexafunctional cyclotriphosphazene core, with five dansyl terminal groups and one carbamate G(0v) and one oxybenzaldehyde function G(0v)' have been recorded. The structural optimization and normal mode analysis were performed for dendron G(0v)' on the basis of the density functional theory (DFT). The calculated geometrical parameters and harmonic vibrational frequencies are predicted in a good agreement with the experimental data. It was found that dendron molecule G(0v)' has a concave lens structure with planar -O-C(6)H(4)-CHO fragments and slightly non-planar cyclotriphosphazene core. The experimental IR and Raman spectra of dendron G(0v)' were interpreted by means of potential energy distributions. Relying on DFT calculations a complete vibrational assignment is proposed. The strong band 1597 cm(-1) show marked changes of the optical density in dependence of substituents in the aromatic ring. The frequencies of nu(N-H) bands in the IR spectra reveal the presence of the different types of H-bonds in the dendrimers. PMID- 21531618 TI - Intermolecular hydrogen bond complexes by in situ charge transfer complexation of o-tolidine with picric and chloranilic acids. AB - A two new charge transfer complexes formed from the interactions between o tolidine (o-TOL) and picric (PA) or chloranilic (CA) acids, with the compositions, [(o-TOL)(PA)(2)] and [(o-TOL)(CA)(2)] have been prepared. The (13)C NMR, (1)H NMR, (1)H-Cosy, and IR show that the charge-transfer chelation occurs via the formation of chain structures O-H?N intermolecular hydrogen bond between 2NH(2) groups of o-TOL molecule and OH group in each PA or CA units. Photometric titration measurements concerning the two reactions in methanol were performed and the measurements show that the donor-acceptor molar ratio was found to be 1:2 using the modified Benesi-Hildebrand equation. The spectroscopic data were discussed in terms of formation constant, molar extinction coefficient, oscillator strength, dipole moment, standard free energy, and ionization potential. Thermal behavior of both charge transfer complexes showed that the complexes were more stable than their parents. The thermodynamic parameters were estimated from the differential thermogravimetric curves. The results indicated that the formation of molecular charge transfer complexes is spontaneous and endothermic. PMID- 21531619 TI - Analysis of the time dependency of ammonia-oxidizing bacterial community dynamics in an activated sludge bioreactor. AB - An autoregressive error term model was applied to examine the dynamic oscillation of ammonia-oxidizing bacterial (AOB) lineages found in an activated sludge bioreactor. The current abundance of AOB lineages was affected by the past abundance of AOB lineages and past environmental and operational factors as well as current influencing factors. PMID- 21531620 TI - The associations between physical activity, screen time and weight from 6 to 14 yrs: the Raine Study. AB - To examine the strength and direction of the relationship between physical activity level, screen use and BMI in a cohort at ages 6, 8, 10 and 14 yrs as part of a prospective longitudinal cohort study. The sample comprised 1403 males and females who participated in the follow-up survey at 14 yrs of age between 2003 and 2005. Exploratory structural equation modelling was used to examine the interrelationships between physical activity level, BMI and screen time at 6, 8, 10 and 14 yrs. Predictors of BMI at 6, 8, 10 and 14 yrs explained 1.3, 76.1, 80.1 and 73.1 percent of the variances, respectively, with previous BMI the largest predictor [chi(2)=43.082, df=36, p=194]. Increased screen time predicted higher BMI and lower physical activity at 8 and 10 yrs but not 14 yrs. At 14 yrs, physical activity predicted BMI. Sedentary patterns of behaviour in early childhood were predictive of later and concurrent obesity, whereas physical activity was predictive of obesity in adolescence. Different intervention targets are required for children and adolescents. PMID- 21531621 TI - The role of the clinical trial nurse in Italy. AB - PURPOSE: To assess the role of the Clinical Trials Nurse (CTN) and to evaluate the quality of the job performed by Clinical Trials Nurses (CTNs) in Italy. METHODS: The study design was descriptive. The sample included 30 CTNs in Italy who were involved in conducting clinical trials in the last years. Respondents completed the Italian Clinical Trials Nursing Questionnaire (CTNQ) developed to measure frequency and importance of clinical trials nursing activities. Data analyses included descriptive statistics, Student's t-test and Chi-Square test. RESULTS: Thirty out of 34 CTNs consented to participate. Respondents were more involved in the experimental drug management, in the protocol implementation and, partially, in the informed consent process. CTNs have a marginal position with respect to the protocol assessment and planning, subject recruitment, data management. CTNs reported high rates for the importance evaluation. Number of years in the nursing role was significantly associated with data management related activities (p = 0.016). Items with minor response rate differences between frequency and importance were not statistically significant (p values ranging from 0.087 to 0.911). The CTNs reported to be autonomous and competent; however, they lack and/or do not perform some nursing-related responsibilities and/or activities. CONCLUSIONS: Although CTNs are not involved in all of the activities listed on the CTNQ, most of them are fully aware to be a key member of research teams. Overall, the Italian CTN role is mostly practical task-oriented and focuses little on data management and organizational activities. PMID- 21531622 TI - Qualitative pharmacology in a quantitative world: diminishing value in the drug discovery process. AB - Preclinical characterization of new chemical entities (NCEs) in terms of efficacy, safety and their pharmacokinetic (PK), pharmacodynamic and pharmaceutical properties, is key to advancing appropriate compounds to clinical trials. The use of high throughput synthetic and screening methodologies has frequently led to NCE characterization becoming highly reductionistic, to the extent that compounds are often selected without adequate characterization. Classical, null hypothesis-based approaches involving the use of concentration/dose response curves and antagonists have been replaced by more qualitative approaches that limit NCE characterization. The return to a more integrated, hierarchical and pharmacologically driven approach will aid in ensuring that the NCEs advanced to clinical status are better understood, strengthening the process and predictivity of the translational approach in drug discovery. PMID- 21531623 TI - The Th1 life cycle: molecular control of IFN-gamma to IL-10 switching. AB - Control of IFN-gamma-secreting T helper (Th) 1 cells prevents autoimmunity and immunopathology during infection. IL-10-mediated suppression of Th1 cells is achieved not only through IL-10 produced extrinsically, but also through a negative feedback loop that induces "intrinsic" IL-10 expression in cells also expressing IFN-gamma, during Th1 lineage differentiation. Targeting this Th1 cell IFN-gamma to IL-10 switching is a tantalising prospect for developing therapeutics for Th1-mediated diseases. In this review, the molecular pathways that regulate IFN-gamma versus IL-10 expression in Th1 cells are examined, with focus on the role of complement regulator and T cell co-stimulatory molecule CD46, and also discussed are challenges and controversies in the field. PMID- 21531624 TI - Control of hematopoietic stem cells by the bone marrow stromal niche: the role of reticular cells. AB - In the bone marrow, hematopoietic stem cells (HSCs) are maintained by special microenvironments, termed niches. The nature and function of these niches, however, remains unclear. HSCs are thought be in contact with bone-lining osteoblasts, but recent studies have suggested that only a small subpopulation of HSCs reside in this endosteal niche. By contrast, many HSCs are associated with the sinusoidal endothelium, which is referred to as the vascular niche. Recent data have suggested that primitive mesenchymal cells, including CXC chemokine ligand 12-abundant reticular cells and nestin-expressing cells act as HSC niches. Here, we review HSC niches, with an emphasis on the emerging role of reticular niches for maintaining HSCs in a proliferative and undifferentiated state. PMID- 21531625 TI - B cell-directed therapies in type 1 diabetes. AB - B cells play a pathogenic role as antigen-presenting cells and autoantibody secretors in the lead up to T cell-mediated autoimmune destruction of insulin producing beta cells in type 1 diabetes (T1D). This has led to significant interest in the use of B cell depletion therapies as a treatment for T1D. In this review, we compare results from five recent studies that used distinct B cell depleting agents and protocols to successfully prevent and even reverse T1D in the non-obese diabetic (NOD) mouse model. We discuss how information gained from animal studies could be used to improve on the positive outcomes of a completed phase II clinical trial of the B cell-depleting drug rituximab in humans with recent-onset T1D. PMID- 21531626 TI - Advances in helminth immunology: optimism for future vaccine design? AB - Intestinal helminths infect approximately 2 billion people worldwide. Worm burdens correlate with disease morbidity and children generally harbor the largest numbers. The majority of intestinal helminths do not replicate within their host, and worm burdens increase through constant reinfection. Current strategies of worm control involve drug administration to school-aged children. Yet the rapid rate of reinfection and the appearance of drug resistant strains in livestock raise concerns over the sustainable nature of this strategy. A combined strategy of drug treatment for the expulsion of adult worms and vaccination designed to halt reinfection would offer the most effective means of control. Before successful vaccines can be developed our knowledge of the initiation and implementation of host immunity must be improved. PMID- 21531627 TI - Harnessing immune responses against Plasmodium for rational vaccine design. AB - In recent years, groundbreaking advances have been made in understanding the biology of and immune mechanisms against the Plasmodium spp. parasite, the causative agent of malaria. Novel features of the Plasmodium life cycle have been unravelled and immune mechanisms, which take place during both infection and immunization, have been dissected. We have undoubtedly enhanced our knowledge, but the question now is how to use this information to manipulate immune responses against Plasmodium and to develop an efficacious malaria vaccine. In this review, we discuss the latest developments in the field and speculate on how immune responses against Plasmodium could be harnessed for rational vaccine design and application. PMID- 21531628 TI - How can immunopathology shape the evolution of parasite virulence? AB - Immunopathology (immune-mediated pathology) is a ubiquitous cause of disease during infection, but how will parasite exploitation strategies evolve in its presence? Immunopathology can act to increase parasite fitness if it increases transmission rate, but can equally act to decrease parasite fitness if it increases host mortality. The focus here is on understanding how immunopathology, mediated through different immune mechanisms, can influence parasite fitness and how experimental manipulations of the immune system can be carried out to examine this. A better understanding of how parasite fitness scales with, or responds to, immunopathology is crucial to understanding the nature of selection acting on parasite virulence traits and will allow more informed predictions to be made regarding the trajectory of parasite virulence evolution. PMID- 21531629 TI - Mitochondrial translation in trypanosomatids: a novel target for chemotherapy? AB - Trypanosomatids cause widespread disease in humans and animals. Treatment of many of these diseases is hampered by the lack of efficient and safe drugs. New strategies for drug development are therefore urgently needed. It has long been known that the single mitochondrion of trypanosomatids exhibits many unique features. Recently, the mitochondrial translation machinery of trypanosomatids has been the focus of several studies, which revealed interesting variations to the mammalian system. It is the aim of this article to review these unique features and to discuss them in the larger biological context. It is our opinion that some of these features represent promising novel targets for chemotherapeutic intervention that should be studied in more detail. PMID- 21531630 TI - The number of circulating CD4+ CD25high Foxp3+ T lymphocytes is transiently elevated in the early childhood of transient hypogammaglobulinemia of infancy patients. PMID- 21531631 TI - Behavioral changes in dogs associated with the development of idiopathic epilepsy. AB - OBJECTIVES: The aim of the study was to demonstrate behavioral changes with the development of epilepsy in dogs, a species proposed as a naturally occurring animal model for human epilepsy. METHODS: Owners of dogs diagnosed with idiopathic epilepsy (n=80) completed a modified, previously-validated behavioral and seizure questionnaire. Principal axis factor analysis identified behavioral factors, the scores for which were compared before and after the development of epilepsy. RESULTS: Drug-naive dogs showed an increase in the behavior factors Fear/Anxiety, Defensive Aggression, and Abnormal Perception. In dogs receiving antiepileptic medication, there were still increases in Fear/Anxiety and Abnormal Perception, but no longer in Defensive Aggression. Additional increases were observed in Abnormal Reactivity, Attachment Disorder, Demented Behavior, and Apathetic Behavior. Pharmacoresistant dogs had larger increases in Controlling Aggression, Abnormal Perception, and Demented Behavior than drug responders. CONCLUSION: Our data suggest that dogs, like humans and rodents, exhibit neurobehavioral comorbidities with the development of epilepsy. PMID- 21531632 TI - The role of 5-HT(3) receptors in the additive anticonvulsant effects of citalopram and morphine on pentylenetetrazole-induced clonic seizures in mice. AB - Citalopram, a selective serotonin reuptake inhibitor (SSRI), is frequently used in the treatment of major depressive disorders. In addition to its antidepressant features, citalopram shows some anticonvulsive properties at lower doses, whereas higher doses, ingested in cases of suicide, have been associated with seizures. Moreover, some reports support the enhancing effect of morphine on different responses of SSRIs such as analgesic and anticonvulsant properties. Although the exact mechanisms of these additive effects are not yet fully understood, 5-HT(3) receptor has recently been shown to play an important role in the central effects of SSRIs and morphine. In this regard, we used a model of clonic seizures induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether morphine and citalopram exhibit additive anticonvulsant effects and, if so, whether this effect is mediated through modulation of 5-HT(3) receptors. In our study, citalopram at lower doses (0.5 and 1 mg/kg, ip) significantly increased the seizure threshold (P<0.01) and at a higher dose (50 mg/kg) had proconvulsive effects. Moreover, morphine at low and noneffective doses had additive effects on the anticonvulsive properties of citalopram. This additive effect was prevented by pretreatment with low and noneffective doses of tropisetron (a 5-HT(3) receptor antagonist) and augmented by 1-(m-chlorophenyl)-biguanide (mCPBG, a 5 HT(3) receptor agonist). Moreover, low doses of morphine (0.1 and 0.5 mg/kg) alone or in combination with potent doses of 5-HT(3) receptor agonist or antagonist could not alter the proconvulsive properties of citalopram at higher dose (50 mg/kg), ruling out the contribution of 5-HT(3) to this effect. In summary, our findings demonstrate that 5-HT(3) receptor mediates the additive anticonvulsant properties of morphine and low-dose citalopram. This could constitute a new approach to augmenting the efficacy and curtailing the adverse effects of citalopram. PMID- 21531633 TI - Risk factors for antiepileptic drug regimen change in patients with newly diagnosed epilepsy. AB - This study aimed to investigate the evolution of treatment within patients with newly diagnosed epilepsy identified from a large US commercial health care database. Postdiagnosis, patient follow-up was divided into observation units defined by consecutive antiepileptic drug (AED) prescriptions. Consecutive prescriptions were compared to assess whether a change in AED regimen had occurred. Factors associated with a regimen change were explored using a logistic regression model with subject random effects. Among 5930 patients with newly diagnosed epilepsy, there was a median of one regimen change in the first year. However, patients prescribed polytherapy regimens early in the course of disease were at a substantially greater risk of a regimen change (polytherapy vs monotherapy odds ratio=10.2, 95% confidence interval=9.2-11.3). Although a seizure during the preceding 90 days significantly increased the risk of a regimen change, it was beyond the scope of the study to determine the proportion of changes directly attributable to uncontrolled seizures. PMID- 21531634 TI - D-Asp: a new player in reproductive endocrinology of the amphibian Rana esculenta. AB - We investigated the involvement of D-Aspartic acid (D-Asp) on ovarian and testicular morphology of the green frog, Rana esculenta, and its effect on the testosterone production. The study has been performed throughout the reproductive cycle. In both ovary and testis a substantial amount of D-Asp is endogenously present and its concentration varies as function of reproduction. In the frog, D Asp content is differently correlated with gonadal and plasmatic levels of testosterone, depending on the sex. In fact, the amount of the D-Asp is inversely linked with that of the testosterone in the ovary, while this correlation directly matched in the testis. In vivo short-term experiments, consisting of a single intra-peritoneal injection of D-Asp (2.0 MUmol/g body weight), demonstrated that the enantiomer is significantly accumulated by both the ovary and testis, reaching after 3 h the highest uptake and thereafter decreasing to baseline values within 24 h. Furthermore, D-Asp influences the synthesis and/or the release of testosterone, causing a decrease of its level in the female, and an increase in the male, respectively. In vivo long-term experiments, D-Asp, chronically administered to the frogs of both sexes, enhances the maturation of both gonads, determining in the oocytes an higher accumulation of carbohydrate yolk plates in the ooplasm, and stimulating the spermatogenesis in the testis. Taken altogether, our results show that D-Asp operates differently in female and male frog gonads, indicating that it has different targets in the reproductive machinery depending on the sex. PMID- 21531635 TI - Determination of sugammadex in human plasma, urine, and dialysate using a high performance liquid chromatography/tandem mass spectrometry assay. AB - Sugammadex (Bridion(r), Merck Sharp & Dohme Corp., Oss, The Netherlands) is a modified gamma-cyclodextrin which has the ability to reverse the neuromuscular blockade induced by the steroidal neuromuscular blocking agents rocuronium and vecuronium. The objective of the current study is to describe the bioanalytical methods that have been developed and validated according to US Food and Drug Administration guidelines on bioanalytical method validation, and subsequently applied to determine total sugammadex (i.e., free sugammadex plus sugammadex bound to the neuromuscular blocking agent) in human heparinized plasma, urine and dialysate. Sugammadex was extracted from human plasma and urine using solid phase extraction with Isolute HAX 96-well extraction plates; no extraction was performed on dialysate samples. Samples from plasma, urine, and dialysate were analyzed on a Polaris(r) C18-A PEEK (polyaryletheretherketone) analytical column (50 mm * 4.6 mm internal diameter, 5 MUm) with a linear mobile phase gradient of 0.1% (v/v) formic acid in water:methanol from 70:30 to 20:80. The flow rate was 1 mL/min with a total run time for each injection of 6 min. Tandem mass spectrometric detection was conducted using multiple reaction monitoring under negative ion mode with a turbo ion-spray interface to quantify the concentration of sugammadex. Inter- and intra-assay precision and accuracy were within pre defined acceptance limits. The presence of rocuronium did not interfere with the assay in plasma, urine or dialysate; similarly, vecuronium did not interfere with the plasma assay (not tested for interference in urine or dialysate). Sugammadex was found to be stable in plasma, urine and dialysate in the short-term at room temperature, in the long-term at -20 degrees C, and after several freeze/thaw cycles. The validated bioanalytical methods developed here have been successfully applied in a series of clinical studies for the determination of total sugammadex in plasma, urine and dialysate. PMID- 21531636 TI - Development and validation of a LC-ESI-MS/MS method for the determination of swertiamarin in rat plasma and its application in pharmacokinetics. AB - A new LC-ESI-MS/MS assay method has been developed and validated for the quantification of swertiamarin, a representative bioactive substance of Swertia plants, in rat plasma using gentiopicroside, an analog of swertiamarin on chemical structure and chromatographic action, as the internal standard (IS). The swertiamarin and IS were extracted from rat plasma using solid-phase extraction (SPE) as the sample clean-up procedure, and they were chromatographed on a narrow internal diameter column (Agilent ZORBAX ECLIPSE XDB-C(18) 100 mm * 2.1 mm, 1.8 MUm) with the mobile phase consisting of methanol and water containing 0.1% acetic acid (25:75, v/v) at a flow rate of 0.2 mL/min. The detection was performed on an Agilent G6410B tandem mass spectrometer by negative ion electrospray ionisation in multiple-reaction monitoring mode while monitoring the transitions of m/z 433 [M+CH(3)COO](-)->179 and m/z 415 [M+CH(3)COO](-)->179 for swertiamarin and IS, respectively. The lower limit of quantification (LLOQ) was 5 ng/mL within a linear range of 5-1000 ng/mL (n=7, r(2)>=0.994), and the limit of detection (LOD) was demonstrated as 1.25 ng/mL (S/N>=3). The method also afforded satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day), accuracy, recovery, freeze/thaw, long-time stability and dilution integrity. This method was successfully applied to determination of the pharmacokinetic properties of swertiamarin in rats after oral administration at a dose of 20 mg/kg. The following pharmacokinetic parameters were obtained (mean): maximum plasma concentration, 1920.1 ng/mL; time to reach maximum plasma concentration, 0.945 h; elimination half-time, 1.10h; apparent total clearance, 5.638 L/h/kg; and apparent volume of distribution, 9.637 L/kg. PMID- 21531637 TI - Heart-cut two-dimensional separation method via hyphenation of micellar electrokinetic capillary chromatography and capillary zone electrophoresis using analyte focusing by micelle collapse. AB - A novel two-dimensional (2D) separation method, which hyphenated micellar electrokinetic capillary chromatography (MEKC) and capillary zone electrophoresis (CZE), was developed for analysis of flavonoids in Leonurus cardiaca. The Leonurus cardiaca sample was separated and purified in first dimension by MEKC. Then only a selected portion of the first dimension separation was transferred into the second dimension by pressure. Finally, the zone of flavonoids was separated by CZE. As the key to successful hyphenation of MEKC and CZE, an analyte focusing by micelle collapse (AFMC) concentration method was employed between the two dimensions to release analytes from the micelle interior to a liquid zone and to overcome the sample zone diffusion caused by mobilization pressure. The whole heart-cut 2D separation process can be performed in a conventional CE analyzer. The relative standard deviation of peak height, peak area and migration time were in the range of 2.3-4.2%, 1.5-3.8% and 3.6-5.5%, respectively, and detection limits (S/N=3) were 15-55 ng/mL. The new methodology was applied with success for the flavonoids separation of Leonurus cardiaca. PMID- 21531638 TI - Unusual characteristics and fatal outcome of a malignant struma ovarii. Case report and literature review. PMID- 21531639 TI - The 'step-up approach' to infected necrotizing pancreatitis: delay, drain, debride. PMID- 21531640 TI - [Whooping cough in the first year of life in a region with high vaccination coverage]. AB - INTRODUCTION: Despite vaccination, reports of cases and outbreaks of pertussis (whooping cough) continue to appear sporadically, sometimes in young children who are at higher risk of severe disease. The aim of the present study was to evaluate the impact of this infection in infants in a region with high vaccination coverage in the pediatric population. PATIENTS AND METHODS: We performed a retrospective observational chart-review study of pertussis cases occurring over a decade (1999-2008), microbiologically confirmed through a polymerase chain reaction technique that amplifies the IS481 Bordetella pertussis sequence. RESULTS: There were 54 confirmed cases, of which 33 (61.1%) occurred in infants aged less than 3 months. Cases were detected in all the study years, with periodic outbreaks (1999, 2004 and 2008). Half of the cases occurred in summer. Due to their young age, 55% of the infants had not received a vaccine dose and only 11% had received the first three doses. Hospitalization was required in 39 cases (72%) and admission to the pediatric intensive care unit in 17 cases (31.5%). One premature infant, with symptoms compatible with malignant pertussis, died at 49 days of life. CONCLUSIONS: Despite the high pertussis vaccination coverage, infants aged less than 6 months continue to be at risk of severe disease. New preventive strategies are required to further reduce the impact of this infection. PMID- 21531641 TI - [Adrenal ganglioneuroma]. PMID- 21531642 TI - [Gastric perforation in a patient with motor neuropathy]. PMID- 21531643 TI - [An outbreak of hand-foot-and-mouth disease caused by Coxsackie virus A16 in the Mallorca island]. PMID- 21531644 TI - Invited commentary. PMID- 21531645 TI - [Acute renal failure in the elderly]. AB - Acute renal failure in elderly patients is common and likely to become more so as life expectancy in France continues to grow. The chances of acute renal failure occurring in the elderly are increased by changes in renal function and the effects of various chronic diseases such as diabetes, hypertension and obstructive urological disorders, all of which increase in incidence with age. The elderly may develop all types of the disease but are most prone to drug related acute renal failure. The diagnostic and therapeutic strategies adopted are the same as those for adult patients but should take into account the potential risks and benefits in this specific age group. However, age should no longer be considered as the sole determining factor in diagnostic and therapeutic decisions. The elderly are among those who benefit most from preventive measures against acute renal failure. PMID- 21531646 TI - Influence of early fate decisions at the two-cell stage on the derivation of mouse embryonic stem cell lines. AB - The first event of differentiation in mammalian embryogenesis is the segregation of the inner cell mass and trophectoderm lineages in the blastocyst. Cellular and molecular events related to this process are still a controversial issue. During the years it was thought that first allocation of blastomeres before the blastocyst stage was done in the late eight-cell stage with the formation of inner and outer cells. Lately, many studies have pointed out that individual blastomeres at the four-cell stage differ in their developmental properties according to their position within the embryo. In this report, we wanted to elucidate whether these early decisions influence the production of mouse embryonic stem cell lines, so that a selective isolation of blastomeres at the four-cell stage to derive the lines could improve the efficiency of the derivation process. Results from blastomere tracking experiments support the idea of a different developmental potential of blastomeres within the four-cell stage embryo. However, we also show a high plasticity in the developmental pattern of blastomeres once isolated from the embryo, thus making all four-cell stage blastomeres equally competent to derive ESC lines. PMID- 21531648 TI - Update--"Big-head": the solution to the problem of hip implant dislocation? AB - New friction couples, initially intended to limit osteolysis risk due to debris, have enabled larger implant head diameters to be developed to resolve the problem of hip implant dislocation. The Symposium demonstrated that, whatever the configuration, increased head diameter significantly reduced the incidence of dislocation, but that none of the friction couples fulfilled the mechanical and/or biomechanical charge-book for consistently reliable use of large diameter heads. The greatest caution is therefore recommended in their implementation. PMID- 21531647 TI - Cell sourcing for bone tissue engineering: amniotic fluid stem cells have a delayed, robust differentiation compared to mesenchymal stem cells. AB - Cell based therapies for bone regeneration are an exciting emerging technology, but the availability of osteogenic cells is limited and an ideal cell source has not been identified. Amniotic fluid-derived stem cells (AFS) and bone-marrow derived mesenchymal stem cells (MSCs) were compared to determine their osteogenic differentiation capacity in both 2D and 3D environments. In 2D culture, the AFS cells produced more mineralized matrix but delayed peaks in osteogenic markers. Cells were also cultured on 3D scaffolds constructed of poly-epsilon-caprolactone for 15 weeks. MSCs differentiated more quickly than AFS cells on 3D scaffolds, but mineralized matrix production slowed considerably after 5 weeks. In contrast, the rate of AFS cell mineralization continued to increase out to 15 weeks, at which time AFS constructs contained 5-fold more mineralized matrix than MSC constructs. Therefore, cell source should be taken into consideration when used for cell therapy, as the MSCs would be a good choice for immediate matrix production, but the AFS cells would continue robust mineralization for an extended period of time. This study demonstrates that stem cell source can dramatically influence the magnitude and rate of osteogenic differentiation in vitro. PMID- 21531649 TI - Managing risk in the operating room: from theory to practice. PMID- 21531650 TI - Painful medial knee compartment syndrome in over-45-year-olds. II--technical note: Biomechanical considerations: theoretic analysis of load distribution in the knee according to plane and to gait phase. AB - Varus deviation as defined by Thomine is the basis for understanding load distribution between the medial and lateral tibial plateau; it was originally defined in the frontal plane. Analysis in the sagittal and horizontal planes leads to a concept of varizing area. Varizing area sheds light on how, during gait, load predominates in the medial and posteromedial knee. It also accounts for the following two findings: (a) degenerative lesions are mainly medial, even when the mid-knee axis is normal; (b) degenerative lesions are mainly posterior. PMID- 21531651 TI - Adherence and effectiveness of rehabilitation in acute ankle sprain. AB - OBJECTIVE: To estimate adherence to and effectiveness of rehabilitation after acute ankle sprain. METHOD: Patients with acute ankle sprain attending four emergency departments were recruited between February and July 2009. After the initial examination (classification of the severity of the sprain), each patient received an Aircast((r)) ankle brace and the same, standardized rehabilitation program. Between two and three months later; the patient was contacted by phone (always by the same investigator) in order to find out whether he/she had performed the prescribed rehabilitation, establish whether the physiotherapist had complied with the prescribed rehabilitation programme and assess subjective recovery. If a patient failed to respond to three phone calls, he/she was excluded from the study. RESULTS: Of the 245 patients initially included, 111 (67 men and 44 women; 17 mild sprains, 67 moderate sprains and 27 severe sprains) answered the "phone questionnaire". In terms of treatment adherence by the patient, 92 patients (82.9%) performed their rehabilitation (beginning an average of 13.8 days after the injury). In terms of prescription compliance by the physiotherapist, 88 patients (95.6%) received massage, 71 (77.2%) underwent physiotherapy, 83 (90.2%) performed weight training and 87 (94.5%) received proprioceptive training. Eighty-two patients said that they had received manipulative therapy that was not part of the prescribed programme. Impact on recovery: 61 patients (55%) considered that their injury had healed (10 mild, 42 medium and nine severe sprains), whereas 50 had not healed (seven mild, 25 medium and 18 severe sprains). There was no statistically significant association between recovery and compliance with rehabilitation. However, the application of massage (p=0.004) and proprioceptive training (p=0.017) were significantly associated with recovery, while physiotherapy, weight training and manipulative therapy were not. CONCLUSION: In acute ankle sprain, adherence with rehabilitation is good and the treating physiotherapists comply with the prescription. However, there was no statistically significant link between rehabilitation compliance and subjective recovery at 3 months. Revaluation of these patients at one year may be necessary for estimating the impact of rehabilitation on ankle function and the rate of injury recurrence. PMID- 21531652 TI - The Office of Health Assessment and Translation: a problem-solving resource for the National Toxicology Program. PMID- 21531653 TI - Phosphorus paradox: scarcity and overabundance of a key nutrient. PMID- 21531654 TI - Fragranced products and VOCs. PMID- 21531655 TI - Window for dioxin damage: sperm quality in men born after the Seveso disaster. PMID- 21531656 TI - Health impact from air pollution in Thailand: current and future challenges. PMID- 21531657 TI - Study to examine health effects in Deepwater Horizon oil spill cleanup workers. PMID- 21531659 TI - Passing down pollution: calculating intergenerational exposure to PCBs. PMID- 21531660 TI - Redefining low lead levels. PMID- 21531661 TI - Epigenetic liver damage: study reveals clues implicating 1,3-butadiene. PMID- 21531663 TI - Can transgenic plants root out pollutants? PMID- 21531662 TI - Arsenic and infectious disease: a potential factor in morbidity among Bangladeshi children. PMID- 21531664 TI - Traffic trigger. PMID- 21531665 TI - Tools for tracking antibiotic resistance. PMID- 21531668 TI - Breast cancer environment centers and advocacy. PMID- 21531669 TI - Patients' experiences with cancer-related fatigue: a review and synthesis of qualitative research. AB - PURPOSE/OBJECTIVES: To systematically review published qualitative reports of descriptions of fatigue by patients with cancer and how cancer-related fatigue (CF) affects their lives. DATA SOURCES: MEDLINE(r), CANCERLIT(r), Cochrane Database of Systematic Reviews, and the Cumulative Index to Nursing and Allied Health Literature. DATA SYNTHESIS: Two researchers conducted independent reviews of 667 patient quotes found in 154 articles published from 1996-2009 to identify concepts and language used to describe CF. CONCLUSIONS: CF is more intense than the tiredness patients recalled from before diagnosis or treatment. Published patient quotes fail to adjudicate whether CF should be approached as a single symptom or a more complex symptom cluster. IMPLICATIONS FOR NURSING: Systematic study of patients with different cancer types and stages is needed to identify effective, valid, and reliable self-reported assessments of CF for clinical practice and trials. PMID- 21531670 TI - Incorporating supportive care into routine cancer care: the benefits and challenges to clinicians' practice. AB - PURPOSE/OBJECTIVES: To investigate clinicians' experiences with supportive care screening and referral, and identify perceived barriers and benefits associated with implementation into the clinical setting. DESIGN: Qualitative, exploratory approach based on interviews. SETTING: A large regional hospital in Victoria, Australia, that provides chemotherapy and radiotherapy services to patients with cancer. SAMPLE: 5 chemotherapy nurses and 1 radiation therapist. METHODS: Semistructured interviews were conducted, documented, and analyzed with qualitative techniques. MAIN RESEARCH VARIABLES: Clinical benefits of supportive care screening and referral, and barriers to clinical implementation. FINDINGS: Clinicians perceived that supportive care screening benefited their practice by improving communication and rapport with patients. Clinicians supported each other during screening implementation, and although they initially were hesitant about the process, they ultimately endorsed screening for wider implementation. Time constraints and scope of practice were identified as significant barriers. CONCLUSIONS: Supportive care screening was endorsed as part of future clinical practice, but barriers to implementation need to be addressed. IMPLICATIONS FOR NURSING: With current psychosocial guidelines recommending routine supportive care screening of patients with cancer and statewide mandatory screening targets set in Australia, healthcare organizations need to carefully consider implementation processes. Although nurses are ideally placed to complete screening, organizations need to ensure that appropriate training and support mechanisms have been developed, as well as adequate resources, to enable integration into routine practice. PMID- 21531671 TI - Investigation of standard care versus sham Reiki placebo versus actual Reiki therapy to enhance comfort and well-being in a chemotherapy infusion center. AB - PURPOSE/OBJECTIVES: To determine whether provision of Reiki therapy during outpatient chemotherapy is associated with increased comfort and well-being. DESIGN: Double-blind, randomized clinical controlled trial. SETTING: Outpatient chemotherapy center. SAMPLE: 189 participants were randomized to actual Reiki, sham Reiki placebo, or standard care. METHODS: Patients receiving chemotherapy were randomly placed into one of three groups. Patients received either standard care, a placebo, or an actual Reiki therapy treatment. A demographic tool and pre and post-tests were given before and after chemotherapy infusion. MAIN RESEARCH VARIABLES: Reiki therapy, sham Reiki placebo therapy, standard care, and self reported levels of comfort and well-being pre- and postintervention. FINDINGS: Although Reiki therapy was statistically significant in raising the comfort and well-being of patients post-therapy, the sham Reiki placebo also was statistically significant. Patients in the standard care group did not experience changes in comfort and well-being during their infusion session. CONCLUSIONS: The findings indicate that the presence of an RN providing one-on-one support during chemotherapy was influential in raising comfort and well-being levels, with or without an attempted healing energy field. IMPLICATIONS FOR NURSING: An attempt by clinic nurses to provide more designated one-to-one presence and support for patients while receiving their chemotherapy infusions could increase patient comfort and well-being. PMID- 21531672 TI - Personality trait and quality of life in colorectal cancer survivors. AB - PURPOSE/OBJECTIVES: To explore the association between quality of life (QOL) and type D personality, which is characterized by the traits of negative affectivity and social inhibition, and to further identify impacts of these traits after controlling for biophysical and psychological factors in colorectal cancer survivors. DESIGN: Cross-sectional and correlational. SETTING: Oncology and surgical outpatient clinics of a medical center in Taiwan. SAMPLE: 124 patients diagnosed with colorectal cancer who had completed active treatment. METHODS: Data were collected using a set of structured questionnaires to explore type D personality, biophysical and psychological factors, and QOL. Their associations were verified with Mann-Whitney U test and Spearman's rho correlation. Significant factors associated with QOL were identified with generalized estimating equations. MAIN RESEARCH VARIABLES: Type D personality and QOL. FINDINGS: Patients with type D personality experienced higher physical and psychological distress than those with non-type D personality. Social inhibition remained an important factor leading to impairment in the mental component of QOL after controlling for other associated factors. Negative affectivity was associated with fatigue intensity and interference of fatigue with life activities. CONCLUSIONS: Personality trait was found to be an important factor associated with QOL. The trait of social inhibition was a significant factor influencing mental aspects of QOL, whereas negative affectivity was associated with fatigue. IMPLICATIONS FOR NURSING: Assessing patients' personality, including negative affectivity and social inhibition, could help nurses to develop supportive groups or social networks for these patients and thereby improve QOL for cancer survivors. PMID- 21531673 TI - Nurses' perceptions and experiences with end-of-life communication and care. AB - PURPOSE/OBJECTIVES: To characterize oncology nurses' attitudes toward care at the end of life (EOL) and their experiences in caring for terminally ill patients, hospice discussions with patients and families, and the use of palliative care practices. DESIGN: Descriptive correlational survey study. SETTING: A Magnet(r) designated hospital in southern California with more than 500 beds. SAMPLE: 31 oncology nurses. METHODS: Nurses completed the adapted version of the Caring for Terminally Ill Patients Nurse Survey. MAIN RESEARCH VARIABLES: Attitudes toward care at EOL and care experiences with terminally ill patients. FINDINGS: Despite having fairly positive attitudes toward hospice and having discussions about prognosis with terminally ill patients, nurses reported missed opportunities for discussions and patient referrals to hospice. On average, nurses cared for more than seven terminally ill patients during a three-month period while only discussing hospice care with a third of these patients and their family members. Most nurses acknowledged that patients would benefit from earlier initiation of hospice care. Specific palliative care practices used by nurses in the past three months varied, with active and passive listening and requesting increased pain medications used most frequently and aromatherapy and guided imagery used least. CONCLUSIONS: Missed opportunities may reflect nurses' attitudes. However, lack of patient and family member acceptance was the most important barrier to discussion of hospice. IMPLICATIONS FOR NURSING: Strategies to enable nurses to have a stronger voice during this critical time for their patients are needed and, when developed, supported in practice to ensure that they are used. PMID- 21531674 TI - Dose effects of relaxation practice on immune responses in women newly diagnosed with breast cancer: an exploratory study. AB - PURPOSE/OBJECTIVES: To determine the dose effects of relaxation practice on immune responses and describe the types of relaxation techniques preferred and the extent of relaxation practice over 10 months. DESIGN: Descriptive, prospective, repeated measures. SETTING: An interdisciplinary breast clinic at a university-affiliated comprehensive cancer center in the United States. SAMPLE: 49 women with newly diagnosed breast cancer and undergoing adjuvant therapy who participated in a stress management intervention. METHODS: Relaxation practice was assessed twice a month for 10 months with immune measurements (e.g., natural killer cell activity; lymphocyte proliferation; interferon [IFN]-gamma; interleukin [IL]-2, -4, -6, and -10) at the beginning and end of 10-month practice. MAIN RESEARCH VARIABLES: Relaxation practice (representing the concepts of stress and adherence), relaxation technique, and immune response. FINDINGS: After adjusting for covariates, the extent of relaxation practice significantly contributed to the variance of natural killer cell activity, lymphocyte proliferation, IL-4, and IL-10 responses in a positive direction; the higher the relaxation practice, the higher the immune responses. In comparison, IFN-gamma, IL-2, and IL-6 responses were not affected. The deep-breathing method was most preferred by participants, followed by progressive relaxation and imagination or visualization. The mean weekly frequency of relaxation practice was 5.29 (SD = 3.35), and the mean duration of relaxation practice was 19.16 (SD = 10.81) minutes per session. CONCLUSIONS: Persistent relaxation practice may have positive effects on multiple immune responses in a dose-dependent manner. IMPLICATIONS FOR NURSING: Allowing the choice of preferred techniques and emphasizing the importance of long-term adherence, a relaxation program may need to be routinely offered to women under high stress. PMID- 21531675 TI - Remembering Rose Mary. PMID- 21531677 TI - Acuity adaptable nursing units in oncology. PMID- 21531678 TI - Aromatase inhibitor-associated bone loss. PMID- 21531679 TI - Examining emotional outcomes among a multiethnic cohort of breast cancer survivors. AB - PURPOSE/OBJECTIVES: To describe emotional concerns among a multiethnic sample of breast cancer survivors from a clinically sensitive approach and to examine differences in emotional items according to demographic characteristics. DESIGN: Cross-sectional design. SETTING: California Cancer Surveillance Program, Los Angeles-area hospitals, and community agencies in southern California. SAMPLE: 703 multiethnic, population-based breast cancer survivors, including European, African, Latina, and Asian Americans. METHODS: Two emotional outcome subscales were assessed, one each from the Functional Assessment of Cancer Therapy-General (FACT-G) and the SF-36(r). MAIN RESEARCH VARIABLES: Emotional outcomes and health related quality of life (HRQOL), as measured by FACT-G, SF-36, and demographic characteristics. FINDINGS: Emotional item responses measured by the FACT-G and SF 36 varied by ethnicity, income, education, employment status, language, and age. Overall, worry about the cancer getting worse or recurrence (FACT-G), as well as negative feelings about sadness or uncertainty (SF-36), were reported as the most bothersome concerns across all breast cancer survivors regardless of ethnic group. CONCLUSIONS: Findings reveal unique patterns relevant to emotional outcomes on overall HRQOL scores. Clinically, this study suggests the need for greater attention and appreciation of the influence of demographic contexts on emotional well-being. IMPLICATIONS FOR NURSING: The findings provide a unique observation of the use of individual item response to inform and enhance the assessment of emotional outcomes for clinical and scientific purposes. PMID- 21531680 TI - Image of God: effect on coping and psychospiritual outcomes in early breast cancer survivors. AB - PURPOSE/OBJECTIVES: To examine the effect of breast cancer survivors' views of God on religious coping strategies, depression, anxiety, stress, concerns about recurrence, and psychological well-being. DESIGN: Exploratory, cross-sectional, comparative survey. SETTING: Outpatients from community and university oncology practices in the southeastern United States. SAMPLE: 130 early breast cancer survivors (6-30 months postdiagnosis). METHODS: Self-report written survey packets were mailed to practice-identified survivors. MAIN RESEARCH VARIABLES: Image of God, religious coping strategies, depression, anxiety, stress, concerns about recurrence, and psychological well-being. FINDINGS: Women who viewed God as highly engaged used more coping strategies to promote spiritual conservation in proportion to coping strategies that reflect spiritual struggle. Women who viewed God as highly engaged maintained psychological well-being when either spiritual conservation or spiritual struggle coping styles were used. No differences in variables were noted for women who viewed God as more or less angry. CONCLUSIONS: The belief in an engaged God is significantly related to increased psychological well-being, decreased psychological distress, and decreased concern about recurrence. IMPLICATIONS FOR NURSING: Addressing survivors' issues related to psychological adjustment and concern about recurrence within their world view would allow for more personalized and effective interventions. Future research should be conducted to establish how the view that God is engaged affects coping and psychological adjustment across diverse groups of cancer survivors and groups with monotheistic, polytheistic, and naturalistic world views. This could lead to a practical method for examining the influence of these world views on individuals' responses to cancer diagnosis, treatment, and survivorship. PMID- 21531681 TI - Lack of communication and control: experiences of distance caregivers of parents with advanced cancer. AB - PURPOSE/OBJECTIVES: To explore the new and complex phenomenon of distance caregiving in the advanced cancer population. RESEARCH APPROACH: Qualitative. SETTING: A large comprehensive cancer center in the midwestern region of the United States. PARTICIPANTS: 14 distance caregivers of parents with advanced cancer. METHODOLOGIC APPROACH: Patients with advanced lung, gastrointestinal, and gynecologic malignancies consented to have their distance caregiving adult children contacted to participate in the study. Responses to three open-ended questions guided the tape-recorded telephone interviews with the distance caregivers. Following transcription, content analysis with inductive coding was performed. FINDINGS: Two major themes, communication and control, and five subthemes, benefits and burdens of distance caregiving, dealing with uncertainty, direct action through information seeking, protecting, and staying connected, emerged from the data. CONCLUSIONS: Distance caregivers experience some of the same stressors that local caregivers of patients with cancer experience. In addition, they have unique psychosocial needs related to the burden of geographic distance. INTERPRETATION: Distance caregivers could benefit from nursing interventions targeted at their unique needs. Innovative interventions using Web based computer technology for improved communication, as well as supportive care interventions, may be helpful. PMID- 21531682 TI - Validity of the Patient Generated Index as a quality-of-life measure in radiation oncology. AB - PURPOSE/OBJECTIVES: To evaluate psychometric properties of an instrument designed to measure individualized health-related quality of life (HRQOL). DESIGN: Repeated measures of self-reported quality of life. SETTING: An outpatient radiation therapy department in the western part of the United States. SAMPLE: 86 adults with cancer receiving their first course of radiation therapy. METHODS: The Patient Generated Index (PGI), the National Comprehensive Cancer Network's Distress Thermometer (DT), and the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core-30 (QLQ-C30). MAIN RESEARCH VARIABLES: Convergent validity, responsiveness, sensitivity, and response shift. FINDINGS: PGI scores were inversely correlated with scores on the DT (r = -0.49, -0.55, -0.44; p < 0.001), as well as the role (r = 0.31, 0.4, 0.38; p < 0.01), emotional (r = 0.33, 0.41, 0.33; p < 0.01), social functioning (r = 0.27, 0.49, 0.42; p < 0.05), pain (r = -0.29, -0.39, -0.39; p < 0.01), and fatigue (r = -0.35, -0.25, -0.47; p < 0.05) QLQ-C30 subscales at all measurement times. The PGI was responsive to those reporting high or low DT scores (t = 4.42, 3.32, 2.9; p < 0.05). A small-to-moderate effect size was detected in those who had an increase (effect size = 0.51) or decrease (effect size = 0.38) in HRQOL over time. Participants reconceptualized HRQOL over time. CONCLUSIONS: Data supported the PGI as a valid measure of individualized HRQOL. IMPLICATIONS FOR NURSING: The PGI potentially provides a more patient-centered measure of HRQOL in patients with cancer. Additional testing is needed in larger, more diverse groups. PMID- 21531683 TI - Patient preferences concerning treatment plans, survivorship care plans, education, and support services. AB - PURPOSE/OBJECTIVES: To examine patient preferences for content and methods of delivering treatment plans, educational information, and survivorship care plans. RESEARCH APPROACH: Thematic analysis of four tape-recorded focus groups of cancer survivors. SETTING: An outpatient clinical cancer center in an academic medical center in the midwestern United States. PARTICIPANTS: 40 cancer survivors who had completed initial treatment. Participants were grouped by disease site: (a) prostate, genitourinary, and skin; (b) breast and gynecologic; (c) gastrointestinal, sarcoma, and head and neck; and (d) brain, pancreas, and lung. METHODOLOGIC APPROACH: An exploratory, descriptive approach with in-depth focus group thematic and comparative analysis methodology. The data are grouped into four major, interconnected themes. MAIN RESEARCH VARIABLES: Survivors' personal experiences with receiving cancer treatment. FINDINGS: Four categories were agreed on using thematic analysis: educational information, treatment plan, survivorship care plan, and patient support. Themes were identified within each category. CONCLUSIONS: The number of cancer survivors continues to grow each year. Approaching each survivor with individualized educational information, an initial treatment plan, a survivorship care plan, and emotional support is imperative. Oncology nurses must assess cancer survivors for their unique needs and intervene accordingly. INTERPRETATION: Because oncology nurses assess and recognize the learning needs of each patient, they are best positioned to develop teaching content, strategies, and timing of interventions. The importance of written educational materials cannot be negated. Oncology nurses also are well positioned to provide a proactive role in the development and delivery of treatment and survivorship plans of care. PMID- 21531684 TI - Adherence to oral chemotherapy in childhood acute lymphoblastic leukemia: an evolutionary concept analysis. AB - PURPOSE/OBJECTIVES: To clarify the concept of adherence to daily oral chemotherapy in children with acute lymphoblastic leukemia (ALL), to examine its implications for clinical practice, and to provide a foundation for further research and knowledge development. DATA SOURCES: Published literature identified through the MEDLINE(r), CINAHL(r), PsycINFO, and ERIC databases. DATA SYNTHESIS: Identified attributes of adherence to oral chemotherapy in childhood ALL included motivation, persistence, collaboration, mindfulness, cognitive capacity, flexibility, active participation, and identification of key participants in the process. Identified antecedents included a diagnosis of leukemia, the perceived value of adherence, and patient, family, and healthcare system-related factors. Identified consequences included the potential for maintaining optimal drug levels and improving disease outcome, as well as increased patient and caregiver esteem through active participation in the process. Adherence in the context of childhood ALL is defined as the active self-care behavior of taking (or having the responsibility for administering) daily oral chemotherapy, in collaboration with and according to the instructions of the healthcare provider over a defined, prolonged treatment period. CONCLUSIONS: Adherence to oral chemotherapy in childhood ALL is a complex, multidimensional behavior that involves not only a willingness to follow the prescribed regimen over a prolonged period, but also the cognitive capacity and psychomotor skills to carry out the process. IMPLICATIONS FOR NURSING: Nurses should recognize the importance of clear communication of medication instructions, reinforcement of adherence-related behaviors, and assistance with common issues such as pill-swallowing skills and reminder systems in caring for children with ALL. PMID- 21531685 TI - The Internet as a source of health information: experiences of cancer survivors and caregivers with healthcare providers. AB - PURPOSE/OBJECTIVES: To describe the experiences of cancer survivors and caregivers with healthcare providers in the context of the Internet as a source of health information. RESEARCH APPROACH: Qualitative description. SETTING: Online cancer communities hosted by the Association of Cancer Online Resources. PARTICIPANTS: Purposive sample of 488 cancer survivors, with varying cancer types and survivorship stages, and caregivers. METHODOLOGIC APPROACH: Secondary data analysis using Krippendorff's thematic clustering technique of qualitative content analysis. MAIN RESEARCH VARIABLES: Survivorship, healthcare relationships, and the Internet. FINDINGS: Disenchantment with healthcare relationships was associated with failed expectations related to evidence-based practice, clinical expertise, informational support, and therapeutic interpersonal communication. Survivors and caregivers exercised power in healthcare relationships through collaboration, direct confrontation, becoming expert, and endorsement to influence and control care decisions. CONCLUSIONS: Disenchantment propelled cancer survivors and caregivers to search the Internet for health information and resources. Conversely, Internet information-seeking precipitated the experience of disenchantment. Through online health information and resources, concealed failures in healthcare relationships were revealed and cancer survivors and caregivers were empowered to influence and control care decisions. INTERPRETATION: The findings highlight failures in cancer survivorship care and underscore the importance of novel interdisciplinary programs and models of care that support evidence-informed decision making, self-management, and improved quality of life. Healthcare professionals need to receive education on survivors' use of the Internet as a source of health information and its impact on healthcare relationships. Future research should include studies examining the relationship between disenchantment and survivorship outcomes. PMID- 21531686 TI - The Patient Care Monitor-Neutropenia Index: development, reliability, and validity of a measure for chemotherapy-induced neutropenia. AB - PURPOSE/OBJECTIVES: To provide an initial evaluation of the psychometric properties of the Patient Care Monitor 1.0 Revised-Neutropenia Index (PCM-N), a symptom-based assessment tool designed to measure health-related quality-of-life (HRQOL) changes associated with chemotherapy-induced neutropenia. DESIGN: Known groups methodology and self-report instrument validation. SETTING: A large community oncology practice in Memphis, TN. SAMPLE: 424 patients with cancer in four samples. METHODS: All patients in the first three samples were assessed at baseline of chemotherapy administration and at a point analogous to midcycle. The fourth sample underwent a cross-sectional evaluation of the ability of the PCM-N to distinguish patients with febrile neutropenia, severe afebrile neutropenia, and no neutropenia. MAIN RESEARCH VARIABLES: PCM-N score, grade of neutropenia, and febrile status. FINDINGS: Internal consistency reliability and factor analysis supported the single additive scale structure of the 13 items of the PCM N. The PCM-N demonstrated good known-groups validity and was able to distinguish patients with grades 3-4 neutropenia from those with grades 0-2. The tool also was able to distinguish patients with febrile neutropenia, severe afebrile neutropenia, and no neutropenia. Receiver operating characteristic analyses provided a psychometrically based threshold score. CONCLUSIONS: The PCM-N is a reliable and valid instrument sensitive to changes in HRQOL associated with moderate-to-severe chemotherapy-induced neutropenia. IMPLICATIONS FOR NURSING: Nurses can use the PCM-N as a rapid and cost-effective tool for monitoring symptoms of neutropenia in patients with cancer. PMID- 21531687 TI - Provider verbal responses to patient distress cues during ambulatory oncology visits. AB - PURPOSE/OBJECTIVES: To explore healthcare provider cue-responding behaviors to patient cues of distress and socioemotional concerns during ambulatory, on treatment oncology visits. DESIGN: Descriptive secondary analysis of a data set of audio recordings of oncology visits and reports of symptoms and quality of life recorded with an electronic self-report assessment-cancer (ESRA-C) tool. SETTING: Comprehensive cancer center, ambulatory care. SAMPLE: 31 randomly selected cases from an existing data set (with one used as a training tool) of 590 audio recordings of patient-provider communication. METHODS: Patients were placed in Group 1 (n = 20) and Group 2 (n = 10) to explore differences in patient provider communication and decrease coder bias. Both groups completed the ESRA-C questionnaire prior to the visit. Providers in Group 2 received a printed ESRA-C summary report for use during the visit. Audio files of the visit were coded using the Medical Interview Aural Rating System (MIARS). MAIN RESEARCH VARIABLES: Patient cues of distress and provider cue-responding behaviors. FINDINGS: Patient cues of distress and socioemotional concerns ranged from 0-13 cues per visit, with a mean of 4.6 cues per visit. Providers acknowledged 57% of patient cues, but only acknowledged and explored 22% of all patient cues. Providers in Group 2 acknowledged patient concerns more often but explored the concerns less frequently. The number of patient cues distanced from by providers was lower in Group 2 and the overall provider score for responsiveness to patient cues of distress was higher, indicating more responsiveness than from Group 1. CONCLUSIONS: The use of a summary report of patient concerns may have enhanced provider responsiveness, in general. Distancing behaviors by providers in response to patient verbal cues may indicate a lack of knowledge, time limitations, or a lack of confidence. IMPLICATIONS FOR NURSING: To effectively support patients with cancer through active therapy, a greater level of acknowledgment, exploration, and responsive action by providers is indicated. These findings have implications for provider education, with regard to appropriate responses, and for researchers to test methods that best prompt and support effective provider behaviors, ultimately improving patient outcomes. PMID- 21531690 TI - Internet skills performance tests: are people ready for eHealth? AB - BACKGROUND: Despite the amount of online health information, there are several barriers that limit the Internet's adoption as a source of health information. One of these barriers is highlighted in conceptualizations of the digital divide which include the differential possession of Internet skills, or "eHealth literacy". Most measures of Internet skills among populations at large use self assessments. The research discussed here applies a multifaceted definition of Internet skills and uses actual performance tests. OBJECTIVE: The purpose of this study was to assess how ready a sample of the general population is for eHealth. More specifically, four types of Internet skills were measured in a performance test in which subjects had to complete health-related assignments on the Internet. METHODS: From November 1, 2009, through February 28, 2010, 88 subjects participated in the study. Subjects were randomly selected from a telephone directory. A selective quota sample was used divided over equal subsamples of gender, age, and education. Each subject had to accomplish assignments on the Internet. The Internet skills accounted for were categorized as operational (basic skills to use the Internet), formal (navigation and orientation), information (finding information), and strategic (using the information for personal benefits). The tests took approximately 1.5 hours and were conducted in a University office, making the setting equally new for all. Successful completion and time spent on the assignments-the two main outcomes-were directly measured by the test leader. RESULTS: The subjects successfully completed an average of 73% (5.8/8) of the operational Internet skill tasks and an average of 73% (2.9/4) of the formal Internet skill tasks. Of the information Internet skills tasks, an average of 50% (1.5/3) was completed successfully and, of the strategic Internet skills tasks, 35% (0.7/2). Only 28% (25/88) of the subjects were able to successfully complete all operational skills tasks, 39% (34/88), all formal skills tasks, 13% (11/88), all information skills tasks, and 20% (18/88), both the strategic skill tasks. The time spent on the assignments varied substantially. Age and education were the most important contributors to the operational and formal Internet skills. Regarding the formal Internet skills, years of Internet experience also had some influence. Educational level of attainment was the most important contributor to the information and strategic Internet skills. CONCLUSIONS: Although the amount of online health-related information and services is consistently growing, it appears that the general population lacks the skills to keep up. Most problematic appear to be the lack of information and strategic Internet skills, which, in the context of health, are very important. The lack of these skills is also problematic for members of younger generations, who are often considered skilled Internet users. This primarily seems to account for the operational and formal Internet skills. The results of the study strongly call for policies to increase the level of Internet skills. PMID- 21531691 TI - What accounts for men's hostile attitudes toward women? The influence of hegemonic male role norms and masculine gender role stress. AB - This study examined masculine gender role stress (MGRS) as a mediator of the relation between adherence to dimensions of a hegemonic masculinity and hostility toward women (HTW). Among a sample of 338 heterosexual men, results indicated that MGRS mediated the relation between adherence to the status and antifemininity norms, but not the toughness norm, and HTW. Adherence to the toughness norm maintained a positive association with HTW. These findings suggest that men's HTW develops via multiple pathways that are associated with different norms of hegemonic masculinity. Implications for the prediction of men's aggression against women are discussed. PMID- 21531692 TI - "Paper abuse": when all else fails, batterers use procedural stalking. AB - Using data from in-depth interviews with women who have exited violent relationships, attorneys, and practitioners/policy specialists, this research note explores the continuation of control as women encounter "paper abuse." The barrage of men's frivolous lawsuits, false reports of child abuse, and other system-related manipulations exerts power, forces contact, and financially burdens their ex-partners. Although these acts are not new, the significance of this continuing abuse has not been fully explored by researchers. Yet attorneys and practitioners recognize the need for better documentation to strengthen protections for women still forced to contend with their former batterers. PMID- 21531693 TI - Health care-associated measles outbreak in the United States after an importation: challenges and economic impact. AB - BACKGROUND: On 12 February 2008, an infected Swiss traveler visited hospital A in Tucson, Arizona, and initiated a predominantly health care-associated measles outbreak involving 14 cases. We investigated risk factors that might have contributed to health care-associated transmission and assessed outbreak associated hospital costs. METHODS: Epidemiologic data were obtained by case interviews and review of medical records. Health care personnel (HCP) immunization records were reviewed to identify non-measles-immune HCP. Outbreak associated costs were estimated from 2 hospitals. RESULTS: Of 14 patients with confirmed cases, 7 (50%) were aged >= 18 years, 4 (29%) were hospitalized, 7 (50%) acquired measles in health care settings, and all (100%) were unvaccinated or had unknown vaccination status. Of the 11 patients (79%) who had accessed health care services while infectious, 1 (9%) was masked and isolated promptly after rash onset. HCP measles immunity data from 2 hospitals confirmed that 1776 (25%) of 7195 HCP lacked evidence of measles immunity. Among these HCPs, 139 (9%) of 1583 tested seronegative for measles immunoglobulin G, including 1 person who acquired measles. The 2 hospitals spent US$799,136 responding to and containing 7 cases in these facilities. CONCLUSIONS: Suspecting measles as a diagnosis, instituting immediate airborne isolation, and ensuring rapidly retrievable measles immunity records for HCPs are paramount in preventing health care associated spread and in minimizing hospital outbreak-response costs. PMID- 21531694 TI - Measles: going, going, but not gone. PMID- 21531695 TI - Dedifferentiated endometrioid adenocarcinoma of the uterus: a clinicopathologic study of a case. AB - Dedifferentiation confers more aggressive malignant behaviour than would be otherwise shown by the original tumor if present alone. This phenomenon has been described in several tumors, both mesenchymal and epithelial. Dedifferentiated endometrioid carcinoma either ovarian or endometrial is the latest addition to this family of tumors. Only 2 papers have appeared in the literature so far on the topic of dedifferentiated endometrioid carcinoma, both from the same institution. We report herein a case of endometrial dedifferentiated endometrioid carcinoma in a 45-year old lady with ovarian metastasis from the undifferentiated component. The primary endometrial tumor showed an undifferentiated component in an otherwise low grade endometrioid carcinoma. The undifferentiated component of these tumors can be misdiagnosed as the solid component of FIGO grade 3 in a pure endometrioid carcinoma. The recognition of an undifferentiated component in an otherwise low grade endometrioid carcinoma is very important, since dedifferentiated endometrioid adenocarcinoma has a worse prognosis when compared with FIGO grade 3 endometrioid carcinoma. PMID- 21531696 TI - Small-cell (basaloid) thyroid carcinoma: a neoplasm with a solid cell nest histogenesis? AB - In the past, undifferentiated (anaplastic) carcinoma of the thyroid included a small-cell variant with either a diffuse or a compact morphology. After the mid 1980s, with the advance of immunohistochemistry, almost all those rare tumors with the former characteristic were reclassified as low-grade lymphomas and those with the latter characteristic as small-cell variants of medullary carcinoma and poorly differentiated ("insular") carcinoma. Since then, no primary thyroid small cell carcinoma has been reported in the literature, with the exception of a case of a small-cell (neuroendocrine) carcinoma, an exceedingly rare neoplasm akin to medullary carcinoma, with expression of neuroendocrine markers but lacking calcitonin immunoreactivity. Here, the authors report a primary small-cell carcinoma of the thyroid displaying a basaloid appearance and lacking any signs of neuroendocrine or C-cell differentiation. PMID- 21531697 TI - The black color in pathology. PMID- 21531698 TI - Small-intestinal rhabdoid gastrointestinal stromal tumor (GIST): mutation analysis and clinical implications of a rare morphological variant. AB - Rhabdoid features in gastrointestinal stromal tumors (GISTs) are rare. To the authors' knowledge, only 51 cases have been reported. Most of these reports consist of case series in which the rhabdoid GISTs comprise a small proportion of the tumors studied. Information regarding site of origin and clinical behavior is sparse. Although the stomach is the only site of origin documented, most reports do not include this data. Malignancy has not been reported, though follow-up is inadequate in most cases to comment on tumor behavior. Exon 11 mutations comprise all previously described KIT mutations, the majority of which are deletions. The authors present the case of a malignant small-intestinal rhabdoid GIST that recurred twice following resection and treatment with tyrosine kinase inhibitors. The tumor harbored a KIT exon 11, 579-580 LY insertion that, to the authors' knowledge, has not been previously reported. This case is the first rhabdoid GIST described in the small intestine and is the first to show documented evidence of malignancy. PMID- 21531699 TI - PhyleasProg: a user-oriented web server for wide evolutionary analyses. AB - Evolutionary analyses of biological data are becoming a prerequisite in many fields of biology. At a time of high-throughput data analysis, phylogenetics is often a necessary complementary tool for biologists to understand, compare and identify the functions of sequences. But available bioinformatics tools are frequently not easy for non-specialists to use. We developed PhyleasProg (http://phyleasprog.inra.fr), a user-friendly web server as a turnkey tool dedicated to evolutionary analyses. PhyleasProg can help biologists with little experience in evolutionary methodologies by analysing their data in a simple and robust way, using methods corresponding to robust standards. Via a very intuitive web interface, users only need to enter a list of Ensembl protein IDs and a list of species as inputs. After dynamic computations, users have access to phylogenetic trees, positive/purifying selection data (on site and branch-site models), with a display of these results on the protein sequence and on a 3D structure model, and the synteny environment of related genes. This connection between different domains of phylogenetics opens the way to new biological analyses for the discovery of the function and structure of proteins. PMID- 21531700 TI - Coordinated regulation of mitochondrial topoisomerase IB with mitochondrial nuclear encoded genes and MYC. AB - Mitochondrial DNA (mtDNA) is entirely dependent on nuclear genes for its transcription and replication. One of these genes is TOP1MT, which encodes the mitochondrial DNA topoisomerase IB, involved in mtDNA relaxation. To elucidate TOP1MT regulation, we performed genome-wide profiling across the 60-cell line panel (the NCI-60) of the National Cancer Institute Developmental Therapeutics Program. We show that TOP1MT mRNA expression varies widely across these cell lines with the highest levels in leukemia (HL-60, K-562) and melanoma (SK-MEL 28), intermediate levels in breast (MDA-MB-231), ovarian (OVCAR) and colon (HCT 116, HCT-15, KM-12), and lowest levels in renal (ACHN, A498), prostate (PC-3, DU 145) and central nervous system cell lines (SF-539, SF-268, SF-295). Genome-wide analyses show that TOP1MT expression is significantly correlated with the other mitochondrial nuclear-encoded genes including the mitochondrial nucleoid genes, and demonstrate an overall co-regulation of the mitochondrial nuclear-encoded genes. We also find very high correlation between the expression of TOP1MT and the proto-oncogene MYC (c-myc). TOP1MT contains E-boxes (c-myc binding sites) and TOP1MT transcription follows MYC up- and down-regulation by MYC promoter activation and siRNA against MYC. Our finding implicates MYC as a novel regulator of TOP1MT and confirms its role as a master regulator of MNEGs and mitochondrial nucleoids. PMID- 21531701 TI - Solution structure and dynamic analysis of chicken MBD2 methyl binding domain bound to a target-methylated DNA sequence. AB - The epigenetic code of DNA methylation is interpreted chiefly by methyl cytosine binding domain (MBD) proteins which in turn recruit multiprotein co-repressor complexes. We previously isolated one such complex, MBD2-NuRD, from primary erythroid cells and have shown it contributes to embryonic/fetal beta-type globin gene silencing during development. This complex has been implicated in silencing tumor suppressor genes in a variety of human tumor cell types. Here we present structural details of chicken MBD2 bound to a methylated DNA sequence from the rho-globin promoter to which it binds in vivo and mediates developmental transcriptional silencing in normal erythroid cells. While previous studies have failed to show sequence specificity for MBD2 outside of the symmetric mCpG, we find that this domain binds in a single orientation on the rho-globin target DNA sequence. Further, we show that the orientation and affinity depends on guanine immediately following the mCpG dinucleotide. Dynamic analyses show that DNA binding stabilizes the central beta-sheet, while the N- and C-terminal regions of the protein maintain mobility. Taken together, these data lead to a model in which DNA binding stabilizes the MBD2 structure and that binding orientation and affinity is influenced by the DNA sequence surrounding the central mCpG. PMID- 21531702 TI - Restoration of G1 chemo/radioresistance and double-strand-break repair proficiency by wild-type but not endonuclease-deficient Artemis. AB - Deficiency in Artemis is associated with lack of V(D)J recombination, sensitivity to radiation and radiomimetic drugs, and failure to repair a subset of DNA double strand breaks (DSBs). Artemis harbors an endonuclease activity that trims both 5' and 3'-ends of DSBs. To examine whether endonucleolytic trimming of terminally blocked DSBs by Artemis is a biologically relevant function, Artemis-deficient fibroblasts were stably complemented with either wild-type Artemis or an endonuclease-deficient D165N mutant. Wild-type Artemis completely restored resistance to gamma-rays, bleomycin and neocarzinostatin, and also restored DSB repair proficiency in G0/G1 phase as measured by pulsed-field gel electrophoresis and repair focus resolution. In contrast, cells expressing the D165N mutant, even at very high levels, remained as chemo/radiosensitive and repair deficient as the parental cells, as evidenced by persistent gamma-H2AX, 53BP1 and Mre11 foci that slowly increased in size and ultimately became juxtaposed with promyelocytic leukemia protein nuclear bodies. In normal fibroblasts, overexpression of wild type Artemis increased radioresistance, while D165N overexpression conferred partial repair deficiency following high-dose radiation. Restoration of chemo/radioresistance by wild-type, but not D165N Artemis suggests that the lack of endonucleolytic trimming of DNA ends is the principal cause of sensitivity to double-strand cleaving agents in Artemis-deficient cells. PMID- 21531703 TI - Care transitions as opportunities for clinicians to use data exchange services: how often do they occur? AB - BACKGROUND: The electronic exchange of health information among healthcare providers has the potential to produce enormous clinical benefits and financial savings, although realizing that potential will be challenging. The American Recovery and Reinvestment Act of 2009 will reward providers for 'meaningful use' of electronic health records, including participation in clinical data exchange, but the best ways to do so remain uncertain. METHODS: We analyzed patient visits in one community in which a high proportion of providers were using an electronic health record and participating in data exchange. Using claims data from one large private payer for individuals under age 65 years, we computed the number of visits to a provider which involved transitions in care from other providers as a percentage of total visits. We calculated this 'transition percentage' for individual providers and medical groups. RESULTS: On average, excluding radiology and pathology, approximately 51% of visits involved care transitions between individual providers in the community and 36%-41% involved transitions between medical groups. There was substantial variation in transition percentage across medical specialties, within specialties and across medical groups. Specialists tended to have higher transition percentages and smaller ranges within specialty than primary care physicians, who ranged from 32% to 95% (including transitions involving radiology and pathology). The transition percentages of pediatric practices were similar to those of adult primary care, except that many transitions occurred among pediatric physicians within a single medical group. CONCLUSIONS: Care transition patterns differed substantially by type of practice and should be considered in designing incentives to foster providers' meaningful use of health data exchange services. PMID- 21531704 TI - Effect of gatifloxacin against Mycoplasma genitalium-related urethritis: an open clinical trial. AB - OBJECTIVES: Mycoplasma genitalium and Chlamydia trachomatis are the primary pathogens detected from non-gonococcal urethritis (NGU). In this study, the efficacy of gatifloxacin was examined against M genitalium-related urethritis. METHODS: The study was an open clinical trial evaluating the effectiveness of gatifloxacin with 200 mg doses twice a day for 7 days against male NGU. RESULTS: Between March and September 2008, 169 male patients were enrolled, and microbiological and clinical cure rates could be evaluated in 86 patients detected with C trachomatis or M genitalium and in 135 with NGU, respectively. Microbiological cure rates of gatifloxacin against C trachomatis and M genitalium were 100% and 83%, respectively, and the total clinical cure rate was 99%. CONCLUSION: Analysis of in-vivo and in-vitro data from the literature of fluoroquinolone efficacies against M genitalium suggests that a MIC90 of 0.125 MUg/ml or less may be useful for optimal activity against M genitalium infection. PMID- 21531705 TI - Structural neuroanatomy of tinnitus and hyperacusis in semantic dementia. AB - INTRODUCTION: Tinnitus and hyperacusis are common symptoms of excessive auditory perception in the general population; however, their anatomical substrates and disease associations continue to be defined. PATIENTS: with semantic dementia (SemD) frequently report tinnitus and hyperacusis but the significance and basis for these symptoms have not been elucidated. METHODS: 43 patients with a diagnosis of SemD attending a specialist cognitive disorders clinic were retrospectively studied. 14 patients (32% of the cohort) reported at least moderately severe chronic auditory symptoms: seven had tinnitus and a further seven had hyperacusis, and all had brain MRI while symptomatic. MRI data from SemD patients with and without auditory symptoms were compared using voxel based morphometry in order to identify neuroanatomical associations of tinnitus and hyperacusis. RESULTS: Compared with SemD patients with no history of auditory symptoms, patients with tinnitus or hyperacusis had relative preservation of grey matter in the posterior superior temporal lobe and reduced grey matter in the orbitofrontal cortex and medial geniculate nucleus. CONCLUSIONS: Tinnitus and hyperacusis may be a significant issue in SemD. Neuroanatomical evidence in SemD supports previous work implicating a distributed cortico-subcortical auditory and limbic network in the pathogenesis of these abnormal auditory percepts. PMID- 21531707 TI - Neurological picture. Bilateral thalamic venous hypertension caused by a tentorial dural arteriovenous fistula: endovascular treatment. PMID- 21531708 TI - WD repeat-containing protein 5, a ubiquitously expressed histone methyltransferase adaptor protein, regulates smooth muscle cell-selective gene activation through interaction with pituitary homeobox 2. AB - WD repeat-containing protein 5 (WDR5) is a common component of mammalian mixed lineage leukemia methyltransferase family members and is important for histone H3 lysine 4 methylation (H3K4me), which has been implicated in control of activation of cell lineage genes during embryogenesis. However, WDR5 has not been considered to play a specific regulatory role in epigenetic programming of cell lineage because it is ubiquitously expressed. Previous work from our laboratory showed the appearance of histone H3K4me within smooth muscle cell (SMC)-marker gene promoters during the early stages of development of SMC from multipotential embryonic cells but did not elucidate the underlying mechanisms that mediate SMC specific and locus-selective H3K4me. Results presented herein show that knockdown of WDR5 significantly decreased SMC-marker gene expression in cultured SMC differentiation systems and in Xenopus laevis embryos in vivo. In addition, we showed that WDR5 complexes within SMC progenitor cells contained H3K4 methyltransferase enzymatic activity and that knockdown of WDR5 selectively decreased H3K4me1 and H3K4me3 enrichment within SMC-marker gene promoter loci. Moreover, we present evidence that it is recruited to these gene promoter loci through interaction with a SMC-selective pituitary homeobox 2 (Pitx2). Taken together, studies provide evidence for a novel mechanism for epigenetic control of SMC-marker gene expression during development through interaction of WDR5, homeodomain proteins, and chromatin remodeling enzymes. PMID- 21531706 TI - Treatment of first tonic-clonic seizure does not affect mortality: long-term follow-up of a randomised clinical trial. AB - BACKGROUND: Information on the effects of early treatment of seizures on mortality is scarce. The authors assessed the survival of patients with a first generalised tonic-clonic seizure, randomised to immediate treatment (treated) versus treatment only in the event of seizure recurrence (untreated), over a 20 year period. METHODS: The authors followed 419 patients. The median follow-up was 19.7 years (range 0.2-21.5) for a total of 7867 person-years. RESULTS: 40 persons (9.6%) died during follow-up, 19 (8.9%) treated and 21 (10.3.%) untreated. The probability of surviving was 100% at 1 year, 97% (95% CI 95% to 99%) at 5 years, 94% (91-97) at 10 years and 91% (87-95) at 20 years in treated patients and 100%, 98% (95-100), 97% (94-99) and 89% (85-94), respectively, in untreated patients (p=0.7). After adjustment for treatment of first seizure and putative risk factors (gender, age, seizure type, previous uncertain seizures, family history of seizures, pre-, peri- and postnatal risk factors, remote aetiological factors for epilepsy, abnormal neurological examination, CT or MRI abnormalities, EEG abnormalities and acute treatment), only the presence of aetiological factors for epilepsy predicted a higher mortality (HR 3.4, 95% CI 2.5 to 4.3%; p<0.01). Patients with remote aetiological factors and who did not achieve 5-year remission had the poorest survival. CONCLUSION: Starting antiepileptic treatment immediately after the first generalised tonic-clonic seizure or only after seizure recurrence did not affect survival over the following 20 years. PMID- 21531709 TI - Oncogenic fusion protein EWS/FLI1 down-regulates gene expression by both transcriptional and posttranscriptional mechanisms. AB - Ewing family tumors are characterized by a translocation between the RNA binding protein EWS and one of five ETS transcription factors, most commonly FLI1. The fusion protein produced by the translocation has been thought to act as an aberrant transcription factor, leading to changes in gene expression and cellular transformation. In this study, we investigated the specific processes EWS/FLI1 utilizes to alter gene expression. Using both heterologous NIH 3T3 and human Ewing Family Tumor cell lines, we have demonstrated by quantitative pre-mRNA analysis that EWS/FLI1 repressed the expression of previously validated direct target genes at the level of transcript synthesis. ChIP experiments showed that EWS/FLI1 decreases the amount of Pol II at the promoter of down-regulated genes in both murine and human model systems. However, in down-regulated target genes, there was a significant disparity between the modulation of cognate mRNA and pre mRNAs, suggesting that these genes could also be regulated at a posttranscriptional level. Confirming this, we found that EWS/FLI1 decreased the transcript half-life of insulin-like growth factor binding protein 3, a down regulated direct target gene in human tumor-derived Ewing's sarcoma cell lines. Additionally, we have shown through reexpression experiments that full EWS/FLI1 mediated transcriptional repression requires intact EWS and ETS domains. Together these data demonstrate that EWS/FLI1 can dictate steady-state target gene expression by modulating both transcript synthesis and degradation. PMID- 21531710 TI - Identification of noncoding transcripts from within CENP-A chromatin at fission yeast centromeres. AB - The histone H3 variant CENP-A is the most favored candidate for an epigenetic mark that specifies the centromere. In fission yeast, adjacent heterochromatin can direct CENP-A(Cnp1) chromatin establishment, but the underlying features governing where CENP-A(Cnp1) chromatin assembles are unknown. We show that, in addition to centromeric regions, a low level of CENP-A(Cnp1) associates with gene promoters where histone H3 is depleted by the activity of the Hrp1(Chd1) chromatin-remodeling factor. Moreover, we demonstrate that noncoding RNAs are transcribed by RNA polymerase II (RNAPII) from CENP-A(Cnp1) chromatin at centromeres. These analyses reveal a similarity between centromeres and a subset of RNAPII genes and suggest a role for remodeling at RNAPII promoters within centromeres that influences the replacement of histone H3 with CENP-A(Cnp1). PMID- 21531711 TI - Molecular recognition of chymotrypsin by the serine protease inhibitor ecotin from Yersinia pestis. AB - Resistance to antibiotics is a problem not only in terms of healthcare but also biodefense. Engineering of resistance into a human pathogen could create an untreatable biothreat pathogen. One such pathogen is Yersinia pestis, the causative agent of plague. Previously, we have used a bioinformatic approach to identify proteins that may be suitable targets for antimicrobial therapy and in particular for the treatment of plague. The serine protease inhibitor ecotin was identified as one such target. We have carried out mutational analyses in the closely related Yersinia pseudotuberculosis, validating that the ecotin gene is a virulence-associated gene in this bacterium. Y. pestis ecotin inhibits chymotrypsin. Here, we present the structure of ecotin in complex with chymotrypsin to 2.74 A resolution. The structure features a biologically relevant tetramer whereby an ecotin dimer binds to two chymotrypsin molecules, similar to what was observed in related serine protease inhibitor structures. However, the vast majority of the interactions in the present structure are distinctive, indicating that the broad specificity of the inhibitor for these proteases is based largely on its capacity to recognize features unique to each of them. These findings will have implications for the development of small ecotin inhibitors for therapeutic use. PMID- 21531712 TI - Active site-labeled prothrombin inhibits prothrombinase in vitro and thrombosis in vivo. AB - Mouse and human prothrombin (ProT) active site specifically labeled with D-Phe Pro-Arg-CH(2)Cl (FPR-ProT) inhibited tissue factor-initiated thrombin generation in platelet-rich and platelet-poor mouse and human plasmas. FPR-prethrombin 1 (Pre 1), fragment 1 (F1), fragment 1.2 (F1.2), and FPR-thrombin produced no significant inhibition, demonstrating the requirement for all three ProT domains. Kinetics of inhibition of ProT activation by the inactive ProT(S195A) mutant were compatible with competitive inhibition as an alternate nonproductive substrate, although FPR-ProT deviated from this mechanism, implicating a more complex process. FPR-ProT exhibited ~10-fold more potent anticoagulant activity compared with ProT(S195A) as a result of conformational changes in the ProT catalytic domain that induce a more proteinase-like conformation upon FPR labeling. Unlike ProT and ProT(S195A), the pathway of FPR-ProT cleavage by prothrombinase was redirected from meizothrombin toward formation of the FPR-prethrombin 2 (Pre 2).F1.2 inhibitory intermediate. Localization of ProT labeled with Alexa Fluor(r) 660 tethered through FPR-CH(2)Cl ([AF660]FPR-ProT) during laser-induced thrombus formation in vivo in murine arterioles was examined in real time wide-field and confocal fluorescence microscopy. [AF660]FPR-ProT bound rapidly to the vessel wall at the site of injury, preceding platelet accumulation, and subsequently to the thrombus proximal, but not distal, to the vessel wall. [AF660]FPR-ProT inhibited thrombus growth, whereas [AF660]FPR-Pre 1, lacking the F1 membrane binding domain did not bind or inhibit. Labeled F1.2 localized similarly to [AF660]FPR-ProT, indicating binding to phosphatidylserine-rich membranes, but did not inhibit thrombosis. The studies provide new insight into the mechanism of ProT activation in vivo and in vitro, and the properties of a unique exosite directed prothrombinase inhibitor. PMID- 21531713 TI - Yeast 3-phosphoinositide-dependent protein kinase-1 (PDK1) orthologs Pkh1-3 differentially regulate phosphorylation of protein kinase A (PKA) and the protein kinase B (PKB)/S6K ortholog Sch9. AB - Pkh1, -2, and -3 are the yeast orthologs of mammalian 3-phosphoinositide dependent protein kinase-1 (PDK1). Although essential for viability, their functioning remains poorly understood. Sch9, the yeast protein kinase B and/or S6K ortholog, has been identified as one of their targets. We now have shown that in vitro interaction of Pkh1 and Sch9 depends on the hydrophobic PDK1-interacting fragment pocket in Pkh1 and requires the complementary hydrophobic motif in Sch9. We demonstrated that Pkh1 phosphorylates Sch9 both in vitro and in vivo on its PDK1 site and that this phosphorylation is essential for a wild type cell size. In vivo phosphorylation on this site disappeared during nitrogen deprivation and rapidly increased again upon nitrogen resupplementation. In addition, we have shown here for the first time that the PDK1 site in protein kinase A is phosphorylated by Pkh1 in vitro, that this phosphorylation is Pkh-dependent in vivo and occurs during or shortly after synthesis of the protein kinase A catalytic subunits. Mutagenesis of the PDK1 site in Tpk1 abolished binding of the regulatory subunit and cAMP dependence. As opposed to PDK1 site phosphorylation of Sch9, phosphorylation of the PDK1 site in Tpk1 was not regulated by nitrogen availability. These results bring new insight into the control and prevalence of PDK1 site phosphorylation in yeast by Pkh protein kinases. PMID- 21531714 TI - Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain containing protein (SPRED1), a tyrosine-protein phosphatase non-receptor type 11 (SHP2) substrate in the Ras/extracellular signal-regulated kinase (ERK) pathway. AB - SHP2 is a tyrosine phosphatase involved in the activation of the Ras/ERK signaling pathway downstream of a number of receptor tyrosine kinases. One of the proposed mechanisms involving SHP2 in this context is to dephosphorylate and inactivate inhibitors of the Ras/ERK pathway. Two protein families bearing a unique, common domain, Sprouty and SPRED proteins, are possible candidates because they have been reported to inhibit the Ras/ERK pathway upon FGF activation. We tested whether any of these proteins are likely substrates of SHP2. Our findings indicate that Sprouty2 binds to the C-terminal tail of SHP2, which is an unlikely substrate binding site, whereas SPRED proteins bind to the tyrosine phosphatase domain that is known to be the binding site for its substrates. Overexpressed SHP2 was able to dephosphorylate SPREDs but not Sprouty2. Finally, we found two tyrosine residues on SPRED1 that are required, when phosphorylated, to inhibit Ras/ERK activation and identified Tyr-420 as a specific dephosphorylation target of SHP2. The evidence obtained indicates that SPRED1 is a likely substrate of SHP2, whose tyrosine dephosphorylation is required to attenuate the inhibitory action of SPRED1 in the Ras/ERK pathway. PMID- 21531715 TI - Structural and functional studies indicating altered redox properties of hemoglobin E: implications for production of bioactive nitric oxide. AB - Hemoglobin (Hb) E (beta-Glu26Lys) remains an enigma in terms of its contributions to red blood cell (RBC) pathophysiological mechanisms; for example, EE individuals exhibit a mild chronic anemia, and HbE/beta-thalassemia individuals show a range of clinical manifestations, including high morbidity and death, often resulting from cardiac dysfunction. The purpose of this study was to determine and evaluate structural and functional consequences of the HbE mutation that might account for the pathophysiology. Functional studies indicate minimal allosteric consequence to both oxygen and carbon monoxide binding properties of the ferrous derivatives of HbE. In contrast, redox-sensitive reactions are clearly impacted as seen in the following: 1) the ~2.5 times decrease in the rate at which HbE catalyzes nitrite reduction to nitric oxide (NO) relative to HbA, and 2) the accelerated rate of reduction of aquometHbE by L-cysteine (L-Cys). Sol gel encapsulation studies imply a shift toward a higher redox potential for both the T and R HbE structures that can explain the origin of the reduced nitrite reductase activity of deoxyHbE and the accelerated rate of reduction of aquometHbE by cysteine. Deoxy- and CO HbE crystal structures (derived from crystals grown at or near physiological pH) show loss of hydrogen bonds in the microenvironment of betaLys-26 and no significant tertiary conformational perturbations at the allosteric transition sites in the R and T states. Together, these data suggest a model in which the HbE mutation, as a consequence of a relative change in redox properties, decreases the overall rate of Hb-mediated production of bioactive NO. PMID- 21531717 TI - A central interdomain protein joint in elongation factor G regulates antibiotic sensitivity, GTP hydrolysis, and ribosome translocation. AB - The antibiotic fusidic acid potently inhibits bacterial translation (and cellular growth) by lodging between domains I and III of elongation factor G (EF-G) and preventing release of EF-G from the ribosome. We examined the functions of key amino acid residues near the active site of EF-G that interact with fusidic acid and regulate hydrolysis of GTP. Alanine mutants of these residues spontaneously hydrolyzed GTP in solution, bypassing the normal activating role of the ribosome. A conserved phenylalanine in the switch II element of EF-G was important for suppressing GTP hydrolysis in solution and critical for catalyzing translocation of the ribosome along mRNA. These experimental results reveal the multipurpose roles of an interdomain joint in the heart of an essential translation factor that can both promote and inhibit bacterial translation. PMID- 21531716 TI - Inhibitors of histone deacetylases: correlation between isoform specificity and reactivation of HIV type 1 (HIV-1) from latently infected cells. AB - Deacetylation of histone proteins at the HIV type 1 (HIV-1) long terminal repeat (LTR) by histone deactylases (HDACs) can promote transcriptional repression and virus latency. As such, HDAC inhibitors (HDACI) could be used to deplete reservoirs of persistent, quiescent HIV-1 proviral infection. However, the development of HDACI to purge latent HIV-1 requires knowledge of the HDAC isoforms contributing to viral latency and the development of inhibitors specific to these isoforms. In this study, we identify the HDACs responsible for HIV-1 latency in Jurkat J89GFP cells using a chemical approach that correlates HDACI isoform specificity with their ability to reactivate latent HIV-1 expression. We demonstrate that potent inhibition or knockdown of HDAC1, an HDAC isoform reported to drive HIV-1 into latency, was not sufficient to de-repress the viral LTR. Instead, we found that inhibition of HDAC3 was necessary to activate latent HIV-1. Consistent with this finding, we identified HDAC3 at the HIV-1 LTR by chromatin immunoprecipitation. Interestingly, we show that valproic acid is a weak inhibitor of HDAC3 (IC(50) = 5.5 mm) relative to HDAC1 (IC(50) = 170 MUm). Because the total therapeutic concentration of valproic acid ranges from 275 to 700 MUm in adults, these data may explain why this inhibitor has no effect on the decay of latent HIV reservoirs in patients. Taken together, our study suggests an important role for HDAC3 in HIV-1 latency and, importantly, describes a chemical approach that can readily be used to identify the HDAC isoforms that contribute to HIV-1 latency in other cell types. PMID- 21531718 TI - Mutagenesis mapping of the presenilin 1 calcium leak conductance pore. AB - Missense mutations in presenilin 1 (PS1) and presenilin 2 (PS2) proteins are a major cause of familial Alzheimer disease. Presenilins are proteins with nine transmembrane (TM) domains that function as catalytic subunits of the gamma secretase complex responsible for the cleavage of the amyloid precursor protein and other type I transmembrane proteins. The water-filled cavity within presenilin is necessary to mediate the intramembrane proteolysis reaction. Consistent with this idea, cysteine-scanning mutagenesis and NMR studies revealed a number of water-accessible residues within TM7 and TM9 of mouse PS1. In addition to gamma-secretase function, presenilins also demonstrate a low conductance endoplasmic reticulum Ca(2+) leak function, and many familial Alzheimer disease presenilin mutations impair this function. To map the potential Ca(2+) conductance pore in PS1, we systematically evaluated endoplasmic reticulum Ca(2+) leak activity supported by a series of cysteine point mutants in TM6, TM7, and TM9 of mouse PS1. The results indicate that TM7 and TM9, but not TM6, could play an important role in forming the conductance pore of PS1. These results are consistent with previous cysteine-scanning mutagenesis and NMR analyses of PS1 and provide further support for our hypothesis that the hydrophilic catalytic cavity of presenilins may also constitute a Ca(2+) conductance pore. PMID- 21531720 TI - Potent family-18 chitinase inhibitors: x-ray structures, affinities, and binding mechanisms. AB - Six novel inhibitors of Vibrio harveyi chitinase A (VhChiA), a family-18 chitinase homolog, were identified by in vitro screening of a library of pharmacologically active compounds. Unlike the previously identified inhibitors that mimicked the reaction intermediates, crystallographic evidence from 14 VhChiA-inhibitor complexes showed that all of the inhibitor molecules occupied the outer part of the substrate-binding cleft at two hydrophobic areas. The interactions at the aglycone location are well defined and tightly associated with Trp-397 and Trp-275, whereas the interactions at the glycone location are patchy, indicating lower affinity and a loose interaction with two consensus residues, Trp-168 and Val-205. When Trp-275 was substituted with glycine (W275G), the binding affinity toward all of the inhibitors dramatically decreased, and in most structures two inhibitor molecules were found to stack against Trp-397 at the aglycone site. Such results indicate that hydrophobic interactions are important for binding of the newly identified inhibitors by the chitinase. X-ray data and isothermal microcalorimetry showed that the inhibitors occupied the active site of VhChiA in three different binding modes, including single-site binding, independent two-site binding, and sequential two-site binding. The inhibitory effect of dequalinium in the low nanomolar range makes this compound an extremely attractive lead compound for plausible development of therapeutics against human diseases involving chitinase-mediated pathologies. PMID- 21531719 TI - Deimination of human filaggrin-2 promotes its proteolysis by calpain 1. AB - Filaggrin-2 (FLG2), a member of the S100-fused type protein family, shares numerous features with filaggrin (FLG), a key protein implicated in the epidermal barrier functions. Both display a related structural organization, an identical pattern of expression and localization in human epidermis, and proteolytic processing of a large precursor. Here, we tested whether FLG2 was a substrate of calpain 1, a calcium-dependent protease directly involved in FLG catabolism. In addition, deimination being critical for FLG degradation, we analyzed whether FLG2 deimination interfered with its proteolytic processing. With this aim, we first produced a recombinant form of FLG2 corresponding to subunits B7 to B10 fused to a COOH-terminal His tag. Incubation with calpain 1 in the presence of calcium induced a rapid degradation of the recombinant protein and the production of several peptides, as shown by Coomassie Blue-stained gels and Western blotting with anti-FLG2 or anti-His antibodies. MALDI-TOF mass spectrometry confirmed this result and further evidenced the production of non-immunoreactive smaller peptides. The degradation was not observed when a calpain 1-specific inhibitor was added. The calpain cleavage sites identified by Edman degradation were regularly present in the B-type repeats of FLG2. Moreover, immunohistochemical analysis of normal human skin revealed colocalization of FLG2 and calpain 1 in the upper epidermis. Finally, the FLG2 deiminated by human peptidylarginine deiminases was shown to be more susceptible to calpain 1 than the unmodified protein. Altogether, these data demonstrate that calpain 1 is essential for the proteolytic processing of FLG2 and that deimination accelerates this process. PMID- 21531722 TI - Phosvitin plays a critical role in the immunity of zebrafish embryos via acting as a pattern recognition receptor and an antimicrobial effector. AB - How fish embryos that develop externally survive microbial attacks is poorly understood. Here, we clearly demonstrated that the embryo extract of zebrafish and its early embryo both displayed antimicrobial activity against microbes, including pathogenic Aeromonas hydrophila, and phosvitin (Pv), a nutritional protein abundant in eggs, was related to this antimicrobial activity. We also showed that recombinant Pv (rPv) acted as a pattern recognition receptor capable of recognizing the microbial signature molecules LPS, lipoteichoic acid, and peptidoglycan, as well as binding the Gram-negative and -positive microbes Escherichia coli, A. hydrophila, and Staphylococcus aureus and functioned as an antimicrobial agent capable of killing the microbes. Furthermore, we revealed that its C-terminal 55 residues (Pt5) with the functional sites Arg(242) and Ala(201)/Ile(203) were indispensable for Pv antimicrobial activity. Importantly, microinjection of rPv or Pt5 into early embryos significantly enhanced their resistance to A. hydrophila challenge, and this enhanced bacterial resistance was markedly reduced by co-injection of anti-Pv antibody plus rPv (or Pt5) but not by injection of anti-actin antibody plus rPv. Moreover, the generated mutants with in vitro antimicrobial activity, when injected into the embryos, could also promote their resistance to A. hydrophila, but those without in vitro antimicrobial activity could not. It is thus proposed that Pv participates in the protection of early embryos against pathogenic attacks via binding and disrupting potential pathogens. This work also opens a new way for the study of the immunological roles of yolk proteins in oviparous animals that rely on yolk proteins for embryonic development. PMID- 21531721 TI - EGFL6 promotes endothelial cell migration and angiogenesis through the activation of extracellular signal-regulated kinase. AB - Angiogenesis is required for bone development, growth, and repair. It is influenced by the local bone environment that involves cross-talks between endothelial cells and adjacent bone cells. However, data regarding factors that directly contribute to angiogenesis by bone cells remain poorly understood. Here, we report that EGFL6, a member of the epidermal growth factor (EGF) repeat superfamily proteins, induces angiogenesis by a paracrine mechanism in which EGFL6 is expressed in osteoblastic-like cells but promotes migration and angiogenesis of endothelial cells. Co-immunoprecipitation assays revealed that EGFL6 is secreted in culture medium as a homodimer protein. Using scratch wound healing and transwell assays, we found that conditioned medium containing EGFL6 potentiates SVEC (a simian virus 40-transformed mouse microvascular endothelial cell line) endothelial cell migration. In addition, EGFL6 promotes the endothelial cell tube-like structure formation in Matrigel assays and angiogenesis in a chick embryo chorioallantoic membrane. Furthermore, we show that EGFL6 recombinant protein induces phosphorylation of ERK in SVEC endothelial cells. Inhibition of ERK impaired EGFL6-induced ERK activation and endothelial cell migration. Together, these results demonstrate, for the first time, that osteoblastic-like cells express EGFL6 that is capable of promoting endothelial cell migration and angiogenesis via ERK activation. Thus, the EGLF6 mediates a paracrine mechanism of cross-talk between vascular endothelial cells and osteoblasts and might offer an important new target for the potential treatment of bone diseases, including osteonecrosis, osteoporosis, and fracture healing. PMID- 21531723 TI - An intermediate membrane subfraction in cyanobacteria is involved in an assembly network for Photosystem II biogenesis. AB - Early steps in the biogenesis of Photosystem II (PSII) in the cyanobacterium Synechocystis sp. PCC 6803 are thought to occur in a specialized membrane fraction that is characterized by the specific accumulation of the PSII assembly factor PratA and its interaction partner pD1, the precursor of the D1 protein of PSII. Here, we report the molecular characterization of this membrane fraction, called the PratA-defined membrane (PDM), with regard to its lipid and pigment composition and its association with PSII assembly factors, including YCF48, Slr1471, Sll0933, and Pitt. We demonstrate that YCF48 and Slr1471 are present and that the chlorophyll precursor chlorophyllide a accumulates in the PDM. Analysis of PDMs from various mutant lines suggests a central role for PratA in the spatial organization of PSII biogenesis. Moreover, quantitative immunoblot analyses revealed a network of interdependences between several PSII assembly factors and chlorophyll synthesis. In addition, formation of complexes containing both YCF48 and Sll0933 was substantiated by co-immunoprecipitation experiments. The findings are integrated into a refined model for PSII biogenesis in Synechocystis 6803. PMID- 21531724 TI - Kinetic analysis of beta-galactosidase and beta-glucuronidase tetramerization coupled with protein translation. AB - Both beta-galactosidase (GAL) and beta-glucuronidase (GUS) are tetrameric enzymes used widely as reporter proteins. However, little is known about the folding and assembly of these enzymes. Although the refolding kinetics of GAL from a denatured enzyme have been reported, it is not known how the kinetics differ when coupled with a protein translation reaction. Elucidating the assembly kinetics of GAL and GUS when coupled with protein translation will illustrate the differences between these two reporter proteins and also the assembly process under conditions more relevant to those in vivo. In this study, we used an in vitro translation/transcription system to synthesize GAL and GUS, measured the time development of the activity and oligomerization state of these enzymes, and determined the rate constants of the monomer to tetramer assembly process. We found that at similar concentrations, GAL assembles into tetramers faster than GUS. The rate constant of monomer to dimer assembly of GAL was 50-fold faster when coupled with protein translation than that of refolding from the denatured state. Furthermore, GAL synthesis was found to lack the rate-limiting step in the assembly process, whereas GUS has two rate-limiting steps: monomer to dimer assembly and dimer to tetramer assembly. The consequence of these differences when used as reporter proteins is discussed. PMID- 21531725 TI - Water-assisted proton transfer in ferredoxin I. AB - The role of water molecules in assisting proton transfer (PT) is investigated for the proton-pumping protein ferredoxin I (FdI) from Azotobacter vinelandii. It was shown previously that individual water molecules can stabilize between Asp(15) and the buried [3Fe-4S](0) cluster and thus can potentially act as a proton relay in transferring H(+) from the protein to the MU(2) sulfur atom. Here, we generalize molecular mechanics with proton transfer to studying proton transfer reactions in the condensed phase. Both umbrella sampling simulations and electronic structure calculations suggest that the PT Asp(15)-COOH + H(2)O + [3Fe 4S](0) -> Asp(15)-COO(-) + H(2)O + [3Fe-4S](0) H(+) is concerted, and no stable intermediate hydronium ion (H(3)O(+)) is expected. The free energy difference of 11.7 kcal/mol for the forward reaction is in good agreement with the experimental value (13.3 kcal/mol). For the reverse reaction (Asp(15)-COO(-) + H(2)O + [3Fe 4S](0)H(+) -> Asp(15)-COOH + H(2)O + [3Fe-4S](0)), a larger barrier than for the forward reaction is correctly predicted, but it is quantitatively overestimated (23.1 kcal/mol from simulations versus 14.1 from experiment). Possible reasons for this discrepancy are discussed. Compared with the water-assisted process (DeltaE ~ 10 kcal/mol), water-unassisted proton transfer yields a considerably higher barrier of DeltaE ~ 35 kcal/mol. PMID- 21531726 TI - p53 negatively regulates RGS13 protein expression in immune cells. AB - RGS13, a member of the regulator of G protein signaling (RGS) family, inhibits G protein-coupled receptor signaling in B cells and mast cells (MCs) and suppresses IgE-antigen-induced MC degranulation and anaphylaxis. Although RGS13 expression is induced by immune receptor and chemokine receptor stimulation, the molecular regulation of RGS13 transcription is unknown. Here, we investigated the role of two p53 response elements (REs) in the regulation of RGS13 promoter activity and expression. We found that a 1000-bp DNA fragment upstream of the ATG translation start site (TSS) had promoter activity in reporter gene assays, and deletion or mutation of a p53-binding motif nearest the TSS abolished promoter activity. Notably, p53 bound to both REs in the RGS13 promoter in vivo as assessed by chromatin immunoprecipitation, suggesting that the p53 RE most distal to the TSS is physiologically inactive. We detected reduced RGS13 expression in MCs exogenously expressing p53 or treated with doxorubicin, which induces genotoxic stress and leads to p53 accumulation. RNA silencing of p53 up-regulated RGS13 expression in B lymphocytes, and bone marrow-derived MCs from p53(-/-) mice had increased RGS13 expression. Finally, p53-depleted B cells with increased RGS13 expression had reduced Ca(2+) mobilization in response to sphingosine 1 phosphate. These studies indicate that p53 may modulate immune responses through suppression of RGS13 transcription in MCs and B cells. PMID- 21531727 TI - Secretion of endoplasmic reticulum aminopeptidase 1 is involved in the activation of macrophages induced by lipopolysaccharide and interferon-gamma. AB - Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme with an important role in processing antigenic peptides presented to class I major histocompatibility complex in the endoplasmic reticulum. In this study, we found that endoplasmic reticulum-retained ERAP1 was secreted from macrophages in response to activation by treatment with lipopolysaccharide (LPS) and interferon (IFN)-gamma and enhanced their phagocytic activity. Enhancement of the phagocytic activity of murine macrophage RAW264.7 cells induced by LPS/IFN-gamma was inhibited by a potent aminopeptidase inhibitor, amastatin. The addition of recombinant wild-type but not inactive mutant ERAP1 to culture medium enhanced phagocytosis. These results suggest that enhancement of phagocytic activity is at least in part mediated by secreted ERAP1 through the generation of active peptides processed by the enzyme. Our data reveal ERAP1-mediated activation of macrophages for the first time and will provide new insights into the role of this enzyme in innate immunity. PMID- 21531728 TI - Molecular characterization of the interaction between sialylated Neisseria gonorrhoeae and factor H. AB - Human factor H (HufH), a key inhibitor of the alternative pathway of complement, binds to Neisseria gonorrhoeae and constitutes an important mechanism of human specific complement evasion. The C-terminal domain 20 of HufH contains the binding site for sialylated gonococci. We exploited differences in amino acid sequences between human and non-binding chimpanzee fH domain 20 to create cross species mutations to define amino acids important for binding to sialylated gonococci. We used fH/Fc fusion constructs that contained contiguous fH domains 18-20 fused to Fc fragments of murine IgG2a. The Fc region was used both as a tag for detection of each fusion molecule on the bacterial surface and as an indicator for complement-dependent killing. Arg-1203 was critical for binding to both porin (Por) B.1A and PorB.1B strains. Modeling of the R1203N human-to chimpanzee mutation using the crystal structure of HufH19-20 as a template showed a loss of positive charge that protrudes at the C terminus of domain 20. We tested the functional importance of Arg-1203 by incubating sialylated gonococci with normal human serum, in the presence of wild-type HufH18-20/Fc or its R1203A mutant. Gonococci bound and were killed by wild-type HufH18-20/Fc but not by the R1203A mutant. A recombinant fH/Fc molecule that contained chimpanzee domain 20, humanized only at amino acid 1203 (N1203R) also bound to sialylated gonococci and restored killing. These findings provide further insights into the species specificity of gonococcal infections and proof-of-concept of a novel therapeutic approach against gonorrhea, a disease rapidly becoming resistant to conventional antibiotics. PMID- 21531730 TI - A20 is induced by Kaposi sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 and blocks K13-induced nuclear factor-kappaB in a negative feedback manner. AB - Expression of A20, a negative regulator of the NF-kappaB pathway, is frequently lost in several subtypes of Hodgkin and non-Hodgkin lymphoma. We report that A20 is expressed in Kaposi sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma cell lines, and its expression correlates closely with the expression of KSHV-encoded viral FLICE inhibitory protein K13. Ectopic expression of K13 induced A20 expression through NF-kappaB-mediated activation of A20 promoter. In turn, A20 blocked K13-induced NF-kappaB activity and up-regulation of proinflammatory cytokines CCL20 and IL-8 in a negative feedback fashion. Both the N-terminal deubiquitinating domain and the C-terminal zinc finger domain of A20 were involved in the inhibition of K13-induced NF-kappaB activity. Overexpression of A20 blocked K13-induced IkappaBalpha phosphorylation, NF-kappaB nuclear translocation, and cellular transformation. Consistent with the above, K13-induced IkappaBalpha phosphorylation and NF-kappaB transcriptional activation were enhanced in A20-deficient cells. Finally, A20 was found to interact physically with K13. Taken collectively, these results demonstrate that K13 is a key determinant of A20 expression in KSHV-infected cells, and A20 is a key negative regulator of K13-induced NF-kappaB activity. A20 might serve to control the inflammatory response to KSHV infection and protect KSHV-infected cells from apoptosis. PMID- 21531729 TI - Bi-specific aptamers mediating tumor cell lysis. AB - Antibody-dependent cellular cytotoxicity plays a pivotal role in antibody-based tumor therapies and is based on the recruitment of natural killer cells to antibody-bound tumor cells via binding of the Fcgamma receptor III (CD16). Here we describe the generation of chimeric DNA aptamers that simultaneously bind to CD16alpha and c-Met, a receptor that is overexpressed in many tumors. By application of the systematic evolution of ligands by exponential enrichment (SELEX) method, CD16alpha specific DNA aptamers were isolated that bound with high specificity and affinity (91 pm-195 nm) to their respective recombinant and cellularly expressed target proteins. Two optimized CD16alpha specific aptamers were coupled to each of two c-Met specific aptamers using different linkers. Bi specific aptamers retained suitable binding properties and displayed simultaneous binding to both antigens. Moreover, they mediated cellular cytotoxicity dependent on aptamer and effector cell concentration. Displacement of a bi-specific aptamer from CD16alpha by competing antibody 3G8 reduced cytotoxicity and confirmed the proposed mode of action. These results represent the first gain of a tumor effective function of two distinct oligonucleotides by linkage into a bi-specific aptamer mediating cellular cytotoxicity. PMID- 21531731 TI - Formation of a stable RuvA protein double tetramer is required for efficient branch migration in vitro and for replication fork reversal in vivo. AB - In bacteria, RuvABC is required for the resolution of Holliday junctions (HJ) made during homologous recombination. The RuvAB complex catalyzes HJ branch migration and replication fork reversal (RFR). During RFR, a stalled fork is reversed to form a HJ adjacent to a DNA double strand end, a reaction that requires RuvAB in certain Escherichia coli replication mutants. The exact structure of active RuvAB complexes remains elusive as it is still unknown whether one or two tetramers of RuvA support RuvB during branch migration and during RFR. We designed an E. coli RuvA mutant, RuvA2(KaP), specifically impaired for RuvA tetramer-tetramer interactions. As expected, the mutant protein is impaired for complex II (two tetramers) formation on HJs, although the binding efficiency of complex I (a single tetramer) is as wild type. We show that although RuvA complex II formation is required for efficient HJ branch migration in vitro, RuvA2(KaP) is fully active for homologous recombination in vivo. RuvA2(KaP) is also deficient at forming complex II on synthetic replication forks, and the binding affinity of RuvA2(KaP) for forks is decreased compared with wild type. Accordingly, RuvA2(KaP) is inefficient at processing forks in vitro and in vivo. These data indicate that RuvA2(KaP) is a separation-of function mutant, capable of homologous recombination but impaired for RFR. RuvA2(KaP) is defective for stimulation of RuvB activity and stability of HJ.RuvA.RuvB tripartite complexes. This work demonstrates that the need for RuvA tetramer-tetramer interactions for full RuvAB activity in vitro causes specifically an RFR defect in vivo. PMID- 21531732 TI - ADAMTS13--more than just TMA and TTP. AB - ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type-1 motifs 13) has been shown to be of major pathophysiological importance for thrombotic microangiopathy (TMA) in the setting of thrombocytic thrombocytopenic purpura (TTP) when either lacking (inherited TTP) or if antibodies against ADAMTS13 are present (acquired TTP). A potential pathophysiological role of ADAMTS13 has also been postulated in other diseases i.e. myocardial infarction, atrial fibrillation and diabetic angiopathy. Recent data provides evidence, however, for a completely different role of ADAMTS13 in vascular physiology and pathophysiology. In the present issue of Nephrology Dialysis and Transplantation, Bockmeyer et al. documented a physiological expression of ADAMTS13 in arteriolar vascular smooth muscle cells (VSMCs) which is maintained in the early, so-called benign nephrosclerosis, i.e. under conditions of early hypertensive vascular damage, and is completely lost if the damage proceeds to late, fibrotic stages of vascular injury. Thus, the recent report identifies ADAMTS13 as a new marker for the contractile phenotype of VSMC which is maintained in the early, hyalinotic phase of vascular damage, but is lost in later, more fibrotic stages of benign nephrosclerosis. This finding adds a novel and potentially important aspect to the unsolved and underestimated problem of benign or hypertensive nephrosclerosis. PMID- 21531733 TI - The emerging role of microvesicles in cellular therapies for organ/tissue regeneration. PMID- 21531734 TI - The 7th Asia Cancer Forum: from the perspective of human security, how can we collaborate as Asians in order to place cancer on the global health agenda? How can we fill in the gaps that exist among us? AB - This forum has continued to discuss the inclusion of cancer on the global health agenda, and specifically the Millennium Development Goals. The seventh forum presented an overview of activities to date, supplemented by reports from Korea, local governments in Japan and representatives from the pharmaceutical industry. Discussion focused on how to engage in measures to tackle cancer prevention and achieve early detection and effective treatment, using limited resources. It was recognized that with non-communicable diseases gaining increasing attention in international dialogue, it is now of the utmost importance to share an accurate recognition of cancer research and treatment throughout Asia and the wider world. Participants concurred that cancer issues are decoupled from the development aid agenda and that cooperation should be advanced on the basis of international cooperation without recourse to governmental development aid. PMID- 21531735 TI - Multiplex RT-PCR detection of Cucumber mosaic virus subgroups and Tobamoviruses infecting Tomato using 18S rRNA as an internal control. AB - A multiplex reverse-transcription polymerase chain reaction (RT-PCR) protocol was developed for simultaneous detection and discrimination of subgroups of Cucumber mosaic virus (CMV), including its satellite RNA, Tomato mosaic virus (ToMV) and Tobacco mosaic virus (TMV), using 18S rRNA as an internal control. Species- and subgroups-specific primers designed to differentiate CMV subgroups I and II, ToMV and TMV, were assessed using the cDNA clones of viral genomes, CMV satellite RNA and 18S rRNA gene from tomato (Solanum lycopersicum L.) or tobacco (Nicotiana tobacum). Using total RNA extracted from artificial mixture of tomato leaf tissues infected by each virus, the reaction components and cycling parameters were optimized and a multiplex RT-PCR procedure was established. Six fragments of 704, 593, 512, 421, 385, 255 bp, specific to CMV subgroup II, CMV subgroup I, ToMV, TMV, satellite RNA and 18S rRNA, respectively, were simultaneously amplified. The sensitivity of the multiplex RT-PCR method for detecting CMV was 100 times higher than that of double-antibody sandwich-enzyme-linked immunosorbent assay (DAS-ELISA). This method was successfully used for field detection. Among 141 samples collected from East China through tomato growth seasons, 106 single infections with one of the above isolates were detected and 13 mixed infections were found. The results showed the potential use of this method for investigating the epidemiology of viral diseases infecting tomato. PMID- 21531736 TI - Use of a clinical practice guidelines checklist to reduce intravenous catheter related infections. PMID- 21531737 TI - Effect of enteral versus parenteral nutrition on outcome of medical patients requiring mechanical ventilation. AB - BACKGROUND: Early enteral nutrition (EN) in patients receiving mechanical ventilation commonly has been advocated, based mainly on studies conducted in mixed populations of trauma and surgery patients. In this study, ventilator associated pneumonia rates and outcomes were compared in mechanically ventilated medical intensive care unit (ICU) patients receiving enteral versus parenteral nutrition. METHODS: Patients fulfilling inclusion criteria between February 1, 2004, and January 31, 2006, were included. Patients were randomized to enteral or parenteral nutrition (PN) within 48 hours of intubation. Development of ventilator-associated pneumonia, assessment as to whether day feeding goal was attained, duration of mechanical ventilation, ICU and hospital length of stay (LOS), and mortality rates were recorded. RESULTS: Of 249 consecutive patients receiving mechanical ventilation, 71 patients were included. Thirty (42.3%) patients received EN, and 41 (57.7%) received PN. There was no difference between groups for age, sex, body mass index, and scores on the Acute Physiology and Chronic Health Evaluation II. Ventilator-associated pneumonia rate, ICU and hospital LOS, and mortality rates were similar for both groups. In the parenterally fed group, duration of mechanical ventilation was longer (p = .023), but the feeding goal was attained earlier (p = .012). CONCLUSIONS: In mechanically ventilated patients in the medical ICU, ventilator-associated pneumonia rates, ICU and hospital lengths of stay, and ICU and hospital mortality rates of patients receiving PN are not significantly different than those in patients receiving EN, and feeding goals can more effectively be attained by PN. Yet, duration of mechanical ventilation is slightly longer in patients receiving PN. PMID- 21531738 TI - Role of nutrition in pediatric chronic liver disease. AB - The liver plays a central role in energy and nutrient metabolism. Malnutrition is highly prevalent among patients with chronic liver disease and leads to increased morbidity and mortality rates. This review addresses the causes of malnutrition, methods used to assess nutrition status, and appropriate treatment strategies in pediatric patients with chronic liver disease. PMID- 21531739 TI - Jeotgalibacillus soli sp. nov., a Gram-stain-positive bacterium isolated from soil. AB - A Gram-staining-positive, motile, rod-shaped, spore-forming bacterium, designated P9(T), was isolated from soil in Portugal. This organism was aerobic and catalase and oxidase-positive. It had an optimum growth temperature of about 35 degrees C and an optimum growth pH of about 8.0-8.5, and grew in medium with 0-9% (w/v) NaCl. The cell-wall peptidoglycan was of the A1alpha type, with L-lysine as the diagnostic diamino acid. The major respiratory quinone was menaquinone 7 (MK-7) and the major fatty acids were anteiso-C(15:0) (45.4%), iso-C(15:0) (22.0%) and anteiso-C(17:0) (11.2%). The genomic DNA G+C content was about 39.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain P9(T) was most closely related to Jeotgalibacillus campisalis DSM 18983(T) (96.8%) and Jeotgalibacillus marinus DSM 1297(T) (96.5%). These two recognized species formed a coherent cluster with strain P9(T) that was supported by a bootstrap value of 99%. On the basis of the phylogenetic analysis and physiological and biochemical characteristics, strain P9(T) (=DSM 23228(T)=LMG 25523(T)) represents a novel species of the genus Jeotgalibacillus, for which the name Jeotgalibacillus soli sp. nov. is proposed. PMID- 21531740 TI - Moorella humiferrea sp. nov., a thermophilic, anaerobic bacterium capable of growth via electron shuttling between humic acid and Fe(III). AB - An anaerobic, thermophilic, spore-forming bacterium (strain 64-FGQ(T)) was isolated from a terrestrial hydrothermal spring from the Kamchatka peninsula, Russia. This strain utilized lactate as an electron donor, insoluble poorly crystalline Fe(III) oxide incorporated into alginate beads as a potential electron acceptor and 9,10-anthraquinone-2,6-disulfonate (AQDS) as an electron shuttling compound. Vegetative cells of strain 64-FGQ(T) were Gram-stain positive, peritrichously flagellated, motile, straight rods, 0.3-0.5 um in diameter and 2.0-5.0 um long, growing singly or forming short chains. Cells formed round refractive endospores in terminal swollen sporangia. The temperature range for growth was 46-70 degrees C, with an optimum at 65 degrees C. The pH range for growth was 5.5-8.5, with an optimum at pH 7.0. The substrates utilized by strain 64-FGQ(T) in the presence of AQDS as an electron acceptor included lactate, malate, succinate, glycerol and yeast extract. The strain fermented galactose, fructose, maltose, sucrose, pyruvate and peptone. Strain 64-FGQ(T) used AQDS, humic acid, thiosulfate, nitrate and perchlorate as electron acceptors for growth. Fe(III) was not directly reduced, but strain 64-FGQ(T) was able to grow and reduce Fe(III) oxide in the presence of small amounts of AQDS or humic acid as electron-shuttling compounds. The G+C content of the DNA of strain 64 FGQ(T) was 51 mol%. 16S rRNA gene sequence analysis placed the isolate in the genus Moorella, with the type strain of Moorella glycerini as its closest relative (97.2% similarity). Based on phylogenetic analysis and physiological characteristics, strain 64-FGQ(T) is considered to represent a novel species of the genus Moorella, for which the name Moorella humiferrea sp. nov. is proposed; the type strain is 64-FGQ(T) (=DSM 23265(T)=VKM B-2603(T)). PMID- 21531741 TI - Deleterious effect of right ventricular apical pacing on left ventricular diastolic function and the impact of pre-existing diastolic disease. AB - AIMS: Right ventricular apex (RVA) pacing may have deleterious effects on left ventricular (LV) systolic function, but its impact on LV diastolic function has not been explored. METHODS AND RESULTS: Ninety-seven patients with sinus node dysfunction and ejection fraction (EF) >= 50% with permanent RVA pacing were randomly programmed to V-sense and V-pace modes and examined by echocardiography. Tissue Doppler imaging was employed to assess myocardial systolic velocity (S') and early diastolic velocity (E') at the mitral annulus. Systolic dyssynchrony was assessed using 12 LV segmental model (Ts-SD). Switching from V-sense to V pace resulted in the worsening of both diastolic and systolic functions as shown by the decreased EF, reduced mean E' and S' velocities, as well as increase in LV volume and Ts-SD (all P< 0.001). Reduction of mean E' and S' of >= 1 cm/s occurred in 35 (36%) and 45 (46%) patients, respectively. In pre-defined subgroup analysis, only patients with pre-existing LV diastolic dysfunction had a significant reduction of mean E' and S' (both P< 0.001) even after age adjustment. Multivariate logistic regression analysis showed that independent factors for the reduction of mean E' >= 1 cm/s or mean S' >= 1 cm/s at V-pace were pre-existing LV diastolic dysfunction [odds ratio (OR): 4.735, P= 0.007 for E'; OR: 3.307, P= 0.022 for S'] and systolic dyssynchrony at V-pace (OR: 5.459, P= 0.007 for E'; OR: 2.725, P= 0.035 for S'). CONCLUSION: In patients with preserved EF, RVA pacing is associated with the deterioration of both LV diastolic and systolic functions, which is particularly obvious in those with pre existing LV diastolic dysfunction and V-pace-induced systolic dyssynchrony. PMID- 21531742 TI - High incidence of acute sub-clinical circumflex artery 'injury' following mitral isthmus ablation. AB - AIMS: Mitral isthmus (MI) ablation is technically challenging, requiring long endocardial ablation times and frequently coronary sinus (CS) ablation. The circumflex artery lies in the epicardium in close proximity to the CS and the mitral annulus and may potentially be injured during radiofrequency ablation. METHODS AND RESULTS: Fifty-four patients underwent catheter ablation procedures that included MI ablation for treatment of atrial fibrillation. Irrigated ablation catheters were used with the following settings: endocardial surface (max power: 40/50 W at the annular end; max temperature: 48 degrees C); CS (max power: 25/30 W; max temperature: 48 degrees C). Coronary angiography was performed pre- and post-ablation and analysed by two cardiologists with quantitative coronary angiography. Mitral isthmus block was achieved in 89% of patients (60% required CS ablation). Fifteen patients (28%) had angiographic changes following ablation: eight had mid-circumflex narrowing only, one had circumflex and obtuse marginal (OM) artery narrowing, one had OM narrowing only, and five had distal circumflex occlusion/narrowing. Five patients had significant narrowing (50-84%), which resolved with intracoronary glycerine trinitrate. Fourteen (93%) of the patients with circumflex 'injury' had CS ablation and a longer mean CS ablation time (5.0 +/- 3.0 vs. 2.6 +/- 3.3 min, P = 0.03). Patients with distal circumflex occlusion had significantly smaller vessel diameter (1.0 +/- 0.1 vs. 2.1 +/- 0.2 mm, P = 0.03). A shorter distance between the circumflex and the CS was also associated with circumflex 'injury' (3.2 +/- 1.9 vs. 5.6 +/- 3.2 mm, P = 0.04). There were no electrocardiographic or echocardiographic abnormalities and no angina symptoms during follow-up. CONCLUSION: Acute sub-clinical circumflex 'injury' following MI ablation is not uncommon. Ablation within the CS, proximity of the circumflex and the CS, and a small distal circumflex were risk factors for 'injury'. PMID- 21531744 TI - Remifentanil for fetal immobilization and analgesia during the ex utero intrapartum treatment procedure under combined spinal-epidural anaesthesia. AB - Remifentanil undergoes extensive placental transfer and has been used to provide fetal immobilization and anaesthesia for in utero fetal endoscopic interventions. We report three cases of the ex utero intrapartum treatment performed under neuraxial anaesthesia where the maternal administration of remifentanil was used to provide fetal immobilization and analgesia. Fetal pathology included goiter and arthrogryposis, with one case requiring a tracheostomy. The longest time on placental circulation was 21 min. No clinically significant maternal sedation or respiratory depression was observed. In all cases, remifentanil provided adequate fetal immobilization and obviated the need to administer other analgesics or neuromuscular blocking agents. Remifentanil is a useful adjunct for ex utero fetal procedures. PMID- 21531745 TI - Reversibility of rocuronium-induced profound neuromuscular block with sugammadex in younger and older patients. AB - BACKGROUND: This study compared the reversibility of rocuronium-induced profound neuromuscular block with sugammadex in younger and older patients. METHODS: Fifteen younger (20-50 yr) and 15 older (>=70 yr) patients were sequentially enrolled in this study. After induction of anaesthesia and laryngeal mask insertion, contraction of the adductor pollicis muscle in response to ulnar nerve stimulation was quantified using acceleromyography during 1.0-1.5% end-tidal sevoflurane and remifentanil anaesthesia. All patients initially received rocuronium 1 mg kg(-1), followed by 0.02 mg kg(-1) when a post-tetanic count (PTC) of 1 or 2 was observed. After completion of surgery, at reappearance of 1-2 PTC, the time required for a single bolus dose of 4 mg kg(-1) sugammadex to produce recovery to a train-of-four (TOF) ratio of 0.9 was recorded. RESULTS: There were no differences in the total dose of rocuronium administered between the younger [mean (sd): 93.4 (17.5) mg] and the older [97.5 (32.2) mg] groups. In all patients, adequate recovery of the TOF ratio to 0.9 was achieved after administration of sugammadex, although it was significantly slower in the older [3.6 (0.7) min, P<0.0001] than in the younger group [1.3 (0.3) min]. There were no clinical events attributable to recurarization. CONCLUSIONS: Sugammadex can adequately restore neuromuscular function in older patients, although a longer time is required to recover from profound rocuronium-induced neuromuscular block than in younger patients. PMID- 21531746 TI - Discussions about safety criteria and guidelines for radioactive waste management. AB - In Japan, the clearance levels for uranium-bearing waste have been established by the Nuclear Safety Commission (NSC). The criteria for uranium-bearing waste disposal are also necessary; however, the NSC has not concluded the discussion on this subject. Meanwhile, the General Administrative Group of the Radiation Council has concluded the revision of its former recommendation 'Regulatory exemption dose for radioactive solid waste disposal', the dose criteria after the institutional control period for a repository. The Standardization Committee on Radiation Protection in the Japan Health Physics Society (The Committee) also has developed the relevant safety criteria and guidelines for existing exposure situations, which are potentially applicable to uranium-bearing waste disposal. A new working group established by The Committee was initially aimed at developing criteria and guidelines specifically for uranium-bearing waste disposal; however, the aim has been shifted to broader criteria applicable to any radioactive wastes. PMID- 21531747 TI - Development of new analytical method based on beta-alpha coincidence method for selective measurement of 214Bi-214Po-application to dust filter used in radiation management. AB - The radionuclide pair (214)Bi and (214)Po which belongs to the uranium series interferes with airborne radionuclide measurement needed for the radiation management of a nuclear facility. Time intervals between (214)Bi (beta) and (214)Po (alpha) are much shorter than artificial radionuclides due to the short half-life of (214)Po (164 MUs). The purpose of this study is to develop of a new analytical method (time interval analysis: TIA) based on the beta-alpha coincidence method for selective measurement of (214)Bi-(214)Po. The developed method was applied to an actual dust-filter measurement. The TIA system was highly effective in measuring of the filter with background subtraction. PMID- 21531748 TI - Dose conversion coefficients for neutron exposure to the lens of the human eye. AB - Dose conversion coefficients for the lens of the human eye have been calculated for neutron exposure at energies from 1 * 10(-9) to 20 MeV and several standard orientations: anterior-to-posterior, rotational and right lateral. MCNPX version 2.6.0, a Monte Carlo-based particle transport package, was used to determine the energy deposited in the lens of the eye. The human eyeball model was updated by partitioning the lens into sensitive and insensitive volumes as the anterior portion (sensitive volume) of the lens being more radiosensitive and prone to cataract formation. The updated eye model was used with the adult UF-ORNL mathematical phantom in the MCNPX transport calculations. PMID- 21531749 TI - Centring radiological protection on today's global challenges in energy, climate change, environment and health--with nuclear energy playing a key role. AB - The climate change issue includes meeting the growing demand for electricity while reducing the impacts from energy sources. Applying carbon capture and storage technology to fossil fuel energy and increasing renewable energy pose greater challenges than increasing nuclear energy. International Energy Agency's (IEA) electricity demand of 30 000 TWh by 2030 can be met with 10 000 TWh each from renewable, nuclear and fossil fuel energy. However, the ill-imposed very strict control of tiny public exposure to ionising radiation from nuclear energy continues to pose a serious hindrance. Effort needs to be re-balanced to produce an even-handed control of public exposure with emphasis on the most significant sources (i.e. natural background radiation and medical use) and vice versa. The on-going revision of the International Atomic Energy Agency Basic Safety Standards (BSS) provides an opportunity to achieve this internationally so that national regulations can be subsequently remediated. There can be no urgency in a BSS revision that fails to encompass such perspective. PMID- 21531750 TI - Monte Carlo calculations for efficiency calibration of a whole-body monitor using BOMAB phantoms of different sizes. AB - Internal contamination due to high-energy photon (HEP) emitters is assessed using a scanning bed whole-body monitor housed in a steel room at the Bhabha Atomic Research Centre (BARC). The monitor consists of a (203 mm diameter * 102 mm thickness) NaI(Tl) detector and is calibrated using a Reference BOMAB phantom representative of an average Indian radiation worker. However, a series of different size physical phantoms are required to account for size variability in workers, which is both expensive and time consuming. Therefore, a theoretical approach based on Monte Carlo techniques has been employed to calibrate the system in scanning geometry with BOMAB phantoms of different sizes characterised by their weight (W) and height (H) for several radionuclides of interest ((131)I, (137)Cs, (60)Co and (40)K). A computer program developed for this purpose generates the detector response and the detection efficiencies (DEs) for the BARC Reference phantom (63 kg/168 cm), ICRP Reference male phantom (70 kg/170 cm) and several of its scaled versions. The results obtained for different size phantoms indicated a decreasing trend of DEs with the increase in W/H values of the phantoms. The computed DEs for uniform distribution of (137)Cs in BOMAB phantom varied from 3.52 * 10(-3) to 2.88 * 10(-3) counts per photon as the W/H values increased from 0.26 to 0.50. The theoretical results obtained for the BARC Reference phantom have been verified with experimental measurements. The Monte Carlo results from this study will be useful for in vivo assessment of HEP emitters in radiation workers of different physiques. PMID- 21531743 TI - Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. AB - Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (>= 1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal. PMID- 21531751 TI - Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. AB - BACKGROUND: Preimplantation genetic screening (PGS) has increasingly been used in the past decade. Here we present a systematic review and meta-analysis of RCTs on the effect of PGS on the probability of live birth after IVF. METHODS: PubMed and trial registers were searched for RCTs on PGS. Trials were assessed following predetermined quality criteria. The primary outcome was live birth rate per woman, secondary outcomes were ongoing pregnancy rate, miscarriage rate, multiple pregnancy rate and pregnancy outcome. RESULTS: Nine RCTs comparing IVF with and without PGS were included in our meta-analysis. Fluorescence in situ hybridization was used in all trials and cleavage stage biopsy was used in all but one trial. PGS significantly lowered live birth rate after IVF for women of advanced maternal age (risk difference: -0.08; 95% confidence interval: -0. 13 to -0.03). For a live birth rate of 26% after IVF without PGS, the rate would be between 13 and 23% using PGS. Trials where PGS was offered to women with a good prognosis and to women with repeated implantation failure suggested similar outcomes. CONCLUSIONS: There is no evidence of a beneficial effect of PGS as currently applied on the live birth rate after IVF. On the contrary, for women of advanced maternal age PGS significantly lowers the live birth rate. Technical drawbacks and chromosomal mosaicism underlie this inefficacy of PGS. New approaches in the application of PGS should be evaluated carefully before their introduction into clinical practice. PMID- 21531752 TI - Gamete competence assessment by polarizing optics in assisted reproduction. AB - BACKGROUND: The purpose of this study was first to give an overview of the historical development of polarization microscopy, second to describe the various applications of this technique in assisted reproduction techniques (ART) and third to discuss the potential benefit of polarization microscopy as a predictor for IVF success. METHODS: The history of polarization microscopy was undertaken by performing a backward search in the scientific literature using Google and internet sites of several Societies for Microscopy and Cell Biology. Studies of polarization microscopy in ART were identified by using a systematic literature search in PubMed and Scopus. RESULTS: A total of 62 articles were identified by the direct search and further relevant articles were found by screening the cited literature in these articles. The topics relevant for assisted reproduction were spindle and zona imaging in combination with IVF success, meiotic cell cycle progression, pharmaceutical studies and cryopreservation. A separate topic was the use of sperm birefringence in ART. CONCLUSIONS: The majority of studies are observational studies and were not performed in a randomized manner and there is no direct comparison of techniques using other gamete selection markers. Despite this, most studies show that polarization microscopy may help us to further increase our knowledge on gametes and meiosis. Whether certain applications such as spindle or zona imaging may lead to an increase in IVF success is unclear at present. Publications on the use of polarization microscopy on sperm are still very limited. PMID- 21531753 TI - Chromosomal mosaicism in human preimplantation embryos: a systematic review. AB - BACKGROUND: Although chromosomal mosaicism in human preimplantation embryos has been described for almost two decades, its exact prevalence is still unknown. The prevalence of mosaicism is important in the context of preimplantation genetic screening in which the chromosomal status of an embryo is determined by the analysis of a single cell from that embryo. METHODS: Here we report a systematic review and meta-analysis of studies on the chromosomal constitution of human preimplantation embryos. In 36 studies, out of 2117 citations that met our search criteria, data were provided extensively enough to allow classification of each analysed embryo with prespecified criteria for its chromosomal makeup. The main outcome of this classification was the prevalence of chromosomal mosaicism in human preimplantation embryos. RESULTS: A total of 815 embryos could be classified. Of these, 177 (22%) were diploid, 599 (73%) were mosaic, of which 480 (59% of the total number of embryos) were diploid-aneuploid mosaic and 119 (14% of the total number of embryos) were aneuploid mosaic, and 39 (5%) contained other numerical chromosomal abnormalities. The distribution of the embryos over these categories was associated with the developmental stage of the embryos, the method used for analysis and the number of chromosomes analysed. CONCLUSIONS: Diploid-aneuploid mosaicism is by far the most common chromosomal constitution in spare human preimplantation embryos after IVF. This undermines the reliable determination of the ploidy status of a cleavage-stage embryo based on the analysis of a single cell. Future research should determine the origin and developmental potential of mosaic embryos. PMID- 21531754 TI - Ventricular tachycardia ablation in repaired tetralogy of fallot. PMID- 21531755 TI - Chrysin modulates ethanol metabolism in Wistar rats: a promising role against organ toxicities. AB - AIMS: Hepato- and nephro-protective efficacy of chrysin was investigated against sequential increase of ethanol intake on the alteration of alcohol metabolizing enzymes-alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP 2E1), xanthine oxidase (XO) and oxidant/anti-oxidant status. METHODS: Thirty female Wistar rats segregated into five groups, each with six animals, were put to different doses. Group I as control followed by Group II, III and IV were treated with ethanol (5,8,10 and 12 g/kg body weight per week respectively) for 4 weeks. While Group III and IV were administered with chrysin at 20 mg (D1) and 40 mg/kg body weight (D2), respectively, prior to ethanol administration. Group V was given only chrysin (D2). Various oxidative stress and ethanol metabolizing enzymes were estimated in hepatic and renal tissues. RESULTS: Ethanol administration significantly induced CYP 2E1, ADH and XO in liver and kidneys, respectively, along with an enhancement in levels of malondialdehyde and serum alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine and lactate dehydrogenase when compared with the control group and this enhancement is significantly normalized with chrysin administration. Oxidative stress markers: reduced glutathione, glutathione peroxidase, catalase and glutathione reductase were significantly (P < 0.001) depleted in the ethanol-treated group, while chrysin administration significantly restored all of these. Only chrysin administration did not show any adverse effect. CONCLUSION: Results demonstrate that chrysin administration prevents the liver and kidney of Wistar rats against oxidative damage during chronic ethanol consumption by inhibiting the activities of ADH, CYP 2E1, XO and catalase. PMID- 21531756 TI - Regulating preimplantation genetic diagnosis: the case of Down's syndrome. PMID- 21531757 TI - Health research, data protection, and the public interest in notification. PMID- 21531758 TI - Effectiveness of the local or oral delivery of the novel naphthopterocarpanquinone LQB-118 against cutaneous leishmaniasis. AB - OBJECTIVES: This paper describes the antileishmanial properties of LQB-118, a new compound designed by molecular hybridization, orally active in Leishmania amazonensis-infected BALB/c mice. METHODS: In vitro antileishmanial activity was determined in L. amazonensis-infected macrophages. For in vivo studies, LQB-118 was administered intralesionally (15 MUg/kg/day, five times a week), intraperitoneally (4.5 mg/kg/day, five times a week) or orally (4.5 mg/kg/day, five times a week) to L. amazonensis-infected BALB/c mice throughout experiments lasting 85 or 105 days. At the end of the experiments, serum levels of alanine aminotransferase, aspartate aminotransferase and creatinine were measured as toxicological parameters. RESULTS: LQB-118 was active against intracellular amastigotes of L. amazonensis [50% inhibitory concentration (IC(50)) 1.4 MUM] and significantly less so against macrophages (IC(50) 18.5 MUM). LQB-118 administered intralesionally, intraperitoneally or orally was found to control both lesion and parasite growth in L. amazonensis-infected BALB/c mice, without altering serological markers of toxicity. CONCLUSIONS: These results demonstrate that the molecular hybridization of a naphthoquinone core to pterocarpan yielded a novel antileishmanial compound that was locally and orally active in an experimental cutaneous leishmaniasis model. PMID- 21531759 TI - The gentian orthologs of the FT/TFL1 gene family control floral initiation in Gentiana. AB - Gentians are herbaceous perennials blooming in summer through autumn. Although they are popular ornamental flowers in Japan, the regulation of their timing of flowering has not been studied. We identified and characterized gentian orthologs of the Arabidopsis FT/TFL1 gene family to elucidate the mechanisms of flowering initiation. We isolated three gentian orthologs of FT and TFL1, denoted GtFT1, GtFT2 and GtTFL1. Since up-regulation of GtFT1 and GtFT2 as well as down regulation of GtTFL1 promoted floral initiation in gentian plantlets, these genes affected floral initiation in a similar way to Arabidopsis FT and TFL1. The expression levels of GtFT1 and GtFT2 in leaves of late-flowering gentian increased prior to floral initiation, whereas GtTFL1 was highly expressed in shoot apical meristem at the vegetative stage and decreased drastically just before flowering initiation. Comparison of gene expression patterns showed that GtFT1 expression increased earlier in early-flowering than in late-flowering gentian, whereas the timing of the increase in GtFT2 expression was similar in early- and late-flowering plants. The GtTFL1 expression in early-flowering gentian was extremely low throughout the vegetative and reproductive stages. These results indicated that either the up-regulation of GtFT1 or the down regulation of GtTFL1 may determine flowering time. Furthermore, we found that early-flowering but not late-flowering gentians have a 320 bp insertion in the promoter region of GtTFL1. Thus, the negligible expression of GtTFL1 in early flowering lines may be due to this insertion, resulting in a shortened vegetative stage. PMID- 21531760 TI - Fe binding properties of two soybean (Glycine max L.) LEA4 proteins associated with antioxidant activity. AB - Late embryogenesis abundant (LEA) group 4 (LEA4) proteins play an important role in the water stress tolerance of plants. Although they have been hypothesized to stabilize macromolecules in stressed cells, the protective functions and mechanisms of LEA4 proteins are still not clear. In this study, the metal binding properties of two related soybean LEA4 proteins, GmPM1 and GmPM9, were tested using immobilized metal ion affinity chromatography (IMAC). The metal ions Fe(3+), Ni(2+), Cu(2+) and Zn(2+) were observed to bind these two proteins, while Ca(2+), Mg(2+) or Mn(2+) did not. Results from isothermal titration calorimetry (ITC) indicated that the binding affinity of GmPM1 for Fe(3+) was stronger than that of GmPM9. Hydroxyl radicals generated by the Fe(3+)/H(2)O(2) system were scavenged by both GmPM1 and GmPM9 in the absence or the presence of high ionic conditions (100 mM NaCl), although the scavenging activity of GmPM1 was significantly greater than that of GmPM9. These results suggest that GmPM1 and GmPM9 are metal-binding proteins which may function in reducing oxidative damage induced by abiotic stress in plants. PMID- 21531761 TI - Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. AB - Wnt/beta-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream beta-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/beta-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/beta-catenin pathway activation, downregulated Dvl2, decreased downstream beta-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-kappaB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC. PMID- 21531764 TI - Association of specific genotypes in metastatic suppressor HTPAP with tumor metastasis and clinical prognosis in hepatocellular carcinoma. AB - The phosphatidic acid phosphatase HTPAP has been defined as a metastatic suppressor of hepatocellular carcinoma (HCC), but little is known about its function or potential applications as a prognostic marker. In this study, we analyzed patterns of HTPAP genetic variation and gene expression in 864 patients who underwent HCC resection, assessing these patterns for correlations to tumor metastasis potential. Focusing on two tagSNPs that were selected (+357G/C and +1838A/G), we found that only the +357G/C genotype was significantly associated with HTPAP mRNA and protein expression levels and the probability of metastasis. In an independent cohort of 665 HCC patients, we determined that the +357G/C genotype was associated with shorter time to recurrence and overall survival. Together, these results indicated that the HTPAP tagSNP +357 GG+GC genotypes may influence HCC metastatic potential and clinical prognosis by down-regulating HTPAP expression. Extending these results, a global expression profiling analysis identified 41 genes including the pro-inflammatory genes IL-8 and TLR2 that were significantly overexpressed in the +357 GG+GC group, as possible coregulated markers with HTPAP. Together, our findings identify an HTPAP genotype and associated gene expression pattern that favors metastasis progression and that could be used to predict tumor metastasis and prognosis in HCC patients. PMID- 21531763 TI - Considerations for the clinical application of chimeric antigen receptor T cells: observations from a recombinant DNA Advisory Committee Symposium held June 15, 2010. AB - T cells that are genetically modified to express single-chain chimeric antigen receptors (CAR) have shown promise in early cancer immunotherapy clinical trials. Unfortunately, 2 recent deaths in cancer patients treated with CAR T cells have created some uncertainty on how to best mitigate patient risk, while continuing to advance this very promising therapeutic avenue. In order to address these concerns, the Recombinant DNA Advisory Committee (RAC) held a symposium, the objectives of which were to first review the reported treatment-associated toxicities and, second, to discuss methods for improving safety and efficacy. This report highlights the issues raised as part of this discussion, with a specific focus on protocols infusing CAR T cells. Because this was not a consensus conference, the opinions described should not be construed to represent those of any individual RAC member, the RAC as a body, conference participants, the National Institutes of Health, or the U.S. Food and Drug Administration. PMID- 21531765 TI - High-throughput RNAi screening reveals novel regulators of telomerase. AB - Telomerase is considered an attractive anticancer target on the basis of its common and specific activation in most human cancers. While direct telomerase inhibition is being explored as a therapeutic strategy, alternative strategies to target regulators of telomerase that could disrupt telomere maintenance and cancer cell proliferation are not yet available. Here, we report the findings of a high-throughput functional RNA interference screen to globally profile the contribution of kinases to telomerase activity (TA). This analysis identified a number of novel telomerase modulators, including ERK8 kinase, whose inhibition reduces TA and elicited characteristics of telomere dysfunction. Given that kinases represent attractive drug targets, we addressed the therapeutic implications of our findings, such as demonstrating how limiting TA via kinase blockade could sensitize cells to inhibition of the telomere-associated protein tankyrase. Taken together, our findings suggest novel combinatorial approaches to targeting telomere maintenance as a strategy for cancer therapy. PMID- 21531766 TI - ID4 imparts chemoresistance and cancer stemness to glioma cells by derepressing miR-9*-mediated suppression of SOX2. AB - Glioma stem cells (GSC) possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Thus, they are considered to be major drivers for glioma initiation, progression, and recurrence. However, the precise mechanism governing acquisition of their drug resistance remains to be elucidated. Our previous study has shown that inhibitor of differentiation 4 (ID4) dedifferentiates Ink4a/Arf(-/-) mouse astrocytes and human glioma cells to glioma stem-like cells (induced GSCs or iGSCs). In this article, we report that ID4-driven iGSCs exhibit chemoresistant behavior to anticancer drugs through activation of ATP-binding cassette (ABC) transporters. We found that ID4 enhanced SOX2 protein expression by suppressing microRNA-9* (miR-9*), which can repress SOX2 by targeting its 3'-untranslated region. Consequently, ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. Furthermore, we found that short hairpin RNA-mediated knockdown of SOX2 in ID4-driven iGSCs resulted in loss of cancer stemness. Moreover, ectopic expression of SOX2 could dedifferentiate Ink4a/Arf(-/-) astrocytes and glioma cells to iGSCs, indicating a crucial role of SOX2 in genesis and maintenance of GSCs. Finally, we found that the significance of the ID4-miR-9*-SOX2-ABCC3/ABCC6 regulatory pathway is recapitulated in GSCs derived from patients with glioma. Together, our results reveal a novel regulatory mechanism by which ID4-driven suppression of miR-9* induces SOX2, which imparts stemness potential and chemoresistance to glioma cells and GSCs. PMID- 21531767 TI - BRCA1 counteracts progesterone action by ubiquitination leading to progesterone receptor degradation and epigenetic silencing of target promoters. AB - Germ-line mutations in the BRCA1 gene increase the risk of breast cancer in women, but the precise mechanistic basis for this connection remains uncertain. One popular hypothesis to explain breast tissue specificity postulates a link between BRCA1 and the action of the ovarian hormones estrogen and progesterone. Given the relevance of progesterone for normal mammary development and breast cancer formation, we searched for a functional relationship between BRCA1 and progesterone receptor (PR) in the PR-positive breast cancer cell line T47D. Here, we report that BRCA1 inhibits the transcriptional activity of PR by at least 2 mechanisms involving the E3 ubiquitin ligase activity of BRCA1. First, BRCA1 has a direct effect on the cellular level of PR and, hence, on the extent of PR recruitment to target promoters through the promotion of its ligand-independent and -dependent degradation. Through in vitro and in vivo assays, we found that BRCA1/BARD1 may be the main E3 ubiquitin ligase responsible for ubiquitination and degradation of PR in the absence of hormone. Second, after hormone treatment of cells, the BRCA1/BARD1 complex is recruited via interaction with PR to the hormone-responsive regions of PR target genes, affecting local levels of monoubiquitinated histone H2A and contributing to epigenetic silencing of these promoters. The connections between BRCA1/BARD1 and PR activity suggested by our findings may help explain why host mutations in BRCA1 exert a tissue specificity in preferentially elevating the risk of breast cancer. PMID- 21531768 TI - An alkyltransferase-like protein from Thermus thermophilus HB8 affects the regulation of gene expression in alkylation response. AB - Alkylation is a type of stress that is fatal to cells. However, cells have various responses to alkylation. Alkyltransferase-like (ATL) protein is a novel protein involved in the repair of alkylated DNA; however, its repair mechanism at the molecular level is unclear. DNA microarray analysis revealed that the upregulation of 71 genes because of treatment with an alkylating agent N-methyl N'-nitro-N-nitrosoguanidine was related to the presence of TTHA1564, the ATL protein from Thermus thermophilus HB8. Affinity chromatography showed a direct interaction of purified TTHA1564 with purified RNA polymerase holoenzyme. The amino acid sequence of TTHA1564 is homologous to that of the C-terminal domain of Ada protein, which acts as a transcriptional activator. These results suggest that TTHA1564 might act as a transcriptional regulator. The results of DNA microarray analysis also implied that the alkylating agent induced oxidation stress in addition to alkylation stress. PMID- 21531769 TI - A detailed investigation of accessibilities around target sites of siRNAs and miRNAs. AB - MOTIVATION: The importance of RNA sequence analysis has been increasing since the discovery of various types of non-coding RNAs transcribed in animal cells. Conventional RNA sequence analyses have mainly focused on structured regions, which are stabilized by the stacking energies acting on adjacent base pairs. On the other hand, recent findings regarding the mechanisms of small interfering RNAs (siRNAs) and transcription regulation by microRNAs (miRNAs) indicate the importance of analyzing accessible regions where no base pairs exist. So far, relatively few studies have investigated the nature of such regions. RESULTS: We have conducted a detailed investigation of accessibilities around the target sites of siRNAs and miRNAs. We have exhaustively calculated the correlations between the accessibilities around the target sites and the repression levels of the corresponding mRNAs. We have computed the accessibilities with an originally developed software package, called 'Raccess', which computes the accessibility of all the segments of a fixed length for a given RNA sequence when the maximal distance between base pairs is limited to a fixed size W. We show that the computed accessibilities are relatively insensitive to the choice of the maximal span W. We have found that the efficacy of siRNAs depends strongly on the accessibility of the very 3'-end of their binding sites, which might reflect a target site recognition mechanism in the RNA-induced silencing complex. We also show that the efficacy of miRNAs has a similar dependence on the accessibilities, but some miRNAs also show positive correlations between the efficacy and the accessibilities in broad regions downstream of their putative binding sites, which might imply that the downstream regions of the target sites are bound by other proteins that allow the miRNAs to implement their functions. We have also investigated the off-target effects of an siRNA as a potential RNAi therapeutic. We show that the off-target effects of the siRNA have similar correlations to the miRNA repression, indicating that they are caused by the same mechanism. AVAILABILITY: The C++ source code of the Raccess software is available at http://www.ncrna.org/software/Raccess/ The microarray data on the measurements of the siRNA off-target effects are also available at the same site. CONTACT: kiryu h@k.u-tokyo.ac.jp PMID- 21531770 TI - parmigene--a parallel R package for mutual information estimation and gene network reconstruction. AB - MOTIVATION: Inferring large transcriptional networks using mutual information has been shown to be effective in several experimental setup. Unfortunately, this approach has two main drawbacks: (i) several mutual information estimators are prone to biases and (ii) available software still has large computational costs when processing thousand of genes. RESULTS: Here, we present parmigene (PARallel Mutual Information estimation for GEne NEtwork reconstruction), an R package that tries to fill the above gaps. It implements a mutual information estimator based on k-nearest neighbor distances that is minimally biased with respect to the other methods and uses a parallel computing paradigm to reconstruct gene regulatory networks. We test parmigene on in silico and real data. We show that parmigene gives more precise results than existing softwares with strikingly less computational costs. AVAILABILITY AND IMPLEMENTATION: The parmigene package is available on the CRAN network at http://cran.r-project.org/web/packages/. CONTACT: chiara.romualdi@unipd.it PMID- 21531771 TI - Chlamydia control activities in Europe: cross-sectional survey. AB - BACKGROUND: Chlamydia is the most commonly reported bacterial sexually transmitted infection in Europe. The objective of the Screening for Chlamydia in Europe (SCREen) project was to describe current and planned chlamydia control activities in Europe. METHODS: The authors sent a questionnaire asking about different aspects of chlamydia epidemiology and control to public health and clinical experts in each country in 2007. The principles of sexually transmitted infection control were used to develop a typology comprising five categories of chlamydia control activities. Each country was assigned to a category, based on responses to the questionnaire. RESULTS: Experts in 29 of 33 (88%) invited countries responded. Thirteen of 29 countries (45%) had no current chlamydia control activities. Six countries in this group stated that there were plans to introduce chlamydia screening programmes. There were five countries (17%) with case management guidelines only. Three countries (10%) also recommended case finding amongst partners of diagnosed chlamydia cases or people with another sexually transmitted infection. Six countries (21%) further specified groups of asymptomatic people eligible for opportunistic chlamydia testing. Two countries (7%) reported a chlamydia screening programme. There was no consistent association between the per capita gross domestic product of a country and the intensity of chlamydia control activities (P = 0.816). CONCLUSION: A newly developed classification system allowed the breadth of ongoing national chlamydia control activities to be described and categorized. Chlamydia control strategies should ensure that clinical guidelines to optimize chlamydia diagnosis and case management have been implemented before considering the appropriateness of screening programmes. PMID- 21531772 TI - Small socio-economic differences in mortality in Spanish older people. AB - BACKGROUND: Previous studies found smaller mortality inequalities in Southern Europe than in other European populations. This study used a sample of older Spanish adults to identify possible factors explaining these findings. METHODS: A cohort of 4008 persons aged >= 60 years was selected in 2000-01 and followed prospectively until 2008. At baseline, data were collected on education, occupation and major mortality risk factors: social network, lifestyles, diet, obesity and hypertension. Analyses were conducted with Cox regression, and adjusted for the risk factors at baseline. RESULTS: The hazard ratio (HR) and 95% confidence interval (95% CI) for mortality adjusted for age, marital status, region and place of residence in people with low vs. high educational level was 1.13 (0.86-1.50) in men and 1.23 (0.83-1.80) in women. The HR in the manual vs. non-manual occupational class was 0.92 (0.74-1.15) in men and 1.07 (0.86-1.33) in women. Adjustment for the different risk factors decreased or did not change the HR. After full adjustment for all risk factors the mortality HR in those with low education was 0.99 (0.74-1.32) in men and 1.18 (0.80-1.76) in women, while the mortality HR in the manual occupational class was 0.85 (0.68-1.06) in men and 1.04 (0.83-1.30) in women. CONCLUSIONS: From a European perspective, mortality inequalities in Spanish older adults are small. The ubiquitous presence of social networks and the widespread adherence to the Mediterranean diet may be responsible for this finding. PMID- 21531773 TI - Evaluation of a brief intervention designed to increase CPR training among pregnant pool owners. AB - This study evaluated whether a brief videotape could motivate pregnant pool owners to be trained in infant/child cardiopulmonary resuscitation (CPR). Women were recruited from prenatal classes in South Florida. Eligible volunteers were randomized to view a video or receive standard treatment, after completing a questionnaire. The video explained toddler drowning risk, as well as the value of isolation pool fencing and CPR training. Women were contacted by phone 6 months after giving birth to complete a follow-up survey. Sixty-one percent of eligible mothers agreed to study enrollment and 92% of those completed a follow-up interview (n = 101). At baseline, there was no significant difference between the proportion of mothers with current CPR training in the treatment and control groups. At follow-up, 48% of those in the intervention group reported CPR instruction versus 28% of the control group (x(2) = 3.93, P = 0.03). Video viewers were also more likely to report significant changes in perceptions that favored CPR training. Health care facilities located in communities with high rates of toddler drowning may want to screen prenatal students for pool ownership and encourage at-risk families to be trained in infant/child CPR. Such programs should, however, emphasize the primacy of isolation fencing as a preventive measure. PMID- 21531774 TI - Mucociliary interactions and mucus dynamics in ciliated human bronchial epithelial cell cultures. AB - The airway epithelial surface liquid is generally considered to be composed of two layers, a periciliary layer and a continuous thick mucus layer moving in bulk. This view may not be appropriate for all areas of the lung. Our hypothesis, that mucus may form a discontinuous layer with dynamic attachments to the surface, is investigated using a culture system. We used live-cell confocal microscopy to investigate thin mucus layers and fluorescent beads and exogenous MUC5B to visualize mucus dynamics on ciliated human bronchial cultures. A continuous mucus layer was not observed. In sparsely ciliated cultures, mucus attached to ciliated cells; however, in highly ciliated cultures, mucus formed strands several hundred micrometers long. As with increases in ciliation, increases in bead concentration caused the appearance of mucus strands. We confirmed the involvement of mucins in the binding of mucus to cilia by adding labeled purified MUC5B to the cultures. These data suggest that mucins may have an intrinsic ability to form attachments to cilia. The significance of these findings is that aberrant modulation of such an intrinsic property may explain the initiation of highly adherent mucus in cystic fibrosis lung disease. PMID- 21531775 TI - Vanadium pentoxide (V(2)O(5)) induced mucin production by airway epithelium. AB - Exposure to environmental pollutants has been linked to various airway diseases and disease exacerbations. Almost all chronic airway diseases such as chronic obstructive pulmonary disease and asthma are caused by complicated interactions between gene and environment. One of the major hallmarks of those diseases is airway mucus overproduction (MO). Excessive mucus causes airway obstruction and significantly increases morbidity and mortality. Metals are major components of environmental particulate matters (PM). Among them, vanadium has been suggested to play an important role in PM-induced mucin production. Vanadium pentoxide (V(2)O(5)) is the most common commercial source of vanadium, and it has been associated with occupational chronic bronchitis and asthma, both of which are MO diseases. However, the underlying mechanism is not entirely clear. In this study, we used both in vitro and in vivo models to demonstrate the robust inductions of mucin production by V(2)O(5). Furthermore, the follow-up mechanistic study revealed a novel v-raf-1 murine leukemia viral oncogene homolog 1-IKK-NF-kappaB pathway that mediated V(2)O(5)-induced mucin production. Most interestingly, the reactive oxygen species and the classical mucin-inducing epidermal growth factor receptor (EGFR)-MAPK pathway appeared not to be involved in this process. Thus the V(2)O(5)-induced mucin production may represent a novel EGFR-MAPK-independent and environmental toxicant-associated MO model. Complete elucidation of the signaling pathway in this model will not only facilitate the development of the treatment for V(2)O(5)-associated occupational diseases but also advance our understanding on the EGFR-independent mucin production in other chronic airway diseases. PMID- 21531778 TI - Enhanced rapid-onset cortical plasticity in CADASIL as a possible mechanism of preserved cognition. AB - Ischemic small vessel disease (SVD) may lead to cognitive impairment, but cognitive deficits with a given burden of SVD vary significantly. The underlying mechanisms of impaired or preserved cognition are unknown. Here, we investigated the impact of ischemic SVD on rapid-onset cortical plasticity, as induced with a paired-associative stimulation protocol. To exclude concomitant effects of aging, we examined 12 middle-aged patients (48.3 +/- 8.3 years) with cerebral autosomal dominant arteriopathy with subcortical infarctions and leucoencephalopathy (CADASIL) who suffered from severe ischemic SVD and a group of 12 age-matched controls (49.9 +/- 8.3 years). Cognitive status, motor performance and learning, and motor cortex excitability in response to cathodal transcranial direct current stimulation (ctDCS) were assessed. White matter integrity was analyzed by conventional magnetic resonance imaging and diffusion tensor imaging. We found that cognitive and motor functions were largely preserved in CADASIL patients, while rapid-onset cortical plasticity was significantly higher in the CADASIL group compared with controls (repeated measures analysis of variance [group * time] interaction: P = 0.03). This finding was even more pronounced in patients with higher white matter lesion load. ctDCS revealed no evidence of cortical dysplasticity. We conclude that increased rapid-onset cortical plasticity may contribute to largely preserved cognitive and motor function despite extensive ischemic SVD. PMID- 21531777 TI - Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. AB - Hypoxia enhances transforming growth factor-beta (TGF-beta) signaling, inhibiting alveolar development and causing abnormal pulmonary arterial remodeling in the newborn lung. We hypothesized that, during chronic hypoxia, reduced peroxisome proliferator-activated receptor-gamma (PPAR-gamma) signaling may contribute to, or be caused by, excessive TGF-beta signaling. To determine whether PPAR-gamma was reduced during hypoxia, C57BL/6 mice were exposed to hypoxia from birth to 2 wk and evaluated for PPAR-gamma mRNA and protein. To determine whether rosiglitazone (RGZ, a PPAR-gamma agonist) supplementation attenuated the effects of hypoxia, mice were exposed to air or hypoxia from birth to 2 wk in combination with either RGZ or vehicle, and measurements of lung histology, function, parameters related to TGF-beta signaling, and collagen content were made. To determine whether excessive TGF-beta signaling reduced PPAR-gamma, mice were exposed to air or hypoxia from birth to 2 wk in combination with either TGF-beta neutralizing antibody or vehicle, and PPAR-gamma signaling was evaluated. We observed that hypoxia reduced PPAR-gamma mRNA and protein, in association with impaired alveolarization, increased TGF-beta signaling, reduced lung compliance, and increased collagen. RGZ increased PPAR-gamma signaling, with improved lung development and compliance in association with reduced collagen and TGF-beta signaling. However, no reduction was noted in hypoxia-induced pulmonary vascular remodeling. Inhibition of hypoxia-enhanced TGF-beta signaling increased PPAR gamma signaling. These results suggest that hypoxia-induced inhibition of lung development is associated with a mutually antagonistic relationship between reduced PPAR-gamma and increased TGF-beta signaling. PPAR-gamma agonists may be of potential therapeutic significance in attenuating TGF-beta signaling and improving alveolar development. PMID- 21531776 TI - Thrombospondin-1 opens the paracellular pathway in pulmonary microvascular endothelia through EGFR/ErbB2 activation. AB - Thrombospondin-1 (TSP1) is a multidomain protein that contains epidermal growth factor (EGF)-like repeats that indirectly activate the EGF receptor (EGFR) and selected downstream signaling pathways. In these studies, we show that TSP1 opens the paracellular pathway in human lung microvascular endothelial cells (HMVEC-Ls) in a dose-, time-, and protein tyrosine kinase (PTK)-dependent manner. TSP1 increased tyrosine phosphorylation of proteins enriched to intercellular boundaries including the zonula adherens (ZA) proteins, vascular endothelial cadherin, gamma-catenin, and p120 catenin. In HMVEC-Ls, EGFR and ErbB2 are expressed at low levels, and both heterodimerize and tyrosine autophosphorylate in response to TSP1. Prior EGFR-selective PTK inhibition with AG1478 or ErbB2 selective PTK inhibition with AG825 protected against TSP1-induced tyrosine phosphorylation of ZA proteins and barrier disruption. Preincubation of HMVEC-Ls with an EGFR ectodomain-blocking antibody also prevented TSP1-induced opening of the paracellular pathway. Therefore, in HMVEC-Ls, TSP1 increases tyrosine phosphorylation of ZA proteins and opens the paracellular pathway, in part, through EGFR/ErbB2 activation. Surprisingly, recombinant TSP1 EGF-like repeats 1 3 and the high-affinity EGFR ligands, EGF, TGF-alpha, and amphiregulin, each failed to increase paracellular permeability. However, HMVEC-Ls in which EGFR was overexpressed became responsive to the EGF-like repeats of TSP1 as well as to EGF. These studies indicate that TSP1 disrupts the endothelial barrier through EGFR/ErbB2 activation although additional signals are necessary in cells with low receptor expression. PMID- 21531779 TI - Learning-induced changes in the cerebral processing of voice identity. AB - Temporal voice areas showing a larger activity for vocal than non-vocal sounds have been identified along the superior temporal sulcus (STS); more voice sensitive areas have been described in frontal and parietal lobes. Yet, the role of voice-sensitive regions in representing voice identity remains unclear. Using a functional magnetic resonance adaptation design, we aimed at disentangling acoustic- from identity-based representations of voices. Sixteen participants were scanned while listening to pairs of voices drawn from morphed continua between 2 initially unfamiliar voices, before and after a voice learning phase. In a given pair, the first and second stimuli could be identical or acoustically different and, at the second session, perceptually similar or different. At both sessions, right mid-STS/superior temporal gyrus (STG) and superior temporal pole (sTP) showed sensitivity to acoustical changes. Critically, voice learning induced changes in the acoustical processing of voices in inferior frontal cortices (IFCs). At the second session only, right IFC and left cingulate gyrus showed sensitivity to changes in perceived identity. The processing of voice identity appears to be subserved by a large network of brain areas ranging from the sTP, involved in an acoustic-based representation of unfamiliar voices, to areas along the convexity of the IFC for identity-related processing of familiar voices. PMID- 21531780 TI - Monocular visual deprivation suppresses excitability in adult human visual cortex. AB - The adult visual cortex maintains a substantial potential for plasticity in response to a change in visual input. For instance, transcranial magnetic stimulation (TMS) studies have shown that binocular deprivation (BD) increases the cortical excitability for inducing phosphenes with TMS. Here, we employed TMS to trace plastic changes in adult visual cortex before, during, and after 48 h of monocular deprivation (MD) of the right dominant eye. In healthy adult volunteers, MD-induced changes in visual cortex excitability were probed with paired-pulse TMS applied to the left and right occipital cortex. Stimulus response curves were constructed by recording the intensity of the reported phosphenes evoked in the contralateral visual field at range of TMS intensities. Phosphene measurements revealed that MD produced a rapid and robust decrease in cortical excitability relative to a control condition without MD. The cortical excitability returned to preinterventional baseline levels within 3 h after the end of MD. The results show that in contrast to the excitability increase in response to BD, MD acutely triggers a reversible decrease in visual cortical excitability. This shows that the pattern of visual deprivation has a substantial impact on experience-dependent plasticity of the human visual cortex. PMID- 21531781 TI - Acquisition, extinction, and recall of opiate reward memory are signaled by dynamic neuronal activity patterns in the prefrontal cortex. AB - The medial prefrontal cortex (mPFC) comprises an important component in the neural circuitry underlying drug-related associative learning and memory processing. Neuronal activation within mPFC circuits is correlated with the recall of opiate-related drug-taking experiences in both humans and other animals. Using an unbiased associative place conditioning procedure, we recorded mPFC neuronal populations during the acquisition, recall, and extinction phases of morphine-related associative learning and memory. Our analyses revealed that mPFC neurons show increased activity both in terms of tonic and phasic activity patterns during the acquisition phase of opiate reward-related memory and demonstrate stimulus-locked associative activity changes in real time, during the recall of opiate reward memories. Interestingly, mPFC neuronal populations demonstrated divergent patterns of bursting activity during the acquisition versus recall phases of newly acquired opiate reward memory, versus the extinction of these memories, with strongly increased bursting during the recall of an extinction memory and no associative bursting during the recall of a newly acquired opiate reward memory. Our results demonstrate that neurons within the mPFC are involved in both the acquisition, recall, and extinction of opiate related reward memories, showing unique patterns of tonic and phasic activity patterns during these separate components of the opiate-related reward learning and memory recall. PMID- 21531782 TI - Acute postischemic seizures are associated with increased mortality and brain damage in adult mice. AB - Postischemic seizures are associated with worsened outcome following stroke, but the underlying pathophysiology is poorly understood. Here we examined acute seizures in adult mice following hypoxia-ischemia (HI) via combined behavioral, electrophysiological, and histological assessments. C57BL/6 mice aged 4-9 months received a permanent occlusion of the right common carotid artery and then underwent a systemic hypoxic episode. Generalized motor seizures were observed within 72 h following HI. These seizures occurred nearly exclusively in animals with extensive brain injury in the hemisphere ipsilateral to the carotid occlusion, but their generation was not associated with electroencephalographic discharges in bilateral hippocampal and neocortical recordings. Animals exhibiting these seizures had a high rate of mortality, and post-HI treatments with diazepam and phenytoin greatly suppressed these behavioral seizures and improved post-HI animal survival. Based on these data, we conclude that these seizures are a consequence of HI brain injury, contribute to worsened outcome following HI, and that they originate from deep subcortical structures. PMID- 21531783 TI - Responses to subsequent anti-HER2 therapy after treatment with trastuzumab-DM1 in women with HER2-positive metastatic breast cancer. AB - BACKGROUND: Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1). PATIENTS AND METHODS: We retrospectively identified HER2-positive MBC patients treated with T DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan-Meier estimates. RESULTS: We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3-14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively. CONCLUSIONS: In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens. PMID- 21531784 TI - Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer. AB - BACKGROUND: Previous studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer. PATIENTS AND METHODS: This study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments. RESULTS: MCs accounted for 17.4% (n=178) of tumours. Patients with MC had 5- and 8-year overall survival rates of 78.6% and 68.8%, respectively, compared with 72.3% and 63.8%, respectively, for patients with nonmucinous tumours. Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage of disease and adjuvant chemotherapy. No statistically significant interaction between mucinous histology and adjuvant chemotherapy was found. CONCLUSIONS: For patients with stage II and III colon cancer who underwent curative surgery, mucinous histology has no significant correlation with prognosis compared with NMC. This retrospective analysis suggests a comparable benefit from adjuvant chemotherapy for MC compared with NMC. PMID- 21531785 TI - Wnt signaling in the murine diastema. AB - The correct number and shape of teeth are critical factors for an aesthetic and functional dentition. Understanding the molecular mechanisms regulating tooth number and shape are therefore important in orthodontics. Mice have only one incisor and three molars in each jaw quadrant that are divided by a tooth-less region, the diastema. Although mice lost teeth in the diastema during evolution, the remnants of the evolutionary lost teeth are observed as transient epithelial buds in the wild-type diastema during early stages of development. Shh and Fgf signaling pathways that are essential for tooth development have been shown to be repressed in the diastema. It remains unclear however how Wnt signaling, that is also required for tooth development, is regulated in the diastema. In this study we found that in the embryonic diastema, Wnt5a expression was observed in mesenchyme, whereas Wnt4 and Wnt10b were expressed in epithelium. The expression of Wnt6 and Wnt11 was found in both tissues. The Wnt co-receptor, Lrp6, was weakly expressed in the diastema overlapping with weak Lrp4 expression, a co receptor that inhibits Wnt signaling. Secreted Wnt inihibitors Dkk1, Dkk2, and Dkk3 were also expressed in the diastema. Lrp4 mutant mice develop supernumerary teeth in the diastema that is accompanied by upregulation of Wnt signaling and Lrp6 expression. Wnt signaling is thus usually attenuated in the diastema by these secreted and membrane bound Wnt inhibitors. PMID- 21531786 TI - Three-dimensional gender differences in facial form of children in the North East of England. AB - The aim of the prospective cross-sectional morphometric study was to explore three dimensional (3D) facial shape and form (shape plus size) variation within and between 8- and 12-year-old Caucasian children; 39 males age-matched with 41 females. The 3D images were captured using a stereophotogrammeteric system, and facial form was recorded by digitizing 39 anthropometric landmarks for each scan. The x, y, z coordinates of each landmark were extracted and used to calculate linear and angular measurements. 3D landmark asymmetry was quantified using Generalized Procrustes Analysis (GPA) and an average face was constructed for each gender. The average faces were superimposed and differences were visualized and quantified. Shape variations were explored using GPA and PrincipalComponent Analysis. Analysis of covariance and Pearson correlation coefficients were used to explore gender differences and to determine any correlation between facial measurements and height or weight. Multivariate analysis was used to ascertain differences in facial measurements or 3D landmark asymmetry. There were no differences in height or weight between genders. There was a significant positive correlation between facial measurements and height and weight and statistically significant differences in linear facial width measurements between genders. These differences were related to the larger size of males rather than differences in shape. There were no age- or gender-linked significant differences in 3D landmark asymmetry. Shape analysis confirmed similarities between both males and females for facial shape and form in 8- to 12-year-old children. Any differences found were related to differences in facial size rather than shape. PMID- 21531787 TI - Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer. AB - Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10(-8)) with rs10896449 the most significant (P= 7.94 * 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 * 10(-5), adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2)= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 * 10(-3), adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2)= 0.17; rs10896449-rs10896438, r(2)= 0.10; rs12793759-rs10896438, r(2)= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ~123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals. PMID- 21531788 TI - Fine-mapping of colorectal cancer susceptibility loci at 8q23.3, 16q22.1 and 19q13.11: refinement of association signals and use of in silico analysis to suggest functional variation and unexpected candidate target genes. AB - We have previously identified several colorectal cancer (CRC)-associated polymorphisms using genome-wide association (GWA) analysis. We sought to fine-map the location of the functional variants for three of these regions at 8q23.3 (EIF3H), 16q22.1 (CDH1/CDH3) and 19q13.11 (RHPN2). We genotyped two case-control sets at high density in the selected regions and used existing data from four other case-control sets, comprising a total of 9328 CRC cases and 10 480 controls. To improve marker density, we imputed genotypes from the 1000 Genomes Project and Hapmap3 data sets. All three regions contained smaller areas in which a cluster of single nucleotide polymorphisms (SNPs) showed clearly stronger association signals than surrounding SNPs, allowing us to assign those areas as the most likely location of the disease-associated functional variant. Further fine-mapping within those areas was generally unhelpful in identifying the functional variation based on strengths of association. However, functional annotation suggested a relatively small number of functional SNPs, including some with potential regulatory function at 8q23.3 and 16q22.1 and a non-synonymous SNP in RPHN2. Interestingly, the expression quantitative trait locus browser showed a number of highly associated SNP alleles correlated with mRNA expression levels not of EIF3H and CDH1 or CDH3, but of UTP23 and ZFP90, respectively. In contrast, none of the top SNPs within these regions was associated with transcript levels at EIF3H, CDH1 or CDH3. Our post-GWA study highlights benefits of fine-mapping of common disease variants in combination with publicly available data sets. In addition, caution should be exercised when assigning functionality to candidate genes in regions discovered through GWA analysis. PMID- 21531789 TI - Silencing of frataxin gene expression triggers p53-dependent apoptosis in human neuron-like cells. AB - Friedreich's ataxia (FRDA) is an autosomal recessive disease caused by mutations that produce a deficiency in frataxin. Despite the importance of neurodegeneration in FRDA, little is known about the consequences of frataxin deficiency in neuronal cells. Here we describe a neuronal cell model for FRDA based on the use of lentiviral vectors that carry minigenes encoding frataxin specific shRNAs that silence the expression of this gene. These lentivectors can knockdown frataxin expression in human neuroblastoma SH-SY5Y cells, which results in large-scale cell death in differentiated neuron-like cells but not in undifferentiated neuroblastoma cells. Frataxin-deficient neuron-like cells appear to die through apoptosis that is accompanied by up-regulation of p53, PUMA and Bax and activation of caspase-3. No significant autophagy is observed in frataxin deficient neuron-like cells and the pharmacological activation of autophagy does not significantly increase neuronal cell death in response to the frataxin deficiency. Cell death triggered by frataxin knockdown can be impaired by interference with p53, caspase inhibitors and gene transfer of FXN. These results suggest that frataxin gene silencing in human neuron-like cells may constitute a useful cell model to characterize the molecular changes triggered by frataxin deficiency in neurons, as well as to search for therapies that may protect against neurodegeneration. PMID- 21531790 TI - Large-scale recombinant adeno-associated virus production. AB - Since recombinant adeno-associated virus (rAAV) was first described as a potential mammalian cell transducing system, frequent reports purportedly solving the problems of scalable production have appeared. Yet few of these processes have enabled the development of robust and economical rAAV production. Two production platforms have emerged that have gained broad support for producing both research and clinical grade vectors. These processes differ fundamentally in several aspects. One approach is based on adherent mammalian cells and uses optimized chemical transient transfection for introducing the essential genetic components into the cells. The other approach utilizes suspension cultures of invertebrate cells. Baculovirus expression vectors are used for introducing the AAV genes into the cells. In addition, the baculovirus provides the helper functions necessary for efficient AAV DNA replication. The use of suspension cell culture provides an intrinsically more scalable platform system than using adherent cells. The upstream processes for suspension cultures are amenable for automation and are easily monitored and regulated to maintain optimum conditions that produce consistent yields of rAAV. Issues relating to developing new and improving existing rAAV production methods are discussed. PMID- 21531792 TI - Therapeutic effects on atopic dermatitis by anti-RelA short interfering RNA combined with functional peptides Tat and AT1002. AB - Atopic dermatitis (AD) has high morbidity and poor prognosis because safe and effective treatments are scarce. Recently, short interfering RNA (siRNA) has shown promise as an effective treatment for targeting specific aberrantly expressed genes. However, naked siRNAs are too inefficient because of various enzymatic, membrane, and cellular barriers. We previously reported that a Tat analog acting as a cell-penetrating peptide, combined with AT1002, which reversibly increases paracellular transport of molecules across the epidermal barrier in epidermis-disrupted mice and enhances the skin permeation of water soluble siRNA. In the present study, to develop a novel treatment for AD, we determined the intradermal permeation of siRNAs and the antiallergic effects of a siRNA that silences RelA, a member of the nuclear factor-kappaB family, using Tat and AT1002 peptides in an AD mouse model. We first showed that the Tat analog and AT1002 delivered siRNA into the skin of ICR mice and, upon topical application to the AD-induced ears of NC/Nga mice, changed zonula occludens protein 1 expression. In addition, the silencing effects on the mRNA of RelA in JAWS II cells transfected with siRNA oligonucleotides for mouse RelA, complexed with Tat, were as effective as a commercial vector. Furthermore, the ear thickness, clinical skin severity, topical cytokine levels, and serum IgE production in AD model mice treated with anti-RelA siRNA with Tat and AT1002 were improved. PMID- 21531793 TI - Agonist-induced desensitization/resensitization of human G protein-coupled receptor 17: a functional cross-talk between purinergic and cysteinyl-leukotriene ligands. AB - G protein-coupled receptor (GPR) 17 is a P2Y-like receptor that responds to both uracil nucleotides (as UDP-glucose) and cysteinyl-leukotrienes (cysLTs, as LTD(4)). By bioinformatic analysis, two distinct binding sites have been hypothesized to be present on GPR17, but little is known on their putative cross regulation and on GPR17 desensitization/resensitization upon agonist exposure. In this study, we investigated in GPR17-expressing 1321N1 cells the cross-regulation between purinergic- and cysLT-mediated responses and analyzed GPR17 regulation after prolonged agonist exposure. Because GPR17 receptors couple to G(i) proteins and adenylyl cyclase inhibition, both guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding and the cAMP assay have been used to investigate receptor functional activity. UDP-glucose was found to enhance LTD(4) potency in mediating activation of G proteins and vice versa, possibly through an allosteric mechanism. Both UDP-glucose and LTD(4) induced a time- and concentration dependent GPR17 loss of response (homologous desensitization) with similar kinetics. GPR17 homologous desensitization was accompanied by internalization of receptors inside cells, which occurred in a time-dependent manner with similar kinetics for both agonists. Upon agonist removal, receptor resensitization occurred with the typical kinetics of G protein-coupled receptors. Finally, activation of GPR17 by UDP-glucose (but not vice versa) induced a partial heterologous desensitization of LTD(4)-mediated responses, suggesting that nucleotides have a hierarchy in producing desensitizing signals. These findings suggest a functional cross-talk between purinergic and cysLT ligands at GPR17. Because of the recently suggested key role of GPR17 in brain oligodendrogliogenesis and myelination, this cross-talk may have profound implications in fine-tuning cell responses to demyelinating and inflammatory conditions when these ligands accumulate at lesion sites. PMID- 21531791 TI - Chromosome 7p11.2 (EGFR) variation influences glioma risk. AB - While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population corrected statistics, P(c) = 7.72 * 10(-8) and 2.09 * 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk. PMID- 21531794 TI - A rate-limiting role for Dickkopf-1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody. AB - Genetic studies have linked both osteoporotic and high bone mass phenotypes to low-density lipoprotein receptor-related proteins (LRP4, LRP5, and LRP6). LRPs are receptors for inhibitory Dickkopf-1 (DKK1) protein, and treatment modalities that modulate LRP/DKK1 binding therefore may act as stimulators of bone mass accrual. Here, we report that RH2-18, a fully human monoclonal anti-DKK1 antibody elicits systemic pharmacologic bone efficacy and new bone formation at endosteal bone surfaces in vivo in a mouse model of estrogen-deficiency-induced osteopenia. This was paralleled by partial-to-complete resolution of osteopenia (bone mineral density) at all of the skeletal sites investigated in femur and lumbar-vertebral bodies and the restoration of trabecular bone microarchitecture. More importantly, testing of RH2-18 in adult, osteopenic rhesus macaques demonstrated a rate-limiting role of DKK1 at multiple skeletal sites and responsiveness to treatment. In conclusion, this study provides pharmacologic evidence for the modulation of DKK1 bioactivity in the adult osteopenic skeleton as a viable approach to resolve osteopenia in animal models. Thus, data described here suggest that targeting DKK1 through means such as a fully human anti-DKK1 antibody provides a potential bone-anabolic treatment for postmenopausal osteoporosis. PMID- 21531795 TI - The Nudix hydrolase CDP-chase, a CDP-choline pyrophosphatase, is an asymmetric dimer with two distinct enzymatic activities. AB - A Nudix enzyme from Bacillus cereus (NCBI RefSeq accession no. NP_831800) catalyzes the hydrolysis of CDP-choline to produce CMP and phosphocholine. Here, we show that in addition, the enzyme has a 3'->5' RNA exonuclease activity. The structure of the free enzyme, determined to a 1.8-A resolution, shows that the enzyme is an asymmetric dimer. Each monomer consists of two domains, an N terminal helical domain and a C-terminal Nudix domain. The N-terminal domain is placed relative to the C-terminal domain such as to result in an overall asymmetric arrangement with two distinct catalytic sites: one with an "enclosed" Nudix pyrophosphatase site and the other with a more open, less-defined cavity. Residues that may be important for determining the asymmetry are conserved among a group of uncharacterized Nudix enzymes from Gram-positive bacteria. Our data support a model where CDP-choline hydrolysis is catalyzed by the enclosed Nudix site and RNA exonuclease activity is catalyzed by the open site. CDP-Chase is the first identified member of a novel Nudix family in which structural asymmetry has a profound effect on the recognition of substrates. PMID- 21531796 TI - Differential chitinase activity and production within Francisella species, subspecies, and subpopulations. AB - Genotyping of Francisella tularensis (A1a, A1b, A2, and type B) and Francisella novicida has identified multiple differences between species and among F. tularensis subspecies and subpopulations. Variations in virulence, geographic distribution, and ecology are also known to exist among this group of bacteria, despite the >95% nucleotide identity in their genomes. This study expands the description of phenotypic differences by evaluating the ability of F. tularensis and F. novicida to degrade chitin analogs and produce active chitinases. Endochitinase activities were observed to vary among F. tularensis and F. novicida strains. The activity observed for F. tularensis strains was predominantly associated with whole-cell lysates, while the chitinase activity of F. novicida localized to the culture supernatant. In addition, the overall level of chitinase activity differed among the subpopulations of F. tularensis and between the species. Bioinformatic analyses identified two new putative chitinase genes (chiC and chiD), as well as the previously described chiA and chiB. However, the presence of these four open reading frames as intact genes or pseudogenes was found to differ between Francisella species and F. tularensis subspecies and subpopulations. Recombinant production of the putative chitinases and enzymatic evaluations revealed ChiA, ChiB, ChiC, and ChiD possessed dissimilar chitinase activities. These biochemical studies coupled with bioinformatic analyses and the evaluation of chiA and chiC knockouts in F. tularensis A1 and A2 strains, respectively, provided a molecular basis to explain the differential chitinase activities observed among the species and subpopulations of Francisella. PMID- 21531797 TI - The anaerobe-specific orange protein complex of Desulfovibrio vulgaris hildenborough is encoded by two divergent operons coregulated by sigma54 and a cognate transcriptional regulator. AB - Analysis of sequenced bacterial genomes revealed that the genomes encode more than 30% hypothetical and conserved hypothetical proteins of unknown function. Among proteins of unknown function that are conserved in anaerobes, some might be determinants of the anaerobic way of life. This study focuses on two divergent clusters specifically found in anaerobic microorganisms and mainly composed of genes encoding conserved hypothetical proteins. We show that the two gene clusters DVU2103-DVU2104-DVU2105 (orp2) and DVU2107-DVU2108-DVU2109 (orp1) form two divergent operons transcribed by the sigma(54)-RNA polymerase. We further demonstrate that the sigma(54)-dependent transcriptional regulator DVU2106, located between orp1 and orp2, collaborates with sigma(54)-RNA polymerase to orchestrate the simultaneous expression of the divergent orp operons. DVU2106, whose structural gene is transcribed by the sigma(70)-RNA polymerase, negatively retrocontrols its own expression. By using an endogenous pulldown strategy, we identify a physiological complex composed of DVU2103, DVU2104, DVU2105, DVU2108, and DVU2109. Interestingly, inactivation of DVU2106, which is required for orp operon transcription, induces morphological defects that are likely linked to the absence of the ORP complex. A putative role of the ORP proteins in positioning the septum during cell division is discussed. PMID- 21531798 TI - Characterization of CrgA, a new partner of the Mycobacterium tuberculosis peptidoglycan polymerization complexes. AB - The role(s) in cell division of the Mycobacterium tuberculosis Rv0011c gene product, a homolog of the Streptomyces CrgA protein that is responsible for coordinating growth and cytokinesis in sporogenic aerial hyphae, is largely unknown. We show that an enhanced cyan fluorescent protein-M. tuberculosis CrgA (ECFP-CrgA(MT)) fusion protein is localized to the cell membrane, midcell, and cell pole regions in Mycobacterium smegmatis. Furthermore, the ECFP-CrgA(MT) fusion protein colocalized with FtsZ-enhanced yellow fluorescent protein (EYFP) in M. smegmatis. Bacterial two-hybrid assays indicated strong interactions of M. tuberculosis CrgA with FtsZ, FtsQ, and the class B penicillin-binding proteins, FtsI (PBPB) and PBPA. The midcell localization of CrgA(MT) was severely compromised under conditions of FtsZ depletion, which indicated that CrgA localizes to the midcell region after assembly of the FtsZ ring. M. tuberculosis cells with reduced CrgA levels were elongated and grew more slowly than wild-type cells, which indicated defects in cell division, whereas CrgA overproduction did not show growth defects. A M. smegmatis DeltacrgA strain exhibited a bulged cell morphology, elongated cells with a chain-like phenotype, cells with polar bulbous structures, and a modest growth defect. FtsZ and FtsI levels were not affected in cells producing altered levels of CrgA. Septal and membrane localization of GFP FtsI was enhanced by CrgA overproduction and was diminished in a DeltacrgA strain, which indicates that one role of CrgA is to promote and/or stabilize FtsI localization. Overall, these data indicate that CrgA is a novel member of the cell division complex in mycobacteria and possibly facilitates septum formation. PMID- 21531799 TI - Dual function of a tip fimbrillin of Actinomyces in fimbrial assembly and receptor binding. AB - Interaction of Actinomyces oris with salivary proline-rich proteins (PRPs), which serve as fimbrial receptors, involves type 1 fimbriae. Encoded by the gene locus fimQ-fimP-srtC1, the type 1 fimbria is comprised of the fimbrial shaft FimP and the tip fimbrillin FimQ. Fimbrial polymerization requires the fimbria-specific sortase SrtC1, which catalyzes covalent linkage of fimbrial subunits. Using genetics, biochemical methods, and electron microscopy, we provide evidence that the tip fimbrillin, FimQ, is involved in fimbrial assembly and interaction with PRPs. Specifically, while deletion of fimP completely abolished the type 1 fimbrial structures, surface display of monomeric FimQ was not affected by this mutation. Surprisingly, deletion of fimQ significantly reduced surface assembly of the type 1 fimbriae. This defect was rescued by recombinant FimQ ectopically expressed from a plasmid. In agreement with the role of type 1 fimbriae in binding to PRPs, aggregation of A. oris with PRP-coated beads was abrogated in cells lacking srtC1 or fimP. This aggregation defect of the DeltafimP mutant was mainly due to significant reduction of FimQ on the bacterial surface, as the aggregation was not observed in a strain lacking fimQ. Increasing expression of FimQ in the DeltafimP mutant enhanced aggregation, while overexpression of FimP in the DeltafimQ mutant did not. Furthermore, recombinant FimQ, not FimP, bound surface-associated PRPs in a dose-dependent manner. Thus, not only does FimQ function as the major adhesin of the type 1 fimbriae, it also plays an important role in fimbrial assembly. PMID- 21531800 TI - Asp2 and Asp3 interact directly with GspB, the export substrate of the Streptococcus gordonii accessory Sec System. AB - GspB is a serine-rich glycoprotein adhesin of Streptococcus gordonii that is exported to the bacterial surface by the accessory Sec system. This dedicated export pathway is comprised of seven components (SecA2, SecY2, and five accessory Sec proteins [Asp1 to Asp5]). The latter proteins have no known homologs beyond the Asps of other species. Asp1 to Asp3 are absolutely required for export of the substrate GspB, but their roles in this process are unknown. Using copurification analysis and far-Western blotting, we found that Asp2 and Asp3 could individually bind the serine-rich repeat (SRR) domains of GspB. Deletion of both SRR regions of GspB led to a decrease in its export, suggesting that binding of the Asps to the SRR regions is important for GspB transport by the accessory Sec system. The Asps also bound a heterologous substrate for the accessory Sec system containing a slow-folding MalE variant, but they did not bind wild-type MalE. The combined results indicate that the Asps may recognize the export substrate through preferential interactions with its unstructured or unfolded regions. Glycosylation of the SRR domains on GspB prevented Asp binding, suggesting that binding of the Asps to the preprotein occurs prior to its full glycosylation. Together, these findings suggest that Asp2 and Asp3 are likely to function in part as chaperones in the early phase of GspB transport. PMID- 21531801 TI - PtrA is a periplasmic protein involved in Cu tolerance in Pseudomonas aeruginosa. AB - In this work, we demonstrate that PtrA (U. H. Ha et al., Mol. Microbiol. 54:307 320, 2004) is a periplasmic protein, specifically synthesized in the presence of copper, that is involved in the tolerance of Pseudomonas aeruginosa to copper. Our biochemical and genetic analyses challenge its role in transcriptional inhibition of the type III secretion system. PMID- 21531802 TI - The poor growth of Rhodospirillum rubrum mutants lacking RubisCO is due to the accumulation of ribulose-1,5-bisphosphate. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO) catalyzes the first step of CO(2) fixation in the Calvin-Benson-Bassham (CBB) cycle. Besides its function in fixing CO(2) to support photoautotrophic growth, the CBB cycle is also important under photoheterotrophic growth conditions in purple nonsulfur photosynthetic bacteria. It has been assumed that the poor photoheterotrophic growth of RubisCO-deficient strains was due to the accumulation of excess intracellular reductant, which implied that the CBB cycle is important for maintaining the redox balance under these conditions. However, we present analyses of cbbM mutants in Rhodospirillum rubrum that indicate that toxicity is the result of an elevated intracellular pool of ribulose-1,5-bisphosphate (RuBP). There is a redox effect on growth, but it is apparently an indirect effect on the accumulation of RuBP, perhaps by the regulation of the activities of enzymes involved in RuBP regeneration. Our studies also show that the CBB cycle is not essential for R. rubrum to grow under photoheterotrophic conditions and that its role in controlling the redox balance needs to be further elucidated. Finally, we also show that CbbR is a positive transcriptional regulator of the cbb operon (cbbEFPT) in R. rubrum, as seen with related organisms, and define the transcriptional organization of the cbb genes. PMID- 21531803 TI - Characteristic phenotypes associated with ptsN-null mutants in Escherichia coli K 12 are absent in strains with functional ilvG. AB - The phosphotransferase system (PTS), encompassing EI, HPr, and assorted EII proteins, uses phosphoenolpyruvate to import and phosphorylate sugars. A paralog of EIIA of the sugar PTS system known as ptsN has been purported to regulate organic nitrogen source utilization in Escherichia coli K-12. Its known biochemical function, however, relates to potassium homeostasis. The evidence for regulation of organic nitrogen source utilization by ptsN is based primarily on the defective growth of DeltaptsN mutants on amino acid nitrogen sources and other nutrient combinations. These observations were made with E. coli strains MG1655 and W3110, which carry a nonfunctional version of ilvG. There are three isozymes that effectively catalyze the first committed step of branched-chain amino acid biosynthesis, but ilvG is unique for doing so effectively across a range of potassium concentrations. Here we show that all of the nutrient utilization phenotypes attributed to ptsN are manifested selectively in strains lacking functional ilvG. We conclude that the ptsN gene product does not regulate organic nitrogen source utilization as previously proposed. PMID- 21531804 TI - Inference of the transcriptional regulatory network in Staphylococcus aureus by integration of experimental and genomics-based evidence. AB - Transcriptional regulatory networks are fine-tuned systems that help microorganisms respond to changes in the environment and cell physiological state. We applied the comparative genomics approach implemented in the RegPredict Web server combined with SEED subsystem analysis and available information on known regulatory interactions for regulatory network reconstruction for the human pathogen Staphylococcus aureus and six related species from the family Staphylococcaceae. The resulting reference set of 46 transcription factor regulons contains more than 1,900 binding sites and 2,800 target genes involved in the central metabolism of carbohydrates, amino acids, and fatty acids; respiration; the stress response; metal homeostasis; drug and metal resistance; and virulence. The inferred regulatory network in S. aureus includes ~320 regulatory interactions between 46 transcription factors and ~550 candidate target genes comprising 20% of its genome. We predicted ~170 novel interactions and 24 novel regulons for the control of the central metabolic pathways in S. aureus. The reconstructed regulons are largely variable in the Staphylococcaceae: only 20% of S. aureus regulatory interactions are conserved across all studied genomes. We used a large-scale gene expression data set for S. aureus to assess relationships between the inferred regulons and gene expression patterns. The predicted reference set of regulons is captured within the Staphylococcus collection in the RegPrecise database (http://regprecise.lbl.gov). PMID- 21531805 TI - Complete genome sequence and immunoproteomic analyses of the bacterial fish pathogen Streptococcus parauberis. AB - Although Streptococcus parauberis is known as a bacterial pathogen associated with bovine udder mastitis, it has recently become one of the major causative agents of olive flounder (Paralichthys olivaceus) streptococcosis in northeast Asia, causing massive mortality resulting in severe economic losses. S. parauberis contains two serotypes, and it is likely that capsular polysaccharide antigens serve to differentiate the serotypes. In the present study, the complete genome sequence of S. parauberis (serotype I) was determined using the GS-FLX system to investigate its phylogeny, virulence factors, and antigenic proteins. S. parauberis possesses a single chromosome of 2,143,887 bp containing 1,868 predicted coding sequences (CDSs), with an average GC content of 35.6%. Whole genome dot plot analysis and phylogenetic analysis of a 60-kDa chaperonin encoding gene and the glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-encoding gene showed that the strain was evolutionarily closely related to Streptococcus uberis. S. parauberis antigenic proteins were analyzed using an immunoproteomic technique. Twenty-one antigenic protein spots were identified in S. parauberis, by reaction with an antiserum obtained from S. parauberis-challenged olive flounder. This work provides the foundation needed to understand more clearly the relationship between pathogen and host and develops new approaches toward prophylactic and therapeutic strategies to deal with streptococcosis in fish. The work also provides a better understanding of the physiology and evolution of a significant representative of the Streptococcaceae. PMID- 21531806 TI - Binding and spreading of ParB on DNA determine its biological function in Pseudomonas aeruginosa. AB - ParB protein of Pseudomonas aeruginosa belongs to a widely represented ParB family of chromosomally and plasmid-encoded partitioning type IA proteins. Ten putative parS sites are dispersed in the P. aeruginosa chromosome, with eight of them localizing in the oriC domain. After binding to parS, ParB spreads on the DNA, causing transcriptional silencing of nearby genes (A. A. Bartosik et al., J. Bacteriol. 186:6983-6998, 2004). We have studied ParB derivatives impaired in spreading either due to loss of DNA-binding ability or oligomerization. We defined specific determinants outside of the helix-turn-helix motif responsible for DNA binding. Analysis confirmed the localization of the main dimerization domain in the C terminus of ParB but also mapped another self-interactive domain in the N-terminal domain. Reverse genetics were used to introduce five parB alleles impaired in spreading into the P. aeruginosa chromosome. The single amino acid substitutions in ParB causing a defect in oligomerization but not in DNA binding caused a chromosome segregation defect, slowed the growth rate, and impaired motilities, similarly to the pleiotropic phenotype of parB-null mutants, indicating that the ability to spread is vital for ParB function in the cell. The toxicity of ParB overproduction in Pseudomonas spp. is not due to the spreading since several ParB derivatives defective in oligomerization were still toxic for P. aeruginosa when provided in excess. PMID- 21531807 TI - CheY3 of Borrelia burgdorferi is the key response regulator essential for chemotaxis and forms a long-lived phosphorylated intermediate. AB - Spirochetes have a unique cell structure: These bacteria have internal periplasmic flagella subterminally attached at each cell end. How spirochetes coordinate the rotation of the periplasmic flagella for chemotaxis is poorly understood. In other bacteria, modulation of flagellar rotation is essential for chemotaxis, and phosphorylation-dephosphorylation of the response regulator CheY plays a key role in regulating this rotary motion. The genome of the Lyme disease spirochete Borrelia burgdorferi contains multiple homologues of chemotaxis genes, including three copies of cheY, referred to as cheY1, cheY2, and cheY3. To investigate the function of these genes, we targeted them separately or in combination by allelic exchange mutagenesis. Whereas wild-type cells ran, paused (flexed), and reversed, cells of all single, double, and triple mutants that contained an inactivated cheY3 gene constantly ran. Capillary tube chemotaxis assays indicated that only those strains with a mutation in cheY3 were deficient in chemotaxis, and cheY3 complementation restored chemotactic ability. In vitro phosphorylation assays indicated that CheY3 was more efficiently phosphorylated by CheA2 than by CheA1, and the CheY3-P intermediate generated was considerably more stable than the CheY-P proteins found in most other bacteria. The results point toward CheY3 being the key response regulator essential for chemotaxis in B. burgdorferi. In addition, the stability of CheY3-P may be critical for coordination of the rotation of the periplasmic flagella. PMID- 21531808 TI - Roles of cysteine proteases Cwp84 and Cwp13 in biogenesis of the cell wall of Clostridium difficile. AB - Clostridium difficile expresses a number of cell wall proteins, including the abundant high-molecular-weight and low-molecular-weight S-layer proteins (SLPs). These proteins are generated by posttranslational cleavage of the precursor SlpA by the cysteine protease Cwp84. We compared the phenotypes of C. difficile strains containing insertional mutations in either cwp84 or its paralog cwp13 and complemented with plasmids expressing wild-type or mutant forms of their genes. We show that the presence of uncleaved SlpA in the cell wall of the cwp84 mutant results in aberrant retention of other cell wall proteins at the cell surface, as demonstrated by secretion of the proteins Cwp66 and Cwp2 into the growth medium. These phenotypes are restored by complementation with a plasmid expressing wild type Cwp84 enzyme but not with one encoding a Cys116Ala substitution in the active site. The cwp13 mutant cleaved the SlpA precursor normally and had a wild type-like colony phenotype. Both Cwp84 and Cwp13 are produced as proenzymes which are processed by cleavage to produce mature enzymes. In the case of Cwp84, this cleavage does not appear to be autocatalytic, whereas in Cwp13 autocatalysis was demonstrated as a Cys109Ala mutant did not undergo processing. Cwp13 appears to have a role in processing of Cwp84 but is not essential for Cwp84 activity. Cwp13 cleaves SlpA in the HMW SLP domain, which we suggest may reflect a role in cleavage and degradation of misfolded proteins at the cell surface. PMID- 21531809 TI - Biological function and prognostic significance of peroxisome proliferator activated receptor delta in rectal cancer. AB - PURPOSE: To investigate the expression significance of PPAR beta/delta in relation to radiotherapy (RT), clinicopathologic, and prognostic variables of rectal cancer patients. EXPERIMENTAL DESIGN: We included 141 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. Tissue microarray samples from the excised rectal cancers and the adjacent or distant normal mucosa and lymph node metastases were stained with PPAR delta antibody. Survival probability was computed by the Kaplan-Meier method and Cox regression model. The proliferation of colon cancer cell lines KM12C, KM12SM, and KM12L4a was assayed after PPAR delta knockdown. RESULTS: PPAR delta was increased from adjacent or distant normal mucosa to primary cancers, whereas it decreased from primary cancers to lymph node metastases. After RT, PPAR delta was increased in normal mucosa, whereas it decreased in primary cancers and lymph node metastases. In primary cancers, the high expression of PPAR delta was related to higher frequency of stage I cases, lower lymph node metastasis rate, and low expression of Ki-67 in the unirradiated cases, and related to favorable survival in the cases either with or without RT. The proliferation of the KM12C, KM12SM, or KM12L4a cells was significantly accelerated after PPAR delta knockdown. CONCLUSIONS: RT decreases the PPAR delta expression in primary rectal cancers and lymph node metastases. PPAR delta is related to the early development of rectal cancer and inhibits the proliferation of colorectal cancer cells. Increase of PPAR delta predicts favorable survival in the rectal cancer patients either with or without preoperative RT. PMID- 21531810 TI - Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. AB - PURPOSE: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non-small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance. PATIENTS AND METHODS: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations. RESULTS: Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months). CONCLUSIONS: Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed. PMID- 21531812 TI - A low-toxicity IL-2-based immunocytokine retains antitumor activity despite its high degree of IL-2 receptor selectivity. AB - PURPOSE: The goal of the study was to engineer a form of interleukin 2 (IL-2) that, when delivered as a tumor-specific antibody fusion protein, retains the ability to stimulate an antitumor immune response via interaction with the high affinity IL-2 receptor but has lower toxicity because of the reduced activation of the intermediate-affinity IL-2 receptor. EXPERIMENTAL DESIGN: We investigated changes in the proposed toxin motif of IL-2 by introducing a D20T mutation that has little effect on the activity of free IL-2. We expressed this IL-2 variant as a fusion protein with an antibody (NHS76) that targets the necrotic core of tumors and characterized this molecule (NHS-IL2LT) in vitro and in vivo. RESULTS: NHS-IL2LT was shown to have near normal biological activity in vitro by using T cell lines expressing the high-affinity IL-2 receptor, but little or no activity by using cell lines expressing only the intermediate IL-2 receptor. Relative to the control antibody fusion protein containing wild-type IL-2, NHS-IL2LT retained antitumor activity against established neuroblastoma and non-small cell lung cancer metastases in syngeneic mouse tumor models but was much better tolerated in immune-competent mice and in cynomolgus monkeys. CONCLUSIONS: The qualities of low toxicity and single-agent efficacy shown suggest that NHS-IL2LT is a good candidate for therapeutic approaches combining standard cytotoxic and immune therapies. In fact, this molecule (also known as Selectikine or EMD 521873) is currently in phase I clinical trial. PMID- 21531811 TI - Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. AB - PURPOSE: To evaluate if diastolic blood pressure (dBP) >=90 mm Hg during axitinib treatment is a marker of efficacy. EXPERIMENTAL DESIGN: The relationship between dBP >=90 mm Hg and efficacy was retrospectively explored across 5 phase II studies of single-agent axitinib for the treatment of 4 different tumor types. All patients had baseline BP <=140/90 mm Hg and were stratified into 2 groups based on in-clinic BP measurements after initiating therapy: those with dBP <90 mm Hg throughout therapy and those with at least 1 dBP >=90 mm Hg. Median overall survival (mOS), median progression-free survival (mPFS), objective response rate (ORR), and adverse events were evaluated by dBP group in individual and pooled analyses. RESULTS: Two-hundred thirty patients were evaluated. Patients with dBP >=90 mm Hg had a significantly lower relative risk of death than those with dBP <90 mm Hg [adjusted HR (95% CI) = 0.55 (0.39, 0.77); P < 0.001]. The relative risk of progression was also lower in patients with dBP >=90 mm Hg [HR (95% CI) = 0.76 (0.54, 1.06), P = 0.107], and ORR was significantly higher (43.9% vs. 12.0%; P < 0.001). In an 8-week landmark analysis, mOS (25.8 vs. 14.9 months) and mPFS (10.2 vs. 7.1 months) were greater for patients in the >=90 mm Hg group. Adverse events were similar between groups. CONCLUSIONS: Axitinib efficacy correlated with dBP >=90 mm Hg. Further investigation of dBP as a predictive biomarker of efficacy in patients receiving axitinib is warranted. PMID- 21531813 TI - Absence of MMP2 expression correlates with poor clinical outcomes in rectal cancer, and is distinct from MMP1-related outcomes in colon cancer. AB - PURPOSE: Treatments for colorectal cancer (CRC) are primarily disease stage based. However, heterogeneity in outcome within even a single stage highlights its limitations in predicting disease behavior. Recently, the role of gene expression as predictive and prognostic markers has been explored. Our objectives were to identify consistently differentially expressed genes through meta analysis of high-throughput gene-expression studies, and evaluate their predictive and prognostic significance in colon (CC) and rectal (RC) cancers. EXPERIMENTAL DESIGN: Publications applying high-throughput gene- expression technologies to specific CRC stages were identified. A vote counting strategy was used to identify the most significant differentially expressed genes. Their predictive and prognostic values were independently assessed in a tissue microarray of 191 cases of stage II-IV CC/RC from two tertiary care centers. Their biological effects were also examined in vitro. RESULTS: MMP1 and MMP2 were identified as consistently underexpressed in liver metastasis compared with primary CRC. Shorter time to distant metastasis and overall survival occurred in stage III CC lacking MMP1 expression, and in stage III RC lacking MMP2. MMP1 levels in stage II and III CC were associated with increased likelihood of distant metastasis, whereas the risk of local recurrence in stage III RC could be stratified by MMP2. Promotion of cell invasion of CRC cell lines exposed to MMP1/2 inhibitors were confirmed in vitro. CONCLUSIONS: MMP1 and MMP2 may be useful biomarkers that can help stratify patients at higher risk of developing recurrence in colorectal cancer, and guide individualized treatment decisions to achieve better outcomes. PMID- 21531814 TI - Antitumor and antiangiogenic activities of BMS-690514, an inhibitor of human EGF and VEGF receptor kinase families. AB - PURPOSE: The extensive involvement of the HER kinases in epithelial cancer suggests that kinase inhibitors targeting this receptor family have the potential for broad spectrum antitumor activity. BMS-690514 potently inhibits all three HER kinases, and the VEGF receptor kinases. This report summarizes data from biochemical and cellular pharmacology studies, as well as antitumor activity of BMS-690514. EXPERIMENTAL DESIGN: The potency and selectivity of BMS-690514 was evaluated by using an extensive array of enzymatic and binding assays, as well as cellular assays that measure proliferation and receptor signaling. Antitumor activity was evaluated by using multiple xenograft models that depend on HER kinase signaling. The antiangiogenic properties of BMS-690514 were assessed in a matrigel plug assay, and effect on tumor blood flow was measured by dynamic contrast-enhanced MRI. RESULTS: BMS-690514 is a potent and selective inhibitor of epidermal growth factor receptor (EGFR), HER2, and HER4, as well as the VEGF receptor kinases. It inhibits proliferation of tumor cells with potency that correlates with inhibition of receptor signaling, and induces apoptosis in lung tumor cells that have an activating mutation in EGFR. Antitumor activity was observed with BMS-690514 at multiple doses that are well tolerated in mice. There was evidence of suppression of tumor angiogenesis and endothelial function by BMS 690514, which may contribute to its efficacy. CONCLUSIONS: By combining inhibition of two receptor kinase families, BMS-690524 is a novel targeted agent that disrupts signaling in the tumor and its vasculature. PMID- 21531815 TI - Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary. AB - PURPOSE: Accurate identification of tissue of origin (ToO) for patients with carcinoma of unknown primary (CUP) may help customize therapy to the putative primary and thereby improve the clinical outcome. We prospectively studied the performance of a microRNA-based assay to identify the ToO in CUP patients. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded (FFPE) metastatic tissue from 104 patients was reviewed and 87 of these contained sufficient tumor for testing. The assay quantitates 48 microRNAs and assigns one of 25 tumor diagnoses by using a biologically motivated binary decision tree and a K-nearest neighbors (KNN). The assay predictions were compared with clinicopathologic features and, where suitable, to therapeutic response. RESULTS: Seventy-four of the 87 cases were processed successfully. The assay result was consistent or compatible with the clinicopathologic features in 84% of cases processed successfully (71% of all samples attempted). In 65 patients, pathology and immunohistochemistry (IHC) suggested a diagnosis or (more often) a differential diagnosis. Out of those, the assay was consistent or compatible with the clinicopathologic presentation in 55 (85%) cases. Of the 9 patients with noncontributory IHC, the assay provided a ToO prediction that was compatible with the clinical presentation in 7 cases. CONCLUSIONS: In this prospective study, the microRNA diagnosis was compatible with the clinicopathologic picture in the majority of cases. Comparative effectiveness research trials evaluating the added benefit of molecular profiling in appropriate CUP subsets are warranted. MicroRNA profiling may be particularly helpful in patients in whom the IHC profile of the metastasis is nondiagnostic or leaves a large differential diagnosis. PMID- 21531816 TI - The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma. AB - PURPOSE: To determine if the addition of bevacizumab to radiation therapy and temozolomide, followed by bevacizumab, temozolomide, and irinotecan, for newly diagnosed glioblastoma patients is safe and effective. EXPERIMENTAL DESIGN: A total of 75 patients with newly diagnosed glioblastoma were enrolled in the phase II trial that investigated the addition of bevacizumab to standard radiation therapy and daily temozolomide followed by the addition of bevacizumab and irinotecan to adjuvant temozolomide. The bevacizumab was given at 10 mg/kg every 14 days beginning a minimum of 4 weeks postcraniotomy. Two weeks after radiation therapy, the patients began 6 to 12 cycles of 5-day temozolomide with bevacizumab and irinotecan every 14 days. The primary endpoint was the proportion of patients alive 16 months after informed consent. RESULTS: The therapy had moderate toxicity. Three patients, one of whom had a grade 2 central nervous system hemorrhage, came off study during radiation therapy. Seventy patients started the postradiation therapy, and 16 (23%) terminated this adjuvant therapy early because of toxicity. The median overall survival was 21.2 months (95% CI: 17.2 25.4), and 65% of the patients were alive at 16 months (95% CI: 53.4-74.9). The median progression-free survival was 14.2 months (95% CI: 12-16). CONCLUSION: The addition of bevacizumab to standard radiation therapy and temozolomide, followed by bevacizumab, irinotecan, and temozolomide, for the treatment of newly diagnosed glioblastoma has moderate toxicity and may improve efficacy compared with historical controls. The results from phase III trials are required before the role of bevacizumab for newly diagnosed glioblastoma is established. PMID- 21531817 TI - KLF4-mediated negative regulation of IFITM3 expression plays a critical role in colon cancer pathogenesis. AB - PURPOSE: IFITM3, an IFN-inducible gene, is overexpressed in human colorectal cancer. In this study, we sought to determine the clinical significance and underlying mechanisms of its dysregulated expression in human colon tumor specimens and murine models of this disease. EXPERIMENTAL DESIGN: IFITM3 expression in a tissue microarray of tumor and matched normal colon tissue specimens and lymph node metastasis specimens obtained from 203 patients with colon cancer was measured immunohistochemically. RESULTS: IFITM3 was expressed at higher levels in colon tumors and, particularly, nodal metastases than in normal colon tissue. A Cox proportional hazards model showed that IFITM3 expression was an independent prognostic factor for disease-free survival in patients with colon cancer. Knockdown of IFITM3 expression by a specific siRNA significantly suppressed the proliferation, colony formation, migration, and invasion of colon cancer cells in vitro and tumor growth and metastasis in a xenograft model. Restored expression of KLF4, a putative tumor suppressor, downregulated IFITM3 expression in colon cancer cells in vitro. Two KLF4-binding sites in the IFITM3 promoter bound specifically to KLF4 protein in a chromatin immunoprecipitation assay and promoter mutagenesis analyses. Specific deletion of KLF4 led to IFITM3 overexpression in colon mucosa in Villin-Cre(+);Klf4(fl/fl) mice. An inverse correlation between loss of KLF4 expression and IFITM3 overexpression was evident in human colon tumors. CONCLUSION: These clinical and mechanistic findings indicate that IFITM3 is a direct transcriptional target of KLF4 and that dysregulated KLF4 expression leads to aberrant IFITM3 expression, thus contributing to colon cancer progression and metastasis. PMID- 21531819 TI - Detection of tumor DNA at the margins of colorectal cancer liver metastasis. AB - PURPOSE: Defining an adequate resection margin of colorectal cancer liver metastases is essential for optimizing surgical technique. We have attempted to evaluate the resection margin through a combination of histopathologic and genetic analyses. EXPERIMENTAL DESIGN: We evaluated 88 samples of tumor margins from 12 patients with metastatic colon cancer who each underwent partial hepatectomy of one to six liver metastases. Punch biopsies of surrounding liver tissue were obtained at 4, 8, 12, and 16 mm from the tumor border. DNA from these biopsies was analyzed by a sensitive PCR-based technique, called BEAMing, for mutations of KRAS, PIK3CA, APC, or TP53 identified in the corresponding tumor. RESULTS: Mutations were identified in each patient's resected tumor and used to analyze the 88 samples circumscribing the tumor-normal border. Tumor-specific mutant DNA was detectable in surrounding liver tissue in 5 of these 88 samples, all within 4 mm of the tumor border. Biopsies that were 8, 12, and 16 mm from the macroscopic visible margin were devoid of detectable mutant tumor DNA and of microscopically visible cancer cells. Tumors with a significant radiologic response to chemotherapy were not associated with any increase in mutant tumor DNA in beyond 4 mm of the main tumor. CONCLUSIONS: Mutant tumor-specific DNA can be detected beyond the visible tumor margin, but never beyond 4 mm, even in patients whose tumors were larger prior to chemotherapy. These data provide a rational basis for determining the extent of surgical excision required in patients undergoing resection of liver metastases. PMID- 21531820 TI - Baseline circulating tumor cell counts significantly enhance a prognostic score for patients participating in phase I oncology trials. AB - BACKGROUND: High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials. METHODS: This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System. RESULTS: Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (P = 0.006). A multivariate point based risk model was generated using CTCs as a dichotomous variable (>=3 or <3), and incorporated other established prognostic factors, including albumin <35 g/L, lactate dehydrogenase greater than upper limit of normal, and >2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (P < 0.0001): good prognosis [score 0-1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2-3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks). CONCLUSION: CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials. PMID- 21531821 TI - Changes in tumor density in patients with advanced hepatocellular carcinoma treated with sunitinib. AB - PURPOSE: Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the efficacy of targeted therapies. In hepatocellular carcinoma (HCC) studies with sunitinib, RECIST-defined response rates are low, although hypodensity on computed tomography (CT) scans occurs more frequently. This exploratory analysis investigated tumor density as a surrogate endpoint of sunitinib activity in a phase II HCC study. EXPERIMENTAL DESIGN: Patients received sunitinib 50 mg/d (4 weeks on/2 weeks off). Tumor size and density were assessed on CT scans by using RECIST and Choi criteria, the latter of which classify a partial response as a 15% or more reduction in tumor density or a 10% or more reduction in tumor size. The overall percentage volume of tumor necrosis was calculated with volumetric reconstruction. Tumor perfusion parameters were assessed by using perfusion CT scans with specific acquisition. RESULTS: Among the 26 evaluable patients, 1 achieved a partial response and 22 had tumor stabilization by RECIST. In analysis of tumor density, 17 of 26 patients (65.4%) were responders by Choi criteria. Volumetric assessment showed major tumor necrosis (>=30% of tumor volume) in 10 of 21 patients (47.6%). Among four patients evaluated, tumor blood flow was reduced by 58.8% and blood volume by 68.4% after 4 weeks of treatment. The median time to progression (TTP) was 6.4 months. Patients with responses by Choi criteria had a significantly longer TTP (7.5 months) compared with nonresponders (4.8 months; HR = 0.33, two-sided P = 0.0182). CONCLUSIONS: Tumor density assessment suggested that radiologic endpoints in addition to RECIST may be considered to capture sunitinib activity in HCC. PMID- 21531818 TI - Dopamine blocks stress-mediated ovarian carcinoma growth. AB - PURPOSE: Increased adrenergic activity in response to chronic stress is known to promote tumor growth by stimulating the tumor microenvironment. The focus of the current study was to determine whether dopamine, an inhibitory catecholamine, could block the effects of chronic stress on tumor growth. EXPERIMENTAL DESIGN: Expression of dopamine receptors (DR1-DR5) was analyzed by reverse transcriptase PCR and by Western blotting. In vitro effects of dopamine on cell viability, apoptosis, and migration were examined. For in vivo therapy, murine and human DR2 siRNAs were incorporated into chitosan nanoparticles (CH-NP). RESULTS: In this model of chronic stress, tumoral norepinephrine levels remained elevated whereas dopamine levels were significantly decreased compared with nonstressed animals. Daily restraint stress resulted in significantly increased tumor growth in both immunodeficient (SKOV3ip1 and HeyA8) and immunocompetent (ID8) ovarian cancer models. This increase was completely blocked with daily dopamine treatment. Dopamine treatment also blocked the stress-induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack of DR3 expression in ovarian cancer cells. DR2 was responsible for the inhibitory effects of dopamine on tumor growth and microvessel density as well as the stimulatory effect on apoptosis, as the DR2 antagonist eticlopride reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cyclic AMP levels and inhibited norepinephrine and vascular permeability factor/VEGF-induced Src kinase activation. CONCLUSIONS: Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement. PMID- 21531822 TI - Molecular chemotherapy and chemotherapy: a new front against late-stage hormone refractory prostate cancer. AB - PURPOSE: Stemming from its inherent heterogeneity, single-agent treatments are essentially ineffective against castration-resistant prostate cancer (CRPC). Thus, clinically relevant regimens that harness different modalities to maximize treatment efficacy without increasing cumulative toxicities are urgently needed. Based on this rationale, we investigated whether a novel combination of purine nucleoside phosphorylase-mediated, gene-directed enzyme-prodrug therapy (PNP GDEPT) with docetaxel against CRPC has superior efficacy in comparison with individual treatments. METHODS: The in vitro cell growth inhibition in differentially treated murine and human CRPC cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The local and systemic effects of docetaxel and/or PNP-GDEPT were tested in both immunodeficient and immunocompetent mice against human and murine CRPC tumors, respectively. Subsequently, immunohistochemical analyses and an evaluation of serum cytokine and serum toxicity profiles were conducted to characterize the differential host responses to treatment. RESULTS: The combined use of PNP-GDEPT and docetaxel led to strong synergistic cell killing in vitro. Compared with the individual modalities, a combination of the 2 led to a marked reduction in "local and distant" tumor growth in vivo, and importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune cell infiltration and altered serum cytokine levels. Furthermore, a lowering of T helper type 2 cytokines, MCP-1, interleukin (IL)-4, IL-6, and IL-10 marked lower tumor burden and enhanced treatment efficacy. CONCLUSION: PNP-GDEPT and docetaxel are a potent combination against CRPC in immunocompetent and immunodeficient settings; these outcomes have implications of translational potential for improved treatment and management of CRPC patients. PMID- 21531823 TI - The histone-like protein Hlp is essential for growth of Streptococcus pyogenes: comparison of genetic approaches to study essential genes. AB - Selection of possible targets for vaccine and drug development requires an understanding of the physiology of bacterial pathogens, for which the ability to manipulate expression of essential genes is critical. For Streptococcus pyogenes (the group A streptococcus [GAS]), an important human pathogen, the lack of genetic tools for such studies has seriously hampered research. To address this problem, we characterized variants of the inducible Ptet cassette, in both sense and antisense contexts, as tools to regulate transcription from GAS genes. We found that although the three-operator Ptet construct [Ptet(O)3] had low uninduced expression, its induction level was low, while the two-operator construct [Ptet(O)2] was inducible to a high level but showed significant constitutive expression. Use of Ptet(O)3 in the chromosome allowed us to demonstrate previously that RNases J1 and J2 are required for growth of GAS. Here we report that the uninduced level from the chromosomally inserted Ptet(O)2 construct was too high for us to observe differential growth. For the highly expressed histone-like protein (Hlp) of GAS, neither chromosomal insertion of Ptet(O)2 or Ptet(O)3 nor their use on a high-copy-number plasmid to produce antisense RNA specific to hlp resulted in adequate differential expression. However, by replacing the ribosome binding site of hlp with an engineered riboswitch to control translation of Hlp, we demonstrated for the first time that this protein is essential for GAS growth. PMID- 21531824 TI - Coevolutionary analysis enabled rational deregulation of allosteric enzyme inhibition in Corynebacterium glutamicum for lysine production. AB - Product feedback inhibition of allosteric enzymes is an essential issue for the development of highly efficient microbial strains for bioproduction. Here we used aspartokinase from Corynebacterium glutamicum (CgAK), a key enzyme controlling the biosynthesis of industrially important aspartate family amino acids, as a model to demonstrate a fast and efficient approach to the deregulation of allostery. In the last 50 years many researchers and companies have made considerable efforts to deregulate this enzyme from allosteric inhibition by lysine and threonine. However, only a limited number of positive mutants have been identified so far, almost exclusively by random mutation and selection. In this study, we used statistical coupling analysis of protein sequences, a method based on coevolutionary analysis, to systematically clarify the interaction network within the regulatory domain of CgAK that is essential for allosteric inhibition. A cluster of interconnected residues linking different inhibitors' binding sites as well as other regions of the protein have been identified, including most of the previously reported positions of successful mutations. Beyond these mutation positions, we have created another 14 mutants that can partially or completely desensitize CgAK from allosteric inhibition, as shown by enzyme activity assays. The introduction of only one of the inhibition insensitive CgAK mutations (here Q298G) into a wild-type C. glutamicum strain by homologous recombination resulted in an accumulation of 58 g/liter L-lysine within 30 h of fed-batch fermentation in a bioreactor. PMID- 21531825 TI - Identification of mycoparasitism-related genes in Trichoderma atroviride. AB - A high-throughput sequencing approach was utilized to carry out a comparative transcriptome analysis of Trichoderma atroviride IMI206040 during mycoparasitic interactions with the plant-pathogenic fungus Rhizoctonia solani. In this study, transcript fragments of 7,797 Trichoderma genes were sequenced, 175 of which were host responsive. According to the functional annotation of these genes by KOG (eukaryotic orthologous groups), the most abundant group during direct contact was "metabolism." Quantitative reverse transcription (RT)-PCR confirmed the differential transcription of 13 genes (including swo1, encoding an expansin-like protein; axe1, coding for an acetyl xylan esterase; and homologs of genes encoding the aspartyl protease papA and a trypsin-like protease, pra1) in the presence of R. solani. An additional relative gene expression analysis of these genes, conducted at different stages of mycoparasitism against Botrytis cinerea and Phytophthora capsici, revealed a synergistic transcription of various genes involved in cell wall degradation. The similarities in expression patterns and the occurrence of regulatory binding sites in the corresponding promoter regions suggest a possible analog regulation of these genes during the mycoparasitism of T. atroviride. Furthermore, a chitin- and distance-dependent induction of pra1 was demonstrated. PMID- 21531826 TI - Bacterial subfamily of LuxR regulators that respond to plant compounds. AB - Pseudomonas fluorescens are rhizobacteria known for their biocontrol properties. Several antimicrobial functions are crucial for this process, and the experiments described here investigate the modulation of their expression during the plant bacterium interaction. The role of a LuxR family regulator in interkingdom signaling has been investigated using genome-scale transcriptome analysis, gene promoter studies in vivo and in vitro, biocontrol assays, and response to plant compounds. PsoR, a LuxR solo or orphan regulator of P. fluorescens, was identified. PsoR is solubilized and activates a lux-box-containing promoter only in the presence of macerated plants, suggesting the presence of a plant molecule(s) that most likely binds to PsoR. Gene expression profiles revealed that genes involved in the inhibition of plant pathogens were affected by PsoR, including a chitinase gene, iron metabolism genes, and biosynthetic genes of antifungal compounds. 2,4-Diacetylphloroglucinol production is PsoR dependent both in vitro and in vivo. psoR mutants were significantly reduced for their ability to protect wheat plants from root rot, and damping-off caused by Pythium ultimum infection. PsoR most likely senses a molecule(s) in the plant and modulates expression of genes that have a role in biocontrol. PsoR and related proteins form a subfamily of LuxR family regulators in plant-associated bacteria. PMID- 21531827 TI - Modular synthase-encoding gene involved in alpha-olefin biosynthesis in Synechococcus sp. strain PCC 7002. AB - A gene involved in the production of medium-chain alpha-olefins was identified in the cyanobacterium Synechococcus sp. strain PCC 7002. The gene encodes a large multidomain protein with homology to type I polyketide synthases, suggesting a route for hydrocarbon biosynthesis from fatty acids via an elongation decarboxylation mechanism. PMID- 21531829 TI - Molecular characterization of Cronobacter lipopolysaccharide O-antigen gene clusters and development of serotype-specific PCR assays. AB - Cronobacter (formerly Enterobacter sakazakii) is a recently defined genus consisting of six species, C. sakazakii, C. malonaticus, C. dublinensis, C. muytjensii, C. turicensis, and Cronobacter genomospecies 1. In this study, MboII restriction fragment length polymorphism (RFLP) patterns of O-antigen gene clusters, located between galF and gnd, were used to identify serotypes in Cronobacter spp. Seven O-antigen RFLP clusters were generated, including three C. sakazakii clusters, previously identified as serotypes O1, O2, and O3. The O antigen regions of six strains with unique RFLP patterns, including two C. sakazakii strains, two C. malonaticus strains, one C. turicensis strain, and one C. muytjensii strain, revealed three O-antigen gene clusters shared among Cronobacter species. PCR assays were developed, targeting the wzx O-antigen polymerase gene, and used to screen 231 Cronobacter strains to determine the frequency of these newly identified serotypes. PMID- 21531828 TI - Inducible L-alanine exporter encoded by the novel gene ygaW (alaE) in Escherichia coli. AB - We previously isolated a mutant hypersensitive to L-alanyl-L-alanine from a non-L alanine-metabolizing Escherichia coli strain and found that it lacked an inducible l-alanine export system. Consequently, this mutant showed a significant accumulation of intracellular L-alanine and a reduction in the L-alanine export rate compared to the parent strain. When the mutant was used as a host to clone a gene(s) that complements the dipeptide-hypersensitive phenotype, two uncharacterized genes, ygaW and ytfF, and two characterized genes, yddG and yeaS, were identified. Overexpression of each gene in the mutant resulted in a decrease in the intracellular l-alanine level and enhancement of the L-alanine export rate in the presence of the dipeptide, suggesting that their products function as exporters of L-alanine. Since ygaW exhibited the most striking impact on both the intra- and the extracellular L-alanine levels among the four genes identified, we disrupted the ygaW gene in the non-L-alanine-metabolizing strain. The resulting isogenic mutant showed the same intra- and extracellular L-alanine levels as observed in the dipeptide-hypersensitive mutant obtained by chemical mutagenesis. When each gene was overexpressed in the wild-type strain, which does not intrinsically excrete alanine, only the ygaW gene conferred on the cells the ability to excrete alanine. In addition, expression of the ygaW gene was induced in the presence of the dipeptide. On the basis of these results, we concluded that YgaW is likely to be the physiologically most relevant exporter for L alanine in E. coli and proposed that the gene be redesignated alaE for alanine export. PMID- 21531830 TI - BTI1, an azoreductase with pH-dependent substrate specificity. AB - The group II azoreductase BTI1 utilizes NADPH to directly cleave azo bonds in water-soluble azo dyes, including quenchers of fluorescence. Unexpectedly, optimal reduction was dye specific, ranging from a pH of <5.5 for Janus green B, to pH 6.0 for methyl red, methyl orange, and BHQ-10, to pH >8.3 for flame orange. PMID- 21531831 TI - Bacterial diversity across individual lichens. AB - Symbioses are unique habitats for bacteria. We surveyed the spatial diversity of bacterial communities across multiple individuals of closely related lichens using terminal restriction fragment length polymorphism (T-RFLP) and pyrosequencing. Centers of lichens house richer, more consistent assemblages than species-poor and compositionally disparate lichen edges, suggesting that ecological succession plays a role in structuring these communities. PMID- 21531834 TI - Simple enrichment system for hydrogen producers. AB - This study presents a simple enrichment system where gas pressure produced by microbes performs functions that are normally done by labor. The system was tested with Escherichia coli strains with different hydrogen production and growth capabilities. The results show that the system can enrich the best hydrogen producer. PMID- 21531833 TI - Increased fitness and alteration of metabolic pathways during Bacillus subtilis evolution in the laboratory. AB - Five batch cultures of Bacillus subtilis were subjected to evolution in the laboratory for 6,000 generations under conditions repressing sporulation in complex liquid medium containing glucose. Between generations 1,000 and 2,000, variants with a distinct small-colony morphology arose and swept through four of the five populations that had been previously noted for their loss of sporulation (H. Maughan et al., Genetics 177:937-948, 2007). To better understand the nature of adaptation in these variants, individual strains were isolated from one population before (WN715) and after (WN716) the sweep. In addition to colony morphology, strains WN715 and WN716 differed in their motility, aerotaxis, and cell morphology. Competition experiments showed that strain WN716 had evolved a distinct fitness advantage over the ancestral strain and strain WN715 during growth and the transition to the postexponential growth phase, which was more pronounced when WN715 was present in the coculture. Microarray analyses revealed candidate genes in which mutations may have produced some of the observed phenotypes. For example, loss of motility in WN716 was accompanied by decreased transcription of all flagellar, motility, and chemotaxis genes on the microarray. Transcription of alsS and alsD was also lower in strain WN716, and the predicted loss of acetoin production and enhanced acetate production was confirmed by high performance liquid chromatography (HPLC) analysis. The results suggested that the derived colony morphology of strain WN716 was associated with increased fitness, the alteration of several metabolic pathways, and the loss of a typical postexponential-phase response. PMID- 21531832 TI - Squalene-hopene cyclases. AB - Hopanoids and sterols are members of a large group of cyclic triterpenoic compounds that have important functions in many prokaryotic and eukaryotic organisms. They are biochemically synthesized from linear precursors (squalene, 2,3-oxidosqualene) in only one enzymatic step that is catalyzed by squalene hopene cyclase (SHC) or oxidosqualene cyclase (OSC). SHCs and OSCs are related in amino acid sequences and probably are derived from a common ancestor. The SHC reaction requires the formation of five ring structures, 13 covalent bonds, and nine stereo centers and therefore is one of the most complex one-step enzymatic reactions. We summarize the knowledge of the properties of triterpene cyclases and details of the reaction mechanism of Alicyclobacillus acidocaldarius SHC. Properties of other SHCs are included. PMID- 21531835 TI - Associations between fungal species and water-damaged building materials. AB - Fungal growth in damp or water-damaged buildings worldwide is an increasing problem, which has adverse effects on both the occupants and the buildings. Air sampling alone in moldy buildings does not reveal the full diversity of fungal species growing on building materials. One aim of this study was to estimate the qualitative and quantitative diversity of fungi growing on damp or water-damaged building materials. Another was to determine if associations exist between the most commonly found fungal species and different types of materials. More than 5,300 surface samples were taken by means of V8 contact plates from materials with visible fungal growth. Fungal identifications and information on building material components were analyzed using multivariate statistic methods to determine associations between fungi and material components. The results confirmed that Penicillium chrysogenum and Aspergillus versicolor are the most common fungal species in water-damaged buildings. The results also showed Chaetomium spp., Acremonium spp., and Ulocladium spp. to be very common on damp building materials. Analyses show that associated mycobiotas exist on different building materials. Associations were found between (i) Acremonium spp., Penicillium chrysogenum, Stachybotrys spp., Ulocladium spp., and gypsum and wallpaper, (ii) Arthrinium phaeospermum, Aureobasidium pullulans, Cladosporium herbarum, Trichoderma spp., yeasts, and different types of wood and plywood, and (iii) Aspergillus fumigatus, Aspergillus melleus, Aspergillus niger, Aspergillus ochraceus, Chaetomium spp., Mucor racemosus, Mucor spinosus, and concrete and other floor-related materials. These results can be used to develop new and resistant building materials and relevant allergen extracts and to help focus research on relevant mycotoxins, microbial volatile organic compounds (MVOCs), and microparticles released into the indoor environment. PMID- 21531836 TI - Specific developmental window for establishment of an insect-microbe gut symbiosis. AB - The alydid stinkbug Riptortus pedestris is specifically associated with a beneficial Burkholderia symbiont in the midgut crypts. Exceptional among insect microbe mutualistic associations, the Burkholderia symbiont is not vertically transmitted but orally acquired by nymphal insects from the environment every generation. Here we experimentally investigated the process of symbiont acquisition during the nymphal development of R. pedestris. In a field population, many 2nd instar nymphs were Burkholderia free, while all 3rd, 4th, and 5th instar nymphs were infected. When reared on soil-grown potted soybean plants, Burkholderia acquisition occurred at a drastically higher frequency in the 2nd instar than in the other instars. Oral administration of cultured Burkholderia cells showed that 2nd and 3rd instar nymphs are significantly more susceptible to the symbiont infection than 1st, 4th, and 5th instar nymphs. Histological observations revealed rudimentary midgut crypts in the 1st instar, in contrast to well-developed midgut crypts in the 2nd and later instars. These results indicate that R. pedestris acquires the Burkholderia symbiont from the environment mainly during the 2nd instar period and strongly suggest that the competence for the symbiont infection is developmentally regulated by the host side. Potential mechanisms involved in infection competence and possible reasons why the infection preferentially occurs in the 2nd instar are discussed. PMID- 21531837 TI - Effects of bacterial microflora of the lower digestive tract of free-range waterfowl on influenza virus activation. AB - Proteolytic cleavage activation of influenza virus hemagglutinin (HA0) is required for cell entry via receptor-mediated endocytosis. Despite numerous studies describing bacterial protease-mediated influenza A viral activation in mammals, very little is known about the role of intestinal bacterial flora of birds in hemagglutinin cleavage/activation. Therefore, the cloaca of wild waterfowl was examined for (i) representative bacterial types and (ii) their ability to cleave in a "trypsin-like" manner the precursor viral hemagglutinin molecule (HA0). Using radiolabeled HA0, bacterial secretion-mediated trypsin-like conversion of HA0 to HA1 and HA2 peptide products was observed to various degrees in 42 of 44 bacterial isolates suggestive of influenza virus activation in the cloaca of wild waterfowl. However, treatment of uncleaved virus with all bacterial isolates gave rise to substantially reduced emergent virus progeny compared with what was expected. Examination of two isolates exhibiting pronounced trypsin-like conversion of HA0 to HA1 and HA2 peptide products and low infectivity revealed lipase activity to be present. Because influenza virus possesses a complex lipid envelope, the presence of lipid hydrolase activity could in part account for the observed less-than-expected level of viable progeny. A thorough characterization of respective isolate protease HA0 hydrolysis products as well as other resident activities (i.e., lipase) is ongoing such that the role of these respective contributors in virus activation/inactivation can be firmly established. PMID- 21531838 TI - Anti-Listeria activities of Galleria mellonella hemolymph proteins. AB - We report the use of antimicrobial hemolymph proteins from the model host Galleria mellonella as an inhibitor for various Listeria strains, providing a novel source for antilisterial therapeutics. We also have shown that specific virulence-associated genes known to mediate antimicrobial resistance of Listeria in mammalian models indicated a similar function in Galleria. PMID- 21531839 TI - Novel (2R,3R)-2,3-butanediol dehydrogenase from potential industrial strain Paenibacillus polymyxa ATCC 12321. AB - A (2R,3R)-2,3-butanediol dehydrogenase (BDH99::67) from Paenibacillus polymyxa ATCC 12321 was functionally characterized. The genetic characteristics of BDH99::67 are completely different from those of meso- and (2S,3S)-2,3-butanediol dehydrogenases. The results showed that BDH99::67 belongs to the medium-chain dehydrogenase/reductase superfamily and not to the short-chain dehydrogenase/reductase superfamily, to which meso- and (2S,3S)-2,3-butanediol dehydrogenases belong. PMID- 21531841 TI - Properties and construction of plasmid pFW213, a shuttle vector with the oral Streptococcus origin of replication. AB - Streptococcus parasanguinis is among the most successful colonizers of the human body. Strain FW213 harbors a 7.0-kb cryptic plasmid, pFW213, with a copy number at 5 to 10 per chromosome. Sequence and functional analyses of pFW213 revealed that the open reading frame (ORF) encoding the replication protein (Rep) is essential for the replication of pFW213, and the putative plasmid addiction system (RelB and RelE) and an ORF (ORF6) with no known function are required for its stability. The minimal replicon of pFW213 contains the rep gene and its 5' flanking 390-bp region. Within the minimal replicon, an A/T-rich region followed by 5 contiguous 22-bp repeats was located 5' of the ATG of rep. No single stranded replication intermediates were detected in the derivatives of pFW213, suggesting that pFW213 replicates via the theta replication mechanism. The minimal replicon was unstable in streptococcal hosts without selection, but the stability was greatly enhanced in derivatives containing the intact relBE genes. A Streptococcus-Escherichia coli shuttle vector, pCG1, was constructed with the pFW213 replicon. Plasmid pCG1 features a multiple cloning region and a spectinomycin resistance determinant that is expressed in both Streptococcus spp. and E. coli. Various streptococcal DNA fragments were cloned in pCG1, and the recombinant constructs were stably maintained in the streptococcal hosts. Since pCG1 is compatible with the most widely used streptococcal replicon, pVA380-1, pCG1 will provide a much needed tool allowing the cloning of two genes that work in concert in the same host. PMID- 21531840 TI - Molecular definition of vaginal microbiota in East African commercial sex workers. AB - Resistance to HIV infection in a cohort of commercial sex workers living in Nairobi, Kenya, is linked to mucosal and antiinflammatory factors that may be influenced by the vaginal microbiota. Since bacterial vaginosis (BV), a polymicrobial dysbiosis characterized by low levels of protective Lactobacillus organisms, is an established risk factor for HIV infection, we investigated whether vaginal microbiology was associated with HIV-exposed seronegative (HESN) or HIV-seropositive (HIV(+)) status in this cohort. A subset of 44 individuals was selected for deep-sequencing analysis based on the chaperonin 60 (cpn60) universal target (UT), including HESN individuals (n = 16), other HIV seronegative controls (HIV-N, n = 16), and HIV(+) individuals (n = 12). Our findings indicate exceptionally high phylogenetic resolution of the cpn60 UT using reads as short as 200 bp, with 54 species in 29 genera detected in this group. Contrary to our initial hypothesis, few differences between HESN and HIV-N women were observed. Several HIV(+) women had distinct profiles dominated by Escherichia coli. The deep-sequencing phylogenetic profile of the vaginal microbiota corresponds closely to BV(+) and BV(-) diagnoses by microscopy, elucidating BV at the molecular level. A cluster of samples with intermediate abundance of Lactobacillus and dominant Gardnerella was identified, defining a distinct BV phenotype that may represent a transitional stage between BV(+) and BV(-). Several alpha- and betaproteobacteria, including the recently described species Variovorax paradoxus, were found to correlate positively with increased Lactobacillus levels that define the BV(-) ("normal") phenotype. We conclude that cpn60 UT is ideally suited to next-generation sequencing technologies for further investigation of microbial community dynamics and mucosal immunity underlying HIV resistance in this cohort. PMID- 21531842 TI - Diversity of somatic coliphages in coastal regions with different levels of anthropogenic activity in Sao Paulo State, Brazil. AB - Bacteriophages are the most abundant and genetically diverse viruses on Earth, with complex ecology in both quantitative and qualitative terms. Somatic coliphages (SC) have been reported to be good indicators of fecal pollution in seawater. This study focused on determining the concentration of SC and their diversity by electron microscopy of seawater, plankton, and bivalve samples collected at three coastal regions in Sao Paulo, Brazil. The SC counts varied from <1 to 3.4 * 10(3) PFU/100 ml in seawater (73 samples tested), from <1 to 4.7 * 10(2) PFU/g in plankton (46 samples tested), and from <1 to 2.2 * 10(1) PFU/g in bivalves (11 samples tested). In seawater samples, a relationship between the thermotolerant coliforms and Escherichia coli and SC was observed at the three regions (P = 0.0001) according to the anthropogenic activities present at each region. However, SC were found in plankton samples from three regions: Baixada Santista (17/20), Canal de Sao Sebastiao (6/14), and Ubatuba (3/12). In seawater samples collected from Baixada Santista, four morphotypes were observed: A1 (4.5%), B1 (50%), C1 (36.4%), and D1 (9.1%). One coliphage, Siphoviridae type T1, had the longest tail: between 939 and 995 nm. In plankton samples, Siphoviridae (65.8%), Podoviridae (15.8%), Microviridae (15.8%), and Myoviridae (2.6%) were found. In bivalves, only the morphotype B1 was observed. These SC were associated with enteric hosts: enterobacteria, E. coli, Proteus, Salmonella, and Yersinia. Baixada Santista is an area containing a high level of fecal pollution compared to those in the Canal de Sao Sebastiao and Ubatuba. This is the first report of coliphage diversity in seawater, plankton, and bivalve samples collected from Sao Paulo coastal regions. A better characterization of SC diversity in coastal environments will help with the management and evaluation of the microbiological risks for recreation, seafood cultivation, and consumption. PMID- 21531843 TI - Cost-effective smoke-free multiunit housing media campaigns: connecting with local communities. AB - Presented are cost-effective paid media strategies to educate Californians to advocate for stronger smoke-free multiunit housing (SF-MUH) policies between 2006 and 2008. Included is a summary of general market and specific ethnic market costs that correspond to SF-MUH attitudes and home smoking bans. Statewide questionnaires indicated that half of the intended general market saw an antitobacco TV ad and half of the intended ethnic markets heard radio ads. Analyses indicated that it cost $0.67 and $0.78 per person to see Caution Tape and Apartment TV ads, respectively. Slightly higher per capita costs corresponded with positive attitudes toward SF-MUH: $0.87 for Caution Tape and $1.00 for Apartment. Lessons learned from this campaign included effectiveness of specific ads in ethnic markets, impact on SF-MUH work plan policy objectives, and the need for collaborations among state and local partners throughout the message development process. PMID- 21531845 TI - Farrowing induction induces transient alterations in prolactin concentrations and colostrum composition in primiparous sows. AB - Hormonal changes involved in the farrowing process partly control the initiation of lactation. Inducing farrowing by injection of PG may alter the normal prepartum hormonal cascade. The aim of the study was to investigate the consequences of farrowing induction on colostrum yield and composition, as well as newborn piglet growth. Gilts were treated with 2 mg of alfaprostol on d 113 of gestation (induced farrowing, IF, n = 9) or were injected with 1 mL of a saline solution (natural farrowing, NF, n = 11). Colostrum production was estimated during 24 h, starting at the onset of parturition, based on piglet BW gains. Colostrum samples were collected during the 36 h after the onset of parturition. Blood samples were collected from sows as of d 112 of pregnancy until d 2 postpartum (d 0 being the day of parturition). Piglet blood samples were obtained at birth, on d 1, and on d 21. Litter size and litter weight at birth did not differ between groups (P > 0.10). Farrowing induction did not influence (P > 0.10) colostrum yield (3.96 +/- 0.20 kg) or piglet BW gain during d 1 postpartum (116 +/- 8 g). At the onset of farrowing (T0), lactose content in colostrum was greater in IF sows than in NF sows (P < 0.05), whereas colostrum ash and protein contents were less (P < 0.05) in IF sows. Concentrations of IgG in colostrum were similar in both groups of sows, whereas concentrations of IgA at T0 were less in IF than in NF sows (P < 0.01). Overall, endocrine changes in blood from d -2 until d 2 (cortisol, prolactin, progesterone, and estradiol-17beta) were not altered by farrowing induction (P > 0.10), but 1 h after the injection of alfaprostol, IF sows had greater circulating concentrations of prolactin (P < 0.01) and cortisol (P < 0.10) than NF sows. The greater concentration of lactose in colostrum from IF sows could be attributed to this transient increase in prolactin and cortisol. At birth, concentrations of white blood cells were less in piglets born from IF sows (P < 0.01). On d 1 and 21, piglets from IF sows had similar IgG concentrations in plasma to piglets from NF sows (P > 0.1). In conclusion, farrowing induction at 113 d of pregnancy induced transient hormonal changes in sows and alterations in colostrum composition, without significantly affecting colostrum yield. It also modified some hematological variables of piglets at birth. PMID- 21531844 TI - Modeling the efficiency of phosphorus utilization in growing pigs. AB - Microbial phytase has been used to reduce P excretion from swine to mitigate environmental pollution. The objective of the study was to quantify the effect of feeding a low-P phytase-supplemented diet on growth and P utilization in growing pigs using mathematical models. A total of 20 weaned piglets (BW = 6.5 kg) housed in metabolism cages were randomly assigned to a standard diet (STD) or P-amended diet containing reduced P content and supplemented with phytase (AMN) with 10 pigs/diet. Body weight and feed consumption were recorded weekly so complete growth and cumulative P intake (cPI) curves could be modeled. A function with fixed point of inflexion (Gompertz) and a variable point of inflexion (generalized Michaelis-Menten) were considered in determining bioequivalence by analyzing BW vs. age relationships, whereas the monomolecular function was used to describe BW vs. cPI. All functions were incorporated into a nonlinear mixed effects model, and a first-order autoregressive correlation structure was implemented to take into account repeated measures. There was no difference between the 2 groups in final BW when the Gompertz equation was fitted (176 vs. 178 kg with SE of 7 kg for the STD and AMN, respectively) or the rate parameter (0.0140 vs. 0.0139 with SE of 0.0004 for the STD and AMN, respectively). The generalized Michaelis-Menten equation also showed a similar trend. When BW was expressed as a function of cPI the derivative with respect to cPI represented P efficiency, so it was possible to analyze the expected difference of the 2 diets in using P for BW gain and express it as a continuous function of cPI. The analysis showed through the entire growth period the difference in P efficiency was different from zero. On average, 56 g of supplemented inorganic P was consumed by a pig fed the AMN to reach market weight. In contrast, 309 g of supplemented inorganic P was consumed by the group fed the STD to reach similar BW. It would depend on other factors, but feeding pigs the AMN can result in economic benefit. Pigs fed the AMN excreted 19% less P compared with those fed the STD. In conclusion, nonlinear mixed model analysis (with repeated measures) was suitable for growth and efficiency analysis and showed that pigs fed the AMN consumed less than 20% of the inorganic P and performed as well as those fed the traditional inorganic P supplemented diet. The implications for mitigating P pollution, especially in areas where P loading is already problematic, are substantial. PMID- 21531846 TI - Adaptation of healthy adult cats to select dietary fibers in vivo affects gas and short-chain fatty acid production from fiber fermentation in vitro. AB - Nine young adult (1.73 +/- 0.03 yr) male cats were used to determine the effects of microbial adaptation to select dietary fiber sources on changes in pH in vitro and on total and hydrogen gas, short-chain fatty acid (SCFA), and branched-chain fatty acid (BCFA) production. Cats were adapted to diets containing 4% cellulose, fructooligosaccharides (FOS), or pectin for 30 d before fecal sampling. Each cat was used as a single donor, and fecal inoculum was reacted with each of the aforementioned fiber substrates. Adaptation to dietary FOS resulted in a greater change in pH when exposed to FOS than pectin (adaptation * substrate, P < 0.001). When exposed to the FOS substrate, adaptation to dietary FOS or pectin increased hydrogen gas production (adaptation * substrate, P = 0.021). Adaptation to dietary FOS increased acetate and total SCFA production when exposed to FOS substrate in vitro (adaptation * substrate, P = 0.001). When exposed to the FOS substrate, propionate production tended to increase with adaptation to dietary cellulose (adaptation * substrate, P = 0.060). The BCFA + valerate tended to decrease with adaptation to dietary FOS when exposed to FOS substrate in vitro (adaptation * substrate, P = 0.092). Fructooligosaccharides resulted in the greatest change in pH and production of total gas (P < 0.001), hydrogen gas (P < 0.001), acetate (P < 0.001), propionate (P < 0.001), butyrate (P < 0.001), total SCFA (P < 0.001), and total BCFA + valerate production (P < 0.001). Adaptation to the FOS or pectin diet increased production of hydrogen gas with FOS and pectin substrates. Adaptation to pectin increased (P = 0.033) total gas production with FOS and pectin substrates. Overall, adaptation to either FOS or pectin led to greater SCFA and gas production, but adaptation to FOS resulted in the greatest effect overall. PMID- 21531847 TI - Effects of pasture management and off-stream water on temporal/spatial distribution of cattle and stream bank characteristics in cool-season grass pastures. AB - A 2-yr grazing experiment was conducted to assess the effects of grazing management on cattle distribution and pasture and stream bank characteristics. Six 12.1-ha cool-season grass pastures in central Iowa were allotted to 1 of 3 treatments: continuous stocking with unrestricted stream access (CSU), continuous stocking with stream access restricted to 4.9-m-wide stabilized crossings (CSR), or rotational stocking with stream access restricted to a riparian paddock (RP). Pastures were stocked with 15 fall-calving Angus cows (Bos taurus L.) from mid May to mid-October for 153 d in 2008 and 2009. A global positioning system (GPS) collar recording cow position every 10 min was placed on at least 1 cow per pasture for 2 wk of each month from May through September. Off-stream water was provided to cattle in CSU and CSR treatments during the second of the 2 wk when GPS collars were on the cattle. A black globe temperature relative humidity index (BGTHI) was measured at 10-min intervals to match the time of the GPS measurements. Each month of the grazing season, forage characteristics (sward height, forage mass, and CP, IVDMD, and P concentrations) and bare and fecal covered ground were measured. Stream bank erosion susceptibility was visually scored in May, August, and October (pre-, mid-, and post-stocking). Cattle in RP and CSR treatments spent less time (P < 0.10) within the stream zone (0 to 3 m from stream center) in June and August and in the streamside zone (0 to 33 m from stream zone) in May through August and May through September, respectively, than cattle in CSU pastures. However, off-stream water had no effect on cattle distribution. Compared with the CSU treatment, the CSR treatment reduced the probability (P < 0.10) that cattle were within the riparian zone (0 to 36 m from stream center) at BGTHI of 50 to 100. Bare ground was greater (P < 0.10) in pastures with the CSU than CSR and RP treatments in the stream and streamside zones in September and October and in July and September. Streams in pastures with the CSU treatment had less stable banks (P < 0.10) mid- and post-stocking than RP or CSR treatments. Results show that time spent by cattle near pasture streams can be reduced by RP or CSR treatments, thereby decreasing risks of sediment and nutrient loading of pasture streams even during periods of increased BGTHI. PMID- 21531848 TI - Behavior of piglets after castration with or without carbon dioxide anesthesia. AB - Surgical castration of male piglets without anesthesia is a routine management practice conducted on commercial pig farms. For animal welfare reasons, it would be beneficial to develop methods of practical pain relief. The objective of this study was to evaluate the effect of providing CO2 anesthesia before castration on the behavior of piglets for up to 8 d after castration in comparison with piglets castrated without anesthesia. In 3 successive replicates, the behavior of 186 male piglets castrated with (n = 95) or without (n = 91) anesthesia was observed for up to 8 d after castration. All piglets in a given replicate were castrated on the same day, before 8 d of age. Behavioral observations were carried out in accordance with a continuous focal sampling procedure that began immediately after castration and continued for a period of 1 wk. Barrows anesthetized with CO2 before castration displayed more interactive behaviors during the overall observation period than the other barrows (P = 0.0412), which may indicate better welfare. Assessing all observation periods separately, differences in activity at the udder, lying, walking, and interactive behaviors appeared to support the beneficial effect of providing CO2 anesthesia before castration. However, these differences varied over time between treatment groups. The most important conclusion was that piglets castrated with or without CO2 anesthesia displayed behaviors indicative of pain and discomfort for up to 6 d after castration. Therefore, additional analgesia may be necessary to eliminate the long-term pain caused by castration even in piglets anesthetized with CO2 before castration. PMID- 21531849 TI - Effects of purified zearalenone on growth performance, organ size, serum metabolites, and oxidative stress in postweaning gilts. AB - Zearalenone (ZEA), an estrogenic mycotoxin, is produced mainly by Fusarium fungi. Previous studies indicated that acute ZEA exposure induced oxidative stress and damage in multiple organs. Therefore, the present study was designed to investigate the adverse effects of dietary ZEA (1.1 to 3.2 mg/kg of diet) on oxidative stress and organ damage in postweaning gilts. A total of 20 gilts (Landrace * Yorkshire * Duroc) weaned at d 21 with an average BW of 10.36 +/- 1.21 kg was used in the study. Gilts were housed in a temperature-controlled room, divided into 4 treatments, and fed a basal diet only (control) or basal diet supplemented with purified ZEA at a dietary concentration of 1 (ZEA1), 2 (ZEA2), or 3 (ZEA3) mg/kg of diet for 18 d ad libitum. The actual ZEA contents (analyzed) were 0, 1.1 +/- 0.02, 2.0 +/- 0.01, and 3.2 +/- 0.02 mg/kg for control, ZEA1, ZEA2, and ZEA3, respectively. Gilts fed different amounts of dietary ZEA grew similarly with no difference (P > 0.05) in feed intake. Vulva size increased linearly over the 18 d of feeding in gilts fed diets containing 1.1 mg of ZEA/kg or greater (P < 0.001). Relative weight of genital organs, liver, and kidney increased linearly (P < 0.05) in a ZEA-dose-dependent manner. Serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamate transferase, urea, and creatinine (P < 0.05), and malondialdehyde concentrations in both serum and liver (P < 0.001) were also increased linearly in a ZEA-dose-dependent manner. However, spleen relative weight (P = 0.002) and activities of total superoxide dismutase and glutathione peroxidase (in both serum and liver (P < 0.05) were decreased linearly as dietary ZEA increased. Results showed that besides genital organs, the liver, kidney, and spleen may also be target tissues in young gilts fed diets containing 1.1 to 3.2 mg of ZEA/kg for 18 d. Increased key liver enzymes in the serum suggest progressive liver damage caused by feeding ZEA, and an increase in oxidative stress in gilts is another potential impact of ZEA toxicity in pigs. PMID- 21531850 TI - Polwarth and Texel ewe parturition duration and its association with lamb birth asphyxia. AB - The objective of the present study was to test the hypothesis that parturition duration is related to birth asphyxia in lambs and that asphyxia affects newborn lamb viability and vigor. Two sire and dam genotypes (Texel: TX; Polwarth: PW) and their crosses were represented in the study. Eighty lambs (25 PW sire * PW dam, 13 TX * TX, 25 TX * PW, and 17 PW * TX) born to 69 grazing ewes were used. At birth, the log10 length of the second stage of parturition, birth weight, placental weight, and several body measurements were recorded on all lambs, and jugular blood samples were analyzed with the i-Stat Portable Clinical Analyzer (Abbott, Montevideo, Uruguay). A modified Apgar viability score at birth and lamb behavior during their first hour of life were recorded. Brain weight, muscle:bone ratio, and bone density were recorded in 20 male lambs (5 from each breed group) that were euthanized and dissected 24 h after birth. Data were analyzed by linear regression, least squares ANOVA, and ordinal and binary logistic regressions. Mean blood gas and acid-base variables were 7.21 +/- 0.09 for pH, 18.4 +/- 9.8 mmHg for partial pressure of oxygen, 53 +/- 12.5 mmHg for partial pressure of carbon dioxide, and -4 +/- 5.1 mmol/L for extracellular fluid base excess. Parturition duration increased with birth weight (P < 0.001) and was shorter in TX ewes (P < 0.001), female lambs (P < 0.05), twins (P < 0.09), and twin females (sex * litter size interaction, P < 0.02). Twenty-six (32.9%) lambs were born asphyxiated (pO2 < 10 mmHg or pH <7.1). Parturition duration increased the risk of asphyxia (P < 0.001), decreased the viability score (P < 0.001), and increased the latency to suckle the udder (P < 0.05). Twin-born lambs presented at birth a 16-fold greater risk of asphyxia (P < 0.01) and reduced placental efficiency (P < 0.05). Texel-sired lambs appeared immature at birth, with less bone density (P < 0.05), smaller brain (P < 0.05), shorter forelimbs (P < 0.05), greater anterior (P < 0.001) and posterior (P < 0.05) neck circumference, and greater muscle:bone ratio (P < 0.05). Immaturity may explain greater TX biotype survival. Together these results demonstrate that a relationship exists between parturition duration, neonatal viability and behavior, and acid-base balance values in single and twin-born lambs, suggesting that birth asphyxia is an important risk factor in perinatal lamb mortality. PMID- 21531851 TI - Growth curves of crossbred cows sired by Hereford, Angus, Belgian Blue, Brahman, Boran, and Tuli bulls, and the fraction of mature body weight and height at puberty. AB - The objective of this study was to evaluate the growth curves of females to determine if mature size and relative rates of maturation among breeds differed. Body weight and hip height data were fitted to the nonlinear function BW = f(age) = A - Be(k*age), where A is an estimate of mature BW and k determines the rate that BW or height moves from B to A. Cows represented progeny from 28 Hereford, 38 Angus, 25 Belgian Blue, 34 Brahman, 8 Boran, and 9 Tuli sires. Bulls from these breeds were mated by AI to Angus, Hereford, and MARC III composite (1/4 Angus, 1/4 Hereford, 1/4 Red Poll, and 1/4 Pinzgauer) cows to produce calves in 1992, 1993, and 1994. These matings resulted in 516 mature cows whose growth curves were subsequently evaluated. Hereford-sired cows tended to have heavier mature BW, as estimated by parameter A, than Angus- (P=0.09) and Brahman-sired cows (P=0.06), and were heavier than the other breeds (P < 0.001). Angus-sired cows were heavier than Boran- (P < 0.001) and Tuli-sired cows (P < 0.001), and tended to be heavier than Belgian Blue-sired cows (P=0.097). Angus-sired cows did not differ from Brahman-sired cows (P=0.94). Brahman-sired cows had a heavier mature BW than Boran- (P < 0.001), Tuli- (P < 0.001), and Belgian Blue-sired cows (P < 0.04). Angus-sired cows matured faster (k) than cows sired by Hereford (P=0.03), Brahman (P < 0.001), Boran (P=0.03), and Tuli (P < 0.001) sires, but did not differ from Belgian Blue-sired (P=0.13) cows. Brahman-sired cows took longer to mature than Boran- (P=0.03) or Belgian Blue-sired cows (P=0.003). Belgian Blue-sired cows were faster maturing than Tuli-sired cows (P=0.02). Brahman-sired cows had reached a greater proportion of their mature BW at puberty than had Hereford- (P < 0.001), Tuli- (P=0.003), and Belgian Blue-sired cows (P=0.001). Boran-sired cows tended to have reached a greater proportion of their mature BW at puberty than had Angus-sired cows (P=0.09), and had reached a greater proportion of their mature BW at puberty than had Hereford- (P < 0.001), Tuli- (P < 0.001), and Belgian Blue-sired cows (P < 0.001). Within species of cattle, the relative range in proportion of mature BW at puberty (Bos taurus 0.56 through 0.58, and Bos indicus 0.60) was highly conserved, suggesting that proportion of mature BW is a more robust predictor of age at puberty across breeds than is absolute weight or age. PMID- 21531852 TI - Administration of human chorionic gonadotropin to suckled beef cows before ovulation synchronization and fixed-time insemination: replacement of gonadotropin-releasing hormone with human chorionic gonadotropin. AB - Two experiments were conducted to evaluate whether hCG administered 7 d before initiating the CO-Synch + controlled internal drug release (CIDR) ovulation synchronization protocol (Exp. 1 and 2), or replacing GnRH with hCG at the time of AI (Exp. 1), would improve fertility to a fixed-time AI (TAI) in suckled beef cows. In addition, the effects of hCG on follicle dynamics, corpus luteum development, and concentrations of progesterone (P4) were evaluated. In Exp. 1, cows were stratified by days postpartum, age, and parity and assigned randomly to a 2 * 2 factorial arrangement of 4 treatments: 1) cows received 100 ug of GnRH at CIDR insertion (d -7) and 25 mg of PGF(2alpha) at CIDR removal (d 0), followed in 64 to 68 h by a TAI plus a second injection of GnRH at TAI (CG; n = 29); 2) same as CG but the second injection of GnRH at the time of insemination was replaced by hCG (CH; n = 28); 3) same as CG, but cows received hCG 7 d (d -14) before CIDR insertion (HG; n = 28); and 4) same as HG, but cows received hCG 7 d (d -14) before CIDR insertion (HH; n = 29). Pregnancy rates were 52, 41, 59, and 38% for GG, GH, HG, and HH, respectively. Cows receiving hCG (39%) in place of GnRH at TAI tended (P = 0.06) to have poorer pregnancy rates than those receiving GnRH (56%). Pre-CO-Synch hCG treatment increased (P < 0.05) the percentage of cows with concentrations of P4 >1 ng/mL at d -7, increased (P < 0.02) concentration of P4 on d -7, and decreased (P < 0.001) the size of the dominant follicle on d 0 and 3, compared with cows not treated with hCG on d -14. In Exp. 2, cows were stratified based on days postpartum, BCS, breed type, and calf sex and then assigned to the CG (n = 102) or HG (n = 103) treatments. Overall pregnancy rates were 51%, but no differences in pregnancy rates were detected between treatments. Pre-CO-Synch hCG treatment increased (P < 0.05) the percentage of cows cycling on d -7 and increased (P < 0.05) concentrations of P4 on d -7 compared with pre-CO Synch controls. Therefore, pretreatment induction of ovulation after hCG injection 7 d before initiation of CO-Synch + CIDR protocol failed to enhance pregnancy rates, but replacing GnRH with hCG at the time of AI may reduce pregnancy rates. PMID- 21531854 TI - Tribute to my friend and colleague, Dr. Marsha Heims. PMID- 21531855 TI - It starts with access! A grounded theory of family members working to get through critical illness. AB - The critical illness of an adult constitutes a crisis for the patient's family. They relinquish primary responsibility for the physical well-being of the patient to health providers, but remain involved, working to get through the situation. What constitutes this "work"? Results of two grounded theory studies revealed that family members were engaged first in the pivotal work of gaining access because of their overarching need to be present with and for their critically ill relative. Other work included patient-related work, nurse/physician-related work, and self-related work. These findings extend our understanding of their experiences beyond current knowledge and paternalistic perceptions of burden, stress and coping, and need recognition and fulfillment. Critical care nurses are exhorted to support family members in their work by removing barriers to patient, staff, and information access and to partnering opportunities. PMID- 21531856 TI - Individual and family adaptation in Taiwanese families living with down syndrome. AB - The primary aim of this study was to examine the effects of family demographics, family demands, and family appraisal on adaptation in Taiwanese families of children with Down syndrome. A second aim was to assess the potential mediating effect of family appraisal on the relationship between family demands and adaptation. Eighty-three families completed mailed questionnaires. Data were analyzed using a principal component analysis and a mixed linear modeling. Gender, family demands, and family appraisal were significantly associated with individual health. Age of the child with Down syndrome, family demands, and family appraisal significantly accounted for family functioning. Family appraisal partially mediated the relationship between family demands and individual and family adaptation. Identification of family factors that influence adaptation will help in the development of culturally sensitive interventions to improve outcomes in Taiwanese families of children with Down syndrome. PMID- 21531857 TI - Surrogate mothers: aboriginal grandmothers raising grandchildren in Taiwan. AB - The purpose of this qualitative study was to understand the experiences of Taiwanese aboriginal grandmothers when raising their grandchildren. Adopting a phenomenological approach, interviews were conducted with 15 Taiwanese aboriginal grandmothers who served as primary caregiver to a grandchild or grandchildren. Data were analyzed using Giorgi's phenomenological method. Four themes emerged from the data analysis, reflecting the parenting experience of grandmothers: using aged bodies to do energetic work: represented the physical effects of raising grandchildren; conflicting emotions: reflected the psychological effects of raising grandchildren; lifelong and privative obligation: described the cultural and societal beliefs of raising grandchildren; and coping strategies for raising grandchildren outlined methods the grandmothers used to cope with parenting their grandchildren. The results of this study offers insights into surrogate parenting within an underresearched group in Taiwan and will enable health care providers to be more aware of the physical, emotional, and social effects of the role of grandparent parenting. PMID- 21531858 TI - The nature and scope of stressful spousal caregiving relationships. AB - The caregiving literature provides compelling evidence that caregiving burden and depressive symptoms are linked with stressful care relationships, however, relational difficulties around caregiving are seldom described in the literature. This article presents findings from content analysis of baseline interviews with 40 Alzheimer's disease (AD) and Parkinson's disease (PD) spousal caregivers enrolled in a home care skill-training trial who identified their care relationship as a source of care burden. Disappointment and sadness about the loss of the relationship; tension within the relationship; and care decision conflicts within the relationship were recurrent themes of relational stress in caregiving. These spousal caregivers had relationship quality scores below the mean and burden and depressive symptom scores above the means of other caregivers in the study. These findings provide support for developing dyadic interventions that help spouses manage relational losses, care-related tensions, and care decision-making conflicts. PMID- 21531859 TI - Family members' experiences of everyday life when a child is dependent on a ventilator: a metasynthesis study. AB - Children using mechanical ventilation for survival represent a small, but growing, vulnerable population in society. The aim of this study was to describe the existing qualitative research that examined family members' experiences when a child is dependent on ventilator at home. A metasynthesis is an interpretative integration of qualitative research findings based on a systematic literature search. Twelve original research reports focusing on the life situation of ventilator- and technology-dependent children and their families published between 1998 and 2006 were selected as data. Themes from the metasynthesis included experiences of the ill child, siblings, and parents and the meaning of space and place. These findings provide an understanding of the family members' experiences when a child is dependent on a ventilator for survival. Recommendations for future research with this population of families include a greater focus on professional support systems and family strengths and the use of longitudinal research methods using observation and interviews. PMID- 21531860 TI - Project report: analysis of the contents of the journal of family nursing (1995 2007). PMID- 21531863 TI - Retraction: Extracorporeal shock wave therapy enhances early tendon-bone healing and reduces bone tunnel enlargement in hamstring autograft anterior cruciate ligament reconstruction. PMID- 21531862 TI - In plant and animal cells, detergent-resistant membranes do not define functional membrane rafts. PMID- 21531864 TI - Autologous chondrocyte implantation in the adolescent knee. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) has been shown to have favorable results in the treatment of symptomatic chondral and osteochondral lesions. However, there are few reports on the outcomes of this technique in adolescents. PURPOSE: The aim of this study was to assess pain relief and functional outcome in adolescents undergoing ACI. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Thirty-five adolescent patients undergoing ACI or matrix-assisted chondrocyte implantation (MACI) were identified from a larger cohort. Four patients were lost to follow-up, leaving 31 patients (24 ACI, 7 MACI). The mean age was 16.3 years (range, 14-18 years) with a mean follow-up of 66.3 months (range, 12-126 months). There were 22 male and 9 female patients. All patients were symptomatic; 30 had isolated lesions and 1 had multiple lesions. Patients were assessed preoperatively and postoperatively using the visual analog scale (VAS) score for pain, the Bentley Functional Rating Score, and the Modified Cincinnati Rating System. At 1 year postoperatively, patients were recalled for a diagnostic biopsy, which was successfully attained in 21 patients. RESULTS: The mean pain scores improved from 5 preoperatively to 1 postoperatively. The Bentley Functional Rating Score improved from 3 to 0, while the Modified Cincinnati Rating System improved from 48 preoperatively to 92 postoperatively with 84% of patients achieving excellent or good results. All postoperative scores exhibited significant improvement from preoperative scores. One patient underwent graft hypertrophy and 1 patient's graft failed and was revised. Biopsy results revealed hyaline cartilage in 24% of cases, mixed fibro/hyaline cartilage in 19%, and fibrocartilage in 57%. CONCLUSION: Results show that, in this particular group who received ACI, patients experienced a reduction in pain and significant improvement in postoperative function after ACI or MACI. The authors believe that ACI is appropriate in the management of carefully selected adolescents with symptomatic chondral and osteochondral defects. PMID- 21531865 TI - Exome sequencing identifies an MYH3 mutation in a family with distal arthrogryposis type 1. AB - BACKGROUND: Few genes responsible for distal arthrogryposis type 1 are known, although genes coding for the proteins in the sarcomere have been implicated in other types of distal arthrogryposis. Cost-effective sequencing methods are now available to examine all genes in the human genome for the purpose of establishing the genetic basis of musculoskeletal disorders. METHODS: A multigenerational family with distal arthrogryposis type 1 characterized by clubfoot and mild hand contractures was identified, and exome sequencing was performed on DNA from one of the affected family members. Linkage analysis was used to confirm whether a genetic variant segregated with distal arthrogryposis. RESULTS: Exome sequencing identified 573 novel variants that were not present in control databases. A missense mutation in MYH3 (a gene coding for the heavy chain of myosin), causing an F437I amino acid substitution, was identified that segregated with distal arthrogryposis in this family. Linkage analysis confirmed that this MYH3 mutation was the only exome variant common to all six affected individuals. CONCLUSIONS: Identification of an MYH3 mutation in this family with distal arthrogryposis type 1 broadens the phenotype associated with MYH3 mutations to include distal arthrogryposis types 1, 2A (Freeman-Sheldon syndrome), and 2B (Sheldon-Hall syndrome). Exome sequencing is a useful and cost effective method to discover causative genetic mutations, although data from extended families may be needed to confirm the importance of the hundreds of identified variants. PMID- 21531866 TI - Increase in outpatient knee arthroscopy in the United States: a comparison of National Surveys of Ambulatory Surgery, 1996 and 2006. AB - BACKGROUND: This study was proposed to investigate the changes in the utilization of knee arthroscopy in an ambulatory setting over the past decade in the United States as well as its implications. METHODS: The National Survey of Ambulatory Surgery, last carried out in 1996, was conducted again in 2006 by the Centers for Disease Control and Prevention. We analyzed the cases with procedure coding indicative of knee arthroscopy or anterior cruciate ligament reconstruction. To produce estimates for all arthroscopic procedures on the knee in an ambulatory setting in the United States for each year, we performed a design-based statistical analysis. RESULTS: The number of arthroscopic procedures on the knee increased 49% between 1996 and 2006. While the number of arthroscopic procedures for knee injury had dramatically increased, arthroscopic procedures for knee osteoarthritis had decreased. In 1996, knee arthroscopies performed in freestanding ambulatory surgery centers comprised only 15% of all orthopaedic procedures, but the proportion increased to 51% in 2006. There was a large increase in knee arthroscopy among middle-aged patients regardless of sex. In 2006, >99% of arthroscopic procedures on the knee were in an outpatient setting. Approximately 984,607 arthroscopic procedures on the knee (95% confidence interval, 895,999 to 1,073,215) were performed in an outpatient setting in 2006. Among those, 127,446 procedures (95% confidence interval, 95,124 to 159,768) were for anterior cruciate ligament reconstruction. Nearly 500,000 arthroscopic procedures were performed for medial or lateral meniscal tears. CONCLUSIONS: This study revealed that the knee arthroscopy rate in the United States was more than twofold higher than in England or Ontario, Canada, in 2006. Our study found that nearly half of the knee arthroscopic procedures were performed for meniscal tears. Meniscal damage, detected by magnetic resonance imaging, is commonly assumed to be the source of pain and symptoms. Further study is imperative to better define the symptoms, physical findings, and radiographic findings that are predictive of successful arthroscopic treatment. PMID- 21531868 TI - Treatment of trigger-point hypersensitivity of gag reflex following surgical treatment of obstructive sleep apnea. PMID- 21531869 TI - An unusual cause of bullous myringitis with acute otitis media. PMID- 21531870 TI - Initial impact of the acute otitis externa clinical practice guideline on clinical care. AB - Objectives. Determine the influence of the acute otitis externa clinical practice guideline on clinical care. Study Design. Cross-sectional study with historical controls. Setting. Outpatient departments in the United States. Methods. Cases of acute otitis externa occurring in 2004-2005 (before guideline publication) and 2007-2008 (after guideline publication) were extracted from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Care Survey. Prescribing rates for ototopical medications, analgesic recommendations, and oral antibiotics were determined and compared before and after guideline publication and relative to guideline recommendations. Results. An estimated 5.50 (standard error of the estimated mean, 0.38) million visits (mean age, 27.7 [1.7] years; 49.8% male) with a primary and singular coded diagnosis of acute otitis externa were studied (2.64 [0.26] million visits for 2004-2005 and 2.86 [0.28] million visits for 2007-2008). Prescribing rates for ototopical preparations were 67.2% (5.3%) and 67.6% (5.0%) before and after guideline publication, respectively (P = .955). Recommendation rates for analgesics were 14.2% (3.3%) and 20.6% (3.9%), respectively (P = .248). Prescription rates for oral antibiotics were 21.7% (4.8%) and 30.5% (3.6%), before and after, respectively (P = .166). Conclusion. Clinician behavior in the medical treatment of acute otitis externa has not significantly changed after guideline publication, despite clear, evidence-based guideline recommendations. These data have important implications for performance measures based on the guideline. Further efforts toward guideline dissemination are likely needed. PMID- 21531871 TI - Paxillin and phospholipase D interact to regulate actin-based processes in Dictyostelium discoideum. AB - The actin cytoskeleton forms a membrane-associated network whose proper regulation is essential for numerous processes, including cell differentiation, proliferation, adhesion, chemotaxis, endocytosis, exocytosis, and multicellular development. In this report, we show that in Dictyostelium discoideum, paxillin (PaxB) and phospholipase D (PldB) colocalize and coimmunoprecipitate, suggesting that they interact physically. Additionally, the phenotypes observed during development, cell sorting, and several actin-required processes, including cyclic AMP (cAMP) chemotaxis, cell-substrate adhesion, actin polymerization, phagocytosis, and exocytosis, reveal a genetic interaction between paxB and pldB, suggesting a functional interaction between their gene products. Taken together, our data point to PldB being a required binding partner of PaxB during processes involving actin reorganization. PMID- 21531872 TI - Characterization, localization, essentiality, and high-resolution crystal structure of glucosamine 6-phosphate N-acetyltransferase from Trypanosoma brucei. AB - A gene predicted to encode Trypanosoma brucei glucosamine 6-phosphate N acetyltransferase (TbGNA1; EC 2.3.1.4) was cloned and expressed in Escherichia coli. The recombinant protein was enzymatically active, and its high-resolution crystal structure was obtained at 1.86 A. Endogenous TbGNA1 protein was localized to the peroxisome-like microbody, the glycosome. A bloodstream-form T. brucei GNA1 conditional null mutant was constructed and shown to be unable to sustain growth in vitro under nonpermissive conditions, demonstrating that there are no metabolic or nutritional routes to UDP-GlcNAc other than via GlcNAc-6-phosphate. Analysis of the protein glycosylation phenotype of the TbGNA1 mutant under nonpermissive conditions revealed that poly-N-acetyllactosamine structures were greatly reduced in the parasite and that the glycosylation profile of the principal parasite surface coat component, the variant surface glycoprotein (VSG), was modified. The significance of results and the potential of TbGNA1 as a novel drug target for African sleeping sickness are discussed. PMID- 21531873 TI - Three mitochondrial DNA polymerases are essential for kinetoplast DNA replication and survival of bloodstream form Trypanosoma brucei. AB - Trypanosoma brucei, the causative agent of human African trypanosomiasis, has a complex life cycle that includes multiple life cycle stages and metabolic changes as the parasite switches between insect vector and mammalian host. The parasite's single mitochondrion contains a unique catenated mitochondrial DNA network called kinetoplast DNA (kDNA) that is composed of minicircles and maxicircles. Long standing uncertainty about the requirement of kDNA in bloodstream form (BF) T. brucei has recently eroded, with reports of posttranscriptional editing and subsequent translation of kDNA-encoded transcripts as essential processes for BF parasites. These studies suggest that kDNA and its faithful replication are indispensable for this life cycle stage. Here we demonstrate that three kDNA replication proteins (mitochondrial DNA polymerases IB, IC, and ID) are required for BF parasite viability. Silencing of each polymerase was lethal, resulting in kDNA loss, persistence of prereplication DNA monomers, and collapse of the mitochondrial membrane potential. These data demonstrate that kDNA replication is indeed crucial for BF T. brucei. The contributions of mitochondrial DNA polymerases IB, IC, and ID to BF parasite viability suggest that these and other kDNA replication proteins warrant further investigation as a new class of targets for the development of antitrypanosomal drugs. PMID- 21531874 TI - Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis. AB - Candida dubliniensis is an emerging pathogenic yeast species closely related to Candida albicans and frequently found colonizing or infecting the oral cavities of HIV/AIDS patients. Drug resistance during C. dubliniensis infection is common and constitutes a significant therapeutic challenge. The calcineurin inhibitor FK506 exhibits synergistic fungicidal activity with azoles or echinocandins in the fungal pathogens C. albicans, Cryptococcus neoformans, and Aspergillus fumigatus. In this study, we show that calcineurin is required for cell wall integrity and wild-type tolerance of C. dubliniensis to azoles and echinocandins; hence, these drugs are candidates for combination therapy with calcineurin inhibitors. In contrast to C. albicans, in which the roles of calcineurin and Crz1 in hyphal growth are unclear, here we show that calcineurin and Crz1 play a clearly demonstrable role in hyphal growth in response to nutrient limitation in C. dubliniensis. We further demonstrate that thigmotropism is controlled by Crz1, but not calcineurin, in C. dubliniensis. Similar to C. albicans, C. dubliniensis calcineurin enhances survival in serum. C. dubliniensis calcineurin and crz1/crz1 mutants exhibit attenuated virulence in a murine systemic infection model, likely attributable to defects in cell wall integrity, hyphal growth, and serum survival. Furthermore, we show that C. dubliniensis calcineurin mutants are unable to establish murine ocular infection or form biofilms in a rat denture model. That calcineurin is required for drug tolerance and virulence makes fungus specific calcineurin inhibitors attractive candidates for combination therapy with azoles or echinocandins against emerging C. dubliniensis infections. PMID- 21531875 TI - Type II Toxoplasma gondii KU80 knockout strains enable functional analysis of genes required for cyst development and latent infection. AB - Type II Toxoplasma gondii KU80 knockouts (Deltaku80) deficient in nonhomologous end joining were developed to delete the dominant pathway mediating random integration of targeting episomes. Gene targeting frequency in the type II Deltaku80 Deltahxgprt strain measured at the orotate (OPRT) and the uracil (UPRT) phosphoribosyltransferase loci was highly efficient. To assess the potential of the type II Deltaku80 Deltahxgprt strain to examine gene function affecting cyst biology and latent stages of infection, we targeted the deletion of four parasite antigen genes (GRA4, GRA6, ROP7, and tgd057) that encode characterized CD8(+) T cell epitopes that elicit corresponding antigen-specific CD8(+) T cell populations associated with control of infection. Cyst development in these type II mutant strains was not found to be strictly dependent on antigen-specific CD8(+) T cell host responses. In contrast, a significant biological role was revealed for the dense granule proteins GRA4 and GRA6 in cyst development since brain tissue cyst burdens were drastically reduced specifically in mutant strains with GRA4 and/or GRA6 deleted. Complementation of the Deltagra4 and Deltagra6 mutant strains using a functional allele of the deleted GRA coding region placed under the control of the endogenous UPRT locus was found to significantly restore brain cyst burdens. These results reveal that GRA proteins play a functional role in establishing cyst burdens and latent infection. Collectively, our results suggest that a type II Deltaku80 Deltahxgprt genetic background enables a higher throughput functional analysis of the parasite genome to reveal fundamental aspects of parasite biology controlling virulence, pathogenesis, and transmission. PMID- 21531876 TI - The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans. AB - In the mucosa, the immune pathways discriminating between colonizing and invasive Candida, thus inducing tolerance or inflammation, are poorly understood. Th17 responses induced by Candida albicans hyphae are central for the activation of mucosal antifungal immunity. An essential step for the discrimination between yeasts and hyphae and induction of Th17 responses is the activation of the inflammasome by C. albicans hyphae and the subsequent release of active IL-1beta in macrophages. Inflammasome activation in macrophages results from differences in cell-wall architecture between yeasts and hyphae and is partly mediated by the dectin-1/Syk pathway. These results define the dectin-1/inflammasome pathway as the mechanism that enables the host immune system to mount a protective Th17 response and distinguish between colonization and tissue invasion by C. albicans. PMID- 21531877 TI - 21-year-old man with chest pain, respiratory distress, and altered mental status. PMID- 21531879 TI - The electronic health record: is it meaningful yet? PMID- 21531880 TI - Prevalence of airway obstruction assessed by lung function questionnaire. AB - OBJECTIVE: To estimate the prevalence of unidentified chronic obstructive pulmonary disease (COPD) and determine the screening accuracy of the Lung Function Questionnaire (LFQ). PATIENTS AND METHODS: Cigarette smokers who had a smoking history of 10 or more pack-years and were aged 30 years or older were recruited from 36 centers from February 18, 2009, to May 29, 2009. A total of 1575 patients completed a Web-based survey including the 5-item LFQ. Spirometry was performed on patients with an LFQ total score of 18 or less and on a subset scoring more than 18. The primary outcome was the proportion of patients at risk of airflow obstruction as measured by the LFQ (score, <= 18) in whom an airflow obstruction was confirmed by spirometry. RESULTS: Of the patients who completed the LFQ, 849 (54%) had standardized spirometry data available. On the basis of LFQ and spirometry results, the estimated prevalence of possible COPD was 17.9% (95% confidence interval, 15.3%-20.6%). At a cut point of 18 or less, sensitivity, specificity, positive predictive value, and negative predictive value of the LFQ were 88%, 25%, 21%, and 90%, respectively. Approximately 1 in 5 patients (21%) aged 30 years or older and 1 in 4 (26%) aged 50 years or older scored 18 or less on the LFQ and had a ratio of forced expiratory volume in the first second of expiration to forced vital capacity less than 0.70. CONCLUSION: On the basis of postbronchodilator spirometry results using weighted estimates, approximately 1 in 5 patients (21%) aged 30 years or older with a smoking history of 10 or more pack-years seen in a primary care setting is likely to have COPD. The LFQ could be a helpful COPD case-finding tool for clinicians to identify patients who need further evaluation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01013948. PMID- 21531882 TI - Thrombocytopenia in Staphylococcus aureus bacteremia: risk factors and prognostic importance. AB - OBJECTIVE: To identify risk factors and outcomes associated with thrombocytopenia at sepsis onset in Staphylococcus aureus bacteremia. PATIENTS AND METHODS: This single-center, retrospective, cohort study consists of all adult patients with a first episode of clinical S aureus bacteremia between April 1, 1988, and September 30, 1994, and between January 1, 1999, and December 31, 2007. Thrombocytopenia was defined as a platelet count less than 150 * 10(9)/L. The primary outcome was 30-day all-cause mortality. Risk factors for 30-day all-cause mortality were identified using univariate and multivariable analyses. Multivariable analysis was conducted using forward step logistic regression analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for risk of death. RESULTS: A total of 1052 patients had clinical S aureus bacteremia. Thrombocytopenia at sepsis onset was present in 235 patients (22.3%). Thrombocytopenia was associated with community-acquired bacteremia, infections caused by methicillin-sensitive S aureus, high-magnitude bacteremia (defined as >4 positive blood cultures [>= 3 separate positive blood culture sets]), and endocarditis. Patients with thrombocytopenia presented more commonly with severe sepsis reflected by septic shock and acute renal failure. Thirty-day mortality was significantly higher among patients with thrombocytopenia (132/235 [56.2%]) vs those without thrombocytopenia (281/817 [34.4%]; P<.001). Higher mortality was associated with the degree of thrombocytopenia. In multivariable analysis, thrombocytopenia at baseline remained an independent risk factor for 30-day mortality (OR, 2.82; 95% CI, 1.87-4.24). The adjusted association between thrombocytopenia and death remained similar among the 917 patients with monomicrobial bacteremia (OR, 2.88; 95% CI, 1.83-4.53) and the 945 patients who did not die within the first 48 hours (OR, 2.88; 95% CI, 1.87-4.45.). CONCLUSION: We observed a strong association between thrombocytopenia at sepsis onset and all cause mortality in S aureus bacteremia, possibly related to mechanisms other than sepsis alone. PMID- 21531881 TI - Derivation and validation of automated electronic search strategies to identify pertinent risk factors for postoperative acute lung injury. AB - OBJECTIVE: To develop and validate time-efficient automated electronic search strategies for identifying preoperative risk factors for postoperative acute lung injury. PATIENTS AND METHODS: This secondary analysis of a prospective cohort study included 249 patients undergoing high-risk surgery between November 1, 2005, and August 31, 2006. Two independent data-extraction strategies were compared. The first strategy used a manual review of medical records and the second a Web-based query-building tool. Web-based searches were derived and refined in a derivation cohort of 83 patients and subsequently validated in an independent cohort of 166 patients. Agreement between the 2 search strategies was assessed with percent agreement and Cohen kappa statistics. RESULTS: Cohen kappa statistics ranged from 0.34 (95% confidence interval, 0.00-0.86) for amiodarone to 0.85 for cirrhosis (95% confidence interval, 0.57-1.00). Agreement between manual and automated electronic data extraction was almost complete for 3 variables (diabetes mellitus, cirrhosis, H(2)-receptor antagonists), substantial for 3 (chronic obstructive pulmonary disease, proton pump inhibitors, statins), moderate for gastroesophageal reflux disease, and fair for 2 variables (restrictive lung disease and amiodarone). Automated electronic queries outperformed manual data collection in terms of sensitivities (median, 100% [range, 77%-100%] vs median, 87% [range, 0%-100%]). The specificities were uniformly high (>= 96%) for both search strategies. CONCLUSION: Automated electronic query building is an iterative process that ultimately results in accurate, highly efficient data extraction. These strategies may be useful for both clinicians and researchers when determining the risk of time-sensitive conditions such as postoperative acute lung injury. PMID- 21531884 TI - Role of maintenance therapy after autologous stem cell transplant for multiple myeloma: lessons for cancer therapy. PMID- 21531883 TI - No change in physician dictation patterns when visit notes are made available online for patients. AB - OBJECTIVE: To determine whether physicians document office visits differently when they know their patients have easy, online access to visit notes. PATIENTS AND METHODS: We conducted a natural experiment with a pre-post design and a nonrandomized control group. The setting was a multispecialty group practice in Minnesota. We reviewed a total of 400 visit notes: 100 each for patients seen in a rheumatology department (intervention group) and a pulmonary medicine department (control group) from July 1 to August 30, 2005, before online access to notes, and 100 each for patients seen in these 2 departments 1 year later, from July 1 to August 30, 2006, when only rheumatology patients had online access to visit notes. We measured changes in visit note content related to 9 hypotheses for increased patient understanding and 5 for decreased frank or judgmental language. RESULTS: Changes occurred for 2 of the 9 hypotheses related to patient understanding, both in an unpredicted direction. The proportion of acronyms or abbreviations increased more in the notes of rheumatologists than of pulmonologists (0.6% vs 0.1%; P=.01), whereas the proportion of anatomy understood decreased more in the notes of rheumatologists than of pulmonologists (-5.9% vs -0.8%; P=.02). One change (of 5 possible) occurred related to the use of frank or judgmental terms. Mentions of mental health status decreased in rheumatology notes and increased in pulmonology notes (-8% vs 7%; P=.02). CONCLUSION: Dictation patterns appear relatively stable over time with or without online patient access to visit notes. PMID- 21531885 TI - Ethics and values in clinical practice: whom do they help? PMID- 21531886 TI - Recognition, pathogenesis, and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. AB - Nephropathy is a common microvascular complication among patients with type 2 diabetes mellitus and a major cause of kidney failure. It is characterized by albuminuria (>= 300 mg/d) and a reduced glomerular filtration rate and is often present at the time of diabetes diagnosis after the kidney has been exposed to chronic hyperglycemia during the prediabetic phase. A low glomerular filtration rate (<60 mL/min/1.73 m(2)) is also an independent risk factor for cardiovascular events and death. Detection of diabetic nephropathy during its initial stages provides the opportunity for early therapeutic interventions to prevent or delay the onset of complications and improve outcomes. An intensive and multifactorial management approach is needed that targets all risk determinants simultaneously. The strategy should comprise lifestyle modifications (smoking cessation, weight loss, increased physical activity, and dietary changes) coupled with therapeutic achievement of blood glucose, blood pressure, and lipid goals that are evidence based. Prescribing decisions should take into account demographic factors, level of kidney impairment, adverse effects, risk of hypoglycemia, tolerability, and effects on other risk factors and comorbidities. Regular and comprehensive follow up assessments with appropriate adjustment of the therapeutic regimen to maintain risk factor control is a vital component of care, including referral to specialists, when required. PMID- 21531887 TI - Improving the recognition and diagnosis of fibromyalgia. AB - Fibromyalgia (FM) is a chronic widespread pain disorder often seen in primary care practices. Advances in the understanding of FM pathophysiology and clinical presentation have improved the recognition and diagnosis of FM in clinical practice. Fibromyalgia is a clinical diagnosis based on signs and symptoms and is appropriate for primary care practitioners to make. The hallmark symptoms used to identify FM are chronic widespread pain, fatigue, and sleep disturbances. Awareness of common mimics of FM and comorbid disorders will increase confidence in establishing a diagnosis of FM. PMID- 21531888 TI - 78-year-old man with nausea and chest pain. PMID- 21531889 TI - Underlying reasons for smoking. PMID- 21531890 TI - Protein kinase CK2/PTEN pathway plays a key role in platelet-activating factor mediated murine anaphylactic shock. AB - Platelet-activating factor (PAF) is a major mediator in the induction of fatal hypovolemic shock in murine anaphylaxis. This PAF-mediated effect has been reported to be associated with PI3K/Akt-dependent eNOS-derived NO. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is phosphatidylinositol phosphate phosphatase, which negatively controls PI3K by dephosphorylating the signaling lipid, phosphatidylinositol 3,4,5-triphosphate. In this study, we examined the possible involvement of PTEN in PAF-mediated anaphylactic shock. Induction of anaphylaxis or PAF injection resulted in a rapid decrease in PTEN activity, followed by increases in PI3K activity and phosphorylation of Akt and eNOS. Systemic administration of adenoviruses carrying PTEN cDNA (adenoviral PTEN), but not the control AdLacZ, not only attenuated anaphylactic symptoms, but also reversed anaphylaxis- or PAF-induced changes in PTEN and PI3K activities, as well as phosphorylation of Akt and eNOS. We found that the decreased PTEN activity was associated with PTEN phosphorylation, the latter effect being prevented by the protein kinase CK2 inhibitor, DMAT. DMAT also inhibited anaphylactic symptoms as well as the anaphylaxis- or PAF-mediated PTEN/PI3K/Akt/eNOS signaling cascade. CK2 activity was increased by PAF. The present data provide, as the key mechanism underlying anaphylactic shock, PAF triggers the upstream pathway CK2/PTEN, which ultimately leads to the activation of PI3K/Akt/eNOS. Therefore, CK2/PTEN may be a potent target in the control of anaphylaxis and other many PAF-mediated pathologic conditions. PMID- 21531893 TI - Donor CD8 T cells and IFN-gamma are critical for sex-based differences in donor CD4 T cell engraftment and lupus-like phenotype in short-term chronic graft versus-host disease mice. AB - The transfer of unfractionated DBA/2J (DBA) splenocytes into B6D2F(1) (DBA -> F(1)) mice results in greater donor CD4 T cell engraftment in females at day 14 that persists long-term and mediates greater female lupus-like renal disease. Although donor CD8 T cells have no demonstrated role in lupus pathogenesis in this model, we recently observed that depletion of donor CD8 T cells prior to transfer eliminates sex-based differences in renal disease long-term. In this study, we demonstrate that greater day 14 female donor CD4 engraftment is also critically dependent on donor CD8 T cells. Male DBA -> F(1) mice exhibit stronger CD8-dependent day 8-10 graft-versus-host (GVH) and counter-regulatory host-versus graft (HVG) responses, followed by stronger homeostatic contraction (days 10-12). The weaker day 10-12 GVH and HVG in females are followed by persistent donor T cell activation and increasing proliferation, expansion, and cytokine production from days 12 to 14. Lastly, greater female day 14 donor T cell engraftment, activation, and cytokine production were lost with in vivo IFN-gamma neutralization from days 6 to 14. We conclude the following: 1) donor CD8 T cells enhance day 10 proliferation of donor CD4 T cells in both sexes; and 2) a weaker GVH/HVG in females allows prolonged survival of donor CD4 and CD8 T cells, allowing persistent activation. These results support the novel conclusion that sex-based differences in suboptimal donor CD8 CTL activation are critical for shaping sex-based differences in donor CD4 T cell engraftment at 2 wk and lupus like disease long-term. PMID- 21531892 TI - Th17 cells induce colitis and promote Th1 cell responses through IL-17 induction of innate IL-12 and IL-23 production. AB - Both Th1 and Th17 cells have been implicated in the pathogenesis of inflammatory bowel disease and experimental colitis. However, the complex relationship between Th1 and Th17 cells and their relative contributions to the pathogenesis of inflammatory bowel disease have not been completely analyzed. Although it has been recently shown that Th17 cells can convert into Th1 cells, the underlying in vivo mechanisms and the role of Th1 cells converted from Th17 cells in the pathogenesis of colitis are still largely unknown. In this study, we report that Th17 cells from CBir1 TCR transgenic mice, which are specific for an immunodominant microbiota Ag, are more potent than Th1 cells in the induction of colitis, as Th17 cells induced severe colitis, whereas Th1 cells induced mild colitis when transferred into TCRbetaxdelta(-/-) mice. High levels of IL-12 and IL-23 and substantial numbers of IFN-gamma(+) Th1 cells emerged in the colons of Th17 cell recipients. Administration of anti-IL-17 mAb abrogated Th17 cell induced colitis development, blocked colonic IL-12 and IL-23 production, and inhibited IFN-gamma(+) Th1 cell induction. IL-17 promoted dendritic cell production of IL-12 and IL-23. Furthermore, conditioned media from colonic tissues of colitic Th17 cell recipients induced IFN-gamma production by Th17 cells, which was inhibited by blockade of IL-12 and IL-23. Collectively, these data indicate that Th17 cells convert to Th1 cells through IL-17 induction of mucosal innate IL-12 and IL-23 production. PMID- 21531891 TI - Upregulation of IL-21 receptor on B cells and IL-21 secretion distinguishes novel 2009 H1N1 vaccine responders from nonresponders among HIV-infected persons on combination antiretroviral therapy. AB - Mechanisms underlying failure of novel 2009 H1N1 influenza vaccine-induced Ab responses in HIV-infected persons are poorly understood. This study prospectively evaluated 16 HIV-infected patients on combination antiretroviral therapy and eight healthy controls (HC) who received a single 15 MUg dose of nonadjuvanted novel 2009 H1N1 influenza vaccine during the 2009 H1N1 epidemic. Peripheral blood was collected at baseline (T0) and at 7 d (T1) and 28 d (T2) postvaccination for evaluation of immune responses. Prevaccination hemagglutination inhibition Ab titer was <1:20 in all except one study participant. At T2, all HC and 8 out of 16 patients (50%) developed a vaccine-induced Ab titer of >= 1:40. Vaccine responder (R) and vaccine nonresponder patients were comparable at T0 in age, CD4 counts, virus load, and B cell immunophenotypic characteristics. At T2, HC and R patients developed an expansion of phenotypic and functional memory B cells and ex vivo H1N1-stimulated IgG Ab-secreting cells in an ELISPOT assay. The memory B cell response was preceded by a significant expansion of plasmablasts and spontaneous H1N1-specific Ab-secreting cells at T1. At T2, HC and R patients also exhibited significant increases in serum IL-21 levels and in the frequency and mean fluorescence intensity of IL-21R-expressing B cells, which correlated with serum H1N1 Ab titers. Vaccine nonresponder patients failed to develop the above described vaccine-induced immunologic responses. The novel association of novel 2009 H1N1 vaccine-induced Ab responses with IL-21/IL-21R upregulation and with development of memory B cells and plasmablasts has implications for future research in vaccine design. PMID- 21531894 TI - Endothelin-1 signaling promotes fibrosis in vitro in a bronchopulmonary dysplasia model by activating the extrinsic coagulation cascade. AB - Neonatal respiratory distress syndrome can progress to bronchopulmonary dysplasia (BPD), a serious pulmonary fibrotic disorder. Given the involvement of the extrinsic coagulation cascade in animal models of lung fibrosis, we examined its role in BPD. We observed a higher number of neutrophils expressing tissue factor (TF) in bronchoalveolar lavage fluid (BALF) from infants with BPD than from those with uncomplicated respiratory distress syndrome together with a parallel decrease in TF and connective tissue growth factor (CTGF) in BALF supernatants during the disease course. The involvement of coagulation in the fibrotic process associated with BPD was further evaluated by treating primary human colonic myofibroblasts with BALF supernatants from infants with BPD. These human colonic myofibroblasts demonstrated an enhanced C5a- and thrombin-dependent migration. Moreover, they expressed TF in an endothelin-1-dependent manner, with subsequent activation of the extrinsic coagulation cascade and CTGF production mediated by protease-activator receptor-1 signaling. These data provide a novel mechanism for the development of BPD and indicate that endothelin-1 signaling contributes to fibrosis by upregulating a TF/thrombin amplification loop responsible for CTGF production, and offer novel and specific therapeutic targets for pulmonary fibrotic disease. PMID- 21531895 TI - Suppressive CD8+ T cells arise in the absence of CD4 help and compromise control of persistent virus. AB - There is an urgent need to develop novel therapies for controlling chronic virus infections in immunocompromised patients. Disease associated with persistent gamma-herpesvirus infection (EBV, human herpesvirus 8) is a significant problem in AIDS patients and transplant recipients, and clinical management of these conditions is difficult. Immune surveillance failure followed by gamma herpesvirus recrudescence can be modeled using murine gamma-herpesvirus (MHV)-68 in mice lacking CD4(+) T cells. In contrast with other chronic infections, no obvious defect in the functional capacity of the viral-specific CD8(+) T cell response was detected. We show in this article that adoptive transfer of MHV-68 specific CD8(+) T cells was ineffective at reducing the viral burden. Together, these indicate the potential presence of T cell extrinsic suppressive factors. Indeed, CD4-depleted mice infected with MHV-68 express increased levels of IL-10, a cytokine capable of suppressing the function of both APCs and T cells. CD4 depleted mice developed a population of CD8(+) T cells capable of producing IL-10 that suppressed viral control. Although exhibiting cell surface markers indicative of activation, the IL-10-producing cells expressed increased levels of programmed death-1 but were not enriched in the MHV-68-specific compartment, nor were they uniformly CD44(hi). Therapeutic administration of an IL-10R blocking Ab enhanced control of the recrudescent virus. These data implicate IL-10 as a promising target for the restoration of immune surveillance against chronic gamma herpesvirus infection in immunosuppressed individuals. PMID- 21531896 TI - Papillomavirus-specific CD4+ T cells exhibit reduced STAT-5 signaling and altered cytokine profiles in patients with recurrent respiratory papillomatosis. AB - Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus type 6 (HPV-6) or HPV-11. Specific HLA-DR haplotypes DRB1*01:02 and DRB1*03:01 are associated with the development of RRP, disease severity, and Th2-like responses to HPV early proteins. Th1-like responses to HPV proteins have been shown to be protective in animal models. Therefore, we investigated the hypothesis that RRP patients have dysfunctional Th1-like, HPV-specific T cell responses. Using MHC class II tetramers, we identified immunogenic peptides within HPV-11 early proteins. Two distinct peptides (E6(113-132) and E2(1-20)) contained DRB1*01:02- or DRB1*03:01-restricted epitopes, respectively. An additional peptide (E2(281 300)) contained an epitope presented by both alleles. Peptide binding, tetramer, and proliferation assays identified minimal epitopes within these peptides. These epitopes elicited E2/E6-specific CD4(+) T cell responses in RRP patients and healthy control subjects, allowing the isolation of HPV-specific T cell lines using tetramers. The cytokine profiles and STAT signaling of these tetramer positive T cells were measured to compare the polarization and responsiveness of HPV-specific T cells from patients with RRP and healthy subjects. HPV-specific IFN-gamma secretion was substantially lower in T cells from RRP patients. HPV specific IL-13 secretion was seen at modest levels in T cells from RRP patients and was absent in T cells from healthy control subjects. HPV-specific T cells from RRP patients exhibited reduced STAT-5 phosphorylation and reduced IL-2 secretion, suggesting anergy. Levels of STAT-5 phosphorylation and IFN-gamma secretion could be improved through addition of IL-2 to HPV-specific T cell lines from RRP patients. Therapeutic vaccination or interventions aimed at restoring Th1-like cytokine responses to HPV proteins and reversing anergy could improve clinical outcomes for RRP patients. PMID- 21531898 TI - Discovery of rare mutations in populations: TILLING by sequencing. AB - Discovery of rare mutations in populations requires methods, such as TILLING (for Targeting Induced Local Lesions in Genomes), for processing and analyzing many individuals in parallel. Previous TILLING protocols employed enzymatic or physical discrimination of heteroduplexed from homoduplexed target DNA. Using mutant populations of rice (Oryza sativa) and wheat (Triticum durum), we developed a method based on Illumina sequencing of target genes amplified from multidimensionally pooled templates representing 768 individuals per experiment. Parallel processing of sequencing libraries was aided by unique tracer sequences and barcodes allowing flexibility in the number and pooling arrangement of targeted genes, species, and pooling scheme. Sequencing reads were processed and aligned to the reference to identify possible single-nucleotide changes, which were then evaluated for frequency, sequencing quality, intersection pattern in pools, and statistical relevance to produce a Bayesian score with an associated confidence threshold. Discovery was robust both in rice and wheat using either bidimensional or tridimensional pooling schemes. The method compared favorably with other molecular and computational approaches, providing high sensitivity and specificity. PMID- 21531897 TI - Early transcriptional defense responses in Arabidopsis cell suspension culture under high-light conditions. AB - The early transcriptional defense responses and reactive oxygen species (ROS) production in Arabidopsis (Arabidopsis thaliana) cell suspension culture (ACSC), containing functional chloroplasts, were examined at high light (HL). The transcriptional analysis revealed that most of the ROS markers identified among the 449 transcripts with significant differential expression were transcripts specifically up-regulated by singlet oxygen ((1)O(2)). On the contrary, minimal correlation was established with transcripts specifically up-regulated by superoxide radical or hydrogen peroxide. The transcriptional analysis was supported by fluorescence microscopy experiments. The incubation of ACSC with the (1)O(2) sensor green reagent and 2',7'-dichlorofluorescein diacetate showed that the 30-min-HL-treated cultures emitted fluorescence that corresponded with the production of (1)O(2) but not of hydrogen peroxide. Furthermore, the in vivo photodamage of the D1 protein of photosystem II indicated that the photogeneration of (1)O(2) took place within the photosystem II reaction center. Functional enrichment analyses identified transcripts that are key components of the ROS signaling transduction pathway in plants as well as others encoding transcription factors that regulate both ROS scavenging and water deficit stress. A meta-analysis examining the transcriptional profiles of mutants and hormone treatments in Arabidopsis showed a high correlation between ACSC at HL and the fluorescent mutant family of Arabidopsis, a producer of (1)O(2) in plastids. Intriguingly, a high correlation was also observed with ABA deficient1 and more axillary growth4, two mutants with defects in the biosynthesis pathways of two key (apo)carotenoid-derived plant hormones (i.e. abscisic acid and strigolactones, respectively). ACSC has proven to be a valuable system for studying early transcriptional responses to HL stress. PMID- 21531901 TI - Optimizing statin treatment decisions for diabetes patients in the presence of uncertain future adherence. AB - BACKGROUND: Statins are an important part of the treatment plan for patients with type 2 diabetes. However, patients who are prescribed statins often take less than the prescribed amount or stop taking the drug altogether. This suboptimal adherence may decrease the benefit of statin initiation. OBJECTIVE: To estimate the influence of adherence on the optimal timing of statin initiation for patients with type 2 diabetes. METHOD: The authors use a Markov decision process (MDP) model to optimize the treatment decision for patients with type 2 diabetes. Their model incorporates a Markov model linking adherence to treatment effectiveness and long-term health outcomes. They determine the optimal time of statin initiation that minimizes expected costs and maximizes expected quality adjusted life years (QALYs). RESULTS: In the long run, approximately 25% of patients remain highly adherent to statins. Based on the MDP model, generic statins lower costs in men and result in a small increase in costs in women relative to no treatment. Patients are able to noticeably increase their expected QALYs by 0.5 to 2 years depending on the level of adherence. CONCLUSIONS: Adherence-improving interventions can increase expected QALYs by as much as 1.5 years. Given suboptimal adherence to statins, it is optimal to delay the start time for statins; however, changing the start time alone does not lead to significant changes in costs or QALYs. PMID- 21531902 TI - Team clinical supervision in acute hospital wards: a feasibility study. AB - Clinical supervision provides a strategy to mitigate nurses' workplace stress and enhance retention, but the literature provides little guidance about its implementation beyond mental health nursing. This study explored the feasibility of implementing and evaluating ward-based team clinical supervision for general nurses on two separate wards at one public and one private hospital. Nurses completed the Work Environment Questionnaire pre- (n = 36) and postintervention (n = 27), and focus groups (n = 20) explored their perceptions of supervision. Staff were unfamiliar with clinical supervision, so information sessions were required. The questionnaire may not have been suitable to evaluate this type of intervention. Focus group findings revealed that team supervision improved communication, enhanced working relationships, and empowered nurses to challenge existing practices, which had a positive impact on their perceived stress. This study provides insights to guide implementation and evaluation of clinical supervision in acute settings. PMID- 21531899 TI - Coupling virus-induced gene silencing to exogenous green fluorescence protein expression provides a highly efficient system for functional genomics in Arabidopsis and across all stages of tomato fruit development. AB - Since the advent of the postgenomic era, efforts have focused on the development of rapid strategies for annotating plant genes of unknown function. Given its simplicity and rapidity, virus-induced gene silencing (VIGS) has become one of the preeminent approaches for functional analyses. However, several problems remain intrinsic to the use of such a strategy in the study of both metabolic and developmental processes. The most prominent of these is the commonly observed phenomenon of "sectoring" the tissue regions that are not effectively targeted by VIGS. To better discriminate these sectors, an effective marker system displaying minimal secondary effects is a prerequisite. Utilizing a VIGS system based on the tobacco rattle virus vector, we here studied the effect of silencing the endogenous phytoene desaturase gene (pds) and the expression and subsequent silencing of the exogenous green fluorescence protein (gfp) on the metabolism of Arabidopsis (Arabidopsis thaliana) leaves and tomato (Solanum lycopersicum) fruits. In leaves, we observed dramatic effects on primary carbon and pigment metabolism associated with the photobleached phenotype following the silencing of the endogenous pds gene. However, relatively few pleiotropic effects on carbon metabolism were observed in tomato fruits when pds expression was inhibited. VIGS coupled to gfp constitutive expression revealed no significant metabolic alterations after triggering of silencing in Arabidopsis leaves and a mild effect in mature green tomato fruits. By contrast, a wider impact on metabolism was observed in ripe fruits. Silencing experiments with an endogenous target gene of interest clearly demonstrated the feasibility of cosilencing in this system; however, carefully constructed control experiments are a prerequisite to prevent erroneous interpretation. PMID- 21531903 TI - The human proteome project: Current state and future direction. AB - After successful completion of the Human Genome Project (HGP), HUPO has recently officially launched a global Human Proteome Project (HPP) which is designed to map the entire human protein set. Given the presence of about 30% undisclosed proteins out of 20,300 protein gene products, a systematic global effort is necessary to achieve this goal with respect to protein abundance, distribution, subcellular localization, interaction with other biomolecules, and functions at specific time points. As a general experimental strategy, HPP groups employ the three working pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools and knowledge base. The HPP participants will take advantage of the output and cross-analyses from the ongoing HUPO initiatives and a chromosome-based protein mapping strategy, termed C-HPP with many national teams currently engaged. In addition, numerous biologically-driven projects will be stimulated and facilitated by the HPP. Timely planning with proper governance of HPP will deliver a protein parts list, reagents and tools for protein studies and analyses, and a stronger basis for personalized medicine. HUPO urges each national research funding agency and the scientific community at large to identify their preferred pathways to participate in aspects of this highly promising project in a HPP consortium of funders and investigators. PMID- 21531900 TI - DNA free energy-based promoter prediction and comparative analysis of Arabidopsis and rice genomes. AB - The cis-regulatory regions on DNA serve as binding sites for proteins such as transcription factors and RNA polymerase. The combinatorial interaction of these proteins plays a crucial role in transcription initiation, which is an important point of control in the regulation of gene expression. We present here an analysis of the performance of an in silico method for predicting cis-regulatory regions in the plant genomes of Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) on the basis of free energy of DNA melting. For protein-coding genes, we achieve recall and precision of 96% and 42% for Arabidopsis and 97% and 31% for rice, respectively. For noncoding RNA genes, the program gives recall and precision of 94% and 75% for Arabidopsis and 95% and 90% for rice, respectively. Moreover, 96% of the false-positive predictions were located in noncoding regions of primary transcripts, out of which 20% were found in the first intron alone, indicating possible regulatory roles. The predictions for orthologous genes from the two genomes showed a good correlation with respect to prediction scores and promoter organization. Comparison of our results with an existing program for promoter prediction in plant genomes indicates that our method shows improved prediction capability. PMID- 21531904 TI - Pseudogene-derived small interference RNAs regulate gene expression in African Trypanosoma brucei. AB - Pseudogenes have been shown to acquire unique regulatory roles from more and more organisms. We report the observation of a cluster of siRNAs derived from pseudogenes of African Trypanosoma brucei using high through-put analysis. We show that these pseudogene-derived siRNAs suppress gene expression through RNA interference. The discovery that siRNAs may originate from pseudogenes and regulate gene expression in a unicellular eukaryote provides insights into the functional roles of pseudogenes and into the origin of noncoding small RNAs. PMID- 21531905 TI - Experimental evolution of selfish policing in social bacteria. AB - Cooperative organisms evolve within socially diverse populations. In populations harboring both cooperators and cheaters, cooperators might adapt by evolving novel interactions with either social type or both. Diverse animal traits suppress selfish behaviors when cooperation is important for fitness, but the potential for prokaryotes to evolve such traits is unclear. We allowed a strain of the bacterium Myxococcus xanthus that is proficient at cooperative fruiting body development to evolve while repeatedly encountering a non-evolving developmental cheater. Evolving populations greatly increased their fitness in the presence of the cheater, both relative to their ancestor and in terms of absolute spore productivity. However, the same evolved lineages exhibited a net disadvantage to the ancestor in the cheater's absence. Evolving populations reversed a large ancestral disadvantage to the cheater into competitive superiority and also evolved to strongly suppress cheater productivity. Moreover, in three-party mixes with the cheater, evolved populations enhanced their ancestor's productivity relative to mixes of only the ancestor and cheater. Thus, our evolved populations function as selfish police that inhibit cheaters, both to their own advantage and to the benefit of others as well. Cheater suppression was general across multiple unfamiliar cheaters but was more pronounced against the evolutionarily familiar cheater. Also, evolution generated three new mutually beneficial relationships, including complementary defect rescue between evolved cells and the selection-regime cheater. The rapid evolution of cheater suppression documented here suggests that coevolving social strategies within natural populations of prokaryotes are more diverse and complex than previously appreciated. PMID- 21531906 TI - Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory. AB - Remodeling of cortical connectivity is thought to allow initially hippocampus dependent memories to be expressed independently of the hippocampus at remote time points. Consistent with this, consolidation of a contextual fear memory is associated with dendritic spine growth in neurons of the anterior cingulate cortex (aCC). To directly test whether such cortical structural remodeling is necessary for memory consolidation, we disrupted spine growth in the aCC at different times following contextual fear conditioning in mice. We took advantage of previous studies showing that the transcription factor myocyte enhancer factor 2 (MEF2) negatively regulates spinogenesis both in vitro and in vivo. We found that increasing MEF2-dependent transcription in the aCC during a critical posttraining window (but not at later time points) blocked both the consolidation associated dendritic spine growth and subsequent memory expression. Together, these data strengthen the causal link between cortical structural remodeling and memory consolidation and, further, identify MEF2 as a key regulator of these processes. PMID- 21531908 TI - Analysis of MECP2 gene copy number in boys with autism. AB - Autism is a severe neurodevelopmental disorder with a strong genetic basis.The methyl-CpG binding protein 2 gene (MECP2) is a dosage-sensitive gene in brain development and has been implicated as a candidate gene for autism. Duplication of the MECP2 gene has been reported in a few boys with autistic features. To further investigate the association of MECP2 duplication with autism, the authors performed real-time quantitative polymerase chain reaction (PCR) to detect copy number variations of the MECP2 gene in 82 autistic boys. No copy number variation was found in these patients, indicating that duplication of the MECP2 gene is not frequent in autistic patients. The authors consider that duplication of the MECP2 gene has no major effect on the susceptibility to autism. Replication of studies in a large-sized sample and a well-characterized subgroup of autism are warranted to further identify the association of MECP2 gene duplication with autism. PMID- 21531907 TI - Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma. AB - TRIM24 (TIF1alpha), TRIM28 (TIF1beta), and TRIM33 (TIF1gamma) are three related cofactors belonging to the tripartite motif superfamily that interact with distinct transcription factors. TRIM24 interacts with the liganded retinoic acid (RA) receptor to repress its transcriptional activity. Germ line inactivation of TRIM24 in mice deregulates RA-signaling in hepatocytes leading to the development of hepatocellular carcinoma (HCC). Here we show that TRIM24 can be purified as at least two macromolecular complexes comprising either TRIM33 or TRIM33 and TRIM28. Somatic hepatocyte-specific inactivation of TRIM24, TRIM28, or TRIM33 all promote HCC in a cell-autonomous manner in mice. Moreover, HCC formation upon TRIM24 inactivation is strongly potentiated by further loss of TRIM33. These results demonstrate that the TIF1-related subfamily of TRIM proteins interact both physically and functionally to modulate HCC formation in mice. PMID- 21531909 TI - Sterilization for individuals with mental disabilities: the other half of the equation. AB - Medical ethics can be defined as the study of moral values and judgments as they apply to medicine. Healthcare providers, or for that matter all who make contributions to the field of medicine, are regularly confronted by ethical dilemmas. Like other predicaments, ethical dilemmas require thoughtful consideration. The overarching goal of Ethical Crossroads is to provide a forum for opinions on a contemporary ethical challenge that, at least tangentially, impacts the practice of child neurology. PMID- 21531910 TI - Sterilization: an option for all women. PMID- 21531911 TI - Arguments against sterilization of developmentally disabled minors. PMID- 21531912 TI - A claim for caution in the use of promising bumetanide to treat neonatal seizures. PMID- 21531914 TI - Chromosomopathy manifesting as mitochondrial disease. PMID- 21531916 TI - Mineral trioxide aggregate inhibits osteoclastic bone resorption. AB - Mineral trioxide aggregate (MTA), a commonly used endodontic repair material, is useful for both basic and clinical research, and the effect of MTA on osteoblast differentiation has been well-defined. However, the effects of MTA on osteoclastic bone resorption are not fully understood. Hence, the aim of this study is to examine the effect of MTA solution in the regulation of osteoclast bone-resorbing activity using osteoclasts formed in co-cultures of primary osteoblasts and bone marrow cells. MTA solution dose-dependently reduced the total area of pits formed by osteoclasts. The reduction of resorption induced by 20% MTA treatment was due to inhibition of osteoclastic bone-resorbing activity and had no effect on osteoclast number. A 20% MTA solution disrupted actin ring formation, a marker of osteoclastic bone resorption, by reducing phosphorylation and kinase activity of c-Src, and mRNA expressions of cathepsin K and mmp-9. A high concentration of MTA solution (50%) induced apoptosis of osteoclasts by increasing the expression of Bim, a member of the BH3-only (Bcl-2 homology) family of pro-apoptotic proteins. Taken together, our results suggest that MTA is a useful retrofilling material for several clinical situations because it both stimulates osteoblast differentiation and inhibits bone resorption. PMID- 21531917 TI - Identification of unrecognized diabetes and pre-diabetes in a dental setting. AB - Many diabetic patients remain undiagnosed, and oral findings may offer an unrealized opportunity for the identification of affected individuals unaware of their condition. We recruited 601 individuals who presented for care at a dental clinic, were >=40 years old, if non-Hispanic white, and >=30 years old, if Hispanic or non-white, and had never been told they have pre-diabetes or diabetes. Those with at least one self-reported diabetes risk factor (N=535) received a periodontal examination and a point-of-care hemoglobin A1c (HbA1c) test. A fasting plasma glucose (FPG) test was used as the study outcome, signifying potential diabetes or pre-diabetes. Performance characteristics of simple models of dysglycemia (FPG>=100 mg/dL) identification were evaluated and optimal cut-offs identified. A model including only two dental variables had an estimated area under the receiver operating characteristic curve (AUC) of 0.65. The addition of a point-of-care HbA1c test improved the AUC to 0.79 (p<0.001). The presence of >=26% deep pockets or >=4 missing teeth correctly identified 73% of true cases; the addition of an HbA1c>=5.7% increased correct identification to 92%. Analysis of our data suggests that oral healthcare professionals have the opportunity to identify unrecognized diabetes and pre-diabetes in dental patients and refer them to a physician for further evaluation and care. PMID- 21531918 TI - Dendritic cells, antibodies reactive with oxLDL, and inflammation. AB - Periodontitis appears to promote chronic inflammatory diseases, including atherosclerosis, but relevant mechanisms need clarification. Oral bacteria induce antibodies that bind not only bacteria, but also oxLDL. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans induce remarkable IgG responses that are dominated by IgG2, and IgG2 is IFN-gamma-dependent and is promoted by dendritic cells (DCs). LDL-reactive antibodies induced by P. gingivalis and A. actinomycetemcomitans include anti-phosphorylcholine (alpha-PC) and beta2 glycoprotein-1-dependent anticardiolipin (alpha-CL), and these antibodies may link chronic inflammatory diseases at a mechanistic level. Antibody-mediated uptake of oxLDL or bacteria dramatically enhances DC-IL-12, and DC-IL-12 induces NK-cell-IFN-gamma responses that promote Th-1 responses and sustained inflammation. DCs may be derived from monocytes, and this is striking in cultures of aggressive periodontitis (AgP) monocytes, where DC numbers are about double control levels. Moreover, serum alpha-CL levels in individuals with AgP are frequently elevated, and these antibodies promote atherosclerosis in persons with antiphospholipid syndrome. Elevated serum levels of soluble-intercellular adhesion molecule, soluble-vascular cell adhesion molecule, and soluble-E selectin are atherosclerosis-associated indicators of vascular inflammation, and these markers are elevated in the subset of AgP patients with high alpha-CL. We reason that periodontitis patients with elevated antibodies reactive with oxLDL could be a subgroup at high risk for cardiovascular sequelae. PMID- 21531919 TI - The specific binding to 21-nt double-stranded RNAs is crucial for the anti silencing activity of Cucumber vein yellowing virus P1b and perturbs endogenous small RNA populations. AB - RNA silencing mediated by siRNAs plays an important role as an anti-viral defense mechanism in plants and other eukaryotic organisms, which is usually counteracted by viral RNA silencing suppressors (RSSs). The ipomovirus Cucumber vein yellowing virus (CVYV) lacks the typical RSS of members of the family Potyviridae, HCPro, which is replaced by an unrelated RSS, P1b. CVYV P1b resembles potyviral HCPro in forming complexes with synthetic siRNAs in vitro. Electrophoretic mobility shift assays showed that P1b, like potyviral HCPro, interacts with double-stranded siRNAs, but is not able to bind single-stranded small RNAs or small DNAs. These assays also showed a preference of CVYV P1b for binding to 21-nt siRNAs, a feature also reported for HCPro. However, these two potyvirid RSSs differ in their requirements of 2-nucleotide (nt) 3' overhangs and 5' terminal phosphoryl groups for siRNA binding. Copurification assays confirmed in vivo P1b-siRNA interactions. We have demonstrated by deep sequencing of small RNA populations interacting in vivo with CVYV P1b that the size preference of P1b for small RNAs of 21 nt also takes place in the plant, and that expression of this RSS causes drastic changes in the endogenous small RNA populations. In addition, a site directed mutagenesis analysis strongly supported the assumption that P1b-siRNA binding is decisive for the anti-silencing activity of P1b and localized a basic domain involved in the siRNA-binding activity of this protein. PMID- 21531922 TI - Hepatitis C--removing barriers to diagnosing the "silent epidemic". PMID- 21531921 TI - Genome reduction by deletion of paralogs in the marine cyanobacterium Prochlorococcus. AB - Several isolates of the marine cyanobacterial genus Prochlorococcus have smaller genome sizes than those of the closely related genus Synechococcus. In order to test whether loss of protein-coding genes has contributed to genome size reduction in Prochlorococcus, we reconstructed events of gene family evolution over a strongly supported phylogeny of 12 Prochlorococcus genomes and 9 Synechococcus genomes. Significantly, more events both of loss of paralogs within gene families and of loss of entire gene families occurred in Prochlorococcus than in Synechococcus. The number of nonancestral gene families in genomes of both genera was positively correlated with the extent of genomic islands (GIs), consistent with the hypothesis that horizontal gene transfer (HGT) is associated with GIs. However, even when only isolates with comparable extents of GIs were compared, significantly more events of gene family loss and of paralog loss were seen in Prochlorococcus than in Synechococcus, implying that HGT is not the primary reason for the genome size difference between the two genera. PMID- 21531920 TI - Solution structure of RNase P RNA. AB - The ribonucleoprotein enzyme ribonuclease P (RNase P) processes tRNAs by cleavage of precursor-tRNAs. RNase P is a ribozyme: The RNA component catalyzes tRNA maturation in vitro without proteins. Remarkable features of RNase P include multiple turnovers in vivo and ability to process diverse substrates. Structures of the bacterial RNase P, including full-length RNAs and a ternary complex with substrate, have been determined by X-ray crystallography. However, crystal structures of free RNA are significantly different from the ternary complex, and the solution structure of the RNA is unknown. Here, we report solution structures of three phylogenetically distinct bacterial RNase P RNAs from Escherichia coli, Agrobacterium tumefaciens, and Bacillus stearothermophilus, determined using small angle X-ray scattering (SAXS) and selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis. A combination of homology modeling, normal mode analysis, and molecular dynamics was used to refine the structural models against the empirical data of these RNAs in solution under the high ionic strength required for catalytic activity. PMID- 21531923 TI - Justifying changes in clinical practice. PMID- 21531924 TI - Dental insurance. PMID- 21531925 TI - Pregnancy and periodontal disease. PMID- 21531926 TI - Measuring clinical performance. PMID- 21531927 TI - Note from the American Dental Association's Division of Legal Affairs. PMID- 21531928 TI - Another viewpoint. PMID- 21531929 TI - More about pregnancy. PMID- 21531931 TI - The pulpal anesthetic efficacy of articaine versus lidocaine in dentistry: a meta analysis. AB - BACKGROUND: The authors evaluated published evidence from controlled clinical trials regarding the efficacy of two local anesthetic solutions in providing successful pulpal anesthesia. METHODS: The authors searched MEDLINE and Embase databases to identify peer-reviewed randomized controlled trials in which researchers directly compared articaine and lidocaine local anesthetic solutions in adult participants. They extracted study characteristics and outcomes data as a basis for meta-analysis. They completed subgroup analyses for both infiltration and mandibular inferior alveolar block anesthetic techniques. RESULTS: Articaine solutions had a probability of achieving anesthetic success superior to that of lidocaine, with an odds ratio of 2.44 (95 percent confidence interval [CI], 1.59 3.76; P < .0001). The greater odds ratio for articaine increased to 3.81 (95 percent CI, 2.71-5.36; P < .00001) when the authors analyzed only infiltration data. There was weaker, but still significant, evidence of articaine's being superior to lidocaine for mandibular block anesthesia, with an odds ratio of 1.57 (95 percent CI, 1.12-2.21; P = .009), and no difference when the authors considered only symptomatic teeth. CLINICAL IMPLICATIONS: Research evidence supports using articaine versus lidocaine for achieving pulpal anesthesia when the infiltration mode of administration is used. It is premature to recommend articaine for mandibular block anesthesia in cases involving irreversible pulpitis. PMID- 21531932 TI - Osteonecrosis of the jaw in patients with cancer who received zoledronic acid and bevacizumab. AB - BACKGROUND: The authors investigated the incidence of and risk factors for osteonecrosis of the jaw (ONJ) in patients with metastases to the bone who received the bisphosphonate agent zoledronic acid (ZOL) and chemotherapy combined with the antiangiogenic agent bevacizumab (BEV). METHODS: The authors evaluated 59 participants (34 with breast cancer and 25 with nonsmall-cell lung cancer). All of the participants received 4 milligrams of ZOL via intravenous (IV) infusion every four weeks and 15 mg per kilogram of BEV every three weeks. They conducted a dental examination in participants at baseline and every three months until the patients died or were lost to follow-up. If needed, participants received periodontal disease treatment and underwent tooth extraction before they started receiving ZOL and BEV. RESULTS: The median time the participants received ZOL therapy was 18.8 months (range, 3.1-28.9 months); 36 participants (61.0 percent) received ZOL therapy for more than one year. The median time participants received BEV therapy was 16.7 months (range, 2.8-29.6 months). None of the participants required dentoalveolar surgery while undergoing cancer treatment. After a median follow-up period of 19.7 months, none of the participants developed bisphosphonate-related ONJ. CONCLUSIONS AND CLINICAL IMPLICATIONS: ZOL combined with BEV did not predispose to ONJ participants with cancer that had metastasized to the bone who underwent a baseline dental examination and preventive dental measures. The study results must be considered in the context of the study's protocols and the follow-up period. PMID- 21531933 TI - An unusual case of gingival hyperplasia with gingival ulcerations. PMID- 21531934 TI - Dentist-patient communication techniques used in the United States: the results of a national survey. AB - BACKGROUND: The authors conducted a national survey to determine the communication techniques that dentists use routinely and variations in their use. METHODS: American Dental Association Survey Center staff members mailed an 86 item questionnaire to a random sample of 6,300 U.S. dentists in private practice. Participants reported routine use ("most of the time" or "always") during a typical week of 18 communication techniques, of which seven are basic techniques. The authors used analysis of variance and ordinary least squares regression models to test the association of communication, provider and practice characteristics with the number of techniques. RESULTS: Dentists routinely use an average of 7.1 of the 18 techniques and 3.1 of the seven basic techniques. Two thirds or more of dentists used four of the techniques (hand out printed materials, speak slowly, use models or radiographs to explain, use simple language). Less than one-fourth of dentists used any of the techniques in the teach-back method or patient-friendly practice domains. A dentist's age, race/ethnicity, education outside the United States and area of dentistry affected use. Health literacy variables (awareness, education in communication, practice-level change, outcome expectancy) and lack of time were associated with the number of techniques used. CONCLUSIONS: Routine use of all of the communication techniques is low among dentists, including some techniques thought to be most effective with patients with low literacy skills. PRACTICE IMPLICATIONS: Professional education is needed to improve knowledge about communication techniques and to ensure that they are used effectively. A firm foundation for these efforts requires the development, evaluation and dissemination of communication guidelines for dental care professionals. PMID- 21531935 TI - Trigeminal nerve injury associated with injection of local anesthetics: needle lesion or neurotoxicity? AB - BACKGROUND: The authors used comprehensive national registry and clinical data to conduct a study of adverse drug reactions (ADRs), in particular neurosensory disturbance (NSD), associated with local anesthetics used in dentistry METHODS: The study included data sets of annual sales of local anesthetics (from 1995 through 2007), 292 reports to the Danish Medicines Agency, Copenhagen, Denmark, of adverse reactions to local anesthetic drugs, and a clinical sample of 115 patients with NSD associated with local anesthetics. The authors assessed lidocaine 2 percent, mepivacaine 2 percent and 3 percent, prilocaine 3 percent, and articaine 4 percent sold in cartridges. RESULTS: The study results showed a highly significant overrepresentation of NSDs associated with articaine 4 percent, in particular with mandibular blocks. CONCLUSIONS: The distribution of NSDs was disproportionate to the market share of three of the four drugs in both national registry data and clinical data. These findings indicate that the main cause of injury was neurotoxicity resulting from administration of the local anesthetic rather than the needle penetration. CLINICAL IMPLICATIONS: Clinicians may consider avoiding use of high-concentration (4 percent) anesthetic formulations for block anesthesia in the trigeminal area in cases in which there are viable alternatives. PMID- 21531937 TI - Glass ionomer cement and resin-based fissure sealants are equally effective in caries prevention. PMID- 21531936 TI - Wisconsin Medicaid enrollees' recurrent use of emergency departments and physicians' offices for treatment of nontraumatic dental conditions. AB - BACKGROUND: Medicaid enrollees experience a number of barriers that prevent them from seeking care in dental offices, leading some to repeatedly seek treatment for nontraumatic dental conditions (NTDCs) in emergency departments (EDs) and physicians' offices (POs). The authors examined the rate of return visits to EDs and POs for treatment of NTDCs among Wisconsin Medicaid enrollees and sought to characterize frequent and typical users of such care in this population. METHODS: The authors conducted a retrospective analysis of all Wisconsin Medicaid dental claims for NTDCs to EDs and POs from 2001 through 2003. They used finite mixture models, allowing for covariate dependence, to model separate rates of return for NTDC-related visits corresponding to typical and frequent users of EDs and POs. RESULTS: Overall, 23,999 enrollees had made NTDC-related visits to EDs and POs, with 6.5 percent estimated to be frequent users of such care. Typical and frequent users had a mean (+/- standard error) rate of return visits of 0.2 +/- 0.01 and 4.0 +/- 0.08 per year, respectively. Male enrollees and people aged 19 to 42 years were more likely to be frequent users, with African American and Hispanic enrollees having lower odds of being frequent users than did white enrollees. The effect of living in an area with a shortage of dental health care professionals did not affect the likelihood of being a frequent user of EDs and POs for such care. CONCLUSIONS: Male and middle-aged enrollees were significantly more likely to be frequent users of EDs and POs for treatment of NTDCs. Compared with white enrollees, African American and Hispanic enrollees were less likely to be frequent users and had lower rates of recurrent visits for NTDCs among typical users. CLINICAL IMPLICATIONS: Improved access to dental care for Medicaid enrollees that is best managed by dental care providers should reduce the rates of recurrent NTDC-related visits to EDs and POs. PMID- 21531938 TI - From conflict to consensus. PMID- 21531939 TI - For the dental patient: oral health during pregnancy. PMID- 21531940 TI - A convincing case--for the psychologically informed physical therapist. PMID- 21531941 TI - Psychosocial influences on low back pain: why should you care? PMID- 21531942 TI - Invited commentary. PMID- 21531943 TI - On "Supervised exercises compared with radial extracorporeal shock-wave therapy..." Engebretsen K, Grotle M, Bautz-Holter E, et al. Phys Ther. 2011;91:37 47. PMID- 21531944 TI - Erythroid phenotypes associated with KLF1 mutations. PMID- 21531945 TI - JAK2V617F/TET2 mutations: does the order matter? PMID- 21531946 TI - Impact of molecular prognostic factors in cytogenetically normal acute myeloid leukemia at diagnosis and relapse. PMID- 21531947 TI - Life beyond the disease: relationships, parenting, and quality of life among survivors of childhood cancer. PMID- 21531948 TI - ATS International Conference preview: where today's science will meet tomorrow's care. PMID- 21531949 TI - Polymorphonuclear neutrophils move into the fast lane in chronic obstructive pulmonary disease. PMID- 21531950 TI - A metabolic window into acute respiratory distress syndrome: stretch, the "baby" lung, and atelectrauma. PMID- 21531951 TI - Strengths and limitations of the six-minute-walk test: a model biomarker study in idiopathic pulmonary fibrosis. PMID- 21531952 TI - Pro: the illegitimate crusade against corticosteroids for severe H1N1 pneumonia. PMID- 21531953 TI - Con: corticosteroids are not indicated for treatment of acute lung injury from H1N1 viral pneumonia. PMID- 21531954 TI - Update in acute lung injury and critical care 2010. PMID- 21531956 TI - Common drive in hypoglossal and trigeminal motor neurons. PMID- 21531955 TI - An official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome. AB - RATIONALE: Acute lung dysfunction of noninfectious etiology, known as idiopathic pneumonia syndrome (IPS), is a severe complication following hematopoietic stem cell transplantation (HSCT). Several mouse models have been recently developed to determine the underlying causes of IPS. A cohesive interpretation of experimental data and their relationship to the findings of clinical research studies in humans is needed to better understand the basis for current and future clinical trials for the prevention/treatment of IPS. OBJECTIVES: Our goal was to perform a comprehensive review of the preclinical (i.e., murine models) and clinical research on IPS. METHODS: An ATS committee performed PubMed and OVID searches for published, peer-reviewed articles using the keywords "idiopathic pneumonia syndrome" or "lung injury" or "pulmonary complications" AND "bone marrow transplant" or "hematopoietic stem cell transplant." No specific inclusion or exclusion criteria were determined a priori for this review. MEASUREMENTS AND MAIN RESULTS: Experimental models that reproduce the various patterns of lung injury observed after HSCT have identified that both soluble and cellular inflammatory mediators contribute to the inflammation engendered during the development of IPS. To date, 10 preclinical murine models of the IPS spectrum have been established using various donor and host strain combinations used to study graft-versus-host disease (GVHD). This, as well as the demonstrated T cell dependency of IPS development in these models, supports the concept that the lung is a target of immune-mediated attack after HSCT. The most developed therapeutic strategy for IPS involves blocking TNF signaling with etanercept, which is currently being evaluated in clinical trials. CONCLUSIONS: IPS remains a frequently fatal complication that limits the broader use of allogeneic HSCT as a successful treatment modality. Faced with the clinical syndrome of IPS, one can categorize the disease entity with the appropriate tools, although cases of unclassifiable IPS will remain. Significant research efforts have resulted in a paradigm shift away from identifying noninfectious lung injury after HSCT solely as an idiopathic clinical syndrome and toward understanding IPS as a process involving aspects of both the adaptive and the innate immune response. Importantly, new laboratory insights are currently being translated to the clinic and will likely prove important to the development of future strategies to prevent or treat this serious disorder. PMID- 21531957 TI - ABPA or AFAA: That Is the Question. PMID- 21531958 TI - An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. AB - Acute lung injury (ALI) is well defined in humans, but there is no agreement as to the main features of acute lung injury in animal models. A Committee was organized to determine the main features that characterize ALI in animal models and to identify the most relevant methods to assess these features. We used a Delphi approach in which a series of questionnaires were distributed to a panel of experts in experimental lung injury. The Committee concluded that the main features of experimental ALI include histological evidence of tissue injury, alteration of the alveolar capillary barrier, presence of an inflammatory response, and evidence of physiological dysfunction; they recommended that, to determine if ALI has occurred, at least three of these four main features of ALI should be present. The Committee also identified key "very relevant" and "somewhat relevant" measurements for each of the main features of ALI and recommended the use of least one "very relevant" measurement and preferably one or two additional separate measurements to determine if a main feature of ALI is present. Finally, the Committee emphasized that not all of the measurements listed can or should be performed in every study, and that measurements not included in the list are by no means "irrelevant." Our list of features and measurements of ALI is intended as a guide for investigators, and ultimately investigators should choose the particular measurements that best suit the experimental questions being addressed as well as take into consideration any unique aspects of the experimental design. PMID- 21531960 TI - Guest editorial: policy strategies for reducing health disparities. PMID- 21531959 TI - Pregnancy and fetal outcome in women with primary Sjogren's syndrome compared with women in the general population: a nested case-control study. AB - OBJECTIVE: To study pregnancy and fetal outcome in women with primary SS (pSS) compared with women in the general population. METHODS: In a nested case-control setting, variables related to pregnancy and fetal outcomes were compared. Cases (n = 16) were identified through registry linkage (Malmo pSS registry and a database entailing information of all pregnancies and deliveries in Malmo from 1990 through 2006). For each pregnancy with pSS, the following five deliveries from the same registry were chosen as controls (n = 80). RESULTS: All cases fulfilled the American European Consensus Criteria for pSS and were positive for ANA and anti-SSA antibodies. Date of diagnosis was before pregnancy in 10 women and after delivery in 6. Mean age at delivery was significantly higher in women with pSS (33.6 years) vs controls (29.8 years). While pregnancy duration did not differ, mean birthweight was significantly lower in offspring of pSS mothers (3010 g) vs babies of control mothers (3458 g). Normal partus in contrast to vacuum extraction or Caesarean section was significantly more frequent in healthy women than in pSS women (83 vs 56%). Other pregnancy outcomes such as parity, miscarriages and Apgar score did not differ. There were no significant differences between women with a pSS diagnosis before or after the index pregnancy. Only one of the included pregnancies was complicated by intrauterine AV block. CONCLUSION: Pregnancy occurs later in life in pSS women. Mothers with pSS give birth to offspring with lower birthweight and less commonly have normal partus. PMID- 21531961 TI - Medicaid and state regulation of nurse-midwives: the challenge of data retrieval. AB - This article discusses one of four findings of a larger descriptive correlational health policy study, the purpose of which was to investigate relationships among state regulation of nurse-midwifery practice, utilization of certified nurse midwives (CNM) for Medicaid funded prenatal care, and maternal newborn outcomes. The larger study showed that use of accurate data about CNM practice and subsequent health care outcomes creates a challenge for researchers because of the paucity of data related to services provided by CNMs. Barriers to adequate data collection related to CNM services, specifically those funded by Medicaid, preclude legitimate conclusions about subsequent health care policy. Methods of workforce data collection need to be addressed by health care and health policy groups to facilitate further investigation of the relationships among state regulation of CNM practice, utilization of CNMs for Medicaid-funded prenatal care and maternal newborn outcomes as they affect access to care for vulnerable populations. PMID- 21531962 TI - Removing barriers to APRN practice in the state of Hawai'i. AB - An informal coalition of nurses, educators, health care providers and policy makers recognizing that administrative rules for advanced practice registered nurse (APRN) practice limited consumer access to care in Hawai'i, developed an initiative to bring about legislative and regulatory change using the National Council of State Boards of Nursing APRN Scope of Nursing Practice and Standards Related to the APRN. The authors report on the process including challenges and keys to success toward the passage of Hawai'i Act 169 (2009). The authors also discuss key components of the legislation, which removed barriers to full scope of practice for APRNs. The potential for comprehensive reform was realized due to the actions of a broad coalition in support of increasing access to care for underserved and rural populations in Hawai'i. PMID- 21531963 TI - Care coordination: a priority for health reform. AB - Care coordination is one of the priorities to transform the health care system (Institute of Medicine). Nurses have taken on the central role in care coordination for decades, and are now being recognized for expertise in care coordination. Attention has focused on nursing models that use care coordination and report outcomes. Nursing care coordination models emphasize patient education, engagement of patients and families in prevention, self-care, and adoption of health information technology to improve access to information. Policy recommendations needed to enhance care coordination include the following: (a) facilitate better information transfer with wider use of information technology, (b) include Nurse Practitioners (NPs) as equal practitioners in reimbursement, (c) create incentives to improve coordination of care, (d) reward the use of evidence-based practices, and (e) advocate for better care coordination models that include interdisciplinary teams and greater health system integration. PMID- 21531964 TI - Recruiting and retaining a diverse workforce in nursing: from evidence to best practices to policy. AB - Health policy makers, providers, clinicians, and social scientists are among those who have identified racial and ethnic diversification of the health care workforce as one strategy for solving the seemingly intractable problem of health disparities in the U.S. population. But evidence supporting the impact of such diversification on narrowing health disparities is lacking, thus making it unclear if the push for workforce diversification is empirically or politically driven. Moreover, data are largely derived from the study of physicians, making it difficult to generalize findings to nursing and other health professions. This article reviews the evidence that supports the impact of a diverse workforce on patient outcomes and delivery services. Assuming a positive social value in the absence of the data, the authors review the approaches that have been successful in diversifying the nursing workforce. The authors conclude with recommendations for research and policies, including best practices, for enhancing recruitment and retention of a diverse nursing workforce. PMID- 21531965 TI - Do smoke-free laws in rural, distressed counties encourage cessation? AB - The authors examined the association between smoke-free laws and smoking/cessation behaviors and secondhand smoke exposure among current and former smokers in rural, distressed counties. A quasi-experimental, two-group design compared outcomes between participants from a county with a longstanding smoke-free law (n = 252) and those living in four demographically similar counties without smoke-free laws ( n = 250). Participants were recruited using random digit dialing. Controlling for demographic factors, those in the treatment group reported greater nicotine dependence, were more likely to have smoke-free workplaces, and less likely to have smoke-free homes. There were no differences in smoking status, past-year quit attempts, intent to quit in 5 years, cigarettes per day, or time since last cigarette. Smokers in the treatment group were just as likely to attempt to quit, despite greater nicotine dependence. Findings showed that making nonsmoking the social norm through policy change may be more difficult in rural, distressed areas. PMID- 21531967 TI - Walking the talk: insights into dynamics of race and gender for nurses. AB - This article explores how the dynamics of violence and support for nurses are influenced by the intersections of race, gender, and other social relations in various practice settings. Utilizing a qualitative study design, situated in the naturalistic and critical paradigms, this article is grounded in the experiences of key informants (KIs), each possessing significant expertise on issues of equity and violence, as well as insight into the current practice settings in Ontario, Canada. The individual KI interviews were analyzed using conventional qualitative content analysis, with its focus on capturing emerging insights. The findings reflect the everyday nature of gendered and racialized violence, the influence of setting and the effectiveness of existing resources. Professional, organizational, and broader policy implications are discussed to support diversely situated nurses within their various practice environments. PMID- 21531966 TI - Medicare readmissions policies and racial and ethnic health disparities: a cautionary tale. AB - Beginning in 2009, the Centers for Medicare & Medicaid Services started publicly reporting hospital readmission rates as part of the Hospital Compare website. Hospitals will begin having payments reduced if their readmission rates are higher than expected starting in fiscal year 2013. Value-based purchasing initiatives including public reporting and pay-for-performance incentives have the potential to increase quality of care. There is concern, however, that hospitals providing service to minority communities may be disproportionately penalized as a result of these policies due to higher rates of readmissions among racial and ethnic minority groups. Using 2008 Medicare data, we assess the risk for readmission for minorities and discuss implications for minority-serving institutions. PMID- 21531969 TI - DIC and granulomatous vasculitis in a dog with disseminated histoplasmosis. AB - Disseminated histoplasmosis and disseminated intravascular coagulopathy were diagnosed in a 7 mo old, female spayed mixed-breed dog. The dog improved transiently with supportive care, but deteriorated shortly after initiation of antifungal therapy. The dog was subsequently euthanized. At necropsy, marked granulomatous vasculitis was identified in all affected organs. The tunicae and laminae of the arteries and arterioles were obscured by epithelioid macrophages and multinucleated giant cells admixed with necrotic material. Intracytoplasmic yeast were present within some of these macrophages. To the authors' knowledge, this is the first reported case of granulomatous vasculitis associated with Histoplasma capsulatum in a dog. PMID- 21531970 TI - Segmental jejunal entrapment, volvulus, and strangulation secondary to intra abdominal adhesions in a dog. AB - A 4 yr old, castrated male dachshund was presented for lethargy, restlessness, a "hunched" posture, and a painful abdomen. A gastric foreign body had been surgically removed 24 mo previously. Exploratory celiotomy revealed a devitalized segment of jejunum with twisted mesentery. Several adhesions and fibrous bands were present within the abdomen, presumptively from the previous gastric foreign body surgery. Histopathology determined that a fibrous tissue band caused entrapment of the segment of intestine and its mesentery resulting in volvulus and ischemic necrosis of the intestine. This case is unique because it involved a focal area of the jejunum that was incarcerated in fibrous adhesions. PMID- 21531971 TI - Disseminated histoplasmosis accompanied by cutaneous fragility in a cat. AB - A 4 yr old, spayed female domestic shorthair was referred with a 2 mo history of weight loss, anorexia, and diarrhea. Skin fragility was noted on presentation and a large skin tear measuring 5 cm * 5 cm was obvious over the dorsal cervical region. The patient was previously treated with short-term prednisone that was discontinued 6 wk before presentation. Initial diagnostics (complete blood count and biochemistry) did not indicate an endocrine disorder, the most common cause of acquired feline skin fragility. Necropsy revealed diffuse histoplasmosis (most significantly affecting the skin), epidermal atrophy, dermal collagen separation, and infiltration in the dermis and subcutis by inflammatory cells containing yeast organisms consistent with Histoplasma spp. Infiltrative fungal infection should be considered as a potential cause of acquired feline skin fragility. PMID- 21531974 TI - Fracture patterns of the nasal septum. PMID- 21531972 TI - Bioidentical hormone therapy. AB - The change in hormonal milieu associated with perimenopause and menopause can lead to a variety of symptoms that can affect a woman's quality of life. Postmenopausal hormone therapy (HT) is an effective, well-tolerated treatment for these symptoms. However, combined HT consisting of conjugated equine estrogen and medroxyprogesterone acetate has been associated with an increased number of health risks when compared with conjugated equine estrogen alone or placebo. As a result, some women are turning to alternative hormonal formulations known as compounded bioidentical HT because they perceive them to be a safer alternative. This article defines compounded bioidentical HT and explores the similarities and differences between it and US Food and Drug Administration-approved HT. We will examine the major claims made by proponents of compounded bioidentical HT and recommend strategies for management of patients who request bioidentical HT from physicians. PMID- 21531977 TI - IL-7 receptor expression identifies suicide gene-modified allospecific CD8+ T cells capable of self-renewal and differentiation into antileukemia effectors. AB - In allogeneic hematopoietic cell transplantation (HSCT), donor T lymphocytes mediate the graft-versus-leukemia (GVL) effect, but induce graft-versus-host disease (GVHD). Suicide gene therapy-that is, the genetic induction of a conditional suicide phenotype into donor T cells-allows dissociating the GVL effect from GVHD. Genetic modification with retroviral vectors after CD3 activation reduces T-cell alloreactivity. We recently found that alloreactivity is maintained when CD28 costimulation, IL-7, and IL-15 are added. Herein, we used the minor histocompatibility (mH) antigens HA-1 and H-Y as model alloantigens to directly explore the antileukemia efficacy of human T cells modified with the prototypic suicide gene herpes simplex virus thymidine kinase (tk) after activation with different stimuli. Only in the case of CD28 costimulation, IL-7, and IL-15, the repertoire of tk(+) T cells contained HA-1- and H-Y-specific CD8(+) cytotoxic T cells (CTL) precursors. Thymidine kinase-positive HA-1- and H Y-specific CTLs were capable of self-renewal and differentiation into potent antileukemia effectors in vitro, and in vivo in a humanized mouse model. Self renewal and differentiation coincided with IL-7 receptor expression. These results pave the way to the clinical investigation of T cells modified with a suicide gene after CD28 costimulation, IL-7, and IL-15 for a safe and effective GVL effect. PMID- 21531978 TI - R723, a selective JAK2 inhibitor, effectively treats JAK2V617F-induced murine myeloproliferative neoplasm. AB - The activating mutations in JAK2 (including JAK2V617F) that have been described in patients with myeloproliferative neoplasms (MPNs) are linked directly to MPN pathogenesis. We developed R723, an orally bioavailable small molecule that inhibits JAK2 activity in vitro by 50% at a concentration of 2nM, while having minimal effects on JAK3, TYK2, and JAK1 activity. R723 inhibited cytokine independent CFU-E growth and constitutive activation of STAT5 in primary hematopoietic cells expressing JAK2V617F. In an anemia mouse model induced by phenylhydrazine, R723 inhibited erythropoiesis. In a leukemia mouse model using Ba/F3 cells expressing JAK2V617F, R723 treatment prolonged survival and decreased tumor burden. In V617F-transgenic mice that closely mimic human primary myelofibrosis, R723 treatment improved survival, hepatosplenomegaly, leukocytosis, and thrombocytosis. R723 preferentially targeted the JAK2-dependent pathway rather than the JAK1- and JAK3-dependent pathways in vivo, and its effects on T and B lymphocytes were mild compared with its effects on myeloid cells. Our preclinical data indicate that R723 has a favorable safety profile and the potential to become an efficacious treatment for patients with JAK2V617F positive MPNs. PMID- 21531979 TI - Autoimmunity associated with immunotherapy of cancer. AB - In this age of promise of new therapies for cancer, immunotherapy is emerging as an exciting treatment option for patients. Vaccines and cytokines are being tested extensively in clinical trials, and strategies using monoclonal antibodies and cell transfer are mediating dramatic regression of tumors in patients with certain malignancies. However, although initially advocated as being more specific for cancer and having fewer side effects than conventional therapies, it is becoming increasingly clear that many immunotherapies can lead to immune reactions against normal tissues. Immunotoxicities resulting from treatment can range from relatively minor conditions, such as skin depigmentation, to severe toxicities against crucial organ systems, such as liver, bowel, and lung. Treatment-related toxicity has correlated with better responses in some cases, and it is probable that serious adverse events from immune-mediated reactions will increase in frequency and severity as immunotherapeutic approaches become more effective. This review introduces immunotherapeutic approaches to cancer treatment, provides details of toxicities arising from therapy, and discusses future potential ways to avoid or circumvent these side effects. PMID- 21531980 TI - Incidence of the myelodysplastic syndromes using a novel claims-based algorithm: high number of uncaptured cases by cancer registries. AB - The myelodysplastic syndromes (MDSs) are hematologically diverse hematopoietic stem cell malignancies primarily affecting older individuals. The incidence of MDS in the United States is estimated at 3.3 per 100 000; however, evidence suggests underreporting of MDS to centralized cancer registries. Contrary to clinical recommendations, registry guidelines from 2001-2010 required the capture of only one malignancy in the myeloid lineage and did not require blood count (BC) or bone marrow (BM) biopsy for MDS confirmation. To address these potential limitations, we constructed 4 claims-based algorithms to assess MDS incidence, applied the algorithms to the 2000-2008 Surveillance Epidemiology and End Results (SEER)-Medicare database, and assessed algorithm validity using SEER-registered MDS cases. Each algorithm required one or more MDS claims and accounted for recommended diagnostic services during the year before the first claim: 1+, 2+, 2 + BC, and 2 + BCBM (ordered by sensitivity). Each had moderate sensitivities (78.05%-92.90%) and high specificities (98.49%-99.84%), with the 2 + BCBM algorithm demonstrating the highest specificity. Based on the 2 + BCBM algorithm, the annual incidence of MDS is 75 per 100 000 persons 65 years or older-much higher than the 20 per 100 000 reported by SEER using the same sample. PMID- 21531982 TI - Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression. AB - Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with increased production of terminally differentiated cells. The disease course is generally chronic, but some patients show disease progression (secondary myelofibrosis or accelerated phase) and/or leukemic transformation. We investigated chromosomal aberrations in 408 MPN samples using high-resolution single-nucleotide polymorphism microarrays to identify disease associated somatic lesions. Of 408 samples, 37.5% had a wild-type karyotype and 62.5% harbored at least 1 chromosomal aberration. We identified 25 recurrent aberrations that were found in 3 or more samples. An increased number of chromosomal lesions was significantly associated with patient age, as well as with disease progression and leukemic transformation, but no association was observed with MPN subtypes, Janus kinase 2 (JAK2) mutational status, or disease duration. Aberrations of chromosomes 1q and 9p were positively associated with disease progression to secondary myelofibrosis or accelerated phase. Changes of chromosomes 1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q were positively associated with post-MPN acute myeloid leukemia. We mapped commonly affected regions to single target genes on chromosomes 3p (forkhead box P1 [FOXP1]), 4q (tet oncogene family member 2 [TET2]), 7p (IKAROS family zinc finger 1 [IKZF1]), 7q (cut-like homeobox 1 [CUX1]), 12p (ets variant 6 [ETV6]), and 21q (runt-related transcription factor 1 [RUNX1]). Our data provide insight into the genetic complexity of MPNs and implicate new genes involved in disease progression. PMID- 21531981 TI - Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived beta-glucans. AB - beta-glucans have been reported to function as a potent adjuvant to stimulate innate and adaptive immune responses. However, beta-glucans from different sources are differential in their structure, conformation, and thus biologic activity. Different preparations of beta-glucans, soluble versus particulate, further complicate their mechanism of action. Here we show that yeast-derived particulate beta-glucan activated dendritic cells (DCs) and macrophages via a C type lectin receptor dectin-1 pathway. Activated DCs by particulate beta-glucan promoted Th1 and cytotoxic T-lymphocyte priming and differentiation in vitro. Treatment of orally administered yeast-derived particulate beta-glucan elicited potent antitumor immune responses and drastically down-regulated immunosuppressive cells, leading to the delayed tumor progression. Deficiency of the dectin-1 receptor completely abrogated particulate beta-glucan-mediated antitumor effects. In contrast, yeast-derived soluble beta-glucan bound to DCs and macrophages independent of the dectin-1 receptor and did not activate DCs. Soluble beta-glucan alone had no therapeutic effect but significantly augmented antitumor monoclonal antibody-mediated therapeutic efficacy via a complement activation pathway but independent of dectin-1 receptor. These findings reveal the importance of different preparations of beta-glucans in the adjuvant therapy and allow for the rational design of immunotherapeutic protocols usable in clinical trials. PMID- 21531983 TI - Integrating diverse databases into an unified analysis framework: a Galaxy approach. AB - Recent technological advances have lead to the ability to generate large amounts of data for model and non-model organisms. Whereas, in the past, there have been a relatively small number of central repositories that serve genomic data, an increasing number of distinct specialized data repositories and resources have been established. Here, we describe a generic approach that provides for the integration of a diverse spectrum of data resources into a unified analysis framework, Galaxy (http://usegalaxy.org). This approach allows the simplified coupling of external data resources with the data analysis tools available to Galaxy users, while leveraging the native data mining facilities of the external data resources. DATABASE URL: http://usegalaxy.org. PMID- 21531986 TI - Nerve injury triggers changes in the brain. AB - It is well known that the adult brain is capable of profound plasticity. Much of our understanding of the mechanisms underlying injury-induced changes in the brain is based on animal models. The development of sophisticated noninvasive neuroimaging techniques over the past decade provides a unique opportunity to examine brain plasticity in humans. In this article, the authors examine the consequences of nerve injury and surgical repair on peripheral nerve degeneration and regeneration and review classic animal literature that laid the foundation of injury-induced plasticity research. They relate these concepts to recent findings of functional and structural changes in the human brain following peripheral nerve injury. They then present a working theoretical model that links behavioral outcomes of nerve injury with functional and structural brain plasticity and personality. PMID- 21531987 TI - Endocannabinoids and retrograde modulation of synaptic transmission. AB - Since the first reports of endocannabinoid-mediated retrograde signaling in 2001, great advances have been made toward understanding the molecular basis and functions of the endocannabinoid system. Electrophysiological studies have revealed that the endocannabinoid system is functional at various types of synapses throughout the brain. Basic mechanisms have been clarified as to how endocannabinoids are produced and released from postsynaptic neurons and regulate neurotransmitter release through activating presynaptic cannabinoid CB(1) receptors, although there remain unsolved questions and some discrepancies. In addition to this major function, recent studies suggest diverse functions of endocannabinoids, including control of other endocannabinoid-independent forms of synaptic plasticity, regulation of neuronal excitability, stimulation of glia neuron interaction, and induction of CB(1)R-independent plasticity. Using recently developed pharmacological and genetic tools, behavioral studies have elucidated the roles of the endocannabinoid system in various aspects of neural functions. In this review, we make a brief overview of molecular mechanisms underlying the endocannabinoid-mediated synaptic modulation and also summarize recent findings, which shed new light on a diversity of functional roles of endocannabinoids. PMID- 21531988 TI - Hippocampal volume reduction in first-episode and chronic schizophrenia: a review and meta-analysis. AB - Several magnetic resonance imaging studies have reported hippocampal volume reduction in patients with schizophrenia, but other studies have reported contrasting results. In this review and meta-analysis, the authors aim to clarify whether a reduction in hippocampal volume characterizes patients with schizophrenia by considering illness phase (chronic and first episode) and hippocampus side separately. They made a detailed literature search for studies reporting physical volumetric hippocampal measures of patients with schizophrenia and healthy control (HC) participants and found 44 studies that were eligible for meta-analysis. Individual meta-analyses were also performed on 13 studies of first-episode patients and on 22 studies of chronic patients. The authors also detected any different findings when only males or both males and females were considered. Finally, additional meta-analyses and analyses of variance investigated the role of the factors "illness phase" and "side" on hippocampal volume reduction. Overall, the patient group showed significant bilateral hippocampal volume reduction compared with HC. Interestingly, first-episode and chronic patients showed same-size hippocampal volume reduction. Moreover, the left hippocampus was smaller than the right hippocampus in patients and HC. This review and meta-analysis raises the question about whether hippocampal volume reduction in schizophrenia is of neurodevelopmental origin. Future studies should specifically investigate this issue. PMID- 21531985 TI - The aging hippocampus: interactions between exercise, depression, and BDNF. AB - Late adulthood is associated with increased hippocampal atrophy and dysfunction. Although there are multiple paths by which hippocampal deterioration occurs in late life, the authors discuss the evidence that a single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene and age-related changes in BDNF protein or receptor expression contribute to hippocampal atrophy. The authors conclude that few studies have tested whether BDNF mediates age-related hippocampal atrophy and memory impairment. However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. Importantly, the most consistent associations between BDNF and hippocampal dysfunction have emerged from research on BDNF protein expression in rodents and serum and plasma concentrations of BDNF in humans. Current research suggests that the BDNF val66met polymorphism may be only weakly associated with hippocampal atrophy in late adulthood. These conclusions are interpreted in relation to age-related memory impairment and preventions for hippocampal atrophy. PMID- 21531989 TI - A brief questionnaire for assessing patient healthcare experiences in low-income settings. AB - OBJECTIVE: The aim of this study was to develop and to assess the validity and reliability of two brief questionnaires for assessing patient experiences with hospital and outpatient care in a low-income setting. DESIGN: Using literature review and data from focus groups (n = 14), we developed questionnaires to assess patient experiences with inpatient (I-PAHC) and with outpatient (O-PAHC) care in a low-income setting. Questionnaires were administered in person by trained interviewers. Construct validity was assessed with factor analysis; convergent validity was assessed by correlating summary scores for each scale with overall patient evaluations, and reliability was assessed with Cronbach's alpha coefficients. SETTING: Eight health facilities in Ethiopia. PARTICIPANTS: Patients >18 years old who had a hospital stay >1 day (n = 230), and patients who received outpatient care (n = 486). MAIN OUTCOME MEASURES: Patient evaluations of health care experiences. RESULTS: The factor analysis revealed 12 items that loaded on five factors for the I-PAHC questionnaire. The O-PAHC showed similar results with 13 items that loaded on four factors. Summary scores for nearly all factors were significantly associated (P-value < 0.05) with the patient's overall evaluation score. The measure of reliability, Cronbach's alpha coefficients, showed good to excellent internal consistency for all scales. CONCLUSIONS: The I PAHC on O-PAHC questionnaires can be useful in assessing patients' evaluations of care delivery in low-income settings. The questionnaires are brief and can be integrated into health systems strengthening efforts with the support of leadership at the health facility and the country levels. PMID- 21531990 TI - Effect of reproductive tract environment following controlled ovarian hyperstimulation treatment on embryo development and global transcriptome profile of blastocysts: implications for animal breeding and human assisted reproduction. AB - BACKGROUND: In mammals, the reproductive tract plays a crucial role in the success of early reproductive events and provides an optimal microenvironment for early embryonic development. However, changes in the reproductive tract environment associated with controlled ovarian hyperstimulation and the influence on the embryo transcriptome profile have not been investigated. Therefore, we investigated differences in the development rate and the transcriptome profile of bovine blastocysts developing in the reproductive tract of unstimulated or superovulated heifers. METHODS: Nineteen Simmental heifers were synchronized, superovulated and artificially inseminated; nine heifers were flushed on Day 2 after insemination and 2-4-cell stage embryos were recovered and endoscopicaly transferred to the ipsilateral oviduct of unstimulated (i.e. single-ovulating) synchronized recipients (n= 4 recipients; 25-50 embryos per recipient). The remaining 10 superovulated heifers and the unstimulated recipients were then non surgically flushed on Day 7 to collect embryos. The blastocyst transcriptome profile was examined using the Affymetrix GeneChip Bovine Genome Array. RESULTS: The proportion of embryos, which developed to the blastocyst stage, was lower in superovulated heifers than unstimulated heifers (P< 0.05). Blastocysts that developed under the abnormal endocrine conditions associated with ovulation induction showed higher cellular and metabolic activities, as genes involved in the oxidative phosphorylation pathway, different metabolic processes and translation and transcription processes, in addition to genes expressed in response to stress, were highly expressed compared with embryos that developed in the oviduct of unstimulated animals. CONCLUSIONS: The environment in which the embryo develops in the oviduct/uterus significantly alters gene expression patterns, especially those genes that regulate metabolic activity in the embryo. PMID- 21531991 TI - Editorial commentary: do not put all your eggs in one basket. PMID- 21531992 TI - In situ visualization of damaged DNA in human sperm by Raman microspectroscopy. AB - BACKGROUND: Beyond determining the percentage of damaged sperm, current methods of DNA assessment are of limited clinical utility as they render the sample unusable. We evaluated Raman microspectroscopy, a laser-based non-invasive technique that provides detailed chemical 'fingerprints' of cells and which potentially could be used for nuclear DNA-based sperm selection. METHODS: Eight healthy donors provided ejaculates. After system optimization, a minimum of 200 air-dried sperm/sample/donor, prior to/and after UVB irradiation, were assessed by two observers. Spectra were analysed by Principal Component, Spectral Angle and Wavelet Analyses. RESULTS: Spectra provided a chemical map delineating each sperm head region. Principal Component Analysis showed clear separation between spectra from UV-irradiated and untreated samples whilst averaged data identified two regions of interest (1040 and 1400 cm(-1)). Local spectral analysis around the DNA PO(4) backbone peak (1042 cm(-1)), showed that changes in this region were indicative of DNA damage. Wavelet decomposition confirmed both the 1042 cm( 1) shift and a second UVB susceptible region (1400-1600 cm(-1)) corresponding to protein-DNA interactions. No difference was found between observer measurements. CONCLUSIONS: Raman microspectroscopy can provide accurate and reproducible assessment of sperm DNA structure and the sites and location of damage. PMID- 21531993 TI - Follow-up of children born after ICSI with epididymal spermatozoa. AB - BACKGROUND: To evaluate the safety of ICSI with epididymal sperm, this study compared children born after ICSI treatment with epididymal sperm and children conceived after IVF and ICSI with ejaculated sperm. Additionally, the results of a multidisciplinary, multicentre follow-up of the children conceived with epididymal sperm at 2 years of age are described. METHODS: This follow-up study included 378 children conceived after ICSI with epididymal sperm (percutaneous epididymal sperm aspiration: PESA group) and a control group of 1192 IVF and 1126 ICSI (with ejaculated sperm) children, all with a gestational age of 20 weeks or more. Questionnaires were sent at birth, 1 year and 4 years of age, collecting data on parental, pregnancy and child factors. A total of 148 PESA children were assessed at 2 years of age for motor performance, mental- and language development and compared with the Dutch norms. RESULTS: PESA children showed no increased risks for stillbirths, total deaths and malformations. They also did not differ from IVF and ICSI children in gender rate, birthweight and gestational age. The mental Bayley score was higher (P < 0.05) for PESA singletons and parents reported fewer (P < 0.05) behavioural problems in the PESA group than the Dutch reference group. The scores for syntactic and lexical development for the PESA singletons were better (P < 0.05) than the Dutch standards. CONCLUSIONS: ICSI with epididymal sperm does not lead to more stillbirths or congenital malformations in comparison to IVF and ICSI with ejaculated sperm and does not lead to poor development in comparison with the Dutch reference group. PMID- 21531994 TI - Live birth chances in women with extremely low-serum anti-Mullerian hormone levels. AB - BACKGROUND: To determine whether women with extremely low-serum anti-Mullerian hormone (AMH) levels (<0.1-0.4 ng/ml) still demonstrate live birth potential with assisted reproduction and whether such potential is age dependent. METHODS: Between January 2006 and October 2009, 128 consecutive infertility patients with AMH <=0.4 ng/ml were retrospectively evaluated for pregnancy chances and live birth rates after IVF. RESULTS: Patients presented at a mean (+/-SD) age of 40.8 +/- 4.1 years, with mean (+/-SD) baseline FSH of 15.7 +/- 11.1 mIU/ml and mean (+/-SD) AMH of 0.2 +/- 0.1 ng/ml. One hundred and twenty-eight women underwent a total of 254 IVF cycles. Twenty clinical pregnancies were recorded (7.9% per cycle start [95% confidence interval (CI): 4.9-11.9%]; 15.6% cumulative [CI: 9.8 23.1%]). These pregnancies resulted in 13 live births in 12 women (i.e. 11 singletons and a pair of twins) and 8 patients miscarried. Eight deliveries occurred after the first cycle (6.3% per cycle start) and four after subsequent IVF cycles (3.2%). When evaluated according to female age, 70 women <=42 years presented with 16 clinical pregnancies that resulted in 10 deliveries (14.3%), while 58 patients >42 years presented with four clinical pregnancies that resulted in 2 deliveries (3.4%), representing a reduced pregnancy chance (P = 0.013) and delivery rate (P = 0.036) versus age <=42 years. CONCLUSIONS: With extremely low-serum AMH levels, moderate, but reasonable pregnancy and live birth rates are still possible. Extremely low AMH levels do not seem to represent an appropriate marker for withholding fertility treatment. PMID- 21531995 TI - Clinical impact of scavenger receptor class B type I gene polymorphisms on human female fertility. AB - BACKGROUND: The goal of this study was to evaluate the association of SCARB1 single nucleotide polymorphisms (SNPs) and fertility outcomes in women undergoing IVF. METHODS: Between November 2007 and March 2010, granulosa cells and follicular fluid were collected from women undergoing IVF. Five SCARB1 SNPs were sequenced and progesterone levels were measured in the follicular fluid. Fertility measurements were defined as the presence of gestational sac(s) and fetal heartbeat(s). RESULTS: The study group consisted of 274 women (mean age of 36.4 +/- 4.6 years). The racial/ethnic composition was 55% Caucasian (n = 152), 25% African-American (n = 68), 12% Asian (n = 34), 5% Hispanic, (n = 14) and 2% other (n = 6). There was a significant difference in the genotype frequencies of the SCARB1 SNPs across the groups. Subjects who were homozygous for the minor allele in the rs5888 SNP had higher follicular progesterone levels than those who were homozygous for the major allele (P = 0.03). In the Caucasian group, carriers of the minor A allele of the rs4238001 SNP had lower follicular progesterone levels compared with homozygous carriers of the major G allele (P = 0.04). In this group, follicular progesterone levels were highly predictive of the rs4238001 SNP (P = 0.03). In the entire cohort, minor allele carriers of rs4238001 did not have any viable fetuses at Day 42 following embryo transfers (P = 0.04). In the African-American group in particular, there was also an association between rs10846744 and gestational sac(s) (P = 0.006), and fetal heartbeat(s) (P = 0.005). CONCLUSIONS: In part, SCARB1 rs4238001 and rs10846744 SNPs may contribute to human female infertility. PMID- 21531996 TI - Integrin beta3 in rat blastocysts and epithelial cells is essential for implantation in vitro: studies with Ishikawa cells and small interfering RNA transfection. AB - BACKGROUND: Integrins are involved in the process of embryo-endometrium interaction during implantation. We investigated the localization of integrin beta3 in the rat blastocyst and Ishikawa cells using an in vitro co-culture model of implantation. METHODS: Zona pellucida-free rat blastocysts were co-cultured with the Ishikawa cells (endometrial adenocarcinoma cell line) to observe the attachment between the embryo and endometrium. Immunofluorescence staining was used to investigate the localization of integrin beta3 in rat embryos at different stages of development (each n= 3 embryos) and at the embryo/endometrium interface, observed by confocal microscopy. The Ishikawa cells were transfected with integrin beta3 small interfering RNA (siRNA) for 48 h and then co-cultured with Day 5 rat blastocysts to observe the effect on attachment. RESULTS: Integrin beta3 staining in the rat embryos increased at the blastocyst stage being highly concentrated in the cytoplasm of trophoblast cells (n= 9 embryos). Integrin beta3 was localized on the apical surface of the Ishikawa cells (n= 3 experiments). However, integrin beta3 relocated to the apical membrane of trophoblast cells in response to attachment to Ishikawa cells (n= 6 embryos). Moreover, when Ishikawa cells were transfected with integrin beta3 siRNA, blastocyst attachment was significantly reduced compared with those transfected with control siRNA (16.7 versus 92.3%, respectively, P< 0.05). CONCLUSIONS: Integrin beta3, localized apically in the blastocyst and the Ishikawa cells, is important during initial attachment of the blastocyst to endometrial cells. This study provides further evidence of the importance of integrins during implantation and may aid in elucidating the molecular mechanism of implantation failure and infertility in women. PMID- 21531997 TI - Ultrasonographic prediction of early miscarriage. AB - BACKGROUND: The aim of this retrospective study was to assess the value of maternal history and ultrasound scan findings at 6-10 weeks for predicting early miscarriage. METHODS: Embryonic crown-rump length (CRL), heart rate (HR), gestational sac diameter (GSD) and yolk sac diameter (YSD) were compared in two groups of women with singleton pregnancies attending an early pregnancy unit. In the first group the initial scan demonstrated a live embryo but in a subsequent visit the scan showed a dead embryo, complete or incomplete miscarriage. In the second group with a live embryo there was subsequent live birth of a normal neonate. RESULTS: There were 729 pregnancies with miscarriage and 4698 with normal outcome. Logistic regression analysis demonstrated that in the prediction of miscarriage the risk was higher in women of African racial origin [odds ratio (OR) 1.62], cigarette smokers (OR 1.91) and those with vaginal bleeding (OR 2.03) and increased with maternal age (OR 1.05) and YSD (OR 1.88) and was inversely related to CRL (OR 0.79), HR (OR 0.96) and GSD (OR 0.84). At false-positive rate of 30%, the detection rate of miscarriage in screening by vaginal bleeding was 45%, 53% by the addition of maternal history factors and 85.7% by the addition of ultrasound findings. CONCLUSIONS: In early pregnancy a prediction of miscarriage can be provided by a combination of maternal characteristics and ultrasound findings and the estimated risk can be used to rationalize follow-up. Our multivariate model requires prospective evaluation in a new sample population. PMID- 21531998 TI - Tailored expectant management: risk factors for non-adherence. AB - INTRODUCTION: Prediction models for spontaneous pregnancy are useful tools to prevent overtreatment, complications and costs in subfertile couples with a good prognosis. The use of such models and subsequent expectant management in couples with a good prognosis are recommended in the Dutch fertility guidelines, but not fully implemented. In this study, we assess risk factors for non-adherence to tailored expectant management. METHODS: Couples with mild male, unexplained and cervical subfertility were included in this multicentre prospective cohort study. If the probability of spontaneous pregnancy within 12 months was >=40%, expectant management for 6-12 months was advised. Multivariable logistic regression was used to identify patient and clinical characteristics associated with non adherence to tailored expectant management. RESULTS: We included 3021 couples of whom 1130 (38%) had a >=40% probability of a spontaneous pregnancy. Follow-up was available for 1020 (90%) couples of whom 214 (21%) had started treatment between 6 and 12 months and 153 (15%) within 6 months. A higher female age and a longer duration of subfertility were associated with treatment within 6 months (OR: 1.06, 95% CI: 1.01-1.1; OR: 1.4; 95% CI: 1.1-1.8). A fertility doctor in a clinical team reduced the risk of treatment within 6 months (OR: 0.62; 95% CI: 0.39-0.99). CONCLUSIONS: In couples with a favorable prognosis for spontaneous pregnancy, there is considerable overtreatment, especially if the woman is older and duration of the subfertility is longer. The presence of a fertility doctor in a clinic may prevent early treatment. PMID- 21531999 TI - Relationships in IVF couples 20 years after treatment. AB - BACKGROUND: Involuntary childlessness is a psychological and social dilemma for at least one but usually both members of the childless couples and is thought to have a lifelong impact on many of these couples. Studies of the long-term effects are scarce and the participation rate in published studies is generally very low. We therefore intended to analyse relationships and family structure in couples 20 23 years after the women in these couples had received IVF treatment. METHODS: The data are drawn from answers from 788 individuals-81% of the individuals treated. ENRICH has been used to analyse the relationships in those couples who stated that they have remained a couple since their IVF treatment. In total, 412 men and women (206 couples) answered the ENRICH inventory. A total of 14 men and 137 women answered the ENRICH, without their spouse answering the inventory. RESULTS: We found that the majority of all couples show a stable relationship 20 years or more after the date of IVF treatment. However, the group of couples who remained childless (9.2% of the total study population) during the 20 years following the IVF treatment differ from the majority on the subscale 'Children and Parent' measuring aspects on attitudes and feelings about having and raising children. Another difference seen in the couples that were childless was that men scored significantly higher on 'Conflict resolution' and the couples had a higher average score on positive agreement on the issues on 'Communication' indicating a skill in communication in the relationship and also an agreement that they are communicating well. CONCLUSIONS: We found that the majority of IVF couples (90.8%) who had been treated ~20 years prior to follow-up had added at least one biological or adopted child to the family during that time. The relationships in couples who had continued to stay together during that period were generally described as being good, whether the couples had become parents or not. PMID- 21532000 TI - Rape myths, alcohol intoxication and condom use among males accused of sexual assault in Kabale, rural Uganda. AB - Through a cross-sectional study conducted at Kabale Regional Hospital, among 111 men accused of rape and admitted for forensic examination from June 2009 to June 2010, we assessed whether the characteristics of perpetrators and the circumstances of the alleged sexual assault differ in acquaintance and stranger rape. Using a semi-structured interviewer-administered questionnaire and records review, data were collected on socio-demographic variables, circumstances of the alleged offense and the relation of the accused to the survivors. The mean age was 26.6 years (+/- 10.1 years), 30 (27.0) had been drunk and 67.2% (75) knew their accuser. There was no difference in the socio-demographic and lifestyle characteristics between stranger and acquaintance rape. There were no differences regarding whether the alleged crime occurred at the assailant's/survivor's home or outside either the survivor's or the assailant's home setting. Respondents either trivialized or justified the accusations against them. Our study shows that rape myths and drinking alcohol were common in all types of sexual assault. PMID- 21532001 TI - Concurrent infections of hepatitis C and HIV in hepatitis B patients in the north east of Iran. AB - Co-infection of HBV, HCV and HIV is common because of shared routes of viral transmission with increased risk of morbidity and mortality. Anti-HCV and HIV antibodies of 168 HBV patients were assayed. Co-infection of HCV in HBV patients was seen in four cases (2.4%). Simultaneous infection of HIV in HBV patents was seen in three cases (1.8%). There was no simultaneous co-infection of HCV, HIV and HBV. It is recommended that all patients are screened for possible co infections before initiating treatment. PMID- 21532002 TI - Renal dysfunction in leprosy: a historical cohort of 923 patients in Brazil. AB - We investigated the factors associated with renal dysfunction in leprosy patients from Brazil. We report on a historical cohort of leprosy patients followed in two hospitals in Fortaleza City in northeastern Brazil. The factors associated with renal dysfunction were investigated. A total of 923 patients were included, with a mean age of 41.5 +/- 19.1 years, and 53.3% were male. Renal dysfunction was found in 35 cases (3.8%). Proteinuria was found in 4.8% of cases, haematuria in 6.8% and leukocyturia in 10.4%. Factors associated with renal dysfunction by multivariate analysis were: reaction episode (odds ratio [OR] = 3.9, P = 0.03), multibacillary classification (OR = 3.5, P = 0.02) and advanced age (OR = 1.04, P = 0.01). Four patients (0.4%) died. Leprosy is associated with renal dysfunction, especially in older patients and those presenting with reaction episode and multibacillary classification. PMID- 21532003 TI - Prevalence of clinical and subclinical thyroid disease in a peritoneal dialysis population. AB - AIMS: We investigated dialysis duration, dose of erythropoietin (EPO), and clinical manifestations in peritoneal dialysis (PD) patients with subclinical hypothyroidism. METHODS: This cross-sectional study, performed in 3 centers, assessed 122 adult patients on PD for more than 6 months with regard to demographic data, dialysis duration, thyroid function, biochemical data, EPO dose, and clinical manifestations. Thyroid dysfunction was determined by serum thyroid-stimulating hormone, free thyroxine, total thyroxine, total triiodothyronine, antithyroid peroxidase antibodies, and auto-antibodies against thyroglobulin. RESULTS: Of the 122 study patients, 98 (80.3%) were assessed as having euthyroidism; 19 (15.6%), subclinical hypothyroidism; and 5 (4.1%), subclinical hyperthyroidism. The proportion of women (74.2% vs. 57.1%, p = 0.038), the mean duration of PD (58.1 months vs. 37.9 months, p = 0.032), and the weighted mean monthly EPO dose (1.22 MUg/kg vs. 1.64 MUg/kg, p = 0.009) were significantly higher in the subclinical hypothyroidism group than in the euthyroidism group, but the prevalences of coronary artery disease and cerebrovascular disease were not. From the multivariate model, PD duration was more significant than sex as a risk factor for subclinical hypothyroidism (p = 0.0132). CONCLUSIONS: Subclinical hypothyroidism is frequent in PD patients, especially female patients and patients with a longer PD duration. Compared with euthyroid patients, patients with subclinical hyperthyroidism need a higher dose of EPO to maintain a stable hemoglobin level. PMID- 21532004 TI - Presence of peripheral arterial disease predicts loss of residual renal function in incident CAPD patients. AB - BACKGROUND: Accelerated cardiovascular disease (CVD), including peripheral arterial disease (PAD), is very common in patients with end-stage renal disease. Residual renal function (RRF) is a strong predictor of patient survival that is suggested to be linked to the degree of CVD. However, the relationship between PAD and decline in RRF has not previously been measured. METHODS: We studied incident continuous ambulatory peritoneal dialysis patients from Peking University Third Hospital. An ankle brachial index of less than 0.9 was used to diagnose PAD. Residual renal function (RRF) was determined as the mean of 24-hour urea and creatinine clearances (glomerular filtration rate). The Cox proportional hazards model was used to identify factors predicting loss of RRF. RESULTS: The study included 86 patients (age: 61 +/- 14 years; men: 51%), 23 of whom had PAD at baseline. Mean follow-up was 19 months (median: 18 months; range: 6 - 30 months). In univariate analysis, baseline PAD, peritonitis during follow-up, inflammation (C-reactive protein), serum uric acid, Ca*P, and serum phosphate were all significantly associated with a greater-than-50% decrease in RRF during follow-up. In multivariate analysis, only baseline PAD, Ca*P, and peritonitis were independently associated with a decline in RRF. CONCLUSIONS: Our study suggests that PAD may be a clinically important marker of CVD predicting the loss of RRF. It remains to be determined whether interventions aimed at decreasing PAD may also improve renal vascular status and thus slow the rate of RRF decline. PMID- 21532005 TI - Fluid flow stress affects peritoneal cell kinetics: possible pathogenesis of peritoneal fibrosis. AB - BACKGROUND: Peritoneal fibrosis is an essential precursor condition to the development of encapsulating peritoneal sclerosis (EPS). This serious complication leads to a high mortality rate in peritoneal dialysis (PD) patients. Although several factors, including highly concentrated glucose in the dialysis solution, are believed to be potent agents for peritoneal fibrosis, the underlying mechanism remains unclear. During PD, the dialysis solution continuously generates fluid flow stress to the peritoneum under peristalsis and body motion. Fluid flow stress has been implicated as playing a critical role in the physiologic responses of many cell types. We therefore hypothesized that fluid flow stress may be involved in the pathogenesis of peritoneal fibrosis leading to EPS. METHODS: To generate fluid flow stress, culture containers were placed on a rotatory shaker in a thermostatic chamber. In this system, the shaker rotated at a speed of 25 rpm with a radius of 1.5 cm. Mesothelial cells were cultured in low-glucose (1000 mg/L) or high-glucose (4500 mg/L) complete medium with and without flow stress. RESULTS: Fluid flow stress promoted hyperplasia and epithelial-mesenchymal transition (EMT) of mesothelial cells independent of glucose concentration. Fluid flow stress inhibited expression of ERK (extracellular signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) in mesothelial cells. Administration of ERK and p38 MAPK inhibitors replicated the stress-induced morphology of mesothelial cells. CONCLUSIONS: The present data indicate that fluid flow stress promotes hyperplasia and EMT of mesothelial cells via the MAPK axis, suggesting that fluid flow stress may be involved in the pathogenesis of peritoneal fibrosis. PMID- 21532006 TI - Clinical course and outcomes of single-organism Enterococcus peritonitis in peritoneal dialysis patients. AB - BACKGROUND AND OBJECTIVES: Enterococci are part of the normal flora of the gastrointestinal tract. They can cause enteric peritonitis, which is a serious complication of peritoneal dialysis (PD). However, the clinical course and outcome of PD-related Enterococcus peritonitis remains unclear. METHODS: We reviewed all Enterococcus peritonitis episodes occurring in our dialysis unit from 1995 to 2009. RESULTS: During the study period, 1421 episodes of peritonitis were recorded. Of 29 episodes (2.0%) that were attributable to single-organism Enterococcus, 12 episodes were caused by E. faecalis; 9, by E. faecium; and the remaining 8, by other Enterococcus species. The overall rate of ampicillin resistance was 41.4%. Recent use of antibiotics was associated with the development of ampicillin-resistant Enterococcus (ARE) peritonitis (hazard ratio: 12.53; p = 0.04). The primary response rate of Enterococcus peritonitis was significantly higher than that of Escherichia coli peritonitis (89.7% vs. 69.9%, p = 0.038), but the primary response rate was not significantly lower for ARE peritonitis than for ampicillin-susceptible Enterococcus (ASE) peritonitis (83.3% vs. 94.1%, p = 0.553). However, significantly more patients with ARE had received vancomycin (83.3% vs. 23.5%, p = 0.003), with a longer mean duration of vancomycin treatment (11.8 +/- 6.9 days vs. 3.7 +/- 6.8 days, p = 0.005). CONCLUSIONS: Recent use of antibiotics was a risk factor for the development of ARE peritonitis. Outcomes in ASE and ARE peritonitis were similar, but vancomycin was required during treatment for ARE peritonitis, in turn possibly predisposing the patients to infections caused by vancomycin-resistant organisms. PMID- 21532007 TI - Characterization, treatment, and outcome of intracranial neoplasms in the first 120 days of life. AB - Little is known about brain tumors in early infancy. Investigators reviewed the records of 27 patients (12 boys and 15 girls) diagnosed within 120 days of birth. The median age was 66 days (range, 0-110 days) at diagnosis. All patients underwent surgery; 18 received adjuvant chemotherapy, and 3 received adjuvant chemotherapy and radiation therapy. The median follow-up was 2.1 years (range, 0.2-21.6 years). At last encounter, 15 patients were alive, and 11 had no evidence of disease. Ten patients died of progressive disease, and 2 died of treatment-related complications. All survivors experienced late effects, including endocrine, neurologic, and cognitive deficits. Of the 13 patients who completed neurocognitive assessments, 7 had an IQ score less than 70. Children in whom brain tumors arise during early infancy can be cured with conventional therapy; however, contemporary approaches can adversely affect long-term function, and families need to be aware of these effects when making therapeutic decisions. PMID- 21532008 TI - Spectrum-to-spectrum searching using a proteome-wide spectral library. AB - The unambiguous assignment of tandem mass spectra (MS/MS) to peptide sequences remains a key unsolved problem in proteomics. Spectral library search strategies have emerged as a promising alternative for peptide identification, in which MS/MS spectra are directly compared against a reference library of confidently assigned spectra. Two problems relate to library size. First, reference spectral libraries are limited to rediscovery of previously identified peptides and are not applicable to new peptides, because of their incomplete coverage of the human proteome. Second, problems arise when searching a spectral library the size of the entire human proteome. We observed that traditional dot product scoring methods do not scale well with spectral library size, showing reduction in sensitivity when library size is increased. We show that this problem can be addressed by optimizing scoring metrics for spectrum-to-spectrum searches with large spectral libraries. MS/MS spectra for the 1.3 million predicted tryptic peptides in the human proteome are simulated using a kinetic fragmentation model (MassAnalyzer version2.1) to create a proteome-wide simulated spectral library. Searches of the simulated library increase MS/MS assignments by 24% compared with Mascot, when using probabilistic and rank based scoring methods. The proteome wide coverage of the simulated library leads to 11% increase in unique peptide assignments, compared with parallel searches of a reference spectral library. Further improvement is attained when reference spectra and simulated spectra are combined into a hybrid spectral library, yielding 52% increased MS/MS assignments compared with Mascot searches. Our study demonstrates the advantages of using probabilistic and rank based scores to improve performance of spectrum-to spectrum search strategies. PMID- 21532009 TI - Nanodisc-based co-immunoprecipitation for mass spectrometric identification of membrane-interacting proteins. AB - Proteomic identification of protein interactions with membrane associated molecules in their native membrane environment pose a challenge because of technical problems of membrane handling. We investigate the possibility of employing membrane nanodiscs for harboring the membrane associated molecule to tackle the challenges. Nanodiscs are stable, homogenous pieces of membrane with a discoidal shape. They are stabilized by an encircling amphipatic protein with an engineered epitope tag. In the present study we employ the epitope tag of the nanodiscs for detection and co-immunoprecipitation of interaction partners of the glycolipid ganglioside GM1 harbored by nanodiscs. Highly specific binding activity for nanodisc-GM1 immobilized on sensorchips was observed by surface plasmon resonance in culture media from enterotoxigenic Escherischia coli. To isolate the interaction partner(s) from enterotoxigenic Escherischia coli, GM1 nanodiscs were employed for co-immunoprecipitation. The B subunit of heat labile enterotoxin was identified as a specific interaction partner by mass spectrometry, thus demonstrating that nanodisc technology is useful for highly specific detection and identification of interaction partners to specific lipids embedded in a membrane bilayer. PMID- 21532012 TI - Preventing and managing antimicrobial resistance: imperative for chest physicians. PMID- 21532010 TI - Discovering mercury protein modifications in whole proteomes using natural isotope distributions observed in liquid chromatography-tandem mass spectrometry. AB - The identification of peptides that result from post-translational modifications is critical for understanding normal pathways of cellular regulation as well as identifying damage from, or exposures to xenobiotics, i.e. the exposome. However, because of their low abundance in proteomes, effective detection of modified peptides by mass spectrometry (MS) typically requires enrichment to eliminate false identifications. We present a new method for confidently identifying peptides with mercury (Hg)-containing adducts that is based on the influence of mercury's seven stable isotopes on peptide isotope distributions detected by high resolution MS. Using a pure protein and E. coli cultures exposed to phenyl mercuric acetate, we show the pattern of peak heights in isotope distributions from primary MS single scans efficiently identified Hg adducts in data from chromatographic separation coupled with tandem mass spectrometry with sensitivity and specificity greater than 90%. Isotope distributions are independent of peptide identifications based on peptide fragmentation (e.g. by SEQUEST), so both methods can be combined to eliminate false positives. Summing peptide isotope distributions across multiple scans improved specificity to 99.4% and sensitivity above 95%, affording identification of an unexpected Hg modification. We also illustrate the theoretical applicability of the method for detection of several less common elements including the essential element, selenium, as selenocysteine in peptides. PMID- 21532013 TI - Inhaler devices for asthma: a call for action in a neglected field. PMID- 21532014 TI - Asthma nervosa: old concept, new insights. PMID- 21532015 TI - Randomised controlled trials in cystic fibrosis: what, when and how? PMID- 21532016 TI - Diagnosing pulmonary hypertension: is there a revival of the electrocardiogram? PMID- 21532017 TI - CPAP treatment of sleep apnoea in the early phase of stroke: growing evidence of effectiveness. PMID- 21532018 TI - Failing a re-treatment regimen does not predict MDR/XDR tuberculosis: is "blind" treatment dangerous? PMID- 21532019 TI - Impaired pulmonary function and the risk of tuberculosis: a population-based cohort study. PMID- 21532020 TI - Bringing light to the sirens of night: laryngoscopy in catathrenia during sleep. PMID- 21532021 TI - The search for autoantibodies against elastin, collagen and decorin in COPD. PMID- 21532022 TI - Nocturnal release of leukocyte-derived microparticles in males with obstructive sleep apnoea. PMID- 21532023 TI - Limitations of calculating "true" regression slope: impact on estimates of minimal important difference. PMID- 21532024 TI - Obesity and risk of pneumonia in patients with influenza. PMID- 21532025 TI - Obesity and risk of pneumonia in patients with influenza. PMID- 21532026 TI - The effect of nanoparticles on airway allergy in mice. PMID- 21532028 TI - Expanding on forty years of reflection. PMID- 21532029 TI - Arcuate nucleus - a gateway for insulin's action on sympathetic activity. PMID- 21532030 TI - Hypoxia: just say NO? PMID- 21532031 TI - Comfortable at just below your critical speed: how is blood flow distribution coupled to muscle fibre recruitment during exercise? PMID- 21532032 TI - An expanding view of dynamic electrical coupling in the mammalian retina. PMID- 21532033 TI - Reactive oxygen and nitrogen species in skeletal muscle: acute and long-term effects. PMID- 21532036 TI - Electrical stimulation of acupuncture points and blood pressure responses to postural changes: a pilot study. AB - BACKGROUND: Application of transcutaneous electrical stimulation over acupuncture points (Acu-TENS) facilitates heart rate recovery after exercise and restores hemodynamic stability after open heart surgery. The role of Acu-TENS on cardiovascular parameters in response to postural changes has not been reported. OBJECTIVE: To investigate (1) the effect of Acu-TENS on blood pressure responses to -10o head-down postural change and (2) whether such effects were associated with modulation by the autonomic nervous system. METHOD: Sixteen healthy volunteers, mean age 22.8 (SD, 3.1) years, were subjected to a -10o head-down tilt from the supine position on 3 separate occasions and received in random order the following 3 intervention protocols for 40 minutes before the postural change: Acu-TENS (over bilateral acupuncture points, PC6), sham-TENS (TENS applied to the skin over the patellae), and control (no electrical output from the TENS device applied at PC6). Mean arterial pressure, large artery elasticity index, cardiac output, and heart rate were recorded and compared at different stimulation protocols in the supine and -10o head-down tilt positions. Spectral analysis of heart rate variability was used to determine any modulation by the autonomic nervous system. RESULTS: Change in large artery elasticity index was observed only in the Acu-TENS group (P < .05) and mean arterial pressure appeared most stable during Acu-TENS. Autonomic nervous system modulation was not apparent with spectral analysis, irrespective of intervention. Sympathetic activity predominated in all positions. CONCLUSION: Acu-TENS seems to reduce blood pressure changes with -10o head-down tilt with concomitant changes in arterial vessel tone. PMID- 21532034 TI - Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q. AB - Myelodysplastic syndromes (MDS) are characterized by abnormal and dysplastic maturation of all blood lineages. Even though epigenetic alterations have been seen in MDS marrow progenitors, very little is known about the molecular alterations in dysplastic peripheral blood cells. We analyzed the methylome of MDS leukocytes by the HELP assay and determined that it was globally distinct from age-matched controls and was characterized by numerous novel, aberrant hypermethylated marks that were located mainly outside of CpG islands and preferentially affected GTPase regulators and other cancer-related pathways. Additionally, array comparative genomic hybridization revealed that novel as well as previously characterized deletions and amplifications could also be visualized in peripheral blood leukocytes, thus potentially reducing the need for bone marrow samples for future studies. Using integrative analysis, potentially pathogenic genes silenced by genetic deletions and aberrant hypermethylation in different patients were identified. DOCK4, a GTPase regulator located in the commonly deleted 7q31 region, was identified by this unbiased approach. Significant hypermethylation and reduced expression of DOCK4 in MDS bone marrow stem cells was observed in two large independent datasets, providing further validation of our findings. Finally, DOCK4 knockdown in primary marrow CD34(+) stem cells led to decreased erythroid colony formation and increased apoptosis, thus recapitulating the bone marrow failure seen in MDS. These findings reveal widespread novel epigenetic alterations in myelodysplastic leukocytes and implicate DOCK4 as a pathogenic gene located on the 7q chromosomal region. PMID- 21532035 TI - The linker region of macroH2A promotes self-association of nucleosomal arrays. AB - MacroH2A is a histone variant found in higher eukaryotes localized at the inactive X chromosome and is known to maintain heterochromatic regions in the genome. MacroH2A consists of a conserved histone domain and a macro domain connected by a linker region. To understand the contributions of the three domains to chromatin condensation, we incorporated various constructs of macroH2A into defined nucleosomal arrays and analyzed their impact on in vitro chromatin compaction. The folding and oligomerization properties of arrays containing full length macroH2A (macroH2A(FL)), macroH2A(1-161) (encompassing the histone domain and linker region), and macroH2A(1-122) (histone domain only) were compared with major-type H2A arrays. Analytical ultracentrifugation and atomic force microscope imaging indicate that macroH2A(1-161)-containing arrays favor condensation under conditions where major-type arrays are nearly fully extended. In contrast, arrays with macroH2A(FL) exhibit behavior similar to that of major-type arrays. This suggests that the linker region of macroH2A facilitates array condensation and that this behavior is inhibited by the macro domain. Furthermore, chimeric major type H2A arrays containing the macroH2A linker domain (H2A(ML)) exhibited the same condensation properties as macroH2A(1-161) arrays, thus emphasizing the intriguing behavior of the macroH2A linker region. PMID- 21532037 TI - Time-motion analysis of health care workers' contact with patients and workers' hand hygiene: open vs closed units. AB - BACKGROUND: The effects of open (care provided by general medicine teams with a pulmonary intensivist consultant) vs closed (care provided by a dedicated critical care team) intensive care units on health care workers' contact with patients and their hand hygiene is uncertain. OBJECTIVE: To determine if closed intensive care units have fewer visits of patients by health care providers and greater hand-washing compliance among providers than do open units. METHODS: Time motion analysis was used to observe 2 rooms in a medical intensive care unit at a teaching hospital affiliated with Indiana University School of Medicine, Indianapolis, for 96 hours before and after closure of the unit. The main outcome measures were frequency of health care providers' visits and their hand-washing hygiene compliance rates. RESULTS: Mean number of visits per room per hour by physicians (1.53 in the open unit vs 1.27 in the closed unit; P = .93) and nurses (3.98 in open unit vs 4.14 in closed unit; P = .60) did not differ. No differences were observed in gold-standard hand washing among physicians (0.00% in open unit vs 2.63% in closed unit; P = .11) or nurses (2.50% in open unit vs 3.49% in closed unit; P = .51). However, hand washing decreased significantly in nurses in the closed unit (40.94% in open unit vs 29.84% in closed unit; P = .002). CONCLUSION: Closing the intensive care unit did not decrease the number of contacts between health care providers and patients nor did it increase the providers' compliance with hand hygiene. PMID- 21532038 TI - Critical care and the future of nursing. PMID- 21532040 TI - Understanding health care professionals' views of family presence during pediatric resuscitation. AB - OBJECTIVE: To examine the conflicting perceptions that health care professionals hold regarding family presence during pediatric resuscitation. METHODS: In phase 1, 137 health care professionals completed a 23-item questionnaire about their views on family presence and their perceptions of their opponents' views on family presence. In phase 2, 12 phase 1 respondents were interviewed about the effects that family presence may have on patients' families and on trauma teams. RESULTS: All respondents indicated that legal concerns and risks were important factors during family presence; however, respondents in favor of family presence believed that legal concerns and risks were minimized when patients' families were present whereas respondents who were opposed believed the opposite. Respondents who were opposed assumed that respondents who were in favor of family presence were less sympathetic and concerned about families, trauma teams, and health care providers; respondents in favor of family presence assumed that respondents who were opposed were overly preoccupied with legal concerns and potential risks involved with family presence during pediatric resuscitations. All respondents believed that patients' families and trauma teams are affected by family presence. Specifically, respondents in favor of family presence believed that families and trauma team members are positively affected whereas opponents believed the opposite. CONCLUSIONS: These findings provide a deeper understanding of the views of health care professionals and how these views might affect the delivery of family-centered care. PMID- 21532041 TI - Cardiac index based on measurements obtained in a bedside chair and in bed. AB - BACKGROUND: Accurate measurements for determining cardiac index can be obtained while patients are supine in bed at various backrest elevations. It is not clear if these measurements are accurate when patients are in a bedside chair. OBJECTIVE: To determine if cardiac index based on measurements obtained with the patient in a chair is similar to cardiac index based on measurements obtained with the patient in bed. METHODS: A convenience sample of cardiac surgical patients and a method-comparison design were used to compare cardiac index values based on measurements obtained with patients in 2 different positions: in a chair and in the bed. A standard thermodilution technique was used to measure cardiac output. Measurement of cardiac output in the second position was obtained immediately after measurement in the first position. Positions were randomly assigned. Bias and precision were calculated and graphed with the Bland-Altman method. Differences in cardiac index of 0.50 or more were considered clinically significant. Analysis of variance was used to determine differences between cardiac index values for the 2 positions. RESULTS: A total of 27 postoperative cardiac surgical patients were studied. Cardiac index values based on measurements obtained with patients in the 2 different positions did not differ significantly (F(1,50) = 0.446; P = .51). The mean difference score (bias) between the 2 positions was -0.07 (precision, 0.30). CONCLUSIONS: The practice of putting cardiac surgical patients whose hemodynamic status is stable back to bed before obtaining measurements for calculation of cardiac index may not be required for accurate values. PMID- 21532042 TI - Gastrointestinal bleeding and outcomes after percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - BACKGROUND: Gastrointestinal bleeding is a hemorrhagic complication after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To determine predictors of gastrointestinal bleeding and the impact of gastrointestinal bleeding on outcomes in STEMI patients undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: Gastrointestinal bleeding occurred in 18 (3.5%) of 519 consecutive patients with STEMI undergoing primary percutaneous coronary intervention. Univariate predictors of gastrointestinal bleeding were previous gastrointestinal bleeding (33% vs 4%, P < .001), impaired renal function (89% vs 37%, P<.001), Killip class IV at presentation (61% vs 18%, P<.001), higher peak creatinine kinase level (mean [SD], 3801.6 [3280.2] vs 2721.3 [2286.6] IU/L, P=.05), and mechanical ventilator support (44% vs 12%, P<.001). Coprescription of proton-pump inhibitors did not reduce the risk of gastrointestinal bleeding (22.2% vs 13.4%, P=.22). Multivariate analysis showed an odds ratio (95% confidence interval) for gastrointestinal bleeding of 22.1 (5.6-86.89, P<.001) for previous gastrointestinal bleeding, 6.74 (1.30-34.89, P=.02) for impaired renal function, and 4.68 (1.35-16.2, P=.01) for Killip class IV at presentation. Gastrointestinal bleeding was associated with longer intensive care unit stay (mean [SD], 5.4 [6.7] vs 3.6 [3.6] days, P=.04), and higher in-hospital (44% vs 9%, P<.001) and overall (44% vs 13%, P<.001) mortality rate. CONCLUSIONS: Although rare, gastrointestinal bleeding in patients with STEMI significantly prolongs intensive care unit stay and increases mortality. Previous gastrointestinal bleeding, impaired renal function, and Killip class IV at presentation are associated with higher incidence of gastrointestinal bleeding. PMID- 21532043 TI - Continuous ST-segment monitoring: nurses' attitudes, practices, and quality of patient care. AB - BACKGROUND: Continuous ischemia monitoring helps identify patients with acute, but often silent, myocardial ischemia. Evidence suggests nurses do not activate ischemia monitoring because they think it is difficult to use. ST-Map software incorporates graphic displays to make monitoring of ongoing ischemia easier. OBJECTIVES: To determine if nurses' use of and attitude toward ischemia monitoring and the quality of patient care improve with use of ST-Map. METHODS: The study included 61 nurses and 202 patients with acute coronary syndrome in a cardiac intensive care unit. Baseline data on nurses' use of and attitude toward ischemia monitoring and quality of care were obtained. Education was then provided and ST-Map software was installed on all monitors. Follow-up data were obtained 4 months later. RESULTS: The percentage of nurses who had ever used ischemia monitoring was 13% before ST Map and 90% afterward (P < .001). The most common reason for not using ischemia monitoring before ST Map was inadequate knowledge (62%). The most common reason for liking ischemia monitoring after ST Map was knowing when a patient has ischemia (80%). Time to acquisition of a 12 lead electrocardiogram in response to symptoms or ST-segment changes was 5 to 15 minutes before ST Map and always less than 5 minutes afterward (P < .001). Time to return to the catheterization laboratory did not differ before and after ST Map. CONCLUSIONS: ST Map was associated with more frequent use of ischemia monitoring, improved attitudes of nurses toward ischemia monitoring, and shorter time to obtaining 12-lead electrocardiograms. PMID- 21532044 TI - Continuous ST-Segment Monitoring. PMID- 21532046 TI - Rethinking interventions to improve surrogate decision making in intensive care units. PMID- 21532047 TI - Exercise stress treadmill testing. PMID- 21532045 TI - Evidence to support tooth brushing in critically ill patients. AB - Tooth brushing in critically ill patients has been advocated by many as a standard of care despite the limited evidence to support this practice. Attention has been focused on oral care as the evidence accumulates to support an association between the bacteria in the oral microbiome and those respiratory pathogens that cause pneumonia. It is plausible to assume that respiratory pathogens originating in the oral cavity are aspirated into the lungs, causing infection. A recent study of the effects of a powered toothbrush on the incidence of ventilator-associated pneumonia was stopped early because of a lack of effect in the treatment group. This review summarizes the evidence that supports the effectiveness of tooth brushing in critically ill adults and children receiving mechanical ventilation. Possible reasons for the lack of benefit of tooth brushing demonstrated in clinical trials are discussed. Recommendations for future trials in critically ill patients are suggested. With increased emphasis being placed on oral care, the evidence that supports this intervention must be evaluated carefully. PMID- 21532048 TI - Fat embolism syndrome after femur fracture with intramedullary nailing: case report. AB - Fat embolism syndrome is a life-threatening condition that can develop after orthopedic injury and surgery. This syndrome developed in a 19-year-old man after a traumatic femoral fracture that was surgically repaired with intramedullary nailing. The complications experienced by the patient highlight the importance of prevention and early detection of fat embolism syndrome. Although minimization of the syndrome focuses primarily on prehospital care and early stabilization of a patient's condition, prevention of the potential consequences requires early detection by bedside nurses who care for trauma and orthopedic patients. Detailed nursing assessment and rapid recognition and reporting of the signs and symptoms associated with fat embolism syndrome are key to improving the outcomes of these patients. PMID- 21532049 TI - Editorial: Fly fishing with RNAi catches novel effectors of phagocytosis. PMID- 21532050 TI - Editorial: Neutrophils live on a two-way street. PMID- 21532051 TI - Up the down pay scale: teachers vs. football coaches. PMID- 21532052 TI - Eric Kandel and Charlie Rose: a stylish synapse. Review of The Brain Series, (televised on The Charlie Rose Show, syndicated by the Public Broadcasting System, now available on DVD). PMID- 21532053 TI - The resolution of inflammation: the devil in the flask and in the details. PMID- 21532054 TI - Comparison of the EQ-5D and the SF-6D utility measures in 813 patients with early arthritis: results from the ESPOIR cohort. AB - OBJECTIVE: The revolution of early aggressive therapy in early arthritis (EA) has fueled the search for better approaches to establish cost-effectiveness. Our objective was to compare the EuroQol EQ-5D health outcome measure and the SF-6D and to investigate their relationship to clinical variables in a large prospective cohort of patients with EA. METHODS: The EQ-5D and SF-6D utility measures were longitudinally assessed in 813 patients with EA. Agreement and aspects of validity (construct validity, discrimination) were assessed. RESULTS: At baseline, mean values for EQ-5D were 0.52 +/- 0.31 (range -0.59 to 1.0) and for SF-6D were 0.58 +/- 0.11 (range 0.30 to 0.92), with a bimodal distribution for the EQ-5D. Agreement was low for patients with severe disability or active disease: the utility was systematically lower with EQ-5D. The intraclass correlation coefficient was 0.42 at baseline and increased to 0.53 at 6 months and 0.57 at 1 and 2 years. Correlations between the 2 utility scores and the Health Assessment Questionnaire were good, and remained similar and stable over 2 years (r = -0.70). Correlations with the Disease Activity Score for 28 joints and the physical component of the MOS 36-item Short-form Health Survey (SF-36) were moderate to good and stable. In contrast, correlation with the mental component of the SF-36 was better with the SF-6D, and the correlation with pain, weak at baseline, improved at 6 months and remained stable thereafter. The SF-6D was better able to discriminate patients with high disease activity. CONCLUSION: There was systematic disagreement between EQ-5D and SF-6D in EA, especially in patients with worse clinical outcomes. Using the 2 instruments could be appropriate to conduct sensitivity analyses of cost-utility ratios because the instruments measure utility with closely similar measured properties, but at different levels. PMID- 21532055 TI - Preferential accumulation of activated Th1 cells not only in rheumatoid arthritis but also in osteoarthritis joints. AB - OBJECTIVE: It was previously found that Th1 but not Th17 cells were predominant in the joints of rheumatoid arthritis (RA). To verify whether this is a unique feature of CD4 T cells in RA joints, we performed comparative flow cytometric analysis of CD4 T cells in RA and osteoarthritis (OA) joints. METHODS: Mononuclear cells were isolated from peripheral blood (PB), synovial membrane (SM), and synovial fluid (SF) from a total of 18 RA and 12 OA patients. The expression of surface molecules and cytokine production of CD4 T cells was examined by a flow cytometer. RESULTS: Most CD4 T cells in RA joints expressed memory/activation markers, such as CD45RO, HLA-DR, and CD69. CCR5 was highly expressed on CD4 T cells in SF but not in PB or SM. With regard to Th17-related molecules, CD4 T cells expressing CCR6 were not enriched in either SF or SM. In contrast, CD161-positive cells were abundant in the joint, many of which, however, produced interferon-gamma but not interleukin 17A. Virtually all T cells in OA joints, although much less numerous than in RA joints, expressed activation markers. Th1 cells were predominant in both OA and RA joints, while there were a few Th17 cells. The frequency of Th17 cells in the joint tended to be lower in OA than RA. CONCLUSION: There was a quantitative but not qualitative difference in CD4 T cells, including the expression of activation markers and cytokine profiles, between RA and OA joints. PMID- 21532056 TI - Mannose-binding lectin expression genotype in pediatric-onset systemic lupus erythematosus: associations with susceptibility to renal disease and protection against infections. AB - OBJECTIVE: To study possible associations between extended mannose-binding lectin (MBL) expression genotypes and clinical manifestations and infections in children with systemic lupus erythematosus (SLE). METHODS: Clinical and laboratory variables for a cohort of 125 patients with pediatric-onset SLE were obtained by clinical examinations and chart reviews. Controls were 137 age-matched and sex matched healthy children and adolescents. MBL gene polymorphisms were genotyped by polymerase chain reaction. Serum MBL concentrations were measured by ELISA. RESULTS: The frequencies of extended MBL expression genotypes did not differ between patients and controls. There were 82 patients with SLE who had high MBL expression genotypes and 43 who had medium and low MBL expression genotypes. Patients with the high MBL expression genotype had renal disorders more frequently than patients in the group with medium and low MBL expression genotypes [54/82 (65.9%) vs 18/43 (41.9%), respectively; p = 0.013] and fewer serious bacterial infections [22/82 (26.8%) vs 20/43 (46.5%); p = 0.030]. Using logistic regression for patients with SLE, a high MBL expression genotype was independently associated with renal disorders (OR 2.49, 95% CI 1.15-5.39, p = 0.021) and had a protective effect against serious bacterial infections (OR 0.29, 95% CI 0.12-0.71, p = 0.007). MBL levels decreased significantly when patients with active SLE reached an inactive stage (1.56 +/- 0.55 MUg/ml vs 1.08 +/- 0.65 MUg/ml; p = 0.001), but these levels were still higher than those in controls. CONCLUSION: Our findings suggest that a high MBL expression genotype is a risk factor for renal disorder, while it has a protective effect against infections. Serum MBL levels reflect SLE activity. PMID- 21532057 TI - The accuracy of administrative data diagnoses of systemic autoimmune rheumatic diseases. AB - OBJECTIVE: To examine the validity of case definitions for systemic autoimmune rheumatic diseases [SARD; systemic lupus erythematosus (SLE), systemic sclerosis (SSc), myositis, Sjogren's syndrome, vasculitis, and polymyalgia rheumatica] based on administrative data, compared to rheumatology records. METHODS: A list of rheumatic disease diagnoses was generated from population-based administrative billing and hospitalization databases. Subjects who had been seen by an arthritis center rheumatologist were identified, and the medical records reviewed. RESULTS: We found that 844 Nova Scotia residents had a diagnosis of one of the rheumatic diseases of interest, based on administrative data, and had had >= 1 rheumatology assessment at a provincial arthritis center. Charts were available on 824 subjects, some of whom had been identified in the administrative database with > 1 diagnosis. Thus a total of 1136 diagnoses were available for verification against clinical records. Of the 824 subjects, 680 (83%) had their administrative database diagnoses confirmed on chart review. The majority of subjects who were "false-positive" for a given rheumatic disease on administrative data had a true diagnosis of a similar rheumatic disease. Most sensitivity estimates for specific administrative data-based case definitions were > 90%, although for SSc, the sensitivity was 80.5%. The specificity estimates were also > 90%, except for SLE, where the specificity was 72.5%. CONCLUSION: Although health administrative data may be a valid resource, there are potential problems regarding the specificity and sensitivity of case definitions, which should be kept in mind for future studies. PMID- 21532058 TI - Improving the quality of care in children with juvenile idiopathic arthritis: a step in the right direction. PMID- 21532059 TI - Uptake of best arthritis practice in primary care--no quick fixes. PMID- 21532060 TI - Bayesian inference: statistical gimmick or added value? PMID- 21532061 TI - Primary hypertrophic osteoarthropathy with gastric hypertrophy. PMID- 21532062 TI - Walking before an ultrasound assessment increases the enthesis score significantly. PMID- 21532063 TI - IL18 polymorphism is associated with Behcet's disease but not lupus in patients from Turkey. PMID- 21532064 TI - Anti-CADM-140 antibody-positive juvenile dermatomyositis with rapidly progressive interstitial lung disease and cardiac involvement. PMID- 21532065 TI - Cytomegalovirus colitis and hypo-IgG after rituximab therapy for rheumatoid arthritis. PMID- 21532066 TI - Combination of hypertrophic pachymeningitis, PR3-ANCA-positive vasculitis, and relapsing polychondritis. PMID- 21532067 TI - Coercion is not mental health care. PMID- 21532068 TI - Best practices: wellness self-management: an adaptation of the illness management and recovery program in New York State. AB - Wellness Self-Management (WSM) is a recovery-oriented, curriculum-based practice designed to help adults with serious mental health problems make informed decisions and take action to manage symptoms and improve their quality of life. WSM is an adaptation of the illness management and recovery program, a nationally recognized best practice. WSM uses comprehensive personal workbooks for group facilitators and consumers and employs a structured and easy-to-implement group facilitation framework. Currently, more than 100 adult mental health agencies are implementing WSM in New York State. The authors describe the development and key features of WSM and an initiative to promote widespread adoption and sustainability. PMID- 21532069 TI - International variation in treatment procedures for ADHD: social context and recent trends. AB - OBJECTIVE: Scientific and clinical interest in attention-deficit hyperactivity disorder (ADHD) is increasing worldwide. This article presents data from a cross national workshop and survey related to questions of variability in diagnostic and, particularly, treatment procedures. METHODS: Representatives of nine nations (Australia, Brazil, Canada, China, Germany, Israel, the Netherlands, Norway, and the United Kingdom), plus the United States, who attended a 2010 workshop on ADHD, responded to a survey that addressed diagnostic procedures for ADHD; treated prevalence of medication approaches, as well as psychosocial interventions; types of medications and psychosocial treatments in use; payment systems; beliefs and values of the education system; trends related to adult ADHD; and cultural and historical attitudes and influences related to treatment. RESULTS: Use of both medication and psychosocial treatment for ADHD varies widely within and across nations. More expensive long-acting formulations of medications are becoming more widespread. Nations with socialized medical care provide a wide array of evidence-based interventions. Economic, historical, and political forces and cultural values are related to predominant attitudes and practices. Strong antipsychiatry and antimedication voices remain influential in many nations. CONCLUSIONS: There is considerable variation in implementation of care for ADHD. Recognition of the social context of ADHD is an important step in ensuring access to evidence-based interventions for this prevalent, chronic, and impairing condition. PMID- 21532070 TI - Coercion in psychiatric care: systematic review of correlates and themes. AB - OBJECTIVE: This study systematically examined the empirical literature on the themes and correlates of coercion as defined by the subjective experience of patients in psychiatric care. METHODS: The study was a systematic review of the literature on coercion as covered in MEDLINE, PsycINFO, and CINAHL. From qualitative studies, themes that the authors identified were extracted. From quantitative studies, correlational and outcome data were extracted. RESULTS: The final analysis included 27 articles. Themes related to perceived coercion were almost all negative. Correlation and outcome data were insufficiently homogeneous to allow meaningful combined statistical analysis. There was no strong quantitative evidence that the experience of coercion is negatively or positively associated with psychopathology or general well-being. CONCLUSIONS: Coercion was commonly felt by patients as dehumanizing. Compulsory actions likely to increase perceived coercion had mixed correlates, and it was therefore difficult to predict who is at greatest risk of experiencing coercion as a "side effect" of intervention. Clinicians should routinely consider that all patients have the potential to experience an intervention as coercive. PMID- 21532071 TI - Perceived coercion and the therapeutic relationship: a neglected association? AB - OBJECTIVE: Increasing patient autonomy and decreasing coercion are frequently cited goals in mental health care. Research suggests that the therapeutic relationship and patients' experiences of coercion may be associated. This study investigated the association between the therapeutic relationship and perceived coercion in psychiatric admissions. METHODS: Associations between perceived coercion and the therapeutic relationship and sociodemographic and clinical variables were examined by using data from structured interviews with 164 patients consecutively admitted to two psychiatric hospitals in Oxford, England. RESULTS: High levels of coercion were experienced by 48% of voluntarily and 89% of involuntarily admitted patients. A high perceived coercion score was significantly associated with involuntary admission and a poor rating of the therapeutic relationship. The therapeutic relationship confounded legal status as a predictor of perceived coercion. CONCLUSIONS: Similar factors may influence patients' experience of both coercion and the therapeutic relationship during psychiatric hospital admission. Hospitalization, even when voluntary, was viewed as more coercive when patients rated their relationship with the admitting clinician negatively. Interventions to improve the therapeutic relationship may reduce perceptions of coercion. PMID- 21532072 TI - Systematic investigation of initiatives to reduce seclusion and restraint in a state psychiatric hospital. AB - OBJECTIVES: This study used an experimental design to examine the effect of systematic implementation of behavioral interventions on the rate of seclusion and restraint in an inpatient psychiatric hospital. METHODS: With a variant of the multiple-baseline design, a model designed to reduce seclusion and restraint was implemented at a large state-funded hospital in the southeastern United States. The implementation schedule was established such that each of five inpatient units was randomly assigned to implement the intervention components in a different order, and each unit served as its own control. Participants were patients and staff, for a total of 89,783 patient-days over a 3.5-year period from January 2005 through June 2008. The components included trauma-informed care training, changes to unit rules and language, changes to the physical characteristics of the therapeutic environment, and involvement of patients in treatment planning. The rate of inpatient psychiatric seclusion and restraint (per patient day) was tracked continuously during the 3.5-year period. RESULTS: A significant reduction of 82.3% (p=.008) in the rate of seclusion and restraint was observed between the baseline phase (January 2005 through February 2006) and the follow-up, postintervention phase (April 2008 through June 2008). After control for illness severity and nonspecific effects associated with an observation-only phase, changes to the physical environment were uniquely associated with a significant reduction in rate of seclusion and restraint during the intervention rollout period. CONCLUSIONS: These data suggest that substantial reductions in use of seclusion and restraint are possible in inpatient psychiatric settings and that changes to the physical characteristics of the therapeutic environment may have a significant effect on use of seclusion and restraint. PMID- 21532073 TI - Staff perceptions and organizational factors as predictors of seclusion and restraint on psychiatric wards. AB - OBJECTIVE: Several factors have been shown to be involved in decisions to use seclusion and restraint in psychiatric inpatient settings. This study examined whether staff perceptions of factors related to the care team and violence on the ward predicted use of seclusion and restraint in psychiatric wards. METHODS: A total of 309 staff members (nurses, rehabilitation instructors, and nurse's aides) providing care to patients with serious mental disorders were recruited from eight university psychiatric hospitals and general-hospital psychiatric units in the province of Quebec. Factors assessed included sociodemographic characteristics, psychological distress, staff perceptions of aggression and of interaction between members of the psychiatric team (team climate), and organizational factors. RESULTS: Bivariate analyses showed that certain aspects of the team climate, staff perceptions of aggression, and organizational factors were associated with greater use of seclusion and restraint. The final multivariate model indicated that the following factors independently predicted greater use: type of hospital ward (emergency department and intensive care unit), staff perception of a higher level of expression of anger and aggression among team members, perception of the frequency of incidents of physical aggression against the self among patients, and perception of insufficient safety measures in the workplace. CONCLUSIONS: These findings represent the first stage of a research program aimed at reducing use of seclusion and restraint in psychiatric settings. They underscore the importance of evaluating a variety of factors, including perceptions of safety and violence, when examining reasons for use of these controversial interventions. PMID- 21532074 TI - Characteristics of psychiatric inpatients who experienced restraint and those who did not: a case-control study. AB - OBJECTIVE: Use of restraint in acute psychiatric wards is highly controversial. Knowledge is limited about the characteristics of patients who are restrained and the predictors of use of restraint. This study examined whether restrained patients differed from nonrestrained patients in demographic, clinical, and medicolegal variables and to what extent the variables predicted use of restraint. METHODS: A two-year retrospective case-control design was used. The sample comprised all restrained patients (N=375) and a randomly selected control group of nonrestrained patients (N=374) from three catchment-area-based acute psychiatric wards in Norway. Data sources were restraint protocols and electronic patient files. RESULTS: The restrained patients were significantly younger and more likely to be men, to reside outside the wards' catchment areas, and to have an immigrant background. Restrained patients also had more admissions and longer inpatient stays than nonrestrained patients and were more likely to be involuntarily referred and to have one or more of the following ICD-10 diagnoses: a substance use disorder, schizophrenia or a related psychotic disorder, and bipolar disorder. Binary logistic regression analyses, adjusting for age, gender, immigrant background, and catchment area, indicated that the number of admissions, length of stay, legal basis for referral, and diagnosis each independently predicted the use of restraint. No interactions were found. CONCLUSIONS: Use of restraint was predicted by multiple admissions, long inpatient stays, involuntary admission, and serious mental illness. Identifying patients at risk may inform the development of alternatives to restraint for these patients. PMID- 21532075 TI - Factors contributing to mental health professionals' decision to use seclusion. AB - OBJECTIVE: The authors constructed an explanatory model of factors contributing to the decision to use seclusion. METHODS: Experts helped develop 64 vignettes that manipulated multiple patient and environmental variables. Eighty-two mental health professionals working on inpatient wards in four institutes in the Netherlands rated the vignettes. A univariate general linear model examined vignette variables and rater characteristics influencing the decision to use seclusion. RESULTS: Almost half of the decision to seclude (46%) could be explained by a combination of rater characteristics and vignette variables. Rater characteristics explained 31.7%, and vignette variables explained 27.9% (with a 13.6% interaction effect). Rater characteristics, in order of explanatory influence, were type of care provided by the professional (such as on a crisis intensive care or an observation-diagnostic unit), current frequency of participation in seclusion, the specific institute where the professional was employed (of the four participating institutes), experience using seclusion (number of years), and being in training to be a psychiatrist or a community mental health nurse. The primary vignette variables, in order of influence, were the approachability of the patient, seriousness of danger, availability of patient rooms and space, primary diagnosis, the professional's perceived trust in colleagues, staff-patient ratio during the shift, and voluntary or involuntary status. CONCLUSIONS: The model explained nearly half of the decision by mental health professionals to seclude vignette patients. Rater characteristics were at least as important as patient variables, including problem behaviors and diagnosis, and ward features. Because perceived approachability of the patient was a key factor, seclusion reduction policies should focus on supporting professionals in their efforts to manage inpatients with problem behaviors in an appropriate way. PMID- 21532076 TI - Arrest outcomes associated with outpatient commitment in New York State. AB - OBJECTIVE: This study examined whether assisted outpatient treatment (AOT) under New York's "Kendra's Law" is associated with reduced arrests for violent and nonviolent offenses. METHODS: Arrest records of 183 study participants attending outpatient clinics in New York City, 86 of whom were ever and 97 of whom were never assigned to AOT, were compiled to yield 16,890 months of observation. For each month the data indicated whether an arrest did or did not occur and whether a participant was or was not assigned to AOT. Generalized estimating equations and fixed-effects analyses were used to compare arrest rates within different periods (before, during or shortly after, and more than six months after) for those ever assigned and between the ever- and never-assigned groups. RESULTS: For those who received AOT, the odds of any arrest were 2.66 times greater (p<.01) and the odds of arrest for a violent offense 8.61 times greater (p<.05) before AOT than they were in the period during and shortly after AOT. The group never receiving AOT had nearly double the odds (1.91, p<.05) of arrest compared with the AOT group in the period during and shortly after assignment. CONCLUSIONS: Outpatient commitment under Kendra's Law in New York State is associated with a reduced risk of arrest. The coercion necessitated by application of the law may forestall, at least for some people, the potentially more potent and consequential coercion they would have experienced in the criminal justice system. PMID- 21532077 TI - Impact of illness management and recovery programs on hospital and emergency room use by Medicaid enrollees. AB - OBJECTIVE: Illness management and recovery is a structured program that helps consumers with severe mental illness learn effective ways to manage illness and pursue recovery goals. This study examined the impact of the program on health service utilization. METHODS: This was a retrospective cohort study of five assertive community treatment (ACT) teams in Indiana that implemented illness management and recovery. With Medicaid claims data from July 1, 2003, to June 30, 2008, panel data were created with person-months as the level of analysis, resulting in 14,261 observations for a total of 498 unique individuals. Zero inflated negative binomial regression models were used to predict hospitalization days and emergency room visits, including covariates of demographic characteristics, employment status, psychiatric diagnosis, and concurrent substance use disorder. The main predictor variables of interest were receipt of illness management and recovery services, dropout from the program, and program graduation status. RESULTS: Consumers who received some illness management and recovery services had fewer hospitalization days than those receiving only ACT. Graduates had fewer emergency room visits than did ACT-only consumers. CONCLUSIONS: This is the first study to examine the impact of illness management and recovery on service utilization. Controlling for a number of background variables, the study showed that illness management and recovery programs were associated with reduced inpatient hospitalization and emergency room use over and above ACT. PMID- 21532078 TI - Monitoring gender equity in mental health in a low-, middle-, and high-income country in the Americas. AB - OBJECTIVE: Gender disparities in mental health highlight the need to include gender equity measures when planning, implementing, and evaluating mental health programs at national, state or provincial, and municipal levels. This study aimed to identify, select, and assess the feasibility of comparing gender-sensitive mental health indicators in a low- (Peru), middle- (Colombia), and high- (Canada) income country. METHODS: The indicators were selected by a multidisciplinary group of experts who used criteria and a framework proposed by the World Health Organization. Data from national, population-based databases from each country were used to measure the indicators. RESULTS: Seven indicators (12-month prevalence of the following: depression, psychological distress, generalized anxiety disorder, suicide attempts, alcohol dependence, mental health service use, and psychological impairment) were feasible for measurement in at least two countries. Only five indicators were comparable between two countries, and only one was comparable among all countries (suicide attempts). The indicators that showed the greatest inequities between men and women were depression, anxiety, suicide attempts, use of mental health services, and alcohol dependence. Female to-male ratios for prevalence of mental illness ranged from .1 to 2.3, and ratios for service use ranged from 1.3 to 1.9. Significant trends were found when the indicators were considered by age, education, marital status, and income. CONCLUSIONS: Some of these indicators can be used to identify populations most vulnerable to gender inequities in mental health. The results from this study may provide useful information to program planners who aim to implement, improve, and monitor national mental health strategies that reduce gender inequities under different national conditions. PMID- 21532079 TI - Clinician factors related to outcome differences between black and white patients at CMHCs. AB - OBJECTIVES: Data are limited on how clinicians contribute to outcome differences between black patients and white patients. Because the clinician-patient relationship is the foundation of mental health services, understanding clinicians' role in outcome differences may help identify evidence-based interventions that decrease disparities and capitalize on positive differences. Symptoms and functioning in a sample of black and white adults receiving outpatient services were examined to determine the effects of their primary clinician on those patterns. METHODS: The study included 551 patients (25% black) with serious mental illness and 62 mental health professionals (21% black) identified as the patients' primary clinician. Treatment outcomes were measured at baseline and two follow-ups (two and four months) with the Behavior and Symptom Identification Scale, a measure of symptoms and functioning. Data were analyzed with hierarchical linear modeling. Clinicians' levels of multicultural competence, burnout, and education were analyzed. RESULTS: Clinicians moderated the relationship between patient race and outcome differences. There was significant variability among clinicians: approximately 20% had black patients whose outcomes were worse than those of their white patients, and 40% had black patients with better outcomes than their white patients. The only clinician factor predicting these differences was clinician's general experiences and relationships with people from racial-ethnic and cultural groups other than their own. CONCLUSIONS: The occurrence of outcome differences varied across clinicians, with some clinicians magnifying outcome differences between black and white patients and others minimizing them. Factors other than clinicians' race, multicultural competence, education, and burnout may contribute to outcome differences between black and white patients. PMID- 21532080 TI - Preferences for depression treatment among elderly home health care patients. AB - OBJECTIVE: The authors hypothesized that the depression treatment preferences of elderly home care patients would vary by their experience of depression and that preferences for active treatment would be associated with current depression and with antidepressant treatment. METHODS: The authors conducted cross-sectional secondary analyses of data from the TRIAD study (Training in the Assessment of Depression) of 256 randomly selected elderly patients newly admitted to home care. The study assessed preference for active treatments (medication or psychotherapy) and nonactive or complementary approaches (such as religious activities or doing nothing). Nondepressed patients were asked to choose as if they had serious depression. Two separate indicators of depression experience were used: a current diagnosis of major or minor depression and current or previous antidepressant treatment. RESULTS: Of the 256 patients, 16% (N=41) met criteria for major or minor depression. Forty-seven percent of the sample (N=121) preferred an active treatment as their first choice, and others preferred nonactive or complementary approaches. Logistic regression indicated that current antidepressant use, previous psychotherapy experience, white or Hispanic race ethnicity (versus black), greater impairment in instrumental activities of daily living, and less personal stigma about depression were independently associated with preference for an active treatment. CONCLUSIONS: Elderly home care patients had a variety of treatment preferences, ranging from active treatments, to religious or spiritual activities, to no treatment. Several factors were associated with a preference for active treatment, including treatment experience, physical impairment, race-ethnicity, and attitudes and beliefs. An understanding of patient preferences may help engage older depressed home care patients in treatment. PMID- 21532081 TI - Diagnosed depression among Medicare home health patients: national prevalence estimates and key characteristics. AB - OBJECTIVES: This study estimated the prevalence of diagnosed depression among elderly Medicare fee-for-service home health patients and identified demographic, functional, and care utilization characteristics associated with the diagnosis. METHODS: Data from the 2007 National Home and Hospice Care Survey were analyzed to generate nationally representative estimates. Chi square and Wald tests, corrected for the sampling design, tested for differences in categorical and continuous measures, respectively. RESULTS: Nationally, 6.4% (N=42,192) of the study population received a diagnosis of depression, which was associated with younger age (p=.016), lack of a primary caregiver other than the home care agency (p<.001), a lower likelihood of receiving medical social services (p=.010), and a greater likelihood of using antidepressants (p<.001). CONCLUSIONS: The rate of diagnosed depression was higher than the rate found in a previous study but lower than rates in studies that used diagnostic interviews or screening tools. Diagnosed depression was associated with a limited number of patient characteristics. PMID- 21532082 TI - Effectiveness of peer support in reducing readmissions of persons with multiple psychiatric hospitalizations. AB - OBJECTIVE: The study examined the feasibility and effectiveness of using peer support to reduce recurrent psychiatric hospitalizations. METHODS: A randomized controlled design was used, with follow-up at nine months after an index discharge from an academically affiliated psychiatric hospital. Patients were 18 years or older with major mental illness and had been hospitalized three or more times in the prior 18 months. Seventy-four patients were recruited, randomly assigned to usual care (N=36) or to a peer mentor plus usual care (N=38), and assessed at nine months. RESULTS: Participants who were assigned a peer mentor had significantly fewer rehospitalizations (.89 +/- 1.35 versus 1.53 +/- 1.54; p=.042 [one-tailed]) and fewer hospital days (10.08 +/- 17.31 versus 19.08 +/- 21.63 days; p<.03, [one tailed]). CONCLUSIONS: Despite the study's limitations, findings suggest that use of peer mentors is a promising intervention for reducing recurrent psychiatric hospitalizations for patients at risk of readmission. PMID- 21532083 TI - Enrollment in supported employment services for clients with a co-occurring disorder. AB - OBJECTIVE: People with serious mental illnesses and co-occurring substance use disorders are often excluded from vocational services, despite the lack of evidence that having a substance use disorder prevents them from being able to work. This study explored enrollment in supported employment services among clients with and without co-occurring substance use disorders. METHODS: With data from electronic medical records from a psychiatric rehabilitation agency, relationships between co-occurring substance use disorders and supported employment were examined among 1,748 clients with serious mental illnesses who were consecutively admitted to the agency over a two-year period. RESULTS: Despite a similar interest in employment, clients with a co-occurring substance use disorder were 52% less likely than those without to enroll in a supported employment program. Those who were enrolled had similar competitive employment rates (25% for those with co-occurring disorders and 28% for those without). CONCLUSIONS: People with co-occurring substance disorders have reduced rates of enrollment in supported employment services. PMID- 21532084 TI - Responding to stigma: first-time caregivers of young people with first-episode psychosis. AB - OBJECTIVE: This study explored how caregivers of young adults who had experienced a first episode of psychosis coped with stigma while maintaining their caregiving role. METHODS: Qualitative interviews were undertaken with 20 caregivers in Melbourne, Australia. RESULTS: Some caregivers adopted an open approach about disclosing their young person's illness. Alternatively, some were secretive about the illness, because of fears of and experiences with stigmatization if others found out. Caregivers also suggested ways to minimize the stigma that intensified their burden of care. CONCLUSIONS: The findings showed the kinds of roles that family members and others have in supporting caregivers. Caregivers who were secretive about their situation were particularly vulnerable to feeling burdened and needed additional support from clinicians. Caregivers need increased support to enable them to better cope with and respond to stigma. PMID- 21532085 TI - Quantifying the contribution of VA service-connected disability pensions to the "check effect". AB - OBJECTIVE: The study attempted to quantify the effect of receiving a disability pension check at the beginning of the month on the timing of substance-related hospitalizations in Department of Veterans Affairs (VA) facilities. METHODS: All substance-related hospitalizations during fiscal year 2005 were identified in the VA National Psychosis Registry (13,402 hospitalizations among 8,813 individuals) and in a random sample of VA patients without serious mental illness (689 hospitalizations among 508 individuals). Multivariable logistic regression examined the impact of pension check receipt on timing of hospitalizations while controlling for other predictors of substance-related hospitalizations. RESULTS: Receipt of a service-connected pension was associated with an increased risk of admission during the first two weeks of the month (odds ratio=1.08; 95% confidence interval=1.01-1.16). CONCLUSIONS: Staggering the disbursement of VA disability pensions (sending half the checks at the beginning and half in the middle of the month) might modestly reduce peak demand for substance-related inpatient services. PMID- 21532086 TI - Colocated general medical care and preventable hospital admissions for veterans with serious mental illness. AB - OBJECTIVE: This study examined whether veterans with serious mental illness in mental health settings with colocated general medical care had fewer hospitalizations for ambulatory care-sensitive conditions than veterans in other settings. METHODS: Using 2007 data, the study examined hospitalizations for ambulatory care-sensitive conditions with zero-inflated negative binomial regression controlling for demographic, clinical, and facility characteristics. RESULTS: Of 92,268 veterans with serious mental illness, 9,662 (10.5%) received care at ten sites with colocated care and 82,604 (89.5%) at 98 sites without it. At sites without colocation, 5.1% had a hospitalization for an ambulatory care sensitive condition, compared with 4.3% at sites with colocation. Attendance at sites with colocated care was associated with an adjusted count of hospitalizations of .76 compared with attendance at sites with no colocation (beta=-.28, 95% confidence interval=.47 to -.09, p=.004). CONCLUSIONS: Colocation of general medical services in the mental health setting was associated with significantly fewer preventable hospitalizations. PMID- 21532087 TI - Interrater reliability of using brief standardized outcome measures in a community mental health setting. AB - OBJECTIVE: Given psychiatry's need to implement measurement-based care, the study examined whether direct-care staff could reliably administer brief positive and negative symptom instruments to track symptom changes and inform clinical decision making. METHODS: Raters (82 case managers) were assessed at baseline. Training was provided for individuals not meeting reliability criteria. These individuals were reassessed to determine the effect of training. In addition, rater drift was assessed for raters judged to be reliable at baseline. RESULTS: Seventy-seven percent of direct-care staff met criteria for reliability either at baseline or after they received additional training. CONCLUSIONS: A majority of direct-care staff can be trained to reliability on brief scales of positive and negative symptoms that can be used to guide clinical decision making. PMID- 21532088 TI - Creating a medical home for homeless persons with serious mental illness. PMID- 21532089 TI - "Keshet": enhancing cognitive communication skills in families. PMID- 21532091 TI - Inpatient care in the 21st century: who needs it? PMID- 21532092 TI - Is "medication visit" a misnomer? Psychotherapy challenges in 90862. PMID- 21532093 TI - Hong Kong physicians' views on who should treat mild depression. PMID- 21532094 TI - Portrayal of schizophrenia in a prestigious newspaper in Brazil. PMID- 21532096 TI - Denosumab an option for patients with bone metastasis from breast cancer. PMID- 21532097 TI - Sunscreen use in adults is beneficial in preventing melanoma. PMID- 21532098 TI - Detecting and monitoring lymphoma with high-throughput sequencing. PMID- 21532099 TI - Receiver operating characteristic (ROC) curve for medical researchers. AB - Sensitivity and specificity are two components that measure the inherent validity of a diagnostic test for dichotomous outcomes against a gold standard. Receiver operating characteristic (ROC) curve is the plot that depicts the trade-off between the sensitivity and (1-specificity) across a series of cut-off points when the diagnostic test is continuous or on ordinal scale (minimum 5 categories). This is an effective method for assessing the performance of a diagnostic test. The aim of this article is to provide basic conceptual framework and interpretation of ROC analysis to help medical researchers to use it effectively. ROC curve and its important components like area under the curve, sensitivity at specified specificity and vice versa, and partial area under the curve are discussed. Various other issues such as choice between parametric and non-parametric methods, biases that affect the performance of a diagnostic test, sample size for estimating the sensitivity, specificity, and area under ROC curve, and details of commonly used softwares in ROC analysis are also presented. PMID- 21532100 TI - Patent ductus arteriosus in preterm infants. AB - Patent ductus arteriosus (PDA) is a major morbidity in preterm infants, especially in extremely premature infants less than 28 weeks. The clinical signs and symptoms of PDA in preterm infants are non specific and insensitive for making an early diagnosis of significant ductal shunting. Functional echocardiography is emerging as a new valuable bedside tool for early diagnosis of hemodynamically significant ductus, even though there are no universally accepted criteria for grading the hemodynamic significance. Echocardiography has also been used for early targeted treatment of ductus arteriosus, though the long term benefits of such strategy are debatable. The biomarkers like BNP and N terminal pro BNP are currently under research as diagnostic marker of PDA. The primary mode of treatment for PDA is pharmacological closure using cyclo oxygenase inhibitors with closure rate of 70-80%. Oral ibuprofen is emerging as a better alternative especially in Indian scenario where parenteral preparations of indomethacin are unavailable and side effects are comparatively lesser. Though pharmacological closure of PDA is an established treatment modality, there is still lack of evidence for long term benefits of such therapy as well as there is some evidence for the possible adverse effects like increased ROP and BPD rates, especially if treated prophylactically. Hence, it is prudent to reserve treatment of PDA to infants with clinically significant ductus on the basis of gestation, birth weight, serial echocardiography and clinical status to individualize the decision to treat. PMID- 21532101 TI - Tryptophan for the treatment of excessive daytime sleepiness in Prader-Willi syndrome. AB - An 8-year old girl with Prader-Willi Syndrome presenting with excessive daytime sleepiness improved following treatment with tryptophan; possibly by consolidation of her fragmented sleep. Improvement was recorded on a follow-up sleep study, one year after initiating treatment with tryptophan. We conclude that tryptophan may be an useful medication for excessive sleepiness in children with Prader-Willi Syndrome. PMID- 21532102 TI - Umbilical myiasis in newborn. AB - Umbilical myiasis is rare in newborns. We are reporting two cases of umbilical myiasis from rural West Bengal (India) that were infected by larval forms of blow fly (Chrysomya megacephala). One of them subsequently developed septicemia while the other one was clinically well. PMID- 21532103 TI - Hormone dust exposure a reversible cause of precocious pseudopuberty in siblings. AB - A seven year old female child presented with two episodes of vaginal bleeding and bilateral breast development. Examination showed normal anthropometric measurements and external genitalia of prepubertal type. Her 5-year old younger brother and her father had gynaecomastia. Search for a structural cause for precocious puberty was negative. Occupational exposure of her father to hormonal dust was identified as the cause. All pubertal changes reverted to normal after observing suitable precautions. PMID- 21532104 TI - MRI abnormalities of the anterior temporal lobe: a new indicator of congenital cytomegalovirus infection. AB - Abnormalities of the anterior part of the temporal lobe (abnormal and swollen white matter, cysts, and focal enlargement of the anterior part of the inferior horn- either alone or more often in combination) suggest congenital cytomegalovirus (CMV) infection. This is not widely known. These can be seen in neonatal period and they continue to persist in later life. PMID- 21532105 TI - Correlation of nasal smear eosinophilia with class of allergic rhinitis. AB - We correlated the grade of nasal smear eosinophilia with severity of allergic rhinitis, in 50 children in a cross sectional study conducted at a tertiary care referral hospital, between August 2007 to July 2009. The grade of nasal smear eosinophilia correlated well with increasing severity of allergic rhinitis (P<0.001)(r=0.83). PMID- 21532106 TI - High sensitivity C reactive protein in classical Kawasaki disease. PMID- 21532107 TI - Comparison of alert verbal painful unresponsiveness scale and the Glasgow Coma Score. AB - To determine how the AVPU (alert, verbal, painful, unresponsiveness) scale corresponds to Glasgow Coma Score (GCS), we compared the two scales. Two months to 12 years old patients were included in the study. The median GCS score (inter quartile range) for A/V/P/U were 14 (12-15), 11 (10-12), 6 (5.5-8) and 3 (3-4), respectively. PMID- 21532109 TI - Progressive symmetric Erythrokeratodermia. PMID- 21532108 TI - Persistence of stunting after highly active antiretroviral therapy in HIV infected children in South India. AB - After one year of antiretroviral treatment in 49 HIV infected children compared to 53 children without, weight for age improved significantly and was highly correlated with baseline immune status and CD4% increase but height for age did not change. Stunting is a common feature of pediatric HIV, both on and off HAART. PMID- 21532110 TI - Cutaneous leishmaniasis. PMID- 21532111 TI - Erythema infectiosum rash. PMID- 21532112 TI - [Lifestyle-related disease and fracture risk]. AB - Meta analysis of fracture risk in diabetes indicates that the risk of proximal femoral fracture in type-2 diabetes is increased 1.4-1.7 times. It is well known that increased fracture risk is observed in serious kidney disease. However, it has recently been reported that increased fracture risk is also observed in the early stages of chronic kidney disease (CKD) . The risk of proximal femoral fracture increases in early stages after stroke, but gradually decreases in subsequent stages. Some reports indicate decreased fracture risk in metabolic syndrome and hyperlipidemia and increased fracture risk in hypertension, arterial calcification and ischemic heart disease, while other reports indicate contradictory results. PMID- 21532113 TI - [Bone quality in lifestyle-related diseases]. AB - Lifestyle-related diseases deteriorate bone quality in terms of material properties. Collagen cross-link formation is thought to be a determinant of material strength. Hyperglycemia, oxidative stress, carbonyl stress, and hyperhomocysteinemia induce the reduction in beneficial enzymatic cross-links and the accumulation of disadvantageous non-enzymatic cross-link, Advanced glycation end products (AGEs, Pentosidine) in bone. In this review, we describe that lifestyle-related diseases are crucial determinants of detrimental crosslinking of bone collagen that have been reported in the literature. PMID- 21532114 TI - [Effects of drugs for lifestyle-related diseases on bone metabolism]. AB - Accumulating evidence indicates several drugs for lifestyle-related diseases are involved in bone metabolism. Drugs that might reduce fracture incidence are statins, beta-blockers and thiazide diuretics, and those that might increase fractures are thiazolidinediones and loop diuretics. It is yet controversial whether ACE inhibitors, angiotensin receptor- II blockers and aldosterone receptor antagonists are indeed involved in the increase or the decrease in fracture incidence. PMID- 21532115 TI - [Diabetes Mellitus and bone metabolism]. AB - Deranged bone metabolism including osteoporosis is now clinically recognized as one of the diabetic complications. Diabetes could affect bone through multiple mechanisms, insulin deficiency, insulin resistance, hyperglycemia, atherosclerosis, etc. However, the exact mechanisms by which bone derangement is brought about in diabetes are yet unknown. In type 2 diabetes, fracture risk is increased despite high bone mineral density (BMD) through deteriorated "bone quality" , of which assessment is clinically difficult. Thus, it would be important for physicians to recognize diabetes as a fracture risk, and to assess each patient's fracture risk using available tools i.e. BMD, metabolic bone markers, etc. Intense treatment for osteoporosis is warranted in diabetics who have other established fracture risks such as those with prevalent fractures or postmenopausal state. PMID- 21532116 TI - [Bone metabolism in dyslipidemia and metabolic syndrome]. AB - Dyslipidemia and osteoporosis are etiologically related to each other. Experiments show that oxidized LDL suppresses the differentiation of bone marrow stromal cells to osteoblasts, while it promotes that to adipocytes, which may result in fatty marrow and bone mass reduction. Inactivation of LRP5/6 is linked to hypercholesterolemia as well as bone mass reduction, indicating the involvement of Wnt signaling in both disorders. A few clinical studies suggest that high serum triglyceride levels may lower the risk of vertebral fractures. Metabolic syndrome, especially visceral fat accumulation, may have a beneficial effect on bone possibly through mechanical stress from gravity, as long as patients are devoid of advanced type 2 diabetes and are less affected by hyperglycemia or oxidative stress. PMID- 21532117 TI - [Hypertension, CKD and bone metabolism]. AB - The patients with "Hypertension" and "Chronic Kidney Disease (CKD) " are accompanied with an osteoporosis. In hypertension patients, excess urinary calcium secretion induces secondary parathyroidsim to increase serum calcium (Ca) level, which may lead to Ca release from bone. In this aspect, there are several reports that anti-hypertensive drugs, especially thiazides, increase bone mineral density and decrease the incidence of bone fracture. In addition, we demonstrated that renin-angiotensin system can be involved in the process of osteoporosis. Angiotensin II significantly induced the expression of RANKL (receptor activator of NF-kappaB ligand) in osteoblasts, leading to the activation of osteoclasts, while these effects were completely blocked by an Ang II type 1 receptor blockade. As for CKD, excess phosphorus (P) due to renal dysfunction induces secondary parathyroidism to decrease serum P level, which similarly leads to osteoporosis. Moreover, excess P can increase FGF23 expression and decrease activated vitamin D, which also resulted in progression of osteoporosis. Both "Hypertension" and "Chronic Kidney Disease (CKD) " are inducible factor to osteoporosis. PMID- 21532118 TI - [Control of bone metabolism by central nervous system]. AB - It has been believed that bone is controlled by local environment through the action of hormone and cytokines, independently of other organs. However, the discovery that leptin regulates bone formation through the central nervous system shed light on a new regulatory system of bone metabolism, i.e., neuronal control. Moreover, recent discovery that osteocalcin regulates glucose metabolism and fertility clearly demonstrated that bone forms a regulatory network of metabolism, together with other organs. PMID- 21532119 TI - [Inflammatory control on lifestyle-related diseases and bone metabolism]. AB - Recent findings suggest that chronic inflammation is involved in lifestyle related diseases and osteoporosis. Members of nuclear receptor superfamily have regulatory effects on inflammatory processes and cytokine responses which contribute to prevention and treatment of above diseases. Here, recent studies are described that these nuclear receptors have regulatory roles called transrepression in chronic inflammatory diseases through their interactions with transcription factors and cell-signaling systems. PMID- 21532120 TI - [Adipocytes and bone metabolism]. AB - Adipocytes, osteoblasts and chondrocytes derive from common mesenchymal stem cells. A number of factors were reported to regulate differentiation of multiple cell types among adipocytes, osteoblasts and chondrocytes. Thiazolidinediones are prescribed to treat diabetes in obese subjects, but recent clinical data suggested that it increases a risk of bone fracture especially in postmenopausal women. Here, we will review recent advances in the researches of mutual connection between adipocytes and bone metabolism. PMID- 21532121 TI - [Bone remodeling and glucose/lipid metabolism]. AB - It has been demonstrated that osteocalcin, osteoblast-derived molecule, regulates glucose/lipid metabolism through increasing insulin secretion from pancreas and insulin sensitivity in peripheral tissues. This finding established that bone is an important endocrine organ to regulate glucose/lipid metabolism. Recently, it has been reported that insulin signaling in osteoblasts was a positive regulator of bone acquisition, but also of bone resorption. Interestingly, insulin signaling in osteoblasts activated osteocalcin embedded in bone ECM by stimulating resorption activity in osteoclast. This finding indicated that the osteoblasts is an important target cells used by insulin which playing a central role in glucose/lipid metabolism. The bone/glucose metabolism interaction established by these studies will be important to a study of the two fields in the future, particularly a clinical field. PMID- 21532122 TI - [Diet, exercise and bone metabolism]. AB - Osteoporosis is a major public health issue in Japan, and key factors for its prevention are diet and exercise. Vitamin D and K are strongly associated with bone metabolism. The recommended daily vitamin D and K requirements are 400-800 IU and 250-300MUg, respectively. In addition, exercise is effective for the improvement of bone mineral density in the elderly. Regular exercise and improvement of diet are important for the prevention of osteoporosis in the aging society. PMID- 21532123 TI - [Exercise for prevention of osteoporosis and other lifestyle-related diseases]. AB - The prevalence of lifestyle-related diseases including hypertension, dyslipidemia (hyperlipidemia) and diabetes increases with aging, and all these conditions are risk factors of arteriosclerotic diseases such as cerebrovascular event (stroke) and myocardial infarction. The term "metabolic domino" has been used to describe the collective concept of the development and progression of these lifestyle related diseases, the sequence of events, and the progression process of complications. Like the first tile of a domino toppling game, undesirable lifestyle such as overeating and underexercising first triggers obesity, and is followed in succession by onset of an insulin resistance state (underlied by a genetic background indigenous to Japanese) , hypertension, hyperlipidemia, and further postprandial hyperglycemia (the pre-diabetic state) , the so-called metabolic syndrome, at around the same time. On the other hand, apart from the other lifestyle-related diseases, the prevalence of osteoporosis also increases rapidly accompanying aging. Osteoporosis is known to be strongly related to disorders due to the metabolic domino such as arteriosclerosis and vascular calcification, and a new disease category called "osteo-vascular interaction" has attracted attention recently. Regarding "osteo-vascular interaction" , a close relation between bone density loss or osteoporotic changes and vascular lesion associated lifestyle-related diseases such as hypertension, dyslipidemia and diabetes has been reported. Therefore, as a common preventive factor for bone mass loss or osteoporosis and lifestyle-related diseases including hypertension, dyslipidemia and diabetes (osteo-vascular interaction) , exercise has been recognized anew as an important non-pharmaceutical therapy that should take top priority. This article overviews the evidence of exercise therapy for the prevention of osteoporosis and other lifestyle-related diseases, from the viewpoint of health promotion, especially of the skeletal system (motor system) . PMID- 21532124 TI - [Diet for lifestyle-related diseases to maintain bone health]. AB - Dieting methods for preventing age-related diseases such as cardiovascular disease, hypertension and diabetes, as well as osteoporosis are proposed here. Losing weight to prevent and ameliorate metabolic syndrome can lead to loss of bone and muscle mass. However, when subjects had milk before dinner while dieting, their fat mass was efficiently decreased and their muscle mass increased without any change of bone mass. Increased intake of vitamin D enhanced these effects. Therefore we suggest that people with high risk of metabolic disorders should take more low fat dairy products and fish, together with fruits, vegetables, and soy in order to increase their intake of calcium, vitamin D, n-3 polyunsaturated fatty acids, protein, antioxidants, various vitamins and minerals, and fiber to protect them from the deterioration of arteries and bones. PMID- 21532125 TI - [Pharmacotherapy of osteoporosis accompanied by lifestyle-related diseases]. AB - Lifestyle-related diseases, such as diabetes mellitus, hypertension and dyslipidemias, are often accompanied by osteoporosis. Treatment of osteoporosis in such cases is essentially the same as that for primary osteoporosis, but it is important to be aware of the interference between osteoporosis treatment and the drugs used for the lifestyle-related diseases. Raloxifene, bisphosphonates and activated vitamin D are commonly used for treatment of osteoporosis, and they are reported to have a positive effect on atherosclerosis. Beta-blocker use, particularly selective beta-blocker, is associated with reduced fracture risk. Statin is also reported to stimulate bone formation via bone morphogenetic protein-2 expression, but their clinical utility has not yet been confirmed. One class of antidiabetic drugs, thiazolidinediones, causes bone loss and further increases fracture risk, placing thiazolidinediones in the category of drugs causing secondary osteoporosis. PMID- 21532126 TI - [Whether bone quality matters or not in durability of total hip arthroplasty? Bone quality matters in durability of total hip arthroplasty]. AB - Evolution in surgical techniques and prosthetic designs and materials has improved durability of total hip arthroplasty (THA) . As a result, bone quality of the hip joint has become an important risk factor limiting the durability of THA. In preparation of the acetabular bony bed, the subchondral bone or eburnated bone of good bone quality should be preserved. Sockets fixed in joints with atrophic osteoarthrosis were at a higher risk for loosening than those in joints with normotrophic or hypertrophic osteoarthrosis. Femoral components set in the proximal femurs with a stovepipe canal were at a higher risk for loosening than these in the proximal femurs without. To further improve the durability of THA, the issues of poor bone quality and structure of the hip joint should be overcome. PMID- 21532127 TI - [Whether bone quality matters or not in durability of total hip arthroplasty? Little relationship between bone quality of the hip and durability of total hip arthroplasty]. AB - The durability of total hip arthroplasty (THA) is affected by patient-related factors such as age, gender, body weight, disease, and bone quality, as well as the materials and design factors of the hip implants, and the surgical technique employed. Bone quality may relate to the longevity of hip implants via the risk of periprosthetic fractures, but nowadays this is not a big issue due to the advancement of materials, designs, and techniques in THA. PMID- 21532128 TI - Experimental arrest of cerebral blood flow in human subjects: the red wing studies revisited. AB - Loss of consciousness in pilots during rapid ascent after bombing missions was a major problem in World War II, and experiments were undertaken to study the cause of this phenomenon. Postulating impaired cerebral blood flow as a likely mechanism, the investigators developed a neck device, the KRA Cuff, which when inflated could shut off blood supply to the brain. With cessation of blood flow for up to 100 seconds, the investigators observed a sequence of responses, including unconsciousness, followed by dilated pupils, tonic/clonic movements, loss of bladder and eventually bowel control, and appearance of pathological reflexes. This study, carried out in prisoners and patients with schizophrenia in 1941-42, largely disappeared from public discourse for a number of years. It has received occasional attention subsequently and been considered controversial. Recently discovered records, including extensive written and photographic data from the studies, shed new light on the methods and motives of the research team. We describe here this new information and its implications for the scientific and ethical assessment of the study. PMID- 21532129 TI - A reformulation of the social brain theory for schizophrenia: the case for out group intolerance. AB - This article proposes a reformulation of the social brain theory of schizophrenia. Contrary to those who consider schizophrenia to be an inherently human condition, we suggest that it is a relatively recent phenomenon, and that the vulnerability to it remained hidden among our hunter-gatherer ancestors. Hence, we contend that schizophrenia is the result of a mismatch between the post Neolithic human social environment and the design of the social brain. We review the evidence from human evolutionary history of the importance of the distinction between ingroup and out-group membership that lies at the heart of intergroup conflict, violence, and xenophobia. We then review the evidence for the disparities in schizophrenia incidence around the world and for the higher risk of this condition among immigrants and city dwellers. Our hypothesis explains a range of epidemiological findings on schizophrenia related to the risk of migration and urbanization, the improved prognosis in underdeveloped countries, and variations in the prevalence of the disorder. However, although this hypothesis may identify the ultimate causation of schizophrenia, it does not specify the proximate mechanisms that lead to it. We conclude with a number of testable and refutable predictions for future research. PMID- 21532130 TI - A consumer's guide to superorganisms. AB - The organism, like the molecule, the cell, and the species, is one of the fundamental levels in our hierarchical classification of life and its components. The units ranked at these levels, being concrete, particular things, are individuals in the broadest philosophical sense. But in a much narrower and more familiar sense, individual means an individual organism. Like species, the term individual is hard to define, but in most biological discourse it has meant the unit of philosophical autonomy. Some authors have attempted to revise this terminology, restricting individual to organisms, and redefining organism to include families and other units. Such semantic surgery is unnecessary if the goal is merely to justify selection at more than one level. Analogies between levels may be interesting, but many of them do not deserve to be taken seriously. PMID- 21532131 TI - Prescribing psychotherapy. AB - Psychotherapy has long been an integral treatment modality for patients with psychiatric conditions, but recent evidence suggests that the practice of psychotherapy by psychiatrists has greatly diminished. Between 1996 and 2005, the percentage of psychiatry office visits involving psychotherapy decreased from about 44% to 29%, a 35% reduction in less than 10 years. Although the increasing availability of medications to treat psychiatric disorders has played a role in this decline, it is not the only factor. This essay reviews the multiple forces effecting this shift and highlights the limited knowledge base regarding the impact of this change on patients. The essay concludes with a call for research to prevent unintended and potentially harmful consequences to patients and to inform the continued role of psychotherapy in residency education. PMID- 21532132 TI - Medical cure and progress: the case of type-1 diabetes. AB - Medicine often defines progress in terms of medical cures; however, such cures are rare. At best, medical progress generally consists of managing patients more efficiently or competently, especially in terms of relieving their symptoms. Today, medicine stands on the edge of curing a number of diseases. However, before achieving such cures, biomedical scientists need to understand in finer detail the mechanisms of physiological and pathological processes, especially from a systems perspective, and students of biomedical studies need to understand more precisely what a medical cure is conceptually or philosophically. This article utilizes type-1 diabetes to explore the issues surrounding medical progress with respect to defining medical cure, especially in terms of distinguishing it from managing a patient's illness. PMID- 21532133 TI - Classification, disease, and diagnosis. AB - Classification shapes medicine and guides its practice. Understanding classification must be part of the quest to better understand the social context and implications of diagnosis. Classifications are part of the human work that provides a foundation for the recognition and study of illness: deciding how the vast expanse of nature can be partitioned into meaningful chunks, stabilizing and structuring what is otherwise disordered. This article explores the aims of classification, their embodiment in medical diagnosis, and the historical traditions of medical classification. It provides a brief overview of the aims and principles of classification and their relevance to contemporary medicine. It also demonstrates how classifications operate as social framing devices that enable and disable communication, assert and refute authority, and are important items for sociological study. PMID- 21532134 TI - "A gentle and humane temper": humility in medicine. AB - Humility is the medical virtue most difficult to understand and practice. This is especially true in contemporary medicine, which has developed a culture more characterized by arrogance and entitlement than by self-effacement and moderation. In such a culture, humility suggests weakness, indecisiveness, or even deception, as in false modesty. Nonetheless, an operational definition of medical humility includes four distinct but closely related personal characteristics that are central to good doctoring: unpretentious openness, honest self-disclosure, avoidance of arrogance, and modulation of self-interest. Humility, like other virtues, is best taught by means of narrative and role modeling. We may rightly be proud of contemporary medical advances, while at the same time experiencing gratitude and humility as healers. PMID- 21532135 TI - Genomics and the Ark: an ecocentric perspective on human history. AB - Views of ourselves in relationship to the rest of the biosphere are changing. Theocentric and anthropocentric perspectives are giving way to more ecocentric views on the history, present, and future of humankind. Novel sciences, such as genomics, have deepened and broadened our understanding of the process of anthropogenesis, the coming into being of humans. Genomics suggests that early human history must be regarded as a complex narrative of evolving ecosystems, in which human evolution both influenced and was influenced by the evolution of companion species. During the agricultural revolution, human beings designed small-scale artificial ecosystems or evolutionary "Arks," in which networks of plants, animals, and microorganisms coevolved. Currently, our attitude towards this process seems subject to a paradoxical reversal. The boundaries of the Ark have dramatically broadened, and genomics is not only being used to increase our understanding of our ecological past, but may also help us to conserve, reconstruct, or even revivify species and ecosystems to whose degradation or (near) extinction we have contributed. This article explores the role of genomics in the elaboration of a more ecocentric view of ourselves with the help of two examples, namely the renaissance of Paleolithic diets and of Pleistocene parks. It argues that an understanding of the world in ecocentric terms requires new partnerships and mutually beneficial forms of collaboration and convergence between life sciences, social sciences, and the humanities. PMID- 21532136 TI - The physician-administrator as patient: distinctive aspects of medical care. AB - This article examines distinctive aspects of medical care experienced by a 55 year-old hospitalized for quintuple coronary artery bypass surgery who was also a senior physician-administrator (chief of gastroenterology) at the same hospital. The article describes eight distinctive aspects of administrator-physicians as patients, including special patient treatment; exalted patient expectations by hospital personnel; patient suppression of emotions; patient denial; self doctoring; job stress contributing to disease; self-sacrifice to achieve better health; and rational medical decisions when not under stress. Health-care workers should recognize how these distinctive aspects of medical care and behavior affect administrator-physicians as patients, in order to mitigate their negative effects, potentiate their positive effects, and optimize the care of these patients. PMID- 21532137 TI - Medicine, methodology, and values: trade-offs in clinical science and practice. AB - The current guidelines of evidence-based medicine (EBM) presuppose that clinical research and clinical practice should advance from rigorous scientific tests as they generate reliable, value-free knowledge. Under this presupposition, hypotheses postulated by doctors and patients in the process of their decision making are preferably tested in randomized clinical trials (RCTs), and in systematic reviews and meta-analyses summarizing outcomes from multiple RCTs. Since testing under this scheme is predominantly focused on the criteria of generality and precision achieved through methodological rigor, at the cost of the criterion of realism, translating test results to clinical practice is often problematic. Choices concerning which methodological criteria should have priority are inevitable, however, as clinical trials, and scientific research in general, cannot meet all relevant criteria at the same time. Since these choices may be informed by considerations external to science, we must acknowledge that science cannot be value-free in a strict sense, and this invites a more prominent role for value-laden considerations in evaluating clinical research. The urgency for this becomes even more apparent when we consider the important yet implicit role of scientific theories in EBM, which may also be subjected to methodological evaluation and for which selectiveness in methodological focus is likewise inevitable. PMID- 21532138 TI - Teaching quality and cost in the tumultuous era of health-care reform. AB - The passage of the 2010 Affordable Care Act has not ended bitter debates around the policies and practice patterns required to appropriately balance access, quality, and cost in the U.S. health-care system. While many physicians have asked simply "to be left alone" to continue practicing as they see fit, this is an increasingly untenable position, given the notably high costs and very mixed clinical outcomes in the United States relative to other developed nations. A new multi-author text on Medical Quality Management stresses physician involvement in health-care quality, safety, and efficiency and lays out key concepts to help readers better understand many of the national challenges and opportunities that lie ahead. This essay extends lessons from this book and the national debate on health-care reform and suggests promising areas for clinician engagement in the ongoing evolution of the U.S. health-care system. PMID- 21532139 TI - Baseball pitching: understanding the mechanics of throwing a baseball may help protect the shoulder and elbow. AB - Whether you are the pitcher, coach, or concerned parent, the health of the athlete's throwing arm is very important. A better understanding of the forces that occur during different types of baseball throws could lead to improved guidelines, helping to boost performance while preventing injuries. A study published in the May 2011 issue of JOSPT provides new insight into the forces placed on the shoulder and elbow during flat-ground and long-toss throws. PMID- 21532140 TI - A nonfunctioning pituitary adenoma in a patient with dizziness. PMID- 21532141 TI - Persistent lateral foot pain in a patient with a fifth metatarsal fracture. PMID- 21532144 TI - The neuroprotection of oxymatrine in cerebral ischemia/reperfusion is related to nuclear factor erythroid 2-related factor 2 (nrf2)-mediated antioxidant response: role of nrf2 and hemeoxygenase-1 expression. AB - Cerebral ischemia-reperfusion (CI/R) injury remains a major medical problem due to the lack of effective therapies. Previous studies have shown that increasing the activity of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and gene targets in cell culture and stroke animal models is highly neuroprotective. Oxymatrine is the major quinolizidine alkaloid extracted from the root of Sophora flavescens AIT, and has been proved to be protective after ischemia in recent studies. The present study was designed to investigate the potential effect of oxymatrine in ischemia-reperfusion injury in rat's brain and to explore the possible role of oxymatrine in Nrf2 pathway. The results indicated that the ischemic infarct and edema were significantly reduced in rats that received oxymatrine, with a corresponding improvement in neurological function after CI/R. In immunohistochemistry and Western blotting analyses, Nrf2 and hemeoxygenase-1 (HO-1) were up-regulated in ischemic cortex, beginning at 6 h, peaking at 48 h and declining at 72 h after CI/R. Intraperitoneal injection of oxymatrine inhibited the production of lipid peroxidation and increased the activities of Nrf2 and HO-1 in rats brain after CI/R. Taken together, these results suggest that oxymatrine administered systemically protected brain against focal ischemia-reperfusion damage at the early stage of stroke, and that activating Nrf2/HO-1 pathway may contribute to the neuroprotective action of oxymatrine in rat focal brain ischemia-reperfusion model. Thus, treatment of stroke with oxymatrine may prevent severe consequences after brain attack. PMID- 21532142 TI - Bilateral absence of the A3 pulleys in a rock climber. PMID- 21532145 TI - Inhibition of Akt (ser473) phosphorylation and rapamycin-resistant cell growth by knockdown of mammalian target of rapamycin with small interfering RNA in vascular endothelial growth factor receptor-1-targeting vector. AB - Previously we developed dicetyl phosphate-tetraethylenepentamine-based polycation liposomes (TEPA-PCL) for use in small interfering RNA (siRNA) therapy. In the present study, mammalian target of rapamycin (mTOR) expression in cancer cells was silenced with mTOR-siRNA (simTOR) formulated in TEPA-PCL modified with Ala Pro-Arg-Pro-Gly (APRPG), a peptide having affinity for vascular endothelial growth factor receptor-1 (VEGFR-1). We investigated the effects of inhibition of mTOR, focusing on the differences between cells treated with simTOR and those with rapamycin in terms of Akt (ser473) phosphorylation and antiproliferative effects. Rapamycin treatment is known to induce Akt (ser473) phosphorylation which attenuates the antiproliferative effects of rapamycin. As a result, knockdown of mTOR did not alter or only slightly reduced Akt (ser473) phosphorylation in phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-null (LNCaP and MDA-MB-468 cells) and PTEN-positive (DU 145 and MDA-MB 231) cells, although rapamycin induced Akt (ser473) phosphorylation of these cells. Rapamycin suppressed the growth of PTEN-null cells, in which the rapamycin sensitive mTOR complex 1 (mTORC1) is excessively activated. On the other hand, rapamycin did not suppress the growth of PTEN-positive cells possibly through a negative feedback mechanism via the rapamycin-insensitive mTOR complex 2 (mTORC2) signaling pathway. In contrast, simTOR significantly suppressed the growth of cancer cells regardless of the presence of PTEN, possibly through inhibition of both mTORC1 and mTORC2. These results indicate that mTOR knockdown using APRPG TEPA-PCL/simTOR is likely to be an effective strategy for cancer siRNA therapy. PMID- 21532146 TI - Protective effects of glycyrrhizin against beta2-adrenergic receptor agonist induced receptor internalization and cell apoptosis. AB - It has been reported that treatment with beta2 adrenergic receptor (beta2AR) agonist bronchodilators may result in airway beta2ARs internalization and cardiac muscle cells apoptosis. This could lead to the loss of pharmacological effect of beta2AR agonists and increase adverse cardiovascular events in asthma patients receiving beta2AR agonist therapy. Glycyrrhizin, the major bioactive component of licorice root extract, has been reported to exhibit protective effect on respiratory system. Here, we investigate the effects of glycyrrhizin against beta2AR agonist salbutamol-induced receptor internalization and cell apoptosis. In our study, the live cell confocal imaging and fixed-cell enzyme-linked immunosorbent assay (ELISA) assay revealed that glycyrrhizin significantly inhibited salbutamol-induced surface beta2AR internalization. The underlying mechanisms were then identified to be that glycyrrhizin could reduce the association of beta2ARs with beta-arrestins and clathrin heavy chain as well as the level of G protein-coupled receptor kinase (GRK) mediated phosphorylation of beta2ARs. The inhibition of receptor internalization by glycyrrhizin further lead to stabilization of the beta2AR mRNA and protein expression, thus amplified the transmembrane signaling via the beta2ARs. We also proved that glycyrrhizin could profoundly attenuate salbutamol-induced early cellular apoptosis by regulating the expressions of B-cell lymphoma 2 (Bcl-2) family genes. Taken together, our results suggest that glycyrrhizin exhibits protective effects against beta2AR agonist-induced receptor internalization and cell apoptosis. These findings might have practical implications for future strategies of combined application of glycyrrhizin with beta2AR receptor agonists to improve the efficacy of bronchodilators in patients with asthma and chronic obstructive pulmonary disease (COPD). PMID- 21532147 TI - Inhibition of reactive oxygen species/extracellular signal-regulated kinases pathway by pioglitazone attenuates advanced glycation end products-induced proliferation of vascular smooth muscle cells in rats. AB - Advanced glycation end products (AGEs) have been shown to induce the proliferation of vascular smooth muscle cells (VSMCs) and contribute to atherogenesis and diabetes. In the present study, we investigated the effects of pioglitazone, a peroxisome proliferator activated receptor gamma (PPARgamma) agonist, on AGE-induced rat VSMC growth and the underlying mechanism. In cultured rat VSMCs, AGE treatment induced VSMC proliferation in time- and dose-dependent manner, while down-regulated the expression of PPARgamma. Pretreatment of pioglitazone not only prevented the down-regulation of PPARgamma, but inhibited VSMC proliferation and prevented S-phase entry of cell via a G0-G1 block in the presence of AGEs. Western blotting analysis showed that AGE treatment potentiated to activate extracelluar signal-regulated kinases (ERK1/2) by the induction of intracellular reactive oxygen species (ROS) production, since ROS scavenger N acetyl-L-cysteine pretreatment significantly inhibited AGE-induced ERK1/2 activation. Further, pretreatment with either N-acetyl-L-cysteine or the inhibitor of ERK1/2 activation suppressed AGE-induced proliferation of VSMCs, suggesting a role of ROS/ERK1/2 signaling. Notably, we demonstrated that pretreatment of pioglitazone significantly attenuated AGE-induced ROS and ERK1/2 activation. Collectively, these results suggest that pioglitazone inhibits AGE induced VSMC proliferation via increasing PPARgamma expression and inhibiting ROS/ERK1/2 signaling pathway. PMID- 21532148 TI - High-frequency genetic contents variations in clinical Candida albicans isolates. AB - Genome plasticity is a hallmark of Candida albicans and is believed to be an adaptation strategy. But the extent of such genomic variability is not well investigated. In this study, genetic contents of clinical C. albicans isolates were investigated at whole-genome level with array-based comparative genomic hybridization (array CGH) technology. It was revealed that C. albicans possessed variations of genetic contents, as well as aneuploidy. The variable genes were scattered across the chromosomes, as well clustered in particular regions, including sub-telomeric regions, retrotransposon-insertion sites and a variable region on chromosome 6. PMID- 21532149 TI - Modulation of iron-uptake systems by a mutation of luxS encoding an autoinducer-2 synthase in Vibrio vulnificus. AB - Vibrio vulnificus possesses multiple iron-uptake systems which are mediated by VuuA (vulnibactin receptor), IutA (aerobactin receptor) and HupA (heme receptor). In this study, we determined the effect of a mutation of luxS encoding autoinducer-2 (AI-2) synthase on the expressions of the three receptors. A mutation and an in trans complementation of luxS did not affect the growing ability of V. vulnificus in iron-deficient conditions. Nevertheless, the luxS mutation slightly decreased vuuA expression, but slightly increased iutA and hupA expressions in the transcriptional reporter assay or Western blot analysis. These changes were all recovered by the luxS complementation. These results suggest that AI-2-mediated quorum sensing system may be involved in the fine modulation of V. vulnificus iron-uptake systems, positively affecting vuuA expression but negatively affecting iutA and hupA expressions. PMID- 21532150 TI - Antimicrobial activity of Gel-entrapped catechins toward oral microorganisms. AB - The oral cavity contains almost half of the commensal bacterial population present in the human body. An increase in the number of these microorganisms may result in systemic diseases such as infective endocarditis and aspiration pneumonia as well as oral infections. It is essential to control the total numbers of these microorganisms in order to suppress disease onset. Thus, we examined the antimicrobial activity of a newly developed gel-entrapped catechin (GEC) preparation against oral microorganisms. The minimum inhibitory concentration (MIC) of GEC was determined based on the relationship between a modified agar diffusion method and a broth microdilution method. GEC inhibited the growth of the Actinomyces, periodontopathic bacteria and Candida strains tested, but did not inhibit the growth of the oral streptococci that are important in the normal oral flora. Commercially available moisture gels containing antimicrobial components showed antimicrobial activity against all of the tested strains. After a series of washes and after a 24-h incubation, GEC retained the antimicrobial activity of the catechins. Catalase prevented GEC induced growth inhibition of Actinomyces naeslundii and Streptococcus mutans suggesting that hydrogen peroxide may be involved in the antimicrobial activity of catechins. These results suggest that GEC may be useful for controlling oral microorganism populations and reducing the accumulation of dental plaque, thereby helping to prevent periodontal disease and oral candidiasis. PMID- 21532151 TI - Berberine-improved visceral white adipose tissue insulin resistance associated with altered sterol regulatory element-binding proteins, liver x receptors, and peroxisome proliferator-activated receptors transcriptional programs in diabetic hamsters. AB - The diabetic "lipotoxicity" hypothesis presents that fat-induced visceral white adipose tissue insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Berberine, a hypolipidemic agent, has been reported to have antidiabetic activities. The molecular mechanisms for this property are, however, not well clarified. Therefore in this study type 2 diabetic hamsters were induced by high-fat diet with low-dose streptozotocin. Then, we investigated the gene expression alterations and explored the molecular mechanisms underlying the therapeutic effect of berberine on fat-induced visceral white adipose tissue insulin resistance in diabetic hamsters by microarray analysis followed by real time reverse transcription-polymerase chain reaction (RT-PCR) confirmation. Type 2 diabetic hamsters exhibited hyperglycemia and relative hyperinsulinemia, glucose intolerance, insulin resistance, intra-adipocyte lipid accumulation, significant increase in body weight and visceral white adipose tissue weight, abnormal serum adipokines levels, and deleterious dyslipidemia. Furthermore, they had increased sterol regulatory element-binding proteins (SREBPs) expression and decreased liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) expression in visceral white adipose tissue. After 9-week berberine treatment, fat-induced insulin resistance and diabetic phenotype in type 2 diabetic hamsters were significantly improved. Compared with diabetic hamsters, expression of LXRs and PPARs significantly increased and SREBPs significantly decreased in visceral white adipose tissue from berberine-treated diabetic hamsters. These results suggest that altered visceral white adipose tissue LXRs, PPARs, and SREBPs transcriptional programs are involved in the therapeutic mechanisms of berberine on fat-induced visceral white adipose tissue insulin resistance in type 2 diabetic hamsters. PMID- 21532152 TI - The enantiomers of etodolac, a racemic anti-inflammatory agent, play different roles in efficacy and gastrointestinal safety. AB - The anti-inflammatory agent etodolac is used worldwide and it has a good gastrointestinal safety profile. Etodolac consists of two enantiomers, S- and R etodolac. Here, we investigated the beneficial activities of racemic etodolac and its enantiomers. First, we compared S- and R-etodolac in terms of their inhibition of cyclooxygenase (COX) activity in vitro and their suppression of paw swelling in adjuvant-induced arthritic rats. The COX-2 inhibitory and anti inflammatory effects of etodolac were found to be due to the S-enantiomer. We previously reported that etodolac attenuates allodynia in a mouse model of neuropathic pain by a COX-2-independent mechanism [N. Inoue et al., J. Pharmacol. Sci., 109, 600-605 (2009)]. In the present study, we showed that the anti allodynic effects of etodolac in mice were also due to the S-enantiomer. In addition, we investigated the ulcerogenic activity of racemic etodolac and its enantiomers. At high doses, racemic etodolac showed a lower gastric lesion index in rats than the equivalent dose of S-etodolac. In contrast, R-etodolac showed no ulcerogenic activity and even showed protection against HCl/ethanol-induced gastric damage in rats. In conclusion, S-etodolac exhibited anti-inflammatory effects mediated by COX-2 inhibition and anti-allodynic effects that were independent of COX-2 inhibition, while R-etodolac showed gastroprotective effects that may contribute to the low gastrointestinal toxicity of racemic etodolac. Our results show that each enantiomer plays a different role in the efficacy and gastrointestinal safety of etodolac. PMID- 21532153 TI - Innovative preparation of curcumin for improved oral bioavailability. AB - Curcumin is a polyphenol that is commonly used for its perceived health benefits. However, the absorption efficacy of curcumin is too low to exhibit beneficial effects. We have successfully developed a highly absorptive curcumin dispersed with colloidal nano-particles, and named it THERACURMIN. The absorption efficacy of THERACURMIN was investigated and compared with that of curcumin powder. The area under the blood concentration-time curve (AUC) after the oral administration of THERACURMIN was found to be more than 40-fold higher than that of curcumin powder in rats. Then, healthy human volunteers were administered orally 30 mg of THERACURMIN or curcumin powder. The AUC of THERACURMIN was 27-fold higher than that of curcumin powder. In addition, THERACURMIN exhibited an inhibitory action against alcohol intoxication after drinking in humans, as evidenced by the reduced acetaldehyde concentration of the blood. These findings demonstrate that THERACURMIN shows a much higher bioavailability than currently available preparations. Thus, THERACURMIN may be useful to exert clinical benefits in humans at a lower dosage. PMID- 21532154 TI - Effect of heat exposure on aminophylline-induced convulsions in mice. AB - Theophylline-associated convulsions are frequently exacerbated by fever, but the mechanisms behind it are still not completely understood. We investigated whether N-methyl-D-aspartic acid (NMDA) and gamma aminobutyric acid (GABA) receptors are involved in aminophylline (theophylline-2-ethylenediamine)-induced convulsions that are augmented by heat exposure-induced hyperthermia in mice. Mice exposed to 33 degrees C temperatures for 2 h had significantly increased body temperature (0.94 degrees C). Heat exposure significantly decreased time required for the onset of convulsions induced by an intraperitoneal (i.p.) injection of aminophylline (300 mg/kg). The shortened time for onset of convulsions was blocked by the NMDA receptor antagonist dizocilpine (0.1, 0.3 mg/kg, i.p.). However, the GABA(A) receptor agonist muscimol (1, 2 mg/kg, i.p.) did not have any effect. The pro-convulsant action of NMDA (100-125 mg/kg, i.p.) was enhanced by the heat exposure of 33 degrees C. However, the pro-convulsant actions of picrotoxin (3-4 mg/kg, i.p.), a GABA(A) receptor antagonist, were not affected by increased temperatures. These results suggest that NMDA receptors in the brain play a role in aminophylline-induced convulsions, which are augmented by heat exposure-induced hyperthermia in mice. PMID- 21532155 TI - Nateglinide stimulates glucagon-like peptide-1 release by human intestinal L cells via a K(ATP) channel-independent mechanism. AB - A reduced incretin effect is one of the well-known characteristics of patients with type 2 diabetes, and impaired release of glucagon-like peptide-1 (GLP-1) has been reported to be at least partly involved. In this study, we investigated the effect of nateglinide on GLP-1 release in vivo and in vitro. The GLP-1 level in the portal blood at 20 min after oral administration of nateglinide to Wistar rats was about twice that in vehicle-treated rats. To clarify whether this effect of nateglinide was related to direct stimulation of intestinal cells, in vitro studies were performed using human intestinal L cells (NCI-H716). Nateglinide stimulated GLP-1 release in a concentration-dependent manner from 500 uM, along with transient elevation of the intracellular calcium level. However, diazoxide, nitrendipine, and dantrolene did not block this effect of nateglinide. In addition, the major metabolite of nateglinide, tolbutamide, and mitiglinide, all of which augment insulin secretion by the pancreatic islets, had no effect on GLP 1 release by this cell line. On the other hand, capsazepine significantly inhibited the promotion of GLP-1 release by nateglinide in a concentration dependent manner. These findings indicate that nateglinide directly stimulates GLP-1 release by intestinal L cells in a K(ATP) channel-independent manner. A novel target of nateglinide may be involved in increasing intracellular calcium to stimulate GLP-1 release, e.g., the transient receptor potential channels. Taken together, the present findings indicate that promotion of GLP-1 release from intestinal L cells may be another important mechanism by which nateglinide restores early-phase insulin secretion and regulates postprandial glucose metabolism. PMID- 21532156 TI - Anticancer activity of S-allylmercapto-L-cysteine on implanted tumor of human gastric cancer cell. AB - Allylmercapto glutathione S-conjugate, S-allylmercapto-L-cysteine (SAMC), which is biotransformed from allyl sulfides and from naturally occurring water-soluble garlic derivatives, has been known to inhibit tumorigenesis. We found that SAMC was able to induce apoptosis in gastric cancer cells in vitro. We report that SAMC inhibited tumor growth rate by 31.36% and 37.78% at doses of 100 and 300 mg/kg, respectively. Apoptosis in the implanted tumor cells was manifested by apoptotic characteristics, including morphological changes of chromatin crescent, cell shrinkage and membrane blebbing. The apoptosis index of 100 mg/kg and 300 mg/kg of SAMC was 20.74 +/- 2.50% and 30.61 +/- 2.42%, respectively, by terminal deoxy-nucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining. The positive rate of B-cell lymphoma 2 (bcl-2) protein expression of control, 100 mg/kg SAMC and 300 mg/kg SAMC was 15.20 +/- 1.67%, 10.94 +/- 1.57%, and 8.24 +/- 1.07%, respectively, by immunohistochemical staining. The positive rate of bax protein expression of control, 100 mg/kg SAMC and 300 mg/kg SAMC was 15.30 +/- 1.90%, 23.18 +/- 1.81%, and 25.26 +/- 3.03%, respectively. We also observed decreases in bcl-2 mRNA and increases in bax mRNA by SAMC in a dose-dependent manner by reverse transcription-polymerase chain reaction (RT-PCR). These results suggest that SAMC may regulate bcl-2 and bax to induce apoptosis in transplanted tumor cells. PMID- 21532157 TI - Inhibitory effects of dexamethasone on epidermal growth factor-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. AB - We investigated the effects of dexamethasone on epidermal growth factor (EGF) induced DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. Isolated hepatocytes were cultured at a density of 3.3 * 104 cells/cm2 in Williams' medium E containing 5% bovine calf serum and various concentrations of dexamethasone for 1, 2 and 3 h. After the 3-h attachment period, the medium was changed, and cells were cultured in serum-free and dexamethasone-free Williams' medium E with or without glucocorticoid receptor antagonists. The growth-stimulating effects of EGF (20 ng/ml) on the primary cultured hepatocytes were time- and concentration-dependently inhibited by dexamethasone added to the culture medium. The mineral corticoid aldosterone (10 7 M) did not produce the same growth-inhibitory effects as dexamethasone (10-8 M). The inhibitory effects of dexamethasone were reversed by treatment with the glucocorticoid receptor antagonist mifepristone (RU486, 10-6 M) or a monoclonal antibody against glucocorticoid receptor (100 ng/ml). In addition, the growth inhibitory effects of dexamethasone did not affect EGF-induced p42 mitogen activated protein (MAP) kinase phosphorylation. These results indicate that dexamethasone concentration-dependently delays and inhibits the EGF-induced DNA synthesis and proliferation through its own intracellular receptor in primary cultures of adult rat hepatocytes. PMID- 21532158 TI - Intrathecal disposition of ARTCEREB(r) irrigation and perfusion solution for cerebrospinal surgery in rats. AB - We investigated the disposition of ARTCEREB(r) irrigation and perfusion solution (Artcereb) during intrathecal perfusion in a lateral ventricle-cisternal perfusion model in conscious rats. In this perfusion model, the perfusion rate was set at 0.35 ml/kg/h, taking into consideration the clinical perfusion rate (500 ml/60 kg/d). The influence of Artcereb on electrolytes in cerebrospinal fluid (CSF) and blood were then investigated. After 24 h of ventriculocisternal perfusion with Artcereb using the push-pull method, output of K(+), Na(+) and Cl( ) to the cistern magna was very similar to input of these electrolytes in Artcereb infused intraventricularly. Recovery rates of K(+), Na(+) and Cl(-) after perfusion were 102%, 105% and 100% when calculated using the recovered perfusion solution. In addition, concentrations of K(+), Na(+) and Cl(-) in blood remained almost constant at near baseline levels throughout perfusion. Thus, intrathecally perfused Artcereb did not affect electrolyte balance in the CSF and blood. To confirm the dynamics of Artcereb distribution, a whole body autoradiography study was performed at 1 and 6 h after perfusion with 14C-inulin added Artcereb. Radioactivity was detected in the entire CSF space of the brain, and the cribriform plate in the nasal cavity, and the cerebrospinal cavity. Radioactivity was observed in the bladder, thus suggesting that some 14C-inulin was transferred to the bloodstream via a physiological route, and was excreted renally. PMID- 21532159 TI - Losartan and pioglitazone ameliorate nephropathy in experimental metabolic syndrome rats. AB - It is well known that metabolic syndrome (MS) is a risk factor for proteinuria and chronic kidney disease. Losartan (angiotensin II receptor blocker, ARB) and pioglitazone (peroxisome proliferator-activated receptor-gamma, PPARgamma agonist) have been shown to confer renoprotection. However, to date, whether or not an ARB and a PPARgamma agonist have synergistic renoprotective effects remains controversial. Thus, the present study was designed to evaluate a combined treatment with losartan and pioglitazone in Sprague-Dawley rats fed with a high-fat, high-salt (HFS) diet and 20% sucrose solution for 16 weeks, an animal model of MS accompanying with renal lesions. Losartan, pioglitazone, and their combination were orally administered in the MS rats from 8 weeks to the end of this study. At 16 weeks, the MS rats showed the elevation in systolic blood pressure (SBP), urinary albumin excretion (UAE), and glomerulosclerosis (GS) score, but creatinine clearance, urinary protein excretion, and score of tubulointerstitial damage were not affected. Renal vascular endothelial growth factor (VEGF) protein level, mRNA and protein expression, which were respectively measured by enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction (RT-PCR), and Western blot analysis, were obviously decreased in the MS rats. Treatment with the combination of losartan and pioglitazone provided synergistic effects in reducing the SBP, UAE, and GS score when compared with monotherapy. These effects were not associated with ameliorated the downregulation of renal VEGF expression. Our data suggest that combined treatment with losartan and pioglitazone may offer additional advantages in treating MS nephropathy. PMID- 21532160 TI - Hydrocortisone inhibits cellular proliferation by downregulating hepatocyte growth factor synthesis in human osteoblasts. AB - Glucocorticoids have multiple systemic effects that may influence bone metabolism but also directly affect osteoblasts by decreasing their proliferation. Using human osteoblastic SaM-1 cells, we examined whether the effects of hydrocortisone on cellular proliferation are mediated by hepatocyte growth factor (HGF). Human osteoblasts constitutively express both HGF and c-Met, its receptor. Hydrocortisone decreased the gene and protein expression of HGF as well as proliferation in SaM-1 cells. These hydrocortisone (0.01-1 uM)-induced decreases in HGF synthesis and cellular proliferation occurred in a concentration-dependent manner. However, no hydrocortisone (0.01-1 uM)-induced decrease in cellular proliferation was observed in human osteosarcoma-derived cells (HOS and SaOS-2), which are not able to produce HGF. In the cellular proliferation in SaM-1 cells, the decrease was blocked concentration-dependently by exogenously applied HGF (0.01-3 ng/ml). Furthermore, SU11274 (1 uM), a highly specific inhibitor of c Met, suppressed the proliferation of SaM-1 cells, but not HOS cells. From these results, we concluded that hydrocortisone inhibits the proliferation of SaM-1 cells by interrupting the autocrine/paracrine loop via the downregulation of HGF synthesis. PMID- 21532161 TI - Decreased motility of the lower esophageal sphincter in a rat model of gastroesophageal reflux disease may be mediated by reductions of serotonin and acetylcholine signaling. AB - To elucidate the altered function of the lower esophageal sphincter (LES) in gastroesophageal reflux disease (GERD), we evaluated the motility proximal to LES using force transducers, contraction and relaxation responses to neurotransmitters in LES strips, and gene expression of neurotransmitter receptors in GERD rats. Force transducers were applied to the proximal LES, and contraction of the LES was monitored during free moving. In addition, LES was isolated from sham-operated and GERD rats to investigate the LES function in an organ bath, and to determine gene expression. The in vivo motility proximal to LES (% motility index) in conscious rats was decreased by atropine treatment and increased by cisapride (5-HT(4) receptor agonist) treatment. Acetylcholine- and serotonin (5-HT)-induced LES contraction and sodium nitroprusside-induced relaxation in LES strips of GERD rats markedly decreased compared to sham operated rats. The mRNA expressions of 5-HT(4) and muscarinic acetylcholine 3 receptors were significantly reduced in esophageal LES strips of GERD rats compared with sham-operated rats. Intraperitoneal administration of cisapride improves the erosive damage in the esophagus in GERD rats. It is suggested that the reduction of 5-HT-induced contraction in LES strips in GERD rats may be partly due to the decrease in 5-HT(4)-receptor activation. The reduction of LES function may be due to the decrease in neurotransmitters signal transduction, leading to the deterioration of histopathological damage in GERD. PMID- 21532162 TI - Effective drug delivery system for duchenne muscular dystrophy using hybrid liposomes including gentamicin along with reduced toxicity. AB - It is known that gentamicin (GM) could be a possible treatment for Duchenne Muscular Dystrophy (DMD). However, GM therapy has been hindered by several problems such as severe side effects of GM. In order to resolve these problems, we developed the drug delivery system (DDS) of GM using hybrid liposomes (HL) composed of L-alpha-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene(23) lauryl ether (C12(EO)23). The hydrodynamic diameters of HL including GM (GM-HL) were 60-90 nm with a narrow range of the size distribution and the sizes were kept almost constant for over 4 weeks, suggesting that GM-HL could avoid the reticuloendothelial system in vivo. Furthermore, GM-HL accumulated more to the skeletal muscle cells of X chromosome-linked muscular distrophy (mdx) mice as compared to those of normal mice. Significantly, we succeeded in increasing dystrophin positive fibers in skeletal muscle cells of mdx mice using GM-HL along with the reduction of ototoxicity. It is suggested that GM should be carried more efficiently into the muscular cells of mdx mice by HL. These results indicate that HL could be an effective carrier in the DDS of GM therapy for DMD. PMID- 21532163 TI - Genetic diversity of Ephedra plants in mongolia inferred from internal transcribed spacer sequence of nuclear ribosomal DNA. AB - Ephedrae herba has been used for treating colds, relieving coughs and asthma from ancient times. We previously reported the distribution of Ephedra sinica, E. equisetina, E. przewalskii, E. regeliana, E. monosperma and Ephedra sp. in Mongolia, and among them E. sinica and E. equisetina were potential new resources of Ephedrae herba of Japanese pharmacopoeia grade, based on our field survey and subsequent molecular and chemical assessments. However, the Ephedra population in southwestern areas showed a high possibility of having hybrid origins. Further field surveys in southwestern areas, and sequence analysis of the partial nuclear internal transcribed spacer 1 (ITS1) region, besides trnK and 18S ribosomal RNA (rRNA) gene regions, were conducted in order to obtain detailed evidence of hybridization status. As a result, the distribution of E. glauca in western area and E. lomatolepis in western-most area was confirmed. The ITS sequences from all 8 Ephedra species collected in Mongolia were roughly divided into 5 types (types I-V). Type II sequence, having several additive nucleotides, was found in Ephedra sp., E. glauca, E. regeliana and E. sinica, which provided useful information for tracing hybrid origins. Morphological, genetic and distribution evidence suggested that the hybridization of Ephedra species occurred widely in southwestern Mongolia, and several Ephedra species including E. przewalkskii and E. intermedia were involved in these events. Integrated with our previous report, trnK-, 18S- and ITS-types from pure lines of each species are proposed. In addition, we propose a practicable method for detecting additive peaks on a direct sequencing electropherogram. PMID- 21532164 TI - Effects of S/B remedy containing Scutellaria baicalensis and Bupleurum scorzonerifolfium on hepatic interleukin-6 related signal transducer and activator of transcription 3 activation in mice through cell-cell interaction. AB - Signal transducer and activator of transcription 3 (STAT3) plays an important role in regulating interleukin 6 (IL-6) related growth control of the liver. Our previous study demonstrated that a mixture containing Scutellaria baicalensis and Bupleurum scorzonerifolfium (S/B remedy) modulated the growth of hepatocytes during liver regeneration after 2/3 partial hepatectomy. The aim of this study was to investigate whether S/B remedy induced mouse hepatic STAT3 activation directly in hepatocytes or indirectly via non-parenchymal cell-hepatocyte interaction. Direct S/B remedy effects were studied using primarily isolated hepatocytes; while C57BL/6J mice were used to study indirect effects of S/B remedy using gadolinium chloride to deplete Kupffer cells' function. The results showed that S/B remedy and its active constituents did not directly activate growth-related signaling in primarily isolated hepatocytes. However, S/B remedy induced STAT3 and subsequently suppressor of cytokine signaling (SOCS3) activation in mouse liver and increased serum IL-6 level in a dose-dependent manner, which could be partially blocked by pretreatment with gadolinium chloride. Oligonucloetide microarray analysis from S/B remedy-treated peripheral blood leukocytes demonstrated an up-regulation of IL-6 gene expression. We conclude that S/B remedy did not directly induce STAT3 activation in vitro, but induced hepatic IL-6 related STAT3 activation through non-parenchymal cell hepatocyte interaction in vivo. The results provide important information on the molecular mechanisms of S/B remedy for treatment of human liver diseases. PMID- 21532165 TI - In vitro characterization of the cytochrome P450 isoforms involved in the metabolism of 6-methoxy-2-napthylacetic acid, an active metabolite of the prodrug nabumetone. AB - The cytochrome P450 (CYP) isoforms that catalyze the oxidation metabolism of 6 methoxy-2-napthylacetic acid (6-MNA), an active metabolite of nabumetone, were studied in rats and humans. Using an extractive reversed-phase HPLC assay with fluorescence detection, monophasic Michaelis-Menten kinetics was obtained for the formation of 6-hydroxy-2-naphthylacetic acid (6-HNA) in liver microsomes of rats and humans, and kinetic analysis showed that the K(m) and V(max) values for the formation of 6-HNA in humans and rats were 640.0 +/- 30.9 and 722.9 +/- 111.7 uM, and 1167.5 +/- 33.0 and 1312.7 +/- 73.8 pmol min-1 mg protein-1, respectively. The CYPs responsible for metabolism of 6-MNA in liver microsomes of rats and humans were identified using correlation study, recombinant CYP supersomes, and specific CYP inhibitors and antibodies. Recombinant human CYP2C9 exhibited appreciable catalytic activity with respect to 6-HNA formation from 6-MNA. Among 14 recombinant rat CYPs examined, CYP2C6, CYP2C11 and CYP1A2 were involved in the metabolism of 6-MNA. Sulfaphenazole (a selective inhibitor of CYP2C9) inhibited the formation of 6-HNA in pooled human microsomes by 89%, but failed to inhibit this reaction in rat liver microsomes. The treatment of pooled human liver microsomes with an antibody against CYP2C9 inhibited the formation of 6-HNA by about 80%. The antibody against CYP2C11 suppressed the activity by 20 to 30% in rat microsomes, whereas that of CYP1A2 microsomes did not show drastic inhibition. These findings suggest that CYP2C9 has the highest catalytic activity of 6-MNA metabolism in humans. In contrast, metabolism of 6-MNA is suggested to be mediated mainly by CYP2C6 and CYP2C11 in rats. PMID- 21532166 TI - Intranasal administration of milnacipran in rats: evaluation of the transport of drugs to the systemic circulation and central nervous system and the pharmacological effect. AB - Recently, transnasal drug delivery has attracted a great deal of attention as an administration route to deliver drugs directly to the central nervous systems (CNS) and drug targeting of the CNS is expected to increase. In the present study, we investigated the possibility of using a transnasal delivery system for milnacipran, a serotonin-noradrenaline reuptake inhibitor (SNRI), by evaluating the transport to the systemic circulation and cerebrospinal fluid (CSF) and the pharmacological effect after intranasal (i.n.) administration. Moreover, the effect of chitosan as a bioadhesive material on the transport to the systemic circulation and CSF and the pharmacological effect after i.n. administration were evaluated. As a result, i.n. administration of milnacipran was found to produce a higher direct delivery to the CNS as well as to the systemic circulation, suggesting that this is a promising route of administration and an alternative to peroral (p.o.) administration. Furthermore, the i.n. co-administration with chitosan led to increased plasma and CSF concentrations and an enhanced pharmacological effect, evaluated by means of the forced swimming test. The results suggested that chitosan produced a long residence time of milnacipran in the nasal cavity due to its bioadhesive effect, leading to the enhanced transport of milnacipran from the systemic circulation to the CNS via the blood-brain barrier by an increase in systemic absorption as well as direct transport to the CNS, resulting in a higher antidepressant effect compared to that with p.o. administration. PMID- 21532167 TI - Macelignan inhibits melanosome transfer mediated by protease-activated receptor-2 in keratinocytes. AB - Skin pigmentation is the result of melanosome transfer from melanocytes to keratinocytes. Protease-activated receptor-2 (PAR-2) is a key mediator of melanosome transfer, which occurs as the melanocyte extends its dendrite toward surrounding keratinocytes that take up melanosomes by phagocytosis. We investigated the effects of macelignan isolated from Myristica fragrans HOUTT. (nutmeg) on melanosome transfer and the regulation of PAR-2 in human keratinocytes (HaCaT). HaCaT cells stimulated by the PAR-2-activating peptide Ser Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL) were treated with macelignan; PAR-2 expression was then determined by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunocytochemistry. We evaluated the effects of macelignan on calcium mobilization and keratinocyte phagocytosis. In addition, B16F10 melanoma cells and keratinocytes were co-cultured to assess the effects of macelignan on prostaglandin E2 (PGE2) secretion and subsequent dendrite formation. Macelignan decreased HaCaT PAR-2 mRNA and protein levels in a dose-dependent manner. Furthermore, macelignan markedly reduced intracellular calcium mobilization and significantly downregulated keratinocyte phagocytosis, as shown by decreased ingestion of Escherichia coli bioparticles and fluorescent microspheres. In co culture experiments, macelignan reduced keratinocyte PGE2 secretion, thereby preventing dendrite formation in B16F10 melanoma cells compared with SLIGRL treated controls. Macelignan inhibits melanosome transfer by downregulating PAR 2, thereby reducing keratinocyte phagocytosis and PGE2 secretion, which in turn inhibits dendrite formation in B16F10 melanoma cells. Taken together, our findings suggest that macelignan could be used as a natural depigmenting agent to ameliorate hyperpigmentation. PMID- 21532169 TI - Rab5a regulates surface expression of FcepsilonRI and functional activation in mast cells. AB - Surface expression levels of high-affinity immunoglobulin E (IgE) receptors (FcepsilonRI) on mast cells are regulated by constitutive internalization from the plasma membrane, which is thought to be an important determinant of FcepsilonRI-mediated signaling potential. However, molecular mechanism of FcepsilonRI trafficking has remained poorly understood. Rab proteins are small guanosine 5'-triphosphatases (GTPases) involved in the regulation of membrane traffic. In particular, Rab5 has been shown to regulate transport in the early endocytic pathway, whereas it is not known whether the FcepsilonRI surface expression levels are regulated by Rab5. In this study, we investigated the role of individual Rab5 isoforms in mast cells by small interfering RNA knockdown method. Our results demonstrate that Rab5a knockdown enhanced FcepsilonRI dependent mast cell activation and upregulated FcepsilonRI surface expression in its steady state. In contrast, Rab5c knockdown caused suppression of the activation. These findings revealed modulatory and individual roles of Rab5 isoforms in mast cell functions. PMID- 21532168 TI - Pharmacokinetic variability of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in remission maintenance phase. AB - The aim of this study was to identify factors affecting the pharmacokinetics of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG) in systemic lupus erythematosus (SLE) patients. Thirty-one SLE patients in remission maintenance phase treated with mycophenolate mofetil (median 1500 mg/d) and prednisolone and followed-up for up to 56 months (median 13 months) were enrolled. Creatinine clearance and metal medication were significant predictors accounting for interindividual variability in the dose-normalized predose plasma concentration (C0) of MPA (adjusted R2=0.305, p=0.01) in a multivariate analysis. Dose normalized MPAG C0 was significantly correlated with only creatinine clearance (adjusted R2=0.135, p=0.03). The free fraction of MPA was significantly correlated with only serum albumin (adjusted R2=0.700, p<0.01). The free fraction of MPAG was significantly correlated with serum albumin, metal medication, and age (adjusted R2=0.598, p=0.02). In conclusion, renal function and co administered metal influenced the pharmacokinetics of MPA and MPAG in SLE patients in remission maintenance phase. PMID- 21532170 TI - Asynchronously enhanced spiking activity of ischemic neuronal networks. AB - Cerebral ischemia causes the depletion of oxygen and nutrition from brain tissues, and when persistent, results in irreversible damage to the cell function and survival. The cellular response to ischemic conditions and its mechanisms have been investigated widely in in vivo and in vitro experimental models, yet no study has addressed the response of a whole neuronal network to energy deprivation with the single-cell resolution. Observations at the level of network are necessary, because the activity of individual neurons is nonlinearly integrated through a network and thereby gives rise to unexpectedly complex dynamics. Here we used functional multineuron calcium imaging (fMCI), an optical recording technique with high temporal and spatial resolution, to visualize the activity of neuron populations in hippocampus CA1 region under ischemia-like conditions ex vivo. We found that, although neurons responded to oxygen and glucose deprivation with an increase in the event frequency, they maintained an asynchronous network state. This is in contrast with other well known pathological states, in which the network hyperexcitability is usually accompanied by an increase in synchrony. We suggest that under ischemic conditions, at least to some time point, the neuronal network maintains the excitatory and inhibitory balance as a whole, whether actively or as a consequence of the cellular response to energy deprivation. PMID- 21532171 TI - A glycosidic spinasterol from Koreana stewartia promotes procollagen production and inhibits matrix metalloproteinase-1 expression in UVB-irradiated human dermal fibroblasts. AB - Methanol extract of Koreana stewartia leaves (SKE) stimulated collagen production in ultraviolet-B (UVB)-irradiated human fibroblast cells. An active compound was isolated from SKE by successive partitioning and chromatography, and the chemical structure was determined to be 3-O-beta-D-glucopyranosylspinasterol (spinasterol Glc) by spectroscopic characterization. Spinasterol-Glc increased collagen production in the supernatant of UVB-irradiated dermal fibroblast cell cultures in a dose-dependent manner. The effects of spinasteol-Glc on expression of procollagen and matrix metalloproteinase-1 (MMP-1) were further evaluated. We found that the compound stimulated collagen production in UVB-treated fibroblasts than in vehicle-treated control cells by about 3-fold. In addition, we also demonstrate that the compound increased the mRNA and protein levels of procollagen in UVB-treated fibroblast cells, while it inhibited expression of MMP 1. These results indicate that spinasterol-Glc protects fibroblast cells from the adverse effects of UV radiation via stimulation of procollagen synthesis as well as inhibition of MMP-1 expression. Spinasterol-Glc may be useful in the future development of therapeutic and cosmetic applications. PMID- 21532172 TI - Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. AB - Cyclooxygenase enzymes (COX-1 and COX-2) catalyse the production of prostaglandins from arachidonic acid. Prostaglandins are important mediators in the inflammatory process and their production can be reduced by COX-inhibitors. Endocannabinoids, endogenous analogues of the plant derived cannabinoids, occur normally in the human body. The Endocannabinoids are structurally similar to arachidonic acid and have been suggested to interfere with the inflammatory process. They have also been shown to inhibit cancer cell proliferation. Anti inflammatory effects of cannabinoids and endocannabinoids have been observed, however the mode of action is not yet clarified. Anti-inflammatory activity (i.e., inhibition of COX-2) is proposed to play an important role in the development of colon cancer, which makes this subject interesting to study further. In the present work, the six cannabinoids tetrahydrocannabinol (Delta9 THC), tetrahydrocannabinolic acid (Delta9-THC-A), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG) and cannabigerolic acid (CBGA), isolated from Cannabis sativa, were evaluated for their effects on prostaglandin production. For this purpose an in vitro enzyme based COX-1/COX-2 inhibition assay and a cell based prostaglandin production radioimmunoassay were used. Cannabinoids inhibited cyclooxygenase enzyme activity with IC50 values ranging from 1.7.10-3 to 2.0.10-4 M. PMID- 21532173 TI - Identification of dendrobium species used for herbal medicines based on ribosomal DNA internal transcribed spacer sequence. AB - Stems of genus Dendrobium (Orchidaceae) have been traditionally used as an herbal medicine (Dendrobii Herba) in Eastern Asia. Although demand for Dendrobium is increasing rapidly, wild resources are decreasing due to over-collection. This study aimed to identify plant sources of Dendrobii Herba on the market based on sequences of the internal transcribed spacer (ITS) regions of nuclear ribosomal DNA. We constructed an ITS1-5.8S-ITS2 sequence database of 196 Dendrobium species, and the database was employed to identify 21 herbal samples. We found that 13 Dendrobium species (D. catenatum, D. cucullatum, D. denudans, D. devonianum, D. eriiflorum, D. hancockii, D. linawianum, D. lituiflorum, D. loddigesii, D. polyanthum, D. primulinum, D. regium, and D. transparens) were possibly used as plant sources of Dendrobii Herba, and unidentified species allied to D. denudans, D. eriiflorum, D. gregulus, or D. hemimelanoglossum were also used as sources. Furthermore, it is clear that D. catenatum is one of the most important sources of Dendrobii Herba (5 out of 21 samples). PMID- 21532174 TI - Strong statins as the major players for dyslipidemia in high-risk patients: are they all the same or not? PMID- 21532175 TI - Possible new role of vascular endothelial growth factor-D during the acute phase of Kawasaki disease. PMID- 21532176 TI - Stent thrombosis after drug eluting stent implantation. PMID- 21532177 TI - Mechanisms of smooth muscle cell proliferation and endothelial regeneration after vascular injury and stenting: approach to therapy. AB - Bare metal stents (BMS) successfully prevented abrupt artery closure and reduced the restenosis rate compared with balloon angioplasty. This review summarizes laboratory and recent clinical investigations concerning neointimal formation and endothelial regeneration after vascular injury. BMS efficacy was severely hampered by proliferating vascular smooth muscle cells (VSMCs), and the resultant neointimal hyperplasia, which is the only mechanism responsible for restenosis after metal stent placement. The advent of drug-eluting stents (DES) in 2002 have since then revolutionized interventional cardiology. By using the stent struts as a platform coated with polymers to elute drugs targeting VSMC proliferation, a substantial attenuation of in-stent restenosis is feasible. As with any medical innovation this technology still has restrictive factors, and novel approaches are promoted to improve the safety and efficacy of DES. Indeed, the antiproliferative properties of DES impair and/or delay endothelialization, hence leading to late stent thrombosis. Improvements in percutaneous coronary intervention procedures include the use of the so-called "second-generation DES", together with new coating technologies, bioabsorbable stents, and non-drug-based stent coatings. Particular emphasis will be placed on the concept that endothelial regeneration might be pursued as well as reduction of VSMC proliferation to allow stable successful revascularization after DES deployment. PMID- 21532178 TI - Cardiac resynchronization therapy: refocus on the electrical substrate. AB - Cardiac resynchronization therapy (CRT) is an established treatment for selected heart failure patients with conduction disease. Many studies aimed at quantifying mechanical dyssynchrony in CRT candidates when it became apparent that 30-50% of CRT recipients showed no improvement after implantation. As these, often echocardiography-based, measurements have not yet succeeded in estimating the mechanical substrate in an accurate and reproducible manner, interest in electrical substrate has renewed. In this review, current knowledge concerning electrical substrate in CRT candidates will be explored and applied to current CRT practice, highlighting why the electrical substrate is both essential and sufficient for successful CRT. Finally, novel ways to better measure and treat the electrical substrate are discussed. PMID- 21532179 TI - Noninvasive assessment of coronary plaque using multidetector row computed tomography: does MDCT accurately estimate plaque vulnerability? (Con). AB - As a result of the advent and advances of multidetector row computed tomography (MDCT), coronary computed tomography (CT) has become popular and is performed at many institutions. Coronary CT is useful for diagnosing cases of moderate risk of coronary artery disease. On the other hand, it has been shown that most cardiac infarctions (? 70%) occur from mild to moderate stenoses (ie, <= 50%). Thus, conventional cardiac angiographic findings alone cannot predict developing cardiac infarction. The mechanism by which ruptured plaque and subsequent thrombus leads to developing cardiac infarction has been shown, so determining which plaque tended to rupture, the so-called "vulnerable plaque", and treatment of it are in the spotlight. Coronary CT can visualize and evaluate non-invasively not only the lumen but also the arterial wall. The findings that are suspicious for vulnerable plaque on coronary CT are low-density plaque, positive remodeling, and spotty calcification. However, CT is restricted in its resolution (temporal, spatial and contrast resolution). The diagnosis of vulnerable plaque by CT is still challenging. This report demonstrates the present conditions and problems for the characterization of the plaque using coronary CT. PMID- 21532180 TI - Multidetector row computed tomography may accurately estimate plaque vulnerability: does MDCT accurately estimate plaque vulnerability? (Pro). AB - Over the past decade, multidetector row computed tomography (MDCT) has become the most reliable and established of the noninvasive examination techniques for detecting coronary heart disease. Now MDCT is chasing intravascular ultrasound (IVUS) in terms of spatial resolution. Among the components of vulnerable plaque, MDCT may detect lipid-rich plaque, the lipid pool, and calcified spots using computed tomography number. Plaque components are detected by MDCT with high accuracy compared with IVUS and angioscopy when assessing vulnerable plaque. The TWINS study and TOGETHAR trial demonstrated that angioscopic loss of yellow color occurred independently of volumetric plaque change by statin therapy. These 2 studies showed that plaque stabilization and regression reflect independent processes mediated by different mechanisms and time course. Noncalcified plaque and/or low-density plaque was found to be the strongest predictor of cardiac events, regardless of lesion severity, and act as a potential marker of plaque vulnerability. MDCT may be an effective tool for early triage of patients with chest pain who have a normal ECG and cardiac enzymes in the emergency department. MDCT has the potential ability to analyze coronary plaque quantitatively and qualitatively if some problems are resolved. MDCT may become an essential tool for detecting and preventing coronary artery disease in the future. PMID- 21532181 TI - Quality of life as an independent predictor for cardiac events and death in patients with heart failure. AB - BACKGROUND: Little is known about health-related quality of life (QOL) in Japanese patients with heart failure. The purpose of this study was to identify factors related to QOL using a disease-specific QOL instrument, and to clarify whether QOL independently predicts clinical outcomes among Japanese patients with heart failure. METHODS AND RESULTS: A total of 114 outpatients with heart failure were enrolled (mean age 64.7 +/- 15.8 years; 73.7% males). The Minnesota Living with Heart Failure Questionnaire (MLHFQ) to assess patient's QOL was used. At baseline, depressive symptoms and chronic kidney disease were significantly associated with worse QOL in multiple regression analysis. During a 2-year follow up, patients with a MLHFQ score >= 26, indicating worse QOL, had a higher incidence of the combined endpoint of cardiac death or hospitalization for heart failure, and a higher all-cause mortality than those with a score < 26 (25.3% vs. 7.5%, P = 0.011; 18.5% vs. 6.4%, P = 0.018; respectively). Multivariate Cox proportional hazard models demonstrated that a higher MLHFQ score was significantly associated with increased risks of cardiac events (hazard ratio, 1.02, 95% confidential interval, 1.001-1.05, P = 0.038) and of all-cause death (hazard ratio, 1.04, 95% confidential interval, 1.02-1.07, P = 0.001). CONCLUSIONS: Depressive symptoms and chronic kidney disease are major determinants of impaired QOL, and the MLHFQ score is an independent predictor of both cardiac events and death among Japanese patients with heart failure. PMID- 21532182 TI - Impact of diabetes on cardiovascular outcomes in hemodialysis patients undergoing coronary revascularization. AB - BACKGROUND: Among hemodialysis (HD) patients, those who have diabetes have poorer cardiovascular outcomes than non-diabetic patients, but the impact of diabetes on cardiovascular outcomes has not been fully elucidated in HD patients undergoing coronary revascularization. METHODS AND RESULTS: We identified 375 HD patients (203 diabetes, 172 non-diabetes) and 9,006 patients without HD (3,455 diabetes, 5,551 non-diabetes) in the database of the CREDO-Kyoto registry of patients undergoing their first coronary revascularization. In non-HD patients, significantly higher risks of death (10.8% vs. 7.7%, P < 0.0001; adjusted hazard ratio (HR) 1.29, P < 0.0001) and major adverse cardiovascular events (MACE), a composite of death, myocardial infarction and stroke (18.8% vs. 13.3%, P < 0.0001; HR 1.36, P < 0.0001) were seen in diabetic patients than in non-diabetic patients through 4-year follow-up. Analysis in HD patients showed that the duration of HD before first coronary revascularization was significantly shorter in diabetic patients than in non-diabetic patients (median interval: 858 vs. 2,216 days, P < 0.0001). In contrast to the results in non-HD patients, the risks of death (41.9% vs. 39.1%, P=0.75; HR 0.98, P=0.93) and MACE (45.6% vs. 45.8%, P=0.83; HR 0.87, P=0.50) after first revascularization were comparable between diabetic and non-diabetic HD patients. There were significant interactions between HD and diabetes for death and for MACE. CONCLUSIONS: HD patients who require coronary revascularization have extremely poor outcomes irrespective of concomitant diabetes. PMID- 21532183 TI - Acute modulation of vasoconstrictor responses by pravastatin in small vessels. AB - BACKGROUND: Statins have been shown to inhibit conduit vessel constrictor responses via the endothelial nitric oxide (NO) pathway. Clinical studies have implicated an effect in microvascular resistance vessels; however, direct effects of therapeutically relevant statin concentrations have not been examined. We examined the effect of acute pravastatin pretreatment on vasoconstrictor responsiveness of isolated rat mesenteric small vessels. METHODS AND RESULTS: Pravastatin (112 nmol/L) pretreatment for 60 min reduced both the potency and maximal constrictor responses to phenylephrine, thromboxane (U46619) and serotonin in small vessels. This effect was abolished by endothelial denudation, NO synthase (NOS) inhibition with N-omega-nitro-L-arginine methyl ester (L-NAME 300 umol/L) and Akt inhibition (Akt1/2 kinase inhibitor 500 nmol/L), confirming an endothelium-dependent mechanism and implicating a NO-mediated effect via the Akt pathway. Maximal superoxide scavenging with polyethylene glycol-superoxide dismutase (PEG-SOD), 150 U/ml did not influence phenylephrine constrictor responses but potentiated pravastatin's effect, suggesting that the statin did not increase NO bioavailability merely via an antioxidant mechanism. In contrast, pravastatin did not affect endothelin-1 (ET-1) constrictor responses. However, after pre-incubation with a selective endothelin-B (ET(B)) receptor antagonist (BQ788 3 umol/L) pravastatin inhibited ET-1 constriction, suggesting that its effect is via the same mechanistic pathway as the ET(B) receptor. CONCLUSIONS: In small vessels, pravastatin inhibits constrictor responses by increasing endothelial NO bioavailability via the Akt pathway. Furthermore, ET(B) receptor blockade unmasks this effect in ET-1 constrictor responses. PMID- 21532184 TI - Atrial fibrillation and anticoagulation therapy: different race, different risk, and different management? PMID- 21532185 TI - Mevalonate pathway is a novel target for hypertension. PMID- 21532186 TI - Paradigm shift from myocardium-derived to plaque-derived biomarkers for very early diagnosis of acute myocardial infarction. PMID- 21532187 TI - Formulation variation and in vitro-in vivo correlation for a rapidly swellable three-layered tablet of tamsulosin HCl. AB - In order to develop a preferable once-a-day oral tablet formulation, various formulations of three-layered tablets containing tamsulosin HCl as a hydrophilic model drug were evaluated and compared with a commercial reference, tamsulosin OCAS(r). When the test tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid layer rapidly. Volume expansion showed faster and enough swelling of the three layered tablet up to 2 h. Larger amount of barrier layers caused reduced release kinetics and a high molecular weight polymer showed more resistance against agitation force. A formulation with water-soluble mid-layer showed fast erosion decreasing its volume significantly. On the pharmacokinetic study, the mean ratio of area under the curve (AUC) and C(max) for the test formulation to the reference was 0.69 and 0.84, respectively, showing that the absorption of the drug was less complete than the reference. Plasma concentration at 24 h of the test formulation was higher than the reference. The Wagner-Nelson method showed that decreased initial dissolution rate might be the cause of the less complete absorption. On considering in vitro-in vivo correlation (IVIVC), level A, the reference (R2=0.981) showed more linear relationship than the test (R2=0.918) due to the decreased dissolution and absorption rate of the formulation. This result suggests that the in vitro dissolution profiles and release kinetics might be useful in correlating absorption kinetics as well as overall plasma drug concentration-time profiles for formulation studies. PMID- 21532188 TI - Synergistic effects of sour taste and low temperature in suppressing the bitterness of Aminoleban(r) EN. AB - Aminoleban(r) EN, a nutritional product for patients with liver failure, contains three branched-chain amino acids (BCAAs): L-leucine, L-isoleucine, and L-valine. As BCAAs are extremely bitter, Aminoleban(r) EN has a low palatability, which is a major cause of patient noncompliance. Nutrients for liver failure often need to be taken for long periods, and poor medication compliance can cause serious problems, such as encephalopathy. Therefore it is important to suppress the bitter taste of Aminoleban(r) EN and thereby improve patient compliance. There are already six different flavoured powders (coffee, green-tea, apple, fruit, plum and pineapple) which can be added to Aminoleban(r) EN to reduce its unpleasant taste and smell, but it is possible that other factors, such as temperature, may also improve the palatability of Aminoleban(r) EN. In this study, flavours alone significantly decreased the bitterness intensity of Aminoleban(r) EN. It was thought that the sweetness and sourness of the flavoured powder would be the main factors involved in decreasing the bitterness. However, low temperature (0-5 degrees C) decreased the bitterness intensity of Aminoleban(r) EN, with or without the flavoured powders, compared with normal room temperature (25-30 degrees C). The sourness intensity of flavoured powders was not decreased at low temperatures, but the sweetness intensity of some flavoured powders did decrease. These results suggest that sourness can be tasted even at low temperatures. As not only the addition of flavoured powders but also low temperatures can reduce the bitterness of Aminioleban(r) EN, the combination of a sour-flavoured powder and a low temperature will improve the palatability of Aminoleban(r) EN the most. PMID- 21532189 TI - Comparative study of Puerariae lobatae and Puerariae thomsonii by HPLC-diode array detection-flow injection-chemiluminescence coupled with HPLC-electrospray ionization-MS. AB - An on-line HPLC-diode array detection-flow injection chemiluminescence (HPLC-DAD FICL) method was applied to estimate the difference of Puerariae lobatae and Puerariae thomsonii. Their chemical and active profiles could be obtained by HPLC DAD-FICL in one run. Seventeen compounds in two species were tentatively identified by HPLC-electrospray ionization-MS (HPLC-ESI-MS) method. The main antioxidants were rapidly screened by active fingerprints coupled with MS data. Similarity and Hierarchical clustering analysis (HCA) were used to distinguish different samples. The results suggested that the chemical fingerprints of 16 batches of samples were similar by similarity evaluation, while HCA could discriminate the two species. The active fingerprints of Puerariae lobatae and Puerariae thomsonii were significantly different. More antioxidants were found in Puerariae lobatae than in Puerariae thomsonii. Main antioxidants, including 3' hydroxypuerarin, genistein 8-C-glycoside-xyloside, puerarin, 6"-O xylosylpuerarin, mirificin and daidzein in two species, may be reasonable markers for the discrimination of the two species. The integrated fingerprint based on the chemical and active characteristics may provide an objective quality evaluation for Puerariae lobatae and Puerariae thomsonii. PMID- 21532190 TI - Traditional processing strongly affects metabolite composition by hydrolysis in Rehmannia glutinosa roots. AB - The processing of biological raw materials is considered to have an important role in the therapeutic application in Traditional Chinese Medicine. The root of Rehmannia glutinosa has to be processed by nine cycles of rice wine immersing, steaming and drying before using in clinical applications. In order to understand the chemical changes resulting from the processing, a comprehensive analysis of Rehmanniae radix was made using (1)H-NMR and Fourier transform (FT)-mass spectrometry in combination with multivariate data analysis. After (1)H-NMR and principle component analysis, hydrolysis was found to be the major chemical process during the treatments. Catalpol, raffinose and stachyose levels gradually decreased during processing, whereas monosaccharides including galactose and glucose were found to be higher in processed roots. The metabolic profile changed gradually through the processing cycles although the differences became smaller after the fifth processing cycle. The positive and negative ion-mode mass spectra by high resolution FT-MS revealed several series of ion clusters with mass differences of 162.053 Da, indicating a difference of a hexose moiety. During the processing, the number and signal intensity of the smaller glycosides were increased. Therefore, these results indicate that the fresh Rehmanniae radix is rich in polysaccharides, which are hydrolyzed during the processing. PMID- 21532191 TI - Stabilization mechanism of clarithromycin tablets under gastric pH conditions. AB - It has been reported that tablets of clarithromycin (CAM), a 14-membered macrolide antibiotic, are especially stable under low pH conditions such as in gastric fluid, and showed excellent antibacterial efficiency even though CAM molecules themselves are rapidly decomposed. Therefore, we aimed to clarify the stabilization mechanism of CAM tablets under low pH conditions. From the results of stability and dissolution tests, the optimal decomposition rate constant (K(dec)) and dissolution rate constant (K(dis)) at various pH values were calculated by curve-fitting to consecutive reactions. Consequently, log(K(dec)) increased as pH decreased. On the other hand, log(K(dis)) increased as pH decreased from 3.0 to 1.5, but decreased as pH decreased from 1.5 to 1.0. In addition, the disintegration time of commercially available tablets at pH 1.0 and 1.2 was found to be delayed, resulting in a decrease of K(dis). Furthermore, from powder X-ray diffraction, HPLC and elemental analysis, the delay in disintegration time might be attributable to the formation of a transparent gel, formed by the reaction between CAM molecule and hydrochloric acid under low pH conditions, on the surface of CAM tablet. On the basis of these results, this report can be considered the first case where a transparent gel prevents gastric fluid from penetrating the tablet, resulting in reduced decomposition of CAM following oral administrating. PMID- 21532192 TI - Block ionomer complex micelles based on the self-assembly of poly(ethylene glycol)-block-poly(acrylic acid) and CdCl2 for anti-tumor drug delivery. AB - A novel block ionomer complex micelles as drug carrier is developed utilizing self-assemble of poly(ethylene glycol)-block-poly(acrylic acid) (PEG-b-PAA) and cadmium chloride. This micelles are characterized to be have good bio compatibility, hydrophilicity, passive targeting and sustained slow release property which shows great potential for liver cancer therapy. Block ionomer complex micelles based on PEG-b-PAA and cadmium chloride can self-assemble in distilled water, and Cd(2+) agent is entrapped into the core stabilized by PEG shells. Results showed the block ionomer complex micelles to be spherically shaped. Cadmium was incorporated easily into the ionic core with remarkably high efficiency (34.25% weight (wt)/wt). The cadmium-loaded polymeric micelles exhibited sustained and slow release behavior of cadmium and a potent cytotoxicity against SMMC-7721 in vitro. This novel block ionomer complex micelles with cores of metal antitumor drug indicates to be potential carriers for effective drug delivery. PMID- 21532193 TI - Erythrinan alkaloids from seeds of Erythrina velutina. AB - Four new Erythrinan alkaloids (1-4) were isolated from the seeds of Erythrina velutina. The structures of these new compounds 1-4 were elucidated by spectroscopic methods including 2D-NMR. Three of four were found to be novel sulfated Erythrinan alkaloids. PMID- 21532194 TI - Synthesis, antibacterial activity and quantum-chemical studies of novel 2 arylidenehydrazinyl-4-arylthiazole analogues. AB - A new series of 2-arylidenehydrazinyl-4-arylthiazole derivatives (2a-k) was designed and synthesized through a rapid, simple, and efficient methodology in excellent isolated yield. These compounds were screened for in vitro antimicrobial activities against eight bacteria, e.g. Bacillus cereus, Staphylococcus aureus, Bacillus subtilis, Bacillus megaterium, Pseudomonas aeruginosa, Shigella dysenteriae, Salmonella typhi, Escherichia coli, and three fungi e.g. Aspergillus oryzae, Candida albicans, and Saccharomyces cerevis. The results indicate that some of the compounds exhibit strong antibacterial activity, depending on the bacterial strain, but show virtually no antifungal activity. The structure-antibacterial activity relationships were studied using some physicochemical and quantum-chemical parameters with the ab initio Hartree Fock model at the RHF/6-31G level of theory. A good qualitative correlation between predicted lipophilic parameters and antibacterial activity has been found. PMID- 21532195 TI - A novel synthetic approach to very late antigen-4 antagonist trans-4-[1-[[2,5 dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S) pyrrolidinylmethoxy]cyclohexanecarboxylic acid via tert-butyl trans-[(4S)-Methoxy (2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate as a key intermediate. AB - This contribution describes a novel synthetic approach to very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3 indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S) pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1) via tert-butyl trans-[(4S) methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate. The synthesis, which includes n-Bu4NSO3H that catalyzed basic etherification of 12 and iodine-mediated cyclization to provide the 2,4 disubstituted pyrrolidine frame of 2b, is designed to utilize trans-4 hydroxycyclohexanecarboxylic acid (9) as a commercially available starting material. PMID- 21532196 TI - Synthesis and matrix metalloproteinase-12 inhibitory activity of ageladine A analogs. AB - Synthesis of the 37 ageladine A analogs was accomplished by employing the total synthetic route of natural ageladine A previously explored by us. From the matrix metalloproteinase-12 (MMP-12) inhibitory activity assay carried out using the novel analogs, it appeared evident that the halogen atom at the 2-position of pyrrole ring was essential for the inhibitory activity and that the introduction of a bromine atom into the 4-position of pyrrole ring is very effective for producing potent activity. In addition, exchange of the pyrrole ring to an imidazole ring was extremely effective in increasing activity, and the analog 29 thus obtained was found to show approximately 4 times more potent activity than natural ageladine A. PMID- 21532197 TI - Novel des-fatty acyl-polymyxin B derivatives with Pseudomonas aeruginosa-specific antimicrobial activity. AB - Polymyxin B (PMB) is a cationic cyclic decapeptide antibiotic with a fatty acyl (FA) modification at the alpha-amino group of Dab1 (Dab: L-alpha,gamma diaminobutyric acid). In this study, which is part of a series of PMB structure activity relationship investigations focused on identifying clinically useful peptide antibiotics, we synthesized ten des-FA PMB derivatives whose N-terminal moieties were changed to basic or hydrophilic amino acids. The antimicrobial and lipopolysaccharide (LPS) binding activities of these synthetic analogs were tested. The analogs showed more potent antimicrobial activity against Pseudomonas aeruginosa (P. aeruginosa) compared with the PMB nonapeptide. In particular, [Ser2-Dap3]-PMB(2-10), Guanyl-[Thr2-Dab3]-PMB(2-10), Guanyl-[Dab1-Thr2-Dab3] PMB(1-10), and N(alpha,gamma)-diguanyl-[Dap3]-PMB(3-10) had antimicrobial activity equivalent to PMB. In LPS binding assays, the displacement curves shifted in a manner proportional to the number of positive charges available to bind to Escherichia coli (E. coli) and P. aeruginosa. Furthermore, peptides with basic side chains were comparable to PMB in binding activity assays against E. coli and P. aeruginosa. The acute toxicities of the peptides were evaluated by intravenously administering the peptides to mice through the tail vein. The toxicities of [Ser2-Dap3]-PMB(2-10), [Dap3]-PMB(3-10), and [Ser3]-PMB(3-10) were lower that of PMB (LD50, 4.8 umol/kg). PMID- 21532198 TI - Assessment of processing and polymorphic form effect on the powder and tableting properties of microcrystalline celluloses I and II. AB - Microcrystalline cellulose I (MCCI) is an excipient used as a diluent, disintegrant, glidant and binder for the production of pharmaceutical tablets. In this work, microcrystalline cellulose II (MCCII) was obtained from cotton fibers by basic treatment with 7.5 N NaOH followed by an acid hydrolysis. MCCI and MCCII materials were processed by wet granulation, dry granulation and spray drying. Either the polymorphic form or processing had no effects on the particle morphology or particle size. However, MCCII powders had a higher porosity, less packing tendency, degree of crystallinity, degree of polymerization and density, but a faster disintegration than MCCI. The tensile strength of MCCI was highly affected by the wet and dry granulation processes. Most of the resulting powder and tableting properties were dependent on the polymorphic form of cellulose, rather than on the processing employed. PMID- 21532199 TI - Reliability evaluation of the design space of the granulation process of mefenamic acid tablets using a bootstrap resampling technique. AB - The design space of the granulation process of mefenamic acid tablets, based on Box and Behnken design datasets, was described by a response surface method incorporating multivariate spline interpolation. The reliability of the optimal solutions and the acceptance ranges were evaluated by a bootstrap (BS) resampling technique. The distribution of the BS optimal solutions was almost symmetrical; however, several solutions, which were quite different from the original solution, were mixed. The reason for this problem was considered to be the mixing of the global and the local optima. Therefore, we applied self-organizing map (SOM) clustering for dividing data into several clusters and identified the cluster containing the global optima. The accuracy and reproducibility of the optimal solution in the cluster containing the optimal solution were quantitatively evaluated. In addition, the response surfaces modeled from all the BS datasets contained in the cluster were plotted into the same coordinates with the original response surface. The plots of BS optimal solutions were distributed around the original solution. Moreover, the average of all the BS response surfaces sufficiently corresponded with the original response surface. The conservative limits of the 95% confidence intervals of the acceptance ranges in three response variables could be calculated using the standard deviations of the BS response surfaces. Consequently, it was considered that a novel evaluation method based on BS resampling and SOM could be used for quantitatively evaluating the precision of the nonlinear response surface model. PMID- 21532200 TI - Application of Ulex europaeus agglutinin I-modified liposomes for oral vaccine: Ex Vivo bioadhesion and in Vivo immunity. AB - The conjugation of Ulex europaeus agglutinin I (UEAI) onto surface of liposomes has been demonstrated to effectively improve the intestinal absorption of antigen, subsequently induced strong mucosal and systemic immune responses. In this context, we prepared bovine serum albumin (BSA)-encapsulating UEAI-modified liposomes (UEAI-LIP) and unmodified ones (LIP). The specific bioadhesion on mice gastro-intestinal mucosa was studied ex vivo. An important increase of interaction between UEAI-conjugated liposomes and the intestinal segments with Peyer's Patches (PPs) was observed compared with the unconjugated one (p<0.01). However, under the presence of alpha-L-fucose, which is the reported specific sugar for UEAI, specifically inhibited the activity of these conjugates. The immune-stimulating activity in vivo was studied by measuring immunoglobulin G (IgG) levels in serum and immunoglobulin A (IgA) levels in intestinal mucosal secretions following oral administration of BSA solution, LIP and UEAI-LIP in mice. Results indicate that antigen encapsulated in liposomes, especially the UEAI-modified ones, was favorable for inducing immune response. At 42 d after the first immunization, the highest IgG and IgA antibody levels produced by UEAI-LIP occurred, respectively showing 4.4-fold and 5-fold higher levels compared to those of the groups receiving BSA alone. This data demonstrated high potential of UEAI-modified liposomes for their use as carrier for oral vaccines. PMID- 21532201 TI - Effect of cholesterol on distribution of stable, hydrophobic perchlorotriphenylmethyl triethylester radical incorporated in lecithin liposomal membranes. AB - Perchlorotriphenylmethyl triethylester radical (PTM-TE) is a hydrophobic, stable radical giving a narrow singlet ESR signal with a small satellite signal for (13)C in organic solvents. In order to use PTM-TE as a label of liposomal membranes, its manner of incorporation into liposomal membranes was studied. Two components, broad and narrow signals, were observed on the ESR spectrum of PTM-TE incorporated into liposomal membranes composed of egg yolk phosphatidylcholine (egg-PC). The broad signal was increased by the presence of cholesterol in the membranes. The spectral anisotropy of the broad signal was very small as analyzed with oriented planar multilamellar membranes. The narrow signal increased with an increase in temperature in the absence of cholesterol, whereas only a small increase in the signal was observed in the presence of cholesterol. The g-value and line width of the narrow signal were very close to those of PTM-TE in mineral oil, whose viscosity is close to the microviscosity in the hydrophobic region of egg-PC membranes. On the other hand, the g-value and line width of the broad signal were close to those of solid PTM-TE. These observations indicate that the broad signal observed in liposomes originates from PTM-TE clusters in the membranes. The clusters were dissolved in egg-PC membranes at a PTM-TE/egg-PC molar ratio of less than 0.017. However, the clusters were hardly dissolved in the presence of cholesterol. PMID- 21532202 TI - Physicochemical characterization and dissolution study of solid dispersions of ketoconazole with nicotinamide. AB - PURPOSE: The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug ketoconazole using solid dispersion technique. METHODS: Solid dispersions of ketoconazole were prepared in ratios of 90 : 10, 70 : 30, 50 : 50, 30 : 70 and 10 : 90 by the melting method using nicotinamide as carrier. These solid dispersions were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectroscopy to ascertain if there were any physicochemical interactions between drug and carrier that could affect dissolution. Solubility and dissolution studies were conducted with pure ketoconazole, physical mixtures and solid dispersions. RESULTS: Solubility studies indicated that nicotinamide increased significantly the solubility of ketoconazole in water. The Gibbs free energy (DeltaG degrees (tr)) values were negative indicating the spontaneous nature of ketoconazole solubilization, and it decreased with increase in concentration of the carrier, demonstrating that the reaction became more favorable as the concentration of the carrier increased. The cumulative release of ketoconazole within 120 min from solid dispersion at a drug to-nicotinamide ratio of 10 : 90 (w/w) was 6 times higher than the pure drug in phosphate buffer of pH 6.8. CONCLUSION: Solid state characterization indicated that there is no interaction between ketoconazole and nicotinamide in the solid state. In contrast to the very slow dissolution rate of pure ketoconazole, the dispersion of the drug in nicotinamide considerably enhanced the dissolution rate. The drug dissolution rate was highest at a drug-to-nicotinamide ratio of 10 : 90 (w/w). PMID- 21532203 TI - Silica-supported boric acid with ionic liquid: a novel recyclable catalytic system for one-pot three-component Mannich reaction. AB - A rapid and efficient silica-supported boric acid/ionic liquid ([bmim][PF6]), catalyzed, one-pot three-component Mannich reaction has been carried out to synthesize beta-amino carbonyl compounds at room temperature. The reaction afforded desired products in excellent yields with moderate to good diastereoselectivity. The method provides a novel modification of three-component Mannich reaction in terms of mild reaction conditions, clean reaction profiles, low amount of catalyst, recyclability of catalyst and a simple workup procedure. The present report first time describes the preparation of H3BO3-SiO3 catalyst and its use with [bmim][PF6], to synthesize Mannich products. The catalyst can be reused at least seven times. PMID- 21532204 TI - Dissolution enhancement of artemisinin with beta-cyclodextrin. AB - The main objective of this research is to improve the dissolution rate of artemisinin (ART) by fabrication with beta-cyclodextrin (beta-CD) as a hydrophilic carrier. Artemisinin nanoparticles and ART/beta-CD complexes were successfully fabricated by means of evaporative precipitation of nanosuspension. Characterization of the samples was done by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and dissolution tester. Percent dissolution efficiency, mean dissolution time, relative dissolution and similarity factor were calculated for the statistical analysis of dissolution data. FT-IR showed some interaction between ART and beta-CD, which can be due to the formation of some ART/beta-CD complexes. XRD study indicated the presence of two polymorphs of ART, i.e. orthorhombic and triclinic form. Original ART particles and ART nanoparticles fabricated were orthorhombic whereas the free ART in the ART/beta CD complexes (not forming complex with beta-CD) was of triclinic form. The crystallinity of ART reduced and more and more ART/beta-CD complexes were formed with increasing concentration of beta-CD as indicated by the DSC, XRD and FT-IR studies. Artemisinin nanoparticles and ART/beta-CD complexes showed significantly faster dissolution than the pure drug due to smaller size (larger surface area), formation of the inclusion complex with beta-CD, formation of the triclinic form for remaining free ART (not forming complex with beta-CD), and amorphous state formation. Evaporative precipitation of nanosuspension was able to successfully fabricate artemisinin in the nanoparticles and complex forms with significantly faster dissolution rates than that of the original artemisinin. The two polymorphic forms of ART were also fabricated and studied. PMID- 21532205 TI - Flavonoids from Daphne aurantiaca and their inhibitory activities against nitric oxide production. AB - Chemical examination of the methanolic extract from the stem bark of Daphne aurantiaca led to the isolation of three new flavonoids (1-3), and 29 known flavonoids. All 32 compounds were isolated for the first time from Daphne aurantiaca. The isolates were tested for inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 21 and 24 showed potent inhibitory activities against the production of NO with IC50 values of 0.006 and 0.076 uM, respectively. PMID- 21532206 TI - A new method to evaluate the unfolding activity of chaperone unit ClpA based on Fe-S cluster disruption. AB - ATP-dependent proteases unfold their substrates and then refold (via chaperone activity) or degrade (via protease activity) them. The proteases choose between these two activities by selecting their substrates; however, little is known about their substrate selection mechanism. The present study attempts to clarify this mechanism by investigating the role of the Escherichia coli (E. coli) ATP dependent protease ClpAP. To address this, a reaction system that can measure both chaperone and protease activities simultaneously must be constructed. However, the chaperone activities cannot be evaluated in the presence of protease units. Green fluorescent protein (GFP) is usually used as a model substrate of ClpAP; the fluorescence decrease reflects the degradation of substrates. However, it is difficult to evaluate the chaperone activity of ClpAP using this system, because it cannot distinguish between intact and refolded substrates. Therefore, it is necessary to evaluate the exact unfolding activity while avoiding restoration of substrate spectroscopic characteristics due to chaperone activity. In this study, E. coli Ferredoxin (Fd) was used as a new model substrate for ClpAP to evaluate its unfolding activity. Intact and refolded substrates may be distinguished by the existence of an Fd Fe-S cluster. To verify this hypothesis, the absorption spectrum of Fd complexed with ClpA, the chaperone unit of ClpAP, was measured. A decrease in two peaks derived from the Fe-S cluster was observed, indicating that the Fe-S cluster of Fd was disrupted by the ClpA chaperone. This reaction system should prove useful to evaluate the exact unfolding activity of ATP-dependent proteases. PMID- 21532207 TI - Relationships between the particle velocity and introduction of drug-loaded microparticles into the skin in a microparticulate bombardment system. AB - Recently, it has been suggested that a microparticulate bombardment system would be a very useful tool for the delivery of a variety of powdered drugs as an alternative to parenteral injection via a needle. However the relationship between the particle dynamics and introduction into the skin has not been researched using this system. In the present study, we analyzed the velocity of microparticles bombarded by the Helios(TM) gun system under various conditions using particle image velocimetry (PIV). The particle kinetic energy, which depended on the particle velocity and particle mass, was increased with increasing helium pressure and particle size, decreasing bombardment dose, resulting in the increased percentage introduction and relative bioavailability (F(0-24 h)). The particle velocity had a greater influence than the particle mass. Therefore, in order to be the most effective system for introduction into the skin, it is necessary to use a high helium pressure and microparticles of high density. However, it is also necessary to consider the skin damage after bombardment. PMID- 21532208 TI - Triterpenoid saponins from the seeds of Celosia argentea and their anti inflammatory and antitumor activities. AB - Three new triterpenoid saponins, named celosin E (1), celosin F (2) and celosin G (3), together with a known compound cristatain (4), were isolated from the seeds of Celosia argentea L. (Amaranthaceae). All the isolated compounds were obtained for the first time from this plant. The structures of new compounds were characterized on the basis of extensive NMR experiments and mass spectrometry data. The antitumor and anti-inflammatory activities of the four compounds were tested in vitro. PMID- 21532209 TI - Pycnalin, a new alpha-glucosidase inhibitor from Acer pycnanthum. AB - A new compound, pycnalin (1), together with four known compounds, ginnalins A (2), B (3), C (4), and 3,6-di-O-galloyl-1,5-anhydro-D-glucitol (3,6-di-GAG) (5), were isolated from Acer pycnanthum. The structure of 1 was determined on the basis of 2D-NMR spectral data and synthesis of 1. Pycnalin (1) is the first 1,5 anhydro-D-mannitol linked to a gallic acid, while compounds 2-5 were 1,5-anhydro D-glucitol linked to gallic acids. All compounds were tested in vitro for alpha glucosidase inhibitory and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities. Pycnalin (1) exhibited moderate alpha-glucosidase inhibitory activity as well as free radical scavenging activity. Ginnalin A (2) and 3,6-di-GAG (5), which have two galloyl groups, exhibited potent alpha glucosidase inhibition, compared to those of other compounds 1, 3, and 4 containing a galloyl group. These results suggest that alpha-glucosidase inhibition is influenced by the number of galloyl groups. PMID- 21532210 TI - Oplopanphesides A-C, three new phenolic glycosides from the root barks of Oplopanax horridus. AB - Three new phenolic glycosides, named oplopanphesides A-C (1-3), have been isolated from the root barks of Oplopanax horridus. Their structures were elucidated by a combination of spectroscopic analyses, including 1D- and 2D-NMR techniques. These phenolic glycosides possess a novel feature in their sugar moieties that a 3-hydroxy-3-methylglutaryl moiety was connected with C-6 of the beta-D-glucopyranosyl group. Those compounds showed no cytotoxic effects against human cancer cell lines (MDA-231 and MCF-7) by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) method. PMID- 21532211 TI - Assessment of drug metabolites. PMID- 21532212 TI - Pharmacokinetics of tolbutamide in acute renal failure induced by glycerol: speculative thoughts and perspectives. PMID- 21532213 TI - Changes in vasopressin release and autonomic function induced by manipulating forebrain GABAergic signaling under euvolemia and hypovolemia in conscious rats. AB - The anteroventral third ventricular region (AV3V) is a pivotal area for osmotic responses and integration of autonomic functions. The purpose of this study was to investigate whether the gamma-aminobutyric acid (GABA)-ergic activity in the AV3V may be involved in the regulation of arginine vasopressin (AVP) secretion and related phenomena under the conditions with or without hypovolemia. Experiments were performed in conscious rats. We found that AV3V infusion with the GABA(A) receptor antagonist bicuculline in euvolemic rats caused prompt increases in plasma AVP, osmolality, glucose, arterial pressure and heart rate. The effects of the bicuculline infusion were abolished by prior infusion of a GABA(A) receptor agonist, muscimol. When repeated twice with a 10-min interval, removal of systemic blood (10 mL/kg body weight) lowered arterial pressure and enhanced plasma AVP, osmolality, glucose and angiotensin II. Muscimol infusion in the AV3V, but not in the cerebral ventricle, inhibited the responses of plasma AVP and glucose, despite having no effect in a sham hemorrhagic state. The inhibition of the AVP response by the muscimol infusion was also verified in rats given a combined stimulus of bleeding plus an osmotic load. In contrast, AV3V infusion with the GABA(B) receptor agonist baclofen tended to intensify the hemorrhagic responses of plasma AVP and glucose, despite its potency to prevent the hemorrhagic fall in arterial pressure. These results, taken together with our previous data, suggest that hypovolemic stimuli, like hyperosmotic stimuli, may promote AVP secretion by causing the inhibition of AV3V GABA(A)-ergic activity responsible for potentiation of glutamatergic activity. PMID- 21532215 TI - Goserelin plus letrozole as first- or second-line hormonal treatment in premenopausal patients with advanced breast cancer. AB - A promising new option as the treatment of choice for premenopausal patients with metastatic breast cancer (MBC) could be the combination of a luteinising hormone releasing hormone analog and an aromatase inhibitor. Very little data about the use of goserelin with anastrozole in advanced breast cancer are available, and no cohort studies on the efficacy of goserelin with letrozole in advanced premenopausal breast cancer patients have been reported. We present the single centre, retrospective, experience of goserelin plus letrozole in a total of 52 premenopausal women with MBC. All patients received goserelin 3.6 mg by subcutaneous injection every 4 weeks along with letrozole 2.5 mg daily as first line (n=36) and second-line (n=16) hormonal treatment. The median duration of goserelin with letrozole treatment was 11 (range, 2-61) months, and the median duration of overall follow-up was 31 (range, 3-66) months. The objective response rate (ORR) was 21.1%, with two complete response (CR) (3.8%) and nine partial response (PR) (17.3%). Stable disease (SD) lasting more than 6 months was achieved by 26 patients (50.0%). Thus, goserelin with letrozole conferred clinical benefit (CB) in 37 women (71.1%). The progression-free survival (PFS) was 10 months. CR was exclusively observed in hormone receptor-double-positive patients. Drug therapy was well tolerated; no grade 3/4 toxicities were reported. Goserelin plus letrozole appears to be an efficacious and well-tolerated regimen in women with advanced breast cancer. Further prospectively randomized studies involving more patients and longer follow-up are indicated. PMID- 21532214 TI - Three-day continuous glucose monitoring for rapid assessment of hypoglycemic events and glycemic variability in type 1 diabetic patients. AB - This study was to determine whether glycemic variability is related to hypoglycemic events in type 1 diabetic patients, and whether the hypoglycemic events during a short-term continuous glucose monitoring system (CGMS) period parallel those measured during a 4-week self-monitoring of blood glucose (SMBG) period. We also evaluated whether glycemic variability indexes from a short-term CGMS correlate with those from a 4-week SMBG. A total of 49 type 1 diabetic patients wore CGMS devices for 3 days. These patients also performed SMBG for 4 weeks. Several indexes from the CGMS data were compared with indexes from the SMBG data. Hypoglycemic events (glucose levels <70 mg/dL) that occurred during the 3-day CGMS and 4-week SMBG periods were evaluated and compared. Hypoglycemic events were detected in 33 patients (67%) during the 3-day CGMS period. The patients with hypoglycemic events had a significantly higher glycemic variability index divided by mean glucose of CGMS, and a higher number of hypoglycemic events during the 4-week SMBG, compared to those with non-hypoglycemic events during the 3-day CGMS period. The percentage of hypoglycemic events using the 3-day CGMS was correlated with that from the 4-week SMBG (r=0.49, P<0.05) and low blood glucose index (r=0.51, P<0.05). The glycemic variability indexes from the 4-week SMBG correlated with the glycemic variability indexes from the 3-day CGMS. The short term CGMS appears to be clinically useful for rapidly assessing the risk of hypoglycemic events and glycemic variability. PMID- 21532216 TI - Low-dose aspirin delays gastric healing after Helicobacter pylori eradication. AB - BACKGROUND AND AIM: Helicobacter pylori (H. pylori) and aspirin are the major causes of gastric injury, and eradication of H. pylori can restore mucosal injury such as gastric ulcer. The aim of the present study was to investigate the effects of low-dose aspirin on the healing process, determined by endoscopic features, after H. pylori eradication. METHODS: From 2001 to 2008, 12,887 patients underwent endoscopic examination at our hospital. From these, 100 patients with and 100 patients without H. pylori infection were analyzed to identify the endoscopic features characteristic of H. pylori-infected stomach. Based on these characteristic features, we observed the healing process of 89 patients not taking low-dose aspirin and 12 patients taking low-dose aspirin for 6 months, 1 year, and 5 years, which was successful in eradicating H. pylori. RESULTS: Diffuse redness (DR) of the fundic mucosa was the characteristic feature of H. pylori-infected stomach, whereas reddish streaks (RS) on the greater curvature of the antrum was the characteristic finding in non-infected stomach. In the no aspirin group, DR faded by 6 months and new expression of RS was observed 1 year after H. pylori eradication. In contrast, in the aspirin group, both fading of DR and the expression of RS were observed 5 years after eradication. CONCLUSION: Low-dose aspirin delayed the early phase of the healing process in the gastric mucosa after H. pylori eradication. PMID- 21532217 TI - Comparison between Japanese and non-Japanese features of lupus cystitis based on case reports including novel therapy and a literature review. AB - OBJECTIVE: This study was carried out to determine the characteristics of lupus cystitis and to compare those of Japanese cases with those of non-Japanese cases. We also report a novel therapy for lupus cystitis refractory to corticosteroid. METHODS: For the literature search, published reports on lupus cystitis were searched by MEDLINE and ICHUSHI WEB. The inclusion criterion was interstitial cystitis, fulfilling the SLE classification criteria of American College of Rheumatology in 1997 and with either hydronephrosis detected by image studies (either computed tomography or ultrasonography) or bladder histopathology consistent with lupus cystitis. Interstitial cystitis without the fulfillment of the classification criteria was excluded. Patient demographic data and clinical data were retrieved from the literature and analyzed. RESULTS: Including the present 2 cases, a total of 78 cases were identified as definitive cases of lupus cystitis (35 non-Japanese cases and 43 Japanese cases). Female patients accounted for 90.7%. The preceding gastrointestinal symptoms and subsequent urinary symptoms were the most frequent. Anti-double strand DNA antibody most often expressed in the 76.1% of the patients. Mean age and the prevalence of vomiting were significantly higher among Japanese patients compared to non-Japanese cases and the prevalence of CNS involvement was lower among Japanese patients (p=0.03, 0.04 and 0.001). We report a novel therapy (cetirizine hydrochloride) for lupus cystitis refractory to corticosteroid in one of the present cases. CONCLUSION: Lupus enteritis, female gender, and positive anti-dsDNA antibody are risk factors for lupus cystitis. Japanese cases showed older age, a higher prevalence of vomiting and a lower prevalence of CNS involvement. We also report the efficacy of the novel use of cetirizine hydrochloride for lupus cystitis refractory to corticosteroid. PMID- 21532218 TI - Relationship between hyponatremia and in-hospital outcomes in Chinese patients with ST-elevation myocardial infarction. AB - OBJECTIVE: This study was investigated to determine the relationship between hyponatremia and in-hospital outcomes in Chinese patients with ST-elevation myocardial infarction. METHODS: Plasma sodium concentration was obtained in all patients on admission and analyzed as hyponatremia versus normalnatremia. The relationships between hyponatremia and in-hospital mortality as well as heart failure were assessed. RESULTS: Of 1,620 patients, 212 (13.1%) patients had hyponatremia on presentation (sodium <135 mmol/L). Patients with hyponatremia had higher rates of in-hospital mortality (13.7% vs. 7.3%, p=0.002) and heart failure (30.2% vs. 18%, p<0.001). Patients with a sodium level of <130 mmol/L had an adverse event rate of 22.9% versus 11.0% in patients with a sodium level of 130 to 135 mmol/L (p=0.034). In multivariate logistic regression, hyponatremia was independently correlated with in-hospital mortality (OR: 1.77, 95% CI: 1.02-3.06, p=0.042) and heart failure (OR: 1.61, 95% CI: 1.06-2.43, p=0.025). CONCLUSION: Hyponatremia is independently associated with in-hospital adverse outcomes in Chinese patients with acute ST-elevation myocardial infarction, and the risk of in-hospital mortality was increased with the severity of hyponatremia. PMID- 21532219 TI - Clinical features and outcomes of eosinophilic myocarditis patients treated with prednisolone at a single institution over a 27-year period. AB - BACKGROUND: Eosinophilic myocarditis is a rare clinical entity characterized by eosinophilia and myocardial inflammation with infiltrating eosinophils. The prognosis of patients with eosinophilic myocarditis is difficult to determine due the disease's rarity and varied causes; consequently, standard treatment has not been established. OBJECTIVE: To elucidate the clinical characteristics and treatment outcome of eosinophilic myocarditis, we retrospectively studied 7 patients fulfilling the criteria of the Japanese Circulation Society for eosinophilic myocarditis from among 64 patients admitted to our institution with eosinophilia over a 27-year period. RESULTS: The patients' ages at diagnosis ranged from 36 to 83 years (median: 52 years). The etiologies of the eosinophilic myocarditis were found to be idiopathic (3 patients), Churg-Strauss syndrome (2 patients), parasitic infection (1 patient) and chronic eosinophilic leukemia (CEL) (1 patient). In addition to treatment for the underlying disease, we also administered prednisolone at a dose appropriate to the disease severity (6 of 7 patients). The patient who was diagnosed with a parasitic infection was treated only with albendazole, because eosinophilic myocarditis was mild. The patient with CEL was positive for the FIP1 L1-PDGFRalpha fusion gene and was treated with imatinib. Eosinophilic cationic protein was a useful marker for assessing disease activity and treatment efficacy. At the end of the study, of the seven patients treated, six were alive (86%), giving a mean survival time of 37 +/- 40 months (mean +/- SD). CONCLUSION: Because eosinophilic myocarditis has various etiologies, it is essential to identify the etiology of the underlying disease. In the majority of eosinophilic myocarditis patients, administration of prednisolone may be an effective therapeutic modality producing a good outcome. PMID- 21532220 TI - Contrast-induced nephropathy after percutaneous coronary intervention in simple lesions: risk factors and incidence are affected by the definition utilized. AB - AIM: To compare the incidence, and risk factors, in-hospital and at the 18-month prognosis of contrast-induced nephropathy (CIN) according to the definition utilized: as an increase in serum creatinine (Scr) >= 0.5 mg/dL (CIN 1) or as an increase in Scr >= 25% above baseline values (CIN 2). METHODS AND RESULTS: We prospectively evaluated CIN according to two different definitions in 150 patients who underwent percutaneous coronary intervention (PCI) in simple lesions employing a low-medium dose of contrast media. Incidence of CIN was higher using the CIN 2 definition than CIN 1 (9.3% vs. 4%; p=0.0133). Patients with CIN 1 had a higher incidence of chronic kidney disease (CKD) (66.7% vs. 13.9%; p=0.006), higher mean serum creatinine levels (1.35+/-0.42 vs. 0.98+/-0.35; p=0.001) and lower mean eGFR levels (58.3+/-19.6 vs. 84+/-25.9; p=0.002). Patients with CIN 2 had a higher incidence of anemia (57.1% vs. 30.9%; p=0.049) and a higher mean contrast media volume was used (142.6+/-62.2 mL vs. 110.6+/-57.2 mL; p=0.05). In the multivariate analysis the only significant variable associated with CIN (CIN 2) was a higher volume of contrast media (OR=1.01; p=0.04). There were no differences in the major in-hospital events, but patients with CIN (both definitions) had a longer in-hospital stay. A persistent rise in serum creatinine at discharge occurred in only one patient. There were no differences between patients with and without CIN in events at the follow-up, with the exception of an increased risk of new hospitalization in patients with CIN 2. CONCLUSION: After PCI employing low-medium dose of contrast media the incidence of CIN varied according to the definition used. Neither of the two definitions offers additional information compared with the other. Chronic kidney disease and baseline parameters of renal function are the risk factors associated with CIN 1; anemia and higher volume of contrast media are associated with CIN 2. PMID- 21532221 TI - Clinical study concerning the relationship between community-acquired pneumonia and viral infection in northern Thailand. AB - OBJECTIVE: The etiological agents associated with community-acquired pneumonia (CAP) in Thailand have been studied extensively in bacterial pathogens, but not in viral pathogens. To clarify the association of viral pathogens with CAP, we conducted a comprehensive study of viral and bacterial pathogens in patients with CAP. METHODS: We enrolled 119 hospitalized patients with CAP in Nakornping Hospital, Chiang Mai, Thailand between 2006 and 2008. The severity of pneumonia was classified and the risk factors for death were estimated. Bacterial and fungal pathogens were determined from specimens taken from blood and sputum, and viral pathogens were identified from nasopharyngeal specimens by RT-PCR using primers specific for 7 respiratory viruses. RESULTS: Overall, 29 patients were HIV-infected and 90 patients were non-HIV-infected. The microbial pathogens most commonly isolated among HIV-infected patients were: 4 Klebsiella pneumoniae, 4 Mycobacterium tuberculosis and 3 Haemophilus influenzae. Among non-HIV infected patients, predominant microbial pathogens were: 6 Pseudomonas aeruginosa, 5 Haemophilus influenzae and 4 Klebsiella pneumoniae. As for viral pathogens for CAP, influenza virus was identified from 2 HIV-infected patients and 5 non-HIV infected patients. In addition, human rhinovirus (HRV) and respiratory syncytial virus (RSV) were identified from 2 patients each among non-HIV-infected patients. CONCLUSION: Our study demonstrates that the most common viral agent was influenza virus (5%), followed by HRV (2%) and RSV (2%) among CAP patients in northern Thailand. The underlying chronic obstructive pulmonary disease (COPD) seems to be correlated with the severity of illness. PMID- 21532222 TI - Plasma fibrinogen, global cognitive function, and cerebral small vessel disease: results of a cross-sectional study in community-dwelling Japanese elderly. AB - OBJECTIVE: Recent studies suggest that hemostatic and endothelial factors play a pivotal role in the development of cerebral small vessel disease (SVD). Although plasma fibrinogen is an essential factor in the coagulation cascade, the relationship among fibrinogen, cognitive function, and SVD has not been clarified in community-based Asian populations. Because fibrinogen levels of Asians have been reported to be lower than these of Caucasians, the impact of fibrinogen on the development of SVD or dementia in Asians may be different from that of Caucasians. METHODS: We performed a cross-sectional study using MRI to determine the relationships among fibrinogen, cognitive function, and subclinical SVD in community-based Japanese elderly. RESULTS: Subjects with raised fibrinogen levels tended to have more lacunes and higher grades of white matter lesions (WMLs). Additionally, an independent association between fibrinogen and WMLs was determined by logistic regression analyses. Subjects with high fibrinogen levels accompanied by high von Willebrand factors or thrombomodulin levels had an increased tendency for the presence of WMLs. The relationship between the mean Mini-Mental State Examination (MMSE) scores and the quartiles of fibrinogen levels was not statistically significant after controlling for age, gender, and WMLs; however, the mean MMSE scores in subjects without WML were related to the tertiles of the fibrinogen levels even after adjusting for conventional risks and high sensitivity C-reactive protein. CONCLUSION: The present study suggests that there is a close relationship between fibrinogen levels and subclinical WMLs, which are independent of conventional risk factors and inflammation, in community based Japanese elderly. PMID- 21532223 TI - Efficacy and safety of colistin in the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa in patients with hematologic malignancy: a matched pair analysis. AB - OBJECTIVE: A rise in infections with multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is a significant contributor to increased morbidity and mortality of patients with hematologic malignancies. The aim of this study was to determine the efficacy and safety of colistin (colistimethate sodium) in the treatment of serious infections caused by MDR-PA in these patients. PATIENTS AND METHODS: A matched pair analysis of renal function, toxicities, and outcome of 26 patients receiving colistin and control subjects was done. All patients had clinical signs of sepsis; P. aeruginosa was isolated from blood in 69% of patients in colistin group and 84% in control group. Patients treated with colistin received 3 million units every 8 hours for a median duration of 13 days. Additionally, patients received at least two additional antimicrobial or antifungal drugs. RESULTS: Resolution of infection was achieved in twenty patients (76.9%) receiving colistin and in 17 (65.4%) control subjects. Mortality rate was 11% in both groups. There was no statistically significant difference in the level of serum creatinine, creatinine clearance, or potassium levels before and after treatment between groups. Only one patient receiving colistin developed de novo renal failure and one displayed transient neurologic toxicity. CONCLUSION: Our results suggest that in patients with hematologic malignancies, colistin is effective in treating severe infections caused by MDR-PA while maintaining an acceptable toxicity profile. Prospective randomized studies comparing efficacy and safety of colistin with those of other antipseudomonal drugs are needed. PMID- 21532224 TI - A case of drug-induced hepatic injury associated with sitagliptin. AB - A 58-year-old man with a 10-year history of type II diabetes mellitus presented with progressive jaundice that began three days before admission. Thorough history-taking revealed that the patient had started on a new medication, sitagliptin, one month previously for the treatment of diabetes mellitus. Laboratory investigations showed severe liver dysfunction. Ultrasonography detected no extrahepatic biliary duct dilatation or gallstones. Abdominal computed tomography excluded pancreatic and hepatic focal lesions. Liver function improved upon discontinuation of sitagliptin. Drugs are an important, often unrecognized, cause of acute liver injury. This report presents a rare case in which sitagliptin was responsible for acute hepatic damage. As demonstrated, a thorough drug history is helpful in any case of unexplained liver injury. PMID- 21532225 TI - Inappropriate pacing inhibition triggered by QT prolongation due to T wave oversensing in an ICD recipient presenting with long QT syndrome. AB - Inappropriate inhibition of atrial pacing due to T-wave oversensing (TWOS) was observed in a patient presenting with congenital long QT syndrome, treated with an implantable cardioverter defibrillator (ICD) and beta-adrenergic blocker. Development of TWOS was associated with further QT interval prolongation in the absence of amplitude changes in the intracardiac T and R waves. Replacement of the ICD generator with a sensing filter designed to attenuate the intracardiac T wave suppressed TWOS and normalized the pacing functions. PMID- 21532226 TI - Pseudoaneurysmal formation in abdominal aorta associated with Escherichia coli infection. AB - Early and accurate diagnosis of infective aortic aneurysms (IAA) is critical for adequate treatment to optimize patient outcome. We report the case of an 84-year old man who complained of severe back pain with high fever and was finally diagnosed as Escherichia coli-related IAA. Computed tomography showed a periaortic soft tissue density and irregular fringe adjacent to the non-dilated abdominal aorta suggesting the presence of pseudoaneurysm. In addition to intravenous antibiotic injection, an aneurysmectomy with extensive debridement and an in situ graft, were successfully performed. The case emphasizes the potential for rapid IAA change and the need for frequent radiologic follow-up. PMID- 21532227 TI - False-positive accumulation of metaiodobenzylguanidine in a case with acute intermittent porphyria. AB - We report a 36-year-old woman presenting with hypertensive encephalopathy followed by bulbar palsy and quadriplegia. After an extensive screening for secondary causes of hypertension, the patient was suspected of having pheochromocytoma due to increased levels of catecholamines in the plasma and the urine, and positive (131)I-metaiodobenzylguanidine (MIBG) accumulation in the gallbladder. However, MIBG accumulation was not reproducible without any tumors accompanying this accumulation in the gallbladder. A diagnosis of acute intermittent porphyria was finally confirmed based on the characteristic pictures, increased urinary excretion of porphobilinogen, and identification of a heterozygous missense mutation of R173W in the hydroxymethylbilane synthase gene. This case highlights a pitfall in utilizing MIBG to detect a source of excessive catecholamine and also suggests the importance of having a complete clinical history and extensive work-up of any possible differential diagnosis. We also review the potential mechanism by which false-positive MIBG accumulation occurs. PMID- 21532228 TI - Temporal artery involvement in microscopic polyangitis. AB - An 81-year-old man was hospitalized because of fever and pain in the temporal region. Temporal artery biopsy revealed temporal arteritis; steroid therapy was started. Chest computed tomography and kidney biopsy revealed interstitial pneumonia and necrotizing crescentic glomerulonephritis, respectively. Because his myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) level was 215.0 U/mL, a diagnosis of microscopic polyangitis (MPA) was made. The patient was discharged after reduction of the steroid dose. However, his respiratory symptoms exacerbated, necessitating rehospitalization. He died 1 week later due to respiratory failure. MPA rarely involves the temporal artery. In the cases of large vessel lesions, ruling out MPA is important. PMID- 21532229 TI - Late onset pulmonary Lophomonas blattarum infection in renal transplantation: a report of two cases. AB - Lophomonas blattarum, a rare protozoa, was involved in pulmonary infections of transplant recipients. We report 2 cases of late onset pulmonary L. blattarum infection in renal transplant recipients with normal graft function and relative normal immune function. The diagnosis in both cases was confirmed by bronchoscopy and broncho alveolar lavage (BAL) fluid examination. Both cases were sensitive to metronidazole treatment, but one case did not completely recover during the follow-up. The diagnosis and treatment were discussed to facilitate improvement in the recognition of this rare infection, especially in transplant recipients. PMID- 21532230 TI - Does a proton pump inhibitor cause hypokalemia? AB - Proton pump inhibitors (PPIs) act only in the stomach, although the proton pump, H(+),K(+)-ATPase exists and contributes to H(+) and K(+) homeostasis in the kidney. We encountered two hypokalemic cases receiving omeprazole. These cases were women ages 69 and 80 years old. Their serum potassium levels decreased with accelerated urinary potassium excretion with the use of omeprazole, and recovered by potassium-supplement and the discontinuation of omeprazole. Because inhibitory effects of PPIs on H(+),K(+)-ATPase are exerted only in acidic condition, hypokalemia is not generally introduced by PPIs alone. However, in extreme alkalosis or impaired K(+)-recycling system, PPIs may cause hypokalemia unrelated to hypomagnesemia. PMID- 21532231 TI - First case report of acquired pure red cell aplasia associated with micafungin. AB - A 70-year-old Japanese man with chronic kidney disease under treatment with oral prednisolone for organizing pneumonia developed pulmonary aspergilloma. The patient was started on micafungin (MCFG), with no addition of any other new drug. About 5 weeks later, aggravation of his normocytic anemia associated with a low reticulocyte count was observed. Bone marrow puncture and biopsy revealed intense hypoplasia of the erythroblasts. As there was no evidence of malignancy, human parvovirus B19 infection, autoimmune diseases or hemorrhage, the patient was diagnosed as having acquired pure red cell aplasia (PRCA). The anemia improved along with an increase of the reticulocyte count to the normal level within 12 weeks of discontinuation of the MCFG therapy. The patient showed no evidence subsequently of any recurrence of the normocytic normochromic anemia or relapse of the PRCA. This is the first reported case of PRCA associated with MCFG. PMID- 21532232 TI - Occult adenocarcinoma of the lung mimicking rapid progression of asbestosis. AB - We herein present an autopsy case of occult lung adenocarcinoma that masqueraded as rapid progression of preexisting asbestosis. A 66-year-old man with an initial diagnosis of asbestosis experienced progressive dyspnea for over four years, and eventually died of respiratory failure. A series of chest computed tomography scans showed progression of extensive fibrosis from the right lower lobe to the left lobes. An autopsy revealed that well-differentiated adenocarcinoma with prominent reactive fibrosis was diffusely distributed within the fibrotic lesions in addition to the underlying asbestosis, and the unusually rapid progression of asbestosis was attributed to the reactive fibrosis of occult lung adenocarcinoma. PMID- 21532233 TI - Two cases of cerebral embolism caused by apical thrombi in midventricular obstructive cardiomyopathy. AB - Midventricular obstructive hypertrophic cardiomyopathy (MOHC) is a rare form of cardiomyopathy that was demonstrated to have caused embolic stroke in two patients. In both cases, the embolic sources of stroke were thrombi in an apical aneurysm caused by turbulent stasis of blood flow and subsequent injury of myocardial endocardium. Even without atrial fibrillation, apical aneurysm can induce emboligenic stroke in MOHC. PMID- 21532234 TI - Repeated non-enhancing tumefactive lesions in a patient with a neuromyelitis optica spectrum disorder. AB - A 51-year-old woman had developed fever and consciousness disturbance at 47 years of age. Brain magnetic resonance imaging (MRI) revealed acute disseminating encephalomyelitis (ADEM)-like lesions without gadolinium enhancement (GDE). One year later, she had an episode of bilateral optic neuritis and cerebellar ataxia. Speech deficit and right hand weakness occurred at the age of 51 years. Neurological examination showed motor aphasia, finger agnosia, right-left disorientation, and right hand paresis. Neuromyelitis optica (NMO)-IgG was seropositive. Cerebrospinal fluid examination showed negative results for myelin basic protein and oligoclonal IgG band. The IgG index was normal. Brain MRI revealed a tumefactive lesion in the left temporo-parietal region and conglomerate ovoid lesions in the pericallosal regions. No GDE was found in the brain lesions. Visual evoked potential test showed bilateral prolongation of P100 latencies. She was treated twice with methylprednisolone pulse therapy followed by oral prednisolone, but the motor aphasia did not respond to steroid treatment. She had no prior history of myelitis and was diagnosed as NMO spectrum disorder (NMOSD). Similar to previous studies of NMO-IgG seropositive extensive brain lesions, this patient with NMOSD indicated no GDE in tumefactive lesions at two episodes of encephalopathy. Compared to multiple sclerosis (MS), a high frequency of non-enhancing tumefactive lesions is reported in patients with NMO or NMOSD. The absence of GDE in tumefactive lesions could help to differentiate between NMO and MS. PMID- 21532235 TI - Rheumatoid arthritis following a treatment with IFN-alpha/ribavirin against HCV infection. AB - We report a 48-year-old man who developed rheumatoid arthritis (RA) after a successful treatment with peg-IFN-alpha plus ribavirin for chronic hepatitis C virus (HCV) infection. He had a history of smoking and a single copy of the HLA DRB1 shared epitope (SE). In a retrospective analysis, he exhibited the anti-CCP antibodies before the start of IFN plus ribavirin treatment. However, the titers of anti-CCP antibodies and BAFF levels were elevated by the IFN plus ribavirin therapy. These observations suggest that IFN plus ribavirin therapy may work as a "trigger" for RA in genetically and environmentally predisposed individuals by affecting the cytokine network. PMID- 21532236 TI - Pulmonary Mycobacterium massiliense disease with septicemia during immunosuppressive treatment. AB - A 75-year-old man with interstitial pneumonia due to ANCA-related vasculitis requiring immunosuppressive treatment was admitted to our hospital because of fever and rapidly progressive dyspnea. Chest CT showed diffuse ground-glass opacity with infiltration shadow in the bilateral lungs. We established a definitive diagnosis by isolating Mycobacterium massiliense on culture examination of acid-fast bacilli from peripheral blood and sputum. We began to administer CAM, LVFX, AMK, IPM/CS to this patient two weeks after admission. However, he died of respiratory failure and septic shock. There are few case reports of pulmonary lesion with septicemia due to Mycobacterium massiliense. PMID- 21532237 TI - A case of acquired Fanconi syndrome induced by zoledronic acid. AB - A 61-year-old woman with metastatic breast cancer was diagnosed as having acquired Fanconi syndrome. In this case, the cause of this syndrome was most likely zoledronic acid (Zometa), which had been infused intravenously at a dose of 4 mg over 15 minutes weekly because of malignancy-associated hypercalcemia. Zoledronic acid is nephrotoxic and may induce severe tubular dysfunction, which can cause development of Fanconi syndrome. Therefore, close monitoring of proximal tubular function is recommended during therapy with zoledronic acid, especially when frequent administration of zoledronic acid is needed. PMID- 21532238 TI - Central blood pressure--a possible latent factor affecting CAVI. PMID- 21532241 TI - [Evaluation of 320-row area detector computed tomography (ADCT) coronary angiography for patients with atrial fibrillation]. AB - The aim of this study was to evaluate 320-row area detector CT (ADCT) for patients with atrial fibrillation (Af) based on simulated exposure using electrocardiogram RR intervals and comparison with the findings of coronary CT angiography (CCTA) using 64-row multi slice CT (MSCT). The probability of including RR intervals of 900 ms or more was calculated when the acquisition time was varied from 1 to 4 beats. Overall, 51 patients with Af who underwent CCTA were examined. The exposure time for CCTA, the total dose length product (DLP) for the examination, and the image quality (scored 0 to 3: poor to excellent) were compared between ADCT and MSCT. The probability of including RR intervals of 900 ms or more was highly significantly increased at 3 beats of acquisition time. The exposure time using ADCT was reduced by 75% compared with MSCT (ADCT/MSCT: 2.8/11.3 s), and the total DLP was reduced by 40% (ADCT/MSCT: 1398/2277 mGy.cm). Moreover, ADCT provided diagnosable images in all cases, and the mean image quality score for ADCT was significantly higher than that for MSCT (ADCT/MSCT: 2.8/2.4). Thus, 320-row ADCT at 3 beats of acquisition time can provide CCTA images of acceptable quality for patients with Af. PMID- 21532240 TI - Relationship between socioeconomic variables and obesity in Korean adolescents. AB - BACKGROUND: Despite the importance of obesity and its association with socioeconomic status, little is known about this condition in Korean adolescents. We examined the relationship between obesity in Korean adolescents and several socioeconomic variables and compared the association of obesity with conventional and subjective indicators of socioeconomic status. METHODS: The study comprised 60 643 Korean adolescents aged 12 to 18 years who participated in the 2007 Korea Youth Risk Behavior Web-Based Survey. The dependent variable, obesity, and the independent variables of parental education levels, family affluence scale, subjective family economic status, and subjective school achievement were collected by using a self-administered anonymous questionnaire. Data on behavioral and psychological characteristics were also collected and used as confounding factors. Multivariate logistic regression was conducted to identify associations between socioeconomic status and obesity. RESULTS: In the descriptive analysis, adolescents with low parental education, low family affluence level, low subjective family economic status, and low subjective school achievement were more likely to be obese. However, after controlling for other risk factors in multivariate analysis, only the associations with subjective family economic status and subjective school achievement remained statistically significant. CONCLUSIONS: Our results provide further evidence that the prevalent pattern of obesity in Korean adolescents-i.e., the inverse relationship between obesity and socioeconomic status-is similar to that in developed countries. In addition, these findings support the hypothesis that, as compared with objective socioeconomic status, subjective social status is more closely related to obesity. PMID- 21532239 TI - Albuminuria as a risk factor for peripheral arterial disease in a general population: the Hisayama study. AB - AIMS: To elucidate the relationship between albuminuria and the prevalence of peripheral arterial disease (PAD), and to examine the effect of albuminuria on the ability to assess the likelihood of PAD in a general Japanese population. METHODS: In 3,061 community-dwelling subjects aged. 40 years, we investigated the association of urinary albumin-creatinine ratio (UACR) levels with the prevalence of PAD, defined as an ankle-brachial index < 0.9. The odds ratio for the presence of PAD was estimated using the logistic regression model. To compare the accuracy of the assessment for the likelihood of prevalent PAD between models adjusted for potential risk factors with and without UACR levels, the receiver operating characteristic (ROC) curves were plotted. RESULTS: Overall, 1.47% of the study participants had PAD. The age- and sex-adjusted prevalence of PAD increased linearly for UACR levels of < 5.6, 5.6-10.8, 10.9-29.9, 30.0-300.0, and >300.0 mg/g, being 0.34, 0.80, 2.02, 2.50, and 2.53%, respectively (p for trend <0.001). The multivariate-adjusted odds ratio for the presence of PAD was 1.85 (95% confidence interval 1.12-3.06) for every 10-fold increment in UACR. The area under the ROC curve significantly increased when UACR levels were incorporated into a model with potential risk factors for PAD (0.80 vs. 0.77, p= 0.02). CONCLUSION: Greater UACR levels are associated linearly with a higher prevalence of PAD, even within the normoalbuminuric range, in the general Japanese population, and combining UACR levels with potential risk factors substantially improves the performance to assess the likelihood of PAD. PMID- 21532242 TI - [Comparison of detectability of liquid crystal displays (LCDs) and film using phantoms of small adenocarcinomas as abnormalities]. AB - Following the trend of the digitalization of the modalities used for diagnostic imaging, the devices for such imaging have increasingly included monitors. The present study was undertaken to evaluate the usefulness of soft-copy (liquid crystal display; LCD) images of phantoms of small adenocarcinomas using receiver operating characteristic (ROC) analysis of two different display systems: LCD and hard copy (film). A two-tailed paired t-test and the jackknife method (parametric methods) were performed, and no significant differences were found in the area under the ROC curve (AUC) for the pulmonary fields, lungs, ribs, or mediastinum between the film and LCD display systems, and the detectability did not differ between the film and LCD monitors. A Mann-Whitney U test, which is a non parametric method that applies to the analysis of a small sample, also showed no significant differences in the AUC. The results of this study suggest that LCDs can replace hard-copy film as a display system if the signals. PMID- 21532243 TI - [Computerized classification of pneumoconiosis radiographs based on grey level co occurrence matrices]. AB - Pneumoconiosis is diagnosed as categories 0-4 according to the Pneumoconiosis Law. Physicians have difficulty precisely categorizing many chest images. Therefore, we have developed a computerized method for automatically categorizing pneumoconiosis from chest radiographs. First, we extracted the rib edge regions from lung ROIs. Second, texture features were extracted using a dot enhancement filter, line enhancement filter, and grey level co-occurrence matrix. Third, the rib edge regions were removed from these processed images. Finally, we used a support vector machine for feature analysis. In a consistency test, 56 cases (69.7%) were classified correctly, and 45 cases (61.8%) were classified correctly in a validation test. These results show that the proposed features and removal of the rib edge are effective in classifying the profusion of opacities that indicate pneumoconiosis. PMID- 21532244 TI - [Applicability of PROSET-MRA for evaluating pediatric moyamoya disease]. AB - MR angiography (MRA) for pediatric moyamoya disease is important as a non invasive examination to diagnose blood flow in the brain. Generally, the conventional 3D-TOF MRA is used for moyamoya disease. However, retrobulbar and subcutaneous fat of the head show high intensity signals. We found that using the conventional MRA to diagnose the details of brain blood flow is difficult and that it cannot differentiate moyamoya vessels and fat. It similarly obscures the ophthalmic artery and superficial temporal artery that overlap with fat in the direction of the maximum intensity projection (MIP). Therefore, we devised an MRA technique with fat suppression to diagnose blood flow in moyamoya disease patients: MR angiography with the principle of selective excitation technique (PROSET). The scan time does not need to be increased. We studied the TOF effect in constant and pulsatile flows and the water selective excitation method with the binominal pulse (PROSET) for the fat suppression effect for moyamoya disease. The results showed that PROSET-MRA achieved better image results than conventional MRA. The development of collaterals of the superficial temporal artery and occipital artery in pre- and post-operation moyamoya disease could be clearly visualized and evaluated. The PROSET-MRA method is useful for evaluating pre- and post-operation (encephalo-duro-arterio-synangiosis, encephalo-myo synangiosis) blood flow reconstruction for patients who have moyamoya disease. PMID- 21532245 TI - [Lumbar spinal nerve roots imaging using balanced sequence with inversion recovery (IR) pulse]. AB - We devised a method for visualizing the distal portion of lumbar spinal nerve roots in the direction of the long axis using a three-dimensional balanced sequence with inversion recovery pulse, and we established the imaging parameters. This pulse sequence was used with the following parameters: 260 mm field of view, 4.8 ms repetition time, 2.4 ms echo time, 90 degree flip angle, 1.5 mm slice thickness (0.75 mm overlap), and low-high radial k-space profile order. We assessed the signal intensity and contrast for the phantom and healthy volunteer images with different inversion times (TI). Moreover, we evaluated this method by using the optimal TI in clinical cases. The optimal TI obtained from the phantom and human studies was 600 ms. In clinical cases, this method with 600 ms of TI provided the best definition in images of abnormal pathway and compression of the lumbar spinal nerve roots. Our imaging method makes it possible to clearly and noninvasively visualize the lumbar spinal nerve roots. PMID- 21532246 TI - [Quantitative evaluation of calcium (content) in the coronary artery using hybrid iterative reconstruction (iDose) algorithm on low-dose 64-detector CT: comparison of iDose and filtered back projection]. AB - To evaluate the usefulness of hybrid iterative reconstruction (iDose) for quantification of calcium content in the coronary artery on 64-detector computed tomography (CT), an anthropomorphic cardiac CT phantom containing cylinders with known calcium content was scanned at tube current-time products of 15, 20, 25, and 50 mAs using 64-detector CT. The images obtained at 15, 20, 25, and 50 mAs were reconstructed using filtered back projection (FBP), and those at 15, 20, and 25 mAs were also reconstructed using iDose. Then the volume and mass of the calcium content in the cylinders were calculated and compared with the true values. The Agatston score was also evaluated. The Agatston score and mass of calcium obtained at 50 mAs using FBP were 656.92 and 159.91 mg, respectively. In contrast, those obtained at 25 mAs using iDose were 641.91 and 159.05 mg, respectively. No significant differences were found in the calcium measurements obtained using FBP and iDose. In addition, the Agatston score and mass of calcium obtained at 15 mAs and 20 mAs using iDose were not significantly different from those obtained at 25 mAs with iDose. By using iDose, accurate quantification of calcium in the coronary artery can be achieved at 15 mAs using 64-detector CT. The radiation dose can be significantly reduced in coronary artery calcium scoring without impairing the detection and quantification of coronary calcification. PMID- 21532247 TI - [Assessment of cross-sectional area and diameter of carotid artery using time-of flight MR angiography and CT angiography]. AB - PURPOSE: In carotid artery stenosis, precisely assessing the vessel cross sectional area and diameter is important because this result determines the treatment strategy for patients. The purpose of our study was to evaluate the vessel sizes of normal and stenotic carotid arteries using time-of-flight magnetic resonance angiography (TOF-MRA) and X-ray CT angiography (CTA). METHOD AND MATERIALS: The TOF-MRA and the CTA data were obtained using 3D TOF-MRA on a 1.5-T MR scanner (1.0 mm slice thickness) and dynamic contrast-enhanced multi detector row CT (0.5 mm slice thickness). In thirty-three normal patients (20 men, 13 women, mean age of 66.9+/-9.0 years) and eighteen patients with carotid artery stenosis (12 men, 6 women, mean age of 74.4+/-6.4 years), we measured the vessel cross-sectional areas and the diameters of the internal and common carotid arteries (ICAs and CCAs) using TOF-MRA and CTA and a vessel-analytic program of the workstation. RESULTS: The mean cross-sectional areas and diameters of normal ICAs and CCAs determined using TOF-MRA were significantly smaller than those determined using CTA. The percentages of area and diameter stenoses found using TOF-MRA were 7.7 and 14.3% higher than those found using CTA. In six cases in the stenotic group, the stenotic artery showed no signal using TOF-MRA, but the CTA depicted it. CONCLUSION: In both normal and stenotic carotid arteries, TOF-MRA underestimates vessel size more than CTA does. PMID- 21532248 TI - [Investigation of quality control and average glandular dose and image quality in digital mammography in Hokkaido]. AB - A questionnaire survey about mammography in Hokkaido was mailed to 121 facilities from August to September 2009. We surveyed the conditions of digital mammography with regard to quality control (QC) and average glandular dose at 79 facilities in Hokkaido in 2009, and the results of the survey were compared with those of 2004. We found that digital mammography techniques were widely used across Hokkaido and that computed radiography (CR) systems were quite widespread, with 70% of facilities having them. The average glandular dose ranged from 1.04 to 2.3 mGy (mean: 1.73 mGy) for digital equipment. The results revealed several problems. Although the use of 1-, 2-, and 3-megapixel (MP) liquid crystal displays (LCDs) was not uncommon, 5-MP LCDs were used in most cases when reading digital mammograms. Facilities that have mammography equipment are unlikely to have quality control instruments for mammography. Although daily QC is performed in most facilities, further quality control for digital mammography should be developed, including that for monitors. In a second study, we evaluated the 1 Shot Phantom M Plus (1 Shot Phantom), which enables objective evaluation by providing for one physical measurement rather than a subjective visual analysis. The results indicated that the 1 Shot Phantom was very useful for digital mammography systems in daily QC testing because it enabled objectivity. PMID- 21532249 TI - [Symposium 1: Advantages and disadvantages of filmless age]. PMID- 21532250 TI - [Scheduling and management of information system implimentation prosess: IT project management based on work breakdown structure]. PMID- 21532251 TI - [Science of similar images: quantitative evaluation on the similarity of images to be used in the next generation CAD]. PMID- 21532253 TI - [Reference X-ray field for mammography dosimetry in Japan]. PMID- 21532252 TI - [Qualitative research methodology]. PMID- 21532254 TI - [Recognition system for maintenance engineer promoted by JIRA]. PMID- 21532256 TI - A self-contained culture platform using carbon dioxide produced from a chemical reaction supports mouse blastocyst development in vitro. AB - Elevated CO(2) is required for in vitro embryo culture to maintain proper media pH and to supply embryo metabolic pathways. As an alternative to current approaches using gas cylinders, we examined use of a chemical reaction to supply CO(2). A closed culture system was constructed and chemicals added to generate CO(2), which was then supplied to developing embryos. This system was shown to provide a stable pH (7.2-7.4) over 4 days of use. One-cell mouse embryos were cultured in the device and no difference in blastocyst formation or cell number was apparent between embryos grown in a closed system with CO(2) supplied by a chemical reaction or positive controls grown in a an open system in a CO(2) incubator. This approach provides a highly purified, inexpensive, and easily obtainable gas source and offers potential for development of new, self-contained culture platforms. PMID- 21532257 TI - Multiplex polymerase chain reaction used for bovine embryo sex determination. AB - Widely used bovine sexing primers were compared in terms of suitability in determining the sex of bovine embryos. Under optimized multiplex PCR conditions, the ConBV/ConEY couple primers did not show accurate results when combined together in multiplex PCR, but worked well when the couple primers were used separately. The S4BF/S4BR primers showed accurate results; however, some unexpected bands were detected. When the BY/BSP couple primers were used to determine one-cell, two-cell, four-cell and eight-cell stage embryos of known sexed SCNT-derived embryos, the results showed 100% accuracy. The BY/BSP couple primers were also able to identify the sex of one-cell and two-cell IVF-derived embryos. PMID- 21532258 TI - Mycobacterium ulcerans infection in an Indian flap-shelled turtle (Lissemys punctata punctata). AB - We report an atypical mycobacterial infection in an Indian flap-shelled turtle, Lissemys punctata punctata, that died in an aquarium in Japan. At necropsy, the turtle showed multiple white nodules on the capsular surface and parenchyma of various organs such as the liver, spleen, intestine, and lung. Histologically, granulomatous inflammation surrounding a central zone of necrosis was observed. Sections stained by the Ziehl-Neelsen method revealed numerous acid-fast bacilli in the cytoplasm of macrophages and in the central area of necrosis. The organisms were identified as a mycobacterial species by PCR and nucleotide sequence analysis and revealed 98-100% homology to M. ulcerans. This is, to our knowledge, the first report of mycobacteriosis due to M. ulcerans in a turtle. PMID- 21532259 TI - Bisphenol-A (BPA) affects reproductive formation across generations in mice. AB - To understand effects of Bisphenol-A (BPA) exposure on the reproductive organ across generations, we analyzed morphology of the uterus and ovary, and the methylation pattern of HOXA10 gene of the 2(nd) generation. Pregnant mice (F0) were treated with sc injection of BPA in sesame oil at various doses of 0-1,000 mg/kg Bwt on days 12-16 of gestation. Their offspring (F1) were bred by foster mice, and the offspring (F2) from F1 mice were prepared. That is, F1 mice experienced in utero BPA exposure during the developmental period of reproductive organs, while F2 mice did not at all. Using these F2 mice, the present study was carried out. Comparing to the control, the body weights in BPA exposure groups were significantly increased. Correlating with the increase of body weight, the relative weights of the ovary and uterus in each group were decreased. The histological analysis revealed expansion or emphraxis of the uterine lumen and partial loss of the uterine epithelium. Unmethylation of HOXA10 gene in the uterus was observed in the intron region. The present study suggested that BPA exposure to F0 mice could affect reproductive organ of F2 mice who were not exposed to BPA. PMID- 21532260 TI - An experimental infection in pigs using a foot-and-mouth disease virus isolated from the 2010 epidemic in Japan. AB - In this study, we carried out an experimental infection in pigs using a foot-and mouth disease virus isolated from the 2010 epidemic in Japan to analyze the clinical manifestation, antibody response and virus shedding patterns in pigs. We found that the virus was virulent in pigs, producing a synchronous disease in the inoculated pigs and efficient spread to direct contact pigs. These results are useful for epidemiologically investigating the 2010 epidemic in Japan and improving the measures for controlling possible future FMD outbreaks in Japan or elsewhere. PMID- 21532261 TI - Immunolocalization of inhibin/activin subunit proteins during the breeding season in testes and scented glands of muskrats (Ondatra zibethicus). AB - The objective of this study was to investigate the cellular immunolocalization of inhibin a and inhibin/activin (beta(A) and beta(B)) subunits in the muskrat testes and scented glands during the breeding season. Inhibin alpha and inhibin/activin (beta(A) and beta(B)) subunits were expressed in Sertoli cells and Leydig cells of testes and glandular cells of scented glands, respectively. Also, positive signals of inhibin alpha and inhibin/activin (beta(A) and beta(B)) subunits by Western blotting were both observed in testicular and scented glandular tissues. These results suggested that the testes and scented glands of the muskrats had the ability to synthesize inhibins and activins and that activins and inhibins might play an important role in testicular and scented glandular function in muskrats. PMID- 21532262 TI - Role of the nitric oxide on relaxation of the human umbilical artery during cooling. AB - In the present study, the effects of cooling (to 28 degrees C) on the vasodilatation induced by diazoxide (10(-9)-3*10(-4) M), isoproterenol (10(-9) 3*10(-4) M) and magnesium sulphate (0.1-30 mM) on serotonin-pre-contracted human umbilical artery and the role of nitric oxide in these effects were analyzed. Diazoxide, isoproterenol and magnesium produced concentration-dependent relaxation of human umbilical artery precontracted with serotonin (10(-6) M). During cooling, the pIC(50) values and maximal responses to these agents were significantly lower than at 37 degrees C. Cooling to 28 degrees C in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) did not modify the effects of temperature on diazoxide, isoproterenol and magnesium-induced relaxations. These results suggest that cooling-induced changes of diazoxide, isoproterenol, and magnesium sulphate in human umbilical artery are independent of nitric oxide. PMID- 21532263 TI - [Investigation of the factors that contribute to the onset of insomnia in hypertensive patients by using a post-marketing surveillance database]. AB - Many factors contribute to the onset of insomnia. However, few studies have identified the factors related to the onset of insomnia in hypertensive patients. We conducted a pharmacoepidemiologic study to examine the incidence of insomnia in hypertensive patients by using a post-marketing surveillance database. The insomnia onset was defined as the time of first prescription of hypnotics. The insomnia incidence rate in hypertensive patients under antihypertensive therapy was 0.77/100 person-years. The median insomnia onset date was 5 weeks. The insomnia type in 50.2% of the patients was difficulty in initiating sleep. We assessed the factors contributing to insomnia by using a nested case-control design. We selected 10 time-matched controls for every case. The hypotensive effect induced by antihypertensive therapy on the case group was lesser than that on the control group (p<0.01). The odds ratios (ORs) were estimated using multivariate conditional logistic regression. The factors contributing to insomnia onset were alpha blockers (OR, 2.38; 95% confidence interval [CI], 1.14 4.98), beta blockers (OR, 1.54; 95% CI, 0.99-2.39), and calcium channel blockers (OR, 0.62; 95% CI, 0.43-0.90) compared with angiotensin-converting enzyme inhibitors; female sex (OR, 1.76; 95% CI, 1.27-2.44); complication of gastric/duodenal disorders (OR, 2.35; 95% CI, 1.14-4.86) or musculoskeletal system/connective tissue disorders (OR, 2.43; 95% CI, 1.23-4.79); and concomitant antihypertensive therapy (OR, 0.44; 95% CI, 0.31-0.63). This study identified the potential factors that may help to predict insomnia onset in hypertensive patients under antihypertensive therapy. PMID- 21532264 TI - [Furanocoumarins contents and cytochrome P450 3A (CYP3A) inhibitory activities of various processed fruit peel products: outflow of 6',7'-Dihydroxybergamottin during processing treatment of peel]. AB - Furanocoumarins (FCs) such as bergamottin (BG) and 6',7'-dihydroxybergamottin (DHBG) contained in grapefruits are known to be cytochrome P450 3A4 (CYP3A4) inhibitors. These are contained in larger quantity in peel than in pulp, and therefore, processed peel products possibly have strong CYP3A4 inhibitory activity. The CYP3A4 inhibitory potency of these processed peel products, however, remains to be elucidated. The FC content and CYP3A inhibitory activities of various processed fruit peel products were investigated. CYP3A inhibitory activities of crystallized grapefruit peel, grapefruit marmalade, lemon peel and bitter orange slice were close to that of 100% grapefruit juice, while the activities of yuzu slice, pomelo (buntan) marmalade and crystallized iyokan peel were very weak, 1/8-1/20 of 100% grapefruit juice. The maximum BG content was 5.6 ug/g in lemon peel. The maximum DHBG content was 7.2 ug/g in crystallized grapefruit peel, about 1/30 that of raw peel. Grapefruit marmalade and crystallized grapefruit peel contained similar amounts of FCs to 100% grapefruit juice, but FCs were not detected in pomelo (buntan) marmalade or crystallized iyokan peel. Good correlation (r=0.78) was observed between the FC contents of these peel products and those CYP3A inhibitory activities. Preparation of homemade grapefruit marmalade and crystallized peel revealed that considerably lower DHBG content in these products and lower CYP3A inhibitory activity than anticipated were attributable to outflow of DHBG to broth during boiling of the raw peel. PMID- 21532265 TI - Use of anonymous Web communities and websites by medical consumers in Japan to research drug information. AB - In this study, we investigated the status of researching drug information online, and the type of Internet user who uses anonymous Web communities and websites. A Web-based cross-sectional survey of 10875 male and female Internet users aged 16 and over was conducted in March 2010. Of 10282 analyzed respondents, excluding medical professionals, about 47% reported that they had previously searched the Internet for drug information and had used online resources ranging from drug information search engines and pharmaceutical industry websites to social networking sites and Twitter. Respondents who had researched drug information online (n=4861) were analyzed by two multivariable logistic regressions. In Model 1, the use of anonymous websites associated with age (OR, 0.778; 95% CI, 0.742 0.816), referring to the reputation and the narrative of other Internet users on shopping (OR, 1.640; 95% CI, 1.450-1.855), taking a prescription drug (OR, 0.806; 95% CI, 0.705-0.922), and frequent consulting with non-professionals about medical care and health (OR, 1.613; 95% CI, 1.396-1.865). In Model 2, use of only anonymous websites was associated with age (OR, 0.753; 95% CI, 0.705-0.805), using the Internet daily (OR, 0.611; 95% CI, 0.462-0.808), taking a prescription drug (OR, 0.614; 95% CI, 0.505-0.747), and experience a side effect (OR, 0.526; 95% CI, 0.421-0.658). The analysis revealed the profiles of Internet users who researched drug information on social media sites where the information providers are anonymous and do not necessarily have adequate knowledge of medicine and online information literacy. PMID- 21532266 TI - Enteric microsphere formulations of papain for oral delivery. AB - Enteric microspheres formulations of papain were prepared by w/o/w emulsion solvent evaporation using hydroxypropyl methylcellulose phthalate (HPMCP), Eudragit L 100 and Eudragit S 100, to avoid gastric inactivation of papain. Smaller internal and external aqueous phase volume provided maximum encapsulation efficiency (74.49-79.76%), least particle size (52.4-60.2 um) and 21-26% loss of enzyme activity. Release studies in 0.1 N HCl confirmed the gastro-resistance of formulations. The anionic microspheres, zeta potential between -18.21 and -20.06 mV, aggregated in 0.1 N HCl (i.e., gastric pH 1.2), due to protonation of carboxylic groups of enteric polymer and loss of surface charge with subsequent change in zeta potential. The aggregates being <500 um size would not impede gastric emptying. However, at pH>5.0 (duodenal pH) the microspheres showed de aggregation due to restoration of surface charge. HPMCP and Eudragit L 100 microspheres facilitated almost complete release of papain within an hour at pH 6.0 and 6.8, respectively while Eudragit S 100 microspheres released 84.56% papain at pH 7.4, following Higuchi kinetics. FTIR spectroscopy revealed entrapment of enzyme; PXRD & DSC indicated amorphous character and SEM showed spherical shape of microspheres. In simulated gastro-intestinal pH condition, HPMCP, Eudragit L 100 and Eudragit S 100 microspheres showed good digestion of paneer and milk protein. Thus, enteric microspheres formulations could serve as potential carrier for oral enzyme delivery. Stability studies indicated the formulations with around 5% overage would ensure 2 years shelf life at room temperature. PMID- 21532267 TI - [Dissolution characteristics of composite particles using a spray freeze drying]. AB - A spray freeze drying (SFD) method, using a spray nozzle, liquid N(2) and a lyophilizer, was developed to prepare composite particles of a poorly water soluble drug. The resultant particles were found to have a porous structure. The purpose of the present research was to prepare a sustained release formulation using the SFD technique. Tolbutamide (TBM)and Eudragit S were used as model drugs and pH-dependent carrier, respectively. Eudragit S is a polymer that is soluble at or above pH 7.0. Morphological evaluation of the composite particles revealed that they had a porous structure with a significantly larger specific surface area than bulk TBM. The physicochemical properties of the particles were found to be dependent on the drug to carrier ratio, with the crystallinity of the TBM decreasing as the proportion of Eudragit S increased. Dissolution tests in solutions of pH 1.2 and pH 6.8 showed that the release profiles of TBM from the SFD composite particles were improved compared to bulk TBM, through the use of the pH-dependent carrier. On the other hand, following compression of the composite particles, sustained release was observed in a solution of pH 6.8, whereas almost no dissolution occurred in a solution of pH 1.2. PMID- 21532268 TI - HPLC determination of strychnine and brucine in rat tissues and the distribution study of processed semen strychni. AB - A simple and low-cost HPLC method with UV absorbance detection was developed and validated to simultaneously determine strychnine and brucine, the most abundant alkaloids in the processed Semen Strychni, in rat tissues (kidney, liver, spleen, lung, heart, stomach, small intestine, brain and plasma). The tissue samples were treated with a simple liquid-liquid extraction prior to HPLC. The LOQs were in the range of 0.039-0.050 ug/ml for different tissue or plasma samples. The extraction recoveries varied from 71.63 to 98.79%. The linear range was 0.05-2 ug/ml with correlation coefficient of over 0.991. The intra- and inter-day precision was less than 15%. Then the method was used to measure the tissue distribution of strychnine and brucine after intravenous administration of 1 mg/kg crude alkaloids fraction (CAF) extracted from the processed Semen Strychni. The results revealed that strychnine and brucine possessed similar tissue distribution characterization. The highest level was observed in kidney, while the lowest level was found in brain. It was indicated that kidney might be the primary excretion organ of prototype strychnine and brucine. It was also deduced that strychnine and brucine had difficulty in crossing the blood-brain barrier. Furthermore, no long-term accumulation of strychnine and brucine was found in rat tissues. PMID- 21532269 TI - Mechanism of pigmentation by minocycline in murine B16 melanoma cells. AB - Long-term treatment with minocycline is known to induce pigmentation or discoloration in tissues but how remains unclear. We investigated the mechanism of pigmentation using B16 melanoma cells. First, we confirmed that intracellular melanin levels increased on minocycline treatment. Then, using the reverse transcriptase-polymerase chain reaction (RT-PCR), we found the expression of mRNA of tyrosinase, tyrosinase-related protein (TRP)-1 and TRP-2, to also be significantly increased by treatment with minocycline at 5 ug/ml for 72 h. These results suggest that the minocycline-induced stimulation of melanogenesis occurs at the transcriptional level. Western-blotting revealed slight phosphorylation of extracellular signal-regulated kinase (ERK) 30-60 min after the minocycline treatment. The mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor U0126 and the p38 inhibitor SB203580 were used to examine the signaling pathway associated with the mRNA expression of tyrosinase, TRP-1, or TRP-2 when B16 melanoma cells were treated with minocycline. The SB203580 inhibited the mRNA expression of tyrosinase and TRP-1, suggesting the minocycline-induced melanogensis occurred via a p38 signaling pathway. PMID- 21532270 TI - Alpha lipoic acid treatment improved endothelium-dependent relaxation in diabetic rat aorta. AB - The aim of this study was to ascertain the effects of alpha-lipoic acid (ALA) treatment on relaxant responses of acetylcholine (ACh) and isoprenaline (ISO) in aortic rings precontracted with serotonin (5-HT, 10(-6) M) obtained from streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in the rats by 50 mg/kg streptozotocin (STZ) via an intraperitoneal injection. Rat body and aorta weights were measured. The isometric tension to ACh (10(-9)-3*10(-6) M) and ISO (10(-9)-10(-4) M) of 5-HT-precontracted diabetic and non-diabetic rat (control), diabetic-ALA-treated, and ALA-treated aortas, in organ baths were recorded. Six weeks after STZ treatment blood glucose was elevated compared to control rats. In aortic rings from diabetic rats ACh and ISO-induced relaxations were impaired whereas endothelium-independent relaxation to sodium nitroprusside (SNP) was unaffected. ALA (100 mg/kg/day) treatment for 5 weeks enhanced ACh and ISO-induced relaxation in diabetic aortas. This recovering effect was via NO because prevented by incubating the vessels with N(G)-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor). It may be assumed that ALA treatment in vivo, can protect against impaired vascular responsiveness in STZ-induced diabetic rats. PMID- 21532271 TI - Analysis of body constitution of fifty-two patients with Stevens-Johnson Syndrome (SJS) using Kampo Medical Questionnaires: prediction of SJS based on body constitution using decision tree. AB - Reports have indicated a relationship between adverse drug reaction (ADR) and Human Leukocyte Antigen (HLA) polymorphism and a relationship between Body Constitution (BC) and HLA polymorphism. Thus, a relationship between ADR and BC is suggested. We therefore created a questionnaire (hereinafter "Questionnaire") to survey the typical BC of Stevens-Johnson Syndrome (SJS) patients to determine how they differ from healthy persons, and studied the relationship between the development of SJS and BC. The Questionnaire had 30 typical items selected from those relevant to the BC necessary for the diagnosis and therapy of Sho-syndrome in Kampo Medicine. In the comparison of the prevalence of BCs between SJS patients and control persons, the prevalence of three BCs in the SJS group was significantly higher than that in the control group: 1) Does your throat ever feel closed up? ANSWER: Yes, 2) Do you easily feel hot flashes or burning cheeks even though your hands and feet feel cold? ANSWER: Yes, and 3) Do your lips or gums look dull red? ANSWER: Yes. In the analysis using the decision tree, the concentrated group of SJS patients (eighty-fold) was extracted using two decision trees consisting of 3 index variables. Persons with BCs from any of 1) to 3) are suggested to be at high risk of developing SJS. PMID- 21532272 TI - [Selective elimination of the transformed hepatic stem cells using hybrid liposomes]. AB - To realize regenerative medicine, it is very important to eliminate the transformed stem cells selectively included in iPS cells, ES cells and adult stem cells derived from organs, because the transformed stem cells have a risk of tumorigenesis after the cell transplantation. Ueoka et al., have developed hybrid liposomes (HL) which selectively accumulated to membranes of tumor cells and have high inhibitory effects on the growth of tumor cells along with the induction of apoptosis. Therefore, we have investigated the application of HL23 (DMPC/10 mol%C(12)(EO)(23)) to the selective elimination of transformed stem cells using hepatoblast, which we could induce from human fetal hepatocytes by the treatment of 1 mM sodium butyrate for 8 days. During the induction process, the transformed cells appeared and produced abnormal prothrombin (PIVKA-II), which is a clinical marker for hepatoma, and also formed colonies in soft agar plate, which is a criteria for neoplastic cell transformation. On the other hand, by the treatment with 0.33 mM HL23 for 96 h during the induction process, PIVKA-II production rate of the cells and colonies formed in the soft agar plate also remarkably decreased less than those of the normal cells. Furthermore, the population of hepatoblasts in the remaining cells increased about four times. These results suggest that the transformed hepatic stem cells could be selectively eliminated by the treatment of HL23, and HL treatment of the stem cells would be a useful culture method for quality control of the stem cells to reduce a risk of tumorigenesis after the cell transplantation. PMID- 21532273 TI - Detailed analysis of clinical test data on chemotherapy for colorectal cancer. AB - We reported previously that spline interpolation is effective as a pretreatment before analyzing clinical data by time series. However, further improvement is required to understand the detailed tendency of clinical data. In this study, the tendency of interpolated hematological data was investigated in the period between the most tolerated dose (MTD) and low-dose chemotherapy (LDC) for colorectal cancer. All patients were received both MTD and LDC. Hematological data, white blood cell count (WBC), red blood cell count (RBC) and mean corpuscular volume (MCV), were interpolated. The accuracy of interpolation was verified using leave-one-out cross-validation. The difference, Delta(i), was calculated from interpolated data and exhibited as a function of time. The predictions of RBC and MCV were accurate with high correlation coefficients, although the interpolation of WBC data was inaccurate. A marked difference was observed in the trend of Delta(i) between LDC and MTD periods. SD-RBC showed significant differences between LDC and MTD periods. The SD-MCV average in the LDC period was larger than in the MTD period. SD-MCV showed no significant difference. An attractor plot of Delta(i) in RBC clarified the tendency of the interpolated RBC data. There is a possibility that Delta(i) of RBC and/or SD-RBC may contribute to monitoring adverse reactions and decision of medication. Moreover, it is also useful to check on attractor plot of Delta(i) in RBC together with SD-RBC in order to find out untoward reactions and decision of medication. PMID- 21532274 TI - [Experimental therapeutic effects of hybrid liposomes on the Alzheimer's disease in vitro]. AB - Accumulation of beta amyloid (Abeta) peptides to nerve cells should be associated with the onset of Alzheimer's disease (AD). We prepared hybrid liposomes (HL) composed of 90 mol% phospholipids having various charged head groups (cationic L alpha-dimyristoyltrimethyl ammonium propane (DMTAP), anionic L-alpha dimyristoylphosphatidylserine (DMPS) or zwitterionic L-alpha dimyristoylphosphatidylcholine (DMPC)) and 10 mol% polyoxyethylene(23) dodecyl ether (C(12)(EO)(23))), and investigated the inhibitory effects of HL on the accumulation of Abeta(1-40) peptides into human neuroblastoma (SH-SY5Y) cells in vitro. It is noteworthy that remarkable inhibitory effects on the accumulation of Abeta(1-40) peptides were observed for SH-SY5Y cells treated with anionic HL DMPS, though the accumulation was not inhibited by cationic HL-DMTAP. On the other hand, the immediate fusion of HL-DMTAP into SH-SY5Y cells was confirmed using a confocal laser microscope. Interestingly, the specific interactions between anionic HL-DMPS and Abeta(1-40) peptides were observed using the thioflavin T (ThT) assay. In addition, the cytotoxicity of Abeta(1-42) peptides on the SH-SY5Y cells decreased after the treatment with HL-DMPS. These results suggest that anionic HL-DMPS could be used as a novel medicine for AD in the future. PMID- 21532275 TI - [Opinion survey about purchasing nonprescription drugs over the internet in remote islands--survey among internet-literate inhabitants]. AB - The revised Pharmaceutical Affairs Act that came into force in June 2009 prohibits the sales of nonprescription drugs by mail. However, as a provisional measure, regular users and inhabitants of remote islands that do not have pharmacies or drug stores would be able to purchase nonprescription drugs by mail for two years. However, this regulation is now being discussed from the perspectives of safety and convenience. The purpose of this study was to conduct a survey on the purchasing of nonprescription drugs over the Internet by inhabitants of remote islands belonging to Goto City in Nagasaki prefecture. The results showed that approximately 78.0% of the Internet-literate respondents living on large islands (with pharmacies, drug stores, and pharmacists, e.g., Fukue-shima), 65.4% of the Internet-literate respondents living on small islands scattered around large islands (where pharmacies, drug stores, and pharmacists are not located, e.g., Mae-shima) had purchased necessities except nonprescription drugs, but the rate of purchasing nonprescription drugs over the Internet was approximately less than 10%. The results of this survey suggest that it is not necessary to purchase nonprescription drugs over the Internet. However, owing to a small but significant minority of inhabitants who need to purchase nonprescription drugs over the Internet, there is an urgent need for establishing an optimum system for supplying medicinal products to remote islands. PMID- 21532276 TI - [Influence of mineral water on absorption of oral alendronate in rats]. AB - Alendronate, an oral bisphosphonate (e.g., Fosamax((r))), is effective in the treatment of osteoporosis, and the Fosamax((r)) package insert advises that the bioavailability is reduced when taken with mineral water containing high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards regarding the water used when taking alendronate are unclear. In this study, the influence of mineral water on the absorption of oral alendronate was investigated based on urinary excretion of its unchanged form in rats. Alendronate was diluted in each water sample and administered orally (0.7 mg/kg) to male Wistar rats after 24-hour fast. Urine samples were collected until 24 h after dosing. Urine samples were alkalinized, and alendronate in urine was precipitated as a calcium salt, followed by loading on an anion exchange cartridge. Eluted alendronate was derivatized with 9-fluorenylmethoxycarbonyl (Fmoc) chloride and determined by HPLC with fluorescent detection. Cumulative urinary excretion recoveries of alendronate were calculated from the amounts of urinary excretion. Alendronate was rapidly excreted in the first 6 h, and similar elimination rate constants were seen (from 0.28 to 0.45 h(-1/2)) among the water samples. Cumulative urinary excretion recoveries with tap water, evian((r)) and 100% deep ocean water were 0.98+/-0.17%, 0.80+/-0.18% and 1.01+/-0.16% (mean+/-S.E., n=4). Those with Contrex((r)) (0.33+/-0.07%) were significantly lower when compared with ultrapure water (1.56+/-0.35%, p<0.01). These findings suggest that the absorption of alendronate decreases based on the calcium concentration of mineral water. In conclusion, mineral water containing high levels of calcium is not recommended when alendronate is taken. PMID- 21532277 TI - [Development of rapid genotyping methods for single nucleotide polymorphisms of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) and their clinical application in pediatric patients with epilepsy]. AB - Genetic polymorphism of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) is widely known to contribute to interindividual differences in the pharmacokinetics of some antiepileptic drugs. We developed a rapid detection assay of polymorphisms of CYP2C9 and CYP2C19, using the Light Cycler((r)) polymerase chain reaction (PCR) system. Using this assay, we examined polymorphisms in 20 Japanese pediatric patients prescribed phenytoin for the treatment of epilepsy, and classified their polymorphisms into four groups: group I, CYP2C9*1/*1 and CYP2C19*1/*1; group II, CYP2C9*1/*1 and CYP2C19*1/*2 or *1/*3; group III, CYP2C9*1/*1 and CYP2C19*2/*2; and group IV, CYP2C9*1/*3 and CYP2C19*1/*2 or *1/*3. The mean maximal elimination rates (V(max)) in groups I, II, III and IV were 13.1, 11.2, 10.2 and 8.0 mg/day/kg, respectively, with statistically significant differences among groups (p=0.012, Kruskal-Wallis analysis). The intrinsic metabolic activity (V(max)/K(m)) of groups I, II, III and IV were 2.9, 2.2, 1.5 and 1.1 l/day/kg, respectively (p=0.009), again with significant differences among groups. These findings indicate that polymorphism of CYP2C9 and CYP2C19 plays an important role in phenytoin metabolism in children. With a total processing time for this assay of less than 3 hours, prediction of the optimal phenytoin dosage based on the CYP2C9 and CYP2C19 genotypes will be possible before commencement of therapy, resulting in the prevention of phenytoin overdoses in pediatric patients with epilepsy. PMID- 21532278 TI - [Covariance structure analysis of pharmacists' attitudes toward medication history]. AB - Keeping track of patients' medication histories is an important component of pharmacy practice. In this study, we conducted a questionnaire survey on medication histories among pharmacists and performed covariance structure analysis to investigate pharmacists' attitudes toward medication histories. The survey was conducted among pharmacists who work at pharmacies. With regard to the questions on medication histories, factor analysis and covariance structure analysis were performed to create a path diagram. The response rate to the questionnaire was 97.0%. The factor analysis revealed six factors, including: "patient assessment", "learning attitude", "practicing the recording of medication histories", "conscious effort to improve medication histories", "uniformity in medication histories" and "issues regarding medication histories". Meanwhile, covariance structure analysis revealed that the five-factor model excluding "issues regarding medication histories" was the best-fitted model. According to this model, it was clear that the pharmacists were extremely conscious about introducing improvements to the content of medication histories. In this study, covariance structure analysis enabled the effective analysis of the attitudes of pharmacists toward medication histories. We believe that creating and conducting a training program to clarify and resolve issues related to medication histories and then reviewing the outcome of such a training program will lead to quality improvement and standardization of the future management of medication histories. PMID- 21532279 TI - [Simple and rapid screening for methamphetamine and 3,4 methylenedioxymethamphetamine (MDMA) and their metabolites in urine using direct analysis in real time (DART)-TOFMS]. AB - An ionization technique, direct analysis in real time (DART) has recently been developed for the ambient ionization of a variety samples. The DART coupled with time-of-flight mass spectrometry (TOFMS) would be useful as a simple and rapid screening for the targeted compounds in various samples, because it provides the molecular information of these compounds without time-consuming extraction. In this study, we investigated rapid screening methods of illicit drugs and their metabolites, such as methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA), amphetamine (AP) and 3,4-methylenedioxyamphetamine (MDA) in human urine using DART-TOFMS. As serious matrix effects caused by urea in urine samples and ionizations of the targeted compounds were greatly suppressed in the DART-TOFMS analyses, simple pretreatment methods to remove the urea from the samples were investigated. When a pipette tip-type solid-phase extraction with a dichloromethane and isopropanol mixed solution as an eluent was used for the pretreatment, the limits of detection (LODs) of 4 compounds added to control urine samples were 0.25 ug/ml. On the other hand, the LODs of these compounds were 0.5 ug/ml by a liquid-liquid extraction using a dichloromethane and hexane mixed solution. In both extractions, the recoveries of 4 compounds from urine samples were over 70% and these extraction methods showed good linearity in the range of 0.5-5 ug/ml by GC-MS analyses. In conclusion, our proposed method using DART-TOFMS could simultaneously detect MA, MDMA and their metabolites in urine at 0.5 ug/ml without time-consuming pretreatment steps. Therefore it would be useful for screening drugs in urine with the molecular information. PMID- 21532280 TI - [Surveillance study on use of over-the-counter drug and health food by school pharmacist for grade-schooler, junior high school student, and high school students]. AB - In recent years, it is necessary to acquire knowledge not only about medicine but also over-the-counter (OTC) drugs and health food for children, because lowering trend in the age of the health hazard by improper use of health food is reported. Therefore, in order to estimate the extent of use of OTC drugs and health food, the school pharmacists administered a questionnaire to students in grade-school (n=123), junior high school (n=303), and high school (n=115) in Fukuyama city. As a result of the questionnaire survey, surprisingly, the usage ratio of OTC drugs and health food showed the most increase in grade-schooler. The trigger of use of health food is "parents' recommendations" in the lower grades, otherwise the ratio of "use by themselves" was increased in the higher grades. Moreover, a remarkable difference was observed by the kinds of use in students with or without exercise. Interestingly, exercise group expected "physical strength" effects than no exercise group. In addition, the ratio of consultation to the pharmacist at the time of purchase of OTC drugs and health food was low in all grade students. In particular, the ratio of consultation to the pharmacist at the time of purchase of health food was very low in high school students. Therefore, to provide accurate information of medicine and health food for students, the school pharmacist should engage not only in routine work but also in positive guidance about OTC drugs and health food in the future. PMID- 21532281 TI - [Research survey on the information gathering methods, attitudes, and requests from care managers about the pharmaceutical service by pharmacists in home care]. AB - Care Managers (CMs) were surveyed to clarify the issues involving the promotion of cooperation between care managers and pharmacists in long-term-care and explore solutions. The length of work experience, occupational background, experience of pharmaceutical service; pharmacist visit patients' home for providing medicine and pharmaceutical care into a care plan, degree of understanding on pharmaceutical service, and awareness of work involved in pharmaceutical service were studied to see whether there made differences in the requests from CMs for information on pharmacists and for information gathering methods. The chi(2) test was used to this end. The opinions and requests described by the CMs were validated through text mining. More CMs tended to obtain information and knowledge through training sessions and professional magazines than those who did so through cooperation with pharmacists on a practical level. However, the survey strongly indicated that CMs with high level of understanding and awareness of pharmaceutical service wished to obtain information on pharmacists through cooperation with them on a practical level, and CMs with low level of understanding and awareness of pharmaceutical service wished to obtain such information through training sessions and professional magazines. Results of text mining showed that CMs wished pharmacists to strengthen the cooperation with physicians and provide information on pharmaceutical service. These findings have led to the conclusion that the issues surrounding the promotion of cooperation between CMs and pharmacists centered around "work cooperation on a practical level" and "provision of information to CMs about the roles of pharmacies and pharmacists and their work." PMID- 21532282 TI - [Effect of nonsteroidal anti-inflammatory drugs on pharmacokinetics of methotrexate: a meta-analysis]. AB - It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) affect the pharmacokinetics of methotrexate, but there are several reports showing negative consequences. In this study, we evaluated drug interactions by performing a meta analysis on published data examining the effect of NSAIDs on pharmacokinetic parameters of methotrexate. The combined standardized mean difference of the maximum blood concentration after oral administration of methotrexate was calculated to be -0.00 (95% confidence interval, -0.30 to 0.30) based on 6 clinical trials, and there was no significant effect of NSAIDs (p=0.9967). However, it is also represented that the NSAIDs significantly increased the area under the blood concentration-time curve of methotrexate (combined standardized mean difference, 0.73; 95% confidence interval, 0.32 to 1.14; p=0.0004; 11 trials). Furthermore, the combined standardized mean differences in total and renal clearance of methotrexate were estimated to be -0.80 (95% confidence interval, -1.41 to -0.18; p=0.0109; 6 trials) and -0.76 (95% confidence interval, -1.40 to -0.11; p=0.0220; 11 trials), respectively, implying that NSAIDs interfere with urinary excretion of methotrexate. In conclusion, the integration of the published reports by these meta-analyses shows that NSAIDs increase blood levels of methotrexate by influencing renal excretion of the antifolate. PMID- 21532283 TI - Factors affecting health-related quality of life in patients after femoral neck fracture. AB - Quality of life in patients with femoral neck fracture is an issue frequently discussed in the literature. There is ongoing research on identifying factors that have an impact on quality of life in this particular group of patients. A great variety of factors affecting quality of life and lack of information on their importance encouraged us to perform a systematic literature review analyzing quality of life of patients who sustained femoral neck fracture. The search was performed in the PubMed and Medline databases according to the selected key words. In our systematic review, we included clinical and clinical randomized trials investigating patients with femoral neck fracture and their quality of life. Our analysis showed that treatment of femoral neck fracture with hip replacement was superior to osteosynthesis with regard to patients' quality of life. The data regarding the impact of different rehabilitation programs on quality of life were controversial; a few reports showed that special rehabilitation programs were associated with better health-related quality life. However, other studies did not report any differences in patients' quality of life when different rehabilitation programs were applied. Patient's nutrition may be an important factor affecting the quality of life in patients with femoral neck fractures; however, data supporting this fact are insufficient. PMID- 21532284 TI - Antibiotic prescription for the treatment of endodontic pathology: a survey among Lithuanian dentists. AB - OBJECTIVE: To describe a pattern of antibiotic prescription during root canal treatment procedures based on the reports of Lithuanian general dental practitioners. MATERIALS AND METHODS: Questionnaires concerning endodontic treatment were sent to all 2850 Lithuanian dental practitioners registered on the database of the Lithuanian Dental Chamber. Only the questions containing general information and individual decisions about antibiotic prescription for endodontic treatment were selected for the analysis. RESULTS: The response rate was 53.8%. Of the 1532 responses, 1431 questionnaires received from licensed general dental practitioners were analyzed. More than 60% of the respondents reported prescribing antibiotics in cases of symptomatic apical periodontitis. Majority of the respondents (83.9%) reported symptomatic apical periodontitis with periostitis being a clear indication for the prescription of antibiotics. Nearly 2% of the respondents reported prescribing antibiotics in cases of symptomatic pulpitis. With an increasing duration of professional activity, an increase in the proportion of the respondents reporting prescription of antibiotics was observed. Amoxicillin was the most preferable antibiotic during endodontic treatment, followed by amoxicillin with clavulanic acid. An increase in reporting penicillin prescription and decline in prescribing amoxicillin and amoxicillin with clavulanic acid with regard to the increasing age of respondents was observed. CONCLUSIONS: Lithuanian dentists, particularly those with longer duration of professional activity, tended to exceed general recommendations for the antibiotics prescription in cases of endodontic infections. However, a trend toward prescription of broader spectrum antibiotics by younger dentists, compared with those with longer professional activity, was observed. PMID- 21532286 TI - [Associations between color perception and optic nerve disk drusen]. AB - The aim of this study was to determine the association between color perception determined by maximum color contrast sensitivity and Farnsworth-Munsell 100-hue tests and visual acuity in the presence of optic nerve disk drusen. MATERIAL AND METHODS: A case-control study, including 137 persons, was performed. Thirty-seven patients (67 eyes) with optic nerve disk drusen and 100 healthy controls (200 eyes) were examined. For visual acuity testing, a typical Snellen chart (the direction of the gap in Landolt C) was used. A computerized Farnsworth-Munsell 100-hue test and maximum color contrast sensitivity programs were used for color discrimination. RESULTS: The results of maximum color contrast sensitivity test, and the Farnsworth-Munsell 100-hue test were better in healthy controls than patients (1.94 +/- 0.66 vs. 2.2 +/- 0.85, P=0.02; 94.1 +/- 53.9 vs. 120.6 +/- 61, P=0.003, respectively). CONCLUSION: The study revealed that the presence of optic nerve disk drusen was associated with decreased perception of colors. PMID- 21532285 TI - [Impact of p53 protein and HER2 overexpression on survival of patients with stage II breast cancer]. AB - OBJECTIVE: To assess the prognostic significance and impact of p53 protein and human epidermal growth factor receptor 2 (HER2) overexpression on 5-year survival in young patients with stage II breast cancer (aged less than 50 years). MATERIAL AND METHODS: Material from medical records and archived tumor tissues from 34 young women diagnosed with stage II breast cancer and obtained between 2001 and 2003 was analyzed retrospectively. Twelve (35%) patients died from breast cancer. Using archived tumor tissues, p53 protein and HER2 over-expression was determined immunohistochemically. Using medical records, and adjuvant chemotherapy, adequacy of anthracycline dose, and hormonotherapy administered for the patients were analyzed. RESULTS: p53 protein and HER2 overexpression was documented in 20.6% and 26.4% of women, respectively. Kaplan-Meier survival analysis showed that patients with tumors positive for p53 protein and negative estrogen receptors, and treated with an inadequate dose of anthracyclines died within shorter period after diagnosis (log-rank P=0.016, log-rank P=0.027, log-rank P=0.013, respectively). There were no significant associations between HER2 overexpression and 5-year survival in this population (log-rank P=0.51). Multivariate analysis revealed that an inadequate dose of anthracyclines (P=0.028) was the only independent factor for poor outcome. CONCLUSIONS: p53 protein overexpression, negative estrogen receptors in tissue samples, and inadequate chemotherapy with anthracyclines were associated with reduced overall survival in young women with stage II breast cancer. Inadequate adjuvant therapy with anthracyclines was the only independent prognostic factor. PMID- 21532287 TI - Diagnosis and treatment of conduct disorder related to frontal lobe syndrome in a 16-year-old girl. AB - Conduct disorders are the most frequent psychiatric diagnosis in the pediatric and adolescent population, with different etiology and difficult to treat. Delinquent, aggressive, and impulsive behavior, lack of empathy and inability to predict possible consequences of the behavior lead to significant desadaptation and danger for these patients. In clinical practice, focus is usually given on social and psychological causes of conduct disorders ignoring possible biological factors in etiology and pathophysiology. A clinical case described in this article shows the linkage between frontal brain dysfunction and behavioral symptoms. The first clues of organic brain disorder were multiple and severe symptoms of disinhibition resistant to treatment with dopaminergic drugs and the results of neuropsychological testing. Computed tomography, magnetic resonance imagining, and single-photon emission computed tomography findings were minor and not supported by associated neurological symptoms. However, the location of alterations of brain structure and perfusion significantly correlated with psychopathology. Clarification of the organic cause of the conduct disorder allowed choosing an effective strategy of psychopharmacologic treatment. A positive clinical effect was achieved after switching the treatment from dopaminergic antipsychotic drugs to carbamazepine, which modulates the GABAergic system. Presenting this clinical case, we intended to emphasize the importance of careful attention to the findings of neurovisual and neuropsychological testing diagnosing conduct disorders and individually choosing the most effective psychopharmacologic treatment. PMID- 21532288 TI - Cost-effectiveness and cost-utility of the treatment of chronic hepatitis B with peginterferon alfa-2a, interferon alfa, and lamivudine in Lithuania. AB - BACKGROUND: Chronic hepatitis B infection is an important health care problem worldwide. According to the World Health Organization, 10% to 15% of population is infected with hepatitis B virus. Nearly 100 new cases of acute hepatitis B are annually registered in Lithuania, but official statistics covers only 8-25% of all disease incidence. The aim of this study was to evaluate the cost effectiveness of the treatment of chronic hepatitis B with peginterferon alfa-2a and compare it to treatment with interferon alfa and lamivudine in Lithuania. MATERIAL AND METHODS: A Markov model was used to evaluate long-term cost effectiveness of the treatment with peginterferon alfa-2a and to compare it with treatment with interferon alfa and lamivudine. Peginterferon alfa-2a was administered by subcutaneous injections at a dosage of 180 MUg every week for 48 weeks; interferon alfa, 6 million IU three times a week for 24 weeks; and lamivudine, 100 mg per day from 48 weeks to 5 years for HBeAg-positive chronic hepatitis B and 100 mg per day up to 5 years in HBeAg-negative chronic hepatitis B. RESULTS: Treatment with peginterferon alfa-2a gained 1.179 life years as compared to 0.658 life years gained with treatment with interferon alfa; incremental costs per incremental life-year gained (LYG) were 51,256.92 Lt (14,845.03 ?). Treatment with peginterferon alfa-2a gained 0.545 quality-adjusted life-years (QALYs) with incremental costs per incremental QALY of 48,980.08 Lt (14,185.61 ?). Treatment with peginterferon alfa-2a had twice higher cost effectiveness than treatment with interferon alfa: 50,4167.00 Lt (146,016.85 ?) vs. 954,020.08 Lt (276,303.31 ?), respectively. Costs for a complete response were also twice lower. Treatment with peginterferon alfa-2a gained 0.757 incremental LYG more compared to lamivudine (48-week course). Comparing incremental cost-effectiveness using peginterferon alfa-2a for treatment, incremental costs per incremental LYG were 41,993.67 Lt (12,162.21 ?); additionally there was a gain of 0.792 incremental QALYs, while incremental costs for incremental QALY were 40,096.19 Lt (11,612.66 ?). Complete response costs were 83,515.98 Lt (24,187.89 ?) less compared to lamivudine (48-week course). CONCLUSIONS: Treatment of chronic hepatitis B prolongs patients' overall survival and quality-adjusted life. Peginterferon alfa-2a was the most effective drug registered in Lithuania for CHB treatment. PMID- 21532289 TI - Changes in health-related quality of life among patients with coronary artery disease: a 2-year follow-up. AB - The aim of this study was to evaluate the changes in health-related quality of life in patients with coronary heart disease according to age, gender, and treatment method. MATERIAL AND METHODS: The study enrolled 167 patients after acute myocardial infarction (MI), percutaneous transluminal coronary angioplasty (PTCA), and coronary artery bypass grafting (CABG). The mean age was 59.3 years; there were 71.9% of males. General health-related quality of life was measured using the SF-36 questionnaire. Patients were examined at the beginning of rehabilitation and after 6-, 12-, 18-, and 24-month follow-up. Effect sizes were computed to assess the changes in health-related quality of life over time. RESULTS: Health-related quality of life significantly improved at 6 months, but improvements did not continue over time. The largest effect size was seen in the pain domain. Effect sizes were greater in the physical health domains among male patients and among female patients in the mental health domain. With regard to age, effect sizes were greater in the physical functioning domain among older patients. With regard to treatment method, at baseline, the CABG patients had the poorest health-related quality of life; however, the largest effect sizes were seen in this group. CONCLUSIONS: Health-related quality of life improved over 2 years; the greatest improvement was seen at 6 months. Males better improved on the physical component summary domain; there was no significant improvement in the mental component summary domain in males and females. Older patients improved better on the physical activity and physical component summary domains. Changes in health-related quality of life were related to treatment method. PMID- 21532290 TI - [The relationship of quality of life with social and demographic factors among stroke survivors]. AB - The aim of the study was to determine the associations between the quality of life and social and demographic factors in stroke survivors and control group. MATERIAL AND METHODS: The case group consisted of 508 inhabitants of Kaunas city who were aged 25-84 years and had survived a stroke. The control group included 508 age- and sex-matched inhabitants of Kaunas city randomly selected from the stroke-free population. The SF-12 questionnaire was used in the study. Quality of life in the physical and mental health domains with respect to social and demographic factors was analyzed. RESULTS: A significant inverse correlation was found between the evaluation of physical health and age in both the stroke survivors and controls (r=-0.34, P<0.05, and r=-0.64, P<0.05, respectively). The comparison of the evaluation of physical health between men and women showed that only in the control group, men demonstrated significantly better physical health than women (P=0.0005), while no statistically significant difference in this respect was found comparing male and female stroke survivors. Stroke survivors of Lithuanian nationality reported better physical health as compared to individuals of other nationalities (P=0.008). Both the controls (P=0.01) and stroke survivors (P=0.008) who were not living alone scored higher on the physical health domain than their counterparts living alone. Employed subjects - both the controls and stroke survivors - presented better evaluations of their physical health (P=0.005 in both the groups). CONCLUSIONS: Quality of life in the physical health domain worsened with age both in the stroke survivors and controls. Both in the stroke survivors and controls, males and females with higher education levels, not living alone, and having employment demonstrated better evaluations of their quality of life in the physical health domain compared to those with poorer education, living alone, or unemployed. PMID- 21532291 TI - [Characteristics of social support and their associations with depressiveness among Lithuanian adult rural population]. AB - BACKGROUND AND OBJECTIVE: Data of recent scientific studies have showed strong associations between person's social environment and physical and mental health. The aim of this study was to evaluate the characteristics of social support and disclose their associations with depressiveness in rural adult population. MATERIAL AND METHODS: In 2006-2007, the survey was carried out in a random sample of population aged 25-64 years in five rural regions of Lithuania within the framework of the international CINDI program. A total of 1754 participants were interviewed using structured questionnaires. The associations between depressiveness and indicators of social support were assessed using logistic regression analysis. RESULTS: About one-third (34.7%) of respondents had little social support in their closest social environment, and 4.5% had no supporting persons at all. A lack of social support was more characteristic of women and less educated persons. The greater likelihood of depressiveness was related to worse indicators of social support: small social network, lack of support, and difficulties in communication with a husband/wife and relatives. Older and less educated women and men and those having poor relationships were more likely of being depressed. Depressiveness among men was also associated with being divorced. CONCLUSIONS: One-third of Lithuanian adult rural population reported a lack of social support. The established associations between social support and depressiveness indicate that the development of social skills is an important resource for mental health improvement. PMID- 21532292 TI - Environmental factors and breast cancer. AB - This review summarizes the results of studies on the effects of environment on breast cancer risk. As known risk factors such as reproductive life, inheritance, and socioeconomic status are estimated to explain only about half of the breast cancer cases, it has been thought that environmental factors could also be related to the risk of this disease. It is known that ionizing radiation is an environmental risk factor increasing the risk of breast cancer. The data of experimental studies show that some organochlorines could be associated with breast cancer risk although the data from epidemiological studies are not consistent due to the difficulties to assess exposure and other risk factors. Recent experimental studies show that cadmium is an environmental factor that mimics the effects of estradiol in estrogen-responsive breast cancer cell lines while solar radiation possibly decreases the risk due to protective effect of vitamin D. The data on the effect of electromagnetic fields are not consistent. Although evidence about the effect of environmental factors on the risk of breast cancer is not convincing, some of these factors together with inheritance, reproductive life, and age at exposure could be associated with an increased risk of the disease. PMID- 21532293 TI - QT dispersion in patients with rheumatic mitral stenosis and its relation with echocardiographic findings and serum NT-proBNP levels. AB - OBJECTIVES: We evaluated the value of QT interval dispersion in patients with rheumatic mitral stenosis (MS) in association with echocardiographic parameters and serum N-terminal pro brain natriuretic peptide (NT-proBNP) levels. STUDY DESIGN: The study consisted of 46 patients (39 women, 7 men; mean age 46.9+/-9.7 years) with moderate-to-severe rheumatic MS. All patients underwent echocardiographic examination. Blood samples for NT-proBNP were collected immediately after ECG recording. QT interval and QRS complex were measured manually on standard 12-lead surface ECGs. Electrocardiographic and echocardiographic findings and serum NT-proBNP levels were compared with those of a control group consisting of 30 healthy subjects (26 women, 4 men; mean age 46.1+/-7.3 years). RESULTS: Compared to controls, serum NT-proBNP levels were significantly higher in MS patients (284.6+/-206.5 vs. 70.2+/-9.3 pg/ml, p<0.001). The mean QT interval, QTc interval, and QT dispersion were significantly prolonged in MS patients compared to controls (378+/-25 vs. 349+/ 21, 420+/-22 vs. 401+/-19, and 61+/-21 vs. 38+/-15 msec, respectively; p<0.005). QT and QTc dispersions were negatively correlated with mitral valve area (QT: r= 0.311, p=0.03; QTc: r=-0.327, p=0.02), and positively correlated with serum NT proBNP level (QT: r=0.583, p<0.001; QTc: r=0.637, p<0.001). QTc dispersion was also an independent predictor of serum NT-proBNP level in regression analysis (beta=0.330, p=0.03). CONCLUSION: Our results indicate that QT dispersion is related to the echocardiographic degree of rheumatic mitral valve disease and serum NT-proBNP levels in rheumatic MS. Being a noninvasive, easy, and inexpensive method, QT dispersion may be used as a complementary tool to the clinical and echocardiographic evaluation of patients with rheumatic MS. PMID- 21532294 TI - The relationship between echocardiographic parameters and brain natriuretic peptide levels in acute and chronic mitral regurgitation. AB - OBJECTIVES: Plasma brain natriuretic peptide (BNP) level increases with symptoms and severity of mitral regurgitation (MR). We aimed to determine the relationship between plasma BNP levels and echocardiographic parameters in patients with acute and chronic MR. STUDY DESIGN: The study included 55 patients (31 males, 24 females) with isolated moderate-to-severe MR. Of these, 31 patients had acute MR, and 24 patients had chronic MR. All the patients were assessed by transthoracic, transesophageal and Doppler echocardiography and plasma BNP levels were determined. RESULTS: Clinical characteristics and functional capacity were similar in the two groups. Patients with acute MR had significantly higher left ventricular (LV) ejection fraction (EF) (p=0.001), and significantly lower LV end systolic diameter (p=0.016), end-systolic volume (p=0.027), end-diastolic diameter (p=0.011), left atrial volume (LAV) (p=0.003), and plasma BNP levels (p=0.036). Effective regurgitation orifice area was also significantly higher in patients with acute MR (p=0.038). In multiple linear regression analysis, the natural logarithm of BNP was significantly correlated with E/Ea ratio (beta=0.50, p=0.002) and LAV (beta=0.38, p=0.015) in patients with acute MR, and with systolic pulmonary artery pressure (beta=0.60, p=0.002) and EF (beta=-0.36, p=0.039) in patients with chronic MR. CONCLUSION: Although the echocardiographic degree of MR was more pronounced in patients with acute MR, serum BNP levels tended to be lower in this group. Correlation of serum BNP with E/Ea and LAV in this group may be an important finding. PMID- 21532295 TI - C825T polymorphism of the G-protein beta3 subunit and its association with essential hypertension in Uzbek males. AB - OBJECTIVES: We investigated the association between the C825T polymorphism of the G-protein beta3 subunit (GNB3) gene with essential hypertension (EH) and cardiovascular remodeling markers in Uzbek males. STUDY DESIGN: The study included 174 Uzbek men (mean age 49+/-10 years) with untreated EH of stage 1-2 and 60 normotensive males. The C825T polymorphism of the GNB3 gene in the patient and control groups was determined by polymerase chain reaction. The patients were assessed with blood pressure measurements, ambulatory blood pressure monitoring, body mass index (BMI), carotid artery intima-media thickness (IMT), flow-mediated dilation (FMD) of the brachial artery, echocardiography, and urinary albumin excretion (UAE) level. RESULTS: The frequencies of the CC, CT, and TT genotypes were 36.8%, 53.5%, and 9.8% in hypertensive men, and 0%, 83.3%, and 16.7% in healthy men, respectively (p=0.0001). The frequencies of the C and T alleles were 63.8% and 36.2% in the hypertensive group, and 41.7% and 58.3% in the control group, respectively (p=0.0001). The CC genotype exhibited a significantly greater risk for hypertension compared to CT and TT genotypes (OR=72.38, 95% CI 4.40 1190.34). The C825 allele showed a higher association with hypertension in comparison to the 825T allele (OR 2.41, 95% CI 1.58-3.68). Compared to patients with the CT+TT genotypes, the CC genotype carriers had significantly higher BMI (p=0.0001), systolic (p=0.0001) and diastolic (p=0.003) blood pressures (SBP/DBP), higher nighttime DBP (p=0.042), a greater nighttime variability in both SBP and DBP (p=0.002), and greater carotid artery IMT (p=0.0001) and UAE (p=0.015) values. CONCLUSION: Our findings show a significant association between the GNB3/C825T gene polymorphism and EH, with the CC genotype exhibiting higher blood pressure, BMI, and vascular remodeling markers in Uzbek hypertensive men. PMID- 21532296 TI - [Serum gamma-glutamyltransferase activity: a new marker for coronary artery bypass graft disease]. AB - OBJECTIVES: Serum gamma-glutamyltransferase (GGT) activity has been shown to be related to the development of atherosclerosis and cardiovascular events. We evaluated the association between GGT and severe graft disease in patients undergoing coronary artery bypass graft (CABG) surgery. STUDY DESIGN: We evaluated 113 patients (mean age 62+/-9 years; range 21 to 81 years) who underwent control coronary angiography after a mean of 39 months (range 18 to 84 months) following CABG surgery. A graft was considered patent if there was <70% stenosis or severely diseased if there was >=70% stenosis on coronary angiography. Preoperative serum GGT levels were measured in all the patients and none had severe systemic or hepatobiliary disease. The association between serum GGT level and severe graft disease was investigated. The grafts were also evaluated separately. RESULTS: Coronary angiography showed severe graft disease involving at least one graft in 65 patients (57.5%). Serum GGT level was significantly higher in patients with severe graft disease (p=0.001). ROC curve analysis yielded a cut-off value of 29.5 U/l for serum GGT level to predict severe graft disease (area under the curve: 0.69) with 48% sensitivity and 82% specificity. While GGT levels were similar for internal mammary artery grafts (p>0.05), radial artery grafts and saphenous vein grafts (SVG) with severe graft disease were associated with significantly higher GGT levels (p=0.003 and p<0.001, respectively). In multivariate analysis, family history of coronary artery disease at a young age (OR 2.46, 95% CI 1.08-5.61, p=0.03) and serum GGT (OR 1.03, 95% CI 1.00-1.07, p=0.05) were independent predictors of severe graft disease. Separate analysis based on the graft types showed that GGT was an independent predictor of severe graft disease for only SVG (OR 1.02, 95% CI 1.00 1.04, p=0.03). CONCLUSION: Serum GGT level may be an independent marker for the development of severe SVG disease in patients undergoing CABG surgery. PMID- 21532298 TI - [Procedural success and short- and mid-term results of percutaneous closure of persistent arterial duct with the Amplatzer Duct Occluder II]. AB - OBJECTIVES: We evaluated the effectiveness and reliability of percutaneous closure of persistent arterial duct (PAD) with the Amplatzer Duct Occluder II (ADO II), together with short- and mid-term results. STUDY DESIGN: The study included 16 patients (10 girls, 6 boys; median age 6 years; range 5 months to 12 years) who underwent percutaneous PAD closure with the ADO II device. The ductus diameter was less than 6 mm in all the cases. According to the Krichenko classification, 10 patients had type A, five patients had type E, and one patient had residual PAD. The patients were assessed by aortography and echocardiography. The mean follow-up was 13.9 months (range 2 to 23 months). RESULTS: Closure of PAD was successfully performed via the arterial approach in all the patients. The median ductus waist diameter was 3 mm (range 2 to 5 mm), the median device waist diameter was 4 mm (range 3 to 6 mm), and the waist length was 4 or 6 mm. The mean fluoroscopy time and the mean procedure time were 10.6 min (range 4 to 39 min) and 30 min (range 18 to 80 min), respectively. Immediate aortography following the procedure showed shunt only through the device lumen. No residual shunt or increases in aortic and left pulmonary flow velocities were observed in echocardiographic examinations. No complications occurred during the procedure and follow-up. CONCLUSION: In all the cases, the ADO II device was found effective and reliable for closure of PADs of less than 6 mm. PMID- 21532297 TI - [Our initial experience with stent implantation for aortic coarctation in adults]. AB - OBJECTIVES: We evaluated the procedural success and short-mid term results of stent implantation for aortic coarctation in adults. STUDY DESIGN: The study included 15 consecutive patients (9 women, 6 men; mean age 27+/-7 years; range 17 to 45 years) treated with stent implantation for aortic coarctation. Fourteen patients had native, one patient had recurrent coarctation. Nine patients received bare metal and six patients received covered Cheatham-Platinum stents. Covered stents were used in patients with accompanying patent ductus arteriosus (n=2), severe coarctation (n=3), and recurrent coarctation (n=1). Procedural success was defined as the reduction in the pressure gradient across the coarctation site to less than 20 mmHg. The mean follow-up period was 10.4+/-4.6 months (range 3 to 18 months). RESULTS: Stent implantation was successful in all the patients. Compared to the preprocedure figures, systolic gradient across the aortic coarctation decreased from 37.2+/-11.3 mmHg to 3.5+/-2.9 mmHg, the diameter of the coarcted aortic segment increased from 5.4+/-1.5 mm to 17.2+/-1.4 mm, and systolic blood pressure declined from 154+/-9.7 mmHg to 130+/-7.3 mmHg following stenting (for all, p<0.001). There were no procedure-related major complications. CONCLUSION: Stent implantation for aortic coarctation in adults is a safe and effective alternative to surgical correction. PMID- 21532299 TI - Spontaneous right coronary artery dissection possibly associated with clonidine transdermal patch. AB - We report on a 44-year-old female who developed spontaneous right coronary artery dissection associated with the use of a clonidine transdermal patch. The lesion was successfully treated with percutaneous coronary intervention with placement of three bare metal stents. The patient had an uneventful recovery. To our knowledge, this is the first reported case of spontaneous coronary artery dissection associated with clonidine effect. PMID- 21532300 TI - Warfarin-induced bilateral renal hematoma causing acute renal failure. AB - Acute renal failure due to bilateral hematoma is a rare complication of anticoagulant warfarin therapy. A 43-year-old man presented with complaints of hematuria and abdominal pain. He had been receiving warfarin for six years, after placement of an aortic valve prosthesis. One week prior to admission, he sustained a urinary tract infection which was treated with third-generation cephalosporin and indomethacin. His serum creatinine level was 1.8 mg/dl with an INR of 15. Three days later, he developed anuria and was treated with hemodialysis. Renal ultrasonography disclosed moderate bilateral hydronephrosis. Computed tomography without contrast enhancement showed bilateral extensive hyperdense thickening of the renal and ureteral walls and high-attenuation areas. Conservative treatment was preferred and diuresis resumed spontaneously, lumbar pain disappeared, and serum creatinine level returned to normal. One month later, renal computed tomography was found normal. PMID- 21532301 TI - Transcatheter closure of a fistula between the right pulmonary artery and left atrium using the Amplatzer septal occluder. AB - A congenital fistula between the right pulmonary artery (RPA) and left atrium (LA) is a rare condition that results in central cyanosis. An 11-year-old boy was admitted with exertional dyspnea and easy fatigability. He had severe cyanosis of the lips and limbs with clubbing of the fingers. Systemic oxygen saturation was 70%. There was no abnormal finding on electrocardiography, chest radiography, and echocardiography. Agitated saline injection showed early appearance of contrast bubbles in the LA. A pulmonary arteriovenous fistula was suspected and diagnostic cardiac catheterization was performed. Angiography demonstrated a large fistula between the proximal RPA and LA. The narrowest part of the fistula was 13.8 mm in balloon sizing. A 14-mm Amplatzer septal occluder was deployed at the narrowest site; however, the device migrated to the LA and then to the aortic arch. The device was removed and was successfully reimplanted to the fistula. After the procedure, arterial oxygen saturation increased from 70% to 96% and control angiography demonstrated complete occlusion of the fistula. The patient was symptom-free on follow-up evaluations at 6, 12, and 18 months, with a mean oxygen saturation of 96%. This case represents the first pediatric patient in whom a septal occluder was used. PMID- 21532302 TI - Simultaneous conduction over the fast and slow pathways during induction of atrioventricular nodal reentrant arrhythmia with a rate of less than 100 bpm and infra-His block after radiofrequency ablation of the slow pathway. AB - Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common form of paroxysmal regular supraventricular tachycardia in adults. It is typically induced with an anterograde block over the fast pathway (FP) and conduction over the slow pathway (SP), with subsequent retrograde conduction over the FP. Rarely, a simultaneous conduction of a premature atrial complex occurs over the FP and SP to induce AVNRT and is called "one for two phenomenon". We present a 46-year-old woman with atrioventricular nodal rhythm with a rate of 95 beats per minute with distinct electrophysiological characteristics showing simultaneous conduction over the FP and SP during induction of tachycardia and an infra-His block after radiofrequency ablation of the SP. PMID- 21532303 TI - [Fistula between the left internal mammary artery and pulmonary artery: a rare cause of recurrent angina after coronary bypass grafting]. AB - Left internal mammary artery (LIMA) to pulmonary vasculature fistula is a rare complication after coronary artery bypass surgery. In most cases, the duration between bypass grafting and fistula formation ranges from 2 to 5 years. We present a 62-year-old man who presented with anginal symptoms five years after bypass surgery. On coronary angiography, selective catheterization of the LIMA showed fistula formation to the pulmonary artery, which probably led to coronary steal syndrome and myocardial ischemia. He underwent surgery and the connection between the LIMA and pulmonary artery was terminated. After surgery, his anginal complaints improved and echocardiography showed improvement in the wall motion abnormality detected before surgery. PMID- 21532304 TI - [An effective and safe alternative to epicardial pacemaker placement for permanent pacemaker implantation in a patient with mechanical tricuspid valve: stimulation of the left ventricle through the coronary sinus]. AB - Implantation of a transvenous endocardial pacemaker is contraindicated in patients with a mechanical tricuspid valve. An epicardial left ventricular pacemaker lead was placed by a transvenous route through the coronary sinus into the lateral cardiac vein in a 58-year-old woman with mechanical aortic, mitral, and tricuspid valves, for permanent pacing due to chronic atrial fibrillation with a slow ventricular rate accompanied by syncope. This lead was then connected to a single-chamber pacemaker. The patient had no problem in the following three months. Placement of an epicardial pacing lead through the coronary sinus provides a safe and effective pacing in patients with a mechanical tricuspid valve, thus obviating major cardiac surgery. PMID- 21532305 TI - [Heart health policies of the European Union and Turkey]. AB - Cardiovascular diseases cause 4.3 and 2 million deaths in Europe and the European Union countries each year, respectively, ischemic heart diseases and stroke being the leading causes of death. This review aims to present a brief appraisal of heart health policies of the European Union and Turkey. PMID- 21532306 TI - Massive lipomatous hypertrophy of the interatrial septum. PMID- 21532307 TI - Anomalous right coronary artery originating from the pulmonary artery. PMID- 21532308 TI - A huge noncoronary sinus of Valsalva aneurysm in a patient with Marfan syndrome. PMID- 21532309 TI - Twiddler's syndrome in an asymptomatic case. PMID- 21532310 TI - [Thoracic outlet syndrome presenting as a pseudostenosis image of the right subclavian artery]. PMID- 21532311 TI - [Comment on: Turkey's publication output in cardiovascular medicine declined in 2010 both in quantity and quality (Turk Kardiyol Dern Ars 2011;39:72-84)]. PMID- 21532313 TI - [Comment on: Turkey's publication output in cardiovascular medicine declined in 2010 both in quantity and quality (Turk Kardiyol Dern Ars 2011;39:72-84)]. PMID- 21532314 TI - Effects of combined mechanical stimulation on the proliferation and differentiation of pre-osteoblasts. AB - We observed how combined mechanical stimuli affect the proliferation and differentiation of pre-osteoblasts. For this research, a bioreactor system was developed that can simultaneously stimulate cells with cyclic strain and ultrasound, each of which is known to effectively stimulate bone tissue regeneration. MC3T3-E1 pre-osteoblasts were chosen for bone tissue engineering due to their osteoblast-like characteristics. 3-D scaffolds were fabricated with polycaprolactone and poly-L-lactic acid using the salt leaching method. The cells were stimulated by the bioreactor with cyclic strain and ultrasound. The bioreactor was set at a frequency of 1.0 Hz and 10 % strain for cyclic strain and 1.0 MHz and 30 mW/cm(2) for ultrasound. Three experimental groups (ultrasound, cyclic strain, and combined stimulation) and a control group were examined. Each group was stimulated for 20 min/day. Mechanical stimuli did not affect MC3T3-E1 cell proliferation significantly up to 10 days when measured with the cell counting kit-8. However, gene expression analysis of collagen type-I, osteocalcin, RUNX2, and osterix revealed that the combined mechanical stimulation accelerated the matrix maturation of MC3T3-E1 cells. These results indicate that the combined mechanical stimulation can enhance the differentiation of pre osteoblasts more efficiently than simple stimuli, in spite of no effect on cell proliferation. PMID- 21532316 TI - Influence of varying degree of salinity-sodicity stress on enzyme activities and bacterial populations of coastal soils of Yellow Sea, South Korea. AB - To study the effects of salinity-sodicity on bacterial population and enzyme activities, soil samples were collected from the Bay of Yellow Sea, Incheon, South Korea. In the soils nearest to the coastline, pH, electrical conductivity (ECe), sodium adsorption ratio (SAR), and exchangeable sodium percentage (ESP) were greater than the criteria of salinesodic soil, and soils collected from sites 1.5-2 km away from the coastline were not substantially affected by the intrusion and spray of seawater. Halotolerant bacteria showed similar trends, whereas non-tolerant bacteria and enzymatic activities had opposite trends. Significant positive correlations were found between EC, exchangeable Na+, and pH with SAR and ESP. In contrast, ECe, SAR, ESP, and exchangeable Na+ exhibited significant negative correlations with bacterial populations and enzyme activities. The results of this study indicate that the soil chemical variables related with salinity-sodicity are significantly related with the sampling distance from the coastline and are the key stress factors, which greatly affect microbial and biochemical properties. PMID- 21532315 TI - Effects of field-grown genetically modified Zoysia grass on bacterial community structure. AB - Herbicide-tolerant Zoysia grass has been previously developed through Agrobacterium-mediated transformation. We investigated the effects of genetically modified (GM) Zoysia grass and the associated herbicide application on bacterial community structure by using culture-independent approaches. To assess the possible horizontal gene transfer (HGT) of transgenic DNA to soil microorganisms, total soil DNAs were amplified by PCR with two primer sets for the bar and hpt genes, which were introduced into the GM Zoysia grass by a callus-type transformation. The transgenic genes were not detected from the total genomic DNAs extracted from 1.5 g of each rhizosphere soils of GM and non-GM Zoysia grasses. The structures and diversities of the bacterial communities in rhizosphere soils of GM and non-GM Zoysia grasses were investigated by constructing 16S rDNA clone libraries. Classifier, provided in the RDP II, assigned 100 clones in the 16S rRNA gene sequences library into 11 bacterial phyla. The most abundant phyla in both clone libraries were Acidobacteria and Proteobacteria. The bacterial diversity of the GM clone library was lower than that of the non- GM library. The former contained four phyla, whereas the latter had seven phyla. Phylogenetic trees were constructed to confirm these results. Phylogenetic analyses of the two clone libraries revealed considerable difference from each other. The significance of difference between clone libraries was examined with LIBSHUFF statistics. LIBSHUFF analysis revealed that the two clone libraries differed significantly (P<0.025), suggesting alterations in the composition of the microbial community associated with GM Zoysia grass. PMID- 21532318 TI - Molecular classification of commercial Spirulina strains and identification of their sulfolipid biosynthesis genes. AB - Cyanobacterial strains of the genus Spirulina have recently been identified as an excellent source of sulfolipids, some of which possess anti-HIV properties. Thus, to investigate the distribution of sufolipid biosynthesis pathways in Spirulina, a genetic screening/phylogentic study was performed. Five different strains of Spirulina [Spirulina (Jiangmen), Spirulina sp., S. platensis, S. maxima, and Spirulina seawater] sourced from different locations were initially classified via 16S rDNA sequencing, and then screened for the presence of the sulfolipid biosynthesis genes sqdB and sqdX via a PCR. To assess the suitability of these strains for human consumption and safe therapeutic use, the strains were also screened for the presence of genes encoding nonribosomal peptide synthases (NRPSs) and polyketide synthases (PKSs), which are often associated with toxin pathways in cyanobacteria. The results of the 16S rDNA analysis and phylogenetic study indicated that Spirulina sp. is closely related to Halospirulina, whereas the other four Spirulina strains are closely related to Arthrospira. Homologs of sqdB and sqdX were identified in Spirulina (Jiangmen), Spirulina sp., S. platensis, and the Spirulina seawater. None of the Spirulina strains screened in this study tested positive for NRPS or PKS genes, suggesting that these strains do not produce NRP or PK toxins. PMID- 21532319 TI - Proteomic profiles of mouse neuro N2a cells infected with variant virulence of rabies viruses. AB - We characterized the proteomes of murine N2a cells following infection with three rabies virus (RV) strains, characterized by distinct virulence phenotypes (i.e., virulent BD06, fixed CVS-11, and attenuated SRV9 strains), and identified 35 changes to protein expression using two-dimensional gel electrophoresis in whole cell lysates. The annotated functions of these proteins are involved in various cytoskeletal, signal transduction, stress response, and metabolic processes. Specifically, a-enolase, prx-4, vimentin, cytokine-induced apoptosis inhibitor 1 (CIAPIN1) and prx-6 were significantly up-regulated, whereas Trx like-1 and galectin-1 were down-regulated following infection of N2a cells with all three rabies virus strains. However, comparing expressions of all 35 proteins affected between BD06-, CVS-11-, and SRV9-infected cells, specific changes in expression were also observed. The up-regulation of vimentin, CIAPIN1, prx-4, and 14-3-3 theta/delta, and downregulation of NDPK-B and HSP-1 with CVS and SRV9 infection were >= 2 times greater than with BD06. Meanwhile, Zfp12 protein, splicing factor, and arginine/serine-rich 1 were unaltered in the cells infected with BD06 and CVS- 11, but were up-regulated in the group infected with SRV9. The proteomic alterations described here may suggest that these changes to protein expression correlate with the rabies virus' adaptability and virulence in N2a cells, and hence provides new clues as to the response of N2a host cells to rabies virus infections, and may also aid in uncovering new pathways in these cells that are involved in rabies infections. Further characterization of the functions of the affected proteins may contribute to our understanding of the mechanisms of RV infection and pathogenesis. PMID- 21532320 TI - Metagenome resource for D-serine utilization in a DsdA-disrupted Escherichia coli. AB - To find alternative genetic resources for D-serine dehydratase (E.C. 4.3.1.18, dsdA) mediating the deamination of D-serine into pyruvate, metagenomic libraries were screened. The chromosomal dsdA gene of a wild-type Escherichia coli W3110 strain was disrupted by inserting the tetracycline resistance gene (tet), using double-crossover, for use as a screening host. The W3110 dsdA::tet strain was not able to grow in a medium containing D-serine as a sole carbon source, whereas wild-type W3110 and the complement W3110 dsdA::tet strain containing a dsdA expression plasmid were able to grow. After introducing metagenome libraries into the screening host, a strain containing a 40-kb DNA fragment obtained from the metagenomic souce derived from a compost was selected based on its capability to grow on the agar plate containing D-serine as a sole carbon source. For identification of the genetic resource responsible for the D-serine degrading capability, transposon- micron was randomly inserted into the 40-kb metagenome. Two strains that had lost their D-serine degrading ability were negatively selected, and the two 6-kb contigs responsible for the D-serine degrading capability were sequenced and deposited (GenBank code: HQ829474.1 and HQ829475.1). Therefore, new alternative genetic resources for D-serine dehydratase was found from the metagenomic resource, and the corresponding ORFs are discussed. PMID- 21532321 TI - Effects of Pseudomonas aureofaciens 63-28 on defense responses in soybean plants infected by Rhizoctonia solani. AB - The objective of this work was to investigate the ability of the plant growth promoting rhizobacterium Pseudomonas aureofaciens 63-28 to induce plant defense systems, including defense-related enzyme levels and expression of defense related isoenzymes, and isoflavone production, leading to improved resistance to the phytopathogen Rhizoctonia solani AG-4 in soybean seedlings. Seven-dayold soybean seedlings were inoculated with P. aureofaciens 63-28, R. solani AG-4, or P. aureofaciens 63-28 plus R. solani AG-4 (P+R), or not inoculated (control). After 7 days of incubation, roots treated with R. solani AG-4 had obvious damping off symptoms, but P+R-treated soybean plants had less disease development, indicating suppression of R. solani AG-4 in soybean seedlings. Superoxide dismutase (SOD) and catalase (CAT) activities of R. solani AG-4-treated roots increased by 24.6% and 54.0%, respectively, compared with control roots. Ascorbate peroxidase (APX) and phenylalanine ammonia lyase (PAL) activities of R. solani AG-4-treated roots were increased by 75.1% and 23.6%, respectively. Polyphenol oxidase (PPO) activity in soybean roots challenged with P. aureofaciens 63-28 and P+R increased by 25.0% and 11.6%, respectively. Mn-SOD (S1 band on gel) and Fe-SOD (S2) were strongly induced in P+R-treated roots, whereas one CAT (C1) and one APX (A3) were strongly induced in R. solani AG-4- treated roots. The total isoflavone concentration in P+Rtreated shoots was 27.2% greater than the control treatment. The isoflavone yield of R. solani AG-4-treated shoots was 60.9% less than the control. PMID- 21532322 TI - Evaluation of the potential risk of porcine endogenous retrovirus (PERV) infection in nude mice. AB - Nude mice (BALB/c) were grafted with human 293 cells and PERV (porcine endogenous retrovirus)-IRES-EGFP (a packageable retroviral vector plasmid containing an internal ribosome entry site-enhanced green fluorescent protein)-producing pig PK15 cells in order to determine whether the pig cells could transmit PERV-IRES EGFP to mice and human 293 cells in vivo. None of the transplanted human 293 cell lines were infected by PERV, but PCR analysis identified PERV-B provirus integration into both the heart and salivary gland of the inoculated nude mice. Our data indicate that hearts and salivary glands can be used to identify PERV-B receptors. PMID- 21532324 TI - Curative effect of selenium against indomethacin-induced gastric ulcers in rats. AB - Indomethacin is a nonsteroid anti-inflammatory agent that is known to induce severe gastric mucosal lesions. In this study, we investigated the effect of selenium on gastric mucosal lesions in rats. To confirm the curative effect of selenium against indomethacin-induced gastric ulcers, gastric ulcers were induced by oral administration of 25 mg/kg indomethacin, and then different doses (10, 50, and 100 microgram/kg of body weight) of selenium or vehicle were treated by oral gavage for 3 days. Oral administration of indomethacin clearly increased the gastric ulcer area in the stomach, whereas selenium applied for 3 days significantly decreased the gastric ulcer area in a dose-dependent manner. In addition, selenium markedly reduced the increase of lipid peroxidation induced by indomethacin in the gastric mucosa and increased activities of radical scavenging enzymes such as superoxide dismutase, catalase, and glutathione peroxidase in a dose-dependent manner. These results reveal that selenium can heal indomethacininduced gastric ulcers through elimination of the lipid peroxides and activation of radical scavenging enzymes. PMID- 21532323 TI - An innate bactericidal oleic acid effective against skin infection of methicillin resistant Staphylococcus aureus: a therapy concordant with evolutionary medicine. AB - Free fatty acids (FFAs) are known to have bacteriocidal activity and are important components of the innate immune system. Many FFAs are naturally present in human and animal skin, breast milk, and in the bloodstream. Here, the therapeutic potential of FFAs against methicillin-resistant Staphylococcus aureus (MRSA) is demonstrated in cultures and in mice. Among a series of FFAs, only oleic acid (OA) (C18:1, cis-9) can effectively eliminate Staphylococcus aureus (S. aureus) through cell wall disruption. Lauric acid (LA, C12:0) and palmitic acid (PA, C16:0) do not have this ability. OA can inhibit growth of a number of Gram-positive bacteria, including hospital and community-associated MRSA at a dose that did not show any toxicity to human sebocytes. The bacteriocidal activities of FFAs were also demonstrated in vivo through injection of OA into mouse skin lesions previously infected with a strain of MRSA. In conclusion, our results suggest a promising therapeutic approach against MRSA through boosting the bacteriocidal activities of native FFAs, which may have been co-evolved during the interactions between microbes and their hosts. PMID- 21532325 TI - The adjuvant effect of Sophy beta-glucan to the antibody response in poultry immunized by the avian influenza A H5N1 and H5N2 vaccines. AB - Avian influenza virus vaccines produced in oil-emulsified inactivated form with antigen content of at least 160 hemagglutinin units (HAU) induced immunity in birds. However, in addition to enhancing the effect of the adjuvant(s), other additional supplemented biological compounds included in inactivated vaccines could produce higher levels of antibody. We examined in chickens, Vietnamese ducks, and muscovy ducks the adjuvant effect of Sophy beta-glucan (SBG), a beta 1,3-1,6 glucan produced by the black yeast Aureobasidium pollulans strain AF0 202, when administered with an avian influenza H5 subtype vaccine. In Experiment 1, 40 chickens (ISA Brown hybrid), allocated to four groups of ten each, were immunized with Oil-H5N1(VN), Oil-H5N1(CN), Oil-H5N2(CN), and saline (control group), respectively. In Experiment 2, chickens (ISA Brown hybrid), muscovy ducks (French hybrid), and Vietnamese ducks (indigenous Vietnamese) were used to further assess the effect of SBG on immunogenicity of the Oil-H5N1(VN) Vietnamese vaccine. ELISA and hemagglutination inhibition (HI) assays were used to assess the antibody response. The H5 subtype vaccines initiated significantly higher immune responses in the animals dosed with SBG, with 1.0-1.5 log2 higher HI titers and 10-20% ELISA seroconversion, compared with those not dosed with beta glucan. Notably, some of the animals dosed with SBG induced HI titers higher than 9.0 log2 following boosting immunization. Taken together, our serial studies indicated that SBG is a potential effector, such as enhancing the immune response to the H5 vaccines tested. PMID- 21532326 TI - Evidence of an alternative route of cellobiase secretion in the presence of brefeldin A in the filamentous fungus Termitomyces clypeatus. AB - Secretion of cellobiase occurred in a brefeldin A (BFA) uninhibited manner in the filamentous fungus Termitomyces clypeatus. Fluorescence confocal microscopy revealed that application of the drug at a concentration of 50 microgram/ml caused arrest of Spitzenkorper assembly at the hyphal tip. This resulted in greater than 30% inhibition of total protein secretion in the culture medium. However, the cellobiase titer increased by 17%, and an additional 13% was localized in the vacuolar fraction en route secretion. The secretory vacuoles formed in the presence of the drug were also found to be bigger (68 nm) than those in the control cultures (40 nm). The enzyme secreted in the presence and absence of BFA revealed a single activity band in both cases in native PAGE and had similar molecular masses (approx. 120 kDa) in SDS-PAGE. The BFA enzyme retained 72% of native glycosylation. It also exhibited a higher stability and retained 98% activity at 50 degrees C, 93.3% activity at pH 9, 63.64% activity in the presence of 1M guanidium hydrochloride, and 50% activity at a glucose concentration of 10 mg/ml in comparison to 68% activity, 75% activity, 36% activity, and 19% activity for the control enzyme, respectively. The observations collectively aimed at the operation of an alternative secretory pathway, distinct from the target of brefeldin A, which bypassed the Golgi apparatus, but still was able to deliver the cargo to the vacuoles for secretion. This can be utilized in selectively enhancing the yield and stability of glycosidases for a successful industrial recipe. PMID- 21532317 TI - Analysis of expressed sequence tags from the wood-decaying fungus Fomitopsis palustris and identification of potential genes involved in the decay process. AB - Fomitopsis palustris, a brown-rot basidiomycete, causes the most destructive type of decay in wooden structures. In spite of its great economic importance, very little information is available at the molecular level regarding its complex decay process. To address this, we generated over 3,000 expressed sequence tags (ESTs) from a cDNA library constructed from F. palustris. Clustering of 3,095 high-quality ESTs resulted in a set of 1,403 putative unigenes comprising 485 contigs and 918 singlets. Homology searches based on BlastX analysis revealed that 78% of the F. palustris unigenes had a significant match to proteins deposited in the nonredundant databases. A subset of F. palustris unigenes showed similarity to the carbohydrateactive enzymes (CAZymes), including a range of glycosyl hydrolase (GH) family proteins. Some of these CAZymeencoded genes were previously undescribed for F. palustris but predicted to have potential roles in biodegradation of wood. Among them, we identified and characterized a gene (FpCel45A) encoding the GH family 45 endoglucanase. Moreover, we also provided functional classification of 473 (34%) of F. palustris unigenes using the Gene Ontology hierarchy. The annotated EST data sets and related analysis may be useful in providing an initial insight into the genetic background of F. palustris. PMID- 21532327 TI - LC-MS/MS analysis of surface layer proteins as a useful method for the identification of lactobacilli from the Lactobacillus acidophilus group. AB - For precise identification of a Lactobacillus K1 isolate, LC-MS/MS analysis of the putative surface layer protein was performed. The results obtained from LTQ FT-ICR mass spectrometry confirmed that the analyzed protein spot is the surface layer protein originating from Lb. helveticus species. Moreover, the identified protein has the highest similarity with the surface layer protein from Lb. helveticus R0052. To evaluate the proteomic study, multilocus sequence analysis of selected housekeeping gene sequences was performed. Combination of 16S rRNA sequencing with partial sequences for the genes encoding the RNA polymerase alpha subunit (rpoA), phenylalanyl-tRNA synthase alpha subunit (pheS), translational elongation factor Tu (tuf), and Hsp60 chaperonins (groEL) also allowed to classify the analyzed isolate as Lb. helveticus. Further classification at the strain level was achieved by sequencing of the slp gene. This gene showed 99.8% identity with the corresponding slp gene of Lb. helveticus R0052, which is in good agreement with data obtained by nano-HPLC coupled to an LTQ-FT-ICR mass spectrometer. Finally, LC-MS/ MS analysis of surface layer proteins extracted from three other Lactobacillus strains proved that the proposed method is the appropriate molecular tool for the identification of S-layer-possessing lactobacilli at the species and even strain levels. PMID- 21532329 TI - Genome-wide response of Deinococcus radiodurans on cadmium toxicity. AB - Deinococcus radiodurans is extremely resistant to various genotoxic conditions and chemicals. In this study, we characterized the effect of a sublethal concentration (100 microM) of cadmium (Cd) on D. radiodurans using a whole-genome DNA microarray. Time-course global gene expression profiling showed that 1,505 genes out of 3,116 total ORFs were differentially expressed more than 2-fold in response to Cd treatment for at least one timepoint. The majority of the upregulated genes are related to iron uptake, cysteine biosynthesis, protein disulfide stress, and various types of DNA repair systems. The enhanced upregulation of genes involved in cysteine biosynthesis and disulfide stress indicate that Cd has a high affinity for sulfur compounds. Provocation of iron deficiency and growth resumption of Cd-treated cells by iron supplementation also indicates that CdS forms in iron-sulfur-containing proteins such as the [Fe-S] cluster. Induction of base excision, mismatch, and recombinational repair systems indicates that various types of DNA damage, especially base excision, were enhanced by Cd. Exposure to sublethal Cd stress reduces the growth rate, and many of the downregulated genes are related to cell growth, including biosynthesis of cell membrane, translation, and transcription. The differential expression of 52 regulatory genes suggests a dynamic operation of complex regulatory networks by Cd-induced stress. These results demonstrate the effect of Cd exposure on D. radiodurans and how the related genes are expressed by this stress. PMID- 21532328 TI - Effects of dissolved oxygen and agitation on production of serratiopeptidase by Serratia marcescens NRRL B-23112 in stirred tank bioreactor and its kinetic modeling. AB - The effects of the agitation and aeration rates on the production of serratiopeptidase (SRP) in a 5-L fermentor (working volume 2-l) were systematically investigated using Serratia marcescens NRRL B-23112. The dissolved oxygen concentration, pH, biomass, SRP yield, and maltose utilization were all continuously measured during the course of the fermentation runs. The efficiencies of the aeration and agitation were evaluated based on the volumetric mass transfer coefficient (K(L)a). The maximum SRP production of 11,580 EU/ml with a specific SRP productivity of 78.8 EU/g/h was obtained with an agitation of 400 rpm and aeration of 0.075 vvm, which was 58% higher than the shake-flask level. The KLa for the fermentation system supporting the maximum production (400 rpm, 0.075 vvm) was 11.3 h(-1). Under these fermentor optimized conditions, kinetic modeling was performed to understand the detailed course of the fermentation process. The resulting logistic and Luedeking-Piret models provided an effective description of the SRP fermentation, where the correlation coefficients for cell growth, SRP formation, and substrate consumption were 0.99, 0.94, and 0.84, respectively, revealing a good agreement between the model predicted and experimental results. The kinetic analysis of the batch fermentation process for the production of SRP demonstrated the SRP production to be mixed growth associated. PMID- 21532332 TI - Under stress: p53 controls EMT and stemness in pancreatic epithelial cells. PMID- 21532331 TI - Effects of hyperthyroidism, hypothyroidism, and thyroid autoimmunity on female sexual function. AB - INTRODUCTION: Thyroid hormones affect male and female sexual functions, but data in hypo- and hyperthyroid women are scanty. AIM: To investigate sexual function in hypo- and hyperthyroid women before and immediately after restoration of euthyroidism and in women with euthyroid Hashimoto's thyroiditis (HT). PATIENTS AND CONTROLS: Fifty-six women with thyroid diseases (age 19-50 yr; 22 with hyperthyroidism, 17 with hypothyroidism, and 17 with euthyroid HT) and 30 age matched healthy women. MAIN OUTCOME MEASURES: Hypoactive sexual desire, disorders of sexual arousal, vaginal lubrication, orgasm, satisfaction, and sexual pain (SPD) were assessed by Female Sexual Function Index. Serum TSH, free T4 (FT4) and thyroid autoantibodies (anti-thyroglobulin, anti-thyroperoxidase, and TSH receptor antibodies) were assessed at the diagnosis; FT4 and TSH were repeated after treatment to confirm normalization of thyroid function. RESULTS: All sexual domains scores were significantly reduced (p ranging <0.0001-<0.05) in both hypo- and hyperthyroid women. Correction of hypothyroidism was associated to normalization of desire, satisfaction, and pain, while arousal and orgasm remained unchanged. In hyperthyroid women therapy normalized sexual desire, arousal/lubrication, satisfaction, and pain, while orgasm remained significantly impaired. Interestingly, euthyroid HT women displayed a significant decrease in sexual desire (p<0.0005), with no changes in the other sexual domains. CONCLUSIONS: Both hypo- and hyperthyroidism markedly impair female sexual function. A rapid improvement is observed with the restoration of euthyroidism, although a longer period of time may be needed for full normalization. Preliminary data suggest that thyroid autoimmunity may selectively impair sexual desire, independently from thyroid function. PMID- 21532330 TI - Glycometabolic control in acromegalic patients with diabetes: a study of the effects of different treatments for growth hormone excess and for hyperglycemia. AB - BACKGROUND: Diabetes mellitus is frequently observed in patients with acromegaly. Current therapies for acromegaly may impact glucose regulation, influencing insulin sensitivity and secretion. The question whether these therapies modify control and progression of diabetes once present is still open. AIM: Aim of our study is to analyze glucose control in acromegalic patients with diabetes, evaluating the relation with treatments for GH excess and for diabetes. METHODS: Seventy patients with acromegaly and diabetes were studied. Duration and treatments of acromegaly and diabetes were recorded, together with clinical and metabolic parameters. RESULTS: Most patients (92.8%) were treated with somatostatin analogs (SSA), either alone or in combination with dopamine-agonists (20%) or pegvisomant (15.7%); 7.1% of patients had been treated by surgery alone. Metformin (65.7%), alone or in combination with other hypoglycemic drugs, was the most frequent treatment for diabetes, followed by insulin (21.5%). Only 15.7% were treated with diet alone. The whole cohort showed a very good control of diabetes and acromegaly. Median glycated hemoglobin was 6.4% (5.9-7). IGF-I was within normal range for age in most patients. No relation was observed between duration of acromegaly or diabetes and metabolic control. SSA had a negative effect on insulin secretion, but these effects did not influence glucose control. Finally, we observed a low prevalence of nephropathy (6%) and retinopathy (20%). CONCLUSIONS: Our study shows that a good control of hyperglycemia can be obtained with success in the majority of acromegalic patients with diabetes, independently of the type of treatment for GH excess. PMID- 21532333 TI - A new role for E2F1 in DNA repair: all for the greater good. PMID- 21532334 TI - SOM230 combined with celecoxib prolongs the survival in nude mice with HepG-2 xenografts. AB - A new non-cytotoxic therapy that SOM230 (pasireotide),a somatostatin analogue (SSTA) combined with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor was tested in nude mice bearing HepG2 xenografts. Two agents did not markedly arrest the growth of HepG2 cells but greatly down-regulated vascular endothelial growth factor expression. An imbalance between the vigorous demand and insufficient supply of nutrients and oxygen for tumor growth resulted in the massive necrosis of xenografts. The combination synergistically induced the early apoptosis of HepG2 cells and achieved longest survival without adverse reaction. This impressive strategy appears promising as a systemic therapy for patients with hepatocellular carcinoma (HCC). PMID- 21532335 TI - L-carnitine ameliorates cancer cachexia in mice by regulating the expression and activity of carnitine palmityl transferase. AB - Cancer cachexia is characterized by progressive weight loss with the depletion of adipose tissue and skeletal muscle. Impaired fatty acid oxidation mainly resulting from the decrease of carnitine palmitoyltransferase I and II activities in the liver is an important factor that contributes to cancer cachexia . Although recent studies suggest a potential application of L-carnitine in treatment of cancer cachexia, the underlying mechanisms are unknown. In the present study, we aim to assess the effects of L-carnitine on the activity and expression of CPT I and II in the liver of cachectic cancer mice. Our results show that the inoculation of colon-26 adenocarcinoma cells into mice led to cancer cachexia characterized by notable decreases in food intake, gastrocnemius muscle and epididymus fat weight. In addition, the mRNA level and activity of liver carnitine palmitoyltransferase (CPT) I and II, and serum levels of free carnitine and acetylcarnitine were markedly decreased in cachectic mice, accompanied by marked increases in serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). A continuous oral treatment with L carnitine at 18 mg/kg per day increased dietary uptake, gastrocnemius muscle weight and epididymus fat weight, increased blood glucose and serum albumin levels, and decreased total cholesterol level in cancer cachectic mice, but did not affect tumor growth. These effects of L-carnitine on cancer cachexia mice were accompanied by the upregulation of mRNA level of CPT I and II and increased enzyme activity of CPT I in the liver, as well as the downregulation of serum TNF alpha and IL-6 levels. Moreover, free carnitine levels were negatively correlated with serum TNF-alpha or IL-6 level. These results indicate that L-carnitine ameliorates cancer cachexia by regulating serum TNF-alpha and IL-6 levels and modulating the expression and activity of CPT in the liver. PMID- 21532336 TI - Combination therapy of recurrent prostate cancer with the proteasome inhibitor bortezomib plus hormone blockade. AB - A single arm phase II trial of single-agent bortezomib (BZM) alone or combined with hormone blockade was conducted in patients with early PSA recurrence after definitive local therapy. The primary endpoint of this study was to determine the time to PSA relapse after BZM therapy alone or when BZM was combined with hormone blockade. The secondary endpoint was to determine the safety of combination therapy. Part A of the treatment schedule consisted of three cycles of BZM 1.3 mg/m2 IV given on days 1,4,8,11. If patients progressed on Part A, they were entered on Part B which consisted of a single dose of LH-RH antagonist, daily oral antiandrogen, and weekly BZM 1.3 mg/m2 for three out of four weeks for a total of three months. BZM treatment significantly decreased the slope of the log PSA (p=0.024) demonstrating that this agent alone was capable of slowing the rise of the PSA. Of eight patients treated with BZM alone five had stable disease, two progressed and 1 went off study secondary to toxicity. The major toxicity was neurotoxicity requiring discontinuation of therapy in three patients and treatment interruption in nine patients. Of those receiving Parts A and B or B only, there were 11 of 15 CRs with the average time to progression of 5.5 months. BZM treatment can change the slope of PSA rise and can be combined with hormone deprivation therapy without significant additional side effects; these agents are associated with a median time to CR of 42 days. PMID- 21532337 TI - Identification of STAT3-independent regulatory effects for protein inhibitor of activated STAT3 by binding to novel transcription factors. AB - Protein Inhibitor of Activated Signal Transducer and Activators of Transcription 3 (PIAS3) is a molecule that regulates STAT3 and has antiproliferative properties. Glioblastoma and squamous cell lung cancer lack PIAS3 expression. To test the hypothesis that PIAS3 transcriptional effects are STAT3-independent, we developed models for STAT3 knockdown and PIAS3 over-expression. PIAS3 expression results in a distinct transcriptional profile that does not occur with STAT3 knockdown. We identify novel transcription factor binding partners for PIAS3 including ETS, EGR1, NR1I2, and GATA1. PIAS3 binds to these factors and regulates their transcriptional effects resulting in alterations in canonical pathways including Wnt/beta-catenin signaling and functions such as cell death and proliferation. A model is proposed by which PIAS3 effects EGR1 regulated pathways. PMID- 21532338 TI - Oral RKS262 reduces tumor burden in a neuroblastoma xenograft animal model and mediates cytotoxicity through SAPK/JNK and ROS activation in vitro. AB - Patients diagnosed with high-risk neuroblastoma (NB), an extracranial solid tumor in children, have metastases and low survival (30%) despite aggressive multi modal therapy. Therefore new therapies are urgently needed. We show significant in vitro and in vivo antitumor efficacy of RKS262 in NB. RKS262 showed superior cytotoxicity (IC(50) = 6-25 MUM) against six representative NB cell lines compared to its parent analog Nifurtimox (currently in phase 2). Pre-formulated RKS262 (150 mg/kg/daily) pellets administered orally, suppressed tumor growth (60%, p = 0.021) in NB xenograft mice within 28 days. RKS262-treated SMSKCNR cells showed TUNEL-positive DNA nicks and activation of ROS, MAPKs (SAPK/JNK), caspase-3, and p53, along with suppression of the IGF-1R/PI3K/PKC pathway and the Bcl2 family of proteins. RKS262 caused G(2)/M-phase arrest and suppressed cdc-2, cyclin B1, p21, and cyclin D1/D4 expression. N-acetyl-cysteine (NAC; 10 mM) pre treatment rescued cell viability of RKS262 (23 uM)-treated SMSKCNR cells, and pre treatment with ascorbic acid (100 MUM) and a MAPK inhibitor SB203580 (20 MUM) reversed SAPK/JNK, caspase-3 activation, PARP-1 cleavage, and suppression of IGF 1R, PI3K, and PKC phosphorylation. Further, treatment with exogenous BDNF (50 nM) did not suppress SAPK/JNK or ROS activation due to RKS262. Rather, BDNF (50 nM), EGF (100 nM) and IGF-1 (100 nM) co-treatment with RKS262 induced a remarkable S phase arrest rather than a G(2)/M phase arrest when RKS262 was used alone. In summary, RKS262 shows oral efficacy in NB xenograft animals, and induces apoptosis in vitro in SMSKCNR cells via cell cycle arrest, MAPK and ROS activation, and suppression of IGF-1R/PI3K/PKC and Bcl2 family proteins in a growth factor (BDNF/EGF/IGF-1)-independent fashion. PMID- 21532339 TI - Gallotannin inhibits NFKB signaling and growth of human colon cancer xenografts. AB - Gallotannin (GT), the polyphenolic hydrolyzable tannin, exhibits anti inflammatory and anticancer activities through mechanisms that are not fully understood. Several effects modulated by GT have been shown to be linked to interference with inflammatory mediators. Considering the central role of nuclear factor kappa B (NF-KB) in inflammation and cancer, we investigated the effect of GT on NF-KB signaling in HT-29 and HCT-116 human colon cancer cells. DNA binding assays revealed significant suppression of tumor necrosis factor (TNF-alpha) induced NFKB activation which correlated with the inhibition of IKBalpha phosphorylation and degradation. Sequentially, p65 nuclear translocation and DNA binding were inhibited. GT also down-regulated the expression of NFKB-regulated inflammatory cytokines (IL-8, TNF-alpha, IL-1alpha) and caused cell cycle arrest and accumulation of cells in pre-G 1 phase. In vivo, GT (25 mg/kg body weight) injected intraperitoneally (i.p.) prior to or after tumor inoculation significantly decreased the volume of human colon cancer xenografts in NOD/SCID mice. GT-treated xenografts showed significantly lower microvessel density (CD31) as well as lower mRNA expression levels of IL-6, TNF-alpha and IL-1alpha and of the proliferation (Ki-67) and angiogenesis (VEGFA) proteins, which may explain GTs in vivo anti-tumorigenic effects. Overall, our results indicate that the anti inflammatory and antitumor activities of GT may be mediated in part through the suppression of NF-KB activation. PMID- 21532340 TI - Pannexin channels are not gap junction hemichannels. AB - Pannexins, a class of membrane channels, bear significant sequence homology with the invertebrate gap junction proteins, innexins and more distant similarities in their membrane topologies and pharmacological sensitivities with the gap junction proteins, connexins. However, the functional role for the pannexin oligomers, or pannexons, is different from connexin oligomers, the connexons. Many pannexin publications have used the term "hemichannels" to describe pannexin oligomers while others use the term "channels" instead. This has led to confusion within the literature about the function of pannexins that promotes the idea that pannexons serve as gap junction hemichannels and thus have an assembly and functional state as gap junctional intercellular channels. Here we present the case that unlike the connexin gap junction intercellular channels, so far, pannexin oligomers have repeatedly been shown to be channels that are functional in single membranes, but not as intercellular channel in appositional membranes. Hence, they should be referred to as channels and not hemichannels. Thus, we advocate that in the absence of firm evidence that pannexins form gap junctions, the use of the term "hemichannel" be discontinued within the pannexin literature. PMID- 21532341 TI - Kir4.1 K+ channels are regulated by external cations. AB - The inwardly rectifying potassium channel (Kir), Kir4.1 mediates spatial K(+) buffering in the CNS. In this process the channel is potentially exposed to a large range of extracellular K(+) concentrations ([K(+)]o). We found that Kir4.1 is regulated by K(+)o. Increased [K(+)]o leads to a slow (mins) increase in the whole-cell currents of Xenopus oocytes expressing Kir4.1. Conversely, removing K(+) from the bath solution results in a slow decrease of the currents. This regulation is not coupled to the pHi-sensitive gate of the channel, nor does it require the presence of K67, a residue necessary for K(+)o-dependent regulation of Kir1.1. The voltage-dependent blockers Cs(+) and Ba(2+) substitute for K(+) and prevent deactivation of the channel in the absence of K(+)o. Cs(+) blocks and regulates the channel with similar affinity, consistent with the regulatory sites being in the selectivity-filter of the channel. Although both Rb(+) and NH4(+) permeate Kir4.1, only Rb(+) is able to regulate the channel. We conclude that Kir4.1 is regulated by ions interacting with specific sites in the selectivity filter. Using a kinetic model of the permeation process we show the plausibility of the channel's sensing the extracellular ionic environment through changes in the selectivity occupancy pattern, and that it is feasible for an ion with the selectivity properties of NH4(+) to permeate the channel without inducing these changes. PMID- 21532342 TI - Enhanced PKCepsilon mediated phosphorylation of connexin43 at serine 368 by a carboxyl-terminal mimetic peptide is dependent on injury. AB - The gap junction (GJ) protein connexin (Cx43) is important for organized action potential propagation between mammalian cardiomyocytes. Disruption of the highly ordered distribution of Cx43 GJs is characteristic of cardiac tissue after ischemic injury. We recently demonstrated that epicardial administration of a peptide mimetic of the Cx43 carboxyl-terminus reduced pathologic remodeling of Cx43 GJs and protected against induced arrhythmias following ventricular injury. Treatment of injuries with the carboxyl-terminal peptide was associated with an increase in phosphorylation at serine 368 of the Cx43 carboxyl-terminus. Here, we report that Cx43 peptide treatment of uninjured hearts does not prompt a similar increase in phosphorylation. Moreover, we show that peptide treatment of undisturbed cultured HeLa cells expressing a Cx43 construct also exhibit no changes in Cx43 phosphorylation at serine 368. However, in parallel with the results in vivo, a trend of increasing phosphorylation at serine 368 was observed in Cx43-expressing HeLa cells following scratch wounding of cultured monolayers. These results suggest that peptide-enhanced phosphorylation of the Cx43 carboxyl terminus is dependent on injury-mediated cellular responses. PMID- 21532343 TI - A role for GPN-loop GTPase yGPN1 in sister chromatid cohesion. AB - Sister chromatid cohesion and separation, involving the cohesin complex, are crucial for accurate inheritance of genetic information. This complex is also fundamental for efficient post-replicative repair of DNA double-strand breaks and has a key role in the mechanisms of gene transcription control. Cohesin is subjected to many post-translational modifications but the regulators implicated in the control of its activity have been poorly described. Here, we show that the conserved and essential GPN loop GTPase yGPN1 in Saccharomyces cerevisiae is involved in sister chromatid cohesion mechanisms. Based on a sister chromatid cohesion assay, we found that over-expression of the yGPN1 gene promotes sister chromatid separation during anaphase. The sharp slowdown in progression of the S phase observed in cells where yGPN1 expression is down-regulated strongly suggests that yGPN1 is necessary for DNA replication. Moreover, analysis of yGPN1 protein-protein interaction network highlights the yGPN1 links with DNA replication, sister chromatid cohesion/separation and the gene expression process. PMID- 21532344 TI - CsfG, a sporulation-specific, small non-coding RNA highly conserved in endospore formers. AB - Endospore formation is a characteristic shared by some Bacilli and Clostridia that involves the creation of two cell types, the forespore and the mother cell. Hundreds of protein-encoding genes have been shown to be transcribed in a cell specific fashion during this developmental process in Bacillus subtilis. We have used a phylogenetic profiling procedure to identify clusters of B. subtilis coding and non-coding sequences that co-occur in other endospore formers. One such cluster shows a strong bias for sporulation-related genes (42 % among 156 genes) and is enriched in potential non-coding RNAs. We have studied one RNA candidate, encoded in the ylbG-ylbH interval. In vivo analysis using a transcriptional fusion to the Escherichia coli lacZ gene demonstrates that this region of the chromosome contains a gene, csfG, encoding a 147-nucleotide RNA that is transcribed only during sporulation, specifically in the forespore. csfG is present in many endospore formers, mostly Bacilli and some Clostridia, whereas it is absent from bacteria that do not produce endospores. All CsfG RNAs contain a strongly conserved, pyrimidine-rich, central motif that overlaps a potential stem-loop structure. The remarkable conservation of this sequence in widely divergent bacteria suggests that it plays a conserved physiological role, presumably by interacting with an unidentified target in the forespore, where it contributes to the acquisition of the spore properties. PMID- 21532345 TI - LSINCT5 is over expressed in breast and ovarian cancer and affects cellular proliferation. AB - More than 98% of the human genome is comprised of non-protein coding sequences. Interestingly, a considerable fraction of these sequences is transcribed into non protein coding RNA transcripts. These transcripts range in size from very small RNAs such as the miRNAs (20-25 base pairs) to transcripts that can range up to 100 kb or more. Some longer non-coding RNAs (lncRNAs) have been found to play important regulatory roles within cells. In this report, we demonstrate that LSINCT5 is a 2.6 Kb polyadenylated, long stress-induced non-coding transcript that is on the negative strand, localized in the nucleus and potentially transcribed by RNA polymerase III. LSINCT5 is overexpressed in breast and ovarian cancer cell lines and tumor tissues, relative to their normal counterpart. In addition, knocking down the expression of LSINCT5 in cancer-derived cell lines causes a decrease in cellular proliferation. Finally, we identified 95 genes with more than 2-fold changes when knocking down LSINCT5 expression by using the Affymetrix U133 Plus 2 array. We chose a subset of these genes to validate using qPCR and found that ten of these genes were indeed significantly affected by the LSINCT5 knockdown. Interestingly, two genes that were significantly downregulated were the lncRNA NEAT-1 and a protein coding gene PSPC1. We have therefore characterized a novel lncRNA that is overexpressed in breast and ovarian cancers, enhances cellular proliferation and may play a significant role in multiple processes. PMID- 21532346 TI - Therapeutic nihilism: the next hurdle in improving the treatment of breathlessness. PMID- 21532347 TI - Nonpharmacological interventions for breathlessness. AB - PURPOSE OF REVIEW: Breathlessness is difficult to palliate and nonpharmacological interventions are effective management strategies currently available for mobile patients. These are a diverse group of interventions, currently poorly defined and inconsistently used. This review concentrates on identifying and recommending the most effective nonpharmacological strategies for breathlessness, to aid clinical practice. RECENT FINDINGS: Much of the evidence presented is based on a Cochrane Review, which demonstrated that facial cooling, by handheld fan, mobility aids (e.g. rollators) and neuromuscular electrical stimulation all had evidence to support their use in breathlessness. Breathing exercises, pacing and positioning are frequently used to manage breathlessness, but need definition and further research. Anxiety reduction techniques and carer support are used in chronic disease management and applicable for breathlessness, but act indirectly. Exercise is a long established management strategy in both respiratory and other chronic diseases to maintain fitness (which reduces breathlessness) and increase psychological well being. SUMMARY: All patients with breathlessness should learn appropriate nonpharmacological interventions. Some can be taught by clinicians without specialist training, but others require specialist skills and high levels of engagement by cognitively intact and highly motivated people. Specialist breathlessness services may be more effective in delivering complex nonpharmacological interventions, but more research is needed. PMID- 21532348 TI - Update on the role of palliative oxygen. AB - PURPOSE OF REVIEW: Breathlessness remains a frequent and burdensome symptom for individuals with life-limiting symptoms in both malignant and nonmalignant settings. As oxygen therapy is frequently given as part of the management of breathlessness and is associated with costs, treatment burden and potential dangers, it is timely to review the efficacy and appropriateness of palliative oxygen therapy. RECENT FINDINGS: Despite the widespread use of oxygen therapy in clinical and community settings, data supporting this approach is sparse. The benefits of long-term oxygen therapy for severely hypoxaemic people with chronic obstructive pulmonary disease are proven; however, mounting evidence suggests that oxygen does not confer additional benefit over medical air for the relief of refractory breathlessness in people with mild or absent hypoxaemia. SUMMARY: On the basis of the findings of this review, the routine use of palliative oxygen therapy without detailed assessment of pathogenesis and reversibility of symptoms cannot be justified. Promoting self-management strategies, such as cool airflow across the face, exercise and psychological support for patients and carers, should be considered before defaulting to oxygen therapy. If palliative oxygen therapy is considered for individuals with transient or mild hypoxaemia, a therapeutic trial should be conducted with clinical review after 3 days to assess the net clinical benefit and patient preference. PMID- 21532349 TI - Overcoming pain as a barrier to work. AB - PURPOSE OF REVIEW: To consider whether pain is a barrier to work and if so how this can be overcome. RECENT FINDINGS: Recent findings demonstrate that in addition to absence, pain can lead to a significant loss of productivity. The reasons why employees take absence or attend work while ill are complex and include personal, social and moral pressures around absence, and personally and institutionally mediated presenteeism. Interventions have moved on from a purely biomedical or psychosocial focus towards integrated programmes supporting individuals in managing their pain in the workplace. SUMMARY: Pain is one of the leading causes of absenteeism and presenteeism with related costs for both employees and employers. Ongoing pain presents a number of physical, psychological and social obstacles to work, which may or may not be modifiable. A range of interventions has been tested in randomized trials with a recent move towards identifying and tackling musculoskeletal pain in the wider context as conceptualized by the flags framework. However, in order for any intervention to be successful in ensuring employees overcome pain as a barrier to work, there needs to be widespread change in behaviour with regard to occupational health in general and effective interventions need to be implemented in both workplace and healthcare settings. PMID- 21532350 TI - The use of psychostimulants in cancer patients. AB - PURPOSE OF REVIEW: This article reviews the most recent studies that examine the efficacy of psychostimulants for the relief of symptoms such as asthenia and depression in cancer patients. RECENT FINDINGS: Although most research to date has focused on the use of methylphenidate for the relief of symptoms such as asthenia and depression in cancer patients, there is growing interest in the use of modafinil, a psychostimulant with a structure and mechanism that differs from other drugs belonging to this group. Initial studies mainly investigated the treatment of depressive symptoms in patients with advanced cancer; however, more recent studies have evaluated the use of psychostimulants in cancer-related fatigue identifying subgroups of patients and clinical settings in which psychostimulants are most efficient. SUMMARY: For the relief of chemotherapy symptoms in cancer patients, methylphenidate and modafinil were no more effective than placebo, although findings suggest that these psychostimulants may provide some benefit in patients who are suffering more severe asthenia or who are at advanced stages of the cancer. Methylphenidate showed marginal improvement in relation to symptoms such as asthenia and depression in studies in which it was compared with placebo; data from the only phase III study suggest that modafinil is an effective drug for advanced oncology patients. PMID- 21532351 TI - Assessing the role of hydration in delirium at the end of life. AB - PURPOSE OF REVIEW: Delirium is the most frequent neuropsychiatric disorder that affects the advanced cancer population who are receiving palliative care. There is limited evidence and much debate about the role of hydration in delirium management at the end of life. The purpose of this article is to review the literature on delirium management with regards to pharmacological management and hydration. RECENT FINDINGS: Pharmacological management is the first line of treatment for delirium, whereby antipsychotics are the medication of choice. However, they have not been approved by the United States Food and Drug Administration for delirium management as there is insufficient evidence supporting their use. Hydration is a believed to be a key component of delirium reversibility; yet there are conflicting results on its efficacy as an intervention for delirium management. As there are few studies of good methodological quality on the topic and large variations in practice, the effectiveness of hydration as an alternative management option for delirium is unclear. SUMMARY: More work is required to assess the role of hydration in delirium at the end of life. Given the lack of evidence-based research on hydration, more randomized clinical trials are needed to elucidate the effects of hydration as a delirium intervention. PMID- 21532354 TI - Accelerated exercise rehabilitation after ankle sprain. PMID- 21532355 TI - Proprioceptive training to prevent ankle injuries in basketball. PMID- 21532353 TI - Exercise therapy for patellofemoral pain syndrome costs society less than usual care. PMID- 21532352 TI - Autonomic nervous system reactivity: children with and without sickle cell disease. AB - BACKGROUND: Previous studies of healthy children have indicated a link between autonomic nervous system (ANS) reactivity and health outcomes, but there is limited research on whether ANS reactivity is similar for children with chronic conditions. OBJECTIVE: The aim of this study was to determine if ANS reactivity differs for children with sickle cell disease (SCD) compared with a community sample of children without SCD. METHOD: In two cross-sectional, descriptive studies, 32 public school children without chronic health problems were compared with 33 children with SCD. The children were 5-8 years old and they completed standardized protocols measuring ANS responses (respiratory sinus arrhythmia and preejection period) during rest and challenge conditions in social, cognitive, sensory, and emotion domains. Reactivity was calculated as the difference between challenge response minus rest for each domain and overall. RESULTS: There were differences in the distributions of the samples in parent education and child age, so these variables were adjusted for in subsequent analyses. The community sample showed parasympathetic withdrawal (low respiratory sinus arrhythmia scores) and greater parasympathetic reactivity (low respiratory sinus arrhythmia difference scores and percentage of negative scores) compared with the children with SCD in the social (p < .05) and sensory (p < .05) domains. The children with SCD showed greater sympathetic reactivity (low preejection period difference scores) compared with the community children in the cognitive domain (p < .05), and a greater percentage of children with SCD versus the community children showed negative preejection period difference scores (sympathetic reactivity) in the social domain (p < .05). The community sample, but not the children with SCD, showed changes in respiratory sinus arrhythmia across domains (p < .05). DISCUSSION: Children with SCD may display a different pattern of ANS responses to laboratory challenges compared with children without SCD from the same community. PMID- 21532356 TI - Evidence for interferential current to treat musculoskeletal pain remains weak. PMID- 21532358 TI - Current world literature. PMID- 21532360 TI - Current world literature. PMID- 21532361 TI - Efficacy, safety, and tolerability of sertraline on depressive symptoms in women with comorbid migraine: an open-label study. PMID- 21532362 TI - Aripiprazole augmentation in clozapine-associated obsessive-compulsive symptoms. PMID- 21532363 TI - Aripiprazole-associated leukopenia with coadministration of fluoxetine: a case report. PMID- 21532364 TI - Perinatal use of aripiprazole: a case report. PMID- 21532365 TI - Paliperidone-related rabbit syndrome. PMID- 21532366 TI - Use of paliperidone in elderly patients with schizophrenia and schizoaffective disorder: a prospective open-label short-term pilot study. PMID- 21532367 TI - Incidence of extrapyramidal syndromes and tardive dyskinesia. PMID- 21532369 TI - Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrome. PMID- 21532370 TI - Baseline lipid levels and acute treatment response to paroxetine and tianeptine in depressed women. PMID- 21532371 TI - Treatment with antidepressants increases insulin-like growth factor-I in cerebrospinal fluid. PMID- 21532372 TI - Generalized action myoclonus associated with escitalopram in a patient with mixed dementia. PMID- 21532373 TI - Psychotropic medication use, hyponatremia, and falls in an inpatient population: a retrospective study. PMID- 21532374 TI - Zuclopenthixol acetate treatment in children with bipolar disorder and severe aggression. PMID- 21532376 TI - An importance of dose in antipsychotic combination therapy for schizophrenia. PMID- 21532377 TI - Comment on "dose-dependent effects of adjunctive treatment with aripiprazole on hyperprolactinemia induced by risperidone in female patients with schizophrenia". PMID- 21532379 TI - Frontal lobe seizures. AB - BACKGROUND AND OBJECTIVE: Frontal lobe epilepsy is the second most common localization-related or focal epilepsy. Frontal lobe seizures are challenging to diagnose as the clinical manifestations are diverse due to the complexity and variability of the patterns of epileptic discharges, and the scalp electroencephalograph (EEG) can often be normal or misleading. This review focuses on the clinical and EEG features of seizures arising from the frontal lobe. REVIEW SUMMARY: The clinical manifestations in patients with frontal lobe epilepsy are varied. Frontal lobe seizures can be divided into perirolandic, supplementary sensorimotor area, dorsolateral, orbitofrontal, anterior frontopolar, opercular, and cingulate types. Seizures originating from the perirolandic and supplementary sensorimotor areas are clinically distinct, characterized by motor activity or asymmetric tonic posturing with preserved awareness. Seizures arising from dorsolateral, orbitofrontal, frontopolar, and cingulate areas are not as well characterized and have more variable clinical manifestations. Scalp EEG recording is sometimes helpful in localization but is usually normal or misleading in frontal lobe epilepsy. The treatment is similar to other localization-related or focal epilepsies. Medications are the first line of therapy, and surgery is considered for patients who fail to respond to medications. The surgical outcome in frontal lobe resections is less favorable than in anterior temporal lobectomies due to the challenge in locating the epileptogenic zone and the presence of functional areas (eloquent cortex) that can limit the resection. CONCLUSIONS: Frontal lobe seizures are characterized by diverse behavioral manifestations. Only a few well-described frontal lobe syndromes exist. The variety of clinical manifestations reflects both the varying sites of seizure origin and propagation routes that seizures may take. Although this review provides a framework for the understanding of these seizures, one should remain cautious in diagnosing seizure localization based on clinical or EEG description. Only a few patients have well-described syndromes and can be diagnosed with confidence. For most patients, new diagnostic methods and genetic testing may help improve our ability to diagnose and treat the conditions discussed in this study. PMID- 21532380 TI - Rheumatoid meningitis mimicking progressive supranuclear palsy. AB - INTRODUCTION: Rheumatoid meningitis is an uncommon manifestation of longstanding rheumatoid arthritis and few cases have been described. The clinical presentation is extremely variable as reported in medical literature. CASE REPORT: We report a 71-year-old woman with 15 years of seropositive rheumatoid arthritis who developed neurological complications: cognitive deterioration; hypomimia; limitation on vertical gaze; and axial stiffness, resembling progressive supranuclear palsy and seizures. Brain magnetic resonance imaging showed a diffuse dural plaque on both frontal and temporal lobes exhibiting homogeneous gadolinium enhancement. There was diffuse leptomeningeal enhancement and hyperintense white matter lesions. The final diagnosis made by image-guided biopsy showed rheumatoid pachymeningitis. After the definitive diagnosis, high doses of corticosteroids and immunosuppressive treatment were started. CONCLUSIONS: We emphasize the diagnostic importance of the biopsy in cases of chronic pachymeningitis and stress that diverse entities can cause progressive supranuclear palsy-like phenotypes. PMID- 21532381 TI - A case of Hashimoto encephalopathy: clinical manifestation, imaging, pathology, treatment, and prognosis. AB - INTRODUCTION: Hashimoto encephalopathy is a rare encephalopathy with positive antithyroid antibodies and normal thyroid function. We describe the clinical manifestations, neuroimaging, and histopathologic changes in a 52-year-old female with Hashimoto encephalopathy. RESULTS: The neuroimaging changes are multifocal abnormalities in cortical and subcortical areas bilaterally not enhanced by gadolinium. After high doses of corticosteroid therapy, the changes rapidly disappeared with marked improvement of clinical symptoms. CONCLUSIONS: This case shows the importance of assessment of antithyroid antibodies in patients with rapidly progressive cognitive dysfunction with/without the history of abnormality of thyroid function. PMID- 21532382 TI - Myasthenia gravis as a cause of head drop in Parkinson disease. AB - Head drop is characterized by marked anterior flexion of the cervical spine. As a result, the affected patient presents with the head tilted forward and the chin resting on the chest. We report a 75-year-old male patient with parkinsonism and head drop caused by isolated myasthenic weakness of the neck extensor muscles. Our case is the second report of isolated head drop as a presenting symptom of myasthenia gravis in a patient with parkinsonism. PMID- 21532383 TI - Neurological symptoms and signs in Behcet disease: a Western Turkey experience. AB - AIM: To assess the clinical patterns of neurologic involvement and the frequencies and characteristics of different types of headaches in patients with Behcet disease. METHODS: Total 530 patients with Behcet disease were evaluated for the presence of neurologic involvement and/or headache. RESULTS: Of the 54 patients (10.2%) with neurological involvement, 36 (66.7%) had parenchymal and 16 (29%) had vascular involvement. There was a patient with optic neuropathy and another patient with peripheral nerve involvement. There were 46 patients (8.7%) with headache without any evidence of neurological involvement and 25 of them (4.7%) were diagnosed with migraine. CONCLUSIONS: The prevalence of neurologic involvement in our group was higher than the studies published previously from the same country. Migraine prevalence on the other hand was low. PMID- 21532384 TI - Isolated orbito-cerebral mucormycosis. AB - Rhino-orbito-cerebral mucormycosis is a fatal infection in immunocompromised hosts. Prompt recognition of this clinical condition is essential for early diagnosis to avoid a delay of treatment. The presence of black eschar, usually in the nasal cavity, is the most alerting sign to the diagnosis. We present a patient with extremely fulminant ROCM in which the disease might be acquired via an orbital infection without nasal or paranasal involvement. With black eschars appearing at the bilateral canthi as the first alarm to extensive vascular involvement, the lethal infection rapidly evolved to occlusion of the bilateral ophthalmic arteries and eventually major intracranial arteries. PMID- 21532385 TI - Biventricular hydrocephalus due to idiopatic occlussion of foramina of Monro. AB - Total congenital occlusion of the foramina of Monro in adults is extremely rare. Only 9 cases have been reported. Clinically, this manifest as a biventricular hydrocephalus and the most frequent presenting symptom is headache. The diagnosis can be confirmed by computed tomographic scan or magnetic resonance imaging. Regarding treatment, neuroendoscopy constitutes the procedure of choice. The prognosis is usually good. We describe a 35-year-old woman with a 2-month headache and sudden nausea, vomiting, and syncope. The patient was studied with computed tomograph, magnetic resonance imaging, and a ventricular infusion test, and subsequently treated with endoscopic foraminoplasty and a ventriculoperitoneal shunt. The protacted normal neurological history with late and rapid onset of symptoms speaks for a progressive restriction of the size of the foramina of Monro, which allows adaptation to the changes in cerebrospinal fluid dynamics. Regarding treatment, in almost every cases of bilateral occlusion of foramina of Monro reported to date, but in 1 case both: neuroendoscopy fenestration and the ventriculoperitoneal shunt were needed. Time is needed to allow cerebrospinal fluid dynamics and the ventricular system to normalize. PMID- 21532386 TI - Reversible splenial lesion of the corpus callosum in migraine with aura. AB - INTRODUCTION: Migraine with aura has long been believed to be related to the phenomenon of cortical spreading depression. Clinically, there are no consistent neuroimaging findings corresponding to an attack of migraine with aura. CASE REPORT: We describe a patient suffering from migraine with aura associated with a transient abnormality in the midline of the splenium of the corpus callosum, showed by a magnetic resonance imaging. Features of edema and restricted diffusion indicated that there was cytotoxic edema. CONCLUSIONS: There have been reports of various etiologies associated with a temporary focal lesion in the splenium of the corpus callosum manifested as obviously restricted diffusion. These findings may be the consequence of a high vulnerability of the splenium of the corpus callosum to cytotoxic damage. Migraine with aura was considered to be the cause of the reversible focal injury of the splenium in this case. This association has not been reported earlier. PMID- 21532387 TI - Primary diffuse leptomeningeal gliomatosis mimicking meningeal tuberculosis. AB - Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare condition, with only 45 cases recorded to date, characterized by infiltration of the meninges by glial cells without evidence of primary tumor in the brain or spinal cord parenchyma. Here, we describe a patient with PDLG who was managed with tuberculostatic drugs owing to multiple findings that were suggestive of tuberculous meningitis. A 19 year-old woman presented with headaches and behavioral changes. A sudden decrease in visual acuity with papilledema, bilateral sixth nerve palsies, and neck stiffness developed. Lumbar puncture showed elevated opening pressure (50 cm H2O). Cerebrospinal fluid (CSF) analysis showed glucose 30 mg/dL, protein 26.5 mg/dL, white blood cell count 150 (60% lymphocytes, 40% neutrophils). The second sample of CSF provided adenosine deaminase activity 21.9 U/L. Polymerase chain reaction for Koch's bacillus was positive in the third CSF sample. Magnetic resonance imaging revealed meningeal thickening of the quadrigeminal cistern, tentorium cerebelli, cerebral convexity, and spinal cord, with gadolinium enhancement in nodular lesions. The patient died 22 weeks after symptom onset owing to brainstem infarction. Postmortem pathologic studies revealed PDLG. This entity should be included in the differential diagnosis of tuberculous meningitis that does not respond to treatment with antituberculous drugs. Surgical biopsy should be considered in contrast-enhanced areas in magnetic resonance imaging. PMID- 21532388 TI - Blood-brain barrier disruption is involved in seizure and hemianopsia in nonketotic hyperglycemia. AB - INTRODUCTION: Nonketotic hyperglycemia (NKH) is a clinical syndrome consisting of severe hyperglycemia, hyperosmolarity, and intracellular dehydration without ketoacidosis. Diverse neurologic symptoms have been described in patients with NKH, including hemichorea, seizure, hemianopsia, and coma, but the pathogenic explanation for these neurologic symptoms remains unclear. CASE REPORT: A 65-year old female with poorly controlled diabetes presented with intermittent jerky movements in the left arm and blurred vision in the left visual field of both eyes. She was diagnosed as NKH on laboratory analysis. Focal cortical hyperintensity and subcortical hypointensity around the right parietal area was noted on T2-weighted and fluid-attenuated inversion recovery (FLAIR) magnetic resonance images. After intravenous gadolinium enhancement, minimal overlying cerebrospinal fluid (CSF) space enhancement around the right parietal area was noted. Delayed FLAIR images, obtained 12 hours later without additional gadolinium, showed prominent CSF space enhancement without parenchymal changes. Delayed gadolinium enhancement of the CSF space on FLAIR imaging was resolved in parallel to clinical improvement during the 2 months' follow-up. CONCLUSIONS: Delayed gadolinium enhancement was first observed in patients with acute infarction who underwent thrombolytic therapy, and it has been considered a marker of blood-brain barrier (BBB) disruption associated with reperfusion injury. Considering that increased BBB permeability is an important mechanism for neurologic complications in diabetes, and BBB leakage occurs during epileptogenesis and contributes to the progression of epilepsy in the chronic phase, we suggest that seizures in NKH patients may be a consequence of, or at minimum have an association with, hyperglycemia-induced BBB disruption. PMID- 21532389 TI - A neurofibromatosis type 1 patient with thoracic encapsulated fluid and intracranial hypotension syndrome: a case report. AB - INTRODUCTION: Spinal meningoceles are uncommon entities, mostly associated with neurofibromatosis type 1 (NF-1). Their intrusion into the thoracic cavity, which compresses lung tissue, is quite often mistaken as a "pleural effusion." The withdrawal of a large amount of "pleural effusion" can lead to the intracranial hypotension syndrome (IHS), herniation, or even death. CASE REPORT: A 43-year-old woman, with NF-1 and a large "pleural effusion" which compressed lung tissue, was admitted to the Thoracic Department due to the patient's shortness of breath during her physical activities. The patient complained of headache shortly after withdrawal of about 250 mL of "pleural effusion." She was diagnosed with IHS according to the typical symptoms of postural headache, low cerebrospinal fluid (CSF) pressure and magnetic resonance imaging findings of diffuse pachymeningeal gadolinium enhancement. The "pleural effusion" was examined and found to be CSF. CONCLUSION: The reported case is the first 1 in the literature in which the intrusion of the NF-1 patient's spinal meningoceles into the thoracic cavity was diagnosed as a "pleural effusion" and large CSF withdrawal led to IHS. We highlight the possibility that thoracic meningoceles can coexist with a thoracic spinal deformity and the caution that needs to be taken when cases with similar symptoms are subjected to withdrawal of fluid. PMID- 21532390 TI - Multiple sclerosis, idiopathic dilated cardiomyopathy, and insulin-dependent diabetes mellitus: a common mechanism of irregular immune regulation. AB - BACKGROUND: Multiple sclerosis (MS), idiopathic dilated cardiomyopathy (DCM), and diabetes mellitus-1 (DM-1) are polygenic autoimmune diseases with a pivotal autoimmune component affecting young adults. They share a number of characteristics, thereby suggesting common underlying pathways or mechanisms. Typically, the aforementioned diseases are organ-specific autoimmune disorders of unknown etiology, but with strong evidence of tissue-destructive activity of the humoral and/or cellular immune system in the end-organ tissues affected (ie, the myelin components in MS, the myocytes of myocardium in DCM, and the insulin secreting beta islets in DM-1). CASE REPORT: We herein describe a 35-year-old white Greek man who presented with coexisting MS, DCM, and DM-1 diagnosed over a period of 7 years. The patient was successfully treated and is asymptomatic until present time. CONCLUSION: The clustering of these 3 autoimmune diseases in our patient supports the concept of an immune-mediated damage in these diseases, an important aspect for an effective therapeutic choice by neurologists. However, the immunopathogenetic association between MS and other autoimmune remains speculative, thereby warranting further clarification. PMID- 21532391 TI - Timing of antiepileptic drug withdrawal in adult epilepsy patients after neocortical surgical resection: a critically appraised topic. AB - BACKGROUND: The ideal efficacy outcome after surgery for medically refractory epilepsy is seizure freedom without need for antiepileptic drug (AED) therapy but the appropriate timing of AED withdrawal and other prognostic factors remain unclear. OBJECTIVE: To critically evaluate current evidence regarding factors that influence the risk of seizure relapse after tapering AEDs in adult postepilepsy surgery patients. METHODS: The objective was addressed through the development of a structured, critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of epilepsy. RESULTS: A structured literature search led to selection and appraisal of a retrospective cohort study. Of 147 patients who underwent AED tapering after epilepsy surgery, 61 (41.5%) ended up seizure-free off AEDs, 47 (32%) were seizure-free with AED continuation, and 39 (26.5%) continued to have seizures while on AEDs. Risk factors associated with seizure recurrence included: less time to AED reduction [<9 mo vs. >=9 mo; P<0.001; hazard ratio (HR)=2.83; 95% confidence interval (CI)=1.62-4.94), seizure recurrence before AED reduction (P=0.002; HR=2.43; 95% CI=1.37-4.31], normal preoperative magnetic resonance imaging (P=0.01; HR=1.96; 95% CI=1.15-3.34), and longer epilepsy duration (>11 y vs. <=11 y; P=0.02; HR=1.75; 95% CI=1.09-2.81). Cortical location of the epileptic focus was not associated with taper success. CONCLUSION: In adults who have undergone neocortical resection surgery for medically refractory epilepsy, longer time from surgery to beginning AED taper (eg, greater than 9 months) is associated with a greater proportion of patients maintaining seizure freedom. Other risk factors associated with lower rate of seizure freedom after AED taper include longer duration of epilepsy, normal preoperative magnetic resonance imaging, and occurrence of postoperative seizures before initiation of AED withdrawal, but not cortical location of the epilepsy focus. PMID- 21532392 TI - Directed differentiation of motor neuron cell-like cells from human adipose derived stem cells in vitro. AB - The capacity of human adipose-derived stem cells (hADSCs) to differentiate into motor neurons and the identity of molecular factors that confer hADSCs with the competence of motor neurons have yet to be elucidated. Here, retinoic acid and sonic hedgehog were applied to examine whether hADSCs could be differentiated into motor neurons. As early as 6 h after induction, hADSCs were changed toward neuronal morphology. After induction, hADSCs showed positive immunocytochemical staining for beta-III-tubulin, choline acetyltransferase, and neuron-specific enolase. Reverse-transcriptase polymerase chain reaction characterization indicated that cells differentiated from hADSCs were restricted to the ventral spinal fate (Nkx2.2, Pax6, Hb9, and Olig2). Our results suggest that hADSCs may be a potential candidate in cellular therapy for motor neuron disease. PMID- 21532393 TI - Neuronal effects of neurokinin B on the rat subfornical organ. AB - The subfornical organ is an essential central nucleus for angiotensin II-induced body fluid regulation. Similar to angiotensin II, centrally injected neurokinin B (NKB) may induce cardiovascular responses by the subfornical organ; however, it does not induce water intake. To clarify this inconsistency, we investigated the neuronal effects of NKB on subfornical organ neurons in slice preparations along with its behavioral effects in vivo. In electrophysiological extracellular recordings, NKB excited angiotensin II-insensitive and inhibited angiotensin II sensitive neurons. Centrally injected NKB inhibited peripherally injected angiotensin II-induced water intake. These results suggest that NKB-mediated neuronal effects on the subfornical organ are likely to be involved in antidipsogenic responses in addition to the previously reported cardiovascular responses. PMID- 21532394 TI - Studies on blast traumatic brain injury using in-vitro model with shock tube. AB - One of the major limitations in studying the mechanisms of blast-induced traumatic brain injury (bTBI) or screening therapeutics for protection is the lack of suitable laboratory model systems that can closely mimic the complex blast exposure. Although animal models of bTBI that use shock tubes to mimic blast exposure are available, no high throughput shock tube-based in-vitro models have been reported. Here, we report an in-vitro bTBI model using a compressed air driven shock tube and mouse neuroblastoma/rat glioblastoma hybrid cells (NG108 15) or SH-SY5Y human neuroblastoma cells in tissue culture plates. Our data showed significant neurobiological effects with decreased adenosine triphosphate levels, increased cellular injury, lactate dehydrogenase release, and reactive oxygen species formation after blast exposure. PMID- 21532395 TI - Mouse auditory organ development required bone morphogenetic protein signaling. AB - To investigate roles of bone morphogenetic protein (BMP) signaling on the development of mouse cochlear sensory organ, we isolated initial auditory epithelium from embryo and cultured with agonist or antagonist of BMP signaling. When BMP signaling was blocked with noggin cochlear epithelia were disordered, with hair cells in abnormal arrangement and disheveled hair bundles. The number of myosin VIIA and SRY (sex-determining region Y)-box 2 (SOX2)-positive cells also decreased dramatically. Conversely, an increase of myosin VIIA and SRY (sex determining region Y)-box 2-positive cells was observed when auditory epithelia were treated with exogenous BMP4. Cell proliferation and cell death were not changed significantly by BMP signaling. Collectively, our results indicated that BMP signaling is essential to cochlear sensory formation and hair cell differentiation. PMID- 21532396 TI - Age-specific effects of early MK-801 treatment on working memory in female rats. AB - The N-methyl-D-aspartate receptor plays a crucial role in developmental plasticity. Evidence shows that neonatal exposure to N-methyl-D-aspartate receptor antagonists impairs cognition in adult rats. This study investigated whether neonatal MK-801 treatment would produce long-term and age-specific effects on working memory and sensorimotor gating in adolescent and adult female rats. After treatment with MK-801 at postnatal days (PND) 5-14, female rats exhibited slightly impaired working memory during adolescence (PND: 35-42). In contrast, working memory was remarkably disrupted in adult (PND: 63-70) female rats. However, prepulse inhibition and startle amplitudes were not significantly affected at both ages. These findings indicate that neonatal MK-801 elicits working memory deficits, especially in the postpuberty female rats. PMID- 21532405 TI - Management of local-regional recurrence following immediate breast reconstruction in patients with early breast cancer treated without postmastectomy radiotherapy. AB - BACKGROUND: Young age is an independent risk factor for local-regional recurrence after mastectomy in patients with T1/T2 tumors with zero or one to three positive lymph nodes. The authors evaluated the current incidence and management of local regional recurrence after immediate breast reconstruction in patients with T1/T2 tumors and zero to three positive lymph nodes who did not receive postmastectomy radiotherapy. METHODS: Clinical and pathologic factors were identified for 495 patients with T1/T2 tumors and zero to three positive lymph nodes who were treated with mastectomy and immediate breast reconstruction between 1997 and 2002 and did not receive primary systemic chemotherapy or postmastectomy radiation therapy. RESULTS: Autologous tissue-based reconstruction was performed in 70 percent of patients, and 30 percent had tissue expander placement. At a median follow-up of 7.5 years, local-regional recurrence had occurred in 16 patients (3.2 percent). Independent predictors of local-regional recurrence were age 40 years or less, estrogen receptor-negative tumors, and T2 (versus T1) tumors (p < 0.05). Multimodality therapy was utilized for all 16 patients with local-regional recurrence. Nine patients (56.3 percent) who had an isolated local-regional recurrence had a 100 percent local control rate and were treated with curative intent. The 10-year overall survival rate for patients with an isolated local regional recurrence (87.5 percent) was not significantly different from that for patients without a local-regional recurrence (90.3 percent; p = 0.234). CONCLUSIONS: Routine use of postmastectomy radiation therapy in this heterogeneous patient population should be discouraged to allow more patients to undergo immediate breast reconstruction and ease the burden on plastic surgeons who have had to confront the problems of reconstruction in the face of perioperative radiation in an ever-increasing number of patients. PMID- 21532404 TI - Adult peripheral nerve disorders: nerve entrapment, repair, transfer, and brachial plexus disorders. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Describe the pathophysiologic bases for nerve injury and how they apply to patient evaluation and management. 2. Recognize the wide variety of injury patterns and associated patient complaints and physical findings associated with peripheral nerve pathology. 3. Evaluate and recommend further tests to aid in defining the diagnosis. 4. Specify treatment options and potential risks and benefits. SUMMARY: Peripheral nerve disorders comprise a gamut of problems, ranging from entrapment neuropathy to direct open traumatic injury and closed brachial plexus injury. The pathophysiology of injury defines the patient's symptoms, examination findings, and treatment options and is critical to accurate diagnosis and treatment. The goals of treatment include management of the often associated pain and improvement of sensory and motor function. Understanding peripheral nerve anatomy is critical to adopting novel nerve transfer procedures, which may provide superior options for a variety of injury patterns. PMID- 21532406 TI - Risk factors influencing transfusion rates in DIEP flap breast reconstruction. AB - BACKGROUND: As the popularity of deep inferior epigastric perforator (DIEP) flap breast reconstruction grows, there remains little information on the transfusion rate of this more technically challenging procedure. The purpose of this study was to examine the perioperative blood loss and patient characteristics of women undergoing DIEP flap breast reconstruction in an attempt to identify independent risk factors that predict increased blood loss and transfusion requirements. METHODS: A retrospective chart review identified 144 patients who underwent DIEP flap breast reconstruction performed at Queen Elizabeth II Health Sciences Center between January of 2002 and July of 2009. Intraoperative blood loss, hemoglobin and hematocrit drop, length of hospital stay, incidence of perioperative blood transfusions, and complications were reviewed. This study assessed the effects of older age, obesity, bilateral reconstruction, immediate reconstruction, tamoxifen treatment, and length of surgery on the incidence of perioperative blood transfusion and complications. RESULTS: A total of 18.8 percent of patients required perioperative blood transfusions. These patients were older and more obese, underwent more immediate and bilateral reconstructions, and had longer mean operative times and hospital stays. Patients who underwent lengthy bilateral DIEP reconstructions were at increased risk of receiving a perioperative blood transfusion (bilateral: relative risk, 2.4; odds ratio, 4.4; long surgery: relative risk, 3.9; odds ratio, 7.3). Blood transfusion recipients had an increased risk and greater odds of experiencing any postoperative complication (relative risk, 2.3; odds ratio, 3.4). CONCLUSIONS: Bilateral reconstruction and length of surgery were the only factors to significantly increase the risk of perioperative blood transfusion. Patients receiving blood transfusions had an increased risk of experiencing a postoperative complication. PMID- 21532407 TI - Feasibility of internal mammary vessel use in breast reconstruction versus coronary artery bypass surgery: an anatomic, cadaveric evaluation. AB - BACKGROUND: Autologous free flap breast reconstruction using the internal mammary artery is common; however, its use may compromise treatment of occult coronary artery disease. The authors investigated whether internal mammary artery harvest for breast reconstruction is compatible with future use for coronary bypass. METHODS: An anatomic analysis of 10 preserved female cadavers was performed. Internal mammary artery measurements, including the length from its origin to the third, fourth, and fifth intercostal spaces, were taken, and the minimum length required to reach the left anterior descending coronary artery was determined. RESULTS: The left internal mammary artery reached the left anterior descending target at a mean length of 10.0 cm. The mean lengths to the left third, fourth, and fifth intercostal spaces were 8.2 cm, 11.3 cm, and 13.7 cm, respectively, on the left, and 7.6 cm, 10.7 cm, and 13.2 cm, respectively, on the right. The right internal mammary artery reached the left anterior descending target at a mean of 12.0 cm. CONCLUSIONS: The left internal mammary artery was found to reach the estimated coronary target by the level of the fourth intercostal space consistently, while the right was more variable and required a greater length. If the fourth intercostal space was used to harvest the internal mammary artery, the length necessary for in situ coronary bypass surgery is preserved on the left, and may still be used as a free graft on the right. PMID- 21532408 TI - Prospective computerized analyses of sensibility in breast reconstruction with non-reinnervated DIEP flap. AB - BACKGROUND: The deep inferior epigastric perforator (DIEP) flap is considered the definitive standard for autologous breast reconstruction because of its ability to restore shape, its consistency, and its static and dynamic symmetry, but the degree of spontaneous sensory recovery is still widely discussed. To clarify the real need for sensitive nerve coaptation, return of sensibility in DIEP flaps was investigated using a pressure-specifying sensory device. METHODS: Thirty consecutive patients with breast cancer scheduled for modified radical mastectomy, axillary node dissection, and immediate reconstruction with cutaneous adipose DIEP flaps without nerve repair were enrolled in the study. Sensibility for one and two points, static and moving, was tested preoperatively on the breasts and abdomen, and postoperatively at 6 and 12 months on the DIEP flaps. A t test was used for comparison of paired data and to investigate which factors affected sensory recovery. RESULTS: Preoperative healthy breast and abdomen pressure thresholds were lower for two-point than one-point discrimination and for moving discriminations compared with static ones at 6 and 12 months. Although they were significantly higher than those for contralateral healthy breasts (p < 0.05), pressure thresholds in DIEP flaps at 12 months were lower than at 6 months, showing a significant progressive sensory recovery (p < 0.05). At 12 months postoperatively, the best sensibility recovery was found at the inferior lateral quadrant, the worst at the superior medial quadrant. Age and flap weight were factors related to the performance of sensory recovery. CONCLUSIONS: DIEP flap transfer for immediate breast reconstruction undergoes satisfactory progressive spontaneous sensitive recovery at 6 and 12 months after surgery, and operative time spent dissecting sensitive perforator branches and their coaptation in recipient site could be spared. PMID- 21532409 TI - Patterns and correlates of postmastectomy breast reconstruction by U.S. Plastic surgeons: results from a national survey. AB - BACKGROUND: : Concern exists that plastic surgeons have lost interest in postmastectomy breast reconstruction, which has helped enable the oncoplastic movement by general surgery. The authors evaluated patterns and correlates of postmastectomy breast reconstruction among U.S. plastic surgeons. METHODS: A survey was mailed to a national sample of 500 randomly selected members of the American Society of Plastic Surgeons (73 percent of eligible subjects responded; n = 312). The dependent variable was surgeon's annual volume of breast reconstructions (dichotomized into >50 and <= 50 cases per year). Logistic regression was used to evaluate factors associated with annual volume, including surgeon demographic and practice characteristics, community support for reconstruction, and surgeons' attitudes toward insurance reimbursement. RESULTS: Ninety percent found doing breast reconstruction personally rewarding, and nearly all enjoyed the technical aspects of the procedure. The majority of surgeons, however, were low-volume to moderate-volume providers, and 43 percent reported decreasing their volume over the past year due to poor reimbursement. Resident availability was significantly associated with high volume (odds ratio, 4.93; 95 percent CI, 2.31 to 10.49); years in practice and perceived financial constraints by third-party payers were inversely associated with high volume (>20 years compared with <= 10 years: odds ratio, 0.23. 95 percent CI, 0.07 to 0.71; odds ratio, 0.22, 95 percent CI, 0.08 to 0.56, respectively). CONCLUSIONS: Although plastic surgeons find breast reconstruction professionally rewarding, many are decreasing their practice. Factors associated with low volume include lack of resident coverage and perceived poor reimbursement. Advocacy efforts must be directed at facilitating reconstructive services for this highly demanding patient population. PMID- 21532410 TI - Microsurgical lymphaticovenous implantation targeting dermal lymphatic backflow using indocyanine green fluorescence lymphography in the treatment of postmastectomy lymphedema. AB - BACKGROUND: Microsurgical lymphaticovenous implantation in lymphedema is done to create a lymphaticovenous shunt by an implantation of collecting lymphatics into the small vein, as reported previously. The authors have recently introduced ultrasonograpy and indocyanine green fluorescence lymphography into this procedure. METHODS: Nine cases of postmastectomy lymphedema had received preoperative venous marking using ultrasonography and lymphatic mapping using indocyanine green fluorescence lymphography. The concept of modification is to pick up the most effective point for microsurgical lymphaticovenous implantation that involves both subcutaneous veins and the dermal backflow of excess lymphatics. Objective improvement was analyzed by the percent reduction of edema circumference at two points of the affected forearm. RESULTS: Preoperative lymphography showed a spotty image for dermal backflow in all nine extremities, a linear image on the dorsal hand in six extremities, and a linear image on the forearm in three extremities. With an average follow-up of 17 months, three patients had excellent results with the reduction of edema circumference more than 50 percent for both the distal and proximal sites of the treated forearm. Four patients had good results with the reduction of edema circumference more than 50 percent at the distal or proximal sites, two patients had fair results, and no patients had poor results. The average number of modified microsurgical lymphaticovenous implantations was 3.7 per case. CONCLUSION: Modified microsurgical lymphaticovenous implantation is expected to provide favorable results with a minimum number of these modified implantations, even though no linear lymph channel was detected by preoperative indocyanine green fluorescence lymphography. PMID- 21532411 TI - Ex vivo transfer of adenovirus-mediated CTLA4Ig gene combined with a short course of rapamycin therapy prolongs free flap allograft survival. AB - BACKGROUND: Adenovirus-mediated cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin (AdCTLA4Ig) gene transfer has been reported to enhance both organ and composite tissue grafts survival in rodent transplantation models. The authors tested the efficacy of local expression of CTLA4Ig gene on the survival of rat free flap allografts. METHODS: Brown Norway rat groin flaps were transplanted in Lewis rat recipients. The donor flaps were perfused ex vivo with AdCTLA4Ig via the afferent artery before transplantation. The distribution and duration of CTLA4Ig transgene expression in the flaps were assessed by immunohistochemical staining and semiquantitative reverse transcriptase polymerase chain reaction after transplantation. A mixed lymphocyte reaction was performed to test the antigen-specific immune response. Flow cytometry was used to detect the variations of CD4+25+Foxp3+ T cells in recipients' spleens. RESULTS: Immunohistochemical staining and reverse transcriptase polymerase chain reaction demonstrated expression of CTLA4Ig transgene in AdCTLA4Ig-perfused free flap allografts. AdCTLA4Ig-perfused free flap allografts survived significantly longer compared with survival of enhanced green fluorescent protein adenovirus perfused free flap allografts. When combined with a short course of rapamycin, the survival time of AdCTLA4Ig-perfused free flap allografts was remarkably prolonged. The mixed lymphocyte reaction results indicate that ex vivo transfer of AdCTLA4Ig induces antigen-specific unresponsiveness. AdCTLA4Ig perfusion did not change the proportion of CD4+25+Foxp3+ T cells in recipients' spleens. CONCLUSION: The authors demonstrated that a singular ex vivo perfusion of AdCTLA4Ig gene induced efficient transduction of the flaps and, when combined with a short course of rapamycin, promoted the remarkably longer survival of flap allografts. PMID- 21532412 TI - Comparison of extracorporal shock wave pretreatment to classic surgical delay in a random pattern skin flap model. AB - BACKGROUND: Extracorporal shock wave therapy has a significant positive effect on rescuing the ischemic zone of flap tissue if applied immediately after surgical intervention. The purpose of this study was to determine the potential preoperative effect of noninvasive extracorporal shock wave therapy to precondition flap tissue compared with the well-established surgical delay procedure. METHODS: Thirty-two male Wistar rats were randomized into four groups, and an oversized, random-pattern flap was raised in each animal. In group D7, a surgical delay was carried out 1 week before full flap harvest. In group E7, the whole flap area was treated with extracorporal shock wave therapy to induce mechanical delay. Group E7D7 was treated preoperatively with a combination of surgical delay and extracorporal shock wave therapy. Group C constituted the control group, in which the skin flap was harvested without any prior intervention. Seven days after flap harvest, flap survival, perfusion, microvessel density, and vascular endothelial growth factor concentration were assessed. RESULTS: Flap survival, perfusion, and microvessel density were significantly increased in the delay group (group D7) and the extracorporal shock wave therapy group (group E7) compared with the control group (group C). Combining both pretreatments (group E7D7) did not have a favorable cumulative effect. Vascular endothelial growth factor expression was not significantly increased in any group. CONCLUSIONS: Although not superior to surgical delay, the authors see many advantages of extracorporal shock wave therapy; it is noninvasive, easily applicable, less time- consuming, and less expensive. Thus, it may constitute an alternative procedure in clinical situations that warrant a noninvasive, fast, and easily applicable treatment. PMID- 21532413 TI - Colistin-loaded silk membranes against wound infection with Pseudomonas aeruginosa. AB - BACKGROUND: Wound infections caused by multidrug-resistant bacteria are a major issue in wound care. An occlusive dressing delivering an antimicrobial agent to the wound may be advantageous. The objective of this study was to evaluate an occlusive silk membrane loaded with colistin to establish an effective antimicrobial wound dressing against Gram-negative bacteria in vitro and in vivo. METHODS: ST-silk protein membranes (thickness, 100 MUm; pore size, <100 nm) were loaded with log-scale colistin dilutions (0.027 to 270 mg/ml) and tested in a modified microbroth dilution assay against Pseudomonas aeruginosa (American Type Culture Collection 27853). A rat burn infection model was used to demonstrate the antimicrobial activity of ST-silk membranes loaded with 270 mg/ml colistin. Finally, a porcine wound infection model was used to study dose response (2.7, 27, and 270 mg/ml colistin loading concentration) in a time-dependent manner (0, 2, 4, and 6 days). RESULTS: The in vitro study demonstrated a concentration dependent antimicrobial effect against P. aeruginosa, with complete elimination at the highest loading concentrations (2.7, 27, and 270 mg/ml). All colistin membranes demonstrated lower colony-forming unit counts compared with the corresponding phosphate-buffered saline or carrier controls. The rat burn infection model demonstrated a colony-forming unit reduction of greater than 3 log-scales for the colistin-loaded ST-silk membranes after 3 days. On average, the wounds' colony-forming unit quantity remained at greater than 1000 during the entire follow-up of 6 days, apart from three wounds where complete bacterial clearance was observed. CONCLUSION: This study demonstrates that occlusive ST silk membranes loaded with an antimicrobial agent may be an effective dressing for infected wounds. PMID- 21532414 TI - Application of micro-computed tomographic scanning to characterize patterns of murine cranial suture fusion. AB - BACKGROUND: In the murine model of suture fusion, it is widely accepted that the posterior frontal suture progresses from a state of patency on day 25 through complete fusion by day 45. The present study was performed to evaluate the process of normal posterior frontal suture fusion and to quantitate patterns of suture morphology in prefusion and postfusion mouse calvariae. METHODS: The calvariae of mice euthanized on day 25 (n = 7) and day 45 (n = 7) of postnatal life were analyzed by micro-computed tomography with 21-mm sections from each posterior frontal suture and analyzed by a nonblinded investigator for patency or fusion in the ectocranial, central, and endocranial segments. RESULTS: Both the ectocranial and central surface of the posterior frontal suture demonstrate a statistically significant difference in percentage fusion on day 25 versus day 45 of postnatal life. When compiled as a single suture complex, patterns of patency and fusion across the three defined levels showed a distinct trend toward patency at 25 days (19.8 +/- 4.4 percent) and fusion at 45 days (48.6 +/- 6.7 percent), but this relationship was not absolute. CONCLUSIONS: Although it has previously been thought that the posterior frontal suture in the mouse is fully patent on day 25 and fused on day 45, micro-computed tomographic analysis of the suture suggests otherwise. Accurate characterization of the timing and pattern of fusion in the mouse posterior frontal suture is an essential component to our understanding of the murine model, which serves as a widely studied analogue for suture fusion in humans. PMID- 21532415 TI - Interval cranioplasty: comparison of current standards. AB - BACKGROUND: Although different cranioplasty storage methods are currently in use, no study has prospectively compared these methods. The authors compare freezing and subcutaneous storage methods in a rat model. METHODS: Trephine defects (10 mm) were created in 45 Sprague-Dawley rats. The cranial bone grafts were stored in an autologous subcutaneous pocket (n = 15), frozen at -80 degrees C (n = 15), immediately analyzed (n = 12), or immediately replanted into the defect (n = 3). After 10 days of storage, the subcutaneous or frozen grafts were either replanted (subcutaneous, n = 3; frozen, n = 3) or analyzed (subcutaneous, n = 12; frozen, n = 12). Grafts underwent histologic analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, alkaline phosphatase assay, mechanical testing, and micro-computed tomographic imaging. RESULTS: After 10 days of storage, physiologic assays demonstrated a significant decrease in cellular functionality (e.g., alkaline phosphatase assay concentration: fresh, 18.8 +/- 0.77 mM/mg; subcutaneous, 12.2 +/- 0.63 mM/mg; frozen, 8.07 +/- 1.1 mM/mg; p < 0.012 for all comparisons). Mechanical integrity (maximal load) of fresh grafts was greatest (fresh, 9.26 +/- 0.29 N; subcutaneous, 6.27 +/- 0.64 N; frozen, 4.65 +/- 0.29 N; fresh compared with frozen, p < 0.001; fresh compared with subcutaneous, p = 0.006). Replantation of subcutaneously stored and frozen grafts resulted in limited bony union and considerable resorption after 12 weeks; in contrast, replanted fresh grafts demonstrated bony union and little resorption. CONCLUSIONS: Current preservation methods for interval cranioplasty do not maintain bone graft viability. Subcutaneous storage appears to provide a small advantage compared with freezing. PMID- 21532416 TI - BMP-2-mediated regeneration of large-scale cranial defects in the canine: an examination of different carriers. AB - BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered on an absorbable collagen sponge is a U.S. Food and Drug Administration-approved therapy shown to be an effective means of generating bone formation in multiple clinical settings. However, the optimum dose and delivery of rhBMP-2 to the calvaria are undetermined. The aim of the authors' study was to investigate the use of rhBMP-2 in addressing calvarial defects in a large-animal model through a variety of modifications to this U.S. Food and Drug Administration-approved therapy. METHODS: Twenty-three adult canines underwent the creation of a standard calvarial defect and received either no treatment, 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge, 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge with corticocancellous chips, 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge with MasterGraft Granules, or 0.4 mg/ml rhBMP-2 in a compression-resistant matrix carrier. Direct comparisons of defect radiopacity were performed at 0, 8, 16, and 24 weeks postoperatively before the animals were euthanized. All specimens were evaluated qualitatively with histology. RESULTS: Surgical control animals had an average defect radiopacity of 32.7 percent at study completion compared with an average of 99.95 percent across all treatment groups. Ectopic bone formation was found consistently in all treatment groups with varying degrees of severity. Regenerated bone thickness, compactness, and organization varied qualitatively between groups. CONCLUSIONS: Treatment with 0.2 mg/ml rhBMP-2 in an absorbable collagen sponge with MasterGraft Granules showed the least amount of ectopic bone formation and the most compact bone formation within the defect, and produced reasonably consistent bony thickness across the defect. Future studies should focus on spatial regulation of rhBMP-2 to minimize unwanted bone formation. PMID- 21532417 TI - Pathways of sensory recovery after face transplantation. AB - BACKGROUND: Severely disfiguring facial injuries have a devastating impact on the patient's quality of life. The advent of facial allotransplantation has allowed optimal anatomical reconstruction to be achieved; however, the need for lifelong immunosuppression and unpredictable functional outcomes preclude it from routine acceptance in clinical practice. Evidence from published reports on the first four face transplant recipients indicates improved and accelerated return of sensation to the facial allograft despite suboptimal repair of the sensory nerves. METHODS: The authors performed a comparative analysis of the sensory outcomes following face transplantation with the sensory recovery achieved after conventional nerve repair, autologous face and scalp replantation, and vascularized free tissue transfer. RESULTS: Sensory recovery following face transplantation, even when the sensory nerves were not repaired, was comparable to the outcome of microsurgical repair of the peripheral branches of the trigeminal nerve and innervated free flaps. CONCLUSIONS: Nearly normal sensory recovery can be expected following facial allotransplantation with or without repair of the sensory nerves. The mechanisms responsible for this surprising outcome include preservation of normal density of the receptors within the facial allograft, regeneration from the recipient bed and allograft margins, transmission of the sensory inputs through afferent fibers contained in the facial nerve, nervi nervorum of the facial nerve, or trigeminofacial communicating rami. Furthermore, immunosuppressive therapy with tacrolimus contributes to the accelerated nerve regeneration. The minimum requirements for quantitative sensory testing and timing of the follow-up assessments are outlined to facilitate comparison of sensory outcomes after face transplantation. PMID- 21532418 TI - Discussion. Pathways of sensory recovery after face transplantation. PMID- 21532419 TI - Facial reanimation using the masseter-to-facial nerve transfer. AB - BACKGROUND: This article describes facial reanimation using the transfer of the trigeminal motor nerve branch of the masseter muscle (masseter nerve) to the facial nerve (masseter-to-facial nerve transfer). METHODS: A retrospective review was performed of 10 consecutive facial paralysis patients treated with a masseter to-facial nerve transfer for reanimation of the midface and perioral region over a 7-year period. Patients were evaluated with physical examination, direct measurement of commissure excursion, and video analysis. RESULTS: All patients regained oral competence, good resting tone, and a smile, with a vector and strength comparable to those of the normal side. Motion developed an average of 5.6 months after masseter-to-facial nerve transfer, with 40 percent of patients developing an effortless smile by postoperative month 19. CONCLUSIONS: The masseter-to-facial nerve transfer is an effective method for reanimation of the midface and perioral region in a select group of facial paralysis patients. The technique is advocated for its limited donor-site morbidity, avoidance of interposition nerve grafts, and potential for cerebral adaptation, producing a strong, potentially effortless smile. PMID- 21532420 TI - Voice reconstruction with free ileocolon flap transfer: implications for the lower respiratory tract. AB - BACKGROUND: Free ileocolon flap surgery is an effective technique for voice reconstruction in hypopharyngolaryngectomy defects. A tracheoesophageal fistula is created using an intestinal conduit characterized by secretions and a resident microbial flora. The aim of this study was to investigate the respiratory complications and modifications of the regional flora following ileocolon flap transfer. METHODS: A retrospective study was conducted on 35 patients who underwent voice reconstruction with the free ileocolon flap. The prevalence of respiratory symptoms, aspiration, and respiratory tract infections was studied and the management of respiratory complications was recorded. Ten patients were included in a cross-sectional study to evaluate the bacterial flora of the voice tube and the tracheostomy site. RESULTS: Six patients experienced aspiration of food into the trachea caused by incompetence of the ileocecal valve (n = 5) or pathologic tracheoesophageal fistula (n = 1). Four patients presented with pneumonia. In one case, pneumonia was consequent to aspiration caused by incompetence of the ileocecal valve. Radiotherapy, chemotherapy, and age older than 55 years did not influence the continence of the ileocecal valve. Mean follow-up was 34.2 months. Escherichia coli was the organism cultured most frequently. CONCLUSIONS: Reconstruction with the free ileocolon flap was shown to be a possible therapeutic option when considering the consequences on the lower respiratory tract. Aspiration was the main complication and was avoided by internal plication of the valve and by reduction of the ileocecal angle. Awareness of the nature of the bacterial flora colonizing the trachea and voice tube could be helpful in guiding the empirical antibiotic therapy in case of infection. PMID- 21532421 TI - Aesthetic restoration of parotidectomy contour deformity using the supraclavicular artery island flap. PMID- 21532422 TI - Anterolateral thigh flap-based reconstruction for oncologic vulvar defects. AB - BACKGROUND: Vulvar defects after tumor extirpation always require immediate reconstruction. Transferring a skin flap from a distant region may be required for large defects. Although the anterolateral thigh flap has gained popularity in other types of oncoplastic surgery, it has rarely been reported for vulvar reconstruction. The aims of this retrospective study were to evaluate the outcome of anterolateral thigh flap-based vulvar reconstruction and to develop an operative strategy. METHODS: Eleven patients with vulvar carcinoma underwent resection and immediate reconstruction with the anterolateral thigh flap between 2005 and 2009. Based on defect type and local soft-tissue quality, four types of anterolateral thigh flap-based reconstructions were performed: unilateral anterolateral thigh flap, ipsilateral anterolateral thigh flap combined with contralateral advancement flap or local flap, fenestrated anterolateral thigh flap, and split anterolateral thigh flap. Postoperative complications were recorded and clinical outcomes were evaluated. RESULTS: Partial flap necrosis occurred in one patient with a fenestrated anterolateral thigh flap for bilateral reconstruction. One wound dehiscence occurred in the contralateral local flap. Two patients had prolonged serous drainage. Mean follow-up was 8 months. One patient developed stricture of the urethral meatus and another had regional metastasis. CONCLUSION: With careful design, the anterolateral thigh flap may provide reliable and durable soft-tissue coverage for various vulvar defects with good outcomes and minimal donor-site morbidity. PMID- 21532423 TI - Vasculature at the medial aspect of the foot and clinical application of flaps based on it for forefoot reconstruction. AB - BACKGROUND: Detailed knowledge of the vasculature of the medial aspect of the foot has rarely been reported, but it is of tremendous importance for harvesting the flap in this area to cover defects of the foot and hand. Repair of soft tissue defects at the dorsal forefoot remains a challenge in reconstructive surgery. The authors describe the use of the distally based saphenous neurovenofasciocutaneous flap at the medial aspect of the foot to cover this region. METHODS: This study was divided into two parts: an anatomical study and clinical application. In the anatomical study, 35 cadaveric feet were injected with red gelatin, five others were made as corrosive vascular casts, and then the main vessels distributed at the medial aspect of the foot were observed. Clinically, six cases of soft-tissue defects at the dorsal forefoot were reconstructed with distally based saphenous neurovenofasciocutaneous flaps. RESULTS: The anatomical study showed that (1) the vasculature pattern could roughly be classified into three types and (2) there were constant anastomoses between the above-mentioned arteries around the midpoint of the first metatarsal bone. In terms of clinical application, all flaps completely survived, and one patient had partial loss of skin graft. CONCLUSIONS: The blood supply to the medial aspect of the foot has multiple origins, on the basis of which of several flaps can be harvested, either a pedicled or free. Of particular clinical significance is the distally based saphenous neurovenofasciocutaneous flap, which is thin, is in the immediate vicinity of the forefoot, and has a reliable retrograde blood supply. This flap should be considered as a preferential way to reconstruct soft-tissue defects of the dorsal forefoot. PMID- 21532424 TI - Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns. AB - BACKGROUND: Indocyanine green lymphography has been a highly useful modality in the clinical examination and surgical management of patients with lymphedema. No formal classification system of indocyanine green imaging findings according to the severity of lymphedema exists, however. The purpose of this study was to describe, analyze, and classify characteristic indocyanine green lymphography findings to uniformly guide surgical management of lymphedema using this modality. METHODS: Forty-five patients (78 limbs) with lower extremity lymphedema underwent indocyanine green lymphography. All lymphography images were recorded in photographs and videos. Images were reviewed and analyzed to classify characteristic findings according to clinical severity as determined by Campisi clinical lymphedema staging. RESULTS: Lymphography findings were classifiable into two patterns. Mild cases of lymphedema were characterized by a linear lymphatic channel pattern (linear pattern). In more severe cases, lymphatic channels demonstrated retrograde lymphatic flow (dermal backflow pattern) and diminution or absence of linear channel patterning. Three dermal backflow patterns, splash, stardust, and diffuse, were identified and correlated with the progression of lymphedema severity. These findings supported the generation of a novel anatomical lymphedema severity staging system, the dermal backflow staging system. CONCLUSIONS: Indocyanine green lymphography is a safe, minimally invasive, and useful tool for the surgical evaluation of extremity lymphedema. Characteristic indocyanine green lymphography patterns are consistent and correlate with clinical severity. The dermal backflow staging system can facilitate patient stratification, discussion between referring parties, and surgical planning. PMID- 21532425 TI - Lambda-shaped anastomosis with intravascular stenting method for safe and effective lymphaticovenular anastomosis. AB - BACKGROUND: Lymphaticovenular anastomosis has become an increasingly common treatment for lymphedema. Supermicrosurgical techniques are essential for the successful performance of lymphaticovenular anastomosis. A positive correlation between the number of lymphaticovenular anastomoses performed and therapeutic efficacy has been reported, and in performing these anastomoses, the establishment of as many bypasses as possible is important. METHODS: Forty limbs of 20 patients with lower extremity lymphedema who underwent lymphaticovenular anastomosis in our department were assessed. All cases were performed under local anesthesia using two to four surgical microscopes. A new method of anastomosis, lambda-shaped anastomosis assisted by intravascular stenting, was chosen in required cases. RESULTS: Lymphaticovenular anastomoses resulted in 186 anastomoses on 20 patients with lower extremity lymphedema; the average number of anastomoses per case was 9.3 (range, five to 18). The number of surgical microscopes used ranged from two to four (average, 3.3), and the duration of the operation ranged from 3 to 5 hours (average, 4.1). In the cases of lambda-shaped anastomosis (n = 11), the number of anastomoses was significantly greater than in the cases without lambda-shaped anastomosis (n = 9; 10.2 +/- 2.3 versus 8.2 +/- 1.4; p < 0.05). CONCLUSIONS: Lambda-shaped anastomosis assisted by intravascular stenting is a safe and relatively easy method that can be performed by surgeons with less than 1 year of experience in microsurgery. This in turn allows efficient lymphaticovenular anastomoses to be performed simultaneously by a team of surgeons, resulting in an increased number of bypasses. PMID- 21532426 TI - Improvement of the radial forearm flap donor defect by prelamination with human acellular dermal matrix. PMID- 21532427 TI - Distraction osteogenesis of costocartilaginous rib grafts and treatment algorithm for severely hypoplastic mandibles. AB - BACKGROUND: In craniofacial microsomia, patients with severely hypoplastic mandibles (Pruzansky type III) require replacement of the ramus and condyle unit. Autogenous costocartilaginous rib graft and distraction osteogenesis are the most important techniques used, but long-term results need to be looked at to determine optimal management. METHODS: Of the 485 patients with craniofacial microsomia and mandibular abnormality identified by the authors' craniofacial multidisciplinary clinic, 31 patients were identified with Pruzansky type III mandibles who underwent treatment and were available for study. Patients primarily had either costocartilaginous grafts or mandibular distraction after molar extraction. Outcomes assessed rib failure, undergrowth, or overgrowth. Reoperation included regrafting for graft failure, rib distraction for undergrowth, and mandibular setback for overgrowth. Details surrounding complications for each modality including osteotomy site were recorded. RESULTS: For primary mandibular reconstruction, 27 patients underwent costocartilaginous rib graft surgery (30 grafts, three bilateral) at 9.9 +/- 4.1 years; four patients underwent mandibular distraction at 7.4 +/- 2.3 years. Rib graft failure in seven of 30 cases (23 percent) required regrafting. Undergrowth in 17 cases (57 percent) required rib distraction. Overgrowth in three cases (10 percent) required correction at the time of orthognathic correction. For rib graft distraction, osteotomy site locations included native mandible (25 percent), rib mandible junction (19 percent), and rib graft (56 percent). The rib-mandible junction site had graft-related complications (100 percent) that the other sites did not. CONCLUSIONS: For the severely hypoplastic mandibles (Pruzansky type III), costocartilaginous grafts are an accepted modality. However, when rib graft growth is insufficient, secondary distraction should be performed within the native mandible or rib graft and not at the rib graft-mandible junction site. PMID- 21532428 TI - Audiologic findings in Saethre-Chotzen syndrome. AB - BACKGROUND: Hearing loss has been described in Apert syndrome but is poorly documented in other craniosynostosis disorders. METHODS: The authors retrospectively reviewed the audiologic and otologic records of patients with Saethre-Chotzen syndrome to define the incidence, type, and extent of hearing loss. Only patients with documented audiologic examinations were included. Hearing loss was categorized by American Speech-Language-Hearing Association guidelines (i.e., mild, 26 to 40 dB; moderate, 41 to 55 dB; moderate/severe, 56 to 70 dB; severe, 71 to 90 dB; and profound, >90 dB). RESULTS: Twenty-nine patients met inclusion criteria. Mean age at initial audiologic evaluation was 6.7 years (range, 0.7 to 24.5 years). Seventeen patients (59 percent) had at least one abnormal audiogram; in 15 patients, the deficit was mild. Eight patients demonstrated sensorineural hearing loss. Five cases resolved and, thus, had been mischaracterized. Six patients had conductive hearing loss on at least one examination; follow-up testing in four patients revealed normal hearing. Two patients had unspecified hearing loss by sound field method. One patient had mixed hearing loss on consecutive audiograms. Twenty-one patients (72 percent) had normal hearing on their last audiogram. CONCLUSIONS: Most patients with Saethre-Chotzen syndrome had hearing loss at some point during childhood. This was typically mild and correlated with middle ear abnormality and eustachian tube dysfunction. Usually, the hearing deficit resolved. Early mischaracterization of mixed hearing loss or conductive hearing loss as sensorineural hearing loss was common. PMID- 21532429 TI - Alloplastic augmentation of the facial skeleton: an occasional adjunct or alternative to orthognathic surgery. AB - BACKGROUND: Alloplastic implants can be adjunctive to orthognathic surgery by correcting contour irregularities or disharmonies after skeletal movements. Implant augmentation can also simulate the visual effect of osteotomies in patients with skeletal deficiencies whose occlusion is normal or has been corrected. Although sometimes it is an adjunct or an alternative to facial skeletal rearrangements, facial skeleton augmentation is not a substitute for orthognathic surgery. METHODS: Alloplastic implants designed specifically to augment the infraorbital rim can correct the residual upper midface deficiency remaining after Le Fort I maxillary advancement. When used with paranasal and malar implants, they can simulate the visual effect of the Le Fort III osteotomy with advancement. Paranasal implants can simulate the appearance after Le Fort I advancement. Mandible and extended chin implants can correct skeletal irregularities and deficiencies after sagittal and horizontal osteotomies. They can also simulate the visual effect of these osteotomies. RESULTS: The application of these concepts has been effective, with low morbidity, in 294 patients. No implants extruded or migrated. Eight patients (3 percent) had early postoperative infections. There were no late infections. Ten of 108 patients (9 percent) with midface implants had implant visibility with time. CONCLUSION: Alloplastic augmentation of the facial skeleton can be a useful adjunct or an alternative to orthognathic surgical procedures in situations when the occlusion is normal or has been corrected. PMID- 21532430 TI - Intralesional bleomycin injection treatment for vascular birthmarks: a 5-year experience at a single United Kingdom unit. AB - BACKGROUND: The authors present their experience using an established chemotherapeutic agent as a scarless treatment for vascular birthmarks. One hundred sixty-four of more than 600 patients seen in the authors' center received intralesional bleomycin injection over 5 years. METHODS: Patient demographics, clinical response, treatment, and complication details were recorded prospectively. Respiratory surveillance was provided by adult and pediatric pulmonologists. Eighty-one venous malformations, 39 hemangiomas, 26 lymphatic malformations, 10 mixed malformations, two arteriovenous malformations, two cystic hygromas, two capillary malformations, and two angiokeratomas underwent intralesional bleomycin injection. RESULTS: The authors observed that 45.7 percent of patients completed treatment in a mean of 3.8 sessions and mean duration of 107 days. Complete resolution occurred in 56.0 percent, with a 93.3 percent overall response rate, and 82.7 percent of lesions demonstrated complete response or significant improvement. Three patients developed transient skin hyperpigmentation. One patient each developed skin ulceration, blistering, infection, swelling, headache, bruising, and rash. One patient required intubation following treatment of a panfacial and thoracic lymphatic malformation. A full recovery ensued. No patients developed pulmonary fibrosis. One venous malformation recurred. CONCLUSIONS: The authors' single-site multidisciplinary team has successfully treated complex and recurrent vascular anomalies with acceptable complication and recurrence profiles. These findings represent the authors' experience and provide a reference for the management of these challenging lesions. PMID- 21532431 TI - Speech outcomes following pharyngeal flap in patients with velocardiofacial syndrome. AB - BACKGROUND: Velocardiofacial syndrome is the most common defined disorder associated with palatal insufficiency. The authors' purpose is to evaluate one surgeon's experience with correction of velopharyngeal insufficiency in velocardiofacial syndrome using a tailored pharyngeal flap. METHODS: The authors reviewed the records of all children with velocardiofacial syndrome and velopharyngeal insufficiency who were managed with a pharyngeal flap between 1983 and 2009. Data collected included age at operation, preoperative videofluoroscopic findings, speech outcomes, complications, and need for a secondary operation. RESULTS: The authors identified 33 patients with velocardiofacial syndrome and velopharyngeal insufficiency who had postoperative speech evaluations. Velopharyngeal insufficiency was diagnosed at a median age of 5 years. Palatal findings were: Veau type I (n = 4), overt submucous (n = 6), or occult submucous (n = 23). Median preoperative lateral pharyngeal wall movement was 22 percent (range, 0 to 90 percent). Successful correction of velopharyngeal insufficiency was achieved in 29 of 33 patients (88 percent). One patient had a medially displaced right internal carotid artery, and evidenced intraoperative bleeding and required a blood transfusion. One patient developed obstructive sleep apnea. CONCLUSION: A tailored pharyngeal flap is highly effective for correction of velopharyngeal insufficiency in velocardiofacial syndrome with few complications. PMID- 21532432 TI - Discussion. Speech outcomes following pharyngeal flap in patients with velocardiofacial syndrome. PMID- 21532433 TI - Discussion. Malar augmentation assessed by magnetic resonance imaging in patients after face lift and fat injection. PMID- 21532434 TI - The face lift SMAS plication flap for reconstruction of large temporofrontal defects: reconstructive surgery meets cosmetic surgery. AB - BACKGROUND: Reconstruction of large defects in the temporal region can be performed with skin grafts or pedicled or free flaps. Results are often not optimal because of the patch of a skin graft, lack of availability of local flaps, and distant skin from free flaps. A technique for reconstruction of these defects with local tissue is presented in this article that uses superficial musculoaponeurotic system (SMAS) plication to allow wide advancement of a cervicofacial flap. METHODS: Once the defect is outlined, a face-lift-like skin incision is used to raise the flap. The SMAS is plicated with two purse-string sutures that relieve tension on the flap and allow maximal advancement. Thirteen face-lift SMAS plication flaps were used in 12 patients (mean age, 70.2 years) after cancer resection, which was bilateral in one case. Defects up to 8 cm in largest diameter can be closed. In one case of an 8 * 6-cm defect, a 1 * 1.5-cm skin graft was necessary. RESULTS: All flaps healed uneventfully, and no reoperation was necessary. Scars are almost completely hidden and the cosmetic result is satisfactory. The asymmetrical face-lift effect fades out within 6 months. CONCLUSIONS: The face-lift SMAS plication (FLISP) flap allows reconstruction of large defects in the temporal region with a local flap providing an excellent cosmetic result and avoiding the need for distant tissue and multiple scarring. This flap provides an example of how reconstructive surgery and cosmetic surgery are complementary and can be mutually beneficial. PMID- 21532435 TI - Mandibular tubercle resection: a means of maximizing the benefits of reduction mandibuloplasty. AB - BACKGROUND: A square mandible is considered unattractive in Asia; as a result, mandibular reduction is the most common type of operation performed. The authors review the importance of mandibular tubercles in the lower margin of the parasymphysis area and introduce their resection techniques and results. METHODS: From April of 2005 to September of 2009, 178 patients underwent tubercle resection in the parasymphyseal area. The procedures used were as follows: mandibular angle reduction in 139, genioplasty in 39, and mandibular angle reduction with simultaneous malar reduction in 58 patients. In the chin area, horizontal osteotomy was performed in 35 patients to reduce chin length. Other patients underwent mandibular tubercle resection and burring. RESULTS: With the exception of one patient who developed hyperesthesia in the left lower lip 2 years after the procedure, all patients achieved satisfactory aesthetic results after mandibular tubercle resection and concurrent mandibular reduction. CONCLUSION: The authors consider mandibular tubercle resection, either as a single procedure or combined with mandible reduction, essential for patients who require a slimmer, more feminine lower face. PMID- 21532436 TI - Contouring of a square jaw on a short face by narrowing and sliding genioplasty combined with mandibular outer cortex ostectomy in orientals. AB - BACKGROUND: A square face is considered unattractive in Orientals; thus, it has become a frequently encountered reason for patients undergoing face contouring surgery. While reviewing the unsatisfactory cases of mandibular reduction, the authors discovered that some failed cases were related to a square jaw on a short face. The conventional procedures fix only the posterior region of the mandible, resulting in increased prominence of the stunted or square chin and short face. Thus, the authors applied a narrowing and sliding genioplasty procedure combined with a mandibular outer cortex ostectomy technique to reshape a wide, weak chin, and a square jaw on a short lower facial contour into a slender and attractive oval face. METHODS: From July of 2005 to October of 2009, there were a total of 57 patients in this study who underwent a narrowing and sliding genioplasty combined with a mandibular outer cortex ostectomy procedure to correct a square jaw on a short face. RESULTS: The postoperative appearance of all 57 cases showed that the lower face had narrowed and had become softer, slender, and oval, with a slick mental region. CONCLUSION: Narrowing and sliding genioplasty combined with a mandibular outer cortex ostectomy procedure could efficiently adjust the shape and position of the chin to obtain a good proportion of the lower face and change a square, short face to a slender, oval one in a single operation in accordance with fashionable aesthetics in Orientals. PMID- 21532437 TI - Diathermocoagulation in cutting mode and large flap dissection. AB - BACKGROUND: The aim of this study was to determine the overall complication rate associated with the use of diathermocoagulation in cutting mode for flap dissection. METHODS: Because of the high rate of complications generally associated with abdominoplasty, a large flap, abdominoplasty, or abdominal dermolipectomy model was chosen. A retrospective review was conducted regarding 647 abdominoplasty procedures, 320 of which were performed with the monopolar diathermocoagulation in the cutting mode and 327 of which were performed with a steel scalpel. The two groups were similar regarding morphologic characteristics, prescriptions, and procedures. In both cases, hemostasis was performed with punctual monopolar coagulation current. Analysis was performed regarding the frequency of major general complications (e.g., deep vein thrombosis and pulmonary embolism), major surgical complications (e.g., acute hemorrhage), and "minor" complications (e.g., postoperative secondary collections or delayed wound healing). RESULTS: In the electrosurgery group, the incidence of noninfectious collections was significantly higher, as was the production of the drains. No difference was seen in terms of reintervention for acute hematoma, postoperative infectious collections, blood loss, hospital stay, or thromboembolic complications. Operations took significantly longer with the steel scalpel. The follow-up was significantly longer in the diathermocoagulation group. CONCLUSIONS: Monopolar diathermocoagulation has already proven its place in the general work of every surgeon. Moreover, this technique remains superior in terms of the rapidity with which surgery can be performed when dissecting large areas. Nevertheless, the higher rate of surgical complications leads to a longer follow up period that, in part, runs counter to this advantage. PMID- 21532438 TI - Adherence to practice guidelines based on American Board of Plastic Surgery Maintenance of Certification data. AB - BACKGROUND: The American Board of Plastic Surgery Maintenance of Certification program includes the submission of 10 consecutive cases in one of 20 tracer modules for Performance in Practice evaluation. This has resulted in a wealth of data on the practice patterns of Board diplomates. The specific aim of this project was to examine these data to determine whether diplomates are adhering to evidence-based practice guidelines. METHODS: The authors searched the Agency for Healthcare Research and Quality National Guideline Clearinghouse for guidelines. Once the guidelines were identified, the authors compared the recommendations with data entered by Board diplomates for the tracer modules in question. It is important to note that guidelines are recommendations based on the best available evidence and that all guidelines are subject to change, pending periodic reexamination of the evidence. RESULTS: Diplomates are adhering to guidelines regarding age of cosmetic breast augmentation patients, use of prophylactic antibiotics and deep venous thrombosis prophylaxis in abdominoplasty patients, and use of carpal tunnel release in the treatment of carpal tunnel syndrome. Half the diplomates, however, are using splints following carpal tunnel release, despite recommendations to the contrary. In addition, only half the diplomates are following guidelines recommending mammography before breast augmentation. Furthermore, 90 percent of diplomates are not following recommendations against the use of deep venous thrombosis prophylaxis for patients with acute lower limb trauma. CONCLUSIONS: This study revealed that there were few guidelines with which to compare diplomate performance. Steps should be taken to increase the number of evidence-based practice guidelines for plastic surgery procedures. PMID- 21532439 TI - Avoiding litigation in breast modification. PMID- 21532442 TI - Sepsis after autologous fat grafting: role of atypical mycobacteria. PMID- 21532443 TI - Myotomy of the levator labii superioris muscle and lip repositioning: a combined approach for the correction of gummy smile. PMID- 21532445 TI - Facial plexiform neurofibromatosis remodeling technique for lower face. PMID- 21532446 TI - Comparison between fasciocutaneous and jejunum flaps in pharyngolaryngoesophageal reconstruction. PMID- 21532449 TI - Relationship between venous congestion and intraflap venous anatomy in DIEP flaps using contrast-enhanced magnetic resonance angiography. PMID- 21532450 TI - Randomized prospective study comparing reverse and direct flow island flaps in digital pulp reconstruction of the fingers. PMID- 21532452 TI - Seroma after lipoabdominoplasty: fat thickness of the abdominal wall is probably a contributory factor. PMID- 21532454 TI - Integra, negative-pressure wound therapy, triple-nerve decompression, and the reconstructive ladder in diabetic patients with ulcerations. PMID- 21532456 TI - Excising value at a marginal cost: rethinking the management of Basal cell carcinoma. PMID- 21532457 TI - The presence of "ghost" citations in an applicant pool of an integrated plastic surgery residency program. PMID- 21532461 TI - The rivers of Lethe and Mnemosyne converge: propofol and memory consolidation. PMID- 21532462 TI - Stress-induced hyperalgesia: any clinical relevance for the anesthesiologist? PMID- 21532463 TI - Propofol enhances memory formation via an interaction with the endocannabinoid system. AB - BACKGROUND: Propofol is associated with postoperative mood alterations and induces a higher incidence of dreaming compared with other general anesthetics. These effects might be mediated by propofol's inhibitory action on fatty acid amide hydrolase, the enzyme that degrades the endocannabinoid anandamide. Because propofol is also associated with a higher incidence of traumatic memories from perioperative awareness and intensive care unit treatment and the endocannabinoid system is involved in regulating memory consolidation of emotional experiences, the authors investigated whether propofol, at anesthetic doses, modulates memory consolidation via an activation of the endocannabinoid system. METHODS: Male Sprague-Dawley rats were trained on an inhibitory avoidance task in which they received an inescapable foot shock upon entering the dark compartment of the apparatus. Drugs were administered intraperitoneally immediately or 30, 90, or 180 min after training. On the retention test 48 h later, the latency to reenter the dark compartment was recorded and taken as a measure of memory retention. RESULTS: The anesthetic doses of propofol administered after training significantly increased latencies of 48-h inhibitory avoidance performance (483.4 +/- 181.3, 432.89 +/- 214.06, 300 and 350 mg/kg, respectively; mean +/- SD) compared with the corresponding vehicle group (325.33 +/- 221.22, mean +/- SD), which is indicative of stronger memory consolidation in propofol treated rats. Administration of a nonimpairing dose of the cannabinoid receptor antagonist rimonabant blocked the memory enhancement induced by propofol (123.39 +/- 133.10, mean +/- SD). Delayed administration of propofol 90 and 180 min after training or immediate posttraining administration of the benzodiazepine midazolam or the barbiturate pentobarbital did not significantly alter retention. CONCLUSIONS: These findings indicate that propofol, in contrast to other commonly used sedatives, enhances emotional memory consolidation when administered immediately after a stressful event by enhancing endocannabinoid signaling. PMID- 21532464 TI - Inspiratory oxygen fraction and postoperative complications in obese patients: a subgroup analysis of the PROXI trial. AB - BACKGROUND: Obese patients are at a high risk of postoperative complication, including surgical site infection (SSI). Our aim was to evaluate the effect of a high inspiratory oxygen fraction (80%) on SSI and pulmonary complications in obese patients undergoing laparotomy. METHODS: This study was a planned analysis of the obese patients (body mass index >= 30 kg/m2) recruited in the Danish multicenter, patient- and observer-blinded, PROXI Trial of 1,400 patients undergoing acute or elective laparotomy. Patients were randomized to receive either 80% or 30% oxygen during and for 2 h after surgery. The primary outcome was SSI within 14 days. Secondary outcomes were atelectasis, pneumonia, and respiratory failure. RESULTS: Two hundred thirteen patients had a body mass index >= 30 kg/m2. The median (5-95% range) body mass index was 34 kg/m2 (30-44) and 33 kg/m2 (30-41) in patients allocated to the 80% and 30% oxygen group. SSI occurred in 32 of 102 (31%) versus 29 of 111 (26%) patients given 80% and 30% oxygen, respectively (odds ratio, 1.29; 95% CI, 0.71-2.34; P = 0.40). In addition, the incidence of pulmonary complications was not significantly different, with atelectasis occurring in 9% versus 6%, pneumonia in 6% versus 5%, and respiratory failure in 8% versus 5% in patients given 80% and 30% oxygen, respectively. CONCLUSION: Administration of 80% oxygen, compared with 30% oxygen, did not reduce the frequency of SSI in obese patients. Moreover, no significant association was found between oxygen fraction and the risk of pulmonary complications. PMID- 21532465 TI - Farewell and thank you. PMID- 21532466 TI - Comparison between endoscopic and surgical resection of mucosal esophageal adenocarcinoma in Barrett's esophagus at two high-volume centers. AB - BACKGROUND AND OBJECTIVE: Esophagectomy has previously been the gold standard for patients with mucosal adenocarcinoma in Barrett's esophagus (Barrett's carcinoma, BC). Because of the minimal invasiveness and excellent results obtained with endoscopic resection (ER), the latter has become an accepted alternative. However, few data have so far been published comparing the 2 treatment methods. METHODS: A total of 114 patients with mucosal BC who were treated surgically or endoscopically in 2 high-volume centers were included in this study. Between 1996 and 2009, 38 patients with mucosal BC received transthoracic esophageal resection with 2-field lymphadenectomy (median 29 lymph nodes removed; all pN0) in the Department of Surgery at the University of Cologne. Seventy-six patients with BC treated with ER followed by argon-plasma-coagulation of the remaining non dysplastic Barrett's esophagus in the Department of Gastroenterology in Wiesbaden were matched according to the following criteria: age, gender, infiltration depth (pT1m1-3), differentiation grade (G1/2 vs. 3) and follow-up period. RESULTS: There were no significant differences between the 2 groups with regard to epidemiologic and tumor criteria. Complete remission (CR) was achieved in all patients in the surgery group and all but 1 patient in the ER group (98.7%; the patient died of other causes before CR was achieved). Major complications after surgery occurred in 32% of the patients, significantly more often than in the ER group (0% major complications, P < 0.001). The 90-day mortality rates were 0% in the ER group and 2.6% in the surgical group (1 of 38; P = 0.333). The median follow-up periods were 4.1 years in the ER group and 3.7 years in the surgical group. During this period, 1 patient in the ER group had a local recurrence and 4 had metachronous neoplasia (overall recurrence rate 6.6%). However, repeat endoscopic treatment was possible in all of the patients, and the long-term CR rates in the surgical and ER groups were 100% and 98.7%, respectively. No tumor related mortality was observed in either group. CONCLUSIONS: For patients with mucosal BC, both surgery and ER are effective treatment modalities. Surgery is associated with a higher morbidity rate and shows a risk for procedure-related mortality. However, the recurrence rate is higher in patients treated with ER, so that thorough follow-up procedures are mandatory. PMID- 21532467 TI - Trends in patient reported outcomes of conservative and surgical treatment of primary chronic venous disease contradict current practices. AB - OBJECTIVE: To analyze patient-reported quality of life (QOL) and symptoms in a prospective cohort of CVD patients who was managed within the framework of existing policies. STUDY DESIGN: Prospective cohort study of 150 patients with C2 C4 clinical class of primary chronic venous disease (CVD). Management consisted of initial conservative measures, following which, the patients were given a choice of continuing conservative therapy, or surgical treatment. Patients completed Specific Quality of Life and Outcome Response--Venous (SQOR-V) tool before initial visit, after completion of conservative treatment, and at 1 and 12 month follow up visits after surgical treatment. Management consisted of initial conservative measures. QOL score and symptom score (SS) part of this instrument was analyzed separately. RESULTS: Conservative treatment resulted in improvement of symptom score in 85(57%) patients, and the QOL in 111(74%) patients. Despite this improvement, the majority of patients (121) chose surgical option. At the 1 month follow up after surgical treatment 97 (80%) patients reported significant improvement of their symptoms and 114 (94%) in the QOL compare to their status after conservative therapy. The QOL improvement was due mainly to improvement in symptom score. Patients who improved after conservative therapy were more than 15 times more likely to have symptoms relief at 1 month (RR = 15.6, 95% CI 4.3 56.5), and 21 times higher at 1 year after surgery (RR = 21.3, 95% CI 4.7-96.9) compared with those who did not change the SS. CONCLUSIONS: Surgical treatment resulted in a better relief of symptoms compare to conservative therapy. The relief of symptoms after conservative therapy predicts better outcomes of surgical treatment. These findings suggest that success of conservative therapy should be considered as an indication, and the failure of conservative therapy should not be an indication to surgical treatment. PMID- 21532468 TI - How to test electronic adherence monitoring devices for use in daily life: a conceptual framework. AB - Electronic monitoring devices are increasingly used in healthcare to monitor health behaviors on a day-to-day basis. As a prerequisite to their application in clinical studies or daily practice, the performance of those electronic monitoring devices should be tested. Such testing includes a demonstration of technically correct function and of correspondence between the recorded data and the actual patient behavior, that is, objective testing of reliability and validity. Furthermore, from the patient's perspective, the operation of these devices should be easy to learn and to perform, and their use should be acceptable. These aspects of usability need to be tested from a user's subjective point of view. We propose a conceptual framework that builds on existing literature, for example, the framework on "obtrusiveness" of Hensel et al [J Am Med Inform Assoc. 2006;13(4):428-431], the assumptions regarding valid electronic monitoring of Denhaerynck et al [BMC Med Res Methodol. 2008;8:5], and empirical evidence. The framework integrates an objective and a subjective dimension. The objective dimension encompasses both reliability (accuracy and precision) and internal and external validity. The subjective dimension describes the user's perspective on usability along subdimensions of user performance, satisfaction, and acceptability. This framework can be used as a road map to test existing and future electronic monitoring devices before their widespread application in clinical studies or daily practice. PMID- 21532469 TI - Exploring the clinical information system implementation readiness activities to support nursing in hospital settings. AB - The implementation of clinical information systems can have a profound impact on nurses and their productivity. Poorly implemented systems can lead to unintended consequences that may have a negative impact on clinical processes and patient outcomes. Executives must have adequate knowledge to address nurses' concerns related to implementation. This study explored the clinical information system implementation readiness activities adopted by chief nurse executivesin hospital settings. A descriptive qualitative design was used, including interviews with six chief nurse executives, held from December 2003 through March 2004. The constant comparative method was used to analyze the interviews to extract readiness activity themes and compare these to the literature. The synthesized themes showed that the executives were knowledgeable about and engaged in several key areas, but not all, of the implementation readiness process. The majority of responses were classified into the thematic areas of champion support, staff preparation for change, training, organizational alignment, planning, and vendor support. The theme of a lack of vendor support was not identified in previous studies but was clear in the responses of the chief nurse executives interviewed. PMID- 21532470 TI - Pain management documentation: analyzing one hospital's computerized clinical records. AB - Pain management documentation, consisting of assessment, interventions, and reassessment, can help provide an important means of communication among practitioners to individualize care. Standard-setting organizations use pain management documentation as a key indicator of quality. Adoption of the electronic medical record alters the presentation of pain management documentation data for clinical and quality evaluation use. The purpose of this study was to describe pain management documentation output from the electronic medical record to gain an understanding of its presentation and evaluate the quantity and quality of the output. After institutional review board approval, data were abstracted from 51 electronic records of postsurgical patients in a 100 bed community hospital. Time-variant pain assessments, interventions, and reassessments were organized into pain management episodes to provide clinically interpretable data for evaluation. Data sources were identified. Data generated 1499 episodes for analysis. Analysis of variance results implied that pain management documentation changes with pain severity. Despite legibility and date and time stamping, inconsistencies and omitted and duplicated documentation were identified. Inconsistent data origination posed difficulty for interpreting clinically relevant associations. Improvements are required to streamline fields and consolidate entries to allow for output in alignment with care. PMID- 21532471 TI - Dynamic and volumetric variables of fluid responsiveness fail during immediate postresuscitation period. AB - OBJECTIVE: Fluid therapy after resuscitation from cardiac arrest is challenging since both hypovolemia and fluid overload may cause circulatory failure. Therefore, prediction of fluid responsiveness is a major issue in optimizing hemodynamic therapy. The aim of the present study was to evaluate the performance of stroke volume variation, pulse pressure variation, variation of Doppler derived velocity time integral, and global end-diastolic volume index to predict fluid responsiveness in the postcardiac arrest period. DESIGN: Prospective animal study. SETTING: University-affiliated research laboratory. SUBJECTS: Twenty anesthetized and ventilated Goettinger minipigs. INTERVENTION: Animals were equipped with a central venous catheter, a thermistor-tipped arterial catheter, and a transesophageal echo probe. Electrically induced cardiac arrest of 8 mins was followed by cardiopulmonary resuscitation. Hemodynamic measurements were performed before and after a two-step fluid bolus at baseline and both 1 and 4 hrs after return of spontaneous circulation. Fluid responsiveness was defined by an increase in stroke volume of at least 15%. Performance of variables was analyzed using receiver operator characteristics analysis. MEASUREMENT AND MAIN RESULTS: Variables reliably indicated fluid responsiveness at baseline. Fifteen animals were successfully resuscitated. Left ventricular ejection fraction was significantly reduced 1 hr after return of spontaneous circulation (52.6% +/- 6.4%; p < .01) compared with baseline (69.9% +/- 5.3%). One hour after return of spontaneous circulation, fluid responsiveness could not be predicted by any variable. In contrast, pulse pressure variation, variation of the velocity time integral, and global end-diastolic volume index, but not stroke volume variation, were able to predict fluid responsiveness 4 hrs after return of spontaneous circulation, since area under the curve was 0.85 (p < .01), 0.94 (p < .01), 0.77 (p = .02), and 0.68 (p = .12), respectively. CONCLUSIONS: Prediction of fluid responsiveness failed 1 hr after successful cardiopulmonary resuscitation from cardiac arrest. Four hours after return of spontaneous circulation, however, the variables pulse pressure variation, variation of the velocity time integral, and global end-diastolic volume index, but not stroke volume variation, enabled prediction of fluid responsiveness and may, therefore, be considered for subsequent hemodynamic optimization after successful cardiopulmonary resuscitation. PMID- 21532472 TI - Computerized decision support system improves fluid resuscitation following severe burns: an original study. AB - OBJECTIVE: Several formulas have been developed to guide resuscitation in severely burned patients during the initial 48 hrs after injury. These approaches require manual titration of fluid that may result in human error during this process and lead to suboptimal outcomes. The goal of this study was to analyze the efficacy of a computerized open-loop decision support system for burn resuscitation compared to historical controls. DESIGN: Fluid infusion rates and urinary output from 39 severely burned patients with >20% total body surface area burns were recorded upon admission (Model group). A fluid-response model based on these data was developed and incorporated into a computerized open-loop algorithm and computer decision support system. The computer decision support system was used to resuscitate 32 subsequent patients with severe burns (computer decision support system group) and compared with the Model group. SETTING: Burn intensive care unit of a metropolitan Level 1 Trauma center. PATIENTS: Acute burn patients with >20% total body surface area requiring active fluid resuscitation during the initial 24 to 48 hours after burn. MEASUREMENTS AND MAIN RESULTS: We found no significant difference between the Model and computer decision support system groups in age, total body surface area, or injury mechanism. Total crystalloid volume during the first 48 hrs post burn, total crystalloid intensive care unit volume, and initial 24-hr crystalloid intensive care unit volume were all lower in the computer decision support system group. Infused volume per kilogram body weight (mL/kg) and per percentage burn (mL/kg/total body surface area) were also lower for the computer decision support system group. The number of patients who met hourly urinary output goals was higher in the computer decision support system group. CONCLUSIONS: Implementation of a computer decision support system for burn resuscitation in the intensive care unit resulted in improved fluid management of severely burned patients. All measures of crystalloid fluid volume were reduced while patients were maintained within urinary output targets a higher percentage of the time. The addition of computer decision support system technology improved patient care. PMID- 21532474 TI - Necrotizing soft-tissue infections. AB - OBJECTIVE: To provide a contemporary review of the diagnosis and management of necrotizing soft-tissue infections. DATA SOURCES: Scientific literature and internet sources. STUDY SELECTION: Major articles of importance in this area. CONCLUSIONS: The mortality for necrotizing soft-tissue infections appears to be decreasing, possibly due to improved recognition and earlier delivery of more effective therapy. Establishing a diagnosis and initiating treatment as soon as possible provides the best opportunity for a good outcome. PMID- 21532473 TI - The value of positive end-expiratory pressure and Fio2 criteria in the definition of the acute respiratory distress syndrome. AB - OBJECTIVES: The criteria that define acute lung injury and the acute respiratory distress syndrome include PaO2/Fio2 but not positive end-expiratory pressure or Fio2. PaO2/Fio2 ratios of some patients increase substantially after mechanical ventilation with positive end-expiratory pressure of 5-10 cm H2O, and the mortality of these patients may be lower than those whose PaO2/Fio2ratios remain <200. Also, PaO2/Fio2 may increase when Fio2 is raised from moderate to high levels, suggesting that patients with similar PaO2/Fio2 ratios but different Fio2 levels have different risks of mortality. The primary purpose of this study was to assess the value of adding baseline positive end-expiratory pressure and Fio2 to PaO2/Fio2 for predicting mortality of acute lung injury/acute respiratory distress syndrome patients enrolled in Acute Respiratory Distress Syndrome Network clinical trials. We also assessed effects of two study interventions on clinical outcomes in subsets of patients with mild and severe hypoxemia as defined by PaO2/Fio2. DESIGN: Analysis of baseline physiologic data and outcomes of patients previously enrolled in clinical trials conducted by the National Institutes of Health Acute Respiratory Distress Syndrome Network. SETTING: Intensive care units of 40 hospitals in North America. PATIENTS: Two thousand three hundred and twelve patients with acute lung injury/acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Only 1.3% of patients enrolled in Acute Respiratory Distress Syndrome Network trials had baseline positive end-expiratory pressure < 5 cm H2O, and 50% had baseline positive end-expiratory pressure >=10 cm H2O. Baseline PaO2/Fio2 predicted mortality, but after controlling for PaO2/Fio2, baseline positive end-expiratory pressure did not predict mortality. In contrast, after controlling for baseline PaO2/Fio2, baseline Fio2 did predict mortality. Effects of two study interventions (lower tidal volumes and fluid-conservative hemodynamic management) were similar in mild and severe hypoxemia subsets as defined by PaO2/Fio2 ratios. CONCLUSION: At Acute Respiratory Distress Syndrome Network hospitals, the addition of baseline positive end-expiratory pressure would not have increased the value of PaO2/Fio2 for predicting mortality of acute lung injury/acute respiratory distress syndrome patients. In contrast, the addition of baseline Fio2 to PaO2/Fio2 could be used to identify subsets of patients with low or high mortality. PMID- 21532475 TI - Does linezolid modulate lung innate immunity in a murine model of methicillin resistant Staphylococcus aureus pneumonia? AB - OBJECTIVES: Methicillin-resistant Staphylococcus aureus is an important cause of mortality among nosocomial infections. Recent investigations suggest that linezolid is superior to vancomycin in achieving clinical cure in patients with nosocomial pneumonia. We hypothesized that linezolid may exhibit anti inflammatory properties in vivo model of pneumonia. DESIGN: Prospective interventional study. SETTING: University affiliated laboratory. SUBJECTS: BALB/c mice. INTERVENTIONS: Three groups of BALB/c mice were inoculated with methicillin resistant S. aureus American Type Culture Collection 33,591 to induce pneumonia. Each group (n = 6) underwent bronchoalveolar lavage at 24 hrs, 48 hrs, and 72 hrs after inoculation after treatment with vancomycin, linezolid, or no antibiotic. Bronchoalveolar lavage fluid levels of monocyte chemotactic protein-5 and interleukin-6 were quantified using cytometric bead array. Metalloproteinase-9 was detected by enzyme-linked immunosorbent assay and gelatin zymography. Neutrophil apoptosis in bronchoalveolar lavage was assessed by annexin V and 7 aminoactinomycin D staining. Neutrophil activity was determined by myeloperoxidase enzyme activity. Phagocytosis of apoptotic neutrophils by linezolid- vs. vancomycin treated-alveolar macrophages was examined in vitro. MEASUREMENTS AND MAIN RESULTS: Infected mice had a significant reduction in lung bacterial titers compared with controls (p < .05) after treatment with linezolid or vancomycin. There was no difference in bronchoalveolar lavage levels of monocyte chemotactic protein-5 or interleukin-6 between vancomycin- and linezolid treated groups. Both antimicrobials were comparable in modulating the expression of matrix metalloproteinase-9 in bronchoalveolar lavage. Neutrophil apoptosis was comparable in both vancomycin- and linezolid-treated groups at all three time points. Vancomycin showed lower myeloperoxidase activity compared with linezolid in the first 24 hrs after inoculation (p = .03), but the difference was undetectable at 48 hrs and 72 hrs. Neither compound had an impact on the process of removal of apoptotic neutrophils by alveolar macrophages. CONCLUSIONS: Linezolid did not display an advantage over vancomycin in modulating pulmonary innate immune response in a murine model of methicillin-resistant S. aureus pneumonia. PMID- 21532476 TI - Red cell distribution width and all-cause mortality in critically ill patients. AB - OBJECTIVE: Red cell distribution width is a predictor of mortality in the general population. The prevalence of increased red cell distribution width and its significance in the intensive care unit are unknown. The objective of this study was to investigate the association between red cell distribution width at the initiation of critical care and all cause mortality. DESIGN: Multicenter observational study. SETTING: Two tertiary academic hospitals in Boston, MA. PATIENTS: A total of 51,413 patients, aged >= 18 yrs, who received critical care between 1997 and 2007. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The exposure of interest was red cell distribution width as a predictor of mortality in the general population. The prevalence of increased red cell distribution width and its significance in the intensive care unit are unknown and categorized a priori in quintiles as <= 13.3%, 13.3% to 14.0%, 14.0% to 14.7%, 14.7% to 15.8%, and >15.8%. Logistic regression examined death by days 30, 90, and 365 postcritical care initiation, inhospital mortality, and bloodstream infection. Adjusted odds ratios were estimated by multivariable logistic regression models. Adjustment included age, sex, race, Deyo-Charlson index, coronary artery bypass grafting, myocardial infarction, congestive heart failure, hematocrit, white blood cell count, mean corpuscular volume, blood urea nitrogen, red blood cell transfusion, sepsis, and creatinine. Red cell distribution width was a particularly strong predictor of all-cause mortality 30 days after critical care initiation with a significant risk gradient across red cell distribution width quintiles after multivariable adjustment: red cell distribution width 13.3% to 14.0% (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.08-1.30; p <.001); red cell distribution width 14.0% to 14.7% (OR, 1.28; 95% CI, 1.16-1.42; p <.001); red cell distribution width 14.7% to 15.8% (OR, 1.69; 95% CI, 1.52-1.86; p <.001); red cell distribution width >15.8% (OR, 2.61; 95% CI, 2.37-2.86; p <.001), all relative to patients with red cell distribution width <= 13.3%. Similar significant robust associations postmultivariable adjustments are seen with death by days 90 and 365 postcritical care initiation as well as inhospital mortality. In a subanalysis of patients with blood cultures drawn (n = 18,525), red cell distribution width at critical care initiation was associated with the risk of bloodstream infection and remained significant after multivariable adjustment. The adjusted risk of bloodstream infection was 1.40- and 1.44-fold higher in patients with red cell distribution width values in the 14.7% to 15.8% and >15.8% quintiles, respectively, compared with those with red cell distribution width <= 13.3%. Estimating the receiver operating characteristic area under the curve shows that red cell distribution width has moderate discriminative power for 30-day mortality (area under the curve = 0.67). CONCLUSION: Red cell distribution width is a robust predictor of the risk of all cause patient mortality and bloodstream infection in the critically ill. Red cell distribution width is commonly measured, inexpensive, and widely available and may reflect overall inflammation, oxidative stress, or arterial underfilling in the critically ill. PMID- 21532478 TI - Health-related quality of life in Australian survivors of critical illness. AB - OBJECTIVE: To document health-related quality of life of an Australian sample of intensive care unit survivors 6 months after intensive care unit discharge and compare this with preadmission health-related quality of life, health-related quality of life of national population norms, and international samples of intensive care unit survivors. DESIGN: Prospective observational single-center study. SETTING: Eighteen-bed medical-surgical tertiary intensive care unit of an Australian metropolitan hospital. PATIENTS: Of the 122 eligible patients, 100 were recruited (intensive care unit length of stay >48 hrs, age >18 yrs, not imminently at risk of death) and the final sample comprised 67 patients, age (median [interquartile range], 61 yrs [49-73 yrs]), 60% male admitted to the intensive care unit for a median [interquartile range] 101 hrs (68-149 hrs). Normative age- and sex-matched Australian Short-Form 36 data from the Australian Bureau of Statistics, selected international cohorts of intensive care unit survivors, and their respective national age-matched normative data were included for comparison. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-seven participants provided responses to questions rating health-related quality of life (Australian Short-Form 36) at preadmission (on admission to the intensive care unit or through retrospective recall as soon as able) and 6 months after intensive care unit discharge. Ten additional participants were unable to provide study data without proxy input and were excluded from analysis. Participants reported clinically meaningful improvements in bodily pain (p = .001), social functioning (p = .03), role-emotional domains of the Short-Form 36 (p = .04), and mental component summary score (p = .01) at 6 months after intensive care unit discharge, mostly attributable to the patients undergoing cardiac surgery, whereas remaining Short-Form 36 domains showed no difference between preadmission and 6 months (p > .05). Participants reported clinically meaningful decrements in preadmission Short-Form 36 data compared with the Australian normative population with role-physical (p < .001) and physical functioning (p < .001) most affected at follow-up. Health-related quality of life in this sample was comparable with international samples of intensive care unit survivors. CONCLUSIONS: Although the majority of health-related quality of life domains did not differ between preadmission and 6-month follow-up, participants reported significant and clinically meaningful improvements in pain and mental health at follow-up. Critical illness survivors' health-related quality of life remained within 1 sd of Australian norms at follow-up and physical function health-related quality of life was most affected. Health-related quality of life in these Australian survivors of the intensive care unit was comparable with international survivors 6 months after intensive care unit admission. PMID- 21532479 TI - High medicine prices and poor affordability. AB - PURPOSE OF REVIEW: In developing countries, most people who need medicines have to pay for them out of their own pockets. This review focuses on publications to explore the affordability gap of medicines and ways to close it. RECENT FINDINGS: Cardiovascular medicines were unaffordable in low-income to middle-income countries, whereas dementia medicines were only affordable in regions of wealth. In urban Mozambique, local mark-ups are up to two-thirds of final price in private pharmacies, whereas some governments consistently paid higher prices above the international reference prices to procure a number of medicines. Generics competition from India made an originator brand manufacturer of a AIDS drug willing to supply the drug at a cheaper rate to poorer countries, whereas a Brazilian national program to produce nonprofit generics against protected patent of originator brand products to provide free AIDS drugs had cut the number of people dying by half and hospitalization by 80%, which saved about half a billion US dollars, making the program almost fund itself. SUMMARY: Although lowering the manufacturer's price has a greater effect on the cost, policies to eliminate duties and taxes on medicines and regulate mark-ups are practical strategies to avoid excessive add-on costs. PMID- 21532477 TI - Brainstem responses can predict death and delirium in sedated patients in intensive care unit. AB - OBJECTIVES: In critically ill patients, the assessment of neurologic function can be difficult because of the use of sedative agents. It is not known whether neurologic signs observed under sedation can predict short-term outcomes. The objective of this study was to assess whether abnormal brainstem responses within the first 24 hrs of sedation are associated with mortality and altered mental status postsedation. DESIGN: Observational prospective study including an initial single-center and a subsequent multicenter study to develop and then validate the prognostic models. SETTING: Three mixed and two medical intensive care units. PATIENTS: Mechanically ventilated intensive care unit patients sedated with midazolam (+/- sufentanyl). INTERVENTIONS: Neurologic examination including the Glasgow Coma Scale, the Assessment to Intensive Care Environment score, cranial nerve examination, response to noxious stimuli, and the cough reflex was performed. MEASUREMENTS AND MAIN RESULTS: Seventy-two patients were included in the initial group and 72 in a subsequent validation study. Neurologic responses were independent of sedative dose. Twenty-two patients in the development cohort and 21 (29%) in the validation group died within 28 days of inclusion. Adjusted for Simplified Acute Physiology Score II score, absent cough reflex was independently associated with 28-day mortality in the development (adjusted odds ratio [OR], 7.80; 95% confidence interval [CI], 2.00-30.4; p = .003) and validation groups (adjusted OR, 5.44; 95% CI, 1.35-22.0; p = .017). Absent oculocephalic response, adjusted for Simplified Acute Physiology Score II score, was independently associated with altered mental status after the withdrawal of sedation in the development (adjusted OR, 4.54; 95% CI, 1.34-15.4; p = .015) and validation groups (adjusted OR, 6.10; 95% CI, 1.18-25.5; p = .012). CONCLUSIONS: Assessment of brainstem responses is feasible in sedated critically ill patients and loss of selected responses is predictive of mortality and altered mental status. PMID- 21532480 TI - Ethnic factors in managing black and minority ethnic patients. AB - PURPOSE OF REVIEW: To understand pathways into healthcare people of minority ethnic groups use and if these differ from those of the majority. RECENT FINDINGS: The current literature shows that some forms of treatment are seen as less stigmatizing and more acceptable. The treatment expectations also dictate choice of healthcare providers. SUMMARY: Black and ethnic minority patients may have different explanatory models, which will influence the way they seek help and the sources of help available to them. There are also clear ethnic variations in prevalence of different psychiatric disorders and thus in accessing mental healthcare services. Engaging patients into therapeutic adherence is crucial in the context of their expectations and explanatory models. PMID- 21532481 TI - Age of onset and timing of treatment for mental and substance use disorders: implications for preventive intervention strategies and models of care. AB - PURPOSE OF REVIEW: To provide an update of the recent studies on the age of onset of the major mental illnesses, with a special focus on the prospects for prevention and early intervention. RECENT FINDINGS: The studies reviewed here confirm previous reports on the age of onset of the major mental disorders. While the behaviour disorders, and certain anxiety disorders, emerge during childhood, most of the high prevalence disorders (anxiety, mood and substance use) emerge during adolescence and early adulthood, as do the psychotic disorders. Early age of onset has been shown to be associated with a longer duration of untreated illness and poorer clinical and functional outcomes. SUMMARY: Although the onset of most mental disorders usually occurs during the first three decades of life, effective treatment is typically not initiated until a number of years later. Although there is increasing evidence to suggest that intervention during the early stages of a disorder may help reduce the severity and/or the persistence of the initial or primary disorder and prevent secondary disorders, additional research is needed into appropriate treatment for early stage cases as well as the long-term effects of early intervention, and to appropriate service design for those in the early stages of a mental illness. This will mean not only the strengthening and re-engineering of existing systems but also, crucially, the construction of new streams of care for young people in transition to adulthood. PMID- 21532482 TI - Ill-health and intellectual disabilities. AB - PURPOSE OF REVIEW: Adults with intellectual disabilities are recognized globally as a group of individuals with poorer access to appropriate healthcare and have worse health outcomes than the general population, including significantly reduced life expectancy. This article reviews the evidence base published over the past 12-24 months, highlighting how public health policy is influencing the literature on the health needs of people with intellectual disabilities. RECENT FINDINGS: Recent studies looking at information from death certificates found people with intellectual disabilities died 15 years younger than people without intellectual disabilities. Using standardized mortality rates, the overall mortality for people with intellectual disabilities is three times higher than for the general population. People with intellectual disabilities have higher rates of asthma and oral disease, but similar rates of hypertension. There is limited high-quality evidence on drugs used to treat epilepsy in this population, despite epilepsy being one of the leading causes of premature deaths. SUMMARY: Recent evidence continues to show that people with intellectual disabilities have poorer health outcomes than the general population. However, the quality of evidence available on the wider health needs remains limited, but, with the move to a public health approach through health surveillance, this may increase the quality of evidence available, so influencing health outcomes for people with intellectual disabilities. PMID- 21532483 TI - Infection and rheumatoid arthritis: still an open question. AB - PURPOSE OF REVIEW: This review focuses on recent research that explores the role of infectious organisms in the development of autoimmunity and rheumatoid arthritis (RA). RECENT FINDINGS: Human and animal studies provide further evidence supporting a role for the periodontal pathogen, Porphyromonas gingivalis, in the development of RA. The microbiome plays a key role in the developing immune system. Alterations in the bowel microbiome lead to altered innate and adaptive immune responses potentially relevant to the development or persistence of RA. SUMMARY: Microbes and the host response to microbes are important factors in the maintenance of health. Abnormalities or imbalances in these responses can lead to the development of autoimmune inflammatory conditions such as RA. PMID- 21532484 TI - Infections in the lupus patient: perspectives on prevention. AB - PURPOSE OF REVIEW: Infections are one of the most common causes of morbidity, hospitalization and death in patients with systemic lupus erythematosus (SLE). The aim of the review is to describe an approach to screening and prevention of infections in patients with SLE based on recent evidence. RECENT FINDINGS: This review summarizes what is known about the incidence and risk factors for infection in SLE as well as the limitations of the current literature. An approach to screening for infections such as tuberculosis and viral hepatitis is described as well as use of prophylactic agents and vaccinations. SUMMARY: We recommend screening for infectious comorbidities such as tuberculosis and viral hepatitis at the first clinical encounter in patients with lupus in addition to recommending pneumococcal vaccination and yearly influenza vaccination. There is currently limited evidence to support antibiotic prophylaxis for SLE patients on immunosuppressive agents to prevent penumocystis or to support screening for cytomegalovirus and further study is required. Lastly, timely antibiotic treatment in patients with lupus who are hospitalized with infectious complications is important, as delayed antibiotic treatment may be associated with increased mortality. PMID- 21532485 TI - Effects of inflammation on bone: an update. AB - PURPOSE OF REVIEW: To present an updated summary of the relationship between inflammation and localized and generalized bone loss in the rheumatic diseases. RECENT FINDINGS: In addition to the well established role of inflammatory cytokines in promoting enhanced osteoclast function and bone loss, recent work has discovered the cytokine milieu may also inhibit osteoblast function and bone repair. The WNT and bone morphogenetic protein pathways provide molecular links between inflammation and altered bone homeostasis in chronic inflammatory states. These pathways and others have been the targets of emerging therapies for the management of inflammatory bone loss. SUMMARY: Inflammation and bone loss are linked through a number of molecular pathways. Both of these processes need to be addressed when designing an effective treatment strategy for the rheumatic diseases. PMID- 21532486 TI - Obesity, bariatric surgery, and bone. AB - PURPOSE OF REVIEW: A greater number of morbidly obese individuals are undergoing bariatric surgery, expanding the postbariatric surgery population. Both obesity and bariatric surgery are accompanied by a variety of vitamin and mineral deficiencies, with some affecting bone health. Currently, there is no consensus regarding bone health evaluation and its management in obese and postbariatric population. RECENT FINDINGS: This review will focus on nutritional deficiencies in obese and postbariatric surgical patients, with a special focus on bone health. The latest findings on the complicated relationship between adipose tissue and bone will be discussed. And the presumed protective effect of obesity on osteoporosis will be evaluated. SUMMARY: Nutritional deficiencies in postbariatric patients already exist prior to the surgery. Therefore, a comprehensive nutritional evaluation prior to bariatric surgery is imperative, to prevent further decline of the already deficient nutrients. Nutrients such as calcium and vitamin D have an effect on bone health. Therefore, monitoring their level is important in preventing bone loss. Taking a multivitamin with minerals postbariatric surgery is a standard of practice. PMID- 21532487 TI - Detection of a frequent duplicated CYP21A2 gene carrying a Q318X mutation in a general population with quantitative PCR methods. AB - Earlier we had reported a large prevalence of the Q318X mutation in the CYP21A2 gene with 35.3% in Tunisian patients with a classical form of 21-hydroxylase deficiency, in contrast with 0.5% to 13.8% as described in other populations. Here we present the analysis of the Q318X mutation in a healthy Tunisian population. We screened 136 individuals by the polymerase chain reaction (PCR)/random fragment length polymorphism method, which was confirmed by direct sequencing. Surprisingly, 17 Q318X carriers were identified, for a carrier frequency of 12.5% (95% confidence interval: 7.86-19.20). To explain this unexpectedly high rate we suggest that the haplotype with Q318X mutation and duplicated CYP21A2 gene could be very frequent in the Tunisian population. To test our hypothesis, we used 2 different quantitative PCR methods, that is, multiplex ligation-dependent probe amplification and real-time PCR. The molecular studies showed the presence of a duplicated CYP21A2 gene in all 17 heterozygous Q318X mutation carriers. In addition, both quantitative PCR methods used in this study represent a sensitive and useful approach to detecting copy number variations of the CYP21A2 gene. We have identified a very high frequency of carriers with duplicated CYP21A2 gene haplotype in a healthy Tunisian population. This finding complicates the molecular diagnosis of 21-hydroxylase deficiency and we recommend that, whenever a Q318X is identified, the structure of the CYP21A2 region should be determined to discriminate between the severe Q318X mutation and the normal Q318X variant. PMID- 21532488 TI - Quantification of heteroplasmic mitochondrial DNA mutations for DNA samples in the low picogram range by nested real-time ARMS-qPCR. AB - In many mitochondrial diseases, different clinical manifestations are related to tissue-specific distribution of mutated mitochondrial DNA (mtDNA). In this study, we describe an assay for the determination of mutated mtDNA copy number in small clinical samples, using standard polymerase chain reaction (PCR) followed by SYBR Green real-time allelic-specific PCR [amplification refractory mutation system quantitative PCR (ARMS-qPCR)]. To assess the degree of heteroplasmy in a patient harboring 2 cosegregating mtDNA mutations (4415A>G and 9922A>C) starting from picogram amounts of DNA, we first amplified the mutated target sequence by standard PCR, and then analyzed it by real-time ARMS-qPCR. To validate this method, we analyzed by real-time ARMS-qPCR the PCR amplification products derived from different mixtures containing known proportions of mutant and wild-type cloned mtDNA fragments. The correlation coefficient of 0.994 between expected and observed values for the percentage of mutant A4415G confirms that the relative proportion of mutated and wild-type mtDNA was maintained after the first PCR amplification. This method allows the precise quantification of heteroplasmic mutations in DNA samples extracted from hairs, urine, small stomach biopsies, and, more importantly, single-muscle fiber, with a limit of detection close to 0.5%. This nested real-time ARMS-PCR represents a rapid, efficient, and less expensive method for the detection and quantification of heteroplasmic mutant mtDNA, even in very small clinical samples. PMID- 21532489 TI - MxA RNA quantification in febrile patients who underwent hematopoietic cell transplantation for primary immunodeficiency. AB - The presence of myxovirus resistance protein A (MxA) RNA was studied in 55 febrile children with primary immunodeficiency, 27 of whom underwent hematopoietic cell transplantation, and in 28 age-matched controls. The level of MxA RNA was above the cutoff, established as the 95th percentile found in controls, with primary immunodeficiency either undergoing transplantation or not in febrile patients, and with a documented diagnosis of infection by adenovirus, cytomegalovirus, Epstein-Barr virus, respiratory syncytial virus, and rotavirus. The presence of rare viral infections, unrecognized among those that more frequently occur in patients with primary immunodeficiency and in patients undergoing transplantation, may explain the high MxA RNA levels observed in some patients with fever but undetectable genomes or antibodies for the more common viruses. The level of MxA in febrile patients with acute graft versus host disease was below the cutoff, with a median level comparable with that observed in patients with primary immunodeficiency, who did not undergo transplantation and were without fever and infections, but significantly lower compared with controls. The level of MxA was well correlated with viral infections in follow-up samples. These data indicate that the measurement of MxA RNA is simple and useful to detect viral infections and in distinguishing them from acute graft versus host disease after allogeneic cell transplantation. PMID- 21532490 TI - Silver-enhanced in situ hybridization for detection of polyomavirus DNA in patients with BK virus nephropathy. AB - BK virus nephropathy is not an infrequent complication of renal transplantation associated with high rates of graft loss. Although antibodies against SV40 antigen detect different viruses of the polyomavirus family, immunohistochemistry is widely used to confirm the diagnosis of BK virus nephropathy in renal biopsies. Here we aimed to validate the novel silver-enhanced in situ hybridization (SISH) technique for the automated detection of BK virus in renal transplant biopsies. Two different patient cohorts were included. Twenty-nine consecutive patients suspicious for BK virus infection were investigated by SISH and chromogenic in situ hybridization. An additional 26 renal biopsies positive by SV40 immunohistochemistry from 19 patients were analyzed by SISH. Polyomavirus DNA serum levels, as determined by nested PCR analysis, were available for all of these patients. The presence of BK virus DNA in renal tubular cells was identified in 5 of the suspicious cases by both, SISH and chromogenic in situ hybridization . One additional patient was only positive in the SISH. In the second cohort, SISH was positive in all SV40 positive biopsies, but SISH signals were less extensive than SV40 immunohistochemistry. Our results show that the BK virus SISH is an ancillary tool for the detection of polyomavirus DNA in renal biopsies using bright-field microscopy. However, its diagnostic value in comparison with standard immunohistochemistry seems to be limited. PMID- 21532491 TI - Impact of HPV assay on observed population prevalence. AB - Type-specific surveillance of human papillomavirus (HPV) has been proposed as an early indicator of vaccine impact. Longitudinal comparison of HPV typing results requires stable assays with high type-specific reproducibility. Assays are evolving and the impact of even minor changes in the assay format may be difficult to anticipate. We initiated a population-based study of HPV with the prototype line blot (PLB) assay. These reagents were replaced by the research use only Linear Array (LA) HPV Genotyping kit. The assays are similar in principle and earlier comparisons found increased sensitivity and detection of more types per sample with LA; however, in samples from women with cervical abnormalities, the overall concordance was good. Slight changes in sensitivity may be more significant in samples from a general population with lower viral loads in the samples. Residual extracts from 3001 self-collected vaginal swabs from women in the general US population originally tested with PLB were retested with LA. With LA, all the samples were hybridized. PLB hybridization was restricted to samples with probable amplicon in gel electrophoresis. For HPV detection, the agreement between the 2 assays was 78.6% (kappa=0.55) with a positive concordance of 52.8%. However, this masks the observation that repeat testing with LA led to the detection of HPV in nearly twice as many samples. Agreement improves if comparison was restricted to the samples hybridized. These results emphasize that assay comparisons should consider the clinical-epidemiologic context of sample collection. Studies designed to examine temporal trends in type-specific prevalence should archive residual material to permit retesting if assays change. PMID- 21532492 TI - Clinicopathologic characteristics of patients with stage III/IV (M(0)) advanced gastric cancer, according to HER2 status assessed by immunohistochemistry and fluorescence in situ hybridization. AB - Despite recent advances in chemotherapy, the prognosis for patients with advanced gastric cancer (GC) or gastroesophageal junction cancer remains poor. Human epidermal growth factor receptor 2 (HER2) is a novel target for biologic therapy in metastatic GC. We analyzed the association between HER2 overexpression and the clinicopathologic characteristics of advanced GC. Formalin-fixed, paraffin embedded tumor samples were collected from patients with stage III or to IV (M(0)) GC who subsequently underwent curative surgery followed by adjuvant chemotherapy with 5-fluorouracil and cisplatin. All the samples were analyzed for HER2 status by immunohistochemistry (IHC) and fluorescence in situ hybridization. Of 142 samples analyzed, 7.1% scored IHC 2+ and 8.6% scored IHC 3+, whereas 9.3% were HER2-amplified. Of HER2-amplified cases, 76.9% (10/13) scored IHC 3+, showing the correlation between HER2 amplification and overexpression (P=0.01). HER2 IHC 3+ cases were more common in the intestinal-type tumors compared with diffuse-type tumors (16.7% vs. 5.1%, respectively; P=0.049), and a nonsignificant trend was observed using fluorescence in situ hybridization (14.3% vs. 9.2%, respectively; P=0.399). HER2 gene amplification was more frequent in stage IV (M(0)) than stage III disease (15.4% vs. 4.0%, respectively; P=0.037). Interestingly, HER2-amplified disease was more common than nonamplified disease in patients with nodal stage 3 tumors (76.9% vs. 38.6%, respectively; P=0.009); a similar pattern was observed using IHC. HER2 overexpression correlated with nodal stage, and a lymph node ratio greater than 0.5 was more common in HER2-amplified tumors than HER2-nonamplified tumors (69.2% vs. 43.3%, respectively; P=0.086). These findings suggest that further investigations of adjuvant therapy with HER2 targeted therapy for advanced GC are warranted. PMID- 21532493 TI - Interlaboratory comparison of K-ras testing by real-time PCR and RFLP in colorectal cancer samples. AB - Activating mutations of K-ras have been described in approximately 40% of patients with colorectal cancer, and are associated with resistance to epidermal growth factor receptor-targeted antibodies, such as cetuximab and panitumumab. Cost-effective and easy methods to determine K-ras mutations are urgently needed. Samples from 31 patients were tested. In laboratory 1, a real-time polymerase chain reaction (PCR)-based technique was used. All samples (n=31) were additionally tested using a restriction fragment length polymorphism (RFLP) analysis in laboratory 2. All results were confirmed by direct sequencing. In the first run, a concordance of real-time PCR and RFLP was observed in 77.4% (24 of 31) of samples. After resampling and reevaluation, a concordance of 93.5% (30 of 31) could be achieved. One of 7 (6.5%) initial discordant cases showed a mutation using real-time PCR and no mutation using RFLP, but the mutation was confirmed by direct sequencing. Real-time PCR and RFLP can be considered as valid K-ras mutation detection techniques. However, in patient probes with lower amounts of tumor cells and wild-type K-ras, reanalysis of further tumor tissue is recommended. PMID- 21532494 TI - Rapid and sensitive detection of KRAS mutation after fast-COLD-PCR enrichment and high-resolution melting analysis. AB - KRAS mutations exhibit significant predictive and prognostic value in cancer. Efficient, sensitive, and accurate molecular approaches are required to evaluate KRAS mutation status, even when mutant alleles are restricted to a small portion of a clinical sample, which otherwise contains wild-type alleles. We describe a highly sensitive method to detect KRAS mutations by high-resolution melting (HRM) analysis after mutation enrichment by fast-COLDpolymerase chain reaction (PCR). Using 10 ng of starting DNA and after fast-COLD-PCR of a 76-bp region containing KRAS codons 12 and 13; the amplicons undergo a nested conventional PCR reaction followed by HRM analysis. Samples exhibiting aberrant melting profiles are sequenced to identify mutation type and position. Serial dilution experiments indicate a sensitivity of approximately 0.3% mutant-to-wild type for HRM-based mutation detection and the ability to directly sequence mutation-containing samples. A number of lung adenocarcinoma specimens earlier characterized were screened. Fast-COLD-PCR-HRM analysis correctly identified KRAS mutations and also showed a previously undetected, low-level missense GGT > TTT complex mutation. On account of the short target regions and low requirement of starting DNA, this rapid, cost-effective, and sensitive fast-COLD-PCR-HRM approach is expected to find broad application for detecting low-abundance KRAS mutations in a wide range of clinical specimens. PMID- 21532495 TI - HMGA2 expression analysis in cytological and paraffin-embedded tissue specimens of thyroid tumors by relative quantitative RT-PCR. AB - The distinction between benign and malignant thyroid tumors in some cytological and histological specimens remains challenging. The aim of this study was to evaluate the use of High Mobility Group A2 (HMGA2) mRNA expression to distinguish benign from malignant thyroid tumors in cytological and histological specimens. RNA samples from 170 thyroid formalin-fixed paraffin-embedded (FFPE) tissues and 226 fine needle aspiration (FNA) specimens were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The FFPE tissues included 34 follicular adenomas, 10 Hurthle cell adenomas (HA), 6 hyperplastic nodules, 4 atypical adenomas, 44 classic papillary thyroid carcinomas (PTC), 29 follicular variant of PTC, 23 follicular thyroid carcinomas, 17 Hurthle cell carcinomas (HC), and 3 anaplastic thyroid carcinomas. The FNA specimens included 55 follicular adenomas, 34 HA, 20 hyperplastic nodules, 8 Hashimoto thyroiditis, 32 PTC, 24 follicular variant of PTC, 30 follicular thyroid carcinomas, 21 HC, and 2 anaplastic thyroid carcinomas. HMGA2 mRNA levels were expressed as relative fold change after normalizing with a calibrator. HMGA2 expression in thyroid carcinomas (16.8-fold for FFPE and 18.2-fold for FNA) was significantly higher than in benign lesions (0.8-fold for FFPE and 0.8-fold for FNA). HMGA2 expression in HC was relatively low (1.8-fold for FFPE and 8.5-fold for FNA) compared with the other types of carcinomas. HMGA2 expression values of 4.5-fold and 5.9-fold were used as cutoff points for FFPE and FNA (excluding HA and HC), respectively, to separate benign and malignant thyroid tumors, with 97.5% clinical specificity and 79.8% sensitivity for FFPE, and 95.2% clinical specificity and 88.6% sensitivity for the FNA specimens. Conventional RT-PCR supported the qRT-PCR results. Detection of HMGA2 mRNA expression by qRT-PCR may be a useful tool to assist in the diagnosis of well-differentiated thyroid carcinomas. The 1-step qRT PCR method is a sensitive, accurate, and reliable technique for gene expression analysis of thyroid tumors. PMID- 21532496 TI - Molecular classification of adult renal epithelial neoplasms using microRNA expression and virtual karyotyping. AB - Oncocytoma, chromophobe renal cell carcinoma (chRCC), and the eosinophilic variant of clear cell RCC (ccRCC) are morphologically similar tumors with significantly different clinical courses. These renal tumor subtypes show characteristic structural genetic changes; however, the mRNA expression patterns of oncocytoma and chRCC are strikingly similar. MicroRNAs (miRNA) are small RNA molecules that regulate the expression of many genes and have been shown to be useful for tumor classification and identification. The miRNA expression was analyzed from formalin-fixed paraffin-embedded tissue in 5 cases each of oncocytoma, ccRCC, papillary RCC, chRCC, and 4 normal kidney tissues using microarrays. Affymetrix single-nucleotide polymorphism arrays were used to detect chromosomal imbalances in each of the tumors. Eighteen miRNAs were significantly different among the 4 tumor types. The microRNA miR-21, a known oncogenic miRNA, was found to be upregulated in papillary and clear cell carcinomas. Four miRNAs could differentiate oncocytomas from chRCCs and the 3 could differentiate papillary RCC from ccRCC, including miR-126, a known vasculogenic miRNA. Of the 18 differentially expressed miRNAs, only 2 correlated with copy number changes in the chromosomal region harboring these genes. One tumor, originally diagnosed as an oncocytoma by morphology, showed a virtual karyotype and miRNA expression pattern consistent with chromophobe carcinoma. Further investigation of the tumor showed vascular invasion. Our study suggests that miRNA expression can be used to differentiate the common subtypes of renal epithelial neoplasms but further validation is necessary. In addition, the lack of correlation between miRNA expression and virtual karyotype suggests a non-copy-number-related mechanism for miRNA gene expression regulation in renal neoplasia. PMID- 21532497 TI - Conservative management of the pseudoaneurysms of ascending aortic graft: a case of spontaneous regression at follow-up. AB - Pseudoaneurysms of thoracic aorta represent life-threatening complications of cardiac surgery. We present a case report of a patient who underwent urgent aortic valvular replacement with a biological prosthesis and ascending aortic replacement with graft interposition and developed postoperative ascending aortic pseudoaneurysms. The pseudoaneurysms did not increase in the postoperative stay and a conservative management was chosen. At follow-up, the two pseudoaneurysms had completely regressed. The therapeutic steps for aortic pseudoaneurysms should be tailored to the patient and even conservative management could be effective if selected after an evaluation of the clinical status of the patient. PMID- 21532498 TI - Early use of cardiac magnetic resonance reduces hospitalization time and costs in patients with acute myocarditis and preserved left ventricular function: a single center experience. PMID- 21532499 TI - Percutaneous antegrade transarterial treatment of iatrogenic radial arteriovenous fistula. AB - Site of access vascular complications is infrequent after transradial interventions. We report the case of a 66-year-old man referred to our hospital because of right forearm swelling, oedema and pain with functional forearm disability, 1 year after a transradial primary percutaneous coronary intervention (PCI). The diagnostic and procedural issues are discussed. This is the first description of a successful and well-tolerated radial arteriovenous fistula (AVF) treatment by means of percutaneous antegrade approach with the use of a short introducer and a biocompatible covered stent. PMID- 21532500 TI - Ethnic differences in survival outcome in patients with advanced stage non-small cell lung cancer: results of a meta-analysis of randomized controlled trials. AB - INTRODUCTION: Although interethnic differences in survival to cytotoxic chemotherapy in patients with non-small cell lung cancer exist, an analysis of survival outcomes based on ethnicity has not yet been fully evaluated systematically using large patient cohorts. Furthermore, recent trial results may be confounded by the use of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). METHODS: A meta-analysis was performed using trials identified through MEDLINE. Summary data on median overall survival (OS), time to progression, progression-free survival, and overall response rate (ORR) were collected from randomized controlled trials. Outcomes were compared between Asian and Caucasian studies. RESULTS: Of the 1182 citations identified, 391 treatment arms (Asian 90 and Caucasian 301) were analyzed. The median OS and ORR in Asian and Caucasian studies for all chemotherapy regimens was 10.1 and 8.0 months (p < 0.001) and 32.2 and 25.9% (p < 0.001), respectively. The median OS in Asian and Caucasian studies for monotherapy, platinum doublets, and three drugs or more combination was 9.9 and 6.8 months, 10.4 and 8.6 months, and 9.4 and 8.0 months, respectively (all p < 0.001). In studies published pre-EGFR TKI, the median OS and ORR in Asian and Caucasian studies for all chemotherapy regimens was 9.1 versus 7.3 months (p < 0.001), respectively, and 29.0 and 23.0% (p < 0.006), respectively. The median OS in Asian and Caucasian studies for monotherapy, platinum doublets, and three drugs or more combination pre-EGFR TKI was 8.9 and 6.5 months (p < 0.005), 9.1 and 7.5 months (p < 0.001), and 9.3 and 7.6 months (p < 0.003), respectively. In third-generation platinum doublets, the median OS in Asian and Caucasian studies was 11.3 and 9.5 months (p < 0.001), respectively, and ORR was 35.0 and 29.8% (p < 0.001), respectively. CONCLUSION: Ethnic differences in survival and response rate to chemotherapy exist and should be considered in clinical trial designs especially in the global context. PMID- 21532501 TI - Split-course chemoradiotherapy for locally advanced non-small cell lung cancer: a single-institution experience of 144 patients. AB - BACKGROUND: Concurrent chemoradiotherapy (CRT) is a standard of care in the treatment of unresectable locally advanced non-small cell lung cancer (NSCLC). At Rush University Medical Center, patients with locally advanced NSCLC are treated with split-course CRT in an attempt to maximize efficacy and tolerability. We reviewed our experience in advanced NSCLC since 1999. Subset analysis was performed on poor-risk patients. METHODS: All patients with a diagnosis of stage IIIA/IIIB NSCLC and treated with definitive split-course CRT between January 1999 and December 2008 were included in this retrospective study. The primary end point was overall survival. Poor-risk patients were defined in accordance with ongoing cooperative group trials. RESULTS: One hundred forty-four patients were identified, 35% stage IIIA and 65% stage IIIB. There were 52 poor-risk patients and 92 average-risk patients. Median survival for all patients was 20.4 months with an actuarial 32.1% 3-year overall survival rate. Poor-risk patients demonstrated a median survival of 22.1 months, statistically indistinguishable from the remainder of the cohort (p = 0.21). Acute esophagitis was mild, with a 3% rate of grade 3 esophagitis and no cases of grade 4 or 5. CONCLUSIONS: Split course CRT appeared effective and was delivered with a favorable toxicity profile. Poor-risk patients experienced better than expected survival. Prospective evaluation of split-course CRT must be completed before it can be considered a standard treatment option in locally advanced NSCLC. PMID- 21532502 TI - Intensity-modulated radiotherapy after extrapleural pneumonectomy in the combined modality treatment of malignant pleural mesothelioma. AB - INTRODUCTION: Local therapy is becoming increasingly important as a part of the definitive treatment for malignant pleural mesothelioma after extrapleural pneumonectomy (EPP) because of the emergence of trimodality therapy consisted of chemotherapy, EPP, and adjuvant radiotherapy. Herein, we explore the current evidence and indications for adjuvant intensity-modulated radiotherapy (IMRT), as well as how to further improve this technique and adapt new technology in the delivering adjuvant radiotherapy in the setting of trimodality therapy. METHODS: A systematic review of relevant studies identified through PubMed, ISI Web of Knowledge (Web of Science), the Cochrane Library, and the National Guideline Clearinghouse search engines was performed. RESULTS: Local control remains poor despite the inclusion of conventional adjuvant radiation therapy in trimodality therapy. This can be improved by the delivery of adjuvant IMRT. However, IMRT can be associated with severe pulmonary toxicity if the radiation dose to the remaining lung is not kept to a very low level. This is especially true when patients are receiving chemotherapy. New advances in technology can allow for lower doses to the contralateral lung, decreased treatment delivery time, and improved target dose coverage. CONCLUSION: Excellent local control can be achieved through adjuvant IMRT after EPP for malignant pleural mesothelioma. Severe pulmonary toxicity may be avoided by setting stringent dose constraints for the contralateral lung. This can be aided by the advances in technology. Post treatment surveillance may be reliably conducted by periodical [18F] fluorodeoxyglucose-positron emission tomography imaging. PMID- 21532503 TI - Improved response to nab-paclitaxel compared with cremophor-solubilized paclitaxel is independent of secreted protein acidic and rich in cysteine expression in non-small cell lung cancer. AB - BACKGROUND: The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that is produced by tumor and/or neighboring stroma. SPARC expression is thought to facilitate the intracellular accumulation of nanoparticle albumin-bound paclitaxel (nab-paclitaxel, abraxane [ABX]). Gene hypermethylation is a common mechanism for loss of SPARC expression in non-small cell lung cancer (NSCLC). We aim to demonstrate the role of SPARC expression as biomarker for treatment selection using ABX in NSCLC and to evaluate the presence of synergistic antitumor effect when a demethylating agent is combined with ABX. METHODS: We analyzed the SPARC messenger RNA expression and SPARC gene methylation status in 13 NSCLC cell lines and 22 minimally passaged patient derived (PD) NSCLC tumors using real-time (RT) polymerase chain reaction. The effect of ABX on tumor growth was compared with cremophor-solubilized paclitaxel (taxol) in severe combined immunodeficiency mice bearing SPARC-positive PD xenografts. The effect of pretreatment with a demethylating agent, 5-Aza-2' deoxycytidine (DEC) in SPARC-negative tumors was assessed. RESULTS: SPARC expression was weak to absent in 62% of established NSCLC cell lines and 68% of PD NSCLC tumor xenografts. SPARC expression could be up-regulated/restored by DEC treatment in both SPARC-negative cell lines and PD xenografts in vitro and in vivo. ABX demonstrated better antitumor efficacy than equitoxic dose of taxol in SPARC-expressing xenografts and some SPARC-negative xenografts. At equimolar doses in vitro, there was similar increased cytotoxicity on DEC pretreatment with either ABX or taxol in SPARC-negative cell lines. At equitoxic doses, there was similar additive antitumor activity of DEC with either ABX or taxol in SPARC negative PD xenografts. CONCLUSION: Endogenous SPARC status is somewhat uncorrelated with response to ABX in NSCLC. The greater antitumor effect of ABX compared with equitoxic dose of taxol observed in SPARC-expressing NSCLC tumors can also be seen in some SPARC-negative tumors. DEC pretreatment similarly enhanced antitumor activity with either ABX or taxol in SPARC-negative tumors. PMID- 21532504 TI - A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of paclitaxel-carboplatin alone or with endostar for advanced non-small cell lung cancer. AB - INTRODUCTION: Recombinant human endostatin is a novel inhibitor of tumor angiogenesis that acts specifically on neovascular endothelial cells. Studies have shown that endostar plus vinorelbine-cisplatin chemotherapy could improve objective response rates (ORR) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients. This study is to explore the clinical efficacy of endostar plus paclitaxel-carboplatin (TC) in advanced NSCLC patients. METHODS: A phase II, multicenter, randomized, double-blind, placebo-controlled study was carried out. Patients were randomly assigned to the treatment (TC + endostar) or the control group (TC + placebo). The efficacy was evaluated at the end of each cycle. Follow-up continued until disease progression or death. RESULTS: A total of 126 patients were enrolled, of whom 122 were evaluable, with 61 in each group. ORR was 39.3% in the treatment group versus 23.0% in the control group (p = 0.078), and the disease control rate was 90.2% versus 67.2% (p = 0.004), respectively. The median progression-free survival (PFS) was 7.1 versus 6.3 months (p = 0.522) in the treatment and control groups, the 24-week rate of PFS was 78% versus 59% (p = 0.017), and the median OS was 17.6 versus 15.8 months (p = 0.696), respectively. There were no significant differences, either in the incidence of adverse events or serious adverse events, between the two groups. CONCLUSIONS: In previously untreated, advanced NSCLC patients, treatment with TC plus endostar seemed to improve ORR. However, the differences in PFS or OS between the two groups were not statistically significant. Treatment with TC plus endostar exhibited a good safety profile. PMID- 21532505 TI - Comprehensive analysis of epidermal growth factor receptor gene status in lung adenocarcinoma. AB - INTRODUCTION: The epidermal growth factor receptor (EGFR) gene status including tyrosine kinase domain somatic mutations, increased copy number, and protein overexpression are reported to be associated with response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer. The purpose of this study was to elucidate the prevalence of activated EGFR gene and the association between mutation, copy number, and protein overexpression. PATIENTS AND METHODS: In a cohort of consecutive patients with lung adenocarcinoma, polymerase chain reaction and direct sequencing (n = 89) were conducted through exons 18 to 21. Fluorescence in situ hybridization (FISH) (n = 89) and single nucleotide polymorphism (SNP) array 6.0 (n = 77) were used to detect the gene copy number. The protein expression of EGFR was detected by standard immunohistochemistry (IHC) (n = 89). RESULTS: Fifty-nine (66.3%) patients harbored somatic mutations of EGFR in tyrosine kinase domain, 55.1% were positive by IHC and 44.9% were positive by FISH, and 66.2% showed gain of copy number according to SNP array 6.0. EGFR somatic mutations are more common in women, never smokers, and tumors with better differentiation. Increased copy number detected by both FISH and SNP array 6.0 analysis is significantly correlated with mutations of EGFR. CONCLUSIONS: The EGFR somatic mutation rate is significantly higher in Chinese patients with lung adenocarcinoma than western countries. Nevertheless, we found comparable FISH and IHC-positive rates between different ethnics. Considering that FISH may be affected by tumor heterogeneity and other factors, SNP array 6.0 analysis is a good alternative method to detect EGFR copy number variations. PMID- 21532506 TI - A randomized, double-blind, placebo-controlled, phase II study of oral talactoferrin in combination with carboplatin and paclitaxel in previously untreated locally advanced or metastatic non-small cell lung cancer. AB - INTRODUCTION: The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated stage IIIB/IV non-small cell lung cancer. METHODS: Patients (n = 110) were randomly assigned to receive C/P plus either TLF (C/P/T) or placebo (C/P/P). The primary objective of this exploratory study was assessment of confirmed response rate (RR) in the prospectively defined evaluable population with a one-tailed p = 0.05. Secondary objectives included assessment of progression-free survival (PFS), duration of response, overall survival (OS), and safety. RESULTS: The trial met the primary end point of improvement in confirmed RR in the prospectively defined evaluable population. Compared with the C/P/P group, RR increased in the C/P/T group by 18% (29-47%; p = 0.05) and 15% (27-42%; p = 0.08) in the evaluable and intent-to-treat populations, respectively. Compared with the C/P/P group, the C/P/T group had a longer median PFS (4.2 versus 7.0 months), OS (8.5 versus 10.4 months), and duration of response (5.5 versus 7.6 months), although the differences were not statistically significant. Adverse events (AEs) were consistent with C/P therapy. There were fewer total AEs (472 versus 569; two-tailed p = 0.003) and grade 3/4 AEs (78 versus 105; p = 0.05) in the C/P/T group compared with the C/P/P group. CONCLUSION: TLF, in combination with C/P, demonstrated an apparent improvement in RR, PFS, and OS in patients with previously untreated stage IIIB/IV non-small cell lung cancer and appears to enhance activity without significant additional toxicity. These results need to be confirmed in a phase III trial. PMID- 21532507 TI - Baseline plasma proteomic analysis to identify biomarkers that predict radiation induced lung toxicity in patients receiving radiation for non-small cell lung cancer. AB - PURPOSE: To identify new plasma proteomic markers before radiotherapy start to predict later grade >=2 radiation-induced lung toxicity (RILT2). METHODS: Fifty seven patients with non-small cell lung cancer received radiotherapy (RT) were eligible. Forty-eight patients with minimum follow-up of 1 year, nine with RILT2 with tumor stage matched to 39 without RILT2, were enrolled for this analysis. Platelet-poor plasma was obtained within 2 weeks before radiotherapy. The plasma proteomes were compared using a multiplexed quantitative proteomics approach involving ExacTag labeling, reverse-phase high-performance liquid chromatography, and nano liquid chromatography electrospray ionization tandem mass spectrometry. Z scores and Bonferroni-adjusted p values for the two-sample mean comparison were used to identify the differential protein expression between patients with and without RILT2. RESULTS: More than 200 proteins were identified and quantified. After excluding proteins that were not detected in at least 40% of the 48 patient samples, C4b-binding protein alpha chain and vitronectin had significantly higher (p < 0.001 and p = 0.02) expression levels in patients with RILT2 compared with patients without RILT2. These two proteins were validated by Western blot. Ingenuity pathway analysis revealed that they both play important roles in the inflammatory response and are associated with the known pathways of radiation induced lung damage. CONCLUSIONS: This proteomic approach demonstrates new plasma protein biomarkers before treatment for future studies on RILT2 prediction. PMID- 21532508 TI - Preoperative taxane-based chemotherapy and celecoxib for carcinoma of the esophagus and gastroesophageal junction: results of a phase 2 trial. AB - PURPOSE: The primary objective of this study was to determine the rate of pathological response after preoperative celecoxib and concurrent taxane-based chemotherapy in patients with cancer of the esophagus and gastroesophageal junction. METHODS: Thirty-nine patients were enrolled in this single-arm, phase II clinical trial. Patients were administered daily celecoxib in combination with two to three cycles of carboplatin and paclitaxel with preoperative intent. Levels of cyclooxygenase (COX)-2 expression in resected tumors were analyzed by immunohistochemistry and correlated with clinical outcome measures. Postoperatively, patients were administered daily celecoxib for 1 year or until documented tumor recurrence. RESULTS: All patients received two to three cycles of chemotherapy plus celecoxib 800 mg/d. Toxicities were as expected. A major clinical response (complete response + partial response) was noted in 22 patients (56%); six patients (15%) had a complete clinical response. Thirty-seven patients underwent esophagectomy. Five patients had a major pathological response (12.8%). Four-year overall and disease-free survivals were 40.9% and 30.3%, respectively. Patients with tumors expressing COX-2 demonstrated a higher likelihood of a major clinical response response (62% versus 50%) and an improved overall survival, compared with patients with COX-2-negative tumors. CONCLUSIONS: Preoperative celecoxib with concurrent chemotherapy demonstrated sufficient effect on pathologic response to warrant further study. Patients with tumors expressing COX 2 demonstrated trends toward improved response to preoperative therapy and improved overall survival compared with nonexpressors. PMID- 21532510 TI - Constructing a composite quality score for the care of acute myocardial infarction patients at discharge: impact on hospital ranking. AB - OBJECTIVE: To determine the impact on hospital ranking of different aggregation methods when creating a composite score from a set of quality indicators relating to a single clinical condition. DESIGN: The analysis was based on 14966 medical records taken from all French hospitals that treated over 30 patients with acute myocardial infarction in 2008 (n=275). Five quality indicators measuring the quality of care delivered to patients with acute myocardial infarction at hospital discharge were aggregated by 5 methods issued from a variety of activity sectors (indicator average, all-or-none, budget allocation process, benefit of the doubt, and unobserved component model). MAIN OUTCOME MEASURES: Each aggregation method was used to rank hospitals into 3 categories depending on the position of the 95% confidence interval of the composite score relative to the overall mean. Variations in rank according to method were estimated using weighted kappa coefficients. RESULTS: Agreement between methods ranged from poor (kappa=0.20) to almost perfect (kappa=0.84). A change of method led to a change in rank for 71% (196 of 275) of hospitals. Only 14 of 121 hospitals which were ranked top and 20 of 118 which were ranked bottom, by at least 1 of the 5 methods, held their rank on a switch to the 4 other methods. CONCLUSION: Hospital ranking varied widely according to 5 aggregation methods. If one method has to be chosen, for instance for reporting to governments, regulatory agencies, payers, health care professionals, and the public, it is necessary to provide its rationale and characteristics, and information on score uncertainty. PMID- 21532509 TI - Cross-validation study for epidermal growth factor receptor and KRAS mutation detection in 74 blinded non-small cell lung carcinoma samples: a total of 5550 exons sequenced by 15 molecular French laboratories (evaluation of the EGFR mutation status for the administration of EGFR-TKIs in non-small cell lung carcinoma [ERMETIC] project--part 1). AB - INTRODUCTION: The Evaluation of the epidermal growth factor receptor (EGFR) Mutation status for the administration of EGFR-Tyrosine Kinase Inhibitors in non small cell lung Carcinoma (NSCLC) (ERMETIC) project part 1 assessed the accuracy of EGFR and KRAS mutations detection in NSCLC among 15 French centers. METHODS: The 15 ERMETIC centers selected 74 NSCLC surgical specimens from previously untreated patients. Paraffin and paired frozen DNA were sequenced for EGFR exons 18 to 21 and KRAS exon 2 by an external molecular laboratory, yielding a gold standard. The 74 blinded paraffin DNAs were redistributed to the 15 ERMETIC laboratories for sequencing of a total of 5550 exons. Results were compared with the gold standard and between centers by discordance rates and kappa statistics. RESULTS: The gold standard included 39 mutated samples with 22 EGFR and 17 KRAS mutated samples. Kappa statistics showed that 10, 6, and 6 of the 15 ERMETIC centers had a moderate to good kappa score, when compared with external laboratory for EGFR exon 19, EGFR exon 21, and KRAS exon 2, respectively. Kappa statistics showed moderate score between centers which increased to good for EGFR exon 19 mutation when removing 16 poor-quality samples with high nonamplificable rates. CONCLUSIONS: Paraffin-embedded specimens may represent a suitable source of DNA for sequencing analyses in ERMETIC centers. EGFR exon 19 deletions were most accurately detected by ERMETIC centers. Ease and accuracy of results, depended more on the quality of sample than on the difference in molecular sequencing procedures between centers, emphasize the need of preanalytical quality control programs. PMID- 21532511 TI - Timing of hormone therapy, type of menopause, and coronary disease in women: data from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation. AB - OBJECTIVE: The aim of this study was to assess the relationship of the timing of hormone therapy (HT) use with angiographic coronary artery disease (CAD) and cardiovascular disease (CVD) events in women with natural versus surgical menopause. METHODS: We studied 654 postmenopausal women undergoing coronary angiography for the evaluation of suspected ischemia. Timing and type of menopause, HT use, and quantitative angiographic evaluations were obtained at baseline, and the women were followed for a median of 6 years for CVD events. RESULTS: Ever users of HT had a significantly lower prevalence of obstructive CAD compared with never users (age-adjusted odds ratio, 0.41 [0.28-0.60]). Women with natural menopause initiating HT before age 55 years had lower CAD severity compared with never users (age-adjusted beta [SE] = -6.23 [1.50], P < 0.0001), whereas those initiating HT at age 55 years or more did not differ statistically from never users (-3.34 [2.13], P = 0.12). HT use remained a significant predictor of obstructive CAD when adjusted for a "healthy user" model (odds ratio, 0.44 [0.30-0.73]; P = 0.002). An association between HT and fewer CVD events was observed only in the natural menopause group (hazard ratio [95% CI], 0.60 [0.41-0.88]; P = 0.009) but became nonsignificant when adjusted for the presence or severity of obstructive CAD. CONCLUSIONS: Using the quantitative measurements of the timing and type of menopause and HT use, earlier initiation of HT was associated with less angiographic CAD in women with natural but not surgical menopause. Our data suggest that the effect of HT use on reduced cardiovascular event rates is mediated by the presence or absence of angiographic obstructive atherosclerosis. PMID- 21532512 TI - Randomized trial of estradiol vaginal ring versus oral oxybutynin for the treatment of overactive bladder. AB - OBJECTIVE: The aim of this study was to compare the efficacy of the ultralow-dose estradiol vaginal ring with that of oral oxybutynin in the treatment of overactive bladder in postmenopausal women. METHODS: Postmenopausal women with an overactive bladder were recruited from the general gynecology clinic. Participants were randomized to receive either the ultralow-dose estradiol vaginal ring or oral oxybutynin for 12 weeks. The primary outcome was a decrease in the number of voids in 24 hours. The secondary outcomes were quality-of-life questionnaires, vaginal pH levels, and vaginal maturation index. RESULTS: Fifty nine women were enrolled. Thirty-one were randomized to receive oxybutynin, whereas 28 received the estradiol vaginal ring. Women who received oxybutynin had a mean decrease of 3.0 voids per day, and women who received the vaginal ring had a mean decrease of 4.5 voids per day, with no significant difference between the groups. There was a significant improvement in Urogenital Distress Inventory and Incontinence Impact Questionnaire scores in both groups, with no significant difference in improvement between the two groups. CONCLUSIONS: Ultralow-dose estradiol-releasing vaginal ring and oral oxybutynin seem to be similarly effective in decreasing the number of daily voids in postmenopausal women with overactive bladder. PMID- 21532513 TI - The presence of a membrane-bound progesterone receptor sensitizes the estradiol induced effect on the proliferation of human breast cancer cells. AB - OBJECTIVE: Breast cancer risk is still an important topic regarding hormone therapy as well as oral contraception. Evidence that progestogens may play a crucial role is accumulating. Progesterone receptor membrane component 1 (PGRMC1) expressed in breast cancer may be important in tumorigenesis and thus may increase breast cancer risk. The aim of this project was to investigate the influence of different estradiol (E2) concentrations and the addition of two progestogens on MCF-7 breast cancer cells overexpressing PGRMC1. METHODS: MCF-7 cells were stably transfected with PGRMC1 expression plasmid (MCF-7/PGRMC1-3HA [WT-12]). To test the effects of E2 and progestogens on cell proliferation, MCF-7 and WT-12 cells were stimulated with different concentrations of E2 (10 and 10 M) alone and in combination with progesterone and medroxyprogesterone acetate (each 10 M). RESULTS: E2 elicited a concentration-dependent proliferative effect on both cell lines, which was much more pronounced in WT-12 cells (50% vs 200%). This effect could be completely abrogated by the addition of the E2 antagonist fulvestrant. Addition of progesterone had no influence on the E2-induced effect, whereas medroxy-progesterone acetate enhanced the E2-induced effect at a low E2 concentration, which was, again, more pronounced in the WT-12 cells. The figures were between 20% and 40% in MCF-7 and between 60% and 250% in WT-12 cells. CONCLUSIONS: Overexpression of PGRMC1 sensitizes the proliferative response of the MCF-7 breast cancer cell line to estradiol. The effect of progestogens on breast cancer tumorigenesis may depend on the specific progestogen used for hormone therapy or oral contraception. PMID- 21532514 TI - Psychophysical and electrophysiological testing in ocular hypertension. AB - PURPOSE: The purpose of this study was to compare psychophysical and electrophysiological testings in early optic nerve dysfunction in a group of clinically asymptomatic subjects with suspect ocular hypertension (OHT). METHODS: Forty eyes of 40 patients with suspect OHT and asymmetrical horizontal cup/disc ratio (0.2/0.4), 22 eyes of 22 patients with open-angle glaucoma (OAG), and 40 eyes of 40 healthy controls were evaluated by using frequency-doubling technology perimetry (FDT), contrast sensitivity (CS), pattern electroretinography (PERG), and pattern visual-evoked potentials (VEP). The VEP were elicited by checkerboard stimuli with large (VEP 120), medium (VEP 45), and small (VEP 15) checks; then the values of the amplitude (A) and latency (L) of P100 peaks were studied. Receiver operator characteristic (ROC) curves were calculated to determine the sensitivity, specificity, and optimal cutoff points of abnormal values. A logistic regression analysis was performed to determine which tests were providing the most useful information. In addition, Kruskal-Wallis test was performed to test the differences between the control group and the OHT group. RESULTS: VEP P100 peak latency (VEP L15 and VEP L45) and amplitude (VEP A120), PERG N95 peak amplitude, CS at medium spatial frequencies (CS 4SF), and FDT pattern standard deviation (PSD) yielded the greatest sensitivity (85.0 to 60.0%) and specificity (80.0 to 60.0%) ratio, displaying the largest ROC curve areas; whereas PERG N95 peak latency ROC curve had the smallest areas. Kruskal-Wallis test showed that most diagnostic tests were able to differentiate the OHT group from the control group. Stepwise logistic regression analysis identified VEP L15 (p < 0.001), CS 4SF (p = 0.023), FDT PSD (p = 0.032), and VEP A120 (p = 0.072) as tests that could be useful to distinguish controls from OHT. CONCLUSIONS: Our data confirm that psychophysical and electrophysiological tests are useful for early detection of patients at risk of developing OAG. PMID- 21532515 TI - Crowding in children's visual acuity tests--effect of test design and age. AB - PURPOSE: The aim of this study was to investigate the effect of test design (crowding) and age on visual acuity in a sample of young children. METHODS: Vision was measured in 103 children aged between 4 and 9 years using five different visual acuity tests. The tests included three crowded tests: logMAR Crowded test, the Sonksen logMAR test, and the Crowded Kay Picture test, and two single optotype tests: the Single Kay Picture and Sheridan Gardiner tests. Tests were presented in a random order using standardized instructions and a defined end-point. Results were analyzed in two age groups, younger (4 to 6 years) and older (7 to 9 years). RESULTS: In both groups, there was a significant main effect of test on acuity (younger: F = 63.92, dF = 4, p < 0.001; older: F = 63.59, dF = 4, p < 0.001). In the younger group, an effect of crowding was seen in all three crowded tests, but in the older group, an effect of crowding was seen only in the crowded letter tests. In both groups, mean acuity was lowest with the logMAR Crowded test, which has the closest interoptotype spacing (0.5), slightly higher with the Sonksen test (with interoptotype spacing of 1.0) and highest with the single optotype tests (no crowding). More crowding was seen in the younger children. CONCLUSIONS: Our results show that maturation of line acuity is still taking place between the ages of 4 and 9 years. Measured acuity is affected by the amount of contour interaction induced by the type of optotype (letter or picture) and by the interoptotype separation. Another factor, probably a maturation of gaze control or selective attention is responsible for the reduction in crowding with age. PMID- 21532516 TI - Visual effect and residence time of artificial tears in dry eye subjects. AB - PURPOSE: The purpose of this investigation was to examine the relationship between the visual effect (VE) and residence time (RT) of artificial tears (ATs) in dry eye subjects. METHODS: The VEs and RTs were measured after administration of 25 MUl of an AT into the inferior fornix of 18 dry eye subjects. The VE was investigated by measuring contrast sensitivity before and after AT administration. The return to baseline sensitivity (RTBS) was taken as the time it took to return to within 1 SD of baseline contrast sensitivity. RT was measured using fluorescent formulations and a scanning fluorometer. RESULTS: No correlation was found between RTBS and RT for a low viscosity (saline-F) and a medium viscosity AT (CMC-F; p>0.05). There was a moderate correlation for a higher viscosity AT (PEG-F; p=0.03). For all solutions, RT was significantly longer than RTBS (p<0.001). There was a significant difference in RTBS between saline-F and PEG-F (p=0.002) but not between saline-F and CMC-F (p=0.87). There was a significant difference in RT between saline-F and both PEG-F and CMC-F (p<0.001 and p=0.018, respectively). CONCLUSIONS: No correlation was found between RTBS and RT for saline-F or CMC-F (moderate correlation for PEG-F). These ATs are present on the eye for a significantly longer time than their adverse affect on vision. An ideal AT would result in minimal if any initial blur on instillation while remaining in the eye for an extended period of time. PMID- 21532517 TI - Corneal power after DSAEK using microkeratome-prepared tissues. AB - PURPOSE: To investigate changes of corneal power after descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: Anterior, posterior, and true-net (anterior + posterior) power of post-DSAEK and contralateral transparent corneas were measured, using the Pentacam rotating Scheimpflug camera (Oculus Wetzlar, Germany), 6 months after surgery in 23 consecutive patients who had undergone unilateral DSAEK at the same medical center. Moreover, in each cornea, Pentacam pachimetry was measured at the vertex and at 3 mm from the vertex, to calculate corneal thickness increase (CTI). RESULTS: In post-DSAEK corneas, the anterior power on average decreased by -0.24 +/- 0.61 diopters (D), the negative posterior power increased by -0.96 +/- 0.42 D, and the true-net power decreased by -1.19 +/- 0.74 D (range: +0.17 to -2.23 D). Differences vs. contralateral transparent corneas did not reach statistical significance for anterior (p = 0.09) but were significant (p < 0.001) for posterior and true-net corneal power. CTI at 3 mm from the vertex was statistically larger (p < 0.0001) in post-DSAEK corneas (mean values 0.27 +/- 0.07 vs. 0.12 +/- 0.05); CTI values showed a statistically significant (p < 0.05) correlation with negative posterior corneal power values in post-DSAEK (r = -0.55) and in contralateral corneas (r = -0.67). CONCLUSIONS: In comparison with contralateral corneas, post-DSAEK corneas show a moderate reduction of the true-net corneal power measured by Pentacam. Knowledge of true-net corneal power changes might be useful in adjusting K values and calculating intraocular lens power, in eyes scheduled for DSAEK combined with intraocular lens implantation/exchange. PMID- 21532518 TI - Comparisons of nerve fiber layer thickness measurements between Stratus, Cirrus, and RTVue OCTs in healthy and glaucomatous eyes. AB - PURPOSE: To compare retinal nerve fiber layer (RNFL) measurements obtained by two spectral-domain optical coherence tomographies (SD OCTs; Cirrus-HD OCT and RTVue) and a time domain OCT (TD OCT; Stratus OCT). The diagnostic ability of the three instruments for glaucoma has also been compared. METHODS: One hundred eight open angle glaucoma patients and 46 normal controls were enrolled. Three OCT scans were repeated to obtain peripapillary RNFL thickness measurements from all participants on the same day. The relationships between RNFL measurements from three OCTs were evaluated with regression analyses. RESULTS: The thickest RNFL measurements were generally obtained with the RTVue, followed by the Stratus, and finally by the Cirrus OCT (mixed model, p < 0.05). However, the tendency was reversed or no longer present in severe glaucomatous eyes and nasal quadrant maps. Regression analysis between the TD OCT and the two SD OCTs revealed a quadratic relation (linear vs. non-linear, Akaike information criterion, all p < 0.05), whereby RNFL measurements of the TD OCT became exponentially thinner than those by the SD OCTs in thin RNFL thicknesses. Comparing the two SD OCTs, RTVue measured thicker values consistently regardless of the RNFL thickness (pairwise comparisons, p < 0.05). There were no significant differences in the diagnostic ability of all three instruments in average and each quadrants of RNFL thickness (p > 0.05). CONCLUSIONS: Direct comparisons of RNFL thickness measurements among OCT instruments may be misleading as there are considerable differences among devices. The measurement differences between SD OCT and TD OCT differed according to the RNFL thickness and also possibly to severity of the glaucoma. The diagnostic ability of each instrument for glaucoma detection was not significantly different. PMID- 21532519 TI - Update on geographic atrophy in age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the main cause of legal blindness in older patients in developed countries, and geographic atrophy (GA) represents the advanced form of dry AMD. Although it accounts for one third of the cases of late AMD and is responsible for 20% of the cases of severe visual loss due to the disorder. GA currently lacks effective treatment, whereas antiangiogenic therapies have been shown to be successful in managing choroidal neovascularization, the other form of late AMD. Recent advances in GA epidemiology, etiology, genetics, and imaging techniques have renewed the interest in this entity, which is a cause of progressive visual loss even in treated patients with neovascular AMD. This knowledge has triggered many clinical trials targeting different molecules shown to be associated with the disease, and it is hoped that this research will translate into effective drugs for GA in the near future. PMID- 21532520 TI - The variable clinical presentation of tuberculosis otitis media and the importance of early detection. AB - BACKGROUND: Tuberculosis (TB) is a rare cause of otitis media. This study aims to increase awareness on the clinical presentation of TB otitis media and illustrate how early detection affects treatment outcome. METHODS: Chart review of 12 patients (13 ears) from a tertiary hospital in Manila, Philippines, seen from 2004 to 2009. Clinical predictors of the disease were summarized. Clinical, radiologic, and audiometric outcomes after treatment were compared between treatment groups. RESULTS: The 5 otoscopic presentations were multiple perforations, single perforation with refractory otorrhea and exuberant granulation tissue formation, single perforation with minimal otorrhea and no granulation tissue formation, intact tympanic membrane with middle ear effusion, and intact tympanic membrane with tumorlike tissue in the middle ear. Clinical predictors of the disease were history of pulmonary TB, work-related contamination of the infection, positive purified protein derivative test, positive chest radiographic finding and intraoperative granulation tissue with cheesy material, and temporal bone computed tomographic scan findings. Patients who had no middle ear surgery showed significantly better clinical, radiologic, and audiometric outcomes than those who were diagnosed late and had more complicated surgical procedure. CONCLUSION: The clinical presentation of TB otitis media is variable. Early detection of the early forms entail less surgical intervention and favors better treatment results. PMID- 21532521 TI - Challenges in the microbiological diagnosis and management of hVISA infections. AB - AIMS: To highlight the challenges involved in diagnosing and managing complicated heterogeneous vancomycin intermediate Staphylococcus aureus (hVISA) infections and to improve clinical recognition of such infections. METHODS: A retrospective review of patients with proven hVISA infections was undertaken in two major referral centres of North Queensland from 2006 to 2010. All isolates had population analysis profiling (PAP) done along with hVISA screening performed by the macro-Etest (MET). RESULTS: Five patients were identified, two of whom died of hVISA-related sepsis. Their population analysis profiling-area-under-the-curve ratio (PAP-AUC) ranged between 0.96 and 1.43. CONCLUSIONS: The identification of hVISA isolates in the diagnostic laboratory presents specific challenges. Clinical failure with vancomycin or MICs to vancomycin of >=2 mg/L should alert the laboratory to proceed with the more specific methods of MET and PAP to identify hVISA or VISA isolates. Alternatives to vancomycin are limited and not always efficacious or tolerated. PMID- 21532522 TI - Microbial contamination of autologous peripheral blood stem cell products: incidence, clinical outcome, quality control and management strategies. AB - BACKGROUND: Microbial screening is part of quality control for autologous peripheral blood stem cell (PBSC) manipulation. The incidence of culture positive products varies widely. The clinical significance of infusing culture positive products is uncertain, with no consensus on the interventions required. METHODS: Microbial cultures of 606 consecutive autologous PBSC products from 278 patients between 1995 and 2005 were retrospectively analysed to determine the incidence of culture positivity and classified according to likely clinical significance. Clinical outcomes of patients who received culture positive products were reviewed. Using the baseline probability of contamination, a quality control method to detect a systematic source of contamination during product manipulation was developed. RESULTS: Eleven (1.8%) of 606 products were culture positive in eight (2.9%) patients. Ten products yielded coagulase negative Staphylococcus species and one Corynebacterium accolens. One patient had catheter sepsis during collection. Five patients received culture positive products, with prophylactic antibiotics when there was known coagulase negative Staphylococcus species. None had clinical evidence of infection following product infusion. CONCLUSIONS: The incidence of culture positive products was comparable to published series. Only skin commensals were isolated. Infusion of skin commensal positive products appears safe with antibiotic prophylaxis. Using local and published experience, clinical and laboratory policies were developed for culture positive products. PMID- 21532523 TI - Validation of a minimal panel of antibodies for the diagnosis of malignant pleural mesothelioma. AB - AIMS: We previously established the use of a minimal panel of antibodies as sufficient to diagnose most epithelial malignant mesothelioma (MPM). We aimed to validate this approach and investigate the utility of a D2-40 antibody. METHODS: A series of 80 MPM patients selected for surgery and 21 consecutive patients with pleural metastatic carcinoma were included. A minimal panel of antibodies, consisting of calretinin, BG8 and CD15, and D2-40 was investigated. RESULTS: There were 61 epithelial and 19 biphasic MPM as well as 12 metastatic lung, six breast (5 ductal adenocarcinomas, 1 mixed ductal/lobular adenocarcinoma), two serous papillary ovarian carcinomas and one moderately differentiated colorectal adenocarcinoma. The sensitivity of positive calretinin labelling to confirm the diagnosis of MPM was 97.5%, while the 'diagnostic sensitivities' of lack of labelling for BG8 and CD15 were 91.3% and 97.5%, respectively. The use of calretinin, BG8 and CD15 resulted in correct classification in 97.5% of all MPMs. All MPM cases investigated showed at least focal positive D2-40 labelling. CONCLUSIONS: We have validated the usefulness of a minimal panel of antibodies with calretinin, BG8 and CD15 as the initial step to the diagnosis of MPM. D2-40 emerged as a helpful diagnostic tool for cases where our initial approach failed to conclusively diagnose MPM. PMID- 21532524 TI - Extraventricular neurocytomas: a morphological and histogenetic consideration. A study of six cases. AB - AIMS: Various molecular markers have been used for diagnosis, management and prognostication of gliomas. Neurocytomas are close morphological mimics of oligodendrogliomas. While combined 1p/19q deletion has been used as a molecular signature of oligodendroglial tumours, it has also been variably reported to occur in neurocytomas, especially those in extraventricular locations (EVN). In recent studies, presence of IDH1 mutation has shown immense prognostic significance in glial tumours including oligodendrogliomas, but its role in neurocytoma pathogenesis remains unexplored. In this study, EVN cases were analysed for histomorphological features, IDH1 mutation using an antibody for specifically detecting mutant IDH1 protein, and 1p/19q deletion by fluorescence in situ hybridisation (FISH) assay. RESULTS: Over a period of 10 years (2000 2009), 60 cases of neurocytoma were diagnosed, of which six were EVN. These six cases were assessed for histomorphology, IDH1 mutation and 1p/19q deletion. Five cases showed atypical histological features. While none showed mIDH1, four of the five atypical cases harboured 1p/19q deletion either in isolation or in combination. The only case which was well-differentiated (typical) did not show 1p/19q loss. CONCLUSIONS: EVNs are more commonly associated with aggressive histological features. IDH1 mutations, although frequent in oligodendrogliomas, are not seen in EVN. However, similar to oligodendrogliomas, 1p/19q deletion is found in these tumours. Thus, a potential histogenetic link between oligodendrogliomas and EVN remains debatable. This molecular alteration may also have prognostic connotations, being associated with atypical morphological features. Due to the rarity of these tumours, multicentric pooling of larger studies is needed to have an insight into the impact of these molecular aberrations on their biological behaviour. PMID- 21532525 TI - Immunosuppression increases latent infection of brain by JC polyomavirus. AB - AIMS: Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of JC polyomavirus (JCV). Increased JCV reactivation in kidney, as indicated by JCV viruria is reported during immunosuppression; however, the relevance of systemic to neural reactivation remains unknown. METHODS: Brain and kidney tissue from 138 non-PML patients (78 immunocompetent; 60 immunosuppressed) was assessed for JCV large T (LT) and viral protein (VP)1 DNA with nested PCR. Immunohistochemistry was performed to detect presence of JCV protein. Autopsy findings were reviewed and all brains underwent neuropathological examination. RESULTS: JCV LT DNA was detected in 31% of kidney and 30% of brain from non-PML patients. Of non-PML patients with brain JCV LT DNA, 66% did not have kidney JCV LT DNA, indicating brain JCV LT DNA was independent of kidney JCV LT DNA (p = 0.69). JCV VP1 DNA was detected in 12% of non-PML kidney and 8% of non-PML brain. JCV LT DNA was more likely to be found in the kidney (p < 0.001) and brain (p = 0.009) of immunosuppressed than immunocompetent patients. HIV/AIDS patients with brain JCV LT DNA had lower CD4 counts than those without brain JCV LT DNA (p = 0.05). CONCLUSIONS: Immunosuppression drives increased brain JCV latency independent of systemic latency. PMID- 21532526 TI - RANK signalling in bone lesions with osteoclast-like giant cells. AB - AIMS: The interactions between the receptor activator of NF-kappaB (RANK), its ligand (RANKL), and the decoy receptor for RANKL, osteoprotegerin (OPG), play a pivotal role in promoting osteoclast differentiation and activation leading to bone resorption. Giant cell tumours, chondroblastomas, and aneurysmal bone cysts harbour osteolytic lesions containing osteoclast-like giant cells. We investigated the characteristics of the RANKL signalling pathway in each of these bone lesions. METHODS: We evaluated 44 cases of giant cell tumour, 12 cases of chondroblastoma, six cases of aneurysmal bone cyst, and five cases of metastatic giant cell tumour (including paired primary giant cell tumours). We assessed RANK, RANKL, and OPG expression in chondroblastomas, giant cell tumours, and aneurysmal bone cysts using immunohistochemical methods. RESULTS: Our findings revealed that RANK, RANKL, and OPG expression differed significantly among disease types. Giant cells of chondroblastomas showed significantly higher RANK expression than the giant cells of giant cell tumours and aneurysmal bone cysts; similarly, stromal cells of chondroblastomas showed significantly higher OPG expression than the stromal cells of giant cell tumours and aneurysmal bone cysts. Furthermore, giant cells of giant cell tumours expressed significantly more RANK than the giant cells of aneurysmal bone cysts. CONCLUSIONS: The expression of RANK, RANKL, and OPG in osteoclast-like giant cells differs significantly by disease; OPG expression differs significantly between giant cell tumours and chondroblastomas. PMID- 21532527 TI - Sex differences in newborn myocardial metabolism and response to ischemia. AB - In children with congenital heart disease, female sex has been linked to greater in-hospital mortality associated with low cardiac output, yet the reasons for this are unclear. Therefore, we examined whether newborn sex differences in the heart's metabolic response to ischemia exist. Left ventricular (LV) in vivo and ischemic biopsies of newborn male and female piglets were compared. Tissue ATP, creatine phosphate (CP), glycogen, anaerobic end-products lactate and hydrogen ion (H), and key regulatory enzymes were measured. Compared with males, newborn females displayed 14% lower ATP, 22% lower CP, and 32% lower glycogen reserves (p < 0.05) at baseline. During ischemia, newborn females accumulated 17% greater lactate and 40% greater H accumulation (p < 0.02), which was associated with earlier cessation of glycolysis and lower ischemic ATP levels (p < 0.02) compared with males. Newborn females demonstrated a greater ability to use their glycogen reserves, resulting in significantly lower (p < 0.003) glycogen levels throughout the ischemic period. Thus, newborn females are at a metabolic disadvantage because they exhibited lower energy levels and greater tissue lactic acidosis, both linked to an increase susceptibility to ischemic injury and impair myocardial function on reperfusion. PMID- 21532528 TI - Urinary nitrate might be an early biomarker for pediatric acute kidney injury in the emergency department. AB - NO is involved in normal kidney function and perturbed in acute kidney injury (AKI). We hypothesized that urinary concentration of NO metabolites, nitrite, and nitrate would be lower in children with early AKI presenting to the emergency department (ED), when serum creatinine (SCr) was uninformative. Patients up to 19 y were recruited if they had a urinalysis and SCr obtained for routine care. Primary outcome, AKI, was defined by pediatric Risk, Injury, Failure, Loss of function, End-stage renal disease (pRIFLE) criteria. Urinary nitrite and nitrate were determined by HPLC. A total of 252 patients were enrolled, the majority (93%) of whom were without AKI. Although 18 (7%) had AKI by pRIFLE, 50% may not have had it identified by the SCr value alone at the time of visit. Median urinary nitrate was lower for injury versus risk (p = 0.03); this difference remained significant when the injury group was compared against the combined risk and no AKI groups (p = 0.01). Urinary nitrite was not significantly different between groups. Thus, low urinary nitrate is associated with AKI in the pediatric ED even when SCr is normal. Predictive potential of this putative urinary biomarker for AKI needs further evaluation in sicker patients. PMID- 21532529 TI - Chronic hypoxia impairs murine hippocampal development and depletes the postnatal progenitor pool by attenuating mammalian target of rapamycin signaling. AB - Chronic hypoxia (CH) is a major risk factor for impaired cognitive function in various disease states, particularly in the context of cyanotic congenital heart disease. Although most brain development occurs prenatally, the dentate gyrus (DG) of the hippocampus harbors progenitor stem cells that contribute to its ongoing development postnatally. It is unclear how exposure to CH might affect postnatal hippocampal development, so we used a transgenic mouse that expresses enhanced green fluorescent protein (eGFP) within this progenitor population to determine the effect of CH on the DG. We find that exposure to 10% oxygen from postnatal d 3 to 28 results in a smaller DG with long-term impairment of hippocampal neurogenesis. Because the mammalian target of rapamycin (mTOR) pathway is a well-known regulator of cell proliferation and growth and is sensitive to hypoxia, we investigated its activation on exposure to CH and find it to be attenuated specifically in neural progenitor cells. Systemic inhibition of the mTOR pathway using rapamycin also caused impairment of hippocampal neurogenesis that mimics exposure to CH. Our findings demonstrate that CH results in long-term impairment of hippocampal neurogenesis and is mediated, in part, by attenuation of the mTOR pathway. PMID- 21532530 TI - Outcome following surgical management of corrosive strictures of the esophagus. AB - OBJECTIVE: To analyze the short- and long-term outcomes following surgical treatment for corrosive stricture of the esophagus. BACKGROUND: Surgery is a well established treatment for corrosive strictures of the esophagus and involves either resection or bypass of the damaged esophagus and replacement by a conduit. The need for resection and the choice of the ideal conduit for esophageal replacement in these patients continues to be debated and there are only a few studies reporting on the long-term outcome following the surgical treatment. METHODS: This was a retrospective analysis of patients with corrosive stricture of the esophagus who were managed surgically between 1983 and 2009. The type of surgery performed (resection or bypass), the conduit used, the short- and long term outcomes were assessed. RESULTS: One hundred seventy-six corrosive strictures of the esophagus were managed surgically (resection: 64, bypass: 112). A transhiatal resection could be accomplished in 59 of 62 patients in whom it was attempted. Stomach conduits were used in 107 patients and colonic conduits in 69. The mean operating time was 4.3 +/- 1.5 hours and the mean estimated blood loss 592 +/- 386 mL. Cervical anastomotic leak occurred in 22 patients (12.5%). Follow up of more than 10 years was available for 78 patients (44.3%) and more than 15 years for 54 patients (30.7%). Recurrent dysphagia developed in 33 patients (18.7%). There were no differences in the short- or long-term outcomes in patients who underwent resection or bypass. The mean duration of surgery, intraoperative blood loss, incidence of conduit necrosis, and in-hospital mortality was significantly lower in patients with stomach conduits as compared with colonic conduits. There was a higher incidence of recurrent laryngeal nerve palsy, recurrent dysphagia, and aspiration after surgery in patients with strictures involving the upper end of the esophagus at or near the hypopharynx. CONCLUSIONS: Satisfactory outcomes are achieved after surgery for corrosive strictures of the esophagus. Resection of scarred esophagus may be done without a substantial increase in the morbidity and mortality; however, the outcomes are not significantly different from bypass. Stomach is a good conduit and the colon should be reserved for cases where the stomach is not available. Long-term outcomes in patients with hypopharyngeal strictures, however, continue to be poor. PMID- 21532531 TI - Health care workers as second victims of medical errors. AB - INTRODUCTION: "Second victims" are health care providers who are involved with patient adverse events and who subsequently have difficulty coping with their emotions. Growing attention is being paid to making system improvements to create safer health care and to the appropriate handling of patients and families harmed during the provision of medical care. In contrast, there has been little attention to helping health care workers cope with adverse events. OBJECTIVES: The aim of the study was to emphasize the importance of support structures for second victims in the handling of patient adverse events and in building a culture of safety within hospitals. METHODS: A survey was administered to health care workers who participated in a patient safety meeting. The total number of registered participants was 350 individuals from various professions and different institutions within Johns Hopkins Medicine. The first part of the survey was paper-based and the second was administered online. RESULTS: The survey results reflected a need in "second victim" support strategies within health care organizations. Overall, informal emotional support and peer support were among the most requested and most useful strategies. CONCLUSIONS: When there is a serious patient adverse event, there are always second victims who are health care workers. The Johns Hopkins Hospital has established a "Second Victims" Work Group that will develop support strategies, particularly a peer support program, for health care professionals within the system. PMID- 21532532 TI - Increase in plasma sCD23 levels precedes immunoglobulin E elevation after coronary artery bypass graft surgery. AB - INTRODUCTION: Recent reports have confirmed an increase in plasma immunoglobulin E (IgE), which had been previously observed in clinical situations associated with tissue injury. Studies on the regulation of IgE levels have pointed to the role of low-affinity IgE receptor, i.e., sFcepsilonRII (soluble CD23 [sCD23]). OBJECTIVES: The aim of the study was to assess the changes in the levels of this receptor in response to surgical injury during coronary artery bypass grafting. PATIENTS AND METHODS: The study group consisted of 33 patients (28 men and 5 women, aged 45-75 years). Blood samples were obtained from all patients before surgery and 24, 48, 72, and 120 hours after the surgery. The expression of FcepsilonRII on B cells was measured using flow cytometry and plasma levels of sCD23 were determined by an enzyme-linked immunosorbent assay. RESULTS: We observed a significant increase in the total number of leukocytes and a significant decrease in the total number of lymphocytes with a simultaneous increase in the proportion of B cells (P <0.001). At the same time, the percentage of CD23-positive B cells (CD19/23+) decreased significantly (P <0.001) at 24 hours after surgery and remained low over the period of 72 hours. The plasma levels of sCD23 increased significantly (P <0.05) at 24 hours after surgery and remained elevated until the end of follow-up. All the above changes in the immune status preceded an increase in plasma IgE levels (P <0.001), which reached peak values on the fifth day after surgery (120 h). CONCLUSIONS: Surgical procedures are associated with a transient increase in plasma IgE levels, which is preceded by an increase in the level of sCD23 and a simultaneous decrease in the expression of CD23 on B cells. FcepsilonRII (CD23) and sFcepsilonRII (sCD23) may be involved in the regulation of IgE levels after trauma. PMID- 21532534 TI - Associations between parameters of nutritional status and disease activity in patients with rheumatoid arthritis. AB - INTRODUCTION: In patients with rheumatoid arthritis (RA), the loss of body cell mass is observed, known as rheumatoid cachexia. Cachexia is associated with increased morbidity and premature mortality of RA patients. OBJECTIVES: The aim of the study was to assess the effect of chronic inflammation and disease activity on nutritional status in RA patients. PATIENTS AND METHODS: In 140 patients with RA (111 women, 29 men), RA activity was measured using the Disease Activity Score in 28 joints (DAS28) and using the Modified Health Assessment Questionnaire (M-HAQ). The nutritional status was assessed with the following parameters: serum albumin and total cholesterol (TC), body mass index (BMI), hand grip strength (HGS), and tricipital skinfold thickness. RESULTS: There was a significant association between the parameters of nutritional status and the markers of inflammatory disease activity (number of swollen and tender joints, C reactive protein, hemoglobin) and physical disability (M-HAQ). Swollen joint count and M-HAQ were inversely correlated with several nutritional parameters. In patients with high disease activity, significantly lower HGS and serum albumin levels were observed. Advanced stages of the disease (erosive and/or long standing RA) were associated with lower HGS and higher TC levels. CONCLUSIONS: The nutritional status of RA patients is determined by the intensity of chronic inflammatory process observed in the course of the disease and by disease duration. PMID- 21532533 TI - Comparison of the VASP assay and platelet aggregometry in the evaluation of platelet P2Y12 receptor blockade. AB - INTRODUCTION: It has been shown that incomplete blockade of platelet reactivity is a risk factor for future ischemic events in patients with cardiovascular diseases. Despite these findings, there is yet no gold standard of platelet reactivity estimation. The 2 most commonly used methods in platelet testing are platelet aggregometry and vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay. They both showed the predictive value for future adverse events in cardiac patients; however, there are few data that compare these 2 methods. OBJECTIVES: The aim of the study was to compare the results of aggregometry (multi-electrode aggregometer [MEA]) and flow cytometric VASP assay used to determine platelet reactivity after the administration of P2Y12 receptor blockers. PATIENTS AND METHODS: The study included 17 healthy volunteers (12 men, 5 women; aged 41 +/-10 years) and 12 patients (men, aged 62 +/-12 years) with stable coronary artery disease treated with elective percutaneous coronary intervention with stent implantation. In volunteers, the blood was collected and tests were performed before and after 10-minute incubation with 5 nmol/l of cangrelol. In patients, the blood was collected for measurements before and after ingestion of 300 mg of clopidogrel. Aggregometry measurements included adenosine diphosphate (ADP)-induced maximal aggregation (A(max)) and ADP-induced area under the aggregation curve (AUC). The platelet reactivity index (PRI) was determined using the VASP assay. RESULTS: The use of cangrelor and clopidogrel was associated with a significant inhibition of platelet reactivity measured using the above methods. In both groups, the degree of inhibition was significantly greater when measured with the aggregation method compared with the VASP assay. The only significant coefficient of correlation between the VASP assay and aggregation results was observed in volunteers after platelet incubation with cangrelor (r= 0.81 between PRI and A(max), r = 0.68 between PRI and AUC). CONCLUSIONS: Compared with the VASP assay, ADP-induced platelet aggregation shows a greater ability to detect a decrease in platelet aggregation after P2Y12 antagonists. These tests are not interchangeable because they measure different aspects of the P2Y12 receptor blockade. PMID- 21532535 TI - Gastrointestinal motility disorders in endocrine diseases. AB - Endocrine diseases may have systemic involvement. The aim of this paper is to review gastrointestinal and motility dysfunction in endocrine diseases. We review motility disturbances in thyroid disorders, acromegaly, Cushing syndrome, neurohypophysis disorders, diabetes, parathyroid diseases, and multiple endocrine neoplasia, with emphasis placed on the correlation with the blood levels of gastrointestinal hormones that may interfere with the brain-gut axis at various levels. PMID- 21532536 TI - Brain amyloid imaging: the challenge of the third millennium. PMID- 21532537 TI - Alzheimer's disease: genetic basis and amyloid imaging as endophenotype. AB - To date, all known Alzheimer's disease genes influence amyloid beta (Abeta). Imaging of Abeta deposition in the human brain using positron emission tomography (PET) tracers as [11C]Pittsburgh Compound B ([(11)C]PiB) or [18F]FDDNP offers the possibility of using cortical tracer binding as a quantitative endophenotype for genetic studies of late-onset Alzheimer's disease (AD). In this review we investigate the association between cerebral Abeta burden, as measured by amyloid PET imaging, and different genetic risk factors involved in AD. Through a look at the major genetic risk factors for both early-onset familial and late-onset sporadic forms of AD, we discuss the possible role of amyloid PET imaging as an endophenotype in AD. Several PET studies confirmed the high heritability of amyloid load estimated by PET imaging and its association with the major genetic risk factors for early and late onset AD, suggesting that cerebral binding of these amyloid tracers could represent an useful trait for large-scale genetic studies of AD. PMID- 21532538 TI - The dynamic marker hypothesis of Alzheimer's disease and its implications for clinical imaging. AB - In the last ten years the literature on Alzheimer's disease has focused on in vivo neurobiological changes. Extracellular beta-amyloid and intracellular hyperphosphorilated tau deposition are pivotal features and several authors have described their progression over time in pathological specimens. The revised criteria for Alzheimer's disease suggest that in vivo biomarkers reflecting neurobiological changes are useful for early diagnosis in the clinical practice. The most widely used biomarkers for the Alzheimer's disease are: Abeta42 and Tau levels in the cerebrospinal fluid (CSF); brain glucose hypometabolism detected by positron emission tomography (PET) using the 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG); brain structural and functional changes detected by magnetic resonance imaging and amyloid burden by PET using Carbon-11-labelled Pittsburgh compound-B [(11)C]PiB). In order to explain the latest in vivo observations, the dynamic biomarker hypothesis has been recently developed, integrating both pathological and clinical knowledge, and indicating which biomarkers might be more sensitive to disease state and progression at different stages. In this review, we will outline studies that support the dynamic hypothesis by: 1) testing slope differences among biomarkers; 2) describing how biomarkers map all neuropathological and clinical changes starting from the detection of amyloid burden, to neurodegeneration, and symptoms; and finally 3) identifying the best combination of biomarkers sensitive to prodromal AD in clinical practice. PMID- 21532540 TI - Amyloid imaging as a surrogate marker in clinical trials in Alzheimer's disease. AB - New treatments against Alzheimer's disease (AD) may be just around the corner. A common approach in developing these disease-modifying treatments is to target beta-amyloid (Abeta). Abeta is excessively present in the AD brain and it likely starts to accumulate long before clinical symptoms become apparent. As Abeta is hypothesized to be the causative agent in the pathophysiological cascade leading to progressive neurodegeneration in AD, efforts to e.g. prevent its formation, to promote its clearance from brain tissue, and to inhibit its toxicity, are warranted. This quest for an effective AD treatment needs valid biomarker outcome measures, for instance because clinical benefit takes long to present itself and is difficult to measure, and also because treatment would likely be most efficacious if administered already before symptoms occur. In vivo amyloid imaging has evolved in the past decade to be a feasible means to monitor brain Abeta deposits in the human brain. It effectively differentiates AD patients from healthy age-matched controls, and also shows promise in the early, even presymptomatic, detection of AD. Amyloid imaging will likely also broaden and deepen our understanding of AD and other neurodegenerative disorders. It could prove valuable e.g. in subject selection and stratification for clinical trials, in safety and proof-of-concept assessments, and in monitoring of treatment effects. This article aims to review the motives, prerequisites, potential, and challenges of using amyloid imaging as a surrogate marker in clinical therapeutic trials in AD. PMID- 21532539 TI - FDG- and amyloid-PET in Alzheimer's disease: is the whole greater than the sum of the parts? AB - The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to subtle brain changes occurring prior to the onset of clinical symptoms, when the potential for preservation of function is at the greatest. In vivo brain imaging is a promising tool for the early detection of AD through visualization of abnormalities in brain structure, function and histopathology. Currently, positron emission tomography (PET) imaging with amyloid-beta (Abeta) tracers and 2-[(18)F]fluoro-2 Deoxy-D-glucose (FDG) is largely utilized in the diagnosis of AD. This paper reviews brain Abeta- and FDG-PET studies in AD patients as well as in non demented individuals at risk for AD. We then discuss the potential of combining symptoms-sensitive FDG-PET measures with pathology-specific Abeta-PET to improve the early detection of AD. PMID- 21532541 TI - Current research in nuclear medicine and molecular imaging in Italy: highlights of the 10th National Congress of the Italian Association of Nuclear Medicine and Molecular Imaging. AB - The 10th National Congress of the Italian Association of Nuclear Medicine and Molecular Imaging (AIMN) took place in Rimini on March 18-21, 2011 under the chairmanship of Professor Stefano Fanti. The program was of excellent quality and put a further step for the settlement of the standardized AIMN congress structure. A large industrial exhibition demonstrated the latest technological innovations and developments within the field. The congress was a great success with more than 1100 total participants and more than 360 abstracts received. Of these, 40 abstracts were accepted for oral and 285 for poster presentations. The original investigations presented were related to different areas of nuclear medicine and molecular imaging, with particular focus on advances in instrumentation and data processing, progress in radiochemistry and pharmacy, novel diagnostics and therapeutics, and new insights in well established areas of clinical application, such as oncology, cardiology, neurology, psychiatry, endocrinology, paediatrics, and infection and inflammation. Noteworthy, several presentations at this congress, focusing on quantitative interpretation of the imaging data and on pragmatic endpoints, such as adverse outcomes, identified when nuclear medicine procedures achieved clinical effectiveness for patient care and patient management and further demonstrated that nuclear medicine plays a crucial role in the contemporary medical scenario. This highlights lecture is only a brief summary of the large amount of data presented and discussed, which can be found in much greater detail in the congress abstract book, published as volume 55, supplement 1 of the Q J Nucl Med Mol Imaging in April 2011. PMID- 21532542 TI - Improved visual [(123)I]FP-CIT SPECT interpretation for evaluation of parkinsonism by visual rating of parametric distribution volume ratio images. AB - AIM: Imaging of presynaptic dopamine transporters (DAT) by single-photon emission computed tomography (SPECT) and [(123)I]FP-CIT is an established method for differentiating between neurodegenerative and non-neurodegenerative parkinsonism. Whereas a region-of-interest (ROI) analysis is the method of choice for analyzing [(123)I]FP-CIT SPECT studies, visual image interpretations can also provide highly accurate results. The present study was undertaken to validate a visual reading system for parametric volume of distribution (DVR) [(123)I]FP-CIT SPECT images that combines the quantitative nature of ROI analyses and the simplicity of visual readings. METHODS: A 9-step linear visual rating template for semi quantitative DVR ratings of caudate nucleus and putamen was developed (VRDVR). The conventional 4-step visual reading system that is mainly based on the [(123)I]FP-CIT uptake pattern was used for comparison (VRP method). Six independent observers retrospectively rated the [(123)I]FP-CIT scans of 30 consecutive parkinsonism and tremor patients (N.=16 neurodegenerative, N.=14 non neurodegenerative) using VRDVR and VRP. In addition, a highly trained investigator performed manual ROI analyses. RESULTS: The ROI analysis provided complete separation of both patient groups by comparing the lower DAT binding of both putamina (i.e., putamen contralateral to clinically most affected side in neurodegenerative parkinsonism). Using VRP, the two most experienced observers correctly classified all patients while 20 false-positive ratings occurred in the less experienced observers (mean area under the receiver operating characteristic curve [AUCROC] of all observers 0.93+/-0.07). The VRDVR ratings of the two most experienced observers did not overlap between patient groups, although at different VRDVR score cut-offs. Using the same VRDVR score cut-off for all observers, only six false-negative and one false-positive ratings occurred in total (AUCROC 0.99+/-0.01). Inter-observer agreement was good for VRP and VRDVR. Moreover, semi-quantitative VRDVR and quantitative ROI analyses showed a strong correlation in all observers (Spearman's rho, 0.85-0.91). CONCLUSIONS: The proposed VRDVR method offers a very promising visual analysis method for [(123)I]FP-CIT SPECT studies in parkinsonism. The accuracy of VRDVR readings was found to be superior to conventional VRP, while it provided a diagnostic accuracy in less experienced observers that is comparable to manual ROI analyses by a highly trained investigator. PMID- 21532543 TI - Novel series of (177)Lu-labeled bombesin derivatives with amino acidic spacers for selective targeting of human PC-3 prostate tumor cells. AB - AIM: Bombesin (BBN) has demonstrated the ability to bind with high affinity and specificity to GRP receptor, overexpressed on human prostate cancer. A large number of BBN derivatives have been synthesized for this purpose but most of them exhibit high abdominal accumulation, which may represent a problem in their clinical use due to serious side effects to patients. In this study we describe the results of radiolabeling with lutetium-177, stability and in vivo studies of novel phenyl-glycine-extended bombesin derivatives. The spacers were inserted to improve bombesin in vivo properties and to reduce its target to non-tumor sites. METHODS: Preliminary studies were done to establish the ideal conditions for labeling bombesin derivatives. Chromatography systems were applied to determine free lutetium and the stability of the preparations was evaluated either after storing at 2-8 oC or incubation in human serum at 37 oC. In vivo experiments included biodistribution, pharmacokinetics and SPECT images and were performed in Balb-c and Nude mice bearing PC-3 xenografts. RESULTS: The derivatives were labeled with high yield and kept stable at 2-8 oC and are metabolized by human serum enzymes. In vivo studies showed fast blood clearance of labeled peptides and rapid excretion, performed mainly by renal pathway. In addition, biodistribution and imaging studies showed low abdominal accumulation and significant and specific tumor uptake of (177)Lu-labeled derivatives. CONCLUSIONS: The derivative with longer spacer holds a higher potential as radiopharmaceutical for prostate tumor diagnosis and the derivatives with shorter spacers are potential radiopharmaceuticals for prostate tumor treatment. PMID- 21532544 TI - Influence of PET/CT on radiologists and contrast-enhanced CT on nuclear medicine physicians in patients with lymphoma. AB - AIM: We assessed in this study the influence of contrast-enhanced CT (ceCT) on PET/CT interpretation and PET/CT on ceCT interpretation in patients with lymphoma, before and after chemotherapy. METHODS: Fifty patients with Hodgkin disease (N.=17) or non-Hodgkin lymphomas (N.=33) were assessed before and after chemotherapy. PET/CT were performed 60 minutes after injection of FDG. Iopamidol was then injected and followed, 50 seconds later, by another CT. PET images were successively reconstructed using non-enhanced CT (PET-) and ceCT (PET+). Four nuclear physicians rated PET- and PET+ in random order. Three radiologists initially rated ceCT alone and then ceCT along with PET+. RESULTS: Before chemotherapy, global agreement (GA) was 99% (k=0.96) when PET- was compared to PET+. Nine (5%) lesions were discordant, 5 according to PET- and 4 to PET+. After chemotherapy, GA was 99% (k=0.91). Eight (15%) lesions were discordant, 3 according to PET- and 5 to PET+. Before chemotherapy, GA was 97% (k=0.91) when ceCT was compared to ceCT with PET+. Twenty-one (12%) lesions were discordant, 16 when ceCT were analyzed alone and 5 when ceCT was analyzed with PET+. After chemotherapy, GA was 95% (k=0.76). All 30 (35%) discordant lesions were positive according to ceCT alone. A significant difference between the 2 procedures was found in the pelvis and in the groin (P<0.05). CONCLUSION: PET+ did not differ from PET-, before and after chemotherapy. Fewer abnormalities were observed, when ceCT was analyzed with PET+, particularly after chemotherapy, due to residual masses that are better analyzed with functional imaging. PMID- 21532545 TI - Squamous cell and adenosquamous carcinomas of the gallbladder: clinicopathological analysis of 34 cases identified in 606 carcinomas. AB - The information in the literature on squamous cell and adenosquamous carcinomas of the gallbladder is highly limited. In this study, 606 resected invasive gallbladder carcinoma cases were analyzed. Squamous differentiation was identified in 41 cases (7%). Those without any identifiable glandular-type invasive component were classified as pure squamous cell carcinomas (8 cases) and those with the squamous component constituting 25-99% of the tumors were classified as adenosquamous carcinomas (26 cases) and included into the analysis. The remaining 7 that had <25% squamous component were classified as adenocarcinoma with focal squamous change and excluded. The clinicopathological characteristics of adenosquamous carcinoma/squamous cell carcinomas were documented and contrasted with that of ordinary gallbladder adenocarcinomas. The average patient age was 65 years (range 26-81); female/male ratio, 3.8. In only 13%, there was a preoperative clinical suspicion of malignancy. Grossly, 58% presented as thickening and hardening of the wall and 6% were polypoid. In 12%, mucosa adjacent to the tumor revealed squamous metaplasia. All pure squamous cell carcinomas had prominent keratinization. Giant cells and tumor-infiltrating eosinophils were observed in 29 and 51% of the squamous cell carcinomas/adenosquamous carcinomas versus 10% (P=0.02) and 6% (P=0.001) in gallbladder adenocarcinomas, respectively. All but three cases had 'advanced' (pT2 and above) carcinomas. Follow-up was available in 31 patients: 25 died of disease (median=5 months, range 0-20), and 6 were alive (median=64 months, range 5-112.5). The survival of patients with squamous cell carcinomas/adenosquamous carcinomas was significantly worse than that of gallbladder adenocarcinomas (P=0.003), and this adverse prognosis persisted when compared with stage-matched advanced gallbladder adenocarcinoma cases (median=11.4 months, P=0.01). In conclusion, squamous differentiation was noted in 7% of gallbladder carcinomas. The incidence of adenosquamous carcinoma (defined as 25-99% of the tumor being squamous) was 4%, and that of pure squamous cell carcinoma (without any documented invasive glandular component) was 1%. Pure squamous cell carcinomas often showed prominent keratinization. The overall prognosis of adenosquamous carcinoma/squamous cell carcinoma appears to be even worse than that of ordinary adenocarcinomas. Most patients died within a few months; however, those few who were alive beyond 2 years in this cohort experienced long-term survival. PMID- 21532546 TI - Atypical ductal hyperplasia: interobserver and intraobserver variability. AB - Interobserver reproducibility in the diagnosis of benign intraductal proliferative lesions has been poor. The aims of the study were to investigate the inter- and intraobserver variability and the impact of the addition of an immunostain for high- and low-molecular weight keratins on the variability. Nine pathologists reviewed 81 cases of breast proliferative lesions in three stages and assigned each of the lesions to one of the following three diagnoses: usual ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ. Hematoxylin and eosin slides and corresponding slides stained with ADH-5 cocktail (cytokeratins (CK) 5, 14. 7, 18 and p63) by immunohistochemistry were evaluated. Concordance was evaluated at each stage of the study. The interobserver agreement among the nine pathologists for diagnosing the 81 proliferative breast lesions was fair (kappa-value=0.34). The intraobserver kappa-value ranged from 0.56 to 0.88 (moderate to strong). Complete agreement among nine pathologists was achieved in only nine (11%) cases, at least eight agreed in 20 (25%) cases and seven or more agreed in 38 (47%) cases. Following immunohistochemical stain, a significant improvement in the interobserver concordance (overall kappa value=0.50) was observed (P=0.015). There was a significant reduction in the total number of atypical ductal hyperplasia diagnosis made by nine pathologists after the use of ADH-5 immunostain. Atypical ductal hyperplasia still remains a diagnostic dilemma with wide variation in both inter- and intraobserver reproducibility among pathologists. The addition of an immunohistochemical stain led to a significant improvement in the concordance rate. More importantly, there was an 8% decrease in the number of lesions classified as atypical ductal hyperplasia in favor of usual hyperplasia; in clinical practice, this could lead to a decrease in the number of surgeries carried out for intraductal proliferative lesions. PMID- 21532547 TI - Reflections on the Innovative Medicines Initiative. AB - The pharmaceutical industry is developing new collaborative models for drug development. This article discusses the experience so far of the Innovative Medicines Initiative, which is currently the largest public-private partnership that is dedicated to pharmaceutical innovation, highlighting lessons learned for the success of precompetitive consortia. PMID- 21532548 TI - Bridging the drug-diagnostic divide. PMID- 21532549 TI - Dual fronts poised to transform melanoma therapy. PMID- 21532551 TI - Trial watch: Phase II failures: 2008-2010. PMID- 21532552 TI - Deal watch: HGS and FivePrime in FGF 'ligand trap' deal. PMID- 21532553 TI - Deal watch: Intra-Cellular Therapies and Takeda to develop PDE1 inhibitors for schizophrenia. PMID- 21532555 TI - An audience with... Fergus Sweeney. Interview by Asher Mullard. PMID- 21532556 TI - Innovative drug R&D in China. PMID- 21532557 TI - Belimumab. PMID- 21532558 TI - Autoimmune diseases: New route to targeting TNF. PMID- 21532559 TI - Anticancer drugs: SRC hits the mark. PMID- 21532561 TI - Autoimmune disease: New drug target for MS? PMID- 21532560 TI - Cardiovascular disease: Powering up a failing heart. PMID- 21532563 TI - Anticancer drugs: Think globally, act globally. PMID- 21532564 TI - European regulation on orphan medicinal products: 10 years of experience and future perspectives. AB - In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments. PMID- 21532565 TI - Harnessing synthetic lethal interactions in anticancer drug discovery. AB - Unique features of tumours that can be exploited by targeted therapies are a key focus of current cancer research. One such approach is known as synthetic lethality screening, which involves searching for genetic interactions of two mutations whereby the presence of either mutation alone has no effect on cell viability but the combination of the two mutations results in cell death. The presence of one of these mutations in cancer cells but not in normal cells can therefore create opportunities to selectively kill cancer cells by mimicking the effect of the second genetic mutation with targeted therapy. Here, we summarize strategies that can be used to identify synthetic lethal interactions for anticancer drug discovery, describe examples of such interactions that are currently being investigated in preclinical and clinical studies of targeted anticancer therapies, and discuss the challenges of realizing the full potential of such therapies. PMID- 21532566 TI - Anti-inflammatory therapeutics for the treatment of atherosclerosis. AB - Atherosclerosis is the primary cause of heart disease and stroke and is thus the underlying pathology of the leading causes of death in the western world. Although risk can be reduced by lowering lipid levels, the equally important contribution of inflammation to the development of cardiovascular disease is not adequately addressed by existing therapies. Here, we summarize the evidence supporting a role for inflammation in the pathogenesis of atherosclerosis, discuss agents that are currently in the clinic and provide a perspective on the challenges faced in the development of drugs that target vascular inflammation. PMID- 21532568 TI - Pneumococcal glycoconjugate vaccines produce antibody responses that strongly correlate with function. PMID- 21532567 TI - Priorities in Parkinson's disease research. AB - The loss of dopaminergic neurons in the substantia nigra pars compacta leads to the characteristic motor symptoms of Parkinson's disease: bradykinesia, rigidity and resting tremors. Although these symptoms can be improved using currently available dopamine replacement strategies, there is still a need to improve current strategies of treating these symptoms, together with a need to alleviate non-motor symptoms of the disease. Moreover, treatments that provide neuroprotection and/or disease-modifying effects remain an urgent unmet clinical need. This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address these treatment goals. Progress will rely on understanding genetic mutations or susceptibility factors that lead to Parkinson's disease, better translation between preclinical animal models and clinical research, and improving the design of future clinical trials. PMID- 21532569 TI - A sponsor's experience with the Voluntary Harmonization Procedure for clinical trial applications in the European Union. PMID- 21532570 TI - Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice. AB - Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people. Although 4 million people are bilaterally blind from ACG, the causative molecular mechanisms of ACG remain to be defined. High intraocular pressure induces glaucoma in ACG. High intraocular pressure traditionally was suggested to result from the iris blocking or closing the angle of the eye, thereby limiting aqueous humor drainage. Eyes from individuals with ACG often have a modestly decreased axial length, shallow anterior chamber and relatively large lens, features that predispose to angle closure. Here we show that genetic alteration of a previously unidentified serine protease (PRSS56) alters axial length and causes a mouse phenotype resembling ACG. Mutations affecting this protease also cause a severe decrease of axial length in individuals with posterior microphthalmia. Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG. PMID- 21532571 TI - Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. AB - We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 * 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 * 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 * 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 * 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma. PMID- 21532572 TI - Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. AB - DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases. PMID- 21532573 TI - Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. AB - The HMG-box transcription factor Sox2 plays a role throughout neurogenesis and also acts at other stages of development, as illustrated by the multiple organs affected in the anophthalmia syndrome caused by SOX2 mutations. Here we combined proteomic and genomic approaches to characterize gene regulation by Sox2 in neural stem cells. Chd7, a chromatin remodeling ATPase associated with CHARGE syndrome, was identified as a Sox2 transcriptional cofactor. Sox2 and Chd7 physically interact, have overlapping genome-wide binding sites and regulate a set of common target genes including Jag1, Gli3 and Mycn, genes mutated in Alagille, Pallister-Hall and Feingold syndromes, which show malformations also associated with SOX2 anophthalmia syndrome or CHARGE syndrome. Regulation of disease-associated genes by a Sox2-Chd7 complex provides a plausible explanation for several malformations associated with SOX2 anophthalmia syndrome or CHARGE syndrome. Indeed, we found that Chd7-haploinsufficient embryos showed severely reduced expression of Jag1 in the developing inner ear. PMID- 21532574 TI - General properties of transcriptional time series in Escherichia coli. AB - Gene activity is described by the time series of discrete, stochastic mRNA production events. This transcriptional time series shows intermittent, bursty behavior. One consequence of this temporal intricacy is that gene expression can be tuned by varying different features of the time series. Here we quantify copy number statistics of mRNA from 20 Escherichia coli promoters using single molecule fluorescence in situ hybridization in order to characterize the general properties of these transcriptional time series. We find that the degree of burstiness is correlated with gene expression level but is largely independent of other parameters of gene regulation. The observed behavior can be explained by the underlying variation in the duration of bursting events. Using Shannon's mutual information function, we estimate the mutual information transmitted between an outside stimulus, such as the extracellular concentration of inducer molecules, and intracellular levels of mRNA. This suggests that the outside stimulus transmits information reflected in the properties of transcriptional time series. PMID- 21532575 TI - Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells. AB - The molecular mechanisms that underlie T cell quiescence are poorly understood. Here we report that mature naive CD8(+) T cells lacking the transcription factor Foxp1 gained effector phenotype and function and proliferated directly in response to interleukin 7 (IL-7) in vitro. Foxp1 repressed expression of the IL-7 receptor alpha-chain (IL-7Ralpha) by antagonizing Foxo1 and negatively regulated signaling by the kinases MEK and Erk. Acute deletion of Foxp1 induced naive T cells to gain an effector phenotype and proliferate in lympho-replete mice. Foxp1 deficient naive CD8(+) T cells proliferated even in lymphopenic mice deficient in major histocompatibility complex class I. Our results demonstrate that Foxp1 exerts essential cell-intrinsic regulation of naive T cell quiescence, providing direct evidence that lymphocyte quiescence is achieved through actively maintained mechanisms that include transcriptional regulation. PMID- 21532576 TI - Functional dependence of neuroligin on a new non-PDZ intracellular domain. AB - Neuroligins, a family of postsynaptic adhesion molecules, are important in synaptogenesis through a well-characterized trans-synaptic interaction with neurexin. In addition, neuroligins are thought to drive postsynaptic assembly through binding of their intracellular domain to PSD-95. However, there is little direct evidence to support the functional necessity of the neuroligin intracellular domain in postsynaptic development. We found that presence of endogenous neuroligin obscured the study of exogenous mutated neuroligin. We therefore used chained microRNAs in rat organotypic hippocampal slices to generate a reduced background of endogenous neuroligin. On this reduced background, we found that neuroligin function was critically dependent on the cytoplasmic tail. However, this function required neither the PDZ ligand nor any other previously described cytoplasmic binding domain, but rather required a previously unknown conserved region. Mutation of a single critical residue in this region inhibited neuroligin-mediated excitatory synaptic potentiation. Finally, we found a functional distinction between neuroligins 1 and 3. PMID- 21532577 TI - NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents. AB - KCC2 is a neuron-specific K(+)-Cl(-) co-transporter that maintains a low intracellular Cl(-) concentration that is essential for hyperpolarizing inhibition mediated by GABA(A) receptors. Deficits in KCC2 activity occur in disease states associated with pathophysiological glutamate release. However, the mechanisms by which elevated glutamate alters KCC2 function are unknown. The phosphorylation of KCC2 residue Ser940 is known to regulate its surface activity. We found that NMDA receptor activity and Ca(2+) influx caused the dephosphorylation of Ser940 in dissociated rat neurons, leading to a loss of KCC2 function that lasted longer than 20 min. Protein phosphatase 1 mediated the dephosphorylation events of Ser940 that coincided with a deficit in hyperpolarizing GABAergic inhibition resulting from the loss of KCC2 activity. Blocking dephosphorylation of Ser940 reduced the glutamate-induced downregulation of KCC2 and substantially improved the maintenance of hyperpolarizing GABAergic inhibition. Reducing the downregulation of KCC2 therefore has therapeutic potential in the treatment of neurological disorders. PMID- 21532578 TI - NMDA receptor-dependent metaplasticity at hippocampal mossy fiber synapses. AB - Hippocampal mossy fiber synapses have been reported to lack NMDA receptor (NMDAR) dependent long-term potentiation (LTP) of AMPA excitatory postsynaptic currents (EPSCs), unlike conventional glutamatergic synapses. An explanation for this difference may reside in the relatively low number of NMDARs at these synapses. Because mossy fiber synapses display LTP selective for NMDARs, we examined whether this would affect the plasticity rules at mossy fiber-CA3 synapses in mouse hippocampal slices. We found that LTP of NMDARs serves as a metaplastic switch making mossy fiber synapses competent for generating NMDAR-dependent LTP of AMPA EPSCs. PMID- 21532580 TI - Neuronal activity drives matching of pre- and postsynaptic function during synapse maturation. AB - The structure and function of presynaptic and postsynaptic compartments varies markedly in neurons, but little is known about how they are functionally arranged with respect to each other. In rat hippocampal neurons, we found that, although they are structurally correlated from the early moments of formation, synapses only gradually become functionally matched and that this process is dependent on ongoing electrical activity. PMID- 21532579 TI - Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. AB - Amyloid-beta (Abeta) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Abeta deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Abeta, which drives local Abeta aggregation. Using in vivo microdialysis, we show that ISF Abeta concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Abeta, and unilateral vibrissal deprivation decreased ISF Abeta and lactate, in contralateral barrel cortex. Long term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Abeta deposition in Alzheimer's disease. PMID- 21532581 TI - Analysis of repetitive DNA in chromosomes by flow cytometry. AB - We developed a flow cytometry method, chromosome flow fluorescence in situ hybridization (FISH), called CFF, to analyze repetitive DNA in chromosomes using FISH with directly labeled peptide nucleic acid (PNA) probes. We used CFF to measure the abundance of interstitial telomeric sequences in Chinese hamster chromosomes and major satellite sequences in mouse chromosomes. Using CFF we also identified parental homologs of human chromosome 18 with different amounts of repetitive DNA. PMID- 21532583 TI - Optimization of the thermoelectric figure of merit in the conducting polymer poly(3,4-ethylenedioxythiophene). AB - Thermoelectric generators (TEGs) transform a heat flow into electricity. Thermoelectric materials are being investigated for electricity production from waste heat (co-generation) and natural heat sources. For temperatures below 200 degrees C, the best commercially available inorganic semiconductors are bismuth telluride (Bi(2)Te(3))-based alloys, which possess a figure of merit ZT close to one. Most of the recently discovered thermoelectric materials with ZT>2 exhibit one common property, namely their low lattice thermal conductivities. Nevertheless, a high ZT value is not enough to create a viable technology platform for energy harvesting. To generate electricity from large volumes of warm fluids, heat exchangers must be functionalized with TEGs. This requires thermoelectric materials that are readily synthesized, air stable, environmentally friendly and solution processable to create patterns on large areas. Here we show that conducting polymers might be capable of meeting these demands. The accurate control of the oxidation level in poly(3,4 ethylenedioxythiophene) (PEDOT) combined with its low intrinsic thermal conductivity (lambda=0.37 W m(-1) K(-1)) yields a ZT=0.25 at room temperature that approaches the values required for efficient devices. PMID- 21532582 TI - BrainAligner: 3D registration atlases of Drosophila brains. AB - Analyzing Drosophila melanogaster neural expression patterns in thousands of three-dimensional image stacks of individual brains requires registering them into a canonical framework based on a fiducial reference of neuropil morphology. Given a target brain labeled with predefined landmarks, the BrainAligner program automatically finds the corresponding landmarks in a subject brain and maps it to the coordinate system of the target brain via a deformable warp. Using a neuropil marker (the antibody nc82) as a reference of the brain morphology and a target brain that is itself a statistical average of data for 295 brains, we achieved a registration accuracy of 2 MUm on average, permitting assessment of stereotypy, potential connectivity and functional mapping of the adult fruit fly brain. We used BrainAligner to generate an image pattern atlas of 2954 registered brains containing 470 different expression patterns that cover all the major compartments of the fly brain. PMID- 21532584 TI - High-performance flat-panel solar thermoelectric generators with high thermal concentration. AB - The conversion of sunlight into electricity has been dominated by photovoltaic and solar thermal power generation. Photovoltaic cells are deployed widely, mostly as flat panels, whereas solar thermal electricity generation relying on optical concentrators and mechanical heat engines is only seen in large-scale power plants. Here we demonstrate a promising flat-panel solar thermal to electric power conversion technology based on the Seebeck effect and high thermal concentration, thus enabling wider applications. The developed solar thermoelectric generators (STEGs) achieved a peak efficiency of 4.6% under AM1.5G (1 kW m(-2)) conditions. The efficiency is 7-8 times higher than the previously reported best value for a flat-panel STEG, and is enabled by the use of high performance nanostructured thermoelectric materials and spectrally-selective solar absorbers in an innovative design that exploits high thermal concentration in an evacuated environment. Our work opens up a promising new approach which has the potential to achieve cost-effective conversion of solar energy into electricity. PMID- 21532585 TI - PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B. AB - Reversible histone methylation and demethylation are highly regulated processes that are crucial for chromatin reorganization and regulation of gene transcription in response to extracellular conditions. However, the mechanisms that regulate histone-modifying enzymes are largely unknown. Here, we characterized a protein kinase A (PKA)-dependent histone lysine demethylase complex, PHF2-ARID5B. PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. These findings suggest that the PHF2-ARID5B complex is a signal-sensing modulator of histone methylation and gene transcription, in which phosphorylation of PHF2 enables subsequent formation of a competent and specific histone demethylase complex. PMID- 21532586 TI - WWP2 is an E3 ubiquitin ligase for PTEN. AB - PTEN, a lipid phosphatase, is one of the most frequently mutated tumour suppressors in human cancer. Several recent studies have highlighted the importance of ubiquitylation in regulating PTEN tumour-suppressor function, but the enzymatic machinery required for PTEN ubiquitylation is not clear. In this study, by using a tandem affinity-purification approach, we have identified WWP2 (also known as atrophin-1-interacting protein 2, AIP-2) as a PTEN-interacting protein. WWP2 is an E3 ubiquitin ligase that belongs to the NEDD4-like protein family, which is involved in regulating transcription, embryonic stem-cell fate, cellular transport and T-cell activation processes. We show that WWP2 physically interacts with PTEN and mediates its degradation through a ubiquitylation dependent pathway. Functionally, we show that WWP2 controls cellular apoptosis and is required for tumorigenicity of cells. Collectively, our results reveal a functional E3 ubiquitin ligase for PTEN that plays a vital role in tumour-cell survival. PMID- 21532587 TI - Sequential interactions with Sec23 control the direction of vesicle traffic. AB - How the directionality of vesicle traffic is achieved remains an important unanswered question in cell biology. The Sec23p/Sec24p coat complex sorts the fusion machinery (SNAREs) into vesicles as they bud from the endoplasmic reticulum (ER). Vesicle tethering to the Golgi begins when the tethering factor TRAPPI binds to Sec23p. Where the coat is released and how this event relates to membrane fusion is unknown. Here we use a yeast transport assay to demonstrate that an ER-derived vesicle retains its coat until it reaches the Golgi. A Golgi associated kinase, Hrr25p (CK1delta orthologue), then phosphorylates the Sec23p/Sec24p complex. Coat phosphorylation and dephosphorylation are needed for vesicle fusion and budding, respectively. Additionally, we show that Sec23p interacts in a sequential manner with different binding partners, including TRAPPI and Hrr25p, to ensure the directionality of ER-Golgi traffic and prevent the back-fusion of a COPII vesicle with the ER. These events are conserved in mammalian cells. PMID- 21532588 TI - A single-atom quantum memory. AB - The faithful storage of a quantum bit (qubit) of light is essential for long distance quantum communication, quantum networking and distributed quantum computing. The required optical quantum memory must be able to receive and recreate the photonic qubit; additionally, it must store an unknown quantum state of light better than any classical device. So far, these two requirements have been met only by ensembles of material particles that store the information in collective excitations. Recent developments, however, have paved the way for an approach in which the information exchange occurs between single quanta of light and matter. This single-particle approach allows the material qubit to be addressed, which has fundamental advantages for realistic implementations. First, it enables a heralding mechanism that signals the successful storage of a photon by means of state detection; this can be used to combat inevitable losses and finite efficiencies. Second, it allows for individual qubit manipulations, opening up avenues for in situ processing of the stored quantum information. Here we demonstrate the most fundamental implementation of such a quantum memory, by mapping arbitrary polarization states of light into and out of a single atom trapped inside an optical cavity. The memory performance is tested with weak coherent pulses and analysed using full quantum process tomography. The average fidelity is measured to be 93%, and low decoherence rates result in qubit coherence times exceeding 180 microseconds. This makes our system a versatile quantum node with excellent prospects for applications in optical quantum gates and quantum repeaters. PMID- 21532589 TI - Improved molecular replacement by density- and energy-guided protein structure optimization. AB - Molecular replacement procedures, which search for placements of a starting model within the crystallographic unit cell that best account for the measured diffraction amplitudes, followed by automatic chain tracing methods, have allowed the rapid solution of large numbers of protein crystal structures. Despite extensive work, molecular replacement or the subsequent rebuilding usually fail with more divergent starting models based on remote homologues with less than 30% sequence identity. Here we show that this limitation can be substantially reduced by combining algorithms for protein structure modelling with those developed for crystallographic structure determination. An approach integrating Rosetta structure modelling with Autobuild chain tracing yielded high-resolution structures for 8 of 13 X-ray diffraction data sets that could not be solved in the laboratories of expert crystallographers and that remained unsolved after application of an extensive array of alternative approaches. We estimate that the new method should allow rapid structure determination without experimental phase information for over half the cases where current methods fail, given diffraction data sets of better than 3.2 A resolution, four or fewer copies in the asymmetric unit, and the availability of structures of homologous proteins with >20% sequence identity. PMID- 21532590 TI - Learning-related feedforward inhibitory connectivity growth required for memory precision. AB - In the adult brain, new synapses are formed and pre-existing ones are lost, but the function of this structural plasticity has remained unclear. Learning of new skills is correlated with formation of new synapses. These may directly encode new memories, but they may also have more general roles in memory encoding and retrieval processes. Here we investigated how mossy fibre terminal complexes at the entry of hippocampal and cerebellar circuits rearrange upon learning in mice, and what is the functional role of the rearrangements. We show that one-trial and incremental learning lead to robust, circuit-specific, long-lasting and reversible increases in the numbers of filopodial synapses onto fast-spiking interneurons that trigger feedforward inhibition. The increase in feedforward inhibition connectivity involved a majority of the presynaptic terminals, restricted the numbers of c-Fos-expressing postsynaptic neurons at memory retrieval, and correlated temporally with the quality of the memory. We then show that for contextual fear conditioning and Morris water maze learning, increased feedforward inhibition connectivity by hippocampal mossy fibres has a critical role for the precision of the memory and the learned behaviour. In the absence of mossy fibre long-term potentiation in Rab3a(-/-) mice, c-Fos ensemble reorganization and feedforward inhibition growth were both absent in CA3 upon learning, and the memory was imprecise. By contrast, in the absence of adducin 2 (Add2; also known as beta-adducin) c-Fos reorganization was normal, but feedforward inhibition growth was abolished. In parallel, c-Fos ensembles in CA3 were greatly enlarged, and the memory was imprecise. Feedforward inhibition growth and memory precision were both rescued by re-expression of Add2 specifically in hippocampal mossy fibres. These results establish a causal relationship between learning-related increases in the numbers of defined synapses and the precision of learning and memory in the adult. The results further relate plasticity and feedforward inhibition growth at hippocampal mossy fibres to the precision of hippocampus-dependent memories. PMID- 21532591 TI - Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. AB - The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity. However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity. PMID- 21532592 TI - UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. AB - Although the functional interaction between ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) is essential in ubiquitin (Ub) signalling, the criteria that define an active E2-E3 pair are not well established. The human E2 UBCH7 (also known as UBE2L3) shows broad specificity for HECT-type E3s, but often fails to function with RING E3s in vitro despite forming specific complexes. Structural comparisons of inactive UBCH7-RING complexes with active UBCH5-RING complexes reveal no defining differences, highlighting a gap in our understanding of Ub transfer. Here we show that, unlike many E2s that transfer Ub with RINGs, UBCH7 lacks intrinsic, E3-independent reactivity with lysine, explaining its preference for HECTs. Despite lacking lysine reactivity, UBCH7 exhibits activity with the RING-in-between-RING (RBR) family of E3s that includes parkin (also known as PARK2) and human homologue of ariadne (HHARI; also known as ARIH1). Found in all eukaryotes, RBRs regulate processes such as translation and immune signalling. RBRs contain a canonical C3HC4-type RING, followed by two conserved Cys/His-rich Zn(2+)-binding domains, in-between-RING (IBR) and RING2 domains, which together define this E3 family. We show that RBRs function like RING/HECT hybrids: they bind E2s via a RING domain, but transfer Ub through an obligate thioester-linked Ub (denoted ~Ub), requiring a conserved cysteine residue in RING2. Our results define the functional cadre of E3s for UBCH7, an E2 involved in cell proliferation and immune function, and indicate a novel mechanism for an entire class of E3s. PMID- 21532593 TI - Tuning protein autoinhibition by domain destabilization. AB - Activation of many multidomain signaling proteins requires rearrangement of autoinhibitory interdomain interactions that occlude activator binding sites. In one model for activation, the major inactive conformation exists in equilibrium with activated-like conformations that can be stabilized by ligand binding or post-translational modifications. We established the molecular basis for this model for the archetypal signaling adaptor protein Crk-II by measuring the thermodynamics and kinetics of the equilibrium between autoinhibited and activated-like states. We used fluorescence and NMR spectroscopies together with segmental isotopic labeling by means of expressed protein ligation. The results demonstrate that intramolecular domain-domain interactions both stabilize the autoinhibited state and induce the activated-like conformation. A combination of favorable interdomain interactions and unfavorable intradomain structural changes fine-tunes the population of the activated-like conformation and allows facile response to activators. This mechanism suggests a general strategy for optimization of autoinhibitory interactions of multidomain proteins. PMID- 21532594 TI - Structural adaptation of the plant protease Deg1 to repair photosystem II during light exposure. AB - Deg1 is a chloroplastic protease involved in maintaining the photosynthetic machinery. Structural and biochemical analyses reveal that the inactive Deg1 monomer is transformed into the proteolytically active hexamer at acidic pH. The change in pH is sensed by His244, which upon protonation, repositions a specific helix to trigger oligomerization. This system ensures selective activation of Deg1 during daylight, when acidification of the thylakoid lumen occurs and photosynthetic proteins are damaged. PMID- 21532595 TI - A role for central nervous system PPAR-gamma in the regulation of energy balance. AB - The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences. PPAR-gamma is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain. Here we report a previously unknown role for central nervous system (CNS) PPAR-gamma in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-gamma, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-gamma and the viral transcriptional activator VP16 (VP16-PPAR-gamma), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-gamma with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity. PMID- 21532596 TI - Brain PPAR-gamma promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. AB - In adipose tissue, muscle, liver and macrophages, signaling by the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a determinant of insulin sensitivity and this receptor mediates the insulin sensitizing effects of thiazolidinediones (TZDs). As PPAR-gamma is also expressed in neurons, we generated mice with neuron-specific Pparg knockout (Pparg brain knockout (BKO)) to determine whether neuronal PPAR-gamma signaling contributes to either weight gain or insulin sensitivity. During high-fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparg-BKO mice compared to Pparg(f/f) mice, resulting in reduced weight gain. Pparg-BKO mice also responded better to leptin administration than Pparg(f/f) mice. When treated with the TZD rosiglitazone, Pparg-BKO mice were resistant to rosiglitazone induced hyperphagia and weight gain and, relative to rosiglitazone-treated Pparg(f/f) mice, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the increase in hepatic insulin sensitivity induced by rosiglitazone treatment during HFD feeding was completely abolished in Pparg-BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor signal transduction. We conclude that excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPAR-gamma signaling to limit thermogenesis and increase food intake. Neuronal PPAR-gamma signaling is also required for the hepatic insulin sensitizing effects of TZDs. PMID- 21532597 TI - A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. AB - Although previous studies have described CD25 expression and production of interleukin-2 (IL-2) by mature dendritic cells (mDCs), it remains unclear how these molecules participate in the activation of T cells. In search of the mechanisms by which daclizumab, a humanized monoclonal antibody against CD25, inhibits brain inflammation in multiple sclerosis, we observed that although the drug has limited effects on polyclonal T cell activation, it potently inhibits activation of antigen-specific T cells by mDCs. We show that mDCs (and antigen experienced T cells) secrete IL-2 toward the mDC-T cell interface in an antigen specific manner, and mDCs 'lend' their CD25 to primed T cells in trans to facilitate early high-affinity IL-2 signaling, which is crucial for subsequent T cell expansion and development of antigen-specific effectors. Our data reveal a previously unknown mechanism for the IL-2 receptor system in DC-mediated activation of T cells. PMID- 21532598 TI - Conformational capture of the SAM-II riboswitch. AB - Riboswitches are gene regulation elements in mRNA that function by specifically responding to metabolites. Although the metabolite-bound states of riboswitches have proven amenable to structure determination efforts, knowledge of the structural features of riboswitches in their ligand-free forms and their ligand response mechanisms giving rise to regulatory control is lacking. Here we explore the ligand-induced folding process of the S-adenosylmethionine type II (SAM-II) riboswitch using chemical and biophysical methods, including NMR and fluorescence spectroscopy, and single-molecule fluorescence imaging. The data reveal that the unliganded SAM-II riboswitch is dynamic in nature, in that its stem-loop element becomes engaged in a pseudoknot fold through base-pairing with nucleosides in the 3' overhang containing the Shine-Dalgarno sequence. Although the pseudoknot structure is highly transient in the absence of its ligand, S-adenosylmethionine (SAM), it becomes conformationally restrained upon ligand recognition, through a conformational capture mechanism. These insights provide a molecular understanding of riboswitch dynamics that shed new light on the mechanism of riboswitch-mediated translational regulation. PMID- 21532599 TI - Molecular insights into the ligand-controlled organization of the SAM-I riboswitch. AB - S-adenosylmethionine (SAM) riboswitches are widespread in bacteria, and up to five different SAM riboswitch families have been reported, highlighting the relevance of SAM regulation. On the basis of crystallographic and biochemical data, it has been postulated, but never demonstrated, that ligand recognition by SAM riboswitches involves key conformational changes in the RNA architecture. We show here that the aptamer follows a two-step hierarchical folding selectively induced by metal ions and ligand binding, each of them leading to the formation of one of the two helical stacks observed in the crystal structure. Moreover, we find that the anti-antiterminator P1 stem is rotated along its helical axis upon ligand binding, a mechanistic feature that could be common to other riboswitches. We also show that the nonconserved P4 helical domain is used as an auxiliary element to enhance the ligand-binding affinity. This work provides the first comprehensive characterization, to our knowledge, of a ligand-controlled riboswitch folding pathway. PMID- 21532600 TI - Prostate-specific antigen (PSA) velocity: a test of controversial benefit in the era of increased prostate cancer screening. PMID- 21532601 TI - Current therapeutic strategies for premature ejaculation and future perspectives. AB - Premature ejaculation (PE) is a common sexual disorder in men that is mediated by disturbances in the peripheral and central nervous systems. Although all pharmaceutical treatments for PE are currently used 'off-label', some novel oral agents and some newer methods of drug administration now provide important relief to PE patients. However, the aetiology of this condition has still not been unified, primarily because of the lack of a standard animal model for basic research and the absence of a widely accepted definition and assessment tool for evidence-based clinical studies in patients with PE. In this review, we focus on the current therapeutic strategies and future treatment perspectives for PE. PMID- 21532602 TI - The moderating impact of lifestyle factors on sex steroids, sexual activities and aging in Asian men. AB - The present study sought to evaluate the relative associations of exercise, sleep and other lifestyle habits with aging, sex hormones, percent body fat (%BF) and sexual activities in men living in the community. A better understanding of this complex interrelationship is important in helping the formulation of modalities for a holistic approach to the management of aging men. The results showed that age is a major determinant for many physiological parameters, including sleep, hormonal and metabolic parameters, some lifestyle factors and sexual activities. Testosterone (T), bioavailable testosterone (BioT) and dehydroepiandrosterone sulphate (DHEAS) concentrations decreased with age, while estradiol (E2), sex hormone-binding globulin (SHBG) and %BF increased with age. In addition, there exist intricate associations among hormonal and lifestyle factors, %BF and age. High-intensity exercise and longer duration of sleep were associated with higher concentrations of T and BioT. T was shown to be associated positively with men who were engaged in masturbation. DHEAS was associated with men wanting more sex and with good morning penile rigidity. Older Singaporean men tended to sleep for shorter duration, but exercised more intensely than younger men. Coital and masturbation frequencies decreased with age, and a significantly greater number of younger men were engaged in masturbation. Relationship between the partners is a key determinant of sexuality in men. It appears that T may have a limited, while dehydroepiandrosterone (DHEA) have a greater role than previously suggest, as a motivational signal for sexual function in men. Both biological and psychosocial factors interact with each other to influence sexual functions in men. Hence, a biopsychosocial approach may be more appropriate for a more lasting resolution to sexual dysfunctions in men. PMID- 21532604 TI - Midlife moments. PMID- 21532603 TI - Epigenetic marks in zebrafish sperm: insights into chromatin compaction, maintenance of pluripotency, and the role of the paternal genome after fertilization. PMID- 21532607 TI - The ideal vaccine: until death do us part. PMID- 21532608 TI - Therapeutic delivery of mRNA: the medium is the message. PMID- 21532609 TI - Sensor and sensitivity: a screen for elite shRNAs. PMID- 21532610 TI - A barrel of monkeys: scAAV8 gene therapy for hemophilia in nonhuman primates. PMID- 21532611 TI - Moving forward toward a cure for Parkinson's: neuropathology of the nigrostriatal pathway determines the location of growth factor delivery. PMID- 21532612 TI - Intrapleural delivery of mesenchymal stem cells: a novel potential treatment for pleural diseases. AB - AIM: To develop a method to deliver mesenchymal stem cells (MSCs) into the pleural cavity for the treatment of pleural diseases. METHODS: MSCs were isolated from rat bone marrow of rats and labeled with 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) or green fluorescent protein (GFP) using a lentiviral vector. Eighteen Sprague-Dawley (SD) rats were inoculated intrapleurally with 1*10(6) MSCs-DAPI. The distribution of the fluorescent cells was observed using fluorescent microscopy for the following 30 d. Another 12 rats inoculated intrapleurally with 1*10(6) MSCs-GFP were observed for 14 d. RESULTS: The isolated cells were typical MSC phenotypes and could differentiate into adipocytes, osteoblasts, and chondroblasts in vitro. Microscopic analysis revealed that the labeled cells adhered to the surface of the pleural cavity. The highest number of the labeled cells was found to be adhered to all specimens from the mediastinal pleura, but no labeled cells were detected in the lung parenchyma or other tissues/organs, such as the liver, kidney, spleen, and mesenterium. Incidentally, stomas were found in the mediastinal pleura. The recovered MSCs-GFP from the pleural cavity retained their ability to adhere and proliferate. CONCLUSION: We have established a novel method for intrapleural delivery of MSCs. The distribution of intrapleurally delivered MSCs was found to be limited to the pleurae and the pleural cavity, thereby providing us with a new approach to further investigation of the therapeutic roles of MSCs in pleural diseases. PMID- 21532613 TI - Nanodiamond delivery circumvents tumor resistance to doxorubicin. PMID- 21532614 TI - Depletion of insulin receptor substrate 2 reverses oncogenic transformation induced by v-src. AB - AIM: To investigate the role of insulin receptor substrate 2 (IRS-2) in oncogenic transformation induced by v-src. METHODS: IRS-2 gene was silenced using small interfering RNAs (siRNAs). Nuclear translocation and interaction of IRS-2 with v src was determined using subcellular fractionation, confocal microscopy, and immunoprecipitation. The activity of the cyclin D1 promoter and r-DNA promoter was measured with a luciferase assay. RESULTS: Depletion of IRS-2 inhibited R-/v src cell growth and reverse the oncogenic transformation. IRS-2 bound to src via its two PI3-K binding sites, which are critical for activities involved in the transformation. Nuclear IRS-2 occupied the cyclin D1 and rDNA promoters. The combination of IRS-2 and v-src increased the activity of the two promoters, especially the rDNA promoter. CONCLUSION: Depletion of insulin receptor substrate 2 could reverse oncogenic transformation induced by v-src. PMID- 21532615 TI - Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer. AB - The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer. PMID- 21532617 TI - Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers. AB - Prostate cancer and breast cancer are the most common malignancies in the western world. Androgen receptor (AR) and PTEN both have been well documented to have important roles in prostate carcinogenesis. In contrast, AR and PTEN in breast carcinogenesis have not been well studied. Furthermore, the crosstalk and connection between those two pathways remain unclear. Increased AR expression in prostate cancers, combined with decreased PTEN expression, portends a poor clinical outcome. Paradoxically, both high AR and high PTEN levels, detected by immunohistochemistry, in primary breast carcinomas have been associated with better disease-free survival. Here, we performed in silico analysis of publicly available microarray data sets from prostate or breast carcinomas. We found an inverse correlation between AR and PTEN transcript expression in prostate cancer tissues in contrast to the positive correlation in breast cancer. These data led us to hypothesize that AR may directly affect PTEN transcriptional regulation in prostate and breast cancer cells. Here, we show for the first time that AR inhibits PTEN transcription in prostate cancer cells, whereas AR upregulates PTEN transcription in breast cancer cells, which mechanistically explains both the immunohistochemical PTEN-AR expressional data noted in clinical trials and in our in silico analysis of the transcriptomes of breast and prostate cancers. In addition, we have fine-mapped the AR-binding motif within the PTEN promoter. Here we show that, in patients with Cowden syndrome, an inherited cancer syndrome caused by germline mutations scattered throughout PTEN, point variants affecting the 3' end of the AR-binding motif result in abrogation of androgen-mediated transcriptional regulation of PTEN expression. We may speculate that the differential AR effect on PTEN may begin to explain organ-specific and perhaps sex-specific neoplasia predisposition in Cowden syndrome, as well as why only a fraction of women with germline PTEN mutations develop breast cancer, depending on the androgen steroid milieu and levels. PMID- 21532616 TI - Akt1 deficiency delays tumor progression, vascular invasion, and distant metastasis in a murine model of thyroid cancer. AB - Akt activation is common in progressive thyroid cancer. In breast cancer, Akt1 induces primary cancer growth, but is reported to inhibit metastasis in vivo in several model systems. In contrast, clinical and in vitro studies suggest a metastasis-promoting role for Akt1 in thyroid cancer. The goal of this study was to determine the functional role of Akt1 in thyroid cancer growth and metastatic progression in vivo using thyroid hormone receptor (TR) beta(PV/PV) knock-in (PV) mice, which develop metastatic thyroid cancer. We crossed Akt1(-/-) and PV mice and compared tumor development, local progression, metastasis and histology in TRbeta(PV/PV)/Akt1(+/+) (PVPV-Akt1WT) and TRbeta(PV/PV)/Akt1(-/-) (PVPV-Akt1KO) mice. Mice were killed at 3, 6, 9, 12 and 15 months; necropsy was performed and serum thyroid stimulating hormone (TSH) was measured. Thyroid hyperplasia occurred in both groups beginning at 3 months; the thyroid size was greater in the PVPV-Akt1WT mice (P<0.001). In comparison with PVPV-Akt1WT mice, thyroid cancer development was delayed in the PVPV-Akt1KO mice (P=0.003) and the degree of tumor invasiveness was reduced. The PVPV-Akt1WT mice displayed pulmonary metastases at 12 and 15 months of age, by contrast PVPV-Akt1KO mice did not develop distant metastases at 15 months of age. Despite continued expression of Akt2 or Akt3, pAkt levels were decreased and there was evidence of reduced Akt effect on p27 in the PVPV-Akt1KO thyroids. TSH levels were similarly elevated in PV mice regardless of Akt1 expression. In conclusion, thyroid cancer development and progression in TR beta(PV/PV) mice are Akt1-dependent, consistent with a tumor progression-promoting role in this murine thyroid cancer model. PMID- 21532619 TI - The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6. AB - Human T cell leukemia virus type-1 (HTLV-1) is the causative agent of a fatal adult T-cell leukemia. Through deregulation of multiple cellular signaling pathways the viral Tax protein has a pivotal role in T-cell transformation. In response to stressful stimuli, cells mount a cellular stress response to limit the damage that environmental forces inflict on DNA or proteins. During stress response, cells postpone the translation of most cellular mRNAs, which are gathered into cytoplasmic mRNA-silencing foci called stress granules (SGs) and allocate their available resources towards the production of dedicated stress management proteins. Here we demonstrate that Tax controls the formation of SGs and interferes with the cellular stress response pathway. In agreement with previous reports, we observed that Tax relocates from the nucleus to the cytoplasm in response to environmental stress. We found that the presence of Tax in the cytoplasm of stressed cells prevents the formation of SGs and counteracts the shutoff of specific host proteins. Unexpectedly, nuclear localization of Tax promotes spontaneous aggregation of SGs, even in the absence of stress. Mutant analysis revealed that the SG inhibitory capacity of Tax is independent of its transcriptional abilities but relies on its interaction with histone deacetylase 6, a critical component of SGs. Importantly, the stress-protective effect of Tax was also observed in the context of HTLV-1 infected cells, which were shown to be less prone to form SGs and undergo apoptosis under arsenite exposure. These observations identify Tax as the first virally encoded inhibitory component of SGs and unravel a new strategy developed by HTLV-1 to deregulate normal cell processes. We postulate that inhibition of the stress response pathway by Tax would favor cell survival under stressful conditions and may have an important role in HTLV-1-induced cellular transformation. PMID- 21532618 TI - The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma. AB - Rap1GAP is a critical tumor suppressor gene that is downregulated in multiple aggressive cancers, such as head and neck squamous cell carcinoma, melanoma and pancreatic cancer. However, the mechanistic basis of rap1GAP downregulation in cancers is poorly understood. By employing an integrative approach, we demonstrate polycomb-mediated repression of rap1GAP that involves Enhancer of Zeste Homolog 2 (EZH2), a histone methyltransferase in head and neck cancers. We further demonstrate that the loss of miR-101 expression correlates with EZH2 upregulation, and the concomitant downregulation of rap1GAP in head and neck cancers. EZH2 represses rap1GAP by facilitating the trimethylation of histone 3 at lysine 27, a mark of gene repression, and also hypermethylation of rap1GAP promoter. These results provide a conceptual framework involving a microRNA oncogene-tumor suppressor axis to understand head and neck cancer progression. PMID- 21532620 TI - FZD7 has a critical role in cell proliferation in triple negative breast cancer. AB - Breast cancer is genetically and clinically heterogeneous. Triple negative breast cancer (TNBC) is a subtype of breast cancer that is usually associated with poor outcome and lack of benefit from targeted therapy. We used microarray analysis to perform a pathway analysis of TNBC compared with non-triple negative breast cancer (non-TNBC). Overexpression of several Wnt pathway genes, such as frizzled homolog 7 (FZD7), low density lipoprotein receptor-related protein 6 and transcription factor 7 (TCF7) was observed in TNBC, and we directed our focus to the Wnt pathway receptor, FZD7. To validate the function of FZD7, FZD7shRNA was used to knock down FZD7 expression. Notably, reduced cell proliferation and suppressed invasiveness and colony formation were observed in TNBC MDA-MB-231 and BT-20 cells. Study of the possible mechanism indicated that these effects occurred through silencing of the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of beta-catenin and decreased transcriptional activity of TCF7. In vivo studies revealed that FZD7shRNA significantly suppressed tumor formation, through reduced cell proliferation, in mice bearing xenografts without FZD7 expression. Our findings suggest that FZD7-involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC, and thus, FZD7 shows promise as a biomarker and a potential therapeutic target for TNBC. PMID- 21532621 TI - Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells. AB - Nodal, a member of the transforming growth factor-beta superfamily, has been recently shown to suppress cell proliferation and to stimulate the expression of cyclin G2 (CCNG2) in human epithelial ovarian cancer cells. However, the precise mechanisms underlying these events are not fully understood. In this study, we investigated the transcriptional regulation of CCNG2 by the Nodal signaling pathway. In ovarian cancer cells, overexpression of Nodal or its receptors, activin receptor-like kinase 7 (ALK7) or ALK4, resulted in an increase in the CCNG2 promoter activity. Several putative Forkhead box class O (FoxO)3a-binding sites are present in the human CCNG2 promoter and overexpression of FoxO3a enhanced the CCNG2 promoter activity. The functional FoxO3a-binding element (FBE) was mapped to a proximal region located between -398 and -380 bp (FBE1) through deletion and mutation analyses, as well as chromatin immunoprecipitation (IP) assay. Interestingly, mutation of the FBE1 not only abolished the effect of FoxO3a, but also blocked Nodal-induced CCNG2 transcription. Nodal stimulated FoxO3a mRNA and protein expression through the canonical Smad pathway and suppressed FoxO3a inactivation by inhibiting AKT activity. Silencing of FoxO3a using small interfering RNA significantly reduced the effect of Nodal on the CCNG2 promoter activity. On the other hand, overexpression of Smad2 and Smad3 enhanced the FoxO3a-induced CCNG2 promoter activity whereas knockdown of Smad4 blocked the activity of FoxO3a. Furthermore, IP assays revealed that FoxO3a formed complexes with Smad proteins and that Nodal enhanced the binding of FoxO3a to the CCNG2 promoter. Finally, silencing of FoxO3a reversed the inhibitory effect of Nodal on cell proliferation. Taken together, these findings demonstrated that Nodal signaling promotes CCNG2 transcription by upregulating FoxO3a expression, inhibiting FoxO3a phosphorylation and enhancing its synergistic interaction with Smads. These results also suggest that FoxO3a is an important mediator of Nodal signaling in ovarian cancer cells. PMID- 21532622 TI - E2F1 suppresses Wnt/beta-catenin activity through transactivation of beta-catenin interacting protein ICAT. AB - Deregulation of the pRb/E2F or Wnt/beta-catenin pathway occurs frequently in human cancers, which is often associated with inappropriate cell proliferation. Although the oncogenic roles of pRb/E2F1 and Wnt/beta-catenin pathways have been well studied, the functional interaction between the two pathways has only recently been characterized. In particular, E2F1 has been recently reported to negatively regulate Wnt/beta-catenin activity in human colorectal cancers, though the mechanism underlying this regulation is not fully understood. Here we provide evidence that beta-catenin interacting protein 1 (CTNNBIP1), also known as ICAT (inhibitor of beta-catenin and TCF4), functions as a crucial node to mediate the cross talk between E2F1 and beta-catenin signaling. We show that ICAT is a direct transcriptional target of E2F1, and that activation of ICAT by E2F1 is required for E2F1 to inhibit beta-catenin activity. This study provides a mechanistic insight into the antagonistic interaction between E2F1 and beta-catenin signaling. PMID- 21532623 TI - HAb18G/CD147 promotes epithelial-mesenchymal transition through TGF-beta signaling and is transcriptionally regulated by Slug. AB - Epithelial-mesenchymal transition (EMT) induced by transforming growth factor beta (TGF-beta) is implicated in hepatocarcinogenesis and hepatocellular carcinoma (HCC) metastasis. HAb18G/CD147, which belongs to the CD147 family, is an HCC-associated antigen that has a crucial role in tumor invasion and metastasis. The goal of this study was to investigate the role of HAb18G/CD147 during EMT in hepatocarcinogenesis. Human normal hepatic cell lines QZG and L02, primary mouse hepatocytes and nude mouse models were used to determine the role of HAb18G/CD147 in EMT, and the involvement of the TGF-beta-driven pathway. A dual-luciferase reporter assay and ChIP were used to investigate the transcriptional regulation of the CD147 gene. Samples from patients with liver disease were assessed to determine the relationship between HAb18G/CD147 and typical markers for EMT. Our results show that upregulation of HAb18G/CD147 is induced by TGF-beta coupled with downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The expression of HAb18G/CD147 is controlled by the cell survival PI3K/Akt/GSK3beta signaling pathway, and is directly regulated by the transcription factor Slug. Transfection of CD147 also induces an elevated expression of TGF-beta. CD147-transfected hepatocytes have mesenchymal phenotypes that accelerate tumor formation and tumor metastasis in vivo. Immunohistochemistry analysis shows a negative correlation between HAb18G/CD147 and E-cadherin expression (r(s)=-0.3622, P=0.0105), and a positive correlation between HAb18G/CD147 and Slug expression (r(s)=0.3064, P=0.0323) in human HCC tissues. Our study uncovers a novel role of HAb18G/CD147 in mediating EMT in the process of HCC progression and showed that CD147 is a Slug target gene in the signaling cascade TGF-beta->PI3K/Akt->GSK3beta->Snail->Slug->CD147. Our results suggest that CD147 may be a potential target for the treatment and prevention of HCC. PMID- 21532624 TI - A novel tumor-derived SGOL1 variant causes abnormal mitosis and unstable chromatid cohesion. AB - Mitosis is the most conspicuous cell cycle phase, because it is the phase in which the dynamic physical distributions of cellular components into the two daughter cells occur. The separation of sister chromatids is especially important during mitosis, because of the extreme accuracy required for distribution to the next generation of cells. Shugoshin-like 1 (SGOL1) is a key protein in protecting sister chromatids from precocious separation. We have reported finding that chromosome instability is more likely in SGOL1-downregulated colorectal cancers, but it is still unknown whether there is an association between cancer and SGOL1 transcript variation. Here, we identified a novel SGOL1 variant, SGOL1-P1, in human colon cancer. The SGOL1-P1 transcript contains an exon-skip of exon 3 that results in a stop codon occurring within exon 4. Overexpression of SGOL1-P1 in HCT116 cells resulted in an increased number of cells with aberrant chromosome alignment, precociously separated chromatids and delayed mitotic progression, occasionally followed by inaccurate distribution of the chromosomes. These phenotypes, observed when SGOL1-P1 was present, were also observed very frequently in SGOL1-knockdown cells. Furthermore, the overexpression of SGOL1-P1 inhibited the localization of endogenous SGOL1 and cohesin subunit RAD21/SCC1 to the centromere. These results suggest that SGOL1-P1 may function as a negative factor to native SGOL1, and that abundant expression of SGOL1-P1 may be responsible for chromosomal instability. PMID- 21532625 TI - Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer. AB - Progenitor cells are considered an important cell of origin of human malignancies. However, there has not been any single gene that can define mammary bipotential progenitor cells, and as such it has not been possible to use genetic methods to introduce oncogenic alterations into these cells in vivo to study tumorigenesis from them. Keratin 6a is expressed in a subset of mammary luminal epithelial cells and body cells of terminal end buds. By generating transgenic mice using the Keratin 6a (K6a) gene promoter to express tumor virus A (tva), which encodes the receptor for avian leukosis virus subgroup A (ALV/A), we provide direct evidence that K6a(+) cells are bipotential progenitor cells, and the first demonstration of a non-basal location for some biopotential progenitor cells. These K6a(+) cells were readily induced to form mammary tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding the polyoma middle T antigen. Tumors in this K6a-tva line were papillary and resembled the normal breast-like subtype of human breast cancer. This is the first model of this subtype of human tumors and thus may be useful for preclinical testing of targeted therapy for patients with normal-like breast cancer. These observations also provide direct in vivo evidence for the hypothesis that the cell of origin affects mammary tumor phenotypes. PMID- 21532626 TI - Chk1 is dispensable for G2 arrest in response to sustained DNA damage when the ATM/p53/p21 pathway is functional. AB - In the presence of sustained DNA damage occurring in S-phase or G2, normal cells arrest before mitosis and eventually become senescent. The checkpoint kinases Chk1/Chk2 and the CDK inhibitor p21 are known to have important complementary roles in this process, in G2 arrest and cell cycle exit, respectively. However, additional checkpoint roles have been reported for these regulators and it is not clear to what extent their functions are redundant. Here we compared the respective roles of Chk1, Chk2 and p21 in DNA damage-induced G2 arrest in normal human fibroblasts, normal epithelial cells and frequently used p53 proficient cancer cells. We show that in normal cells, Chk1, but not Chk2, is involved in G2 arrest whereas neither are essential. In contrast, p21 is required. However, Chk1, but not Chk2, becomes necessary for arrest in U2OS osteosarcoma cells. We find that their ATM/p53/p21 response in G2 phase is defective, like in other cancer cells with wild-type p53, and conclude that cross-talk between the Chk1 and p21 pathways allows them to switch dependency for G2 arrest onto Chk1. Using the specific ATM inhibitor KU-55933 we confirm the essential role of ATM in the induction of p21 for G2 arrest of normal cells. Efficient p21 induction is required for nuclear sequestration of inactive cyclin B1-Cdk1 complexes preceding irreversible cell cycle exit in G2. Our results demonstrate that p21 is able to fulfill the Chk1 functions in G2 arrest under continuous genotoxic stress, which has important implications for cancer chemotherapy. PMID- 21532627 TI - Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. AB - LKB1/STK11 is a tumor suppressor and a negative regulator of mammalian target of rapamycin signaling. It is inactivated in 30% of lung cancer cell lines but only 5-15% of primary lung adenocarcinomas. There is evidence that homozygous deletion (HD) of chromosome 19p at the LKB locus contributes to the inactivation of the gene in primary human lung cancers. Here, we used several complementary genetic approaches to assess the LKB1 locus in primary non-small cell lung cancers (NSCLCs). We first analyzed 124 NSCLC cases for allelic imbalance using eight microsatellite markers on chromosome 19p, which revealed an overall rate of 65% (80 of 124) loss of heterozygosity (LOH). We next used chromogenic in situ hybridization (CISH) to directly examine the chromosomal status of the LKB1 locus. In all, 65 of 124 LOH tested samples were available for CISH and 58 of those (89%) showed either loss of one copy of chromosome 19p (LOH, 40 of 65 cases, 62%) or both copies (HD 18 of 65 cases, 28%). The occurrence of HD was significantly more frequent in Caucasian (35%) than in African-American patients (6%) (P=0.04). A total of 62 of 124 samples with LOH at one or both markers immediately flanking the LKB1 gene were further analyzed by directly sequencing the complete coding region, which identified 7 of 62 (11%) tumors with somatic mutations in the gene. Jointly, our data identified total inactivation of the LKB1 gene by either HD or LOH with somatic mutation in 39% of tested samples, whereas loss of chromosome 19p region by HD or LOH at the LKB1 region occured in 90% of NSCLC. PMID- 21532633 TI - Connective tissue diseases: an inside job on T-cell signaling in SLE-dipyridamole blocks expression of key molecules. PMID- 21532628 TI - CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation. AB - We have studied the effects of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) on tumor angiogenesis in murine ductal mammary adenocarcinomas. We crossed transgenic mice with whey acidic protein promoter driven large T-antigen expression (WAP-T mice) with oncogene-induced mammary carcinogenesis with CEACAM1null mice, and with Tie2-Ceacam1 transgenics, in which the Tie2 promoter drives endothelial overexpression of CEACAM1 (WAP-T * CEACAM1(endo+) mice), and analyzed tumor vascularization, angiogenesis and vessel maturation in these mice. Using flat-panel volume computed tomography (fpVCT) and histology, we found that WAP-T * CEACAM1(endo+) mice exhibited enhanced tumoral vascularization owing to CEACAM1(+) vessels in the tumor periphery, and increased intratumoral angiogenesis compared with controls. In contrast, vascularization of CEACAM1null/WAP-T-derived tumors was poor, and tumor vessels were dilated, leaky and showed poor pericyte coverage. Consequently, the tumoral vasculature could not be visualized in CEACAM1null/WAP-T mice by fpVCT, and we observed poor organization of the perivascular extracellular matrix (ECM), accompanied by the accumulation of collagen IV-degrading matrix metalloproteinase 9(+) (MMP9(+)) leukocytes and stromal cells. Vascular instability and alterations in ECM structure were accompanied by a significant increase in pulmonary metastases in CEACAM1null/WAP-T mice, whereas only occasional metastases were observed in CEACAM1(+) hosts. In CEACAM1(+) hosts, intratumoral vessels did not express CEACAM1, but they were intact, extensively covered with pericytes and framed by a well-organized perivascular ECM. MMP9(+) accessory cells were largely absent. Orthotopic transplantation of primary WAP-T- and CEACAM1null/WAP-T tumors into all three mouse lines confirmed that a CEACAM1(+) host environment is a prerequisite for productive angiogenic remodeling of the tumor microenvironment. Hence, CEACAM1 expression in the tumor periphery determines the vascular phenotype in a tumor, whereas systemic absence of CEACAM1 interferes with the formation of an organized tumor matrix and intratumoral vessel maturation. PMID- 21532635 TI - Rheumatoid arthritis: rituximab-induced changes in type 1 IFN response correlate with outcome. PMID- 21532636 TI - Inflammation: new approach to TNF inhibition. PMID- 21532637 TI - Rheumatoid arthritis: spontaneous release of cytokines from synovial tissue is blocked by anti-TLR2. PMID- 21532638 TI - Connective tissue diseases: targeting B cells in SLE: good news at last! PMID- 21532639 TI - Crystal arthritis: calcium pyrophosphate deposition-nothing 'pseudo' about it! PMID- 21532640 TI - Rheumatoid arthritis: understanding joint damage and physical disability in RA. PMID- 21532641 TI - [Influenza A (H1N1): act two]. PMID- 21532642 TI - [Health-related quality of life in the oncology departments of the hospital of Navarra. The EORTC Quality of Life Group]. AB - Quality of life assessment is one of the key elements of the care that is offered to cancer patients. The aim of this work is to present the research line on quality of life that has been carried out since 1992 in the Oncology Departments of the Hospital de Navarra. These departments actively collaborate with the European Organisation of Research and Treatment of Cancer - EORTC - Quality of Life Group in creating questionnaires and also in other projects of this group. Our institution has coordinated the development process of the EORTC information module. Different EORTC questionnaires have been validated for use in our country. Quality of life studies have been carried out in the main tumour sites and in other areas, such as patients' satisfaction with care. This research line has a direct benefit on the attention that patients receive. PMID- 21532643 TI - [Patients' opinions and expectations about the dialysis care process]. AB - BACKGROUND: To determine the experiences and needs of patients on dialysis, in order to identify critical points of the care process and develop proposals for improvement. METHODS: Qualitative study using semistructured interviews with 22 patients on hemodialysis and peritoneal dialysis, from the Andalusian Health Service. Discourse analysis, using the SERVQUAL model. Triangulation of results. RESULTS: The diagnostic stage is described as the hardest moment as it requires acceptance of the disease. During hemodialysis, we see both positive adaptation and the perception of a diminished quality of life. The technique of peritoneal dialysis is evaluated positively, enabling greater independence, despite requiring more responsibility for self care. The contact with patients' organizations or the provision of a counseling service are valued as an aid in the process. With respect to different dimensions of the SERVQUAL model, human treatment and professional competence are valued. The critical points are lack of coordination, malfunctioning of transportation and lack of transparency in the management of waiting lists. Shortcomings in dealing with informal caregivers and the level of knowledge of professionals from areas other than Nephrology, also appear as deficiencies. CONCLUSIONS: The main proposals for improving the dialysis process are: attention to psychosocial aspects, the improvement of organizational aspects such as transport, and greater attention to informal caregivers. PMID- 21532644 TI - [Opinions and expectations of patients with health problems associated to asbestos exposure]. AB - BACKGROUND: The prevalence of diseases related to asbestos exposure requires the development of monitoring programs and specific health care protocols. The aim of this study is to determine the opinions and expectations of former workers of an asbestos factory, in order to adapt the care process to the needs of the affected population, and to learn about the activity of the association that represents them. METHODS: Qualitative study. Focus groups with former employees of a corrugated asbestos factory, members of the association AVIDA (Seville). Recording and transcription of interviews. Discourse analysis with Nudist Vivo 1.0. RESULTS: All respondents have health problems, including asbestosis, lung cancer and mesothelioma. Through the association, they are involved in an ongoing process of negotiation with the public administration, to improve healthcare, achieve recognition as having an occupational disease and the payment of compensation. The lack of monitoring and continuity in care is designated as the major problem in the current care process. They welcome the creation of special care units, the good treatment received and the quality of technical instruments in the public health system. On the contrary, they criticize the difficulties in finding an accurate diagnosis, the lack of continuity of care, and the bureaucratic difficulties and lack of specific care directed to affected relatives. The participants' expectations highlight their intention to participate in the development of future programs and protocols. CONCLUSIONS: This study confirms the multifactor nature of diseases related to asbestos exposure and the importance of determining the needs and demands of the affected population in order to improve health care. PMID- 21532645 TI - [Allergic sensitization profile in the immigrant population living in the central region of Spain]. AB - INTRODUCTION: The prevalence of allergic diseases has increased worldwide in the last two decades, particularly in developed countries. Respiratory allergy is determined by genetic heredity, influenced by environmental factors. Migration is a good epidemiological model for assessing the influence of the environment. We present the clinical characteristics of respiratory allergy in immigrants in the central region of Spain. METHODS: We prospectively collected data on all immigrants referred to the allergy units of 7 different hospitals in Madrid, Cuenca and Ciudad Real in March 2010. Respiratory Allergy was diagnosed using a standard study for allergic diseases. Results in immigrants were compared with data from a similar Spanish population. RESULTS: Sixty-two immigrants and 32 Spanish patients were evaluated (63% female, mean age 28.4 years). Their countries of origin were uniformly distributed among 3 macroareas (North of Africa, Latin America, and Eastern Europe). More than 96% presented rhinitis, although persistent rhinitis was more prevalent amongst Latin Americans (76.9%) than in the Spanish population (48%). No differences were observed in asthma prevalence, although immigrants had higher rates of non-controlled and partially controlled asthma. The mean time of onset of symptoms after immigration was 43 months. Grass pollen was the most relevant allergen with the exception of Arab patients. Sensitization to polcalcin was rare. Otherwise, 44.1% of the Spanish population was sensitized to profilin (only 4.88% among immigrants) although this sensitization did not associate allergy to fruits or other vegetables. CONCLUSIONS: In summary, a multicentric study is presented where significant differences have been observed in the sensitization pattern and clinical evolution of respiratory allergy in immigrants and the Spanish population. PMID- 21532646 TI - [Utility and validity of indicators from the Nursing Outcomes Classification as a support tool for diagnosing Ineffective Self Health Management in patients with chronic conditions in primary health care]. AB - BACKGROUND: Self-care and management of therapeutic regime (drugs adherence, preventive behaviours and development of healthy life-styles) are key components for managing chronic diseases. Nursing has standardized languages which describe many of these situations, such as the diagnosis "Ineffective Self Health Management" (ISHM) or many of the Nursing Outcomes Classification (NOC) indicators. The aims of this study were to determine the interobserver reliability of a NOC-based instrument for assessment and aid in diagnosis of the ISHM in patients with chronic conditions in Primary Health Care, to determine its diagnostic validity and to describe the prevalence of patients with this problem. METHODS: Cross-sectional validation study developed in the provinces of Malaga, Cadiz and Almeria from 2006 to 2009. Each patient was assessed by 3 independent observers: the first two observers evaluated scoring of the NOC indicators and the third one acted as the "gold-standard". RESULTS: Two hundred and twenty-eight patients were included, 37.7% of them with more than one chronic condition. NOC indicators showed a high interobserver reliability (ICC>0,70) and a consistency (Cronbach's alpha: 0.81). With a cut-point of 10.5, sensitivity was 61% and specificity 85%, and the area under the curve was 0.81 (CI95%: 0.77 to 0.85). The prevalence of patients with ISHM was 36% (CI 95%: 34 to 40). CONCLUSIONS: The use of NOC indicators allows evaluation of management of the therapeutic regime in people with chronic conditions with a satisfactory validity and it provides new approaches for dealing with this problem. PMID- 21532647 TI - [How is an instrument for measuring health to be validated?]. AB - It is increasingly necessary to have a measuring instrument available in the health field that can be used in clinical practice and research. In order to guarantee the quality of their measurements it is essential that the instruments should be subjected to a process of validation. This process consists in adapting the instrument culturally to the setting where its psychometric characteristics are to be administered and checked, such as: reliability, validity, sensitivity and feasibility. There are measuring instruments from the health field available in other languages but that have not been validated into Spanish. Besides, the methodology for validating an instrument is little understood by the health professionals, which explains the indiscriminate use of instruments that have only been adapted or validated in a way that is not very consistent. The aim of this review is to bring up to date the process of validating an instrument for measuring health, and what it involves, in a practical way. The accessibility of evaluation instruments that have been culturally adapted and validated in different languages will facilitate the comparison of results obtained with the same instrument and the development international studies in different cultures. PMID- 21532648 TI - [Confidentiality and the medical record. Ethical-legal considerations]. AB - Confidentiality is a key aspect in the relationship between health professionals and patients. It involves the cession by the patient of a reserved part of herself and the ethical principles of autonomy and non-maleficency that are closely linked to its preservation. There are also numerous legal regulations that make professional secrecy obligatory, in some cases imposing hard sanctions that are often not known about. As the medical record is the document where the relationship with the patient is recorded, it requires extraordinary protection due to the especially sensitive nature of the information it contains. It should be compulsory that the professional who works with it should know some basic aspects of the fundamental laws that regulate it in different aspects. This article reviews questions that at times are only known in the abstract, but that are contained in the legal regulations, such as ownership of the medical record, subjective annotations, its custody and rectification or who can have access to it and why. PMID- 21532649 TI - [Atrial fibrillation surgery]. AB - Atrial fibrillation surgery is based on creating scars in the atrium, in order to avoid re-entry phenomena that may initiate and perpetuate arrhythmia, and driving the normal stimuli from the sinus node to the atrio-ventricular node. The complexity and increased risk of the initial surgical technique, based on a "cut and-sew" procedure, have enhanced other current procedures, in which different energies are used making it possible to perform scars in a safer and less invasive way. At present, atrial fibrillation surgery is not performed routinely in all cardiothoracic surgical centers, and there is no consensus in which is the best type of technique. Even if the results are good, they depend on multiples factors such as duration of arrhythmia, atrial size and type of technique employed. In addition, there is some variability in the description within the scientific community of the results and procedures used, which makes its analysis confusing. In this paper we review the different techniques described, the results and their application in minimally invasive surgery. PMID- 21532650 TI - [Doctor, I'm Falling!]. PMID- 21532651 TI - [Spontaneous massive idiopathic haemopneumothorax in a young woman]. PMID- 21532652 TI - [Delayed diagnosis of alpha-1 antitrypsin deficiency]. AB - Alpha-1 antitrypsin deficiency (AAT-D) is a genetic disease, relatively common in populations of European ancestry. AAT-D remains undiagnosed in many patients, and there are often long delays between the onset of respiratory symptoms and diagnosis. AAT-D can be readily diagnosed by measurement of the serum or plasma protein level, which should be confirmed by assessing the genotype or protein phenotype when AAT levels are below the normal range. Close monitoring for the development or progression of lung disease or liver disease is required, and can improve the prognosis. We show the case of a 69 year old woman with recurrent respiratory infections and asthma symptoms. The serum levels of AAT were below the normal range, and ZZ genotype was confirmed. The delayed diagnosis of our patient seems to emphasize the need to remind the doctors about AAT-D, frequently associated with asthma or COPD symptoms. PMID- 21532653 TI - [Chronic necrotizing pulmonary aspergillosis as a complication of silicosis]. AB - Chronic necrotizing pulmonary aspergillosis is un uncommon disease which is found in people with underlying lung disease or in mildly immunocompromised patients. It is an exceptional complication in silicosis and its diagnosis is difficult because it simulates other diseases like tuberculosis and cancer which are more common in such patients. We report on three cases with a long history of silica dust exposure with pulmonary aspergillosis complicating progressive massive fibrosis (PMF). We review their clinical, radiological and treatment features. PMID- 21532654 TI - [Metformin-induced lactic acidosis due to acute renal failure]. AB - Lactic acidosis is a serious but uncommon side effect of metformin use. We discuss the pathophysiological mechanisms of lactic acidosis with particular regard to the role played by the drug as a potential cause of the entity. We report on a severe case of this kind of drug toxicity in a patient with type 2 diabetes mellitus, admitted to the emergency department with acute renal failure symptoms. The diagnosis was supported by elevated serum levels of the biguanide, a procedure scarcely used in clinical practice. The management of this complication consists in drug discontinuation and hemodialysis with bicarbonate that provides symptomatic and ethiological treatment by removing both the lactate and the hypoglycemic agent from the serum. Since the symptoms of metformin associated lactic acidosis are unspecific and its onset is subtle, a high level of suspicion is needed to establish an early diagnosis. PMID- 21532655 TI - Optical image encryption using a jigsaw transform for silhouette removal in interference-based methods and decryption with a single spatial light modulator. AB - Interference-based optical encryption schemes have an inherent silhouette problem due to the equipollent nature of the phase-only masks (POMs) generated using an analytical method. One of the earlier methods suggested that removing the problem by use of exchanging process between two masks increases the computational load. This shortcoming is overcome with a noniterative method using the jigsaw transformation (JT) in a single step, with improved security because the inverse JT of these masks, along with correct permutation keys that are necessary to decrypt the original image. The stringent alignment requirement of the POMs in two different arms during the experiment is removed with an alternative method using a single spatial light modulator. Experimental results are provided to demonstrate the decryption process with the proposed method. PMID- 21532656 TI - High-precision and efficient alignment of cubic phase plate based on Zernike polynomials. AB - Cubic phase plates are key optical elements in the wavefront coding system. Unlike for traditional optical lenses, their free-form shape makes it difficult to determine the correct position. This article presents a precise and efficient alignment method using Zernike polynomials by analytical analysis and numerical simulation and considering position deviations of rotation and offset. In addition, to help determine what kind of position deviation exists, the relationship between position deviation and introduced surface errors is analyzed and demonstrated. The proposed method is especially useful for optical design and manufacture. It improves the accuracy of measurements by eliminating error resulting from misplacement. An optical test system using a phase shift interferometer and the result of a cubic phase plate is demonstrated. PMID- 21532657 TI - Effective random laser action in Rhodamine 6G solution with Al nanoparticles. AB - We have studied the random laser action in Rhodamine 6G (Rh6G) ethylene glycol solution with Al nanoparticles. The experiment results are obtained by pumping with a nanosecond (7 ns) laser pulse, which demonstrated the existence of effective random laser emission. It is found that the threshold of the random laser depends on the concentration of the Rh6G and the concentration of Al nanoparticles. The concentration and diameter of Al nanoparticles have effects on the optical path; a higher concentration or a larger diameter results in a shorter optical path length. Also multimode survival and mode competition have been observed at a relatively high concentration (0.08 M) of Rh6G, where the concentration of Al nanoparticles is 0.0015 M. PMID- 21532658 TI - Modeling and experimental observation of an on-chip two-dimensional far-field interference pattern. AB - In this paper, we model and experimentally observe the far-field radiation produced by interfering beams propagating in two-dimensional (2D) slab waveguides. Using a transmission-line analogy, we compare the 2D propagation with standard three-dimensional (3D) far-field representations and derive the 2D conditions for using standard far-field approximations. Then we test our theoretical results by experimentally observing the 2D far-field pattern produced by a 1*3 multimode interference (MMI) coupler on a silicon nanomembrane. The MMI outputs are connected to a slab silicon waveguide, and the far field is observed at the edge of the silicon slab. This represents the observation of 2D far-field pattern produced by an array of on-chip radiators. PMID- 21532659 TI - Analysis of voltage effect on holographic gratings by modulation transfer function. AB - The experimental data allow us to determine the imaging quality of holographic gratings with photosensitive film using organic material based on a polyvinyl alcohol matrix doped with potassium dichromate and nickel (II) chloride hexahydrate. The diffraction efficiency is estimated by different spatial frequencies, and the readout image quality is analyzed by the modulation transfer function. The experiment is carried out, with and without voltage application, at different spatial frequencies to obtain the image quality of photosensitive film. PMID- 21532660 TI - Performance and scalability of Fourier domain optical coherence tomography acceleration using graphics processing units. AB - Fourier domain optical coherence tomography (FD-OCT) provides faster line rates, better resolution, and higher sensitivity for noninvasive, in vivo biomedical imaging compared to traditional time domain OCT (TD-OCT). However, because the signal processing for FD-OCT is computationally intensive, real-time FD-OCT applications demand powerful computing platforms to deliver acceptable performance. Graphics processing units (GPUs) have been used as coprocessors to accelerate FD-OCT by leveraging their relatively simple programming model to exploit thread-level parallelism. Unfortunately, GPUs do not "share" memory with their host processors, requiring additional data transfers between the GPU and CPU. In this paper, we implement a complete FD-OCT accelerator on a consumer grade GPU/CPU platform. Our data acquisition system uses spectrometer-based detection and a dual-arm interferometer topology with numerical dispersion compensation for retinal imaging. We demonstrate that the maximum line rate is dictated by the memory transfer time and not the processing time due to the GPU platform's memory model. Finally, we discuss how the performance trends of GPU based accelerators compare to the expected future requirements of FD-OCT data rates. PMID- 21532661 TI - Implementation of vibrational phase contrast coherent anti-Stokes Raman scattering microscopy. AB - Detection of molecules using vibrational resonances in the fingerprint region for narrowband coherent anti-Stokes Raman scattering (CARS) is challenging. The spectrum is highly congested resulting in a large background and a reduced specificity. Recently we introduced vibrational phase contrast CARS (VPC-CARS) microscopy as a technique capable of detecting both the amplitude and phase of the CARS signal, providing background-free images and high specificity. In this paper we present a new implementation of VPC-CARS based on a third-order cascaded phase-preserving chain, where the CARS signal is generated at a single (constant) wavelength independent of the vibrational frequency that is addressed. This implementation will simplify the detection side considerably. PMID- 21532663 TI - Experimental observation of extremely weak optical scattering from an interlocking carbon nanotube array. AB - We experimentally demonstrate a nearly wavelength-independent optical reflection from an extremely rough carbon nanotube sample. The sample is made of a vertically aligned nanotube array, is a super dark material, and exhibits a near perfect blackbody emission at T=450 K-600 K. No other material exhibits such optical properties, i.e., ultralow reflectance accompanied by a lack of wavelength scaling behavior. This observation is a result of the lowest ever measured reflectance (R=0.0003) of the sample over a broad infrared wavelength of 3 MUm < lambda < 13 MUm. This discovery may be attributed to the unique interlocking surface of the nanotube array, consisting of both a global, large scale and a short-range randomness. PMID- 21532662 TI - Polymeric optofluidic Fabry-Perot sensor by direct laser machining and hot embossing. AB - We present a polymeric-based Fabry-Perot optofluidic sensor fabricated by combining direct laser machining and hot embossing. This technique provides a more elegant solution to conventional hot embossing by increasing the production rate, improving the reproducibility, and further reducing the cost, providing a large working area and flexibility in design modification and customization. As a proof of concept, a Fabry-Perot (F-P) optofluidic sensor was fabricated in polymethyl methacrylate (PMMA) from a micromachined stamp. The experimental results of the sensor agree well with analytical calculations and show a sensitivity of 2.13*10-3 RIU/nm for fluid refractive index change. PMID- 21532664 TI - Revised minimum reciprocity configuration and actualization methodology of interferometric all-fiber-optic gyroscopes. AB - We propose a revised minimum reciprocity configuration (MRC) of an interferometric all-fiber-optic gyroscope (all-fiber I-FOG), based on our design of a fused-taper polarization-maintaining fiber coupler. This MRC reduces the insertion loss and production cost of the optical path, yet maintains the principle of reciprocity. Experimental results show that this I-FOG with five optical components exhibits better performance than a conventional I-FOG with six optical components. Using the revised MRC, the angle random walk and the bias instability of an I-FOG are improved from 0.025 deg/?hr to 0.011 deg/?hr, and 0.48 deg/hr to 0.21 deg/hr, respectively. PMID- 21532665 TI - Image registration method for multimodal images. AB - A new image registration method for multimodal images is proposed in this paper. This method is a combination of the modified scale invariant feature transform (SIFT) feature extraction algorithm and the shape-context feature descriptor. Salient points of multimodal images are extracted by using the modified SIFT feature extraction algorithm. Then each salient point is described by using the shape-context descriptor that formed a feature vector from the orientation histograms of the subregion around each salient point. After salient points matching by using Euclidean distance, random sample consensus algorithm is used to eliminate wrong corresponding pairs. At last, multimodal images registration is achieved by affine transformation and bilinear interpolation. Experimental results for registration of IR images and electro-optical images show that this method has a good registration result. PMID- 21532666 TI - Femtosecond laser-inscribed fiber Bragg gratings for strain monitoring in power cables of offshore wind turbines. AB - A fiber Bragg grating sensor system used for monitoring the effects of strain on the power cable of an offshore wind turbine is presented. The Bragg grating structure was inscribed into coated nonphotosensitive standard telecommunication fibers using an IR femtosecond laser and the point-by-point writing technique. Because of the presence of the protective coating of the fiber, the mechanical stability of the resultant sensor device is better than that of a sensor consisting of a bare fiber. A system containing this sensing element was to our knowledge for the first time successfully installed and tested in an offshore wind turbine prototype (REpower 6M, REpower Systems, AG, Germany) in February 2010, near Ellhoft (Germany). The fabrication process of the fiber Bragg gratings, measurement results of the online monitoring, and a comparison between the sensor signal and commonly used sensing techniques are presented. PMID- 21532667 TI - Sensitive acoustic vibration sensor using single-mode fiber tapers. AB - Optical fiber sensors are a good alternative to piezoelectric devices in electromagnetic sensitive environments. In this study, we reported a fiber acoustic sensor based on single-mode fiber (SMF) tapers. The fiber taper is used as the sensing arm in a Mach-Zehnder interferometer. Benefiting from their micrometer dimensions, fiber tapers have shown higher sensitivities to the acoustic vibrations than SMFs. Under the same conditions, the thinnest fiber taper in this report, with a diameter of 1.7 um, shows a 20 dB improvement in the signal to noise ratio as compared to that of an SMF. This acoustic vibration sensor can detect the acoustic waves over the frequencies of 30 Hz-40 kHz, which is limited by the acoustic wave generator in experiments. We also discussed the phase changes of fiber tapers with different diameters under acoustic vibrations. PMID- 21532668 TI - Optical lens design based on metallic nanoslits with variant widths. AB - Designs of optical lenses based on metallic nanoslits are carried out based on the phase and amplitude modulation by tuning the slit widths. The slits are perforated on thin metallic film, and the width of each slit is achieved by simulated annealing algorithms, which is connected with both the amplitude and phase modulation. Two kinds of focal lenses, which can realize one or two focus points, have been designed. The finite-difference time-domain method is employed to check the performance of the designed lenses. Simulation results show that the designed lenses can perform the preset functions well. Using this method, multiple optical elements with different functions can be conveniently achieved in subwavelength scale. PMID- 21532669 TI - Terahertz quasi-time-domain spectroscopy imaging. AB - We demonstrate terahertz (THz) imaging with a quasi-time-domain spectrometer. This type of THz system is inexpensive, compact, and relatively easy to set up. Beating the simultaneously emitted equidistant modes of a compact diode laser allows for analysis of samples at multiple frequencies with a single measurement. Thus, this technique merges the potential of terahertz time-domain spectrometers with the simplicity of continuous wave lasers. Multiple imaging applications and stability issues are discussed. PMID- 21532670 TI - Image quality enhancement of computational integral imaging reconstruction for partially occluded objects using binary weighting mask on occlusion areas. AB - This paper presents an image quality enhancement of computational integral imaging reconstruction (CIIR) method by using a binary weighting mask on occlusion areas in elemental images. The proposed method utilizes a block matching algorithm to estimate the occlusion areas in elemental images. Then, a binary weighting mask generated from the estimated occlusion area is applied to our CIIR method. This minimizes the overlapping effect of occluding objects in the reconstructed plane images and thus improves visual quality dramatically. To show the usefulness of our proposed scheme, we conduct several experiments and present the results. The experimental results indicate that our method is superior to the existing methods. PMID- 21532671 TI - Twin mirrors for laser interferometric gravitational-wave detectors. AB - Gravitational-wave detectors such as Virgo and the laser interferometric gravitational-wave observatory (LIGO) use a long-baseline Michelson interferometer with Fabry-Perot cavities in the arms to search for gravitational waves. The symmetry between the two Fabry-Perot cavities is crucial to reduce the interferometer's sensitivity to the laser amplitude and frequency noise. To this purpose, the transmittance of the mirrors in both cavities should be as close as possible. This paper describes the realization and the characterization of the first twin large low-loss mirrors with transmissions differing by less than 0.01%. PMID- 21532672 TI - Tunable microwave generation based on a dual-wavelength single-longitudinal-mode fiber laser using a phase-shifted grating on a triangular cantilever. AB - Frequency tunable microwave signal generation, based on a dual-wavelength single longitudinal-mode (SLM) erbium-doped fiber (EDF) laser, incorporating a phase shifted fiber Bragg grating (PS-FBG) with two pi-phase shifts, is demonstrated. In the proposed configuration, the PS-FBG with two ultranarrow transmission bands is embedded in a triangular cantilever to serve as a wavelength spacing tunable filter with a fixed center wavelength by applying various strains on the cantilever. A section of unpumped EDF is employed as a saturable absorber to ensure SLM operation in each of the two lasing lines. By beating the two wavelengths at a photodiode, a tunable microwave signal ranging from 8.835 to 24.360 GHz is successfully achieved. PMID- 21532673 TI - Variant of the anastigmatic telescope with three mirrors for back focal length. AB - In this paper, an optical design is presented for an anastigmatic telescope with back focal length corrected with exact ray tracing to eliminate spherical, coma, and astigmatism aberrations. The telescope is formed of three conical mirrors, two of them polished on the same substratum. The optical design is divided into three stages: we began the design obtaining the Gaussian parameters in a first order solution; posteriorly, were obtained analytically the three mirrors' asphericity in a third-order design. The final design stage consists of the implementation of the Fermat's principle, the Abbe sine condition, and the Coddington equations for the exact correction for the three aforementioned aberrations. PMID- 21532674 TI - Extremely sensitive detection of NO2 employing off-axis integrated cavity output spectroscopy coupled with multiple-line integrated absorption spectroscopy. AB - We report on the development of a new sensor for NO2 with ultrahigh sensitivity of detection. This has been accomplished by combining off-axis integrated cavity output spectroscopy (OA-ICOS) (which can provide large path lengths of the order of several kilometers in a small volume cell) with multiple-line integrated absorption spectroscopy (MLIAS) (where we integrate the absorption spectra over a large number of rotational-vibrational transitions of the molecular species to further improve the sensitivity). Employing an external cavity quantum cascade laser operating in the 1601-1670 cm-1 range and a high-finesse optical cavity, the absorption spectra of NO2 over 100 transitions in the R band have been recorded. From the observed linear relationship between the integrated absorption versus concentration of NO2 and the standard deviation of the integrated absorption signal, we report an effective sensitivity of detection of approximately 28 ppt (parts in 1012) for NO2 To the best of our knowledge, this is among the most sensitive levels of detection of NO2 to date. PMID- 21532675 TI - Adaptive target detection with a polarization-sensitive optical system. AB - We developed an adaptive polarimetric target detector (APTD) to determine the optimum combination strategy for a multichannel polarization-sensitive optical system. The proposed algorithm is based on scene-derived polarization properties of the target and background, and it seeks to find an optimum multichannel combination of linear polarizing filters that maximizes the signal-to-clutter ratio (SCR) in intensity and Stokes parameter images. The algorithm is validated by performing RX anomaly detection and a generalized likelihood ratio test on both synthetic and real imagery. The experimental results are analyzed through calculated SCR and receiver operating characteristic curves. Compared with several conventional operation methods, we find that better target detection performance is achieved with the APTD algorithm. PMID- 21532677 TI - Sample preparation method for glass welding by ultrashort laser pulses yields higher seam strength. AB - Glass welding by ultrashort laser pulses allows joining without the need of an absorber or a preheating and postheating process. However, cracks generated during the welding process substantially impair the joining strength of the welding seams. In this paper a sample preparation method is described that prevents the formation of cracks. The measured joining strength of samples prepared by this method is substantially higher than previously reported values. PMID- 21532676 TI - Long-distance optical guiding of colloidal particles using holographic axilens. AB - We report the use of an aspheric holographic optical element (axilens) that essentially combines the properties of the long focal depth of an axicon and the high energy concentration of a conventional spherical lens for long-distance guiding of microscopic objects. With the use of the axilens, polystyrene spheres (~6 MUm diameter) could be transported over a distance of ~16 mm that was ~3 times longer compared with that obtained using a spherical lens of focal length identical to the mean focal length of the axilens. Further, due to the availability of good on-axis power density, even objects having very marginally higher refractive index than the medium (differing only at third decimal place) could be guided with a guiding speed of ~5 MUm/s. PMID- 21532678 TI - Optical properties and residual stress in aluminum nitride films prepared by alternating-current dual reactive magnetron sputtering. AB - Aluminum nitride films were deposited by alternating-current dual reactive magnetron sputtering. The influence of different nitrogen flow and working pressures at a sputtering power of 5 kW on the refractive index, extinction coefficient, crystalline structure, residual stress, and surface roughness of aluminum nitride films was discussed. The aluminum nitride film would have high refractive index, low extinction coefficient and small residual stress at suitable nitrogen flow rate and low working pressure. PMID- 21532679 TI - Long-term instrumental parameter investigation of a Fabry-Perot spectrometer at an isolated field station. AB - To insure that long-term determinations of Doppler width and shift--derived from observations of atmospheric emissions--are internally consistent and reliable, we have developed a method to both continuously and nonintrusively determine and monitor the instrumental constants of the Fabry-Perot spectrometer making the observations. We have used this method at our isolated field experiment at South Pole, Antarctica, because the instrument is only accessible to us for a few days every year. Here we report both the method and the Fabry-Perot stability results for the past 22 years of operation. The method involves the description of real Fabry-Perot instrumental constants as a small departure from those of an ideal Fabry-Perot. In general, this model is applicable for most observations. However, experimentally, there are times when the small-departure model is not applicable, thus indicating how to best reduce the observations into physical quantities for the utmost consistency in the geophysical results. PMID- 21532680 TI - Experimental study on GaP surface damage threshold induced by a high repetition rate femtosecond laser. AB - The surface damage threshold of undoped bulk <110> GaP induced by a high repetition rate femtosecond pulse at 1040 nm with a duration of 61 fs was studied. The threshold value was obtained by a linear fit of the incident single pulse fluence and was confirmed with a breakdown test around the threshold level. The result will be useful in high intensity, high repetition rate laser applications and ultrafast processes. PMID- 21532681 TI - Resolution and stability analysis of localized surface plasmon lithography on the geometrical parameters of soft mold. AB - We have recently shown that patterns with 30 nm line width and micrometer scale periodicity could be steadily fabricated by employing localized surface plasmons lithography based on a soft mold [Opt. Lett. 35, 13 (2009)]. In this paper, the dependence of the resolution (pattern periodicity), critical dimension, and electric field intensity on the geometrical parameters of the soft mold, such as ridge width, mold periodicity, ridge depth, and slope, have been systematically studied and analyzed. The relevant simulation results by finite-difference time domain demonstrate that the critical dimension exhibits a perfect stabilization and the value of electric field intensity would be especially large, when the ridge depth is in the range from 100 to 270 nm and the slope angle is below 35 degrees . Importantly, the optimal resolution and critical dimension can reach 100 and 17 nm, respectively, by reasonably designing the corresponding mold periodicity and ridge width, which indicates that the method is particularly suitable for obtaining patterns with high density and is extremely promising for bio-sensing and photonic crystals application. PMID- 21532682 TI - On the relation between power and astigmatism near an umbilic line. AB - The relation between the variation of power and astigmatism in a progressive power optical element is considered. The classical Minkwitz identity is revisited. Then, it is shown how to extend this identity, which applies to the geometry of surfaces, to optical parameters that are determined by the geometry of reflected or refracted wavefronts. PMID- 21532683 TI - Field singularities at lossless metal-dielectric right-angle edges and their ramifications to the numerical modeling of gratings. AB - We mathematically prove and numerically demonstrate that the source of the convergence problem of the analytical modal method and the Fourier modal method for modeling some lossless metal-dielectric lamellar gratings in TM polarization recently reported by Gundu and Mafi [J. Opt. Soc. Am. A 27, 1694 (2010)] is the existence of irregular field singularities at the edges of the grating grooves. We show that Fourier series are incapable of representing the transverse electric field components in the vicinity of an edge of irregular field singularity; therefore, any method, not necessarily of modal type, using Fourier series in this way is doomed to fail. A set of precise and simple criteria is given with which, given a lamellar grating, one can predict whether the conventional implementation of a modal method of any kind will converge without running a convergence test. PMID- 21532684 TI - Numerical approach for computing the Jacobian matrix between boundary variable vector and system variable vector for optical systems containing prisms. AB - The design of optical systems containing prisms is comparatively difficult since each prism may contain multiple boundary surfaces. Many geometrical optical merit functions have been proposed based on first-order derivatives of the geometrical quantities of the system with respect to the boundary variable vector X(i). However, transferring the computed quantities into the system variable vector X(sys) is still highly challenging. Accordingly, this study proposes a new numerical method for determining the Jacobian matrix between X(i) and X(sys) directly. The proposed methodology can be easily implemented in computer code and provides a potential basis for the future development of a numerical technique for computing the second-order derivatives of the geometrical quantities of an optical system. PMID- 21532685 TI - Development and analysis of a photon-counting three-dimensional imaging laser detection and ranging (LADAR) system. AB - In this paper, a photon-counting three-dimensional imaging laser detection and ranging (LADAR) system that uses a Geiger-mode avalanche photodiode (GAPD) of relatively short dead time (45 ns) is described. A passively Q-switched microchip laser is used as a laser source and a compact peripheral component interconnect system, which includes a time-to-digital converter (TDC), is set up for fast signal processing. The combination of a GAPD with short dead time and a TDC with a multistop function enables the system to operate in a single-hit or a multihit mode during the acquisition of time-of-flight data. The software for the three dimensional visualization and an algorithm for the removal of noise are developed. For the photon-counting LADAR system, we establish a theoretical model of target-detection and false-alarm probabilities in both the single-hit and multihit modes with a Poisson statistic; this model provides the prediction of the performance of the system and a technique for the acquisition of a noise image with a GAPD. Both the noise image and the three-dimensional image of a scene acquired by the photon-counting LADAR system during the day are presented. PMID- 21532686 TI - Projection-slice theorem: a compact notation. AB - The notation normally associated with the projection-slice theorem often presents difficulties for students of Fourier optics and digital image processing. Simple single-line forms of the theorem that are relatively easily interpreted can be obtained for n-dimensional functions by exploiting the convolution theorem and the rotation theorem of Fourier transform theory. The projection-slice theorem is presented in this form for two- and three-dimensional functions; generalization to higher dimensionality is briefly discussed. PMID- 21532687 TI - Minimizing light reflection from dielectric textured surfaces. AB - In this paper, we consider antireflective properties of textured surfaces for all texture size-to-wavelength ratios. Existence and location of the global reflection minimum with respect to geometrical parameters of the texture is a subject of our study. We also investigate asymptotic behavior of the reflection with the change of the texture geometry for the long and short wavelength limits. As a particular example, we consider silicon-textured surfaces used in solar cells technology. Most of our results are obtained with the help of the finite difference time-domain (FDTD) method. We also use effective medium theory and geometric optics approximation for the limiting cases. The FDTD results for these limits are in agreement with the corresponding approximations. PMID- 21532688 TI - Damping of the dipole vortex. AB - When a circular electric dipole moment, rotating in the x-y plane, is embedded in a material with relative permittivity epsilon(r) and relative permeability MU(r), the field lines of energy flow of the emitted radiation are dramatically influenced by the surrounding material. For emission in free space, the field lines swirl around the z axis and lie on a cone. The direction of rotation of the field lines around the z axis is the same as the direction of rotation of the dipole moment. We found that when the real part of epsilon(r) is negative, the rotation of the field lines changes direction, and hence the energy counter rotates the dipole moment. When there is damping in the material, due to an imaginary part of epsilon(r), the cone turns into a funnel, and the density of the field lines diminishes near the location of the source. In addition, all radiation is emitted along the z axis and the x-y plane, whereas for emission in free space, the radiation is emitted in all directions. It is also shown that the displacement of the dipole image in the far field depends on the material parameters and that the shift can be much larger than the shift of the image in free space. PMID- 21532689 TI - Space-bandwidth ratio as a means of choosing between Fresnel and other linear canonical transform algorithms. AB - The product of the spatial and spatial frequency extents of a wave field has proven useful in the analysis of the sampling requirements of numerical simulations. We propose that the ratio of these quantities is also illuminating. We have shown that the distance at which the so-called "direct method" becomes more efficient than the so-called "spectral method" for simulations of Fresnel transforms may be written in terms of this space-bandwidth ratio. We have proposed generalizations of these algorithms for numerical simulations of general ABCD systems and derived expressions for the "transition space-bandwidth ratio," above which the generalization of the spectral method is the more efficient algorithm and below which the generalization of the direct method is preferable. PMID- 21532690 TI - Generalized radiometry model for the propagation of light within anisotropic and chiral media. AB - An exact radiometric model is proposed for the nonparaxial propagation of fully or partially coherent electromagnetic radiation within anisotropic and/or chiral media in terms of rectilinear ray propagation. The definition of the generalized radiance is motivated by a geometric interpretation, based on the plane-wave decomposition of the field in the medium. The new representations are illustrated through two examples, corresponding to the propagation of two-dimensional fields within birefringent and chiral media. PMID- 21532691 TI - Error propagation: a comparison of Shack-Hartmann and curvature sensors. AB - Phase estimates in adaptive-optics systems are computed by use of wavefront sensors, such as Shack-Hartmann or curvature sensors. In either case, the standard error of the phase estimates is proportional to the standard error of the measurements; but the error-propagation factors are different. We calculate the ratio of these factors for curvature and Shack-Hartmann sensors in dependence on the number of sensors, n, on a circular aperture. If the sensor spacing is kept constant and the pupil is enlarged, the ratio increases as n(0.4). When more sensing elements are accommodated on the same aperture, it increases even faster, namely, proportional to n(0.8). With large numbers of sensing elements, this increase can limit the applicability of curvature sensors. PMID- 21532692 TI - Analysis of digital images into energy-angular momentum modes. AB - The measurement of continuous wave fields by a digital (pixellated) screen of sensors can be used to assess the quality of a beam by finding its formant modes. A generic continuous field F(x, y) sampled at an N * N Cartesian grid of point sensors on a plane yields a matrix of values F(q(x), q(y)), where (q(x), q(y)) are integer coordinates. When the approximate rotational symmetry of the input field is important, one may use the sampled Laguerre-Gauss functions, with radial and angular modes (n, m), to analyze them into their corresponding coefficients F(n, m) of energy and angular momentum (E-AM). The sampled E-AM modes span an N2 dimensional space, but are not orthogonal--except for parity. In this paper, we propose the properly orthonormal "Laguerre-Kravchuk" discrete functions Lambda(n, m)(q(x), q(y)) as a convenient basis to analyze the sampled beams into their E-AM polar modes, and with them synthesize the input image exactly. PMID- 21532693 TI - Lens design of LED searchlight of high brightness and distant spot. AB - The study related in this paper is the design of a ship-mounted LED of high brightness and distant spot. The freeform lens design obeying the edge ray principle and Snell's law is presented first. Then, to fit the illumination requirement of the searchlight, we designed a freeform lens to collimate all the light rays coming from the LED. However, theoretical analysis proves that there is a critical angle for incident rays beyond which the rays cannot be collimated, and 55% is the light-efficiency limit for polymethyl methacrylate freeform lens. We then designed a combination of a freeform lens-coupled parabolic reflector that improved light efficiency to 70%. In this paper, the design of the freeform lens-coupled parabolic reflector is given in detail. In addition, tolerance analysis and the effect of manufacturing defect are presented. PMID- 21532694 TI - Multinodal fifth-order optical aberrations of optical systems without rotational symmetry: the astigmatic aberrations. AB - Building on earlier work on the nodal aberration theory of third-order aberrations and a subset of fifth-order terms, this paper presents the multinodal field dependence of the family of aberrations describing the shape of the medial focal surface (the focal surface upon which the minimum RMS wavefront error is measured) and the astigmatic aberrations with respect to this surface through the fifth order. Specifically, the multinodal field dependence for W(420M) and W422 (the field-quartic medial surface and field-quartic astigmatism) are derived and presented as well as their influence on the magnitude and nodal field dependence of the companion lower-order terms, W(220M) and W222. This paper provides the first derivations of field-quartic aberrations presented by the author in the refereed literature. PMID- 21532695 TI - Self-healing of tightly focused scalar and vector Bessel-Gauss beams at the focal plane. AB - The property of self-healing at the focal plane for both scalar and vector Bessel Gauss (BG) beams is investigated in the tight focusing condition. For the BG beam, which is partially obstructed at the pupil plane, the spatial intensity distribution at the focal plane is well recovered. Furthermore, recovery of not only intensity but also polarization distribution is observed for an obstructed vector BG beam. This self-healing effect for both the intensity and polarization components is recognized even when the half of the beam is obstructed by a semicircular obstacle. The effect of the size of the obstacle on recovery of polarization and intensity distribution is studied. The role of the beam size at the pupil plane is also discussed. PMID- 21532696 TI - Diffraction of a Gaussian beam by a logarithmic axicon. AB - We derive an explicit analytical relationship to describe the axial light intensity when a Gaussian beam is diffracted by the logarithmic axicon (LA). An evaluation formula for the effective radius of the diffraction pattern that we deduce shows the said radius to be in inverse proportion to the LA "force" parameter. The finite-difference time-domain-based simulation has shown that using the LA makes it possible to go beyond the diffraction limit: in the LA vicinity, the FWHM of the light beam can be as small as one fifth of the illumination wavelength. PMID- 21532697 TI - Optical trapping of microrods: variation with size and refractive index. AB - Optical traps can be characterized in terms of two simple parameters: the stiffness, given by the gradient of the force at mechanical equilibrium, and the strength, as expressed by the maximum restoring force available for displacement in a given direction. We present numerical calculations of these quantities for dielectric microrods of varying radius and refractive index held horizontally in pairs of holographically generated Gaussian beams. The resulting variations are seen to be influenced by optical resonances, as well as by the relative sizes of the beam waist and rod diameter. In addition, it is shown that trapping in these systems is sensitive to the polarization state of the incident field; i.e., for certain rods, trapping will occur for beams polarized perpendicular to the long axis of the rod, but not for beams polarized parallel to the long axis. Finally, friction coefficients are evaluated and used to estimate the maximum rates at which the rods may be dragged through the ambient medium. PMID- 21532698 TI - Perturbation approach applied to modal diffraction methods. AB - Eigenvalue computation is an important part of many modal diffraction methods, including the rigorous coupled wave approach (RCWA) and the Chandezon method. This procedure is known to be computationally intensive, accounting for a large proportion of the overall run time. However, in many cases, eigenvalue information is already available from previous calculations. Some of the examples include adjacent slices in the RCWA, spectral- or angle-resolved scans in optical scatterometry and parameter derivatives in optimization. In this paper, we present a new technique that provides accurate and highly reliable solutions with significant improvements in computational time. The proposed method takes advantage of known eigensolution information and is based on perturbation method. PMID- 21532699 TI - Finite-difference time-domain and near-field-to-far-field transformation in the spectral domain: application to scattering objects with complex shapes in the vicinity of a semi-infinite dielectric medium. AB - We present the study of a spectral-domain near-field-to-far-field (NFTFF) transformation, taking into account an interface in the vicinity of a particle. This technique is associated with a three-dimensional finite-difference time domain (FDTD) model, which solves the Maxwell equations in the time domain. Moreover, material properties are considered with the use of dispersion models. First, particular attention is paid to the description of the modeling, especially concerning the NFTFF transformation using the dyadic Green tensors. Second, several simulation cases are considered to evaluate the ability of the developed technique to model the scattering by different kinds of "particles/interface" configurations and for various illuminating waves. Then validation test cases are used in order to assess the model accuracy through comparisons with T-matrix simulations. Finally, perspectives to this work and its application to near-field detection devices are discussed. PMID- 21532701 TI - Evaluation of cuspoid and umbilic diffraction catastrophes of codimension four. AB - The evaluation of the two diffraction catastrophes of codimension four, namely, the butterfly and the parabolic umbilic, is here proposed by means of a simple computational approach developed in the past to characterize the whole hierarchy of the structurally stable diffraction patterns produced by optical diffraction in three-dimensional space. In particular, after expanding the phase integral representations of butterfly and parabolic umbilic in terms of (slowly) convergent power series, the retrieving action of the Weniger transformation on them is investigated through several numerical experiments. We believe that the methodology and the results presented here could also be of help for the dissemination of catastrophe optics to the widest scientific audience. PMID- 21532700 TI - Electromagnetic enhancement by a periodic array of nanogrooves in a metallic substrate. AB - We present comprehensive investigations of the electromagnetic enhancement by a periodic array of rectangular nanogrooves in a metallic substrate. The impacts of array parameters and of illumination conditions on the enhanced electric-field intensity are explored using fully vectorial methods. The calculations are performed mainly for gold and for the visible and infrared wavelengths. The fully vectorial results are reproduced and explained by a simple Fabry-Perot model. Compared with the case of a single groove, the electric-field enhancement of the groove array is found to be much higher by almost 1 order of magnitude, which is shown to be related to the excitation of surface plasmon polaritons with the aid of the model. Practical considerations of a finite groove number and of a finite groove length are also provided. PMID- 21532702 TI - Ambiguity function and phase-space tomography for nonparaxial fields. AB - A nonparaxial generalization of the ambiguity function that retains several properties of its paraxial counterpart is presented, in both two and three dimensions. This generalization is used to extend into the nonparaxial regime a scheme for the recovery of the coherence properties of scalar partially coherent fields in two-dimensional space. PMID- 21532703 TI - Effect of polarization on a solid immersion lens of arbitrary thickness. AB - A solid immersion lens can be applied for high-resolution subsurface analysis of integrated circuits and other physical systems. We present a thorough analysis of the focal field distribution of a solid immersion lens system of arbitrary thickness. Cases of linearly and radially polarized illumination are examined and accurate expressions derived for the electric field in the image space. The effect of the spherical interface on both transverse and axial intensity profiles is analyzed. The performance and practicality of configurations deviating from the hemispherical and aplanatic cases are studied. The results show that optimal resolution is obtained at focal positions between the hemispherical and aplanatic points when radially polarized illumination is applied. PMID- 21532704 TI - Generalized modified atmospheric spectral model for optical wave propagating through non-Kolmogorov turbulence. AB - A new generalized modified atmospheric spectral model is derived theoretically for wave propagating through non-Kolmogorov turbulence, which has been reported recently by increasing experimental evidence and theoretical investigation. The generalized, modified atmospheric spectrum considers finite turbulence inner and outer scales and has a spectral power law value in the range of 3 to 5 instead of the standard power law value of 11/3. When the inner scale and outer scale are set to zero and infinity, respectively, this spectral model is reduced to the classical non-Kolmogorov spectrum. PMID- 21532705 TI - Arbitrary moments of elliptical Gaussian-Schell beam in turbulent atmosphere. AB - Arbitrary moments of elliptical Gaussian-Schell beams in turbulent atmosphere is studied. An analytical formula for arbitrary moments of elliptical Gaussian Schell beams in turbulent atmosphere is derived. As an example, the kurtosis parameter for elliptical Gaussian-Schell beams in turbulent atmosphere is investigated in detail. The comparison between the variations of the kurtosis parameter for elliptical Gaussian-Schell beams with different parameters is made. Meanwhile, the difference between the kurtosis parameter in vacuum and in turbulent atmosphere is analyzed and discussed. PMID- 21532706 TI - In-phase supermode selection in ring-type and concentric-type multicore fibers using large-mode-area single-mode fiber. AB - We propose an all-fiber-optic supermode selection scheme based on large-mode-area single-mode fiber for multicore fiber (MCF). The supermode selection in terms of the coupling coefficient is investigated and compared for various ring-type and concentric-type MCFs. The in-phase supermode is found to have a significantly higher coupling coefficient than other supermodes--demonstrating significant and desirable supermode selection characteristics. This scheme has shown better in phase supermode selection performance than the conventional free-space Talbot cavity. It is found to be effective in selecting the in-phase supermode for both ring-type and concentric-type MCFs and promising for all-fiber MCF lasers with high power output and good beam quality. PMID- 21532707 TI - Moire pattern movement compensation and quadrature averaging phase retrieval from time series of speckled arbitrary phase shift interferograms for automatic computation of fundus pulsation curve of the human eye. AB - PURPOSE: the method described here allows for automatic calculation of the fundus pulse from interferometric measurements. METHOD: a low intensity laser beam is coupled into the eye. Two strong reflections, one of the cornea and one of the retina, interfere on a high-speed complementary metal-oxide-semiconductor camera chip. After eye movement compensation, a speckle-free phase of the interferograms is calculated from a series of interference fringes. Then, the fundus pulsation is calculated from the phase shift between two consecutive interferograms. PROBLEMS: occurring speckle perturbs the fringe images, and therefore, classical geometrical movement compensation algorithms do not work with sufficient accuracy. The movement compensation algorithm needs to work without prior knowledge of the phase. RESULTS: the proposed algorithms yield the fundus pulse from speckled interferograms, overcoming the above mentioned problems. PMID- 21532708 TI - Illumination estimation via thin-plate spline interpolation. AB - Thin-plate spline interpolation is used to interpolate the chromaticity of the color of the incident scene illumination across a training set of images. Given the image of a scene under unknown illumination, the chromaticity of the scene illumination can be found from the interpolated function. The resulting illumination-estimation method can be used to provide color constancy under changing illumination conditions and automatic white balancing for digital cameras. A thin-plate spline interpolates over a nonuniformly sampled input space, which in this case is a training set of image thumbnails and associated illumination chromaticities. To reduce the size of the training set, incremental k medians are applied. Tests on real images demonstrate that the thin-plate spline method can estimate the color of the incident illumination quite accurately, and the proposed training set pruning significantly decreases the computation. PMID- 21532709 TI - Notes on the application of the standardized residual sum of squares index for the assessment of intra- and inter-observer variability in color-difference experiments. AB - The standardized residual sum of squares index was proposed to examine the significant merit of a given color-difference formula over another with respect to a given set of visual color-difference data [J. Opt. Soc. Am. A 24, 1823-1829, 2007]. This index can also be employed to determine intra- and inter-observer variability, although the full complexity of this variability cannot be described by just one number. Appropriate utilization of the standardized residual sum of squares index for the assessment of observer variability is described with a view to encourage its use in future color-difference research. The main goal of this paper is to demonstrate that setting the F parameters of the standardized residual sum of squares index to 1 results in a loss of essential properties of the index (for example, symmetry), and is therefore strongly discouraged. PMID- 21532710 TI - A study on antimicrobial susceptibility pattern in clinical isolates of Staphylococcus aureus in Eritrea. AB - BACKGROUND: Staphylococcus aureus is a major pathogen in skin and soft tissue infections. Methicillin resistant S.aureus (MRSA) is prevalent in most of the countries wherever it is sought for. MRSA is one of the important pathogens implicated in hospital acquired infection. The main objectives of this study was to find out the antimicrobial susceptibility pattern of S.aureus isolates, the prevalence of methicillin resistant S.aureus (MRSA) and nasal carriage rate in healthy hospital staff. METHOD: A total of 278 S.aureus strains isolated from clinical specimens were tested for antimicrobial susceptibility and 30 anterior nares swabs from healthy hospital staff were screened for S.aureus organisms using standard methods. RESULTS: High resistance was observed against ampicillin, penicillin and tetracycline. High sensitivity was recorded against amikasin, amoxicillin-c and ciprofloxacin. Of the 278 isolates 26 (9%) isolates were methicillin resistant S.aureus (MRSA). 17 % of the hospital staff were positive for nasal carriage of Staphylococcus aureus . CONCLUSION: Our study emphasizes the need for continuous monitoring of the antimicrobial susceptibility pattern of S.aureus isolates including MRSA for the selection of appropriate therapy. In Eritrea, from the present findings it appears that the spread of MRSA in community and hospital settings is limited. PMID- 21532711 TI - The influence of gender on the primary care management of diabetes in Tunisia. AB - BACKGROUND: Gender differences in access to high quality care for chronic illnesses have been suggested yet little work in this potentially vital area of health care inequality has been undertaken in Africa. We explored the influence of patient gender on the care of people with diabetes within a multi-method, national study of diabetes management in primary care in Tunisia. METHODS: Methodologies used were quantitative (nationwide randomized study of 2160 medical records) and qualitative (participant observation, focus groups and interviews of patients and health care professionals). RESULTS: Differences in patient characteristics, treatments prescribed, process and outcome data and access to care variables were demonstrated. The most striking disparity found was the high female to male ratio of patients attending for diabetes care (61.1%). A number of possible explanations for this emerged: Men were thought to under-attend for practical, financial and behavioural reasons whereas women were thought to have increased morbidity and potentially over-attend for social and psychological reasons. CONCLUSION: We have demonstrated a number of disparities in the care of men and women with diabetes in Tunisian primary care. In particular, a dual but related problem emerges from the data: more women than men attend for diabetes care and yet women do not get the same level of risk factor control as men. A number of local explanations for these disparities have emerged, which inform our analysis of the impact of gendered beliefs on diabetes care. Strategies to address these disparities will require a careful consideration of local beliefs and practices. PMID- 21532712 TI - Have tsetse flies disappeared from Brazzaville town? AB - BACKGROUND: From 1980 to 1985, the zoological park of Brazzaville was the only tsetse resting site located in downtown which supplied others temporary sites. The last trapping survey carried out in this area in 1987 showed that there were no more tsetse flies. Knowing that areas free of tsetse used to be reinvaded many years later, we have carried out an entomological survey in the area with the aim to verify what has happened more than twenty years later; given that suitable environmental conditions for Glossina are still available. METHODS: Sixteen pyramidal traps were set out at the edge of the forest, along paths and around animal's cages and were examined twice a day, at 10 a.m. and 4 p.m. during four days. RESULTS: No tsetse fly was captured. Using the formula previously described; the probability of capturing a tsetse fly is 0.002. CONCLUSION: The zoological park seems close to be free of tsetse flies. Long-lasting surveys within the town and around are required before stating a complete disappearance of tsetse in the town. PMID- 21532713 TI - Provider Initiated Testing and Counseling (PITC) for HIV in resource-limited clinical settings: important questions unanswered. PMID- 21532714 TI - E-Learning and North-South collaboration: the experience of two public health schools in France and Benin. AB - INTRODUCTION: Distance learning (e-learning) can facilitate access to training. Yet few public health E-learning experiments have been reported; institutes in developing countries experience difficulties in establishing on-line curricula, while developed countries struggle with adapting existing curricula to realities on the ground. In 2005, two schools of public health, one in France and one in Benin, began collaborating through contact sessions organised for Nancy University distance-learning students. This experience gave rise to a partnership aimed at developing training materials for e-Learning for African students. The distance-learning public health course at Nancy teaches public health professionals through a module entitled "Health and Development." The module is specifically tailored for professionals from developing countries. To promote student-teacher exchanges, clarify content and supervise dissertations, contact sessions are organized in centres proximate and accessible to African students. The Benin Institute's main feature is residential team learning; distance learning courses are currently being prepared. OUTCOME: The two collaborating institutions have developed a joint distance-learning module geared toward developing countries. The collaboration provides for the development, diffusion, and joint delivery of teaching modules featuring issues that are familiar to African staff, gives the French Institute credibility in assessing research work produced, and enables modules on specific African issues and approaches to be put online. LESSONS LEARNED: While E-learning is a viable educational option for public health professionals, periodic contact can be advantageous. Our analysis showed that the benefit of the collaboration between the two institutions is mutual; the French Institute extends its geographical, cultural and contextual reach and expands its pool of teaching staff. The Benin Institute benefits from the technical partnership and expertise, which allow it to offer distance learning for Africa-specific contexts and applications. PMID- 21532715 TI - Meckel's diverticulum: a case report from the University Hospital Center Yaounde, Cameroon. AB - To the best of our knowledge there is no reported case of Meckel's diverticulum (MD) in Cameroon. The prevalence of MD in the general population is 2-3 %. The aim of this paper is to recapitulate the role of this pathology in acute abdomens and abdominal pain of uncertain aetiology in young patients and to review the medical literature. PMID- 21532716 TI - A review of anaesthesia for emergency laparotomy in paediatric intestinal obstruction in Enugu, Nigeria. AB - BACKGROUND: To review the anaesthetic management and outcome for emergency laparotomy for paediatric intestinal obstruction in the University of Nigeria Teaching Hospital, Enugu, Nigeria. METHODS: The anaesthetic charts and folders of pediatric patients that had emergency laparotomy for intestinal obstruction in the general operating theatre of the University of Nigeria Teaching Hospital (UNTH), Enugu, Nigeria, from October 2007 - September 2008 were reviewed. The records were examined for anaesthetic technique, patient primary diagnosis, intra operative events, blood and fluid therapy and patient outcome. Patients above thirteen years were excluded. RESULTS: Forty-four out of 285 (15.7%) paediatric patients underwent emergency laparotomy for intestinal obstruction in the general operating theatre. There were 29 males and 15 females. The average age of the patients was 3.75 years. There were a total of 1674 anesthetics in the general operating theatre during the study. The leading causes of intestinal obstruction in this study were typhoid peritonitis (14 or 31.8%), intussusceptions (14 or 31.8%) and congenital anomalies (11 or 25%). Six patients (13%) had a preoperative packed cell volume of less than 30%, while ten patients received intra-operative blood transfusion (21.7%). There was one anesthetic death to give a case mortality rate of 2.2%. CONCLUSION: The mortality rate in this study shows the importance and relevance of trained providers of anaesthesia managing paediatric patients in the developing world. Early presentation of patients allowed time for resuscitation and fewer complications before surgery. PMID- 21532717 TI - Inauguration of the cameroonian society of human genetics. AB - The conjunction of "hard genetics" research centers, with well established biomedical and bioethics research groups, and the exceptional possibility to hold the 6th annual meeting of the African Society of Human Genetics (AfSHG, 13th-15th March 2009) was an excellent opportunity to get together in synergy the entire Cameroonian "DNA/RNA scientists" . This laid to the foundation of the Cameroonian Society of Human Genetics (CSHG) that was privilege to hold its inaugural meeting in conjunction to the 6th annual meeting of the AfSHG. The theme was "Human Origin, Genetic Diversity and Health". The AfSHG and CSHG invited leading African and international scientists in genomics and population genetics to review recent data and provide an understanding of the state-of-knowledge of Human Origin and Genetic Diversity. Overall one opening ceremony eight session, five keynote and guest speakers, 18 invited oral communications, 13 free oral communications, 43 posters and two social events could summarize the meeting. This year's conference was graced by the presence of one Nobel Prize winner Dr Richard Roberts (Physiology and Medicine 1993). The meeting registered up to ten contributions of Cameroonian scientists from the Diaspora (currently in USA, Belgium, Gambia, Sudan and Zimbabwe). Such Diaspora participation is an opportunity to generate collaborations with home country scientists and ultimately turn the "brain drain" to "brain circulation" that could reduce the impact of the migration of health professional from Africa. Interestingly, the personal implication of the Cameroonian Ministry of Public Heath who opened the meeting in the presence of the Secretary General of the Ministry of Higher Education and a representative of the Ministry of Scientific Research and Innovation was a wonderful opportunity for advocacy of genetic issues at the decision-makers level. Beyond our expectation, a major promise of the Cameroonian government was the creation of the National Human Genome Institute. If this goal comes true, this will be a critical step to bring more genetics for the purpose of Public Health to the Cameroonian people. The sub-Saharan African Region needs significant capacity building in the broad area of basic research in general and Genetics (especially Human Genetics) in particular. In that respect, the existence and current activities of the AfSHG and its impact at the National levels in Africa, is a major development for the continent and an initiative that needs further encouragement from the international community. PMID- 21532718 TI - Can donor aid for health be effective in a poor country? Assessment of prerequisites for aid effectiveness in Uganda. AB - BACKGROUND: Inadequate funding for health is a challenge to attaining health related Millennium Development Goals. Significant increase in health funding was recommended by the Commission for Macroeconomics and Health. Indeed Official Development Assistance has increased significantly in Uganda. However, the effectiveness of donor aid has come under greater scrutiny. This paper scrutinizes the prerequisites for aid effectiveness. The objective of the study was to assess the prerequisites for effectiveness of donor aid, specifically, its proportion to overall health funding, predictability, comprehensiveness, alignment to country priorities, and channeling mechanisms. METHODS: Secondary data obtained from various official reports and surveys were analyzed against the variables mentioned under objectives. This was augmented by observations and participation in discussions with all stakeholders to discuss sector performance including health financing. RESULTS: Between 2004-2007, the level of aid increased from US$6 per capita to US$11. Aid was found to be unpredictable with expenditure varying between 174-8722;360 percent from budgets. More than 50% of aid was found to be off budget and unavailable for comprehensive planning. There was disproportionate funding for some items such as drugs. Key health system elements such as human resources and infrastructure have not been given due attention in investment. The government's health funding from domestic sources grew only modestly which did not guarantee fiscal sustainability. CONCLUSION: Although donor aid is significant there is need to invest in the prerequisites that would guarantee its effective use. PMID- 21532719 TI - Setting-up nurse-led pilot clinics for the management of non-communicable diseases at primary health care level in resource-limited settings of Africa. AB - BACKGROUND: This article describes the setting-up process for nurse-led pilot clinics for the management of four chronic diseases: asthma, type 2 diabetes mellitus, epilepsy and hypertension at the primary health care level in urban and rural Cameroon. METHODS: The Biyem-Assi urban and the Bafut rural health districts in Cameroon served as settings for this study. International and local guidelines were identified and adapted to the country's circumstances. Training and follow-up tools were developed and nurses trained by experienced physicians in the management of the four conditions. Basic diagnostic and follow-up materials were provided and relevant essential drugs made available. RESULTS: Forty six nurses attended six training courses. By the second year of activity, three and four clinics were operational in the urban and the rural areas respectively. By then, 925 patients had been registered in the clinics. This represented a 68.5% increase from the first year. While the rural clinics relied mainly on essential drugs for their prescriptions, a prescription pattern combining generic and proprietary drugs was observed in the urban clinics. CONCLUSION: In the quest for cost-effective health care for NCD in sub-Saharan Africa, rethinking health workforce and service delivery has relevance. Nurse-led clinics, algorithm driven service delivery stands as alternatives to overcome the shortage of trained physicians and other issues relating to access to care. PMID- 21532720 TI - Morbidity patterns in general practice settings of the province of Sousse, Tunisia. AB - BACKGROUND: Primary health care is one of the most important pillars of the Tunisian health care system. However, very little information is available regarding the specificities of general practice and the patterns of morbidity encountered. METHODS: We conducted a descriptive study from June 2002 to May 2003 in 85 primary health centres in Sousse during 12 randomly selected weeks in order to describe the variability of the morbidity in all seasons; (3 weeks were randomly selected in each season). Each working day of selected weeks, a systematic sample of patients was identified in each health centre by taking every fifth registered patient. There were 16,271 consultations. The International Classification of Primary Care (ICPC-2) was used to code recorded data of the consultation. RESULTS: There were 24,882 reasons for encounter, a total of 18,097 problems managed by general practitioners (GPs), and 40,190 interventions. There was a predominance of females (62%) and a relatively young population attending the primary health care settings as 50% was aged less than 25 years. According to ICPC-2 chapters, we found that respiratory diseases were the main problems managed in primary health care (43%), followed by digestive (10.1%), locomotive (8.9%), cardiovascular affections (8.7%) and skin diseases (8.4%). These five conditions alone constituted about 80% of the total cases. However, genital conditions for both males and females (1%) as well as psychological and social problems (0.85%) were rarely managed in primary care. CONCLUSION: The findings will be useful in helping to revise the educational curriculum of medical studies as required in general practice and to plan relevant vocational training for GPs. They will also be important for health policy makers in Tunisia. PMID- 21532721 TI - Congenital pulmonary arteriovenous malformation: a rare cause of cyanosis in childhood. AB - Pulmonary arteriovenous malformation (PAVM) is a rare condition in which there is abnormal connection between pulmonary arteries and veins. The disorder usually appears in late childhood or early adult life, with dyspnea on exertion, clubbing or cyanosis. We present two patients with severe cyanosis and their work-up to diagnosis of PAVM, as a rare cause of cyanosis in childhood. PMID- 21532722 TI - [Desmoid tumors of the chest wall: report of 12 cases]. PMID- 21532723 TI - Muscle cell membrane damage by very low serum sodium. AB - A 63-year-old male was admitted with complaints of upper gastrointestinal symptoms with fatigue and myalgia. Investigations revealed severe hyponatremia with elevated creatine phosphokinase levels. Following further workup, it was diagnosed as a case of hyponatremia induced rhabdomyolysis. Because of prompt correction of hyponatremia, his renal function was preserved and myoglobinuria induced renal failure was avoided. The importance of early recognition of this potentially dangerous condition is emphasized. PMID- 21532724 TI - Male breast cancer: 22 case reports at the National Hospital of Niamey-Niger (West Africa). AB - BACKGROUND: Male breast cancer (MBC) is rare. The objective of the study is to report clinicopathological characteristics, treatment patterns, and outcomes of MBC. METHOD: This study, which includes two parts (retrospective and prospective), focused on all hospitalized male patients with breast cancer during 17 years (1992-2008) with histological confirmation. RESULTS: The series included 22 patients. The mean age was 52.8 years (range: 28-80 years). MBC represented 5.7% of all breast cancers. Most patients had an advanced disease with skin ulceration and inflammation T3 (31.9%) and T4 (59.1%). The majority of patients came from rural areas (63.6%). The duration of signs ranged from 1 to 7 years. Histology found infiltrating ductal carcinoma in 14 cases (63.6%), sarcoma in 3 cases (13.6%), papillary carcinoma in 2 cases (9%), and lobular carcinoma, medullar carcinoma, and mucinous carcinoma in 4.6% each of the others cases. The treatment had consisted of a radical mastectomy (Halsted or Patey) in 19 cases (86.4%) with axillary clearance and incomplete resection in 3 cases (13.6%). In the retrospective study follow-up of 14 patients, we lost sight of 13 patients 6 months after surgery. In the prospective study of 8 patients 10 to 36 months after mastectomy, 4 patients were deceased (50%), 4 were alive with 1 case having a local recurrence and pulmonary metastasis. CONCLUSION: The advanced clinical forms of MBC are most frequent with skin ulceration and nodal enlargement. The absence of radiotherapy and the low access of chemotherapy limited the treatment to radical mastectomy (Halsted) in the majority of cases. PMID- 21532725 TI - The African Teledermatology Project: Providing access to dermatologic care and education in sub-Saharan Africa. AB - BACKGROUND: Telemedicine allows health providers in remote areas to transfer information for medical consultation anywhere in the world and serves to support local health workers through discussion and access to pertinent educational materials. Many developing nations have a dire shortage of doctors and other health resources. Therefore, affordable, easy-to-use technologies are imperative for providing care and much needed educational opportunities as well as reducing the limitations imposed by scarce resources. METHODS: To identify the current extent of the Africa Teledermatology Project and key areas for improvements, an analysis of all consultations received to date was completed. RESULT: Between February 2007 and February 2009, 345 consultations from sites in thirteen Sub Saharan African nations were received and processed via the project website. Although a wide range of mucocutaneous conditions were seen, the most frequent diagnoses included adverse drug reactions, atopic dermatitis and eczema, cutaneous infections, psoriasis and HIV/AIDS-related cutaneous diseases. Educational materials were designed to target these conditions. CONCLUSION: This research supports the value of store-and-forward teledermatology services for facilitating access to assistance in the diagnosis and management of cutaneous disease and increasing access to educational materials. The work demonstrates the feasibility and usefulness for a teledermatology network such as the African Teldermatology Project in improving the provision of care for skin diseases in sub-Saharan Africa. Additionally, this technology can be seen as a practical and effective manner to distribute information to local health workers with the hope of significantly improving their ability to recognize, diagnose and treat cutaneous conditions. PMID- 21532726 TI - A review on laboratory liver function tests. AB - Laboratory liver tests are broadly defined as tests useful in the evaluation and treatment of patients with hepatic dysfunction. The liver carries out metabolism of carbohydrate, protein and fats. Some of the enzymes and the end products of the metabolic pathway which are very sensitive for the abnormality occurred may be considered as biochemical marker of liver dysfunction. Some of the biochemical markers such as serum bilirubin, alanine amino transferase, aspartate amino transferase, ratio of aminotransferases, alkaline phosphatase, gamma glutamyl transferase, 5' nucleotidase, ceruloplasmin, alpha-fetoprotein are considered in this article. An isolated or conjugated alteration of biochemical markers of liver damage in patients can challenge the clinicians during the diagnosis of disease related to liver directly or with some other organs. The term "liver chemistry tests" is a frequently used but poorly defined phrase that encompasses the numerous serum chemistries that can be assayed to assess hepatic function and/or injury. PMID- 21532727 TI - Current knowledge, attitudes and practices of expectant women toward routine sonography in pregnancy at Naguru health centre, Uganda. AB - BACKGROUND: Ultrasound has become a routine part of care for pregnant women in Uganda, being one of a range of techniques used in screening. However, it differs from most others because it allows women to view their babies. Routine obstetric sonography is now globally recognized as one of the ways through which maternal mortality can be reduced. This study aimed at finding out the knowledge, attitudes and practices of pregnant women towards prenatal sonography at Naguru Health Centre, Uganda. METHOD: Exploratory -descriptive study using interviewer administered questionnaires. Thematic analysis was employed for qualitative data and bivariate, multivariate and logistic regression analysis was used for quantitative data. RESULTS: Three themes emerged; Knowledge, Attitude and Practices. Women's knowledge, attitude and practices of obstetric sonography were influenced mainly by their biosocial factors like gravidity, education level and occupation. All women expressed concern that obstetric sonography could lead to cancer. CONCLUSION: Obstetric sonography is highly appreciated as being vital for antenatal care. However, there is need for mothers and health care providers to be well informed about the safety and specific purposes of obstetric sonography and what it can and cannot achieve. PMID- 21532728 TI - Laparoscopic cholecystectomy in sickle cell patients in Niger. AB - BACKGROUND: We report the results of our experience on laparoscopic cholecystectomy in sickle cell disease patients in Niger, which is included in the sickle cell belt. METHODS: A prospective study covering a period of 45 months, from July 2004 to March 2008. We included all sickle cell disease patients that underwent laparoscopic cholecystectomy. Blood transfusion was done for patients with haemoglobin (Hb) levels less than 9g/dl. Homozygous and composite heterozygous patients were admitted in intensive care unit for 24 hours or plus post operatively. RESULTS: The series included 47 patients operated by the same surgeon, 31 females (66%) and 16 males (34%) (Ratio: 0.51). The average age was 22.4 years (range: 11 to 46 years) and eleven (23.4%) of them were aged less than 15 years. The types of sickle cell disease found were 37 SS, 2 SC, 1 S beta-thalassemia and 7 AS. Indications for surgery were biliary colic in 29 cases (61.7%) and acute cholecystitis in 18 cases (38.3%). The mean operative time was 64 min (range: 42 to 103 min). Conversion to open cholecystectomy in 2 cases (4.2 %) for non recognition of Calot's triangle structures. The postoperative complications were: four (4) cases of vaso-occlusive crisis and one case of acute chest syndrome. The mean postoperative hospital stay was 3,5days (range: 1 to 9 days). No mortality was encountered. CONCLUSION: Laparoscopic cholecystectomy is a safe procedure in sickle cell patients. It should be a multidisciplinary approach and involve a haematologist, an anaesthesiologist and a surgeon. PMID- 21532730 TI - Burns in pregnancy: a case report from Buea Regional Hospital, Cameroon. AB - BACKGROUND: To the best of our knowledge similar cases of severe burns in pregnancy have not been published in Cameroon; indicating the rarity of this devastating condition and therefore the dilemma that practitioners may be confronted with in its management. This report is to help the Physician understand the factors that should determine his/her management decisions by reviewing the limited literature of burns in pregnancy. A multidisciplinary approach by a team of Obstetricians, Anesthetist/Intensive care Physicians, Pediatricians and Surgeons is indispensible. Adequate resuscitation, fight against sepsis, the gestational age and the severity of the burn will determine the outcome or prognosis. PMID- 21532729 TI - Scimitar syndrome and evolution of managements. AB - The Scimitar syndrome is a rare congenital anomaly that consists in part of total or partial anomalous venous drainage of the right lung to the inferior vena cava (IVC). This descending vein is visible on CXR as a curvilinear density along the right heart border and resembles the curved Turkish sword that gives the condition its name. Scimitar syndrome forms part of the large spectrum of associated conditions known as venolobar syndrome. These include right lung hypoplasia or sequestered segments of the right lung, congenital heart disease and various others. Surgical approaches to the Scimitar syndrome have varied according to the anatomic and pathologic features presented in each case. Here we review the clinical signs and symptoms, diagnostic dilemmas, current medical and surgical managements of Scimitar syndrome. PMID- 21532731 TI - Late presentation of rheumatic heart disease: a justification for renewal of preventive methods? AB - Rheumatic heart disease continues to contribute greatly to the burden of cardiovascular disease in Sub-saharan Africa despite advances in medical care. Evidence suggests that the prevalence is far greater than reported. There is therefore the need to emphasize routine screening for at-risk subjects and to appropriately institute adequate therapy and other preventive measures to avert the late and awry manifestation of the disease as presented in this case. This is a case report of one of numerous cases that may eventually suffer the same fate if urgent preventive measures are not instituted. A 20-year old Nigerian woman with past history of recurrent sore throat and a 10-year history of recurrent easy fatiguability and markedly dilated left atrium and pulmonary hypertension presented when she developed severe pulmonary hypertension. A concerted action at all levels of prevention is needed to reduce the burden of this disease among the young population in developing countries. PMID- 21532732 TI - Dynamic analysis of stochastic transcription cycles. AB - In individual mammalian cells the expression of some genes such as prolactin is highly variable over time and has been suggested to occur in stochastic pulses. To investigate the origins of this behavior and to understand its functional relevance, we quantitatively analyzed this variability using new mathematical tools that allowed us to reconstruct dynamic transcription rates of different reporter genes controlled by identical promoters in the same living cell. Quantitative microscopic analysis of two reporter genes, firefly luciferase and destabilized EGFP, was used to analyze the dynamics of prolactin promoter directed gene expression in living individual clonal and primary pituitary cells over periods of up to 25 h. We quantified the time-dependence and cyclicity of the transcription pulses and estimated the length and variation of active and inactive transcription phases. We showed an average cycle period of approximately 11 h and demonstrated that while the measured time distribution of active phases agreed with commonly accepted models of transcription, the inactive phases were differently distributed and showed strong memory, with a refractory period of transcriptional inactivation close to 3 h. Cycles in transcription occurred at two distinct prolactin-promoter controlled reporter genes in the same individual clonal or primary cells. However, the timing of the cycles was independent and out-of-phase. For the first time, we have analyzed transcription dynamics from two equivalent loci in real-time in single cells. In unstimulated conditions, cells showed independent transcription dynamics at each locus. A key result from these analyses was the evidence for a minimum refractory period in the inactive phase of transcription. The response to acute signals and the result of manipulation of histone acetylation was consistent with the hypothesis that this refractory period corresponded to a phase of chromatin remodeling which significantly increased the cyclicity. Stochastically timed bursts of transcription in an apparently random subset of cells in a tissue may thus produce an overall coordinated but heterogeneous phenotype capable of acute responses to stimuli. PMID- 21532734 TI - Claims about the misuse of insecticide-treated mosquito nets: are these evidence based? PMID- 21532733 TI - Retinoic acid functions as a key GABAergic differentiation signal in the basal ganglia. AB - Although retinoic acid (RA) has been implicated as an extrinsic signal regulating forebrain neurogenesis, the processes regulated by RA signaling remain unclear. Here, analysis of retinaldehyde dehydrogenase mutant mouse embryos lacking RA synthesis demonstrates that RA generated by Raldh3 in the subventricular zone of the basal ganglia is required for GABAergic differentiation, whereas RA generated by Raldh2 in the meninges is unnecessary for development of the adjacent cortex. Neurospheres generated from the lateral ganglionic eminence (LGE), where Raldh3 is highly expressed, produce endogenous RA, which is required for differentiation to GABAergic neurons. In Raldh3-/- embryos, LGE progenitors fail to differentiate into either GABAergic striatal projection neurons or GABAergic interneurons migrating to the olfactory bulb and cortex. We describe conditions for RA treatment of human embryonic stem cells that result in efficient differentiation to a heterogeneous population of GABAergic interneurons without the appearance of GABAergic striatal projection neurons, thus providing an in vitro method for generation of GABAergic interneurons for further study. Our observation that endogenous RA is required for generation of LGE-derived GABAergic neurons in the basal ganglia establishes a key role for RA signaling in development of the forebrain. PMID- 21532735 TI - Helminth and intestinal protozoa infections, multiparasitism and risk factors in Champasack province, Lao People's Democratic Republic. AB - BACKGROUND: Detailed investigations of multiparasitism are scarce in the Mekong River basin. We assessed helminth (trematode, nematode, and cestode), and intestinal protozoa infections, and multiparasitism in random population samples from three different eco-epidemiological settings in Champasack province, southern Lao People's Democratic Republic (Lao PDR), and determined underlying risk factors. METHODOLOGY: Two stool samples were collected from 669 individuals aged >= 6 months over consecutive days and examined for helminth infections using the Kato-Katz method. Additionally, one stool sample per person was subjected to a formalin-ethyl acetate concentration technique for diagnosis of helminth and intestinal protozoa infections. Questionnaires were administered to obtain individual and household-level data pertaining to behavior, demography and socioeconomic status. Risk factors for hepato-biliary and intestinal parasitic infections and multiparasitism were determined using multiple logistic regressions analyses. PRINCIPAL FINDINGS: MULTIPLE SPECIES INTESTINAL PARASITE INFECTIONS WERE COMMON: 86.6% of the study participants harbored at least two and up to seven different parasites concurrently. Regarding nematode infections, hookworm was the most prevalent species (76.8%), followed by Ascaris lumbricoides (31.7%) and Trichuris trichiura (25.0%). Regarding trematodes, Opisthorchis viverrini and Schistosoma mekongi infections were found in 64.3% and 24.2% of the participants, respectively. Infections with intestinal protozoa were rare. CONCLUSIONS/SIGNIFICANCE: There is a pressing need to intensify and sustain helminth control interventions in the southern part of Lao PDR. Given the high prevalence with nematode and trematode infections and the extent of multiparasitism, preventive chemotherapy is warranted. This intervention should be coupled with health education and improved access to clean water and adequate sanitation to consolidate morbidity control and enhance sustainability. PMID- 21532736 TI - Oviposition site selection by the dengue vector Aedes aegypti and its implications for dengue control. AB - BACKGROUND: Because no dengue vaccine or antiviral therapy is commercially available, controlling the primary mosquito vector, Aedes aegypti, is currently the only means to prevent dengue outbreaks. Traditional models of Ae. aegypti assume that population dynamics are regulated by density-dependent larval competition for food and little affected by oviposition behavior. Due to direct impacts on offspring survival and development, however, mosquito choice in oviposition site can have important consequences for population regulation that should be taken into account when designing vector control programs. METHODOLOGY/PRINCIPAL FINDINGS: We examined oviposition patterns by Ae. aegypti among 591 naturally occurring containers and a set of experimental containers in Iquitos, Peru. Using larval starvation bioassays as an indirect measure of container food content, we assessed whether females select containers with the most food for their offspring. Our data indicate that choice of egg-laying site is influenced by conspecific larvae and pupae, container fill method, container size, lid, and sun exposure. Although larval food positively influenced oviposition, our results did not support the hypothesis that females act primarily to maximize food for larvae. Females were most strongly attracted to sites containing immature conspecifics, even when potential competitors for their progeny were present in abundance. CONCLUSION/SIGNIFICANCE: Due to strong conspecific attraction, egg-laying behavior may contribute more to regulating Ae. aegypti populations than previously thought. If highly infested containers are targeted for removal or larvicide application, females that would have preferentially oviposited in those sites may instead distribute their eggs among other suitable, previously unoccupied containers. Strategies that kill mosquitoes late in their development (i.e., insect growth regulators that kill pupae rather than larvae) will enhance vector control by creating "egg sinks," treated sites that exploit conspecific attraction of ovipositing females, but reduce emergence of adult mosquitoes via density-dependent larval competition and late acting insecticide. PMID- 21532737 TI - A phase two randomised controlled double blind trial of high dose intravenous methylprednisolone and oral prednisolone versus intravenous normal saline and oral prednisolone in individuals with leprosy type 1 reactions and/or nerve function impairment. AB - BACKGROUND: Leprosy Type 1 reactions are a major cause of nerve damage and the preventable disability that results. Type 1 reactions are treated with oral corticosteroids and there are few data to support the optimal dose and duration of treatment. Type 1 reactions have a Th1 immune profile: cells in cutaneous and neural lesions expressing interferon-gamma and interleukin-12. Methylprednisolone has been used in other Th1 mediated diseases such as rheumatoid arthritis in an attempt to switch off the immune response and so we investigated the efficacy of three days of high dose (1 g) intravenous methylprednisolone at the start of prednisolone therapy in leprosy Type 1 reactions and nerve function impairment. RESULTS: Forty-two individuals were randomised to receive methylprednisolone followed by oral prednisolone (n = 20) or oral prednisolone alone (n = 22). There were no significant differences in the rate of adverse events or clinical improvement at the completion of the study. However individuals treated with methylprednisolone were less likely than those treated with prednisolone alone to experience deterioration in sensory function between day 29 and day 113 of the study. The study also demonstrated that 50% of individuals with Type 1 reactions and/or nerve function impairment required additional prednisolone despite treatment with 16 weeks of corticosteroids. CONCLUSIONS: The study lends further support to the use of more prolonged courses of corticosteroid to treat Type 1 reactions and the investigation of risk factors for the recurrence of Type 1 reaction and nerve function impairment during and after a corticosteroid treatment. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN31894035. PMID- 21532738 TI - Direct observation of the myosin Va recovery stroke that contributes to unidirectional stepping along actin. AB - Myosins are ATP-driven linear molecular motors that work as cellular force generators, transporters, and force sensors. These functions are driven by large scale nucleotide-dependent conformational changes, termed "strokes"; the "power stroke" is the force-generating swinging of the myosin light chain-binding "neck" domain relative to the motor domain "head" while bound to actin; the "recovery stroke" is the necessary initial motion that primes, or "cocks," myosin while detached from actin. Myosin Va is a processive dimer that steps unidirectionally along actin following a "hand over hand" mechanism in which the trailing head detaches and steps forward ~72 nm. Despite large rotational Brownian motion of the detached head about a free joint adjoining the two necks, unidirectional stepping is achieved, in part by the power stroke of the attached head that moves the joint forward. However, the power stroke alone cannot fully account for preferential forward site binding since the orientation and angle stability of the detached head, which is determined by the properties of the recovery stroke, dictate actin binding site accessibility. Here, we directly observe the recovery stroke dynamics and fluctuations of myosin Va using a novel, transient caged ATP controlling system that maintains constant ATP levels through stepwise UV-pulse sequences of varying intensity. We immobilized the neck of monomeric myosin Va on a surface and observed real time motions of bead(s) attached site-specifically to the head. ATP induces a transient swing of the neck to the post-recovery stroke conformation, where it remains for ~40 s, until ATP hydrolysis products are released. Angle distributions indicate that the post-recovery stroke conformation is stabilized by >= 5 k(B)T of energy. The high kinetic and energetic stability of the post-recovery stroke conformation favors preferential binding of the detached head to a forward site 72 nm away. Thus, the recovery stroke contributes to unidirectional stepping of myosin Va. PMID- 21532739 TI - Global health philanthropy and institutional relationships: how should conflicts of interest be addressed? PMID- 21532740 TI - Diagnostic accuracy of Kato-Katz and FLOTAC for assessing anthelmintic drug efficacy. AB - BACKGROUND: Sensitive diagnostic tools are required for an accurate assessment of prevalence and intensity of helminth infections in areas undergoing regular deworming, and for monitoring anthelmintic drug efficacy. We compared the diagnostic accuracy of the Kato-Katz and FLOTAC techniques in the frame of a drug efficacy trial. METHODOLOGY/PRINCIPAL FINDINGS: Stool samples from 343 Zanzibari children were subjected to duplicate Kato-Katz thick smears and the FLOTAC basic technique in a baseline screening in early 2009. The FLOTAC showed a higher sensitivity than the Kato-Katz method for the diagnosis of Trichuris trichiura (95% vs. 88%, p = 0.012) and Ascaris lumbricoides (88% vs. 68%, p = 0.098), but a lower sensitivity for hookworm diagnosis (54% vs. 81%, p = 0.006). Considering the combined results from both methods as 'gold' standard, the prevalences of T. trichiura, hookworm and A. lumbricoides were 71% (95% confidence interval (CI): 66-75%), 22% (95% CI: 17-26%) and 12% (95% CI: 8-15%), respectively. At follow up, 3-5 weeks after 174 among the 269 re-examined children were administered anthelmintic drugs, we observed cure rates (CRs) against A. lumbricoides, hookworm and T. trichiura of 91% (95% CI: 80-100%), 61% (95% CI: 48-75%) and 41% (95% CI: 34-49%), respectively, when using the Kato-Katz method. FLOTAC revealed lower CRs against A. lumbricoides (83%, 95% CI: 67-98%) and T. trichiura (36%, 95% CI: 29-43%), but a higher CR against hookworm (69%, 95% CI: 57-82%). These differences, however, lacked statistical significance. Considerable differences were observed in the geometric mean fecal egg counts between the two methods with lower egg reduction rates (ERRs) determined by FLOTAC. CONCLUSION/SIGNIFICANCE: Our results suggest that the FLOTAC technique, following further optimization, might become a viable alternative to the Kato-Katz method for anthelmintic drug efficacy studies and for monitoring and evaluation of deworming programs. The lower CRs and ERRs determined by FLOTAC warrant consideration and could strategically impact future helminth control programs. PMID- 21532741 TI - Transplacental transmission of Leishmania infantum as a means for continued disease incidence in North America. AB - BACKGROUND: Dogs are the predominant domestic reservoir for human L. infantum infection. Zoonotic visceral leishmaniasis (ZVL) is an emerging problem in some U.S. dog breeds, with an annual quantitative PCR prevalence of greater than 20% within an at-risk Foxhound population. Although classically Leishmania is transmitted by infected sand flies and phlebotomine sand flies exist in the United States, means of ongoing L. infantum transmission in U.S. dogs is currently unknown. Possibilities include vertical (transplacental/transmammary) and horizontal/venereal transmission. Several reports have indicated that endemic ZVL may be transmitted vertically. AIMS: Our aims for this present study were to establish whether vertical/transplacental transmission was occurring in this population of Leishmania-infected US dogs and determine the effect that this means of transmission has on immune recognition of Leishmania. METHODOLOGY: A pregnant L. infantum-infected dam donated to Iowa State University gave birth in house to 12 pups. Eight pups humanely euthanized at the time of birth and four pups and the dam humanely euthanized three months post-partum were studied via L. infantum-kinetoplast specific quantitative PCR (kqPCR), gross and histopathological assessment and CD4+ T cell proliferation assay. KEY RESULTS: This novel report describes disseminated L. infantum parasites as identified by kqPCR in 8 day old pups born to a naturally-infected, seropositive U.S. dog with no travel history. This is the first report of vertical transmission of L. infantum in naturally-infected dogs in North America, emphasizing that this novel means of transmission could possibly sustain infection within populations. MAJOR CONCLUSIONS: Evidence that vertical transmission of ZVL may be a driving force for ongoing disease in an otherwise non-endemic region has significant implications on current control strategies for ZVL, as at present parasite elimination efforts in endemic areas are largely focused on vector-borne transmission between canines and people. Determining frequency of vertical transmission and incorporating canine sterilization with vector control may have a more significant impact on ZVL transmission to people in endemic areas than current control efforts. PMID- 21532742 TI - Triatoma dimidiata infestation in Chagas disease endemic regions of Guatemala: comparison of random and targeted cross-sectional surveys. AB - BACKGROUND: Guatemala is presently engaged in the Central America Initiative to interrupt Chagas disease transmission by reducing intradomiciliary prevalence of Triatoma dimidiata, using targeted cross-sectional surveys to direct control measures to villages exceeding the 5% control threshold. The use of targeted surveys to guide disease control programs has not been evaluated. Here, we compare the findings from the targeted surveys to concurrent random cross sectional surveys in two primary foci of Chagas disease transmission in central and southeastern Guatemala. METHODOLOGY/PRINCIPAL FINDINGS: Survey prevalences of T. dimidiata intradomiciliary infestation by village and region were compared. Univariate logistic regression was used to assess the use of risk factors to target surveys and to evaluate indicators associated with village level intradomiciliary prevalences >5% by survey and region. Multivariate logistic regression models were developed to assess the ability of random and targeted surveys to target villages with intradomiciliary prevalence exceeding the control threshold within each region. Regional prevalences did not vary by survey; however, village prevalences were significantly greater in random surveys in central (13.0% versus 8.7%) and southeastern (22.7% versus 6.9%) Guatemala. The number of significant risk factors detected did not vary by survey in central Guatemala but differed considerably in the southeast with a greater number of significant risk factors in the random survey (e.g. land surface temperature, relative humidity, cropland, grassland, tile flooring, and stick and mud and palm and straw walls). Differences in the direction of risk factor associations were observed between regions in both survey types. The overall discriminative capacity was significantly greater in the random surveys in central and southeastern Guatemala, with an area under the receiver-operator curve (AUC) of 0.84 in the random surveys and approximately 0.64 in the targeted surveys in both regions. Sensitivity did not differ between surveys, but the positive predictive value was significantly greater in the random surveys. CONCLUSIONS/SIGNIFICANCE: Surprisingly, targeted surveys were not more effective at determining T. dimidiata prevalence or at directing control to high risk villages in comparison to random surveys. We recommend that random surveys should be selected over targeted surveys whenever possible, particularly when the focus is on directing disease control and elimination and when risk factor association has not been evaluated for all regions under investigation. PMID- 21532744 TI - The quality of medical care in low-income countries: from providers to markets. PMID- 21532743 TI - Different origins of gamma rhythm and high-gamma activity in macaque visual cortex. AB - During cognitive tasks electrical activity in the brain shows changes in power in specific frequency ranges, such as the alpha (8-12 Hz) or gamma (30-80 Hz) bands, as well as in a broad range above ~80 Hz, called the high-gamma band. The role or significance of this broadband high-gamma activity is unclear. One hypothesis states that high-gamma oscillations serve just like gamma oscillations, operating at a higher frequency and consequently at a faster timescale. Another hypothesis states that high-gamma power is related to spiking activity. Because gamma power and spiking activity tend to co-vary during most stimulus manipulations (such as contrast modulations) or cognitive tasks (such as attentional modulation), it is difficult to dissociate these two hypotheses. We studied the relationship between high-gamma power, gamma rhythm, and spiking activity in the primary visual cortex (V1) of awake monkeys while varying the stimulus size, which increased the gamma power but decreased the firing rate, permitting a dissociation. We found that gamma power became anti-correlated with the high-gamma power, suggesting that the two phenomena are distinct and have different origins. On the other hand, high gamma power remained tightly correlated with spiking activity under a wide range of stimulus manipulations. We studied this relationship using a signal processing technique called Matching Pursuit and found that action potentials are associated with sharp transients in the LFP with broadband power, which is visible at frequencies as low as ~50 Hz. These results distinguish broadband high-gamma activity from gamma rhythms as an easily obtained and reliable electrophysiological index of neuronal firing near the microelectrode. Further, they highlight the importance of making a careful dissociation between gamma rhythms and spike-related transients that could be incorrectly decomposed as rhythms using traditional signal processing methods. PMID- 21532745 TI - Genetic characterization of human T-cell lymphotropic virus type 1 in Mozambique: transcontinental lineages drive the HTLV-1 endemic. AB - BACKGROUND: Human T-Cell Lymphotropic Virus Type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It has been estimated that 10-20 million people are infected worldwide, but no successful treatment is available. Recently, the epidemiology of this virus was addressed in blood donors from Maputo, showing rates from 0.9 to 1.2%. However, the origin and impact of HTLV endemic in this population is unknown. OBJECTIVE: To assess the HTLV-1 molecular epidemiology in Mozambique and to investigate their relationship with HTLV-1 lineages circulating worldwide. METHODS: Blood donors and HIV patients were screened for HTLV antibodies by using enzyme immunoassay, followed by Western Blot. PCR and sequencing of HTLV-1 LTR region were applied and genetic HTLV-1 subtypes were assigned by the neighbor-joining method. The mean genetic distance of Mozambican HTLV-1 lineages among the genetic clusters were determined. Human mitochondrial (mt) DNA analysis was performed and individuals classified in mtDNA haplogroups. RESULTS: LTR HTLV-1 analysis demonstrated that all isolates belong to the Transcontinental subgroup of the Cosmopolitan subtype. Mozambican HTLV-1 sequences had a high inter-strain genetic distance, reflecting in three major clusters. One cluster is associated with the South Africa sequences, one is related with Middle East and India strains and the third is a specific Mozambican cluster. Interestingly, 83.3% of HIV/HTLV-1 co-infection was observed in the Mozambican cluster. The human mtDNA haplotypes revealed that all belong to the African macrohaplogroup L with frequencies representatives of the country. CONCLUSIONS: The Mozambican HTLV-1 genetic diversity detected in this study reveals that although the strains belong to the most prevalent and worldwide distributed Transcontinental subgroup of the Cosmopolitan subtype, there is a high HTLV diversity that could be correlated with at least 3 different HTLV-1 introductions in the country. The significant rate of HTLV-1a/HIV-1C co infection, particularly in the Mozambican cluster, has important implications for the controls programs of both viruses. PMID- 21532746 TI - Quality of private and public ambulatory health care in low and middle income countries: systematic review of comparative studies. AB - BACKGROUND: In developing countries, the private sector provides a substantial proportion of primary health care to low income groups for communicable and non communicable diseases. These providers are therefore central to improving health outcomes. We need to know how their services compare to those of the public sector to inform policy options. METHODS AND FINDINGS: We summarised reliable research comparing the quality of formal private versus public ambulatory health care in low and middle income countries. We selected studies against inclusion criteria following a comprehensive search, yielding 80 studies. We compared quality under standard categories, converted values to a linear 100% scale, calculated differences between providers within studies, and summarised median values of the differences across studies. As the results for for-profit and not for-profit providers were similar, we combined them. Overall, median values indicated that many services, irrespective of whether public or private, scored low on infrastructure, clinical competence, and practice. Overall, the private sector performed better in relation to drug supply, responsiveness, and effort. No difference between provider groups was detected for patient satisfaction or competence. Synthesis of qualitative components indicates the private sector is more client centred. CONCLUSIONS: Although data are limited, quality in both provider groups seems poor, with the private sector performing better in drug availability and aspects of delivery of care, including responsiveness and effort, and possibly being more client orientated. Strategies seeking to influence quality in both groups are needed to improve care delivery and outcomes for the poor, including managing the increasing burden of non-communicable diseases. PMID- 21532747 TI - High prevalence of persistent parasitic infections in foreign-born, HIV-infected persons in the United States. AB - BACKGROUND: Foreign-born, HIV-infected persons are at risk for sub-clinical parasitic infections acquired in their countries of origin. The long-term consequences of co-infections can be severe, yet few data exist on parasitic infection prevalence in this population. METHODOLOGY/PRINCIPAL FINDINGS: This cross-sectional study evaluated 128 foreign-born persons at one HIV clinic. We performed stool studies and serologic testing for strongyloidiasis, schistosomiasis, filarial infection, and Chagas disease based on the patient's country of birth. Eosinophilia and symptoms were examined as predictors of helminthic infection. Of the 128 participants, 86 (67%) were male, and the median age was 40 years; 70 were Mexican/Latin American, 40 African, and 18 from other countries or regions. Strongyloides stercoralis antibodies were detected in 33/128 (26%) individuals. Of the 52 persons from schistosomiasis-endemic countries, 15 (29%) had antibodies to schistosome antigens; 7 (47%) had antibodies to S. haematobium, 5 (33%) to S. mansoni, and 3 (20%) to both species. Stool ova and parasite studies detected helminths in 5/85 (6%) persons. None of the patients tested had evidence of Chagas disease (n = 77) or filarial infection (n = 52). Eosinophilia >400 cells/mm(3) was associated with a positive schistosome antibody test (OR 4.5, 95% CI 1.1-19.0). The only symptom significantly associated with strongyloidiasis was weight loss (OR 3.1, 95% CI 1.4-7.2). CONCLUSIONS/SIGNIFICANCE: Given the high prevalence of certain helminths and the potential lack of suggestive symptoms and signs, selected screening for strongyloidiasis and schistosomiasis or use of empiric antiparasitic therapy may be appropriate among foreign-born, HIV-infected patients. Identifying and treating helminth infections could prevent long-term complications. PMID- 21532748 TI - Snakebite mortality in India: a nationally representative mortality survey. AB - BACKGROUND: India has long been thought to have more snakebites than any other country. However, inadequate hospital-based reporting has resulted in estimates of total annual snakebite mortality ranging widely from about 1,300 to 50,000. We calculated direct estimates of snakebite mortality from a national mortality survey. METHODS AND FINDINGS: We conducted a nationally representative study of 123,000 deaths from 6,671 randomly selected areas in 2001-03. Full-time, non medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. Discrepancies were resolved by anonymous reconciliation or, failing that, by adjudication. A total of 562 deaths (0.47% of total deaths) were assigned to snakebites. Snakebite deaths occurred mostly in rural areas (97%), were more common in males (59%) than females (41%), and peaked at ages 15-29 years (25%) and during the monsoon months of June to September. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6-4.5), with higher rates in rural areas (5.4/100,000; 99% CI 4.8-6.0), and with the highest state rate in Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). CONCLUSIONS: Snakebite remains an underestimated cause of accidental death in modern India. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Community education, appropriate training of medical staff and better distribution of antivenom, especially to the 13 states with the highest prevalence, could reduce snakebite deaths in India. PMID- 21532749 TI - Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis. AB - BACKGROUND: Development of Type 2 diabetes, like obesity, is promoted by a genetic predisposition. Although several genetic variants have been identified they only account for a small proportion of risk. We have asked if genetic risk is associated with abnormalities in storing excess lipids in the abdominal subcutaneous adipose tissue. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 164 lean and 500 overweight/obese individuals with or without a genetic predisposition for Type 2 diabetes or obesity. Adipose cell size was measured in biopsies from the abdominal adipose tissue as well as insulin sensitivity (HOMA index), HDL-cholesterol and Apo AI and Apo B. 166 additional non-obese individuals with a genetic predisposition for Type 2 diabetes underwent a euglycemic hyperinsulinemic clamp to measure insulin sensitivity. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, was associated with inappropriate expansion of the adipose cells, reduced insulin sensitivity and a more proatherogenic lipid profile in non-obese individuals. However, obesity per se induced a similar expansion of adipose cells and dysmetabolic state irrespective of genetic predisposition. CONCLUSIONS/SIGNIFICANCE: Genetic predisposition for Type 2 diabetes, but not obesity, is associated with an impaired ability to recruit new adipose cells to store excess lipids in the subcutaneous adipose tissue, thereby promoting ectopic lipid deposition. This becomes particularly evident in non-obese individuals since obesity per se promotes a dysmetabolic state irrespective of genetic predisposition. These results identify a novel susceptibility factor making individuals with a genetic predisposition for Type 2 diabetes particularly sensitive to the environment and caloric excess. PMID- 21532750 TI - Differential expression of microRNAs in tumors from chronically inflamed or genetic (APC(Min/+)) models of colon cancer. AB - BACKGROUND: Chronic inflammation associated with ulcerative colitis predisposes individuals to increased colon cancer risk. The aim of these studies was to identify microRNAs that are aberrantly regulated during inflammation and may participate in transformation of colonic epithelial cells in the inflammatory setting. METHODOLOGY/PRINCIPAL FINDINGS: We have use quantitative PCR arrays to compare microRNA (miRNA) expression in tumors and control colonic epithelial cells isolated from distal colons of chronically inflamed mice and APC(Min/+) mice. Rank order statistics was utilized to identify differentially regulated miRNAs in tumors that arose due to chronic inflammation and/or to germline APC mutation. Eight high priority miRNAs were identified: miR-215, miR-137, miR-708, miR-31, and miR-135b were differentially expressed in APC tumors and miR-215, miR 133a, miR-467d, miR-218, miR-708, miR-31, and miR-135b in colitis-associated tumors. Four of these (miR-215, miR-708, miR-31, and miR-135b) were common to both tumors types, and dysregulation of these miRNAs was confirmed in an independent sample set. Target prediction and pathway analysis suggests that these microRNAs, in the aggregate, regulate signaling pathways related to MAPK, PI3K, WNT, and TGF-beta, all of which are known to be involved in transformation. CONCLUSIONS/SIGNIFICANCE: We conclude that these four miRNAs are dysregulated at some very early stage in transformation of colonic epithelial cells. This response is not dependent on the mechanism of initiation of transformation (inflammation versus germline mutation), suggesting that the miRNAs that we have identified are likely to regulate critical signaling pathways that are central to early events in transformation of colonic epithelial cells. PMID- 21532751 TI - Activation of multiple apoptotic pathways in human nasopharyngeal carcinoma cells by the prenylated isoflavone, osajin. AB - Osajin is a prenylated isoflavone showing antitumor activity in different tumor cell lines. The underlying mechanism of osajin-induced cancer cell death is not clearly understood. In the present study, the mechanisms of osajin-induced cell death of human nasopharyngeal carcinoma (NPC) cells were explored. Osajin was found to significantly induce apoptosis of NPC cells in a dose- and time dependent manner. Multiple molecular effects were observed during osajin treatment including a significant loss of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, enhanced expression of Fas ligand (FasL), suppression of glucose-regulated protein 78 kDa (GRP78), and activation of caspases-9, -8, -4 and -3. In addition, up-regulation of proapoptotic Bax protein and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, osajin induces apoptosis in human NPC cells through multiple apoptotic pathways, including the extrinsic death receptor pathway, and intrinsic pathways relying on mitochondria and endoplasmic reticulum stress. Thus, osajin could be developed as a new effective and chemopreventive compound for human NPC. PMID- 21532752 TI - Chemokine (C-C motif) ligand 2 (CCL2) in sera of patients with type 1 diabetes and diabetic complications. AB - BACKGROUND: Chemokine (C-C motif) ligand 2 (CCL2), commonly known as monocyte chemoattractant protein-1 (MCP-1), has been implicated in the pathogenesis of many diseases characterized by monocytic infiltration. However, limited data have been reported on MCP-1 in type 1 diabetes (T1D) and the findings are inconclusive and inconsistent. METHODS: In this study, MCP-1 was measured in the sera from 2,472 T1D patients and 2,654 healthy controls using a Luminex assay. The rs1024611 SNP in the promoter region of MCP-1 was genotyped for a subset of subjects (1764 T1D patients and 1323 controls) using the TaqMan-assay. RESULTS: Subject age, sex or genotypes of MCP-1 rs1024611SNP did not have a major impact on serum MCP-1 levels in either healthy controls or patients. While hemoglobin A1c levels did not have a major influence on serum MCP-1 levels, the mean serum MCP-1 levels are significantly higher in patients with multiple complications (mean = 242 ng/ml) compared to patients without any complications (mean = 201 ng/ml) (p = 3.5*10(-6)). Furthermore, mean serum MCP-1 is higher in controls (mean = 261 ng/ml) than T1D patients (mean = 208 ng/ml) (p<10(-23)). More importantly, the frequency of subjects with extremely high levels (>99(th) percentile of patients or 955 ng/ml) of serum MCP-1 is significantly lower in the T1D group compared to the control group (odds ratio = 0.11, p<10(-33)). CONCLUSION: MCP-1 may have a dual role in T1D and its complications. While very high levels of serum MCP-1 may be protective against the development of T1D, complications are associated with higher serum MCP-1 levels within the T1D group. PMID- 21532753 TI - Dual testing algorithm of BED-CEIA and AxSYM Avidity Index assays performs best in identifying recent HIV infection in a sample of Rwandan sex workers. AB - BACKGROUND: To assess the performance of BED-CEIA (BED) and AxSYM Avidity Index (Ax-AI) assays in estimating HIV incidence among female sex workers (FSW) in Kigali, Rwanda. METHODOLOGY AND FINDINGS: Eight hundred FSW of unknown HIV status were HIV tested; HIV-positive women had BED and Ax-AI testing at baseline and >=12 months later to estimate assay false-recent rates (FRR). STARHS-based HIV incidence was estimated using the McWalter/Welte formula, and adjusted with locally derived FRR and CD4 results. HIV incidence and local assay window periods were estimated from a prospective cohort of FSW. At baseline, 190 HIV-positive women were BED and Ax-AI tested; 23 were classified as recent infection (RI). Assay FRR with 95% confidence intervals were: 3.6% (1.2-8.1) (BED); 10.6% (6.1 17.0) (Ax-AI); and 2.1% (0.4-6.1) (BED/Ax-AI combined). After FRR-adjustment, incidence estimates by BED, Ax-AI, and BED/Ax-AI were: 5.5/100 person-years (95% CI 2.2-8.7); 7.7 (3.2-12.3); and 4.4 (1.4-7.3). After CD4-adjustment, BED, Ax-AI, and BED/Ax-AI incidence estimates were: 5.6 (2.6-8.6); 9.7 (5.0-14.4); and 4.7 (2.0-7.5). HIV incidence rates in the first and second 6 months of the cohort were 4.6 (1.6-7.7) and 2.2 (0.1-4.4). CONCLUSIONS: Adjusted incidence estimates by BED/Ax-AI combined were similar to incidence in the first 6 months of the cohort. Furthermore, false-recent rate on the combined BED/Ax-AI algorithm was low and substantially lower than for either assay alone. Improved assay specificity with time since seroconversion suggests that specificity would be higher in population-based testing where more individuals have long-term infection. PMID- 21532754 TI - A role for fetal hemoglobin and maternal immune IgG in infant resistance to Plasmodium falciparum malaria. AB - BACKGROUND: In Africa, infant susceptibility to Plasmodium falciparum malaria increases substantially as fetal hemoglobin (HbF) and maternal immune IgG disappear from circulation. During the first few months of life, however, resistance to malaria is evidenced by extremely low parasitemias, the absence of fever, and the almost complete lack of severe disease. This resistance has previously been attributed in part to poor parasite growth in HbF-containing red blood cells (RBCs). A specific role for maternal immune IgG in infant resistance to malaria has been hypothesized but not yet identified. METHODS AND FINDINGS: We found that P. falciparum parasites invade and develop normally in fetal (cord blood, CB) RBCs, which contain up to 95% HbF. However, these parasitized CB RBCs are impaired in their binding to human microvascular endothelial cells (MVECs), monocytes, and nonparasitized RBCs--cytoadherence interactions that have been implicated in the development of high parasite densities and the symptoms of malaria. Abnormal display of the parasite's cytoadherence antigen P. falciparum erythrocyte membrane protein-1 (PfEMP-1) on CB RBCs accounts for these findings and is reminiscent of that on HbC and HbS RBCs. IgG purified from the plasma of immune Malian adults almost completely abolishes the adherence of parasitized CB RBCs to MVECs. CONCLUSIONS: Our data suggest a model of malaria protection in which HbF and maternal IgG act cooperatively to impair the cytoadherence of parasitized RBCs in the first few months of life. In highly malarious areas of Africa, an infant's contemporaneous expression of HbC or HbS and development of an immune IgG repertoire may effectively reconstitute the waning protective effects of HbF and maternal immune IgG, thereby extending the malaria resistance of infancy into early childhood. PMID- 21532755 TI - The effects of network neighbours on protein evolution. AB - Interacting proteins may often experience similar selection pressures. Thus, we may expect that neighbouring proteins in biological interaction networks evolve at similar rates. This has been previously shown for protein-protein interaction networks. Similarly, we find correlated rates of evolution of neighbours in networks based on co-expression, metabolism, and synthetic lethal genetic interactions. While the correlations are statistically significant, their magnitude is small, with network effects explaining only between 2% and 7% of the variation. The strongest known predictor of the rate of protein evolution remains expression level. We confirmed the previous observation that similar expression levels of neighbours indeed explain their similar evolution rates in protein protein networks, and showed that the same is true for metabolic networks. In co expression and synthetic lethal genetic interaction networks, however, neighbouring genes still show somewhat similar evolutionary rates even after simultaneously controlling for expression level, gene essentiality and gene length. Thus, similar expression levels and related functions (as inferred from co-expression and synthetic lethal interactions) seem to explain correlated evolutionary rates of network neighbours across all currently available types of biological networks. PMID- 21532756 TI - Genomic and resistance gene homolog diversity of the dominant tallgrass prairie species across the U.S. Great Plains precipitation gradient. AB - BACKGROUND: Environmental variables such as moisture availability are often important in determining species prevalence and intraspecific diversity. The population genetic structure of dominant plant species in response to a cline of these variables has rarely been addressed. We evaluated the spatial genetic structure and diversity of Andropogon gerardii populations across the U.S. Great Plains precipitation gradient, ranging from approximately 48 cm/year to 105 cm/year. METHODOLOGY/PRINCIPAL FINDINGS: Genomic diversity was evaluated with AFLP markers and diversity of a disease resistance gene homolog was evaluated by PCR-amplification and digestion with restriction enzymes. We determined the degree of spatial genetic structure using Mantel tests. Genomic and resistance gene homolog diversity were evaluated across prairies using Shannon's index and by averaging haplotype dissimilarity. Trends in diversity across prairies were determined using linear regression of diversity on average precipitation for each prairie. We identified significant spatial genetic structure, with genomic similarity decreasing as a function of distance between samples. However, our data indicated that genome-wide diversity did not vary consistently across the precipitation gradient. In contrast, we found that disease resistance gene homolog diversity was positively correlated with precipitation. SIGNIFICANCE: Prairie remnants differ in the genetic resources they maintain. Selection and evolution in this disease resistance homolog is environmentally dependent. Overall, we found that, though this environmental gradient may not predict genomic diversity, individual traits such as disease resistance genes may vary significantly. PMID- 21532757 TI - Competing interactions in DNA assembly on graphene. AB - We study the patterns that short strands of single-stranded DNA form on the top graphene surface of graphite. We find that the DNA assembles into two distinct patterns, small spherical particles and elongated networks. Known interaction models based on DNA-graphene binding, hydrophobic interactions, or models based on the purine/pyrimidine nature of the bases do not explain our observed crossover in pattern formation. We argue that the observed assembly behavior is caused by a crossover in the competition between base-base pi stacking and base graphene pi stacking and we infer a critical crossover energy of 0.3-0.5 eV. The experiments therefore provide a projective measurement of the base-base interaction strength. PMID- 21532758 TI - An administrative claims model for profiling hospital 30-day mortality rates for pneumonia patients. AB - BACKGROUND: Outcome measures for patients hospitalized with pneumonia may complement process measures in characterizing quality of care. We sought to develop and validate a hierarchical regression model using Medicare claims data that produces hospital-level, risk-standardized 30-day mortality rates useful for public reporting for patients hospitalized with pneumonia. METHODOLOGY/PRINCIPAL FINDINGS: Retrospective study of fee-for-service Medicare beneficiaries age 66 years and older with a principal discharge diagnosis of pneumonia. Candidate risk adjustment variables included patient demographics, administrative diagnosis codes from the index hospitalization, and all inpatient and outpatient encounters from the year before admission. The model derivation cohort included 224,608 pneumonia cases admitted to 4,664 hospitals in 2000, and validation cohorts included cases from each of years 1998-2003. We compared model-derived state level standardized mortality estimates with medical record-derived state-level standardized mortality estimates using data from the Medicare National Pneumonia Project on 50,858 patients hospitalized from 1998-2001. The final model included 31 variables and had an area under the Receiver Operating Characteristic curve of 0.72. In each administrative claims validation cohort, model fit was similar to the derivation cohort. The distribution of standardized mortality rates among hospitals ranged from 13.0% to 23.7%, with 25(th), 50(th), and 75(th) percentiles of 16.5%, 17.4%, and 18.3%, respectively. Comparing model-derived risk standardized state mortality rates with medical record-derived estimates, the correlation coefficient was 0.86 (Standard Error = 0.032). CONCLUSIONS/SIGNIFICANCE: An administrative claims-based model for profiling hospitals for pneumonia mortality performs consistently over several years and produces hospital estimates close to those using a medical record model. PMID- 21532759 TI - IgE mediated autoallergy against thyroid peroxidase--a novel pathomechanism of chronic spontaneous urticaria? AB - BACKGROUND: Chronic spontaneous urticaria (csU), which is characterized by recurrent episodes of mast cell-driven wheal and flare-type skin reactions, is often associated with elevated total IgE levels and thyroid autoimmunity. We speculate that some csU patients express IgE autoantibodies against thyroid antigens such as thyroid peroxidase (TPO), which could bind to skin mast cells and induce their activation. METHODS: We developed and used a site-directed human IgE capture ELISA to quantify IgE-anti-TPO. We used this assay and investigated csU patients (n = 478) and healthy control subjects (n = 127) for IgE-anti-TPO and then assessed IgE-anti-TPO-positive and -negative csU patients for clinical and serological differences. PRINCIPAL FINDINGS: CsU patients were found to express more than 2fold higher IgE-anti-TPO serum levels as compared to healthy control subjects (p<0.001). 54% of csU patients had serum levels higher than the cut off ( = 5 IU/ml). By distribution analyses we identified two distinct subpopulations of csU patients: 1) IgE-anti-TPO(low) ( = 39%, IgE-anti-TPO: median 2.17 interquartile range 0.86-5.44, = comparable to healthy controls) and 2) IgE-anti-TPO(high) ( = 61%, IgE-anti-TPO: median 6.67, interquartile range 5.39-8.24). IgE-anti-TPO-positive and -negative csU patients had very similar distributions of age and gender as well as disease activity and duration. IgE anti-TPO-positive csU patients exhibited significantly higher IgG-anti-TPO levels and lymphocyte counts as well as decreased C4 complement levels. CONCLUSION: Our findings show that a sizeable subgroup of csU patients expresses IgE antibodies against thyroid peroxidase. These autoantibodies could cause "autoallergic" mast cell activation, a novel pathomechanism of chronic spontaneous urticaria. PMID- 21532761 TI - Equitable access to healthcare services and income replacement for cancer: is critical illness insurance a help or a hindrance? AB - Canada's publicly funded healthcare system ensures that medically necessary hospital and physician services are available without financial barriers, but not all community-based care is covered. Consequently, many patients experience financial shocks (FS) related to community-based healthcare services not funded by government, and perhaps also from lost income, a situation that may be difficult for patients to avoid. Critical illness insurance (CII) offers a patient-funded alternative to those who qualify and desire protection against FS, leaving those without CII exposed. The author discusses the benefits and limitations of CII to mitigate financially derived healthcare access inequities, using cancer as an example. PMID- 21532762 TI - Living environments for people with moderate to severe acquired brain injury. AB - OBJECTIVES: This study examines the issue of living environments for persons with acquired brain injury (ABI), with the aim of identifying factors that enable or act as barriers to appropriate living environments. METHODS: A qualitative study involving 31 semi-structured interviews conducted with 56 key informants representing various relevant sectors: institutional, community, residential and non-residential, consumer/advocacy and government/policy from six regions in the province of Ontario, Canada. RESULTS: The study identified such barriers as lack of ABI-specific facilities, beds and trained staff and a poorly coordinated system in many areas, with long wait lists for specialized residential settings. Clients with ABI need individualized treatment, making development of a standardized model of care difficult, particularly for those with co-morbid conditions. Solutions such as more flexible options for clients and better trained staff emerged. CONCLUSIONS: The study presents solutions to challenges and limitations in addressing appropriate living environments for persons with ABI. PMID- 21532763 TI - Exploring wait list prioritization and management strategies for publicly funded ambulatory rehabilitation services in ontario, Canada: further evidence of barriers to access for people with chronic disease. AB - BACKGROUND: Timely access to publicly funded health services is a priority issue across the healthcare continuum in Canada. The purpose of this study was to examine wait list management strategies for publicly funded ambulatory rehabilitation services in Ontario, Canada. METHODS: Ambulatory rehabilitation services were defined as community occupational therapy (OT) and physiotherapy (PT) services. A mailed self-administered questionnaire was sent to all 374 Ontario publicly funded sites. Descriptive statistics were used to explore management strategies. RESULTS: The response rate was 57.2%. Client acuity was the most common method used to prioritize access across all settings. The most frequently reported methods to manage wait lists included teaching self management strategies (85.0%), implementing attendance policies (69.5%) and conducting wait list audits (67.3%). CONCLUSION: Ambulatory rehabilitation settings have implemented a number of strategies for wait list management. The results of this study suggest that an increasing number of Ontarians encounter barriers when accessing publicly funded ambulatory rehabilitation services. PMID- 21532765 TI - The Buzz about the Upcoming G8 Summit and Global Health. PMID- 21532764 TI - Anthropological approach of adherence factors for antihypertensive drugs. AB - OBJECTIVE: Uncontrolled high blood pressure leads clinicians to wonder about adherence degree among hypertensive patients. In this context, our study aims to describe and analyze patients' experience of antihypertensive drugs in order to shed light on the multiple social and symbolic logics, forming part of the cultural factors shaping personal medication practices. METHODS: The medical inductive and comprehensive anthropological approach implemented is based on an ethnographic survey (observations of consultations and interviews). Semi structured interviews were conducted with 68 hypertensive patients (39 women and 29 men, between the ages of 40 and 95, of whom 52 were over 60) who had been receiving treatment for over a year. RESULTS: Antihypertensive drugs are reinterpreted when filtered through the cultural model of physiopathology (the body as an engine). This symbolic dimension facilitates acceptance of therapy but leads to a hierarchization of other prescribed drugs and of certain therapeutic classes (diuretics). Prescription compliance does not solely depend on the patient's perception of cardiovascular risk, but also on how the patient fully accepts the treatment and integrates it into his or her daily life; this requires identification with the product, building commitment and self-regulation of the treatment (experience, managing treatment and control of side effects, intake and treatment continuity). Following the prescription requires a relationship based on trust between the doctor and patient, which we have identified in three forms: reasoned trust, emotional trust and conceded trust. CONCLUSION: Consideration and understanding of these pragmatic and symbolic issues by the treating physician should aid practitioners in carrying out their role as medical educators in the management of hypertension. This paper was originally published in French, in the journal Pratiques et organisation des soins 39(1): 3-12. PMID- 21532766 TI - Tough on Crime? Pfizer and the CIHR. AB - The appointment of Dr. Bernard Prigent, vice-president and medical director of Pfizer Canada, to the Governing Council of the Canadian Institutes of Health Research, outraged many Canadian health researchers. Pfizer has been a "habitual offender," persistently engaging in illegal and corrupt marketing practices, bribing physicians and suppressing adverse trial results. Since 2002 the company and its subsidiaries have been assessed $3 billion in criminal convictions, civil penalties and jury awards. The $2.3-billion settlement in September 2009 - a month before Dr. Prigent's appointment - set a new record for both criminal fines and total penalties. A link with Pfizer might well advance the commercialization of Canadian research - unhindered by law or morality. Is that now the only mandate, Dr. Beaudet? PMID- 21532767 TI - Gardasil(r) - The New HPV Vaccine: The Right Product, the Right Time? A Commentary. AB - The federal and provincial governments have undertaken a universal immunization program to protect school-aged girls against cervical cancer using the new human papillomavirus vaccine Gardasil(r). While the vaccine appears to be effective and safe, there are a number of important unanswered questions regarding it and the effects of the immunization program. Here we briefly review key literature about the vaccine and then use the Erickson criteria, which offer an evidence basis for decision-making regarding national immunization strategies, to evaluate whether the program is congruent with sound public health policy. Our analysis of the national decision to recommend and fund a vaccination program using Gardasil(r) raises significant questions about the basis for this program. PMID- 21532768 TI - Compulsory school-entry vaccination laws and exemptions: who is opting out in ontario and why does it matter? AB - School-entry vaccination regulations are a policy instrument that has been widely used in some jurisdictions as a mechanism to ensure high immunization coverage rates. Exemptions to school-entry vaccination, which can be allowed on medical or non-medical grounds, present a number of ethical and policy challenges. In this paper, we consider the situation in Canada, where school-entry vaccination laws are rare. We present newly available aggregate-level registry data from Ontario comparing the use of medical and non-medical immunization exemptions to school entry vaccination and the implications for population health. PMID- 21532769 TI - Perspectives of an interdisciplinaryg research team to engage practice: lessons from a knowledge exchange trainee experience. AB - End-of-life (EOL) care is an area of health services that will ultimately affect us all. To share the knowledge emerging from EOL research and to address inequities in the quality of EOL care in Nova Scotia, a knowledge exchange (KE) trainee was hired to translate research and surveillance into a Surveillance Report. The purpose of this paper is to reflect upon this initiative and share the research team's perspectives on their KE experiences. We describe four key competencies of the KE trainee selected, and discuss lessons learned from this KE trainee experience, to expand our understanding of KE. PMID- 21532770 TI - A Case Study on the Substitution Effect between the Length of GP Consultation and Drug Prescribing Practices. AB - The relationship between the length of GP consultation in primary care and drug prescribing practices is still a subject for debate. Patients' morbidity, generating both very long consultation times and large volumes of prescriptions, may mask an underlying substitution among GPs regarding the length of time they offer to patients versus the alternative of prescribing pharmaceuticals. We propose to pursue the debate by analyzing the results of a case vignette, submitted to 1,900 GPs, in which patient morbidity is controlled for by definition. In this case - a hypothetical patient suffering from mild depression we observe the choice between three types of treatment strategy: psychotherapy, drug therapy and a combination of the two. We observe that the GPs with the highest consultation rates were twice as likely to adopt the drug therapy option as their counterparts with lower rates of consultation. Moreover, for more than 50% of drug prescriptions, the medical decisions contradict clinical practice guidelines. PMID- 21532771 TI - Public perceptions of physician - pharmaceutical industry interactions: a systematic review. AB - BACKGROUND: Interactions between physicians and the pharmaceutical industry have led to concerns about conflict of interest (COI), resulting in COI guidelines that suggest a threshold beyond which interactions may be considered unacceptable. Guidelines have also outlined the importance of public opinion on the topic. Consequently, we conducted a systematic review to determine the Canadian public's opinions of physician-pharmaceutical industry interactions. METHODS: A systematic review of the standard health sciences literature as well as grey literature was conducted and a number of experts were contacted. Pre determined eligibility criteria were used to identify appropriate studies. Meta analysis of the study findings was not possible owing to the variety of methods of reporting outcomes, the types of interactions studied and the diversity of populations studied. RESULTS: No studies on Canadian opinions were identified. Ten international studies (n=13,637), seven with patient groups and three with public citizens, were identified that examined opinions on aspects of awareness, acceptability, disclosure and perceived effects of physician-pharmaceutical industry interactions. Heterogeneity was observed in the awareness, acceptability and perceived effects of physician-pharmaceutical industry interactions; however, there appeared to be greater acceptability and fewer perceived effects with smaller, less costly interactions that directly benefit patients or a medical practice. Desire for disclosure of these interactions was consistent across studies. INTERPRETATION: Research on the public's perception of physician pharmaceutical industry interactions has been inadequate internationally and non existent in Canada, and is urgently needed to help shape policies regarding potential conflict of interest. PMID- 21532772 TI - Clinical Practice Settings Associated with GPs Who Take on Patients with Mental Disorders. AB - In light of current reforms to reinforce primary mental healthcare and service integration, this paper assesses general practitioners' (GPs') management of patients with mental disorders (PMD) and its associated practice settings and clinical characteristics. The study is based on a survey of 398 Quebec GPs. Results showed that GPs who receive patients with moderate and transient mental disorders (PMD-M) usually follow them on a continuous basis; conversely, only a quarter of GPs who see patients with severe and persistent mental disorders (PMD S) provide follow-up. With the exception of walk-in clinics, all clinical settings are associated with GPs who take on PMD-M. No setting was found to be significantly associated with GPs taking on PMD-S. Competency, skills and confidence seem to be core factors in decisions to take on PMD. Group practice models (CLSCs, network clinics) and shared-care initiatives should be encouraged to manage more complex PMD cases. PMID- 21532774 TI - Genetics of congenital heart disease. AB - Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown but genetic factors are being recognized as playing an increasingly important role. Advances in our molecular understanding of normal heart development have led to the identification of numerous genes necessary for cardiac morphogenesis. This work has aided the discovery of an increasing number of monogenic causes of human cardiovascular malformations. More recently, studies have identified single nucleotide polymorphisms and submicroscopic copy number abnormalities as having a role in the pathogenesis of congenital heart disease. This review discusses these discoveries and summarizes our increasing understanding of the genetic basis of congenital heart disease. PMID- 21532773 TI - The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease. AB - Endothelium plays a crucial role in the maintenance of vascular tone and structure. Endothelial dysfunction is known to precede overt coronary artery disease. A number of cardiovascular risk factors, as well as metabolic diseases and systemic or local inflammation cause endothelial dysfunction. Nitric oxide (NO) is one of the major endothelium derived vaso-active substances whose role is of prime importance in maintaining endothelial homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in human circulation. Elevated levels of ADMA inhibit NO synthesis and therefore impair endothelial function and thus promote atherosclerosis. ADMA levels are increased in people with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic renal failure. A number of studies have reported ADMA as a novel risk marker of cardiovascular disease. Increased levels of ADMA have been shown to be the strongest risk predictor, beyond traditional risk factors, of cardiovascular events and all cause and cardiovascular mortality in people with coronary artery disease. Interventions such as treatment with L-arginine have been shown to improve endothelium-mediated vasodilatation in people with high ADMA levels. However the clinical utility of modifying circulating ADMA levels remains uncertain. PMID- 21532775 TI - Myocardial Perfusion SPECT Imaging in Patients after Percutaneous Coronary Intervention. AB - Coronary artery disease (CAD) is the most prevalent form of cardiovascular disease affecting about 13 million Americans, while more than one million percutaneous transluminal intervention (PCI) procedures are performed annually in the USA. The relative high occurrence of restenosis, despite stent implementation, seems to be the primary limitation of PCI. Over the last decades, single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), has proven an invaluable tool for the diagnosis of CAD and patients' risk stratification, providing useful information regarding the decision about revascularization and is well suited to assess patients after intervention. Information gained from post-intervention MPI is crucial to differentiate patients with angina from those with exo-cardiac chest pain syndromes, to assess peri-intervention myocardial damage, to predict-detect restenosis after PCI, to detect CAD progression in non-revascularized vessels, to evaluate the effects of intervention if required for occupational reasons and to evaluate patients' long term prognosis. On the other hand, chest pain and exercise electrocardiography are largely unhelpful in identifying patients at risk after PCI.Although there are enough published data demonstrating the value of myocardial perfusion SPECT imaging in patients after PCI, there is still debate on whether or not these tests should be performed routinely. PMID- 21532776 TI - Current concepts underlying benefits of exercise training in congestive heart failure patients. AB - The pathophysiology of several conditions including heart failure is partly attributable to a failure of the cell energy metabolism. Studies have shown that exercise training (ET) improves quality of life (QOL) and is beneficial in terms of reduction of symptoms, mortality and duration of hospitalization. Increasingly, ET is now achieving acceptance as complimentary therapy in addition to routine clinical practice in patients with chronic heart failure (CHF). However, the mechanisms underlying the beneficial effects of ET are far less understood and need further evaluation. Evidence suggests that while CHF induces generalized metabolic energy depletion, ET largely enhances the overall function of the heart muscle. Hence, research efforts are now aiming to uncover why ET is beneficial as a complimentary treatment of CHF in the context of improving endothelial function and coronary perfusion, decreasing peripheral resistance, induction of cardiac and skeletal muscle cells remodeling, increasing oxygen uptake, substrate oxidation, and resistance to fatigue. Here we discuss the current evidence that suggest that there are beneficial effects of ET on cardiac and skeletal muscle cells oxidative metabolism and intracellular energy transfer in patients with CHF. PMID- 21532777 TI - Impact of Fenofibrate on Type 2 Diabetes Patients with Features of the Metabolic Syndrome: Subgroup Analysis From FIELD. AB - Given evidence of increasing prevalence in developed and developing countries, as a result of obesity trends and sedentary lifestyles, the metabolic syndrome represents an increasing burden on healthcare systems. Management guidelines for dyslipidaemia have primarily focused on LDL-C reduction; however, this approach fails to sufficiently address other lipid abnormalities associated with the metabolic syndrome. Atherogenic dyslipidaemia (characterized by elevated triglycerides and low HDL-C) is strongly associated with insulin-resistant states, such as type 2 diabetes and the metabolic syndrome, and is also a common finding among patients receiving treatment for dyslipidaemia. Intervening against atherogenic dyslipidaemia may address a substantial modifiable fraction of residual cardiovascular risk that remains after treatment with a statin. Recent findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study support this view. Fenofibrate treatment was shown to be especially effective in treating marked atherogenic dyslipidaemia, with a significant 27% relative risk reduction for cardiovascular events (P=0.0005, vs. 11%, P=0.035 for all patients) relative to placebo. These data, together with the earlier demonstration of significant microvascular benefits associated with this treatment, suggest a role for fenofibrate, in addition to statin therapy and lifestyle intervention, for reducing global vascular risk in type 2 diabetes patients and for impacting atherogenic dyslipidaemia associated with the metabolic syndrome. PMID- 21532778 TI - Physiologic tailoring of treatment in resistant hypertension. AB - Resistant hypertension is a major opportunity for prevention of cardiovascular disease. Despite widespread dissemination of consensus guidelines, most patients are uncontrolled with approaches that assume that all patients are the same. Causes of resistant hypertension include 1) non-compliance 2) consumption of substances that aggravate hypertension (such as salt, alcohol, nonsteroidal anti inflammatory drugs, licorice, decongestants) and 3) secondary hypertension. Selecting the appropriate therapy for a patient depends on finding the cause of the hypertension. Once rare causes have been eliminated (such as pheochromocytoma, licorice, adult coarctation of the aorta), the cause will usually be found by intelligent interpretation (in the light of medications then being taken) of plasma renin and aldosterone.If stimulated renin is low and the aldosterone is high, the problem is primary aldosteronism, and the best treatment is usually aldosterone antagonists (spironolactone or eplerenone; high-dose amiloride for men where eplerenone is not available). If the renin is high, with secondary hyperaldosteronism, the best treatment is angiotensin receptor blockers or aliskiren. If the renin and aldosterone are both low the problem is over activity of renal sodium channels and the treatment is amiloride. This approach is particularly important in patients of African origin, who are more likely to have low-renin hypertension. PMID- 21532780 TI - Cardiac MRI in infiltrative disorders: a concise review. AB - Cardiac MR imaging is an effective method for noninvasive imaging of the heart. The technology has been limited in the past because of imaging difficulties associated with cardiac motion. In recent years, however, cardiac MR imaging has broadened its spectrum of applications in cardiovascular disease with impressive advances in spatial and temporal resolution and increased imaging speeds. This review presents the current clinical applications of cardiac MR imaging for evaluation of cardiac disease in infiltrative disorders such as amyloidosis, hemochromatosis, and sarcoidosis. PMID- 21532779 TI - Proteomics and mass spectrometry: what have we learned about the heart? AB - The emergence of new platforms for the discovery of innovative therapeutics has provided a means for diagnosing cardiac disease in its early stages. Taking into consideration the global health burden of cardiac disease, clinicians require innovations in medical diagnostics that can be used for risk stratification. Proteomic based studies offer an avenue for the discovery of proteins that are differentially regulated during disease; such proteins could serve as novel biomarkers of the disease state. For instance, in clinical practice, the abundance of such biomarkers in blood could be correlated with the severity of the disease state. As such, early detection of biomarkers would enable an improvement in patient prognosis. In this review, we outline advancements in various proteomic platforms used to study the disease proteome and their applications to the field of clinical medicine. Specifically, we highlight the contributions of proteomic-based profiling experiments to the analysis of cardiovascular diseases. PMID- 21532781 TI - Successful treatment of pill-swallowing difficulties with head posture practice. AB - BACKGROUND: Clinics often encounter neurologically intact patients who are unable to swallow pills. All of the interventions published previously have used traditional behavioural techniques, which are time consuming and often not helpful. OBJECTIVE: To determine whether children who had never been able to swallow a whole pill could become successful as a result of an intervention based on head posture. METHOD: A novel intervention was developed based on published research showing that changing head position alters swallowing dynamics. The method was developed in two studies of 240 adults and children, pilot tested in a study of 108 university students with very mild pill-swallowing discomfort, and then evaluated in a study of 41 children who had never successfully swallowed a pill in spite of much instruction and coaxing. Children were recruited from a tertiary paediatric hospital: 34 were clinic patients, four were their siblings or friends, and three were children of hospital staff. The primary intervention involved teaching five head positions (centre, up, down, left and right) followed by a two-week period of daily practice. RESULTS: EIGHT CHILDREN (ALL CLINIC REFERRALS) WITHDREW WITHOUT PRACTICING: four were too ill to practice (primarily due to sedation or nausea) and four simply refused to do the homework practice. All 33 of the children who were able and willing to practice daily were successful. CONCLUSION: Practice with head posture variations was successful in treating pill-swallowing difficulties in all 33 children who practiced for 14 days. A training video can be viewed at www.ucalgary.ca/research4kids/pillswallowing. PMID- 21532782 TI - [Not Available]. PMID- 21532783 TI - How does one manage to have a good job, balanced life and enjoy their work? PMID- 21532784 TI - Renal disease in youth with type 2 diabetes: Need for early detection. PMID- 21532785 TI - Letter to the editor. PMID- 21532786 TI - Letter to the editor. PMID- 21532787 TI - Case 1: Altered mental status - a state of confusion. PMID- 21532788 TI - Case 2: Chronic daily headache in a teenager. PMID- 21532789 TI - Patent ductus arteriosus in premature infants: A never-closing act. PMID- 21532790 TI - Hypoglycemia in term newborns with a birth weight below the 10th percentile. AB - BACKGROUND: Current recommendations suggest that routine screening for hypoglycemia should be performed in all term newborns with a birth weight (BW) below the 10th percentile. The impact of updated growth curves on the incidence of hypoglycemia in small-for-gestational-age (SGA) newborns has not been evaluated. OBJECTIVES: To evaluate the occurrence and severity of hypoglycemia in term newborns with a BW between the 10th and fifth percentile, and below the fifth percentile, using recently updated growth curves. DESIGN: A one-year prospective cohort study. METHODS: Inclusion criteria were gestational age of 37 weeks or greater and BW below the 10th percentile. Neonatal hypoglycemia was defined as a blood glucose level of less than 2.6 mmol/L measured after 2 h of life. Blood glucose was measured routinely for all SGA infants during the first 36 h of life. RESULTS: A total of 187 SGA infants met the study criteria: 85 infants with a BW between the 10th and fifth percentile, and 102 infants with a BW below the fifth percentile. The characteristics of the study cohort were similar between BW groups. Twenty-six per cent of the infants screened had at least one episode of hypoglycemia: 22% of infants in the 10th to fifth percentile group and 28% in the less than fifth percentile group. Hypoglycemia was symptomatic in four infants, all of whom were below the fifth percentile for BW. The mean (+/- SD) lowest blood glucose level was 2.1+/-0.4 mmol/L (range 0.6 mmol/L to 2.5 mmol/L) in the 10th to fifth percentile group and 2.0+/-0.5 mmol/L (range 0.8 mmol/L to 2.5 mmol/L) in the less than fifth percentile group (P=0.05). CONCLUSION: The present study demonstrates a high incidence of hypoglycemia among SGA infants with a BW below the 10th percentile using updated growth curves. There was no difference in the incidence of hypoglycemia among SGA infants with a BW below the fifth percentile versus those with a BW between the 10th and fifth percentile. PMID- 21532791 TI - Current trends in nontuberculous mycobacteria infections in Canadian children: A pediatric investigators collaborative network on infections in Canada (PICNIC) study. AB - BACKGROUND: Nontuberculous mycobacteria (NTM) infections appear to be increasing in number and severity in developed countries worldwide. Surgical excision has been considered the standard treatment for NTM lymphadenitis, but the use of medical therapy seems to be increasing. OBJECTIVE: To determine the disease characteristics as well as the current therapeutic management of NTM infections in Canadian children. METHODS: Cases of definite or probable NTM infections were identified prospectively in children up to 18 years of age seen in 10 Canadian paediatric tertiary care centres from September 2005 to August 2006. Clinical, microbiological and pathological data were collected. RESULTS: A total of 60 cases were identified. Data were complete for 45 patients, including 34 cases of lymphadenitis, four cases of skin and soft tissue infection, and seven cases of pulmonary NTM infection. Seventy-nine per cent of children (27 of 34) with lymphadenitis had an unsuccessful course of antibiotics before diagnosis. Sixty eight per cent of purified protein derivative tests (15 of 22) were positive. NTM was detected in 76% of samples (29 of 38), of which 62% were Mycobacterium avium complex. All patients with lymphadenitis underwent surgical therapy and most patients (74%) also received antimicrobials. CONCLUSIONS: Current trends indicate that the majority of the study centres are using medical therapy with variable regimen and duration as an adjunct to surgical excision in the treatment of NTM lymphadenitis. Larger numbers and longer follow-up times are needed to better evaluate the efficacy of medical therapy and outcome of disease. A randomized controlled study comparing surgical therapy alone and chemotherapy for NTM lymphadenitis is required. PMID- 21532792 TI - The relation between weight-based teasing and psychological adjustment in adolescents. AB - OBJECTIVE: To determine the prevalence of weight-based teasing, and evaluate its association with depression, anxiety and unhealthy eating behaviour in a large sample of adolescents in the Ottawa (Ontario) area. METHODS: A total of 1491 adolescents from public and private middle schools and high schools in rural and urban areas of Ottawa responded confidentially to surveys. RESULTS: More girls than boys reported that they experienced weight-based teasing (33% versus 18%). The prevalence of weight-based teasing by peers was significantly higher among overweight and obese youth than among normal weight youth (45% versus 22%). Teasing about body weight was consistently associated with anxiety, psychological distress and disordered eating, and these associations held for both boys and girls, and were independent of weight status. CONCLUSIONS: Weight-based teasing is a common experience among Ottawa-area adolescents, especially among overweight girls, and was found to be associated with psychological morbidity. Effective interventions are needed to help victims cope with and prevent further weight based teasing and its harmful psychological sequelae. PMID- 21532793 TI - Mothers' beliefs about analgesia during childhood immunization. AB - BACKGROUND: Immunization injections are the most common painful medical procedures experienced during childhood, yet there is a discrepancy between recommendations for the effective use of topical anesthetics to reduce vaccine injection pain and actual practice. OBJECTIVE: To improve our understanding of mothers' experiences and practices regarding their children's routine immunizations. METHOD: Adopting an interpretive, naturalistic paradigm, semi structured interviews were conducted with 15 mothers to examine their perceptions and experiences of their children's immunization pain and pain management. RESULTS: The findings demonstrated three main themes: attitudes toward immunization pain, immunization pain management and physicians as sources of information. Participants described feeling distressed while their children were being immunized, but most managed these difficulties by focusing on the benefits of immunization and by minimizing or justifying the pain. All of the participants used non-pharmacological techniques to manage immunization injection pain. Few mothers were aware of the availability of topical anesthetics. When participants did use pharmacological analgesic approaches, oral analgesics were most likely to be used for prophylaxis and treatment of fever, and participants were unaware of evidence-based approaches to managing pain. Participants viewed their physicians as trusted sources of information, and the majority said that they would likely use a topical anesthetic in the future if recommended or approved by their physician. CONCLUSION: The present findings provide direction for future knowledge translation activities to enhance the knowledge of mothers and clinicians regarding pain during immunization injections and its effective management. PMID- 21532794 TI - Letter to the editor. PMID- 21532795 TI - Invasive group A streptococcal disease: Management and chemoprophylaxis. AB - Given the potentially devastating consequences of severe invasive group A streptococcal disease, attention has been directed toward the role of chemoprophylaxis and the optimization of management strategies. In response to this issue, Canadian guidelines were previously developed. However, the uptake of these recommendations is variable across Canada. The present document summarizes key components of the recommendations for use by Canadian physicians. The importance of penicillin in the treatment of group A streptococcal disease is reaffirmed, and the role of clindamycin is discussed. In addition, in situations in which chemoprophylaxis may be considered, the preferred agents are summarized. PMID- 21532796 TI - Vegetarian diets in children and adolescents. AB - A well-balanced vegetarian diet can provide for the needs of children and adolescents. However, appropriate caloric intake should be ensured and growth monitored. Particular attention should be paid to adequate protein intake and sources of essential fatty acids, iron, zinc, calcium, and vitamins B12 and D. Supplementation may be required in cases of strict vegetarian diets with no intake of any animal products. Pregnant and nursing mothers should also be appropriately advised to ensure that the nutritional needs of the fetus and infant are adequately met. Recommendations are provided. Adolescents on restricted vegetarian or other such diets should be screened for eating disorders. PMID- 21532798 TI - Acknowledgment of authors. PMID- 21532800 TI - States rule. PMID- 21532797 TI - Multidisciplinary Versus One-on-One Setting: A Qualitative Study of Clinicians' Perceptions of Their Relationship With Patients With Prostate Cancer. AB - PURPOSE: Previous studies indicate that a multidisciplinary approach could be suitable for dealing with the complex issues faced by physicians in the management of prostate cancer; however, few studies have investigated clinicians' perceptions of multidisciplinary care. Our aim was to evaluate clinicians' perceptions of the patient-clinician relationship in a multidisciplinary context, and to compare this with physicians' perceptions of providing care independently. METHODS: A qualitative observational study was performed in 2009. Three radiation oncologists, three urologists, three medical oncologists and one psychologist from the multidisciplinary clinic (MDC) team at the Prostate Program of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, were interviewed to assess their perceptions of their relationship with the patient. RESULTS: Clinicians reported that the MDC has advantages regarding providing patients with more accurate information and acquiring information from patients, but a clear preference for a multidisciplinary setting did not emerge. Clinicians reported that in one-on-one examinations (1) they feel more comfortable listening to the patient and more able to manage communication, and that (2) the process of building trust is easier. CONCLUSION: Clinicians appear to recognize the value of the MDC in terms of effective communication with patients but feel that other aspects of relationship building are hindered in a multidisciplinary setting. Organizational and teamwork issues need to be addressed to optimize the implementation of a multidisciplinary approach. PMID- 21532801 TI - Medication safety of five oral chemotherapies: a proactive risk assessment. AB - PURPOSE: Oral chemotherapies represent an emerging risk area in ambulatory oncology practice. To examine the hazards associated with five oral chemotherapies, we performed a proactive risk assessment. METHODS: WE CONVENED INTERDISCIPLINARY TEAMS AND CONDUCTED FAILURE MODE AND EFFECTS ANALYSES (FMEAS) FOR FIVE ORAL CHEMOTHERAPY AGENTS: capecitabine, imatinib, temozolomide, 6 mercaptopurine, and an investigational agent. This involved the creation of process maps for each medication, identification of failure modes, selection of high-risk failure modes, and development of recommendations to mitigate these risks. We analyzed the number of steps and types of failure modes and compared this information across the study drugs. RESULTS: Key vulnerabilities include patient education about drug handling and adverse effects, prescription writing, patient self-administration and medication adherence, and failure to monitor and manage toxicities. Many of these failure modes were common across the five oral chemotherapies, suggesting the presence of common targets for improvement. Streamlining the FMEA itself may promote the dissemination of this method. CONCLUSION: Each stage of the medication process poses risks to the safe use of oral chemotherapies. FMEAs may identify opportunities to improve medication safety and reduce the risk of patient harm. PMID- 21532802 TI - Safe handling of oral chemotherapeutic agents in clinical practice: recommendations from an international pharmacy panel. AB - Although there has been a significant increase in the availability and use of oral chemotherapeutic agents, the guidelines around their safe handling are still evolving. Although oral chemotherapy is associated with ease of administration, it has the same exposure risks to health care practitioners, patients, and their caregivers as intravenous formulations, and because it is administered in the home, to the families of patients. However, the general misconception appears to be that exposure risk is low and therefore oral chemotherapeutic agents present little risk and are safer to handle. In a series of three roundtable meetings, a team of international pharmacists from North America and Europe reviewed existing guidelines and identified gaps in recommendations that we believe are important for safe handling. The present article is a compilation of these gaps, especially applicable to manufacturers and distributors, storage and handling, and patient education regarding safe handling. These recommendations, on the basis of our experience and of best practices, provide an international perspective and can be adapted by institutions and practices for development of standardized procedures specific to their needs for the safe handling of oral chemotherapeutic agents. PMID- 21532803 TI - Evaluation of chemotherapy-induced severe myelosuppression incidence in obese patients with capped dosing. AB - PURPOSE: Clinicians typically cap an obese patient's chemotherapy regimen as a result of concern for excessive toxicity, without adequate clinical evidence. The purpose of this study was to evaluate the incidence of grade 3 or 4 myelosuppression in obese patients versus nonobese patients with capped dosing on the basis of body surface area (BSA). METHODS: A retrospective chart review was conducted comparing obese patients (body mass index [BMI] >= 30 kg/m(2)) with capped dosing who received capped chemotherapy doses at a BSA of 2.2 m(2) with nonobese (BMI < 25 kg/m(2)) patients with lung, colorectal, or hormone-refractory prostate cancer. RESULTS: Forty-one obese patients with capped dosing and 244 nonobese patients were included. The obese patient group received on average significantly more cycles of chemotherapy (6 v 4 cycles) compared with the nonobese group. The overall incidence of any chemotherapy-related toxicity was 34% in the obese patient group, compared with 42% in the nonobese patient group (P = .356). The incidence of grade 3 or 4 myelosuppression was lower, but not statistically significant, in obese patients with capped dosing compared with the nonobese patient group (22% v 27%; P = .493). CONCLUSIONS: Overall, obese patients with capped dosing experienced a lower incidence of severe myelosuppression and tolerated more cycles of chemotherapy compared with nonobese patients. The better tolerability of chemotherapy in obese patients with capped dosing suggests that there is room to increase the dose in obese patients above the nationally recognized BSA cap of 2.0 m(2), especially in early-stage lung or colon cancers in which the intention of treatment is curative. PMID- 21532804 TI - Commentary: chemotherapy dosing in obese patients with cancer-the need for evidence-based clinical practice guidelines. PMID- 21532805 TI - Multidisciplinary health care professionals' perceptions of the use and utility of a symptom assessment system for oncology patients. AB - PURPOSE: Despite growing implementation of electronic symptom assessment in oncology settings, few studies have described how standardized symptom assessment can enhance multidisciplinary care. The Edmonton Symptom Assessment System (ESAS) is a validated measure of symptom burden that has been adopted by Ontario's cancer centers to assess symptoms for patients with cancer. This study examines the perceived value of the ESAS among clinical teams and barriers to its use in enhancing multidisciplinary care. METHODS: Self-completed surveys were administered online to clinical teams at various disease-site clinics at a cancer center in Ontario, Canada. RESULTS: One hundred twenty-eight nurses, oncology physicians, and allied health professions completed the survey. The majority of nurses (89%), physicians (55%), and other providers (57%) reported referring to ESAS in clinic either "always" or "most of the time." Many of those who either "never" or "rarely" looked at ESAS scores reported finding it more efficient to talk to the patient or do their own assessment to determine symptom issues. Although most of the nurses and allied health professions found the ESAS to enhance patient care, help patients to articulate their symptom issues, and facilitate follow-up with patients with past symptom issues, only approximately half of the physicians agreed with these statements. CONCLUSION: Variable adoption of the ESAS by physicians may limit its potential to improve both interprofessional communication and comprehensive symptom control. To encourage consistent use, a symptom assessment system needs to be complementary to the perceived roles of all multidisciplinary team members, including physicians. PMID- 21532806 TI - Commentary: encouraging clinicians to incorporate longitudinal patient-reported symptoms in routine clinical practice. PMID- 21532807 TI - Factors influencing treatment recommendations in node-negative breast cancer. AB - PURPOSE: To assess factors influencing recommendations for adjuvant chemotherapy (CT) in relation to perceived benefits in women with stage 1 breast cancer and to determine the degree to which recommendations were followed. METHODS: Recommendations from multidisciplinary team meetings at Royal North Shore Hospital (Sydney, Australia) during 2007 and 2008 for postoperative patients with invasive, primary breast cancer were reviewed. Treatment data were collected from patients' medical records. Estimated benefits of adjuvant CT on 10-year survival for node-negative patients were calculated using Adjuvant! Online. Univariate and multivariate analyses were performed using SPSS. RESULTS: Of 345 patients (mean age, 59 years), 51 were unsuitable for CT as a result of comorbidity and/or age > 80 years. All 93 patients with nodal macrometastases who were suitable for CT and 20 (80%) of 25 with micrometastases were recommended for CT, compared with 92 (53%) of 175 node-negative patients. Tumor size > 2 cm, grade 3, estrogen receptor negativity, and age less than 45 years were independent factors influencing CT recommendation. The mean estimated benefit of CT in node-negative patients who received this recommendation was 5.7% versus 1.3% in patients not recommended for CT. Twenty-one (23%) node-negative patients declined CT after discussion with a medical oncologist. A higher proportion of node-negative patients were recommended for CT in 2008 versus 2007 (60% v 44%, P = .04). CONCLUSIONS: Grade, tumor size, estrogen receptor status, and younger age are the most significant factors influencing CT recommendation in node-negative patients. The minimum level of benefit to recommend CT is approximately 2%. A significant proportion of patients do not proceed with CT after individualized review. PMID- 21532808 TI - Cancer portal project: a multidisciplinary approach to cancer care among Hispanic patients. AB - PURPOSE: This study investigates the impact of a multilingual, multidisciplinary team targeting social and economic determinants of cancer treatment adherence among at-risk Hispanic immigrants. METHODS: Patients were recruited at 10 hospital-based cancer clinics in New York City between December 2008 and November 2009. This is a nested cohort study of Hispanic patients and their sociodemographic characteristics, areas of needed assistance, and reported impact of meeting service needs on keeping appointments. At the core of the intervention is the trained, bilingual Portal Access Facilitator, who assesses needs and synchronizes an individualized set of transdisciplinary services for each patient. RESULTS: A total of 328 Hispanic patients participated in the study. Of these, 89% preferred to speak Spanish in the health care setting, and 17% had no health insurance. The most common cancer diagnosis among participants was breast cancer (35%) followed by GI (17%) and gynecologic (16%) cancers. Patients most commonly requested financial support (59%), food support (37%), transportation assistance (21%), social work services (14%), psychosocial support (6%), help with health insurance issues (5%), and legal services (5%). In a follow-up assessment of high-need patients in urgent need of financial support, 86% reported that portal services helped them attend cancer care and treatment appointments, and 72% reported that portal services decreased worry about their care. CONCLUSION: Most patients reported that financial, social, and logistical support would help them attend their appointments for cancer care and treatment. Further multidisciplinary interventions should be implemented and evaluated to address social and economic determinants in cancer care for this population. PMID- 21532809 TI - Ingredients for success: a familial cancer clinic in an oncology practice setting. AB - PURPOSE: Genetic cancer risk assessment (GCRA) has become increasingly important in clinical cancer care. Almost all published information on genetic risk assessment has come from academic institutions. However, a majority of patients with cancer are seen in the community practice setting. METHODS: We describe the evolution of a community oncology practice GCRA clinic. RESULTS: Over a 10-year period, 445 patients were seen for a possible genetic cancer syndrome. This included 325 patients with family history of breast or ovarian cancer, 92 patients with family history of colorectal cancer or polyposis, and 28 families with another familial cancer predisposition. Fifty-three unique families with a genetic mutation were identified. CONCLUSION: A GCRA clinic can be incorporated into an oncology practice setting and can enhance the standard of care for the entire community. We present data reflecting a 10-year experience with such a clinic and provide recommendations for establishing a successful one. PMID- 21532810 TI - Prospective study of combined colon and endometrial cancer screening in women with lynch syndrome: a patient-centered approach. AB - BACKGROUND: Endometrial and colorectal cancers are the most common cancers in Lynch syndrome. Consensus guidelines recommend annual endometrial biopsy (EMB) and regular colonoscopies. We assessed the feasibility of concurrently performing EMB and colonoscopy and evaluated women's perception of pain, satisfaction, and acceptability. METHODS: From July 2002 to December 2009, women who had a gene mutation for Lynch syndrome, met the Amsterdam II criteria, or had a high-risk situation that required screening were prospectively enrolled. After conscious sedation, the procedures were sequentially performed. Patients completed pre- and postprocedure questionnaires assessing pain, level of satisfaction, and acceptability. The Wilcoxon rank test and Mann-Whitney test were used to compare pain scores. RESULTS: Forty-two women completed the study. Median age was 37 years (range, 25 to 73). Nineteen had previously had an EMB in the office setting. Women reported significantly lower median levels of pain in the combined procedure compared with previous office setting biopsies (P < .001). Regardless of parity, women reported significantly less pain for an EMB as part of the combined screen compared with an office EMB (parous, P = .003; nulliparous, P = .026). Women also reported a high level of satisfaction and more convenience in the combined procedure. All participants preferred combined to separately scheduled procedures and would recommend the combined procedure to their relatives. CONCLUSION: Combined colon and endometrial cancer screening is a patient-centered approach that is feasible, acceptable, and may improve adherence to Lynch syndrome screening recommendations. PMID- 21532811 TI - Palliative care consultations in patients with cancer: a mayo clinic 5-year review. AB - PURPOSE: We sought to characterize the aggregate features and survival of patients who receive inpatient palliative care consultation, particularly focusing on patients with cancer, to identify opportunities to improve clinical outcomes. METHODS: We reviewed prospectively collected data on patients seen by the Palliative Care Inpatient Consult Service at Mayo Clinic (Rochester, MN) from January 2003 to September 2008. Demographics, consultation characteristics, and survival were analyzed using Kaplan-Meier survival curves and Cox survival models. RESULTS: Cancer was the most common primary diagnosis (47%) in the 1,794 patients seen over the 5-year period. A significant growth in the annual number of palliative care consultations has been observed (113 in 2003 v 414 in 2007), despite stable total hospital admissions. Frequently encountered reasons for consultation included clarification of care goals (29%), assistance with dismissal planning (19%), and pain control (17%). Although patients with cancer had the highest median survival after consultation in this cohort versus patients with other diagnoses, we observed a 5-year trend of decreasing survival from admission to death and from consultation to death. Median time from admission to death for patients with cancer was 36 days in 2003 and only 19 days in 2008 (P < .01). Median time from consultation to death decreased from 33 days in 2003 to only 11.5 days in 2008 (P < .01). CONCLUSION: Patients with cancer often have complex needs that must be met within a short window for intervention. We highlight opportunities for improved multidisciplinary care for patients with advanced cancer and their families, including opportunity for earlier palliative care involvement, even in the outpatient setting. PMID- 21532812 TI - Strategic use of clinical pathways. AB - Clinical pathways are detailed, evidence-based processes for delivering cancer care for specific patient presentations. Some oncologists have embraced clinical pathways, while others resist. PMID- 21532813 TI - Part 2: implementing clinical trials: a review of the attributes of exemplary clinical trial sites. AB - Part two of this series focuses on the remaining three exemplary attributes: quality assurance, multidisciplinary involvement in the clinical trial process, and clinical trials awareness programs. PMID- 21532815 TI - Challenges for small animal medicine. PMID- 21532814 TI - Perspectives on adherence and persistence with oral medications for cancer treatment. AB - Ensuring persistence, continuing treatment for the prescribed duration, and adherence-taking medication as prescribed-have been challenges for management of patients with oral cancer and for health care cost containment in real-world settings. PMID- 21532816 TI - Veterinary medical ethics. An ethicist's commentary on the case of the client who abuses disease surveillance results. PMID- 21532817 TI - Assessment of fetal well-being in cattle by ultrasonography in normal, high-risk, and cloned pregnancies. AB - This study determined ultrasonographic parameters of fetuses and uterine adnexa in late pregnancy in normal, cloned, and high-risk pregnancies in relation to perinatal and neonatal outcome. Ten cows with normal pregnancies (CONTROL, mean pregnancy length 273 d), 10 sick cows with potentially compromised pregnancies (HIGH-RISK, mean pregnancy length 267 d), and 10 heifers with cloned pregnancies (CLONED, mean pregnancy length 274 d) were examined at more than 260 d of gestation. There was no difference in mean fetal heart rates among the groups. The cloned calves were heavier (57 +/- 8 kg) than calves from CONTROL group (36 +/- 7 kg), and calves from HIGH-RISK group (37 +/- 13 kg) (P = 0.003). The diameter of the thoracic aorta was positively correlated (R = 0.62) with fetal birth weight in the CONTROL group (P = 0.01). Fetal activity was not associated with survival. The results suggest that transabdominal ultrasonographic assessment of the fetal well-being may serve as a potential tool for evaluation of the fetoplacental unit. PMID- 21532818 TI - Therapy resistant septic enteritis due to a jejunal malformation in a 5-day-old Thoroughbred colt. AB - A 5-day-old Thoroughbred colt was presented with profuse watery diarrhea, hypovolemic shock, and a patent urachus. Despite intensive medical therapy, the colt was euthanized 15 d later due to poor clinical response. Necropsy revealed a small intestinal structural abnormality that formed a closed jejunal ring. Although rare, intestinal malformations should be considered in neonatal foals with clinical signs resembling enteritis. PMID- 21532819 TI - Syringohydromyelia in horses: 3 cases. AB - Syringomyelia and hydromyelia are cavitary lesions of the spinal cord that may be acquired or congenital. These lesions are not frequently reported in large animal species. The presenting complaints, clinical, gross pathological, and histopathologic findings of 2 cases of syringomyelia and 1 case of hydromyelia in horses are described. PMID- 21532820 TI - Antimicrobial susceptibility of Staphylococcus aureus and Staphylococcus pseudintermedius isolated from various animals. AB - This study characterized the antimicrobial susceptibility of 221 Staphylococcus aureus isolated from various species, and 60 canine Staphylococcus pseudintermedius isolated from 1986 through 2000 at the Western College of Veterinary Medicine (WCVM). Resistance of S. aureus was most common to penicillin (31%) and tetracycline (14%); resistance of S. pseudintermedius to penicillin was present in 8% and to tetracycline in 34% of isolates. Resistance to trimethoprim/sulfamethoxazole was only seen among S. pseudintermedius, and there was no resistance to amoxicillin/clavulanate, ampicillin/sulbactam, cephalothin, amikacin, gentamicin, enrofloxacin, chloramphenicol, or rifampin among any isolate. Inducible clindamycin resistance was found in both S. aureus and S. pseudintermedius, highlighting the need for careful interpretation of culture and susceptibility test results. There were significant differences in the minimum inhibitory concentrations of penicillin, ciprofloxacin, enrofloxacin, clindamycin, erythromycin, chloramphenicol, and tetracycline between avian, bovine, equine, and porcine isolates. PMID- 21532821 TI - Does examination of fecal samples 24 hours after cestocide treatment increase the sensitivity of Anoplocephala spp. detection in naturally infected horses? AB - Fecal samples were examined immediately before and 24 to 48 h after cestocide treatment for a comparative detection of tapeworm-positive horses. In early winter, 17 weanlings, 20 yearlings, 15 2-year-old horses, 24 breeding mares, and 2 stallions were treated with praziquantel in combination with a macrocyclic lactone. The horses were presumed to be naturally infected with tapeworms after pasture grazing. Fecal samples were collected before treatment (Day 0), at 24 or 48 h after treatment (Day 1-2), and 16 to 21 d after treatment (Day 16-21). A Wisconsin test was done on all fecal samples. Odds of detection of infection for all age groups increased by a factor of 2.04 [95% confidence interval (CI): 1.30 to 3.20] from Day 0 to Day 1-2 (P = 0.002). PMID- 21532822 TI - Urinary tract infection caused by methicillin-resistant Staphylococcus pseudintermedius in a dog. AB - A young neutered male pug dog was presented for evaluation of acute onset pollakiuria and hematuria. Culture and susceptibility testing of urine identified a methicillin-resistant Staphylococcus pseudintermedius, which was susceptible to only tetracycline among commonly used antimicrobials. Treatment with doxycycline led to bacteriological cure and resolution of clinical signs. PMID- 21532823 TI - Successful therapy of coumatetralyl rodenticide induced pericardial effusion with pericardiocentesis in a dog. AB - A 5-year-old, intact male, golden retriever was presented with an acute onset of lethargy and respiratory distress. The dog was diagnosed as having rodenticide intoxication with pericardial effusion. Pericardiocentesis was successfully performed and was followed with a blood transfusion. This case suggests that rodenticide intoxication might cause pericardial effusion in dogs. PMID- 21532824 TI - Acquired myasthenia gravis in a poodle. AB - An 11-year-old, spayed female, teacup poodle was evaluated for a chronic cough, lethargy, hindlimb weakness, and reluctance to exercise. Thoracic radiographs revealed megaesophagus and aspiration pneumonia. Serum antibodies against acetylcholine receptors confirmed the diagnosis of myasthenia gravis. The unusual clinical history and case outcome are discussed. PMID- 21532825 TI - Congenital enlargement of the suburethral diverticulum in a Holstein calf. AB - A 3-month-old, female Holstein calf was examined because of marked perineal swelling and tenesmus of 4-days duration. A congenitally enlarged urethral diverticulum was diagnosed using fluoroscopic and ultrasonographic imaging techniques. The urethral diverticulum was surgically resected and the perineal area was reconstructed. PMID- 21532826 TI - Clinical and computed tomography features of secondary renal hyperparathyroidism. AB - An atypical case of secondary renal hyperparathyroidism was diagnosed in a 9-year old miniature schnauzer after a skull computed tomography (CT) showed the presence of 2 bilateral and symmetrical soft tissue maxillary masses, and osteopenia of the skull. PMID- 21532827 TI - Intraocular nematodiasis in a llama (Lama glama). AB - This report describes a unique case of presumed migration of Parelaphastrongylus tenuis through the spinal cord into the eye of a llama where it survived and matured within the ocular environment. Blindness of the eye was most likely attributable to migration of the parasite through the central nervous tissue. PMID- 21532828 TI - An observational study on the prevalence and impact of Isospora suis in suckling piglets in southwestern Ontario, and risk factors for shedding oocysts. AB - An observational study was conducted to determine the prevalence of Isospora suis oocysts in fecal samples from suckling piglets in Ontario, and to evaluate the relationship between the presence of I. suis oocysts and diarrhea. Fifty farms and 709 litters of piglets were included in the study. Oocysts were detected on 70% of farms, with 187 litters infected. A litter of pigs that was positive for oocysts was significantly more likely to exhibit diarrhea than a litter that was negative [odds ratio (OR) = 4.0; 95% confidence interval (CI) = 2.8 to 5.8; P < 0.001]. Management and housing factors were examined with respect to risk factors for the presence of I. suis. Farms that did not use a detergent when cleaning farrowing crates were 10-times more likely to be positive for I. suis than those that used a detergent (P = 0.007). It was concluded that coccidiosis is a common problem on Ontario swine farms. PMID- 21532829 TI - Zooeyia: an essential component of "One Health". AB - One Health is dedicated to improving the health of all species through the integration of human and veterinary medicine. To date, initiatives have primarily focussed on controlling zoonoses. This paper discusses zooeyia, the positive benefits to human health from interacting with animals, focussing on the companion animal. PMID- 21532830 TI - Type I idiopathic non-erosive immune-mediated polyarthritis in a mixed-breed dog. AB - A young adult dog was presented with an acute onset of stiffness, weakness, marked muscle atrophy and rapid weight loss. The dog was inappetent, lethargic, and had grossly visible distension of multiple joints. Synovial fluid analysis, routine bloodwork, and radiography confirmed immune-mediated polyarthritis; the dog responded favorably to treatment with prednisone and analgesics. PMID- 21532831 TI - When words fail. PMID- 21532832 TI - Stimulating bone growth in the small animal patient: Grafts and beyond! PMID- 21532834 TI - Plant plastid engineering. AB - Genetic material in plants is distributed into nucleus, plastids and mitochondria. Plastid has a central role of carrying out photosynthesis in plant cells. Plastid transformation is becoming more popular and an alternative to nuclear gene transformation because of various advantages like high protein levels, the feasibility of expressing multiple proteins from polycistronic mRNAs, and gene containment through the lack of pollen transmission. Recently, much progress in plastid engineering has been made. In addition to model plant tobacco, many transplastomic crop plants have been generated which possess higher resistance to biotic and abiotic stresses and molecular pharming. In this mini review, we will discuss the features of the plastid DNA and advantages of plastid transformation. We will also present some examples of transplastomic plants developed so far through plastid engineering, and the various applications of plastid transformation. PMID- 21532835 TI - Lung Cancer: Are we up to the Challenge? AB - Lung cancer is the leading cause of cancer deaths worldwide among both men and women, with more than 1 million deaths annually. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers.Although recent advances have been made in diagnosis and treatment strategies, the prognosis of NSCLC patients is poor and it is basically due to a lack of early diagnostic tools.However, in the last years genetic and biochemical studies have provided more information about the protein and gene's mutations involved in lung tumors. Additionally, recent proteomic and microRNA's approaches have been introduced to help biomarker discovery.Here we would like to discuss the most recent discoveries in lung cancer pathways, focusing on the genetic and epigenetic factors that play a crucial role in malignant cell proliferation, and how they could be helpful in diagnosis and targeted therapy. PMID- 21532833 TI - Saturation of the human phenome. AB - The phenome is the complete set of phenotypes resulting from genetic variation in populations of an organism. Saturation of a phenome implies the identification and phenotypic description of mutations in all genes in an organism, potentially constrained to those encoding proteins. The human genome is believed to contain 20-25,000 protein coding genes, but only a small fraction of these have documented mutant phenotypes, thus the human phenome is far from complete. In model organisms, genetic saturation entails the identification of multiple mutant alleles of a gene or locus, allowing a consistent description of mutational phenotypes for that gene. Saturation of several model organisms has been attempted, usually by targeting annotated coding genes with insertional transposons (Drosophila melanogaster, Mus musculus) or by sequence directed deletion (Saccharomyces cerevisiae) or using libraries of antisense oligonucleotide probes injected directly into animals (Caenorhabditis elegans, Danio rerio). This paper reviews the general state of the human phenome, and discusses theoretical and practical considerations toward a saturation analysis in humans. Throughout, emphasis is placed on high penetrance genetic variation, of the kind typically asociated with monogenic versus complex traits. PMID- 21532836 TI - Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review. AB - PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and Acne) is an autosomal dominant, hereditary auto-inflammatory disease arising from mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q. These mutations produce a hyper phosphorylated PSTPIP1 protein and alter its participation in activation of the "inflammasome" involved in interleukin-1 (IL-1beta) production. Overproduction of IL-1beta is a clear molecular feature of PAPA syndrome. Ongoing research is implicating other biochemical pathways that may be relevant to the distinct pyogenic inflammation of the skin and joints characteristic of this disease. This review summarizes the recent and rapidly accumulating knowledge on these molecular aspects of PAPA syndrome and related disorders. PMID- 21532837 TI - Clinical proteomics of breast cancer. AB - Despite the lifetimes that increased in breast cancers due to the the early screening programs and new therapeutic strategies, many cases still are being lost due to the metastatic relapses. For this reason, new approaches such as the proteomic techniques have currently become the prime objectives of breast cancer researches. Various omic-based techniques have been applied with increasing success to the molecular characterisation of breast tumours, which have resulted in a more detailed classification scheme and have produced clinical diagnostic tests that have been applied to both the prognosis and the prediction of outcome to the treatment. Implementation of the proteomics-based techniques is also seen as crucial if we are to develop a systems biology approach in the discovery of biomarkers of the early diagnosis, prognosis and prediction of the outcome of the breast cancer therapies. In this review, we discuss the studies that have been conducted thus far, for the discovery of diagnostic, prognostic and predictive biomarkers, and evaluate the potential of the discriminating proteins identified in this research for clinical use as breast cancer biomarkers. PMID- 21532840 TI - A polymorphism in the GALNT2 gene and ovarian cancer risk in four population based case-control studies. AB - Recent epidemiologic evidence supports a role for MUC1 in ovarian carcinogenesis; therefore, we hypothesized that common genetic variation in the genes responsible for glycosylation of MUC1 may influence ovarian cancer risk. In a genome-wide association study of ovarian cancer, we observed an association between a non synonymous SNP (rs2271077) in the UDP-N-acetyl-alpha-d-galactosamine: polypeptide N-acetylgalactosainyltransferase 2 (GALNT2) gene and ovarian cancer risk (p=0.005). We sought to validate the association in four population based ovarian cancer case-control studies collaborating through the Ovarian Cancer Association Consortium. Although rs2271077 was associated with a significantly increased risk (Odds Ratio (OR) = 1.37, 95% Confidence Interval (CI) = 1.06-1.77) in one study with 961 cases and 922 controls, we observed no association in the remaining three studies including 1452 cases and 1954 controls (OR=0.83, 95% CI= 0.66 1.04). Therefore, there appears to be no strong evidence of association between GALNT2 SNP rs2271077 and ovarian cancer risk. PMID- 21532841 TI - Interaction of CYP1B1, cigarette-smoke carcinogen metabolism, and lung cancer risk. AB - A previously published case-control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found a significant relationship of serum levels of total NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides) to prospective lung cancer risk. The present paper examines this relationship in the context of single-nucleotide polymorphisms (SNPs) in genes important in the metabolism of tobacco smoke carcinogens. DNA was extracted from the subjects' lymphocytes and analyzed for SNPs in 11 locations on four genes related to tobacco carcinogen metabolism. Logistic regressions on case control status were used to estimate main effects of SNPs and biomarkers and their interactions adjusting for potential confounders. Of the 11 SNPs, only one, in CYP1B1, significantly interacted with total NNAL affecting risk for lung cancer. At low NNAL levels, the variant appeared protective. However, for those with the minor variant, the risk for lung cancer increased with increasing NNAL five times as rapidly compared to those without it, so that at high NNAL levels, this SNP's protection disappears. Analyzing only adenocarcinomas, the effect of the variant was even stronger, with the risk of cancer increasing six times as fast. A common polymorphism of CYP1B1 may play a role in the risk of NNK, a powerful lung carcinogen, in the development of lung cancer in smokers. PMID- 21532839 TI - Metabolic imbalance and prostate cancer progression. AB - There is substantial evidence implicating environmental factors in the progression of prostate cancer. The metabolic consequences of a western lifestyle, such as obesity, insulin resistance and abnormal hormone production have been linked to prostate carcinogenesis through multiple overlapping pathways. Insulin resistance results in raised levels of the mitogens insulin and insulin-like growth factor-1, both of which may affect prostate cancer directly, or through their effect on other metabolic regulators. Obesity is associated with abnormal levels of adipocyte-derived peptides (adipokines), sex hormones and inflammatory cytokines. Adipokines have been shown to influence prostate cancer in both cell culture studies and observational, population level studies. Testosterone appears to have a complex relationship with prostate carcinogenesis, and it has been suggested that the lower levels associated with obesity may select for more aggressive androgen independent prostate cancer cells. Prostatic inflammation, caused by infection, urinary reflux or dietary toxins, frequently occurs prior to cancer development and may influence progression to advanced disease. High levels of omega-6 fatty acids in the diet may lead to the production of further inflammatory molecules that may influence prostate cancer. Increased fatty acid metabolism occurs within tumour cells, providing a potential target for prostate cancer therapies. Aberrations in amino acid metabolism have also been identified in prostate cancer tissue, particularly in metastatic cancer. This evidence indicates lifestyle interventions may be effective in reducing the incidence of clinical disease. However, much more research is needed before recommendations are made. PMID- 21532842 TI - CYP2D6 and CYP2C19 in Papua New Guinea: High frequency of previously uncharacterized CYP2D6 alleles and heterozygote excess. AB - PURPOSE: A high frequency of previously unknown CYP2D6 alleles have been reported in Oceania populations. Genetic and functional properties of these alleles remain unknown. METHODS: We performed analyses of the genetic variability of CYP2D6 and CYP2C19 genes using AmpliChip genotyping in cohorts from two distinct Papua New Guinea (PNG) populations (Kunjingini, n=88; Alexishafen, n=84) focussing on the genetic characterisation of PNG-specific alleles by re-sequencing. RESULTS: Previously unknown CYP2D6 alleles have population frequencies of 24% (Kunjingini) and 12% (Alexishafen). An allele similar to CYP2D6*1, but carrying the 1661G>C substitution, was the second most frequent CYP2D6 allele (20% Kunjingini and 10% Alexishafen population frequency). Sequencing suggests the CYP2D6* 1661G>C allele originated from a cross-over between CYP2D6*1 and *2 and thus is predicted to confer fully active CYP2D6 enzyme. Two additional predicted full activity alleles [1661G>C;4180G>C] and 31G>A were found in the Kunjingini cohort (frequencies 3 c/c and 1%, respectively) and a novel predicted reduced activity allele [100C>T;1039C>T] was found in the Alexishafen cohort (frequency 2%). A high frequency of ultra-rapid (15%) and notably low frequencies of intermediate and poor CYP2D6 metabolizers (<5%) and a high frequency of poor CYP2C19 metabolizers were observed in PNG. Both CYP2D6 and CYP2C19 showed heterozygote excess that may be explained by exogamy and recent introduction of alleles by migration that are yet to reach HWE in relatively isolated populations. CONCLUSION: The CYP2D6*1661 allele common in Oceania may be regarded as functionally equivalent to the full activity CYP2D6*1 allele. PMID- 21532844 TI - Microchimerism: covert genetics? AB - While the world of genetics has been dominated over the last decade by technological advances allowing the identification of common variants underlying the major complex diseases, it is increasingly clear that other genetic mechanisms are also involved in genetic susceptibility and resistance to disease. One understudied contender is microchimerism (maternal and foetal), resulting from bi-directional transfer of cells across the placental barrier in pregnancy. Data from several diseases suggest that elevated levels of microchimerism are associated with autoimmunity. Theories differ however on the role of these cells in the disease process. Some suggest that they increase genetic susceptibility while others suggest that these cells are effectors of the immune response, or that they represent the target of the immune response while another proposes that elevated levels in disease are caused by ongoing repair of damaged tissue. Intriguingly these semi allogeneic cells are tolerated in healthy individuals, albeit at a lower level than in disease scenarios and recent studies in cancer suggest that foetal microchimeric cells may provide surveillance and repair. Many questions remain to be answered about this new avenue of genetics. It is likely that as technology advances our understanding of, and ability to manipulate these cells for therapeutic gain, will push forward new frontiers in medicine. PMID- 21532843 TI - Interaction between use of non-steroidal anti-inflammatory drugs and selected genetic polymorphisms in ovarian cancer risk. AB - Inflammation and non-steroidal anti-inflammatory agents (NSAIDs) may play important role in ovarian cancer. However, epidemiologic data are inconsistent, possibly reflecting inter-individual genetic differences affecting the metabolism of NSAIDs. We examined whether common polymorphisms affecting the metabolism of NSAIDs modify the association between NSAIDs and ovarian cancer risk. We genotyped 1,353 DNA samples from women who developed ovarian cancer and 1,823 samples from matched controls participating in the New England Case-Control study and the Nurses' Health Studies. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with regular use of NSAIDs and with relevant polymorphisms on ovarian cancer risk. Multivariable unconditional logistic regression estimated the association of NSAID use across stratum of each genotype. Regular use of NSAIDs was not associated with ovarian cancer risk. Multivariable OR (95% CI) associated with use NSAIDs was 0.85 (95% CI: 0.71-1.02). Associations between NSAID use and ovarian cancer risk did not differ significantly across strata of genotypes. None of the studied polymorphisms was associated with ovarian cancer risk. The multivariable ORs (95% CI) associated with CYP2C9 and UGT1A6 variant genotypes were 0.99 (0.90-1.08) and 0.93 (0.82-1.05), respectively. The multivariable ORs (95% CI) associated with PPAR-gamma, COX-2 -765G>C, and COX-2 Ex10+837T>C polymorphisms were 1.02 (0.87 1.20), 0.87 (0.75-1.00), and 0.97 (0.87-1.09), respectively. In this relatively large study, we found no convincing evidence supporting an association between NSAIDs use and ovarian cancer risk. Furthermore, data did not suggest interaction between selected polymorphisms and use of NSAIDs in relation to ovarian cancer risk. PMID- 21532845 TI - Functional polymorphisms in two pre-microRNAs and cancer risk: a meta-analysis. AB - Since the identification of two functional polymorphisms in pre-miRNAs {miR-146a rs2910164 and miR-196a2 rsll614913), a number of studies were published in the past several years to evaluate the associations between the two SNPs and cancer risk. However, the findings remain conflicting rather than conclusive. This meta analysis included 12 published case-control studies, 5,916 cancer patients and 6,869 control subjects for SNP rs2910164, and 6,574 cases and 7,601 controls for SNP rsll614913. The allele C of rsll614913 was associated with a significantly increased risk of overall cancers (CC vs. TT: OR=1.18; 95%CI: 1.02-1.37; CT vs. TT: OR=1.11; 95% CI: 1.02-1.21; CC/CT vs. TT: OR=1.13; 95%CI: 1.04-1.23). However, we failed to find main effects for rs2910164 on overall cancer risk in different genetic models tested, while significantly increased risk was evident among cancers other than breast (GG/GC vs. CC: OR=1.30, 95%CI: 1.03-1.64; between study heterogeneity test: P = 0.007). The two functional SNPs may represent tissue specific effect on cancer susceptibility; however, additional well designed large studies are required for the validation of the associations. PMID- 21532838 TI - MicroRNA: Biogenesis, Function and Role in Cancer. AB - MicroRNAs are small, highly conserved non-coding RNA molecules involved in the regulation of gene expression. MicroRNAs are transcribed by RNA polymerases II and III, generating precursors that undergo a series of cleavage events to form mature microRNA. The conventional biogenesis pathway consists of two cleavage events, one nuclear and one cytoplasmic. However, alternative biogenesis pathways exist that differ in the number of cleavage events and enzymes responsible. How microRNA precursors are sorted to the different pathways is unclear but appears to be determined by the site of origin of the microRNA, its sequence and thermodynamic stability. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC). MicroRNA assembles into RISC, activating the complex to target messenger RNA (mRNA) specified by the microRNA. Various RISC assembly models have been proposed and research continues to explore the mechanism(s) of RISC loading and activation. The degree and nature of the complementarity between the microRNA and target determine the gene silencing mechanism, slicer-dependent mRNA degradation or slicer-independent translation inhibition. Recent evidence indicates that P-bodies are essential for microRNA mediated gene silencing and that RISC assembly and silencing occurs primarily within P-bodies. The P-body model outlines microRNA sorting and shuttling between specialized P-body compartments that house enzymes required for slicer -dependent and -independent silencing, addressing the reversibility of these silencing mechanisms. Detailed knowledge of the microRNA pathways is essential for understanding their physiological role and the implications associated with dysfunction and dysregulation. PMID- 21532846 TI - Adducin 1 (alpha) Gly460Trp variant is associated with left ventricular geometry in Caucasians and African Americans: The HyperGEN Study. AB - Normal left ventricular (LV) mass and geometry is required for optimal LV functioning. Abnormalities in either result in increased morbidity and mortality. The adducing 1 (alpha) gene (ADD1) Gly460Trp polymorphism has been associated with high blood pressure and increased plasma volume, both predictors of LV mass and function. In this cross-sectional study, we evaluate the association between this polymorphism and LV mass and geometry. LV mass, relative wall thickness (RWT), and systolic and diastolic parameters were measured using echocardiography in 3483 African American and Caucasian subjects from the Hypertension Genetic Epidemiology Network (HyperGEN). Analysis of covariance was used to estimate the polymorphism's association with echocardiograph parameters, stratified by race. The model was adjusted for age, diastolic and systolic blood pressure, glomerular filtration rate, smoking, low and high density lipoprotein cholesterol, urinary sodium, and body mass index. In Caucasians, the Trp allele was associated with higher ejection fraction (EF) (P = .02), fractional shortening (FS) (P = .02), and RWT (P = .03). In African Americans, the Trp allele was negatively associated with RWT (P = .02), but no association was found with EF (P= .08) or FS (P= .09). The polymorphism was not associated with diastolic function parameters in either racial group. We found no association of ADD1 Gly460Trp with LV mass in Caucasians or African Americans; however, it was associated with unfavorable LV geometry (higher RWT) in Caucasians and favorable LV geometry (lower RWT) in African Americans after controlling for factors that would affect plasma volume. PMID- 21532847 TI - Heart transplantation in pediatric patients: twelve-year experience of the Asan Medical Center. AB - Heart transplantation is a standard treatment for end-stage heart disease. Pediatric heart transplantation, however, is not frequently performed due to the shortage of pediatric heart donors. This is the first report of pediatric heart transplantation in Korea. Our retrospective study included 37 patients younger than 18 yr of age who underwent heart transplantation at Asan Medical Center between August 1997 and April 2009. Preoperative diagnosis was either cardiomyopathy (n = 29, 78.3%) or congenital heart disease (n = 8, 22.7%). Mean follow up period was 56.9 +/- 44.6 months. There were no early death, but 7 late deaths (7/37, 18.9%) due to rejection after 11, 15, 41 months (n = 3), infection after 5, 8, 10 months (n = 3), suspicious ventricular arrhythmia after 50 months (n = 1). There was no significant risk factor for survival. There were 25 rejections (25/37, 67.6%); less than grade II occurred in 17 patients (17/25, 68%) and more than grade II occurred in 8 patients (8/25, 32%). Actuarial 1, 5, and 10 yr survival was 88.6%, 76.8%, and 76.8%. Our midterm survival of pediatric heart transplantation showed excellent results. We hope this result could be an encouraging message to do more pediatric heart transplantation in Korean society. PMID- 21532848 TI - Long-term mortality in adult orthotopic heart transplant recipients. AB - Heart transplantation is now regarded as the treatment of choice for end-stage heart failure. To improve long-term results of the heart transplantation, we analyzed causes of death relative to time after transplantation. A total of 201 consecutive patients, 154 (76.6%) males, aged >= 17 yr underwent heart transplantation between November 1992 and December 2008. Mean ages of recipients and donors were 42.8 +/- 12.4 and 29.8 +/- 9.6 yr, respectively. The bicaval anastomosis technique was used since 1999. Mean follow up duration was 6.5 +/- 4.4 yr. Two patients (1%) died in-hospital due to sepsis caused by infection. Late death occurred in 39 patients (19.4%) with the most common cause being sepsis due to infection. The 1-, 5-, and 10-yr survival rates in these patients were 95.5% +/- 1.5%, 86.9% +/- 2.6%, and 73.5% +/- 4.1%, respectively. The surgical results of heart transplantation in adults were excellent, with late mortality due primarily to infection, malignancy, and rejection. Cardiac deaths related to cardiac allograft vasculopathy were very rare. PMID- 21532849 TI - Molecular epidemiologic analysis of methicillin-resistant Staphylococcus aureus isolates from bacteremia and nasal colonization at 10 intensive care units: multicenter prospective study in Korea. AB - We investigated molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) isolated at 10 intensive care units (ICUs) in Korea. MRSA isolates from bacteremia and nasal colonization were collected prospectively from October 2008 through May 2009 at 10 University-affiliated hospital ICUs. A total of 83 and 175 MRSA strains were isolated from bacteremia and nasal colonization, respectively. Acquired group accounted for 69.9% (n = 58) of bacteremia and 73.1% (n = 128) of nasal colonization. Pulsed-field gel electrophoresis (PFGE) type B (SCCmec type II/ST5) was dominant in the acquired group followed by PFGE type D (SCCmec type IVA/ST72; a community genotype). Seven of 58 (12.1%) acquired bacteremia and 15 of 128 (11.8%) acquired nasal colonizations had SCCmec type IVA/ST72 genotype, which indicated that the community genotype had already emerged as a cause of ICU acquired MRSA infection or colonization. Antibiotic resistance rates to ciprofloxacin, tetracycline, clindamycin and trimethoprim/ sulfamethoxazole were 84.4%, 67.1%, 78.1%, and 12.0%, respectively. Susceptibility to ciprofloxacin best predicted a community genotype (sensitivity 96.5%; specificity 96.9%; odds ratio 861; 95% confidence interval 169-4,390, P < 0.001) and the positive predictive value was 90.2%. Among 23 nasal re-colonized strains, 7 MRSA strains (30.4%) were different from the originally colonized strains on the basis of PFGE types. PMID- 21532850 TI - Pseudomonas aeruginosa bacteremia in children over ten consecutive years: analysis of clinical characteristics, risk factors of multi-drug resistance and clinical outcomes. AB - This study aimed to evaluate the clinical profiles, antibiotic susceptibility, risk factors of multi-drug resistance (MDR) and outcomes of P. aeruginosa bacteremia in children by retrospective methods at a tertiary teaching children's hospital in Seoul, Korea during 2000-2009. A total of 62 episodes were evaluated and 59 patients (95.2%) had underlying diseases. Multivariate analysis demonstrated that an intensive care unit (ICU) stay within the previous one month was the only independent risk factor for MDR P. aeruginosa bacteremia (odds ratio [OR], 6.8; 95% confidence interval [CI], 1.3-35.8, P = 0.023). The overall fatality rate associated with P. aeruginosa bacteremia was 14.5% (9 of 62). The fatality rate in patients with MDR P. aeruginosa was 57.1%, compared with 9.1% in non-MDR patients (OR 13.3; 95% CI 2.3-77.2, P = 0.006). However, the presence of respiratory difficulty was the only independent risk factor for overall fatality associated with P. aeruginosa bacteremia according to multivariate analysis (OR 51.0; 95% CI 7.0-369.0, P < 0.001). A previous ICU stay and presentation with respiratory difficulty were associated with acquisition of MDR P. aeruginosa and a higher fatality rate, respectively. Future efforts should focus on the prevention and treatment of P. aeruginosa bacteremia in high-risk children. PMID- 21532851 TI - Cancer rehabilitation: experience, symptoms, and needs. AB - The aim of this study was to examine the experience of cancer patients undergoing rehabilitation, to identify symptoms associated with rehabilitation from cancer, and to assess the need for rehabilitation services for cancer patients. Cancer patients (n = 402) at the Asan Medical Center (Seoul, Korea) were enrolled from June to September 2008. A chart review was used to collect demographic and clinical data, including type of cancer, current treatment, time from initial diagnosis to screening, and cancer stage. Each participant provided informed consent and was then given a questionnaire that asked about experience with rehabilitation, symptoms associated with rehabilitation, and the need for different types of rehabilitation services. Clinicians recommended rehabilitation for 8.5% of patients, and 6.7% underwent rehabilitation. Among study patients, 83.8% had one or more symptoms associated with rehabilitation, and 71.6% of patients with symptoms wanted rehabilitation management. The need for rehabilitation was associated with the presence of metastasis, advanced cancer stage, time to diagnosis, and type of current treatment. Our results provide specific information about particular functional symptoms and the rehabilitative needs of subgroups of cancer patients. It is suggested to develop and implement rehabilitation programs for cancer patients. PMID- 21532852 TI - Plasma proGRP concentration is sensitive and specific for discriminating small cell lung cancer from nonmalignant conditions or non-small cell lung cancer. AB - To date, most clinical data on pro-gastrin-releasing peptide (proGRP) have been based on serum concentrations. This study evaluated the agreement between proGRP levels in fresh serum and plasma in patients with various lung diseases. Pairs of serum and EDTA plasma were collected from 49 healthy individuals. At the same time, EDTA plasma of 118 lung cancer patients and 23 patients with benign pulmonary diseases were prospectively collected. Compared to serum, plasma proGRP concentrations were higher by an average of 103.3%. Plasma proGRP was higher in malignancy (336.4 +/- 925.4 pg/mL) than in benign conditions (40.1 +/- 11.5 pg/mL). Small cell lung cancer (SCLC) patients showed higher levels of proGRP (1,256.3 +/- 1,605.6 pg/mL) compared to other types of lung cancer. Based on the ROC curve analyses at a specificity of 95%, the diagnostic sensitivity of plasma proGRP was estimated to be 83.8% in distinguishing SCLC from all the other conditions, and 86.5% for discriminating SCLC from the nonmalignant cases. Among the SCLC cases, limited stage disease had lower levels of plasma proGRP than extensive disease. When measuring circulating levels of proGRP, the use of plasma is preferred over serum. Plasma proGRP has a potential marker for discriminating SCLC from nonmalignant conditions or non-small cell lung cancer. PMID- 21532853 TI - Apolipoprotein B is highly associated with the risk of coronary heart disease as estimated by the Framingham risk score in healthy Korean men. AB - The aim of this study was to examine the association between serum apolipoprotein B (apoB) and the risk of coronary heart disease (CHD) using Framingham risk score (FRS) in healthy Korean men. A total of 13,523 men without medication history of diabetes and hypertension were enrolled in this study. The FRS is based on six coronary risk factors. FRS >= 10% was defined as more-than-a-moderate risk group and FRS >= 20% as high risk group, respectively. The logistic regression analyses were conducted. When quartile 1 (Q1) set as a reference, in unadjusted analyses, the Q2, Q3, Q4 of apoB level had increased odds ratio (OR) for the risk of CHD in both more-than-a-moderate risk and high risk group, respectively. After adjusting for confounding variables, multivariable-adjusted logistic regression analyses showed a strong relationship between the quartiles of apoB level and more-than-a moderate risk and high risk group, respectively. These associations were attenuated, but still remained statistically significant. ApoB is found to be independently related to the risk of CHD using FRS in healthy Korean men, and the link between apoB and the risk of CHD is dose-dependent. PMID- 21532854 TI - Time trend and age-period-cohort effects on acute myocardial infarction mortality in Korean adults from 1988 to 2007. AB - We examined time trend and age-period-cohort effects on acute myocardial infarction (AMI) mortality in Korean adults from 1988 to 2007. Annual AMI mortality data and population statistics from 1988 to 2007 were obtained from the STATISTICS KOREA website. Age adjusted mortality for four 5-yr calendar periods (1988-1992 to 2003-2007) was calculated by direct standardization using the Year 2000 WHO world standard population. A log-linear Poisson regression model was used to estimate age, period, and cohort effects on AMI mortality. In both genders, age-adjusted AMI mortality increased from period one (1988-1992) to period three (1998-2002) but decreased in period four (2003-2007). An exponential age effect was noted in both genders. The rate ratio of the cohort effect increased up to the 1943 birth cohort and decreased gradually thereafter, and the rate ratio of the period effect increased up to period three (1998-2002) and decreased thereafter. Our results suggest that AMI mortality in Korean adults has decreased since the period 1998-2002 and age, period, and cohort effects have influenced on AMI mortality. PMID- 21532855 TI - Prevalence and risk factor of erosive esophagitis observed in Korean National Cancer Screening Program. AB - Prevalence of erosive esophagitis (EE) has been increasing in Korea. The purpose of this study was to estimate prevalence of EE among low socioeconomic population in Korea and to investigate risk factors for EE. We reviewed the medical records of 7,278 subjects who were examined by upper endoscopy in the Korean National Cancer Screening Program at Chung-Ang University Yong-san Hospital from March 2003 to March 2008. The study population included subjects >= 40 yr of age who were Medicaid recipients and beneficiaries in the National Health Insurance Corporation. Multivariate analysis was used to determine risk factors for EE. Prevalence of EE was 6.7% (486/7,278). According to the LA classification system, LA-A in 344 subjects, LA-B in 135 subjects, and LA-C and D in 7 subjects. In multivariate analysis, age >= 60 yr, male sex, BMI >= 25, current smoking, alcohol consumption, fasting glucose level >= 126 mg/dL, and endoscopic hiatal hernia were significant risk factors for EE. The prevalence of EE in low socioeconomic Korean population is similar to that in personal annual medical check-ups. Risk factors for EE among them include old age, male sex, BMI >= 25, current smoking, alcohol consumption, fasting glucose level >= 126 mg/dL, and hiatal hernia. PMID- 21532856 TI - CDX1 and CDX2 expression in intestinal metaplasia, dysplasia and gastric cancer. AB - Intestinal metaplasia (IM) has been regarded as a premalignant condition. However, the pathogenesis of IM is not fully understood. The aim of this study was to evaluate the role of CDX1 and CDX2 in the formation of IM and the progression to dysplasia and gastric cancer (GC). A total of 270 subjects included 90 with GC, dysplasia and age- and sex-matched controls. Real-time PCR (RT-PCR) was performed with body specimens for CDX1 and CDX2. The expression of CDX2 was significantly higher in H. pylori positive group than H. pylori negative group (P = 0.045). CDX1 and CDX2 expression increased proportional to the IM grade of the body (P < 0.001). CDX2 expression was significantly higher in incomplete type of IM than in complete type (P = 0.045). The expression of CDX1 in dysplasia group was significantly higher than in the control group (P = 0.001); in addition, CDX1 and CDX2 in cancer group was significantly higher than control group (P < 0.001, and P < 0.001, respectively). Aberrant expression of CDX1 and CDX2 correlated with H. pylori infection and grade of IM in the body. Furthermore, the results suggest that CDX1 and CDX2 play a role in the progression to GC and dysplasia. PMID- 21532857 TI - Helicobacter pylori infection is associated with elevated low density lipoprotein cholesterol levels in elderly Koreans. AB - This study was conducted to investigate the association between Helicobacter pylori (H. pylori) infection and the lipid profile among elderly Koreans. A total of 462 subjects (mean age 66.2 +/- 7.6 yr, 84% males) who underwent health check up were investigated. Each subject underwent gastroduodenoscopy with gastric mucosal biopsy, and H. pylori infection was determined by histopathological examination using the updated Sydney System score. The presence of H. pylori infection was significantly associated with the elevated serum levels of total cholesterol and low density lipoprotein (LDL) cholesterol (P < 0.05 for each) in univariate analysis. H. pylori infection was not associated with triglyceride and high density lipoprotein (HDL) cholesterol levels (P > 0.05 for each). After controlling confounders, multiple logistic regression analysis showed that the odds ratio of H. pylori infection for high LDL cholesterol level (> 140 mg/dL) was 3.113 (95% confidence interval, 1.364-7.018; P = 0.007). There were no significant associations between the presence of H. pylori infection and elevated total cholesterol levels (> 200 mg/dL) in this model (P = 0.586). The results of this study demonstrate that H. pylori infection is associated with the elevated serum LDL cholesterol levels in elderly Koreans, supporting the hypothesis that H. pylori plays a role in promoting atherosclerosis by modifying lipid metabolism. PMID- 21532858 TI - Association of IL10, IL10RA, and IL10RB polymorphisms with benign prostate hyperplasia in Korean population. AB - Cytokines such as interleukin 10 (IL10) may play an important role in the process of inflammation. The aim of this study was to analyze the association between IL10, IL10RA and IL10RB single nucleotide polymorphisms (SNPs), and benign prostate hyperplasia (BPH) in Korean population. All patients with BPH were divided into two groups according to international prostate symptom score (IPSS), prostate specific antigen (PSA) level, Q(max), and prostate volume. We selected two IL10 SNPs (rs1518111 and rs1554286), three IL10RA SNPs (rs2256111, rs4252243, and rs2228054), and two IL10RB SNPs (rs999788 and rs2834167). Genotypes of seven SNPs were determined through direct sequencing. The G/G genotype of IL10RB polymorphism (rs2834167) was associated with a high PSA level compared with the A/G + A/A genotypes (P = 0.009). Of IL10 SNP, the A/A genotype of rs1518111 and T/T genotype of rs1554286 were associated with small prostate volume, respectively (P = 0.011, P = 0.014). Moreover, the T/T genotype of IL10RB polymorphism (rs999788) was associated with high prostatic volume compared with the T/C + C/C genotypes (P = 0.033). The linkage disequilibrium (LD) blocks were formed in IL10 and IL10RA. However, haplotypes in the LD block were not associated with BPH. It is concluded that there is a strong association between the IL10 and IL10RB SNPs, and BPH in Korean population. PMID- 21532859 TI - Altered brain activation in ventral frontal-striatal regions following a 16-week pharmacotherapy in unmedicated obsessive-compulsive disorder. AB - Recent studies have reported that cognitive inflexibility associated with impairments in a frontal-striatal circuit and parietal region is a core cognitive deficit of obsessive-compulsive disorder (OCD). However, few studies have examined progressive changes in these regions following clinical improvement in obsessive-compulsive symptoms. To determine if treatment changes the aberrant activation pattern associated with task switching in OCD, we examined the activation patterns in brain areas after treatment. The study was conducted on 10 unmedicated OCD patients and 20 matched controls using event-related functional magnetic resonance imaging. Treatment improved the clinical symptoms measured by the Yale-Brown Obsessive Compulsive Scale and behavioral flexibility indicated by the switching cost. At baseline, OCD showed significantly less activation in the dorsal and ventral frontal-striatal circuit and parietal regions under the task switch minus task-repeat condition compared with controls. After treatment, the neural responses in the ventral frontal-striatal circuit in OCD were partially normalized, whereas the activation deficit in dorsal frontoparietal regions that mediate shifting attention or behavioral flexibility persisted. It is suggested that altered brain activation in ventral frontal-striatal regions in OCD patients is associated with their cognitive flexibility and changes in these regions may underlie the pathophysiology of OCD. PMID- 21532860 TI - Association of alcohol consumption with the risk of ocular trauma. AB - This study was conducted to evaluate the influence of alcohol consumption on the risk of ocular trauma. We retrospectively reviewed the medical records of 1,024 patients who visited emergency department and received ophthalmologic examination from January 1 to December 31, 2009. The patients were divided into 2 groups: those with ocular trauma (n = 494) and those without (n = 530); the influence of alcohol consumption was compared between these 2 groups. In the ocular trauma group, the association of the causes and types of ocular trauma with alcohol consumption was evaluated. One of 530 patients of no trauma group and 117 (23.7%) of 494 patients of trauma group were related with alcohol intake, and the difference was statistically significant (P < 0.001). Concerning the causes, physical assault was significantly more common in alcohol-associated injury (P < 0.001). Regarding the types of injury, orbital wall fracture and hyphema showed a significant association with alcohol consumption (P < 0.001). Older age and nighttime injury were significantly related to the increased risk of alcohol associated ocular trauma (P = 0.018 and < 0.001, respectively). In conclusion, alcohol consumption significantly increases the risk of ocular trauma. PMID- 21532861 TI - Bacteremia caused by Laribacter hongkongensis misidentified as Acinetobacter lwoffii: report of the first case in Korea. AB - Laribacter hongkongensis is an emerging pathogen in patients with community acquired gastroenteritis and traveler's diarrhea. We herein report a case of L. hongkongensis infection in a 24-yr-old male with liver cirrhosis complicated by Wilson's disease. He was admitted to a hospital with only abdominal distension. On day 6 following admission, he complained of abdominal pain and his body temperature reached 38.6C. The results of peritoneal fluid evaluation revealed a leukocyte count of 1,180/uL (polymorphonuclear leukocyte 74%). Growth on blood culture was identified as a gram-negative bacillus. The isolate was initially identified as Acinetobacter lwoffii by conventional identification methods in the clinical microbiology laboratory, but was later identified as L. hongkongensis on the basis of molecular identification. The patient was successfully treated with cefotaxime. To the best of our knowledge, this case is the first report of hospital-acquired L. hongkongensis bacteremia with neutrophilic ascites. PMID- 21532863 TI - Marginal zone B-cell lymphoma of MALT in small intestine associated with amyloidosis: a rare association. AB - A 62-yr-old man presented with a 5-yr history of intermittent abdominal distention and pain. These symptoms persisted for several months and subsided without treatment. A diagnosis of suspected small bowel lymphoma was made based on plain radiograph and computerized tomogram findings, and he was referred to our institution for further evaluation. Segmental resection of the small intestine was performed and the diagnosis of marginal zone B-cell lymphoma associated with amyloidosis was made. This is the first case of marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) in the small intestine associated with amyloidosis in Korea. PMID- 21532862 TI - A case of piperacillin-induced occupational anaphylaxis: detection of serum IgE to piperacillin-HSA conjugate. AB - This is the first reported detection of serum IgE antibody to piperacillin-human serum albumin (HSA) conjugate in a patient presenting with anaphylaxis that developed after occupational exposure. A 24-yr-old nurse, who had worked at a University Hospital for 2 yr, experienced chest tightness, dizziness, generalized urticaria, abdominal pain, and diarrhea 10 min after administering a piperacillin injection. She had previously suffered from atopic dermatitis. A skin prick test for common inhalant allergens was entirely negative; in contrast, her serum total IgE was elevated (283 IU/mL). A high level of piperacillin-specific serum IgE was detected by ELISA using piperacillin-HSA conjugate. Significant inhibition upon addition of both free piperacillin and piperacillin-HSA conjugate was detected by inhibition ELISA. These data suggest that piperacillin exposure in the workplace can induce occupational anaphylaxis and urticaria mediated by an interaction of IgE with the hapten of piperacillin. PMID- 21532864 TI - Unusual cause of acute right ventricular dysfunction: rapid progression of superior vena cava aneurysm complicated by thrombosis and pulmonary thromboembolism. AB - Aneurysms of the major thoracic veins are rare. They are usually asymptomatic and thus treated conservatively. We report an extremely rare case of rapidly progressing superior vena cava (SVC) aneurysm complicated by thrombosis and acute pulmonary thromboembolism (PTE) with right ventricular dysfunction. Thrombolytic therapy for hemodynamically significant acute PTE was harmful to the patient in the present case, because it induced further thrombosis and mobilization of the thrombi within the aneurysm, subsequently causing de novo PTE. Surgical aneurysmectomy combined with pulmonary artery embolectomy would be a treatment of choice in patients with SVC aneurysm complicated by acute PTE. PMID- 21532865 TI - Oral azithromycin for treatment of intractable rosacea. AB - Rosacea is a common chronic cutaneous disorder that primarily occurs on the convex surfaces of the central face and is often characterized by exacerbations and remissions. A case of a 52-yr-old woman visited our clinic in February 2008 complaining typical features of rosacea including multiple pinhead to rice-sized erythematous papules. We applied various conventional treatments including topical benzoyl peroxide and metronidazole as well as oral metronidazole, isotretinoin, and doxycycline. The lesions were not controlled but were rather aggravated by complications from these treatments. Therefore, we prescribed oral azithromycin, which has anti-inflammatory effects and reduces reactive oxygen species. Ten weeks after the administration of oral azithromycin, 500 mg per day for 2 weeks, the lesions had mostly disappeared and no specific side effects related to the azithromycin were noted. Oral azithromycin dosing 500 mg/day for 2 weeks is effective for treatment of intractable rosacea. PMID- 21532866 TI - Extracellular high-mobility group box 1 is increased in patients with Behcet's disease with intestinal involvement. AB - High-mobility group box 1 (HMGB1) protein has been demonstrated to play an important role in chronic inflammatory diseases including rheumatoid arthritis, and systemic lupus erythematosus. This study investigated the association between extracellular HMGB1 expression and disease activity, and clinical features of Behcet's disease (BD). Extracellular HMGB1 expression in the sera of 42 BD patients was measured and was compared to that of 22 age- and sex-matched healthy controls. HMGB1 expression was significantly increased in BD patients compared to healthy controls (78.70 +/- 20.22 vs 10.79 +/- 1.90 ng/mL, P = 0.002). In addition, HMGB1 expression was significantly elevated in BD patients with intestinal involvement compared to those without (179.61 +/- 67.95 vs 61.89 +/- 19.81 ng/mL, P = 0.04). No significant association was observed between HMGB1 concentration and other clinical manifestations, or disease activity. It is suggested that extracellular HMGB1 may play an important role in the pathogenesis of BD. PMID- 21532867 TI - Differentiating glaucomatous from non-glaucomatous optic nerve cupping by optical coherence tomography. AB - BACKGROUND: In clinical practice, the differentiation of glaucomatous from non glaucomatous cupping can be difficult, even for experienced observers. The purpose of this study was to evaluate the role of optical coherence tomography (OCT) in differentiating glaucomatous from non-glaucomatous optic nerve cupping in a cross-sectional pilot study. METHODS: Eleven consecutive patients presenting to the Duke Eye Center from September 2007 to July 2008 with non-glaucomatous optic nerve cupping and 12 patients with glaucomatous optic nerve cupping were identified. All patients underwent Stratus(r) OCT imaging: fast macular map, fast retinal nerve fiber layer (RNFL) 3.4 thickness, and fast optic disc protocols. Automated visual field perimetry was performed on the date of OCT scan in non glaucomatous cupping patients, and from 0-9 months of scan date in glaucoma patients. Eyes were matched by optic nerve cup-to-disc area ratio; average and mean deviation were calculated for each variable. RESULTS: For a similar average RNFL, patients with non-glaucomatous optic nerve cupping had lower nasal and temporal RNFL thickness, as well as lower macular thickness and volume compared to patients with glaucomatous optic nerve cupping. CONCLUSION: OCT appears to be a useful technology in differentiating glaucomatous from non-glaucomatous optic nerve cupping. The pattern of RNFL loss appears more diffuse in non-glaucomatous optic nerve cupping compared to glaucomatous optic nerve cupping. Future studies with larger sample size and specific neuro-ophthalmic causes of optic nerve cupping may further elucidate the role of OCT in this clinical setting. PMID- 21532868 TI - DJ-1 Mutations are Rare in a Swedish Parkinson Cohort. AB - Mutations in the PARK7 gene, DJ-1, have been reported to cause early-onset and familial Parkinson's disease (PD). The function of DJ-1 and how it contributes to the development of the disease is not clear today, but several studies report that DJ-1 is responsive to oxidative stress and important for the maintenance of mitochondria. We have screened three coding regions of DJ-1 (exon 2, 5 and 7) in a Swedish Parkinson cohort. The Swedish PD material consisted of 67 patients with a self reported positive family history of PD and 77 patients with early-onset of disease (<=50 years old). We detected two patients with the previously reported synonymous mutation, Ala167Ala (c.501A>G, rs71653621), in exon 7. No Ala167Ala carriers were identified among 213 neurologically healthy Swedish controls. Mechanisms by which the synonymous Ala167Ala mutation can have consequences are unknown. It may affect the mRNA stability, secondary structure of mRNA, synthesis, turnover, protein folding and function. We could show a 1.3% decrease in DJ-1 mRNA folding energy in the Astage III) disease at diagnosis and also the limited efficacy of currently available therapies. Consequently, there is clearly a great need to develop improved upfront and salvage therapies for ovarian cancer. Here, we investigated the efficacy of metformin alone and in combination with cisplatin in vivo. A2780 ovarian cancer cells were injected intraperitoneally in nude mice; A2780-induced tumors in nude mice, when treated with metformin in drinking water, resulted in a significant reduction of tumor growth, accompanied by inhibition of tumor cell proliferation (as assessed by immunohistochemical staining of Ki-67, Cyclin D1) as well as decreased live tumor size and mitotic cell count. Metformin-induced activation of AMPK/mTOR pathway was accompanied by decreased microvessel density and vascular endothelial growth factor expression. More importantly, metformin treatment inhibited the growth of metastatic nodules in the lung and significantly potentiated cisplatin-induced cytotoxicity resulting in approximately 90% reduction in tumor growth compared with treatment by either of the drugs alone. Collectively, our data show for the first time that, in addition to inhibiting tumor cell proliferation, metformin treatment inhibits both angiogenesis and metastatic spread of ovarian cancer. Overall, our study provides a strong rationale for use of metformin in ovarian cancer treatment. PMID- 21532888 TI - p38gamma mitogen-activated protein kinase contributes to oncogenic properties maintenance and resistance to poly (ADP-ribose)-polymerase-1 inhibition in breast cancer. AB - p38gamma MAPK, one of the four members of p38 mitogen-activated protein kinases (MAPKs), has previously been shown to harbor oncogenic functions. However, the biologic function of p38gamma MAPK in breast cancer has not been well defined. In this study, we have shown that p38gamma MAPK is overexpressed in highly metastatic human and mouse breast cancer cell lines and p38gamma MAPK expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. Ectopic expression of p38gamma MAPK did not lead to an increase in oncogenic properties in vitro in most tested mammary epithelial cells. However, knockdown of p38gamma MAPK expression resulted in a dramatic decrease in cell proliferation, colony formation, cell migration, invasion in vitro and significant retardation of tumorigenesis, and long-distance metastasis to the lungs in vivo. Moreover, knockdown of p38gamma MAPK triggered the activation of AKT signaling. Inhibition of this feedback loop with various PI3K/AKT signaling inhibitors facilitated the effect of targeting p38gamma MAPK. We further found that overexpression of p38gamma MAPK did not promote cell resistance to chemotherapeutic agents doxorubicin and paclitaxel but significantly increased cell resistance to PJ-34, a DNA damage agent poly (ADP-ribose)-polymerase-1 (PARP) inhibitor in vitro and in vivo. Finally, we identified that p38gamma MAPK overexpression led to marked cell cycle arrest in G(2)/M phase. Our study for the first time clearly demonstrates that p38gamma MAPK is a promising target for the design of targeted therapies for basal-like breast cancer with metastatic characteristics and for overcoming potential resistance against the PARP inhibitor. PMID- 21532891 TI - Determinants of retention in care in an antiretroviral therapy (ART) program in urban Cameroon, 2003-2005. AB - BACKGROUND: Retention in long-term antiretroviral therapy (ART) program remains a major challenge for effective management of HIV infected people in sub-Saharan Africa. Highly Active Antiretroviral Therapy (ART) discontinuation raises concerns about drug resistance and could negate much of the benefit sought by ART programs. METHODS: Based on existing patient records, we assessed determinants of retention in HIV care among HIV patients enrolled in an urban ART at two urban hospitals in Cameroon. Extended Cox regression procedures were used to identify significant predictors of retention in HIV care. RESULTS: Of 455 patients, 314 (69%) were women, median (IQR) age and baseline CD4 cell count were respectively 36 years (30 - 43) and 110 cells/MUL (39 - 177). Forty patients (9%) had active tuberculosis (TB) at enrollment. After a median (IQR) follow-up of 18 months (10 18), 346 (75%) were still in care, 8 (2%) were known dead, and 101 (22%) were lost to follow-up (LFU). Severe immunosuppression (CD4 cell count <= 50 cells/MUL) at baseline (aHR 2.3; 95% CI 1.4 - 3.7) and active tuberculosis upon enrollment (aHR 1.8; 95% CI 1.0 - 3.6) were independent predictors of cohort losses to follow-up within the first 6 months after HAART initiation. CONCLUSION: These data suggest that three-quarter of HIV patients initiated on HAART remained in care and on HAART by 18 months; however, those with compromised immunologic status at treatment initiation, and those co-infected with TB were at increased risk for being lost to follow-up within the first 6 months on treatment. PMID- 21532892 TI - Immunological role of nasal staphylococcus aureus carriage in patients with persistent allergic rhinitis. AB - Nasal carriage of staphylococcus aureus (S.aureus) exerts immunomodulatory effect in patients with atopic dermatitis and it may contribute to airway inflammation and allergic response in patients with allergic rhinitis. We Aim to investigate the frequency of nasal S.aureus carriage in patients with persistent allergic rhinitis and its possible influence on their symptoms and immune markers. We chosed 20 non smoker patients with house dust mite (HDM) allergy causing allergic rhinitis and 20 non smoker healthy subjects matched for age and sex. For all subjects rhinoscopy was done, skin prick test, nasal culture for S.aureus, nasal interleukin 4,nasal total IgE, serum total IgE and serum specific IgE(SSIgE) for HDM. Nasal S.aureus was detected in 16/20 patients (80%) and 5/20 (25%) in healthy subjects with highly significant statistical difference p<0.01. Correlation of nasal staph.aureus count and different systemic and local immune markers revealed highly significant positive correlation between nasal S.aureus count and serum total IgE (r = 0.78, p<0.01) and significant positive correlation with SSIgE (HDM) (r = 0.53, p<0.05), nasal total IgE (r = 0.39, p<0.05) and nasal IL-4 (r = 0.55, p<0.05). Nasal staph.aureus actively modulated the immune reaction in persistent allergic rhinitis patients by promoting local IgE production, so we recommend early detection and treatment of S.aureus carriage in patients. PMID- 21532893 TI - Locked-in Syndrome in a Nigerian male with Multiple Sclerosis: a case report and literature review. AB - BACKGROUND: Locked-in syndrome is an extremely difficult neurologic condition to recognize, especially by the non-specialists. A case of locked-in syndrome in a 41-year old Niger Deltan Nigerian with relapsing remitting form of multiple sclerosis (MS) is presented, including a detailed literature review. PATIENT AND CASE REPORT: The patient was in a state of spastic quadriplegia, motionless and aphasic (mute), with the preservation of consciousness and the ability to open and blink the eyes and move them vertically. Two episodes of the disease, varying in duration, have been described. The diagnosis of MS was made from the history and the typical clinical presentation: history of relapsing and remitting signs and clinical evidence of multi-focal involvement of the central nervous system. CONCLUSION: Patient died at the age of 45 years, from pulmonary complications. This article may enhance easy recognition and management of the syndrome by all clinicians. PMID- 21532894 TI - Performance, priorities, and future of biomedical research publications in Africa: Need for networks between scientists in developed and developing countries. PMID- 21532895 TI - Antiretroviral prophylaxis to prevent post-natal transmission of HIV through breastfeeding. PMID- 21532896 TI - Pan African Medical Journal (PAMJ) - African Field Epidemiology Network (AFENET): A partnership for the future of medical publishing in Africa. PMID- 21532897 TI - Pregnancy follow-up in a patient with mechanical valve: possible in sub-Saharan Africa? AB - BACKGROUND: In Africa in general and in Cameroon in particular, post rheumatic cardiopathies are a health care problem, one of the causes of infertility in the women population and a major cause of death among children and adults. Management of a pregnant woman with mechanical heart valve is a complex issue for all health care providers involved in the care of such patients. PATIENT AND CASE REPORT: Miss A is 26-years old and consulted for cardiac assessment; referred from Bamenda (North-West province of Cameroon) for better management of a cardiac problem including arrhythmia and a history of recurrent tonsillitis. The cardiac echo-dopplerography showed severe post-rheumatic mitral valve regurgitation with pulmonary hypertension and a dysfunctional left ventricle. The patient was later evacuated in a surgical centre in Milan San Donato (Italy) where a St. Jude mechanical heart valve N.27 was implanted. Two years after surgery, during a follow-up visit, the patient brought a pelvic ultrasound showing a single live intrauterine foetus, gestational age estimated at 7 weeks. CONCLUSION: Management of mechanical valve in a pregnancy context, resulting in a favourable outcome (no thromboembolic events and the delivery of a healthy baby) is possible in sub Saharan Africa. Close observation, adherence to existing clinical guidelines, patient cooperation and an appropriate technical infrastructure are critical factors to consider. PMID- 21532898 TI - The effects of exclusive versus non-exclusive breastfeeding on specific infant morbidities in Conakry. AB - BACKGROUND: This study examines the effect of exclusive versus non-exclusive breastfeeding on specific infant morbidities from birth to nine months, in Conakry (Guinea). METHOD: A cross-sectional study was conducted on 1,167 mother infant pairs who visited one of 20 immunization centres in Conakry for vaccination between the 45(th) and 270(th) days of the child's life. Two data sources were used: the infant health book and an orally administered questionnaire completed with the mother. Data analyses included univariate cross tabulations and multivariate logistic regression models to estimate the effect of breastfeeding on infant morbidity. RESULTS: Exclusive breastfeeding decreased with the infant's age. At six months of age, the proportion of infants who were exclusively breastfed was only 15.5%. After adjusting for the infant's age, and the interaction between the type of breastfeeding and the infant's age, exclusive breastfeeding significantly protected the infants against many of the studied morbidities (OR: 0.28, CI: 0.15-0.51) and specifically against diarrhoea (OR: 0.38; 95% CI: 0.17 - 0.86), respiratory infections (OR: 0.27; 95% CI: 0.14 - 0.50), and low growth rate (OR: 0.11; 95% CI: 0.02 - 0.46), but not for otitis, urinary infection, or meningitis. CONCLUSION: This investigation confirmed the protective effects of exclusive breastfeeding on some specific infant's morbidities during the first nine months of life. The results of this study are of great importance for the development of an information program designed to encourage the exclusive breastfeeding among the mothers of Conakry, Guinea. PMID- 21532899 TI - Improving communication for immunisation in Africa: contribution of the Vaccines for Africa website. AB - ABOUT THE AUTHORS: C. Wiysonge is a medical epidemiologist and Vaccinology Programme Manager at the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. He previously worked for the Expanded Programme on Immunisation in Cameroon and has been a consultant on vaccines and immunisation for WHO and the GAVI Alliance. Z. Waggie is a Paediatrician and Senior Clinical Research Officer at the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. L. Rhoda is a communications specialist and Communications Manager at the South African Tuberculosis Vaccine Initiative, University of Cape Town, South Africa. G. Hussey is a Paediatric Infectious Diseases Clinical Specialist and Professor of Child and Adolescent Health, Director of the Institute of Infectious Disease and Molecular Medicine, and Director of the South African Tuberculosis Vaccine Initiative, University of Cape Town, South Africa. He has been a WHO part-time consultant on vaccines and immunisation for the past 10 years. PMID- 21532900 TI - [The involvement of non-governmental organizations in health systems in developing countries: example of Shisong Cardiac Centre]. PMID- 21532901 TI - Epidemiology of Orofacial clefts in Africa: Methodological challenges in ascertainment. AB - BACKGROUND: To carry out a systematic review of the birth prevalence of cleft lip with or without cleft palate (CLP) and cleft palate (CP) in Africa based on available published data. METHOD: Using the Cochrane search strategy and the following keywords words "cleft palate", "prevalence", "incidence", "cleft lip" and "Africa" to screen Ovid Medline {1966 to March 2007), Cinahl {1982-March 2007}, Pub Med, Scopus, and Web-Google. All identified published, prospective and retrospective studies on the birth prevalence of CLP and CP in Africa were included. The dates, location, sources, number of births (live births, still births, number of cleft cases, prevalence rates, sex ratio, cleft types, and clefts with associated anomalies were extracted. RESULTS: Ascertainment of cases was through the hospitals. Overall there were 57 CL/P, 56 CL and 36 CP reported from all the studies. From seven studies combined, 21 males and 20 females had CL, 10 males and 22 females with CP and 26 males and 24 females with CL/P. There were 3 cases with CL/P, 2 with CP and 2 with CL from the three studies that reported clefts with associated anomalies. CONCLUSION: For an improved ascertainment of cleft cases, there is a need to set up a birth defects surveillance system in the form of a national birth registry. Future studies should then aim to include the entire population in geographically defined regions. Reliable data on incidence is an essential pre-requisite for studies into aetiology and prevention. PMID- 21532902 TI - Epi InfoTM: Now an Open-source application that continues a long and productive "life" through CDC support and funding. AB - ABOUT THE AUTHORS: Enrique Nieves Jr is the Acting Director of the Division of Integrated Surveillance Systems and Services (DISSS), National Center for Public for Health Informatics (NCPHI), Coordinating Center for Health information and Service (CCHIS), Centers for Disease Control and Prevention (CDC), Atlanta, USA. Jay Jones is a BearingPoint Consultant to the CDC/NCPHI Division of Alliance Management and Consultation (DAMC), National Center for Public for Health Informatics (NCPHI), Coordinating Center for Health information and Service (CCHIS), Centers for Disease Control and Prevention (CDC), Atlanta, USA. PMID- 21532903 TI - Eclampsia and seasonal variation in the tropics - a study in Nigeria. AB - BACKGROUND: A retrospective observational study on the seasonal variation in the admission of eclampsia patients to the multi-disciplinary intensive care unit (ICU) of National Hospital, Abuja, Nigeria over a five-year span (March 2000 - March 2005) was carried out. METHOD: The patient's case files and ICU records were used to extract the needed data. The diagnosis of eclampsia was based on clinical and laboratory findings by the obstetricians. RESULTS: There were a total of 5,987 deliveries during the study period. Forty-six eclamptics were admitted to the ICU during the study period giving an ICU admission rate of 7.6/1000 deliveries. The average age of the patients was 28.6 years. Six patients (13%) were booked for antenatal care in the hospital, while forty patients (87%) were referred. Average duration of stay in the ICU was 4.6 days (range 1-42 days). Thirty-one eclamptics (67.4%) were admitted to the ICU during the rainy season (April to October) and fifteen (32.6%) during the dry season (November to April). The rainy season is associated with a lower average high temperature and a higher humidity than the dry season. There is a view that holds that increasing humidity and a lower temperature is associated with increased incidence of eclampsia. There were thirteen deaths giving a case fatality rate of 28.2%. The causes of death were HELLP (haemolysis, elevated liver enzymes, low platelet count) syndrome in six patients, disseminated intravascular coagulation in two patients, and acute renal failure (ARF) in two patients. Septicemia, lobar pneumonia/heart failure and cerebrovascular accident accounted for one death each. CONCLUSION: In this study, we found an association between the rainy season and the incidence of eclampsia to our intensive care unit. This association should be further explored. PMID- 21532904 TI - Extrathoracic heart in northern Cameroon: a case report. AB - Sternal clefts, ectopia cordis, and Cantrell's pentalogy continue to be very rare congenital anomalies in pediatric surgery. The prenatal diagnosis is easily made with ultrasound by visualizing the heart outside the thoracic cavity. Ectopia cordis is frequently associated with other congenital defects involving multiple organ systems. We report a case of ectopia cordis with successful surgical correction on a 7 months old child from northern Cameroon. PMID- 21532905 TI - The impact of pre-menarcheal training on menstrual practices and hygiene of Nigerian school girls. AB - BACKGROUND: The menstrual practices of adolescents derive largely from health issues associated with their adjustment to reproductive life. The objective of the study was to assess the effect of pre-menarcheal training on the menstrual and hygiene practices of Nigerian school girls. METHOD: A cross-sectional questionnaire-based survey of randomly selected post-menarcheal school girls using a pre-tested, semi-structured questionnaire was done. RESULTS: The mean age of the school girls was 14.9 +/- 1.7 years. Pre-menarcheal training was given to 273 (55.2%) of them. Mothers (74.7%) were the more common source of information. Inappropriate experience of menarche, adverse effect of menstruation on schooling and social life and the use of unhygienic menstrual absorbents were common in girls who had no pre-menarcheal training than those who did. CONCLUSION: Lack of timely information results in inappropriate menstrual experiences and poor menstrual hygiene practices. Ways to promote menstrual education and hygiene practices are suggested. PMID- 21532906 TI - Retained sponge after abdominal surgery: experience from a third world country. AB - BACKGROUND: Retained abdominal sponge after surgery is a quite rare condition which can have heavy medico-legal consequences; its frequency is generally underestimated. Few reports of these conditions are available in African environment with specific technical and medico-legal background. We present our local experience of retained sponges after abdominal surgery and review current literature. METHOD: A retrospective analysis of the medical files of 14 consecutive patients with a retained surgical sponge after abdominal and urological surgery. RESULTS: The incidence was 1every 677 abdominal operations; no metallic foreign body described, only sponges; the female sex predominated with 10/14 patients. 85.71% of retained sponge occurred after an emergency procedure and 64.28% were gynecological or obstetrical procedures. Most cases presented as intestinal obstruction, localized persistent pain or abdominal mass and pre-operative diagnosis could be done only in 28.57% of cases. A falsely correct sponge count was reported in 71.42% of cases 92.85% of patients were re operated and the morbidity was low; no death was reported. None of our cases ended in a medico-legal claim despite proper counseling. CONCLUSION: The incidence of retained sponge might be significantly higher in an environment with reduced medico-legal threat; most cases of retained sponges are still related to human errors; the incidence will probably be reduced by a greater awareness about the condition. PMID- 21532907 TI - Fibroadenoma in women in Ghana. AB - BACKGROUND: Fibroadenoma is the commonest benign tumor of female breast. It is particularly common in young women in Africa. METHOD: This paper describes the clinicopathologic features of fibroadenoma of breast in African women from central Ghana and compares them to the data from African-American women. RESULTS: Fibroadenomas constituted 47.7% of all palpable breast masses. The median age of women was 22 years (range 14-49). Almost a third of the cases occurred in teenager. The mean size of masses was 3.8 cm (range 1-9 cm), with 22.5% showing larger sizes. A total of 16.1% had multiple and/or bilateral lesions. CONCLUSION: Women from Central Ghana tend to have proportionately more fibroadenomas and larger (>5 cm) variants compared to published data from African-American women, however, the average age, size, multifocality and bilaterality do not differ significantly between these two groups of women. PMID- 21532908 TI - The Defining Moment: Children's Conceptualization of Race and Experiences with Racial Discrimination. AB - This paper examines whether children of marginalized racial/ethnic groups have an awareness of race at earlier ages than youth from non-marginalized groups, documents their experiences with racial discrimination, and utilizes a modified racism-related stress model to explore the relationship between perceived racial discrimination and self-esteem. Data were collected for non-Hispanic black, non Hispanic white, and Hispanic children aged 7 - 12 using face-to-face interviews (n = 175). The concept of race was measured by assessing whether children could define race, if not a standard definition was provided. Racial discrimination was measured using the Williams Every-day-Discrimination Scale, self-esteem was measured using the Rosenberg Scale, and ethnic identity was assessed using the Multi-group Ethnic Identity Measure. Non-Hispanic black children were able to define race more accurately, but overall, Hispanic children encountered more racial discrimination, with frequent reports of ethnic slurs. Additionally, after accounting for ethnic identity, perceived racial discrimination remained a salient stressor that contributed to low self-esteem. PMID- 21532909 TI - Does Enhancing Work-Time Control and Flexibility Reduce Turnover? A Naturally Occurring Experiment. AB - We investigate the turnover effects of an organizational innovation (ROWE-Results Only Work Environment) aimed at moving away from standard time practices to focus on results rather than time spent at work. To model rates of turnover, we draw on survey data from a sample of employees at a corporate headquarters (N = 775) and institutional records of turnover over eight months following the ROWE implementation. We find the odds of turnover are indeed lower for employees participating in the ROWE initiative, which offers employees greater work-time control and flexibility, and that this is the case regardless of employees' gender, age, or family life stage. ROWE also moderates the turnover effects of organizational tenure and negative home-to-work spillover, physical symptoms, and job insecurity, with those in ROWE who report these situations generally less likely to leave the organization. Additionally, ROWE reduces turnover intentions among those remaining with the corporation. This research moves the "opting-out" argument from one of private troubles to an issue of greater employee work-time control and flexibility by showing that an organizational policy initiative can reduce turnover. PMID- 21532910 TI - Chiral oxazolidinones as electrophiles: Intramolecular cyclization reactions with carbanions and preparation of functionalized lactams. AB - The intramolecular cyclizations of oxazolidinones with carbanions adjacent to sulfones, sulfoxides and phosphonates proceed in high yields to obtain functionalized gamma and delta lactams. The chiral oxazolidinone precursors can be readily synthesized from commercial amino acids. The lactams from this study are useful synthetic intermediates, as demonstrated by the synthesis of a precursor for levetiracetam, an antiepileptic drug. PMID- 21532912 TI - Effect partitioning under interference in two-stage randomized vaccine trials. AB - In the presence of interference, the exposure of one individual may affect the outcomes of others. We provide new effect partitioning results under interferences that express the overall effect as a sum of (i) the indirect (or spillover) effect and (ii) a contrast between two direct effects. PMID- 21532911 TI - Signaling and Dynamics of Activation of LFA-1 and Mac-1 by Immobilized IL-8. AB - The dynamic response of neutrophils to interleukin-8 (IL-8) is of central interest in inflammation. Chemokine -induced beta(2) integrin dependent adhesion can take several minutes after initial contact with IL-8 as evidenced by increased cell adhesion to intracellular adhesion molecule 1 (ICAM-1). The goal of this study is to identify signaling events that are critical for this response. We demonstrate that neither the PI3K inhibitor wortmannin, nor the PKC inhibitor bisindolymaleimide had any effect on IL-8 induced adhesion to ICAM-1. However, inhibition of PLC with U73122 or stopping the release of intracellular calcium by its downstream effector IP3 with caffeine or 2-aminoethoxydiphenyl borate completely blocked the adhesive response. Chelation of intracellular calcium with BAPTA or extracellular calcium with EGTA completely abrogated neutrophil adhesion to ICAM-1. This adhesion is mediated by LFA-1 (alpha(L)beta(2)) within first 300 seconds after chemokine stimulation, followed by Mac-1 (alpha(M)beta(2)) mediated adhesion, beginning 350 seconds after stimulus. Inhibition of p38MAP kinase results in a time course similar to Mac-1 inhibition, consistent with published evidence that Mac-1 mediated adhesion is p38MAP kinase dependent. These findings confirm a PLC dependent, PKC independent pathway from chemokine stimulus to integrin activation previously identified in other cell types, and demonstrate distinct dynamics and different requirements for LFA-1 vs. Mac-1 activation in primary human neutrophils. PMID- 21532913 TI - Advocacy Recruiting for Huntington's Disease Clinical Trials. AB - Recent clinical trials for Huntington's disease (HD) have been slowed by the inability to complete enrollment in a timely manner. We report a successful advocacy-based recruiting approach at Evergreen Neuroscience Institute, a new Huntington Study Group (HSG) investigative site that lacked an HD patient base. By partnering with community advocates and utilizing web-based advocacy group alerts, Evergreen ranked third of 27 North American sites conducting the Study of ACR16 for the Treatment of Huntington's disease (HART) for number of participants, and first for rate of recruitment -- all while decreasing the time and financial resources needed for site-based recruiting. To our knowledge this is the first published outcome study for advocacy recruiting in any disease population. PMID- 21532914 TI - ADAPTIVE BEHAVIORS IN YOUNG CHILDREN: A UNIQUE CULTURAL COMPARISON IN ITALY. AB - On account of a series of unique historical events, the present-day denizens of South Tyrol inhabit a cultural, political, and linguistic autonomous region that intercalates Italians and Austrian/German Italians. We compared contemporary Italian and Austrian/German Italian girls' and boys' adaptive behaviors in everyday activities in this region. Using the Vineland Adaptive Behavior Scales, we first interviewed mothers about their children's communication, daily living, socialization, and motor skills. Main effects of local culture (and no interactions with gender) emerged: Austrian/German Italian children were rated higher than Italian children in both adaptive daily living and socialization skills. Next, we explored ethnic differences in childrearing. Austrian/German Italians reported fostering greater autonomy in their children than Italians, and children's autonomy was associated with their adaptive behavior. Children living in neighboring Italian and Austrian/German Italian cultural niches appear to experience subtle but consequentially different conditions of development that express themselves in terms of differing levels of adaptive behaviors. PMID- 21532915 TI - Emotion Socialization by Mothers and Fathers: Coherence among Behaviors and Associations with Parent Attitudes and Children's Social Competence. AB - This study examined interrelations among different types of parental emotion socialization behaviors in 88 mothers and 76 fathers (co-residing with participating mothers) of 8-year-old children. Parents completed questionnaires assessing emotion socialization behaviors, emotion-related attitudes, and their children's social functioning. An observed parent-child emotion discourse task and a child social-problem solving interview were also performed. Parent gender differences and concordance within couples in emotion socialization behaviors were identified for some but not all behaviors. Fathers' reactions to child emotion, family expressiveness, and fathers' emotion coaching during discussion cohered, and a model was supported in which the commonality among these behaviors was predicted by fathers' emotion-coaching attitudes, and was associated with children's social competence. A cohesive structure for the emotion socialization construct was less clear for mothers, although attitudes predicted all three types of emotion socialization behavior (reactions, expressiveness, and coaching). Implications for developmental theory and for parent-focused interventions are discussed. PMID- 21532916 TI - All-comers versus enrichment design strategy in phase II trials. AB - Designs for biomarker validation have been proposed and utilized in the Phase III oncology clinical trial setting. Broadly speaking, these designs follow either an enrichment (i.e., targeted) strategy or an all-comers (i.e., unselected) strategy. An enrichment design screens patients for the presence or absence of a marker or a panel of markers, and then only includes patients who either have or do not have a certain marker characteristic or profile. In contrast, all patients meeting the eligibility criteria (regardless of a particular biomarker status) are entered into an all-comers design. The strength of the preliminary evidence, the prevalence of the marker, the reproducibility and validity of the assay and the feasibility of real time marker assessment play a major role in the choice of the design. In this report, we discuss the parameters under which the enrichment or an all-comers design strategy would be appropriate for Phase II trials. PMID- 21532917 TI - Patient exposures and consequent risks from nuclear medicine procedures. PMID- 21532918 TI - Association between alcohol use and HIV viral load. PMID- 21532919 TI - Joint trajectories for social and physical aggression as predictors of adolescent maladjustment: internalizing symptoms, rule-breaking behaviors, and borderline and narcissistic personality features. AB - This investigation examined the relation between developmental trajectories jointly estimated for social and physical aggression and adjustment problems at age 14. Teachers provided ratings of children's social and physical aggression in Grades 3, 4, 5, 6, and 7 for a sample of 255 children (131 girls, 21% African American, 52% European American, 21% Mexican American). Participants, parents, and teachers completed measures of the adolescent's adjustment to assess internalizing symptoms, rule-breaking behaviors, and borderline and narcissistic personality features. Results showed that membership in a high and rising trajectory group predicted rule-breaking behaviors and borderline personality features. Membership in a high desister group predicted internalizing symptoms, rule-breaking behaviors, and borderline and narcissistic personality features. The findings suggest that although low levels of social and physical aggression may not bode poorly for adjustment, individuals engaging in high levels of social and physical aggression in middle childhood may be at greatest risk for adolescent psychopathology, whether they increase or desist in their aggression through early adolescence. PMID- 21532920 TI - The efficacy of assertive community treatment to treat substance use. AB - BACKGROUND: Assertive Community Treatment (ACT) has been studied extensively in people with severe mental illness, but there have only been a few clinical trials in which substance use was one of the measured outcomes. OBJECTIVE: The goal of this article was to describe the efficacy of ACT in treating co-occurring substance use disorders and suggest approaches to make it more efficacious. DESIGN: A literature review was conducted and randomized clinical trials describing ACT's impact on substance use were reviewed. RESULTS: Four randomized clinical trials of ACT that measured substance abuse adequately were identified, all of which showed small to no effect on substance abuse compared with control conditions. Methodological issues might account for the small effects. ACT might further reduce substance use by being paired with evidenced-based substance abuse treatment, helping clients become housed or helping them manage their money better. CONCLUSION: Integrated ACT, in which the ACT team provides substance abuse counseling, has the potential to reduce substance use by several mechanisms, but this has been difficult to demonstrate in clinical trials when participants in control groups receive similar interventions. PMID- 21532921 TI - RELN rs7341475 and schizophrenia risk: confusing, yet somehow intriguing. PMID- 21532922 TI - Nonstandard work schedules and developmentally generative parenting practices: An application of propensity score techniques. AB - Data from the National Institute for Child Health and Human Development (NICHD) Study of Early Child Care (Phase I) and propensity score techniques were used to determine if working fulltime in a nonstandard schedule job during the child's first year predicted parenting practices over 3 years. Results indicated that women who worked fulltime in a nonstandard schedule job during the first year had poorer maternal sensitivity at 24 and 36 months. Modest differences in HOME scores were also observed at 36 months. The results provide strong evidence that fulltime maternal employment in nonstandard schedule jobs may interfere with the creation and maintenance of developmentally generative parenting practices. PMID- 21532923 TI - Development and characterization of novel derivatives of the antiepileptic drug lacosamide that exhibit far greater enhancement in slow inactivation of voltage gated sodium channels. AB - The novel antiepileptic drug, (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R) lacosamide, Vimpat((r)) ((R)-1)), was recently approved in the US and Europe for adjuvant treatment of partial-onset seizures in adults. (R)-1 preferentially enhances slow inactivation of voltage-gated Na(+) currents, a pharmacological process relevant in the hyperexcitable neuron. We have advanced a strategy to identify lacosamide binding partners by attaching affinity bait (AB) and chemical reporter (CR) groups to (R)-1 to aid receptor detection and isolation. We showed that select lacosamide AB and AB&CR derivatives exhibited excellent activities similar to (R)-1 in the maximal electroshock seizure model in rodents. Here, we examined the effect of these lacosamide AB and AB&CR derivatives and compared them with (R)-1 on Na(+) channel function in CNS catecholaminergic (CAD) cells. Using whole-cell patch clamp electrophysiology, we demonstrated that the test compounds do not affect the Na(+) channel fast inactivation process, that they were far better modulators of slow inactivation than (R)-1, and that modulation of the slow inactivation process was stereospecific. The lacosamide AB agents that contained either an electrophilic isothiocyanate ((R)-5) or a photolabile azide ((R)-8) unit upon AB activation gave modest levels of permanent Na(+) channel slow inactivation, providing initial evidence that these compounds may have covalently reacted with their cognate receptor(s). Our findings support the further use of these agents to delineate the (R)-1-mediated Na(+) channel slow inactivation process. PMID- 21532924 TI - Impact of Adolescent Alcohol and Drug Use on Neuropsychological Functioning in Young Adulthood: 10-Year Outcomes. AB - BACKGROUND: Alcohol and other substance use disorders (AUD/SUD) are common among youth and often continue into adulthood; therefore, the neurocognitive effects of substance use are of great concern. Because neuromaturation continues into young adulthood, youth with AUD/SUD may be at risk for lasting cognitive decrements. This study prospectively examines neuropsychological functioning over 10 years as a function of AUD/SUD history and outcomes. METHODS: The 51 participants consisted of 18 youth with persisting AUD/SUD, 19 youth with remitted AUD/SUD, and 14 community youth with no AUD/SUD history followed over 10 years (ages 16 to 27 on average) with neuropsychological testing and substance use interviews on 8 occasions. Neuropsychological performance from baseline to 10-year follow-up was compared between the three groups. RESULTS: Despite scoring higher than controls at intake, both AUD/SUD groups showed a relative decline in visuospatial construction at 10-year follow-up (p=.001). Regressions showed that alcohol use (beta=-.33, p < .01) and drug withdrawal symptoms (beta=-.31, p<.05) over follow up were predictive of year 10 visuospatial function. Alcohol use also predicted verbal learning and memory (beta=-.28, p<.05), while stimulant use predicted visual learning and memory function (beta=-.33, p=.01). More recent substance use was associated with poorer executive function (beta=.28, p<.05). DISCUSSION: These findings confirm prior studies suggesting that heavy, chronic alcohol and other substance use persisting from adolescence to young adulthood may produce cognitive disadvantages, primarily in visuospatial and memory abilities. Youth who chronically consume heavy quantities of alcohol and/or experience drug withdrawal symptoms may be particularly at risk for cognitive deterioration by young adulthood. PMID- 21532925 TI - Time-reversed ultrasonically encoded optical focusing into scattering media. AB - Light focusing plays a central role in biomedical imaging, manipulation, and therapy. In scattering media, direct light focusing becomes infeasible beyond one transport mean free path. All previous methods1-3 to overcome this diffusion limit lack a practical internal "guide star."4 Here we proposed and experimentally validated a novel concept, called Time-Reversed Ultrasonically Encoded (TRUE) optical focusing, to deliver light into any dynamically defined location inside a scattering medium. First, diffused coherent light is encoded by a focused ultrasonic wave to provide a virtual internal "guide star"; then, only the encoded light is time-reversed and transmitted back to the ultrasonic focus. The TRUE optical focus-defined by the ultrasonic wave-is unaffected by multiple scattering of light. Such focusing is especially desirable in biological tissue where ultrasonic scattering is ~1000 times weaker than optical scattering. Various fields including biomedical and colloidal optics can benefit from TRUE optical focusing. PMID- 21532926 TI - Racial Prejudice and Spending on Drug Rehabilitation: The Role of Attitudes Toward Blacks and Latinos. AB - We enhance understanding of the prejudice-induced "color coding" phenomenon among whites by determining whether racial and ethnic prejudices are associated with a previously unexplored policy outcome, spending on drug rehabilitation. We examine attitudes toward both blacks and Latinos; the latter is a group largely ignored in previous research. We assess the impact of several types of racial/ethnic views, including those that manifest modern/indirect prejudice (e.g., stereotypes about violence, individualistic causal attributions) and those that reflect social-distance-based traditional prejudice (opposition to residential proximity and to interracial marriage). These relationships are examined using data from the General Social Survey. Bivariate results support the linkage between both traditional and modern prejudice and rehabilitation spending. Logistic regression analyses also indicate that support for rehabilitation is racialized: Attributing race differences in socioeconomic outcomes to "structural" factors, namely discrimination and lack of chance for education, is associated with believing rehabilitation spending is inadequate, controlling for the effects of other racial/ethnic attitudes and background factors. The relationship between this measure of modern prejudice and the outcome is consistent with color coding. The implications of the findings are discussed, and suggestions for future research that further examine the scope of color coding are offered. PMID- 21532927 TI - Recent developments in functional and structural imaging of aphasia recovery after stroke. AB - BACKGROUND: Functional and structural neuroimaging techniques can increase our knowledge about the neural processes underlying recovery from post-stroke language impairments (aphasia). AIMS: In the present review we highlight recent developments in neuroimaging research of aphasia recovery. MAIN CONTRIBUTION: We review (a) cross-sectional findings in aphasia with regard to local brain functions and functional connectivity, (b) structural and functional imaging findings using longitudinal (intervention) paradigms, (c) new adjunct treatments that are guided by functional imaging techniques (e.g., electrical brain stimulation) and (d) studies related to the prognosis of language recovery and treatment responsiveness after stroke. CONCLUSIONS: More recent developments in data acquisition and analysis foster better understanding and more realistic modelling of the neural substrates of language recovery after stroke. Moreover, the combination of different neuroimaging protocols can provide converging evidence for neuroplastic brain remodelling during spontaneous and treatment induced recovery. Researchers are also beginning to use sophisticated imaging analyses to improve accuracy of prognosis, which may eventually improve patient care by allowing for more efficient treatment planning. Brain stimulation techniques offer a new and exciting way to improve the recovery potential after stroke. PMID- 21532928 TI - In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery. AB - INTRODUCTION: Microdialysis is an important in vivo sampling technique, useful in the assay of extracellular tissue fluid. The technique has both pre-clinical and clinical applications but is most widely used in neuroscience. The in vivo microdialysis technique allows measurement of neurotransmitters such as acetycholine (ACh), the biogenic amines including dopamine (DA), norepinephrine (NE) and serotonin (5-HT), amino acids such as glutamate (Glu) and gamma aminobutyric acid (GABA), as well as the metabolites of the aforementioned neurotransmitters, and neuropeptides in neuronal extracellular fluid in discrete brain regions of laboratory animals such as rodents and non-human primates. AREAS COVERED: In this review we present a brief overview of the principles and procedures related to in vivo microdialysis and detail the use of this technique in the pre-clinical measurement of drugs designed to be used in the treatment of chemical addiction, neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and as well as psychiatric disorders such as attention deficit/hyperactivity disorder (ADHD) and schizophrenia. This review offers insight into the tremendous utility and versatility of this technique in pursuing neuropharmacological investigations as well its significant potential in rational drug discovery. EXPERT OPINION: In vivo microdialysis is an extremely versatile technique, routinely used in the neuropharmacological investigation of drugs used for the treatment of neurological disorders. This technique has been a boon in the elucidation of the neurochemical profile and mechanism of action of several classes of drugs especially their effects on neurotransmitter systems. The exploitation and development of this technique for drug discovery in the near future will enable investigational new drug candidates to be rapidly moved into the clinical trial stages and to market thus providing new successful therapies for neurological diseases that are currently in demand. PMID- 21532930 TI - Prototype Personality Diagnosis in Clinical Practice: A Viable Alternative for DSM-V and ICD-11. AB - Several studies suggest that a prototype matching approach yields diagnoses of comparable validity to the more complex diagnostic algorithms outlined in DSM-IV. Furthermore, clinicians prefer prototype diagnosis of personality disorders (PDs) to the current categorical diagnostic system or alternative dimensional methods. An important extension of this work is to investigate the degree to which clinicians are able to make prototype diagnoses reliably. The aim of this study is to assess the inter-rater reliability of a prototype matching approach to personality diagnosis in clinical practice. Using prototypes derived empirically in prior research, outpatient clinicians diagnosed patients' personality after an initial evaluation period. External evaluators independently diagnosed the same patients after watching videotapes of the same clinical hours. Inter-rater reliability for prototype diagnosis was high, with a median r = .72. Cross correlations between disorders were low, with a median r = .01. Clinicians and clinically trained independent observers can assess complex personality constellations with high reliability using a simple prototype matching procedure, even with prototypes that are relatively unfamiliar to them. In light of its demonstrated reliability, efficiency, and versatility, prototype diagnosis appears to be a viable system for DSM-V and ICD-11 with exceptional utility for research and clinical practice. PMID- 21532929 TI - Perspectives on biological growth and remodeling. AB - The continuum mechanical treatment of biological growth and remodeling has attracted considerable attention over the past fifteen years. Many aspects of these problems are now well-understood, yet there remain areas in need of significant development from the standpoint of experiments, theory, and computation. In this perspective paper we review the state of the field and highlight open questions, challenges, and avenues for further development. PMID- 21532931 TI - Virtual Screening with AutoDock: Theory and Practice. AB - IMPORTANCE TO THE FIELD: Virtual screening is a computer-based technique for identifying promising compounds to bind to a target molecule of known structure. Given the rapidly increasing number of protein and nucleic acid structures, virtual screening continues to grow as an effective method for the discovery of new inhibitors and drug molecules. AREAS COVERED IN THIS REVIEW: We describe virtual screening methods that are available in the AutoDock suite of programs, and several of our successes in using AutoDock virtual screening in pharmaceutical lead discovery. WHAT THE READER WILL GAIN: A general overview of the challenges of virtual screening is presented, along with the tools available in the AutoDock suite of programs for addressing these challenges. TAKE HOME MESSAGE: Virtual screening is an effective tool for the discovery of compounds for use as leads in drug discovery, and the free, open source program AutoDock is an effective tool for virtual screening. PMID- 21532932 TI - Why Early Intervention Works: A Systems Perspective. AB - A systems perspective is put forward designed to place the many diverse conceptual and practice approaches and accomplishments in the early intervention field within a common framework. Complex reciprocal patterns of influence are described emphasizing risk and protective factors operating at 3 levels: child social and cognitive competence, family patterns of interaction, and family resources. It is argued that this framework can provide an understanding with respect to why early intervention works when it does as well as establish a new assessment and intervention approach firmly grounded in developmental science. PMID- 21532934 TI - Mechanistic aspects of photooxidation of polyhydroxylated molecules on metal oxides. AB - Polyhydroxylated molecules, including natural carbohydrates, are known to undergo photooxidation on wide-gap transition metal oxides irradiated by ultraviolet light. In this study, we examine mechanistic aspects of this photoreaction on aqueous TiO(2), alpha-FeOOH, and alpha-Fe(2)O(3) particles using electron paramagnetic resonance (EPR) spectroscopy and site-selective deuteration. We demonstrate that the carbohydrates are oxidized at sites involved in the formation of oxo-bridges between the chemisorbed carbohydrate molecule and metal ions at the oxide surface. This bridging inhibits the loss of water (which is the typical reaction of the analogous free radicals in bulk solvent) promoting instead a rearrangement that leads to elimination of the formyl radical. For natural carbohydrates, the latter reaction mainly involves carbon-1, whereas the main radical products of the oxidation are radical arising from H atom loss centered on carbon-1, -2, and -3 sites. Photoexcited TiO(2) oxidizes all of the carbohydrates and polyols, whereas alpha-FeOOH oxidizes some of the carbohydrates, and alpha-Fe(2)O(3) is unreactive. These results serve as a stepping stone for understanding the photochemistry on mineral surfaces of more complex biomolecules such as nucleic acids. PMID- 21532933 TI - Intimate Partner Violence among Female Sex Workers in Two Mexico-U.S. Border Cities: Partner Characteristics and HIV Risk-behaviors as Correlates of Abuse. AB - Intimate partner violence (IPV) has been associated with greater vulnerability to HIV infection among women. We examined prevalence and correlates of IPV among female sex workers (FSWs) in Tijuana and Ciudad Juarez, two large Mexico-U.S. border cities where HIV prevalence is rising. Participants were 300 FSWs with a current spouse or a steady partner. Participants' mean age was 33 years, and mean number of years as a sex worker was 6 years. The prevalence of IPV in the past 6 months among participants was 35%. Using multivariate logistic regression, factors independently associated with IPV included having experienced abuse as a child, a partner who had sex with someone else, and lower sexual relationship power. Our findings suggest the need for previous abuse screening and violence prevention services for FSWs in the Mexico-U.S. border region. Careful consideration of relationship dynamics such as infidelity and relationship power is warranted when assessing for IPV risk. PMID- 21532935 TI - Integrating the Chronic Care Model into a Novel Medical Student Course. AB - OBJECTIVE: To determine if integration of the Chronic Care Model into undergraduate medical education is associated with anticipated use of the Model and if student perceptions match actual integration of the Model into their community projects. DESIGN: This was a cross-sectional study using qualitative and quantitative data. SETTING: A novel fourth-year medical student community health improvement course. METHOD: The study included 45 students who had enrolled in the course before introduction of the Model and 32 formally introduced to the Model through a lecture. Perceptions were measured through a survey and a focus group with data analyzed amongst and between cohorts. Projects were reviewed for actual integration of Model elements and these data were compared with reported student perceptions. RESULTS: Although they were in general utilizing most elements of the Model, student perceptions of their use of Model elements significantly differed from actual use of particular elements (p<0.001). For instance, whereas the majority believed that their projects focused on the element of Community Resources, most projects actually focused on Self-Management Support. Students formally introduced to the Model trended toward the belief that it would enhance their ability to care for patients more than students without formal exposure to it (p=0.0516). CONCLUSIONS: Although medical students may not recognize it, they may already focus their actions and thinking regarding health improvement toward patient self-management of their chronic disease. Although students require education and training if the Model is to be widely used, they may be naturally attracted to it. PMID- 21532936 TI - An ordinary differential equation based solution path algorithm. AB - Efron, Hastie, Johnstone and Tibshirani (2004) proposed Least Angle Regression (LAR), a solution path algorithm for the least squares regression. They pointed out that a slight modification of the LAR gives the LASSO (Tibshirani, 1996) solution path. However it is largely unknown how to extend this solution path algorithm to models beyond the least squares regression. In this work, we propose an extension of the LAR for generalized linear models and the quasi-likelihood model by showing that the corresponding solution path is piecewise given by solutions of ordinary differential equation systems. Our contribution is twofold. First, we provide a theoretical understanding on how the corresponding solution path propagates. Second, we propose an ordinary differential equation based algorithm to obtain the whole solution path. PMID- 21532937 TI - Drug-loaded, bivalent-bottle-brush polymers by graft-through ROMP. AB - Graft-through ring-opening metathesis polymerization (ROMP) using ruthenium N heterocyclic carbene catalysts has enabled the synthesis of bottle-brush polymers with unprecedented ease and control. Here we report the first bivalent-brush polymers; these materials were prepared by graft-through ROMP of drug-loaded polyethylene-glycol (PEG) based macromonomers (MMs). Anticancer drugs doxorubicin (DOX) and camptothecin (CT) were attached to a norbornene-alkyne-PEG MM via a photocleavable linker. ROMP of either or both drug-loaded MMs generated brush homo- and co-polymers with low polydispersities and defined molecular weights. Release of free DOX and CT from these materials was initiated by exposure to 365 nm light. All of the CT and DOX polymers were at least 10-fold more toxic to human cancer cells after photoinitiated drug release while a copolymer carrying both CT and DOX displayed 30-fold increased toxicity upon irradiation. Graft through ROMP of drug-loaded macromonomers provides a general method for the systematic study of structure-function relationships for stimuli-responsive polymers in biological systems. PMID- 21532938 TI - Response to Comment on "The Origins of Sexually Transmitted HIV Among Men Who Have Sex with Men" AB - In this investigation, we evaluated explanations for the unusual degree of genetic diversity in HIV populations within the sampled seminal cell and plasma compartments observed in our previous study. These analyses included clonal sequencing of HIV DNA in peripheral blood mononuclear cells, ultradeep sequencing of HIV RNA in blood plasma, human leukocyte antigen (HLA) haplotyping of previously used samples, and a BLAST screen against both a local and public repository of HIV-1 sequences, and the investigations to determine whether these observations were secondary to contamination or artifact were unsuccessful. As there are very few HIV sequences from seminal cell tissues and transmission pairs described in the literature, future studies that evaluate more transmission pairs with sampling from multiple anatomic compartments and at multiple time points will most likely be required to resolve this controversy. PMID- 21532939 TI - Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery? AB - INTRODUCTION: Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. AREAS COVERED: Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. EXPERT OPINION: While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and -independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics. PMID- 21532940 TI - Structural and socio-psychological influences on adolescents' educational aspirations and subsequent academic achievement. AB - Previous literature indicates that educational aspirations are an important predictor of achievement at school and beyond. This paper examines the factors that are associated with high educational aspirations. It also looks at the relationship between aspirations and achievement at the General Certificate of Secondary Education in a deprived area of London. The results show that educational aspirations are associated with individual characteristics. Girls were more likely than boys to express a wish to remain in education beyond the age of 16. For the most academic route post-16, there were substantial ethnic differences, with minority ethnic groups generally being more likely to state a desire to follow this path. Students who were eligible for free school meals tended to have lower aspirations. Socio-psychological variables were also shown to be of importance, particularly self-esteem and psychological distress. Importantly, educational aspirations had a strong association with actual achievement at age 16, remaining associated even after controlling for a number of other variables, including prior achievement. These findings are discussed in light of previous research and potential intervention strategies. PMID- 21532941 TI - Rapid Synthesis of Block and Cyclic Copolymers via Click Chemistry in the Presence of Copper Nanoparticles. AB - A new method for the rapid and efficient coupling of homopolymers to yield di- and triblock copolymers as well as cyclic polymers using the 3 + 2 pi Huisgen copper catalyzed cyclo-addition reaction has been developed. This facile method utilizes commercially available Cu nanoparticles that are tolerant to O(2), easily removable and recyclable. PMID- 21532942 TI - Syntheses of meta-[F]Fluorobenzaldehyde and meta-[F]Fluorobenzylbromide from Phenyl(3-Formylphenyl) Iodonium Salt Precursors. AB - (18)F-labeled fluorobenzaldehydes and fluorobenzylbromides are useful synthons for the preparation of PET radiopharmaceuticals. Whereas ortho- and para [(18)F]fluorobenzaldehydes can easily be prepared with high yields, the corresponding meta- derivatives are more problematic. In order to improve the yield of meta-[(18)F]fluorobenzaldehyde we used the corresponding diaryliodonium salt precursors, since diaryliodonium salts had already been used as precursors in preparations of (18)F-labeled electron rich, as well as electron deficient, aromatic rings. Diaryliodonium salts with different counter ions [PhIPhCHO]X (X = Cl, Br, OTs, OTf) were synthesized. (18)F radiolabeling was performed using different bases at different temperatures in the presence of a radical scavenger, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO). The best conversion (~80%) to meta [(18)F] fluorobenzaldehyde was obtained using CsHCO(3) base at a reaction temperature of 110 degrees C. To study iodonium salt counter ion effects on radiofluorination, each precursor was separately treated with CsF[(18)F]/CsHCO(3) in DMF at 110 degrees C for 5 min in the presence of TEMPO. Our observed reactivity order was OTs= 9 h on an average week night) was assessed once between 1997-1999, baseline for the present study, and once between 2002-2004, average follow-up 5.4 years. Cognitive function was measured (2002-2004) using 6 tests: verbal memory, inductive reasoning (Alice Heim 4-I), verbal meaning (Mill Hill), phonemic and semantic fluency, and the Mini Mental State Examination (MMSE). In analyses adjusted for age, sex, and education, and corrected for multiple testing, adverse changes in sleep between baseline and follow-up (decrease from 6, 7, or 8 h, increase from 7 or 8 h) were associated with lower scores on most cognitive function tests. Exceptions were memory, and, for a decrease from 6-8 h only, phonemic fluency. Further adjustment for occupational position attenuated the associations slightly. However, firm evidence remained for an association between an increase from 7 or 8 h sleep and lower cognitive function for all tests, except memory, and between a decrease from 6-8 h sleep and poorer reasoning, vocabulary, and the MMSE. The magnitude of these effects was equivalent to a 4-7 year increase in age. CONCLUSIONS: These results suggest that adverse changes in sleep duration are associated with poorer cognitive function in the middle-aged. PMID- 21532950 TI - Short or long sleep duration is associated with memory impairment in older Chinese: the Guangzhou Biobank Cohort Study. AB - STUDY OBJECTIVES: To examine the association between sleep-related factors and memory impairment. DESIGN: Cross-sectional study SETTING: Community-based study in Guangzhou, China. PARTICIPANTS: 28,670 older Chinese (20,776 women and 7,894 men) aged 50 to 85 years. MEASUREMENTS AND RESULTS: Demographic and socioeconomic data, sleep-related factors, and cognitive function were collected by face-to face interview. Potential confounders, such as employment and occupational status, smoking, alcohol and tea use, physical activity, self-rated health, anthropometry, blood pressure, and fasting plasma glucose and lipids were measured. After adjusting for multiple potential confounders, an inverted U shaped association between sleep duration and delayed word recall test (DWRT) score, a validated measure of memory impairment, was found, with 7 to 8 h of habitual sleep duration showing the highest score (P-values for trend from 3 to 7 h and from 7 to >= 10 h were all <= 0.001). Compared to sleep duration of 7 h, the adjusted odds ratio for memory impairment from the sleep duration of 3 to 4 or >= 10 h was 1.29 (95% confidence interval 1.07-1.56) and 1.52 (1.25-1.86), respectively. Subjects with daily napping, morning tiredness, or insomnia had significantly lower DWRT scores than those without (P ranged from < 0.001 to 0.01). CONCLUSIONS: Short or long sleep duration was an important sleep-related factor independently associated with memory impairment and may be a useful marker for increased risk of cognitive impairment in older people. PMID- 21532951 TI - Maximizing sensitivity of the psychomotor vigilance test (PVT) to sleep loss. AB - STUDY OBJECTIVES: The psychomotor vigilance test (PVT) is among the most widely used measures of behavioral alertness, but there is large variation among published studies in PVT performance outcomes and test durations. To promote standardization of the PVT and increase its sensitivity and specificity to sleep loss, we determined PVT metrics and task durations that optimally discriminated sleep deprived subjects from alert subjects. DESIGN: Repeated-measures experiments involving 10-min PVT assessments every 2 h across both acute total sleep deprivation (TSD) and 5 days of chronic partial sleep deprivation (PSD). SETTING: Controlled laboratory environment. PARTICIPANTS: 74 healthy subjects (34 female), aged 22-45 years. INTERVENTIONS: TSD experiment involving 33 h awake (N = 31 subjects) and a PSD experiment involving 5 nights of 4 h time in bed (N = 43 subjects). MEASUREMENTS AND RESULTS: In a paired t-test paradigm and for both TSD and PSD, effect sizes of 10 different PVT performance outcomes were calculated. Effect sizes were high for both TSD (1.59-1.94) and PSD (0.88-1.21) for PVT metrics related to lapses and to measures of psychomotor speed, i.e., mean 1/RT (response time) and mean slowest 10% 1/RT. In contrast, PVT mean and median RT outcomes scored low to moderate effect sizes influenced by extreme values. Analyses facilitating only portions of the full 10-min PVT indicated that for some outcomes, high effect sizes could be achieved with PVT durations considerably shorter than 10 min, although metrics involving lapses seemed to profit from longer test durations in TSD. CONCLUSIONS: Due to their superior conceptual and statistical properties and high sensitivity to sleep deprivation, metrics involving response speed and lapses should be considered primary outcomes for the 10-min PVT. In contrast, PVT mean and median metrics, which are among the most widely used outcomes, should be avoided as primary measures of alertness. Our analyses also suggest that some shorter-duration PVT versions may be sensitive to sleep loss, depending on the outcome variable selected, although this will need to be confirmed in comparative analyses of separate duration versions of the PVT. Using both sensitive PVT metrics and optimal test durations maximizes the sensitivity of the PVT to sleep loss and therefore potentially decreases the sample size needed to detect the same neurobehavioral deficit. We propose criteria to better standardize the 10-min PVT and facilitate between study comparisons and meta-analyses. PMID- 21532952 TI - Light-induced changes of the circadian clock of humans: increasing duration is more effective than increasing light intensity. AB - STUDY OBJECTIVES: To evaluate the effect of increasing the intensity and/or duration of exposure on light-induced changes in the timing of the circadian clock of humans. DESIGN: Multifactorial randomized controlled trial, between and within subject design SETTING: General Clinical Research Center (GCRC) of an academic medical center PARTICIPANTS: 56 healthy young subjects (20-40 years of age) INTERVENTIONS: Research subjects were admitted for 2 independent stays of 4 nights/3 days for treatment with bright or dim-light (randomized order) at a time known to induce phase delays in circadian timing. The intensity and duration of the bright light were determined by random assignment to one of 9 treatment conditions (duration of 1, 2, or 3 hours at 2000, 4000, or 8000 lux). MEASUREMENTS AND RESULTS: Treatment-induced changes in the dim light melatonin onset (DLMO) and dim light melatonin offset (DLMOff) were measured from blood samples collected every 20-30 min throughout baseline and post-treatment nights. Comparison by multi-factor analysis of variance (ANOVA) of light-induced changes in the time of the circadian melatonin rhythm for the 9 conditions revealed that changing the duration of the light exposure from 1 to 3 h increased the magnitude of light-induced delays. In contrast, increasing from moderate (2,000 lux) to high (8,000 lux) intensity light did not alter the magnitude of phase delays of the circadian melatonin rhythm. CONCLUSIONS: Results from the present study suggest that for phototherapy of circadian rhythm sleep disorders in humans, a longer period of moderate intensity light may be more effective than a shorter exposure period of high intensity light. PMID- 21532953 TI - The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response. AB - BACKGROUND: Although insomnia is a prevalent complaint with significant morbidity, it often remains unrecognized and untreated. Brief and valid instruments are needed both for screening and outcome assessment. This study examined psychometric indices of the Insomnia Severity Index (ISI) to detect cases of insomnia in a population-based sample and to evaluate treatment response in a clinical sample. METHODS: Participants were 959 individuals selected from the community for an epidemiological study of insomnia (Community sample) and 183 individuals evaluated for insomnia treatment and 62 controls without insomnia (Clinical sample). They completed the ISI and several measures of sleep quality, fatigue, psychological symptoms, and quality of life; those in the Clinical sample also completed sleep diaries, polysomnography, and interviews to validate their insomnia/good sleep status and assess treatment response. In addition to standard psychometric indices of reliability and validity, item response theory analyses were computed to examine ISI item response patterns. Receiver operating curves were used to derive optimal cutoff scores for case identification and to quantify the minimally important changes in relation to global improvement ratings obtained by an independent assessor. RESULTS: ISI internal consistency was excellent for both samples (Cronbach alpha of 0.90 and 0.91). Item response analyses revealed adequate discriminatory capacity for 5 of the 7 items. Convergent validity was supported by significant correlations between total ISI score and measures of fatigue, quality of life, anxiety, and depression. A cutoff score of 10 was optimal (86.1% sensitivity and 87.7% specificity) for detecting insomnia cases in the community sample. In the clinical sample, a change score of -8.4 points (95% CI: -7.1, -9.4) was associated with moderate improvement as rated by an independent assessor after treatment. CONCLUSION: These findings provide further evidence that the ISI is a reliable and valid instrument to detect cases of insomnia in the population and is sensitive to treatment response in clinical patients. PMID- 21532954 TI - Predictability of sleep in patients with insomnia. AB - STUDY OBJECTIVES: To evaluate whether the night-to-night variability in insomnia follows specific predictable patterns and to characterize sleep patterns using objective sleep and clinical variables. DESIGN: Prospective observational study. SETTING: University-affiliated sleep disorders center. PARTICIPANTS: 146 participants suffering from chronic and primary insomnia. MEASUREMENTS AND RESULTS: Daily sleep diaries were completed for an average of 48 days and self reported questionnaires once. Three nights were spent in the sleep laboratory for polysomnographic (PSG) assessment. Sleep efficiency, sleep onset latency, wake after sleep onset, and total sleep time were derived from sleep diaries and PSG. Time-series diary data were used to compute conditional probabilities of having an insomnia night after 1, 2, or 3 consecutive insomnia night(s). Conditional probabilities were submitted to a k-means cluster analysis. A 3-cluster solution was retained. One cluster included 38 participants exhibiting an unpredictable insomnia pattern. Another included 30 participants with a low and decreasing probability to have an insomnia night. The last cluster included 49 participants exhibiting a high probability to have insomnia every night. Clusters differed on age, insomnia severity, and mental fatigue, and on subjective sleep variables, but not on PSG sleep variables. CONCLUSION: These findings replicate our previous study and provide additional evidence that unpredictability is a less prevalent feature of insomnia than suggested previously in the literature. The presence of the 3 clusters is discussed in term of sleep perception and sleep homeostasis dysregulation. PMID- 21532955 TI - Longitudinal study of cognitive function in idiopathic REM sleep behavior disorder. AB - STUDY OBJECTIVES: To assess the longitudinal course of cognitive functions in a cohort of patients with idiopathic REM sleep behavior disorder (iRBD). DESIGN: Prospective study with baseline and 2-year follow-up. SETTING: Sleep disorders center. PARTICIPANTS: Twenty-four cognitively asymptomatic iRBD patients (18 M; mean age: 69.5 +/- 7.3 y) and 12 sex-, age-, and education-matched healthy subjects. INTERVENTIONS: Participants underwent to a video-PSG, a focused neuropsychological evaluation and a neurological examination. Following the first evaluation, subjects were reassessed after a mean interval of 25.8 months. MEASUREMENTS AND RESULTS: Executive functions, attention and language were normal at baseline and at 2 year follow-up examination. At baseline, iRBD patients showed poorer performance than controls in delayed verbal memory (story recall test: P = 0.001) and in visuo-constructional abilities (Copy of the Rey Osterrieth complex figure: P = 0.0005). At follow-up, they not only performed worse than controls in the same tests (story recall: P = 0.0001; Copy of the Rey Osterrieth complex figure: P = 0.0004), but they also showed an impairment in visuo-spatial learning (Corsi supraspan test; P < 0.0001). ANOVAs showed a significant worsening in visuo-spatial learning over time in RBD compared to controls (P = 0.0001). Furthermore, 3 patients fulfilled the UK Brain Bank criteria for Parkinson disease, but this was unrelated to cognitive deterioration. CONCLUSIONS: Although no patients developed dementia, the decline observed in some tests involving the memory and visuo-constructional domains in idiopathic RBD suggests the presence of an underlying evolving degenerative process. PMID- 21532956 TI - Presentations of primary hypersomnia in Chinese children. AB - OBJECTIVE: To retrospectively describe childhood presentations of primary hypersomnia with an emphasis on narcolepsy-cataplexy in a Chinese population. METHODS: A total of 417 children (< 18 years old) successively presenting with complaints of hypersomnia without anatomic cause or sleep apnea risk were evaluated using the Stanford Sleep Inventory, human leukocyte antigen (HLA) DQB1*0602 typing, and MSLT recordings. CSF hypocretin-1 was measured in 47 cases to document hypocretin deficiency. A subgroup ("narcolepsy/hypocretin deficiency") with likely hypocretin deficiency (low hypocretin-1 or HLA positive with clear-cut cataplexy) was further examined for presentations prior to, around, or after puberty. RESULTS: Narcolepsy with (n = 361) or without (n = 17) cataplexy presented at an earlier age and with increased male predominance when compared to idiopathic hypersomnia (n = 39, P < 0.01). Nearly 70% of those with narcolepsy/hypocretin deficiency (n = 271) had disease onset before age 10 y, and 15% had onset before age 6, an unusually young age distribution. Onset was prior to puberty in 78% of cases. Clinical features were similar in presentations across puberty groups except for sleep paralysis, which increased in frequency with age/puberty. Mean sleep latency (MSL) decreased and the number of sleep onset REM periods (SOREMPs) increased with age/puberty, but MSLT diagnosis criteria (MSL <= 8 min, >= 2 SOREMPs) were similarly positive across groups. Familial clustering was present in only 1.7% of probands. CONCLUSION: In children presenting with a complaint of primary hypersomnia to a sleep clinic in China, 86% (361/417) meet criteria for narcolepsy with cataplexy. Puberty did not affect positivity on the MSLT as a diagnostic feature. Sleep paralysis was the only symptom that increased with increasing age. In addition, narcolepsy with cataplexy in our clinic population appeared to begin at a younger age than usually reported in other studies. PMID- 21532957 TI - Factors that influence weekday sleep duration in European children. AB - STUDY OBJECTIVES: To compare nocturnal sleep duration in children from 8 European countries and identify its determinants. DESIGN: Cross-sectional. SETTING: Primary schools and preschools participating in the IDEFICS study. PARTICIPANTS: 8,542 children aged 2 to 9 years from 8 European countries with complete information on nocturnal sleep duration. INTERVENTIONS: Not applicable. MEASUREMENTS: Nocturnal sleep duration was assessed by means of a computer based parental 24-h recall. Data on personal, social, environmental, and behavioral factors were collected by means of standardized parental questionnaire. Physical activity was surveyed with accelerometers. RESULTS: Nocturnal sleep duration in the participating countries ranged from 9.5 h (SD 0.8) in Estonia to 11.2 h (SD 0.7) in Belgium and differed significantly between countries (P < 0.001) in univariate as well as in multivariate analyses, with children from northern countries sleeping the longest. Sleep duration decreased by about 6 min with each year of age over all countries. No effect of season, daylight duration, overweight, parental education level, or lifestyle factors could be seen. CONCLUSION: Sleep duration differs significantly between countries. Our findings allow for the conclusion that regional affiliation, including culture and environmental characteristics, seems to overlay individual determinants of sleep duration. PMID- 21532958 TI - Infant growth in length follows prolonged sleep and increased naps. AB - STUDY OBJECTIVES: The mechanisms underlying infant sleep irregularity are unknown. This study tests the hypothesis that sleep and episodic (saltatory) growth in infant length are temporally coupled processes. STUDY DESIGN: Daily parental diaries continuously recorded sleep onset and awakening for 23 infants (14 females) over 4-17 months (n = 5798 daily records). Multiple model independent methods compared day-to-day sleep patterns and saltatory length growth. MEASUREMENTS AND RESULTS: Approximate entropy (ApEn) quantified temporal irregularity in infant sleep patterns; breastfeeding and infant sex explained 44% of inter-individual variance (P = 0.001). Random effects mixed-model regression identified that saltatory length growth was associated with increased total daily sleep hours (P < 0.001) and number of sleep bouts (P = 0.001), with breastfeeding, infant sex, and age as covariates. Infant size and illness onset were non-contributory. CLUSTER analysis identified peaks in individual sleep of 4.5 more h and/or 3 more naps per day, compared to intervening intervals, that were non-randomly concordant with saltatory length growth for all individuals (P < 0.05), with a time lag of 0-4 days. Subject-specific probabilities of a growth saltation associated with sleep included a median odds ratio of 1.20 for each additional hour (n = 8, 95% CI 1.15 to 1.29) and 1.43 for each additional sleep bout (n = 12, 95% CI 1.21-2.03). Increased sleep bout duration predicted weight (P < 0.001) and abdominal skinfold accrual (P = 0.05) contingent on length growth, and truncal adiposity independent of growth (P < 0.001). CONCLUSIONS: Sleeping and length growth are temporally related biological processes, suggesting an integrated anabolic system. Infant behavioral state changes may reflect biological mechanisms underlying the timing and control of human growth. PMID- 21532959 TI - A review of evidence for the claim that children are sleeping less than in the past. AB - STUDY OBJECTIVES: The notion that children are sleeping less than they used to is widespread. This study examined the strength of the evidence for this idea by tracing a "scholarly genealogy" of the claims presented within the literature. DESIGN: A systematic review of peer-reviewed literature was conducted to identify claims of a secular trend in children's sleep. For each identified claim, the references cited were reviewed. MEASUREMENTS AND RESULTS: The review identified 51 studies. Of these, 17 evinced evidence (2 reported increases, 3 reported no change, 6 reported mixed trends, 6 reported decreases) and 34 provided statements without evidence. Although the evidence that sleep duration has declined is contested, all 34 studies reported a decline. Examination of the references cited revealed that 17 papers referred directly to studies which provided evidence, 4 papers referred indirectly to studies which provided evidence, 9 papers did not provide any evidence and 4 papers referred to studies which could not be located. Of the papers that did provide evidence, 85% referred to one of 3 sources of evidence, each of which was of moderate quality. CONCLUSIONS: The genealogy of the notion of secular declines in children's sleep reveals a limited scientific basis. The apparent evidence base is inflated by repeated references to the same sources of evidence, reference to secondary sources, mis-referencing, and a failure to cite contrary evidence. PMID- 21532960 TI - Habitual sleep/wake patterns in the Old Order Amish: heritability and association with non-genetic factors. AB - STUDY OBJECTIVES: We sought to evaluate the contribution of genetic and non genetic factors on habitual sleep/wake patterns in a community-dwelling agrarian population using a physical activity monitoring device, the Actical. DESIGN: Cross-sectional population-based study of healthy Old Order Amish enrolled in the Heredity and Phenotype Intervention (HAPI) Heart Study. SETTING: Lancaster County, PA, USA. PARTICIPANTS: 723 healthy adults (54% men) with a mean age of 43.3 +/- 13.8 years (range: 20-80). 96% of the subjects were connected into one 5 generation pedigree. INTERVENTIONS: N/A. MEASUREMENTS: Participants wore Actical accelerometers 24 hours/day for 7 days to determine physical activity level, as well as habitual wake time, bedtime, and sleep duration. Participants completed the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ), a modified Epworth Sleepiness Scale (ESS), and a lifestyle questionnaire. A sub-study of 164 participants kept sleep diaries. RESULTS: Habitual wake time and bedtime determined by Actical were highly correlated with results from sleep diaries (r = 0.82 for wake time and 0.72 for bedtime, both P < 0.0001). After adjustment for age, sex, occupation, and season, higher activity level was associated with earlier wake time but not with bedtime, and correspondingly with shorter sleep duration. After adjustment for the aforementioned factors and the effects of a shared household, habitual wake time, MEQ score, and ESS score showed significant heritability (wake time h(2) = 0.20, MEQ h(2) = 0.21, and ESS h(2) = 0.17). CONCLUSIONS: Objectively measured wake time, self-reported morningness eveningness preference, and daytime sleepiness appear heritable and wake time may be associated with physical activity level. PMID- 21532961 TI - Sleep-wake behavior in chronic fatigue syndrome. AB - STUDY OBJECTIVES: Disturbances of the internal biological clock manifest as fatigue, poor concentration, and sleep disturbances-symptoms reminiscent of chronic fatigue syndrome (CFS) and suggestive of a role for circadian rhythm disturbance in CFS. We examined circadian patterns of activity, sleep, and cortisol secretion in patients with CFS. DESIGN: Case-control study, 5-day behavioral observation. SETTING: Natural setting/home environment PARTICIPANTS: 15 patients with CFS and 15 healthy subjects of similar age, sex, body mass index (BMI), and activity levels. INTERVENTIONS: N/A. MEASUREMENTS: Self-report questionnaires were used to obtain medical history and demographic information and to assess health behaviors, somatic and psychological symptoms, and sleep quality. An actiwatch accelerometer recorded activity and sleep patterns over 5 days with concurrent activity and symptom logs. Diurnal salivary cortisol secretion was measured. Additionally, overnight heart rate monitoring and pain sensitivity assessment was undertaken. RESULTS: Ratings of symptoms, disability, sleep disturbance, and pain sensitivity were greater in patients with CFS. No between-group differences were found in the pattern or amount of sleep, activity, or cortisol secretion. Afternoon activity levels significantly increased evening fatigue in patients but not control subjects. Low nocturnal heart rate variability was identified as a biological correlate of unrefreshing sleep. CONCLUSIONS: We found no evidence of circadian rhythm disturbance in CFS. However, the role of autonomic activity in the experience of unrefreshing sleep warrants further assessment. The activity symptom-relationship modelled here is of clinical significance in the approach to activity and symptom management in the treatment of CFS. PMID- 21532962 TI - Do mice habituate to "gentle handling?" A comparison of resting behavior, corticosterone levels and synaptic function in handled and undisturbed C57BL/6J mice. AB - STUDY OBJECTIVES: "Gentle handling" has become a method of choice for 4-6 h sleep deprivation in mice, with repeated brief handling applied before sleep deprivation to induce habituation. To verify whether mice do indeed habituate, we assess how 6 days of repeated brief handling impact on resting behavior, on stress, and on the subunit content of N-methyl-D-aspartate receptors (NMDARs) at hippocampal synapses, which is altered by sleep loss. We discuss whether repeated handling biases the outcome of subsequent sleep deprivation. DESIGN: Adult C57BL/6J mice, maintained on a 12 h-12 h light-dark cycle, were left undisturbed for 3 days, then handled during 3 min daily for 6 days in the middle of the light phase. Mice were continuously monitored for their resting time. Serum corticosterone levels and synaptic NMDAR subunit composition were quantified. RESULTS: Handling caused a ~25% reduction of resting time throughout all handling days. After six, but not after one day of handling, mice had elevated serum corticosterone levels. Six-day handling augmented the presence of the NR2A subunit of NMDARs at hippocampal synapses. CONCLUSION: Repeated handling induces behavioral and neurochemical alterations that are absent in undisturbed animals. The persistently reduced resting time and the delayed increase in corticosterone levels indicate that mice do not habituate to handling over a 1-week period. Handling-induced modifications bias effects of gentle handling-induced sleep deprivation on sleep homeostasis, stress, glutamate receptor composition and signaling. A standardization of sleep deprivation procedures involving gentle handling will be important for unequivocally specifying how acute sleep loss affects brain function. PMID- 21532963 TI - Psychological Functioning of Children and Adolescents With Eosinophil-Associated Gastrointestinal Disorders. AB - This study examined health-related quality of life and adjustment among children with eosinophil- associated gastrointestinal disorders (EGID) compared with an age-matched sample without acute or chronic illness. Participants were youth ages 2 to 18 years. Children and caregivers completed measures of psychological symptoms and health-related quality of life (HRQOL). Significant group differences were found for child report of depressive, as well as anxiety symptoms. Significant group differences were also found for caregiver report of psychological symptoms and social skills. Finally, based on parent and youth report, HRQOL and greater school absenteeism were associated with EGID diagnosis. PMID- 21532965 TI - Adolescent Family Factors Promoting Healthy Adult Functioning: A Longitudinal Community Study. AB - BACKGROUND: Although long-held wisdom and current research suggests that accepting and supportive family relationships may positively influence adult psychosocial functioning, few studies have prospectively investigated these associations. This study examined whether positive family factors during adolescence are associated with healthy adult functioning. METHOD: The 353 participants were part of a single-age cohort whose psychosocial development has been prospectively traced. Two aspects of family functioning - feeling highly valued as a family member and having a family confidant - were measured at age 15. Developmentally-relevant areas of functioning were assessed at age 30. RESULTS: Both positive family factors were predictive of adaptive adult functioning across several domains, including mental health and social/interpersonal functioning. CONCLUSIONS: Findings provide evidence about the salient relationships between positive family relationships and later healthy functioning. PMID- 21532966 TI - Frontiers in Outreach and Education: The Florida Red Tide Experience. AB - To enhance information sharing and garner increased support from the public for scientific research, funding agencies now typically require that research groups receiving support convey their work to stakeholders. The National Institute of Environmental Health Sciences-(NIEHS) funded Aerosolized Florida Red Tide P01 research group (Florida Red Tide Research Group) has employed a variety of outreach strategies to meet this requirement. Messages developed from this project began a decade ago and have evolved from basic print material (fliers and posters) to an interactive website, to the use of video and social networking technologies, such as Facebook and Twitter. The group was able to track dissemination of these information products; however, evaluation of their effectiveness presented much larger challenges. The primary lesson learned by the Florida Red Tide Research Group is that the best ways to reach specific stakeholders is to develop unique products or services to address specific stakeholders needs, such as the Beach Conditions Reporting System. Based on the experience of the Group, the most productive messaging products result when scientific community engages potential stakeholders and outreach experts during the very initial phases of a project. PMID- 21532967 TI - The Inner Ear and its Coupling to the Swim Bladder in the Deep-Sea Fish Antimora rostrata (Teleostei: Moridae). AB - The inner ear structure of Antimora rostrata and its coupling to the swim bladder were analyzed and compared with the inner ears of several shallow-water species that also have similar coupling. The inner ear of Antimora has a long saccular otolith and sensory epithelium as compared to many other fishes. Some parts of the membranous labyrinth are thick and rigid, while other parts are thinner but attached tightly to the bony capsule. The partially rigid membranous labyrinth, along with its intimate connection to the swim bladder, may help the inner ear follow the sound oscillations from the swim bladder with better precision than would occur in a less rigid inner ear. In addition, the saccular sensory epithelium has an elaborate structure and an anterior enlargement that may be correlated with increased hearing sensitivity. Some of the features in the inner ear of Antimora may reflect the functional specialization of deep-water living and support the hypothesis that there is enhanced inner ear sensitivity in some deep-sea fishes. PMID- 21532964 TI - The Role of Obesity in Preeclampsia. AB - The incidence of obesity is increasing at an alarming rate. There is compelling evidence that obesity increases the risk of preeclampsia about 3-fold, and in developed countries is the leading attributable risk for the disorder. In this presentation we explore this relationship and propose targets for future studies guided by the much more extensively studied relationship of obesity to cardiovascular disease. We further address the hypothesis that asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, may be one convergence point for the mechanism by which obesity increases the risk of preeclampsia. We conclude with consideration of the clinical implications of this information. PMID- 21532969 TI - Testing and Validating Machine Learning Classifiers by Metamorphic Testing. AB - Machine Learning algorithms have provided core functionality to many application domains - such as bioinformatics, computational linguistics, etc. However, it is difficult to detect faults in such applications because often there is no "test oracle" to verify the correctness of the computed outputs. To help address the software quality, in this paper we present a technique for testing the implementations of machine learning classification algorithms which support such applications. Our approach is based on the technique "metamorphic testing", which has been shown to be effective to alleviate the oracle problem. Also presented include a case study on a real-world machine learning application framework, and a discussion of how programmers implementing machine learning algorithms can avoid the common pitfalls discovered in our study. We also conduct mutation analysis and cross-validation, which reveal that our method has high effectiveness in killing mutants, and that observing expected cross-validation result alone is not sufficiently effective to detect faults in a supervised classification program. The effectiveness of metamorphic testing is further confirmed by the detection of real faults in a popular open-source classification program. PMID- 21532968 TI - Ecological genetics and genomics of plant defenses: Evidence and approaches. AB - Herbivores exert significant selection on plants, and plants have evolved a variety of constitutive and inducible defenses to resist and tolerate herbivory. Assessing the genetic mechanisms that influence defenses against herbivores will deepen our understanding of the evolution of essential phenotypic traits.Ecogenomics is a powerful interdisciplinary approach that can address fundamental questions about the ecology and evolutionary biology of species, such as: which evolutionary forces maintain variation within a population? and What is the genetic architecture of adaptation? This field seeks to identify gene regions that influence ecologically-important traits, assess the fitness consequences under natural conditions of alleles at key quantitative trait loci (QTLs), and test how the abiotic and biotic environment affects gene expression.Here, we review ecogenomics techniques and emphasize how this framework can address long standing and emerging questions relating to anti-herbivore defenses in plants. For example, ecogenomics tools can be used to investigate: inducible vs. constitutive defenses; tradeoffs between resistance and tolerance; adaptation to the local herbivore community; selection on alleles that confer resistance and tolerance in natural populations; and whether different genes are activated in response to specialist vs. generalist herbivores and to different types of damage.Ecogenomic studies can be conducted with model species, such as Arabidopsis, or their relatives, in which case myriad molecular tools are already available. Burgeoning sequence data will also facilitate ecogenomic studies of non-model species. Throughout this paper, we highlight approaches that are particularly suitable for ecological studies of non-model organisms, discuss the benefits and disadvantages of specific techniques, and review bioinformatic tools for analyzing data.We focus on established and promising techniques, such as QTL mapping with pedigreed populations, genome wide association studies, transcription profiling strategies, population genomics, and transgenic methodologies. Many of these techniques are complementary and can be used jointly to investigate the genetic architecture of defense traits and selection on alleles in nature. PMID- 21532970 TI - Diverse Family Types and Out-Of-School Learning Time of Young School Age Children. AB - =Sources of differentials in out-of-school learning time between children in first marriage biological parent families and children in six nontraditional family types are identified. Analyses of time diaries reveal that children in four of the six nontraditional family types spend fewer minutes learning than do children in first marriage biological parent families. In all four cases, however, the differentials are explained by the presence of siblings age 18+, lower levels of family income, or younger maternal age. PMID- 21532972 TI - How do prescription opioid users differ from users of heroin or other drugs in psychopathology: results from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVES: To study substance use and psychiatric disorders among prescription opioid users, heroin users, and non-opioid drug users in a national sample of adults. METHODS: Analyses of data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N=43,093). RESULTS: Four groups were identified among 9140 illicit or non-prescribed drug users: heroin-other opioid users (1.0%; used heroin and other opioids), other opioid-only users (19.8%; used other opioids but never heroin), heroin-only users (0.5%; used heroin but never other opioids), and non-opioid drug users (78.7%; used drugs but never heroin or other opioids). After adjusting for variations in socioeconomic characteristics, history of substance abuse treatment, and familial substance abuse, heroin-other opioid users had greater odds of several substance use disorders (cocaine, hallucinogen, sedative, amphetamine, and tranquilizer) as compared with the other groups; heroin-only users had reduced odds of sedative and tranquilizer use disorders as compared with other opioid-only users. Non-opioid drug users had reduced odds of all substance use disorders and other mental disorders (mood, anxiety, pathological gambling, and personality) as compared with other opioid only users. Past-year other opioid-only users also reported slightly lower scores on quality of life than past-year non-opioid drug users. CONCLUSIONS: All opioid use groups had higher rates of substance use disorders than non-opioid drug users, and these rates were particularly elevated among heroin-other opioid users. Findings suggest the need to distinguish between these four groups in research and treatment as they may have different natural histories and treatment needs. PMID- 21532971 TI - Rare Cell Capture in Microfluidic Devices. AB - This article reviews existing methods for the isolation, fractionation, or capture of rare cells in microfluidic devices. Rare cell capture devices face the challenge of maintaining the efficiency standard of traditional bulk separation methods such as flow cytometers and immunomagnetic separators while requiring very high purity of the target cell population, which is typically already at very low starting concentrations. Two major classifications of rare cell capture approaches are covered: (1) non-electrokinetic methods (e.g., immobilization via antibody or aptamer chemistry, size-based sorting, and sheath flow and streamline sorting) are discussed for applications using blood cells, cancer cells, and other mammalian cells, and (2) electrokinetic (primarily dielectrophoretic) methods using both electrode-based and insulative geometries are presented with a view towards pathogen detection, blood fractionation, and cancer cell isolation. The included methods were evaluated based on performance criteria including cell type modeled and used, number of steps/stages, cell viability, and enrichment, efficiency, and/or purity. Major areas for improvement are increasing viability and capture efficiency/purity of directly processed biological samples, as a majority of current studies only process spiked cell lines or pre-diluted/lysed samples. Despite these current challenges, multiple advances have been made in the development of devices for rare cell capture and the subsequent elucidation of new biological phenomena; this article serves to highlight this progress as well as the electrokinetic and non-electrokinetic methods that can potentially be combined to improve performance in future studies. PMID- 21532973 TI - Foibles, Follies, and Fusion: Assessment of Statistical Label Fusion Techniques for Web-Based Collaborations using Minimal Training. AB - Labeling or parcellation of structures of interest on magnetic resonance imaging (MRI) is essential in quantifying and characterizing correlation with numerous clinically relevant conditions. The use of statistical methods using automated methods or complete data sets from several different raters have been proposed to simultaneously estimate both rater reliability and true labels. An extension to these statistical based methodologies was proposed that allowed for missing labels, repeated labels and training trials. Herein, we present and demonstrate the viability of these statistical based methodologies using real world data contributed by minimally trained human raters. The consistency of the statistical estimates, the accuracy compared to the individual observations and the variability of both the estimates and the individual observations with respect to the number of labels are discussed. It is demonstrated that the Gaussian based statistical approach using the previously presented extensions successfully performs label fusion in a variety of contexts using data from online (Internet based) collaborations among minimally trained raters. This first successful demonstration of a statistically based approach using "wild-type" data opens numerous possibilities for very large scale efforts in collaboration. Extension and generalization of these technologies for new application spaces will certainly present fascinating areas for continuing research. PMID- 21532974 TI - Covering more Territory to Fight Resistance: Considering Nurses' Role in Antimicrobial Stewardship. AB - The potential contribution nurses can make to the management of antimicrobials within an in-patient setting could impact on the development of antimicrobial resistance (AMR) and healthcare associated infections (HCAIs). Current initiatives promoting prudent antimicrobial prescribing and management have generally failed to include nurses, which subsequently limits the extent to which these strategies can improve patient outcomes. For antimicrobial stewardship (AS) programmes to be successful, a sustained and seamless level of monitoring and decision making in relation to antimicrobial therapy is needed. As nurses have the most consistent presence as patient carer, they are in the ideal position to provide this level of service. However, for nurses to truly impact on AMR and HCAIs through increasing their profile in AS, barriers and facilitators to adopting this enhanced role must be contextualised in the implementation of any initiative. PMID- 21532975 TI - Ligniera junci, a plasmodiophorid re-discovered in roots of Juncus in Austria. AB - Ligniera junci, a plasmodiophorid parasite of Juncus spp. was found at three locations in Tyrol. The morphologically similar plasmodiophorid of Poaceae Polymyxa graminis was found to co-occur at two of these locations. This is the first record of these species in Austria. Colour photographs of resting spores of Ligniera junci in roots of Juncus triglumis and Polymyxa graminis in roots of Poaceae are given. A description of Ligniera junci supported by light micrographs of different stages of the life-cycle (sporosori, zoosporangia, zoospores) is presented. PMID- 21532976 TI - Long-term changes in tree-ring - climate relationships at Mt. Patscherkofel (Tyrol, Austria) since the mid 1980s. AB - Although growth limitation of trees at Alpine and high-latitude timberlines by prevailing summer temperature is well established, loss of thermal response of radial tree growth during last decades has repeatedly been addressed. We examined long-term variability of climate-growth relationships in ring width chronologies of Stone pine (Pinus cembra L.) by means of moving response functions (MRF). The study area is situated in the timberline ecotone (c. 2000 - 2200 m a.s.l.) on Mt. Patscherkofel (Tyrol, Austria). Five site chronologies were developed within the ecotone with constant sample depth (>= 19 trees) throughout most of the time period analysed. MRF calculated for the period 1866-1999 and 1901-1999 for c. 200 and c. 100 yr old stands, respectively, revealed that mean July temperature is the major and long-term stable driving force of Pinus cembra radial growth within the timberline ecotone. However, since the mid 1980s, radial growth in timberline and tree line chronologies strikingly diverges from the July temperature trend. This is probably a result of extreme climate events (e.g. low winter precipitation, late frost) and/or increasing drought stress on cambial activity. The latter assumption is supported by a < 10 % increase in annual increments of c. 50 yr old trees at the timberline and at the tree line in 2003 compared to 2002, when extraordinary hot and dry conditions prevailed during summer. Furthermore, especially during the second half of the 20(th) century, influence of climate variables on radial growth show abrupt fluctuations, which might also be a consequence of climate warming on tree physiology. PMID- 21532977 TI - Interaction Effects of the Amount of Practice, Preferred Cane Technique, and Type of Cane Technique Used on Drop-off Detection Performance. AB - This study examined the interaction effects of the amount of practice and the cane technique used in drop-off detection with a sample of 32 adults who were blind. The advantage of the constant contact technique over the two-point touch technique was significantly greater for the less experienced cane users than for the more experienced ones. PMID- 21532978 TI - Changes in private alcohol importation after alcohol tax reductions and import allowance increases in Denmark. AB - AIMS: This paper examines changes in alcohol import in Denmark between 2003 and 2006, after the excise tax on spirits in Denmark was lowered by 45% on October 1, 2003 and travellers' allowances for alcohol import were increased on January1, 2004. Additionally, the paper seeks to develop a profile of alcohol importers and analyse the relation between the distance to the German border and import behaviour, as Germany is the main alcohol import country for Denmark. DATA: Cross sectional and panel data from Denmark, from 2003 to 2006, were analyzed. Samples were collected by telephone interviews, using random digit dialing. RESULTS: While the percentage of people who imported alcohol fell over time, the amount of alcohol purchased rose for those who did import. Distance to the German border was inversely related to the likelihood of importing and the level of imported amounts. Heavy drinkers and those with higher incomes were more likely to import, and heavy drinkers imported higher amounts than moderate drinkers or abstainers. CONCLUSION: Distance of residence from the German border, socio-economic status and drinking behaviour are related to private alcohol import in Denmark. Policy changes resulted in a shift to fewer people importing higher amounts of alcohol so that the overall import level did not change substantially. PMID- 21532979 TI - Treatment of Adolescent Eating Disorders: Progress and Challenges. AB - OBJECTIVE: Although eating disorders are common psychiatric disorders that usually onset during adolescence, few evidence-based treatments for this age group have been identified. A critical review of treatments used for Anorexia Nervosa (AN) and Bulimia Nervosa (BN) and related conditions (EDNOS) is provided that summarizes the rationale for the treatments, evidence of effectiveness available, and outcomes. METHOD: Critical review of published randomized clinical trials (RCTs). RESULTS: There are only seven published RCTs of psychotherapy for AN in adolescents with a total of 480 subjects. There are only two published RCTs for outpatient psychotherapy for adolescent BN with a total of 165 subjects. There are no published RCTs examining medications for adolescent AN or BN. For adolescent AN, Family-Based Treatment (FBT) is the treatment with the most evidence supporting its use. Three RCTs suggest that FBT is superior to individual therapy at the end of treatment; however, at follow-up differences between individual and family approaches are generally reduced. For adolescent BN, one study found no differences between Cognitive Behavioral Therapy and FBT at the end of treatment or follow-up, while the other found FBT superior to individual therapy. CONCLUSIONS: Although the evidence remains limited, FBT appears to be the first line treatment for adolescent AN. There is little evidence to support a specific treatment for adolescent BN. There is a need for additional studies of treatment of child and adolescent eating disorders. New treatments studies may build on current evidence as well as examine new approaches based on novel findings in the neurosciences about cognitive and emotional processes in eating disorders. PMID- 21532980 TI - Alternatively Spliced Genes as Biomarkers for Schizophrenia, Bipolar Disorder and Psychosis: A Blood-Based Spliceome-Profiling Exploratory Study. AB - OBJECTIVE: Transcriptomic biomarkers of psychiatric diseases obtained from a query of peripheral tissues that are clinically accessible (e.g., blood cells instead of post-mortem brain tissue) have substantial practical appeal to discern the molecular subtypes of common complex diseases such as major psychosis. To this end, spliceome-profiling is a new methodological approach that has considerable conceptual relevance for discovery and clinical translation of novel biomarkers for psychiatric illnesses. Advances in microarray technology now allow for improved sensitivity in measuring the transcriptome while simultaneously querying the "exome" (all exons) and "spliceome" (all alternatively spliced variants). The present study aimed to evaluate the feasibility of spliceome profiling to discern transcriptomic biomarkers of psychosis. METHODS: We measured exome and spliceome expression in peripheral blood mononuclear cells from 13 schizophrenia patients, nine bipolar disorder patients, and eight healthy control subjects. Each diagnostic group was compared to each other, and the combined group of bipolar disorder and schizophrenia patients was also compared to the control group. Furthermore, we compared subjects with a history of psychosis to subjects without such history. RESULTS: After applying Bonferroni corrections for the 21,866 full-length gene transcripts analyzed, we found significant interactions between diagnostic group and exon identity, consistent with group differences in rates or types of alternative splicing. Relative to the control group, 18 genes in the bipolar disorder group, eight genes in the schizophrenia group, and 15 genes in the combined bipolar disorder and schizophrenia group appeared differentially spliced. Importantly, thirty-three genes showed differential splicing patterns between the bipolar disorder and schizophrenia groups. More frequent exon inclusion and/or over-expression was observed in psychosis. Finally, these observations are reconciled with an analysis of the ontologies, the pathways and the protein domains significantly over-represented among the alternatively spliced genes, several of which support prior discoveries. CONCLUSIONS: To our knowledge, this is the first blood-based spliceome-profiling study of schizophrenia and bipolar disorder to be reported. The battery of alternatively spliced genes and exons identified in this discovery oriented exploratory study, if replicated, may have potential utility to discern the molecular subtypes of psychosis. Spliceome-profiling, as a new methodological approach in transcriptomics, warrants further work to evaluate its utility in personalized medicine. Potentially, this approach could also permit the future development of tissue-sampling methodologies in a form that is more acceptable to patients and thereby allow monitoring of dynamic and time-dependent plasticity in disease severity and response to therapeutic interventions in clinical psychiatry. PMID- 21532981 TI - A Theoretical Investigation of the Ni(II)-Catalyzed Hydrovinylation of Styrene. AB - We report a detailed and full computational investigation on the hydrovinylation reaction of styrene with the Ni(II)-phospholane catalytic system, which was originally presumed to proceed through a cationic mechanism involving a nickel hydride intermediate. The following general features emerge from this study on a specific catalyst complex that was found to give quantitative yield and moderate selectivity: (a) the activation barrier for the initiation (18.8 kcal/mol) is higher than that for the reaction due to a low-lying square-planar pentenyl chelate intermediate originating from a Ni(II)-allyl catalyst precursor. Consequently there is an induction period for the catalysis; (b) the exit of product from the catalyst is via a beta-H-transfer step instead of the usual beta H elimination pathway, which has a very high activation energy due to a trans effect of the phospholane ligand; (c) the turnover-limiting and enantio- determining transition state is also the beta-H-transfer; (d) because of the absence of a hydride intermediate, the unwanted isomerization of the product is prevented; (e) since the enantio-discrimination is decided at the H-transfer stage itself, the configuration of the product in a catalytic cycle influences the enantioselectivity in the subsequent cycle; (f) the trans effect of the sole strong ligand in the d8 square-planar Ni(II), the stability of the eta(3)-benzyl intermediate, and the availability of three coordination sites enable regioselective hydrovinylation over the possible oligomerization/polymerization of the olefin substrates and linear hydrovinylation. This work has also confirmed the previously recognized role of the hemilabile group at various stages in the mechanism. PMID- 21532982 TI - The Mitoscriptome in Aging and Disease. AB - Mitochondria are the major sites where energy is produced in the cell. Functions of organs such as the heart which has high energy demand are seriously affected by dysfunction of mitochondria. The functional changes in energy-dependent organs such as heart due to aging or any other cause are expected to be reflected in changes in expression of genes related to mitochondrial structure and function. Conversely, alteration of mitochondrial gene expression by any reason may also adversely affect function of organs such as heart that are energy-dependent. Molecular profiling of mitochondrial gene expression is therefore critical to understanding the mechanism of organ dysfunction. Mitochondrial structure and function are controlled by genes in the nuclear DNA and those in the mitochondrial DNA (mtDNA). The transcriptome from these two sources, together, contributing to the structure and function of mitochondria may be called mitoscriptome. This review elaborates on data gathered using a gene chip, RoMitochip, developed in our laboratory to study mitochondrial functional alteration in cardiomyocytes and left ventricular tissue following hypoxia or hemorrhagic injury. RoMitochip consists of probesets representing genes from nuclear DNA and mtDNA of both mice and rats. Our experiments using this chip in in vitro model of hypoxia and in vivo hemorrhagic injury model determined mitoscriptome signatures following hypoxia and hemorrhage, respectively. In addition, we also discuss past initiatives from other investigators that led to the development of microarray tools to profile mitoscriptome. PMID- 21532983 TI - Psychological and behavioral implications of connectedness to communities with opposing values and beliefs. AB - Without a doubt, people can feel simultaneously connected to multiple communities (e.g., Deaux, 1993; Roccas & Brewer, 2002). But, to what degree can people feel simultaneously connected to communities with opposing beliefs and values? And, more importantly, what are the psychological implications of being dually connected to these communities? Capitalizing on a sample of individuals positioned to potentially feel connected to two very distinct communities, we examined jail inmates' (N = 256) sense of connectedness to the criminal community and to the community at large. Results indicated that (a) connectedness to the community at large is orthogonal to connectedness to the criminal community, supporting the supposition that it is possible to be dually connected to opposing communities; and (b) connectedness to the community at large moderated the relationship between criminal connectedness and indicators of psychological distress, suggesting that connectedness to the criminal community is especially problematic when it occurs in tandem with connectedness to the community at large. These findings are consistent with predictions from the self-expansion model. PMID- 21532984 TI - An unusual case of adrenal metastasis from colorectal cancer: computed tomography and fluorine 18-fluoro-deoxy-glucose positron emission tomography-computed tomography features and literature review. AB - Incidentally discovered adrenal masses are a common diagnostic problem. While computed tomography (CT) and magnetic resonance (MR) imaging can adequately characterize most benign or malignant adrenal masses, in some cases the results are indeterminate. We report and discuss a case of an adrenal metastasis with misleading clinical and CT features, in which an abnormal metabolic uptake detected through fluorine 18-fluoro-deoxy-glucose positron emission tomography ((18)F-FDG PET)-CT raised the suspicion of adrenal metastasis relatively early compared with apparently normal results on repeated follow-up CT examinations. PMID- 21532985 TI - Neurofibromatosis without Neurofibromas: Confirmation of a Genotype-Phenotype Correlation and Implications for Genetic Testing. AB - Neurofibromatosis type 1 (NF1) is a multisystem disease with autosomal dominant inheritance and complete penetrance diagnosed by clinical findings. Cutaneous neurofibromas are present in almost all adult patients in the dermis, epidermis or along the peripheral nerves. Plexiform neurofibromas are subcutaneous or deep lesions involving nerve plexuses or roots. Neurofibromas can degenerate into malignant tumors, with important prognostic implications. NF1 shows a broad clinic variability even within a single family. Exceptions are cases reporting the in-frame microdeletion c.2970_2972delAAT, presenting with the typical pigmentary features of NF1, but no cutaneous or plexiform neurofibromas. We report a patient with a de novo c.2970_2972delAAT mutation who had few cafe-au lait spots, only 2 of which measured >15 mm, axillary and submammary freckling, a flat angioma extending over the neck, arm and trunk, a high arched palate, micrognathia, macrocephaly, pes cavus and scoliosis. There was complete absence of observable cutaneous neurofibromas as well as external plexiform neurofibromas. She had had epileptic seizures since childhood; however, a diagnosis of NF1 had not been confirmed until she was 38, partly due to the paucity of characteristic cutaneous stigmata. We confirm the association of the c.2970_2972delAAT mutation in NF1 with a particular clinical phenotype, especially with lack of detectable neurofibromas. For an appropriate management of patients and family counseling, molecular study of the NF1 gene should be considered in patients not fulfilling NIH criteria when other features suggestive of NF1 are present. In the absence of neurofibromas, starting NF1 testing with the screening of exon 17 may be worthwhile. PMID- 21532986 TI - Systemic thrombolytic therapy alone and in combination with mechanical revascularization in acute ischemic stroke in two children. AB - Thrombolytic therapy is not recommended for acute ischemic stroke (AIS) in patients under the age of 18 and published experience is limited. In this case report, we describe two children treated with systemic thrombolytic therapy. One child received additional mechanical revascularization and achieved a good clinical outcome. The differences in the fibrinolytic system and the different etiology of AIS in childhood may limit a simple extrapolation of the adult guidelines for systemic thrombolytic therapy. Acute multimodal imaging to clarify the etiology of AIS might help to select the most appropriate treatment modality. PMID- 21532987 TI - Penetrating keratoplasty after radial keratotomy and recurrent immune overreaction. AB - A 32-year-old man suffering from keratoconus was treated with radial keratotomy. Twenty weeks later, he presented visual deterioration, edema and corneal perforation. A penetrating keratoplasty was required. The postoperative course was regular, but after 9 months, the patient presented kerato-uveitis. Subsequent phlogistic relapses occurred approximately every 6 months during the following 5 years. The performed cultures were positive only during the first episode. Radial keratotomy is not indicated in keratoconus. The multiple relapses of kerato uveitis could not be explained by infection, and we hypothesized that they may be due to a 'traumatic memory' of the cornea caused by the several suffered traumatisms, without clinical features of corneal graft rejection. The risks of new penetrating keratoplasty and cataract surgery are high. As the cornea is the tissue with the highest sensitivity in the body, we tried to explain the relapsing kerato-uveitis as a consequence of the disruption of the nervous corneal network. PMID- 21532988 TI - A mathematical model for foreign body reactions in 2D. AB - The foreign body reactions are commonly referred to the network of immune and inflammatory reactions of human or animals to foreign objects placed in tissues. They are basic biological processes, and are also highly relevant to bioengineering applications in implants, as fibrotic tissue formations surrounding medical implants have been found to substantially reduce the effectiveness of devices. Despite of intensive research on determining the mechanisms governing such complex responses, few mechanistic mathematical models have been developed to study such foreign body reactions. This study focuses on a kinetics-based predictive tool in order to analyze outcomes of multiple interactive complex reactions of various cells/proteins and biochemical processes and to understand transient behavior during the entire period (up to several months). A computational model in two spatial dimensions is constructed to investigate the time dynamics as well as spatial variation of foreign body reaction kinetics. The simulation results have been consistent with experimental data and the model can facilitate quantitative insights for study of foreign body reaction process in general. PMID- 21532989 TI - Functional expression of human adenine nucleotide translocase 4 in Saccharomyces cerevisiae. AB - The adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP across the inner mitochondrial membrane. The human genome encodes multiple ANT isoforms that are expressed in a tissue-specific manner. Recently a novel germ cell-specific member of the ANT family, ANT4 (SLC25A31) was identified. Although it is known that targeted depletion of ANT4 in mice resulted in male infertility, the functional biochemical differences between ANT4 and other somatic ANT isoforms remain undetermined. To gain insight into ANT4, we expressed human ANT4 (hANT4) in yeast mitochondria. Unlike the somatic ANT proteins, expression of hANT4 failed to complement an AAC-deficient yeast strain for growth on media requiring mitochondrial respiration. Moreover, overexpression of hANT4 from a multi-copy plasmid interfered with optimal yeast growth. However, mutation of specific amino acids of hANT4 improved yeast mitochondrial expression and supported growth of the AAC-deficient yeast on non-fermentable carbon sources. The mutations affected amino acids predicted to interact with phospholipids, suggesting the importance of lipid interactions for function of this protein. Each mutant hANT4 and the somatic hANTs exhibited similar ADP/ATP exchange kinetics. These data define common and distinct biochemical characteristics of ANT4 in comparison to ANT1, 2 and 3 providing a basis for study of its unique adaptation to germ cells. PMID- 21532990 TI - Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells. AB - Immunocytochemical studies have shown that protocadherin-15 (PCDH15) and cadherin 23 (CDH23) are associated with tip links, structures thought to gate the mechanotransducer channels of hair cells in the sensory epithelia of the inner ear. The present report describes functional and structural analyses of hair cells from Pcdh15(av3J) (av3J), Pcdh15(av6J) (av6J) and Cdh23(v2J) (v2J) mice. The av3J and v2J mice carry point mutations that are predicted to introduce premature stop codons in the transcripts for Pcdh15 and Cdh23, respectively, and av6J mice have an in-frame deletion predicted to remove most of the 9th cadherin ectodomain from PCDH15. Severe disruption of hair-bundle morphology is observed throughout the early-postnatal cochlea in av3J/av3J and v2J/v2J mice. In contrast, only mild-to-moderate bundle disruption is evident in the av6J/av6J mice. Hair cells from av3J/av3J mice are unaffected by aminoglycosides and fail to load with [(3)H]-gentamicin or FM1-43, compounds that permeate the hair cell's mechanotransducer channels. In contrast, hair cells from av6J/av6J mice load with both FM1-43 and [(3)H]-gentamicin, and are aminoglycoside sensitive. Transducer currents can be recorded from hair cells of all three mutants but are reduced in amplitude in all mutants and have abnormal directional sensitivity in the av3J/av3J and v2J/v2J mutants. Scanning electron microscopy of early postnatal cochlear hair cells reveals tip-link like links in av6J/av6J mice, substantially reduced numbers of links in the av3J/av3J mice and virtually none in the v2J/v2J mice. Analysis of mature vestibular hair bundles reveals an absence of tip links in the av3J/av3J and v2J/v2J mice and a reduction in av6J/av6J mice. These results therefore provide genetic evidence consistent with PCDH15 and CDH23 being part of the tip-link complex and necessary for normal mechanotransduction. PMID- 21532991 TI - p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. AB - Consistent with the excellent clinical results in testicular germ cell tumors (TGCT), most cell lines derived from this cancer show an exquisite sensitivity to Cisplatin. It is well accepted that the high susceptibility of TGCT cells to apoptosis plays a central role in this hypersensitive phenotype. The role of the tumor suppressor p53 in this response, however, remains controversial. Here we show that siRNA-mediated silencing of p53 is sufficient to completely abrogate hypersensitivity not only to Cisplatin but also to non-genotoxic inducers of p53 such as the Mdm2 antagonist Nutlin-3 and the proteasome inhibitor Bortezomib. The close relationship between p53 protein levels and induction of apoptosis is lost upon short-term differentiation, indicating that this predominant pro-apoptotic function of p53 is unique in pluripotent embryonal carcinoma (EC) cells. RNA interference experiments as well as microarray analysis demonstrated a central role of the pro-apoptotic p53 target gene NOXA in the p53-dependent apoptotic response of these cells. In conclusion, our data indicate that the hypersensitivity of TGCT cells is a result of their unique sensitivity to p53 activation. Furthermore, in the very specific cellular context of germ cell derived pluripotent EC cells, p53 function appears to be limited to induction of apoptosis. PMID- 21532993 TI - Late-onset anterior dislocation of a posterior chamber intraocular lens in a patient with pseudoexfoliation syndrome. AB - Here, we report on a patient with pseudoexfoliation syndrome who developed acute angle-closure glaucoma with a marked myopic shift due to anterior dislocation of the posterior chamber intraocular lens almost 16 months after an uneventful phacoemulsification. Examination with a Scheimpflug camera was extremely useful in confirming the diagnosis. This is the fist case of late-onset angle-closure glaucoma with a significant myopic shift due to anterior dislocation of the posterior chamber intraocular lens, which resulted in a permanent alteration of the postoperative target refraction. PMID- 21532992 TI - Trans-repression of gene activity upstream of T-DNA tagged RLK902 links Arabidopsis root growth inhibition and downy mildew resistance. AB - Receptor-like kinases (RLKs) constitute a large family of signal perception molecules in Arabidopsis. The largest group of RLKs is the leucine-rich repeat (LRR) class that has been described to function in development and defense. Of these, CLAVATA1 (CLV1) and ERECTA (ER) receptors function in maintaining shoot meristem homeostasis and organ growth, but LRR RLKs with similar function in the root remain unknown. For the interaction of Arabidopsis with the oomycete pathogen Hyaloperonospora arabidopsidis the involvement of LRR RLKs has not been demonstrated. A set of homozygous T-DNA insertion lines mutated in LRR RLKs was investigated to assess the potential role of these receptors in root meristem maintenance and compatibility. One mutant line, rlk902, was discovered that showed both reduced root growth and resistance to downy mildew in a recessive manner. The phenotypes of this mutated line could not be rescued by complementation, but are nevertheless linked to the T-DNA insertion. Microarray studies showed that gene expression spanning a region of approximately 84 kb upstream of the mutated gene was downregulated. The results suggest T-DNA mediated trans-repression of multiple genes upstream of the RLK902 locus links both phenotypes. PMID- 21532994 TI - Relapse of Vogt-Koyanagi-Harada Disease during Interferon-alpha and Ribavirin Therapy in a Case of Chronic Viral Hepatitis C. AB - A 60-year-old woman, who had been diagnosed with and treated for Vogt-Koyanagi Harada (VKH) disease 17 years before, was receiving pegylated interferon-? and ribavirin therapy for chronic hepatitis C virus. Three weeks after the start of therapy, she complained of visual blurring, eye pain, and an increased hearing loss. Based on a slit lamp and fundus examination, she was diagnosed with a relapse of VKH disease. After discontinuation of the pegylated interferon-alpha and ribavirin therapy and administration of corticosteroid therapy, her visual acuity returned to 1.0 in both eyes without ocular inflammation, and remained stable thereafter. When interferon therapy is administered to hepatitis C virus patients, those who also have a history of VKH disease must be closely monitored for ophthalmologic complications. PMID- 21532995 TI - Endogenous Klebsiella endophthalmitis associated with liver abscess: first case report from iran. AB - PURPOSE: To report the first case of endogenous Klebsiella endophthalmitis associated with liver abscess in Iran. CASE REPORT: A 79-year-old man was referred to our hospital due to severe pain and visual loss in the left eye. On physical examination, conjunctival hyperemia, corneal edema, hypopyon and severe vitreous cellular reaction were identified in the left eye; however, yellowish conjunctival discoloration was more apparent in the right eye. Abdominal CT scan showed a right liver lobe abscess that was confirmed by sonographically guided percutaneous liver mass biopsy. Blood, vitreous and liver mass aspirate cultures revealed Klebsiella pneumoniae growth. The patient was thus diagnosed with endogenous Klebsiella endophthalmitis secondary to bacteremia associated with liver abscess. CONCLUSION: This report suggests that, rather than being confined to Taiwan, endogenous endophthalmitis secondary to a liver abscess due to K. pneumoniae may be a global problem. Therefore, physicians should be aware of the possibility of endophthalmitis whenever a patient with K. pneumoniae liver abscess complains of ocular symptoms. PMID- 21532996 TI - Pars plana vitrectomy in advanced coats' disease. AB - PURPOSE: To report 5 cases of advanced Coats' disease managed with pars plana vitrectomy and silicone oil tamponade. METHODS: Five patients with advanced Coats' disease and serous or tractional retinal detachment underwent pars plana vitrectomy with internal drainage, endolaser photocoagulation and silicone oil tamponade. One patient had combined phacoemulsification-vitrectomy surgery. Of the 5 patients, 1 had intravitreal hemorrhage and a retinal macrocyst and 1 had a retinal cyst. Follow-up period was 1-6 years. RESULTS: All patients had improved visual acuity after surgery. No intraoperative or postoperative complications were observed in any of the patients. The retina was attached and the disease was stable in all patients during follow-up. Two patients had cataract formation, and in one of them the cataract was successfully managed with phacoemulsification surgery. CONCLUSION: Pars plana vitrectomy, subretinal fluid drainage, and long term silicone oil tamponade are effective methods in the management of advanced Coats' disease. Early and prompt management can prevent visual loss and secondary complications. PMID- 21532997 TI - Does Written Emotional Disclosure about Stress Improve College Students' Academic Performance? Results from Three Randomized, Controlled Studies. AB - Several early studies and subsequent reviews suggested that written emotional disclosure (WED)-writing repeatedly about personal stressful experiences-leads to improved academic performance of college students. Yet a critical review of available studies casts some doubt on this, so we conducted three randomized, controlled experiments of the effects of WED versus control writing on grade point average (GPA) of college students. In all three studies, WED writing was implemented effectively-it contained more negative emotion language and generated more negative mood than did control writing. In Study 1, WED did not influence GPA during either the writing semester or subsequent semester among 96 students with headaches. In Study 2, WED had no effect on GPA compared with either control writing or no writing conditions among 124 students with unresolved stress. In Study 3, WED did not influence GPA or retention among 68 academically at-risk ethnic minority students, although secondary analyses suggested some benefits of WED among students who wrote more than once, particularly men. These three studies challenge the belief that WED improves academic performance of college students, and research should examine subgroups of students who might benefit from WED. PMID- 21532998 TI - A generalized linear mixed model for longitudinal binary data with a marginal logit link function. AB - Longitudinal studies of a binary outcome are common in the health, social, and behavioral sciences. In general, a feature of random effects logistic regression models for longitudinal binary data is that the marginal functional form, when integrated over the distribution of the random effects, is no longer of logistic form. Recently, Wang and Louis (2003) proposed a random intercept model in the clustered binary data setting where the marginal model has a logistic form. An acknowledged limitation of their model is that it allows only a single random effect that varies from cluster to cluster. In this paper, we propose a modification of their model to handle longitudinal data, allowing separate, but correlated, random intercepts at each measurement occasion. The proposed model allows for a flexible correlation structure among the random intercepts, where the correlations can be interpreted in terms of Kendall's tau. For example, the marginal correlations among the repeated binary outcomes can decline with increasing time separation, while the model retains the property of having matching conditional and marginal logit link functions. Finally, the proposed method is used to analyze data from a longitudinal study designed to monitor cardiac abnormalities in children born to HIV-infected women. PMID- 21532999 TI - A Field-Based Testing Protocol for Assessing Gross Motor Skills in Preschool Children: The CHAMPS Motor Skills Protocol (CMSP). AB - The purpose of the study was to develop a valid and reliable tool for use in assessing motor skills in preschool children in field based settings. The development of the CHAMPS (Children's Activity and Movement in Preschool Study) Motor Skills Protocol (CMSP) included evidence of its reliability and validity for use in field-based environments as part of large epidemiological studies. Following pilot work, 297 children (3-5 years old) from 22 preschools were tested using the final version of the CMSP and the TGMD-2. Reliability of the CMSP and interobserver reliability were determined using intraclass correlation procedures (ICC; ANOVA). Concurrent validity was assessed using Pearson correlation coefficients to compare the CMSP to the original Test of Gross Motor Development (2(nd) Edition) (TGMD-2). Results indicated that test reliability, interobserver reliability and validity coefficients were all high, generally above R/r = 0.90. Significant age differences were found. Outcomes indicate that the CMSP is an appropriate tool for assessing motor development of 3-, 4-, and 5-year-old children in field-based settings that are consistent with large-scale trials. PMID- 21533000 TI - Slope Estimation for Bivariate Longitudinal Outcomes Adjusting for Informative Right Censoring Using Discrete Survival Model: Application to the Renal Transplant Cohort. AB - Patients undergoing renal transplantation are prone to graft failure which causes lost of follow-up measures on their blood urea nitrogen and serum creatinine levels. These two outcomes are measured repeatedly over time to assess renal function following transplantation. Loss of follow-up on these bivariate measures results in informative right censoring, a common problem in longitudinal data that should be adjusted for so that valid estimates are obtained. In this study, we propose a bivariate model that jointly models these two longitudinal correlated outcomes and generates population and individual slopes adjusting for informative right censoring using a discrete survival approach. The proposed approach is applied to the clinical dataset of patients who had undergone renal transplantation. A simulation study validates the effectiveness of the approach. PMID- 21533001 TI - SYSTEMS THINKING AS A TEAM-BUILDING APPROACH. PMID- 21533002 TI - Tandem BRCT Domains: DNA's Praetorian Guard. AB - The cell's ability to sense and respond to specific stimuli is a complex system derived from precisely regulated protein-protein interactions. Some of these protein-protein interactions are mediated by the recognition of linear peptide motifs by protein modular domains. BRCT (BRCA1 C-terminal) domains and their linear motif counterparts, which contain phosphoserines, are one such pair-wise interaction system that seems to have evolved to serve as a surveillance system to monitor threats to the cell's genetic integrity. Evidence indicates that BRCT domains found in tandem can cooperate to provide sequence-specific binding of phosphorylated peptides as is the case for the breast and ovarian cancer susceptibility gene BRCA1 and the PAX transcription factor-interacting protein PAXIP1. Particular interest has been paid to tandem BRCT domains as "readers" of signaling events in the form of phosphorylated serine moieties induced by the activation of DNA damage response kinases ATM, ATR, and DNA-PK. However, given the diversity of tandem BRCT-containing proteins, questions remain as to the origin and evolution of this domain. Here, we discuss emerging views of the origin and evolving roles of tandem BRCT domain repeats in the DNA damage response. PMID- 21533004 TI - Early childhood lead exposure and exceptionality designations for students. AB - The achievement gap continues to be an important educational issue, with disadvantaged groups exhibiting poorer school performance. Recently, literature has shown that even very low levels of early lead exposure affect cognitive and academic performance. As individuals at the lower end of the socioeconomic spectrum are more likely to be exposed to lead, this exposure may be an important contributor to the achievement gap. In this paper, we explore whether early childhood blood lead levels are associated with membership in exceptionality designation groups. In addition, we examine the racial and socioeconomic composition of these exceptional groups. Data from the North Carolina Childhood Lead Poisoning Prevention Program surveillance registry were linked at the individual child level to educational outcomes available through the North Carolina Education Research Data Center. Designation into exceptionality groups was obtained from the end-of-grade (EOG) data. Both standard bivariate and multivariate analyses were employed. Bivariate analyses indicate that blood lead levels and reading EOG scores differ by exceptionality, as well as by race and enrollment in free/reduced lunch. Logistic regression confirmed the relationship between blood lead levels and likelihood of exceptionality. Contextual factors - enrollment in the free/reduced lunch program, race, and parental education - are also significant with regard to exceptionality. This study demonstrates that early childhood lead exposure significantly influences the likelihood of being designated exceptional. These results provide additional evidence that early childhood lead exposure is a significant explanator of the achievement gap. PMID- 21533005 TI - A Tale of Two Counties:Bereavement in Socio-Demographically Diverse Places. AB - The "Living After Loss" study was designed to test the effectiveness of the dual process model (DPM) of coping with bereavement. In order to obtain a larger and more diverse sample we studied 328 recently widowed men and women (61%) age 50+ in two counties, Salt Lake (n=197) and San Francisco (n=131) in two states, Utah and California. This paper does not report on the effects of the intervention but focuses on a comparison of the bereaved spouses/partners in these two cites. First, the only socio-demographic differences we found between those in SF and SL were that those in San Francisco were more racially, ethnically and religiously diverse, higher in education, had slightly fewer years in their relationship to the deceased and were two weeks longer in their grief process. Second, there were far more similarities than differences between SF and SL regarding nearly all of the study variables. Third, we found that those in SF had more positive qualitative features in their friendship support networks and that for bereaved in both counties, we found strong associations with having highly supportive friend-based networks and more positive bereavement adjustments (especially experiencing lower levels of loneliness and depression). Limitations and suggestions for future research are described. PMID- 21533003 TI - Breast ductal lavage for assessment of breast cancer biomarkers. AB - Lavage of the ductal systems of the breast provides fluid (DLF) containing hormones and products of hormone actions that may represent more accurately the composition of the breast than samples collected from blood or urine. The present study was undertaken to assess the presence of potential cancer biomarkers, their variation among individuals at high risk for breast cancer, and differences associated with menopause and tamoxifen treatment. Seventy seven tamoxifen eligible subjects with a 5-year breast cancer risk estimate (Gail > 1.6%)(N = 53) or recently diagnosed breast cancer (N = 24) were offered tamoxifen therapy; those not accepting tamoxifen were under observation only. After six months, all subjects underwent ductal lavage (DL) in an unaffected breast. Estradiol (E2), estrone sulfate, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate, progesterone, cathepsin D and epidermal growth factor (EGF) were measured in DLF by immunoassays. Data were expressed as the mass of analyte per mg of protein in DLF and normalized by natural log transformation. With the exception of DHEA, none of the analytes measured were significantly lower in postmenopausal women than in premenopausal women. The mean log(e) concentration difference in estradiol was 10.9%. Tamoxifen treatment for 6 months did not result in a significantly greater concentration of E2 or in any of the other analytes in DLF of pre- or postmenopausal women. The between-duct variance of the concentration of free steroids within the same breast averaged 51% less than that between subjects, and was similar to that of non-diffusible proteins. The maintenance of estradiol concentrations in the breast after menopause demonstrates the importance of local biosynthesis. The fact that DLF E2 does not reflect the high serum concentrations of E2 during tamoxifen treatment indicates that breast concentrations of estradiol may be under feedback control. Unlike studies of low risk populations, progesterone concentrations were not significantly less in postmenopausal than in premenopausal women. The similarity in variance of free steroids and protein analytes between ducts of a breast indicates little transfer of steroids between lobules. PMID- 21533007 TI - Open vessel mode microwave-assisted synthesis of 2-oxazolines from carboxylic acids. AB - Microwave-assisted synthesis of 2-oxazolines from carboxylic acids using the open vessel technique is described. This efficient method involves direct condensation of carboxylic acids with excess 2-amino-2-methyl-1-propanol at 170 degrees C to give the corresponding 2-oxazolines in moderate to excellent yields. PMID- 21533006 TI - Mitogenic Signaling by the gep Oncogene Involves the Upregulation of S-Phase Kinase-Associated Protein 2. AB - The gep oncogene, defined by the activated mutant of the alpha-subunit of the G protein G(12) (Galpha(12)Q229L or Galpha(12)QL), potently stimulates the proliferation of many different cell types in addition to inducing neoplastic transformation of several fibroblast cell lines. While it has been demonstrated that Galpha(12)QL accelerates G1- to S-phase cell cycle progression, the precise mechanism through which Galpha(12) communicates to cell cycle machinery is largely unknown. In the present study, we report that the activated-mutational as well as receptor-mediated-Galpha(12) transmits its proliferative signals to cell cycle machinery by modulating the levels of the S-phase kinase-associated protein 2 (Skp2), an E3 ubiquitin ligase, involved in the regulation of the cyclin dependent kinase inhibitor (CKI), p27(Kip1). Our results show that the expression of Galpha(12)QL leads to an increase in the levels of Skp2 with a correlatable decrease in p27(Kip1) levels and subsequent increase in the activities of specific CDKs. By demonstrating that the transient expression of Galpha(12)QL induces an increase in Skp2 levels with resultant downregulation of p27(Kip1) in both NIH3T3 and human astrocytoma 1321N1 cells, we establish here that the effect of Galpha(12) on Skp2/p27(Kip1) is cell type independent. In addition, we demonstrate that LPA-stimulated proliferation and changes in Skp2 and p27(Kip1) levels in 1321N1 cells could be inhibited by the expression of a dominant negative mutant of Galpha(12), thereby pointing to the critical role of Galpha(12) in LPA-mediated mitogenic signaling. Our findings also indicate that LPA as well as Galpha(12)-mediated upregulation of Skp2 requires a yet to be characterized mechanism involving JNK. Since Skp2 has been identified as an oncogene, and it is overexpressed in many cancers, our results presented here describe for the first time that Skp2 is a novel target in the cell cycle machinery through which Galpha(12) and its cognate receptors transmit their oncogenic signals. PMID- 21533008 TI - A HISTORY OF THE THEORY OF PRENATAL ATTACHMENT. AB - John Bowlby's theory of human attachment has become widely applied across disciplines and across the stages of human development. This discussion explores the evolution of an application of Bowlby's theory to the experience of pregnancy, from both maternal and paternal perspectives. Although the theoretical construct of maternal fetal attachment (MFA) requires continued theoretically driven research, existing studies have associated this proposed construct with health behaviors, marital relationship, depressive symptoms, and the postpartum mother-infant relationship, pointing toward its relevance for academicians and clinicians devoted to the service of women and infants. PMID- 21533009 TI - MONITORING FIDELITY IN THE ADOLESCENT COMMUNITY REINFORCEMENT APPROACH (A-CRA): THE TRAINING PROCESS FOR A-CRA RATERS. AB - Ensuring evidence-based treatments are delivered with a high degree of fidelity is an important aspect of transporting these practices to community-based treatment providers. Just as training is critical for clinicians who plan to deliver the Adolescent Community Reinforcement Approach (A-CRA), a process of training and vetting individuals who assess sessions for fidelity also is critical. This article describes the training process for session raters who assess fidelity of A-CRA during the clinician training and certification process. A-CRA is currently being implemented in 32 independent community-based agencies as part of a large initiative funded by the Center for Substance Abuse Treatment. PMID- 21533010 TI - NICKEL-CATALYZED ENANTIOSELECTIVE NEGISHI CROSS-COUPLINGS OF RACEMIC SECONDARY alpha-BROMO AMIDES WITH ALKYLZINC REAGENTS: (S)-N-BENZYL-7-CYANO-2-ETHYL-N PHENYLHEPTANAMIDE. PMID- 21533011 TI - Homebodies and army brats: Some effects of early linguistic experience and residential history on dialect categorization. AB - Early linguistic experience has been shown to affect speech perception in a variety of ways. The present experiment investigated the effects of early linguistic experience on dialect perception. Two groups of participants listened to sentences read by talkers from six American English dialects and were asked to identify where they thought the talkers were from using a forced-choice categorization task. We found that "army brats," who had lived in at least three different states, performed better than "homebodies," who had lived only in Indiana, in terms of overall categorization accuracy. Army brats who had lived in a given region also categorized talkers from that region more accurately than army brats who had not lived there. Clustering analyses on the stimulus-response confusion matrices revealed significant differences in the perceptual similarity spaces for the two listener groups. These results suggest that early exposure to linguistic variation affects how well listeners can identify where unfamiliar talkers are from. PMID- 21533012 TI - Fundamentals of clinical trial design. AB - Most errors in clinical trials are a result of poor planning. Fancy statistical methods cannot rescue design flaws. Thus careful planning with clear foresight is crucial. Issues in trial conduct and analyses should be anticipated during trial design and thoughtfully addressed. Fundamental clinical trial design issues are discussed. PMID- 21533013 TI - Although visually cued imitation training may increase peer imitation, the preexisting skills necessary for success should be identified. PMID- 21533014 TI - Nucleophilic reactivity of thiolate, hydroxide and phenolate ions towards a model O-arylated diazeniumdiolate prodrug in aqueous and cationic surfactant media. AB - The kinetics of aromatic nucleophilic substitution of the nitric oxide generating diazeniumdiolate ion, DEA/NO, by thiols, (L-glutathione, L-cysteine, DL homocysteine, 1-propanethiol, 2-mercaptoethanol and sodium thioglycolate) from the prodrug, DNP-DEA/NO, has been examined in aqueous solution and in solutions of cationic DOTAP vesicles. Second-order rate constants in buffered aqueous solutions (k(RS(-) ) = 3.48 - 30.9 M(-1)s(-1); 30 degrees C) gave a linear Bronsted plot (beta(nuc) = 0.414 +/- 0.068) consistent with rate-limiting S(N)Ar nucleophilic attack by thiolate ions. Cationic DOTAP vesicles catalyze the thiolysis reactions with rate enhancements between 11 and 486-fold in Tris-HCl buffered solutions at pH 7.4. The maximum rate increase was obtained with thioglycolate ion. Thiolysis data are compared to data for nucleophilic displacement by phenolate (k(PhO(-) ) = 0.114 M(-1)s(-1)) and hydroxide (k(OH(-) ) = 1.82 * 10(-2) M(-1)s(-1), 37 degrees C) ions. The base hydrolysis reaction is accelerated by CTAB micelles and DODAC vesicles with vesicles being ca 3-fold more effective as catalysts. Analysis of the data using pseudophase ion-exchange formalism implies that the rate enhancement of the thiolysis and base hydrolysis reactions is due primarily to reactant concentration in the surfactant pseudophase. PMID- 21533015 TI - Substance Abuse Disorders Among Homeless and Runaway Adolescents. AB - This paper presents lifetime and 12-month prevalence rates and comorbidity data for substance abuse disorders among homeless and runaway adolescents. Data are from baseline interviews of a longitudinal diagnostic study of 428 (187 males and 241 females) homeless and runaway adolescents aged 16 to 19 years (mean age = 17.4 year, SD = 1.05). The data were collected by full-time interviewers on the streets and in shelters in eight Midwestern cities of various populations. About two thirds (60.5%) of the runaways met lifetime criteria for at least one of three substance disorders (alcohol abuse, alcohol dependence, drug abuse), and nearly one half (48.1%) met 12-month criteria for at least one of the disorders. Nearly all of the adolescents (93%) who met criteria for a substance disorder met criteria for at least one other mental disorder. Those factors most predictive of meeting lifetime criteria Include parenting practices, experience of abuse, and association with deviant peers. PMID- 21533016 TI - Emerging Concepts in the Analysis of Transcriptional Targets of the MYC Oncoprotein: Are the Targets Targetable? AB - Activation of the MYC oncoprotein is among the most ubiquitous events in human cancer. MYC functions in part as a sequence-specific regulator of transcription. Although early searches for direct downstream target genes that explain MYC's potent biological activity were met with enthusiasm, the postgenomic decade has brought the realization that MYC regulates the transcription of not just a manageably small handful of target genes but instead up to 15% of all active loci. As the dust has begun to settle, two important concepts have emerged that reignite hope that understanding MYC's downstream targets might still prove valuable for defining critical nodes for therapeutic intervention in cancer patients. First, it is now clear that MYC target genes are not a random sampling of the cellular transcriptome but instead fall into specific, critical biochemical pathways such as metabolism, chromatin structure, and protein translation. In retrospect, we should not have been surprised to discover that MYC rewires cell physiology in a manner designed to provide the tumor cell with greater biosynthetic properties. However, the specific details that have emerged from these studies are likely to guide the development of new clinical tools and strategies. This raises the second concept that instills renewed optimism regarding MYC target genes. It is now clear that not all MYC target genes are of equal functional relevance. Thus, it may be possible to discern, from among the thousands of potential MYC target genes, those whose inhibition will truly debilitate the tumor cell. In short, targeting the targets may ultimately be a realistic approach after all. PMID- 21533017 TI - MicroRNA in Cancer: The Involvement of Aberrant MicroRNA Biogenesis Regulatory Pathways. AB - MicroRNAs (miRNAs) are small, noncoding RNAs that influence diverse biological outcomes through the repression of target genes during normal development and pathological responses. In particular, the alteration of miRNA expression has dramatic consequences for the progression of tumorigenesis. miRNAs undergo two processing steps that transform a long primary transcript into the mature miRNA. Although the general miRNA biogenesis pathway is well established, it is clear that not all miRNAs are created equally. Recent studies show that miRNA expression is controlled by diverse mechanisms in response to cellular stimuli. In this review, we discuss the mechanisms that govern the regulation of miRNA biogenesis with particular focus on how these mechanisms are perturbed in cancer. PMID- 21533018 TI - Hepatic PTP1B Deficiency: The Promise of a Treatment for Metabolic Syndrome? AB - Metabolic syndrome and type 2 diabetes are complex disorders that are associated with obesity, aging, and genetic predisposition. The increasing prevalence of metabolic abnormalities worldwide presents a serious public health problem, with rates of obesity and diabetes reaching unprecedented levels. A common feature of these disorders is the development of insulin resistance, resulting in decreased insulin-stimulated glucose uptake, failure to suppress hepatic glucose production, and accumulation of hepatic lipid. Recent studies in mice have shown that deficiency of the non-receptor protein tyrosine phosphatase, PTP1B, in liver leads to a host of improvements in metabolic parameters, including improved hepatic insulin sensitivity, reduced liver triglycerides, lower serum and hepatic cholesterol levels, and protection against high-fat diet-induced endoplasmic reticulum (ER) stress. Based on these promising studies, PTP1B inhibitors may prove to be a valuable therapeutic tool in the fight against metabolic syndrome and its associated comorbidities. In this review, the role of PTP1B in hepatic insulin sensitivity, hepatic lipid accumulation, and ER stress are discussed. PMID- 21533019 TI - Protein phosphatase 2A controls ethylene biosynthesis by differentially regulating the turnover of ACC synthase isoforms. AB - The gaseous hormone ethylene is one of the master regulators of development and physiology throughout the plant life cycle. Ethylene biosynthesis is stringently regulated to permit maintenance of low levels during most phases of vegetative growth but to allow for rapid peaks of high production at developmental transitions and under stress conditions. In most tissues ethylene is a negative regulator of cell expansion, thus low basal levels of ethylene biosynthesis in dark-grown seedlings are critical for optimal cell expansion during early seedling development. The committed steps in ethylene biosynthesis are performed by the enzymes 1-aminocyclopropane 1-carboxylate synthase (ACS) and 1 aminocyclopropane 1-carboxylate oxidase (ACO). The abundance of different ACS enzymes is tightly regulated both by transcriptional control and by post translational modifications and proteasome-mediated degradation. Here we show that specific ACS isozymes are targets for regulation by protein phosphatase 2A (PP2A) during Arabidopsis thaliana seedling growth and that reduced PP2A function causes increased ACS activity in the roots curl in 1-N-naphthylphthalamic acid 1 (rcn1) mutant. Genetic analysis reveals that ethylene overproduction in PP2A deficient plants requires ACS2 and ACS6, genes that encode ACS proteins known to be stabilized by phosphorylation, and proteolytic turnover of the ACS6 protein is retarded when PP2A activity is reduced. We find that PP2A and ACS6 proteins associate in seedlings and that RCN1-containing PP2A complexes specifically dephosphorylate a C-terminal ACS6 phosphopeptide. These results suggest that PP2A dependent destabilization requires RCN1-dependent dephosphorylation of the ACS6 C terminus. Surprisingly, rcn1 plants exhibit decreased accumulation of the ACS5 protein, suggesting that a regulatory phosphorylation event leads to ACS5 destabilization. Our data provide new insight into the circuitry that ensures dynamic control of ethylene synthesis during plant development, showing that PP2A mediates a finely tuned regulation of overall ethylene production by differentially affecting the stability of specific classes of ACS enzymes. PMID- 21533020 TI - The history of African gene flow into Southern Europeans, Levantines, and Jews. AB - Previous genetic studies have suggested a history of sub-Saharan African gene flow into some West Eurasian populations after the initial dispersal out of Africa that occurred at least 45,000 years ago. However, there has been no accurate characterization of the proportion of mixture, or of its date. We analyze genome-wide polymorphism data from about 40 West Eurasian groups to show that almost all Southern Europeans have inherited 1%-3% African ancestry with an average mixture date of around 55 generations ago, consistent with North African gene flow at the end of the Roman Empire and subsequent Arab migrations. Levantine groups harbor 4%-15% African ancestry with an average mixture date of about 32 generations ago, consistent with close political, economic, and cultural links with Egypt in the late middle ages. We also detect 3%-5% sub-Saharan African ancestry in all eight of the diverse Jewish populations that we analyzed. For the Jewish admixture, we obtain an average estimated date of about 72 generations. This may reflect descent of these groups from a common ancestral population that already had some African ancestry prior to the Jewish Diasporas. PMID- 21533021 TI - Epigenetic regulation of cell type-specific expression patterns in the human mammary epithelium. AB - Differentiation is an epigenetic program that involves the gradual loss of pluripotency and acquisition of cell type-specific features. Understanding these processes requires genome-wide analysis of epigenetic and gene expression profiles, which have been challenging in primary tissue samples due to limited numbers of cells available. Here we describe the application of high-throughput sequencing technology for profiling histone and DNA methylation, as well as gene expression patterns of normal human mammary progenitor-enriched and luminal lineage-committed cells. We observed significant differences in histone H3 lysine 27 tri-methylation (H3K27me3) enrichment and DNA methylation of genes expressed in a cell type-specific manner, suggesting their regulation by epigenetic mechanisms and a dynamic interplay between the two processes that together define developmental potential. The technologies we developed and the epigenetically regulated genes we identified will accelerate the characterization of primary cell epigenomes and the dissection of human mammary epithelial lineage-commitment and luminal differentiation. PMID- 21533023 TI - Adaptations to climate-mediated selective pressures in humans. AB - Humans inhabit a remarkably diverse range of environments, and adaptation through natural selection has likely played a central role in the capacity to survive and thrive in extreme climates. Unlike numerous studies that used only population genetic data to search for evidence of selection, here we scan the human genome for selection signals by identifying the SNPs with the strongest correlations between allele frequencies and climate across 61 worldwide populations. We find a striking enrichment of genic and nonsynonymous SNPs relative to non-genic SNPs among those that are strongly correlated with these climate variables. Among the most extreme signals, several overlap with those from GWAS, including SNPs associated with pigmentation and autoimmune diseases. Further, we find an enrichment of strong signals in gene sets related to UV radiation, infection and immunity, and cancer. Our results imply that adaptations to climate shaped the spatial distribution of variation in humans. PMID- 21533022 TI - Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. AB - Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to 1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies. PMID- 21533024 TI - Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. AB - Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 * 10(-9)), PNPLA3 (rs738409, P = 5.8 * 10(-9)), RELA (rs1049728, P = 2.7 * 10(-16)), and SH2B3 (rs3184504, P = 2.9 * 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function. PMID- 21533025 TI - Climate change or land use dynamics: do we know what climate change indicators indicate? AB - Different components of global change can have interacting effects on biodiversity and this may influence our ability to detect the specific consequences of climate change through biodiversity indicators. Here, we analyze whether climate change indicators can be affected by land use dynamics that are not directly determined by climate change. To this aim, we analyzed three community-level indicators of climate change impacts that are based on the optimal thermal environment and average latitude of the distribution of bird species present at local communities. We used multiple regression models to relate the variation in climate change indicators to: i) environmental temperature; and ii) three landscape gradients reflecting important current land use change processes (land abandonment, fire impacts and urbanization), all of them having forest areas at their positive extremes. We found that, with few exceptions, landscape gradients determined the figures of climate change indicators as strongly as temperature. Bird communities in forest habitats had colder-dwelling bird species with more northern distributions than farmland, burnt or urban areas. Our results show that land use changes can reverse, hide or exacerbate our perception of climate change impacts when measured through community-level climate change indicators. We stress the need of an explicit incorporation of the interactions between climate change and land use dynamics to understand what are current climate change indicators indicating and be able to isolate real climate change impacts. PMID- 21533026 TI - Shared molecular and functional frameworks among five complex human disorders: a comparative study on interactomes linked to susceptibility genes. AB - BACKGROUND: Genome-wide association studies (gwas) are invaluable in revealing the common variants predisposing to complex human diseases. Yet, until now, the large volumes of data generated from such analyses have not been explored extensively enough to identify the molecular and functional framework hosting the susceptibility genes. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the relationships among five neurodegenerative and/or autoimmune complex human diseases (Parkinson's disease--Park, Alzheimer's disease--Alz, multiple sclerosis -MS, rheumatoid arthritis--RA and Type 1 diabetes--T1D) by characterising the interactomes linked to their gwas-genes. An initial study on the MS interactome indicated that several genes predisposing to the other autoimmune or neurodegenerative disorders may come into contact with it, suggesting that susceptibility to distinct diseases may converge towards common molecular and biological networks. In order to test this hypothesis, we performed pathway enrichment analyses on each disease interactome independently. Several issues related to immune function and growth factor signalling pathways appeared in all autoimmune diseases, and, surprisingly, in Alzheimer's disease. Furthermore, the paired analyses of disease interactomes revealed significant molecular and functional relatedness among autoimmune diseases, and, unexpectedly, between T1D and Alz. CONCLUSIONS/SIGNIFICANCE: The systems biology approach highlighted several known pathogenic processes, indicating that changes in these functions might be driven or sustained by the framework linked to genetic susceptibility. Moreover, the comparative analyses among the five genetic interactomes revealed unexpected genetic relationships, which await further biological validation. Overall, this study outlines the potential of systems biology to uncover links between genetics and pathogenesis of complex human disorders. PMID- 21533027 TI - Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum. AB - The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (~ 1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome. PMID- 21533028 TI - Artificially induced epithelial-mesenchymal transition in surgical subjects: its implications in clinical and basic cancer research. AB - BACKGROUND: Surgical samples have long been used as important subjects for cancer research. In accordance with an increase of neoadjuvant therapy, biopsy samples have recently become imperative for cancer transcriptome. On the other hand, both biopsy and surgical samples are available for expression profiling for predicting clinical outcome by adjuvant therapy; however, it is still unclear whether surgical sample expression profiles are useful for prediction via biopsy samples, because little has been done about comparative gene expression profiling between the two kinds of samples. METHODOLOGY AND FINDINGS: A total of 166 samples (77 biopsy and 89 surgical) of normal and malignant lesions of the esophagus were analyzed by microarrays. Gene expression profiles were compared between biopsy and surgical samples. Artificially induced epithelial-mesenchymal transition (aiEMT) was found in the surgical samples, and also occurred in mouse esophageal epithelial cell layers under an ischemic condition. Identification of clinically significant subgroups was thought to be disrupted by the disorder of the expression profile through this aiEMT. CONCLUSION AND SIGNIFICANCE: This study will evoke the fundamental misinterpretation including underestimation of the prognostic evaluation power of markers by overestimation of EMT IN past cancer research, and will furnish some advice for the near future as follows: 1) Understanding how long the tissues were under an ischemic condition. 2) Prevalence of biopsy samples for in vivo expression profiling with low biases on basic and clinical research. 3) Checking cancer cell contents and normal- or necrotic-tissue contamination in biopsy samples for prevalence. PMID- 21533029 TI - Cannabis use in patients with fibromyalgia: effect on symptoms relief and health related quality of life. AB - BACKGROUND: The aim of this study was to describe the patterns of cannabis use and the associated benefits reported by patients with fibromyalgia (FM) who were consumers of this drug. In addition, the quality of life of FM patients who consumed cannabis was compared with FM subjects who were not cannabis users. METHODS: Information on medicinal cannabis use was recorded on a specific questionnaire as well as perceived benefits of cannabis on a range of symptoms using standard 100-mm visual analogue scales (VAS). Cannabis users and non-users completed the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index (PSQI) and the Short Form 36 Health Survey (SF-36). RESULTS: Twenty eight FM patients who were cannabis users and 28 non-users were included in the study. Demographics and clinical variables were similar in both groups. Cannabis users referred different duration of drug consumption; the route of administration was smoking (54%), oral (46%) and combined (43%). The amount and frequency of cannabis use were also different among patients. After 2 hours of cannabis use, VAS scores showed a statistically significant (p<0.001) reduction of pain and stiffness, enhancement of relaxation, and an increase in somnolence and feeling of well being. The mental health component summary score of the SF-36 was significantly higher (p<0.05) in cannabis users than in non-users. No significant differences were found in the other SF-36 domains, in the FIQ and the PSQI. CONCLUSIONS: The use of cannabis was associated with beneficial effects on some FM symptoms. Further studies on the usefulness of cannabinoids in FM patients as well as cannabinoid system involvement in the pathophysiology of this condition are warranted. PMID- 21533030 TI - In-vitro activity of polymyxin B, rifampicin, tigecycline alone and in combination against carbapenem-resistant Acinetobacter baumannii in Singapore. AB - OBJECTIVE: Carbapenem-resistant Acinetobacter baumannii (CR-AB) is an emerging cause of nosocomial infections worldwide. Combination therapy may be the only viable option until new antibiotics become available. The objective of this study is to identify potential antimicrobial combinations against CR-AB isolated from our local hospitals. METHODS: AB isolates from all public hospitals in Singapore were systematically collected between 2006 and 2007. MICs were determined according to CLSI guidelines. All CR-AB isolates were genotyped using a PCR-based method. Clonal relationship was elucidated. Time-kill studies (TKS) were conducted with polymyxin B, rifampicin and tigecycline alone and in combination using clinically relevant (achievable) unbound concentrations. RESULTS: 31 CR AB isolates were identified. They are multidrug-resistant, but are susceptible to polymyxin B. From clonal typing, 8 clonal groups were identified and 11 isolates exhibited clonal diversity. In single TKS, polymyxin B, rifampicin and tigecycline alone did not exhibit bactericidal activity at 24 hours. In combination TKS, polymyxin plus rifampicin, polymyxin B plus tigecycline and tigecycline plus rifampicin exhibited bactericidal killing in 13/31, 9/31 and 7/31 isolates respectively at 24 hours. Within a clonal group, there may be no consensus with the types of antibiotics combinations that could still kill effectively. CONCLUSION: Monotherapy with polymyxin B may not be adequate against polymyxin B susceptible AB isolates. These findings demonstrate that in-vitro synergy of antibiotic combinations in CR AB may be strain dependant. It may guide us in choosing a pre-emptive therapy for CR AB infections and warrants further investigations. PMID- 21533031 TI - Excellent adherence to antiretrovirals in HIV+ Zambian children is compromised by disrupted routine, HIV nondisclosure, and paradoxical income effects. AB - INTRODUCTION: A better understanding of pediatric antiretroviral therapy (ART) adherence in sub-Saharan Africa is necessary to develop interventions to sustain high levels of adherence. METHODOLOGY/PRINCIPAL FINDINGS: Adherence among 96 HIV infected Zambian children (median age 6, interquartile range [IQR] 2,9) initiating fixed-dose combination ART was measured prospectively (median 23 months; IQR 20,26) with caregiver report, clinic and unannounced home-based pill counts, and medication event monitoring systems (MEMS). HIV-1 RNA was determined at 48 weeks. Child and caregiver characteristics, socio-demographic status, and treatment-related factors were assessed as predictors of adherence. Median adherence was 97.4% (IQR 96.1,98.4%) by visual analog scale, 94.8% (IQR 86,100%) by caregiver-reported last missed dose, 96.9% (IQR 94.5,98.2%) by clinic pill count, 93.4% (IQR 90.2,96.7%) by unannounced home-based pill count, and 94.8% (IQR 87.8,97.7%) by MEMS. At 48 weeks, 72.6% of children had HIV-1 RNA <50 copies/ml. Agreement among adherence measures was poor; only MEMS was significantly associated with viral suppression (p = 0.013). Predictors of poor adherence included changing residence, school attendance, lack of HIV disclosure to children aged nine to 15 years, and increasing household income. CONCLUSIONS/SIGNIFICANCE: Adherence among children taking fixed-dose combination ART in sub-Saharan Africa is high and sustained over two years. However, certain groups are at risk for treatment failure, including children with disrupted routines, no knowledge of their HIV diagnosis among older children, and relatively high household income, possibly reflecting greater social support in the setting of greater poverty. PMID- 21533032 TI - Propagating cell-membrane waves driven by curved activators of actin polymerization. AB - Cells exhibit propagating membrane waves which involve the actin cytoskeleton. One type of such membranal waves are Circular Dorsal Ruffles (CDR) which are related to endocytosis and receptor internalization. Experimentally, CDRs have been associated with membrane bound activators of actin polymerization of concave shape. We present experimental evidence for the localization of convex membrane proteins in these structures, and their insensitivity to inhibition of myosin II contractility in immortalized mouse embryo fibroblasts cell cultures. These observations lead us to propose a theoretical model which explains the formation of these waves due to the interplay between complexes that contain activators of actin polymerization and membrane-bound curved proteins of both types of curvature (concave and convex). Our model predicts that the activity of both types of curved proteins is essential for sustaining propagating waves, which are abolished when one type of curved activator is removed. Within this model waves are initiated when the level of actin polymerization induced by the curved activators is higher than some threshold value, which allows the cell to control CDR formation. We demonstrate that the model can explain many features of CDRs, and give several testable predictions. This work demonstrates the importance of curved membrane proteins in organizing the actin cytoskeleton and cell shape. PMID- 21533034 TI - The seroprevalence of pandemic influenza H1N1 (2009) virus in China. AB - BACKGROUND: Mainland China experienced pandemic influenza H1N1 (2009) virus (pH1N1) with peak activity during November-December 2009. To understand the geographic extent, risk factors, and attack rate of pH1N1 infection in China we conducted a nationwide serological survey to determine the prevalence of antibodies to pH1N1. METHODOLOGY/PRINCIPAL FINDINGS: Stored serum samples (n = 2,379) collected during 2006-2008 were used to estimate baseline serum reactogenicity to pH1N1. In January 2010, we used a multistage-stratified random sampling method to select 50,111 subjects who met eligibility criteria and collected serum samples and administered a standardized questionnaire. Antibody response to pH1N1 was measured using haemagglutination inhibition (HI) assay and the weighted seroprevalence was calculated using the Taylor series linearization method. Multivariable logistic regression analyses were used to examine risk factors for pH1N1 seropositivity. Baseline seroprevalence of pH1N1 antibody (HI titer >=40) was 1.2%. The weighted seroprevalence of pH1N1 among the Chinese population was 21.5%(vaccinated: 62.0%; unvaccinated: 17.1%). Among unvaccinated participants, those aged 6-15 years (32.9%) and 16-24 years (30.3%) had higher seroprevalence compared with participants aged 25-59 years (10.7%) and >=60 years (9.9%, P<0.0001). Children in kindergarten and students had higher odds of seropositivity than children in family care (OR: 1.36 and 2.05, respectively). We estimated that 207.7 million individuals (15.9%) experienced pH1N1 infection in China. CONCLUSIONS/SIGNIFICANCE: The Chinese population had low pre-existing immunity to pH1N1 and experienced a relatively high attack rate in 2009 of this virus. We recommend routine control measures such as vaccination to reduce transmission and spread of seasonal and pandemic influenza viruses. PMID- 21533035 TI - CD4 dynamics over a 15 year-period among HIV controllers enrolled in the ANRS French observatory. AB - BACKGROUND: There are few large published studies of HIV controllers with long term undetectable viral load (VL). We describe the characteristics and outcomes of 81 French HIV controllers. METHODS AND RESULTS: HIV controllers were defined as asymptomatic, antiretroviral-naive persons infected >=10 years previously, with HIV-RNA <400 copies/mL in >90% of plasma samples. All available CD4 and VL values were collected at enrolment. Mixed-effect linear models were used to analyze CD4 cell count slopes since diagnosis. HIV controllers represented 0.31% of all patients managed in French hospitals. Patients infected through intravenous drug use were overrepresented (31%) and homosexual men were underrepresented (26% of men) relative to the ANRS SEROCO cohort of subjects diagnosed during the same period. HIV controllers whose VL values were always below the detection limit of the assays were compared with those who had rare "blips" (<50% of VL values above the detection limit) or frequent blips (>50% of VL values above the detection limit). Estimated CD4 cell counts at HIV diagnosis were similar in the three groups. CD4 cell counts remained stable after HIV diagnosis in the "no blip" group, while they fell significantly in the two other groups (-0.26?CD4 and -0.28?CD4/mm(3)/year in the rare and frequent blip groups, respectively). No clinical, immunological or virological progression was observed in the no blip group, while 3 immunological and/or virological events and 4 cancers were observed in the blip subgroups. CONCLUSIONS: Viral blips in HIV controllers are associated with a significant decline in CD4 T cells and may be associated with an increased risk of pathological events, possibly owing to chronic inflammation/immune activation. PMID- 21533036 TI - Somatic mutagenesis with a Sleeping Beauty transposon system leads to solid tumor formation in zebrafish. AB - Large-scale sequencing of human cancer genomes and mouse transposon-induced tumors has identified a vast number of genes mutated in different cancers. One of the outstanding challenges in this field is to determine which genes, when mutated, contribute to cellular transformation and tumor progression. To identify new and conserved genes that drive tumorigenesis we have developed a novel cancer model in a distantly related vertebrate species, the zebrafish, Danio rerio. The Sleeping Beauty (SB) T2/Onc transposon system was adapted for somatic mutagenesis in zebrafish. The carp beta-actin promoter was cloned into T2/Onc to create T2/OncZ. Two transgenic zebrafish lines that contain large concatemers of T2/OncZ were isolated by injection of linear DNA into the zebrafish embryo. The T2/OncZ transposons were mobilized throughout the zebrafish genome from the transgene array by injecting SB11 transposase RNA at the 1-cell stage. Alternatively, the T2/OncZ zebrafish were crossed to a transgenic line that constitutively expresses SB11 transposase. T2/OncZ transposon integration sites were cloned by ligation mediated PCR and sequenced on a Genome Analyzer II. Between 700-6800 unique integration events in individual fish were mapped to the zebrafish genome. The data show that introduction of transposase by transgene expression or RNA injection results in an even distribution of transposon re-integration events across the zebrafish genome. SB11 mRNA injection resulted in neoplasms in 10% of adult fish at ~10 months of age. T2/OncZ-induced zebrafish tumors contain many mutated genes in common with human and mouse cancer genes. These analyses validate our mutagenesis approach and provide additional support for the involvement of these genes in human cancers. The zebrafish T2/OncZ cancer model will be useful for identifying novel and conserved genetic drivers of human cancers. PMID- 21533037 TI - Protein phosphatase-1 activates CDK9 by dephosphorylating Ser175. AB - The cyclin-dependent kinase CDK9/cyclin T1 induces HIV-1 transcription by phosphorylating the carboxyterminal domain (CTD) of RNA polymerase II (RNAPII). CDK9 activity is regulated by protein phosphatase-1 (PP1) which was previously shown to dephosphorylate CDK9 Thr186. Here, we analyzed the effect of PP1 on RNAPII phosphorylation and CDK9 activity. The selective inhibition of PP1 by okadaic acid and by NIPP1 inhibited phosphorylation of RNAPII CTD in vitro and in vivo. Expression of the central domain of NIPP1 in cultured cells inhibited the enzymatic activity of CDK9 suggesting its activation by PP1. Comparison of dephosphorylation of CDK9 phosphorylated by ((32)P) in vivo and dephosphorylation of CDK9's Thr186 analyzed by Thr186 phospho-specific antibodies, indicated that a residue other than Thr186 might be dephosphorylated by PP1. Analysis of dephosphorylation of phosphorylated peptides derived from CDK9's T-loop suggested that PP1 dephosphorylates CDK9 Ser175. In cultured cells, CDK9 was found to be phosphorylated on Ser175 as determined by combination of Hunter 2D peptide mapping and LC-MS analysis. CDK9 S175A mutant was active and S175D--inactive, and dephosphorylation of CDK9's Ser175 upregulated HIV-1 transcription in PP1 dependent manner. Collectively, our results point to CDK9 Ser175 as novel PP1 regulatory site which dephosphorylation upregulates CDK9 activity and contribute to the activation of HIV-1 transcription. PMID- 21533033 TI - Classification of plant associated bacteria using RIF, a computationally derived DNA marker. AB - A DNA marker that distinguishes plant associated bacteria at the species level and below was derived by comparing six sequenced genomes of Xanthomonas, a genus that contains many important phytopathogens. This DNA marker comprises a portion of the dnaA replication initiation factor (RIF). Unlike the rRNA genes, dnaA is a single copy gene in the vast majority of sequenced bacterial genomes, and amplification of RIF requires genus-specific primers. In silico analysis revealed that RIF has equal or greater ability to differentiate closely related species of Xanthomonas than the widely used ribosomal intergenic spacer region (ITS). Furthermore, in a set of 263 Xanthomonas, Ralstonia and Clavibacter strains, the RIF marker was directly sequenced in both directions with a success rate approximately 16% higher than that for ITS. RIF frameworks for Xanthomonas, Ralstonia and Clavibacter were constructed using 682 reference strains representing different species, subspecies, pathovars, races, hosts and geographic regions, and contain a total of 109 different RIF sequences. RIF sequences showed subspecific groupings but did not place strains of X. campestris or X. axonopodis into currently named pathovars nor R. solanacearum strains into their respective races, confirming previous conclusions that pathovar and race designations do not necessarily reflect genetic relationships. The RIF marker also was sequenced for 24 reference strains from three genera in the Enterobacteriaceae: Pectobacterium, Pantoea and Dickeya. RIF sequences of 70 previously uncharacterized strains of Ralstonia, Clavibacter, Pectobacterium and Dickeya matched, or were similar to, those of known reference strains, illustrating the utility of the frameworks to classify bacteria below the species level and rapidly match unknown isolates to reference strains. The RIF sequence frameworks are available at the online RIF database, RIFdb, and can be queried for diagnostic purposes with RIF sequences obtained from unknown strains in both chromatogram and FASTA format. PMID- 21533038 TI - Tasting soil fungal diversity with earth tongues: phylogenetic test of SATe alignments for environmental ITS data. AB - An abundance of novel fungal lineages have been indicated by DNA sequencing of the nuclear ribosomal ITS region from environmental samples such as soil and wood. Although phylogenetic analysis of these novel lineages is a key component of unveiling the structure and diversity of complex communities, such analyses are rare for environmental ITS data due to the difficulties of aligning this locus across significantly divergent taxa. One potential approach to this issue is simultaneous alignment and tree estimation. We targeted divergent ITS sequences of the earth tongue fungi (Geoglossomycetes), a basal class in the Ascomycota, to assess the performance of SATe, recent software that combines progressive alignment and tree building. We found that SATe performed well in generating high-quality alignments and in accurately estimating the phylogeny of earth tongue fungi. Drawing from a data set of 300 sequences of earth tongues and progressively more distant fungal lineages, 30 insufficiently identified ITS sequences from the public sequence databases were assigned to the Geoglossomycetes. The association between earth tongues and plants has been hypothesized for a long time, but hard evidence is yet to be collected. The ITS phylogeny showed that four ectomycorrhizal isolates shared a clade with Geoglossum but not with Trichoglossum earth tongues, pointing to the significant potential inherent to ecological data mining of environmental samples. Environmental sampling holds the key to many focal questions in mycology, and simultaneous alignment and tree estimation, as performed by SATe, can be a highly efficient companion in that pursuit. PMID- 21533039 TI - Quantifying relative diver effects in underwater visual censuses. AB - Diver-based Underwater Visual Censuses (UVCs), particularly transect-based surveys, are key tools in the study of coral reef fish ecology. These techniques, however, have inherent problems that make it difficult to collect accurate numerical data. One of these problems is the diver effect (defined as the reaction of fish to a diver). Although widely recognised, its effects have yet to be quantified and the extent of taxonomic variation remains to be determined. We therefore examined relative diver effects on a reef fish assemblage on the Great Barrier Reef. Using common UVC methods, the recorded abundance of seven reef fish groups were significantly affected by the ongoing presence of SCUBA divers. Overall, the diver effect resulted in a 52% decrease in the mean number of individuals recorded, with declines of up to 70% in individual families. Although the diver effect appears to be a significant problem, UVCs remain a useful approach for quantifying spatial and temporal variation in relative fish abundances, especially if using methods that minimise the exposure of fishes to divers. Fixed distance transects using tapes or lines deployed by a second diver (or GPS-calibrated timed swims) would appear to maximise fish counts and minimise diver effects. PMID- 21533040 TI - Serum calcium levels are associated with novel cardiometabolic risk factors in the population-based CoLaus study. AB - BACKGROUND: Associations of serum calcium levels with the metabolic syndrome and other novel cardio-metabolic risk factors not classically included in the metabolic syndrome, such as those involved in oxidative stress, are largely unexplored. We analyzed the association of albumin-corrected serum calcium levels with conventional and non-conventional cardio-metabolic risk factors in a general adult population. METHODOLOGY/PRINCIPAL FINDINGS: The CoLaus study is a population-based study including Caucasians from Lausanne, Switzerland. The metabolic syndrome was defined using the Adult Treatment Panel III criteria. Non conventional cardio-metabolic risk factors considered included: fat mass, leptin, LDL particle size, apolipoprotein B, fasting insulin, adiponectin, ultrasensitive CRP, serum uric acid, homocysteine, and gamma-glutamyltransferase. We used adjusted standardized multivariable regression to compare the association of each cardio-metabolic risk factor with albumin-corrected serum calcium. We assessed associations of albumin-corrected serum calcium with the cumulative number of non conventional cardio-metabolic risk factors. We analyzed 4,231 subjects aged 35 to 75 years. Corrected serum calcium increased with both the number of the metabolic syndrome components and the number of non-conventional cardio-metabolic risk factors, independently of the metabolic syndrome and BMI. Among conventional and non-conventional cardio-metabolic risk factors, the strongest positive associations were found for factors related to oxidative stress (uric acid, homocysteine and gamma-glutamyltransferase). Adiponectin had the strongest negative association with corrected serum calcium. CONCLUSIONS/SIGNIFICANCE: Serum calcium was associated with the metabolic syndrome and with non conventional cardio-metabolic risk factors independently of the metabolic syndrome. Associations with uric acid, homocysteine and gamma-glutamyltransferase were the strongest. These novel findings suggest that serum calcium levels may be associated with cardiovascular risk via oxidative stress. PMID- 21533041 TI - Music alters visual perception. AB - BACKGROUND: Visual perception is not a passive process: in order to efficiently process visual input, the brain actively uses previous knowledge (e.g., memory) and expectations about what the world should look like. However, perception is not only influenced by previous knowledge. Especially the perception of emotional stimuli is influenced by the emotional state of the observer. In other words, how we perceive the world does not only depend on what we know of the world, but also by how we feel. In this study, we further investigated the relation between mood and perception. METHODS AND FINDINGS: We let observers do a difficult stimulus detection task, in which they had to detect schematic happy and sad faces embedded in noise. Mood was manipulated by means of music. We found that observers were more accurate in detecting faces congruent with their mood, corroborating earlier research. However, in trials in which no actual face was presented, observers made a significant number of false alarms. The content of these false alarms, or illusory percepts, was strongly influenced by the observers' mood. CONCLUSIONS: As illusory percepts are believed to reflect the content of internal representations that are employed by the brain during top down processing of visual input, we conclude that top-down modulation of visual processing is not purely predictive in nature: mood, in this case manipulated by music, may also directly alter the way we perceive the world. PMID- 21533042 TI - Effects of an early handling-like procedure and individual housing on anxiety like behavior in adult C57BL/6J and DBA/2J mice. AB - Manipulations of rearing conditions have been used to examine the effects of early experience on adult behavior with varying results. Evidence suggests that postnatal days (PND) 15-21 are a time of particular susceptibility to environmental influences on anxiety-like behavior in mice. To examine this, we subjected C57BL/6J and DBA/2J mice to an early handling-like procedure. Pups were separated from dams from PND 12-20 for 30 minutes daily or received standard care. On PND 21, pups were weaned and either individually- or group-housed. On PND 60, anxiety-like behavior was examined on the elevated zero-maze. Although individually-housed animals took longer to enter an open quadrant of the maze, they spent more time in the open than group-housed animals. Additionally, we observed a trend of reduced anxiety-like behavior in C57BL/6J, but not DBA/2J mice that underwent the handling-like procedure. PMID- 21533043 TI - Top-level categories of constitutively organized material entities--suggestions for a formal top-level ontology. AB - BACKGROUND: Application oriented ontologies are important for reliably communicating and managing data in databases. Unfortunately, they often differ in the definitions they use and thus do not live up to their potential. This problem can be reduced when using a standardized and ontologically consistent template for the top-level categories from a top-level formal foundational ontology. This would support ontological consistency within application oriented ontologies and compatibility between them. The Basic Formal Ontology (BFO) is such a foundational ontology for the biomedical domain that has been developed following the single inheritance policy. It provides the top-level template within the Open Biological and Biomedical Ontologies Foundry. If it wants to live up to its expected role, its three top-level categories of material entity (i.e., 'object', 'fiat object part', 'object aggregate') must be exhaustive, i.e. every concrete material entity must instantiate exactly one of them. METHODOLOGY/PRINCIPAL FINDINGS: By systematically evaluating all possible basic configurations of material building blocks we show that BFO's top-level categories of material entity are not exhaustive. We provide examples from biology and everyday life that demonstrate the necessity for two additional categories: 'fiat object part aggregate' and 'object with fiat object part aggregate'. By distinguishing topological coherence, topological adherence, and metric proximity we furthermore provide a differentiation of clusters and groups as two distinct subcategories for each of the three categories of material entity aggregates, resulting in six additional subcategories of material entity. CONCLUSIONS/SIGNIFICANCE: We suggest extending BFO to incorporate two additional categories of material entity as well as two subcategories for each of the three categories of material entity aggregates. With these additions, BFO would exhaustively cover all top-level types of material entity that application oriented ontologies may use as templates. Our result, however, depends on the premise that all material entities are organized according to a constitutive granularity. PMID- 21533044 TI - Identification of a phytase gene in barley (Hordeum vulgare L.). AB - BACKGROUND: Endogenous phytase plays a crucial role in phytate degradation and is thus closely related to nutrient efficiency in barley products. The understanding of genetic information of phytase in barley can provide a useful tool for breeding new barley varieties with high phytase activity. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative trait loci (QTL) analysis for phytase activity was conducted using a doubled haploid population. Phytase protein was purified and identified by the LC-ESI MS/MS Shotgun method. Purple acid phosphatase (PAP) gene was sequenced and the position was compared with the QTL controlling phytase activity. A major QTL for phytase activity was mapped to chromosome 5 H in barley. The gene controlling phytase activity in the region was named as mqPhy. The gene HvPAP a was mapped to the same position as mqPhy, supporting the colinearity between HvPAP a and mqPhy. CONCLUSIONS/SIGNIFICANCE: It is the first report on QTLs for phytase activity and the results showed that HvPAP a, which shares a same position with the QTL, is a major phytase gene in barley grains. PMID- 21533045 TI - Analysis of the plant bos1 mutant highlights necrosis as an efficient defence mechanism during D. dadantii/Arabidospis thaliana interaction. AB - Dickeya dadantii is a broad host range phytopathogenic bacterium provoking soft rot disease on many plants including Arabidopsis. We showed that, after D. dadantii infection, the expression of the Arabidopsis BOS1 gene was specifically induced by the production of the bacterial PelB/C pectinases able to degrade pectin. This prompted us to analyze the interaction between the bos1 mutant and D. dadantii. The phenotype of the infected bos1 mutant is complex. Indeed, maceration symptoms occurred more rapidly in the bos1 mutant than in the wild type parent but at a later stage of infection, a necrosis developed around the inoculation site that provoked a halt in the progression of the maceration. This necrosis became systemic and spread throughout the whole plant, a phenotype reminiscent of that observed in some lesion mimic mutants. In accordance with the progression of maceration symptoms, bacterial population began to grow more rapidly in the bos1 mutant than in the wild type plant but, when necrosis appeared in the bos1 mutant, a reduction in bacterial population was observed. From the plant side, this complex interaction between D. dadantii and its host includes an early plant defence response that comprises reactive oxygen species (ROS) production accompanied by the reinforcement of the plant cell wall by protein cross-linking. At later timepoints, another plant defence is raised by the death of the plant cells surrounding the inoculation site. This plant cell death appears to constitute an efficient defence mechanism induced by D. dadantii during Arabidopsis infection. PMID- 21533046 TI - Loss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development. AB - The AP-1 family transcription factor ATF2 is essential for development and tissue maintenance in mammals. In particular, ATF2 is highly expressed and activated in the brain and previous studies using mouse knockouts have confirmed its requirement in the cerebellum as well as in vestibular sense organs. Here we present the analysis of the requirement for ATF2 in CNS development in mouse embryos, specifically in the brainstem. We discovered that neuron-specific inactivation of ATF2 leads to significant loss of motoneurons of the hypoglossal, abducens and facial nuclei. While the generation of ATF2 mutant motoneurons appears normal during early development, they undergo caspase-dependent and independent cell death during later embryonic and foetal stages. The loss of these motoneurons correlates with increased levels of stress activated MAP kinases, JNK and p38, as well as aberrant accumulation of phosphorylated neurofilament proteins, NF-H and NF-M, known substrates for these kinases. This, together with other neuropathological phenotypes, including aberrant vacuolisation and lipid accumulation, indicates that deficiency in ATF2 leads to neurodegeneration of subsets of somatic and visceral motoneurons of the brainstem. It also confirms that ATF2 has a critical role in limiting the activities of stress kinases JNK and p38 which are potent inducers of cell death in the CNS. PMID- 21533047 TI - The transcriptional mediator component Med12 is required for hindbrain boundary formation. AB - BACKGROUND: Rhombomere boundaries form during hindbrain segmentation and are critical for maintaining segmental integrity and regulating migration in the hindbrain. Some genetic models affecting hindbrain boundary formation have been described, but involvement of components of the transcriptional mediator complex in boundary formation has not reported so far. PRINCIPAL FINDINGS: The kto/med12 mutant zebrafish, which affects the Mediator component Med12, causes specific loss of rhombomere boundary cells even though segmentation of the hindbrain takes place at least in part. In kto mutant embryos, cells forming rhombomere boundaries were largely absent as indicated by the use of several marker genes. While no obvious increase in cell death was observed, we found a notable reduction of cell proliferation in the hindbrain of kto mutant zebrafish. CONCLUSIONS: The kto/med12 mutation results in specific defects of boundary cell formation in the zebrafish hindbrain. PMID- 21533048 TI - Malaria prevalence, risk factors and spatial distribution in a hilly forest area of Bangladesh. AB - BACKGROUND: Malaria is a major public health concern in Bangladesh and it is highly endemic in the Chittagong Hill Tracts where prevalence was 11.7% in 2007. One sub-district, Rajasthali, had a prevalence of 36%. Several interventions were introduced in early 2007 to control malaria. This study was undertaken to evaluate the impacts of these intensive early stage interventions on malaria in Bangladesh. This prevalence study assesses whether or not high malaria prevalence remains, and if so, which areas and individuals remain at high risk of infection. METHODS AND PRINCIPAL FINDINGS: A 2-stage cluster sampling technique was used to sample 1,400 of 5,322 (26.3%) households in Rajasthali, and screened using a rapid diagnostic test (Falci-vax). Overall malaria prevalence was 11.5%. The proportions of Plasmodium falciparum, Plasmodium vivax and infection with both species were 93.2%, 1.9% and 5.0%, respectively. Univariate, multivariate logistic regression, and spatial cluster analyses were performed separately. Sex, age, number of bed nets, forest cover, altitude and household density were potential risk factors. A statistically significant malaria cluster was identified. Significant differences among risk factors were observed between cluster and non-cluster areas. CONCLUSION AND SIGNIFICANCE: Malaria has significantly decreased within 2 years after onset of intervention program. Both aspects of the physical and social environment, as well as demographic characteristics are associated with spatial heterogeneity of risk. The ability to identify and locate these areas provides a strategy for targeting interventions during initial stages of intervention programs. However, in high risk clusters of transmission, even extensive coverage by current programs leaves transmission ongoing at reduced levels. This indicates the need for continued development of new strategies for identification and treatment as well as improved understanding of the patterns and determinants of parasitaemia. PMID- 21533049 TI - Oligomerization of the E. coli core RNA polymerase: formation of (alpha2betabeta'omega)2-DNA complexes and regulation of the oligomerization by auxiliary subunits. AB - In this work, using multiple, dissimilar physico-chemical techniques, we demonstrate that the Escherichia coli RNA polymerase core enzyme obtained through a classic purification procedure forms stable (alpha(2)betabeta'omega)(2) complexes in the presence or absence of short DNA probes. Multiple control experiments indicate that this self-association is unlikely to be mediated by RNA polymerase-associated non-protein molecules. We show that the formation of (alpha(2)betabeta'omega)(2) complexes is subject to regulation by known RNA polymerase interactors, such as the auxiliary SWI/SNF subunit of RNA polymerase RapA, as well as NusA and sigma(70). We also demonstrate that the separation of the core RNA polymerase and RNA polymerase holoenzyme species during Mono Q chromatography is likely due to oligomerization of the core enzyme. We have analyzed the oligomeric state of the polymerase in the presence or absence of DNA, an aspect that was missing from previous studies. Importantly, our work demonstrates that RNA polymerase oligomerization is compatible with DNA binding. Through in vitro transcription and in vivo experiments (utilizing a RapA(R599/Q602) mutant lacking transcription-stimulatory function), we demonstrate that the formation of tandem (alpha(2)betabeta'omega)(2)-DNA complexes is likely functionally significant and beneficial for the transcriptional activity of the polymerase. Taken together, our findings suggest a novel structural aspect of the E. coli elongation complex. We hypothesize that transcription by tandem RNA polymerase complexes initiated at hypothetical bidirectional "origins of transcription" may explain recurring switches of the direction of transcription in bacterial genomes. PMID- 21533050 TI - Long astral microtubules and RACK-1 stabilize polarity domains during maintenance phase in Caenorhabditis elegans embryos. AB - Cell polarity is a very well conserved process important for cell differentiation, cell migration, and embryonic development. After the establishment of distinct cortical domains, polarity cues have to be stabilized and maintained within a fluid and dynamic membrane to achieve proper cell asymmetry. Microtubules have long been thought to deliver the signals required to polarize a cell. While previous studies suggest that microtubules play a key role in the establishment of polarity, the requirement of microtubules during maintenance phase remains unclear. In this study, we show that depletion of Caenorhabditis elegans RACK-1, which leads to short astral microtubules during prometaphase, specifically affects maintenance of cortical PAR domains and Dynamin localization. We then investigated the consequence of knocking down other factors that also abolish astral microtubule elongation during polarity maintenance phase. We found a correlation between short astral microtubules and the instability of PAR-6 and PAR-2 domains during maintenance phase. Our data support a necessary role for astral microtubules in the maintenance phase of cell polarity. PMID- 21533051 TI - Multiple Wnt/beta-catenin responsive enhancers align with the MYC promoter through long-range chromatin loops. AB - Inappropriate activation of c-Myc (MYC) gene expression by the Wnt/beta-catenin signaling pathway is required for colorectal carcinogenesis. The elevated MYC levels in colon cancer cells are attributed in part to beta-catenin/TCF4 transcription complexes that are assembled at proximal Wnt/beta-catenin responsive enhancers (WREs). Recent studies suggest that additional WREs that control MYC expression reside far upstream of the MYC transcription start site. Here, I report the characterization of five novel WREs that localize to a region over 400 kb upstream from MYC. These WREs harbor nucleosomes with post translational histone modifications that demarcate enhancer and gene promoter regions. Using quantitative chromatin conformation capture, I show that the distal WREs are aligned with the MYC promoter through large chromatin loops. The chromatin loops are not restricted to colon cancer cells, but are also found in kidney epithelial and lung fibroblast cell lines that lack de-regulated Wnt signaling and nuclear beta-catenin/TCF4 complexes. While each chromatin loop is detected in quiescent cells, the positioning of three of the five distal enhancers with the MYC promoter is induced by serum mitogens. These findings suggest that the architecture of the MYC promoter is comprised of distal elements that are juxtaposed through large chromatin loops and that beta-catenin/TCF4 complexes utilize this conformation to activate MYC expression in colon cancer cells. PMID- 21533052 TI - Crystallographic and molecular dynamics analysis of loop motions unmasking the peptidoglycan-binding site in stator protein MotB of flagellar motor. AB - BACKGROUND: The C-terminal domain of MotB (MotB-C) shows high sequence similarity to outer membrane protein A and related peptidoglycan (PG)-binding proteins. It is believed to anchor the power-generating MotA/MotB stator unit of the bacterial flagellar motor to the peptidoglycan layer of the cell wall. We previously reported the first crystal structure of this domain and made a puzzling observation that all conserved residues that are thought to be essential for PG recognition are buried and inaccessible in the crystal structure. In this study, we tested a hypothesis that peptidoglycan binding is preceded by, or accompanied by, some structural reorganization that exposes the key conserved residues. METHODOLOGY/PRINCIPAL FINDINGS: We determined the structure of a new crystalline form (Form B) of Helicobacter pylori MotB-C. Comparisons with the existing Form A revealed conformational variations in the petal-like loops around the carbohydrate binding site near one end of the beta-sheet. These variations are thought to reflect natural flexibility at this site required for insertion into the peptidoglycan mesh. In order to understand the nature of this flexibility we have performed molecular dynamics simulations of the MotB-C dimer. The results are consistent with the crystallographic data and provide evidence that the three loops move in a concerted fashion, exposing conserved MotB residues that have previously been implicated in binding of the peptide moiety of peptidoglycan. CONCLUSION/SIGNIFICANCE: Our structural analysis provides a new insight into the mechanism by which MotB inserts into the peptidoglycan mesh, thus anchoring the power-generating complex to the cell wall. PMID- 21533053 TI - GPS-CCD: a novel computational program for the prediction of calpain cleavage sites. AB - As one of the most essential post-translational modifications (PTMs) of proteins, proteolysis, especially calpain-mediated cleavage, plays an important role in many biological processes, including cell death/apoptosis, cytoskeletal remodeling, and the cell cycle. Experimental identification of calpain targets with bona fide cleavage sites is fundamental for dissecting the molecular mechanisms and biological roles of calpain cleavage. In contrast to time consuming and labor-intensive experimental approaches, computational prediction of calpain cleavage sites might more cheaply and readily provide useful information for further experimental investigation. In this work, we constructed a novel software package of GPS-CCD (Calpain Cleavage Detector) for the prediction of calpain cleavage sites, with an accuracy of 89.98%, sensitivity of 60.87% and specificity of 90.07%. With this software, we annotated potential calpain cleavage sites for hundreds of calpain substrates, for which the exact cleavage sites had not been previously determined. In this regard, GPS-CCD 1.0 is considered to be a useful tool for experimentalists. The online service and local packages of GPS-CCD 1.0 were implemented in JAVA and are freely available at: http://ccd.biocuckoo.org/. PMID- 21533054 TI - Efficient conversion of phenylpyruvic acid to phenyllactic acid by using whole cells of Bacillus coagulans SDM. AB - BACKGROUND: Phenyllactic acid (PLA), a novel antimicrobial compound with broad and effective antimicrobial activity against both bacteria and fungi, can be produced by many microorganisms, especially lactic acid bacteria. However, the concentration and productivity of PLA have been low in previous studies. The enzymes responsible for conversion of phenylpyruvic acid (PPA) into PLA are equivocal. METHODOLOGY/PRINCIPAL FINDINGS: A novel thermophilic strain, Bacillus coagulans SDM, was isolated for production of PLA. When the solubility and dissolution rate of PPA were enhanced at a high temperature, whole cells of B. coagulans SDM could effectively convert PPA into PLA at a high concentration (37.3 g l(-1)) and high productivity (2.3 g l(-1) h(-1)) under optimal conditions. Enzyme activity staining and kinetic studies identified NAD-dependent lactate dehydrogenases as the key enzymes that reduced PPA to PLA. CONCLUSIONS/SIGNIFICANCE: Taking advantage of the thermophilic character of B. coagulans SDM, a high yield and productivity of PLA were obtained. The enzymes involved in PLA production were identified and characterized, which makes possible the rational design and construction of microorganisms suitable for PLA production with metabolic engineering. PMID- 21533055 TI - Behavioural adjustment in response to increased predation risk: a study in three duck species. AB - Predation directly triggers behavioural decisions designed to increase immediate survival. However, these behavioural modifications can have long term costs. There is therefore a trade-off between antipredator behaviours and other activities. This trade-off is generally considered between vigilance and only one other behaviour, thus neglecting potential compensations. In this study, we considered the effect of an increase in predation risk on the diurnal time-budget of three captive duck species during the wintering period. We artificially increased predation risk by disturbing two groups of 14 mallard and teals at different frequencies, and one group of 14 tufted ducks with a radio-controlled stressor. We recorded foraging, vigilance, preening and sleeping durations the week before, during and after disturbance sessions. Disturbed groups were compared to an undisturbed control group. We showed that in all three species, the increase in predation risk resulted in a decrease in foraging and preening and led to an increase in sleeping. It is worth noting that contrary to common observations, vigilance did not increase. However, ducks are known to be vigilant while sleeping. This complex behavioural adjustment therefore seems to be optimal as it may allow ducks to reduce their predation risk. Our results highlight the fact that it is necessary to encompass the whole individual time-budget when studying behavioural modifications under predation risk. Finally, we propose that studies of behavioural time-budget changes under predation risk should be included in the more general framework of the starvation-predation risk trade off. PMID- 21533056 TI - X linkage of AP3A, a homolog of the Y-linked MADS-box gene AP3Y in Silene latifolia and S. dioica. AB - BACKGROUND: The duplication of autosomal genes onto the Y chromosome may be an important element in the evolution of sexual dimorphism. A previous cytological study reported on a putative example of such a duplication event in a dioecious tribe of Silene (Caryophyllaceae): it was inferred that the Y-linked MADS-box gene AP3Y originated from a duplication of the reportedly autosomal ortholog AP3A. However, a recent study, also using cytological methods, indicated that AP3A is X-linked in Silene latifolia. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we hybridized S. latifolia and S. dioica to investigate whether the pattern of X linkage is consistent among distinct populations, occurs in both species, and is robust to genetic methods. We found inheritance patterns indicative of X linkage of AP3A in widely distributed populations of both species. CONCLUSIONS/SIGNIFICANCE: X linkage of AP3A and Y linkage of AP3Y in both species indicates that the genes' ancestral progenitor resided on the autosomes that gave rise to the sex chromosomes and that neither gene has moved between chromosomes since species divergence. Consequently, our results do not support the contention that inter-chromosomal gene transfer occurred in the evolution of SlAP3Y from SlAP3A. PMID- 21533057 TI - Positive interspecific relationship between temporal occurrence and abundance in insects. AB - One of the most studied macroecological patterns is the interspecific abundance occupancy relationship, which relates species distribution and abundance across space. Interspecific relationships between temporal distribution and abundance, however, remain largely unexplored. Using data for a natural assemblage of tabanid flies measured daily during spring and summer in Nova Scotia, we found that temporal occurrence (proportion of sampling dates in which a species occurred in an experimental trap) was positively related to temporal mean abundance (number of individuals collected for a species during the study period divided by the total number of sampling dates). Moreover, two models that often describe spatial abundance-occupancy relationships well, the He-Gaston and negative binomial models, explained a high amount of the variation in our temporal data. As for the spatial abundance-occupancy relationship, the (temporal) aggregation parameter, k, emerged as an important component of the hereby named interspecific temporal abundance-occurrence relationship. This may be another case in which a macroecological pattern shows similarities across space and time, and it deserves further research because it may improve our ability to forecast colonization dynamics and biological impacts. PMID- 21533058 TI - The cytoplasmic domain of MUC1 induces hyperplasia in the mammary gland and correlates with nuclear accumulation of beta-catenin. AB - MUC1 is an oncoprotein that is overexpressed in up to 90% of breast carcinomas. A previous in vitro study by our group demonstrated that the cytoplasmic domain of MUC1 (MUC1-CD), the minimal functional unit of MUC1, contributes to the malignant phenotype in cells by binding directly to beta-catenin and protecting beta catenin from GSK3beta-induced degradation. To understand the in vivo role of MUC1 CD in breast development, we generated a MUC1-CD transgenic mouse model under the control of the MMTV promoter in a C57BL/6J background, which is more resistant to breast tumor. We show that the expression of MUC1-CD in luminal epithelial cells of the mammary gland induced a hyperplasia phenotype characterized by the development of hyper-branching and extensive lobuloalveoli in transgenic mice. In addition to this hyperplasia, there was a marked increase in cellular proliferation in the mouse mammary gland. We further show that MUC1-CD induces nuclear localization of beta-catenin, which is associated with a significant increase of beta-catenin activity, as shown by the elevated expression of cyclin D1 and c-Myc in MMTV-MUC1-CD mice. Consistent with this finding, we observed that overexpression of MUC1-C is associated with beta-catenin nuclear localization in tumor tissues and increased expression of Cyclin D1 and c-Myc in breast carcinoma specimens. Collectively, our data indicate a critical role for MUC1-CD in the development of mammary gland preneoplasia and tumorigenesis, suggesting MUC1-CD as a potential target for the diagnosis and chemoprevention of human breast cancer. PMID- 21533059 TI - A tethered bilayer assembled on top of immobilized calmodulin to mimic cellular compartmentalization. AB - BACKGROUND: Biomimetic membrane models tethered on solid supports are important tools for membrane protein biochemistry and biotechnology. The supported membrane systems described up to now are composed of a lipid bilayer tethered or not to a surface separating two compartments: a "trans" side, one to a few nanometer thick, located between the supporting surface and the membrane; and a "cis" side, above the synthetic membrane, exposed to the bulk medium. We describe here a novel biomimetic design composed of a tethered bilayer membrane that is assembled over a surface derivatized with a specific intracellular protein marker. This multilayered biomimetic assembly exhibits the fundamental characteristics of an authentic biological membrane in creating a continuous yet fluid phospholipidic barrier between two distinct compartments: a "cis" side corresponding to the extracellular milieu and a "trans" side marked by a key cytosolic signaling protein, calmodulin. METHODOLOGY/PRINCIPAL FINDINGS: We established and validated the experimental conditions to construct a multilayered structure consisting in a planar tethered bilayer assembled over a surface derivatized with calmodulin. We demonstrated the following: (i) the grafted calmodulin molecules (in trans side) were fully functional in binding and activating a calmodulin-dependent enzyme, the adenylate cyclase from Bordetella pertussis; and (ii) the assembled bilayer formed a continuous, protein-impermeable boundary that fully separated the underlying calmodulin (trans side) from the above medium (cis side). CONCLUSIONS: The simplicity and robustness of the tethered bilayer structure described here should facilitate the elaboration of biomimetic membrane models incorporating membrane embedded proteins and key cytoplasmic constituents. Such biomimetic structures will also be an attractive tool to study translocation across biological membranes of proteins or other macromolecules. PMID- 21533060 TI - Assessment of cardiovascular fibrosis using novel fluorescent probes. AB - Cardiovascular fibrosis resulted from pressure overload or ischemia could alter myocardial stiffness and lead to ventricular dysfunction. Fluorescently labeled collagen-binding protein CNA 35, derived from the surface component of Staphylococcus aureus, and a novel synthetic biphenylalanine containing peptide are applied to stain fibrosis associated collagen and myocytes, respectively. Detailed pathological characteristics of cardiovascular fibrosis could be identified clearly in 2 hours. This staining pair requires only simple staining and brief washing, generating less than 10 ml of waste. The image information collected by this novel fluorescent staining pair is compatible with it collected by the traditional Masson's Trichrome and Picrosirius Red staining which are widely used to stain cardiovascular fibrosis and isolated cells. PMID- 21533061 TI - Mapping the binding between the tetraspanin molecule (Sjc23) of Schistosoma japonicum and human non-immune IgG. AB - BACKGROUND: Schistosomal parasites can establish parasitization in a human host for decades; evasion of host immunorecognition including surface masking by acquisition of host serum components is one of the strategies explored by the parasites. Parasite molecules anchored on the membrane are the main elements in the interaction. Sjc23, a member of the tetraspanin (TSP) family of Schistosoma japonicum, was previously found to be highly immunogenic and regarded as a vaccine candidate against schistosomiasis. However, studies indicated that immunization with Sjc23 generated rapid antibody responses which were less protective than that with other antigens. The biological function of this membrane-anchored molecule has not been defined after decades of vaccination studies. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we explored affinity pull-down and peptide competition assays to investigate the potential binding between Sjc23 molecule and human non-immune IgG. We determined that Sjc23 could bind human non-immune IgG and the binding was through the interaction of the large extra-cellular domain (LED) of Sjc23 (named Sjc23-LED) with the Fc domain of human IgG. Sjc23 had no affinity to other immunoglobulin types. Affinity precipitation (pull-down assay) in the presence of overlapping peptides further pinpointed to a 9-amino acid motif within Sjc23-LED that mediated the binding to human IgG. CONCLUSION AND SIGNIFICANCE: S. japonicum parasites cloak themselves through interaction with human non-immune IgG, and a member of the tetraspanin family, Sjc23, mediated the acquisition of human IgG via the interaction of a motif of 9 amino acids with the Fc domain of the IgG molecule. The consequence of this interaction will likely benefit parasitism of S. japonicum by evasion of host immune recognition or immunoresponses. This is the first report that an epitope of schistosomal ligand and its immunoglobulin receptor are defined, which provides further evidence of immune evasion strategy adopted by S. japonicum. PMID- 21533062 TI - LARGE expression augments the glycosylation of glycoproteins in addition to alpha dystroglycan conferring laminin binding. AB - Mutations in genes encoding glycosyltransferases (and presumed glycosyltransferases) that affect glycosylation and extracellular matrix binding activity of alpha-dystroglycan (alpha-DG) cause congenital muscular dystrophies (CMDs) with central nervous system manifestations. Among the identified genes, LARGE is of particular interest because its overexpression rescues glycosylation defects of alpha-DG in mutations of not only LARGE but also other CMD-causing genes and restores laminin binding activity of alpha-DG. It is not known whether LARGE protein glycosylates other proteins in addition to alpha-DG. In this study, we overexpressed LARGE in DG-deficient cells and analyzed glycosylated proteins by Western blot analysis. Surprisingly, overexpression of LARGE in alpha-DG deficient cells led to glycosylation dependent IIH6C4 and VIA4-1 immunoreactivity, despite the prevailing view that these antibodies only recognize glycosylated alpha-DG. Furthermore, the hyperglycosylated proteins in LARGE-overexpressing cells demonstrated the functional capacity to bind the extracellular matrix molecule laminin and promote laminin assembly at the cell surface, an effect that was blocked by IIH6C4 antibodies. These results indicate that overexpression of LARGE catalyzes the glycosylation of at least one other glycoprotein in addition to alpha-DG, and that this glycosylation(s) promotes laminin binding activity. PMID- 21533063 TI - AtPV42a and AtPV42b redundantly regulate reproductive development in Arabidopsis thaliana. AB - BACKGROUND: The conserved SNF1/AMPK/SnRK1 complexes are global regulators of metabolic responses in eukaryotes and play a key role in the control of energy balance. Although alpha-type subunits of the SnRK1 complex have been characterized in several plant species, the biological function of beta-type and gamma-type subunits remains largely unknown. Here, we characterized AtPV42a and AtPV42b, the two homologous genes in Arabidopsis, which encode cystathionine-beta synthase (CBS) domain-containing proteins that belong to the PV42 class of gamma type subunits of the plant SnRK1 complexes. METHODOLOGY/PRINCIPAL FINDINGS: Real time polymerase chain reaction was performed to examine the expression of AtPV42a and AtPV42b in various tissues. Transgenic plants that expressed artificial microRNAs targeting these two genes were created. Reproductive organ development and fertilization in these plants were examined by various approaches, including histological analysis, scanning electron microscopy, transmission electron microscopy, and phenotypic analyses of reciprocal crosses between wild-type and transgenic plants. We found that AtPV42a and AtPV42b were expressed in various tissues during different developmental stages. Transgenic plants where AtPV42a and AtPV42b were simultaneously silenced developed shorter siliques and reduced seed sets. Such low fertility phenotype resulted from deregulation of late stamen development and impairment of pollen tube attraction conferred by the female gametophyte. CONCLUSIONS: Our results demonstrate that AtPV42a and AtPV42b play redundant roles in regulating male gametogenesis and pollen tube guidance, indicating that the Arabidopsis SnRK1 complexes might be involved in the control of reproductive development. PMID- 21533064 TI - New insights into the Lake Chad Basin population structure revealed by high throughput genotyping of mitochondrial DNA coding SNPs. AB - BACKGROUND: Located in the Sudan belt, the Chad Basin forms a remarkable ecosystem, where several unique agricultural and pastoral techniques have been developed. Both from an archaeological and a genetic point of view, this region has been interpreted to be the center of a bidirectional corridor connecting West and East Africa, as well as a meeting point for populations coming from North Africa through the Saharan desert. METHODOLOGY/PRINCIPAL FINDINGS: Samples from twelve ethnic groups from the Chad Basin (n = 542) have been high-throughput genotyped for 230 coding region mitochondrial DNA (mtDNA) Single Nucleotide Polymorphisms (mtSNPs) using Matrix-Assisted Laser Desorption/Ionization Time-Of Flight (MALDI-TOF) mass spectrometry. This set of mtSNPs allowed for much better phylogenetic resolution than previous studies of this geographic region, enabling new insights into its population history. Notable haplogroup (hg) heterogeneity has been observed in the Chad Basin mirroring the different demographic histories of these ethnic groups. As estimated using a Bayesian framework, nomadic populations showed negative growth which was not always correlated to their estimated effective population sizes. Nomads also showed lower diversity values than sedentary groups. CONCLUSIONS/SIGNIFICANCE: Compared to sedentary population, nomads showed signals of stronger genetic drift occurring in their ancestral populations. These populations, however, retained more haplotype diversity in their hypervariable segments I (HVS-I), but not their mtSNPs, suggesting a more ancestral ethnogenesis. Whereas the nomadic population showed a higher Mediterranean influence signaled mainly by sub-lineages of M1, R0, U6, and U5, the other populations showed a more consistent sub-Saharan pattern. Although lifestyle may have an influence on diversity patterns and hg composition, analysis of molecular variance has not identified these differences. The present study indicates that analysis of mtSNPs at high resolution could be a fast and extensive approach for screening variation in population studies where labor intensive techniques such as entire genome sequencing remain unfeasible. PMID- 21533065 TI - Quantifying the relative contributions of divisive and subtractive feedback to rhythm generation. AB - Biological systems are characterized by a high number of interacting components. Determining the role of each component is difficult, addressed here in the context of biological oscillations. Rhythmic behavior can result from the interplay of positive feedback that promotes bistability between high and low activity, and slow negative feedback that switches the system between the high and low activity states. Many biological oscillators include two types of negative feedback processes: divisive (decreases the gain of the positive feedback loop) and subtractive (increases the input threshold) that both contribute to slowly move the system between the high- and low-activity states. Can we determine the relative contribution of each type of negative feedback process to the rhythmic activity? Does one dominate? Do they control the active and silent phase equally? To answer these questions we use a neural network model with excitatory coupling, regulated by synaptic depression (divisive) and cellular adaptation (subtractive feedback). We first attempt to apply standard experimental methodologies: either passive observation to correlate the variations of a variable of interest to system behavior, or deletion of a component to establish whether a component is critical for the system. We find that these two strategies can lead to contradictory conclusions, and at best their interpretive power is limited. We instead develop a computational measure of the contribution of a process, by evaluating the sensitivity of the active (high activity) and silent (low activity) phase durations to the time constant of the process. The measure shows that both processes control the active phase, in proportion to their speed and relative weight. However, only the subtractive process plays a major role in setting the duration of the silent phase. This computational method can be used to analyze the role of negative feedback processes in a wide range of biological rhythms. PMID- 21533066 TI - Engineered resistance to Plasmodium falciparum development in transgenic Anopheles stephensi. AB - Transposon-mediated transformation was used to produce Anopheles stephensi that express single-chain antibodies (scFvs) designed to target the human malaria parasite, Plasmodium falciparum. The scFvs, m1C3, m4B7, and m2A10, are derived from mouse monoclonal antibodies that inhibit either ookinete invasion of the midgut or sporozoite invasion of salivary glands. The scFvs that target the parasite surface, m4B7 and m2A10, were fused to an Anopheles gambiae antimicrobial peptide, Cecropin A. Previously-characterized Anopheles cis-acting DNA regulatory elements were included in the transgenes to coordinate scFv production with parasite development. Gene amplification and immunoblot analyses showed promoter-specific increases in transgene expression in blood-fed females. Transgenic mosquito lines expressing each of the scFv genes had significantly lower infection levels than controls when challenged with P. falciparum. PMID- 21533067 TI - In silico elucidation of the recognition dynamics of ubiquitin. AB - Elucidation of the mechanism of biomacromolecular recognition events has been a topic of intense interest over the past century. The inherent dynamic nature of both protein and ligand molecules along with the continuous reshaping of the energy landscape during the binding process renders it difficult to characterize this process at atomic detail. Here, we investigate the recognition dynamics of ubiquitin via microsecond all-atom molecular dynamics simulation providing both thermodynamic and kinetic information. The high-level of consistency found with respect to experimental NMR data lends support to the accuracy of the in silico representation of the conformational substates and their interconversions of free ubiquitin. Using an energy-based reweighting approach, the statistical distribution of conformational states of ubiquitin is monitored as a function of the distance between ubiquitin and its binding partner Hrs-UIM. It is found that extensive and dense sampling of conformational space afforded by the us MD trajectory is essential for the elucidation of the binding mechanism as is Boltzmann sampling, overcoming inherent limitations of sparsely sampled empirical ensembles. The results reveal a population redistribution mechanism that takes effect when the ligand is at intermediate range of 1-2 nm from ubiquitin. This mechanism, which may be depicted as a superposition of the conformational selection and induced fit mechanisms, also applies to other binding partners of ubiquitin, such as the GGA3 GAT domain. PMID- 21533068 TI - Innate immune sensing of DNA. PMID- 21533069 TI - A Yersinia effector with enhanced inhibitory activity on the NF-kappaB pathway activates the NLRP3/ASC/caspase-1 inflammasome in macrophages. AB - A type III secretion system (T3SS) in pathogenic Yersinia species functions to translocate Yop effectors, which modulate cytokine production and regulate cell death in macrophages. Distinct pathways of T3SS-dependent cell death and caspase 1 activation occur in Yersinia-infected macrophages. One pathway of cell death and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an acetyltransferase that inactivates MAPK kinases and IKKbeta to cause TLR4 dependent apoptosis in naive macrophages. A YopJ isoform in Y. pestis KIM (YopJ(KIM)) has two amino acid substitutions, F177L and K206E, not present in YopJ proteins of Y. pseudotuberculosis and Y. pestis CO92. As compared to other YopJ isoforms, YopJ(KIM) causes increased apoptosis, caspase-1 activation, and secretion of IL-1beta in Yersinia-infected macrophages. The molecular basis for increased apoptosis and activation of caspase-1 by YopJ(KIM) in Yersinia-infected macrophages was studied. Site directed mutagenesis showed that the F177L and K206E substitutions in YopJ(KIM) were important for enhanced apoptosis, caspase-1 activation, and IL-1beta secretion. As compared to YopJ(CO92), YopJ(KIM) displayed an enhanced capacity to inhibit phosphorylation of IkappaB-alpha in macrophages and to bind IKKbeta in vitro. YopJ(KIM) also showed a moderately increased ability to inhibit phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1beta secretion occurred in IKKbeta-deficient macrophages infected with Y. pestis expressing YopJ(CO92), confirming that the NF-kappaB pathway can negatively regulate inflammasome activation. K+ efflux, NLRP3 and ASC were important for secretion of IL-1beta in response to Y. pestis KIM infection as shown using macrophages lacking inflammasome components or by the addition of exogenous KCl. These data show that caspase-1 is activated in naive macrophages in response to infection with a pathogen that inhibits IKKbeta and MAPK kinases and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis may represent an early innate immune response to highly virulent pathogens such as Y. pestis KIM that have evolved an enhanced ability to inhibit host signaling pathways. PMID- 21533070 TI - Accessing a hidden conformation of the maltose binding protein using accelerated molecular dynamics. AB - Periplasmic binding proteins (PBPs) are a large family of molecular transporters that play a key role in nutrient uptake and chemotaxis in Gram-negative bacteria. All PBPs have characteristic two-domain architecture with a central interdomain ligand-binding cleft. Upon binding to their respective ligands, PBPs undergo a large conformational change that effectively closes the binding cleft. This conformational change is traditionally viewed as a ligand induced-fit process; however, the intrinsic dynamics of the protein may also be crucial for ligand recognition. Recent NMR paramagnetic relaxation enhancement (PRE) experiments have shown that the maltose binding protein (MBP) - a prototypical member of the PBP superfamily - exists in a rapidly exchanging (ns to us regime) mixture comprising an open state (approx 95%), and a minor partially closed state (approx 5%). Here we describe accelerated MD simulations that provide a detailed picture of the transition between the open and partially closed states, and confirm the existence of a dynamical equilibrium between these two states in apo MBP. We find that a flexible part of the protein called the balancing interface motif (residues 175-184) is displaced during the transformation. Continuum electrostatic calculations indicate that the repacking of non-polar residues near the hinge region plays an important role in driving the conformational change. Oscillations between open and partially closed states create variations in the shape and size of the binding site. The study provides a detailed description of the conformational space available to ligand-free MBP, and has implications for understanding ligand recognition and allostery in related proteins. PMID- 21533071 TI - The Clostridium difficile cell wall protein CwpV is antigenically variable between strains, but exhibits conserved aggregation-promoting function. AB - Clostridium difficile is the main cause of antibiotic-associated diarrhea, leading to significant morbidity and mortality and putting considerable economic pressure on healthcare systems. Current knowledge of the molecular basis of pathogenesis is limited primarily to the activities and regulation of two major toxins. In contrast, little is known of mechanisms used in colonization of the enteric system. C. difficile expresses a proteinaceous array on its cell surface known as the S-layer, consisting primarily of the major S-layer protein SlpA and a family of SlpA homologues, the cell wall protein (CWP) family. CwpV is the largest member of this family and is expressed in a phase variable manner. Here we show CwpV promotes C. difficile aggregation, mediated by the C-terminal repetitive domain. This domain varies markedly between strains; five distinct repeat types were identified and were shown to be antigenically distinct. Other aspects of CwpV are, however, conserved. All CwpV types are expressed in a phase variable manner. Using targeted gene knock-out, we show that a single site specific recombinase RecV is required for CwpV phase variation. CwpV is post translationally cleaved at a conserved site leading to formation of a complex of cleavage products. The highly conserved N-terminus anchors the CwpV complex to the cell surface. Therefore CwpV function, regulation and processing are highly conserved across C. difficile strains, whilst the functional domain exists in at least five antigenically distinct forms. This hints at a complex evolutionary history for CwpV. PMID- 21533072 TI - Linking microscopic spatial patterns of tissue destruction in emphysema to macroscopic decline in stiffness using a 3D computational model. AB - Pulmonary emphysema is a connective tissue disease characterized by the progressive destruction of alveolar walls leading to airspace enlargement and decreased elastic recoil of the lung. However, the relationship between microscopic tissue structure and decline in stiffness of the lung is not well understood. In this study, we developed a 3D computational model of lung tissue in which a pre-strained cuboidal block of tissue was represented by a tessellation of space filling polyhedra, with each polyhedral unit-cell representing an alveolus. Destruction of alveolar walls was mimicked by eliminating faces that separate two polyhedral either randomly or in a spatially correlated manner, in which the highest force bearing walls were removed at each step. Simulations were carried out to establish a link between the geometries that emerged and the rate of decline in bulk modulus of the tissue block. The spatially correlated process set up by the force-based destruction lead to a significantly faster rate of decline in bulk modulus accompanied by highly heterogeneous structures than the random destruction pattern. Using the Karhunen Loeve transformation, an estimator of the change in bulk modulus from the first four moments of airspace cell volumes was setup. Simulations were then obtained for tissue destruction with different idealized alveolar geometry, levels of pre strain, linear and nonlinear elasticity assumptions for alveolar walls and also mixed destruction patterns where both random and force-based destruction occurs simultaneously. In all these cases, the change in bulk modulus from cell volumes was accurately estimated. We conclude that microscopic structural changes in emphysema and the associated decline in tissue stiffness are linked by the spatial pattern of the destruction process. PMID- 21533074 TI - GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma. AB - Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL associated locus on 6p21.32, rs2647012 (OR(combined) = 0.64, P(combined) = 2 * 10(-21)) located 962 bp away from rs10484561 (r(2)<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:OR(adjusted) = 0.70, P(adjusted) = 4 * 10(-12); rs10484561:OR(adjusted) = 1.64, P(adjusted) = 5 * 10(-15)). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (OR(combined) = 1.36, P(combined) = 1.4 * 10(-7)). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL. PMID- 21533073 TI - Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response. AB - We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autologous T cells in vitro, which were analyzed by multi-color flow cytometry. Deletion of the NS1, but not NS2, protein resulted in three major effects: (i) an increased activation and proliferation of CD8+ T cells that express CD103, a tissue homing integrin that directs CD8+ T cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of Th17 cells, which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of IL-4-producing CD4+ T cells--which are associated with enhanced RSV disease--and reduced proliferation of total CD4+ T cells. Except for total CD4+ T cell proliferation, none of the T cell effects appeared to be due to increased IFN-I signaling. In the infected DC, deletion of the NS1 and NS2 genes strongly up-regulated the expression of cytokines and other molecules involved in DC maturation. This was partly IFN-I-independent, and thus might account for the T cell effects. Taken together, these data demonstrate that the NS1 protein suppresses proliferation and activation of two of the protective cell populations (CD103+ CD8+ T cells and Th17 cells), and promotes proliferation and activation of Th2 cells that can enhance RSV disease. PMID- 21533075 TI - NK cell receptor/H2-Dk-dependent host resistance to viral infection is quantitatively modulated by H2q inhibitory signals. AB - The cytomegalovirus resistance locus Cmv3 has been linked to an epistatic interaction between two loci: a Natural Killer (NK) cell receptor gene and the major histocompatibility complex class I (MHC-I) locus. To demonstrate the interaction between Cmv3 and H2(k), we generated double congenic mice between MA/My and BALB.K mice and an F(2) cross between FVB/N (H-2(q)) and BALB.K (H2(k)) mice, two strains susceptible to mouse cytomegalovirus (MCMV). Only mice expressing H2(k) in conjunction with Cmv3(MA/My) or Cmv3(FVB) were resistant to MCMV infection. Subsequently, an F(3) cross was carried out between transgenic FVB/H2-D(k) and MHC-I deficient mice in which only the progeny expressing Cmv3(FVB) and a single H2-D(k) class-I molecule completely controlled MCMV viral loads. This phenotype was shown to be NK cell-dependent and associated with subsequent NK cell proliferation. Finally, we demonstrated that a number of H2(q) alleles influence the expression level of H2(q) molecules, but not intrinsic functional properties of NK cells; viral loads, however, were quantitatively proportional to the number of H2(q) alleles. Our results support a model in which H-2(q) molecules convey Ly49-dependent inhibitory signals that interfere with the action of H2-D(k) on NK cell activation against MCMV infection. Thus, the integration of activating and inhibitory signals emanating from various MHC-I/NK cell receptor interactions regulates NK cell-mediated control of viral load. PMID- 21533076 TI - Ribosomal DNA deletions modulate genome-wide gene expression: "rDNA-sensitive" genes and natural variation. AB - The ribosomal rDNA gene array is an epigenetically-regulated repeated gene locus. While rDNA copy number varies widely between and within species, the functional consequences of subtle copy number polymorphisms have been largely unknown. Deletions in the Drosophila Y-linked rDNA modifies heterochromatin-induced position effect variegation (PEV), but it has been unknown if the euchromatic component of the genome is affected by rDNA copy number. Polymorphisms of naturally occurring Y chromosomes affect both euchromatin and heterochromatin, although the elements responsible for these effects are unknown. Here we show that copy number of the Y-linked rDNA array is a source of genome-wide variation in gene expression. Induced deletions in the rDNA affect the expression of hundreds to thousands of euchromatic genes throughout the genome of males and females. Although the affected genes are not physically clustered, we observed functional enrichments for genes whose protein products are located in the mitochondria and are involved in electron transport. The affected genes significantly overlap with genes affected by natural polymorphisms on Y chromosomes, suggesting that polymorphic rDNA copy number is an important determinant of gene expression diversity in natural populations. Altogether, our results indicate that subtle changes to rDNA copy number between individuals may contribute to biologically relevant phenotypic variation. PMID- 21533077 TI - Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. AB - About half of the mitochondrial DNA (mtDNA) mutations causing diseases in humans occur in tRNA genes. Particularly intriguing are those pathogenic tRNA mutations than can reach homoplasmy and yet show very different penetrance among patients. These mutations are scarce and, in addition to their obvious interest for understanding human pathology, they can be excellent experimental examples to model evolution and fixation of mitochondrial tRNA mutations. To date, the only source of this type of mutations is human patients. We report here the generation and characterization of the first mitochondrial tRNA pathological mutation in mouse cells, an m.3739G>A transition in the mitochondrial mt-Ti gene. This mutation recapitulates the molecular hallmarks of a disease-causing mutation described in humans, an m.4290T>C transition affecting also the human mt-Ti gene. We could determine that the pathogenic molecular mechanism, induced by both the mouse and the human mutations, is a high frequency of abnormal folding of the tRNA(Ile) that cannot be charged with isoleucine. We demonstrate that the cells harboring the mouse or human mutant tRNA have exacerbated mitochondrial biogenesis triggered by an increase in mitochondrial ROS production as a compensatory response. We propose that both the nature of the pathogenic mechanism combined with the existence of a compensatory mechanism can explain the penetrance pattern of this mutation. This particular behavior can allow a scenario for the evolution of mitochondrial tRNAs in which the fixation of two alleles that are individually deleterious can proceed in two steps and not require the simultaneous mutation of both. PMID- 21533079 TI - Chimpanzee vocal signaling points to a multimodal origin of human language. AB - The evolutionary origin of human language and its neurobiological foundations has long been the object of intense scientific debate. Although a number of theories have been proposed, one particularly contentious model suggests that human language evolved from a manual gestural communication system in a common ape human ancestor. Consistent with a gestural origins theory are data indicating that chimpanzees intentionally and referentially communicate via manual gestures, and the production of manual gestures, in conjunction with vocalizations, activates the chimpanzee Broca's area homologue--a region in the human brain that is critical for the planning and execution of language. However, it is not known if this activity observed in the chimpanzee Broca's area is the result of the chimpanzees producing manual communicative gestures, communicative sounds, or both. This information is critical for evaluating the theory that human language evolved from a strictly manual gestural system. To this end, we used positron emission tomography (PET) to examine the neural metabolic activity in the chimpanzee brain. We collected PET data in 4 subjects, all of whom produced manual communicative gestures. However, 2 of these subjects also produced so called attention-getting vocalizations directed towards a human experimenter. Interestingly, only the two subjects that produced these attention-getting sounds showed greater mean metabolic activity in the Broca's area homologue as compared to a baseline scan. The two subjects that did not produce attention-getting sounds did not. These data contradict an exclusive "gestural origins" theory for they suggest that it is vocal signaling that selectively activates the Broca's area homologue in chimpanzees. In other words, the activity observed in the Broca's area homologue reflects the production of vocal signals by the chimpanzees, suggesting that this critical human language region was involved in vocal signaling in the common ancestor of both modern humans and chimpanzees. PMID- 21533078 TI - PDP-1 links the TGF-beta and IIS pathways to regulate longevity, development, and metabolism. AB - The insulin/IGF-1 signaling (IIS) pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase), AGE-1 (PI 3-kinase), and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-beta signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-beta signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-beta signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease. PMID- 21533080 TI - Proline-rich tyrosine kinase 2 (Pyk2) promotes cell motility of hepatocellular carcinoma through induction of epithelial to mesenchymal transition. AB - AIMS: Proline-rich tyrosine kinase 2 (Pyk2), a non-receptor tyrosine kinase of the focal adhesion kinase (FAK) family, is up-regulated in more than 60% of the tumors of hepatocellular carcinoma (HCC) patients. Forced overexpression of Pyk2 can promote the proliferation and invasion of HCC cells. In this study, we aimed to explore the underlying molecular mechanism of Pyk2-mediated cell migration of HCC cells. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that Pyk2 transformed the epithelial HCC cell line Hep3B into a mesenchymal phenotype via the induction of epithelial to mesenchymal transition (EMT), signified by the up-regulation of membrane ruffle formation, activation of Rac/Rho GTPases, down-regulation of epithelial genes E-cadherin and cytokeratin as well as promotion of cell motility in presence of lysophosphatidic acid (LPA). Suppression of Pyk2 by overexpression of dominant negative PRNK domain in the metastatic HCC cell line MHCC97L transformed its fibroblastoid phenotype to an epithelial phenotype with up regulation of epithelial genes, down-regulation of mesenchymal genes N-cadherin and STAT5b, and reduction of LPA-induced membrane ruffle formation and cell motility. Moreover, overexpression of Pyk2 in Hep3B cells promoted the phosphorylation and localization of mesenchymal gene Hic-5 onto cell membrane while suppression of Pyk2 in MHCC97L cells attenuated its phosphorylation and localization. CONCLUSION: These data provided new evidence of the underlying mechanism of Pyk2 in controlling cell motility of HCC cells through regulation of genes associated with EMT. PMID- 21533081 TI - TLR2-dependent induction of IL-10 and Foxp3+ CD25+ CD4+ regulatory T cells prevents effective anti-tumor immunity induced by Pam2 lipopeptides in vivo. AB - 16 S-[2,3-bis(palmitoyl)propyl]cysteine (Pam2) lipopeptides act as toll-like receptor (TLR)2/6 ligands and activate natural killer (NK) cells and dendritic cells (DCs) to produce inflammatory cytokines and cytotoxic NK activity in vitro. However, in this study, we found that systemic injection of Pam2 lipopeptides was not effective for the suppression of NK-sensitive B16 melanomas in vivo. When we investigated the immune suppressive mechanisms, systemic injection of Pam2 lipopeptides induced IL-10 in a TLR2-dependent manner. The Pam2 lipopeptides increased the frequencies of Foxp3(+)CD4(+) regulatory T (T reg) cells in a TLR2- and IL-10- dependent manner. The T reg cells from Pam2-lipopeptide injected mice maintained suppressor activity. Pam2 lipopeptides, plus the depletion of T reg with an anti-CD25 monoclonal antibody, improved tumor growth compared with Pam2 lipopeptides alone. In conclusion, our data suggested that systemic treatment of Pam2 lipopeptides promoted IL-10 production and T reg function, which suppressed the effective induction of anti-tumor immunity in vivo. It is necessary to develop an adjuvant that does not promote IL-10 and T reg function in vivo for the future establishment of an anti-cancer vaccine. PMID- 21533083 TI - Coastal upwelling supplies oxygen-depleted water to the Columbia River estuary. AB - Low dissolved oxygen (DO) is a common feature of many estuarine and shallow-water environments, and is often attributed to anthropogenic nutrient enrichment from terrestrial-fluvial pathways. However, recent events in the U.S. Pacific Northwest have highlighted that wind-forced upwelling can cause naturally occurring low DO water to move onto the continental shelf, leading to mortalities of benthic fish and invertebrates. Coastal estuaries in the Pacific Northwest are strongly linked to ocean forcings, and here we report observations on the spatial and temporal patterns of oxygen concentration in the Columbia River estuary. Hydrographic measurements were made from transect (spatial survey) or anchor station (temporal survey) deployments over a variety of wind stresses and tidal states during the upwelling seasons of 2006 through 2008. During this period, biologically stressful levels of dissolved oxygen were observed to enter the Columbia River estuary from oceanic sources, with minimum values close to the hypoxic threshold of 2.0 mg L(-1). Riverine water was consistently normoxic. Upwelling wind stress controlled the timing and magnitude of low DO events, while tidal-modulated estuarine circulation patterns influenced the spatial extent and duration of exposure to low DO water. Strong upwelling during neap tides produced the largest impact on the estuary. The observed oxygen concentrations likely had deleterious behavioral and physiological consequences for migrating juvenile salmon and benthic crabs. Based on a wind-forced supply mechanism, low DO events are probably common to the Columbia River and other regional estuaries and if conditions on the shelf deteriorate further, as observations and models predict, Pacific Northwest estuarine habitats could experience a decrease in environmental quality. PMID- 21533082 TI - Lysophosphatidic acid activates peroxisome proliferator activated receptor-gamma in CHO cells that over-express glycerol 3-phosphate acyltransferase-1. AB - Lysophosphatidic acid (LPA) is an agonist for peroxisome proliferator activated receptor-gamma (PPARgamma). Although glycerol-3-phosphate acyltransferase-1 (GPAT1) esterifies glycerol-3-phosphate to form LPA, an intermediate in the de novo synthesis of glycerolipids, it has been assumed that LPA synthesized by this route does not have a signaling role. The availability of Chinese Hamster Ovary (CHO) cells that stably overexpress GPAT1, allowed us to analyze PPARgamma activation in the presence of LPA produced as an intracellular intermediate. LPA levels in CHO-GPAT1 cells were 6-fold higher than in wild-type CHO cells, and the mRNA abundance of CD36, a PPARgamma target, was 2-fold higher. Transactivation assays showed that PPARgamma activity was higher in the cells that overexpressed GPAT1. PPARgamma activity was enhanced further in CHO-GPAT1 cells treated with the PPARgamma ligand troglitazone. Extracellular LPA, phosphatidic acid (PA) or a membrane-permeable diacylglycerol had no effect, showing that PPARgamma had been activated by LPA generated intracellularly. Transient transfection of a vector expressing 1-acylglycerol-3-phosphate acyltransferase-2, which converts endogenous LPA to PA, markedly reduced PPARgamma activity, as did over-expressing diacylglycerol kinase, which converts DAG to PA, indicating that PA could be a potent inhibitor of PPARgamma. These data suggest that LPA synthesized via the glycerol-3-phosphate pathway can activate PPARgamma and that intermediates of de novo glycerolipid synthesis regulate gene expression. PMID- 21533084 TI - Surplus photosynthetic antennae complexes underlie diagnostics of iron limitation in a cyanobacterium. AB - Chlorophyll fluorescence from phytoplankton provides a tool to assess iron limitation in the oceans, but the physiological mechanism underlying the fluorescence response is not understood. We examined fluorescence properties of the model cyanobacterium Synechocystis PCC6803 and a DeltaisiA knock-out mutant of the same species grown under three culture conditions which simulate nutrient conditions found in the open ocean: (1) nitrate and iron replete, (2) limiting iron and high-nitrate, representative of natural high-nitrate, low-chlorophyll regions, and (3) iron and nitrogen co-limiting. We show that low variable fluorescence, a key diagnostic of iron limitation, results from synthesis of antennae complexes far in excess of what can be accommodated by the iron restricted pool of photosynthetic reaction centers. Under iron and nitrogen co limiting conditions, there are no excess antennae complexes and variable fluorescence is high. These results help to explain the well-established fluorescence characteristics of phytoplankton in high-nutrient, low-chlorophyll ocean regions, while also accounting for the lack of these properties in low iron, low-nitrogen regions. Importantly, our results complete the link between unique molecular consequences of iron stress in phytoplankton and global detection of iron stress in natural populations from space. PMID- 21533087 TI - Ubiquitin-dependent control of class II MHC localization is dispensable for antigen presentation and antibody production. AB - Controlled localization of class II MHC molecules is essential for proper class II MHC-restricted antigen presentation and the subsequent initiation of an adaptive immune response. Ubiquitination of class II MHC molecules on cytosolic lysine (K225) of the beta-chain has been shown to affect localization of the complex. We generated mice in which the endogenous beta-chain locus is replaced with a GFP tagged mutant version that lacks the cytosolic lysine residue (I-A beta-K225R-EGFP). These mice have elevated levels of class II MHC as compared to I-A-beta-EGFP mice, and immature bone marrow-derived dendritic cells show redistribution of class II MHC to the cell surface. Nonetheless, in these same cells efficiency of antigen presentation is unaffected in I-A-beta-K225R-EGFP mice, as assayed for presentation of ovalbumin to appropriately specific T cells. The I-A-beta-K225R-EGFP animals have normal CD4 T cell populations and are capable of generating antigen-specific antibody in response to model antigens and viral infection. We therefore conclude that in our experimental system modulation of trafficking by ubiquitination of residue K225 of the beta-chain is not essential for the function of class II MHC products in antigen presentation or antibody production. PMID- 21533085 TI - Modeling the TNFalpha-induced apoptosis pathway in hepatocytes. AB - The proinflammatory cytokine TNFalpha fails to provoke cell death in isolated hepatocytes but has been implicated in hepatocyte apoptosis during liver diseases associated with chronic inflammation. Recently, we showed that TNFalpha is able to sensitize primary murine hepatocytes cultured on collagen to Fas ligand induced apoptosis and presented a mathematical model of the sensitizing effect. Here, we analyze how TNFalpha induces apoptosis in combination with the transcriptional inhibitor actinomycin D (ActD). Accumulation of reactive oxygen species (ROS) in response to TNFR activation turns out to be critical for sustained activation of JNK which then triggers mitochondrial pathway-dependent apoptosis. In addition, the amount of JNK is strongly upregulated in a ROS dependent way. In contrast to TNFalpha plus cycloheximide no cFLIP degradation is observed suggesting a different apoptosis pathway in which the Itch-mediated cFLIP degradation and predominantly caspase-8 activation is not involved. Time resolved data of the respective pro- and antiapoptotic factors are obtained and subjected to mathematical modeling. On the basis of these data we developed a mathematical model which reproduces the complex interplay regulating the phosphorylation status of JNK and generation of ROS. This model was fully integrated with our model of TNFalpha/Fas ligand sensitizing as well as with a published NF-kappaB-model. The resulting comprehensive model delivers insight in the dynamical interplay between the TNFalpha and FasL pathways, NF-kappaB and ROS and gives an example for successful model integration. PMID- 21533086 TI - Optogenetic long-term manipulation of behavior and animal development. AB - Channelrhodopsin-2 (ChR2) is widely used for rapid photodepolarization of neurons, yet, as it requires high-intensity blue light for activation, it is not suited for long-term in vivo applications, e.g. for manipulations of behavior, or photoactivation of neurons during development. We used "slow" ChR2 variants with mutations in the C128 residue, that exhibit delayed off-kinetics and increased light sensitivity in Caenorhabditis elegans. Following a 1 s light pulse, we could photodepolarize neurons and muscles for minutes (and with repeated brief stimulation, up to days) with low-intensity light. Photoactivation of ChR2(C128S) in command interneurons elicited long-lasting alterations in locomotion. Finally, we could optically induce profound changes in animal development: Long-term photoactivation of ASJ neurons, which regulate larval growth, bypassed the constitutive entry into the "dauer" larval state in daf-11 mutants. These lack a guanylyl cyclase, which possibly renders ASJ neurons hyperpolarized. Furthermore, photostimulated ASJ neurons could acutely trigger dauer-exit. Thus, slow ChR2s can be employed to long-term photoactivate behavior and to trigger alternative animal development. PMID- 21533088 TI - Modelling the protective efficacy of alternative delivery schedules for intermittent preventive treatment of malaria in infants and children. AB - BACKGROUND: Intermittent preventive treatment in infants (IPTi) with sulfadoxine pyrimethamine (SP) is recommended by WHO where malaria incidence in infancy is high and SP resistance is low. The current delivery strategy is via routine Expanded Program on Immunisation contacts during infancy (EPI-IPTi). However, improvements to this approach may be possible where malaria transmission is seasonal, or where the malaria burden lies mainly outside infancy. METHODS AND FINDINGS: A mathematical model was developed to estimate the protective efficacy (PE) of IPT against clinical malaria in children aged 2-24 months, using entomological and epidemiological data from an EPI-IPTi trial in Navrongo, Ghana to parameterise the model. The protection achieved by seasonally-targeted IPT in infants (sIPTi), seasonal IPT in children (sIPTc), and by case-management with long-acting artemisinin combination therapies (LA-ACTs) was predicted for Navrongo and for sites with different transmission intensity and seasonality. In Navrongo, the predicted PE of sIPTi was 26% by 24 months of age, compared to 16% with EPI-IPTi. sIPTc given to all children under 2 years would provide PE of 52% by 24 months of age. Seasonally-targeted IPT retained its advantages in a range of transmission patterns. Under certain circumstances, LA-ACTs for case management may provide similar protection to EPI-IPTi. However, EPI-IPTi or sIPT combined with LA-ACTs would be substantially more protective than either strategy used alone. CONCLUSION: Delivery of IPT to infants via the EPI is sub-optimal because individuals are not protected by IPT at the time of highest malaria risk, and because older children are not protected. Alternative delivery strategies to the EPI are needed where transmission varies seasonally or the malaria burden extends beyond infancy. Long-acting ACTs may also make important reductions in malaria incidence. However, delivery systems must be developed to ensure that both forms of chemoprevention reach the individuals who are most exposed to malaria. PMID- 21533089 TI - Short interspersed element (SINE) depletion and long interspersed element (LINE) abundance are not features universally required for imprinting. AB - Genomic imprinting is a form of gene dosage regulation in which a gene is expressed from only one of the alleles, in a manner dependent on the parent of origin. The mechanisms governing imprinted gene expression have been investigated in detail and have greatly contributed to our understanding of genome regulation in general. Both DNA sequence features, such as CpG islands, and epigenetic features, such as DNA methylation and non-coding RNAs, play important roles in achieving imprinted expression. However, the relative importance of these factors varies depending on the locus in question. Defining the minimal features that are absolutely required for imprinting would help us to understand how imprinting has evolved mechanistically. Imprinted retrogenes are a subset of imprinted loci that are relatively simple in their genomic organisation, being distinct from large imprinting clusters, and have the potential to be used as tools to address this question. Here, we compare the repeat element content of imprinted retrogene loci with non-imprinted controls that have a similar locus organisation. We observe no significant differences that are conserved between mouse and human, suggesting that the paucity of SINEs and relative abundance of LINEs at imprinted loci reported by others is not a sequence feature universally required for imprinting. PMID- 21533090 TI - Arabidopsis plasmodesmal proteome. AB - The multicellular nature of plants requires that cells should communicate in order to coordinate essential functions. This is achieved in part by molecular flux through pores in the cell wall, called plasmodesmata. We describe the proteomic analysis of plasmodesmata purified from the walls of Arabidopsis suspension cells. Isolated plasmodesmata were seen as membrane-rich structures largely devoid of immunoreactive markers for the plasma membrane, endoplasmic reticulum and cytoplasmic components. Using nano-liquid chromatography and an Orbitrap ion-trap tandem mass spectrometer, 1341 proteins were identified. We refer to this list as the plasmodesmata- or PD-proteome. Relative to other cell wall proteomes, the PD-proteome is depleted in wall proteins and enriched for membrane proteins, but still has a significant number (35%) of putative cytoplasmic contaminants, probably reflecting the sensitivity of the proteomic detection system. To validate the PD-proteome we searched for known plasmodesmal proteins and used molecular and cell biological techniques to identify novel putative plasmodesmal proteins from a small subset of candidates. The PD-proteome contained known plasmodesmal proteins and some inferred plasmodesmal proteins, based upon sequence or functional homology with examples identified in different plant systems. Many of these had a membrane association reflecting the membranous nature of isolated structures. Exploiting this connection we analysed a sample of the abundant receptor-like class of membrane proteins and a small random selection of other membrane proteins for their ability to target plasmodesmata as fluorescently-tagged fusion proteins. From 15 candidates we identified three receptor-like kinases, a tetraspanin and a protein of unknown function as novel potential plasmodesmal proteins. Together with published work, these data suggest that the membranous elements in plasmodesmata may be rich in receptor-like functions, and they validate the content of the PD-proteome as a valuable resource for the further uncovering of the structure and function of plasmodesmata as key components in cell-to-cell communication in plants. PMID- 21533091 TI - Reversal of diabetic nephropathy by a ketogenic diet. AB - Intensive insulin therapy and protein restriction delay the development of nephropathy in a variety of conditions, but few interventions are known to reverse nephropathy. Having recently observed that the ketone 3-beta hydroxybutyric acid (3-OHB) reduces molecular responses to glucose, we hypothesized that a ketogenic diet, which produces prolonged elevation of 3-OHB, may reverse pathological processes caused by diabetes. To address this hypothesis, we assessed if prolonged maintenance on a ketogenic diet would reverse nephropathy produced by diabetes. In mouse models for both Type 1 (Akita) and Type 2 (db/db) diabetes, diabetic nephropathy (as indicated by albuminuria) was allowed to develop, then half the mice were switched to a ketogenic diet. After 8 weeks on the diet, mice were sacrificed to assess gene expression and histology. Diabetic nephropathy, as indicated by albumin/creatinine ratios as well as expression of stress-induced genes, was completely reversed by 2 months maintenance on a ketogenic diet. However, histological evidence of nephropathy was only partly reversed. These studies demonstrate that diabetic nephropathy can be reversed by a relatively simple dietary intervention. Whether reduced glucose metabolism mediates the protective effects of the ketogenic diet remains to be determined. PMID- 21533092 TI - Plasmodium falciparum gametocyte carriage is associated with subsequent Plasmodium vivax relapse after treatment. AB - Mixed P. falciparum/P. vivax infections are common in southeast Asia. When patients with P. falciparum malaria are treated and followed for several weeks, a significant proportion will develop P. vivax malaria. In a combined analysis of 243 patients recruited to two malaria treatment trials in western Cambodia, 20/43 (47%) of those with P. falciparum gametocytes on admission developed P. vivax malaria by Day 28 of follow-up. The presence of Pf gametocytes on an initial blood smear was associated with a 3.5-fold greater rate of vivax parasitemia post treatment (IRR = 3.5, 95% CI 2.0-6.0, p<0.001). The increased rate of post treatment P. vivax infection persisted when correlates of exposure and immunity such as a history of malaria, male gender, and age were controlled for (IRR = 3.0, 95% CI 1.9-4.7, p<0.001). Polymerase chain reaction (PCR) confirmed that only a low proportion of subjects (5/55 or 9.1%) who developed vivax during follow-up had detectable Pv parasites in the peripheral blood at baseline. Molecular detection of falciparum gametocytes by reverse transcriptase PCR in a subset of patients strengthened the observed association, while PCR detection of Pv parasitemia at follow-up was similar to microscopy results. These findings suggest that the majority of vivax infections arising after treatment of falciparum malaria originate from relapsing liver-stage parasites. In settings such as western Cambodia, the presence of both sexual and asexual forms of P. falciparum on blood smear at presentation with acute falciparum malaria serves as a marker for possible occult P. vivax coinfection and subsequent relapse. These patients may benefit from empiric treatment with an 8-aminoquinolone such as primaquine. PMID- 21533093 TI - The evolution of social orienting: evidence from chicks (Gallus gallus) and human newborns. AB - BACKGROUND: Converging evidence from different species indicates that some newborn vertebrates, including humans, have visual predispositions to attend to the head region of animate creatures. It has been claimed that newborn preferences for faces are domain-relevant and similar in different species. One of the most common criticisms of the work supporting domain-relevant face biases in human newborns is that in most studies they already have several hours of visual experience when tested. This issue can be addressed by testing newly hatched face-naive chicks (Gallus gallus) whose preferences can be assessed prior to any other visual experience with faces. METHODS: In the present study, for the first time, we test the prediction that both newly hatched chicks and human newborns will demonstrate similar preferences for face stimuli over spatial frequency matched structured noise. Chicks and babies were tested using identical stimuli for the two species. Chicks underwent a spontaneous preference task, in which they have to approach one of two stimuli simultaneously presented at the ends of a runway. Human newborns participated in a preferential looking task. RESULTS AND SIGNIFICANCE: We observed a significant preference for orienting toward the face stimulus in both species. Further, human newborns spent more time looking at the face stimulus, and chicks preferentially approached and stood near the face-stimulus. These results confirm the view that widely diverging vertebrates possess similar domain-relevant biases toward faces shortly after hatching or birth and provide a behavioural basis for a comparison with neuroimaging studies using similar stimuli. PMID- 21533094 TI - Lestaurtinib inhibition of the Jak/STAT signaling pathway in hodgkin lymphoma inhibits proliferation and induces apoptosis. AB - Standard cytotoxic chemotherapy for Hodgkin Lymphoma (HL) has changed little in 30 years; the treatment for patients with relapsed or refractory disease remains challenging and novel agents are under development. JAK/STAT constitutive activation plays an important role in the pathogenesis of HL. Lestaurtinib is an orally bioavailable multikinase inhibitor that has recently been shown to inhibit JAK2 in myeloproliferative disorders. The potential role of Lestaurtinib in HL therapy is unknown. We have analyzed the effect of Lestaurtinib treatment in five HL cell lines from refractory patients, L-428, L-1236, L-540, HDML-2 and HD-MY-Z. At 48 h, a dose-dependent cell growth inhibition (23%-66% at 300 nM) and apoptotic increment (10%-64% at 300 nM) were observed. Moreover, Lestaurtinib inhibited JAK2, STAT5 and STAT3 phosphorylation and reduced the mRNA expression of its downstream antiapoptotic target Bcl-xL. In addition, we have analyzed the effect of Lestaurtinib treatment in lymph nodes from four classic HL patients. We observed a decrease in cell viability at 24 hours of treatment in three patients (mean decrease of 27% at 300 nM). Our findings provide, for the first time, a molecular rationale for testing JAK2 inhibitors, specifically Lestaurtinib, in HL patients. PMID- 21533095 TI - Acoustic intensity causes perceived changes in arousal levels in music: an experimental investigation. AB - Listener perceptions of changes in the arousal expressed by classical music have been found to correlate with changes in sound intensity/loudness over time. This study manipulated the intensity profiles of different pieces of music in order to test the causal nature of this relationship. Listeners (N = 38) continuously rated their perceptions of the arousal expressed by each piece. An extract from Dvorak's Slavonic Dance Opus 46 No 1 was used to create a variant in which the direction of change in intensity was inverted, while other features were retained. Even though it was only intensity that was inverted, perceived arousal was also inverted. The original intensity profile was also superimposed on three new pieces of music. The time variation in the perceived arousal of all pieces was similar to their intensity profile. Time series analyses revealed that intensity variation was a major influence on the arousal perception in all pieces, in spite of their stylistic diversity. PMID- 21533096 TI - The stem species of our species: a place for the archaic human cranium from Ceprano, Italy. AB - One of the present challenges in the study of human evolution is to recognize the hominin taxon that was ancestral to Homo sapiens. Some researchers regard H. heidelbergensis as the stem species involved in the evolutionary divergence leading to the emergence of H. sapiens in Africa, and to the evolution of the Neandertals in Europe. Nevertheless, the diagnosis and hypodigm of H. heidelbergensis still remain to be clarified. Here we evaluate the morphology of the incomplete cranium (calvarium) known as Ceprano whose age has been recently revised to the mid of the Middle Pleistocene, so as to test whether this specimen may be included in H. heidelbergensis. The analyses were performed according to a phenetic routine including geometric morphometrics and the evaluation of diagnostic discrete traits. The results strongly support the uniqueness of H. heidelbergensis on a wide geographical horizon, including both Eurasia and Africa. In this framework, the Ceprano calvarium--with its peculiar combination of archaic and derived traits--may represent, better than other penecontemporaneous specimens, an appropriate ancestral stock of this species, preceding the appearance of regional autapomorphic features. PMID- 21533097 TI - Towards a synthetic chloroplast. AB - BACKGROUND: The evolution of eukaryotic cells is widely agreed to have proceeded through a series of endosymbiotic events between larger cells and proteobacteria or cyanobacteria, leading to the formation of mitochondria or chloroplasts, respectively. Engineered endosymbiotic relationships between different species of cells are a valuable tool for synthetic biology, where engineered pathways based on two species could take advantage of the unique abilities of each mutualistic partner. RESULTS: We explored the possibility of using the photosynthetic bacterium Synechococcus elongatus PCC 7942 as a platform for studying evolutionary dynamics and for designing two-species synthetic biological systems. We observed that the cyanobacteria were relatively harmless to eukaryotic host cells compared to Escherichia coli when injected into the embryos of zebrafish, Danio rerio, or taken up by mammalian macrophages. In addition, when engineered with invasin from Yersinia pestis and listeriolysin O from Listeria monocytogenes, S. elongatus was able to invade cultured mammalian cells and divide inside macrophages. CONCLUSION: Our results show that it is possible to engineer photosynthetic bacteria to invade the cytoplasm of mammalian cells for further engineering and applications in synthetic biology. Engineered invasive but non-pathogenic or immunogenic photosynthetic bacteria have great potential as synthetic biological devices. PMID- 21533098 TI - Classical Mus musculus Igkappa enhancers support transcription but not high level somatic hypermutation from a V-lambda promoter in chicken DT40 cells. AB - Somatic hypermutation (SHM) of immunoglobulin genes is initiated by activation induced cytidine deaminase (AID) in activated B cells. This process is strictly dependent on transcription. Hence, cis-acting transcriptional control elements have been proposed to target SHM to immunoglobulin loci. The Mus musculus Igkappa locus is regulated by the intronic enhancer (iE/MAR) and the 3' enhancer (3'E), and multiple studies using transgenic and knock-out approaches in mice and cell lines have reported somewhat contradictory results about the function of these enhancers in AID-mediated sequence diversification. Here we show that the M. musculus iE/MAR and 3'E elements are active solely as transcriptional enhancer when placed in the context of the IGL locus in Gallus gallus DT40 cells, but they are very inefficient in targeting AID-mediated mutation events to this locus. This suggests that either key components of the cis-regulatory targeting elements reside outside the murine Igkappa transcriptional enhancer sequences, or that the targeting of AID activity to Ig loci occurs by largely species-specific mechanisms. PMID- 21533099 TI - Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis. AB - BACKGROUND: More than 200 clinical trials have been performed using dendritic cells (DC) as cellular adjuvants in cancer. Yet the key question whether there is a link between immune and clinical response remains unanswered. Prostate and renal cell cancer (RCC) have been extensively studied for DC-based immunotherapeutic interventions and were therefore chosen to address the above question by means of a systematic review and meta-analysis. METHODOLOGY/PRINCIPAL FINDINGS: Data was obtained after a systematic literature search from clinical trials that enrolled at least 6 patients. Individual patient data meta-analysis was performed by means of conditional logistic regression grouped by study. Twenty nine trials involving a total of 906 patients were identified in prostate cancer (17) and RCC (12). Objective response rates were 7.7% in prostate cancer and 12.7% in RCC. The combined percentages of objective responses and stable diseases (SD) amounted to a clinical benefit rate (CBR) of 54% in prostate cancer and 48% in RCC. Meta-analysis of individual patient data (n = 403) revealed the cellular immune response to have a significant influence on CBR, both in prostate cancer (OR 10.6, 95% CI 2.5-44.1) and in RCC (OR 8.4, 95% CI 1.3-53.0). Furthermore, DC dose was found to have a significant influence on CBR in both entities. Finally, for the larger cohort of prostate cancer patients, an influence of DC maturity and DC subtype (density enriched versus monocyte derived DC) as well as access to draining lymph nodes on clinical outcome could be demonstrated. CONCLUSIONS/SIGNIFICANCE: As a 'proof of principle' a statistically significant effect of DC-mediated cellular immune response and of DC dose on CBR could be demonstrated. Further findings concerning vaccine composition, quality control, and the effect of DC maturation status are relevant for the immunological development of DC-based vaccines. PMID- 21533100 TI - Host specific diversity in Lactobacillus johnsonii as evidenced by a major chromosomal inversion and phage resistance mechanisms. AB - Genetic diversity and genomic rearrangements are a driving force in bacterial evolution and niche adaptation. We sequenced and annotated the genome of Lactobacillus johnsonii DPC6026, a strain isolated from the porcine intestinal tract. Although the genome of DPC6026 is similar in size (1.97 mbp) and GC content (34.8%) to the sequenced human isolate L. johnsonii NCC 533, a large symmetrical inversion of approximately 750 kb differentiated the two strains. Comparative analysis among 12 other strains of L. johnsonii including 8 porcine, 3 human and 1 poultry isolate indicated that the genome architecture found in DPC6026 is more common within the species than that of NCC 533. Furthermore a number of unique features were annotated in DPC6026, some of which are likely to have been acquired by horizontal gene transfer (HGT) and contribute to protection against phage infection. A putative type III restriction-modification system was identified, as were novel Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) elements. Interestingly, these particular elements are not widely distributed among L. johnsonii strains. Taken together these data suggest intra-species genomic rearrangements and significant genetic diversity within the L. johnsonii species and indicate towards a host-specific divergence of L. johnsonii strains with respect to genome inversion and phage exposure. PMID- 21533101 TI - The Guinea-Bissau family of Mycobacterium tuberculosis complex revisited. AB - The Guinea-Bissau family of strains is a unique group of the Mycobacterium tuberculosis complex that, although genotypically closely related, phenotypically demonstrates considerable heterogeneity. We have investigated 414 M. tuberculosis complex strains collected in Guinea-Bissau between 1989 and 2008 in order to further characterize the Guinea-Bissau family of strains. To determine the strain lineages present in the study sample, binary outcomes of spoligotyping were compared with spoligotypes existing in the international database SITVIT2. The major circulating M. tuberculosis clades ranked in the following order: AFRI (n = 195, 47.10%), Latin-American-Mediterranean (LAM) (n = 75, 18.12%), ill-defined T clade (n = 53, 12.8%), Haarlem (n = 37, 8.85%), East-African-Indian (EAI) (n = 25, 6.04%), Unknown (n = 12, 2.87%), Beijing (n = 7, 1.68%), X clade (n = 4, 0.96%), Manu (n = 4, 0.97%), CAS (n = 2, 0.48%). Two strains of the LAM clade isolated in 2007 belonged to the Cameroon family (SIT61). All AFRI isolates except one belonged to the Guinea-Bissau family, i.e. they have an AFRI_1 spoligotype pattern, they have a distinct RFLP pattern with low numbers of IS6110 insertions, and they lack the regions of difference RD7, RD8, RD9 and RD10, RD701 and RD702. This profile classifies the Guinea-Bissau family, irrespective of phenotypic biovar, as part of the M. africanum West African 2 lineage, or the AFRI_1 sublineage according to the spoligtyping nomenclature. Guinea-Bissau family strains display a variation of biochemical traits classically used to differentiate M. tuberculosis from M. bovis. Yet, the differential expression of these biochemical traits was not related to any genes so far investigated (narGHJI and pncA). Guinea-Bissau has the highest prevalence of M. africanum recorded in the African continent, and the Guinea-Bissau family shows a high phylogeographical specificity for Western Africa, with Guinea-Bissau being the epicenter. Trends over time however indicate that this family of strains is waning in most parts of Western Africa, including Guinea-Bissau (p = 0.048). PMID- 21533102 TI - Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse. AB - The pharmacological chaperone, isofagomine (IFG), enhances acid beta-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFalpha levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates. PMID- 21533103 TI - Bordetella pertussis infection exacerbates influenza virus infection through pertussis toxin-mediated suppression of innate immunity. AB - Pertussis (whooping cough) is frequently complicated by concomitant infections with respiratory viruses. Here we report the effect of Bordetella pertussis infection on subsequent influenza virus (PR8) infection in mouse models and the role of pertussis toxin (PT) in this effect. BALB/c mice infected with a wild type strain of B. pertussis (WT) and subsequently (up to 14 days later) infected with PR8 had significantly increased pulmonary viral titers, lung pathology and mortality compared to mice similarly infected with a PT-deficient mutant strain (DeltaPT) and PR8. Substitution of WT infection by intranasal treatment with purified active PT was sufficient to replicate the exacerbating effects on PR8 infection in BALB/c and C57/BL6 mice, but the effects of PT were lost when toxin was administered 24 h after virus inoculation. PT had no effect on virus titers in primary cultures of murine tracheal epithelial cells (mTECs) in vitro, suggesting the toxin targets an early immune response to increase viral titers in the mouse model. However, type I interferon responses were not affected by PT. Whole genome microarray analysis of gene expression in lung tissue from PT treated and control PR8-infected mice at 12 and 36 h post-virus inoculation revealed that PT treatment suppressed numerous genes associated with communication between innate and adaptive immune responses. In mice depleted of alveolar macrophages, increase of pulmonary viral titers by PT treatment was lost. PT also suppressed levels of IL-1beta, IL-12, IFN-gamma, IL-6, KC, MCP-1 and TNF-alpha in the airways after PR8 infection. Furthermore PT treatment inhibited early recruitment of neutrophils and NK cells to the airways. Together these findings demonstrate that infection with B. pertussis through PT activity predisposes the host to exacerbated influenza infection by countering protective innate immune responses that control virus titers. PMID- 21533104 TI - Height of nations: a socioeconomic analysis of cohort differences and patterns among women in 54 low- to middle-income countries. AB - BACKGROUND: Adult height is a useful biological measure of long term population health and well being. We examined the cohort differences and socioeconomic patterning in adult height in low- to middle-income countries. METHODS/FINDINGS: We analyzed cross-sectional, representative samples of 364,538 women aged 25-49 years drawn from 54 Demographic and Health Surveys (DHS) conducted between 1994 and 2008. Linear multilevel regression models included year of birth, household wealth, education, and area of residence, and accounted for clustering by primary sampling units and countries. Attained height was measured using an adjustable measuring board. A yearly change in birth cohorts starting with those born in 1945 was associated with a 0.0138 cm (95% CI 0.0107, 0.0169) increase in height. Increases in heights in more recent birth year cohorts were largely concentrated in women from the richer wealth quintiles. 35 of the 54 countries experienced a decline (14) or stagnation (21) in height. The decline in heights was largely concentrated among the poorest wealth quintiles. There was a strong positive association between height and household wealth; those in two richest quintiles of household wealth were 1.988 cm (95% CI 1.886, 2.090) and 1.018 cm (95% CI 0.916, 1.120) taller, compared to those in the poorest wealth quintile. The strength of the association between wealth and height was positive (0.05 to 1.16) in 96% (52/54) countries. CONCLUSIONS: Socioeconomic inequalities in height remain persistent. Height has stagnated or declined over the last decades in low- to middle-income countries, particularly in Africa, suggesting worsening nutritional and environmental circumstances during childhood. PMID- 21533105 TI - Resistance to hemi-biotrophic F. graminearum infection is associated with coordinated and ordered expression of diverse defense signaling pathways. AB - Fusarium species cause serious diseases in cereal staple food crops such as wheat and maize. Currently, the mechanisms underlying resistance to Fusarium-caused diseases are still largely unknown. In the present study, we employed a combined proteomic and transcriptomic approach to investigate wheat genes responding to F. graminearum infection that causes Fusarium head blight (FHB). We found a total of 163 genes and 37 proteins that were induced by infection. These genes and proteins were associated with signaling pathways mediated by salicylic acid (SA), jasmonic acid (JA), ethylene (ET), calcium ions, phosphatidic acid (PA), as well as with reactive oxygen species (ROS) production and scavenging, antimicrobial compound synthesis, detoxification, and cell wall fortification. We compared the time-course expression profiles between FHB-resistant Wangshuibai plants and susceptible Meh0106 mutant plants of a selected set of genes that are critical to the plants' resistance and defense reactions. A biphasic phenomenon was observed during the first 24 h after inoculation (hai) in the resistant plants. The SA and Ca(2+) signaling pathways were activated within 6 hai followed by the JA mediated defense signaling activated around 12 hai. ET signaling was activated between these two phases. Genes for PA and ROS synthesis were induced during the SA and JA phases, respectively. The delayed activation of the SA defense pathway in the mutant was associated with its susceptibility. After F. graminearum infection, the endogenous contents of SA and JA in Wangshuibai and the mutant changed in a manner similar to the investigated genes corresponding to the individual pathways. A few genes for resistance-related cell modification and phytoalexin production were also identified. This study provided important clues for designing strategies to curb diseases caused by Fusarium. PMID- 21533107 TI - Rapid temporal control of Foxp3 protein degradation by sirtuin-1. AB - Maintenance of Foxp3 protein expression in regulatory T cells (Treg) is crucial for a balanced immune response. We have previously demonstrated that Foxp3 protein stability can be regulated through acetylation, however the specific mechanisms underlying this observation remain unclear. Here we demonstrate that SIRT1 a member of the lysine deacetylase Sirtuin (SIRT) family, but not the related SIRTs 2-7, co-localize with Foxp3 in the nucleus. Ectopic expression of SIRT1, but not SIRTs 2-7 results in decreased Foxp3 acetylation, while conversely inhibition of endogenous SIRT activity increased Foxp3 acetylation. We show that SIRT1 inhibition decreases Foxp3 poly-ubiquitination, thereby increasing Foxp3 protein levels. Co-transfection of SIRT1 with Foxp3 results in increased Foxp3 proteasomal degradation, while SIRT inhibition increases FOXP3 transcriptional activity in human Treg. Taken together, these data support a central role for SIRT1 in the regulation of Foxp3 protein levels and thereby in regulation of Treg suppressive capacity. Pharmacological modulation of SIRT1 activity in Treg may therefore provide a novel therapeutic strategy for controlling immune responses. PMID- 21533106 TI - Functional genomics unique to week 20 post wounding in the deep cone/fat dome of the Duroc/Yorkshire porcine model of fibroproliferative scarring. AB - BACKGROUND: Hypertrophic scar was first described over 100 years ago; PubMed has more than 1,000 references on the topic. Nevertheless prevention and treatment remains poor, because 1) there has been no validated animal model; 2) human scar tissue, which is impossible to obtain in a controlled manner, has been the only source for study; 3) tissues typically have been homogenized, mixing cell populations; and 4) gene-by-gene studies are incomplete. METHODOLOGY/PRINCIPAL FINDINGS: We have assembled a system that overcomes these barriers and permits the study of genome-wide gene expression in microanatomical locations, in shallow and deep partial-thickness wounds, and pigmented and non-pigmented skin, using the Duroc(pigmented fibroproliferative)/Yorkshire(non-pigmented non fibroproliferative) porcine model. We used this system to obtain the differential transcriptome at 1, 2, 3, 12 and 20 weeks post wounding. It is not clear when fibroproliferation begins, but it is fully developed in humans and the Duroc breed at 20 weeks. Therefore we obtained the derivative functional genomics unique to 20 weeks post wounding. We also obtained long-term, forty-six week follow-up with the model. CONCLUSIONS/SIGNIFICANCE: 1) The scars are still thick at forty-six weeks post wounding further validating the model. 2) The differential transcriptome provides new insights into the fibroproliferative process as several genes thought fundamental to fibroproliferation are absent and others differentially expressed are newly implicated. 3) The findings in the derivative functional genomics support old concepts, which further validates the model, and suggests new avenues for reductionist exploration. In the future, these findings will be searched for directed networks likely involved in cutaneous fibroproliferation. These clues may lead to a better understanding of the systems biology of cutaneous fibroproliferation, and ultimately prevention and treatment of hypertrophic scarring. PMID- 21533108 TI - Genetic control of susceptibility to infection with Candida albicans in mice. AB - Candida albicans is an opportunistic pathogen that causes acute disseminated infections in immunocompromised hosts, representing an important cause of morbidity and mortality in these patients. To study the genetic control of susceptibility to disseminated C. albicans in mice, we phenotyped a group of 23 phylogenetically distant inbred strains for susceptibility to infection as measured by extent of fungal replication in the kidney 48 hours following infection. Susceptibility was strongly associated with the loss-of-function mutant complement component 5 (C5/Hc) allele, which is known to be inherited by approximately 40% of inbred strains. Our survey identified 2 discordant strains, AKR/J (C5-deficient, resistant) and SM/J (C5-sufficient, susceptible), suggesting that additional genetic effects may control response to systemic candidiasis in these strains. Haplotype association mapping in the 23 strains using high density SNP maps revealed several putative loci regulating the extent of C. albicans replication, amongst which the most significant were C5 (P value = 2.43*10(-11)) and a novel effect on distal chromosome 11 (P value = 7.63*10(-9)). Compared to other C5-deficient strains, infected AKR/J strain displays a reduced fungal burden in the brain, heart and kidney, and increased survival, concomitant with uniquely high levels of serum IFNgamma. C5-independent genetic effects were further investigated by linkage analysis in an [A/JxAKR/J]F2 cross (n = 158) where the mutant Hc allele is fixed. These studies identified a chromosome 11 locus (Carg4, Candida albicans resistance gene 4; LOD = 4.59), and a chromosome 8 locus (Carg3; LOD = 3.95), both initially detected by haplotype association mapping. Alleles at both loci were inherited in a co-dominant manner. Our results verify the important effect of C5-deficiency in inbred mouse strains, and further identify two novel loci, Carg3 and Carg4, which regulate resistance to C. albicans infection in a C5-independent manner. PMID- 21533109 TI - Trimeric form of intracellular ATP synthase subunit beta of Aggregatibacter actinomycetemcomitans binds human interleukin-1beta. AB - Bacterial biofilms resist host defenses and antibiotics partly because of their decreased metabolism. Some bacteria use proinflammatory cytokines, such as interleukin (IL)-1beta, as cues to promote biofilm formation and to alter virulence. Although one potential bacterial IL-1beta receptor has been identified, current knowledge of the bacterial IL-1beta sensing mechanism is limited. In chronic biofilm infection, periodontitis, Aggregatibacter actinomycetemcomitans requires tight adherence (tad)-locus to form biofilms, and tissue destroying active lesions contain more IL-1beta than inactive ones. The effect of IL-1beta on the metabolic activity of A. actinomycetemcomitans biofilm was tested using alamarBlueTM. The binding of IL-1beta to A. actinomycetemcomitans cells was investigated using transmission electron microscopy and flow cytometry. To identify the proteins which interacted with IL 1beta, different protein fractions from A. actinomycetemcomitans were run in native-PAGE and blotted using biotinylated IL-1beta and avidin-HRP, and identified using mass spectroscopy. We show that although IL-1beta slightly increases the biofilm formation of A. actinomycetemcomitans, it reduces the metabolic activity of the biofilm. A similar reduction was observed with all tad locus mutants except the secretin mutant, although all tested mutant strains as well as wild type strains bound IL-1beta. Our results suggest that IL-1beta might be transported into the A. actinomycetemcomitans cells, and the trimeric form of intracellular ATP synthase subunit beta interacted with IL-1beta, possibly explaining the decreased metabolic activity. Because ATP synthase is highly conserved, it might universally enhance biofilm resistance to host defense by binding IL-1beta during inflammation. PMID- 21533110 TI - Glycogen synthase kinase 3beta contributes to proliferation of arterial smooth muscle cells in pulmonary hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is a rare progressive pulmonary vascular disorder associated with vascular remodeling and right heart failure. Vascular remodeling involves numerous signaling cascades governing pulmonary arterial smooth muscle cell (PASMC) proliferation, migration and differentiation. Glycogen synthase kinase 3beta (GSK3beta) is a serine/threonine kinase and can act as a downstream regulatory switch for numerous signaling pathways. Hence, we hypothesized that GSK3beta plays a crucial role in pulmonary vascular remodeling. METHODS: All experiments were done with lung tissue or isolated PASMCs in a well established monocrotaline (MCT)-induced PAH rat model. The mRNA expression of Wnt ligands (Wnt1, Wnt3a, Wnt5a), upstream Wnt signaling regulator genes (Frizzled Receptors 1, 2 and secreted Frizzled related protein sFRP-1) and canonical Wnt intracellular effectors (GSK3beta, Axin1) were assessed by real-time polymerase chain reaction and protein levels of GSK3beta, phospho-GSK3beta (ser 9) by western blotting and localization by immunohistochemistry. The role of GSK3beta in PASMCs proliferation was assessed by overexpression of wild-type GSK3beta (WT) and constitutively active GSK3beta S9A by [(3)H]-thymidine incorporation assay. RESULTS: Increased levels of total and phosphorylated GSK3beta (inhibitory phosphorylation) were observed in lungs and PASMCs isolated from MCT-induced PAH rats compared to controls. Further, stimulation of MCT-PASMCs with growth factors induced GSK3beta inactivation. Most importantly, treatment with the PDGFR inhibitor, Imatinib, attenuated PDGF-BB and FCS induced GSK3beta phosphorylation. Increased expression of GSK3beta observed in lungs and PASMC isolated from MCT induced PAH rats was confirmed to be clinically relevant as the same observation was identified in human iPAH lung explants. Overexpression of GSK3beta significantly increased MCT-PASMCs proliferation by regulating ERK phosphorylation. Constitutive activation of GSK3beta (GSK3beta S9A, 9th serine replaced to alanine) inhibited MCT-PASMCs proliferation by decreasing ERK phosphorylation. CONCLUSION: This study supports a central role for GSK3beta in vascular remodeling processes and suggests a novel therapeutic opportunity for the treatment of PAH. PMID- 21533112 TI - A volumetric method for quantifying atherosclerosis in mice by using microCT: comparison to en face. AB - Precise quantification of atherosclerotic plaque in preclinical models of atherosclerosis requires the volumetric assessment of the lesion(s) while maintaining in situ architecture. Here we use micro-computed tomography (microCT) to detect ex vivo aortic plaque established in three dyslipidemic mouse models of atherosclerosis. All three models lack the low-density lipoprotein receptor (Ldlr(-/-)), each differing in plaque severity, allowing the evaluation of different plaque volumes using microCT technology. From clearly identified lesions in the thoracic aorta from each model, we were able to determine plaque volume (0.04-3.1 mm(3)), intimal surface area (0.5-30 mm(2)), and maximum plaque (intimal-medial) thickness (0.1-0.7 mm). Further, quantification of aortic volume allowed calculation of vessel occlusion by the plaque. To validate microCT for future preclinical studies, we compared microCT data to intimal surface area (by using en face methodology). Both plaque surface area and plaque volume were in excellent correlation between microCT assessment and en face surface area (r(2) = 0.99, p<0.0001 and r(2) = 0.95, p<0.0001, respectively). MicroCT also identified internal characteristics of the lipid core and fibrous cap, which were confirmed pathologically as Stary type III-V lesions. These data validate the use of microCT technology to provide a more exact empirical measure of ex vivo plaque volume throughout the entire intact aorta in situ for the quantification of atherosclerosis in preclinical models. PMID- 21533111 TI - Epistatic roles for Pseudomonas aeruginosa MutS and DinB (DNA Pol IV) in coping with reactive oxygen species-induced DNA damage. AB - Pseudomonas aeruginosa is especially adept at colonizing the airways of individuals afflicted with the autosomal recessive disease cystic fibrosis (CF). CF patients suffer from chronic airway inflammation, which contributes to lung deterioration. Once established in the airways, P. aeruginosa continuously adapts to the changing environment, in part through acquisition of beneficial mutations via a process termed pathoadaptation. MutS and DinB are proposed to play opposing roles in P. aeruginosa pathoadaptation: MutS acts in replication-coupled mismatch repair, which acts to limit spontaneous mutations; in contrast, DinB (DNA polymerase IV) catalyzes error-prone bypass of DNA lesions, contributing to mutations. As part of an ongoing effort to understand mechanisms underlying P. aeruginosa pathoadaptation, we characterized hydrogen peroxide (H(2)O(2))-induced phenotypes of isogenic P. aeruginosa strains bearing different combinations of mutS and dinB alleles. Our results demonstrate an unexpected epistatic relationship between mutS and dinB with respect to H(2)O(2)-induced cell killing involving error-prone repair and/or tolerance of oxidized DNA lesions. In striking contrast to these error-prone roles, both MutS and DinB played largely accurate roles in coping with DNA lesions induced by ultraviolet light, mitomycin C, or 4-nitroquinilone 1-oxide. Models discussing roles for MutS and DinB functionality in DNA damage-induced mutagenesis, particularly during CF airway colonization and subsequent P. aeruginosa pathoadaptation are discussed. PMID- 21533113 TI - When is visual information used to control locomotion when descending a kerb? AB - BACKGROUND: Descending kerbs during locomotion involves the regulation of appropriate foot placement before the kerb-edge and foot clearance over it. It also involves the modulation of gait output to ensure the body-mass is safely and smoothly lowered to the new level. Previous research has shown that vision is used in such adaptive gait tasks for feedforward planning, with vision from the lower visual field (lvf) used for online updating. The present study determined when lvf information is used to control/update locomotion when stepping from a kerb. METHODOLOGY/PRINCIPAL FINDINGS: 12 young adults stepped down a kerb during ongoing gait. Force sensitive resistors (attached to participants' feet) interfaced with an high-speed PDLC 'smart glass' sheet, allowed the lvf to be unpredictably occluded at either heel-contact of the penultimate or final step before the kerb-edge up to contact with the lower level. Analysis focussed on determining changes in foot placement distance before the kerb-edge, clearance over it, and in kinematic measures of the step down. Lvf occlusion from the instant of final step contact had no significant effect on any dependant variable (p>0.09). Occlusion of the lvf from the instant of penultimate step contact had a significant effect on foot clearance and on several kinematic measures, with findings consistent with participants becoming uncertain regarding relative horizontal location of the kerb-edge. CONCLUSION/SIGNIFICANCE: These findings suggest concurrent feedback of the lower limb, kerb-edge, and/or floor area immediately in front/below the kerb is not used when stepping from a kerb during ongoing gait. Instead heel-clearance and pre-landing-kinematic parameters are determined/planned using lvf information acquired in the penultimate step during the approach to the kerb-edge, with information related to foot placement before the kerb-edge being the most salient. PMID- 21533114 TI - A small RNA controls expression of the chitinase ChiA in Listeria monocytogenes. AB - In recent years, more than 60 small RNAs (sRNAs) have been identified in the gram positive human pathogen Listeria monocytogenes, but their putative roles and mechanisms of action remain largely unknown. The sRNA LhrA was recently shown to be a post-transcriptional regulator of a single gene, lmo0850, which encodes a small protein of unknown function. LhrA controls the translation and degradation of the lmo0850 mRNA by an antisense mechanism, and it depends on the RNA chaperone Hfq for efficient binding to its target. In the present study, we sought to gain more insight into the functional role of LhrA in L. monocytogenes. To this end, we determined the effects of LhrA on global-wide gene expression. We observed that nearly 300 genes in L. monocytogenes are either positively or negatively affected by LhrA. Among these genes, we identified lmo0302 and chiA as direct targets of LhrA, thus establishing LhrA as a multiple target regulator. Lmo0302 encodes a hypothetical protein with no known function, whereas chiA encodes one of two chitinases present in L. monocytogenes. We show here that LhrA acts as a post-transcriptional regulator of lmo0302 and chiA by interfering with ribosome recruitment, and we provide evidence that both LhrA and Hfq act to down regulate the expression of lmo0302 and chiA. Furthermore, in vitro binding experiments show that Hfq stimulates the base pairing of LhrA to chiA mRNA. Finally, we demonstrate that LhrA has a negative effect on the chitinolytic activity of L. monocytogenes. In marked contrast to this, we found that Hfq has a stimulating effect on the chitinolytic activity, suggesting that Hfq plays multiple roles in the complex regulatory pathways controlling the chitinases of L. monocytogenes. PMID- 21533115 TI - Viral and atypical bacterial detection in acute respiratory infection in children under five years. AB - BACKGROUND: Acute respiratory infection (ARI) is a leading cause of morbidity and mortality in children worldwide. This study aimed to determine the viral and atypical bacterial causes of different severities and clinical manifestations of ARI in preschool children from low-income families in North-East Brazil. METHODS: Clinical/demographic data and nasopharyngeal aspirates (NPA) were prospectively collected from children <5 years presenting with ARI over one year to a paediatric A&E department. Disease severity was grouped according to presence of lower respiratory tract signs, need for hospital admission and need for oxygen. Clinical manifestation of ARI was based on discharge diagnosis from hospital with four conditions predominating: bronchiolitis, pneumonia, episodic viral wheeze/asthma and upper respiratory tract infection. Multiplex PCR was used to detect 17 common respiratory viral and atypical bacterial pathogens in NPA. FINDINGS: 407 children with a median age of eight months were recruited. Pathogens were detected in 85.5% samples with co-infection being particularly common (39.5%). Respiratory Syncytial Virus (RSV; 37%), Adenoviruses (AdV; 25%), Rhinoviruses (hRV; 19%), Bocavirus (hBoV; 19%), human Meta-pneumovirus (hMPV; 10%) and Mycoplasma pneumoniae (Mpp; 10%) were most prevalent. Detection and co infection rates were similar in all severities and clinical manifestations of ARI apart from RSV, which was associated with more severe disease and specifically more severe cases of bronchiolitis, and Mpp, which was associated with more severe cases of pneumonia. Mpp was detected in 17% of children admitted to hospital with pneumonia. INTERPRETATION: This study underlines the importance of viral and atypical bacterial pathogens in ARI in pre-school children and highlights the complex epidemiology of these pathogens in this age group. Generally, viruses and atypical bacteria were detected in all severities and clinical manifestations of ARI but RSV and Mpp were associated with more severe cases of bronchiolitis and pneumonia respectively. PMID- 21533116 TI - Functional connectivity fMRI of the rodent brain: comparison of functional connectivity networks in rat and mouse. AB - At present, resting state functional MRI (rsfMRI) is increasingly used in human neuropathological research. The present study aims at implementing rsfMRI in mice, a species that holds the widest variety of neurological disease models. Moreover, by acquiring rsfMRI data with a comparable protocol for anesthesia, scanning and analysis, in both rats and mice we were able to compare findings obtained in both species. The outcome of rsfMRI is different for rats and mice and depends strongly on the applied number of components in the Independent Component Analysis (ICA). The most important difference was the appearance of unilateral cortical components for the mouse resting state data compared to bilateral rat cortical networks. Furthermore, a higher number of components was needed for the ICA analysis to separate different cortical regions in mice as compared to rats. PMID- 21533117 TI - On the origin and trigger of the notothenioid adaptive radiation. AB - Adaptive radiation is usually triggered by ecological opportunity, arising through (i) the colonization of a new habitat by its progenitor; (ii) the extinction of competitors; or (iii) the emergence of an evolutionary key innovation in the ancestral lineage. Support for the key innovation hypothesis is scarce, however, even in textbook examples of adaptive radiation. Antifreeze glycoproteins (AFGPs) have been proposed as putative key innovation for the adaptive radiation of notothenioid fishes in the ice-cold waters of Antarctica. A crucial prerequisite for this assumption is the concurrence of the notothenioid radiation with the onset of Antarctic sea ice conditions. Here, we use a fossil calibrated multi-marker phylogeny of nothothenioid and related acanthomorph fishes to date AFGP emergence and the notothenioid radiation. All time constraints are cross-validated to assess their reliability resulting in six powerful calibration points. We find that the notothenioid radiation began near the Oligocene-Miocene transition, which coincides with the increasing presence of Antarctic sea ice. Divergence dates of notothenioids are thus consistent with the key innovation hypothesis of AFGP. Early notothenioid divergences are furthermore congruent with vicariant speciation and the breakup of Gondwana. PMID- 21533118 TI - Sequence-based predictions of lipooligosaccharide diversity in the Neisseriaceae and their implication in pathogenicity. AB - Endotoxin [Lipopolysaccharide (LPS)/Lipooligosaccharide (LOS)] is an important virulence determinant in gram negative bacteria. While the genetic basis of endotoxin production and its role in disease in the pathogenic Neisseria has been extensively studied, little research has focused on the genetic basis of LOS biosynthesis in commensal Neisseria. We determined the genomic sequences of a variety of commensal Neisseria strains, and compared these sequences, along with other genomic sequences available from various sequencing centers from commensal and pathogenic strains, to identify genes involved in LOS biosynthesis. This allowed us to make structural predictions as to differences in LOS seen between commensal and pathogenic strains. We determined that all neisserial strains possess a conserved set of genes needed to make a common 3-Deoxy-D-manno octulosonic acid -heptose core structure. However, significant genomic differences in glycosyl transferase genes support the published literature indicating compositional differences in the terminal oligosaccharides. This was most pronounced in commensal strains that were distally related to the gonococcus and meningococcus. These strains possessed a homolog of heptosyltransferase III, suggesting that they differ from the pathogenic strains by the presence a third heptose. Furthermore, most commensal strains possess homologs of genes needed to synthesize lipopolysaccharide (LPS). N. cinerea, a commensal species that is highly related to the gonococcus has lost the ability to make sialyltransferase. Overall genomic comparisons of various neisserial strains indicate that significant recombination/genetic acquisition/loss has occurred within the genus, and this muddles proper speciation. PMID- 21533119 TI - Vascular endothelial growth factor receptor-2 couples cyclo-oxygenase-2 with pro angiogenic actions of leptin on human endothelial cells. AB - BACKGROUND: The adipocyte-derived hormone leptin influences the behaviour of a wide range of cell types and is now recognised as a pro-angiogenic and pro inflammatory factor. In the vasculature, these effects are mediated in part through its direct leptin receptor (ObRb)-driven actions on endothelial cells (ECs) but the mechanisms responsible for these activities have not been established. In this study we sought to more fully define the molecular links between inflammatory and angiogenic responses of leptin-stimulated human ECs. METHODOLOGY/PRINCIPAL FINDINGS: Immunoblotting studies showed that leptin increased cyclo-oxygenase-2 (COX-2) expression (but not COX-1) in cultured human umbilical vein ECs (HUVEC) through pathways that depend upon activation of both p38 mitogen-activated protein kinase (p38(MAPK)) and Akt, and stimulated rapid phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) on Tyr(1175). Phosphorylation of VEGFR2, p38(MAPK) and Akt, and COX-2 induction in cells challenged with leptin were blocked by a specific leptin peptide receptor antagonist. Pharmacological inhibitors of COX-2, the phosphatidylinositol 3 kinase (PI3K)/Akt pathway and p38(MAPK) abrogated leptin-induced EC proliferation (assessed by quantifying 5-bromo-2'-deoxyuridine incorporation, calcein fluorescence and propidium iodide staining), slowed the increased migration rate of leptin-stimulated cells (in vitro wound healing assay) and inhibited leptin induced capillary-like tube formation by HUVEC on Matrigel. Inhibition of VEGFR2 tyrosine kinase activity reduced leptin-stimulated p38(MAPK) and Akt activation, COX-2 induction, and pro-angiogenic EC responses, and blockade of VEGFR2 or COX-2 activities abolished leptin-driven neo-angiogenesis in a chick chorioallantoic membrane vascularisation assay in vivo. CONCLUSIONS/SIGNIFICANCE: We conclude that a functional endothelial p38(MAPK)/Akt/COX-2 signalling axis is required for leptin's pro-angiogenic actions and that this is regulated upstream by ObRb dependent activation of VEGFR2. These studies identify a new function for VEGFR2 as a mediator of leptin-stimulated COX-2 expression and angiogenesis and have implications for understanding leptin's regulation of the vasculature in both non obese and obese individuals. PMID- 21533120 TI - Comparative gene expression profiles induced by PPARgamma and PPARalpha/gamma agonists in human hepatocytes. AB - BACKGROUND: Several glitazones (PPARgamma agonists) and glitazars (dual PPARalpha/gamma agonists) have been developed to treat hyperglycemia and, simultaneously, hyperglycemia and dyslipidemia, respectively. However, most have caused idiosyncratic hepatic or extrahepatic toxicities through mechanisms that remain largely unknown. Since the liver plays a key role in lipid metabolism, we analyzed changes in gene expression profiles induced by these two types of PPAR agonists in human hepatocytes. METHODOLOGY/PRINCIPAL FINDINGS: Primary human hepatocytes and the well-differentiated human hepatoma HepaRG cells were exposed to different concentrations of two PPARgamma (troglitazone and rosiglitazone) and two PPARalpha/gamma (muraglitazar and tesaglitazar) agonists for 24 h and their transcriptomes were analyzed using human pangenomic Agilent microarrays. Principal Component Analysis, hierarchical clustering and Ingenuity Pathway Analysis(r) revealed large inter-individual variability in the response of the human hepatocyte populations to the different compounds. Many genes involved in lipid, carbohydrate, xenobiotic and cholesterol metabolism, as well as inflammation and immunity, were regulated by both PPARgamma and PPARalpha/gamma agonists in at least a number of human hepatocyte populations and/or HepaRG cells. Only a few genes were selectively deregulated by glitazars when compared to glitazones, indicating that PPARgamma and PPARalpha/gamma agonists share most of their target genes. Moreover, some target genes thought to be regulated only in mouse or to be expressed in Kupffer cells were also found to be responsive in human hepatocytes and HepaRG cells. CONCLUSIONS/SIGNIFICANCE: This first comprehensive analysis of gene regulation by PPARgamma and PPARalpha/gamma agonists favor the conclusion that glitazones and glitazars share most of their target genes and induce large differential changes in gene profiles in human hepatocytes depending on hepatocyte donor, the compound class and/or individual compound, thereby supporting the occurrence of idiosyncratic toxicity in some patients. PMID- 21533121 TI - Directed evolution reveals the binding motif preference of the LC8/DYNLL hub protein and predicts large numbers of novel binders in the human proteome. AB - LC8 dynein light chain (DYNLL) is a eukaryotic hub protein that is thought to function as a dimerization engine. Its interacting partners are involved in a wide range of cellular functions. In its dozens of hitherto identified binding partners DYNLL binds to a linear peptide segment. The known segments define a loosely characterized binding motif: [D/S](-4)K(-3)X(-2)[T/V/I]( 1)Q(0)[T/V](1)[D/E](2). The motifs are localized in disordered segments of the DYNLL-binding proteins and are often flanked by coiled coil or other potential dimerization domains. Based on a directed evolution approach, here we provide the first quantitative characterization of the binding preference of the DYNLL binding site. We displayed on M13 phage a naive peptide library with seven fully randomized positions around a fixed, naturally conserved glutamine. The peptides were presented in a bivalent manner fused to a leucine zipper mimicking the natural dimer to dimer binding stoichiometry of DYNLL-partner complexes. The phage-selected consensus sequence V(-5)S(-4)R(-3)G(-2)T(-1)Q(0)T(1)E(2) resembles the natural one, but is extended by an additional N-terminal valine, which increases the affinity of the monomeric peptide twentyfold. Leu-zipper dimerization increases the affinity into the subnanomolar range. By comparing crystal structures of an SRGTQTE-DYNLL and a dimeric VSRGTQTE-DYNLL complex we find that the affinity enhancing valine is accommodated in a binding pocket on DYNLL. Based on the in vitro evolved sequence pattern we predict a large number of novel DYNLL binding partners in the human proteome. Among these EML3, a microtubule-binding protein involved in mitosis contains an exact match of the phage-evolved consensus and binds to DYNLL with nanomolar affinity. These results significantly widen the scope of the human interactome around DYNLL and will certainly shed more light on the biological functions and organizing role of DYNLL in the human and other eukaryotic interactomes. PMID- 21533122 TI - Imatinib treatment induces CD5+ B lymphocytes and IgM natural antibodies with anti-leukemic reactivity in patients with chronic myelogenous leukemia. AB - Imatinib mesylate is a first line treatment of Chronic Myelogenous Leukemia and of a rare form of gastrointestinal stromal cancer, where the response to the drug is also linked to the immune system activation with production of antineoplastic cytokines. In this study, forty patients in the chronic phase of disease, treated with imatinib mesylate, were analyzed. Bone marrow aspirates were drawn at diagnosis, after 3, 6, 12, 18 months for haematological, cytofluorimetric, cytogenetic, biomolecular evaluation and cytokine measurement. Responder and non responder patients were defined according to the European LeukemiaNet recommendations. In responder patients (n = 32), the percentage of bone marrow CD20(+)CD5(+)sIgM(+) lymphocytes, and the plasma levels of IgM, were significantly higher, at 3 months and up to 9 months, than in non responders. These IgM reacted with O-linked sugars expressed by leukemic cells and could induce tumor cell apoptosis. In responder patients the stromal-derived factor-1 and the B-lymphocyte-activating factor of the tumor necrosis factor family significantly raised in the bone marrow after imatinib administration, together with the bone morphogenetic proteins-2 and -7. All patients with high number of CD20(+)CD5(+)sIgM(+) cells and high stromal-derived factor-1 and B lymphocyte activating factor levels, underwent complete cytogenetic and/or molecular remission by 12 months. We propose that CD20(+)CD5(+)sIgM(+) lymphocytes producing anti-carbohydrate antibodies with anti-tumor activity, might contribute to the response to imatinib treatment. As in multivariate analysis bone marrow CD20(+)CD5(+)sIgM(+) cells and stromal-derived factor-1 and B-lymphocyte activating factor levels were significantly related to cytogenetical and molecular changes, they might contribute to the definition of the pharmacological response. PMID- 21533123 TI - Optimization of microCT imaging and blood vessel diameter quantitation of preclinical specimen vasculature with radiopaque polymer injection medium. AB - Vascular networks within a living organism are complex, multi-dimensional, and challenging to image capture. Radio-angiographic studies in live animals require a high level of infrastructure and technical investment in order to administer costly perfusion mediums whose signals metabolize and degrade relatively rapidly, diminishing within a few hours or days. Additionally, live animal specimens must not be subject to long duration scans, which can cause high levels of radiation exposure to the specimen, limiting the quality of images that can be captured. Lastly, despite technological advances in live-animal specimen imaging, it is quite difficult to minimize or prevent movement of a live animal, which can cause motion artifacts in the final data output. It is demonstrated here that through the use of postmortem perfusion protocols of radiopaque silicone polymer mediums and ex-vivo organ harvest, it is possible to acquire a high level of vascular signal in preclinical specimens through the use of micro-computed tomographic (microCT) imaging. Additionally, utilizing high-order rendering algorithms, it is possible to further derive vessel morphometrics for qualitative and quantitative analysis. PMID- 21533124 TI - MicroRNA let-7f inhibits tumor invasion and metastasis by targeting MYH9 in human gastric cancer. AB - BACKGROUND: MicroRNAs (miRNAs) are important regulators that play key roles in tumorigenesis and tumor progression. A previous report has shown that let-7 family members can act as tumor suppressors in many cancers. Through miRNA array, we found that let-7f was downregulated in the highly metastatic potential gastric cancer cell lines GC9811-P and SGC7901-M, when compared with their parental cell lines, GC9811 and SGC7901-NM; however, the mechanism was not clear. In this study, we investigate whether let-7f acts as a tumor suppressor to inhibit invasion and metastasis in gastric cancers. METHODOLOGY/PRINCIPAL: Real-time PCR showed decreased levels of let-7f expression in metastatic gastric cancer tissues and cell lines that are potentially highly metastatic. Cell invasion and migration were significantly impaired in GC9811-P and SGC7901-M cell lines after transfection with let-7f-mimics. Nude mice with xenograft models of gastric cancer confirmed that let-7f could inhibit gastric cancer metastasis in vivo after transfection by the lentivirus pGCsil-GFP- let-7f. Luciferase reporter assays demonstrated that let-7f directly binds to the 3'UTR of MYH9, which codes for myosin IIA, and real-time PCR and Western blotting further indicated that let 7f downregulated the expression of myosin IIA at the mRNA and protein levels. CONCLUSIONS/SIGNIFICANCE: Our study demonstrated that overexpression of let-7f in gastric cancer could inhibit invasion and migration of gastric cancer cells through directly targeting the tumor metastasis-associated gene MYH9. These data suggest that let-7f may be a novel therapeutic candidate for gastric cancer, given its ability to reduce cell invasion and metastasis. PMID- 21533125 TI - Quantitative analysis of serum procollagen type I C-terminal propeptide by immunoassay on microchip. AB - BACKGROUND: Sandwich enzyme-linked immunosorbent assay (ELISA) is one of the most frequently employed assays for clinical diagnosis, since this enables the investigator to identify specific protein biomarkers. However, the conventional assay using a 96-well microtitration plate is time- and sample-consuming, and therefore is not suitable for rapid diagnosis. To overcome these drawbacks, we performed a sandwich ELISA on a microchip. METHODS AND FINDINGS: The microchip was made of cyclic olefin copolymer with straight microchannels that were 300 um wide and 100 um deep. For the construction of a sandwich ELISA for procollagen type I C-peptide (PICP), a biomarker for bone formation, we used a piezoelectric inkjet printing system for the deposition and fixation of the 1st anti-PICP antibody on the surface of the microchannel. After the infusion of the mixture of 2.0 ul of peroxidase-labeled 2nd anti-PICP antibody and 0.4 ul of sample to the microchannel and a 30-min incubation, the substrate for peroxidase was infused into the microchannel; and the luminescence intensity of each spot of 1st antibody was measured by CCD camera. A linear relationship was observed between PICP concentration and luminescence intensity over the range of 0 to 600 ng/ml (r(2) = 0.991), and the detection limit was 4.7 ng/ml. Blood PICP concentrations of 6 subjects estimated from microchip were compared with results obtained by the conventional method. Good correlation was observed between methods according to simple linear regression analysis (R(2) = 0.9914). The within-day and between days reproducibilities were 3.2-7.4 and 4.4-6.8%, respectively. This assay reduced the time for the antigen-antibody reaction to 1/6, and the consumption of samples and reagents to 1/50 compared with the conventional method. CONCLUSION: This assay enabled us to determine serum PICP with accuracy, high sensitivity, time saving ability, and low consumption of sample and reagents, and thus will be applicable to clinic diagnosis. PMID- 21533126 TI - The anti-apoptotic Bcl-x(L) protein, a new piece in the puzzle of cytochrome c interactome. AB - A structural model of the adduct between human cytochrome c and the human anti apoptotic protein Bcl-x(L), which defines the protein-protein interaction surface, was obtained from solution NMR chemical shift perturbation data. The atomic level information reveals key intermolecular contacts identifying new potentially druggable areas on cytochrome c and Bcl-x(L). Involvement of residues on cytochrome c other than those in its complexes with electron transfer partners is apparent. Key differences in the contact area also exist between the Bcl-x(L) adduct with the Bak peptide and that with cytochrome c. The present model provides insights to the mechanism by which cytochrome c translocated to cytosol can be intercepted, so that the apoptosome is not assembled. PMID- 21533128 TI - Is there evidence for aetiologically distinct subgroups of idiopathic congenital talipes equinovarus? A case-only study and pedigree analysis. AB - BACKGROUND: Idiopathic congenital talipes equinovarus (CTEV) is a common developmental foot disorder, the aetiology of which remains largely unknown. Some aspects of the epidemiology suggest the possibility of aetiologically distinct subgroups. Previous studies consider CTEV as a homogenous entity which may conceal risk factors in particular subgroups. We investigate evidence for aetiologically distinct subgroups of CTEV. METHODS: Parents of 785 probands completed a postal questionnaire. Family pedigrees were compiled by telephone. Case-only analysis was used to investigate interactions between risk factors and sex of the proband, CTEV laterality and CTEV family history. RESULTS: The male:female ratio was 2.3:1, 58% of probands were affected bilaterally and 11% had a first-second degree family history. There were modest interactions between family history and twin births (multivariate case - only odds ratio [ORca] = 3.87, 95%CI 1.19-12.62) and family history and maternal use of folic acid supplements in early pregnancy (ORca = 0.62, 95%CI 0.38-1.01); and between sex of the proband and maternal alcohol consumption during pregnancy (female, positive history and alcohol consumed: ORca = 0.33, 95%CI 0.12-0.89). Previous reports of an interaction between maternal smoking and family history were not confirmed. Relatives of female probands were affected more often than relatives of male probands. CONCLUSIONS: These results provide tentative evidence for aetiologically distinct CTEV subgroups. They support the 'Carter effect', suggesting CTEV develops though a multifactorial threshold model with females requiring a higher risk factor 'load', and suggest areas where future aetiological investigation might focus. Large multi-centre studies are needed to further advance understanding of this common condition. PMID- 21533127 TI - Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy. AB - Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33*10(-35); ADD: P = 7.48*10(-30); REC: P = 5.27*10(-6)). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies. PMID- 21533129 TI - Comparative pathogenesis of three human and zoonotic SARS-CoV strains in cynomolgus macaques. AB - The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. While there were significant differences in the number of host genes differentially regulated during the host responses between the three SARS-CoV strains, the top pathways and functions were similar and only apparent early during infection with the majority of genes associated with interferon signaling pathways. This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use. PMID- 21533130 TI - Chronic delivery of antibody fragments using immunoisolated cell implants as a passive vaccination tool. AB - BACKGROUND: Monoclonal antibodies and antibody fragments are powerful biotherapeutics for various debilitating diseases. However, high production costs, functional limitations such as inadequate pharmacokinetics and tissue accessibility are the current principal disadvantages for broadening their use in clinic. METHODOLOGY AND PRINCIPAL FINDINGS: We report a novel method for the long term delivery of antibody fragments. We designed an allogenous immunoisolated implant consisting of polymer encapsulated myoblasts engineered to chronically release scFv antibodies targeted against the N-terminus of the Abeta peptide. Following a 6-month intracerebral therapy we observed a significant reduction of the production and aggregation of the Abeta peptide in the APP23 transgenic mouse model of Alzheimer's disease. In addition, functional assessment showed prevention of behavioral deficits related to anxiety and memory traits. CONCLUSIONS AND SIGNIFICANCE: The chronic local release of antibodies using immunoisolated polymer cell implants represents an alternative passive vaccination strategy in Alzheimer's disease. This novel technique could potentially benefit other diseases presently treated by local and systemic antibody administration. PMID- 21533131 TI - First hominoid from the Late Miocene of the Irrawaddy Formation (Myanmar). AB - For over a century, a Neogene fossil mammal fauna has been known in the Irrawaddy Formation in central Myanmar. Unfortunately, the lack of accurately located fossiliferous sites and the absence of hominoid fossils have impeded paleontological studies. Here we describe the first hominoid found in Myanmar together with a Hipparion (s.l.) associated mammal fauna from Irrawaddy Formation deposits dated between 10.4 and 8.8 Ma by biochronology and magnetostratigraphy. This hominoid documents a new species of Khoratpithecus, increasing thereby the Miocene diversity of southern Asian hominoids. The composition of the associated fauna as well as stable isotope data on Hipparion (s.l.) indicate that it inhabited an evergreen forest in a C3-plant environment. Our results enlighten that late Miocene hominoids were more regionally diversified than other large mammals, pointing towards regionally-bounded evolution of the representatives of this group in Southeast Asia. The Irrawaddy Formation, with its extensive outcrops and long temporal range, has a great potential for improving our knowledge of hominoid evolution in Asia. PMID- 21533133 TI - Functional energetics of CD4+-cellular immunity in monoclonal antibody-associated progressive multifocal leukoencephalopathy in autoimmune disorders. AB - BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system- (CNS-) infection that typically occurs in a subset of immunocompromised individuals. An increasing incidence of PML has recently been reported in patients receiving monoclonal antibody (mAb) therapy for the treatment of autoimmune diseases, particularly those treated with natalizumab, efalizumab and rituximab. Intracellular CD4(+)-ATP-concentration (iATP) functionally reflects cellular immunocompetence and inversely correlates with risk of infections during immunosuppressive therapy. We investigated whether iATP may assist in individualized risk stratification for opportunistic infections during mAb-treatment. METHODOLOGY/PRINCIPAL FINDINGS: iATP in PHA-stimulated, immunoselected CD4(+)-cells was analyzed using an FDA-approved assay. iATP of mAb associated PML (natalizumab (n = 8), rituximab (n = 2), efalizumab (n = 1)), or other cases of opportunistic CNS-infections (HIV-associated PML (n = 2), spontaneous PML, PML in a psoriasis patient under fumaric acids, natalizumab associated herpes simplex encephalitis (n = 1 each)) was reduced by 59% (194.5+/ 29 ng/ml, mean+/-SEM) in comparison to healthy controls (HC, 479.9+/-19.8 ng/ml, p<0.0001). iATP in 14 of these 16 patients was at or below 3(rd) percentile of healthy controls, similar to HIV-patients (n = 18). In contrast, CD4(+)-cell numbers were reduced in only 7 of 15 patients, for whom cell counts were available. iATP correlated with mitochondrial transmembrane potential (DeltaPsi(m)) (iATP/DeltaPsi(m)-correlation:tau = 0.49, p = 0.03). Whereas mean iATP of cross-sectionally analysed natalizumab-treated patients was unaltered (448.7+/-12 ng/ml, n = 150), iATP was moderately decreased (316.2+/-26.1 ng/ml, p = 0.04) in patients (n = 7) who had been treated already during the pivotal phase III trials and had received natalizumab for more than 6 years. 2/92 (2%) patients with less than 24 months natalizumab treatment revealed very low iATP at or below the 3(rd) percentile of HC, whereas 10/58 (17%) of the patients treated for more than 24 months had such low iATP-concentrations. CONCLUSION: Our results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders. PMID- 21533132 TI - Systems-scale analysis reveals pathways involved in cellular response to methamphetamine. AB - BACKGROUND: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, including energy metabolism, spermatogenesis, and maintenance of oxidative status. However, many components of the molecular underpinnings of METH toxicity have yet to be established. Network analyses of integrated proteomic, transcriptomic and metabolomic data are particularly well suited for identifying cellular responses to toxins, such as METH, which might otherwise be obscured by the numerous and dynamic changes that are induced. METHODOLOGY/RESULTS: We used network analyses of proteomic and transcriptomic data to evaluate pathways in Drosophila melanogaster that are affected by acute METH toxicity. METH exposure caused changes in the expression of genes involved with energy metabolism, suggesting a Warburg-like effect (aerobic glycolysis), which is normally associated with cancerous cells. Therefore, we tested the hypothesis that carbohydrate metabolism plays an important role in METH toxicity. In agreement with our hypothesis, we observed that increased dietary sugars partially alleviated the toxic effects of METH. Our systems analysis also showed that METH impacted genes and proteins known to be associated with muscular homeostasis/contraction, maintenance of oxidative status, oxidative phosphorylation, spermatogenesis, iron and calcium homeostasis. Our results also provide numerous candidate genes for the METH-induced dysfunction of spermatogenesis, which have not been previously characterized at the molecular level. CONCLUSION: Our results support our overall hypothesis that METH causes a toxic syndrome that is characterized by the altered carbohydrate metabolism, dysregulation of calcium and iron homeostasis, increased oxidative stress, and disruption of mitochondrial functions. PMID- 21533134 TI - Proteomics of buccal cavity mucus in female tilapia fish (Oreochromis spp.): a comparison between parental and non-parental fish. AB - Mouthbrooding is an elaborate form of parental care displayed by many teleost species. While the direct benefits of mouthbrooding such as protection and transportation of offsprings are known, it is unclear if mouthbrooding offers additional benefits to embryos during incubation. In addition, mouthbrooding could incur negative costs on parental fish, due to limited feeding opportunities. Parental tilapia fish (Oreochromis spp.) display an elaborated form of parental care by incubating newly hatched embryos in oral buccal cavity until the complete adsorption of yolk sac. In order to understand the functional aspects of mouthbrooding, we undertake a proteomics approach to compare oral mucus sampled from mouthbrooders and non-mouthbrooders, respectively. Majority of the identified proteins have also been previously identified in other biological fluids or mucus-rich organs in different organisms. We also showed the upregulation of 22 proteins and down regulation of 3 proteins in mucus collected from mouthbrooders. Anterior gradient protein, hemoglobin beta-A chain and alpha 2 globin levels were lower in mouthbrooder samples. Mouthbrooder oral mucus collectively showed increase levels of proteins related to cytoskeletal properties, glycolytic pathway and mediation of oxidative stress. Overall the findings suggest cellular stress response, probably to support production of mucus during mouthbrooding phase. PMID- 21533135 TI - The PLIN4 variant rs8887 modulates obesity related phenotypes in humans through creation of a novel miR-522 seed site. AB - PLIN4 is a member of the PAT family of lipid storage droplet (LSD) proteins. Associations between seven single nucleotide polymorphisms (SNPs) at human PLIN4 with obesity related phenotypes were investigated using meta-analysis followed by a determination if these phenotypes are modulated by interactions between PLIN4 SNPs and dietary PUFA. Samples consisted of subjects from two populations of European ancestry. We demonstrated association of rs8887 with anthropometrics. Meta-analysis demonstrated significant interactions between the rs8887 minor allele with PUFA n3 modulating anthropometrics. rs884164 showed interaction with both n3 and n6 PUFA modulating anthropometric and lipid phenotypes. In silico analysis of the PLIN4 3'UTR sequence surrounding the rs8887 minor A allele predicted a seed site for the human microRNA-522 (miR-522), suggesting a functional mechanism. Our data showed that a PLIN4 3'UTR luciferase reporter carrying the A allele of rs8887 was reduced in response to miR-522 mimics compared to the G allele. These results suggest variation at the PLIN4 locus, and its interaction with PUFA as a modulator of obesity related phenotypes, acts in part through creation of a miR-522 regulatory site. PMID- 21533136 TI - Simultaneously hermaphroditic shrimp use lipophilic cuticular hydrocarbons as contact sex pheromones. AB - Successful mating is essentially a consequence of making the right choices at the correct time. Animals use specific strategies to gain information about a potential mate, which is then applied to decision-making processes. Amongst the many informative signals, odor cues such as sex pheromones play important ecological roles in coordinating mating behavior, enabling mate and kin recognition, qualifying mate choice, and preventing gene exchange among individuals from different populations and species. Despite overwhelming behavioral evidence, the chemical identity of most cues used in aquatic organisms remains unknown and their impact and omnipresence have not been fully recognized. In many crustaceans, including lobsters and shrimps, reproduction happens through a cascade of events ranging from initial attraction to formation of a mating pair eventually leading to mating. We examined the hypothesis that contact pheromones on the female body surface of the hermaphroditic shrimp Lysmata boggessi are of lipophilic nature, and resemble insect cuticular hydrocarbon contact cues. Via chemical analyses and behavioural assays, we show that newly molted euhermaphrodite-phase shrimp contain a bouquet of odor compounds. Of these, (Z)-9 octadecenamide is the key odor with hexadecanamide and methyl linoleate enhancing the bioactivity of the pheromone blend. Our results show that in aquatic systems lipophilic, cuticular hydrocarbon contact sex pheromones exist; this raises questions on how hydrocarbon contact signals evolved and how widespread these are in the marine environment. PMID- 21533137 TI - The immune cellular effectors of terrestrial isopod Armadillidium vulgare: meeting with their invaders, Wolbachia. AB - BACKGROUND: Most of crustacean immune responses are well described for the aquatic forms whereas almost nothing is known for the isopods that evolved a terrestrial lifestyle. The latter are also infected at a high prevalence with Wolbachia, an endosymbiotic bacterium which affects the host immune system, possibly to improve its transmission. In contrast with insect models, the isopod Armadillidium vulgare is known to harbor Wolbachia inside the haemocytes. METHODOLOGY/PRINCIPAL FINDINGS: In A. vulgare we characterized three haemocyte types (TEM, flow cytometry): the hyaline and semi-granular haemocytes were phagocytes, while semi-granular and granular haemocytes performed encapsulation. They were produced in the haematopoietic organs, from central stem cells, maturing as they moved toward the edge (TEM). In infected individuals, live Wolbachia (FISH) colonized 38% of the haemocytes but with low, variable densities (6.45+/-0.46 Wolbachia on average). So far they were not found in hyaline haemocytes (TEM). The haematopoietic organs contained 7.6+/-0.7*10(3)Wolbachia, both in stem cells and differentiating cells (FISH). While infected and uninfected one-year-old individuals had the same haemocyte density, in infected animals the proportion of granular haemocytes in particular decreased by one third (flow cytometry, Pearson's test = 12 822.98, df = 2, p<0.001). CONCLUSIONS/SIGNIFICANCE: The characteristics of the isopod immune system fell within the range of those known from aquatic crustaceans. The colonization of the haemocytes by Wolbachia seemed to stand from the haematopoietic organs, which may act as a reservoir to discharge Wolbachia in the haemolymph, a known route for horizontal transfer. Wolbachia infection did not affect the haemocyte density, but the quantity of granular haemocytes decreased by one third. This may account for the reduced prophenoloxidase activity observed previously in these animals. PMID- 21533138 TI - Massive-scale RNA-Seq analysis of non ribosomal transcriptome in human trisomy 21. AB - Hybridization- and tag-based technologies have been successfully used in Down syndrome to identify genes involved in various aspects of the pathogenesis. However, these technologies suffer from several limits and drawbacks and, to date, information about rare, even though relevant, RNA species such as long and small non-coding RNAs, is completely missing. Indeed, none of published works has still described the whole transcriptional landscape of Down syndrome. Although the recent advances in high-throughput RNA sequencing have revealed the complexity of transcriptomes, most of them rely on polyA enrichment protocols, able to detect only a small fraction of total RNA content. On the opposite end, massive-scale RNA sequencing on rRNA-depleted samples allows the survey of the complete set of coding and non-coding RNA species, now emerging as novel contributors to pathogenic mechanisms. Hence, in this work we analysed for the first time the complete transcriptome of human trisomic endothelial progenitor cells to an unprecedented level of resolution and sensitivity by RNA-sequencing. Our analysis allowed us to detect differential expression of even low expressed genes crucial for the pathogenesis, to disclose novel regions of active transcription outside yet annotated loci, and to investigate a plethora of non polyadenylated long as well as short non coding RNAs. Novel splice isoforms for a large subset of crucial genes, and novel extended untranslated regions for known genes--possibly novel miRNA targets or regulatory sites for gene transcription- were also identified in this study. Coupling the rRNA depletion of samples, followed by high-throughput RNA-sequencing, to the easy availability of these cells renders this approach very feasible for transcriptome studies, offering the possibility of investigating in-depth blood-related pathological features of Down syndrome, as well as other genetic disorders. PMID- 21533139 TI - Predicting diabetic nephropathy using a multifactorial genetic model. AB - AIMS: The tendency to develop diabetic nephropathy is, in part, genetically determined, however this genetic risk is largely undefined. In this proof-of concept study, we tested the hypothesis that combined analysis of multiple genetic variants can improve prediction. METHODS: Based on previous reports, we selected 27 SNPs in 15 genes from metabolic pathways involved in the pathogenesis of diabetic nephropathy and genotyped them in 1274 Ashkenazi or Sephardic Jewish patients with Type 1 or Type 2 diabetes of >10 years duration. A logistic regression model was built using a backward selection algorithm and SNPs nominally associated with nephropathy in our population. The model was validated by using random "training" (75%) and "test" (25%) subgroups of the original population and by applying the model to an independent dataset of 848 Ashkenazi patients. RESULTS: The logistic model based on 5 SNPs in 5 genes (HSPG2, NOS3, ADIPOR2, AGER, and CCL5) and 5 conventional variables (age, sex, ethnicity, diabetes type and duration), and allowing for all possible two-way interactions, predicted nephropathy in our initial population (C-statistic = 0.672) better than a model based on conventional variables only (C = 0.569). In the independent replication dataset, although the C-statistic of the genetic model decreased (0.576), it remained highly associated with diabetic nephropathy (chi(2) = 17.79, p<0.0001). In the replication dataset, the model based on conventional variables only was not associated with nephropathy (chi(2) = 3.2673, p = 0.07). CONCLUSION: In this proof-of-concept study, we developed and validated a genetic model in the Ashkenazi/Sephardic population predicting nephropathy more effectively than a similarly constructed non-genetic model. Further testing is required to determine if this modeling approach, using an optimally selected panel of genetic markers, can provide clinically useful prediction and if generic models can be developed for use across multiple ethnic groups or if population-specific models are required. PMID- 21533140 TI - Expression of measles virus nucleoprotein induces apoptosis and modulates diverse functional proteins in cultured mammalian cells. AB - BACKGROUND: Measles virus nucleoprotein (N) encapsidates the viral RNA, protects it from endonucleases and forms a virus specific template for transcription and replication. It is the most abundant protein during viral infection. Its C terminal domain is intrinsically disordered imparting it the flexibility to interact with several cellular and viral partners. PRINCIPAL FINDINGS: In this study, we demonstrate that expression of N within mammalian cells resulted in morphological transitions, nuclear condensation, DNA fragmentation and activation of Caspase 3 eventuating into apoptosis. The rapid generation of intracellular reactive oxygen species (ROS) was involved in the mechanism of cell death. Addition of ascorbic acid (AA) or inhibitor of caspase-3 in the extracellular medium partially reversed N induced apoptosis. We also studied the protein profile of cells expressing N protein. MS analysis revealed the differential expression of 25 proteins out of which 11 proteins were up regulated while 14 show signs of down regulation upon N expression. 2DE results were validated by real time and semi quantitative RT-PCR analysis. CONCLUSION: These results show the pro-apoptotic effects of N indicating its possible development as an apoptogenic tool. Our 2DE results present prima facie evidence that the MV nucleoprotein interacts with or causes differential expression of a wide range of cellular factors. At this stage it is not clear as to what the adaptive response of the host cell is and what reflects a strategic modulation exerted by the virus. PMID- 21533141 TI - Higher rates of hemolysis are not associated with albuminuria in Jamaicans with sickle cell disease. AB - BACKGROUND: Albuminuria is a marker of glomerular damage in Sickle Cell Disease (SCD). In this study, we sought to determine the possible predictors of albuminuria in the two more prevalent genotypes of SCD among the Jamaica Sickle Cell Cohort Study participants. METHODS: An age-matched cohort of 122 patients with HbSS or HbSC genotypes had measurements of their morning urine albumin concentration, blood pressure, body mass index, haematology and certain biochemistry parameters done. Associations of albuminuria with possible predictors including hematological parameters, reticulocyte counts, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels were examined using multiple regression models. RESULTS: A total of 122 participants were recruited (mean age 28.6 years +/-2.5 years; 85 HbSS, 37 HbSC). 25.9% with HbSS and 10.8% with HbSC disease had microalbuminuria (urine albumin/creatinine ratio = 30-300 mg/g of creatinine) whereas 16.5% of HbSS and 2.7% of HbSC disease had macroalbuminuria (urine albumin/creatinine ratio>300 mg/g of creatinine). Mean arterial pressure, hemoglobin levels, serum creatinine, reticulocyte counts and white blood cell counts were statistically significant predictors of albuminuria in HbSS, whereas white blood cell counts and serum creatinine predicted albuminuria in HbSC disease. Both markers of chronic hemolysis, i.e. AST and LDH levels, showed no associations with albuminuria in either genotype. CONCLUSIONS: Renal disease, as evidenced by excretion of increased amounts of albumin in urine due to a glomerulopathy, is a common end-organ complication in SCD. It is shown to be more severe in those with HbSS disease than in HbSC disease. Rising blood pressure, lower hemoglobin levels and higher white blood cell counts are hints to the clinician of impending renal disease, whereas higher rates of hemolysis do not appear to play a role in this complication of SCD. PMID- 21533142 TI - Functional cohesion of gene sets determined by latent semantic indexing of PubMed abstracts. AB - High-throughput genomic technologies enable researchers to identify genes that are co-regulated with respect to specific experimental conditions. Numerous statistical approaches have been developed to identify differentially expressed genes. Because each approach can produce distinct gene sets, it is difficult for biologists to determine which statistical approach yields biologically relevant gene sets and is appropriate for their study. To address this issue, we implemented Latent Semantic Indexing (LSI) to determine the functional coherence of gene sets. An LSI model was built using over 1 million Medline abstracts for over 20,000 mouse and human genes annotated in Entrez Gene. The gene-to-gene LSI derived similarities were used to calculate a literature cohesion p-value (LPv) for a given gene set using a Fisher's exact test. We tested this method against genes in more than 6,000 functional pathways annotated in Gene Ontology (GO) and found that approximately 75% of gene sets in GO biological process category and 90% of the gene sets in GO molecular function and cellular component categories were functionally cohesive (LPv<0.05). These results indicate that the LPv methodology is both robust and accurate. Application of this method to previously published microarray datasets demonstrated that LPv can be helpful in selecting the appropriate feature extraction methods. To enable real-time calculation of LPv for mouse or human gene sets, we developed a web tool called Gene-set Cohesion Analysis Tool (GCAT). GCAT can complement other gene set enrichment approaches by determining the overall functional cohesion of data sets, taking into account both explicit and implicit gene interactions reported in the biomedical literature. AVAILABILITY: GCAT is freely available at http://binf1.memphis.edu/gcat. PMID- 21533143 TI - The effects of irreversible electroporation (IRE) on nerves. AB - BACKGROUND: If a critical nerve is circumferentially involved with tumor, radical surgery intended to cure the cancer must sacrifice the nerve. Loss of critical nerves may lead to serious consequences. In spite of the impressive technical advancements in nerve reconstruction, complete recovery and normalization of nerve function is difficult to achieve. Though irreversible electroporation (IRE) might be a promising choice to treat tumors near or involved critical nerve, the pathophysiology of the nerve after IRE treatment has not be clearly defined. METHODS: We applied IRE directly to a rat sciatic nerve to study the long term effects of IRE on the nerve. A sequence of 10 square pulses of 3800 V/cm, each 100 us long was applied directly to rat sciatic nerves. In each animal of group I (IRE) the procedure was applied to produce a treated length of about 10 mm. In each animal of group II (Control) the electrodes were only applied directly on the sciatic nerve for the same time. Electrophysiological, histological, and functional studies were performed on immediately after and 3 days, 1 week, 3, 5, 7 and 10 weeks following surgery. FINDINGS: Electrophysiological, histological, and functional results show the nerve treated with IRE can attain full recovery after 7 weeks. CONCLUSION: This finding is indicative of the preservation of nerve involving malignant tumors with respect to the application of IRE pulses to ablate tumors completely. In summary, IRE may be a promising treatment tool for any tumor involving nerves. PMID- 21533144 TI - LINE-1 hypomethylation during primary colon cancer progression. AB - BACKGROUND: Methylation levels of genomic repeats such as long interspersed nucleotide elements (LINE-1) are representative of global methylation status and play an important role in maintenance of genomic stability. The objective of the study was to assess LINE-1 methylation status in colorectal cancer (CRC) in relation to adenomatous and malignant progression, tissue heterogeneity, and TNM stage. METHODOLOGY/PRINCIPAL FINDINGS: DNA was collected by laser-capture microdissection (LCM) from normal, adenoma, and cancer tissue from 25 patients with TisN0M0 and from 92 primary CRC patients of various TNM-stages. The paraffin embedded tissue sections were treated by in-situ DNA sodium bisulfite modification (SBM). LINE-1 hypomethylation index (LHI) was measured by absolute quantitative analysis of methylated alleles (AQAMA) realtime PCR; a greater index indicated enhanced hypomethylation. LHI in normal, cancer mesenchymal, adenoma, and CRC tissue was 0.38 (SD 0.07), 0.37 (SD 0.09), 0.49 (SD 0.10) and 0.53 (SD 0.08), respectively. LHI was significantly greater in adenoma tissue compared to its contiguous normal epithelium (P = 0.0003) and cancer mesenchymal tissue (P<0.0001). LHI did not differ significantly between adenoma and early cancer tissue of Tis stage (P = 0.20). LHI elevated with higher T-stage (P<0.04), was significantly greater in node-positive than node-negative CRC patients (P = 0.03), and was significantly greater in stage IV than all other disease stages (P<0.05). CONCLUSION/SIGNIFICANCE: By using in-situ SBM and LCM cell selection we demonstrated early onset of LINE-1 demethylation during adenomatous change of colorectal epithelial cells and demonstrated that LINE-1 demethylation progression is linear in relation to TNM-stage progression. PMID- 21533145 TI - Chromatin immunoprecipitation to analyze DNA binding sites of HMGA2. AB - BACKGROUND: HMGA2 is an architectonic transcription factor abundantly expressed during embryonic and fetal development and it is associated with the progression of malignant tumors. The protein harbours three basically charged DNA binding domains and an acidic protein binding C-terminal domain. DNA binding induces changes of DNA conformation and hence results in global overall change of gene expression patterns. Recently, using a PCR-based SELEX (Systematic Evolution of Ligands by Exponential Enrichment) procedure two consensus sequences for HMGA2 binding have been identified. METHODOLOGY/PRINCIPAL FINDINGS: In this investigation chromatin immunoprecipitation (ChIP) experiments and bioinformatic methods were used to analyze if these binding sequences can be verified on chromatin of living cells as well. CONCLUSION: After quantification of HMGA2 protein in different cell lines the colon cancer derived cell line HCT116 was chosen for further ChIP experiments because of its 3.4-fold higher HMGA2 protein level. 49 DNA fragments were obtained by ChIP. These fragments containing HMGA2 binding sites have been analyzed for their AT-content, location in the human genome and similarities to sequences generated by a SELEX study. The sequences show a significantly higher AT-content than the average of the human genome. The artificially generated SELEX sequences and short BLAST alignments (11 and 12 bp) of the ChIP fragments from living cells show similarities in their organization. The flanking regions are AT-rich, whereas a lower conservation is present in the center of the sequences. PMID- 21533146 TI - Gene expression profiling in a mouse model identifies fetal liver- and placenta derived potential biomarkers for Down Syndrome screening. AB - BACKGROUND: As a first step to identify novel potential biomarkers for prenatal Down Syndrome screening, we analyzed gene expression in embryos of wild type mice and the Down Syndrome model Ts1Cje. Since current Down Syndrome screening markers are derived from placenta and fetal liver, these tissues were chosen as target. METHODOLOGY/PRINCIPAL FINDINGS: Placenta and fetal liver at 15.5 days gestation were analyzed by microarray profiling. We confirmed increased expression of genes located at the trisomic chromosomal region. Overall, between the two genotypes more differentially expressed genes were found in fetal liver than in placenta. Furthermore, the fetal liver data are in line with the hematological aberrations found in humans with Down Syndrome as well as Ts1Cje mice. Together, we found 25 targets that are predicted (by Gene Ontology, UniProt, or the Human Plasma Proteome project) to be detectable in human serum. CONCLUSIONS/SIGNIFICANCE: Fetal liver might harbor more promising targets for Down Syndrome screening studies. We expect these new targets will help focus further experimental studies on identifying and validating human maternal serum biomarkers for Down Syndrome screening. PMID- 21533147 TI - Impaired cellular responses to cytosolic DNA or infection with Listeria monocytogenes and vaccinia virus in the absence of the murine LGP2 protein. AB - Innate immune signaling is crucial for detection of and the initial response to microbial pathogens. Evidence is provided indicating that LGP2, a DEXH box domain protein related to the RNA recognition receptors RIG-I and MDA5, participates in the cellular response to cytosolic double-stranded DNA (dsDNA). Analysis of embryonic fibroblasts and macrophages from mice harboring targeted disruption in the LGP2 gene reveals that LGP2 can act as a positive regulator of type I IFN and anti-microbial gene expression in response to transfected dsDNA. Results indicate that infection of LGP2-deficient mice with an intracellular bacterial pathogen, Listeria monocytogenes, leads to reduced levels of type I IFN and IL12, and allows increased bacterial growth in infected animals, resulting in greater colonization of both spleen and liver. Responses to infection with vaccinia virus, a dsDNA virus, are also suppressed in cells lacking LGP2, reinforcing the ability of LGP2 to act as a positive regulator of antiviral signaling. In vitro mechanistic studies indicate that purified LGP2 protein does not bind DNA but instead mediates these responses indirectly. Data suggest that LGP2 may be acting downstream of the intracellular RNA polymerase III pathway to activate anti microbial signaling. Together, these findings demonstrate a regulatory role for LGP2 in the response to cytosolic DNA, an intracellular bacterial pathogen, and a DNA virus, and provide a plausible mechanistic hypothesis as the basis for this activity. PMID- 21533148 TI - Extracellular heat shock protein (Hsp)70 and Hsp90alpha assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. AB - Breast cancer is second only to lung cancer in cancer-related deaths in women, and the majority of these deaths are caused by metastases. Obtaining a better understanding of migration and invasion, two early steps in metastasis, is critical for the development of treatments that inhibit breast cancer metastasis. In a functional proteomic screen for proteins required for invasion, extracellular heat shock protein 90 alpha (Hsp90alpha) was identified and shown to activate matrix metalloproteinase 2 (MMP-2). The mechanism of MMP-2 activation by Hsp90alpha is unknown. Intracellular Hsp90alpha commonly functions with a complex of co-chaperones, leading to our hypothesis that Hsp90alpha functions similarly outside of the cell. In this study, we show that a complex of co chaperones outside of breast cancer cells assists Hsp90alpha mediated activation of MMP-2. We demonstrate that the co-chaperones Hsp70, Hop, Hsp40, and p23 are present outside of breast cancer cells and co-immunoprecipitate with Hsp90alpha in vitro and in breast cancer conditioned media. These co-chaperones also increase the association of Hsp90alpha and MMP-2 in vitro. This co-chaperone complex enhances Hsp90alpha-mediated activation of MMP-2 in vitro, while inhibition of Hsp70 in conditioned media reduces this activation and decreases cancer cell migration and invasion. Together, these findings support a model in which MMP-2 activation by an extracellular co-chaperone complex mediated by Hsp90alpha increases breast cancer cell migration and invasion. Our studies provide insight into a novel pathway for MMP-2 activation and suggest Hsp70 as an additional extracellular target for anti-metastatic drug development. PMID- 21533149 TI - Senescence and sexual selection in a pelagic copepod. AB - The ecology of senescence in marine zooplankton is not well known. Here we demonstrate senescence effects in the marine copepod Oithona davisae and show how sex and sexual selection accelerate the rate of ageing in the males. We show that adult mortality increases and male mating capacity and female fertility decrease with age and that the deterioration in reproductive performance is faster for males. Males have a limited mating capacity because they can fertilize < 2 females day(-1) and their reproductive life span is 10 days on average. High female encounter rates in nature (>10 day(-1)), a rapid age-dependent decline in female fertility, and a high mortality cost of mating in males are conducive to the development of male choosiness. In our experiments males in fact show a preference for mating with young females that are 3 times more fertile than 30 day old females. We argue that this may lead to severe male-male competition for young virgin females and a trade-off that favours investment in mate finding over maintenance. In nature, mate finding leads to a further elevated mortality of males, because these swim rapidly in their search for attractive partners, further relaxing fitness benefits of maintenance investments. We show that females have a short reproductive period compared to their average longevity but virgin females stay fertile for most of their life. We interpret this as an adaptation to a shortage of males, because a long life increases the chance of fertilization and/or of finding a high quality partner. The very long post reproductive life that many females experience is thus a secondary effect of such an adaptation. PMID- 21533150 TI - The formation of collective silk balls in the spider mite Tetranychus urticae Koch. AB - Tetranychus urticae is a phytophagous mite that forms colonies of several thousand individuals. These mites construct a common web to protect the colony. When plants become overcrowded and food resources become scarce, individuals gather at the plant apex to form a ball composed of mites and their silk threads. This ball is a structure facilitating group dispersal by wind or animal transport. Until now, no quantitative study had been done on this collective form of migration. This is the first attempt to understand the mechanisms that underlie the emergence and growth of the ball. We studied this collective behaviour under laboratory conditions on standardized infested plants. Our results show that the collective displacement and the formation of balls result from a recruitment process: by depositing silk threads on their way up to the plant apex, mites favour and amplify the recruitment toward the balls. A critical threshold (quorum response) in the cumulative flow of mites must be reached to observe the emergence of a ball. At the beginning of the balls formation, mites form an aggregate. After 24 hours, the aggregated mites are trapped inside the silk balls by the complex network of silk threads and finally die, except for recently arrived individuals. The balls are mainly composed of immature stages. Our study reconstructs the key events that lead to the formation of silk balls. They suggest that the interplay between mites' density, plant morphology and plant density lead to different modes of dispersions (individual or collective) and under what conditions populations might adopt a collective strategy rather than one that is individually oriented. Moreover, our results lead to discuss two aspects of the cooperation and altruism: the importance of Allee effects during colonization of new plants and the importance of the size of a founding group. PMID- 21533151 TI - Induction of influenza-specific mucosal immunity by an attenuated recombinant Sendai virus. AB - BACKGROUND: Many pathogens initiate infection at the mucosal surfaces; therefore, induction of mucosal immune responses is a first level of defense against infection and is the most powerful means of protection. Although intramuscular injection is widely used for vaccination and is effective at inducing circulating antibodies, it is less effective at inducing mucosal antibodies. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a novel recombinant, attenuated Sendai virus vector (GP42-H1) in which the hemagglutinin (HA) gene of influenza A virus was introduced into the Sendai virus genome as an additional gene. Infection of CV-1 cells by GP42-H1 resulted in cell surface expression of the HA protein. Intranasal immunization of mice with 1,000 plaque forming units (pfu) of GP42-H1 induced HA-specific IgG and IgA antibodies in the blood, bronchoalveolar lavage fluid, fecal pellet extracts and saliva. The HA-specific antibody titer induced by GP42-H1 closely resembles the titer induced by sublethal infection by live influenza virus; however, in contrast to infection by influenza virus, immunization with GP42-H1 did not result in disease symptoms or the loss of body weight. In mice that were immunized with GP42-H1 and then challenged with 5LD(50) (1250 pfu) of influenza virus, no significant weight loss was observed and other visual signs of morbidity were not detected. CONCLUSIONS: These results demonstrate that the GP42-H1 Sendai virus recombinant is able to confer full protection from lethal infection by influenza virus, supporting the conclusion that it is a safe and effective mucosal vaccine vector. PMID- 21533153 TI - Path and ridge regression analysis of seed yield and seed yield components of Russian wildrye (Psathyrostachys juncea Nevski) under field conditions. AB - The correlations among seed yield components, and their direct and indirect effects on the seed yield (Z) of Russina wildrye (Psathyrostachys juncea Nevski) were investigated. The seed yield components: fertile tillers m(-2) (Y(1)), spikelets per fertile tillers (Y(2)), florets per spikelet(-) (Y(3)), seed numbers per spikelet (Y(4)) and seed weight (Y(5)) were counted and the Z were determined in field experiments from 2003 to 2006 via big sample size. Y(1) was the most important seed yield component describing the Z and Y(2) was the least. The total direct effects of the Y(1), Y(3) and Y(5) to the Z were positive while Y(4) and Y(2) were weakly negative. The total effects (directs plus indirects) of the components were positively contributed to the Z by path analyses. The seed yield components Y(1), Y(2), Y(4) and Y(5) were significantly (P<0.001) correlated with the Z for 4 years totally, while in the individual years, Y(2) were not significant correlated with Y(3), Y(4) and Y(5) by Peason correlation analyses in the five components in the plant seed production. Therefore, selection for high seed yield through direct selection for large Y(1), Y(2) and Y(3) would be effective for breeding programs in grasses. Furthermore, it is the most important that, via ridge regression, a steady algorithm model between Z and the five yield components was founded, which can be closely estimated the seed yield via the components. PMID- 21533152 TI - Betaglycan is required for the establishment of nephron endowment in the mouse. AB - Betaglycan is an accessory receptor for the transforming growth factor-beta (TGFbeta) superfamily, many members of which play key roles in kidney development. The purpose of this study was to define the role of this co-receptor on fetal murine kidney development. Stereological examination of embryonic and adult betaglycan heterozygous kidneys revealed augmented nephron number relative to littermate controls. Fetal heterozygous kidneys exhibited accelerated ureteric branching, which correlated with augmented nephron development at embryonic day (e) 15.5. In contrast, betaglycan null kidneys exhibited renal hypoplasia from e13.5 and reduced nephron number at e15.5. Quantitative real-time PCR analysis of e11.5-e14.5 kidneys demonstrated that heterozygous kidneys exhibited a transient decrease in Bmp4 expression at e11.5 and a subsequent cascade of changes in the gene regulatory network that governs metanephric development, including significant increases in Pax2, Eya1, Gdnf, Ret, Wnt4, and Wt1 expression. Conversely, gene expression in null kidneys was normal until e13.5, when significant reductions were detected in the expression of Bmp4 as well as other key metanephric regulatory genes. Tgfb1 and Tgfb2 mRNA expression was down regulated in both nulls and heterozygotes at e13.5 and e14.5. The opposing morphological and molecular phenotypes in betaglycan heterozygote and null mutants demonstrate that the levels of betaglycan must be tightly regulated for optimal kidney development. PMID- 21533154 TI - Identification of amino acids that account for long-range interactions in two triosephosphate isomerases from pathogenic trypanosomes. AB - For a better comprehension of the structure-function relationship in proteins it is necessary to identify the amino acids that are relevant for measurable protein functions. Because of the numerous contacts that amino acids establish within proteins and the cooperative nature of their interactions, it is difficult to achieve this goal. Thus, the study of protein-ligand interactions is usually focused on local environmental structural differences. Here, using a pair of triosephosphate isomerase enzymes with extremely high homology from two different organisms, we demonstrate that the control of a seventy-fold difference in reactivity of the interface cysteine is located in several amino acids from two structurally unrelated regions that do not contact the cysteine sensitive to the sulfhydryl reagent methylmethane sulfonate, nor the residues in its immediate vicinity. The change in reactivity is due to an increase in the apparent pKa of the interface cysteine produced by the mutated residues. Our work, which involved grafting systematically portions of one protein into the other protein, revealed unsuspected and multisite long-range interactions that modulate the properties of the interface cysteines and has general implications for future studies on protein structure-function relationships. PMID- 21533156 TI - A quantitative model of honey bee colony population dynamics. AB - Since 2006 the rate of honey bee colony failure has increased significantly. As an aid to testing hypotheses for the causes of colony failure we have developed a compartment model of honey bee colony population dynamics to explore the impact of different death rates of forager bees on colony growth and development. The model predicts a critical threshold forager death rate beneath which colonies regulate a stable population size. If death rates are sustained higher than this threshold rapid population decline is predicted and colony failure is inevitable. The model also predicts that high forager death rates draw hive bees into the foraging population at much younger ages than normal, which acts to accelerate colony failure. The model suggests that colony failure can be understood in terms of observed principles of honey bee population dynamics, and provides a theoretical framework for experimental investigation of the problem. PMID- 21533155 TI - Stroma regulates increased epithelial lateral cell adhesion in 3D culture: a role for actin/cadherin dynamics. AB - BACKGROUND: Cell shape and tissue architecture are controlled by changes to junctional proteins and the cytoskeleton. How tissues control the dynamics of adhesion and cytoskeletal tension is unclear. We have studied epithelial tissue architecture using 3D culture models and found that adult primary prostate epithelial cells grow into hollow acinus-like spheroids. Importantly, when co cultured with stroma the epithelia show increased lateral cell adhesions. To investigate this mechanism further we aimed to: identify a cell line model to allow repeatable and robust experiments; determine whether or not epithelial adhesion molecules were affected by stromal culture; and determine which stromal signalling molecules may influence cell adhesion in 3D epithelial cell cultures. METHODOLOGY/PRINCIPAL FINDINGS: The prostate cell line, BPH-1, showed increased lateral cell adhesion in response to stroma, when grown as 3D spheroids. Electron microscopy showed that 9.4% of lateral membranes were within 20 nm of each other and that this increased to 54% in the presence of stroma, after 7 days in culture. Stromal signalling did not influence E-cadherin or desmosome RNA or protein expression, but increased E-cadherin/actin co-localisation on the basolateral membranes, and decreased paracellular permeability. Microarray analysis identified several growth factors and pathways that were differentially expressed in stroma in response to 3D epithelial culture. The upregulated growth factors TGFbeta2, CXCL12 and FGF10 were selected for further analysis because of previous associations with morphology. Small molecule inhibition of TGFbeta2 signalling but not of CXCL12 and FGF10 signalling led to a decrease in actin and E-cadherin co-localisation and increased paracellular permeability. CONCLUSIONS/SIGNIFICANCE: In 3D culture models, paracrine stromal signals increase epithelial cell adhesion via adhesion/cytoskeleton interactions and TGFbeta2-dependent mechanisms may play a key role. These findings indicate a role for stroma in maintaining adult epithelial tissue morphology and integrity. PMID- 21533157 TI - Lack of chemokine signaling through CXCR5 causes increased mortality, ventricular dilatation and deranged matrix during cardiac pressure overload. AB - RATIONALE: Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. OBJECTIVE: We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. METHODS AND RESULTS: Mice harboring a systemic knockout of the CXCR5 (CXCR5(-/-)) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5(-/-) developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5(-/-) compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5(-/-) mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. CONCLUSIONS: Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly. PMID- 21533158 TI - Latency antigen alpha-crystallin based vaccination imparts a robust protection against TB by modulating the dynamics of pulmonary cytokines. AB - BACKGROUND: Efficient control of tuberculosis (TB) requires development of strategies that can enhance efficacy of the existing vaccine Mycobacterium bovis Bacille Calmette Guerin (BCG). To date only a few studies have explored the potential of latency-associated antigens to augment the immunogenicity of BCG. METHODS/PRINCIPAL FINDINGS: We evaluated the protective efficacy of a heterologous prime boost approach based on recombinant BCG and DNA vaccines targeting alpha-crystallin, a prominent latency antigen. We show that "rBCG prime DNA boost" strategy (R/D) confers a markedly superior protection along with reduced pathology in comparison to BCG vaccination in guinea pigs (565 fold and 45 fold reduced CFU in lungs and spleen, respectively, in comparison to BCG vaccination). In addition, R/D regimen also confers enhanced protection in mice. Our results in guinea pig model show a distinct association of enhanced protection with an increased level of interleukin (IL)12 and a simultaneous increase in immuno-regulatory cytokines such as transforming growth factor (TGF)beta and IL10 in lungs. The T cell effector functions, which could not be measured in guinea pigs due to technical limitations, were characterized in mice by multi-parameter flow cytometry. We show that R/D regimen elicits a heightened multi-functional CD4 Th1 cell response leading to enhanced protection. CONCLUSIONS/SIGNIFICANCE: These results clearly indicate the superiority of alpha crystallin based R/D regimen over BCG. Our observations from guinea pig studies indicate a crucial role of IL12, IL10 and TGFbeta in vaccine-induced protection. Further, characterization of T cell responses in mice demonstrates that protection against TB is predictable by the frequency of CD4 T cells simultaneously producing interferon (IFN)gamma, tumor necrosis factor (TNF)alpha and IL2. We anticipate that this study will not only contribute toward the development of a superior alternative to BCG, but will also stimulate designing of TB vaccines based on latency antigens. PMID- 21533159 TI - HVEM signalling promotes colitis. AB - BACKGROUND: Tumor necrosis factor super family (TNFSF) members regulate important processes involved in cell proliferation, survival and differentiation and are therefore crucial for the balance between homeostasis and inflammatory responses. Several members of the TNFSF are closely associated with inflammatory bowel disease (IBD). Thus, they represent interesting new targets for therapeutic treatment of IBD. METHODOLOGY/PRINCIPAL FINDINGS: We have used mice deficient in TNFSF member HVEM in experimental models of IBD to investigate its role in the disease process. Two models of IBD were employed: i) chemical-induced colitis primarily mediated by innate immune cells; and ii) colitis initiated by CD4(+)CD45RB(high) T cells following their transfer into immuno-deficient RAG1(-/ ) hosts. In both models of disease the absence of HVEM resulted in a significant reduction in colitis and inflammatory cytokine production. CONCLUSIONS: These data show that HVEM stimulatory signals promote experimental colitis driven by innate or adaptive immune cells. PMID- 21533160 TI - Morphological shifts of the external flight apparatus across the range of a passerine (Northern Wheatear) with diverging migratory behaviour. AB - We studied morphological differentiation in the flight apparatus of the four currently recognised sub-species of Northern Wheatears, Oenanthe oenanthe. Considering all measured birds without assigning them a priori to any sub-species we found a clinal morphological shift. Relative wing length, wing pointedness, and the degree of tail forking were positively correlated with migratory distance, whereas tail length (relative to wing length) was negatively correlated. The large-sized, long-distance migrant "Greenland" Wheatear, O. o. leucorhoa, is characterized by relatively longer, broader and more pointed wings and more forked tails, similar to the smaller-sized nominate Northern Wheatear, O. o. oenanthe, from North Europe, Siberia and Russia. In contrast, the short distance migrant "Seebohm's" Wheatear, O. o. seebohmi, from northwest Africa, possesses much rounder wings, and the tail is relatively longer and less forked. Sub-species with intermediate migratory habits (different populations of nominate Northern Wheatear, O. o. oenanthe, and "Mediterranean" Northern Wheatear, O. o. libanotica) show, as expected, intermediate features according to their intermediate migratory behaviour. Our results are congruent with other inter- and intraspecific studies finding similar adaptations for energy-effective flight in relation to migration distance (morphological migratory syndrome). PMID- 21533161 TI - What the public was saying about the H1N1 vaccine: perceptions and issues discussed in on-line comments during the 2009 H1N1 pandemic. AB - During the 2009 H1N1 pandemic, a vaccine was made available to all Canadians. Despite efforts to promote vaccination, the public's intent to vaccinate remained low. In order to better understand the public's resistance to getting vaccinated, this study addressed factors that influenced the public's decision making about uptake. To do this, we used a relatively novel source of qualitative data- comments posted on-line in response to news articles on a particular topic. This study analysed 1,796 comments posted in response to 12 articles dealing with H1N1 vaccine on websites of three major Canadian news sources. Articles were selected based on topic and number of comments. A second objective was to assess the extent to which on-line comments can be used as a reliable data source to capture public attitudes during a health crisis. The following seven themes were mentioned in at least 5% of the comments (% indicates the percentage of comments that included the theme): fear of H1N1 (18.8%); responsibility of media (17.8%); government competency (17.7%); government trustworthiness (10.7%); fear of H1N1 vaccine (8.1%); pharmaceutical companies (7.6%); and personal protective measures (5.8%). It is assumed that the more frequently a theme was mentioned, the more that theme influenced decision making about vaccination. These key themes for the public were often not aligned with the issues and information officials perceived, and conveyed, as relevant in the decision making process. The main themes from the comments were consistent with results from surveys and focus groups addressing similar issues, which suggest that on-line comments do provide a reliable source of qualitative data on attitudes and perceptions of issues that emerge in a health crisis. The insights derived from the comments can contribute to improved communication and policy decisions about vaccination in health crises that incorporate the public's views. PMID- 21533162 TI - Dose-dependent immunomodulation of human dendritic cells by the probiotic Lactobacillus rhamnosus Lcr35. AB - The response of the immune system to probiotics remains controversial. Some strains modulate the cytokine production of dendritic cells (DCs) in vitro and induce a regulatory response, while others induce conversely a pro-inflammatory response. These strain-dependent effects are thought to be linked to specific interactions between bacteria and pattern recognition receptors. We investigated the effects of a well characterized probiotic strain, Lactobacillus rhamnosus Lcr35, on human monocyte-derived immature DCs, using a wide range of bacterial concentrations (multiplicity of infection, MOI, from 0.01 to 100). DNA microarray and qRT-PCR analysis showed that the probiotic induced a large-scale change in gene expression (nearly 1,700 modulated genes, with 3-fold changes), but only with high doses (MOI, 100). The upregulated genes were mainly involved in immune response and identified a molecular signature of inflammation according to the model of Torri. Flow cytometry analysis also revealed a dose-dependent maturation of the DC membrane phenotype, until DCs reached a semi-mature state, with an upregulation of the membrane expression of CD86, CD83, HLA-DR and TLR4, associated with a down-regulation of DC-SIGN, MR and CD14. Measurement of the DC secreted cytokines showed that Lcr35 induced a strong dose-dependent increase of the pro-Th1/Th17 cytokine levels (TNFalpha, IL-1beta, IL-12p70, IL-12p40 and IL 23), but only a low increase in IL-10 concentration. The probiotic L. rhamnosus Lcr35 therefore induce a dose-dependent immunomodulation of human DCs leading, at high doses, to the semi-maturation of the cells and to a strong pro-inflammatory effect. These results contribute to a fuller understanding of the mechanism of action of this probiotic, and thus of its potential clinical indications in the treatment of either infectious or IgE-dependent allergic diseases. PMID- 21533163 TI - Analysis of Jak2 catalytic function by peptide microarrays: the role of the JH2 domain and V617F mutation. AB - Janus kinase 2 (JAK2) initiates signaling from several cytokine receptors and is required for biological responses such as erythropoiesis. JAK2 activity is controlled by regulatory proteins such as Suppressor of Cytokine Signaling (SOCS) proteins and protein tyrosine phosphatases. JAK2 activity is also intrinsically controlled by regulatory domains, where the pseudokinase (JAK homology 2, JH2) domain has been shown to play an essential role. The physiological role of the JH2 domain in the regulation of JAK2 activity was highlighted by the discovery of the acquired missense point mutation V617F in myeloproliferative neoplasms (MPN). Hence, determining the precise role of this domain is critical for understanding disease pathogenesis and design of new treatment modalities. Here, we have evaluated the effect of inter-domain interactions in kinase activity and substrate specificity. By using for the first time purified recombinant JAK2 proteins and a novel peptide micro-array platform, we have determined initial phosphorylation rates and peptide substrate preference for the recombinant kinase domain (JH1) of JAK2, and two constructs comprising both the kinase and pseudokinase domains (JH1-JH2) of JAK2. The data demonstrate that (i) JH2 drastically decreases the activity of the JAK2 JH1 domain, (ii) JH2 increased the K(m) for ATP (iii) JH2 modulates the peptide preference of JAK2 (iv) the V617F mutation partially releases this inhibitory mechanism but does not significantly affect substrate preference or K(m) for ATP. These results provide the biochemical basis for understanding the interaction between the kinase and the pseudokinase domain of JAK2 and identify a novel regulatory role for the JAK2 pseudokinase domain. Additionally, this method can be used to identify new regulatory mechanisms for protein kinases that provide a better platform for designing specific strategies for therapeutic approaches. PMID- 21533165 TI - Discretization provides a conceptually simple tool to build expression networks. AB - Biomarker identification, using network methods, depends on finding regular co expression patterns; the overall connectivity is of greater importance than any single relationship. A second requirement is a simple algorithm for ranking patients on how relevant a gene-set is. For both of these requirements discretized data helps to first identify gene cliques, and then to stratify patients.We explore a biologically intuitive discretization technique which codes genes as up- or down-regulated, with values close to the mean set as unchanged; this allows a richer description of relationships between genes than can be achieved by positive and negative correlation. We find a close agreement between our results and the template gene-interactions used to build synthetic microarray like data by SynTReN, which synthesizes "microarray" data using known relationships which are successfully identified by our method.We are able to split positive co-regulation into up-together and down-together and negative co regulation is considered as directed up-down relationships. In some cases these exist in only one direction, with real data, but not with the synthetic data. We illustrate our approach using two studies on white blood cells and derived immortalized cell lines and compare the approach with standard correlation-based computations. No attempt is made to distinguish possible causal links as the search for biomarkers would be crippled by losing highly significant co expression relationships. This contrasts with approaches like ARACNE and IRIS.The method is illustrated with an analysis of gene-expression for energy metabolism pathways. For each discovered relationship we are able to identify the samples on which this is based in the discretized sample-gene matrix, along with a simplified view of the patterns of gene expression; this helps to dissect the gene-sample relevant to a research topic--identifying sets of co-regulated and anti-regulated genes and the samples or patients in which this relationship occurs. PMID- 21533164 TI - Evidence for reductive genome evolution and lateral acquisition of virulence functions in two Corynebacterium pseudotuberculosis strains. AB - BACKGROUND: Corynebacterium pseudotuberculosis, a gram-positive, facultative intracellular pathogen, is the etiologic agent of the disease known as caseous lymphadenitis (CL). CL mainly affects small ruminants, such as goats and sheep; it also causes infections in humans, though rarely. This species is distributed worldwide, but it has the most serious economic impact in Oceania, Africa and South America. Although C. pseudotuberculosis causes major health and productivity problems for livestock, little is known about the molecular basis of its pathogenicity. METHODOLOGY AND FINDINGS: We characterized two C. pseudotuberculosis genomes (Cp1002, isolated from goats; and CpC231, isolated from sheep). Analysis of the predicted genomes showed high similarity in genomic architecture, gene content and genetic order. When C. pseudotuberculosis was compared with other Corynebacterium species, it became evident that this pathogenic species has lost numerous genes, resulting in one of the smallest genomes in the genus. Other differences that could be part of the adaptation to pathogenicity include a lower GC content, of about 52%, and a reduced gene repertoire. The C. pseudotuberculosis genome also includes seven putative pathogenicity islands, which contain several classical virulence factors, including genes for fimbrial subunits, adhesion factors, iron uptake and secreted toxins. Additionally, all of the virulence factors in the islands have characteristics that indicate horizontal transfer. CONCLUSIONS: These particular genome characteristics of C. pseudotuberculosis, as well as its acquired virulence factors in pathogenicity islands, provide evidence of its lifestyle and of the pathogenicity pathways used by this pathogen in the infection process. All genomes cited in this study are available in the NCBI Genbank database (http://www.ncbi.nlm.nih.gov/genbank/) under accession numbers CP001809 and CP001829. PMID- 21533166 TI - A PiggyBac-based recessive screening method to identify pluripotency regulators. AB - Phenotype driven genetic screens allow unbiased exploration of the genome to discover new biological regulators. Bloom syndrome gene (Blm) deficient embryonic stem (ES) cells provide an opportunity for recessive screening due to frequent loss of heterozygosity. We describe a strategy for isolating regulators of mammalian pluripotency based on conversion to homozygosity of PiggyBac gene trap insertions combined with stringent selection for differentiation resistance. From a screen of 2000 mutants we obtained a disruptive integration in the Tcf3 gene. Homozygous Tcf3 mutants showed impaired differentiation and enhanced self renewal. This phenotype was reverted in a dosage sensitive manner by excision of one or both copies of the gene trap. These results provide new evidence confirming that Tcf3 is a potent negative regulator of pluripotency and validate a forward screening methodology to identify modulators of pluripotent stem cell biology. PMID- 21533167 TI - AGEs decrease insulin synthesis in pancreatic beta-cell by repressing Pdx-1 protein expression at the post-translational level. AB - Advanced glycation end products (AGEs) have been implicated in diverse pathological settings of many diabetic complications, and the possible mechanisms have been widely reported. However, the relationship between AGEs and pancreatic beta-cell dysfunction is still poorly understood. Recent studies have shown that AGEs can impair beta-cell function by inducing apoptosis or decreasing insulin secretion. Our previous research revealed that AGEs could significantly down regulate insulin transcription and reduce beta-cell glucose-stimulated insulin secretion (GSIS). Here, we investigated the possible mechanisms underlying AGE related suppression of insulin synthesis. In the rat pancreatic beta-cell line INS-1, we found that AGEs induced dephosphorylation of Foxo1 and increased its accumulation in the nucleus. The translocation of Foxo1 subsequently inhibited pancreatic-duodenal homeobox factor-1 (Pdx-1) levels in both nuclear and cytoplasmic compartments. We observed that with AGEs treatment, Pdx-1 protein levels decreased after 4 h, but there was no change in the Pdx-1 mRNA level or promoter activity at the same time point; this demonstrated that the decrease in Pdx-1 expression was not regulated at the transcriptional level. In our study, the decrease in Pdx-1 protein level was related to its reduced stability, overexpression of DN-Foxo1 could partially reverse the inhibition of Pdx-1 expression. Pretreatment with AGEs receptor (RAGE) antibody also prevented the AGE-induced diminution of Pdx-1 protein and insulin mRNA expression. In summary, AGEs induced nuclear accumulation of Foxo1; this in turn reduced Pdx-1 expression by decreasing its protein stability, ultimately affecting insulin synthesis. PMID- 21533168 TI - Confocal laser scanning microscopy for detection of Schistosoma mansoni eggs in the gut of mice. AB - BACKGROUND: The gold standard for diagnosing Schistosoma mansoni infections is the detection of eggs from stool or biopsy specimens. The viability of collected eggs can be tested by the miracidium hatching procedure. Direct detection methods are often limited in patients with light or early infections, whereas serological tests and PCR methods fail to differentiate between an inactive and persistent infection and between schistosomal species. Recently, confocal laser scanning microscopy (CLSM) has been introduced as a diagnostic tool in several fields of medicine. In this study we evaluated CLSM for the detection of viable eggs of S. mansoni directly within the gut of infected mice. METHODOLOGY/PRINCIPAL FINDINGS: The confocal laser scanning microscope used in this study is based on the Heidelberg Retina Tomograph II scanning laser system in combination with the Rostock Cornea Module (image modality 1) or a rigid endoscope (image modality 2). Colon sections of five infected mice were examined with image modalities 1 and 2 for schistosomal eggs. Afterwards a biopsy specimen was taken from each colon section and examined by bright-field microscopy. Visualised eggs were counted and classified in terms of viability status. CONCLUSIONS/SIGNIFICANCE: We were able to show that CLSM visualises eggs directly within the gut and permits discrimination of schistosomal species and determination of egg viability. Thus, CLSM may be a suitable non-invasive tool for the diagnosis of schistosomiasis in humans. PMID- 21533169 TI - Multifaceted intervention by the Hsp90 inhibitor ganetespib (STA-9090) in cancer cells with activated JAK/STAT signaling. AB - There is accumulating evidence that dysregulated JAK signaling occurs in a wide variety of cancer types. In particular, mutations in JAK2 can result in the constitutive activation of STAT transcription factors and lead to oncogenic growth. JAK kinases are established Hsp90 client proteins and here we show that the novel small molecule Hsp90 inhibitor ganetespib (formerly STA-9090) exhibits potent in vitro and in vivo activity in a range of solid and hematological tumor cells that are dependent on JAK2 activity for growth and survival. Of note, ganetespib treatment results in sustained depletion of JAK2, including the constitutively active JAK2(V617F) mutant, with subsequent loss of STAT activity and reduced STAT-target gene expression. In contrast, treatment with the pan-JAK inhibitor P6 results in only transient effects on these processes. Further differentiating these modes of intervention, RNA and protein expression studies show that ganetespib additionally modulates cell cycle regulatory proteins, while P6 does not. The concomitant impact of ganetespib on both cell growth and cell division signaling translates to potent antitumor efficacy in mouse models of xenografts and disseminated JAK/STAT-driven leukemia. Overall, our findings support Hsp90 inhibition as a novel therapeutic approach for combating diseases dependent on JAK/STAT signaling, with the multimodal action of ganetespib demonstrating advantages over JAK-specific inhibitors. PMID- 21533170 TI - Evolution of surname distribution under gender-equality measures. AB - We consider a model for the evolution of surname distribution under a gender equality measure currently being discussed by the Spanish Parliament (whereby children would adopt their mother's and father's surnames in alphabetical order). We quantify how this would bias the alphabetical distribution of surnames, and analyze its effect on the present distribution of surnames in Spain. PMID- 21533171 TI - ITPKC single nucleotide polymorphism associated with the Kawasaki disease in a Taiwanese population. AB - Kawasaki disease (KD) is characterized by systemic vasculitis with unknown etiology. Previous studies from Japan indicated that a gene polymorphism of ITPKC (rs28493229) is responsible for susceptibility to KD. We collected DNA samples from 1,531 Taiwanese subjects (341 KD patients and 1,190 controls) for genotyping ITPKC. In this study, no significant association was noted for the ITPKC polymorphism (rs28493229) between the controls and KD patients, although the CC genotype was overrepresented. We further combined our data with previously published case/control KD studies in the Taiwanese population and performed a meta-analysis. A significant association between rs28493229 and KD was found (Odds Ratio:1.36, 95% Confidence Interval 1.12-1.66). Importantly, a significant association was obtained between rs28493229 and KD patients with aneurysm formation (P = 0.001, under the recessive model). Taken together, our results indicated that C-allele of ITPKC SNP rs28493229 is associated with the susceptibility and aneurysm formation in KD patients in a Taiwanese population. PMID- 21533172 TI - Exosomes released from M. tuberculosis infected cells can suppress IFN-gamma mediated activation of naive macrophages. AB - BACKGROUND: Macrophages infected with Mycobacterium tuberculosis (M.tb) are known to be refractory to IFN-gamma stimulation. Previous studies have shown that M.tb express components such as the 19-kDa lipoprotein and peptidoglycan that can bind to macrophage receptors including the Toll-like receptor 2 resulting in the loss in IFN-gamma responsiveness. However, it is unclear whether this effect is limited to infected macrophages. We have previously shown that M.tb-infected macrophages release exosomes which are 30-100 nm membrane bound vesicles of endosomal origin that function in intercellular communication. These exosomes contain mycobacterial components including the 19-kDa lipoprotein and therefore we hypothesized that macrophages exposed to exosomes may show limited response to IFN-gamma stimulation. METHODOLOGY/PRINCIPAL FINDINGS: Exosomes were isolated from resting as well as M.tb-infected RAW264.7 macrophages. Mouse bone marrow derived macrophages (BMMO) were treated with exosomes +/- IFN-gamma. Cells were harvested and analyzed for suppression of IFN-gamma responsive genes by flow cytometry and real time PCR. We found that exosomes derived from M.tb H37Rv infected but not from uninfected macrophages inhibited IFN-gamma induced MHC class II and CD64 expression on BMMO. This inhibition was only partially dependent on the presence of lipoproteins but completely dependent on TLR2 and MyD88. The exosomes isolated from infected cells did not inhibit STAT1 Tyrosine phosphorylation but down-regulated IFN-gamma induced expression of the class II major histocompatibility complex transactivator; a key regulator of class II MHC expression. Microarray studies showed that subsets of genes induced by IFN-gamma were inhibited by exosomes from H37Rv-infected cells including genes involved in antigen presentation. Moreover, this set of genes partially overlapped with the IFN-gamma-induced genes inhibited by H37Rv infection. CONCLUSIONS: Our study suggests that exosomes, as carriers of M.tb pathogen associated molecular patterns (PAMPs), may provide a mechanism by which M.tb may exert its suppression of a host immune response beyond the infected cell. PMID- 21533173 TI - 14-3-3 Proteins regulate exonuclease 1-dependent processing of stalled replication forks. AB - Replication fork integrity, which is essential for the maintenance of genome stability, is monitored by checkpoint-mediated phosphorylation events. 14-3-3 proteins are able to bind phosphorylated proteins and were shown to play an undefined role under DNA replication stress. Exonuclease 1 (Exo1) processes stalled replication forks in checkpoint-defective yeast cells. We now identify 14 3-3 proteins as in vivo interaction partners of Exo1, both in yeast and mammalian cells. Yeast 14-3-3-deficient cells fail to induce Mec1-dependent Exo1 hyperphosphorylation and accumulate Exo1-dependent ssDNA gaps at stalled forks, as revealed by electron microscopy. This leads to persistent checkpoint activation and exacerbated recovery defects. Moreover, using DNA bi-dimensional electrophoresis, we show that 14-3-3 proteins promote fork progression under limiting nucleotide concentrations. We propose that 14-3-3 proteins assist in controlling the phosphorylation status of Exo1 and additional unknown targets, promoting fork progression, stability, and restart in response to DNA replication stress. PMID- 21533174 TI - A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1. AB - BACKGROUND: Urothelial carcinoma (UC) is characterized by frequent gene mutations of which activating mutations in FGFR3 are the most frequent. Several downstream targets of FGFR3 are also mutated in UC, e.g., PIK3CA, AKT1, and RAS. Most mutation studies of UCs have been focused on single or a few genes at the time or been performed on small sample series. This has limited the possibility to investigate co-occurrence of mutations. METHODOLOGY/PRINCIPAL FINDINGS: We performed mutation analyses of 16 genes, FGFR3, PIK3CA, PIK3R1 PTEN, AKT1, KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, TSC1, TSC2, APC, CTNNB1, and TP53, in 145 cases of UC. We show that FGFR3 and PIK3CA mutations are positively associated. In addition, we identified PIK3R1 as a target for mutations. We demonstrate a negative association at borderline significance between FGFR3 and RAS mutations, and show that these mutations are not strictly mutually exclusive. We show that mutations in BRAF, ARAF, RAF1 rarely occurs in UC. Our data emphasize the possible importance of APC signaling as 6% of the investigated tumors either showed inactivating APC or activating CTNNB1 mutations. TSC1, as well as TSC2, that constitute the mTOR regulatory tuberous sclerosis complex were found to be mutated at a combined frequency of 15%. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a significant association between FGFR3 and PIK3CA mutations in UC. Moreover, the identification of mutations in PIK3R1 further emphasizes the importance of the PI3-kinase pathway in UC. The presence of TSC2 mutations, in addition to TSC1 mutations, underlines the involvement of mTOR signaling in UC. PMID- 21533176 TI - Towards establishment of a rice stress response interactome. AB - Rice (Oryza sativa) is a staple food for more than half the world and a model for studies of monocotyledonous species, which include cereal crops and candidate bioenergy grasses. A major limitation of crop production is imposed by a suite of abiotic and biotic stresses resulting in 30%-60% yield losses globally each year. To elucidate stress response signaling networks, we constructed an interactome of 100 proteins by yeast two-hybrid (Y2H) assays around key regulators of the rice biotic and abiotic stress responses. We validated the interactome using protein protein interaction (PPI) assays, co-expression of transcripts, and phenotypic analyses. Using this interactome-guided prediction and phenotype validation, we identified ten novel regulators of stress tolerance, including two from protein classes not previously known to function in stress responses. Several lines of evidence support cross-talk between biotic and abiotic stress responses. The combination of focused interactome and systems analyses described here represents significant progress toward elucidating the molecular basis of traits of agronomic importance. PMID- 21533175 TI - Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms. AB - Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 * 10(-36)), SULT2A1 (rs2637125; p = 2.61 * 10(-19)), ARPC1A (rs740160; p = 1.56 * 10(-16)), TRIM4 (rs17277546; p = 4.50 * 10(-11)), BMF (rs7181230; p = 5.44 * 10(-11)), HHEX (rs2497306; p = 4.64 * 10(-9)), BCL2L11 (rs6738028; p = 1.72 * 10(-8)), and CYP2C9 (rs2185570; p = 2.29 * 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS. PMID- 21533177 TI - Highly precise and developmentally programmed genome assembly in Paramecium requires ligase IV-dependent end joining. AB - During the sexual cycle of the ciliate Paramecium, assembly of the somatic genome includes the precise excision of tens of thousands of short, non-coding germline sequences (Internal Eliminated Sequences or IESs), each one flanked by two TA dinucleotides. It has been reported previously that these genome rearrangements are initiated by the introduction of developmentally programmed DNA double-strand breaks (DSBs), which depend on the domesticated transposase PiggyMac. These DSBs all exhibit a characteristic geometry, with 4-base 5' overhangs centered on the conserved TA, and may readily align and undergo ligation with minimal processing. However, the molecular steps and actors involved in the final and precise assembly of somatic genes have remained unknown. We demonstrate here that Ligase IV and Xrcc4p, core components of the non-homologous end-joining pathway (NHEJ), are required both for the repair of IES excision sites and for the circularization of excised IESs. The transcription of LIG4 and XRCC4 is induced early during the sexual cycle and a Lig4p-GFP fusion protein accumulates in the developing somatic nucleus by the time IES excision takes place. RNAi-mediated silencing of either gene results in the persistence of free broken DNA ends, apparently protected against extensive resection. At the nucleotide level, controlled removal of the 5'-terminal nucleotide occurs normally in LIG4-silenced cells, while nucleotide addition to the 3' ends of the breaks is blocked, together with the final joining step, indicative of a coupling between NHEJ polymerase and ligase activities. Taken together, our data indicate that IES excision is a "cut-and-close" mechanism, which involves the introduction of initiating double-strand cleavages at both ends of each IES, followed by DSB repair via highly precise end joining. This work broadens our current view on how the cellular NHEJ pathway has cooperated with domesticated transposases for the emergence of new mechanisms involved in genome dynamics. PMID- 21533178 TI - MicroRNAs dynamically remodel gastrointestinal smooth muscle cells. AB - Smooth muscle cells (SMCs) express a unique set of microRNAs (miRNAs) which regulate and maintain the differentiation state of SMCs. The goal of this study was to investigate the role of miRNAs during the development of gastrointestinal (GI) SMCs in a transgenic animal model. We generated SMC-specific Dicer null animals that express the reporter, green fluorescence protein, in a SMC-specific manner. SMC-specific knockout of Dicer prevented SMC miRNA biogenesis, causing dramatic changes in phenotype, function, and global gene expression in SMCs: the mutant mice developed severe dilation of the intestinal tract associated with the thinning and destruction of the smooth muscle (SM) layers; contractile motility in the mutant intestine was dramatically decreased; and SM contractile genes and transcriptional regulators were extensively down-regulated in the mutant SMCs. Profiling and bioinformatic analyses showed that SMC phenotype is regulated by a complex network of positive and negative feedback by SMC miRNAs, serum response factor (SRF), and other transcriptional factors. Taken together, our data suggest that SMC miRNAs are required for the development and survival of SMCs in the GI tract. PMID- 21533179 TI - Association of HIV diversity and survival in HIV-infected Ugandan infants. AB - BACKGROUND: The level of viral diversity in an HIV-infected individual can change during the course of HIV infection, reflecting mutagenesis during viral replication and selection of viral variants by immune and other selective pressures. Differences in the level of viral diversity in HIV-infected infants may reflect differences in viral dynamics, immune responses, or other factors that may also influence HIV disease progression. We used a novel high resolution melting (HRM) assay to measure HIV diversity in Ugandan infants and examined the relationship between diversity and survival through 5 years of age. METHODS: Plasma samples were obtained from 31 HIV-infected infants (HIVNET 012 trial). The HRM assay was used to measure diversity in two regions in the gag gene (Gag1 and Gag2) and one region in the pol gene (Pol). RESULTS: HRM scores in all three regions increased with age from 6-8 weeks to 12-18 months (for Gag1: P = 0.005; for Gag2: P = 0.006; for Pol: P = 0.016). Higher HRM scores at 6-8 weeks of age (scores above the 75(th) percentile) were associated with an increased risk of death by 5 years of age (for Pol: P = 0.005; for Gag1/Gag2 (mean of two scores): P = 0.003; for Gag1/Gag2/Pol (mean of three scores): P = 0.002). We did not find an association between HRM scores and other clinical and laboratory variables. CONCLUSIONS: Genetic diversity in HIV gag and pol measured using the HRM assay was typically low near birth and increased over time. Higher HIV diversity in these regions at 6-8 weeks of age was associated with a significantly increased risk of death by 5 years of age. PMID- 21533180 TI - Characterization of structural features controlling the receptiveness of empty class II MHC molecules. AB - MHC class II molecules (MHC II) play a pivotal role in the cell-surface presentation of antigens for surveillance by T cells. Antigen loading takes place inside the cell in endosomal compartments and loss of the peptide ligand rapidly leads to the formation of a non-receptive state of the MHC molecule. Non receptiveness hinders the efficient loading of new antigens onto the empty MHC II. However, the mechanisms driving the formation of the peptide inaccessible state are not well understood. Here, a combined approach of experimental site directed mutagenesis and computational modeling is used to reveal structural features underlying "non-receptiveness." Molecular dynamics simulations of the human MHC II HLA-DR1 suggest a straightening of the alpha-helix of the beta1 domain during the transition from the open to the non-receptive state. The movement is mostly confined to a hinge region conserved in all known MHC molecules. This shift causes a narrowing of the two helices flanking the binding site and results in a closure, which is further stabilized by the formation of a critical hydrogen bond between residues alphaQ9 and betaN82. Mutagenesis experiments confirmed that replacement of either one of the two residues by alanine renders the protein highly susceptible. Notably, loading enhancement was also observed when the mutated MHC II molecules were expressed on the surface of fibroblast cells. Altogether, structural features underlying the non-receptive state of empty HLA-DR1 identified by theoretical means and experiments revealed highly conserved residues critically involved in the receptiveness of MHC II. The atomic details of rearrangements of the peptide-binding groove upon peptide loss provide insight into structure and dynamics of empty MHC II molecules and may foster rational approaches to interfere with non-receptiveness. Manipulation of peptide loading efficiency for improved peptide vaccination strategies could be one of the applications profiting from the structural knowledge provided by this study. PMID- 21533181 TI - Regionally specific white matter disruptions of fornix and cingulum in schizophrenia. AB - Limbic circuitry disruptions have been implicated in the psychopathology and cognitive deficits of schizophrenia, which may involve white matter disruptions of the major tracts of the limbic system, including the fornix and the cingulum. Our study aimed to investigate regionally specific abnormalities of the fornix and cingulum in schizophrenia using diffusion tensor imaging (DTI). We determined the fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) profiles along the fornix and cingulum tracts using a fibertracking technique and a brain mapping algorithm, the large deformation diffeomorphic metric mapping (LDDMM), in the DTI scans of 33 patients with schizophrenia and 31 age-, gender-, and handedness-matched healthy controls. We found that patients with schizophrenia showed reduction in FA and increase in RD in bilateral fornix, and increase in RD in left anterior cingulum when compared to healthy controls. In addition, tract-based analysis revealed specific loci of these white matter differences in schizophrenia, that is, FA reductions and AD and RD increases occur in the region of the left fornix further from the hippocampus, FA reductions and RD increases occur in the rostral portion of the left anterior cingulum, and RD and AD increases occur in the anterior segment of the left middle cingulum. In patients with schizophrenia, decreased FA in the specific loci of the left fornix and increased AD in the right cingulum adjoining the hippocampus correlated with greater severity of psychotic symptoms. These findings support precise disruptions of limbic-cortical integrity in schizophrenia and disruption of these structural networks may contribute towards the neural basis underlying the syndrome of schizophrenia and clinical symptomatology. PMID- 21533182 TI - Variable pathogenicity determines individual lifespan in Caenorhabditis elegans. AB - A common property of aging in all animals is that chronologically and genetically identical individuals age at different rates. To unveil mechanisms that influence aging variability, we identified markers of remaining lifespan for Caenorhabditis elegans. In transgenic lines, we expressed fluorescent reporter constructs from promoters of C. elegans genes whose expression change with age. The expression levels of aging markers in individual worms from a young synchronous population correlated with their remaining lifespan. We identified eight aging markers, with the superoxide dismutase gene sod-3 expression being the best single predictor of remaining lifespan. Correlation with remaining lifespan became stronger if expression from two aging markers was monitored simultaneously, accounting for up to 49% of the variation in individual lifespan. Visualizing the physiological age of chronologically-identical individuals allowed us to show that a major source of lifespan variability is different pathogenicity from individual to individual and that the mechanism involves variable activation of the insulin-signaling pathway. PMID- 21533183 TI - DNA damage, somatic aneuploidy, and malignant sarcoma susceptibility in muscular dystrophies. AB - Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD-pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD-gene defects and strain background strongly influence sarcoma incidence, latency, localization, and gender prevalence. Combined loss of dystrophin and dysferlin, as well as dystrophin and calpain-3, leads to accelerated tumor formation. Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1), amplification of oncogenes (Met, Jun), recurrent duplications of whole chromosomes 8 and 15, and DNA damage. Remarkably, these sarcoma-specific genetic lesions are already regularly present in skeletal muscles in aged MD mice even prior to sarcoma development. Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies. These novel aspects of molecular pathologies common to muscular dystrophies and tumor biology will potentially influence the strategies to combat these diseases. PMID- 21533184 TI - GATA2 mediates thyrotropin-releasing hormone-induced transcriptional activation of the thyrotropin beta gene. AB - Thyrotropin-releasing hormone (TRH) activates not only the secretion of thyrotropin (TSH) but also the transcription of TSHbeta and alpha-glycoprotein (alphaGSU) subunit genes. TSHbeta expression is maintained by two transcription factors, Pit1 and GATA2, and is negatively regulated by thyroid hormone (T3). Our prior studies suggest that the main activator of the TSHbeta gene is GATA2, not Pit1 or unliganded T3 receptor (TR). In previous studies on the mechanism of TRH induced activation of the TSHbeta gene, the involvements of Pit1 and TR have been investigated, but the role of GATA2 has not been clarified. Using kidney-derived CV1 cells and pituitary-derived GH3 and TalphaT1 cells, we demonstrate here that TRH signaling enhances GATA2-dependent activation of the TSHbeta promoter and that TRH-induced activity is abolished by amino acid substitution in the GATA2-Zn finger domain or mutation of GATA-responsive element in the TSHbeta gene. In CV1 cells transfected with TRH receptor expression plasmid, GATA2-dependent transactivation of alphaGSU and endothelin-1 promoters was enhanced by TRH. In the gel shift assay, TRH signal potentiated the DNA-binding capacity of GATA2. While inhibition by T3 is dominant over TRH-induced activation, unliganded TR or the putative negative T3-responsive element are not required for TRH-induced stimulation. Studies using GH3 cells showed that TRH-induced activity of the TSHbeta promoter depends on protein kinase C but not the mitogen-activated protein kinase, suggesting that the signaling pathway is different from that in the prolactin gene. These results indicate that GATA2 is the principal mediator of the TRH signaling pathway in TSHbeta expression. PMID- 21533186 TI - Streptococcus pneumoniae clonal complex 199: genetic diversity and tissue specific virulence. AB - Streptococcus pneumoniae is an important cause of otitis media and invasive disease. Since introduction of the heptavalent pneumococcal conjugate vaccine, there has been an increase in replacement disease due to serotype 19A clonal complex (CC)199 isolates. The goals of this study were to 1) describe genetic diversity among nineteen CC199 isolates from carriage, middle ear, blood, and cerebrospinal fluid, 2) compare CC199 19A (n = 3) and 15B/C (n = 2) isolates in the chinchilla model for pneumococcal disease, and 3) identify accessory genes associated with tissue-specific disease among a larger collection of S. pneumoniae isolates. CC199 isolates were analyzed by comparative genome hybridization. One hundred and twenty-seven genes were variably present. The CC199 phylogeny split into two main clades, one comprised predominantly of carriage isolates and another of disease isolates. Ability to colonize and cause disease did not differ by serotype in the chinchilla model. However, isolates from the disease clade were associated with faster time to bacteremia compared to carriage clade isolates. One 19A isolate exhibited hypervirulence. Twelve tissue specific genes/regions were identified by correspondence analysis. After screening a diverse collection of 326 isolates, spr0282 was associated with carriage. Four genes/regions, SP0163, SP0463, SPN05002 and RD8a were associated with middle ear isolates. SPN05002 also associated with blood and CSF, while RD8a associated with blood isolates. The hypervirulent isolate's genome was sequenced using the Solexa paired-end sequencing platform and compared to that of a reference serotype 19A isolate, revealing the presence of a novel 20 kb region with sequence similarity to bacteriophage genes. Genetic factors other than serotype may modulate virulence potential in CC199. These studies have implications for the long-term effectiveness of conjugate vaccines. Ideally, future vaccines would target common proteins to effectively reduce carriage and disease in the vaccinated population. PMID- 21533185 TI - Specific activation of estrogen receptor alpha and beta enhances male sexual behavior and neuroplasticity in male Japanese quail. AB - Two subtypes of estrogen receptors (ER), ERalpha and ERbeta, have been identified in humans and numerous vertebrates, including the Japanese quail. We investigated in this species the specific role(s) of each receptor in the activation of male sexual behavior and the underlying estrogen-dependent neural plasticity. Castrated male Japanese quail received empty (CX) or testosterone-filled (T) implants or were daily injected with the ER general agonist diethylstilbestrol (DES), the ERalpha-specific agonist PPT, the ERbeta-specific agonist DPN or the vehicle, propylene glycol. Three days after receiving the first treatment, subjects were alternatively tested for appetitive (rhythmic cloacal sphincter movements, RCSM) and consummatory aspects (copulatory behavior) of male sexual behavior. 24 hours after the last behavioral testing, brains were collected and analyzed for aromatase expression and vasotocinergic innervation in the medial preoptic nucleus. The expression of RCSM was activated by T and to a lesser extent by DES and PPT but not by the ERbetaagonist DPN. In parallel, T fully restored the complete sequence of copulation, DES was partially active and the specific activation of ERalpha or ERbeta only resulted in a very low frequency of mount attempts in few subjects. T increased the volume of the medial preoptic nucleus as measured by the dense cluster of aromatase-immunoreactive cells and the density of the vasotocinergic innervation within this nucleus. DES had only a weak action on vasotocinergic fibers and the two specific ER agonists did not affect these neural responses. Simultaneous activation of both receptors or treatments with higher doses may be required to fully activate sexual behavior and the associated neurochemical events. PMID- 21533187 TI - Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. AB - Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome. PMID- 21533188 TI - Expression and distribution of ectonucleotidases in mouse urinary bladder. AB - BACKGROUND: Normal urinary bladder function requires bidirectional molecular communication between urothelium, detrusor smooth muscle and sensory neurons and one of the key mediators involved in this intercellular signaling is ATP. Ectonucleotidases dephosphorylate nucleotides and thus regulate ligand exposure to P2X and P2Y purinergic receptors. Little is known about the role of these enzymes in mammalian bladder despite substantial literature linking bladder diseases to aberrant purinergic signaling. We therefore examined the expression and distribution of ectonucleotidases in the mouse bladder since mice offer the advantage of straightforward genetic modification for future studies. PRINCIPAL FINDINGS: RT-PCR demonstrated that eight members of the ectonucleoside triphosphate diphosphohydrolase (NTPD) family, as well as 5'-nucleotidase (NT5E) are expressed in mouse bladder. NTPD1, NTPD2, NTPD3, NTPD8 and NT5E all catalyze extracellular nucleotide dephosphorylation and in concert achieve stepwise conversion of extracellular ATP to adenosine. Immunofluorescent localization with confocal microscopy revealed NTPD1 in endothelium of blood vessels in the lamina propria and in detrusor smooth muscle cells, while NTPD2 was expressed in cells localized to a region of the lamina propria adjacent to detrusor and surrounding muscle bundles in the detrusor. NTPD3 was urothelial-specific, occurring on membranes of intermediate and basal epithelial cells but did not appear to be present in umbrella cells. Immunoblotting confirmed NTPD8 protein in bladder and immunofluorescence suggested a primary localization to the urothelium. NT5E was present exclusively in detrusor smooth muscle in a pattern complementary with that of NTPD1 suggesting a mechanism for providing adenosine to P1 receptors on the surface of myocytes. CONCLUSIONS: Ectonucleotidases exhibit highly cell specific expression patterns in bladder and therefore likely act in a coordinated manner to regulate ligand availability to purinergic receptors. This is the first study to determine the expression and location of ectonucleotidases within the mammalian urinary bladder. PMID- 21533189 TI - Positive autoregulation delays the expression phase of mammalian clock gene Per2. AB - In mammals, cellular circadian rhythms are generated by a transcriptional translational autoregulatory network that consists of clock genes that encode transcriptional regulators. Of these clock genes, Period1 (Per1) and Period2 (Per2) are essential for sustainable circadian rhythmicity and photic entrainment. Intriguingly, Per1 and Per2 mRNAs exhibit circadian oscillations with a 4-hour phase difference, but they are similarly transactivated by CLOCK BMAL1. In this study, we investigated the mechanism underlying the phase difference between Per1 and Per2 through a combination of mathematical simulations and molecular experiments. Mathematical analyses of a model for the mammalian circadian oscillator demonstrated that the slow synthesis and fast degradation of mRNA tend to advance the oscillation phase of mRNA expression. However, the phase difference between Per1 and Per2 was not reproduced by the model, which implemented a 1.1-fold difference in degradation rates and a 3-fold difference in CLOCK-BMAL1 mediated inductions of Per1 and Per2 as estimated in cultured mammalian cells. Thus, we hypothesized the existence of a novel transcriptional activation of Per2 by PER1/2 such that the Per2 oscillation phase was delayed. Indeed, only the Per2 promoter, but not Per1, was strongly induced by both PER1 and PER2 in the presence of CLOCK-BMAL1 in a luciferase reporter assay. Moreover, a 3-hour advance was observed in the transcriptional oscillation of the delta-Per2 reporter gene lacking cis-elements required for the induction by PER1/2. These results indicate that the Per2 positive feedback regulation is a significant factor responsible for generating the phase difference between Per1 and Per2 gene expression. PMID- 21533190 TI - Pogostick: a new versatile piggyBac vector for inducible gene over-expression and down-regulation in emerging model systems. AB - BACKGROUND: Non-traditional model systems need new tools that will enable them to enter the field of functional genetics. These tools should enable the exploration of gene function, via knock-downs of endogenous genes, as well as over-expression and ectopic expression of transgenes. METHODOLOGY: We constructed a new vector called Pogostick that can be used to over-express or down-regulate genes in organisms amenable to germ line transformation by the piggyBac transposable element. Pogostick can be found at www.addgene.org, a non-profit plasmid repository. The vector currently uses the heat-shock promoter Hsp70 from Drosophila to drive transgene expression and, as such, will have immediate applicability to organisms that can correctly interpret this promotor sequence. We detail how to clone candidate genes into this vector and test its functionality in Drosophila by targeting a gene coding for the fluorescent protein DsRed. By cloning a single DsRed copy into the vector, and generating transgenic lines, we show that DsRed mRNA and protein levels are elevated following heat-shock. When cloning a second copy of DsRed in reverse orientation into a flanking site, and transforming flies constitutively expressing DsRed in the eyes, we show that endogenous mRNA and protein levels drop following heat shock. We then test the over-expression vector, containing the complete cDNA of Ultrabithorax (Ubx) gene, in an emerging model system, Bicyclus anynana. We produce a transgenic line and show that levels of Ubx mRNA expression rise significantly following a heat-shock. Finally, we show how to obtain genomic sequence adjacent to the Pogostick insertion site and to estimate transgene copy number in genomes of transformed individuals. SIGNIFICANCE: This new vector will allow emerging model systems to enter the field of functional genetics with few hurdles. PMID- 21533191 TI - A flow cytometry-based screen of nuclear envelope transmembrane proteins identifies NET4/Tmem53 as involved in stress-dependent cell cycle withdrawal. AB - Disruption of cell cycle regulation is one mechanism proposed for how nuclear envelope protein mutation can cause disease. Thus far only a few nuclear envelope proteins have been tested/found to affect cell cycle progression: to identify others, 39 novel nuclear envelope transmembrane proteins were screened for their ability to alter flow cytometry cell cycle/DNA content profiles when exogenously expressed. Eight had notable effects with seven increasing and one decreasing the 4N:2N ratio. We subsequently focused on NET4/Tmem53 that lost its effects in p53( /-) cells and retinoblastoma protein-deficient cells. NET4/TMEM53 knockdown by siRNA altered flow cytometry cell cycle/DNA content profiles in a similar way as overexpression. NET4/TMEM53 knockdown did not affect total retinoblastoma protein levels, unlike nuclear envelope-associated proteins Lamin A and LAP2alpha. However, a decrease in phosphorylated retinoblastoma protein was observed along with a doubling of p53 levels and a 7-fold increase in p21. Consequently cells withdrew from the cell cycle, which was confirmed in MRC5 cells by a drop in the percentage of cells expressing Ki-67 antigen and an increase in the number of cells stained for beta-galactosidase. The beta-galactosidase upregulation suggests that cells become prematurely senescent. Finally, the changes in retinoblastoma protein, p53, and p21 resulting from loss of NET4/Tmem53 were dependent upon active p38 MAP kinase. The finding that roughly a fifth of nuclear envelope transmembrane proteins screened yielded alterations in flow cytometry cell cycle/DNA content profiles suggests a much greater influence of the nuclear envelope on the cell cycle than is widely held. PMID- 21533192 TI - Domain movement within a gene: a novel evolutionary mechanism for protein diversification. AB - A protein function is carried out by a specific domain localized at a specific position. In the present study, we report that, within a gene, a specific amino acid sequence can move between a certain position and another position. This was discovered when the sequences of restriction-modification systems within the bacterial species Helicobacter pylori were compared. In the specificity subunit of Type I restriction-modification systems, DNA sequence recognition is mediated by target recognition domain 1 (TRD1) and TRD2. To our surprise, several sequences are shared by TRD1 and TRD2 of genes (alleles) at the same locus (chromosomal location); these domains appear to have moved between the two positions. The gene/protein organization can be represented as x-(TRD1)-y-x (TRD2)-y, where x and y represent repeat sequences. Movement probably occurs by recombination at these flanking DNA repeats. In accordance with this hypothesis, recombination at these repeats also appears to decrease two TRDs into one TRD or increase these two TRDs to three TRDs (TRD1-TRD2-TRD2) and to allow TRD movement between genes even at different loci. Similar movement of domains between TRD1 and TRD2 was observed for the specificity subunit of a Type IIG restriction enzyme. Similar movement of domain between TRD1 and TRD2 was observed for Type I restriction-modification enzyme specificity genes in two more eubacterial species, Streptococcus pyogenes and Mycoplasma agalactiae. Lateral domain movements within a protein, which we have designated DOMO (domain movement), represent novel routes for the diversification of proteins. PMID- 21533193 TI - Gamma-secretase inhibitor treatment promotes VEGF-A-driven blood vessel growth and vascular leakage but disrupts neovascular perfusion. AB - The Notch signaling pathway is essential for normal development due to its role in control of cell differentiation, proliferation and survival. It is also critically involved in tumorigenesis and cancer progression. A key enzyme in the activation of Notch signaling is the gamma-secretase protein complex and therefore, gamma-secretase inhibitors (GSIs)--originally developed for Alzheimer's disease--are now being evaluated in clinical trials for human malignancies. It is also clear that Notch plays an important role in angiogenesis driven by Vascular Endothelial Growth Factor A (VEGF-A)--a process instrumental for tumor growth and metastasis. The effect of GSIs on tumor vasculature has not been conclusively determined. Here we report that Compound X (CX), a GSI previously reported to potently inhibit Notch signaling in vitro and in vivo, promotes angiogenic sprouting in vitro and during developmental angiogenesis in mice. Furthermore, CX treatment suppresses tumor growth in a mouse model of renal carcinoma, leads to the formation of abnormal vessels and an increased tumor vascular density. Using a rabbit model of VEGF-A-driven angiogenesis in skeletal muscle, we demonstrate that CX treatment promotes abnormal blood vessel growth characterized by vessel occlusion, disrupted blood flow, and increased vascular leakage. Based on these findings, we propose a model for how GSIs and other Notch inhibitors disrupt tumor blood vessel perfusion, which might be useful for understanding this new class of anti-cancer agents. PMID- 21533194 TI - Infant brain atlases from neonates to 1- and 2-year-olds. AB - BACKGROUND: Studies for infants are usually hindered by the insufficient image contrast, especially for neonates. Prior knowledge, in the form of atlas, can provide additional guidance for the data processing such as spatial normalization, label propagation, and tissue segmentation. Although it is highly desired, there is currently no such infant atlas which caters for all these applications. The reason may be largely due to the dramatic early brain development, image processing difficulties, and the need of a large sample size. METHODOLOGY: To this end, after several years of subject recruitment and data acquisition, we have collected a unique longitudinal dataset, involving 95 normal infants (56 males and 39 females) with MRI scanned at 3 ages, i.e., neonate, 1 year-old, and 2-year-old. State-of-the-art MR image segmentation and registration techniques were employed, to construct which include the templates (grayscale average images), tissue probability maps (TPMs), and brain parcellation maps (i.e., meaningful anatomical regions of interest) for each age group. In addition, the longitudinal correspondences between age-specific atlases were also obtained. Experiments of typical infant applications validated that the proposed atlas outperformed other atlases and is hence very useful for infant-related studies. CONCLUSIONS: We expect that the proposed infant 0-1-2 brain atlases would be significantly conducive to structural and functional studies of the infant brains. These atlases are publicly available in our website, http://bric.unc.edu/ideagroup/free-softwares/. PMID- 21533195 TI - Response of estrogen receptor-positive breast cancer tumorspheres to antiestrogen treatments. AB - Estrogen signaling plays a critical role in the pathogenesis of breast cancer. Because the majority of breast carcinomas express the estrogen receptor ERalpha, endocrine therapy that impedes estrogen-ER signaling reduces breast cancer mortality and has become a mainstay of breast cancer treatment. However, patients remain at continued risk of relapse for many years after endocrine treatment. It has been proposed that cancer recurrence may be attributed to cancer stem cells (CSCs)/tumor-initiating cells (TICs). Previous studies in breast cancer have shown that such cells can be enriched and propagated in vitro by culturing the cells in suspension as mammospheres/tumorspheres. Here we established tumorspheres from ERalpha-positive human breast cancer cell line MCF7 and investigated their response to antiestrogens Tamoxifen and Fulvestrant. The tumorsphere cells express lower levels of ERalpha and are more tumorigenic in xenograft assays than the parental cells. Both 4-hydroxytamoxifen (4-OHT) and Fulvestrant attenuate tumorsphere cell proliferation, but only 4-OHT at high concentrations interferes with sphere formation. However, treated tumorsphere cells retain the self-renewal capacity. Upon withdrawal of antiestrogens, the treated cells resume tumorsphere formation and their tumorigenic potential remains undamaged. Depletion of ERalpha shows that ERalpha is dispensable for tumorsphere formation and xenograft tumor growth in mice. Surprisingly, ERalpha depleted tumorspheres display heightened sensitivity to 4-OHT and their sphere forming capacity is diminished after the drug is removed. These results imply that 4-OHT may inhibit cellular targets besides ERalpha that are essential for tumorsphere growth, and provide a potential strategy to sensitize tumorspheres to endocrine treatment. PMID- 21533196 TI - Endocytic and recycling endosomes modulate cell shape changes and tissue behaviour during morphogenesis in Drosophila. AB - During development tissue deformations are essential for the generation of organs and to provide the final form of an organism. These deformations rely on the coordination of individual cell behaviours which have their origin in the modulation of subcellular activities. Here we explore the role endocytosis and recycling on tissue deformations that occur during dorsal closure of the Drosophila embryo. During this process the AS contracts and the epidermis elongates in a coordinated fashion, leading to the closure of a discontinuity in the dorsal epidermis of the Drosophila embryo. We used dominant negative forms of Rab5 and Rab11 to monitor the impact on tissue morphogenesis of altering endocytosis and recycling at the level of single cells. We found different requirements for endocytosis (Rab5) and recycling (Rab11) in dorsal closure, furthermore we found that the two processes are differentially used in the two tissues. Endocytosis is required in the AS to remove membrane during apical constriction, but is not essential in the epidermis. Recycling is required in the AS at early stages and in the epidermis for cell elongation, suggesting a role in membrane addition during these processes. We propose that the modulation of the balance between endocytosis and recycling can regulate cellular morphology and tissue deformations during morphogenesis. PMID- 21533197 TI - Bayesian modeling of perceived surface slant from actively-generated and passively-observed optic flow. AB - We measured perceived depth from the optic flow (a) when showing a stationary physical or virtual object to observers who moved their head at a normal or slower speed, and (b) when simulating the same optic flow on a computer and presenting it to stationary observers. Our results show that perceived surface slant is systematically distorted, for both the active and the passive viewing of physical or virtual surfaces. These distortions are modulated by head translation speed, with perceived slant increasing directly with the local velocity gradient of the optic flow. This empirical result allows us to determine the relative merits of two alternative approaches aimed at explaining perceived surface slant in active vision: an "inverse optics" model that takes head motion information into account, and a probabilistic model that ignores extra-retinal signals. We compare these two approaches within the framework of the bayesian theory. The "inverse optics" bayesian model produces veridical slant estimates if the optic flow and the head translation velocity are measured with no error; because of the influence of a "prior" for flatness, the slant estimates become systematically biased as the measurement errors increase. The bayesian model, which ignores the observer's motion, always produces distorted estimates of surface slant. Interestingly, the predictions of this second model, not those of the first one, are consistent with our empirical findings. The present results suggest that (a) in active vision perceived surface slant may be the product of probabilistic processes which do not guarantee the correct solution, and (b) extra-retinal signals may be mainly used for a better measurement of retinal information. PMID- 21533198 TI - Circulating matrix metalloproteinases in infective endocarditis: a possible marker of the embolic risk. AB - BACKGROUND: Embolic events (EE) in infective endocarditis (IE) are caused by fragmentation of vegetations or valvular tissue. Vegetation length is considered to be the most potent predictor of EE, but does not take into account the degree of friability of the vegetation and of the surrounded infected tissue. Matrix metalloproteinases (MMPs) are enzymes involved in degradation of matrix extracellular components and play a role in the pathophysiology of IE. We aimed to determine whether, in addition to the vegetation size, circulating MMPs could provide accurate predictive value of embolism in IE. METHODS: Among 145 patients referred for a native valve IE, we prospectively included 16 patients who experienced EE during antibiotic therapy (new-EE) and 30 patients without new-EE and treated without valvular surgery. A control group of 38 patients with a degenerative valvular heart disease was also included. In addition to clinical, microbiological and echocardiographic assessment, blood MMPs and their inhibitors were assayed in all patients at admission. RESULTS: MMP-9 serum level was significantly higher in patients with new-EE compared to controls (median [interquartile range]; 250 ng/mL [175-455] vs. 111 ng/mL [70-144], respectively; p<0.0001) and patients with no new-EE (250 ng/mL [175-455] vs. 138 ng/mL [95 232]; p<0.01). A higher MMP-9 activity in patients who experienced new-EE was further confirmed by gelatin zymography analysis. Circulating MMP-9 remains a predictor of new-EE after adjustment for vegetation length and other potential confounders. This parameter provided incremental predictive value over vegetation measurements. CONCLUSIONS: MMP-9 serum level is associated with the risk of embolism during IE. This marker might help physicians in the management of the disease, but further prospective studies are need to confirm these preliminary results. PMID- 21533199 TI - Biphasic electrical currents stimulation promotes both proliferation and differentiation of fetal neural stem cells. AB - The use of non-chemical methods to differentiate stem cells has attracted researchers from multiple disciplines, including the engineering and the biomedical fields. No doubt, growth factor based methods are still the most dominant of achieving some level of proliferation and differentiation control- however, chemical based methods are still limited by the quality, source, and amount of the utilized reagents. Well-defined non-chemical methods to differentiate stem cells allow stem cell scientists to control stem cell biology by precisely administering the pre-defined parameters, whether they are structural cues, substrate stiffness, or in the form of current flow. We have developed a culture system that allows normal stem cell growth and the option of applying continuous and defined levels of electric current to alter the cell biology of growing cells. This biphasic current stimulator chip employing ITO electrodes generates both positive and negative currents in the same culture chamber without affecting surface chemistry. We found that biphasic electrical currents (BECs) significantly increased the proliferation of fetal neural stem cells (NSCs). Furthermore, BECs also promoted the differentiation of fetal NSCs into neuronal cells, as assessed using immunocytochemistry. Our results clearly show that BECs promote both the proliferation and neuronal differentiation of fetal NSCs. It may apply to the development of strategies that employ NSCs in the treatment of various neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. PMID- 21533200 TI - Role of germination in murine airway CD8+ T-cell responses to Aspergillus conidia. AB - Pulmonary exposure to Aspergillus fumigatus has been associated with morbidity and mortality, particularly in immunocompromised individuals. A. fumigatus conidia produce beta-glucan, proteases, and other immunostimulatory factors upon germination. Murine models have shown that the ability of A. fumigatus to germinate at physiological temperature may be an important factor that facilitates invasive disease. We observed a significant increase in IFN-gamma producing CD8(+) T cells in bronchoalveolar lavage fluid (BALF) of immunocompetent mice that repeatedly aspirated A. fumigatus conidia in contrast to mice challenged with A. versicolor, a species that is not typically associated with invasive, disseminated disease. Analysis of tissue sections indicated the presence of germinating spores in the lungs of mice challenged with A. fumigatus, but not A. versicolor. Airway IFN-gamma(+)CD8(+) T-cells were decreased and lung germination was eliminated in mice that aspirated A. fumigatus conidia that were formaldehyde-fixed or heat-inactivated. Furthermore, A. fumigatus particles exhibited greater persistence in the lungs of recipient mice when compared to non viable A. fumigatus or A. versicolor, and this correlated with increased maintenance of airway memory-phenotype CD8(+) T cells. Therefore, murine airway CD8(+) T cell-responses to aspiration of Aspergillus conidia may be mediated in part by the ability of conidia to germinate in the host lung tissue. These results provide further evidence of induction of immune responses to fungi based on their ability to invade host tissue. PMID- 21533201 TI - Characterization of constricted fruit (ctf) mutant uncovers a role for AtMYB117/LOF1 in ovule and fruit development in Arabidopsis thaliana. AB - Pistil and fruit morphogenesis is the result of a complex gene network that is not yet fully understood. A search for novel genes is needed to make a more comprehensive model of pistil and fruit development. Screening for mutants with alterations in fruit morphology generated by an activation tagging strategy resulted in the isolation of the ctf (constricted fruit) mutant. It is characterized by a) small and wrinkled fruits, with an enlarged replum, an amorphous structure of the septum and an irregular distribution of ovules and seeds; b) ectopic carpelloid structures in sepals bearing ovule-like structures and c) dwarf plants with curled rosette leaves. The overexpressed gene in ctf was AtMYB117, also named LOF1 (LATERAL ORGAN FUSION1). AtMYB117/LOF1 transcripts were localized in boundary regions of the vegetative shoot apical meristem and leaf primordia and in a group of cells in the adaxial base of petioles and bracts. Transcripts were also detected in the boundaries between each of the four floral whorls and during pistil development in the inner of the medial ridges, the placenta, the base of the ovule primordia, the epidermis of the developing septum and the outer cell layers of the ovule funiculi. Analysis of changes of expression of pistil-related genes in the ctf mutant showed an enhancement of SHATTERPROOF1 (SHP1) and SHP2 expression. All these results suggest that AtMYB117/LOF1 is recruited by a variety of developmental programs for the establishment of boundary regions, including the development of floral organs and the initiation of ovule outgrowth. PMID- 21533202 TI - Evaluating ortholog prediction algorithms in a yeast model clade. AB - BACKGROUND: Accurate identification of orthologs is crucial for evolutionary studies and for functional annotation. Several algorithms have been developed for ortholog delineation, but so far, manually curated genome-scale biological databases of orthologous genes for algorithm evaluation have been lacking. We evaluated four popular ortholog prediction algorithms (MultiParanoid; and OrthoMCL; RBH: Reciprocal Best Hit; RSD: Reciprocal Smallest Distance; the last two extended into clustering algorithms cRBH and cRSD, respectively, so that they can predict orthologs across multiple taxa) against a set of 2,723 groups of high quality curated orthologs from 6 Saccharomycete yeasts in the Yeast Gene Order Browser. RESULTS: Examination of sensitivity [TP/(TP+FN)], specificity [TN/(TN+FP)], and accuracy [(TP+TN)/(TP+TN+FP+FN)] across a broad parameter range showed that cRBH was the most accurate and specific algorithm, whereas OrthoMCL was the most sensitive. Evaluation of the algorithms across a varying number of species showed that cRBH had the highest accuracy and lowest false discovery rate [FP/(FP+TP)], followed by cRSD. Of the six species in our set, three descended from an ancestor that underwent whole genome duplication. Subsequent differential duplicate loss events in the three descendants resulted in distinct classes of gene loss patterns, including cases where the genes retained in the three descendants are paralogs, constituting 'traps' for ortholog prediction algorithms. We found that the false discovery rate of all algorithms dramatically increased in these traps. CONCLUSIONS: These results suggest that simple algorithms, like cRBH, may be better ortholog predictors than more complex ones (e.g., OrthoMCL and MultiParanoid) for evolutionary and functional genomics studies where the objective is the accurate inference of single-copy orthologs (e.g., molecular phylogenetics), but that all algorithms fail to accurately predict orthologs when paralogy is rampant. PMID- 21533203 TI - Impact of different economic factors on biological invasions on the global scale. AB - Social-economic factors are considered as the key to understand processes contributing to biological invasions. However, there has been few quantified, statistical evidence on the relationship between economic development and biological invasion on a worldwide scale. Herein, using principal factor analysis, we investigated the relationship between biological invasion and economic development together with biodiversity for 91 economies throughout the world. Our result indicates that the prevalence of invasive species in the economies can be well predicted by economic factors (R(2) = 0.733). The impact of economic factors on the occurrence of invasive species for low, lower-middle, upper-middle and high income economies are 0%, 34.3%, 46.3% and 80.8% respectively. Greenhouse gas emissions (CO(2), Nitrous oxide, Methane and Other greenhouse gases) and also biodiversity have positive relationships with the global occurrence of invasive species in the economies on the global scale. The major social-economic factors that are correlated to biological invasions are different for various economies, and therefore the strategies for biological invasion prevention and control should be different. PMID- 21533204 TI - Finding single copy genes out of sequenced genomes for multilocus phylogenetics in non-model fungi. AB - Historically, fungal multigene phylogenies have been reconstructed based on a small number of commonly used genes. The availability of complete fungal genomes has given rise to a new wave of model organisms that provide large number of genes potentially useful for building robust gene genealogies. Unfortunately, cross-utilization of these resources to study phylogenetic relationships in the vast majority of non-model fungi (i.e. "orphan" species) remains an unexamined question. To address this problem, we developed a method coupled with a program named "PHYLORPH" (PHYLogenetic markers for ORPHans). The method screens fungal genomic databases (107 fungal genomes fully sequenced) for single copy genes that might be easily transferable and well suited for studies at low taxonomic levels (for example, in species complexes) in non-model fungal species. To maximize the chance to target genes with informative regions, PHYLORPH displays a graphical evaluation system based on the estimation of nucleotide divergence relative to substitution type. The usefulness of this approach was tested by developing markers in four non-model groups of fungal pathogens. For each pathogen considered, 7 to 40% of the 10-15 best candidate genes proposed by PHYLORPH yielded sequencing success. Levels of polymorphism of these genes were compared with those obtained for some genes traditionally used to build fungal phylogenies (e.g. nuclear rDNA, beta-tubulin, gamma-actin, Elongation factor EF-1alpha). These genes were ranked among the best-performing ones and resolved accurately taxa relationships in each of the four non-model groups of fungi considered. We envision that PHYLORPH will constitute a useful tool for obtaining new and accurate phylogenetic markers to resolve relationships between closely related non-model fungal species. PMID- 21533205 TI - Mechanics of the IL2RA gene activation revealed by modeling and atomic force microscopy. AB - Transcription implies recruitment of RNA polymerase II and transcription factors (TFs) by DNA melting near transcription start site (TSS). Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites), located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studies, result in the progressive positioning of curvature apex towards the TSS, likely facilitating local DNA melting. In vitro assays confirm specific binding of the General Transcription Factors (GTFs) TBP and TFIIB over TATA-TSS position, where an inhibitory nucleosome prevented preinitiation complex (PIC) formation and uncontrolled DNA melting. These findings represent a substantial advance showing, first, that the structural properties of the IL2RA promoter are encoded in the DNA sequence and second, that during the initiation process DNA conformation is dynamic and not static. PMID- 21533206 TI - Island invasion by a threatened tree species: evidence for natural enemy release of mahogany (Swietenia macrophylla) on Dominica, Lesser Antilles. AB - Despite its appeal to explain plant invasions, the enemy release hypothesis (ERH) remains largely unexplored for tropical forest trees. Even scarcer are ERH studies conducted on the same host species at both the community and biogeographical scale, irrespective of the system or plant life form. In Cabrits National Park, Dominica, we observed patterns consistent with enemy release of two introduced, congeneric mahogany species, Swietenia macrophylla and S. mahagoni, planted almost 50 years ago. Swietenia populations at Cabrits have reproduced, with S. macrophylla juveniles established in and out of plantation areas at densities much higher than observed in its native range. Swietenia macrophylla juveniles also experienced significantly lower leaf-level herbivory (~3.0%) than nine co-occurring species native to Dominica (8.4-21.8%), and far lower than conspecific herbivory observed in its native range (11%-43%, on average). These complimentary findings at multiple scales support ERH, and confirm that Swietenia has naturalized at Cabrits. However, Swietenia abundance was positively correlated with native plant diversity at the seedling stage, and only marginally negatively correlated with native plant abundance for stems >=1 cm dbh. Taken together, these descriptive patterns point to relaxed enemy pressure from specialized enemies, specifically the defoliator Steniscadia poliophaea and the shoot-borer Hypsipyla grandella, as a leading explanation for the enhanced recruitment of Swietenia trees documented at Cabrits. PMID- 21533207 TI - Quantitative mass spectrometry analysis reveals similar substrate consensus motif for human Mps1 kinase and Plk1. AB - BACKGROUND: Members of the Mps1 kinase family play an essential and evolutionarily conserved role in the spindle assembly checkpoint (SAC), a surveillance mechanism that ensures accurate chromosome segregation during mitosis. Human Mps1 (hMps1) is highly phosphorylated during mitosis and many phosphorylation sites have been identified. However, the upstream kinases responsible for these phosphorylations are not presently known. METHODOLOGY/PRINCIPAL FINDINGS: Here, we identify 29 in vivo phosphorylation sites in hMps1. While in vivo analyses indicate that Aurora B and hMps1 activity are required for mitotic hyper-phosphorylation of hMps1, in vitro kinase assays show that Cdk1, MAPK, Plk1 and hMps1 itself can directly phosphorylate hMps1. Although Aurora B poorly phosphorylates hMps1 in vitro, it positively regulates the localization of Mps1 to kinetochores in vivo. Most importantly, quantitative mass spectrometry analysis demonstrates that at least 12 sites within hMps1 can be attributed to autophosphorylation. Remarkably, these hMps1 autophosphorylation sites closely resemble the consensus motif of Plk1, demonstrating that these two mitotic kinases share a similar substrate consensus. CONCLUSIONS/SIGNIFICANCE: hMps1 kinase is regulated by Aurora B kinase and its autophosphorylation. Analysis on hMps1 autophosphorylation sites demonstrates that hMps1 has a substrate preference similar to Plk1 kinase. PMID- 21533208 TI - A major role for side-chain polyglutamine hydrogen bonding in irreversible ataxin 3 aggregation. AB - The protein ataxin-3 consists of an N-terminal globular Josephin domain (JD) and an unstructured C-terminal region containing a stretch of consecutive glutamines that triggers the neurodegenerative disorder spinocerebellar ataxia type 3, when it is expanded beyond a critical threshold. The disease results from misfolding and aggregation, although the pathway and structure of the aggregation intermediates are not fully understood. In order to provide insight into the mechanism of the process, we monitored the aggregation of a normal (AT3Q24) ataxin-3, an expanded (AT3Q55) ataxin-3, and the JD in isolation. We observed that all of them aggregated, although the latter did so at a much slower rate. Furthermore, the expanded AT3Q55 displayed a substantially different behavior with respect to the two other variants in that at the latest stages of the process it was the only one that did the following: i) lost its reactivity towards an anti-oligomer antibody, ii) generated SDS-insoluble aggregates, iii) gave rise to bundles of elongated fibrils, and iv) displayed two additional bands at 1604 and 1656 cm(-1) in FTIR spectroscopy. Although these were previously observed in other aggregated polyglutamine proteins, no one has assigned them unambiguously, yet. By H/D exchange experiments we show for the first time that they can be ascribed to glutamine side-chain hydrogen bonding, which is therefore the hallmark of irreversibly SDS-insoluble aggregated protein. FTIR spectra also showed that main-chain intermolecular hydrogen bonding preceded that of glutamine side-chains, which suggests that the former favors the latter by reorganizing backbone geometry. PMID- 21533209 TI - Age-dependent maturation of Toll-like receptor-mediated cytokine responses in Gambian infants. AB - The global burden of neonatal and infant mortality due to infection is staggering, particularly in resource-poor settings. Early childhood vaccination is one of the major interventions that can reduce this burden, but there are specific limitations to inducing effective immunity in early life, including impaired neonatal leukocyte production of Th1-polarizing cytokines to many stimuli. Characterizing the ontogeny of Toll-like receptor (TLR)-mediated innate immune responses in infants may shed light on susceptibility to infection in this vulnerable age group, and provide insights into TLR agonists as candidate adjuvants for improved neonatal vaccines. As little is known about the leukocyte responses of infants in resource-poor settings, we characterized production of Th1-, Th2-, and anti-inflammatory-cytokines in response to agonists of TLRs 1-9 in whole blood from 120 Gambian infants ranging from newborns (cord blood) to 12 months of age. Most of the TLR agonists induced TNFalpha, IL-1beta, IL-6, and IL 10 in cord blood. The greatest TNFalpha responses were observed for TLR4, -5, and -8 agonists, the highest being the thiazoloquinoline CLO75 (TLR7/8) that also uniquely induced cord blood IFNgamma production. For most agonists, TLR-mediated TNFalpha and IFNgamma responses increased from birth to 1 month of age. TLR8 agonists also induced the greatest production of the Th1-polarizing cytokines TNFalpha and IFNgamma throughout the first year of life, although the relative responses to the single TLR8 agonist and the combined TLR7/8 agonist changed with age. In contrast, IL-1beta, IL-6, and IL-10 responses to most agonists were robust at birth and remained stable through 12 months of age. These observations provide fresh insights into the ontogeny of innate immunity in African children, and may inform development of age-specific adjuvanted vaccine formulations important for global health. PMID- 21533210 TI - Discovering biological progression underlying microarray samples. AB - In biological systems that undergo processes such as differentiation, a clear concept of progression exists. We present a novel computational approach, called Sample Progression Discovery (SPD), to discover patterns of biological progression underlying microarray gene expression data. SPD assumes that individual samples of a microarray dataset are related by an unknown biological process (i.e., differentiation, development, cell cycle, disease progression), and that each sample represents one unknown point along the progression of that process. SPD aims to organize the samples in a manner that reveals the underlying progression and to simultaneously identify subsets of genes that are responsible for that progression. We demonstrate the performance of SPD on a variety of microarray datasets that were generated by sampling a biological process at different points along its progression, without providing SPD any information of the underlying process. When applied to a cell cycle time series microarray dataset, SPD was not provided any prior knowledge of samples' time order or of which genes are cell-cycle regulated, yet SPD recovered the correct time order and identified many genes that have been associated with the cell cycle. When applied to B-cell differentiation data, SPD recovered the correct order of stages of normal B-cell differentiation and the linkage between preB-ALL tumor cells with their cell origin preB. When applied to mouse embryonic stem cell differentiation data, SPD uncovered a landscape of ESC differentiation into various lineages and genes that represent both generic and lineage specific processes. When applied to a prostate cancer microarray dataset, SPD identified gene modules that reflect a progression consistent with disease stages. SPD may be best viewed as a novel tool for synthesizing biological hypotheses because it provides a likely biological progression underlying a microarray dataset and, perhaps more importantly, the candidate genes that regulate that progression. PMID- 21533211 TI - Network archaeology: uncovering ancient networks from present-day interactions. AB - What proteins interacted in a long-extinct ancestor of yeast? How have different members of a protein complex assembled together over time? Our ability to answer such questions has been limited by the unavailability of ancestral protein protein interaction (PPI) networks. To overcome this limitation, we propose several novel algorithms to reconstruct the growth history of a present-day network. Our likelihood-based method finds a probable previous state of the graph by applying an assumed growth model backwards in time. This approach retains node identities so that the history of individual nodes can be tracked. Using this methodology, we estimate protein ages in the yeast PPI network that are in good agreement with sequence-based estimates of age and with structural features of protein complexes. Further, by comparing the quality of the inferred histories for several different growth models (duplication-mutation with complementarity, forest fire, and preferential attachment), we provide additional evidence that a duplication-based model captures many features of PPI network growth better than models designed to mimic social network growth. From the reconstructed history, we model the arrival time of extant and ancestral interactions and predict that complexes have significantly re-wired over time and that new edges tend to form within existing complexes. We also hypothesize a distribution of per-protein duplication rates, track the change of the network's clustering coefficient, and predict paralogous relationships between extant proteins that are likely to be complementary to the relationships inferred using sequence alone. Finally, we infer plausible parameters for the model, thereby predicting the relative probability of various evolutionary events. The success of these algorithms indicates that parts of the history of the yeast PPI are encoded in its present day form. PMID- 21533212 TI - On being the right size: the impact of population size and stochastic effects on the evolution of drug resistance in hospitals and the community. AB - The evolution of drug resistant bacteria is a severe public health problem, both in hospitals and in the community. Currently, some countries aim at concentrating highly specialized services in large hospitals in order to improve patient outcomes. Emergent resistant strains often originate in health care facilities, but it is unknown to what extent hospital size affects resistance evolution and the resulting spillover of hospital-associated pathogens to the community. We used two published datasets from the US and Ireland to investigate the effects of hospital size and controlled for several confounders such as antimicrobial usage, sampling frequency, mortality, disinfection and length of stay. The proportion of patients acquiring both sensitive and resistant infections in a hospital strongly correlated with hospital size. Moreover, we observe the same pattern for both the percentage of resistant infections and the increase of hospital-acquired infections over time. One interpretation of this pattern is that chance effects in small hospitals impede the spread of drug-resistance. To investigate to what extent the size distribution of hospitals can directly affect the prevalence of antibiotic resistance, we use a stochastic epidemiological model describing the spread of drug resistance in a hospital setting as well as the interaction between one or several hospitals and the community. We show that the level of drug resistance typically increases with population size: In small hospitals chance effects cause large fluctuations in pathogen population size or even extinctions, both of which impede the acquisition and spread of drug resistance. Finally, we show that indirect transmission via environmental reservoirs can reduce the effect of hospital size because the slow turnover in the environment can prevent extinction of resistant strains. This implies that reducing environmental transmission is especially important in small hospitals, because such a reduction not only reduces overall transmission but might also facilitate the extinction of resistant strains. Overall, our study shows that the distribution of hospital sizes is a crucial factor for the spread of drug resistance. PMID- 21533213 TI - HYR1-mediated detoxification of reactive oxygen species is required for full virulence in the rice blast fungus. AB - During plant-pathogen interactions, the plant may mount several types of defense responses to either block the pathogen completely or ameliorate the amount of disease. Such responses include release of reactive oxygen species (ROS) to attack the pathogen, as well as formation of cell wall appositions (CWAs) to physically block pathogen penetration. A successful pathogen will likely have its own ROS detoxification mechanisms to cope with this inhospitable environment. Here, we report one such candidate mechanism in the rice blast fungus, Magnaporthe oryzae, governed by a gene we refer to as MoHYR1. This gene (MGG_07460) encodes a glutathione peroxidase (GSHPx) domain, and its homologue in yeast was reported to specifically detoxify phospholipid peroxides. To characterize this gene in M. oryzae, we generated a deletion mutantDeltahyr1 which showed growth inhibition with increased amounts of hydrogen peroxide (H2O2). Moreover, we observed that the fungal mutants had a decreased ability to tolerate ROS generated by a susceptible plant, including ROS found associated with CWAs. Ultimately, this resulted in significantly smaller lesion sizes on both barley and rice. In order to determine how this gene interacts with other (ROS) scavenging-related genes in M. oryzae, we compared expression levels of ten genes in mutant versus wild type with and without H2O2. Our results indicated that the HYR1 gene was important for allowing the fungus to tolerate H2O2 in vitro and in planta and that this ability was directly related to fungal virulence. PMID- 21533214 TI - A new model to produce infectious hepatitis C virus without the replication requirement. AB - Numerous constraints significantly hamper the experimental study of hepatitis C virus (HCV). Robust replication in cell culture occurs with only a few strains, and is invariably accompanied by adaptive mutations that impair in vivo infectivity/replication. This problem complicates the production and study of authentic HCV, including the most prevalent and clinically important genotype 1 (subtypes 1a and 1b). Here we describe a novel cell culture approach to generate infectious HCV virions without the HCV replication requirement and the associated cell-adaptive mutations. The system is based on our finding that the intracellular environment generated by a West-Nile virus (WNV) subgenomic replicon rendered a mammalian cell line permissive for assembly and release of infectious HCV particles, wherein the HCV RNA with correct 5' and 3' termini was produced in the cytoplasm by a plasmid-driven dual bacteriophage RNA polymerase based transcription/amplification system. The released particles preferentially contained the HCV-based RNA compared to the WNV subgenomic RNA. Several variations of this system are described with different HCV-based RNAs: (i) HCV bicistronic particles (HCVbp) containing RNA encoding the HCV structural genes upstream of a cell-adapted subgenomic replicon, (ii) HCV reporter particles (HCVrp) containing RNA encoding the bacteriophage SP6 RNA polymerase in place of HCV nonstructural genes, and (iii) HCV wild-type particles (HCVwt) containing unmodified RNA genomes of diverse genotypes (1a, strain H77; 1b, strain Con1; 2a, strain JFH-1). Infectivity was assessed based on the signals generated by the HCV RNA molecules introduced into the cytoplasm of target cells upon virus entry, i.e. HCV RNA replication and protein production for HCVbp in Huh-7.5 cells as well as for HCVwt in HepG2-CD81 cells and human liver slices, and SP6 RNA polymerase-driven firefly luciferase for HCVrp in target cells displaying candidate HCV surface receptors. HCV infectivity was inhibited by pre-incubation of the particles with anti-HCV antibodies and by a treatment of the target cells with leukocyte interferon plus ribavirin. The production of authentic infectious HCV particles of virtually any genotype without the adaptive mutations associated with in vitro HCV replication represents a new paradigm to decipher the requirements for HCV assembly, release, and entry, amenable to analyses of wild type and genetically modified viruses of the most clinically significant HCV genotypes. PMID- 21533217 TI - Structure-function analysis of the Anopheles gambiae LRIM1/APL1C complex and its interaction with complement C3-like protein TEP1. AB - Malaria threatens half the world's population and exacts a devastating human toll. The principal malaria vector in Africa, the mosquito Anopheles gambiae, encodes 24 members of a recently identified family of leucine-rich repeat proteins named LRIMs. Two members of this family, LRIM1 and APL1C, are crucial components of the mosquito complement-like pathway that is important for immune defense against Plasmodium parasites. LRIM1 and APL1C circulate in the hemolymph exclusively as a disulfide-bonded complex that specifically interacts with the mature form of the complement C3-like protein, TEP1. We have investigated the specificity of LRIM1/APL1C complex formation and which regions of these proteins are required for interactions with TEP1. To address these questions, we have generated a set of LRIM1 and APL1C alleles altering key conserved structural elements and assayed them in cell culture for complex formation and interaction with TEP1. Our data indicate that heterocomplex formation is an intrinsic ability of LRIM1 and APL1C and identify key homologous cysteine residues forming the intermolecular disulfide bond. We also demonstrate that the coiled-coil domain is the binding site for TEP1 but also contributes to the specificity of LRIM1/APL1C complex formation. In addition, we show that the LRIM1/APL1C complex interacts with the mature forms of three other TEP proteins, one of which, TEP3, we have characterized as a Plasmodium antagonist. We conclude that LRIM1 and APL1C contain three distinct modules: a C-terminal coiled-coil domain that can carry different TEP protein cargoes, potentially with distinct functions, a central cysteine-rich region that controls complex formation and an N-terminal leucine rich repeat with a putative role in pathogen recognition. PMID- 21533216 TI - Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. AB - HIV-1 entry requires the cell surface expression of CD4 and either the CCR5 or CXCR4 coreceptors on host cells. Individuals homozygous for the ccr5Delta32 polymorphism do not express CCR5 and are protected from infection by CCR5-tropic (R5) virus strains. As an approach to inactivating CCR5, we introduced CCR5 specific zinc-finger nucleases into human CD4+ T cells prior to adoptive transfer, but the need to protect cells from virus strains that use CXCR4 (X4) in place of or in addition to CCR5 (R5X4) remains. Here we describe engineering a pair of zinc finger nucleases that, when introduced into human T cells, efficiently disrupt cxcr4 by cleavage and error-prone non-homologous DNA end joining. The resulting cells proliferated normally and were resistant to infection by X4-tropic HIV-1 strains. CXCR4 could also be inactivated in ccr5Delta32 CD4+ T cells, and we show that such cells were resistant to all strains of HIV-1 tested. Loss of CXCR4 also provided protection from X4 HIV-1 in a humanized mouse model, though this protection was lost over time due to the emergence of R5-tropic viral mutants. These data suggest that CXCR4-specific ZFNs may prove useful in establishing resistance to CXCR4-tropic HIV for autologous transplant in HIV-infected individuals. PMID- 21533218 TI - A ChIP-Seq benchmark shows that sequence conservation mainly improves detection of strong transcription factor binding sites. AB - BACKGROUND: Transcription factors are important controllers of gene expression and mapping transcription factor binding sites (TFBS) is key to inferring transcription factor regulatory networks. Several methods for predicting TFBS exist, but there are no standard genome-wide datasets on which to assess the performance of these prediction methods. Also, it is believed that information about sequence conservation across different genomes can generally improve accuracy of motif-based predictors, but it is not clear under what circumstances use of conservation is most beneficial. RESULTS: Here we use published ChIP-seq data and an improved peak detection method to create comprehensive benchmark datasets for prediction methods which use known descriptors or binding motifs to detect TFBS in genomic sequences. We use this benchmark to assess the performance of five different prediction methods and find that the methods that use information about sequence conservation generally perform better than simpler motif-scanning methods. The difference is greater on high-affinity peaks and when using short and information-poor motifs. However, if the motifs are specific and information-rich, we find that simple motif-scanning methods can perform better than conservation-based methods. CONCLUSIONS: Our benchmark provides a comprehensive test that can be used to rank the relative performance of transcription factor binding site prediction methods. Moreover, our results show that, contrary to previous reports, sequence conservation is better suited for predicting strong than weak transcription factor binding sites. PMID- 21533215 TI - Human cytomegalovirus IE1 protein elicits a type II interferon-like host cell response that depends on activated STAT1 but not interferon-gamma. AB - Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-gamma and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-gamma responsive promoters. However, neither synthesis nor secretion of IFN-gamma or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity. PMID- 21533219 TI - An evolutionary genomic approach to identify genes involved in human birth timing. AB - Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition. PMID- 21533220 TI - Aspects of benthic decapod diversity and distribution from rocky nearshore habitat at geographically widely dispersed sites. AB - Relationships of diversity, distribution and abundance of benthic decapods in intertidal and shallow subtidal waters to 10 m depth are explored based on data obtained using a standardized protocol of globally-distributed samples. Results indicate that decapod species richness overall is low within the nearshore, typically ranging from one to six taxa per site (mean = 4.5). Regionally the Gulf of Alaska decapod crustacean community structure was distinguishable by depth, multivariate analysis indicating increasing change with depth, where assemblages of the high and mid tide, low tide and 1 m, and 5 and 10 m strata formed three distinct groups. Univariate analysis showed species richness increasing from the high intertidal zone to 1 m subtidally, with distinct depth preferences among the 23 species. A similar depth trend but with peak richness at 5 m was observed when all global data were combined. Analysis of latitudinal trends, confined by data limitations, was equivocal on a global scale. While significant latitudinal differences existed in community structure among ecoregions, a semi-linear trend in changing community structure from the Arctic to lower latitudes did not hold when including tropical results. Among boreal regions the Canadian Atlantic was relatively species poor compared to the Gulf of Alaska, whereas the Caribbean and Sea of Japan appeared to be species hot spots. While species poor, samples from the Canadian Atlantic were the most diverse at the higher infraordinal level. Linking 11 environmental variables available for all sites to the best fit family based biotic pattern showed a significant relationship, with the single best explanatory variable being the level of organic pollution and the best combination overall being organic pollution and primary productivity. While data limitations restrict conclusions in a global context, results are seen as a first cut contribution useful in generating discussion and more in-depth work in the still poorly understood field of biodiversity distribution. PMID- 21533221 TI - Genome analysis reveals interplay between 5'UTR introns and nuclear mRNA export for secretory and mitochondrial genes. AB - In higher eukaryotes, messenger RNAs (mRNAs) are exported from the nucleus to the cytoplasm via factors deposited near the 5' end of the transcript during splicing. The signal sequence coding region (SSCR) can support an alternative mRNA export (ALREX) pathway that does not require splicing. However, most SSCR containing genes also have introns, so the interplay between these export mechanisms remains unclear. Here we support a model in which the furthest upstream element in a given transcript, be it an intron or an ALREX-promoting SSCR, dictates the mRNA export pathway used. We also experimentally demonstrate that nuclear-encoded mitochondrial genes can use the ALREX pathway. Thus, ALREX can also be supported by nucleotide signals within mitochondrial-targeting sequence coding regions (MSCRs). Finally, we identified and experimentally verified novel motifs associated with the ALREX pathway that are shared by both SSCRs and MSCRs. Our results show strong correlation between 5' untranslated region (5'UTR) intron presence/absence and sequence features at the beginning of the coding region. They also suggest that genes encoding secretory and mitochondrial proteins share a common regulatory mechanism at the level of mRNA export. PMID- 21533222 TI - A biomimetic membrane device that modulates the excessive inflammatory response to sepsis. AB - OBJECTIVE: Septic shock has a clinical mortality rate approaching fifty percent. The major clinical manifestations of sepsis are due to the dysregulation of the host's response to infection rather than the direct consequences of the invading pathogen. Central to this initial immunologic response is the activation of leukocytes and microvascular endothelium resulting in cardiovascular instability, lung injury and renal dysfunction. Due to the primary role of leukocyte activation in the sepsis syndrome, a synthetic biomimetic membrane, called a selective cytopheretic device (SCD), was developed to bind activated leukocytes. The incorporation of the SCD along an extracorporeal blood circuit coupled with regional anticoagulation with citrate to lower blood ionized calcium was devised to modulate leukocyte activation in sepsis. DESIGN: Laboratory investigation. SETTING: University of Michigan Medical School. SUBJECTS: Pigs weighing 30-35 kg. INTERVENTIONS: To assess the effect of the SCD in septic shock, pigs were administered 30*10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in an extracorporeal circuit containing SCD. MEASUREMENTS AND MAIN RESULTS: In this animal model, the SCD with citrate compared to control groups without the SCD or with heparin anticoagulation ameliorated the cardiovascular instability and lung sequestration of activated leukocytes, reduced renal dysfunction and improved survival time compared to various control groups. This effect was associated with minimal elevations of systemic circulating neutrophil activation. CONCLUSIONS: These preclinical studies along with two favorable exploratory clinical trials form the basis of an FDA-approved investigational device exemption for a pivotal multicenter, randomized control trial currently underway. PMID- 21533223 TI - Oxidative stress accumulates in adipose tissue during aging and inhibits adipogenesis. AB - Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G(1)->S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction. PMID- 21533224 TI - Delineation of stage specific expression of Plasmodium falciparum EBA-175 by biologically functional region II monoclonal antibodies. AB - BACKGROUND: The malaria parasite Plasmodium falciparum EBA-175 binds its receptor sialic acids on glycophorin A when invading erythrocytes. The receptor-binding region (RII) contains two cysteine-rich domains with similar cysteine motifs (F1 and F2). Functional relationships between F1 and F2 domains and characterization of EBA-175 were studied using specific monoclonal antibodies (mAbs) against these domains. METHODS AND FINDINGS: Five mAbs specific for F1 or F2 were generated. Three mAbs specific for F2 potently blocked binding of EBA-175 to erythrocytes, and merozoite invasion of erythrocytes (IC(50) 10 to 100 ug/ml IgG in growth inhibition assays). A mAb specific for F1 blocked EBA-175 binding and merozoite invasion less effectively. The difference observed between the IC(50) of F1 and F2 mAbs was not due to differing association and disassociation rates as determined by surface plasmon resonance. Four of the mAbs recognized conformation dependent epitopes within F1 or F2. Used in combination, F1 and F2 mAbs blocked the binding of native EBA-175 to erythrocytes and inhibited parasite invasion synergistically in vitro. MAb R217, the most potent, did not recognize sporozoites, 3-day hepatocyte stage parasites, nor rings, trophozoites, gametocytes, retorts, ookinetes, and oocysts but recognized 6-day hepatocyte stage parasites, and schizonts. Even though efficient at blocking binding to erythrocytes and inhibiting invasion into erythrocytes, MAb R217 did not inhibit sporozoite invasion and development in hepatocytes in vitro. CONCLUSIONS: The role of the F1 and F2 domains in erythrocyte invasion and binding was elucidated with mAbs. These mAbs interfere with native EBA-175 binding to erythrocyte in a synergistic fashion. The stage specific expression of EBA-175 showed that the primary focus of activity was the merozoite stage. A recombinant RII protein vaccine consisting of both F1 and F2 domains that could induce synergistic activity should be optimal for induction of antibody responses that interfere with merozoite invasion of erythrocytes. PMID- 21533225 TI - Novel evolved immunoglobulin (Ig)-binding molecules enhance the detection of IgM against hepatitis C virus. AB - Detection of specific antibodies against hepatitis C virus (HCV) is the most widely available test for viral diagnosis and monitoring of HCV infections. However, narrowing the serologic window of anti-HCV detection by enhancing anti HCV IgM detection has remained to be a problem. Herein, we used LD5, a novel evolved immunoglobulin-binding molecule (NEIBM) with a high affinity for IgM, to develop a new anti-HCV enzyme-linked immunosorbent assay (ELISA) using horseradish peroxidase-labeled LD5 (HRP-LD5) as the conjugated enzyme complex. The HRP-LD5 assay showed detection efficacy that is comparable with two kinds of domestic diagnostic kits and the Abbott 3.0 kit when tested against the national reference panel. Moreover, the HRP-LD5 assay showed a higher detection rate (55.9%, 95% confidence intervals (95% CI) 0.489, 0.629) than that of a domestic diagnostic ELISA kit (Chang Zheng) (53.3%, 95% CI 0.463, 0.603) in 195 hemodialysis patient serum samples. Five serum samples that were positive using the HRP-LD5 assay and negative with the conventional anti-HCV diagnostic ELISA kits were all positive for HCV RNA, and 4 of them had detectable antibodies when tested with the established anti-HCV IgM assay. An IgM confirmation study revealed the IgM reaction nature of these five serum samples. These results demonstrate that HRP-LD5 improved anti-HCV detection by enhancing the detection of anti-HCV IgM, which may have potential value for the early diagnosis and screening of hepatitis C and other infectious diseases. PMID- 21533226 TI - Reprogramming of embryonic human fibroblasts into fetal hematopoietic progenitors by fusion with human fetal liver CD34+ cells. AB - Experiments with somatic cell nuclear transfer, inter-cellular hybrid formation_ENREF_3, and ectopic expression of transcription factors have clearly demonstrated that cell fate can be dramatically altered by changing the epigenetic state of cell nuclei. Here we demonstrate, using chemical fusion, direct reprogramming of the genome of human embryonic fibroblasts (HEF) into the state of human fetal liver hFL CD34+ (hFL) hematopoietic progenitors capable of proliferating and differentiating into multiple hematopoietic lineages. We show that hybrid cells retain their ploidy and can differentiate into several hematopoietic lineages. Hybrid cells follow transcription program of differentiating hFL cells as shown by genome-wide transcription profiling. Using whole-genome single nucleotide polymorphism (SNP) profiling of both donor genomes we demonstrate reprogramming of HEF genome into the state of hFL hematopoietic progenitors. Our results prove that it is possible to convert the fetal somatic cell genome into the state of fetal hematopoietic progenitors by fusion. This suggests a possibility of direct reprogramming of human somatic cells into tissue specific progenitors/stem cells without going all the way back to the embryonic state. Direct reprogramming of terminally differentiated cells into the tissue specific progenitors will likely prove useful for the development of novel cell therapies. PMID- 21533227 TI - Tissue-autonomous function of Drosophila seipin in preventing ectopic lipid droplet formation. AB - Obesity is characterized by accumulation of excess body fat, while lipodystrophy is characterized by loss or absence of body fat. Despite their opposite phenotypes, these two conditions both cause ectopic lipid storage in non-adipose tissues, leading to lipotoxicity, which has health-threatening consequences. The exact mechanisms underlying ectopic lipid storage remain elusive. Here we report the analysis of a Drosophila model of the most severe form of human lipodystrophy, Berardinelli-Seip Congenital Lipodystrophy 2, which is caused by mutations in the BSCL2/Seipin gene. In addition to reduced lipid storage in the fat body, dSeipin mutant flies accumulate ectopic lipid droplets in the salivary gland, a non-adipose tissue. This phenotype was suppressed by expressing dSeipin specifically within the salivary gland. dSeipin mutants display synergistic genetic interactions with lipogenic genes in the formation of ectopic lipid droplets. Our data suggest that dSeipin may participate in phosphatidic acid metabolism and subsequently down-regulate lipogenesis to prevent ectopic lipid droplet formation. In summary, we have demonstrated a tissue-autonomous role of dSeipin in ectopic lipid storage in lipodystrophy. PMID- 21533228 TI - Early growth response gene-2 (Egr-2) regulates the development of B and T cells. AB - BACKGROUND: Understanding of how transcription factors are involved in lymphocyte development still remains a challenge. It has been shown that Egr-2 deficiency results in impaired NKT cell development and defective positive selection of T cells. Here we investigated the development of T, B and NKT cells in Egr-2 transgenic mice and the roles in the regulation of distinct stages of B and T cell development. METHODS AND FINDINGS: The expression of Egr1, 2 and 3 were analysed at different stages of T and B cell development by RT-PCT and results showed that the expression was strictly regulated at different stages. Forced expression of Egr-2 in CD2(+) lymphocytes resulted in a severe reduction of CD4(+)CD8(+) (DP) cells in thymus and pro-B cells in bone marrow, which was associated with reduced expression of Notch1 in ISP thymocytes and Pax5 in pro-B cells, suggesting that retraction of Egr-2 at the ISP and pro-B cell stages is important for the activation of lineage differentiation programs. In contrast to reduction of DP and pro-B cells, Egr-2 enhanced the maturation of DP cells into single positive (SP) T and NKT cells in thymus, and immature B cells into mature B cells in bone marrow. CONCLUSIONS: Our results demonstrate that Egr-2 expressed in restricted stages of lymphocyte development plays a dynamic, but similar role for the development of T, NKT and B cells. PMID- 21533229 TI - Pre-existing adenovirus immunity modifies a complex mixed Th1 and Th2 cytokine response to an Ad5/HIV-1 vaccine candidate in humans. AB - The results of the recent Step Study highlight a need to clarify the effects of pre-existing natural immunity to a vaccine vector on vaccine-induced T-cell responses. To investigate this interaction, we examined the relationship between pre-existing Ad5 immunity and T-cell cytokine response profiles in healthy, HIV uninfected recipients of MRKAd5 HIV-1 gag vaccine (HVTN 050, ClinicalTrials.gov #NCT00849732). Participants were grouped by baseline Ad5 neutralizing antibody titer as either Ad5-seronegative (titer <=18; n = 36) or Ad5-seropositive (titer >200; n = 34). Samples from vaccine recipients were analyzed for immune responses to either HIV-1 Gag peptide pools or Ad5 empty vector using an ex vivo assay that measures thirty cytokines in the absence of long-term culture. The overall profiles of cytokine responses to Gag and Ad5 had similar combinations of induced Th1- and Th2-type cytokines, including IFN-gamma, IL-2, TNF-alpha, IP-10, IL-13, and IL-10, although the Ad5-specific responses were uniformly higher than the Gag specific responses (p<0.0001 for 9 out of 11 significantly expressed analytes). At the peak response time point, PBMC from Ad5-seronegative vaccinees secreted significantly more IP-10 in response to Gag (p = 0.008), and significantly more IP-10 (p = 0.0009), IL-2 (p = 0.006) and IL-10 (p = 0.05) in response to Ad5 empty vector than PBMC from Ad5-seropositive vaccinees. Additionally, similar responses to the Ad5 vector prior to vaccination were observed in almost all subjects, regardless of Ad5 neutralizing antibody status, and the levels of secreted IFN-gamma, IL-10, IL-1Ra and GM-CSF were blunted following vaccination. The cytokine response profile of Gag-specific T cells mirrored the Ad5-specific response present in all subjects before vaccination, and included a number of Th1 and Th2-associated cytokines not routinely assessed in current vaccine trials, such as IP-10, IL-10, IL-13, and GM-CSF. Together, these results suggest that vector-specific humoral responses may reduce vaccine-induced T-cell responses by previously undetected mechanisms. PMID- 21533230 TI - IL-12Rbeta1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco, and Turkey. AB - BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rbeta1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of principle that tuberculosis in otherwise healthy children may result from single gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rbeta1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rbeta1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rbeta1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-gamma is an effective treatment for mycobacterial infections in IL-12Rbeta1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity. PMID- 21533232 TI - Survival with treated and well-controlled blood pressure: findings from a prospective cohort study. AB - AIM: To compare survival and incident cardiovascular disease between normotensive, untreated hypertensive, treated and poorly-controlled hypertensive and treated and well-controlled hypertensive adults. METHODS AND RESULTS: Data from the British Regional Heart Study (men) and British Women's Heart and Health Study (women) were used (N = 6476). Blood pressure and treatment were assessed at baseline (1998-2001) when participants were aged 60-79 years and participants were followed up for a median of 8 years. Date and cause of death were obtained from death certificates and non-fatal cardiovascular disease events were obtained from repeat detailed medical record reviews. Of the whole cohort 52% of women and 49% of men had untreated hypertension and a further 22% and 18%, respectively, had poorly treated hypertension. Just 3% of women and 4% of men had treated and well controlled hypertension and 23% and 29%, respectively, were normotensive. Compared to normotensive individuals, incident cardiovascular disease (fatal and non-fatal) was increased in those with poorly-controlled hypertension (Hazard Ratio (HR): 1.88; 95%CI: 1.53, 2.30), those with untreated hypertension (HR 1.46; 95%CI 1.22, 1.75) and those who were well-controlled hypertension (HR 1.38; 95%CI 0.94, 2.03). Adjustment for baseline differences in mean blood pressure between the groups resulted in attenuation of the increased risk in the poorly-controlled (1.52 (1.18, 1.97) and untreated groups (1.21 (0.97, 1.52), but did not change the association in the well-controlled group. All-cause mortality was also increased in all three hypertension groups but estimates were imprecise with wide confidence intervals. CONCLUSIONS: Half of women and men aged 60-79 in Britain had untreated hypertension and only a very small proportion of those with diagnosed and treated hypertension were well controlled. Those with hypertension, irrespective of whether this was treated and controlled or not, were at greater risk of future cardiovascular disease than those who are normotensive. PMID- 21533231 TI - Prediction of antimicrobial peptides based on sequence alignment and feature selection methods. AB - Antimicrobial peptides (AMPs) represent a class of natural peptides that form a part of the innate immune system, and this kind of 'nature's antibiotics' is quite promising for solving the problem of increasing antibiotic resistance. In view of this, it is highly desired to develop an effective computational method for accurately predicting novel AMPs because it can provide us with more candidates and useful insights for drug design. In this study, a new method for predicting AMPs was implemented by integrating the sequence alignment method and the feature selection method. It was observed that, the overall jackknife success rate by the new predictor on a newly constructed benchmark dataset was over 80.23%, and the Mathews correlation coefficient is 0.73, indicating a good prediction. Moreover, it is indicated by an in-depth feature analysis that the results are quite consistent with the previously known knowledge that some amino acids are preferential in AMPs and that these amino acids do play an important role for the antimicrobial activity. For the convenience of most experimental scientists who want to use the prediction method without the interest to follow the mathematical details, a user-friendly web-server is provided at http://amp.biosino.org/. PMID- 21533233 TI - Do zebra finch parents fail to recognise their own offspring? AB - Individual recognition systems require the sender to be individually distinctive and the receiver to be able to perceive differences between individuals and react accordingly. Many studies have demonstrated that acoustic signals of almost any species contain individualized information. However, fewer studies have tested experimentally if those signals are used for individual recognition by potential receivers. While laboratory studies using zebra finches have shown that fledglings recognize their parents by their "distance call", mutual recognition using the same call type has not been demonstrated yet. In a laboratory study with zebra finches, we first quantified between-individual acoustic variation in distance calls of fledglings. In a second step, we tested recognition of fledgling calls by parents using playback experiments. With a discriminant function analysis, we show that individuals are highly distinctive and most measured parameters show very high potential to encode for individuality. The response pattern of zebra finch parents shows that they do react to calls of fledglings, however they do not distinguish between own and unfamiliar offspring, despite individual distinctiveness. This finding is interesting in light of the observation of a high percentage of misdirected feedings in our communal breeding aviaries. Our results demonstrate the importance of adopting a receiver's perspective and suggest that variation in fledgling contact calls might not be used in individual recognition of offspring. PMID- 21533234 TI - Multiscale modelling of vascular tumour growth in 3D: the roles of domain size and boundary conditions. AB - We investigate a three-dimensional multiscale model of vascular tumour growth, which couples blood flow, angiogenesis, vascular remodelling, nutrient/growth factor transport, movement of, and interactions between, normal and tumour cells, and nutrient-dependent cell cycle dynamics within each cell. In particular, we determine how the domain size, aspect ratio and initial vascular network influence the tumour's growth dynamics and its long-time composition. We establish whether it is possible to extrapolate simulation results obtained for small domains to larger ones, by constructing a large simulation domain from a number of identical subdomains, each subsystem initially comprising two parallel parent vessels, with associated cells and diffusible substances. We find that the subsystem is not representative of the full domain and conclude that, for this initial vessel geometry, interactions between adjacent subsystems contribute to the overall growth dynamics. We then show that extrapolation of results from a small subdomain to a larger domain can only be made if the subdomain is sufficiently large and is initialised with a sufficiently complex vascular network. Motivated by these results, we perform simulations to investigate the tumour's response to therapy and show that the probability of tumour elimination in a larger domain can be extrapolated from simulation results on a smaller domain. Finally, we demonstrate how our model may be combined with experimental data, to predict the spatio-temporal evolution of a vascular tumour. PMID- 21533235 TI - Caucasian infants scan own- and other-race faces differently. AB - Young infants are known to prefer own-race faces to other race faces and recognize own-race faces better than other-race faces. However, it is entirely unclear as to whether infants also attend to different parts of own- and other race faces differently, which may provide an important clue as to how and why the own-race face recognition advantage emerges so early. The present study used eye tracking methodology to investigate whether 6- to 10-month-old Caucasian infants (N = 37) have differential scanning patterns for dynamically displayed own- and other-race faces. We found that even though infants spent a similar amount of time looking at own- and other-race faces, with increased age, infants increasingly looked longer at the eyes of own-race faces and less at the mouths of own-race faces. These findings suggest experience-based tuning of the infant's face processing system to optimally process own-race faces that are different in physiognomy from other-race faces. In addition, the present results, taken together with recent own- and other-race eye tracking findings with infants and adults, provide strong support for an enculturation hypothesis that East Asians and Westerners may be socialized to scan faces differently due to each culture's conventions regarding mutual gaze during interpersonal communication. PMID- 21533236 TI - Association of Mycobacterium avium subsp. paratuberculosis with multiple sclerosis in Sardinian patients. AB - Mycobacterium avium subsp. paratuberculosis (MAP) infection is highly spread in the ruminant herds of Sardinia, in the Western Mediterranean. The objective of this study was to investigate prevalence of MAP infection in association with Multiple Sclerosis (MS) using clinical specimen from patients and controls. We analyzed samples for the presence of MAP specific DNA and to demonstrate humoral response to a MAP protein (MAP2694), a predicted homologue of the T-cell receptor gamma-chain/complement component 1 of the host. We found presence of MAP DNA in 42% of the MS patients and an extremely significant humoral immune response revealed by the MS patients against the MAP protein. In our opinion, this is the first report that significantly associates MAP infection with MS. Further studies will be required to confirm if MAP could be one of the triggers of MS, according to the molecular mimicry theory, in susceptible (and genetically at risk) individuals. PMID- 21533237 TI - Binge-pattern alcohol exposure during puberty induces long-term changes in HPA axis reactivity. AB - Adolescence is a dynamic and important period of brain development however, little is known about the long-term neurobiological consequences of alcohol consumption during puberty. Our previous studies showed that binge-pattern ethanol (EtOH) treatment during pubertal development negatively dysregulated the responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis, as manifested by alterations in corticotrophin-releasing hormone (CRH), arginine vasopressin (AVP), and corticosterone (CORT) during this time period. Thus, the primary goal of this study was to determine whether these observed changes in important central regulators of the stress response were permanent or transient. In this study, juvenile male Wistar rats were treated with a binge-pattern EtOH treatment paradigm or saline alone for 8 days. The animals were left undisturbed until adulthood when they received a second round of treatments consisting of saline alone, a single dose of EtOH, or a second binge-pattern treatment paradigm. The results showed that pubertal binge-pattern EtOH exposure induced striking long lasting alterations of many HPA axis parameters. Overall, our data provide strong evidence that binge-pattern EtOH exposure during pubertal maturation has long term detrimental effects for the healthy development of the HPA axis. PMID- 21533238 TI - Methicillin-susceptible Staphylococcus aureus as a predominantly healthcare associated pathogen: a possible reversal of roles? AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) strains have become common causes of skin and soft tissue infections (SSTI) among previously healthy people, a role of methicillin-susceptible (MSSA) isolates before the mid 1990s. We hypothesized that, as MRSA infections became more common among S. aureus infections in the community, perhaps MSSA infections had become more important as a cause of healthcare-associated infection. METHODS: We compared patients, including children and adults, with MRSA and MSSA infections at the University of Chicago Medical Center (UCMC) from all clinical units from July 1, 2004-June 30, 2005; we also compared the genotypes of the MRSA and MSSA infecting bacterial strains. RESULTS: Compared with MRSA patients, MSSA patients were more likely on bivariate analysis to have bacteremia, endocarditis, or sepsis (p = 0.03), to be an adult (p = 0.005), to be in the intensive care unit (21.9% vs. 15.6%) or another inpatient unit (45.6% vs. 40.7%) at the time of culture. MRSA (346/545) and MSSA (76/114) patients did not differ significantly in the proportion classified as HA-S. aureus by the CDC CA-MRSA definition (p = 0.5). The genetic backgrounds of MRSA and MSSA multilocus sequence type (ST) 1, ST5, ST8, ST30, and ST59 comprised in combination 94.5% of MRSA isolates and 50.9% of MSSA isolates. By logistic regression, being cared for in the Emergency Department (OR 4.6, CI 1.5-14.0, p = 0.008) was associated with MRSA infection. CONCLUSION: Patients with MSSA at UCMC have characteristics consistent with a health-care-associated infection more often than do patients with MRSA; a possible role reversal has occurred for MSSA and MRSA strains. Clinical MSSA and MRSA strains shared genotype backgrounds. PMID- 21533239 TI - A topological framework for the computation of the HOMFLY polynomial and its application to proteins. AB - Polymers can be modeled as open polygonal paths and their closure generates knots. Knotted proteins detection is currently achieved via high-throughput methods based on a common framework insensitive to the handedness of knots. Here we propose a topological framework for the computation of the HOMFLY polynomial, an handedness-sensitive invariant. Our approach couples a multi-component reduction scheme with the polynomial computation. After validation on tabulated knots and links the framework was applied to the entire Protein Data Bank along with a set of selected topological checks that allowed to discard artificially entangled structures. This led to an up-to-date table of knotted proteins that also includes two newly detected right-handed trefoil knots in recently deposited protein structures. The application range of our framework is not limited to proteins and it can be extended to the topological analysis of biological and synthetic polymers and more generally to arbitrary polygonal paths. PMID- 21533240 TI - A dopa decarboxylase modulating the immune response of scallop Chlamys farreri. AB - BACKGROUND: Dopa decarboxylase (DDC) is a pyridoxal 5-phosphate (PLP)-dependent enzyme that catalyzes the decarboxylation of L-Dopa to dopamine, and involved in complex neuroendocrine-immune regulatory network. The function for DDC in the immunomodulation remains unclear in invertebrate. METHODOLOGY: The full-length cDNA encoding DDC (designated CfDDC) was cloned from mollusc scallop Chlamys farreri. It contained an open reading frame encoding a polypeptide of 560 amino acids. The CfDDC mRNA transcripts could be detected in all the tested tissues, including the immune tissues haemocytes and hepatopancreas. After scallops were treated with LPS stimulation, the mRNA expression level of CfDDC in haemocytes increased significantly (5.5-fold, P<0.05) at 3 h and reached the peak at 12 h (9.8-fold, P<0.05), and then recovered to the baseline level. The recombinant protein of CfDDC (rCfDDC) was expressed in Escherichia coli BL21 (DE3)-Transetta, and 1 mg rCfDDC could catalyze the production of 1.651+/-0.22 ng dopamine within 1 h in vitro. When the haemocytes were incubated with rCfDDC-coated agarose beads, the haemocyte encapsulation to the beads was increased significantly from 70% at 6 h to 93% at 24 h in vitro in comparison with that in the control (23% at 6 h to 25% at 24 h), and the increased haemocyte encapsulation was repressed by the addition of rCfDDC antibody (which is acquired via immunization 6-week old rats with rCfDDC). After the injection of DDC inhibitor methyldopa, the ROS level in haemocytes of scallops was decreased significantly to 0.41-fold (P<0.05) of blank group at 12 h and 0.47-fold (P<0.05) at 24 h, respectively. CONCLUSIONS: These results collectively suggested that CfDDC, as a homologue of DDC in scallop, modulated the immune responses such as haemocytes encapsulation as well as the ROS level through its catalytic activity, functioning as an indispensable immunomodulating enzyme in the neuroendocrine-immune regulatory network of mollusc. PMID- 21533241 TI - Shift work in nurses: contribution of phenotypes and genotypes to adaptation. AB - BACKGROUND: Daily cycles of sleep/wake, hormones, and physiological processes are often misaligned with behavioral patterns during shift work, leading to an increased risk of developing cardiovascular/metabolic/gastrointestinal disorders, some types of cancer, and mental disorders including depression and anxiety. It is unclear how sleep timing, chronotype, and circadian clock gene variation contribute to adaptation to shift work. METHODS: Newly defined sleep strategies, chronotype, and genotype for polymorphisms in circadian clock genes were assessed in 388 hospital day- and night-shift nurses. RESULTS: Night-shift nurses who used sleep deprivation as a means to switch to and from diurnal sleep on work days (~25%) were the most poorly adapted to their work schedule. Chronotype also influenced efficacy of adaptation. In addition, polymorphisms in CLOCK, NPAS2, PER2, and PER3 were significantly associated with outcomes such as alcohol/caffeine consumption and sleepiness, as well as sleep phase, inertia and duration in both single- and multi-locus models. Many of these results were specific to shift type suggesting an interaction between genotype and environment (in this case, shift work). CONCLUSIONS: Sleep strategy, chronotype, and genotype contribute to the adaptation of the circadian system to an environment that switches frequently and/or irregularly between different schedules of the light dark cycle and social/workplace time. This study of shift work nurses illustrates how an environmental "stress" to the temporal organization of physiology and metabolism can have behavioral and health-related consequences. Because nurses are a key component of health care, these findings could have important implications for health-care policy. PMID- 21533242 TI - Diet-independent remodeling of cellular membranes precedes seasonally changing body temperature in a hibernator. AB - Polyunsaturated fatty acids (PUFA) have a multitude of health effects. Their incorporation into membrane phospholipids (PL) is generally believed to depend directly on dietary influx. PL influence transmembrane protein activity and thus can compensate temperature effects; e.g. PL n-6 PUFA are thought to stabilize heart function at low body temperature (T(b)), whereas long chain (>C18) n-3 PUFA may boost oxidative capacity. We found substantial remodeling of membranes in free-living alpine marmots which was largely independent of direct dietary supply. Organ PL n-6 PUFA and n-6 to n-3 ratios were highest at onset and end of hibernation after rapid increases during a brief transitional period prior to hibernation. In contrast, longer chain PL n-3 PUFA content was low at end of summer but maximal at end of hibernation. After termination of hibernation in spring, these changes in PL composition were rapidly reversed. Our results demonstrate selective trafficking of PUFA within the body, probably governed by a circannual endogenous rhythm, as hibernating marmots were in winter burrows isolated for seven months from food and external cues signaling the approaching spring. High concentrations of PL n-6 PUFA throughout hibernation are in line with their hypothesized function of boosting SERCA 2a activity at low T(b). Furthermore, we found increasing rate of rewarming from torpor during winter indicating increasing oxidative capacity that could be explained by the accumulation of long-chain PL n-3 PUFA. It may serve to minimize the time necessary for rewarming despite the increasing temperature range to be covered, because rewarming is a period of highest metabolic rate and hence production of reactive oxygen species. Considering the importance of PUFA for health our results may have important biomedical implications, as seasonal changes of T(b) and associated remodeling of membranes are not restricted to hibernators but presumably common among endothermic organisms. PMID- 21533243 TI - Porphyromonas gingivalis participates in pathogenesis of human abdominal aortic aneurysm by neutrophil activation. Proof of concept in rats. AB - BACKGROUND: Abdominal Aortic Aneurysms (AAAs) represent a particular form of atherothrombosis where neutrophil proteolytic activity plays a major role. We postulated that neutrophil recruitment and activation participating in AAA growth may originate in part from repeated episodes of periodontal bacteremia. METHODS AND FINDINGS: Our results show that neutrophil activation in human AAA was associated with Neutrophil Extracellular Trap (NET) formation in the IntraLuminal Thrombus, leading to the release of cell-free DNA. Human AAA samples were shown to contain bacterial DNA with high frequency (11/16), and in particular that of Porphyromonas gingivalis (Pg), the most prevalent pathogen involved in chronic periodontitis, a common form of periodontal disease. Both DNA reflecting the presence of NETs and antibodies to Pg were found to be increased in plasma of patients with AAA. Using a rat model of AAA, we demonstrated that repeated injection of Pg fostered aneurysm development, associated with pathological characteristics similar to those observed in humans, such as the persistence of a neutrophil-rich luminal thrombus, not observed in saline-injected rats in which a healing process was observed. CONCLUSIONS: Thus, the control of periodontal disease may represent a therapeutic target to limit human AAA progression. PMID- 21533244 TI - Proteomic-based identification of CD4-interacting proteins in human primary macrophages. AB - BACKGROUND: Human macrophages (Mphi) express low levels of CD4 glycoprotein, which is constitutively recycled, and 40-50% of its localization is intracellular at steady-state. Although CD4-interacting proteins in lymphoid cells are well characterised, little is known about the CD4 protein interaction-network in human Mphi, which notably lack LCK, a Src family protein tyrosine kinase believed to stabilise CD4 at the surface of T cells. As CD4 is the main cellular receptor used by HIV-1, knowledge of its molecular interactions is important for the understanding of viral infection strategies. METHODOLOGY/PRINCIPAL FINDINGS: We performed large-scale anti-CD4 immunoprecipitations in human primary Mphi followed by high-resolution mass spectrometry analysis to elucidate the protein interaction-network involved in induced CD4 internalization and degradation. Proteomic analysis of CD4 co-immunoisolates in resting Mphi showed CD4 association with a range of proteins found in the cellular cortex, membrane rafts and components of clathrin-adaptor proteins, whereas in induced internalization and degradation CD4 is associated with components of specific signal transduction, transport and the proteasome. CONCLUSIONS/SIGNIFICANCE: This is the first time that the anti-CD4 co-immunoprecipitation sub-proteome has been analysed in human primary Mphi. Our data have identified important Mphi cell surface CD4-interacting proteins, as well as regulatory proteins involved in internalization and degradation. The data give valuable insights into the molecular pathways involved in the regulation of CD4 expression in Mphi and provide candidates/targets for further biochemical studies. PMID- 21533245 TI - RNA captor: a tool for RNA characterization. AB - BACKGROUND: In the genome era, characterizing the structure and the function of RNA molecules remains a major challenge. Alternative transcripts and non-protein coding genes are poorly recognized by the current genome-annotation algorithms and efficient tools are needed to isolate the less-abundant or stable RNAs. RESULTS: A universal RNA-tagging method using the T4 RNA ligase 2 and special adapters is reported. Based on this system, protocols for RACE PCR and full length cDNA library construction have been developed. The RNA tagging conditions were thoroughly optimized and compared to previous methods by using a biochemical oligonucleotide tagging assay and RACE PCRs on a range of transcripts. In addition, two large-scale full-length cDNA inventories relying on this method are presented. CONCLUSION: The RNA Captor is a straightforward and accessible protocol. The sensitivity of this approach was shown to be higher compared to previous methods, and applicable on messenger RNAs, non-protein-coding RNAs, transcription-start sites and microRNA-directed cleavage sites of transcripts. This strategy could also be used to study other classes of RNA and in deep sequencing experiments. PMID- 21533247 TI - Non-disruptive tactics of suppression are superior in countering terrorism, insurgency, and financial panics. AB - BACKGROUND: Suppressing damaging aggregate behaviors such as insurgency, terrorism, and financial panics are important tasks of the state. Each outcome of these aggregate behaviors is an emergent property of a system in which each individual's action depends on a subset of others' actions, given by each individual's network of interactions. Yet there are few explicit comparisons of strategies for suppression, and none that fully incorporate the interdependence of individual behavior. METHODS AND FINDINGS: Here I show that suppression tactics that do not require the removal of individuals from networks of interactions are nearly always more effective than those that do. I find using simulation analysis of a general model of interdependent behavior that the degree to which such less disruptive suppression tactics are superior to more disruptive ones increases in the propensity of individuals to engage in the behavior in question. CONCLUSIONS: Thus, hearts-and-minds approaches are generally more effective than force in counterterrorism and counterinsurgency, and partial insurance is usually a better tactic than gag rules in quelling financial panics. Differences between suppression tactics are greater when individual incentives to support terrorist or insurgent groups, or susceptibilities to financial panic, are higher. These conclusions have utility for policy-makers seeking to end bloody conflicts and prevent financial panics. As the model also applies to mass protest, its conclusions provide insight as well into the likely effects of different suppression strategies undertaken by authoritarian regimes seeking to hold on to power in the face of mass movements seeking to end them. PMID- 21533246 TI - A novel signaling pathway mediated by the nuclear targeting of C-terminal fragments of mammalian Patched 1. AB - BACKGROUND: Patched 1 (Ptc1) is a polytopic receptor protein that is essential for growth and differentiation. Its extracellular domains accept its ligand, Sonic Hedgehog, while the function of its C-terminal intracellular domain is largely obscure. PRINCIPAL FINDINGS: In this study, we stably expressed human Ptc1 protein in HeLa cells and found that it is subjected to proteolytic cleavage at the C-terminus, resulting in the generation of soluble C-terminal fragments. These fragments accumulated in the nucleus, while the N-terminal region of Ptc1 remained in the cytoplasmic membrane fractions. Using an anti-Ptc1 C-terminal domain antibody, we provide conclusive evidence that C-terminal fragments of endogenous Ptc1 accumulate in the nucleus of C3H10T1/2 cells. Similar nuclear accumulation of endogenous C-terminal fragments was observed not only in C3H10T1/2 cells but also in mouse embryonic primary cells. Importantly, the C terminal fragments of Ptc1 modulate transcriptional activity of Gli1. CONCLUSIONS: Although Ptc1 protein was originally thought to be restricted to cell membrane fractions, our findings suggest that its C-terminal fragments can function as an alternative signal transducer that is directly transported to the cell nucleus. PMID- 21533248 TI - Rapid estimation of binding activity of influenza virus hemagglutinin to human and avian receptors. AB - A critical step for avian influenza viruses to infect human hosts and cause epidemics or pandemics is acquisition of the ability of the viral hemagglutinin (HA) to bind to human receptors. However, current global influenza surveillance does not monitor HA binding specificity due to a lack of rapid and reliable assays. Here we report a computational method that uses an effective scoring function to quantify HA-receptor binding activities with high accuracy and speed. Application of this method reveals receptor specificity changes and its temporal relationship with antigenicity changes during the evolution of human H3N2 viruses. The method predicts that two amino acid differences at 222 and 225 between HAs of A/Fujian/411/02 and A/Panama/2007/99 viruses account for their differences in binding to both avian and human receptors; this prediction was verified experimentally. The new computational method could provide an urgently needed tool for rapid and large-scale analysis of HA receptor specificities for global influenza surveillance. PMID- 21533249 TI - Structure-activity determinants in antifungal plant defensins MsDef1 and MtDef4 with different modes of action against Fusarium graminearum. AB - Plant defensins are small cysteine-rich antimicrobial proteins. Their three dimensional structures are similar in that they consist of an alpha-helix and three anti-parallel beta-strands stabilized by four disulfide bonds. Plant defensins MsDef1 and MtDef4 are potent inhibitors of the growth of several filamentous fungi including Fusarium graminearum. However, they differ markedly in their antifungal properties as well as modes of antifungal action. MsDef1 induces prolific hyperbranching of fungal hyphae, whereas MtDef4 does not. Both defensins contain a highly conserved gamma-core motif (GXCX(3-9)C), a hallmark signature present in the disulfide-stabilized antimicrobial peptides, composed of beta2 and beta3 strands and the interposed loop. The gamma-core motifs of these two defensins differ significantly in their primary amino acid sequences and in their net charge. In this study, we have found that the major determinants of the antifungal activity and morphogenicity of these defensins reside in their gamma core motifs. The MsDef1-gamma4 variant in which the gamma-core motif of MsDef1 was replaced by that of MtDef4 was almost as potent as MtDef4 and also failed to induce hyperbranching of fungal hyphae. Importantly, the gamma-core motif of MtDef4 alone was capable of inhibiting fungal growth, but that of MsDef1 was not. The analysis of synthetic gamma-core variants of MtDef4 indicated that the cationic and hydrophobic amino acids were important for antifungal activity. Both MsDef1 and MtDef4 induced plasma membrane permeabilization; however, kinetic studies revealed that MtDef4 was more efficient in permeabilizing fungal plasma membrane than MsDef1. Furthermore, the in vitro antifungal activity of MsDef1, MsDef1-gamma4, MtDef4 and peptides derived from the gamma-core motif of each defensin was not solely dependent on their ability to permeabilize the fungal plasma membrane. The data reported here indicate that the gamma-core motif defines the unique antifungal properties of each defensin and may facilitate de novo design of more potent antifungal peptides. PMID- 21533250 TI - Your flaws are my pain: linking empathy to vicarious embarrassment. AB - People vicariously experience embarrassment when observing others' public pratfalls or etiquette violations. In two consecutive studies we investigated the subjective experience and the neural correlates of vicarious embarrassment for others in a broad range of situations. We demonstrated, first, that vicarious embarrassment was experienced regardless of whether the observed protagonist acted accidentally or intentionally and was aware or unaware that he/she was in an embarrassing situation. Second, using functional magnetic resonance imaging (fMRI), we showed that the anterior cingulate cortex and the left anterior insula, two cortical structures typically involved in vicarious feelings of others' pain, are also strongly implicated in experiencing the 'social pain' for others' flaws and pratfalls. This holds true even for situations that engage protagonists not aware of their current predicament. Importantly, the activity in the anterior cingulate cortex and the left anterior insula positively correlated with individual differences in trait empathy. The present findings establish the empathic process as a fundamental prerequisite for vicarious embarrassment experiences, thus connecting affect and cognition to interpersonal processes."When we are living with people who have a delicate sense of propriety, we are in misery on their account when anything unbecoming is committed. So I always feel for and with Charlotte when a person is tipping his chair. She cannot endure it." [Elective Affinities, J. W. Goethe]. PMID- 21533251 TI - Hrk1 plays both Hog1-dependent and -independent roles in controlling stress response and antifungal drug resistance in Cryptococcus neoformans. AB - The HOG (High Osmolarity Glycerol response) pathway plays a central role in controlling stress response, ergosterol biosynthesis, virulence factor production, and differentiation of Cryptococcus neoformans, which causes fatal fungal meningoencephalitis. Recent transcriptome analysis of the HOG pathway discovered a Hog1-regulated gene (CNAG_00130.2), encoding a putative protein kinase orthologous to Rck1/2 in Saccharomyces cerevisiae and Srk1 in Schizosaccharomyces pombe. Its function is not known in C. neoformans. The present study functionally characterized the role of Hrk1 in C. neoformans. Northern blot analysis confirmed that HRK1 expression depends on the Hog1 MAPK. Similar to the hog1Delta mutant, the hrk1Delta mutant exhibited almost complete resistance to fludioxonil, which triggers glycerol biosynthesis via the HOG pathway. Supporting this, the hrk1Delta mutant showed reduced intracellular glycerol accumulation and swollen cell morphology in response to fludioxonil, further suggesting that Hrk1 works downstream of the HOG pathway. However, Hrk1 also appeared to have Hog1-independent functions. Mutation of HRK1 not only further increased osmosensitivity of the hog1Delta mutant, but also suppressed increased azole-resistance of the hog1Delta mutant in an Erg11-independent manner. Furthermore, unlike the hog1Delta mutant, Hrk1 was not involved in capsule biosynthesis. Hrk1 was slightly involved in melanin production but dispensable for virulence of C. neoformans. These findings suggest that Hrk1 plays both Hog1-dependent and -independent roles in stress and antifungal drug susceptibility and virulence factor production in C. neoformans. Particularly, the finding that inhibition of Hrk1 substantially increases azole drug susceptibility provides a novel strategy for combination antifungal therapy. PMID- 21533252 TI - The rostral migratory stream plays a key role in intranasal delivery of drugs into the CNS. AB - BACKGROUND: The blood brain barrier (BBB) is impermeable to most drugs, impeding the establishment of novel neuroprotective therapies and strategies for many neurological diseases. Intranasal administration offers an alternative path for efficient drug delivery into the CNS. So far, the anatomical structures discussed to be involved in the transport of intranasally administered drugs into the CNS include the trigeminal nerve, olfactory nerve and the rostral migratory stream (RMS), but the relative contributions are debated. METHODS AND FINDINGS: In the present study we demonstrate that surgical transection, and the resulting structural disruption of the RMS, in mice effectively obstructs the uptake of intranasally administered radioligands into the CNS. Furthermore, using a fluorescent cell tracer, we demonstrate that intranasal administration in mice allows agents to be distributed throughout the entire brain, including olfactory bulb, hippocampus, cortex and cerebellum. CONCLUSIONS: This study provides evidence of the vital role the RMS has in the CNS delivery of intranasally administered agents. The identification of the RMS as the major access path for intranasally administered drugs into the CNS may contribute to the development of treatments that are tailored for efficient transport within this structure. Research into the RMS needs to continue to elucidate its limitations, capabilities, mechanisms of transport and potential hazards before we are able to advance this technique into human research. PMID- 21533253 TI - Serum HER2 level measured by dot blot: a valid and inexpensive assay for monitoring breast cancer progression. AB - Human epidermal growth factor receptor 2 (HER2) is one of the most important prognostic and predictive factors for breast cancer patients. Recently, serum HER2 ECD level of patients detected by enzyme-linked immunoabsorbent assay (ELISA) has been shown to predict tumor HER2 status and reveal its association with tumor progression, recurrence and poor prognosis. In this study, we established a new method, dot blot assay, to measure the serum HER2 level in breast cancer patients and further to evaluate the clinical value for monitoring breast cancer progression. We found that the serum HER2 level measured by dot blot assay was significantly correlated with tissue HER2 status in breast cancer patients (P = 0.001), and also significantly correlated with HER2 level measured by ELISA (P = 1.06*10(-11)). Compared with ELISA method, the specificity and sensitivity of dot blot assay were 95.3% and 65.0%, respectively. The serum HER2 levels of patients with grade III or ER-negative were higher than those with grade I-II (P = 0.004) and ER-positive (P = 0.033), respectively. Therefore, the novel dot blot method to detect serum HER2 level is a valid and inexpensive assay with potential application in monitoring breast cancer progression in clinical situations. PMID- 21533254 TI - Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. AB - To investigate how cholinergic systems regulate aspects of the sleep disorder narcolepsy, we video-monitored mice lacking both orexin (hypocretin) receptors (double knockout; DKO mice) while pharmacologically altering cholinergic transmission. Spontaneous behavioral arrests in DKO mice were highly similar to those reported in orexin-deficient mice and were never observed in wild-type (WT) mice. A survival analysis revealed that arrest lifetimes were exponentially distributed indicating that random, Markovian processes determine arrest lifetime. Low doses (0.01, 0.03 mg/kg, i.p.), but not a high dose (0.08 mg/kg, i.p.) of the cholinesterase inhibitor physostigmine increased the number of arrests but did not alter arrest lifetimes. The muscarinic antagonist atropine (0.5 mg/kg, i.p.) decreased the number of arrests, also without altering arrest lifetimes. To determine if muscarinic transmission in pontine areas linked to REM sleep control also influences behavioral arrests, we microinjected neostigmine (50 nl, 62.5 uM) or neostigmine + atropine (62.5 uM and 111 uM respectively) into the nucleus pontis oralis and caudalis. Neostigmine increased the number of arrests in DKO mice without altering arrest lifetimes but did not provoke arrests in WT mice. Co-injection of atropine abolished this effect. Collectively, our findings establish that behavioral arrests in DKO mice are similar to those in orexin deficient mice and that arrests have exponentially distributed lifetimes. We also show, for the first time in a rodent narcolepsy model, that cholinergic systems can regulate arrest dynamics. Since perturbations of muscarinic transmission altered arrest frequency but not lifetime, our findings suggest cholinergic systems influence arrest initiation without influencing circuits that determine arrest duration. PMID- 21533255 TI - Extended longevity of reproductives appears to be common in Fukomys mole-rats (Rodentia, Bathyergidae). AB - African mole-rats (Bathyergidae, Rodentia) contain several social, cooperatively breeding species with low extrinsic mortality and unusually high longevity. All social bathyergids live in multigenerational families where reproduction is skewed towards a few breeding individuals. Most of their offspring remain as reproductively inactive "helpers" in their natal families, often for several years. This "reproductive subdivision" of mole-rat societies might be of interest for ageing research, as in at least one social bathyergid (Ansell's mole-rats Fukomys anselli), breeders have been shown to age significantly slower than non breeders. These animals thus provide excellent conditions for studying the epigenetics of senescence by comparing divergent longevities within the same genotypes without the inescapable short-comings of inter-species comparisons. It has been claimed that many if not all social mole-rat species may have evolved similar ageing patterns, too. However, this remains unclear on account of the scarcity of reliable datasets on the subject. We therefore analyzed a 20-year breeding record of Giant mole-rats Fukomys mechowii, another social bathyergid species. We found that breeders indeed lived significantly longer than helpers (ca. 1.5-2.2fold depending on the sex), irrespective of social rank or other potentially confounding factors. Considering the phylogenetic positions of F. mechowii and F. anselli and unpublished data on a third Fukomys-species (F. damarensis) showing essentially the same pattern, it seems probable that the reversal of the classic trade-off between somatic maintenance and sexual reproduction is characteristic of the whole genus and hence of the vast majority of social mole-rats. PMID- 21533256 TI - Lichen endozoochory by snails. AB - Endozoochory plays a prominent role for the dispersal of seed plants. However, for most other plant taxa it is not known whether this mode of dispersal occurs at all. Among those other taxa, lichens as symbiotic associations of algae and fungi are peculiar as their successful dispersal requires movement of propagules that leaves the symbiosis functional. However, the potential for endozoochorous dispersal of lichen fragments has been completely overlooked. We fed sterile thalli of two foliose lichen species (Lobaria pulmonaria and Physcia adscendens) differing in habitat and air-quality requirements to nine snail species common in temperate Europe. We demonstrated morphologically that L. pulmonaria regenerated from 29.0% of all 379 fecal pellets, whereas P. adscendens regenerated from 40.9% of all 433 fecal pellets, showing that lichen fragments survived gut passage of all snail species. Moreover, molecular analysis of regenerated lichens confirmed the species identity for a subset of samples. Regeneration rates were higher for the generalist lichen species P. adscendens than for the specialist lichen species L. pulmonaria. Furthermore, lichen regeneration rates varied among snail species with higher rates after gut passage of heavier snail species. We suggest that gastropods generally grazing on lichen communities are important, but so far completely overlooked, as vectors for lichen dispersal. This opens new ecological perspectives and questions the traditional view of an entirely antagonistic relationship between gastropods and lichens. PMID- 21533257 TI - I know my neighbour: individual recognition in Octopus vulgaris. AB - BACKGROUND: Little is known about individual recognition (IR) in octopuses, although they have been abundantly studied for their sophisticated behaviour and learning capacities. Indeed, the ability of octopuses to recognise conspecifics is suggested by a number of clues emerging from both laboratory studies (where they appear to form and maintain dominance hierarchies) and field observations (octopuses of neighbouring dens display little agonism between each other). To fill this gap in knowledge, we investigated the behaviour of 24 size-matched pairs of Octopus vulgaris in laboratory conditions. METHODOLOGY/PRINCIPAL FINDINGS: The experimental design was composed of 3 phases: Phase 1 (acclimatization): 12 "sight-allowed" (and 12 "isolated") pairs were maintained for 3 days in contiguous tanks separated by a transparent (and opaque) partition to allow (and block) the vision of the conspecific; Phase 2 (cohabitation): members of each pair (both sight-allowed and isolated) were transferred into an experimental tank and were allowed to interact for 15 min every day for 3 consecutive days; Phase 3 (test): each pair (both sight-allowed and isolated) was subject to a switch of an octopus to form pairs composed of either familiar ("sham switches") or unfamiliar conspecifics ("real switches"). Longer latencies (i.e. the time elapsed from the first interaction) and fewer physical contacts in the familiar pairs as opposed to the unfamiliar pairs were used as proxies for recognition. CONCLUSIONS: Octopuses appear able to recognise conspecifics and to remember the individual previously met for at least one day. To the best of our knowledge, this is the first experimental study showing the occurrence of a form of IR in cephalopods. Future studies should clarify whether this is a "true" IR. PMID- 21533258 TI - The prognostic value of non-linear analysis of heart rate variability in patients with congestive heart failure--a pilot study of multiscale entropy. AB - AIMS: The influences of nonstationarity and nonlinearity on heart rate time series can be mathematically qualified or quantified by multiscale entropy (MSE). The aim of this study is to investigate the prognostic value of parameters derived from MSE in the patients with systolic heart failure. METHODS AND RESULTS: Patients with systolic heart failure were enrolled in this study. One month after clinical condition being stable, 24-hour Holter electrocardiogram was recording. MSE as well as other standard parameters of heart rate variability (HRV) and detrended fluctuation analysis (DFA) were assessed. A total of 40 heart failure patients with a mea age of 56+/-16 years were enrolled and followed-up for 684+/-441 days. There were 25 patients receiving beta-blockers treatment. During follow-up period, 6 patients died or received urgent heart transplantation. The short-term exponent of DFA and the slope of MSE between scale 1 to 5 were significantly different between patients with or without beta blockers (p = 0.014 and p = 0.028). Only the area under the MSE curve for scale 6 to 20 (Area(6-20)) showed the strongest predictive power between survival (n = 34) and mortality (n = 6) groups among all the parameters. The value of Area(6 20)21.2 served as a significant predictor of mortality or heart transplant (p = 0.0014). CONCLUSION: The area under the MSE curve for scale 6 to 20 is not relevant to beta-blockers and could further warrant independent risk stratification for the prognosis of CHF patients. PMID- 21533259 TI - MartiTracks: a geometrical approach for identifying geographical patterns of distribution. AB - Panbiogeography represents an evolutionary approach to biogeography, using rational cost-efficient methods to reduce initial complexity to locality data, and depict general distribution patterns. However, few quantitative, and automated panbiogeographic methods exist. In this study, we propose a new algorithm, within a quantitative, geometrical framework, to perform panbiogeographical analyses as an alternative to more traditional methods. The algorithm first calculates a minimum spanning tree, an individual track for each species in a panbiogeographic context. Then the spatial congruence among segments of the minimum spanning trees is calculated using five congruence parameters, producing a general distribution pattern. In addition, the algorithm removes the ambiguity, and subjectivity often present in a manual panbiogeographic analysis. Results from two empirical examples using 61 species of the genus Bomarea (2340 records), and 1031 genera of both plants and animals (100118 records) distributed across the Northern Andes, demonstrated that a geometrical approach to panbiogeography is a feasible quantitative method to determine general distribution patterns for taxa, reducing complexity, and the time needed for managing large data sets. PMID- 21533260 TI - Non-AIDS associated Kaposi's sarcoma: clinical features and treatment outcome. AB - BACKGROUND: Kaposi's sarcoma (KS) in HIV negative patients is rare and has to be distinguished from AIDS associated KS. Two groups are at risk to develop non-AIDS related KS: elderly men mainly of Mediterranean origin and persons with iatrogenic immunosuppression. PATIENTS AND METHODS: In order to define risk groups and major clinical features we retrospectively evaluated clinical data of all patients with non-AIDS associated KS presenting to the Department of Dermatology, University Hospital Tuebingen between 1987 and 2009. Data were extracted from the tumor registry of the Comprehensive Cancer Center Tuebingen and from patient records. RESULTS: 20 patients with non-AIDS KS have been identified. The average age at KS onset was 66.6 years; the male-to-female-ratio was 3:1. Most of the patients were immigrants from Mediterranean or Eastern European countries (60%). 15 cases of classic KS versus 5 cases of iatrogenic KS were observed. In 95% of the cases, KS was limited to the skin, without mucosal, lymph node or visceral manifestation. KS lesions were in all cases multiple and mostly bilateral, the most common localization was the skin of the lower extremities. Tumor control was achieved in nearly all cases by the use of local or systemic therapy. No patient died from KS. CONCLUSIONS: Unlike KS in AIDS patients, non-AIDS associated KS is a rather localized process which rarely involves lymph nodes or organs. It is mostly seen in elderly males from Mediterranean or Eastern European countries and in most cases responsive on local or systemic therapeutic strategies. PMID- 21533261 TI - Propionibacterium acnes CAMP factor and host acid sphingomyelinase contribute to bacterial virulence: potential targets for inflammatory acne treatment. AB - BACKGROUND: In the progression of acne vulgaris, the disruption of follicular epithelia by an over-growth of Propionibacterium acnes (P. acnes) permits the bacteria to spread and become in contact with various skin and immune cells. METHODOLOGY/PRINCIPAL FINDINGS: We have demonstrated in the present study that the Christie, Atkins, Munch-Peterson (CAMP) factor of P. acnes is a secretory protein with co-hemolytic activity with sphingomyelinase that can confer cytotoxicity to HaCaT keratinocytes and RAW264.7 macrophages. The CAMP factor from bacteria and acid sphingomyelinase (ASMase) from the host cells were simultaneously present in the culture supernatant only when the cells were co cultured with P. acnes. Either anti-CAMP factor serum or desipramine, a selective ASMase inhibitor, significantly abrogated the P. acnes-induced cell death of HaCaT and RAW264.7 cells. Intradermal injection of ICR mouse ears with live P. acnes induced considerable ear inflammation, macrophage infiltration, and an increase in cellular soluble ASMase. Suppression of ASMase by systemic treatment with desipramine significantly reduced inflammatory reaction induced by intradermal injection with P. acnes, suggesting the contribution of host ASMase in P. acnes-induced inflammatory reaction in vivo. Vaccination of mice with CAMP factor elicited a protective immunity against P. acnes-induced ear inflammation, indicating the involvement of CAMP factor in P. acnes-induced inflammation. Most notably, suppression of both bacterial CAMP factor and host ASMase using vaccination and specific antibody injection, respectively, cooperatively alleviated P. acnes-induced inflammation. CONCLUSIONS/SIGNIFICANCE: These findings envision a novel infectious mechanism by which P. acnes CAMP factor may hijack host ASMase to amplify bacterial virulence to degrade and invade host cells. This work has identified both CAMP factor and ASMase as potential molecular targets for the development of drugs and vaccines against acne vulgaris. PMID- 21533262 TI - Ontogenetic development of weberian ossicles and hearing abilities in the African bullhead catfish. AB - BACKGROUND: The weberian apparatus of otophysine fishes facilitates sound transmission from the swimbladder to the inner ear to increase hearing sensitivity. It has been of great interest to biologists since the 19(th) century. No studies, however, are available on the development of the weberian ossicles and its effect on the development of hearing in catfishes. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the development of the weberian apparatus and auditory sensitivity in the catfish Lophiobagrus cyclurus. Specimens from 11.3 mm to 85.5 mm in standard length were studied. Morphology was assessed using sectioning, histology, and X-ray computed tomography, along with 3D reconstruction. Hearing thresholds were measured utilizing the auditory evoked potentials recording technique. Weberian ossicles and interossicular ligaments were fully developed in all stages investigated except in the smallest size group. In the smallest catfish, the intercalarium and the interossicular ligaments were still missing and the tripus was not yet fully developed. Smallest juveniles revealed lowest auditory sensitivity and were unable to detect frequencies higher than 2 or 3 kHz; sensitivity increased in larger specimens by up to 40 dB, and frequency detection up to 6 kHz. In the size groups capable of perceiving frequencies up to 6 kHz, larger individuals had better hearing abilities at low frequencies (0.05-2 kHz), whereas smaller individuals showed better hearing at the highest frequencies (4-6 kHz). CONCLUSIONS/SIGNIFICANCE: Our data indicate that the ability of otophysine fish to detect sounds at low levels and high frequencies largely depends on the development of the weberian apparatus. A significant increase in auditory sensitivity was observed as soon as all weberian ossicles and interossicular ligaments are present and the chain for transmitting sounds from the swimbladder to the inner ear is complete. This contrasts with findings in another otophysine, the zebrafish, where no threshold changes have been observed. PMID- 21533263 TI - Improved xenobiotic metabolism and reduced susceptibility to cancer in gluten sensitive macaques upon introduction of a gluten-free diet. AB - BACKGROUND: A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta). METHODOLOGY: Stages of remission and relapse were accomplished in gluten sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes. PRINCIPAL FINDINGS: When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories--cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin collagen deposition, neuronal and unknown function--this study focused on cancer related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes. CONCLUSIONS/SIGNIFICANCE: A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research. PMID- 21533264 TI - Evaluation of multidrug efflux pump inhibitors by a new method using microfluidic channels. AB - Fluorescein-di-beta-D-galactopyranoside (FDG), a fluorogenic compound, is hydrolyzed by beta-galactosidase in the cytoplasm of Escherichia coli to produce a fluorescent dye, fluorescein. We found that both FDG and fluorescein were substrates of efflux pumps, and have developed a new method to evaluate efflux inhibitory activities in E. coli using FDG and a microfluidic channel device. We used E. coli MG1655 wild-type, DeltaacrB (DeltaB), DeltatolC (DeltaC) and DeltaacrBDeltatolC (DeltaBC) harboring plasmids carrying the mexAB-oprM (pABM) or mexXY-oprM (pXYM) genes of Pseudomonas aeruginosa. Two inhibitors, MexB-specific pyridopyrimidine (D13-9001) and non-specific Phe-Arg-beta-naphthylamide (PAbetaN) were evaluated. The effects of inhibitors on pumps were observed using the microfluidic channel device under a fluorescence microscope. AcrAB-TolC and analogous pumps effectively prevented FDG influx in wild-type cells, resulting in no fluorescence. In contrast, DeltaB or DeltaC easily imported and hydrolyzed FDG to fluorescein, which was exported by residual pumps in DeltaB. Consequently, fluorescent medium in DeltaB and fluorescent cells of DeltaC and DeltaBC were observed in the microfluidic channels. D13-9001 substantially increased fluorescent cell number in DeltaBC/pABM but not in DeltaBC/pXYM. PAbetaN increased medium fluorescence in all strains, especially in the pump deletion mutants, and caused fluorescein accumulation to disappear in DeltaC. The checkerboard method revealed that D13-9001 acts synergistically with aztreonam, ciprofloxacin, and erythromycin only against the MexAB-OprM producer (DeltaBC/pABM), and PAbetaN acts synergistically, especially with erythromycin, in all strains including the pump deletion mutants. The results obtained from PAbetaN were similar to the results from membrane permeabilizer, polymyxin B or polymyxin B nonapeptide by concentration. The new method clarified that D13-9001 specifically inhibited MexAB-OprM in contrast to PAbetaN, which appeared to be a substrate of the pumps and permeabilized the membranes in E. coli. PMID- 21533265 TI - Serpin induced antiviral activity of prostaglandin synthetase-2 against HIV-1 replication. AB - The serine protease inhibitors (serpins) are anti-inflammatory proteins that have various functions. By screening a diverse panel of viruses, we demonstrate that the serpin antithrombin III (ATIII) has a broad-spectrum anti-viral activity for HIV-1, HCV and HSV. To investigate the mechanism of action in more detail we investigated the HIV-1 inhibition. Using gene-expression arrays we found that multiple host cell signal transduction pathways were activated by ATIII in HIV-1 infected cells but not in uninfected controls. Moreover, the signal pathways initiated by ATIII treatment, were more than 200-fold increased by the use of heparin-activated ATIII. The most up-regulated transcript in HIV-1 infected cells was prostaglandin synthetase-2 (PTGS2). Furthermore, we found that over expression of PTGS2 reduced levels of HIV-1 replication in human PBMC. These findings suggest a central role for serpins in the host innate anti-viral response. Host factors such as PTGS2 elicited by ATIII treatment could be exploited in the development of novel anti-viral interventions. PMID- 21533266 TI - Data integration workflow for search of disease driving genes and genetic variants. AB - Comprehensive characterization of a gene's impact on phenotypes requires knowledge of the context of the gene. To address this issue we introduce a systematic data integration method Candidate Genes and SNPs (CANGES) that links SNP and linkage disequilibrium data to pathway- and protein-protein interaction information. It can be used as a knowledge discovery tool for the search of disease associated causative variants from genome-wide studies as well as to generate new hypotheses on synergistically functioning genes. We demonstrate the utility of CANGES by integrating pathway and protein-protein interaction data to identify putative functional variants for (i) the p53 gene and (ii) three glioblastoma multiforme (GBM) associated risk genes. For the GBM case, we further integrate the CANGES results with clinical and genome-wide data for 209 GBM patients and identify genes having effects on GBM patient survival. Our results show that selecting a focused set of genes can result in information beyond the traditional genome-wide association approaches. Taken together, holistic approach to identify possible interacting genes and SNPs with CANGES provides a means to rapidly identify networks for any set of genes and generate novel hypotheses. CANGES is available in http://csbi.ltdk.helsinki.fi/CANGES/ PMID- 21533268 TI - Peer review, program officers and science funding. AB - Increased competition for research funding has led to growth in proposal submissions and lower funding-success rates. An agent-based model of the funding cycle, accounting for variations in program officer and reviewer behaviors, for a range of funding rates, is used to assess the efficiency of different proposal submission strategies. Program officers who use more reviewers and require consensus can improve the chances of scientists submitting fewer proposals. Selfish or negligent reviewers reduce the effectiveness of submitting more proposals, but have less influence as available funding declines. Policies designed to decrease proposal submissions reduce reviewer workload, but can lower the quality of funded proposals. When available funding falls below 10-15% in this model, the most effective strategy for scientists to maintain funding is to submit many proposals. PMID- 21533267 TI - A comprehensive peptidome profiling technology for the identification of early detection biomarkers for lung adenocarcinoma. AB - The mass spectrometry-based peptidomics approaches have proven its usefulness in several areas such as the discovery of physiologically active peptides or biomarker candidates derived from various biological fluids including blood and cerebrospinal fluid. However, to identify biomarkers that are reproducible and clinically applicable, development of a novel technology, which enables rapid, sensitive, and quantitative analysis using hundreds of clinical specimens, has been eagerly awaited. Here we report an integrative peptidomic approach for identification of lung cancer-specific serum peptide biomarkers. It is based on the one-step effective enrichment of peptidome fractions (molecular weight of 1,000-5,000) with size exclusion chromatography in combination with the precise label-free quantification analysis of nano-LC/MS/MS data set using Expressionist proteome server platform. We applied this method to 92 serum samples well-managed with our SOP (standard operating procedure) (30 healthy controls and 62 lung adenocarcinoma patients), and quantitatively assessed the detected 3,537 peptide signals. Among them, 118 peptides showed significantly altered serum levels between the control and lung cancer groups (p<0.01 and fold change >5.0). Subsequently we identified peptide sequences by MS/MS analysis and further assessed the reproducibility of Expressionist-based quantification results and their diagnostic powers by MRM-based relative-quantification analysis for 96 independently prepared serum samples and found that APOA4 273-283, FIBA 5-16, and LBN 306-313 should be clinically useful biomarkers for both early detection and tumor staging of lung cancer. Our peptidome profiling technology can provide simple, high-throughput, and reliable quantification of a large number of clinical samples, which is applicable for diverse peptidome-targeting biomarker discoveries using any types of biological specimens. PMID- 21533269 TI - Regeneration of cryoinjury induced necrotic heart lesions in zebrafish is associated with epicardial activation and cardiomyocyte proliferation. AB - In mammals, myocardial cell death due to infarction results in scar formation and little regenerative response. In contrast, zebrafish have a high capacity to regenerate the heart after surgical resection of myocardial tissue. However, whether zebrafish can also regenerate lesions caused by cell death has not been tested. Here, we present a simple method for induction of necrotic lesions in the adult zebrafish heart based on cryoinjury. Despite widespread tissue death and loss of cardiomyocytes caused by these lesions, zebrafish display a robust regenerative response, which results in substantial clearing of the necrotic tissue and little scar formation. The cellular mechanisms underlying regeneration appear to be similar to those activated in response to ventricular resection. In particular, the epicardium activates a developmental gene program, proliferates and covers the lesion. Concomitantly, mature uninjured cardiomyocytes become proliferative and invade the lesion. Our injury model will be a useful tool to study the molecular mechanisms of natural heart regeneration in response to necrotic cell death. PMID- 21533270 TI - Experimental tuberculosis in the Wistar rat: a model for protective immunity and control of infection. AB - BACKGROUND: Despite the availability of many animal models for tuberculosis (TB) research, there still exists a need for better understanding of the quiescent stage of disease observed in many humans. Here, we explored the use of the Wistar rat model for the study of protective immunity and control of Mycobacterium tuberculosis (Mtb) infection. METHODOLOGY/PRINCIPAL FINDINGS: The kinetics of bacillary growth, evaluated by the colony stimulating assay (CFU) and the extent of lung pathology in Mtb infected Wistar rats were dependent on the virulence of the strains and the size of the infecting inoculums. Bacillary growth control was associated with induction of T helper type 1 (Th1) activation, the magnitude of which was also Mtb strain and dose dependent. Histopathology analysis of the infected lungs demonstrated the formation of well organized granulomas comprising epithelioid cells, multinucleated giant cells and foamy macrophages surrounded by large numbers of lymphocytes. The late stage subclinical form of disease was reactivated by immunosuppression leading to increased lung CFU. CONCLUSION: The Wistar rat is a valuable model for better understanding host-pathogen interactions that result in control of Mtb infection and potentially establishment of latent TB. These properties together with the ease of manipulation, relatively low cost and well established use of rats in toxicology and pharmacokinetic analyses make the rat a good animal model for TB drug discovery. PMID- 21533271 TI - Dynamic changes in neurexins' alternative splicing: role of Rho-associated protein kinases and relevance to memory formation. AB - The three neurexins genes (NRXN1/2/3) encode polymorphic synaptic membrane proteins that are involved in cognitive functioning. Neurexins' selectivity of function is presumably conferred through differential use of 2 promoters and 5 alternative splicing sites (SS#1/2/3/4/5). In day-old rat brain neurons grown in culture, activation (depolarization) induces reversible, calcium dependent, repression of NRXN2alpha SS#3 insert. The effects of depolarization on NRXN1/2/3alpha splicing and biochemical pathways mediating them were further studied in these neurons. NRXN1/2/3alpha splicing in the course of memory formation in vivo was also explored, using fear conditioning paradigm in rats in which the animals were trained to associate an aversive stimulus (electrical shock) with a neutral context (a tone), resulting in the expression of fear responses to the neutral context.In the cultured neurons depolarization induced, beside NRXN2alpha SS#3, repression of SS#3 and SS#4 exons in NRXN3alpha but not NRXN1alpha. The repressions were mediated by the calcium/protein kinase C/Rho associated protein kinase (ROCK) pathway. Fear conditioning induced significant and transient repressions of the NRXN1/2/3alpha SS#4 exons in the rat hippocampus. ROCK inhibition prior to training attenuated the behavioral fear response, the NRXN1/2/3alpha splicing repressions and subsequent recovery and the levels of excitatory (PSD95) and inhibitory (gephyrin) synaptic proteins in the hippocampus. No such effects were observed in the prefrontal cortex. Significant correlations existed between the fear response and hippocampal NRXN3alpha and NRXN2alpha SS#4 inserts as well as PSD95 protein levels. Hippocampal NRXN1alpha SS#4 insert and gephyrin levels did not correlate with the behavioral response but were negatively correlated with each other.These results show for the first time dynamic, experience related changes in NRXN1/2/3alpha alternative splicing in the rat brain and a role for ROCK in them. Specific neurexins' transcripts may be involved in synaptic remodeling occurring at an intermediate (hours) time scale in the course of memory formation. PMID- 21533273 TI - Efficacious and safe tissue-selective controlled gene therapy approaches for the cornea. AB - Untargeted and uncontrolled gene delivery is a major cause of gene therapy failure. This study aimed to define efficient and safe tissue-selective targeted gene therapy approaches for delivering genes into keratocytes of the cornea in vivo using a normal or diseased rabbit model. New Zealand White rabbits, adeno associated virus serotype 5 (AAV5), and a minimally invasive hair-dryer based vector-delivery technique were used. Fifty microliters of AAV5 titer (6.5*10(12) vg/ml) expressing green fluorescent protein gene (GFP) was topically applied onto normal or diseased (fibrotic or neovascularized) rabbit corneas for 2-minutes with a custom vector-delivery technique. Corneal fibrosis and neovascularization in rabbit eyes were induced with photorefractive keratectomy using excimer laser and VEGF (630 ng) using micropocket assay, respectively. Slit-lamp biomicroscopy and immunocytochemistry were used to confirm fibrosis and neovascularization in rabbit corneas. The levels, location and duration of delivered-GFP gene expression in the rabbit stroma were measured with immunocytochemistry and/or western blotting. Slot-blot measured delivered-GFP gene copy number. Confocal microscopy performed in whole-mounts of cornea and thick corneal sections determined geometric and spatial localization of delivered-GFP in three dimensional arrangement. AAV5 toxicity and safety were evaluated with clinical eye exam, stereomicroscopy, slit-lamp biomicroscopy, and H&E staining. A single 2 minute AAV5 topical application via custom delivery-technique efficiently and selectively transduced keratocytes in the anterior stroma of normal and diseased rabbit corneas as evident from immunocytochemistry and confocal microscopy. Transgene expression was first detected at day 3, peaked at day 7, and was maintained up to 16 weeks (longest tested time point). Clinical and slit-lamp eye examination in live rabbits and H&E staining did not reveal any significant changes between AAV5-treated and untreated control corneas. These findings suggest that defined gene therapy approaches are safe for delivering genes into keratocytes in vivo and has potential for treating corneal disorders in human patients. PMID- 21533272 TI - Single cell genome amplification accelerates identification of the apratoxin biosynthetic pathway from a complex microbial assemblage. AB - Filamentous marine cyanobacteria are extraordinarily rich sources of structurally novel, biomedically relevant natural products. To understand their biosynthetic origins as well as produce increased supplies and analog molecules, access to the clustered biosynthetic genes that encode for the assembly enzymes is necessary. Complicating these efforts is the universal presence of heterotrophic bacteria in the cell wall and sheath material of cyanobacteria obtained from the environment and those grown in uni-cyanobacterial culture. Moreover, the high similarity in genetic elements across disparate secondary metabolite biosynthetic pathways renders imprecise current gene cluster targeting strategies and contributes sequence complexity resulting in partial genome coverage. Thus, it was necessary to use a dual-method approach of single-cell genomic sequencing based on multiple displacement amplification (MDA) and metagenomic library screening. Here, we report the identification of the putative apratoxin. A biosynthetic gene cluster, a potent cancer cell cytotoxin with promise for medicinal applications. The roughly 58 kb biosynthetic gene cluster is composed of 12 open reading frames and has a type I modular mixed polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) organization and features loading and off-loading domain architecture never previously described. Moreover, this work represents the first successful isolation of a complete biosynthetic gene cluster from Lyngbya bouillonii, a tropical marine cyanobacterium renowned for its production of diverse bioactive secondary metabolites. PMID- 21533274 TI - The extraordinarily complex but highly structured organization of intestinal mucus-gel unveiled in multicolor images. AB - The mucus that coats the gastrointestinal tract of all mammals is a dynamic and sticky gel layer and represents the first protective barrier between the host and the hostile environment. There is, however, a lack of detailed knowledge about the mucus gel organization because of the high water content and the complexity of MUC2, the main gel-forming molecule in the intestine. Histological staining and a multilabel immunofluorescence method were used to examine mucus blankets and Muc2 in mouse colon and ileum samples fixed in Carnoy's solution, unveiling an extraordinarily complex but highly structured mucus gel organization. The inner firmly adherent mucus blanket consists of alternating layers. The thicker outer loosely adherent mucus blanket in the colon is made of alternating laminated layers and loose curl-like structures. The layers consist of Muc2 molecules with different fucosylation states and glycoforms remain unmixed in the mucus. Importantly, distinct goblet cell subpopulations throughout the ileum along the crypt-to-villus axis with an alternation of goblet cells secreting fucosylated and non-fucosylated Muc2 are observed. A better understanding of the mucus structure should contribute to improve the efficiency of DNA and drug delivery and will allow for a better understanding and treatment of inflammatory and infectious intestinal diseases. PMID- 21533275 TI - Quality of reporting on the vegetative state in Italian newspapers. The case of Eluana Englaro. AB - BACKGROUND: Media coverage of the vegetative state (VS) includes refutations of the VS diagnosis and describes behaviors inconsistent with VS. We used a quality score to assess the reporting in articles describing the medical characteristics of VS in Italian newspapers. METHODOLOGY/PRINCIPAL FINDINGS: Our search covered a 7-month period from July 1, 2008, to February 28, 2009, using the online searchable databases of four major Italian newspapers: Corriere della Sera, La Repubblica, La Stampa, and Avvenire. Medical reporting was judged as complete if three core VS characteristics were described: patient unawareness of self and the environment, preserved wakefulness (eyes open), and spontaneous respiration (artificial ventilator not needed). We retrieved 2,099 articles, and 967 were dedicated to VS. Of these, 853 (88.2%) were non-medical and mainly focused on describing the political, legal, and ethical aspects of VS. Of the 114 (11.8%) medical articles, 53 (5.5%) discussed other medical problems such as death by dehydration, artificial nutrition, neuroimaging, brain death, or uterine hemorrhage, and 61 (6.3%) described VS. Of these 61, only 18 (1.9%) reported all three CORE characteristics and were judged complete. We found no differences among the four investigated newspapers (Fisher's exact = 0.798), and incomplete articles were equally distributed between journalistic pieces and expert opinions (chi(2) = 1.8854, P = 0.170). Incorrect descriptions of VS were significantly more common among incomplete articles (13 of 43 vs. 1 of 18; Fisher's exact P = 0.047). CONCLUSIONS/SIGNIFICANCE: Core VS characteristics are rarely reported in Italian newspaper articles, which can alter adequate comprehension of new developments and (mis)inform political, legal, and ethical decisions. PMID- 21533276 TI - Calcineurin signaling and membrane lipid homeostasis regulates iron mediated multidrug resistance mechanisms in Candida albicans. AB - We previously demonstrated that iron deprivation enhances drug susceptibility of Candida albicans by increasing membrane fluidity which correlated with the lower expression of ERG11 transcript and ergosterol levels. The iron restriction dependent membrane perturbations led to an increase in passive diffusion and drug susceptibility. The mechanisms underlying iron homeostasis and multidrug resistance (MDR), however, are not yet resolved. To evaluate the potential mechanisms, we used whole genome transcriptome and electrospray ionization tandem mass spectrometry (ESI-MS/MS) based lipidome analyses of iron deprived Candida cells to examine the new cellular circuitry of the MDR of this pathogen. Our transcriptome data revealed a link between calcineurin signaling and iron homeostasis. Among the several categories of iron deprivation responsive genes, the down regulation of calcineurin signaling genes including HSP90, CMP1 and CRZ1 was noteworthy. Interestingly, iron deprived Candida cells as well as iron acquisition defective mutants phenocopied molecular chaperone HSP90 and calcineurin mutants and thus were sensitive to alkaline pH, salinity and membrane perturbations. In contrast, sensitivity to above stresses did not change in iron deprived DSY2146 strain with a hyperactive allele of calcineurin. Although, iron deprivation phenocopied compromised HSP90 and calcineurin, it was independent of protein kinase C signaling cascade. Notably, the phenotypes associated with iron deprivation in genetically impaired calcineurin and HSP90 could be reversed with iron supplementation. The observed down regulation of ergosterol (ERG1, ERG2, ERG11 and ERG25) and sphingolipid biosynthesis (AUR1 and SCS7) genes followed by lipidome analysis confirmed that iron deprivation not only disrupted ergosterol biosynthesis, but it also affected sphingolipid homeostasis in Candida cells. These lipid compositional changes suggested extensive remodeling of the membranes in iron deprived Candida cells. Taken together, our data provide the first novel insight into the intricate relationship between cellular iron, calcineurin signaling, membrane lipid homeostasis and drug susceptibility of Candida cells. PMID- 21533277 TI - A preliminary study of genetic factors that influence susceptibility to bovine tuberculosis in the British cattle herd. AB - Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB) impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test ('reactors'). Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors) with implications for the current debate concerning badger-culling. PMID- 21533278 TI - Turtle carapace anomalies: the roles of genetic diversity and environment. AB - BACKGROUND: Phenotypic anomalies are common in wild populations and multiple genetic, biotic and abiotic factors might contribute to their formation. Turtles are excellent models for the study of developmental instability because anomalies are easily detected in the form of malformations, additions, or reductions in the number of scutes or scales. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we integrated field observations, manipulative experiments, and climatic and genetic approaches to investigate the origin of carapace scute anomalies across Iberian populations of the European pond turtle, Emys orbicularis. The proportion of anomalous individuals varied from 3% to 69% in local populations, with increasing frequency of anomalies in northern regions. We found no significant effect of climatic and soil moisture, or climatic temperature on the occurrence of anomalies. However, lower genetic diversity and inbreeding were good predictors of the prevalence of scute anomalies among populations. Both decreasing genetic diversity and increasing proportion of anomalous individuals in northern parts of the Iberian distribution may be linked to recolonization events from the Southern Pleistocene refugium. CONCLUSIONS/SIGNIFICANCE: Overall, our results suggest that developmental instability in turtle carapace formation might be caused, at least in part, by genetic factors, although the influence of environmental factors affecting the developmental stability of turtle carapace cannot be ruled out. Further studies of the effects of environmental factors, pollutants and heritability of anomalies would be useful to better understand the complex origin of anomalies in natural populations. PMID- 21533279 TI - Requirement of podocalyxin in TGF-beta induced epithelial mesenchymal transition. AB - Epithelial mesenchymal transition (EMT) is characterized by the development of mesenchymal properties such as a fibroblast-like morphology with altered cytoskeletal organization and enhanced migratory potential. We report that the expression of podocalyxin (PODXL), a member of the CD34 family, is markedly increased during TGF-beta induced EMT. PODXL is enriched on the leading edges of migrating A549 cells. Silencing of podocalyxin expression reduced cell ruffle formation, spreading, migration and affected the expression patterns of several proteins that normally change during EMT (e.g., vimentin, E-cadherin). Cytoskeleton assembly in EMT was also found to be dependent on the production of podocalyin. Compositional analysis of podocalyxin containing immunoprecipitates revealed that collagen type 1 was consistently associated with these isolates. Collagen type 1 was also found to co-localize with podocalyxin on the leading edges of migrating cells. The interactions with collagen may be a critical aspect of podocalyxin function. Podocalyxin is an important regulator of the EMT like process as it regulates the loss of epithelial features and the acquisition of a motile phenotype. PMID- 21533280 TI - Steroids in the treatment of IgA nephropathy to the improvement of renal survival: a systematic review and meta-analysis. AB - BACKGROUND: Studies have shown that steroids can improve kidney survival and decrease the risk of proteinuria in patients with Immunoglobulin A nephropathy, but the overall benefit of steroids in the treatment of Immunoglobulin A nephropathy remains controversial. The aim of this study was to evaluate the benefits and risks of steroids for renal survival in adults with Immunoglobulin A nephropathy. METHODOLOGY AND PRINCIPAL FINDINGS: We searched the Cochrane Renal Group Specialized Register, Cochrane Controlled Trial Registry, MEDLINE and EMBASE databases. All eligible studies were measuring at least one of the following outcomes: end-stage renal failure, doubling of serum creatinine and urinary protein excretion. Fifteen relevant trials (n = 1542) that met our inclusion criteria were identified. In a pooled analysis, steroid therapy was associated with statistically significant reduction of the risk in end-stage renal failure (RR: 0.46, 95% CI: 0.27 to 0.79), doubling of serum creatinine (RR = 0.34, 95%CI = 0.15 to 0.77) and reduced urinary protein excretion (MD = -0.47 g/day, 95%CI = -0.64 to -0.31). CONCLUSIONS/SIGNIFICANCE: We identified that steroid therapy was associated with a decrease of proteinuria and with a statistically significant reduction of the risk in end-stage renal failure. Moreover, subgroup analysis also suggested that long-term steroid therapy had a higher efficiency than standard and short term therapy. PMID- 21533281 TI - Expression and activity of a novel cathelicidin from domestic cats. AB - Cathelicidins are small cationic antimicrobial peptides found in many species including primates, mammals, marsupials, birds and even more primitive vertebrates, such as the hagfish. Some animals encode multiple cathelicidins in their genome, whereas others have only one. This report identifies and characterizes feline cathelicidin (feCath) as the sole cathelicidin in domestic cats (Felis catus). Expression of feCath is predominantly found in the bone marrow, with lower levels of expression in the gastrointestinal tract and skin. By immunocytochemistry, feCath localizes to the cytoplasm of neutrophils in feline peripheral blood. Structurally, the mature feCath sequence is most similar to a subgroup of cathelicidins that form linear alpha-helices. feCath possesses antimicrobial activity against E. coli D31, Salmonella enterica serovar Typhimurium (IR715), Listeria monocytogenes and Staphylococcus pseudintermedius (clinical isolate) similar to that of the human ortholog, LL-37. In contrast, feCath lacks the DNA binding activity seen with LL-37. Given its similarity in sequence, structure, tissue expression, and antimicrobial activity, the cathelicidin encoded by cats, feCath, belongs to the subgroup of linear cathelicidins found not only in humans, but also non-human primates, dogs, mice, and rats. PMID- 21533282 TI - Cell-type specific expression of a dominant negative PKA mutation in mice. AB - We employed the Cre recombinase/loxP system to create a mouse line in which PKA activity can be inhibited in any cell-type that expresses Cre recombinase. The mouse line carries a mutant Prkar1a allele encoding a glycine to aspartate substitution at position 324 in the carboxy-terminal cAMP-binding domain (site B). This mutation produces a dominant negative RIalpha regulatory subunit (RIalphaB) and leads to inhibition of PKA activity. Insertion of a loxP-flanked neomycin cassette in the intron preceding the site B mutation prevents expression of the mutant RIalphaB allele until Cre-mediated excision of the cassette occurs. Embryonic stem cells expressing RIalphaB demonstrated a reduction in PKA activity and inhibition of cAMP-responsive gene expression. Mice expressing RIalphaB in hepatocytes exhibited reduced PKA activity, normal fasting induced gene expression, and enhanced glucose disposal. Activation of the RIalphaB allele in vivo provides a novel system for the analysis of PKA function in physiology. PMID- 21533283 TI - Assessing the influence of different ROI selection strategies on functional connectivity analyses of fMRI data acquired during steady-state conditions. AB - In blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI), assessing functional connectivity between and within brain networks from datasets acquired during steady-state conditions has become increasingly common. However, in contrast to connectivity analyses based on task-evoked signal changes, selecting the optimal spatial location of the regions of interest (ROIs) whose timecourses will be extracted and used in subsequent analyses is not straightforward. Moreover, it is also unknown how different choices of the precise anatomical locations within given brain regions influence the estimates of functional connectivity under steady-state conditions. The objective of the present study was to assess the variability in estimates of functional connectivity induced by different anatomical choices of ROI locations for a given brain network. We here targeted the default mode network (DMN) sampled during both resting-state and a continuous verbal 2-back working memory task to compare four different methods to extract ROIs in terms of ROI features (spatial overlap, spatial functional heterogeneity), signal features (signal distribution, mean, variance, correlation) as well as strength of functional connectivity as a function of condition. We show that, while different ROI selection methods produced quantitatively different results, all tested ROI selection methods agreed on the final conclusion that functional connectivity within the DMN decreased during the continuous working memory task compared to rest. PMID- 21533285 TI - Win-win for wind and wildlife: a vision to facilitate sustainable development. AB - Wind energy offers the potential to reduce carbon emissions while increasing energy independence and bolstering economic development. However, wind energy has a larger land footprint per Gigawatt (GW) than most other forms of energy production, making appropriate siting and mitigation particularly important. Species that require large unfragmented habitats and those known to avoid vertical structures are particularly at risk from wind development. Developing energy on disturbed lands rather than placing new developments within large and intact habitats would reduce cumulative impacts to wildlife. The U.S. Department of Energy estimates that it will take 241 GW of terrestrial based wind development on approximately 5 million hectares to reach 20% electricity production for the U.S. by 2030. We estimate there are ~7,700 GW of potential wind energy available across the U.S., with ~3,500 GW on disturbed lands. In addition, a disturbance-focused development strategy would avert the development of ~2.3 million hectares of undisturbed lands while generating the same amount of energy as development based solely on maximizing wind potential. Wind subsidies targeted at favoring low-impact developments and creating avoidance and mitigation requirements that raise the costs for projects impacting sensitive lands could improve public value for both wind energy and biodiversity conservation. PMID- 21533286 TI - Health outcome measures in atopic dermatitis: a systematic review of trends in disease severity and quality-of-life instruments 1985-2010. AB - BACKGROUND: A number of disease-severity and quality-of-life (QoL) instruments have emerged in atopic dermatitis (AD) in the last decade. OBJECTIVES: To identify trends in outcomes instruments used in AD clinical trials and to provide a useful summary of the dimensions and validation studies for the most commonly used measures. METHOD: All randomized control trials (RCTs) from 1985 to 2010 in the treatment of AD were examined. RESULTS: Among the 791 RCTs reviewed, we identified 20 disease-severity and 14 QoL instruments. Of these outcomes instruments, few have been validated. SCORAD, EASI, IGA and SASSAD were the most commonly used disease-severity instruments and CDLQI, DFI, DLQI and IDQOL were the most frequently used QoL measures. LIMITATIONS: The small number of RCTs using QoL scales makes identifying trends for QoL instruments difficult. CONCLUSION: Overall, there is an increase in the use of disease-severity and QoL instruments in AD clinical trials. PMID- 21533287 TI - Environmental barcoding: a next-generation sequencing approach for biomonitoring applications using river benthos. AB - Timely and accurate biodiversity analysis poses an ongoing challenge for the success of biomonitoring programs. Morphology-based identification of bioindicator taxa is time consuming, and rarely supports species-level resolution especially for immature life stages. Much work has been done in the past decade to develop alternative approaches for biodiversity analysis using DNA sequence based approaches such as molecular phylogenetics and DNA barcoding. On-going assembly of DNA barcode reference libraries will provide the basis for a DNA based identification system. The use of recently introduced next-generation sequencing (NGS) approaches in biodiversity science has the potential to further extend the application of DNA information for routine biomonitoring applications to an unprecedented scale. Here we demonstrate the feasibility of using 454 massively parallel pyrosequencing for species-level analysis of freshwater benthic macroinvertebrate taxa commonly used for biomonitoring. We designed our experiments in order to directly compare morphology-based, Sanger sequencing DNA barcoding, and next-generation environmental barcoding approaches. Our results show the ability of 454 pyrosequencing of mini-barcodes to accurately identify all species with more than 1% abundance in the pooled mixture. Although the approach failed to identify 6 rare species in the mixture, the presence of sequences from 9 species that were not represented by individuals in the mixture provides evidence that DNA based analysis may yet provide a valuable approach in finding rare species in bulk environmental samples. We further demonstrate the application of the environmental barcoding approach by comparing benthic macroinvertebrates from an urban region to those obtained from a conservation area. Although considerable effort will be required to robustly optimize NGS tools to identify species from bulk environmental samples, our results indicate the potential of an environmental barcoding approach for biomonitoring programs. PMID- 21533289 TI - Skin of color: progress made, challenges remain. PMID- 21533288 TI - Why do women reject bisphosphonates for osteoporosis? A videographic study. AB - BACKGROUND: Despite access to effective, safe, and affordable treatment for osteoporosis, at-risk women may choose not to start bisphosphonate therapy. Understanding the reasons women give for rejecting a clinician's offer of treatment during consultations and how clinician's react to these reasons may help clinicians develop more effective strategies for fracture prevention and medication adherence. METHODS: We conducted a videographic evaluation of encounters in the Osteoporosis Choice randomized trial of a decision aid about bisphosphonates vs. usual primary care. Eligible videos involved consultations with women with an estimated 10-year fragility fracture risk >20% who verbalized at least one reason to not take bisphosphonates. Two reviewers independently reviewed eligible videos and verbatim transcripts, classifying patient views about bisphosphonate use, clinicians response to those views, and patient adherence at 6 months post visit. RESULTS: Eighteen video recordings (12 with decision aid) were eligible for analyses. We identified 37 reasons for and against bisphosphonate therapy. Eleven patients rejected treatment, offering 9 (average of 2 per patient) unique reasons against initiating bisphosphonates (most common: side effects 39% and distrust of medications in general 33%). When physicians conceded to patient views the outcome was no bisphosphonate use. Adherence to choices at 6 months was 100%. CONCLUSIONS: The expression of patient preferences is sometimes unfavorable to bisphosphonates treatment even among well informed patients at high risk for osteoporotic fractures. At 6 months, patients who expressed concerns about these medicines behaved consistently with the decision made during the visit. PMID- 21533292 TI - Advances in the treatment of keloids. AB - Occurring with higher proportions in skin of color, keloid formation is seen in individuals of all races, with the lowest incidence in albinos. Interestingly, prevalence of keloids is correlated to skin pigmentation, with dark-skinned individuals suffering disproportionately. Many factors are taken into consideration when deciding which modalities to use in the treatment of keloids, including size, anatomical site, cause, symptoms, duration of treatment and not least importantly, pigmentation of the patient. In patients with skin of darker color it is necessary to communicate the effects these treatments may have on epidermal pigmentation to the patient. Of course, the best treatment for keloids remains prevention. Physicians should be alert to delays in wound healing, persistent erythema, or pruritus as impending symptoms of possible keloid formation and make all reasonable attempts to reduce inflammation and tension on the skin with appropriate methods. PMID- 21533284 TI - Deregulation of MYCN, LIN28B and LET7 in a molecular subtype of aggressive high grade serous ovarian cancers. AB - Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5) of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous ovarian cancers we provide a novel strategy for targeted therapeutic intervention. PMID- 21533293 TI - Topical retinoids for pigmented skin. AB - Topical retinoids are an important class of drugs for treating several dermatoses occurring more frequently in patients with pigmented skin, such as melasma, post inflammatory hyperpigmentation, pseudofolliculits barbae and keloids. They also play a role in managing acne, psoriasis, photoaging, cutaneous T-cell lymphoma, Kaposi sarcoma and disorder of hyperkeratosis in this demographic as well. In general, topical retinoids are well tolerated in pigmented skins. There is little evidence to suggest that patients with darker skin are at increased risk of irritation. However, retinoid dermatitis can induce post-inflammatory hyperpigmentation and attempts should be made to reduce its occurrence by modifying treatment regimens in patients with pigmented skins. PMID- 21533295 TI - Fillers in the skin of color population. AB - The skin of color population in the United States is rapidly growing and the cosmetic industry is responding to the demand for skin of color targeted treatments. The aging face in skin of color patients has a unique pattern that can be successfully augmented by dermal fillers. Though many subjects with skin of color were not included in the pre-market dermal filler clinical trials, some post-market studies have examined the safety and risks of adverse events in this population. The safety data from a selection of these studies was examined. Though pigmentary changes occurred, there have been no reports of keloid development. Developing a patient-specific care plan and instituting close follow up is emphasized. PMID- 21533296 TI - Progressive macular hypomelanosis. AB - Progressive macular hypomelanosis is an under-recognized disorder characterized by the presence of numerous ill-defined hypopigmented macules and patches on the trunk of young adults. Although common, particularly in Fitzpatrick skin types IV VI, this condition is frequently misdiagnosed and treated inadequately with antifungals or topical steroids resulting in patient frustration. The exact pathogenesis of progressive macular hypomelanosis is unknown; however, recent studies suggest hypopigmentation results from decreased melanin formation and altered melanosome distribution in response to Proprionibacterium. While there are no well-established or consistently effective therapies for progressive macular hypomelanosis, our growing understanding of its pathogenesis urges consideration of alternative treatment strategies. Here, we report five patients with progressive macular hypomelanosis who benefitted from topical and systemic antimicrobial therapy and summarize the current clinical, pathological and treatment paradigms of this disorder. PMID- 21533297 TI - Topical tacrolimus is more effective for treatment of vitiligo in patients of skin of color. AB - BACKGROUND: Vitiligo vulgaris is a chronic autoimmune depigmenting disorder affecting individuals of all skin colors. Lesions are commonly noted in the periorificial face and over the upper and lower extremities in areas of friction. Although there have been many published reports of successful therapies for vitiligo, few have assessed differential response based on skin color. OBJECTIVE: To determine if topical tacrolimus is more effective at treating vitiligo in individuals of color. METHODS: An IRB-approved chart review of patients with a diagnosis of vitiligo was conducted including patients seen between May 2001 and April 2006. Patients with vitiligo were treated with tacrolimus 0.03% for children ages 2-15 years of age and tacrolimus 0.1% ointment for individuals 16 years of age or older, applied twice-daily to all hypopigmented or depigmented lesions. A review of clinical features, Fitzpatrick skin type and response to topical tacrolimus were recorded. RESULTS: Topical tacrolimus was effective in all Fitzpatrick skin types, with superior efficacy on body lesions in individuals of Fitzpatrick types 3-4 (Fisher exact test, P=0.03). Further, individuals with Fitzpatrick type 3-4 skin had shorter interval to greater than 75 percent improvement of lesions on the body (Kaplan-Meier Log-rank, P=0.03) and head and neck (P=0.016). CONCLUSION: Topical tacrolimus is an effective treatment for vitiligo irrespective of skin tone, with greatest benefit in Fitzpatrick type 3-4 skin. Repigmentation of lesions on the head and neck is superior to repigmentation of the body and extremities in all racial subgroups. PMID- 21533298 TI - Scalp hyperkeratosis and alopecia in children of color. AB - BACKGROUND: Scalp hyperkeratosis and/or alopecia are common pediatric dermatologic findings. In Caucasian children, scalp hyperkeratosis of childhood is most often associated with atopic and seborrheic dermatides. Recent data is lacking on the clinical meaning of scalp hyperkeratosis and alopecia in children of color. OBJECTIVE: To determine diagnosis associated with scalp hyperkeratosis and/or alopecia in a predominately Black and Hispanic pediatric patient population. METHODS: A retrospective chart review was conducted for all children (0-17 years of age) seen at our institution who had a scalp fungal culture for the evaluation of scalp hyperkeratosis and/or alopecia from January 2007 to September 2009. Fungal culture was performed using cotton swab technique, plating onto Sabouraud's and Mycosel media. Demographic features, fungal culture results, clinical symptoms, physical findings and final diagnosis were reviewed. RESULTS: 164 children were identified who were eligible for inclusion in the study, 75 of whom were Black and 56 Hispanic/Latino. Scalp hyperkeratosis was noted in 106 patients and alopecia was noted in 71 subjects. Tinea capitis was the final diagnosis in 50 out of 80 children who had hyperkeratosis without alopecia (60%), 16 of 43 children with alopecia alone (37.2%) and 23 of 28 children with both hyperkeratosis and alopecia (82.1%, P=0.0007). The odds ratio of tinea capitis in the presence of hyperkeratosis with alopecia was 7.49 with a 95 percent confidence limit of 2.19-25.70. CONCLUSION: Scalp hyperkeratosis, especially when accompanied by alopecia, is usually associated with tinea capitis in Black and Hispanic children. Fungal culture and empirical anti-fungal therapy are warranted in children of color with scalp hyperkeratosis. PMID- 21533299 TI - Melasma in Latin Americans. AB - Melasma is an acquired skin condition characterized by irregular brown or hyperpigmented patches typically located on the forehead, cheeks, nose, chin and upper lip. The pathogenesis of melasma is not completely understood, but is thought to be influenced by genetics, UV exposure, thyroid dysfunction and hormonal influences from either pregnancy or hormonal therapeutic medications. Peoples of Latin descent comprise a vast array of skin colors and skin phototypes. Similarly, disorders of pigmentation, particularly melasma, occur more frequently in people of Latin descent when compared to the general population. Melasma can be particularly distressing to patients and has been shown to impact a patient's quality of life in several studies. These factors can raise significant quality of life issues and therefore treatment is not only significant for improving patient clinical outcomes, but is crucial in improving important psychological and emotional aspects of patients' overall well being. This article provides a stepwise approach to the treatment of melasma based on current literature recommendations. PMID- 21533300 TI - A survey of skin conditions and concerns in South Asian Americans: a community based study. AB - BACKGROUND: South Asians represent a rapidly growing part of the U.S. population, increasing 188 percent from 1990 to 2000 (0.27% to 0.78%). Studies investigating the epidemiology of skin disorders in South Asian Americans are lacking. OBJECTIVE: We sought to determine common skin conditions and concerns among this population. METHODS: This was a community-based survey study. The IRB-approved survey tool was distributed to South Asians adults in the New York City area. All data was self-reported. RESULTS: 190 surveys were completed. 54 percent of responders were female and 46 percent were male. The age of participants ranged from 18-74 years. The respondents were predominantly foreign born (76%), but a large minority (32%) reported living in the U.S. for over 20 years. Nearly half (49%) of the study population reported having visited a dermatologist in the past. The five most common dermatologic diagnoses included: acne (37%), eczema (22%), fungal infection (11%), warts (8%) and moles (8%). The five most common concerns included: dry skin (25%), hair loss (22%), uneven tone (21%), dark spots (18%) and acne (17%). CONCLUSIONS: Our results suggest that the leading skin conditions and concerns in South Asian Americans are similar to those reported in other populations with skin of color. PMID- 21533301 TI - An over-the-counter moisturizer is as clinically effective as, and more cost effective than, prescription barrier creams in the treatment of children with mild-to-moderate atopic dermatitis: a randomized, controlled trial. AB - BACKGROUND: Atopic dermatitis (AD) is a prevalent skin disorder with significant cost of treatment. Several prescription device moisturizers have been approved by the FDA to treat AD but are significantly more expensive than well-crafted over the-counter (OTC) moisturizers. No studies have been performed to compare both the clinical efficacy and cost-efficacy of these prescription devices to OTC moisturizers. PURPOSE: The purpose of this study is to compare the clinical efficacy and cost-efficacy of a glycyrrhetinic acid-containing barrier repair cream (BRC-Gly, Atopiclair(r)), a ceramide-dominant barrier repair cream (BRC Cer, EpiCeram(r)) and an OTC petroleum-based skin protectant moisturizer (OTC Pet, Aquaphor Healing Ointment(r)) as monotherapy for mild-to-moderate AD in children. METHODS: Thirty-nine patients, age 2-17 years, with mild-to-moderate AD were randomized 1:1:1 to receive one of three treatments-BRC-Gly, BRC-Cer or OTC Pet-with instructions to apply the treatment three times daily for three weeks. Disease severity and improvement was assessed at baseline and on days 7 and 21. RESULTS: No statistically significant difference for any efficacy assessment was found between the three groups at each time point. The OTC-Pet was found to be at least 47 times more cost-effective than BRC-Gly or BRC-Cer. LIMITATIONS: The relatively small sample size of 39 subjects was not sufficient to establish OTC Pet as superior treatment in AD. CONCLUSIONS: OTC-Pet is as effective in treating mild-to-moderate AD as both BRC-Gly and BRC-Cer and is at least 47 times more cost-effective. NAME OF REGISTRY: II-AF-ATD-Aquaphor, Comparing the Efficacy and Cost-Effectiveness of Aquaphor to Atopiclair and EpiCeram in Children with Mild to Moderate Atopic Dermatitis. REGISTRATION IDENTIFIER: NCT01093469. PMID- 21533302 TI - Infliximab treatment for psoriasis in 120 patients on therapy for a minimum of one year: a review. AB - Infliximab is a chimeric monoclonal antibody, which acts by binding to both the soluble and membrane-bound tumor necrosis factor-?. In clinical practice, it is used as either monotherapy or in combination with other systemic therapies, particularly methotrexate. This study reviews clinical response and adverse events in 120 psoriasis patients with moderate-to-severe psoriasis who have received infliximab for a minimum of one year. The medical records of 120 infliximab-treated psoriasis patients at our referral psoriasis clinic in Dallas between 2002-2008 were reviewed for response rates, side effects and concomitant therapies. Of 120 charts reviewed, 112 (93%) patients had plaque type psoriasis, six (5%) had recalcitrant palmoplantar disease and two (1.6%) had severe acropustulosis of Hallopeau. Eighty-four (70%) patients had symptomatic psoriatic arthritis. The mean follow-up time was 2.2+/-1.1 years. One hundred and nine (91%) of the 120 patients had clearance of their psoriasis (response of more than 90% of initial BSA) at a median time of 12 weeks. Concomitant systemic treatments, primarily methotrexate, were given to 62 (52%) patients. Nineteen patients (16%) discontinued infliximab in the post-one-year treatment period for a variety of reasons, primarily failure to maintain adequate response. One hundred and four (87%) of patients required more than the standard dose of 5 mg/kg every eight weeks to maintain clearance. Infliximab either as monotherapy or in combination with traditional antipsoriatic agents is an effective and well tolerated treatment option for patients with moderate to severe psoriasis and psoriatic arthritis on therapy for over one year and continuing for the long term. PMID- 21533303 TI - Pyoderma gangrenosum following breast reconstructive surgery:a case report of treatment with immunosuppression and adjunctive xenogeneic matrix scaffolds. PMID- 21533304 TI - What's new in treatment of keloids? New applications for common therapies, new treatments to come. PMID- 21533305 TI - Monitoring dressing activity failures through RFID and video. AB - BACKGROUND: Monitoring and evaluation of Activities of Daily Living in general, and dressing activity in particular, is an important indicator in the evaluation of the overall cognitive state of patients. In addition, the effectiveness of therapy in patients with motor impairments caused by a stroke, for example, can be measured through long-term monitoring of dressing activity. However, automatic monitoring of dressing activity has not received significant attention in the current literature. OBJECTIVES: Considering the importance of monitoring dressing activity, the main goal of this work was to investigate the possibility of recognizing dressing activities and automatically identifying common failures exhibited by patients suffering from motor or cognitive impairments. METHODS: The system developed for this purpose comprised analysis of RFID (radio frequency identification) tracking and computer vision processing. Eleven test subjects, not connected to the research, were recruited and asked to perform the dressing task by choosing any combination of clothes without further assistance. Initially the test subjects performed correct dressing and then they were free to choose from a set of dressing failures identified from the current research literature. RESULTS: The developed system was capable of automatically recognizing common dressing failures. In total, there were four dressing failures observed for upper garments and three failures for lower garments, in addition to recognizing successful dressing. The recognition rate for identified dressing failures was between 80% and 100%. CONCLUSIONS: We developed a robust system to monitor the dressing activity. Given the importance of monitoring the dressing activity as an indicator of both cognitive and motor skills the system allows for the possibility of long term tracking and continuous evaluation of the dressing task. Long term monitoring can be used in rehabilitation and cognitive skills evaluation. PMID- 21533306 TI - Pathologic findings in synovial tissue of the musculoskeletal system: role of MRI in therapeutic clinic assessment. AB - OBJECTIVES: The clinical diagnosis of synovial lesions is difficult and radiographic findings may establish a confident diagnosis only in some cases. MR imaging has become the technique of choice in evaluating these lesions, because a presumptive diagnosis can be made in most cases. The purpose of this study was to evaluate the joint synovial disease through intravenous contrast MRI examination and the following histological validation. MATERIALS AND METHODS: Forty-eight patients were considered, twenty-seven women and twenty-one men, with pain relief or collectively determined by a known joint synovial disease, who underwent MRI at our institution between 2000 and the second half of 2010. All patients underwent magnetic resonance imaging using a low field magnet (0.2 Tesla) or high field magnet (1,5Tesla). RESULTS: Only nine patients were diagnosed with an inflammatory arthropathy, in the remaining cases non-inflammatory arthropathy of which the most frequent form was pigmented villonodular synovitis (PVNS) was diagnosed. CONCLUSIONS: MRI is able to provide an accurate representation of all the pathological changes involved in the joint space following acute or chronic inflammation and to define the characteristic features useful in differential diagnosis. PMID- 21533307 TI - Investigation about causes of blindness and low vision among members of Blind and Visually Impaired Italian Union (UICI). AB - PURPOSE: To evaluate the prevalence of the most important causes of blindness among visually impaired and blind, members of UICI (Blind and Visually Impaired Italian Union). The main aim is to get information about the most important ocular diseases which make people blind or visually impaired in Italy. Further purpose is to make our data useful to provide economical evaluations about public expense due to blindness and low vision. MATERIALS AND METHODS: A retrospective analysis was carried out on UICI database to get information about members of the most important UICI Provincial Centers. The Centers were selected depending on specific inclusion criteria. The descriptive analysis was performed with SAS System 9.1.3 and Microsoft Excel 2007. RESULTS: Data were available for 15,725 UICI members, whose 39% (n=6,133) were visually impaired and 61% (n=9.592) were blind. Pathologic myopia was responsible for low vision and blindness in 11.78%, AMD in 11%, cataract in 8.92%, glaucoma in 8.31%, diabetic retinopathy in 8.23%, retinitis pigmentosa in 6.96%. DISCUSSION: The analyzed sample allows to get only a rough, although useful, estimate of low vision and blindness in Italy. The causes of visual impairment we found are quite in line with those provided by other international studies. The main difference from previous studies concerns pathologic myopia and retinitis pigmentosa as the most important causes of low vision and blindness among working-age people. Our epidemiological study should be mixed with economical cost-effectiveness evaluations in order to provide further impulses to efficient prevention programs. PMID- 21533308 TI - [Economic evaluation of telehomecare in chronic lung diseases]. AB - OBJECTIVES: We attempted to quantify the cost-effectiveness ratio in telemonitoring lung function of patients affected by Cystic Fibrosis (CF). MATERIALS AND METHODS: We examined the costs of Telehomecare (THC) in the follow up of CF patients. We considered the failed hospitalizations as incomes. A standardized questionnaire was submitted by e-mail to verify the patient satisfaction and expectation levels. We studied 3 groups of patients: a) 17 CF patients in THC; b) 28 CF patients not followed by THC and c) 28 non-CF patients affected by chronic diseases and not followed by THC. Some parameters with no market value were evaluated using "willingness to pay" (WTP). RESULTS: An annual saving of ?.5241 was calculated for single FC patient followed by THC. The WTP analysis showed that patients affected by chronic diseases expected very much from new technologies. CONCLUSIONS: The THC use in CF shows several advantages as fewer hospitalization and economical saving in a general trend of limited economical resources. Further studies are needed to confirm our data. PMID- 21533309 TI - [Knee osteoarthritis and SPA therapy: assessment of joint function and quality of life]. AB - OBJECTIVES: In industrialized countries the increase in life expectancy of the population has led to an increase in chronic diseases such as osteoarthritis (OA). Knee osteoarthritis for the high disability and psychological stress, not considered adequately, has negative impact on the quality of life. In this pathology SPA therapy, in particular the sulphur mud-bath therapy, can provide a stage of the therapeutic strategy. However, studies on the impact of SPA therapy on the quality of life in knee osteoarthritis are insufficient. The aim research was to evaluate the effectiveness of SPA therapy on chronic pain, joint function and psychological distress that characterize knee osteoarthritis. PATIENTS AND METHODS: The study has been performed on 44 subjects affected by knee Osteoarthritis, being 27 (61%) women and 17 (39%) men (mean age: 58+/-8.7 years, age range: 42-76 years). The investigated subjects were treated with a cycle of a combination of daily locally applied mud-packs and bicarbonate-sulphurous mineral bath water from Terme of Telese SpA (Benevento-Italy). At the beginning and at the end of the Spa therapy was evaluated the level of pain (using VAS scale), the degree of knee flexion (using goniometer), the level of anxiety and depression (using SDS Zung Test and SAS Zung test) and the impact of sulphurous mud-bath treatment on quality of life (using the algofunctional Lequesne indice). RESULTS: At the end of Spa therapy the results of our study have shown a significant (p<0.05) reduction of the pain (1.8+/-1.6 -> 0,9+/-1,3) and a significant (p<0.01) increase of the knee flexion (79 degrees +/-22 -> 91.3 degrees +/-19) with an improved quality of life. CONCLUSIONS: The data from this investigation seem to indicate that the SPA therapy may be useful in improving joint function and quality of life in knee osteoarthritis. PMID- 21533310 TI - A case of lichen amyloidosus treated with acitretin. AB - Lichen amyloidosus is a cutaneous dermatosis clinically characterized by an hyperkeratotic brownish-grey papular eruption located on trunk and extremities, associated to severe pruritus. Histologically it is characterized by amyloid deposits in the papillary derma. Amyloid is an amorphous substance, probably derived by apoptotic keratinocites and other protein such as Apolipoprotein E. The exact pathogenesis of this deposition is not yet understood but some factors can act as favourable agents, such as pruritus. In fact this dermatosis is often associated to intensely pruritic conditions. Its treatment is very difficult but is important, because patients refer a bad quality of life. In literature have been described a lot of therapeutic options, often unefficacious. We describe herein the case of a 39-year old patient affected by Lichen amyloidosis, treated with acitretin a good improvement of cutaneous lesions and a complete resolution of pruritus after only three weeks of treatment. At actual follow-up of eight months the results are maintained. PMID- 21533311 TI - Acute myopia: might be a presenting symptom of rheumatic disease? A case report. AB - This is a case-report of a patient who came to our Eye Emergency Room for acute onset of myopia and asthenia. The purpose is to evaluate the causes of acute myopia in a 28 year old woman with a family history of rheumatic diseases and a positive antibody titer (ANA). The UBM-study showed a 360 degrees choroidal effusion and the hematological analysis showed mild anemia, lymphocytosis and ANA antibodies were positive. All that signs could suggest a vasculitis-like onset of an autoimmune disease, involving the eye first. Although the diagnosis of Systemic Lupus Erythematosus (SLE) or other autoimmune diseases cannot be confirmed according to the rheumatologic criteria, the vasculitic ocular manifestations with positive antibodies in the young woman need further evaluation because it seems to be enough to refer the patient to a rheumatology follow-up. PMID- 21533312 TI - Narrative medicine: the modern communication between patient and doctor. AB - In Modern Medicine the ability to communicate represents a true and unique operative methodology which is the basis of Narrative Medicine. This type of approach does not represent an alternative to the traditional model, but rather expands its boundaries while preserving its scientific base; where the feelings, expectations, and desires of the Patient and his interpretation of the disease, more or less obvious, are read in the broad context in which the Patient himself exhibits. Two principle themes in medical training have by now been clearly identified and can be summarized as follows: the ability to understand and to explain (what to say to the patient) and the ability to listen and to comprehend (how to speak to the patient). In this regard the modern Narrative Medicine is a holistic approach to the complexity of the method known as the most effective and most efficient - not only in patient-centered medicine, but also in the improvement of services rendered to both the individual and society at large. PMID- 21533313 TI - Tocotrienol rich fraction (TRF) supplementation protects against oxidative DNA damage and improves cognitive functions in Wistar rats. AB - AIM: Oxidative stress is caused by imbalance between the productions of reactive oxygen species (ROS) and antioxidant defense mechanisms. Palm oil antioxidants such as tocotrienol rich fraction (TRF) is known to have neuroprotective effects on neurones by acting against free radical induced neuronal cell death. This study was undertaken to elucidate the effect of TRF on oxidative DNA damage and cognitive functions in experimental rats. MATERIALS AND METHODS: A total of 20 male Wistar rats (aged 3 months) were divided into 2 groups: (i) control group fed with distilled water and (ii) experimental group fed with TRF (200 mg/ kg body weight) for 8 months. DNA damage was determined using Comet assay. Antioxidant enzymes like superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were assessed in the blood. The Morris Water Maze (MWM) test was used to evaluate the cognitive functions. RESULTS: DNA damage was significantly reduced in the experimental group supplemented with TRF compared to the control group (p <0.05). In the group supplemented with TRF, the percentage of DNA damage was 2.87 +/- 0.48% compared to 5.96 +/- 0.43% in the control group. SOD, GPx, and CAT enzyme activities increased in experimental group. Results from MWM showed improvement in cognitive functions as determined by latency to target platform, swim path and average speed between TRF and control groups. CONCLUSIONS: Continuous supplementation of TRF for 8 months reduced DNA damage and exhibited positive influence in spatial learning and memory. PMID- 21533314 TI - [Sacrococcygeal teratoma: single center experience and functional long-term follow-up]. AB - OBJECTIVE: To propose long-term follow-up protocol to analyse clinical and functional aspects and evaluate the Quality of Life (QoL) of patients with Sacrococcygeal Teratoma (SCT). MATERIALS AND METHODS: The long-term follow-up of 14 out of 28 patients has been assessed through the retrospective review of data related to antenatal diagnosis, obstetric pathology and surgery, collected from July 1985 to December 2009. It has been accomplished by analysing functional and aesthetic outcomes and the QoL experienced by the patients with an average observation range of 121 months for each patient. RESULTS: Concerning the anorectal functionality, 14% of patients reported impairment of fecal continence while 36% had completely normal bowel habits. Other health problems varying from urinary incontinence to neurogenic bladder were reported by 36% of patients. Dealing with the functionality of lower limbs, 20% of patients exhibited minor dysfunctions while 7% major ones. Optimal aesthetic outcome of the surgical scar has been reported only by 21% of the specimen. The evaluation of QoL pointed out that 64% of patients are moderately satisfied while 36% presented problems. CONCLUSIONS: We believe that functional sequelae should play an important role during antenatal counselling and that the urological and anorectal follow-up for SCT patients should be long-term evaluated. Furthermore, aesthetic aspects and psychological support should be taken into account carefully especially during childhood. PMID- 21533315 TI - [Diagnosis of deficit and attention/hyperactivity disorders (ADHD) in patients with bipolar or unipolar depression: an experimental study]. AB - INTRODUCTION: The present research study starts up from the current scientific and academic interest concerning Deficit and Attention/Hyperactivity Disorders, which in this period seems to have an "epidemic" diffusion. Some authors have proved how the Deficit and Attention/Hyperactivity Disorder may predispose to the development of other psychopathological attitude in adulthood. A recent study has underlined a common comorbidity between ADHD in childhood and Bipolar Disorder. The aim of the present was to verify the existence of an ADHD diagnosis in patients with depression (Unipolar and Bipolar) and to verify if such syndrome overstays in the present psychopathological picture. Moreover there has been even the intention to investigate on a difference in ADHD symptomatology in patients with Bipolar and Unipolar Depression. MATERIALS AND METHODS: The study has been conducted on a sample of 67 patients with depression diagnosis (35 patients with bipolar depression diagnosis, 32 patients with depression unipolar diagnosis) enrolled at the Bipolar Disorders Unit of the Clinical Psychiatry and Drug Dependence Institute of the Policlinico Universitario A. Gemelli in Rome. The evaluation has been performed through the supply of the following psychometric tests: Neo Personality Inventory (Mole-pi-R), Brown Attention Deficit Disorder Scale (Brown ADD-Scale), Adult ADHD Self-Report Staircases (ASRS-v1.1), Criteria of the Deficit and Attention / Hyperactivity Disorder for childhood according to the DSM-IV-Tr. RESULTS: The achieved results point out that 42% of the sample has satisfied the ADHD Criterions during their childhood according to the DSM-IV-Tr and that symptomatology seems to remain in the present psychopathological picture. As to polarity of depression it has emerged that patients with Bipolar Depression diagnosis have satisfied with a greater frequency the ADHD criteria during their childhood than patients with Unipolar Depression. CONCLUSIONS: Our results seem to confirm the hypothesis that patients with bipolar depression diagnosis have more Deficit and Attention / Hyperactivity Disorders comorbidity diagnosis than others. PMID- 21533316 TI - The extended-release formulation of quetiapine fumarate (quetiapine XR) adjunctive treatment in partially responsive generalized anxiety disorder (GAD): An open label naturalistic study. AB - AIMS: To assess the effect of adjunctive treatment with extended-release formulation of quetiapine fumarate (quetiapine XR) to other antidepressants in the treatment of partially responsive, poorly functioning patients with generalized anxiety disorder was assessed. MATERIALS AND METHODS: Twenty four consenting adult outpatients with confirmed DSM-IV diagnosis of generalized disorder were identified. All patients failed at least one 8-week treatment trial with SSRI or SNRI antidepressant. All were treated with quetiapine XR as an add on treatment to citalopram or vanlafaxine antidepressant for at least 12 weeks. The primary efficacy measure was the Clinical Global Impression Scale (CGI-S). Other scales included; the Hamilton Anxiety Scale (HAM-A) scale, Sheehan Disability Scale, and the Abnormal Involuntary Movement Scale (AIMS). Baseline measures prior to adding quetiapine XR were compared to those at 4, 8 and 12 weeks with the adjunctive treatment. RESULTS: Twenty three patients completed the trial. There was significant rapid resolution of the anxiety symptoms in all effectiveness measures, including the symptoms of anxiety as shown by changes from baseline in HAM-A, and CGI at four weeks. Improvement was maintained to week twelve. Impairments in work, social, and home responsibilities were also reduced significantly, and there were no significant changes in weight at 12 weeks. Patients tolerated the adjunctive treatment well. CONCLUSION: Quetiapine XR may have anxiolytic properties and could be used effectively as adjunctive treatment with SSRIs in GAD patients with partial response to SSRs or SNRISs. However double blind randomized trials are needed to support these results. PMID- 21533317 TI - [Urban stressors and thyroid hormones]. AB - OBJECTIVES: The aim of the study is to evaluate whether occupational exposure to urban stressors could cause alterations in thyroid hormones plasma levels (TSH, FT3 and FT4) in female outdoor workers vs. administrative. MATERIALS AND METHODS: The study has been performed on an initial sample of 198 female subjects divided in two groups (occupationally exposed and not exposed to urban stressors). After excluding the subjects with the main confounding factors, female outdoor workers and administrative staff were matched by age, working life and drinking habit. RESULTS: In 40 female outdoor workers mean plasma TSH levels were significantly higher compared to 40 administrative staff. The distribution of TSH values in outdoor workers and in administrative staff was significant. Plasma FT3 and FT4 levels were not significantly different in the two groups. Our results suggest that exposure to urban stressors (chemical, physical and psycho-social), can alter the plasma concentration of TSH. CONCLUSIONS: According to our previous research, plasma TSH levels may be used as an early biological marker of chronic exposure to urban stressors, in occupational set even before the onset of the related disorders. PMID- 21533318 TI - Cerebral haemorrhage in a patient with systemic lupus erythematosus and vasculitis treated with intravenous immunoglobulins for a long-time and in absence of other risk factors. AB - Central nervous system involvement has been reported in up to 60% of patients with systemic lupus erythematosus (SLE). Cerebral vasculitis in SLE is rare and its incidence in post-mortem studies has been documented from 7% to 15% of cases. Cerebral haemorrhage is described in 0.4-7% of cases and it is usually due to inherent or iatrogenic factors (e.g., arterial hypertension, thrombocytopenia or anticoagulation). We report a case of cerebral haemorrhage in a patient with SLE and histologically proven cerebral vasculitis, leading to the death of the patient within 12 months. In the patient presented herein, the cerebral haemorrhage was not correlated to possible known causes of these events, apart from the long-term use of intravenous immunoglobulins. The authors discuss the possible role of intravenous immunoglobulin therapy as pathogenetic factor for cerebral vasculitis in this patient. PMID- 21533319 TI - Long-term survival after transarterial chemoembolization for hepatocellular carcinoma. AB - Hepatocellular carcinoma is a main challenge in oncologic care. Surgery is the mainstay of treatment. Transarterial chemoembolization is the most widely used palliative treatment for hepatocellular carcinoma. The Authors present a case report of a 61-year old man with hepatocellular carcinoma, belonging to Child Pugh class A. The advanced age and the previous history of bladder carcinoma made the patient not suitable for liver transplantation. The patient refused hepatic resection so that transarterial chemoembolization was proposed. During 14-year follow-up there was intrahepatic progression of the tumor after the first treatment, followed by reduction in size and number of the lesions after subsequent treatments. In spite of the ominous prognosis of hepatocellular carcinoma, in this case-report transarterial chemoembolization allowed us to achieve a unique long-term survival. PMID- 21533320 TI - Reconstructing medical history: historiographical features, approaches and challenges. AB - Medical historiography deals with the concepts, theories, and approaches adopted in the reconstruction and discussion of the history of medicine. The expression has changed through time and according to different scholars and contexts, and it largely depends on the general standpoint from which the medicine of the past is examined. From an Evidence Based History of Medicine perspective, an accurate and complete examination of all available sources must be carried out to draw a picture of the medical theme examined, and, to reach this aim, the issue of the reliability of sources is a preliminary point to take into account. Different historiographical models adopted in the twentieth century will be discussed in this paper. The current ample discussion on the characterising features, methods and challenges of medical historiography documents the wide extent of the debate on the ways available today for the reconstruction of medical history. It also testifies to the relevance, inter-disciplinarity and remarkable vitality of the topic in current academic, scientific and social contexts. Medical and health history is an essential part of current medicine, and the study of the development of medicine through time is an extremely formative experience, which should not be confined to historians and professionals, but which, in appropriate formats and in correct methodological terms, should have full right of citizenship in current health care initiatives. PMID- 21533321 TI - [Specificity of action of anticancer agents]. AB - Since the first cancer chemotherapy use, efforts have been made in identifying drugs with an antitumor specific action, but cancer is a very complex situation to be cured with a single agent, and to increase drugs selective cytotoxicity new agent combinations, or innovative cellular cycle related schedule, or the use of pro-drugs have been developed. Notwithstanding some relevant improvements in results, chemotherapy remains often a palliative approach. The improved knowledge of the biology of cancer, and of molecular mechanisms and specific targets, has recently modified the approach to various tumors. In particular, the identification of a single and specific genetic alteration in some tumors such as myeloid chronic leukaemia or gastrointestinal stromal tumors (GIST) led to the development of imatinib, a "target" drug with a multikinase inhibitor activity towards the specific genetic alteration; this unique opportunity is not applicable to other tumors, because usually tumors have multiple genetic alterations with very complex molecular pathways. The development of drugs with a multitarget action is probably the best approach to the majority of human cancers, but other possibility are the combination of multiple agents, each with known selective activity towards a specific molecular target, or the choice of a chemotherapic drug in combination with one or more molecularly targeted drugs. The knowledge of the multiple and extremely complex molecular pathways of the neoplastic cells will hopefully drive oncologic science towards a more "exact" science, with the use of "personalized" treatment in each cancer patient. PMID- 21533322 TI - [Quick guide to communicate important news to terminally ill patients]. AB - The aim of this work is to be able to publish the information concerning communication with cancer patients as recommended in England. The observation and the study protocol during the stay abroad have been given the opportunity to stylize specific information on the methodology of communication of important information to terminally ill patients. It seems readily apparent as they characterized by both technical precision and sensivity to emotions and descriptions for the individual patient. How is shared by all chronic pain is predominantly complex emotion, a mix of additions and perceived physical and emotional pain - emotional. Because accurate information is beneficial to the patient and that really is not turned, so to speak, a "bullet" it is necessary that you have created, over time, a concrete "therapeutic alliance" between body physician, patient and possibly family. This arises, for sure, even at first accepted the patient during the clinical visit attentive to detail, is renewed in the definition of the common objective to be achieved, so analgesia and it is expressed in the certainty that the physician provides all the resources realistically available. It is then up to the sensitivity of the operator, doctor and/or nurse, described in the "take charge" find, from time to time, the words and manners, verbal and nonverbal, to respond fully to questions of the patient same. PMID- 21533323 TI - [Post-infectious irritable bowel syndrome]. AB - Acute infectious gastroenteritis is the strongest known risk factor for the development of irritable bowel syndrome (IBS), one of the most common functional gastrointestinal disorders. The knowledge about the incidence and prevalence of post-infectious IBS (PI-IBS) in the general population is still limited. Risk factors have been identified in the development of PI-IBS. These include the virulence of the pathogen, younger age, female sex, the long duration of the initial illness and the presence of psychological disturbances. Histopathologic data demonstrate a low-grade mucosal inflammation in a subset of patients with IBS. Furthermore, a change in intestinal microflora could also be involved although confirmatory studies are required. The use of probiotics or non absorbable antibiotics during the acute infective episode could play a preventive role. Nonetheless, the discovery that an infective episode may trigger the development of IBS has not substantially changed the clinical management of this subset of patients compared to the classical (non infective) form of IBS. Future studies aimed at identifying specific therapies are waited. PMID- 21533324 TI - [An essay about science and linguistics]. AB - Both the methodology and epistemology of science provided the criteria by which the scientific research can describe and interpret data and results of its observational or experimental studies. When the scientist approaches the conclusive inference, it is mandatory to think that both the knowledge and truth imply the use of words semantically and etymologically (semiologically) appropriate, especially if neologisms are required. Lacking a vocabulary, there will be the need of popularizing the inference to the linguistics of the context to which the message is addressed. This could imply a discrepancy among science, knowledge, truth and linguistics, that can be defined "semiologic bias". To avoid this linguistic error, the scientist must feel the responsibility to provide the scientific community with the new words that are semantically and etymologically coherent with what it has been scientifically discovered. PMID- 21533325 TI - Differences in itch characteristics between psoriasis and atopic dermatitis patients: results of a web-based questionnaire. AB - Differences in itch characteristics between different inflammatory dermatoses are not well described. The aim of this study was to assess differences in itch characteristics between patients with psoriasis and atopic dermatitis using a previously validated web-based questionnaire that was made available through the National Psoriasis Foundation and National Eczema Association for Science and Education websites. Participants rated frequency and intensity of itch, associated symptoms, itch descriptors, and effect of scratching. A total of 524 subjects with atopic dermatitis and 195 subjects with psoriasis completed the survey. Atopic dermatitis responders experienced more frequent and more intense itch. Associated sweating and heat sensation were also more common in atopic dermatitis. Scratching was considered pleasurable in both atopic dermatitis and psoriasis; pleasurability correlated weakly with itch intensity in atopic dermatitis. Psoriasis respondents reported higher embarrassment associated with itch. Itch sensation is experienced differently among patients with atopic dermatitis and psoriasis. Future therapeutic interventions may be developed to target these differences. PMID- 21533326 TI - Bibliometric indicators and international publishing in physical and rehabilitation medicine. PMID- 21533327 TI - Survival after spinal cord injury in Finland. AB - OBJECTIVE: Mortality, cause of death and risk indicators for death among patients with traumatic spinal cord injury were investigated over a 30-year period. DESIGN: A cross-sectional study with retrospective data. SUBJECTS: All patients (n = 1647) aged 16 years and over who had sustained traumatic spinal cord injury during the period 1976-2005, who were admitted to Kapyla Rehabilitation Centre, Helsinki, Finland, participated in the study. METHODS: Demographic and clinical data were collected from the registers of Kapyla Rehabilitation Centre. Cause specific mortality was assessed using Statistics Finland's official cause-of death register. RESULTS: During the observation period (1976-2007) 419 patients died. The main causes of death were respiratory disease (28%), cardiovascular disease (21%), suicide (10%) and external causes (9.5%). The mean age at death was 55.5 years for men and 58.2 years for women. Ten-year survival was 97.9%. Mortality was significantly affected by age at onset of injury, neurological level and extent of lesion. Survival of traumatic spinal cord injury patients was approximately 50% that of the general population, and survival of the general population was 80% during the follow-up period. CONCLUSION: These results support the need for improvements in long-term rehabilitative care and regular follow-up of patients with traumatic spinal cord injury. The importance of psychosocial follow-up services must be emphasized. PMID- 21533329 TI - Guided internet-based cognitive behavioural treatment for chronic back pain reduces pain catastrophizing: a randomized controlled trial. AB - OBJECTIVE: The aim of this study was to investigate whether an Internet-based cognitive behavioural intervention would have an effect on the symptoms of chronic back pain. DESIGN: Experimental design with a treatment group and a control group measured before and after a treatment period. SUBJECTS: Participants who met the criteria for chronic back pain (n = 54). METHODS: All participants were screened in a live, structured interview before inclusion. The study period was 12 weeks and the treatment consisted of education, cognitive skills acquisition, behavioural rehearsal, generalization and maintenance. The main outcome of interest was the catastrophizing subscale of the Coping Strategies Questionnaire. RESULTS: There were statistically significant reductions from pre- to post-treatment in catastrophizing in the treatment group, and an improvement in quality of life for the treatment group. However, most outcome measures did not indicate a positive treatment outcome. On a scale measuring pain catastrophizing, 58% (15/26) of the treated participants showed reliable improvement, compared with 18% (5/28) of the control group. CONCLUSION: Internet-based cognitive behavioural therapy can serve as a complement for individuals with chronic pain who prefer this treatment and have difficulties accessing specialist treatment facilities. PMID- 21533328 TI - Efficacy and safety of treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complexing proteins; NT 201) in post-stroke upper limb spasticity. AB - OBJECTIVE: To investigate the efficacy and safety of repeated treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complexing proteins; NT 201) in post-stroke upper limb spasticity. PATIENTS AND DESIGN: After completing a double-blind, placebo- controlled, multicentre study (up to 20 weeks), 145 patients received up to 5 additional sets of NT 201 injections for an open-label extension period of up to 69 weeks. METHODS: Upper limb muscle groups were treated as clinically indicated; injection intervals were >= 12 weeks. Outcome was assessed 4 weeks after each injection session and at the end of the study. RESULTS: Muscle tone (flexors of wrist, elbow, finger, and thumb, and forearm pronators) improved throughout the study (response rate: up to 80.6%, p < 0.0001, Ashworth Scale). Continuous and significant improvements were also observed in disability (p < 0.05, Disability Assessment Scale). The majority of investigators, patients and caregivers rated NT 201 efficacy as very good or good (56-84%). Adverse events considered treatment-related occurred in 11% of patients. Formation of neutralizing antibodies was not observed in any patient after repeated treatments. CONCLUSION: Treatment with NT 201 showed sustained improvements in muscle tone and functionality (median dose 400 units) over a study duration of up to 89 weeks, and was well tolerated during repeated treatments for post-stroke upper limb spasticity. PMID- 21533330 TI - Long-term effectiveness of neuromuscular electrical stimulation for promoting motor recovery of the upper extremity after stroke. AB - OBJECTIVE: To investigate the long-term efficacy of neuromuscular electrical stimulation in enhancing motor recovery in the upper extremities of stroke patients. METHODS: A total of 46 patients with stroke were assigned to a neuromuscular electrical stimulation group or a control group. All patients received a standard rehabilitation programme. Patients in the neuromuscular electrical stimulation group received neuromuscular electrical stimulation for 30 min, 5 days a week for 3 weeks. Measurements were recorded before treatment, at the 2nd and 3rd week of treatment and 1, 3 and 6 months after treatment ended. The Modified Ashworth Scale for spasticity, the upper extremity section of the Fugl-Meyer motor assessment, and the Modified Barthel Index were used to assess the results. RESULTS: Significant improvements were found in both groups in terms of Fugl-Meyer motor assessment, and Modified Ashworth Scale scores after the 3rd week of treatment. The significant improvements persisted 1 month after treatment had been discontinued. At 3 and 6 months after treatment was discontinued the average scores in the neuromuscular electrical stimulation group were significantly better than those in the control group. CONCLUSION: Three weeks of neuromuscular electrical stimulation to the affected upper extremity of patients with stroke improves motor recovery. The effect persists for at least 6 months. PMID- 21533331 TI - Treatment of spasticity related to multiple sclerosis with intrathecal baclofen: a long-term follow-up. AB - BACKGROUND: Spasticity is a frequent disabling symptom in patients with multiple sclerosis, which contributes to functional deterioration. OBJECTIVE: To evaluate the long-term effect of intrathecal baclofen therapy in multiple sclerosis related spasticity and to evaluate the side-effects of long-term therapy, and the doses of baclofen required. METHODS: Fourteen patients with multiple sclerosis were followed up clinically for a mean of 62 months (range 19-137 months). Clinical evaluation was made using individual goals, modified Ashworth scale, and Kurtzke Expanded Disability Status Scale. RESULTS: Spasticity, measured with the modified Ashworth score, decreased in all patients by a mean of 1 point. The score on the Expanded Disability Status Scale improved in 2 cases. Prior to implantation, 10 patients (72%) reported severe pain. After implantation 3 improved and 7 became pain-free. The daily doses needed for treatment were highly individual. The effect of intrathecal baclofen on spasticity lasted observation time. One patient experienced progressive cognitive impairment as a side-effect of baclofen. CONCLUSION: Intrathecal baclofen is well-tolerated and the effect lasts for up to 12 years. A thorough continuous clinical assessment is required because the differentiation between symptoms of multiple sclerosis progression and side-effects of baclofen may be difficult. Intrathecal baclofen should be considered as an option for long-term treatment of patients with advanced spasticity. Pain control can also be achieved by optimized intrathecal baclofen treatment. PMID- 21533332 TI - Factors affecting functional outcome of Sichuan-earthquake survivors with tibial shaft fractures: a follow-up study. AB - OBJECTIVE: The aim of this study was to analyse the various factors affecting functional recovery of earthquake survivors with tibial shaft fractures in Sichuan, China, and to provide a clinical reference for the future management of people injured in earthquakes. METHODS: A total of 174 earthquake survivors with tibial shaft fractures were investigated using a face-to-face survey 15 months after the earthquake. Functional recovery after fracture was evaluated by Johner Wruhs' criteria. Thirteen of the parameters that may influence functional recovery after fracture were included. Univariate and multiple stepwise logistic regression analyses were employed. RESULTS: Functional recovery was positively associated with rehabilitation intervention (odds ratio 5.3 (95% confidence interval 2.38-11.67)), but negatively correlated with the immobilization duration (odds ratio (per 10 days increase) 0.87 (95% confidence interval 0.798-0.947)), age (odds ratio (per 10 years increase) 0.54 (95% confidence interval 0.418 0.707)) and depressive symptomatology (odds ratio 0.21 (95% confidence interval 0.063-0.716)). CONCLUSION: Functional recovery of post-earthquake survivors with tibial shaft fractures is related mainly to availability of rehabilitation intervention, duration of immobilization, post-earthquake depressive symptomatology, and age. These results may support the future development of strategies for optimizing functional recovery of survivors with lower limb fracture after massive natural disasters. PMID- 21533333 TI - Effects of a prolonged exercise program on key health outcomes in women with fibromyalgia: a randomized controlled trial. AB - OBJECTIVE: To assess the impact of a long-term exercise programme vs usual care on perceived health status, functional capacity and depression in patients with fibromyalgia. DESIGN: Randomized controlled trial. SUBJECTS: Forty-two women with fibromyalgia were allocated randomly to 1 of 2 groups: an experimental group that carried out aerobic, strength and flexibility exercises for 24 weeks and a usual care control group. METHODS: Health status and functional capacity were evaluated using the Fibromyalgia Impact Questionnaire and the Short Form Health Survey 36. Depression was evaluated with the Beck Depression Inventory. RESULTS: Significant improvements were observed in health status and functional capacity for the exercise group over the control group. The magnitude of the effect size of these improvements, expressed as Cohen's d, was medium. The effect size (95% confidence interval) for the Fibromyalgia Impact Questionnaire was 0.58 (-14.12, -2.35), for the Short Form Health Survey 36. global score 0.54 (1.28, 14.52), and in the mental health domain of the Short Form Health Survey 36. 0.51 (1.20, 16.26). There was a large effect size in vitality. All the aforementioned improvements can be considered as clinically important changes. CONCLUSION: Results confirm that a long-term combination of aerobic exercise, strengthening and flexibility improves psychological health status and health-related quality of life in patients with fibromyalgia. PMID- 21533334 TI - Wii-based movement therapy to promote improved upper extremity function post stroke: a pilot study. AB - BACKGROUND: Virtual-reality is increasingly used to improve rehabilitation outcomes. The Nintendo Wii offers an in-expensive alternative to more complex systems. OBJECTIVE: To investigate the efficacy of Wii-based therapy for post stroke rehabilitation. METHODS: Seven patients (5 men, 2 women, aged 42-83 years; 1-38 months post-stroke, mean 15.3 months) and 5 healthy controls (3 men, 2 women, aged 41-71 years) undertook 1 h of therapy on 10 consecutive weekdays. Patients progressively increased home practice to 3 h per day. RESULTS: Functional ability improved for every patient. The mean performance time significantly decreased per Wolf Motor Function Test task, from 3.2 to 2.8 s, and Fugl-Meyer Assessment scores increased from 42.3 to 47.3. Upper extremity range of-motion increased by 20.1o and 14.33o for passive and active movements, respectively. Mean Motor Activity Log (Quality of Movement scale) scores increased from 63.2 to 87.5, reflecting a transfer of functional recovery to everyday activities. Balance and dexterity did not improve significantly. No significant change was seen in any of these measures for healthy controls, despite improved skill levels for Wii games. CONCLUSION: An intensive 2-week protocol resulted in significant and clinically relevant improvements in functional motor ability post-stroke. These gains translated to improvement in activities of daily living. PMID- 21533335 TI - Physical therapists' perceptions and use of standardized assessments of walking ability post-stroke. AB - OBJECTIVES: To determine physical therapists' perceptions and use of standardized assessments of walking ability post-stroke. DESIGN: Cross-sectional survey. METHODS: A questionnaire was posted to physical therapists in neurological practice registered in Ontario, Canada (n = 1155). Of the 705 responders, 270 treated adults with stroke and completed the questionnaire. RESULTS: Assessment tools most frequently used with > 6/10 patients were the Chedoke-McMaster Stroke Assessment (61.1%), Functional Independence Measure (45.2%), and gait speed test (32.2%). Only 11.1% consistently used the 6-minute walk test. The tools were used to evaluate (44.6%), monitor change over time (42.9%), form a prognosis (19.4%) or judge readiness for discharge (28.4%). Some therapists (40.1%) were unaware or unsure that valid and reliable measures of walking exist. As many as 80.5% of respondents agreed or strongly agreed that clinical practice guidelines should recommend specific measures of walking ability for use post-stroke. CONCLUSION: A moderate number of physical therapists consistently use standardized assessment tools to evaluate or monitor change in walking limitation post-stroke. Interventions to improve use must increase awareness, in addition to the perceived relevance and applicability, of recommended assessment tools. PMID- 21533336 TI - Enhancement of homing capability of endothelial progenitor cells to ischaemic myocardium through physiological ischaemia training. AB - OBJECTIVE: To investigate the effects of physiological ischaemia training on the quantity and activity of endothelial progenitor cells in rabbits with intermittent myocardial ischaemia. METHODS: A reversible coronary artery water balloon occluder (5.0 mm inner diameter) was placed around the proximal left ventricular branch and intermittent myocardial ischaemia was induced by deflation and inflation of the occluder. A wire electrode was inserted longitudinally into the epineurium of the sciatic nerve to generate physiological ischaemia training through isometric contraction induced by electrical stimulation. Rabbits were randomly divided into 3 groups: a sham operated group (SO), an intermittent myocardial ischaemia-only group (MI), and an MI plus physiological ischaemia training group (PT). Intermittent myocardial ischaemia was induced with 2-min ischaemia followed by 1-h reperfusion. Physiological ischaemia training was induced by electrical stimulation (40% maximum current strength, 1 ms, 40 Hz), 4 min per session, twice a day, 5 days per week for 4 weeks. At the end-points, endothelial progenitor cells were isolated and cultured for analysis of their migration ability. Endothelial progenitor cells were identified by dual-staining with Dil-labelled acetylated low-density lipoprotein and fluorescein isothiocyanate-labelled Ulex europaeus agglutinin-1. Circulating endothelial progenitor cells (CD34(+)/Flk-1(+)) were counted by fluorescence-activated cell sorter, and capillary density was evaluated by immunohistochemistry examination. RESULTS: Group PT showed the highest migration capacity of endothelial progenitor cells (151 cells, standard deviation 16/high power field) and the highest increase in circulating endothelial progenitor cells (p < 0.01) after 4 weeks' physiological ischaemia training. Capillary density in the myocardium was also significantly enhanced in group PT (p < 0.05). Pearson's analysis demonstrated a positive correlation between the number circulating endothelial progenitor cells and capillary density in the myocardium after 4 weeks' physiological ischaemia training (p < 0.05). CONCLUSION: Physiological ischaemia training may enhance the quantity and activity of endothelial progenitor cells in the blood, resulting in an increase in angiogenesis in the ischaemic heart region. PMID- 21533338 TI - Genetic aberrations in squamous cell carcinoma of the head and neck (SCCHN), with reference to oral carcinoma (review). AB - Squamous cell carcinoma of the head and neck (SCCHN) arises as a consequence of multiple molecular events induced by the effects of various habits such as tobacco and use of alcoholic beverages, influenced by environmental factors, possibly viruses in some instances, against a background of heritable resistance or susceptibility. Oral squamous cell cancers have a similar aetiology. Genetic damage affects many chromosomes and genes, including oncogenes and tumour suppressor genes, and it is the accumulation of such genetic damage, possibly along with an impaired ability to repair this damage - an inherited trait in some cases - that appears to lead to carcinoma in some instances, sometimes via a clinically evident pre-malignant, or potentially malignant, lesion. This communication reviews the advances in the understanding of this complex and rapidly developing area of research over the past decade. Cytogenetic and molecular analyses have shown changes in several chromosomes in oral cancer, particularly in chromosomes 3, 9, 11, 13 and 17. Analyses of allelic losses has allowed for the identification of chromosomal regions harbouring tumour suppressor genes (TSGs). Impaired function of such genes or their products, or activation of oncogenes, or both, may be involved in carcinogenesis. Probably the most significant findings thus far have been in relation to TSGs with the discovery of p53 mutations on chromosome 17 as in many other tumours, indicating disturbed function of this TSG and some on chromosomes 3 and 9 (MTS-1) which may be of comparable or greater significance. Over-expression of oncogenes, especially those on chromosome 11 (PRAD-1, Int-2, hst-l, and bcl-1 in particular) has also been implicated in carcino-genesis. The analysis of microsatellite instability (MI or RER, replication error repair) in tumour specimens, which are associated with defects in DNA repair genes has provided a further method of assessing genetic damage in the genome of sporadic cancers. Microsatellite instability (MI) has been demonstrated in several carcinomas as well as SCCHN. These research findings have now reached the stage where it is becoming possible to begin to introduce them into clinical practice for the more sensitive detection of potentially malignant lesions, better diagnosis and prognostication, and hopefully, to start to develop novel therapies such as gene therapy. PMID- 21533339 TI - Expression of basic fibroblast growth factor is necessary but insufficient for production of metastasis. AB - We determined whether overexpression of basic fibroblast growth factor (bFGF) is necessary for enhanced growth and production of metastasis by murine K-1735 melanoma cells. The bFGF gene was transfected into three nonmetastatic clones (C IO, C-19, and C-23) that do not express bFGF mRNA and protein and one metastatic clone that expresses high levels of bFGF mRNA and protein. Control cells were transfected with a dominant selectable marker neomycin resistance gene (neo). All bFGF-transduced cells expressed bFGF-specific mRNA transcripts and cellular bFGF protein and proliferated in culture with medium containing low concentrations of serum. Anchorage-independent growth in hard agarose was enhanced only in bFGF transfected nonmetastatic C-10 cells which, subsequent to the transfection, also expressed high levels of collagenase IV/gelatinase A activity. The treatment of C 10, C-19, and C-23 cells with exogenous bFGF induced collagenase IV/gelatinase expression, as did the addition of lysates from C-10/bFGF and C-23/bFGF cells. C 10/bFGF cells (but not C-19/bFGF or C-23/bFGF) produced highly vascular and rapidly growing subcutaneous tumors as well as a high incidence of lung metastasis. These data suggest that overexpression of bFGF is necessary but in itself not sufficient to convert nonmetastatic K-1735 cells to the metastatic phenotype and that enhanced tumorigenicity and metastasis require at least concurrent expression of bFGF and collagenase type TV genes. PMID- 21533340 TI - Growth suppression of non-small cell lung carcinoma cells by the introduction of the p16(INK4A) gene. AB - The p16(INK4A) gene is frequently inactivated in nonsmall cell lung carcinoma (NSCLC) by either mutations, deletions or DNA methylations. To assess the biological significance of p16(INK4A) inactivation in the development of NSCLC, full-length p16(INK4A) cDNA was introduced into NSCLC cell lines, A549 and H322, in which p16(INK4A) was homozygously deleted. NSCLC cells transfected with the p16(INK4A) expression vector formed colonies in 20-68% of those with a control vector, and exogenous p16(INK4A) protein was expressed in 4 of 68 A549-derived clones and none of 29 H322-derived clones, respectively. A549-derived clones which stably expressed the exogenous p16(INK4A) gene showed significant decrease in growth rate in vitro and tumorigenicity in vivo in proportion to the level of p16(INK4A) expression. Furthermore, the cell cycle of these cells significantly delayed with accumulation of cells in G1 phase. Micro-injection of p16(INK4A) expression vector also revealed that p16(INK4A) blocked S phase entry in both A549 and H322 cells. These results suggest that the restoration of the p16(INK4A) function suppresses the growth of NSCLC cells by induction of G1 arrest in the cells. Therefore, inactivation of p16(INK4A) may play an important role in the enhancement of unregulated NSCLC growth in vivo. PMID- 21533342 TI - Normal human oral keratinocytes are more sensitive to N-methyl-N'-nitro-N nitrosoguanidine-induced cytotoxicity and apoptosis than HPV-immortalized oral keratinocytes. AB - Exposure of HPV-immortalized, but not normal human oral keratinocytes, to the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) renders the cells tumorigenic. The underlying mechanism of this differential response of normal and immortalized cells was investigated. Normal primary human oral keratinocytes and three HPV-immortalized human oral keratinocyte cell lines exposed to MNNG were evaluated for survival rate, single and double-strand DNA breaks, and the expression of p53 and bcl-2 proteins. MNNG exposure for 2 h induced both greater cytotoxicity and a more rapid kinetic of cell death in normal keratinocytes than in the immortalized cells. Further, normal keratinocytes were more sensitive to lower concentrations of MNNG that were subtoxic for the immortalized cells. Likewise, with lower concentration of MNNG (50 mu M), significant single-strand DNA breaks in normal keratinocytes were induced whereas no such effect was seen in the immortalized cells. Double-strand DNA fragmentation (apoptosis) was observed in normal keratinocytes exposed to 50 mu M MNNG but not in the immortalized cells. Higher concentrations of MNNG (100 mu M) were toxic to both normal and immortalized cells although the normal cells were still more sensitive and with faster kinetics of cell death. MNNG-induced apoptosis was not attributable to down regulation of the anti-apoptotic product bcl-2 in normal cells; however, exposure of normal keratinocytes to MNNG did result in induction of the apoptotic gene p53. No change in p53 level was seen in the immortalized cells. These findings suggest that the selective sensitivity of normal keratinocytes to MNNG-induced apoptosis is in part due to the induction of p53. The HPV-immortalized cells are resistant to MNNG-induced apoptosis and therefore are capable of undergoing mutations affecting cell proliferation and resulting in tumori-genicity. PMID- 21533341 TI - Biological predictors of response to radiotherapy in cervical carcinomas. AB - On 21 patients with T1b-T3b tumours subjected to external radiotherapy and brachytherapy, the expression of P53 and glutathione S-transferase pi [GST-pi], immunohistochemically detected, the S-phase cells fraction (H-3-thymidine labeling index, TLI) and DNA content evaluated by image analysis were determined on biopsies before and after the first 10 Gy. P53 accumulation was reduced in 60% of P53-overexpressing tumours and not induced in P53-negative tumours, GST-pi was induced in about 40% of pretreatment GST-pi-negative cases, TLI was reduced in 70% of the cases regardless of pretreatment values, and DNA profiles remained unchanged in two-thirds of the cases. P53 accumulation was a predictor of 3-year relapse-free survival after radiotherapy, followed by GST-pi expression, whereas TLI did not influence prognosis. PMID- 21533343 TI - The quinolinone derivative vesnarinone potentiates the cytotoxicity of doxorubicin in HL-60 leukemia cells. AB - Vesnarinone, (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1- piperazinyl]-2(1H) quinolinone), a quinolinone derivative, is a positive inotropic agent. We examined the cytotoxicity either by vesnarinone alone or in combination with doxorubicin (DXR), in vitro. The cytotoxic effect of vesnarinone against HL-60 cells did not increase, even at concentrations as high as (50 mu g/ml). The cytotoxicity of DXR, however, was enhanced after being combined with 30 mu g/ml of vesnarinone. The intracellular level of DXR increased when DXR was administered after incubation with vesnarinone and the efflux of DXR was delayed when the cells were incubated in the presence of vesnarinone after DXR exposure. Flow cytometry showed that the combination of DXR and vesnarinone increased the cell population below the G(0)/G(1) region. Vesnarinone induced DNA ladder formation, but only when these cells were incubated for 72 h, while in addition, when DXR was combined with vesnarinone, the DNA ladder formation was enhanced. Based on the above findings, we thus conclude that the cytotoxicity of DXR was enhanced when combined with vesnarinone. PMID- 21533344 TI - Expression analyses of a c-src related gene in sponges. AB - Applying different hybridization techniques we could confirm existence and transcription of sequences related to the proto-oncogene c-src in freshwater and marine species of sponges, the most primitive metazoan animals. By using the in situ hybridization technique, we were able to demonstrate for the first time that the cell-type-specific expression, characteristic for c-src related genes in higher vertebrates, is even realized in a freshwater sponge (Spongilla lacustris). The highest amount of c-src related transcripts was found in the omnipotent stem cells, the archaeocytes, and in the cells forming the inner epithelia, the endopinacocytes, which probably are involved in signal transduction. PMID- 21533345 TI - Microsatellite instability in early gastric cancer. AB - Microsatellite replication errors (RERs), consisting in random tumour-associated allele contractions or expansions, represent a frequent genetic alteration in gastric cancer and appear to be associated with important clinicopathologic parameters. To verify the role of microsatellite instability in the initial phases of gastric carcinogenesis, we analysed the status of II microsatellites in paired microdissected samples of tumour and unaffected mucosa from 30 cases of early gastric carcinoma. Fifteen tumours (50%) demonstrated RERs: these included 7 cases with RERs at one locus and 8 cases with RERs at 2 or more loci. Cases with 2 or more RERs were more frequent among intramucosal tumours, compared to tumours with submucosal spread (43% vs. 12%) and among tumours staged T1NOMx, compared to tumours staged T1N1Mx (35% vs. 0%). RER-positive microsatellite typings were statistically more frequent among tumours with intramucosal extension, lower stage (T1NOMx) and excavated growth pattern (macroscopic type III), compared to tumours with submucosal extension, higher stage (T1N1Mx) and elevated, flat or depressed growth patterns (macroscopic types IIa-IIb-IIc respectively). The above findings indicate that microsatellite instability occurs early in the progression of sporadic gastric cancer and tends to be associated with good prognostic indicators. PMID- 21533346 TI - Expression of the invasive phenotype by MCF-7 human breast cancer cells transfected to overexpress protein kinase C-alpha or the erbB2 proto-oncogene. AB - Transfection of the estrogen dependent and poorly invasive MCF-7 cell line to overexpress erbB2 was reported to increase athymic nude mouse mammary fat pad tumor growth; similar PKC-alpha overexpression produced a rapidly growing and metastatic transfectant. We investigated the invasive capacities of the two transfectants in vitro, their secretion of the proteolytic enzymes metalloproteinase (MMP)-9 and -2 and urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1), together with membrane uPA receptor (uPAR) levels as determined by ELISA. Compared with the MCF-7 cells, the erbB2 transfectant was more invasive and secreted higher levels of MMP-9 and uPA; also there was a greatly enhanced PAI-1 secretion and cellular uPAR expression. The PKC-alpha transfectant cells secreted extremely high levels of uPA and some MMP-9 and MMP-2, with an intermediate increase in uPAR; however, they were so poorly adherent that it was not possible to assess invasiveness in vitro. Thus, erbB2-overexpressing MCF-7 cells possessed several features associated with the invasive phenotype. The reportedly aggressive metastatic phenotype induced by PKC alpha overexpression, however, was notable only for its uPA hypersecretion. PMID- 21533347 TI - Genetically modified tumour vaccines. AB - Two genes, the gene coding for IL-2 and the gene encoding the CD80 molecule, were inserted into murine sarcoma MC12 cells. Tumorigenicity of a variety of cell clones with different expression of the inserted genes was assessed. Most of the genetically manipulated MC12 cell clones were less tumorigenic than the parental MC12 cell population. Tumorigenicity of the clones declined with increasing production of IL-2 as well as with the increasing expression of the CD80 molecule. When the tumorigenicity of the clones carrying an inserted IL-2 gene was compared with that of the clones carrying an inserted CD80 gene, it was found that the insertion of the IL-2 gene suppresses tumorigenicity more efficiently than insertion of the CD80 gene. Admixture of the IL-2-producing MC12 clones to the tumorigenic CD80(+) MC12 cell doses could completely inhibit the tumorigenicity of the CD80(+) cells. Insertion of the CD80 gene into sarcoma cells substantially enhanced the adhesive interaction between the MC12 sarcoma and syngeneic T lymphocytes. PMID- 21533348 TI - Interphase-FISH examinations in paraffin sections from benign, precancerous, and cancerous lesions of the skin and oral mucosa. AB - In a preliminary pilot study centromeric probes for chromosomes #7, #8, #11, and #17 and two-colour-FISH were applied on interphase nuclei of 10 coded histologic thin sections obtained from archival paraffin material from precancerous lesions and malignant tumors of the mouth epithelium. Brilliant signals could be obtained in this material without any computerized processing. Among the ten coded probes, localized malignant areas within grade 2 leukoplakias could be detected by their increased number of aneusomic cells, as could the samples from carcinomas. In extension of this study archival paraffin material from 30 epithelial tumors of the skin were examined. The studied squamous cell and Bowen carcinomas were characterized by a large number of chromosomally aberrant subclones and gains of chromosomes were the prevailing finding. In contrast, keratoacanthomas showed distinctly less clonal variation, their majority exhibiting small, but significant clones with chromosome loss, particularly of chromosome #7, less distinctly of chromosome #17. PMID- 21533349 TI - Chromosome gain and loss in paraffin sections from malignant melanomas of the skin. AB - Alphoid DNA probes specific for the chromosomes #6, #7, #9, and #17 were used to screen interphase nuclei for numerical chromosome aberrations in histologic thin sections obtained from archival paraffin material of 25 human melanomas of different type, thickness and stage of progression. An alphoid probe for chromosome #3 was applied in four of these tumors. Besides a general large variation of the number of subpopulations of cells characterized by gains and losses of the studied chromosomes, there was a trend to higher variability in metastatic melanomas as compared to small (<1.5 mm thickness) non-metastatic ones and, particularly, to normal skin tissue. Chromosomes #6 and #9 were those often affected by loss in thick melanomas (>2 mm), while subpopulations showing a gain of these chromosomes, and, in addition, of chromosome #7 seemed more frequently to be associated with thin and non-metastatic ones. The frequency of cases showing gain of chromosome #17 clearly exceeded those with loss of this chromosome in the studied melanomas, but was most pronounced in thicker metastatic tumors. PMID- 21533350 TI - Differential regulation of cdk2 and cyclin D1 in irradiated human glioma cells. AB - We have utilized a series of glioma cell lines to study the effects of ionizing radiation on the regulation of proteins that contribute to cell cycle progression. While no alterations of cyclin E or cdk4 were detected, a high percentage of glioma cell lines exhibited constitutive overexpression of cdk2 protein and aberrant patterns of cyclin D1 protein. The fraction of glioma cells expressing cdk2 was similar to that observed in normal astrocytes, but individual glioma cells overexpressed cdk2. In response to ionizing radiation, both cyclin D1 and cdk2 accumulated in control cells but not in gliomas with overexpressed cdk2 or aberrant cyclin D1. These novel findings provide the first evidence of altered cyclin-cdk regulation in gliomas in response to ionizing radiation. PMID- 21533351 TI - Pulmonary adenocarcinoma angiogenesis. AB - The basic fibroblast growth factor (bFGF), the transforming growth factor (TGF) beta 1, and the vascular endothelial growth factor (VEGF) expressions have been studied individually and in combinations with the factor 8-related antigen (F8RA) in relation to the microvascular density and prognosis of a pulmonary adenocarcinoma. The findings have revealed that the bFGF, TGF-beta 1 and VEGF expressions all correlated with microvascular density and the prognosis. A reduced expression of all three angiogenic factors correlated with-less tumor angiogenesis and a better prognosis. A multivariate analysis of the three prognostic factors also revealed that the the bFGF expression correlated with survival. These findings indicate that bFGF, TGF-beta 1, and VEGF expressions play important roles in tumor angiogenesis, and that the bFGF expression is a useful prognostic marker for assessing the outcome bf a pulmonary adenocarcinoma. PMID- 21533352 TI - Second-look hepatectomy after 5FU arterial infusion in patients with primary unresectable hepatic colorectal metastases. AB - We treated primary unresectable hepatic colorectal metastases by hepatic arterial chemotherapy (HAC) combined with resection of the tumor. Patients underwent a resection of the primary colorectal tumor and a placement of HAC system, and received a 5-fluorouracil (5FU) administration once a week (320 mg/m(2)/day). Five patients underwent a 'second-look' hepatectomy in this series. Their shrinkage rate of the primary lesion ranged from 80-99%, as seen by computed tomography. The resected liver tumors were characterized as p53-positive and proliferating cell nuclear antigen-positive. The levels of fluorodeoxyuridylate (FdUMP) and thymidylate synthetase inhibition were low in the tumor tissue. These results might reflect a kind of resistance to 5FU therapy. Hepatectomy is one of the possible options to eradicate the residual SFU-resistant component of the malignancy. Our preliminary experience possibly indicates longer survival from combination approach than from HAC alone. PMID- 21533353 TI - bcl-2 expression confers androgen independence in androgen sensitive prostatic carcinoma. AB - Expression of the bcl-2 proto-oncogene is associated with the progression of prostate cancer to androgen-independence. Dunning R3327G (DG) cells were engineered to express high levels of bcl-2 protein. The parental DG (DG-P) cell line and bcl-2 transfectant (DG-B) clones were grown as subcutaneous tumor explants in male athymic nude mice. The rate of tumor growth after castration was significantly lower in DG-P tumors but was unaffected in DG-B tumors. The proliferative indices (PI) in DG-P and DG-B tumors were similar, however, apoptotic indices (ApI) were significantly lower in DG-B tumors before castration. Following castration the PI and ApI decreased significantly in DG-P but not DG-B tumors. Bax upregulation was not observed in the DG-P or DG-B tumors, but did occur in the ventral prostate, after castration. These findings support a role for bcl-2 expression in conferring androgen-independent growth during prostate cancer progression. PMID- 21533354 TI - Protection of mitomycin C induced skin extravasation with the nitroxide, 3 carbamoyl-PROXYL (3-CP). AB - Extravasation tissue injury from chemotherapeutic drugs is a serious clinical problem. A swine model has been useful for studying skin extravasation and evaluating potential antidotes. Mitomycin C (MMC) skin extravasation was studied. Nitroxides, a class of compounds which are protective against a variety of oxidative stresses in vitro, including MMC, were tested as antidotes. Miniature swine were anesthetized and given intradermal (ID) injections of MMC. MMC alone caused skin necrosis and ulceration. Several nitroxides were screened as protectors of MMC induced skin necrosis. 3-carbamoyl-PROXYL (3-CP) was the lone nitroxide which protected if given 5 min after extravasation. Administration of 3 CP 10 min after MMC injection was not protective. In vitro studies with monolayered V79 cells showed that 3-CP had a direct protective effect against MMC cytotoxicity in a concentration-dependent fashion. Therefore, in the swine model doses of 3-CP ranging from 25-100 mM were tested and found to protect against MMC skin necrosis 90 days after injection. Histologic sections of the 3-CP- and MMC treated pig skin showed a marked reduction in the degree of acute inflammation and the absence of deep dermal scarring when compared to MMC alone. PMID- 21533355 TI - Combined expression of urokinase-type plasminogen activator and proliferating cell nuclear antigen at the deepest invasive portion correlates with colorectal cancer prognosis. AB - To examine the relationship among the expression of urokinase-type plasminogen activator (u-PA), invasive/metastatic potential and prognosis of colorectal cancer (CRC), 58 patients with surgically resected advanced CRC were studied. u PA expression and proliferating cell nuclear antigen labeling index (PCNA-LI) at the deepest invasive portion were examined immunohistochemically. u-PA expression was detected in 37 (63.8%) of 58 lesions. Lesions with liver metastasis showed a significantly (p < 0.01) higher incidence of u-PA expression than those without liver metastasis. Dukes staging also revealed a significant correlation with u-PA expression. The combination of u-PA expression and elevated PCNA-LI at the deepest invasive portion correlated significantly with prognosis. These results indicate that u-PA expression is an important predictor of CRC development and liver metastasis. Furthermore, combined analysis of u-PA expression and PCNA-LI at the deepest invasive portion is very useful in predicting CRC prognosis. PMID- 21533356 TI - Analysis of tumour-specific alterations in native specimens by PCR. AB - Native tumours, in contrast to cell lines, are usually heterogeneous, consisting of tumour cells, stroma, infiltrating leukocytes, necrotic cells, and surrounding normal tissue. Therefore, when using non-linear amplification and detection methods such as the PCR, the verification of the DNA from the tumour cells is mandatory to avoid equivocal or false results. Here, current methods to isolate tumour cells from native tumours are reviewed. The methods are: i) a variety of microdissection techniques including microdissection of membrane-mounted native tissue (MOMeNT), ii) Selective ultraviolet radiation fractionation (SURF), iii) antibody-based tumour cell selection and flow cytometric cell or cell nucleus sorting, and iv) in situ PCR. Each of the methods has been used, and overall preference cannot be given to any of them. Accuracy, reproducibility, documentation, cost, and applicability in a routine setting are discussed, from which fields of preferencial use may emerge for the different methods. PMID- 21533357 TI - Intercellular induction of apoptosis of transformed cells is modulated by their intracellular glutathione concentration. AB - Reduction of the intracellular glutathione concentration increased the sensitivity of transformed fibroblasts for intercellular induction of apoptosis by TGF-beta-treated nontransformed cells. This finding demonstrates a modulating role of glutathione for the induction of apoptosis in transformed cells and strengthens the involvement of reactive oxygen species in this process. Reduction of the intracellular glutathione concentration however, did not render nontransformed cells sensitive for intercellular induction of apoptosis or abrogate the resistance of BPV-transformed cells. Therefore, the intracellular glutathione concentration is not the key that determines sensitivity of transformed cells, insensitivity of nontransformed cells or resistance of BPV transformed cells. PMID- 21533358 TI - Potential circulating markers for the management of kidney cancer (Review). AB - The prognosis of renal cell carcinoma (RCC) is generally poor. An easier detection of this tumor and a better monitoring of RCC patients would be possible if serum markers with acceptable sensitivity and specificity were available. In RCC, as opposed to other cancers, no circulating serum markers with sufficient renal specificity have been discovered. In fact, even when the hybridoma technology allowed the production of several monoclonal antibodies against RCC structures, none of them led to any available diagnostic immunoassays. Other possible circulating tumor markers of potential application in RCC patients include different substances such as acute phase reactant proteins, enzymes, mucins, cytokeratins, proteins, interleukins, that demonstrated some relationship with the presence and the changes in the RCC evolution. In this general review we report and discuss the results in the literature obtained by serum assays of these substances which have been shown to be of some help for the prognosis and monitoring of RCC. The greater part of these biomolecules are already measured in clinical practice for the management of other malignancies, but their application in RCC could give interesting clinical information. PMID- 21533359 TI - Mass-spectrometric analysis of naturally processed peptides recognized by ovarian tumor-associated CD8(+) CTL. AB - Antigens recognized by cytotoxic T cells (CTL) are expressed as peptides presented by MHC class I molecules. To isolate peptides from the MHC molecule HLA A2.1 and identify epitopes that define the activity profile of ovarian CD8(+) CTL, peptides were separated by reverse-phase high-pressure liquid chromatography (HPLC), and analyzed by electrospray ionization-tandem mass spectrometry (ES-MS). HLA-A2.1-bound peptides were extracted from the ovarian tumor line SKOV3 transfected with the HLA-A2.1 (clone 1E4) and C1R.A2 cells transfected with HCA A2.1 and HER-2 (clone HER-2.J) by immunoaffinity chromatography. At least five peaks of distinct retention times (termed 1, 2A, 2B, 2C, and 3) were recognized by an ovarian HER-2(high) (HER-2(hi)) tumor-associated HLA-A2(+), CD8(+) CTL line. ES-MS analysis was performed for peak 2B peptides from both types of cells. In the four consecutive fractions of peak 2B, at least 27 and 16 ion species of mass-to-charge (m/z) ratio between 760-1300 were detected in 1E4 and HER-2.J cells, respectively. The abundance of four 1E4 and six HER-2.J ions believed to be peptides in four consecutive HPLC fractions in this peak matched the CTL activity profile. Of these, two ions with actual m/z ratios 497.3-498.4 and 792.8 793.2, were found in the peak 2B from both types of cells. Since little is known about the tumor Ag recognized in human cancers, characterization of these ions may lead to identification of novel tumor Ag in breast and ovarian cancers. This may also be useful in developing quantitative approaches to the identification of tumor Ag and the determination of epitope density on tumor and normal cells. This may help characterize the relationship between tumor immunity and epitope tolerance in human epithelial cancers. PMID- 21533360 TI - Expression of CD44 spliced variants with both exons v9 and v10 in primary N(-)M( ) breast carcinomas correlates with metastasis. AB - We analyzed the representation of CD44 isoforms with both exons v9 and v10 among CD44 total amount and also examined correlation between their expression, clinical parameters and survival. We used a semi-quantitative RT-PCR reaction and a panel of 25 normal breast specimens, 10 mammary fibroadenomas, 8 cystic samples and 52 primary breast tumors. CD44 expression level was statistically higher in malignant tumors than in normal breast tissues (p = 0.038) or in fibroadenomas (p = 0.047) and correlated with histological grading, p = 0.047. Ratios CD44 variants with both exons v9 and v10/ total CD44 were similar in normal breast tissues and fibroadenomas but lower in the cystic samples. In primary N(-)M(-) breast tumors, unfavourable outcome and relapse were correlated with low ratios. PMID- 21533361 TI - Presence of urokinase plasminogen activator, its inhibitor and receptor in small cell lung cancer and non-small cell lung cancer. AB - Spreading of cancer cells is dependent on the combined action of several proteolytic enzymes, such as serine proteases, comprising the urokinase pathway of plasminogen activation. Previous studies of lung cancer indicate that expression, localization and prognostic impact of the components of the plasminogen activation system differ in the different non-small cell lung cancer (NSCLC) types, whereas the expression of the components in small cell lung cancer (SCLC) has only sparingly been investigated. In the present study we investigate the presence of the components of the plasminogen activation system, and compare the levels of uPA, PAI-1 and uPAR in extracts of NSCLC-tissue and SCLC-tissue. A statistically significant difference, P = 0.037, was found between uPA-levels in NSCLC-patients (n = 75) and SCLC-patients (n = 8), the highest levels being found in NSCLC. No such difference was found for the two other components investigated, although a trend towards increased uPAR-levels was observed in SCLC, P = 0.055. The relationship between the levels of each of the components and other known clinical parameters was also analysed. No relationship was found between any of the components and the clinical parameters. This is the first report of a study using a quantitative method to compare levels of the components of the plasminogen activation system in tissue extracts from the two major lung cancer groups. The study shows that uPA, PAI-1 and uPAR are present in SCLC-tissue, suggesting that the plasminogen activation system could play a role in this type of cancer during invasion. In addition a difference in the levels of the components of the plasminogen activation system in NSCLC and SCLC is found, which could contribute to the differences in biology. PMID- 21533362 TI - Adhesion of human gastric and pancreatic cancer cells to peritoneal mesothelial cells is mediated by CD44 and beta(1) integrin. AB - Peritoneal dissemination is a common cause of the recurrence of gastric or pancreatic cancer after patients have undergone surgery. The presence of peritoneal metastasis after surgery affects the prognosis of patients with gastric or pancreatic cancer. Very little is known about the biochemical processes involved in the initial attachment of cancer cells to peritoneal mesothelial cells. We conducted in vitro and in vivo studies to assess the role of adhesion molecules in this process, using 5 cell lines derived from human gastric and pancreatic cancers. NUGC-4 and SW1990 cells, which disseminate earlier than the other 3 types of cancer cells after inoculation into the abdominal cavity of nude mice, express large amounts of CD44H. We found that NUGC 4 and SW1990 cells adhere to monolayers of mesothelial cells more firmly than the other cell lines, as shown by adhesion assays performed at 4 degrees C. The adhesion of NUGC-4 and SW1990 cells to mesothelial cells was partially inhibited by antibodies against CD44H or the beta(1) subunit of integrin, and they almost completely blocked adhesion when these 2 antibodies were used in combination in vitro. These 2 antibodies also inhibited the peritoneal metastasis of NUGC-4 and SW1990 cells and prolonged their mean survival time in vivo. These findings suggest that CD44H and beta(1) integrin play important roles in the initial attachment of gastric and pancreatic cancer cells to mesothelial cells. Our results suggest that changes in the expression of CD44H and beta(1) integrin in cancer cells is associated with their ability to adhere to peritoneal mesothelial cells, and thus with the peritoneal metastatic ability of gastric and pancreatic cancer cells. Therefore, the expression of CD44H and beta(1) integrin in gastric and pancreatic cancers could be used as prognostic indicators of peritoneal metastasis. It is possible that a treatment strategy that interferes with the functions of CD44H or beta(1) integrin may result in decreased intra-abdominal spread of cancer. PMID- 21533363 TI - Organ preferential metastasis related to tissue- and serum-selective growth or migration properties of hamster pancreatic carcinoma cells. AB - We have investigated tissue- and serum-selective growth or migration activities of two hamster pancreatic carcinoma cell lines, KH-PC and HapT1. In experimental metastatic models, multiple liver metastases were observed for hamsters injected with KH-PC cells, while HapT1 had little tendency to metastasize to the liver. Micrometastases in the lung were observed for both KH-PC and HapT1. Liver extract inhibited the growth of HapT1 cells when compared to a 1% bovine serum albumin control, while KH-PC growth was not inhibited by liver extract. Liver extract showed chemoattractive activity to KH-PC but not to HapT1 cells. No notable differences were shown in either chemoattractive or growth properties of lung extract toward either cell line. These activities of lung extracts were weaker than those of liver extract to KH-PC. Hamster portal vein serum (PVS) had higher mitogenic activity toward both KH-PC and HapT1 cells, compared with serum derived from the vena cava (VS). Chemokinetic activity of PVS or VS toward KH-PC was slightly higher than that toward HapT1. In a chemoinvasion assay with liver extract and PVS, a 6-fold greater number of invasive cells was observed for KH-PC cells when compared to HapT1 cells. In a chemoinvasion assay with lung extract and VS, there was no difference between the cell lines. Our results suggest that complex activities of tissue- and serum-selective growth or migration were related to organ preferential metastasis of these hamster pancreatic carcinoma cell lines. PMID- 21533364 TI - Biochemical properties of Xenopus laevis p53. AB - The p53 gene has evolutionarily highly conserved boxes from rainbow trout to man whereas other regions are divergent in different species. In order to define conserved and species specific properties of p53 we analyzed frog p53. Since the commonly available monoclonal antibodies do not react with Xenopus p53 we expressed a recently cloned Xenopus laevis cDNA in bacteria and this protein was used to generate polyclonal antibodies. This antibody recognizes p53 from Xenopus laevis oocytes, baculovirus infected insect cells and p53 from an in vitro transcription/translation reaction but not from somatic Xenopus tissue cells. In contrast to p53 from other species Xenopus p53 is mainly found in the cytoplasm. Xenopus p53 forms mainly tetramers as p53 from other species. Like p53 from other species Xenopus p53 is tightly associated with a protein kinase activity and phosphorylated by this associated enzyme. Xenopus p53 binds strongly to its own RNA without any influence on the translation of p53 mRNA. Thus, Xenopus p53 seems to have some properties in common with p53 from other species and some additional species specific features. PMID- 21533365 TI - The role of fibroblast growth factor (FGF) in neoplasms induced by MoMuSV-349. AB - Previous results from our laboratory have demonstrated that intraperitoneal inoculation of newborn BALB/c mice with MoMuSV-349 virus induced multiorgan disseminated angiomatous tumors. Changes in histological pattern, from sarcomatous to angiosarcomatous, stimulated our interest in investigating the possible role of angiogenic growth factors released by the spindled (sarcomatous) cells in angiosarcoma development in this model. Cell lines were obtained from various tumors and assayed for production of acidic (a) and basic (b) fibroblast growth factors (FGFs). All tumor cell lines released detectable amounts of growth factor(s) into the cultured media that induced proliferation of endothelial cells and mitogenesis of mouse fibroblasts. This growth factor(s) bound to heparin Sepharose (HS) beads and its effects on cell proliferation were partially blocked by a neutralizing bFGF antibody. Proteins released by tumor cells into the conditioned medium were detected by bFGF antibodies on Western blots. In addition, proteins that reacted with both bFGF and aFGF antibodies were detected in various conditioned media by ELISA. This protein(s) from the FGF family detected in the conditioned media from various tumor cell lines might be responsible for the angiomatous proliferation observed in the late (angiosarcomatous) stage of MoMuSV-induced tumors. PMID- 21533366 TI - Clinical and immunological evaluation of schizophyllan (SPG) in combination with standard chemotherapy in patients with head and neck squamous cell carcinoma. AB - A phase II randomized controlled trial was carried out to evaluate the clinical efficacy and tolerability of Schizophyllan (SPG) used in combination with standard chemotherapy in the neoadjuvant setting in patients with locally advanced head and neck squamous cell carcinoma. Several immunological parameters were considered to assess the immunoregulatory activity of SPG in the: same patients. The clinical and immunological evaluations were performed both before and at the end of the study (4 months later). All patients received standard chemotherapy for head and neck squamous cell carcinoma according to one of the following treatment regimens: 1) cisplatin 100 mg/m(2) i.v, day 1, 5-FU 1,000 mg/m(2) i.v. continuous infusion days 1 to 5; 2) cisplatin 80 mg/m(2) i.v, day 1, 5-FU 600 mg/m(2) i.v. over 4 h days 2 to 5, vinorelbine 20 mg/m(2) i.v. days 2 and 8. Antineoplastic regimens were repeated every 28 days x 4 cycles for approximately 4 months. SPG was administered weekly at a single dose of 40 mg intramuscularly for 4 months in addition to standard chemotherapy. Twenty-six patients were enrolled in the study, 22 of whom were evaluable. Thirteen patients were assigned to Arm A (treatment with SPG associated with chemotherapy, regimen 1 or 2) and 9 patients to Arm B (treatment with chemotherapy, regimen 1 or 2, alone). The overall response rate was not significantly different between the two Arms (92.3% in Arm A vs. 100% in Arm B), although a higher number of complete responses (CR) (3 = 23.1%) was registered in Arm A. Overall, the SPG treatment does not seem to have induced significant changes of the immunological parameters of our patients: this may be due to both the advanced cancer stage and the effect of chemotherapy, which are both well known causes of immunodepression. The significant differences between the two Arms were only: the CD8(+) lymphocytes were decreased in the patients treated with SPG and increased in controls; serum levels of IL-1 alpha was lower in patients treated with SPG than in the control group; the production in culture of IL-1 alpha was higher in Arm A than in Arm B and IL-6 was higher in Arm B than in Arm A. Treatment with SPG was proven safe and was well-toleratedby all patients. PMID- 21533367 TI - Inhibition of the glucocorticoid receptor expression by diverse tumor promoters in SENCAR mouse epidermis. AB - Glucocorticoid hormones are very potent inhibitors of keratinocyte proliferation. Their function is mediated by the glucocorticoid receptor (GR) which is highly expressed in mouse epidermis. In the study reported here we compared the effect of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and non-phorbol ester tumor promoters such as okadaic acid, chrysarobin, and benzoyl peroxide on the levels of GR protein and mRNA in SENCAR mouse epidermis. Glucocorticoid binding assay and Northern blot analysis revealed that all four tumor promoters decreased both GR protein and mRNA levels in keratinocytes in vivo. We also found that TPA and okadaic acid inhibited GR expression in keratinocyte cell line. These results suggest that GR inhibition may play an important role in mouse skin hyperplasia and promotion of skin carcinogenesis. PMID- 21533368 TI - Loss of heterozygosity and microsatellite instability in larynx cancer. AB - We have examined 48 squamous cell cancers of the larynx for loss of heterozygosity (LOH) and microsatellite instability at chromosome 9p near the p16 tumour suppressor locus, at chromosome 17p at the p53 tumour suppressor locus, and at 17p at another microsatellite locus (D17S520). In p53 LOH was higher (33 45%) than in D17S520 (21%). Near the p16 locus LOH varied from 28-38%. Replication errors were found from at least one locus in 23% of the patients. These data suggest that p53 is an important gene in laryngeal cancer while loci around p16 appear less likely candidates. PMID- 21533369 TI - The progestin ORG2058 but not retinoic acid stimulates BRCA1 mRNA expression in MCF-7 human breast cancer cells. AB - BRCA1 has been characterized as one of the major breast cancer susceptibility genes. Although no BRCA1 mutations have been reported in sporadic breast cancer, altered levels of BRCA1 are found in non hereditary breast malignant lesions. Therefore, BRCA1 is potentially playing a key role in the genesis of breast cancer. In this study, we explored the effects of estradiol and two differentiating agents, the progestin ORG2058 and retinoic acid, on BRCA1 mRNA expression in human estrogen and progesterone receptor positive MCF-7 cells. Using RNAse protection assay, we have demonstrated that ORG2058 induces a major (50 times) stimulation of BRCA1 mRNA expression. The maximum induction effect was obtained at the pharmacological dose of 100 nM and after 48 h of treatment. While estradiol generated an expected increase of BRCA1 mRNA, retinoic acid did not produce any effects. Our results demonstrate for the first time that BRCA1 is specifically up-regulated by a progestin, a steroid known to induce the differentiation of epithelial mammary cells. The absence of retinoic acid effect suggests that a specific progesterone-dependent pathway, could control BRCA1 expression. PMID- 21533370 TI - DPC 4/SMAD 4 in non-pancreatic tumors with frequent LOH 18q21 and in hematological malignancies. AB - Recently, a novel candidate tumor suppressor gene, DPC 4/SMAD 4, has been implicated in the development of pancreatic cancers. Its location at human chromosome 18q21 prompted us to investigate this gene in a large series of primary tumors located outside the gastrointestinal tract which have been associated with loss of heterozygocity (LOH) at this locus. One hundred and thirty primary solid tumor samples (28 breast, 34 non-small cell lung, and 20 prostate cancers, and 40 osteosarcomas), 32 cell lines as well as 162 leukemia and lymphoma cases were analysed by Southern blotting and PCR-SSCP for deletions and mutations of the DPC 4 gene. In the breast cancer cell line MDA-MB-468, the gene was found to be homozygously deleted. Neither the primary solid tumor samples nor hematological malignancies had detectable abnormalities. Our study suggests that alterations of the DPC 4 gene, unlike in pancreatic cancer, are rare in breast, nonsmall cell lung and prostate cancers, osteosarcomas and hematopoietic malignancies. PMID- 21533371 TI - Focal hepatic glycogenosis. AB - Foci of altered hepatocytes (FAH) including clear cell foci excessively storing glycogen (focal hepatic glycogenosis) are well known as preneoplastic lesions in animal models of hepatocarcinogenesis induced by chemical, physical or viral agents. The occurrence of similar lesions has been studied in a series of 67 explanted and 2 resected human livers using histological and histochemical approaches. A high incidence of FAH was found in the liver of patients suffering from hepatocellular carcinoma(HCC, 14/14) and liver cirrhosis (21/42). FAH were also detected in one patient each with inborn hepatic glycogenosis type 1a, and cholangiocellular carcinoma. Two patients with focal nodular hyperplasia had FAH like enzymatic changes within these lesions. No FAH were found in 5 donor livers. FAH excessively storing glycogen including clear and mixed cell foci predominated in most cases with these lesions. The focal hepatic glycogenosis was associated with a significantly increased cell proliferation compared to the extrafocal parenchyma, and with alterations in the activity of various enzymes. In the 175 FAH studied by enzyme histochemistry, two enzymes involved in glycogen breakdown, namely glycogen phosphorylase and glucose-6-phosphatase, showed the most consistent changes, being reduced in 98% and 95%, respectively. In addition, the activities of adenosine triphosphatase and gamma-glutamyltransferase were reduced in 46% and 53% of FAH, respectively. Inconsistent changes were observed in FAH concerning a number of other enzymes. The 14 HCCs investigated histochemically often contained clear cell populations rich in glycogen in well differentiated portions, but were poor in glycogen in moderately and poorly differentiated tumors or tumor components. There were some similarities in the enzyme histochemical pattern of HCC and FAH but also important differences were evident. In contrast to FAH, all HCCs (except one carcinoma of the fibrolamellar type) showed an increase in the activity of the mitochondrial glycerol-3-phosphate dehydrogenase, and 50% of the cases had increased glucose-6-phosphate dehydrogenase activity. The activities of glucose-6-phosphatase and gamma glutamyltransferase usually showed a reactivation, or even an increase compared to the extrafocal parenchyma, in moderately and poorly differentiated HCCs. Our results indicate that the focal hepatic glycogenosis is a putative preneoplastic lesion in human beings similar to laboratory animals. The focal hepatic glycogenosis appears to be a frequent initial step in neoplastic transformation of hepatocytes, a process associated with a fundamental shift in energy metabolism. PMID- 21533372 TI - Phenotypes of human esophageal squamous cell carcinoma based on matrix metalloproteinase production. AB - We investigated the effects of epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) on cell growth and on regulation of matrix metalloproteinases (MMPs) in four cell lines of human esophageal squamous cell carcinomas (TE8, TE9, TE10, and TE11). EGF stimulated the production of proforms of gelatinase B (MMP-9) by three cell lines that could synthesize EGF by themselves, with TE9 being the exception. Particularly, both the production of MMP-9 and DNA synthesis in TE10 were stimulated significantly by EGF. TGF-beta slightly stimulated DNA synthesis in two cell lines, TE9 and TE11, and TGF-beta secretion by TE9 was detected. The production of proforms of gelatinases A (MMP 2) and MMP-9 was gradually induced by TGF-beta in a concentration-dependent manner in all the cell lines except for TE9. Flow cytometric analysis revealed that all the lines expressed both EGF- and TGF-beta-receptors. In conclusion, our present results indicate that at least there are possibly two distinct phenotypes in human esophageal squamous cell carcinoma: one (TE10) depends on autocrine EGF production that enhances DNA synthesis and MMP-9 production; and the other (TE9) on autocrine TGF-beta that stimulates DNA synthesis but not in relation to gelatinase production. PMID- 21533373 TI - A human xenograft model for testing early events of epithelial neoplastic invasion. AB - We report on a model of human prostate tumor cell invasion using the SCID (severe combined immunodeficient) mouse diaphragm. Tumor cells were injected into SCID mice intraperitoneally and the diaphragms harvested three to five weeks later. Electron microscopy showed tumor cell penetration of the mesothelial cell layer and adhesion to the underlying basement membrane on the inferior surface of the mouse diaphragm, where colonies developed. Immunohistochemistry showed invasion by tumor cells through the basement membrane into the muscle of the diaphragm, presence of human tumor cells among the muscle cells and the presence of selected proteins on the invasion front of the tumor cells. Digital image analysis enabled quantitative comparison of events in the metastatic cascade by variants of the tumor cell line and evaluation of the effectiveness of a putative tumor inhibitor. Results suggest that the SCID mouse diaphragm model is a convenient, effective, easily oriented and reproducible in vivo model of the early events associated with human prostate tumor cell invasion. PMID- 21533374 TI - Influence of 1 alpha,25-dihydroxyvitamin D-3 on growth regulation through epidermal growth factor receptor in human breast cancer cell lines. AB - We investigated the relationship between epidermal growth factor (EGF) dependent cell growth and antiproliferative effects of 1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) in hormone responsive breast cancer cell lines in vitro. MCF-7 breast cancer cells and GMC-M, which is a serum-independent, hormone receptor positive subtype derived from MCF-7, were used in this study. EGF stimulated the growth Of both cell lines, and 1,25(OH)(2)D-3 inhibited the EGF-stimulated cell growth in a dose dependent fashion. But treatment with 1,25(OH)(2)D-3 did not change the EGF receptor (EGFR) level significantly in either cell line. GMC-M had a higher level of EGFR and was more sensitive to EGF than MCF-7. These results suggest that other mechanisms of action, which are different from EGFR modulation, concern with the growth inhibitory effect of 1,25(OH)(2)D-3, and that 1,25(OH)(2)D-3 will be a new effective treatment for breast cancer irrespective of EGFR. PMID- 21533375 TI - ras and myc analysis in primary and metastatic colorectal carcinomas. AB - Paired primary colorectal adenocarcinoma and normal frozen tissue samples from 60 patients were prospectively studied to determine the frequency of point mutations in K-ras and the occurrence of structural alterations in c-myc. Parallel investigations were performed on liver metastatic specimens from 16 of the patients. 47% of the primary tumors presented point mutations in K-ras; 71% of these were in codon 12. Significant associations were found between codon 13 ras mutations and Dukes' D stage (p<0.05), and between mutations in codon 12 and mucinous type (p<0.01). The c-myc gene structure was altered in 5/60 cases (8%). In 4/16 cases, the K-ras gene status in the primary carcinoma and in the metastatic tissue from the same patient was found to be different. Our results suggest that codon 13 I-as mutations may be associated with an increased invasive and metastatic potential, while codon 12 mutations may have a role in the mucinous differentiation pathway. PMID- 21533376 TI - Nuclear localization signal peptides for the import of plasmid DNA in gene therapy (review). AB - Failure of cells to import specific proteins into nuclei can lead to carcinogenesis. Trafficking of nuclear proteins from the site of their synthesis in the cytoplasm to the sites of function in the nucleus through pore complexes is mediated by the presence of nuclear localization signals (NLSs) on proteins to be imported into nuclei. mRNA is exported through the same route as a complex with nuclear proteins. During gene therapy the foreign DNA needs to enter nuclei for its transcription in order to express the therapeutic protein; a pathway is proposed involving the complexation of plasmids and oligonucleotides with nascent nuclear proteins possessing NLSs as a prerequisite for their nuclear import. Covalent linkage of NLS peptides to oligonucleotides and plasmids or formation of complexes of plasmids with proteins possessing multiple NLS peptides is proposed to increase their import rates and the efficiency of gene expression. We suggest that cancer cells import more efficiently foreign DNA into nuclei compared with terminally differentiated cells because of their increased rates of proliferation and protein import and are easier targets for expression of foreign genes. PMID- 21533377 TI - Establishment and characterization of ovarian endometrioid adenocarcinoma cell line in nude mice and analyses of the immunohistochemical property among the original, recurred, and heterotransplanted tumor. AB - The establishment and characterization of a new human endometrioid adenocarcinoma cell line (KOC-8e) derived from the malignant ascites is described. The original tumor at the initial operation showed positive in TPA, and SLX immunohistochemically. By contrast, recurred tumor showed positive for CA125, TPA, SLX, MUC-1, and p53. In addition, the heterotransplanted tumor showed positive for CA125, TPA, SLX, MUG-1, and p53. The DNA index was similar in the primary, recurred, and nude mouse tumor ranging between 1.93 and 2.05. The tumor growths were suppressed dose dependently by CDDP and CPT-11. CA125 showed useful as a tumor marker of this tumor, however, the nude mice had detectable tumor without elevation of CA125 after low dose application of CDDP and CPT-11. Thus, clinical determination of chemotherapeutic effect and residual tumor cannot be made only by CA125. KOC-8e cells could be useful to study histological analysis and chemosensitivity. PMID- 21533378 TI - Histones, protamine, and polylysine but not poly(E:K) enhance transfection efficiency. AB - Liposomal gene delivery has a great potential for the treatment of cancer and other human diseases. In this work we have investigated the optimal conditions for liposome-mediated transfer of the luciferase gene to human erythroleukemia K562 cells. DDAB:DOPE liposomes were more efficient than lysyl-DOPE:DOPE (1:2) and DDAB:cholesterol for transfection. Total histones from bovine thymus, salmon sperm protamine, and polylysine at an optimal ratio of 0.5 mg protein/mg DNA enhanced up to 7-fold the transfection efficiency of luciferase plasmids; on the contrary, the synthetic polymer poly(E:K), containing glutamic acid and lysine residues in a random order at a ratio 1:4, diminished luciferase expression. Transfection was nearly zero at high histone:DNA ratio by reversal of the charge of the particle from negative to positive leading:to its inability to interact with cationic liposomes. The increase in luciferase gene expression by DNA binding proteins might arise from an increased transfer across the cell membrane of the liposome-DNA-protein complex but also by an increase in nuclear import of the DNA-protein complex because of the presence of nuclear localization signals on the protein molecule used for DNA condensation. PMID- 21533379 TI - Clinical and ethical issues in the diagnosis of hereditary breast cancer (review). AB - A small subset of breast and ovarian cancers is related to the mutation of dominant susceptibility genes. The recent isolation of BRCA1 and BRCA2 has created great interest and expectations among members of families with a positive history for breast/ovarian cancer. We reviewed the literature to explore the clinical implications of genetic testing for BRCA1 and BRCA2 mutations among high risk women. Both the value of the information provided by the test and the efficacy of the preventive and diagnostic measures presently available have been examined. We also specifically address the issue of ethical dilemmas arising from widespread availability of genetic information, including psycological reactions of those who receive the test, genetic discrimination by health insurance companies or employers and prenatal testing for BRCA1 mutations. PMID- 21533380 TI - Optimal duration of whole body hyperthermia when combined with cis diamminedichloroplatinum(II). AB - We examined the optimal duration of whole body hyperthermia (WBH, 41.5 degrees C) when administered simultaneously with cis-diamminedichloroplatinum(II) (CDDP) using F344 rat fibrosarcoma model. The antitumor efficacy was measured by tumor growth delay (TGD) and nephrotoxicity was evaluated by the day 5 blood urea nitrogen (BUN) associated with different duration of WBH (0.5, 1, 1.5, 2 or 3 h) with a constant dose of CDDP (2 mg/kg i.v. bolus). There was significant increase in TGD from 2.8 days to 5.4 days when the WBH duration was increased from 0.5 to 1 h (p<0.001). CDDP-induced nephrotoxicity was also enhanced by WBH. We estimated specific therapeutic efficacy (STE) for each treatment using the ratio of antitumor effect measured by TGD to nephrotoxicity calculated from the degree of increment of BUN. CDDP combined with 1 h WBH produced the best STE of 2.2. We conclude, that to maximize the therapeutic gain, a 1 h duration is optimal in the present setting of thermochemotherapy. PMID- 21533381 TI - Serum vascular endothelial growth factor (VEGF), a prognostic indicator in sarcoma and carcinoma patients. AB - Tumor growth and the development of metastases are dependent on the local formation of new blood vessels. A major role in the induction of angiogenesis has been assigned to vascular endothelial growth factor (VEGF), a tumor cell-derived endothelium-specific mitogen. We studied whether blood levels of VEGF are increased in sarcoma and carcinoma patients. In addition, we tested whether data from measurements of serum VEGF are of prognostic value with respect to tumor remission during chemotherapy courses of sarcoma patients. First, we measured the concentration of VEGF in the sera of 60 normal volunteers and of 25 untreated patients suffering from solid tumors (13 sarcomas, 12 carcinomas). Second, we studied the level of serum VEGF in 9 tumor patients during 4 courses of ICE chemotherapy (ifosfamide, carboplatin, etoposide). VEGF was measured by enzyme linked immunoassay. The concentrations of serum VEGF were significantly higher (P <0.0001) in untreated sarcoma (933+/-132 pg/ml) and carcinoma (1,257+/-169 pg/ml) patients compared to those of normal subjects (239+/-21 pg/ml). The concentration of VEGF was roughly proportional to the tumor mass. A significant fall in serum VEGF occurred in the 6 patients who responded to chemotherapy with tumor remission but not in the patient who were resistant. The concentration of serum VEGF is an indicator of tumor growth in sarcoma and carcinoma patients and thus of prognostic value. Serum VEGF measurements may be clinically useful for monitoring tumor regression in sarcoma patients undergoing chemotherapy. PMID- 21533382 TI - Monoclonal antibodies directed against the EGF receptor show differential bindings of amphiregulin and EGF to the EGF receptor. AB - Amphiregulin (AR), a new member of the EGF family of ligand, is a glycoprotein containing a 78 or 84 amino acid core polypeptide that was originally purified from the conditioned medium of the breast carcinoma cell line MCF-7 after treatment with phorbol 12-myristate 13-acetate. The aim of the present study was to determine whether, like EGF, TGF alpha, heparin binding EGF-related growth factor (HB-EGF) and betacellulin (ETC), the recombinant 78 amino acid form of mature human AR transmits its biological effects following binding to the EGF receptor (EGFR). We show that unlike EGF, TGF alpha, HB-EGF and BTC, the mature AR is not effective in blocking the binding of I-125-EGF or the iodinated anti EGFR antibodies (mAbs) I-125-ICR62 and I-125-ICR80 to the external domain of the EGF receptor on EJ cells. Again, in contrast to other EGF ligands, AR is not effective in enhancing the binding of another anti-EGFR mAb ICR9 to the EGFR on EJ cells. Like EGF, TGF alpha and HB-EGF, AR could inhibit the growth in culture of EGFR overexpressing tumour cell lines, namely HN5, HSC-1 and MDA-MB468 cells, and again compared to other ligands AR was moderately effective at low concentration. Despite these differences, we show that like EGF, AR could induce the tyrosine phosphorylation of the 170 kDa EGF receptor on HN5 cells and that this effect could be blocked in the presence of anti-EGFR mAbs ICR62 and ICR80. Moreover, like EGF, the AR-induced growth inhibition of MDA-MB468 cells could also be reversed in the presence of anti-EGFR mAbs ICR62 and ICR80. On the basis of our results we conclude that, unlike the EGF, TGF alpha, HB-EGF and BTC, the AR-induced activation of the EGFR may involve another receptor. PMID- 21533383 TI - BRCA1-p53 relationship in hereditary breast cancer. AB - BRCA1, a major gene predisposing to breast and ovarian cancers, encodes a ring finger-containing protein. Its function is still unknown. Recently, the existence of a new structural domain called BRCT was postulated. This domain has some similarity with the 53BP1 human protein involved in p53 binding process. To test for a possible relationship between BRCA1 and p53, we compared p53 expression by immunohistochemical analysis in 29 BRCA1-associated breast cancers from 19 families, and in 200 consecutive sporadic breast cancers. We observed a prevalence of tumors with p53 positive staining in the BRCA1 population (p=0.003). In addition, p53 expression was affected by the site of the germ line mutation in the BRCA1 gene. p53 staining was found more consistently in tumors associated with mutations that lead to a truncation of BRCA1 in the ring finger region (p=0.0048). These results favor the hypothesis of a cooperation between BRCA1 and p53. Further experiments are needed to explore the full bilogical relevance of this phenomenon. PMID- 21533384 TI - Peritoneal dissemination is inhibited by treatment with antibodies against CD44H, beta(1) integrin, and carcinostatic agents in NUGC-4 human gastric cancer cells. AB - Peritoneal dissemination frequently occurs after surgery in patients with gastric cancer. The presence of peritoneal metastasis after surgery affects the prognosis, therefore, a way must be found to effectively prevent the development of peritoneal dissemination. Very little is known about the biochemical processes involved in the initial attachment of gastric cancer cells to peritoneal mesothelial cells. We conducted in vitro and in vivo studies to assess the role of adhesion molecules and TGF-beta 1 in this process, using 4 gastric cancer cell lines. NUGC-4 cells, which disseminate early after inoculation into the abdominal cavity of nude mice, predominantly expressed CD44H and beta(1) integrin. We found that NUGC-4 cells adhered to monolayers of mesothelial cells more firmly than other cell lines. Adhesion of NUGC-4 cells to mesothelial cells was partially inhibited by antibodies against CD44H or the beta(1) subunit of integrin, and was completely blocked by a combination of these 2 antibodies. Treatment with ligands for CD44H and beta(1) integrin also inhibited this adhesion. In the NUGC-4 cell culture medium, larger amounts of transforming growth factor beta 1(TGF-beta 1) was detected in proportion to the increase in cancer cells than in the other cell lines. TGF-beta 1 increased the expression of CD44H in NUGC-4 cells and in mesothelial cells, and augmented the adhesion and implantation of NUGC-4 cells to mesothelial cells accompanied by accumulation of extracellular matrix (ECM) components. Carcinostatic agents decreased the expression of CD44H but increased the expression of E-cadherin in NUGC-4 cells. Treatment with carcinostatic agents and antibodies against CD44H and beta(1) integrin inhibited the dissemination of NUGC-4 cells in the peritoneal cavity of nude mice, and prolonged their survival time. These findings suggest that CD44H and integrins mediate in the initial attachment of gastric cancer cells to mesothelial cells, and TGF-beta 1 participates in the promotion of the disease. It is possible that a treatment strategy that interferes with CD44H or integrins function and increases the functions of E-cadherin immediately after surgery may result in the decreased intra-abdominal spread of gastric cancer. PMID- 21533385 TI - Differential regulation of glucose transporter-1 and -2 gene expression by hepatocyte growth factor in human hepatoblastoma cells. AB - Glucose transporters, GLUT-1 and GLUT-2, are key factors involved in facilitative glucose transport to hepatocytes. The aim of the present study was to clarify how hepatocyte growth factor (HGF) regulates expression of both genes in HepG2 human hepatoblastoma cells. HGF dose-dependently suppressed cell growth, but enhanced cellular glucose uptake together with increased expression of GLUT-1 protein. This increase resulted from elevation of its transcript. In contrast, no changes were found in expression of GLUT-2 protein or its transcript by HGF treatment. These results indicate that HGF stimulates glucose incorporation through the selective up-regulation of GLUT-1 gene expression in HepG2 cells. PMID- 21533386 TI - Antitumorigenic and antipromoting activities of ellagic acid, ellagitannins and oligomeric anthocyanin and procyanidin. AB - We previously showed that ellagic acid (EA) was inhibiting lung tumorigenesis induced by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) in A/J mice. In the present study, we observed that the inhibition of lung tumorigenesis was independent of the solvent used to purified EA. Pomegranate peels extract containing punicalagin (alpha and beta anomers) (10 g/kg diet) and oligomeric anthocyanins (6 g/kg diet) did not inhibit lung tumorigenesis. Raspberry extract (2x15 mg) containing sanguiin H6 and lambertianin D as well as oligomeric procyanidins (2x15 mg) inhibit 12-O tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity by about 30%. The same treatments inhibit TPA-stimulated hydroperoxide (HPx) production by about 30 and 70%. Raspberry ellagitannins and oligomeric procyanidins respectively inhibit TPA stimulated DNA synthesis by 42 and 26%. Our results su est that hydrolyzable and condensed tannins from various sources, which can inhibit the ODC, HPx, and DNA responses to TPA, might also inhibit the tumor-promoting activity of this agent. The results of this study show that EA and ellagitannins have different antitumorigenic and antipromoting activities. PMID- 21533387 TI - Modulation of growth and urokinase secretion by vasopressin and closely related nonapeptides in metastatic mouse mammary tumor cells. AB - We examined the effects of the neuropeptide hormones vasopressin and oxytocin, and their respective synthetic derivatives desmopressin and isotocin, on F3II mouse mammary carcinoma cells. Vasopressin and desmopressin at concentrations ranging from 0.1 to 1 mu M were mitogenic for F3II cells and induced protein accumulation. On the contrary, oxytocin and isotocin were moderately growth inhibitory at similar doses. In confluent monolayers vasopressin stimulated the secretion of urokinase, a profibrinolytic enzyme involved in hematogenous metastasis. However, the net effect of the peptide on tumor-derived proteolytic activity was dependent on cell density. Stimulation of cell growth and urokinase production by vasopressin was strongly linked with calcium mobilization. These data suggest that vasopressin and its synthetic analog desmopressin may be important modulators of the behavior of metastatic mammary tumor cells. PMID- 21533388 TI - Differences of ploidy status in progression of head and neck melanomas. AB - Thirty-three common naevi, 26 dysplastic naevi, 58 primary melanomas of facial skin, 24 oral melanomas, 32 lymph nodes and 12 distant melanoma metastases were stained using Feulgen method to evaluate the ploidy status by image analysis GAS 200 system. Eight percent of common naevi, 22% of dysplastic naevi, 43% of facial melanomas, 65% of oral melanomas, 40% of lymph nodes with melanoma metastases and 66% of distant melanoma metastases were classified as aneuploid. In facial melanomas the percentage of aneuploid cases increased with Clark level. Survival time of patients was significantly shorter for aneuploid cases as compared to euploid ones (p <0.01). PMID- 21533389 TI - Differential production of gamma delta T cells in the urine of bladder cancer patients receiving Bacillus Calmette Guerin immunotherapy. AB - Bacillus Calmette Guerin (BCG) intravesical therapy of bladder cancer is arguably the most effective immunotherapy for any human solid tumour. It combines a high incidence of remission induction with a low level of side effects and a low rate of recurrence. Its mechanism, however, remains poorly understood. In this study we have investigated whether gamma delta T lymphocytes, which are known to be activated by mycobacteria, are preferentially induced in patients urine following therapy. This has necessitated the development of a procedure which facilitates the preservation, enrichment and detection of small number of lymphocytes [especially of those bearing gamma delta T cell receptor (TCR)I which appear in patients urine. Here we describe in detail a method for phenotyping of a minor subpopulation of lymphocytes in patients' urine, namely, gamma delta T lymphocytes which comprised less than 0.1% of all urinary sells. Using this technique we have found gamma delta T cells in the urine of all patients. Furthermore, the patients could be separated into 2 distinct groups, with low and high numbers of gamma delta cells (0.5-5% and 5-20% respectively of the CD3 positive cells). The elevation of gamma delta T cells was observed locally but not in peripheral blood and the detected gamma delta T were almost entirely of the V delta 2 gamma 9 subset. PMID- 21533390 TI - A multicentre, double-blind, randomised trial comparing ondansetron versus ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced delayed emesis. AB - The aim was to compare the efficacy of ondansetron and a combination of ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced delayed emesis over three consecutive courses of chemotherapy. Cancer patients scheduled to receive for the first time cisplatin (>50 mg/m(2)) in combination with other cytotoxic agents, were recruited in a multicentre, randomised, double-blind study and treated with ondansetron 8 mg i.v. and dexamethasone 20 mg i.v. Twenty-four hours after the start of chemotherapy, patients were randomised to treatment either with oral ondansetron 8 mg bd plus placebo on days 2-5 (group A) or with oral ondansetron 8 mg bd plus oral dexamethasone 8 mg bd on days 2-3, and 4 mg bd on days 4 and 5 (group B). Two hundred and thirty-six cancer patients were recruited into the study. Complete protection from delayed vomiting/nausea in group A and group B was Obtained in 50/39% and in 63/42% of patients, respectively in the first course; in 55/34% and in 64/40% in the second and in 49/31% and 60/37% in the third. Logistic regression analysis reveals a statistically significant difference in incidence of emesis between the combination of ondansetron plus dexamethasone and ondansetron alone (P<0.05). The same model, however, shows no difference in incidence of nausea between the two treatment regimens. Ondansetron plus dexamethasone reduces the risk of delayed emesis following cisplatin chemotherapy as compared to ondansetron alone. PMID- 21533391 TI - p53 alterations in breast cancer of the Parsi ethnic group. AB - Mutations in p53 are the most common genetic abnormality yet found in human cancers. p53 mutations vary among tumor types, ranging from 0-60% in major cancers. The frequency of p53 mutations in breast cancer averages around 25%. The incidence rate and the type of mutations at specific codons seem to be influenced by geographical location as well as racial and ethnic specificities. Women of the Parsi ethnic group living mostly in defined geographical areas around metropolitan Bombay are reported to have a markedly high incidence of breast cancer. In the present work, the p53 gene alterations in the Parsis were investigated using SSCP analysis. The results confirm an earlier observation that over 60% of the Parsi breast tumors harbour p53 alterations. This figure is higher than that observed in other communities. The relevance of the finding in the light of the high breast cancer incidence in the Parsis is discussed. PMID- 21533392 TI - Interaction of p53 with protein kinase CK2 during SV40 induced entrance of quiescent cells into the cell cycle. AB - Quiescent non-permissive cells re-enter the cell cycle upon infection with the DNA tumor virus SV40. Before the expression of virus specific proteins and other cellular reactions there is an induced expression of the growth suppressor protein p53. p53 is known to be a substrate for protein kinase CK2 and in addition it is tightly associated with CK2 and both proteins are implicated in cell cycle regulation. No phosphorylation of p53 was observed in vivo until late in G(1)- or early S-phase. Immunopurified p53 from the early G(1)-phase of the cell cycle was not phosphorylated by an associated protein kinase activity. Furthermore, protein kinase CK2 could not phosphorylate p53 from the early G(1) phase of the cell cycle and also immunopurified p53 from late G(1)- and S-phase which were dephosphorylated by alkaline and acid phosphatases. p53 from cells in S-phase is an efficient substrate. Moreover, in the presence of okadaic acid, a potent inhibitor of protein phosphatase PP2a, phosphorylation of p53 is detectable early in G(1)-phase of the cell cycle. PMID- 21533393 TI - Vanadium-mediated suppression of diethylnitrosamine-induced chromosomal aberrations in rat hepatocytes and its correlation with induction of hepatic glutathione and glutathione S-transferase. AB - Vanadium, a dietary micronutrient, has recently been found to possess a potent antitumor activity during chemically induced rat liver carcinogenesis. In the present study, attempts have been made to understand the basic mechanism of the antitumor response of vanadium by monitoring its effect on chromosomal aberrations (CA) in rat liver cells during the early preneoplastic steps of diethylnitrosamine (DENA)-induced hepatocarcinogenesis. Supplementary vanadium at 0.5 ppm was found to afford a unique protection against DENA-evoked CA 96 h after DENA injection. Concurrent administration of glutathione (GSH) at 200 mg/kg 2 h before DENA treatment potentiated the suppressive effect of vanadium against CA when the rats were sacrificed 96 h after the carcinogenic insult. Pretreatment nf rate with buthionine sulfoximine (890 mg/kg) and/or diethylmaleate (600 mg/kg) 0.5 or 2 h prior to DENA injection resulted in a significant inhibition of vanadium-mediated protection of CA with a concomitant fall in hepatic GSH level. Rats given injection of bromosulfophthalein (250 mg/kg), a substrate inhibitor of glutathione S-transferase (GST), 0.5 h before DENA treatment displayed a prominent suppression of the protective effect of vanadium on DENA-induced CA. Long-term supplementation of vanadium also triggered protective effect against the induction of CA 15, 30 or 45 days following DENA treatment which was maximally observed on structural aberrations followed by numerical aberrations. At these time points, vanadium was found to lower the mitotic index of hepatic cells which was otherwise elevated with DENA alone. Vanadium restored DENA dependent decrement in the ratio of polychromatic erythrocytes (PCE) to normochromatic erythrocytes (NCE) in rat liver cells. The DENA-induced increased frequency of micronucleated PCE as well as NCE was also attenuated following vanadium supplementation. The anticlastogenic effect of vanadium was found to be parallel to its ability to induce the activity of hepatic GST with a concurrent induction of hepatic GSH pool which were rather decreased in DENA control group. The results of this study, thus, provide evidence that vanadium-dependent induction of GSH-mediated GST-catalyzed detoxificational capacity of the host is presumably related to its suppressive effect against CA. This may explain, in part, the antitumor efficacy of this trace element. PMID- 21533394 TI - Tumor oxygenation after hyperthermia in the rat 13762 mammary carcinoma and the DU-145 human prostate carcinoma. AB - Tumor oxygenation was measured in the rat 13762 mammary carcinoma over a time course from 30 min to 3 days after hyperthermia treatment of 43 degrees C, 30 min or 40 degrees C, 80 min, while the animals breathed air, carbogen or after administration of a perflubron emulsion with air or carbogen breathing. Shortly (30 min and 3 h) after treatment with 43 degrees C, 30 min, the 13762 tumors were more hypoxic, as determined by the percent of pO(2) readings <5 mmHg and median pO(2), than prior to treatment and by 24 h had returned to initial oxygenation. Administration of the perflubron emulsion and carbogen breathing abrogated the increase in hypoxia and improved tumor oxygenation. Athymic mice bearing the DU 145 human prostate carcinoma were treated with hyperthermia regimens 40 degrees C, 41 degrees C, 42 degrees C or 43 degrees C for 60 min and tumor oxygenation was then measured over a time course while the animals breathed air or carbogen. Shortly (30 min) after hyperthermia, the DU-145 tumors were more hypoxic than initially when the animals breathed air. Three days later, the DU-145 tumors treated with 41 degrees C: 42 degrees C or 43 degrees C remained hypoxic but the tumors treated with 40 degrees C were better oxygenated than initially. When the animals bearing the DU-145 tumor breathed carbogen during the tumor oxygenation measurements only tumors treated with 43 degrees C were more hypoxic shortly after hyperthermia treatment. Three days after hyperthermia, the DU-145 tumors treated with 40 degrees C and 43 degrees C were better oxygenated than initially while those treated with 41 degrees C and 42 degrees C were less oxygenated when the animals breathed carbogen during the oxygen measurements. Thus, the effect of hyperthermia on tumor physiology can persist for days post treatment and vary with the temperature of the treatment. PMID- 21533395 TI - Possible involvement of protein phosphatase type 2A in tumor necrosis factor alpha-induced tissue factor expression in endothelial cells. AB - The involvement of protein Ser/Thr phosphatase types 2A (PP2A) and 1 (PP1) in tumor necrosis factor alpha (TNF alpha)-induced tissue factor (TF) expression of human umbilical vein endothelial cells (HUVEC) was investigated. PP2A was more abundant than PP1 in the cytosol of HUVEC. CAL-A (0.5 nM) and OKA (2 nM), cell permeable inhibitors of PP1 and PP2A, augmented TNF alpha-induced TF expression, although TF expression induced by either TPA or thrombin was unchanged in the presence of GAL-A. Addition of CAL-A (0.5 nM) to TNF alpha-stimulated cultures led to an increase in the accumulation of TF transcripts. CAL-A (0.5 nM) also augmented the TNF alpha-induced phosphorylation of I kappa B-alpha, an inhibitor of NF-kappa B. Since PP2A is more sensitive to OKA than PP1, these results suggest that PP2A may be involved in regulating TNF alpha-induced TF expression in HUVEC through I kappa B-alpha dephosphorylation. PMID- 21533396 TI - Modulation of alterations in p53 tumor suppressor gene and its association with activation of ras proto-oncogenes during chemoprevention of colon cancer. AB - Previously, we reported (Carcinogenesis 15: 1317-1323, 1994) a high rate of activating point mutations in I ns proto-oncogenes in azoxymethane (AOM)-induced colon tumors, and a significant suppression of these mutations by dietary administration of chemopreventive agents, D,L-alpha-difluoromethylornithine (DFMO) and piroxicam. To understand the role of p53 tumor suppressor gene in chemoprevention of colon cancer and to study the association of p53 gene alterations with activation of ras genes, we determined point mutations in conserved regions (exons 5-9) of p53 gene and analyzed the occurrence of double event of ms activation acid p53 mutation. Groups of male F344 rats were fed the modified AIN-76A diet containing 0, 4000 ppm DFMO, or 150 ppm piroxicam and administered s.c. AOM at a dose rate of 15 mg/kg body wt, once weekly, for 4 weeks. Vehicle controls received s.c. equal volume of normal saline. Animals were sacrificed 32 weeks after the last AOM or saline injection and their grossly visible colon tumors were analyzed to determine p53 mutations by PCR amplification based single strand conformation polymorphism (SSCP) and direct DNA sequencing. Our results demonstrate that about 57% tumors from animals fed the control diet contained predominantly missense but also nonsense mutations, whereas only 30% tumors from animals on piroxicam diet, and none (0%) from animals fed the DFMO diet had similar mutations. Analysis of data revealed that about half of the tumors from animals on control diet possessed both ms and p53 mutations together, only 27% of colon tumors from animals on piroxicam diet and none of the tumors from animals on DFMO diet exhibited both ms and p53 mutations. These results indicate that the administration of piroxicam, a non-steroidal anti inflammatory drug, and DFMO, a irreversible inhibitor of ornithine decarboxylase, may inhibit selective proliferation of initiated cells containing activated las and/or mutant p53. Dietary DFMO exerted more pronounced inhibition of selective amplification of initiated cells containing mutated ras and/or p53. PMID- 21533397 TI - In situ downregulation of VLA-4 integrin cell surface expression during lymphoma growth and liver metastasis. AB - The role of VLA-4 integrin in liver metastasis of lymphoma cells was investigated. ESbL-lacZ lymphoma cells in vitro exhibited high surface expression of VLA-4, adhered to CS-1 fibronectin and VCAM-1 and cell adhesion was inhibited by anti-VLA-4 MAb PS/2. When injected in vivo, however, PS/2 did not interfere with spontaneous liver metastasis and had no effect on survival. Ex vivo analysis of VLA-4 surface expression was facilitated by a new reisolation method for tumor and host cells derived from metastatic target organs. Freshly ex vivo isolated tumor cells from metastatic livers revealed VLA-4 surface downregulation as early as 3 days after tumor injection, which continued during the course of metastasis. VLA-4 downregulation in liver metastasis was also seen at the mRNA transcriptional level. Primary tumor cells showed similar VLA-4 downregulation suggesting that the in vivo phenotype was induced by the microenvironment at the primary tumor site. In support of this hypothesis, re-isolated tumor cells from metastatic livers recovered the high VLA-4 expression in host-depleted cell cultures. This study suggests that VLA-4 expression on tumor cells can be modulated in situ during tumor growth and metastasis formation. PMID- 21533398 TI - Activated endothelial cells induce apoptosis in lymphoma cells. AB - We have previously shown that the arrest or regression of mouse liver metastases formed by lacZ-transduced ESbL T lymphoma cells (ESbL-lacZ) is associated with the stimulation of nitric oxide (NO) production by liver endothelial cells in sis. Here we studied in vitro the NO-mediated cytotoxicity against ESbL-lacZ target cells using well-characterized bovine endothelial cells (BEG) as effector cells. It was found that the co-culture of BEC with human TNF-alpha caused an increase of NO synthesis which could be completely blocked by the treatment with inducible NO synthase (iNOS) inhibitor N-G-monomethyl-L-arginine (NMMA). Incubation of activated BEC with metastatic lymphoma cells led to the death of the latter cells as evidenced by staining with propidium iodide and FAGS analysis. This cytotoxicity was considerably reduced after pretreatment of BEC with NMMA. Cytotoxic effects were also demonstrated after incubation of tumor cells with NO donor glycerol trinitrate (GTN). Non-activated BEC were not able to produce NO and showed a substantially lower level of cytotoxicity. The anti-tumor cytotoxicity exerted by activated BEC includes the stimulation of apoptosis in metastatic lymphoma cells which is mediated to a large extent by NO. These data reveal a novel role of endothelial cells in the elimination of metastatic cells through the induction of programmed cell death. PMID- 21533399 TI - Frequent expression of MDR1 and MDR3 genes in acute myelocytic leukemia cells with t(8;21) (q22;q22). AB - Multidrug resistance (MDR) 1 and MDR3 gene expression were examined in acute myelocytic leukemia (AML) cells from 126 Japanese patients. In 119 AML patients at diagnosis 52 were revealed to have P-gp/MDR1 (43.7%). AML cases with t(8;21) had a higher incidence of P-gp expression (13/17; 76.5%) than cases with other karyotypes (33/89; 37.1%) (p=0.0062). CD19(+) cases expressed P-gp frequently (17/25) as did CD7(+) cases (24/35). In 17 CD19(+) AML with P-gp expression, 12 had t(8;21) abnormality. In 68 AML samples examined, MDR3 mRNA was detected in 11 cases, 9 of which had the t(8;21) abnormality. The MDR3(+) t(8;21) AML samples were also positive for CD19. We analyzed P-gp expression at both diagnosis and relapse in 18 AML patients. All 11 P-gp(+) cases at relapse, in which 5 patients were P-gp negative at diagnosis, showed either t(8;21) or CD7 positivity. Our data demonstrated that expression of MDR1 and MDR3 in AML is closely associated with chromosome abnormality t(8;21) and expression of immature lymphoid antigen CD19 as well as CD7. Kasumi-1, a t(8;21) AML cell line, was demonstrated to lose P-gp by the treatment of 1,25(OH)(2)D-3, a monocyte/macropharge differentiation inducer, suggesting the possible contribution to the therapy for AML. PMID- 21533400 TI - Effects of thymic peptides, in vitro, on the impaired immunocytotoxicity of peripheral blood mononuclear cells from tumor patients. AB - The effects of a thymic peptide preparation (TP) on the immunocytotoxicity and cytokine secretion of peripheral blood lymphocytes and monocytes from patients with colorectal tumors, breast tumors and melanoma were studied in vitro. On average, breast tumor and melanoma patients showed significantly lower natural killer (NK) cell activities than colorectal tumor patients and normal controls. In contrast, the generation of lymphokine (IL-2) activated killer (LAK) cells was found to be comparable within the different tumor diseases (24% cytotoxicity), but lower than in the group of normal controls. TP, being without any effects on NK cell activity in all groups, increased the deficient LAK cell activity of breast tumor and melanoma patients, as well as of normal controls? without significant effects on PBL from colorectal tumor patients. This increase was found to be associated with an increase of the IL-2 induced IFN-gamma and, on a lower level, TNF-alpha secretion, especially from breast tumor and melanoma patients. In addition, monocytes from these patients showed a deranged tumoristatic activity, compared to colorectal tumor patients and normal controls. The stimulation of monocytes by IFN-gamma greatly elevated the mean of the antitumor activity in all groups studied. TP being slightly effective on monocytes from melanoma patients, did not further enhance monocyte-mediated cytotoxicity when applied alone or in combination with IFN-gamma. Reduced basal monocytic chemokine levels were only found in the groups of melanoma (IL-8) and colorectal tumor patients (MCP-1), whereas RANTES secretion was increased, compared to normal controls. TP was active only in reducing the IL-8 secretion of monocytes from colon tumor patients. The results indicate that selected functions of peripheral blood mononuclear cells can be partially improved by the thymic peptide preparation. PMID- 21533401 TI - Subcutaneous recombinant interleukin-2 plus alpha interferon and vinblastine in metastatic renal cell carcinoma. AB - The management of metastatic renal cell carcinoma (RCC) constitutes a therapeutic challenge and no standard therapy has yet been established. This phase II study aimed to verify the efficacy and tolerability of subcutaneous low dose recombinant interleukin-2 (IL-2) plus alpha interferon (IFN) and vinblastine (VLB) in patients with metastatic RCC. Twenty-three evaluable adult patients were enrolled in the study. A total of 19 patients were previously subjected to radical nephrectomy and four had been treated with adjuvant immunotherapy. The I nest frequent metastatic sites were lung/pleura, bone, liver, lymph nodes, and abdominal mass. The following treatment schedule was administered: VLB at 6 mg/m(2) on day 1: IL-2 at 4.5 million IU twice daily from day 1 to 5 and day 8 to 12; IFN at 3 million IU three times weekly intramuscularly. The therapy was recycled every 21 days, except for the IFN which was administered continuously. Five patients demonstrated remission (21.6%) including one complete response persisting for 6 months, and four partial responses with a duration of 41+, 20, 8, and 18+ months. Moreover, 15 patients (65%) showed stable disease for 4-20 months (median 6 months), and three patients progressed. Overall median survival of the 23 patients was 11 months, with 27+ months for responders, 11 months for patients with stable disease, and 8 months for patients with rapid progression. Regressions occurred in lung, pleura, bone, and abdominal mass. Treatment was relatively well tolerated and easily manageable. This study was mainly administered as outpatient care. This study confirms the manageability and tolerability of subcutaneous IL-2 used in association with IFN alpha and chemotherapy. Even though a minority of patients responded, the duration of responses and the high percentage of long stable diseases represent the most interesting aspect of this study. PMID- 21533402 TI - Clinical significance of pyrimidine nucleoside phosphorylase in colorectal carcinoma. AB - The expression of pyrimidine nucleoside phosphorylase (PyNPase) mRNA in tumor (T) and normal (N) biopsy specimens obtained from 41 cases of colorectal carcinoma was examined by the reverse transcriptase/polymerase chain reaction (RT-PCR). The higher T/N ratio of the expression of PyNPase mRNA correlated significantly with the presence of lymph vessel invasion (p=0.039), the positive lymph node metastasis (p=0.014) and the advanced stage of the disease (p=0.014). There was a significant con-elation between the results determined by enzyme activity and those determined by RT-PCR (p=0.005). The findings suggested that the determination of PyNPase mRNA by RT-PCR may give useful information on tumor aggressiveness of colorectal carcinoma and this method can be used instead of enzyme activity. PMID- 21533403 TI - Analysis of sex chromosomal numerical aberrations in human astrocytomas by FISH. AB - Although sex chromosomal aberrations in astrocytomas have been frequently reported by cytogeneticists, their biologic significance is still unclear. The aim of this study was to investigate sex chromosomal aberrations of astrocytomas by fluorescence in situ hybridization (FISH) and to determine whether there is a relationship between these aberrations and abnormalities of chromosomes 7 and 10. The astrocytoma specimens were obtained from 14 male and 11 female patients. The centromeric probes DYZ1, DXZ1, D7Z1 and D10Z1 were used to determine the numerical changes in chromosomes Y, X, 7, and 10 by FISH. The hybridization spots were counted by fluorescence microscopy. Three cases showed chromosome X aberrations, including two cases with loss of chromosome X and one case with a complex chromosome X aberration among 11 female astrocytomas. Eight cases with loss of chromosome Y were seen among 14 male astrocytomas; one was grade II, three grade III, and four grade IV tumors. One case of disomy X was observed among male grade II tumors. Seven of the eight tumors with loss of chromosome Y had additional complex chromosome aberrations. Our results suggest that sex chromosome aberrations in malignant astrocytomas are non-random and frequent. These changes suggest an association with aberrations of chromosomes 7 and 10. These sex chromosome aberrations seem to be a part of a complex chromosome pattern of aberrations in astrocytomas. The observed abnormalities may not necessarily be a part of the neoplastic progression in malignant astrocytomas, but they may be of biologic significance. PMID- 21533404 TI - Cyclooxygenase-2 gene expression in human breast cancer. AB - Expression of the inducible isoform of the cyclooxygenase gene (PGHS-2, COX-2) which codes for the enzyme that catalyzes formation of prostaglandins, was detected in 13/13 human breast tumors of high grade but not in samples of normal breast tissue. There was a statistically significant linear association between COX-2 gene expression and high (>50%) tumor cell density (p<0.01), with COX-2 protein localized to tumor cells. These results indicate that COX-2 gene expression may be useful as a molecular biomarker for human breast tumors and may also predict sensitivity to treatment with nonsteroidal anti-inflammatory drugs. PMID- 21533405 TI - Carboplatin (CBDCA) plus ifosfamide (IFO) as first-line chemotherapy in advanced (FIGO III and IV) ovarian cancer. AB - A phase II study of advanced FIGO III and IV ovarian cancer treated with carboplatin and ifosfamide was performed to define the efficacy and tolerability of this regimen as first-line chemotherapy. From November 1990 to December 1994, 30 women with advanced ovarian cancer or residual disease after initial surgery were treated with carboplatin (300 mg/m(2) intravenously on day 1) and ifosfamide (1,500 mg/m(2) intravenously on days 1-3, with MESNA) every 3 weeks. The overall response rate was 67% (complete response 27%, partial response 40%) and the median duration of response was 14 months (range, 6-36). After a median follow-up of 31 months, the median survival was 24.9 months. Time to progression (p<0.05) and overall survival were longer in the patient group subjected to debulking. This regimen was easily manageable with good activity and acceptable toxicity, and most patients were treated on an outpatient basis. PMID- 21533406 TI - Overexpression of a hexa-histidine and T7 peptide-tagged human ribonucleotide reductase small subunit, R2 in Escherichia coli and the generation of human R2 antibodies. AB - Human ribonucleotide reductase (hRR) consists of two non-identical subunits: the large regulatory subunit, R1, with a molecular mass of approximately 90 kD; and the small catalytic subunit, R2, with a molecular mass of approximately 45 kD. In most human cells, R2 protein levels correlate closely with hRR holoenzyme activity. Since hRR is essential for the DNA replication and DNA repair synthesis, it has been considered as a potential target for cancer therapy. To facilitate further study of the regulation of the human R2 protein and hRR and their potential targeting for chemotherapy, a fusion protein tagged with 6 residues of histidine and an 11 amino acid sequence from the T7 capsid protein at the N-terminus of human R2 cDNA was overproduced in E. coli. The fusion protein was purified to near homogeneity and used to generate polyclonal antibodies in rabbits. The antibodies recognized the 48 kD recombinant protein and a major band of a 45 kD protein consistent with human R2 by Western blot in three human cancer cell lines including Caski, a cervix cancer cell line, KB, a nasopharyngeal cancer cell line, and KB-R, a KB derived cell line which is resistant to hydroxyurea (HU) and has a 3x overexpression of R2 protein. In contrast, the YL1/2 monoclonal antibody against yeast alpha-tubulin, which was previously reported to cross-react with human R2, required higher (>10x) concentrations and exposure times to detect the R2 protein in the 3 human cancer cell lines while also detecting two other proteins (alpha tubulin and an unidentified protein). We conclude that these new human polyclonal antibodies, with greater sensitivity and specificity than the YL 1/2 antibody, should better facilitate studies of the regulation of the human R2 protein and hRR. PMID- 21533407 TI - p53 status and prognosis in stage I-IIIa non-small cell lung cancer. AB - To investigate the role of p53 abnormalities in predicting the survival of patients with non-small cell lung cancer (NSCLC), polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) and immunohistochemical analyses were performed on 74 and 67 tumor samples, respectively, from patients with pathological stage I-IIIa NSCLC. An abnormally migrating SSCP band was observed in 21 of 74 (28%) tumor specimens. DNA sequence analysis revealed 23 intragenic mutations including 3 small deletions and 20 point mutations. Immunohistochemical analysis using the DO-7 monoclonal antibody showed abnormal expression of p53 in 27 of 67 (40%) patients. The concordance rate between immunohistochemical and PCRSSCP analyses was 73% (49/67) in this study. Univariate and multivariate analyses demonstrated that abnormal expression of p53 may be associated with prolonged survival (p=0.0997 and 0.0099, respectively). In contrast, no relationship was observed between p53 mutation and overall survival (0.6968). These results suggest that p53 status and the survival outcome changes between immunohistochemical and mutational analyses in stage I-IIIa NSCLC. PMID- 21533408 TI - Facts, myths, and reflections on the use of maximum tolerated dose in chemical carcinogenesis (review). AB - The introduction and the subsequent use of maximum tolerated dose (MTD) or, more correctly, the estimated maximum tolerated dose (EMTD) in chemical carcinogenesis is reviewed. A historical perspective followed by the chronological development of the concept is described and commented on. The justifications and the criticisms of the EMTD are outlined and rebuttals of the criticisms are presented. The extrapolation of estimated risk from animal bioassay to humans is given and the notion of the ideal experiment is elaborated upon briefly. It is concluded that the EMTD is a necessary, crucial method in determining the carcinogenic activity of chemical substances and natural products until a better replacement is found. PMID- 21533409 TI - Allelic imbalance on the long arm of chromosome 5 in oral squamous cell carcinoma. AB - To obtain a more detailed estimate of chromosome 5 loci involvement in oral squamous cell carcinoma (SCC), thirty-two oral SCCs were examined for loss of heterozygosity (LOH) on the long arm of chromosome 5 (5q) by PCR-LOH assay using thirteen microsatellite markers. LOH was observed in 16 (51.6%) of 31 informative cases. The incidence or the number of regions showing LOH was significantly higher in moderately and poorly differentiated tumors than in the well differentiated ones. Among the loci tested, D5S178 exhibited LOH in 11 (39.3%) of 28 cases, suggesting this to be the site, at 5q, of a novel candidate tumor suppressor gene. These data indicate that the incidence of LOH at chromosome 5q is high and is associated with oral tumor differentiation. PMID- 21533410 TI - Viral gene mutation as determinant of low grade malignancy of lesions induced by perinatal retrovirus infection. AB - Of 108 Wistar/Ma rats perinatally injected with Snyder-Theilen feline sarcoma virus, 75 developed tumors within 60 days (group A), and 25 after more than 117 days (group B). Metastases were detected in 59.1% and 11.8% in group A and B respectively. Antibody to v-fes gene product was found to occur before tumor development in group B and after tumor development in group A. v-Ses was found to be down-regulated and extensively mutated in tumors of group B. These results suggest viral gene mutation as a determinant of low grade malignancy of lesions induced. PMID- 21533411 TI - Radiosensitivity of human biliary tract cancer cell lines in vitro. AB - The prognosis of biliary tract cancer is still poor. Although a number of clinical studies have suggested a role for radiation therapy in advanced biliary tract cancer, its value remains controversial. Moreover, the intrinsic radiosensitivity of bile duct cancer cell lines has not been described, and the molecular basis for the response of these tumors to ionizing radiation is poorly understood. The present study was designed to examine the intrinsic radiation sensitivity of human biliary tract cancer cells and its relationship to p53 status. Radiation response expressed by the parameters n, D-0, D-10, alpha, beta, (D) over bar (mean inactivation dose), and SF, of seven cell lines derived from gallbladder and bile duct cancers was determined. The results suggest that biliary tract cancer cell lines as a group are relatively radioresistant. The mean X-ray survival parameters for these seven cancer cell lines were D-0=2.13+/ 0.29 Gy, D-10=5.73+/-0.59 Gy, (D) over bar=2.76+/-0.25 Gy, alpha=0.25+/-0.03, and SF2=0.54+/-0.05. One of the seven lines was more radiosensitive than the others (D-0=0.77+/-0.02 Gy, D-10=2.95+/-0.06 Gy, (D) over bar=1.57 Gy, alpha=0.35, SF2=0.35+/-0.03). Five of six lines examined expressed mutant p53 including the radiosensitive line; one radioresistant line expressed wild-type p53. Thus, although loss of wild-type p53 expression occurred frequently in these biliary cancer cell lines, radiosensitivity did not correlate with p53 status. In view of the intrinsic radioresistance of this type of tumor cell coupled with the poor tolerance of surrounding normal tissues, maximal surgical debulking and intraoperative radiation therapy may contribute to increased local control over resection and/or conventional fractionated radiotherapy. PMID- 21533412 TI - Upregulation of CD44s in c-sis-transformed balb/c 3T3 cells by autocrine growth factor mechanisms, including PDGF. AB - Regulation of CD44s by the c-sis oncogene product was investigated. Both CD44s protein and mRNA were comparably upregulated, consistent with some degree of transcriptional regulation; its ligand binding was also activated in confluent but not in sparse cultures of sis-transformed Balb/c 3T3 cells. CD44s was also elevated in confluent cultures of parental 3T3 cells treated with conditioned media from confluent c-sis transformants (but not from 3T3 cells); these media (but not media from ras transformants or parental 3T3 cells) contained platelet derived growth factor (PDGF)-immunoreactive material. CD44s upregulation by these media could be partially blocked by anti-PDGF antibodies. These media also induced activation via tyrosine autophosphorylation and activation-dependent downregulation of PDGF beta-receptors. sis-transformed 3T3 cells contained low levels of PDGF receptor, but CD44 levels could still be increased in these cells by addition of PDGF. These results suggest that CD44s is upregulated in confluent cultures of c-sis-transformed cells by autocrine growth factors, including PDGF, secreted into the cell's microenvironment. PMID- 21533413 TI - Hyaluronate activates tyrosine phosphorylation of cellular proteins including focal adhesion kinase via CD44 in human glioma cells. AB - To search for the signaling pathway of glioma cells relevant to its aggressive behavior, we examined hyaluronate-CD44 signaling. CD44, a hyaluronate receptor, is known to be highly expressed in glioma and its expression showed good correlation with invasiveness of the tumor. Treatment of glioma cells with hyaluronate activated rapid and transient tyrosine phosphorylation of several proteins including p125(FAK), while neuroblastoma cells that express no detectable CD44 had no response to the treatment. This hyaluronate-dependent tyrosine phosphorylation was blocked by anti-CD44 antibody, suggesting its direct mediation by CD44. Moreover, we found that hyaluronate-treatment activated mitogen activated protein (MAP) kinase. These results strongly suggest that hyaluronate-CD44 signaling may play a role in tumor invasion and proliferation by activation of p125(FAK) and MAP kinase in human glioma cells. PMID- 21533414 TI - Cancer cachexia. AB - Cancer cachexia is a complex syndrome accounting for nearly a third of cancer deaths, characterized by weight loss, anorexia, weakness, anaemia and asthenia. The complications associated with the appearance of the cachectic syndrome affect both the physiological and biochemical balance of the patient, and have effects on the efficiency of the anticancer treatment. At the metabolic level, cachexia is associated with loss of skeletal muscle protein together with a depletion of body lipid stores. The metabolic changes are partially mediated by alterations in circulating hormone concentrations or in their effectiveness. On the other hand, a large number of observations point towards cytokines as the molecules responsible for the referred metabolic derangements. The present study reviews the changes in metabolic environment which are found in the host during tumour burden, as well as the possible role of TNF (tumour necrosis factor) as a mediator of cachexia. PMID- 21533415 TI - Meat intake, heterocyclic amines and risk of colorectal cancer. AB - A case-control study was conducted in Uruguay, in order to investigate the relationship between heterocyclic amine intake and colorectal cancer risk. The study included 250 cases of colorectal cancer and 500 controls, frequency-matched with the cases on age, sex, and residence. A significant increase in risk of colorectal cancer associated with red meat, beef and fried meat was observed. Heterocyclic amines were associated with a significant increase in the risk of colorectal cancer in males and females. This increased risk persisted after controlling for total energy, total meat and total fat intake. On the other hand, total meat and total fat intake were not longer significant. This latter finding suggests that heterocyclic amine exposure is central in colorectal carcinogenesis. PMID- 21533416 TI - Bcl-2 protein expression in breast cancer and its relationship to prognosis. AB - The expression of bcl-2 protein was studied in invasive breast cancer by immunohistochemistry. Fourty-six (56.8%) bcl-2 protein-positive tumors were found in 81 breast cancers. There was no significant correlation between the bcl-2 protein immunoreactivity and histologic type, primary tumor status, or lymph node metastasis. However, a strong positive relationship was demonstrated between bcl 2 immunoreactivity and estrogen receptor status. The 5-year survival rate and disease-free survival rates were 73.7% and 71.1% of patients with bcl-2-positive tumors, and 62.5% and 58.0% of those with bcl-2-negative tumors; these differences between the two groups of patients wete significant (p<0.05). In multivariate analysis using Cox regression model, bcl-2 immunoreactivity emerged as an independent prognostic indicator in breast cancer patients. PMID- 21533417 TI - Incidence of human papillomavirus type 33 in premalignant and malignant skin lesions from organ transplant recipients. AB - Human papillomavirus (HPV) type 33 belongs to potentially oncogenic types in genital cancers, but its infection corresponds to an intermediate risk for progression towards malignancy. We studied by in situ hybridization with biotinylated probes the incidence of HPV 33 infection in a series of 106 skin lesions and 12 mucosal lesions from heart and renal transplant recipients, 34 skin lesions and 17 mucosal lesions from normal population. We have shown that skin lesions from both populations could harbor HPV 33. In transplant recipients, HPV 33 was identified in 12/77 premalignant and malignant lesions and one oral leukoplakia; in the normal population, HPV 33 was detected in 2/13 warts and 2/15 mucosal lesions. The analysis of in sial hybridization signal pattern of the 17 HPV 33 positive samples suggests that a strong viral DNA signal was uniformly distributed in the nuclei of positive cell foci in 11 cases and punctate signals were seen in the nuclei of dispersed cells of 6 skin biopsies. The significance of the presence of HPV 33 DNA in skin lesions is not clear; the hybridization signal pattern may be important, mainly in premalignant actinic keratodses of organ transplant recipients although other factors are most likely involved to change the epithelial environment. PMID- 21533418 TI - Local hyperthermia, hyperfractionated radiation, and cisplatin in preirradiated recurrent lymph node metastases of recurrent head and neck cancer. AB - Large tumor size is a negative prognostic variable for attaining complete regression (CR) with local hyperthermia (HT) and radiotherapy (RT). Such poor prognosis lesions (i.e., >7 cm(2) or >14 cm(3)) have an expected CR rate of similar to 30+/-8%. To improve on this result we added cisplatin to HT and RT with standard fractionation (std Fx) in an earlier study, and observed a 19% CR rate in head and neck (H&N) patients. We now report the results of a second generation trial combining HT, cisplatin (40 mg/m(2)) and hyperfractionated RT in a series of 13 pretreated poor prognosis H&N patients. Therapy encompassed 44 triple modality sessions and was well tolerated: toxicity included one episode of grade-3 skin reaction and one grade 1 leukopenia. Although the overall remission rate was 92%, the CR rate was only 8%; this resulted in early closure of this trial concluding that hyperfractionated RT had no (over std Fx RT) benefit in this combined modality approach. PMID- 21533419 TI - Associations of retinoids, tamoxifen and alpha-interferon 2a in human breast cancer. AB - We evaluated in vitro the potentiating and/or synergistic antitumor effects among retinoids (all-trans-retinoic acid, tRA, and 13-cis-retinoic acid, 13cRA), alpha interferon 2a (alpha-IFN 2a) and tamoxifen (TAM) on both estrogen receptor positive (ER(+)) and negative (ER(-)) human breast cancer cell lines. In our experimental model, the three studied agents showed antiproliferative activity in ER(+) cell lines MCF-7 and ZR-75.1, while alpha-IFN 2a was the most effective drug in the ER(-) cell line MDA-MB-231. Retinoids and TAM exerted a strong apoptotic effect in MCF-7 cells, while such an effect was obtained in MDA-MB-231 cells by alpha-IFN 2a. The tested combinations displayed different effects in the different evaluated cell lines: i) in MCF-7 cells tRA + TAM showed additive activity, both tRA + alpha-IFN 2a and TAM + alpha-IFN 2a association displayed a synergistic effect, and a further potentiation of the antiproliferative action was detected with the triple combination; ii) in ZR-75.1 cell line an additive activity was showed by tRA + TAM and TAM + alpha-IFN 2a, while tRA + alpha-IFN 2a produced synergistic action; iii) in MDA-MB-231 cell line only alpha-IFN 2a displayed a strong antiproliferative effect, and no significant potentiation was exerted by any drug association. The feasibility and activity of such combinations have been tested in two pilot clinical trials on patients with metastatic breast cancer: both the tested associations were tolerable, with good treatment compliance and low toxicity. The different antiproliferative and apoptotic effects observed in vitro on apparently similar breast cancer cell lines prompted us to a further investigation of the mutual biological modulations of these drug combinations, in view of a better selection of patients who might potentially benefit from these treatments. PMID- 21533420 TI - The uptake of a monoclonal antibody (Po66) in lung tumour cell aggregates involves a phagocytose-like phenomenon. AB - The efficacy of radioimmunotherapy with radiolabelled monoclonal antibody (Mab) depends on the amount of antibody taken up by the tumour and on its intratumoral distribution. Multicellular spheroids (MTS) of lung cell carcinoma was investigated to study cellular and subcellular distribution of a Mab Po66 labelled with I-125. We have shown that the incorporation of Po66 in MTS regularly increases during 3 days while Py, a non specific Mab, remains low. The distribution of radiolabelled studied by light and electron microscopy autoradiography have demonstrated that Po66 first localized on extra cellular debris, is then phagocyted and observed in the cytoplasm of viable cells. This mechanism of penetration and distribution of Mab Po66 is a new and interesting phenomenon, and emphasizes contribution of transmission electron microscopy in nuclear medicine. PMID- 21533421 TI - Non-coexpression of collagenase and transin in malignant epithelial cells. AB - Increased synthesis and secretion of the matrix metalloproteinase has been associated with the acquisition of the invasive properties of malignant cells. In a rat malignant anaplastic cell line (T952/F7) sporadic expression of mRNA for collagenase-3 against a background of high transin-l mRNA has been shown. Sporadic induction of either metalloproteinase was not found in the benign precursor cells (A5P/B10) of T952/F7 cells, but a coordinate mRNA induction profile for these two genes could be induced by the addition of 12-O tetradecanoylphorbol-13-acetate. In a different uncloned neoplastic epithelial cell line (BCl) fluctuations in the levels of collagenase and transin appeared coordinately, but coordinate expression was not a feature in cloned lines derived from BCl. The loss of coordinate regulation of the two matrix metalloproteinases may relate to the variability in metastatic potential seen in clonal cell lines. PMID- 21533422 TI - A randomized phase II trial of cisplatinum plus mitomycin-C plus vinorelbine and carboplatin plus vinorelbine in advanced non-small cell lung cancer. AB - Vinorelbine represents one of the most active agents in advanced non-small cell lung cancer (NSCLC), with response rates of 14-33%. We therefore evaluated the activity and tolerability of two novel vinorelbine-containing regimens in stage IIIB-IV NSCLC. Fifty-two patients were enrolled in a randomized phase II study of cisplatinum (100 mg/m(2)) day 1, mitomycin-C (8 mg/m(2)) day 1, and vinorelbine (25 mg/m(2)) days 1 and 8 (Arm A); and carboplatin (400 mg/m(2)) day 1, in combination with vinorelbine (25 mg/m(2)) days 1 and 8 (Arm B). Cycles were repeated every 3 weeks. All patients were assessable for reponse and side effects. Patients were well balanced between the two Arms in terms of major characteristics. A total of 98 and 91 cycles were delivered respectively in Arm A and Arm B. Eleven objective responses (42%; 95% confidence interval 26-63%) were observed in Arm A and 7 responses (27%; 95% confidence interval 12-48%) in Arm B. Main toxicity was mild or moderate, nausea and vomiting for Arm A and hematological for Arm B. Other side effects included infections and phlebitis and were similar for the two Arms. In conclusion, both schedules demonstrated activity in advanced NSCLC. The three-drug regimen appeared very promising in terms of activity and manageable toxicity. PMID- 21533423 TI - Expression of matrix metalloproteinases 1 and 2 genes in a possible association with metastatic abilities of human pancreatic cancer cells. AB - We determined if any extracellular matrix degradative proteases were possibly associated with metastatic potentials of human pancreatic cancer cells. Liver metastatic abilities of six human pancreatic cancer cell lines were examined in nude mice, and divided into two high (2 lines) and low (4 lines) metastatic cell lines. Of six cell lines, matrix metalloproteinases-1 (MMP-1) was overexpressed in two high metastatic cell lines: and MMP-2 was overexpressed in one high metastatic cell line. Of the four low metastatic lines, two cell lines had relatively higher mRNA levels of tissue inhibitors of metalloproteinases-3 (TIMP 3). MMP activities due to MMP-1 and MMP-2 might be positively associated with liver metastasis of pancreatic cancer cells. Moreover, expression of TIMP-3 might be partly involved in the low metastatic potentials of pancreatic cancer. PMID- 21533424 TI - Does a passive transport between modified plasma lipoproteins and cell membranes exist in cancer disease? AB - Malignant diseases increase the level of total lipids in blood and modify their distribution in lipoprotein carriers affecting lipid exchanges between serum and tissues. These exchanges take place by active and/or passive ways which coexist in most tissues. This work concerns the exploration of passive diffusion, using the red blood cell mechanism as a model. Lipid components of normal and cancerous rat erythrocytes have been investigated by Proton and Carbon high resolution Magnetic Resonance Spectroscopy (H-1 and C-13 MRS). As previously established, MRS yields the usual molar ratio cholesterol/phospholipids and moreover provides information on the length and degree of unsaturation of the phospholipid fatty acyl chains. No modification has been recorded in erythrocyte lipids between cancer and control populations. These data would suggest that erythrocytes can maintain membrane lipid homeostastis during malignancy. The numerous abnormalities noted in their membrane fuction remain to be explained. PMID- 21533425 TI - Detection and significance of glutathione-S-transferase pi in osteogenic tumors of dogs. AB - In this study we describe a relationship between the percentage of tumor cells staining positive for GST pi and the response to cisplatin treatment in dogs with appendicular osteosarcoma. Clinical resistance to platinum compounds has been attributed to tumor cell resistance to the drug. An overexpression of glutathione S-transferase pi has been implicated in the resistance of tumor cells in vitro to cisplatin. In this study, the relative concentration of GST pi was quantified immunohistochemically in formalin-fixed, paraffin-embedded histologic specimens obtained from dogs with appendicular osteosarcoma prior to cisplatin treatment. The percentage of tumor cells staining positive for GST pi was compared with patient response (remission and survival times) following treatment. Those osteosarcoma-bearing dogs having a low pre-treatment tumor expression of GST pi (<50%; n=13) had a significantly longer (p <0.01) median remission and survival time (24.0 and 33.7 weeks, respectively) than those dogs with a high pre treatment tumor expression of GST pi (>50%; n=8; median remission and survival times 14.2 and 24.0 weeks, respectively). The relative staining of GST pi in primary canine bone tumors has therapeutic importance and warrants further evaluation as a therapeutic model for human osteosarcoma. PMID- 21533426 TI - Time trends of consumption and costs of drugs in a cancer referral centre. AB - This study is a descriptive analysis of the consumption and the costs of antineoplastic chemotherapeutic agents and of the major groups of drugs used for supportive therapy during the 1990-1995 period, at the National Cancer Institute of Naples, Italy. Increasing consumption trends were observed for methotrexate, vinorelbine, oxazophorines (cyclophosphamide + ifosfamide), epirubicin, dacarbazine and 5-fluorouracil; stable trends for etoposide, mitomycin C, bleomycin, vincristine + vindesine, and platinum compounds (cisplatin + carboplatin); decreasing trends in procarbazine, nitrosoureas, mitozantrone and vinblastine consumption. Among BRM's, since 1992-1993, a decrease in consumption was observed both for immunomodulators and interferons; Cr-CSF consumption has increased during the last 3 years. Starting in 1992, among antiemetic drugs there was a decrease in alizapride and methoclopramide consumption contemporarily with the launch on the market of 5-HT3 antagonists; for the tatter drugs, a plateau seemed to have been reached in 1995. In 1992 the highest value of costs was reached (almost 2 billion Italian lire). Since 1993 the reduction in interferons and immunomodulator agents has paralleled the reduction in total costs, reaching about 1.5 billion in 1994. In 1995 the increasing consumption of G-CSF and taxol induced an increase in total costs. Reported data could reliably reflect the reality of Italian cancer referral centres; further reports from other European institutions could be beneficial to a more extensive debate. PMID- 21533427 TI - HLA class I and advanced melanoma in Israeli Jews. AB - KLA class I antigen was studied in Jewish melanoma patients. The frequency of HLA A24, A26 and B38 was significantly higher in the melanoma patients (34.7%, 39.1% and 38.6%, respectively) compared to controls (16.6%, 18.5% and 20.6%, respectively) (p<0.005). HLA A24 antigen was significantly higher in the metastatic patients (44.8%) compared to the non-metastatic (11.1%) (p<0.001). The frequency of this antigen was also higher in the patients with recurrent disease (16.6%) than in the high risk patients with no recurrence (11.1%). HLA class I and A24 may play a role in the biologic behavior of malignant melanoma. PMID- 21533428 TI - Activation of Raf kinase by phorbol ester does not correlate with enhanced phosphorylation or transactivation activity of tumor suppressor protein p53. AB - The tumor suppressor protein p53 appears to be regulated by various means including phosphorylation. We investigated a possible influence of the raf kinase on phosphorylation and transactivation of p53. The phosphorylation pattern of p53 was analysed in normal or v-raf-transformed rat cells or in insect cells which were co-infected with recombinant baculoviruses encoding p53, protein kinase C and c-Raf. The presence of activated v-raf kinase or treatment of cells with PMA, which resulted in activation of both v-raf and c-Raf kinases, did not reveal any additional phosphorylation sites in p53 nor did any of the known sites show enhanced phosphorylation, neither in rat nor in baculovirus-infected insect cells. Instead, PMA treatment led to reduced phosphorylation of p53. This latter effect was similar in normal and v-raf-transformed cells suggesting that it is mediated by a PKC-dependent but raf-independent mechanism. Okadaic acid treatment compensated this reduced phosphorylation of p53 suggesting that it was due to activation of phosphatase(s). The transactivation activity of p53 was assayed under the same conditions, using an mdm2-promoter luciferase reporter gene construct. In this case, we obtained conflicting results: in normal rat cells both PMA and okadaic acid had a stimulatory effect which was additive. In the v raf transformed cells, on the other hand, PMA alone reduced, whereas okadaic acid alone enhanced transcriptional activation and application of both drugs resulted in a slight net increase in transactivation. Thus, PMA seemed to have separable effects on phosphorylation and transactivation activity of p53. Our data suggest i) that neither Raf-l kinase nor PKC phosphorylate p53 directly in vivo, ii) that the reduced phosphorylation observed upon PMA treatment is independent of Raf, and perhaps mediated by indirect activation of phosphatases, iii) that the effects of PMA on p53-dependent transcription are not mediated by changes in the phosphorylation state of p53 itself. PMID- 21533429 TI - Prognostic implications of loss of heterozygosity in the 17q21 region in breast cancer. AB - Sporadic breast cancer is the commonest form of this malignancy. Genetic changes are frequent events in breast cancer. We investigated the implication of LOH in the 17q21 region as a prognostic factor in this disease. Fifty-three patients were studied and 14 clinico-pathological parameters were evaluated for comparison between the patients with LOH and patients without LOH. A LOH rate of 21% was found and, upon comparison of the two subgroups, a significantly lower rate of recurrence after adjuvant chemotherapy in patients with LOH was observed. This suggests that LOH occurring in this region in breast cancer could help to design new adjuvant treatment strategies. PMID- 21533430 TI - Characterization of chimeric proteins constructed from human epidermal growth factor (EGF) and the Drosophila EGF-receptor antagonist argos. AB - The Drosophila argos protein is a natural ligand antagonist of Drosophila EGF receptor (DER), but does not interact with the human EGF receptor (EGFR). With a view to generating a corresponding EGFR antagonist, we, have designed five chimeric proteins featuring selected characteristic parts of argos within the framework of the human EGF ligand. These chimeras were expressed in bacteria, purified, refolded and characterized. We tested their ability to bind to EC;FR, to effect receptor tyrosine phosphorylation and to inhibit EGF-induced EGFR phosphorylation. PMID- 21533431 TI - p53 mutation and protein overexpression in the early stages of esophageal tumorigenesis utilizing endoscopically obtained biopsy specimens. AB - It is unclear whether p53 abnormality in the early esophageal tumorigenesis causes clonal expansion with tumor growth. In this study, we analyzed p53 abnormalities by PCR-SSCP and immunohistochemistry in 86 esophageal endoscopic biopsy specimens. Eleven of 27 specimens (39%) of mild dysplasias showed p53 mutations. Six moderate or mild dysplasias were followed by endoscopy (average 73 weeks) and continually exhibited the same p53 mutation, but none of them showed apparent tumor growth and subepithelial epithelial invasion. These results suggest that p53 mutations occur very early in the esophageal tumorigenesis and contribute to cell proliferation, but cannot be related with malignant phenotype directly. PMID- 21533432 TI - Structural specificity and tumoricidal action of methyl-3,5-diiodo-4-(4' methoxyphenoxy) benzoate (DIME). AB - Seventeen homologs and analogs of methyl-3,5-diiodo-4(4'-methoxyphenoxy) benzoate (DIME), a hormonally inactive analog of thyroid hormones, have been synthesized and their antitumor activity scored by assaying their antitumorigenic effect in vivo following pretreatment of E-ras 20 cells with the drug. In vivo feeding of DIME in large doses had a similar antitumor effect on human tumor xenogafts in vivo without noticeable toxicity of DIME. Inhibition of clonogenicity with MDA-MB 231 cells by DIME yielded I-50 values similar to those found in tests measuring cell growth inhibition (median I-50 less than 1.0 mu M) The apparent ultimate signal for cytocidal action of DIME is the development of dose-dependent double strand cuts of DNA. All human tumor cells so far tested, with the exception of A 549 cells (lung cancer), show high sensitivity to DIME (I-50 1.0 mu M or below). The partially refractory behavior of A-549 cells to DIME is due to the presence of an esterase that cleaves the methyl ester group of DIME. Other tumor cells have negligible esterase activity, while such activity in homogenates of normal mouse tissues is high. Cells in culture take up DIME and the magnitude of uptake parallels drug sensitivity to DIME. Extrapolation from the correlations between drug efficacy, drug uptake, esterase activity and the absence of significant in vivo toxicity of DIME point to uptake of DIME by cells in culture but not by normal cells operating in intact organs in vivo. In contrast, tumor cells in vivo take up DIME and succumb to its cytocidal action just like cells in culture. PMID- 21533433 TI - Immunohistochemical and soluble expression of CD44 in primary and metastatic human prostate cancers. AB - Immunohistochemical expression of standard and v6 isoforms of CD44 was performed on specimens from three groups of prostate cancer patients: Group I, primary prostate cancers (N=31); Group II? lymph node metastases (N=18); and Group III, bone metastases (N=15). In addition, serum from all Group I patients was analyzed for soluble CD44 expression. Benign glands exhibited strong CD44s and CD44v6 expression in basal cells. Weak basolateral staining was identified in superficial luminal cells. Malignant glands and metastatic tumors revealed diminished or absent expression of both CD44s and CD44vG with a heterogeneous pattern. Pretreatment with chondroitinase did not significantly alter CD44 expression. Soluble CD44 was present in all serum samples, however, expression was variable. There was no statistically significant correlation between immunohistochemical CD44 expression, soluble CD44 expression, and clinical progression. PMID- 21533434 TI - In vivo gene therapy of murine melanoma mediated by recombinant vaccinia virus encoding human IL-2 gene. AB - Direct gene transfer into somatic tissue iii vivo is a developing technology with potential application for cancer gene therapy. In this study, recombinant vaccinia virus encoding human IL-2 gene (rVV-IL-2) was used as a candidate vector in mediating iii vivo gene therapy. After rVV-IL-2 was expanded in VERO cells for 72 h, high titer (10(8)-10(10) PFU/ml) rVV-IL-2 were harvested. When 10(6) murine melanoma cells (F16-F10) were infected with rVV-IL-2, about 200 U/ml IL-2 activity was detected in the supernatants at 8 h, and the up-regulation of ICAM-1 and MHC-I expressions on the melanoma cells were observed. The treatment of murine melanoma model by local injection of rVV-IL-2 into the tumor site showed that rVV-IL-2 transfection significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice. The splenocytes from rVV-IL-2 treated mice showed higher cytotoxicities of NK, LAK and CTL in comparison with those from the controls. These results suggest that in vivo transfection mediated by rVV-IL-2 has potential effectiveness in enhancing host immunity and would be a useful approach to cancer gene therapy. PMID- 21533435 TI - Disease type-associated increases of the plasma levels and ligand expression for natural alpha- or beta-galactoside-binding immunoglobulin G subfractions in patients with lung cancer. AB - The presence of natural carbohydrate-binding antibodies may play a role in host defence against malignant cells in addition to elicitation of an immune response by artificial carbohydrate antigens. Human serum contains immunoglobulin G(2) (IgG) fractions with selectivity to alpha- and to beta-galactosides, respectively, irrespective of the type of blood group of the donor. To determine whether these naturally occurring subfractions may have any relevance for tumor disease control, their binding to malignant cells was ascertained by cytofluorimetric assays in vitro with a number of human tumor cell lines of different histogenetic origin. The affinity of cell binding was comparable to that of binding to lactosylated or melibiosylated neoglycoconjugates as model ligands in solid-phase assays and K-D values were found to be in the range of 5 300 nM. Cross-reactivity of the anomer-selective subfractions to the other type of ligand was observed to be rather low. When the IgG contents of plasma samples of patients with diverse types of lung cancer were assessed, the concentrations of both galactoside-binding immunoglobulin G subfractions were significantly increased in association with presence of small cell lung carcinoma and of metastatic lesions to the lung without any marked change in the overall IgG plasma level. Such an apparently general enhancement was seen for patients with adenocarcinoma and included both subfractions with no impact on their percentage in the total IEC content. When detergent extracts of tumor and tumor-free specimens of the same patient were analyzed with the affinity purified antibody subfractions to comparatively determine ligand presentation, increases in sugar inhibitable binding were especially noted for the tumor tissue of small cell lung carcinomas and apparently tumor-free samples of cases with lung metastasis. Material from other types of lung cancer revealed no significant indication for disease-related alterations with the exception of carcinoids. These data demonstrate that plasma levels and ligand expression for two types of natural galactoside-binding immunoglobulin G fractions can show nonuniform responses in patients within the class of lung cancer. They encourage to deliberately monitor these parameters of the natural carbohydrate-directed antibody fractions in cancer patients with various types of disease to clarify the clinical significance of respective malignancy-associated changes. PMID- 21533436 TI - Chlorophylls as anticarcinogens (review). AB - Chlorophylls, chlorins, and other porphyrins have been used clinically for many years, including photodynamic therapy of tumors. More recently, the cancer chemopreventive properties of chlorophylls have come to be recognized. Chlorophylls exhibit anti-mutagenic activity in short-term genotoxicity assays, and protect against various intermediate biomarkers of cancer in vivo. The anticarcinogenic activity of sodium-copper chlorophyllin (CHL), a clinically-used water soluble salt of chlorophyll, has been studied in several species. Collectively, the results from these studies support a chemopreventive role for CHL against aromatic carcinogens (aflatoxins, polycyclic aromatic hydrocarbons, heterocyclic amines) in various target organs of rats, mice, and rainbow trout. In vivo mechanism studies indicate that inhibition is most effective when CHL is administered simultaneously with the carcinogen, thereby allowing direct interaction (molecular complex formation) between CHL and the carcinogen. Studies of post-initiation treatment with CHL have provided conflicting results, with evidence for inhibition or promotion of carcinogenesis. These findings are discussed in terms of the inhibitory and promotional mechanisms of CHL, the relevance of such mechanisms to natural chlorophylls present in the diet, and the current use of CHL as a health supplement. PMID- 21533437 TI - Gene therapy for prostate cancer targeting transcription factor E2F/DRTF. AB - The heterodimeric transcription factor E2F/DRTF plays a key role in integrating the transactivation of DNA replication-associated genes with cell cycle progression. Strictly regulated in a tissue-specific manner, the prostate specific antigen promoter (PSAP) can be used to direct prostate-specific gene therapy. Employing PSAP and taking advantage of dominant negative suppression and antisense counteraction, we constructed three PSAP-driven plasmids targeting E2F/DRTF: PSAP-E2FL, PSAP-E2FS, and PSAP-antiE2F-1, which, upon induction, would express two truncated E2F-1 proteins lacking the DNA-binding domain and an antisense E2F-1 transcript. Lipofection-mediated gene transfers were performed in three prostate cancer cell lines (DU-145, PC-3 and LNCaP) and six cell lines of other origin (HL-60, KG-1: Hep G2, Cos-l, NCI H460, and SW480). In DU-145, PC-3, and LNCaP, PSAP-E2FL exhibited a growth inhibition of >99%, 94.8%, and 36.9%, respectively; PSAP-E2FS induced growth inhibition at 48.3%, 43.7%, and 34%; PSAP antiE2F-1 suppressed the growth by 9.5%, 16.3%, and 46.8%. None of these constructs showed significant growth inhibition in cells of hematopoietic (HL-60, KG-1), hepatic (Hep G2), renal (Cos-l), pulmonary (NCI H460) or colon (SW480) origin. Examination on DU-145 transfectants by RT-PCR revealed that PSAP-E2FL suppressed the expression of c-myc and DNA polymerase-alpha by 82.5% and 65.8%, respectively. The inhibition of DNA synthesis was further confirmed by an ill situ BrdU incorporation analysis in DU-145 and PC-3 transfectants. Without damaging other cells, the PSAP-driven genetic constructs targeting E2F/DRTF proved to be potent in inducing tissue-specific cytotoxicity solely in cells of prostate origin. PMID- 21533438 TI - Evaluation of the automated fluorescent analysis of the H-ras minisatellite after optimized PCR amplification in comparison with a standardized Southern blot technique. AB - Determination of allele sizes? loss of heterozygosity or genetic instability at minisatellite VNTR loci, are routinely performed by the conventional Southern technique. We have investigated the potential use of automated DNA sequencer for the analysis of the H-ras minisatellite. We report the modifications of amplification parameters and electrophoresis conditions on the sequencer. Seventy one colorectal carcinomas and the corresponding normal tissues were amplified with fluorescent-labeled primers, analyzed on sequencer, and concurrently controlled by Southern blotting. The results on sequencer showed that a Hydrolink matrix used in non-denaturing conditions and a specific analysis software facilitate a more accurate fragment size calculation. PMID- 21533439 TI - Gender influences tumour growth in a model of human oral squamous cell carcinoma. AB - The pattern of tumour growth was investigated using our unique syngeneic animal model of human oral squamous cell carcinoma of the head and neck (SCCHN). Gender conditioned tumour fragments of near equal size were transplanted into recipient animals and the pattern of tumour growth was assessed by monitoring tumour size in vivo and/or the weight of tumour al termination of the experiment. Our results confirmed the epithelial nature of tumour cells on fresh tumour tissue sections using morphological and immunocytochemical examination. The mean weights of tumour per animal (n=10) after transplant from female (F) to F recipients, and across and between same gender showed differences if the animals were sexually mature. The results indicated an endocrine sensitive (sex hormone) component of tumour growth. In separate experiments, the recipient animals were immunised with a mechanically dissociated single cell suspension from fresh tumour after irradiation (500 cGys). The test,group (n=5) and control group (n=5, saline injected) animals received tumour fragments by grafting and following a Eur ther three weeks post immunisation, the tumours were removed and weighed. The test and control groups were different with a p-value of 0.001, suggesting an immune participation in the growth of this tumour. The results, taken together, thus suggest the participation of both the endocrine and the immune systems on the pattern of tumour growth in this animal model. The possible clinical relevance of these results is discussed. PMID- 21533441 TI - Induction of human adenocarcinoma cell differentiation by the phytoestrogen genistein is independent of its antiestrogenic function. AB - The objective of the present study was to determine if genistein can induce human breast adenocarcinoma cell maturation. To gain understanding on its mechanism of action, we used estrogen receptor-positive (ER(+)) MCF-7, and ER MDA-MB-468 cells. Treating these cells with genistein resulted in growth inhibition accompanied by increased cell maturation, which was evaluated by the production of casein and lipids. These maturation markers were optimally expressed after nine days of treatment with 30 mu M of genistein. Since both ER(+) and ER(-) cells became differentiated, we conclude that the ER is not a component of the genistein-initiated scheme of cellular differentiation. PMID- 21533440 TI - The p53-positive phenotype of breast cancers. AB - One hundred and eighty-one breast cancer specimens were analyzed for nuclear p53 staining by immunochemical methods. There were 123 fine-needle cytological specimens and 58 frozen tissue sections of surgical biopsies. The microscopic evaluation of the staining fitted with a 4 group classification. Ninety-one samples (50.6%) were devoid of any staining (-), while 42 (23.3%) showed only few stained nuclei (+/-), typically around 1%. Thirty-two (17.8%) samples presented with strong nuclear staining (++) which in practically all cases concerned more than 50% of the nuclei, but a few cases showed staining heterogeneity. A further 17 cases (9.4%) presented with nuclear staining which concerned 10-20% of the cancer cells (+). This four class system was used to compare p53 expression with other prognostic parameters. A strong inverse correlation was observed with steroid hormone receptor content and p53 positivity was highly significantly associated with higher S-phase. All but one of the highly positive cases were aneuploid. Twenty-five percent (29/120) of the aneuploid tumors were strongly stained and a further 10% were considered positive (+). On the other hand, only 5 out of 59 DNA-diploid tumors were considered as + and one ++. The DNA index distribution according to p53 positivity showed peaks of positivity for hypodiploid, triploid and hypertetraploid values. Negative tumors were in all regards similar to those with only few stained nuclei, in particular mean S phases of 2.8 and 3.3% respectively. Altogether, the typical strong p53 phenotype concerned a DNA-aneuploid tumor with above median S-phase fraction (mean of 7.1%), negative steroid hormone receptors and cytoprognostic index III. The p53 positive cases (+), were frequently steroid hormone receptor positive and had on the average intermediate S-phase fractions (4.3%). The proportion of immunochemical positivity (27% in our series), is compatible with the published frequency of p53 mutations detected in breast cancers, but the differences in the phenotype according to the level of positivity should be further investigated. PMID- 21533442 TI - Lectin-histochemical reactivity of sialic acid in breast cancer and its relationship to prognosis using limulus polyphemus agglutinin. AB - Studies of circulating sialic acid have revealed its relationship with a variety of malignant tumors. It is not vet clear whether sialic acid could be used as a prognostic marker of breast cancer, and few studies have examined sialic acid expression in the cell membrane and cytoplasm of breast cancer cells by means of the lectin-histochemical technique. In the present study, we used biotinylated limulus polyphemus agglutinin (LPA), a special binding lectin of sialic acid, to stain sialic acid in breast cancer cells. Of the 104 cases of breast cancer examined, 59 (56.7%) positive cases were observed. There was a significant correlation between the LPA staining and the clinicopathologic features of all patients, including pathological stage and lymph node metastasis. Among the 100 patients who underwent curative operation, the mean disease-free survival rate of the 45 patients who were LPA-negative was significantly higher than that of the 55 LPA-positive patients (p<0.05). These results suggest that the positive expression of sialic acid in breast cancer could be used as a marker of malignancy potential, as well as a poor survival factor, and the biotinylated LPA assay may provide a convenient and useful method to predict the prognosis of breast cancer. PMID- 21533443 TI - Transformation of rodent fibroblasts by ICP4, the major transactivating protein of herpes simplex virus type 1. AB - Rat fibroblasts were transfected with a plasmid containing the IE3 gene derived from the temperature sensitive HSV-1 mutant tsK. Three of four clones expressing biologically active, temperature-sensitive ICP4, formed a substantial number of colonies in soft agar at the permissive temperature. During the first passages of cells, the transformed state of the major proportion of transformed cells was dependent on the continuous activity of ICP4. In a smaller and distinct subpopulation of transformed cells, as well as after longer subcloning of cells, ICP4 was no longer required for the maintenance of the transformed state, pointing to the induction of stable genomic changes by ICP4. Our data show that ICP4 of HSV-1 is involved in transformation of fibroblasts. Transformed cells are, however, subject to intracellular and intercellular control mechanisms. PMID- 21533444 TI - Drug resistance to ganciclovir observed in suicide gene therapy is due to the loss of integrated herpes simplex virus-thymidine kinase gene. AB - Human pancreatic cancer cells (AsPC-1) expressing the herpes simplex virus thymidine kinase (HSV-TK) gene were inoculated into nude mice and ganciclovir (GCV) was administrated for the treatment. At the initial course of treatment we observed a notable reduction of tumor masses. However, therapeutic effect of GCV to the recurrent tumors decreased significantly. This reduced sensitivity of the AsPC-1/HSV-TK cells to GCV was also confirmed by an in vitro test. Examination of HSV-TK gene in the drug resistant cells showed a loss of the integrated gene. These data indicate that repeated GCV administration results in the loss of integrated HSV-TK gene and confers GCV resistance. PMID- 21533445 TI - Cytolytic and tumor inhibitory antibodies against UK114 protein in the sera of cancer patients. AB - UK114 is a 14 kDa protein identified in the perchloric acid soluble extract of goat liver. Anti-UK114 antibodies identify this protein as expressed by the membrane of human cancer cells. In the present study, anti-UK114 antibodies were detected in the sera of cancer patients by ELISA and by immunofluorescence tests using human cancer cell lines as a target. UK114 protein is antigenic in cancer patients. Human anti-UK114 antibodies have cytolytic effects in vitro and their presence correlates with inhibition of growth of human carcinoma cells xenografted in nu/nu mice. This finding may open new prospects for immunotherapy. PMID- 21533446 TI - Patients with multiple gastric cancers have poorer prognosis than patients with single gastric cancer. AB - The postoperative survival of patients with multiple gastric cancers (MGC) was evaluated in a comparison with that of patients with single gastric cancer (SGC). During the past 30 years, 2,405 patients with gastric cancer underwent gastrectomy in our clinic. Of these patients, 2,241 (93.2%) had SGC and 164 (6.8%) had MGC. The survival of patients With MGC was significantly poorer than that of patients with SGC. The incidence of deaths caused by gastric cancer, by malignancies in organs other than the stomach and by nontumorous diseases other than malignancies was greater in each case in patients with MGC. While, there was no single, independent factor that explained the poorer prognosis of patients with MGC, the significantly greater age of patients with MGC might be responsible for an increased incidence of occurrence not only of other malignancies but also of nontumorous diseases associated with aging. PMID- 21533447 TI - Tumor cell markers in uveal melanoma. AB - Monoclonal antibodies to the melanoma-associated antigens HMB-45 and NKI/C3, and for S-100 protein were applied to archival tissue of 43 intraocular melanomas. Tn addition, the expression of the oncoproteins ras-p21 (ras 10) and mutated Ha-ras (E 184) as well as neu/erb-B2 (p185) were immunohistochemically evaluated. Incubation with antibodies to HMB-45 and NKI/C3 revealed consistently moderate to strong staining in all cases. Comparable ras-p21 immunostaining with normal epithelium observed in infiltrating components with a pronounced heterogeneous pattern, was particulary evident in epitheloid tumor cells. In melanomas of the spindle cell type B there was a tendency for patients with neu/erb-B2 positivity to have a worse prognosis. Using the chi-squared test for trend a significant correlation was found between S-100 reactivity, neu/erb-B2 amplification and the clinical outcome. PMID- 21533448 TI - p53 protein accumulation and p53 gene alterations (RFLP, VNTR and p53 gene mutations) in non-invasive versus invasive human transitional bladder cancer. AB - Eleven non-invasive and 24 invasive transitional cell bladder cancers were analysed for molecular alterations to the p53 gene and nuclear accumulation of the p53 protein. 9% (1/11) of non-invasive rumours and 21% (5/24) of invasive tumours revealed nuclear accumulation in more than 50% of the tumour cells. PCR analysis of D17S30 showed loss of heterozygosity (LOH) in invasive tumours (3/24; 12%). Two invasive tumours harboured point mutations in exon 6 and exon 7, respectively (8%). Our results indicate that p53 protein overexpression correlates with tumour progression, p53 gene mutations and LOH detected by PCR. PMID- 21533449 TI - Cell biologic factors and cancer spread. AB - There is an increasing body of literature linking expression of cell biologic factors such as proteases and bioactive peptides with tumor malignancy. Cancer cells and/or the surrounding stromal cells produce and secrete a series of different factors which may facilitate tumor cell invasion and subsequent metastasis. Several reviews that cover the literature on the role of these factors are available. Therefore in this report, we focus on the work in our own laboratories. We will review our previous studies of five cell biologic factors which are differentially involved in cancer progression, including urokinase, tissue-type plasminogen activator, polymorphonuclear leukocyte elastase, group II phospholipase A(2), and endothelin-1. PMID- 21533450 TI - Effect of specific activity on organ uptake of iodine-123-meta iodobenzylguanidine in humans. AB - Radioiodinated meta-iodobenzylguanidine (MIBG), an analogue of norepinephrine, has been used in management of neuroendocrine tumors. Recent studies reveal that distribution of radioiodinated MIBG in animals depends on the specific activity of this radiopharmaceutical. In order to clarify the effect of specific activity on organ uptake of radioiodinated MIBG. the kinetics of no-carrier-added (n.c.a.) [I-123]MIBG (greater than or equal to 7.4 TBq/mu mol) were compared with those of commercial (com.) [I-123]MIBG (similar to 74 MBq/mu mol) in 3 healthy volunteers by serial imaging and blood sampling. The organ uptake of radioiodinated MIBG did not remarkably differ between the two specific activities. Due to rapid degradation a more pronounced accumulation of radioactivity was present in plasma alter n.c.a. than after com. [I-123]MIBG resulting in a higher background and thyroid activity. In addition due to a prolonged residence time of the radioactivity, the radiation exposure to organs was in general slightly higher with n.c.a. [I-123]MIBG as compared to com. [I-123]MIBG. This finding highlights the higher in vivo deiodination of n.c.a. [I-123]MIBG than of com. [I-123]MIBG in humans. In the treatment of children suffering from neuroblastoma, therefore, degradation of n.c.a. [I-123]MIBG may decrease the concentration of radioiodinated MIBG available for binding at tumor sites and result in higher radiation exposure of non-tumor tissue. PMID- 21533451 TI - Involvement of interleukin-1 in the differentiation-inducing activity of tumor necrosis factor-alpha on a murine myeloid leukemia (WEHI-3B JCS). AB - We have shown previously that tumor necrosis factor-alpha (TNF-alpha) inhibits the growth and induces the differentiation of a murine myelomonocytic leukemia (WEHI-3B JCS cells) into macrophage-like cells. In this study, using reverse transcription polymerase chain reaction, we found that both endogenous interleukin-1 alpha and beta (IL-1 alpha, IL-1 beta) mRNA were up-regulated upon TNF-alpha induction. Exogenous IL-1 alpha and IL-1 beta also inhibited the growth as well as induced the differentiation of JCS cells, with IL-1 beta exerting a greater growth-inhibitory effect. Neutralizing anti-IL-1 alpha, anti-IL-1 beta and anti-TNF-alpha antibodies were further used to elucidate the role of IL-1 alpha, IL-1 beta and TNF-alpha in JCS cell differentiation. The results show that the IL-1 alpha-induced monocytic differentiation of JCS cells was effectively blocked by anti-IL-1 beta as well as anti-IL-1 beta antibodies and to a lesser extent by anti-TNF-alpha antibody. In contrast, the differentiation-inducing effect of IL-1 beta on JCS cells was only blocked by anti-IL-1 beta antibody but not by anti-IL-1 alpha or anti-TNF-alpha antibody. Finally, the TNF-alpha-induced monocytic differentiation of JCS cells was significantly blocked by anti-TNF alpha and to a lesser extent by anti-IL-1 alpha and anti-IL-1 beta antibodies. Collectively, our results suggest that IL-1 beta alone may directly trigger JCS cell differentiation whereas the differentiation-inducing effect of IL-1 alpha may be via the endogenous production of IL-1 beta and/or TNF-alpha. In addition, IL-1 alpha and IL-1 beta may be involved, at least in part, in TNF-alpha-induced monocytic differentiation of the JCS leukemia cells. PMID- 21533452 TI - Purification and characterisation of soluble intercellular adhesion molecule-1 (sICAM-1) and its effect on cell-mediated cytolysis of tumour cells. AB - The aim of this study was to determine the effects of highly purified soluble ICAM-1 (sICAM-1) from a variety of sources on lymphokine-activated killer (LAK) cell-mediated cytolysis of bladder tumour cells. Soluble ICAM-1 was isolated by immunoaffinity chromatography using two different anti-ICAM-1 monoclonal antibody (mAb) columns from normal human serum, bladder tumour cell culture supernatants and the urine of patients receiving bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer. Soluble ICAM-1 from all sources resolved as a single diffuse band with a molecular weight of 80 to 90 kilodaltons (kDa) on Western blots under both non-reducing and reducing conditions, consistent with the predicted molecular weight for monomeric sICAM-1. Monomeric sICAM-1 isolated from serum retained its ability to inhibit the binding of an anti-ICAM-1 mAb to ICAM-1 positive target cells. In contrast, monomeric sICAM-1 isolated from serum and urine failed to inhibit LAK cell-mediated cytolysis of four bladder tumour cell lines. These results are in agreement with recent observations that the monomeric form of sICAM-1 binds to its receptor LFA-1 with extremely low affinity, indicating that at physiological concentrations sICAM-1 does not interfere in ICAM-1/LFA-1 mediated cellular adhesion events. PMID- 21533453 TI - Control of cell cycle regulatory proteins and modulation of STAT1 proteins by IFN gamma in human prostatic JCA-1 cells. AB - The addition of human recombinant IFN-gamma (10(2) and 10(3) IU/ml) inhibited human prostatic JCA-1 cell growth by 27% and 64%, respectively. Since the high dose of IFN-gamma elicited an increase in G(1) concomitant with a decrease in G(2)/M phases of the cell cycle, changes in the expression of cell cycle regulatory protein molecules were analyzed by Western blots. Results of these experiments show that IFN-gamma down regulated the G(1)/S transition molecules, e.g., cyclin D1, the cyclin-dependent protein kinase Cdk4, and the retinoblastoma gene product (pRB), but increased the G(2)/M transition molecules, e.g., cyclin B1 and p34(cdc2) (Cdk1). Possible modulation of Cdk-inhibitors (CDKIs), e.g., p53 and p21(WAF1), which have checkpoint functions in the cell cycle, by IFN-gamma, was also studied. The p53 was induced by both 10(2) and 10(3) IU/ml IFN-gamma. At 10(3) IU/ml, IFN-gamma inhibited p21(WAF1), increased the expression of STAT1 alpha, and sustained the elevated STAT1 alpha for up to 96 h. Thus several mechanisms may be involved in the antiproliferative effects of IFN-gamma. PMID- 21533454 TI - Identification of a gp100 epitope recognized by HLA-A3 restricted melanoma infiltrating lymphocytes. AB - The large majority of known melanoma-associated antigenic peptides presented by MHC class I molecules are presented by the most frequent allele, HLA-A*0201. Thus although a significant percentage of Caucasians express HLA-A3, no melanoma associated antigenic peptide presented by this allele has yet been identified. We show here that the T cell clone M45-10 isolated from tumor infiltrating lymphocytes recovered from a melanoma biopsy recognizes the gp100-derived peptide ALLAVGATK presented by HLA-A*0301. Since gp100 is expressed on most melanoma cells, our results imply that the gp100-based anti-melanoma strategies developed for individuals expressing HLA-A2 will also be applicable to those expressing HLA AS (about one Caucasian in four). gp100 is therefore a particularly promising melanoma antigen, as different peptides derived from it can be presented by at least two different frequently encountered HLA class I molecules. PMID- 21533455 TI - Nuclear medicine imaging in lung cancer. AB - The evaluation of the anatomical dissemination of lung cancer has a pivotal role in the choice of the most appropriate treatment modality. The techniques of nuclear medicine are founded on the use of different radiopharmaceuticals capable of exploiting the specific characteristics of malignant tissues. They may recognise diverse cell densities, growth rates, metabolic pathways, antigenic and surface receptor expressions. In the past, the use of Co-57-bleomycin and, then, of (67)Gallium has encountered a mixed acceptance among nuclear medicine specialists, with favourable reports claiming their utility, and others with more sceptical opinions. It is generally admitted that both Co-57-bleomycin and (67)Gallium scintigraphies are quite sensitive and rather accurate. Their use, however, is almost abandoned in favour of more innovative and encouraging approaches, including non-specific radio-tracers ((201)Thallium and Tc-99m sestamibi), substances useful in particular clinical applications (the somatostatin analogues I-123-tyr(3) and the In-111 octreotide for neuronendocrine tumours), radio-labelled monoclonal antibodies, and the recently introduced positron emission tomography. Promising results with each of these techniques need to be further substantiated, before their entering into clinical practice. However, the abundance of choices offered by nuclear medicine might reasonably bring forward the ideal noninvasive test. We review the many scintigraphic methods investigated so far and their clinical significance. PMID- 21533456 TI - Transient transformation of mammalian cells by MN protein, a tumor-associated cell adhesion molecule with carbonic anhydrase activity. AB - The MN protein is associated with certain human carcinomas, but absent in most normal tissues. It is a transmembrane protein; its extracellular part contains a domain homologous with carbonic anhydrases (CAs) and a proteoglycan-like region. In the present study, we observed that cells (human CGL1 and mouse NIH3T3 cells) transfected with MN cDNA showed morphologic transformation, but reverted to normal phenotype after 4-5 weeks. This reversion was not due to the loss, silencing, or mutations of MN insert. We also found that MN protein exerted CA enzymatic activity, but this was not relevant for morphologic transformation of cells. MN is an adhesion protein, involved in cell-to-cell contacts, this probably could explain its role in tumorigenesis. PMID- 21533457 TI - Regression of rat Dunning R-3327-H prostate carcinoma by treatment with targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 containing 2 pyrrolinodoxorubicin. AB - The effects of AN-207, a new targeted cytotoxic analog of LH-RH, were evalued in rats bearing hormone-dependent Dunning R-3327-H prostate carcinomas. AN-207 consists of the agonist [D-Lys(6)]LH-RH linked to 2-pyrrolino-doxorubicin, an intensely potent derivative of doxorubicin. In the first experiment, 2 pyrrolinodoxorubicin was administered at a concentration of 50 nmol/kg, as a single drug (AN-201) and as an unconjugated mixture with [D-Lys(6)]LH-RH or conjugated to the carrier [D-Lys(6)]LH-RH (AN-207). Following the second administration of radical AN-201 alone or mixed with the carrier, all rats died with signs of general toxicity, but all animals treated with the conjugate AN 207, survived. After 5 weeks of treatment with a total dose of 150 nmol/kg AN 207, the tumors regressed from an initial volume of 8.35 +/- 1.7 cm(3) to 4.47 +/ 0.8 cm(3), while tumors in the control group measured 17.84 +/- 2.2 cm(3). The therapy with AN-207 also significantly reduced tumor weight and tumor burden. In the second experiment, we compared the efficacy and toxicity of 3 injections of 25 nmol/kg AN-201 or 25 nmol/kg and 50 nmol/kg AN-207. The initial tumor volume in all groups was between 3.9 and 4.5 cm(3). After 5 weeks of therapy, the tumors of rats treated with 50 nmol/kg AN-207 regressed to 2.3 +/- 0.51 cm(3), whereas 25 nmol/kg AN-201 was still toxic in contrast to 25 nmol/kg AN-207, while the reduction in final tumor volume was similar (6.76 +/- 1.4 cm(3) and 6.74 +/- 1 cm(3), respectively), as compared to 15.6 +/- 2.2 cm(3) for untreated animals. High capacity LH-RH receptors were found in the membranes of untreated Dunning tumor specimens, but after treatment with AN-207, they could no longer be detected. This is the first demonstration that the new targeted cytotoxic LH-RH analog AN-207 is an effective antitumor agent. Our work indicates that the cytotoxic analog AN-207 is much less toxic than the antineoplastic radical (AN 201) incorporated, and significantly more active in inhibiting tumor growth. Further development of approaches based on targeted cytotoxic analog AN-207 may lead to major improvements in current palliative therapy of prostate cancer. PMID- 21533459 TI - Protease inhibitor TPCK represses Ha-ras (Val12) transformation and nuclear factor-kappa B activation. AB - Certain chymotrypsin-like protease inhibitors such as TPCK exhibit a well described anti-tumorigenic activity by an as yet undescribed mechanism. One potential cellular target for TPCK in transformed cells is the ms-inducible NF kappa B family of transcription factors. We therefore used TPCK to examine the physiologic role of NF-kappa B during Ha-ras induced transformation, independent of another major downstream effector of Ha-ras, AP-1. Using a conditionally transformed NIH3T3 cell line, we found that TPCK (but not the control inhibitor TLME) inhibited the anchorage-independent growth of Ha-ras transformed cells, but not their anchorage-dependent growth on plastic tissue culture dishes. Likewise, TPCK reduced the ability of Ha-ras to stimulate DNA synthesis in growth factor depleted cells, but not the ability of serum to stimulate DNA synthesis in the same growth factor depleted cells. Gel shift analysis and reporter gene expression indicated that TPCK blocked Ha-ras-induced NF-kappa B activity, while only having minimal effects on Ha-ras-induced AP-1 activity. TPCK is therefore able to Inhibit the Ha-ras transformed phenotype of cells by inhibiting the transcriptional activity of NF-kappa B, while having little effect upon transcriptional activity of AP-1. PMID- 21533458 TI - Topoisomerase II levels and drug response in small cell lung cancer. AB - Acquired resistance to chemotherapy is the major obstacle to cure of small cell lung cancer (SCLC). Some of the most active drugs in the treatment of this tumor exert their cytotoxicity by interacting with the nuclear enzyme topoisomerase II (topo II), which in mammalian cells occurs in two isoforms, alpha and beta. We examined the relationship between levels of topo II alpha and beta and drug response in a panel of 25 unselected SCLC cell lines. Chemosensitivity to several topo II-interactive drugs, as well as other chemotherapeutic agents, was quantitated previously using a modified MTT assay. Topo II levels were determined by immunoblot analysis of whole cell lysates, with topo II alpha and beta isoform specific antibodies, and results were expressed relative to levels found in NCI H209 cells which had the highest topo II alpha in this series of cell lines. Levels of topo II alpha and beta mRNA were determined by Northern blotting. Pearson correlation analysis was used to determine the significance of the relationship between topo II alpha and beta levels and response to the various chemotherapeutic drugs, as well as the treatment history of the patients from whom the cell lines were derived. These analyses revealed an inverse correlation between topo II alpha levels and resistance to all of the tested drugs, including several drugs which are not known to interact with topo II. This correlation was statistically significant for doxorubicin, cisplatin, epirubicin, melphalan, nitrogen mustard, and vinblastine. With one exception (cisplatin), there were no significant correlations between topo II beta levels and drug response. There was no significant correlation between topo II alpha and beta levels and treatment history. Taken together, our results are consistent with the hypothesis that levels of topo II alpha are important determinants of drug response in SCLC. PMID- 21533460 TI - Autoimmunity and cancer - Beneficial relationships. AB - Autoimmune diseases are the consequence of the immune system attack on the self. Autoimmunity, sometimes, is reflected through the production of autoantibodies to various self antigens leading to cellular malfunction or destruction. In the current study we employ such autoantibodies for the treatment of cancer originated from the respective normal cells. This concept is wide and entails many autoimmune disorders and diversity of malignant conditions. To illustrate the therapeutic and practical potential we depicted four examples: vitiligo and melanoma - vitiligo is considered dermatologic autoimmune disorder presented as depigmented skin areas. The destruction of the pigmented cells (melanocytes) is mediated by autoantibodies. We have purified these anti-melanocyte antibodies from patients with vitiligo and showed their cytotoxic effect towards malignant melanoma cells in vitro and in vivo; anti-phospholipid syndrome (APLS) and cancer cancer cells differ from normal cells by the expression of phosphatydilserine (PS) on their outer membrane surface. We have used such anti-PS autoantibodies, derived from patients with APLS, as effective treatment for melanoma in a murine system; Autoimmune hemolytic anemia (AIHA) and hematological malignancies - in patients with AIHA, the red blood cells (RBC) destruction is mediated by binding of autoantibodies to RBC. We have shown the specific binding of these anti-RBC autoantibodies to RBC and to malignant cells of the erythroid lineage. Thus, these autoantibodies may have diagnostic/therapeutic potential for conditions such as erythroleukemia and polycythemia vera; anti-lymphocyte antibodies and lymphoproliferative diseases - in SLE and other systemic autoimmune conditions autoantibodies directed against lymphocytes can be found. These cytotoxic antibodies can be targeted against lymphocytes of lymphoproliferative diseases such as chronic lymphocytic leukemia, or lymphoma. The diversity of autoimmune diseases provides a great source for human preformed highly specific autoantibodies which can be used as an effective immunotherapy by themselves, for diagnostic purposes, as a cell specific carrier conjugated to other cytotoxic agents and in combined therapy in the combat against cancer. PMID- 21533462 TI - Inhibition of the GTP-dependent polymerization of tubulin by methyl-3,5-diiodo-4 (4'-methoxyphenoxy) benzoate (DIME). AB - The hormonally inactive thyroid hormone analog methyl-3,5-diiodo-4-(4' methoxyphenoxy) benzoate (DIME) at 1-5 mu M concentrations inhibits the GTP dependent polymerization of MTP as determined by an optical test. This inhibition is critically dependent on the concentration of GTP. The quantitative correlation between the concentrations of DIME and GTP, under conditions of a linear rat of MTP polymerization, follows Michaelis-Menten kinetics and the inhibition portrays a 'mixed' type, where k(m) for GTP and V-max are altered simultaneously. Chemical analogs of DIME inhibit MTP polymerization parallel to their antitumorigenic action in vivo. The MTP site is one of the early cellular response sites of DIME. PMID- 21533461 TI - Cellular analysis of the mode of action of methyl-3,5-diiodo-4-(4' methoxyphenoxy) benzoate (DIME) on tumor cells. AB - The hormonally inactive methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME) at 1-4 mu M concentration induces morphologic changes in E-ras 20 and MDA-MB-231 and other human cancer cells such as multinucleation and enlargement and arrests the cell cycle in the M phase without affecting interphase. Time-lapse videomicroscopy allowed us to follow individual cells. Cells exposed to DIME divided in an abnormal manner, leading to 20% cell fusion and multinucleation. Chromosome painting demonstrated a large accumulation of chromosomes after 5 days of treatment with DIME, consistent with the failure of cells to divide normally. Chromosome breakage was not observed. On the other hand, highly abnormal tubulin containing structures ensue upon exposure to DIME (1 mu M for 18 h) treatment, indicating an early biochemical action of DIME on the spindle assembly system. PMID- 21533463 TI - The peripheral myelin protein 22 kDa (PMP22) gene is amplified in cell lines derived from glioma and osteogenic sarcoma. AB - Two glioma (SF188, SF763) and two osteogenic sarcoma cell lines (RH30, SA1) were examined for the presence of an amplification of the PMP22 gene by means of fluorescence in situ hybridization (FISH). In one cell line of both cell types, we found about 10 copies of the PMP22 (peripheral myelin protein 22 kDa) gene, located on different marker chromosomes within homogeneously staining regions. Surrounding chromosome 17p material was found to be coamplified, but coamplification of TP53 (17p13) and erbB2/Her2 (17q11.12) were excluded by FISH for both cell lines, SF763 and RH30. This is the first report of a PMP22 amplification in cell lines derived from human tumors. PMID- 21533464 TI - Absence of the microsatellite mutator phenotype in human bronchial epithelial cells transformed by alpha particles. AB - The immortalized human bronchial epithelial cell line, BEP2D, can become malignantly transformed following its irradiation with alpha particles. Exposed cells progress through a latent period of eight to ten weeks prior to exhibiting malignant properties. The molecular basis for this delay is unclear, however it is thought to involve a manifestation of genomic instability brought on by ionizing radiation. In this study we addressed whether the microsatellite mutator phenotype which arises in cells that lack mismatch repair function could have played a role in the radiation-induced transformation of BEP2D cells. Three cell lines, including BEP2D and two transformed clonal derivatives, H2BT2L and R30T1L, were examined for the presence of the microsatellite mutator phenotype using a selectable reporter system developed in our laboratory. This reporter system is based on the ability of stably transduced cells to restore the reading frame of a hygromycin B phosphotransferase transferase gene rendered out of frame by the insertion of a (CA)(13) repeat tract immediately downstream of the ATG start codon. The parental BEP2D cell line had a relatively low hygromycin B resistant colony formation frequency of 2.36 x 10(-4). This value was similar to the frequencies of two malignantly transformed derivatives H2BT2L (0.996 x 10(-4)) and R30T1L (1.87 x 10(-4)). We therefore conclude that the H2BT2L and R30T1L cell lines are not deficient in their hMSH2, hMLH1, hPMS2 or hMSH3 mismatch repair gene functions, and that other factors orchestrated the alpha particle induced malignant transformation of H2BT2L and R30T1L cells. PMID- 21533465 TI - Current follow-up strategies after potentially curative resection of upper aerodigestive tract epidermoid carcinoma. AB - The follow-up of patients after potentially curative resection of squamous cell carcinoma of the upper aerodigestive tract (UADT) mucosa has important clinical and financial implications for patients and society, yet the ideal surveillance strategy is unknown. The aim of this study was to determine the current follow-up practice patterns of a large, diverse group of experts. The 824 members of The Society of Head and Neck Surgeons (SHNS) were asked, via a detailed questionnaire, how often they request 14 discrete follow-up evaluations in their patients treated for cure with TNM stage I, II, and III + (resectable) IV UADT cancer over the first five post-treatment years. The results indicate that SHNS members generally follow their patients personally after performing UADT cancer surgery rather than sending them back to their referral source. Routine office visit is the most frequently performed item for each of the 5 years. The only imaging test commonly used is chest X-ray. There is variation in the pattern of use of most tests. SHNS members from other countries tend to follow their patients more closely than do those living in the USA. Many clinicians use the same surveillance strategy for all TNM stages. PMID- 21533466 TI - Mechanisms of resistance off NSCLC to interferons. AB - Interferons (IFNs) are naturally occurring cytokines which have pleiotropic actions including regulation of cell growth and differentiation, important for control of tumour growth and development. In this study we investigated the association between the presence of IFN genes in NSCLC cell lines, receptor expression and function, and sensitivity to IFNs. Some of the NSCLC lines had partial or complete IFN gene deletion but others contained all genes. However, all NSCLC lines were resistant to the antiproliferative effects of IFN alpha 2 and IFN beta ser. While the lack of sensitivity to IFNs did not appear to be associated with the presence of IFN genes, numbers of receptors or with low binding affinities it did correlate with abnormal regulation of receptor expression. When analyzed by Northern blotting it was notable that IFNA receptor expression on a sensitive cell line, Daudi, was upregulated following IFN exposure however, in the insensitive NSCLC lines IFN mediated upregulation of receptors did not occur. This defect in the regulation of receptor expression in NSCLC lines could contribute to the insensitivity of the antiproliferative effects of IFN's and thus potentiate tumour development or progression. PMID- 21533467 TI - Thymoma, thymic hyperplasia, thymectomy and autoimmune diseases (Review). AB - There is a bidirectional relationship between autoimmunity and cancer: on the one hand, patients with autoimmune conditions develop neoplastic diseases, and on the other hand, malignant conditions are associated with paraneoplastic autoimmune syndromes. Thymoma is an epithelial tumor which is often accompanied by autoimmune diseases: about a third of the patients with thymoma have myasthenia gravis. Pure red cell aplasia, pemphigus and systemic lupus erythematosus, might also coexist with this tumor. Thymectomy is an optional treatment in some autoimmune diseases (i.e. myasthenia gravis, multiple sclerosis, autoimmune hemolytic anemia, ulcerative colitis, and systemic lupus erythematosus). In this communication we review and discuss the coexistence of autoimmune diseases, thymoma or thymic hyperplasia, and the dual effects of thymectomy on their course. PMID- 21533468 TI - Adjuvant radiotherapy in early stage ovarian carcinoma. AB - In a series of 228 women diagnosed with malignant ovarian tumors during the years 1980-87 radiotherapy was added as postoperative adjuvant therapy. Twenty-three cases with epithelial borderline carcinomas and 18 cases with nonepithelial tumors were excluded from the analysis. The remaining 187 cases of invasive epithelial ovarian carcinoma in FIGO stage I-II was a complete, consecutive, and total geographic series. After primary staging surgery lower abdomino-pelvic or whole abdominal radiotherapy was administered. The dose to the upper part of the abdomen was 20 Gy (fraction dose 1.0 Gy) and to the lower part and the pelvis 40 Gy (fraction dose 1.7 Gy). The patients were followed up for at least 10 years. During the follow-up 75 tumors (40%) recurred and were then treated with cisplatin-containing chemotherapy. Abdomino-pelvic (18%) and abdomino-pelvic distant metastases (11%) were most frequent. Mean time to recurrence was 26 months. The 5-year overall survival of the complete series was 57% and the cancer specific survival 66%. FIGO stage and tumor grade were the only independent and significant prognostic factors in a Cox multivariate analysis. Only cases in FIGO stage IA and grade 1 could be classified as low-risk cases with 5-year survival of 87%. All other cases showed a significantly worse prognosis and should be classified as intermediate or high-risk cases. Early radiation reactions were frequent (80%) but of little clinical significance. In 21 cases (11%) late radiation reactions were recorded. In 8 cases (4%) the reactions were regarded as severe and required surgical intervention or disabled the patient significantly. The results compare well with others reported in the literature. PMID- 21533469 TI - Regression of human colon cancer xenografts in SCID mice following oral administration of water-insoluble camptothecins. AB - Gastrointestinal cancers pose major public health problems worldwide, in part because little progress has been made in the treatment of colorectal cancers. The present study explored the potential use of natural product topoisomerase I inhibitors, 10-hydroxycamptothecin (HCPT) and camptothecin (CPT), in the treatment of human colon cancers. HCPT and CPT are indole alkaloids originally isolated from th. Chinese tree, Camptotheca acuminata. They have been shown to have a wide spectrum of anticancer activity both in vitro and in vivo. The use of these camptothecins, however, has been hampered by their water-insolubility. In the present study, following screening of their in vitro antitumor activity, we determined their in vivo antitumor effects using C.B-17-scid/scid mice bearing LS174T or DLD-1 xenografts. Tumor-bearing mice were treated with oral doses of HCPT (1, 3, or 6 mg/kg/day) or CPT (1 or 3 mg/kg/day), 5 days per week for 2 weeks (LS 174T) or 3 weeks (DLD-1). Growth of the xenografts was significantly inhibited by HCPT and CPT in a dose-dependent manner, with marked reductions in tumor mass occurring in those groups given HCPT at 6 mg/kg/day or CPT at 3 mg/kg/day. Pathologic examination confirmed the dose-dependent atrophy of the adenocarcinomas. In summary, this study demonstrates the potential use of water insoluble camptothecins when given by the oral route for treatment of human colon cancer, and provides the basis for the design of future human trials with these anticancer drugs. PMID- 21533470 TI - Enhancement by hyperthermia of the in vivo antitumour effect of doxorubicin hydrochloride (DOX) and buthionine sulfoximine (BSO)-hydroxyapatite (HAP) complex. AB - We have developed a new type of drug delivery system (DDS) comprising a complex of porous hydroxyapatite (HAP) with the anticancer drug doxorubicin hydrochloride (DOX) and the glutathione inhibitor buthionine sulfoximine (BSO) (DOX and BSO-HAP complex). We then studied the antitumour effect of DOX and BSO-HAP combined with 44 degrees C hyperthermia for 40 min. It was found that in mice this combined treatment suppressed the growth of sarcoma 180 in terms of tumour volume to 36% in comparison viith mice given plain HAP, and was more effective than HAP + hyperthermia or DOX- and BSO-HAP. These results were also confirmed by histological observation. PMID- 21533471 TI - Thalidomide and chemotherapy combination. AB - Angiogenesis has been shown to be important in tumor growth and metastasis. Thalidomide, an oral sedative, has recently been found to inhibit angiogenesis. We therefore set out to ask whether thalidomide can be used as therapy for breast cancer. In a mouse model of breast cancer, we found that thalidomide alone did not suppress tumor growth. However, mice treated with thalidomide in combination with cytoxan and adriamycin had significantly smaller tumors than those given the two chemotherapeutic agents alone (3,432 +/- 303 mm(3) versus 4,643 +/- 203 mm(3), p = 0.0005). We proceeded to administer thalidomide together with chemotherapy to seven breast cancer patients in the context of a Phase I trial. Side effects attributed to thalidomide were minimal, and included constipation and a rash. We concluded that an approach at cancer therapeutics combining an antiangiogenic agent such as thalidomide with conventional chemotherapy may be feasible and deserves further studies. PMID- 21533472 TI - A possible correlation between p53 overexpression and prognosis after radiotherapy combined surgery for rectal carcinoma. AB - One hundred and twenty patients with rectal carcinoma in the lower two-thirds of the rectum were treated with preoperative radiotherapy and radical surgery between October 1986 and March 1996. The expression of p53 was examined in 58 of these patients, all of whom had undergone surgery more than 5 years previously and whose prognosis had been recorded. Eighteen of 58 (31%) cases showed pS3 overexpression. Clinicopathological variables other than pathological T stage did not correlate with p53 expression. The proportion of residual tumor cells in p53 positive group was significantly higher than that in the negative group. Survival time was significantly shorter in p53 positive than in p53 negative patients (p = 0.0042). The proportion of cumulative local recurrence in the p53 negative group was 2.8%, while that of the p53 positive group was 43.2% (p = 0.01). The cumulative survival rate in the p53 negative group was 76.3%, while that in the p53 positive group was 24.4% (p = 0.04). The amount of p53 positive cells in both local and distant recurrence cases was significantly higher than that without recurrence (p < 0.0001, p = 0.0016) respectively. These results suggest that p53 overexpression might predict a poor outcome at the resection of the irradiated rectal carcinoma. PMID- 21533473 TI - Changes in chromosomes 1 and 6 associated with human cell immortalisation. AB - A normal diploid human fibroblast cell line infected with HL60 c-myc has become immortal in vitro following continuous passage. At early passage post-infection the cells exhibited a normal diploid karyotype and in the absence of karyotypic changes grew well beyond the normal passage at which senescence occurred in the normal non-transfected parental cell line or the vector-infected control. Immortalisation of both the infected population and a subclone taken prior to karyotypic change was associated with two independent events involving chromosome 1. The subcloned population also possessed a deletion of the long arm of chromosome 6. PMID- 21533474 TI - Role of urokinase-type plasminogen activator and inhibitory effect of protease inhibitor in invasion and metastasis of pancreatic cancer. AB - We investigated the association of urokinase-type plasminogen activator (u-PA) with tumor cell invasion and hepatic metastasis using human pancreatic cancer cell lines (SW1990, PANC-1, and RWP-1). We also examined the effect of the protease inhibitor, gabexate mesilate. SW1990 cells showed a higher u-PA activity (41.2 U/ml) in substrate assay and invasiveness (21.6% IV) than PANC-1 (14.3 U/ml, 10.3% IV) and RWP-1 (22.1, 13.5), which correlated with in vivo hepatic metastasis. Gabexate mesilate significantly reduced the u-PA activity, invasiveness, and hepatic metastasis of SW1990 cells. These findings suggest the possible application of protease inhibitors to prevent tumor invasion and metastasis. PMID- 21533475 TI - Regulation of interleukin 3 expression in normal and autocrine transformed hematopoietic cells (Review). AB - Over the past decade, the regulation of cytokine expression has been intensively studied. Control of cytokine expression has important clinical implications. Cytokine therapy has been utilized in the treatment of many diseases including: cancer, bone marrow transplantation, inflammation, rheumatoid arthritis, multiple sclerosis and AIDS. Interleukin 3 (IL-3) affects the growth of hematopoietic, neurological, as well as other cells. This review will focus on understanding the regulation of IL-3 in normal and autocrine transformed cells. The mechanisms by which IL-3 transduces its growth and survival functions in appropriate target cells will also be discussed. An understanding of the means by which IL-3 and other hematopoietic cytokines exert their effects will aid our understanding of normal and abnormal cell growth as well as providing novel treatments for patients who suffer from hematopoietic, neurological, as well as many other diseases. PMID- 21533476 TI - Clinicopathological study of superficial-type invasive carcinoma of the colorectum. AB - We investigated the relationship between histological parameters such as the level of invasion (scanty submucosal invasion, sm-s or massive submucosal invasion, sm-m), histologic grade (presence or absence of grade III carcinoma), lymphatic invasion, venous invasion, budding and lymph node metastasis in 33 lesions of superficial-type invasive colorectal carcinoma. On statistical analysis, there was no definite influence of any histological parameter on lymph node metastasis. None of 6 sm-s lesions showed lymph node metastasis, however, 7 sm-m lesions were found to have lymph node metastasis (25.9%). Whereas only 16.7% (1/6) of the lesions showing sm-s had one or more unfavorable histological parameters, 85.2% (23/27) of the lesions showing sm-m had one or more of unfavorable histological parameters. There was a significant difference between the two types of lesions (p<0.003). Consequently, in the treatment of superficial type invasive carcinoma, sm-s lesions without unfavorable histological parameters could be radically cured by endoscopic mucosal resection alone. PMID- 21533477 TI - The close association of pi-class glutathione S-transferase with drug sensitivity to alkylating agents and cisplatin in human cancer cells. AB - Buthionine sulfoximine (BSO) is a synthetic amino acid that irreversibly inhibits glutathione biosynthesis. A BSO-resistant line, KB/BSO3, was established from human epidermoid cancer KB cells; and other BSO-resistant lines, HLE/BSO1 and HLE/BSO2, were from human hepatic cancer HLE cells. Cellular level of pi-class glutathione S-transferase (GSTP1) in KB/BSO3 was less than 10% of the parental KB, and those in HLE/BSO1 and HLE/BSO2 wa 30-40% of the parental HLE cells. KB/BSO3, HLE/BSO1 and HLE/BSO2 had collateral sensitivities to a potent anticancer agent, cisplatin, and alkylating agents including melphalan and nitrosourea. The GSTP1 cDNA transfectant KB/BSO3-pi established from KB/BSO3, and also HLE/BSO1-pi and HLE/BSO2-pi established from HLE/BSO1 and HLE/BSO2, restored cellular sensitivities to cisplatin and alkylating agents to similar levels as KB and HLE cells. Our present results indicate that GSTP1 levels apparently limit cellular sensitivities to cisplatin and alkylating agents, suggesting that GSTP1 is a useful diagnostic marker for drug sensitivities to these agents in human cancer cells. PMID- 21533478 TI - Growth suppression induced by antitumor drug vitamin K-3 in human hepatoma HepG2 cells is accompanied by downregulation of proliferating cell nuclear antigen expression. AB - The effects of VK3 on the expression of proliferating cell nuclear antigen (PCNA) and tumor suppresser p53 were investigated in human hepatoma HEPG2 cells. VK3 (50 250 mu M) for 3 h-treatment, induced 2- to 5-fold increase in PCNA mRNA. Cells treated with 100 mu M of VK3 for 0-8 h, showed PCNA mRNA initially increased but subsequently decreased. PCNA protein decreased in 75-100 mu M VK3-treated asynchronous cells but decreased slightly in 100 mu M VK3-treated synchronized cells. p53 protein increased 2-fold in VK3-treated synchronized cells. No changes in PCNA were noted with coincubation of VK3 and actinomycin D, alpha-amanitin, or cycloheximide. This evidence shows that VK3-induced cell growth inhibition and cell cycling events are accompanied by down-regulation of PCNA protein expression. PMID- 21533479 TI - Markers of human T lymphotropic virus type I in patients with cancer of uterine cervix in Amazon, Brazil. AB - Human T lymphotropic virus type I(HTLV-I) has been implicated in various human diseases. Serum samples of 390 Brazilian Amazonians with cancer of various types were tested for HTLV-I antibodies by Gelatin particle agglutination test, Enzyme linked immunosorbent assay and Western blotting. Of 134 sera from patients with cancer of uterine cervix, 4 were positive by all the methods. Three of these were from non-transfused patients. DNA was extracted from 2 of 4 seropositive sera that gave strong reactions and were analyzed by PCR-SSCP for HTLV-I sequences. One was positive for all HTLV-I genes tested while the other one was positive for LTR and tax and negative for gag. In view of a possible pathway of the virus by sexual contact, the involvement of HTLV-I in cervical cancer warrants further studies. PMID- 21533480 TI - Neurofibromatosis 2 gene has novel alternative splicings which controls intracellular protein binding. AB - Three novel isoforms of the neurofibromatosis 2 (NF2) gene transcripts generated from alternative splicing were identified from normal human brain, schwannoma and glioma tissues. The 3 novel transcripts lack exon 2, exons 2 and 3, exons 2-4, respectively. Recombinant isoform proteins encoded by those new transcripts have lost the previously reported ability to bind S-35-methionine labeled cellular proteins. Two of seven glioblastoma tissues expressed significantly high levels of the shorter transcripts whereas low grade astrocytomas expressed levels similar to those found in normal brain, suggesting that genomic mutation or aberrant alternative splicing of the NF2 gene may contribute to the progression of malignant gliomas. PMID- 21533481 TI - Radiation-initiated, immortal Syrian hamster embryo fibroblasts release elevated levels of H2O2 and show divergent MnSOD and catalase activities. AB - To characterize molecular events associated with the neoplastic conversion of primary cells by ionizing radiation, we studied the activities and mRNA expression of manganese superoxide dismutase (MnSOD) and catalase (CAT) in Syrian hamster embryo fibroblasts during the early stages of immortalization after treatment with gamma-rays. The irradiated cells showed divergent MnSOD and CAT responses relative to unirradiated controls. At passage 6, MnSOD activity was increased about 50-fold, although the concentration of MnSOD mRNA increased only 1.6-fold. By contrast, CAT activity diminished 2-fold despite an increase of 1.6 fold in the concentration of CAT mRNA. This divergence between the MnSOD and CAT activities was maintained upon culturing and, at passage 12, MnSOD was 35-fold increased and CAT 3.7-fold decreased, relative to unirradiated cells. The amount of H2O2 released into the culture medium by the radiation-initiated cells was 6 fold greater than in control media. Because H2O2 is a causative agent in the induction of malignant transformation in vitro, our results suggest that the elevated production of H2O2 caused by the imbalance between the activities of MnSOD and CAT may participate in the immortalization and subsequent malignant conversion of Syrian hamster embryo fibroblasts by ionizing radiation. PMID- 21533482 TI - Isolation of DNAs that selectively bind a baculovirus produced mutant p53 (Ala 143) protein but not an RRL or WGL produced mutant p53 protein. AB - A PCR-based technique was used to generate a large pool of random sequence double stranded DNAs. Four DNA sequences that selectively bound in vitro to a mutant p53 143A protein, synthesized in baculovirus infected cells, were characterized. The four DNA sequences all approximated the known consensus sequence for wild-type p53. Wild-type p53 also bound the four DNA sequences. Two other mutant p53 proteins (His 175 or Trp 248) did not bind. The ability of mutant p53 143A protein to bind to DNA is totally dependent on the irt vitro system used to synthesize the p53 protein. Rabbit reticulocyte lysate (RRL) or wheat germ lysate (WGL) produced mutant p53 143A is unable to bind to DNA but does bind to a known protein partner, hdm2, thus these activities can be uncoupled. PMID- 21533483 TI - Loss of heterozygosity on chromosome 14 in primary nasopharyngeal carcinoma. AB - Multiple genetic alterations are believed to be involved in the pathogenesis of nasopharyngeal carcinomas (NPC). Loss of heterozygosity (LOH) of chromosomes 3p, 9p and 11q were previously reported in NPC. In order to further define the genetic alterations in NPC, 42 pairs of normal and tumor DNA of NPC were examined for LOH on chromosomes 5p, 5q, 6q, 14q, 15q, 16p, 16q, 17q using 16 polymorphic microsatellite markers. Frequent LOH (33%; 7 out of 21 cases) was observed in chromosome 14q at locus D14s81 (14q31). In order to define the common region of deletion, nine polymorphic microsatellite markers on 14q were examined for LOH in NPC. A common region of deletion was defined in NPC at chromosome 14q24.3-q32.1 flanked by two microsatellite markers D14s76 and D14s45. The common region of deletion (14q24.3-32.1) identified in NPC overlapped with the deleted regions of 14q reported in several human cancers. In 2 cases of NPC, the pattern of LOH revealed the presence of another commonly deleted region defined by loci D14s63 and D14s69 (mapped to 14q11.1-24.1) and located proximal to locus D14s76(14q24.3). This study suggests that multiple tumor suppressor genes present on chromosome 14q are involved in the pathogenesis of NPC. PMID- 21533484 TI - Factors regulating pS2-reporter gene expression in MCF-7 breast cancer cell line. AB - From the estrogen receptor containing breast cancer cell line MCF-7, several genes were shown to be hormone-inducible. The regulatory components involved in transcriptional regulation of one of them, the pS2 gene, was determined using 1100 bp of its 5'-flanking region to drive the luciferase reporter gene in transiently transfected cells. MCF-7 breast cancer cells expressed 4-times as much luciferase compared to the pancreatic cell line PANG-I, that has ceased endogenous pS2 expression, as well as the colonic cell line CX-1. In MCF-7, pS2 triggered reporter gene expression is greatly enhanced by the tumor promoter TPA, and, to some extend by EGF, demonstrating that pS2 gene expression is due to specific trans-activating factors present in MCF-7, but not in PANG-I or CX-1. Cotransfection by estrogen receptor stimulated expression 10-fold, and combination with TPA had a synergistic effect, inducing expression 100-fold. EGF and estrogen receptor also work synergistically. The enhancing effect was abolished by deleting cis-acting regulatory sequences near the estrogen responsive element, suggesting that the corresponding regulatory factors may physically interact. This luciferase reporter gene assay quickly and conveniently tests the responsiveness to exogenous stimuli and the presence of specific transcription factors in different tumor cell lines. PMID- 21533485 TI - Cellular resistance to oxidative stress enhances in vitro and in situ liposome mediated gene transfer. AB - Both H2O2-resistant fibroblast (lines OC5 and OC14) and photodynamic therapy (PDT)-resistant fibrosarcoma (line RIF-8A) cells, known to be cross-resistant to cisplatin, were more transfectable in vitro and in vivo than their parental HA1 and RIF-1 cells, respectively. The transfection efficiencies of OC14 and the most cisplatin-resistant OC5 cells were similar, indicating that transfectability was not directly correlated to the level of cisplatin resistance. Irt situ lipofection was much greater in the cells resistant to H2O2 than to PDT. In situ CAT transgene expression was significantly elevated in the cisplatin-resistant variant 2008C13* cells grown as a subcutaneous tumor and was further increased when 2008C13* tumor-bearing SCID mice were resensitized by i.p. injection of cisplatin. These results suggest that the enhanced gene transfer by cationic liposomes in the cells resistant to cisplatin may be, in part, due to cellular resistance to oxidative stress. PMID- 21533486 TI - In vitro assessment of melphalan induced cytotoxicity and interstrand-DNA-cross links in lymphocytes from patients with lymphoproliferative disorders. AB - The relationship between in vitro cytotoxicity and melphalan induced interstrand DNA-cross-linking was studied in lymphocytes from healthy persons and from patients with a variety of lymphoproliferative disorders. Interstrand-DNA-cross link formation, as measured by ethidium bromide fluorescence assay showed a highly significant correlation with in vitro cytotoxicity in normal lymphocytes an in those from patients with lymphoproliferative disorders. However, the melphalan concentration at which such cross-linking occurred, differed significantly when normal lymphocytes and those in patients with lymphoproliferative disorders were compared. The kinetics of interstrand-DNA cross-link formation and removal following treatment with melphalan also differed, with lymphocytes from patients with lymphoproliferative disorders, particularly those having had prior alkylating agent exposure, showing a more rapid rate of disappearance of cross-links as compared to normal lymphocytes. These findings suggest an increased rate of DNA repair occurring in lymphocytes from patients with lymphoproliferative disorders. In a clinical correlation study in vitro melphalan resistance correlated with in vivo resistance to treatment with alkylating agent based chemotherapy. These results suggest a rapid and simple method for determining alkylator resistance in patients with lymphoproliferative disorders. PMID- 21533487 TI - Interaction of interleukin-11 (rhIL-11) with cytotoxic therapies in the human HT 29 colon carcinoma. AB - The cytokine interleukin-11 (rhIL-11) has been shown to enhance the recovery of bone marrow, oral epithelium and intestinal crypt cells after cytotoxic insult by anticancer drugs or ionizing radiation. 5-Fluorouracil based chemotherapy and radiation therapy are frequently used in the treatment of colon cancer. Simultaneous exposure of human HT-29 colon carcinoma cells in culture to rhIL-11 and 5-fluorouracil for 24 h resulted in enhanced cell killing of the HT-29 cells with lower concentrations (1-10 mu M) of 5-fluorouracil compared with the drug alone. Exposure of HT-29 cells to rhIL-11 prior to, during and after radiation delivery did not alter the killing of normally oxygenated or hypoxic HT-29 cells by the radiation. In vivo treatment of nude mice bearing HT-29 colon tumor xenografts with rhIL-11 prior to and during administration of 5-fluorouracil did not alter the killing of the tumor cells or the killing of the bone marrow CFU-GM by the drug. In the tumor growth delay experiments, administration of rhIL-11 to nude mice bearing HT-29 colon tumor xenografts did not alter the growth of the tumor and did not alter the response of the tumor to 5-fluorouracil. However, administration of rhIL-11 to these animals increased the response of the tumor to fractionated radiation therapy resulting in a radiation dose-modifying factor of 1.5+/-0.2. These results indicate that rhIL-11 may be a selective protector of normal tissues without affecting the response of the tumor to therapy. PMID- 21533488 TI - p53 protein accumulation and genetic alterations in human giant cell tumors of bone (osteoclastomas). AB - Inactivation of tumor suppressor genes represents a critical determinant in the development of a large proportion of human cancers. The tumor suppressor gene p53 is the most frequently altered gene in human cancers. In the present study, p53 protein accumulation, gene mutation and the association between p53 alteration and clinicopathological parameters was analyzed in 29 giant cell tumors of bone. p53 overexpression was detected by immunohistochemistry in 23 of 29 (79%) primary tumors but not in adjacent bone tissue. p53 gene mutations in exons 5-8 were detected in 15 of 29 (52%) of the tumors by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. In 15 (52%) of 29 patient specimens, p53 immunostaining and mutations in exons 5-8 were concordant. Eleven (38%) of 29 tumors overexpressed p53 in the absence of mutations in exons 5-8. No significant association between p53 alterations and clinicopathological parameters was found. The present study represents the first report to assess p53 protein content and gene mutation in a substantial number of giant cell tumors of bone and suggests that p53 alterations play an important role in the development of this neoplasm. PMID- 21533489 TI - Regulation of components of the inflammatory response by 5-iodo-6-amino-1,2 benzopyrone, an inhibitor of poly(ADP-ribose) synthetase and pleiotropic modifier of cellular signal pathways. AB - Chronic inflammation is known to facilitate carcinogenic transformation in various tissues. 5-iodo-6-amino-1,2-benzopyrone (INH2BP), a novel inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (pADPRT) has recently been shown to regulate a variety of cellular signal transduction pathways and to abrogate in vivo tumorigenicity by a Ha-ms transfected endothelial cell line. Here we have investigated the effect of INH2BP on the activation by endotoxin (bacterial lipopolysaccharide, LPS) on the production of the inflammatory mediators tumor necrosis factor alpha (TNF alpha), interleukin-10 (IL-10) and interleukin-6 (IL 6), nitric oxide (NO) and prostaglandins in vitro and in vivo. In addition, we studied the effect of INH2BP on the activation of mitogen-activated protein kinase (MAP kinase) and nuclear factor kappa B (NF-kappa B) in vitro. In cultured J774 and RAW 264.7 macrophages, LPS induced the production of prostaglandin metabolites, the release of TNF and the expression of the inducible isoform of NO synthase (iNOS). The production of prostaglandins and of NO were inhibited by INH2BP in a dose-dependent manner, while the short-term release of TNF alpha was unaffected. INH2BP markedly suppressed LPS-mediated luciferase activity in RAW cells transiently transfected with a full length (-1,592 bp) murine macrophage iNOS promoter-luciferase construct, but not in a deletional construct consisting of -367 bp. In vivo, INH2BP pretreatment inhibited the induction of iNOS by LPS in rats, did not affect the LPS-induced TNF and IL-6 response, but enhanced LPS induced IL-10 production. INH2BP pretreatment markedly improved the survival of mice in a lethal model of endotoxin shock. Our results demonstrate that INH2BP has potent anti-inflammatory actions in vitro and in vivo. PMID- 21533490 TI - Establishment of a novel B-lymphoma cell line, CTB-1, with strong Pas antigen expression having chromosomal translocation (14;22). AB - We established a new lymphoma cell line, designated CTB-1, from pericardial effusion of a patient with diffuse large B-cell lymphoma. This cell line showing vigorous growth ability has undergone 260 passages over a period of 34 months in suspension culture, and is heterotransplantable to nude mice. The cultured cells were positive for CD10, CD19, CD20, CD21, HLA-DR, and surface IgG kappa, and negative for T cell antigens. Chromosomal analysis revealed a t(14;22)(q32;q11) that is consistent with original lymphoma cells. CTB-1 cells show the high cell surface expression level of Fas antigen/APO-1. However, ligation of Fas antigen with anti-Fas monoclonal antibody (clone CH-11) did not induce apoptosis of CTB-1 cells. This suggests that Fas itself or the downstream signaling pathways of Fas may be impaired in this cell line. This new cell line may provide a useful in vitro system to study the biology and pathogenesis of B-cell lymphoma which is independent of Fas-mediated apoptosis. PMID- 21533491 TI - Differential expression and regulation of p53 in human prostatic cells. AB - Although genetic analysis has convincingly shown the association possibly existing between alterations in p53 tumor suppressor gene and a broad spectrum of human tumors including prostate cancer, surprisingly little is known about ways in which p53 at the protein level is controlled. To determine factors that may play a role in its regulation and expression, changes in p53 protein was investigated by using the androgen-insensitive JCA-1, DU-145, PC-3 and the androgen-responsive LNCaP cells. With the exception of PC-3 cells in which p53 is missing, multiple distinct forms of p53 were found in the other 3 prostate cell lines. A single p53 band was detected in the JCA-1 cell extracts, whereas two and three p53 immunoreactive bands were correspondingly observed in the DU-145 and LNCaP cells. The relative abundance and distribution of the different forms of p53 in the latter two cell types varied with proliferation of cells in culture. In the presence of charcoal-stripped fetal bovine serum (cFBS), LNCaP took on the morphology of neuroendocrine cells, a phenotypic change which was accompanied by a greater than 80% reduction in p53 expression, concurrent with elimination of the two slow migrating forms of p53. Induction of apoptosis in JCA-1 cells by treatment with the retinoid 4-HPR caused the virtual disappearance of p53, which coincided with specific processing of p53 into lower molecular weight 28 kD fragments. We propose that rapid and dynamic posttranslational changes in p53 may actively participate in determining mutually exclusive functional cellular events such as proliferation, differentiation, and apoptosis. PMID- 21533492 TI - High frequency of the expression of the MAGE gene family in human esophageal carcinoma. AB - The human gene MAGE encodes tumor specific peptide antigens and consists of at least 12 families. Some antigens coded by the MAGE genes may be potentially useful for cancer specific immunotherapy. There is, however, so far little information on the expression of these gene families in human esophageal carcinomas. We investigated the expression of MAGE-1, -2, -3, -4, -6, -8, -9, 10, -11, and -12 genes in 24 human esophageal carcinoma cell lines, and in 50 pairs of tumor and corresponding normal tissue specimens from the human esophagus by means of reverse transcription polymerase chain reaction. The expression rate varied from 13% of MAGE-6 and 8 to 79% of MAGE-4 in the esophageal carcinoma cell lines, and from 6% of MAGE-6 to 62% of MAGE-4 in clinical tumor samples. The most frequently and the least expressed gene were the MAGE-4 and MAGE-6 genes, respectively, in both the cell lines and the clinical samples. Forty-seven of the 50 clinical tumors expressed at least one MAGE gene. No significant clinicopathologic difference between the tumor cases was observed, regardless of the presence or absence of MAGE gene expression. The findings of this study thus demonstrated that the MAGE gene family is frequently expressed in clinical samples as well as in the cell lines of human esophageal carcinomas. Therefore, to identify the MAGE gene family may be useful, not only for esophageal tumor specific immunotherapy but for molecular diagnostic usage as well. PMID- 21533493 TI - Suppression of apoptosis in COLO 205 cells by the phorbol ester TPA may be mediated by the PKC isoenzyme alpha. AB - Apoptosis induced by an antibody to CD95/APO-1/FAS in the colon carcinoma cells COLO 205 and HT-29 is suppressed by the phorbol ester TPA. Inhibition is much more effective in COLO 205 than in HT-29 cells. The TPA effect is abrogated by the protein kinase C (PKC)-specific inhibitor Go6983 indicating a role of PKC in this process. Bryostatin 1, unlike TPA, is unable to suppress apoptosis, but inhibits the TPA-induced suppression of apoptosis. TPA also inhibits indomethacin induced apoptosis in COLO 205 cells. COLO 205 and HT-29 cells contain the PKC isoenzymes alpha, beta(II) delta, epsilon, eta, mu and zeta. Expression and activity of PKC alpha are at least 5 times higher in COLO 205 than in HT-29 cells. This correlates with the fact that inhibition of CD95-mediated apoptosis by TPA is more prominent in COLO 205 than in HT-29 cells. Thus, these findings suggest that PKC alpha has an important role in the TPA-induced inhibition of apoptosis. PMID- 21533494 TI - Potent tumoricidal effects of a human cytotoxic T-cell line (TALL-104) against prostate cancer. AB - The human TALL-104 cell line possesses major histocompatibility complex non restricted cytotoxic activity against a large variety of tumor targets. Adequate therapies for prostate cancer that has spread outside its capsule are lacking. In order to identify effective therapies for this problem, we investigated the antiproliferative effects of TALL-104 cells against three prostate cancer cell lines (LNCaP, PC-3, DU-145). A Cr-51-release: cytotoxicity assay showed that TALL 104 cells were very cytotoxic against the prostate cancer cells. For example, at a 1:1 ratio of TALL-104 cells to prostate cancer cells, the percent release of Cr 51 at 18 h were 50, 40, and 45% for LNCaP, PC-3, and DU-145, respectively. Analysis by inhibition of clonogenic growth of prostate cancer cells also showed that TALL-104 cells were extremely effective. For instance, a short-term (4 h or 18 h) pre-incubation of TALL-104 cells with these tumor cells at the effector to target ratio of 10:1 prior to clonogenic assay resulted in a substantial reduction in clonogenic tumor growth (90%, 65%, and 50% clonal growth inhibition for LNCaP, PC-3, and DU-145, respectively). Further experiments using both Cr-51 release and clonogenic assays showed that irradiated TALL-104 cells were also effective in their anti-prostatic cancer activities. We also examined if TALL-104 cells plus a chemotherapeutic agent might complement each other in their cytotoxic effects. Preincubation of prostate cancer cell targets with etoposide (0.2-20 mu g/ml) for 18 h markedly increased their susceptibility to TALL-104 lysis. The anti-tumor efficacy of TALL-104 cells was also demonstrated in vivo utilizing the BNX murine model engrafted with subcutaneous PC-3 prostate cancer cells. A substantial reduction in PC-3 tumor cell progression was observed in mice injected with irradiated TALL-104 cells (1x10(7) cells intraperitoneally or intratumorally for 5 days beginning on days 24 and 45 after implantation) as compared to mice injected with tumors only. Taken together, these findings suggest that TALL-104 cells may be utilized as a potent anti-tumor agent, either alone or in combination with other agents (such as etoposide) in metastatic prostate cancer. PMID- 21533495 TI - Regulation of neuroblastoma growth and differentiation by the POU family transcription factors Brn-3a and Brn-3b (Review). AB - Brn-3a and Brn-3b are closely related members of the POU family of transcription factors which have opposite effects on the activity of target promoters. When mouse or human neuroblastoma cells are induced to differentiate to a non-dividing phenotype bearing numerous neuronal processes, the levels of Brn-3a rise dramatically whilst Brn-3b levels fall. Inhibition of Brn-3a expression using an antisense approach or over-expression of Brn-3b, prevents the differentiation of neuroblastoma cells in response to stimuli which normally induce it. Conversely, over-expression of Brn-3a induces differentiation in the absence of such stimuli. Hence the balance between Brn-3a and Brn-3b plays a key role in regulating neuroblastoma differentiation via the activation by Brn-3a or repression by Brn 3b of specific genes whose protein products are required for this process. PMID- 21533496 TI - Single carcinoma cells at the deepest invasive portion correlate with metastatic potential of advanced colorectal carcinoma. AB - The clinical significance of detecting single carcinoma cells (SC) at the deepest invasive portion of a tumor in terms of metastatic potential and prognosis was examined in 57 patients with surgically resected advanced colorectal carcinoma. SC were detected using an immunohistochemical stain for cytokeratin in these sections. The deepest invasive portions of tumors were subclassified by histology into three grades as follows: well-differentiated (W), moderately-well differentiated (Mw; a type that more closely resembles the W tumor), and moderately-poorly differentiated (Mp; more closely resembling poorly differentiated tumor). SC detection was defined positive if more than three single cancer cells with clear cytoplasmic expression of cytokeratin was seen distinct from carcinoma glands and tumor sheets in mid-power (x100) field. SC were detected in 51 (89%) of the 57 carcinomas. There were 5 W or Mw (W/Mw) tumors without SC, 34 W/Mw tumors with SC, 1 Mp tumor without SC, and 17 Mp tumors with SC. W/Mw tumors with SC had a significantly higher (p<0.01) incidence of lymph node metastasis than W/Mw tumors without SC. There was no lesion with lymph node or liver metastasis of W/Mw tumors without SC. SC detection, when combined with histologic subclassification at the deepest invasive portion of a tumor, correlated with prognosis. These results indicate that a combination of the tumor histologic subclassification and SC detection at the deepest invasive portion is a useful predictor of metastatic potential and prognosis in advanced colorectal carcinoma. PMID- 21533497 TI - Antitumor activity and pharmacokinetics following oral administration of natural product DNA topoisomerase I inhibitors 10-hydroxycamptothecin and camptothecin in SCID mice bearing human breast cancer xenografts. AB - The DNA topoisomerase I inhibitors, 10-hydroxycamptothecin (HCPT) and camptothecin (CPT), are indole alkaloids isolated from the Chinese tree, Camptotheca acuminata. They have been shown to have a wide spectrum of anticancer activity both in vitro and in vivo. However, their use has been limited due to their water-insolubility. The purpose of the present study was 2-fold, to determine the in vitro and in vivo activity of HCPT and CPT against human breast cancer and to determine the pharmacokinetics of the two drugs to better understand how they can best be used therapeutically. The bl vitro inhibitory effect on tumor growth was observed with breast cancer cell line MDA-MB-468. The in vivo antitumor effects were then determined using severe combined immunodeficient (SCID) mice bearing MDA-MB-468 xenografts. The tumor-bearing mice were orally administered HCPT (1, 3, 6, 9 mg/kg/day, 5 days per week) or CPT (1, 3, 6 mg/kg/day, 5 days per week) for 3 weeks. Growth of the MDA-MB-468 cells was inhibited by HCPT and CPT in vitro and in vivo in a dose-dependent manner. Complete regression of the tumor xenografts, determined by tumor measurement and microscopic examination, occurred in the groups of animals treated with doses of HCPT or CPT of 3 mg/kg/day or more. In general, HCPT was more effective and less toxic than CPT. To determine the potential mechanisms for the pharmacologic differences, the comparative pharmacokinetics of HCPT and CPT were determined in tumor-bearing SCID mice following i.v. or oral administration of H-3-HCPT or H-3 CPT. Parent drugs and their metabolites in plasma, urine, feces, and various tissues were quantified by a recently developed reversed-phase HPLC method. Significant absorption of both HCPT and CPT was observed after oral administration, with CPT having a higher bioavailability. HCPT and CPT were distributed widely into various tissues including the tumor, enterohepatic system, kidneys, and bone marrow. These studies indicate that HCPT and CPT are of potential use in treatment of breast cancer, providing the basis for the design of future human trials with these anticancer drugs. PMID- 21533498 TI - Involvement of human T lymphotropic virus type I in human neoplasia. AB - Of 211 human tissues analyzed by PCR-SSCP and direct sequencing for HTLV-I genes, 165 (78.2%) gave positive signals. Signals detected in family members of adult T cell leukemia (ATL) patients showed mutations distinct from those in ATL. HTLV-I gene sequences showed variability in same persons examined at different times. Lymphocytes with prototypic HTLV-I genes showed higher sister chromatid exchange following MNNG treatment than those without. Nasopharyngeal carcinomas carrying both HTLV-I and Epstein-Barr virus genes showed markedly abnormal gene product expression. HTLV-I genes in human DNA may cause deregulation of host cell genes upon exposure to carcinogens including viruses. PMID- 21533499 TI - Deletion type hepatocyte growth factor has different effects on growth and c-met expression in 10 different human hepatocellular carcinoma cell lines. AB - We examined expression of c-met protein, and the mitogenic and morphologic effects of deletion type hepatocyte growth factor (dHGF) by using 10 human hepatocellular carcinoma (HCC) cell lines having different morphologic and biologic features. c-met protein was detected at varying levels in all cells, regardless of the histological grades. Among the 7 lines expressing c-met at high levels, mitogenic effects of dHGF were stimulative for 2 lines; suppressive for 3 lines; and not distinguishable for the other 2 lines. Furthermore, mitogenic effects of dHGF were different in two clonally related cell lines, having different morphologic and biologic features, even though expression of c-met protein was comparable. dHGF induced scattering of cells and morphologic changes in two lines with suppressing and unaffected growth. In the 3 lines expressing c met at relatively low levels, no remarkable mitogenic or morphogenic effects were detected. These results suggest that the expression levels of c-met protein were not related to the differentiation levels of HCC cells, and dHGF may cause different biological effects on the cells with almost identical c-met protein expression. PMID- 21533500 TI - Interaction between human cancer cells and cultured murine endothelial cells, and its relationship with metastatic potential. AB - The hematogenous metastasis of cancer consists of a multistep process. It is surmised that a number of interactions between cancer and endothelial cells occur, with cell adhesion molecules playing certain roles in this process. The authors conducted an investigation on the interaction between human cancer cells and cultured murine endothelial cells (F-2 cells) in vitro, and on its relationship with the metastatic activity of cancer cells in vivo. A correlation was found between the degree of expression of carbohydrate antigens on the cell surface and adhesion of cancer cells to F-2 cells. Five of 13 examined cell lines showed liver metastasis after inoculation to the spleen of nude mice. These cell lines showed not only a strong binding activity to F-2 cells but implantation in F-2 cells in vitro was also observed. These findings suggest that adhesion to, and implantation in endothelial cells are necessary for the induction of distant metastasis. Treatment with antibodies against carbohydrate antigens inhibited the formation of liver metastasis in nude mice. It is possible that strategies to interfere with the function of cell adhesion molecules may be formulated to result in the decreased distant metastasis of cancer. PMID- 21533501 TI - Intrasplenic combination immunotherapy with OK-432 and interleukin-2 on liver metastasis of colorectal carcinoma in a mouse model. AB - We investigated the inhibitory effects of intrasplenic combination therapy with OK-432 and recombinant interleukin-2 (IL-2) on liver metastasis of colorectal carcinoma. Intrasplenic administration group significantly inhibited the development of liver metastasis compared with subcutaneous administration group (p<0.05). Combination therapy significantly inhibited the development of subclinical liver metastasis compared with that in the control group. Combination therapy decreased the percentage of cells expressing CD8a, which may be a part of effective factors of combination therapy, and improved overall survival rate. These findings suggested intrasplenic combination therapy with OK-432 and IL-2 might be effective in inhibiting liver metastasis of colorectal carcinoma. PMID- 21533502 TI - Tyrphostin AG-555 inhibits early and late stages of Moloney murine leukemia virus replication cycle. AB - We have previously shown that certain tyrphostin derivatives, known as protein tyrosine blockers, inhibited Moloney murine leukemia virus (Mo-MuLV) replication in acutely and chronically infected NIH/3T3 cells, without affecting cell viability or growth. In our present work, we examined the stages in the viral life cycle that are affected by tyrphostin AG-555. We found that this drug inhibited the integration of the viral DNA into the host genome in acutely infected cells. This compound also reduced the level of viral RNA and specifically inhibited viral protein synthesis in NIH/3T3/Mo-MuLV chronically infected cells while no effect on the cellular beta-actin was observed. Since tyrphostin AG-555 inhibited both the early stages (integration process) and the late stages (viral protein synthesis) in the virus life cycle, it offers a potential advantage over other compounds which affect only one stage in the viral life cycle. Therefore, tyrphostin AG-555 may be considered as a potent antiretroviral drug. PMID- 21533503 TI - Expression of variant forms of fibroblast growth factor receptor 2 mRNA in human breast carcinomas. AB - FGF (fibroblast growth factors) and FGF receptors may play a role in stroma epithelium relationships in the mammary gland. Dysregulation of their interactions may be important in mammary carcinogenesis. Isoforms of the FGFR2 receptor, differing in the structure of the extracellular region, are expressed in the mammary gland and may diversely affect stroma-epithelium relationships. We determined the mRNA variants encoding these isoforms in human cell lines and breast carcinomas. All possible combinations of variants were found. No correlation was observed between the presence of a particular variant and the expression of any FGF gene tested, or the status of any histoclinical parameter. PMID- 21533504 TI - Stimulation of beta-adrenoceptor enhances sensitivity to cisplatin in non-small cell lung cancer cell lines. AB - Cisplatin is a key drug in chemotherapy for lung cancer. It has been reported that intracellular accumulation of cisplatin is an important step as a determinant for resistance to cisplatin, which may be modulated by Na+, K+-ATPase activity. And it has been reported that beta-adrenoceptor agonists modulate the Na+, K+-ATPase in some organs. In this study, the effects of a beta-adrenoceptor agonist and an antagonist on membrane Na+, K+-ATPase activity were evaluated using human non-small cell (NSCLC) lung cancer cell lines. In the NSCLC cell lines, sensitivity to cisplatin was improved by treatment with isoproterenol. Na+, K+-ATPase was activated and intracellular accumulation of cisplatin increased with the treatment. But the antagonist, propranolol, did not modulate sensitivity to cisplatin or Na+, K+-ATPase activity. These results suggest that beta-adrenoceptors may be one of the determinant for sensitivity to cisplatin in NSCLC, but endogenous catecholamine dose not play a role in the intracellular accumulation of cisplatin in these cell lines. Exogenous beta-adrenoceptor agonists may improve the antitumor effect of chemotherapy involving cisplatin. PMID- 21533505 TI - p53 gene alterations are associated with a decreased responsiveness to neoadjuvant chemotherapy in human breast cancer. AB - Recent evidence indicates that alterations of the p53 tumor suppressor gene can modulate the response of tumor cells to DNA-damaging agents and increase drug resistance. To evaluate whether p53 alterations affect response to chemotherapy in breast cancer, we examined the p53 status before and after treatment of primary tumors from 44 patients who received neoadjuvant chemotherapy. p53 status was determined by gene mutations and by mRNA expression levels. Eleven patients (25%) showed alterations in the p53 gene. Comparison of the clinical response between subgroups with or without p53 alterations revealed that p53 alterations were strongly associated to clinical resistance to chemotherapy (p<0.001). PMID- 21533506 TI - Tumor necrosis factor alpha-induced stimulation of neoplastic progression of preneoplastic, hyperplastic alveolar nodule line C4. AB - Lymphocytic infiltrates of the mouse mammary preneoplastic, hyperplastic alveolar nodule (HAN) line C4 have elevated reactivity which correlates positively with the progression of HAN to mammary adenocarcinoma. In this study we investigated the hypothesis that the immunoregulatory mechanisms of HAN infiltrating lymphocytes (HILs) on mammary neoplastic progression are mediated, at least in part, by tumor necrosis factor alpha (TNF alpha). C4 HAN epithelial cells express mRNA for both the p55-60 receptor and the p75-80 TNF alpha receptors. High levels of both TNF alpha and TNF beta are expressed by HILs, whereas only TNF alpha is expressed by the C4 HAN epithelial cells. Treatment of C4 HAN bearers with TNF alpha in vivo decreases the latency period and enhances the frequency of HAN progression to tumor. Proliferation of monolayer cultures of epithelial cells from mammary glands of normal and C4 HAN-bearing mice, as well as C4 tumor cells, is enhanced by TNF alpha. Growth of normal mammary cells in 3-dimensional collagen cultures is also significantly stimulated by TNF alpha. Our results suggest that stimulation of epithelial cell proliferation by HIL-produced TNF alpha is one mechanism responsible for the 'immune stimulation' of neoplastic progression in the HAN model. PMID- 21533507 TI - The possible relevance of the expression of MHC antigens and of EGF receptor in aggressive oral tumours. AB - In this study the intensity of expression of major histocompatibility complex (MHC) class I and II antigens, adhesion molecule i.e. ICAM-1, epidermal growth factor receptor i.e. EGFr, T cell marker and cytokeratin were compared in oral squamous cell carcinoma (OSCC) and in the benign ameloblastoma of the jaws. The results showed that: a) There was strong expression of both monomorphic and of polymorphic class I MHC antigens (90% of cases) in both basal and suprabasal cells of controls from normal mucose. b) Whereas up to 4% of OSCCs and 27% of ameloblastomas showed complete loss of monomorphic class I antigens, the frequency of polymorphic class I abnormalities was even more marked in both tumour types. c) Strong expression of class II MHC antigens and of ECFr was observed in the basal cells of most normal controls. d) Both class II (50% of cases) and ICAM-1 (30% of cases) showed strong expression in OSCC but not in ameloblastoma. The statistical values between OSCC and normal basal cells for class II and ICAM-1 were not significant whilst the corresponding values for OSCC compared with ameloblastoma were p<0.001 and p<0.001. In the case of OSCC, there were a large number of infiltrating T cells expressing activation marker i.e. class II antigen. e) Strong expression of EGFr was seen in more than 90% of the OSCC cases compared with only 16% of ameloblastomas (0.01

0.001). Our working hypothesis to explain these abnormalities is that although both tumour types (more so in the case of ameloblastoma) have in place an escape mechanism from the immune system, the overexpression of EGFr in OSCC may in part be responsible for the more aggressive behaviour of the malignancy compared with the locally invasive but benign ameloblastoma. PMID- 21533508 TI - The role of tumour-derived mIL-4 on rat C6 glioma regression. AB - Interleukin-4 (IL-4) has been demonstrated to possess anti-tumourigenic properties in vivo which is attributed to the infiltration of eosinophils in addition to an inhibition of tumour vascularisation. We have previously generated stable transfectants of C6 glioma cells that express mouse IL-4 (mIL-4) under a tetracycline-responsive promoter system, enabling us to apply tight regulatory control of mIL-4 expression in vivo. We have demonstrated that the subcutaneous implantation of mIL-4 expressing rat C6 glioma cell lines in nu/nu mice resulted in an inhibition of tumour growth. In this study, we have investigated the ability of mIL-4 to potentiate the regression of established subcutaneous rat C6 tumours in nu/nu mice. Induction of mIL-4 re-expression in established tumours did not cause a regression of tumour growth as determined by external tumour volume measurements. However, histological analysis revealed that mIL-4 re expressing tumours were highly necrotic, were infiltrated by eosinophils and had a reduced level of vascularisation. These results suggest that mIL-4 can potentiate an anti-tumourigenic response in established C6 tumours in nu/nu mice. Furthermore, this study illustrates the need for detailed and defined tumour histopathology as tumour volume measurements alone can lead to inaccurate and misleading results. PMID- 21533509 TI - Human DNA topoisomerase II-alpha. AB - DNA topoisomerase II-alpha (topo II-alpha) is the molecular target of several types of clinically useful anticancer drugs such as etoposide, teniposide, doxorubicin, and mitoxantrone. The enzyme is also a proliferation marker in normal cells and tissues. High levels of enzyme are present in the S and G2 phases of the cell cycle. New data are emerging which suggest that anticancer drugs which target the topoisomerases may be useful in the treatment of patients with ovarian neoplasms. However, there is relatively little data on the expression of these enzymes in human ovarian cancer. We have recently developed an in situ immunohistochemical stain which can detect the presence of topo II alpha in formalin-fixed paraffin-embedded human tissue sections. In order to determine topo II-alpha levels in ovarian tumors, we immunostained for topo II alpha, 30 ovarian neoplasms which ranged from benign to highly malignant. We correlated our results with expression of MIB1 in order to determine if topo II alpha expression correlates with cell proliferation. Since the gene for topo II alpha is closely linked to the gene for the c-erbB-2 oncogene, we also evaluated the cases for amplification of c-erbB-2. Our results indicate that topo II-alpha correlates well with MIB1 indicating that topo II-alpha may be useful in estimating cell proliferation in ovarian tumors. In addition, 1 of 15 patients with a malignant neoplasm had a carcinoma which expressed high levels of topo II alpha. Since the sensitivity of cells to topo II targeted drugs is dependent on high topo II levels, this suggests that topo II-alpha immunostaining in ovarian cancer may also identify a subset of patients potentially treatable with topo II targeted drugs. None of the ovarian neoplasms showed amplification of c-erbB-2. PMID- 21533510 TI - Loss of heterozygosity on chromosome 17p13 (p53) and 13q14 (Rb1) in squamous cell carcinoma of head and neck. AB - Loss of chromosome sequences at 13q14 (Rbl) and 17p13 (p53) associated with squamous cell carcinoma of head and neck (SCCHN) was evaluated in 12 recurrent tumors and 51 primary tumors from 63 patients. The incidence of LOH at 17p13 was 19 of 50 (38%) tumors, and at 13q14 was 21 of 57 (37%). LOH affecting Rbl and/or p53 was observed in 30 of 63 (48%) SCCHN. Coincident LOH at Rbl and p53 was detected in 10 of 46 (22%) tumors. There were nine cases in which primary and metastatic tumors were obtained from the same patient. Of these, seven were informative and five of these (71%) manifested LOH at p53 in both primary and metastatic sites. Examination of Rbl in these same tumors showed LOH in six of the nine metastases, and of these six, only three revealed LOH in the primary tumor. LOH at p53 or Rbl alone showed no correlation with clinical outcome. However, tumors that manifested LOH at both loci were associated with poorer patient outcome and poorer histological differentiation. PMID- 21533511 TI - The role of p53 tumor-associated protein in colon cancer detection and prevention (Review). AB - The role of the cytoplasmic fraction of p53 protein in the detection and prevention of colon cancer was analyzed by comparing results of the author's studies with data published in the literature. In cancer detection, although immunochemical methods are widely used for diagnostic purposes positive results are not always obtained. Using a new modification of affinity chromatography columns, we isolated the cytoplasmic, soluble form of tumor-associated antigens (TAA) from the serum of colon cancer patients. p53 protein was found to be one of the main components of such TAA. The serum level of p53 antigen was related to tumorigenicity: the correlation and regression coefficients between the serum level of p53 protein and the progress in colon cancer were 0.48 and 0.88, respectively, p<0.01. Thus HPLC-determination of the serum concentration of this protein could serve as a screening tool for cancer detection. The sensitivity and specificity of the method reached 92% and its accuracy was 88%. The method can be used to detect cancer development either as a primary disease or as a recurrent disorder. In cancer prevention, a few attempts have been made to utilize p53 protein as a tumor suppressor. IgG generated against the cytoplasmic p53 antigen from tumor-bearing rats prevents the carcinogenic effect of 1,2-dimethylhydrazine decreasing significantly the number of tumor-bearing rats in vaccinated group compared with non-vaccinated controls. Anti-p53 IgG not only had an antitumor effect but also prevents benign tumors from becoming malignant: the number of malignant tumors in vaccinated rats was half that in controls (29% and 58%, respectively). The antitumor effect of vaccination is accompanied with a significant increase in the serum-level of p53 antigen in vaccinated rats compared with non-vaccinated controls. p53 protein plays an important role in colon cancer: the unique mechanism involved in both cancer development and in cancer prevention appears to include high production of this protein. PMID- 21533512 TI - Establishment and characterization of a new human gallbladder carcinoma cell line (OCUG-1) producing TA-4. AB - A new human cell line (OCUG-1) was established from peritoneal effusion of a patient with malignant gallbladder carcinoma. OCUG-1 cells proliferated mainly in clusters of cells partially floating in a monolayered sheet. The population doubling time is 47.1 h. DNA analysis showed that OCUG-1 cells were aneuploid and had two G(0)/G(1) peaks. The number of chromosomes was distributed in a broad range from 52 to 139. Subcutaneous injections of the cells induced tumor formation in all nude mice. The reconstituted tumors were poorly differentiated adenocarcinoma. High levels of SLX, CA19-9, SPan-1 and TA-4 were found in the serum of the original patient, but OCUG-1 cells produced only TA-4. We speculate that OCUG-1 may be a transitional form from adenocarcinoma to squamous cell carcinoma. Since OCUG-1 produces a high level of TA-4, it will be useful for the study of the biological nature of this carcinoma and the relationship between the expression of TA-4 and squamatization. PMID- 21533513 TI - Induction of cdk2 after gamma-ray irradiation is dependent on p53 status. AB - We show that expression of cdk2 induced after gamma-ray irradiation is dependent on the p53 status in two human glioblastoma cell lines, one bearing the wild-type p53 gene and the other the mutant gene. This result indicates that wtp53 induces the expression of not only WAF1 but also cdk2. Our results suggest that p53 dependent WAF1 induction would act to prevent gene amplification and mutation in cells which sustain DNA damage in G(1) phase and p53-dependent cdk2 induction might act to prevent aneuploidy through E2F-1-DP-1 inactivation in cells which sustain DNA damage in G(2) phase. PMID- 21533514 TI - Glutathione S-transferases and cancer (Review). AB - Cytosolic glutathione S-transferases are a family of enzymes involved in the metabolism of drugs, toxins, carcinogens and also of anticancer drugs. Recent studies have indicated that glutathione S-transferases (GSTs) may play an important role in the resistance of cells to toxins and carcinogens but also to anticancer drugs. This report reviews the current literature concerning the role of glutathione S-transferases in anticancer drug resistance. Moreover, the significance of GST pi in carcinogenesis and its role as prognostic factor is discussed. PMID- 21533515 TI - Altered biochemical profile and gene expression in aflatoxin B-1-transformed C3H10T1/2 cells. AB - A transformed cell line 7SA, obtained by transformation of C3H10T1/2 cells with irt vitro activated aflatoxin B-1 (AFB(1)), was used to investigate biochemical and molecular alterations associated with transformation by AFB(1). 7SA cells demonstrate an altered biochemical phenotype characterized by alterations in phase I and phase II enzymes in a manner that would allow these cells to survive in a hostile chemical environment. Investigations of the molecular basis of transformation revealed no mutations in codons 12/13 and 61 of ras genes (Ha-, Ki and N-ras) and in exons 5, 6, 7 and 8 of p53 tumor suppressor gene. However, subtractive hybridization led to the isolation of seven novel cDNA clones that demonstrated 2 to 10-fold overexpression of the mRNAs corresponding to the five cDNAs (SK1, SK2, SK3, SK4 and SK5) and >400 fold overexpression of the mRNAs corresponding to the other two cDNAs (SK67 and SK153). In addition, part of the sequence of the cDNA clone SK5 demonstrated >88% identity with L1-like mobile genetic element and Southern analysis of the DNA with SK5 cDNA as a probe revealed gene rearrangement in 7SA DNA, compared to DNA from C3H10T1/2 cells. PMID- 21533516 TI - Sequential alpha-interferon and tamoxifen. AB - Tamoxifen and alpha-interferon have interesting and complementary biologic effects which may be relevant for breast cancer growth and regression. The hormone responsive cell line MCF-7 was used as a model to study the biologic effects of sequential administration of these two agents. Interferon had a significant antiproliferative effect and increased ER and TGF-beta expression. The combination had at least additive antiproliferative effects as well as effects on expression of ER, TGF-beta, c-erbB-2, P24 and Ki67. alpha-IFN modulates TMX induced biologic effects and the sequential administration of alpha IFN and TMX may lead to potentially important modulation of biologic endpoints. Further studies are appropriate. PMID- 21533517 TI - Antiepileptic drug use in community-dwelling and institutionalized elderly: a nationwide study of over 1,300,000 older people. AB - PURPOSE: To investigate whether institutionalization is associated with the use of antiepileptic drugs (AEDs) and to compare the association between use of AEDs and psychotropics in community-dwelling and institutionalized elderly, after adjustment for age, sex and co-morbidity (i.e. number of other drugs). METHODS: We analyzed data on age, sex and dispensed drugs for individuals aged >=65 years registered in the Swedish Prescribed Drug Register from July to September 2008, record-linked to the Swedish Social Services Register (n = 1,345,273: 1,258,565 community-dwelling and 86 708 institutionalized elderly). Multivariate logistic regression analysis was used to analyze whether institutionalization and use of psychotropics (i.e. antipsychotics, anxiolytics, hypnotics/sedatives and antidepressants) were associated with the use of AEDs. RESULTS: AEDs were used by 2% of the community-dwelling and 9% of the institutionalized elderly. The most commonly used AEDs were carbamazepine, gabapentin, pregabalin, valproic acid and lamotrigine. Institutionalization was strongly associated with AED use (OR(adjusted) = 3.98; 95% CI 3.86-4.10). In community-dwelling elderly, AED use was associated with an increased probability of use of all types of psychotropics. However, among institutionalized elderly, the associations between use of AEDs and psychotropics showed a mixed pattern. CONCLUSIONS: AED use seems to be common among Swedish institutionalized elderly, and institutionalization is a strong determinant of AED use. Our results may also indicate an off-label prescribing of AEDs as an alternative to psychotropics in the institutional setting. This finding needs to be confirmed by others and evaluated with respect to outcomes of this treatment in institutionalized elderly. PMID- 21533518 TI - Xiangtong Zhang's study on dendritic function: gold is shining everywhere. PMID- 21533521 TI - Can a small endoscopic sphincterotomy plus a large-balloon dilation reduce the use of mechanical lithotripsy in patients with large bile duct stones? AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (EST) is technically difficult in the patients with large extrahepaic bile duct stones. Small endoscopic sphincterotomy combined with large balloon dilation (ESLBD) currently seems to be a promising alternative for patients with difficult bile duct stones that cannot be extracted by EST. This study compared the therapeutic benefits and complication rates of ESLBD with those of EST alone. METHODS: This study investigated 149 patients treated for stones (>=10 mm) or multiple stones in the extrahepatic bile duct. The ESLBD group (n = 72) was compared with the conventional EST group (n = 77). Mechanical lithotripsy was performed when the stone could not be removed using a Dormia basket. RESULTS: The two groups did not differ significantly in terms of mean bile duct diameter, common bile duct angulation, and presence of periampullary diverticulum. The ESLBD group compared with the EST-alone group had similar outcomes in terms of overall successful stone removal but showed significant differences in complete stone removal during the first session (87.5 vs. 74.0%; P = 0.036) and the use of mechanical lithotripsy for large bile duct stones (>=15 mm) (17.9 vs. 45.8%; P = 0.026). For the patients with a periampullary diverticulum, ESLBD and EST showed similar results only for efficacy and complications. CONCLUSIONS: The ESLBD technique may be a safe, effective alternative to conventional EST for endoscopic removal of large common bile duct stones, and it can reduce the use of mechanical lithotripsy compared with EST alone. PMID- 21533520 TI - Endoscopic findings and outcomes of revisional procedures for patients with weight recidivism after gastric bypass. AB - BACKGROUND: Significant weight regain occurs for 10% to 20% of patients after Roux-en-Y gastric bypass (RYGB). Potential causative factors include anatomic abnormalities such as enlargement of the gastric pouch and gastrojejunostomy (GJ). This report describes endoscopic findings for patients referred for investigation of weight regain and presents the outcomes of revisional therapy for patients with abnormal anatomy. METHODS: To evaluate gastric pouch and stoma size, RYGB patients referred for weight regain underwent upper endoscopy. A GJ was defined as enlarged if it had a diameter greater than 2 cm in any dimension, and a pouch was defined as enlarged if its length exceeded 6 cm long or its width exceeded 5 cm. Patients with abnormal anatomy who subsequently underwent revisional procedures were arbitrarily categorized into three groups based on the interval from RYGB to endoscopic evaluation: less than 5 years (group 1), 5 to 10 years (group 2), longer than 10 years (group 3). The percentage of regained weight lost (%RWL) after revision was compared between the groups. RESULTS: In this study, 205 RYGB patients (176 women with a mean age of 47 +/- 10 years and a current body mass index [BMI] of 43.4 +/- 8.4 kg/m(2)) were evaluated. The mean time from primary RYGB was 6.9 +/- 3.7 years, and the increase in BMI from its nadir was 9.78 +/- 5.80 kg/m(2). Abnormal endoscopic findings (n = 146, 71.2%) included large GJ (n = 86, 58.9%), large pouch (n = 42, 28.8%), or both (n = 18, 12.3%). Of the 205 patients, 51 (24.9%) underwent a revisional surgical or endoluminal procedure. At a mean follow-up assessment 13 months after revision, group 1 (n = 12) had a mean %RWL of 103% +/- 89.3%, and 62% of these patients lost all their regained weight. The mean %RWL was 45% +/- 12.6% in group 2 (n = 30) and 40% +/- 13.6% in group 3 (n = 9). CONCLUSION: Endoscopy is a valuable tool for evaluating weight regain after bariatric surgery that can identify abnormal post-RYGB anatomy in a majority of patients. Revisional procedures to restore normal RYGB anatomy appear to be most successful if performed within 5 years after the primary procedure. PMID- 21533522 TI - Biologic hernia implants in experimental intraperitoneal onlay mesh plasty repair: the impact of proprietary collagen processing methods and fibrin sealant application on tissue integration. AB - BACKGROUND: Biologic implants have been recommended for reinforcement in routine and challenging hernia repair. However, experimental and clinical studies have reported adverse effects (e.g., slow implant integration and pronounced foreign body reaction). To evaluate the impact of different material processing methods (cross-linking vs. non-cross-linking of collagen) and implant design, four different biologic hernia implants were compared directly in experimental intraperitoneal onlay mesh plasty (IPOM). Tissue integration, shrinkage, and foreign body reaction were primary outcome parameters. METHODS: In this study, 48 Sprague-Dawley rats were randomized to four treatment groups. Open IPOM repair was performed. One peritoneal defect per animal was covered with 2 * 2 cm patches of cross-linked or non-cross-linked implants including CollaMend (n = 12), Peripatch (n = 12), Surgisis (n = 12), and Tutomesh (n = 12). In half of the animals, fibrin sealant was applied for additional fixation and to cover sutures. The observation period was 60 days. The primary outcome parameters were implant integration, shrinkage, and foreign body reaction. Macroscopic and histologic assessments were performed. RESULTS: The integration of implants was insufficient in all the groups. The implants could be detached easily from the underlying tissue, and the penetration of fibroblasts and vessels was limited to the perforations. Foreign body reaction was pronounced with CollaMend and Surgisis, leading to persistent granulomatous inflammation. Shrinkage was excessive with Surgisis, whereas Tutomesh and Peripatch yielded sufficient anti-adhesion and elicited no foreign body reaction. CONCLUSION: At 2 months, cross-linked and non cross-linked biologic hernia implants were poorly integrated. Cross-linking led to a more pronounced foreign body reaction. Less inflammatory response may reduce local complications, but did not enhance implant integration in this study. PMID- 21533523 TI - Differential growth-related gene expression in abalone (Haliotis midae). AB - The slow growth rate of Haliotis midae impedes the optimal commercial production of this most profitable South African aquaculture species. To date, no comprehensive effort has been made to identify genes associated with growth variation in farmed H. midae. The aim of this study was therefore to investigate growth variation in H. midae and to identify and quantify the expression of selected growth-related genes. Towards this aim, molecular methodologies and cell cultures were combined as a time-efficient and economical way of studying abalone transcriptomics and cell biology. Modern Illumina sequencing-by-synthesis technology and subsequent sequence annotation were used to elucidate differential gene expression between two sibling groups of abalone demonstrating significant growth variation. The expression of selected target genes involved in growth was subsequently analysed by quantitative real-time PCR (qPCR). Fast- and slow growing abalone and in vitro primary haemocyte cultures treated with different growth-stimulating factors were used. The results obtained from transcriptome analysis and qPCR revealed significant differences in gene expression between large and small abalone, and between treated and untreated haemocyte cell cultures. Throughout in vivo and in vitro qPCR experiments, the up-regulation of genes involved in the insulin signalling pathway suggests that insulin may be involved in enhanced growth rate for various H. midae tissues. PMID- 21533524 TI - Characterization of bevacizumab dose response relationship in U87 brain tumors using magnetic resonance imaging measures of enhancing tumor volume and relative cerebral blood volume. AB - Despite the early promising results with the anti-angiogenic agent, bevacizumab, to prolong time to progression in patients with brain tumors, the optimal dose and drug combinations have not yet been defined. The purpose of this study was to characterize the bevacizumab dose-response relationship for brain tumors by measuring the contrast-agent enhanced tumor volumes and relative cerebral blood volume (rCBV) using dynamic susceptibility contrast (DSC) imaging. The studies, performed in the U87 brain tumor model using doses of bevacizumab ranging from 0 to 10 mg/kg, demonstrate that tumor growth and vascularity are inhibited at all doses used, compared to untreated controls. However, only the maximum dose showed a statistically significant difference in growth rate. Conversely tumor vascularity, as measured with rCBV, was inhibited equally well for all doses used with no clear indication that higher doses are more effective. PMID- 21533525 TI - Clinical significance of vasculogenic mimicry in human gliomas. AB - Vasculogenic mimicry (VM) is known as non-endothelial tumor cell-lined microvascular channels in aggressive tumors. We have previously found the presence of VM in high-grade gliomas. In this study, we aimed to identify VM patterns in gliomas and to explore their clinical significance. Tumor samples as well as their detailed clinical/prognostic data were collected from 101 patients. Vasculogenic mimicry in the glioma samples was determined by dual staining for endothelial marker CD34 and periodic acid-Schiff (PAS). Tumor samples were also immunohistochemically stained for Ki-67, VEGF, COX-2 and MMP-9. The association between VM and the clinical characteristics of the patients were analyzed. A Kaplan-Meier survival analysis and log-rank tests were performed to compare survival times of the patients. Vasculogenic mimicry was present in 13 out of 101 samples. The higher grade gliomas had a higher incidence of VM than that of lower grade gliomas (P = 0.006). Vasculogenic mimicry channels were associated with the expression of COX-2 and MMP-9 (P < 0.05). While there was no association between the existence of VM and the sex, age and preoperative epilepsy of the patients, or expression of Ki-67 and VEGF. However, patients with VM-positive gliomas survived a shorter period of time than those with VM negative gliomas (P = 0.027). Interestingly, in high-grade gliomas, the level of microvascular density was lower in VM positive tumors than those VM negative tumors (P = 0.039). Our results suggest that VM channels in gliomas correlate with increasing malignancy and higher aggressiveness, and may provide a complementation to the tumor's blood supply, especially in less vascularized regions, which may aid in the identification of glioma patients with a poorer prognosis. PMID- 21533526 TI - Bizarre parosteal osteochondromatous proliferation: a locally aggressive benign tumor. AB - BACKGROUND: Bizarre parosteal osteochondromatous proliferation (BPOP) is a benign lesion of bone, and numerous questions remain unresolved regarding its etiology, diagnosis, and treatment. QUESTIONS/PURPOSES: We present the Scottish Bone Tumour Registry experience of this rare lesion. PATIENTS AND METHODS: We performed a retrospective analysis of the Scottish Bone Tumour Registry records. Histologic specimens were reexamined by a musculoskeletal pathologist. Radiographs were reevaluated by a musculoskeletal radiologist. RESULTS: From 1983 to 2009, 13 cases (13 patients; six male, seven female) were identified. Their ages ranged from 13 to 65 years. All patients presented with localized swelling. Pain was present in five. Antecedent trauma was present in two. Nine lesions affected the hand, three the foot, and one the tibial tuberosity. Twelve lesions were excised and one was curetted. There were seven recurrences of which six were excised. One lesion recurred a second time and was excised. There were no metastases. Radiographs showed densely mineralized lesions contiguous with an uninvolved cortex. Cortical breakthrough was present in one case and scalloping in another. Histologic analysis characteristically showed hypercellular cartilage with pleomorphism and calcification/ossification without atypia, bone undergoing maturation, and a spindle cell stroma. CONCLUSIONS: BPOP is a rare benign lesion that probably is neoplastic, with no gender predilection, and affecting patients over a wide age range. Previously trauma was considered an etiologic factor, but this no longer seems to be the case. The rate of recurrence was 50%, which may indicate a more extensive resection is required for this locally aggressive lesion. No metastases were reported. BPOP should not be mistaken for, or treated as, a malignant tumor. LEVEL OF EVIDENCE: Level IV, retrospective case series. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21533527 TI - Vascularized bone grafting in a canine carpal avascular necrosis model. AB - BACKGROUND: Limited experimental research has been performed on the treatment of avascular necrosis (AVN) by vascularized bone grafting. QUESTIONS/PURPOSES: A new model simulating carpal AVN was created to investigate surgical revascularization of necrotic bone. METHODS: In seven mongrel dogs, AVN was induced by removal of the radial carpal bones bilaterally, deep-freezing, coating in cyanoacrylate, and reimplantation. A reverse-flow vascularized bone graft from the distal radius was implanted in the avascular radial carpal bone. The contralateral side served as an untreated ischemic control. Bone blood flow, bone volume, radiography, histomorphometry, histology, and MRI were analyzed at 4 weeks. RESULTS: Blood flow was substantially higher in grafted bones when compared with controls (14.68 +/- 15.43 versus 0.27 +/- 0.28 mL/minute/100 g). Blood flow correlated with increased osteoid formation and higher levels of bone turnover. T1 and T2 signals on MRI did not correlate with quantitative bone blood flow measurements. Necrotic bones with no blood flow had normal T1 and T2 signals, whereas revascularized bones had signal changes when compared with adjacent carpal bones. No major collapse occurred in any radiocarpal bone. CONCLUSION: In a canine experimental model, investigation of carpal AVN shows the ability of vascularized bone grafting to revascularize and remodel avascular bone. CLINICAL RELEVANCE: Surgical revascularization of necrotic bone induced by vascularized bone grafting results in increased bone perfusion and bone remodeling as compared with untreated necrotic bone. MRI T1 and T2 signals can be normal in necrotic avascular bone. PMID- 21533528 TI - Internal rotation of the tibial component is frequent in stiff total knee arthroplasty. AB - BACKGROUND: Stiffness complicating TKA is a complex and multifactorial problem. We suspected internally rotated components compromised motion because of pain, patellar maltracking, a tight medial flexion gap, and limited femoral rollback on a conforming lateral tibial condyle. QUESTIONS/PURPOSES: We sought to determine: (1) the incidence of internal rotation of the femoral and tibial components in stiff TKAs; (2) if revision surgery that included correction of rotational positioning improved pain, ROM, and patellar tracking; and (3) if revision altered nonrotational radiographic parameters. METHODS: From a cohort of 52 patients with TKAs revised for stiffness, we performed CT scans of 34 before and 18 after revision to quantify rotational positioning of the femoral and tibial components using a previously validated scanning protocol. RESULTS: All 34 patients with TKAs had internal rotation of the summed values for tibial and femoral components (mean, 14.8 degrees ; range, 2.7 degrees -33.7 degrees ) before revision for stiffness. The incidence of internal rotation was 24 of 34 femoral (mean, 3.1 degrees ; internal) and 33 of 34 tibial components (mean, 13.7 degrees internal). Revision arthroplasty improved Knee Society function, knee, and pain scores. Mean extension improved from a contracture of 10.1 degrees to 0.8 degrees and flexion from 71.5 degrees to 100 degrees . Postrevision CT scans confirmed correction of component rotation. Nonrotational parameters were unchanged. CONCLUSIONS: We recommend CT scanning of patients with stiff TKAs before surgical intervention to identify the presence of internally rotated components. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21533529 TI - Mimic peptides bonding specifically with the first and second extracellular loops of the CC chemokine receptor 5 derived from a phage display peptide library are potent inhibitors of experimental autoimmune encephalomyelitis. AB - PURPOSE: To obtain mimic peptides that specifically bind with the first and second extracellular loops (ECL1, ECL2) of the CC chemokine receptor 5 (CCR5) and to study their treatment effects on experimental autoimmune encephalomyelitis (EAE) mice. METHODS: A phage display peptide library was applied to screen peptides that bond with ECL1 and ECL2. ELISA and DNA sequence analysis were used to identify positive clones. EAE mice were treated with synthesized peptides by intraperitoneal injection. RESULTS: Eighteen positive clones were obtained and four peptides with sequences STFTTTL, TPIPQLL, SLPLPKP and QTSSAAL were identified. These peptides could significantly protect against and reduce the severity of EAE. The infiltration of monocytes and lymphocytes into the spinal cord decreased significantly in treated mice, while abundant inflammatory cells and demyelination were observed in spinal cords of EAE mice. CONCLUSION: CCR5 mimic peptides provided a significant protective effect to EAE mice. These potent inhibitory mimic peptides could be useful in the clinical treatment of multiple sclerosis. PMID- 21533530 TI - Mutation analysis of RAD51L1 (RAD51B/REC2) in multiple-case, non-BRCA1/2 breast cancer families. AB - Although a significant proportion of familial aggregation of breast cancer remains unexplained, many of the currently known breast cancer susceptibility genes, including BRCA1, BRCA2 and TP53, play a role in maintaining genome integrity by engaging in DNA repair. RAD51L1 is one of the five RAD51 paralogs involved in homologous recombination (HR) repair of DNA double-strand breaks (DSBs); it also interacts directly with p53. Deleterious mutations have been found in one RAD51 paralog, RAD51C (RAD51L2), in non-BRCA1/2 breast and ovarian cancer families, which suggests that all five paralogs are strong candidate breast cancer susceptibility genes. A genome-wide association study (GWAS) has already identified a single nucleotide polymorphism (SNP) deep within intron 10 of RAD51L1 as a risk locus for breast cancer. Based on its biological functions and association with RAD51C, there is reason to suggest that RAD51L1 (RAD51B/REC2) may also contain high risk mutations in the gene that give rise to multiple-case breast cancer families. In order to investigate this hypothesis, we have used high resolution melt (HRM) analysis to screen RAD51L1 for germline mutations in 188 non-BRCA1/2 multiple-case breast cancer families and 190 controls. We identified a total of seven variants: one synonymous, three intronic, and three previously identified SNPs, but no truncating or nonsense changes. Therefore, our results suggest that RAD51L1 is unlikely to represent a high-penetrance breast cancer susceptibility gene. PMID- 21533531 TI - The effect of system-level access factors on receipt of reconstruction among Latina and white women with DCIS. AB - Treatment decisions associated with ductal carcinoma in situ (DCIS), including the decision to undergo breast reconstruction, may be more problematic for Latinas due to access and language issues. To help understand the factors that influence patients' receipt of reconstruction following mastectomy for DCIS, we conducted a population-based study of English- and Spanish-speaking Latina and non-Latina white women from 35 California counties. The objectives of this study were to identify the role of ethnicity and language in the receipt of reconstruction, the relationship between system-level factors and the receipt of reconstruction, and women's reasons for not undergoing reconstruction. Women aged 18 and older, who self-identified as Latina or non-Latino white and were diagnosed with DCIS between 2002 and 2005 were selected from eight California Cancer Registry (CCR) regions encompassing 35 counties. Approximately 24 months after diagnosis, they were surveyed about their DCIS treatment decisions. Survey data were merged with CCR records to obtain tumor and treatment data. The survey was successfully completed by 745 women, 239 of whom had a mastectomy and represent the sample included in this study. Whites had a higher completion rate than Latinas (67 and 55%, respectively). Analysis included descriptive statistics and logistic regression modeling. Mean age was 54 years. A greater proportion of whites had reconstruction (72%) compared to English-speaking Latinas (69%) and Spanish-speaking Latinas (40%). Multivariate analysis showed that women who were aged 65 and older, unemployed, and had a lower ratio of plastic surgeons in their county were less likely to have reconstructive surgery after mastectomy. The most frequent reasons mentioned not to receive reconstruction included lack of importance and desire to avoid additional surgery. Although ethnic/language differences in treatment selection were observed, multivariable analysis suggests that these differences could be explained by differential employment levels and geographic availability of plastic surgeons. PMID- 21533532 TI - COX2 overexpression is a prognostic marker for Stage III breast cancer. AB - To determine the significance of (Cyclooxygenase 2) COX2 for clinical outcome in breast cancer, we analyzed the correlation between COX2 overexpression and survival in 687 patients with invasive breast cancer. Cytoplasmic immunoreactivity of COX2 was determined as positive in 325 of 687 (47.3%) invasive breast cancers. COX2 positivity was significantly correlated with high histologic grade, negative estrogen receptor (ER), high Ki67, luminal B and triple-negative tumors, Bcl2 negativity, and p53 overexpression. In univariate analysis, COX2 overexpression resulted in significantly shorter relapse-free survival (RFS) [hazard ratio (HR) 1.487, 95% CI 1.035-2.110, P = 0.032]. Multivariate analysis revealed no significant association between COX2 overexpression and either overall survival (OS) or RFS. Kaplan-Meier analysis of the whole patient group showed significantly reduced RFS in patients with high COX2 expression, compared to those that did not overexpress COX2 (91 vs. 162 months, P = 0.031). Stratified subgroup analysis by TNM stage disclosed marked differences in OS and RFS rates in Stage III patients. We observed a significant association of COX2 overexpression with shorter RFS in the ER-negative subgroup of Stage III patients. The results show that COX2 overexpression is a significant unfavorable prognostic factor in Stage III breast cancer, and provide selective criteria for COX2 inhibitor combinations for invasive breast cancer therapy. PMID- 21533533 TI - PAPP-A levels of late pregnancy in preeclampsia and HELLP syndrome. AB - PURPOSE: To determine the relationship between pregnancy-associated plasma protein-A (PAPP-A) levels and preeclampsia and HELLP syndrome at last trimester and to investigate if the severity of preeclampsia would be associated with PAPP A levels. METHODS: Four groups were constructed; mild-preeclampsia group consisted of 19 women, severe-preeclampsia group 17, HELLP group 5 and control group 32 women. All groups were matched strictly for gestational age at last trimester. Maternal blood samples for PAPP-A were collected as soon as the patients were diagnosed as preeclampsia or HELLP syndrome at last trimester and compared. RESULTS: Mean ages of participants, parity, gestational week, and fetal weights were similar. Mean PAPP-A levels were significantly higher in preeclampsia and HELLP groups compared to control group. PAPP-A levels were not different among mild-severe preeclampsia and HELLP groups. There was significant, positive and strong correlation between gestational age and PAPP-A level and also between fetal weight and PAPP-A levels (correlation coefficents = 0.83 and 0.78 respectively). CONCLUSION: PAPP-A level at last trimester increases in all mild severe preeclampsia and HELLP syndrome, but is not predictive for severity of preeclampsia or HELLP syndrome. PMID- 21533534 TI - Rotator cuff re-tear or non-healing: histopathological aspects and predictive factors. AB - PURPOSE: The aim of the study was to evaluate the histopathological changes that occur in the tendon and subacromial bursal tissue in patients with rotator cuff tear trying to correlate these changes to their healing capability. METHODS: Eighty-four patients were clinically evaluated with the Constant Scale. Radiographs and MRI were performed preoperatively and ultrasound were performed postoperatively. For each patient, a biopsy of the supraspinatus tendon and subacromial bursa was performed, and the specimens were histopathologically analyzed. RESULTS: Tendons histopathological features consisted of loss of structural organization, poor or absent neoangiogenesis, chondral metaplasia, and fibrosis. Bursal features consisted of neoangiogenesis, absence of chondral metaplasia, hyperplasia/hypertrophy, and absence of necrosis. Direct correlation was seen between tendon and bursal hyperplasia and time of the onset of symptoms; between tendon chondral metaplasia, fibrosis, bursal neoangiogenesis, inflammation, and patient age; between tendon neoangiogenesis, hyperplasia, necrosis, fibrosis, bursal necrosis, inflammation, and lesion size; on the contrary, tendon fibrosis, necrosis, and bursal tissue inflammation decrease as time passes from the onset of symptoms. Tendon fibers disarray, neoangiogenesis, and inflammation decreases as the patient's age increases. Bursal tissue fibrosis decreases as lesion size increases. CONCLUSIONS: Simple histopathological techniques should be employed routinely to assess the tissue quality, with the aim to predict future clinical evolution (repair or non-repair). Comparing the histopathological data with the demographical information and the descriptive statistics, it is possible to define the RCT repair at risk and identify which RCT will be able to heal. PMID- 21533535 TI - The effect of multiple channeling on the structural integrity of repaired rotator cuff. AB - PURPOSE: The purpose of this study was to investigate the effect of adding multiple channeling of the greater tuberosity on the structural integrity of the repaired rotator cuff tendon. METHODS: Fifty-six consecutive patients who underwent arthroscopic rotator cuff repair and postoperative computed tomography arthrography (CTA) were included in this study; 31 consecutive patients that underwent conventional repair and 25 subsequent patients that underwent conventional repair with multiple channeling. Using CTA, the repaired rotator cuff was evaluated as either intact, incomplete, or complete leakage at the insertion and in the tendon separately. The integrity type and overall integrity was then determined by the combination of the insertion and tendon grade. Factors affecting integrity were also evaluated. RESULTS: At the insertion, multiple channeling significantly improved integrity; complete leakage in 35.5% in the conventional group and 4.0% in the multiple channeling group (P = 0.017). In the tendon, no significant difference was observed between the two groups. Integrity types were significantly different between the two groups (P = 0.009). For overall integrity, discontinuity was more frequently identified in the conventional group (35.5%) than in the multiple channeling group (16.0%), but it was not statistically significant. With regard to causes of discontinuity, all were due to retears in the conventional group, while 75% were due to new tears in the multiple channeling group (P = 0.009). CONCLUSION: Multiple channeling is simple and easily performed without any special instrument and might augment the healing of repaired rotator cuff tendons. It could be a useful technique in rotator cuff repair helping healing. PMID- 21533536 TI - The superficial medial collateral ligament reconstruction of the knee: effect of altering graft length on knee kinematics and stability. AB - PURPOSE: The purpose of this study was to evaluate and compare the resulting knee kinematics and stability of an anatomic superficial MCL (sMCL) reconstruction and a non-anatomic sMCL reconstruction. METHODS: In a cadaveric model, normal knee stability and kinematics were compared with sMCL deficient knees and with two experimental sMCL reconstructions. The first reconstruction (AnatRecon) attempted to anatomically reconstruct the sMCL. The second reconstruction (ShortRecon) used a shorter graft to mimic the effect of failing to reproduce the anatomic length of the sMCL. Changes in position of the femur with respect to the tibia were measured with an electromagnetic tracking system during simulated active knee extension and during passive knee stability testing in the sMCL intact knee, the sMCL deficient knee, and the two experimental reconstructions. RESULTS: Simulated active knee extension demonstrated a significant increase in external tibial rotation of ShortRecon compared to AnatRecon between 30 degrees and 80 degrees of knee flexion (mean difference <3.0 degrees over the range of knee flexion angles; P < 0.008), and a significant increase in external tibial rotation of ShortRecon compared to the intact sMCL was found at 60 degrees and 70 degrees of knee flexion (mean difference <2.0 degrees over the range of knee flexion angles; P < 0.008). Passive joint stability testing demonstrated that division of the sMCL produced approximately 6 degrees of valgus laxity at 30 degrees of knee flexion and increased external tibial rotation of approximately 5 degrees at 30 degrees , 9 degrees at 60 degrees , and 10 degrees at 90 degrees of knee flexion, respectively. AnatRecon restored normal knee kinematics and stability. Additionally, passive stability testing demonstrated a significant increase in external tibial rotation of ShortRecon compared to AnatRecon at 60 degrees (mean difference = 3.7 degrees ; P < 0.05) and 90 degrees of knee flexion (mean difference = 4.9 degrees ; P < 0.05). CONCLUSION: Anatomic reconstruction of the sMCL effectively restored knee kinematics and stability in the sMCL deficient knee. Altering the normal ligament length resulted in measurable changes in knee kinematics and stability. This study suggests that in cases of chronic valgus knee instability, anatomic sMCL reconstruction would provide better results than non-anatomic sMCL reconstruction. PMID- 21533537 TI - Clinical outcomes of medial patellofemoral ligament repair in recurrent (chronic) lateral patella dislocations. AB - PURPOSE: The specific aim of this project was to review a homogenous group of patients who had chosen to undergo medial patellofemoral ligament (MPFL) repair to stabilize their patella after repeat (chronic) patellofemoral dislocations and to record the success of this procedure in stabilizing the patella against further lateral dislocations. METHODS: This is a retrospective study of 55 knees in 48 patients who underwent a repair of the medial patellofemoral ligament by a single surgeon over a 4-year period. The endpoint of the study was a documented patellofemoral dislocation or a minimum 2-year follow-up. RESULTS: Fifty-five knees in 48 patients underwent a MPFL repair/reattachment. Patella alta, as defined by the Insall-Salvati (I/S) ratio, was within normal limits in 6 (14%). The I/S ratio was greater than 1.2 in 38 patients (86%) and greater than 1.4 in 23 patients (52%). Trochlear dysplasia as defined by a positive crossing sign on a true lateral radiograph and/or a sulcus angle on axial view of greater than 145 was present in 45/47 (96%). Successful management of the knee as defined by no further patella dislocation occurred in 22 knees. Nineteen knees sustained a redislocation event (46%). CONCLUSIONS: The surgical procedure of operative repair (reattachment) of the MPFL to its femoral attachment had a significantly high rate of failure in this patient group of chronic (repeat) lateral patellar dislocators. PMID- 21533538 TI - MRI analysis of the attachment of the anteromedial and posterolateral bundles of anterior cruciate ligament using coronal oblique images. AB - PURPOSE: The purpose of this study was to evaluate the course of the anteromedial bundle (AMB) and the posterolateral bundle (PLB) of the anterior cruciate ligament (ACL) with magnetic resonance imaging (MRI) in order to clarify the relationship between the bundles and surrounding anatomic landmarks. METHODS: Eighty-eight knees with intact ACLs were included in this study. MRI coronal oblique images were obtained with the knee in extension and used to assess the following characteristics of the AMB and PLB: (1) course of the ligament, (2) location of the tibial attachment, and (3) femoral attachment and geometry of the lateral femoral condyle inner wall. RESULTS: In terms of the tibial attachment, the AMB was confluent with the apex of the medial intercondylar ridge (MIR) in all cases. Sixty-five PLBs (74%) inserted into the region between the apex and the slope of the MIR. The resident's ridge was detected in 91% of the knees in the AMB image, whereas the ridge was clearly visualized in only 17% of the knees in the PLB image. A bony eminence was observed at the inner articular margin of the lateral femoral condyle in the PLB image. CONCLUSION: In terms of the tibial attachment, the AMB was confluent with the apex of the medial intercondylar ridge in all cases. Most of the PLBs attached to the region between the apex and the slope of the MIR. Because the bone tunnel location influences clearance between the grafts and the surrounding tissues, these results should be considered during anatomic double-bundle ACL reconstruction. PMID- 21533539 TI - Major functional deficits persist 2 years after acute Achilles tendon rupture. AB - PURPOSE: The purpose of this prospective randomized controlled study was to evaluate the long-term results after an acute Achilles tendon rupture in patients treated surgically or non-surgically. The focus was to evaluate whether any improvements occurred between the one and 2-year evaluation. METHOD: Eighty-one patients (67 men, 14 women) with a mean (SD) age of 42 (9.1) were included in this study. Forty-two patients were treated surgically, and 39 treated non surgically otherwise the treatment was identical for the two groups. All patients were evaluated using the Achilles tendon Total Rupture Score (ATRS), the Physical Activity Scale (PAS) and validated functional tests one and 2 years after injury. RESULTS: There were significant functional deficits on the injured side compared with the contralateral side 2 years after Achilles tendon rupture, regardless of treatment. Only minor improvements, even though statistically significant, occurred between the 1- and 2-year evaluations. The physical activity level remained significantly reduced as compared with prior to injury, but the ATRS mean was relatively high in both groups (89 and 90). CONCLUSION: This long-term follow-up indicates that the majority of patients with an Achilles tendon rupture have not fully recovered (in regards to symptoms, physical activity level and function) 2 years after injury regardless of surgical or non-surgical treatment. Furthermore, only minor improvements occur between the 1- and 2-year evaluations. This indicates that to enhance the final outcome the focus should be on improvements in treatment within the first year. The patients appear to have adjusted to their impairments since the patient-reported outcome is relatively high in spite of functional deficits and lower activity level compared with pre injury. LEVEL OF EVIDENCE: Prospective randomized study, Level I. PMID- 21533540 TI - Patellofemoral evaluation with magnetic resonance imaging in 51 knees of asymptomatic subjects. AB - PURPOSE: The objective of this study is to evaluate patellofemoral joint imaging on magnetic resonance imaging (MRI) in asymptomatic subjects to assess normal values and to test statistical correlation and reliability of MRI scan. METHODS: An analysis of 51 standard MRI examinations was performed. Sulcus angle (SA), patellar axis (PA), lateral patellofemoral angle (LPFA), and lateral patellofemoral length (LPL) were measured. None of the patients suffered from patellofemoral complaints. Patients with patella alta and significant hydrops were excluded. The measurements were assessed with a 2-week interval by two raters under blinded conditions. Statistical analysis was applied by an independent analyst. RESULTS: The mean SA referenced 142.4 +/- 6.9 degrees , PA 5.3 +/- 3.8 degrees , LPFA 13 +/- 4.4 degrees , and LPL 0.8 +/- 2.9 mm. Inter observer variability showed high correlation for LPL and PA, as the repeatability coefficient was high (LPL; 1.49 (LN), 5.7 (ST) and PA; 4.1 (LN), 5.8 (ST). Also, intra-observer variability showed good correlation for LPL and PA. CONCLUSION: The results represent patellofemoral values in the normal population. They indicate that MRI is a reliable imaging technique to determine lateral patellofemoral length and patellar axis. Lateral patellofemoral angle and sulcus angle showed a poor correlation and should not be used for decision making. LEVEL OF EVIDENCE: Development of diagnostic criteria in a consecutive series of patients and a universally applied "gold" standard, Level II. PMID- 21533542 TI - Synaptic Wnt signaling-a contributor to major psychiatric disorders? AB - Wnt signaling is a key pathway that helps organize development of the nervous system. It influences cell proliferation, cell fate, and cell migration in the developing nervous system, as well as axon guidance, dendrite development, and synapse formation. Given this wide range of roles, dysregulation of Wnt signaling could have any number of deleterious effects on neural development and thereby contribute in many different ways to the pathogenesis of neurodevelopmental disorders. Some major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders, are coming to be understood as subtle dysregulations of nervous system development, particularly of synapse formation and maintenance. This review will therefore touch on the importance of Wnt signaling to neurodevelopment generally, while focusing on accumulating evidence for a synaptic role of Wnt signaling. These observations will be discussed in the context of current understanding of the neurodevelopmental bases of major psychiatric diseases, spotlighting schizophrenia, bipolar disorder, and autism spectrum disorder. In short, this review will focus on the potential role of synapse formation and maintenance in major psychiatric disorders and summarize evidence that defective Wnt signaling could contribute to their pathogenesis via effects on these late neural differentiation processes. PMID- 21533543 TI - The emerging role of mammalian target of rapamycin inhibitors in the treatment of sarcomas. AB - The mammalian target of rapamycin (mTOR) is a protein kinase that functions as a key regulator of cell growth, proliferation and differentiation, cell-cycle progression, angiogenesis, protein degradation, and apoptosis. Following activation by a number of oncogenic signals such as growth factors, energy and nutrients, mTOR stimulates several downstream effectors including the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4 E binding protein-1 (4 EBP-1), as well as a complex network of regulatory loops. Activation of the mTOR pathway plays a critical role in the development of many tumor types, including renal cell and breast carcinomas, neuroendocrine tumors, and sarcomas. Bone and soft tissue sarcomas are rare, heterogeneous tumors that are curable by local treatments if diagnosed at early stages; however advanced or metastatic sarcomas are rarely curable and very few drugs are efficacious in this setting. Several disruptions in phosphatidylinositol-3 kinase (PI3K)-Akt-mTOR signaling are associated with malignant transformation or progression in various sarcoma sub-types. The PI3K-Akt-mTOR pathway is therefore an exciting target for therapy of sarcomas, and its blockade represents an opportunity to improve outcomes in this poor-prognosis disease. Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments. This article discusses the mTOR signaling pathway and summarizes the clinical experience with mTOR inhibitors in patients with advanced or metastatic sarcoma. PMID- 21533544 TI - Predictive biomarkers for the activity of mammalian target of rapamycin (mTOR) inhibitors. AB - In the quest for personalized medicine, only a few biological parameters are routinely used to select patients prior to the initiation of anticancer targeted therapies, including mTOR inhibitors. Identifying biological factors that may predict efficacy or resistance to mTOR inhibitors represents an important challenge since rapalogs may exert antitumor effects through multiple mechanisms of action. Despite the fact that no such a factor is currently available, several molecular patterns are emerging, correlating with sensitivity and/or resistance to rapalogs. While activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, overexpression of cyclin D1, and functional apoptosis seem to sensitize tumor cells to rapalogs, Bcl2 overexpression or KRAS mutations are reported to be associated with resistance to mTOR inhibitors in several preclinical models. Translational research aimed at validating those parameters in clinical trials is ongoing. PMID- 21533545 TI - Identification of novel subregions of LOH in gastric cancer and analysis of the HIC1 and TOB1 tumor suppressor genes in these subregions. AB - Previously, we identified 3 overlapping regions showing loss of heterozygosity (LOH, R(1)-R(3) from 11 to 30 cM) on chromosome 17 in 45 primary gastric cancers (GCs). The data indicated the presence of tumor suppressor genes (TSGs) on chromosome 17 involved in GC. Among the putative TSGs in these regions, HIC1 (in SR(1)) and TOB1 (in SR(3)) remain to be examined in GC. By immunohistochemistry (IHC), methylation-specific PCR (MSP) and western blot, we evaluated the expression and regulation status for HIC1 and TOB1 protein in GC. We narrowed down the deletion intervals on chromosome 17 and defined five smaller LOH subregions, SR(1)-SR(5) (0.54 to 3.42 cM), in GC. We found that HIC1 had downregulated expression in 86% (91/106) and was methylated in 87% (26/30) of primary GCs. Of the primary GCs showing downregulation of HIC1 protein, 75% (18/24) had methylated HIC1 gene. TOB1 was either absent or expressed at reduced levels in 75% (73/97) of the GC samples. In addition, a general reduction was found in total and the ratio of unphosphorylated to phosphorylated TOB1 protein levels in the differentiated GC cell lines. Further analysis revealed significant simultaneous downregulation of both HIC1 and TOB1 protein in GC tissue microarray samples (67%, 52/78) and in primary GCs (65%, 11/17). These results indicate that silencing of HIC1 and TOB1 expression is a common occurrence in GC and may contribute to the development and progression of the disease. PMID- 21533546 TI - Neural Wiskott-Aldrich syndrome protein is required for accurate chromosome congression and segregation. AB - The accurate distribution and segregation of replicated chromosomes through mitosis is crucial for cellular viability and development of organisms. Kinetochores are responsible for the proper congression and segregation of chromosomes. Here, we show that neural Wiskott-Aldrich syndrome protein (N-WASP) localizes to and forms a complex with kinetochores in mitotic cells. Depletion of NWASP by RNA interference causes chromosome misalignment, prolonged mitosis, and abnormal chromosomal segregation, which is associated with decreased proliferation of N-WASP-deficient cells. N-WASP-deficient cells display defects in the kinetochores recruitment of inner and outer kinetochore components, CENP A, CENP-E, and Mad2. Live-cell imaging analysis of GFP-alpha-tubulin revealed that depletion of N-WASP impairs microtubule attachment to chromosomes in mitotic cells. All these results indicate that N-WASP plays a role in efficient assembly of kinetochores and attachment of microtubules to chromosomes, which is essential for accurate chromosome congression and segregation. PMID- 21533547 TI - Hypoxia inducible factor-1alpha directly induces the expression of receptor activator of nuclear factor-kappaB ligand in periodontal ligament fibroblasts. AB - During orthodontic tooth movement, local hypoxia and enhanced osteoclastogenesis are observed in the compression side of periodontal tissues. The receptor activator of nuclear factor-kappaB ligand (RANKL) is an osteoblast/stromal cell derived factor that is essential for osteoclastogenesis. In this study, we examined the effect of hypoxia on RANKL expression in human periodontal ligament fibroblasts (PDLFs) to investigate the relationship between local hypoxia and enhanced osteoclastogenesis in the compression side of periodontal tissues. Hypoxia significantly enhanced the levels of RANKL mRNA and protein as well as hypoxia inducible factor-1alpha (HIF-1alpha) protein in PDLFs. Constitutively active HIF-1alpha alone significantly increased the levels of RANKL expression in PDLFs under normoxic conditions, whereas dominant negative HIF-1alpha blocked hypoxia-induced RANKL expression. To investigate further whether HIF-1alpha directly regulates RANKL transcription, a luciferase reporter assay was performed using the reporter vector containing the RANKL promoter sequence. Exposure to hypoxia or overexpression of constitutively active HIF-1alpha significantly increased RANKL promoter activity, whereas dominant negative HIF-1alpha blocked hypoxia-induced RANKL promoter activity. Furthermore, mutations of putative HIF 1alpha binding elements in RANKL promoter prevented hypoxia-induced RANKL promoter activity. The results of chromatin immunoprecipitation showed that hypoxia or constitutively active HIF-1alpha increased the DNA binding of HIF 1alpha to RANKL promoter. These results suggest that HIF-1alpha mediates hypoxia induced up-regulation of RANKL expression and that in compression side periodontal ligament, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in PDLFs. PMID- 21533548 TI - Identification of proteins differentially expressed in gastric cancer cells with high metastatic potential for invasion to lymph nodes. AB - In a search for proteins involved in cancer metastasis, we analyzed proteomes of the human gastric cancer cell OCUM-2M and its metastatic subline OCUM-2MLN. We observed that aspartate aminotransferase (AAT), D-site binding protein (DBP), and anterior gradient protein 2 (AGR2) are differentially expressed in metastatic OCUM-2MLN cells. Measurement of protein expression in clinical samples indicated that DBP and AAT are also down-regulated in metastatic adenocarcinoma. Additionally, urokinase-type tissue plasminogen activator is up-regulated in OCUM 2MLN cells and also in metastatic gastric cancer samples. Collectively, these results raise a possibility that AAT, DBP and AGR2 are functionally implicated in the invasiveness of gastric cancer cells. PMID- 21533549 TI - The role of the miR399-PHO2 module in the regulation of flowering time in response to different ambient temperatures in Arabidopsis thaliana. AB - A moderate change in ambient temperature significantly affects plant physiology including flowering time. MiR399 and its target gene PHOSPHATE 2 (PHO2) are known to play a role in the maintenance of phosphate homeostasis. However, the regulation of flowering time by the miR399-PHO2 module has not been investigated. As we have previously identified miR399 as an ambient temperature-responsive miRNA, we further investigated whether a change in expression of the miR399-PHO2 module affects flowering time in response to ambient temperature changes. Here, we showed that miR399b-overexpressing plants and a loss-of-function allele of PHO2 (pho2) exhibited an early flowering phenotype only at normal temperature (23 degrees C). Interestingly, their flowering time at lower temperature (16 degrees C) was similar to that of wild-type plants, suggesting that alteration in flowering time by miR399 and its target PHO2 was seen only at normal temperature (23 degrees C). Flowering time ratio (16 degrees C/23 degrees C) revealed that miR399b-overexpressing plants and pho2 mutants showed increased sensitivity to ambient temperature changes. Expression analysis indicated that expression of TWIN SISTER OF FT (TSF) was increased in miR399b-overexpressing plants and pho2 mutants at 23 degrees C, suggesting that their early flowering phenotype is associated with TSF upregulation. Taken together, our results suggest that miR399, an ambient temperature-responsive miRNA, plays a role in ambient temperature-responsive flowering in Arabidopsis. PMID- 21533551 TI - Mapping signals that are important for nuclear and nucleolar localization in MCRS2. AB - MCRS2 is an oncoprotein that is sequestered in the nucleolus. When in the nucleolus, it promotes the transcription of the rRNA gene. MCRS2 also brings proteins into the nucleolus to change their function. This study analyzes the sequence of MCRS2 and determines that the nuclear localization signal, which has the sequence KRKK, is situated between amino acids 66 and 69. Meanwhile, MCRS2 contains a bipartite nucleolar localization signal, which comprises a KKSK motif, located between amino acids 133 and 136, and a downstream 152-amino acid region, from amino acid 314 to 465. The results of this study are important to understand the function of MCRS2. PMID- 21533550 TI - Identification and characterization of the duplicate rice sucrose synthase genes OsSUS5 and OsSUS7 which are associated with the plasma membrane. AB - Systematic searches using the complete genome sequence of rice (Oryza sativa) identified OsSUS7, a new member of the rice sucrose synthase (OsSUS) gene family, which shows only nine single nucleotide substitutions in the OsSUS5 coding sequence. Comparative genomic analysis revealed that the synteny between OsSUS5 and OsSUS7 is conserved, and that significant numbers of transposable elements are scattered at both loci. In particular, a 17.6-kb genomic region containing transposable elements was identified in the 5' upstream sequence of the OsSUS7 gene. GFP fusion experiments indicated that OsSUS5 and OsSUS7 are largely associated with the plasma membrane and partly with the cytosol in maize mesophyll protoplasts. RT-PCR analysis and transient expression assays revealed that OsSUS5 and OsSUS7 exhibit similar expression patterns in rice tissues, with the highest expression evident in roots. These results suggest that two redundant genes, OsSUS5 and OsSUS7, evolved via duplication of a chromosome region and through the transposition of transposable elements. PMID- 21533554 TI - Loss of legs: is it or not a handicap for an orb-weaving spider? AB - Leg loss is a common phenomenon in spiders, and according to the species 5% to 40% of the adults can present at least one missing leg. There is no possibility of regeneration after adult moult and the animal must manage with its missing appendages until its death. With the loss of one or more legs, female orb-weaving spiders can be penalized twice: firstly, because the legs are necessary for web construction and secondly, the legs are essential for the control of the prey after its interception by the web. During development, spiders may be also penalized because regeneration has energetic costs that take away resources for survival, growth and reproduction. All these consequences should influence negatively the development of the spider and thus its fitness. We investigated the impact of leg loss in the orb-weaving spider, Zygiella x-notata by studying its frequency in a natural population and web building and prey capture behaviours in laboratory. In field populations, 9.5% to 13%, of the adult females presented the loss of one or more legs; the majority of individuals had lost only one leg (in 48% of cases, a first one). Leg loss seems to affect all the adult spiders, as there is no difference of mass between intact spiders and those with missing leg. Data obtained with laboratory-reared spiders, showed that the loss of legs due to the moult is rare (less than 1%). Considering changes in web design, spiders with missing legs decreased their silk investment, increased the distance between spiral turns but did not change the capture surface of the web. Under our laboratory experimental conditions, spiders with one or two lost legs did not present any difference in prey capture efficiency. In laboratory conditions, spiders with lost leg(s) did not show any difference in egg sac production or in longevity (adult lifespan) compared to intact spiders. PMID- 21533552 TI - Kinetics of the cell biological changes occurring in the progression of DNA damage-induced senescence. AB - Cellular senescence is characterized by cell-cycle arrest accompanied by various cell biological changes. Although these changes have been heavily relied on as senescence markers in numerous studies on senescence and its intervention, their underlying mechanisms and relationship to each other are poorly understood. Furthermore, the depth and the reversibility of those changes have not been addressed previously. Using flow cytometry coupled with confocal microscopy and Western blotting, we quantified various senescence-associated cellular changes and determined their time course profiles in MCF-7 cells undergoing DNA damage induced senescence. The examined properties changed with several different kinetics patterns. Autofluorescence, side scattering, and the mitochondria content increased progressively and linearly. Cell volume, lysosome content, and reactive oxygen species (ROS) level increased abruptly at an early stage. Meanwhile, senescence associated beta-galactosidase activity increased after a lag of a few days. In addition, during the senescence progression, lysosomes exhibited a loss of integrity, which may have been associated with the accumulation of ROS. The finding that various senescence phenotypes matured at different rates with different lag times suggests multiple independent mechanisms controlling the expression of senescence phenotypes. This type of kinetics study would promote the understanding of how cells become fully senescent and facilitate the screening of methods that intervene in cellular senescence. PMID- 21533553 TI - Oxidative stress mediates chemical hypoxia-induced injury and inflammation by activating NF-kappab-COX-2 pathway in HaCaT cells. AB - Hypoxia of skin is an important physiopathological process in many diseases, such as pressure ulcer, diabetic ulcer, and varicose ulcer. Although cellular injury and inflammation have been involved in hypoxia-induced dermatic injury, the underlying mechanisms remain largely unknown. This study was conducted to investigate the effects of cobalt chloride (CoCl(2)), a hypoxia-mimicking agent, on human skin keratinocytes (HaCaT cells) and to explore the possible molecular mechanisms. Exposure of HaCaT cells to CoCl(2) reduced cell viability and caused overproduction of reactive oxygen species (ROS) and oversecretion of interleukin 6 (IL-6) and interleukin-8 (IL-8). Importantly, CoCl(2) exposure elicited overexpression of cyclooxygenase-2 (COX-2) and phosphorylation of nuclear factor kappa B (NF-kappaB) p65 subunit. Inhibition of COX-2 by NS-398, a selective inhibitor of COX-2, significantly repressed the cytotoxicity, as well as secretion of IL-6 and IL-8 induced by CoCl(2). Inhibition of NF-kappaB by PDTC (a selective inhibitor of NF-kappaB) or genetic silencing of p65 by RNAi (Si-p65), attenuated not only the cytotoxicity and secretion of IL-6 and IL-8, but also overexpression of COX-2 in CoCl(2)-treated HaCaT cells. Neutralizing anti-IL-6 or anti-IL-8 antibody statistically alleviated CoCl(2)-induced cytotoxicity in HaCaT cells. N-acetyl-L-cysteine (NAC), a well characterized ROS scavenger, obviously suppressed CoCl(2)-induced cytotoxicity in HaCaT cells, as well as secretion of IL-6 and IL-8. Additionally, NAC also repressed overexpression of COX-2 and phosphorylation of NF- B kappa p65 subunit induced by CoCl(2) in HaCaT cells. In conclusion, our results demonstrated that oxidative stress mediates chemical hypoxia-induced injury and inflammatory response through activation of NF-kappaB COX-2 pathway in HaCaT cells. PMID- 21533555 TI - A co-culture system with preantral follicular granulosa cells in vitro induces meiotic maturation of immature oocytes. AB - Development of technologies to mature oocytes in vitro is important for in vitro fertilization research. Here, we investigated the ability of preantral follicular granulosa cells (PAGCs) to restrain apoptosis and to promote the growth and meiotic resumption of immature murine oocytes in vitro. The oocytes of 55-65 MUm derived from 12 to 14 days old juvenile mice were co-cultured with PAGCs in vitro. The results showed that the oocytes co-cultured with PAGCs for 7 days grew faster and 14.6% of immature oocytes were able to complete the first meiotic division and arrive at the MII stage. 71 oocytes co-cultured with PAGCs were fertilized and 16 embryos were able to form morula-blastocysts. Following the co culture of immature oocytes with/without PAGCs for 7 days, the percentage of apoptotic oocytes were 33.5 and 51.4%, respectively (p < 0.01). Furthermore, the inhibition of apoptosis was communicated between oocytes and PAGCs through the GDF9-PI3 K-Akt signaling pathway. In conclusion, the co-culture with PAGCs has a beneficial effect on the growth and maturation of immature oocytes. PMID- 21533556 TI - Differential integration of visual and kinaesthetic signals to upright stance. AB - The present experiment was designed to assess the effect of active (deliberate) maintenance of a small forward (FL) or backward body lean (BL) (about 2 degrees ankle flexion) with respect to the spontaneous direction of balance (or neutral posture, N) on postural balance. We questioned whether BL and FL stances, which impose a volitional proprioceptive control of the body-on-support angle, could efficiently reduce mediolateral displacements of the centre of pressure (CoP) induced by the visual motion of a room and darkness. Subjects (n = 15) were asked to stand upright quietly feet together while confronted to a large visual scene rolling to 10 degrees on either side in peripheral vision (and surrounding vertical visual references in central vision) at 0.05 Hz. CoP displacements were recorded using a force platform. Analysis of medio-lateral CoP root-mean square showed that the effect of the moving room depends on the subject's postural stability performance in the eyes open N stance condition. Two significant postural behaviours emerged. (1) The most stable subjects (G1) were not affected by the conditions of altered vision, but swayed more in BL stance than in the N stance. (2) The unstable subjects (G2) exhibited (i) larger CoP displacements in altered visual conditions and a greater coupling of the CoP with the motion of the visual scene, (ii) enhanced visual dependency with postural leaning, and (iii) decreased CoP displacements when leaning forward in the eyes open motionless scene. Interestingly, the visual quotient positively correlated with the proprioceptive quotient, indicating that the more the subjects relied heavily on the visual frame of reference (FOR) the more they were influenced by body leaning. This result suggested hence a lesser ability to use efficiently body ground proprioceptive cues. On the whole, the present findings indicate that body leaning could provide a useful mean to assess the subject's ability to use body ground proprioceptive cues not only to improve postural stability during eyes opening (especially during forward leaning), but also as a mean to disclose subjects' visual dependency and their associated difficulties to shift from visual to proprioceptive-based FOR. PMID- 21533557 TI - Covert motor activity on NoGo trials in a task sharing paradigm: evidence from the lateralized readiness potential. AB - Previous studies on task sharing propose that a representation of the co-actor's task share is generated when two actors share a common task. An important function of co-representation seems to lie in the anticipation of others' upcoming actions, which is essential for one's own action planning, as it enables the rapid selection of an appropriate response. We utilized measures of lateralized motor activation, the lateralized readiness potential (LRP), in a task sharing paradigm to address the questions (1) whether the generation of a co representation involves motor activity in the non-acting person when it is other agent's turn to respond, and (2) whether co-representation of the other's task share is generated from one's own egocentric perspective or from the perspective of the actor (allocentric). Results showed that although it was the other agent's turn to respond, the motor system of the non-acting person was activated prior to the other's response. Furthermore, motor activity was based on egocentric spatial properties. The findings support the tight functional coupling between one's own actions and actions produced by others, suggesting that the involvement of the motor system is crucial for social interaction. PMID- 21533558 TI - Adventitious sporulation in Fusarium keratitis. PMID- 21533559 TI - Early histological alteration of the retina following photocoagulation treatment in diabetic retinopathy as measured by spectral-domain optical coherence tomography. PMID- 21533560 TI - Prospects for laser-induced breakdown spectroscopy for biomedical applications: a review. AB - We review the different spectroscopic techniques including the most recent laser induced breakdown spectroscopy (LIBS) for the characterization of materials in any phase (solid, liquid or gas) including biological materials. A brief history of the laser and its application in bioscience is presented. The development of LIBS, its working principle and its instrumentation (different parts of the experimental set up) are briefly summarized. The generation of laser-induced plasma and detection of light emitted from this plasma are also discussed. The merit and demerits of LIBS are discussed in comparison with other conventional analytical techniques. The work done using the laser in the biomedical field is also summarized. The analysis of different tissues, mineral analysis in different organs of the human body, characterization of different types of stone formed in the human body, analysis of biological aerosols using the LIBS technique are also summarized. The unique abilities of LIBS including detection of molecular species and calibration-free LIBS are compared with those of other conventional techniques including atomic absorption spectroscopy, inductively coupled plasma atomic emission spectroscopy and mass spectroscopy, and X-ray fluorescence. PMID- 21533561 TI - A fatal case of Churg-Strauss syndrome presenting with acute polyneuropathy mimicking Guillain-Barre syndrome. AB - A 64-year-old woman, with asthma and sinusal polyposis in her history, suddenly developed a painful polyneuropathy with diplopia. Nerve conduction studies, performed at the very onset of the neuropathy, could not definitely rule out a Guillain-Barre syndrome (GBS) and high-dose i.v. immunoglobulins were administered. Clinical and laboratory findings subsequently supported the diagnosis of Churg-Strauss syndrome; corticosteroid therapy was started and clinical stabilisation of neuropathy was apparently achieved. No indicators of unfavourable outcome were present at that time. Nevertheless, 30 days after the onset the patient acutely worsened with severe polyneuropathy relapse and fatal systemic diffusion to heart, kidney and mesenteric district, which a single cyclophosphamide pulse failed to control. This case highlights the possibility that a GBS-like onset of Churg-Strauss syndrome neuropathy should be regarded as a part of multiorgan, severe or even life-threatening vasculitic involvement, requiring the most aggressive treatments, regardless of the presence of recognised factors of poor outcome. PMID- 21533562 TI - Septo-optic dysplasia-plus and dyskinetic cerebral palsy in a child. AB - Septo-optic dysplasia (SOD), also called De Morsier's syndrome, is a highly heterogeneous condition comprising a spectrum of central nervous system malformations that involves in various degrees the optic nerves, the hypothalamic pituitary axis, and other midline structures such as the septum pellucidum and the corpus callosum. In a discrete number of cases, schizencephaly, agenesis of the corpus callosum or other cortical malformations are associated (SOD-plus). The authors present a 6-year-old boy with dyskinetic cerebral palsy (athetoid dystonic subtype) associated with SOD-plus. Cranial magnetic resonance imaging (cMRI) revealed the total absence of septum pellucidum, optic nerve hypoplasia, hypoplasia of the corpus callosum and right occipital cortical dysplasia. The patient was diagnosed with septo-optic dysplasia-plus syndrome based on the cMRI findings. To the best of our knowledge, this is the first reported case in which defects of midline brain structures, like in SOD-plus, are associated with a significant hyperkinetic movement disorder such as dyskinesia. PMID- 21533563 TI - Acute medical complications in patients admitted to a stroke unit and safe transfer to rehabilitation. AB - Acute medical complications often prevent patients with stroke from being transferred from stroke units to rehabilitation units, prolonging the occupation of hospital beds and delaying the start of intensive rehabilitation. This study defined incidence, timing, duration and risk factors of these complications during the acute phase of stroke. A retrospective case note review was made of hospital admissions of patients with stroke not associated with other disabling conditions, admitted to a stroke unit over 12 months and requiring rehabilitation for gait impairment. In this cohort, a search was made of hypertension, oxygen de saturation, fever, and cardiac and pulmonary symptoms requiring medical intervention. Included were 135 patients. Hypertension was the most common complication (16.3%), followed by heart disease (14.8%), oxygen de-saturation (7.4%), fever (6.7%) and pulmonary disease (5.2%). Heart disease was the earliest and shortest complication. Most complications occurred during the first week. Except for hypertension, all complications resolved within 2 weeks. PMID- 21533564 TI - Prevalence of bifid median nerve at wrist assessed through ultrasound. AB - We performed a prospective study to evaluate the prevalence of bifid median nerve (BMN) and if it has a higher prevalence in carpal tunnel syndrome (CTS) patients than symptom-free subjects. We evaluated by ultrasound (US) 162 median nerves at wrist of 89 consecutive patients with symptoms suggestive of CTS and 104 of 52 consecutive symptom-free subjects. Neurophysiological evaluation confirmed CTS diagnosis. All patients underwent ultrasonographic evaluation of median nerve in the elbow-palm segment through high-frequency probe; BMN was arbitrarily classified as "complete" and "incomplete" on the basis of US results. BMN was observed in 16/104 wrists (15.4%) in control group and in 30/162 (18.5%) wrists in CTS group. Our study showed that BMN is frequent, not always bilateral, more often is "incomplete" and it has similar prevalence in CTS and control group. These findings suggest that BMN is not a risk factor of developing CTS. PMID- 21533565 TI - Multiple intracranial capillary hemangiomas and transient cerebrovascular insufficiency. AB - Hemangiomas constitute a heterogeneous group of benign vascular proliferations of skin and mucous membranes and very rarely known to develop in the brain or spinal cord. We report here a case of multiple intracranial capillary hemangiomas presenting with transient neurological deficit. The patient underwent stealth MRI brain utilizing 15 ml of Magnevist for stereotactic localization and biopsy was done to establish the diagnosis. It is pivotal to differentiate benign hemangiomas from primary cerebral vascular tumors including hemangioblastoma, hemangioendothelioma and hemangiopericytoma, as later are known for more aggressive biologic behavior. PMID- 21533566 TI - [Intraoperative interruption of an accessory pathway: is it always a long-term cure for arrhythmia?]. AB - We report the case of a male patient who had undergone successful cardiac surgery about 20 years previously for a posteroseptal accessory pathway that caused almost incessant orthodromic AV reentrant tachycardia, but presented again recently with new onset cardiac arrhythmia. 3D mapping demonstrated scar-related reentrant tachycardia in the right atrium with a critical isthmus between the atriotomy scar and terminal crest, which could be successfully treated using irrigated-tip high-frequency catheter ablation. PMID- 21533567 TI - Dabigatran: an oral direct thrombin inhibitor for use in atrial fibrillation. AB - Atrial fibrillation (AF) is well known as one of the leading causes of stroke and systemic embolism. Anticoagulation therapy is recommended in all patients at moderate-to-high risk of stroke. The vitamin K antagonist warfarin has traditionally been used in these patients but presents challenges in dosing and monitoring in these patients. The oral direct thrombin inhibitor dabigatran etexilate (Pradaxa(r); Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA) was recently approved for use in the US for preventing stroke and systemic embolism in patients with nonvalvular AF. Clinical trials have shown it to reduce the risk of stroke and systemic embolism when compared with warfarin (goal international normalized ratio [INR] 2-3) with a similar risk for severe bleeding. It can be given twice daily, with the dose adjusted for renal function. It does not have any dietary restrictions, has few drug interactions (except involving permeability [P]-glycoprotein [P-gp] agents), and does not require routine laboratory monitoring. Patients may experience significant dyspepsia with its use. Compared with warfarin there is increased risk for gastrointestinal bleeding and perhaps myocardial infarction. Currently, no reversal agent exists for use in situations of overdose or severe bleeding although some strategies have been suggested. Despite its high acquisition cost compared with warfarin, analysis using theoretical models has shown it to be cost-effective. Dabigatran offers a unique alternative to warfarin in patients with nonvalvular AF and can be beneficial in patients requiring anticoagulation therapy. PMID- 21533568 TI - Outcome of intensive integrated intervention in participants with impaired glucose regulation in China. AB - INTRODUCTION: This study investigated the outcomes and identified influencing factors of intensive integrated intervention over 2 years in Chinese patients with impaired glucose regulation (IGR). METHODS: Adults in Beijing, China, were screened for IGR using the 75 g oral glucose tolerance test. Participants with IGR received lifestyle and health education; those who still had IGR after 1 year were randomly assigned to either a routine care group or to an intensive integrated intervention group. RESULTS: Of 2344 adults screened, 463 had IGR. Of these, 210 adults had IGR after 1 year and were therefore recruited and randomized to an intensive integrated intervention group (n=106) or a control group (n=104). The percentage of patients who reached the set targets of plasma glucose, blood pressure, body mass index, or triglycerides was significantly higher in the intensive integrated intervention group. None of the patients within the intensive integrated intervention group progressed to diabetes, whereas eight (9.3%) cases of the control group developed type 2 diabetes mellitus (T2DM). Logistic regression analysis showed that both an increase in waist circumference and systolic blood pressure (SBP) were positively correlated with the development of T2DM, whereas improvement in islet beta cell function was negatively correlated with the development of T2DM. CONCLUSIONS: Intensive integrated intervention may significantly decrease the conversion rate of IGR to T2DM, and increase the conversion ratio to normal glucose tolerance. The increase of waist circumference or SBP and the deterioration of islet beta cell function may be important risk factors for progression from prediabetes to diabetes. PMID- 21533569 TI - Weight-based determination of fluid overload status and mortality in pediatric intensive care unit patients requiring continuous renal replacement therapy. AB - PURPOSE: In pediatric intensive care unit (PICU) patients, fluid overload (FO) at initiation of continuous renal replacement therapy (CRRT) has been reported to be an independent risk factor for mortality. Previous studies have calculated FO based on daily fluid balance during ICU admission, which is labor intensive and error prone. We hypothesized that a weight-based definition of FO at CRRT initiation would correlate with the fluid balance method and prove predictive of outcome. METHODS: This is a retrospective single-center review of PICU patients requiring CRRT from July 2006 through February 2010 (n = 113). We compared the degree of FO at CRRT initiation using the standard fluid balance method versus methods based on patient weight changes assessed by both univariate and multivariate analyses. RESULTS: The degree of fluid overload at CRRT initiation was significantly greater in nonsurvivors, irrespective of which method was used. The univariate odds ratio for PICU mortality per 1% increase in FO was 1.056 [95% confidence interval (CI) 1.025, 1.087] by the fluid balance method, 1.044 (95% CI 1.019, 1.069) by the weight-based method using PICU admission weight, and 1.045 (95% CI 1.022, 1.07) by the weight-based method using hospital admission weight. On multivariate analyses, all three methods approached significance in predicting PICU survival. CONCLUSIONS: Our findings suggest that weight-based definitions of FO are useful in defining FO at CRRT initiation and are associated with increased mortality in a broad PICU patient population. This study provides evidence for a more practical weight-based definition of FO that can be used at the bedside. PMID- 21533570 TI - Do centrally pre-prepared solutions achieve more reliable drug concentrations than solutions prepared on the ward? AB - PURPOSE: To compare the concentration conformity of infusion solutions manually prepared on intensive care units (ICU) with solutions from pharmacy-based, automated production. METHODS: A prospective observational study conducted in a university hospital in Germany. Drug concentrations of 100 standardised infusion solutions manually prepared in the ICU and 100 matching solutions from automated production containing amiodarone, noradrenaline or hydrocortisone were measured by high-performance liquid chromatography analysis. Deviations from stated concentrations were calculated, and the quality of achieved concentration conformity of the two production methods was compared. RESULTS: Actual concentrations of 53% of the manually prepared and 16% of the machine-made solutions deviated by >5% above or below the stated concentration. A deviation of >10% was measured in 22% of the manually prepared samples and in 5% of samples from automated production. Of the manually prepared solutions, 15% deviated by >15% above or below the intended concentration. The mean concentration of the manually prepared solutions was 97.2% (SD 12.7%, range 45-129%) and of the machine-made solutions was 101.1% (SD 4.3%, range 90-114%) of the target concentration (p < 0.01). CONCLUSIONS: In this preliminary study, ward-based, manually prepared infusion solutions showed clinically relevant deviations in concentration conformity significantly more often than pharmacy-prepared, machine made solutions. Centralised, automated preparation of standardised infusion solutions may be an effective means to reduce this type of medication error. Further confirmatory studies in larger settings and under conditions of routine automated production are required. PMID- 21533571 TI - Understanding the microcirculation in sepsis: still a long way to go... PMID- 21533572 TI - Temporal changes in tissue cardiorespiratory function during faecal peritonitis. AB - PURPOSE: Sepsis affects both macro- and micro-circulatory transport of oxygen to tissues, causing regional hypoxia. However, this relationship is poorly characterized with respect to inter-organ variability, disease severity and the evolution to organ dysfunction. We hypothesized that an early circulatory insult precedes the development of organ dysfunction, and is more severe in predicted non-survivors. Consequently, we assessed temporal changes in myocardial function and regional tissue oxygenation in peripheral and deep organs in a rat model of faecal peritonitis. We also examined the utility of a dynamic oxygen challenge test to assess the microcirculation. METHODS: Awake, tethered, fluid-resuscitated male Wistar rats were randomized to receive intraperitoneal injection of faecal slurry, or to act as controls. At either 6 or 24 h post insult, rats were anaesthetized and underwent echocardiography, arterial cannulation and placement of tissue oxygen probes in peripheral (muscle, bladder) and deep (liver and renal cortex) organ beds. Measurements were repeated during fluid loading and an oxygen challenge test (administration of high oxygen concentrations). RESULTS: Early sepsis (6 h) was characterized by a fall in global oxygen delivery with concurrent decreases in muscle, renal cortical and, especially, liver tissue PO2. By contrast, during established sepsis (24 h), myocardial and circulatory function had largely recovered despite increasing clinical unwellness, hyperlactataemia and biochemical evidence of organ failure. O2 challenge revealed an early depression of response that, by 24 h, had improved in all organ beds bar the kidney. CONCLUSIONS: This long-term septic model exhibited an early decline in tissue oxygenation, the degree of which related to predicted mortality. Clinical and biochemical deterioration, however, progressed despite cardiovascular recovery. Early circulatory dysfunction may thus be an important trigger for downstream processes that result in multi-organ failure. Furthermore, the utility of tissue PO2 monitoring to highlight the local oxygen supply-demand balance, and dynamic O2 challenge testing to assess microcirculatory function merit further investigation. PMID- 21533573 TI - Accumulation of microcystins in Nile tilapia, Oreochromis niloticus L., and effects of a complex cyanobacterial bloom on the dietetic quality of muscles. AB - The aim of this study was to investigate the kinetics of accumulation and elimination of microcystins in the tissues of Nile tilapia (Oreochromis niloticus) and to evaluate the effect of cyanobacterial exposure on fish muscle quality (levels of total fat and ash, protein, dry matter and the composition of saturated, monounsaturated and polyunsaturated fatty acids). Fish were exposed for 28 days to a natural cyanobacterial bloom with total microcystin concentration around 1,200 MUg g-1 biomass dry weight. The hepatopancreas accumulated microcystins up to 350 ng g-1 fresh weight, but concentrations in muscle were generally below the detection limit (2 ng g-1 fresh weight). Following the exposure, fish were moved to the clean water, but only minor microcystin removal from the hepatopancreas was observed during a 4 week depuration period. Exposures of tilapia to the complex cyanobacterial bloom had only minor and temporary impacts on the investigated parameters of dietetic quality. PMID- 21533574 TI - Risk assessment of dissolved trace metals in drinking water of Karachi, Pakistan. AB - Health risk caused by the exposure to trace metals in water through different exposure pathways was investigated. Graphite furnace atomic absorption spectrometry was used for the determination of trace metals (nickel, copper, chromium, lead, cobalt, manganese and iron) in drinking water samples. The concentration of metals was compared with the world health organization (WHO) drinking water quality guideline values. Risk of metals on human health was evaluated using Hazard Quotient (HQ). Hazard quotients of all metals through oral ingestion and dermal absorption are found in the range of 1.11 * 10-2 to 1.35 * 10-1 and 8.52 * 10-5 to 9.75 * 10-2, respectively. The results of the present study reflect the unlikely potential for adverse health effects to the inhabitants of Karachi due to the oral ingestion and dermal absorption of water containing these metals. PMID- 21533576 TI - Aggressive large cell medulloblastoma extending to the extracranial region in brain-dead state. AB - INTRODUCTION: The authors describe the case of a 29-month-old boy who presented with acute non-communicating hydrocephalus caused by a small tumor in the fourth ventricle. He became brain-dead immediately and remained stable in that condition. MATERIALS AND METHODS: Six months later, despite being in a brain-dead state, a rapid direct tumor extension from the intracranial to extracranial region was observed, and chemoradiotherapy was performed following tumor biopsy. The histopathological diagnosis was large cell medulloblastoma. Although treatment was initially effective, the tumor again aggressively invaded the cervical muscles via the spinal canal. Comparative genomic hybridization (metaphase) analysis revealed a pattern of aberrations predictive of a poor prognosis (+1q, ?17p, +17q, and probable amplification of c-myc gene), and he eventually died 11 months after onset. RESULTS: Direct invasion of medulloblastoma from the intracranial to extracranial region is extremely rare, and, to our knowledge, this is the first report of medulloblastoma exhibiting rapid extension to the extracranial region in brain-dead state. CONCLUSIONS: For patients with medulloblastomas, careful observation is needed even in brain-dead state. The etiology of this rare condition as well as the genetic characteristics responsible for aggressive tumor behavior are discussed. PMID- 21533575 TI - Diffuse intrinsic pontine glioma-current status and future strategies. AB - INTRODUCTION: Diffuse intrinsic pontine gliomas which constitute 15% of all childhood brain tumors are inoperable and response to radiation and chemotherapy has not improved long-term survival. Due to lack of newer effective therapies, mean survival after diagnosis has remained less than 12 months. Trials investigating chemotherapy and/or radiation have proven disappointing. As biopsy of these tumors are rarely performed due to the high eloquence of the brain stem, information about the pathology and biology remains elusive hindering development of novel biologic agents. Poor access of most chemotherapeutic agents to these tumors due to the blood-brain barrier continues to undermine therapeutic efficacy. Thus, to date, we remain at a virtual standstill in our attempts to improve the prognosis of children with these tumors. METHODS: An extensive review of the literature was performed concerning children with diffuse brain stem gliomas including clinical trials, evolving molecular biology, and newer therapeutic endeavors. CONCLUSION: A pivotal approach in improving the prognosis of these tumors should include the initiation of biopsy and encouraging families to consider autopsy to study the molecular biology. This will help in redefining this tumor by its molecular signature and profiling targeted therapy. Continued advances should be pursued in neuroimaging technology including identifying surrogate markers of early disease progression. Defining strategies to enhance local delivery of drugs into tumors with the help of newer surgical techniques are important. Exhaustive research in all these aspects as a multidisciplinary approach could provide hope to children with these fatal tumors. PMID- 21533577 TI - Molecular cloning and characterization of a novel SGNH arylesterase from the goat rumen contents. AB - An esterase-encoding gene, estR5, was directly obtained from the genomic DNA of goat rumen contents. The 555-bp full-length gene encodes a 184-residue polypeptide (EstR5) without putative signal peptide. Deduced EstR5 shared the highest identity (50%) to a putative arylesterase from Ruminococcaceae bacterium D16. Phylogenetic analysis indicated that EstR5 was closely related with microbial esterases of gastrointestinal source. A comparison of the conserved motifs shared with GDSL proteins revealed that EstR5 could be grouped into the GDSL family and was further classified into the subfamily of SGNH hydrolases. The gene estR5 was expressed in Escherichia coli BL21 (DE3) and purified to electrophoretic homogeneity. Recombinant EstR5 exhibited highest catalytic efficiency towards alpha-naphthyl acetate followed by phenyl acetate and p nitrophenyl acetate and had no activity towards PNP esters with acyl chains longer than C8. The enzyme exhibited optimal activity at around 60 degrees C and pH 8.0, was stable at pH ranging from 6.0 to 11.0 and was slightly activated by detergent Tween, Nonidet P-40, and Triton X-100. These properties suggest that EstR5 has great potential for basic research and industrial applications. To our knowledge, this is the first arylesterase obtained from rumen microenvironment. PMID- 21533578 TI - Transgenic microalgae expressing Escherichia coli AppA phytase as feed additive to reduce phytate excretion in the manure of young broiler chicks. AB - Microbial phytases are widely used as feed additive to increase phytate phosphorus utilization and to reduce fecal phytates and inorganic phosphate (iP) outputs. To facilitate the process of application, we engineered an Escherichia coli appA phytase gene into the chloroplast genome of the model microalga, Chlamydomonas reinhardtii, and isolated homoplasmic plastid transformants. The catalytic activity of the recombinant E. coli AppA can be directly detected in the whole-cell lysate, termed Chlasate, prepared by freeze-drying the transgenic cell paste with liquid nitrogen. The E. coli AppA in the Chlasate has a pH and temperature optima of 4.5 and 60 degrees C, respectively, which are similar to those described in the literature. The phytase-expressed Chlasate contains 10 phytase units per gram dry matter at pH 4.5 and 37 degrees C. Using this transgenic Chlasate at 500 U/kg of diet for young broiler chicks, the fecal phytate excretion was reduced, and the iP was increased by 43% and 41%, respectively, as compared to those of the chicks fed with only the basal diet. The effectiveness of the Chlasate to break down the dietary phytates is compatible with the commercial Natuphos fungal phytase. Our data provide the first evidence of functional expression of microbial phytase in microalgae and demonstrate the proof of concept of using transgenic microalgae as a food additive to deliver dietary enzymes with no need of protein purification. PMID- 21533579 TI - Production and characterization of LEA29Y, a variant of cytotoxic T-lymphocyte antigen 4-immunoglobulin, in Pichia pastoris. AB - Blocking the CD28/B7 costimulatory pathway is a promising strategy in the treatment of graft rejection, graft-versus-host disease and autoimmune diseases. LEA29Y, a high-affinity variant of cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig), is a more potent inhibitor of the interaction between CD28 and B7 than is CTLA4Ig. In a previous study, LEA29Y was produced in a mammalian cell system, which is time-consuming and expensive. To obtain LEA29Y more efficiently and cost effectively, we attempted to produce LEA29Y using a Pichia pastoris expression system. The gene encoding LEA29Y, with an additional 6 His tag at the N-terminus, was cloned into the yeast vector pPIC9K and expressed in the P. pastoris strain GS115. Under the optimized induction conditions for protein expression (inoculum density, OD(600) = 80; methanol concentration added daily, 1.0-3.0%; induction time point, 72-96 h; culture medium pH = 6.0), the yield of purified LEA29Y was approximately 30 mg l(-1) by one-step Ni-agarose affinity chromatography. PNGase F treatment showed the purified LEA29Y to be post translational modified by N-linked glycosylation. In biological function assays, LEA29Y expressed in P. pastoris demonstrated specific binding to B7-1/B7-2 positive Raji cells and also suppressed lymphocyte proliferation in a dose dependent manner. These results suggest that LEA29Y produced in P. pastoris is biologically active and will be useful for experimental therapy on immunotherapy for transplant rejection and autoimmune diseases. PMID- 21533580 TI - Acetone production in solventogenic Clostridium species: new insights from non enzymatic decarboxylation of acetoacetate. AB - Development of a butanologenic strain with high selectivity for butanol production is often proposed as a possible route for improving the economics of biobutanol production by solventogenic Clostridium species. The acetoacetate decarboxylase (aadc) gene encoding acetoacetate decarboxylase (AADC), which catalyzes the decarboxylation of acetoacetate into acetone and CO(2), was successfully disrupted by homologous recombination in solventogenic Clostridium beijerinckii NCIMB 8052 to generate an aadc ( - ) mutant. Our fermentation studies revealed that this mutant produces a maximum acetone concentration of 3 g/L (in P2 medium), a value comparable to that produced by wild-type C. beijerinckii 8052. Therefore, we postulated that AADC-catalyzed decarboxylation of acetoacetate is not the sole means for acetone generation. Our subsequent finding that non-enzymatic decarboxylation of acetoacetate in vitro, under conditions similar to in vivo acetone-butanol-ethanol (ABE) fermentation, produces 1.3 to 5.2 g/L acetone between pH 6.5 and 4 helps rationalize why various knock-out and knock-down strategies designed to disrupt aadc in solventogenic Clostridium species did not eliminate acetone production during ABE fermentation. Based on these results, we discuss alternatives to enhance selectivity for butanol production. PMID- 21533582 TI - Successful closure of guidewire-induced coronary perforation with intracoronary thrombin injection. PMID- 21533581 TI - Optimizing of thienopyridine therapy by multiple electrode platelet aggregometry in clopidogrel low responders undergoing PCI. AB - AIMS: One possible cause of stent thrombosis is an insufficient effect of clopidogrel. In a prospective study, we aimed to optimize the platelet inhibition of clopidogrel low responders (CLR) by multiple electrode platelet aggregometry (MEA)-guided therapy modifications and to evaluate specific major adverse cardiac and cerebrovascular events (MACCE). METHODS AND RESULTS: ADP-induced platelet aggregation was measured by MEA in 1,005 consecutive patients after stent implantation and 600 mg clopidogrel loading dose. All patients received at least 100 mg aspirin/day. In 118 patients (11.7%), ADP values remained in the reference range generated in 150 controls and were defined as CLR. Significant independent predictors of CLR were acute coronary syndrome (ACS) (OR = 6.54), diabetes (OR = 2.07), use of diuretics (OR = 1.93) or proton pump inhibitors (OR = 1.64) and male gender (OR = 1.83). Ninety-nine CLR were switched to clopidogrel 150 mg/day, leading to an adequate response in 54/99. Subsequently, 44 patients were changed to ticlopidine 2 * 250 mg/day, resulting in an inhibition in 24/44. The remaining 20 patients received 2 * 100 mg cilostazol/day in addition to 75 mg clopidogrel/day. After its recent availability, 19/118 primary CLR were treated with 5-10 mg prasugrel/day. One patient was a prasugrel low responder. The total thienopyridine low response-rate was 2% in our population. The specific MACCE rate (death, non-fatal target vessel myocardial infarction, non-fatal stroke) of the CLR under optimized treatment (except prasugrel) was 2.0% at 30 days and 3.0% during a mean follow-up of 44 weeks. CONCLUSION: Clopidogrel low response is present in 1/10 patients and more frequent in ACS-PCI. MEA-guided optimizing of thienopyridine therapy is feasible and results in a very low specific MACCE rate. Low response to all thienopyridines is rare. PMID- 21533583 TI - Cancer prevention interdisciplinary education program at Purdue University: overview and preliminary results. AB - Cancer prevention is a broad field that crosses many disciplines; therefore, educational efforts to enhance cancer prevention research focused on interdisciplinary approaches to the field are greatly needed. In order to hasten progress in cancer prevention research, the Cancer Prevention Internship Program (CPIP) at Purdue University was designed to develop and test an interdisciplinary curriculum for undergraduate and graduate students. The hypothesis was that course curriculum specific to introducing interdisciplinary concepts in cancer prevention would increase student interest in and ability to pursue advanced educational opportunities (e.g., graduate school, medical school). Preliminary results from the evaluation of the first year which included ten undergraduate and five graduate students suggested that participation in CPIP is a positive professional development experience, leading to a significant increase in understanding of interdisciplinary research in cancer prevention. In its first year, the CPIP project has created a successful model for interdisciplinary education in cancer prevention research. PMID- 21533584 TI - Overweight and obese patients do not seem to adequately recognize their own risk for colorectal cancer. AB - Being overweight is a risk factor for colorectal cancer; patients' adequate perception of their risk may lead to better involvement in management. The purpose of this study was to measure perception of risk for colorectal cancer in overweight and obese patients. A consecutive sample of overweight adult patients (n = 195) attending to nutritional counseling was submitted to clinical questionnaire addressing personal and family data, awareness about colorectal cancer risk factors, health status, and estimates of their own risk. Only 32% identified obesity among CCR risk factors. For 57% of participants, their own current BMI status did not confer any increased risk for CRC. Also, for half (46%) of the patients, their BMI status will not lead to an increased risk during lifetime. For 36%, an increased risk was accurately estimated as two or more. Accurate estimates tend to be made by older patients (p = 0.033), those with GI complaints (p = 0.040), or with familial history (p = 0.016). Even among patients attending to a nutritional consultation, only a third of patients seem to adequately consider their own overweight as a potential risk for colorectal cancer during lifetime. PRACTICE IMPLICATIONS: health education programs concerning obesity must include colorectal cancer as a potential outcome for overweight patients. PMID- 21533585 TI - Reliability of hypothalamic-pituitary-adrenal axis assessment methods for use in population-based studies. AB - Population-based studies have been hampered in exploring hypothalamic-pituitary adrenal axis (HPA) activity as a potential explanatory link between stress related and metabolic disorders due to their lack of incorporation of reliable measures of chronic cortisol exposure. The purpose of this review is to summarize current literature on the reliability of HPA axis measures and to discuss the feasibility of performing them in population-based studies. We identified articles through PubMed using search terms related to cortisol, HPA axis, adrenal imaging, and reliability. The diurnal salivary cortisol curve (generated from multiple salivary samples from awakening to midnight) and 11 p.m. salivary cortisol had the highest between-visit reliabilities (r = 0.63-0.84 and 0.78, respectively). The cortisol awakening response and dexamethasone-suppressed cortisol had the next highest between-visit reliabilities (r = 0.33-0.67 and 0.42 0.66, respectively). Based on our own data, the inter-reader reliability (r(s)) of adrenal gland volume from non-contrast CT was 0.67-0.71 for the left and 0.47 0.70 for the right adrenal glands. While a single 8 a.m. salivary cortisol is one of the easiest measures to perform, it had the lowest between-visit reliability (R = 0.18-0.47). Based on the current literature, use of sampling multiple salivary cortisol measures across the diurnal curve (with awakening cortisol), dexamethasone-suppressed cortisol, and adrenal gland volume are measures of HPA axis tone with similar between-visit reliabilities which likely reflect chronic cortisol burden and are feasible to perform in population-based studies. PMID- 21533586 TI - The decline and residues of hexaconazole in tomato and soil. AB - The decline and terminal residues of hexaconazole in tomato and soil in open field were studied. Hexaconazole residues were determined by gas chromatography coupled with an electron capture detector. Recoveries were between 89% and 110% with RSD of 2.99-5.88% in tomato and 90-119% with RSD of 1.15-5.76% in soil at spiked levels of 0.01, 0.1, and 1 mg/kg, respectively. The limit of detection of hexaconazole was 6.3 * 10(-12) g. The decline rates of hexaconazole were described using first-order kinetics and the mean half-lives of hexaconazole in tomato and soil were 4.3 and 18.1 days, respectively. The terminal residues in tomato at interval of 7 days at the dosage of 150 g.a.i./hm(2) for three or four times were all below 0.1 mg/kg. This work would be the guidance of establishing the maximum residue limit of hexaconazole in tomato in China. PMID- 21533587 TI - A case of serious laryngeal edema unpredictably detected during laryngoscopy for orotracheal intubation following induction of anesthesia. AB - We report a case of unpredictable and serious laryngeal edema probably caused by preoperative esophagogastroduodenoscopy (EGD). A 54-year-old man with type 2 diabetes mellitus was scheduled to undergo coronary artery bypass grafting (CABG). Two days before surgery, EGD was performed to explore the cause of occult bleeding, resulting in a slightly sore throat and an increased white blood cell count (18,300/MUl). Without premedication, general anesthesia was uneventfully induced with intravenous midazolam (10 mg) and fentanyl (50 MUg), followed by inhalation of sevoflurane (3%) and intravenous rocuronium (50 mg). Thereafter, manual ventilation was easily performed with a bag and mask. However, on laryngoscopy for orotracheal intubation, serious swelling with rubor and light pus in the epiglottis extending to the arytenoid cartilage was detected, leading to the cancellation of surgery. Immediately following intravenous drip of hydrocortisone (300 mg) and bolus of sugammadex (200 mg), the patient recovered smoothly from anesthesia without complications such as dyspnea, but his sore throat persisted. He was diagnosed with acute epiglottitis. Treatment consisted of intravenous cefazolin (2 g/day) and hydrocortisone (300 mg/day tapered to 100 mg/day) for 9 consecutive days. Consequently, the patient recovered gradually from the inflammation and underwent CABG as scheduled 28 days later. Anesthesiologists should be aware that EGD performed just before anesthesia could unpredictably cause acute epiglottitis, especially in immunocompromised patients, such as those with diabetes. PMID- 21533589 TI - Acute appendicitis secondary to a granular cell tumor of the appendix in a 19 year-old male. AB - INTRODUCTION: Granular cell tumors are rare, usually benign, neoplasms presenting as solitary small nodules in the skin or subcutaneous tissue. Involvement of the gastrointestinal tract is unusual, particularly of the appendix, and it is characterized by indolent, submucosal lesions usually diagnosed as an incidental finding. CASE REPORT: We describe the rare case of acute appendicitis secondary to a granular cell tumor of the appendix in a 19-year-old male. PMID- 21533590 TI - Improved artificial saliva for studying the cariogenic effect of carbohydrates. AB - Saliva is a complex fluid that possesses many important functions regarding oral health. Many in vitro studies require relatively large quantities of saliva. While natural saliva would be the material of choice, it is difficult to obtain in sufficient quantities and varies in composition. Substitutes mimicking the physicochemical properties of saliva have been developed, but these are not appropriate to study the growth of mutans streptococci. Brain Heart Infusion (BHI) has been commonly used for this, but this medium is richer in nutrients than saliva. We therefore developed artificial saliva (AS) with nutrient levels resembling those in natural saliva as a substitute for natural human saliva (HS) to study the influence of different carbon sources on mutans streptococci growth. Growth of a wild-type Streptococcus mutans strain and S. mutans ATCC 15175 in BHI, HS, and AS was monitored anaerobically. Growth of S. mutans in the modified AS was very similar to the growth in HS, both in the absence and presence of different carbon sources. We therefore conclude that the developed AS is suitable for in vitro tests on S. mutans growth. PMID- 21533591 TI - The measurement of backscatter factors of kilovoltage X-ray beams using GafchromicTM EBT2 film. AB - Backscatter factors are essential in the determination of radiation dose for kilovoltage X-ray beams. The accurate measurement of backscatter factors in water (B (W)) is difficult and published values are based largely on Monte Carlo calculations. A number of studies have found that the measurement of B (W) in the energy range from 50 to 300 kVp is possible using Gafchromic EBT film, but this film is no longer commercially available. In this work, we evaluated whether the newer Gafchromic EBT2 film is suitable for the determination of B (W) for kilovoltage X-ray beams. B (W) were measured with Gafchromic EBT2 film for beam qualities of 50, 100 and 280 kVp and field sizes of 2, 3, 4 and 6 cm diameter and compared with tabulated values published in the AAPM TG-61 protocol. We found that rotation of the film position during readout had a small but non-negligible effect on the optical density readings. The agreement between measured and published B (W) was better than 3%, with the largest difference of occurring for the 2 cm diameter field with the 50 kVp X-ray beam. However, these differences are consistent with the total estimated uncertainty for the measurements, as calculated by the ISO GUM. Our results demonstrate that Gafchromic EBT2 film is a suitable dosimeter for B (W) measurements for clinical kilovoltage X-ray beams. PMID- 21533592 TI - Successful treatment of an intra-abdominal desmoid tumor with irinotecan, fluorouracil, and leucovorin plus bevacizumab in a patient with familial adenomatous polyposis. PMID- 21533593 TI - [Early esophageal cancer: pro-endoscopic resection]. AB - In several publications including more than 1,000 endoscopically treated patients it could be demonstrated that endoscopic treatment of early esophageal cancer is effective and safe. A combination of endoscopic resection (ER) of early Barrett's neoplasia followed by ablation of the remaining non-dysplastic Barrett's mucosa was able to significantly reduce the rate of recurrence and metachronous neoplasia. Long-term complete remission rates of more than 95% can be achieved. Compared to esophagectomy, endoscopic treatment has only a very low complication rate and almost no mortality. Therefore, ER is the treatment of choice and recommended by several international guidelines. Esophageal resection only plays a minor role in patients with early esophageal cancer. PMID- 21533594 TI - [Brain imaging in autism spectrum disorders. A review]. AB - In the past two decades, an increasing number of functional and structural brain imaging studies has provided insights into the neurobiological basis of autism spectrum disorders (ASD). This article summarizes pertinent functional brain imaging studies addressing the neuronal underpinnings of ASD symptomatology (impairments in social interaction and communication, repetitive and restrictive behavior) and associated neuropsychological deficits (theory of mind, executive functions, central coherence), complemented by relevant structural imaging findings. The results of these studies show that although cognitive functions in ASD are generally mediated by the same brain regions as in typically developed individuals, the degree and especially the patterns of brain activation often differ. Therefore, a hypothesis of aberrant network connectivity has increasingly been favored over one of focal brain dysfunction. PMID- 21533595 TI - [Public perceptions of hospital autopsies: results of a representative survey]. AB - BACKGROUND: The number of hospital autopsies has been declining for many years-in Germany as well as in other western countries. One possible reason for this could be the public's negative view of autopsies. METHODS: Therefore, a representative survey was conducted to study the attitudes of the German population on postmortem examinations. RESULTS: In total, 84% of respondents generally accept hospital autopsies, while only 10% are in principle opposed to this practice. Many respondents (72%) would agree to the autopsy of their own dead body and 65% to the autopsy of relatives. Altogether, 9% of respondents had already been in a situation where a relative had died in a hospital and they were asked for permission to perform an autopsy. Of these 90, 56% agreed to and 44% refused autopsy. CONCLUSION: The data suggest that the attitudes of the public are surprisingly positive and do not explain declining autopsy rates. Medical and institutional reasons must be considered instead as the possible cause of declining autopsy rates. PMID- 21533597 TI - Surgical treatment of thoracic disc herniations via tailored posterior approaches. AB - We present clinical findings, radiological characteristics and surgical modalities of various posterior approaches to thoracic disc herniations and report the clinical results in 27 consecutive patients. Within an 8-year period 27 consecutive patients (17 female, 10 male) aged 30-83 years (mean 53 years.) were surgically treated for 28 symptomatic herniated thoracic discs in our department. Six of these lesions (21%) were calcified. In all cases surgery was performed via individually tailored posterior approaches. We evaluated the pre- and postoperative clinical status and the complication rate in a retrospective study. Nearly one half of the lesions (46.4%) were located at the three lowest thoracic segments. Clinical symptoms included back pain or radicular pain (77.8%), altered sensitivity (77.8%), weakness (40.7%), impaired gait (51.9%) or bladder dysfunction (22%). Costotransversectomy was performed in 8 patients, 1 lateral extracavitary approach, 2 foraminotomies, 15 transfacet and/or transpedicular approaches and 2 interlaminar approaches were used for removing the pathologies. After a mean follow-up of 38.6 months (3-100 months), complete normalization or reduction of local pain was recorded in 87% of the patients and of radicular pain in 70% of the cases, increased motor strength could be achieved in 55%, sensitivity improved in 76.2% and improvement of myelopathy was noted in 71.4%. Two patients suffered from postoperative impairment of sensory deficits, which in one case was discrete. The overall recovery rate within the modified JOA score was 39.5%. In 1 patient, two revisions were required because of instability and a persisting osteophyte, respectively. The rate of major complications was 7.1% (2/28). Surgical treatment of thoracic disc herniations via posterior approaches tailored to the individual patient produces satisfying results referring to clinical outcome. Posterior approaches remain a viable alternative for a large proportion of patients with symptomatic thoracic disc herniations. PMID- 21533598 TI - Postoperative trunk shift in Lenke 1 and 2 curves: how common is it? and analysis of risk factors. AB - The goal of surgical treatment for adolescent idiopathic scoliosis (AIS) is to achieve a solid fusion in a balanced spine. While many previous studies analyzed coronal balance, there is a paucity of studies that comment on postoperative trunk shift, which has shown to have impact on clinical outcome. The purpose of this retrospective, multicenter data analysis was to analyze the incidence of postoperative trunk shift in patients with surgical treatment for AIS. We conducted a retrospective, multicenter data analysis of 1,555 patients with AIS. Patients with a Lenke type 1 or 2 curve pattern and a minimum follow-up of 24 months after surgery were included. A >2 cm deviation of the trunk in relation to the pelvis was considered positive trunk shift. A subanalysis was performed to identify potential risk factors for trunk shift. 273 patients meeting the inclusion criteria were analyzed. While the preoperative prevalence of trunk shift was surgically reduced from 29.3 to 13.6%, 24 patients (8.8%) with postoperative trunk shift had not had preoperative trunk shift, and the trunk shift was considered iatrogenic. Undercorrection of the lumbar curve was identified as potential risk factor, whereas thoracic correction, coronal balance, angulation and translation of the lowest instrumented vertebra did not seem to influence postoperative trunk shift. Iatrogenic postoperative trunk shift has an incidence of 8.8% in the surgical treatment of AIS. PMID- 21533599 TI - Are intravertebral vacuum phenomena benign lesions? AB - We retrospectively reviewed plain radiographs from patients with four different diseases that can cause vertebral collapse: osteoporotic vertebral collapse, spinal infection, spinal metastasis, and multiple myeloma. The objective of the study was to find the percentages of intravertebral vacuum phenomena and vertebral collapse rates in the four groups. The vacuum phenomenon is often observed in osteoporotic compression fractures. However, these phenomena are rarely seen in spinal infection and malignant lesions. Whether the vacuum phenomenon is a benign indicator is not known. We retrospectively reviewed plain radiographs from four groups of patients, including 328 osteoporotic vertebral collapse patients, 317 spinal infection patients, 302 spinal metastasis patients, and 325 multiple myeloma patients. The pattern and occurrence rates of intravertebral vacuum phenomena and vertebral body collapse were analyzed. The occurrence rate of intravertebral vacuum phenomena in patients with osteoporotic vertebral collapse was approximately 18.9%. Only one case of intravertebral vacuum phenomena was observed in patients with spinal infection. Vacuum phenomena were not observed in patients with spinal metastasis. The occurrence rate of intravertebral vacuum phenomena in patients with multiple myeloma was 6.4%. The patterns of intravertebral vacuum phenomena were also analyzed. Intravertebral vacuum phenomena are common in patients with osteoporotic vertebral collapse. Most cases of intravertebral vacuum phenomena are of a benign nature. Moreover, intravertebral vacuum phenomena occur extremely rarely in patients with spinal infection. Such phenomena are also found in patients with multiple myeloma. PMID- 21533600 TI - Depressive disorders in school children of suburban India: an epidemiological study. AB - PURPOSE: There is a dearth of research on the prevalence of depressive disorders in children from suburban and rural areas in the Indian subcontinent. Therefore, the present study was aimed at assessing the prevalence of depressive disorders and the associated risk factors in the primary and secondary school children in suburban India. METHODS: This was a cross-sectional, school-based epidemiological study involving 1,851 children from standard I to VII age group. Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS-PL), a semi structured interview was used to diagnose depression in this sample. RESULTS: Using K-SADS-PL, prevalence of depressive disorder was 3.13% (n = 58); major depressive disorder was diagnosed in 15 (0.81%), dysthymia in 28 (1.51%) and depressive disorder NOS in 15 (0.81%). Age (OR 1.396, CI 1.121-1.738), class attendance (OR 0.251, CI 0.103-0.613), family history of psychiatric illness (OR 0.204, CI 0.069-0.605) and birth complications (OR 0.128, CI 0.029-0.558) emerged as significant predictors of depression; the model explained 24.1-32.3% of the variance in this sample. CONCLUSION: The present study confirms the findings from previous studies that childhood depression is a distinct diagnostic entity affecting a significant number of children and adolescents. PMID- 21533601 TI - [Audiological results with cochlear implants for single-sided deafness]. AB - INTRODUCTION: Single-sided deafness has a strong impact on quality of life. Besides the difficulties in sound localization, patients also require increased effort to hear. The latter makes it difficult to follow conversations for an extended period, leading to social isolation. Cochlear implantation (CI) represents a possible treatment option for deafness in one ear. METHODS: In the present study, 13 patients with unilateral deafness where treated with CI. All patients were examined by pure tone audiometry and speech tests (Freiburger; HSM; OlSa), as well as sound localisations tests. The single-sided deaf situation is compared to CI-aided binaural hearing. RESULTS: At 100%, the acceptance rate was very high. The two different auditory inputs were well integrated. Patients reported satisfactory restoration of acoustic orientation and sound localization as well as great ease of listening in noisy surroundings. There was no negative impact on the normal hearing side. CONCLUSION: These preliminary results confirm the effectiveness of CI treatment in unilateral deafness. PMID- 21533602 TI - Successful treatment of recurrent malignancy-associated hemophagocytic lymphohistiocytosis with a modified HLH-94 immunochemotherapy and allogeneic stem cell transplantation. AB - Acquired hemophagocytic lymphohistiocytosis (HLH) triggered by a known or still to be recognized malignancy is a life-threatening hyperinflammatory syndrome due to massive cytokine release from activated lymphocytes and macrophages. Malignancy-associated HLH (M-HLH) often impedes adequate treatment of malignancy and has the worst outcome compared with any other form of HLH. The incidence of M HLH is unknown, and there are no published treatment recommendations addressed to this HLH form. Here, we report the case of a young woman with recurrent ALK1 positive anaplastic large T-cell lymphoma and M-HLH successfully treated with a modified HLH-94 protocol, allogeneic stem cell transplantation (alloSCT) and donor lymphocyte infusion (DLI). More than 3 years after DLI, the patient is alive, in complete remission from her malignancy and HLH-free, although suffering from extensive chronic graft-versus-host disease. AlloSCT and, if needed, DLI performed to consolidate remission of malignancy and HLH may have a curative impact on both entities. We propose that when discussing possible treatment options for patients with M-HLH, alloSCT should be considered in eligible individuals. PMID- 21533603 TI - Effect of short hairpin RNA of Bcl-xL gene on biological behaviors of HepG-2 cells. AB - To investigate the inhibitory effect of short hairpin RNA (shRNA) targeting the Bcl-xL gene on the apoptosis and proliferation of hepatocellular carcinoma HepG-2 cells. We constructed Bcl-xL shRNA, and transfected it into HepG-2 cells, then detected Bcl-xL gene expression on mRNA and protein levels by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry, respectively. Cell proliferation was detected by MTT assay. Cell apoptosis and Bcl-2 and Bax expression were detected by flow cytometry. The expression of Bcl xL was obviously inhibited by RNA interference. The inhibition rates of Bcl-xL mRNA and protein were 86.6 and 70.2%, respectively. Bcl-xL shRNA inhibited cell proliferation (P < 0.05), whereas promoted apoptosis (P < 0.01). After transfection of Bcl-xL shRNA in HepG-2 cells, the expression of Bcl-2 did not change, but Bax increased significantly. Bcl-xL shRNA effectively inhibits Bcl-xL gene expression and proliferation of HepG-2 cells and promotes apoptosis. PMID- 21533604 TI - Post-mortem decapitation by domestic dogs: three case reports and review of the literature. AB - Post-mortem animal depredation is not an uncommon phenomenon in routine forensic autopsies. We present three cases of complete post-mortem decapitation by domestic German shepherd dogs. In two cases, the head had been bitten off, defleshed and left lying near the body, while in one case it had been completely devoured by two dogs; only small skull fragments and crowned teeth could be found. Two of the three bodies were putrefied; all dog bite injuries had been inflicted after death. The cause of death was drug toxicity in two cases and fatal hemorrhage from ruptured esophageal varices in one case. These rare injuries due to post-mortem animal depredation are discussed in the light of earlier studies and case reports. PMID- 21533605 TI - Multiple lung abscesses secondary to a uterine empyema caused by an intrauterine device. PMID- 21533606 TI - Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer's disease: a long-term follow up study. AB - Cerebral amyloid angiopathy is manifested as accumulation of amyloid beta (Abeta) peptide in the wall of meningeal and cerebral arteries, arterioles and capillaries and is frequently found postmortem in sporadic Alzheimer's disease (sAD) patients. It is difficult to assess when and how cerebral amyloid angiopathy develops and progresses in humans in vivo, which is why animal AD models are used. Streptozotocin-intracerebroventricularly (STZ-icv) treated rats have been recently proposed as the model of sAD which develops insulin resistant brain state preceding Abeta pathology development. Vascular Abeta deposits in the brain of STZ-icv-treated rats (3 months old at the time of icv treatment) were visualized by Thioflavine-S staining, Congo red staining and Abeta immunohistochemistry. Thioflavine-S and Congo red staining revealed diffuse congophilic deposits in the wall of meningeal and cortical blood vessels both 6 and 9 months after the STZ-icv treatment. Preliminary Abeta1-42 and Abeta1-16 immunohistochemistry experiments showed positive staining in blood vessels 3 and 9 months after the STZ-icv treatment, respectively. Results suggest that cerebral amyloid angiopathy observed 6 and 9 months after the STZ-icv treatment seems to be a continuation and progression of the amyloid pathology observed already 3 months following the STZ-icv treatment in this non-transgenic sAD animal model. PMID- 21533608 TI - Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. AB - The increasing number of effective agents allows rescue therapy of patients with light-chain (AL) amyloidosis refractory to >=2 previous treatments. Lenalidomide is effective in this disease and its toxicity profile encourages its use in salvage regimens. All the patients with AL amyloidosis refractory to both melphalan and bortezomib referred to our center between July 2007 and July 2009 were treated with the combination of lenalidomide and dexamethasone. Twenty-four consecutive patients were enrolled. Seventy-nine percent were also refractory to thalidomide. Two patients died before evaluation of response, and 50% experienced severe adverse events. Survival was significantly shorter in subjects with troponin I >0.1 ng/mL and in patients diagnosed <18 months before treatment initiation. Hematologic response was observed in 41% of patients and prolonged survival (median 10 months vs. not reached, P = 0.005) independently from troponin I concentration and from pre-treatment disease duration. Salvage therapy beyond second line of treatment can improve survival in AL amyloidosis and lenalidomide plus dexamethasone is a valuable option in this setting. PMID- 21533607 TI - Chromogranin peptides in brain diseases. AB - Synaptic disturbances may play a key role in the pathophysiology of neuropsychiatric diseases. In this article, we review immunohistological findings of chromogranin peptides in neurodegenerative and neurodevelopmental disorders, with particular emphasis on Alzheimer's disease, the disorder chromogranins have been studied most extensively. Data was collected from existing and new experimental data and medline research. This review focuses on synaptic changes elicited by chromogranin peptides immunoreactivity in Alzheimer's disease, as well in schizophrenia and amyotrophic lateral sclerosis (ALS). An imbalanced availability of chromogranin peptides may be responsible for impaired neurotransmission and a reduced functioning of dense core vesicles. Since chromogranin A was postulated as a potent proinflammatory agent, we focused on chromogranin A in neuroinflammation in Alzheimer's disease and ALS. Further understanding of role and function of chromogranin peptides in neuropathological conditions is still required. PMID- 21533609 TI - [Sources of error in Goldmann applanation tonometry]. AB - Reliable measurements of the intraocular pressure (IOP) are necessary for glaucoma patients. The measuring procedure, anatomical changes of the eye or extraocular influences can lead to errors during applanation tonometry. The IOP is overestimated if measured through the wrong eyepiece of the slit lamp, if a force is interfering with the tonometer arm during the measurement, if the lid comes into contact with the tonometer tip, if blepharospasm occurs, if there is lid retraction or if a Valsalva maneuver is present. An underestimation of the IOP occurs if staining with fluorescein is absent or insufficient, if the illumination is not bright enough, if a corneal stromal edema is present, after LASIK, during accommodation, during repeated measures within a few minutes or during systemic blood pressure drop. Discrepancies of the IOP in both directions can appear if the calibration of the tonometer is irregular, if abnormal central corneal thickness or astigmatism is present. For correct measurements calibrations are advised once or twice a year. PMID- 21533610 TI - Validity of Type D personality in Iceland: association with disease severity and risk markers in cardiac patients. AB - Type D personality has been associated with poor prognosis in cardiac patients. This study investigated the validity of the Type D construct in Iceland and its association with disease severity and health-related risk markers in cardiac patients. A sample of 1,452 cardiac patients completed the Type D scale (DS14), and a subgroup of 161 patients completed measurements for the five-factor model of personality, emotional control, anxiety, depression, stress and lifestyle factors. The Icelandic DS14 had good psychometric properties and its construct validity was confirmed. Prevalence of Type D was 26-29%, and assessment of Type D personality was not confounded by severity of underlying coronary artery disease. Regarding risk markers, Type D patients reported more psychopharmacological medication use and smoking, but frequency of previous mental problems was similar across groups. Type D is a valid personality construct in Iceland, and is associated with health-related risk markers, but not cardiac disease severity. PMID- 21533611 TI - The non-psychoactive plant cannabinoid, cannabidiol affects cholesterol metabolism-related genes in microglial cells. AB - Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that is clinically used in a 1:1 mixture with the psychoactive cannabinoid Delta(9)-tetrahydrocannabinol (THC) for the treatment of neuropathic pain and spasticity in multiple sclerosis. Our group previously reported that CBD exerts anti-inflammatory effects on microglial cells. In addition, we found that CBD treatment increases the accumulation of the endocannabinoid N-arachidonoyl ethanolamine (AEA), thus enhancing endocannabinoid signaling. Here we proceeded to investigate the effects of CBD on the modulation of lipid-related genes in microglial cells. Cell viability was tested using FACS analysis, AEA levels were measured using LC/MS/MS, gene array analysis was validated with real-time qPCR, and cytokine release was measured using ELISA. We report that CBD significantly upregulated the mRNAs of the enzymes sterol-O-acyl transferase (Soat2), which synthesizes cholesteryl esters, and of sterol 27-hydroxylase (Cyp27a1). In addition, CBD increased the mRNA of the lipid droplet-associated protein, perilipin2 (Plin2). Moreover, we found that pretreatment of the cells with the cholesterol chelating agent, methyl-beta-cyclodextrin (MBCD), reversed the CBD-induced increase in Soat2 mRNA but not in Plin2 mRNA. Incubation with AEA increased the level of Plin2, but not of Soat2 mRNA. Furthermore, MBCD treatment did not affect the reduction by CBD of the LPS-induced release of the proinflammatory cytokine IL 1beta. CBD treatment modulates cholesterol homeostasis in microglial cells, and pretreatment with MBCD reverses this effect without interfering with CBD's anti inflammatory effects. The effects of the CBD-induced increase in AEA accumulation on lipid-gene expression are discussed. PMID- 21533612 TI - Eosinophilic esophagitis without abundant eosinophils? The expanding spectrum of a disease that is difficult to define. PMID- 21533613 TI - Epigenetic silencing of microRNA-375 regulates PDK1 expression in esophageal cancer. AB - BACKGROUND: MicroRNAs (miRNAs) are a class of small (19-25 nucleotides) noncoding RNAs that regulate the expressions of a wide variety of genes, including some involved in cancer development. Some recent studies show that DNA methylation contributes to down-regulation of microRNA-375 (miR-375) during tumorigenesis. Whether or not down-regulation of miR-375 also exists in esophageal cancer is unknown. AIM: Our aim was to test the hypothesis that down-regulation of miR-375 also exists in esophageal cancer. METHODS: Expression of levels of miR-375 were examined using real-time PCR on paired esophageal cancer and adjacent non cancerous tissues. The methylation status is detected by methylation specific-PCR (MSP). RESULTS: The results show that miR-375 is downregulated by hypermethylation of the promoter in esophageal cancer tissues. Epigenetic silencing of miR-375 induced an up-regulation of its targets, 3-phosphoinositide dependent protein kinase-1 (PDK1). Restoration of the miR-375 expression in esophageal cancer cell lines downregulated the PDK1 expression. Furthermore, the miR-375 expression was found to be inversely correlated with PDK1 expression in esophageal cancer. CONCLUSION: Thus, miR-375 is frequently down-regulated in esophageal cancer and is a negative regulator of PDK1. PMID- 21533614 TI - [Physical exposure by travelling]. AB - Approximately 40 million Germans travel abroad every year. Air travel is the most frequently used mean of transportation followed by the automobile. During airplane flights rheumatic patients are subjected to numerous physical, biological and climatic factors which can cause stress and adverse effects on general health. Therefore, preventive strategies are helpful to protect against health damage, provided that there is general fitness for air travel. The present article focuses on physical and biological stress as well as psychological aspects during air travel and reviews prophylactic measures. PMID- 21533615 TI - Merits of the fat-tailed Barbarine sheep raised in different production systems in Tunisia: digestive, productive and reproductive characteristics. AB - Barbarine sheep is the dominant breed in Tunisia. This fat-tailed breed present in all production systems is characterised by metabolic and digestive adaptation to the contrasting environment conditions prevailing in the country (heat stress, water deprivation, salinity etc.). The fat tail (1.5 to 7 kg) is an energy reservoir that is used in periods of feed scarcity. Moreover, the rumen of this breed harbours a microflora enabling it to valorize low-quality roughages and native range vegetation. Barbarine sheep could make benefit from a wide range of local feed resources like fodder shrubs (e.g. cactus and oldman saltbushes), tannin-containing shrubs (e.g. Acacia cyanophylla) and agro-industrial by products (e.g. olive cake, bran etc. conserved in the form of feed blocks or pellets). It has a very shallow anoestrous, the intensity of which is dependant upon nutrition conditions rather than day length as temperate breeds. Productive and reproductive performances of late pregnant-early suckling, pre-mating ewes and also rams of this breed are not affected when some alternative feed resources replace common feedstuffs which are expensive and cannot afford regularly to smallholders. In brief, the merits of the Barbarine sheep in the production systems and other main adaptive mechanisms of this breed are discussed in this paper. The prospective of Barbarine sheep husbandry in the system dynamics, climate change and the evolution of the socioeconomic context are also envisaged. PMID- 21533616 TI - Mycorrhiza status of Gnetum spp. in Cameroon: evaluating diversity with a view to ameliorating domestication efforts. AB - A field survey was carried out to investigate the diversity of mycorrhizal fungi associated with Gnetum spp. in Cameroon. The extent and variation of ectomycorrhizal colonisation as well as the degree of host specificity were evaluated. Gnetum spp. were found to be almost always ectomycorrhizal in all sites visited. There were just two ectomycorrhizal morphotypes ('yellow' and 'white') associated with this plant. Such low diversity is unusual for an ectomycorrhizal plant. The yellow morphotype was the most widespread and prevalent and was identified by morphological and molecular methods to have been formed with Scleroderma sinnamariense. Propagules of this fungus were present in soil collected from farm lands, cocoa plantations, Chromolaena and bush fallows, as well as in a relatively undisturbed forest harbouring ectomycorrhizal legumes. The fungus responsible for the white morphotype was identified as also belonging to the genus Scleroderma by ITS sequence similarity. Arbuscular mycorrhizal structures were absent in cleared and stained portions of the roots. PMID- 21533617 TI - Importance of patient satisfaction with care in predicting osteoarthritis specific health-related quality of life one year after total joint arthroplasty. AB - PURPOSE: After previous results observed with a generic health-related quality of life (HRQoL) instrument, we aimed to confirm that immediate postoperative patient satisfaction with care predicts self-perceived health 1 year after total hip replacement/total knee replacement (THR/TKR), using an osteoarthritis (OA) specific HRQoL questionnaire. METHODS: This was a French multicenter prospective cohort study of patients after THR/TKR. HRQoL was assessed by the OsteoArthritis Knee and Hip Quality Of Life (OAKHQOL) instrument before and after surgery and satisfaction with care by the Quality of Care Scale (QCS). RESULTS: A total of 189 patients were followed up 12 months after discharge (mean age 68.9 SD = 8.5; 41.9% male). After adjustment for relevant variables, patients satisfied with care postoperatively showed greater 1-year postoperative HRQOL than those less satisfied with care. Patients satisfied with medical information had a higher postoperative HRQoL score than patients less satisfied in 3 of 5 OAKHQOL dimensions (P < 0.001 to P = 0.02), and patients satisfied with relationships with staff and daily routine scored higher on all HRQoL dimensions than did less satisfied patients (all P < 0.001). CONCLUSIONS: These new findings with an OA specific HRQOL questionnaire confirm that immediate postoperative satisfaction with care after THR/TKR for OA is a good predictor of self-perceived health status 1 year after surgery. Satisfaction with care therefore represents a relevant indicator of patient-reported health and is quickly accessible to clinicians. PMID- 21533620 TI - Space-time network connectivity and cortical activations preceding spike wave discharges in human absence epilepsy: a MEG study. AB - To describe the spatial and temporal profiles of connectivity networks and sources preceding generalized spike-and-wave discharges (SWDs) in human absence epilepsy. Nonlinear associations of MEG signals and cluster indices obtained within the framework of graph theory were determined, while source localization in the frequency domain was performed in the low frequency bands with dynamic imaging of coherent sources. The results were projected on a three-dimensional surface rendering of the brain using a semi-realistic head model and MRI images obtained for each of the five patients studied. An increase in clustering and a decrease in path length preceding SWD onset and a rhythmic pattern of increasing and decreasing connectivity were seen during SWDs. Beamforming showed a consistent appearance of a low frequency frontal cortical source prior to the first generalized spikes. This source was preceded by a low frequency occipital source. The changes in the connectivity networks with the onset of SWDs suggest a pathologically predisposed state towards synchronous seizure networks with increasing connectivity from interictal to preictal and ictal state, while the occipital and frontal low frequency early preictal sources demonstrate that SWDs are not suddenly arising but gradually build up in a dynamic network. PMID- 21533621 TI - Bacterial diversity of periodontal and implant-related sites detected by the DNA Checkerboard method. AB - The aim of this study was to compare the microbial composition of the subgingival biofilm from teeth and implant sulci in relation to contents originating from internal parts of the implant, abutment and implant prosthesis. Twenty subgingival biofilm samples from the mesial and distal aspects of each tooth/implant and 29 samples from the internal parts of titanium implants, abutments and implant prostheses were evaluated for the presence of 18 bacterial species using DNA Checkerboard and the differences between samples from teeth and implants were assessed with Pearson's correlation analysis. The periodontal and peri-implantar sulci presented significantly higher bacterial counts than the implant-related sites (p < 0.05 and p < 0.01, respectively). The highest counts were observed for Capnocytophaga gingivalis, Prevotella intermedia, P. nigrescens and P. micra. The correlation between the counts in the periodontal and peri implantar sulci was r = 0.66 (p < 0.001). Weaker correlations between samples from the internal parts of the implants and periodontal sulcus (r = 0.49; p < 0.001) or peri-implant sulcus (r = 0.42; p < 0.001) were found. All 18 bacterial species were detected to be colonising the subgingival sulcus of teeth and implants, and implant components in the evaluated patients. Significant correlations between the microbiota were found, the strongest being between the periodontal and peri-implantar sulci. PMID- 21533622 TI - Fungal infection in a patient with multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system, whose causes are still unknown. We have proposed that MS, as well as some ophthalmologic diseases, are associated with fungal infection. In the present study, we closely monitored a patient with MS over a three-year period. Antibodies against different Candida spp. were detected in peripheral blood serum, although the titer of these antibodies fluctuated. The presence of fungal macromolecules, such as proteins, polysaccharides, and DNA, was also tested. In several sera samples, antigens related to C. famata were evidenced by the slot blot test using a rabbit polyclonal antibody against these species, while high levels of beta-1,3 glucan were detected with the commercial Fungitell assay. Despite the variations by sample, we concluded that all fungal macromolecules, that is, proteins, polysaccharides, and DNA, were present in blood from the MS patient which was analyzed. Several fungal species were identified using polymerase chain reaction (PCR) followed by sequencing. Antibodies against Candida spp. as well as C. famata-related antigens were also detected in cerebrospinal fluid (CSF). Our findings provide support for the notion that disseminated mycosis is present in this patient. PMID- 21533623 TI - Prospective associations between HIV-related stigma, transmission risk behaviors, and adverse mental health outcomes in men who have sex with men. AB - BACKGROUND: The vast majority of research on HIV-related stigma has been cross sectional, and few studies have examined whether experiencing stigma is associated with sexual risk behaviors. PURPOSE: The purpose of this study is to examine the prospective relationships between experiencing HIV-related stigma and symptoms of anxiety and depression, as well as sexual transmission risk behavior. METHODS: The sample included HIV-infected men who have sex with men (n = 314) who participated in a secondary HIV-prevention study at their primary care site. Participants were assessed at baseline, and then completed follow-up assessments at 3, 6, 9, and 12 months. RESULTS: Experiencing HIV-related stigma was prospectively associated with symptoms of depression (beta = 0.16, p < .001), panic (beta = 0.11, p = .01), and generalized anxiety (beta = 0.05, p = .05). In addition, perceiving HIV-related stigma was prospectively associated with transmission risk behaviors, including unprotected receptive or insertive anal intercourse with HIV-seronegative or status unknown partners (beta = 0.06, p = .047). CONCLUSIONS: Experiencing HIV-related stigma may increase risk for sexual transmission risk behavior and mental health problems. PMID- 21533624 TI - Impact of framing on intentions to vaccinate daughters against HPV: a cross cultural perspective. AB - BACKGROUND: Effective promotion of the human papilloma virus (HPV) vaccine across ethnic/racial groups may help curtail disparities in cervical cancer rates. PURPOSE: This study aims to investigate mothers' intentions to vaccinate daughters against HPV as a function of message framing (gain versus loss) across three cultural groups: Hispanic, non-Hispanic white, and non-Hispanic African American. METHODS: One hundred fifty mothers were recruited from city department of health clinics and asked to respond to information about the HPV vaccine for their daughters. In a repeated-measures experiment, two different frames (gain and loss) were used to present the information. RESULTS: The results indicated that both frames are equally effective in promoting vaccination intentions in non Hispanic white mothers. Conversely, a loss frame message was more effective in non-Hispanic African-American and Hispanic mothers. CONCLUSIONS: Information sharing campaigns, aimed at promoting the HPV vaccine among ethnic minority groups should be modified to not focus exclusively on the benefits of vaccination. PMID- 21533625 TI - Fleshy fruit characteristics in a temperate deciduous forest of Japan: how unique are they? AB - This study investigated the fleshy fruit characteristics of 28 woody species in a Japanese temperate forest where large sedentary seed-dispersing mammals are present. We tested whether the findings in previous studies in temperate forests of Europe and North America are universal or not. Results have suggested that fruits of all species were eaten both by birds and mammals except for four species with larger fruits, which were eaten only by mammals. A gradient was found from a syndrome characterized by small, oily, and large-seeded fruits to a syndrome characterized by large, succulent, non-oily, and small-seeded fruits. The sizes and colors of the fruits were not conspicuously different from previous findings in Europe and North America. On the other hand, nitrogen and lipids in the fleshy part did not show seasonally increasing trends, or even seasonally decreasing trends in terms of dry weight. This result, suggesting the absence of community-level adaptation of fruit traits to migratory bird dispersers, contrasted with findings in Europe and North America. Large sedentary arboreal or tree-climbing mammals may have a greater effect on the evolution of fruit disperser relations than opportunistic migratory birds. PMID- 21533626 TI - Wnt signaling and renal medulla formation. AB - The renal medulla, the inner compartment of the metanephric kidney, plays vital roles in the regulation of body water, electrolyte homeostasis, and systemic blood pressure. It is composed of the loops-of-Henle, the medullary collecting ducts, the vasa recta, and the medullary interstitium. Its epithelial and endothelial components display ordered spatial organization. This organization serves as the structural basis for its function in urine concentration. The urine concentration ability of a renal medulla is also related to its length among species. In this review, the current understanding of the molecular and cellular mechanisms underlying renal medulla formation (elongation) is summarized, with a focus on the role of Wnt signaling in this developmental process. Renal medulla blunting and effacement is a common symptom of many renal and urological destructions. The knowledge in renal medulla formation should assist efforts in repair and regeneration of a damaged renal medulla, so to improve renal physiology in diseased situations. PMID- 21533627 TI - Soy protein prevents renal damage in a fructose-induced model of metabolic syndrome via inhibition of NF-kB in male rats. AB - The study determines the effect of soy protein on inflammatory status and expression of nuclear factor-kappa B (NF-kappaB P(65)) and receptor for advanced glycation end products (RAGE) in a metabolic syndrome (MS) model. MS was induced in adult male rats by feeding them a high fructose diet (60 g/100 g diet). The rats were randomised into six groups by feeding one of the following semi synthetic diets for 60 days: corn starch (60%) and casein (20%; CCD), fructose (60%) and casein (20%; FCD), fructose (60%) and soy protein (20%; FSD) or corn starch (60%) and soy protein (20%; CSD). The expression of NF-kappaB P(65), transforming growth factor-beta1 (TGF-beta1) and RAGE, histochemical localization of alpha-smooth muscle actin (alpha-SMA), tumour necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) assays, collagen deposition and ultrastructural analysis were performed. FCD rats displayed inflammatory changes and increased expression of growth factors and nuclear factors. FSD rats showed reduction in inflammation, fibrogenesis, collagen deposition, NF-kappaB activation and mitigated the ultrastructural changes. Soy protein prevents inflammation and early nephropathic changes in the MS model secondary to the attenuation of NF kappaB activation. PMID- 21533628 TI - Psychological correlates of enuresis: a case-control study on an Italian sample. AB - The psychological correlates of enuresis are receiving growing attention, coherently with a multi-factorial approach to this problem, but to date the empirical findings are still inconsistent and incomplete. The aim of this study is to contribute to the understanding of the socio-affective functioning of enuretic children by exploring four central dimensions: attachment, self-esteem, self-control, and temperament. Twenty-two enuretic children with their mothers were enrolled in the study and matched, based on gender and age, to a control group of continent healthy children. Measures were collected through mothers' reports and individual administrations to all children. Controlling for socio demographic variables, we found a significantly lower incidence of secure attachment, lower self-esteem, and higher rates of behavioral problems among the enuretic group, compared with the control group. No differences in the temperamental dimensions were found. These preliminary findings support the view of enuresis as a bio-behavioral problem and, from a practical standpoint, underline the urgency for physicians not to underestimate this disturbance, but, indeed, to treat the problem through medical strategies and to devote attention to the psychological difficulties of these patients. PMID- 21533630 TI - Motion and color generate coactivation at postgrouping identification stages. AB - Response times (RTs) were measured in a postgrouping visual identification task. Shapes composed of multiple elements were distinguished by color, motion, orientation, and spatial frequency alone or in pairwise conjunctions. The largest amount of redundancy gain, requiring coactivation as revealed by a race model analysis, was obtained with color-motion conjunctions. In contrast, RTs for a pregrouping detection task using the same target shape as in the identification task, distinguished by color, motion, or a conjunction of these features, showed no evidence for coactivation. The results provide psychophysical evidence for coactivation of color and motion signals in cortical regions specialized for grouping and object identification, as opposed to separate processing of these features in cortical area V1, believed to limit performance in visual search and pregrouping detection. PMID- 21533629 TI - Effect of diet, enalapril, or losartan in post-diarrheal hemolytic uremic syndrome nephropathy. AB - Proteinuria is the main indicator of renal disease progression in many chronic conditions. There is currently little information available on the efficacy, safety, and individual tolerance of patients with post-diarrheal hemolytic uremic syndrome (D+ HUS) nephropathy to therapies involving diet, enalapril, or losartan. A multicenter, double-blind, randomized controlled trail was conducted to evaluate the effect of a normosodic-normoproteic diet (Phase I) and the effect of normosodic-normoproteic diet plus enalapril (0.18-0.27 mg/kg/day) or losartan (0.89-1.34 mg/kg/day) (Phase II) on children with D+ HUS, normal renal function, and persistent, mild (5.1-49.9 mg/kg/day) proteinuria. Dietary intervention reduced the mean protein intake from 3.4 to 2.2 mg/kg/day. Of 137 children, proteinuria normalized in 91 (66.4 %) within 23-45 days; the remaining 46 patients were randomized to diet plus placebo (group 1, n = 16), plus losartan (group 2, n = 16), or enalapril (group 3, n = 14). In groups 1, 2, and 3, proteinuria was reduced by 30.0, 82.0, and 66.3%, respectively, and normalized in six (37.5%), three (81.3%), and 11 (78.6%) patients, respectively (chi(2)= 8.9, p = 0.015). These results suggest that: (1) a normosodic-normoproteic diet can normalize proteinuria in the majority of children with D+ HUS with mild sequelae, (2) the addition of enalapril or losartan to such dietary restrictions of protein further reduces proteinuria, and (3) these therapeutic interventions are safe and well tolerated. Whether these short-term effects can be extended to the long-term remains to be demonstrated. PMID- 21533631 TI - Dual energy CT pulmonary blood volume assessment in acute pulmonary embolism - correlation with D-dimer level, right heart strain and clinical outcome. AB - OBJECTIVE: To investigate the role of perfusion defect (PD) size on dual energy CT pulmonary blood volume assessment as predictor of right heart strain and patient outcome and its correlation with d-dimer levels in acute pulmonary embolism (PE). METHODS: 53 patients with acute PE who underwent DECT pulmonary angiography were retrospectively analyzed. Pulmonary PD size caused by PE was measured on DE iodine maps and quantified absolutely (VolPD) and relatively to the total lung volume (RelPD). Signs of right heart strain (RHS) on CT were determined. Information on d-dimer levels and readmission for recurrent onset of PE and death was collected. RESULTS: D-dimer level was mildly (r = 0.43-0.47) correlated with PD size. Patients with RHS had significantly higher VolPD (215 vs. 73 ml) and RelPD (9.9 vs. 2.9%) than patients without RHS (p < 0.003). There were 2 deaths and 1 readmission due of PE in 18 patients with >5% RelPD, while no such events were found for patients with <5% RelPD. CONCLUSION: Pulmonary blood volume on DECT in acute PE correlates with RHS and appears to be a predictor of patient outcome in this pilot study. PMID- 21533632 TI - ECG-triggered non-contrast-enhanced MR angiography (TRANCE) versus digital subtraction angiography (DSA) in patients with peripheral arterial occlusive disease of the lower extremities. AB - OBJECTIVE: To prospectively determine the diagnostic value of electrocardiography triggered non-contrast-enhanced magnetic resonance angiography (TRANCE) of the lower extremities including the feet versus DSA. METHODS: All 43 patients with symptomatic peripheral arterial occlusive disease (PAOD) underwent TRANCE before DSA. Quality of MRA vessel depiction was rated by two independent radiologists on a 3-point scale. Arterial segments were graded for stenoses using a 4-point scale (grade 1: no stenosis; grade 2: moderate stenosis; grade 3: severe stenosis; grade 4: occlusion). Findings were compared with those of DSA. RESULTS: In the 731 vessel segments analysed, intra-arterial DSA revealed 283 stenoses: 33.6% moderate, 16.6% severe and 49.8% occlusions. TRANCE yielded a mean sensitivity, specificity, positive and negative predictive value and diagnostic accuracy to detect severe stenoses or occlusions of 95.6%, 97.4%, 87.2%, 99.2%, 97.1% for the thigh segments and 95.2%, 87.5%, 83.2%, 96.6%, 90.5% for the calf segments. Excellent overall image quality was observed for TRANCE in 91.4% versus 95.7% (DSA) for the thigh and in 60.7% versus 91.0% for the calves, while diagnostic quality of the pedal arteries was rated as insufficient. CONCLUSION: TRANCE achieves high diagnostic accuracy in the thigh and calf regions, whereas the pedal arteries showed limited quality. PMID- 21533633 TI - Biodegradable polydioxanone stents: a new option for therapy-resistant anastomotic strictures of the colon. AB - OBJECTIVES: To assess the outcome of self-expandable, biodegradable stent insertion for anastomotic strictures following treatment for rectosigmoid carcinoma. METHODS: Three male patients (median age 66) developed benign strictures after radiotherapy and resection of a recto-sigmoid carcinoma. These were resistant to balloon dilatation and prevented stoma reversal. Biodegradable stent insertion was performed as an experimental treatment on a named-patient basis with approval of the institutional review board. Patients had monthly follow-up with endoscopy and contrast medium enemas to monitor performance and degradation of the stents. RESULTS: All stents were placed successfully without complications after pre-dilatation to 20 mm under fluoroscopic guidance. Stent degradation occurred in all patients 4-5 months following implantation, and long term anastomotic patency was demonstrated in all. This allowed reversal of the colostomy and physiological defecation in two patients. Reversal was not undertaken in one due to subsequent development of liver metastases. No stent migration or occlusion occurred. CONCLUSIONS: Biodegradable stents can maintain an adequate lumen across anastomotic strictures resistant to balloon dilatation. They seem to allow stricture re-modelling resulting in maintained dilatation after degradation. This potentially allows reversal of a colostomy, which might otherwise be prevented by stricture recurrence. PMID- 21533634 TI - Incremental value of diffusion weighted and dynamic contrast enhanced MRI in the detection of locally recurrent prostate cancer after radiation treatment: preliminary results. AB - OBJECTIVES: To assess the incremental value of diffusion-weighted (DW-MRI) and dynamic contrast-enhanced MRI (DCE-MRI) to T2-weighted MRI (T2WI) in detecting locally recurrent prostate cancer after radiotherapy. METHODS: Twenty-four patients (median age, 70 years) with a history of radiotherapy-treated prostate cancer underwent multi-parametric MRI (MP-MRI) and transrectal prostate biopsy. Two readers independently scored the likelihood of cancer on a 1-5 scale, using T2WI alone and then adding DW-MRI and DCE-MRI. Areas under receiver operating characteristic curves (AUCs) were estimated at the patient and prostate-side levels. The apparent diffusion coefficient (ADC) from DW-MRI and the K(trans), k(ep), v(e), AUGC90 and AUGC180 from DCE-MRI were recorded. RESULTS: Biopsy was positive in 16/24 (67%) and negative in 8/24 (33%) patients. AUCs for readers 1 and 2 increased from 0.64 and 0.53 to 0.95 and 0.86 with MP-MRI, at the patient level, and from 0.73 and 0.66 to 0.90 and 0.79 with MP-MRI, at the prostate-side level (p values < 0.05). Biopsy-positive and biopsy-negative prostate sides differed significantly in median ADC [1.44 vs. 1.68 (*10(-3) mm(2)/s)], median K(trans) [1.07 vs. 0.34 (1/min)], and k(ep) [2.06 vs 1.0 (1/min)] (p values < 0.05). CONCLUSIONS: MP-MRI was significantly more accurate than T2WI alone in detecting locally recurrent prostate cancer after radiotherapy. PMID- 21533636 TI - Novel cyanobacterial bioreporters of phosphorus bioavailability based on alkaline phosphatase and phosphate transporter genes of Anabaena sp. PCC 7120. AB - There is heterogeneity in the way cyanobacteria respond to P starvation and subsequently how they adapt to environments with low or fluctuating P concentrations. In this study, we have fused the promoterless lux operon luxCDABE to the promoter regions of Anabaena sp. PCC 7120 phoA genes putatively encoding alkaline phosphatases, phoA (all2843) and phoA-like (alr5291) and to the promoter region of one operon putatively encoding a high affinity phosphate transporter pst1 (all4575-4572). The self-bioluminescent strains constructed in this way, Anabaena AP (phoA promoter), Anabaena AP-L (phoA-like promoter), and Anabaena PST (pst1 promoter) have been used to study the expression of these genes in response to P starvation and P re-feeding with inorganic and organic phosphate sources. Our data showed that the pst1 promoter was activated at much higher level than the phoA-like promoter following P starvation; however, we did not observe activation of the phoA promoter. The P re-feeding experiments revealed that both strains, Anabaena (A.) PST and A. AP-L could be used as novel bioreporters of P availability in environmental samples. Both strains were used to estimate bioavailable P in environmental samples (fresh- and wastewaters) with a wide range of soluble P concentrations. The results indicated that most of the P in the water samples was in chemical forms available to the cyanobacterium; however there were some differences in the estimates given by both strains as A. PST appeared to be more adequate for the samples with the lowest P load while A. AP-L gave similar or even higher values of P concentrations than those chemically measured in samples with higher P load. PMID- 21533635 TI - Association between pneumonia and oral care in nursing home residents. AB - Pneumonia remains the leading cause of death in nursing home residents. The accumulation of dental plaque and colonization of oral surfaces and dentures with respiratory pathogens serves as a reservoir for recurrent lower respiratory tract infections. Control of gingivitis and dental plaques has been effective in reducing the rate of pneumonia but the provision of dental care for institutionalized elderly is inadequate, with treatment often sought only when patients experience pain or denture problems. Direct mechanical cleaning is thwarted by the lack of adequate training of nursing staff and residents' uncooperativeness. Chlorhexidine-based interventions are advocated as alternative methods for managing the oral health of frail older people; however, efficacy is yet to be demonstrated in randomized controlled trials. Development and maintenance of an oral hygiene program is a critical step in the prevention of pneumonia. While resources may be limited in long-term-care facilities, incorporating oral care in daily routine practice helps to reduce systemic diseases and to promote overall quality of life in nursing home residents. PMID- 21533638 TI - Microbial genotoxicity bioreporters based on sulA activation. AB - A bacterial genotoxicity reporter strain was constructed in which the tightly controlled strong promoter of the Escherichia coli SOS response gene sulA was fused to the alkaline phosphatase-coding phoA reporter gene. The bioreporter responded in a dose-dependent manner to three model DNA-damaging agents-hydrogen peroxide, nalidixic acid (NA), and mitomycin C (MMC)-detected 30-60 min after exposure. Detection thresholds were 0.15 MUM for MMC, 7.5 MUM for nalidixic acid, and approximately 50 MUM for hydrogen peroxide. A similar response to NA was observed when the bioreporter was integrated into a specially designed, portable electrochemical detection platform. Reporter sensitivity was further enhanced by single and double knockout mutations that enhanced cell membrane permeability (rfaE) and inhibited DNA damage repair mechanisms (umuD, uvrA). The rfaE mutants displayed a five- and tenfold increase in sensitivity to MMC and NA, respectively, while the uvrA mutation was advantageous in the detection of hydrogen peroxide. A similar sensitivity was displayed by the double rfaE/uvrA mutant when challenged with the pre-genotoxic agents 2-amino-3-methylimidazo[4,5 f]quinoline and 2-aminoanthracene following metabolic activation with an S9 mammalian liver fraction. PMID- 21533639 TI - Determination of tandospirone in human plasma by a liquid chromatography-tandem mass spectrometry method. AB - A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometry method for the detection of tandospirone in human plasma is described. It was employed in a pharmacokinetic study. The analyte and internal standard diphenhydramine were extracted from plasma using liquid-liquid extraction, then separated on a Zorbax XDB C(18) column using a mobile phase of methanol-water formic acid (80:20:0.5, v/v/v). The detection was performed with a tandem mass spectrometer equipped with an electrospray ionization source. Linearity was established in the concentration range of 10.0-5,000 pg/ml. The lower limit of quantification was 10.0 pg/ml. The intraday and interday relative standard deviation across three validation runs over the entire concentration range was less than 13%. Accuracy determined at three concentrations (25.0, 200, and 4,000 pg/ml for tandospirone) ranged from 94.4 to 102.1%. Each plasma sample was chromatographed within 3.4 min. The method proved to be highly selective and suitable for bioequivalence evaluation of different formulations containing tandospirone and clinical pharmacokinetic investigation of tandospirone. PMID- 21533640 TI - Standoff detection of explosives: critical comparison for ensuing options on Raman spectroscopy-LIBS sensor fusion. AB - In general, any standoff sensor for the effective detection of explosives must meet two basic requirements: first, a capacity to detect the response generated from only a small amount of material located at a distance of several meters (high sensitivity) and second, the ability to provide easily distinguishable responses for different materials (high specificity). Raman spectroscopy and laser-induced breakdown spectroscopy (LIBS) are two analytical techniques which share similar instrumentation and, at the same time, generate complementary data. These factors have been taken into account recently for the design of sensors used in the detection of explosives. Similarly, research on the proper integration of both techniques has been around for a while. A priori, the different operational conditions required by the two techniques oblige the acquisition of the response for each sensor through sequential analysis, previously necessary to define the proper hierarchy of actuation. However, such an approach does not guarantee that Raman and LIBS responses obtained may relate to each other. Nonetheless, the possible advantages arising from the integration of the molecular and elemental spectroscopic information come with an obvious underlying requirement, simultaneous data acquisition. In the present paper, strong and weak points of Raman spectroscopy and LIBS for solving explosives detection problems, in terms of selectivity, sensitivity, and throughput, are critically examined, discussed, and compared for assessing the ensuing options on the fusion of the responses of both sensing technologies. PMID- 21533641 TI - Ultra-trace analysis of 36Cl by accelerator mass spectrometry: an interlaboratory study. AB - A first international (36)Cl interlaboratory comparison has been initiated. Evaluation of the final results of the eight participating accelerator mass spectrometry (AMS) laboratories on three synthetic AgCl samples with (36)Cl/Cl ratios at the 10(-11), 10(-12), and 10(-13) level shows no difference in the sense of simple statistical significance. However, more detailed statistical analyses demonstrate certain interlaboratory bias and underestimation of uncertainties by some laboratories. Following subsequent remeasurement and reanalysis of the data from some AMS facilities, the round-robin data indicate that (36)Cl/Cl data from two individual AMS laboratories can differ by up to 17%. Thus, the demand for further work on harmonising the (36)Cl-system on a worldwide scale and enlarging the improvement of measurements is obvious. PMID- 21533642 TI - Quantitative comparison of preparation methodologies for X-ray fluorescence microscopy of brain tissue. AB - X-ray fluorescence microscopy (XFM) facilitates high-sensitivity quantitative imaging of trace metals at high spatial resolution over large sample areas and can be applied to a diverse range of biological samples. Accurate determination of elemental content from recorded spectra requires proper calibration of the XFM instrument under the relevant operating conditions. Here, we describe the manufacture, characterization, and utilization of multi-element thin-film reference foils for use in calibration of XFM measurements of biological and other specimens. We have used these internal standards to assess the two dimensional distribution of trace metals in a thin tissue section of a rat hippocampus. The data used in this study was acquired at the XFM beamline of the Australian Synchrotron using a new 384-element array detector (Maia) and at beamline 2-ID-E at the Advanced Photon Source. Post-processing of samples by different fixation techniques was investigated, with the conclusion that differences in solvent type and sample handling can significantly alter elemental content. The present study highlights the quantitative capability, high statistical power, and versatility of the XFM technique for mapping trace metals in biological samples, e.g., brain tissue samples in order to help understand neurological processes, especially when implemented in conjunction with a high performance detector such as Maia. PMID- 21533643 TI - Prospective randomised comparison of arthroscopic versus mini-open rotator cuff repair of the supraspinatus tendon. AB - PURPOSE: The aim of the study was to evaluate whether arthroscopic (ASC) repair of rotator cuff ruptures causes less postoperative pain and better range of motion (ROM) in the early postoperative period than a mini-open (MO) technique. METHODS: Inclusion criteria were a rupture of the supraspinatus tendon with retraction with a maximum to the apex of the humeral head and minor fatty degeneration and atrophy of the muscle. Each group (n = 17) had similar demographics and preoperative magnetic resonance imaging (MRI) findings (mean age 60.1 years, SD 8.8, range 43-71). The ASC group underwent double-row repair with resorbable anchors; the MO group received a transosseous repair. The postoperative rehabilitation was standardised and equivalent in both groups. RESULTS: In the first week fewer nonsteroidal anti-inflammatory drug (NSAID) tablets were needed in the ASC group. Pain scores on the visual analogue scale were similar in the first three weeks; however, from week four to eight the MO group had less pain (p < 0.05). After six months, the Constant-Murley score and the ROM improved significantly (p < 0.05) in both groups without differences between the groups. Postoperative MRI revealed in three of 16 patients a discontinuity of the tendon in both groups; in the ASC group there were more patients (n = 9) with a thinning of the tendon compared to the MO group (n = 6). CONCLUSIONS: There was less use of NSAIDs in the first postoperative week in the ASC group, indirectly indicating less pain, but higher pain scores in the later course (weeks four to eight) compared to the MO group. ROM, MRI findings and the scores were similar after six months, demonstrating that both techniques are equivalent regarding the outcome in this period. PMID- 21533644 TI - A nodulin/glutamine synthetase-like fusion protein is implicated in the regulation of root morphogenesis and in signalling triggered by flagellin. AB - The nodulin/glutamine synthetase-like protein (NodGS) that we identified proteomically in Arabidopsis thaliana is a fusion protein composed of an N terminal amidohydrolase domain that shares homology with nodulins and a C terminal domain of prokaryotic glutamine synthetase type I. The protein is homologous to the FluG protein, a morphogenetic factor in fungi. Although genes encoding NodGS homologues are present in many plant genomes, their products have not yet been characterized. The Arabidopsis NodGS was present in an oligomeric form of ~700-kDa, mainly in the cytosol, and to a lesser extent in the microsomal membrane fraction. The oligomeric NodGS was incorporated into large heterogeneous protein complexes >700 kDa and partially co-immunoprecipitated with gamma tubulin. In situ and in vivo microscopic analyses revealed a NodGS signal in the cytoplasm, with endomembranes, particularly in the perinuclear area. NodGS had no detectable glutamine synthetase activity. Downregulation of NodGS by RNAi resulted in plants with a short main root, reduced meristematic activity and disrupted development of the root cap. Y2H analysis and publicly available microarray data indicated a role for NodGS in biotic stress signalling. We found that flagellin enhanced the expression of the NodGS protein, which was then preferentially localized in the nuclear periphery. Our results point to a role for NodGS in root morphogenesis and microbial elicitation. These data might help in understanding the family of NodGS/FluG-like fusion genes that are widespread in prokaryotes, fungi and plants. PMID- 21533648 TI - Central compartment neck dissection for thyroid cancer: a surgical technique. AB - Several professional societies have in the past few years joined forces to standardize and define terminology for central compartment neck dissection, with the objective of improving communication among professionals and encouraging a more uniform surgical approach to neck nodes. Precisely defining and describing a technique has the advantage of providing a basis for communication and for discussion. A basic technique should be reproducible with low morbidity and teachable to surgeons in training. We herein describe a basic technique for bilateral central compartment neck dissection for thyroid cancer. PMID- 21533646 TI - Manganese induces oxidative stress, redox state unbalance and disrupts membrane bound ATPases on murine neuroblastoma cells in vitro: protective role of silymarin. AB - Manganese (Mn) is an essential trace element required for ubiquitous enzymatic reactions. Chronic overexposure to this metal may promote potent neurotoxic effects. The mechanism of Mn toxicity is not well established, but several studies indicate that oxidative stress play major roles in the Mn-induced neurodegenerative processes. Silymarin (SIL) has antioxidant properties and stabilizes intracellular antioxidant defense systems. The aim of this study was to evaluate the toxic effects of MnCl(2) on the mouse neuroblastoma cell lines (Neuro-2A), to characterize the toxic mechanism associated with Mn exposure and to investigate whether SIL could efficiently protect against neurotoxicity induced by Mn. A significant increase in LDH release activity was observed in Neuro-2A cells associated with a significant decrease in cellular viability upon 24 h exposure to MnCl(2) at concentrations of 200 and 800 MUM (P < 0.05) when compared with control unexposed cells. In addition, exposure cells to MnCl(2) (200 and 800 MUM), increases oxidant biomarkers and alters enzymatic and non enzymatic antioxidant systems. SIL treatment significantly reduced the levels of LDH, nitric oxide, reactive oxygen species and the oxidants/antioxidants balance in Neuro-2A cells as compared to Mn-exposed cells. These results suggested that silymarin is a powerful antioxidant through a mechanism related to its antioxidant activity, able to interfere with radical-mediated cell death. SIL may be useful in diseases known to be aggravated by reactive oxygen species and in the development of novel treatments for neurodegenerative disorders such as Alzheimer or Parkinson diseases. PMID- 21533647 TI - Twenty years of experience in the treatment of spontaneous aorto-venous fistulas in a developing country. AB - BACKGROUND: One of the rare forms of abdominal aortic aneurysm (AAA) rupture is the rupture into great abdominal veins such as the inferior vein cava (IVC), the iliac veins, or the left renal vein, with the formation of direct or indirect aorto-caval fistula (ACF). The purpose of the present study was to summarize 20 years of experience at a single referral center for vascular surgery in a developing country, and to discuss the clinical presentation, diagnosis, treatment options, and outcome of patients with spontaneous aorto-venous fistulas (AVF) caused by ruptured aortic aneurysms. MATERIALS AND METHODS: Retrospective database review identified 50 patients treated in our institution for aorto venous fistulas (AVF) caused by spontaneous AAA rupture in the 20 years 1991 2010. Pulsating abdominal mass and low back pain were the leading symptoms on admission in our patients. Signs of shock, congestive heart failure, or pelvic and lower extremity venous hypertension were present in 48%, 26%, and 75% of the patients, respectively. Diagnosis of AVF was based on physical examination, duplex ultrasonography, conventional angiography, or multislice computed tomography (MSCT). In 40% of the patients the presence of AVF has not been recognized before surgery. All patients were treated with open surgery. RESULTS: After proximal and distal bleeding control the fistula was closed with direct suture (92%) or patch angioplasty (8%). Aortic reconstruction followed with tubular (22%) or bifurcated (78%) synthetic graft. Six (12%) patients died. The causes of death were excessive intraoperative blood loss, myocardial infarction, left colon gangrene and multiple organ failure. CONCLUSIONS: Spontaneous AVFs caused by aneurysmal rupture are not uncommon, and they require prompt surgical or endovascular treatment. Routine use of multislice CT in patients with acute aortic syndrome is probably the best way to the correct diagnosis of aorto-venous fistulas and planning of the optimal treatment. PMID- 21533645 TI - The chloroplast proteome: a survey from the Chlamydomonas reinhardtii perspective with a focus on distinctive features. AB - The unicellular green alga Chlamydomonas reinhardtii has emerged to be an important model organism for the study of oxygenic eukaryotic photosynthesis as well as other processes occurring in the chloroplast. However, the chloroplast proteome in C. reinhardtii has only recently been comprehensively characterized, made possible by proteomics emerging as an accessible and powerful tool over the last decade. In this review, we introduce a compiled list of 996 experimentally chloroplast-localized proteins for C. reinhardtii, stemming largely from our previous proteomic dataset comparing chloroplasts and mitochondria samples to localize proteins. In order to get a taste of some cellular functions taking place in the C. reinhardtii chloroplast, we will focus this review particularly on metabolic differences between chloroplasts of C. reinhardtii and higher plants. Areas that will be covered are photosynthesis, chlorophyll biosynthesis, carbon metabolism, fermentative metabolism, ferredoxins and ferredoxin interacting proteins. PMID- 21533649 TI - Dimethyl sulfoxide induces heme oxygenase-1 expression via JNKs and Nrf2 pathways in human umbilical vein endothelial cells. AB - Dimethyl sulfoxide (DMSO) has recently been proposed as an anti-inflammatory and free radical scavenging agent. However, the mechanisms by which DMSO mediates its therapeutic effects are unclear. In this paper, we investigated the capability of DMSO to up-regulate heme oxygenase-1(HO-1) expression, as well as the possible underlying mechanisms in human umbilical vein endothelial cells (HUVECs). DMSO induced HO-1 expression both at the level of mRNA and protein in dose-and time dependent manners in HUVECs, resulting in increased HO-1 activity. The pharmacological inhibition of cJun-N-terminal kinases (JNKs) blocked the DMSO induced HO-1 up-regulation, while inhibition of extracellular regulated kinase and p38-MAPK did not block heme oxygenase-1 up-regulation. In addition, the phosphorylation of JNKs was initiated by DMSO, indicating the involvement of this kinase in the observed response. DMSO increased the nuclear translocation of NF E2-related factor 2 (Nrf2) and enhanced its binding to the anti-oxidant response element. Inhibition of Nrf2 synthesis by small interfering RNA molecules subsequently inhibited HO-1 expression induced by DMSO, indicating DMSO's role in inducing HO-1 expression via Nrf2 activation. Utilizing these findings, the present study identified DMSO as a novel inducer of HO-1 expression and identified the underlying mechanisms involved in this process. PMID- 21533650 TI - Immunohistochemical expression and localization of somatostatin receptor subtypes in androgen ablated prostate cancer. AB - OBJECTIVE: The aim was to examine the expression and localization of the five somatostatin receptors (termed SSTR1 to 5) in radical prostatectomies (RPs) from patients with prostatic adenocarcinoma (PCa) under complete androgen ablation (CAA) before operation. MATERIAL: The five SSTRs were evaluated in the epithelial, smooth muscle and endothelial cells of normal-looking epithelium (Nep), high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa in 20 RPs with clinically detected PCa from patients under CAA. Twenty RPs with clinically detected PCa from hormonally untreated patients were used as control group. RESULTS: Concerning the secretory cells (i) Membrane staining was seen for SSTR3 and SSTR4; the mean percentages of positive cells, higher in SSTR3 than in SSTR4, decreased sharply in HGPIN and PCa compared with Nep; the mean percentages in the androgen ablated group were 30% to 90% lower than in the untreated; (ii) Cytoplasmic staining was seen for all five SSTRs; the mean percentages of positive cells in Nep, HGPIN and PCa of the untreated group were similar, and in general as high as 80% or more; in the treated group, the Nep values were similar to those in the untreated, whereas the values in HGPIN and PCa were lower for SSTR1, three and five, with a decrease of 30% for SSTR1; (iii) Nuclear staining was seen with SSTR4 and SSTR5, the mean percentages for the former being much lower than for the latter; treatment affected both HGPIN and PCa, whose proportions of stained cells were 30% to 55% lower than in the untreated group. Cytoplasmic staining in the basal cells was seen for all five SSTRs, both in Nep and HGPIN. The values in the treated group were lower than in the other, the difference between the two group being in general comprised between 10% and 40%. Treatment did not affect SSTR staining in the smooth muscle and endothelial cells. CONCLUSIONS: The present study expands our knowledge on the expression and localization of the five SSTRs in the prostate following CAA. PMID- 21533651 TI - Tibiofibular syndesmosis in acute ankle fractures: additional value of an oblique MR image plane. AB - OBJECTIVE: To evaluate the additional value of a 45 degrees oblique MRI scan plane for assessing the anterior and posterior distal tibiofibular syndesmotic ligaments in patients with an acute ankle fracture. MATERIALS AND METHODS: Prospectively, data were collected for 44 consecutive patients with an acute ankle fracture who underwent a radiograph (AP, lateral, and mortise view) as well as an MRI in both the standard three orthogonal planes and in an additional 45 degrees oblique plane. The fractures on the radiographs were classified according to Lauge-Hansen (LH). The anterior (ATIFL) and posterior (PTIFL) distal tibiofibular ligaments, as well as the presence of a bony avulsion in both the axial and oblique planes was evaluated on MRI. MRI findings regarding syndesmotic injury in the axial and oblique planes were compared to syndesmotic injury predicted by LH. Kappa and the agreement score were calculated to determine the interobserver agreement. The Wilcoxon signed rank test and McNemar's test were used to compare the two scan planes. RESULTS: The interobserver agreement (kappa) and agreement score [AS (%)] regarding injury of the ATIFL and PTIFL and the presence of a fibular or tibial avulsion fracture were good to excellent in both the axial and oblique image planes (kappa 0.61-0.92, AS 84-95%). For both ligaments the oblique image plane indicated significantly less injury than the axial plane (p < 0.001). There was no significant difference in detection of an avulsion fracture in the axial or oblique plane, neither anteriorly (p = 0.50) nor posteriorly (p = 1.00). With syndesmotic injury as predicted by LH as comparison, the specificity in the oblique MR plane increased for both anterior (to 86% from 7%) and posterior (to 86% from 48%) syndesmotic injury when compared to the axial plane. CONCLUSION: Our results show the additional value of an 45 degrees oblique MR image plane for detection of injury of the anterior and posterior distal tibiofibular syndesmoses in acute ankle fractures. Findings of syndesmotic injury in the oblique MRI plane were closer to the diagnosis as assumed by the Lauge-Hansen classification than in the axial plane. With more accurate information, the surgeon can better decide when to stabilize syndesmotic injury in acute ankle fractures. PMID- 21533652 TI - Definition and testing of the GROMOS force-field versions 54A7 and 54B7. AB - New parameter sets of the GROMOS biomolecular force field, 54A7 and 54B7, are introduced. These parameter sets summarise some previously published force field modifications: The 53A6 helical propensities are corrected through new phi/psi torsional angle terms and a modification of the N-H, C=O repulsion, a new atom type for a charged -CH(3) in the choline moiety is added, the Na(+) and Cl(-) ions are modified to reproduce the free energy of hydration, and additional improper torsional angle types for free energy calculations involving a chirality change are introduced. The new helical propensity modification is tested using the benchmark proteins hen egg-white lysozyme, fox1 RNA binding domain, chorismate mutase and the GCN4-p1 peptide. The stability of the proteins is improved in comparison with the 53A6 force field, and good agreement with a range of primary experimental data is obtained. PMID- 21533653 TI - Susceptibility of non-target invertebrates to Brazilian microbial pest control agents. AB - Microbial pest control agents or entomopathogens have been considered an interesting alternative to use instead of chemical insecticides. Knowledge of ecotoxicity data is very important to predict the hazard of any product released in the environment and subsidize the regulation of these products by governmental agencies. In the present study four new Brazilian strains of Bacillus and one fungus were tested to evaluate their acute toxicity to the microcrustacean Daphnia similis, the snail Biomphalaria glabrata and the dung beetle Digitonthophagus gazella. The microcrustaceans and the snails were exposed to entomopathogens in synthetic softwater and the beetles were exposed directly in cattle dung. Obtained data reveal low susceptibility of the non-target species to tested microorganisms, with lethal concentrations being observed only at much higher concentrations than that effective against target insects. These results show that the tested strains are selective in their action mode and seem to be non-hazardous to non-target species. PMID- 21533654 TI - [Treatment of advanced metastatic melanoma]. AB - In the past therapy of advanced melanoma with distant metastases was characterized by limited success. In recent years the increased understanding of the pathogenesis of melanoma as well as tumor immunology, however, has allowed the development of new promising therapeutic options for certain subgroups of melanoma patients. In the present review these molecular-targeted and immune modulating therapies, as well as already established therapies such as radiation or chemotherapy, will be discussed. PMID- 21533655 TI - Temperature and burn injury prediction of human skin exposed to microwaves: a model analysis. AB - A one-dimensional multi-layer model is presented to characterize skin temperature rises and burn processes resulting from skin exposure to microwaves. Temperature variations and damage function analyses in the skin tissue exposed to microwaves were predicted depending on blood perfusion rate, thermal conductivity, power density, and exposure time. Thermal wave model was applied and the bio-heat transfer equation was solved using the finite difference time domain method. The thermal wave model of bio-heat transfer predicts a lower temperature rise than a model that uses Pennes' equation. When approaching steady state, the solutions overlaps with that obtained using the Pennes' equation. The results obtained may help to analyze the consequences of short-time high-power MW exposures in biological tissues. PMID- 21533656 TI - Integrated analysis of prognostic gene expression profiles from hepatitis B virus positive hepatocellular carcinoma and adjacent liver tissue. AB - BACKGROUND: The tissue environment in the region of hepatocellular carcinoma (HCC) influences both vascular invasion and recurrence. Thus, HCC patient prognosis depends on the characteristics not only of the tumor but also those of adjacent surrounding liver tissue. MATERIALS AND METHODS: Expression profiles of both tumor and adjacent liver tissue following curative resection were measured to discriminate 56 hepatitis B virus-positive HCC patients into subgroups based on survival risk. This approach was further tested in 40 patients. RESULTS: Expression profiles of both tumor and adjacent liver tissue successfully discriminated 56 training samples into 2 subgroups, those at low- or high-risk for survival and recurrence. However, the prognostic gene set selected for tumor tissue was quite different from that for adjacent tissues. This variation in prognostic genes resulted in a change in allocation of patients within each low- or high-risk group. Combination of survival subgroups from tumor and adjacent liver tissue significantly improved the prediction of prognostic outcome. This integrative approach was confirmed to be effective in a further 40 test patients. A clinicopathological study showed that survival subgroups divided by tumor and adjacent liver tissue gene expression were also statistically associated with UICC stage and extent of cell differentiation, respectively. CONCLUSIONS: Variation in gene expression during the nontumor stage as well as the tumor stage may affect the prognosis of HCC patients, and integration of the gene expression profiles of HCC and adjacent liver tissue increases discriminatory effectiveness between patient groups, predicting clinical outcomes with enhanced statistical reliability. PMID- 21533657 TI - A multicentered, randomized, controlled trial comparing radioguided seed localization to standard wire localization for nonpalpable, invasive and in situ breast carcinomas. AB - BACKGROUND: Studies suggest radioguided seed localization (RSL) yields fewer positive margins than wire-guided localization (WL). The goal of this study is to determine whether RSL is superior to WL. METHODS: Women with confirmed invasive or ductal carcinoma in situ (DCIS) undergoing localization and breast conserving surgery were enrolled. Outcomes measured include positive margin and reoperation rates, specimen weight, operative and localization times, and surgeon and radiologist ranking of procedural difficulty. RESULTS: Randomization was centralized, concealed, and stratified by surgeon with 153 patients in the WL group and 152 in RSL group. Localizations were performed using either ultrasound (70%) or mammographic guidance (30%). Pathology was either DCIS (18%) or invasive carcinoma (82%). Procedures were performed at 3 sites, by 7 surgeons. Only difference found for patient and tumor characteristics was more multifocal disease in RSL group. Using intention-to-treat analysis, there were no differences in positive margins rates for RSL (10.5%) and WL (11.8%), (P=.99) or for positive or close margins (<1 mm) (RSL 19% and WL 22%; P=.61). Mean operative time (minutes) was shorter for RSL (RSL 19.4 vs WL 22.2; P<.001). Specimen volume, weight, reoperation and localization times were similar. Surgeons ranked the seed technique as easier (P=.008), while radiologists ranked them similarly. Patient's pain rankings during wire localization were higher (P=.038). CONCLUSIONS: In contrast to other trials positive margin and reoperation rates were similar for RSL and WL. However, for RSL operative times were shorter, and the technique was preferred by surgeons, making it an acceptable method for localization. PMID- 21533658 TI - Pubertal timing and substance use in middle adolescence: a 2-year follow-up study. AB - Earlier research has associated early puberty with emotional and behavioral symptoms particularly among girls, while among boys, findings have been contradictory as to whether risks are associated with early or late pubertal timing. We studied the association between pubertal timing and substance use behaviors in middle adolescence in a 2-year follow up study of 2,070 (mean age 15.5 years, SD 0.36; 56.4% females) Finnish adolescents. Pubertal timing was measured by age at menarche/oigarche. Eleven years or less was classified as early, 12-13 years as normative and 14 years or later as late pubertal timing. Substance use behaviors were elicited by a number of questions related to alcohol use patterns, smoking and cannabis use. As factors that could explain the association between pubertal timing and substance use, we studied depressive symptoms, delinquency and aggression, and parental monitoring. In boys, all these substance use behaviors were the more common the earlier the puberty and the associations persisted at age 17. Among girls, early pubertal timing was similarly associated with substance use behaviors at age 15, but no longer at age 17. The associations between pubertal timing and substance use behaviors persisted when symptom dimensions and parental monitoring were added into the models. Early puberty is a risk factor for substance use particularly among boys. Among girls, the impact of pubertal timing already tempers off during adolescence. PMID- 21533659 TI - Religiosity and adolescent substance use in central Mexico: exploring the influence of internal and external religiosity on cigarette and alcohol use. AB - This study explores the multidimensional nature of religiosity on substance use among adolescents living in central Mexico. From a social capital perspective, this article investigates how external church attendance and internal religious importance interact to create differential pathways for adolescents, and how these pathways exert both risk and protective influences on Mexican youth. The data come from 506 self-identified Roman Catholic youth (ages 14-17) living in a semi-rural area in the central state of Guanajuato, Mexico, and attending alternative secondary schools. Findings indicate that adolescents who have higher church attendance coupled with higher religious importance have lower odds of using alcohol, while cigarette use is lower among adolescents who have lower church attendance and lower religious importance. Adolescents are most at risk using alcohol and cigarettes when church attendance is higher but religious importance is lower. In conclusion, incongruence between internal religious beliefs and external church attendance places Mexican youth at greater risk of alcohol and cigarette use. This study not only contributes to understandings of the impact of religiosity on substance use in Mexico, but highlights the importance of understanding religiosity as a multidimensional phenomenon which can lead to differential substance use patterns. PMID- 21533660 TI - Combined simultaneous transcranial and transsphenoidal resection of large-to giant pituitary adenomas. AB - BACKGROUND: While large-to-giant pituitary adenomas (PAs) may be safely removed by experienced surgeons through a single route, the procedure is technically challenging. We present the outcome of a simultaneous combined transcranial and transsphenoidal approach and discuss its applications. METHODS: A retrospective review was conducted on 12 consecutive patients. Surgical complications, visual and endocrinological functions, and tumour control were reviewed. RESULTS: There were four men and eight women, with a mean age of 47.6 years. All but one patient had non-functioning PAs. The mean tumour height was 4.1 cm (range: 2.3-5.5). The predominant presenting symptoms were visual field loss in eight patients, headache in three patients and mental confusion in one patient. There was no operative mortality. Post-operative cerebrospinal fluid leakage occurred in one patient. Five of the eight patients who presented with visual field loss achieved full recovery, and three had partial improvement. Two patients developed permanent diabetes insipidus after surgery. Panhypopituitarism occurred in one patient. Gross total removal (GTR) was achieved in five, and subtotal removal (STR) in seven patients. Seven patients received post-operative external irradiation. All patients who had GTR remained tumour-free and all those with STR had stable diseases after a mean follow-up period of 53.1 months (range: 14.1 92.1). CONCLUSION: The simultaneous 'above and below' approach is a safe and effective surgical strategy for large-to-giant PAs, particularly when expertise in endoscopic transsphenoidal surgery is unavailable. Its use, however, should be limited to a carefully selected group of patients, and tailored to individual user's expertise and experience. PMID- 21533662 TI - Autologous cell-enriched fat grafting for breast augmentation. AB - Autologous fat grafting for breast augmentation has faced some historical hurdles. However, in recent years it has been gaining acceptance from the medical community. This prospective, nonrandomized open-label study of 20 Japanese women supports the use of autologous fat grafting in breast augmentation and explores enhancement of fat graft tissue with autologous adipose-derived regenerative cells (ADRCs). After adipose harvesting using syringe liposuction, the tissue is processed in the Celution 800 System((r)), which washes the graft and isolates ADRCs. The average cells per gram of harvested adipose tissue was 3.42 * 10(5), and the mean cell viability measured using an automated cell counting system before graft delivery was 85.3%. All patients demonstrated improvement in circumferential breast measurement (BRM) from their baseline state, and breast measurements were stable by 3 months after surgery. The mean BRM 9 months after surgery had increased 3.3 cm from preoperative measurements. Through 9 months, overall physician satisfaction was 69% and patient satisfaction was 75%. No serious or unexpected adverse events were reported, and the procedure was safe and well tolerated in all patients. Postoperative cyst formation was seen in two patients. These prospective results demonstrate that ADRC-enriched fat grafts processed with a closed automated system maintain high cell viability and that the procedure is safe and effective, with all patients showing improvement after a single treatment. PMID- 21533661 TI - Simulating the effects of acculturation and return migration on the maternal and infant health of Mexican immigrants in the United States: a research note. AB - A significant body of research on minority health shows that although Latino immigrants experience unexpectedly favorable outcomes in maternal and infant health, this advantage deteriorates with increased time of residence in the United States. This study evaluates the underlying assumptions of two competing hypotheses that explain this paradox. The first hypothesis attributes this deterioration to possible negative effects of acculturation and behavioral adjustments made by immigrants while living in the United States, and the second hypothesis attributes this deterioration to the mechanism of selective return migration. Hypothetical probabilistic models are simulated for assessing the relationship between duration and birth outcomes based on the assumptions of these two hypotheses. The results are compared with the empirical research on the maternal and infant health of first-generation, Mexican-origin immigrant women in the United States. The analysis provides evidence that a curvilinear pattern of duration and birth outcomes can be explained by the joint effects of both acculturation and selective return migration in which the former affects health status over the longer durations, and the latter affects health status at shorter durations. PMID- 21533663 TI - Oropharyngeal leak pressure with the laryngeal mask airway SupremeTM at different intracuff pressures: a randomized controlled trial. AB - BACKGROUND: A higher oropharyngeal leak pressure (OLP) is a marker of efficacy and safety when using laryngeal mask airway devices. The new disposable laryngeal mask airway (LMATM) SupremeTM has lower OLP compared with the LMA ProSealTM. Increased intracuff pressure of laryngeal mask airway devices may improve OLP but may result in more postoperative pharyngolaryngeal adverse events. This study was designed to compare the OLP of the LMA Supreme at varying intracuff pressures. METHODS: One hundred and twenty-three patients were divided randomly into three groups. General anesthesia was standardized using a propofol-fentanyl induction and desflurane in air-oxygen for maintenance. Intracuff pressures of the LMA Supreme were adjusted to 80 cm H(2)O, 60 cm H(2)O, and 40 cm H(2)O according to group allocation. The primary outcome was OLP. Secondary outcomes included postoperative pharyngolaryngeal adverse events and the satisfaction scores of patients and anesthesiologists. The OLP was compared amongst groups using analysis of variance with Bonferroni correction. All reported P values are two sided. RESULTS: The OLP with an intracuff pressure of 80 cm H(2)O was significantly higher compared with 60 cm H(2)O and 40 cm H(2)O (26 [6] vs 20 [6] vs 18 [5] cm H(2)O, respectively; P < 0.001). The incidence of postoperative pharyngolaryngeal adverse events (P = 0.6), patient satisfaction scores (P = 0.2), and anesthesiologist satisfaction scores (P = 0.8) were comparable amongst the three groups. CONCLUSION: An intracuff pressure of 80 cm H(2)O with the LMA Supreme is associated with a higher OLP compared with 60 cm H(2)O or 40 cm H(2)O without a greater incidence of postoperative pharyngolaryngeal adverse events. For a superior glottic seal when using the LMA Supreme, we recommend intracuff pressures up to 80 cm H(2)O. PMID- 21533664 TI - Empirical study of an adaptive multiscale model for simulating cardiac conduction. AB - We modify and empirically study an adaptive multiscale model for simulating cardiac action potential propagation along a strand of cardiomyocytes. The model involves microscale partial differential equations posed over cells near the action potential upstroke and macroscale partial differential equations posed over the remainder of the tissue. An important advantage of the modified model of this paper is that, unlike our original model, it does not require perfect alignment between myocytes and the macroscale computational grid. We study the effects of gap-junctional coupling, ephaptic coupling, and macroscale grid spacing on the accuracy of the multiscale model. Our simulations reveal that the multiscale method accurately reproduces both the wavespeed and the waveform, including both upstroke and recovery, of fully microscale models. They also reveal that perfect alignment between myocytes and the macroscale grid is not necessary to reproduce the dynamics of a traveling action potential. Further, our simulations suggest that the macroscale grid spacing used in an adaptive multiscale model need not be much finer than the spatial width of an action potential. These results are demonstrated to hold under high, low, and zero gap junctional coupling regimes. PMID- 21533665 TI - Salinity-induced subcellular accumulation of H(2)O (2) in leaves of rice. AB - The localization of salt-induced H(2)O(2) accumulation in the leaves of rice was examined using 3,3-diaminobenzidine and CeCl(3) staining at ultrastructure level. When the 3-week-old rice plants were affected by 100 mM NaCl for 14 days, the swelling of thylakoids and the destruction of thylakoid membranes were observed. H(2)O(2) accumulation was also observed in the chloroplast of the leaf treated with NaCl. The electron dense products of 3,3-diaminobenzidine and CeCl(3) were mainly observed especially around the swelling of thylakoids. H(2)O(2) accumulation and any ultrastructural changes were not observed in the chloroplasts under dark condition. Furthermore, treatment with ascorbic acid suppressed both H(2)O(2) accumulation and the changes in chloroplast ultrastructure. These results suggest that light-induced production of excess H(2)O(2) under salinity is responsible for the changes in chloroplast ultrastructure. H(2)O(2) accumulation was also observed in the mitochondria, peroxisomes, plasma membrane, and cell walls under light but not dark, suggesting that these organelles are also the source of H(2)O(2) and the production is light dependent under salinity. PMID- 21533666 TI - Effective generation of transgenic reporter and gene trap lines of the medaka (Oryzias latipes) using the Ac/Ds transposon system. AB - In model teleost fishes like the medaka and the zebrafish many genes which have been identified in genome sequencing projects await their functional characterization. Techniques for the effective generation of transgenic animals are a prerequisite for this challenging task, and, due to their transparency, fish offer the possibility to combine the use of fluorescent proteins and developmental analysis in vivo. Here we describe the application of the Ac/Ds transposon system to generate transgenic medaka reporter and gene trap lines. We determined a germline transmission rate of 30% in our experiments using constructs ranging in size from 1.8 to 6 kilobase pairs. The genomic integration site of the Ds-elements can be easily identified which is an important feature for gene trap mutagenesis experiments and similar approaches. We constructed gene trap vectors with functional elements of medaka sequences that produce in frame fusions of the endogenous sequence to EGFP. These vectors mimic endogenous expression of the trapped allele in transgenic animals and are capable to interfere with the expression of the wild type allele in the homozygous individuals. PMID- 21533667 TI - Fidelity of a BAC-EGFP transgene in reporting dynamic expression of IL-7Ralpha in T cells. AB - Interleukin-7 receptor alpha chain (IL-7Ralpha)-derived signals are critical for normal T cell development, mature T cell homeostasis, and longevity of memory T cells. IL-7Ralpha expression in T cells is dynamically regulated at different developmental and antigen-responding stages. However, the molecular mechanism underlying the dynamic regulation is not completely understood. Here we describe generation of a bacterial artificial chromosome (BAC)-based reporter transgenic mouse strain, which contains 210 kb DNA sequence flanking the Il7r locus. We used in vitro validated EGFP reporter and insulator sequences to facilitate the reporter transgene expression. Consistent with endogenous IL-7Ralpha expression, the BAC transgene was expressed in mature T cells, a portion of natural killer cells but not in mature B cells. In the thymus, the EGFP reporter and endogenous IL-7Ralpha showed synchronized silencing in CD4(+)CD8(+) double positive stage, were both upregulated in CD4(+) or CD8(+) single positive thymocytes, and both continued to be co-expressed in naive T cells in the periphery. Upon encountering antigen, the antigen-specific effector CD8(+) T cells downregulated both endogenous IL-7Ralpha and the EGFP reporter, which were upregulated in synchrony in antigen-specific memory CD8 T cells. These results indicate that the BAC-EGFP transgene reports endogenous IL-7Ralpha regulation with high fidelity, and further suggest that the 210 kb sequence flanking the Il7r locus contains sufficient genetic information to regulate its expression changes in T lineage cells. Our approach thus represents a critical initial step towards systematic dissection of the cis regulatory elements controlling dynamic IL-7Ralpha regulation during T cell development and cellular immune responses. PMID- 21533668 TI - Shine-Dalgarno sequence of bacteriophage T4: GAGG prevails in early genes. AB - Translation initiation is governed by a limited number of mRNA sequence motifs within the translation initiation region (TIR). In bacteria and bacteriophages, one of the most important determinants is a Shine-Dalgarno (SD) sequence that base pairs with the anti-SD sequence GAUCACCUCCUUA localized in the 3' end of 16S rRNA. This work assesses a diversity of TIR features in phage T4, focusing on the SD sequence, its spacing to the start codon and relationship to gene expression and essentiality patterns. Analysis shows that GAGG is predominant of all core SD motifs in T4 and its related phages, particularly in early genes. Possible implication of the RegB activity is discussed. PMID- 21533669 TI - Early identification of poor responders to transarterial chemoembolization for hepatocellular carcinoma. AB - PURPOSE: Transarterial chemoembolization (TACE) is used to treat unresectable hepatocellular carcinoma (HCC). However, HCC patients may have an even shorter survival after TACE. This study aimed to identify poor responders to TACE at an early stage. PATIENTS AND METHODS: A total of 624 and 122 patients with HCC undergoing TACE and best supportive care (BSC), respectively, were analyzed. Poor responders were defined as patients who died after TACE or had viable tumor(s), but not eligible for further treatment at 3 months of treatment. RESULTS: A total of 102 (16%) patients were identified as poor responders. Poor responders had a significantly decreased long-term survival than other patients receiving TACE and a tendency of higher risk of mortality than patients receiving BSC (p < 0.001 and p = 0.054, respectively). The comparison of 24-month survival showed significantly worse outcome in poor responders than patients receiving BSC (p = 0.04). Serum alpha-fetoprotein (AFP) level >40 ng/mL (p = 0.024) and albumin level 3.8 g/dL (p = 0.016), Child-Turcotte-Pugh (CTP) class B (p = 0.011), performance status 1 (p < 0.001), total tumor volume (TTV) >65 cm(3) (p = 0.001), and vascular invasion (p = 0.005) were independent risk factors predicting poor response at 3 months in the multivariate logistic regression analysis. Among the four HCC staging systems, the Barcelona Clinic Liver Cancer (BCLC) classification showed the highest predictive accuracy for the identification of poor responders. CONCLUSIONS: Poor responders have an increased risk of mortality due to rapid disease progression after TACE. Advanced BCLC stages may better predict a poor response to TACE. PMID- 21533670 TI - The psychosocial factors at work related to depression among female white-collar workers in Vilnius (Lithuania). AB - OBJECTIVES: The aim of this study is to establish which psychosocial factors at work are related to depression among female white-collar workers in Vilnius. MATERIALS AND METHODS: The data was collected in a case-control study in 2002 2004. The cases were selected from patients treated at Vilnius mental health centers. The controls were randomly selected from employed Vilnius residents. A descriptive statistic and logistic regression was applied. RESULTS: 3 psychosocial factors and possible confounders within the evaluated model were statistically reliable (model chi(2): 44.47, p < 0.05 ). The adjusted odds ratio for uneven work distribution was 2.17 (95% CI: 1.38-3.51, p < 0.005), the odds ratio for possibility to control was 10.81 (95% CI: 2.13-54.71, p < 0.005), and the odds ratio for family esteem was 2.13 (95% CI: 1.01-4.59, p < 0.005). CONCLUSION: This study suggests that work distribution, possibility to control and family esteem, together with stressful life events and mental health disorders in the family, are related to depression among female white-collar workers. PMID- 21533671 TI - Manganese accumulation in the CNS and associated pathologies. AB - Manganese (Mn) is an essential metal for life. It is a key constituent of clue enzymes in the central nervous system, contributing to antioxidant defenses, energetic metabolism, ammonia detoxification, among other important functions. Until now, Mn transport mechanisms are partially understood; however, it is known that it shares some mechanisms of transport with iron. CNS is susceptible to Mn toxicity because it possesses mechanisms that allow Mn entry and favor its accumulation. Cases of occupational Mn exposure have been extensively reported in the literature; however, there are other ways of exposure, such as long-term parental nutrition and liver failure. Manganism and hepatic encephalopathy are the most common pathologies associated with the effects of Mn exposure. Both pathologies are associated with motor and psychiatric disturbances, related in turn to mechanisms of damage such as oxidative stress and neurotransmitters alterations, the dopaminergic system being one of the most affected. Although manganism and Parkinson's disease share some characteristics, they differ in many aspects that are discussed here. The mechanisms for Mn transport and its participation in manganism and hepatic encephalopathy are also considered in this review. It is necessary to find an effective therapeutic strategy to decrease Mn levels in exposed individuals and to treat Mn long term effects. In the case of patients with chronic liver failure it would be worthwhile to test a low-Mn diet in order to ameliorate symptoms of hepatic encephalopathy possibly related to Mn accumulation. PMID- 21533673 TI - Cervical spine model to predict capsular ligament response in rear impact. AB - Predicting neck kinematics and tissue level response is essential to evaluate the potential for occupant injury in rear impact. A detailed 50th percentile male finite element model, previously validated for frontal impact, was validated for rear impact scenarios with material properties based on actual tissue properties from the literature. The model was validated for kinematic response using 4 g volunteer and 7 g cadaver rear impacts, and at the tissue level with 8 g isolated full spine rear impact data. The model was then used to predict capsular ligament (CL) strain for increasing rear impact severity, since CL strain has been implicated as a source of prolonged pain resulting from whiplash injury. The model predicted the onset of CL injury for a 14 g rear impact, in agreement with motor vehicle crash epidemiology. More extensive and severe injuries were predicted with increasing impact severity. The importance of muscle activation was demonstrated for a 7 g rear impact where the CL strain was reduced from 28 to 13% with active muscles. These aspects have not previously been demonstrated experimentally, since injurious load levels cannot be applied to live human subjects. This study bridges the gap between low intensity volunteer impacts and high intensity cadaver impacts, and predicts tissue level response to assess the potential for occupant injury. PMID- 21533672 TI - The effect of body weight on some welfare indicators in feedlot cattle in a hot environment. AB - Heat stress has important effects on the welfare of livestock. The effects of heat stress in cattle include changes in biological functions and behaviors. The aim of this study was to investigate the behavioral differences between light and heavy feedlot cattle reared in a hot environment. Sixteen male Holstein feedlot cattle were allocated to light (353.8 +/- 15.5 kg, n = 8) and heavy (737.1 +/- 15.8 kg, n = 8) groups according to their live weight and were kept in a semi open feedlot barn. The individual behavioral response variables measured were standing, lying, feeding, drinking, ruminating, locomotor activity and elimination (urinating and defecating). The effects of group, day, observation time, replicate and all interactions were included in an explanatory statistical (GLM) model. The data were analyzed using the PROC GLM procedure of SAS. Overall, the heavy cattle spent more time standing (P < 0.001), lying (P < 0.001), and eliminating (P < 0.05) compared to the light group. In contrast, the light group spent more time eating, drinking and ruminating (P < 0.001). Locomotor activity did not differ significantly between groups (P > 0.05). During the day, heavy cattle spent more time standing (at 1600 hours) and less time eating in comparison with the light cattle (P < 0.001) (at 1300 and 1600 hours). Light and heavy feedlot cattle behaved differently in a hot environment. The findings of the study indicate that the welfare of the heavy Holstein feedlot cattle was impacted negatively when the ambient temperature was high (at 1300 hours). PMID- 21533675 TI - [Researcher of the month]. PMID- 21533677 TI - Ambulatory assessment of skin conductivity during first thesis presentation: lower self-confidence predicts prolonged stress response. AB - In this field study self-confidence was tested to predict the course of galvanic electrodermal stress response prior, during and after public speaking. Ten graduate students initially rated their self-confidence and afterwards presented their thesis proposals orally in a 10-min presentation to their supervisor and peers. Galvanic skin response level was measured throughout and analysed for 10 min prior to, during, and 10 min after the presentation. Two major galvanic electrodermal stress response types were observed. Five students showed a 'healthy response', i.e. an anticipatory increase in electrodermal conductance, followed by a decrease after termination of the presentation. The other five students showed a steady increase of skin conductance during and after their presentation ('prolonged response'). In line with the allostatic load model the 'prolonged response' group reported significantly lower self-confidence before presentation than the 'healthy response' group (p < 0.01). Self-confidence is a resource in novices facing an unfamiliar stressor. PMID- 21533678 TI - Exploring the effectiveness of a computer-based heart rate variability biofeedback program in reducing anxiety in college students. AB - Given the pervasiveness of stress and anxiety in our culture it is important to develop and implement interventions that can be easily utilized by large numbers of people that are readily available, inexpensive and have minimal side effects. Two studies explored the effectiveness of a computer-based heart rate variability biofeedback program on reducing anxiety and negative mood in college students. A pilot project (n = 9) of highly anxious students revealed sizable decreases in anxiety and negative mood following utilizing the program for 4 weeks. A second study (n = 35) employing an immediate versus delayed treatment design replicated the results, although the magnitude of the impact was not quite as strong. Despite observing decreases in anxiety, the expected changes in psychophysiological coherence were not observed. PMID- 21533679 TI - The dopamine system in mediating alcohol effects in humans. AB - Recent brain-imaging studies revealed that the development and maintenance of alcohol dependence is determined by a complex interaction of different neurotransmitter systems and multiple psychological factors. In this context, the dopaminergic reinforcement system appears to be of fundamental importance. We focus on the excitatory and depressant effects of acute versus chronic alcohol intake and its impact on dopaminergic neurotransmission. Furthermore, we describe alterations in dopaminergic neurotransmission as associated with symptoms of alcohol dependence. We specifically focus on neuroadaptations to chronic alcohol consumption and their effect on central processing of alcohol-associated and reward-related stimuli. Dysfunctional reward processing, impaired reinforcement learning and increased salience attribution to alcohol-associated stimuli enable alcohol cues to drive alcohol seeking and consumption. Finally, we will discuss how the neurobiological and neurochemical mechanisms of alcohol-associated alterations in reward processing and learning can interact with personality traits, cognition and emotion processing. PMID- 21533680 TI - The impact of age-related ovarian hormone loss on cognitive and neural function. AB - On average, women now live one-third of their lives after menopause. Because menopause has been associated with an elevated risk of dementia, an increasing body of research has studied the effects of reproductive senescence on cognitive function. Compelling evidence from humans, nonhuman primates, and rodents suggests that ovarian sex-steroid hormones can have rapid and profound effects on memory, attention, and executive function, and on regions of the brain that mediate these processes, such as the hippocampus and prefrontal cortex. This chapter will provide an overview of studies in humans, nonhuman primates, and rodents that examine the effects of ovarian hormone loss and hormone replacement on cognitive functions mediated by the hippocampus and prefrontal cortex. For humans and each animal model, we outline the effects of aging on reproductive function, describe how ovarian hormones (primarily estrogens) modulate hippocampal and prefrontal physiology, and discuss the effects of both reproductive aging and hormone treatment on cognitive function. Although this review will show that much has been learned about the effects of reproductive senescence on cognition, many critical questions remain for future investigation. PMID- 21533681 TI - A nanomembrane-based nucleic acid sensing platform for portable diagnostics. AB - In this perspective article, we introduce a potentially transformative DNA/RNA detection technology that promises to replace DNA microarray and real-time PCR for field applications. It represents a new microfluidic technology that fully exploits the small spatial dimensions of a biochip and some new phenomena unique to the micro- and nanoscales. More specifically, it satisfies all the requisites for portable on-field applications: fast, small, sensitive, selective, robust, label- and reagent-free, economical to produce, and possibly PCR-free. We discuss the mechanisms behind the technology and introduce some preliminary designs, test results, and prototypes. PMID- 21533682 TI - Overview of plant RNAi. AB - In the last decade, much progress has been made towards a basic understanding of RNA silencing mechanisms in plants, like in animals and other eukaryotes. Many events that were already known, such as pathogen-derived resistance, posttranscriptional gene silencing, and microRNA (miRNA)-mediated regulation, were found to share a fundamentally similar mechanism. By taking advantage of such mechanisms, whether deliberately or not, we can suppress some biological activities by targeting a specific gene function. This type of applied approach is known as RNA interference (RNAi). For many years, scientists have been trying to modify inherent activities of plants to improve their yield and quality. Suppression of some biological activities by RNAi would help to achieve such goals. PMID- 21533683 TI - Caveat of RNAi in plants: the off-target effect. AB - RNA interference (RNAi), mediated by short interfering RNAs (siRNAs), is one of the widely used functional genomics method for suppressing the gene expression in plants. Initially, gene silencing by RNAi mechanism was believed to be specific requiring sequence homology between siRNA and target mRNA. However, several recent reports have showed that non-specific effects often referred as off-target gene silencing can occur during RNAi. This unintended gene silencing can lead to false conclusions in RNAi experiments that are aimed to study the functional role of a particular target gene in plants. This especially is a major problem in large-scale RNAi-based screens aiming for gene discovery. Hence, understanding the off-target effects is crucial for minimizing such effects to better conclude gene function analyzed by RNAi. We discuss here potential problems of off-target gene silencing and focus on possibilities that favor this effect during post transcriptional gene silencing. Suggestions to overcome the off-target effects during RNAi studies are also presented. We believe that information available in present-day plant science literature about specificity of siRNA actions is inadequate. In-depth systematic studies to understand their molecular basis are necessary to enable improved design of more specific RNAi vectors. In the meantime, gene function and phenotype results from present-day RNAi studies need to be interpreted with caution. PMID- 21533684 TI - Plant gateway vectors for RNAi as a tool for functional genomic studies. AB - Gateway((r)) system takes advantage of high-throughput creation of various expression vectors from one entry vector. This technology is also applied to RNAi vectors for functional analysis of plant genomics. To date, several plant Gateway vectors have been developed and distributed to plant science community. Here I would like to introduce unique plant Gateway vectors developed for functional analysis of the metabolic pathway in root tissues. The protocol shown here is basically applied to other plant Gateway vectors for RNAi. PMID- 21533685 TI - Heat-inducible RNAi for gene functional analysis in plants. AB - Controlling gene expression during plant development is an efficient method to explore gene function and RNA interference (RNAi) is now considered as a powerful technology for gene functional analysis. However, constitutive gene silencing cannot be used with genes involved in fundamental processes such as embryo viability or plant growth and alternative silencing strategies avoiding these limitations should be preferred. Tissue-specific and inducible promoters, able to control gene expression at spatial and/or temporal level, can be used to circumvent viability problems. In this chapter, after a rapid overview of the inducible promoters currently used for transgenic approaches in plants, we describe a method we have developed to study gene function by heat-inducible RNAi. This system is easy to use and complementary to those based on chemical gene inducer treatments and might be useful for both research and biotechnological applications. PMID- 21533686 TI - Gene function analysis by artificial microRNAs in Physcomitrella patens. AB - MicroRNAs (miRNAs) are ~21 nt long small RNAs transcribed from endogenous MIR genes which form precursor RNAs with a characteristic hairpin structure. miRNAs control the expression of cognate target genes by binding to reverse complementary sequences resulting in cleavage or translational inhibition of the target RNA. Artificial miRNAs (amiRNAs) can be generated by exchanging the miRNA/miRNA sequence of endogenous MIR precursor genes, while maintaining the general pattern of matches and mismatches in the foldback. Thus, for functional gene analysis amiRNAs can be designed to target any gene of interest. During the last decade the moss Physcomitrella patens emerged as a model plant for functional gene analysis based on its unique ability to integrate DNA into the nuclear genome by homologous recombination which allows for the generation of targeted gene knockout mutants. In addition to this, we developed a protocol to express amiRNAs in P. patens that has particular advantages over the generation of knockout mutants and might be used to speed up reverse genetics approaches in this model species. PMID- 21533687 TI - Virus-induced gene silencing in ornamental plants. AB - Virus-induced gene silencing (VIGS) provides an attractive tool for high throughput analysis of the functional effects of gene knockdown. Virus genomes are engineered to include fragments of target host genes, and the infected plant recognizes and silences the target genes as part of its viral defense mechanism. The consequences of gene inactivation, even of key metabolic, regulatory, or embryo-lethal genes, can thus be readily analyzed. A number of viral vectors have been developed for VIGS; one of the most frequently employed is based on tobacco rattle virus (TRV) due to its wide host range, efficiency, ease of application, and limited disease symptoms. TRV-based VIGS comprises two vectors. One (RNA2) includes a multiple cloning site into which fragments of target genes can be inserted. We have shown that the TRV/VIGS system can simultaneously silence as many as five independent genes. TRV is a mosaic-type virus, and silencing also occurs in a mosaic pattern. It is therefore desirable to have a reporter that can show where target genes have been silenced. The photobleaching induced by silencing phytoene desaturase (PDS) and the loss of purple pigmentation induced by silencing chalcone synthase (CHS) have successfully been used to indicate the location of coordinate silencing of other target genes. In this chapter, we outline our protocols for the use of VIGS for analysis of gene function, focusing particularly on the use of TRV with petunia and tomato. PMID- 21533688 TI - Local RNA silencing mediated by agroinfiltration. AB - Agroinfiltration is a very fast and powerful method to express in planta any sequences in a transient fashion. Agroinfiltration has proven very useful for the overexpression of proteins in the infiltrated zone when a short-term effect can be informative. However, it has been a real success story in the induction of local and eventually systemic silencing. Here, we describe the use of agroinfiltration for the induction of local silencing of an endogene or a transgene, for the systemic silencing of a transgene and for co-infiltration assays. We also provide protocols for the evaluation of the efficiency of the assay, by detecting the specific siRNAs characteristic of RNA silencing and measuring the effects on the target sequences. PMID- 21533689 TI - Direct transfer of synthetic double-stranded RNA into protoplasts of Arabidopsis thaliana. AB - Double-stranded (ds) RNA interference (RNAi) is widely used as a reverse genetic approach for functional analysis of plant genes. Constitutive or transient RNAi effects in plants have been achieved via generating stable transformants expressing dsRNAs or artificial microRNAs (amiRNAs) in planta or by viral-induced gene silencing (VIGS). Although these tools provide outstanding resources for functional genomics, they require generation of vectors expressing dsRNAs or amiRNAs against targeted genes, transformation and propagation of transformed plants, or maintenance of multiple VIGS lines and thus impose time, labor, and space requirements. As we showed recently, these limitations can be circumvented by inducing RNAi effects in protoplasts via transfecting them with in vitro synthesized dsRNAs. In this chapter we detail the procedure for transient gene silencing in protoplasts using synthetic dsRNAs and provide examples of approaches for subsequent functional analyses. PMID- 21533690 TI - Detection of long and short double-stranded RNAs. AB - In RNA interference (RNAi), long double-stranded RNAs (dsRNAs) of more than 100 nucleotides (nt) are diced into short dsRNAs (small interfering RNAs, siRNAs) of about 21-24 nt, the guide strand of which is incorporated into the RNA-induced silencing complex (RISC) that slices a specific mRNA. Consequently viral dsRNAs are known as potent inducers for RNAi, which probably originated from a defense mechanism against nucleic acid parasites. Therefore detection of long and short dsRNAs must be crucial techniques for RNAi or virus research. The methods for simple and sensitive detection of short dsRNAs (siRNAs) by northern hybridization, isolation of long dsRNAs by CF-11 cellulose chromatography, and detection of long dsRNAs by agarose gel electrophoresis and northern hybridization are described here. PMID- 21533691 TI - Quantitative stem-loop RT-PCR for detection of microRNAs. AB - Plant microRNAs (miRNAs) are a class of endogenous small RNAs that are essential for plant development and survival. They arise from larger precursor RNAs with a characteristic hairpin structure and regulate gene activity by targeting mRNA transcripts for cleavage or translational repression. Efficient and reliable detection and quantification of miRNA expression has become an essential step in understanding their specific roles. The expression levels of miRNAs can vary dramatically between samples and they often escape detection by conventional technologies such as cloning, northern hybridization and microarray analysis. The stem-loop RT-PCR method described here is designed to detect and quantify mature miRNAs in a fast, specific, accurate and reliable manner. First, a miRNA-specific stem-loop RT primer is hybridized to the miRNA and then reverse transcribed. Next, the RT product is amplified and monitored in real time using a miRNA specific forward primer and the universal reverse primer. This method enables miRNA expression profiling from as little as 10 pg of total RNA and is suitable for high-throughput miRNA expression analysis. PMID- 21533692 TI - Large-scale sequencing of plant small RNAs. AB - Deep sequencing technologies have become very powerful tools in the identification and quantification of small RNAs involved in gene regulation. Small interfering RNA (siRNA) and miRNA are two classes of DCL-dependent small RNAs known to affect phenotype, developmental regulation, and various traits in plants. These small RNAs function by selectively repressing gene expression mainly by guiding cleavage, resulting in degradation of target transcripts. In this chapter, we describe a method for preparation of 5(')-phosphate-dependent small RNA libraries, a hallmark of RNase III-like DCL products, for high throughput sequencing, and recommendations for small RNA analysis. This method is useful for determining small RNA involvement in critical pathways in plants, identifying and quantifying novel small RNAs, and examining small RNA global expression patterns. PMID- 21533693 TI - Computational prediction of plant miRNA targets. AB - MicroRNAs (miRNAs) are a specific class of 21-nt small RNAs. They regulate the expression of specific target genes by various types of post-transcriptional regulation mechanisms, such as transcript cleavage and translation suppression. The biological function of an miRNA is therefore intimately associated with the function of their target genes. Target gene identification becomes an essential step towards understanding miRNA functions. In this protocol, we describe a computational procedure for plant miRNA target prediction. It involves two key steps: (1) search of transcript sequence databases for target sequences that have a near-perfect sequence complementarity to the miRNA sequence using the "scan_for_matches" program and (2) evaluation of the miRNA:target sequence pair for pairing complementarity using specific rules, such as positional dependent penalty score and minimum free energy ratio filter, to identify the most likely candidate targets. PMID- 21533694 TI - Bisulfite sequencing for cytosine-methylation analysis in plants. AB - RNA silencing is a sequence-specific RNA degradation mechanism conserved in eukaryotes including fungi, plants, and animals. One of the three RNA silencing pathways is DNA methylation which is the result of interaction between DNA and siRNA, a hallmark of RNA silencing. Bisulfite sequencing can be very powerful for DNA methylation analysis in this context. This method includes DNA extraction, digestion of DNA with restriction enzyme, treatment of DNA with bisulfite, PCR amplification of DNA, cloning of amplified DNA fragments, sequencing of DNA fragments, and analysis of DNA sequences. Based on this method, increased levels of cytosine methylation were obtained in both symmetrical (CpG, CpNpG) and non symmetrical (CpHpH) contexts in silenced lines of transgenic plants (CG>CNG>CHH), while the methylation levels were low in nonsilenced, over-expressing lines. Through grafting, RNA silencing was induced in the non-silenced scions from silenced rootstocks; however, the methylation level of DNA in the scions did not increase. PMID- 21533695 TI - Using nuclear run-on transcription assays in RNAi studies. AB - RNA interference (RNAi) is a mechanism regulating gene transcript levels either by transcriptional gene silencing or by posttranscriptional gene silencing, which act in the genome maintenance and the regulation of gene expression which is typically inferred from measuring transcript abundance. Nuclear "run-on" (or "run off") transcription assays have been used to obtain quantitative information about the relative rates of transcription of different genes in nuclei isolated from a particular tissue or organ. Basically, these assays exploit the activity of RNA polymerases to synthesize radiolabeled transcripts that then can be hybridized to filter-bound, cold, excess single-stranded DNA probes representing genes of interest. The protocol presented here streamlines, adapts, and optimizes nuclear run-on transcription assays for use in RNAi studies. PMID- 21533696 TI - Proteomic analysis of RNA interference induced knockdown plant. AB - RNA interference (RNAi) is a useful research tool for the specific deletion, or knockdown, of target genes that can be exploited both in cultured plant cells and in whole plants. In RNAi, hairpin RNA (hpRNA)-transduced lines are used to identify loss-of-function mutations in multi-copy genes with redundant functions in polyploid plant species. Plants transformed with hpRNA exhibit a range of phenotypes resulting from complete knockdown to weak suppression or tissue- and stage-specific knockdown. Functional genomics using proteomic analysis with two dimensional gel electrophoresis (2-DE) and mass spectrometry provides valuable information about altered levels of expression of specific genes in biological samples. Here, we describe the proteomic analysis of Oryza sativa (Os) thioredoxin m (Ostrxm) knockdown using 2-DE and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). PMID- 21533697 TI - Comparative analysis of phosphoprotein expression using 2D-DIGE. AB - Two-dimensional gel electrophoresis (2-DE) has often been used to compare protein expression pattern between different samples. This method is also useful to compare protein expression between wild-type and RNAi plants. 2D-DIGE (difference gel electrophoresis) was developed to perform quantitative proteomics of two or more samples. In this method, proteins are fluorescently labeled by Cy2, Cy3, or Cy5 and are mixed and subjected to electrophoresis on the same gel, thereby gel to-gel variations are eliminated. We perform phosphoproteomics between Arabidopsis wild-type and a stress-activated MAPK (mitogen-activated protein kinase) mutant after the phytotoxin treatment. For this purpose, proteins are extracted from both samples, and then phosphorylated proteins are purified by phosphoprotein enrichment columns. Purified proteins are fluorescently labeled by different CyDyes using the minimum labeling method. The labeled protein samples are separated on the same gel by 2-DE, and gels are scanned by a variable mode laser imager. Then, high-resolution images are analyzed by 2D analysis software. Thus, we identified several phosphoprotein spots that were differentially accumulated between wild-type and mapk mutant. PMID- 21533698 TI - Deliberate utilization of interaction torques brakes elbow extension in a fast throwing motion. AB - We tested the hypothesis that in fast arm movements the CNS deliberately utilizes interaction torques to decelerate (brake) joint rotations. Twelve subjects performed fast 2-D overarm throws in which large elbow extension velocities occurred. Joint motions were computed from recordings made with search coils; joint torques were calculated using inverse dynamics. After ball release, a large follow-through shoulder extension acceleration occurred that was initiated by shoulder extensor muscle torque. This shoulder acceleration produced a flexor interaction torque at the elbow that initiated elbow deceleration (braking). An instantaneous mechanical interaction of passive torques then occurred between elbow and shoulder, i.e., elbow extension deceleration produced a large shoulder extensor interaction torque that contributed to the shoulder extension acceleration which, simultaneously, produced a large elbow flexor interaction torque that contributed to elbow extension deceleration, and so on. Late elbow flexor muscle torque also contributed to elbow deceleration. The interaction of passive torques between shoulder and elbow was braked by shoulder flexor muscle torque. In this mechanism, shoulder musculature contributed to braking elbow extension in two ways: shoulder extensors initiated the mechanical interaction of passive torques between shoulder and elbow and shoulder flexors dissipated kinetic energy from elbow braking. It is concluded that, in fast 2-D throws, the CNS deliberately utilizes powerful interaction torques between shoulder and elbow to brake motion at the elbow. PMID- 21533699 TI - Differing roles for the dominant and non-dominant hands in the hand laterality task. AB - Determining the handedness of visually presented stimuli is thought to involve two separate stages--a rapid, implicit recognition of laterality followed by a confirmatory mental rotation of the matching hand. In two studies, we explore the role of the dominant and non-dominant hands in this process. In Experiment 1, participants judged stimulus laterality with either their left or right hand held behind their back or with both hands resting in the lap. The variation in reactions times across these conditions reveals that both hands play a role in hand laterality judgments, with the hand which is not involved in the mental rotation stage causing some interference, slowing down mental rotations and making them more accurate. While this interference occurs for both lateralities in right-handed people, it occurs for the dominant hand only in left-handers. This is likely due to left-handers' greater reliance on the initial, visual recognition stage than on the later, mental rotation stage, particularly when judging hands from the non-dominant laterality. Participants' own judgments of whether the stimuli were 'self' and 'other' hands in Experiment 2 suggest a difference in strategy for hands seen from an egocentric and allocentric perspective, with a combined visuo-sensorimotor strategy for the former and a visual only strategy for the latter. This result is discussed with reference to recent brain imaging research showing that the extrastriate body area distinguishes between bodies and body parts in egocentric and allocentric perspective. PMID- 21533700 TI - Intercepting moving targets: does memory from practice in a specific condition of target displacement affect movement timing? AB - This investigation aimed at assessing the extent to which memory from practice in a specific condition of target displacement modulates temporal errors and movement timing of interceptive movements. We compared two groups practicing with certainty of future target velocity either in unchanged target velocity or in target velocity decrease. Following practice, both experimental groups were probed in the situations of unchanged target velocity and target velocity decrease either under the context of certainty or uncertainty about target velocity. Results from practice showed similar improvement of temporal accuracy between groups, revealing that target velocity decrease did not disturb temporal movement organization when fully predictable. Analysis of temporal errors in the probing trials indicated that both groups had higher timing accuracy in velocity decrease in comparison with unchanged velocity. Effect of practice was detected by increased temporal accuracy of the velocity decrease group in situations of decreased velocity; a trend consistent with the expected effect of practice was observed for temporal errors in the unchanged velocity group and in movement initiation at a descriptive level. An additional point of theoretical interest was the fast adaptation in both groups to a target velocity pattern different from that practiced. These points are discussed under the perspective of integration of vision and motor control by means of an internal forward model of external motion. PMID- 21533701 TI - Effect of weight-related labels on corticospinal excitability during observation of grasping: a TMS study. AB - Recent studies of corticospinal excitability during observation of grasping and lifting of objects of different weight have highlighted the role of agent's kinematics in modulating observer's motor excitability. Here, we investigate whether explicit weight-related information, provided by written labels on the objects, modulate the excitability of the observer's motor system and how this modulation is affected when there is a conflict between label and object's weight. We measured TMS-evoked motor potentials (MEPs) from right hand intrinsic muscles, while subjects were observing an actor lifting objects of different weights, in some trials labeled (heavy/light) in congruent or incongruent way. Results confirmed a weight-related modulation of MEPs based on kinematic cues. Interestingly, any conflict between the labels and the actual weight (i.e., explicit versus implicit information), although never consciously noticed by the observer, deeply affected the mirroring of others' actions. Our findings stress the automatic involvement of the mirror-neuron system. PMID- 21533703 TI - Behavioral factors in the placebo response. AB - Given its presence in almost every clinical trial, the placebo is the most frequently studied substance in clinical research. Demonstration of treatment efficacy demands that the target (active) agent must be shown to be statistically significantly superior to an inert substance (placebo) not believed to be a specific therapy for the target condition. In clinical practice, enhancing the non-specific factors that contribute to an enhanced treatment outcome is desirable to maximize the likelihood of therapeutic benefit. Variables affecting the impact of placebo on clinical research and practice remain poorly understood, however, as they have not been systematically studied. The present article will discuss behavioral factors that have been found to be relevant in placebo mechanisms. PMID- 21533704 TI - Comorbidity between migraine and depression: update on traditional and alternative treatments. AB - Migraine is often comorbid with depression. Although much of the research on migraine and depression is of an epidemiologic nature, there is an emerging appreciation of clinical issues and the need to adequately treat depression in migraine sufferers. The present article reviews traditional pharmacological and psychological treatments for depression, with special emphasis on migraine patients. It then reviews the evidence base for some of the complementary and alternative treatments for depression that are very popular in both Europe and the United States. PMID- 21533705 TI - Acupuncture in primary headache treatment. AB - Acupuncture has a long tradition of use for the treatment of many pain conditions, including headache. Its effectiveness has been studied mainly for primary headaches, particularly for migraine and tension-type headache (TTH). Traditional Chinese Medicine (TCM) has two diagnostic frameworks for headaches: meridian diagnoses, based on the location of the pain and on the meridians (or channels) that pass through it; syndrome diagnoses, dependent on external or internal factors and on the characteristics of the pain. The four meridians involved in headache are Shaoyang (TE-GB channels, on the temporal sides of the head); Taiyang (SI-BL channels, occiput); Yangming (LI-ST channels, forehead) and Jueyin (PC-LR channels, vertex). The syndromes may be due to excess or deficit. Very generally, the excess syndromes correspond in the majority of cases to migraine and the deficit syndromes to TTH. Acupuncture is a complex intervention, which is also characterized by a close interaction between patient and therapist. The complicated system of TCM classification of headaches has frequently generated great diversity among the various therapeutic approaches used in the different studies on acupuncture in headache treatment. Despite these differences, the recent Cochrane systematic reviews on acupuncture in migraine and in TTH suggest that acupuncture is an effective and valuable option for patients suffering from migraine or frequent TTH. Moreover, acupuncture seems to be a cost-effective treatment. PMID- 21533706 TI - What future for treatment of chronic migraine with medication overuse? AB - Chronic headaches have increasingly become a focus within the field of head pain. Most of the patients with frequent headache eventually overuse their medications, and if it happens [the percentage is approximately 4%], the diagnosis of chronic migraine with medication-overuse headache is clinically important, because patients rarely respond to preventive medications while overusing acute medications. This kind of headache is recognized as a biobehavioral disorder, a complex condition wherein emotion and pain are intermingled. Properly treating medication overuse with adequate strategies by different and specific steps are essential components for helping these patients to improve and for preventing relapses. The clinical experience performed at our Headache Unit, the necessity of withdrawal, different treatment schedules, and different treatment strategies of our center were discussed. PMID- 21533707 TI - Neuromodulation in drug-resistant primary headaches: what have we learned? AB - In the last years neurostimulation procedures have been introduced to treat primary neurovascular headaches, namely cluster headache and migraine. Hypothalamic stimulation is now accepted as therapeutic procedure to treat drug resistant chronic cluster headache when patients suffer from daily multiple attacks. The inadequacy of the definition of the term "chronic" according to the International Headache Society criteria for both cluster headache and migraine when it is used to select patients for neurostimulation procedures is now evident. On the same side, there is no agreement about the use of the term "drug resistant" again when it is used to select patients for neurostimulation procedures. We have proposed that only patients suffering from daily neurovascular headaches in the last 1-2 years, with complete drug-resistance should be proposed for invasive procedures. PMID- 21533709 TI - Female reproductive steroids and neuronal excitability. AB - Oestrogen and progesterone have specific receptors in the central nervous system and are able to regulate neuronal development and plasticity, neuronal excitability, mitochondrial energy production, and neurotransmitter synthesis, release, and transport. On neuronal excitability, estradiol and progesterone seem to have an opposite effect, with estradiol being excitatory and progesterone and its derivative allopregnanolone being inhibitory. Estradiol augments N-methyl-D aspartate-mediated glutamate receptor activity, while progesterone enhances gamma aminobutyric acid-mediated chloride conductance. Sex steroid regulation of the balance of neuroexcitatory and neuroinhibitory activities may have a role in modulating clinical susceptibility to different neurological conditions such as migraine, catamenial epilepsy, premenstrual dysphoric disorder, and premenstrual syndrome. PMID- 21533708 TI - Pain emotion and homeostasis. AB - Pain has always been considered as part of a defensive strategy, whose specific role is to signal an immediate, active danger. This definition partially fits acute pain, but certainly not chronic pain, that is maintained also in the absence of an active noxa or danger and that nowadays is considered a disease by itself. Moreover, acute pain is not only an automatic alerting system, but its severity and characteristics can change depending on the surrounding environment. The affective, emotional components of pain have been and are the object of extensive attention and research by psychologists, philosophers, physiologists and also pharmacologists. Pain itself can be considered to share the same genesis as emotions and as a specific emotion in contributing to the maintenance of the homeostasis of each unique subject. Interestingly, this role of pain reaches its maximal development in the human; some even argue that it is specific for the human primate. PMID- 21533710 TI - Brain white matter lesions in migraine: what's the meaning? AB - Migraine has been associated with structural brain damage. Several studies have reported an association between migraine and brain white matter lesions or clinically silent infarct-like abnormalities in the posterior circulation territory. The origin of these lesions is still unclear. The cause is commonly interpreted as ischemic, which is consistent with the association of migraine, particularly with aura, with vascular risk factors. The relationship between increased volume of white matter hyperintensities and a history of severe headache per se is under debate. The clinical relevance of this brain damage deserves further investigations even if an association between cognitive impairment and migraine or headache of any type is not confirmed. PMID- 21533711 TI - The contribution of fMRI to elucidate the pathophysiology of primary headaches. AB - Understanding the pathophysiology of head pain is an essential prerequisite for unraveling enigmas related to the clinical management of primary headaches. Functional magnetic resonance imaging (fMRI) is now sufficiently sophisticated to provide data for testing hypotheses about the pathophysiology of chronic and primary headache forms generated from clinical and other observations. The aim of this paper is to assess the use of fMRI in headache pathophysiology considered an imbalance between behavioral and pain responses. PMID- 21533712 TI - Does NDPH exist? Some clinical considerations. AB - The analysis of case series of new daily persistent headache (NDPH) reported so far in the literature and the clinical evaluation of affected patients seen at headache clinics suggest that the current International Classification of Headache Disorders (ICHD-II) diagnostic criteria for NDPH are not adequate. In particular, in several instances headache features are not consistent with those of tension-type headache, as the ICHD-II expects. Before making a diagnosis of primary NDPH, it is imperative to rule out that it may be due to any underlying systemic disease. Just as importantly, the presence of psychiatric comorbidity and the possible role played by stressful life factors in triggering NDPH onset should also be searched for. Probably, it will only be through some future improvement in the classification of headache attributed to psychiatric disorder (chapter 12 of the ICHD-II) on the one hand, and through a careful psychological evaluation of patients currently diagnosed as NDPH sufferers on the other, that we will finally know whether primary NDPH actually exists. PMID- 21533713 TI - Sleep and primary headaches. AB - The relationship between sleep and primary headaches has been known for over a century, particularly for headaches occurring during the night or early morning. Migraine, tension-tyre headache, and cluster headache may cause sleep fragmentation, insomnia, and hypersomnia, causing considerable social and economical costs and several familial problems. By contrast, sleep disorders may themselves trigger headache attacks. Finally, headaches and sleep disorders can also be symptoms of other underlying pathologies. Despite this background, there is still no clarity about the mechanism that links these two entities and their interdependence remains to be defined. Patients with primary headache should undergo a careful assessment of sleep habits. PMID- 21533714 TI - Thunderclap headache and benign angiopathy of the central nervous system: a common pathogenetic basis. AB - Thunderclap headache (TCH) is a head pain that begins suddenly and is severe at onset; TCH might be the first sign of different neurological illnesses, and primary TCH is diagnosed when no underlying cause is discovered. Patients with TCH who have evidence of reversible, segmental, cerebral vasoconstriction of circle of Willis arteries and normal or near-normal results on cerebrospinal fluid assessment are thought to have reversible cerebral vasoconstriction syndrome (RCVS). Herein, we discuss the differential diagnosis of TCH and offer pathophysiological considerations for TCH and RCVS. PMID- 21533715 TI - Pain as an evolutionary necessity. AB - The proposed title "Pain as an evolutionary necessity" could lead to a broad debate with implications covering many chapters of the medicine and particularly of clinical neurology. In the present perspective, the discussion will focus on migraine and cluster headache chosen as elective examples of biological and not only clinical conditions, that unveil the bond between pain and necessity. Migraine, cluster headache, and perhaps other primary headaches begin to be depicted in terms of recurrent activation of innate bio-behavioral specific patterns, with a crucial and highly conserved evolutionarily adaptive significance. The pan-mammalian sickness behavior and the fight or flight response, selectively activated by different kinds of pain, are here proposed as paradigmatic of migraine and cluster headache attacks associated behaviors, allowing to reformulate these forms as the inappropriate recurrent presentation of coordinated allostatic processes, modeled along million of years of natural evolution. In this light, all the multifaceted characteristics of migraine and cluster headache attacks can be reinterpreted as complex and integrated allostatic defensive reactions to an inescapable or to an escapable pain, respectively aimed to the restoration of biologic homeostasis through a temporary disengagement from active interaction with environment (migraine associated sickness behavior) or, on the contrary, to promote the coordinated biological changes preparatory to emergency and defensive behaviors (cluster headache related fight or flight response). PMID- 21533716 TI - New disposition for pain therapy in Italy, center for headache should be integrated in the network. AB - On March 15th 2010, Italy adopted the Law no. 38 "Disposizioni per garantire l'accesso alle cure palliative e alla terapia del dolore" (Provisions aimed at ensuring access to palliative care and pain therapy). The aim of pain therapy is to enable patients with chronic diseases to achieve pain control. Palliative care, as defined by the World Health Organization, aims at "improving the quality of life of patients and families, who face the problems associated with incurable diseases, through prevention and relief from suffering, achieved through an early identification and treatment of pain by pharmacological medication and other physical, psychosocial and spiritual techniques". The main issues addressed by the law concern the monitoring of pain (the doctors will have to record on the clinical report form every level of pain intensity suffered by the patient, the appropriate therapy administered, and the pain relief achieved. This report must be kept accurately in all settings: hospital, day hospital and in outpatients). The law also suggests the establishment of two kinds of regional networks. One network (including Hospices) ensures the administration of palliative care to terminally ill patients; the other, including clinics and centers of pain therapy, provides assistance to patients with chronic pain. These networks involve general practitioners, hospital specialists and pain therapy specialists in order to ensure the best patient care. Simplification of the prescription of opiate drugs is also included in the law. In the prescription of opiates, the National Health Service medical staff can use the normal prescription form, and opiates will reimbursed by the NHS, like all other drugs. In addition, the technical papers provide precise indications of the appropriate modality of administration. The law allocates (art. 12, paragraph 2) 100 million euros per year and ? 2,450,000 in the biennium 2010-2011 to implement experimental regional projects: "hospital-territory without pain". The Ministry of Health has established a deadline within which this law must be implemented at the regional level, and further establishes a specific National Observatory, an annual report on the use of drugs in the treatment of pain, and other provisions. The levels of spending by region will also be monitored in compliance with this law; university courses and masters are required to update professionals involved in pain treatment. In July 2010, in Florence, during the interdisciplinary IMPACT 2010 summit, Institutions and Scientific Societies met to define the concrete implementation of Law No. 38, in terms of the arrangements to ensure access to palliative care and pain management. Subsequently, last November, a new meeting was held bringing together medical directors from public hospitals; further meetings are planned with Regional Health Authorities to reaffirm the importance of this law and to implement it. The most important molecules in the opioids are traditionally divided into two groups: weak and strong. Among the strong analgesics are morphine, methadone, buprenorphine, fentanyl, oxycodone, hydromorphone. Among the weak are codeine and tramadol, or opiates administered at low doses, such as oxycodone combined with acetaminophen. IMPACT's aim is also to stimulate scientific association to consider with attention and continuous medical education on the appropriates of diagnosis and administration of these medications according to data flow sheets approved in Italy. Regarding the headaches, it should be noted that the law 38 cited above includes all forms of pain, and headaches should be integrated into the care networks. In this context, several multi-disciplinary professionals within the centers (hub and spoke) or territory (GPs, specialists from neurologists and other professionals involved) should be integrated to offer the best response to the needs of the citizen. The diagnosis and treatment of various forms of headache have to be integrated into the path of pain, both National and Regional, in line with the rest of the organization. PMID- 21533717 TI - Disability in chronic daily headache: state of the art and future directions. AB - Aim of this literature review is to summarize the most relevant research findings on disability in subjects with chronic daily headache (CDH) and chronic migraine (CM) measured with the MIDAS and the HIT-6, and to address issues for further research in the field. Research strategy aimed to find papers published after 2001 that focused on disability in patients with CDH, CM and transformed migraine. Both, general population surveys or clinical series were included if they reported total scores, or distribution of the different disability levels, derived from the MIDAS and/or from the HIT-6. Fifteen papers were selected. Studies demonstrated that these subjects report a remarkable impact on functioning, with high disability scores, and reduced ability in work and non work activities. Modern definitions of disability conceptualize it as the result of the interaction between a health condition and environmental factors. Research strategies should therefore recognize that disability may represent a global evaluation which should be added to more specific endpoints, using instruments that measure disability in a multi-dimensional way, such as the WHO-DAS II. PMID- 21533718 TI - Italian Law "measures to guarantee the access to palliative and pain treatments": rebound on headaches' management. AB - The Italian Law 38/2010 assures the citizens' right to have access to palliative care and to antalgic centres in case of either oncologic or non-oncologic pain. It represents an opportunity for headaches' managements in Italy, promoting the creation of regional and national networks of headache centres and local diagnostic and therapeutic clinical pathways for patient affected with headache. This law should also support collaborations between both antalgic and headache centres networks in order to promote innovative or experimental procedures for chronic and refractory headaches. Moreover, art. 10 of the Law 38/2010 may facilitate the prescription of many headache prophylactic drugs but it may be a risk for opioids overuse headache. Educational programs and the Continuous Professional Development for physicians and all different healthcare professionals in headache area are warranted. PMID- 21533719 TI - Consultation-liaison psychiatry for patients with headaches. AB - Screening of headache patients for psychiatric disorders is needed, because of the well-known high rates of comorbidity with depression and anxiety. Screening for both depression and anxiety is highly advisable in order to identify subjects who need psychiatric consultation and therapy. Screening tools for depression and anxiety range from informal questions to self-report instruments to structured interviews and the choice is up to the clinician and the setting of the clinical evaluation. Data on psychiatric disorders and medication overuse are till now not consistent. The treatment of mood and anxiety disorders in headache patients needs to take into account the possible drug interactions with headache therapies. The collaboration between neurologists and consultation-liaison psychiatrists helps the identification of headache patients who need a psychiatric therapeutic program and follow-up. PMID- 21533721 TI - The role of the visual system in migraine: an update. AB - The visual system plays a prominent role in migraine headache, especially migraine with aura. Anatomical and functional studies in migraine are showing an increasing role linking the visual system to migraine and its multiple and complex clinical expressions. Recent research on photophobia highlights the progress of our understanding of these relationships. This review overviews a practicing neurologist's view of some of the roles of the visual system in migraine and how a clinical understanding of this relationship is enhanced by recent research and discovery in this in this important area. PMID- 21533720 TI - Migraine and depression: common pathogenetic and therapeutic ground? AB - Migraine and depression are recognized as comorbid disorders on the basis of several epidemiological data and on the possibility of shared mechanisms. On the other hand, there is a lack of studies concerning therapeutic strategies in patients with this comorbidity. The aim of this paper is to briefly review the literature about the migraine and depression comorbidity and on the putative common neurobiological mechanisms, as well to discuss the possible therapeutic options in treating patients with both disorders. PMID- 21533722 TI - Frovatriptan versus other triptans in the acute treatment of migraine: pooled analysis of three double-blind, randomized, cross-over, multicenter, Italian studies. AB - The objective of the study is to systematically review the efficacy and safety of frovatriptan (F) versus rizatriptan (R), zolmitriptan (Z) and almotriptan (A), through a pooled analysis of three individual studies. 414 subjects with a history of migraine with or without aura (IHS criteria) were randomized to F 2.5 mg or R 10 mg (study 1), F 2.5 mg or Z 2.5 mg (study 2), and F 2.5 mg or A 12.5 mg (study 3). The studies had an identical multicenter, randomized, double blind, cross-over design, with each of the two treatment periods lasting not more than 3 months. The number of pain free (PF) and pain relief (PR) episodes at 2 h, and the number of sustained pain free (SPF) and recurrent episodes within the 48 h were the efficacy endpoints. 346 patients were included in the intention-to-treat analysis. Rate of PF episodes at 2 h was 30% with F and 34% with comparators (p = NS). PR episodes at 2 h were 55% for F and 59% for comparators (p = NS). SPF episodes at 48 h were also similar between the two groups (22% F vs. 21% comparators). Rate of recurrence was significantly (p < 0.001) lower under F (27 vs. 40% comparators). Drug-related adverse events were significantly (p < 0.05) less under F, particularly cardiovascular symptoms. Our systematic analysis of individual studies suggests that F has a similar immediate efficacy, but a more sustained effect and a better tolerability than R, Z and A. PMID- 21533724 TI - New frontiers in headache therapy. AB - There are numerous headache therapies available for our patients, more for migraine than for any of the other primary headache disorders. Only four medications have been approved for migraine prevention in the last few decades in the US and onabotulinumtoxinA was recently approved in the UK and the US for chronic migraine. We have been more fortunate in the acute care arena where in the US we have had seven triptans and one nonsteroidal anti-inflammatory medication approved by the FDA and currently available. There are several other acute care medications in various stages of development and there are two new methods of administering a triptan and others under investigation. We are always looking for faster, easier and more efficient administration of medications with fewer adverse events, as optimal migraine therapy requires these characteristics. What follows is a brief review of the progress in development for four of the many new acute care medications being investigated: the CGRP antagonist tablet telcagepant, the sumatriptan iontophoretic patch, sumatriptan powder for use in the OptiNose apparatus and the dihydroergotamine oral inhaler. I will not include transcranial magnetic stimulation, a 5-HT(1F) agonist, large conductance calcium activated potassium channel openers, glial modulators or other medications and devices in early stages of development [1]. PMID- 21533723 TI - Efficacy of frovatriptan in the acute treatment of menstrually related migraine: analysis of a double-blind, randomized, multicenter, Italian, comparative study versus zolmitriptan. AB - Menstrually related migraine (MRM) is a particularly difficult-to-treat pain condition, associated with substantial disability. Aim of this study was to compare the efficacy and safety of frovatriptan and zolmitriptan in the treatment of MRM attacks, analyzing data from a multicenter, randomized, double blind, cross-over study. We analyzed the subset of 76 regularly menstruating women who participated in one head-to-head multicenter, randomized, double blind, cross over clinical trial and who took the study drugs to treat MRM attacks. In a randomized sequence, each patient received frovatriptan 2.5 mg or zolmitriptan 2.5 mg: after treating three episodes of migraine in no more than 3 months with the first treatment, the patient had to switch to the other treatment. MRM was defined according to the criteria listed in the Appendix of the last Classification of Headache disorders of the International Headache Society. A total of 73 attacks, classified as MRM, were treated with frovatriptan and 65 with zolmitriptan. Rate of pain relief at 2 h was 52% for frovatriptan and 53% for zolmitriptan (p = NS), while rate of pain free at 2 h was 22 and 26% (p = NS), respectively. At 24 h, 74 and 83% of frovatriptan-treated and 69 and 82% of zolmitriptan-treated patients were pain free and had pain relief, respectively (p = NS). Recurrence at 24 h was significantly (p < 0.05) lower with frovatriptan (15 vs. 22% zolmitriptan). Frovatriptan proved to be effective in the immediate treatment of MRM attacks, similarly to zolmitriptan, but showed lower recurrence rates, and thus a better sustained relief. PMID- 21533725 TI - Migraine prophylaxis: what is new and what we need? AB - A wide array of options are now available for migraine prophylaxis. Conventional treatments include beta-blockers, anticonvulsants, antidepressants, calcium antagonists and antiserotoninergic drugs. Emerging medications such as ACE inhibitors, sartans and nutritional supplements are gaining favour for migraine prophylaxis. Botulinum toxin type A is a promising therapeutic tool for chronic migraine. Tonabersat is likely to be a step forward for the treatment of migraine with aura. However, much work is needed to identify predictive clinical features of successful responsiveness and to better define the duration of prophylaxis. PMID- 21533726 TI - Treatment of alterations in CSF dynamics. AB - Alterations of the intracranial pressure (ICP) may be present in several conditions. The aim of this brief review is to focus on two relatively rare conditions characterized by alterations in cerebro-spinal fluid dynamics- Spontaneous Intracranial hypotension (SIH) and Idiopathic Intracranial hypertension (IIH)--in which headache is one of the key symptoms. The most relevant clinical features, the expected MRI findings, and the therapeutic options regarding both conditions are discussed. PMID- 21533727 TI - Migraine with aura: conventional and non-conventional treatments. AB - Migraine with aura (MwA) is a primary headache that affects up 30% of migraine patients. Although the frequency of MwA attacks is usually low and the majority of migraine sufferers do not need prophylactic treatment(s), same particular patients do. This occurs when the neurological symptoms, that characterize the auras, determine anxiety to the migraine sufferers and when the frequency of MwA attacks is or becomes high. In this study, we review the few therapeutic conventional options specifically devoted to cure MwA attacks present in the literature together with those, recent, non-conventional. PMID- 21533728 TI - Nose and headache: what have we learned? Naso e cefalee: cosa abbiamo imparato. AB - Sinonasal involvement in secondary headache has long been interpreted as sinusitis and overestimation has been a problem in the past. In the last 20 years, the innovative interpretation of contact points between the lateral nasal wall and the septum as triggering cause of facial pain via the trigeminovascular system has gained importance in nasal secondary headaches. Also in this case, the prevalence and relevance has been misinterpreted in the beginning, undermining the success rate of pain improvement after surgical removal of these contact points. Therefore, studies have started to concentrate on the need of suitable preoperative evaluation to define the ideal, responsive candidate for surgical management of this form of headache. This article analyzes the outcome of these studies and tries to highlight the need for long-term follow-up to finally determine the relevance of surgical treatment for this particular headache form. PMID- 21533729 TI - Oral contraceptives in migraine therapy. AB - Even if sometimes combined oral contraceptives (COCs) can initiate or aggravate headaches, in particular migraine, the headaches generally tend to improve after the first months of COC use. If migraine persists, in many patients the attacks are more likely to occur during the pill-free week, and an oral contraceptive induced menstrual migraine (OCMM) occurs. In case of OCMM, some hormonal manipulations are available, by eliminating or reducing the hormone-free interval (HFI), in order to prevent this estrogen-withdrawal headache. It is possible to use a continuous COCs regimen, to shorten the HFI to less than the traditional 7 days, to use a low-dose estrogen supplementation after the 21 days of COCs or to prescribe a progestogen-only pill (POP). Interestingly, the use of a POP is a safe option also for women suffering from migraine with aura (in which COCs are absolutely contraindicated) and a recent trial suggests that its use can reduce the frequency of migraine attacks and the duration of aura symptoms too. PMID- 21533730 TI - The genetic features of 24 patients affected by familial and sporadic hemiplegic migraine. AB - Familial hemiplegic migraine (FHM) is the only migraine subtype for which a monogenic mode of inheritance, autosomal dominant has been clearly established. It is genetically heterogeneous and at least three different genes exist (CACNA1A, ATP1A2, and SCN1A), the so-called FHM1, FHM2, and FHM3 genes, respectively. Sporadic hemiplegic migraine (SHM) is a disorder, in which some patients may have their pathophysiology identical to FHM, but others, possibly the majority, may have different pathophysiology, probably related to the mechanisms of typical migraine with aura. In our study, we have screened the DNA of 24 patients affected by FHM and SHM. Only in three patients, 2 sporadic and 1 familial cases, we have described genetic mutations, all of them in the ATP1A2 gene. In our opinion, these results demonstrate a more frequent involvement of the ATP1A2 gene not only in the sporadic form, but probably also in the Italian FHM patients without permanent cerebellar signs. Moreover, the absence of CACNA1A, ATP1A2 and SCN1A mutations in the other 12 familial cases suggests the involvement of still unknown genes. PMID- 21533731 TI - The role of instrumental examinations in delayed migraine diagnosis. AB - Patients affected by migraine without aura very often consult different specialists who, misunderstanding the correct diagnosis, submit them to different instrumental examinations. The objective of the study was to assess if each instrumental examination was really useful for a faster migraine definition, or on the contrary, it increased the time delay for a correct diagnosis. We enrolled 300 consecutive patients referring to our Headache Center with a first diagnosis of migraine without aura and submitted them to a face-to-face interview about time from disease's onset to a correct diagnosis. In each patient, the first instrumental examination performed to specifically investigate migraine-related symptoms was defined. Brain MRI, brain CT, sinus CT, sinus X-rays, cervical spine X-rays and EEG were the most often performed examinations. All the exams, with the exception of brain CT, determined a significant increase of time delay in migraine diagnosis (p < 0.05). Brain CT was significantly associated with a higher probability to obtain a correct diagnosis in less than 1 year. Migraine without aura patients are usually addressed to perform radiological and other instrumental examinations. This attitude may increase the risk of time delay to obtain a correct diagnosis. The performance of a careful clinical history evaluation and neurological examination, with the addition of a brain CT when appropriate, is the best approach for a rapid and correct diagnosis of migraine without aura. PMID- 21533732 TI - Possible relationships between headache-allodynia and nocturnal sleep breathing. AB - Sleep and headache are linked in a bidirectional way. Breathing quality during sleep may be a possible link between them. The objective of this study were to evaluate the prevalence of headache--and of allodynia--in a population of subjects who underwent cardiopulmonary monitoring during sleep for presumed respiratory problems; to evaluate the possible relationships between the presence of headaches--and of allodynia--and respiratory parameters. We studied 181 subjects, 112 without headache (mean age 59.4 +/- 13.1 years, 97 men and 15 women); 69 with history of headache (42 men and 27 women; 41 migraineurs and 28 with tension type headache). Headache diagnosis was made according to ICHD-II criteria. A semi-structured ad hoc questionnaire was used to evaluate the presence of allodynia. Full cardiopulmonary monitoring was performed by SOMNO check((r)) effort (WEINMANN) with SaO(2), T90 and AHI determination. Headache and headache-associated allodynia were particularly frequent in this population, suggesting a positive correlation between breathing problems during sleep and head pain, and allodynia. The observation that better respiratory parameters were found among headache sufferers with respect to those without headache, even in allodynic subjects, seems to reverse this point of view: headache and allodynia may possibly have an allostatic function preventing deep sleep and, in turn, avoiding prolonged apneas. PMID- 21533733 TI - Quality of life of multiple sclerosis patients with comorbid migraine. AB - The aim of the present study was to investigate the impact of comorbid migraine on quality of life (QoL) of patients with multiple sclerosis (MS). Forty-four MS patients with comorbid migraine and 44 sex/age-matched MS subjects free from primary headache were evaluated. Although we observed that comorbid migraine did not affect the physical and mental composite scores of the MS QoL-54 questionnaire, MS patients with migraine had worse scores than those without in role limitation due to physical problems (RL-P) (p = 0.035), bodily pain (BP) (p = 0.030) and health perception (HP) (p = 0.023) subscales. These findings were confirmed by multivariate regression analyses adjusted for demographic, clinical and psychometric variables. Significant correlations between MIDAS score and RL-P (r = -0.43, p = 0.003), BP (r = -0.51; p < 0.001), and HP (r = -0.38; p = 0.01) were also found. In conclusion, we suggest that investigating and treating migraine in MS patients might contribute to improve their QoL. PMID- 21533734 TI - Restless legs syndrome is not associated with migraine with aura: a clinical study. AB - Based on recent data about the association between restless legs syndrome (RLS) and migraine, we performed an observational study on the occurrence of RLS in patients affected by "pure" migraine with aura (pMA). We recruited 63 patients (33 females and 30 males) affected by MA without other types of primary headache among all patients referred in five Italian headache centers in a 1-year period. The prevalence of RLS in pMA patients (9.5%) is similar to that observed in Italian headache-free subjects (8.3%). No significant differences were found between pMA patients with and without RLS about clinical features of MA attacks and systemic and psychiatric diseases were investigated. Moreover, no association appeared between RLS and familial cases of MA. Differently from migraine without aura, our data do not confirm the existence of an association between RLS and MA, not even when a genetic factor is involved. PMID- 21533735 TI - Headache and neuropsychic disorders in the puerperium: a case report with suspected deficiency of urea cycle enzymes. AB - An enzymatic abnormality of the urea cycle is a metabolic disorder occasionally seen in adults, but particularly in the puerperium. The main risk is acute hyperammoniemic encephalopathy, leading to psychosis, coma and even death if not diagnosed promptly and treated appropriately. Headache is frequent in the puerperium normally manifesting between 3 and 6 days after delivery. We describe here a 39-year-old woman, who 3 days after delivery presented diffuse tension type headache and depression, followed by behavioral disorders, psychomotor agitation, epileptic seizures, and finally coma 2 days later. Pregnancy and normal delivery: routine blood chemistry findings, CT scan, MR imaging, angio-MR of the brain, and lumbar puncture were normal. EEG when seizures started, it showed diffuse slowing, as in the case of metabolic encephalopathy. This led us to assay blood ammonia, which was high at >400 mmol. Liver function and abdominal US were normal; hence, we suspected a urea cycle enzymatic abnormality, and requested for genetic tests. These confirmed a congenital primary metabolic deficiency of arginine succinate synthetase, with high citrullinemia (type II, adult form). Dialysis was started promptly, with initially iv arginine, then orally, plus medical therapy for the hyperammoniemia and a low protein diet; plasma ammonia dropped swiftly to normal, and her state of consciousness gradually improved until all the clinical symptoms had resolved. Ammonia assay should always be considered in the first few days of the puerperium in women with headache and behavioral disorders, to exclude an inborn deficiency of the urea cycle, which may have gone unnoticed until then. PMID- 21533736 TI - Chronic daily headache: suggestion for the neuromuscular oral therapy. AB - Tweny patients (M: 4, F: 16, mean age 37 +/- 11 years) with diagnosis of chronic daily headache (CDH), after drug withdrawal, were under electromyography, kinesiography and masticatory muscle deprogramming by TENS to identify the physiological rest position of the mandible. Our purpose was to clarify a possible role of the neuromuscular stomatognathic system. Examinations showed that 17 patients needed a neuromuscular orthosis, an occlusal device, to provisionally correct the detected discrepancies of jaw position. Of those, the 10 patients who showed an occlusal sagittal discrepancy higher than 2 mm and/or a lateral deviation higher than 0.4 mm, associated with more than three parafunctional activities, had a meaningful decrease on frequency/intensity of migraine crisis and/or of days of headache. VAS pain score during crisis decreased from 9.0 +/- 0.9 to 4.9 +/- 2.7; frequency of crisis were from 20.7 +/- 5.2 to 9.5 +/- 7.7. Baseline pain were from 5.3 +/- 1.2 to 3.0 +/- 1.3. Satisfying clinical results can be reached combining behavioural education and neuromuscular orthosis. This can be very helpful in patients who show significant discrepancy of jaw position that only TENS deprogramming can reveal and kinesiography can detect with such accuracy. PMID- 21533737 TI - Interictal cortical reorganization in episodic migraine without aura: an event related fMRI study during parametric trigeminal nociceptive stimulation. AB - The aim of our study was to explore the pain processing network in patients with migraine during trigeminal nociceptive stimulation. Sixteen patients with episodic migraine without aura and 16 healthy controls performed functional magnetic resonance imaging during thermal stimuli (at 41, 51 and 53 degrees C). Patients with migraine showed a greater activation in the perigenual part of anterior cingulate cortex at 51 degrees C and less activation in the bilateral somatosensory cortex at 53 degrees C compared to healthy controls. There were no differences in experimental pain perception between groups. Our findings demonstrate a functional reorganization of cerebral areas known to be involved in pain processing in patients with migraine. PMID- 21533738 TI - Sinus venous stenosis-associated IIHWOP is a powerful risk factor for progression and refractoriness of pain in primary headache patients: a review of supporting evidences. AB - Reported prevalence of idiopathic intracranial hypertension without papilledema (IIHWOP) in series of patients with chronic or transformed migraine is significantly higher than expected; yet, IIHWOP is not included among the risk factors for migraine progression. However, several studies provided evidences suggesting that IIHWOP could represent a possible, largely underestimated, risk factor for progression of pain in migraine and, possibly, in other primary headaches. Data from two recent studies, albeit aimed to different end-points, strongly support this hypothesis. In the first study, conducted on a large series of neurological patients without any sign or symptom of raised intracranial pressure (ICP), including chronic headache, the prevalence of bilateral central venous stenosis at magnetic resonance venography (MRV) was 23% and an IIHWOP at opening pressure was found in 48% of this subgroup (11% of the whole sample) while it was not detected in any of the subjects with normal MRV. This indicates that IIHWOP may be much more prevalent than believed in general population and that it can run without any symptom or sign of raised ICP in most of affected subjects. In the second paper, sinus venous stenosis-associated IIHWOP has been found in about one half of a large chronic primary headache patients series with poor response to treatments and in none of those with normal MRV. Moreover, after the diagnostic lumbar puncture, a transient improvement of headache frequency has been observed in the majority of intracranial hypertensive chronic headache subjects. Taken together, the data of these two recent papers rise the following hypothesis: (1) asymptomatic IIHWOP is much more prevalent than expected in general population; (2) IIHWOP is a powerful and largely unrecognized risk factor for progression of pain in primary headache patients; (3) sinus venous stenosis at MRV is a reliable predictor of raised intracranial hypertension also in asymptomatic patients; (4) sinus venous stenosis has a causative role in IIH pathophysiology. These assumptions share a potential high clinical impact and need to be urgently tested in adequately designed controlled studies. PMID- 21533739 TI - Ear acupuncture in the treatment of migraine attacks: a randomized trial on the efficacy of appropriate versus inappropriate acupoints. AB - Ear acupuncture can be a useful mean for controlling migraine pain. It has been shown that a technique called the Needle Contact Test (NCT) can identify the most efficacious ear acupoints for reducing current migraine pain through just a few seconds of needle contact. The majority of the points were located on the antero internal part of the antitragus (area M) on the same side of pain. The aim of this study was to verify the therapeutic value of area M and to compare it with an area of the ear (representation of the sciatic nerve, area S) which probably does not have a therapeutic effect on migraine attacks. We studied 94 females suffering from migraine without aura, diagnosed according to the ICHD-II criteria, during the attack. They were randomly subdivided into two groups: in group A, tender points located in area M, positive to NCT were inserted; in group B, the unsuitable area (S) was treated. Changes in pain intensity were measured using a VAS scale at various times of the study. During treatment, there was a highly significant trend in the reduction of the VAS value in group A (Anova for repeated measures: p < 0.001), whereas no significance was observed in group B. VAS values were significantly lower in group A than in group B at 10, 30, 60 and 120 min after needle insertion. This study suggests that the therapeutic specificity of auricular points exists and is linked to the somatotopic representation of our body on the ear. PMID- 21533740 TI - Psychopathological profile of patients with chronic migraine and medication overuse: study and findings in 50 cases. AB - Patients with chronic migraine (CM) have high frequence of psychiatric comorbidity or psychological distress. The presence of depression, anxiety, panic or obsessive disorders in these patients contributes to poor quality of life and can influence prognosis and treatment. A systematic investigation of psychiatric comorbidity is needed in patients with CM especially in those with medication overuse (MO), in order to reach a more comprehensive clinical management. We assessed the psychological profile of 50 patients, 40 women and 10 men suffering from CM with MO. The Spectrum Project, a complementary way of describing and assessing psychopathology with structured clinical interviews, was used for the psychological evaluation of the patients to explore personality traits. Spectrum instruments mood disorders (MOODS), panic agoraphobic disorders (PAS) and obsessive-compulsive disorder (OBS) were applied to study patients. OBS questionnaire was positive in 28% of the patients, MOODS-questionnaire in 44%, PAS-questionnaire in 46%. 19 on 50 patients (38%) presented positivity to 2 or to all questionnaires in variable associations. None of the patients of the studied group had complete normal findings in the questionnaires. Clinical records of patients with OBS-questionnaire positivity showed a worse clinical course and tendency to relapse. These results suggest that psychological assessment is an essential step in the evaluation and treatment of patients with CM and MO. The remarkable percentage of OBS-questionnaire positivity in this group indicates that obsessive-compulsive trait represents besides depression and anxiety, a major risk of chronification and overusing. PMID- 21533741 TI - Undertreatment in patients with primary headaches attending headache centres. AB - Undertreatment in patients with primary headaches was evaluated in 600 patients attending 7 headache centres in Lombardy by assessing the rates of acute and prophylactic treatments used before the first visit and the rates of prescription of acute and prophylactic treatments after the visit at the headache centre. Our results clearly showed that most headache patients are likely to receive suboptimal treatments, confirming the utility of headache centres as well as the need for promoting education of GPs and the development of appropriate networks to reduce undertreatment rates, in order to highlight the negative impact caused by primary headache on individuals and on the society. PMID- 21533742 TI - Polytherapy for the prophylaxis of chronic migraine: an Italian survey. AB - Chronic migraine (CM) represents an important medical issue, due to morbidity, high disability, presence of comorbidities, and medication overuse (MO). The prophylaxis of CM has not been extensively explored so far. Patients with CM are often treated with two or more compounds, although there is no clear evidence that polytherapy may be superior to monotherapy. We evaluated the percentage of prescription of polytherapy for the prophylaxis of CM in a clinical sample. We examined the charts of 98 CM patients admitted to our Headache Center for inpatient withdrawal program to stop MO. Results showed that only one drug for prophylaxis was prescribed in 20.4% cases, two or more drugs in 79.6%, with 63.3% of the total sample falling in the group "true polytherapy", i.e. all the drugs prescribed on daily basis were given to treat CM, and not only to treat concomitant conditions. In more than 60% cases a combination of drugs indicated for migraine prophylaxis and drugs only indicated for other conditions (mainly for psychiatric disorders) was prescribed. Our survey indicates that polytherapy may be rather common in CM, and suggests that comorbidities may strongly influence treatment choices. PMID- 21533743 TI - A longitudinal evaluation of changes in disability and quality of life in a sample of women with migraine. AB - Migraine's high prevalence, which rises up to 25% among women in the productive age, determines a strong reduction in health-related quality of life (HRQoL) and increased disability. Aim of this study is to longitudinally describe disability and HRQoL in a sample of adult women with migraine attending to a specialty centre. HRQoL was measured with the SF-36 and disability with the WHO-DAS II. One sample t test was used to assess deterioration in disability and HRQoL scales compared to normative scores; effect size was calculated to describe magnitude of change after 3 months. Majority of scales were significantly deteriorated, and changes between baseline and follow-up were negligible to small for most of SF-36 scales, and small to moderate for WHO-DAS II scales. In conclusion, women with migraine showed pervasive deterioration in disability and HRQoL. Wider improvements were observed at follow-up for activities in which relational skills are relevant, while those with a physical component, or that are predominantly performed autonomously, remained almost unchanged. PMID- 21533744 TI - Evolution of headache in a population of young Italian headache sufferers: a brief report. AB - Headache is a common symptom in children and adolescence. In this retrospective analysis, we interviewed a population of young patients who were arrived to our observation 10 years before, in order to: (1) determine if the first diagnosis was still adequate and (2) which percentage of these young patients developed chronic forms (more than 15 days/month) from episodic forms. One hundred and seventy-seven patients suffering from different forms of headache were contacted and interviewed. The original diagnosis was confirmed in all the population of patients and the percentage of chronic forms developed from episodic forms was not significant. From this retrospective study, it does not seem the evolution of episodic forms in young age is necessarily a chronic form in adult as this depends from other behavioural or biological or environmental factors. PMID- 21533745 TI - Gingkolide B as migraine preventive treatment in young age: results at 1-year follow-up. AB - Primary headaches, migraine and tension-type headaches are some of the most frequent conditions in young age. Even before pharmacological treatment, it is mainly useful in these patients to adopt an appropriate lifestyle, with regular sleep, meals, computer and TV, sport, and avoiding triggers. Any specific and effective pharmacological treatment for migraine and tension-type headache is never lacking in side effects. Gingkolide B, an herbal constituent extract from Ginko biloba tree leaves, is a natural anti platelet activating factor (PAF). PAF is a potent pro inflammatory and nociceptive agent released during the inflammation process. Therefore, Gingkolide B can be considered a promising non pharmacological tool for treatment of migraine with and without aura. In an earlier clinical report, we described our initial attempts to assess the clinical utility of Gingkolide B in a small group of young migraine patients. A small sample of 30 young patients suffering from migraine without aura entered the open label prospective trial. Migraine without aura was diagnosed according to International Headache Society (IHS) criteria. The treatment was well tolerated and the compliance was good. Despite the uncontrolled open-label design of this study and the small sample of patients, these data show that Gingkolide B seems to be effective as preventive treatment in reducing migraine attack frequency and in attenuating the use of symptomatic medication in our small series of children with primary headache. PMID- 21533748 TI - Current clinical trials in castrate-resistant prostate cancer. AB - Seven years passed since docetaxel/prednisone demonstrated and overall survival benefit, leading to its approval by the FDA for metastatic castration resistant prostate cancer. In 2010, two new treatments, sipuleucel-T and cabazitaxel, were approved by the United States Food and Drug Administration for men with castration-resistant prostate cancer, based upon improvement in overall survival. The progress that has been made in understanding the biological basis of disease progression, particularly the role of the continued activation of the androgen receptor, have led to new treatments that will further improve survival in these patients. Abiraterone, a drug that depletes both intracellular and extracellular sources of testosterone, demonstrated a 3.9-month improvement in survival in patients who failed docetaxel-based chemotherapy. Other drugs targeting the androgen-receptor axis, such as TAK-700 and MDV3100, have demonstrated significant activity in phase 1 and 2 studies, and are currently in phase 3. Agents that target angiogenesis, bone, and novel apoptotic proteins currently are under investigation, either as single agents or in combination with chemotherapy. The challenge for the development of clinical trials will be how these compounds will be sequenced in the future. PMID- 21533747 TI - The role of phenotyping in chronic prostatitis/chronic pelvic pain syndrome. AB - Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a chronic pain syndrome identified by the presence of noninfectious pelvic or perineal pain lasting longer than 3 months. Current diagnoses and treatments for the syndrome solely depend on and target symptoms, respectively. Thus far, the mechanistic disturbances responsible for the pathogenesis of CP/CPPS have remained largely elusive and treatments, and therefore, continue to be ineffective. To move toward successful management and treatment of CP/CPPS, it is necessary to elicit the underlying biological mechanisms responsible for the syndrome. Therefore, a phenotyping system that is able to bridge the gap between current symptom-based diagnosis and future mechanistic approaches to diagnosis and treatment is needed. In this article, we examine current CP/CPPS phenotyping systems, analyze their utility, and make suggestions for changes in clinical approaches to the syndrome that would both promulgate a mechanistic understanding and advance treatment approaches. PMID- 21533749 TI - Genetic predisposition of some Bulgarian sheep breeds to the scrapie disease. AB - The aim of this study is to investigate the profile of ovine PrP gene by amino acid polymorphism at codons 136, 141, 154, and 171 for determining the genetic predisposition to the Scrapie disease for the tribal sheep and rams, with different numbers and distribution in Bulgaria. Three hundred twenty four animals originating from 41 tribal herds comprising eight breeds were included in the study. DNA was isolated from blood samples specifically amplified by PCR and sequenced. The alignments of codons 136, 141, 154, and 171 were determined. Based on the sequencing, it was established that Bulgarian breeds belong to the second and third risk groups, those with low and moderate risk of Scrapie disease. Establishment of 11 genotypes in Synthetic Population Bulgarian Milk breed reveals it to have the highest risk of the Scrapie disease; moreover, the conducting of the program will be more difficult in comparison with other investigated breeds. Evidence for the internal cross breeding is the presence of the five or six genotypes in the Copper-Red Shoumen, Replian, Karakachan, and Duben Bulgarian native breeds. PMID- 21533750 TI - Molecular analysis of the complete genomic sequences of four isolates of Gooseberry vein banding associated virus. AB - The presence of Gooseberry vein banding associated virus (GVBaV), a badnavirus in the family Caulimoviridae, is strongly correlated with gooseberry vein banding disease in Ribes spp. In this study, full-length genomic sequences of four GVBaV isolates from different hosts and geographic regions were determined to be 7649 7663 nucleotides. These isolates share identities of 96.4-97.3% for the complete genomic sequence, indicating low genetic diversity among them. The GVBaV genome contains three open reading frames (ORFs) on the plus strand that potentially encode proteins of 26, 16, and 216 kDa. The size and organization of GVBaV ORFs 1 3 are similar to those of most other badnaviruses. The putative amino acid sequence of GVBaV ORF 3 contained motifs that are conserved among badnavirus proteins including aspartic protease, reverse transcriptase, and ribonuclease H. The highly conserved putative plant tRNA(met)-binding site is also present in the 935-bp intergenic region of GVBaV. The identities of the genomic sequences of GVBaV and other badnaviruses range from 49.1% (Sugarcane bacilliform Mor virus) to 51.7% (Pelargonium vein banding virus, PVBV). Phylogenetic analysis using the amino acid sequence of the ORF 3 putative protein shows that GVBaV groups most closely to Dioscorea bacilliform virus, PVBV, and Taro bacilliform virus. These results confirm that GVBaV is a pararetrovirus of the genus Badnavirus in the family Caulimoviridae. PMID- 21533751 TI - Managing magnetic resonance imaging machines: support tools for scheduling and planning. AB - We devise models and algorithms to estimate the impact of current and future patient demand for examinations on Magnetic Resonance Imaging (MRI) machines at a hospital radiology department. Our work helps improve scheduling decisions and supports MRI machine personnel and equipment planning decisions. Of particular novelty is our use of scheduling algorithms to compute the competing objectives of maximizing examination throughput and patient-magnet utilization. Using our algorithms retrospectively can help (1) assess prior scheduling decisions, (2) identify potential areas of efficiency improvement and (3) identify difficult examination types. Using a year of patient data and several years of MRI utilization data, we construct a simulation model to forecast MRI machine demand under a variety of scenarios. Under our predicted demand model, the throughput calculated by our algorithms acts as an estimate of the overtime MRI time required, and thus, can be used to help predict the impact of different trends in examination demand and to support MRI machine staffing and equipment planning. PMID- 21533752 TI - Tumour doubling times and the length bias in breast cancer screening programmes. AB - Screening for early detection of breast cancer is considered to be an important element of preventive medicine. In this paper, we use numerical simulations to examine the length bias in regular interval screening programmes, by computing the doubling times of breast cancer tumours detected through regular mammographies compared to self-detection. Our analysis shows that doubling times of tumours detected by a regular screening programme are longer than doubling times in the original whole population and considerably longer than those self detected. Hence regular interval mammographies may be missing a high proportion of fast growing tumours and therefore the benefits of current screening programmes may need to be re-evaluated. We examine the likely size of the length bias for the present UK breast cancer screening programme and perform a sensitivity analysis by varying the screen detection probabilities to reflect future advances in mammographic detection. PMID- 21533753 TI - Ginseng root water-extracted pectic polysaccharides originate from secretory cavities. AB - A range of molecular probes for cell wall polysaccharides has been used to explore the structure and location of water-extracted pectic polysaccharides occurring in fractions isolated from ginseng roots. The LM19 homogalacturonan (HG) epitope was abundant in an HG fraction and analysis of LM19 binding to a rhamnogalacturonan-I (RG-I) rich-fraction indicated that the LM19 epitope is sensitive to acetylation. A specific RG-I epitope (LM16), four arabinogalactan protein (AGP) epitopes (LM2, LM14, JIM16, MAC207) and an extensin epitope (JIM20) were found to be abundant and co-located in several isolated polysaccharide fractions including an arabinogalactan fraction and two RG-I fractions. Detection of the RG-I, AGP and extensin epitopes identified in isolated polysaccharide fractions in sections of ginseng roots indicated that they were most abundant in secretory cavities found in the cortical regions of ginseng roots. In addition, the immunocytochemical study indicated that polysaccharide epitope masking is a widespread phenomenon in the primary cell walls of ginseng roots. PMID- 21533754 TI - Evidence for a role of raffinose in stabilizing photosystem II during freeze-thaw cycles. AB - A role of non-reducing sugars like sucrose and raffinose in the protection of plant cells against damage during freezing has been proposed for many species, but reports on physiological effects are conflicting. Non-aqueous fractionation of mesophyll cell compartments in Arabidopsis thaliana was used to show that sucrose and raffinose accumulate in plastids during low temperatures, pointing to a physiological role in protecting the photosynthetic apparatus. Comparing a previously described raffinose synthase (RS) mutant of A. thaliana with its corresponding wild type, accession Col-0, revealed that a lack of raffinose has no effect on electrolyte leakage from leaf cells after freeze-thaw cycles, supporting that raffinose is not essential for protecting the plasma membrane. However, in situ chlorophyll fluorescence showed that maximum quantum yield of PS II photochemistry (F (v)/F (m)) and other fluorescence parameters of cold acclimated leaves subjected to freeze-thaw cycles were significantly lower in the raffinose synthase mutant than in the corresponding wild type, indicating that raffinose is involved in stabilizing PS II of cold acclimated leaf cells against damage during freezing. PMID- 21533755 TI - Web-assisted assessment of professional behaviour in problem-based learning: more feedback, yet no qualitative improvement? AB - Although other web-based approaches to assessment of professional behaviour have been studied, no publications studying the potential advantages of a web-based instrument versus a classic, paper-based method have been published to date. This study has two research goals: it focuses on the quantity and quality of comments provided by students and their peers (two researchers independently scoring comments as correct and incorrect in relation to five commonly used feedback rules (and resulting in an aggregated score of the five scores) on the one, and on the feasibility, acceptability and perceived usefulness of the two approaches on the other hand (using a survey). The amount of feedback was significantly higher in the web-based group than in the paper based group for all three categories (dealing with work, others and oneself). Regarding the quality of feedback, the aggregated score for each of the three categories was not significantly different between the two groups, neither for the interim, nor for the final assessment. Some, not statistically significant, but nevertheless noteworthy trends were nevertheless noted. Feedback in the web-based group was more often unrelated to observed behaviour for several categories for both the interim and final assessment. Furthermore, most comments relating to the category 'Dealing with oneself' consisted of descriptions of a student's attendance, thereby neglecting other aspects of personal functioning. The survey identified significant differences between the groups for all questionnaire items regarding feasibility, acceptability and perceived usefulness in favour of the paper-based form. The use of a web-based instrument for professional behaviour assessment yielded a significantly higher number of comments compared to the traditional paper-based assessment. Unfortunately, the quality of the feedback obtained by the web-based instrument as measured by several generally accepted feedback criteria did not parallel this increase. PMID- 21533756 TI - Prostate cancer radiotherapy in Austria: overview on number of patients, intention to treat, and treatment techniques based on data from 2007. AB - PURPOSE: Aim of this analysis was to assess the current status of prostate cancer radiotherapy in Austria and compare these numbers to patients treated with surgery. MATERIAL AND METHODS: A questionnaire was sent to all 14 Austrian departments asking about numbers of prostate cancer patients treated and indication of treatment (primary, postoperative), as well as the treatment technique used (3D-CRT, IMRT, brachytherapy), treatment volumes (with/without pelvic irradiation), dose applied, and differences in treatment concepts. Data investigated were based on the year 2007. RESULTS: Of the 14 departments (65%), 9 departments decided to participate. A total of 1,191 prostate cancer patients were treated (847 primary, 344 postoperative). Primary patients were treated by external beam technique (91%) and permanent interstitial brachytherapy (9%). All postoperative patients were treated by 3D-CRT. Dose ranged from 70-78 Gy for primary patients and from 60-72 Gy for postoperative patients. A risk-adapted dose prescription was performed in 5 centers. Additional pelvic lymph node irradiation was based on signs of positive nodes in 4 departments and based on Roach formula/Partin table in 5 departments. CONCLUSION: About 25% of prostate cancer patients receive primary radiotherapy. This number reflects a high potential to conduct national studies. Treatment technique and dose applied was in all centers investigated in accordance with the German S3 guidelines. PMID- 21533757 TI - kV cone-beam CT-based IGRT: a clinical review. AB - AIMS AND METHODS: Delivery of high radiation doses while simultaneously sparing organs at risk requires advanced imaging for target volume definition, highly conformal dose distributions of intensity modulated radiotherapy (IMRT), and narrow planning target volume (PTV) margins. Three-dimensional image-guided radiotherapy (IGRT) with cone-beam computer tomography (CBCT), which results in more precise target localization, is quickly replacing two-dimensional (2D) IGRT. An overview on the clinical applications of kilovoltage gantry-mounted CBCT systems with emphasis on the most frequently targeted body sites (prostate, lung, head and neck) is provided based on a review of the relevant literature. Alternative imaging methods and their advantages/disadvantages are discussed. RESULTS: IGRT with soft tissue detection improves set-up accuracy and is currently replacing 2D verification and frame-based stereotactic treatments; safety margins are significantly reduced by this IGRT technology. In addition, systematic changes of tumor volume and shape and of the normal tissue can be monitored allowing for adaptation of radiotherapy. IGRT in combination with conformal treatment planning allows for hypofractionated dose escalation, which results in improved rates of local tumor control with low rates of toxicity. CONCLUSION: CBCT allows for daily pretreatment position verification and online correction of set-up errors which improves the precision of patient repositioning with the possibility of shrinking safety margins, sparing organs at risk, and escalating radiation doses. A trend for better clinical outcome can be observed. PMID- 21533758 TI - Prognostic value of radiobiological hypoxia during fractionated irradiation for local tumor control. AB - BACKGROUND AND PURPOSE: Previous experiments showed that the fraction of radiobiologically hypoxic tumor cells (rHF) in un-treated tumors did not accurately predict local tumor control after fractionated irradiation. Thus, the prognostic value of rHF determined during fractionated irradiation was investigated. MATERIALS AND METHODS: Six human squamous cell carcinoma lines were transplanted into nude mice and then irradiated with 15 fractions over 3 weeks. Thereafter, single dose irradiation under normal and clamped blood flow was given. Local tumor control rates were used to calculate the rHF and the TCD50, i.e., the radiation dose necessary to control 50% of the tumors, after single dose irradiation. These values were compared with the in parallel determined TCD50 after 30 fractions in 6 weeks. RESULTS: The rHF after 15 fractions varied between 28% and 100%. No correlation was found with the TCD50 after 30 fractions in 6 weeks. Single dose top-up TCD50 under ambient and clamp conditions after 15 fractions significantly correlated with TCD50 after 30 fractions in 6 weeks. CONCLUSION: rHF after 15 fractions is not a prognostic parameter for the outcome after fractionated irradiation. In contrast, the radiobiological parameters number of tumor stem cells, intrinsic radiosensitivity, and number of radiobiologically hypoxic tumor cells appear promising to predict outcome after fractionated irradiation. PMID- 21533759 TI - Retrospective, monocentric analysis of late effects after Total Body Irradiation (TBI) in adults. AB - PURPOSE: Total body irradiation (TBI) is a standard treatment modality within the multidisciplinary approach for allogeneous stem cell or bone marrow transplantation. However, surviving patients are at risk for developing a variety of late sequelae. This analysis aimed to retrospectively characterize late effects after TBI in adults treated in a single center. PATIENTS AND METHODS: Patients >= 18 years treated with fractionated TBI (4-12 Gy) between 1996 and 2008 were included in this study. Treatment data were collected retrospectively from the treating departments. Late effects were evaluated using the clinic charts and/or were obtained from the general practitioners using a standardized questionnaire. Analyses were performed by calculation of the cumulative incidences using the Kaplan-Meier method and the log rank test. RESULTS: A total of 308 patients >= 18 years were treated including a TBI of whom 78 patients were excluded from further analysis due to death within less than 1 year after TBI. Patients suffered from leukemia in most cases. Late toxicity follow-up was available in 120 patients (mean age 46.1 years; range, 18-70 years) after a mean follow-up of 23 months (range, 12-96 months). The cumulative incidences (CI) at 3 years were 28% for pulmonary event, 8% for pulmonary toxicity, 25% for kidney toxicity, 8% for cataract, 17% for bone toxicity, and 10% for secondary malignancy. The CI of bone toxicity was higher in female than in male patients (p = 0.019). CONCLUSION: Late effects after TBI in the context of allogeneous stem cell or bone marrow transplantation can frequently be observed. Regular follow-up examinations are advised for the early registration and treatment of adverse effects. PMID- 21533760 TI - Adjuvant low single dose cisplatin-based concurrent radiochemotherapy of oral cavity and oropharynx carcinoma: impact of extracapsular nodal spread on distant metastases. AB - BACKGROUND: The aim of this study was to analyze the prognostic importance of extracapsular nodal spread (ECS) in patients with locally advanced squamous cell carcinoma (SCC) of the oral cavity or oropharynx, and the impact of adjuvant low single dose cisplatin-based radiochemotherapy on distant metastases-free survival (DMFS). PATIENTS AND METHODS: The study population was selected from 195 patients with high-risk oral cavity or oropharyngeal cancer, who had either adjuvant radiotherapy (RT) or radiochemotherapy (RCT) between January 1, 1997 and December 31, 2006, at the University Clinic of Radiation Oncology of the Martin-Luther University Halle-Wittenberg. A total of 42 matched pairs of patients with UICC stage III-IVa,b disease were analyzed. The patients were matched (one to one) according to tumor site, sex, T stage, N stage, ECS, resection margin status, and Karnofsky performance status. To analyze the correlation between the treatment modality (RT vs. RCT) and the impact of ECS on DMFS, the Cox proportional hazard model was used. Survival rates were calculated using the Kaplan-Meier method. RESULTS: There was a strong correlation between the degree of nodal involvement and ECS (pN1: 33%; pN2b: 45%; pN2c: 71%). Moreover, the 5-year locoregional control rates (LC) in patients with ECS were 76% vs. 63% (n.s.) for RT and RCT, respectively. However, for patients without ECS, the LC was more favorable after RCT (RT vs. RCT: 62% vs. 88%, p < 0.05). DMFS again was better after RT, and this observation was independent of the presence or absence of ECS. Finally, in multivariate analyses, the presence of ECS significantly decreased the DMFS (p = 0.04, hazard ratio (HR) 2.64). CONCLUSIONS: Patients with ECS have an increased risk of distant metastases. Adjuvant low single dose cisplatin-based concurrent chemotherapy seems to have no influence on occult microscopic systemic disease. PMID- 21533761 TI - Iodine-125 orbital brachytherapy with a prosthetic implant in situ. AB - PURPOSE: Brachytherapy is one method of irradiating the orbit after enucleation of an eye with a malignant tumor that has a potential to recur. It consists of 6 trains of I-125 seeds placed around the periphery of the orbit, a shorter central train, and a metal disc, loaded with seeds, placed beneath the eyelids. The presence of a prosthetic orbital implant requires omission of the central train and adjustment of the activity of the seeds in the anterior orbit around the prosthesis. PATIENTS AND METHODS: This is a retrospective review of the technical modifications and outcome of 12 patients treated in this manner: 6 with retinoblastoma, 5 with malignant melanoma, and 1 with an intraocular rhabdomyosarcoma. The median dose was 35.5 Gy in 73 hours for retinoblastoma and 56 Gy in 141 hours for malignant melanoma. Patients with retinoblastoma and rhabdomyosarcoma also received chemotherapy. RESULTS: The tubes can be placed satisfactorily around the prosthesis. The increased activity in the anterior half of the tubes produced comparable dose distributions. There have been no orbital recurrences, no extrusion of the prosthesis, and cosmesis is good. CONCLUSION: Insertion of a prosthetic implant at the time of enucleation greatly enhances the subsequent cosmetic appearance. This should be encouraged unless there is frank tumor in the orbit. Orbital brachytherapy without the central train continues to give excellent local control. The short treatment time and good cosmesis are added advantages. The patient is spared the expense and inconvenience of removing and replacing the prosthetic implant. PMID- 21533762 TI - "My husband usually makes those decisions": gender, behavior, and attitudes toward the marine environment. AB - Human behavior impacts the environment we live in. In order to better understand how one group, boat owners, in three Nordic countries adjacent to the Baltic Sea; Sweden, Finland and Denmark, viewed the relationship between the marine environment, leisure boats and issues of responsibility, a survey study was conducted (n = 1701). The results show that there are differences between gender in many areas and those women in general are more environmentally friendly than men in their views and behavior. Men and women seek information about boating by different channels and this knowledge may be used in future information campaigns. Both men and women ranked boat owners as having the lowest impact on the marine environment and perceived these to be responsible for addressing environmental issues caused by leisure boat activities. The results also show that it is important to prove the effectiveness of an environmentally safe product since this factor is ranked higher than price when considering buying a product. The results suggest that once environmentally friendly behavior is established, such as recycling, this behavior continues. One implication of this study is that small changes in human behavior are seen as acceptable but larger commitments are more difficult to achieve. If individuals do not feel responsible for causing environmental damage, this aspect needs to be addressed in information aimed at this group. Novel approaches on framing the information and new ways of disseminating information are needed. PMID- 21533763 TI - Parathyroid hormone regulates osteoblast differentiation in a Wnt/beta-catenin dependent manner. AB - Intermittent parathyroid hormone (PTH) administration shows an anabolic effect on bone. However, the mechanisms are not fully studied. Recent studies suggest that Wnt signaling is involved in PTH-induced bone formation. The current study was to examine if Wnt/beta-catenin pathway is required during PTH-induced osteoblast differentiation. Osteoblastic MC3T3-E1 cells were treated with human PTH (1-34) (hPTH [1-34]) and expression levels of osteoblast differentiation markers were detected by real-time PCR. RNA levels of beta-catenin, Runx2, Osteocalcin, Alkaline phosphatase, and Bone sialoprotein were significantly up-regulated after treatment with 10(-8) M of hPTH (1-34) for 6 h. Alkaline phosphatase activity and protein expression of beta-catenin were also increased after 6 days of intermittent treatment with hPTH (1-34) in MC3T3-E1 cells. hPTH (1-34) significantly enhanced Topflash Luciferase activity after 6 h of treatment. More important, PTH-induced Alkaline phosphatase activity was significantly inhibited by knocking down beta-catenin expression in cells using siRNA. Real-time RT-PCR results further showed down regulation of Runx2, Osteocalcin, Alkaline phosphatase, Bone sialoprotein gene expression in beta-catenin siRNA transfected cells with/without PTH treatment. These results clearly indicate that PTH stimulates Wnt/beta-catenin pathway in MC3T3-E1 cells and osteoblast differentiation markers expression was up-regulated by activation of Wnt/beta catenin signaling. Our study demonstrated that PTH-induced osteoblast differentiation mainly through activation of Wnt/beta-catenin pathway in osteoblastic MC3T3-E1 cells. PMID- 21533764 TI - The elevated homocysteine stimulates changes of haemostatic function of plasma isolated from breast cancer patients. AB - The aim of our study was to explain the effect of elevated homocysteine (measured by HPLC) on haemostatic activity of plasma from breast cancer patients (fibrin polymerization and lysis; the thrombin and prothrombin time), because homocysteine (Hcys) induces changes in haemostasis, as well blood clotting as fibrinolysis. Patients were hospitalized in Department of Oncological Surgery, Medical University of Lodz, Poland. All patients have not had preadjuvant therapy, and samples from patients were taken before surgery. We observed that changes of selected parameters of haemostatic properties of plasma, e.g., the prothrombin time and thrombin time were prolonged in plasma from invasive breast cancer when compared with the control group (healthy subjects) and patients with benign breast diseases. Our results showed also that the correlation between the increased amount of Hcys and changes of selected parameters of haemostasis in invasive breast cancer patients exists. Considering the data presented in this study, we suggest that the elevated Hcys in invasive breast cancer patients may induce the changes of haemostatic properties of plasma isolated from these patients. PMID- 21533765 TI - Zinc stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-kappaB activation. AB - Zinc is essential for numerous biochemical pathways in the body and is known to significantly affect the skeleton. Zinc has a profound effect on bone turnover promoting bone formation and mineralization, but paradoxically inhibiting osteoclastic bone breakdown (resorption). How zinc regulates these disparate effects on bone cells, however, is poorly understood. We recently characterized several pharmacological and nutritional factors that are likewise endowed with the capacity to promote bone formation and suppress bone resorption and demonstrated that a common centralized mechanism for achieving such actions is through suppression of NF-kappaB activation. NF-kappaB is a pathway required for osteoclastogenesis, but suppresses osteoblast differentiation. In this study, we investigated the actions of zinc on NF-kappaB activation in osteoclast and osteoblast precursors in vitro. Our data show that zinc suppressed osteoclast differentiation and promoted osteoblast mineralization and did indeed act as a potent NF-kappaB activation antagonist in both osteoclast and osteoblast precursors. Importantly, zinc antagonized NF-kappaB activation driven by TNFalpha, a potent inflammatory mediator or bone resorption and suppressor of bone formation in vitro and in vivo. Zinc further alleviated the suppressive effect of TNFalpha on Smad activation induced by TGFbeta and BMP2, cytokines that play critical roles in osteoblast commitment, differentiation, and recruitment to sites of bone remodeling. In conclusion, our data reveal for the first time that a major mechanism by which zinc promotes osteoblastogenesis and suppresses osteoclastogenesis may center on the antagonism of NF-kappaB activation. PMID- 21533766 TI - The organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one induces oxidative stress in heart, liver, and kidney of rats. AB - The objective of this study was to investigate the in vitro effects of the organochalcogen 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on some parameters of oxidative stress in liver, kidney, and heart of 10-day-old rats. The homogenates of liver, kidney, and heart were incubated for 1 h in the absence (control) or in the presence of 1, 10, or 30 MUM of the organoselenium and thiobarbituric acid reactive substances, carbonyl, and the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were measured. First, we tested the influence of the compound on 1,1-diphenyl-2-picrylhydrazyl (DPPH(*)) radical scavenging and verified that the organochalcogen did not have any antioxidant properties. We observed an increase of lipid peroxidation in all concentrations tested in heart and kidney, while in liver only in the concentrations of 10 and 30 MUM. Moreover, we also verified an enhance of protein oxidation in the concentrations of 10 and 30 MUM in kidney. On the other hand, the compound caused a reduction on the activity of CAT in heart (10 and 30 MUM), liver (30 MUM), and kidney (30 MUM). The activity of SOD was increased in heart (10 and 30 MUM), while in liver (30 MUM) and in kidney (10 and 30 MUM) the activity was reduced. Our findings indicate that this organoselenium compound induces oxidative stress in liver, heart, and kidney of immature rats, collaborating to the fact that these tissues are potential targets for the organochalcogen action. PMID- 21533767 TI - Berberine cooperates with adrenal androgen dehydroepiandrosterone sulfate to attenuate PDGF-induced proliferation of vascular smooth muscle cell A7r5 through Skp2 signaling pathway. AB - Platelet-derived growth factor (PDGF) is released from vascular smooth muscle cell (VSMC), after percutaneous coronary intervention and is related with neointimal proliferation and restenosis. Adrenal steroid dehydroepiandrosterone sulfate (DHEAS), the sulfated prohormone of dehydroepiandrosterone has shown remarkable biological activity against proliferation of VSMC in some animal and clinical studies. Combinations of DHEAS with other agents have also shown promising results, with acquiring more efficient effect. Berberine is a naturally occurring isoquinoline alkaloid. To investigate their effects in combination, a VSMC cell line A7r5 was stimulated by PDGF-BB (dimer of the B chain of PDGF), and then treated with berberine and/or DHEAS in the current study. Cell proliferation assay, cell cycle assay, Western blot, and co-immunoprecipitation were analyzed in A7r5 cells. Antiproliferative effects of berberine and/or DHEAS targeting the Skp2/p27 pathways were evaluated. Berberine and DHEAS can both inhibit the growth of A7r5 cells. Berberine induces cell cycle arrest and potentiates the inhibitory effect of DHEAS through disrupting the binding of p27, p21 with Skp2. Berberine and DHEAS decreased the expression of CDK2, CDK4, PCNA, cyclin D1, and cyclin E, which was induced by PDGF-BB. Being treated with berberine and DHEAS also promoted p27 and p21 bind to CDK2, so the proliferation of A7r5 cells induced by PDGF-BB was inhibited. The data provide evidence that berberine acts through the inhibition of p27-Skp2 and p21-Skp2 with subsequent activation of the cell cycle arrest, which leads to the increase in sensitivity to DHEAS. In summary, the findings suggest that combined berberine and DHEAS will be active in the prevention of restenosis after angioplasty treatment, and the treatment of atherosclerosis. PMID- 21533768 TI - Chronic unpredictable stress exacerbates 7,12-dimethylbenz (a) anthracene induced hepatotoxicity and nephrotoxicity in Swiss albino mice. AB - Oxidative stress, a pervasive condition induced by stress has been implicated and recognized to be a prominent feature of various pathological states including cancer and their progression. The present study sought to validate the effectiveness of chronic unpredictable stress (CUS) on hepatic and renal toxicity in terms of alterations of various in vivo biochemical parameters, oxidative stress markers and the extent of DNA damage in Swiss albino mice. Animals were randomized into different groups based on their exposure to CUS alone, 7,12 dimethylbenz (a) anthracene (DMBA) alone (topical), DMBA-12-O tetradecanoylphorbol-13-acetate (TPA) (topical), and exposure to CUS prior to DMBA or DMBA-TPA treatment, and sacrificed after 16 weeks of treatment. Prior exposure to CUS increased the pro-oxidant effect of carcinogen as depicted by significantly compromised levels of antioxidants; superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, reduced glutathione in hepatic and renal tissues accompanied by a significant elevation of thiobarbituric acid reactive species (TBARS) as compared to DMBA alone or DMBA-TPA treatments. Loss of structural integrity at the cellular level due to stress-induced oxidative damage was demonstrated by significant increases in the hepatic levels of intracellular marker enzymes such as glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and alkaline phosphatase, and significantly reduced levels of uric acid in kidney tissues. The results of DNA damage studies further positively correlated with all the above biochemical measurements. Thus, exposure to physical or psychological stress may significantly enhance the hepatotoxic and nephrotoxic potential of carcinogens through enhanced oxidative stress even if the treatment is topical. PMID- 21533769 TI - S-nitrosation of arginase 1 requires direct interaction with inducible nitric oxide synthase. AB - Arginase constrains endothelial nitric oxide synthase activity by competing for the common substrate, L -Arginine. We have recently shown that inducible nitric oxide synthase (NOS2) S-nitrosates and activates arginase 1 (Arg1) leading to age associated vascular dysfunction. Here, we demonstrate that a direct interaction of Arg1 with NOS2 is necessary for its S-nitrosation. The specific domain of NOS2 that mediates this interaction is identified. Disruption of this interaction in human aortic endothelial cells prevents Arg1 S-nitrosation and activation. Thus, disruption of NOS2-Arg1 interaction may represent a therapeutic strategy to attenuate age related vascular endothelial dysfunction. PMID- 21533770 TI - What job can a bug give? A controversy over the arsenic-guzzling bacterium cultured by NASA. PMID- 21533771 TI - Contribution of cancer stem cells to tumor vasculogenic mimicry. AB - Vasculogenic mimicry (VM), a newly-defined pattern of tumor blood supply, provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis. The biological features of the tumor cells that form VM remain unknown. Cancer stem cells (CSCs) are believed to be tumor-initiating cells, capable of self-renewal and multipotent differentiation, which resemble normal stem cells in phenotype and function. Recently CSCs have been shown to contribute to VM formation as well as angiogenesis. These findings challenge the previous understanding of the cellular basis of VM formation. In this review, we present evidence for participation of CSCs in VM formation. We also discuss the potential mechanisms and possible interaction of CSCs with various elements in tumor microenvironment niche. Based on the importance of VM in tumor progression, it constitutes a novel therapeutic target for cancer. PMID- 21533772 TI - Activation and maturation of SARS-CoV main protease. AB - The worldwide outbreak of the severe acute respiratory syndrome (SARS) in 2003 was due to the transmission of SARS coronavirus (SARS-CoV). The main protease (M(pro)) of SARS-CoV is essential for the viral life cycle, and is considered to be an attractive target of anti-SARS drug development. As a key enzyme for proteolytic processing of viral polyproteins to produce functional non-structure proteins, M(pro) is first auto-cleaved out of polyproteins. The monomeric form of M(pro) is enzymatically inactive, and it is activated through homo-dimerization which is strongly affected by extra residues to both ends of the mature enzyme. This review provides a summary of the related literatures on the study of the quaternary structure, activation, and self-maturation of M(pro) over the past years. PMID- 21533773 TI - Removal of methyl parathion and tetrachlorvinphos by a bacterial consortium immobilized on tezontle-packed up-flow reactor. AB - A tezontle-packed up-flow reactor (TPUFR) with an immobilized bacterial consortium for biological treatment of methyl-parathion and tetrachlorvinphos was evaluated. These organophosphate pesticides are widely used in Mexico for insect and mite control, respectively. With the aim of developing a tool for pesticide biodegradation, four flow rates (0.936, 1.41, 2.19, and 3.51 l/h) and four hydraulic residence times (0.313, 0.206, 0.133, and 0.083 h) were evaluated in a TPUFR. In the bioreactor, with an operating time of 8 h and a flow of 0.936 l/h, we obtained 75% efficiency in the removal of methyl-parathion and tetrachlorvinphos. Their adsorptions in the volcanic rock were 9% and 6%, respectively. It was demonstrated that the removal of pesticides was due to the biological activity of the immobilized bacterial consortium. We confirmed the decrease in toxicity in the treated effluent from the bioreactor through the application of acute toxicity tests on Eisenia foetida. Immobilization of a bacterial consortium using tezontle as a support is innovative and an economical tool for the treatment of mixtures of organophosphorus pesticide residues. PMID- 21533774 TI - Topological analysis of enzymatic actions on DNA polyhedral links. AB - Current synthetic biology has witnessed a revolution that natural DNA molecule steps onto a broad scientific area by assembling a large variety of three dimensional structures with the connectivity of polyhedra. A mathematical model of these biomolecules is crucial to clarify the biological self-assembly principle, and unravel a first-step understanding of biological regulation and controlling mechanisms. In this paper, mechanisms of two different enzymatic actions on DNA polyhedra are elucidated through theoretical models of polyhedral links: (1) topoisomerase that untangles DNA polyhedral links produces separated single-stranded DNA circles through the crossing change operation; (2) recombinase generates a class of polyhedral circular paths or polyhedral knots by applying the crossing smoothing operation. Furthermore, we also discuss the possibility of applying two theoretical operations in molecular design of DNA polyhedra. Thus, our research provides a new sight of how geometry and topology of DNA polyhedra can be manipulated and controlled by enzymes, as well as has implications for molecular design and structural analysis of structural genome organization. PMID- 21533775 TI - Combined effects of malathion and nitrate on early growth, abnormalities, and mortality of wood frog (Rana sylvatica) tadpoles. AB - Use of pesticides and other agro-chemicals adversely influence amphibians either directly by killing them or by inducing sublethal, chronic effects. Many studies have investigated the effect of mixtures of pesticides or fertilizers. We studied the combined effects of nitrate and malathion ([(dimethoxy phosphino thioyl] butanediotae) on the early growth, expression of abnormalities, and mortality of Wood Frog (Rana sylvatica) tadpoles in a laboratory experiment. Tadpoles were treated with factorial combinations of 0, 8, and 16 mg NO(3)-N l(-1) and 0, 250, 500, and 1,000 MUg malathion l(-1) for a period of 14 days. Feeding behaviour, total length, mean tadpole mass, frequencies of abnormalities, and survivorship in each treatment were recorded. Malathion showed a significant negative influence on all parameters and strongly influenced the frequencies of morphological anomalies. In contrast, nitrate alone did not produce any significant effects on behavior, total length, tadpole mass, or the frequency of abnormalities during the experiment. Malathion and nitrate had an interactive effect on tadpole length and mass, but did not affect any other parameters. Our results suggest that exposure to malathion, even at relatively low concentrations can have serious negative consequences for Wood Frog tadpoles. In addition, our results also indicate that there was little synergistic interaction between malathion and nitrate exposure under laboratory conditions. PMID- 21533776 TI - Dahuang zhechong pill containing serum inhibited platelet-derived growth factor stimulated vascular smooth muscle cells proliferation by inducing G1 arrest partly via suppressing protein kinase C alpha-extracellular regulated kinase 1/2 signaling pathway. AB - OBJECTIVE: To investigate effects of dahuang zhechong pill ( DHZCP) on the cell cycle and the related signal pathways in vascular smooth muscle cells (VSMCs) stimulated by platelet-derived growth factor (PDGF) with the method of serum pharmacology. METHODS: DNA synthesis in VSMCs was examined by detecting 5'-bromo 2'-deoxyuridine incorporation with the immunocytochemical method. The cycle of VSMCs was evaluated with flow cytometry. Expressions of cyclin D1, p27, protein kinase Calpha (PKCalpha), and phosphorylated extracellular signal regulated kinase 1/2 (ERK1/2) were quantified by Western blot method. RESULTS: DHZCP containing serum significantly inhibited DNA synthesis of PDGF-stimulated VSMCs, arrested the cells in G G(1) phase, modulated the protein expressions of cyclin D D(1) and p27, and suppressed the activation of PKCalpha and ERK1/2. CONCLUSION: DHZCP containing serum inhibits VSMCs proliferation via modulating the expressions of cell cycle proteins to arrest the cell in G G(1) phase, which is attributed to, at least in part, suppressing PKCalpha-ERK1/2 signaling in VSMCs. PMID- 21533777 TI - Fresh-frozen human bone graft to repair defect after mandibular giant follicular cyst removal: a case report. AB - The purpose of this article is to report the clinical, radiographical and histological findings about a case of a young woman affected by a mandibular giant follicular cyst. Conservative tumor resection was followed by immediate reconstructive treatment using fresh frozen human bone graft, instead of autologous bone graft, as material for bone regeneration. Follicular cyst is a benign, non invasive lesion with slow but progressive growth. Radiological and histological examination of the lesion confirmed the presence of a follicular cyst which underwent biopsy evaluation before enucleation. According to literature, conservative treatment was performed with optimal prognosis. At 24 months post surgery no evidence of recurrency was objective; the CT scan revealed optimal bone formation inside the reconstructed site. The use of fresh frozen bone allograft, thanks to its osteoinductive and osteoconductive properties, can be a safe choice for reconstruction of bone defects after jaw cysts removal. PMID- 21533778 TI - Percutaneous transcatheter device closure of an isolated congenital LV diverticulum: first case report. AB - A congenital left ventricular diverticulum is a rare cardiac malformation. It is a developmental anomaly that occurs during embryogenesis. Presentations vary from asymptomatic patients to sudden death. To date, the treatment described has been surgical correction. The authors report the first transcatheter closure of an isolated congenital left ventricular diverticulum in a 12-year-old symptomatic girl. PMID- 21533779 TI - Ellis-van Creveld syndrome and congenital heart defects: presentation of an additional 32 cases. AB - Ellis-van Creveld (EVC) syndrome is a rare genetic abnormality that has been linked to a mutation in the EVC or EVC2 genes. Common atrium (CA) is an uncommon cardiac malformation, and yet it is commonly found in patients with EVC. We performed a retrospective review of the cases submitted to the Pediatric Cardiac Care Consortium (PCCC) between 1982 and 2007. A review of the English-language literature for previously published cases, as well as current genetic research findings, was also performed. Thirty-two pediatric patients with congenital heart disease (CHD) and EVC syndrome were identified in the PCCC database. Twenty-eight (88%) had an endocardial cushion defect, with 15 of these having primary failure of atrial septation resulting in CA. Persistent left superior vena cava (LSVC) and pulmonary venous connection abnormalities were common. The incidence of persistent LSVC and pulmonary venous abnormalities were greater than previously reported for patients with EVC. Our study reviews the reported literature and adds 32 additional cases from the PCCC database. Review of the cardiac phenotype in patients with EVC syndrome reveals a characteristic pattern of atrioventricular canal defects with systemic and pulmonary venous abnormalities. The frequent association of these abnormalities is strongly reminiscent of the cardiac phenotype found in patients with heterotaxy syndromes. Emerging molecular and developmental studies suggest that EVC and EVC2 proteins may be important for cilia function, which is implicated in the pathogenesis of heterotaxy syndromes. It is speculated that coordinate function between the EVC proteins is required for a cilia-dependent cardiac morphogenesis. PMID- 21533780 TI - A rare congenital aorto-cardiac fistula. PMID- 21533781 TI - Changes of curdlan biosynthesis and nitrogenous compounds utilization characterized in ntrC mutant of Agrobacterium sp. ATCC 31749. AB - The regulatory function of global regulator NtrC on curdlan biosynthesis and nitrogen consumption under nitrogen-limited condition in Agrobacterium sp. ATCC 31749 was investigated. The ntrC mutant of Agrobacterium sp. was constructed by homologous recombination. The ability to utilize NH4Cl and KNO3 was impaired in the mutant. Other nitrogenous compounds, such as glutamic acid and glutamine, were utilized normally. Curdlan production capability was impaired severely in the mutant. Curdlan production was 5-fold lower than the wild type strain in batch fermentation with NH4Cl as the sole nitrogen source. However, up to 6.5 g l(-1) of a newly found alkali-insoluble biopolymer was produced by the ntrC mutant when glutamic acid was used as nitrogen source. The new biopolymer had glycosidic bond and hydroxyl group but no beta-configuration absorption peak on IR spectrum was found as different from curdlan. In addition, the mutant exhibited a rapid morphological change from the dot to rod form. These results deduced that the global regulator NtrC was involved in curdlan and other biopolymer biosynthesis in Agrobacterium sp. ATCC 31749 in response to nitrogen limited condition. PMID- 21533783 TI - Does pilonidal abscess heal quicker with off-midline incision and drainage? AB - BACKGROUND: No clinical trials have been done to guide the surgeon in the optimal technique of draining a pilonidal abscess. The aim of our study was to investigate whether the location of the incision influences wound healing. METHODS: Electronic records from the surgical database at our 200-bed district general hospital were reviewed for operative technique (midline vs. lateral) for patients who underwent incision and drainage for acute pilonidal abscess between January 2003 and February 2010. These patients were admitted from the Emergency Department with a pilonidal abscess, underwent operative drainage, and returned for follow-up. The main outcome measure was wound healing time. RESULTS: Two hundred and forty-three pilonidal abscesses were drained, 134 with a lateral and 74 with a midline incision. All patients underwent simple longitudinal incision. No patient underwent de-roofing, marsupialisation, or closure. Forty-eight patients with midline drainage who returned for follow-up were matched for gender, age, and microbiology culture results with patients who underwent lateral drainage. Almost all were drained under general anesthesia with a median postoperative stay of 1 day. The overall length of follow-up was the same in both groups (P = 0.13). Abscesses that did not heal were followed-up for the same period of time irrespective of incision type (P = 0.48). Abscesses that healed after midline incision took approximately 3 weeks longer than those drained via a lateral incision (P = 0.02). Our study has limitations since it was a retrospective study that did not capture patients whose abscess drained spontaneously or were drained in the emergency department. CONCLUSIONS: Pilonidal abscess should be drained away from the midline. PMID- 21533784 TI - Immune response in symptomatic and asymptomatic neurocysticercosis. AB - Innate immune system is crucial in the pathogenesis of neurocysticercosis (NCC) and helminth glycans can induce anti-inflammatory milieu via toll-like receptor 4 (TLR4) dependent mechanisms. The association of TLR4 and cytokines is yet to be explored in NCC. Therefore, the present study detected the serum levels of cytokines and soluble intercellular adhesion molecule (sICAM)-1 in asymptomatic and symptomatic NCC and their association with TLR4 expression. Sixty eight patients with NCC (asymptomatic, 36 and symptomatic, 32), and age and gender matched 37 healthy controls were enrolled to determine the levels of different pro- and anti-inflammatory cytokines, sICAM-1 in the serum by ELISA and expression of TLR4 in peripheral blood mononuclear cells (PBMCs) by flow cytometry. In asymptomatic NCC cases, the levels of IL-10 and IL-4 were significantly elevated compared to healthy controls and symptomatic NCC patients whereas the levels of IFN-gamma, TNF-alpha, IL-17, IL-23 and sICAM-1 were higher in symptomatic NCC patients compared to healthy controls and asymptomatic NCC individuals. Frequency of TLR4 expressing PBMCs and CD14 positive cells were significantly higher in both groups of NCC. Although the number of TLR4 expressing cells was almost similar in both asymptomatic and symptomatic groups, the median fluorescence intensity was significantly higher in symptomatic group indicating that higher levels of TLR4 expression in symptomatic patients correlated with enhanced pro-inflammatory cytokine production. PMID- 21533785 TI - Treatment with IP-10 induces host-protective immune response by regulating the T regulatory cell functioning in Leishmania donovani-infected mice. AB - Visceral leishmaniasis (VL), caused by the protozoan parasite, Leishmania donovani, is characterized by an infection in the liver and spleen. The failure of the first-line drugs has led to the development of new strategies for combating VL. Recently, our group has shown that interferon-gamma-inducible protein (IP)-10, a CXC chemokine, renders protection against VL. In the present study, we have elucidated the mechanism by which IP-10 renders protection in in vivo L. donovani infection. We observed that IP-10-treated parasitized BALB/c mice showed a strong host-protective T helper cell (Th) 1 immune response along with marked decrease in immunosuppressive cytokines, tumor growth factor (TGF) beta, and interleukin (IL)-10 secreting CD4(+) T cells. This IP-10-mediated decrease in immunosuppressive cytokines was correlated with the reduction in the elevated frequency of CD4(+)CD25(+) T regulatory (Treg) cells along with the reduced TFG-beta production from these Treg cells in Leishmania-infected mice. This reduction in TGF-beta production was due to effective modulation of TGF-beta signaling by IP-10, which reduced the immunosuppressive activity of Treg cells. Thus, these findings put forward a detailed mechanistic insight into IP-10 mediated regulation of the Treg cell functioning during experimental VL, which might be helpful in combating Leishmania-induced pathogenesis. PMID- 21533786 TI - Specific detection of antibodies to different flaviviruses using a new immune complex ELISA. AB - Immune complex (IC) ELISAs for IgG antibodies to various virus antigens have turned out to be both highly specific and sensitive. During incubation of a labelled antigen with the serum samples, ICs are formed, which bind to microtiter plates coated with rheumatoid factor (RF) IgM. Here, we describe an improved coating of the solid-phase support comparing various Fc-receptor molecules. IC ELISAs were applied to detect human IgG antibodies to the highly virus-specific ED3 domain of West Nile- and tick-borne encephalitis virus envelopes. Compared with other Fc-receptor molecules like RF or C1q, FcgammaRIIA (CD32) turned out to bind the ICs composed of IgG antibodies and peroxidase-labelled ED3 antigens more efficiently. Due to low background reactions, sera could be tested at a dilution of 1:10. Moreover, using CD32 instead of RF coating, anti-flavivirus antibodies could be detected in various animal species. PMID- 21533782 TI - 16S rRNA gene sequence analysis of drinking water using RNA and DNA extracts as targets for clone library development. AB - The bacterial composition of chlorinated drinking water was analyzed using 16S rRNA gene clone libraries derived from DNA extracts of 12 samples and compared to clone libraries previously generated using RNA extracts from the same samples. Phylogenetic analysis of 761 DNA-based clone sequences showed that unclassified bacteria were the most abundant group, representing nearly 62% of all DNA sequences analyzed. Other phylogenetic groups identified included Proteobacteria (20%), Actinobacteria (9%), Cyanobacteria (4%), and Bacteroidetes (2%). The composition of RNA-based libraries (1122 sequences) was similar to the DNA-based libraries with a few notable exceptions: Proteobacteria were more dominant in the RNA clone libraries (i.e., 35% RNA; 20% DNA). Differences in the Proteobacteria composition were also observed; alpha-Proteobacteria was 22 times more abundant in the RNA-based clones while beta-Proteobacteria was eight times more abundant in the DNA libraries. Nearly twice as many DNA operational taxonomic units (OTUs) than RNA OTUs were observed at distance 0.03 (101 DNA; 53 RNA). Twenty-four OTUs were shared between all RNA- and DNA-based libraries (OTU0.03) representing only 18% of the total OTUs, but 81% (1527/1883) of all sequences. Such differences between clone libraries demonstrate the necessity of generating both RNA- and DNA derived clone libraries to compare these two different molecular approaches for community analyses. PMID- 21533787 TI - NMR-based structural biology of proteins in supercooled water. AB - NMR-based structural biology of proteins can be pursued efficiently in supercooled water at temperatures well below the freezing point of water. This enables one to study protein structure, dynamics, hydration and cold denaturation in an unperturbed aqueous solution at very low temperatures. Furthermore, such studies enable one to accurately measure thermodynamic parameters associated with protein cold denaturation. Presently available approaches to acquire NMR data for supercooled aqueous protein solutions are surveyed, new insights obtained from such studies are summarized, and future perspectives are discussed. PMID- 21533788 TI - The use of echocardiography in Wolff-Parkinson-White syndrome. AB - Endocardial mapping and radiofrequency catheter ablation are well established modalities for the diagnosis and treatment of patients with Wolff-Parkinson-White (WPW) syndrome associated with tachyarrhythmias. However, the electrophysiologic techniques are invasive, require radiation exposure, and lack spatial resolution of cardiac structures. A variety of echocardiographic techniques have been investigated as a non-invasive alternative for accessory pathway localization. Conventional M-mode echocardiography can detect the fine premature wall motion abnormalities associated with WPW syndrome. However, it is unable to identify the exact site of accessory pathway with sufficient accuracy. 2D, 2D-guided M-mode, and 2D phase analysis techniques are limited by image quality and endocardial border definition. Various modalities of tissue Doppler echocardiography significantly increase the accuracy of left-sided accessory pathway localization to 80-90% even in patients with poor acoustic window. However, right-sided pathways remain a diagnostic challenge. Strain echocardiography by speckle tracking has recently been evaluated and appears promising. Different cardiac abnormalities have been detected by echocardiography in WPW patients. Patients with WPW syndrome and tachyarrhythmias have impaired systolic and diastolic function which improves after radiofrequency ablation. Echocardiography is useful in identifying patient with accessory pathway-associated left ventricular dyssynchrony and dysfunction who may benefit from ablation therapy. Transesophageal and intracardiac echocardiography have been used to guide ablation procedure. Ablation-related complications detected by routine echocardiography are infrequent, rarely clinically relevant, and of limited value. PMID- 21533789 TI - Antenatal three-dimensional sonographic features of Roberts syndrome. AB - INTRODUCTION: We present a fetus whose characteristics most likely represent Roberts syndrome. CASE REPORT: Prenatal diagnosis at 21 weeks and 1 day age of gestation was made employing conventional two-dimensional (2D) sonography, showing shortened upper and lower extremities. An umbilical cord cyst was also noted. Three-dimensional (3D) sonography revealed additional abnormalities which included bilateral hypoplastic and proximal implantation of the thumb, exophthalmic eyes, and suspected cleft lip. Shortened upper extremities, contracted legs, and an umbilical cord cyst were also clearly confirmed. Transparent X-ray mode uncovered the absence of radial and ulnar bones. Subtle fetal structures were readily discernible with 3D sonography so that the family could understand the fetal condition in utero. They underwent counseling, and opted for termination of the pregnancy. The sonographic findings were confirmed after delivery, supported by a 3D computed tomographic skeletal survey. CONCLUSION: To the best of our knowledge, this is the first report of Roberts syndrome employing antenatal 3D sonographic imaging. PMID- 21533790 TI - Natriuretic peptides in heart failure: where we are, where we are going. PMID- 21533792 TI - Sequential modelling of a full-scale wastewater treatment plant using an artificial neural network. AB - This work proposes a sequential modelling approach using an artificial neural network (ANN) to develop four independent multivariate models that are able to predict the dynamics of biochemical oxygen demand (BOD), chemical oxygen demand (COD), suspended solid (SS), and total nitrogen (TN) removal in a wastewater treatment plant (WWTP). Suitable structures of ANN models were automatically and conveniently optimized by a genetic algorithm rather than the conventional trial and error method. The sequential modelling approach, which is composed of two parts, a process disturbance estimator and a process behaviour predictor, was also presented to develop multivariate dynamic models. In particular, the process disturbance estimator was first employed to estimate the influent quality. The process behaviour predictor then sequentially predicted the effluent quality based on the estimated influent quality from the process disturbance estimator with other process variables. The efficiencies of the developed ANN models with a sequential modelling approach were demonstrated with a practical application using a data set collected from a full-scale WWTP during 2 years. The results show that the ANN with the sequential modelling approach successfully developed multivariate dynamic models of BOD, COD, SS, and TN removal with satisfactory estimation and prediction capability. Thus, the proposed method could be used as a powerful tool for the prediction of complex and nonlinear WWTP performance. PMID- 21533791 TI - Synergistic anticancer effects of combined gamma-tocotrienol with statin or receptor tyrosine kinase inhibitor treatment. AB - Systemic chemotherapy is the only current method of treatment that provides some chance for long-term survival in patients with advanced or metastatic cancer. gamma-Tocotrienol is a natural form of vitamin E found in high concentrations in palm oil and displays potent anticancer effects, but limited absorption and transport of by the body has made it difficult to obtain and sustain therapeutic levels in the blood and target tissues. Statins are inhibitors of 3-hydroxy-3 methylglutaryl-coenzyme A (HMGCoA) reductase and are an example of a promising cancer chemotherapeutic agent whose clinical usefulness has been limited due to high-dose toxicity. Similarly, erlotinib and gefitinib are anticancer agents that inhibit the activation of individual HER/ErbB receptor subtypes, but have shown limited clinical success because of heterodimerization between different EGF receptor family members that can rescue cancer cells from agents directed against a single receptor subtype. Recent studies have investigated the anticancer effectiveness of low-dose treatment of various statins or EGF receptor inhibitors alone and in combination with gamma-tocotrienol on highly malignant +SA mouse mammary epithelial cells in vitro. Combined treatment with subeffective doses of gamma-tocotrienol with these other chemotherapeutic agents resulted in a synergistic inhibition of +SA cell growth and viability. These findings strongly suggest that combined treatment of gamma-tocotrienol with other anticancer agents may not only provide an enhanced therapeutic response but also provide a means to avoid the toxicity, low bioavailability, or limited therapeutic action associated with high-dose monotherapy. PMID- 21533793 TI - Promoting shared decision-making in rehabilitation: development of a framework for situations when patients with Dysphagia refuse diet modification recommended by the treating team. AB - To address the risks of aspiration pneumonia, patients with dysphagia may be prescribed a modified diet. The goal of diet modification is to decrease the risk of patients aspirating food due to their diminished swallowing reflex. Some patients may not accept diet modification or may not adhere to the treatments identified by the interdisciplinary team. Such scenarios may result in important moral uncertainty and concern for clinicians. As a result of several ethics consultations related to this issue, a working group of the Clinical Ethics Committee at the Jewish Rehabilitation Hospital in Laval, Quebec, Canada, developed a framework for responding to situations when patients do not adhere to recommended diet modification. The goal of this tool is to facilitate discussion and collaboration between clinicians and patients, to clarify assumed versus real risk, and to promote shared decision-making in dysphagia care. In this article we examine the clinical context of diet modification for patients with dysphagia in rehabilitation hospitals, explore ethical aspects of this topic, present the clinical algorithm, and discuss our experience with developing and piloting this tool. PMID- 21533794 TI - Temporal lobe association fiber tractography as compared to histology and dissection. AB - OBJECTIVES: To compare the temporal lobe white matter fiber bundles obtained by diffusion tensor imaging-based tractography to that by histology and dissection, and to study the interindividual variability of the obtained tracts. MATERIALS AND METHODS: DTI (diffusion tensor imaging) acquisitions (30 directions) were obtained from nine healthy volunteers. Imaging post-processing was performed with FSL (FMRIB Software Library) software. Uncinate fasciculus, longitudinal inferior fasciculus and optic radiations were tracked after positioning of the region of interest (ROI) in predetermined anatomical landmarks. Histological data were obtained by cutting 15 um coronal sections in one left brain hemisphere and staining with modified Heidenhain-Woelcke myelin stain. Dissection was performed on the left brain hemisphere prepared in accordance with the Klingler method. Tractography of each bundle was compared to histology and dissection data. To highlight the interindividual variability of the considered fiber tracts, all the images were affinely registered on an arbitrarily chosen reference image by considering the B0 images. Fiber tracts were then warped according to the corresponding estimated transformation and an average fiber tract image was then computed. RESULTS: Our results demonstrated a good concordance between tractography of the temporal lobe white matter bundles and dissection and histological data. The interindividual reproducibility of each tract seemed to be good, particularly in the middle part. The variability was more important at both ends, probably in relation to the dispersion of fiber bundles. CONCLUSION: Diffusion tensor imaging-based tractography of temporal lobe white matter tracts seemed to be in accordance with histological and dissection data. Taking into account some limitations, it could be of particular interest for the presurgical planning of temporal lobectomy. PMID- 21533795 TI - Quantification of clomiphene metabolite isomers in human plasma by rapid resolution liquid chromatography-electrospray ionization-tandem mass spectrometry. AB - Since the 1960s, clomiphene citrate is used for ovulation induction. Since nonresponse to clomiphene therapy is still not well understood, interindividual variability of clomiphene metabolism has been considered to be a plausible explanation. Therefore, a comprehensive, rapid, sensitive, and specific analytical method for the quantification of (E)- and (Z)-isomers of clomiphene and their putative N-desethyl, N,N-didesethyl, 4-hydroxy, and 4-hydroxy-N desethyl metabolites, and the N-oxides in human plasma has been newly developed, using HPLC-tandem mass spectrometry and stable isotope-labeled internal standards. All standards other than the parent drug were synthesized in our laboratory. Following protein precipitation analytes were separated on a ZORBAX Eclipse plus C18 1.8 MUm column with a gradient of 0.1% formic acid in water and 0.1% formic acid in acetonitrile and detected on a triple quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction monitoring mode. Lower limit of quantification for metabolites ranged from 0.06 ng/mL for clomiphene-N-oxides to 0.3 ng/mL for (E)-N-desethylclomiphene. The assay was validated according to FDA guidelines. Plasma levels of clomiphene and its metabolites were measured in two women after single-dose treatment with clomiphene. PMID- 21533796 TI - Comparison of quartz and Teflon filters for simultaneous collection of size separated ultrafine aerosol particles and gas-phase zero samples. AB - In this research, the two most common filter media, quartz and Teflon, were tested to obtain information about the possible adsorption of gas-phase compounds onto filters during long sample collection of atmospheric aerosols. Particles of nanometer-size for off-line chemical characterization were collected using a recently introduced differential mobility analyzer for size separation. Samples were collected at an urban site (Helsinki, SMEARIII station) during spring 2010. Sampling time was 4 to 10 days for particles 50, 40, or 30 nm in diameter. Sample air flow was 4 L/min. The sampling setup was arranged so that two samples were obtained for each sampling period almost simultaneously: one containing particles and adsorbed gas-phase compounds and one containing adsorbed gas-phase compounds only. Filters were extracted and analyzed for the presence of selected carboxylic acids, polyols, nitrogen-containing compounds, and aldehydes. The results showed that, in quartz filter samples, gas-phase adsorption may be responsible for as much as 100% of some compound masses. Whether quartz or Teflon, simultaneous collection of gas-phase zero samples is essential during the whole sampling period. The dependence of the adsorption of gas-phase compounds on vapor pressure and the effect of adsorption on the deposited aerosol layer are discussed. PMID- 21533797 TI - Mercury speciation analysis in seafood by species-specific isotope dilution: method validation and occurrence data. AB - Methylmercury (MeHg) and total mercury (THg) in seafood were determined using species-specific isotope dilution analysis and gas chromatography combined with inductively coupled plasma mass spectrometry. Sample preparation methods (extraction and derivation step) were evaluated on certified reference materials using isotopically enriched Hg species. Solid-liquid extraction, derivation by propylation and automated agitation gave excellent accuracy and precision results. Satisfactory figures of merit for the selected method were obtained in terms of limit of quantification (1.2 MUg Hg kg(-1) for MeHg and 1.4 MUg Hg kg( 1) for THg), repeatability (1.3-1.7%), intermediate precision reproducibility (1.5% for MeHg and 2.2% for THg) and trueness (bias error less than 7%). By means of a recent strategy based on accuracy profiles (beta-expectation tolerance intervals), the selected method was successfully validated in the range of approximately 0.15-5.1 mg kg(-1) for MeHg and 0.27-5.2 mg kg(-1) for THg. Probability beta was set to 95% and the acceptability limits to +/-15%. The method was then applied to 62 seafood samples representative of consumption in the French population. The MeHg concentrations were generally low (1.9-588 MUg kg(-1)), and the percentage of MeHg varied from 28% to 98% in shellfish and from 84% to 97% in fish. For all real samples tested, methylation and demethylation reactions were not significant, except in one oyster sample. The method presented here could be used for monitoring food contamination by MeHg and inorganic Hg in the future to more accurately assess human exposure. PMID- 21533798 TI - Determination of steroid hormones in blood by GC-MS/MS. AB - This paper presents the development, optimization and validation of a methodology to determine nine key steroid hormones (viz. pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, dihydrotestosterone, estrone, 17alpha-estradiol and 17beta-estradiol) expressed in the steroidogenesis in biological fluids. The analytical method allows for the determination of steroid hormones in blood plasma and serum down to 0.08-0.16 ng/mL for estrogens, 0.20-0.36 ng/mL for androgens and 0.36-0.43 ng/mL for progestagens. These limits of detection were obtainable using a two-step solid-phase clean-up for fractionation and elimination of interfering lipids (fatty acids, phospholipids, glycerides and sterols) from the steroid hormones. The accuracy of the method was 50-112% in the range 0.10 to 2.00 ng/mL. PMID- 21533799 TI - Drugs of abuse screening in urine as part of a metabolite-based LC-MSn screening concept. AB - Today, immunoassays and several chromatographic methods are in use for drug screening in clinical and forensic toxicology and in doping control. For further proof of the authors' new metabolite-based liquid chromatography-mass spectrometry (LC-MS(n)) screening concept, the detectability of drugs of abuse and their metabolites using this screening approach was studied. As previously reported, the corresponding reference library was built up with MS(2) and MS(3) wideband spectra using a LXQ linear ion trap with electrospray ionization in the positive mode and full scan information-dependent acquisition. In addition to the parent drug spectra recorded in methanolic solution, metabolite spectra were identified after protein precipitation of urine from rats after administration of the corresponding drugs and added to the library. This consists now of data of over 900 parent compounds, including 87 drugs of abuse, and of over 2,300 metabolites and artifacts, among them 436 of drugs of abuse. Recovery, process efficiency, matrix effects, and limits of detection for selected drugs of abuse were determined using spiked human urine, and the resulting data have been acceptable. Using two automatic data evaluation tools (ToxID and SmileMS), the intake of 54 of the studied drugs of abuse could be confirmed in urine samples of drug users after protein precipitation and LC separation. The following drugs classes were covered: stimulants, designer drugs, hallucinogens, (synthetic) cannabinoids, opioids, and selected benzodiazepines. The presented LC-MS(n) method complements the well-established gas chromatography-mass spectroscopy procedure in the authors' laboratory. PMID- 21533800 TI - Intra-operative optical diagnostics with vibrational spectroscopy. AB - Established methods for characterization of tissue and diagnostics, for example histochemistry, magnetic resonance imaging (MRI), X-ray tomography, or positron emission tomography (PET), are mostly not suitable for intra-operative use. However, there is a clear need for an intra-operative diagnostics especially to identify the borderline between normal and tumor tissue. Currently, vibrational spectroscopy techniques (both Raman and infrared) complement the standard methods for tissue diagnostics. Vibrational spectroscopy has the potential for intra operative use, because it can provide a biochemically based profile of tissue in real time and without requiring additional contrast agents, which may perturb the tissue under investigation. In addition, no electric potential needs to be applied, and the measurements are not affected by electromagnetic fields. Currently, promising approaches include Raman fiber techniques and nonlinear Raman spectroscopy. Infrared spectroscopy is also being used to examine freshly resected tissue ex vivo in the operating theater. The immense volume of information contained in Raman and infrared spectra requires multivariate analysis to extract relevant information to distinguish different types of tissue. The promise and limitations of vibrational spectroscopy methods as intra operative tools are surveyed in this review. PMID- 21533801 TI - Highly selective and sensitive enrichment of phosphopeptides via NiO nanoparticles using a microwave-assisted centrifugation on-particle ionization/enrichment approach in MALDI-MS. AB - The strategy to concentrate phosphopeptides has become a critical issue for mapping protein phosphorylation sites, which are well known as posttranslational modifications in proteomics. In this study, we propose a simple and highly sensitive method for phosphopeptide enrichment on NiO nanoparticles (NPs) from a trypsin predigested phosphoprotein complex solution in a microwave oven. Furthermore, this technique was combined with centrifugation on-particle ionization/enrichment of phosphopeptides and phosphopeptides were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Weak magnetism of these NPs and a positive surface charge effect at low pH accomplished rapid and selective phosphopeptide enrichment within 30s. Trypsin digested products of phosphoproteins such as alpha-casein and beta-casein, human blood serum, nonfat milk, and egg white were also investigated to explore their phosphopeptide enrichment from complex samples by this approach. The results demonstrate that NiO NPs exhibit good affinity to trace the phosphopeptides even in the presence of 30 times higher molar concentration of complex solution of non phosphopeptide proteolytic predigested bovine serum albumin. The detection limits of NiO NPs for alpha-casein and beta-casein were 2.0 * 10(-9) M, with good signal to-noise ratio in the mass spectrum. NiO NPs were found to be effective and selective for enrichment of singly and multiply phosphorylated peptides at a trace level in complex samples in a microwave oven. The cost of preparing NiO NPs is low, the NiO NPs are thermally stable, and therefore, they hold great promise for use in phosphopeptide enrichment. PMID- 21533802 TI - Are these liquids explosive? Forensic analysis of confiscated indoor fireworks. AB - Complete forensic analysis of several confiscated liquids and gels putatively used as firework components was achieved by combining Raman, FTIR spectroscopy, and scanning electron microscopy combined with energy-dispersive spectroscopy (SEM-EDS). The chemical composition of the liquids was consistent with their use as indoor fireworks. Alcohols (methanol and isopropyl alcohol) were used to solubilise compounds producing coloured flames. Boric acid, recently introduced in the list of Substances of Very High Concern (SVHC) for the REACH Regulation of the European Union, was found in one of the samples. PMID- 21533803 TI - Using LabVIEW to demonstrate instrumentation principles. PMID- 21533804 TI - GC-TOFMS analysis of metabolites in adherent MDCK cells and a novel strategy for identifying intracellular metabolic markers for use as cell amount indicators in data normalization. AB - Cultured cell lines are useful models in biomedical research that characterize metabolic responses to various stimuli (e.g., pathogens, toxins, or drugs/chemicals) and explore the underlying mechanisms. However, data from cell metabolomic studies must be normalized to the amount of cells, which is dependent on diverse treatments. The currently used methods of cell counting and protein assay involve extra work and delay the quenching of intracellular metabolism. To develop a convenient, alternative approach, in this study, intracellular metabolites were extracted from a series amount of cultured adherent cells and profiled by gas chromatography-time-of-flight mass spectrometry (GC-TOFMS). The GC-TOFMS signal intensities for 11 intracellular markers present in two different cell lines showed good linearity with the protein content, with inositol and pantothenate most promising (correlation coefficient > 0.970). Despite the various amounts of cells, the data normalized to the metabolic markers and protein amounts showed similar effectiveness, resulted in better separation of the two cell lines, closer clustering within each group(cell line) on a principal components analysis scores plot, and had lower relative standard deviations for intracellular metabolites than those of the non-normalized data, suggesting that these markers were effective indicators of cell amounts and independent of cell lines. PMID- 21533805 TI - Highly integrated flow assembly for automated dynamic extraction and determination of readily bioaccessible chromium(VI) in soils exploiting carbon nanoparticle-based solid-phase extraction. AB - An automated dynamic leaching test integrated in a portable flow-based setup is herein proposed for reliable determination of readily bioaccessible Cr(VI) under worst-case scenarios in soils containing varying levels of contamination. The manifold is devised to accommodate bi-directional flow extraction followed by processing of extracts via either in-line clean-up/preconcentration using multi walled carbon nanotubes or automatic dilution at will, along with Cr(VI) derivatization and flow-through spectrophotometric detection. The magnitude of readily mobilizable Cr(VI) pools was ascertained by resorting to water extraction as promulgated by current standard leaching tests. The role of carbon nanomaterials for the uptake of Cr(VI) in soil leachates and the configuration of the packed column integrated in the flow manifold were investigated in detail. The analytical performance of the proposed system for in vitro bioaccessibility tests was evaluated in chromium-enriched soils at environmentally relevant levels and in a standard reference soil material (SRM 2701) with a certified value of total hexavalent chromium. The automated method was proven to afford unbiased assessment of water-soluble Cr(VI) in soils as a result of the minimization of the chromium species transformation. By combination of the kinetic leaching profile and a first-order leaching model, the water-soluble Cr(VI) fraction in soils was determined in merely 6 h against >24 h taken in batchwise steady-state standard methods. PMID- 21533806 TI - Influence of accurate and inaccurate 'split-time' feedback upon 10-mile time trial cycling performance. AB - The objective of the study is to examine the impact of accurate and inaccurate 'split-time' feedback upon a 10-mile time trial (TT) performance and to quantify power output into a practically meaningful unit of variation. Seven well-trained cyclists completed four randomised bouts of a 10-mile TT on a SRMTM cycle ergometer. TTs were performed with (1) accurate performance feedback, (2) without performance feedback, (3) and (4) false negative and false positive 'split-time' feedback showing performance 5% slower or 5% faster than actual performance. There were no significant differences in completion time, average power output, heart rate or blood lactate between the four feedback conditions. There were significantly lower (p < 0.001) average [Formula: see text] (ml min(-1)) and [Formula: see text] (l min(-1)) scores in the false positive (3,485 +/- 596; 119 +/- 33) and accurate (3,471 +/- 513; 117 +/- 22) feedback conditions compared to the false negative (3,753 +/- 410; 127 +/- 27) and blind (3,772 +/- 378; 124 +/- 21) feedback conditions. Cyclists spent a greater amount of time in a '20 watt zone' 10 W either side of average power in the negative feedback condition (fastest) than the accurate feedback (slowest) condition (39.3 vs. 32.2%, p < 0.05). There were no significant differences in the 10-mile TT performance time between accurate and inaccurate feedback conditions, despite significantly lower average [Formula: see text] and [Formula: see text] scores in the false positive and accurate feedback conditions. Additionally, cycling with a small variation in power output (10 W either side of average power) produced the fastest TT. Further psycho-physiological research should examine the mechanism(s) why lower [Formula: see text] and [Formula: see text] scores are observed when cycling in a false positive or accurate feedback condition compared to a false negative or blind feedback condition. PMID- 21533807 TI - Effects of hyperbaric oxygenation on oxidative stress in acute transient focal cerebral ischemic rats. AB - The aim of this study was to investigate the effects of hyperbaric oxygenation (HBO) after brain ischemia. Middle cerebral artery occlusion (MCAO) procedure was used to induce the brain ischemia. Rats were assigned to control or HBO group after brain ischemia. In order to examine the role of glutathione after HBO treatment, another group of brain ischemic rats were included to receive the glutathione synthesis inhibitor and HBO treatment. HBO was administered at a pressure of 3 atmospheres absolute for 1 h with 100% oxygen, starting at 3 h post brain ischemia in HBO groups. Animals in control group were placed in their home cage and exposed to normobaric room air. The infarct volume (IV), activation of astrocyte, and level of total glutathione and lipid peroxidation (LP) were assessed 24 h post-reperfusion. Significant reduction in IV was noted in HBO group when compared with control group. The activation of astrocyte was significantly increased in the right cerebral cortex and right striatum in the HBO group when compared with those of the control group. The glutathione level was higher with lower LP level in right cortex and right striatum after HBO as compared with those of the control. However, such effects of HBO treatment were markedly reduced by glutathione synthesis inhibitor administration. These results show that inhibiting glutathione synthesis dramatically reduces the effectiveness of HBO in acute transient focal cerebral ischemia. PMID- 21533808 TI - Reproducibility of pacing strategy during simulated 20-km cycling time trials in well-trained cyclists. AB - The aim of the study was to assess the reproducibility of pacing strategy, physiological and perceptual responses during simulated 20-km cycling time trials. Seventeen well-trained male cyclists ([Formula: see text] = 4.70 +/- 0.33 L min(-1)) completed three 20-km time trials on a Velotron Pro cycle ergometer within a maximum duration of 14 days. During all trials power output, cadence and respiratory exchange were recorded throughout, rating of perceived exertion and affective response were recorded every 2-km and capillary blood was sampled and assayed for the determination of lactate concentration every 4-km. Power output data was assigned to 1-km 'bins' and expressed relative to the mean to quantify pacing strategy. Reproducibility of the pacing strategy and the whole trial mean responses was subsequently quantified using typical error (TE) with 90% confidence intervals. The pacing strategy adopted was similar across repeat trials, though there was a higher degree of variability at the start and end of the trial (TE = 6.6 and 6.8% for the first and last 1-km), and a trend for a progressively blunted start on repeat trials. The reproducibility of performance, cardiorespiratory and perceptual measures was good (TE range 1.0-4.0%), but blood lactate exhibited higher variability (TE = 17.7%). The results demonstrate the performance, perceptual and physiological response to self-paced 20-km time trials is reproducible in well-trained cyclists. Future research should acknowledge that variability in pacing strategy at the start and end of a self paced bout is likely regardless of any intervention employed. PMID- 21533810 TI - Development of cancer needs questionnaire for parents and carers of adolescents and young adults with cancer. AB - PURPOSE: In order to improve the service delivery for the parents and carers of adolescents and young adults (AYAs) with cancer, it is important to develop measures which assess the specific issues and concerns faced by this group. The aims of this study were to describe the development and acceptability of a measure of unmet needs of parents and carers of AYA cancer survivors and to assess the prevalence of unmet needs among the respondents. METHODS: A literature search and focus groups with consumers and health professionals were used to inform item development. AYA cancer survivors and their parents and carers were identified from seven hospitals in Australia. Parents and carers who consented for their contact details to be released to the research team were sent a paper and-pencil questionnaire. One mailed reminder and one phone call reminder were made to non-responders. RESULTS: The unmet needs survey consisted of eight domains and 150 items: (1) cancer treatment staff, (2) cancer treatment centre, (3) study, (4) work, (5) information, (6) feelings, (7) relationships and (8) daily life. Eighty-three parents and carers completed the survey. The mean number of high or very high unmet needs reported was 24, with information needs among the most prevalent high/very high unmet needs. CONCLUSIONS: The questionnaire developed has demonstrable face and content validity and acceptability. Unmet needs are prevalent among parents and carers of AYA cancer survivors, suggesting the need for further psychometric testing of the measure. PMID- 21533809 TI - Unilateral lower limb suspension: integrative physiological knowledge from the past 20 years (1991-2011). AB - In 1991, Hans Berg and colleagues published the first research investigation using unilateral lower limb suspension (ULLS) as a human model to study the influence of unloading on skeletal muscle. ULLS requires a participant to perform all activities with axillary crutches while wearing one thick-soled shoe. The elevated shoe eliminates ground contact with the adjacent foot, thereby unloading the lower limb. Today, ULLS is a well-known ground-based analog for microgravity. The present review will synthesize the physiological findings from investigations using ULLS to study the deleterious effects of unloading. Compromised human performance and the neuromuscular, musculoskeletal and circulatory mechanisms leading to altered function will be a major emphasis of the work. Results from prolonged bed rest will also be included in order for general comparisons to be made between analogs. Finally, the efficacy of exercise to mitigate the negative consequences of unloading is presented. PMID- 21533811 TI - Comparative clinical effectiveness of various 5-HT3 RA antiemetic regimens on chemotherapy-induced nausea and vomiting associated with hospital and emergency department visits in real world practice. AB - PURPOSE: The aim of this study was to compare the risk of chemotherapy-induced nausea and vomiting (CINV) events for various 5-HT(3) RAs in patients who received moderately (MEC) or highly emetogenic chemotherapy (HEC) by evaluating hospital or emergency department (ED) admissions. METHODS: PharMetrics claims database was used to identify patients diagnosed with breast cancer (BC) who were initiated on cyclophosphamide-based adjuvant chemotherapy or with lung cancer (LC) initiated on carboplatin-based or cisplatin-based chemotherapy between 2005 and 2008. Patients were stratified in two groups: those initiated and maintained on palonosetron versus those treated with any other 5-HT(3) RA regimens in the 6 month post first chemotherapy. Risk for CINV events, identified by ICD-9-CM for nausea, vomiting, and/or dehydration, were estimated using logistic regressions, controlling for age, gender, comorbidity, and total chemotherapy doses or days. RESULTS: Of the 4,868 cyclophosphamide-treated BC, 5,414 carboplatin-treated LC, and 1,692 cisplatin-treated LC identified, there were 1,864 BC (38.5%), 1,806 carboplatin-treated LC (33.4%), and 390 cisplatin-treated LC (23.0%) in the palonosetron-only group. Palonosetron-only group had significantly lower probability of CINV events associated with ED/hospital admissions in all three cohorts (3.5% vs. 6.3% in BC, 9.5% vs. 13.8% in carboplatin-treated LC, and 16.4% vs. 22.6% in cisplatin-treated LC, all at p < 0.05). Logistic regressions found palonosetron-only group had significantly lower risk of CINV events (odds ratios = 0.550, 0.653, and 0.689 in BC, carboplatin-treated LC and cisplatin-treated LC, respectively, p < 0.05). CONCLUSION: Patients with lung or breast cancer receiving MEC or HEC had significantly lower risk of CINV events associated with hospital/ED admissions if initiated and maintained on palonosetron relative to patients receiving 5-HT(3) RA regimens. PMID- 21533812 TI - Differential expression of cytokines in breast cancer patients receiving different chemotherapies: implications for cognitive impairment research. AB - PURPOSE: Altered levels of cytokines and chemokines may play a role in cancer- and cancer treatment-related cognitive difficulties. In many neurodegenerative diseases, abnormal concentrations of cytokines and chemokines affect neuronal integrity leading to cognitive impairments, but the role of cytokines in chemotherapy-related cognitive difficulties in cancer patients is not well understood. Patients receiving doxorubicin-based (with cyclophosphamide, or cyclophosphamide plus fluorouracil; AC/CAF) chemotherapy or cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy report experiencing cognitive difficulties; because these regimens work by different modes of action, it is possible that they differentially affect cytokine levels. METHODS: This study examined the relationships between cytokine levels (i.e., IL-6, IL-8, and MCP-1) and type of chemotherapy among 54 early-stage breast cancer patients receiving AC/CAF or CMF. Cytokine levels were assessed at two time-points: prior to on study chemotherapy cycle 2 (cycle 2) and after two consecutive chemotherapy cycles (prior to on-study cycle 4; cycle 4). MAIN RESULTS: Analyses of variance using cycle 2 levels as a covariate (ANCOVA) were used to determine differences between chemotherapy groups. Levels of IL-6, IL-8, and MCP-1 increased in the AC/CAF group and decreased in the CMF group; the only significant between-group change was in IL-6 (p < 0.05). CONCLUSIONS: These results, although preliminary based on the small sample size, suggest that AC/CAF chemotherapy is more cytokine inducing than CMF. Future studies should confirm these results and explore the distinct inflammatory responses elicited by different chemotherapy regimens when assessing cognitive function in cancer patients. PMID- 21533813 TI - Fatigue assessment and rehabilitation outcomes in patients with brain tumors. AB - OBJECTIVES: This study seeks to investigate the fatigue severity and the relationship among fatigue and other associated factors in patients with brain tumors, and to evaluate the rehabilitation outcome on fatigue. DESIGN: We assessed 25 patients in whom brain tumors had been resected and transferred to the rehabilitation department of our hospital. Patients were evaluated for fatigue severity using the Piper Fatigue Scale (PFS) and the Brief Fatigue Inventory (BFI), for mood using the Beck Depression Inventory, for motor function using the Motricity Index (MI), for functional status using the Karnofsky Performance Status (KPS) scale and the Modified Barthel Index (MBI), and for quality-of-life using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30). We also measured the levels of serum hemoglobin, C-reactive protein, albumin, and creatine kinase; and anthropometric variables before and 4 weeks after rehabilitation. RESULTS: Of the 25 patients, 21 (84.0%) reported fatigue during the previous week. The average PFS score was 4.6 +/- 1.8 and the average BFI score 5.2 +/- 2.2, indicating the moderate level of fatigue. Patients with recurrent tumors had significantly higher PFS scores than did those with initial tumors. Fatigue correlated significantly with the KPS, MBI, and EORTC QLQ-C30 physical functioning and insomnia scales. In addition, insomnia was a significant predictor of fatigue before rehabilitation, and the baseline fatigue scales, MBI, MI, and EORTC QLQ-C30 physical functioning scale were the important independent predictors of fatigue after rehabilitation. During rehabilitation, the KPS, MBI, and MI scores improved significantly, whereas total PFS and BFI scores did not change. CONCLUSIONS: These findings suggest that patients with brain tumors commonly complain of moderate level of fatigue, which may reduce daily functioning and quality of life, with sleep disturbance being a significant predictor of fatigue. During rehabilitation, functional outcomes and motor power showed improvements in those patients, not aggravating fatigue. PMID- 21533814 TI - Frequent AV node reentrant tachycardia induced by oversized port catheter. AB - PURPOSE: Here, we describe the efficiency of interventional electrophysiology therapy in a critically ill patient with heart failure because of incessant AV node reentrant tachycardia after surgical port implantation. METHODS: Electrophysiology diagnostic and radio frequency ablation were utilized in the study. RESULT: We presented a 78-year-old patient with colorectal cancer, surgical port implantation, and progressive heart failure due to an incessant AV node reentrant tachycardia (AVNRT). This rhythm disturbance was refractory to any conventional pharmaceutical treatment. The electrophysiology diagnostic obtained an AVNRT. During fluoroscopy, an oversized port catheter with a loop touching the tricuspid valve annulus was discovered. This port catheter was responsible for premature beats, which induced incessant AVNRT. A manual reposition of the port edge and additional AV node slow pathway modification terminated further tachycardia. CONCLUSION: Electrophysiology diagnostic and radiofrequency ablation procedures are promising techniques also in critically ill patients with hemodynamic compromising supraventricular tachycardia. PMID- 21533815 TI - Variation in circulating corticosterone levels is associated with altitudinal range expansion in a passerine bird. AB - Organisms frequently need to adjust physiological mechanisms to successfully breed in novel habitats. To explore how some populations physiologically acclimate to novel environmental conditions while others do not, we examine three subspecies of the white-crowned sparrow, Zonotrichia leucophrys. Of these subspecies, Z. l. pugetensis has expanded its breeding range to high altitude over the last 60 years. We investigate physiological acclimation to high altitude conditions by comparing circulating levels of glucocorticoids among Z. l. gambelii, which only breeds at high altitude, Z. l. nuttalli, which only breeds at low altitude, a population of Z. l. pugetensis that breeds at low altitude, and a Z. l. pugetensis population that now breeds at high altitude. Glucocorticoids mediate physiological and behavioral responses to environmental conditions and are constitutively secreted, but can also be released facultatively. We hypothesized that elevation of the glucocorticoid corticosterone (CORT) may facilitate breeding in high altitude environments. We tested this hypothesis by comparing baseline and stress-induced CORT levels of subspecies breeding at low altitude, Z. l. pugetensis and Z. l. nuttalli, to subspecies breeding at high altitude, Z. l. pugetensis and Z. l. gambelii. We found that populations breeding at high altitude exhibit higher baseline and stress-induced levels of CORT. Additionally, we found that Z. l. pugetensis exhibit greater variation in the stress-induced CORT response. These results suggest an importance of modulation of hormonal mechanisms in facilitating breeding in high altitude environments, and that variation in these mechanisms may be associated with facilitating altitudinal range expansion. PMID- 21533816 TI - Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway. AB - Arsenic pollution is a major public health problem worldwide. Inorganic arsenic (iAs) is usually more harmful than organic ones. iAs pollution increases the risk of human diseases such as peripheral vascular disease and cancer. However, the toxicological effects of iAs in the brain are mostly unclear. Here, we investigated the toxic effects and possible mechanisms of iAs in the cerebrum of mice after exposure to iAs (0.5 and 5 ppm (mg/l) As(2)O(3), via the drinking water), which was the possible human exposed dose via the ingestion in iAs contaminated areas, for 6 consecutive weeks. iAs dose-dependently caused an increase of LPO production in the plasma and cerebral cortex. iAs also decreased the reduced glutathione levels and the expressions of NQO1 and GPx mRNA in the cerebral cortex. These impairments in the cerebral cortex caused by iAs exposure were significantly correlated with the accumulation of As. Moreover, iAs induced the production of apoptotic cells and activation of caspase-3, up-regulation of Bax and Bak, and down-regulation of Mcl-1 in the cerebral cortex. Exposure to iAs also triggered the expression of ER stress-related genes, including GRP78, GRP94, and CHOP. Meanwhile, an increase of p38 activation and dephosphorylation of ERK1/2 were shown in the cerebral cortex as a result of iAs-exposed mice. These iAs-induced damages and apoptosis-related signals could be significantly reversed by NAC. Taken together, these results suggest that iAs-induced oxidative stress causes cellular apoptosis in the cerebrum, signaling of p38 and ERK1/2, and ER stress may be involved in iAs-induced cerebral toxicity. PMID- 21533817 TI - Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. AB - The 7th amendment to the EU Cosmetics Directive prohibits to put animal-tested cosmetics on the market in Europe after 2013. In that context, the European Commission invited stakeholder bodies (industry, non-governmental organisations, EU Member States, and the Commission's Scientific Committee on Consumer Safety) to identify scientific experts in five toxicological areas, i.e. toxicokinetics, repeated dose toxicity, carcinogenicity, skin sensitisation, and reproductive toxicity for which the Directive foresees that the 2013 deadline could be further extended in case alternative and validated methods would not be available in time. The selected experts were asked to analyse the status and prospects of alternative methods and to provide a scientifically sound estimate of the time necessary to achieve full replacement of animal testing. In summary, the experts confirmed that it will take at least another 7-9 years for the replacement of the current in vivo animal tests used for the safety assessment of cosmetic ingredients for skin sensitisation. However, the experts were also of the opinion that alternative methods may be able to give hazard information, i.e. to differentiate between sensitisers and non-sensitisers, ahead of 2017. This would, however, not provide the complete picture of what is a safe exposure because the relative potency of a sensitiser would not be known. For toxicokinetics, the timeframe was 5-7 years to develop the models still lacking to predict lung absorption and renal/biliary excretion, and even longer to integrate the methods to fully replace the animal toxicokinetic models. For the systemic toxicological endpoints of repeated dose toxicity, carcinogenicity and reproductive toxicity, the time horizon for full replacement could not be estimated. PMID- 21533818 TI - Validation of the FACIT-fatigue subscale, selected items from FACT thrombocytopenia, and the SF-36v2 in patients with chronic immune thrombocytopenia. AB - PURPOSE: To assess the validity and reliability of the fatigue subscale of the Functional Assessment of Chronic Illness Therapy (FACIT-F), a 6-item subset from the thrombocytopenia subscale of the Functional Assessment of Cancer Therapy (FACT-Th6) and the Short Form-36 Version 2 (SF-36v2) in 2 clinical trials of the thrombopoietin receptor agonist eltrombopag in chronic immune thrombocytopenia (ITP) patients. METHODS: In the 6-month, RAndomized placebo-controlled ITP Study with Eltrombopag (RAISE; n = 197), the FACIT-F, FACT-Th6, and SF-36v2 were administered at baseline, day 43, weeks 14 and 26, or early withdrawal. In the ongoing open-label extension study, Eltrombopag EXTENDed Dosing Study (EXTEND; n = 154), measures were administered at baseline, at the beginning of each stage, and at permanent discontinuation of study medication. RESULTS: FACIT-F, FACT-Th6, and SF-36v2 demonstrated acceptable internal consistency reliability (i.e., all Cronbach's alphas >0.70) and test-retest reliability (all intraclass correlation coefficients >0.70). Construct validity was supported by moderate (0.35 < r < 0.50) to strong (r > 0.50) inter-measure correlations for baseline and change scores. A small to medium magnitude of effect was captured by the FACIT-F and FACT-Th6 among patients who experienced sustained platelet responses. CONCLUSIONS: Results provide support for the validity, reliability, and responsiveness of the FACIT-F, FACT-Th6, and SF-36v2 in chronic ITP patients. PMID- 21533819 TI - Recall of recent and more remote depressive episodes in a prospective cohort study. AB - BACKGROUND: In psychiatric epidemiology, symptoms are often assessed retrospectively. This raises concerns about the accuracy of the information recalled. In this study, we sought to examine the level of agreement between survey items assessing recent and more remote depressive episodes. METHODS: Data from the Canadian National Population Health Survey (NPHS) were used. The NPHS is a prospective study following a representative cohort of household residents sampled in 1994 and 1995. Every 2 years, participants are administered the Composite International Diagnostic Interview Short Form for Major Depression (CIDI-SFMD). The 2004 NPHS interview also included items asking about past episodes of depression and diagnoses of depression done by health professionals. We used cross-tabulation and logistic regression to explore the relationship between these responses. RESULTS: Approximately, 90% of respondents with CIDI SFMD-defined major depressive episodes in the year preceding the 2004 interview also reported lifetime episodes or professional diagnoses of depression in 2004. However, responses to the 2004 lifetime items corresponded less closely to CIDI SFMD results from the same individuals earlier in the longitudinal survey. Only 40.8% of respondents having the most recently identified episode in 1994 subsequently affirmed a past episode of depression in 2004. CONCLUSIONS: Reporting of depressive episodes diminishes with time, suggesting that retrospective assessment of such episodes may be vulnerable to inaccuracy. PMID- 21533820 TI - Proteasomal activities in the claw muscle tissue of European lobster, Homarus gammarus, during larval development. AB - Decapod crustaceans grow discontinuously and gain size through complex molt processes. The molt comprises the loss of the old cuticle and, moreover, substantial reduction and re-organization of muscles and connective tissues. In adult lobsters, the muscle tissue of the massive claws undergoes significant atrophy of 40-75% before ecdysis. The degradation of this tissue is facilitated by calcium-dependent proteases and by the proteasome, an intra-cellular proteolytic multi-enzyme complex. In contrast to the adults, the involvement of the proteasome during the larval development is yet not validated. Therefore, we developed micro-methods to measure the 20S and the 26S proteasomal activities within mg- and sub-mg-quantities of the larval claw tissue of the European lobster, Homarus gammarus. Within the three larval stages (Z1-3) we distinguished between sub-stages of freshly molted/hatched (post-molt), inter-molt, and ready to molt (pre-molt) larvae. Juveniles were analyzed in the post-molt and in the inter-molt stage. The trypsin-like, the chymotrypsin-like, and the peptidyl glutamyl peptide hydrolase activity (PGPH) of the 20S proteasome increased distinctly from freshly hatched larvae to pre-molt Z1. During the Z2 stage, the activities were highest in the post-molt animals, decreased in the inter-molt animals and increased again in the pre-molt animals. A similar but less distinct trend was evident in the Z3 stages. In the juveniles, the proteasomal activities decreased toward the lowest values. A similar pattern was present for the chymotrypsin-like activity of the 26S proteasome. The results show that the proteasome plays a significant role during the larval development of lobsters. This is not only reflected by the elevated activities, but also by the continuous change of the trypsin/chymotrypsin-ratio which may indicate a shift in the subunit composition of the proteasome and, thus, a biochemical adjustment to better cope with elevated protein turnover rates during larval development. PMID- 21533821 TI - The gestural repertoire of the wild chimpanzee. AB - Great ape gestural communication is known to be intentional, elaborate and flexible; yet there is controversy over the best interpretation of the system and how gestures are acquired, perhaps because most studies have been made in restricted, captive settings. Here, we report the first systematic analysis of gesture in a population of wild chimpanzees. Over 266 days of observation, we recorded 4,397 cases of intentional gesture use in the Sonso community, Budongo, Uganda. We describe 66 distinct gesture types: this estimate appears close to asymptote, and the Sonso repertoire includes most gestures described informally at other sites. Differences in repertoire were noted between individuals and age classes, but in both cases, the measured repertoire size was predicted by the time subjects were observed gesturing. No idiosyncratic usages were found, i.e. no gesture type was used only by one individual. No support was found for the idea that gestures are acquired by 'ontogenetic ritualization' from originally effective actions; moreover, in detailed analyses of two gestures, action elements composing the gestures did not closely match those of the presumed original actions. Rather, chimpanzee gestures are species-typical; indeed, many are 'family-typical', because gesture types recorded in gorillas, orangutans and chimpanzee overlap extensively, with 24 gestures recorded in all three genera. Nevertheless, chimpanzee gestures are used flexibly across a range of contexts and show clear adjustment to audience (e.g. silent gestures for attentive targets, contact gestures for inattentive ones). Such highly intentional use of a species-typical repertoire raises intriguing questions for the evolution of advanced communication. PMID- 21533822 TI - Evaluation of guanylyl cyclase C lymph node status for colon cancer staging and prognosis. AB - PURPOSE: The prognostic significance of guanylyl cyclase C (GCC) gene expression in lymph nodes (LNs) was evaluated in patients with stage II colon cancer who were not treated with adjuvant chemotherapy. We report a planned analysis performed on 241 patients. METHODS: GCC mRNA was quantified by RT-qPCR using formalin-fixed LN tissues from patients with untreated stage II colon cancer who were diagnosed from 1999-2006 with at least ten LNs examined and blinded to clinical outcomes. Lymph node ratio (LNR) is the number of GCC-positive nodes divided by total number of informative LNs. Risk categories of low (0-0.1) and high (>0.1) for LNR were chosen by significance using Cox regression models. The data were tested for association with time to recurrence. RESULTS: Twenty-nine patients (12%) had a disease recurrence or cancer death. The LNR significantly predicted higher recurrence risk for 84 patients (34.9%) classified as high risk (hazard ratio (HR), 2.38; P=0.02). The estimated 5-year recurrence rates were 10% and 27% for the low- and high-risk groups, respectively. After adjusting for age, T stage, number of nodes assessed, and MMR status, a significant association remained (HR, 2.61; P=0.02). In a subset of patients (n=181) with T3 tumor, >=12 nodes examined and negative margins, a significant association between the GCC LNR and recurrence risk also was observed (HR, 5.06; P=0.003). CONCLUSIONS: Our preliminary results suggest that detection of GCC mRNA in LNs is associated with risk of disease recurrence in patients with untreated stage II colon cancer. A larger validation study is ongoing. PMID- 21533824 TI - Evaluative conditioning may occur with and without contingency awareness. AB - Evaluative conditioning (EC) is considered to play an important role in the attitude formation. One of the ongoing debates in this field concerns the impact of contingency awareness (i.e., awareness of the contingent relationship between conditioned and unconditioned stimulus, CS-US) on the EC occurrence. Despite the claims that EC does not require awareness of CS-US contingencies, the recent studies have claimed just the opposite. However, a number of methodological issues can be raised to undermine those claims. In two experiments, we tried to eliminate potential faults and sought to learn whether EC occurs with or without contingency awareness of either US identity or US valence. We report significant EC effects both with and without contingency awareness. These results provide support for the claim that the EC effects might be produced by independent mechanisms linked to awareness. We also argue that those mechanisms are differently captured by available measures of EC. PMID- 21533823 TI - Depression and medication adherence in the treatment of chronic diseases in the United States: a meta-analysis. AB - OBJECTIVE: To conduct a meta-analysis of the association between depression and medication adherence among patients with chronic diseases. Poor medication adherence may result in worse outcomes and higher costs than if patients fully adhere to their medication regimens. DATA SOURCES: We searched the PubMed and PsycINFO databases, conducted forward searches for articles that cited major review articles, and examined the reference lists of relevant articles. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: We included studies on adults in the United States that reported bivariate relationships between depression and medication adherence. We excluded studies on special populations (e.g., substance abusers) that were not representative of the general adult population with chronic diseases, studies on certain diseases (e.g., HIV) that required special adherence protocols, and studies on interventions for medication adherence. STUDY APPRAISAL AND SYNTHESIS METHODS: Data abstracted included the study population, the protocol, measures of depression and adherence, and the quantitative association between depression and medication adherence. Synthesis of the data followed established statistical procedures for meta-analysis. RESULTS: The estimated odds of a depressed patient being non-adherent are 1.76 times the odds of a non-depressed patient, across 31 studies and 18,245 participants. The association was similar across disease types but was not as strong among studies that used pharmacy records compared to self-report and electronic cap measures. LIMITATIONS: The meta-analysis results are correlations limiting causal inferences, and there is some heterogeneity among the studies in participant characteristics, diseases studied, and methods used. CONCLUSIONS: This analysis provides evidence that depression is associated with poor adherence to medication across a range of chronic diseases, and we find a new potential effect of adherence measurement type on this relationship. Although this study cannot assess causality, it supports the importance that must be placed on depression in studies that assess adherence and attempt to improve it. PMID- 21533825 TI - Gender effect on time to levodopa-induced dyskinesias. AB - Levodopa-induced dyskinesias (LID) are commonly observed during long-term treatment of patients with Parkinson's disease (PD). The impact of non pharmacological factors on the latency to LID appearance is not known. The aim of the paper was to identify factors associated with time to appearance of LID. Consecutive PD patients treated with levodopa (n = 155) were included in this historical prospective analysis and LID and non-LID groups were compared. The relationship between possible risk factors and the time of LID onset was explored using the Kaplan-Meier method and the Cox multivariate regression model, controlling for the confounding effects of gender, age of disease onset, time to initiation of levodopa treatment, and history of smoking. Patients with LID (57.4%) were significantly younger at disease onset and had a slightly longer latency from diagnosis to levodopa treatment than those without; disease duration and age had no effect on LID appearance. Female gender was associated with a shorter time to LID and the median time to LID was 6 years for males and 4 years for females (p = 0.004). In the multivariate survival analysis a younger age of onset of PD and a longer time from diagnosis to levodopa treatment initiation were also associated with a shorter time to LID appearance (p = 0.030 and 0.036, respectively). Female gender is associated with a significantly shorter latency to LID appearance. Younger age at PD diagnosis and a longer time until starting levodopa are associated with both higher likelihood to develop LID, and a shorter latency until LID were observed. PMID- 21533826 TI - Nature and frequency of respiratory involvement in chronic progressive external ophthalmoplegia. AB - Chronic progressive external ophthalmoplegia (CPEO) is a relatively common mitochondrial disorder. Weakness of the extra-ocular, limb girdle and laryngeal muscles are established clinical features. Respiratory muscle involvement however has never been studied systematically, even though respiratory complications are one of the main causes of death. We therefore determined the prevalence and nature of respiratory muscle involvement in 23 patients with genetically confirmed CPEO. The main finding was decreased respiratory muscle strength, both expiratory (76.8% of predicted, p = 0.002) and inspiratory (79.5% of predicted, p = 0.004). Although the inspiratory vital capacity (92.5% of predicted, p = 0.021) and the forced expiratory volume in 1 s (89.3% of predicted, p = 0.002) were below predicted values, both were still within the normal range in the majority of patients. Expiratory weakness was associated with a decreased vital capacity (rho = 0.502, p = 0.015) and decreased peak expiratory flow (rho = 0.422, p = 0.045). Moreover, expiratory muscle strength was lower in patients with limb girdle weakness (62.6 +/- 26.1% of predicted vs. 98.9 +/- 22.5% in patients with normal limb girdle strength, p = 0.003), but was not associated with other clinical features, subjective respiratory complaints, disease severity or disease duration. Since respiratory involvement in CPEO is associated with severe morbidity and mortality, the present data justify periodic assessment of respiratory functions in all CPEO patients. PMID- 21533827 TI - Nationwide survey of Alexander disease in Japan and proposed new guidelines for diagnosis. AB - Alexander disease (AxD) is a rare neurodegenerative disorder characterized by white matter degeneration and formation of cytoplasmic inclusions. Glial fibrillary acidic protein (GFAP) mutations have been reported in various forms of AxD since 2001. However, a definitive diagnosis remains difficult because of uncertain prevalence, and different clinical features seen in infantile AxD and adult AxD may lead to confusion and misdiagnosis. Here we report an epidemiological study conducted in Japan. Two nationwide questionnaire-based surveys were conducted using tentative diagnostic criteria. We gathered information regarding prevalence, neurological findings, magnetic resonance imaging (MRI) findings, electrophysiological findings, genetic information, and the results of therapeutic interventions and home care. Prevalence of various forms of AxD was determined as 27.3% (infantile), 24.2% (juvenile), and 48.5% (adult). Prevalence of AxD in Japan was estimated to be approximately 1 case per 2.7 million individuals. The main characteristics of infantile and juvenile AxD include delayed psychomotor development or mental retardation, convulsions, macrocephaly, and predominant cerebral white matter abnormalities in the frontal lobe on brain MRI. The main characteristics of adult AxD include bulbar signs, muscle weakness with hyperreflexia, and signal abnormalities and/or atrophy of medulla oblongata and cervical spinal cord on MRI. To ensure correct diagnosis of AxD, the physician should understand the importance of the process of GFAP genetic testing, which provides definitive diagnosis. Therefore, we propose new clinical guidelines for diagnosing AxD based on simplified classifications: cerebral AxD (type 1), bulbospinal AxD (type 2), and intermediate form (type 3). PMID- 21533829 TI - Assessment of exposure to lead in humans and turtles living in an industrial site in Coatzacoalcos Veracruz, Mexico. AB - The intake of lead from the environment may occur thru various receptors. In order to measure lead levels absorbed, samples were taken from Children who live in three localities surrounding an industrial complex in Coatzacoalcos, Veracruz. Samples were also taken from turtles. Samples were analyzed and results were compared against the general population. In children tested, over 75% of all values were determined to be above CDC's safety levels of (10 MUg/dL). The geometric mean lead concentration was 11.4 MUg/dL, which is clearly higher around the industrial complex than in the general population. In turtles, lead blood levels in the exposed population were 2-fold above (24.2 MUg/dL) those of turtles in the reference population (10.1 MUg/dL). Lead levels observed represent a risk for both human and fauna health. PMID- 21533828 TI - Management of atrial fibrillation by primary care physicians in Germany: baseline results of the ATRIUM registry. AB - BACKGROUND: In contrast to surveys in cardiologist settings, presentation and management of atrial fibrillation (AF) in primary care patients is less well studied. METHODS AND RESULTS: The prospective ATRIUM (Outpatient Registry Upon Morbidity of Atrial Fibrillation) collected data from patients with AF seen by 730 physicians representing a random sample of all primary care physicians in Germany. ATRIUM enrolled 3,667 patients (mean age, 72 +/- 9 years; 58% male, mean CHADS(2) score 2.2 +/- 1.3), 994 (27.1%) with paroxysmal, 944 (25.7%) with persistent or long-standing persistent and 1,525 (41.6%) with permanent AF (no AF type was specified in 204 patients). Mean duration since initial diagnosis of AF was 61 +/- 66 months (median 42, interquartile range 14-88). Reported symptoms included palpitations (43%), shortness of breath (49%), fatigue (49%), dizziness (37%) and angina (20%). Most common concomitant conditions were hypertension (84%), heart failure (43%), coronary artery disease (345%), diabetes (35%) and chronic kidney disease (20%). Prior myocardial infarction was present in 11% of patients, prior stroke in 10% and prior transient ischemic attack in 10%. Antithrombotic medication was used by 93% of the patients (oral anticoagulants, 83%). Rate control therapy was reported in 75% and rhythm control therapy in 33%, often added to rate control. Drugs for rhythm and rate control included beta blockers (75%), calcium antagonists (15%), digitalis (29%), sodium channel blockers of type IA (quinidine, 1.0%) or IC (flecainide or propafenone, 5%), and potassium channel blockers including amiodarone (11%). In the year prior to enrollment, 46% of the patients had been cardioverted (23% by drugs, 22% electrically), catheter ablation had been performed in 5%, and 10% received a pacemaker or defibrillator. A high proportion (44%) of the patients were hospitalized in the year prior to enrollment. CONCLUSIONS: Patients with AF managed in primary care often receive guideline-conforming therapy including antithrombotic therapy, rate control and rhythm control (numbers given above). Despite this apparent adherence, almost half of the patients were hospitalized in the year prior to enrollment, suggesting that the therapies applied do not stabilize patients sufficiently to keep them out of hospital. PMID- 21533830 TI - Residues and dissipation of the herbicide fenoxaprop-P-ethyl and its metabolite in wheat and soil. AB - A method for residue analysis of fenoxaprop-P-ethyl and its metabolite (i.e., fenoxaprop-P) was developed using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). This method was then used to evaluate the residual level and dissipation rate of fenoxaprop-P-ethyl and fenoxaprop-P in the soil and wheat. The half-life of fenoxaprop-P-ethyl in wheat plants and soil was 1.50, 2.36 days in Beijing, and 2.28, 1.79 days in Hubei, respectively. The ultimate residues of the two compounds were undetected in soil, wheat grain and stem at the harvest time, suggesting that fenoxaprop-P-ethyl could be safely used in wheat crops with an appropriate dosage and application. PMID- 21533831 TI - Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. AB - Chronic pressure-overload and diabetes mellitus are two frequent disorders affecting the heart. We aimed to characterize myocardial structural and functional changes induced by both conditions. Pressure-overload was established in Wistar-han male rats by supra-renal aortic banding. Six-weeks later, diabetes was induced by streptozotocin (65 mg/kg,ip), resulting in four groups: SHAM, banding (BA), diabetic (DM) and diabetic-banding (DB). Six-weeks later, pressure volume loops were obtained and left ventricular samples were collected to evaluate alterations in insulin signalling pathways, extracellular matrix as well as myofilament function and phosphorylation. Pressure-overload increased cardiomyocyte diameter (BA 22.0 +/- 0.4 MUm, SHAM 18.2 +/- 0.3 MUm) and myofilament maximal force (BA 25.7 +/- 3.6 kN/m(2), SHAM 18.6 +/- 1.4 kN/m(2)), Ca(2+) sensitivity (BA 5.56 +/- 0.02, SHAM 5.50 +/- 0.02) as well as MyBP-C, Akt and Erk phosphorylation, while decreasing rate of force redevelopment (K (tr); BA 14.9 +/- 1.1 s(-1), SHAM 25.2 +/- 1.5 s(-1)). At the extracellular matrix level, fibrosis (BA 10.8 +/- 0.9%, SHAM 5.3 +/- 0.6%), pro-MMP-2 and MMP-9 activities increased and, in vivo, relaxation was impaired (tau; BA 14.0 +/- 0.9 ms, SHAM 12.9 +/- 0.4 ms). Diabetes increased cardiomyocyte diameter, fibrosis (DM 21.4 +/ 0.4 MUm, 13.9 +/- 1.8%, DB 20.6 +/- 0.4 MUm, 13.8 +/- 0.8%, respectively), myofilament Ca(2+)sensitivity (DM 5.57 +/- 0.02, DB 5.57 +/- 0.01), advanced glycation end-product deposition (DM 4.9 +/- 0.6 score/mm(2), DB 5.1 +/- 0.4 score/mm(2), SHAM 2.1 +/- 0.3 score/mm(2)), and apoptosis, while decreasing K (tr) (DM 13.5 +/- 1.9 s(-1), DB 15.2 +/- 1.4 s(-1)), Akt phosphorylation and MMP 9/TIMP-1 and MMP-1/TIMP-1 ratios. Diabetic hearts were stiffer (higher end diastolic-pressure: DM 7.0 +/- 1.2 mmHg, DB 6.7 +/- 0.7 mmHg, SHAM 5.3 +/- 0.4 mmHg, steeper end-diastolic-pressure-volume relation: DM 0.59 +/- 0.18, DB 0.83 +/- 0.17, SHAM 0.41 +/- 0.10), and hypo-contractile (decreased end-systolic pressure-volume-relation). DB animals presented further pulmonary congestion (Lungs/body-weight: DB 5.23 +/- 0.21 g/kg, SHAM 3.80 +/- 0.14 g/kg) as this group combined overload-induced relaxation abnormalities and diabetes-induced stiffness. Diabetes mellitus and pressure overload led to distinct diastolic dysfunction phenotypes: while diabetes promoted myocardial stiffening, pressure overload impaired relaxation. The association of these damages accelerates the progression of diastolic heart failure progression in diabetic-banded animals. PMID- 21533832 TI - The TIR/BB-loop mimetic AS-1 prevents cardiac hypertrophy by inhibiting IL-1R mediated MyD88-dependent signaling. AB - Activation of NF-kappaB contributes to cardiac hypertrophy and the interleukin-1 receptor (IL-1R)-mediated MyD88-dependent signaling pathway predominately activates NF-kappaB. Recent studies have shown that the TIR/BB-Loop mimetic (AS 1) disrupted the interaction of MyD88 with the IL-1R, resulting in blunting of NF kappaB activation. We have examined the effects of AS-1 on the IL-1beta-induced hypertrophic response using cultured neonatal cardiac myocytes in vitro and transverse aortic constriction (TAC) pressure overload-induced cardiac hypertrophy in vivo. Neonatal cardiac myocytes were treated with AS-1 15 min prior to IL-1beta stimulation for 24 h. AS-1 treatment significantly attenuated IL-1beta-induced hypertrophic responses of cardiac myocytes. In vivo experiments showed that AS-1 administration prevented cardiac hypertrophy and dysfunction induced by pressure overload. AS-1 administration disrupted the interaction of IL 1R with MyD88 in the pressure overloaded hearts and prevented activation of NF kappaB. In addition, AS-1 prevented increases in activation of the MAPK pathway (p38 and p-ERK) in TAC-induced hypertrophic hearts. Our data suggest that the IL 1R-mediated MyD88-dependent signaling pathway plays a role in the development of cardiac hypertrophy and AS-1 attenuation of cardiac hypertrophy is mediated by blocking the interaction between IL-1R and MyD88, resulting in decreased NF kappaB binding activity and decreased MAPK activation. PMID- 21533833 TI - Keeping track of the distance from home by leaky integration along veering paths. AB - When humans use vision to gauge the travel distance of an extended forward movement, they often underestimate the movement's extent. This underestimation can be explained by leaky path integration, an integration of the movement to obtain distance. Distance underestimation occurs because this integration is imperfect and contains a leak that increases with distance traveled. We asked human observers to estimate the distance from a starting location for visually simulated movements in a virtual environment. The movements occurred along curved paths that veered left and right around a central forward direction. In this case, the distance that has to be integrated (i.e., the beeline distance between origin and endpoint) and the distance that is traversed (the path length along the curve) are distinct. We then tested whether the leak accumulated with distance from the origin or with traversed distance along the curved path. Leaky integration along the path makes the seemingly counterintuitive prediction that the estimated origin-to-endpoint distance should decrease with increasing veering, because the length of the path over which the integration occurs increases, leading to a larger leak effect. The results matched the prediction: movements of identical origin-to-endpoint distance were judged as shorter when the path became longer. We conclude that leaky path integration from visual motion is performed along the traversed path even when a straight beeline distance is calculated. PMID- 21533834 TI - Engineering and the problem of moral overload. AB - When thinking about ethics, technology is often only mentioned as the source of our problems, not as a potential solution to our moral dilemmas. When thinking about technology, ethics is often only mentioned as a constraint on developments, not as a source and spring of innovation. In this paper, we argue that ethics can be the source of technological development rather than just a constraint and technological progress can create moral progress rather than just moral problems. We show this by an analysis of how technology can contribute to the solution of so-called moral overload or moral dilemmas. Such dilemmas typically create a moral residue that is the basis of a second-order principle that tells us to reshape the world so that we can meet all our moral obligations. We can do so, among other things, through guided technological innovation. PMID- 21533835 TI - The problem of many hands: climate change as an example. AB - In some situations in which undesirable collective effects occur, it is very hard, if not impossible, to hold any individual reasonably responsible. Such a situation may be referred to as the problem of many hands. In this paper we investigate how the problem of many hands can best be understood and why, and when, it exactly constitutes a problem. After analyzing climate change as an example, we propose to define the problem of many hands as the occurrence of a gap in the distribution of responsibility that may be considered morally problematic. Whether a gap is morally problematic, we suggest, depends on the reasons why responsibility is distributed. This, in turn, depends, at least in part, on the sense of responsibility employed, a main distinction being that between backward-looking and forward-looking responsibility. PMID- 21533836 TI - Teaching authorship and publication practices in the biomedical and life sciences. AB - Examination of a limited number of publisher's Instructions for Authors, guidelines from two scientific societies, and the widely accepted policy document of the International Committee of Medical Journal Editors (ICMJE) provided useful information on authorship practices. Three of five journals examined (Nature, Science, and the Proceedings of the National Academy of Sciences) publish papers across a variety of disciplines. One is broadly focused on topics in medical research (New England Journal of Medicine) and one publishes research reports in a single discipline (Journal of Bacteriology). Similar elements of publication policy and accepted practices were found across the policies of these journals articulated in their Instructions for Authors. A number of these same elements were found in the professional society guidelines of the Society for Neuroscience and the American Chemical Society, as well as the ICMJE Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Taken together, these sources provide the basis for articulating best practices in authorship in scientific research. Emerging from this material is a definition of authorship, as well as policy statements on duplicative publication, conflict of interest disclosure, electronic access, data sharing, digital image integrity, and research requiring subjects' protection, including prior registration of clinical trials. These common elements provide a foundation for teaching about scientific authorship and publication practices across biomedical and life sciences disciplines. PMID- 21533837 TI - Mapping Fusarium wilt race 1 resistance genes in cotton by inheritance, QTL and sequencing composition. AB - Knowledge of the inheritance of disease resistance and genomic regions housing resistance (R) genes is essential to prevent expanding pathogen threats such as Fusarium wilt [Fusarium oxysporum f.sp. vasinfectum (FOV) Atk. Sny & Hans] in cotton (Gossypium spp.). We conducted a comprehensive study combining conventional inheritance, genetic and quantitative trait loci (QTL) mapping, QTL marker-sequence composition, and genome sequencing to examine the distribution, structure and organization of disease R genes to race 1 of FOV in the cotton genome. Molecular markers were applied to F(2) and recombinant inbred line (RIL) interspecific mapping populations from the crosses Pima-S7 (G. barbadense L.) * 'Acala NemX' (G. hirsutum L.) and Upland TM-1 (G. hirsutum) * Pima 3-79 (G. barbadense), respectively. Three greenhouse tests and one field test were used to obtain sequential estimates of severity index (DSI) of leaves, and vascular stem and root staining (VRS). A single resistance gene model was observed for the F(2) population based on inheritance of phenotypes. However, additional inheritance analyses and QTL mapping indicated gene interactions and inheritance from nine cotton chromosomes, with major QTLs detected on five chromosomes [Fov1-C06, Fov1 C08, (Fov1-C11 ( 1 ) and Fov1-C11 ( 2)) , Fov1-C16 and Fov1-C19 loci], explaining 8-31% of the DSI or VRS variation. The Fov1-C16 QTL locus identified in the F(2) and in the RIL populations had a significant role in conferring FOV race 1 resistance in different cotton backgrounds. Identified molecular markers may have important potential for breeding effective FOV race 1 resistance into elite cultivars by marker-assisted selection. Reconciliation between genetic and physical mapping of gene annotations from marker-DNA and new DNA sequences of BAC clones tagged with the resistance-associated QTLs revealed defenses genes induced upon pathogen infection and gene regions rich in disease-response elements, respectively. These offer candidate gene targets for Fusarium wilt resistance response in cotton and other host plants. PMID- 21533838 TI - Therapy-associated secondary tumors in patients with non-germinomatous malignant germ cell tumors. AB - We report three patients with non-germinomatous malignant germ cell tumor (NGMGCT) who developed therapy-associated secondary tumors. They were diagnosed as having NGMGCT by elevated serum levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), or beta-HCG. Preoperatively, all patients received a combination of etoposide and platinum-based chemotherapy and radiotherapy; neo adjuvant therapy (NAT) was followed by complete excision of the residual tumor. Postoperatively, all underwent maintenance chemotherapy and all remained free of NGMGCT without recurrence. However, they developed therapy-associated secondary tumors, i.e. glioblastoma, meningioma, or cavernous angioma after 10.1, 9.8, and 8.2 years, respectively. The patient with glioblastoma died one year after its detection. The other two patients are currently alive; the meningioma was completely removed and the cavernous angioma is being monitored without additional treatment. To the best of our knowledge, therapy-associated secondary tumors in patients treated for NGMGCT are rare. PMID- 21533839 TI - Sarcoma arising as a distinct nodule within glioblastoma: a morphological and molecular perspective on gliosarcoma. AB - Gliosarcoma is a variant of glioblastoma and is characterized by distinct glial and sarcomatous components. Typically, there is no macroscopic boundary between the components and special stains are often required to distinguish the glial and sarcomatous elements. Some studies suggest similar genetic alterations in both components pointing to a common origin. We present an extreme case of gliosarcoma arising as a discrete fibrous nodule adjacent to a typical glioblastoma. A 65 year-old woman presented with progressive weakness, seizures and right-sided hemiparesis. CT scan demonstrated an irregular enhancing left frontal lobe mass and an adjacent discrete nodule with different imaging characteristics. The unique nature of this macroscopically biphasic neoplasm allowed us to compare the molecular characteristics of glial and sarcomatous elements which were strikingly similar except for small losses and gains in Chr 3. Studies are under way to determine the significance of chromosome 3 alterations in gliosarcomas. PMID- 21533840 TI - Molecular cloning and functional characterization of genes associated with flowering in citrus using an early-flowering trifoliate orange (Poncirus trifoliata L. Raf.) mutant. AB - To isolate differentially expressed genes during the juvenile-to-adult phase transition of an early-flowering trifoliate orange mutant (precocious trifoliate orange, Poncirus trifoliata), suppression subtractive hybridization was performed. In total, 463 cDNA clones chosen by differential screening of 1,920 clones were sequenced and 178 differentially expressed genes were identified, among which 41 sequences did not match any known nucleotide sequence. Analysis of expression profiles of the differentially expressed genes through hybridization on customized chips revealed their expression change was associated with the phase transition from juvenile to adult in the mutant. Open reading frames of nine selected genes were successfully determined by rapid amplification of cDNA ends. Expression analysis of these genes by real-time RT-PCR showed that transcript levels of several genes were associated with floral induction and inflorescence development. Among these genes, HM596718, a sequence sharing a high degree of similarity with Arabidopsis EARLY FLOWERING 5 (AtELF5) was discovered. Real-time PCR and in situ hybridization indicated its expression pattern was closely correlated with floral induction and flowering of the mutant. Ectopic expression of the gene in Arabidopsis caused early flowering; however, its functional characterization is different than the role of AtELF5 observed in Arabidopsis. A yeast two-hybrid assay indicated that PtELF5 significantly interacted with DUF1336 domain of a hypothetical protein, which has not yet been functionally characterized in woody plants. These findings suggest that PtELF5 may be a novel gene that plays an important role during the early flowering of precocious trifoliate orange. PMID- 21533841 TI - An autoregulatory feedback loop involving PAP1 and TAS4 in response to sugars in Arabidopsis. AB - miR828 in Arabidopsis triggers the cleavage of Trans-Acting SiRNA Gene 4 (TAS4) transcripts and production of small interfering RNAs (ta-siRNAs). One siRNA, TAS4 siRNA81(-), targets a set of MYB transcription factors including PAP1, PAP2, and MYB113 which regulate the anthocyanin biosynthesis pathway. Interestingly, miR828 also targets MYB113, suggesting a close relationship between these MYBs, miR828, and TAS4, but their evolutionary origins are unknown. We found that PAP1, PAP2, and TAS4 expression is induced specifically by exogenous treatment with sucrose and glucose in seedlings. The induction is attenuated in abscisic acid (ABA) pathway mutants, especially in abi3-1 and abi5-1 for PAP1 or PAP2, while no such effect is observed for TAS4. PAP1 is under regulation by TAS4, demonstrated by the accumulation of PAP1 transcripts and anthocyanin in ta-siRNA biogenesis pathway mutants. TAS4-siR81(-) expression is induced by physiological concentrations of Suc and Glc and in pap1-D, an activation-tagged line, indicating a feedback regulatory loop exists between PAP1 and TAS4. Bioinformatic analysis revealed MIR828 homologues in dicots and gymnosperms, but only in one basal monocot, whereas TAS4 is only found in dicots. Consistent with this observation, PAP1, PAP2, and MYB113 dicot paralogs show peptide and nucleotide footprints for the TAS4-siR81(-) binding site, providing evidence for purifying selection in contrast to monocots. Extended sequence similarities between MIR828, MYBs, and TAS4 support an inverted duplication model for the evolution of MIR828 from an ancestral gymnosperm MYB gene and subsequent formation of TAS4 by duplication of the miR828* arm. We obtained evidence by modified 5'-RACE for a MYB mRNA cleavage product guided by miR828 in Pinus resinosa. Taken together, our results suggest that regulation of anthocyanin biosynthesis by TAS4 and miR828 in higher plants is evolutionarily significant and consistent with the evolution of TAS4 since the dicot-monocot divergence. PMID- 21533842 TI - Identification and characterization of a pyridoxal reductase involved in the vitamin B6 salvage pathway in Arabidopsis. AB - Vitamin B6 (pyridoxal phosphate) is an essential cofactor in enzymatic reactions involved in numerous cellular processes and also plays a role in oxidative stress responses. In plants, the pathway for de novo synthesis of pyridoxal phosphate has been well characterized, however only two enzymes, pyridoxal (pyridoxine, pyridoxamine) kinase (SOS4) and pyridoxamine (pyridoxine) 5' phosphate oxidase (PDX3), have been identified in the salvage pathway that interconverts between the six vitamin B6 vitamers. A putative pyridoxal reductase (PLR1) was identified in Arabidopsis based on sequence homology with the protein in yeast. Cloning and expression of the AtPLR1 coding region in a yeast mutant deficient for pyridoxal reductase confirmed that the enzyme catalyzes the NADPH-mediated reduction of pyridoxal to pyridoxine. Two Arabidopsis T-DNA insertion mutant lines with insertions in the promoter sequences of AtPLR1 were established and characterized. Quantitative RT-PCR analysis of the plr1 mutants showed little change in expression of the vitamin B6 de novo pathway genes, but significant increases in expression of the known salvage pathway genes, PDX3 and SOS4. In addition, AtPLR1 was also upregulated in pdx3 and sos4 mutants. Analysis of vitamer levels by HPLC showed that both plr1 mutants had lower levels of total vitamin B6, with significantly decreased levels of pyridoxal, pyridoxal 5' phosphate, pyridoxamine, and pyridoxamine 5'-phosphate. By contrast, there was no consistent significant change in pyridoxine and pyridoxine 5'-phosphate levels. The plr1 mutants had normal root growth, but were significantly smaller than wild type plants. When assayed for abiotic stress resistance, plr1 mutants did not differ from wild type in their response to chilling and high light, but showed greater inhibition when grown on NaCl or mannitol, suggesting a role in osmotic stress resistance. This is the first report of a pyridoxal reductase in the vitamin B6 salvage pathway in plants. PMID- 21533843 TI - Temperature-dependent development and life table parameters of Typhlodromus bagdasarjani (Phytoseiidae) fed on two-spotted spider mite. AB - The predatory mite Typhlodromus bagdasarjani Wainstein and Arutunjan (Acari: Phytoseiidae) is an indigenous and widespread species of the Middle East fauna. In this paper we assess the effect of temperature on developmental rate and reproduction potential of T. bagdasarjani under laboratory conditions. The development of this species was determined at 15, 20, 25, 30, 35 and 37.5 +/- 1 degrees C, 60 +/- 10% RH and L16:D8 h photoperiod. The total developmental time averaged 28.2, 15.0, 8.9, 7.6, 7.2 and 7.4 days at 15-37.5 degrees C, respectively, when feeding on immature stages of two-spotted spider mite, Tetranychus urticae Koch. The lower developmental threshold (T ( 0 )) and thermal constant (K) for the development of this predator were estimated 9.2 degrees C and 162 degree-days by the Ikemoto linear model. The life table parameters were estimated at 15-35 degrees C. The shortest life span of females at 35 degrees C was 45.0 days, followed by 50.7, 50.9, 103.3 and 136.8 days at 30, 25, 20 and 15 degrees C, respectively. Mated females laid on average 19.9, 26.3, 41.1, 39.6 and 31.3 eggs per female at 15-35 degrees C, respectively. The intrinsic rate of increase (r ( m )) and finite rate of increase (lambda) increased significantly with increasing temperature. The r ( m ) values ranged from 0.021 (15 degrees C) to 0.186 (35 degrees C) days(-1). The highest value of net reproductive rate (R (0)) was 13.6 females progeny/female/generation at 25 degrees C. The results demonstrated that T. bagdasarjani is well adapted to high temperatures. However, the efficiency to control spider mites may be affected by behavioral characteristics of the predator and its prey under real conditions. PMID- 21533844 TI - Explicit reformulations of the Lambert W-omega function for calculations of the solutions to one-compartment pharmacokinetic models with Michaelis-Menten elimination kinetics. AB - The exact closed-form solutions to the integrated rate equations for one compartment pharmacokinetic models that obey Michaelis-Menten elimination kinetics were derived recently (Tang and Xiao in J Pharmacokin Pharmacodyn 34:807 827, 2007). These solutions are expressed in terms of the Lambert W(x)-omega function; however, unfortunately, most of the available computer programs are not set up to handle equations that involve the W(x) function. Therefore, in this article, I provide alternative explicit analytical equations expressed in terms of elementary mathematical functions that accurately approximate exact solutions and can be simply calculated using any optional standard software. PMID- 21533845 TI - The right to enjoy the benefits of scientific progress: in search of state obligations in relation to health. AB - After having received little attention over the past decades, one of the least known human rights--the right to enjoy the benefits of scientific progress and its applications--has had its dust blown off. Although included in the Universal Declaration of Human Rights (UDHR) and in the International Covenant on Economic, Social and Cultural Rights (ICESCR)--be it at the very end of both instruments this right hardly received any attention from States, UN bodies and programmes and academics. The role of science in societies and its benefits and potential danger were discussed in various international fora, but hardly ever in a human rights context. Nowadays, within a world that is increasingly turning to science and technology for solutions to persistent socio-economic and development problems, the human dimension of science also receives increased attention, including the human right to enjoy the benefits of scientific progress and its applications. This contribution analyses the possible legal obligations of States in relation to the right to enjoy the benefits of scientific progress and its applications, in particular as regards health. PMID- 21533846 TI - Therapist perspectives on community mental health services for children with autism spectrum disorders. AB - This mixed methods study examined therapist perspectives on serving children with autism spectrum disorders (ASD) in community mental health (CMH) clinics. One hundred therapists completed a survey about their experiences with this population and 17 participated in subsequent focus groups to clarify and expand survey results. Results indicate that CMH therapists serve many children with ASD for behavior or other psychiatric problems and perceive serving this population as challenging and frustrating due to their limited training. Therapists are highly motivated for comprehensive ASD training on ASD characteristics and intervention strategies. These data were used to tailor and package evidence based intervention strategies for delivery in CMH services. PMID- 21533847 TI - Burnout in mental health services: a review of the problem and its remediation. AB - Staff burnout is increasingly viewed as a concern in the mental health field. In this article we first examine the extent to which burnout is a problem for mental health services in terms of two critical issues: its prevalence and its association with a range of undesirable outcomes for staff, organizations, and consumers. We subsequently provide a comprehensive review of the limited research attempting to remediate burnout among mental health staff. We conclude with recommendations for the development and rigorous testing of intervention approaches to address this critical area. PMID- 21533848 TI - Predisposing, enabling, and need factors associated with high service use in a public mental health system. AB - The purpose of this study was twofold: (1) To investigate the individual- and system-level characteristics associated with high utilization of acute mental health services according to a widely-used theory of service use-Andersen's Behavioral Model of Health Service Use -in individuals enrolled in a large, public-funded mental health system; and (2) To document service utilization by high use consumers prior to a transformation of the service delivery system. We analyzed data from 10,128 individuals receiving care in a large public mental health system from fiscal years 2000-2004. Subjects with information in the database for the index year (fiscal year 2000-2001) and all of the following 3 years were included in this study. Using logistic regression, we identified predisposing, enabling, and need characteristics associated with being categorized as a single-year high use consumer (HU: >3 acute care episodes in a single year) or multiple-year HU (>3 acute care episodes in more than 1 year). Thirteen percent of the sample met the criteria for being a single-year HU and an additional 8% met the definition for multiple-year HU. Although some predisposing factors were significantly associated with an increased likelihood of being classified as a HU (younger age and female gender) relative to non-HUs, the characteristics with the strongest associations with the HU definition, when controlling for all other factors, were enabling and need factors. Homelessness was associated with 115% increase in the odds of ever being classified as a HU compared to those living independently or with family and others. Having insurance was associated with increased odds of being classified as a HU by about 19% relative to non-HUs. Attending four or more outpatient visits was an enabling factor that decreased the chances of being defined as a HU. Need factors, such as having a diagnosis of schizophrenia, bipolar disorder or other psychotic disorder or having a substance use disorder increased the likelihood of being categorized as a HU. Characteristics with the strongest association with heavy use of a public mental health system were enabling and need factors. Therefore, optimal use of public mental services may be achieved by developing and implementing interventions that address the issues of homelessness, insurance coverage, and substance use. This may be best achieved by the integration of mental health, intensive case management, and supportive housing, as well as other social services. PMID- 21533849 TI - Knowledge of cervical cancer among 25-54-year-old women in Beijing. AB - The purpose of this study is to examine knowledge of cervical cancer and the relationship between knowledge of human papillomavirus (HPV) infection and cervical disease in a largely representative Beijing population. A questionnaire based survey was conducted in a Beijing population sample of married women ages 25 to 54 years (n = 6,339), evaluating knowledge and relevant factors with regard to cervical cancer. Knowledge levels were low; only 52.5% (n = 3,328) of the respondents knew that cervical cancer can be detected in its early stage. Only 26.9% reported that human HPV infections were risk factors for cervical cancer. The level of knowledge was lower among older, with less education, less income, unstable profession, and non-Beijing Hukou women (all P < 0.01). An increasing level of knowledge may impact positively on intentions to participate in cervical cancer screening. Education schemes to improve knowledge of cervical cancer should be performed in a multimodel, multichannel method. PMID- 21533850 TI - Use and evaluation of an individually tailored website for counselees prior to breast cancer genetic counseling. AB - This article explores the use and evaluation of a pre-visit website which aims to prepare counselees who are the first in their family to request breast cancer genetic counseling. This website E-info gene(ca) provides computer-tailored information and a blank question prompt sheet (QPS) on which counselees can formulate their questions for the consultation. The objectives of this study are: first, to assess which factors influence the use of E-info gene(ca), including the duration of site and page views, the influence of topic sequence in the menu bar on the sequence of page views, and the relation between website use and the use of the QPS; second, to explore counselees' evaluations of E-info gene(ca) and relations with counselee characteristics. User statistics were analyzed to describe duration of site and page views. Multivariate analyses were used to predict duration of web and page views, sequence of page views, QPS use, and site evaluations. Independent variables were sociodemographic background, disease status, psychological functioning, and information needs. All 101 counselees who were provided with a login accessed the website and spent, on average, 21 min viewing the website. Counselees affected with breast cancer spent more time on the website than unaffected counselees. Half of all page views were within the sequence of topics in the menu and older counselees, and those who made less use of the internet more often navigated according to the menu sequence than others. Having viewed information about why it is important to ask questions increased QPS use. Counselees who had higher information needs considered the information more helpful. This hospital-provided website for breast cancer genetic counselees was accessible and was evaluated positively, even concerning older counselees and those who had not searched the internet for information about hereditary cancer. Counselees might navigate hospital-provided websites more in line with the sequence of topics in the menu bar, than generally accessible health websites. PMID- 21533851 TI - The effect of acute back muscle fatigue on postural control strategy in people with and without recurrent low back pain. AB - Back muscle fatigue decreases the postural stability during quiet standing, but it is not known whether this fatigue-induced postural instability is due to an altered proprioceptive postural control strategy. Therefore, the aim of the study was to evaluate if acute back muscle fatigue may be a mechanism to induce or sustain a suboptimal proprioceptive postural control strategy in people with and without recurrent low back pain (LBP). Postural sway was evaluated on a force platform in 16 healthy subjects and 16 individuals with recurrent LBP during a control (Condition 1) and a back muscle fatigue condition (Condition 2). Back muscle fatigue was induced by performing a modified Biering-Sorensen test. Ankle and back muscle vibration, a potent stimulus for muscle spindles, was used to differentiate proprioceptive postural control strategies during standing on a stable and unstable support surface, where the latter was achieved by placing a foam pad under the feet. Ankle signals were predominantly used for postural control in all subjects although, in each condition, their influence was greater in people with LBP compared to healthy subjects (p < 0.001). The latter group adapted their postural control strategy when standing on an unstable surface so that input from back muscles increased (p < 0.001). However, such adaptation was not observed when the back muscles were fatigued. Furthermore, people with LBP continued to rely strongly on ankle proprioception regardless of the testing conditions. In conclusion, these findings suggest that impaired back muscle function, as a result of acute muscle fatigue or pain, may lead to an inability to adapt postural control strategies to the prevailing conditions. PMID- 21533852 TI - Polymethylmethacrylate augmentation of the pedicle screw: the cement distribution in the vertebral body. AB - Many studies have proven that the polymethylmethacrylate (PMMA) augmentation of the pedicle screw can significantly increase stiffness and strength of spinal fixation. Some major complications have also been reported. However, there are no reports discussing cement distribution and its morphology in the osteoporotic vertebral body, which is critical in the analysis of the biomechanical strength of the pedicle screw and the risk of cement leakage after pedicle screw augmentation. In this study, we used computed tomography (CT) to evaluate the cement distribution in the osteoporotic vertebral body after PMMA augmentation of a pedicle screw and to analyze the factors leading to cement leakage. Two groups of patients were studied. Group A consisted 25 osteoporotic patients (mean age of 73 years) with spinal instrumentation who had a total of 145 pedicle screws and cement augmentation with biopsy needles. Group B consisted of 23 osteoporotic patients (mean age of 74.6 years) with spinal instrumentation who had a total of 125 cannulated pedicle screws with cement augmentation. All patients had CT evaluation of the cement distribution in the vertebral body after the surgery. The cement distribution in the vertebrae was divided into four zones in the axial CT view: anterior one-third, middle third, and posterior third of vertebral body, and the pedicle. The morphology of the cement distribution around the pedicle screw was defined as scattered type or concentrate type. The leakage pattern was divided to anterior-lateral, posterior-lateral, and canal leakage. The correlations among bone mineral density (BMD), the cement leakage rate, and cement distribution morphology were also analyzed. The results showed that most augmented pedicle screws had cement extension into three of the four zones of the vertebral body (66.3%), followed by two zones (20%), all four zones (11.5%), and only one zone (2.2%). Overall, 123 screws (84.8%) in Group A and 108 screws (86.4%) in Group B had cement concentrate type distribution. The cement leakage rate in Group A is 18.3% and 13.6% in Group B. Patients with a BMD <0.6 g/cm(2) had significantly higher rates of cement leakage and tended toward a scattered cement distribution. There was only one patient who had a symptomatic leakage (sciatica) in Group B. We concluded that the cement distribution after pedicle screw augmentation with biopsy needle or cannulated screw technique was mostly localized in three zones of the vertebral body, and patients with lower BMD had a higher risk of cement leakage and scattered cement distribution. PMID- 21533853 TI - A retrospective study of congenital scoliosis and associated cardiac and intraspinal abnormities in a Chinese population. AB - Our objective is to assess the incidence of cardiac and intraspinal abnormities in Chinese congenital scoliosis (CS) patients and to study the relationship between the associated abnormities and the different CS types. Five-hundred and thirty-nine consecutive Chinese patients with CS were retrospectively studied, and the records of echocardiography, plain radiograph of the entire spine, magnetic resonance imaging of the entire spine and/or myelogram were reviewed. The results indicated that the incidence of cardiac and intraspinal abnormities in CS patients was 14.1 and 24.5%, respectively. There was no difference in the incidence of associated cardiac and intraspinal abnormities in different CS types (P > 0.05). The most common cardiac abnormities in CS patients was mitral valve prolapse, which was followed by congenital heart diseases, including atrial septal defect, ventricular septal defect, bicuspid aortic valve and patent ductus ateriosus. The cardiac abnormities were not likely to be concurrent with intraspinal abnormities in CS patients (P = 0.04). The intraspinal abnormities were more common in female and older patients (all P < 0.05). One or more abnormities mentioned above could be found in 36.8% CS patients and were more likely to be found in female patients (P < 0.01). We concluded that CS is not a simple abnormity, due to the high incidence of associated deformities of other organs, comprehensive assessment was strongly recommended before the surgical correction for CS patients. PMID- 21533855 TI - Primary lack of efficacy of infliximab therapy for rheumatoid arthritis: pharmacokinetic characterization and assessment of switching to tocilizumab. AB - To characterize primary failure to infliximab and determine the efficacy of switching to tocilizumab in patients with rheumatoid arthritis (RA), we examined 24 RA patients who had started on infliximab therapy (3 mg/kg) as their first biological agent. Nine of the 24 patients were found to be primary nonresponders, defined as patients who had never achieved a 20% clinical improvement according to the American College of Rheumatology criteria (ACR20) during induction therapy. The remaining 15 patients had achieved an ACR20 response to infliximab, without any relapses, for at least the first 14 weeks. A higher baseline health assessment questionnaire score was markedly associated with primary unresponsiveness to infliximab (p = 0.0005). Six of the 9 primary nonresponders showed rapid clearance of infliximab: their trough concentrations of infliximab were under 1 MUg/ml. The other 3 were classified as exhibiting the residual type of unresponsiveness, which was defined as unresponsiveness in patients who maintained serum infliximab levels above 1 MUg/ml. Human antichimeric antibody was not detected in the rapid-clearance nonresponders. Dose escalation (5 mg/kg) was insufficiently effective. Primary nonresponders to infliximab were started on tocilizumab therapy (8 mg/kg, every 4 weeks), and their responses were assessed after 24 weeks of this second attempt at therapy. All the nonresponders, except for a single rapid-clearance patient, had achieved an ACR20 clinical improvement at the time of assessment. In conclusion, primary nonresponders to infliximab can be classified into rapid-clearance and residual types, based on their trough concentrations of infliximab, but both types of nonresponders seem to benefit from an early decision to discontinue infliximab therapy and switch to tocilizumab. PMID- 21533854 TI - Pre- and post-synaptic cortical cholinergic deficits are proportional to amyloid plaque presence and density at preclinical stages of Alzheimer's disease. AB - Amyloid imaging has identified cognitively normal older people with plaques as a group possibly at increased risk for developing Alzheimer's disease-related dementia. It is important to begin to thoroughly characterize this group so that preventative therapies might be tested. Existing cholinotropic agents are a logical choice for preventative therapy as experimental evidence suggests that they are anti-amyloidogenic and clinical trials have shown that they delay progression of mild cognitive impairment to dementia. A detailed understanding of the status of the cortical cholinergic system in preclinical AD is still lacking, however. For more than 30 years, depletion of the cortical cholinergic system has been known to be one of the characteristic features of AD. Reports to date have suggested that some cholinergic markers are altered prior to cognitive impairment while others may show changes only at later stages of dementia. These studies have generally been limited by relatively small sample sizes, long postmortem intervals and insufficient definition of control and AD subjects by the defining histopathology. We, therefore, examined pre- and post-synaptic elements of the cortical cholinergic system in frontal and parietal cortex in 87 deceased subjects, including non-demented elderly with and without amyloid plaques as well as demented persons with neuropathologically confirmed AD. Choline acetyltransferase (ChAT) activity was used as a presynaptic marker while displacement of (3)H-pirenzepine binding by oxotremorine-M in the presence and absence of GppNHp was used to assess postsynaptic M1 receptor coupling. The results indicate that cortical ChAT activity as well as M1 receptor coupling are both significantly decreased in non-demented elderly subjects with amyloid plaques and are more pronounced in subjects with AD and dementia. These findings confirm that cortical cholinergic dysfunction in AD begins at the preclinical stage of disease and suggest that cholinotropic agents currently used for AD treatment are a logical choice for preventative therapy. PMID- 21533856 TI - Diagnostic features of mild cellulitis phlegmon in patients with rheumatoid arthritis treated with tocilizumab: a report of two cases. AB - Two cases of subcutaneous soft tissue infection in 30 RA patients treated with tocilizumab are reported. In both patients, local redness, swelling, and heat were observed around the affected site. WBC spikes and such local findings were suggested to be clinically useful for the early detection of low-grade subcutaneous infection in RA patients whose disease is tightly controlled with tocilizumab. Of note, the C-reactive protein (CRP) level and temperature lacked clinical utility for such detection. PMID- 21533857 TI - Plasma VEGF levels may not accurately reflect the truth all the time. PMID- 21533860 TI - Morphoscopic analysis of experimentally produced bony wounds from low-velocity ballistic impact. AB - Understanding how bone behaves when subjected to ballistic impact is of critical importance for forensic questions, such as the reconstruction of shooting events. Yet the literature addressing microscopic anatomical features of gunshot wounds to different types of bone is sparse. Moreover, a biomechanical framework for describing how the complex architecture of bone affects its failure during such impact is lacking. The aim of this study was to examine the morphological features associated with experimental gunshot wounds in slaughtered pig ribs. We shot the 4th rib of 12 adult pigs with .22 mm subsonic bullets at close range (5 cm) and examined resultant wounds under the light microscope, scanning electron microscope SEM and micro tomograph MUCT. In all cases there was a narrow shot channel followed by spall region, with evidence of plastic deformation with burnishing of the surface bone in the former, and brittle fracture around and through individual Haversian systems in the latter. In all but one case, the entrance wounds were characterized by superficially fractured cortical bone in the form of a well-defined collar, while the exit wounds showed delamination of the periosteum. Inorganic residue was evident in all cases, with electron energy dispersive spectroscopy EDS confirming the presence of carbon, phosphate, lead and calcium. This material appeared to be especially concentrated within the fractured bony collar at the entrance. We conclude that gunshot wounds in flat bones may be morphologically divided into a thin burnished zone at the entry site, and a fracture zone at the exit. PMID- 21533858 TI - Implications of transcriptional factor, OCT-4, in human bladder malignancy and tumor recurrence. AB - OCT-4, which is also known as POU5f1, is a key regulator of self-renewal in embryonic stem cells. The new cancer stem cell concept proposes that the expression of such genes is potentially correlated with tumorigenesis and can affect some aspects of the cancer behavior, such as recurrence or metastasis. This study investigated the association between OCT-4 expression in cancer tissues obtained by transurethral surgery and the clinical data to clarify the involvement of OCT-4 in human bladder malignancy. Immunohistochemical analysis demonstrated that a positive rate of OCT-4 expression was significantly associated with the higher-grade cancer (G2 and G3) in comparison with that of the lower grade (G1). In addition, positive OCT-4 expression was significantly associated with the intra-bladder tumor recurrence after the operation. The staining intensity of OCT-4 expression was also correlated with tumor recurrence. These data indicate that positive OCT-4 expression may be involved in the development of high-grade bladder cancer and with the bladder cancer recurrence. This is the first study showing a correlation between the expression of OCT-4 and bladder cancer recurrence. OCT-4 may be a valuable clinical marker for the progression of bladder cancer and may be an attractive therapeutic target for the development of new medicines for the treatment of malignancy. PMID- 21533861 TI - Inferior vena cava and renal vein thrombosis in a patient with ventricular septal defect. PMID- 21533862 TI - Endogenous production of hydrogen sulfide in isolated bovine eye. AB - Hydrogen sulfide (H(2)S) is a novel gasotransmitter with physiological and pathological functions in vascular homeostasis, cardiovascular system and central nervous system. In the present study, we determined the endogenous levels of H(2)S in various tissues of the bovine eye. We also examined the basal levels of H(2)S in response to donors (sodium hydrosulfide, NaHS and sodium sulfide, Na(2)S), substrate (L: -cysteine), inhibitors (propargylglycine, PAG and aminooxyacetic acid, AOA) and activator (S-adenosyl-L: -methionine, SAM) of this gas in the bovine retina. H(2)S was measured using a well established spectrophotometric method. The highest concentration of endogenous H(2)S was detected in cornea (19 +/- 2.85 nmoles/mg protein, n = 6) and retina (17 +/- 2.1 nmoles/mg protein, n = 6). Interestingly, H(2)S was not present in vitreous humor. The inhibitors of CSE and CBS; PAG (1 mM) and AOA (1 mM), significantly attenuated the production of H(2)S in the bovine retina by 56.8 and 42%, respectively. On the other hand the activator of CBS; SAM (100 MUM), H(2)S donors; NaHS (1 MUM) and Na(2)S (100 MUM), significantly increased endogenous levels of H(2)S in bovine retina. L: -cysteine (10-300 MUM) produced a significant (P < 0.05) concentration-dependent increase in H(2)S levels reaching a maximal at 300 MUM. We conclude that H(2)S is endogenously produced in various tissues of the isolated bovine eye. Moreover, endogenous levels of H(2)S are enhanced in the presence of substrate (L: -cysteine), an activator of CBS (SAM) and H(2)S donors but are blocked by inhibitors of enzymes that synthesize this gas in neural retina. PMID- 21533863 TI - Genetic influences on Alzheimer's disease: evidence of interactions between the genes APOE, APOC1 and ACE in a sample population from the South of Brazil. AB - Alzheimer's disease is a complex neurodegenerative disorder. Several genes have been suggested as Alzheimer's susceptibility factors, the apolipoprotein E (APOE) gene being an established susceptibility gene and the genes coding angiotensin converting enzyme (ACE) and apolipoprotein C1 (APOC1) being considered possible candidate genes for the disease. The objective of this study was to investigate the association of ACE and APOC1 gene polymorphisms with susceptibility to Alzheimer's disease and dementia in general, both alone and combined with the APOE gene. Forty-seven patients with dementia in general (35 of them with Alzheimer's disease) and 85 controls were investigated. The haplotypes E*3/ 317*ins and E*4/-317*ins of APOE/APOC1 genes were significantly more frequent in the groups with Alzheimer's disease and dementia in general (P < 0.001). The frequency of the ACE*ins allele was also greater in the groups with Alzheimer's disease and dementia in general (P = 0.022; P = 0.045), but genotype frequencies were only different in groups without the E*4/-317*ins haplotype (P = 0.012 for Alzheimer's disease; P = 0.04 for dementia). Our data point to important genetic interactions involved in these diseases. PMID- 21533864 TI - Accuracy of coronary artery stenosis detection with CT versus conventional coronary angiography compared with composite findings from both tests as an enhanced reference standard. AB - OBJECTIVE: To prospectively compare the accuracy of coronary CT angiography (CCTA) and conventional coronary angiography (CCA) for stenosis detection using composite findings from both tests as an enhanced reference standard. METHODS: One hundred thirteen patients underwent CCTA and CCA. Per-segment and per-patient accuracy of CCTA compared with initial CCA interpretation were determined. Angiographers were then unblinded to the CCTA results and re-evaluation of the CCA studies was performed with knowledge of CCTA findings, which was used as an enhanced reference standard to compare the diagnostic accuracy of CCTA versus CCA. RESULTS: When using the enhanced reference standard instead of initial CCA interpretation, CCTA accuracy for identifying segments (patients) with >=50% stenosis increased from 97.7% (96.5%) to 98.1% (98.2%), sensitivity from 90.5% (100%) to 90.8% (100%), and specificity from 98.4% (94.3%) to 98.9% (97.1%). CCTA identified six segments and two patients with stenoses >=50% missed on initial CCA interpretation. Compared with the enhanced reference standard the accuracies of CCTA and of initial CCA interpretation were not different (p = 0.87). CONCLUSION: CCTA compares favourably with CCA for stenosis detection. Use of a composite reference standard combining findings from both tests can control for the effect of false-negative CCA results when evaluating the accuracy of CCTA. PMID- 21533865 TI - A feasibility study of percutaneous Radiofrequency Ablation followed by Radiotherapy in the management of painful osteolytic bone metastases. AB - OBJECTIVES: To determine whether Radiofrequency Ablation (RFA) followed by Radiotherapy (RT) (RFA-RT) produces better palliation in terms of pain than RT alone in patients with osteolytic bone metastases. METHODS: Patients with solitary bone metastases and a pain score of least 5 or more on the VAS scale were selected. Fifteen patients were treated with RFA-RT (20 Gy delivered in 5 fractions of 4 Gy over 1 week) and were compared with a matched group (30 subjects) treated by RT. RESULTS: A complete response in terms of pain relief at 12 weeks was documented in 16.6% (5/30) and 53.3% (8/15) of the subjects treated by RT or RFA-RT, respectively (p = 0.027). The overall response rate at 12 weeks was 93.3% (14 patients) in the group treated by RFA-RT and 59.9% (18 patients) in the group treated by RT (p = 0.048). Although recurrent pain was documented more frequently after RT (26.6%) than after RFA-RT (6.7%) the difference did not reach statistical significance. The morbidity related to RT did not significantly differ when this treatment was associated with RFA. CONCLUSIONS: Our results suggest that RFA-RT is safe and more effective than RT. The findings described here should serve as a framework around which to design future clinical trials. PMID- 21533866 TI - Umbilical venous catheter position: evaluation by ultrasound. AB - OBJECTIVE: Umbilical venous catheter (UVC) insertion is frequently performed in critically ill neonates, with catheter position evaluated by an abdominal radiograph. The position of the catheter can be difficult to assess based on supine film alone. We aimed to determine whether ultrasound enables precise evaluation of the catheter tip position. METHODS: We prospectively evaluated UVC position in 75 neonates by ultrasound and supine abdominal radiograph. Distance from the catheter tip to the diaphragm was measured for both modalities. Anatomical location of the catheter was recorded for both studies. The Student's t-test was used to compare the means of the differences in catheter position on radiograph and ultrasound. RESULTS: In 46 patients there was no difference in the distance between the catheter tip and the diaphragm on ultrasound and radiograph. In 29 babies there was a difference of 1-to-7 mm. Ultrasound identified malposition of the catheter in three cases in which the position of the catheter on the plain film was deemed acceptable. CONCLUSIONS: Our study suggests that ultrasound is reliable and may replace plain radiograph for the identification of the UVC position, preventing complications from malposition, and reducing exposure to ionizing radiation. PMID- 21533867 TI - Percutaneous transhepatic biliary drainage (PTBD) with or without stenting complications, re-stent rate and a new risk stratification score. AB - OBJECTIVES: To review the success rate and number of complications in patients with obstructive jaundice treated with percutaneous transhepatic biliary drainage (PTBD), and to stratify the procedural risk of both PTBD and biliary stenting. SUBJECTS AND METHODS: 948 procedures performed in 704 consecutive patients with obstructive jaundice over a 7 year period were reviewed: 345 male; 359 females, mean age 70.1 years (range 48-96 years). Statistical analysis included X ( 2 ) test and multivariate logistic regression analysis. RESULTS: The technical success rate was 99%. The mortality related to the procedure was 2% and the 30 day mortality 13%. 91 (13%) stents inserted occluded during the study period. Predictors for stent failure and re-stenting were a diagnosis of cholangiocarcinoma, a lesion in the distal CBD, a high bilirubin, high urea and high white cell count and post procedure cholangitis. Factors significantly related to complications and 30-day mortality were retrospectively reviewed to devise a risk stratification score. CONCLUSIONS: PTBD and stenting offer a safe and effective method in providing palliative treatment for patients with biliary obstruction. Patients likely to have high levels of morbidity and mortality can be predicted before PTBD, using a risk stratification score, highlighting the need for closer clinical observation and delayed stent placement. PMID- 21533868 TI - Renal function and kidney length in preterm infants with nephrocalcinosis: a longitudinal study. AB - Renal injury in early life may lead to hypertension and renal disease in adulthood. In this prospective study, we estimated renal glomerular and tubular function and kidney length (KL) during the first 2 years of life of preterm infants with nephrocalcinosis (NC) associated with prematurity. The study cohort comprised 107 preterm children, 63 with NC and 44 control subjects without NC who were matched for gender, gestational age and birth weight. Kidney function was estimated based on measurements of serum creatinine (Scr), estimated glomerular filtration rate (eGFR), fractional excretion (FE) of sodium (Na), potassium (K), phosphate (P), magnesium (Mg) and uric acid (UA) and on the ratios of urinary Ca, oxalate (UOx) and citrate (UCit) to urinary creatinine (UCa/Ucr, UOx/Ucr and UCit/Ucr, respectively) calculated from morning urine collections. KL was measured by ultrasonography. Measurements were made at 40 weeks postmenstrual age and at 3, 6, 12 and 24 months of age. At 3 and 6 months, the NC group had higher UCa/Ucr, FEK and FEUA than the control group; at 12 months, only the UCa/Ucr and FEUA was still higher. The UCa/UCit ratio was higher in the NC group. Scr and eGFR did not differ between the groups at any time point. The NC group had a shorter KL up to 12 months of life (left kidney) or 24 months (right kidney). Based on these results, we conclude that NC in the preterm infants enrolled in our study was associated with impaired renal tubular function and a shorter KL in the first year of life. PMID- 21533869 TI - Should we consider MMF therapy after rituximab for nephrotic syndrome? AB - The management of steroid-dependent nephrotic syndrome, especially in patients who have failed to respond to cytotoxic drugs, such as cyclophosphamide, remains challenging. Rituximab represents a new (off-label) therapeutic option. In a significant portion of patients, it has a short serum half-life following the recovery of CD20-positive cells. The addition of mycophenolate mofetil (MMF) as a maintenance therapy is also an attractive option, but one which requires testing in a prospective randomized clinical trial with therapeutic drug monitoring and mechanistic ancillary studies. PMID- 21533870 TI - Nephrotic syndrome in The Netherlands: a population-based cohort study and a review of the literature. AB - Nephrotic syndrome (NS) is a clinical diagnosis with proteinuria, hypoalbuminaemia and oedema. NS is rare in children, and its incidence in The Netherlands is unknown. The aim of this study was to estimate the incidence of idiopathic NS in the Netherlands. All paediatric patients (age 0-18 years) with a newly diagnosed NS in the Netherlands were registered by the Dutch Pediatric Surveillance Unit during the years 2003 until 2006, secondary NS was excluded. All paediatricians filled out questionnaires about the first clinical findings of the patients and incidences were calculated. A literature review on incidences of childhood NS was conducted. The incidence of NS in children in the Netherlands in the years 2003 until 2006 was 1.52/ 100, 000 children/ year. The median age at diagnosis was 3.88 years with a mean age of 5.08 years. A significant male:female ratio of 2.04:1 was found. This prospective study of NS in the Netherlands revealed an incidence of 1.52:100, 000 children/year, and is similar to the incidences found all over the world. PMID- 21533872 TI - RGS22, a novel cancer/testis antigen, inhibits epithelial cell invasion and metastasis. AB - RGS22 is a novel testis specific gene. It is located within chromosome 8q22.2, which shows high relevance with tumor chromosomal aberrations. We investigated the potential role of RGS22 in human tumorigenesis. We examined the level of RGS22 expression by tumor tissue arrays, immunohistochemistry and by analyzing the expression levels of four human esophageal cancer cell lines with different metastatic potential using western blot. In addition, we examined the role of RGS22 over-expression in the processes of invasion and metastasis using a highly metastatic cancer cell line. We show that RGS22 are expressed in many tumor types, but specific to cancers with epithelial origin and associated with cancer metastasis. In addition, we identified the association of RGS22 to tumor invasion in cancer cell lines. Over-expression of RGS22 in a highly metastatic esophageal cancer cell line causes decrease in cell migration and reduction in the invasive potential of the cells. RGS22 is over-expressed in low metastatic epithelial cancers and involved in the processes of cell migration and invasion in esophageal cancer cell lines. Therefore, RGS22 may be an important tumor suppressor gene in tumorigenesis, a potential new diagnostic and prognostic biomarker for metastasis and may translate to therapeutic opportunities for the preventive treatment of epithelial cancer metastasis. PMID- 21533871 TI - Differential expression of FAK and Pyk2 in metastatic and non-metastatic EL4 lymphoma cell lines. AB - The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to phorbol 12-myristate 13-acetate (PMA). In sensitive cells, PMA causes Erk MAPK activation and Erk-mediated growth arrest. In resistant cells, PMA induces a low level of Erk activation, without growth arrest. A relatively unexplored aspect of the phenotypes is that resistant cells are more adherent to culture substrate than are sensitive cells. In this study, the roles of the protein tyrosine kinases FAK and Pyk2 in EL4 phenotype were examined, with a particular emphasis on the role of these proteins in metastasis. FAK is expressed only in PMA-resistant (or intermediate phenotype) EL4 cells, correlating with enhanced cell-substrate adherence, while Pyk2 is more highly expressed in non adherent PMA-sensitive cells. PMA treatment causes modulation of mRNA for FAK (up regulation) and Pyk2 (down-regulation) in PMA-sensitive but not PMA-resistant EL4 cells. The increase in Pyk2 mRNA is correlated with an increase in Pyk2 protein expression. The roles of FAK in cell phenotype were further explored using transfection and knockdown experiments. The results showed that FAK does not play a major role in modulating PMA-induced Erk activation in EL4 cells. However, the knockdown studies demonstrated that FAK expression is required for proliferation and migration of PMA-resistant cells. In an experimental metastasis model using syngeneic mice, only FAK-expressing (PMA-resistant) EL4 cells form liver tumors. Taken together, these studies suggest that FAK expression promotes metastasis of EL4 lymphoma cells. PMID- 21533873 TI - Proteomic profiling of lipid rafts in a human breast cancer model of tumorigenic progression. AB - Tumor biomarkers assist in the early detection of cancer, act as therapeutic targets for intervention, and function as diagnostic indicators for the evaluation of therapeutic responses. To identify novel human breast cancer biomarkers, we have analyzed the protein content of lipid rafts isolated from a series of human mammary epithelial cell lines with increasing tumorigenic potential. Since lipid rafts function as platforms for protein interaction critical to several biological processes, we hypothesized that the abundance of proteins associated with proliferation, invasion and metastasis would be dysregulated in highly transformed cells. For this purpose, the MCF10A epithelial lineage, which include benign MCF10A cells, premalignant AT and TG3B cells, and malignant CA1a tumor cells, was utilized. Detergent-resistant membranes were isolated from each line and proteins were identified and relatively quantitated using iTRAQTM reagents and tandem mass spectrometry. 57 proteins were identified, and 1667 peptide identifications, mapping to 49 proteins, contained sufficient information for semi-quantitative analysis. When comparing malignant to benign cells, we observed consistent alterations in groups of proteins, such as a 5.7 fold average decrease in G protein content (n = 5), 2.7-fold decrease in glycosylphosphatidylinositol-linked proteins (n = 7) and 3.3-fold increase in intermediate filaments (n = 9). Several of the identified proteins, including caveolin-1, filamin A, keratins 5, 6 and 17, and vimentin, are bona fide or candidate biomarkers in clinical studies, underscoring the usefulness of the MCF10A series as a model to better understand the biological mechanisms underlying cancer progression. PMID- 21533874 TI - Leishmaniasis: new insights from an old and neglected disease. AB - Leishmaniases are a clinically heterogeneous group of diseases caused by protozoa of the genus Leishmania. There is growing evidence that the true incidence of the disease is underestimated, especially in hyperendemic regions. Moreover, climate changes together with the increasing movement of humans and animals raise concerns about the possible introduction of Leishmania infection in previously spared areas. The disease is emerging in immunocompromised patients undergoing bone marrow or solid organ transplantation or treatment with biologic drugs. Furthermore, the deployment of military troops and travel to endemic areas are associated with the observation of a growing number of patients with cutaneous disease. Improvement in diagnostic methods, both in the field and in specialized laboratories, has been obtained through the implementation of molecular amplification methods and using the rK39 antigen as the substrate. Finally, new therapeutic approaches are gaining attention, such as the use of miltefosine for cutaneous leishmaniasis and paromomycin for visceral leishmaniasis, as well as the use of various antileishmanial drugs in combination. PMID- 21533876 TI - Optimal phenotypic testing of AmpC beta-lactamases using boronic acid solutions. AB - Plasmid-mediated class C beta-lactamases are reported from Escherichia coli and Klebsiella pneumoniae with increasing frequency. No screening and confirmatory tests have been uniformly established for these strains. We investigated for the presence of plasmid-mediated AmpC production in 51 clinical isolates of Enterobacteriaceae, comparing two different boronic acid formulations, phenylboronic acid (PB) and 3-(N-Boc-amino)phenylboronic acid (APB), using polymerase chain reaction (PCR). PB performed better than APB. PMID- 21533875 TI - Risk factors and severity scores in hospitalized patients with community-acquired pneumonia: prediction of severity and mortality. AB - Morbidity and mortality in patients with moderate to severe community-acquired pneumonia (CAP) is a global problem, and CAP is a leading cause of death due to infectious diseases. Prompt initiation of expanded-spectrum antimicrobials is essential for the prevention of unnecessary mortality and complications in patients, particularly in the elderly and other at-risk populations, and the treatment decisions made by practitioners have important implications for healthcare systems when hospitalization is required. Empirical antimicrobial treatment and the appropriate management of CAP patients will initially require the proper assessment of severity and patient risk for increased mortality, as well as risk factors for difficult-to-treat bacteria. This review will examine risk factors and scoring systems that may be predictive of moderate to severe CAP, which is often linked to increased risk of mortality. Understanding and recognizing potential risk factors will allow practitioners to proactively identify patients at the highest risk for severe illness or complications, thereby, guiding site-of-care decisions, as well as the choices for empiric antibiotic regimens. The decision to hospitalize a patient with CAP should include not only a clinical perspective and laboratory and radiographic findings, but also at least one objective tool of risk assessment, all in combination with sound clinical judgment. PMID- 21533878 TI - Infection and colonization with methicillin resistant Staphylococcus aureus ST398 versus other MRSA in an area with a high density of pig farms. AB - The purpose of this study was to evaluate the impact of the emergence of animal related methicillin resistant Staphylococcus aureus ST398 in an area with a high density of pig farms. A retrospective analysis was performed of all MRSA isolates in the laboratory database from 2002 till 2008 including typing results and clinical data from infection control archives and patient charts. The implementation of the screening of people in contact with pigs and veal calves for MRSA led to an increase in the average number of newly identified carriers from 16 per year between July 2002 and July 2006 to 148 between July 2006 and December 2008. This is a 925% increase of which 82% (108/132) was due to ST398. The majority (74%) came from targeted screening but 7% was due to unexpected findings. A wide range of infections with ST398 occurred in patients with and without contact with livestock varying from post-operative wound infections to sepsis and post-trauma osteomyelitis with an overrepresentation of spa type t567 among the clinical isolates. ST398 isolates were more often multi-resistant than isolates of other spa-types. The emergence of MRSA ST398 led to an increase in both MRSA carriers and MRSA infections. PMID- 21533879 TI - Blood drawn through valved catheter hub connectors carries a significant risk of contamination. AB - Infection Control became concerned when bloodstream infection (BSI) rates increased after implementing a needleless valved hub connector. During a 21-month period three different needleless catheter hub connectors were evaluated by quantitatively culturing blood drawn through hub connectors that would have ordinarily been discarded (DBC). DBC drawn through ClearlinkTM catheter hub connectors were found to be twice as likely to be positive as DBC drawn through Clave(r) or Q-syteTM hub connectors (P < 0.04). DBC grew pathogens 46% of the time and skin organisms 54% of the time. Patients with positive DBC were three times more likely to meet Centers for Disease Control (CDC) BSI criteria by DBC cultures than by physician-ordered blood cultures (CBC; P < 0.001). For patients growing pathogens in DBC, 64% had no CBC drawn, the average temperature was lower than for patients with pathogens in CBC (99.3 +/- 1.5 ve 100.6 +/- 1.9, P = 0.015), and 92% of discharged patients (11 out of 12) were not treated with an antibiotic active against the DBC pathogen. Drawing BC through a catheter hub connector carries a risk of false-positives that could increase BSI rates by up to 3-fold. Further work is necessary to evaluate this concern. PMID- 21533877 TI - Coagulase-negative staphylococci: update on the molecular epidemiology and clinical presentation, with a focus on Staphylococcus epidermidis and Staphylococcus saprophyticus. AB - Coagulase-negative staphylococci (CoNS), originally described as ubiquitous commensals of the healthy human skin and mucosa, have emerged as important opportunistic pathogens primarily causing healthcare-associated infections in patients with indwelling medical devices. Recent studies, utilizing new molecular typing methods, particularly on Staphylococcus epidermidis, have increased our understanding of the mechanisms that contribute to the evolutionary success of these extremely versatile microorganisms. In the following mini-review, we summarize recent research in this area focusing on the molecular methods and epidemiology of S. epidermidis and S. saprophyticus. PMID- 21533880 TI - Reinforcing the staple line during laparoscopic sleeve gastrectomy: prospective randomized clinical study comparing two different techniques. Preliminary results. AB - BACKGROUND: Sleeve gastrectomy involves the creation of small gastric reservoir based on lesser curvature of the stomach, which is fashioned by a longitudinal gastrectomy that preserves the antrum and pylorus together with its vagal innervation. The main complications in the early postoperative course are bleeding and gastric leak. In order to reduce these complications the staple line can be reinforced in many different ways. The purpose of this study was to randomly compare two different techniques in laparoscopic sleeve gastrectomy (LSG): buttressing the staple line at the gastroesophageal junction (angle of Hiss) with Gore Seamguard and staple-line suturing with PDS 2.0. METHODS: Between July 2009 and July 2010, 90 patients were prospectively and randomly enrolled in the two different techniques of handling the staple line during LSG. Forty-eight of these patients belonged in group A (application of Gore Seamguard) and 42 in group B (application of a continuous suture). Operative and postoperative complications were recorded. RESULTS: Postoperative leak affected two patients in group A (4.2%) and bleeding occurred in one patient of group A (2%). Total complication rate was 6.2% for group A. No major surgical complication occurred in group B. The differences between the two groups did not reach statistical significance. CONCLUSIONS: No significant difference is evidenced in terms of bleeding and postoperative leak between the two techniques of enhancing the staple line in LSG. Suturing of the staple line may be more time consuming but costs are considerably less. PMID- 21533881 TI - Observations regarding 'quality of life' and 'comfort with food' after bariatric surgery: comparison between laparoscopic adjustable gastric banding and sleeve gastrectomy. AB - BACKGROUND: Although laparoscopic adjustable gastric banding (LAGB) and laparoscopic sleeve gastrectomy (LSG) are coexisting first-choice restrictive procedures for bariatric surgery candidates, it is possible, given their different modes of action, that these procedures have different effects on quality of life (QOL). We hypothesized that improvement of QOL and comfort with food could be better with LSG compared to LAGB. METHODS: This cohort study included 131 obese patients who had either LAGB (n = 102) or LSG (n = 29). Patients were assessed during preoperative and at 6- and 12-month postoperative visits. Five QOL dimensions were assessed using the 'Quality of Life, Obesity and Dietetics' rating scale: physical impact, psycho-social impact, impact on sex life, comfort with food and diet experience. We compared QOL evolution between LAGB and LSG using linear mixed models adjusted for gender and body mass index at each visit. RESULTS: Excess weight loss was 28.4 +/- 14.7% and 34.8 +/- 18.4% for LAGB and 35.7 +/- 14.3% and 43.8 +/- 17.8% for LSG at 6 and 12 months postoperatively, respectively. Both LAGB and LSG provided significant improvement in the physical, psycho-social, sexual and diet experience dimensions of QOL. LSG was associated with better improvement than LAGB in short-term (6-month) comfort with food. CONCLUSIONS: Our results add further evidence to the benefit of LSG and LAGB in obesity management. Within the first year of follow-up, there is no lasting difference in the comfort with food dimension between LSG and LABG. PMID- 21533882 TI - Hearing others' pain: neural activity related to empathy. AB - The human voice is one of the principal conveyers of social and affective communication. Recent neuroimaging studies have suggested that observing pain in others activates neural representations similar to those from the first-hand experience of pain; however, studies on pain expressions in the auditory channel are lacking. We conducted a functional magnetic resonance imaging study to examine brain responses to emotional exclamations of others' pain. The control condition comprised positive (e.g., laughing) or negative (e.g., snoring) stimuli of the human voice that were not associated with pain and suffering. Compared to these control stimuli, pain-related exclamations elicited increased activation in the superior and middle temporal gyri, left insula, secondary somatosensory cortices, thalamus, and right cerebellum, as well as deactivation in the anterior cingulate cortex. The left anterior insular and thalamic activations correlated significantly with the Empathic Concern subscale of the Interpersonal Reactivity Index. Thus, the brain regions involved in hearing others' pain are similar to those activated in the empathic processing of visual stimuli. Additionally, the findings emphasise the modulating role of interindividual differences in affective empathy. PMID- 21533883 TI - Processing the emotions in words: the complementary contributions of the left and right hemispheres. AB - A dual-process model is suggested for the processing of words with emotional meaning in the cerebral hemispheres. While the right hemisphere and valence hypotheses have long been used to explain the results of research on emotional stimulus processing, including nonverbal and verbal stimuli, data on emotional word processing are mostly inconsistent with both hypotheses. Three complementary lines of research data from behavioral, electrophysiological, and neuroimaging studies seem to suggest that both hemispheres have access to the meanings of emotional words, although their time course of activation may be different. The left hemisphere activates these words automatically early in processing, whereas the right hemisphere gains access to emotional words slowly when attention is recruited by the meaning of these words in a controlled manner. This processing dichotomy probably corroborates the complementary roles the two hemispheres play in data processing. PMID- 21533884 TI - Obesity and postpartum depression: does prenatal care utilization make a difference? AB - To identify (1) the association between pre-pregnancy BMI (PP-BMI) and PPD symptoms, and (2) the association between PP-BMI and PPD symptoms after considering PNC utilization as a moderating variable. Data from the 2004 and 2005 Pregnancy Risk Assessment Monitoring System (PRAMS) were analyzed from 15 states. The study design utilized two risk-adjustment approaches. One approach included all women in the dataset and used statistical analyses to risk-adjust for pregnancy risk status, and the other approach, through a sensitivity analysis, modified the design of the study by truncating the sample to include only women with healthy pregnancies. An initial association was seen between obesity and PPD symptoms, and PNC and PPD symptoms in the multivariate analyses. However, the inclusion of case-mix variables into the multivariate models removed these associations. Overall, for both approaches, there was no indication of a moderating effect of PNC utilization. Results also revealed that many of the women were significantly affected by a variety of high-risk maternal morbidity (case-mix) variables. Although PNC is important for the health of mothers and babies, it does not appear to moderate the association of PP-BMI and PPD symptoms. However, since this study revealed associations between several high risk maternal morbidities (included as case-mix variables), and PPD symptoms, it is recommended that future research further investigate the possible association of these morbidities with PPD symptoms. For practice, it is suggested that PNC providers focus on their patients, and establish suitable interventions accordingly. PMID- 21533885 TI - Seasonal influenza vaccination among homebound elderly receiving home-based primary care in New York City. AB - Seasonal influenza vaccination is recommended for all persons aged >=50 years to reduce influenza related morbidity and mortality, but vaccination coverage among community-dwelling elderly remains low. Homebound elderly receiving home-based primary care (HBPC) have fewer barriers to vaccination than other community dwelling elderly. The Mount Sinai Visiting Doctors (MSVD) program provides HBPC to homebound elderly in New York City. This study assessed seasonal influenza vaccination coverage within an urban HBPC program and identified factors associated with vaccine refusal. A cross-sectional analysis of data from the 2008 2009 influenza season was completed and influenza vaccination coverage was assessed. The association between social, demographic and health-related characteristics and vaccine refusal was evaluated using bivariate analysis and multivariable logistic regression. Of 689 people aged >65 eligible for influenza vaccination, 578 (84%) accepted and 111 (16%) refused vaccination. In multivariable analysis, vaccine refusal was positively associated with female gender (adjusted odds ratio [AOR] = 1.85, 95% confidence interval [CI] 1.02, 3.35), black race (AOR = 2.04, 95% CI 1.28, 3.25), and living alone (AOR = 1.71, 95% CI 1.10, 2.67), and negatively associated with dementia (AOR = 0.59, 95% CI 0.37, 0.91). Seasonal influenza vaccine coverage in the MSVD program was high compared to nursing home and community-dwelling elderly. Offering patients vaccination at home without additional expense will likely improve vaccine coverage among urban homebound elderly. Understanding why vaccine refusal rates are higher among females, black patients, and those living alone should guide interventions to increase vaccine acceptance among this population. PMID- 21533886 TI - Circumstances surrounding the community needle-stick injuries in Georgia. AB - Community needle-stick injuries are important public health problem due to concern of blood-borne pathogen transmission. Purpose of this study was to describe circumstances related to non-occupational needle-stick injuries in Georgia. Data were collected from one outpatient clinic in Tbilisi. Medical records from 2002 to 2007 were reviewed. Blood tests were performed on HBV, HCV and HIV at first visit and 6 months after exposure. 25 (54.4%) study subjects were children playing in street/yard and being accidentally stuck by used needle. Most frequent circumstances related to needle stick among adult individuals were recapping or discarding used needle while taking care of family member needed home injections (12 cases). Eight participants (17.4%) reported accidentally stepping on used needle at sea shore. No infection with HIV and HCV were documented. Only one case of HBV infection occurred in female patient taking care of mother with chronic HBV infection. Study suggests that seroconversion for blood-borne infections after community needle-stick injuries is very low. Family members of patients receiving home injections should be informed about potential risks and advised using infection-control measures. Parents/teachers should be educated about the circumstances related to exposure to used needles among children. PMID- 21533887 TI - The twin epidemics of poverty and diabetes: understanding diabetes disparities in a low-income Latino and immigrant neighborhood. AB - In the United States, low-income immigrant groups experience greater health disparities and worse health-related outcomes than Whites, including but not limited to higher rates of type 2 diabetes (T2DM). The prevention and adequate management of T2DM are, to a great extent, contingent on access to healthy food environments. This exploratory study examines "upstream" antecedent factors contributing to "downstream" health disparities, with a focus on disparities in the structural sources of T2DM risk, especially food environments. Our target group is Latino immigrants receiving services from a non-profit organization (NGO) in Northern California. Methods are mixed and data include focus groups and surveys of our target group, interviews to NGO staff members, and estimation of the thrifty food market basket in local grocery stores. We find that while participants identify T2DM as the greatest health problem in the community, access to healthy foods is severely restricted, geographically, culturally, and economically, with 100% of participants relying on formal or informal food assistance and local food stores offering limited variety of healthy foods and at unaffordable prices. While this article is empirical, its goal is primarily conceptual--to integrate empirical findings with the growing literature underscoring the sociopolitical context of the social determinants of health in general and of T2DM disparities in particular. We propose that interventions to reduce T2DM and comparable health disparities must incorporate a social justice perspective that guarantees a right to adequate food and other health-relevant environments, and concomitantly, a right to health. PMID- 21533888 TI - "Minimally invasive" lumbar spine surgery: a critical review. AB - BACKGROUND: Minimal-access technology has evolved rapidly with "tubular" or "percutaneous" approaches for decompression and stabilization in the lumbar spine. Potential benefits (smaller scars, diminished local pain, reduced blood loss, reduced postoperative wound pain, shorter hospital stays) have to be weighed against possible drawbacks (reduced orientation, steep learning curve, increased radiation exposure, dependency on technology, cost). While non comparative case series are often rather enthusiastic, comparative studies and particularly RCTs are scarce and might convey a more realistic appreciation. METHODS: A MEDLINE search via PubMed was performed to find all English-language studies comparing "open" or "traditional" or "conventional" with "minimally invasive" or "percutaneous" or "tubular" approaches in degenerative lumbar spine surgery. RESULTS: Only nine comparative studies could be retrieved altogether. No clear benefit could be found for minimally invasive procedures in lumbar disc herniation, TLIF, or PLIF. There seems to be a slight advantage in terms of hardware safety in open procedures. CONCLUSIONS: This review, based solely on the very limited number of available comparative studies, shows no relevant benefit from minimally invasive techniques, and a tendency for more safety in open procedures in lumbar disc herniation, TLIF and PLIF. PMID- 21533889 TI - CCN2/decorin interactions: a novel approach to combating fibrosis? AB - CCN2 (connective tissue growth factor, CTGF), a member of the CCN family is overexpressed in fibrotic disease and is essential for the development of experimental fibrosis. Drugs targeting CCN2 action may therefore prove to be useful anti-fibrotic approaches. CCN2 acts via integrins and heparan sulfate containing proteoglycans (HSPGs). In a recent study, Vial and colleagues (2011) show that decorin can bind CCN2. A peptide corresponding to the leucine rich repeats peptide 12 region of decorin can neutralize CCN2-mediated activity on C2C12 cells in vitro. Thus it is conceivable that this peptide could be used in the future as a novel antifibrotic approach. PMID- 21533890 TI - CCN2 is not required for skin development. AB - Mice lacking the pro-adhesive matricellular protein connective tissue growth factor (CTGF/CCN2) display an embryonic lethal phenotype due to defects in bone and cartilage. However, the specific role of CCN2 in skin development is unknown. Here, we generated mice deleted for CCN2 in the entire body (using a cre/lox system in which CCN2 is deleted in the entire body due to the presence of a constitutively expressed cre recombinase). We found that CCN2 was not required for the development of skin as defined by skin thickness measurements, trichrome staining and immunostaining with anti-CD31 (to detect endothelial cells) and anti alpha-SMA (to detect smooth muscle cells and pericytes) antibodies. Thus, although recently we have shown that CCN2 is required for fibrogenesis in postnatal mice, CCN2 is not required for skin development during embryogenesis. PMID- 21533891 TI - Elucidating the principles of the molecular organization of heteropolymeric tight junction strands. AB - Paracellular barrier properties of tissues are mainly determined by the composition of claudin heteropolymers. To analyze the molecular organization of tight junctions (TJ), we investigated the ability of claudins (Cld) to form homo- and heteromers. Cld1, -2, -3, -5, and -12 expressed in cerebral barriers were investigated. TJ-strands were reconstituted by claudin-transfection of HEK293 cells. cis-Interactions and/or spatial proximity were analyzed by fluorescence resonance energy transfer inside and outside of strands and ranked: Cld5/Cld5 > Cld5/Cld1 > Cld3/Cld1 > Cld3/Cld3 > Cld3/Cld5, no Cld3/Cld2. Classic Cld1, -3, and -5 but not non-classic Cld12 showed homophilic trans-interaction. Freeze fracture electron microscopy revealed that, in contrast to classic claudins, YFP tagged Cld12 does not form homopolymers. Heterophilic trans-interactions were analyzed in cocultures of differently monotransfected cells. trans-Interaction of Cld3/Cld5 was less pronounced than that of Cld3/Cld1, Cld5/Cld1, Cld5/Cld5 or Cld3/Cld3. The barrier function of reconstituted TJ-strands was demonstrated by a novel imaging assay. A model of the molecular organization of TJ was generated. PMID- 21533892 TI - Pay for obesity? Pay-for-performance metrics neglect increased complication rates and cost for obese patients. AB - BACKGROUND: Rates of surgical complications are increasingly being used for pay for-performance reimbursement structures. We hypothesize that morbid obesity has a significant effect on complication rates and costs following commonly performed general surgical procedures. METHODS: We studied 30,502 patients who underwent cholecystectomy for cholecystitis and 6,390 patients who underwent appendectomy for acute appendicitis using administrative claims data from seven Blue Cross and Blue Shield Plans over a 7-year period (2002-2008). We compared 30-day complications as well as total 30-day direct medical costs for obese and non obese patients. Multivariate regressions were performed to determine the relationship of morbid obesity to complications and cost. RESULTS: Obese patients were more likely to have a complication within 30 days after surgery than non obese patients (19.2% vs. 15.7% for cholecystectomy, p < 0.0001; 20.2% vs. 15.2%, p < 0.0001, for appendectomy). The mean total 30-day postoperative cost for obese patients were $1,109 higher following a cholecystectomy (p < 0.0001) and $666 higher following an appendectomy (p = 0.09). CONCLUSION: Morbid obesity is associated with a higher rate of complications for two commonly performed general surgical procedures and is associated with higher costs for cholecystectomy. Pay for-performance metrics should account for the increased risk of complications and higher cost in this population. PMID- 21533894 TI - Phosphaturic mesenchymal tumor with chondromyxoid fibroma-like feature: an unusual morphological appearance. AB - Phosphaturic mesenchymal tumor (PMT) is a rare and distinctive tumor almost always associated with oncogenic osteomalacia. This tumor is often misdiagnosed due to its widely varied histomorphological spectrum. More recently the term PMT or its variants has been used whatever the histomorphological features. Herein, we present a case of a 32-year-old woman who presented with a 2-year history of oncogenic osteomalacia. The clinical examination failed to detect any tumor. The F-18 FDG PET scan and subsequent MRI revealed a tumor in the soft tissues of the right popliteal fossa. The histological features resembled a chondromyxoid fibroma (CMF), a feature documented only in two cases so far. PMID- 21533895 TI - Prof. Dr. Kurt Jellinger: an appreciation on the occasion of his anniversary. PMID- 21533896 TI - Molecular and pedigree analysis applied to conservation of animal genetic resources: the case of Brazilian Somali hair sheep. AB - The first registers of Somali sheep in Brazil are from the beginning of the 1900s. This breed, adapted to the dry climate and scarce food supply, is restricted in the northeast region of the country. Molecular marker technologies, especially those based on genotyping microsatellite and mtDNA loci, can be used in conjunction with breeding (pedigree analysis) and consequently the maintenance of genetic variation in herds. Animals from the Brazilian Somali Conservation Nuclei from Embrapa Sheep and Goats in Ceara State were used to validate genetic monitoring by traditional pedigree methods and molecular markers. Nineteen microsatellite markers and 404 base pairs from the control region of mtDNA were used. For total herd diversity, an average 5.32 alleles were found, with expected heterozygosity of 0.5896, observed heterozygosity of 0.6451, 0.4126 for molecular coancestrality, and coefficient of inbreeding (F (IS)) was -0.095. Comparing molecular coancestrality means over the years, there was a consistent increase in this parameter within the herd, increasing from 0.4157 to 0.4769 in 2 years (approx. 12% variation). Sixteen mtDNA haplotypes were identified. Inbreeding and other estimates from genealogical analyses confirm the results from molecular markers. From these results, it is possible to state that microsatellites are useful tools in genetic management of herds, especially when routine herd recording is not carried out, or there were gaps in recent generations. As well as pedigree control, genetic diversity can be optimized. Based on the results, and despite herd recording in the herd of Brazilian Somali of Embrapa Sheep and Goats, additional management measures need to be carried out in this herd to reduce inbreeding and optimize genetic variation. PMID- 21533897 TI - A study on possibility of Rosa canina seed use as feed ingredient in diets of Morkaraman male lambs. AB - This experiment was carried out to evaluate the ground Rosa canina seed at various levels (0%, 5%, and 15%) in barley-soybean-based concentrates offered to Morkaraman male lambs at approximately 8 months of age, on fattening performance, carcass, and meat quality characteristics. The lambs were divided into three treatment groups including R1 (concentrate without R. canina seed; n = 12), R2 (concentrate with 5% R. canina seed; n = 12), and R3 (concentrate with 15% R. canina seed; n = 12) at the beginning of fattening period. The soybean meal was used as main protein source in treatment groups. All of the groups were fed a diet consisting of concentrate offered ad libitum and 300 g of grass hay per lamb per day during 60-day fattening period. The effect of diet on daily weight gain was found statistically significant. The control group had higher daily weight gain than R3 groups with 15% of ground R. canina seed. The hot carcass and cold carcass weights and dressing percentage values were affected by diets, and R3 group fed concentrate with 15% R. canina seed had higher carcass weights and dressing percentages than R1 and R2 groups. Differences among the groups in terms of leg, rib, and hindshank weights were found highly significant. While R1 and R2 groups were not significantly different, R3 group was significantly higher to R1 and R2 groups in leg, rib, and hindshank weights. In addition, meat color parameters and pH values were not affected by diets in present study. PMID- 21533898 TI - Non-invasive investigation of kidney disease in type 1 diabetes by magnetic resonance imaging. AB - AIMS/HYPOTHESIS: Pathophysiological abnormalities in early diabetic nephropathy are poorly understood. We employed MRI to characterise renal perfusion, tissue oxygenation and kidney size in non-diabetic volunteers and type 1 diabetic patients without and with early renal disease. METHODS: We studied ten control participants (C; age 40.0 [range 31-54] years), nine longstanding normotensive type 1 diabetic patients (T1Normo; age 40.1 [31-50] years, estimated glomerular filtration rate [eGFR] 83.4 +/- 10.6 ml min(-1) 1.73 m(-2)) and eight microalbuminuric type 1 diabetic patients (T1Micro; age 42.4 [33-52] years, eGFR 71.6 +/- 13.7 ml min(-1) 1.73 m(-2)). Six microalbuminuric patients were restudied after 4 weeks without renin-angiotensin-aldosterone system inhibitors. Phase contrast angiography and kidney blood oxygen level dependent (BOLD) (R(2)(*)) MRI were performed, before and during water diuresis. Contrast-enhanced MRI was performed at baseline urine flow rate. Renal artery flow, renal vascular resistance (RVR), cortical and medullary volumes, and R(2)(*) were determined. RESULTS: Renal cortical and medullary volumes were similar in all groups (cortex: C 108 +/- 16, T1Normo 112 +/- 21, T1Micro 111 +/- 10 cm(3)/1.73 m(2); medulla: C 35 +/- 14, T1Normo 29 +/- 10, 33 +/- 6 cm(3)/1.73 m(2)). RVR increased from control to normoalbuminuric to microalbuminuric type 1 diabetic patients (C 0.061 +/- 0.018, T1Normo 0.077 +/- 0.014, T1Micro 0.093 +/- 0.024 mmHg ml(-1) min(-1) 1.73 m(-2), ANOVA p = 0.012). RVR correlated inversely with eGFR in normoalbuminuric, but not in microalbuminuric diabetic patients. Renal artery flow was lower in the whole diabetes cohort (control 740 +/- 205 vs diabetes 591 +/- 128 ml min(-1) 1.73 m(-2), p = 0.035). CONCLUSIONS/INTERPRETATION: Cortical and medullary volumes remain normal in early diabetic nephropathy. Decreased renal flow in longstanding normoalbuminuric type 1 diabetic patients may reflect intrarenal vascular stiffening, whereas in the microalbuminuric patients it may also reflect increased intraglomerular pressure. PMID- 21533899 TI - The HLA-B 3906 allele imparts a high risk of diabetes only on specific HLA-DR/DQ haplotypes. AB - AIMS/HYPOTHESIS: We investigated the risk associated with HLA-B*39 alleles in the context of specific HLA-DR/DQ haplotypes. METHODS: We studied a readily available dataset from the Type 1 Diabetes Genetics Consortium that consists of 2,300 affected sibling pair families genotyped for both HLA alleles and 2,837 single nucleotide polymorphisms across the major histocompatibility complex region. RESULTS: The B*3906 allele significantly enhanced the risk of type 1 diabetes when present on specific HLA-DR/DQ haplotypes (DRB1 0801-DQB1 0402: p = 1.6 * 10( 6), OR 25.4; DRB1 0101-DQB1 0501: p = 4.9 * 10(-5), OR 10.3) but did not enhance the risk of DRB1 0401-DQB1 0302 haplotypes. In addition, the B 3901 allele enhanced risk on the DRB1 1601-DQB1 0502 haplotype (p = 3.7 * 10(-3), OR 7.2). CONCLUSIONS/INTERPRETATION: These associations indicate that the B 39 alleles significantly increase risk when present on specific HLA-DR/DQ haplotypes, and HLA-B typing in concert with specific HLA-DR/DQ genotypes should facilitate genetic prediction of type 1 diabetes, particularly in a research setting. PMID- 21533900 TI - Transgenic production of arachidonic acid in oilseeds. AB - We describe a transgenic microalgal Delta9-elongase pathway transformed in both Brassica napus and Arabidopsis thaliana seed resulting in the production of arachidonic acid (ARA). This pathway is noteworthy for both the production of ARA in seed tissue and the low levels of intermediate C20 fatty acids that accumulate. We also demonstrate that the arachidonic acid is naturally enriched at the sn2 position in triacylglycerol. This is the first report of ARA production by the Delta9-elongase pathway in an oilseed. PMID- 21533901 TI - Expression of hGM-CSF in silk glands of transgenic silkworms using gene targeting vector. AB - The silk gland of the silkworm is a highly specialized organ that has the wonderful ability to synthesize and secrete silk protein. To express human granucyto-macrophage colony-stimulating factor (hGM-CSF) in the posterior silk glands of gene-targeted silkworms, a targeting vector pSK-FibL-L-A3GFP-PH-GMCSF LPA-FibL-R was constructed, harboring a 1.2 kb portion of the left homogenous arm (FibL-L), a 0.5 kb portion of the right homogenous arm (FibL-R), fibroin H-chain promoter-driven hGM-CSF and silkworm actin 3-promoter-driven gfp. The targeting vector was then introduced into the eggs of silkworm, and the transgenic silkworms were verified by PCR and DNA hybridization after being screened for the gfp gene. Western blotting analysis using an antibody against hGM-CSF demonstrated a specific band with a molecular weight of 22 kD in the silk glands of the G3 generation transgenic silkworms. The level of expression of hGM-CSF in the posterior silk glands of the G3 generation transgenic silkworms was approximately 2.70 ng/g of freeze-dried powdered posterior silk gland. These results showed that the heterologous gene could be introduced into the silkworm genome and expressed successfully. Further more, the exogenous genes existing in the G5 transgenic silkworm identified by PCR confirmed its integration stability. In addition, the silk glands containing expressed hGM-CSF performed the function of significantly increasing leukocyte count of CY-treated mice in a time-and-dose dependent manner. PMID- 21533902 TI - Production of transgenic rice new germplasm with strong resistance against two isolations of Rice stripe virus by RNA interference. AB - Rice stripe disease, with the pathogen Rice stripe virus (RSV), is one of the most widespread and severe virus diseases. Cultivating a resistant breed is an essential and efficient method in preventing rice stripe disease. Following RNA interference (RNAi) theory, we constructed three RNAi binary vectors based on coat protein (CP), special-disease protein (SP) and chimeric CP/SP gene sequence. Transgenic lines of rice cv. Yujing6 were generated through Agrobacterium mediated transformation. We inoculated T1 generation plants from each line derived from CP/SP, CP, and SP transgenic rice plants with two RSV isolates from Shandong Province and Jiangsu Province using viruliferous vector insects. In these resistance assays, chimeric CP/SP RNAi lines showed stronger resistance against two isolates than CP or SP single RNAi lines. Stable integration and expression of RNAi transgenes were confirmed by Southern and northern blot analysis of independent transgenic lines. In the resistant transgenic lines, lower levels of transgene transcripts and specific short interference RNAs were observed relative to the susceptible transgenic plant, which showed that virus resistance was increased by RNAi. Genetic analysis demonstrated that transgene and virus resistance was stably inherited in the T2 progeny plants. PMID- 21533903 TI - Mechanisms underlying the protective effect of zinc and selenium against cadmium induced oxidative stress in zebrafish Danio rerio. AB - The present study was designed to elucidate the protective effect mechanism of Zinc (Zn) and Selenium (Se) on cadmium (Cd)-induced oxidative stress in zebrafish. For this purpose we investigate the response of oxidative stress markers, metallothionein accumulation and gene expression in liver and ovary of female zebrafish exposed to 0,4 mg/l Cd in water and supplemented with Zn (5 mg kg(-1)) and/or Se (2 mg kg(-1)) for 21 days in their diet. Liver and ovary Cd uptake was evaluated after the exposure period. Cd exposure significantly inhibited the antioxidant enzyme activities termed as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxydase (GPx) and caused a pronounced malondialdehyde (MDA) accumulation in both organs. Co-administration of Zn and Se reversed the Cd-induced toxicity in liver and ovary measured as MDA accumulation. Interestingly, gene expression patterns of Cat, CuZnSod and Gpx were up-regulated when related enzymatic activities were altered. Zebrafish metallothionein transcripts (zMt) significantly decreased in tissues of fish supplemented with Zn and/or Se when compared to Cd-exposed fish. Our data would suggest that Zn and Se protective mechanism against Cd-induced oxidative stress is more depending on the correction of the proteins biological activities rather than on the transcriptional level of related genes. PMID- 21533904 TI - Epidemiology and microbiology of nosocomial pediatric candidemia at a northern Indian tertiary care hospital. AB - The availability and aggressive use of chemotherapeutic and immunosuppressive agents as well as broad-spectrum antibacterial agents have created a large population of patients who are at increased risk of acquiring infections with fungal organisms, especially Candida species. Present work was undertaken to study the epidemiology and microbiology of candidemia and Candida colonization in hospitalized children. A total of 323 suspected cases of septicemia were enrolled, of which blood culture from 7.4% subjects was positive for Candida species. In total, 57.3% subjects were colonized by Candida species at least at one of the tested sites. Of 337 isolates, 24.3, 71.5, 2.9, 0.59, and 0.59% were Candida albicans, Candida tropicalis, Candida krusei, Candida kefyr, and Candida lusitaniae, respectively. Antifungal susceptibility results show that fluconazole, itraconazole, and amphotericin B resistance is prevalent in 18.2, 2.4, and 3.6% of C. albicans isolates, and 21.1, 4.6, and 0.04% of C. tropicalis isolates, respectively. In a large number of cases, source of blood infection was patient's own colonizers, as shown by genetic matching. It was also noted that some strain types are circulating within the ward. High prevalence of non albicans candidemia with high resistance to fluconazole is prevalent in North Indian hospitalized children. PMID- 21533905 TI - Molecular cloning, sequence analysis and structure modeling of OmpR, the response regulator of Aeromonas hydrophila. AB - The ability of bacteria to survive and proliferate in changing environmental conditions, and during host cell invasion is the key to their pathogenicity. In order to achieve this, the bacteria use a signal transduction system, the two component regulatory system, which consists of a sensor kinase and a response regulator. The EnvZ/OmpR system regulates the porin genes ompF/ompC in response to changes in osmolarity. In the present study, the ompR gene of Aeromonas hydrophila (isolate Ah17) was cloned, sequenced and characterized. Further an attempt was made to analyze the structural characteristics of the OmpR protein from Aeromonas hydrophila. The three dimensional structure of the protein was predicted by homology modeling and the modeled structure was compared to other members of two component response regulators. This study would be helpful for structure based drug design approaches to generate drugs against this harmful pathogen to control its proliferation in both human and fish hosts. PMID- 21533906 TI - CD45-CD14 +CD34 + murine bone marrow low-adherent mesenchymal primitive cells preserve multilineage differentiation potential in long-term in vitro culture. AB - Bone marrow-derived cells have been postulated as a source of multipotent mesenchymal stem cells (MSC). However, the whole fraction of MSC remains heterogeneous and the expansion of primitive subset of these cells is still not well established. Here, we optimized the protocol for propagating the low adherent subfraction of MSC which results in long-term expansion of population characterized by CD45(-)CD14(+)CD34(+) phenotype along with expression of common MSC markers. We established that the expanded MSC are capable of differentiating into endothelial cells highly expressing angiogenic markers and exhibiting functional properties of endothelium. Moreover, we found these cells to be multipotent and capable of giving rise into cells from neuronal lineages. Interestingly, the expanded MSC form characteristic cellular spheres in vitro indicating primitive features of these cells. In sum, we isolated the novel multipotent subpopulation of CD45(-)CD14(+) CD34(+) bone marrow-derived cells that could be maintained in long-term culture without losing this potential. PMID- 21533907 TI - Modified apolipoprotein (apo) A-I by artificial sweetener causes severe premature cellular senescence and atherosclerosis with impairment of functional and structural properties of apoA-I in lipid-free and lipid-bound state. AB - Long-term consumption of artificial sweeteners (AS) has been the recent focus of safety concerns. However, the potential risk of the AS in cardiovascular disease and lipoprotein metabolism has not been investigated sufficiently. We compared the influence of AS (aspartame, acesulfame K, and saccharin) and fructose in terms of functional and structural correlations of apolipoprotein (apo) A-I and high-density lipoproteins (HDL), which have atheroprotective effects. Long-term treatment of apoA-I with the sweetener at physiological concentration (3 mM for 168 h) resulted in loss of antioxidant and phospholipid binding activities with modification of secondary structure. The AS treated apoA-I exhibited proteolytic cleavage to produce 26 kDa-fragment. They showed pro-atherogenic properties in acetylated LDL phagocytosis of macrophages. Each sweetener alone or sweetener treated apoA-I caused accelerated senescence in human dermal fibroblasts. These results suggest that long-term consumption of AS might accelerate atherosclerosis and senescence via impairment of function and structure of apoA-I and HDL. PMID- 21533909 TI - To be or not to be accepted: the role of immunogenicity of neural stem cells following transplantation into the brain in animal and human studies. AB - Grafting of neural stem cells into the mammalian central nervous system (CNS) has been performed for some decades now, both in basic research and clinical applications for neurological disorders such as Parkinson's and Huntington's disease, stroke, and spinal cord injuries. Albeit the "proof of principle" status that neural grafts can reinstate functional deficits and rebuild damaged neuronal circuitries, many critical scientific questions are still open. Among them are the manifold immunological aspects that are encountered during the graft-host interaction in vivo. For example, the experience with allografted cells in absence of immunosuppressant drugs has raised serious doubts about an immunological privileged site within the CNS as compared to other engraftment sites in the body. This review discusses recent experimental and clinical findings demonstrating that neural stem cells have unique characteristics that help them modulate the host immunological defense, but, under some conditions, may still trigger a rejection process. Implications of these findings on neural grafting and potential new therapeutic applications are discussed. PMID- 21533910 TI - Serious upper gastrointestinal complications of NSAIDs and COX-2 selective agents. PMID- 21533908 TI - Death and inflammation following somatic cell transplantation. AB - The fields of regenerative medicine and cellular therapy have been the subject of tremendous hype and hope. In particular, the perceived usage of somatic cells like mesenchymal stromal stem cells (MSCs) has captured the imagination of many. Clinical trials are currently evaluating the therapeutic efficacy of MSCs in disorders ranging from heart disease to pediatric graft-vs-host disease; however, numerous questions still remain regarding mechanism of action, effective dose, and whether these cells can be used in the allogeneic setting. One of the major issues surrounding the development of somatic cell therapies like MSCs is that despite evoking a positive response, long-term engraftment and persistence of these cells is rare. Consequently, very large cell doses need be administered raising production, delivery, and efficacy issues. In this review, we will discuss causes for this lack of persistence and highlight some of the methodologies be used to enhance cell survival post-transplantation. PMID- 21533911 TI - Comparison of sleep problems in children with anxiety and attention deficit/hyperactivity disorders. AB - This cross-sectional case-control study compared sleep problems in consecutively referred children aged 7-13 years meeting DSM-IV criteria for anxiety disorder, attention deficit/hyperactivity disorder (ADHD), comorbid anxiety disorder and ADHD, and a group of control children of similar age and gender. Diagnoses were assessed with the Kiddie-SADS PL interview, parent form, and the sleep problems with a standardized sleep questionnaire, the Children's Sleep Habits Questionnaire (CSHQ), as reported by the mother. A total of 141 children were included (anxiety disorder (n = 41), ADHD (n = 39), comorbid condition (n = 25), controls (n = 36)). Children in the clinical groups had more sleep problems than controls. Children with anxiety disorders and children with comorbid condition were reported to have more sleep problems than children with ADHD alone. Night waking was associated with comorbid anxiety disorder and ADHD. Bedtime resistance was associated with anxiety disorder, while daytime sleepiness affected all clinical groups. Clinical management of children with ADHD and anxiety disorders needs to include assessment of sleep problems. PMID- 21533912 TI - Juvenile diffuse systemic sclerosis/systemic lupus erythematosus overlap syndrome -a case report. AB - We report a rare case of diffuse systemic sclerosis (SSc) evolving into diffuse SSc/systemic lupus erythematosus (SLE) overlap syndrome. A 15-year-old boy was diagnosed as diffuse SSc with initial presentations of Raynaud's phenomenon and skin tightening. He underwent Chinese herbal treatment and clinical symptoms deteriorated in the following 3 years. On admission to our ward, serositis with pleural effusion, severe pulmonary fibrosis with moderate pulmonary hypertension, swallowing difficulty, and polyarthritis were observed. Autoantibody profiles revealed concurrence of anti-double-stranded DNA, anti-Smith, anti-topoisomerase I, and anti-ribonucleoprotein antibodies. The patient fulfills the criteria for both diffuse SSc and SLE. After drainage for pleural effusion accompanied by oral prednisolone and sildenafil, there were improvement of respiratory distress, swallowing difficulty, and pulmonary hypertension. In conclusion, connective tissue diseases may overlap with each other during the disease course. Serial follow-up for clinical symptoms as well as serological changes is recommended. PMID- 21533913 TI - Experimental verification and validation of a computer model for light-tissue interaction. AB - Laser light is frequently used in both diagnostics and treatment of patients. For any laser treatment to be effective it is important to deliver the correct dose at the treatment site. Human skin scatters and absorbs laser light in the visible wavelength region, which results in a decrease in fluence some distance into the skin. Computer simulations can be used to predict the fluence at the treatment site. Liquid and solid phantoms were prepared and the optical properties were measured. These values were then used as input values to a commercial software package simulating the different layers of skin representing phantoms. The transmission and reflected fractions of the different phantoms were measured with an integrating sphere and compared with the computer simulations. The results showed very good agreement with the measured values and the model can therefore be used with confidence to predict fluence at any treatment site inside the skin. PMID- 21533914 TI - Engineering Bacillus subtilis for isobutanol production by heterologous Ehrlich pathway construction and the biosynthetic 2-ketoisovalerate precursor pathway overexpression. AB - In the present work, Bacillus subtilis was engineered as the cell factory for isobutanol production due to its high tolerance to isobutanol. Initially, an efficient heterologous Ehrlich pathway controlled by the promoter P(43) was introduced into B. subtilis for the isobutanol biosynthesis. Further, investigation of acetolactate synthase of B. subtilis, ketol-acid reductoisomerase, and dihydroxy-acid dehydratase of Corynebacterium glutamicum responsible for 2-ketoisovalerate precursor biosynthesis showed that acetolactate synthase played an important role in isobutanol biosynthesis. The overexpression of acetolactate synthase led to a 2.8-fold isobutanol production compared with the control. Apart from isobutanol, alcoholic profile analysis also confirmed the existence of 1.21 g/L ethanol, 1.06 g/L 2-phenylethanol, as well as traces of 2 methyl-1-butanol and 3-methyl-1-butanol in the fermentation broth. Under microaerobic condition, the engineered B. subtilis produced up to 2.62 g/L isobutanol in shake-flask fed-batch fermentation, which was 21.3% higher than that in batch fermentation. PMID- 21533915 TI - Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy. AB - BACKGROUND: About 2-7% of familial cardiomyopathy cases are caused by a mutation in the gene encoding cardiac troponin I (TNNI3). The related clinical phenotype is usually severe with early onset. Here we report on all currently known mutations in the Dutch population and compared these with those described in literature. METHODS: TheTNNI3 gene was screened for mutations in all coding exons and flanking intronic sequences in a large cohort of cardiomyopathy patients. All Dutch index cases carrying a TNNI3 mutation that are described in this study underwent extensive cardiological evaluation and were listed by their postal codes. RESULTS: In 30 families, 14 different mutations were identified. Three TNNI3 mutations were found relatively frequently in both familial and non familial cases of hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy (RCM). Haplotype analysis showed that p.Arg145Trp and p.Ser166Phe are founder mutations in the Netherlands, while p.Glu209Ala is not. The majority of Dutch TNNI3 mutations were associated with a HCM phenotype. Mean age at diagnosis was 36.5 years. Mutations causing RCM occurred less frequently, but were identified in very young children with a poor prognosis. CONCLUSION: In line with previously published data, we found TNNI3 mutations to be rare and associated with early onset and severe clinical presentation. PMID- 21533916 TI - Cationic antimicrobial peptides in penaeid shrimp. AB - Penaeid shrimp aquaculture has been consistently affected worldwide by devastating diseases that cause a severe loss in production. To fight a variety of harmful microbes in the surrounding environment, particularly at high densities (of which intensive farming represents an extreme example), shrimps have evolved and use a diverse array of antimicrobial peptides (AMPs) as part of an important first-line response of the host defense system. Cationic AMPs in penaeid shrimps composed of penaeidins, crustins, and anti-lipopolysaccharide factors are comprised of multiple classes or isoforms and possess antibacterial and antifungal activities against different strains of bacteria and fungi. Shrimp AMPs are primarily expressed in circulating hemocytes, which is the main site of the immune response, and hemocytes expressing AMPs probably migrate to infection sites to fight against pathogen invasion. Indeed, most AMPs are produced as early as the nauplii developmental stage to protect shrimp larvae from infections. In this review, we discuss the sequence diversity, expression, gene structure, and antimicrobial activities of cationic AMPs in penaeid shrimps. The information available on antimicrobial activities indicates that these shrimp AMPs have potential therapeutic applications in the control of disease problems in aquaculture. PMID- 21533918 TI - Calcium invigorates the cadmium-stressed Brassica napus L. plants by strengthening their photosynthetic system. AB - INTRODUCTION: Cadmium (Cd) in plants interrupts numerous metabolic processes and reduces the water and nutrient uptake that cause chlorosis, growth retardation, and ultimately plant death. Response of Brassica napus L. to calcium (Ca) enrichment in growth medium for reducing Cd toxicity stress by strengthening the photosynthesis organelles and their functionality was explored in this study. MATERIALS AND METHODS: B. napus seedlings of two cultivars (ZS 758 and ZS 72) were exposed to Cd toxicity at 500 MUM in hydroponics, and it was ameliorated with Ca at 2.0 mM. The study included determinations and evaluations pertaining to physiological attributes of plant growth, chlorophyll, and photosynthesis. RESULTS AND DISCUSSION: Cadmium stress significantly depressed the seedling growth and reduced photosynthetic rate (Pn), stomatal conductivity (Gs), and transpiration rate (Tr). Further, Cd toxicity markedly decreased the electron transport rate of PSII, effective quantum yield of photochemical energy conversion in PSII [Y(II)], photosynthetic active radiation, coefficient of photochemical quenching (qP), and chlorophyll fluorescence decrease ratio (R(Fd)). Addition of Ca in Cd-stressed plants antagonized the toxicity effects on all the above-mentioned attributes. Calcium amendment also reversed the Cd stress induced increase in intercellular CO(2) concentration (Ci) and non-photochemical quenching, and countered the Cd accumulation in seedlings. CONCLUSION: This study suggests that Ca(2+) in the proximity of plasma membrane is proficient in alleviating Cd toxicity by reducing the cell-surface negativity and competing for Cd(2+) ion influx. Consequently, both the plant growth and activity of diurnal photosynthetic system remain the least altered under Cd-provoked toxicity stress. PMID- 21533919 TI - Prevention of cisplatin-induced hearing loss by administration of a thiosulfate containing gel to the middle ear in a guinea pig model. AB - PURPOSE: Thiosulfate may reduce cisplatin-induced ototoxicity, most likely by relieving oxidative stress and by forming inactive platinum complexes. This study aimed to determine the concentration and protective effect of thiosulfate in the cochlea after application of a thiosulfate-containing high viscosity formulation of sodium hyaluronan (HYA gel) to the middle ear prior to i.v. injection of cisplatin in a guinea pig model. METHODS: The release of thiosulfate (0.1 M) from HYA gel (0.5% w/w) was explored in vitro. Thiosulfate in the scala tympani perilymph of the cochlea 1 and 3 h after application of thiosulfate in HYA gel to the middle ear was quantified with HPLC and fluorescence detection. Thiosulfate in blood and CSF was also explored. The potential otoprotective effect was evaluated by hair cell count after treatment with thiosulfate in HYA gel applied to the middle ear 3 h prior to cisplatin injection (8 mg/kg b.w.). RESULTS: HYA did not impede the release of thiosulfate. Middle ear administration of thiosulfate in HYA gel gave high concentrations in the scala tympani perilymph while maintaining low levels in blood, and it protected against cisplatin-induced hair cell loss. CONCLUSION: HYA gel is an effective vehicle for administration of thiosulfate to the middle ear. Local application of a thiosulfate-containing HYA gel reduces the ototoxicity of cisplatin most likely without compromising its antineoplastic effect. This provides a minimally invasive protective treatment that can easily be repeated if necessary. PMID- 21533917 TI - The role of HBIg as hepatitis B reinfection prophylaxis following liver transplantation. AB - BACKGROUND AND INTRODUCTION: Without adequate prophylaxis, liver transplantation (LTx) is frequently followed by hepatitis B virus (HBV) reinfection, which results in rapidly progressing liver disease and significantly decreased overall survival. In the last two decades, significant progress has been made in the prophylaxis and treatment of HBV. DISCUSSION: We present an overview of different protocols and regimens used for prophylaxis of HBV reinfection after LTx and describe the protocol implemented at our center. Following LTx, HBV reinfection can be effectively prevented by administration of anti-hepatitis B immunoglobulin (HBIg) alone or more recently in combination with antiviral nucleoside/nucleotide analogs (NUCs). Several studies reported good results with the use of HBIg alone, but combination treatment with HBIg and NUCs has proven to be a superior prophylactic regimen for HBV recurrence. At present, combination therapy (HBIg and a nucleoside or nucleotide analog) is the gold standard used in many transplantation centers. This preventive regimen reduces the risk of a recurrence of HBV infection and thereby the need for re-transplantation. Future and ongoing studies will show how long HBIg must be given after transplantation, especially when used in combination with potent antivirals, such as entecavir or tenofovir. PMID- 21533920 TI - Flexible endoscopic Zenkers diverticulotomy with a novel bipolar forceps: a pilot study and comparison with needleknife dissection. AB - BACKGROUND: Zenker's diverticulum (ZD) is the most common diverticulum of the upper gastrointestinal tract. Various flexible endoscopic techniques have been used for division of the septum. However, the learning curve associated with these techniques might be difficult to overcome given the overall rarity of this condition. This can lead either to complications or to potential recurrence of symptoms. The authors hypothesized that a flexible bipolar hemostasis forceps developed for natural orifice translumenal surgery (NOTES) procedures would facilitate precise endoscopic diverticulotomy and simultaneously enable sealing of divided tissue edges. METHODS: Because the pharyngeal diverticulum (PD) in the pig is comparable with a human ZD, this nonsurvival model was used to perform endoscopic diverticulotomy using two energy technologies. The PD septum was dissected with either a flexible and a rotating bipolar forceps (n = 5) or with standard needleknife cautery (NK; n = 3). The feasibility and safety of the two technologies were compared. RESULTS: In contrast to NK myotomy, the bipolar forceps could easily be readjusted before any tissue dissection in all (5/5) interventions, and energy was applied only on the tissue to be divided. Tissue bonding at the edges of the septum was observed in all cases. The monopolar energy in NK dissection made precise and centered division of the septum difficult to achieve and did not bond the edges of the septum. One perforation occurred with NK (1/3). CONCLUSIONS: The flexible bipolar forceps used for Zenker's diverticulotomy is appealing due to its ease of application and potential to coaptate mucomuscular tissue edges. Although further evaluation with a survival model is necessary, it also seems to be a safer approach than NK. This novel tool could facilitate performance of surgical endoscopists and may make flexible endoscopy the preferred method for Zenker's ablation. PMID- 21533921 TI - The interaction between memorized objects and abrupt onsets in oculomotor capture. AB - Recent evidence has been found for a source of task-irrelevant oculomotor capture (defined as when a salient event draws the eyes away from a primary task) that originates from working memory. An object memorized for a nonsearch task can capture the eyes during search. Here, an experiment was conducted that generated interactions between the presence of a memorized object (a colored disk) with the abrupt onset of a new object during visual search. The goal was to compare memory driven oculomotor capture to oculomotor capture caused by an abrupt onset. This has implications for saccade programming theories, which have little to say about saccades that are influenced by object working memory. Results showed that memorized objects capture the eyes at nearly the same rate as abrupt onsets. When the abrupt onset and a memorized color coincide in the same object, this combination leads to even greater oculomotor capture. Finally, latencies support the competitive integration model: Shorter saccade latencies were found when the memorized color combined with the onset captured the eyes, as compared to either color or onset only. Longer latencies were also found when the color and onset occurred in the same display but were spatially separated. PMID- 21533923 TI - Hyperglycemic unilateral choreoathetosis: hyperdensity of the contralateral basal ganglia on CT. PMID- 21533927 TI - [Emphasis on pediatrics]. PMID- 21533928 TI - Spontaneous haemoptysis as a late complication of plombage in a tuberculosis patient. AB - The endemic spread of tuberculosis after World War II and the deficiency of appropriate antituberculous drugs had led to a renaissance of the surgical tuberculosis therapy until the early 1950s. Late complications of plombage performed decades before are rare and are mainly related to infection and/or migration of the inserted foreign material and are scarcely recognized today. We report on a 73-year-old male patient, who was admitted to the emergency room of our hospital with acute massive haemoptysis for four days. On physical examination the patient presented with decreased breath sounds over the left lung and an old left-sided thoracotomy scar. Radiological findings and bronchoscopy revealed an empyema and a fistula as late complications 53 years after collapse therapy with insertion of a plombage for the treatment of pulmonary tuberculosis. The endobronchial nylon threads in the left bronchial tree and the fistula ending in the left lower bronchus confirmed our diagnosis. The patient was successfully treated by resection of the affected lower lobe. The present casuistic demonstrates a rare cause of spontaneous haemoptysis: late complications after extrapleural pneumolysis and plombage for cavitary tuberculosis over 50 years after the initial operation. PMID- 21533929 TI - Diagnosis and treatment of pancreaticobiliary maljunction in children. AB - Pancreaticobiliary maljunction (PBM), which may be called by synonymous terms such as "anomalous arrangement of the pancreaticobiliary duct" or "anomalous union of biliopancreatic ducts," is defined as an anatomical maljunction of the pancreatic duct and the biliary duct outside of the duodenal wall beyond the influence of the sphincter of Oddi. Pancreaticobiliary maljunction is classified into three groups according to the type of the pancreaticobiliary junction. Pancreaticobiliary maljunction is diagnosed mainly by endoscopic retrograde cholangiopancreatography; however, in pediatric patients, it may be diagnosed by intraoperative cholangiography, and more recently has been diagnosed by computed tomographic cholangiography or contrast-enhanced helical computed tomography. Children with PBM without choledochal cysts usually do not show any symptoms except for abdominal pain and hyperamylasemia. Pancreaticobiliary maljunction is considered to be a major risk factor for biliary tract malignancy. In patients with PBM, free reflux of pancreatic juice into the biliary tract might induce biliary tract damage and biliary carcinogenesis. Thus, total resection of the extrahepatic bile duct and hepaticojejunostomy are recommended in children diagnosed with PBM with choledochal cyst. Early diagnosis and early surgical treatment provide a good prognosis with few complications. In addition, successive follow-up is necessary for early detection of biliary tract malignancy, especially in patients demonstrating postoperative complications. PMID- 21533930 TI - gammadelta T-cell immunotherapy for lung cancer. AB - Lung cancer is the leading cause of cancer death worldwide, yet there are still no satisfactory protocols available for treating this disease, emphasizing the urgency for more effective therapies. Recent clinical trials have provided encouraging evidence of the benefits of certain forms of immunotherapy. Here, we summarize recent developments in the area of gammadelta T-cell therapy for lung cancer in our center. gammadelta T cells constitute 2%-10% of T lymphocytes in human blood and play a role in immune surveillance against microbial pathogens and, possibly, cancer. These T cells recognize phosphoantigens via polymorphic gammadelta T-cell antigen receptors (TCR), as well as the major histocompatibility complex (MHC) class I chain-related molecules, A and B (MICA and MICB), via nonpolymorphic NKG2D receptors in an MHC-unrestricted manner. This implies that gammadelta T cells could retain antitumor effects despite reduced expression of MHC and tumor antigens on cancer cells. Thus, clinical trials have been conducted to evaluate the safety and efficacy of gammadelta T-cell-based immunotherapies for non-Hodgkin lymphoma, multiple myeloma, and solid tumors. This review focuses on the current status of gammadelta T-cell-based immunotherapy for lung cancer. PMID- 21533931 TI - Gastric tube perforation after esophagectomy for esophageal cancer. AB - We searched for cases of perforation of the gastric tube after esophagectomy for esophageal cancer by reviewing the literature. Only 13 cases were found in the English literature, and serious complications were seen in all cases, especially in cases of posterior mediastinal reconstruction. However, in the Japanese literature serious complications were also frequently seen in retrosternal reconstruction. Gastric tubes are at a higher risk of developing an ulcer than the normal stomach, including an ulcer due to Helicobacter pylori infection, insufficient blood supply, gastric stasis, and bile juice regurgitation. H. pylori eradication and acid-suppressive medications are important preventive therapies for ordinary gastric ulcers, but for gastric tube ulcers the effects of such treatments are still controversial. We tried to determine the most appropriate treatment to avoid serious complications in the gastric tubes, but we could not confirm an optimal route because each had advantages and disadvantages. However, at least in cases with severe atrophic gastritis due to H. pylori infection or a history of frequent peptic ulcer treatment, the antesternal route is clearly the best. Many cases of gastric tube ulcers involve no pain, and vagotomy may be one of the reasons for this absence of pain. Therefore, periodic endoscopic examination may be necessary to rule out the presence of an ulcer. PMID- 21533932 TI - Ischemia/reperfusion injury in liver resection: a review of preconditioning methods. AB - Ischemic preconditioning is one of the therapeutic interventions aiming at preventing ischemia/reperfusion-related injury. Numerous experimental studies and a few clinical series have shown that during liver resections, ischemic preconditioning is a promising strategy for optimizing the postoperative outcome. Moreover, various types of pharmacological intervention as well as different types of preconditioning, such as remote preconditioning, the use of heat shock, and hyperbaric oxygen, have been developed to attenuate the functional impairment accompanying ischemia/reperfusion injury. This review summarizes the various forms of preconditioning, thus suggesting that close cooperation between surgeons and anesthesiologists paves the way to apply novel strategies to improve the outcome of liver resection. PMID- 21533933 TI - Twenty years of countermeasures against postoperative methicillin-resistant Staphylococcus aureus infections. AB - PURPOSE: A total of 7345 cases of digestive organ surgery were investigated over the course of 20 years. METHODS: Owing to the increasing incidence of methicillin resistant Staphylococcus aureus (MRSA) infections, we classified our countermeasures into periods A (September 1987 to February 1990), B (March 1990 to February 1997), C (March 1997 to February 1999), D (March 1999 to October 2004), and E (November 2004 to August 2007), and compared the number of infections during these periods. In period B, cefazolin and cefotiam were administered as prophylaxis. The treatment continued for 4 days, including the day of surgery. The patients undergoing endotracheal intubation or tracheotomy were managed with nonscreening pre-emptive isolation and cohorting (NSPEI&C), regardless of whether MRSA was present. However, NSPEI&C was halted in period C, but it was thereafter implemented again, and prophylactic antibiotics were administered only on the day of surgery during period D. In period E, prophylactic antibiotics were administered for 3 days. RESULTS: In period A, MRSA was contracted in 4.1% (34/833) of patients. In period B, the MRSA isolation rate decreased to 0.3% (8/2722). In period C, the MRSA isolation rate increased to 3.4% (23/681). In period D, the MRSA isolation rate fell to 2.2% (40/1807). In period E, MRSA isolation cases significantly decreased to 0.4% (5/1302; P < 0.002 vs period D). CONCLUSION: The comprehensive management, selection of prophylactic antibiotics, and NSPEI&C were all considered to be effective. PMID- 21533934 TI - Peroral placement of a self-expandable covered metallic stent using an overtube for malignant gastroduodenal obstructions. AB - PURPOSE: To evaluate the technical feasibility and safety of overtube-guided covered metallic stent placement as palliative treatment for patients with inoperable malignant gastric outlet obstructions. METHODS: To relieve the symptoms of severe nausea and recurrent vomiting in five patients with inoperable gastric cancer, we used an overtube (Long overtube; Sumitomo Bakelite, Tokyo, Japan) to place large-diameter, self-expandable, covered esophageal Ultraflex stents (inner diameter 22-28 mm, length 10 or 12 cm; Boston Scientific, Watertown, MA, USA). Success was defined both technically and clinically. RESULTS: The stent placement was technically successful in all patients and resulted in improvement of symptoms in all five patients, four of whom were thereafter able to ingest solid food. The remaining patient, a 94-year-old man, was unable to ingest food because of dysmasesis. During the mean follow-up of 17 weeks, there was no stent reocclusion and no life-threatening complications developed. CONCLUSIONS: The placement of a large diameter, self-expandable, covered esophageal stent using an overtube appears to be effective for the palliative treatment of malignant gastric outlet obstruction. PMID- 21533935 TI - Modified triangulating stapling technique for closure of a temporary loop stoma. AB - PURPOSE: To describe a new stapling technique for closure of a temporary loop stoma and report the results of a retrospective investigation of its efficacy. METHODS: Thirty-nine patients underwent a total of 40 loop stoma closure procedures, performed by the same surgeon using the same method, between 2004 and 2009. Thirty-six procedures were performed after rectal surgery, 1 was done for rectal malignant lymphoma, 2 were performed in the same patient after resection of rectal gastrointestinal stromal tumor, and 1 was performed after colonic surgery. The short-term outcomes were evaluated retrospectively. For this technique, after the minimum necessary dissection of both limbs of the bowel from the abdominal wall, the everted part of the oral limb is returned to its proper anatomy. The stoma is closed in the vertical direction using two lines of staples in an everted fashion. RESULTS: The stoma was located in the terminal ileum (n = 36), transverse colon (n = 3), or sigmoid colon (n = 1). The mean operating time was 55 min and the estimated blood loss was 32 g. There were two postoperative wound infections and one anastomotic stenosis. CONCLUSION: Stapling closure of a temporary loop stoma with two lines of staples may be a feasible alternative that decreases morbidity and reduces the operating time. PMID- 21533936 TI - Laparoscopic one-stage resection of right and left colon complicated diverticulitis equivalent to Hinchey stage I-II. AB - PURPOSE: The safety and effectiveness of laparoscopic surgery is well established for recurrent, uncomplicated diverticular disease, but not for complicated diverticular disease. Using the Hinchey classification, we compared laparoscopic colon resection (LAPH) with conventional open colon resection (OPH) for the treatment of complicated diverticulitis equivalent to Hinchey stage I-II. METHODS: In this study, the Hinchey classification (I-IV) was also adopted for right-sided diverticulitis (I'-IV'). We reviewed the clinical records of 58 patients who underwent colon resection for complicated colon diverticulitis (Hinchey stage I-IV or I'-IV') between May 1994 and December 2008. Fifty-two patients underwent colon resection for Hinchey I-II or I'-II' disease; as LAPH in 36 and as OPH in 16. Only one patient required conversion to the open procedure after laparoscopy. RESULTS: The overall complication rate was significantly higher in the OPH group (43.8%) than in the LAPH group (16.7%; P < 0.05). Wound infection was significantly more common in the OPH group (37.5%) than in the LAPH group (11.1%; P < 0.05). Hospital stay was significantly shorter in the LAPH group (P < 0.05). Hartmann procedure was performed in one patient from each group. No anastomotic leakage occurred in either group. CONCLUSION: Our findings indicate that laparoscopic surgery can be performed safely and effectively even for patients with Hinchey I-II, I'-II' colonic diverticulitis. PMID- 21533937 TI - Nonoperative management of pancreatic injuries in pediatric patients. AB - PURPOSE: Nonoperative management of minor pancreatic injury is the generally accepted approach. However, the management of major pancreatic injury remains controversial in pediatric patients. The aim of the present study was to determine the safety and efficacy of nonoperative management of pancreatic injury in pediatric patients. METHODS: Between 2003 and 2009, 31 patients, 28 male and 3 female, with pancreatic injury due to blunt abdominal trauma were treated in our clinic. All patients were evaluated by ultrasonography, computed tomography (CT), and evaluation of serum amylase levels. Patients with ongoing hemodynamic instability after resuscitation or signs of bowel perforation underwent immediate laparotomy, and the remaining patients were conservatively treated. Conservative treatment consisted of nasogastric tube replacement, total parenteral nutrition, monitoring of amylase levels, and serial clinical examination. RESULTS: The most common mechanism of injury was a fall (35.4%). Ten patients (32.2%) had associated extra-abdominal injuries, and 18 patients (58.1%) had associated abdominal injuries. The spleen was the most common site of intra-abdominal injury that was associated with pancreatic trauma. Initial amylase levels were normal in 5 patients, whose CT scans revealed pancreatic injury. Twenty-five patients (80.6%) were conservatively treated. Six patients (19.4%) required surgical intervention because of a hollow viscus or diaphragmatic injury and hemodynamic instability. A pseudocyst developed in 11 of the 25 patients who were nonoperatively treated; 6 patients required intervention for the pseudocyst (percutaneous drainage and cystogastrostomy). No patient succumbed to injury. CONCLUSIONS: The majority of the pancreatic injuries in pediatric patients can be successfully treated conservatively, unless there is hemodynamic instability and a hollow viscus injury. The most common complication is a pseudocyst. PMID- 21533938 TI - Post-endoscopic retrograde cholangiopancreatography perforation managed by surgery or percutaneous drainage. AB - PURPOSE: Post-endoscopic retrograde cholangiopancreatography (ERCP) perforation usually resolves conservatively; however, intervention is sometimes needed, and there is a paucity of literature regarding the best management approach. We evaluated our experience of managing post-ERCP perforations to help define the role of surgery with percutaneous drainage (PCD). METHODS: A retrospective chart review revealed 14 cases of post-ERCP perforation with intra-abdominal sepsis referred for intervention. We analyzed data pertaining to clinical details, management, and outcome. RESULTS: There were 12 patients with duodenal perforation and 2 with biliary perforation. Most (10/14; 72%) had symptom onset within 48 h, but delayed diagnosis or referral resulted in a mean delay until intervention of 6.6 days (range 1-18 days). Computed tomography revealed localized collections in 9 (64%) patients. Seven patients with localized collections and no or minimal contrast leak underwent PCD and rest, and 7 underwent surgery. The indications for surgery were free perforation, generalized peritonitis, and major contrast leak. Overall morbidity was 50% and there was one early postoperative death, caused by severe sepsis. CONCLUSION: There should be a high index of suspicion of perforation when abdominal signs and symptoms develop after ERCP. Computed tomography is the investigation of choice for diagnosis and guiding therapy. With judicious selection of surgery or PCD based on clinical and imaging features, patients can be managed with acceptable morbidity and low mortality. PMID- 21533939 TI - Intraoperative cholangiography using an endoscopic nasobiliary tube during a laparoscopic cholecystectomy. AB - PURPOSE: The goals of this report are to present the characteristics of biliary complications associated with laparoscopic cholecystectomies (LC) performed at a single center, and to evaluate the efficacy of intraoperative cholangiography (IOC) using an endoscopic nasobiliary tube (ENBT) during an LC in order to prevent biliary complications. METHODS: A retrospective audit was conducted on a total of 657 patients who underwent either LC or open cholecystectomies (OC). There were 19 patients who developed bile duct injury (BDI; n = 9) or bile leakage (BL; n = 10) during an LC and were actively treated. After May of 1999, the patients with a higher risk of developing biliary complications were selected for preoperative placement of an ENBT, and IOC was performed. RESULTS: Intraoperative cholangiography using ENBT was performed on 93 (27.1%) out of 343 patients who underwent either LC or OC after May of 1999. An LC was performed in 335 cases (97.7%), and a conversion from an LC to OC was necessary in only three cases. Even though BDI never occurred, BL from the cystic duct and gallbladder bed were recognized in five cases. CONCLUSIONS: The selective use of IOC using ENBT may help to prevent BDI during LC, thereby expanding the indications for LC, while also reducing the rate of conversion to open procedures. PMID- 21533940 TI - CYP3A4 expression to predict treatment response to docetaxel for metastasis and recurrence of primary breast cancer. AB - PURPOSE: Tumors expressing high levels of CYP3A4 are likely to have a poor treatment response to docetaxel (DOC), which is metabolized by CYP3A4. Tissue samples of recurrent breast cancer are sometimes hard to obtain just before treatment because the tumor is often difficult to access. Using immunohistochemistry, we measured CYP3A4 expression in primary lesions and compared their treatment responses to DOC with those of recurrent breast cancer lesions. METHODS: The subjects of this study were 42 patients who had undergone surgery for breast cancer, and had metastasis or recurrence treated by DOC (60 mg/m(2) every 3 weeks). Tumor samples resected at surgery were immunostained for CYP3A4 and its expression levels were compared with the response rate to ongoing DOC treatment. RESULTS: Patients with CYP3A4-negative tumors (n = 19) showed a significantly higher response rate (63.2%) to DOC treatment than did those with CYP3A4-positive tumors (n = 23) (26.1%). The predictive value, negative predictive value, and diagnostic accuracy of CYP3A4 expression in the prediction response to DOC were 63.2%, 73.9%, and 68.6%, respectively. CONCLUSIONS: Measuring CYP3A4 expression immunohistochemically in the primary breast cancer lesion was useful for predicting the treatment response to DOC of tumors that recurred after a long interval. PMID- 21533941 TI - Physiological evaluation of residual stomach motility after local resection in conscious dogs. AB - PURPOSE: To investigate the phenomenon of remnant gastric motility and emptying after local resection. METHODS: Fifteen dogs were divided into three groups: a control (CONT) group, a group that underwent local resection of the greater (GREAT) curvature, and a group that underwent resection of the lesser (LESS) curvature. We conducted a strain gauge force transducer study, a [(13)C]octanoic acid breath test ((13)C-OBT), and a mosapride citrate effect test. Based on these results, we worked out the receptive relaxation (RR), motility index (MI), and postprandial period (PP) in the postprandial state, and the frequency, duration, and MI of phase III in the fasted state. The half emptying time (T (1/2)) of (13)C-OBT was also calculated. The MI was compared according to the mosapride effect test results. RESULTS: Postprandial RR, antro-pyloro-duodenal coordination, and fasting contractions were maintained in all three groups. Receptive relaxation was significantly shorter in the LESS group than in the other groups. Motility index was significantly lower in both treatment groups than in the CONT group. The PP was significantly longer in the GREAT group than in the other two groups. The (13)CO(2) excretion curves did not differ significantly among the groups. The duration of phase III was remarkably less in the treatment groups than in the CONT group, and MI was significantly lower in the LESS group than in the other groups in the fasted state. The MI increased remarkably after mosapride administration in the CONT group, showing no differences in other objective groups. CONCLUSION: Gastric function was maintained after gastric local resection, although its motility decreased. PMID- 21533942 TI - Expression of bone morphogenic protein-4 is inversely related to prevalence of lymph node metastasis in gastric adenocarcinoma. AB - PURPOSE: Bone morphogenic proteins (BMPs) are the largest subfamily of the transforming growth factor-beta superfamily. Initially characterized as factors that induce bone and cartilage formation, BMPs have been found to be critical during mesoderm formation, organogenesis, and cellular differentiation. Bone morphogenic proteins are also known to modulate the morphologic alteration, adhesion, motility, and invasion of carcinoma cells derived from several organs. However, BMP-4 expression in gastric adenocarcinoma has not yet been clarified. We conducted the present study to define the clinical significance of BMP-4 expression in gastric carcinoma. METHODS: Using immunohistochemistry, we investigated the expression of BMP-4 in normal mucosae and gastric adenocarcinoma samples from 64 patients with gastric carcinoma. RESULTS: The expression of BMP-4 was significantly higher in the adenocarcinoma than in the normal mucosae. Moreover, increased BMP-4 expression was associated with the presence of Helicobacter pylori infection. By contrast, the BMP-4 expression rate in gastric carcinoma was inversely related to the prevalence of lymph node metastasis and tumor invasiveness. CONCLUSIONS: The findings of this study suggest that BMP-4 expression may be a useful prognostic factor for predicting the outcome of patients with gastric carcinoma. Continued investigation to define the pathophysiologic mechanism underlying the role of BMP-4 in gastric carcinoma is warranted. PMID- 21533944 TI - Small intestinal perforation due to metastasis of breast carcinoma: report of a case. AB - A 79-year-old female patient underwent breast-conservation surgery following a diagnosis of right breast cancer in July 2007. In November 2008, the patient presented at our hospital with acute onset of lower abdominal pain. She was diagnosed with panperitonitis due to gastrointestinal perforation, and underwent an emergency operation. At the time of the operation, one site of free perforation was found in the small intestine, and a 2-3-cm nodule was found in the 50-cm anal side from the site of this perforation. Multiple metastases to the para-aortic lymph nodes and mesenteric lymph nodes were also found. The patient recovered without complications and was discharged from the hospital, but 3 months after surgery she succumbed due to multiple liver metastases. It is important to identify metastatic intestinal tumors in patients who have breast cancer. PMID- 21533943 TI - The alpha-lipoic acid derivative sodium zinc dihydrolipoylhistidinate reduces chemotherapy-induced alopecia in a rat model: a pilot study. AB - PURPOSE: Alopecia is one of the most common side effects of chemotherapy for which treatments have not been developed. In the present study, we evaluated the effects of sodium zinc dihydrolipoylhistidinate (DHLHZn), a new derivative of the multifunctional antioxidant alpha-lipoic acid, to treat chemotherapy-induced alopecia. METHODS: Wistar rats (8 days old) were treated with cytosine arabinoside (AraC; 20 mg/kg by daily intraperitoneal injection; days 0-6) and DHLHZn (0%, 0.5%, or 1% topically applied in a white petrolatum base; days 0-12). A control group received daily saline injections (days 0-6) and topical application of white petrolatum (days 0-12). On day 12, we evaluated hair loss and histologic changes to scalp tissue for each group (n = 10). RESULTS: Rats treated with AraC and 0% DHLHZn cream exhibited complete hair loss; however, treatment with 0.5% or 1% DHLHZn significantly reduced chemotherapy-induced hair loss. Histological analysis revealed that AraC treatment promoted inflammatory cell infiltration of the hair follicles, but this inflammatory response was attenuated by DHLHZn. CONCLUSIONS: Our findings demonstrate that DHLHZn attenuates chemotherapy-induced alopecia, indicating the potential use of this alpha-lipoic acid derivative as a therapeutic agent against this common side effect of chemotherapy. PMID- 21533945 TI - Catamenial hemoptysis treated by video-assisted thoracic surgery: report of a case. AB - A 22-year-old woman presenting with repetitive hemoptysis was clinically diagnosed based on the fact that her symptoms corresponded with her menstruation cycle. Computed tomography revealed a specifically localized opacity in the right middle lobe of the lung at the time of each episode of hemoptysis. Following a right middle lobectomy, which was performed under video thoracoscopy, the symptoms subsided. We also briefly herein review the 73 similar cases with catamenial hemoptysis that have been reported since 1956. PMID- 21533946 TI - Paraplegia due to spinal epidural hematoma after mitral valve surgery: report of a case. AB - Spinal epidural hematomas are rare entities that can be associated with spinal traumatic injuries and vascular lesions or that can spontaneously arise. Several reports have linked these hematomas to heart valve surgery. We herein describe a 71-year-old female patient who developed postoperative paraplegia immediately after mitral valve repair. Magnetic resonance imaging revealed an epidural hematoma of the spinal cord from C7 to Th4. A laminectomy was not performed because the patient's paraplegia gradually improved. After continuous rehabilitation, the patient regained sufficient muscle strength to perform standing exercises. She is presently capable of routine activities at home and is undergoing bethanechol chloride treatment for a neurogenic urinary bladder. Motor and sensory deficits of both lower limbs in a patient that arise immediately after heart surgery must be examined by early imaging to rule out space-occupying pathologies such as spinal epidural hematomas. PMID- 21533947 TI - Ruptured left colic arterial aneurysm treated by transcatheter arterial embolization alone and without a subsequent laparotomy: report of a case. AB - We herein report the case of a 49-year-old male patient with a ruptured aneurysm originating in the left colic artery, which was successfully treated by transcatheter arterial embolization (TAE) Abdominal computed tomography revealed a large hematoma with a central small aneurysm in the left upper abdomen. Celiac and superior mesenteric arteriography showed no dye extravasation. Subsequent aortography showed an aneurysm arising from the branch of the left colic artery that was successfully treated by selective TAE. Further surgery for subsequent ischemia was not performed. In cases presenting with an unclear source of intraabdominal bleeding, an aneurysm of the inferior mesenteric arterial branch should be considered. Transcatheter arterial embolization is a plausible initial treatment option as an effective therapeutic approach because it provides a curative and less invasive alternative to other therapies. Based on our experience and a review of the literature, surgery may not necessarily be imperative, even in cases of a ruptured aneurysm of a colic arterial branch after TAE. PMID- 21533948 TI - Surgical management of coronary artery stenosis and peripheral artery occlusive disease of the lower extremity in a patient with neurofibromatosis: report of a case. AB - We herein report the case of a patient demonstrating both coronary artery and peripheral artery occlusive disease with neurofibromatosis, which were successfully treated during the same session with coronary artery bypass graft surgery and a femoropopliteal bypass graft surgery procedure. The recognition of a possible association between neurofibromatosis and coronary artery and other vascular structures will further facilitate the successful surgery and clinical management of this rare clinical entity. PMID- 21533949 TI - Biological mesh for abdominal wall hernia synthetic mesh multidrug-resistant Pseudomonas aeruginosa infection: report of a case. AB - The use of biological mesh for the treatment of synthetic mesh-related infections in patients who undergo ventral hernia repair has been considered over the past few years. Removal of the infected synthetic mesh, which may be required in such cases, can result in recurring herniation. Biological implants have thus been recently used for the reconstruction of the existing defect. We herein present the case of a patient who developed multidrug-resistant Pseudomonas aeruginosa synthetic mesh infection following hernia repair, which was managed by the removal of the material and the application of a biological mesh in the contaminated area. PMID- 21533950 TI - Simultaneous total gastrectomy and endovascular repair of an abdominal aortic aneurysm: report of a case. AB - We herein present the case of a 66-year-old man with both gastric cancer and an infrarenal abdominal aneurysm. The patient's medical history included bladder cancer, chronic renal failure, and ischemic heart disease. We performed a simultaneous endovascular aneurysm repair (EVAR) and total gastrectomy. Following the procedure, the patient remained in the intensive care unit for 3 days. Oral feeding was resumed on postoperative day 7, and the patient was discharged from the hospital on postoperative day 13 with no complications. Despite the patient's medical problems and higher operative risk, he tolerated simultaneous EVAR and total gastrectomy, and had a good outcome after undergoing these simultaneous procedures. PMID- 21533951 TI - Neonatal intestinal volvulus and preduodenal portal vein associated with situs ambiguus: report of a case. AB - Situs ambiguus is a rare lateralization anomaly that is frequently associated with other malformations, including preduodenal portal vein (PDPV), intestinal malrotation, and cardiovascular anomalies. This is a case report on a newborn that was clinically diagnosed with situs ambiguus and midgut volvulus. During surgery the patient was found to have intestinal malrotation, Meckel's diverticulum, and PDPV that was not a direct cause of duodenal obstruction. The patient was treated with Ladd's procedure and resection of Meckel's diverticulum. It is important to be familiar with the spectrum of situs anomalies to prevent trauma to the portal vein with serious complications during surgery. PMID- 21533952 TI - Intra-abdominal desmoid tumor mimicking locoregional recurrence after colectomy in a patient with sporadic colon cancer: report of a case. AB - Desmoid tumors are rare, benign fibromatous lesions that result from the abnormal proliferation of myofibroblasts. A 61-year-old man underwent laparoscopy-assisted right hemicolectomy for ascending colon cancer. The final TNM stage was stage IIIB (T3N1M0). Follow-up computed tomography (CT), done 12 months after primary surgery, showed a nodular, enhancing soft-tissue density mass, 12 mm in size, in the mesentery, near the anastomosis. Another CT scan, done 4 months later, revealed that the tumor had enlarged to 27 mm in size. We suspected locoregional recurrence of colon cancer and resected the tumor, together with the distal ileum and colon, including the previous anastomotic site. The tumor was histologically diagnosed as a desmoid tumor. The patient remains well 24 months after his last operation. Differentiating between the desmoid tumor and locoregional recurrent tumor was difficult, and surgical resection was the optimal treatment. PMID- 21533953 TI - Sigmoid colon perforation induced by the vascular type of Ehlers-Danlos syndrome: report of a case. AB - The vascular type of Ehlers-Danlos syndrome (vEDS) is a rare inherited disease of the connective tissues, and is caused by abnormal type III collagen resulting from heterogeneous mutations of the type III collagen COL3A1 gene. We herein report the case of a vEDS patient who developed a sigmoid colon perforation and was given a definitive diagnosis by a genetic and biomolecular assay. The patient demonstrated clinical manifestations caused by tissue weakness such as frequent pneumothorax events and a detached retina. During the operation, we noticed easy bruising and thin skin with visible veins on the patient's abdominal wall. Finally, a diagnosis was confirmed by the reduction of type III collagen synthesis and by the identification of a mutation in the gene for type III collagen. We conclude that it is difficult to diagnose a vEDS patient without clinical experiences and specialized genetic methods. Furthermore, all organs must be treated gently during therapy, because the tissues of vEDS patients are extremely fragile. PMID- 21533954 TI - Nonfunctioning pancreatic endocrine tumor with extension into the main pancreatic duct: report of a case. AB - Pancreatic endocrine tumors (PETs) rarely involve the main pancreatic duct. We report a case of malignant nonfunctioning pancreatic endocrine tumor (NFPET) with prevalent intraductal growth. A 47-year-old woman was referred to us after ultrasonography at a routine health check showed diffuse swelling of the pancreas. Preoperative imaging showed a solid mass in the tail of the pancreas and a bulging intraductal mass in the main pancreatic duct. We performed total pancreatectomy because the tumor occupied almost the entire lumen of the main pancreatic duct. Histological examination confirmed well-differentiated endocrine carcinoma. We review reported cases of the intraductal growth of NFPETs and discuss the pathogenesis of these unusual tumors. PMID- 21533955 TI - Isolated tuberculous liver abscess invading the abdominal wall: report of a case. AB - Isolated tuberculous liver parenchymal and subcapsular abscesses are unusual,^but an abdominal wall abscess secondary to a tubercular liver abscess is extremely rare. To our knowledge, there is only one reported case of an abdominal wall abscess occurring secondary to a subcapsular liver abscess. We report the first documented case of direct invasion of the abdominal wall from an isolated tuberculous liver parenchymal abscess, diagnosed by imaging, surgical, and pathological findings. Although ultrasonography and computed tomography showed nonspecific hypoechoic and hypodense findings with peripheral contrast enhancement, T2-weighted magnetic resonance imaging (MRI) revealed a heterogeneous mass with characteristic hypointensity, suggesting the presence of free radicals produced by macrophages during active phagocytosis in tuberculosis. Although our case is extremely unusual, when hypointensity on T2-weighted MRI is seen, the possibility of tuberculosis should be considered and the results of polymerase chain reaction, culture, and histopathological diagnosis must be taken into account to avoid needless invasive surgery. PMID- 21533956 TI - Fluctuations and symmetries in two-dimensional active gels. AB - Motivated by the unique physical properties of biological active matter, e.g., cytoskeletal dynamics in eukaryotic cells, we set up effective two-dimensional (2d) coarse-grained hydrodynamic equations for the dynamics of thin active gels with polar or nematic symmetries. We use the well-known three-dimensional (3d) descriptions (K. Kruse et al., Eur. Phys. J. E 16, 5 (2005); A. Basu et al., Eur. Phys. J. E 27, 149 (2008)) for thin active-gel samples confined between parallel plates with appropriate boundary conditions to derive the effective 2d constitutive relations between appropriate thermodynamic fluxes and generalised forces for small deviations from equilibrium. We consider three distinct cases, characterised by spatial symmetries and boundary conditions, and show how such considerations dictate the structure of the constitutive relations. We use these to study the linear instabilities, calculate the correlation functions and the diffusion constant of a small tagged particle, and elucidate their dependences on the activity or nonequilibrium drive. PMID- 21533957 TI - The coupled-cluster description of electronic structure: perspectives for bioinorganic chemistry. AB - This commentary provides an overview of the challenges and strengths of coupled cluster theory when applied to active sites of metalloproteins. It is argued that thanks to increases in computer power and remarkable methodological developments, coupled-cluster methods will make increasingly important contributions to understanding the structure, properties and reactivity of transition metal cofactors. PMID- 21533958 TI - Pseudoaneurysm of the hepatic artery. AB - INTRODUCTION: Hepatic artery pseudoaneurysms are a rare complication of biliary tract surgery and have an associated mortality that approaches 50%. CASE REPORT: A case of massive haemobilia caused by a hepatic artery pseudoaneurysm several months following laparoscopic cholecystectomy is described. DISCUSSION: It was successfully managed by angiographic embolisation, with the patient making a complete recovery. PMID- 21533959 TI - Clinically enlarged lateral pelvic lymph nodes do not influence prognosis after neoadjuvant therapy and TME in stage III rectal cancer. AB - PURPOSE: The significance of lateral pelvic lymph nodes (LPLN) in rectal cancer remains unclear. The purpose of this study was to determine the outcome of patients with LPLNs identified on pretherapy imaging who were treated with neoadjuvant therapy followed by proctectomy without LPLN dissection. METHODS: Pretherapy imaging of patients with stage III rectal cancer was reviewed to determine perirectal and LPLN enlargement. Data were collected on preoperative therapy, operative resection, adjuvant therapy, and patient outcomes and were correlated to the presence or absence of preoperatively identified LPLNs (LPLN+ and LPLN-). RESULTS: Of the 53 patients identified who were treated between 2000 and 2005, 30 (57%) were LPLN+ on preoperative imaging. All patients received preoperative radiation therapy and total mesorectal excision. The local recurrence was 13%, and there was no difference related to LPLN status. A comparison of the overall and disease-free survival in patients with and without enlarged LPLNs revealed no difference. CONCLUSIONS: The LPLNs that were identified on pretherapy imaging do not affect the overall or disease-free survival after the neoadjuvant therapy and proctectomy in stage III rectal cancer. A lateral pelvic lymph node dissection does not appear to be justified in stage III patients with LPLNs on pretherapy imaging who receive neoadjuvant therapy. PMID- 21533960 TI - Early growth response gene 1 regulates bone properties in mice. AB - Transcriptional regulation of the postnatal skeleton is incompletely understood. Here, we determined the consequence of loss of early growth response gene 1 (EGR 1) on bone properties. Analyses were performed on both the microscopic and molecular levels utilizing micro-computed tomography (micro-CT) and Fourier transform infrared imaging (FTIRI), respectively. Mice deficient in EGR-1 (Egr-1 (-/-)) were studied and compared to sex- and age-matched wild-type (wt) control animals. Femoral trabecular bone in male Egr-1 (-/-) mice demonstrated osteopenic characteristics marked by reductions in both bone volume fraction (BV/TV) and bone mineral density (BMD). Morphological analysis revealed fewer trabeculae in these animals. In contrast, female Egr-1 (-/-) animals had thinner trabeculae, but BV/TV and BMD were not significantly reduced. Analysis of femoral cortical bone at the mid-diaphysis did not show significant osteopenic characteristics but detected changes in cross-sectional geometry in both male and female Egr-1 (-/-) animals. Functionally, this resulted in decreased resistance to three-point bending as indicated by a reduction in maximum load, failure load, and stiffness. Assessment of compositional bone properties, including mineral-to-matrix ratio, carbonate-to-phosphate ratio, crystallinity, and cross-linking, in femurs by FTIRI did not show any significant differences or an appreciable trend between Egr-1 (-/-) and wt mice of either sex. Unexpectedly, rib bone from Egr-1 (-/-) animals displayed distinct osteopenic traits that were particularly pronounced in female mice. This study provides genetic evidence that both sex and skeletal site are critical determinants of EGR-1 activity in vivo and that its site-specific action may contribute to the mechanical properties of bone. PMID- 21533962 TI - The single interval adjustment matrix (SIAM) yes-no task: an empirical assessment using auditory and gustatory stimuli. AB - The SIAM yes-no task is an efficient bias-free adaptive procedure for estimating absolute thresholds, though it arguably requires further evaluation prior to its adoption into mainstream psychological research. We report two experiments undertaken in the auditory and gustatory modalities designed to assess the accuracy and efficiency of the SIAM method. In the first experiment, estimates of absolute thresholds for 1000-Hz tones obtained using a two-alternative forced choice adaptive procedure were compared to those obtained using both the SIAM yes no task and a modification of the SIAM task incorporating the method of free response, the SIAM-rapid. In Experiment 2, we compared absolute thresholds for sucrose in solution obtained with either a two-alternative forced choice adaptive procedure or the SIAM yes-no task. Both experiments demonstrated the efficiency and validity of the SIAM approach, with SIAM thresholds proving to be equivalent to those obtained in the two-alternative forced choice tasks and to those reported in the literature. PMID- 21533961 TI - A dose-dependent relationship between exposure to a street-based drug scene and health-related harms among people who use injection drugs. AB - While the community impacts of drug-related street disorder have been well described, lesser attention has been given to the potential health and social implications of drug scene exposure on street-involved people who use illicit drugs. Therefore, we sought to assess the impacts of exposure to a street-based drug scene among injection drug users (IDU) in a Canadian setting. Data were derived from a prospective cohort study known as the Vancouver Injection Drug Users Study. Four categories of drug scene exposure were defined based on the numbers of hours spent on the street each day. Three generalized estimating equation (GEE) logistic regression models were constructed to identify factors associated with varying levels of drug scene exposure (2-6, 6-15, over 15 hours) during the period of December 2005 to March 2009. Among our sample of 1,486 IDU, at baseline, a total of 314 (21%) fit the criteria for high drug scene exposure (>15 hours per day). In multivariate GEE analysis, factors significantly and independently associated with high exposure included: unstable housing (adjusted odds ratio [AOR] = 9.50; 95% confidence interval [CI], 6.36-14.20); daily crack use (AOR = 2.70; 95% CI, 2.07-3.52); encounters with police (AOR = 2.11; 95% CI, 1.62-2.75); and being a victim of violence (AOR = 1.49; 95 % CI, 1.14-1.95). Regular employment (AOR = 0.50; 95% CI, 0.38-0.65), and engagement with addiction treatment (AOR = 0.58; 95% CI, 0.45-0.75) were negatively associated with high exposure. Our findings indicate that drug scene exposure is associated with markers of vulnerability and higher intensity addiction. Intensity of drug scene exposure was associated with indicators of vulnerability to harm in a dose dependent fashion. These findings highlight opportunities for policy interventions to address exposure to street disorder in the areas of employment, housing, and addiction treatment. PMID- 21533963 TI - Relative adrenal insufficiency in the critical care setting: debunking the classic myth. AB - BACKGROUND: Classic teaching states that chronic adrenal insufficiency is associated with hyponatremia, hyperkalemia, hypercalcemia, hypoglycemia, and eosinophilia. We hypothesize that these diagnostic markers do not predict relative adrenal insufficiency (RAI) in the critically ill or injured patient. METHODS: Chart review of surgical, trauma, and medical patients admitted over 7 years to a critical care unit was performed to evaluate cortisol levels drawn for suspicion of RAI, which was defined as a cortisol concentration <25 mcg/dl. Laboratory parameters were defined as hyponatremia <135 mmol/l, hyperkalemia >5.3 mmol/l, hypercalcemia >2.55 mmol/l (10.2 mg/dl), hypoglycemia <3.89 mmol/l (70 mg/dl), and eosinophilia >5%. RESULTS: A total of 212 patients had cortisol levels drawn. Fifty-seven percent were male and their mean age was 59 years. Fifty-three percent had RAI. Average cortisol level was 30.5 MUg/dl. No significant differences were seen in mean potassium, sodium, calcium, or glucose levels between RAI and non-RAI patients. Few patients had laboratory values consistent with RAI. In fact, many with RAI had opposite findings: 75% had hypernatremia, 90% had hypokalemia, 100% had hypocalcemia, and 97% had hyperglycemia. Eosinophilia was statistically significant (P = 0.026). CONCLUSION: Hyponatremia, hyperkalemia, hypercalcemia, and hypoglycemia do not predominate in RAI and laboratory values are of minimal value in predicting patients with RAI. PMID- 21533964 TI - Laparoscopic simple closure alone is adequate for low risk patients with perforated peptic ulcer. AB - BACKGROUND: Helicobacter pylori (H.P.) eradication has led to a significant decline in peptic ulcer prevalence; however, the number of patients requiring surgical intervention remains relatively unchanged. Laparoscopy suture repair is the most commonly used procedure for perforated peptic ulcer (PPU). Whether omental patch adds any benefit than simple closure alone is not answered. METHODS: From July 2007 to August 2010, patients received emergency surgeries for PPU in our department were enrolled in this study. The demographic data, disease pattern, surgical outcomes were retrospectively collected. Patients who had previous multiple operations, with profound shock, and complicated ulcers were excluded. RESULTS: Totally 73 patients were enrolled. 26 of them received simple closure and the other 47 received simple closure plus an omental patch. There were no difference in age, gender, ASA, Boey risk score, and incidence of co morbidities. The Mannheim Peritonitis index, median operation time and length of stay were not different between groups. CONCLUSIONS: In terms of leakage rate and surgical outcome, the maneuver to cover an omental patch on the repaired PPU did not show additional advantages compared to simple closure alone. Further prospective randomized study is required to clarify the safety and feasibility of simple closure alone without buttressing an omentum patch. PMID- 21533966 TI - Feasibility and safety of total extraperitoneal inguinal hernia repair after previous lower abdominal surgery: a case-control study. AB - BACKGROUND: This study aimed to evaluate the feasibility and safety of totally extraperitoneal (TEP) endoscopic hernia surgery after previous lower abdominal surgery, which may preclude preperitoneal dissection. METHODS: All 331 consecutive patients undergoing TEP surgery between January 2008 and December 2010 were included in a prospective cohort study. This case-control study included a study group and a comparison group. The study group consisted of 23 patients with a history of previous lower abdominal surgery before undergoing TEP endoscopic hernia repair. For the comparison group, 46 patients were randomly selected (two for every patient in the study group) and matched with the study cohort in terms of age, gender, and laterality of inguinal hernia. Perioperative data were obtained for all the patients including demographic data, operation time, length of hospital stay, narcotic dose, conversions, and complications. RESULTS: A total of 69 patients with inguinal hernias underwent TEP surgery: 23 patients with previous abdominal surgery (study group) and 46 patients without such surgery (control group). No conversions were necessary in the control group, but one case (4.4%) in the study group was converted to transabdominal preperitoneal hernia repair (TAPP) (P = 0.33). Peritoneal injury requiring intracorporeal repair was encountered in six study group patients and eight control group patients (P = 0.53). No differences were observed between the two groups in terms of operative times, analgesic use, hospital stay, return to daily activities, or postoperative complications. CONCLUSIONS: In experienced hands, TEP hernia repair for patients with previous lower abdominal surgery can be performed safely. In this study, the operative outcomes were comparable with those for patients who had no history of lower abdominal surgery. PMID- 21533967 TI - Use of laparoscopy as an alternative to computed tomography (CT) and positron emission tomography (PET) scans for the detection of recurrence in patients with gastric cancer: a pilot study. AB - BACKGROUND: This study aimed to evaluate laparoscopy as a diagnostic method for detecting recurrence in patients with advanced gastric cancer. METHODS: Diagnostic laparoscopy was performed for 12 patients with insufficient evidence of intraabdominal gastric cancer recurrence by computed tomography or positron emission tomography. By comparing laparoscopic observations with conventional radiologic results, the diagnostic accuracy of laparoscopy was assessed. RESULTS: In 11 (92%) of 12 cases of recurrence not diagnosed by imaging studies, laparoscopic examination confirmed the case as a recurrence. Using diagnostic laparoscopy, retroperitoneal lymph node recurrence was confirmed in two patients, peritoneal seeding nodules in five patients, and recurrent masses invading the mesocolon in two patients. Two patients had no definitive recurrence grossly but were confirmed as recurrence cases by washing cytology during the laparoscopic procedure. One patient had a duodenal stump recurrence. No patients experienced operation-related morbidity. CONCLUSION: Laparoscopy is a safe and feasible method for detecting recurrence with acceptable accuracy. This approach provides more accurate information than conventional imaging methods. PMID- 21533968 TI - Late accidental dislodgement of a percutaneous endoscopic gastrostomy tube: an underestimated burden on patients and the health care system. AB - BACKGROUND: Since its introduction in 1980, the percutaneous endoscopic gastrostomy (PEG) tube has become an efficient means of providing long-term enteral access. Conveniently, the soft inner bumper allows PEG removal with relatively minimal external traction. Consequently, a major complication is accidental dislodgement, from which significant morbidity may occur. Clinicians have perhaps underestimated and underappreciated this complication, not only in the acute setting but over the lifetime of the PEG tube. METHODS: A retrospective analysis of PEG placements conducted at the authors' institution identified all PEG tubes placed between July 1, 2007 and July 1, 2010 by one faculty surgeon. Patient charts were reviewed for 30-day mortality, complications, and subsequent management. Patients were reviewed until intentional removal of the PEG, cessation of records, or patient mortality. RESULTS: A total of 563 PEGs were identified. The 30-day mortality rate was 7.8% (44/563), and the 7-day early accidental dislodgement rate was 4.1% (23/563). The total lifetime accidental PEG dislodgement rate was 12.8% (72/563). Of the 72 dislodged PEGs, 49 occurred after discharge from rehabilitation or nursing facilities. The vast majority required an emergency department visit, a level 3 surgical consultation, a replacement gastrostomy tube, and a radiographic confirmation of tube positioning, resulting in charges totaling an average of $1,200. CONCLUSION: Many large PEG reviews report an early accidental dislodgement rate of 0.6% to 4.0%. The most clinically significant accidental removals occur in the first 7 days after placement, and open gastrostomy may cause obvious morbidity. The early dislodgement rate in this study (4.1%) is consistent with those currently reported. However, if cases are followed longitudinally, a significantly higher rate of late dislodgement (12.8%) is seen. Frequently placed into neurologically impaired or elderly patients, the PEGs that dislodge months and years later require expensive management. The late removal complication and its associated costs are overlooked and underestimated. PMID- 21533969 TI - Mesh fixation compared to nonfixation in total extraperitoneal inguinal hernia repair: a randomized controlled trial in a rural center in India. AB - BACKGROUND: Several studies have shown that nonfixation of mesh in total extraperitoneal (TEP) inguinal hernia repair is safe and has no disadvantage compared to mesh fixation in terms of recurrence rate, pain scores, and other morbidity parameters. The aim of this study was to compare the effect of nonfixation of mesh with fixation in laparoscopic TEP inguinal hernia repair in a rural hospital in India. METHODS: One hundred four patients were randomized to mesh nonfixation group or a fixation group during TEP. The postoperative pain scores on a visual analog scale (VAS) at 24 h, 1 week, 1 month, and 1 year, urinary retention, seroma formation, length of hospital stay, days taken to resume normal activities, and recurrence after 2 years were analyzed. The trial was registered at www.clinicaltrials.gov (ID: NCT01117337). RESULTS: One hundred four patients (194 hernias) were randomized to mesh nonfixation or fixation. The pain scores at 24 h were comparable (Fix, 1.31 +/- 0.4; Nonfix, 1.42 +/- 0.5, P = 0.23). The length of hospital stay (Fix, 1.12 +/- 0.3 days; Nonfix, 1.15 +/- 0.4 days, P = 0.7) and days taken to resume normal activities (Fix, 7.77 +/- 1.3 days; Nonfix, 7.96 +/- 1.15 days, P = 0.44) were also similar for both groups. The mean pain scores at 1 week (Fix, 1.25 +/- 0.5; Nonfix, 1.34 +/- 0.6, P = 0.42), 1 month (Fix, 1.06 +/- 0.2; Nonfix, 1.17 +/- 0.4, P = 0.12), 1 year (Fix, 1.04 +/- 0.2; Nonfix, 1.13 +/- 0.4, P = 0.11), and 2 years (Fix, 1.03 +/- 0.2; Nonfix, 1.0, P = 0.17) were comparable for both groups. There was no recurrence in either group at a minimum follow-up of 2 years. CONCLUSIONS: There was no significant difference between fixation and nonfixation of mesh in TEP inguinal hernia repair with respect to postoperative pain, length of hospital stay, resumption of normal activities, seroma formation, and recurrence rate. Nonfixation of mesh is safe and recommended in TEP inguinal hernia repair when done by an experienced surgeon, even in a rural setting. The study highlights the potential for universal application of the procedure. PMID- 21533970 TI - Staged restorative proctocolectomy: laparoscopic or open completion proctectomy after laparoscopic subtotal colectomy? AB - BACKGROUND: The aim of this study was to compare outcomes of laparoscopic and open completion proctectomy (CP) and ileal-pouch anal anastomosis (IPAA) after a previous laparoscopic subtotal colectomy (STC). METHODS: From a prospectively maintained ileal pouch database, outcomes for patients who underwent laparoscopic CP after laparoscopic STC (LSTC-LCP group) for ulcerative or indeterminate colitis were compared to those for patients who underwent open CP (LSTC-OCP group). A control group of open CP after open STC (OSTC-OCP group) was case matched to LSTC-OCP at a ratio of 1:2 for age at surgery, gender, body mass index (BMI), year of operation, and American Society of Anesthesiologists (ASA) classification. Demographics, perioperative data, and pouch function were compared. Quality of life was evaluated using the Cleveland Global Quality of Life Scale (CGQL). RESULTS: Between 1997 and 2009, 47 patients underwent LSTC followed by LCP (LSTC-LCP), and 48 patients underwent OCP after LSTC (LSTC-OCP); the latter group was matched to 96 open-open patients (OSTC-OCP). There were no significant differences in demographic and preoperative data among the three groups, except that the OSTC-OCP group patients were younger. Postoperative morbidity, pouch function, and CGQL were similar. LSTC-LCP patients had lower estimated blood loss (EBL) (p < 0.001), less commonly described intraoperative adhesiolysis (p < 0.001), reduced length of hospital stay (LOS) (p = 0.002) but longer operating time (p = 0.001) at CP/IPAA when compared with open-open patients. For patients with previous LSTC, LCP was associated with less commonly described intraoperative adhesiolysis (p = 0.003) and shorter LOS (p = 0.003) than OCP but a longer operating time (p = 0.036). CONCLUSIONS: Laparoscopic CP and IPAA can be performed with safety comparable to that of open surgery after previous laparoscopic STC. The laparoscopic approach is associated with advantages including reduced intraoperative blood loss and earlier recovery as demonstrated by shorter length of hospital stay. PMID- 21533971 TI - Laparoendoscopic single-site liver resection: a preliminary report of 12 cases. AB - BACKGROUND: Laparoendoscopic single-site (LESS) surgery is an emerging laparoscopic procedure previously used for cholecystectomy and appendectomy. However, few studies have examined LESS liver resection, and its benefits require investigation. This study aimed to evaluate the feasibility and safety of LESS liver resection. METHODS: From December 2009 to October 2010, 12 patients were selected for LESS liver resection with institutional review board approval. The LESS technique was performed using a transumbilical TriPort or three 5-mm trocars with a 5-mm linear or flexible laparoscope. Conventional or articulating laparoscopic instruments were used to mobilize and transect the lesions. RESULTS: The LESS liver resection procedure was successfully completed for 10 patients (83.3%), with the remaining 2 patients (16.7%) undergoing conversion to conventional multiport laparoscopy. The procedures consisted of left lateral segment resection (n = 4) and partial resection (n = 8) in addition to concomitant cholecystectomy (n = 3). The mean operative time was 80.4 min (range, 35-160 min), and the mean estimated blood loss was 45 ml (range, 20-800 min). No postoperative complications were noted except for biliary leakage (200 ml/day)in one patient. The mean hospital stay was 4.3 days (range, 2-8 days). No patient required postoperative analgesia, and the pain visual analog score 48 h after surgery was 0.53 (range, 0-2). Pathology identified 10 benign and 2 malignant liver tumors with a clear margin. CONCLUSIONS: Our preliminary data show that LESS liver resection is safe and feasible for selected patients, with potential benefits that include a fast recovery, light pain, and cosmetically acceptable scarring. However, this procedure requires advanced instruments and complicated laparoscopic techniques, with a risk of intraoperative bleeding and postoperative bile leakage. PMID- 21533972 TI - A novel flexible endoluminal stapling device for use in NOTES colotomy closure: a feasibility study using an ex vivo porcine model. AB - BACKGROUND: With advances in endoscopic diagnosis of early-stage gastrointestinal pathology, the need to offer minimally invasive treatment is attracting significant interest. It is essential that secure and consistent closure of full thickness colonic resections and colotomy access be provided in natural orifice translumenal surgery (NOTES). This ex vivo porcine study aimed to evaluate a novel prototype flexible endoscopic stapler device for use in closure of full thickness colonic defects. METHODS: A feasibility study using ex vivo porcine colon was undertaken to explore the potential of the prototype stapler to close and seal a colotomy. A standardized linear colotomy was created in 30 colons. The novel flexible endostapler was used to close 20, interrupted hand-sewn sutures to close 5, and a well-validated linear stapler to close 5 of these colotomies. The colons were subsequently subjected to leak pressure testing. RESULTS: The colotomy closure using the prototype stapler endoluminally required a median time of 280 s. No statistically significant difference in leak pressures between the stapler and the other techniques was described. Although the endostapler without any colotomy was found to have the highest median leak pressures and the interrupted sutures the lowest pressures, no significant difference could be demonstrated (p = 0.52). Furthermore, no significant difference was demonstrated when the closure integrity created by the flexible stapler was compared with that created by the well-validated linear stapler. CONCLUSION: The results suggest that the flexible endoscopic stapler is an effective device for the safe closure of a visceral defect, which in this feasibility study was equivalent to other well-established techniques. Further studies will focus on in vivo application of the prototype stapling device in the setting of full-thickness colonic resection. PMID- 21533973 TI - A new variable-view rigid endoscope evaluated in advanced gynecologic laparoscopy: a pilot study. AB - BACKGROUND: This pilot study aimed to evaluate the optical performance and clinical handling of a new variable-view rigid endoscope with angulation from 0 o to 120 o in gynecologic laparoscopic surgery. METHODS: The EndoCAMeleon endoscope was assessed by experienced surgeons and assistants during a variety of advanced gynecologic laparoscopic procedures. After each procedure, both the surgeon and the assistant each completed questionnaires designed to assess the endoscope's ease of handling and optical performance. RESULTS: The endoscope was assessed during 21 advanced procedures. Questionnaire responses confirmed surgeon and assistant satisfaction with the mechanical handling and vision provided by the endoscope. In particular, the ability to vary the viewing angles enabled the surgeon to visualize the surgical site without moving the endoscope shaft. CONCLUSIONS: The new endoscope performed well in the hands of experienced surgeons and assistants undertaking advanced procedures. The variable-view rigid endoscope allows the use of visual ports during primary port entry and enhances vision. Further study is required to evaluate its performance in routine practice. PMID- 21533974 TI - Single-incision laparoscopic transabdominal preperitoneal herniorrhaphy for recurrent inguinal hernias: preliminary surgical results. AB - BACKGROUND: Since the early 1990s, laparoscopy has provided surgeons with new and innovative ways to treat various surgical problems. Many of these minimally invasive techniques have gained universal acceptance by demonstrating improved patient outcomes. Single-incision laparoscopic surgery (SILS) was developed with the aim of reducing the invasiveness of traditional laparoscopy. Laparoscopic transabdominal preperitoneal (TAPP) herniorrhaphy via the three-trocar technique is widely used for recurrent inguinal hernia. To the author's knowledge, this report describes first series of SILS TAPP for recurrent inguinal hernia repair. METHODS: From April 2009 to March 2010, 15 single-incision laparoscopic TAPP repairs of recurrent inguinal hernia were performed by the same surgical team. The data collected prospectively included patient demographics, type of hernia, operative time, complications, postoperative hospital stay, and recurrence. The umbilicus was the sole point of entry for all patients using a single port, and the same operative technique was used in all cases. RESULTS: The SILS TAPP procedure was performed successfully for all the patients, and none required conversion to an open procedure or a conventional laparoscopic hernia repair by the addition of more entry ports. The mean operative time was 51 +/- 17 min. No intra- or postoperative complications were recorded. There was no evidence of early recurrence during a mean follow-up period of 130 +/- 77 days. CONCLUSION: Based on this experience, the author believes that SILS approach is technically feasible and safe using standard and slightly modified instruments for standard TAPP. The cosmetic benefit is clear, but the advantages of SILS TAPP over conventional laparoscopic surgery during long-term follow-up evaluation will require further randomized clinical trials. PMID- 21533976 TI - Laparoscopic total mesorectal excision following long course chemoradiotherapy for locally advanced rectal cancer. AB - PURPOSE: Laparoscopic total mesorectal excision (TME) of locally advanced rectal cancer after long-course chemoradiotherapy (LCRT) is surgically and oncologically challenging. We have assessed the feasibility, timing, and short-term oncological outcome of laparoscopic TME after LCRT. METHODS: Between 2004 and 2006, 30 patients were selected for LCRT based on clinical examination and MRI. Patients received 3/4 field radiotherapy, 45-50.4 Gy in 25-28 fractions during 5 weeks with either 5-fluorouracil or Uftoral. Clinical assessments were made 4 weeks after completion of radiotherapy and then 2 weekly with sequential 4 weekly MRI, to individualize the timing of surgery at maximal response. Laparoscopic TME was performed using a standard technique. RESULTS: Thirty patients received LCRT and 26 patients (21 men; median age, 63 years) underwent laparoscopic TME at 11 weeks (median) after LCRT. Median operating time was 270 min. Sixteen patients had LAR and ten had APR. There were three conversions. Three patients developed anastomotic leak (18.7%): one was managed conservatively and one patient died of septicemia. Morbidity was seen in 19% of patients. There were 25 (96%) R0 resections with a complete response in 5 (19%) cases and microscopic tumor in lakes of mucin (Tmic) in another 6 (23%). Two patients (7.6%) developed local recurrence (median follow up, 34 months). The median time interval between radiotherapy and surgery was 11 (range, 7-13) weeks, which was based on serial MRI scans after LCRT. CONCLUSIONS: Laparoscopic TME after LCRT is feasible and safe both oncologically and surgically. Serial MRI helps to determine the optimum timing of surgery. PMID- 21533977 TI - Cardiac resynchronization therapy: the issue of non-response. AB - Cardiac resynchronization therapy reduces mortality and morbidity in heart failure patients with wide QRS and severe impairment of left ventricular systolic function, who are symptomatic despite optimal medical therapy. However, a high percentage of patients fail to show clinical or echocardiographic response to this treatment. Beyond current selection criteria, other elements, such as QRS duration and morphology, concomitant medical therapy, degree of right ventricle dysfunction, myocardial viability, presence of left ventricular dyssynchrony, and associated renal dysfunction, play a crucial role in modulating the response to cardiac resynchronization. Consequently, they should be part of the standard pre implant evaluation, as they could be used to identify patients who are very unlikely to be responders. PMID- 21533978 TI - Spatial distribution of polycyclic aromatic hydrocarbons from Lake Taihu, China. AB - A total of 30 sediments, overlying water and porewater samples were collected from Lake Taihu, China for the analysis of PAHs. The total PAHs varied from 209 to 3,843 ng g-1 in sediments, from 238 to 7,422 ng L-1 in overlying water and from 2,012 to 19,899 ng L-1 in porewater, respectively. There are good correlations between sediment-porewater/sediment-overlying water partition coefficients and PAHs' logKow values, with correlation coefficient of 0.94 and 0.95, respectively. The sediment PAHs in Lake Taihu originated from both pyrolytic and petrogenic sources, showing a mixed input pattern. Based on the numerical effect-based sediment quality guidelines of the United States, the sediments from Lake Taihu causing adverse effects by PAHs should have potential biological impact, but should have no impairment. PMID- 21533979 TI - Dissipation study of difenoconazole in/on chili fruit and soil in India. AB - One field experiment was conducted with Difenoconazole (25% EC) on chili crop during December 2009 to January 2010 at two different locations of West Bengal and Maharashtra. The main objective was to understand the residue and persistence behaviour of fungicide difenoconazole in chili fruit and soil samples. Difenoconazole was applied in chili field at 50 mL and 100 mL/100 liter of water. Its residue was analyzed by using LC-MS/MS and it dissipated in chili fruit and soil following first order kinetics. The half life values of difenoconazole were found in the range 2.15-2.32 days and 4.68-8.09 days for chili fruit and soil, respectively. PMID- 21533980 TI - Impaired Rho GTPase activation abrogates cell polarization and migration in macrophages with defective lipolysis. AB - Infiltration of monocytes and macrophages into the site of inflammation is critical in the progression of inflammatory diseases such as atherosclerosis. Cell migration is dependent on the continuous organization of the actin cytoskeleton, which is regulated by members of the small Rho GTPase family (RhoA, Cdc42, Rac) that are also important for the regulation of signal transduction pathways. We have recently reported on reduced plaque formation in an atherosclerotic mouse model transplanted with bone marrow from adipose triglyceride lipase-deficient (Atgl-/-) mice. Here we provide evidence that defective lipolysis in macrophages lacking ATGL, the major enzyme responsible for triacylglycerol hydrolysis, favors an anti-inflammatory M2-like macrophage phenotype. Our data implicate an as yet unrecognized principle that insufficient lipolysis influences macrophage polarization and actin polymerization, resulting in impaired macrophage migration. Sustained phosphorylation of focal adhesion kinase [due to inactivation of its phosphatase by elevated levels of reactive oxygen species (ROS)] results in defective Cdc42, Rac1 and RhoA activation and in increased and sustained activation of Rac2. Inhibition of ROS production restores the migratory capacity of Atgl-/- macrophages. Since monocyte and macrophage migration are a prerequisite for infiltrating the arterial wall, our results provide a molecular link between lipolysis and the development of atherosclerosis. PMID- 21533981 TI - Acid sphingomyelinase in macrophage biology. AB - Macrophages play a central role in innate immune responses, in disposal of cholesterol, and in tissue homeostasis and remodeling. To perform these vital functions macrophages display high endosomal/lysosomal activities. Recent studies have highlighted that acid sphingomyelinase (ASMase), which generates ceramide from sphingomyelin, is involved in modulation of membrane structures and signal transduction in addition to its metabolic role in the lysosome. In this review, we bring together studies on ASMase, its different forms and locations that are necessary for the macrophage to accomplish its diverse functions. We also address the importance of ASMase to several disease processes that are mediated by activated macrophages. PMID- 21533984 TI - Dermaplaning, topical oxygen, and photodynamic therapy: a systematic review of the literature. AB - BACKGROUND: Noninvasive procedures for facial rejuvenation are becoming an increasingly popular component of a comprehensive skin care regimen. Concurrently, many new treatment methods are now available to both the plastic surgeon and the aesthetician. Because these techniques have become an integral part of many cosmetic practices, this study aimed to assess the existing evidence based literature as to their clinical efficacy; to provide an objective overview of some of the most popular noninvasive rejuvenation strategies such as dermaplaning, oxygen therapy, and light therapy; to discuss recent pertinent scientific evidence-based literature; and to provide treatment recommendations based on these findings. METHODS: A systematic review was performed in August 2009 using PubMed and the following keywords: "dermaplaning," "oxygen therapy," and "light therapy." All peer-reviewed articles then were screened independently by three plastic surgeons. RESULTS: The search identified 42 English-written, peer-reviewed manuscripts. The overall amount of scientific data supporting these methods was found to be scarce, anecdotal, and not well documented. Nevertheless, all three noninvasive therapies have become increasingly popular in the cosmetic market because many patients and physicians or surgeons report being pleased with their results. CONCLUSION: Although the evidence supporting these nonsurgical methods is suboptimal, their uses continue to expand. As with any plastic surgery procedure, providing patients with realistic expectations is essential to achieving optimal outcomes and patient satisfaction. Therefore, critical investigation is warranted. In addition, these methods are most effective when included within a comprehensive skin care regimen consisting of sunscreen, vitamin therapy, and lifestyle modification. PMID- 21533985 TI - Treatment protocol for "Mestizo nose" with open rhinoplasty. AB - BACKGROUND: The aim of this study was to develop an operative sequence to guide plastic surgeons on how to handle the challenges of "Mestizo nose" during rhinoplasty. This type of nose has characteristics quite different from the Caucasian nose. Rhinoplasties on Mestizo nose represent a surgical challenge because of the anatomical characteristics of a weak frame and thick skin. The Hispanic population has grown, and nowadays a large number of patients requesting rhinoplasty within the US belong to this ethnic group. METHODS: We have developed an operative sequence for the treatment of Mestizo nose. This operative sequence has been tested in 879 rhinoplasties (92.37% females and 7.62% males, aged 15-63 years, mean age = 39 years). All were primary cases. An algorithm on how to approach the different types of Mestizo nose is presented. RESULTS: We had overall good results using our algorithm, with an improvement in the nasal aesthetics of about 54.75%. Complications were postoperative bleeding (1.37%), pain (0.57%), septal hematoma (0.23%), unaesthetic scars (0.34%), and cartilage extrusion (0.11%). Our revision rate was 5%. We present ten complete cases to show our surgical results. CONCLUSION: This operative sequence has allowed us to get predictable and reliable surgical outcomes when used in Mestizo rhinoplasty operations. We think it can be very useful for every plastic surgeon who performs Mestizo nose rhinoplasty, although not all steps need to be performed in every case. PMID- 21533983 TI - Highly reactive oxygen species: detection, formation, and possible functions. AB - The so-called reactive oxygen species (ROS) are defined as oxygen-containing species that are more reactive than O(2) itself, which include hydrogen peroxide and superoxide. Although these are quite stable, they may be converted in the presence of transition metal ions, such as Fe(II), to the highly reactive oxygen species (hROS). hROS may exist as free hydroxyl radicals (HO.), as bound ("crypto") radicals or as Fe(IV)-oxo (ferryl) species and the somewhat less reactive, non-radical species, singlet oxygen. This review outlines the processes by which hROS may be formed, their damaging potential, and the evidence that they might have signaling functions. Since our understanding of the formation and actions of hROS depends on reliable procedures for their detection, particular attention is given to procedures for hROS detection and quantitation and their applicability to in vivo studies. PMID- 21533986 TI - Management of delayed capsular hematoma after breast reconstruction. AB - Delayed hematoma associated with breast implants, whether for reconstructive or aesthetic purposes, is a rare entity. Most reported cases have been intracapsular. Although several mechanisms for delayed hematoma have been proposed, its exact etiology and mechanism of formation are not yet fully understood. The authors present a unique case of hematoma formation 5 years after breast reconstruction with a textured anatomic cohesive gel breast implant. The patient experienced severe thrombocytopenia secondary to chemotherapy, which most probably was the triggering etiologic factor. The hematoma was both intra- and extracapsular. The authors speculate that the retrocapsular hematoma component was due to firm adhesion of the textured prosthetic membrane to the posterior capsule and propose that for breast reconstruction with prosthetic implants in patients likely to receive chemotherapy, a smooth implant might be better indicated. PMID- 21533982 TI - ATM protein kinase: the linchpin of cellular defenses to stress. AB - ATM is the most significant molecule involved in monitoring the genomic integrity of the cell. Any damage done to DNA relentlessly challenges the cellular machinery involved in recognition, processing and repair of these insults. ATM kinase is activated early to detect and signal lesions in DNA, arrest the cell cycle, establish DNA repair signaling and faithfully restore the damaged chromatin. ATM activation plays an important role as a barrier to tumorigenesis, metabolic syndrome and neurodegeneration. Therefore, studies of ATM-dependent DNA damage signaling pathways hold promise for treatment of a variety of debilitating diseases through the development of new therapeutics capable of modulating cellular responses to stress. In this review, we have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying the complex phenotypes observed in AT patients. PMID- 21533987 TI - Molecular and cytological characterization of repetitive DNA sequences from the centromeric heterochromatin of Sciara coprophila. AB - Sciara coprophila (Diptera, Nematocera) constitutes a classic model to analyze unusual chromosome behavior such as the somatic elimination of paternal X chromosomes, the elimination of the whole paternal, plus non-disjunction of the maternal X chromosome at male meiosis. The molecular organization of the heterochromatin in S. coprophila is mostly unknown except for the ribosomal DNA located in the X chromosome pericentromeric heterochromatin. The characterization of the centromeric regions, thus, is an essential and required step for the establishment of S. coprophila as a model system to study fundamental mechanisms of chromosome segregation. To accomplish such a study, heterochromatic sections of the X chromosome centromeric region from salivary glands polytene chromosomes were microdissected and microcloned. Here, we report the identification and characterization of two tandem repeated DNA sequences from the pericentromeric region of the X chromosome, a pericentromeric RTE element and an AT-rich centromeric satellite. These sequences will be important tools for the cloning of S. coprophila centromeric heterochromatin using libraries of large genomic clones. PMID- 21533988 TI - Selective GABA release as a mechanistic basis of high-frequency stimulation used for the treatment of neuropsychiatric diseases. AB - Electrical high-frequency stimulation (HFS) is applied in many brain areas to treat various clinical syndromes. The nearly identical constellation of stimulation parameters raises the question of a unique mechanism of action of this therapeutic option. The identification of a single HFS mechanism may help to optimize the HFS technology by targeting this single mechanism. Experimentally, only axonal membranes are targets of HFS, but not other membranes of neurons or glial cells. Within all HFS target regions, axons of excitatory glutamatergic and inhibitory GABAergic neurons are present and play roles in all clinical syndromes treated successfully with HFS. Therefore, glutamatergic or GABAergic fibres are likely candidates as mediators of a unique HFS mode of action. The selective involvement of another neuronal fibre type (e.g. monoaminergic, cholinergic, etc.) in the HFS mode of action is highly unlikely since the regional and syndromal dissimilarity of the clinical HFS applications precludes the assumption of such a fibre type as primary HFS site of action. Our recent experimental finding that HFS of human neocortical slices induces the action potential mediated release of GABA, but not of glutamate, simplifies the possibilities to explain the HFS mode of action, as the explanation now may concentrate on GABAergic axons only. Thus, we are analysing, on the basis of the pathophysiological grounds of the various syndromes treated with deep brain stimulation, whether a selective GABA release is a collective explanation of the mode of action of HFS. We suggest that selective GABA release indeed may needfully and sufficiently explain efficacy and side effects of HFS. PMID- 21533989 TI - An ethanolic extract of Lindera obtusiloba stems causes NO-mediated endothelium dependent relaxations in rat aortic rings and prevents angiotensin II-induced hypertension and endothelial dysfunction in rats. AB - Lindera obtusiloba is a medical herb traditionally used in Asia for the improvement of blood circulation, treatment of inflammation, and prevention of liver damage. The possibility that L. obtusiloba affects vascular reactivity remains to be examined. Therefore, the aim of the present study was to evaluate both the in vitro and in vivo vascular effects of an ethanolic extract of L. obtusiloba stems (LOE). Vascular reactivity was assessed in organ chambers using rat aortic rings and the activation of endothelial NO synthase (eNOS) in cultured bovine aortic endothelial cells. LOE induced endothelium-dependent relaxations, which were abolished by inhibitors of nitric oxide synthase (N (omega)-nitro-L: arginine) and guanylyl cyclase (1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-L-one), significantly reduced by inhibitors of PI3 kinase (wortmannin and LY294002), and not affected by inhibitors of cyclooxygenase (indomethacin) and endothelium derived hyperpolarizing factor-mediated responses (charybdotoxin plus apamin). LOE prevented contractile responses to phenylephrine and angiotensin II in rings with endothelium, but not in those without endothelium. LOE caused a concentration-dependent phosphorylation of Akt at Serine473 and eNOS at Serine1177 in endothelial cells. Thereafter, the vasoprotective effect of LOE was investigated in an experimental model of hypertension in rats. Intake of LOE prevented the angiotensin II-induced increase in systolic blood pressure, and endothelial dysfunction to acetylcholine and oxidative stress as assessed using dihydroethidine in aortic rings. The present findings indicate that LOE has vasoprotective and antihypertensive properties most likely by stimulating the endothelial formation of NO and inhibiting oxidative stress. PMID- 21533990 TI - Neuroprotective mechanisms of SMTP-7 in cerebral infarction model in mice. AB - Reactive oxygen species (ROS) formation has been found to induce the brain damage following stroke-like events. The aim of the present study was to investigate the effect of Stachybotrys microspora triprenyl phenol-7 (SMTP-7) on the generation of ROS in ischemia-induced cerebral infarction model and in vitro lipid peroxidation. We used immunohistochemistry and real-time reverse-transcription PCR for ex vivo evaluation and thiobarbituric acid-reactive substance reagent assay for in vitro evaluation. We demonstrated that SMTP-7 did not induce enhancement of 4-hydroxynonenal or neutrophil cytosolic factor 2 like t-PA administration at 3 h after ischemia ex vivo and reduce lipid peroxidation in vitro. This compound is the first low molecular weight compound with triplet activities of thrombolytic, anti-inflammatory, and antioxidant activities. We theorized that SMTP-7 is among the pharmacological agents that reduce ROS formation and have been found to limit the extent of brain damage following stroke-like events. PMID- 21533991 TI - Effects of the dopamine stabilizers (S)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats. AB - Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus alpha-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion. PMID- 21533992 TI - MEK inhibition suppresses the development of lung fibrosis in the bleomycin model. AB - The extracellular signal-regulated kinase (ERK) cascade has long been known to be central to the activation of cellular processes such as proliferation, differentiation, and oncogenic transformation. The mitogen-activated protein (MAP) serine/threonine family of protein kinases, of which ERK is a member, is activated by a mechanism that includes protein kinase cascades. Mitogen-activated protein kinases (MAPKs) are well-conserved enzymes connecting cell surface receptors to intracellular regulatory targets; they are activated in response to a wide variety of stimuli. The aim of this study was to investigate the effects of PD98059, a highly selective inhibitor of MAP/ERK kinase1 (MEK1) activation, on the development of lung inflammation and fibrosis. Lung injury was induced by intratracheal instillation of bleomycin (1 mg/kg), and PD98059 (10 mg/kg, 10% dimethyl sulfoxide, i.p.) was administrated 1 h after bleomycin instillation and daily for 7 days. PD98059 treatment shows therapeutic effects on pulmonary damage, decreasing many inflammatory and apoptotic parameters, such as (1) cytokine production; (2) IkBalpha degradation and NF-kB nuclear translocation; (3) iNOS expression; (4) nitrotyrosine and PAR localization; and (5) the degree of apoptosis, as evaluated by Bax and Bcl-2 balance, FAS ligand expression, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. In particular, to assess whether PD98059 treatment influences MAPKs pathway, we have also investigated the expression of activated ERK and JNK after bleomycin-induced pulmonary fibrosis, showing that the inhibition of the cascade reduces the inflammatory processes that lead to the appearance of the fibrosis. Taken together, all our results clearly show that PD98059 reduces the lung injury and inflammation due to the intratracheal bleomycin administration in mice. PMID- 21533993 TI - Effects of antiepileptic drugs on GABA release from rat and human neocortical synaptosomes. AB - In epilepsy, allegedly, a neurotransmitter imbalance between the inhibitory GABA and the excitatory glutamate prevails. Therefore, some antiepileptic drugs (AEDs) are thought to increase GABA release. Because little is known about corresponding presynaptic effects of AEDs in the human brain, this study investigated the effects of carbamazepine, lamotrigine, phenytoin, gabapentin, pregabalin, levetiracetam, and valproate on (3)H-GABA release from human neocortical synaptosomes preincubated with (3)H-GABA. To obtain information on possible species differences, rat neocortical synaptosomes were investigated concomitantly. Release was evoked by either veratridine (1, 3.2, or 10 MUM), which prevents activated voltage-dependent Na(+) channels from closing, or elevation of extracellular [K(+)] from 3 to 15 mM. The exocytosis inhibitor tetanus toxin (TeT) or withdrawal of buffer Ca(2+) (Ca (e) (2+) ) reduced K(+) evoked release in both species, while blockade of Na(+) channels with tetrodotoxin had no effect. K(+)-evoked release was characterized as predominant, Ca(2+)-dependent and Na(+)-independent, exocytosis. Carbamazepine and phenytoin in the rat and carbamazepine, phenytoin, lamotrigine, and valproate in human tissue reduced K(+)-evoked (3)H-GABA release. With respect to veratridine-evoked release, Ca (e) (2+) withdrawal did not reduce release in the rat; it even increased the release in human tissue. TeT was slightly inhibitory in the rat. Blockade of GABA transport diminished veratridine-evoked (3)H-GABA release in either species. This release was characterized as mediated mainly by transporter reversal. Carbamazepine, lamotrigine, and phenytoin in rat tissue and carbamazepine and phenytoin in human decreased veratridine-induced (3)H-GABA release. Interestingly, no AED increased (3)H-GABA release. The reduction by AEDs of veratridine-evoked release was more intense than that of K(+)-evoked release. In conclusion, reduction of GABA release by AEDs may be the actual objective in a pathologically altered neuronal network where GABA acts in a depolarizing fashion. PMID- 21533994 TI - Characterization of Nme6-like gene/protein from marine sponge Suberites domuncula. AB - Nucleoside diphosphate kinases (NDPKs) are evolutionarily conserved enzymes involved in many biological processes such as metastasis, proliferation, development, differentiation, ciliary functions, vesicle transport and apoptosis in vertebrates. Biochemical mechanisms of these processes are still largely unknown. Sponges (Porifera) are simple metazoans without tissues, closest to the common ancestor of all animals. They changed little during evolution and probably provide the best insight into the metazoan ancestors' genomic features. The purpose of this study was to address structural and functional properties of group II Nme6 gene/protein ortholog from the marine sponge Suberites domuncula, Nme6, in order to elucidate its evolutionary history. Sponge Nme6 gene and promoter were sequenced and analysed with various bioinformatical tools. Nme6 and Nme6Delta31 proteins were produced in E. coli strain BL21 and NDPK activity was measured using a coupled pyruvate kinase-lactate dehydrogenase assay. Subcellular localization in human tumour cells was examined by confocal scanning microscopy. Our results show that the sponge Nme6 compared to human Nme6 does not possess NDPK activity, does not localize in mitochondria at least in human cells although it has a putative mitochondrial signal sequence, lacks two recent introns that comprise miRNAs and have different transcriptional binding sites in the promoter region. Therefore, we conclude that the structure of Nme6 gene has changed during metazoan evolution possibly in correlation with the function of the protein. PMID- 21533995 TI - Inhibition of catechol-O-methyltransferase modifies acute homocysteine rise during repeated levodopa application in patients with Parkinson's disease. AB - Elevation of plasma total homocysteine concentrations were observed in levodopa/dopa decarboxylase inhibitor (DDI)-treated patients with Parkinson's disease (PD). Degradation of levodopa to 3-O-methyldopa via the enzyme catechol-O methyltransferase (COMT) is a methyl group demanding reaction. It generates homocysteine from the methyl group donor methionine. But there are inconsistent outcomes, as most investigators determined homocysteine after an overnight washout of levodopa. They did not consider the acute effects of levodopa/DDI intake in relation with COMT inhibition on homocysteine bioavailability. The purpose of this study is to measure levels of homocysteine, levodopa, and its metabolite 3-O-methyldopa in plasma after reiterated oral levodopa/DDI administration with and without the COMT-inhibitor entacapone (EN). Sixteen PD patients received 100 mg levodopa/carbidopa three times on day 1 and with EN on day 2 under standardized conditions. Homocysteine concentrations increased on day 1 and generally over the whole interval. No significant ascent of homocysteine appeared on day 2 only. Levodopa bioavailability was higher on day 2 due to the COMT inhibition. No change of 3-O-methyldopa appeared between both days. The correlation coefficients between homocysteine, levodopa, and 3-O-methyldopa were higher on day 1 than on day 2. Rise of homocysteine does not only depend on the oral levodopa dose, but also on the acute intake of levodopa/DDI with or without COMT inhibition. Measurements of homocysteine should consider acute repeated levodopa/DDI applications, as homocysteine and metabolically related 3-O methyldopa accumulate due to their long plasma half-life in contrast to short living levodopa. PMID- 21533996 TI - Inhibition of 1,4-butanediol metabolism in human liver in vitro. AB - The conversion of 1,4-butanediol (1,4-BD) to gamma-hydroxybutyric acid (GHB), a drug of abuse, is most probably catalyzed by alcohol dehydrogenase, and potentially by aldehyde dehydrogenase. The purpose of this study was to investigate the degradation of 1,4-BD in cytosolic supernatant of human liver in vitro, and to verify involvement of the suggested enzymes by means of gas chromatography-mass spectrometry. The coingestion of 1,4-BD and ethanol (EtOH) might cause complex pharmacokinetic interactions in humans. Therefore, the effect of EtOH on 1,4-BD metabolism by human liver was examined in vitro. Additionally, the influence of acetaldehyde (AL), which might inhibit the second step of 1,4-BD degradation, was investigated. In case of a 1,4-BD intoxication, the alcohol dehydrogenase inhibitor fomepizole (4-methylpyrazole, FOM) has been discussed as an antidote preventing the formation of the central nervous system depressing GHB. Besides FOM, we tested pyrazole, disulfiram, and cimetidine as possible inhibitors of the formation of GHB from 1,4-BD catalyzed by human liver enzymes in vitro. The conversion of 1,4-BD to GHB was inhibited competitively by EtOH with an apparent K(i) of 0.56 mM. Therefore, the coingestion of 1,4-BD and EtOH might increase the concentrations and the effects of 1,4-BD itself. By contrast AL accelerated the formation of GHB. All antidotes showed the ability to inhibit the formation of GHB. In comparison FOM showed the highest inhibitory effectiveness. Furthermore, the results confirm strong involvement of ADH in 1,4 BD metabolism by human liver. PMID- 21533997 TI - Dome osteotomy of the pelvis using a modified trochanteric osteotomy for acetabular dysplasia. AB - PURPOSE: Kawamura described his dome osteotomy of the pelvis using a standard trochanteric osteotomy. Here we present results of our modification of Kawamura's dome osteotomy using a modified trochanteric osteotomy. METHODS: We retrospectively analysed 34 out of 36 patients operated upon between 1993 and 2008. We reviewed the mid-term functional and radiological results with a mean follow-up of 67 months. There were 23 females and 11 males with a mean age of 30 years. RESULTS: The mean Harris hip score improved from 60 to 85 (p < 0.05) at the final follow-up. The functional results were excellent in 12, good in 14, fair in five and poor in three patients. Pain relief was a constant feature in all patients. Seventeen patients reported improvement in their ability to squat and sit cross-legged, 14 patients reported no change while three reported a worsening. Preoperatively 28 patients had an antalgic gait which improved in 14 patients following the surgery. Centre edge angle, acetabular angle, acetabular head index and weight bearing joint space improved significantly. This improved joint space was maintained at the last follow-up. Three cases had converted to total hip arthroplasty at the last follow-up. CONCLUSION: The mid-term functional and radiological results of the dome osteotomy using modified trochanteric osteotomy were found to be satisfactory. We conclude that it is a reasonable treatment option for young patients with symptomatic acetabular dysplasia. PMID- 21533998 TI - Poly(glycerol adipate-co-omega-pentadecalactone) spray-dried microparticles as sustained release carriers for pulmonary delivery. AB - PURPOSE: The aim of this work was to optimize biodegradable polyester poly(glycerol adipate-co-omega-pentadecalactone), PGA-co-PDL, microparticles as sustained release (SR) carriers for pulmonary drug delivery. METHODS: Microparticles were produced by spray drying directly from double emulsion with and without dispersibility enhancers ((L)-arginine and (L)-leucine) (0.5-1.5%w/w) using sodium fluorescein (SF) as a model hydrophilic drug. RESULTS: Spray-dried microparticles without dispersibility enhancers exhibited aggregated powders leading to low fine particle fraction (%FPF) (28.79 +/- 3.24), fine particle dose (FPD) (14.42 +/- 1.57 MUg), with a mass median aerodynamic diameter (MMAD) 2.86 +/- 0.24 MUm. However, (L)-leucine was significantly superior in enhancing the aerosolization performance ((L-)arginine:%FPF 27.61 +/- 4.49-26.57 +/- 1.85; FPD 12.40 +/- 0.99-19.54 +/- 0.16 MUg and MMAD 2.18 +/- 0.35-2.98 +/- 0.25 MUm, (L) leucine:%FPF 36.90 +/- 3.6-43.38 +/- 5.6; FPD 18.66 +/- 2.90-21.58 +/- 2.46 MUg and MMAD 2.55 +/- 0.03-3.68 +/- 0.12 MUm). Incorporating (L)-leucine (1.5%w/w) reduced the burst release (24.04 +/- 3.87%) of SF compared to unmodified formulations (41.87 +/- 2.46%), with both undergoing a square root of time (Higuchi's pattern) dependent release. Comparing the toxicity profiles of PGA-co PDL with (L)-leucine (1.5%w/w) (5 mg/ml) and poly(lactide-co-glycolide), (5 mg/ml) spray-dried microparticles in human bronchial epithelial 16HBE14o- cell lines, resulted in cell viability of 85.57 +/- 5.44 and 60.66 +/- 6.75%, respectively, after 72 h treatment. CONCLUSION: The above data suggest that PGA co-PDL may be a useful polymer for preparing SR microparticle carriers, together with dispersibility enhancers, for pulmonary delivery. PMID- 21533999 TI - Complexation and full characterization of the tretinoin and dimethyl-beta cyclodextrin complex. AB - The aim of this work is to prepare tretinoin/dimethyl-beta-cyclodextrin complexes and fully characterize them through various analytical techniques. According to the phase solubility studies performed, the equilibrium for maximum complexation is reached in about 8 days presenting an A(L)-type diagram (soluble complexes) corresponding mainly to 1:1 stoichiometry (K(s) = 13,600 M(-1)), although the possibility of the presence of 1:2 complexes was mathematically proven. Differential scanning calorimetry, X-ray diffraction and all the other analytical techniques have proven the presence of true complex formation in all the preparation methods tested. H-NMR and FTIR spectra allowed the selection of the best complexation method. The comparison between Raman spectra revealed that the more relevant feature is the band at 1,573 cm(-1), which corresponds to the entire delocalization of the superconjugated system, and after inclusion is observed as a positive frequency shift. Based on these results and the data obtained by molecular modelling calculations, it is proposed that the structure of the drug included into the cyclodextrin corresponds to the side chain including the functional group COOH. The complex was also analysed by atomic force microscopy to determine its size distribution which was heterogeneous and polymodal. However, it could be observed that they all have the same phase constitution. PMID- 21534001 TI - Splenic abscess caused by MRSA developing in an infarcted area: case report and literature review. AB - We report a case of a 41-year-old man with a splenic abscess caused by methicillin-resistant Staphylococcus aureus (MRSA). He had been treated with antimicrobials and corticosteroids for interstitial pneumonia caused by Mycoplasma pneumoniae and hemolytic anemia. He developed catheter-related (MRSA) bacteremia during his stay in the ICU and was treated with teicoplanin for 2 weeks. After 4 weeks of outpatient follow-up, he was readmitted to the hospital with fever and pain in the left upper quadrant. A thoracoabdominal CT scan showed subcapsular collection in areas of splenic infarction that had been detected on his first admission. CT-guided percutaneous aspiration resulted in the isolation of MRSA. The patient was treated successfully with teicoplanin for 6 weeks. Our aim in presenting this quite rare case is to highlight the tendency of infarcts that develop as a result of hemolytic attacks during systemic infections to be a focus of infection for nosocomial bacteremia. PMID- 21534000 TI - Dissection of calcium signaling events in exocrine secretion. AB - The secretion of fluid and electrolytes by salivary gland acinar cells requires the coordinated regulation of multiple ion channel and transporter proteins, signaling components, and water transport. Importantly, neurotransmitter stimulated increase in the cytosolic free [Ca(2+)] ([Ca(2+)](i)) is critical for the regulation of salivary gland secretion as it regulates several major ion fluxes that together establish the sustained osmotic gradient to drive fluid secretion. The mechanisms that act to modulate these increases in [Ca(2+)](i) are therefore central to the process of salivary fluid secretion. Such modulation involves membrane receptors for neurotransmitters, as well as mechanisms that mediate intracellular Ca(2+) release, and Ca(2+) entry, as well as those that maintain cellular Ca(2+) homeostasis. Together, these mechanisms determine the spatial and temporal aspects of the [Ca(2+)](i) signals that regulate fluid secretion. Molecular cloning of these transporters and channels as well as development of mice lacking these proteins has established the physiological significance of key components that are involved in regulating [Ca(2+)](i) in salivary glands. This review will discuss these important studies and the findings which have led to resolution of the Ca(2+) signaling mechanisms that determine salivary gland fluid secretion. PMID- 21534002 TI - Initial results of catheter-directed ultrasound-accelerated thrombolysis for thromboembolic obstructions of the aortofemoral arteries: a feasibility study. AB - PURPOSE: This article reports the 30-day technical and clinical outcome of ultrasound (US)-accelerated thrombolysis in patients with aortofemoral arterial thromboembolic obstructions. METHODS: A prospective cohort study was conducted from December 2008 to December 2009 of patients who were treated with US accelerated thrombolysis for thromboembolic obstructions of aortofemoral arteries or bypasses. Urokinase was infused in a dosage of 100,000 IU per hour. Twice daily, a control angiography was performed. Thirty-day follow-up consisted of duplex scanning, combined with magnetic resonance angiography. RESULTS: The study included 21 consecutive patients (20 men; median age, 66 (range, 52-80) years) with 24% artery versus 76% bypass occlusions. Median duration of symptoms was 11 (range, 7-140) days. Median occlusion length was 32 (range, 6-80) cm. In 20 patients (95%), an US-accelerated thrombolysis catheter could be successfully placed. In one patient, placement of an US-accelerated thrombolysis catheter was technically not feasible, and therefore a standard catheter was placed. Median thrombolysis time was 26.5 (range, 8.5-72) hours. Complete thrombolysis (>95% lysis of thrombus) was achieved in 20 patients; in 9 patients within 24 hours. Median ankle-brachial index (ABI) increased from 0.28 (range, 0-0.85) to 0.91 (range, 0.58-1.35). One patient had a thromboembolic complication and needed surgical intervention. No hemorrhagic complications, and no deaths occurred. At 30-day follow-up, 17 of 21 patients (81%) had a patent artery or bypass. CONCLUSIONS: This feasibility study showed a high technical success rate of US accelerated thrombolysis for aortofemoral arterial obstructions. US-accelerated thrombolysis led to complete lysis within 24 hours in almost half of patients, with a low 30-day major complication rate. PMID- 21534003 TI - Evaluation of image quality and radiation dose at prospective ECG-triggered axial 256-slice multi-detector CT in infants with congenital heart disease. AB - BACKGROUND: There are a limited number of reports on the technical and clinical feasibility of prospective electrocardiogram (ECG)-gated multi-detector computed tomography (MDCT) in infants with congenital heart disease (CHD). OBJECTIVE: To evaluate image quality and radiation dose at weight-based low-dose prospectively gated 256-slice MDCT angiography in infants with CHD. MATERIALS AND METHODS: From November 2009 to February 2010, 64 consecutive infants with CHD referred for pre operative or post-operative CT were included. All were scanned on a 256-slice MDCT system utilizing a low-dose protocol (80 kVp and 60-120 mAs depending on weight: 60 mAs for <= 3 kg, 80 mAs for 3.1-6 kg, 100 mAs for 6.1-10 kg, 120 mAs for 10.1-15 kg). RESULTS: No serious adverse events were recorded. A total of 174 cardiac deformities, confirmed by surgery or heart catheterization, were studied. The sensitivity of MDCT for cardiac deformities was 97.1%; specificity, 99.4%; accuracy, 95.9%. The mean heart rate during scan was 136.7 +/- 14.9/min (range, 91-160) with a corresponding heart rate variability of 2.8 +/- 2.2/min (range, 0 8). Mean scan length was 115.3 +/- 11.7 mm (range, 93.6-143.3). Mean volume CT dose index, mean dose-length product and effective dose were 2.1 +/- 0.4 mGy (range, 1.5-2.8), 24.7 +/- 5.9 mGy.cm (range, 14.7-35.8) and 1.6 +/- 0.3 mSv (range, 1.1-2.5), respectively. Diagnostic-quality images were achieved in all cases. Satisfactory diagnostic quality for visualization of all/proximal/distal coronary artery segments was achieved in 88.4/98.8/80.0% of the scans. CONCLUSION: Low-dose prospectively gated axial 256-slice CT angiography is a valuable tool in the routine clinical evaluation of infants with CHD, providing a comprehensive three-dimensional evaluation of the cardiac anatomy, including the coronary arteries. PMID- 21534004 TI - Associations between regional brain volumes at term-equivalent age and development at 2 years of age in preterm children. AB - BACKGROUND: Altered brain volumes and associations between volumes and developmental outcomes have been reported in prematurely born children. OBJECTIVES: To assess which regional brain volumes are different in very low birth weight (VLBW) children without neurodevelopmental impairments ([NDI] cerebral palsy, hearing loss, blindness and significantly delayed cognitive performance) compared with VLBW children with NDI, and to evaluate the association between regional brain volumes at term-equivalent age and cognitive development and neurological performance at a corrected age of 2 years. MATERIALS AND METHODS: The study group consisted of a regional cohort of 164 VLBW children, divided into one group of children without NDI (n = 148) and one group of children with NDI (n = 16). Brain (MRI) was performed at term-equivalent age, from which brain volumes were manually analysed. Cognitive development was assessed with the Bayley Scales of Infant Development II (BSID-II), and neurological performance with the Hammersmith Infant Neurological Examination at the corrected age of 2 years. RESULTS: The volumes of total brain tissue, cerebrum, frontal lobes, basal ganglia and thalami, and cerebellum were significantly smaller, and the volume of the ventricles significantly larger, in the children with NDI than in those without NDI. Even in children without NDI, a smaller cerebellar volume was significantly correlated with poor neurological performance at 2 years of corrected age. CONCLUSION: Volumetric analysis at brain MRI can provide an additional parameter for early prediction of outcome in VLBW children. PMID- 21534005 TI - Executive function on the Psychology Experiment Building Language tests. AB - The measurement of executive function has a long history in clinical and experimental neuropsychology. The goal of the present report was to determine the profile of behavior across the lifespan on four computerized measures of executive function contained in the recently developed Psychology Experiment Building Language (PEBL) test battery http://pebl.sourceforge.net/ and evaluate whether this pattern is comparable to data previously obtained with the non-PEBL versions of these tests. Participants (N = 1,223; ages, 5-89 years) completed the PEBL Trail Making Test (pTMT), the Wisconsin Card Sort Test (pWCST; Berg, Journal of General Psychology, 39, 15-22, 1948; Grant & Berg, Journal of Experimental Psychology, 38, 404-411, 1948), the Tower of London (pToL), or a time estimation task (Time-Wall). Age-related effects were found over all four tests, especially as age increased from young childhood through adulthood. For several tests and measures (including pToL and pTMT), age-related slowing was found as age increased in adulthood. Together, these findings indicate that the PEBL tests provide valid and versatile new research tools for measuring executive functions. PMID- 21534006 TI - Discretionary medical reporting of potentially unfit drivers: a questionnaire based survey in southeast Switzerland. AB - In Switzerland, every physician has the right to report a patient that is potentially unfit to drive to the licensing authority without violating medical confidentiality. Verified information regarding physicians' attitudes concerning this discretionary reporting and the frequency of such reports are not available. In order to answer these questions, 635 resident physicians were sent a questionnaire. The response rate was 52%. On average, the responding physicians- for all specialties--reported 0.31 patients (SD 0.64, 95% CI 0.24-0.38) in the year before the survey and 1.00 patient (SD 1.74, 95% CI 0.81-1.20) in the past 5 years. Seventy-nine percent of the responding physicians indicated knowing the current legal requirements for driving in Switzerland. In applied logistic regression analysis, only two factors correlate significantly with reporting: male sex (odds ratio 5.4) and the specialty "general medicine" (odds ratio 3.4). Ninety-seven percent of the physicians were against abolishing medical discretionary reporting and 29% were in favor of introducing mandatory reporting. The great majority of the questioned physicians supported the discretionary reporting of drivers that are potentially unfit to drive as currently practiced in Switzerland. The importance and the necessity of a regular traffic medicine related continuing education for medical professionals are shown by the low number of reports per physician. PMID- 21534008 TI - TGFbeta biology in breast: 15 years on. PMID- 21534007 TI - Maggots reveal a case of antemortal insect infestation. PMID- 21534010 TI - Efficient transfection method using deacylated polyethylenimine-coated magnetic nanoparticles. AB - Low efficiencies of nonviral gene vectors, such as transfection reagent, limit their utility in gene therapy. To overcome this disadvantage, we report on the preparation and properties of magnetic nanoparticles [diameter (d) = 121.32 +/- 27.36 nm] positively charged by cationic polymer deacylated polyethylenimine (PEI max), which boosts gene delivery efficiency compare with polyethylenimine (PEI), and their use for the forced expression of plasmid delivery by application of a magnetic field. Magnetic nanoparticles were coated with PEI max, which enabled their electrostatic interaction with negatively charged molecules such as plasmid. We successfully transfected 81.1 +/- 4.0% of the cells using PEI max coated magnetic nanoparticles (PEI max-nanoparticles). Along with their superior properties as a DNA delivery vehicle, PEI max-nanoparticles offer to deliver various DNA formulations in addition to traditional methods. Furthermore, efficiency of the gene transfer was not inhibited in the presence of serum in the cells. PEI max-nanoparticles may be a promising gene carrier that has high transfection efficiency as well as low cytotoxicity. PMID- 21534012 TI - Twelve-year experience with the Carpentier-Edwards pericardial aortic valve at a single Japanese center. AB - Our aim was to evaluate the long-term results of implantation of the Carpentier Edwards pericardial (CEP) valve in the aortic position. Between January 1996 and December 2007, 244 patients who underwent aortic valve replacement using the CEP valve were enrolled in this study. A 19-mm valve was used in 39 patients, a 21-mm valve in 94 patients, a 23-mm valve in 81 patients, and a 25-mm valve in 30 patients. The early and the late results were evaluated. Furthermore, echocardiographic examination was performed at follow-up. There were 5 early deaths, with an early mortality rate of 2.0%. Follow-up was performed in 95.4% of the survivors of the operation for a mean period of 4.1 years. Actuarial survival rates at 5, 10, and 12 years were 85.3 +/- 2.8, 80.0 +/- 3.7 and 70.0 +/- 9.8%, respectively. Thromboembolism was observed in 6 patients, endocarditis in 2 patients, reoperation in 4 patients, and structural valve deterioration in 2 patients. Actuarial freedoms from thromboembolism, endocarditis, and reoperation at 10 years were 96.9 +/- 0.14, 97.7 +/- 0.16, and 97.0 +/- 0.16%, respectively. Echocardiographic examination revealed that the pressure gradients across the valve prosthesis for valves of each size were acceptable. Left ventricular mass index decreased significantly in all valve sizes. The long-term results of implantation of the CEP bioprosthesis in the aortic position were satisfactory. The CEP bioprosthesis maintained its hemodynamic performance even as late as 10 years after implantation. PMID- 21534011 TI - Successful bridge to recovery with VAD implantation for anthracycline-induced cardiomyopathy. AB - Anthracyclines are effective antineoplastic drugs, but they are known to be cardiotoxic. Recovery of cardiac function is rare. A few studies on implantation of a ventricular assist device (VAD) have been performed for anthracycline induced cardiomyopathy. Recovery of left ventricular (LV) function with an LVAD is also rare. Recently, several adjunctive therapies were attempted to restore ventricular function. We report a successful bridge to recovery of ventricular function using VAD implantation for anthracycline-induced cardiomyopathy. The patient was a 57-year-old man who had been diagnosed with diffuse large B-cell lymphoma (DLBCL) at age 52. Combination chemotherapy including hydroxydaunorubicin was started. Complete remission was achieved after chemotherapy. Heart failure symptoms such as fatigue, dyspnea on exertion, and weight gain appeared 5 months later. A cardiac resynchronization device was implanted. His heart function deteriorated. He underwent implantation of a Toyobo LVAD and mitral annuloplasty. After implantation, he was prescribed carvedilol with spironolactone. He was weaned from the LVAD on postoperative day (POD) 239 and discharged on POD 37 after weaning. He remained in New York Heart Association classes within the first- to second-degree range, the LV dimention diastolic/systolic ratio was 56/46 mm, ejection fraction 38%, and mitral regurgitation mild at 3 years after weaning from the LVAD. Our patient could be weaned from LVAD probably due to the combination management strategy employing mitral valvuloplasty, use of cardiac resynchronization therapy, and taking carvedilol with spironolactone. Further studies will be needed to clarify the efficacy of these adjunctive therapies. PMID- 21534013 TI - Effect of IFN-gamma and IL-4 levels on the expression of Fas and Bcl-2 in peripheral blood lymphocytes in hemodialysis patients. AB - To study the correlation between the levels of IFN-gamma and IL-4 and the expression of Fas and Bcl-2 in peripheral blood lymphocytes (PBL) in hemodialysis patients, the indirect immune fluorescein labeling method of flow cytometry and solid sandwich enzyme-linked immunosorbent assay were performed for detecting the expression of Fas and Bcl-2 in PBL and the levels of IFN-gamma and IL-4 in the serum of 30 hemodialysis patients, respectively. It was found that the expression of Fas in PBL and the level of IL-4 in the serum of hemodialysis patients were significantly higher (P < 0.01), whereas Bcl-2 in PBL and IFN-gamma in the serum were significantly lower (P < 0.01) than those of the normal controls. According to statistical analysis, the expression of Fas in PBL had a negative correlation with the level of IFN-gamma, but a positive correlation with IL-4 in the serum of hemodialysis patients. Contrarily, the expression of Bcl-2 had a positive correlation with IFN-gamma, but a negative correlation with IL-4 in the serum of hemodialysis patients. These results suggest that hemodialysis patients have a suppressed secretion of Th1-associated cytokine IFN-gamma, but an increased secretion of Th2-associated cytokines IL-4, and these two aspects may play an important role in the abnormal apoptosis of PBL and its accompanying immune deficiency. PMID- 21534014 TI - What is the role of hyperbaric oxygen in the management of diabetic foot disease? AB - Systemic hyperbaric oxygen (HBO) is accomplished when a patient is breathing 100% oxygen in an environment with increased barometric pressure. A typical HBO treatment protocol of diabetic foot ulcer involves 20 to 40 sessions. Treatment is usually given as daily 90- to 120-minute HBO sessions at pressures between 2.0 and 2.5 absolute atmospheres. The wide use of HBO as treatment of diabetic foot ulcers over the past decades has been founded on weak scientific ground (ie, few and small prospective studies with methodologic limitations on top of case series). However, the consistency in positive outcome in these trials evaluating HBO on ulcer healing is noteworthy because these findings are in concert with data from in vitro and physiologic studies supporting the theoretic framework of HBO reversing hypoxia-induced pathology. Two well-designed randomized double blinded placebo-controlled studies have in recent years put HBO on firmer ground as treatment of a selection of diabetic patients with chronic foot. Some evidence indicates that microvascular parameters such as transcutaneous (partial) oxygen pressure (TcPO(2)) could be useful in predicting which patients will benefit from therapy. Health economic studies suggest potential cost-effectiveness of HBO. But because these analyses are limited by their deficient primary clinical data, they should be interpreted with caution. Thus, HBO is only indicated in a selected group of patients with chronic diabetic foot ulcers. Several key issues remain to be addressed such as developing robust criteria to determine which patients are likely to benefit and when to start and stop treatment. PMID- 21534015 TI - Pericarditis: pathophysiology, diagnosis, and management. AB - Pericarditis, the most common disease of the pericardium, may be isolated or a manifestation of a systemic disease. The etiology of pericarditis is varied and includes infectious (especially viral and tuberculosis) and noninfectious causes (autoimmune and autoinflammatory diseases, pericardial injury syndromes, and cancer [especially lung cancer, breast cancer, and lymphomas]). Most cases remain idiopathic with a conventional diagnostic evaluation. A targeted etiologic search should be directed to the most common cause on the basis of the patient's clinical background, epidemiologic issues, specific presentations, and high-risk features associated with specific etiologies or complications (fever higher than 38 degrees C, subacute onset, large pericardial effusion, cardiac tamponade, lack of response to NSAIDs). The management of pericardial diseases is largely empiric because of the relative lack of randomized trials. NSAIDs are the mainstay of empiric anti-inflammatory therapy, with the possible addition of colchicine to prevent recurrences. PMID- 21534016 TI - Microcontextual characteristics of peer victimization experiences and adolescents' daily well-being. AB - Microcontextual factors (i.e., contextual characteristics of the specific victimization incident) may help to explain the association between adolescents' daily peer victimization experiences and well-being. In the present study, daily report methodology was used to assess sixth (N = 150; 53% girls) and ninth grade (N = 150; 50% girls) students' current well-being and peer victimization earlier in the day on 5 random school days within a 2-week period. Associations between peer victimization microcontextual factors (number of aggressors, presence of witnesses, and receipt of help) and fluctuations in adolescents' daily well-being (humiliation, worry, and physical symptoms) were examined in an ethnically diverse sample of White, Latino, Asian, African American, and multiethnic students. Humiliation increased on days in which students reported public victimization, multiple aggressors, and no help. Worry increased on days students experienced private victimization and when boys (but not girls) experienced private victimization, victimization by a single aggressor, and received peer help. Physical symptoms were higher on days that victimization occurred, regardless of context, but only for sixth graders and not ninth graders. These findings suggest that the victimization microcontext can offer insight about the types of peer victimization exposure that might produce the greatest daily risk for adolescents. PMID- 21534017 TI - Development of terminology for mammographic techniques for radiological technologists. AB - We are developing a mammographic ontology to share knowledge of the mammographic domain for radiologic technologists, with the aim of improving mammographic techniques. As a first step in constructing the ontology, we used mammography reference books to establish mammographic terminology for identifying currently available knowledge. This study proceeded in three steps: (1) determination of the domain and scope of the terminology, (2) lexical extraction, and (3) construction of hierarchical structures. We extracted terms mainly from three reference books and constructed the hierarchical structures manually. We compared features of the terms extracted from the three reference books. We constructed a terminology consisting of 440 subclasses grouped into 19 top-level classes: anatomic entity, image quality factor, findings, material, risk, breast, histological classification of breast tumors, role, foreign body, mammographic technique, physics, purpose of mammography examination, explanation of mammography examination, image development, abbreviation, quality control, equipment, interpretation, and evaluation of clinical imaging. The number of terms that occurred in the subclasses varied depending on which reference book was used. We developed a terminology of mammographic techniques for radiologic technologists consisting of 440 terms. PMID- 21534018 TI - Peroneal neuropathy after weight loss: a high-resolution ultrasonographic characterization of the common peroneal nerve. AB - OBJECTIVE: The objective of this study was to use in vivo ultrasonographic imaging to analyze the common peroneal nerve in controls and patients who were diagnosed with peroneal neuropathy (PN) due to significant weight loss. We also looked for a relationship between weight loss (magnitude) and the occurrence of PN. MATERIALS AND METHODS: Fifty controls and six patients who were diagnosed with PN after losing a significant amount of weight were examined by means of ultrasonography (US). On the US images, the structure and reflectivity of the nerve were analyzed. Correlations were made between the ultrasonographic measurements and the body mass index (BMI) of controls. In PN patients, these ultrasonographic parameters were compared between the normal and pathological legs. RESULTS: BMI was positively correlated with the transverse cross-sectional area of the nerve and fibular tunnel in controls. In controls with a high BMI, the peroneal nerve appeared thicker and the US reflectivity of the nerve was higher. A lower US reflectivity was observed in the pathological legs of the six patients who developed PN after weight loss. CONCLUSION: The transverse cross sectional area and reflectivity of the peroneal nerve on the US images could be viable tools in the diagnosis of PN after weight loss. PMID- 21534019 TI - Adaptive control of cardiac contraction to changes in loading: from theory of sarcomere dynamics to whole-heart function. AB - The heart accommodates to rapid changes in demands. This review elucidates the adaptive control of cardiac function by loading conditions, and integrates the sarcomeric control of contraction (SCC) with isolated trabeculae and in vivo whole-heart studies. The SCC includes two feedback mechanisms: (1) cooperativity that regulates cross-bridge (XB) recruitment and the force-length relationship, and (2) mechanical feedback, whereby the filament-sliding velocity determines the XB-weakening rate and the force-velocity relationship. An isolated rat trabeculae study tested the suggested mechanisms during sarcomeric lengthening. The observations indicate that lengthening decreases the XB-weakening rate in a velocity-dependent manner, congruent with the suggested hypothesis and in contrast to alternative theories. A whole-heart level study in sheep reveals the existence of a preload-independent linear relationship between the external work (EW) and pressure-time integral during transient vena cava occlusions, for any given afterload, and not just at isovolumic contractions. The slope of this relationship decreases as the afterload increases. These findings highlight the mechanisms underlying the pressure (Frank's phenomenon) and EW (Starling's phenomenon) generation and the roles that the preload and afterload play. The theoretical, isolated fibers and whole-heart studies provide complementary information that strengthens our understanding of cardiac function from the top down and bottom-up. PMID- 21534021 TI - Risk-adapted dental care prior to intensity-modulated radiotherapy (IMRT). AB - BACKGROUND: At the Clinic for Radiation Oncology at the Zurich University Hospital (UniversitatsSpital Zurich [USZ]), head-and-neck tumor (HNT) patients have been treated with intensity-modulated radiotherapy (IMRT) since 01/2002 (n > 800). This method causes less damage to normal tissues adjacent to the tumor, and thus it was possible in the head/neck region to markedly reduce the rate of osteoradionecrosis (ORN), in addition to reducing the rate of severe xerostomia. Based on these results, risk-adapted dental care (RaDC) was adopted by our clinic as the standard mode of pre-IMRT dental treatment. The guidelines as formulated by Grotz et al. were respected. ORN prophylaxis is one of the most important goals of pre-radiotherapy dental care, and the ORN rate is a measurable parameter for the efficacy of dental care, given a certain radiation technique. The aim of the present study was therefore to evaluate the efficacy of RaDC as reflected by the ORN rate of our IMRT patients. MATERIALS AND METHODS: IN August 2006, RaDC was clinically implemented and has been used for all HNT patients prior to IMRT since then. Before that (01/2002-07/2006), dental restorations were performed according to the usual procedure. RESULTS: The rate of grade-2 ORN was similar in the conventionally treated and RaDC groups (2% and 1%, resp.); grade-3 ORN had not occurred by the time the analysis was conducted. As expected, fewer extractions were performed in the RaDC cohort (no extractions in 47% of the RaDC/IMRT cohort vs. 27% in the IMRT cohort receiving conventional dental care). CONCLUSION: After considerably less invasive dental treatment, no higher-grade ORN occurred and no ORN-related jaw resections were required. Based on the present data, risk-adapted minimally invasive dental care is recommended before IMRT. PMID- 21534022 TI - A content analysis of research on religion and spirituality in general communication and health communication journals. AB - Little research has been conducted within the field of communication regarding the intersection of religious faith and health communication. One step toward addressing the existing gap in health communication literature is to establish an accurate picture of the present state of affairs. The purpose of this study was to describe publication patterns in communication journals over the past 10 years with respect to the intersection and faith and health communication. We conducted a content analysis on four broad-based communication journals that have been identified as central in the communication field, and two health communication journals. We present results regarding specific health conditions, nationalities, faith communities, channels of communication, domains of religion, and purposes of communication studied; methods used; trends in publication across time and communication journals; and comparison to other disciplines. PMID- 21534023 TI - Health claims for food products advertised on Korean television and their regulation: a content analysis. AB - This article reviews the landmark studies of advertising claims and analyzes the health claims for food products advertised on Korean TV. The present study examined 1,479 food commercials aired on three major television networks from 2005 to 2007. The commercials containing health claims accounted for 29.5% of the total. The health claims ranged from the nutrient content to the use of ambiguous expressions such as "healthy." Among the 5 types of health claims considered, specific nutrient claims ranked first (11.1%), followed by general health claims (9.4%). The regulatory policies of Korea concerning such advertising claims were compared with those of the United States. The results of this study are expected to have important implications for Korean policymakers who need better ways to regulate health claims for food products. PMID- 21534024 TI - Interpretations of cigarette advertisement warning labels by Philadelphia Puerto Ricans. AB - This study examined Philadelphia Puerto Ricans' interpretations of the Surgeon General's warnings that appear on cigarette packaging and in advertisements. In home family focus groups in which participants were asked to comment on magazine cigarette advertisements showed a great variety of interpretations of the legally mandated warning labels. These findings (a) corroborate and add to research in public health and communications regarding the possibility of wide variations in message interpretations and (b) support the call for public health messages to be carefully tested for effectiveness among different social groups. The article's focus on Puerto Ricans addresses the problem of misleading conclusions that can arise from aggregating all Latino subpopulations into one group. The use of a naturalistic setting to examine interpretations of messages about smoking departs from the experimental methods typically used for such research and provides new evidence that even a seemingly straightforward message can be interpreted in multiple ways. Understanding and addressing differences in message interpretation can guide public health campaigns aimed at reducing health disparities. PMID- 21534025 TI - Visual flow is interpreted relative to multisegment postural control. AB - To control upright stance, the human nervous system must estimate the movements of multiple body segments based on multisensory information. To investigate how visual information contributes to such multisegmental estimation, participants were exposed to 3 types of visual-scene movement: translation in the anteroposterior direction, rotation about the ankle joint, and rotation about the hip joint. Trunk and leg responses were larger for rotational than for translational movements, but only at lower stimulus frequencies. Based on a feedback-control theoretical framework, these results indicated that visual inputs distinguish between translation and rotation of the head. Also, visual condition effects were similar for the leg and trunk segments, suggesting a control strategy with a single control signal that determines the activation of all muscles. PMID- 21534026 TI - Sexual transformations and intimate behaviors in romantic relationships. AB - To understand the association between sexual transformations (i.e., changes in sexual behavior for the partner), intimate behaviors, and relationship quality among couples in romantic relationships, this study used Actor Partner Interdependence Models to examine frequency of sexual transformations, feelings about sexual transformations, and intimate behaviors as predictors of relationship satisfaction among 96 couples (N = 192). Sexual transformations were also examined as a moderator of the association between intimate behavior and relationship satisfaction. Results indicated that relationship satisfaction was positively associated with partners' frequent sexual transformations, actors' positive feelings about sexual transformations, and intimate behavior from the partner. Further, in less intimate relationships, relationship satisfaction was greater when partners reported making more sexual transformations. PMID- 21534027 TI - Demographic and psychological factors related to sexual desire among heterosexual women in a relationship. AB - This study examined demographic, psychological, and relationship factors that are associated with the experience of sexual desire in women. The contribution of other aspects of sexual function on sexual desire was also investigated. The participants were 741 partnered heterosexual women (mean age = 45.7 years), who completed the Female Sexual Desire Questionnaire online, which evaluated their levels of sexual desire, as well as a range of individual and dyadic variables. For each of the six aspects of sexual desire assessed, the number and frequency of problems in other aspects of women's sexual functioning were the most common predictors. The results demonstrated that sexual desire was lower among older, postmenopausal women and those who had been in their current relationship for a longer period of time. Women who reported that their partner experienced a sexual dysfunction also obtained lower sexual desire scores. These findings demonstrate the strong interrelationship between the different phases of the sexual response cycle for women. Further, they suggest that sexual dysfunction in one partner is likely to be associated with sexual dysfunction in the other partner. The clinical implications of these findings in terms of the treatment for sexual dysfunction among women (and their partners) are discussed. PMID- 21534028 TI - Factors influencing university students' explicit and implicit sexual double standards. AB - Quantitative research has resulted in inconsistent evidence for the existence of a sexual double standard, leading Crawford and Popp ( 2003 ) to issue a call for methodological innovation. The implicit association test (IAT; Greenwald, McGhee, & Schwartz, 1998 ) is a measure that may provide a means to examine the double standard without the contamination of the demand characteristics and social desirability biases that plague self-report research (Marks & Fraley, 2005 ). The purpose of this study was to examine the factors influencing explicit and implicit double standards, and to examine the relationship between these explicit and implicit double standards, and levels of socially desirable responding. One hundred and three university students completed a sexual double standard IAT, an explicit measure of the double standard, and measures of socially desirable responding. Hierarchical regression analysis indicated that levels of socially desirable responding were not related to implicit or explicit double standards. Men endorsed a stronger explicit traditional double standard than women, whereas for implicit sexual standards, men demonstrated a relatively gender-neutral evaluation and women demonstrated a strong reverse double standard. These results suggest the existence of a complex double standard, and indicate that more research of sexual attitudes should include implicit measures. PMID- 21534029 TI - Influence of encoding difficulty, word frequency, and phonological regularity on age differences in word naming. AB - It is presently unclear as to why older adults take longer than younger adults to recognize visually presented words. To examine this issue in more detail, the authors conducted two word-naming studies (Experiment 1: 20 older adults and 20 younger adults; Experiment 2: 60 older adults and 60 younger adults) to determine the relative effects of orthographic encoding (case type), lexical access (word frequency), and phonological regularity (regular vs. irregular phonology). The hypothesis was that older adults attempt to compensate for sensory and motor slowing by using progressively larger perceptual units (holistic encoding). However, if forced to use smaller perceptual units (e.g., by using mixed-case presentation), it was predicted that older adults would be particularly challenged. Older adults did show larger case-mixing effects than younger adults (suggesting that older adults' performances were especially poor when they were forced to use smaller perceptual units), but there were no age differences in word frequency or phonological regularity even though both age groups showed main effects for these variables. These results suggest that lexical access skill remains stable in the addressed (orthographic/semantic) and assembled (phonological) routes over the life span, but that older adults slow down in recognizing words because it takes them longer to normalize (perceptually "clean up") noisier sensory information. PMID- 21534030 TI - Effects of distraction and pictorial illustration on memory for countries in older adults with probable Alzheimer's disease. AB - Eight participants with probable Alzheimer's disease (AD) were trained to recall names of countries using the spaced-retrieval memory intervention. Six training sessions were administered on alternate days over a 2-week period. Half of the participants studied a target country alone and the other half studied a target country along with eight distractor countries. Training stimuli appeared in text only format in half of the sessions and text with a color photograph of the country in the other sessions. On each trial, participants selected the target at increasingly longer retention intervals, contingent upon successful recall. Results indicated that the mean proportion of correct trials and longest duration achieved increased across training sessions, confirming the success of the spaced retrieval intervention. Pictorial illustrations enhanced explicit memory for target country names. Implications of these data for current views on memory remediation in cognitively impaired older adults are discussed. PMID- 21534031 TI - False recognition and source attribution for actions of an emotional event in older and younger adults. AB - In two experiments recognition of actions of a robbery presented in a video was examined in older and younger adults. In both experiments older adults had more false alarms and showed less accurate recognition than younger adults. In addition, when participants were asked in Experiment 1 to indicate Remember/Know/Guess judgments for actions they considered true, older adults accepted more false actions with Remember judgments. And when participants were asked in Experiment 2 to attribute the source (i.e., perpetrator), the older adults were less able to attribute actions that occurred during the robbery to their correct sources. Furthermore, we found a robust positive correlation between source attribution ability and recognition accuracy. Thus, source-memory deficits may contribute to older adults' false memories in real-life eyewitness situations. PMID- 21534032 TI - Selective attentional processing to fall-relevant stimuli among older adults who fear falling. AB - Fear of falling is known to affect more than half of community-dwelling older adults over 60 years of age. This fear is associated with physical and psychological effects that increase the risk of falling. The authors' theory is that attentional processing biases may exist in this population that serve to perpetuate fear of falling and subsequently increase fall risk. As a starting point in testing this proposition, the authors examined selective attentional processing bias to fall-relevant stimuli among older adults. Thirty older adult participants (M(age) = 70.8 +/- 5.8), self-categorized to be Fearful of Falling (FF, n = 15) or Non-Fearful of Falling (NF, n = 15) completed a visual dot-probe paradigm to determine detection latencies to fall-threatening and general-threat stimuli. Attentional processing was defined using three index scores: attentional bias, congruency index, and incongruency index. Bias indicates capture of attention, whereas congruency and incongruency imply vigilance and disengagement difficulty, respectively. Both groups showed an attentional bias to fall-threat words but those who were fearful of falling also showed an incongruency effect for fall-threat words. These findings confirm that selective attentional processing profiles for fall-relevant stimuli differ between older adults who exhibit fear of falling and those who do not have this fear. Moreover, in accordance with current interpretations of selective attentional processing, the incongruency effect noted among fall-fearful older adults presents a possibility for a difficulty disengaging from fall-threatening stimuli. PMID- 21534033 TI - Is fat mass distribution related to impaired mobility in older men and women? Nutrition as a determinant of successful aging: the Quebec longitudinal study. AB - It is established that a high level of fat mass (FM) is related to mobility impairment in older adults. However, FM distribution has received very little attention. In this study, 904 well-functioning older adults aged between 68 and 82 years old were recruited to examine the association between waist circumference, trunk FM, leg FM, and mobility. The results show that waist circumference was the only measure of body fat distribution independently associated with mobility (p <= .001). Therefore, the use of objective measures of FM distribution may not be necessary to examine the impact of FM distribution on mobility. PMID- 21534034 TI - Trajectory stability and factors affecting trajectories over time of the longitudinal age-related change in physical performance among older people. AB - This study used community-based cohort data to explore the trajectory stability (tracking coefficient or stability coefficient) and its influencing factors on the longitudinal age-related change in physical performance among older populations. An integrated statistical method with generalized estimating equations was applied to study trajectory stability. The study particularly demonstrated a mixed representation regarding the significant trajectories of intact and reduced physical performance over time. It is important to note that the trajectory stability of reduced physical performance was higher in females (odds ratio [OR] = 7.76; 95% confidence interval [CI]: 5.04-11.93) than in males (OR = 5.65; 95% CI: 4.09-7.79). However, for intact physical performance, the coefficient was 3.52 (95% CI: 2.76-4.48) in males and 2.55 (95% CI: 1.91-3.41) in females. There are further gender differences based on the influence of demographic, psychological, lifestyle, and biological variables in relation to the trajectories of physical performance. The authors conclude that an understanding of trajectory stability, as well as the factors affecting these trajectories in physical performance, is essential to the development of prevention programs tailored to maintaining functional ability or preventing the loss of physical function among older people. PMID- 21534035 TI - Immunomodulatory effects of cinobufagin isolated from Chan Su on activation and cytokines secretion of immunocyte in vitro. AB - The objective of this study was to evaluate the immunomodulatory effects of cinobufagin (CBG) isolated from Chan Su (Venenum Bufonis) in vitro. In this paper, our results show that CBG significantly stimulated cell proliferation of splenocytes and peritoneal macrophages (PMPhi) and markedly enhanced the phagocytic activation of PMPhi. CBG also significantly increased CD4(+)CD8(+) double-positive T-cell populations and the percentage of S-phase cells of splenic lymphocytes. The levels of several Th1 cytokines, including interferon-gamma and tumor necrosis factor-alpha, are significantly increased after CBG treatment, whereas the levels of the Th2 cytokine interleukin-4 and interleukin-10 are significantly decreased. As a result, the ratio of Th1/Th2 also increased. Taken together, these results indicated that CBG had potential immune system regulatory effects and suggested that this compound could be developed as a novel immunotherapeutic agent to treat immune-mediated diseases such as cancer. PMID- 21534036 TI - Dibenzocyclooctadiene lignans from the fruits of Schisandra rubriflora and their anti-HIV-1 activities. AB - Two new dibenzocyclooctadiene lignans, rubrilignans A and B (1, 2), together with 17 known ones, were isolated from the fruits of Schisandra rubriflora. The structures of 1 and 2 were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Compounds 1 and 2 were also evaluated for their anti-HIV-1 activities and showed weak anti-HIV-1 activity with EC(50) values of 2.26 and 1.82 MUg/ml, and therapeutic index values of 35.5 and 18.6, respectively. PMID- 21534037 TI - Anticancer effect and neurotoxicity of S-(+)-deoxytylophorinidine, a new phenanthroindolizidine alkaloid that interacts with nucleic acids. AB - Phenanthroindolizidine alkaloids are a family of plant-derived compounds with significant antineoplastic activity as well as other effects like antiamebicidal, antiviral, and anti-inflammatory activities. The specific biomolecular targets of these compounds have not yet been clearly identified. S-(+)-Deoxytylophorinidine (CAT) is a new phenanthroindolizidine alkaloid, originally extracted from the roots of Tylophora atrofolliculata and Tylophora ovata. Potent anticancer activity was observed in vitro and in vivo. Neurotoxicity of CAT was also studied and it was far less serious than that of vinblastine. Interactions between this compound and DNA had been studied in detail in our laboratory previously, and we further studied its interactions with RNA. PMID- 21534038 TI - Three new flavone C-glycosides from the aerial parts of Paraquilegia microphylla. AB - Three new flavone C-glycosides, paraquinins A-C, were isolated from the aerial parts of Paraquilegia microphylla (Royle) Dromm. et Hutch, a Tibetan medicine distributed in the Qinghai-Tibet plateau. On the basis of 1D and 2D NMR evidence, their structures were elucidated as acacetin-6-C-beta-D-glucopyranosyl-(1 -> 2) beta-D-glucopyranoside (1), acacetin-6-C-alpha-L-rhamnopyranosyl-(1 -> 2)-beta-D glucopyranosyl-(1 -> 2)-beta-D-glucopyranoside (2), and acacetin-6-C-alpha-L rhamnopyranosyl-(1 -> 2)-(6'''-O-E-feruloyl)-beta-D-glucopyranosyl-(1 -> 2)-beta D-glucopyranoside (3). PMID- 21534039 TI - Synthesis and antitumor activity of novel podophyllotoxin derivatives against multidrug-resistant cancer cells. AB - Seven novel 4beta-N-substituted podophyllotoxin derivatives with indole rings were prepared and evaluated for cytotoxicity against human cancer cell lines HeLa, KB, KBV, K562, and K562/AO2. Most of them demonstrated improved antitumor activity and weak multidrug resistance compared to the drugs currently available. PMID- 21534040 TI - A novel phenolic compound from Pinus yunnanensis. AB - A rare type of phenolic compound, namely, planchol E (1), was isolated from the cones and seeds of Pinus yunnanensis together with 16 known abietane diterpenoids (2-17). The structure of planchol E was established on the basis of extensive spectroscopic analysis, and it was found that the new compound did not show cytotoxic activity against several cancer cell lines. PMID- 21534041 TI - Illudin T, a new sesquiterpenoid from basidiomycete Agrocybe salicacola. AB - A new sesquiterpenoid (1), illudin T, was isolated from the culture of basidiomycete Agrocybe salicacola. The structure of the new compound was elucidated on the basis of spectral data. PMID- 21534042 TI - A new ursane-type triterpenoid from Schefflera heptaphylla (L.) Frodin. AB - A new ursane-type triterpenoid (1), together with 15 known compounds (2-16), was isolated from the barks of Schefflera heptaphylla (L.) Frodin. The structure of the new compound was determined on the basis of extensive spectroscopic data including IR, HR-ESI-MS, 1D and 2D NMR, and further confirmed by single-crystal X ray diffraction. Compounds 2-6 were isolated from Schefflera genus for the first time. PMID- 21534043 TI - Triterpenes and xanthones from the stem bark of Garcinia tetralata. AB - A new compound, 3beta,18,19beta-trihydroxylupane, was isolated from Garcinia tetralata, along with five known compounds, garcinexanthone B, morolic acid acetate, toxyloxanthone A, 6,11-dihydroxy-2,2-dimethylpyrano[3,2-c]xanthen-7(2H) one, and 1,4-dihydroxy-5,6-dimethoxy-xanthone. The structure of the new compound was established by extensive spectroscopic techniques. PMID- 21534044 TI - A novel indole alkaloid from deep-sea sediment metagenomic clone-derived Escherichia coli fermentation broth. AB - To explore secondary metabolites in deep-sea sediment metagenomic clone-derived Escherichia coli fermentation broth, different kinds of chromatography methods were used in the isolation procedures, while the structures of the isolated compounds were assigned based on the MS analysis and their (1)H and (13)C NMR spectra including 2D NMR techniques such as COSY, HMQC, and HMBC experiments. As a result, a novel compound was isolated and characterized as N-{1-[4 (acetylamino)phenyl]-3-hydroxy-1-(1H-indol-3-yl)propan-2-yl}-2,2 dichloroacetamide (1). In addition, eight known compounds were also obtained. Fatty acid amide hydrolase and monoacylglycerol lipase were used to screen analgesic activity, and the new compound showed analgesic activity to some extent in pharmacological test. PMID- 21534045 TI - Advanced research on acteoside for chemistry and bioactivities. AB - Acteoside is one kind of phenylethanoid glycoside, which has shown a lot of biological activities. This article reviewed the study progress of acteoside, such as distribution, preparation, identification, and bioactivities. PMID- 21534046 TI - Annonaceae: bio-resource for tomorrow's drug discovery. AB - One of the rich sources of lead compounds is the Angiosperms. Many of these lead compounds are useful medicines naturally, whereas others have been used as the basis for synthetic agents. These are potent and effective compounds, which have been obtained from plants, including anti-cancer (cytotoxic) agents, anti-malaria (anti-protozoal) agents, and anti-bacterial agents. Today, the number of plant families that have been extensively studied is relatively very few and the vast majorities have not been studied at all. The Annonaceae is the largest family in the order Magnoliales. It includes tropical trees, bushes, and climbers, which are often used as traditional remedies in Southeast Asia. Members of the Annonaceae have the particularity to elaborate a broad spectrum of natural products that have displayed anti-bacterial, anti-fungal, and anti-protozoal effects and have been used for the treatment of medical conditions, such as skin diseases, intestinal worms, inflammation of the eyes, HIV, and cancer. These special effects and the vast range of variation in potent compounds make the Annonaceae unique from other similar families in the Magnoliales and the Angiosperms in general. This paper attempts to summarize some important information and discusses a series of hypotheses about the effects of Annonaceae compounds. PMID- 21534047 TI - Effects of stress, attributional style and perceived parental support on depressive symptoms in early adolescence: a prospective analysis. AB - This study prospectively examined the role of attributional style and perceived parental support as intrapersonal and interpersonal risk and resilience factors to increases in depressive symptoms in the face of stress with a sample of 497 middle school students. Results demonstrated that boys with a pessimistic attributional style and low or moderate levels of parental support had higher levels of depressive symptoms than boys with high levels of support under high levels of stress but not under low levels of stress. Girls with a pessimistic attributional style and low or moderate levels of perceived parental support had higher levels of depressive symptoms than those with an optimistic attributional style, regardless of the level of stress. These results highlight the need to consider more complex models with multiple moderators, such as cognitive styles and parental support, as well as gender differences, in understanding the development of depressive symptoms in early adolescence. PMID- 21534048 TI - An examination of the tripartite model of depressive and anxiety symptoms in African American youth: stressors and coping strategies as common and specific correlates. AB - The purpose of the current study was to examine the tripartite model of depression and anxiety in a community-based sample of 278 African American adolescents (M age = 12.89) from low-income communities and to identify stressors and coping strategies that were associated with the specific features of each disorder. Participants reported on depression, anxiety, stressors, and coping strategies. As predicted, the three-factor structure of the tripartite model was a valid representation of anxiety and depression in African American youth. Further, stressors and coping strategies showed specific associations to features of depression and anxiety. The findings provide evidence of factors that may help to distinguish between internalizing symptoms in African American youth. PMID- 21534049 TI - Diagnosis of posttraumatic stress disorder in preschool children. AB - This study investigated the existing diagnostic algorithms for posttraumatic stress disorder (PTSD) to determine the most developmentally sensitive and valid approach for diagnosing this disorder in preschoolers. Participants were 130 parents of unintentionally burned children (1-6 years). Diagnostic interviews were conducted with parents to assess for PTSD in their child at 1 and 6 months postinjury and the Child Behavior Checklist for 1.5-5 was also completed. The proposed algorithm for PTSD in preschool children for the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) provided the most developmentally sensitive and valid measure of PTSD. The rate of PTSD diagnosis was 25% at 1 month and 10% at 6 months. The predictive utility of Criterion A was not demonstrated. These findings provide support for the inclusion of the proposed algorithm for PTSD in preschool children. PMID- 21534050 TI - Family stress and coping for Mexican origin adolescents. AB - Family-related stressors pose special challenges for adolescents of Mexican origin, given traditional cultural norms that compel youths to get involved with family problems despite their limited ability to effect change. The current study examines the prospective effects of coping strategies (i.e., active, distraction, avoidance, support-seeking, and religious coping) on psychological symptoms in the context of family stress with a sample (N = 189) of Mexican Origin adolescents (11-14). Hypotheses on the limits of coping were partially supported. Stress-coping interaction effects were further moderated by gender. Stress buffering effect of active coping for internalizing symptoms was only found for girls and only at low levels of family stress for boys. Support-seeking and distraction coping both increased internalizing symptoms for boys at high levels of family stress. PMID- 21534051 TI - The effects of domestic violence on the stability of attachment from infancy to preschool. AB - We hypothesized that trajectories of domestic violence (DV), maternal depression, and household income (from pregnancy to age 4) would be differentially associated with instability and stability of attachment, as measured by the Strange Situation at ages 1 and 4. Participants were 150 women and children. Women were first assessed during pregnancy and then yearly when the children were 1 to 4 years old. Overall, attachment was unstable for 56% of the sample from age 1 to age 4. Trajectories of DV and income both predicted attachment patterns. Positive outcomes (secure-secure and insecure-secure) were related to initially low levels of DV that stayed constant or became lower as well as initially high or low levels of income that increased over time. PMID- 21534052 TI - Leaving the parental nest: adjustment problems, attachment representations, and social support during the transition from high school to military service. AB - Adjustment to the transition from high school to military service in Israel was examined in a longitudinal study with a sample of 120 late-adolescent girls. During their senior year in high school (Time 1) the young women were administered the Adult Attachment Interview. Their coping and adjustment to the new environment were assessed (at two further points in time after the transition) by reports of the young women, their mothers, their fathers, and their friends. Young women with preoccupied attachment representations demonstrated the lowest levels of adjustment at both the second and third time points. Young women with dismissing attachment representations did not differ from those with autonomous attachment representations. Satisfaction with social support from parents mediated the association between attachment representations and adjustment (assessed by the young women's reports). PMID- 21534053 TI - Emotional Eating Scale for children and adolescents: psychometric characteristics in a Spanish sample. AB - The aims of this study were to validate the Emotional Eating Scale version for children (EES-C) in a Spanish population and study the differences in emotional eating among children with binge eating (BE), overeating (OE), and no episodes of disordered eating (NED). The questionnaire was completed by 199 children aged 9 to 16 years. Confirmatory factor analysis revealed five scales: eating in response to anger, anxiety, restlessness, helplessness, and depression. The EES-C showed good internal consistency and test-retest reliability, and it showed moderate relationships with measures of disordered-eating [Children's Eating Attitudes Test-26 (ChEAT-26), Questionnaire of Eating and Weight Patterns Adolescent Version (QEWP-A)] and psychopathology (State-Trait Anxiety Inventory for Children, Children's Depression Inventory, Child Behavior Checklist). There were significant differences between the BE/NED groups (with the OE group in the middle position) in desire to eat when Anger (the girls in BE group, and the oldest children in OE group obtaining higher scores) or Helplessness were present. Eating due to Depression was higher in the older groups. Multiple regression analysis conducted showed that anxiety-trait was the best predictor of emotional eating. Results support the potential utility of the EES-C in the study of emotional eating in children and its validity in the Spanish population. PMID- 21534054 TI - The comparison and interdependence of maternal and paternal influences on young children's behavior and resilience. AB - We investigated how mothers' and fathers' depressed mood and father-child and mother-child relationship predicted preschool children's problem behavior. The sample was 11,286 continuously intact, two-parent biological families of the United Kingdom's Millennium Cohort Study. We found that mother-child relationship and maternal depressed mood had larger effects on children's problem behavior than father-child relationship and paternal depressed mood. The effect of paternal depressed mood was completely mediated by quality of father-child relationship. There were significant moderator effects but only on internalizing problems. There was little evidence to suggest that, among children of this developmental stage, quality of father-child relationship buffers the effect of contextual risk (i.e., promotes resilience). Quality of mother-child relationship, in contrast, buffered the effect of socioeconomic disadvantage but only on emotional symptoms. PMID- 21534055 TI - Trajectories of adolescent mother-grandmother psychological conflict during early parenting and children's problem behaviors at age 7. AB - This study extends the determinants of parenting model to adolescent mothers by examining how adolescent mother-grandmother psychological conflict and perceptions of infant fussiness from birth through age 2 years relate to children's problem behaviors at age 7. Participants were 181 adolescent mother, child, and grandmother triads living in multigenerational households and recruited at delivery. Psychological conflict was characterized by two stable trajectories. In multivariate models that included maternal depression, both psychological conflict and perceptions of infant fussiness predicted externalizing behavior at age 7. Perceptions of infant fussiness, but not psychological conflict, predicted internalizing behavior at age 7. PMID- 21534056 TI - International comparisons of behavioral and emotional problems in preschool children: parents' reports from 24 societies. AB - International comparisons were conducted of preschool children's behavioral and emotional problems as reported on the Child Behavior Checklist for Ages 11/2-5 by parents in 24 societies (N = 19,850). Item ratings were aggregated into scores on syndromes; Diagnostic and Statistical Manual of Mental Disorders-oriented scales; a Stress Problems scale; and Internalizing, Externalizing, and Total Problems scales. Effect sizes for scale score differences among the 24 societies ranged from small to medium (3-12%). Although societies differed greatly in language, culture, and other characteristics, Total Problems scores for 18 of the 24 societies were within 7.1 points of the omnicultural mean of 33.3 (on a scale of 0-198). Gender and age differences, as well as gender and age interactions with society, were all very small (effect sizes < 1%). Across all pairs of societies, correlations between mean item ratings averaged .78, and correlations between internal consistency alphas for the scales averaged .92, indicating that the rank orders of mean item ratings and internal consistencies of scales were very similar across diverse societies. PMID- 21534057 TI - Parenting and trajectories of children's maladaptive behaviors: a 12-year prospective community study. AB - This study investigated how parenting accounted for interindividual differences in developmental trajectories of different child behaviors across childhood and adolescence. In a cohort sequential community sample of 1,049 children, latent class growth analysis was applied to three parent-reported dimensions (monitoring, positive parenting, inconsistent discipline) across 12 annual assessments (ages 6-18). Four longitudinal parenting styles (authoritative, authoritarian, indulgent, uninvolved) were differentiated on the basis of levels and rates of change in the constituent parenting dimensions. Multigroup analyses demonstrated that these parenting styles were differentially related to changes in parent- and child-reported measures of children's alcohol and cigarette use, antisocial behavior, and internalizing symptoms, with the authoritative parenting class being related to the most optimal long-term development. PMID- 21534058 TI - Patients' contexts and their effects on clinicians' impressions of conduct disorder symptoms. AB - The purpose of this study was to examine whether contextual information about patients' clinical presentations affected clinicians' judgments of conduct disorder symptoms. Forty-five clinicians read vignettes describing hypothetical patients who displayed one conduct disorder symptom alongside information about the patients' home, school, and peer contexts. Clinicians judged the likelihood of patients meeting conduct disorder criteria. Contextual information highly affected judgments and these effects varied across the 15 conduct disorder symptoms. It is important to note that clinical judgments were not in agreement on the symptoms affected by context. PMID- 21534059 TI - Relationship quality and depressive symptoms among adolescents: a short-term multiwave investigation of longitudinal, reciprocal associations. AB - This study used a multiwave design to examine the short-term longitudinal and bidirectional associations between depressive symptoms and peer relationship qualities among a sample of early to middle adolescents (N = 350, 6th-10th graders). Youth completed self-report measures of relationship quality and depressive symptoms at three time points spaced about 5 weeks apart. Results indicated that depressive symptoms predicted increases in negative qualities and decreases in positive qualities. However, neither positive nor negative relationship qualities predicted increases in depressive symptoms. Findings inform a developmentally based interpersonal model of depression by advancing knowledge on the longitudinal direction of effects between depressive symptoms and relationship quality in adolescence. PMID- 21534060 TI - Domains of chronic stress and suicidal behaviors among inpatient adolescents. AB - Little is known about the role of chronic stress in youth suicidal behaviors. This study examined the relations between specific domains of chronic stress and suicidal behaviors among 131 inpatient youth (M age = 15.02 years) who completed measures of stress, suicidal ideation, suicide attempt, and suicide intent. After controlling for demographics, diagnostic status, past history of attempt, and life event stress, the predictors of suicidal ideation were chronic stress in family relationships, close friendship, and physical health. Chronic close friendship stress also predicted suicide intent among attempters after controlling for covariates. No domain robustly predicted the presence of an attempt or moderated the relation between life event stress and suicidal behaviors. These findings highlight the role of certain domains of chronic stress in suicidal ideation and suicide intent. PMID- 21534061 TI - A prospective study of risk factors for the development of depression and disordered eating in adolescents. AB - There is evidence that females display higher levels of depressive symptoms and disordered eating than males from adolescence onward. This study examined whether different risk factors and their interaction with sex (moderator effect) prospectively predicted depressive symptoms and disordered eating in adolescents. A total of 415 female adolescents and 413 male adolescents were evaluated at 2 different times: In the first evaluation (T1) the mean age of the participants was 12.8 years, and in the second evaluation (T2) it was 14.9 years. Differences between sexes were observed in relation to depressive symptoms at T2 and in disordered eating at T1 and T2. Body dissatisfaction was a significant predictor of both depressive symptoms and disordered eating. In addition, moderation tests indicated that the interaction between self-esteem and sex and the interaction between body mass index and sex significantly predicted depressive symptoms and disordered eating, respectively. PMID- 21534063 TI - Making our case(s). AB - Health care chaplaincy needs to develop a body of published case studies. Chaplains need these case studies to provide a foundation for further research about the efficacy of chaplains' spiritual care. Case studies can also play an important role in training new chaplains and in continuing education for experienced chaplains, not to mention educating health care colleagues and the public about the work of health care chaplains. Guidelines for writing case studies are described, herein, as is a project in which three experienced oncology chaplains worked together to write case studies about their work. Steps that chaplains, and professional chaplain organizations, can take to further the writing and publishing of case studies are described. PMID- 21534064 TI - Case study of a chaplain's spiritual care for a patient with advanced metastatic breast cancer. AB - The case study seeks to describe an oncology chaplain's pastoral relationship with a 64-year-old woman with advanced metastatic breast cancer. The patient's distress was complicated by a history of anxiety and other chronic medical conditions. Approximately 16 pastoral encounters occurred during the last year of the patient's life. The patient, chaplain, and the pastoral conversations are presented as well as a retrospective assessment of them. The chaplain's interventions were appropriate for the patient's spiritual needs, particularly in regard to her fear of death, loneliness, grief that her life was "too short" and estrangement from her inherited faith tradition, with observable benefits for the patient. The oncology chaplain has a distinctive role in the healthcare team as one who can meet the patient at the point of their spiritual need, provide appropriate interventions and, thereby, ameliorate the distress, particularly in regard to death anxiety, peace of mind, and issues of meaning. PMID- 21534065 TI - Touched by an angel: a chaplain's response to the case study's key interventions, styles, and themes/outcomes. AB - This article is a response by a long-term oncology chaplain to a case by another oncology chaplain. The author notes interventions key to the relationship and outcomes, highlights differences in chaplaincy styles, and summarizes significant outcomes that are common in oncology chaplaincy. The purpose of the response is to further demonstrate how chaplains think about and engage patients/families in chaplaincy care as well as to stimulate the reflective process of the readers of the case study. PMID- 21534066 TI - A psychologist's response to the case study: application of theory and measurement. AB - This article represents a psychologist's perspective on the case study of Doris, a middle-aged woman with metastatic breast cancer who is initially referred to Chaplain Rhonda for assistance with death anxiety. In the field of psychology, it has long been accepted that good clinical research is informed by theory. As such, Chaplain Rhonda's intervention with Doris will be examined through the lens of object relations theory. Specifically, we will see how Rhonda's relationship and interaction with Doris improves her image of God and, by doing so, decreases her death anxiety. In psychological research, it is also important to accurately measure the effects or outcomes of clinical interventions. In this light, several suggestions are offered for the measurement of constructs relevant to the case of Doris, namely God image and death anxiety. Finally, a simple case study research design, applying the aforementioned theory and measurement, is provided as a suggested starting point for research on the efficacy of chaplaincy interventions. PMID- 21534067 TI - Ethical issues in case study publication: "making our case(s)" ethically. AB - As chaplains develop richly detailed case studies for publication, ethical questions about case study construction and publication are emerging. Concerns about seeking patients' permission to publish material about them suggest additional questions and raise broad confidentiality and privacy issues. Confidentiality-related practices in health care and psychotherapy provide the most extensive guidance for chaplains, but healthcare chaplaincy has roots in religious and professional traditions with distinct notions of confidentiality that deserve consideration. Single case studies do not appear to be "research" requiring informed consent, yet their publication exposes patients to some risk of harm. Obtaining the patient's/"case study subject's" permission to publish, disguising non-essential information, and allowing the patient to review the case study can mitigate the risks. Striking a balance between protecting patients and providing sufficient detail to make case studies useful is a central ethical challenge of case study publication. PMID- 21534068 TI - Grief in healthcare chaplains: an investigation of the presence of disenfranchised grief. AB - We examined how chaplains respond to grief and determined the prevalence of disenfranchised grief (i.e., grief that is not or cannot be acknowledged or supported by society) in healthcare chaplains. We conducted an online survey of members of the Association of Professional Chaplains. Of 3131 potential participants, 577 (18%) responded to the survey. In response to grief in the workplace, chaplains stated they would have low energy (78%), feel sad or moody (63%), feel like they had no time for themselves (44%), go through the motions (41%), and distance themselves from others (31%). As an indicator of disenfranchised grief, 21% of chaplains felt that their grief was not supported and affirmed in the workplace and 63% listed circumstances of death about which they felt very uncomfortable hearing or talking about. The results suggest that grief, and disenfranchised grief in particular, may be an important concern to address in healthcare chaplaincy. PMID- 21534069 TI - The use of dreams in spiritual care. AB - This paper explores the use of dreams in the context of pastoral care. Although many people dream and consider their dreams to hold some significant spiritual meaning, spiritual care providers have been reluctant to incorporate patients' dreams into the therapeutic conversation. Not every dream can be considered insightful, but probing the meaning of some dreams can enhance spiritual care practice. Hill's Cognitive-Experimental Dream Interpretation Model is applied in the current article as a useful framework for exploring dreams, gaining insight about spiritual problems, and developing a therapeutic plan of action. Bulkeley's criteria for dream interpretation were used to furnish safeguards against inappropriate application of dream interpretation to spiritual assessment and interventions. PMID- 21534070 TI - Masculinities and sexualities in sport and physical cultures: three decades of evolving research. AB - This article traces the foundation of the study between sport and physical cultures and masculinities and sexualities principally by examining the homophobic zeitgeist by which the academic discipline was formed. I show that the intense homophobia of the mid-1980s waned throughout the 1990s, and that during the new millennia, researchers found more inclusive forms of heterosexuality. Indeed, research on masculinities and homophobia today shows that, even in the traditionally conservative institution of sport, matters have shifted dramatically. This has resulted not only in improved conditions for sexual minorities, but it has also promoted a culture of softer, more tactile and emotional forms of heterosexual masculinities. These studies, alongside those within this special issue of the Journal of Homosexuality, highlight the necessity of developing new ways of theorizing the changing dynamics between masculinities, sexualities, and physical cultures in the next decade. PMID- 21534071 TI - "Josh wears pink cleats": inclusive masculinity on the soccer field. AB - In this ethnographic research of a college-based soccer team at a large liberal college in Northeast America, I document the existence of more inclusive versions of masculinity that contrast conventional understandings of male teamsport athletes. Using participant observation and 21 in-depth interviews, I show that these men demonstrate metrosexual and inclusive behaviors and attitudes. The styles of masculinity these men enact are more relaxed, liberal, and inclusive; they are well styled, well groomed, gay friendly, and they are emotionally and physically close to other men. They are far removed from the traditional orthodox sporting masculinities of previous generations. Symbolizing their difference, their gendered expressions also extend to the wearing of pink soccer boots (cleats), without homophobic judgment from teammates. I discuss the wearing of pink cleats as a symbolic sociological moment, revealing the changing nature of masculinities among this group of college-based soccer players. PMID- 21534072 TI - Sport fans' impressions of gay male athletes. AB - The purpose of this study was to examine sport fans' impressions of gay male athletes. Participants formed impressions of a fictional athlete from their favorite team after reading a short scenario about the player. The scenarios described the athlete as being gay or straight, and either becoming a distraction or not causing a distraction to the team. While males' ratings of the athlete did not significantly differ, female fans formed significantly more positive impressions of the gay male player than the straight athlete. These results are discussed in terms of the ingroup bias and the shifting culture of homophobia in sport. PMID- 21534073 TI - Clubbing masculinities: gender shifts in gay men's dance floor choreographies. AB - This article adopts an interdisciplinary approach to understanding the intersections of gender, sexuality, and dance. It examines the expressions of sexuality among gay males through culturally popular forms of club dancing. Drawing on political and musical history, I outline an account of how gay men's gendered choreographies changed throughout the 1970s, 80s, and 90s. Through a notion of "technologies of the body," I situate these developments in relation to cultural levels of homophobia, exploring how masculine expressions are entangled with and regulated by musical structures. My driving hypothesis is that as perceptions of cultural homophobia decrease, popular choreographies of gay men's dance have become more feminine in expression. Exploring this idea in the context of the first decade of the new millennium, I present a case study of TigerHeat, one of the largest weekly gay dance club events in the United States. PMID- 21534074 TI - Men at sport: gay men's experiences in the sport workplace. AB - Research on sexual identity and sport has revealed a shifting narrative about the experiences of gay men. While some suggest the atmosphere is hostile, others posit that homophobia and sexual prejudice are playing less of a role in gay men's experiences. This research focuses on the experiences of 10 gay men working in professional, collegiate, and club sport, as part of a larger dataset of 37 male and female employees. Five of the men were overtly and publicly out at work, while five were closeted (to varying degrees). This article focuses on three themes for gay men working in sport: 1) the importance of coming out in the workplace; 2) the role of the locker room as a contested terrain, and 3) the disconnect between their experiences at work and their perceptions of the workplace environment as negative or positive. Men in this study were basing their impressions on their total experience in sport (as current and former players, as employees, and as fans). It also suggests that the public "story" of gay men working in sport represents one of two extremes-either the proverbial "horror story," or the extremely positive representation of gay men's experiences. This research suggests that gay men's experiences in sport are more complex and nuanced than the public narrative implies. PMID- 21534075 TI - The benefits of sexual orientation diversity in sport organizations. AB - While sexual orientation diversity can potentially serve as a source of competitive advantage, researchers have largely failed to fully articulate the theoretical linkage between this diversity form and organizational effectiveness. As such, we propose a theoretical framework to understand these dynamics. Sexual orientation diversity is posited to positively contribute to organizational effectiveness through three mechanisms: enhanced decision making capabilities, improved marketplace understanding, and goodwill associated with engaging in socially responsible practices. We also propose two approaches to leveraging the benefits of sexual orientation diversity: targeting the categorization process and creating a proactive and inclusive diversity culture. Contributions and implications are discussed. PMID- 21534076 TI - Mapping the terrain of homosexually-themed language. AB - In this article, I present a new model for understanding homosexually-themed language. By detailing how old conceptualizations of homophobic language no longer maintain heuristic utility in explaining the social dynamics of many sport and educational settings, I situate other conceptualizations of homosexually themed language depending on the cultural context. I argue that whether language is considered homophobic, or whether it is better conceptualized as fag discourse, gay discourse or pro-gay language, is primarily dependent on the homohysteria of a setting. This model should enable scholars and educators to understand the operation of homosexually-themed language in society and properly evaluate the homophobia of a setting. PMID- 21534077 TI - Homophobic and sexist yet uncontested: examining football fan postings on Internet message boards. AB - Although a homophobic and sexist archetype of heterosexual masculinity has been thought to permeate competitive teamsport, matters have been rapidly changing. This is evident in research on openly gay athletes, attitudes among heterosexual athletes, and recent studies on decreasing homophobia among sport media content. In this research, however, we examine how some men still adhere to a homophobic and sexist masculine deposition when discussing sport on the Internet. A textual analysis was used to analyze hegemonic masculinity from a popular American football message board. Although posts related to hegemonic masculinity did not permeate the data, we found that this traditional form of masculinity was upheld through misogyny, homophobia, and the objectification of women. Thus, whereas mainstream sport media is increasingly policed for homophobia and sexism, this research shows that the anonymity of the Internet permits hegemonic masculinity to flourish in specific locations, without contestation. PMID- 21534081 TI - Development and evaluation of a semi-empirical two-zone dust exposure model for a dusty construction trade. AB - Drywall finishing is a dusty construction activity. We describe a mathematical model that predicts the time-weighted average concentration of respirable and total dusts in the personal breathing zone of the sander, and in the area surrounding joint compound sanding activities. The model represents spatial variation in dust concentrations using two-zones, and temporal variation using an exponential function. Interzone flux and the relationships between respirable and total dusts are described using empirical factors. For model evaluation, we measured dust concentrations in two field studies, including three workers from a commercial contracting crew, and one unskilled worker. Data from the field studies confirm that the model assumptions and parameterization are reasonable and thus validate the modeling approach. Predicted dust C(twa) were in concordance with measured values for the contracting crew, but under estimated measured values for the unskilled worker. Further characterization of skill related exposure factors is indicated. PMID- 21534082 TI - Effect of exit spacing in a multiple-jet nozzle on noise levels at audible frequencies. AB - This work investigated the effect of exit spacing on audible noise levels generated by a multiple-jet nozzle, which replaces the single exit in a common nozzle with multiple smaller exits to reduce the risk of hearing damage. Sound measurements and 1/3-octave band analyses were performed for multiple-jet nozzles with varying exit diameters and exit spacings. Results show that the effect of exit spacing is evident below a certain frequency range, which falls in the relatively low frequency part of the sound spectrum. The frequency range affected by exit spacing was found to extend to higher frequencies if the exits were more closely distributed. It was found that decreasing the exit spacing will shift the sound spectrum toward the low frequency side, which has been shifted toward the high frequency side by the use of smaller exits, and will increase the sound pressure levels at lower frequencies. When the exits were confined in a limited area, to maintain a constant total exit area, decreasing the exit diameters will increase the number of exits and reduce the exit spacing. Smaller exit diameters will increase the sound frequency and shift the sound spectrum toward the high frequency side, while decreased exit spacing has the opposite effect of shifting the spectrum toward the low frequency side. Due to these two opposing effects, for a multiple-jet nozzle with a limited size, there is an optimum exit diameter that, depending on the method used to evaluate the overall sound pressure level, generates the lowest sound pressure levels in the audible frequency range. If there is no limit to its physical size, a multiple-jet nozzle should avoid using an exit spacing that is too small. The minimum exit spacing required to avoid the adverse effects of a small exit spacing requires more extensive studies. PMID- 21534083 TI - Multiple modes of action of asbestos and related mineral fibers. PMID- 21534084 TI - Applying definitions of "asbestos" to environmental and "low-dose" exposure levels and health effects, particularly malignant mesothelioma. AB - Although asbestos research has been ongoing for decades, this increased knowledge has not led to consensus in many areas of the field. Two such areas of controversy include the specific definitions of asbestos, and limitations in understanding exposure-response relationships for various asbestos types and exposure levels and disease. This document reviews the current regulatory and mineralogical definitions and how variability in these definitions has led to difficulties in the discussion and comparison of both experimental laboratory and human epidemiological studies for asbestos. This review also examines the issues of exposure measurement in both animal and human studies, and discusses the impact of these issues on determination of cause for asbestos-related diseases. Limitations include the lack of detailed characterization and limited quantification of the fibers in most studies. Associated data gaps and research needs are also enumerated in this review. PMID- 21534085 TI - Morphological and chemical mechanisms of elongated mineral particle toxicities. AB - Much of our understanding regarding the mechanisms for induction of disease following inhalation of respirable elongated mineral particles (REMP) is based on studies involving the biological effects of asbestos fibers. The factors governing the disease potential of an exposure include duration and frequency of exposures; tissue-specific dose over time; impacts on dose persistence from in vivo REMP dissolution, comminution, and clearance; individual susceptibility; and the mineral type and surface characteristics. The mechanisms associated with asbestos particle toxicity involve two facets for each particle's contribution: (1) the physical features of the inhaled REMP, which include width, length, aspect ratio, and effective surface area available for cell contact; and (2) the surface chemical composition and reactivity of the individual fiber/elongated particle. Studies in cell-free systems and with cultured cells suggest an important way in which REMP from asbestos damage cellular molecules or influence cellular processes. This may involve an unfortunate combination of the ability of REMP to chemically generate potentially damaging reactive oxygen species, through surface iron, and the interaction of the unique surfaces with cell membranes to trigger membrane receptor activation. Together these events appear to lead to a cascade of cellular events, including the production of damaging reactive nitrogen species, which may contribute to the disease process. Thus, there is a need to be more cognizant of the potential impact that the total surface area of REMP contributes to the generation of events resulting in pathological changes in biological systems. The information presented has applicability to inhaled dusts, in general, and specifically to respirable elongated mineral particles. PMID- 21534086 TI - Pulmonary endpoints (lung carcinomas and asbestosis) following inhalation exposure to asbestos. AB - Lung carcinomas and pulmonary fibrosis (asbestosis) occur in asbestos workers. Understanding the pathogenesis of these diseases is complicated because of potential confounding factors, such as smoking, which is not a risk factor in mesothelioma. The modes of action (MOA) of various types of asbestos in the development of lung cancers, asbestosis, and mesotheliomas appear to be different. Moreover, asbestos fibers may act differentially at various stages of these diseases, and have different potencies as compared to other naturally occurring and synthetic fibers. This literature review describes patterns of deposition and retention of various types of asbestos and other fibers after inhalation, methods of translocation within the lung, and dissolution of various fiber types in lung compartments and cells in vitro. Comprehensive dose-response studies at fiber concentrations inhaled by humans as well as bivariate size distributions (lengths and widths), types, and sources of fibers are rarely defined in published studies and are needed. Species-specific responses may occur. Mechanistic studies have some of these limitations, but have suggested that changes in gene expression (either fiber-catalyzed directly or by cell elaboration of oxidants), epigenetic changes, and receptor-mediated or other intracellular signaling cascades may play roles in various stages of the development of lung cancers or asbestosis. PMID- 21534087 TI - Nonpulmonary outcomes of asbestos exposure. AB - The adverse pulmonary effects of asbestos are well accepted in scientific circles. However, the extrapulmonary consequences of asbestos exposure are not as clearly defined. In this review the potential for asbestos to produce diseases of the peritoneum, immune, gastrointestinal (GIT), and reproductive systems are explored as evidenced in published, peer-reviewed literature. Several hundred epidemiological, in vivo, and in vitro publications analyzing the extrapulmonary effects of asbestos were used as sources to arrive at the conclusions and to establish areas needing further study. In order to be considered, each study had to monitor extrapulmonary outcomes following exposure to asbestos. The literature supports a strong association between asbestos exposure and peritoneal neoplasms. Correlations between asbestos exposure and immune-related disease are less conclusive; nevertheless, it was concluded from the combined autoimmune studies that there is a possibility for a higher-than-expected risk of systemic autoimmune disease among asbestos-exposed populations. In general, the GIT effects of asbestos exposure appear to be minimal, with the most likely outcome being development of stomach cancer. However, IARC recently concluded the evidence to support asbestos-induced stomach cancer to be "limited." The strongest evidence for reproductive disease due to asbestos is in regard to ovarian cancer. Unfortunately, effects on fertility and the developing fetus are under-studied. The possibility of other asbestos-induced health effects does exist. These include brain-related tumors, blood disorders due to the mutagenic and hemolytic properties of asbestos, and peritoneal fibrosis. It is clear from the literature that the adverse properties of asbestos are not confined to the pulmonary system. PMID- 21534088 TI - Non-neoplastic and neoplastic pleural endpoints following fiber exposure. AB - Exposure to asbestos fibers is associated with non-neoplastic pleural diseases including plaques, fibrosis, and benign effusions, as well as with diffuse malignant pleural mesothelioma. Translocation and retention of fibers are fundamental processes in understanding the interactions between the dose and dimensions of fibers retained at this anatomic site and the subsequent pathological reactions. The initial interaction of fibers with target cells in the pleura has been studied in cellular models in vitro and in experimental studies in vivo. The proposed biological mechanisms responsible for non neoplastic and neoplastic pleural diseases and the physical and chemical properties of asbestos fibers relevant to these mechanisms are critically reviewed. Understanding mechanisms of asbestos fiber toxicity may help us anticipate the problems from future exposures both to asbestos and to novel fibrous materials such as nanotubes. Gaps in our understanding have been outlined as guides for future research. PMID- 21534091 TI - Military sexual trauma: current knowledge and future directions. PMID- 21534092 TI - Unreliability and error in the military's "gold standard" measure of sexual harassment by education and gender. AB - The Department of Defense's "gold standard" sexual harassment measure, the Sexual Harassment Core Measure (SHCore), is based on an earlier measure that was developed primarily in college women. Furthermore, the SHCore requires a reading grade level of 9.1. This may be higher than some troops' reading abilities and could generate unreliable estimates of their sexual harassment experiences. Results from 108 male and 96 female soldiers showed that the SHCore's temporal stability and alternate-forms reliability was significantly worse (a) in soldiers without college experience compared to soldiers with college experience and (b) in men compared to women. For men without college experience, almost 80% of the temporal variance in SHCore scores was attributable to error. A plain language version of the SHCore had mixed effects on temporal stability depending on education and gender. The SHCore may be particularly ill suited for evaluating population trends of sexual harassment in military men without college experience. PMID- 21534093 TI - Veterans Health Administration mental health treatment settings of patients who report military sexual trauma. AB - The comprehensive Veterans Health Administration (VHA) policies on military sexual trauma (MST) include provider education and training at each VHA facility. No published data exist that indicate the settings in which VHA mental health patients with MST are treated. Such information could help set priorities for targeted MST-related education and training. The major aim of this article was to describe the VHA mental health outpatient settings in which patients with MST are most likely to be treated. National data from 79,903 female and 889,998 male veteran patients with at least one face-to-face outpatient mental health encounter at any VHA facility in fiscal year 2008 were analyzed. Among all veterans in VHA outpatient mental health care, 35.8% of women and 2.4% of men reported MST. The proportion of MST-positive patients ranged from 25.9% to 81.0% of women and from 1.5% to 56.1% of men across 9 major clinic setting categories. Proportions of women with MST were substantial across specialty MST clinics, specialty posttraumatic stress disorder clinics, psychosocial rehabilitation, and substance use disorder clinics, reflecting a wide range of settings. These settings should be prioritized for MST-related provider education and training. By contrast, male MST patients represented only a small proportion of patients in all clinics, with the exception of MST specialty clinics. Tailored conceptualizations of trauma-informed care are proposed for settings that encounter MST patients, even if these settings do not directly focus on the treatment of traumatic stress. PMID- 21534094 TI - Military sexual trauma in men: a review of reported rates. AB - Military sexual trauma (MST) has historically been associated with female service members, but it is also experienced by male service members. This article reviews reported prevalence and incidence rates of men's MST in 29 studies. Sources for these studies included the Department of Defense, the U.S. military service academies, and the Department of Veterans Affairs. There is significant variability in reported rates of men's MST. Averaging across studies covering the past 30 years, we found that MST is reported by approximately 0.09% of male service members each year, with a range of 0.02% to 6%. MST is reported by 1.1% of male service members over the course of their military careers, with a range of 0.03% to 12.4%. Determining prevalence and incidence rates for both men's and women's MST is fraught with limitations, including (a) cross-study variations in sample, method, definitions, and assessment and (b) barriers to reporting MST. Each of these limitations is reviewed with an eye toward identifying male specific issues. PMID- 21534090 TI - Factors that impact susceptibility to fiber-induced health effects. AB - Asbestos and related fibers are associated with a number of adverse health effects, including malignant mesothelioma (MM), an aggressive cancer that generally develops in the surface serosal cells of the pleural, pericardial, and peritoneal cavities. Although approximately 80% of individuals with MM are exposed to asbestos, fewer than 5% of asbestos workers develop MM. In addition to asbestos, other mineralogical, environmental, genetic, and possibly viral factors might contribute to MM susceptibility. Given this complex etiology of MM, understanding susceptibility to MM needs to be a priority for investigators in order to reduce exposure of those most at risk to known environmental carcinogens. In this review, the current body of literature related to fiber associated disease susceptibility including age, sex, nutrition, genetics, asbestos, and other mineral exposure is addressed with a focus on MM, and critical areas for further study are recommended. PMID- 21534095 TI - Posttraumatic sequelae associated with military sexual trauma in female veterans enrolled in VA outpatient mental health clinics. AB - The purpose of this study was to explore the relationship between military sexual assault (MSA) and posttraumatic stress disorder (PTSD) and other symptoms associated with trauma, referred to as disorders of extreme stress not otherwise specified (DESNOS) or complex PTSD within a Veterans Affairs (VA) Medical Center outpatient mental health treatment-seeking sample. The present results focus on female Veterans only because of the low rates of endorsement of MSA among male Veterans resulting in a sample too small to use in analyses. Compared with those who did not endorse MSA, those who did reported greater frequency of other potentially traumatic events; PTSD symptoms; and symptoms characteristic of DESNOS, such as difficulties with interpersonal relationships, emotion regulation, dissociation, somatization, and self-perception. When childhood and other adulthood interpersonal trauma were both taken into account, MSA continued to contribute unique variance in predicting PTSD and DESNOS symptoms. VA patients reporting MSA may represent notably heterogeneous groups that include more complex posttraumatic reactions. Treatment interventions focused on complex PTSD may be warranted for a subset of female veterans who endorse MSA. PMID- 21534096 TI - Posttraumatic stress symptomatology as a mediator of the association between military sexual trauma and post-deployment physical health in women. AB - This study examined posttraumatic stress symptomatology (PSS) as a mediator of the association between military sexual trauma and post-deployment physical health. Relationships were examined in a sample of 83 female veterans of the first Gulf War (1990-1991) approximately 10 years post-deployment. Participants reported on the frequency of sexual harassment and sexual assault experienced during deployment. Physical health was measured using participants' self-reports of pre-deployment and post-deployment symptoms within 7 body systems. Sexual harassment exposure was not found to be associated with PSS-mediated associations with physical health symptoms. However, sexual assault during deployment was found to be associated with PSS and 4 of the 7 health symptom clusters assessed: gastrointestinal, genitourinary, musculoskeletal, and neurological symptoms. Furthermore, PSS was found to be a significant mediator of the sexual assault physical health relationship in each of these domains, with the indirect path accounting for 74% to 100% of the relationship. The findings from the current study indicate that sexual assault has detrimental associations with physical health and that PSS plays a primary role in that relationship. PMID- 21534097 TI - Is military sexual trauma associated with trading sex among women veterans seeking outpatient mental health care? AB - A robust association between sexual trauma and trading sex has been documented in civilian samples but has not been examined in veterans. Women veterans experience high rates of sexual victimization across the lifespan, including during military service (military sexual trauma [MST]). Associations between MST and trading sex were examined in 200 women enrolled in a crosssectional study of HIV risks and seroprevalence among women receiving outpatient mental health care at a Veterans Affairs (VA) medical center. Each woman completed an assessment interview composed of validated measures that queried childhood sexual trauma; substance use; and risk behaviors, including trading sex for money, drugs, shelter, food, or other things. History of MST was derived from mandated VA screening results and chart notes. Overall, 19.7% reported a history of trading sex. Those who reported trading sex had a higher rate of MST than those who did not report trading sex (87.2% vs. 62.9%, respectively). A multivariable logistic regression model examined the relationship between trading sex and MST, controlling a priori for substance abuse and childhood sexual trauma (both associated with trading sex in civilian samples) and education, which was associated with trading sex in our sample. In this adjusted model, MST was associated with trading sex: odds ratio = 3.26, p = .025, 95% confidence interval = [1.16, 9.18]. To our knowledge, this is the 1st report of an association between MST and trading sex. Results extend previously observed associations between sexual trauma and trading sex in civilian cohorts and underscore the pernicious influence of sexual victimization across the lifespan. PMID- 21534098 TI - Reengineering gender relations in modern militaries: an evolutionary perspective. AB - This article presents an evolutionary framework for understanding the sexual assault of women in the military. We specify the evolutionary underpinnings of tensions among heterosexual males, among heterosexual females, and between males and females and discuss how these tensions have played out in the strongly gendered context of warrior culture. In the absence of cultural interventions that take into account deep-seated conceptions of women in the military as unwelcome intruders, sexual resources for military men, or both, military women operate in an environment in which sexual assault may be deployed to enact and defend traditional military structures. We discuss how unit norms are likely to affect the choice of strategies by men and by women and how the resulting behaviors-including celibacy, consensual sex, and sexual assault-should affect horizontal and vertical unit cohesion. The framework is intended to guide future data collection in theoretically coherent ways and to inform the framing and enforcement of policies regarding both consensual and non-consensual sex among military personnel. PMID- 21534089 TI - Role of mutagenicity in asbestos fiber-induced carcinogenicity and other diseases. AB - The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases. This article summarizes the findings from existing literature with a focus on genetic changes, specifically, mutagenicity of asbestos fibers. Thus far, experimental evidence suggesting the involvement of mutagenesis in asbestos carcinogenicity is more convincing than asbestos-induced fibrotic diseases. The potential contributions of mutagenicity to asbestos induced diseases, with an emphasis on carcinogenicity, are reviewed from five aspects: (1) whether there is a mutagenic mode of action (MOA) in fiber-induced carcinogenesis; (2) mutagenicity/carcinogenicity at low dose; (3) biological activities that contribute to mutagenicity and impact of target tissue/cell type; (4) health endpoints with or without mutagenicity as a key event; and finally, (5) determinant factors of toxicity in mutagenicity. At the end of this review, a consensus statement of what is known, what is believed to be factual but requires confirmation, and existing data gaps, as well as future research needs and directions, is provided. PMID- 21534099 TI - Military sexual trauma research: a proposed agenda. AB - Military sexual trauma (MST) is a widespread problem associated with negative psychological and physical health problems. This article presents the current state of MST research and highlights specific areas in need of more focused study. Areas that have produced the greatest body of knowledge include MST prevalence and psychological and physical health correlates. We propose a research agenda based on gaps noted in our research review and empirical and theoretical evidence of issues relevant to but not studied directly in MST populations. We present evidence that MST is qualitatively distinct from other forms of sexual maltreatment in terms of its relational and vocational context as well as the severity of associated psychological distress, examine underexplored gender and sexual issues in MST, and discuss the lack of treatment and prevention studies specific to MST. Specific recommendations are made throughout in an attempt to guide and advance the field. PMID- 21534101 TI - Journal of Women & Aging. From the editor. PMID- 21534102 TI - Retired women and volunteering: the good, the bad, and the unrecognized. AB - In this article, we examine varied attitudes and practices toward volunteering in later life, as shared by a group of 40 retired women. We categorize women based on their engagement in retirement and label the categories according to societal expectations as follows: traditional volunteers as "good," nonvolunteers as "bad," and caregiving volunteers as "unrecognized." Using critical gerontology and a feminist framework, we juxtapose the lived experiences of retired women with a prevailing discourse on successful aging and civic engagement. We advocate for societal recognition of caregiving as a valuable form of volunteering, as well as the need to respect multiple ways in which older women experience and find meaning in later life. PMID- 21534103 TI - Emotional strain in caregiving among African American grandmothers raising their grandchildren. AB - African Americans are disproportionately represented in the number of grandparents raising their grandchildren. Using Role Strain Theory and Socioemotional Selectivity Theory, this study examines how older grandmothers fare relative to their younger counterparts. Eighty-five custodial African American grandmothers, aged 33-88 years old, completed demographic questionnaires and scales of Role Demand, Emotional Strain, Caregiving Strain Index, and Level of Care. Results showed older grandmothers experienced less emotional and caregiving strain relative to younger grandmothers. Furthermore, married grandmothers experienced less caregiving strain, and their age did not insulate them from the strain associated with the level of care. Implications are discussed. PMID- 21534104 TI - Sustainable caregiving? Demands upon and resources of female carers of adults with intellectual disability. AB - Female carers of adults with an intellectual disability are increasing in our communities as those with intellectual disability live into middle and old age. Twenty-seven carers between the ages of 45 and 85 years responded to questionnaires about demands, resources, and their health. Almost all were in the clinical range on the measure of psychological functioning. Demands contributed significantly to poorer functioning; however, other measures did not. The women in this study appeared to underreport the level of difficulties they experienced. The caregiving role undertaken by these women does not appear to be sustainable under their current circumstances. PMID- 21534105 TI - Time use and well-being in older widows: adaptation and resilience. AB - Research on widowhood mostly emphasizes negative outcomes, but some studies suggest widows are resilient. This study evaluated the in-depth daily experiences of older widows compared to married women. Participants included 75 widows and 125 married women from the National Study of Daily Experiences II, who completed daily diaries over 8 days. For long-term widows, there were no differences compared to married women in daily and general well-being, and a few differences in time use. Results add to the literature by using daily diary data to illustrate the general resilience of older women many years after the death of a spouse. PMID- 21534106 TI - The ending of menstruation: perspectives and experiences of lesbian and heterosexual women. AB - This article aims to theorize how a sample of menopausal women, lesbian and heterosexual, construct the ending of their periods, and what the experience means for them. Findings indicate that for most of the lesbian participants (who were in a sizeable minority), emotions of loss at the ending of periods were simultaneously expressed alongside positive feelings, and they engaged in greater introspection around the issue than did heterosexual women. However, lesbians did not all take up a singular subject position in relation to menstruation, indicating that there is fragmentation and plurality in how the body is experienced across a group. PMID- 21534109 TI - Web 2.0 support for residents' and fellows' patient care and educational needs. AB - This article discusses librarian support of medical education programs and patient care with blogs and wikis. Pedagogical background for using Web 2.0 tools in educational settings is explored and example applications given. A survey of health sciences libraries usage of blogs and wikis was conducted in 2009-2010. Using the results from the survey plus five years of experience using blogs and wikis at the University of Washington Health Sciences Library, best practices were compiled and are presented for guidance in establishing new blogs and wikis. PMID- 21534110 TI - Library links on medical school home pages. AB - The purpose of this study was to assess the websites of American Association of Medical Colleges (AAMC)-member medical schools for the presence of library links. Sixty-one percent (n = 92) of home pages of the 150 member schools of the AAMC contain library links. For the 58 home pages not offering such links, 50 provided a pathway of two or three clicks to a library link. The absence of library links on 39% of AAMC medical school home pages indicates that the designers of those pages did not consider the library to be a primary destination for their visitors. PMID- 21534111 TI - Customized USB flash drives used to promote library resources and services to first-year medical and dental students. AB - In line with its institution's commitment to keep new student orientation/welcome events "green," Columbia University's Health Sciences Library (HSL) applied for a National Network of Libraries of Medicine Middle Atlantic Region (NN/LM MAR) Small Projects Award(1) in Spring/Summer 2009 to explore paperless modes of outreach. This article describes the project that resulted from this funding, whose purpose was to determine whether customized 1 GB USB flash drives are a good vehicle for distributing library promotional materials to incoming medical and dental students. This project gave HSL librarians the opportunity to connect with students in a way that had not been done before and to consider how these new students use/view the information the library produces. PMID- 21534112 TI - Live and online: using co-streaming to reach users. AB - The increase in distance education students and the changing preferences for online instruction led the Health Sciences Library to seek creative approaches to traditional classroom instruction. Library instructors compared two different class formats: online-only classes and in-person classes with online sections. The second format, called "co-streaming," provided instruction in traditional classroom and virtual environments at the same time. A postclass survey was used to gather users' evaluations of the instruction and the format via which it was offered. This paper examines the user response to, and satisfaction with, the co streaming classes. PMID- 21534113 TI - Shaping up: boot camp and other programs addressing professional development needs of science librarians. AB - Scientists work collaboratively with online tools, relying almost exclusively on online resources and sharing publications freely online while generating and utilizing large datasets. As a result, librarians charged with providing services to the scientific community face both opportunities and challenges in keeping up in this electronic, digital environment. To meet these challenges, library leaders from the five campuses of the University of Massachusetts System established an on-going e-Science initiative. This initiative focuses on increasing awareness and understanding of the principles of e-Science while improving general knowledge within different scientific disciplines. Programs of varying lengths and focus provide local and affordable professional development opportunities that improve the working librarian's ability to better serve scientific researchers and students. PMID- 21534114 TI - Health sciences librarians' research on medical students' use of information for their studies at the medical school, University of Queensland, Australia. AB - This study reports the findings of research undertaken by health sciences librarians at the University of Queensland Library into how medical students use information for their studies, particularly resources and services provided by the Library. The methods utilized were an online survey and focus groups. Results indicated that students favor print resources over electronic, value accessing resources on a one-stop basis, and prefer training to be delivered flexibly. The implication of these results for future resource selection, service provision, and instructional design and delivery is discussed. PMID- 21534115 TI - Isabel, a clinical decision support system. AB - A clinical decision support system (CDSS) is an interactive tool designed to assist clinicians in making decisions, such as determining a diagnosis. The Isabel Database is a CDSS featuring a clinical checklist and topic-specific knowledge components. This column contains an overview of the database, provides searching tips, and places Isabel within the context of the CDSS field. PMID- 21534116 TI - e-Science and data management resources on the Web. AB - The way research is conducted has changed over time, from simple experiments to computer modeling and simulation, from individuals working in isolated laboratories to global networks of researchers collaborating on a single topic. Often, this new paradigm results in the generation of staggering amounts of data. The intensive use of data and the existence of networks of researchers characterize e-Science. The role of libraries and librarians in e-Science has been a topic of interest for some time now. This column looks at tools, resources, and projects that demonstrate successful collaborations between libraries and researchers in e-Science. PMID- 21534117 TI - Hospital libraries: stand up and be counted! AB - Hospital librarians must ensure they are contributing positively to the organization's goals and are proactive in meeting user needs while making the best use of scarce resources. Therefore, effective communication with library clients is essential. Client audits are useful tools, but response rates are often poor as the audit can get lost in the overwhelming amount of unsolicited mail received by clinical practitioners, who quickly become expert at selecting and culling. This column shares lessons learned through conducting the audit, highlights key findings from the audit itself, and examines ways to use the audit process to promote and develop a library's services. PMID- 21534118 TI - Extreme makeover: library orientation for postgraduate dental residents. AB - Bibby Library at the University of Rochester provides a library orientation to new post-graduate dental students. The original class utilized a lecture format and included content that was no longer relevant. Students were bored and did not retain the information. This article describes the design and implementation of a new orientation class. The class includes a series of exercises designed to familiarize students with pertinent resources. Student response to the class and implications for the library are discussed. PMID- 21534123 TI - Framework for the design of physician remuneration methods in primary health care. AB - Economists have generated a large body of theoretical and empirical knowledge with respect to the design of physician remuneration methods (PRM). This knowledge is difficult to use for a policy maker, because of its technical nature and its fragmentation. The article brings together the scattered elements of theory and evidence into a structured framework that adds practical use value to economic theory, useful in the applied practice of policy development, design, implementation, and evaluation. The article argues that the optimal choice of PRM depends on the goals of the health care system, and on external contextual factors. Fee-for-service payments are best when the goals are quantity of care and risk acceptance. Capitation is best when the goals are collaboration between providers and delivery of preventive services and health promotion. Salaries are best when population density is low, and the goal is to recruit physicians to rural and remote areas. Blended payment models are recommended for the achievement of multiple goals. As a demonstration of use value, the framework is applied to the assessment of Canadian PRM. PMID- 21534124 TI - An alternate HIV preventive strategy: sex scripts in media for women of color. AB - New cases of HIV/AIDS among women of color in the United States highlight the continuing need for the public and private sectors to develop alternate preventive strategies. The author discusses the conceptual basis for using television sex scripts to incorporate women of color relational needs (trust, romance, sexual pressure) to promote HIV risk-reduction messages through a process of association with the television storyline. Sex scripts are a source of implicit knowledge about how to behave in situations that involve sexual intimacy. The article suggests that sexual scripts prevention messages build on the agency of women through the use of power theory-that is supporting woman's self-power by participating in sexual behavioral change. Implications for sexual equality in media programming are discussed. PMID- 21534125 TI - Rural women's access to health care in Bangladesh: swimming against the tide? AB - Large segments of the population in developing countries are deprived of a fundamental right: access to basic health care. The problem of access to health care is particularly acute in Bangladesh. One crucial determinant of health seeking among rural women is the accessibility of medical care and barriers to care that may develop because of location, financial requirements, bureaucratic responses to the patient, social distance between client and provider, and the sex of providers. This article argues that to increase accessibility fundamental changes are required not only in resource allocation but also in the very structure of health services delivery. PMID- 21534126 TI - The second market failure phenomenon in safety-net health systems: the case of a municipal academic medical center from 1980 to 2000. AB - The specific aim of this analysis is to demonstrate how the trade-off between efficiency and equity policy approaches affects the ability of at-risk children to access quality health care services at the King/Drew Medical Center of Los Angeles County from 1980 to 2000. The concept of a second market phenomenon is used as a framework to illustrate how efficiency-seeking behaviors of federal, state, and local government actors affected government intervention efforts initiated to remedy health care access hardships created by market failure in low income communities. A second market failure occurs when government failure results from the reintroduction of market protocols in an environment where the market had originally failed to facilitate the distribution of basic goods and services. The review suggest that financial austerity at the Los Angeles County Department of Health Services in the context of federal, state, and local government policies that emphasized allocative efficiencies, compromised equity values by undermining access to quality pediatric services at the King/Drew Medical Center which was a municipal academic medical center. PMID- 21534127 TI - International perspectives in postgraduate medical training in addiction medicine. PMID- 21534128 TI - The international certification of addiction medicine: validating clinical knowledge across borders. AB - The experience of the International Society of Addiction Medicine in setting up the first international certification of clinical knowledge is reported. The steps followed and the results of a psychometric analysis of the tests from the first 65 candidates are reported. Lessons learned in the first 5 years and challenges for the future are identified. PMID- 21534129 TI - Specialized training on addictions for physicians in the United States. AB - In the United States accredited residency programs in addiction exist only for psychiatrists specializing in addiction psychiatry (ADP); nonpsychiatrists seeking training in addiction medicine (ADM) can train in nonaccredited "fellowships," or can receive training in some ADP programs, only to not be granted a certificate of completion of accredited training. Information about ADP residency programs has been tabulated, but it is not available for ADM fellowships. The authors conducted a national survey to compile information about the location, structure, curriculum, and other characteristics of active ADM fellowships. Of the 40 accredited ADP residency programs, 7 offered training in addiction to nonpsychiatrists. The authors identified 14 nonaccredited ADM fellowships. In 2009 and 2010, there were approximately 15 nonpsychiatrists in ADP programs and 25 in ADM fellowships. Clinical experiences included inpatient services, outpatient treatment services such as methadone maintenance or buprenorphine maintenance, and providing addiction consult services. The most common academic activities included weekly lectures and the teaching of medical students. PMID- 21534130 TI - Addiction medicine in Canada: challenges and prospects. AB - In Canada, the qualification of physicians is the jurisdiction of the College of Family Physicians and the Royal College of Physicians and Surgeons. The Colleges have promoted the training of "generalists" in family medicine and "sophisticated generalists" among the traditional specialties, and the development of subspecialties has not been encouraged. Nevertheless, due to the increasing number of family physicians and specialists practicing a range of new subspecialties, including addiction medicine, the College of Family Physicians has recognized special interest or focused practices, whereas the Royal College has recognized, in psychiatry, 3 subspecialties (child, geriatric, forensic) requiring an extra year of training and may offer others a diploma recognition. These new opportunities will shape the training requirements of addiction medicine leading to available certification through the International and American Medical Societies of Addiction Medicine. PMID- 21534131 TI - Developing a competence-based addiction medicine curriculum in Indonesia: the training needs assessment. AB - Indonesia has one of the fastest growing, injecting drugs user-driven, human immunodeficiency virus (HIV) epidemics in Asia. Coverage of needle and syringe programs (NSPs), opioid substitution therapy (OST), and antiretroviral treatment (ART) is increasing, but is still low, whereas professional training in addiction medicine is not yet established. Urgent development and scaling-up of professional capacity in comprehensive, evidence-based addiction medicine is needed. In this article the results of the first step is presented, being the training needs assessment (TNA) and the process of further developing a national evidence- and competence-based addiction medicine curriculum in Indonesia. PMID- 21534132 TI - The master in addiction medicine program in the Netherlands. AB - Since 2007 there is a full-time, 2-year professional training in addiction medicine in the Netherlands. The aim of this article is to describe in detail the development and present status of the Dutch Master in Addiction Medicine (MiAM) program. In this competency-based professional training, theoretical courses are integrated with learning in clinical practice under guidance of an experienced clinical teacher. The theoretical courses consist of evidence-based medicine, communication and basic psychotherapeutic skills, neurobiology of addiction, addiction medicine, addiction and psychiatry, and public health. The 7 main competencies are made ready for operation in the personal education plan and are evaluated by different styles of examination. PMID- 21534133 TI - Training in addiction medicine in Australia. AB - Barriers to entering addiction medicine (AM) have led to a persisting workforce shortage. To address this problem, the Chapter of Addiction Medicine (AChAM) was formed in 2001 as a subdivision of the Royal Australasian College of Physicians (RACP). Through consultation, AChAM has identified the scope of practice and offered fellowship to suitable established practitioners. The Chapter successfully applied to the Australian Government for recognition of AM as a medical specialty, which was finalized in November 2009. Specialist reimbursement item numbers were incorporated into that decision process and commence operating in November 2010. AChAM has designed and implemented a training scheme using a model similar to that of the RACP internal medicine training program. This comprises 3 years of basic general medical training post internship followed by 3 years of discipline-specific supervised training. The training is broadly based, with experience in both ambulatory care and inpatient care, and including physical health as well as mental health. Assessment is continuous and competency based. There is no exit examination. The overriding clinical approach rests upon the harm minimization framework consistent with long-established national drug policy in Australia and favors evidence-based treatment. PMID- 21534134 TI - Response to open peer commentaries on "Social contexts influence ethical considerations of research". PMID- 21534135 TI - Beyond the IRB: local service versus global oversight. PMID- 21534136 TI - The fetus as a patient and the ethics of human subjects research: response to commentaries on "An ethically justified framework for clinical investigation to benefit pregnant and fetal patients". PMID- 21534137 TI - Mobile contact tracing and counseling for STI's: there's not an app for that. PMID- 21534138 TI - Dealing with the long-term social implications of research. AB - Biomedical and behavioral research may affect strongly held social values and thereby create significant controversy over whether such research should be permitted in the first place. Institutional review boards (IRBs) responsible for protecting the rights and welfare of participants in research are sometimes faced with review of protocols that have significant implications for social policy and the potential for negative social consequences. Although IRB members often raise concerns about potential long-term social implications in protocol review, federal regulations strongly discourage IRBs from considering them in their decisions. Yet IRBs often do consider the social implications of research protocols and sometimes create significant delays in initiating or even prevent such research. The social implications of research are important topics for public scrutiny and professional discussion. This article examines the reasons that the federal regulations preclude IRBs from assessing the social risks of research, and examines alternative approaches that have been used with varying success by national advisory groups to provide such guidance. The article concludes with recommendations for characteristics of a national advisory group that could successfully fulfill this need, including sustainability, independence, diverse and relevant expertise, and public transparency. PMID- 21534139 TI - Power and representation of the public's values in a social implications of research commission. PMID- 21534140 TI - Challenges in a divided assessment of the social benefits and risks of research. PMID- 21534141 TI - The role of controversial research in the IRB's risk/benefit analysis. PMID- 21534142 TI - Targeting funding sources: a strategic mechanism of research regulation. PMID- 21534143 TI - The need for topically focused efforts to deal with the long-term social implications of research. PMID- 21534144 TI - Designing a disconnect? PMID- 21534145 TI - IRBs and the long-term social implications of research. PMID- 21534146 TI - Social contexts influence ethical considerations of research. AB - This article argues that we could improve the design of research protocols by developing an awareness of and a responsiveness to the social contexts of all the actors in the research enterprise, including subjects, investigators, sponsors, and members of the community in which the research will be conducted. "Social context" refers to the settings in which the actors are situated, including, but not limited to, their social, economic, political, cultural, and technological features. The utility of thinking about social contexts is introduced and exemplified by the presentation of a hypothetical case in which one central issue is limitation of the probability of injury to subjects by selection of individuals who are not expected to live long enough for the known risks of the study to become manifest as harms. Benefits of such considerations may include enhanced subject satisfaction and cooperation, community acceptance, and improved data quality, among other desirable consequences. PMID- 21534147 TI - Social considerations in research: consider them but don't use them. PMID- 21534148 TI - Cultural diversity, families, and research subjects. PMID- 21534149 TI - Social contexts, social media, and human subjects research. PMID- 21534150 TI - Research impacting social contexts: the moral import of community-based participatory research. PMID- 21534151 TI - An ethically justified framework for clinical investigation to benefit pregnant and fetal patients. AB - Research to improve the health of pregnant and fetal patients presents ethical challenges to clinical investigators, institutional review boards, funding agencies, and data safety and monitoring boards. The Common Rule sets out requirements that such research must satisfy but no ethical framework to guide their application. We provide such an ethical framework, based on the ethical concept of the fetus as a patient. We offer criteria for innovation and for Phase I and II and then for Phase III clinical trials to improve the health of pregnant patients and of fetal patients and also criteria to responsibly manage the transition from investigation to clinical practice. Basing ethical criteria for research involving pregnant women on the ethical concept of the fetus as a patient insulates the proposed ethical framework and therefore research on pregnant women from the divisive and politicized concepts and discourses of personhood, fetal rights, and unborn child. PMID- 21534152 TI - Reframing the framework: toward fair inclusion of pregnant women as participants in research. PMID- 21534153 TI - Moral status and the fetus: continuation of a dialogue. PMID- 21534154 TI - Emergent obligations to the former fetal research subject. PMID- 21534155 TI - Research in pregnancy: back to first principles. PMID- 21534156 TI - Community, constituency, and morbidity: applying Chervenak and McCullough's criteria. PMID- 21534157 TI - The common rule, pregnant women, and research: no need to "rescue" that which should be revised. PMID- 21534158 TI - Who is a patient and why does it matter? PMID- 21534159 TI - Unacceptable risk in pregnancy: whose choice and responsibility? PMID- 21534160 TI - The two-patient framework for research during pregnancy: a critique and a better way forward. PMID- 21534171 TI - [Admissibility of medical care belonging to a different specialty]. PMID- 21534172 TI - [Therapy oriented retinal diagnostics]. PMID- 21534173 TI - [Special topic "inflammations of the eye in inflammatory systemic diseases"]. PMID- 21534174 TI - [Inflammation of the eye in systemic inflammatory disorders: keratitis]. AB - Systemic inflammatory diseases are associated with keratitis. In addition to the much less frequently occurring non-ulcerative keratitis, ulcerative inflammation of the corneal periphery is common in systemic inflammatory diseases. Significant systemic inflammatory diseases in this context are autoimmune connective tissue diseases (including rheumatoid arthritis, systemic lupus erythematosus or primary vasculitides such as polyarteritis nodosa or Wegener's granulomatosis), systemic autoimmune dermatological disorders (such as the cicatrising pemphigoid or Stevens-Johnson syndrome) and autoimmune diseases of the lacrimal system (such as the lacrimal gland involvement in primary Sjogren's syndrome or in graft-versus host disease). In severe cases of peripheral ulcerative keratitis intensive topical therapy is initially combined with a systemic high-dose steroid therapy. In further progressing ulceration, surgery may help to preserve or restore the integrity of the eye and may suppress the autoimmune response by shielding the corneal antigens from blood and the lymphatic system. Systemic immune modulating therapy has to be done in close consultation with the rheumatologist. PMID- 21534175 TI - [Diagnosis and treatment of scleritis associated to inflammatory systemic diseases]. AB - Because of potential vision-threatening complications and the association to inflammatory systemic diseases with an increased mortality, scleritis patients need an adequate diagnostic work-up and early and aggressive anti-inflammatory systemic treatment. New therapeutic options (such as biologicals) help to achieve remission in otherwise refractory cases. PMID- 21534176 TI - [Graves' orbitopathy]. AB - Graves' orbitopathy (GO) is part of an autoimmune systemic disease (prevalence of 0.5 - 2%) which is composed of hyperthyroidism, orbitopathy, dermopathy and acropachy. Stimulating antibodies against the TSH receptor plays the central pathogenetic role and high levels indicate the risk of a severe course of the disease. The main symproms of GO comprise soft tissue inflammation, proptosis impairment of ocular motility and lid retraction. Inflammatory reactions of orbital fibroblasts are responsible for the symptoms. To restrict damage, anti inflammatory therapy (mainly i. v. systemic steroids, orbital irradiation) is indicated in moderate to severe active disease stages, and surgical orbital decompression is indicated in sight-threatening states. In mild GO selenium administration and otherwise a wait and see strategy is sufficient. In inactive disease stages surgery (orbital decompression, eye muscle surgery and lid surgery) is performed to improve appearance and function. Smoking increases the prevalence and severity of GO and reduces the efficiency of therapy. Restoring euthyroidism leads to an improvement of GO in about 60% of the patients. PMID- 21534177 TI - [Autoimmunity and glaucoma]. AB - Glaucoma is one of the most common causes of irreversible blindness worldwide. The pathogenesis of the disease is not fully understood. Elevated intraocular pressure is still considered to be one of the most important risk factors, but cannot explain all cases of glaucoma disease. The involvement of autoimmune mechanisms may play an important role in the pathogenesis of glaucoma. Evidence to support this theory has been shown by our group in previous studies: glaucoma patients were found to develop antibody alterations against specific retina and optic nerve proteins. In the experimental autoimmune glaucoma model, we demonstrated that an immunisation with these proteins causes retinal ganglion cell loss in an autoimmune context. In spite of these results, it is still unclear whether the changes in antibody patterns have a causal connection with glaucoma development or are merely an epiphenomena of the disease. However, these changes in the natural autoimmunity offer a new approach to gain deeper insight into glaucoma pathophysiology and to develop a diagnostic approach for early diagnosis. PMID- 21534178 TI - [Recommendation of the Retinological Society, the German Ophthalmological Society and the Professional Association of Ophthalmologists in Germany: treatment of diabetic maculopathy]. PMID- 21534179 TI - [The neuroophthalmic supplement to the NEI-VFQ: test statistics and validation with a cohort of patients with pre- and postchiasmatic damage]. AB - BACKGROUND: The National Eye Institute Visual Function Questionnaire (NEI-VFQ) is not sufficient to assess vision-related quality of life in patients with vision impairments caused by neuroophthalmic deficits. The neuroophthalmic supplement to the NEI-VFQ is currently only available in an English version. The supplement was translated into German and three items concerning visual field loss were added. MATERIAL AND METHODS: NEI-VFQ and supplement data were collected from 62 pre- and postchiasmatic patients with visual field defects and from 245 healthy reference persons. NEI-VFQ and supplement were psychometrically tested and validated. Relations between visual field variables and vision-related quality of life were assessed. RESULTS: The patient group showed diminished quality of life in 10 NEI VFQ subscales and in eight supplement items when compared to age-matched healthy controls. Correlations between supplement and visual field diagnostic variables demonstrate moderate relations between visual field loss and deterioration of vision-related quality of life. A Cronbach's alpha of 0.81 for the supplement can be increased to 0.92 in combination with the NEI-VFQ, the sole application of the NEI-VFQ generates an alpha of 0.93 in this sample. A factor analysis reveals four factors that cover the 13 items capturing the following issues: 'severity/problems due to the visual field defect", "unusual eyelid appearances", "blurry vision/double vision" and "diverse vision of both eyes"; 72 % of the variance can be explained by these four factors. CONCLUSION: The German translation of the neuroophthalmic supplement to the NEI-VFQ captures additional vision-specific problems beyond the sole NEI-VFQ that are often reported by patients with vision impairments after brain damage. Although the relevance of some items can be questioned, nevertheless the supplement qualifies for an enhanced outline of subjective vision impairments that are not included in the previous NEI-VFQ. PMID- 21534180 TI - Value of ultrasound (US)-guided percutaneous needle biopsy of detected pathological gastrointestinal (GI) tract lesions but negative or incomplete endoscopy. AB - PURPOSE: The study aim was to investigate the diagnostic value of US-guided percutaneous needle biopsy in the case of suspicious tumor lesion of the GI tract revealed by abdominal US but without detection with endoscopy or with incomplete or no possible endoscopy. PATIENTS AND METHODS: Over a defined time period, all consecutive patients with no appropriate endoscopic diagnostic specimen or finding were registered. The patient, diagnostic, and periinterventional characteristics were documented. RESULTS: In total, 16 patients (7 males; mean age, 63.2 [range, 43 - 90] years) were enrolled in this study representing a rare but possible constellation from endoscopic practice characterized by no detectable intraluminal tumor growth and a suspicious tumor lesion revealed with abdominal US as found in each case (n = 16) from 01 / 01 / 2003 - 12 / 31 / 2006. The main indications for needle biopsy were pathological colonic cockades (n = 7) and tumor lesions of the stomach and small intestine (n = 9). The first needle biopsy attempt was successful in all subjects (technical success rate: 100 %) using the color-coded US mode in each case (100 %). There were no postinterventional complications (rate: 0 %). CONCLUSION: Percutaneous US-guided needle biopsy can be considered a safe diagnostic tool for clarifying the differential diagnosis of suspicious tumor lesions of the GI tract (revealed originally only by abdominal US) as the next favorable diagnostic step in the rare situation that endoscopy cannot provide appropriate information, in order to shorten the diagnostic course, to achieve a therapeutic decision and to decrease effort and costs. PMID- 21534182 TI - [Favourable surgical treatment of lower limb varicose veins in patients with Klippel-Trenaunay Syndrome]. PMID- 21534181 TI - [An algorithm for postoperative pain management in visceral and thoracic surgery: an observational study]. AB - INTRODUCTION: We report the results of an observational study of pain intensity before and after implementation of an algorithm for postoperative pain management. The algorithm included multiple factors for treatment. METHODS: Data of 130 consecutive patients with defined surgical procedures were extracted from charts before and after implementation of the algorithm. Our patients documented pain intensity at rest and on movement on a numerival rating scale (NRS) from 0 (= no pain) to 10 (= worst pain). A successful pain management was definded as maximum pain intensity at rest <= 3 and on movement <= 5 on the NRS. For statistical analysis we used the Wilcoxon and the chi squared test. RESULTS: The frequency of a successful pain management increased from 49 % (individual pain management) to 85 % (algorithm) at rest 8 (p < 0.001), on movement the rates were 42 % and 86 %, respectively (p < 0.001). In the total group, we found a reduction of maximum pain intensity at rest (mean +/- sd) from 4.05 +/- 2.54 to 2.18 +/- 1.82 (p < 0.001) and with movement from 6.04 +/- 2.51 to 3.5 +/- 2.08 (p < 0.001). CONCLUSION: Implementing an algorithm for postoperative pain management resulted in a clinically relevant reduction of postoperative pain. Our findings reflect the result of a complex change in pain management, and therefore cannot be attributed to any single factors involved. PMID- 21534183 TI - [Risk Assessment in the Therapy for Osteomyelitis using Immunological Parameters]. AB - PROBLEM: The treatment of osteomyelitis is based on the surgical eradication of the septic focus and the additional administration of antibiotics (local and/or systemic). In some cases the course of the therapy may be prolonged without any obvious reason in terms of the quality of the surgical treatment, virulence and type of bacteria or the co-morbidities. ISSUE: Can these patients at risk be detected by immunological assessments? Will these immunological features lead to a more individualised therapeutic strategy? PATIENTS: 20 patients suffering from chronic osteomyelitis of the lower extremity were included in our study. Group 1: 15 patients showed a prolonged course of the disease and/or an abnormal high rate of surgery. These courses could not be correlated with the bacterial spectrum or the co-morbidities. Group 2: 5 patients showed a clinical course as expected. METHODS: Blood samples of all patients were analysed by immunological methods: lymphocytes were analysed by using 8 colour flow cytometry. CD4/8 ratio and double negative T cells were calculated. T cell response to recall antigens was determined by elispot testing. RESULTS: In group 1 double negative T cell and cytotoxic T cell counts were significantly lower in comparison to group 2. This was not the case for T cells and T helper cells. In ROC analysis, area under the curve (AUC) analysis revealed best discrimination by double negative T cells (0.88). At a cut-off of 60 double negative T cells/uL, discrimination of septic complications revealed 100 % specificity and 87 % sensitivity. In elispot testing, reactivity to tetanus toxoid established best results (AUC 0.76). CONCLUSION: The analysis of the above data shows that the detection of higk-risk patients during the therapy for osteomyelitis based on immunological features seems to be possible. Further studies are needed to verify the data collected from our pilot study. PMID- 21534184 TI - [Mental practice has influence on limitation of motion and muscle atrophy following immobilisation of the radiocarpal joint - a prospective randomised experimental study]. AB - PURPOSE: Distal radial fracture is the most common bony injury in man. Still there are unsatisfying treatment results, such as limited joint movement, muscle atrophy and pain, resulting from immobilisation while the fracture is healing. During this period, also joint movement seems to be "forgotten". This study experimentally examined if the method of mental practice, meaning the systematic repetition of a consciously imagined movement or action without simultaneous practical execution, can positively influence these findings. MATERIALS AND METHODS: 21 right-handed males had application of a circular forearm plaster for immobilisation of their left radiocarpal joint, simulating a distal radial fracture for three weeks. Following randomisation, half of the study participants learned mental practice for "virtual movement" of their radiocarpal joint and had to perform it, the others were not treated at all. At beginning and end of the experiment, joint movement was measured, and an MRI examination of the forearm muscles was performed. The brain (cortex) areas, responsible for radiocarpal joint movement, were examined concerning their activity with functional MRI at the beginning and also at the end of the three weeks. The experiment was also performed on three "real" patients suffering from a distal radial fracture demanding plaster immobilisation, all of them were mentally treated. RESULTS: Mental practice significantly ameliorated dorsal extension and ulnar abduction after plaster removal in comparison to those not having been mentally trained. Muscle atrophy of forearm muscles, measured via MRI, was significantly less in those having mental training. The cortex areas responsible for radiocarpal joint movements (supplementary motor area, precentral gyrus, putamen, nucleus caudatus, prefrontal cortex, thalamus and cerebellum) showed significant signal changes at the end of the three weeks in those having been mentally trained. There were significant correlations between MRI and functional MRI findings. The findings in the three "real" patients were similiar. CONCLUSIONS: The results of this experimental study show that mental practice can have a positive influence on the outcome of distal radial fractures demanding immobilisation. A study with a larger number of "real patients" should follow. PMID- 21534185 TI - [Imaging diagnostics of osteitis, osteomyelitis and joint infections]. AB - Imaging diagnostics and surgical treatment of bone and joint infections are of paramount interest. The main purpose of our survey is to give a detailed overview about methods, indications, image criteria and efficiency of imaging diagnostics as a state of the art presentation. In conclusion we attempt to give some recommendations for clinical scenarios and diagnostic procedures concerning bone and joint infections. This paper has been prepared under the patronage of the AG Septische Chirurgie of the Deutsche Gesellschaft fur Unfallchirurgie in Germany. It is our aim to update the paper with respect to the technical and clinical improvements and to publish it again after a number of years. PMID- 21534188 TI - [Sonographic analyses of obstructive diseases of the salivary gland using intraductal applications of contrast agent]. AB - Obstructive diseases of the salivary glands are a common problem of the salivary glands; often based on Sialolithiasis, duct stenosis, or other rarer reasons. There exist several diagnostic features to classify the disease; however, ultrasound or conventional radiological imaging does not provide a diagnosis in 5 10% of all cases. The intraductal applied contrast-enhanced ultrasound (IA-CEUS) improves the visualization of obstructive diseases of the salivary glands; simultaneously an evaluation of the parenchyma of the glands is possible. We think IA-CEUS is a promising tool, which improved the diagnostic assessment capabilities of ultrasound and results in a better treatment for patients with obstructive salivary gland diseases. PMID- 21534189 TI - [Global trends in risk factors for cardiovascular diseases]. PMID- 21534190 TI - Neuronavigation in cranioorbital neurosurgery - do we really need it? AB - AIM: The value of neuronavigation in cranioorbital neurosurgery is controversial and relatively unstudied. The aim of this study was to evaluate the application, the usefulness and the reliability of neuronavigation in the neurosurgical treatment of orbital tumours. MATERIAL AND METHODS: A frameless armless infrared based neuronavigation system was applied in the microsurgical removal of 7 orbital tumors. Image guidance was CT-based in 3 cases, MRI-based in another 3 cases and based on image fusion between CT and MRI image sets in one patient. The extradural fronto-orbital approach was performed in 3 cases, lateral orbitotomy in 2 cases, trans-supraciliar approach in 1 case and inferomedial orbitotomy in 1 case. RESULTS: The surgical procedures were successful in all cases. The procedure-related morbidity and mortality rate in the series was zero. The registration accuracy of the neuronavigation ranged between 1.0 and 1.7 mm, with an average of 1.3 mm. Neuronavigated image guidance was evaluated as useful in all patients. Total tumour removal was achieved in 5 patients and partial tumour excision in 1 case. One patient was only biopsied. CONCLUSION: Neuronavigation is not a substitute for surgical knowledge and experience, but it is a valuable complement with significant intraoperative potential in cranioorbital surgery. PMID- 21534191 TI - Noncontrast and perfusion CT provides accurate assessment of head deceleration injury. AB - AIM: To investigate the feasibility of noncontrast computed tomography (NcCT) and perfusion CT (PCT) in the assessment of head deceleration injury (HDI). MATERIAL AND METHODS: A small animal HDI device was developed. A total of 20 healthy adult rabbits with frontal impacts resulting from a 3.5 m drop were included in this study. All subjects underwent NcCT and PCT scans 12 hours before injury and three to four hours after head injury. Brain injuries were evaluated by traditional macroscopic and microscopic examination after CT scans. RESULTS: Microscopic examination revealed hemorrhagic cerebral contusions in 14 subjects and cerebral parenchyma hyperemia in 6 subjects. Contrecoup injuries were more severe than the coup injuries in this study. As verified by pathoanatomical observations, NcCT effectively revealed all of the calvarial fractures and basal skull fractures in 12 subjects. Furthermore, most rabbits suffered acute scalp contusions, subarachnoid hemorrhages and cerebral contusions. PCT analysis revealed much larger and more severe contusions when compared to those observed via NcCT. CONCLUSION: The combination of NcCT and PCT could be an effective approach for detection of acute cerebral contusions, which can provide sufficient experimental evidence for accurate clinical diagnosis and prognosis of HDI. PMID- 21534192 TI - Nonspecific low back pain in a group of young adult men. AB - AIM: Low back pain (LBP) is a common symptom that causes enormous social, psychological, and economical problems. We studied LBP occurrence in a group of young adults referred to an army hospital for a planned health check and evaluated possible causative factors by prospective questionnaires. MATERIAL AND METHODS: This article is based on a prospective study of 871 novice soldiers of the Turkish Army. Studied factors were combined in the form, which was filled by 5 doctors on the basis of self-reports, interview and physical examination of the participants. They were evaluated by factors; low back pain episodes, monthly income, smoking habits, BMI, labor conditions, and educational status. RESULTS: The median age of the studied population was 21.14+/-1.4. Complains regarding LBP were observed in 325 (37%) of participants. Twelve participants had pain episodes up to 10 points. 83.69% of the participants with LBP had psychological problems. Heavy lifting and driving for long periods were determined as serious risk factors. CONCLUSION: Determining the impact factors of LBP in primary care groups can help to prevent development of more serious problems. PMID- 21534193 TI - The influence of subthalamic nucleus deep brain stimulation on physical, emotional, cognitive functions and daily living activities in patients with Parkinson's disease. AB - AIM: To describe effectiveness of deep brain stimulation of subthalamic nucleus (DBS STN) on physical, emotional, cognitive functions and daily activities in Parkinson's patients. MATERIAL AND METHODS: Ten patients (51.20 +/-10.20 yr.) were assessed three times. The Time Up and Go Test, 12 m Walking Test and Chair Stand Test were used to assess mobility and balance. Purdeu Pegboard and hand writing tests were used to evaluate hand function. The Hospital Anxiety and Depression Scale (HAD) was used to detect depressive symptoms and anxiety score. The Unified Parkinson?'s Disease Rating Scale (UPDRS) and Hoehn &Yahr Scale were also used. The Schwab and England Test was used to evaluate the daily activities (ADL). RESULTS: The results showed that all the patients' mobility and balance ability improved after surgery (p < 0.05). Depressive symptoms / anxiety scores were found to be lower than before surgery (p < 0.05). There were differences in terms of ADL and UPDRS scores after surgery (p < 0.05). At six month after surgery; depressive symptoms decreased by 78%. ADL and UPDRS motor and total scores improved by 190%, 72%, and 78% respectively. CONCLUSION: STN DBS is an effective treatment to improve physical functioning, emotional status and daily activities in Parkinson's patients. However, it did not show any positive effect on cognitive function. PMID- 21534194 TI - Spectrum of surgical complications of temporal lobe epilepsy surgery: a single - center study. AB - AIM: Although surgery is the most effective means of eliminating or reducing seizures in cases of medically refractory epilepsy, the expected or unexpected surgical complications must also be kept in mind in order not to decrease patients' quality of life. The aim of this present study was to assess the surgical complications of temporal lobe epilepsy surgery and their effects on the disease course in patients with intractable epilepsy arising from the temporo mesial structures. MATERIAL AND METHODS: The records of 58 patients who underwent temporal lobectomy and/or selective amygdalahippocampectomy at Gulhane Military Medical Academy between January 2000 and August 2010 were reviewed for peri- and post-surgical complications. RESULTS: Post-surgical complications were detected in 7 patients (12%). The most common complication of ES was infection in 2 patients (2.9%). Other complications were hemorrhagic infarction, paresis of the frontal branch of the left facial nerve, subdural effusion, anxiety disorder, depressive disorder and late-onset psychosis. CONCLUSION: The results of our study suggest the importance of post-operative care and long-term follow up in order to achieve favorable seizure outcome after epilepsy surgery. PMID- 21534195 TI - The correlation between hematoma volume and outcome in ruptured posterior fossa arteriovenous malformations indicates the importance of surgical evacuation of hematomas. AB - AIM: The correlation between hematoma volume and outcome in ruptured arteriovenous malformations (AVM) with accompanying posterior fossa hematoma was retrospectively evaluated. MATERIAL AND METHODS: Microsurgery operations were performed on 127 patients with intracranial AVM between January 1998 and January 2009 at our clinic. Fifteen (11.8%) patients were identified as suffering from posterior fossa AVM, and twelve of these patients presented with a cerebellar hematoma. All patients were clinically evaluated according to the following criteria: modified Rankin Scale (mRS) prior to surgery, Spetzler-Martin grade (SMG) of the AVMs, hematoma volume prior to surgery, and mRS following surgery. RESULTS: Postoperative mRS scores were significantly lower than preoperative scores (p=0.0001). Postoperative outcomes were concordant with the SMG of the AVMs (r=0.67, p=0.033), hematoma volume (r=0.537, p=0.072) and preoperative mRS scores (r=0.764, p=0.004). These analyses show that the postoperative mRS score is strongly correlated with a preoperative mRS score, hematoma volume and SMG. CONCLUSION: Posterior fossa AVMs present an increased risk for hemorrhage and for increased morbidity and mortality. Cases with hematoma should be operated on an urgent basis. We conclude that hematoma volume is a factor that impacts postoperative results and prognosis. SMG and preoperative mRS scores were also correlated with outcome. PMID- 21534196 TI - Indirect bypass procedures for moyamoya disease in pediatric patients. AB - AIM: Many direct and indirect surgical intervention methods have been defined for the treatment of moyamoya disease. Indirect surgical procedures have been increasingly used. In this study, indirect surgical intervention methods especially used in combination with pial synangiosis were assessed together with other indirect methods. MATERIAL AND METHODS: 11 patients who were treated with an indirect bypass procedures at our clinic and followed for at least three years were retrospectively examined. 19 surgical interventions were performed for 18 patient hemispheres pertaining to these patients. 4 indirect surgical revascularization methods were used for three patient hemispheres. On the other hand, indirect procedures combined with pial synangiosis were applied in 11 operations. In addition, the "multiple burr-hole surgery" method was used in 4 four operations performed for two patients. RESULTS: The clinical success rate was 66.6% for patients where the techniques were applied with pial synangiosis. No new ischemic or hemorrhagic attack was observed during the follow-up period in any of these patients in this series. CONCLUSION: Pial synangiosis is a modification that Increases the success rate of indirect surgical methods. In addition, high success rates have been reported in recent publications related to multiple burr-hole surgery. This method is a candidate choice of surgical intervention for selected patients. PMID- 21534197 TI - Simple decompression of the ulnar nerve at the elbow via proximal and distal mini skin incisions. AB - The purpose of the present study was to describe a new minimally invasive surgical technique for decompression of the ulnar nerve at the elbow for treatment of cubital tunnel syndrome. Four patients underwent surgical treatment for cubital tunnel syndrome. Preoperative clinical states were classified by using the McGowan grading system and the postoperative states were recorded by using the Wilson and Krout grading system. Preoperative and last follow-up electromyographic results were also recorded. At the last follow-up, three patients were recorded as excellent and one patient was recorded as good according to Wilson and Krout grading system. One patient showed improvement in sensory nerve conduction velocity another showed improvement in motor nerve conduction velocity at the last follow-up. We conclude that simple decompression of the ulnar nerve at elbow via proximal and distal mini skin incisions is an effective, technically simple and safe surgical method in the treatment of cubital tunnel syndrome. PMID- 21534198 TI - Efficacy and safety of surgery for lumbar disc herniation in patients aged 80 and older. AB - AIM: To evaluate the efficacy and safety of surgery for lumbar disc herniation in patients aged 80 or older. MATERIAL AND METHODS: Operative time (OT), intraoperative estimated blood loss (EBL), length of hospital stay (LOS), and complication rate (CR) were used to assess safety of surgery. The Visual Analog Scale (VAS), the Oswestry disability index (ODI) and the North American Spine Society Outcome Questionnaire (NASS-Q) were used to evaluate the clinical effectiveness. RESULTS: There were significant differences between the very elderly and the middle-aged group in LOS (P < 0.001), but not in OT, EBL and CR (all P > 0.05). The preoperative, post-operative and final follow up VAS and ODI scores were not significantly different between the two groups (each P > 0.05). However, the VAS and ODI scores were significantly improved after surgery and at ultimate follow up compared with those before surgery (all P < 0.001). Satisfaction with outcome was expressed by 39 (86.7%) of 45 very elderly patients. CONCLUSION: Conventional laminectomy, discectomy and/or spinal fusion surgery is a feasible, safe and effective treatment in patients over age 80 with lumbar disc herniation compared with middle-aged patients. PMID- 21534199 TI - Experience of Carpal Tunnel Syndrome that operated using a limited uni skin incision. AB - AIM: Releasing the carpal tunnel for Carpal Tunnel Syndrome (CTS) is the most common surgical procedure in neurosurgical practice. In this study, we aimed to analyze the outcome of patients operated on for carpal tunnel syndrome using a limited uni skin incision. MATERIAL AND METHODS: Between June 2007 and November 2009, we performed 143 carpal tunnel releasing procedures for 126 patients. There were 112 (% 89) female and 14 (% 11) male patients with a mean age of 53 (27-81). 79 operations were performed for the right hand and 64 for the left hand. RESULTS: Each patient was evaluated with their history, physical examination and electromyelography (EMG). All patients had brachialgia paraesthetica nocturna and severe CTS by EMG. Pre- and post-operative Visual Analog Scale (VAS) and Visual Analog Patient Satisfaction Scales (VAPSS) were used for clinical evaluation. There was no complication such as bleeding or nerve injury in the operated patients. The mean follow up period was 13 months (3-24 months). The mean VAS score was 7.9 pre-operatively and 2.8 post-operatively and the mean VAPSS score was 8.1. Three patients underwent re-operation because of the recurrence of symptoms. There was no procedure-related complication during the follow-up period. CONCLUSION: The limited uni skin incision is a safe and effective minimal invasive procedure for releasing the carpal tunnel. PMID- 21534200 TI - Anatomical variations of the foramen magnum, occipital condyle and jugular tubercle. AB - AIM: The foramen magnum (FM) is a unique and complex anatomical region. The occipital condyle (OC) and jugular tubercle (JT) are the main bony structures which obscure the anterolaterally situated lesions of the FM.The aim of this study was to revisit the anatomy of the FM region and assess variations of the surrounding structures. MATERIAL AND METHODS: Observations, on thirty dry skulls (dried specimens, 60 sides) and ten formalin-fixed cadaveric heads with perfused vessels, were carried out to define the microsurgical anatomy of the FM region. Morphometric analysis and variations of the FM, OC, JT and hypoglossal canal (HC) were noted. Radiological assessment (3D-computed tomography) of the OC, JT, HC were also conducted on dry skulls. RESULTS: The short and long OC were demonstrated in 5% and 33% of the specimens, respectively. Flat formation of the JT was determined in 10% and tall JT was found in 23% of the specimens. The comparison of the anatomical measurements and the correspondent radiological mean values did not achieve statistical significance. CONCLUSION: The OC and JT are the main bony prominences obstructing the anterolateral surface of the brainstem. Neurosurgeons should be familiar with variations of the structures surrounding the FM in order to perform the safest and widest exposure possible. PMID- 21534201 TI - The effects of impulse noise on the epithelial cells of the choroid plexus. AB - AIM: The aim of this study was to investigate the effects of impulse noise on the epithelial cells of the choroid plexus. MATERIAL AND METHODS: Forty Sprague Dawley rats were used and divided into the 2 groups as control and study groups. In the control group, the rats did not suffer noise injury. The rats were exposed to impulse noise at 20 minute durations at 10 times each day for one month in study group. Then, the rats were sacrificed and the choroid plexuses were examined histologically. The number of cells was counted and the cells were analyzed. RESULTS: There were clear signs of nuclear condensation and cell body shrinkage, suggesting the presence of apoptosis. Severe desquamation of villus and the cell loss were observed in the study group. The numbers of the normal cells decreased, and the number of apoptotic cells increased significantly (p < 0.05). CONCLUSION: Impulse noise causes apoptotic death of epithelial cells in the choroid plexus, decrease the normal cells and increase the apoptotic cells. PMID- 21534202 TI - Effects of parenteral nutritional support with fish-oil emulsion on spinal cord recovery in rats with traumatic spinal cord injury. AB - AIM: Aim of this study is to assess effects of parenteral nutritional support with fish-oil emulsion on spinal cord recovery in rats with traumatic spinal cord injury. MATERIAL AND METHODS: For 5 days after SCI rats were received saline in group C and Omegaven in group O. Locomotor strengths (BBB scale)of animals were rated at Day 0,7,14,21,28, and 35. At Day 35 spinal cord sampling was evaluated immunohistochemically. RESULTS: BBB scores were 0 in early period after SCI was inflicted in both groups. BBB scores were progressively increased after Day 7 in both groups (p < .005). BBB scores were significantly higher in group O when compared with control group after Day 7 in all times (p < .005). Neuronal injury (p < .002) and edema was much more in control group when compared with in group O (p < .005). Scores for white mater cavitation, demyelinization and vessel in growth were similar in both groups. VEGF expression in control group was higher (p=.019). CONCLUSION: At the early period of SCI fish-oil emulsion treatment in rats, its anti-inflammatory effects leaded to decrease in edema and had positive effect at the prevention of neuronal injury. We believe that nutritional support with fish-oil emulsion in patients with SCI will result in patient's better clinical outcome and increase in quality of the patient's life. PMID- 21534203 TI - Antithrombin III and enoxaparin treatment inhibit contusion-triggered cell death, inflammation, hemorrhage and apoptosis after severe traumatic brain injury in rats. AB - AIM: In this study, we aimed to show the neuroprotective effects of AT III and Enoxaparin after severe traumatic brain injury. MATERIAL AND METHODS: The animals were divided into four groups as Group 1; control group, Group 2; trauma group, Group 3; AT III group and Group 4; Enoxaparin group. Severe trauma was performed by the weight dropping technique. These animals were killed 48 hours after injury. Histopathological and immunohistochemical analysis were performed. Specimens were graded for cell death, inflammation, hemorrhage and apoptosis. RESULTS: The control group showed normal ultrastructure of brain tissue. Trauma produced obvious damage. 8 rats (80%) in the trauma group demonstrated minimal inflammation and grade 5 cell death. Trauma increased hemorrhage and apoptosis scores to statistically significant levels (p < 0.001). Enoxaparin was found to reduce neuronal cell death but not as effectively as AT III. A statistically significant difference was observed between the AT III and Enoxaparin group according to inflammation grades. Significant antiapoptotic properties of AT III were observed while hemorrhage was more common in the Enoxaparin group. CONCLUSION: Anticoagulants such as AT III and enoxaparin are promising drugs in the treatment of traumatic brain injuries. PMID- 21534204 TI - Correlation of pulsatility index with intracranial pressure in traumatic brain injury. AB - AIM: In traumatic brain injury (TBI) patients, it is desired to monitor the intracranial pressure (ICP) to assess the cerebral haemodynamics and guide the therapy. The study was designed to see if the pulsatility index (PI) measured by transcranial Doppler ultrasonography (TCD) predicts information about ICP values. MATERIAL AND METHODS: In 52 TBI patients with Glasgow Coma Scale (GCS) score < 9, invasive intracranial monitoring and TCD ultrasonography for PI were performed through five days. ICP, cerebral perfusion pressure (CPP), PI values were recorded and calculated. The correlation and regression analysis between ICP, PI and CPP were investigated in the whole group and in patients with a Glasgow Outcome Score (GOS) of 3-5. RESULTS: The decline in ICP and PI values was significant through five days. The correlation between ICP and PI was strongly significant (p < 0.0001) on days 1, 3 and 5. In patients with a GOS of 3-5, correlation of ICP and PI was also observed. The only significant correlation observed between CPP and PI was on day 5. CONCLUSION: The strong correlation observed between ICP and PI through the management period of TBI patients can lead us to use TCD ultrasonography-derived PI as a guide if invasive monitoring is not available. PMID- 21534205 TI - Primary brain tumors associated with cerebral aneurysm: report of three cases. AB - The primary brain tumors associated with cerebral aneurysms are rare in neurosurgical practice. The present article constitutes an evaluation of the management of coexistent primary brain tumor and cerebral aneurysm. A retrospective study of three cases of primary brain tumor with cerebral aneurysm was performed. We evaluated the complications and clinic outcomes by assessing the clinical and imaging findings. Case 1 presented with a subarachnoid hemorrhage from an aneurysm of the anterior communicating artery, with an incidental left frontal oligodendroglioma. Case 2 presented with chronic headache due to left frontal convexity meningioma, with proximal internal carotid artery aneurysm which was found incidentally during preoperative magnetic resonance angiography. Case 3 was admitted to our hospital complaining of headache, memory disturbance, and weakness in her left lower extremity. Magnetic resonance imaging revealed right frontal lymphoma and an unruptured aneurysm at the left middle cerebral artery. Preoperative magnetic resonance imaging revealed right frontal lymphoma and unruptured left middle cerebral artery. The frequency of primary brain tumor and cerebral aneurysm coexistence is increasing due to improvements in high-resolution imaging. In these complicated cases, the management will differ according to each pathology present, and this is an important problem for a neurosurgeon. PMID- 21534206 TI - Diencephalic juvenile pilomyxoid astrocytoma with leptomeningeal dissemination. AB - Pilomyxoid astrocytoma (PMA) is a recently described neoplasm. PMA shares few features with pilocytic astrocytoma (PA), the most common central nervous system (CNS) tumor in the pediatric population, yet displays histological differences. Previous studies have shown that PMAs have more aggressive biological behavior as compared to PA. These findings suggest that PMA may be a unique and distinct neoplasm. We report a pilomyxoid astrocytoma of the hypothalamic-chiasmatic region with leptomeningeal dissemination in a 3-month old infant. This case report discusses the histological, clinical, and radiographic characteristics of PMA. In addition, the current treatment options and research potential involving this disease are also briefly described. PMID- 21534207 TI - Isolated enchondroma of atlas. AB - Compression at the craniovertebral junction because of tumors is not a very common entity. The commonest tumors present here are neurofibroma and meningioma. Any vertebral tumour can be present at this location. Benign bony tumors are very uncommon at this location and amongst these enchondromas are exceptionally rare. Enchondromas are rare bony tumours of chondrogenic origin. These are benign tumours with a propensity for malignant transformation. There are four histological types: osteochondromas, enchondromas, chondroblastoma and chondromyxoid fibroma. Enchondromas are often asymptomatic because of their slow growth but may have varied presentation. An enchondroma may occur as an individual tumor or as several tumors together. We here report a case of enchondroma arising from the atlas and causing myelopathy. The best treatment is complete excision which we could achieve in our case. PMID- 21534208 TI - Apoplexy in sellar metastasis: a case report and review of literature. AB - Apoplexy in sellar metastasis is very rare with only a few case reports in literature. A case of apoplexy in sellar metastasis from follicular thyroid carcinoma is reported and the literature is briefly reviewed. The patient presented with sudden onset headache and bi-lateral loss of vision following thyroidectomy in a case of follicular carcinoma thyroid with proven sellar metastasis. CT scan showed hyperdense blood in sellar mass suggestive of apoplexy in sellar metastasis. The patient underwent early trans-sphenoidal decompression. Apoplexy in sellar metastasis, although very rare, can be clinico-radiologically indistinguishable from pituitary apoplexy and should be especially considered in the differential diagnosis of patients with known primary neoplastic disease. In view of similar patho-physiological mechanism, sellar metastasis with apoplexy should be managed in a similar manner as pituitary apoplexy. PMID- 21534209 TI - Giant cystic Virchow-Robin spaces with adjacent white matter signal alteration. AB - Perivascular spaces surround the small arteries and veins as they enter into the brain parenchyma from the subarachnoid spaces. Also called as Virchow-Robin spaces, these are prominent in the basal ganglia and high convexity white matter of the elderly. Occasionally VR spaces may get massively enlarged and may mimic a cystic mass lesion. The typical CSF-like signal intensity of the cysts and location on MRI, in the absence of a neurological abnormality help in the diagnosis of the giant VR spaces and thus biopsy is avoided. Typically there is no significant adjacent brain abnormality; however FLAIR images may sometimes reveal perilesional white matter hyperintensity, which may be an indication of gliosis due to the mass effect of the lesion. Such a signal alteration should not deter one from making a diagnosis of giant Virchow-Robin spaces when the rest of the imaging findings are typical. We describe a case of a 50-year-old female with incidental giant Virchow-Robin spaces in the right hemispheric subcortical white matter with adjacent white matter hyperintense signal intensity on T2-weighted and FLAIR images. PMID- 21534210 TI - Existence of two separate facet joints on the same side: case of a congenital anomaly. AB - We present a case that had two separate facet joints on the same side causing an intervertebral instability. The embryological pathogenesis of the congenital existence of two separate facet joints on the same side of the vertebra is not conclusively known. A 68-year-old woman presented with lower back pain and severe left leg pain. Neuroradiological evaluation including dynamic plain radiography, computed tomography, and magnetic resonance imaging of the lumbar spine revealed the existence of two separate facet joints on the same side of the first sacral vertebra, severe degenerative changes of both right and left L5-S1 facet joints, and Grade II L5-S1 spondylolisthesis. Subsequently, she underwent surgery. Intraoperatively, two separate facet joints on the same side of the first sacral vertebra were confirmed. The patient's symptoms were resolved after decompression and fusion surgery. This is a unique case of the congenital existence of two separate facet joints on the same side of the first sacral vertebra. PMID- 21534211 TI - Unilateral hydrocephalus: atypical presentation of intracranial tuberculoma. AB - A 43-year-old male presented with 3-month history of low-grade fever and headache. Radiological investigations revealed unilateral hydrocephalus. Unilateral obstruction of the foramen of Monro due to chronic tubercular ependymal inflammation was suspected and endoscopic septostomy was planned. Though ventriculo-peritoneal shunt is a simple method to treat hydrocephalus, complications related to this procedure are numerous. Neuroendoscopy is a safe method to treat hydrocephalus in selected cases, and also provides access to biopsy the lesion in question. An isolated tuberculoma obstructing the foramen of Monro was seen during endoscopy. Presentation and management of this unusual tuberculoma is reported along with a review of the pertinent literature. PMID- 21534212 TI - Extraabdominal desmoid tumor appearing following resection of thoracolumbar schwannoma. AB - The authors report the case of an adult female patient who developed a thoracic paraspinous desmoid tumor (aggressive fibromatosis) located just cranially to the incision scar of the previous surgery for resection of a spinal schwannoma. To the best of the authors' knowledge, this is the first report of an extraabdominal desmoid tumor occurring after resection of a spinal schwannoma. Desmoid tumors develop from muscle connective tissue, fasciae and aponeuroses. They are known to occur in association with surgical scars or implants. Incidence of this tumor is low. The etiology is still uncertain. Although rare, this distinctive tumor should be kept in mind in the differential diagnosis of palpable masses and especially those occurring around the previous skin incisions. PMID- 21534213 TI - Primary fourth ventricular meningioma: case report and review of the literature. AB - Primary fourth ventricle meningiomas are extremely rare, and they are defined as meningiomas arising from the choroid plexus and lying strictly within the fourth ventricle. In this report we present a 61-year-old man with progressive worsening vertigo and gait disturbance, and new onset of diplopia. Neurological examination revealed bilateral abducens nerve paralysis, horizontal nystagmus, and gait disturbance with truncal ataxia. Neuroimaging revealed a mass lesion in the fourth ventricle with brain stem compression, and obstructive hydrocephalus. The patient was operated in the prone position with suboccipital craniotomy and splitting the lower vermis. Total resection of the tumor was achieved with no intra- or post-operative complications. Histopathologic examination revealed fibroblastic type meningioma (WHO grade I). PMID- 21534214 TI - Pure peroneal intraneural ganglion cyst ascending along the sciatic nerve. AB - Peroneal nerve entrapment is most commonly seen in the popliteal fossa. It is rarely caused by a ganglion. Intraneural ganglia, although uncommon and seldom cause serious complications, are well recognized and most commonly affect the common peroneal (lateral popliteal) nerve. Ganglionic cysts developing in the sheath of a peripheral nerve or joint capsule may cause compression neuropathy. The differential diagnosis should involve L5 root lesions, posttraumatic intraneural hemorrhage, nerve compression near the tendinous arch located at the fibular insertion of the peroneal longus muscle and nerve-sheath tumors. We present a unique case of a pure intraneural ganglion of the common peroneal nerve ascending along the sciatic nerve. This case underscores the importance of consideration of an intraneural ganglion cyst with sciatic nerve involvement. PMID- 21534215 TI - Anterior tarsal tunnel syndrome secondary to missed talus fracture: a case report. AB - The anterior tarsal tunnel syndrome (ATTS) has first been described by Kopell and Thompson in 1963. The anterior tarsal tunnel is formed by the fascia lining the inferior extensor retinaculum and talus as well as the navicular bone. Many ATTS cases with various etiologies have been reported since the first description. We report here an ATSS case resulting from a fibro-osseous structure that occurred after a missed talus fracture. The ATTS diagnosis can be made with a comprehensive clinical neurological examination and electrophysiological study. The treatment is based on the underlying etiology, while surgery is the most common treatment providing successful outcomes in the long term. PMID- 21534216 TI - A new entity: Chiari Zero malformation and its surgical method. AB - Recently, Iskandar et al described "Chiari Zero malformation" to characterize some kind of syringomyelia that exhibits classic Chiari-type symptoms with little to no herniation, but there is some dilemma about whether it is actually present. We presented a 38-year-old-man with a diagnosis of cervical syringomyelia. In his neurological examination, there was monoparesia at the left leg together with hypoesthesia below thoracal 7. He had initially been treated with syringopleural shunting successfully. Nine months after surgery, his syringomyelia had regrown and he clinically deteriorated. It was accepted as "a Chiari zero malformation". We performed craniovertebral decompression only. Although there was no tonsillar herniation, his syringomyelia was completely resolved and his neurological status was improved six months after the craniovertebral decompression, This case suggested that "Chiari zero malformation" description is remarkable and craniovertebral decompression is a suitable surgical approach for this entity. PMID- 21534217 TI - Operative illustrations of the Osborne's ligament. AB - The cubital tunnel syndrome is widely considered as the second most frequent compression neuropathy in the upper extremities although the existence of a compressive cause has not been determined conclusively. As far as we know, operational photography of compression of the ulnar nerve at the elbow is almost never found in the literature. In this paper, operational and pathological photographs of the Osborne's ligament as a cause of ulnar entrapment neuropathy at the elbow are presented. There is still an ambiguity as to whether compressive or tractional etiology or both of these factors may occur progressively to be a factor in the development of neuropathy. This report may be considered as concrete evidence for the compressive etiology for ulnar neuropathies. PMID- 21534218 TI - Congenital and acquired abnormalities of the portal venous system: multidetector CT appearances. AB - A knowledge of normal anatomy as well as the most frequent variants and abnormalities of the portal venous system are of great importance for liver surgery and interventional procedures. An understanding of the varied MDCT appearances of these abnormalities will allow more definitive diagnoses and help avoid false diagnoses. PMID- 21534219 TI - HIV (human immunodeficiency virus) testing and prevention in the cruise industry. AB - BACKGROUND: There are no internationally recognized guidelines regarding HIV for employees on cruise ships. The aim of the study was to survey and compare current practices for crews in the cruise industry regarding HIV testing and prevention. MATERIAL AND METHODS: Medical representatives from cruise companies were invited to complete a questionnaire on their company's practices regarding HIV-related issues. RESULTS: Fifteen of 18 invited representatives completed the questionnaire on behalf of 24 companies with a total of 155 ships. All 8 companies with a medical department had a written HIV policy, versus 4 of 16 companies that handled medical crew issues through independent medical consultant services. Thirteen companies required pre-sea HIV testing, 12 had a written HIV policy regarding HIV testing and prevention, and 18 had free condoms for the crew. A positive HIV test would result in revocation of the employment offer from 5 companies and in another 6 companies establish HIV as a pre-existing condition. Eight companies required HIV+ seafarers to demonstrate stability at regular intervals as a condition for sailing. CONCLUSIONS: Cruise companies have different practices regarding HIV in crew. Large cruise lines with medical departments are more likely to have a written HIV policy than companies using independent medical consultants. About half the companies required pre-sea HIV testing; some to avoid hiring HIV+ seafarers, others to establish HIV as a pre existing condition or to ensure proper follow-up of their HIV+ seafarers. This report may provide input for company discussions about present or future HIV policies. PMID- 21534220 TI - Oral health of seafarers - a review. AB - BACKGROUND: Poor oral health of seafarers is known to cause pain and suffering for individuals and logistical complications for shipping companies during voyages. The aim of the study was to discuss the oral health of seafarers against the backdrop of available publications. MATERIAL AND METHODS: A systematic review of all literature listed in PubMed up to August 2010 plus a hand search analysing origin of article, target group, data presented, and recommendations given. Excluded were papers on forensic dental identification and papers on mercy ships. RESULTS: Most articles deal with oral health issues in the military, are published in English, and originate from the US or Great Britain. Screening systems, organisation of dental services, and the provision of dental treatment ashore and aboard are dominant themes. Papers dealing with the merchant navy, fishing vessels, and cruise ships crews mostly present basic epidemiological data, focus on oral health at sea, and originate from industrialised countries. The growing numbers of cruise ship passengers is the subject of seven studies. Generally, dental care offered to navy crews appears more comprehensive than that offered to civilian crews. CONCLUSIONS: The research base needs to be expanded to cover all seafarers. Dental professional expertise should be sought in policy and guideline development relevant to oral health. A strategy comprising preventive, screening, and treatment service components should be developed and a certificate of dental health introduced. Funding strategies in a complex environment of transnational stakeholders for the improvement of oral-health services for seafarers are needed. Aspects of military oral health care systems could be an example for civilian operators. PMID- 21534221 TI - Risk of misclassification of decompression sickness. AB - Decompression sickness (DCS) is classified on the basis of which organ system is affected, and neurological DCS is considered more severe than DCS in joints and skin with respect to response to recompression treatment and risk of long-term sequelae. Gas bubble formation interstitially in the tissues or in the circulation is considered to be the mechanism for all types of DCS. Ten patients diagnosed as having DCS in joints or skin, by doctors experienced in diving medicine, underwent clinical examination by a neurologist and had an electroencephalogram. Eight of the ten subjects had findings suggesting central nervous system deficits. The findings indicate that DCS of the central nervous system often accompanies DCS of the joints and skin, and that local skin and joint symptoms may draw attention away from cerebral symptoms. We recommend that all cases with DCS should initially be treated as neurological DCS. PMID- 21534222 TI - Should I stay or should I go? Motivational profiles of Danish seafaring officers and non-officers. AB - BACKGROUND: Other studies have shed light on specific types of seafarers' job stressors and job satisfaction. However, so far there have not been any systematic attempts to capture the motivational profile of seafarers when it comes to both work demands and work resources. The purpose of this study is to explore the motivational profiles of seafarers in the Danish merchant fleet by identifying factors which motivate or demotivate seafarers to stay in their specific profession. Furthermore, we examine if there is a difference in work motivators and demotivators between Danish seafaring officers and non-officers. Material and methods. A questionnaire was sent out to 560 Danish-speaking seafarers with a Danish postal address; 346 seafarers returned the questionnaire, equalling a 61% response rate. RESULTS: The work motivators which were identified were: duration of home leave, level of responsibility, and level of challenge. The main demotivating factors that were identified were: being away from home, shipping company's HRM, and regulatory requirements. CONCLUSIONS: The results contribute to a deeper understanding of how seafarers perceive their occupation, and help to identify areas and aspects which might need change if employers want to retain their workforce in the long run. Overall, the results show that most of the job demands and job resources that seafarers perceive are psychosocial. When it comes to the best aspects of seafaring, over 70% of the answers were related to psychosocial factors rather than organizational or structural factors. In relation to the perceived worst aspects in seafaring, about 85% of the responses fell into psychosocial categories. The differences in the motivational profiles of officers and non-officers showed the importance of not only looking at the seafaring profession as a whole but also considering the different characteristics of various jobs onboard. PMID- 21534223 TI - Examinations regarding the prevalence of intestinal parasitic diseases in Polish soldiers contingents assigned to missions abroad. AB - The aim of this paper is to present the program of diagnostic examinations regarding the detection and following treatment of intestinal parasitic diseases in the population of Polish soldiers serving in different climatic and sanitary conditions. Intestinal parasitoses remain one of the health problems of soldiers participating in contemporary military operations. This fact mainly results from unsatisfactory sanitary and hygienic standards in the regions where troops are deployed, contamination of water and soil, inappropriate processes of purifying drinking water, and the terrible condition of sewage systems, water purification plants, or sewage treatment facilities. The occurrence of such diseases is further facilitated by disregard of some basic principles of food and feeding hygiene. Mass examinations of Polish troops to find the prevalence of intestinal parasitoses will cause a decrease in the morbidity rate of parasitic diseases among Polish soldiers deployed in military operations. They can also lead to a decrease in expenditure on medical treatment of disease-related complications and on damages awarded to soldiers who have developed a serious disease while being engaged in a mission abroad. PMID- 21534224 TI - Health problems of peacekeepers carrying out mandatory tasks in Chad, Central Africa. AB - BACKGROUND: The article presents the results of the author's own studies concerning the morbidity profile in the group of soldiers serving in the Polish Military Contingent (PMC) deployed to Chad in the period May 2008-April 2009 within the framework of a European Union operation (EUFOR) and a United Nations peacekeeping mission (MINURCAT). MATERIAL AND METHODS: The conducted analysis was based on medical records of soldiers (n = 540) treated at Level 1 (FOB Iriba) and Level 2 (HQ Abeche) medical centres located in the operational zone where the PMC was stationed. Irrespective of the evaluation of diseases of particular organs and systems, parasitological examination for the presence of intestinal parasitic diseases using a light microscopy were carried out. RESULTS: The research has demonstrated that the most serious health problems occurring in the group of Polish soldiers in the given period included: skin diseases (22.7%), respiratory tract diseases (18.9%), digestive tract diseases (12.9%), and non-battle injuries (9.2%). CONCLUSIONS: Parasitological examinations toward intestinal parasitic diseases, conducted among Polish soldiers (n = 247) in the mission area in April 2009, revealed the occurrence of protozoan pathogens (55 cases of Giardia intestinalis, 2 cases of Entamoeba histolytica/dispar). PMID- 21534225 TI - Health hazards in areas of military operations conducted in different climatic and sanitary conditions. AB - This paper reviews the most common health hazards occurring among personnel of peacekeeping and stabilization missions functioning within armed conflicts in the contemporary world. Military operations have been executed in diverse climatic and sanitary conditions, which are frequently unfamiliar for their participants. Some of them, e.g. the UN peacekeeping missions in the Middle East (Lebanon, the Golan Heights), have been carried out in a relatively stable geopolitical environment; whereas, stabilization missions in Iraq and Afghanistan, which are actually combat activities, undoubtedly fall into the group of the most perilous military operations in the world. Hot or cold climate, poor sanitary and hygienic conditions along with warfare facilitate the occurrence of numerous diseases and body injuries not only among the local people but also among peacekeepers, who represent the population of immigrants. Health hazards which pose major epidemiological threats in combat zones are arthropod-borne, food and water borne, respiratory tract diseases, sexually transmitted diseases, enzootic diseases, battle injuries, and non- -battle injuries, e.g. traffic accidents. Another considerable health problem are psychiatric disorders, which can either appear directly after the occurrence of a traumatic event in a combat zone or indirectly, after some time had elapsed. In addition to the health hazards listed above, environmental factors such as changeable weather conditions and local fauna may also be life threatening. PMID- 21534226 TI - Sickness profile among Polish troops deployed to Afghanistan in the years 2003 2005. AB - BACKGROUND: This article presents the results of individual research concerning the sickness profile in the group of soldiers of the Polish Military Contingent (PMC) deployed to Afghanistan within the international stabilization forces in the years 2003-2005. MATERIAL AND METHODS: Retrospective analysis was based on medical records of 400 Polish troops treated ambulatorily from November 2003 to October 2005 in the PMC out-patients clinic providing medical support in the operation Enduring Freedom in Bagram Air Base (north-eastern Afghanistan). All initial visits (n = 1001) were included in statistical analysis. Incidence rates of diseases and injuries were calculated per 100 persons. RESULTS: The main reasons for ambulant treatment in the group of Polish soldiers were respiratory system diseases (61.8 cases/100 persons), skin diseases (55.0 cases/100 persons), non- -battle injuries (39.8 cases/100 persons), and digestive system diseases (32.8 cases/100 persons). CONCLUSIONS: Health problems occurring among troops of the Polish Military Contingent were closely related to the effects of environmental factors (extreme range of temperature within 24- -hours and throughout the year, unsatisfactory sanitary conditions), and sports accidents in the mission area. PMID- 21534227 TI - Medical support of military operations in Iraq and Afghanistan. AB - The system of medical support in the territory of military operations in Iraq and Afghanistan is based on four levels of medical treatment. Level 4 is organized outside the war theatre, in the territories of the countries that are a part of the stabilization forces of international organizations (NATO). Both the tasks and the structure of medical support are adjusted to fit the requirements of the U.S. Forces. The same tasks and structure are also recognized by medical services of other NATO countries participating in military operations in Iraq and Afghanistan. Each subsequent level of medical support is progressively more highly specialized and capable of providing more advanced medical treatment in comparison to the preceding level. Medical evacuation is executed either by air or overland depending on the type of illness or injury as well as the tactical situation prevailing in the combat zone. The aim of this paper is to present the planning, challenges, and problems of medical assistance in the contemporary battlefield. PMID- 21534228 TI - Reasons for medical evacuation of soldiers serving in Iraqi Freedom Operation. AB - BACKGROUND: This article presents the results of the authors' own studies concerning the evacuation of Polish soldiers serving in the Centre South Zone in Iraq during the Iraqi Freedom Operation. MATERIAL AND METHODS: Analysis was based on the medical and personnel documents of 4800 soldiers of the Multinational Division Centre South in the period August 2003-July 2004. RESULTS: Medical evacuations and rotations at the soldier's own request dominated in the analysed period in the group. The main reasons for medical evacuation (67 persons) were psychiatric disorders (acute stress disorder) requiring pharmacological treatment, followed by battle injuries (gunshot/shrapnel wounds), and non-battle injuries (sports injuries, traffic accidents). Evacuations at the soldier's own request (47 persons) were dominated by non-medical adaptation disorders and family-related problems. CONCLUSIONS: Polish soldiers evacuated to their home country before the scheduled termination of duty accounted for 2.5% of the total number of military personnel assigned to Iraq in the analysed period. PMID- 21534229 TI - Epidemiological investigation in theatres of military operations. AB - The organization and implementation of anti-epidemic support in the Polish Armed Forces carrying out mandatory tasks in theatres of military operations poses a difficult and imperceptible problem in the field of medical assistance of military contingents. One of the operative instruments designed for limitation of the spread of infectious diseases and its health consequences among participants of military operations is an epidemiological investigation. Analysis of the real limitations and possibilities in the management of investigative activities constitutes a complex and varied character of issue. The aim of this paper was to present the legal, diagnostic, and logistic limitations, including medical treatment, health prevention, and evacuation capabilities, which determine the practical, medical activities in military operational conditions. PMID- 21534230 TI - Central venous catheters: legal issues. AB - In dialysis patients, both central venous catheter (CVC) insertion and CVC use during the dialysis procedure pose important legal issues, because of potentially severe, even fatal, complications. The first issue is the decision of the kind of vascular access that should be proposed to patients: an arteriovenous (AV) fistula, a graft, or a CVC. The second issue, when choosing the CVC option, is the choice of CVC: nontunneled versus tunneled. Leaving a temporary nontunneled CVC for a prolonged time increases the risk of complications and could raise a liability issue. Even when choosing a long-term tunneled CVC, nephrologists should systematically explain its potential harms, presenting them as "unsafe for long-term use" unless there is a clear contraindication to an AV native or prosthetic access. Another critical issue is the preparation of a complete, informative, and easy-to-understand consent form. The CVC insertion procedure has many aspects of legal interest, including the choice of CVC, the use of ECG monitoring, the use of ultrasound guidance for cannulation, and the use of fluoroscopy for checking the position of the metal guidewire during the procedure as well as the CVC tip before the end of the procedure. Use of insertion devices and techniques that can prevent complications should obviously be encouraged. Complications of CVC use are mainly thrombosis and infection. These are theoretically expected as pure complications (and not as malpractice effects), but legal issues might relate to inappropriate catheter care (in both the inpatient and outpatient settings) rather than to the event per se. Thus, in the individual case it is indeed very difficult to establish malpractice and liability with a catheter-related infection or thrombosis. In conclusion, we cannot avoid complications completely when using CVCs, but reducing them to a minimum and adopting safe approaches to their insertion and use will reduce legal liability. PMID- 21534231 TI - Effectiveness of a protocol for the prevention of hemodialysis venous catheter related infections. AB - PURPOSE: Infections are a major complication of the use of hemodialysis central venous catheters. In our study we evaluated the efficacy of the hemodialysis central venous catheter protocol management adopted in our center, through a retrospective analysis of all hemodialysis central venous catheters inserted over a period of 6 years. METHODS: Seventy-three tunneled central venous catheters and 75 temporary central venous catheters were inserted in our center from 2003 to 2008 in 148 patients. RESULTS: During the follow-up we observed 30 infective events (16 assessed as bacteremias, 14 subcutaneous tunnel or exit site infections) with a rate of 0.65/1,000 days of central venous catheter implantation. CONCLUSIONS: Our experience confirms, in a 72-month follow-up, the importance of careful central venous catheter management as a crucial feature in reducing the incidence of infective events in patients with central venous catheters in dialytic treatment. PMID- 21534232 TI - Evaluation of radiologically implanted central venous port systems explanted due to complications. AB - PURPOSE: The aim of this study was to evaluate explantations of central venous port systems that were implanted by interventional radiologists in cases where complications demanded the removal of the port device. METHODS: In this retrospective single-center study, explantation rates of central venous port catheter systems (CVPS) associated with complications were investigated over a 10 year period. All CVPS were implanted and explanted in our radiology department's interventional suite. Port catheter dysfunctions were divided into early and late complications, as well as into nonthrombotic and thrombotic events. Indications for implantation and explantation as well as clinical demographics were considered. RESULTS: One hundred and ninety-three CVPS were removed from 182 patients, due to complications. The total indwelling time of all CVPS was 55,132 catheter-days (mean 285.7; range 1-2,704). The most common diagnoses were gastrointestinal cancers 77 (39.9%) and hematological malignancies 32 (16.6%). Bloodstream infections 134 (69.4%) were the most common indication for the explantation procedure. These were followed by catheter-related thrombosis 28 (14.5%), nonthrombotic CVPS dysfunction 18 (9.3%), port pocket infections 9 (4.7%), and others 4 (2.1%). The highest percentages of explantations related to bloodstream infections were observed in patients with malabsorption (81.8%) and hematological malignancies (81.3%). CONCLUSION: Bloodstream infections were the most common cause for port explantation, followed by catheter-related thrombosis. Complication-related explantations were mainly for late-onset complications. Prevention and management strategies should be applied regarding care and usage of port systems to reduce the rate of complication-related explantations. PMID- 21534233 TI - GAVeCeLT* consensus statement on the correct use of totally implantable venous access devices for diagnostic radiology procedures. AB - The use of totally implantable venous access devices in radiology may be associated with complications such as occlusion of the system (because of the high density of some contrast), infection (if the port is not handled in aseptic conditions, using proper barrier protections), and mechanical complications due to the high-pressure administration of contrast by automatic injectors (so-called power injector), including extravasation of contrast media into the soft tissues, subintimal venous or myocardial injection, or serious damage to the device itself (breakage of the external connections, dislocation of the non-coring needle, or breakage of the catheter). The last problem - i.e., the damage of the device from a power injection - is not an unjustified fear, but a reality. A warning by the US Food and Drug Administration of July 2004 reports around 250 complications of this kind, referring to both port and central venous catheters and peripherally inserted central catheter systems, which occurred over a period of several years; in all cases, the damage occurred during the injection of contrast material by means of power injectors for computed tomography or magnetic resonance imaging procedures. Though the risk associated with the use of ports in radiodiagnostics is thus clear, it has been suggested that administration of the contrast material via the port may have some advantage in terms of image quality, increased comfort for the patient, and maybe more accurate reproducibility of the patient's own follow-up exams. This contention needs to be supported by evidence. Also, since many cancer patients who need frequent computed tomography studies already have totally implantable systems, it would seem reasonable to try to define how and when such systems may safely be used. The purpose of this consensus statement is to define recommendations based on the best available evidence, for the safe use of implantable ports in radiodiagnostics. PMID- 21534234 TI - Pregnancy in chronic kidney disease: need for a common language. AB - INTRODUCTION: Chronic kidney disease (CKD) is a growing health care problem, affecting 3% of women of childbearing age. AIM: This study attempted to systematically review the literature for 2000-2009 on pregnancy in CKD, as a guide for counseling. METHODS: Data sources included a Medline search for 2000 2009, employing MESH and free terms on pregnancy and CKD, limited to humans and English-language publications. Only studies observing at least 25 pregnancies were considered. The bibliographic search, abstract screening and data extraction were performed in duplicate. Out of over 3,000 references and 276 full texts, 23 studies fulfilled the selection criteria; 3 were added from references. RESULTS: The 26 studies reported on over 2,000 pregnancies. Five main categories were identified: CKD (399 pregnancies, excluding 2 population studies), lupus nephropathy (431 pregnancies), diabetic nephropathy (386 pregnancies), hematuria (310 pregnancies), kidney donors (586 pregnancies) and other. Definitions of diseases, outcomes and stratifications were nonhomogeneous, thus impairing meta analytic pooling and quantification of the risks. Within these limits, 3 major qualitative determinants of outcome were confirmed as relevant in all subsets: CKD stage, hypertension and proteinuria. Their combination may multiply the interrelated major risks (for the mother: preeclampsia, renal function impairment and proteinuria; for the offspring: small babies, prematurity, death). Specifically, mothers with lupus nephritis have a relevant risk of death (1.15%), and share with diabetic nephropathy, the risk for perinatal death (up to 23% in lupus, 10% in diabetes). Malformations were not increased, except for urinary tract malformation in reflux nephropathy. CONCLUSIONS: There is a strong need to unify definitions and stratifications to allow quantitative evidence-based counseling for pregnant patients with CKD. PMID- 21534235 TI - Impact of short-duration administration of N-acetylcysteine, probucol and ascorbic acid on contrast-induced cytotoxicity. AB - BACKGROUND: The best pharmaceutical prevention of contrast-medium-induced nephropathy for emergency procedures remains unknown. The aim of this study was to examine the impact of short-duration antioxidant pretreatment on contrast medium-induced cytotoxicity. METHODS: Human embryonic kidney cells were treated with three different contrast media: ionic ioxitalamate, non-ionic low-osmolar iopromide, and iso-osmolar iodixanol. The doses and durations of pretreatment with antioxidants were 2 mM/L N-acetylcysteine for 15 minutes, 40 uM/L probucol for 30 minutes, and 30 uM/L ascorbic acid for 30 minutes. A supplementary dose of 2 mM/L N-acetylcysteine was administered 12 hours after contrast medium treatment. Cell viability was determined by tetrazolium MTT assay. RESULTS: All three contrast media caused significant reduction of cell viability at 24 hours (p<0.001). In the groups receiving iopromide or iodixanol, N-acetylcysteine pretreatment significantly improved cell viability compared with no N acetylcysteine pretreatment (p<0.001). In the group receiving ioxitalamate, N acetylcysteine pretreatment followed by a supplementary dose of N-acetylcysteine at 12 hours rather than N-acetylcysteine pretreatment alone significantly improved cell viability compared with no N-acetylcysteine pretreatment (p=0.038). Probucol or ascorbic acid pretreatment was unable to reduce cell death caused by the three contrast media. CONCLUSIONS: Short-duration pretreatment with N acetylcysteine significantly reduced contrast-medium-induced cytotoxicity. These findings provide new insight into the prevention of contrast-medium-induced nephropathy in clinical emergency scenarios. PMID- 21534236 TI - Lipoprotein glomerulopathy: first report of 2 not consanguineous Italian men from the same town. AB - It is well known that the abnormal accumulation of lipids can occur in kidneys of patients affected by some metabolic disorders due either to inherited enzymatic deficiency or to an acquired lipid alteration as in nephrotic syndrome. Lipoprotein glomerulopathy (LG), briefly described in a patient of Koitabashi in 1987 in a review on renal lipidoses authored by Faraggiana and Churg, represents an emerging novel storage renal disease. This rare and unique nephropathy is characterized by the presence of lipoprotein thrombi in dilated glomerular capillary lumina associated with type III hyperlipoproteinemia, and high serum levels of apolipoprotein E (apo E). Several specific studies conducted by Saito et al on his patients from 1989, revealed that it was an hereditary disease with an autosomal recessive pattern that predominantly affects patients of Asian ancestry, mainly the Japanese population, but which very seldom, can also occur in white subjects. The disorder is probably due to an inherited altered lipid metabolism due to a mutation of the apo E genetic code. Clinically, LG is characterized by proteinuria generally associated with nephrotic syndrome and progressive renal insufficiency. We describe the cases of 2 Italian adult white male patients affected by LG, admitted in our nephrology unit in 2004 and in 2009, respectively. PMID- 21534237 TI - The Remission Clinic approach to halt the progression of kidney disease. AB - Randomized multicenter studies in diabetic and nondiabetic patients with chronic proteinuric nephropathies have clearly demonstrated that renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) used alone or in combination, effectively retard renal disease progression. Proteinuria reduction, in addition to arterial blood pressure control, largely mediates the nephroprotective effect of RAS inhibitor therapy. Despite RAS inhibition, however, most patients with chronic kidney disease (CKD) progress to end-stage renal disease (ESRD). This highlights the importance of innovative therapies to halt or revert CKD progression in those at risk. Along this line, a multimodal strategy (Remission Clinic) targeting urinary proteins by dual RAS inhibition with ACE inhibitors and ARBs up-titrated to maximum tolerated doses, by intensified blood pressure control, amelioration of dyslipidemia by statins, smoking cessation and healthy lifestyle implementation was safely and effectively applied at our outpatient clinic to normalize urinary proteins and prevent renal function loss in patients otherwise predicted to rapidly progress to ESRD because of nephrotic-range proteinuria refractory to standard antihypertensive dosages of an ACE inhibitor. This approach achieved remission or regression of proteinuria and stabilized kidney function in most cases, and almost fully prevented progression to ESRD. Provided patients are closely monitored and treatment is cautiously up-titrated according to tolerability, this approach might be safely applied in day-by-day hospital practice. Effective prevention of ESRD would reduce costs of renal replacement therapy by dialysis or transplantation and would be life-saving where these are not available for all patients in need. PMID- 21534239 TI - Ultrafiltration intensification in hemodialysis patients improves hypertension but increases AV fistula complications and cardiovascular events. AB - INTRODUCTION: Hypertension remains a major problem in hemodialysis (HD) patients. METHODS: We performed a pragmatic trial (Pragmatic Clinical Intervention on Blood Pressure Driven by Audit [CLINIDEA]) testing the effectiveness and safety of a 6 month multimodal intervention in hypertensive HD patients regarding the application of higher ultrafiltration (UF) rates or longer or more frequent dialyses in UF-intolerant patients, and an educational intervention to encourage patients to lower their salt and fluid intake. RESULTS: Blood pressure (BP) in hypertensive patients (n=32) fell from 156.8 +/- 13.3 / 81.1 +/- 8.9 mm Hg to 147.9 +/- 18.8 / 77.5 +/- 11.1 mm Hg. UF intensification was well tolerated, and the BP goal was achieved without resorting to longer or more frequent dialyses. BP changes were paralleled by a consistent (p<0.01) fall in dry body weight. The trial largely failed at increasing compliance with salt prescription (salt intake: baseline: 156.9 +/- 64 mEq/day, 6-month: 150.7 +/- 60.3 mEq/day). During the 12 months preceding the trial, the hospitalization rates for arteriovenous (AV) fistula complications and cardiovascular (CV) events were identical in hypertensive and in normotensive patients. However, these complications selectively increased (AV complications: relative risk [RR] = 7.6; CV complication: RR=8.4) in hypertensive patients coinciding with UF intensification during the trial. Increasing the UF rate is an effective BP-lowering intervention in HD patients. However, this intervention is associated with a higher risk for AV complications and CV events. CONCLUSION: Longer and/or more frequent dialyses and better efforts to increase compliance to low salt diets than those put in place in this study are needed to reduce the high prevalence of hypertension in the HD population. PMID- 21534240 TI - Smoking and hyperparathyroidism in patients with end-stage renal disease (ESRD). AB - BACKGROUND AND METHODS: Smoking is associated with hyperparathyroidism in the elderly general population and nicotine, the main component of tobacco smoke, stimulates PTH release in experimental models. Although smoking is a persisting problem in patients with end-stage renal disease (ESRD), the association between smoking and PTH has never been specifically examined in these patients. We investigated the relationship between smoking and hyperparathyroidism in a well characterized group of 161 nondiabetic dialysis patients. RESULTS: Sixty-four patients (40%) were smokers. Heavy smokers had higher intact PTH (median: 280 pg/mL) and PTH1-84 (188 pg/mL) than light smokers (180 pg/mL and 95 pg/mL) and nonsmokers (169 pg/mL and 95 pg/mL). In a multiple regression analysis, smoking was independently associated with intact PTH (beta=0.29, p=0.002) and PTH1-84 (beta=0.29, p=0.002). Fifty-six of 161 patients (35%) were classified as having hyperparathyroidism. In a multiple logistic regression model the odds of hyperparathyroidism were about 4 times higher in heavy smokers (odds ratio 3.88, 95% CI 1.16-12.92, p=0.027) than in nonsmokers. CONCLUSION: In dialysis patients heavy smoking is independently associated with high levels of intact PTH and PTH1 84. Further observational, mechanistic and interventional studies are needed to assess the nature (causal or noncausal) of these links in ESRD. PMID- 21534241 TI - Metabolic syndrome and chronic kidney disease in high-risk Italian hypertensive patients: the I-DEMAND study. AB - BACKGROUND: Metabolic syndrome (MS) and chronic kidney disease (CKD) are well known, independent predictors of increased cardiovascular risk. Both conditions are fairly prevalent in the general population. The aim of this study was to assess the relationship between MS or its individual components and CKD in an Italian population of hypertensive patients with normal or mildly to moderately impaired renal function under specialist care. METHODS: A total of 2,916 patients (mean age 62 +/- 11 years) among those enrolled in the I-DEMAND study were taken into consideration for this analysis. MS was defined according to the NCEP-ATP III criteria. CKD was defined as an estimated GFR (abbreviated MDRD equation) <60 ml/min/1.73m2 or as the presence of microalbuminuria (mean albumin-to-creatinine ratio =2.5 mg/mmol in men and =3.5 mg/mmol in women). RESULTS: MS was present in 59% of our study patients. The prevalence of microalbuminuria, reduced GFR and CKD was 26%, 25%, and 41%, respectively. Patients with MS had higher urinary albumin excretion (p<0.0001), lower GFR (p=0.0077), and a greater prevalence of CKD (p<0.0001), even after adjusting for age and gender. Multivariate logistic regression analysis revealed that MS was significantly associated with CKD, even after adjusting for several potential confounders including its individual components (OR 1.33, 95%CI 1.03-1.71, p=0.0268). The association between MS and CKD was stronger in nondiabetic patients. CONCLUSIONS: Renal abnormalities and MS are frequently associated in hypertensive patients under specialist care. This relationship is independent of several potential confounding factors including the components of MS. PMID- 21534242 TI - Differences in chemical composition and internal structure influence systemic host response to implants of biomaterials. AB - In reconstructive surgery, implantable devices are used to supply a missing function. In tissue engineering, biomaterials serve to guide and eventually deliver cells and/or molecules where a tissue regenerative response is needed. The host organism always reacts to implants of any biomaterial, in some instances even triggering a local cascade of events called the foreign body response (FBR), whose mechanisms are well defined. What has yet to be completely unraveled are the biomarkers systemically mirroring the FBR and the regeneration processes, which would be helpful for assessing the therapeutic efficacy of the bioscaffold. Our goal was to identify a biomarker fingerprint of the systemic reaction of host response to bioscaffold implants. Different biomaterials chosen for their osteoconductive properties, including collagen, hydroxyapatite, in foam or granules, and poly-epsilon-caprolactone, were implanted in immunocompetent mice. We analyzed serum concentrations of cells and cytokines involved in the inflammatory/immune response, and the histological features of grafts. Within two weeks after implantation, a wave of proinflammatory cytokines was flowing in the blood stream and the concentration of blood cells changed, revealing specific patterns depending on the chemistry and structure of the implanted biomaterials. Cells secreting pro-inflammatory, chemoactractant, and pro-angiogenic cytokines required for the early events in tissue repair were locally recruited because of the presence of a bioscaffold. PMID- 21534243 TI - External validation and comparison of three scores to predict renal replacement therapy after cardiac surgery: a multicenter cohort. AB - PURPOSE: Cardiac surgery-associated acute kidney injury requiring renal replacement therapy (RRT) is independently associated with mortality. Several risk scores have been developed to predict the need for RRT after cardiac surgery. We have compared and verified the external validity of the three main available scores for RRT prediction after cardiac surgery: the Thakar score, the Mehta tool, and the Simplified Renal Index. METHODS: The risk scores were calculated in a cohort of 1084 adult patients, 248 of whom required RRT, who underwent open-heart surgery in 24 Spanish hospitals in 2007. The performance of the systems was determined by examining their discrimination (areas under the receiver operating characteristic curves (aROC) and calibration (Lemeshow-Hosmer chi-square goodness-of-fit statistics). RESULTS: The aROCs in the Thakar score, the Mehta tool, and the Simplified Renal Index were 0.82, 0.76 and 0.79, respectively. The three scoring systems were poorly calibrated and tended to underestimate the actual need for RRT. CONCLUSIONS: The Thakar score and the Simplified Renal Index discriminated well between low - and high-risk patients in our cohort, and Thakar outperformed the Mehta tool. These best-performing scores may aid in the selection of optimal therapy, facilitate the planning of hospital resource utilization, improve preoperative counseling, select participants for clinical trials of renal-protective therapies and enable an accurate comparison between different institutions or surgeons. PMID- 21534244 TI - Combination of maintenance hemodialysis with hemoperfusion: a safe and effective model of artificial kidney. AB - OBJECTIVE: To investigate whether the combination of maintenance hemodialysis (MHD) with hemoperfusion (HP) could improve the clearance rate of middle and large molecule uremic toxins so as to improve the quality of life of MHD patients and reduce their mortality rate. METHODS: This study was a prospective, randomized, controlled clinical trial. 100 MHD patients were selected and then randomly divided into two groups after four weeks of run-in period. Group 1 received HD alone 2 times a week and the combined treatment of HD with HP (HD+HP) once a week, whereas Group 2 was given HD alone 3 times a week. This study was followed up for a mean of 2 years. The primary outcome was the death of patients. Secondary end points included normal clinical data, leptin, high sensitive C reactive protein (hsCRP), interleukin-6 (IL-6), beta(2) microglobulin (beta(2) MG), immunoreactive parathyroid hormone (iPTH), tumor necrosis factor-alpha (TNF alpha) and the index of dimensions of Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36 Chinese Edition ). RESULTS: At the end of the two-year observation, the serum concentration of leptin, hsCRP, iPTH, IL-6, beta(2)-MG and TNF-alpha, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), cardiothoracic ratio, left ventricular mass index (LVMI), the EPO doses and the types of antihypertensive drugs used were lower with Group 1 than with Group 2 (p<0.05); Group 1 had higher hemoglobin (Hb), ejection fraction (EF), and body mass index (BMI) (p<0.05). No statistical difference between the two groups was observed in terms of serum albumin, serum iron (SI), total iron binding capacity (TIBC), cardiac output (CO), Kt/V, early/atrial mitral inflow velocities (E/A) (p>0.05). Besides, the SF-36 indicated that the total score of overall dimentions of Group 1 was higher than Group 2 (p<0.05) and the quality of life of Group 1 was evidently better than Group 2. The Kaplan-Meier Survival Curves for the 2-year observation period showed that patients in Group 1 had obvious survival advantage while Log-rank test results showed p<0.05. No serious adverse incidents occurred during the HD+HP treatment. CONCLUSIONS: HD+HP was superior to HD in regularly eliminating middle and large molecule uremic toxins accumulated in the body. These findings suggest a potential role for HD+HP in the treatment to improve the quality of life and survival rate of MHD patients. PMID- 21534245 TI - Continuous blood purification ameliorates RhoA-mediated endothelial permeability in severe acute pancreatitis patients with lung injury. AB - BACKGROUND: In the early phase of severe acute pancreatitis (SAP), serious pulmonary complications which are directly correlated with mortality are very common. Endothelial injury has been shown to play a key role in the pathogenesis of ALI/ARDS. Continuous blood purification (CBP) has been widely used in treating patients with multiple organ dysfunction syndrome (MODS) including ARDS. However, the impact of CBP on endothelial function has been little studied. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to serum samples or replacement fluid taken from patients at specific time points during CBP, or pretreated with Y-27632 followed by treatment with serum, then, changes in cytoskeletal configuration, endothelial monolayer permeability, and RhoA activation were studied. RESULTS: Endothelial permeability, RhoA activity, and stress fiber reorganization increased in HUVECs treated with serum from patients before CBP initiation, and lessened in HUVECs treated with serum from patients after CBP initiation. Endothelial hyperpermeability and stress fiber reorganization reduced in HUVECs pretreated with Rho-kinase inhibitor, Y-27632, and in a dose-dependent fashion. Endothelial permeability and RhoA activity increased in HUVECs treated with waste replacement fluid collected 2 h after CBP initiation. CONCLUSIONS: After CBP treatment, endothelial hyperpermeability induced by serum from SAP patients with lung injury was reduced. The inhibition of RhoA-mediated F-actin remodeling might be the mechanism. PMID- 21534246 TI - Simultaneous blood temperature control and blood volume control reduces intradialytic symptoms. AB - PURPOSE: Intra-dialytic morbid events (IME; e.g. hypotension, cramps, headaches) are frequent complications during hemodialysis (HD), known to be associated with ultrafiltration-induced hypovolemia and body temperature changes. Feedback control of blood volume adjusts the ultrafiltration rate in order to keep the blood volume above the patient's individual limit; feedback control of blood temperature maintains the mean arterial blood temperature at the individual pre dialytic level. Each of these methods reduces the frequency of IME. METHODS: In a randomized clinical trial the simultaneous application of both feedback controls was investigated for the first time. In 15 weeks, each patient went through 3 study phases: an observational screening phase, a standard phase (STD), and a blood temperature- and blood volume-control phase (CTL). Patients with at least 5 sessions with IME out of 15 sessions in the screening phase were eligible for the study and randomized either into sequence STD-CTL or CTL-STD. RESULTS: 26 patients completed the study according to protocol, and 778 HD treatments were analyzed. The general treatment parameters were similar in both study phases: treatment duration (STD: 244 min, CTL: 243 min, NS), pre-dialytic weight (STD: 72.3 kg, CTL: 72.2 kg, NS), and weight loss due to ultrafiltration (STD: 3.26 kg, CTL: 3.15 kg, NS). The proportion of HD treatments with IME was 32.8% during STD and 18.0% during CTL (p=0.024). CONCLUSIONS: The frequency of HD sessions with IME was significantly reduced by 45% compared to standard HD in this randomized clinical trial by use of individualized HD treatments with simultaneous feedback control of blood volume and blood temperature. PMID- 21534247 TI - Extracorporeal membrane oxygenation in 108 patients with low cardiac output - a single-center experience. AB - BACKGROUND: For short-term ventricular and pulmonary support the extracorporeal membrane oxygenation (ECMO) system using the Bio-Medicus centrifugal pump (Medtronic(r), Minneapolis, MN, USA) was applied in 108 patients with cardiac low output. METHODS: From December 1996 to July 2006 the ECMO was implanted in 108 patients (73 adult, mean age: 49.3+/-18.0 yrs and 35 children, mean age: 1.3 +/- 2.7 yrs) with mostly postcardiotomy cardiac low output. The surgical procedures included congenital heart surgery (n=35), heart transplantation (HTx) (n=21), coronary artery bypass operation (CABG) and/or valvular operation (n=33), other operations (n=6) and 13 patients with ECMO support for bridge to recovery. RESULTS: The mean supporting time was 5.1+/-5.6 days. Overall, 30-day-survival was 40.2%. Best survival rates were seen after congenital heart surgery (24/35, 65.7%) and after HTx (9/21, 42.9%); the worst rates were in the group of CABG and/or valvular operations (5/33, 15.2%), only ECMO support (3/13, 23.1%) and other operations (1/6, 16.7%). Fifty-four patients died while supported by ECMO, 15 were weaned from ECMO but died in hospital, 39 patients were weaned and survived. Causes of death were multi-organ failure (40.6%), bleeding (23.2%), persistent cardiac low output (21.7%), thrombembolic events (8.7%), and graft failure (5.8%). Markers for adverse outcome were identified as older age, high body weight, increased AST/GOT levels, and lower thrombocyte count in adults; and as higher levels of serum creatinine in pediatric patients. CONCLUSIONS: ECMO support showed best results in pediatric patients after congenital heart surgery and in patients after HTx in contrast to multimorbid, older patients with often irreversible myocardial damage. PMID- 21534248 TI - Clinical evaluation of the air removal characteristics of an oxygenator with integrated arterial filter in a minimized extracorporeal circuit. AB - The use of minimized extracorporeal circuits (MECC) in cardiac surgery is an important measure to increase the biocompatibility of cardiopulmonary bypass during coronary artery bypass grafting (CABG). These circuits eliminate volume storage reservoirs and bubble traps to minimize the circuit. However, the reduction in volume may increase the risk of gaseous microemboli (GME). The MECC system as used by our group consists of a venous bubble trap, centrifugal pump, and an oxygenator. To further reduce the risk of introducing GME, an oxygenator with an integrated arterial filter was developed based on the concept of minimal volume and foreign surface. We studied the air removal characteristics of this oxygenator with and without integrated arterial filter. The quantity and volume of GME were measured with precision at both the inlet and outlet of the devices. Our results showed that integration of an arterial filter into this oxygenator increased GME reducing capacity from 69.2% to 92%. Moreover, we were able to obtain data on the impact of an arterial filter on the exact size-distribution of GME entering the arterial line. The present study demonstrates that an MECC system and oxygenator with integrated arterial filter significantly reduces the volume and size of GME. The use of an integrated arterial filter in an MECC system may protect the patient from the deleterious effects of CPB and may further improve patient safety. PMID- 21534249 TI - A pulsatile simulator for the in vitro analysis of the mitral valve with tri axial papillary muscle displacement. AB - PURPOSE: We developed a new pulsatile hydrodynamic simulator for the in vitro testing of mitral valve (MV) samples. The required specifications included a 3D positioning system for the papillary muscles (PMs) that is accurate and simple to manage; measurement of the force exerted by the chordae tendineae on the PMs; and the possibility to visually inspect the MV for kinematic analysis. METHODS: An atrial/ventricular chamber system was developed. The ventricular chamber housed a tri-axial actuator system that was aligned to a morphometric Cartesian frame, allowing for PM positioning even while tests are running. Each PM holder had an embedded load cell for force measurement. The atrial chamber was designed so as to permit MV visual inspection, maintaining a non-disturbed flow at the sample inlet. The setup was subjected to trials with fresh porcine MVs. Flow and pressure difference across the MVs and PM forces were measured in different MV configurations, with different PM spatial dislocations. High speed video recordings were acquired. RESULTS: The positioning accuracy was assessed. Tests with MVs showed good usability, even by the non-engineering personnel. The effects of PM displacement on valve function (valve competence and PM forces) was consistent with previously published data, thus confirming the general soundness of the design principles. CONCLUSIONS: The developed simulator is a promising instrument for performing MV in vitro tests in a precise, well-repeatable manner. The ability to completely adjust the PM position while a test is running boosts the simulator's potential for detailed investigations of the pathological and surgically treated MV. PMID- 21534250 TI - Surgical management of congenital pupillary-iris-lens membrane. AB - PURPOSE: To describe the surgical interventions in congenital pupillary-iris-lens membrane. Six patients with congenital pupillary-iris-lens membrane presented with partial or totally occluded pupils, or increased intraocular pressure (IOP). METHODS: We describe the value of creating 2 paracenteses. The first one is made in the lower temporal quadrant and accommodates a 20-gauge anterior chamber maintainer (ACM). The second paracentesis is made in an upper quadrant and serves to cut the membrane with a vitrectomy probe. RESULTS: The technique was performed in 6 eyes of 6 children aged 4 to 10 months from March 2007 to July 2008 at Southwest Eye Hospital. These patients had congenital pupillary-iris-lens membrane with partial or totally occluded pupils, or increased IOP due to iris bombe or angle closure. No secondary glaucoma has been detected in the follow-up period. The visual acuity before the operations was less than 0.05 with preferential looking (PL), while the visual acuity was improved to 0.5 in 4 out of 6 eyes and 0.3 in 2 eyes in the last follow-up. CONCLUSIONS: The ACM and vitrectomy probe are important tools in the surgical management of congenital pupillary-iris-lens membrane because they facilitate the surgical procedure and reduce iatrogenic damage to the lens. Timely surgical intervention can abort the progressive pupillary occlusion or angle closure glaucoma. PMID- 21534251 TI - Comparison between anti-vascular endothelial growth factor therapy and photodynamic therapy for myopic choroidal neovascularization. AB - PURPOSE: To compare the efficacy of anti-vascular endothelial growth factor (VEGF) therapy versus photodynamic therapy (PDT) for myopic choroidal neovascularization (mCNV). METHODS: This study is a retrospective interventional study. Forty-two eyes from 42 patients with mCNV (36 subfoveal, 4 juxtafoveal, and 2 extrafoveal) treated and followed up for more than 6 months were included. Twenty eyes from 20 patients were treated by PDT (PDT group) at 1.5 +/- 0.9 months after the symptoms and 22 eyes from 22 patients were treated by anti-VEGF therapy (anti-VEGF group) at 0.9 +/- 0.8 months after the symptoms. Photodynamic therapy was performed, followed up, and retreated by standard procedures. Anti VEGF therapy was repeated as needed. Gender, age, best-corrected visual acuity (BCVA), greatest linear dimension (GLD), central retinal thickness (CRT), and outer nuclear layer (ONL) thickness at the fovea were then compared between the anti-VEGF and PDT groups. RESULTS: No differences were detected in baseline parameters between the anti-VEGF and PDT groups. The mean BCVA (logMAR) at month 3 and 6 after the initial treatment was improved (-0.30 and -0.29) from baseline in the anti-VEGF group, which was statistically significant (p=0.0048 and 0.021, respectively). In the PDT group, modest improvements were observed in the mean BCVA at the same time periods (-0.05 and -0.10) with no statistical significance (p=0.79 and 0.90, respectively). The mean CRT was significantly reduced from baseline to month 6 in the anti-VEGF and PDT groups. The ONL thickness was significantly reduced in both groups, although the magnitude was significantly greater in the PDT group than the anti-VEGF group. CONCLUSIONS: Treatment with anti-VEGF therapy had significantly better visual outcomes than PDT for mCNV. PMID- 21534252 TI - One-day session LINAC-based stereotactic radiosurgery of posterior uveal melanoma. AB - PURPOSE: LINAC-based stereotactic radiosurgery (SRS) of posterior uveal melanoma is a conservative method to treat uveal melanoma. METHODS: This was a retrospective clinic-based study of patients with posterior uveal melanoma in stage T2/T3 who underwent 1-day session SRS at LINAC accelerator or SRS plus combined methods from 2001 to 2008. RESULTS: Thirty-nine patients with posterior uveal melanoma were treated with SRS (age 25-80 years, median 54 years). Median tumor volume at baseline was 0.6 cm3 (range 0.2-1.3 cm3). The therapeutic dose (TD) was 35.0 Gy, median of maximal dose applied was 49.0 Gy (range 37.0-60.0 Gy). Patient data were analyzed in groups: group 1, single SRS irradiation; group 2, SRS with subsequent endoresection or cyclectomy or additional transpupillary thermotherapy (TTT) or brachytherapy by Ru106 plaques; group 3a, enucleation after single SRS; group 3b, enucleation after SRS and endoresection/cyclectomy or TTT or brachytherapy Ru106. In patients with visual acuity of 20/40 or better, the median rate of best-corrected visual acuity (BCVA) decline was higher than that of the total and significantly higher than the rate of decline in the complementary group of patients with BCVA less than 20/40 (p=0.0077; Mann-Whitney U test). CONCLUSIONS: One-step LINAC-based SRS with a single dose 35.0 Gy is a method to treat middle-stage posterior uveal melanoma and to preserve the eye globe or as the first step of combined methods: irradiation before endoresection or cyclectomy. PMID- 21534254 TI - When should I start getting screened for osteoporosis? PMID- 21534253 TI - Isolation and expansion of regionally defined human glioblastoma cells in vitro. AB - This unit describes a protocol for the surgical collection, isolation, and expansion of regionally defined human glioblastoma multiforme (GBM)-derived cells. Given the important role played by microenvironmental hypoxia in defining cell phenotype and molecular signaling activation, it is important to distinguish between tumor tissues that were originally localized within the partially necrotic tumor core and those located along the peripheral and vascularized areas. The procedures for enzymatic dissociation of GBM tissues and cell culturing under hypoxia described here are optimized to obtain an efficient single-cell suspension and subsequent growth, in an effort to avoid the spontaneous induction of cell commitment normally occurring in long-term cell culture. PMID- 21534255 TI - Rehabilitation: mobility, exercise & sports. Proceedings of the 4th International State-of-the-Art-Congress. April 7-9, 2009. Amsterdam, The Netherlands. PMID- 21534256 TI - Invited commentary. PMID- 21534257 TI - Festschrift in honor of G. Gayle Stephens. PMID- 21534258 TI - Marine genomics: at the interface of marine microbial ecology and biotechnological applications. Proceedings of a CIESM-NSF/EC Workshop. October 12 14, 2008. Monaco. PMID- 21534260 TI - Proceedings of the 28th Manfred Donike Cologne Workshop on Dope Analysis. March 2010. Cologne, Germany. PMID- 21534259 TI - Pichia anomala. Proceedings of the 1st International Pichia anomala Mini Symposium. Uppsala, Sweden. February 10-12, 2010. PMID- 21534261 TI - Advances in Chronic Kidney Disease 2011. Proceedings of the 13th International Conference on Dialysis. January 26-28, 2011. Miami, Florida, USA. PMID- 21534263 TI - Proceedings of MCP2009, 6th International Conference on Multiple Comparison Procedures. March 24-27, 2009. Tokyo, Japan. PMID- 21534262 TI - Developments in botanical dietary supplements research from 1994 to today in honor of Dr. Farnsworth's 80th birthday. Proceedings of the 2010 DSHEA (Dietary Supplements Health and Education Act of 1994) Symposium. March 23, 2010. Chicago, Illinois, USA. PMID- 21534264 TI - Retraction: Non-arteritic anterior ischaemic optic neuropathy and the treatment of erectile dysfunction. PMID- 21534265 TI - Proceedings of the 9th International Workshop on Human Leukocyte Differentiation Antigens. March 2010. Barcelona, Spain. PMID- 21534266 TI - The future of nursing. Leading change, advancing health. PMID- 21534267 TI - An appreciation: Robert (Bob) W. Horne (21st January 1923-13th November 2010). PMID- 21534268 TI - Archaea and the tree of life. Proceedings of an international interdisciplinary meeting. 2009. Fondation Des Treilles. France. PMID- 21534269 TI - Normative collective behavior in the Station building fire. AB - Objective. This article offers a test of the normative explanation of collective behavior by examining the fire at the Station nightclub in Rhode Island that killed 100 and injured nearly 200 persons.Methods. Information on all persons at the club comes from content analysis of documents from the Rhode Island Police Department, the Rhode Island Office of the Attorney General, and The Providence Journal. We use negative binomial regression to test hypotheses about the effects of group-level predictors of the counts of dead and injured in 179 groups at the nightclub.Results. Results indicate that group-level factors such as distance of group members at the start of the fire, the number of intimate relations among them, the extent to which they had visited the nightclub prior to the incident, and the average length of the evacuation route they used predict counts of injured and dead. The research also looks at what behavioral differences exist between survivors and victims, ascertains the existence of role extension among employees of the nightclub, and provides support for the affirmation that dangerous contexts negate the protective influence of intimate relations in groups.Conclusion. We argue for the abandonment of current emphasis on irrationality and herd-like imitative behavior in studies of evacuation from structural fires in buildings and for the inclusion of group-level processes in social psychological explanations of these incidents. PMID- 21534270 TI - The importance of type, amount, and timing of internet use for understanding psychological distress. AB - Objective. Few social scientists have examined how Internet usage, including using the Internet for health purposes, may affect mental health. This study assesses whether the type or amount of online health activities and the timing of Internet use are associated with psychological distress.Methods. We use data from the National Cancer Institute's 2005 Health Information National Trends Survey.Results. When we compare Internet users to non-Internet users, using the Internet and using the Internet for health purposes are negatively associated with distress. However, among Internet users, the number of online health activities is positively associated with distress. Greater distress is also associated with using the Internet on weekdays and looking online for information on sun protection.Conclusions. Internet usage is not necessarily positively associated with psychological distress. The effects depend on the type, amount, and timing of Internet usage. PMID- 21534272 TI - [One health is now also taking shape at the first level standard]. PMID- 21534271 TI - Party control, policy reforms, and the impact on health insurance coverage in the U.S. states. AB - Objectives. One of the major policy concerns at the federal and state level is the rising number of individuals without health insurance. The purpose of this article is to investigate whether party control of government and various state reforms impact the percentage of the state population without health insurance.Methods. Using data from 1987-2007, I empirically examine whether party control and five state policy reforms reduce the uninsured population.Results. The results show that Republicans are more effective than Democrats at the state level at reducing insurance gaps and that three of five policy reforms explored appear to significantly expand insurance coverage.Conclusions. The results provide valuable insight into which components of health-care reform at the national level may help address the health insurance problem. PMID- 21534273 TI - [Expensive pigeon]. PMID- 21534274 TI - [Mandatory reporting of animal abuse gives the veterinarian a boost]. PMID- 21534275 TI - [Practicing veterinarian: know what you are worth!]. PMID- 21534276 TI - [Trends from the GD monitoring]. PMID- 21534277 TI - [Postnatal changes in the ductus arteriosus and brown adipose tissue: a review and an exploratory post-mortem study of lambs]. AB - After a short review of the literature, postnatal changes in the ductus arteriosus Botalli are described in 52 lambs sampled in 1970 and 1971. Five groups of animals were formed on the basis of findings. (I) All lambs (n = 18) that died of asphyxia or prematurity had open ducti and, in most cases, severe adventitial bleeding (2). Completely anatomically closed ducti were found in I week-old lambs (n = 9). Lambs that died within about 4 days of birth were grouped as (3) low-birth weight (dysmaturity) (n = 2), (4) normal weight and died after bacterial infection (n = 7), or (5) normal birth weight and died of other causes (n = 6). The dysmature lambs died because of cold and poor suckling. Compared with the lambs with a normal body weight, the dysmature lambs had almost completely closed ducti. Extensive, often circular, haemorrhages at the periphery of the necrotic muscular tissue of the ductal media were found in the dysmature and infected lambs. In these lambs, the brown adipose tissue surrounding the ductus was red-brownish and often depleted of its fat. This fat depletion and haemorrhages were less severe in lambs that died of other causes. The haemorrhages in the media of the ductus arteriosus, which were not found in older lambs, have not been described previously in other species, including humans. These haemorrhages are most likely the result of a short period of ductal relaxation, resulting in the passage of blood through the vasa vasorum and leakage of blood cells from degenerated capillaries at the border of the necrotic muscular tissue. It is hypothesized that the relaxation results from one or a combination of the following: (i) direct heat from heat-producing brown adipose tissue surrounding the ductus (because of cold or infection), (2) infection or inflammatory mediators, and (3) adipose tissue-derived relaxing factors. PMID- 21534278 TI - [Horse milking industry in The Netherlands and Flanders]. AB - The horse milking industry is expanding in The Netherlands and Flanders. Horse milk has become popular due to its (supposed) health-enhancing properties. A horse-milking farm is not a common client for the Dutch veterinarian. When giving advice in this circumstance it should be recognised that these horses are production animals and that their milk is for human consumption. A review of the literature is given together with the results of an extensive enquiry amongst 13 horse-milking farms in The Netherlands and Flanders. PMID- 21534279 TI - [Surveillance for Newcastle disease outbreak stays pertinent]. PMID- 21534280 TI - [Emergency slaughter is slaughtering in an emergency]. PMID- 21534281 TI - [Does the bulldog still have a future?]. PMID- 21534283 TI - [Window "farmer's chance": 'I just say it as I see it']. PMID- 21534282 TI - [Career switch--what does that mean for your pension?]. PMID- 21534284 TI - [Stan van der Meijs: bring independance and skills together]. PMID- 21534286 TI - [Long QT syndrome]. PMID- 21534285 TI - [Does the veterinarian continue to sell drugs?]. PMID- 21534287 TI - [Transfusion requirements, morbidity and mortality in cardiac surgery and the use of antifibrinolytic agents: a comparison of aprotinin and tranexamic acid]. AB - OBJECTIVE: To evaluate transfusion requirements, morbidity and mortality when 2 antifibrinolytic agents (aprotinin and tranexamic acid) were used in patients undergoing cardiac surgery. PATIENTS AND METHODS: Comparison of the effects of 2 antifibrinolytic agents in 243 patients undergoing cardiac surgery between December 2006 and June 2008. We recorded the surgical procedures used, blood product transfusions required, complications (particularly renal), mortality, and length of hospital stay. RESULTS: The patients were distributed into 2 groups to receive tranexamic acid (n = 144) or aprotinin (n = 99). The incidence of transfusion in the tranexamic acid group (31.94%) was nonsignificantly lower than in the aprotinin group (38.38%) (PF = .31). The mean (SD) number of units of packed red blood cells transfused was 0.67 (1.18) in the tranexamic acid group and 1.01 (1.54) in the aprotinin group (P = .07). The mean preoperative hemoglobin concentration in the tranexamic acid group (11.79 [1.71] mg/dL) was significantly lower than in the aprotinin group (12.35 [1.70] mg/dL) (P < .01). Incipient postoperative renal failure tended to occur more frequently in the aprotinin group (19.6% compared to 16%; P = .47). Mortality at 1 year was 9.02% in the tranexamic acid group (compared to 14.14% in the aprotinin group; PF-.21); the trend for mortality related to postoperative renal failure was similar (7.6% in the tranexamic acid group compared to 12.4% in the aprotinin group; P = .22). No significant differences were observed in postoperative complications or length of hospital stay. However, the lack of randomization and the small sample size do not allow for definitive conclusions. CONCLUSIONS: This study, subject to the aforementioned limitations, shows that tranexamic acid is as effective as aprotinin for reducing transfusion requirements in cardiac surgery in Spain. PMID- 21534288 TI - [Neostigmine-induced neuromuscular blockade in the corrugator supercilii muscle]. AB - OBJECTIVE: To investigate whether a single dose of neostigmine, administered when the adductor pollicis muscle presents 2 twitches in train-of-four (TOF) stimulation, can reduce the TOF ratio in the corrugator supercilii muscle. PATIENTS AND METHODS: We designed a case-control study of patients between 18 and 65 years of age classified ASA 1-2. We used 2 accelerometers--1 for the cubital nerve/thumb adductor muscle and 1 for the facial nerve/corrugator supercilii muscle. Neuromuscular blockade was induced with 0.6 mg x kg(-1) of rocuronium, and 40 microg x kg(-1) of neostigmine was administered at the third twitch in the TOF in the thumb adductor. If the TOF ratio in the corrugator supercilii fell by 10% or more at that time, the patient was classified as a case. We recorded the age, sex, weight, height, body mass index, duration of the procedure, and TOF ratio in the corrugator supercilii muscle when the neostigmine was administered. RESULTS: Ten cases and 10 controls were enrolled. No significant differences between cases and controls were found in any variables except the mean (SD) TOF ratio in the corrugator supercilii muscle: 70.9% (17.8%) in cases and 35.3% (7.8%) in controls (P < .001). CONCLUSIONS: In our patients, administration of neostigmine after the appearance of the third twitch in TOF stimulation of the thumb adductor was associated with a reduction in the TOF ratio in the corrugator supercilii. The similarity between blockades of the corrugator muscle, the diaphragm, and the larynx is of clinical interest. PMID- 21534289 TI - [Anesthetic treatment of patients with osteogenesis imperfecta]. AB - BACKGROUND AND OBJECTIVE: Although the prevalence of osteogenesis imperfecta is low, the effect of this hereditary disease on patients' quality of life is considerable. We report our experience in the perioperative management of patients with this condition in our hospital. PATIENTS AND METHODS: Retrospective study describing the interventions on patients with this disease in our hospital from 1991 to 2009. We analyzed demographic data, disease variants, concomitant disorders, surgical procedures, type of anesthesia, and intraoperative and postoperative complications. RESULTS: From 1991 to 2009, 105 procedures were performed on 29 patients (ages 1 to 25 years) with osteogenesis imperfecta (37.9% women and 62.1% men). The most common type of osteogenesis imperfecta was type III (65.5%). Most patients (93%) had no associated diseases. Two patients were allergic to latex. No complications occurred in 62% of interventions. Reported complications during surgery were 1 case of non-malignant hyperthermia and 1 contralateral femur fracture. CONCLUSIONS: The prevalence of osteogenesis imperfecta is low. Treatment requires a multidisciplinary approach, in which appropriate perioperative management must be based on a proper understanding of the skeletal and extraskeletal abnormalities associated with this disease. PMID- 21534290 TI - [Extracorporeal membrane oxygenation after cardiac surgery in 12 patients with cardiogenic shock]. AB - OBJECTIVES: Mortality is high when cardiogenic shock develops after cardiotomy, making it impossible to discontinue extracorporeal circulation and/or leading to low postoperative cardiac output that is refractory to treatment with vasoactive drugs or implantation of an intra-aortic balloon pump. Extracorporeal membrane oxygenation (ECMO) provides temporary assisted circulation, lending hemodynamic and respiratory support to the patient with cardiogenic shock in order to prevent multiple organ failure and death. MATERIAL AND METHODS: For this retrospective study of cases in which ECMO was applied in our hospital's assisted circulation unit, we analyzed demographic data, indication, score on the European system for cardiac operative risk evaluation (Euroscore), duration of assistance, complications, and survival. RESULTS: In the first 3 years after the assisted circulation unit was established, during which 1375 cardiac interventions took place, ECMO was used postoperatively in 12 patients (0.87%). In 8 of the patients, assistance was provided during cardiac surgery following cardiotomy and in 4 transplant patients it was used following primary graft failure. The mean (SD) patient age was 56.8 (9.1) years. The Euroscore predicted 37.3% (16.7%) of the deaths. ECMO was used for a mean of 5.4 (2.5) days. The most frequent complications were bleeding in the surgical area, cardiac tamponade, and acute renal insufficiency. Overall in-hospital mortality was 50%, lower than rates reported in the literature. CONCLUSIONS: ECMO provided viable temporary support, maintaining adequate cardiac output while the patient's condition could be observed and heart function evaluated. Mortality was reduced. PMID- 21534291 TI - [Continuous spinal anesthesia in obstetrics]. AB - Despite the theoretical advantages of continuous anesthesia in obstetric patients (good-quality blockade at low doses, good hemodynamic stability, rapid onset of effect, and no risk of toxicity), little has been published on this technique and its use in pregnancy. Moreover, few descriptive studies or comparative trials have evaluated the efficacy and safety of continuous spinal anesthesia, probably because of concerns about potential adverse effects-principally neurologic complications and postdural puncture headache. We review the literature on the use of continuous spinal anesthesia in obstetric patients, analyzing the advantages and disadvantages, indications, and adverse effects of this technique. PMID- 21534292 TI - [Sub-tenon block for ocular globe anesthesia: a review]. AB - Sub-Tenon anesthesia is an effective, well-tolerated technique for surgery in the anterior or posterior compartments of the eye. The advantages of this block are comparable to those of peribulbar and retrobulbar anesthesia and complications are minimal. Sub-Tenon anesthesia provides better analgesia than akinesia. Most studies suggest that sub-Tenon anesthesia is a good technique to choose, given that potential adverse effects are fewer than for other regional blocks and analgesia and akinesia are superior. PMID- 21534293 TI - [Extracorporeal membrane oxygenation in acute respiratory distress syndrome after a liver transplant]. AB - Extracorporeal membrane oxygenation (ECMO) is used in the treatment of severe respiratory failure that is potentially reversible. This mode of therapy reduces ventilator-associated lung injury. Although ECMO is costly and not free of complications, its early application by experienced multidisciplinary teams can improve survival. We report a case of acute respiratory distress syndrome in a patient who had received a liver transplant. Respiratory failure was unresponsive to conventional treatment and the patient required ECMO until recovery. PMID- 21534294 TI - [Post-cardiac arrest syndrome after general anesthesia: role of therapeutic hypothermia and remifentanil]. AB - Moderate therapeutic hypothermia is often used in aneurysm surgery and is therefore a technique anesthesiologists are familiar with. We report the case of a patient who had entered into a coma after cardiac arrest in the postanesthetic recovery unit during central venous catheterization; the patient required 35 minutes of advanced cardiopulmonary resuscitation before heart rhythm and tissue perfusion were restored. The protocol for treating post-cardiac arrest syndrome included therapeutic hypothermia, which was maintained for 12 hours. The patient was extubated after 2 days, with no neurologic deficit. Post-cardiac arrest syndrome is associated with multiple biochemical reactions which are attenuated by hypothermia. Currently available evidence does not allow definitive recommendations regarding the different techniques for inducing therapeutic hypothermia, the ideal temperature to maintain, the duration, or the rewarming process. Further studies are required. PMID- 21534295 TI - [Severe acute ethylene glycol poisoning: diagnostic utility of osmolar gap monitoring]. AB - Ethylene glycol intake is a rare cause of alcohol poisoning in our practice setting. Most cases are voluntary, representing suicide attempts. Because delayed treatment leads to serious morbidity and high mortality (up to 50%), early diagnosis is essential for preventing harmful consequences and even death. Diagnosis is based on clinical suspicion and laboratory findings. Given that most hospitals do not have the means to measure the specific toxin in plasma, osmolar gap monitoring usually serves as a rapid diagnostic test for detecting the presence of osmotically active substances like ethylene glycol in plasma. We report a case of voluntary poisoning after the patient swallowed antifreeze. Successful treatment began early, with monitoring of the osmolar gap and plasma level correspondence. We also comment on the range of therapeutic options, emphasizing antidotes such as ethanol and fomepizole which provide the basis for treatment. PMID- 21534296 TI - [The REDESRA project]. PMID- 21534297 TI - [General anesthesia in a man with congenital long QT syndrome]. PMID- 21534298 TI - [Intradural anesthesia for emergency cesarean section in a woman with congenital long QT syndrome]. PMID- 21534299 TI - [Anesthetic implications of Marshall-Smith syndrome]. PMID- 21534300 TI - [Patient undergoing percutaneous radiofrequency ablation of the liver: a case description]. PMID- 21534301 TI - [Perioperative care of a girl with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA syndrome)]. PMID- 21534302 TI - [Launch of a perioperative program for smoking cessation]. PMID- 21534303 TI - [Intraoperative finding of a right tracheal bronchus by fiberoptic bronchoscopy]. PMID- 21534304 TI - [Congenital tracheal bronchus]. PMID- 21534305 TI - [Contribution of ultrasound imaging in the approach to subclavian vein catheterization described by Robert Aubaniac]. PMID- 21534306 TI - [Easily accessible medical records--a right with problems?]. PMID- 21534307 TI - [The effect of light on the mind, and neuroendocrinological function. Let there be light!]. PMID- 21534308 TI - [Patient safety and drugs--concentrate on decision support]. PMID- 21534309 TI - [Connections between drug management and drug reviews. Correct tools can make the drug management better and safer]. PMID- 21534310 TI - [Severe sepsis and septic shock require immediate care]. PMID- 21534311 TI - [Diagnosis and diagnostic coding of severe sepsis and septic shock. ICD-10 should be completed with additional codes]. PMID- 21534312 TI - [National quality registry can improve care in life-threatening sepsis]. PMID- 21534313 TI - [Freedom of choice in psychiatry--an unsuccessful project]. PMID- 21534314 TI - [Strengthen the patient-physician encounter]. PMID- 21534315 TI - [Give correct treatment in eclampsia!]. PMID- 21534316 TI - [Imaging and functional medicine do not meet the need of physiological diagnostics in health care]. PMID- 21534317 TI - [A current question: crammed registries and hollow physicians]. PMID- 21534318 TI - [Eternal life for HIV is no axiom. But the way towards an HIV free world is long and difficult]. PMID- 21534319 TI - [Intergenerational transmission gives HIV eternal life]. PMID- 21534320 TI - [Quality shortages in the diagnostics of thyroid nodules. National guidelines should be introduced]. PMID- 21534321 TI - [The medical education in Gothenburg is being reformed. Professional development, research and internationalization]. PMID- 21534322 TI - [Elderly with co-existing diseases--a challenge for analysts and health economists]. PMID- 21534323 TI - [No ban to connect registries to economic control]. PMID- 21534324 TI - [Increased freedom of choice instead of increased productivity]. PMID- 21534325 TI - [Limits to freedom of choice?]. PMID- 21534326 TI - [To write or to dictate--part 2]. PMID- 21534327 TI - GPs should prescribe more benzodiazepines for the elderly: no. PMID- 21534328 TI - The nurse practitioner provides a substantive opportunity for task substitution in primary care: no. PMID- 21534329 TI - A polypill is the solution to the pharmacological management of cardiovascular risk: no. PMID- 21534330 TI - New Zealand should introduce population screening for prostate cancer using PSA testing: no. PMID- 21534331 TI - Autoimmune cholangitis associated to IgG4 related sclerosing disease. AB - The IgG4-related sclerosing disease is characterized by the presence of plasmatic IgG4 positive cells and T-lymphocytes infiltration in different organs. We herein report a case of cholestasis due to autoimmune cholangitis associated to IgG4 disease. A 40-year-old woman with a history of pruritus, anosmia, Sjogren's syndrome and diabetes, was referred for a pancreatic tumor. Alkaline phosphatase was 24-fold upper limit of normal (ULN), gamma-glutamyl transpeptidase 21-fold ULN, aspartate aminotransferase 3-fold ULN, alanine aminotransferase 2-fold ULN, cholesterol 408 mg/dL, bilirubin normal, gamma-globulin 3.92 g/dL, IgG4 4.6 g/L, antinuclear antibody positive (1/320), and antimitochondrial antibodies negative. Ultrasound scan (US) showed a mass in the pancreatic head and thickening of the gallbladder and the bile duct walls. Dilation and strictures of the main pancreatic duct and intrahepatic bile ducts were detected by MR cholangiopancreatography. Liver biopsy showed chronic inflammatory lesions, ductal damage (autoimmune cholangitis) (METAVIRA2, F2) and IgG4 bearing plasmatic cells. A cervical lymph node showed IgG4 bearing plasmatic cells. After 2 weeks of treatment with meprednisone, ursodeoxycholic acid and insulin, pruritus and anosmia disappeared. After eleven months of treatment imaging studies showed disappearance of the pancreatic tumor, atrophy of the body and the pancreatic tail and normal biochemical parameters, except for alkaline phosphatase 2-fold ULN. The final diagnosis of our patient was autoimmune hepatitis with cholangitis associated to IgG4 systemic diseases. PMID- 21534332 TI - Remembering Ihsan Dogramaci. PMID- 21534333 TI - The status of women and of maternal and perinatal health in Turkey. AB - Turkey has improved the status of women and the maternal and perinatal health statistics in the last decades. However, discrepancies between urban-rural and east-other regions continue, with some improvements. The education of girls is promoted and maternal age at marriage and at first delivery has increased. Birth control measures are increasingly used. Fertility rates decreased to 2.16 children per fertile woman. Antenatal care standards have improved, and achievement of deliveries by health care personnel and postnatal mother/newborn care has increased to 90%. The maternal death rate decreased to 19.5 in 100,000 pregnants. However, uneducated women marry earlier and have a higher risk of dying from pregnancy-related causes. Perinatal mortality decreased to 19 in 1,000 deliveries. Neonatal mortality rate decreased to 13 in 1,000 live deliveries. Uneducated mothers living in rural areas and having more children receive less antenatal and postnatal care and are more likely to lose their newborn. The major causes of neonatal deaths are prematurity and congenital abnormalities. PMID- 21534334 TI - Pediatric pulmonology in a developing country: our focus. AB - This study was designed to determine the profile of our pediatric pulmonology unit in Turkey, a developing country, by investigating the patients admitted to our unit for the first time. Our objectives were: to determine the profile of patients admitted for the first time, to compare their initial diagnoses before referral to our hospital with the diagnoses determined in our unit, to determine the definitive diagnoses for patients requiring advanced intervention with invasive diagnostic methods, and to follow the treatments, operations and invasive-noninvasive mechanical ventilation practices. With these objectives in mind, the records of 412 patients who visited the pediatric pulmonology clinic within a six-month period were reviewed. The referral diagnoses, consisting mostly of primary ciliary dyskinesia, recurrent lung infections caused by immune deficiency and bronchiectasis, as well as definitive diagnoses were recorded. Tuberculosis (14%), cystic fibrosis (7.8%), bronchiectasis (4.6%), immune deficiency (1.6%), hydatid cyst (2%), and primary ciliary dyskinesia (1%) were the most commonly diagnosed diseases. Final diagnosis in 145 of the 412 patients (35.2%) differed from the referral diagnosis. Consanguineous marriages are encountered more commonly in developing countries like Turkey, leading to an increased incidence of genetic diseases such as primary ciliary dysgenesis, cystic fibrosis and immune deficiencies. Infectious diseases such as hydatid cyst and tuberculosis are also common. In any country in which there is a unique distribution of diseases, in other words, a characteristic and unique disease spectrum, courses and instructional fellowship programs should be arranged accordingly. PMID- 21534335 TI - Combination antifungal therapy with voriconazole for persistent candidemia in very low birth weight neonates. AB - The purpose of this article is to report our experience with intravenous voriconazole therapy in the treatment of persistent Candida septicemia in very low birth weight (VLBW) neonates. Candidiasis was defined if an infant had a positive blood culture. Ten VLBW newborns developed Candida sepsis, and candidemia persisted in 6 of them despite 3 to 21 days of antifungal therapy with amphotericin B, either conventional or liposomal, and fluconazole. After the addition of voriconazole, clearance of Candida was achieved within 3-7 days of treatment. Antifungal therapy combination with liposomal amphotericin B and voriconazole was continued for at least two weeks after two negative cultures 48 hours apart. We conclude that considering the hazardous effects of Candida infections in preterm newborns, voriconazole can be added to the treatment of fungal sepsis in newborns who still have persistent candidemia despite conventional antifungal management. More clinical information is needed before voriconazole can be used as a first-line drug in antifungal therapy in newborns. PMID- 21534336 TI - The effect of gonadotropin-releasing hormone analog treatment (leuprolide) on body fat distribution in idiopathic central precocious puberty. AB - Gonadotropin-releasing hormone analog (GnRHa) therapy is used in idiopathic central precocious puberty (ICPP) worldwide. It has also been shown that during this therapy, body mass index (BMI) increases slightly as a side effect. We investigated the side effects of GnRHa treatment in ICPP on body composition and insulin resistance (IR). Twenty girls (7.55 +/- 1.02 y) with ICPP were treated with GnRHa (leuprolide) for an average of 20.83 +/- 4.8 months. Bioelectrical Impedance Analysis (BIA) was used to measure the body's fat balance. Nine patients out of 20 (45%) had significant gain weight. We showed a significant elevation in trunk fat mass compare to baseline values (p < 0.01). These nine patients had high homeostasis model assessment (HOMA)-IR and low glucose/insulin (G/I) index. This study showed a slight increase in BMI, moderate increase in total body fat, and exaggerated elevation in trunk fat mass and IR in GnRHa treated ICPP children. PMID- 21534337 TI - A 10-year single center survey of pediatric patients with histiocytic disorders in Iran. AB - Childhood histiocytosis is a rare and diverse group of proliferative disorders, characterized by accumulation and infiltration of antigen-presenting cells or antigen-processing cells, which can affect any tissue or organ. This study was performed in order to investigate the clinical characteristics of Iranian children with different types of histiocytic disorders. Thirty-five patients, with a median age of 3.5 years, who were referred and diagnosed with histiocytic disorders in a referral Children's Hospital in Iran from 1997-2006, were investigated in this study. According to the World Health Organization classification, 27 patients were in class 1, followed by 6 patients in class 2, and 1 patient in class 3. Moreover, 1 patient was diagnosed with sinus histiocytosis with massive lymphadenopathy. Bone lesions were the most common manifestation, which were detected in 15 cases, followed by skin lesions (11 cases) and fever (10 cases). Nonspecific findings like hepatomegaly and splenomegaly were found in 15 cases. Different types of treatment protocols were used according to the diverse groups of histiocytic disorders and different stages of disease, including surgical excision, radiotherapy, chemotherapy, and stem cell transplantation. Twelve patients did not respond well to the treatment and subsequently died due to complications of their disease. Although histiocytosis is considered a rare condition, it can be problematic for pediatric hematologists because of the unknown etiologies and pathogenesis, variable classifications and subtypes, diagnostic difficulties, poor therapeutic responses with high mortality, and some complications after different therapeutic protocols. PMID- 21534338 TI - Adrenal bleeding in neonates: report of 37 cases. AB - Adrenal hemorrhage is more common in neonates than in children or adults. The incidence of detected cases ranges from 1.7 to 2.1 per 1000 births. Because adrenal bleeding may remain asymptomatic, the real occurrence is probably higher. In this retrospective study, we evaluated epidemiologic properties, risk factors and clinical presentations of adrenal hemorrhage in 37 term newborn babies diagnosed as adrenal hemorrhage with abdominal ultrasonography between January 2003 and July 2007 in Dr. Sami Ulus Children's Hospital Neonatal Intensive Care Unit (NICU). We also evaluated the role of adrenal hemorrhage among the etiologic factors of unexplained jaundice. Abdominal ultrasonography was applied to 2280 newborns, and 37 newborns (25 male, 12 female) were diagnosed as adrenal hemorrhage (1.6%). The male/female ratio was 2.08. The average age and birth weight at admission were 4.9 +/- 0.3 days and 3333 +/- 939 g, respectively. Adrenal hemorrhage was right-sided in 24, left-sided in 9 and bilateral in 4 newborns. Resolution time of adrenal hemorrhage was a minimum of 3 months, maximum of 9 months in ultrasonographic follow-up. The most common clinical feature in infants with adrenal hemorrhage was jaundice, which was observed in 67.6% of cases (n = 25). We advise that, in cases of hyperbilirubinemia of unknown etiology, adrenal hemorrhage must be kept in mind. We recommend abdominal ultrasonography for further evaluation. PMID- 21534339 TI - Abdominal obesity is an independent risk factor for increased carotid intima- media thickness in obese children. AB - We aimed in this study to investigate carotid intima-media thickness (IMT) in obese children and evaluate the relationship of IMT to various cardiovascular risk factors. One-hundred four obese children (9.3 +/- 2.5 years) and 30 healthy age-matched control subjects were enrolled in the study. All children were assessed for fasting levels of glucose, insulin, lipid profile, skinfold thickness (SFT), waist circumference (WC), and blood pressure (BP). Insulin resistance was estimated by the homeostasis model assessment (HOMA) index. Carotid IMT measurements and non-alcoholic fatty liver disease (NAFLD) were diagnosed with ultrasonographic findings. IMT was significantly higher in obese children compared to controls (0.49 +/- 0.05 vs. 0.40 +/- 0.02 mm, p < 0.001). Significant positive correlations were found between increased carotid IMT and body fat percentage (BFP), body mass index (BMI), age, height, systolic BP, WC, SFT, triglyceride and insulin levels, and insulin resistance index. In a linear logistic regression analysis, the only parameter affecting the increase in carotid IMT was WC (beta: 0.589, p < 0.001). Furthermore, IMT was increased significantly in obese children with NAFLD when compared to obese children without NAFLD (0.54 +/- 0.04 vs. 0.48 +/- 0.05 mm, p < 0.001). Children with abdominal obesity are at increased risk for atherosclerosis, and WC can be used to determine the atherosclerosis risk in obese children. PMID- 21534340 TI - Evaluation of sixteen children with pseudotumor cerebri. AB - Pseudotumor cerebri (PTC) is a clinical condition characterized by signs and symptoms of increased intracranial pressure, such as headache and papilledema. A total of 16 patients diagnosed with PTC [12 (75%) female; 4 (25%) male] were included in the study. The age of onset of symptoms was 123.4 +/- 34.3 months (range: 60-168 months). Obesity was found in four (25%) of them. Two patients had venous sinus thrombosis, two had corticosteroid withdrawal, and one had posttraumatic PTC. The most common symptom was headache, recorded in 93.8% of the patients. All patients were treated medically. Two patients in our group also required a lumboperitoneal shunt. In conclusion, PTC in children is rare. Both papilledema and sixth nerve palsy resolved rapidly with treatment. However, children can sustain loss of visual field and visual acuity despite treatment. PMID- 21534341 TI - Heart rate variability during asymptomatic periods in children with recurrent neurocardiogenic syncope. AB - Neurocardiogenic syncope (NS) is a common clinical problem during childhood. In order to characterize the autonomic profile in syncopal children, we evaluated heart rate variability (HRV) of 27 patients, ages 8-17 years, in an asymptomatic period. HRV was calculated over a 24-hour (h) period for the time-domain indices and frequency-domain indices. The obtained results were compared to values in 27 healthy children, ages 10-17 years. Patients with syncope did not have significantly different HRV values in comparison to healthy children. After behavior modification and education, HRV assessment was repeated six months later in the symptomatic group under follow-up, and we found no significantly different values. We conclude that there was no significant difference in baseline autonomic values between children with NS and the healthy control group. After behavior modification and education, none of the patients with NS under follow-up experienced syncope or presyncope during the follow-up period. The major complaint had disappeared but did not reflect the HRV values. There was no significant difference in baseline HRV values of the patients in follow-up. We conclude that patients are predisposed to faint by a triggering autonomic stress, without having constant autonomic instability. PMID- 21534342 TI - Transcutaneous measurement of bilirubin in Turkish newborns: comparison with total serum bilirubin. AB - Routine use of transcutaneous bilirubin (TcB) measurement in the newborn nursery could reduce costs, readmission rates for hyperbilirubinemia and the need for total serum bilirubin (TSB) measurements. The aim of this study was to examine the correlation between TcB measurement, as performed using BiliCheck, and TSB, measured with high-pressure liquid chromatography (HPLC) and with standard laboratory methods, and to determine the TcB cutoff points with desirable sensitivity and specificity values for various clinically relevant TSB levels by HPLC. Fifty-four infants of > or = 30 weeks of gestational age were enrolled in the study. Near simultaneous blood collection for TSB analysis by three methods- bedside bilirubinometer, diazo method and HPLC--and TcB measurement were performed. There was good correlation between TcB and HPLC-bilirubin (B) (r = 0.85), TSB by bilirubinometer and HPLC-B (r = 0.91) and TSB by diazo method and HPLC-B (r = 0.91). The cut-off limits providing a sensitivity of 100% for TcB measurements were TcB > or = 9 mg/dl for HPLC-B > 17 mg/dl and TcB > or = 8 mg/dl for HPLC-B > 15 mg/dl and HPLC-B > 13 mg/dl. Despite having good correlation with HPLC, BiliCheck showed worse performance than bilirubinometer and diazo method at various clinically relevant cut-off values. Since BiliCheck required relatively lower thresholds with false-positive results for having a sensitivity of 100%, it cannot be recommended as a complete substitute for serum bilirubin measurements. PMID- 21534343 TI - Learning disability and oligodendrocyte myelin glycoprotein (OMGP) gene in neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant disease where phenotypic heterogeneity is explained by the effect of modifier genes. Thirty to 65% of patients have learning disability. The oligodendrocyte myelin glycoprotein (OMGP) gene located within the neurofibromatosis type 1 (NF1) gene might affect the phenotype of learning disability because it is expressed in the brain, and OMGP gene mutations have been associated with cognitive disturbances. We analyzed the OMGP gene in NF1 patients with and without learning disability (n = 50 each) and healthy controls (n = 100). The allele distribution of OMGP62 polymorphism was not significantly different between the groups (p = 0.447). These results do not support a relationship between the OMGP gene and the learning disability phenotype observed in NF1. Other modifying genes, post-translational modifications or receptor interactions might be involved in the phenotypic variability of NF1. PMID- 21534344 TI - A novel mutation in the DGUOK gene in a Turkish newborn with mitochondrial depletion syndrome. AB - Deoxyguanosine kinase (DGUOK) catalyzes the first step of the mitochondrial deoxypurine salvage pathway, the phosphorylation of purine deoxyribonucleosides. Mutations in the DGUOK gene have been linked to inherited mitochondrial (mt)DNA depletion syndromes, neonatal liver failure, nystagmus, and hypotonia. We now report a novel homozygous c.34C > T (p.Arg12X) mutation found in an affected newborn of asymptomatic consanguineous parents. Respiratory distress started in the first hours after birth. The patient died at the age of 42 days due to liver failure. This genotype, which is to be expected for a homozygous stop codon mutation in exon 1, is associated with a severe clinical presentation. PMID- 21534345 TI - Secondary childhood acute myeloid leukemia with complex karyotypic anomalies including monosomy 7, monosomy 5 and translocation (1;10) after 131I metaiodobenzylguanidine therapy for relapsed neuroblastoma. AB - The prognosis for relapsing or refractory neuroblastoma (NB) remains dismal, with a five-year disease-free survival of < 20%, and no effective salvage treatment has been identified so far. 131I-metaiodobenzylguanidine (131I-MIBG) has come to play an essential role in the imaging and therapy of NB over the past 30 years. The role of 131I-MIBG in the treatment of NB is continually expanding. 131I-MIBG treatment together with cumulative doses of other alkylating agents has potential serious late side effects such as myelodysplasia and leukemia, although rare. We describe a secondary acute myeloid leukemia case with complex karyotypic anomalies that included monosomy 5, monosomy 7 and translocation (1;10) in a child with relapsed NB who received therapeutic 131I-MIBG. PMID- 21534346 TI - A rare cause of severe periorbital edema and dermonecrotic ulcer of the eyelid in a child: brown recluse spider bite. AB - Spider bites are a worldwide problem. Brown recluse spider bites can lead to severe local or systemic clinical effects, such as edema, necrotic ulcer, rashes, fever, chills, nausea, vomiting, malaise, arthralgia, myalgia, hemolysis, leukocytosis, disseminated intravascular coagulation, renal failure, and death. Eyelid bites from brown recluse spiders are rare. We report a child with severe facial edema and a dermonecrotic ulcer on the eyelid. Upon laboratory examination, leukocytosis with a significant left shift was detected. The patient was treated with antibiotics, systemic corticosteroid and conservative therapy that included saline compresses and ocular lubrication. No surgical excision was required. Vision was not impaired. A dermonecrotic ulcer is a severe complication of brown recluse spider bites. Since the diagnosis is difficult, clinical and epidemiological findings and a detailed history are important for an accurate diagnosis. PMID- 21534347 TI - Aseptic meningitis in a child due to 2009 pandemic influenza A (H1N1) infection. AB - Neurologic manifestations of seasonal influenza 2009 pandemic influenza A (H1N1) are now known to include encephalitis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, transverse myelitis, and acute necrotizing encephalopathy. We report a case of 2009 pandemic influenza A (H1N1) meningitis in a previously healthy six-year-old girl who presented with fever, headache, abdominal pain, and vomiting. The infection was confirmed via nasopharyngeal and throat swabs. She was treated with oseltamivir successfully. To our knowledge, she is the first child diagnosed as pandemic influenza A (H1N1) meningitis. PMID- 21534348 TI - Gyrate atrophy of the choroid and retina: a case report. AB - Gyrate atrophy is a rare metabolic disease characterized by hyperornithinemia, typical retinal and choroidal lesions, high myopia with marked astigmatism, early cataract formation, and autosomal recessive inheritance pattern. In this paper, we describe a 12-year-old boy presenting with high myopia and gyrate fundus lesions, in addition to 10-times elevated serum ornithine level. PMID- 21534349 TI - A case of mitral papillary muscle rupture due to blunt chest trauma. AB - Mitral regurgitation due to papillary muscle rupture after blunt chest trauma is uncommon. Sudden onset severe mitral regurgitation may lead to death due to heart failure if surgical repair is delayed. A previously healthy 12-year-old girl underwent splenectomy and chest tube insertion for pneumothorax after a traffic accident in a vehicle 15 days before. She was discharged from the hospital after a nine-day follow-up. She was presented to our hospital due to respiratory distress. On physical examination, an apical holosystolic murmur radiating to the axillary region was recognized. Transthoracic echocardiogram showed severe mitral regurgitation with freely moving posterior mitral chordae and prolapse of the posterior mitral valve leaflet. She received reimplantation of the complete ruptured posteromedial papillary muscle of the mitral valve. Her medical condition improved after the operation. On the postoperative echocardiogram, the left ventricular systolic function was normal with no mitral regurgitation. PMID- 21534350 TI - A challenging review of childhood incontinence: rare complications of dysfunctional elimination syndrome in an epileptic boy. AB - A multidisciplinary approach is mandatory in defining the cause and directing the treatment of childhood urinary incontinence. Both pediatricians and pediatric urologists should carefully evaluate a child with incontinence for possible overlapping etiologies, before labeling him or her as a refractory case. We report an epileptic boy with dysfunctional elimination syndrome (DES) with associated rare complications of giggle incontinence and idiopathic urethritis, proving the need for a good voiding diary, patient history and structured symptom scores. PMID- 21534351 TI - Cardiovascular findings in a boy with arterial tortuosity syndrome: case report and review of the literature. AB - Arterial tortuosity syndrome (ATS) is a rare hereditary, autosomal recessive, connective tissue disorder. Herein, we describe a five-year-old boy. He had hyperextensible skin, atypical facial features and inguinal hernia. We present his vascular imaging studies of kinking and tortuosity of the aorta and bilateral multiple peripheral pulmonary artery stenoses determined by conventional and magnetic resonance angiographic (MRA) examination. ATS must be considered in patients with connective tissue condition associated with diffuse arterial changes and involvement of the skin, joints and other organs. Vascular imaging studies, especially MRA, are useful in the screening of these vascular abnormalities. PMID- 21534352 TI - Clitoral epidermoid cyst secondary to blunt trauma in a 9-year-old child. AB - Epidermoid cysts are slowly growing tumors arising from invagination of the epidermis into the dermis traumatically or spontaneously. This implantation in the clitoris is most commonly induced by female genital mutilation. The reported cases with spontaneous onset of this clitoral lesion are scarce. Trauma other than female circumcision predisposing to the onset of the cyst has not been mentioned before. A nine-year-old girl was presented for swelling in the pubic region with the onset following an accidental trauma; the diagnosis was determined to be epidermoid cyst of the clitoris after a brief preoperative evaluation and an accurate surgical management. PMID- 21534353 TI - An unexpected parasitic cause of hypereosinophilia: fascioliasis. AB - A six-year-old boy from Eastern Anatolia was admitted to our outpatient clinic with abdominal pain and hyperleukocytosis. His leukocyte count was 50 x 10(9)/L with an 80% eosinophilia. Serological investigation was positive at a titration of 1/2560 for Fasciola hepatica. Hepatomegaly with linear hypoechogenic strains, which is typical for F. hepatica, was seen on abdominal ultrasonography. He was successfully treated with triclabendazole, 10 mg/kg/day. He is now under follow up without any complaints. Hypereosinophilia mimicking leukemia is not an expected finding. To our best knowledge, high leukocyte count with F. hepatica in a child has not been reported in the literature until now. PMID- 21534354 TI - Hepatitis A seroprevalence among infants aged 12 months in Ankara. AB - Seroprevalence studies in various age groups contribute to a better understanding of hepatitis A infection and response to hepatitis A immunization. Hepatitis A seroprevalence in 12-month-old infants from Ankara was studied. Among 601 healthy infants, overall hepatitis A seropositivity was found to be 23.5%. There were no gender differences in seropositivity (22.6% for male and 24.5% for female infants). Although vaccination of infants would be an ideal prevention strategy, presence of maternal anti-hepatitis A virus (HAV) antibody interferes with the immune response to hepatitis A vaccine in infants and young children. Therefore, further knowledge about decay of maternal antibody in infants is important in determining the optimal age for vaccination against hepatitis A. There is no recommendation for routine hepatitis A vaccination in Turkey. However, we need more seroprevalence studies in different age groups to decide the appropriate timing/age of vaccination. PMID- 21534355 TI - A mother and son with Noonan syndrome resulting from a PTPN11 mutation. PMID- 21534356 TI - Red cells in abetalipoproteinemia. PMID- 21534357 TI - Generalized aggressive periodontitis. PMID- 21534358 TI - Obstetric outcomes of teenage pimigravida in Su-Ngai Kolok Hospital, Narathiwat, Thailand. AB - BACKGROUND: Teenage primigravida cause high morbidity and mortality to mother and fetus. OBJECTIVE: To compare obstetric outcomes of teenage pregnancy with reproductive-age pregnancy (20-34 years), with a focus on the risk of low birth weight and anemia. MATERIAL AND METHOD: A historical cohort study of 2922 primigravida women who gave birth between January 2005 and December 2009 at Sungaikolok Hospital Narathiwat was done. The patients were divided into two groups to compare the obstetric outcomes. The study group was composed of 796 cases ofteenage pregnancies (< 20 years) and the control group was composed of 2126 cases of reproductive-age pregnancies (20-34 years). RESULTS: Twenty-seven percent of these patients were teenage pregnancies. The teenage group received less adequate antenatal care (<4 visits), and less education than the reproductive group (p < 0.05). The study group had a significantly higher incidence of anemia (23.6%) low birth weight (16.3%), and pre-term (10.3%) than the reproductive control group, (p < 0.05). After controlling for other factors by logistic regressing analysis, poor antenatal care (<4 visits) was significantly associated with low birth weight and anemia in teenage pregnancy with an odds ratio of 1.9 and 1.5 respectively Private antenatal care was significantly associated with lower anemia (odds ratio 0.7) and low birth weight (odds ratio 0.6). CONCLUSION: Teenage pregnant women had less education and antenatal care than the reproductive-age group. Teenage pregnancy had an increased risk of adverse obstetric outcomes, especially, low birth weight and anemia. PMID- 21534359 TI - Pregnancy outcomes of Southeast Asian immigrant pregnant women compared with Thai pregnant women in Rajavithi Hospital. AB - OBJECTIVE: To determine the pregnancy outcomes of Southeast Asian immigrant women compared to native Thai women in Rajavithi Hospital. MATERIAL AND METHOD: A retrospective cohort study was conducted on singleton Southeast Asian immigrant pregnant women in Thailand between January 2007 and December 2008. RESULTS: One thousand two hundred sixty immigrant pregnant women and 5040 controls were included. After adjusting the odds ratio, the cesarean section rate, postpartum hemorrhage, preterm birth, and neonatal intensive care unit admission of immigrant women are not different from native-born women. The incidence of low Apgar score at 5 minutes and perinatal death were significantly lower in the study group with an odds ratio of 0.506 (95% CI 0.29-0.89) and 0.295 (95% CI 0.10 0.83), respectively. Low birth weight was higher in the study group with an odds ratio of 1.707 (95% CI 1.45-2.01). CONCLUSION: In Thailand, the cesarean section rate, postpartum hemorrhage, preterm birth, and neonatal intensive care unit admission of immigrant women are not different from native-born women. Foreign born status confers a protective effect for low Apgar score at 5 minutes and perinatal death. However, the incidence of low birth weight in foreign-born women is higher than native-born women. PMID- 21534360 TI - Prevalence of abnormal cervical cytology by liquid based cytology in the antenatal care clinic, Thammasat University Hospital. AB - OBJECTIVE: To determine the prevalence of abnormal cervical cytology by liquid based cytology (LBC) in pregnant women who attended the antenatal care clinic at Thammasat University Hospital. MATERIAL AND METHOD: LBC was performed on specimens from the collecting vial containing preserved cell solution (Cytyc, Boxborough, MA) in pregnant women who attended antenatal care at the antenatal care clinic, Thammasat University Hospital between March and July 2010. One hundred forty three pregnant women were recruited in the present study. All cytological reports were reviewed by senior cytopathologists for accurate diagnosis using the Bethesda System 2001 criteria. Patients with abnormal results as "abnormal squamous/glandular cells of undetermined significant" or more over were referred for colposcopic examination. RESULTS: One hundred forty three pregnant women participated in the present study. The average age was 27.09 years. There were 10 abnormal Pap smear results with four, five, and one cases of ASC-US, LSIL and HSIL respectively The prevalence of abnormal cervical cytology in this investigation was 7% with 0.7% high-grade cervical intraepithelial neoplacia. Only 6% of participants had the correct understanding of the necessity of Pap smear testing. Thirty-one percent of multiparous pregnant women in the present study had no previous Pap smear screening. The majority of participants had coitarche before the age of 20. CONCLUSION: The prevalence of abnormal cervical cytology in pregnant patients attending the antenatal care clinic at Thammasat University Hospital was 7%. The cervical cytology and related education were highly recommended in antenatal care clinic to increase cervical cancer screening coverage among reproductive age women. PMID- 21534361 TI - Prevalence of high-grade cervical intraepithelial neoplasia (CIN) in the patients with atypical squamous cells of undetermined significance (ASC-US) pap smears: hospital based, dynamic population area. AB - OBJECTIVE: To determine the prevalence of cervical intraepithelial neoplasia (CIN) 2-3 (high-grade CIN) among women with Atypical Squamous Cells of Undetermined Significance (ASC-US) Pap smear. MATERIAL AND METHOD: A retrospective medical record review of220 women with ASC-US cervical Pap smear, including age, menstruation status, parity, placed of residence, occupation, main complaint, and definite histopathological result between July 2007 and January 2010 was done. RESULTS: The prevalence of high-grade CIN2 and CIN 3 in Thammasat University Hospital were 8.6% and 3.2% respectively No cancer was found in the present study. There was no statistically significant difference in the prevalence of high-grade CIN between the patients who were 50 years old or more and those who were younger. CONCLUSION: Prevalence of high-grade CIN in women with ASC-US was 11.8%. Immediate colposcopy is recommended in women with ASC-US PMID- 21534362 TI - Cadmium bioavailability from vegetable and animal-based foods assessed with in vitro digestion/caco-2 cell model. AB - BACKGROUND: Chronic dietary cadmium (Cd) exposure results in kidney dysfunction and decrease in bone mineral density. OBJECTIVE: To determine and compare the bioavailability of Cd from vegetable and animal-based foods. MATERIAL AND METHOD: Caco-2 cells were exposed to Cd in boiled pig kidney, ark shell, kale, raw kale, mixed boiled pig kidney with raw kale and CdCl2 after in vitro digestion. Then cellular Cd uptake from the digests and reference CdCl2 solution was measured by atomic absorption spectrometry. RESULTS: Cd bioavailability from animal-based foods was higher than that from vegetable-based foods. In addition, raw kale exhibited an inhibitory effect on Cd bioavailability when mixed with boiled pig kidney. However Cd in kale was increasingly absorbed after boiling. CONCLUSION: Cd binding to different molecular species, other food components in vegetable and animal-based foods, food combination, as well as cooking processes influenced the uptake of dietary Cd. A relative bioavailability factor accounted for the food matrix might be necessary for exposure assessment and consequently for estimation and prevention of the risk of dietary Cd. PMID- 21534363 TI - Therapeutic effectiveness of a generic versus original meropenem in serious infections. AB - BACKGROUND: Meropenem plays a significant role in the current antimicrobial treatment of serious infections. Recently, generic meropenems have become widely available in Thailand. OBJECTIVE: Compare the effectiveness and safety ofa generic meropenem (Mapenem) with the original meropenem (Meronem) in clinical practice. MATERIAL AND METHOD: A retrospective cohort study was conducted in hospitalized patients with serious infections that had been treated with either the generic or the original meropenem in nine secondary- and tertiary-care hospitals nationwide. The treatment outcomes at days 3, 7, and 14 after the use ofmeropenem between the two groups were compared. RESULTS: Three hundred ninety seven patients with a mean (SD) age of 66.4 +/- 16.9 years were included. There were 228 (57.4%) males and 169 (42.6%) females. Two hundred and seven (52.1%) and 190 (47.9%) cases fell into the generic and original groups respectively. There were no significant differences regarding age, gender history of underlying disease, body weight, and ward of admission between the two groups. The majority ofpatients had presented with the respiratory tract (48.6%) and bloodstream infections (29.5%). The three most common causative bacteria were Pseudomonas aeruginosa, Acinetobacter baumannii, and extended-spectrum beta-lactamase (ESBL) producing Escherichia coli. The distribution ofthe sites of infection, causative microorganisms, the dosage ofmeropenem, and duration oftreatment were similar between the two groups. The distribution of patients with complete resolution, improvement, stable, worse, diedfrom infection, and died from other causes were similar between the two groups at day 3, 7, and 14 ofmeropenem use (p > 0.05). The drugs were well-tolerated, and less than 2% of patients in both groups discontinued meropenem due to the adverse drug effects. CONCLUSION: The generic meropenem has a similar effectiveness in the treatment of serious bacterial infections when compared with original meropenem. Both formulations are well tolerated among patients with substantial comorbidities. Adverse drug effects that lead to drug discontinuation are uncommon. PMID- 21534364 TI - Validation of the Thai SCOPA-sleep scale for assessment of sleep and sleepiness in patients with Parkinson's disease. AB - OBJECTIVE: To validate the Thai version of the Scale for Outcomes in Parkinson 's disease-Sleep Scale (SCOPA-Sleep scale)for assessment of nighttime sleep problems (NSP) and daytime sleepiness (DS). MATERIAL AND METHOD: A Thai version of SCOPA Sleep scale has been developed with the permission of the originator. Fifty-one patients with Parkinson's disease were asked to complete the Thai SCOPA-Sleep scale (consisting of NSP and DS sections), plus the Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). A second group of twenty patients completed the Thai SCOPA-Sleep scale, twice, two weeks apart. The reliability and validity were subsequently analyzed. RESULTS: The Thai SCOPA-Sleep scale showed a Cronbach 's alpha coefficient of 0.87 and 0.74 for SCOPA-NSP and SCOPA-DS, respectively with no significant difference between initial and follow-up scores. The content validity of SCOPA-NSP and SCOPA-DS were 0.9 and 0.9, respectively. There was a strong correlation between the Thai SCOPA-NSP and PSQI as well as the Thai SCOPA-DS and ESS (p < 0.01 and p < 0.01, respectively). CONCLUSION: The Thai SCOPA-Sleep scale is a reliable, valid instrument for assessing NSP and DS PMID- 21534365 TI - Stand-alone cervical polyetheretherketone (PEEK) cage (cervios) for single to two level degenerative disc disease. AB - OBJECTIVE: To study clinical and radiographic outcome of patients who underwent the Cervios cage-assisted anterior cervical discectomy and fusion (ACDF) without plate fixation in single to two-level degenerative disc disease (DDD). MATERIAL AND METHOD: Sixty-seven patients suffering from cervical DDD with various symptoms such as radiculopathy, myelopathy, or both were retrospectively evaluated. The cervical DDD was confirmed by plain radiographs and MR imaging The patients underwent radiographic evaluation to assess cervical lordosis, intervertebral height (IH), fusion, and subsidence. Clinical assessment was graded using a visual analog scale (VAS), Modified JOA (Japanese Orthopedic Association) score, Neck Disability Index (NDI). RESULTS: There were ninety two ACFD in two levels of operation. Single-level ACDF was performed in 42 patients and two-level in 25. The outcomes revealed the significant improvement of clinical outcome and restoration of cervical lordosis. The fusion rate was 97%, whereas subsidence occurred 7.61% but produced no symptom. There was no anterior or posterior migration of the cage. Complications included transient dysphagia in three patients and superficial wound infection in two patients. CONCLUSION: The present study indicates that one- to two-level stand alone Cervios cage-assisted interbody fusion without plate fixation provides improvement of clinical outcomes, restoration of lordosis and high fusion rate. However subsidence occurred in 7.61% but did not cause clinical symptoms and the patients had to use the cervical collar postoperatively. PMID- 21534366 TI - Anthropometry of eyelid and orbit in four southern Thailand ethnic groups. AB - OBJECTIVE: To study the basic eyelid and orbital measurement in the four main ethnic groups of southern Thailand. MATERIAL AND METHOD: The basic eyelid and orbital surface anatomy of 101 normal subjects aged 20-40 years old were measured in the four ethnic groups of which the majority of people in southern Thailand belong to: Thai, Chinese, Thai-Malay, and Thai-Chinese. RESULTS: Of the 101 subjects, 51 were male and 50 were female. Each ethnic group had at least 12 normal subjects. Male-female data were analyzed separately and compared between groups. The palpebral fissure heights in Thai, Chinese, Thai-Malay, and Thai Chinese males were 9.5, 9.0, 10.2 and 9.6 mm respectively, which demonstrated statistically significant differences between Thai-Malay versus Thai, and Thai Malay versus Chinese. The palpebral fissure lengths were 30.4, 29.8, 30.5 and 30.5 mm, but without statistically significant differences. The marginal reflex distances were 3.2, 2.8, 3.7 and 3.1 mm respectively with a statistically significant difference only between Thai-Malay versus Chinese. The levator functions were 15.2, 15.2, 15.3 and 15.2 mm. The upper lid creases were 7.1, 4.0, 6.6, and 4.4 mm, statistically significantly different in Thai versus Chinese, Thai versus Thai-Chinese and Chinese versus Thai-Malay. The Hertel exophthalmometer measurements were 15.4, 16.3, 16.6 and 15.9 mm without statistically significant differences. The female measurements were overall similar to the male measurements, with some parallel differences between the groups. The eyebrow position in this age group was mostly at and above the orbital rim in both genders and all ethnic groups. An absence of upper lid crease and an epicanthal fold were found in significantly greater numbers in the Chinese group compared to the others, while parallel lid crease was significantly found in greater numbers in the Thai-Malay group than in the others. CONCLUSION: Different eyelid characteristics in diferent ethnic groups are an important feature to note when planning for eyelid surgery. As there is a wide range of ethnic groups in Asia, with many differences in eyelid characteristics, it is important for the ophthalmologist to be aware of and understanding these anatomical variations in clinical assessment and treatment in Asians. PMID- 21534367 TI - Acoustic rhinometry evaluation in allergic rhinitis patients before and after turbinate radiofrequency ablation. AB - OBJECTIVE: To evaluate the outcome of turbinate radiofrequency ablation (RFA) by acoustic rhinometry. MATEIAL AND METHOD: Thirty allergic rhinitis (AR) patients aged 19-62 years old were recruited for this cross sectional prospective study. They all underwent radiofrequency turbinate ablation for chronic nasal obstruction. The acoustic rhinometry evaluation, total nasal symptom score, and nasal obstruction score before and after surgery were analyzed at second, fourth, and eighth week. RESULTS: The mean age of the 30 AR patients was 39.5 years old and two patients required a second operation. After surgery, the total nasal symptom score (TSS) and the difference mean of cross-section area (CSA) I were improved in 2-4 weeks and 4-8 weeks respectively but total nasal volume was not changed. CONCLUSION: The authors can use acoustic rhinometry to evaluate short term result of turbinate radiofrequency ablation. The subjective symptoms were prominently seen in 2-4 weeks after surgery and before the objective result by acoustic rhinometry shown at 4-8 weeks. PMID- 21534369 TI - Comparison of low dose and standard dose MDCT in detection of metastatic pulmonary nodules. AB - OBJECTIVE: Compare low dose (50 mA) and standard dose (300 mA) MDCT in detection of metastatic pulmonary nodules in extrathoracic malignant patients in Siriraj hospital. MATERIAL AND METHOD: Prospectively, 58 patients underwent chest CT examinations by 64-slice MDCT in non-enhanced phase with a reduced tube current of 50 mA (low-dose CT (LDCT)), followed by contrast-enhanced phase with a standard tube current of 300 mA (Standard-dose CT (SDCT)). Otherparameter such as tube voltage 120 kVp, spiral pitch 0.984, and section thickness 1.25 mm, were kept constant. Four hundred twenty two nodules found by SDCT and 427 nodules found by LDCT were analyzed. RESULTS: The sensitivity of LDCT was 94.7% for all nodules, 79% for nodules < or =2 mm, 94.2% for nodules 2.1-3 mm, 97% for nodules 3.1-4 mm, and 100% for nodules 4.1-5 mm. Three types of nodules were found and classified as calcific nodule, non-calcific nodule, and ground-glass nodule of which sensitivity for detection in LDCT were 100% (p = 1.000), 95.9% (p = 0.337) and 77% (p = 0.581), respectively. Most common causes of discrepancy in SDCT were unseen nodules and in LDCT were end-on vessel nodules. Majority of discrepant nodules and retrospective nodules were < or =3 mm. Effective dose ranged from 0.78 mSv.-1.6 mSv in LDCT and 4.22-9.57 mSv in SDCT. CONCLUSION: There is no statistical difference in detection of metastatic pulmonary nodules by using low dose and standard-dose CT images. Low-dose CT images can used to follow-up the treatment responsiveness of the known patient, diagnosed to have pulmonary metastasis. PMID- 21534368 TI - Anatomical consideration of pterion and its related references in Thai dry skulls for pterional surgical approach. AB - OBJECTIVE: Pterion is a crucial surgical landmark for surgical approaches to the middle meningeal artery particular lesions, and tumors in the brain. The present study aimed to analyze the types of the pterion and its location related with nearby landmarks in dry skulls. In addition, variations of pterion in sex, age, and skull side were compared. MATERIAL AND METHOD: Bilateral sides of 268 adult human Thai dry skulls were investigated Pterion types were classified as sphenoparietal, frontotemporal, epipteric, or stellate. To localize the pterion, linear distances were measured from the center of the pterion to neighboring landmarks. RESULTS: The results showed the two most common types of the pterion, the sphenoparietal (81.2%), and the epiteric (17.4%). Externally, the pterion was commonly located 38.48 +/- 4.38 mm superior to the zygomatic arch and 31.12 +/- 4.89 mm posterior to the frontozygomatic suture. Internally, it was located 38.94 +/- 3.76 mm lateral to the optic canal and 11.70 +/- 4.83 mm from the sphenoid ridge. Sex influenced the occurrence of thepterion type, while sex, skull side, and age affected its location. Mean skull thickness at the pterion was 5.13 +/- 1.67 mm. CONCLUSION: The pterion is predominantly sphenoparietal type and is typically located 39 mm superior to the zygomatic arch, 31 mm posterior to the frontozygomatic suture, 39 mm lateral to the optic canal and 12 mm from the sphenoid ridge. The data obtainedfrom the present study should be clinically useful for localizing the position of pterion. PMID- 21534370 TI - Mucin production in prostatic adenocarcinoma: a retrospective study of 190 radical prostatectomy and/ or core biopsy specimens in department of pathology, Siriraj Hospital, Mahidol University, Thailand. AB - BACKGROUND: Diagnoses of prostatic adenocarcinoma are made based on a constellation of architectural, cytological, and ancillary findings, which include intraluminal mucin secretion. Several studies have shown that luminal acid mucin is frequently present in prostatic adenocarcinoma. Immunohistochemical stain (immunostaining) becomes extremely helpful in the diagnosis of prostatic adenocarcinoma, especially in doubtful cases. However, presently, the technique is not available in most hospitals, particularly in the regional or provincial areas. Thus, luminal acid mucin and its detection by histochemical stains may be one ofthe useful tools in diagnosing prostatic adenocarcinoma. OBJECTIVE: To determine the percentage of mucin production in prostatic adenocarcinoma from 190 radical prostatectomy and/or core biopsy specimens in the Department of Pathology, Siriraj Hospital, Mahidol University to compare the percentage of positivity among three different special histochemical stains (mucicarmine, Alcian blue at pH 2.5, and colloidal iron), and to determine the PSA-expression among the prostatic adenocarcinoma that produces mucin by immunohistochemical technique. MATERIAL AND METHOD: The present study is a retrospective study of190 cases that were diagnosed as prostatic adenocarcinoma (with any Gleason's microscopic pattern) from radical prostatectomy and/or core biopsy specimens in Department of Pathology, Siriraj Hospital, Mahidol University between January 2006 and May 2007. All cases were retrieved from a computer filing system of the Department. All H&E slides that contained diagnostic materials were reviewed and stained with all three different special histochemical stains. Positive cases were subsequently studied to find PSA expression by means of immunohistochemical study. Cases with microscopic variants ofprostatic adenocarcinoma and metastasis were excluded. RESULTS: One hundred and seventy seven cases (93%) of these prostatic adenocarcinomas were positive for at least one of three diferent special histochemical stains for acid mucin. Among these, 167 cases (88%) were positive for mucicarmine, 157 (83%) cases were positive for Alcian blue at pH2.5, and 173 cases (91%) were positive for colloidal iron. All 177 cases were positive for PSA immunohistochemical stain. CONCLUSION: Intraluminal acid mucin and its detection by special histochemical stains is one of the useful methods (with a high percentage of positivity) in diagnosing prostatic adenocarcinoma in association with other architectural and cytological criteria. Mucicarmine and colloidal iron stains appear to be more useful than Alcian blue at pH 2.5 stain according to their positivity percentage. However in pathologic practice, mucicarmine stain is more commonly used than colloid iron stain due to the difficulty in preparation and interpretation of the latter There is no correlation between mucin production and PSA expression in prostatic adenocarcinoma but PSA immunohistochemical stain is still useful to confirm the prostatic origin of poorly differentiated carcinomas or metastatic lesions. PMID- 21534371 TI - Attention deficit hyperactivity symptoms in children with autistic disorder: a cross-sectional descriptive study. AB - OBJECTIVE: (1) to examine the co-occurrence of attention deficit and hyperactivity symptoms in children with autistic disorder, and (2) to study the correlation between attention deficit hyperactivity symptoms and the severity of autistic disorder. MATERIAL AND METHOD: This was a clinical based study. The authors used Childhood Autistic Rating scale (CARs) to evaluate the severity of autistic disorder Swanson, Nolan, and Pelham Teacher and Parent Rating Scale, Version IV (SNAP-IV) was used to measure attention deficit and hyperactive symptoms in children with autism. RESULTS: Thirty (n=30) children enrolled in this study. All participants displayed attention deficit symptoms and 18 participants demonstrated hyperactivity as well. Nonparametric correlation showed a high positive correlation (Spa = 0.90, p = 0.00) between the severity of autistic disorder and hyperactivity and not the attention deficit symptoms (Spa = 0.29, p = 0.16). CONCLUSION: The authors finding shows a high comorbid rate of attention deficit and hyperactive symptoms among the participants. PMID- 21534372 TI - Family leader empowerment program using participatory learning process for dengue vector control. AB - OBJECTIVE: Assess the performance of the empowerment program using participatory learning process for the control of Dengue vector The program focuses on using the leaders of families as the main executer of the vector control protocol. MATERIAL AND METHOD: This quasi-experimental research utilized the two-group pretest-posttest design. The sample group consisted of 120 family leaders from two communities in Mueang Municipality, Chachoengsao Province. The research was conducted during an 8-week period between April and June 2010. The data were collected and analyzed based on frequency, percentage, mean, paired t-test, and independent t-test. The result was evaluated by comparing the difference between the mean prevalence index of mosquito larvae before and after the process implementation in terms of the container index (CI) and the house index (HI). RESULTS: After spending eight weeks in the empowerment program, the family leader's behavior in the aspect of Dengue vector control has improved. The Container Index and the House Index were found to decrease with p = 0.05 statistical significance. CONCLUSION: The reduction of CI and HI suggested that the program worked well in the selected communities. The success of the Dengue vector control program depended on cooperation and participation of many groups, especially the families in the community When the family leaders have good attitude and are capable of carrying out the vector control protocol, the risk factor leading to the incidence of Dengue rims infection can be reduced. PMID- 21534373 TI - Meanings and indicators of well-being in health in the perspective of the farmers in the northeast of Thailand. AB - BACKGROUND: Well-being is a complex notion with many different dimensions whose definition is disputed. Therefore, the present study considers the meanings and indicators of well-being in health in the perspective of the farmers of the Northeast of Thailand. The conceptual framework of research is based on well being concepts developed by the Research Group on Wellbeing in Developing Countries (WeD) and further developed by the Research Group on Well-being and Development at Khon Kaen University. The concept is comprised of three main dimensions. The first is what people have or do not have (material and human resources, social relationship). The second is what people do and do not do or cannot do with these resources, and why (social or cultural action). The third is how people judge, assess, and feel about these things, how they make and cannot make sense of what happens (meaning). MATERIAL AND METHOD: The present study is qualitative research. The population of the present research was the farmers in the target area where the data were collected by purposive sampling in Chaiyaphum Province. The main research methodology employed was focus group discussion with district member in one district from each of the three groups of district in Chaiyaphum province. The secondary research method employed was a workshop often qualified representatives of the personnel from both the government and private sectors who were involvedwith the farmers in the province were selected by purposive sampling. Then, the data were analyzed by means of content analysis. The method for reviewing of data was the triangular technique. RESULTS: The results of the present study found that the meanings of "well-being in health in the perspective of the farmers in the Northeast" reflect every perspective: materials and non-materials (objective and subjective well-being). The indicators of well-being in health in the perspective of the farmers of the Northeast of Thailand had eight aspects and forty-five indicators that included both subjective well-being and objective well-being. CONCLUSION: The present study concludes that well-being indicators that developed from the viewpoints of farmers could be employed to enhance well-being of farmers in the development process. PMID- 21534374 TI - Health related quality of life among the Thai people with unilateral lower limb amputation. AB - OBJECTIVE: To study the health related quality of life (HRQOL) among Thai unilateral lower limb amputees and determine the factors associated with a good HRQOL. MATERIAL AND METHOD: A postal survey with the WHOQOL-BREF-Thai questionnaire (26 items) to 1300 people with LLA who received a lower limb prostheses from Siriraj Hospital, Prapokklao Hospital, and Ratchaburi Hospital between 2001 and 2005 was conducted. Descriptive statistics were used to report the level of HRQOL. Chi-Square, independent Sample t-test and multivariate analysis by stepwise logistic regression were used to determine the factors associated with a good QOL. RESULTS: Three hundred and nine questionnaires were completed from the 321 returned questionnaires (response rate 24.7%). Among these, 278 people were with unilateral LLA. They were 221 males and 57 females with mean age 46.9 +/- 13.9 years old. The number of people with LLA who had poor, fair and good QOL were 14 (5%), 241 (86.7%), and 23 (8.3%), respectively. Demographically, the people with LLA who had long duration of amputation (p = 0.001), higher education (p = 0.005), and had been employed after amputation (p < 0.001) had significantly better HRQOL. The amputees who had good wearing comfort (p = 0.04) after wearing the prostheses, had no phantom pain (p = 0.02), used no gait aids (p = 0.01), and had no body image anxiety (p = 0.01) had significantly better HRQOL. The factors associated with the good HRQOL were higher education (OR 3.2), having been employed after amputation (OR 2.1), and having good prosthetic wearing comfort (OR 1.3). CONCLUSION: Thai people with unilateral LLA reported primarily fair HRQOL. Having higher education, having been employed after amputation, and having good prosthetic wearing comfort were associated with the good HRQL. PMID- 21534375 TI - Statin-associated myasthenic weakness. AB - BACKGROUND: Statin-associated myasthenic weakness is uncommonly recognized. Since 2002, there have been 14 cases described in literatures. However, the underlying mechanism is still unknown. CASE REPORT: In 2007, a 50-year-old woman with generalized, limb predominated, myasthenia gravis (MG), whose MG status has been "minimal manifestation" for several years, developed moderately severe fluctuating bulbar weakness a few weeks after starting simvastatin 20 mg/day. Simvastatin was discontinued and dosage of cholinesterase inhibitor was temporarily increased. The symptoms resolved and she was back to her previous status in one month. In 2008, two weeks after re-challenge with simvastatin 10 mg/day, bulbar weakness re-occurred Antibody to acetylcholine receptors was measured 4.25 nmole/L. Serum creatine phosphokinase was normal. Electrophysiologic tests showed evidences of postsynaptic neuromuscular junction disorder without evidence of myopathy. The symptoms were again resolved after discontinuation of statin and temporarily increased dosage of cholinesterase inhibitor. She was back to previous status in two months. Hypercholesterolemia was then controlled with ezetimibe without any worsening in MG status. CONCLUSION: Because of the wide use of statins in clinical practice, physicians should be aware of this potential adverse effect. The incidence ofstatin associated myasthenic weakness should be clearly investigated Challenge with other brands of statin or with reduced dosage is not beneficial in these patients. Non-pharmacological treatment and non-statin medication may be considered PMID- 21534376 TI - There's no place like the patient-centered medical home. PMID- 21534377 TI - Differences between the varicella vaccines; using dabigatran. PMID- 21534378 TI - What caused this spotted, itchy rash on the shins? Seborrheic keratosis. PMID- 21534379 TI - A day in the life. Robert G. Baeten II, MCMS, PA-C. PMID- 21534380 TI - How the medication review can help to reduce risk of falls in older patients. PMID- 21534381 TI - Evaluation and surgical management of melanoma of the head and neck. PMID- 21534382 TI - A rare but serious cause of spinal cord compression in an adolescent female. PMID- 21534383 TI - The female athlete triad: patients do best with a team approach to care. PMID- 21534385 TI - PAs in specialty care: the current trends. PMID- 21534384 TI - Healthy people 2010 and the PCMH. PMID- 21534386 TI - CDC proposes new guidelines for the treatment of STDs. PMID- 21534387 TI - HIV exceptionalism and ethical concerns surrounding HIV testing. PMID- 21534388 TI - Sudden cramps and vaginal bleeding during pregnancy. Molar pregnancy. PMID- 21534389 TI - The art of medicine: having faith in the seeds we plant. PMID- 21534390 TI - Case of the month. Neurocysticercosis. PMID- 21534391 TI - Accountable care and the future of your associations--part 2. PMID- 21534392 TI - Well, well, well: Medicare's new focus on preventive health. PMID- 21534393 TI - Health IT update: the latest on meaningful use, e-prescribing and HIPAA 5010. PMID- 21534394 TI - Unequal pay for unequal work. PMID- 21534395 TI - Will the real PCMH step forward? PMID- 21534396 TI - Should docs own office buildings? PMID- 21534397 TI - Who cares about quality reporting? PMID- 21534398 TI - Independents outpace larger systems with EHR use. PMID- 21534399 TI - Focus on how chronic care models boost quality measures. PMID- 21534400 TI - Quality measures defined: dig beyond financial benchmarks. AB - Financial benchmarking tells only one part of the story. For a complete picture, consider nine quality measures that dig deeper than a balacnce sheet. PMID- 21534401 TI - Stamps provide glimpse of history. PMID- 21534402 TI - The go-to nurses. Finding ways to keep long-time RNs. PMID- 21534403 TI - Nurses' trusted voice--our patients are counting on us to make a difference. PMID- 21534404 TI - Developments in primary care affect APRNs. PMID- 21534405 TI - Providing a path to safe staffing in Illinois. PMID- 21534406 TI - In the service of the board. PMID- 21534407 TI - Employee wellness proves its worth. AB - A growing number of hospitals are using employee wellness programs to control health care costs, and the savviest among them are using data analysis to track their successes. PMID- 21534408 TI - Experts in short supply. AB - As hospitals gear up to achieve meaningful use of electronic health records, the needed IT experts are few and far between. Recruiting and retaining them must become a top priority. PMID- 21534409 TI - Feds refocus on fraud. AB - Provisions in the reform law and a strengthened False Claims Act give the government new tools to fight fraud. Hospitals need to beef up their compliance programs. PMID- 21534410 TI - Obligation and opportunity. PMID- 21534411 TI - The power of education. PMID- 21534412 TI - IT spending. PMID- 21534413 TI - SCIP measures to weigh in Medicare pay starting in 2013. PMID- 21534414 TI - Core measures, accreditation to be linked. PMID- 21534415 TI - Practical prevention: orthopedic SSIs. PMID- 21534416 TI - Verification, validation: what's the difference? PMID- 21534418 TI - Is it time for a surgery center EMR? PMID- 21534417 TI - Is there a standard surgical supply markup? PMID- 21534419 TI - Nurses have much to offer in care of those with diabetes. PMID- 21534420 TI - Celebrating the human capacity to care. PMID- 21534421 TI - Support from NZNO appreciated. PMID- 21534422 TI - Courage, compassion and cohesion at the coal face. PMID- 21534423 TI - Earthquake 2011. PMID- 21534424 TI - Nurses in the community pull together to help the injured. PMID- 21534425 TI - The glucose [corrected] disease--understanding type 2 diabetes mellitus. PMID- 21534426 TI - Nurse education the key to managing diabetes more effectively. PMID- 21534427 TI - Improving the post-natal management of women with diabetes in pregnancy. PMID- 21534428 TI - Nurses positive despite perceived poor pay and restructuring. PMID- 21534429 TI - Supporting EN students. PMID- 21534430 TI - Reaching an education consensus. PMID- 21534431 TI - Reducing rates of child abuse. PMID- 21534432 TI - Constitutional change for NZNO. PMID- 21534433 TI - Changing work patterns. PMID- 21534434 TI - Options, choices and decisions. PMID- 21534435 TI - Making waves. PMID- 21534436 TI - Earthquake has major impact on aged-care residents, staff and facilities. PMID- 21534437 TI - Students at work. PMID- 21534438 TI - How to make a small difference in your chosen profession. PMID- 21534439 TI - Fostering the three Cs of nursing. PMID- 21534440 TI - Predicting NCLEX-PN success with the HESI Exit Exam. AB - Surveys were mailed to directors of 72 randomly selected practical nursing (PN) schools that administered Elsevier's HESI Exit Exam for Practical Nurses (E2-PN) during the 2006-2007 academic year. Data were collected regarding students' NCLEX PN outcomes and the schools' benchmarking and remediation policies. The first version of the E2-PN was 99.48% accurate in predicting NCLEX-PN success. Versions two and three of the E2-PN, which were administered to students who were remediated because they did not achieve the faculty-designated benchmark, were also highly accurate in predicting NCLEX-PN success. Most faculties set 850 as their school's E2-PN benchmark, and 73% of the respondents required remediation for students who did not achieve the benchmark score. The most frequently cited remediation strategy was tutoring. PMID- 21534441 TI - Calcium imbalance, resulting disorders and the available prevention and treatment options. PMID- 21534442 TI - Phentolamine action in permeability of airways at patients with bronchial asthma. AB - In this work, effect of phentolamine as antagonist of alpha-1 adrenergic receptor in patients with bronchial asthma and with obstructive chronic bronchitis was studied. Parameters of the lung function are determined by body plethysmography. Raw and ITGV were registered and SRaw was calculated as well. Aerosolization is done with standard aerosolizing machines--Asthma with a possibility of aerosolization of 0.5 ml per minute. Results gained by this research shows that blockage of alpha-1 adrenergic receptor with phentolamine (10 mg by inhalator and intravenous ways and 20 mg by inhalator ways) has not changed significantly (p > 0.1) the bronchomotor tonus of tracheobronchial tree, by comparing it with the inhalation of natrium chloride solution with percentage of 0.9% (p > 0.1), or of hexoprenaline (2 inh x 0.2 mg) and atropine 1 mg/ml (p < 0.01). This suggests that the activity of alpha-1 adrenergic receptor in the smooth musculature is not a primary mechanism that causes reaction in patients with increased bronchial reactibility, in comparison to agonists of beta2--adrenergic receptor and cholinergic antagonists that expresses their significant action in reduction of specific resistance of airways. PMID- 21534443 TI - Morphometric angiogenesis parameters for indolent and aggressive non-Hodgkin's lymphoma. AB - There is much evidence about importance of angiogenesis in development and progression of solid tumors. The role of angiogenesis, as an indicator of higher malignant potential in non-Hodgkin's lymphoma, is not clear at the moment. Morphometric characteristics of microvessels in lymph node sections, in previously untreated patients with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and diffuse large B-cell lymphoma (DLBCL), were studied and relationship between angiogenesis and histological malignancy grade of NHL was also evaluated. Lymph node biopsies samples of 30 newly diagnosed patients with SLL/CLL (n=30) and DLBCL (n=30) were studied. All samples were fixed in 10% buffered formalin solution and embedded in paraffin. Microvessels were visualized by immunohistochemical staining for anti F-8 antibody. In the area showing the most intense vascularization (i.e. the "hot spot"), microvessel density (MVD), total vascular area (TVA), as well as the size related parameters were estimated, by using image analysis program "analysSIS'. Number and size-related microvessels angiogenic morphometric parameters were statistically higher in group with DLBCL compared with SLL/CLL: MVD (p = 0.002), TVA (p < 0.0001), area (p < 0.0001), perimeter (p < 0.0001), minor axis length (p < 0.0001) and major axis length (p < 0.0001). It is to be noted that positive correlation existed between TVA and MVD in DLBCL and SLL/CLL. The present study supports the view that angiogenesis correlate with histological grade of NHL. PMID- 21534444 TI - Clinical and epidemiological characteristics of novel AHIN1 flu. AB - INTRODUCTION: Swine influenza is respiratory infection caused by virus influenza A H1N1. OBJECTIVE: To show epidemiological and clinical characteristic of patients with confirmed influenza A H1N1 hospitalized at Clinic for Infectious Diseases of University Clinical Center Sarajevo. MATERIAL AND METHODS: We analyzed 127 medical records of patients with microbiologically confirmed pandemic influenza A/H1N1 (nasopharyngeal swab analyzed by PCR method). RESULTS: In our investigation female patients prevail (57%), age from 25 to 45 years old with medium difficult clinical picture (71.55%). Chi-square test showed significant dependence between sex and clinical status of patient (p < 0.05), dyspnea and clinical status of patient (p < 0.05), while statistical significance was nor proved related to comorbidity (p > 0.05), cough (p > 0.05), radiological confirmed pneumonia (p > 0.05), number of prehospital days of diseases (p > 0.05) and length of hospital care (p > 0.05). Significant impact on clinical status of patients is found related to age (p < 0.05), in a way that every year of age increase risk in 2.9% for more severe disease. CONCLUSION: Clinical and epidemiological parameters can impute severity of clinical status and therefore the outcome of disease. PMID- 21534445 TI - Surgical treatement of pulmonary hydatid disease in children--a retrospective study. AB - Hydatide disease is endemic in sheep and cattle-raising areas world wide. Its prevalence is also high in the Mediterranean region including Bosnia and Herzegovina. Retrospective appraisal of the pressentation, approach to surgical treatment and outcome of hydatid disease in children at the Clinic for Pediatric Surgery and Clinic for Thoracic Surgery University of Sarajevo Clinics Centre in period between 2000-2008. We surgically treated 72 patients (57 male, 15 female) with a diagnosis of pulmonary hydatid disease with average age of 10.36 +/- 4.28 (range 4 to 18) years. Chest radiographs, computer tomograms and ultrasonography were the main methods of diagnosis. The basic principle of surgery was to preserve lung parenchyme as much as possible. Clinical assessment of the symptoms, plain and lateral chest X-rays and computed tomograms led to the correct diagnosis in 100% (72/72) of patients. Solitary lung cysts were found in 79.17% (57/72) patients. While the remaining were multiple cysts in one or more lobes of one or both lungs. Intact cysts were found in 48 (52.17%) and rupture cysts in 44 (47.83%) cases. Lung preserving surgical intervention were done in all of the patients. There was no mortality. Recurrent hydatid cysts were observed in 2.78% (2/72) patients. Lung preserving surgical interventions are the treatment of choice for pulmonary hydatid cysts in children. Radical surgical procedures such as segmentectomy, lobectomy and pneumonectomy should be avoided as much as possible in children. PMID- 21534446 TI - The influence of the type of ulcers in the degree of atrophic gastritis. AB - PURPOSE: Chronic Gastritis is the most common manifestation of infection with Helicobacter pylori. Changes in the gastric mucosa have tendency to progress towards mucosal atrophy, most likely in patients with gastric ulcer. We have explored the frequency of the presence of atrophic gastritis in patients with gastric and duodenal ulcers. MATERIAL AND METHOD: We included 175 patients in a prospective study, 119 of whom were patients with duodenal ulcer and 56 suffered from gastric ulcer. The mean age of the patients with duodenal ulcer was 42.27 years, while patients with gastric ulcer had a mean age of 51.87 years. Biopsy was done on all patients with gastric and duodenal ulcer for histopathological examination, in order to confirm the presence of atrophic gastritis. All examined patients were positive for H. Pylori status. RESULTS: The presence of gastritis by type of ulcer, duodenal or gastric, was as follows: type without atrophy 20% and 0%, mild atrophy 61% and 14% and severe atrophy 22% and 86%, respectively. CONCLUSIONS: In patients with duodenal ulcers more often occurs mild atrophic gastritis (p < 0001). In the patients with gastric ulcers most often occur alterations with more pronounced gastric atrophy (p < 0.01). PMID- 21534447 TI - Impact of clinical symptoms on CT ordering policy in minor head injuries. AB - INTRODUCTION: The aim of our study was to determine the impact of clinical signs and symptoms on CT ordering policy in minor head injuries. PATIENTS AND METHODS: The study encompassed 1830 patients that have sustained minor or mild head injury, as assessed by clinical criteria. Basic clinical variables were recorded and a subset of patients meeting either Canadian or New Orleans criteria were subjected to CT. Outcome in terms of "positive" CT scans and number of patients requiring surgery was recorded. RESULTS: The mean age was 30.4 years (ranging from 10 days to 80 years). 176 patients were subjected to CT scan (based on clinical criteria). CT scan revealed intracranial pathology in 29 patients (16.5% of patients subjected to CT scan) and 19 patients were subsequently subjected to surgery (accounting for 10.8% of patients subjected to CT scan and 1.0% of all patients with mild or minor head injuries). Brain contusions were detected in 10 (5.7%) patients, followed by epidural hematomas (10 patients or 5.7% were found to harbor an epidural hematoma) and subdural hematomas, that were found in 7 patients or 4.0% of patients subjected to CT scan. DISCUSSION: Despite numerous studies that have analyzed the importance of clinical signs and CT in the diagnosis and treatment of minor head injuries, there is still much controversy about the mode of treatment of these patients. Canadian protocol really reduces the need for CT of the brain in relation to the New Orleans protocol, which suggests more observation in hospital patients with minor or mild head injury. CONCLUSION: The authors conclude that minor or mild head injuries should prompt a CT as recommended by Canadian or New Orleans guidelines and that the strongest scientific evidence available at this time would suggest that a CT strategy is a safe way to triage patients for admission. PMID- 21534448 TI - Limitations of CHADS2 scoring system in predicting stroke risk--need to change the age criteria. AB - INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia with a strong association with age. The aim of this study was to evaluate the rate of stroke in relation to age and anticoagulation status based on CHADS2 risk criteria. METHODS: This study included all patients with non-valvular atrial fibrillation admitted to our clinic between 1/11/2007 and 1/11/2009, with minimum one year follow up for patients without stroke. We calculated risk based on CHADS2 (C-cardiac failure, H- hypertension, A-age >75 years, D-diabetes mellitus, S-stroke) point system and evaluated anticoagulation status at the moment of first occurrence of stroke. We observed the rate of stroke in different group age. RESULTS: The average of participants with AF was 67.9 +/- 10.3 years. Amongst 302 patients with non-valvular atrial fibrillation, 32.5% had been anticoagulated while 13.9% of experienced stroke. The stroke were more present in patients who used aspirin in age group 65-74 (22.5%, P = 0.014). The mean age of patients who experienced stroke were 67.2, SD +/- 10.8 vs. 71.6, SD +/- 5.1, P = 0.000. Of the patients with stroke from age group 65-74 years, 23 were in CHADS2 0-1 scoring system. CONCLUSION: The higher rate of stroke was in the 65-74 years age group, with CHADS2 scoring system 0-1, and without anticoagulation therapy. Therefore modification has to be considered for the CHADS2 scoring system to account the age as a risk factor for population in different regions. PMID- 21534449 TI - Left ventricular hypertrophy in chronic kidney disease. Is pulse pressure an independent risk factor? AB - BACKGROUND: The study's aim was to evaluate the relations between pulse pressure (PP), hypertension and anemia with left ventricular hypertrophy (LVH). MATERIALS AND METHODS: The risk factors and prevalence of LHV were evaluated in 111 patients with CRF. RESULTS: LVH was diagnosed in 81.9% of all patients. The prevalence of hypertension was 72.6%. Anemia was present in all patients. Of the variables tested lower levels of hemoglobin, systolic blood pressure (SBP) and PP predicted the occurrence of LVH. CONCLUSIONS: This study has shown a strong association between chronic kidney disease (CKD) and LVH in pre dialysis patients. Pulse pressure, SBP and anemia play an important role in the development of left ventricular hypertrophy in CKD patients. PMID- 21534450 TI - Anterior flaps anastomosis in external dacryocystorhinostomy. AB - PURPOSE: To evaluate the outcome of the modified technique of external dacrycystorhinostomy with anterior flaps anastomosis only. METHODS: This prospective study included 52 patients with lacrimal drainage system disorders who underwent the modified technique of external dacrycystorhinostomy with anterior flaps anastomosis only. In this modified procedure of external dacryocystorhinostomy, anastomosis of anterior flaps only was created by suturing anterior flaps of the lacrimal sac and nasal mucosa, whereas posterior flaps were excised. The success rate and potential complications were recorded during the follow-up period. RESULTS: The mean age of the patients was 44.6 +/- 9.9 SD years, including 37 females and 15 males. Mean of follow up was 17.1 +/- 1.8 SD months. Intraoperative complications, hemorrhage occurred in 3 cases (5.8%) and laceration of the nasal mucosa in 2 cases (3.8%). The surgery was uneventful in 47 cases (90.4%). The postoperative complication was closure of the anastomosis that occurred in 2 cases (3.8%). The success rate was evaluated by lacrimal patency to irrigation and relief of epiphora. Fifty patients (96.2%) showed a patent lacrimal system to irrigation and relief of epiphora, 2 patients (3.8%) had recurrence of epiphora and not patent lacrimal system to irrigation. CONCLUSION: This modified technique of external dacryocystorhinostomy with anterior flaps anastomosis only simplifies the surgical procedure and is effective in the management of obstruction of lacrimal drainage system beyond the common canalicular opening. Although it is simpler, quicker and easier to master the surgical technique, external dacryocystorhinostomy with anterior flaps anastomosis only shows a success rate comparable with those found in traditional external dacryocystorhinostomy. Further studies with larger series of cases are necessary. PMID- 21534451 TI - Percutaneous treatment of symptomatic non-parasitic benign liver cysts with 20% NaCl solution. AB - GOAL: The aim of the study is to evaluate efficacy of single-session 20% NaCl solution sclerotherapy in the treatment of symptomatic nonparasitic benign liver cysts. METHODS: 20 patients were chosen (7 man and 13 woman, mean age 52.9 with mean duration of disease before treatment 9.4 months) for a prospective trial. Patients were treated with ultrasound-guided percutaneous aspiration and injection of 20% NaCl solution. Patient demographics, clinical characteristics, treatment outcome and complications were analyzed during the trial. The procedure was considered successful if the cyst disappears. The cyst was considered to have disappeared if it could no longer be visualized on ultrasonography. Other important measures to document the efficacy of treatment included the length of the hospital stay and complications related to the procedure. RESULTS: The average volume reduction was 96.3% (range, 74.9-100%). During the 24-month follow up period, 8 cysts (40.0%) disappeared completely. The hospital stay was one day for all patients. CONCLUSION: Percutaneous treatment and sclerotherapy with hypertonic NaCl (20%) is safe and effective for hepatic non-parasitic cysts. PMID- 21534452 TI - Ten-year epidemiological study on suicide attempts in Skopje, Republic of Macedonia. AB - The aim of our study was to provide basic epidemiological data on suicide attempts that resulted in admission to the University Clinic of Toxicology and Emergency Medicine in Skopje during a 10-year-period (1999-2008). There is a lack of published information regarding suicide attempts in the Republic of Macedonia. METHODS: Participants were 1683 patients from the territory of Skopje, who attempted suicides and who were hospitalized in the University Clinic of Toxicology and Emergency Medicine in School of Medicine, Skopje during the period of ten years (1999-2008). The following variables were included in the analysis: age, gender, religion, method of suicide attempt and admission date. The results were analyzed with the Statistic for Windows program, release 7.0. RESULTS: A significantly higher number of suicide attempts were registered in females than in males from the territory of Skopje during the period of 1999-2008. Men who attempted suicide were older than women. Women of Christian religion affiliation attempted suicide more frequently than women of Muslim religion. The greatest number of attempts was during the summer season. The most common method of suicide attempt was intoxication with medications. CONCLUSIONS: Our study has shown that attempted suicide rate has had a stable trend over the last decade. It has also shown female predominance of suicide attempts with a greater number of attempts during the summer months. There is a need for intervening strategies to be targeted at younger females. PMID- 21534453 TI - Quality of reporting on infectious diseases in Zenica-Doboj Canton. AB - GOAL: Reporting on infectious diseases is one of the most important measures for controlling the infectious diseases. In Bosnia and Herzegovina is in the implementation an archaic system of reporting, older than 20 years, which is incorporated into the partially reformed health system. The aim of this study is to determine and analyze the quality of keeping records of communicable diseases and quality of data obtained. It also sought to identify weaknesses in the system that contributes to poor reporting and poor data quality. METHODS: The study was retrospective-prospective, descriptive and analytical. Data were collected during June 2010 from all health facilities of Zenica-Doboj Canton. The data are collected from regular reports from medical institutions, received reports on contagious diseases, examination of 12.5% of the medical records of patients who were examined in June 2010, and the survey on 19% 9% physicians and 9% nurses. RESULTS: The survey showed that about 40% of infectious diseases do are not reported by individual application forms. Most often not reported are fungal infections (99.7% unreported) and intestinal infectious diseases. From found diseases in a sample of medical records reviewed, only 1.4% of them were reported. Health professionals in 51% agree that reporting is not satisfactory, and in 49% of the cases agree that the great merit of this situation have the management of health institutions and local epidemiologists who do not organize professional meetings regarding the reporting on infectious diseases. A large number of health professionals (40%) do not fill properly report on the illness, so we have a 58% incorrectly filled forms that arrived in the Institute of Public Health. CONCLUSIONS: The health workers from Zenica-Doboj Canton did not sufficiently developed awareness about the need to report infectious diseases. In order to overcome this situation, management of health care institutions must have a responsible attitude towards the medical documentation and records, and binding continued medical education of health professionals to raise awareness about the importance of proper medical documentation management. PMID- 21534454 TI - Development of emergency medicine as academic and distinct clinical discipline in Bosnia & Herzegovina. AB - INTRODUCTION: Emergency medicine is a new academic discipline, as well as a recent independent clinical specialization with the specific principles of practice, education and research. It is also a very important segment of the overall health care and health system. Emergency medicine as a distinct specialty was introduced in the U.S. in 1970. Ten years later and relatively quickly emergency medicine was introduced in the health system in Bosnia and Herzegovina as a specialty with a special education program for specialist and a final exam. GOAL: Compare the development of emergency medicine in Bosnia and Herzegovina with the trends of development of this discipline in the world as a specialization and an academic discipline. Identify specific problems and possible solutions and learn lessons from other countries. METHODS: Reviewed are the literature data on the development of emergency medicine in the world, programs of undergraduate and postgraduate teaching, the organizational scheme of emergency centers and residency. This is then compared with data of the current status of emergency medicine as an academic discipline and a recognized specialization, in Bosnia and Herzegovina. RESULTS: There are substantial differences in the development of emergency medicine in the United States, European Union and Bosnia and Herzegovina. Although Bosnia and Herzegovina relatively early recognized specialty of emergency medicine in academia, it failed to mach the academic progress with the practical implementation. A&E departments in the Community Health Centers failed to meet the desired objectives even though they were led by specialists in emergency medicine. The main reason being the lack of space and equipment as well as staff needed to meet set standards of good clinical practice, education and research. Furthermore the Curriculum of undergraduate education and specialization does not match modern concept of educational programs that meet the principles set out in emergency medicine and learning through practice. CONCLUSION: The Development of emergency medicine as a separate specialization and independent academic discipline has had different way and pace of development, and there is no ideal model that can be applied in all countries. However experiences from countries with well developed emergency medicine, suggest that the model of the simultaneous development of emergency medicine as a distinct academic discipline on independent recognized residencies with a strong national association is the best way for the formation of an efficient health system. The establishment of Emergency centers- departments for emergency medicine at university and cantonal hospitals, introduction of emergency medicine as an academic discipline, implementation of specific post-graduate teaching and continuing medical education through appropriate courses, as well as academic development program for the teaching staff is the most important element of future development of this discipline. It would also contribute to it achieving the appropriate status in both the academic institutions and in practice within the health system of Bosnia and Herzegovina. PMID- 21534455 TI - Proton pump inhibitors in the management of gastroesophageal reflux disease. AB - The primary treatment goals in patients with gastroesophageal reflux disease (GERD) are relief of symptoms, prevention of symptom relapse, healing of erosive esophagitis and prevention of complications. The severity of GERD is directly correlated with the degree and duration of oesophageal acid exposure and is highly pH dependent. Healing of reflux esophagitis is directly correlated with the intragastric pH > 3.5. In patients with GERD, treatment is directed at acid suppression through the use of lifestyle modifications (e.g., elevating the head of the bed, modifying the size and composition of meals) and pharmacologic agents (a histamine H2-receptor antagonist [H2RA] or a proton pump inhibitor [PPI]). The relief of symptoms and the long-term control of the disease are the primary aims of therapy for the majority of patients. The efficacy of antisecretory drugs in healing GERD depends on the strength and duration of acid suppression within a 24 h period, and the duration of the treatment. PPIs are more effective for acid related symptoms and higher endoscopic healing rates in comparison with H2-RAs. Most PPIs (except pantoprazole) inhibit the bioactivation of clopidogrel to its active metabolite as they are associated with the loss of the beneficial effects of clopidogrel as well as an increased risk of reinfarction. Some clinicians reported their experiences that the generic has sometimes shown less effective than the corresponding branded PPIs. We conducted the overview of the effectiveness of PPIs in the treatment of patients with both categories of GERD; nonerosive reflux disease (NERD) and erosive reflux disease (ERD). We also report about interactions between PPIs and other drugs and differences between generic and branded PPIs. PMID- 21534456 TI - Coronary bypass grafting without use of cardiopulmonary bypass for dextrocardia. AB - Dextrocardia is a condition in which the heart is pointed toward the right side of the chest instead of normally pointing to the left. The rate of atherosclerotic heart disease in subjects with this condition is similar to that of the general population. We present a patient with situs inversus totalis with dextrocardia who underwent coronary artery bypass grafting without use of cardiopulmonary bypass (OPCAB). A 74-year-old man who was known to have dextrocardia with situs inversus was admitted to the hospital because of angina. Coronary angiography was performed and showed ostial occlusion of the left anterior descendng artery (LAD) unsuitable for percutaneous coronary interventions but collatereralised from the right coronary artery. Patient underwent OPCAB under general anestesia. Right internal mammary artery was anastomosed to LAD on the beating heart with the surgeon standing on the right side of the patient. The patient's post-operative course was uneventful, and he was discharged on the 6th postoperative day in good condition. Performing OPCAB surgery is not technically more demanding, and present no unusual challenge on patients with dextrocardia. PMID- 21534457 TI - Abnormal insertion of right ureter into the left ureter associated with absence of normal right ureterovesical junction. AB - AIM: There are lots of factors which cause the dilatation of one or both ureteres. Congenital absence of ureterovesical junction was reported as very rare cause of megaureter. Early detection of congenital absence of normal ureterovesical junction offers utilities for reconstruction and prevents the complications such as megaureter and vesicoureteral reflux. MATERIAL AND METHODS: A male patient 16 months old was referred for renal DTPA scintigraphy confirmed previously with diagnosis as megaureter of left kidney associated with consecutive stasis grades III of the left ureter. Dynamic renal scintigraphy was performed after intravenously injection of 37 MBq Tc DTPA. Scintigraphy was carried out on a Dual Head-Siemens gamma camera using a high resolution collimator. During the dynamic scintigraphy patient was positioned in supine position. RESULTS: Male patient 16 month old with vomiting, diarrhoea, fever, indolence during last two weeks were referred for dynamic renal scintigraphy. Meanwhile patient was also performed other laboratory tests such as: RBC = 4.07 x 1012, SRE= 47, Hb = 111, Bun = 5.2, Creatinine=29 and urine proteins ++. Examinations with Ultrasound, CXR and intravenously urography confirmed diagnosis of left megaureter associated with consecutive stasis Gr.III and Stasis of left kidney gr. I-II. With dynamic scintigraphy was confirmed the absence of right ureterovesical junction followed by joining of right and left ureter at the level of the lower part of the left ureter. CONCLUSION: Renal dynamic scintigraphy demonstrates abnormal insertion of right ureter into the left ureter associated with absence of normal right ureterovesical junction, right megaureter and with vesicoureteral reflux. PMID- 21534458 TI - Adenocarcinoma metastaticum of the frontal region. AB - Adenocarcinoma is a carcinoma originating from epithelium of glandular tissue. It has higher incidence in smokers and most often is a common type of lung cancer find in non-smokers women. Adenocarcinoma tumors are highly heterogeneous and there are several major subtypes: adenocarcinoma, papillary adenocarcinoma, bronchoalveolar carcinoma, solid adenocarcinoma with mucin production. Adenocarcinoma of the lung is prone to give metastases to the liver, spleen, brain and most to cervical limphonodes. We present a case of a 55-year-old woman with an unusually localized metastatic adenocarcinoma with its primary focus originating from the lungs. Formation reached size of 15 cm in diametre during three months along with destruction of frontal bone ad intracranial penetration. We couldn't find similary localised metastatic adenocarcinoma in world literature. PMID- 21534459 TI - Evaluation of three essential oils as potential sources of botanical fungicides. AB - In previous study, thirty essential oils were evaluated in vitro against two citrus pathogens namely Penicillium italicum Wehmer and Penicillium digitatum Sacc. Essential oils of Cinnamomum zeylanicum, Cinnamomum verum and Eugenia caryophyllus were selected because of their high inhibitory activities against both pathogens. The present study was undertaken to evaluate the in vivo activity of these essential oils. Fresh orange fruits were wounded and treated with different concentrations of essential oil (0.5, 1, and 5%) before being infected at the wound site with conidia suspensions of the tested pathogens. When applied at 5%, essential oils tested controlled totally the infections. Among the three essential oils tested, C. zeylanicum seems particularly interesting because of its high protection activity at 1% compare to the others. It reduced the disease incidence from 40 to 70% and the disease severity from 65 to 82%. Moreover no visible damage burn induced on the orange cuticle or skin was observed up to 5% of essential oil. These results strengthen the potential use of essential oils in postharvest disease management of citrus fruit as alternative to chemical fungicides. PMID- 21534460 TI - Glycyrrhiza glabra extract protects plants against important phytopathogenic fungi. AB - In previous investigations an ethanolic plant extract from Glycyrrhiza glabra (2.5% w/v) showed 100% efficacy against late blight (Phytophthora infestans) on detached tomato leaves. Based on these findings, the objective of this work was to investigate the effect of this extract against different important plant pathogenic fungi. Tests were carried out on potted plants. Against P. infestans, efficacies of 75% and 58% were achieved on tomato and potato plants with 5% extract concentration, respectively. Against another Oomycete, Pseudoperonospora cubensis, on cucumber, application of a 2.5% extract led to an efficacy of above 90%. The EC50-value was calculated to be 0.5% In a trial on beans against bean rust (Uromyces appendiculatus), G. glabra extract (5% concentration) showed 92% efficacy. In contrast, against powdery mildew on cucumber (Podosphaera xanthii), no disease reduction was found. Overall, the results indicate a high potential for the extract of G. glabra to control a number of important plant pathogens. PMID- 21534461 TI - Control of downy mildew (Pseudoperonospora cubensis) of greenhouse grown cucumbers with alternative biological agents. AB - In organic cucumber production infection with downy mildew (Pseudoperonospora cubensis) is a major problem. Plant extracts from Glycyrrhiza glabra L. (licorice), a plant belonging to the family Fabaceae, and Salvia officinalis (sage) as well as cultures of the bacterium Aneurinibacillus migulanus were investigated for efficacy of disease control under commercial growing conditions. Contrary to bioassays, where sage extract and the microorganism showed highest activity, in the trials of 2008 G. glabra extract was more effective than sage extract or A. migulanus against P. cubensis. Parameters such as concentrations of the preparations or application intervals could have been the reason for this. In the following year's trial (2009) the concentration of these agents was therefore increased somewhat and plants were either treated in seven day application intervals or in ten day application intervals. In the semi-commercial trials of 2009 all alternative biological agents showed good efficacies up to around 80% against infection with downy mildew. The application interval seemed to have a marginal effect only. Again, the licorice extract tended to be the best agent. PMID- 21534462 TI - Synergic interactions between 2-deoxy-D-glucose and Candida saitoana enhances citrus green mould control. AB - The activity of 2-deoxy-D-gLucose (2-DG) alone or in combination with a biocontrol yeast (Candida saitoana, strain 8C) was evaluated in vitro and in vivo against citrus green mould (Penicillium digitatum Sacc.). The in vitro assays were performed on amended potato dextrose agar (PDA) containing 0, 1.5, 3.0, 6.0, 15.0, 30.0 or 60.0 mM of 2-DG. P. digitatum conidia were sown on the amended media and growth inhibition occurred starting from 6.0 mM. A nearly total inhibition of the growth and spore germination occurred with 60.0 mM of 2-DG. The antagonist was not affected by any of the 2-DG concentrations employed and the amended plates resulted well colonized within 2 d post-treatment. In vivo assays were carried out with 'Hamlin' oranges, inoculated with P. digitatum 24 h before treating with: the antagonist; the above reported concentrations of 2-DG, or by combining the two treatments. Seven days post-treatment the inhibition activity exerted by 3.0, 6.0, 15.0, 30.0 and 60.0 mM of 2-DG combined with the yeast was 15, 37, 42, 63 and 84%, respectively. While that exerted by the antagonist was 22% and that by the different concentrations of 2-DG were 7, 11, 27, 42 and 57%, respectively. Compared to single treatments, the co-application significantly and in a synergic mode improved the control of decay. Alterations to the hyphae were observed by SEM when the pathogen was cultured on amended media and into the wounds of inoculated oranges. PMID- 21534463 TI - Use of potassium bicarbonate (Armicarb) on the control of powdery mildew (Sphaerotheca mors-uvae) of gooseberry (Ribes uva-crispa). AB - Powdery mildew (Sphaerotheca mors-uvae) severely infects young shoots, stems and fruits of gooseberry (Ribes uva-crispa). Environmental friendly and biological control measures are being sought throughout the world. Especially in organic gooseberry growing effective control measures are needed, because powdery mildew infections may result in a total loss of the crop. In organic currant growing the number of adequate control methods is very limited. Sulphur as a fungicide against powdery mildew in e.g. gooseberry or table grape growing is not recommendable due to possible bleaching of berries and scorching of tender shoots. Various bicarbonate salts are suggested as a good option to control powdery mildew. In a field trial the effect of potassium bicarbonate (Armicarb) on the on the control of powdery mildew of gooseberry was evaluated. Four treatments; i.e. two preventive strategies and two curative strategies, were applied. PLants were sprayed until runoff. The percent of infected fruits and disease severity were assessed. In the unsprayed control plots very high disease incidences were observed; on average more than 90% of the berries were infected with powdery mildew. The weekly (preventive) spray applications with potassium carbonate reduced the disease incidences on fruits significantly. On average approximately 10% of the fruits were affected by powdery mildew. However, the number of spray applications was high. In conclusion, our results indicate that applications of potassium bicarbonate (as Armicarb) are effective in reducing the incidence and severity of American powdery mildew in gooseberry. Early spray applications are necessary to protect berries against powdery mildew infections. Future research will focus on reducing the number of applications, e.g. warning models based on powdery mildew of rose (Sphaerotheca pannosa). PMID- 21534464 TI - Reduction in bacterial ooze formation on immature fruitlets after preventive treatments of Fosethyl-Al against fire blight Erwinia amylovora. AB - Fire blight, caused by the bacterium Erwinia amylovora (Burill Winslow et al.), is a very important bacterial disease on apple and pear orchards with devastating effects in some production area and in some years. Fire blight control consists in a whole strategy of measures that should start with control measures in and around the fruit tree nurseries. Only the use of Vacciplant (Laminarin), an inducer of the self-defence mechanism, is registered in Belgium since 2009. In other European countries Fosethyl-Al has been registered for fire blight control. Recently, research trials have been done at Pcfruit research station for several years on the activity of ALiette (fosethyl-Al) against fire blight. Fosethyl-Al, also a plant defence enhancing molecule, applied preventively 3 times at a dose of 3.75 kg/ha standard orchard (3 x 3000 g a.i./ha standard orchard), showed a reduction in the host susceptibility and decreased the disease development on artificial inoculated flower clusters and shoots. Also a clear reduction in the ooze droplet formation on artificially inoculated immature fruitlets has been observed with this molecule. This reduction in the bacterial ooze formation is considered as a very important factor in the spread of the disease in the orchard. PMID- 21534465 TI - Evolution of Mycosphaerella graminicola at the wheat leaf level and at the field level. AB - Evolution of M. graminicola wheat field populations from a given French county (Morbihan, 56) between years 2005 and 2006 was investigated for thirty seven strains using molecular fingerprinting by microsatellite markers (ST1A4, ST1E3, ST1E7, and ST1D7), and SSCP analysis study of partial actin and beta-tubulin encoding sequences. In addition, twenty nine strains collected from 3 distinct lesions on a same wheat leaf in 2006 in another French county (Nord, 59) were also investigated for genetic diversity. At the field level, we observed similar gene diversity in the 2005 and in the 2006 populations, with no common clones between the two years. This indicates frequent sexual recombination undergone by the fungus. When considering each marker independently and comparing genetic variability of the two populations, we noticed a decrease in genetic variability of the 2006 strains for three of them (ST1A4, ST1D7 and the partial sequence of actin) and an increase for ST1E3, ST1E7 and the partial sequence of beta-tubulin, revealing the importance of the chosen markers. At the lesion level, 69% of the studied strains were haplotypes with 31% of the clonal population found in 2 lesions out of 3. This suggests that at least parts of the lesions were formed after asexual reproduction and dissemination of pycnidiospores by splashing. We also confirmed the exploitative competition that exists between the strains at the lesion level. PMID- 21534466 TI - Single strand conformation polymorphism is a sensitive method for screening nucleotide variations in Mycosphaerella graminicola. AB - Single Strand Conformation Polymorphism (SSCP) and sequencing were performed in order to assess molecular polymorphism of mating type sequences in the heterothallic ascomycete Mycosphaerella graminicola, the causal agent of Septoria tritici blotch of wheat. The screening was undertaken on mat1-1 and mat1-2 partial sequences of 341 and 657 bp, respectively, amplified with multiplex PCR from 510 French single-conidial strains plus the two reference isolates IPO323 and IPO94269 from The Netherlands. After restriction with Taq1 in order to reduce the fragment sizes, all digested amplicons were subjected to SSCP. Sequencing was then performed when a SSCP pattern deviates from the most frequently occurring profile. Among the assessed strains, 228 ones plus IPO323 were MAT1-1 and 282 ones plus IPO94269 were MAT1-2. Among the MAT1-1 strains, only a single one exhibited a SSCP profile distinct to the other MAT1-1 strains, whereas 10 MAT1-2 strains (among which 2 and 4 with same profiles, respectively) showed a SSCP profile differing to the other MAT1-2 strains. Sequencing revealed that all polymorphisms observed on SSCP gels were single nucleotide variations and all strains displaying the same SSCP profiles showed identical nucleotide sequences. Among the seven disclosed nucleotide variations, only two were non-synonymous and both were non-conservative. This study reports a high sensitivity of SSCP allowing detection of single point mutations in M. graminicola, shows a conservation of mating type idiomorphs in the fungus at both sequence and population scales, but also suggests a difference in polymorphism level between the two mating type sequences. PMID- 21534467 TI - Production of Ascochyta rabiei lacking solanapyrone A toxin production. AB - Ascochyta rabiei, agent of Ascochyta blight of chickpea produces three toxins, Solanapyrones A, B and C of which solanapyrone A is the most toxic. All isolates of the fungus so far examined produce at least one of the Solanapyrone toxins, usually Solanapyrone A. The universality of solanapyrone production argues strongly for the importance of the toxins in virulence or pathogenicity. However, further evidence for this awaits the development of mutants lacking toxin production. Generation and isolation of fungal mutants defective in pathogenicity has been very useful for understanding the genetic and enzymatic processes responsible for infectivity in a number of pathosystems. Numerous tools have been used to transform plants and micro-organisms but the most widely micro-organism employed is Agrobacterium tumefaciens. In the present experiments, two strains of A. tumefaciens, AGL1 and LBA1126, harbouring two different plasmids, both encoding a gene for hygromycin resistance in the T-DNA region were used to transform isolate Tk21 of A. rabiei. The transformation of Ascochyta rabiei, gave rise to 498 colonies which grew on media supplemented with the selective agent; hygromycin B. The 30 sporulated transformants produced solanapyrone A on the specific medium at different rates. Solanapyrone A production, as demonstrated by the absorption of light at 327 nm, varied from 2.11 microg/ml to 4.32 microg/ml, representing a reduction of 74.11% to 46.99% in comparison with the wild type (8.15 microg/ml). PMID- 21534468 TI - Epidemiological research of twig scab on pear as basis for a rational and ecological disease management. AB - Scab is one of the key parasites in fruit growth. In favourable weather conditions for the pathogen, a complete harvest can be destroyed if no control measurements are undertaken. The scab fungi on pear and apple are two distinct species. They have, however, a similar biological cycle. Despite the similarities, there are also clear differences and these differences are significant for the control of the pathogen. Pear scab does not only infect fruit and leaves as apple scab does, but also infects twigs. Especially in organic fruit growing, twig scab is a big problem. Once twig scab occurs, it seems to be impossible to get rid of scab in these orchards. The only possibility for the fruit grower in this case is a strict spraying schedule to ensure no further spread of the infection. The main goal of the project is a thorough study of the pear scab fungi (biology, sensitivity of different plant parts and cultivars, dispersal of the fungi and infection conditions, the pathogenicity and characterization of different biotypes) to unravel the life of the fungi and to develop a better control strategy. A better control strategy means a reduced fungicide use and a reduction of fungicide residue on the fruits at harvest, without a reduction of the quality of the fruits and cost effectiveness for the fruit grower. Special attention in the project goes to the role and the control of twig scab. The first results of this project will be shown. PMID- 21534469 TI - Fusarium head blight: distribution in wheat in Latvia. AB - Fusarium head blight (FHB) of wheat has, in recent years, been a very important worldwide disease in intensive growing of cereal. The objectives of this study were to evaluate the occurrence of FHB in wheat in Latvia and to identify the Fusarium species involved. This paper describes the distribution of Fusarium species that were isolated from samples representing winter and spring wheat varieties in Latvia, identified both by the classical morphological analyses of J. Leslie and B. Summerell (2006) and by PCR. The FHB incidence range in winter wheat was 1-20%, in spring wheat was 1-42%. The most significant factor affecting the incidence of fusarial head blight in wheat in Latvia was heightened temperature at the time of an thesis of wheat. In winter wheat 9 Fusarium species caused FHB: F. culmorum, F. avenaceum, F. graminearum, F. equiseti, F. poae, F. oxysporum, F. cerealis, F. sporotrichoides and F. verticillioides were identified by morphological characterization, and 5 were confirmed by PCR-analysis. After experience of 5 years, it can be concluded that the most frequent in winter wheat were F. poae and F. culmorum. In spring wheat from F. culmorum was dominant among 8 Fusarium species. Among 13 varieties of spring wheat, three were sensitive ('Chamsin', 'W 166', 'Azurite') and one was resistant ('Granny') to FHB in conditions of high natural infection in 2009. The monitoring surveys demonstrate a significant presence of FHB in spring wheat in conditions of heightened temperature at the time of flowering in Latvia. PMID- 21534470 TI - Distribution of airborne Mycosphaerella graminicola inoculum at the field scale. AB - A network of 10 Burkard 7-day spore-recording traps was set up in the Walloon region in Belgium to monitor the airborne inoculum of wheat pathogens. Three spore traps were used to analyse the distribution of Mycosphaerella graminicola inoculum at the field scale, at 1 m above ground level. Two traps were set up in a wheat field 100 m apart. The third trap was placed 70 m away in a sugar beet field adjacent to the wheat field. Total DNA from each fragment of spore trap tape corresponding to 1 day sampling was extracted and the quantity of M. graminicola was assessed using real-time polymerase chain reaction (PCR) assay. The experiment was conducted from July to October 2009. Positive detections were obtained for between 33 and 36 days, depending on the spore traps. When detected, the daily quantities of cDNA, collected from a volume of 14.4 m3, fluctuated between 4.84E+00 and 6.10E+03. Correlation coefficients higher than 0,82 and no significant differences were observed between the quantities of M. graminicola collected by the three spore traps, indicating that, at 1 m above ground level, the distribution of inoculum can be considered as homogenous at the tested field scale. This study confirms that spore traps coupled with real-time PCR could be used to assess the airborne inoculum of M. graminicola and to understand the development of the disease at this scale. PMID- 21534471 TI - Consistency of crown rust evaluation in ryegrass cultivars. AB - Crown rust (Puccinia coronata) is the most important leaf disease in forage ryegrasses (Lolium spp.). In order to evaluate the stability in space and time of crown rust resistance a multisite rust evaluation trial was established by the European breeders association Eucarpia ( Fodder Crops Section). The same seed lots of 33 perennial ryegrass (Lolium perenne) and 18 Italian ryegrass (Lolium multiflorum) varieties were sown in April 2001, 2004 and 2007 at 27 European sites. This paper reports the temporal ranking of the ryegrass varieties for their crown rust susceptibility at the Belgian site and compares this ranking with the mean ranking over the European sites. The crown rust susceptibility was scored in September of each sowing year and of the year after. The rankings of both the perennial and the Italian ryegrass varieties were well correlated between the successive yearly observations at each sowing period. Also the rankings of the varieties of both species were similar over the 3 sowing periods. The rankings at the Belgian site corresponded very well with the mean ranking over the European sites. The crown rust resistance in ryegrass seems to be durable and consistent over a great part of Europe. PMID- 21534472 TI - Both mating types of the wheat pathogen Mycosphaerella graminicola are present in Morocco. AB - Septoria tritici blotch caused by the heterothallic ascomycete Mycosphaerella graminicola is one of the most currently damaging diseases on wheat crops worldwide. So far, no information was reported about the status of sexual reproduction of this pathogen under Moroccan conditions. We investigated here for the first time the occurrence of the two mating types (MAT1-1 and MAT1-2) of M. graminicola in Morocco by sampling 141 single-conidial isolates from 4 important wheat producing regions (Gharb, Sais, Chaouia and Tadla). The mating type of each isolate was determined by amplification with multiplex PCR of a partial sequence from the corresponding idiomorph. Overall, 43% out of the assessed isolates were MAT1-1 and 57 % were MAT1-2. Both mating types were identified within the 3 sampled regions Gharb, Sais and Chaouia, but not in Tadla, where only MAT1-2 isolates were found. The presence of the two mating types highlighted here offers a suitable genetic condition for M. graminicola to occur sexual reproduction in Morocco. The potential of sexual recombination will be examined by the study of mating type frequencies using a large sample size as well as by searching and quantification of pseudothecia in the field. PMID- 21534473 TI - Diversity study on Sclerotinia trifoliorum Erikks., the causal agent of clover rot in red clover crops (Trifolium pratense L.). AB - Since the 16th century, red clover has been an important crop in Europe. Since the 1940s, the European areal of red clover has been severely reduced, due to the availability of chemical fertilizers and the growing interest in maize. Nowadays there is a growing interest in red clover again, although some setbacks still remain. An important setback is the low persistence of red clover crops. Clover rot, caused by the ascomycete fungus Sclerotinia trifoliorum Erikss., is a major disease in Europe and reduces the persistence of red clover crops severely. The fungus infects clover plants through ascospores in the autumn, the disease develops during the winter and early spring and can kill many plants in this period. In early spring, black sclerotia, serving as surviving bodies, are formed on infected plants. Sclerotia can survive up to 7 years in the soil (Ohberg, 2006). The development of clover rot is highly dependent on the weather conditions: a humid fall, necessary for the germination of the ascospores and an overall warm winter with short periods of frost are favourable for the disease. Cold and dry winters slow the mycelial growth down too much and prevent the disease from spreading. Clover rot is difficult to control and completely resistant red clover varieties have yet to be developed. Because of the great annual variation in disease severity, plant breeders cannot use natural infection as an effective means to screen for resistant material. Breeding for resistant cultivars is being slowed down by the lack of a bio-test usable in breeding programs. When applying artificial infections, it is necessary to have an idea of the diversity of the pathogen. A diverse population will require resistance screening with multiple isolates. The objective of this research is to investigate the genetic diversity among isolates from the pathogen S. trifoliorum from various European countries. We assessed diversity using a species identification test based on the sequence of the beta-tubulin gene, vegetative compatibility grouping and AFLP. PMID- 21534474 TI - Detection and identification of Phytophthora alni. AB - In 2004 Brasier et al. described new species--Phytophthora alni, which was especially aeggressive to alder. Now, this Phytophthora disease of alder is widely distributed in Europe as well as in Poland. In this research note we report on identification and detection of P. alni from water and soil samples using PCR method with species-specific primers. Dilution series of P. alni zoospore were used to test the potential sensitivity of the PCR detection methods. Zoospores of P. alni were produced by flooding of 1-week-old Frozen Pea Medium (FPM) cultures in Petri dishes with 30 ml distilled water. The dishes were incubated at 20 degrees C. After 5 days, sporangial production was checked using a binocular microscope and plates were placed at 4 degrees C for 1 h to enhance zoospore release. Zoospores were counted under the microscope using Burker's cabin. A dilution series of zoospores ranging from 5 to 5000 per 200 microl was prepared in autoclaved distilled water and in 1 g samples of autoclaved soil. DNA was extracted from artificially infected water and soil, and purified using the CleanUp Kit (A&A Biotechnology). Zoospores of P. alni in the water were detected by PCR in 5 x 10(3), 5 x 10(2), 5 x 10(1) concentrations. In case of detecting spores in the artificially infected soil it succeeded only for two highest concentrations, i.e. 5 x 10(3), 5 x 10(2) and only when the DNA was additionally purified. PMID- 21534475 TI - Relationship between occurrence of Phytophthora cambivora on plants in hardy ornamental nursery stocks and detection of the pathogen from water ponds. AB - Phytophthora cambivora was isolated from rooted bases and roots of Castanea sativa, Chamaecyparis lawsoniana and Cotoneaster spp. as well as from water ponds Located in HNS. In the laboratory trials the species colonised leaf blades and stem parts of 3 tested plant species. Differentiated reaction of tested plant species on P. cambivora was observed. PMID- 21534476 TI - Efficacy of microorganisms selected from compost to control soil-borne pathogens. AB - Suppression of soil-borne plant pathogens with compost has been widely studied. Compost has been found to be suppressive against several soil-borne pathogens in various cropping systems. However, an increase of some diseases due to compost usage has also been observed, since compost is a product that varies considerably in chemical, physical and biotic composition, and, consequently, also in ability to suppress soil borne diseases. New opportunities in disease management can be obtained by the selection of antagonists from suppressive composts. The objective of the present work was to isolate microorganisms from a suppressive compost and to test them for their activity against soil-borne pathogens. A compost from green wastes, organic domestic wastes and urban sludge's that showed a good suppressive activity in previous trials was used as source of microorganisms. Serial diluted suspensions of compost samples were plated on five different media: selective for Fusarium sp., selective for Trichoderma sp., selective for oomycetes, potato dextrose agar (PDA) for isolation of fungi, lysogeny broth (LB) for isolation of bacteria. In total, 101 colonies were isolated from plates and tested under laboratory conditions on tomato seedlings growing on perlite medium in Petri plates infected with Fusarium oxysporum f.sp. radicis-lycopersici and compared to a commercial antagonist (Streptomyces griserovidis, Mycostop, Bioplanet). Among them, 28 showed a significant disease reduction and were assessed under greenhouse condition on three pathosystems: Fusarium oxysporum f.sp. basilica/basil, Phytophthora nicotianae/tomato and Rhizoctonia solani/bean. Fusarium spp. selected from compost generally showed a good disease control against Fusarium wilts, while only bacteria significantly controlled P. nicotianae on tomato under greenhouse conditions. None of the microorganisms was able to control the three soil-borne pathogens together, in particular Rhizoctonia solani. Results confirmed the good suppressive activity of the compost under study against soil-borne pathogens. The selection of antagonists from compost is a promising strategy for the development of new biological control agents against soil-borne pathogens. PMID- 21534477 TI - Antifungal activity of rhizospheric bacteria. AB - Fluorescent Pseudomonad spp. were isolated from the rhizosphere of potato plants (Algeria) by serial dilutions of rhizosphere soils on Kings B medium and were tested for their antifungal activity. The antifungal activity of the Pseudomonas isolated from Potatoes rhizosphere was tested against Pythium ultimum, Rhizoctonia solani and Fusarium oxysporum in dual culture with bacteria on PDA. The Petri dish was divided into tow, on one the bacteria was spread and on the opposite side fungal plugs were inoculated and incubated for one week. Fourteen bacteria were isolated; only one isolate inhibited the growth of Pythium ultimum, Rhizoctonia solani, Fusarium solani; Fusarium oxysporum f.sp. albedinis and Fusarium oxysporum f. sp. Lycopersici with inhibition zones of 39.9, 33.7, 30.8, 19.9 and 22.5 mm respectively. PMID- 21534478 TI - New remarkable records of microfungi from Sardinia (Italy). AB - In June 2009 we organized a botanical student excursion to the eastern part of Sardinia, Italy. On this occasion we were able to collect and identify over 80 species of microfungi growing on higher plants. The collecting sites were spread over a large area, among them were La Caletta, Capo Comino, Monte Albo, Cala Gonone, Monte Maccione, San Teodoro, Capo Testa. The collected microfungi were parasitic or saprophytic; Basidiomycotina (Uredinales), Ascomycotina and Deuteromycotina (Hyphomycetes, Coelomycetes) were predominant. Examples are Pezicula corticola (Jorg.) NANNF. (new for Sardinia), on Pyrus communis. Puccinia chamaecyparissi TROTT. (new for Sardinia), on Santolina insularis. Sphaceloma oleae CICC. and GRANITI (new for Sardinia) and Phlyctema vagabunda DESM. (new for Sardinia), on Olea europaea and Arbutus unedo. Puccinia pseudosphaeria MONT. (new for Sardinia), on Sonchus oleraceus. Discula umbrinella (BERK. and BR.) SUTTON (new for Sardinia)(D. quercina WEST. and BARK), on Quercus coccifera. Zaghouania phillyreae PAT. (new for Sardinia), on Phillyrea angustifolia. Phymatotrichum omnivorum (DUGGAR) HENNEBERT, new on Verbascum thapsus for Sardinia. Guignardia punctoidea (COOKE) SCHROTER (new for Sardinia), on Quercus ilex. Many of the collected species are rare or unknown for the area of investigation until now. All specimens are located in the Herbarium ESS, Mycotheca Parva collection G.B. Feige and N. Ale-Agha. PMID- 21534479 TI - In vitro selection in resistance breeding of strawberry (Fragaria x ananassa duch.). AB - Genetic resistance to pathogenetic soil-borne fungus Verticillium dahliae Kleb. was examined in two strawberry somaclones. Strawberry somaclones were obtained in sterile culture from runner tips of cultivars 'Merton Dawn' and 'Selva'. In vitro selection was performed with the use of homogenate of liquid cultures of Verticillium dahliae. Microplants of both somaclones were inoculated at stage of 4. Leaves. Disease symptoms were observed at 15., 30., 45., 60. and 75. days post inoculation. Extent of leaf chlorosis was rated on a scale of 0-4. Under the controlled in vitro culture conditions a different response to infection by this pathogenic fungus was observed. After 75. days post inoculation the contribution of necrotic plants in somaclone of 'Merton Dawn' reached the value of 76%, whereas in somaclone of 'Selva' this value reached 86%. In control somaclones of 'Merton Dawn' and 'Selva' the contribution of necrotic plants after 75. days post mock-inoculation with sterile distilled water reached the considerably lower value of 13%. These results revealed that somaclone of 'Merton Dawn' was more genetically resistant to infection by V. dahliae than somaclone of 'Selva'. The observed response to in vitro infection caused by Verticillium dahliae in examined somaclones was similar in comparison with original cultivars. Furthermore, somaclonal variation induced in tissue cultured strawberry was sufficient to select variants that showed enhanced genetic resistance to Verticillium wilt caused by V. dahliae. In vitro selection can be efficiently used as an alternative program to conventional resistance breeding in strawberry. PMID- 21534480 TI - Monitoring for resistance to fungicides in Botrytis cinerea and Sclerotinia sclerotiorum, the pathogens of sweet basil. PMID- 21534481 TI - Effects of paclobutrazol on Botrytis cinerea isolates obtained from potted plants. AB - The growth of different isolates of Botrytis cinerea, collected from potted plants affected by Botrytis blight in southern Spain during recent years, was studied. These isolates, which show wide phenotypic differences when grown in vitro, are differentially affected by growth temperature, gibberellic acid, and paclobutrazol--an efficient plant growth retardant used widely in nursery potted plants to reduce plant size, favouring compactness, a more intense green foliage and increased stress tolerance to maintain quality prior to sale. In addition, paclobutrazol may have a fungicidal effect since it belongs to the triazole chemical group. However, paclobutrazol is only used as a plant growth retardant in Spain. In this work, we evaluate the effect of paclobutrazol dose (0, 0.05, 0.25, 1.25, and 6.25 mg/plate) on the growth of a collection of different B. cinerea isolates obtained from the following potted plants: Cyclamen persicum, Hydrangea macrophylla, Lantana camara and Lonicera japonica. Mycelial growth curves and growth rates assessed from difference in colony areas during the linear phase, conidiation (measured as time of appearance), conidial length (microm), and sclerotia production (number/plate) were evaluated in the isolates, which were grown at 26 degrees C on Petri dishes containing potato dextrose agar for up to 36 days. Mycelial growth curves fitted a typical kinetic equation of fungus grown on solid media. The B. cinerea isolates showed a high degree of variability in their growth kinetics, depending on the isolate and paclobutrazol dose. This triazole delayed mycelial growth during the linear phase in an isolate dependent manner, and isolates from C. persicum and L. japonica were more affected by paclobutrazol than H. macrophylla. On the other hand, 0.25 mg of paclobutrazol was the critical dose to significantly reduce the growth rate in all isolates. 6.25 mg paclobutrazol inhibited conidiation in isolates from C. persicum, and reduced the conidial length in isolates from H. macrophylla and L. camara. The sclerotia production process was blocked at paclobutrazol doses higher than 1.25 mg, while no sclerotia were produced in isolates from C. persicum and L. japonica with 0.25 mg. H. macrophylla was the isolate in which sclerotia production was most influenced by paclobutrazol. It was concluded that the exact effect of paclobutrazol on B. cinerea growth depends on the isolate, and new strategies should be considered for evaluating its use as retardant and fungicide. PMID- 21534483 TI - Natural products alone or with copper vs. grape downy mildew: efficacy, costs, Cu impact. AB - In organic farming copper is one of the few fungicides that can be used and the only effective against downy mildew. Due to the problems of environmental impact associated with the use of this heavy metal, the European Union decided to restrict its use (Annex II Regulation EC n. 889/2008). In order to assess the possibility of replacing the copper or reduce the quantities used, we tested natural products and low rate copper formulations in field trials. The anti-downy mildew activity of these formulations has been studied in an organic vineyard. During the two years of activity we also estimated the economic cost of use of the products to assess their possible use in agricultural practice. PMID- 21534482 TI - The effect of essential oil of Ammoides pusilla (brot.) breistr on the growth and the production of solanapyrone a by Ascochyta rabiei. AB - Biological control such as the use of plant extracts has emerged as promising option to the phenomena of fungi resistance to chemical. Several constituent of essential oil have been studied for their biological activity including antibacterial and antifungal activity. In this study the effect of Ammoides pusilla essential oil with different concentrations was test against the growth of Ascochyta rabiei and the production of solanapyrone A by the fungus. After 14 days the mycelium was collected and the dry weight measured. A. rabiei did not grow at a final concentration of 6 and 3 mg/ml, at 1.5 mg/ml and 0.625ml there was little growth of the fungus with a dry weight of 55 mg and 99 mg respectively compared to the control with 519 mg dry weight, but there was no solanapyrone A produced. However a new compound appeared at the HPLC at 10 min. 30 sec. compared with the solanapyrone A which elutes at nearly 14 minutes. PMID- 21534484 TI - In vitro studies on the effect of some chemicals on the growth and sporification of Penicillium digitatum and P. italicum. AB - The behaviour of Penicillium digitatum and P. italicum was investigated when subjected to different concentrations of methanol (MeOH) and dimethyl sulfoxide (DMSO). The experiments were performed in 9 cm Petri dishes containing PDA amended with 0, 5, 10, 20, 30, 40 or 50 microL/mL of each of the single or combined chemicals. Daily, the formed colonies (cfu), the colony diameter and the degree of sporification were monitored during incubation at 20 degrees C for 5 day. Additionally, the pathogen development and its performance were studied by scanning electron microscopy (SEM). According to the chemical, the mycelium growth rate was affected differently and, compared to the control, only MeOH inhibited the expansion of the colony diameter. This effect was more pronounced for P. italicum. A nearly linear drop of cfu was observed as the concentration of the two chemicals was raised, and a complete inhibition of the two pathogens was attained with 50 microL/mL MeOH. With respect to the sporification degree the two pathogens were influenced similarly, but the tested compounds had opposite effects. Indeed, with MeOH, sporification took place earlier (24-36 h postinoculation) compared to the control (60 h), while during the whole experiment, DMSO at concentrations higher than 0.5 microL/mL, drastically inhibited the sporification. SEM observations of P. digitatum growth on DMSO amended media evidenced a marked increase of mycelium branching and alterations to the conidiophore, while MeOH reduced the mycelium length and fastened the conidiophore formation. The combination of the two compounds produced a synergistic interaction reducing by 40% the concentration required to inhibit completely the germination and growth of P. digitatum. PMID- 21534485 TI - Immersion of 'Coscia' pear fruit in water at 55 degrees C for 60 sec controls Penicillium expansum decay and delays ripening during short storage. AB - 'Coscia' is an early ripening pear with a short postharvest Life (1 month) and chemical treatments to prevent decay are generally not undertaken. This, along with the fast deterioration under shelf-life conditions, makes it difficult to contain postharvest moulds. 1-methylcyclopropene (1-MCP) has been employed with success to delay ripening and, as a co-effect, the development of decay was contained, but this treatment is not allowed for organically grown crops. Here we report the results of an alternative approach employing immersion treatments in water at 45, 50, 55 or 60 degrees C for 0 (control), 15, 30, 45 or 60 sec. Fruit was harvested after the climacteric peak, immediately subjected to the heat treatment and stored for 2 weeks at 1 degrees C followed by a 3 days of a simulated shelf-life at 17 degrees C and 75% RH. Half of the fruit was wounded (3 x 3mm) and inoculated with Penicillium expansum (20 microL of 10(4) conidia mL( 1). Decay inhibition and fruit appearance, rated from 0 to 3 (0 = excellent; 1 = good; 2 = scarce; 3 = not marketable), were monitored and compared to the control after storage and shelf-life. All heat treatments affected the mould development when performed for 45 or 60 sec. The best result in terms of decay control and appearance after storage and shelf-life occurred when fruit was immersed at 55 degrees C for 60 sec with a decay reduction of about 85% compared to control (75% decay) and with a good appearance. PMID- 21534486 TI - Postharvest behaviour of two Sardinian apple varieties following immersion in heated sodium bicarbonate solution. AB - 'Miali' and 'Caddina' are apple varieties of Sardinian germplasm, mainly produced under sustainable conditions. Fruit is rarely subjected to cold storage and postharvest losses are generally high. In order to prolong the marketing period and contain postharvest decay of these local varieties, we investigated on their storage behaviour and on the efficacy of combined alternative postharvest treatments. Pre-climateric fruit was harvested and immersed for 0 (control), 15, 30, 45 or 60 sec. in water at 20, 50, 55 or 60 degrees C with or without 2% (W/V) NaHCO3 (SBC). Then, fruit was stored for 4 months at 5 degrees C and 90% RH followed by a 6 day simulated marketing period (SMP) at 10 degrees C and 75% RH. Decay was monitored at the end of storage and after the SMP, while appearance and physiological disorders were evaluated after SMP. During storage 56 and 62% of the untreated 'Caddina' and 'Miali' apples rotted, respectively. During the SMP, an additional 3% of 'Caddina' and 5% of 'Miali' was lost. Among the treatments the best decay control, for both varieties, was attained when fruit was immersed in the SBC solution at 55 degrees C for 60 sec. Compared to control, decay was reduced by 91 and 95% for 'Caddina' and 'Miali', respectively. This combination induced some rind damage, mainly on 'Caddina' fruit. Superficial scald was evident on 'Caddina' and scored as medium while, cold storage induced a significant deposition of epicuticular wax in 'Miali' fruit, affecting significantly fruit appearance. A significant reduction of decay was also achieved when fruit was immersed at 60 degrees C for 30 or 45 sec., attaining for 'Caddina' a reduction of 82 and 88% of decay, respectively. Other combinations were lesser effective or produced rind damages and most decay was caused by Penicillium expansum. PMID- 21534487 TI - Postharvest behaviour of five Sardinian prune varieties as affected by immersion in heated sodium bicarbonate solution. AB - Storage behaviour of 'Core', 'Core Columbu', 'Fradis' and 'Meloni' white prunes, and a black one ('Sighera') of Sardinian germplasm were evaluated following immersion for 0 (control), 15, 30, 45 or 60 sec in water at 20, 50, 55 or 60 degrees C with or without 2% (w/v) NaHCO3 (SBC). As international varieties, fruit from one white plum ('Shiro') and one black prune ('Stanly') were subjected to the same treatments. Fruit was harvested at commercial maturity, treated and then stored for 1 month at 5 degrees C and 90% RH followed by a simulated marketing period at 20 degrees C and 80% RH for 6 days. Fruit appearance, external damage, firmness and decay percentage were monitored after storage and SMP. Treatments did not induce rind damage (browning or discoloration) to any variety. SBC at 20, 45, 50 or 55 degrees C for 15 or 30 sec was not effective in controlling decay and compared to controls no improvement was observed. Immersion for 45 or 60 sec with SBC at all temperatures improved decay control with respect to controls and best results were obtained at 50 or 55 degrees C. Immersions at 60 degrees C improved decay control, but differences were not significant compared to the control attained with solutions of SBC heated at 55 degrees C. The overall appearance of 'Core', 'Core Columbu', 'Fradis' and 'Shiro' decreased significantly after the SMP period, especially when treated at 55 or 60 degrees C for 60 sec. Fruit shrivel was the main cause of the low rating. SBC did not affect shrivel indicating that heat treatment may be the probable cause. In general, local varieties were less affected by decay than other varieties and they performed well during storage. PMID- 21534488 TI - Antifungal activity of some essential oils against toxigenic Aspergillus species. AB - Increasing attentions have been paid on the application of essential oils and plant extracts for control of postharvest pathogens due to their natural origin and less appearance of resistance in fungi pathogens. Some Aspergillus species are toxigenic and responsible for many cases of food and feed contamination. Some Toxins that produce with some Aspergillus species are known to be potent hepatocarcinogens in animals and humans. The present work evaluated the parameters of antifungal activity of the essential oils of Zataria multiflora, Thymus migricus, Satureja hortensis, Foeniculum vulgare, Carum capticum and thiabendazol fungicide on survival and growth of different species of Aspergillus. Aerial part and seeds of plant species were collected then dried and its essential oils isolated by means of hydrodistillation. Antifungal activity was evaluated in vitro by poisonous medium technique with PDA medium at six concentrations. Results showed that all essential oils could inhibit the growth of Aspergillus species. The essential oil with the best effect and lowest EC50 and MIC (Minimum Inhibitory Concentration) was Z. multiflora (223 microl/l and 650 microl/l, respectively). The chemical composition of the Z. multiflora essential oil was analyzed by GC-MS. PMID- 21534489 TI - Survey of Thymus migricus essential oil on aflatoxin inhibition in Aspergillus flavus. AB - Essential oil components as result of non host disease resistance of plants have high capability to introduce as alternative of chemical pesticides. Thymus migricus essential oil was selected to investigation of its antifungal activity on survival and growth of Aspergillus flavus. For obtain essential oil first Leaves and flowers of Th. migricus collected then dried. The Essential oil was extracted by means of hydro-distillation and afterwards GC-MS analysis was performed to identify their components. The main constituents that resulted were Thymol (44.9%), Geraniol (10.8%), gamma-Terpinene (10.3%), Citronellol (8.5%) and p-Cymene (7.2%). EC50 and MIC (Minimum Inhibitory Concentration) of Th. migricus oil against A. flavus was 324.42 microl/l and 451.62 microl/l, respectively. Whereas EC50 and MIC for chemical thiabendazol was 650 microl/l and 1635 microl/l, respectively. The EC50 and MIC concentrations of Th. migricus oil in antifungal activity examination were used in aflatoxin inhibition test. Result of HPTLC measurement showed that both of concentrations inhibit aflatoxin production completely compares to control with 7.63 ppm aflatoxin production. In other word, Th. migricus oil can suppress aflatoxin production in concentrations lower than EC50 for mycelium growth. PMID- 21534490 TI - An optimized method for extraction and detection of Coconut cadang-cadang viroid(CCCVd) from oil palm. AB - Coconut cadong-cadong viroid (CCCVd) causes the Lethal cadang-cadang disease of coconut palms in the Philippines and it is recently reported to be associated with the orange spotting disease on oil palm in Malaysia. The low concentration of the viroid RNA in oil palm as well as the high content of polyphenols and polysaccharides in this plant which interfere with the purification steps makes it difficult to extract and detect this viroid from oil palm. A previously described method was modified and optimized for extraction and detection of CCCVd from infected oil palms. Briefly, 7 g of leaf material was homogenized in a mortar or a blender using liquid nitrogen. 10 ml of extraction buffer (100 mM Tris-HCl pH 7.5, 100 mM NaCl, 10 mM EDTA) along with 100 mM 2-mercaptoethanol and 10 ml water saturated phenol was added to the frozen powder. After centrifuging at 4 degrees C, 4000 g for 30 min, the aqueous phase was extracted once more with phenol then once with chloroform-isoamyl alcohol (24:1). After adding sodium acetate, pH 5.6 to 200 mM, the mixture was precipitated with 2.5 vol ethanol overnight in -20 freezer and then the pellet was washed with 70% ethanol and air dried. One milliliter of 8 M LiCl was added to the dried pellet and after shaking overnight at 4 degrees C and another centrifugation step the supernatant was collected and precipitated again with ethanol and then the resulting pellet was washed and air-dried. To carry out northern blotting, samples equivalent to 40 g of plant tissue were mixed with formamide buffer and loaded onto a 12% polyacrylamide gel containing 7 M urea and after separation by electrophoresis, were electroblotted onto membrane and fixed by UV cross-linking. Pre hybridization and hybridization using hybridization buffer (50% formamide, 25%SSPE, 0.1% Ficol and PVP, 0.1 % SDS, 0.02 % DNA (5mg/ml)) was carried out at 45 degrees C for 90 min and 16 h, respectively followed by two low stringency washes (0.5 X SSC, 0.1% SDS, at room temperature for 5 min) and one high stringency wash (0.1X SSC, 0.1% SDS at 60 degrees C for 1 hour). In vitro synthesized DIG-labeled full-length CCCVd(-) RNA probe was used in hybridization step. DIG Nucleic Acid Detection Kit (Roche) instructions were followed for detection procedure and as a result the blue bands corresponding to the position of the viroid were appeared on the membrane. The result of this study showed the ability of DIG labeled probe in detection of the viroid and also provided a suitable extraction and hybridization method for the detection of CCCVd from oil palm. PMID- 21534491 TI - Preliminary survey of potato virus Y (PVy) strains in potato samples from Kurdistan (Iran). AB - Potato virus Y (PVY) is the type species in the potyvirus genus of the family potyviridae. This plant pathogenic virus is transmitted through plant sap inoculation by stem and core grafting and by at least 25 aphid species in a non persistent manner. According to potato specialists in most parts of the world, PVY is currently considered as the most harmful virus in cultivated potatoes. This is also the case for potato production in Iran. In this project we investigated potato leaves that were collected in the Kurdistan province in Iran for the presence of PVY with use of different biochemical/molecular techniques as ELISA, RT-PCR and qPCR. The different PVY strains, including PVY-O, PVY-N, PVYN TN, PVY-NWi, were determined by using a triplex RT-PCR. In conclusion, the results demonstrated the presence of PVY-NWi strains in the potato leaf samples from Kurdistan (Iran). The data are discussed in relation to prevalence of PVY strains in Iran. PMID- 21534492 TI - Toward immunomodulation of witches broom disease of lime (WBDL) by targeting immunodominant membrane protein (IMP) of candidatus Phytoplasma aurantifolia. AB - The witches' broom disease of lime (WBDL) caused by Candidatus Phytoplasma aurantifolia is the most devastating disease of acidian lime in southern part of Iran as it destroy thousands of trees yearly throughout these regions. Traditional methods such as eradication of infected trees and insect vector control have shown limited effect on this case. Therefore, alternative approaches such as plantibody-mediated resistance, have been considered. Throughout present study we prepared sufficient amount of antigen that is required for generation of specific monoclonal recombinant antibodies against Immunodominant membrane protein (IMP) which will be exploited for plantibody-mediated resistance approach. The gene encoding IMP protein was obtained by PCR amplification using specific primers and DNA extracted from the infected plants. Amplified fragment was then inserted into T/A cloning vector. Intact clones containing the right sequence was selected after digestion, PCR amplification and subsequent sequencing analysis. IMP encoding region having the right sequence was sub-cloned into pET28a bacterial expression vector. Large scale expression of His tagged recombinant protein was performed in the BL21-de3 strain of E. coli and purification under native conditions was carried out through immobilized metal ion affinity chromatography (IMAC) in a column containing Ni-NTA agarose beads. Successful expression and purification steps were confirmed by SDS-PAGE and western blotting analyses. The results obtained indicated the successful production of about 18 mg purified recombinant IMP protein with a low level of contamination in one liter cultured medium. Finally the purified protein was dialyzed in phosphate saline buffer and applied for immunization of mice. PMID- 21534493 TI - Diabetes at work: a grounded-theory pilot study. AB - Diabetes at Work is a qualitative grounded-theory pilot study designed to examine the factors impacting older adults' experience managing diabetes in the workplace and maintaining gainful employment. Six working adults, 55 years and older, with Type 2 diabetes were interviewed from a symbolic interactionist perspective using grounded-theory methodology. Categories that arose from this study included minimalization, fearing the future, and taking up diabetes self-management at work. The results provide insight for occupational health nurses about the issues faced by older workers with chronic disease, a starting point for planning future interventions with this potentially vulnerable population. PMID- 21534494 TI - Relationship of cardiovascular disease to stress and vital exhaustion in an urban, midwestern police department. AB - This study explored risk factors for cardiovascular disease (CVD) among 336 officers of a Midwestern police force. Instruments used included the Perceived Stress Scale, the Maastricht Questionnaire (measuring vital exhaustion), and a general Health Risk Appraisal. Rates of CVD, hypertension, and hypercholesterolemia were 3%, 28%, and 43%, respectively. The relative risk of hypercholesterolemia for male officers, compared to female officers, was 1.98 (95% confidence interval [CI], 1.10 to 3.56). The officers' average body mass index was 28.6 (SD = 4.9), with 80% being overweight or obese. The average vital exhaustion score was higher for female officers than male officers (p < .05). Bivariate relationships of CVD with perceived stress, vital exhaustion, and age were statistically significant (p < .05). When controlling for age, odds ratios were 1.20 (95% CI, 1.03 to 1.39; p < .05) for perceived stress and 1.31 (95% CI, 1.12 to 1.53; p < .01) for vital exhaustion. PMID- 21534495 TI - Visual function after bilateral implantation of apodized diffractive multifocal IOL with a +3.0 or +4.0 D addition. AB - BACKGROUND AND OBJECTIVE: To evaluate uncorrected distance, intermediate, and near visual acuity (VA), uncorrected near stereoacuity, the preferred reading distance, and reading speed after bilateral implantation of AcrySof ReSTOR SN6AD1 or SN6AD3 multifocal intraocular lens (IOL) (Alcon Laboratories, Fort Worth, TX). PATIENTS AND METHODS: Forty patients (80 eyes) from our hospital were prospectively enrolled in either the SN6AD1 group or the SN6AD3 group. There were 20 patients (40 eyes) in each group. Uncorrected distance and near VA, uncorrected intermediate VA at 40, 63, and 100 cm under high and low contrast, defocus curve, preferred reading distance, uncorrected near stereoacuity, and reading speed were evaluated 3 months postoperatively. RESULTS: Uncorrected intermediate VA at 40, 63, and 100 cm with high or low contrast was significantly better in the SN6AD1 group than in the SN6AD3 group (P < .05), with no difference in uncorrected distance VA or near VA (P > .05). The preferred reading distance in both groups was 38.5 and 32.8 cm, respectively. There were no statistically significant differences between groups in uncorrected near stereoacuity and reading speed (56.7 +/- 45.4 vs 52.5 +/- 35.4 seconds of arc and 174.2 +/- 65.0 vs 195.3 +/- 45.8 words per minute, respectively). CONCLUSION: Patients receiving the SN6AD1 IOL achieved better intermediate VA under high or low contrast and a more comfortable reading distance than patients receiving the SN6AD3 IOL without compromising uncorrected near and distance VA, uncorrected near stereoacuity, and reading speed. PMID- 21534496 TI - Wavefront-optimized ablation versus topography-guided customized ablation in myopic LASIK: comparative study of higher order aberrations. AB - BACKGROUND AND OBJECTIVE: To compare the outcomes of wavefront-optimized ablation and topography-guided ablation in fellow eyes of patients undergoing laser in situ keratomileusis (LASIK) for myopia. PATIENTS AND METHODS: This prospective study included 84 patients who underwent LASIK in both eyes: wavefront-optimized ablation in one eye (group I) and topography-guided ablation in the fellow eye (group II). The Moria2 microkeratome with a 110 single-use head (Moria, Antony, France) was used to create a superior hinged flap and the Allegretto Wave Excimer Laser (Alcon/Wavelight Light Laser Technologie GmbH, Erlangen, Germany) for photoablation. The Allegretto wave analyzer was used to measure the ocular aberrations before and 6 months after LASIK. Refractive visual outcomes and ocular aberration changes were compared between the two treatment modalities. RESULTS: Six months postoperatively, the mean uncorrected visual acuity of group II was statistically better than that of group I (P = .02). Seventy percent of group I and 83% of group II achieved a postoperative spherical equivalent refraction of +/-0.5 diopters. The postoperative total root-mean-square of higher order aberrations (HOAs) of group II was smaller than that of group I, but the difference was not statistically significant (P = .51). There was a decrease in most of the individual terms of HOAs in group II, but it was only statistically significant in Z(3) (-1) (P = .04). The reverse occurred in group I, where most of the individual terms of HOAs increased, but it was not statistically significant. Significant improvement was only noted in Z(5) (3) (P = .05) and Z(5) (5) (P = .04). CONCLUSION: Both wavefront-optimized ablation and topography guided ablation provided good refractive results, but the latter induced fewer HOAs. PMID- 21534497 TI - Simulation-enhanced pediatric clinical orientation. AB - Nursing actively engages various technologies to enhance education and training with increased learner confidence and patient safety. Simulation is a key technology to address the strain on the current nursing education system. The purpose of this study was to determine the effect of simulation-enhanced orientation on pediatric acute care examination scores and pediatric clinical course grades among junior-level baccalaureate nursing students. No significant difference between groups (p < 0.05) was detected for the students' examination scores. Clinical grades of the intervention group (mean = 3.7) were significantly higher (t[75.3] = 5.2, p < 0.001) than those of the control group (mean = 3.4). These results support the expansion of simulation in the curriculum and prompt the proposal of simulation as an appropriate substitution for portions of pediatric clinical experience. Given the strain on the current nursing education system, simulation will be a critical component of nursing education in the future. PMID- 21534498 TI - Integrating quality and safety competencies into undergraduate nursing using student-designed simulation. AB - The purpose of this study was to determine whether an innovative teaching approach, a student-led simulation, was effective in increasing students' quality and safety knowledge, skills, and attitudes in the six Quality and Safety Education for Nurses competency areas. The sample included students (N = 141) enrolled in a traditional and accelerated leadership course in the baccalaureate nursing program at a midwestern public university during the fall 2009 semester. A quasi-experimental pretest and posttest design was used. Paired-samples t tests were used to analyze the data. Overall scores on the self-inventory in the traditional (p < 0.001) and accelerated (p = 0.011) groups significantly increased. Knowledge and safety test scores in both the traditional (knowledge: p < .001; safety: p = 0.028) and accelerated (knowledge: p = 0.027; safety: p = 0.03) groups increased significantly. The innovation significantly improved students' self-efficacy and knowledge related to the quality and safety competencies. PMID- 21534499 TI - Case study of the attitudes and values of nursing students toward caring for older adults. AB - Given the aging population and the complex needs of older adults, there is considerable need for additional gerontological nurses. This pilot study explored fourth-year nursing students' attitudes and values toward caring for older adults and the influence of their experiences with older adults on these attitudes and values. Using Yin's exploratory case study design, 51 fourth-year nursing students constituted the single case. An initial quantitative survey placed students in three embedded units of analysis: neutral, pro-aged, and anti-aged bias toward older adults. Using purposeful sampling from each of the embedded units, 9 students were interviewed. Four main values (respect, caring, independence, and wisdom and experience) and five attitudes (enjoy older adults, see older adults as normal, feel sorry for older adults, are frustrated by older adults, and dislike gerontological nursing) were identified. The authors' findings have important implications for education and practice. PMID- 21534501 TI - Common themes in clinical education partnerships. AB - The concurrent nursing and faculty shortages continue to be critical issues for the nation's health care system. As academic nursing programs struggle with maintaining and increasing enrollment in the midst of a faculty shortage, one solution is to expand the faculty's capacity through innovative academic-service partnerships. Schools and clinical partners identified as having implemented innovative partnerships were invited to participate in this descriptive study. Site visitations to schools in Florida and Texas were conducted to gain in-depth knowledge of the clinical education model, the academic-service partnership, and the strengths and challenges associated with planning, implementing, and sustaining programs. Four underlying features were common across the successful implementation: supportive relationships, goodness of fit, flexibility, and communication. Consideration of the four features will be useful as nursing programs and their clinical partners are developing, implementing, and evaluating new models for increasing educational capacity and lessening the nursing shortage. PMID- 21534500 TI - Success indicators for an accelerated masters entry nursing program: staff RN performance. AB - The purpose of this exploratory research study was to assess employment performance outcomes of students who completed the prelicensure segment of an accelerated graduate entry program, the Masters Entry Program in Nursing (MEPN) at the University of California, San Francisco. MEPN RNs and their managers at three study sites completed a survey constructed from staff RN performance criteria position descriptions and participated in focus groups. Data were used to evaluate staff RN employment performance and how well the educational program prepared students for the staff RN role. Findings indicate that MEPN RNs' self assessment and their managers' performance evaluation were rated as very effective in their staff RN roles, regardless of years of nursing experience. Recommendations for further research are discussed, encouraging the use of employment performance criteria as an additional way to evaluate the quality of nursing educational programs. PMID- 21534502 TI - Nothing to fear but fear itself? AB - As radiation levels around the crippled Fukushima Dai-ichi nuclear plant in Japan increase, the Japanese people as well as individuals around the world have expressed fear of radiation that some experts say could be more unhealthy than the levels of leaked radioactive contamination. This article addresses why individuals fear radiation and provides resources occupational health nurses can consult when answering clients' questions. PMID- 21534503 TI - The future of nursing--opportunities for occupational health nursing. AB - In this article, The Future of Nursing: Leading Change, Advancing Health report is summarized, and opportunities for occupational health nursing are proposed. PMID- 21534504 TI - Phthalate exposures and human health concerns: A review and implications for practice. AB - High levels of exposure to phthalates have been associated with an increased risk for adverse male fetal reproductive development. Although animal studies have consistently demonstrated reproductive health effects, additional human epidemiological studies are needed to fully understand the potential harm to humans. Recent findings reported for humans have demonstrated endocrine disrupting action similar to that associated with phthalate exposures in animals. As a result, phthalate exposure is an emerging public health concern that warrants further review. This article explores the state of the science on phthalate exposure, reviews the literature, and provides recommendations occupational health nurses can use to optimize the health of susceptible populations. PMID- 21534506 TI - Workplace obesity prevention. AB - Employers can effectively reduce obesity, lower their health care costs, reduce absenteeism, and increase employee productivity through workplace obesity prevention programs. PMID- 21534507 TI - Failing retirement: the baby boomers' next best thing. PMID- 21534508 TI - Is this continuing education? AB - Several recent columns have addressed common challenges for provider units. This column focuses on another common challenge-how to determine whether a proposed learning activity is continuing nursing education. Case studies provide an opportunity to examine factors in making this decision. PMID- 21534509 TI - Using evidence to enhance the recovery of patients undergoing colorectal surgery: part 2. AB - This is the second part of a three-part series describing how an enhanced recovery clinical pathway uses a multidisciplinary team to reduce postoperative stress and complications, improve recovery, and decrease hospital length of stay without affecting patient safety for patients undergoing colorectal surgery. Last month, patient education and discharge planning were discussed. This part discusses multimodal analgesia and standardized postoperative nausea and vomiting prophylaxis. Next month, fluids, diet, tubes and drains, and early mobilization will be discussed. PMID- 21534510 TI - Gain attention, enhance memory, and improve learning with brain-based strategies. AB - Applying what we know about brain function to both traditional and online teaching is easy. This column discusses brain function and "tips" for structuring teaching based on it. PMID- 21534513 TI - Returning veterans should have access to health services. PMID- 21534514 TI - Preventing dementia: is there hope for progress? PMID- 21534515 TI - Effectiveness of bronchodilators for bronchiolitis treatment. PMID- 21534516 TI - Screening for the early detection and prevention of oral cancer. PMID- 21534517 TI - FPs lower hospital readmission rates and costs. AB - Hospital readmission after discharge is often a costly failing of the U.S. health care system to adequately manage patients who are ill. Increasing the numbers of family physicians (FPs) is associated with significant reductions in hospital readmissions and substantial cost savings. PMID- 21534519 TI - Sinus infections (sinusitis). PMID- 21534518 TI - Acute rhinosinusitis in adults. AB - Rhinosinusitis is one of the most common conditions for which patients seek medical care. Subtypes of rhinosinusitis include acute, subacute, recurrent acute, and chronic. Acute rhinosinusitis is further specified as bacterial or viral. Most cases of acute rhinosinusitis are caused by viral infections associated with the common cold. Symptomatic treatment with analgesics, decongestants, and saline nasal irrigation is appropriate in patients who present with nonsevere symptoms (e.g., mild pain, temperature less than 101 degrees F [38.3 degrees C]). Narrow-spectrum antibiotics, such as amoxicillin or trimethoprim/sulfamethoxazole, are recommended in patients with symptoms or signs of acute rhinosinusitis that do not improve after seven days, or that worsen at any time. Limited evidence supports the use of intranasal corticosteroids in patients with acute rhinosinusitis. Radiographic imaging is not recommended in the evaluation of uncomplicated acute rhinosinusitis. Computed tomography of the sinuses should not be used for routine evaluation, although it may be used to define anatomic abnormalities and evaluate patients with suspected complications of acute bacterial rhinosinusitis. Rare complications of acute bacterial rhinosinusitis include orbital, intracranial, and bony involvement. If symptoms persist or progress after maximal medical therapy, and if computed tomography shows evidence of sinus disease, referral to an otolaryngologist is warranted. PMID- 21534520 TI - Croup: an overview. AB - Croup is a common illness responsible for up to 15 percent of emergency department visits due to respiratory disease in children in the United States. Croup symptoms usually start like an upper respiratory tract infection, with low grade fever and coryza followed by a barking cough and various degrees of respiratory distress. In most children, the symptoms subside quickly with resolution of the cough within two days. Croup is often caused by viruses, with parainfluenza virus (types 1 to 3) as the most common. However, physicians should consider other diagnoses, including bacterial tracheitis, epiglottitis, foreign body aspiration, peritonsillar abscess, retropharyngeal abscess, and angioedema. Humidification therapy has not been proven beneficial. A single dose of dexamethasone (0.15 to 0.60 mg per kg usually given orally) is recommended in all patients with croup, including those with mild disease. Nebulized epinephrine is an accepted treatment in patients with moderate to severe croup. Most episodes of croup are mild, with only 1 to 8 percent of patients with croup requiring hospital admission and less than 3 percent of admitted patients requiring intubation. PMID- 21534521 TI - Urticaria: evaluation and treatment. AB - Urticaria involves intensely pruritic, raised wheals, with or without edema of the deeper cutis. It is usually a self-limited, benign reaction, but can be chronic. Rarely, it may represent serious systemic disease or a life-threatening allergic reaction. Urticaria has a lifetime prevalence of approximately 20 percent in the general population. It is caused by immunoglobulin E- and nonimmunoglobulin E-mediated mast cell and basophil release of histamine and other inflammatory mediators. Diagnosis is made clinically. Chronic urticaria is usually idiopathic and requires only a simple laboratory workup unless elements of the history or physical examination suggest specific underlying conditions. Treatment includes avoidance of triggers, although these can be identified in only 10 to 20 percent of patients with chronic urticaria. First-line pharmacotherapy for acute and chronic urticaria is nonsedating second-generation antihistamines (histamine H1 blockers), which can be titrated to larger than standard doses. First-generation antihistamines, histamine H2 blockers, leukotriene receptor antagonists, and brief corticosteroid bursts may be used as adjunctive treatment. More than one-half of patients with chronic urticaria will have resolution or improvement of symptoms within one year. PMID- 21534522 TI - Hives: what you should know. PMID- 21534523 TI - Photo quiz. Polypoid skin nodule in the postpartum period. Pyogenic granuloma. PMID- 21534524 TI - Palliative sedation for a patient with terminal illness. PMID- 21534526 TI - A highly enantio- and diastereoselective molybdenum-catalyzed asymmetric allylic alkylation of cyanoesters. AB - An efficient molybdenum-catalyzed asymmetric allylic alkylation (Mo-AAA) of cyanoester nucleophiles is reported. A number of highly functionalized branched cyanoesters containing a quaternary carbon stereocenter with a vicinal tertiary stereocenter are obtained. This method generates a number of functionalized cyanoesters in excellent yield and chemoselectivity in good to excellent diastereoselectivity and enantioselectivity. PMID- 21534527 TI - Inhibition of Myosin ATPase activity by halogenated pseudilins: a structure activity study. AB - Myosin activity is crucial for many biological functions. Strong links have been established between changes in the activity of specific myosin isoforms and diseases such as cancer, cardiovascular failure, and disorders of sensory organs and the central nervous system. The modulation of specific myosin isoforms therefore holds a strong therapeutic potential. In recent work, we identified members of the marine alkaloid family of pseudilins as potent inhibitors of myosin-dependent processes. Here, we report the crystal structure of the complex between the Dictyostelium myosin 2 motor domain and 2,4-dichloro-6-(3,4,5 tribromo-1H-pyrrole-2-yl)phenol (3). Detailed comparison with previously solved structures of the myosin 2 complex with bound pentabromopseudilin (2a) or pentachloropseudilin (4a) provides insights into the molecular basis of the allosteric communication between the catalytic and the allosteric sites. Moreover, we describe the inhibitory potency for a congeneric series of halogenated pseudilins. Insight into their mode of action is gained by applying a combination of experimental and computational approaches. PMID- 21534528 TI - Evidence for concerted electron proton transfer in charge recombination between FADH- and 306Trp* in Escherichia coli photolyase. AB - Proton-coupled electron-transfer (PCET) is a mechanism of great importance in protein electron transfer and enzyme catalysis, and the involvement of aromatic amino acids in this process is of much interest. The DNA repair enzyme photolyase provides a natural system that allows for the study of PCET using a neutral radical tryptophan (Trp(*)). In Escherichia coli photolyase, photoreduction of the flavin adenine dinucleotide (FAD) cofactor in its neutral radical semiquinone form (FADH(*)) results in the formation of FADH(-) and (306)Trp(*). Charge recombination between these two intermediates requires the uptake of a proton by (306)Trp(*). The rate constant of charge recombination has been measured as a function of temperature in the pH range from 5.5 to 10.0, and the data are analyzed with both classical Marcus and semi-classical Hopfield electron transfer theory. The reorganization energy associated with the charge recombination process shows a pH dependence ranging from 2.3 eV at pH <= 7 and 1.2 eV at pH(D) 10.0. These findings indicate that at least two mechanisms are involved in the charge recombination reaction. Global analysis of the data supports the hypothesis that PCET during charge recombination can follow two different mechanisms with an apparent switch around pH 6.5. At lower pH, concerted electron proton transfer (CEPT) is the favorable mechanism with a reorganization energy of 2.1-2.3 eV. At higher pH, a sequential mechanism becomes dominant with rate limiting electron-transfer followed by proton uptake which has a reorganization energy of 1.0-1.3 eV. The observed 'inverse' deuterium isotope effect at pH < 8 can be explained by a solvent isotope effect that affects the free energy change of the reaction and masks the normal, mass-related kinetic isotope effect that is expected for a CEPT mechanism. To the best of our knowledge, this is the first time that a switch in PCET mechanism has been observed in a protein. PMID- 21534529 TI - Rh-catalyzed polymerization of phenylacetylene: theoretical studies of the reaction mechanism, regioselectivity, and stereoregularity. AB - Poly(phenylacetylene) (PPA) has versatile electrical and optical properties due to its intriguing pi-conjugated backbone, configuration, stereoregularity, and helical conformation. Detailed DFT, ONIOM, and ONIOM-MD studies are presented to understand the mechanisms of Rh-catalyzed polymerization of phenylacetylene and the factors that control its regioselectivity and stereochemistry. The polymerization proceeds via the Rh(I) insertion mechanism (DeltaH(?) ~ 9 kcal/mol), although all the Rh(I), Rh(III), and Rh-carbene types of active species are thermodynamically and kinetically plausible in solution; the Rh(III) insertion and the Rh-carbene metathesis mechanisms both have higher activation enthalpies (~22 and ~25 kcal/mol, respectively). Phenylacetylene prefers a 2,1 inserion, leading to head-to-tail regioselective PPA via a unique pi-conjugative transition state. This pi-conjugative characteristic specifically favors the 2,1 insertion due to the steric repulsion. Kinetic factors play a key role in the stereoregularity. The polymerization adopting a cis-transoidal conformation is the most favorable. The kinetic difference for the insertion originates in the conformational constraints of the parent propagation chain in the transition state. These fundamental guidelines should help advance the development of efficient and structurally tailorable PPA catalysts. PMID- 21534530 TI - Highly diastereoselective chelation-controlled additions to alpha-silyloxy ketones. AB - The polar Felkin-Anh, Cornforth-Evans, and Cram-chelation models predict that the addition of organometallic reagents to silyl-protected alpha-hydroxy ketones proceeds via a nonchelation pathway to give anti-diol addition products. This prediction has held true for the vast majority of additions reported in the literature, and few methods for chelation-controlled additions of organometallic reagents to silyl-protected alpha-hydroxy ketones have been introduced. Herein, we present a general and highly diastereoselective method for the addition of dialkylzincs and (E)-di-, (E)-tri-, and (Z)-disubstituted vinylzinc reagents to alpha-silyloxy ketones using alkyl zinc halide Lewis acids, RZnX, to give chelation-controlled products (dr >=18:1). The compatibility of organozinc reagents with other functional groups makes this method potentially very useful in complex molecule synthesis. PMID- 21534531 TI - Protein-binding molecular switches via host-guest stabilized DNA hairpins. AB - Molecular switches, with target protein-binding activity controlled by prior binding to specific input stimuli, are ubiquitously used in Nature. However, the emulation of such responsive systems, especially in a de novo fashion, remains a significant challenge. Herein, we disclose a strategy that harnesses an intramolecular beta-CD/adamantane host-guest interaction to generate a stabilized DNA hairpin (DeltaT(m) = 17 degrees C) that undergoes an input oligonucleotide (ODN)-selective structural transformation from a stem-loop conformation to a duplex. This ODN-induced conformational switch allows for the transition from an inactive state (wherein the adamantane protein-binding headgroup is encapsulated) to an activated protein-binding complex, with a freely accessible adamantane moiety. Given that hairpin domains can be readily modulated to be responsive to alternative ODN triggering sequences and that encapsulating macrocycles, such as beta-CD, are good hosts for a number of protein-binding small molecules, this strategy may furnish a general method to develop ODN-responsive protein-binders. PMID- 21534532 TI - Cyclization reactions of 3,4-diazaheptatrienyl metal compounds. Pyridines from an anionic analogue of the Fischer indole synthesis: experiment and theory. AB - Unsymmetrical N,N'-bisalkylidene hydrazines 7a,b, 10a-c and 13, which are accessible in good to excellent yields from hydrazones 6, 9, and 12 and commercially available alpha,beta-unsaturated carbonyl compounds, are converted into 3,4-diazaheptatrienyl anions 14a,b, 16a-c, and 18 by treatment with KO-t-Bu as base. These anionic species form pyridines 15a,b, 5,6 dihydrobenzo[h]quinolones 17a-c, and bipyridine 19 in moderate yields. We interpret thermodynamics and kinetics of these reactions by quantum chemical calculations and discuss this multistep anionic rearrangement, based on an electrocyclic ring formation with a Mobius aromatic transition structure 22, the N-N bond fission (25), and the 6-exo-trig cyclization (27) as key steps, considering the results of NICS and NBO-charge calculations. This novel anionic reaction sequence bears an interesting analogy to the mechanism of the (cationic) Fischer indole synthesis. Precursor 10c and product 16c could be characterized by X-ray diffraction. PMID- 21534533 TI - Aerobic oxidative transformation of primary azides to nitriles by ruthenium hydroxide catalyst. AB - In the presence of an easily prepared supported ruthenium hydroxide catalyst, Ru(OH)(x)/Al(2)O(3), various kinds of structurally diverse primary azides including benzylic, allylic, and aliphatic ones could be converted into the corresponding nitriles in moderate to high yields (13 examples, 65-94% yields). The gram-scale (1 g) transformation of benzyl azide efficiently proceeded to give benzonitrile (0.7 g, 90% yield) without any decrease in the performance in comparison with the small-scale (0.5 mmol) transformation. The catalysis was truly heterogeneous, and the retrieved catalyst could be reused for the transformation of benzyl azide without an appreciable loss of its high performance. The present transformation of primary azides to nitriles likely proceeds via sequential reactions of imide formation, followed by dehydrogenation (beta-elimination) to produce the corresponding nitriles. The Ru(OH)(x)/Al(2)O(3) catalyst could be further employed for synthesis of amides in water through the transformation of primary azides (benzylic and aliphatic ones) to nitriles, followed by sequent hydration of the nitriles formed. Additionally, direct one pot synthesis from alkyl halides and TBAN(3) (TBA = tetra-n-butylammonium) could be realized with Ru(OH)(x)/Al(2)O(3), giving the corresponding nitriles in moderate to high yields (10 examples, 64-84% yields). PMID- 21534534 TI - Organometallic ruthenium(II) arene compounds with antiangiogenic activity. AB - The antimetastatic ruthenium(II) compounds [Ru(eta(6)-p-cymene)Cl(2)(PTA)] (PTA = 1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) and [Ru(eta(6)-toluene)Cl(2)(PTA)] (RAPTA-T), as well as their analogues [Ru(eta(6)-p-cymene)Cl(2)(DAPTA)] (DAPTA = (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)) (DAPTA-C) and [Ru(eta(6)-toluene)Cl(2)(DAPTA)] (DAPTA-T), respectively, were tested in in vitro bioassays for endothelial cell function. All compounds showed low toxicity profiles and similar dose-dependent antiproliferative effects in endothelial cells at >=100 MUg/mL (~200 MUM). EC migration, measured 6 h after drug exposure, was also efficiently inhibited (ED(50) of ~300 MUg/mL, ~500 MUM, for all compounds). Since no cytostatic effect was noted, the inhibition of proliferation was considered mainly to consist of antiangiogenic activity. RAPTA-T and DAPTA-C were also tested in vivo in the chicken chorioallantoic membrane (CAM) assay and found to inhibit CAM development. Importantly, effective prevention of revascularization of the CAM after vaso-occlusive photodynamic therapy was observed. The reported ruthenium complexes show promising antimetastatic activity involving inhibition of angiogenesis and therefore are attractive agents for development of anticancer therapies based on combination of chemo- and angiostatic treatments. PMID- 21534535 TI - Spectroscopic determination of acid dissociation constants of N-substituted-6 acylbenzothiazolone derivatives. AB - The acid dissociation constants of twelve novel drug precursor N-substituted-6 acylbenzothiazolone derivatives were determined by using the UV-vis spectroscopic technique. The protonation and deprotonation behaviors of the investigated molecules were researched from the super basic to super acid regions (i.e., 8 mol.L(-1) KOH to 98% H(2)SO(4)) including the pH region. It is observed that all of the molecules are protonated in the super acidic region. The calculated relative stability values of possible tautomer structures indicate that the keto form of investigated molecules is favored over the enol form. It was predicted that protonation occurs at the amide (oxo) group found in the keto form. PMID- 21534536 TI - Plasmonic nanohybrid with ultrasmall Ag nanoparticles and fluorescent dyes. AB - We investigate a hybrid nanocomposite combining fluorescent dyes and ultrasmall (<3 nm) silver nanocrystals in a block copolymer micelle. Although the metal nanoparticles are significantly smaller than the electromagnetic skin depth, we observe a modification of the exciton lifetime and the nonradiative energy transfer among the dyes. This behavior is absent in a control experiment with dyes whose energetic levels are far from the plasmonic resonance, establishing the plasmonic nature of the interaction. PMID- 21534537 TI - DNA-directed self-assembly of graphene oxide with applications to ultrasensitive oligonucleotide assay. AB - Controlled graphene or its derivatives' assembly is of growing interest in many areas. However, achieving control over their assembly into precise and predictable architectures has been challenging and is still a bottleneck to their utilization. Herein, we report for the first time the use of DNA hybridization for the controllable assembly of a graphene nanosheet. Moreover, with the help of dynamic light scattering technique, we extended the above studies by exploiting the DNA-graphene dispersed sheets as highly ultrasensitive detection of oligonuleotides for the fabrication of a novel biosensing strategy, which shows high sensitivity and excellent selectivity. This work will show a new general route to graphene-based lamellar composite materials and would bring about advances in the research of graphene-based biofunctional materials for specific applications in biodiagnostics, nanoelectronics, and bionanotechnology. PMID- 21534538 TI - Investigation of mixed oxidation state cyanide-bridged Re(V)oxo (acac(2)en/pn) and Re(I)(bipy)(CO)3 complexes. AB - A series of cyanide-bridged complexes that combine a low-valent photoacceptor rhenium(I) metal center with an electroactive midvalent rhenium(V) complex were prepared. The synthesis involved the preparation of novel asymmetric rhenium(V) oxo compounds, cis-Re(V)O(CN)(acac(2)en) (1) and cis-Re(V)O(CN)(acac(2)pn) (2), formed by reacting trans-[Re(V)O(OH(2))(acac(2)en)]Cl or trans Re(V)O(acac(2)pn)Cl with [NBu(4)][CN]. The MU-bridged cyanide mixed-oxidation Re(V)-Re(I) complexes were prepared by incubating the asymmetric complexes, 1 or 2, with fac-[Re(I)(bipy)(CO)(3)][OTf] to yield cis-[Re(V)O(acac(2)en)(MU-CN 1kappaC:2kappaN)-fac-Re(I)(bipy)(CO)(3)][PF(6)] (3) and [cis-Re(V)O(acac(2)pn)(MU CN-1kappaC:2kappaN)-fac-Re(I)(bipy)(CO)(3)][PF(6)] (4), respectively. PMID- 21534539 TI - Structure and cytotoxicity of diterpenoids from Isodon adenolomus. AB - Twelve new diterpenoids, isoadenolins A-L (1-12), and 24 known ones were isolated from the aerial parts of Isodon adenolomus. Their structures were identified using spectroscopic data, and the absolute configurations of 1 and 14 were determined by single-crystal X-ray diffraction. Selected compounds were evaluated for their in vitro cytotoxicity against human tumor HL-60, SMMC-7721, A-549, MCF 7, and SW-480 cell lines. Compounds 9, 13-16, and 21 showed significant inhibitory effects on all five cells, with IC50 values in the range 0.7-9.7 MUM. PMID- 21534540 TI - Tigliane-type diterpenoid glycosides from Euphorbia fischeriana. AB - Investigation of whole plants of Euphorbia fischeriana afforded three new tigliane-diterpenoid glycosides, fischerosides A-C (1-3), together with 11 known diterpenoids. Fischerosides A-C (1-3) are the first tigliane-type diterpenoid glucosides. Their structures were determined by a combination of 1D and 2D NMR, MS, and acid hydrolysis. Inhibitory activity against HIV-1 was assessed for compounds 1-5. The new compound 3 showed an EC50 value of 0.02 MUM and a therapeutic index (TI) of 17.50, while prostratin (4) and 12-deoxyphorbol-13,20 diacetate (5) showed significantly greater anti-HIV-1 activity. PMID- 21534542 TI - Association of Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS) with age of puberty among children living near a chemical plant. AB - Animal studies suggest that perfluorocarbons (PFCs) may alter sexual maturation. Relationships of human PFC exposure with puberty are not clear. We conducted a cross-sectional study to investigate whether perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) were associated with indicators of sexual maturation in a 2005-2006 survey of residents with PFOA water contamination from the Mid-Ohio Valley. Participants were 3076 boys and 2931 girls aged 8-18 years. They were classified as having reached puberty based on either hormone levels (total >50 ng/dL and free >5 pg/mL testosterone in boys and estradiol >20 pg/mL in girls) or onset of menarche. We estimated the odds of having reached puberty classified by these criteria and the fitted median age of reaching puberty in relation to serum PFOA and PFOS concentrations measured when puberty status was assigned. For boys, there was a relationship of reduced odds of reached puberty (raised testosterone) with increasing PFOS (delay of 190 days between the highest and lowest quartile). For girls, higher concentrations of PFOA or PFOS were associated with reduced odds of postmenarche (130 and 138 days of delay, respectively). In conclusion, our study showed a later age of puberty in this population correlated with PFC concentrations. PMID- 21534541 TI - Antineoplastic agents. 592. Highly effective cancer cell growth inhibitory structural modifications of dolastatin 10. AB - The dolastatin series of unique peptides, originally discovered as constituents of the sea hare Dolabella auricularia, is of increasing importance in providing biological leads, especially to new and useful anticancer drugs. Dolastatin 10 and three analogues, minor structural modifications designated auristatins, are currently in human cancer clinical trials. The present study was undertaken to explore delivery to the cancer sites by way of phosphate or quinoline modifications. The initial objectives, auristatin TP as sodium phosphate 3b (GI50 10(-2)-10(-4) MUg/mL), auristatin 2-AQ (4, GI50 10(-2)-10(-3) MUg/mL), and auristatin 6-AQ (5, GI50 10(-4) MUg/mL), exhibited superior cancer cell growth inhibitory properties. PMID- 21534544 TI - Identification of mobile species in cationic polymer lubricant layer on silicon oxide from AFM and XPS analyses. AB - The nanoscale spreading of a cationic polymer lubricant (CPL) film consisting of polydimethylsiloxane with quaternary ammonium salt side chains on a SiO(2) surface was studied with the disjoining pressure measurements using atomic force microscopy. CPL shows a monotonic decrease in disjoining pressure as the film thickness increases from 1.3 to 4.5 nm, which suggests stable spreading in this thickness range. Comparing the spreading rates calculated from disjoining pressure and the viscosity of CLP to the self-healing time after tribo-contacts revealed that the ionic form may not be the main mobile species. The X-ray photoelectron spectroscopy analysis found that the CPL film on SiO(2) has about 30% of the quaternary ammonium salts (cationic groups) reduced to tertiary amines (neutral groups). The reduced CPL polymer has much lower viscosity than the original CPL polymer and yields a spreading rate consistent with that measured at the macroscale. Thus, the mobile component in the CPL/SiO(2) film responsible for self-healing is concluded to be the reduced tertiary amine components of CPL. PMID- 21534543 TI - Syntheses of alpha-pyrones using gold-catalyzed coupling reactions. AB - Sequential alkyne activation of terminal alkynes and propiolic acids by gold(I) catalysts yields compounds having alpha-pyrone skeletons. Novel cascade reactions involving propiolic acids are reported that give rise to alpha-pyrones with different substitution patterns. PMID- 21534545 TI - Structural profiling and quantification of sphingomyelin in human breast milk by HPLC-MS/MS. AB - The sphingolipid composition of food as well as of physiological samples has received considerable interest due to their positive biological activities. This study quantified the total amount of sphingomyelin (SM) in 20 human breast milk samples from healthy volunteers and determined the structures of SM by detailed mass spectrometric studies in combination with enzymatic cleavage. The quantification of SM was performed by hydrophilic interaction liquid chromatography coupled to electrospray ionization-tandem mass spectrometry (HILIC HPLC-ESI-MS/MS) measuring the characteristic fragment ion of the phosphorylcholine group at m/z 184.2 and by using hexanoylsphingomyelin (C6-SM) and heptadecanoylsphingomyelin (C17-SM) as internal standards. The structures of SM species were identified after enzymatic cleavage with alkaline sphingomyelinase (SMase) to the corresponding ceramides. Structure elucidation of the sphingoid base and fatty acid backbone was performed by reversed-phase HPLC ESI-MS/MS. The method includes the sphingoid bases dihydrosphingosine (d18:0), sphingosine (d18:1(Delta4)), 4,8-sphingadienine (d18:2(Delta4,8)), 4 hydroxysphinganine (phytosphingosine (t18:0)), and 4-hydroxy-8-sphingenine (t18:1(Delta8)) and fatty acids with even-numbered carbon atoms (C12-C26) as well as their (poly)unsaturated and monohydroxylated analogues. The total amount of SM in human breast milk varied from 3.87 to 9.07 mg/100 g fresh weight. Sphingosine (d18:1) was the predominant sphingoid base, with 83.6 +/- 3.5% in human breast milk, followed by 4,8-sphingadienine (d18:2) (7.2 +/- 1.9%) and 4 hydroxysphinganine (t18:0) (5.7 +/- 0.7%). The main SM species contained sphingosine and palmitic acid (14.9 +/- 2.2%), stearic acid (12.7 +/- 1.5%), docosanoic acid (16.2 +/- 3.6%), and tetracosenoic acid (15.0 +/- 3.1%). Interestingly, the fatty acid composition of SM species in this study differs from the total fatty acids in human breast milk, and the fatty acids are not consistently distributed among the different sphingoid bases. PMID- 21534546 TI - Structural photodynamics of camptothecin, an anticancer drug in aqueous solutions. AB - Steady-state and time-resolved picosecond emission studies were carried out to study the role of the proton concentration in the acid-base properties of the anticancer drug camptothecin (CPT) in its ground and electronically first excited states. The results show that, under acidic conditions, the excited-state proton transfer (ESPT) reaction is irreversible, in contrast to previous literature data. We found that the prototropic species are equilibrated at the excited state (pK(a)* = 1.85) only in a restricted range of pH (1.5 < pH < 3), whereas only one species, either the neutral form (tau(N) = 3.76 ns) or the protonated form (tau(C) = 2.83 ns), can be detected at pH > 3 and pH < 1.5, respectively. The proton motion from the acidic solution to the neutral form in the pH 1-2 domain is diffusion-controlled. Within the range of pH 1-2, the reaction rate constant for the formation (k(d)) of the encounter complex between the proton and the neutral form ranges from 1.17 * 10(10) to 7.33 * 10(10) M(-1) s(-1), respectively. Under more acidic conditions (pH 0.9-0.95), the protonation of CPT does not depend on the diffusive step, because of the large amount of protons. The direct proton-transfer rate constant (k(DPT)*) increases with the proton concentration (time constants change from 24 ps to ~1 ns at pH 0.9 and 2, respectively). The number of protons involved in the proton transfer changes from approximately one, for the diffusive regime, to approximately four, for the static regime. We found good agreement between the Birks model for equilibrated flourophores and the Debye-Smoluchowski equation (DSE) to accurately explain the ESPT reaction of CPT with acidic water in the reversible range. The proton motion at pH 2 (equilibrium range) exhibits diffusion-controlled behavior and can be explained using the Smoluchowski model. Our results show that the interaction of CPT with acidic water depends on the concentration of the acid, which changes the nature of both the structure and dynamics. PMID- 21534547 TI - Highly potent activity of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene 1,2-diol in animal models of Parkinson's disease. AB - (1R,2R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 possesses potent antiparkinsonian activity in both MPTP and haloperidol animal models. The use of compound 1 resulted in nearly full recovery of the locomotor and exploratory activities and was as effective as the comparator agent (levodopa). All eight stereoisomers of compound 1 have been synthesized and the influence of the absolute configuration on the antiparkinsonian activity of compound 1 was shown. PMID- 21534548 TI - One-step inversion process to a Janus emulsion with two mutually insoluble oils. AB - High internal phase ratio (HIPR) aqueous Janus emulsions of two immiscible oils, silicone oil (SO) and a vegetable oil (VO), were prepared using a vibration mixer. The simple HIPR Janus emulsions, (VO + SO)/W, were found at weight fractions of the aqueous phase in excess of 0.3, while at a corresponding fraction of 0.1, a triple emulsion was obtained with the Janus emulsion forming a drop inside the vegetable oil to give a double Janus emulsion, (VO + SO)/W/VO, which in turn formed drops in the silicone oil resulting in a triple Janus emulsion (VO + SO)/W/VO/SO. Increasing the aqueous-phase fraction from 0.1 to 0.3 consequently meant an inversion, of which one intermediate stage was observed: a more complex configuration, e.g., one in which large SO drops with highly distorted VO drops attached were dispersed in a regular aqueous emulsion with spherical Janus (VO + SO) drops. A preliminary investigation was made into the destabilization process of the triple emulsions. PMID- 21534549 TI - Detection of 2,4-dinitrotoluene (DNT) as a model system for nitroaromatic compounds via molecularly imprinted short-alkyl-chain SAMs. AB - A 2-D molecularly imprinted monolayer (2-D MIM) approach was used to prepare a simple and robust sensor for nitroaromatic compounds with 2,4-dinitrotoluene (DNT) as the model compound, which is a precursor and analog for explosive 2,4,6 trinitrotoluene (TNT). In contrast to studies utilizing long-chain hexadecylmercaptan self-assembled monolayers (SAM)s for sensing, a shorter-chain alkylthiol (i.e., butanethiol SAM) was utilized for DNT detection. The role of the chain length of the coadsorbed alkylthiol was emphasized with a matched template during solution adsorption. Semiempirical PM3 quantum calculations were used to determine the molecular conformation and complexation of the adsorbates. A switching mechanism was invoked on the basis of the ability of the template analyte to alter the packing arrangement of the alkylthiol SAMs near defect sites as influenced by the DNT-ethanol solvent complex. A 2-D MIM was formed on the Au surface electrode of a quartz crystal microbalance (QCM), which was then used to sense various concentrations of the analyte. Interestingly, the 2-D MIM QCM also enabled the selective detection of DNT even in a mixed solution of competing molecules, demonstrating the selectivity figure of merit. Likewise, electrochemical impedance spectroscopy (EIS) data at different concentrations of DNT confirmed the 2-D MIM effectiveness for sensing based on the interfacial conformation and electron-transport properties of the imprinted butanethiol SAM. PMID- 21534550 TI - Tuning of gate opening of an elastic layered structure MOF in CO2 sorption with a trace of alcohol molecules. AB - It is important to tune the sorption behavior of metal-organic framework (MOF) materials. Ethanol treatment on the hydrated form of [Cu(bpy)(2)(BF(4))(2)], which is a representative flexible MOF showing the fascinating gate phenomenon on CO(2) sorption, induces an easier dehydration and a significant decrease in the CO(2) gate pressure. The results of IR, X-ray diffraction (XRD), and X-ray absorption fine structure (XAFS) measurements indicated that water molecules in the lattice of the hydrated form can be removed even at room temperature after the ethanol treatment and the basic 2D layered structure remains with a slight interlayer expansion. The results of thermogravimetric (TG) and gas chromatograph/mass spectrometry (GC/MS) analyses and of CO(2) sorptions indicated that the change of the gate phenomenon was caused by a trace of residual ethanol molecules included in the structure. Similar phenomena were observed on alcohols with different polarity and molecular size. PMID- 21534551 TI - Enantioselective iridium-catalyzed allylic substitutions with hydroxamic acid derivatives as N-nucleophiles. AB - Enantioselective Ir-catalyzed allylic aminations with hydroxamic acid derivatives are described. Catalysts were prepared in situ from [Ir(cod)Cl](2) or [Ir(dbcot)Cl](2), a phosphoramidite and base. In addition, pure (pi-allyl)Ir complexes containing cod or dbcot as auxiliary ligands were used. Very high degrees of regio- and enantioselectivity were achieved. The reaction products were transformed into piperidine derivatives suited as precursors for aza-sugars. PMID- 21534552 TI - Metal-free catalytic hydrogenation of polar substrates by frustrated Lewis pairs. AB - In 2006, our group reported the first metal-free systems that reversibly activate hydrogen. This finding was extended to the discovery of "frustrated Lewis pair" (FLP) catalysts for hydrogenation. It is this catalysis that is the focal point of this article. The development and applications of such FLP hydrogenation catalysts are reviewed, and some previously unpublished data are reported. The scope of the substrates is expanded. Optimal conditions and functional group tolerance are considered and applied to targets of potential commercial significance. Recent developments in asymmetric FLP hydrogenations are also reviewed. The future of FLP hydrogenation catalysts is considered. PMID- 21534553 TI - Gold nanoparticle-decorated keggin ions/TiO2 photococatalyst for improved solar light photocatalysis. AB - We demonstrate a facile localized reduction approach to synthesizing a Au nanoparticle-decorated Keggin ion/TiO(2) photococatalyst for improved solar light photocatalysis application. This has been achieved by exploiting the ability of TiO(2)-bound Keggin ions to act as a UV-switchable, highly localized reducing agent. Notably, the approach proposed here does not lead to contamination of the resultant cocatalyst with free metal nanoparticles during aqueous solution-based synthesis. The study shows that for Keggin ions (phosphotungstic acid, PTA), being photoactive molecules, the presence of both Au nanoparticles and PTA on the TiO(2) surface in a cocatalytic system can have a dramatic effect on increasing the photocatalytic performance of the composite system, as opposed to a TiO(2) surface directly decorated with metal nanoparticles without a sandwiched PTA layer. The remarkable increase in the photocatalytic performance of these materials toward the degradation of a model organic Congo red dye correlates to an increase of 2.7-fold over that of anatase TiO(2) after adding Au to it and 4.3 fold after introducing PTA along with Au to it. The generalized localized reduction approach to preparing TiO(2)-PTA-Au cocatalysts reported here can be further extended to other similar systems, wherein a range of metal nanoparticles in the presence of different Keggin ions can be utilized. The composites reported here may have wide potential implications toward the degradation of organic species and solar cell applications. PMID- 21534554 TI - Vibrational origin of the thermal stability in the high-performance piezoelectric material GaAsO4. AB - Theoretical calculations and experiments show the absence of libration modes of the tetrahedra in GaAsO(4), the most alpha-quartz-type distorted material. In consequence, the degree of dynamic disorder at high temperature is very low, making GaAsO(4) of high interest for high-temperature applications. This paper shows the importance of the theoretical calculations of vibration in oxide materials. In this way, it could be possible to extend this result to other materials and predict the thermal stability of the materials and their potential applications at high temperature. PMID- 21534555 TI - K3B6O10Cl: a new structure analogous to perovskite with a large second harmonic generation response and deep UV absorption edge. AB - Introduction of the Cl(-) anion in the borate systems generates a new perovskite like phase, K(3)B(6)O(10)Cl, which exhibits a large second harmonic response, about four times that of KH(2)PO(4) (KDP), and is transparent from the deep UV (180 nm) to middle-IR region. K(3)B(6)O(10)Cl crystallizes in the noncentrosymmetric and rhombohedral space group R3m. The structure consists of the A-site hexaborate [B(6)O(10)] groups and the BX(3) Cl-centered octahedral [ClK(6)] groups linked together through vertices to form the perovskite framework represented by ABX(3). PMID- 21534556 TI - Structural basis for the beta-adrenergic receptor subtype selectivity of the representative agonists and antagonists. AB - The beta(3)-adrenegic receptor (beta(3)-AR) selectivity over beta(1)- and beta(2) ARs has been the most important aspect for successful therapeutic agents for obesity and type-II diabetes, as the concomitant activation of beta(1)- and beta(2)-ARs would lead to undesirable side effects, such as increased heart rate. In order to explore the structural basis for the beta-AR subtype selectivity of agonists and anatagonists, a three-dimensional structure of until date unresolved beta(3)-AR has been modeled, compared with the resolved X-ray structures of beta(1)- and beta(2)-ARs, and used to study its stereoselective binding with until-date known diverse classes of representative agonists and antagonist. The obtained binding structures and calculated prime molecular mechanics-generalized Born surface area (MM-GBSA) binding free energies consistently reveal that while the subtype selectivity is strongly governed by the residues present in the extracellular ends of TM3, TM5, TM6, TM7 helices and of the ECL2 domain, the binding affinity is governed by the conserved residues present in the deep pocket limiting the degree of conformational and rotational freedoms to the bound ligand. The study demonstrates that the key structural requirements for the beta(3)-selectivity are: (i) a negatively ionizable group (NIG) for direct interaction with beta(3)-specific residue R315(6.58), (ii) a linker (9-10 A length) between the protonated amine and NIG, and (iii) a substituted aryl ring directly attached to the beta-hydroxyl carbon. The new computational insights acquired in this study are expected to be valuable in structure-based rational design of high-affinity agonists and antagonists with pronounced beta(3) selectivity for successful therapeutic agents for type-II diabetes and obesity. PMID- 21534557 TI - Solvent-controlled intramolecular electron transfer in ionic liquids. AB - The rates of excited-state intramolecular electron transfer in 9-(4-biphenyl)-10 methylacridinium (BPAc(+)), crystal violet lactone (CVL), and bianthryl have been measured in a variety of ionic liquids using time-correlated single-photon counting. All three of these reactions had previously been studied in conventional dipolar solvents and their reaction rates shown to be controlled by solvation dynamics. The main focus of this work is to ask whether the same relationships between reaction and solvation times already established in dipolar solvents also apply in ionic liquids. In BPAc(+), where reaction conforms to a simple two-state kinetic scheme and reaction rates are easily measured, the result is a clear "yes". In the case of bianthryl, whose spectra reflect the more complex kinetics of a barrierless process, the answer is also yes. In contrast to other recent studies of bianthryl, the present results demonstrate that the same equality between (integral) reaction times and solvation times observed in conventional solvents also applies in ionic liquids. Finally, the case of CVL is less clear due to the greater uncertainty associated with the data afforded by this weak fluorophore, combined with a lack of data in conventional solvents having large solvation times. But the CVL reaction can also be reasonably interpreted as exhibiting a common behavior in dipolar and ionic solvents. PMID- 21534558 TI - Secondary organic aerosol coating of synthetic metal-oxide nanoparticles. AB - Secondary organic aerosol (SOA) from the alpha-pinene + ozone reaction readily coats TiO(2) and CeO(2) metal-oxide nanoparticles in smog-chamber experiments under atmospherically relevant conditions. Otherwise identical experiments compared bare nanoparticles and nanoparticles coated with poly(acrylic acid) (PAA). The PAA-coated particles result in significantly higher new-particle formation rates, suggesting that the SOA vapors coat bare metal oxide more readily than the PAA. After particles begin to grow via SOA coating, however, all particles, independent of size or the presence of a metal-oxide core, grow with a rate proportional to their surface area, modified to account for gas-phase diffusion in the transition regime between the kinetic and bulk-flow regimes. This suggests that SOA condensational growth may be modeled based on the size distribution of the condensational sink in the atmosphere. PMID- 21534559 TI - N-linked peptidoresorc[4]arene-based receptors as noncompetitive inhibitors for alpha-chymotrypsin. AB - This paper deals with the design, synthesis, and evaluation of a new series of receptors for protein surface recognition. The design of these agents is based around the attachment of four constrained dipeptide chains onto a central resorc[4]arene scaffold. By varying the sequence, nature, and stereochemistry of the chains we prepared anionically functionalized N-linked peptidoresorc[4]arenes 12, 13, and 17 by Pd/C-catalyzed hydrogenation of the corresponding benzyl esters 10, 11, and 16. From this family of receptors we have identified noncompetitive inhibitors of alpha-chymotrypsin (ChT), which function by binding to the surface of the enzyme in the neighborhood of the active site cleft (K(i) values ranging from 12.4 +/- 5.1 MUM for free carboxylic acid (+)-12b to 0.76 +/- 0.14 MUM for benzyl ester (-)-16a). For anionically functionalized receptors 12, 13, and 17 the ChT inhibition is based essentially on electrostatic interaction, and the bound enzyme can be released from the resorcarene surface by increasing the ionic strength, with its activity almost completely restored. For receptors with terminal benzyl ester groups (10 and 16) a hydrophobic network can be suggested. PMID- 21534560 TI - Bioinspired crystallization of CaCO3 coatings on electrospun cellulose acetate fiber scaffolds and corresponding CaCO3 microtube networks. AB - This article describes the mineralization behavior of CaCO(3) crystals on electrospun cellulose acetate (CA) fibers by using poly(acrylic acid) (PAA) as a crystal growth modifier and further templating synthesis of CaCO(3) microtubes. Calcite film coatings composed of nanoneedles can form on the surfaces of CA fibers while maintaining the fibrous and macroporous structures if the concentration of PAA is in a suitable range. In the presence of a suitable concentration of PAA, the acidic PAA molecules will first adsorb onto the surface of CA fibers by the interaction between the OH moieties of CA and the carboxylic groups of PAA, and then the redundant carboxylic groups of PAA can ionically bind Ca(2+) ions on the surfaces of CA fibers, resulting in the local supersaturation of Ca(2+) ions on and near the fiber surface, which can induce the nucleation of CaCO(3) on the CA fibers instead of in bulk solution. Calcite microtube networks on the macroscale can be prepared by the removal of CA fibers after the CA@CaCO(3) composite is treated with acetone. When the CA fiber scaffold is immersed in CaCl(2) solution with an extended incubation time, the first deposited calcite coatings can act as secondary substrate, leading to the formation of smaller calcite mesocrystal fibers. The present work proves that inorganic crystal growth can occur even at an organic interface without the need for commensurability between the lattices of the organic and inorganic counterparts. PMID- 21534561 TI - Comparative evaluation of in silico systems for ames test mutagenicity prediction: scope and limitations. AB - The predictive power of four commonly used in silico tools for mutagenicity prediction (DEREK, Toxtree, MC4PC, and Leadscope MA) was evaluated in a comparative manner using a large, high-quality data set, comprising both public and proprietary data (F. Hoffmann-La Roche) from 9,681 compounds tested in the Ames assay. Satisfactory performance statistics were observed on public data (accuracy, 66.4-75.4%; sensitivity, 65.2-85.2%; specificity, 53.1-82.9%), whereas a significant deterioration of sensitivity was observed in the Roche data (accuracy, 73.1-85.5%; sensitivity, 17.4-43.4%; specificity, 77.5-93.9%). As a general tendency, expert systems showed higher sensitivity and lower specificity when compared to QSAR-based tools, which displayed the opposite behavior. Possible reasons for the performance differences between the public and Roche data, relating to the experimentally inactive to active compound ratio and the different coverage of chemical space, are thoroughly discussed. Examples of peculiar chemical classes enriched in false negative or false positive predictions are given, and the results of the combined use of the prediction systems are described. PMID- 21534562 TI - Free energy simulations of a GTPase: GTP and GDP binding to archaeal initiation factor 2. AB - Archaeal initiation factor 2 (aIF2) is a protein involved in the initiation of protein biosynthesis. In its GTP-bound, "ON" conformation, aIF2 binds an initiator tRNA and carries it to the ribosome. In its GDP-bound, "OFF" conformation, it dissociates from tRNA. To understand the specific binding of GTP and GDP and its dependence on the ON or OFF conformational state of aIF2, molecular dynamics free energy simulations (MDFE) are a tool of choice. However, the validity of the computed free energies depends on the simulation model, including the force field and the boundary conditions, and on the extent of conformational sampling in the simulations. aIF2 and other GTPases present specific difficulties; in particular, the nucleotide ligand coordinates a divalent Mg(2+) ion, which can polarize the electronic distribution of its environment. Thus, a force field with an explicit treatment of electronic polarizability could be necessary, rather than a simpler, fixed charge force field. Here, we begin by comparing a fixed charge force field to quantum chemical calculations and experiment for Mg(2+):phosphate binding in solution, with the force field giving large errors. Next, we consider GTP and GDP bound to aIF2 and we compare two fixed charge force fields to the recent, polarizable, AMOEBA force field, extended here in a simple, approximate manner to include GTP. We focus on a quantity that approximates the free energy to change GTP into GDP. Despite the errors seen for Mg(2+):phosphate binding in solution, we observe a substantial cancellation of errors when we compare the free energy change in the protein to that in solution, or when we compare the protein ON and OFF states. Finally, we have used the fixed charge force field to perform MDFE simulations and alchemically transform GTP into GDP in the protein and in solution. With a total of about 200 ns of molecular dynamics, we obtain good convergence and a reasonable statistical uncertainty, comparable to the force field uncertainty, and somewhat lower than the predicted GTP/GDP binding free energy differences. The sign and magnitudes of the differences can thus be interpreted at a semiquantitative level, and are found to be consistent with the experimental binding preferences of ON- and OFF-aIF2. PMID- 21534563 TI - Long-lived, charge-shift states in heterometallic, porphyrin-based dendrimers formed via click chemistry. AB - A series of multiporphyrin clusters has been synthesized and characterized in which there exists a logical gradient for either energy or electron transfer between the porphyrins. A central free-base porphyrin (FbP), for example, is equipped with peripheral zinc(II) porphyrins (ZnP) which act as ancillary light harvesters and transfer excitation energy to the FbP under visible light illumination. Additional energy-transfer steps occur at the triplet level, and the series is expanded by including magnesium(II) porphyrins and/or tin(IV) porphyrins as chromophores. Light-induced electron transfer is made possible by incorporating a gold(III) porphyrin (AuP(+)) into the array. Although interesting by themselves, these clusters serve as control compounds by which to understand the photophysical processes occurring within a three-stage dendrimer comprising an AuP(+) core, a second layer formed from four FbP units, and an outer layer containing 12 ZnP residues. Here, illumination into a peripheral ZnP leads to highly efficient electronic energy transfer to FbP, followed by charge transfer to the central AuP(+). Charge recombination within the resultant charge-shift state is intercepted by secondary hole transfer to the ZnP, which occurs with a quantum yield of around 20%. The final charge-shift state survives for some microseconds in fluid solution at room temperature. PMID- 21534564 TI - An aerobic [2 + 2 + 2] cyclization via chloropalladation: from 1,6-diynes and acrylates to substituted aromatic carbocycles. AB - A Pd-catalyzed aerobic [2 + 2 + 2] cyclization of 1,6-diynes and acrylates proceeding through a chloropalladation process has been developed. Polysubstituted five-membered aromatic carbocycles/heterocycles were obtained in good to excellent yields. The results of the mechanistic study are consistent with the proposed reaction mechanism. PMID- 21534565 TI - Influence of flexible spacers on liquid-crystalline self-assembly of T-shaped bolaamphiphiles. AB - T-shaped bolaamphiphiles composed of a biphenyl rigid core, a semiperfluorinated lateral chain, two polar 1,2-diol groups in the terminal positions and flexible alkyl spacers connecting the polar groups with the biphenyl core have been synthesized and investigated by polarizing microscopy, DSC and X-ray scattering. The influence of spacer length and position of the spacer on the self-assembly in liquid-crystalline phases was studied. A series of four different columnar phases (Col(hex)/p6mm, Col(rec)/p2gg, Col(squ)/p4gm and Col(squ)/p4mm), representing liquid-crystalline honeycomb structures composed of cylinders having hexagonal, pentagonal, and square cross section, were found on increasing the spacer length. It is also shown that introduction of aliphatic spacers in the backbone of the T shaped bolaamphiphiles replaces the Col(rec)/c2mm phase made up of rhombic cylinders with the Col(squ)/p4mm phase composed of square cylinders. It also causes the 2d lattice of pentagonal cylinders to increase the symmetry from Col(rec)/p2gg to Col(squ)/p4gm. A temperature-dependent second-order phase transition between these two pentagonal cylinder structures was observed for the first time. Beside these effects on cylinder shape and phase symmetry the flexible spacer units also lead to reduced phase transition temperatures and allow adjustment of cylinder side length to envelop a wider range of side-chain sizes. Electron density maps suggest that this may involve sacrificing some of the hydrogen bonds. PMID- 21534567 TI - Enantioselective allylation of alpha,beta-unsaturated aldehydes with allyltrichlorosilane catalyzed by METHOX. AB - alpha,beta-Unsaturated aldehydes 6a-j undergo an enantioselective allylation with allylic trichlorosilanes 2a,b in the presence of METHOX (4) as a Lewis basic catalyst (<=10 mol %) to produce the homoallylic alcohols 7a-l at good to high enantioselectivity (83-96% ee). This study shows that the reactivity scope of METHOX can be extended from aromatic to nonaromatic aldehydes. PMID- 21534566 TI - Macromolecular crowding fails to fold a globular protein in cells. AB - Proteins perform their functions in cells where macromolecular solutes reach concentrations of >300 g/L and occupy >30% of the volume. The volume excluded by these macromolecules stabilizes globular proteins because the native state occupies less space than the denatured state. Theory predicts that crowding can increase the ratio of folded to unfolded protein by a factor of 100, amounting to 3 kcal/mol of stabilization at room temperature. We tested the idea that volume exclusion dominates the crowding effect in cells using a variant of protein L, a 7 kDa globular protein with seven lysine residues replaced by glutamic acids; 84% of the variant molecules populate the denatured state in dilute buffer at room temperature, compared with 0.1% for the wild-type protein. We then used in-cell NMR spectroscopy to show that the cytoplasm of Escherichia coli does not overcome even this modest (~1 kcal/mol) free-energy deficit. The data are consistent with the idea that nonspecific interactions between cytoplasmic components can overcome the excluded-volume effect. Evidence for these interactions is provided by the observations that adding simple salts folds the variant in dilute solution but increasing the salt concentration inside E. coli does not fold the protein. Our data are consistent with the results of other studies of protein stability in cells and suggest that stabilizing excluded-volume effects, which must be present under crowded conditions, can be ameliorated by nonspecific interactions between cytoplasmic components. PMID- 21534568 TI - Identification of DypB from Rhodococcus jostii RHA1 as a lignin peroxidase. AB - Rhodococcus jostii RHA1, a polychlorinated biphenyl-degrading soil bacterium whose genome has been sequenced, shows lignin degrading activity in two recently developed spectrophotometric assays. Bioinformatic analysis reveals two unannotated peroxidase genes present in the genome of R. jostii RHA1 with sequence similarity to open reading frames in other lignin-degrading microbes. They are members of the Dyp peroxidase family and were annotated as DypA and DypB, on the basis of bioinformatic analysis. Assay of gene deletion mutants using a colorimetric lignin degradation assay reveals that a DeltadypB mutant shows greatly reduced lignin degradation activity, consistent with a role in lignin breakdown. Recombinant DypB protein shows activity in the colorimetric assay and shows Michaelis-Menten kinetic behavior using Kraft lignin as a substrate. DypB is activated by Mn(2+) by 5-23-fold using a range of assay substrates, and breakdown of wheat straw lignocellulose by recombinant DypB is observed over 24-48 h in the presence of 1 mM MnCl(2). Incubation of recombinant DypB with a beta-aryl ether lignin model compound shows time-dependent turnover, giving vanillin as a product, indicating that C(alpha)-C(beta) bond cleavage has taken place. This reaction is inhibited by addition of diaphorase, consistent with a radical mechanism for C-C bond cleavage. Stopped-flow kinetic analysis of the DypB-catalyzed reaction shows reaction between the intermediate compound I (397 nm) and either Mn(II) (k(obs) = 2.35 s(-1)) or the beta-aryl ether (k(obs) = 3.10 s(-1)), in the latter case also showing a transient at 417 nm, consistent with a compound II intermediate. These results indicate that DypB has a significant role in lignin degradation in R. jostii RHA1, is able to oxidize both polymeric lignin and a lignin model compound, and appears to have both Mn(II) and lignin oxidation sites. This is the first detailed characterization of a recombinant bacterial lignin peroxidase. PMID- 21534569 TI - Wave function engineering for ultrafast charge separation and slow charge recombination in type II core/shell quantum dots. AB - The size dependence of optical and electronic properties of semiconductor quantum dots (QDs) have been extensively studied in various applications ranging from solar energy conversion to biological imaging. Core/shell QDs allow further tuning of these properties by controlling the spatial distributions of the conduction-band electron and valence-band hole wave functions through the choice of the core/shell materials and their size/thickness. It is possible to engineer type II core/shell QDs, such as CdTe/CdSe, in which the lowest energy conduction band electron is largely localized in the shell while the lowest energy valence band hole is localized in the core. This spatial distribution enables ultrafast electron transfer to the surface-adsorbed electron acceptors due to enhanced electron density on the shell materials, while simultaneously retarding the charge recombination process because the shell acts as a tunneling barrier for the core localized hole. Using ultrafast transient absorption spectroscopy, we show that in CdTe/CdSe-anthraquinone (AQ) complexes, after the initial ultrafast (~770 fs) intra-QD electron transfer from the CdTe core to the CdSe shell, the shell-localized electron is transferred to the adsorbed AQ with a half-life of 2.7 ps. The subsequent charge recombination from the reduced acceptor, AQ(-), to the hole in the CdTe core has a half-life of 92 ns. Compared to CdSe-AQ complexes, the type II band alignment in CdTe/CdSe QDs maintains similar ultrafast charge separation while retarding the charge recombination by 100-fold. This unique ultrafast charge separation and slow recombination property, coupled with longer single and multiple exciton lifetimes in type II QDs, suggests that they are ideal light-harvesting materials for solar energy conversion. PMID- 21534570 TI - Control of self-assembly of a 3-hexen-1,5-diyne derivative: toward soft materials with an aggregation-induced enhancement in emission. AB - The supramolecular architectures of a fluorophore are controlled through the design of a conjugated polycatenar molecule, the self-assembly of which can be addressed toward a columnar liquid-crystalline phase and organogels. Thus, depending on the environmental conditions for self-assembly, compound CA9 organizes into an unprecedented hexagonal columnar mesophase in the condensed state, in which half a molecule constitutes the slice of the column, or into a rectangular mesomorphic-like organization in the presence of apolar solvents such as cyclohexane and dodecane, at a concentration in which fibers form and gelling conditions are fulfilled. In this Col(r)-type arrangement, the organization within the columns depends on the solvent. All of the materials prepared show luminescence, and moreover, a remarkable 3-fold increase in fluorescence intensity was observed in going from the solution to the gel state. PMID- 21534571 TI - Straightforward, one-step fabrication of ultrathin thermoresponsive films from commercially available pNIPAm for cell culture and recovery. AB - The use of thermoresponsive surfaces as platforms for cell culture and cell regeneration has been explored over the last couple of decades. Poly-N isopropylacrylamide (pNIPAm) is a well characterized thermoresponsive polymer which has an aqueous lower critical solution temperature (LCST) in a physiologically useful range, which allows it to reversibly attract (T < 32 degrees C) and repel water (T > 32 degrees C). It is this phenomenon that is exploited in temperature-controlled cell harvesting. pNIPAm coatings are generally poorly cell compatible and a number of complex or expensive techniques have been developed in order to overcome this issue. This study seeks to design a simple one-step system whereby commercially sourced pNIPAm is used to achieve similar results. Films were deposited using the operationally simple but rheologically complex spin coating technique. Reversible temperature modulated cell adhesion was achieved using a variety of different cell lines. This system offers a simplistic and cheaper alternative to methods used elsewhere. PMID- 21534572 TI - Characterization of dye-decolorizing peroxidases from Rhodococcus jostii RHA1. AB - The soil bacterium Rhodococcus jostii RHA1 contains two dye-decolorizing peroxidases (DyPs) named according to the subfamily they represent: DypA, predicted to be periplasmic, and DypB, implicated in lignin degradation. Steady state kinetic studies of these enzymes revealed that they have much lower peroxidase activities than C- and D-type DyPs. Nevertheless, DypA showed 6-fold greater apparent specificity for the anthraquinone dye Reactive Blue 4 (k(cat)/K(m) = 12800 +/- 600 M(-1) s(-1)) than either ABTS or pyrogallol, consistent with previously characterized DyPs. By contrast, DypB showed the greatest apparent specificity for ABTS (k(cat)/K(m) = 2000 +/- 100 M(-1) s(-1)) and also oxidized Mn(II) (k(cat)/K(m) = 25.1 +/- 0.1 M(-1) s(-1)). Further differences were detected using electron paramagnetic resonance (EPR) spectroscopy: while both DyPs contained high-spin (S = (5)/(2)) Fe(III) in the resting state, DypA had a rhombic high-spin signal (g(y) = 6.32, g(x) = 5.45, and g(z) = 1.97) while DypB had a predominantly axial signal (g(y) = 6.09, g(x) = 5.45, and g(z) = 1.99). Moreover, DypA reacted with H(2)O(2) to generate an intermediate with features of compound II (Fe(IV)?O). By contrast, DypB reacted with H(2)O(2) with a second-order rate constant of (1.79 +/- 0.06) * 10(5) M(-1) s(-1) to generate a relatively stable green-colored intermediate (t(1/2) ~ 9 min). While the electron absorption spectrum of this intermediate was similar to that of compound I of plant-type peroxidases, its EPR spectrum was more consistent with a poorly coupled protein-based radical than with an [Fe(IV)?O Por(*)](+) species. The X-ray crystal structure of DypB, determined to 1.4 A resolution, revealed a hexacoordinated heme iron with histidine and a solvent species occupying axial positions. A solvent channel potentially provides access to the distal face of the heme for H(2)O(2). A shallow pocket exposes heme propionates to the solvent and contains a cluster of acidic residues that potentially bind Mn(II). Insight into the structure and function of DypB facilitates its engineering for the improved degradation of lignocellulose. PMID- 21534573 TI - Adhesive-free transfer of gold patterns to PDMS-based nanocomposite dielectric for printed high-performance organic thin-film transistors. AB - Low-cost, adhesive-free direct transfer of gold patterns onto PDMS-based nanocomposite dielectric layer was investigated to significantly improve contact resistance at electrode-semiconductor interface in organic thin-film transistors (OTFTs). In particular, the nanocomposite film made from PDMS and solution processable titanium dioxide nanoparticles was applied as dielectric layer in OTFTs, while transfer of gold patterns with a resolution lower than 3 MUm is realized without use of any adhesive but through increased adhesion between gold and nanocomposite film of higher thickness and dielectric constant formed by in situ PDMS cross-linking process. Dielectric constant of the nanocomposite shows a dependence on the ratio of titanium dioxide nanoparticles to PDMS and the dielectric thickness was optimized for the best transfer efficiency. The organic transistors fabricated by this process demonstrate a high mobility of 0.038 cm(2)/(V s) and on/off ratio of 1 * 10(4) to 1 * 10(5). The electrode semiconductor interface is evaluated by transmission line model to have width normalized contact resistance of ~100 kOmega cm while the inert property of dielectric-semiconductor interface gives low hysteresis (DeltaV(th) = 1.2 V) and low threshold voltage (V(th) = -1.3 V) in the devices. This process can be readily adapted into a low-cost mass manufacturing process for printed organic electronics. PMID- 21534574 TI - Biomimetic screening of class-B G protein-coupled receptors. AB - The 41-amino acid peptide corticotropin releasing factor (CRF) is a major modulator of the mammalian stress response. Upon stressful stimuli, it binds to the corticotropin releasing factor receptor 1 (CRF(1)R), a typical member of the class-B G-protein-coupled receptors (GPCRs) and a prime target in the treatment of mood disorders. To chemically probe the molecular interaction of CRF with the transmembrane domain of its cognate receptor, we developed a high-throughput conjugation approach that mimics the natural activation mechanism of class-B GPCRs. An acetylene-tagged peptide library was synthesized and conjugated to an azide-modified high-affinity carrier peptide derived from the CRF C-terminus using copper-catalyzed dipolar cycloaddition. The resulting conjugates reconstituted potent agonists and were tested in situ for activation of the CRF(1) receptor in a cell-based assay. By use of this approach we (i) defined the minimal sequence motif that is required for full receptor activation, (ii) identified the critical functional groups and structure-activity relationships, (iii) developed an optimized, highly modified peptide probe with high potency (EC(50) = 4 nM) that is specific for the activation domain of the receptor, and (iv) probed the behavioral role of CRF receptors in living mice. The membrane recruitment by a high-affinity carrier enhanced the potency of the tethered peptides by >4 orders of magnitude and thus allowed the testing of very weak initial fragments that otherwise would have been inactive on their own. As no chromatography purification of the test peptides was necessary, a substantial increase in screening throughput was achieved. Importantly, the peptide conjugates can be used to probe the endogenous receptor in its native environment in vivo. PMID- 21534575 TI - Terahertz spectroscopy. PMID- 21534576 TI - A theoretical investigation of the plausibility of reactions between ammonia and carbonyl species (formaldehyde, acetaldehyde, and acetone) in interstellar ice analogs at ultracold temperatures. AB - We have reexamined the reaction between formaldehyde and ammonia, which was previously studied by us and other workers in modestly sized cluster calculations. Larger model systems with up to 12H(2)O were employed, and reactions of two more carbonyl species, acetaldehyde and acetone, were also carried out. Calculations were performed at the B3LYP/6-31+G** level with bulk solvent effects treated with a polarizable continuum model; limited MP2/6-31+G** calculations were also performed. We found that while the barrier for the concerted proton relay mechanism described in previous work remains modest, it is still prohibitively high for the reaction to occur under the ultracold conditions that prevail in dense interstellar clouds. However, a new pathway emerged in more realistic clusters that involves at least one barrierless step for two of the carbonyl species considered here: ammonia reacts with formaldehyde and acetaldehyde to form a partial charge transfer species in small clusters (4H(2)O) and a protonated hydroxyamino intermediate species in large clusters (9H(2)O, 12H(2)O); modest barriers that decrease sharply with cluster size are found for the analogous processes for the acetone-NH(3) reaction. Furthermore, if a second ammonia replaces one of the water molecules in calculations in the 9H(2)O clusters, deprotonation can occur to yield the same neutral hydroxyamino species that is formed via the original concerted proton relay mechanism. In at least one position, deprotonation is barrierless when zero-point energy is included. In addition to describing the structures and energetics of the reactions between formaldehyde, acetaldehyde, and acetone with ammonia, we report spectroscopic predictions of the observable vibrational features that are expected to be present in ice mixtures of different composition. PMID- 21534577 TI - Strong-field ionization and dissociation studies on small early transition metal carbide clusters via time-of-flight mass spectrometry. AB - In this work, we report experimental results from the strong-field ionization and subsequent Coulomb explosion of narrow distributions of small (<40 atoms) heteronuclear clusters composed of transition metal (Ti, V, Cr, Nb, or Ta) and carbon atoms. Analysis of the resulting multiply charged ions was performed through time-of-flight mass spectrometry, and evidence regarding ionization dynamics was obtained. The data reveal the presence of enhanced ionization during exposure to the ultrashort (~100 fs) pulse resulting in the formation of ions possessing significantly higher charge states than those predicted from atomic species. Regardless of the transition metal species, we observe the absorption of similar amounts of energy from the external field, as indicated by the maximum observed charge states in each experiment. These results are compared to our previously reported study on the strong-field ionization of transition metal oxide clusters. We observe identical maximum observable charge states for each of the transition metal species resulting from both metal oxide and metal carbide clusters. PMID- 21534578 TI - Cholesteric liquid crystalline materials with a dual circularly polarized light reflection band fixed at room temperature. AB - An unpolarized normal-incidence light beam reflected by a cholesteric liquid crystal is left- or right-circularly polarized, in the cholesteric temperature range. In this article, we present a novel approach for fabricating a cholesteric liquid crystalline material that exhibits reflection bands with both senses of polarization at room temperature. A cholesteric liquid crystal that presents a twist inversion at a critical temperature T(c) is blended with a small quantity of photopolymerizable monomers. Upon ultraviolet irradiation above T(c), the liquid crystal becomes a polymer-stabilized liquid crystal. Below T(c), the material reflects a dual circularly polarized band in the infrared. By quenching the experimental cell at a temperature below the blend's melting point, the optical properties of the material in an undercooled state are conserved for months at room temperature, which is critical to potential applications such as heat-repelling windows and polarization-independent photonic devices. PMID- 21534579 TI - Effect of cation symmetry on the morphology and physicochemical properties of imidazolium ionic liquids. AB - In this paper, the morphology and bulk physical properties of 1,3 dialkylimidazolium bis{(trifluoromethane)sulfonyl}amide ([(C(N/2))(2)im][NTf(2)]) are compared to that of 1-alkyl-3-methylimidazolium bis{(trifluoromethane)sulfonyl}amide ([C(N-1)C(1)im][NTf(2)]) for N = 4, 6, 8, and 10. For a given pair of ionic liquids (ILs) with the same N, the ILs differ only in the symmetry of the alkyl substitution on the imidazolium ring of the cation. Small-wide-angle X-ray scattering measurements indicate that, for a given symmetric/asymmetric IL pair, the structural heterogeneities are larger in the asymmetric IL than in the symmetric IL. The correlation length of structural heterogeneities for the symmetric and asymmetric salts, however, is described by the same linear equation when plotted versus the single alkyl chain length. Symmetric ILs with N = 4 and 6 easily crystallize, whereas longer alkyl chains and asymmetry hinder crystallization. Interestingly, the glass transition temperature is found to vary inversely with the correlation length of structural heterogeneities and with the length of the longest alkyl chain. Whereas the densities for a symmetric/asymmetric IL pair with a given N are nearly the same, the viscosity of the asymmetric IL is greater than that of the symmetric IL. Also, an even-odd effect previously observed in molecular dynamics simulations is confirmed by viscosity measurements. We discuss in this paper how the structural heterogeneities and physical properties of these ILs are consistent with alkyl tail segregation. PMID- 21534581 TI - Electrochemical estimation of diffusion anisotropy of N,N,N',N'-tetramethyl-para phenylenediamine within the normal hexagonal lyotropic mesophase of Triton X 100/light water: when can the effects of cross-pseudophase electron transfer be neglected for partitioned reagents? AB - The H(1) lyotropic liquid crystalline phase of Triton X 100 with aqueous 0.1 M potassium chloride is examined as a medium in which to determine the axiosymmetric anisotropy in the diffusion flux of N,N,N',N'-tetramethyl-para phenylenediamine using electrochemical methods (voltammetry and potential step chronoamperometry) at both planar electrodes and two-dimensional flux microdisk electrodes. Comparison of experiment with theory suggests the ratio of anisotropic diffusion coefficients in the directions tangential and perpendicular to the electrode surface varies over two orders of magnitude (from 0.04 to 3.3) with increasing concentration of the redox analyte. This is understood through the occurrence of a long-range charge transfer across the pseudophase | pseudophase boundary interface, occurring as a result of differential diffusivities of the redox probe within the surfactant and aqueous subphases. These data and their dependence on the analyte concentration empower, in a proof of-concept, the estimation of the partition equilibrium constant (K(P)); the value estimated for the small electroactive-drug mimetic considered is log K(P) = 2.01 +/- 0.05 (at 294 +/- 2 K) and is in agreement with that envisaged for its partition between n-octanol and water. It is suggested that only measurements at low analyte loadings allow for interphase electron transfers to be neglected, since then percolation effects appear to dominate the Faradaic current. PMID- 21534580 TI - Methanol strengthens hydrogen bonds and weakens hydrophobic interactions in proteins--a combined molecular dynamics and NMR study. AB - A combined simulation and experimental study was performed to investigate how methanol affects the structure of a model peptide BBA5. BBA5 forms a stable beta hairpin-alpha-helix structure in aqueous solutions. Molecular dynamics simulations were performed in water and methanol/water solutions using all-atom explicit models. NMR experiments were used to test the calculated results. The combined theoretical and experimental studies suggest that methanol strengthens the interactions between the polar backbone of the peptide and thus enhances the secondary structure formation; at the same time methanol weakens the hydrophobic interactions and results in an expansion of the hydrophobic core and an increase in gyration. PMID- 21534582 TI - Isotopic character of nitrous oxide emitted from streams. AB - Global models have indicated agriculturally impacted rivers and streams may be important sources of the greenhouse gas nitrous oxide (N(2)O). However, there is significant uncertainty in N(2)O budgets. Isotopic characterization can be used to help constrain N(2)O budgets. We present the first published measurements of the isotopic character of N(2)O emitted from low (2-4) order streams. Isotopic character of N(2)O varied seasonally, among streams, and over diel periods. On an annual basis, delta(18)O of emitted N(2)O (+47.4 to +51.40/00; relative to VSMOW) was higher than previously reported for larger rivers, but delta(15)N of emitted N(2)O (-16.2 to +2.40/00 among streams; relative to atmospheric N(2)) was similar to that of past studies. On an annual basis, all streams emitted N(2)O with lower delta(15)N than tropospheric N(2)O. Given these streams have elevated nitrate concentrations which are associated with enhanced N(2)O fluxes, this supports the hypothesis that streams are contributing to the accumulation of (15)N-depleted N(2)O in the troposphere. PMID- 21534583 TI - Lathyrane diterpenoids from the roots of Euphorbia micractina and their biological activities. AB - Seventeen new lathyrane diterpenoids (1-17) and two known analogues have been isolated from an ethanolic extract of Euphorbia micractina roots. Their structures including absolute configurations were determined by spectroscopic data interpretation and single-crystal X-ray crystallography. Compound 10 showed activity against HIV-1 replication in vitro, with an IC50 value of 8.2 MUM. Compounds 6, 7, 11, 14, 15, and 18, at 10(-6) M, showed significant vascular relaxing activities against phenylephrine-induced vasoconstriction with relaxation rates of 48%, 41%, 42%, 48%, 50%, and 53%, respectively. PMID- 21534584 TI - Multi-population model of a microbial electrolysis cell. AB - This work presents a multi-population dynamic model of a microbial electrolysis cell (MEC). The model describes the growth and metabolic activity of fermentative, electricigenic, methanogenic acetoclastic, and methanogenic hydrogenophilic microorganisms and is capable of simulating hydrogen production in a MEC fed with complex organic matter, such as wastewater. The model parameters were estimated with the experimental results obtained in continuous flow MECs fed with acetate or synthetic wastewater. Following successful model validation with an independent data set, the model was used to analyze and discuss the influence of applied voltage and organic load on hydrogen production and COD removal. PMID- 21534585 TI - Borate-catalyzed carbon dioxide hydration via the carbonic anhydrase mechanism. AB - The hydration of CO(2) plays a critical role in carbon capture and geoengineering technologies currently under development to mitigate anthropogenic global warming and in environmental processes such as ocean acidification. Here we reveal that borate catalyzes the conversion of CO(2) to HCO(3)(-) via the same fundamental mechanism as the enzyme carbonic anhydrase, which is responsible for CO(2) hydration in the human body. In this mechanism the tetrahydroxyborate ion, B(OH)(4)(-), is the active form of boron that undergoes direct reaction with CO(2). In addition to being able to accelerate CO(2) hydration in alkaline solvents used for carbon capture, we hypothesize that this mechanism controls CO(2) uptake by certain saline bodies of water, such as Mono Lake (California), where previously inexplicable influx rates of inorganic carbon have created unique chemistry. The new understanding of CO(2) hydration provided here should lead to improved models for the carbon cycle in highly saline bodies of water and to advances in carbon capture and geoengineering technology. PMID- 21534586 TI - Extended two-dimensional metal-organic frameworks based on thiolate-copper coordination bonds. AB - Self-assembly and surface-mediated reactions of 1,3,5-tris(4 mercaptophenyl)benzene--a three-fold symmetric aromatic trithiol--are studied on Cu(111) by means of scanning tunneling microscopy (STM) under ultrahigh-vacuum (UHV) conditions. In order to reveal the nature of intermolecular bonds and to understand the specific role of the substrate for their formation, these studies were extended to Ag(111). Room-temperature deposition onto either substrate yields densely packed trigonal structures with similar appearance and lattice parameters. Yet, thermal annealing reveals distinct differences between both substrates: on Cu(111) moderate annealing temperatures (~150 degrees C) already drive the emergence of two different porous networks, whereas on Ag(111) higher annealing temperatures (up to ~300 degrees C) were required to induce structural changes. In the latter case only disordered structures with characteristic dimers were observed. These differences are rationalized by the contribution of the adatom gas on Cu(111) to the formation of metal-coordination bonds. Density functional theory (DFT) methods were applied to identify intermolecular bonds in both cases by means of their bond distances and geometries. PMID- 21534587 TI - Reaction pathways of proton transfer in hydrogen-bonded phenol-carboxylate complexes explored by combined UV-vis and NMR spectroscopy. AB - Combined low-temperature NMR/UV-vis spectroscopy (UVNMR), where optical and NMR spectra are measured in the NMR spectrometer under the same conditions, has been set up and applied to the study of H-bonded anions A..H..X(-) (AH = 1-(13)C-2 chloro-4-nitrophenol, X(-) = 15 carboxylic acid anions, 5 phenolates, Cl(-), Br( ), I(-), and BF(4)(-)). In this series, H is shifted from A to X, modeling the proton-transfer pathway. The (1)H and (13)C chemical shifts and the H/D isotope effects on the latter provide information about averaged H-bond geometries. At the same time, red shifts of the pi-pi* UV-vis absorption bands are observed which correlate with the averaged H-bond geometries. However, on the UV-vis time scale, different tautomeric states and solvent configurations are in slow exchange. The combined data sets indicate that the proton transfer starts with a H-bond compression and a displacement of the proton toward the H-bond center, involving single-well configurations A-H...X(-). In the strong H-bond regime, coexisting tautomers A..H...X(-) and A(-)...H..X are observed by UV. Their geometries and statistical weights change continuously when the basicity of X(-) is increased. Finally, again a series of single-well structures of the type A( )...H-X is observed. Interestingly, the UV-vis absorption bands are broadened inhomogeneously because of a distribution of H-bond geometries arising from different solvent configurations. PMID- 21534588 TI - Carbon nanotube sidewall functionalization with carbonyl compounds--modified Birch conditions vs the organometallic reduction approach. AB - Covalent addition reactions turned out to be one of the most important functionalization techniques for a structural alteration of single walled carbon nanotube (SWCNT) scaffolds. During the last years, several reaction sequences based on an electrophilic interception of intermediately generated SWCNT(n-) carbanions, obtained via Birch reduction or by a nucleophilic addition of organometallic species, have been developed. Nevertheless, the scope and the variety of potential electrophiles is limited due to the harsh reaction conditions requested for a covalent attachment of the functional entities onto the SWCNT framework. Herein, we present a significant modification of the reductive alkylation/arylation sequence, the so-called Billups reaction, which extends the portfolio of electrophiles for covalent sidewall functionalization to carbonyl compounds--ketones, esters, and even carboxylic acid chlorides. Moreover, these carbonyl-based electrophiles can also be used as secondary functionalization reagents for anionic SWCNT intermediates, derived from a primary nucleophilic addition step. This directly leads to the generation of mixed functional SWCNT architectures, equipped with hydroxyl or carbonyl anchor groups, suitable for ongoing derivatization reactions. A correlated absorption and emission spectroscopic study elucidates the influence of the covalent sidewall functionalization degree onto the excitonic transition features of carbon nanotubes. The characterization of the different SWCNT adducts has been carried out by means of Raman, UV-vis/nIR, and fluorescence spectroscopy as well as by thermogravimetric analysis combined with mass spectrometry and X-ray photoelectron spectroscopy analysis. PMID- 21534589 TI - Role of alpha-relaxation on crystallization of amorphous celecoxib above T(g) probed by dielectric spectroscopy. AB - In the present study, the role of alpha-relaxation toward isothermal crystallization of amorphous celecoxib was studied using dielectric spectroscopy (DES). The dielectric response of the alpha-relaxation was measured as a function of frequency (10-1 to 106 Hz), isothermally at every 4 K interval in the range of 303.15 to 443.15 K. The dielectric loss spectrum at each temperature was analyzed using the Havriliak Negami (HN) equation to extract the characteristic relaxation time, tau(HN). Two Vogel-Fulcher-Tammann (VFT) functions were required for representing the temperature dependence of tau(HN) across the temperature range of study. The VFT fit parameters obtained from the two regions varied drastically pointing toward the underlying differences in the dynamics of relaxation above and below the crossover. Later, in situ isothermal crystallization experiments were performed at 363.15, 368.15, 373.15, and 378.15 K. The conversion rate, obtained from the normalized dielectric strength, was modeled using the Avrami model, which indicated the possibility of different crystallization mechanism at higher crystallization temperatures. HN shape parameters, alpha(HN) and product of alpha(HN) and beta(HN), were analyzed during the course of crystallization to understand the dynamics of amorphous phase when crystallites were being evolved. HN shape parameters indicated alpha-like motions were affected, whereas beta-like remained unaffected by the crystallization temperature. Characteristic crystallization time, tau(cr), obtained from Avrami fits, showed Arrhenius type of temperature dependence (R2 = 0.999). A plot between log tau(cr) and log tau(HN) show a linear regression with R2 of 0.997 indicating the direct correlation between these two phenomena. However, the coupling coefficient was found to be varying within the temperature range of study, indicating tendency of crystallization to be more diffusion controlled at higher crystallization temperatures. With different crystalline solid phase crystallizing at higher crystallization temperature, complemented with direct correlation between log tau(cr) and log tau(HN), Avrami modeling of crystallization and HN shape parameter analysis, the role of alpha-relaxation in the crystallization of amorphous celecoxib at T > T(g) is emphasized. PMID- 21534590 TI - (-)-Duryne and its homologues, cytotoxic acetylenes from a marine Sponge Petrosia sp. AB - Six linear acetylenes, (-)-duryne (1) and (-)-durynes B-F (2-6), were isolated from the marine sponge Petrosia sp. Their structures were elucidated by NMR and tandem FABMS analyses. The positions of the olefinic bonds were confirmed by ozonolysis experiments, and the absolute configurations were determined by the modified Mosher's method. Compound 1 was found to be the enantiomer of duryne, a previously reported sponge metabolite. Compounds 1-6 show cytotoxicity against HeLa cells with IC50 values between 0.08 and 0.50 MUM. PMID- 21534591 TI - Characterization of semiconductor nanowires using optical tweezers. AB - We report on the optical trapping characteristics of InP nanowires with dimensions of 30 (+/-6) nm in diameter and 2-15 MUm in length. We describe a method for calibrating the absolute position of individual nanowires relative to the trapping center using synchronous high-speed position sensing and acousto optic beam switching. Through brownian dynamics we investigate effects of the laser power and polarization on trap stability, as well as length dependence and the effect of simultaneous trapping multiple nanowires. PMID- 21534592 TI - Quantum plexcitonics: strongly interacting plasmons and excitons. AB - We present a fully quantum mechanical approach to describe the coupling between plasmons and excitonic systems such as molecules or quantum dots. The formalism relies on Zubarev's Green functions, which allow us to go beyond the perturbative regime within the internal evolution of a plasmonic nanostructure and to fully account for quantum aspects of the optical response and Fano resonances in plasmon-excition (plexcitonic) systems. We illustrate this method with two examples consisting of an exciton-supporting quantum emitter placed either in the vicinity of a single metal nanoparticle or in the gap of a nanoparticle dimer. The optical absorption of the combined emitter-dimer structure is shown to undergo dramatic changes when the emitter excitation level is tuned across the gap-plasmon resonance. Our work opens a new avenue to deal with strongly interacting plasmon-excition hybrid systems. PMID- 21534593 TI - Ubiquitous net volatilization of polycyclic aromatic hydrocarbons from soils and parameters influencing their soil-air partitioning. AB - Soils are a major reservoir of organic pollutants, and soil-air partitioning and exchange are key processes controlling the regional fate of pollutants. Here, we report and discuss the soil concentrations of polycyclic aromatic hydrocarbons (PAHs), their soil fugacities, the soil-air partition coefficients (K(SA)) and soil-air gradients for rural and semirural soils, in background areas of N-NE Spain and N-NW England. Different sampling campaigns were carried out to assess seasonal variability and differences between sampling sites. K(SA) values were dependent on soil temperature and soil organic quantity and type. Soil fugacities of phenanthrene and its alkyl homologues were 1-2 orders of magnitude higher than their ambient air fugacities for all sampling sites and periods. The soil to air fugacity ratio was correlated with soil temperature and soil redox potential. Similar trends for other PAHs were found but with lower fugacity ratios. The ubiquitous source of PAHs from background soils to the atmosphere found in all temperate regions in different seasons provides an indirect evidence of potential in situ generation of two to four ring PAHs and their alkyl homologues in the surface soil. We discuss this hypothetical biogenic source and other potential processes that could drive the high soil to air fugacity ratios of some PAHs. PMID- 21534594 TI - Perfluorinated compounds in fish and blood of anglers at Lake Mohne, Sauerland area, Germany. AB - Perfluorinated compounds (PFCs) were measured in fish samples and blood plasma of anglers in a cross-sectional study at Lake Mohne, Sauerland area, Germany. Human plasma and drinking water samples were analyzed by solid phase extraction, high performance liquid chromatography (HPLC), and tandem mass spectrometry (MS/MS). PFCs in fish fillet were measured by ion pair extraction followed by HPLC and MS/MS. PFOS concentrations in 44 fish samples of Lake Mohne ranged between 4.5 and 150 ng/g. The highest median PFOS concentrations have been observed in perches (median: 96 ng/g) and eels (77 ng/g), followed by pikes (37 ng/g), whitefish (34 ng/g), and roaches (6.1 ng/g). In contrast, in a food surveillance program only 11% of fishes at retail sale contained PFOS at detectable concentrations. One hundred five anglers (99 men, 6 women; 14-88 years old; median 50.6 years) participated in the human biomonitoring study. PFOS concentrations in blood plasma ranged from 1.1 to 650 MUg/L (PFOA: 2.1-170 MUg/L; PFHxS: 0.4-17 MUg/L; LOD: 0.1 MUg/L). A distinct dose-dependent relationship between fish consumption and internal exposure to PFOS was observed. PFOS concentrations in blood plasma of anglers consuming fish 2-3 times per month were 7 times higher compared to those without any fish consumption from Lake Mohne. The study results strongly suggest that human internal exposure to PFC is distinctly increased by consumption of fish from PFC-contaminated sites. PMID- 21534595 TI - Degradation of cyhalofop-butyl (CyB) by Pseudomonas azotoformans strain QDZ-1 and cloning of a novel gene encoding CyB-hydrolyzing esterase. AB - Cyhalofop-butyl (CyB) is a widely used aryloxyphenoxy propanoate (AOPP) herbicide for control of grasses in rice fields. Five CyB-degrading strains were isolated from rice field soil and identified as Agromyces sp., Stenotrophomonas sp., Aquamicrobium sp., Microbacterium sp., and Pseudomonas azotoformans; the results revealed high biodiversity of CyB-degrading bacteria in rice soil. One strain, P. azotoformans QDZ-1, degraded 84.5% of 100 mg L(-1) CyB in 5 days of incubation in a flask and utilized CyB as carbon source for growth. Strain QDZ-1 could also degrade a wide range of other AOPP herbicides. An esterase gene, chbH, which hydrolyzes CyB to cyhalofop acid (CyA), was cloned from strain QDZ-1 and functionally expressed. A chbH-disrupted mutant dchbH was constructed by insertion mutation. Mutant dchbH could not degrade and utilize CyB, suggesting that chbH was the only esterase gene responsible for CyB degradation in strain QDZ-1. ChbH hydrolyzed all AOPP herbicides tested as well as permethrin. The catalytic efficiency of ChbH toward different AOPP herbicides followed the order quizalofop-P-ethyl ~ fenoxaprop-P-ethyl > CyB ~ fluazifop-P-butyl > diclofop methyl ~ haloxyfop-P-methyl; the results indicated that the chain length of the alcohol moiety strongly affected the biodegradability of the AOPP herbicides, whereas the substitutions in the aromatic ring had only a slight influence. PMID- 21534596 TI - Simultaneous quantification of eight biogenic amine compounds in tuna by matrix solid-phase dispersion followed by HPLC-orbitrap mass spectrometry. AB - A method for the extraction of agmatine, cadaverine, histamine, phenyethylamine, putrescine, tryptamine, tyramine, and urocanic acid from canned tuna and frozen tuna loin matrices by matrix solid-phase dispersion, followed by separation and quantification of these compounds by ultrahigh-performance hydrophilic interaction chromatography (UHPLC-HILIC) with orbitrap mass spectrometric detection, is described. Tuna samples are dispersed in a CN-silica sorbent and eluted with a mixture of aqueous ammonium formate buffer and acetonitrile. Separation and detection are carried out on an Agilent 1200 high-performance liquid chromatograph coupled to a Thermo Exactive orbitrap mass spectrometer, and metformin is used as the internal standard. Spike recoveries are determined across a range of 20-100 ppm for each compound, and the method is validated with respect to linearity, reproducibility, accuracy, and limits of quantitation and detection. The method is demonstrated to be suitable for use in quantifying these target compounds in the studied matrices. PMID- 21534597 TI - Highly demanding cross-metathesis in the synthesis of the C16-C30 fragment of dolabelide C. AB - A highly demanding cross-metathesis (CM) reaction for the formation of the C24 C25 trisubstituted olefin of dolabelide C has been optimized. A difference in reactivity between the E and Z enone isomers in this reaction was uncovered, and the selection of the Z isomer of the starting enone was critical for the success of the cross-metathesis. Application to the synthesis of the C16-C30 fragment of dolabelide C is reported. PMID- 21534598 TI - Bionic multisilicon copolymers used as novel cross-linking agents for preparing anion exchange hybrid membranes. AB - Bionic multisilicon copolymers have long-main chains and many branched chains, and contain multifunctional groups of -N(+)(CH(3))(3)Cl(-) and -Si(OCH(3))(3), which are similar to the stem, branch, fruit, and acetabula of a vine from bionic aspect, respectively. They have high flexibility, charge density, and cross linking ability and thus can be used as novel cross-linking agents for preparing anion-exchange hybrid membranes. High content of -Si(OCH(3))(3) groups (68-78%) is suitable to enhance membrane stabilities. The membranes are stable in 65 degrees C water up to 120 h and can keep integrity in 2 mol/L NaOH for 192 h. High content of -N(+)(CH(3))(3)Cl(-) groups (42-55%) is suitable to enhance membrane electrical properties. The membranes have low membrane resistance (R(m), 0.59-0.94 Omega cm(2)) and high diffusion dialysis performance. The acid (H(+)) dialysis coefficients (U(H)) are in the range of 0.007-0.075 m h(-1) at room temperature and 0.015-0.115 m h(-1) at 40 degrees C. The separation factor (S(H/Fe)) can reach up to 43 at room temerature and 49 at 40 degrees C. All of the membranes are highly homogeneous, mechanically stable (21-31 MPa, 25-147%), and thermally stable (227-275 degrees C for halide form membranes, and 157-172 degrees C for OH(-) form membranes). Hence, the investigation of multisilicon copolymers will give rise to a new developing field in material and membrane sciences. PMID- 21534599 TI - Impurity-dependent photoresponse properties in single CdSe nanobelt photodetectors. AB - Impurity-dependent photoresponse properties of semiconductor nanostructures are studied for the first time in the photodetectors (PDs) made from intrinsic (i-) and extrinsic n-type single CdSe nanobelts (NBs). Both ohmic and Schottky contact based CdSe NB PDs were studied. The sizes of i- and n- NBs were purposely chosen to be nearly identical to minimize the size-dependent effect. Our experimental results demonstrate that i-CdSe NBs are more suitable for fast and sensitive PD applications, while n-CdSe NBs are more advantageous for high-gain PD applications. The different photoresponse properties result mainly from the impurity induced traps inside the CdSe NBs. This conclusion can be applicable to other semiconductor nanomaterials. Moreover, we have achieved short response/recovery times (~15/31 MUs) and a high photosensitivity (~100) simultaneously from the i-CdSe NB PDs under a 3500 Hz pulsed illumination. This may be the best reported result so far in the effort of getting fast speed and high photosensitivity simultaneously from nanostructure based PDs for practical applications. PMID- 21534600 TI - Highly enantioselective nitroaldol reactions catalyzed by copper(II) complexes derived from substituted 2-(pyridin-2-yl)imidazolidin-4-one ligands. AB - Ten optically pure substituted 2-(pyridin-2-yl)imidazolidin-4-ones, 1a-d, 2a-4a, and 2b-4b, were prepared and characterized. The absolute configurations of individual ligands were determined by X-ray analysis or NOESY experiments. The Cu(II) complexes of the respective ligands were studied as enantioselective catalysts of the nitroaldol (Henry) reaction of aldehydes with nitromethane, giving the corresponding substituted 2-nitroalkanols. In the case of an anti arrangement of the imidazolidin-4-one ring, the obtained result was 91-96% ee, whereas in the case of syn arrangement, a significant drop to 25-27% ee was observed. PMID- 21534601 TI - Diamond-modified AFM probes: from diamond nanowires to atomic force microscopy integrated boron-doped diamond electrodes. AB - In atomic force microscopy (AFM), sharp and wear-resistant tips are a critical issue. Regarding scanning electrochemical microscopy (SECM), electrodes are required to be mechanically and chemically stable. Diamond is the perfect candidate for both AFM probes as well as for electrode materials if doped, due to diamond's unrivaled mechanical, chemical, and electrochemical properties. In this study, standard AFM tips were overgrown with typically 300 nm thick nanocrystalline diamond (NCD) layers and modified to obtain ultra sharp diamond nanowire-based AFM probes and probes that were used for combined AFM-SECM measurements based on integrated boron-doped conductive diamond electrodes. Analysis of the resonance properties of the diamond overgrown AFM cantilevers showed increasing resonance frequencies with increasing diamond coating thicknesses (i.e., from 160 to 260 kHz). The measured data were compared to performed simulations and show excellent correlation. A strong enhancement of the quality factor upon overgrowth was also observed (120 to 710). AFM tips with integrated diamond nanowires are shown to have apex radii as small as 5 nm and where fabricated by selectively etching diamond in a plasma etching process using self-organized metal nanomasks. These scanning tips showed superior imaging performance as compared to standard Si-tips or commercially available diamond coated tips. The high imaging resolution and low tip wear are demonstrated using tapping and contact mode AFM measurements by imaging ultra hard substrates and DNA. Furthermore, AFM probes were coated with conductive boron-doped and insulating diamond layers to achieve bifunctional AFM-SECM probes. For this, focused ion beam (FIB) technology was used to expose the boron-doped diamond as a recessed electrode near the apex of the scanning tip. Such a modified probe was used to perform proof-of-concept AFM-SECM measurements. The results show that high-quality diamond probes can be fabricated, which are suitable for probing, manipulating, sculpting, and sensing at single digit nanoscale. PMID- 21534602 TI - Innovative polymer nanocomposite electrolytes: nanoscale manipulation of ion channels by functionalized graphenes. AB - The chemistry and structure of ion channels within the polymer electrolytes are of prime importance for studying the transport properties of electrolytes as well as for developing high-performance electrochemical devices. Despite intensive efforts on the synthesis of polymer electrolytes, few studies have demonstrated enhanced target ion conduction while suppressing unfavorable ion or mass transport because the undesirable transport occurs through an identical pathway. Herein, we report an innovative, chemical strategy for the synthesis of polymer electrolytes whose ion-conducting channels are physically and chemically modulated by the ionic (not electronic) conductive, functionalized graphenes and for a fundamental understanding of ion and mass transport occurring in nanoscale ionic clusters. The functionalized graphenes controlled the state of water by means of nanoscale manipulation of the physical geometry and chemical functionality of ionic channels. Furthermore, the confinement of bound water within the reorganized nanochannels of composite membranes was confirmed by the enhanced proton conductivity at high temperature and the low activation energy for ionic conduction through a Grotthus-type mechanism. The selectively facilitated transport behavior of composite membranes such as high proton conductivity and low methanol crossover was attributed to the confined bound water, resulting in high-performance fuel cells. PMID- 21534603 TI - Chiral sum frequency generation spectroscopy for characterizing protein secondary structures at interfaces. AB - In situ and real-time characterization of protein secondary structures at interfaces is important in biological and bioengineering sciences, yet remains technically challenging. In this study, we used chiral sum frequency generation (SFG) spectroscopy to establish a set of vibrational optical markers for characterizing protein secondary structures at interfaces. We discovered that the N-H stretches along the peptide backbones of alpha-helices can be detected in chiral SFG spectra. We further observed that the chiral vibrational signatures of the N-H stretch together with the peptide amide I are unique to alpha-helix, beta sheet, and random coil at interfaces. Using these chiral vibrational signatures, we studied the aggregation of human islet amyloid polypeptide (hIAPP), which is implicated in type II diabetes. We observed in situ and in real time the misfolding of hIAPP from random coils to alpha-helices and then beta-sheets upon interaction with a lipid-water interface. Our findings show that chiral SFG spectroscopy is a powerful tool to follow changes in protein conformations at interfaces and identify interfacial protein secondary structures that elude conventional techniques. PMID- 21534604 TI - Intercalation in layered metal-organic frameworks: reversible inclusion of an extended pi-system. AB - We report the synthesis of layered [Zn(2)(bdc)(2)(H(2)O)(2)] and [Cu(2)(bdc)(2)(H(2)O)(2)] (bdc = benzdicarboxylate) metal-organic frameworks (MOF) carried out using the liquid-phase epitaxy approach employing self assembled monolayer (SAM) modified Au-substrates. We obtain Cu and Zn MOF-2 structures, which have not yet been obtained using conventional, solvothermal synthesis methods. The 2D Cu(2+) dimer paddle wheel planes characteristic for the MOF are found to be strictly planar, with the planes oriented perpendicular to the substrate. Intercalation of an organic dye, DXP, leads to a reversible tilting of the planes, demonstrating the huge potential of these surface-anchored MOFs for the intercalation of large, planar molecules. PMID- 21534605 TI - Design, synthesis, and biological activities of closantel analogues: structural promiscuity and its impact on Onchocerca volvulus. AB - Onchocerciasis, or river blindness, is a neglected tropical disease that affects more than 37 million people worldwide, primarily in Africa and Central and South America. We have disclosed evidence that the larval-stage-specific chitinase, OvCHT1, may be a potential biological target for affecting nematode development. On the basis of screening efforts, closantel, a known anthelmintic drug, was discovered as a potent and highly specific OvCHT1 inhibitor. Originally, closantel's anthelmintic mode of action was believed to rely solely on its role as a proton ionophore; thus, the impact of each of its biological activities on O. volvulus L3 molting was investigated. Structure-activity relationship studies on an active closantel fragment are detailed, and remarkably, by use of a simple salicylanilide scaffold, compounds acting only as protonophores or chitinase inhibitors were identified. From these data, unexpected synergistic protonophore and chitinase inhibition activities have also been found to be critical for molting in O. volvulus L3 larvae. PMID- 21534606 TI - Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents. AB - A structure-guided molecular design approach was used to optimize quercetin diacylglycoside analogues that inhibit bacterial DNA gyrase and topoisomerase IV and show potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. In this paper, such novel 3,7-diacylquercetin, quercetin 6''-acylgalactoside, and quercetin 2'',6''-diacylgalactoside analogues of lead compound 1 were prepared to assess their target specificities and preferences in bacteria. The significant enzymatic inhibition of both Escherichia coli DNA gyrase and Staphylococcus aureus topoIV suggest that these compounds are dual inhibitors. Most of the investigated compounds exhibited pronounced inhibition with MIC values ranging from 0.13 to 128 MUg/mL toward the growth of multidrug-resistant Gram-positive methicillin-resistant S. aureus, methicillin sensitive S. aureus, vancomycin resistant enterococci (VRE), vancomycin intermediate S. aureus, and Streptococcus pneumoniae bacterial strains. Structure-activity relationship studies revealed that the acyl moiety was absolutely essential for activity against Gram-positive organisms. The most active compound 5i was 512-fold more potent than vancomycin and 16-32-fold more potent than 1 against VRE strains. It also has realistic in situ intestinal absorption in rats and showed very low acute toxicity in mice. So far, this compound can be regarded as a leading antibacterial agent. PMID- 21534607 TI - Enantioselective Pd(II)-catalyzed aerobic oxidative amidation of alkenes and insights into the role of electronic asymmetry in pyridine-oxazoline ligands. AB - Enantioselective intramolecular oxidative amidation of alkenes has been achieved using a (pyrox)Pd(II)(TFA)(2) catalyst (pyrox = pyridine-oxazoline, TFA = trifluoroacetate) and O(2) as the sole stoichiometric oxidant. The reactions proceed at room temperature in good-to-excellent yields (58-98%) and with high enantioselectivity (ee = 92-98%). Catalyst-controlled stereoselective cyclization reactions are demonstrated for a number of chiral substrates. DFT calculations suggest that the electronic asymmetry of the pyrox ligand synergizes with steric asymmetry to control the stereochemical outcome of the key amidopalladation step. PMID- 21534609 TI - Predictive power of molecular dynamics receptor structures in virtual screening. AB - Molecular dynamics (MD) simulation is a well-established method for understanding protein dynamics. Conformations from unrestrained MD simulations have yet to be assessed for blind virtual screening (VS) by docking. This study presents a critical analysis of the predictive power of MD snapshots to this regard, evaluating two well-characterized systems of varying flexibility in ligand-bound and unbound configurations. Results from such VS predictions are discussed with respect to experimentally determined structures. In all cases, MD simulations provide snapshots that improve VS predictive power over known crystal structures, possibly due to sampling more relevant receptor conformations. Additionally, MD can move conformations previously not amenable to docking into the predictive range. PMID- 21534612 TI - Redox potential inversion by ionic hydrogen bonding between phenylenediamines and pyridines. AB - In electrochemical oxidations, the second oxidation potential of phenylenediamines (PD) varies because of hydrogen-bonding formation for PD(+*) with pyridines. A linear relationship was obtained for the potential shift as a function of pK(a) of the protonated pyridines and potential inversion could be observed. The oxidized PD(+*) could also form hydrogen bonding with alcohols and the shift of potential exhibits a different pattern. PMID- 21534610 TI - Identification of the GPR55 agonist binding site using a novel set of high potency GPR55 selective ligands. AB - Marijuana is the most widely abused illegal drug, and its spectrum of effects suggests that several receptors are responsible for the activity. Two cannabinoid receptor subtypes, CB1 and CB2, have been identified, but the complex pharmacological properties of exogenous cannabinoids and endocannabinoids are not fully explained by their signaling. The orphan receptor GPR55 binds a subset of CB1 and CB2 ligands and has been proposed as a cannabinoid receptor. This designation, however, is controversial as a result of recent studies in which lysophosphatidylinositol (LPI) was identified as a GPR55 agonist. Defining a biological role for GPR55 requires GPR55 selective ligands that have been unavailable. From a beta-arrestin, high-throughput, high-content screen of 300000 compounds run in collaboration with the Molecular Libraries Probe Production Centers Network initiative (PubChem AID1965), we identified potent GPR55 selective agonists. By modeling of the GPR55 activated state, we compared the GPR55 binding conformations of three of the novel agonists obtained from the screen, CID1792197, CID1172084, and CID2440433 (PubChem Compound IDs), with that of LPI. Our modeling indicates the molecular shapes and electrostatic potential distributions of these agonists mimic those of LPI; the GPR55 binding site accommodates ligands that have inverted-L or T shapes with long, thin profiles that can fit vertically deep in the receptor binding pocket while their broad head regions occupy a horizontal binding pocket near the GPR55 extracellular loops. Our results will allow the optimization and design of second-generation GPR55 ligands and provide a means for distinguishing GPR55 selective ligands from those interacting with cannabinoid receptors. PMID- 21534611 TI - A multistage pathway for human prion protein aggregation in vitro: from multimeric seeds to beta-oligomers and nonfibrillar structures. AB - Aberrant protein aggregation causes numerous neurological diseases including Creutzfeldt-Jakob disease (CJD), but the aggregation mechanisms remain poorly understood. Here, we report AFM results on the formation pathways of beta oligomers and nonfibrillar aggregates from wild-type full-length recombinant human prion protein (WT) and an insertion mutant (10OR) with five additional octapeptide repeats linked to familial CJD. Upon partial denaturing, seeds consisting of 3-4 monomers quickly appeared. Oligomers of ~11-22 monomers then formed through direct interaction of seeds, rather than by subsequent monomer attachment. All larger aggregates formed through association of these beta oligomers. Although both WT and 10OR exhibited identical aggregation mechanisms, the latter oligomerized faster due to lower solubility and, hence, thermodynamic stability. This novel aggregation pathway has implications for prion diseases as well as others caused by protein aggregation. PMID- 21534613 TI - A facile access to enantiomerically pure [60]fullerene bisadducts with the inherently chiral trans-3 addition pattern. AB - The Bingel reaction between C(60) and an enantiopure bismalonate tether equipped with two acetonide moieties led to the synthesis and successful column chromatographic isolation of the enantiomerically pure (f,s)C and (f,s)A bisadducts with the inherently chiral trans-3 addition pattern. Acidic deprotection of the acetonide groups gave access to novel chiral fullerene compounds which combine the inherent chirality of the fullerene core with the functional glycol groups located on the tether. PMID- 21534614 TI - Temperature-dependent spin crossover in neuronal nitric oxide synthase bound with the heme-coordinating thioether inhibitors. AB - A series of L-arginine analogue nitric oxide synthase inhibitors with a thioether tail have been shown to form an Fe-S thioether interaction as evidenced by continuous electron density between the Fe and S atoms. Even so, the Fe-S thioether interaction was found to be far less important for inhibitor binding than the hydrophobic interactions between the alkyl group in the thioether tail and surrounding protein (Martell et al. J. Am. Chem. Soc. 2010 , 132 , 798). However, among the few thioether inhibitors that showed Fe-S thioether interaction in crystal structures, variations in spin state (high-spin or low spin) were observed dependent upon the heme iron oxidation state and temperature. Since modern synchrotron X-ray data collection is typically carried out at cryogenic temperatures, we reasoned that some of the discrepancies between cryo crystal structures and room-temperature UV-visible spectroscopy could be the result of temperature-dependent spin-state changes. We, therefore, have characterized some of these neuronal nitric oxide synthase (nNOS)-thioether inhibitor complexes in both crystal and solution using EPR and UV-visible absorption spectrometry as a function of temperature and the heme iron redox state. We found that some thioether inhibitors switch from high to low spin at lower temperatures similar to the "spin crossover" phenomenon observed in many transition metal complexes. PMID- 21534615 TI - Lanthanide-based coordination polymers assembled from derivatives of 3,5 dihydroxy benzoates: syntheses, crystal structures, and photophysical properties. AB - Two new aromatic carboxylic acids, namely, 3,5-bis(benzyloxy)benzoic acid (HL1) and 3,5-bis(pyridine-2-ylmethoxy)benzoic acid (HL2), have been prepared by replacing the hydroxyl hydrogens of 3,5-dihydroxy benzoic acid with benzyl and pyridyl moieties, respectively. The anions derived from HL1 and HL2 have been used for the support of a series of lanthanide coordination compounds [Eu(3+) = 1 2; Tb(3+) = 3-4; Gd(3+) = 5-6]. The new lanthanide complexes have been characterized on the basis of a variety of spectroscopic techniques in conjunction with an assessment of their photophysical properties. Lanthanide complexes 2, 4, and 6, which were synthesized from 3,5-bis(pyridine-2 ylmethoxy)benzoic acid, were structurally authenticated by single-crystal X-ray diffraction. All three complexes were found to exist as infinite one-dimensional (1-D) coordination polymers with the general formula {[Ln(L2)(3)(H(2)O)(2)].xH(2)O}(n). Scrutiny of the packing diagrams for 2, 4, and 6 revealed the existence of interesting two-dimensional molecular arrays held together by intermolecular hydrogen-bonding interactions. Furthermore, the coordinated benzoate ligands serve as efficient light harvesting chromophores. In the cases of 1-4, the lowest energy maxima fall in the range 280-340 nm [molar absorption coefficient (epsilon) = (0.39-1.01) * 10(4) M(-1) cm(-1)]. Moreover, the Tb(3+) complexes 3 and 4 exhibit bright green luminescence efficiencies in the solid state (Phi(overall) = 60% for 3; 27% for 4) and possess longer excited state lifetimes than the other complexes (tau = 1.16 ms for 3; 1.38 ms for 4). In contrast to the foregoing, the Eu(3+) complexes 1 and 2 feature poor luminescence efficiencies. PMID- 21534616 TI - Potassium hydroxide/dimethyl sulfoxide promoted intramolecular cyclization for the synthesis of benzimidazol-2-ones. AB - A new protocol for intramolecular N-arylations of ureas to form benzimidazol-2 ones has been developed. The cyclization reaction occurs in the presence of KOH and DMSO at close to ambient temperature. Under these conditions the yields are high and a wide range of functional groups are tolerated. PMID- 21534617 TI - Enantioselective recognition in biomimetic single artificial nanochannels. AB - Efficient enantiomer discrimination with a convenient system remains a challenge in the fields of biochemistry, medical science, and pharmaceutics. Here we report a simple enantioselective sensing device based on a single artificial beta cyclodextrin-modified nanochannel system. This nanodevice shows highly selective recognition of histidine enantiomers through monitoring of ionic current signatures. PMID- 21534618 TI - The splice variant of the V2 vasopressin receptor adopts alternative topologies. AB - The V2 receptor gene encodes two receptor variants by alternative splicing, the canonical V2 receptor (V2a receptor) and V2b. The V2b variant has an amino acid sequence identical to that of the V2a receptor up to the sixth transmembrane domain, but the V2b sequences corresponding to the putative seventh transmembrane domain and the carboxyl terminus are different from those of the V2a receptor. Here we investigate the topology and subcellular distribution of the V2b variant. We found that, in contrast to the V2a receptor, the V2b adopted two topologies: one with six transmembrane segments with the C-terminus on the extracellular side of the membrane and another with seven transmembrane segments with the C-terminus on the intracellular side, similar to typical G-protein-coupled receptors. Furthermore, we observed that both topological isoforms oligomerized with the V2a canonical receptor. Unlike the V2a receptor, V2b did not move to the plasma membrane, but it is retained in the ER--Golgi compartments. These findings indicate that the C-terminal sequence beyond the sixth transmembrane of the V2a is required for the stabilization of the seven-transmembrane topology of the receptor and is also essential for the trafficking of the receptor to the plasma membrane. PMID- 21534619 TI - How do aminoadamantanes block the influenza M2 channel, and how does resistance develop? AB - The interactions between channels and their cognate blockers are at the heart of numerous biomedical phenomena. Herein, we unravel one particularly important example bearing direct pharmaceutical relevance: the blockage mechanism of the influenza M2 channel by the anti-flu amino-adamantyls (amantadine and rimantadine) and how the channel and, consequently, the virus develop resistance against them. Using both computational analyses and experimental verification, we find that amino-adamantyls inhibit M2's H(+) channel activity by electrostatic hindrance due to their positively charged amino group. In contrast, the hydrophobic adamantyl moiety on its own does not impact conductivity. Additionally, we were able to uncover how mutations in M2 are capable of retaining drug binding on the one hand yet rendering the protein and the mutated virus resistant to amino-adamantyls on the other hand. We show that the mutated, drug-resistant protein has a larger binding pocket for the drug. Hence, despite binding the channel, the drug remains sufficiently mobile so as not to exert a H(+)-blocking positive electrostatic hindrance. Such insight into the blocking mechanism of amino-adamantyls, and resistance thereof, may aid in the design of next-generation anti-flu agents. PMID- 21534620 TI - A missing enzyme in thiamin thiazole biosynthesis: identification of TenI as a thiazole tautomerase. AB - In many bacteria tenI is found clustered with genes involved in thiamin thiazole biosynthesis. However, while TenI shows high sequence similarity with thiamin phosphate synthase, the purified protein has no thiamin phosphate synthase activity, and the role of this enzyme in thiamin biosynthesis remains unknown. In this contribution, we identify the function of TenI as a thiazole tautomerase, describe the structure of the enzyme complexed with its reaction product, identify the substrates phosphate and histidine 122 as the acid/base residues involved in catalysis, and propose a mechanism for the reaction. The identification of the function of TenI completes the identification of all of the enzymes needed for thiamin biosynthesis by the major bacterial pathway. PMID- 21534621 TI - Silver-catalyzed cycloisomerization of 1,n-allenynamides. AB - A variety of allenynamides can undergo cycloisomerization reactions in the presence of silver triflate thus leading to the formation of N-containing heterocycles incorporating cross-conjugated trienes. Access to new dienic 4 piperidinone and azepane motifs was achieved. An extension to one-pot tandem sequences involving silver-catalyzed cycloisomerization/Diels-Alder reaction was also examined. PMID- 21534622 TI - Shape-memory effects in biopolymer networks with collagen-like transient nodes. AB - In this article we study shape-memory behavior of hydrogels, formed by biodegradable and biocompatible recombinant telechelic polypeptides, with collagen-like end blocks and a random coil-like middle block. The programmed shape of these hydrogels was achieved by chemical cross-linking of lysine residues present in the random coil. This led to soft networks, which can be stretched up to 200% and "pinned" in a temporary shape by lowering the temperature and allowing the collagen-like end blocks to assemble into physical nodes. The deformed shape of the hydrogel can be maintained, at room temperature, for several days, or relaxed within a few minutes upon heating to 50 degrees C or higher. The presented hydrogels could return to their programmed shape even after several thermomechanical cycles, indicating that they remember the programmed shape. The kinetics of shape recovery at different temperatures was studied in more detail and analyzed using a mechanical model composed of two springs and a dashpot. PMID- 21534623 TI - Acute, sublethal cyanide poisoning in mice is ameliorated by nitrite alone: complications arising from concomitant administration of nitrite and thiosulfate as an antidotal combination. AB - Sodium nitrite alone is shown to ameliorate sublethal cyanide toxicity in mice when given from ~1 h before until 20 min after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose-dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase, the effects of the two inhibitors being essentially additive under standard assay conditions rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sublethal levels of cyanide intoxication. PMID- 21534624 TI - Absorption of 6-O-caffeoylsophorose and its metabolites in Sprague-Dawley rats detected by electrochemical detector-high-performance liquid chromatography and electrospray ionization-time-of-flight-mass spectrometry methods. AB - Absorption and metabolism of a natural compound, 6-O-caffeoylsophorose (CS) from acylated anthocyanins in a red vinegar fermented with purple sweet potato, were clarified. The absorption of CS and conjugated CS in blood from orally administrated Sprague-Dawley rats at a dose of 400 mg/kg was investigated by electrochemical detection-high performance liquid chromatography. As a result, CS was successfully detected in rat plasma (AUC(0-6h), 108.6 +/- 8.1 nmol h/mL) and was found to be an intact absorbable polyphenol. In addition, half of the absorbed CS was detected as its conjugates (AUC(0-6h), 50.7 +/- 5.7 nmol h/mL) as well as caffeic and ferulic acids from CS. By a time-of-flight-mass spectrometric analysis of CS-administered plasma sample, glucuronide and methylated conjugates of CS were identified, in addition to glucuronide, methylated, or sulfate conjugates of caffeic and ferulic acids. Consequently, CS was absorbed in intact form into rat blood and partly degraded to caffeic and ferulic acids or metabolized by glucuronidation, methylation, or sulfatation. PMID- 21534625 TI - A scalable synthesis of methano[60]fullerene and congeners by the oxidative cyclopropanation reaction of silylmethylfullerene. AB - 1,2-Dihydromethano[60]fullerene and its congeners have attracted much interest, but they have been synthesized only in very low yields because of several insurmountable problems. A new three-stage synthesis involving addition of a silylmethylmagnesium chloride to [60]- and [70]fullerene and oxidation of the anionic intermediate with CuCl(2) afforded the methano[60]- and methano[70]fullerenes in 90% and 70% overall yield, respectively. The reaction with 1,4-diorgano[60]fullerene also proceeded smoothly to give a diastereomerically pure 56-pi-electron fullerene that has a higher LUMO level than the parent fullerene and gave a higher open-circuit voltage and better power conversion efficiency when fabricated into an organic photovoltaic device. PMID- 21534626 TI - Helimeric porphyrinoids: stereostructure and chiral resolution of meso tetraarylmorpholinochlorins. AB - The synthesis and chiral resolution of free-base and Ni(II) complexes of a number of derivatives of meso-tetraphenylmorpholinochlorins, with and without direct beta-carbon-to-o-phenyl linkages to the flanking phenyl groups, is described. The morpholinochlorins, a class of stable chlorin analogues, were synthesized in two to three steps from meso-tetraphenylporphyrin. The conformations and the relative stereostructures of a variety of free-base and Ni(II) complexes of these morpholinochlorins were elucidated by X-ray diffractometry. Steric and stereoelectronic arguments explain the relative stereoarray of the morpholino substituents, which differ in the free-base and Ni(II) complexes, and in the monoalkoxy, beta-carbon-to-o-phenyl linked morpholinochlorins, and the dialkoxy derivatives. The Ni(II) complexes were all found to be severely ruffled whereas the free-base chromophores are more planar. As a result of the helimeric distortion of their porphyrinoid chromophores, the ruffled macrocycles possess a stable inherent element of chirality. Most significantly, resolution of the racemic mixtures was achieved, both by classical methods via diastereomers and by HPLC on a chiral phase. Full CD spectra were recorded and modeled using quantum chemical computational methods, permitting, for the first time, an assignment of the absolute configurations of the chromophores. The report expands the range of known pyrrole-modified porphyrins. Beyond this, it introduces large chiral porphyrinoid pi-systems that exist in the form of two enantiomeric, stereochemically stable helimers that can be resolved. This forms the basis for possible future applications, for example, in molecular-recognition systems or in materials with chiroptic properties. PMID- 21534627 TI - One-step synthesis of CdS sensitized TiO2 photoanodes for quantum dot-sensitized solar cells by microwave assisted chemical bath deposition method. AB - Sensitized-type solar cells based on TiO2 photoanodes and CdS quantum dots (QDs) as sensitizers have been studied. CdS QDs are grown on TiO2 films, utilizing one step microwave assisted chemical bath deposition (MACBD) method. This method allows a facile and rapid deposition and integration between CdS QDs and TiO2 films. The photovoltaic performances of the cells fabricated using CdS precursor solutions with different concentrations are investigated. The results show that the cell based on MACBD deposited TiO2/CdS electrode achieves a maximum short circuit current density of 7.20 mAcm-2 and power conversion efficiency of 1.18 % at one sun (AM 1.5G, 100 mW cm-2), which is comparable to the ones prepared using conventional techniques. PMID- 21534628 TI - Role of the raw composition of pelagic fish muscle on the development of lipid oxidation and rancidity during storage. AB - The muscle composition of a pelagic fish species, Atlantic mackerel (Scomber scombrus), has been studied to determine the relationship with its susceptibility to develop lipid oxidation during chilled storage. For such an aim, the initial concentrations of the major components (water, total lipids, protein, and PUFAs) and minor pro-oxidant and antioxidant components (ascorbic acid, alpha tocopherol, hemoglobin, total iron, LMW-iron, copper, and zinc) of different batches of mackerel were characterized. For the study, several batches of mackerel were caught during the spring and summer periods. The different batches were subjected to chilled storage, and the onset of lipid oxidation was statistically related with the initial muscle composition. Results showed significant compositional differences among the mackerel lots, especially for the muscle lipid content (2.83-9.50%). In a first step, a Pearson correlation test was used to check the influence of each component on the progress of lipid oxidation. Results showed a significant relationship between shelf life and water and total lipid contents. Multiple regression was performed to reveal the contribution of each component to the susceptibility to lipid oxidation. The model obtained combines the content of PUFAs, total iron, hemoglobin, and ascorbic acid. An accurate prediction of shelf life in terms of rancidity was achieved by the model created (R(2) = 0.9975). These results establish that the levels of endogenous pro-oxidants and antioxidants present in fish muscle together with the polyunsaturated lipids are relevant factors affecting the shelf life of mackerel muscle. PMID- 21534629 TI - Dietary grape-seed procyanidins decreased postweaning diarrhea by modulating intestinal permeability and suppressing oxidative stress in rats. AB - This study was conducted to evaluate the effects of grape-seed procyanidins in controlling weaning diarrhea using a rat model. Weaned rats were fed either the basal diet or basal diet supplemented with either 250 mg/kg grape-seed procyanidins or 2000 mg/kg ZnO. Treated rats had better performance with a reduced incidence of diarrhea (P < 0.05). Both ZnO and grape-seed procyanidins significantly reduced urinary lactulose to mannitol ratios (P < 0.05) and enhanced the mRNA and protein expression of the intestinal mucosal tight junction proteins Ocln/ZO-1 (P < 0.05). Grape-seed procyanidins increased the activities of SOD, GSH-Px, and GSH while decreasing the level of MDA in the intestinal mucosa (P < 0.05). Furthermore, an in vitro investigation revealed that supplementation with grape-seed procyanidins in IEC-6 intestinal epithelial cells significantly enhanced the expression of Ocln/ZO-1 under H(2)O(2)-induced oxidative stress. Collectively, these results indicate that grape-seed procyanidins have the potential to prevent weaning diarrhea by reducing intestinal permeability and improving antioxidant indices. PMID- 21534630 TI - Coordination mode dependent excited state behavior in group 8 phosphino(terthiophene) complexes. AB - The ground and excited state behavior of four Ru(II) and Os(II) bipyridyl complexes containing the 3'-(diphenylphosphino)-2,2':5',2''-terthiophene (PT(3)) ligand in two different coordination modes (P,S and P,C) is reported. The complexes are generally stable under extended photoirradiation, except for [Ru(bpy)(2)PT(3)-P,S](PF(6))(2) which decomposes. Emission lifetimes and transient absorption spectra and lifetimes have been obtained for all the complexes. These data support a PT(3) ligand based lowest excited state in the case of both P,S bound complexes, and a charge separated lowest excited state in both P,C bound complexes, conclusions supported by Density Functional Theory (DFT) calculations. PMID- 21534631 TI - Widespread occurrence of low levels of alternariol in apple and tomato products, as determined by comparative immunochemical assessment using monoclonal and polyclonal antibodies. AB - This study investigated the production of polyclonal (pAB) antibodies and the first time production of monoclonal (mAB) antibodies against the mycotoxin alternariol, and their implementation in enzyme immunoassay (EIA) for the rapid determination of alternariol in foods. Both EIAs were highly sensitive, with detection limits (IC20) of 35 +/- 6.9 pg/mL (mAb EIA) and 59 +/- 16 pg/mL (pAb EIA). Food products (n = 109; apple and tomato products, white wine) from German retail shops were analyzed. At a detection limit of 1-2 MUg/kg, alternariol at 1 13 MUg/kg was found with high frequency in apple (67%) and tomato (93%) products. Tomatoes with visible signs of Alternaria infection, stored at room temperature for up to 4 weeks, contained alternariol at levels up to 50 mg/kg, as determined by EIA and HPLC-FLD. It is concluded that the alternariol immunoassays present a versatile screening tool which could facilitate food control for Alternaria toxins. PMID- 21534633 TI - Generation and reactivity of aza-oxyallyl cationic intermediates: aza-[4 + 3] cycloaddition reactions for heterocycle synthesis. AB - Aza-[4 + 3] cycloadditions of putative aza-oxyallyl cationic intermediates and cyclic dienes are reported. The intermediate is generated by the dehydrohalogenation of alpha-haloamides. The reaction is general to a variety of alpha-haloamides and is diastereoselective. Computational and experimental data suggest that an N-alkoxy substituent stabilizes the aza-oxyallyl cationic intermediate. PMID- 21534632 TI - Triply responsive films in bioelectrocatalysis with a binary architecture: combined layer-by-layer assembly and hydrogel polymerization. AB - In this work, triply responsive films with a specific binary architecture combining layer-by-layer assembly (LbL) and hydrogel polymerization were successfully prepared. First, concanavalin A (Con A) and dextran (Dex) were assembled into {Con A/Dex}(5) LbL layers on electrode surface by the lectin-sugar biospecific interaction between them. The poly(N,N-diethylacrylamide) (PDEA) hydrogels with entrapped horseradish peroxidase (HRP) were then synthesized by polymerization on the surface of LbL inner layers, forming {Con A/Dex}(5)-(PDEA HRP) films. The films demonstrated reversible pH-, thermo-, and salt-responsive on-off behavior toward electroactive probe Fe(CN)(6)(3-) in its cyclic voltammetric responses. This multiple stimuli-responsive films could be further used to realize triply switchable electrochemical reduction of H(2)O(2) catalyzed by HRP immobilized in the films and mediated by Fe(CN)(6)(3-) in solution. The responsive mechanism of the films was explored and discussed. The pH-sensitive property of the system was attributed to the electrostatic interaction between the {Con A/Dex}(5) inner layers and the probe at different pH, and the thermo- and salt-responsive behaviors should be ascribed to the structure change of PDEA hydrogels for the PDEA-HRP outermost layers under different conditions. The concept of binary architecture was also used to fabricate {Con A/Dex}(5)-(PDEA GOD) films on electrodes, where GOD = glucose oxidase, which was applied to realize the triply switchable bioelectrocatalysis of glucose by GOD in the films with ferrocenedicarboxylic acid as the mediator in solution. This film system with the unique binary architecture may establish a foundation for fabricating a novel type of multicontrollable biosensors based on bioelectrocatalysis with immobilized enzymes. PMID- 21534634 TI - Confinement effect on p-nitroaniline electronic spectrum and electric properties. AB - An analysis of the behavior of the p-nitroaniline excitations in confinement is performed. Various confining environments are chosen to demonstrate the chemical pressure exerted by a homogeneous cylindrical structure (single-walled carbon (4,4) nanotube), a heterogeneous cylindrical structure (boron nitride (4,4) nanotube), and a spheroidal homogeneous structure (C(92) fullerene buckyball of the original D(2) symmetry). The highest interaction energy was found for pNA in the carbonaceous cages; however, its estimation must be performed with a careful choice of the approximation. Boron nitride tube with a relatively large band gap appears to be an interesting environment modifying the electronic spectrum of pNA. PMID- 21534635 TI - Novel comprehensive approach for accessible biomarker identification and absolute quantification from precious human tissues. AB - The identification of specific biomarkers obtained directly from human pathological lesions remains a major challenge, because the amount of tissue available is often very limited. We have developed a novel, comprehensive, and efficient method permitting the identification and absolute quantification of potentially accessible proteins in such precious samples. This protein subclass comprises cell membrane associated and extracellular proteins, which are reachable by systemically deliverable substances and hence especially suitable for diagnosis and targeted therapy applications. To isolate such proteins, we exploited the ability of chemically modified biotin to label ex vivo accessible proteins and the fact that most of these proteins are glycosylated. This approach consists of three successive steps involving first the linkage of potentially accessible proteins to biotin molecules followed by their purification. The remaining proteins are then subjected to glycopeptide isolation. Finally, the analysis of the nonglycosylated peptides and their involvement in an in silico method increased the confident identification of glycoproteins. The value of the technique was demonstrated on human breast cancer tissue samples originating from 5 individuals. Altogether, the method delivered quantitative data on more than 400 potentially accessible proteins (per sample and replicate). In comparison to biotinylation or glycoprotein analysis alone, the sequential method significantly increased the number (>=30% and >=50% respectively) of potentially therapeutically and diagnostically valuable proteins. The sequential method led to the identification of 93 differentially modulated proteins, among which several were not reported to be associated with the breast cancer. One of these novel potential biomarkers was CD276, a cell membrane-associated glycoprotein. The immunohistochemistry analysis showed that CD276 is significantly differentially expressed in a series of breast cancer lesions. Due to the fact that our technology is applicable to any type of tissue biopsy, it bears the ability to accelerate the discovery of new relevant biomarkers in a broad spectrum of pathologies. PMID- 21534636 TI - Factors influencing the soil-air partitioning and the strength of soils as a secondary source of polychlorinated biphenyls to the atmosphere. AB - Soils are a major reservoir of persistent organic pollutants, and soil-air partitioning and exchange are key processes controlling the atmospheric concentrations and regional fate of pollutants. Here, we report and discuss the concentrations of polychlorinated biphenyls (PCBs) in soils, their measured fugacities in soil, the soil-air partition coefficients (K(SA)) and soil-air fugacity gradients in rural background areas of N-NE Spain and N-NW England. Four sampling campaigns were carried out to assess seasonal and daily variability and differences between sampling sites. K(SA) values were significantly dependent on soil temperature and soil organic matter quantity, and to a minor extent organic matter type. All the PCB congeners in the soil are close to equilibrium with the atmosphere at rural Ebro sites, but soil fugacities tend to be higher than ambient air fugacities in early and late summer, consistent with the influence of temperature on soil-air partitioning. Therefore, during warm periods, soils increment their strength as secondary sources to the atmosphere. The mixture of PCBs found in the atmosphere is clearly strongly influenced by the mixture of PCBs which escape from soil, with significant correlations between them (R(2) ranging between 0.35 and 0.74 and p-level <0.001 for the Ebro sampling sites). Conversely, the close-to-equilibrium to net sink status of rural UK sites, suggest a close coupling of air and soil concentrations, but it is not possible to elucidate the importance of these soils as secondary sources yet, and presumably there are still significant primary sources to the regional/global environment. PMID- 21534637 TI - Contribution from urban heating to China's 2020 goal of emission reduction. AB - To reduce inhalable particle and SO(x) pollution from coal-based urban central heating (UCH), China has been vigorously developing natural gas-based UCH for years. The CO(2) emissions of UCH, having an average annual growth rate of 10.3%, accounted for 4.4% of China's total CO(2) emissions in 2009. This paper analyzes the feasibility of replacing UCH with heat pump heating (HPH) in China's climatic suitable regions and evaluates the corresponding potential for energy saving and emission reduction. Current strategy of replacing coal-based UCH with natural gas based UCH is expected to decrease CO(2) emissions by 63.5%. However, the CO(2) emissions of HPH are 55.4% less than those of natural gas-based UCH. Replacing coal-based UCH with HPH is capable of decreasing CO(2) emissions by 83.7% and consequently decreases the CO(2) emissions per unit of gross domestic product (GDP) by 4.2% by 2020 compared with 2005 level. This contributes about 10.5% to China's 2020 CO(2) emission reduction target. For controlling environmental pollution and protecting ecological environment better, China should adjust its strategy for CO(2) emission reduction by shifting its attention from replacing coal-based UCH with natural gas-based UCH to popularizing HPH in climatic suitable regions. PMID- 21534638 TI - Medical foods for Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative condition associated with cognitive loss, behavioural changes, functional ability decline and caregiver burden. Given the worldwide public health impact of AD, novel interventions to reduce suffering experienced by AD patients need to be developed. Foods may offer a mechanism for intervention complementary to drugs, devices, biologicals and vaccines. Apart from foods with health claims (including dietary supplements), medical foods are also being explored as an intervention option. The purpose of this article is to describe how medical foods may complement other interventions for AD patients by: (i) defining what a medical food is; (ii) discussing whether AD is a condition amenable to medical food intervention; (iii) reviewing current clinical trial data on medical foods used in participants with AD; and (iv) highlighting steps needed to establish a more comprehensive framework for developing medical foods for AD. While medical foods may be defined differently in other countries, the US Orphan Drug Act of 1998 defined a medical food as a food formulated for enteral intake, taken under physician supervision, and intended to meet the distinctive nutritional requirements identified for a disease or condition. For AD to be amenable to medical food intervention, it must: (i) result in limited or impaired capacity to ingest, digest, absorb or metabolize ordinary foodstuff or certain nutrients; or (ii) have unique, medically determined nutrient requirements; and (iii) require dietary management that cannot be achieved by modification of the normal diet alone. While these criteria are most likely met in advanced AD, identifying unique nutritional requirements in early AD that cannot be met by normal diet modification requires a better understanding of AD pathophysiology. A PubMed search using the terms 'medical food' and 'Alzheimer', limited to clinical trials published in English with human participants with AD aged >65 years and supplemented by other articles known to meet the inclusion criteria, revealed that only two medical foods, AC 1202 and Souvenaid(r) with Fortasyn ConnectTM, have clinical trial results available for discussion. As medical food development for AD is a relatively new endeavour, a window of opportunity exists for all stakeholders to develop a comprehensive framework for assuring that medical food interventions for AD achieve the highest possible scientific and ethical standards to warrant commercialization. PMID- 21534639 TI - Prioritizing comparative effectiveness research: are drug and implementation trials equally worth funding? AB - Comparative effectiveness research (CER) is the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor a clinical condition, or to improve the delivery of care. The purpose of this article is to compare--within the scope of CER--the value of implementation and drug trials. Implementation trials have limitations similar to drug trials in terms of generalizability of results outside the trial setting and ability to identify best practice. However, in contrast to drug trials, implementation trials do not provide value in terms of ruling out harm, as implementation strategies are unlikely to cause harm in the first place. Still, implementation trials may provide good value when there is a high error probability in deciding whether implementation will be cost effective or if costs associated with making an erroneous decision are high. Yet the low risk of implementation programmes to cause harm may also allow for alternative approaches to identify best implementation practice, perhaps outside the scope of rigorous trials and testing. One such approach that requires further investigation is a competitive market for quality of care, where implementation programmes may be introduced without prior evaluation. PMID- 21534640 TI - A randomized controlled trial to assess pharmacist- physician collaborative practice in the management of metabolic syndrome in a university medical clinic in Jordan. AB - BACKGROUND: The prevalence of metabolic syndrome is increasing worldwide, and patients with metabolic syndrome have increased risk of developing cardiovascular disease and type 2 diabetes. Although specific criteria vary, the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) criteria (2002) defined metabolic syndrome as the presence of 3 or more of the following 5 components: waist circumference more than 102 centimeters (cm) for men or more than 88 cm for women; triglycerides 150 milligrams per deciliter (mg per dL) or more; high-density lipoprotein cholesterol (HDL-C) less than 40 mg per dL for men or less than 50 mg per dL for women; blood pressure (BP) 130/85 millimeters mercury (mm Hg) or more; and fasting blood glucose 110 mg per dL or more. OBJECTIVE: To evaluate the effect of a pharmacist-physician collaborative practice compared with usual care in the management of patients with metabolic syndrome as defined by the NCEP/ATP III criteria. METHODS: A prospective, randomized controlled trial conducted in family medicine outpatient clinics in Jordan enrolled 199 patients who met the NCEP/ATP III criteria for metabolic syndrome during an enrollment period from March 15, 2009, through May 10, 2009. Patients were randomized into 2 groups, with 110 in the intervention group (pharmacist-physician collaborative practice) and 89 in usual care (physician only). The patients in the intervention group were provided with pharmacist recommendations and pharmaceutical care counseling. Outcome measures included metabolic syndrome status (binomial) and changes in mean values for each metabolic syndrome component (waist circumference, triglycerides, HDL-C, fasting blood glucose, and systolic and diastolic BP) and for body weight. A 2 ? 2 contingency table with a Pearson chi-square test was used to assess bygroup differences in metabolic syndrome status after 6 months of followup. In difference-in-difference analyses, t-tests (Mann-Whitney U tests when appropriate) were used to assess by-group differences in changes in the individual metabolic syndrome components and body weight. RESULTS: From baseline to follow-up, 39.1% (n = 43) of intervention group patients versus 24.7% (n = 22) of usual care patients were successfully shifted from a status of metabolic syndrome to no metabolic syndrome (P = 0.032). Three of 7 outcome measures were improved more in the intervention group compared with the usual care group. Mean (SD) triglyceride (mg per dL) declined by 30.9 (54.4) from 189.3 (79.6) to 158.4 (77.3) in the intervention group and by 14.5 (50.7) from 202.5 (88.0) to 188.5 (89.0) in the usual care group (P = 0.029). For the intervention and usual care groups, mean baseline systolic BPs were 134.7 (16.2) mm Hg and 134.6 (12.2) mm Hg, respectively, declining after 6 months follow-up by 12.1 (20.1) mm Hg in the intervention group versus 6.9 (14.6) mm Hg in the usual care group (P = 0.018). Mean baseline diastolic BPs were 83.6 (10.7) mm Hg and 83.6 (7.9) mm Hg, respectively, declining by 7.2 (12.6) mm Hg in the intervention group versus 4.9 (8.1) mm Hg in the usual care group (P = 0.049). CONCLUSIONS: Compared with usual care provided by physicians only, pharmacist involvement in the clinical management of patients with metabolic syndrome increased the proportion of patients who no longer met criteria for the syndrome after 6 months follow-up and improved control of BP and triglycerides. PMID- 21534641 TI - Prevalence of achievement of A1c, blood pressure, and cholesterol (ABC) goal in veterans with diabetes. AB - BACKGROUND: The "ABCs of Diabetes" are defined as hemoglobin A1c < 7.0%, blood pressure < 130/80 millimeters mercury (mm Hg), and lowdensity lipoprotein cholesterol (LDL-C) < 100 milligrams per deciliter (mg per dL). Assessments of 3 part goal attainment of A1c, blood pressure, and cholesterol have been reported using data from the National Health and Nutrition Examination Survey (NHANES) for several time periods (e.g., 1988-1994, 1999-2000, 1999-2002, and 2003-2004), Look Action for Health in Diabetes (Look AHEAD, 2001-2004), and community-based endocrinology practice (CBEP, 2000-2004). In 2002, an unpublished analysis of data from 2001-2002 at the Iowa City Veterans Affairs (ICVA) Medical Center found less than 50% of patients met each of the 3 individual goals. In the 5 years following the 2001-2002 assessment, the care for veterans with diabetes at the ICVA was enhanced to include (a) an increased number of diabetes classes and clinics, (b) implementation of the diabetes Care Coordination/Home Telehealth (CCHT) program, and (c) clinical reminders for diabetes performance measures that were added to the electronic medical record (EMR). OBJECTIVES: To (a) describe the prevalence of veterans meeting the ABC goals of diabetes in 1 VA medical center; (b) differentiate the proportion of diabetes patients who met the individual targets for A1c, blood pressure, and LDL-C and compare the results for 2008 through September 2009 with the earlier data from this facility (2001-2002); and (c) examine results reported previously in the literature for NHANES, Look AHEAD, and CBEP data sources. METHODS: Single-center, retrospective analysis of veterans at the ICVA for dates of service from January 1, 2008, through September 30, 2009, who (a) filled at least 1 prescription for an antidiabetic medication and (b) had each of the 3 biomarker values recorded in the EMR for A1c, blood pressure, and LDL-C after the antidiabetic prescription fill date. RESULTS: Of the 5,426 (97.6% male) patients meeting inclusion criteria in 2008-2009, 17.3% (n = 936) achieved the 3-part ABC goal. In this managed care setting, achievement of the 3-part ABC goal surpassed the proportions reported in previous studies in NHANES data (5.2% in 1988-1994, 7.3% in 1999-2000, 7.0% in 1999-2002, 13.2% in 2003-2004), and 10.1% in Look AHEAD 2001-2004, but fell short of the 22.0% reported in CBEP 2000- 2004. When compared with the 2001-2002 results at ICVA, the proportion of patients achieving the individual A1c goal in 2008-2009 increased by 10.8 percentage points (from 43.2% to 54.0%), 12.6 percentage points for blood pressure (from 29.2% to 41.8%), and 17.1 percentage points for LDL-C (from 49.5% to 66.6%, P < 0.001) for the 3 individual comparisons. CONCLUSIONS: The proportion of patients achieving each of the 3 goals for A1c, blood pressure, and LDL-C improved significantly in 2008-2009 compared with the 2001-2002 assessment in this medical center, following implementation of yearly clinical reminders for diabetes care, enhanced patient education, and other program changes that included home-based telephone monitoring with diabetes case management for some patients. Achievement of the 3-part ABC goal in 2008-2009 (17.3%) surpassed 5 assessments reported in the literature but was lower than the CBEP (2000- 2004) performance (22.0%). PMID- 21534642 TI - Analysis of drug and administrative costs allowed by U.S. Private and public third-party payers for 3 intravenous biologic agents for rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a common chronic condition with substantial morbidity that can now be treated with disease-modifying biologic agents that target tumor necrosis factor (TNF) or related mechanisms. The anti TNF biologic agents are available in either intravenous (IV) or subcutaneous dose forms. The biologic agents with an indication for rheumatoid arthritis and administered only by IV infusion in medical offices include abatacept, infliximab, and rituximab. Although the literature on RA treatments, their outcomes, and aspects of their costs is substantial, the costs of administration by the IV route have not been directly studied. OBJECTIVE: To assess the detailed costs of administering IV biologic agents for the treatment of RA in relation to the total cost of the medication itself in the United States. METHODS: The sample included all patients with at least 1 medical claim with an ICD-9-CM diagnosis code for RA (codes 714.XX) in any claim field and at least 1 claim for infliximab, abatacept, or rituximab (HCPCS codes J1745, J0129, and J9310, respectively) at any time from January 1, 2006, through December 31, 2008, in a database associated with billing and claims administration for 72 U.S. medical clinics. Costs were determined using the payer allowed payment, which is the total contractual amount that the provider should receive, including the patient cost share. Costs were measured as the average cost per IV administration visit and in relation to the dose of medication billed. The authors verified that an RA diagnosis was present on 100% of infusion claims for the study drugs. RESULTS: Over the study period for claims with dates of service from January 1, 2006, through December 31, 2008, 72 medical clinics had claims for a total of 4,248 unique patients with RA and a total of 33,354 clinic visits in which these patients received at least 1 infusion of 1 of 3 biologic agents (26,586 for infliximab, 4,807 for abatacept, and 1,961 for rituximab). Mean (SD) total payment for all drugs and other cost components was $2,874 ($1,515) per visit, of which IV administration costs were $226 (7.9%); the mean cost of the biologic agent itself was $2,616 (91.0%), and other visit-related services were $33 (1.1%). For individual agents, the total costs of visits were $2,828, $1,827, and $6,076; and the costs of IV administration were $224, $171, and $390, respectively, for infliximab, abatacept, and rituximab. CONCLUSION: For patients who received an IV biologic agent to treat RA, IV administration costs accounted for 7.9% of the total cost of the visit. PMID- 21534643 TI - The case for standardizing the appearance of bioequivalent medications. PMID- 21534644 TI - Alcohol approach tendencies in heavy drinkers: comparison of effects in a Relevant Stimulus-Response Compatibility task and an approach/avoidance Simon task. AB - Several recent studies suggest that alcohol-related cues elicit automatic approach tendencies in heavy drinkers. A variety of tasks have been used to demonstrate these effects, including Relevant Stimulus-Response Compatibility (R SRC) tasks and variants of Simon tasks. Previous work with normative stimuli suggests that the R-SRC task may be more sensitive than Simon tasks because the activation of approach tendencies may depend on encoding of the stimuli as alcohol-related, which occurs in the R-SRC task but not in Simon tasks. Our aim was to directly compare these tasks for the first time in the context of alcohol use. We administered alcohol versions of an R-SRC task and a Simon task to 62 social drinkers, who were designated as heavy or light drinkers based on a median split of their weekly alcohol consumption. Results indicated that, compared to light drinkers, heavy drinkers were faster to approach, rather than avoid, alcohol-related pictures in the R-SRC task but not in the Simon task. Theoretical implications and methodological issues are discussed. PMID- 21534645 TI - Thinking and drinking: alcohol-related cognitions across stages of adolescent alcohol involvement. AB - Alcohol-related cognitions, particularly expectancies for drinking and nondrinking and motives for nondrinking, are involved in the initiation, maintenance, and cessation of alcohol use and are hypothesized to play key roles in adolescent decision making. This study explored (a) the relationships between alcohol use expectancies, nondrinking expectancies, and nondrinking motives; (b) the roles of these cognitions across hypothesized developmental stages of adolescent alcohol use; and (c) the relationships between these cognitions and recent or intended future changes in drinking behavior in a cross-sectional sample. Surveys assessing alcohol use behaviors and attitudes were administered to 1,648 high school students. Heavier drinkers reported more positive alcohol use expectancies and fewer nondrinking motives than did lighter drinkers or nondrinkers; however, nondrinking expectancies only differed between nondrinkers and rare drinkers and all subsequent drinking classes. Alcohol use expectancies, nondrinking expectancies, and nondrinking motives differentiated students who recently initiated alcohol from those who had not, while nondrinking expectancies and nondrinking motives differentiated binge-drinking students who had made recent efforts to reduce/stop their drinking from those who had not. Intentions to initiate or reduce drinking in the coming month were also associated with these alcohol-related cognitions. Drinking and nondrinking expectancies and motives for not drinking may play critical roles in decisions to alter alcohol use behavior during adolescence. Future exploration of temporal relationships between changes in alcohol-related cognitions and behavioral decision making will be useful in the refinement of effective prevention and intervention strategies. PMID- 21534647 TI - Right-handedness predominance in 162 baboons (Papio anubis) for gestural communication: consistency across time and groups. AB - Whether nonhuman primates exhibit population level right manual bias remains a controversial topic. In captive baboons, population-level right-handedness has been reported for both coordinated bimanual actions and communicative gestures. However, some authors remain skeptical of these findings on both methodological and theoretical grounds. Here, we demonstrated the robustness and the consistency across time of the pattern of right-handedness for a species-specific communicative gesture in olive baboons (Papio anubis). First, we showed significant correlations in the 26 retested baboons for the measures of hand preferences between the first and the second session conducted 4 years later (2005-2009) by an observer blind to the previous handedness data. Second, the replication of the study in 96 novel individuals revealed a similar degree of population-level right-handedness than the one expressed in the first group of 66 subjects investigated in 2005. The implications of the findings are discussed within a theoretical framework about the origin of hemispheric specialization for language. PMID- 21534646 TI - Developmental pathways to adolescent cannabis abuse and dependence: child maltreatment, emerging personality, and internalizing versus externalizing psychopathology. AB - Child maltreatment is strongly associated with adolescent psychopathology and substance abuse and dependence. However, developmental processes unfolding from childhood into adolescence that delineate this trajectory are not well understood. The current study used path analysis in a structural equation modeling framework to examine multiple mediator models, including ego control, ego resiliency, and internalizing and externalizing symptoms to investigate this developmental process. Participants were 415 children, assessed across 3 waves of data, (i.e., at ages 7 to 9, 10 to 12, and 13 to 15). The sample included maltreated (n = 259) and nonmaltreated (n = 156) children; groups were comparable in sociodemographic characteristics. Findings support an transactional-ecological model by revealing a developmental sequence in which severity of early childhood maltreatment potentiates less adaptive childhood personality functioning, followed by externalizing problems in preadolescence, and ultimately adolescent cannabis abuse and dependence symptoms. A developmental pathway from child maltreatment to adolescent cannabis abuse and dependence symptoms via personality and preadolescent internalizing problems was not supported. Understanding developmental pathways by which maltreatment experiences increase risk for substance abuse and dependence symptoms in youth has far-reaching implications for the treatment and prevention of substance use disorders. PMID- 21534648 TI - Amphetamine-induced incentive sensitization of sign-tracking behavior in adolescent and adult female rats. AB - Age-specific behavioral and neural characteristics may predispose adolescents to initiate and escalate use of alcohol and drugs. Adolescents may avidly seek novel experiences, including drugs of abuse, because of enhanced incentive motivation for drugs and natural rewards, perhaps especially when that incentive motivation is sensitized by prior drug exposure. Using a Pavlovian conditioned approach (PCA) procedure, sign-tracking (ST) and goal-tracking (GT) behavior was examined in amphetamine-sensitized and control adolescent and adult female Sprague-Dawley rats, with expression of elevated ST behavior used to index enhanced incentive motivation for reward-associated cues. Rats were first exposed to a sensitizing regimen of amphetamine injections (3.0 mg/kg/ml d-amphetamine per day) or given saline (0.9% wt/vol) once daily for 4 days. Expression of ST and GT was then examined over 8 days of PCA training consisting of 25 pairings of an 8-s presentation of an illuminated lever immediately followed by response-independent delivery of a banana-flavored food pellet. Results showed that adults clearly displayed more ST behavior than adolescents, reflected via both more contacts with, and shorter latencies to approach, the lever. Prior amphetamine sensitization increased ST (but not GT) behaviors regardless of age. Thus, when indexed via ST, incentive motivation was found to be greater in adults than adolescents, with a prior history of amphetamine exposure generally sensitizing incentive motivation for cues predicting a food reward regardless of age. PMID- 21534650 TI - The bystander-effect: a meta-analytic review on bystander intervention in dangerous and non-dangerous emergencies. AB - Research on bystander intervention has produced a great number of studies showing that the presence of other people in a critical situation reduces the likelihood that an individual will help. As the last systematic review of bystander research was published in 1981 and was not a quantitative meta-analysis in the modern sense, the present meta-analysis updates the knowledge about the bystander effect and its potential moderators. The present work (a) integrates the bystander literature from the 1960s to 2010, (b) provides statistical tests of potential moderators, and (c) presents new theoretical and empirical perspectives on the novel finding of non-negative bystander effects in certain dangerous emergencies as well as situations where bystanders are a source of physical support for the potentially intervening individual. In a fixed effects model, data from over 7,700 participants and 105 independent effect sizes revealed an overall effect size of g = -0.35. The bystander effect was attenuated when situations were perceived as dangerous (compared with non-dangerous), perpetrators were present (compared with non-present), and the costs of intervention were physical (compared with non-physical). This pattern of findings is consistent with the arousal-cost-reward model, which proposes that dangerous emergencies are recognized faster and more clearly as real emergencies, thereby inducing higher levels of arousal and hence more helping. We also identified situations where bystanders provide welcome physical support for the potentially intervening individual and thus reduce the bystander effect, such as when the bystanders were exclusively male, when they were naive rather than passive confederates or only virtually present persons, and when the bystanders were not strangers. PMID- 21534651 TI - Psychological treatment for panic disorder with agoraphobia: a randomized controlled trial to examine the role of therapist-guided exposure in situ in CBT. AB - OBJECTIVE: Cognitive-behavioral therapy (CBT) is a first-line treatment for panic disorder with agoraphobia (PD/AG). Nevertheless, an understanding of its mechanisms and particularly the role of therapist-guided exposure is lacking. This study was aimed to evaluate whether therapist-guided exposure in situ is associated with more pervasive and long-lasting effects than therapist-prescribed exposure in situ. METHOD: A multicenter randomized controlled trial, in which 369 PD/AG patients were treated and followed up for 6 months. Patients were randomized to 2 manual-based variants of CBT (T+/T-) or a wait-list control group (WL; n = 68) and were treated twice weekly for 12 sessions. CBT variants were identical in content, structure, and length, except for implementation of exposure in situ: In the T+ variant (n = 163), therapists planned and supervised exposure in situ exercises outside the therapy room; in the T- group (n = 138), therapists planned and discussed patients' in situ exposure exercises but did not accompany them. Primary outcome measures were (a) Hamilton Anxiety Scale, (b) Clinical Global Impression, (c) number of panic attacks, and (d) agoraphobic avoidance (Mobility Inventory). RESULTS: For T+ and T- compared with WL, all outcome measures improved significantly with large effect sizes from baseline to post (range = -0.5 to -2.5) and from post to follow-up (range = -0.02 to -1.0). T+ improved more than T- on the Clinical Global Impression and Mobility Inventory at post and follow-up and had greater reduction in panic attacks during the follow-up period. Reduction in agoraphobic avoidance accelerated after exposure was introduced. A dose-response relation was found for Time * Frequency of Exposure and reduction in agoraphobic avoidance. CONCLUSIONS: Therapist-guided exposure is more effective for agoraphobic avoidance, overall functioning, and panic attacks in the follow-up period than is CBT without therapist-guided exposure. Therapist-guided exposure promotes additional therapeutic improvement- possibly mediated by increased physical engagement in feared situations--beyond the effects of a CBT treatment in which exposure is simply instructed. PMID- 21534652 TI - Internet therapy versus internet self-help versus no treatment for problematic alcohol use: A randomized controlled trial. AB - OBJECTIVE: Problematic alcohol use is the third leading contributor to the global burden of disease, partly because the majority of problem drinkers are not receiving treatment. Internet-based alcohol interventions attract an otherwise untreated population, but their effectiveness has not yet been established. The current study examined the effectiveness of Internet-based therapy (therapy alcohol online; TAO) and Internet-based self-help (self-help alcohol online; SAO) for problematic alcohol users. METHOD: Adult problem drinkers (n = 205; 51% female; mean age = 42 years; mean Alcohol Use Disorders Identification Test score = 20) were randomly assigned to TAO, SAO, or an untreated waiting-list control group (WL). Participants in the TAO arm received 7 individual text-based chat therapy sessions. The TAO and SAO interventions were based on cognitive behavioral therapy and motivational interviewing techniques. Assessments were given at baseline and 3 and 6 months after randomization. Primary outcome measures were alcohol consumption and treatment response. Secondary outcome measures included measures of quality-of-life. RESULTS: Using generalized estimating equation regression models, intention-to-treat analyses demonstrated significant effects for TAO versus WL (p = .002) and for SAO versus WL (p = .03) on alcohol consumption at 3 months postrandomization. Differences between TAO and SAO were not significant at 3 months postrandomization (p = .11) but were significant at 6 months postrandomization (p = .03), with larger effects obtained for TAO. There was a similar pattern of results for treatment response and quality-of-life outcome measures. CONCLUSIONS: Results support the effectiveness of cognitive-behavioral therapy/motivational interviewing Internet-based therapy and Internet-based self-help for problematic alcohol users. At 6 months postrandomization, Internet-based therapy led to better results than Internet based self-help. PMID- 21534649 TI - Decision making and reward in frontal cortex: complementary evidence from neurophysiological and neuropsychological studies. AB - Patients with damage to the prefrontal cortex (PFC)--especially the ventral and medial parts of PFC--often show a marked inability to make choices that meet their needs and goals. These decision-making impairments often reflect both a deficit in learning concerning the consequences of a choice, as well as deficits in the ability to adapt future choices based on experienced value of the current choice. Thus, areas of PFC must support some value computations that are necessary for optimal choice. However, recent frameworks of decision making have highlighted that optimal and adaptive decision making does not simply rest on a single computation, but a number of different value computations may be necessary. Using this framework as a guide, we summarize evidence from both lesion studies and single-neuron physiology for the representation of different value computations across PFC areas. PMID- 21534654 TI - Racial/ethnic disparities in therapist effectiveness: a conceptualization and initial study of cultural competence. AB - As a result of mental health disparities between White and racial/ethnic minority clients, researchers have argued that some therapists may be generally competent to provide effective services but lack cultural competence. This distinction assumes that client racial/ethnic background is a source of variability in therapist effectiveness. However, there have been no direct tests of the therapist as a source of health disparities. We provided an initial test of the distinction between general and cultural competence by examining client racial/ethnic background as a source of variability in therapist effectiveness. We analyzed cannabis use outcomes from a psychotherapy trial (N = 582) for adolescent cannabis abuse and dependence using Bayesian multilevel models for count outcomes. We first tested whether therapists differed in their effectiveness and then tested whether disparities in treatment outcomes varied across therapist caseloads. Results suggested that therapists differed in their effectiveness in general and that effectiveness varied according to client racial/ethnic background. Therapist effectiveness may depend partially on client racial/ethnic minority background, providing evidence that it is valid to distinguish between general and cultural competence. PMID- 21534653 TI - Deficits in emotion-regulation skills predict alcohol use during and after cognitive-behavioral therapy for alcohol dependence. AB - OBJECTIVE: As emotion regulation is widely considered to be a primary motive in the misuse of alcohol, our aim in the study was to investigate whether deficits in adaptive emotion-regulation skills maintain alcohol dependence (AD). METHOD: A prospective study investigated whether emotion-regulation skills were associated with AD and whether these skills predicted alcohol use during and after treatment for AD. Participants were 116 individuals treated for AD with cognitive behavioral therapy. Emotion regulation and severity of AD symptoms were assessed by self-report. Alcohol use during treatment was assessed by Breathalyzer and urine analysis for ethyl glucuronide; alcohol use during the 3-month follow-up interval was assessed by self-report. RESULTS: Pretreatment emotion-regulation skills predicted alcohol use during treatment, and posttreatment emotion regulation skills predicted alcohol use at follow-up, even when controlling for other predictors potentially related to emotion regulation. Among a broad range of specific emotion-regulation skills, the ability to tolerate negative emotions was the only skill that negatively predicted subsequent alcohol consumption when controlling for the other skills. Individuals in the AD sample reported significantly larger deficits in emotion-regulation skills than did those in a nonclinical control sample but significantly less than did those in a sample of individuals exclusively meeting criteria for major depressive disorder. CONCLUSIONS: Enhancement of general emotion-regulation skills, especially the ability to tolerate negative emotions, appears to be an important target in the treatment of AD. PMID- 21534655 TI - Machismo and Mexican American men: an empirical understanding using a gay sample. AB - Machismo continues to be a defining aspect of Mexican American men that informs a wide array of psychological and behavioral dimensions. Although strides have been made in this area of research, understanding of the role of this construct in the lives of gay men remains incomplete. Our purpose in this study was to gain a deeper understanding of machismo using a sample of Mexican American gay men. This study examined for the first time whether a 2-factor model of machismo previously validated with heterosexual, Mexican American men generalized to a sample of 152 gay men of similar ethnic background. Relations between machismo, sexual risk, and internalized homophobia were also explored. Confirmatory factor analysis supported the 2-factor model with the current sample. Results also indicated machismo as predicting internalized homophobia and as an index of risky sex. Limitations are presented and implications are discussed. PMID- 21534656 TI - What comes first? How selective attentional processes regulate the activation of a motor routine in a manual search task. AB - An intriguing error has been observed in toddlers presented with a 3-location search task involving invisible displacements of an object, namely, the C-not-B task. In 3 experiments, the authors investigated the dynamics of the attentional focus process that is suspected to be involved in this task. In Experiment 1, 2.5 year-old children were tested on a new adaptation of the C-not-B task in which the opening of the experimenter's hand between cloths provided visual information about the correct localization of the toy. Children still emitted a strong response bias toward the last hiding place. In Experiment 2, 2.5-year-old children were tested on a new version of the task that was designed to investigate the role of the central location in the task. This 2nd experiment demonstrated that changing the hand's movement from A to C to B did not enable children to succeed in the task. In Experiment 3, 2.5-year-old children were tested in a situation that is analogous to the C-not-B with open hands task except for the fact that the experimenter dropped the toy under the 1st cloth in the path. Toddlers succeeded when the toy was hidden at Location A but not when it was hidden at Location B. Data indicate that attentional focus on the experimenter's hand motion is contingent on whether that stimulus is critical to performing the task. We argue that these findings provide a potential mechanism through which motor routines can be regulated in accordance with strategic intentions. PMID- 21534657 TI - Individual differences in the development of sensation seeking and impulsivity during adolescence: further evidence for a dual systems model. AB - Consistent with social neuroscience perspectives on adolescent development, previous cross-sectional research has found diverging mean age-related trends for sensation seeking and impulsivity during adolescence. The present study uses longitudinal data on 7,640 youth from the National Longitudinal Study of Youth Children and Young Adults, a nationally representative sample assessed biennially from 1994 to 2006. Latent growth curve models were used to investigate mean age related changes in self-reports of impulsivity and sensation seeking from ages 12 to 24 years, as well individual differences in these changes. Three novel findings are reported. First, impulsivity and sensation seeking showed diverging patterns of longitudinal change at the population level. Second, there was substantial person-to-person variation in the magnitudes of developmental change in both impulsivity and sensation seeking, with some teenagers showing rapid changes as they matured and others maintaining relatively constant levels with age. Finally, the correlation between age-related changes in impulsivity and sensation seeking was modest and not significant. Together, these results constitute the first support for the dual systems model of adolescent development to derive from longitudinal behavioral data. PMID- 21534658 TI - Pecunia olet: the role of incidental disgust in the ultimatum game. AB - We address the role of the incidental emotion of disgust in the Ultimatum Game. Participants had to choose whether or not to accept a ?2 offer from a ?10 pot made by another participant; 120 were in a room where a disgusting smell was released and 120 were in a room with no particular smell. Acceptance rates were higher in the room with the disgusting smell. The effect was mainly carried by the male participants who also reported more disgust with the disgusting smell and judged the offer as less unfair than females. We propose a spontaneous discounting explanation. Acceptance rates were higher in the room with the disgusting smell because participants misattributed the disgust induced by the offer to the ambient disgusting smell. PMID- 21534659 TI - Is seeking bad mood cognitively demanding? Contra-hedonic orientation and working memory capacity in everyday life. AB - Hedonism, or wanting to feel good, is central to human motivation. At times, however, people also seek to maintain or enhance negative affect or to dampen positive affect, and this can be instrumental for the later attainment of their goals. Here, we investigate the assumption that such contra-hedonic orientation is cognitively more demanding than prohedonic orientation, above and beyond the effects of momentary affective experience. We provided 378 participants with mobile phones that they carried with them for 3 weeks while pursuing their daily routines. The phones prompted participants at least 54 times to report their current affect-regulation orientation and to work on two trials of a cognitively demanding working memory task. As expected, contra-hedonic orientation was substantially less prevalent than prohedonic orientation. It was reported in 15% of the measurement occasions. Participants who reported on average more contra hedonic orientation showed lower average working memory performance throughout the study interval. Further, controlling for the effects of accompanying affective experiences, momentary occurrences of contra-hedonic orientation were associated with temporary declines in working memory performance within individuals, and this could neither be explained by lacking task compliance nor by other characteristics of the individual or the situation. Prohedonic orientation showed a considerably smaller association with working memory performance. These findings are consistent with the view that contra-hedonic orientation is accompanied by momentarily more diminished cognitive resources than is prohedonic orientation. PMID- 21534660 TI - Cognitive reappraisal in the context of oppression: implications for psychological functioning. AB - Research on emotion regulation has shown cognitive reappraisal to be positively correlated with better psychological functioning. Prior research has failed to account for contextual influences on this important relationship. We examined how this relationship plays out across two United States ethnic groups that represent different contexts of oppression: Puerto Ricans, experiencing distal oppression (societal level) but not proximal oppression (immediate environment), and Latino Americans, experiencing both. We also captured individual beliefs regarding oppression of one's group and implications of that oppression by measuring oppressed minority ideology (OMI). Results confirmed our hypothesis that the relationship between reappraisal and psychological functioning would be moderated by the context of oppression (as measured by ethnic group membership and OMI). For Latino Americans high on OMI, reappraisal was negatively associated with psychological functioning. For Puerto Ricans, regardless of OMI, this relationship remained positive, suggesting a possible benefit for minorities in being surrounded by in-group members. PMID- 21534661 TI - Subjective responses to emotional stimuli during labeling, reappraisal, and distraction. AB - Although multiple neuroimaging studies suggest that affect labeling (i.e., putting feelings into words) can dampen affect-related responses in the amygdala, the consequences of affect labeling have not been examined in other channels of emotional responding. We conducted four studies examining the effect of affect labeling on self-reported emotional experience. In study one, self-reported distress was lower during affect labeling, compared to passive watching, of negative emotional pictures. Studies two and three added reappraisal and distraction conditions, respectively. Affect labeling showed similar effects on self-reported distress as both of these intentional emotion regulation strategies. In each of the first three studies, however, participant predictions about the effects of affect labeling suggest that unlike reappraisal and distraction, people do not believe affect labeling to be an effective emotion regulation strategy. Even after having the experience of affect labels leading to lower distress, participants still predicted that affect labeling would increase distress in the future. Thus, affect labeling is best described as an incidental emotion regulation process. Finally, study four employed positive emotional pictures and here, affect labeling was associated with diminished self-reported pleasure, relative to passive watching. This suggests that affect labeling tends to dampen affective responses in general, rather than specifically alleviating negative affect. PMID- 21534662 TI - To look or not to look: an eye movement study of hypervigilance during change detection in high and low spider fearful students. AB - Previous eye movement studies of attentional bias in spider fear reported inconsistent results with respect to early attentional capture, suggesting that overt attentional capture only reliably occurs under specific circumstances. In addition, none of these studies explored covert attention. The present study examined attentional bias in spider phobia using a change detection paradigm that was expected to provide good conditions for documenting attentional capture. In contrast to our expectations, eye movement data showed that all participants' first fixations were fastest on general negative targets, whereas participants' first fixations on spider targets were slower in the spider fearful than in the nonfearful group. In addition, spider fearful participants made more nontarget fixations before fixating on a spider target than did nonfearful participants. Thus, we found that participants' overt attention was more quickly focused on general negative targets, whereas covert attentional processes enabled initial avoidance of fear-relevant (i.e. spider) stimuli. The present findings have important implications for research on attention and fear as they indicate that fearful individuals are not characterized by static attentional orienting toward threat but, under certain conditions, may avert attention from threat automatically. PMID- 21534663 TI - Concurrent and prospective relations between attention to emotion and affect intensity: an experience sampling study. AB - Theorists contend that emotional awareness is vital to being able to use emotional information adaptively. The extent to which individuals attend to and value their feelings, or attention to emotion, is a facet of emotional awareness. Little research, however, has examined whether attention to emotion affects the magnitude or intensity of emotional experiences. In the present study we examined the relations between attention to emotion and levels of affect in 53 healthy adults. Participants carried hand-held electronic devices for approximately 7 days and were randomly prompted eight times per day to answer a series of questions. At each prompt, participants reported attention to emotion, current negative affect (NA), and positive affect (PA). All findings presented were computed using multilevel modeling. Replicating findings obtained using trait level measures, we found that attention to emotion was associated concurrently with higher levels of both NA and PA. We also found prospectively that attention to emotion at one prompt predicted a decrease in levels of NA, but no change in levels of PA, at the subsequent prompt. These findings suggest that emotional processes serve different functions over time and highlight the role of attention to emotion in affect regulation. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21534664 TI - Pavlovian to instrumental transfer of control in a human learning task. AB - Pavlovian learning tasks have been widely used as tools to understand basic cognitive and emotional processes in humans. The present studies investigated one particular task, Pavlovian-to-instrumental transfer (PIT), with human participants in an effort to examine potential cognitive and emotional effects of Pavlovian cues upon instrumentally trained performance. In two experiments, subjects first learned two separate instrumental response-outcome relationships (i.e., R1-O1 and R2-O2) and then were exposed to various stimulus-outcome relationships (i.e., S1-O1, S2-O2, S3-O3, and S4-) before the effects of the Pavlovian stimuli on instrumental responding were assessed during a non reinforced test. In Experiment 1, instrumental responding was established using a positive-reinforcement procedure, whereas in Experiment 2, a quasi-avoidance learning task was used. In both cases, the Pavlovian stimuli exerted selective control over instrumental responding, whereby S1 and S2 selectively elevated the instrumental response with which it shared an outcome. In addition, in Experiment 2, S3 exerted a nonselective transfer of control effect, whereby both responses were elevated over baseline levels. These data identify two ways, one specific and one general, in which Pavlovian processes can exert control over instrumental responding in human learning paradigms, suggesting that this method may serve as a useful tool in the study of basic cognitive and emotional processes in human learning. PMID- 21534665 TI - Social justifications for moral emotions: when reasons for disgust are less elaborated than for anger. AB - In the present research, we tested the unreasoning disgust hypothesis: moral disgust, in particular in response to a violation of a bodily norm, is less likely than moral anger to be justified with cognitively elaborated reasons. In Experiment 1, participants were asked to explain why they felt anger and disgust toward pedophiles. Participants were more likely to invoke elaborated reasons, versus merely evaluative responses, when explaining their anger, versus disgust. Experiment 2 used a between-participants design; participants explained why they felt either anger or disgust toward seven groups that either violated a sexual or nonsexual norm. Again, elaborated reasons were less prevalent when explaining their disgust versus anger and, in particular, when explaining disgust toward a group that violated a sexual norm. Experiment 3 further established that these findings are due to a lower accessibility of elaborated reasons for bodily disgust, rather than inhibition in using them when provided. From these findings, it can be concluded that communicating external reasons for moral disgust at bodily violations is made more difficult due to the unavailability of those reasons to people. PMID- 21534666 TI - Resolving ambiguous behavioral intentions by means of involuntary prioritization of gaze processing. AB - Anticipation of others' actions is of paramount importance in social interactions. Cues such as gaze direction and facial expressions can be informative, but can also produce ambiguity with respect to others' intentions. We investigated the combined effect of an actor's gaze and expression on judgments made by observers about the end-point of the actor's head rotation toward the observer. Expressions of approach gave rise to an unambiguous intention to move toward the observer, while expressions of avoidance gave rise to an ambiguous behavioral intention (as the expression and motion cues were in conflict). In the ambiguous condition, observers overestimated how far the actor's head had rotated when the actor's gaze was directed ahead of head rotation (compared to congruent or lagging behind). In the unambiguous condition the estimations were not influenced by the gaze manipulation. These results show that social cue integration does not follow simple additive rules, and suggests that the involuntary allocation of attention to another's gaze depends on the perceived ambiguity of the agent's behavioral intentions. PMID- 21534667 TI - Affective dimensions of odor perception: a comparison between Swiss, British, and Singaporean populations. AB - Do affective responses to odors vary as a function of culture? To address this question, we developed two self-report scales in the United Kingdom (Liverpool: LEOS) and in Singapore (city of Singapore: SEOS), following the same procedure as used in the past to develop the Geneva Emotion and Odor Scale (GEOS: Chrea, Grandjean, Delplanque et al., 2009). The final scales were obtained by a three step reduction of an initial pool of 480 affective terms, retaining only the most relevant terms to describe odor-related subjective affective states and comprised of six (GEOS) or seven affective dimensions (LEOS and SEOS). These included dimensions that were common to the three cultures (Disgust, Happiness Well-being, Sensuality Desire, and Energy), common to the two European samples (Soothing Peacefulness), and dimensions that were culture specific (Sensory Pleasure in Geneva; Nostalgia and Hunger Thirst in Liverpool; Intellectual Stimulation, Spirituality, and Negative Feelings in Singapore). A comparative approach showed that the dimensional organization of odor-related affective terms in a given culture better explained data variability for that culture than data variability for the other cultures, thus highlighting the importance of culture-specific tools in the investigation of odor-related affect. PMID- 21534668 TI - A naturalistic observation study of the links between parental depressive symptoms and preschoolers' behaviors in everyday life. AB - Previous research has shown that parental depressive symptoms are linked to a number of negative child outcomes. However, the associations between parental depressive symptoms and actual child behaviors in everyday life remain largely unknown. The aims of this study were to investigate the links between parental depressive symptoms and everyday child behaviors and emotional language use using a novel observational methodology, and to explore the potential moderating role of parent-child conflict. We tracked the behaviors and language use of 35 preschool-aged children for two 1-day periods separated by one year using a child version of the Electronically Activated Recorder, a digital voice recorder that records ambient sounds while participants go about their daily lives. Parental depressive symptoms were positively associated with multiple problem behaviors among children (i.e., crying, acting mad, watching TV) when measured both concurrently and prospectively, and with negative emotion word use prospectively. Further, the links between parental depressive symptoms and child crying were moderated by parents' perceptions of parent-child conflict. This study offers the first empirical evidence of direct links between parental depressive symptoms and child behaviors in daily life and presents a promising research tool for the study of everyday child behaviors. PMID- 21534669 TI - Family ties in tough times: how young adults and their parents view the U.S. economic crisis. AB - The present intergenerational study examined the perceived impact of the recent U.S. economic crisis on a sample of 68 young adult-parent dyads. The relative contribution of perceived economic pressure, reports of adult child-parent relationship quality, and concerns about the economic future in accounting for variation in self-reports of psychological distress for adult children and their middle-aged parents were examined. Parents' concerns about their children's economic future accounted for variation in their reports of anxiety and depressed mood above and beyond that of perceived economic pressures and their views of the parent-child relationship. In contrast, for young adults, reports of personal economic pressure were generally related to self-reported anxiety and depressed mood. Implications of findings for research and practice are discussed. PMID- 21534670 TI - Predictors of supportive coparenting after relationship dissolution among at-risk parents. AB - Supportive coparenting after relationship dissolution is associated with increased father involvement which can buffer against the negative effects of parental relationship dissolution. Low-income, at-risk families are much more likely to experience relationship dissolutions; hence, supportive coparenting after dissolution is particularly important in these families. We examined whether relationship (commitment and quality) and child (difficult temperament and gender) characteristics predicted initial levels of, and change in, supportive coparenting after relationship dissolution in the Fragile Families and Child Wellbeing Study (N = 1,603). We used structural equation modeling of latent growth curves to examine four time points collected at the focal child's birth and first, third, and fifth birthdays. Ninety-percent of the mothers had nonmarital births, and about three-quarters had a high school diploma or less education. Overall, supportive coparenting decreased over time. Mothers in more committed relationships prior to the dissolution initially had significantly lower supportive coparenting. But over time, mothers who had been in more committed relationships increased in supportive coparenting. Mothers who had been in higher quality relationships prior to dissolution initially reported more supportive coparenting. At each time point, if a mother was romantically involved with a new partner, she reported significantly lower supportive coparenting compared to mothers who were single. With regard to child characteristics, mothers who reported their child as more difficult had significantly lower initial supportive coparenting. Similar results for fathers are discussed. Overall, the relationship characteristics of parents were important predictors of supportive coparenting both initially and over time. PMID- 21534671 TI - Coexisting difficulties and couple therapy outcomes: psychopathology and intimate partner violence. AB - Couples presenting for treatment of relationship distress often experience additional problems, including individual psychopathology and intimate partner violence (IPV). Both issues are associated with current and future poor relationship functioning in nontreatment samples, but relatively little is understood about their association with initial presentation and outcomes in couple therapy. The current study examined these associations in a sample of 177 heterosexual couples who received therapy at two Veteran's Affairs clinics. Unlike most studies of couple therapy outcomes, couples were not excluded from treatment specifically because of high levels of psychopathology or IPV. Results of Actor Partner Interdependence Model (APIM) analyses revealed actor and partner effects of depression, actor effects of anxiety, and partner effects of IPV on initial relationship satisfaction, such that greater coexisting difficulties were associated with poorer initial satisfaction. However, improvement in relationship satisfaction over the course of therapy was not associated with psychopathology, and, contrary to hypothesis, was positively associated with men's IPV prior to treatment, even when initial level of satisfaction was controlled. The results suggest that coexisting symptoms of psychopathology or IPV may not necessarily interfere with therapy outcomes and, indeed, therapy may have positive effects for couples with these problems. PMID- 21534672 TI - Relationships among health perceptions vary depending on stage of readiness for colorectal cancer screening. AB - OBJECTIVE: We explored whether relationships among health perceptions differ depending on individuals' stage of readiness for colorectal cancer screening (CRCS). METHODS: Data from the National Cancer Institute's Health Information National Trends Survey (HINTS) were used to stage adults over 50 years of age (N = 2324) using a modified version of the Precaution Adoption Process Model (PAPM) staging algorithm. Health perceptions examined included perceived risk of cancer, worry about cancer, fatalism, and beliefs about ambiguity of cancer prevention recommendations. RESULTS: Meaningful differences in patterns of relationships among health perceptions by stage were found. CONCLUSIONS: The nonlinear patterns that emerged indicate support for the role of these health perceptions in screening, the idea that behavioral readiness may moderate the relationship between important health perceptions, and the use of the stage construct in this context. PMID- 21534673 TI - Do agonistic motives matter more than anger? Three studies of cardiovascular risk in adolescents. AB - OBJECTIVES: Three motivational profiles have been associated with recurring psychological stress in low-income youth and young adults: Striving to control others (agonistic striving), striving to control the self (transcendence striving), and not asserting control (dissipated striving). Agonistic striving has been associated with elevated ambulatory blood pressure during daily activities. Three studies tested the hypotheses that: (1) agonistic striving is associated with poor anger regulation, and (2) agonistic striving and poor anger regulation interactively elevate blood pressure. DESIGN: Motivational profiles, anger regulation, and ambulatory blood pressure were assessed in a multiethnic sample of 264 urban youth. MAIN OUTCOME MEASURES: (1) anger regulation/recovery during laboratory challenge; (2) anger/blood pressure during daily activities (48 hours). RESULTS AND CONCLUSION: Replication of the profiles in distant cities showed they occur with similar frequency across differences of region, race, and gender. Analyses controlling for body size, race, and gender revealed that individuals with the agonistic striving profile had higher ambulatory pressure, especially during social encounters. They became more openly angry and aggressive when challenged but did not exhibit difficulty regulating anger in the laboratory, nor did they feel angrier during monitoring. However, individuals with the agonistic striving profile who did display poor anger regulation in the lab had the highest blood pressure; deficient self-regulatory capability amplified the positive association between agonistic striving and cardiovascular risk in both genders and all ethnic groups. Although anger is thought to increase cardiovascular risk, present findings suggest that anger and elevated blood pressure are coeffects of agonistic struggles to control others. PMID- 21534675 TI - Loneliness, social isolation, and behavioral and biological health indicators in older adults. AB - OBJECTIVE: A number of mechanisms have been proposed through which social isolation and loneliness may affect health, including health-related behavioral and biological factors. However, it is unclear to what extent isolation and loneliness are independently associated with these pathways. The objective of the present analysis was to determine the impact of social isolation and loneliness, individually as well as simultaneously, on health-related behavioral and biological factors using data from the English Longitudinal Study of Ageing (ELSA). METHOD: Data on health behaviors (smoking and physical activity) were analyzed from 8,688 participants and data on blood pressure, cholesterol, and inflammatory markers were analyzed from over 5,000 of these participants who were eligible for a nurse visit and blood sampling. Loneliness was measured using the short form of the Revised UCLA scale and an index of social isolation was computed incorporating marital status; frequency of contact with friends, family, and children; and participation in social activities. RESULTS: Fewer than 2% of participants reported being lonely all the time, while nearly 7% had the highest possible scores on social isolation. Both social isolation and loneliness were associated with a greater risk of being inactive, smoking, as well as reporting multiple health-risk behaviors. Social isolation was also positively associated with blood pressure, C-reactive protein, and fibrinogen levels. CONCLUSIONS: Loneliness and social isolation may affect health independently through their effects on health behaviors. In addition, social isolation may also affect health through biological processes associated with the development of cardiovascular disease. PMID- 21534674 TI - Toward a more complete understanding of the effects of personal mastery on cardiometabolic health. AB - OBJECTIVE: A great deal of research has been devoted to identifying the psychological factors that might be associated with reduced risk for cardiovascular diseases. In particular, coping resources such as personal mastery might attenuate stress-related pathophysiology. The purpose of the present review was to examine the existing literature reporting associations between personal mastery and cardiometabolic health outcomes to determine which outcomes have been studied to date, investigate the extent of inconsistency in the literature, and propose new directions for research. DESIGN: Systematic review of articles examining the associations between personal mastery and cardiometabolic health. MAIN OUTCOME MEASURES: Studies were included if they examined objective measures of cardiometabolic function, cardiovascular events, and/or mortality. RESULTS: Thirty-two studies were identified examining the effect of mastery on the following outcomes: mortality and/or cardiovascular events, psychoneuroendocrine stress systems, cardiovascular reactivity to acute stress, metabolic dysregulation, inflammation/coagulation, and evidence of large vessel disease from imaging methods. CONCLUSIONS: Overall, mastery was associated with better cardiometabolic health and reduced risk for disease and/or death, typically with a small-medium effect size. A relatively small proportion of studies reported contradictory findings that higher mastery was associated with poorer cardiometabolic outcomes. The state of the current research suggests that future investigations should focus on 1) clarifying the mediators and moderators most relevant in the association between mastery and downstream disease, 2) testing the association between mastery and biological outcomes longitudinally, 3) examining the physiological impact of mastery-increasing interventions, and 4) studying the relationship between mastery and disease risk in diverse ethnic or sociocultural groups. PMID- 21534676 TI - Independence centrality as a moderator of the effects of spousal support on patient well-being and physical functioning. AB - OBJECTIVE: In this study, we examined whether the benefits of spousal assistance for patient well-being and physical functioning depend on the fit between amount of assistance provided and the personal importance of completing activities independently. METHODS: Individuals with osteoarthritis of the hip or knee were assessed for independence centrality, depressive symptoms, self-efficacy for managing pain, and physical functioning (N = 159 to 230). Spouses reported the amount of support provided with daily tasks. RESULTS: As predicted, moderation analyses indicated that spousal support was associated with greater self-efficacy for managing pain in patients with low independence centrality, but was not associated with self-efficacy in patients with high independence centrality. Also consistent with our hypotheses, spousal support was associated with greater depressive symptoms and slower walk time in patients with high independence centrality, but there were no effects of spouse support on these outcomes for patients with low independence centrality. CONCLUSIONS: Our findings demonstrate the implications of miscarried spousal support for patient well-being and physical functioning, and they suggest a means of tailoring couple-oriented interventions for chronic illness. PMID- 21534678 TI - Using the Health Action Process Approach and implementation intentions to increase flu vaccine uptake in high risk Thai individuals: a controlled before after trial. AB - OBJECTIVE: Influenza vaccination rates remain suboptimal in many countries, including Thailand. This study compared the effect of a theory-based educational leaflet, based on the Health Action Process Approach (HAPA), and action planning intervention with a standard government information leaflet designed to increase influenza vaccination uptake among high-risk Thai adults. DESIGN: A controlled before and after trial was conducted. Participants in the intervention (n = 99) received a leaflet based on the HAPA and asking them to form an action plan identifying where, when, and how they would seek vaccination. Those in the comparison condition (n = 102) received a standard government information leaflet. MAIN OUTCOMES MEASURES: There are 2 sets of outcome measures: (a) process measures of HAPA related variables taken at T1 and T2, and (b) vaccination rates during the subsequent 2 months. RESULTS: The HAPA intervention resulted in greater changes on measures of risk perception, outcome expectancies, self-efficacy, and intention than the comparison condition. Stronger intentions to obtain vaccination were explained by changes in outcome expectancies, perceived self-efficacy for arranging time and transportation, and planning. No significant difference in vaccination rates was observed between two groups. Influenza vaccination was directly predicted by self-efficacy and intention. CONCLUSION: Results demonstrate that a HAPA-based leaflet may be a useful tool to enhance individual's vaccination intention, but larger trials are required to confirm these findings. PMID- 21534677 TI - Results of the "Active by Choice Today" (ACT) randomized trial for increasing physical activity in low-income and minority adolescents. AB - OBJECTIVE: This study reports the results of the "Active by Choice Today" (ACT) trial for increasing moderate-to-vigorous physical activity (MVPA) in low-income and minority adolescents. DESIGN: The ACT program was a randomized controlled school-based trial testing the efficacy of a motivational plus behavioral skills intervention on increasing MVPA in underserved adolescents. Twenty-four middle schools were matched on school size, percentage minorities, percentage free or reduce lunch, and urban or rural setting before randomization. A total of 1,563 6th grade students (mean age, 11.3 years, 73% African American, 71% free or reduced lunch, 55% female) participated in either a 17-week (over one academic year) intervention or comparison after-school program. MAIN OUTCOME MEASURE: The primary outcome measure was MVPA based on 7-day accelerometry estimates at 2 weeks postintervention and an intermediate outcome was MVPA at midintervention. RESULTS: At midintervention students in the intervention condition engaged in 4.87 greater minutes of MVPA per day (95% CI: 1.18 to 8.57) than control students. Students in intervention schools engaged in 9.11 min (95% CI: 5.73 to 12.48) more of MVPA per day than those in control schools during the program time periods; indicating a 27 min per week increase in MVPA. No significant effect of the ACT intervention was found outside of school times or for MVPA at 2-weeks postintervention. CONCLUSIONS: Motivational and behavioral skills programs are effective at increasing MVPA in low-income and minority adolescents during program hours, but further research is needed to address home barriers to youth MVPA. PMID- 21534679 TI - Fear, anger, fruits, and veggies: interactive effects of emotion and message framing on health behavior. AB - OBJECTIVE: Message framing is a theoretically grounded health communication strategy designed to motivate action by emphasizing either the benefits of engaging in a particular behavior (gains) or the costs of failing to engage in the behavior (losses). This study investigated whether the effectiveness of a framed message depends on the emotional state of the message recipient. We examined effects of fear versus anger, emotions that frequently occur within the context of health decision-making. METHODS: Undergraduate students (N = 133) were randomly assigned to complete a fear or anger induction task after which they read a gain- or loss-framed pamphlet promoting fruit and vegetable consumption. Fruit and vegetable intake (servings per day) subsequently was assessed over the following 2 weeks. RESULTS: As predicted, a significant frame by emotion interaction was observed, such that participants in the fear condition reported eating more servings of fruits and vegetables after exposure to a loss-framed message than to a gain-framed message. In contrast, participants in the anger condition reported eating (marginally) more servings of fruits and vegetables after exposure to a gain-framed message than to a loss-framed message. Greater increases in fruit and vegetable intake from baseline to follow-up were observed when the message frame was matched to the participant's emotional state. CONCLUSION: The effectiveness of framed health communications depends on the message recipient's current emotional state. Affective factors that are incidental to the behavior recommended in a health communication can affect the relative success of gain- and loss-framed appeals. PMID- 21534680 TI - Pilot test of an emotional education intervention component for sexual risk reduction. AB - OBJECTIVE: Emotions are key predictors of sexual risk behavior but have been largely ignored in theory-based intervention development. The present study aims to evaluate whether the addition of an emotional education intervention component to a traditional social-cognitive safer sex intervention increases intervention efficacy, compared with both a social-cognitive only intervention and a no intervention control condition. METHODS: Young adults were randomized in small groups to receive the social-cognitive-emotional (SCE) intervention, the social cognitive (SC) intervention, or standard of care. RESULTS: Analyses of data from 176 participants indicated that intervention arms reported similar increased condom use compared with the no intervention control arm at 3 months' postintervention (beta = .06, p = .41, d = 0.08). However, at 6 months' postintervention, individuals in the SCE intervention arm reported increased condom use compared with both the SC intervention (beta = .27, p = .04, d = 0.38) and control arms (beta = .37, p < .01; d = 0.56), demonstrating preliminary evidence that the addition of an emotional education component may facilitate sustained behavior change. CONCLUSIONS: An emotional education intervention module has the potential to facilitate sustained behavior change at delayed follow-up. Additional research is necessary to replicate findings in a larger sample and to determine the mediators of emotional education intervention efficacy. PMID- 21534681 TI - What can we learn from patients with heart failure about exercise adherence? A systematic review of qualitative papers. AB - OBJECTIVES: Keeping physically active has been shown to bring positive outcomes for patients diagnosed with heart failure (HF). However, a number of individuals with this health problem do not undertake regular exercise. A review of extant qualitative research was conducted to explore what it can tell us about barriers and enablers to physical activity among people with HF. METHODS: A systematic search, involving electronic databases and endeavors to locate gray literature, was carried out to identify relevant qualitative studies published from 1980 onward. Data from retrieved papers were combined using framework analysis. Papers read in full numbered 32, and 20 were included in the review. RESULTS: Synthesis of results from the 20 studies resulted in 4 main themes: Changing soma, negative emotional response, adjusting to altered status, and interpersonal influences. How individuals responded to their diagnosis and their altered physical status related to their activity levels, as did the degree of encouragement to exercise coming from family, friends, and professionals. These findings can be connected to the theory of behavioral change developed by Bandura, known as social cognitive theory (SCT). CONCLUSIONS: SCT may be a useful framework for developing interventions to support patients with HF in undertaking and maintaining regular exercise patterns. Specific components of SCT that practitioners may wish to consider include self-efficacy and outcome expectancies. These were issues referred to in papers for the systematic review that appear to be particularly related to exercise adherence. PMID- 21534682 TI - Generalized full-information item bifactor analysis. AB - Full-information item bifactor analysis is an important statistical method in psychological and educational measurement. Current methods are limited to single group analysis and inflexible in the types of item response models supported. We propose a flexible multiple-group item bifactor analysis framework that supports a variety of multidimensional item response theory models for an arbitrary mixing of dichotomous, ordinal, and nominal items. The extended item bifactor model also enables the estimation of latent variable means and variances when data from more than 1 group are present. Generalized user-defined parameter restrictions are permitted within or across groups. We derive an efficient full-information maximum marginal likelihood estimator. Our estimation method achieves substantial computational savings by extending Gibbons and Hedeker's (1992) bifactor dimension reduction method so that the optimization of the marginal log likelihood requires only 2-dimensional integration regardless of the dimensionality of the latent variables. We use simulation studies to demonstrate the flexibility and accuracy of the proposed methods. We apply the model to study cross-country differences, including differential item functioning, using data from a large international education survey on mathematics literacy. PMID- 21534683 TI - Aggregate and individual replication probability within an explicit model of the research process. AB - We study a model of the research process in which the true effect size, the replication jitter due to changes in experimental procedure, and the statistical error of effect size measurement are all normally distributed random variables. Within this model, we analyze the probability of successfully replicating an initial experimental result by obtaining either a statistically significant result in the same direction or any effect in that direction. We analyze both the probability of successfully replicating a particular experimental effect (i.e., the individual replication probability) and the average probability of successful replication across different studies within some research context (i.e., the aggregate replication probability), and we identify the conditions under which the latter can be approximated using the formulas of Killeen (2005a, 2007). We show how both of these probabilities depend on parameters of the research context that would rarely be known in practice. In addition, we show that the statistical uncertainty associated with the size of an initial observed effect would often prevent accurate estimation of the desired individual replication probability even if these research context parameters were known exactly. We conclude that accurate estimates of replication probability are generally unattainable. PMID- 21534684 TI - A randomized experiment comparing random and cutoff-based assignment. AB - In this article, we review past studies comparing randomized experiments to regression discontinuity designs, mostly finding similar results, but with significant exceptions. The latter might be due to potential confounds of study characteristics with assignment method or with failure to estimate the same parameter over methods. In this study, we correct the problems by randomly assigning 588 participants to be in a randomized experiment or a regression discontinuity design in which they are otherwise treated identically, comparing results estimating both the same and different parameters. Analysis includes parametric, semiparametric, and nonparametric methods of modeling nonlinearities. Results suggest that estimates from regression discontinuity designs approximate the results of randomized experiments reasonably well but also raise the issue of what constitutes agreement between the 2 estimates. PMID- 21534686 TI - MRI correlates of cognitive impairment in childhood-onset multiple sclerosis. AB - OBJECTIVE: Brain MRI measures were correlated with neuropsychological function in 35 pediatric-onset multiple sclerosis (MS) patients and 33 age- and sex-matched healthy controls. METHOD: Mean age of MS patients was 16.3 +/- 2.3 years with average disease duration of 4.3 +/- 3.1 years. Cortical gray matter, thalamic, and global brain volumes were calculated for all participants using a scaling factor computed using normalization of atrophy method to normalize total and regional brain volumes for head size. T1- and T2-weighted lesion volumes were calculated for MS patients. RESULTS: Cognitive impairment (CI) was identified in 29% of the MS cohort. Cognitive deficits predominantly involved attention and processing speed, expressive language, and visuomotor integration. Relative to controls, the MS group showed significantly lower thalamic volume (p < .001), total brain volume (p < .008), and gray matter volume (p < .015). Corpus callosum area and thalamic volume differentiated patients identified as having CI from those without CI (p < .05). Regression models controlling for disease duration and age indicated that thalamic volume accounted for significant incremental variance in predicting global IQ, processing speed, and expressive vocabulary (DeltaR2 ranging from .43 to .60) and was the most robust MRI predictor of cognition relative to other MRI metrics. CONCLUSIONS: The robust association between cognitive function and reduced size of thalamus and global brain volume in pediatric-onset MS patients implicate neurodegenerative processes early in the disease course, and suggest that plasticity of an immature central nervous system is not sufficient to protect patients from the deleterious consequences of MS on cognitive neural networks. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21534685 TI - Psychometrically matched tasks evaluating differential fMRI activation during form and motion processing. AB - OBJECTIVE: Deficits in visual perception and working memory are commonly observed in neuropsychiatric disorders and have been investigated using functional MRI (fMRI). However, interpretation of differences in brain activation may be confounded with differences in task performance between groups. Differences in task difficulty across conditions may also pose interpretative issues in studies of visual processing in healthy subjects. METHOD: To address these concerns, the present study characterized brain activation in tasks that were psychometrically matched for difficulty; fMRI was used to assess brain activation in 10 healthy subjects during discrimination and working memory judgments for static and moving stimuli. For all task conditions, performance accuracy was matched at 70.7%. RESULTS: Areas associated with V2 and V5 in the dorsal stream were activated during motion processing tasks and V4 in the ventral stream were activated during form processing tasks. Frontoparietal areas associated with working memory were also statistically significant during the working memory tasks. CONCLUSIONS: Application of psychophysical methods to equate task demands provides a practical method to equate performance levels across conditions in fMRI studies and to compare healthy and cognitively impaired groups at comparable levels of effort. These psychometrically matched tasks can be applied to patients with a variety of cognitive disorders to investigate dysfunction of multiple a priori defined brain regions. Measuring the changes in typical activation patterns in patients with these diseases can be useful for monitoring disease progression, evaluating new drug treatments, and possibly for developing methods for early diagnosis. PMID- 21534687 TI - Comparison of age and time-to-death in the dedifferentiation of late-life cognitive abilities. AB - The dedifferentiation hypothesis proposes that specific cognitive abilities become more highly associated with general ability in old age as a result of increasing biological constraints on fluid intelligence. There is limited evidence for the hypothesis, and research has not tended to clearly distinguish age dedifferentiation from ability differentiation and other age-related phenomena. The present study examined age dedifferentiation using a structural equation model that controlled for ability differentiation, along with linear and quadratic effects of age. Time-to-death was examined as an alternative time metric to chronological age, as it may better represent biological constraints. The Canberra Longitudinal Study community-based cohort, consisting of 896 Australian adults aged 70 and over, provided data from 687 decedents who were followed for up to 17 years. Results indicated little support for the age dedifferentiation hypothesis, with only two of seven cognitive tests showing significant age dedifferentiation. The time-to-death metric showed more evidence of dedifferentiation, with four of the seven tests exhibiting dedifferentiation. However, after excluding participants with possible cognitive impairment, all of the dedifferentiation effects were attenuated to nonsignificance. Age dedifferentiation effects may therefore reflect dementia and other mortality related pathology rather than being an inevitable outcome of advanced age. Alternative developmental theories for cognitive function must better account for the diversity of late-life abilities and pathology. PMID- 21534688 TI - Age differences in temporal discounting: the role of dispositional affect and anticipated emotions. AB - We examined age differences in temporal discounting, the tendency to devalue delayed outcomes relative to immediate ones, with particular emphasis on the role of affective responses. A life-span sample completed an incentive-compatible temporal discounting task involving both monetary gains and losses. Covariates included demographic characteristics, cognitive functioning, personality traits, affective responses, and subjective health. Advanced age was associated with a lower tendency to discount the future, but this effect reached statistical significance only for the discounting of delayed gains. An examination of covariates suggested that age effects were associated with age differences in mental health and affective responses rather than demographic or cognitive variables. PMID- 21534689 TI - Age and the purchase of prescription drug insurance by older adults. AB - The Medicare Part D Prescription Drug Program places an unprecedented degree of choice in the hands of older adults despite concerns over their ability to make effective decisions and desire to have extensive choice in this context. While previous research has compared older adults to younger adults along these dimensions, our study, in contrast, examines how likelihood to delay decision making and preferences for choice differ by age among older age cohorts. Our analysis is based on responses of older adults to a simulation of enrollment in Medicare Part D. We examine how age, numeracy, cognitive reflection, and the interaction between age and performance on these instruments are related to the decision to enroll in a Medicare prescription drug plan and preference for choice in this context. We find that numeracy and cognitive reflection are positively associated with enrollment likelihood and that they are more important determinants of enrollment than age. We also find that greater numeracy is associated with a lower willingness to pay for choice. Hence, our findings raise concern that older adults, and, in particular, those with poorer numerical processing skills, may need extra support in enrolling in the program: they are less likely to enroll than those with stronger numerical processing skills, even though they show greater willingness to pay for choice. PMID- 21534690 TI - Age differences in trade-off decisions: older adults prefer choice deferral. AB - Our primary purpose in this study was to examine age differences in using choice deferral when young and older adults made trade-off decisions. Ninety-two young and 92 older adults were asked to make a trade-off decision among four cars or to use choice deferral (i.e., not buy any of these cars and keep looking for other cars). High and low emotional trade-off difficulty were manipulated between participants through different attribute labels of available cars. Older adults were more likely than young adults to choose deferral. Older adults who used deferral reported less retrospective negative emotion than those who did not. PMID- 21534691 TI - Contextual information and memory for unfamiliar tunes in older and younger adults. AB - We examined age differences in the effectiveness of multiple repetitions and providing associative facts on tune memory. For both tune and fact recognition, three presentations were beneficial. Age was irrelevant in fact recognition, but older adults were less successful than younger in tune recognition. The associative fact did not affect young adults' performance. Among older people, the neutral association harmed performance; the emotional fact mitigated performance back to baseline. Young adults seemed to rely solely on procedural memory, or repetition, to learn tunes. Older adults benefitted by using emotional associative information to counteract memory burdens imposed by neutral associative information. PMID- 21534692 TI - MMPI-2 characteristics of the Old Order Amish: a comparison of clinical, nonclinical, and United States normative samples. AB - [Correction Notice: An erratum for this article was reported in Vol 23(4) of Psychological Assessment (see record 2011-12640-001). The article contains an error under the Participants and Procedure heading. This is addressed in the correction.] In the current study, we investigated Minnesota Multiphasic Personality Inventory-2 (MMPI-2) characteristics in an Old Order Amish nonclinical sample (N = 84), comparing these data with both the United States normative sample (N = 2,600) and a sample of Old Order Amish outpatients (N = 136). Consistent with our hypothesis, the Old Order Amish nonclinical group scored similarly to the United States normative sample and lower than the Old Order Amish outpatients on most scales. Thus, overall, the MMPI-2 appears to be sensitive to psychopathology, especially depression and psychosis, among Old Order Amish test takers. Still, several Validity, Clinical, Supplementary, Content, and Personality Psychopathology Five (PSY-5) scale score differences materialized between the Old Order Amish nonclinical group and the United States group, suggesting that certain MMPI-2 scales may need to be interpreted differently for Old Order Amish test takers. Further MMPI-2 research is needed with the Old Order Amish to replicate and generalize our findings. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21534693 TI - Development and validation of the social information processing application: a Web-based measure of social information processing patterns in elementary school age boys. AB - The purpose of this study was to evaluate the psychometric properties of an audio computer-assisted self-interviewing Web-based software application called the Social Information Processing Application (SIP-AP) that was designed to assess social information processing skills in boys in 3rd through 5th grades. This study included a racially and ethnically diverse sample of 244 boys ages 8 through 12 (M = 9.4) from public elementary schools in 3 states. The SIP-AP includes 8 videotaped vignettes, filmed from the first-person perspective, that depict common misunderstandings among boys. Each vignette shows a negative outcome for the victim and ambiguous intent on the part of the perpetrator. Boys responded to 16 Web-based questions representing the 5 social information processing mechanisms, after viewing each vignette. Parents and teachers completed measures assessing boys' antisocial behavior. Confirmatory factor analyses revealed that a model positing the original 5 cognitive mechanisms fit the data well when the items representing prosocial cognitions were included on their own factor, creating a 6th factor. The internal consistencies for each of the 16 individual cognitions as well as for the 6 cognitive mechanism scales were excellent. Boys with elevated scores on 5 of the 6 cognitive mechanisms exhibited more antisocial behavior than boys whose scores were not elevated. These findings highlight the need for further research on the measurement of prosocial cognitions or cognitive strengths in boys in addition to assessing cognitive deficits. Findings suggest that the SIP-AP is a reliable and valid tool for use in future research of social information processing skills in boys. PMID- 21534694 TI - The utility of the Kessler Screening Scale for Psychological Distress (K6) in two American Indian communities. AB - The Kessler Screening Scale for Psychological Distress (K6; Kessler et al., 2002) has been used widely as a screener for mental health problems and as a measure of severity of impact of mental health problems. However, the applicability and utility of this measure for assessments within American Indian communities has not been explored. Data were drawn from a large-scale epidemiological study conducted in cooperation with 2 American Indian populations. Participants (N = 3,084) were 15-54 years of age and living on or near their home reservations; each completed an interview that included a version of the Composite International Diagnostic Interview (Robins, Wing, Wittchen, & Helzer, 1988) and the K6. A measure of both physical- and mental-health-related quality of life-the Medical Outcome Study's Short Form-36 (Ware & Sherbourne, 1992)-was used to examine the importance of the K6 over and above psychiatric diagnoses. The K6 was shown to be an appropriate screening and severity measure for mood disorders in these 2 samples. It also predicted health-related quality of life over and above that predicted by diagnoses alone. Inclusion of a measure such as the K6 as a complement to more traditional dichotomous diagnoses in both research and clinical practice is recommended. PMID- 21534695 TI - A bifactor model of negative affectivity: fear and distress components among younger and older youth. AB - The Positive and Negative Affect Schedule for Children (PANAS-C) is a 27-item youth-report measure of positive affectivity and negative affectivity. Using 2 large school-age youth samples (clinic-referred sample: N = 662; school-based sample: N = 911), in the present study, we thoroughly examined the structure of the PANAS-C NA and PA scales and fit a bifactor model to the PANAS-C NA items. Our exploratory factor analytic results demonstrated that negative affectivity is comprised of 2 main components-NA: Fear and NA: Distress-specifically among older youth. A bifactor model also evidenced the best model fit relative to a unidimensional and second-order factor structure of the PANAS-C NA items. The NA: Fear group factor evidenced significant correspondence with external criterion measures of anxiety. However, the original PANAS-C NA scale evidenced equal (and in some cases greater) correspondence with criterion measures of anxiety. We thus recommend continued usage and interpretation of the full PANAS-C NA scale despite the identification of the fear and distress group factors underlying general negative affectivity. The identification of these fear and distress group factors nonetheless suggest that negative affectivity may be comprised largely of a fear and distress component among older youth. The implications of these findings are discussed in relation to better understanding the structure of psychopathology across childhood development and informing the development of future treatments of negative emotions. PMID- 21534697 TI - Development of a measure of experiential avoidance: the Multidimensional Experiential Avoidance Questionnaire. AB - Experiential avoidance (EA) has been conceptualized as the tendency to avoid negative internal experiences and is an important concept in numerous conceptualizations of psychopathology as well as theories of psychotherapy. Existing measures of EA have either been narrowly defined or demonstrated unsatisfactory internal consistency and/or evidence of poor discriminant validity vis-a-vis neuroticism. To help address these problems, we developed a reliable self-report questionnaire assessing a broad range of EA content that was distinguishable from higher order personality traits. An initial pool of 170 items was administered to a sample of undergraduates (N = 312) to help evaluate individual items and establish a structure via exploratory factor analyses. A revised set of items was then administered to another sample of undergraduates (N = 314) and a sample of psychiatric outpatients (N = 201). A 2nd round of item evaluation was performed, resulting in a final 62-item measure consisting of 6 subscales. Cross-validation data were gathered in 3 new, independent samples (students, N = 363; patients, N = 265; community adults, N = 215). The resulting measure (the Multidimensional Experiential Avoidance Questionnaire, or MEAQ) exhibited good internal consistency, was substantially associated with other measures of avoidance, and demonstrated greater discrimination vis-a-vis neuroticism relative to preexisting measures of EA. Furthermore, the MEAQ was broadly associated with psychopathology and quality of life, even after controlling for the effects of neuroticism. PMID- 21534696 TI - Structure and measurement of depression in youths: applying item response theory to clinical data. AB - Our goals in this article were to use item response theory (IRT) to assess the relation of depressive symptoms to the underlying dimension of depression and to demonstrate how IRT-based measurement strategies can yield more reliable data about depression severity than conventional symptom counts. Participants were 3,403 children and adolescents from 12 contributing clinical and nonclinical samples; all participants had received the Kiddie Schedule of Affective Disorders and Schizophrenia for School-Aged Children. Results revealed that some symptoms reflected higher levels of depression and were more discriminating than others. Furthermore, use of IRT-based information about symptom severity and discriminability in the measurement of depression severity was shown to reduce measurement error and increase measurement fidelity. PMID- 21534698 TI - A correction for recruitment bias in norms derived from meta-analysis. AB - Normative comparisons are an integral component of neuropsychological test interpretation and provide the basis for an inference of abnormal function and impairment. In order to remedy a deficit of normative standards for a large number of neuropsychology tests, Mitrushina, Boone, Razani, and D'Elia (2005) used the meta-analysis of studies that incorporated normal volunteers to create a type of normative standard for many tests in neuropsychology that were not adequately normed in the past. The present study examined this method by contrasting meta-analysis norms of the Wechsler Adult Intelligence Scale-Revised (WAIS-R; Wechsler, 1981) with its published quota norms. The study examined 12 experimental studies of the WAIS-R that included normal, control volunteers (N = 2,147). These were combined by meta-analysis, and the summary scores were compared. The meta-analysis revealed a significant sampling bias with studies recruiting more White and higher educated respondents than indicated by the U.S. Census. This bias was successfully corrected using Monte Carlo simulation and adjustments for quota sampling. The corrections could be applied to all meta analysis norms currently in use and bring them in line with the U.S. Census demographics. PMID- 21534699 TI - Cohort differences in Big Five personality factors over a period of 25 years. AB - The notion of personality traits implies a certain degree of stability in the life span of an individual. But what about generational effects? Are there generational changes in the distribution or structure of personality traits? This article examines cohort changes on the Big Five personality factors Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience, among first-year psychology students in The Netherlands, ages 18 to 25 years, between 1982 and 2007. Because measurement invariance of a personality test is essential for a sound interpretation of cohort differences in personality, we first assessed measurement invariance with respect to cohort for males and females separately on the Big Five personality factors, as measured by the Dutch instrument Five Personality Factors Test. Results identified 11 (females) and 2 (males) biased items with respect to cohort, out of a total of 70 items. Analyzing the unbiased items, results indicated small linear increases over time in Extraversion, Agreeableness, and Conscientiousness and small linear decreases over time in Neuroticism. No clear patterns were found on the Openness to Experience factor. Secondary analyses on students from 1971 to 2007 of females and males of different ages together revealed linear trends comparable to those in the main analyses among young adults between 1982 onward. The results imply that the broad sociocultural context may affect personality factors. PMID- 21534700 TI - The benefits of interpersonal regulatory fit for individual goal pursuit. AB - The present work examines whether individual goal pursuit is influenced by advice and suggestions from interaction partners whose regulatory orientation is perceived to fit (vs. not fit) the individual's orientation. We sought to investigate whether such interpersonal regulatory fit yields motivational consequences for goal pursuit that parallel those of intrapersonal regulatory fit. Furthermore, we investigated whether these effects occur in a symmetrical fashion for promotion- and prevention-oriented individuals. The results of 6 experiments revealed that promotion-oriented individuals profit from interpersonal regulatory fit, experiencing motivational benefits when receiving goal-relevant advice from promotion-oriented interaction partners; however, prevention-oriented individuals do not profit from prevention-oriented interaction partners. These findings support the proposal that regulatory fit can fruitfully be examined as an interpersonal phenomenon, highlighting the role that interaction partners may play in the pursuit of personal goals. PMID- 21534701 TI - The costs and benefits of sexism: resistance to influence during relationship conflict. AB - This study tested whether men's and women's hostile sexism (HS) and benevolent sexism (BS) were associated with resistance to influence in couples' conflict interactions. Ninety-one heterosexual couples were recorded while trying to produce desired changes in each other. Participants reviewed their discussions and rated how open they were to their partner's perspective. Objective coders also rated the extent to which each partner exhibited hostile communication. We tested key principles arising from ambivalent sexism theory (Glick & Fiske, 1996). First, BS is necessary because mutual interdependence reduces the power of HS to influence women within intimate relationships. We found that the more men endorsed HS, the less open and more hostile both partners were, and the less successful their discussions were in producing desired change. Second, BS reduces the threat of women's dyadic power by revering and respecting women's interpersonal roles while restricting women's influence outside the relationship domain. We found that men who expressed higher agreement with BS were more open to their partners' influence and behaved with less hostility, and their discussions were more successful. These relationship benefits illustrate why BS is effective at disarming women's resistance to wider inequalities. These benefits, however, were contingent on men adopting BS attitudes. When women strongly endorsed BS but their male partner did not, women were less open, behaved with greater hostility, and perceived their discussions as less successful. These results indicate that, because BS increases the stakes within the relationship domain, women who endorse BS will react more negatively when their expectations are not realized. PMID- 21534702 TI - "What about me?" Perceptions of exclusion and whites' reactions to multiculturalism. AB - A 5-study investigation of reactions of dominant group members (i.e., White Americans) to diversity (relative to racial minority reactions) provides evidence of implicit and explicit associations between multiculturalism and exclusion and of a relationship between perceived exclusion and reactions to diversity. In Study 1, Whites but not racial minorities were faster in an implicit association task at pairing multiculturalism with exclusion than with inclusion. This association diminished in Study 2 through a subtle framing of diversity efforts as targeted toward all groups, including European Americans. In Study 3, in a "Me/Not Me" task, Whites were less likely than minorities to pair multiculturalism concepts with the self and were slower in responding to multiculturalism concepts. Furthermore, associating multiculturalism with the self (Study 3) or feeling included in organizational diversity (Study 4) predicted Whites' endorsement of diversity and also accounted for the oft-cited group status difference in support for diversity initiatives. Study 5 showed that individual differences in need to belong moderated Whites' interest in working for organizations that espouse a multicultural versus a color-blind approach to diversity, with individuals higher in need to belong less attracted to organizations with a multicultural approach. Overall, results show that the purportedly "inclusive" ideology of multiculturalism is not perceived as such by Whites. This may, in part, account for their lower support for diversity efforts in education and work settings. PMID- 21534703 TI - When autocratic leaders become an option--uncertainty and self-esteem predict implicit leadership preferences. AB - We investigated the impact of uncertainty on leadership preferences and propose that the conjunction of self-esteem level and stability is an important moderator in this regard. Self-threatening uncertainty is aversive and activates the motivation to regain control. People with high and stable self-esteem should be confident of achieving this goal by self-determined amelioration of the situation and should therefore show a stronger preference for democratic leadership under conditions of uncertainty. By contrast, people with low and unstable self-esteem should place their trust and hope in the abilities of powerful others, resulting in a preference for autocratic leadership. Studies 1a and 1b validate explicit and implicit leadership measures and demonstrate a general prodemocratic default attitude under conditions of certainty. Studies 2 and 3 reveal a democratic reaction for individuals with stable high self-esteem and a submissive reaction for individuals with unstable low self-esteem under conditions of uncertainty. In Study 4, this pattern is cancelled out when individuals evaluate leadership styles from a leader instead of a follower perspective. PMID- 21534704 TI - Relational regulation theory: a new approach to explain the link between perceived social support and mental health. AB - Perceived support is consistently linked to good mental health, which is typically explained as resulting from objectively supportive actions that buffer stress. Yet this explanation has difficulty accounting for the often-observed main effects between support and mental health. Relational regulation theory (RRT) hypothesizes that main effects occur when people regulate their affect, thought, and action through ordinary yet affectively consequential conversations and shared activities, rather than through conversations about how to cope with stress. This regulation is primarily relational in that the types of people and social interactions that regulate recipients are mostly a matter of personal taste. RRT operationally defines relationships quantitatively, permitting the clean distinction between relationships and recipient personality. RRT makes a number of new predictions about social support, including new approaches to intervention. PMID- 21534705 TI - Expectations and interpretations during causal learning. AB - In existing models of causal induction, 4 types of covariation information (i.e., presence/absence of an event followed by presence/absence of another event) always exert identical influences on causal strength judgments (e.g., joint presence of events always suggests a generative causal relationship). In contrast, we suggest that, due to expectations developed during causal learning, learners give varied interpretations to covariation information as it is encountered and that these interpretations influence the resulting causal beliefs. In Experiments 1A-1C, participants' interpretations of observations during a causal learning task were dynamic, expectation based, and, furthermore, strongly tied to subsequent causal judgments. Experiment 2 demonstrated that adding trials of joint absence or joint presence of events, whose roles have been traditionally interpreted as increasing causal strengths, could result in decreased overall causal judgments and that adding trials where one event occurs in the absence of another, whose roles have been traditionally interpreted as decreasing causal strengths, could result in increased overall causal judgments. We discuss implications for traditional models of causal learning and how a more top-down approach (e.g., Bayesian) would be more compatible with the current findings. PMID- 21534706 TI - How people interpret conditionals: shifts toward the conditional event. AB - We investigated how people interpret conditionals and how stable their interpretation is over a long series of trials. Participants were shown the colored patterns on each side of a 6-sided die and were asked how sure they were that a conditional holds of the side landing upward when the die is randomly thrown. Participants were presented with 71 trials consisting of all combinations of binary dimensions of shape (e.g., circles and squares) and color (e.g., blue and red) painted onto the sides of each die. In 2 experiments (N1 = 66, N2 = 65), the conditional event was the dominant interpretation, followed by conjunction, and material conditional responses were negligible. In both experiments, the percentage of participants giving a conditional event response increased from around 40% at the beginning of the task to nearly 80% at the end, with most participants shifting from a conjunction interpretation. The shift was moderated by the order of shape and color in each conditional's antecedent and consequent: Participants were more likely to shift if the antecedent referred to a color. In Experiment 2 we collected response times: Conditional event interpretations took longer to process than conjunction interpretations (mean difference = 500 ms). We discuss implications of our results for mental models theory and probabilistic theories of reasoning. PMID- 21534707 TI - Reversing the hands of time: changing the mapping from seeing to saying. AB - To describe a scene, speakers must map visual information to a linguistic plan. Eye movements capture features of this linkage in a tendency for speakers to fixate referents just before they are mentioned. The current experiment examined whether and how this pattern changes when speakers create atypical mappings. Eye movements were monitored as participants told the time from analog clocks. Half of the participants did this in the usual manner. For the other participants, the denotations of the clock hands were reversed, making the big hand the hour and the little hand the minute. Eye movements revealed that it was not the visual features or configuration of the hands that determined gaze patterns, but rather top-down control from upcoming referring expressions. Differences in eye-voice spans further suggested a process in which scene elements are relationally structured before a linguistic plan is executed. This provides evidence for structural rather than lexical incrementality in planning and supports a "seeing for-saying" hypothesis in which the visual system is harnessed to the linguistic demands of an upcoming utterance. PMID- 21534710 TI - Breastfeeding prevalence and distribution in the USA and Appalachia by rural and urban setting. AB - INTRODUCTION: Breastfeeding provides health benefits to infants and mothers, yet many women decide against breastfeeding. This study examined differences in the prevalence of breastfeeding among national, urban, rural, and Appalachian regions of the USA. METHODS: Secondary data analysis of the US 2007 National Survey of Children's Health (n=27 388) data were completed for prevalence, insurance coverage, and medical home (a source of comprehensive primary care) determinations according to rural or urban location. RESULTS: The weighted US and Appalachian prevalences of breastfeeding were 0.755 (CI 0.743-0.767) and 0.683 (CI 0.672-0.694). National and Appalachian urban prevalences were 0.770 (CI 0.757 0.784) and 0.715 (CI 0.702-0.728). Rural areas had a significantly lower prevalence of breastfeeding of 0.687 (CI 0.661-0.713). Appalachia was significantly lower than the national rural level at 0.576 (CI 0.554-0.598). Women with Medicaid/State Children's Health Insurance Program (SCHIP) had an odds ratio of 1.79 of not breastfeeding compared with privately insured women. Nationally, 26.6% (CI 24.5-28.7) of children of women who did not breastfeed did not have a medical home. CONCLUSIONS: Anticipatory guidance about breastfeeding with culturally sensitive awareness programs and interventions directed at rural populations, especially in high risk geographic areas such as Appalachia, may be needed. Healthcare professionals have a unique opportunity to provide anticipatory guidance to pregnant women by discussing the benefits of breastfeeding during visits. High school health educational programs should address the benefits of breastfeeding with rural females. PMID- 21534711 TI - The decision-making processes of pharmacists in inland Australia--a pilot study. AB - INTRODUCTION: Little research has been conducted analysing the organisational risks that compound and trigger dispensing and medication errors. This pilot study appraises the attitudes to and behaviours related to the dispensing errors of pharmacists practising in diverse venues and roles in inland Australia. METHODS: Twelve pharmacists working in the Riverina (Wiradjuri country) participated in a structured interview consisting of a brief survey and open ended questions. The interviews were audio-recorded for transcription, then analysed by the interviewer for emerging themes. In this pilot study, the attitudes and actions of pharmacists in response to dispensing errors were explored to determine the nature of organisational strategies implemented to detect and recover 'slips, lapses and mistakes'. The rationale behind investigating attitudes and actions stems from the theory of planned behaviour. RESULTS: While many common themes emerged, the attitudes of each pharmacist were unique. The strategies implemented to prevent errors were venue-specific and purpose-designed to the training level of the staff and physical environment. A diverse mix of attitudes was represented by the sample, with no correlation between worksite, sex, age or role identified. Trends may emerge because, in regard to dispensing errors, subjective norms and perceived behavioural control play a greater role in forming the intention to act, rather than personal attitudes. The majority of examples given by participants was discussion of recorded errors and near misses, which included changes to procedures implemented to prevent the same error occurring. This culture of continuous quality improvement was the overarching common theme. Other common themes were the role of technology in the supply of medicines, privacy implications when drawing staff from a rural or regional centre, workload concerns with regard to management responsibility and the impact of the way error management was demonstrated during the formative early years of practice. Distraction from dispensing, through management roles in pharmacies with moderate prescription volumes, was a common contributor to errors. CONCLUSION: A culture of continuous quality improvement exists amongst pharmacists in Inland Australia, which would benefit from improved dialogue about the impact of organisational risks on the rate of dispensing errors. The safety culture, and behaviour modelling experienced during the internship program has a profound impact on the perceived behavioural control of young pharmacists. This year instils mores, which may be the result of independent survival in remote and regional settings, rather than compliance with professional practice standards. While many of the pressures and demands of minimising errors are common across the profession; unique, venue specific strategies are commonly implemented in the cycle of continuous quality improvement in regional and remote settings. PMID- 21534712 TI - Getting used to assistive devices: ambivalent experiences by frail elderly persons. AB - The aim was to learn how frail elderly people experienced becoming assistive device users and how assistive devices affected their independence in daily activities. Focus-group methodology was used, including people 80 and older with multiple health problems. Five group discussions were conducted with a total of 18 people including 14 women and four men. Each group met once, for 90-120 minutes, and all discussions were audiotaped. Two themes emerged: Confidence in knowledge and experience and getting used to assistive devices in daily activities. Confidence in knowledge and experience was formed by two categories of experiences from the prescription procedure: trust the expert and trust yourself, and to have confidence in having the right information about assistive devices. Getting used to assistive devices in daily activities was formed by five categories of ambivalent experiences when using assistive devices in daily activities: creates opportunities and limitations; provides security but also raises concerns; the need is seen as transient or permanent; the social environment both encourages and restricts; the physical environment both facilitates and complicates, with less extreme experiences in between. This study indicates that frail elderly people need specifically developed support in the process of becoming assistive device users. PMID- 21534714 TI - Combined protocol for treatment of secondary effects from facial nerve palsy. AB - CONCLUSION: Rehabilitation was significantly efficient in both groups of patients with synkinesis, especially in those in whom treatment with botulinum toxin type A (BTX-A) preceded physical rehabilitation. OBJECTIVE: To determine the influence of preventive treatment with BTX-A on synkinesis when physical rehabilitation is planned. METHODS: Twenty patients, who recovered from facial palsy with final House-Brackmann (HB) grade II and III, were randomized to assess the efficacy of preventive BTX-A treatment on final synkinesis score after physical rehabilitation. Synkinesis was graded according to the four-point scale derived from the SunnyBrook Facial Grading System (FGS). Physical rehabilitation was carried out using NeuroMuscular Retraining Therapy (NMRT). In the randomized groups, NMRT was administered with (group a) or without pre-BTX-A treatment (group b). RESULTS: Patients who were preliminarily treated with BTX-A in the affected area showed a 2.1 improvement of score on the SunnyBrook scale (p < 0.001), with significantly better results in comparison to the non-BTX-A group. PMID- 21534715 TI - Development of a Mandarin monosyllable test material with homogenous items (I): homogeneity selection. AB - CONCLUSION: A homogeneity selection could establish a homogenous resource for Chinese Mandarin monosyllabic test lists. OBJECTIVE: This study aimed to develop a set of succinct and phonemically balanced monosyllabic Mandarin recognition test lists with good item homogeneity, in an effort to meet the need for Chinese Mandarin speech recognition test materials. METHODS: In reference to the Chinese phonemes distribution probability, we developed the Phoneme Allocation Table, which decided the occurrence of all consonants, vowels, and semantic tones in each list. A total of 489 monosyllables were selected and organized into 30 lists, with 25 monosyllables in each. A two-factor design was used to screen homogenous items out. Sixty normal-hearing native Mandarin speakers participated in experiment. The performance-intensity (P-I) function curve of each test item was fit by logistic regression. Items were screened out as homogenous ones using the following criteria: 1) regression R value was not <0.9; 2) slope was between 2%/dB and 12%/dB; 3) threshold was between -8 dB HL and 10 dB HL. RESULTS: The Phoneme Allocation Table was established as a framework of 30 lists, providing a basis on which phonemically balanced monosyllabic lists can be developed. In all, 342 monosyllables with good homogeneity were screened out and can be reorganized to establish monosyllabic test lists with good sensitivity. PMID- 21534716 TI - Hearing improvement after cochlear implantation in common cavity malformed cochleae: long-term follow-up results. AB - CONCLUSION: We suggest that cochlear implantation (CI) should be a good therapeutic modality for hearing restoration in patients with common cavity malformed ears. OBJECTIVE: To analyze hearing improvement from CI performed in common cavity malformed cochleae. METHODS: A total of 11 patients (5 male and 6 female, mean age 4.5 +/- 2.8 years) and 12 ears were enrolled in this study. During the insertion of electrodes, we used C-arm fluoroscopy to avoid intrameatal placement. We evaluated hearing improvement every 6 months and the mean follow-up period was 80.5 +/- 24.1 months (53-125 months). RESULTS: During the operation, there were only four cases with fully inserted electrodes. Cerebrospinal fluid gushed out in two cases during the cochleostomy and postoperative meningitis occurred in two patients. One patient had to undergo reimplantation 4 years later due to device failure and recurrent meningitis. During the 48 months follow-up hearing evaluation, the ability of hearing increased along with the age. The final average MAIS, CAP, SIR, and open set one- and two-syllable word scores were 90.3 +/- 18.1%, 4.9 +/- 1.6, 3.1 +/- 0.9, 24.1 +/- 25.9%, and 48.6 +/- 38.7%, respectively. PMID- 21534717 TI - A single nasal dose of CCL20 chemokine induces dendritic cell recruitment and enhances nontypable Haemophilus influenzae-specific immune responses in the nasal mucosa. AB - CONCLUSION: The results of the present study indicate the potential of CCL20 as an effective mucosal adjuvant and suggest that nasal vaccination with P6 in combination with nasal CCL20 might be an effective regimen for the induction of nontypable Haemophilus influenzae (NTHi)-specific protective immunity. OBJECTIVES: Nasal vaccination is an effective therapeutic regimen for preventing upper respiratory infections. In the development of nasal vaccine, an appropriate adjuvant is required. In the present study we examined the efficacy of CCL20 as a mucosal adjuvant. METHODS: CCL20 was administered intranasally to mice, which were then immunized intranasally with P6 protein of NTHi, and P6-specific immune responses were examined. In addition, NTHi challenges were performed and the level of NTHi was quantified in nasal washes. RESULTS: Nasal application of CCL20 induced an increase in the number of dendritic cells in nasal-associated lymphoid tissue. P6-specific nasal wash immunoglobulin (Ig)A and serum IgG titers were elevated significantly after nasal immunization. Enhanced NTHi clearance from the nasopharynx was also observed. PMID- 21534718 TI - Motesanib and advanced NSCLC: experiences and expectations. AB - INTRODUCTION: Benefits from conventional chemotherapy in NSCLC have plateaued. Accordingly, sizeable efforts have gone into developing novel therapies. Tumor angiogenesis mediated principally by VEGF has emerged as an alluring target because of its vital role in tumor growth, sustenance and metastasis. The Eastern Cooperative Oncology Group (ECOG) trial E4599 showed significant improvement in overall survival with addition of bevacizumab, a VEGF monoclonal antibody, to cytotoxic chemotherapy in metastatic NSCLC. A number of compounds targeting tumor angiogenesis have since gone into preclinical and clinical testing. The multifaceted nature of cancer has led to development of multitarget tyrosine kinase inhibitors (MTKIs) that target several pathways concomitantly. Motesanib, an orally administered potent small molecule, targets VEGFR 1 - 3, PDGFR and KIT. Oral bioavailability and preliminary evidence of activity make this compound an appealing choice for additional investigations. AREAS COVERED: This review summarizes the background of angiogenesis and rationale for targeting the VEGF pathway in NSCLC. The authors also review recent clinical trial data evaluating motesanib. EXPERT OPINION: VEGF is a validated target in NSCLC. In early trials motesanib has shown promising activity in NSCLC with tolerable toxicity profile. A Phase III trial with motesanib in combination with chemotherapy is ongoing. PMID- 21534719 TI - Normobaric hyperoxia in traumatic brain injury: does brain metabolic state influence the response to hyperoxic challenge? AB - This study sought to investigate whether normobaric hyperoxia (NH) improves brain oxygenation and brain metabolism in the early phase of severe and moderate traumatic brain injury (TBI) and whether this effect occurs uniformly in all TBI patients. Thirty patients (9 women and 21 men) with a median initial Glasgow Coma Score (GCS) of 6 (range, 3-12) were monitored using a brain microdialysis (MD) catheter with a brain tissue oxygen sensor (PtiO(2)) placed in the least-injured hemisphere. The inspired oxygen fraction was increased to 100% for 2 h. Patients were divided into two groups: Group 1: patients with baseline brain lactate <=3 mmol/L and Group 2: patients with baseline brain lactate >3 mmol/L, and therefore increased anaerobic metabolism in the brain. In Group 1, no significant changes in brain metabolic parameters were found after hyperoxic challenge, whereas a significant increase in glucose and a decrease in the lactate-pyruvate ratio (LPR) were found in Group 2. In this latter group of patients, brain glucose increased on average by 17.9% (95% CI, +9.2% to +26.6%, p<0.001) and LPR decreased by 11.6% (95% CI, -16.2% to -6.9%, p<0.001). The results of our study show that moderate and severe TBI may induce metabolic alterations in the brain, even in macroscopically normal brain tissue. We observed that NH increased PaO(2) and PtiO(2) and significantly decreased LPR in patients in whom baseline brain lactate levels were increased, suggesting that NH improved the brain redox state. In patients with normal baseline brain lactate levels, we did not find any significant changes in the metabolic variables after NH. This suggests that the baseline metabolic state should be taken into account when applying NH to patients with TBI. This maneuver may only be effective in a specific group of patients. PMID- 21534720 TI - Early enteral nutrition and clinical outcomes of severe traumatic brain injury patients in acute stage: a multi-center cohort study. AB - Guidelines for patients with severe traumatic brain injury (sTBI) published in 2007 recommend providing early nutrition after trauma. Early enteral nutrition (EN) started within 48 h post-injury reduces clinical malnutrition, prevents bacterial translocation from the gastrointestinal tract, and improves outcome in sTBI patients sustaining hypermetabolism and hypercatabolism. The aim of this study was to examine the effect of early EN support on survival rate, Glasgow Coma Scale (GCS) score, and clinical outcome of sTBI patients. Medical records of sTBI patients with GCS scores 4-8 were recruited from 18 hospitals in Taiwan, excluding patients with GCS scores <=3. During 2002-2010, data from 145 EN patients receiving appropriate calories and nutrients within 48 h post-trauma were collected and compared with 152 non-EN controls matched for gender, age, body weight, initial GCS score, and operative status. The EN patients had a greater survival rate and GCS score on the 7th day in the intensive care unit (ICU), and a better outcome at 1 month post-injury. After adjusting for age, gender, initial GCS score, and recruitment period, the non-EN patients had a hazard ratio of 14.63 (95% CI 8.58-24.91) compared with EN patients. The GCS score during the first 7 ICU days was significantly improved among EN patients with GCS scores of 6-8 compared with EN patients with GCS scores of 4-5 and non EN patients with GCS scores of 6-8. This finding demonstrates that EN within 48 h post-injury is associated with better survival, GCS recovery, and outcome among sTBI patients, particularly in those with a GCS score of 6-8. PMID- 21534721 TI - Neurosurgical forum. Shunt failure. PMID- 21534722 TI - Genetic variation within and between winter wheat genotypes from Turkey, Kazakhstan, and Europe as determined by nucleotide-binding-site profiling. AB - The genetic diversity within wheat breeding programs across Turkey and Kazakhstan was compared with a selection of European cultivars that represented the genetic diversity across eight European countries and six decades of wheat breeding. To focus the measure of genetic diversity on that relevant to disease-resistant phenotypes, nucleotide-binding-site (NBS) profiling was used to detect polymorphisms associated with the NBS motifs found within the NBS--leucine-rich repeat (LRR) class of resistance (R) genes. Cereal-specific NBS primers, designed specifically to the conserved NBS motifs found within cereal R-genes, provided distinct NBS profiles. Although the genetic diversity associated with NBS motifs was only slightly higher within the Eastern wheat genotypes, the NBS profiles produced by Eastern and European wheat lines differed considerably. Structure analysis divided the wheat genotypes into four groups, which compared well with the origin of the wheat genotypes. The highest levels of genetic diversity were seen for the wheat genotypes from the Genetic Resource Collection held in Ankara, Turkey, as wheat genotypes within breeding programs were genetically more similar. The wheat genotypes from Kazakhstan were the most similar to the European cultivars, reflecting the significant number of eastern European cultivars used in the breeding program in Kazakhstan. In general, the NBS profiles suggested that NBS-LRR R-gene usage in winter wheat breeding in Turkey and Kazakhstan differed from that deployed in European cultivars. PMID- 21534723 TI - Effects of cortical bone thickness at different healing times on microscrew stability. AB - OBJECTIVE: To compare the effects of different cortical bone thicknesses on the stability of microscrews at different healing times. MATERIALS: Sixty-four microscrews were inserted into the femurs of eight beagles, with four microscrews for one femur of one beagle dog. The dogs were sacrificed at 0, 3, 6, and 9 weeks after microscrew placement, respectively. All specimens were prepared for pullout testing. Cortical bone thickness was measured. Statistical analyses were conducted with analysis of variance (ANOVA) and Student-Neuman-Keuls (SNK) tests. RESULTS: Pullout forces in thick cortical bone sites are significantly higher than those in thin sites at 0 week and 3 weeks. For both thick and thin cortical bone thickness sites, the highest pullout forces were seen in the 0 week group and the lowest in the 3 week group. In the thin cortical bone thickness sites, the pullout force of the 3 week group was statistically different from those of the 6 week group and the 9 week group; however, no such differences were noted in thick cortical bone thickness sites. CONCLUSION: Microscrews inserted into thick cortical bone thickness sites had better stability than those inserted into thin cortical bone thickness sites at early healing time. The difference diminished and became insignificant as healing time got longer. Longer healing time may be necessary if microscrews are inserted into thin cortical bone thickness sites. PMID- 21534724 TI - Sex differences in esthetic treatment needs in American black and white adolescent orthodontic patients. AB - OBJECTIVE: To test whether the severity of malocclusions in adolescents who actually entered orthodontic treatment is different between the sexes, as this might explain the preponderance of girls in orthodontic practices. MATERIALS AND METHODS: Severity was gauged with the 10-grade esthetic component of the Index of Orthodontic Treatment Need (IOTN) scored on the pretreatment intraoral photographs (n = 562) in a university-based specialty program. The samples of American White (n = 401) and American Black (n = 161) adolescents were free of craniofacial defects. Nonparametric statistics were used for analysis. RESULTS: There is a significant sex difference in the IOTN in White teenagers due to milder, more esthetic cases among the girls. No sex difference occurs in the sample of Blacks, with both sexes having IOTN scores on a par with White males. The severity of malocclusion is independent of the age at start of treatment (within range of 12 to 19 years). CONCLUSIONS: Greater subjective self perceptions of occlusal issues seem to account for the preponderance of White girls in the patient pool, though why the sex difference is not evident in American Blacks is complex. We speculate that sex differences are larger in private practices, since there are fewer selection criteria for entering treatment. PMID- 21534725 TI - Salivary microbial and nonmicrobial parameters in children with fixed orthodontic appliances. AB - OBJECTIVE: To determine the physiologic changes of salivary flow rate, pH, and buffer capacity and the levels of Streptococcus mutans and Lactobacillus spp in patients undergoing fixed orthodontic treatment. MATERIALS AND METHODS: The study included 23 patients scheduled for fixed orthodontic therapy. All subjects received equal braces, bands, and brackets, bonded with the same material. Stimulated saliva samples were taken before placement of the appliance, and at weeks 6, 12, and 18 during the therapy. Salivary flow rate and salivary pH were measured, and the salivary buffer capacity was determined. Saliva samples were cultivated on selective microbial agar for microorganism detection. RESULTS: A significant (P < .05) increase in stimulated salivary flow rate and salivary pH was found. The salivary levels of S mutans and Lactobacillus spp also inscreased significantly (P < .05), and the major peak was at week 12 of fixed orthodontic therapy. CONCLUSION: The 6th to 12th week of orthodontic therapy is the period of the most intensive intraoral growth of S mutans and Lactobacillus spp and a time of very intensive salivary functions and physiologic response. PMID- 21534726 TI - Cardiovascular responses to static muscle contraction in patients with brachial plexus injury treated with intercostal nerve transfer. AB - Pressor response is carried in afferent fibers of somatic nerves to increase blood pressure (BP) and heart rate (HR) during static exercise in humans. However, there is no information that peripheral responses restore muscle contraction with nerve transfer operation. In this study, we aimed to assess isometric exercise-induced pressor responses in patients with brachial plexus injury (BPI) after intercostal nerve transfer (ICNT) to restore elbow flexor muscles. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR during 2-min sustained isometric muscle contraction of elbow flexors at 20% and 35% of maximal voluntary contraction (MVC) on the unaffected side and the ICNT side, were measured in seven subjects with BPI treated with ICNT. SBP, DBP, and HR during 2-min sustained isometric muscle contraction of elbow flexors at 20% of MVC on the unaffected side were similar to those recorded before and after the exercise. However, the same variables increased significantly (p<0.001) during a similar type of exercise at 35% MVC on the unaffected side. On the ICNT side, no significant differences were noted in elbow flexors at 20% and 35% MVC. Isometric static exercise at 35% of MVC did not induce pressor and HR changes on the ICNT side. The difference in the responses between the two sides could have been caused by incomplete recovery of afferent nerve function following nerve repair, despite the restoration of efferent nerve function. Alternatively, the HR and BP responses to static contraction may depend upon the active muscle mass. PMID- 21534728 TI - Risk stratification and short-term prognosis in acute heart failure syndromes: a review of novel biomarkers. AB - BACKGROUND: Early risk stratification of patients with acute heart failure syndrome (AHFS) can guide the decision to admit the patient to hospital and the choice of therapy. METHODS: Standard review methodology using Medline and Google scholar from the years 2006-present. Papers before 2006 were reviewed when necessary. RESULTS: Biomarkers used in AHFS are broadly classified based on their mechanism of action: inflammation, renal stress, extracellular matrix remodeling, oxidative stress, cardiac myocyte stress, and neurohormonal regulation. CONCLUSION: This paper provides a review for clinicians and medical scientists highlighting the most recent advances in biomarkers with application in AHFS. PMID- 21534727 TI - Progesterone increases circulating endothelial progenitor cells and induces neural regeneration after traumatic brain injury in aged rats. AB - Vascular remodeling plays a key role in neural regeneration in the injured brain. Circulating endothelial progenitor cells (EPCs) are a mediator of the vascular remodeling process. Previous studies have found that progesterone treatment of traumatic brain injury (TBI) decreases cerebral edema and cellular apoptosis and inhibits inflammation, which in concert promote neuroprotective effects in young adult rats. However, whether progesterone treatment regulates circulating EPC level and fosters vascular remodeling after TBI have not been investigated. In this study, we hypothesize that progesterone treatment following TBI increases circulating EPC levels and promotes vascular remodeling in the injured brain in aged rats. Male Wistar 20-month-old rats were subjected to a moderate unilateral parietal cortical contusion injury and were treated with or without progesterone (n=54/group). Progesterone was administered intraperitoneally at a dose of 16mg/kg at 1 h post-TBI and was subsequently injected subcutaneously daily for 14 days. Neurological functional tests and immnunostaining were performed. Circulating EPCs were measured by flow cytometry. Progesterone treatment significantly improved neurological outcome after TBI measured by the modified neurological severity score, Morris Water Maze and the long term potentiation in the hippocampus as well as increased the circulating EPC levels compared to TBI controls (p<0.05). Progesterone treatment also significantly increased CD34 and CD31 positive cell number and vessel density in the injured brain compared to TBI controls (p<0.05). These data indicate that progesterone treatment of TBI improves multiple neurological functional outcomes, increases the circulating EPC level, and facilitates vascular remodeling in the injured brain after TBI in aged rats. PMID- 21534730 TI - Symptoms of psychosis in a patient with anorexia nervosa. PMID- 21534729 TI - Amiloride improves locomotor recovery after spinal cord injury. AB - Amiloride is a drug approved by the United States Food and Drug Administration, which has shown neuroprotective effects in different neuropathological conditions, including brain injury or brain ischemia, but has not been tested in spinal cord injury (SCI). We tested amiloride's therapeutic potential in a clinically relevant rat model of contusion SCI inflicted at the thoracic segment T10. Rats receiving daily administration of amiloride from 24 h to 35 days after SCI exhibited a significant improvement in hindlimb locomotor ability at 21, 28, and 35 days after injury, when compared to vehicle-treated SCI rats. Rats receiving amiloride treatment also exhibited a significant increase in myelin oligodendrocyte glycoprotein (MOG) levels 35 days after SCI at the site of injury (T10) when compared to vehicle-treated controls, which indicated a partial reverse in the decrease of MOG observed with injury. Our data indicate that higher levels of MOG correlate with improved locomotor recovery after SCI, and that this may explain the beneficial effects of amiloride after SCI. Given that amiloride treatment after SCI caused a significant preservation of myelin levels, and improved locomotor recovery, it should be considered as a possible therapeutic intervention after SCI. PMID- 21534731 TI - Intensive insulin therapy in brain injury: a meta-analysis. AB - Many studies have addressed the question of whether intensive insulin therapy (IIT) provides better outcomes for brain-injured patients than does conventional insulin therapy (CIT), with conflicting results. We performed a systematic review and meta-analysis of the literature to estimate the effect of IIT on patients with brain injury. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and citations of key articles and selected "all randomized controlled trials" (RCTs) comparing the effect of IIT to CIT among adult patients with acute brain injury (traumatic brain injury, stroke, subarachnoid hemorrhage, and encephalitis). Of the 2807 studies, we identified 9 RCTs with a total of 1160 patients for analysis. IIT did not appear to decrease the risk of in-hospital or late mortality (RR=1.04, 95% CI=0.75, 1.43 and RR=1.07, 95%CI=0.91, 1.27 respectively). No significant heterogeneity was found (I(2)=0.0%). IIT also did not have a protective effect on long-term neurological outcomes (LTNO) (RR=1.10, 95% CI=0.96, 1.27). IIT, however, did decrease the rate of infections (RR=0.76, 95% CI=0.58, 0.98). Heterogeneity was present (I(2)=64%), which was eliminated upon sensitivity analysis bringing the RR to 0.66 (95% CI=0.55, 0.80, I(2)=0%). IIT increased the rate of hypoglycemic episodes (RR=1.72, 95% CI=1.20, 2.46) however there was intractable heterogeneity present (I(2)=89%), which did not resolve upon sensitivity analysis. We found no evidence of publication bias by Egger's test (p=0.50). To conclude, IIT has no mortality or LTNO benefit to patients with brain injury, but is beneficial at decreasing infection rates. PMID- 21534732 TI - The relationship between mood disorders and MRI findings following traumatic brain injury. AB - BACKGROUND: High rates of depression have been reported in individuals with traumatic brain injury (TBI). The purpose of the current study was to investigate the relationship between structural MRI findings and the development of novel cases of post-injury depression in this population METHODS: The study has a cross sectional design. Assessments were conducted on average 2.2 years post-injury. Participants were 54 individuals (76% male, mean age 35 years, median PTA duration 16 days) who had sustained a TBI. Depression was assessed with the Structured Clinical Interview for DSM-IV (SCID-IV). Structural MRI scans were performed with a 1.5 Tesla machine. RESULTS: The presence of lesions in the frontal, temporal, parietal and the sublobar regions was not related to depression. However, an imbalance of left vs right frontal and parietal viable brain volumes was related to the development of depression. DISCUSSION: These findings are in support of Heller's model of emotion processing, but should be replicated using larger samples. Potential clinical implications are discussed in the manuscript. PMID- 21534733 TI - Head injury in polytrauma-Is there an effect on outcome more than 10 years after the injury? AB - INTRODUCTION: Head injuries are of great relevance for the prognosis of polytrauma patients during acute care. However, knowledge about the impact on the long-term outcome is sparse. Therefore, this study analysed the role of head injuries on the outcome of polytrauma patients more than 10 years after injury in a matched-pair analysis. PATIENTS AND METHODS: Out of 620 polytrauma patients with and without head injury, a matched-pair analysis with comparable age, injury severity and gender distribution and a minimum of 10 years follow-up was performed. The outcome and quality-of-life were measured using the Hannover Score for Polytrauma Outcome (HASPOC), Short Form 12 (SF-12), Glasgow Outcome Scale (GOS) and other parameters. RESULTS: The matched-pair analysis consisted of 125 pairs (age 27.9 +/- 1.2 years, ISS 20.0 +/- 0.8 [head injury] vs ISS 19.8 +/- 0.8 [no head injury]). A significant difference was shown for the GOS Score only (GOS head injury 4.3 +/- 0.3 vs no head injury 4.9 +/- 0.2, p = 0.01). The psychological outcome was similar in both groups. Both groups reported comparable subjective rehabilitation satisfaction. CONCLUSIONS: Matching pairs of equally injured polytrauma patients of same gender with and without head injury 10 years following trauma indicated significantly worse results in the GOS due to head injury. PMID- 21534734 TI - The impact of communication partner and discourse task on a person with traumatic brain injury: the use of multiple perspectives. AB - PRIMARY OBJECTIVE: This study investigated whether varying the communication partner (i.e. mother vs paid caregiver) and discourse task (i.e. casual conversation vs purposeful conversation vs problem-solving task) affected the nature of information exchange for a person with traumatic brain injury (TBI). METHODS: Three discourse tasks were recorded involving a TBI participant with his mother and, on a separate occasion, with his paid caregiver. Texts were analysed using multiple perspectives, comprising exchange structure analysis, ratings by independent observers and self and others' perceptions of communication. RESULTS: The TBI participant was more likely to give information when interacting with his mother than with the paid caregiver, as shown by exchange structure analysis. The participants also varied the way they exchanged information according to the discourse tasks. Results from exchange structure analysis were corroborated by the ratings by independent observers. Additionally, the mother was found to perceive that the TBI participant 'usually' had communication difficulty, while the caregiver perceived that he 'rarely' had communication difficulty. CONCLUSION: The nature of information exchange for a person with TBI varied with the communication partner and discourse task. The multiple perspectives used in this study appeared promising for the examination of discourse ability following TBI. PMID- 21534735 TI - Effect of concurrent cognitive tasks on gait features among children post-severe traumatic brain injury and typically-developed controls. AB - AIM: To investigate and compare the influence of concurrent cognitive tasks on gait characteristics in children post-traumatic brain injury (TBI) and typically developed (TD) controls. METHODS: Fifteen children post-TBI (aged 9.5 +/- 2.2 years) and 15 TD controls (aged 9.9 +/- 1.3 years) were included in the study. The children were asked to walk under three conditions: (1) walking at a self selected speed, (2) walking at a self-selected speed while memorizing and recalling a series of three random numbers and (3) walking at a self-selected speed while listening and identifying commonly experienced sounds. Gait parameters include walking speed, step time and length and step time and length variability as measured with the GAITRite((r)) system. RESULTS: Introduction of a concurrent task led to decreased walking speed and step length and increased step time and step length variability in both groups, but with a significantly prominent effect in children post-TBI. The results also showed that the effect of a concurrent cognitive task on walking depended on the complexity level of the task. CONCLUSION: When children were asked to perform an additional task while they were walking, this had a negative effect on their gait. One may deduce from these results that control of the rhythmic stepping mechanism at a self-selected walking speed in children is dependant to an extent on their ability to focus attention on their gait. In children post-TBI who usually have an attention deficit anyway, this ability is severely disturbed. PMID- 21534736 TI - Participation patterns of children with acquired brain injury. AB - OBJECTIVE: To describe the participation patterns of children and youth with Acquired Brain Injury (ABI) and to compare these patterns with typically developing peers. METHODS: One hundred and thirty-five children with ABI completed the Children Assessment of Participation and Enjoyment (CAPE) to measure their participation diversity and intensity in outside-of-school activities (i.e. recreational, physical, social, self-improvement and skill-based activities). Results were compared to 354 typically-developing peers. ANOVA analyses were performed while controlling for age and gender. RESULTS: Similar to typically-developing children, individuals with ABI proportionally participated mostly in social and recreational activities and were less likely to engage in skill-based activities. However, level of intensity and diversity within each activity type was different between the two groups. Children with ABI participated in fewer activities and were less frequently involved in all the CAPE's activity types except for intensity in social activities. These differences, characterized by small-to-medium effect sizes, were not dependent on the child's age and gender. CONCLUSIONS: Participation of children with ABI is restricted in comparison to their typically-developing peers even in a sample where minor injury is predominant. Future studies might address additional factors that potentially affect participation, e.g. child's preferences and family function. PMID- 21534737 TI - APOE genotype and neuropsychological outcome in mild-to-moderate traumatic brain injury: a pilot study. AB - PRIMARY OBJECTIVE: The influence of apolipoprotein (APOE) on neuropsychological outcome was investigated in 19 patients (25.79 +/- 7.22 years) with mild-to moderate traumatic brain injury and 14 matched healthy control subjects (27.43 +/ 6.65 years). RESEARCH DESIGN: Within- and between-group comparisons were employed. METHODS AND PROCEDURE: APOE genotype was determined using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method. Verbal learning and memory, speed of processing and executive function were assessed at 6 weeks and 6 months post-injury. A three-way [Group*Type*Time] ANOVA with repeated measures on the third factor was employed to determine the differences between groups and APOE genotype. MAIN OUTCOMES AND RESULTS: No Group*APOE Genotype*Time interaction was found for all neuropsychological measures, Auditory Verbal Learning Test (p = 0.484, eta(2 )= 0.017), Trail Making Test-B (p = 0.454, eta(2 )= 0.019), Controlled Oral Word Association (p = 0.107, eta(2 )= 0.087) and Wisconsin Card Sorting Test-64 (p = 0.291, eta(2 )= 0.038). The results of this pilot study support earlier findings that showed no relationship between APOE epsilon4 and poor recovery in the same population. CONCLUSION: The preliminary findings suggest no clear APOE genotype influence on neuropsychological outcome in mild and moderate TBI patients. Large-scale studies with longer follow-up duration are warranted. PMID- 21534738 TI - Protective effects of early hypoxic post-conditioning in cultured cortical neurons. AB - PRIMARY OBJECTIVE: Recent evidence suggests that delayed hypoxic post conditioning is neuroprotective. The aim of the present study was to test whether early post-conditioning applied immediately after hypoxia could protect cultured neurons from hypoxia/reoxygenation (H/R)-induced injuries. METHODS: Primary cortical neuronal culture depleted of microglia was exposed to H/R. Post conditioning started immediately after hypoxia and consisted of three cycles of 15-minutes of reoxygenation and 15-minutes of hypoxia. Cell viability assay was performed using Cell Counting Kit-8 (CCK-8). Apoptosis was evaluated by Hoechst 33258 staining, FITC-Annexin V/PI double staining and Western blot assay (testing the cleaved caspase-3 expression). Reactive oxygen species (ROS), intracellular Ca(2+) and mitochondrial membrane potential (MMP) were examined using confocal laser-scanning microscopy. MAIN RESULTS: H/R significantly reduced cell viability and increased neuronal apoptosis and necrosis. Furthermore, the expression of cleaved caspase-3, ROS production and intracellular Ca(2+) were increased. MMP was attenuated. Injuries induced by H/R were substantially attenuated by early hypoxic post-conditioning. Changes in cleaved caspase-3 expression, ROS production, intracellular Ca(2+) level and MMP in response to H/R were significantly decreased by the post-conditioning. CONCLUSIONS: The findings demonstrated that early hypoxic post-conditioning could protect neurons against H/R-induced injuries independent of microglial cells, possibly by inhibiting ROS over-production and intracellular Ca(2+) accumulation and maintaining MMP. PMID- 21534739 TI - Effects of cyclosporin A administration on gene expression in rat brain. AB - PRIMARY OBJECTIVE: The immunosuppressant cyclosporin A (CsA) is reported to have a strong anti-ischemic effect. Although this neuroprotective effect is speculated to be related to the blockade of a mitochondrial permeability transition pore (mPTP), the underlying molecular mechanism remains to be elucidated. This study focused on the effect of CsA on transcriptional regulation in brain cells. METHODS: CsA and a control substance were injected into rat brains and purified extracted mRNA. Both mRNAs were compared using a cDNA subtraction technique. RESULTS: Nine significantly up-regulated genes and seven significantly down regulated genes were detected following CsA administration. All of the up regulated genes are neurotrophic or reported to have roles in regeneration of brain tissue. Among the down-regulated genes, three are known to be detrimental to neuronal cells and are also reported to facilitate the pathology of Alzheimer's disease (AD) and four genes are related to oxidative metabolism. CONCLUSIONS: Strong immunosuppression would present as a side-effect during CsA use as a neuroprotectant. The results of this study will help to discriminate between the CsA immunosuppressive effect and the neuroprotective effect at the molecular level and may lead to the development of new conceptual and pharmacological tools. PMID- 21534740 TI - Subdural hygroma-related heterotopic ossification in a patient with a stroke: a case report. AB - BACKGROUND: This study presents a patient with a stroke who had total paralysis of his left-side limbs after intracranial haemorrhaging, who later experienced partial weakness of the right-side limbs after a subdural hygroma. Both conditions occurred without major trauma. He received two separate operations, a craniotomy and placement of a ventriculoperitoneal shunt, before the appearance of the subdural hygroma. CASE STUDY: According to the literature, heterotopic ossification is often reported with major trauma-associated diseases, but is less frequently found in patients with non-traumatic conditions, from which this patient suffered. Although the patient had experienced no major trauma, he had multiple heterotopic ossifications on the side of the subdural hygroma-affected limbs, which exhibited better motor control and were less spastic than those of the opposite side. These heterotopic ossifications were around joints of the hip, knee and shoulder on his right side, as proven by plain radiography and a triple phase bone scan and resulted in marked limitations of joint motions. This patient thus had major disabilities of his limbs bilaterally. CONCLUSIONS: The occurrence of heterotopic ossifications in the less-paretic limbs might have worsened this patient's functional outcome. PMID- 21534741 TI - Tics after traumatic brain injury. AB - BACKGROUND: Tics are involuntary non-rhythmic, stereotyped muscle contractions which can be suppressed temporarily. Tics usually start during childhood as part of Tourette syndrome. Adult onset tics are infrequent. This study reports on an adult man who developed tics 1 year after severe traumatic brain injury (TBI). METHODS: Case report and review of literature. RESULTS: A 19-year-old man sustained TBI following a road traffic accident. He did not have tics or features of obsessive compulsive disorder before the brain injury. A year after injury he developed motor and vocal tics. Magnetic resonance image of the brain showed lesions in the basal ganglia. A search of databases Medline, EMBASE and CINHAL found only four publications on tics in adults with TBI. None of these reported cases had lesions in the basal ganglia. CONCLUSION: Tics are a rare complication of TBI. People with early onset post-traumatic tics may have had a previously unrecognized, mild tic disorder or a genetic predisposition for tics, which was unmasked by the TBI. In contrast, late post-traumatic tics could be due to delayed effects of injury on neural circuits connecting the frontal cortex and basal ganglia. PMID- 21534742 TI - Adverse cognitive effects of phenytoin in severe brain injury: a case report. AB - BACKGROUND: The use of prophylactic anticonvulsants following brain injury is controversial. When used for this reason or for treatment of early seizures, anticonvulsants, particularly phenytoin, can cause severe cognitive side-effects. CASE REPORT: This study presents a case of a woman with a severe brain injury with severe cognitive impairment who improved dramatically following withdrawal of phenytoin. The literature regarding such cognitive side-effects is contradictory with no consistent indication of choice of anticonvulsants to use in this situation. CONCLUSION: As a result of the dramatic improvement in this case, one should now routinely withdraw or change phenytoin treatment in all brain injury patients with significant cognitive impairment. PMID- 21534743 TI - Disorders of consciousness: a taxonomy to be changed? PMID- 21534744 TI - Is it time to abandon traditional laparoscopic sterilisation? PMID- 21534745 TI - Three-dimensional power Doppler placental vascularisation indices in early pregnancy: a pilot study. AB - The objective of our study was to assess 1st trimester placental vascularisation using three-dimensional (3D) power Doppler vascular indices. A cross-sectional study was used involving 41 normal pregnancies from 7 to 10 + 6 weeks. Placental volume was obtained using the 30 degrees virtual organ computer-aided analysis (VOCAL) method. The mean, median, standard deviation (SD), minimum and maximum values were calculated for three vascular indices: the VI, vascularisation index; the FI, flow index and the VFI, vascularisation and flow index. Pearson's correlation coefficient (r) was used to assess the correlation between vascular indices and crown-rump length (CRL). Our results showed mean (+/- SD) values ranged from 8.66 +/- 12.04 to 15.34 +/- 13.89 for the VI, from 63.83 +/- 43.61 to 109.22 +/- 33.87 for the FI and from 9.52 +/- 13.86 to 20.59 +/- 22.97 for the VFI. There was no correlation between CRL and VI (r = 0.073, p = 0.630) nor VFI (r = 0.147 and p = 0.037); there was a weak correlation between CRL and FI (r = 0.332, p = 0.037). It was concluded that the FI was the only 3D power Doppler vascular index that was correlated with CRL between 7 and 10 + 6 weeks' gestation. PMID- 21534746 TI - Pregnancy-specific reference ranges for haematological variables in a Scottish population. AB - Using laboratory reference ranges, B12 deficiency is inappropriately diagnosed and treated in pregnancy. We aim to define reference ranges for ferritin, folate, haemoglobin and B12 in a pregnant population with advancing gestation. A total of 190 women participated in a cross-sectional study, 113 in the 1st and 77 in the 3rd trimester. All variables studied except red cell folate, decreased significantly from the 1st to the 3rd trimester. A total of 34% (64/190) of women were found to have 'low' B12 as defined by traditional ranges. In women with anaemia and apparent B12 deficiency, co-existing ferritin deficiency was demonstrated. All women with 'low' B12 levels were invited to attend postnatally for re-testing. A total of 28% (18/64) attended, in whom all B12 levels spontaneously increased. The use of gestation specific reference ranges for haematological variables may reduce inappropriate diagnosis of B12 deficiency. In most women with apparent low B12 levels and anaemia, ferritin deficiency was demonstrated. Therefore iron should be the initial management therapy. PMID- 21534747 TI - Organophosphate poisoning in pregnancy. AB - Organophosphate poisoning during pregnancy is rarely reported in the literature. In our retrospective study, we report the outcome of 21 cases of organophosphate poisoning during pregnancy. All patients received atropine injection until the tracheobronchial tree is cleared of the secretions and most secretions were dried. In addition, ventilatory care was needed in five women. Two patients (9.52%) died of the organophosphorus poisoning during the acute stage of poisoning and three patients were lost to follow-up. One woman had a spontaneous abortion. The remaining 15 women had no significant complication during pregnancy or labour and delivery. There was no congenital abnormality and no neurological deficit in any baby. However, long-term follow-up of neonates was lacking in our study population. PMID- 21534748 TI - An audit of seafood consumption awareness during pregnancy and its association with maternal and fetal outcomes in a Turkish population. AB - This study was conducted to audit maternal seafood intake awareness during pregnancy and to determine whether there is an association between fish consumption and various pregnancy outcomes. In total, 553 low-risk and healthy pregnant women were given a questionnaire concerning fish consumption. Pregnant women who developed gestational diabetes mellitus, pre-term labour-birth, macrosomia, low birth weight and small for gestational age were analysed. Fatty fish consumers tended to have higher birth weight infants than lean fish consumers. Low fish consumption was significantly correlated with low birth weight and small for gestational age (SGA) infants. The more fatty fish that the low fish consumers consumed, the more likely they were to have SGA infants. Fish consumption did not have an impact on the development of gestational diabetes mellitus, macrosomia or pre-term labour-birth. Low fish consumption during pregnancy may be associated with the development of low birth weight and SGA infants in a Turkish population. PMID- 21534749 TI - A randomised comparative study between low-dose intravenous magnesium sulphate and standard intramuscular regimen for treatment of eclampsia. AB - In a randomised control study, we evaluated the efficacy of intravenous low-dose magnesium sulphate for the management of eclampsia. A total of 144 women with eclampsia were divided into a study group and a control group of 72 women each. The study group received 0.75 g/h of magnesium sulphate intravenously after a loading intravenous dose of 4 g and the control group was given the standard intramuscular regimen as advocated by Pritchard. The primary outcome measure was recurrence rate of the seizures. The secondary outcome measures were development of magnesium toxicity if any, and maternal and perinatal outcomes. The difference in the incidence of fit recurrence was statistically insignificant when both groups were compared (7.46% vs 8.57%, p = 0.939). The total dose of magnesium sulphate was significantly lower in the intravenous group (p < 0.0001), in which no patient developed magnesium toxicity. Low-dose intravenous magnesium sulphate was found to be as effective as the standard intramuscular regimen, while maintaining a high safety margin. PMID- 21534750 TI - Induction of labour and the mode of delivery at term. AB - This is a retrospective cohort study to establish the effect of induction of labour (IOL) on the mode of delivery for term pregnancy. Studied population included 11,660 deliveries and out of these, 8,314 were normal vaginal deliveries; 1,775 instrumental deliveries and 1,571 emergency caesarean sections. The frequency of IOL was 23.6%. A univariate analysis was carried out to establish a relationship between IOL and mode of delivery. The multivariable regression analysis was carried out to adjust this relationship for parity, age, gestational age, epidural analgesia and birth weight. IOL at term lowered the risk of instrumental delivery (p=0.009) and had no influence on the rate of caesarean section (p=0.861). Hence, the study demonstrates that women in whom induction is decided upon, the instrumental delivery and caesarean section rate is not any higher than in the group where a spontaneous labour is awaited. PMID- 21534751 TI - Closure vs non-closure of peritoneum at caesarean section: evaluation of pain. AB - We evaluated the effect of closure or non-closure of parietal and visceral peritoneum during caesarean section (CS) on post-caesarean pain and analgesic requirement. A total of 94 primigravidas planned for elective CS were prospectively enrolled into closure (n = 46) and non-closure (n = 48) groups. Analgesia was provided by a patient-controlled analgesia pump (PCA) postoperatively. Pain was evaluated using a visual analogue scale (VAS) and verbal rating scale (VRS). Total dose of analgesics administered through PCA and times of analgesia demand and additional analgesics were also assessed. VAS and VRS scores were similar between the groups. The total dose of analgesics administered were similar (p = 0.095) between groups, however the mean number of analgesic demand (p = 0.020) and the additional analgesics (p < 0.001) were higher in the closure group. As a conclusion, the closure or non-closure of the peritoneum does not have any impact on postoperative pain intensity, however the analgesia demand and additional analgesia requirement decreases with non-closure. PMID- 21534752 TI - Size of Sri Lankan newborns at birth. AB - This prospective population-based study, involving 4,120 births at the Maternity Unit, Teaching Hospital Kandy, in the years 2008 and 2009, was undertaken to determine the mean birth weight of the newborns in the Central Province, Sri Lanka. The mean birth weight of 2,854 g was found to be equivalent with those calculated from several earlier studies. The mean differences in the birth weights of the three major ethnic communities, the Sinhala, the Tamils and the Sri Lankan Moors, were found to be not statistically significant. The gender difference of 60 g (CI 28-92) and the difference between the birth weights of the first and second born, for babies of all three communities were statistically significant, in uniform with those for white Caucasian populations. A graphical production of the mean birth weights is depicted in percentiles, with the mean birth weights of newborns in the UK superimposed on it for comparison. PMID- 21534753 TI - The use of the sisterhood method for estimating maternal mortality ratio in Lagos state, Nigeria. AB - Summary Estimates of maternal mortality are crucial to inform the planning of reproductive health programmes and guide advocacy. The aim of this study was to obtain a population-based estimate of maternal mortality in Lagos State, Nigeria. The sisterhood method was used in 2008 to carry out the survey using a questionnaire in which respondents were asked about their sisters who died during pregnancy, childbirth or within 6 weeks after childbirth. The survey involved 4,315 respondents who provided information on 9,910 ever married sisters. The life-time likelihood (risk) of maternal death for women aged 15-49 years was found to be 0.0239 or 1 in 42. The estimated maternal mortality ratio was 450 per 100,000 live births with a 95% CI of 360 and 530. Out of 111 reported deaths, 35 (31.5%) occurred during pregnancy, 49 (44.1%) occurred during delivery and 27 (24.3%) within 6 weeks of delivery. PMID- 21534754 TI - Peripartum hysterectomy in the first decade of the 21st century. AB - We reviewed the role of peripartum hysterectomy (PH) in the first decade of the 21st century. The study was confined to women who delivered a baby weighing 500 g or more between 2000 and 2009, and who required a hysterectomy within 72 h of delivery for obstetric reasons. Individual case records were reviewed. There were 19 cases of PH in 78,961 deliveries giving an incidence of 1 in 4,156 (0.02%). Of the 19 cases, 95% were delivered by caesarean section and 89% had one or more prior sections. The indications were placental bed pathology (79%), uterine atony (16%) and uterine trauma (5%). Of the 19 hysterectomies, 16 (84%) were total and a gynaecological oncologist was involved in nine (56%) of these cases. There were no maternal or fetal deaths, but a mother required an average blood transfusion of 10 units. The overall rate of PH was remarkably low compared with other studies but it is likely to increase in the future because of the strong association between increasing caesarean section rates and placental bed pathology. The potential involvement of the cervix and other pelvic structures by placental pathology means that PH in the future will be more challenging, and the hysterectomy will need to be total rather than subtotal. PMID- 21534755 TI - British gynaecologists' attitudes in 2008 to the provision of legal abortion. AB - In 2008, we investigated the attitudes and practice of British consultant gynaecologists towards induced abortion, and made comparisons with our similar survey in 1989. A random sample of one in six (217) was selected from the register of the Royal College of Obstetricians and Gynaecologists (RCOG). The response to the postal questionnaire was 70% (152). Satisfaction with the way the 1967 Abortion Act is operating was expressed by 59% (76% in 1989) and an upper limit of 24 weeks was supported by 50% (77% in 1989). Abortion after 20 weeks was approved to protect health by 92%; after rape by 60% and for serious fetal handicap by 87%. A change in the regulations to require the signature of only one doctor (rather than two) to certify the need for abortion was supported by 65%. Only a minority (41%) provided 2nd trimester abortion in person; 61% would separate abortion provision from general gynaecology; 57% suggested there should be separate abortion units for gestations over 13 weeks and 56% felt that fertility control should become be a sub-specialty. Satisfaction with the Abortion Act 1967 has decreased during the last 20 years. Gynaecologists' attitudes to the indications for 2nd trimester abortion remain wide, with clear implications for women seeking abortion. The service to women would be improved if abortion on request was permitted in the 1st trimester and after only one medical signature in the 2nd trimester. Our view is that the decision to end a pregnancy should be made by the woman and that abortion should be decriminalised. PMID- 21534756 TI - Conservatively treated borderline ovarian tumours, followed by IVF treatment: a case series. AB - Borderline ovarian tumours (BOT) often affect young females, in whom conservative treatment may be desired in order to preserve fertility. It is unknown whether in vitro fertilisation (IVF) increases the risk of recurrent disease. This case series will focus on four patients diagnosed with BOT, who were initially treated conservatively and subsequently received IVF. Five recurrences occurred prior to IVF and three recurrences occurred after IVF in three individuals. After a mean follow-up of 104 months after initial conservative treatment and 43 months after IVF treatment, all four patients were alive and disease-free. PMID- 21534757 TI - Comparison of single-dose and two-dose methotrexate protocols for the treatment of unruptured ectopic pregnancy. AB - Summary The purpose of this study was to compare the safety and success rates of single- and two-dose methotrexate (MTX) protocols for the treatment of unruptured tubal ectopic pregnancy. This retrospective study included 87 patients with ectopic pregnancy who were treated with MTX therapy (single-dose protocol: 46 patients; two-dose protocol: 41 patients). Both protocol groups were compared with regard to success rates, beta-hCG and progesterone levels, the presence of cardiac activity, a history of previous ectopic pregnancy, ectopic mass size, gestational age, adverse events, and number of repeat MTX doses. Success rates between the single-dose and two-dose methotrexate therapy groups were comparable (87% vs 90.2%; OR 0.7, 95% CI 0.18-2.75; p = 0.74). No significant differences were found between the groups in factors influencing MTX treatment success rate, including the mean beta-hCG level, mean progesterone level, the presence of a positive cardiac activity, mean ectopic mass size, mean endometrial thickness, and the presence of a yolk sac. There were also no significant between-group difference were found in the percentage of women who needed a repeat dose of MTX (17.3% vs 7.3%; OR 0.3, 95% CI 0.09-1.52; p = 0.20) and in the percentage of adverse events (45.7% vs 58.7%; OR 1.6, 95% CI 0.71-3.93; p = 0.28). In conclusion, medical treatment with single-dose or with two-dose systemic MTX seem to be equal therapeutic options for patients with unruptured ectopic pregnancy. PMID- 21534758 TI - Pain scores during surgical drains removal after obstetrics and gynaecological surgery. AB - Removing surgical drains can be painful. Currently, there is no evidence to predict which patients may experience greater pain than others. This prospective study is the first to determine the predisposing factors to higher pain scores during drains removal. Multivariate analysis determined if operation type, drain type, duration of drainage, speed of drain removal or pain perceived just before drain removal 'background pain' could be used to predict pain during drain removal. A total of 80 consecutive women were included. There was a positive correlation between pain scores during drain removal and background pain scores (p = 0.0007). Pain scores during drain removal were not related to operation type (p = 0.6), drain type (p = 0.9), duration of drainage (p = 0.4), analgesia type (p = 0.4), duration since last analgesics (p = 0.35) or speed of drain removal (p = 0.5). Because of the positive correlation between 'background' pain and pain during drain removal, techniques to reduce pain during drain removal should target women with significant pre-existing discomfort. PMID- 21534759 TI - Spontaneous ovarian hyperstimulation syndrome (OHSS): a rare but important differential diagnosis for abdominal distension in early pregnancy. PMID- 21534760 TI - Maternal sepsis due to Clostridium perfringens after 2nd-trimester genetic amniocentesis. PMID- 21534761 TI - Renal infarction in a postpartum woman with vascular type Ehlers-Danlos syndrome. PMID- 21534762 TI - First presentation of Addison's disease in the 2nd trimester of pregnancy. PMID- 21534763 TI - A case of isolated Tessier 7 cleft in the newborn of a diabetic mother. PMID- 21534764 TI - The role of serial amnioinfusions in the management of previable pre-term premature rupture of membranes. PMID- 21534765 TI - Spontaneous rupture in the posterior wall of an unscarred uterus. PMID- 21534766 TI - Isolated torsion of the fallopian tube in a 16-year-old adolescent girl. PMID- 21534767 TI - A borderline serous broad ligament tumour complicating pregnancy. PMID- 21534768 TI - Androgenic alopecia in postmenopausal ovarian hyperthecosis. PMID- 21534769 TI - Endometrioid adenofibroma arising in an endometriotic cyst. PMID- 21534770 TI - Ovarian small cell carcinoma of hypercalcaemic-type: history of the disease in a patient who refused treatment. PMID- 21534771 TI - A rare case of cervical schistosomiasis in Wales. PMID- 21534772 TI - Cervical intraepithelial neoplasia grade III diagnosed at ERPC. PMID- 21534773 TI - Clitoral metastasis from cervical carcinoma. PMID- 21534774 TI - Superficial angiomyxoma of the vulva: a case report of a rare cutaneous tumour. PMID- 21534775 TI - Re: Narchi H, Skinner A. 2010. Overweight and obesity in pregnancy do not adversely affect neonatal outcomes: new evidence. Journal of Obstetrics and Gynaecology 30:679-686. PMID- 21534821 TI - Effect of surface roughness and low-level laser therapy on removal torque of implants placed in rat femurs. AB - The present study measured removal torque and bone-implant interface resistance of machined implants, acid-etched implants, or machined implants irradiated around the implant area with infrared low-level laser therapy (LLLT; 830 nm) immediately after surgery. There were statistically significant differences between Groups A (control) and B (rough surface) (P = .03). Implants with a rough surface seem to add resistance to the bone-implant interface compared with smooth titanium implants or implants treated with LLLT. PMID- 21534822 TI - Use of titanium mesh in lieu of a fixation screw to stabilize an autogenous block graft: a case report. AB - Localized alveolar augmentation is carried out either before, during, or sometimes after implant placement. The placement of autogenous graft as a block or a particulate alone or in combination with an organic bone mineral has been practiced with a great deal of success. The block graft is secured in place with a screw and protected by a membrane. This case report describes the treatment of a female patient with a bucco-lingual bone deficiency grafted with autogenous block and a titanium mesh. Five months later, implant was placed in the grafted area. The definitive prosthesis was cemented 6 months later and followed up for 2 years. PMID- 21534823 TI - Does supported accommodation improve the clinical and social outcomes for people with severe psychiatric disability? The Project 300 experience. AB - OBJECTIVE: The present study was designed to investigate the clinical and social outcomes for a group of individuals (n = 181) discharged into supported accommodation from three long-stay facilities in Queensland. METHOD: Data were collected prospectively using a battery of standardized measures and individual interviews at 6 weeks pre-discharge and again at 6, 18, 36, and 84 months post discharge. RESULTS: While there was little functional gain at follow up, the clients, as a group, did not deteriorate. Sixty per cent of the clients were engaged in some form of structured community activity and the need for hospitalization decreased significantly in the follow-up period. The ongoing costs of the programme, while remaining high, were significantly less than inpatient alternatives. CONCLUSION: The provision of community accommodation with adequate clinical and non-clinical support is a suitable option for a large proportion of individuals with serious mental illness. PMID- 21534824 TI - Stakeholder analysis in worksite health promotion programming. AB - Stakeholder analysis is a formal management tool that is used primarily for planning purposes and policy development. A number of key planning questions are used to help identify major issues with internal and external stakeholders that can affect, or often are affected by, a worksite health promotion program. Organizational size is correlated with the various likely stakeholders. Desired contributions and strategies for efficient management of stakeholder relationships are also offered. PMID- 21534825 TI - Correlates of park-based physical activity among children in diverse communities: results from an observational study in two cities. AB - PURPOSE: This study examined correlates of park-based physical activity (PA) among children in neighborhood parks. DESIGN: Direct observation was used to assess PA among children. SETTING: Public parks in Tampa, Florida (n=10), and Chicago, Illinois (n=18), from low income and high income and racially/ethnically diverse communities. Subjects. Children (n=3410), coded as anyone who appeared to be 10 years or younger, observed at parks in Tampa and Chicago. MEASURES: Physical activity was measured by a modified version of the System for Observing Play and Leisure Among Youth (SOPLAY). ANALYSIS: Descriptive statistics and multilevel regression models were used in data analysis. RESULTS: At the activity observation level, children's PA was positively related to temperature and unstructured activities in Tampa and Chicago parks. Among park activity area predictors, type of activity area was significantly related to PA. In Tampa, more PA was observed on courts, and less PA was observed in shelter areas compared with open space areas. In Chicago, less PA was observed on courts and fields compared with open space areas. Neighborhood income was associated with lower PA in Tampa parks. Neighborhood race/ethnicity was not a significant predictor of children's PA in either city. CONCLUSIONS: Children's PA was linked to modifiable social and environmental features within parks. Strategies to increase PA among children in parks should promote courts, playgrounds, informal activities, and free play. PMID- 21534826 TI - Perceived environmental correlates of physical activity and walking in African young adults. AB - PURPOSE: Evidence on environmental correlates of physical activity (PA) conducted in Western developed countries may not be generalizable to Africa. This study examined the associations between perception of the neighborhood environment and PA and walking in African young adults. DESIGN: Cross-sectional analysis of self reported survey. SETTING: University of Ibadan, in the capital city of Oyo State, Nigeria. SUBJECTS: A representative sample of undergraduates of a Nigerian university, age 16 to 39 years and 50.7% female. MEASURES: Total walking activity and PA were measured with the short version of the International Physical Activity Questionnaire. Sixteen perceived neighborhood environmental variables were measured using the Physical Activity Neighborhood Environment Scale (PANES), which was used to assess environmental correlates of PA that are internationally relevant. Outcomes were meeting health-related guidelines for sufficient PA and walking activity. RESULTS: After adjustments for demographics and dormitory site, the proximity of bus/transit stop (odds ratio [OR]=1.41), traffic as not a problem (OR=.45; unexpected direction), and not many four-way intersections (OR=.72; unexpected direction) were significantly associated with sufficient PA. Low crime rate at night (OR=1.53), many interesting things to look at (OR=1.90), and seeing many people active (OR=.59; unexpected direction) were significantly associated with sufficient walking. Inconsistent patterns were also observed in gender-specific analyses. CONCLUSION: Few neighborhood environment correlates of PA or walking reported in the international literature were replicated with African young adults. Environmental measures need to be developed that are tailored to low- and middle-income countries, such as those in Africa, so that research in understudied regions can advance. PMID- 21534828 TI - My dad: a balance of physical, emotional, social, intellectual, and spiritual health. PMID- 21534829 TI - Creating a physically active society: the next great challenge. AB - The U.S. National Physical Activity Plan was launched in May 2010 with the goal of weaving physical activity into our culture.Physical inactivity has been shown to be a better predictor of death than traditional medical risk factors, costs employers morein lost productivity than tobacco use, causes more deaths than obesity, and affects more people than high cholesterol, acondition that produces more drug sales than any other condition. Despite its impact on society, it is largely neglected in policyarenas. The authors describe strategies to create a national culture of physical activity. PMID- 21534830 TI - Awareness of Canada's Physical Activity Guide to Healthy Active Living in a large community sample. AB - PURPOSE: Determine the proportion of adults aware of Canada's Physical Activity Guide to Healthy Active Living (Guide) and its specific recommendations (objective 1); whether key demographic factors (objective 2a) and physical activity behavior (objective 2b) are associated with awareness and specific familiarity with the Guide; and if changes in awareness and specific recommendations with the Guide occurred over a 1-year period (objective 3a and 3b). DESIGN: Random selection with computer-assisted telephone interviewing. SETTING: Edmonton, Alberta, Canada. SUBJECTS: A total of 2803 adults 18 years or older completed interviews from 4831 telephone contacts (response rate, 58.0%), and after 1 year, 1423 individuals (55%) completed interviews. MEASURES: Demographic, physical activity, Guide awareness. ANALYSIS: Chi-square, analysis of variance. RESULTS: At baseline, 27.3% were aware of the Guide, and 15.6% were familiar with the Guide's specific recommendations. Younger individuals (p=.01), women (p<.001), and those with a higher education (p<.001) were more likely to be generally aware of the Guide, and women were also more specifically aware (p=.01). Physical activity levels were positively associated with the general (p<.001) and specific (p<.001) awareness of the Guide. Changes in general familiarity and specific recommendations over 1 year were observed. CONCLUSIONS: The majority of those surveyed were not familiar with the Guide. Men, individuals with a lower education, and older individuals may need to be specifically targeted. PMID- 21534831 TI - Using "point of decision" messages to intervene on college students' eating behaviors. AB - PURPOSE: Examine the impact of "point of decision" messages on fruit selection in a single dining hall setting. SETTING: Competitive undergraduate liberal arts college in the southeastern United States. INTERVENTION: "Point of decision" messages were compiled into a 35-slide multimedia PowerPoint presentation. Messages were displayed on a computer screen at a "point of decision" between the cookie and fruit stations during lunch for a total of 9 days. MEASURES: Baseline cookie and fruit consumption was measured 9 days prebaseline and 9 days postbaseline. A random sample of students completed surveys 1 week after the intervention. ANALYSIS: t-tests were used to examine differences between prelevels of fruit consumption and levels measured simultaneously during "point of decision" messages. Descriptive statistics were used to examine perceptions of survey items 1 week postintervention. RESULTS: A significant mean difference in daily fruit consumption was found following the slide presentation (df-8, t= 2.800; p=.023). Average daily fruit consumption at baseline was 408 (SD=73.43). Postbaseline average daily fruit consumption significantly increased (533; SD=102). No significant prebaseline and postbaseline cookie differences were found (p=.226). Approximately 71% of women and 68% of men noticed the "point of decision" messages. Nineteen percent of women and 10% of males reported modifying their food selection as a result of viewing the messages. CONCLUSION: The "point of decision" messaging significantly influenced fruit selection in a single dining hall setting. PMID- 21534832 TI - Associations between youth assets and sexual intercourse by household income. AB - PURPOSE: Evaluate youth assets or potential strengths and sexual intercourse associations by household income. DESIGN: Data consisted of youth and parent responses from randomly selected households from a cross-sectional study and wave one of a longitudinal extension of that study. Youth assets and sexual intercourse were compared for four income categories. SETTING: Midwestern racially diverse, inner-city neighborhoods. SUBJECTS: One adolescent (12-19 years) and one parent (2335 pairs). MEASURES: Adjusted odds ratios (ORs) were calculated using logistic regression. Variables assessed included parent and youth demographics, youth sexual intercourse, and youth assets (adult and peer role models, family communication, use of time [religion or sports], community involvement, future aspirations, responsible choices, and health practices). RESULTS: Youths' mean age was 14.9 (+/- 1.8) years, and 52% were female; 44% of respondents were white. Use of time (religion) was significantly associated with never having sex for all but the lowest income youth (OR range=1.79-2.64). The variable peer role models was significant for the lowest income (O =2.01) and two upper income groups (ORs=2.52 and 4.27, respectively). The variable future aspirations was significant for the lowest income youth (OR=1.77). CONCLUSION: The youth asset variable future aspirations was critical for the lowest income households. Other asset variables, such as peer role models and use of time (religion) were critical regardless of income. PMID- 21534833 TI - Effects of TV in the bedroom on young Hispanic children. AB - PURPOSE: The main purposes of this study were to assess TV viewing among Hispanic young children and to examine effects of having a TV in the child's bedroom (TVIB). DESIGN AND SETTING: A quasi-experimental design was used to evaluate an intervention program that is collecting longitudinal data in West Texas. However, the current report uses only the baseline data of the ongoing study. SUBJECTS: Predominantly low-income and Hispanic parents/guardians (N=315) and their children of 5 to 9 years (N=597). MEASURES: Children's anthropometric measures were obtained. Their overweight status was determined based on age- and gender adjusted body mass index. A demographic questionnaire, acculturation scale (brief version of Acculturation Rating Scale for Mexican Americans II), and family survey were used among parents. ANALYSIS: Descriptive statistics, t-tests, chi(2) tests, and logistic regressions were used. RESULTS: Most children (70%) have TVIB; more than 30% were or were at risk of overweight. Demographic characteristics did not significantly predict TVIB. Children with TVIB spent .93 hours more daily watching TV/DVD (t=3.07; df=283; p=.003), and children (at one site) ate more fast food (chi(2)=5.46; df=1; p=.019), compared with children without TVIB whose parents better supported physical activity (t=2.11; df=275; p=.039). CONCLUSION: Most children in this low-income and Hispanic sample have TVIB, which is associated with unhealthy behaviors. PMID- 21534834 TI - The effects of target behavior choice and self-management skills training on compliance with behavioral self-monitoring. AB - PURPOSE: The purpose of this study was to evaluate two potential methods for increasing participant compliance with behavioral self-monitoring (BSM). DESIGN: A randomized 2 * 2 factorial design was used to evaluate the effects of target behavior choice (choice vs. assigned) and self-management skills training (training vs. no-training) on BSM compliance. In the choice manipulation, participants either chose or were assigned one of seven types of healthful or safe behaviors to self-monitor. In the training manipulation, participants either completed computer-based self-management skills training or received no training. Participants were then asked to complete daily BSM for 2 weeks. SETTING: The study was conducted at a university and teaching hospital. SUBJECTS: Participants (N=60) were predominantly university and hospital employees. MEASURES: The primary dependent measure was percent compliance with BSM. ANALYSIS: A factorial analysis of variance of compliance scores was performed. RESULTS: Mean compliance with prescribed BSM was 52.6% (SD=31.8). The main effect for choice was significant, with choice participants showing 18% higher BSM compliance than those in no-choice conditions (d=.59; p<.05). The effects of self-management skills training and the interaction term were both nonsignificant. CONCLUSION: Although self-management skills training did not appear to affect BSM compliance, offering individuals a choice in target behavior substantially increased both BSM compliance and self-reported behavior change. PMID- 21534835 TI - Computer use, internet access, and online health searching among Harlem adults. AB - PURPOSE: Computer use, Internet access, and online searching for health information were assessed toward enhancing Internet use for health promotion. DESIGN: Cross-sectional random digit dial landline phone survey. SETTING: Eight zip codes that comprised Central Harlem/Hamilton Heights and East Harlem in New York City. SUBJECTS: Adults 18 years and older (N=646). MEASURES: Demographic characteristics, computer use, Internet access, and online searching for health information. ANALYSIS: Frequencies for categorical variables and means and standard deviations for continuous variables were calculated and compared with analogous findings reported in national surveys from similar time periods. RESULTS: Among Harlem adults, ever computer use and current Internet use were 77% and 52%, respectively. High-speed home Internet connections were somewhat lower for Harlem adults than for U.S. adults overall (43% vs. 68%). Current Internet users in Harlem were more likely to be younger, white vs. black or Hispanic, better educated, and in better self-reported health than non-current users (p<.01). Of those who reported searching online for health information, 74% sought information on medical problems and thought that information found on the Internet affected the way they eat (47%) or exercise (44%). CONCLUSIONS: Many Harlem adults currently use the Internet to search for health information. High speed connections and culturally relevant materials may facilitate health information searching for underserved groups. PMID- 21534836 TI - Environmental changes to control obesity: a randomized controlled trial in manufacturing companies. AB - PURPOSE: To determine the effects of an environmental intervention on obesity, disease risk factors, and dietary intake in an employee population. DESIGN: Randomized controlled community trial. SETTING: Eight manufacturing companies in Kentucky with ~150 to 350 employees each. SUBJECTS: Randomly selected employees. INTERVENTION: Multicomponent environmental intervention that included employee advisory committees, point-of-decision prompts, walking paths, cafeteria/vending changes, and educational materials. MEASURES: Height; weight; body fat; blood pressure; fasting lipids, glucose and insulin; and dietary intake were assessed prior to and 3, 6, and 12 months after initiation of the intervention. ANALYSIS: Mixed-model repeat-measure analyses of covariance were used to analyze data collected over the study period. Categorical data were analyzed in contingency tables. A p value of .05 was used to judge statistical significance. RESULTS: There were no intervention effects for outcome variables, with the exception of lower intake of saturated fat and dietary cholesterol in the intervention group compared to the control group. Over the course of the study, changes in anthropometry and biomeasures were similar in both groups. CONCLUSIONS: Findings indicate that subtle environmental changes alone may not impact employees' weight and health; however, such institutional-level approaches may be essential to support healthy lifestyle habits that are initiated by more intensive efforts. Academic researchers should continue to partner with employers and practitioners to develop, implement, and evaluate innovative health promotion strategies including environmental interventions. PMID- 21534837 TI - Participation in fitness-related activities of an incentive-based health promotion program and hospital costs: a retrospective longitudinal study. AB - PURPOSE: A retrospective, longitudinal study examined changes in participation in fitness-related activities and hospital claims over 5 years amongst members of an incentivized health promotion program offered by a private health insurer. DESIGN: A 3-year retrospective observational analysis measuring gym visits and participation in documented fitness-related activities, probability of hospital admission, and associated costs of admission. SETTING: A South African private health plan, Discovery Health and the Vitality health promotion program. PARTICIPANTS: 304,054 adult members of the Discovery medical plan, 192,467 of whom registered for the health promotion program and 111,587 members who were not on the program. INTERVENTION: Members were incentivised for fitness-related activities on the basis of the frequency of gym visits. MEASURES: Changes in electronically documented gym visits and registered participation in fitness related activities over 3 years and measures of association between changes in participation (years 1-3) and subsequent probability and costs of hospital admission (years 4-5). Hospital admissions and associated costs are based on claims extracted from the health insurer database. ANALYSIS: The probability of a claim modeled by using linear logistic regression and costs of claims examined by using general linear models. Propensity scores were estimated and included age, gender, registration for chronic disease benefits, plan type, and the presence of a claim during the transition period, and these were used as covariates in the final model. RESULTS: There was a significant decrease in the prevalence of inactive members (76% to 68%) over 5 years. Members who remained highly active (years 1-3) had a lower probability (p < .05) of hospital admission in years 4 to 5 (20.7%) compared with those who remained inactive (22.2%). The odds of admission were 13% lower for two additional gym visits per week (odds ratio, .87; 95% confidence interval [CI], .801-.949). CONCLUSION: We observed an increase in fitness-related activities over time amongst members of this incentive-based health promotion program, which was associated with a lower probability of hospital admission and lower hospital costs in the subsequent 2 years. PMID- 21534838 TI - Reducing sensitive survey response bias in research on adolescents: a comparison of web-based and paper-and-pencil administration. AB - PURPOSE: Using the Problem Oriented Screening Instrument for Teenagers (POSIT), the effect of mode of administration on (1) students' willingness to disclose sensitive information and (2) response rates was investigated. DESIGN: A 2 * 2 unequal N factorial analysis of variance (ANOVA) design was employed. Mode of administration (paper-and-pencil vs. Web-based) was crossed with grade level (middle vs. high school). SETTING: The study was conducted in two middle and two high schools. SUBJECTS: A total of 628 middle and high school students completed the survey. MEASURES: The POSIT is a self-report measure with 139 yes/no items that identifies stressors in 10 functional areas (e.g., Substance Use). ANALYSIS: An unequal N 2 (mode) * 2 (grade level) factorial ANOVA was employed. RESULTS: No statistically significant differences were found for self-reported risk across modes of administration. Students completing the Web-based version of the survey were four times more likely to skip an item. CONCLUSIONS: Effect of Mode on Reporting of Sensitive Information-Students completed the Web-based surveys in computer labs with other students. The intent of the Web-based survey was to increase perceived privacy but the environment likely negated any effect. Effect of Mode on Response Rates-The higher response rate for the paper-and-pencil survey was the opposite of what was expected and revealed that students were more likely to skip sensitive items on the Web survey. PMID- 21534841 TI - Psychosocial functioning in adults with congenital craniofacial conditions. AB - OBJECTIVE: To examine the psychosocial functioning of adults with congenital craniofacial conditions relative to normative data. DESIGN: Single sample cross sectional design. SETTING: The Australian Craniofacial Unit, Women's and Children's Hospital, Adelaide, which is one of the main craniofacial treatment centers in Australia. PARTICIPANTS: Adults (N = 93) with congenital craniofacial conditions (excluding cleft lip/palate) who were treated in the Australian Craniofacial Unit. MAIN OUTCOME MEASURES: All participants completed self-report scales assessing health-related quality of life (SF-36); life satisfaction, anxiety, and depression (HADS); self-esteem (Rosenberg); appearance related concerns; perceived social support; and social anxiety. RESULTS: Overall, participants were very similar in psychosocial function to the general population. However, adults with craniofacial conditions were less likely to be married and have children (females), were more likely to be receiving a disability pension, and reported more appearance-related concerns and less social support from friends. They also reported more limitations in both their social activities, due to physical or emotional problems, and usual role activities, because of emotional problems, as well as poorer mental health. CONCLUSIONS: These results give cause to be very positive about the long-term outcomes of children who are undergoing treatment for craniofacial conditions, while also identifying specific areas that interventions could target. PMID- 21534842 TI - Gingival recession in individuals with cleft lip and palate: prevalence and severity. AB - OBJECTIVE: To analyze the prevalence and severity of gingival recession in individuals with cleft lip and alveolus with or without cleft palate. DESIGN: Cross-sectional. SETTING: Tertiary referral hospital. PARTICIPANTS: A total of 400 individuals with cleft lip and alveolus with or without cleft palate, aged 15 to 49 years, without any previous periodontal treatment. MAIN OUTCOME MEASURES: Gingival recession was evaluated by measuring the distance from the cementoenamel junction to the most coronal point on the gingival margin, analyzing the prevalence and scoring its severity as mild (<3 mm), moderate (3 to 4 mm), or severe (4 mm). The prevalence and severity of gingival recession was compared between sextant 2 (cleft sextant) and the mean of the other sextants (1, 3, 4, 5, and 6: noncleft sextants). The relationship between gingival recession in the cleft area and gender was evaluated and data were analyzed statistically. The correlation between gingival recession and age was assessed also. RESULTS: There was no statistically significant gender difference in gingival recession. The prevalence and severity of gingival recession increased with age, and most of the affected teeth were premolars and molars. The cleft area did not present a higher prevalence and severity of gingival recession. CONCLUSIONS: Individuals with cleft lip and alveolus with or without cleft palate presented the same prevalence and severity of gingival recession compared with other populations. The area adjacent to the cleft (sextant 2) did not show greater risk of gingival recession than other areas (sextants 1, 3, 4, 5, and 6). PMID- 21534843 TI - Chronic foreign body of the nasal cavity and sphenoid sinus: surgical implications. AB - Chronic sinonasal foreign bodies present unique surgical challenges including tissue integration and anatomic migration. A patient with a history of multiple surgeries for cleft lip, palate, and nasal deformity presented with radiographic findings of a 4.3-cm linear foreign body traversing the nasal cavity and sphenoid sinus. Mucosalization and integration into the sphenoid rostrum were noted at the time of surgery. Endoscopic surgery techniques facilitated removal of the overlying mucosa and encasing bone, allowing successful surgical extraction. On inspection, the foreign body was consistent with a retained Kirschner wire. Potential pathophysiologic and management implications of this case are discussed. PMID- 21534844 TI - Blood cells characteristics as determinants of acute myocardial infarction. AB - BACKGROUND: The aim of this study is to analyse the relation between red blood cells, platelets morphology and acute myocardial infarction (AMI), and to assess whether they could supplement the role of traditional cardiac biomarkers in the early identification of patients with AMI. METHODS: All consecutive patients admitted to our emergency department between the 1st January and the 31st August 2009 due to chest pain of suspected cardiac origin were included in the study. All the patients underwent physical examination, a 12-lead ECG, blood sampling for determination of cardiac troponin I and a complete blood count. RESULTS: A percentage of 6.7% of the 1971 patients had a confirmed diagnosis of AMI. Mean corpuscular volume (MCV), red blood cells distribution width (RDW) and platelets count (Plt) did not differ between patients with and without AMI. However, the mean platelet volume (MPV) was significantly higher in AMI patients (7.9 vs. 7.7 fL; p=0.0457). After stratification for gender, men with AMI displayed a lower RDW (p=0.0464) and a higher MPV (p=0.0062) as compared with those without AMI. The MCV and Plt were not significantly different. Women with AMI had a higher RDW (p=0.0079) as compared with those without AMI, while the MCV, Plt and MPV were not significantly different. CONCLUSIONS: Our study partially confirms previous data on the association between MPV or RDW and AMI. The inclusion of these parameters along with other conventional cardiac biomarkers might be a valuable perspective when evaluating patients with suspected AMI, although gender differences should be taken in account. PMID- 21534845 TI - What would brain-computer interface users want? Opinions and priorities of potential users with amyotrophic lateral sclerosis. AB - Universal design principles advocate inclusion of end users in every design stage, including research and development. Brain-computer interfaces (BCIs) have long been described as potential tools to enable people with amyotrophic lateral sclerosis (ALS) to operate technology without moving. Therefore the objective of the current study is to determine the opinions and priorities of people with ALS regarding BCI design. This information will guide BCIs in development to meet end user needs. A telephone survey was undertaken of 61 people with ALS from the University of Michigan's Motor Neuron Disease Clinic. With regard to BCI design, participants prioritized accuracy of command identification of at least 90% (satisfying 84% of respondents), speed of operation comparable to at least 15-19 letters per minute (satisfying 72%), and accidental exits from a standby mode not more than once every 2-4 h (satisfying 84%). While 84% of respondents would accept using an electrode cap, 72% were willing to undergo outpatient surgery and 41% to undergo surgery with a short hospital stay in order to obtain a BCI. In conclusion, people with ALS expressed a strong interest in obtaining BCIs, but current BCIs do not yet provide desired BCI performance. PMID- 21534846 TI - Predictors of smoking cessation among cancer patients enrolled in a smoking cessation program. AB - Many cancer patients continue to smoke postdiagnosis, which is associated with poorer clinical outcomes. Identifying prospective predictors of smoking cessation among patients currently receiving smoking cessation treatment can help guide the development and implementation of smoking cessation programs with this population. MATERIAL AND METHODS: Data from 246 cancer patients participating in a randomized placebo-controlled smoking cessation clinical trial were used to examine baseline predictors of end-of-treatment and six-month postbaseline smoking cessation outcomes. Baseline demographic, smoking-related, disease related, and psychological variables were examined as predictors of biochemically confirmed point-prevalence abstinence. RESULTS: Multivariate analysis indicated that, for end-of-treatment abstinence, patients were significantly more likely to have quit smoking if they were older (OR = 1.06, 95% CI: 1.03-1.10, p < 0.05) and were diagnosed with a non-tobacco related cancer (OR = 2.54, 95% CI: 1.24-5.20, p < 0.05). Likewise, for six-month abstinence, patients were significantly more likely to have quit smoking if they were older (OR = 1.04, 95% CI: 1.01-1.08, p < 0.05) and were significantly less likely to have quit smoking if they were female (OR = 0.47, 95% CI: 0.22-0.97, p < 0.05). Patients with tobacco-related cancers and female patients reported significantly higher levels of depression symptoms (p < 0.05), which proved predictive of smoking relapse. CONCLUSIONS: Patient age, gender, and cancer-type may be important factors to consider when developing and implementing smoking cessation interventions for cancer patients. PMID- 21534848 TI - A new unique recombinant HIV type 1 isolated from a child born to an HIV-infected mother. AB - The new HIV-1 recombinant, with a B(gag) A(pol)A(env) structure, is described. This recombinant virus differs from the classical "Kaliningrad" (AF193276.1) virus with an A(gag) B(pol)B(env) structure. The number of new HIV cases in Belarus has been increasing in the past few years. Within the 12 months of 2010, 1069 new cases of HIV infection were registered. Molecular epidemiological investigations have shown that though HIV-1 subtype A (84.5%) still dominates in HIV/AIDS patients, the quantity of CRFs has also increased to 7.1%. Although cases with the CRF03_AB virus were previously described in patients from Belarus, CRF06_cpx and CRF02_AG are described in Belarus for the first time. PMID- 21534849 TI - A novel gelatin hydrogel carrier sheet for corneal endothelial transplantation. AB - We examined the feasibility of using gelatin hydrogels as carrier sheets for the transplantation of cultivated corneal endothelial cells. The mechanical properties, transparency, and permeability of gelatin hydrogel sheets were compared with those of atelocollagen sheets. Immunohistochemistry (ZO-1, Na(+)/K(+)-ATPase, and N-cadherin), hematoxylin and eosin staining, and scanning electron microscopy were performed to assess the integrity of corneal endothelial cells that were cultured on gelatin hydrogel sheets. The gelatin hydrogel sheets displayed greater transparency, elastic modulus, and albumin permeability compared to those of atelocollagen sheets. The corneal endothelial cells on gelatin hydrogel sheets showed normal expression levels of ZO-1, Na(+)/K(+) ATPase, and N-cadherin. Hematoxylin and eosin staining revealed the formation of a continuous monolayer of cells attached to the gelatin hydrogel sheet. Scanning electron microscopy observations showed that the corneal endothelial cells were arranged in a regular, mosaic, and polygonal pattern with normal cilia. These results indicate that the gelatin hydrogel sheet is a promising material to transport corneal endothelial cells during transplantation. PMID- 21534850 TI - Comparison of subjective and objective assessments of outcome after traumatic brain injury using the International Classification of Functioning, Disability and Health (ICF). AB - PURPOSE: The aim is to examine two aspects of outcome after traumatic brain injury (TBI). Functional outcome was assessed by the Glasgow Outcome Scale - Extended (GOSE) and by clinician ratings, while health-related quality of life (HRQoL) was assessed by the Quality of Life after Brain Injury (QOLIBRI). METHOD: The GOSE and the QOLIBRI were linked to the International Classification of Functioning, Disability and Health (ICF) to analyse their content. Functional outcome on ICF categories was assessed by rehabilitation clinicians in 55 participants with TBI and was compared to the participants' own judgements of their HRQoL. RESULTS: The QOLIBRI was linked to 42 and the GOSE to 57 two-level ICF categories covering 78% of the categories on the ICF brief core set for TBI. The closest agreement in the views of the professionals and the participants was found on the Physical Problems and Cognition scales of the QOLIBRI. CONCLUSIONS: The problems encountered after TBI are well covered by the QOLIBRI and the GOSE. They capture important domains that are not traditionally sufficiently documented, especially in the domains of interpersonal relationships, social and leisure activities, self and the environment. The findings indicate that they are useful and complementary outcome measures for TBI. In rehabilitation, they can serve as tools in assessment, setting meaningful goals and creating therapeutic alliance. PMID- 21534851 TI - Tantalumpentoxide as a radiopacifier in injectable calcium phosphate cements for bone substitution. AB - The chemical resemblance of calcium phosphate (CaP) cements and the mineral phase of bone is a problem in distinguishing CaP cement from bone tissue by means of common, noninvasive techniques (e.g., X-ray imaging and microcomputed tomography [MUCT]). In this study, the feasibility of using tantalumpentoxide (Ta(2)O(5)) powder as radiopacifier in CaP cements was analyzed. A distal femoral condyle model in male adult Wistar rats was used. After 6 weeks of implantation time, the results were analyzed by means of MUCT and histology. Unambiguous distinction of CaP cement from native bone tissue and volumetric measurements of the materials appeared to be possible by means of MUCT scanning. Furthermore, there was no evidence of either inflammation or fibrous tissue around the implant materials or at the bone-material interface. In conclusion, the addition of Ta(2)O(5) as a radiopacifying additive to CaP cements allows discrimination between bone substitute and surrounding bone tissue. Consequently, Ta(2)O(5) represents an effective and biocompatible additive in CaP cements for in vivo monitoring purposes. PMID- 21534852 TI - Ophthalmia neonatorum: what kind of prophylaxis? AB - OBJECTIVE: Conjunctivitis during neonatal period occurs in 1-12% of all babies. Ophthalmia neonatorum is an acute muco-purulent conjunctivitis occurring in the first month of birth. It is essentially an infection acquired during vaginal delivery. The most frequent infectious agents involved in ophthalmia neonatorum are Chlamydia trachomatis and Neisseria gonorrhoeae. METHODS: Topical ocular prophylaxis must be instituted early after birth. Recommended prophylactic regimen are: 1% nitrate solution; 1% tetracycline solution; 1% erythromycin solution; 2.5% povidone-iodine solution; and fusidic acid. RESULTS: Evidence suggests better outcomes using 1% tetracycline solutions even if there is the risk of selecting drug resistant bacteria. However, even the widespread used nitrate solution can cause a chemical conjunctivitis, arguing against its widespread use. CONCLUSIONS: Fusidic acid is a relatively new promising therapy even if there are still few data about its use. None of the used regimens has the optimal risk-benefit profile to suggest a widespread use. PMID- 21534853 TI - Umbilical sP-selectin levels are different in preeclamptic pregnancies with intrauterine normal growth and growth restricted fetus. AB - OBJECTIVE: The aim of this study was the analysis of the umbilical cord serum sP selectin levels in pregnancies complicated by severe preeclampsia with and without intrauterine growth restriction and in normotensive pregnancies. PATIENTS AND METHODS: The study was carried out on 18 patients with singleton pregnancies complicated by severe preeclampsia with appropriate-for-gestational-age weight infants (group P) and 18 pregnant patients with severe preeclampsia complicated by intrauterine fetal growth restriction (IUGR) (group PI). The control group consisted of 34 patients with singleton uncomplicated pregnancies (group C). Umbilical serum sP-selectin concentrations were estimated using a sandwich ELISA assay according to the manufacturer's instruction (ELISA kit Bender MedSystems Vienna, Austria). RESULTS: Our study revealed different concentrations of soluble P-selectin in the umbilical cord in our both studied groups of preeclamptic women with and without IUGR. The umbilical cord levels of sP-selectin were decreased in the group with preeclampsia complicated by IUGR and increased in the preeclamptic women with the normal intrauterine fetal growth. The mean values of umbilical sP selectin were 839.008 +/- 625.703 ng/ml in group P, 275.873 +/- 174.339 ng/ml in group PI, and 288.719 +/- 199.039 ng/ml in the control group, respectively. CONCLUSIONS: Higher levels of the umbilical sP-selectin may confirm the presence of platelet and endothelial cell activation and confirm a hypercoagulant state in preeclamptic disorder, especially in preeclampsia without IUGR. PMID- 21534854 TI - Serum placental growth factor and fms-like tyrosine kinase 1 during first trimester in Chinese women with pre-eclampsia--a case-control study. AB - OBJECTIVE: To investigate the association between first trimester maternal placental growth factor (PlGF) and fms-like tyrosine kinase 1 (sFlt-1) levels with subsequent development of pre-eclampsia (PE). METHODS: This is a matched case-control study using stored serum samples collected from non-smoking Chinese women with singleton pregnancies who underwent first trimester screening for aneuploidy. Each case that developed PE was matched with a control whose maternal age, weight, gestational age and date of blood collection were within +/- 2 years, +/- 5 kg, +/- 1 day, and +/- 2 weeks of the index case, respectively. Non parametric paired test was used to compare the PlGF and sFlt-1 levels. PlGF and sFlt-1 were transformed to their equivalent multiple of the median (MoM) using the matched control as the expected median value. The 95% confidence interval (CI) of the estimated median PlGF and sFlt-1 MoM in those with PE was determined. RESULTS: The median PlGF level in the 27 study cases with PE was lower than that of the matched controls (42.9 pg/ml versus 59.8 pg/ml; p = 0.001). The median PIGF MoM was 0.71 (95% CI 0.63-0.92). There was no statistically significant difference in sFlt-1 levels between those with PE and their matched control (p = 0.648). The median sFlt-1 MoM was 1.01 (95% CI 0.65-1.3). CONCLUSIONS: Women who developed PE had lower serum PlGF levels but normal sFlt-1 levels in the first trimester. PMID- 21534855 TI - First trimester sonographic diagnosis of ectopia cordis: a case report and review of the literature. AB - A case of ectopia cordis (EC) with gastroschisis in a 27-year-old primigravida was diagnosed at 10(3/7) weeks of gestation. The pregnancy was terminated by suction dilatation and curettage. With the increasing use of first trimester ultrasonography, early detection of fetal abnormalities is becoming more frequent. We review other published cases of EC detected in the first trimester and discuss the possible advantages of early diagnosis including options of termination at earlier gestational ages which might decrease the physical and psychological trauma on some patients. PMID- 21534857 TI - Amniotic fluid stem cells are cardioprotective following acute myocardial infarction. AB - In recent years, various types of stem cells have been characterized and their potential for cardiac regeneration has been investigated. We have previously described the isolation of broadly multipotent cells from amniotic fluid, defined as amniotic fluid stem (AFS) cells. The aim of this study was to investigate the therapeutic potential of human AFS cells (hAFS) in a model of acute myocardial infarction. Wistar rats underwent 30 min of ischemia by ligation of the left anterior descending coronary artery, followed by administration of hAFS cells and 2 h of reperfusion. Infarct size was assessed by 2,3,5-triphenyltetrazolium chloride staining and planimetry. hAFS cells were also analyzed by enzyme-linked immunosorbent assay to detect secretion of putative paracrine factors, such as the actin monomer-binding protein thymosin beta4 (Tbeta4). The systemic injection of hAFS cells and their conditioned medium (hAFS-CM) was cardioprotective, improving myocardial cell survival and decreasing the infarct size from 53.9%+/ 2.3% (control animals receiving phosphate-buffered saline injection) to 40.0%+/ 3.0% (hAFS cells) and 39.7%+/-2.5% (hAFS-CM, P<0.01). In addition, hAFS cells were demonstrated to secrete Tbeta4, previously shown to be both cardioprotective and proangiogenic. Our results suggest that AFS cells have therapeutic potential in the setting of acute myocardial infarction, which may be mediated through paracrine effectors such as Tbeta4. Therefore, AFS cells might represent a novel source for cell therapy and cell transplantation strategies in repair following ischemic heart disease, with a possible paracrine mechanism of action and a potential molecular candidate for acute cardioprotection. PMID- 21534858 TI - A comprehensive evaluation of the toxicology of cigarette ingredients: aromatic carbonyl compounds. AB - CONTEXT: Aromatic carbonyls are typically used in the processing or flavoring of tobacco used in the manufacture of cigarettes. OBJECTIVE: A battery of tests was used to compare the toxicity of mainstream smoke from experimental cigarettes containing different added levels of aromatic carbonyl compounds. MATERIALS AND METHODS: Ten aromatic carbonyl compounds, nine of which have been reported in tobacco or in tobacco smoke, were added individually to experimental cigarettes at three different levels. The tenth compound, not found naturally in tobacco, was 2-phenoxyethyl isobutyrate. The lowest target inclusion level was 100 ppm and the highest was 10,000 ppm. Smoke from each of the 10 experimental cigarette types was evaluated using analytical chemistry, in vitro cytotoxicity, and mutagenicity testing. For one of the compounds, ethyl vanillin, a 90-day smoke inhalation study using rats was also performed. RESULTS: Smoke chemistry was effectively unchanged by the addition of any of the compounds. Cytotoxicity, assessed by the neutral red uptake assay and using both gas-vapor and particulate phases of smoke, was unaffected by the addition of any of the test compounds. Mutagenicity, assessed by five strains of Salmonella typhimurium treated with smoke condensate, also was unaffected by any of the test compounds. In the rat inhalation study, there were effectively no differences between cigarettes without added ethyl vanillin and cigarettes containing ~8000 ppm of ethyl vanillin. CONCLUSION: Even at the exaggerated inclusion levels in cigarette tobacco used in these tests, no adverse toxicological responses occurred for any of aromatic carbonyl compounds tested. PMID- 21534859 TI - The phenylthiourea is a competitive inhibitor of the enzymatic oxidation of DOPA by phenoloxidase. AB - Phenoloxidase is a key enzyme of melanization catalyzing the oxidation of phenols. Phenylthiourea (PTU) is the well-known and widely used inhibitor of phenoloxidase. However, the mechanism of its action is not quite clear. In the present work, the effect of PTU on the enzymatic oxidation of 3-(3,4 dihydroxyphenyl)-l-alanine (DOPA) by phenoloxidase was studied by spectrophotometric methods. The inhibition constant of PTU was estimated as 0.21 +/- 0.09 uM and the competitive type of inhibition was determined for this reaction. PMID- 21534860 TI - Evaluation of in vitro effects of some analgesic drugs on erythrocyte and recombinant carbonic anhydrase I and II. AB - The in vitro effects of the injectable form of analgesic drugs, dexketoprofen trometamol, dexamethasone sodium phosphate, metamizole sodium, diclofenac sodium, thiocolchicoside, on the activity of purified human carbonic anhydrase I and II were evaluated. The effect of these drugs on erythrocyte hCA I and hCA II was compared to recombinant hCA I and hCA II expressed in Ecoli. IC(50) values of the drugs that caused inhibition were determined by means of activity percentage diagrams. The IC(50) concentrations of dexketoprofen trometamol and dexamethasone sodium phosphate on hCA I were 683 MUM and 4250 MUM and for hCA II 950 MUM and 6200 MUM respectively. Conversely, the enzyme activity was increased by diflofenac sodium. In addition, thiocolchicoside has not any affect on hCA I and hCA II. The effect of these drugs on erythrocyte hCA I and hCA II were consistent with the inhibition of recombinant enzymes. PMID- 21534861 TI - Synthesis, characterization and in vitro antimicrobial evaluation of new compounds incorporating oxindole nucleus. AB - New compounds incorporating with the oxindole nucleus were synthesized via the reaction of substituted isatins [5-methyl-, 5-chloro- and 1-hydroxymethyl isatins] with different nucleophiles. The structures of the newly compounds were elucidated on the basis of FTIR, (1)H NMR, (13)CMR spectral data, GC/MS and chemical analysis. Investigation of antimicrobial activity of the new compounds was evaluated using broth dilution technique in terms of minimal inhibitory concentration (MIC) count against four pathogenic bacteria and two pathogenic fungi. Most of the new compounds are significantly active against bacteria and fungi. MIC showed that compound (4a) possesses higher effect on Gram-positive bacteria Bacillus cereus than the selected antibacterial agent sulphamethoxazole, whereas compound (11c) possesses more activity against Gram-negative bacteria Shigella dysenterie. PMID- 21534862 TI - Synthesis, antimicrobial activity and cytotoxicity of novel oxadiazole derivatives. AB - In the present study, 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) were synthesized via the ring closure reactions of appropriate acid hydrazides with carbon disulphide. N-(Benzothiazol-2-yl)-2-[[5-substituted-1,3,4-oxadiazol-2 yl]sulfanyl]acetamide derivatives (3a-j) were obtained by the nucleophilic substitution reactions of 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) with N (benzothiazol-2-yl)-2-chloroacetamides. The chemical structures of the compounds were elucidated by IR, (1)H NMR, (13)C NMR and FAB(+)-MS spectral data and elemental analyses. The synthesized compounds were screened for their antimicrobial activities against Micrococcus luteus, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Listeria monocytogenes and Candida albicans. All compounds except compound 3h exhibited the highest antibacterial activity against P. aeruginosa. Among all compounds (3a j), the compounds bearing 4-methoxyphenoxymethyl moiety on oxadiazole ring (3a-e) exhibited the highest inhibitory activity against C. albicans. Although compound 3j did not possess 4-methoxyphenoxymethyl moiety on oxadiazole ring, this derivative also exhibited the same level of anti-candidal activity. The compounds were also investigated for their cytotoxic effects using MTT (3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Compound 3a exhibited the highest cytotoxic activity, whereas compound 3g possessed the lowest cytotoxic activity against NIH/3T3 cells. PMID- 21534863 TI - Biochemical characterization of an ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP, E.C. 3.1.4.1) from rat cardiac soluble and microsomal fractions. AB - In this study, we have reported the kinetic and biochemical characterization of ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP) activity in rat cardiac fractions, one soluble and the other enriched in vesicles derived from sarcoplasmic reticulum. Both fractions demonstrated E-NPP activities, which could be observed by extracellular hydrolysis of p-nitrophenyl-5'-thymidine monophosphate (p-Nph-5'-TMP) and other biochemical characteristics. The K(M) values for the hydrolysis of p-Nph-5'-TMP in soluble and microsomal fractions were 118.53 +/- 27.28 and 91.92 +/- 12.49 uM, respectively. The V(max) values calculated were 2.56 +/- 0.15 and 113.87 +/- 21.09 nmol p-nitrophenol/min/mg of protein in soluble and microsomal fractions, respectively. Among the compounds tested to evaluate the possible activity of other enzymes on p-Nph-5'-TMP hydrolysis, only suramin (0.25 mM) produced a significant inhibition of substrate hydrolysis. Thus, our results strongly suggest the presence of E-NPP enzymes in subcellular fractions of rat heart, which could be involved in nucleotide signalling in the cardiac tissue. PMID- 21534864 TI - Synthesis, characterization and biological studies of sulfonamide Schiff's bases and some of their metal derivatives. AB - A new series of Schiff base ligands derived from sulfonamide and their metal(II) complexes [cobalt(II), copper(II), nickel(II) and zinc(II)] have been synthesized and characterized. The nature of bonding and structure of all the synthesized compounds has been explored by physical, analytical and spectral data of the ligands and their metal(II) complexes. The authors suggest that all the prepared complexes possess an octahedral geometry. The ligands and metal(II) complexes have been screened for their in vitro antibacterial activity against bacterial strains, Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa, Salmonella typhi and for antifungal activity against fungal strains, Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glabrata. These assays enabled the identification of the metal complexes as an effective antimicrobial agent with low cytotoxicity. PMID- 21534865 TI - High catalytic efficiency and resistance to denaturing in bacterial Rho GTPase activating proteins. AB - Several major bacterial pathogens use the type III secretion system (TTSS) to deliver virulence factors into host cells. Bacterial Rho GTPase activating proteins (RhoGAPs) comprise a remarkable family of type III secreted toxins that modulate cytoskeletal dynamics and manipulate cellular signaling pathways. We show that the RhoGAP activity of Salmonella SptP and Pseudomonas ExoS toxins is resistant to variations in the concentration of NaCl or MgCl(2), unlike the known salt dependant nature of the activity of some eukaryotic GAPs such as p190, RanGAP and p120GAP. Furthermore, SptP-GAP and ExoS-GAP display full activity after treatment at 80 degrees C or with 6 m urea, which suggests that these protein domains are capable of spontaneous folding into an active state following denaturing such as what might occur upon transit through the TTSS needle. We determined the catalytic activity of bacterial GAPs for Rac1, CDC42 and RhoA GTPases and found that ExoS, in addition to Yersinia YopE and Aeromonas AexT toxins, display higher catalytic efficiencies for Rac1 and CDC42 than the known eukaryotic GAPs, making them the most catalytically efficient RhoGAPs known. This study expands our knowledge of the mechanism of action of GAPs and of the ways bacteria mimic host activities and promote catalysis of eukaryotic signaling proteins. PMID- 21534866 TI - Quality of life domains among non-Hodgkin lymphoma survivors: an integrative literature review. AB - Survival rates of individuals with non-Hodgkin lymphoma (NHL) have increased in the past several years, as has the prevalence of older adults who are managing late and long-term effects of the disease and its treatment. In this integrative review, the state of the science for determining the quality of life (QOL) among NHL survivors is outlined. An online search of Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, and the Cochrane Library databases was conducted using the following Keywords: non-Hodgkin lymphoma, health-related quality of life, quality of life, and impact of cancer. Eighteen studies published between 2000 and 2010 are reviewed. Of these, 17 were descriptive, cross-sectional designs, and one was a systematic review. The studies included participants of varying ages and years post-diagnosis as reported in several countries. Importantly, many used one or more QOL measures as outcome variables. Future research is needed on older and minority cancer populations and should include longitudinal and interventional studies. PMID- 21534867 TI - Effects of methylenetetrahydrofolate reductase gene polymorphisms on toxicities during consolidation therapy in pediatric acute lymphoblastic leukemia in a Chinese population. AB - This study aimed to investigate whether there was a correlation between the genotype or haplotype of the methylenetetrahydrofolate reductase gene (MTHFR) and toxicities during consolidation therapy or plasma methotrexate (MTX) levels at 48 h after the first dose of MTX infusion. We retrospectively genotyped 181 children with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated with the Chinese Children's Leukemia Group protocol. In standard- and medium-risk treatment branches, the 677T carriers (CT + TT) had a higher risk of developing thrombocytopenia when compared with carriers of the CC genotype (odds ratio [OR] 5.21, 95% confidence interval [CI] 1.18-23.01, p = 0.017). The 1298AC/CC genotypes were associated with a decrease in skin toxicity, as compared with the common AA genotype (p = 0.037). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. A lower frequency of anemia (OR 0.44, 95% CI 0.21-0.90, p = 0.025) and lower MTX level (p = 0.044) were observed in patients with the 677C-1298C haplotype than in those without. High plasma MTX level was correlated with anemia (p = 0.011) and neutropenia (p = 0.044). In the high-risk group, the polymorphisms or plasma MTX levels were not correlated with any toxicity. Taken together, our data demonstrate that genotyping of MTHFR and measurement of plasma MTX levels might be useful to optimize MTX therapy. PMID- 21534868 TI - A novel bisindolymaleimide derivative (WK234) inhibits proliferation and induces apoptosis through the protein kinase Cbeta pathway, in chronic myelogenous leukemia K562 cells. AB - WK234, a novel bisindolymaleimide derivative, was designed as a protein kinase Cbeta (PKCbeta) inhibitor. The objective of this study was to evaluate the anti tumor activity of WK234 in the human chronic myelogenous leukemia (CML) K562 cell line and to investigate possible mechanisms of its action. The results show that WK234 inhibited K562 cell proliferation in a time- and dose-dependent manner. WK234 increased cytochrome C release and caspase-3 cleavage, which indicates that it induced apoptosis via mitochondria- and caspase-mediated pathways. Western blotting showed that PKCbeta1, PKCbeta2, and their phosphorylation levels were effectively decreased after 2-4 h of WK234 treatment. Meanwhile the phosphorylation status of PKCbeta downstream proteins, glycogen synthase kinase 3alpha/beta (GSK3alpha/beta) and extracellular signal-regulated kinase (ERK), were inhibited. WK234 blocked phorbol myristate acetate (PMA)-induced Ser(660) phosphorylation of PKCbeta2 located at the cell membrane, and increased Ser(660) PKCbeta2 expression within the cytoplasm and the nucleus. These results indicate that WK234 inhibited cell proliferation and induced apoptosis through suppressing the PKCbeta signal pathway. WK234 might be a promising candidate for the treatment of CML. PMID- 21534869 TI - FISHing for answers in proliferation centers of chronic lymphocytic leukemia lymph nodes. PMID- 21534870 TI - Neurological presentation of Hodgkin lymphoma in the Italian Association of Pediatric Hematology and Oncology LH-2004 protocol. AB - Neurological symptoms can represent the first clinical manifestation of central nervous system (CNS) involvement in Hodgkin lymphoma (HL). Because of its rarity, it is often misunderstood for other pathological processes. We report two cases of pediatric CNS HL, presenting with neurological symptoms at diagnosis. We have also reviewed the literature and few cases are reported, only 19 of them concerning children. In both primary and metastatic CNS HL, all patients complained of neurological symptoms at presentation. Despite it being uncommon, physicians should regard the possibility of CNS localization in all children affected by HL presenting with neurological signs and/or symptoms. PMID- 21534871 TI - Assessment of quality of life with imatinib mesylate as first-line treatment in chronic phase-chronic myeloid leukemia. AB - Imatinib mesylate (IM) is a first-line treatment of chronic phase-chronic myeloid leukemia (CP-CML). The primary objective of this study was to assess the quality of life (QOL) in patients with CP-CML treated with IM. Ninety patients with newly diagnosed CP-CML were assessed for QOL with first-line IM. Patients completed the cancer-specific FACT-BRM questionnaire (functional assessment of cancer therapy biologic response modifiers) at baseline and at 3 and 6 months. FACT-BRM consists of subscales including physical well-being (PWB), social and family well-being (SFWB), emotional well-being (EWB), functional well-being (FWB), BRM-physical, and BRM-mental. The primary endpoint was the Trial Outcome Index (TOI), created as a measure of physical function and well-being. An increase of >=5 from baseline was considered to be a clinically significant improvement. The mean TOI score increased from 75.5 at baseline to 85.2 (p<0.0001) at 6 months, representing a healthy QOL. When comparing the individual TOI subscales, there was a mean increase of 16.4 in the daily functioning and well-being score, and a mean decrease of 6.2, 4.9, and 16.1 was noted in fatigue, emotional/cognitive dysfunction, and side-effects scores at 6 months, respectively. Improvement was not affected by age, sex, or Sokal score. With prolonged treatment, IM results in a higher physical well-being, less fatigue and emotional and cognitive dysfunction, and very few side-effects. PMID- 21534872 TI - Lenalidomide can induce long-term responses in patients with multiple myeloma relapsing after multiple chemotherapy lines, in particular after allogeneic transplant. AB - Evidence of long-term response to lenalidomide in heavily pretreated patients with multiple myeloma is lacking. This study sought to assess whether long-term responders exist, long-term responders' characteristics, and predictive factors of a long-term response. One hundred and four patients with multiple myeloma treated with lenalidomide and dexamethasone after >=2 therapy lines (median, 3) were analyzed. Long-term response was defined as at least a partial response (>=PR) lasting >=12 months. The overall response rate was 73%, and 80.3% of the responses were achieved within 5 months. The median response was 14.3 months. Patients evaluable for long-term response numbered 87, and a total of 47% were long-term responders. Compared to non-long-term responders, long-term responders had better overall survival, less light-chain multiple myeloma, and higher incidence of t(11;14). Previous allogeneic transplant (alloSCT) and the response quality predicted a long-term response. In conclusion, patients treated with lenalidomide can become long-term responders; alloSCT and response quality predict long-term response. PMID- 21534873 TI - Subdural hematomas in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy. AB - Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that inhibit BCR ABL have had a favorable impact on the treatment of Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). TKIs are generally well tolerated, but they can induce platelet dysfunction, which is of particular concern in the setting of thrombocytopenia in patients with acute leukemia. We present three patients with Ph+ ALL receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy who developed subdural hematomas (SDHs). All three were thrombocytopenic and had undergone repeated lumbar punctures for prophylactic intrathecal chemotherapy, but they were not coagulopathic and did not have meningeal leukemia. SDHs occurred in three of a total of 10 adult patients with Ph+ ALL receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy at our institution from 2007 to 2010, but in none of 22 adult patients with Ph- ALL receiving the same therapy without imatinib mesylate (p < 0.05). Patients with Ph+ ALL receiving imatinib mesylate, and likely also dasatinib, in conjunction with systemic and intrathecal chemotherapy may be at increased risk of SDH, and should be closely monitored for subtle manifestations of this complication. PMID- 21534874 TI - Prognostic impact of t(1;19)/ TCF3-PBX1 in childhood acute lymphoblastic leukemia in the context of Berlin-Frankfurt-Munster-based protocols. AB - Historically, t(1;19)(q23;p13.3) has been related to pre-B acute lymphoblastic leukemia (ALL) and associated with a poor prognosis. Current treatments have overcome this dismal outcome, but advantages in survival for the unbalanced group have been reported. We compared the outcome of balanced and unbalanced der(19)t(1;19) cases and also patients with t(1;19)/TCF3-PBX1 versus patients without this translocation, to assess its prognostic value. From January 1990 to December 2010, t(1;19)(q23;p13)/TCF3-PBX1 was detected in 48 cases. Patients were treated with Berlin-Frankfurt-Munster (BFM)-based protocols and classified into balanced (n = 17) and unbalanced (n = 23) groups. The probability of event-free survival (pEFS) (standard error) of patients with t(1;19)/TCF3-PBX1 was 85% (6%), for the unbalanced group 78% (10%), and 88% (8%) for the balanced. The pEFS of patients with t(1;19)/TCF3-PBX1 was significantly superior to that of patients without t(1;19)/TCF3-PBX1 (p-value <0.0001). Patients with t(1;19)/TCF3-PBX1 presented a good outcome with no differences between balanced and unbalanced subgroups. Thus, risk-adjustment therapy would not be necessary for cases with t(1;19)/TCF3-PBX1. PMID- 21534875 TI - Hairy cell leukemia, blastic type: description of spleen morphology and immunophenotype of a distinctive case. PMID- 21534876 TI - Anaerobes: not to be forgotten in neutropenic fever. PMID- 21534877 TI - Bone marrow stromal cells protect myeloma cells from bortezomib induced apoptosis by suppressing microRNA-15a expression. AB - Despite unsurpassed anti-tumor activity of bortezomib for multiple myeloma (MM), drug resistance has emerged as a challenge, especially when MM cells adhere to the stroma. This study aimed to determine whether bone marrow stromal cells (BMSCs) have a role in the development of chemoresistance in MM. Our data demonstrate that the secretion of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and cell-to-cell contact with microenvironment-derived stromal cells from patients with multiple myeloma (MM-BMSCs) significantly decreased the sensitivity of myeloma cells to bortezomib treatment. Mechanistically, we found that microRNA (miRNA)- 15a expression was up-regulated in U266 and NCI-H929 cells treated by bortezomib, which was inhibited by MM BMSCs. miRNA-15a transfected myeloma cells were arrested in G1/S checkpoint and secreted less VEGF compared to control transfected cells, although no significant difference was found in VEGF mRNA levels. In conclusion, our data suggest that via suppressing miRNA-15a expression, BMSCs provide survival support and protect myeloma cells from bortezomib induced apoptosis. PMID- 21534878 TI - Management and palliative chemotherapy for metastatic or recurrent squamous cell carcinoma of the head and neck. AB - Squamous cell carcinoma of the head and neck with distant metastases or locoregional relapse not amenable to radical surgery or radiation therapy are incurable. Median overall survival is approximately 10 months and the site of relapse, frequently in the head and neck area, is responsible for important local and regional complications that significantly impact quality of life. This article will focus on the general management and treatment of these recurrent and/or metastatic patients. We will discuss the challenges faced by the clinician when diagnosing tumor recurrence, as well as the indications and the limitations of the locoregional and systemic treatments available to treat this population. PMID- 21534879 TI - Redox pioneer:Professor Christine Helen Foyer. AB - Dr. Christine Foyer (B.Sc. 1974; Ph.D. 1977) is recognized here as a Redox Pioneer because she has published an article on redox biology that has been cited more than 1000 times, 4 other articles that have been cited more than 500 times, and a further 32 articles that have been each cited more than 100 times. During her Ph.D. at the Kings College, University of London, United Kingdom, Dr. Foyer discovered that ascorbate and glutathione and enzymes linking NADPH, glutathione, and ascorbate are localized in isolated chloroplast preparations. These observations pioneered the discovery of the ascorbate-glutathione cycle, now known as Foyer-Halliwell-Asada pathway after the names of the three major contributors, a crucial mechanism for H(2)O(2) metabolism in both animals and plants. Dr. Foyer has made a very significant contribution to our current understanding of the crucial roles of ascorbate and glutathione in redox biology, particularly in relation to photosynthesis, respiration, and chloroplast and mitochondrial redox signaling networks. "My view is that science...is compulsive and you have to keep with it all the time and not get despondent when things do not work well. Being passionate about science is what carries you through the hard times so that it isn't so much work, as a hobby that you do for a living. It is the thrill of achieving a better understanding and finding real pleasure in putting new ideas together, explaining data and passing on knowledge that keeps you going no matter what!" --Prof. Christine Helen Foyer. PMID- 21534880 TI - Prevention of prematurity by single embryo transfer. AB - The development of assisted reproduction techniques (ART) represents an important advance in the treatment of human infertility. However, their great effectiveness has brought with it an excessive increase in multiple pregnancy rates with the serious medical, financial and social consequences that they entail. Now, the scientific societies, the health professionals, and the infertile couples themselves are aware of these risks and have worked together to implement various strategies to deal with this situation. The result that is being obtained from the strategy of selectively reducing the number of embryos transferred is obvious. The pandemic of multiple pregnancies is being brought under control and so we have effective prevention of the obstetric and neonatal complications arising from it. It is to be hoped that it will also contribute to significantly reducing the rates of prematurity and thus of severe neonatal complications. PMID- 21534881 TI - Does prenatal antibiotic therapy compromise the diagnosis of early-onset infection and management of the neonate? AB - AIM: To assess the impact of prenatal antibiotic treatment on procalcitonin (PCT) and C-reactive protein (CRP) concentrations in cord blood, and on the rate of positive neonatal blood cultures. METHODS: Neonates with early-onset infection (Group A; n=46) were compared with healthy controls (Group B; n=240). We evaluated the relationship between prenatal antibiotic therapy and early-onset infection, and for interactions with antibiotic therapy in the neonate immediately after birth. RESULTS: In the Group A antibiotics were administered significantly more often prenatally and more often to neonates just after birth. The percentage of negative blood cultures in infected neonates was higher when antibiotic treatment was instituted prenatally. Differences in cord blood PCT and CRP concentrations were significant between both groups and were independent of prenatal antibiotic treatment. Streptococcus agalactiae was the most frequent species. CONCLUSIONS: Almost one-third of neonates present with early-onset infection in spite of prenatal antibiotic therapy. Cord blood PCT and CRP measurements may be helpful in the diagnosis of infection also in cases when antibiotic therapy was started prenatally. Prenatal antibiotic administration reduced the number of positive blood cultures in neonates with early-onset infection and was associated with a greater rate of antibiotic treatment after birth in neonates without infection. PMID- 21534882 TI - Lamellar bodies: platelet channel particles as predictors of respiratory distress syndrome (RDS) and of transient tachypnea of the newborn. AB - OBJECTIVE: We aimed to find a single numeric cut-off point in order to predict respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN), through quantification of the lamellar bodies (LBs) count. MATERIALS AND METHODS: Two hundred and twenty-seven single pregnancies delivered within 48 h from amniocentesis in a III level university hospital in a period between 1996 and 2007. LBs counts were determined by amniotic fluid (AF) sampling and after centrifugation in a commercially available Coulter counter. LBs counts were performed in order to predict the risk of neonatal RDS and also evaluated against the risk of TTN by means of the most suitable receiver operator characteristic (ROC) curve in order to predict RDS and TTN. RESULTS: The best LBs cut-off to significantly predict TTN was <= 35,000/MUL [sensitivity 86%, specificity 75%, positive predictive value (PPV) 22% and negative predictive value (NPV) at 96%]. An LBs count <= 32,000/MUL was the best compromise between sensitivity and specificity in predicting RDS or TTN [sensitivity 86%, specificity 83%, PPV 37% and NPV at 97%]. CONCLUSIONS: The quantification of LBs is a reliable method, simple to execute, useful in predicting RDS, and may be useful in evaluating suspicion of TTN. PMID- 21534883 TI - Prior exposure to immunosuppressive organophosphorus or organochlorine compounds aggravates the T(H)1- and T(H)2-type allergy caused by topical sensitization to 2,4-dinitrochlorobenzene and trimellitic anhydride. AB - Immunosuppressive environmental chemicals may increase the potency of allergens and thereby play a role in the development of allergic diseases. This study's primary objective was to examine the mechanisms behind the relationship between allergic diseases and the immunosuppression induced by some environmental chemicals. We focused on the modulation of allergic potential in vitro and in mice by the organophosphorus pesticide O,O-diethyl-O-4-nitrophenyl-thiophosphate (parathion) and the organochlorine pesticide 1,1,1-trichloro-2,2-bis(4-methoxy phenyl)ethane (methoxychlor), with respect to the T(H)1-type allergen 2,4 dinitrochlorobenzene (DNCB) and the T(H)2-type allergen trimellitic anhydride (TMA). Mice (4-week-old) were orally administered parathion or methoxychlor. Four weeks after the final dosing, the mice were sensitized to DNCB or TMA, and T lymphocyte proliferation measured in their (using a local lymph node assay [LLNA]). In addition, we analyzed T-lymphocytes via surface antigen expression and local cytokine production in auricular lymph nodes after treatment with 0.1% DNCB or 0.3% TMA. The estimated concentration of DNCB and TMA to yield a stimulation index (SI) of cell proliferation of three decreased markedly in parathion- and methoxychlor-pre-treated mice. Pesticide pre-treatment induced marked increases in the number of helper and cytotoxic T-cells, levels of T(H)1 and T(H)2 cytokines, and gene expression in lymph node cells. According to our results, T(H)1- and T(H)2-type allergies are aggravated by prior exposure to immunosuppressive environmental chemicals. PMID- 21534885 TI - Sitagliptin or exenatide once weekly for type 2 diabetes: comparison of the clinical trials. AB - INTRODUCTION: There is a need for new and improved treatments for type 2 diabetes. Glucagon-like peptide 1 (GLP-1) is a gut hormone that stimulates insulin secretion and the levels of GLP-1 can be increased by inhibiting DPP-4. Sitagliptin is one of the DDP-4 inhibitors used to increase the levels of GLP-1. Exenatide is an agonist at the GLP-1 receptors, which is resistant to breakdown and has a longer action than GLP-1. AREAS COVERED: This review compares the clinical trials of sitagliptin and exenatide once weekly in the treatment of type 2 diabetes. Only peer-reviewed trials listed on PubMed were included. EXPERT OPINION: Both sitagliptin and exenatide once weekly are capable of reducing HbA1c and plasma glucose levels, but exenatide once weekly is more potent than sitagliptin and this may lead to different roles for these agents in the treatment of type 2 diabetes. PMID- 21534884 TI - Effect of maternal exposure to ozone on reproductive outcome and immune, inflammatory, and allergic responses in the offspring. AB - There is growing concern that exposure to air pollutants during pregnancy affects health outcomes in the offspring due to alterations in the development of immune and other homeostatic processes. To assess the risks of maternal inhalation exposure to ozone (O(3)), timed pregnant BALB/c mice were exposed to different concentrations of O(3) (0, 0.4, 0.8, and 1.2 ppm) for 4 h/day for 10 days during gestation (GD9-GD18), and pulmonary inflammation and immune responses were assessed in the offspring at 6 weeks-of-age. Maternal O(3) exposure reduced the number of productive dams by 25% at the highest O(3) concentration (1.2 ppm) and decreased the rate of weight gain in the offspring. Delayed-type hypersensitivity responses to bovine serum albumin were suppressed in the female offspring by maternal exposure to the two highest concentrations of O(3), whereas humoral immune responses to sheep red blood cells were not altered in either sex. Maternal exposure to 1.2 ppm O(3) increased lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluid (BALF) of the offspring but did not affect the number of inflammatory cells or levels of total protein, IFN-gamma, IL-17, and IL 4 cytokines in BALF, or CD4(+), CD8(+), CD25(+), and TCRbeta(+)CD1d(+) T-cells in the spleen. Offspring born from air-exposed dams sensitized early in life (postnatal day [PND] 3) to ovalbumin (OVA) antigen and then challenged as adults developed eosinophilia, elevated levels of LDH activity and total protein in BALF, and increased pulmonary responsiveness to methacholine, compared with animals sensitized at PND42. Maternal O(3) exposure in the 1.2 ppm O(3) group decreased BALF eosinophilia and serum OVA-specific IgE in the female offspring sensitized early in life but did not affect development of allergic airway inflammation by offspring sensitized late in life. In summary, maternal exposure to O(3) affected reproductive outcome and produced modest decreases in immune function and indicators of allergic lung disease in surviving offspring. PMID- 21534886 TI - Antiretroviral use during pregnancy for treatment or prophylaxis. AB - INTRODUCTION: Antiretrovirals are recommended for all pregnant women either for treatment of HIV-1 infection or for prevention of mother-to-child transmission. Distinguishing between HIV-1-infected pregnant women who meet treatment criteria and those who do not (who use antiretrovirals during pregnancy for prophylaxis) is accomplished by assessing the HIV-1 disease stage and has important implications regarding when antiretroviral drugs are initiated during pregnancy, what drugs are used and antiretroviral use after delivery. AREAS COVERED: This review addresses antiretroviral use by HIV-1-infected women during pregnancy. Specifically, the review focuses on antiretroviral therapy for HIV-1-infected pregnant women who meet criteria for treatment and antiretroviral prophylaxis for HIV-1-infected pregnant women (to prevent mother-to-child transmission of HIV-1). The review primarily addresses antiretroviral use in resource-rich settings, but use in resource-poor settings is briefly addressed. EXPERT OPINION: Antiretrovirals represent only one component of the overall management of HIV-1 infected pregnant women and, therefore, cannot be viewed in isolation from other components of optimal care for HIV-1-infected women and from other efficacious interventions to prevent mother-to-child transmission of HIV-1. Antiretrovirals can be used safely and effectively during pregnancy. We concur with current guidelines regarding the threshold that differentiates which women need antiretroviral therapy for HIV-1 infection for their own health versus those who need prophylaxis to prevent transmission of HIV-1 infection to their child. We thus recommend that lifelong antiretroviral therapy be initiated in patients with an AIDS-defining illness, a CD4 count < 350 cells/mm(3) or other co-morbid conditions such as acute opportunistic infections, HIV-1-associated nephropathy or hepatitis B co-infection. Irrespective of whether or not antiretrovirals are used during pregnancy, or whether antiretrovirals during pregnancy are used for treatment or prophylaxis, all infants of HIV-1-infected women should receive antiretroviral post-exposure prophylaxis. PMID- 21534887 TI - Medical treatment of glaucoma: present and future. AB - INTRODUCTION: In the last decades, the therapy of glaucoma has largely shifted from surgery to medical treatment thanks to the introduction of strongly effective formulations, that is, prostaglandin analogs and fixed combinations. This clinical scenario may dramatically change in the future thanks to the progresses in biochemistry, genetics and drug delivery technology. AREAS COVERED: This review covers the strategies currently used to achieve effective medical reduction of intraocular pressure in clinical practice; treatments that are currently been experimented in humans and that may be clinically available in the next few years; treatments at preclinical stages; and future goals of glaucoma treatment (gene therapy, ocular implants and neuroprotection). EXPERT OPINION: Apart from an adequate reduction of intraocular pressure, effective glaucoma treatments should guarantee other characteristics: good tolerability, low problems of adherence and, possibly, multiple ways of action. From this viewpoint, a crucial clinical role may be played by drugs remodeling the trabecular meshwork (i.e., ROCK inhibitors, metalloproteinases). Other strategies such as the use of ocular implants for drug delivery, neuroprotection or gene therapy could renew glaucoma management in the future, but need long-term rigorous verification of safety and efficacy. PMID- 21534888 TI - Volatile and lipid analyses by gas chromatography/mass spectrometry and nutraceutical potential of edible wild Malva aegyptiaca L. (Malvaceae). AB - Volatile and lipid chemical compositions, and nutritional and antioxidant properties of Malva aegyptiaca, an edible wild plant largely distributed in North Africa, were investigated. Forty-nine compounds of volatiles were identified showing large qualitative and quantitative differences during three phenological stages. The flowering stage was characterized by the presence of a high number of terpenic compounds, among them dillapiole was found to be the major one (55.15%). The nutrient composition of leaves and fruits was investigated in the present work. Fruits' lipidic fraction was characterized by its high level of linoleic acid (n-6) (36.17%). Interestingly, leaves' lipidic fraction was characterized by its very high content of camphor (43.69%) and by its relatively high content of linoleinic acid (n-3) (14.69%). Furthermore, our results showed that the phenolic contents varied from 352 to 404 mg gallic acid equivalent/g ethanolic and acetonic extracts, respectively. These extracts revealed interesting antioxidant activities including free radical scavenging activity (EC(50) = 0.38-0.57 mg/ml) and reducing power (EC(50) = 0.12-0.18 mg/ml). PMID- 21534889 TI - Nutritional and sensory quality evaluation of sponge cake prepared by incorporation of high dietary fiber containing mango (Mangifera indica var. Chokanan) pulp and peel flours. AB - Sponge cake prepared by partial substitution of wheat flour with mango pulp and mango peel flours (MPuF and MPeF, respectively) at different concentrations (control, 5%, 10%, 20% or 30%) were investigated for the physico-chemical, nutritional and organoleptic characteristics. Results showed sponge cake incorporated with MPuF and MPeF to have high dietary fiber with low fat, calorie, hydrolysis and predicted glycemic index compared with the control. Increasing the levels of MPuF and MPeF in sponge cake had significant impact on the volume, firmness and color. Sensory evaluation showed sponge cake formulated with 10% MPuF and 10% MPeF to be the most acceptable. MPeF and MPuF have high potential as fiber-rich ingredients and can be utilized in the preparation of cake and other bakery products to improve the nutritional qualities. PMID- 21534890 TI - Defining anthropometric cut-off levels related to metabolic risk in a group of Sri Lankan children. AB - BACKGROUND: Body mass index (BMI) is widely used as a measure of adiposity. However, currently used cut-off values are not sensitive in diagnosing obesity in South Asian populations. AIM: To define BMI and waist circumference (WC), cut-off values representing percentage fat mass (%FM) associated with adverse health outcomes. SUBJECTS AND METHODS: A cross-sectional descriptive study of 285 5-14 year old Sri Lankan children (56% boys) was carried out. Fat mass (FM) was assessed using the isotope (D(2)O) dilution technique based on 2C body composition model. BMI and WC cut-off values were defined based on %FM associated with adverse health outcomes. RESULTS: Sri Lankan children had a low fat free mass index (FFMI) and a high fat mass index (FMI). Individuals with the same BMI had %FM distributed over a wide range. Lean body tissue grew very little with advancing age and weight gain was mainly due to increases in body fat. BMI corresponding to 25% in males and 35% in females at 18 years was 19.2 kg/m(2) and 19.7 kg/m(2), respectively. WC cut-off values for males and females were 68.4 cm and 70.4 cm, respectively. CONCLUSION: This chart analysis clearly confirms that Sri Lankan children have a high %FM from a young age. With age, more changes occur in FM than in fat free mass (FFM). Although the newly defined BMI and WC cut-off values appear to be quite low, they are comparable to some recent data obtained in similar populations. PMID- 21534891 TI - Explorations of clinical trials and pharmacovigilance databases of MF59(r) adjuvanted influenza vaccines for associated cases of narcolepsy. AB - BACKGROUND: A potential association between the new onset of narcolepsy accompanied by cataplexy - a putative autoimmune disorder, and vaccination with an AS03-adjuvanted A(H1N1) pandemic influenza vaccine is under investigation. We sought cases of narcolepsy from the pharmacovigilance database of a pandemic vaccine adjuvanted with another emulsion adjuvant, MF59((r)), and a pooled clinical trials database of MF59-adjuvanted and non-adjuvanted influenza vaccine recipients. METHODS: Using 6 narrowly restrictive and 24 broad sleep disturbance related MedDRA preferred search terms (PT), we analysed spontaneous adverse events (AEs) reports received through July 31, 2010 and adjudicated suspected cases with onset 1 week-3 months after vaccination, against standardized clinical criteria defining narcolepsy. A pooled clinical trials database of 115 trials comprising 79,004 subjects receiving various MF59-adjuvanted and non-adjuvanted influenza vaccines in controlled and uncontrolled trials was analysed for cases with a narrow PT that had onset 1 week after vaccination. RESULTS: Five thousand three hundred and five spontaneous AE reports were received from an estimated 23.26 million MF59-adjuvanted pandemic vaccine doses that had been administered. No case meeting the clinical definition of narcolepsy was discovered. In the pooled database of controlled clinical trials, no cases were discovered using the narrow PT, and rates and adjusted odds ratio for broad search terms for all temporal windows showed no significant difference between subjects receiving MF59 adjuvanted or non-adjuvanted vaccine. CONCLUSIONS: No case of narcolepsy and no evidence of an increased risk of sleep-related AEs were discovered in recipients of MF59-adjuvanted A(H1N1) pandemic and other MF59-adjuvanted influenza vaccine. PMID- 21534892 TI - Cryptococcal lymphadenitis and immune reconstitution inflammatory syndrome: current considerations. AB - HIV-related immune reconstitution inflammatory syndrome (IRIS) is increasingly being recognized in regions with a high burden of opportunistic infections. We describe an unusual manifestation of IRIS- 'unmasking' cryptococcal lymphadenitis in a patient shortly after initiation of antiretroviral therapy. Epidemiology, clinical features and management of cryptococcal IRIS with reference to lymphadenitis presentation are briefly reviewed. Early and accurate diagnosis is essential for appropriate management. Standard antifungal therapy along with continuation of antiretroviral therapy is recommended. Cases with severe inflammation may benefit from anti-inflammatory drugs/corticosteroids. Unusual manifestations like lymphadenitis pose diagnostic difficulties in regions with a high prevalence of tubercular lymphadenitis. PMID- 21534893 TI - Dyspnoea in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. AB - BACKGROUND: Adverse events attributed to the treatment of chronic hepatitis C patients with pegylated interferon (PEG-IFN) and ribavirin have been widely discussed. Lung disorders have been described, but the respiratory function of these patients during treatment has not been well studied. The aim of this study was to investigate the incidence of dyspnoea and possible changes in lung function associated with the use of PEG-IFN and ribavirin. METHODS: We evaluated clinical data and spirometry in 31 patients with chronic hepatitis C infections prior to treatment, in the 2(nd) week of treatment and in the 12(th) week of treatment. RESULTS: During the follow-up period, 19 patients (61.3%) had dyspnoea. Decreased haemoglobin levels were observed during the study, but there was no significant association with dyspnoea. However, patients with a body mass index (BMI) greater than 25 had a higher incidence of dyspnoea. No significant difference was detected between the values of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), or forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio measured during the investigation. However, a significant decrease in FEV1 and FEV1/FVC ratio was observed in patients with later stages of liver fibrosis. CONCLUSIONS: Dyspnoea is a frequently occurring respiratory symptom during chronic hepatitis C treatment, and it is not associated with changes in spirometric parameters in the first 12 weeks of treatment. However, changes in FEV1 and FEV1/FVC can be observed in patients with advanced liver disease in the first 12 weeks of treatment with PEG-IFN and ribavirin. PMID- 21534894 TI - Cuts to the NHMRC budget will undermine the health of all Australians - today and in the future. PMID- 21534895 TI - Does decompressive craniectomy improve outcomes in patients with diffuse traumatic brain injury? PMID- 21534896 TI - Early detection of breast cancer the second time around: mammography in women with a personal history of breast cancer. PMID- 21534897 TI - Is laparoscopic resection for colorectal cancer the way to the future? PMID- 21534898 TI - National trends in the uptake of laparoscopic resection for colorectal cancer, 2000-2008. AB - OBJECTIVE: To examine the trends in the uptake of laparoscopic resection for colorectal cancer. DESIGN AND SETTING: Retrospective analysis of Australia-wide data on elective resections for colorectal cancer over the 8 financial years 2000 01 to 2007-08, obtained from the National Hospital Morbidity Database. MAIN OUTCOME MEASURES: National trends in annual percentage of colorectal resections for cancer that were conducted laparoscopically for each year, stratified by hospitals conducting a high volume of elective resections (40 or more/year) versus a low volume, and by public versus private hospitals. RESULTS: For all Australian hospitals combined, the percentage of resections for colon cancer conducted laparoscopically increased from 2.4% in 2000-01 to 27.5% in 2007-08. For rectal cancer, this increase was from 1.1% to 21.5%. The largest increases were seen in high-volume private hospitals (colon cancer, 2.7% to 34.1%; rectal cancer, 1.5% to 26.2%), but increases also occurred in high-volume public hospitals (colon cancer, 2.7% to 32.2%; rectal cancer, 0.5% to 20.3%), low-volume private (colon cancer, 3.8% to 27.1%; rectal cancer, 2.4% to 25.5%) and low volume public (colon cancer, 1.1% to 17.0%; rectal cancer, 0.5% to 13.8%) hospitals. CONCLUSIONS: The use of laparoscopic resection for colorectal cancer has increased throughout Australian hospitals. Our findings provide the data necessary to ensure adequate resource allocation by the appropriate medical bodies to achieve optimal success in the uptake of laparoscopic resection for colorectal cancer in Australia. PMID- 21534899 TI - Streamlining elective surgery care in a public hospital: the Alfred experience. AB - OBJECTIVE: To evaluate the effectiveness of redesigning and streamlining perioperative services. DESIGN: A before-and-after evaluation, with retrospective analysis of de-identified administrative data. SETTING: A major tertiary hospital, Melbourne, Australia. PARTICIPANTS: Patients undergoing elective surgery, February 2005 - February 2010. INTERVENTION: Implementing a process redesign to streamline clinical pathways for elective surgery, with a focus on the patient journey from referral to discharge, and establishing a separate, dedicated elective surgery facility. MAIN OUTCOME MEASURES: Numbers of patients waiting beyond national recommended waiting times for elective surgery; hospital initiated postponement (HIP) rates for elective surgery; and lengths of stay (LOS), both combined and for specific diagnostic-related groups. RESULTS: The clinical process redesign resulted in a sustained downward trend in the number of elective surgery patients waiting longer than national recommended maximum waiting times. HIP rates were reduced to 1% in the dedicated elective surgery facility, and there was a significant reduction in the combined LOS, as well as the LOS for the most common surgical procedures (P < 0.001). CONCLUSIONS: Clinical process redesign of perioperative services and collocation of a separate elective surgery centre improved (i) timeliness of care for elective surgery patients and (ii) key indicators (LOS and HIP rates) for planned elective admissions. PMID- 21534900 TI - Doctors disciplined for professional misconduct in Australia and New Zealand, 2000-2009. AB - OBJECTIVES: To describe professional discipline cases in Australia and New Zealand in which doctors were found guilty of professional misconduct, and to develop a typology for describing the misconduct. DESIGN AND SETTING: A retrospective analysis of disciplinary cases adjudicated in five jurisdictions (New South Wales, Victoria, Queensland, Western Australia and New Zealand) in 2000-2009. MAIN OUTCOME MEASURES: Characteristics of the cases (setting, misconduct type, patient outcomes, disciplinary measure imposed), characteristics of the doctors involved (sex, specialty, years since qualification) and population-level case rates (by doctor characteristics). RESULTS: The tribunals studied disciplined 485 doctors. Male doctors were disciplined for misconduct at four times the rate of their female colleagues (91 versus 22 cases per 100 000 doctor-years). Obstetrics and gynaecology and psychiatry were the specialties with the highest rates (224 and 178 cases per 100 000 doctor-years). The mean age of disciplined doctors did not differ from that of the general doctor population. The most common types of offences considered as the primary issue were sexual misconduct (24% of cases), illegal or unethical prescribing (21%) and inappropriate medical care (20%). In 78% of cases, the tribunal made no mention of any patient having experienced physical or mental harm as a result of the misconduct. Penalties were severe, with 43% of cases resulting in removal from practice and 37% in restrictions on practice. CONCLUSIONS: Disciplinary cases in Australia and New Zealand have features distinct from those studied internationally. The recent nationalisation of Australia's medical boards offers new possibilities for tracking and analysing disciplinary cases to improve the safety and quality of health care. PMID- 21534901 TI - Public or private: where would you choose to work? - Public. PMID- 21534902 TI - Public or private: where would you choose to work? - Private. PMID- 21534903 TI - Adding flexibility to physician training. AB - Demographic changes among junior doctors are driving demand for increased flexibility in advanced physician training, but flexible training posts are lacking. Suitable flexible training models include flexible full-time, job-share and part-time positions. Major barriers to establishing flexible training positions include difficulty in finding job-share partners, lack of funding for creating supernumerary positions, and concern over equivalence of educational quality compared with full-time training. Pilot flexible training positions should be introduced across the medical specialties and educational outcomes examined prospectively. PMID- 21534904 TI - How can surgical training benefit from theories of skilled motor development, musical skill acquisition and performance psychology? AB - Trainee surgeons must acquire expert status in the context of reduced hours, reduced operating room time and the need to learn complex skills involving screen mediated techniques, computers and robotics. Ever more sophisticated surgical simulation strategies have been helpful in providing surgeons with the opportunity to practise, but not all of these strategies are widely available. Similarities in the motor skills required in skilled musical performance and surgery suggest that models of music learning, and particularly skilled motor development, may be applicable in training surgeons. More attention should be paid to factors associated with optimal arousal and optimal performance in surgical training - lessons learned from helping anxious musicians optimise performance and manage anxiety may also be transferable to trainee surgeons. The ways in which the trainee surgeon moves from novice to expert need to be better understood so that this process can be expedited using current knowledge in other disciplines requiring the performance of complex fine motor tasks with high cognitive load under pressure. PMID- 21534905 TI - Distressed doctors: a hospital-based support program for poorly performing and "at-risk" junior medical staff. AB - Despite "safe-hours" campaigns and doctors health programs, "at-risk" behaviour and suicides still occur in junior doctors. A recent national survey found that 46% of junior doctors believed that their hospital administration was not supportive. The Royal Melbourne Hospital has developed a comprehensive program for preventing and identifying at-risk behaviour and supporting junior doctors, tailored to the individual's needs. Patient and individual doctor safety is paramount, and confidential collaboration between medical workforce and medical education structures, clinical supervisors and the Victorian Doctors Health Program is required. The boundaries of the hospital's "duty of care" for those who do not want assistance is unclear, and balancing increased supervision within a limited workforce is challenging. PMID- 21534906 TI - A synthetic haemoglobin-based oxygen carrier and the reversal of cardiac hypoxia secondary to severe anaemia following trauma. AB - We report a case of compassionate use of a haemoglobin-based oxygen carrier in a severely injured Jehovah's Witness patient, for whom survival was considered unlikely. Severe anaemia and cardiac hypoxia were reversed after slow infusion of this agent. No vasoactive side effects were associated with the treatment, possibly due to the slow infusion, and the patient survived. PMID- 21534908 TI - Implementing US-style anti-fraud laws in the Australian pharmaceutical and health care industries. AB - This article critically analyses the prospects for introducing United States anti fraud (or anti-false claims) laws in the Australian health care setting. Australian governments spend billions of dollars each year on medicines and health care. A recent report estimates that the money lost to corporate fraud in Australia is growing at an annual rate of 7%, but that only a third of the losses are currently being detected. In the US, qui tam provisions - the component of anti-fraud or anti-false claims laws involving payments to whistleblowers - have been particularly successful in providing critical evidence allowing public prosecutors to recover damages for fraud and false claims made by corporations in relation to federal and state health care programs. The US continues to strengthen such anti-fraud measures and to successfully apply them to a widening range of areas involving large public investment. Australia still suffers from the absence of any comprehensive scheme that not only allows treble damages recovery for fraud on the public purse, but crucially supports such actions by providing financial encouragement for whistleblowing corporate insiders to expose evidence of fraud. Potential areas of application could include direct and indirect government expenditure on health care service provision, pharmaceuticals, medical devices, defence, carbon emissions compensation and tobacco-related illness. The creation in Australia of an equivalent to US anti false claims legislation should be a policy priority, particularly in a period of financial stringency. PMID- 21534909 TI - Alcohol and cancer: a position statement from Cancer Council Australia. AB - The Cancer Council Australia (CCA) Alcohol Working Group has prepared a position statement on alcohol use and cancer. The statement has been reviewed by external experts and endorsed by the CCA Board. Alcohol use is a cause of cancer. Any level of alcohol consumption increases the risk of developing an alcohol-related cancer; the level of risk increases in line with the level of consumption. It is estimated that 5070 cases of cancer (or 5% of all cancers) are attributable to long-term chronic use of alcohol each year in Australia. Together, smoking and alcohol have a synergistic effect on cancer risk, meaning the combined effects of use are significantly greater than the sum of individual risks. Alcohol use may contribute to weight (fat) gain, and greater body fatness is a convincing cause of cancers of the oesophagus, pancreas, bowel, endometrium, kidney and breast (in postmenopausal women). The existing evidence does not justify the promotion of alcohol use to prevent coronary heart disease, as the previously reported role of alcohol in reducing heart disease risk in light-to-moderate drinkers appears to have been overestimated. CCA recommends that to reduce their risk of cancer, people limit their consumption of alcohol, or better still avoid alcohol altogether. For individuals who choose to drink alcohol, CCA recommends that they drink only within the National Health and Medical Research Council guidelines for alcohol consumption. PMID- 21534910 TI - Wernicke's encephalopathy in a non-alcoholic patient with a normal blood thiamine level. PMID- 21534911 TI - Scurvy and stroke: is there an association? PMID- 21534912 TI - Misuse of codeine-containing combination analgesics. PMID- 21534913 TI - Academic health science centres in Australia: let's get competitive. PMID- 21534914 TI - Role substitution: a reactionary approach to health care change. PMID- 21534915 TI - Development of a plate-based assay for high-content analysis of individual untethered non-adherent cells. AB - Research involving non-adherent cell lines, primary cells and blood cells is definitely important, but its application in image-based assays, especially in high-content systems, is highly limited. Accordingly, efficient high-content methods to study non-adherent cells are needed not only to improve diagnostics but also for early screening of targeted drugs. A plate-based assay using adhesion reagents for multiparametric measurement with single non-adherent and non-anchored cells in a large cell population in high-content cytometry was developed and optimized. The cells preserved their identity even during extensive biomanipulations. The proposed method is highly robust for better imaging and can be used in various assays in different cellular backgrounds. Furthermore, as exemplary experiments, novel optimized assay protocols were used to study extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activity after cell inhibition with imatinib in chronic myelocytic leukemia K562 cells, revealing the phosphorylation kinetics of ERK MAPK. The results showed that the proposed assay detects kinase phosphorylation with good sensitivity and may be used in rapid drug screening. PMID- 21534916 TI - Identification and characterization of mGlu3 ligands using a high throughput FLIPR assay for detection of agonists, antagonists, and allosteric modulators. AB - When targeting G-protein coupled receptors (GPCRs) in early stage drug discovery, or for novel targets, the type of ligand most likely to produce the desired therapeutic effect may be unknown. Therefore, it can be desirable to identify potential lead compounds from multiple categories: agonists, antagonists, and allosteric modulators. In this study, we developed a triple addition calcium flux assay using FLIPR Tetra to identify multiple ligand classes for the metabotropic glutamate receptor 3 (mGlu3), using a cell line stably co-expressing the human G protein-coupled mGlu3 receptor, a promiscuous G-protein (G(alpha16)), and rat Glast, a glutamate transporter. Compounds were added to the cells followed by stimulation with EC(10) and then EC(80) concentration of glutamate, the physiological agonist for mGlu receptors. This format produced a robust assay, facilitating the identification of agonists, positive allosteric modulators and antagonists/negative allosteric modulators. Follow up experiments were conducted to exclude false positives. Using this approach, we screened a library of approximately 800,000 compounds using FLIPR Tetra and identified viable leads for all three ligand classes. Further characterization revealed the selectivity of individual ligands. PMID- 21534917 TI - A fluorescence polarization based screening assay for identification of small molecule inhibitors of the PICK1 PDZ domain. AB - PDZ (PSD-95/Discs-large/ZO-1 homology) domains represent putative targets in several diseases including cancer, stroke, addiction and neuropathic pain. Here we describe the application of a simple and fast screening assay based on fluorescence polarization (FP) to identify inhibitors of the PDZ domain in PICK1 (protein interacting with C kinase 1). We screened 43,380 compounds for their ability to inhibit binding of an Oregon Green labeled C-terminal dopamine transporter peptide (OrG-DAT C13) to purified PICK1 in solution. The assay was highly reliable with excellent screening assay parameters (Z'~0.7 and Z~0.6). Out of ~200 compounds that reduced FP to less than 80% of the control wells, six compounds were further characterized. The apparent affinities of the compounds were determined in FP competition binding experiments and ranged from ~5.0 uM to ~193 uM. Binding to the PICK1 PDZ domain was confirmed for five of the compounds (CSC-03, CSC-04, CSC-43, FSC-231 and FSC-240) in a non-fluorescence based assay by their ability to inhibit pull-down of PICK1 by a C-terminal DAT GST fusion protein. CSC-03 displayed the highest apparent affinity (5.0 uM) in the FP assay, and was according to fluorescence resonance energy transfer (FRET) experiments capable of inhibiting the interaction between the C-terminus of the GluR2 subunit of the AMPA-type glutamate receptor and PICK1 in live cells. Additional experiments suggested that CSC-03 most likely is an irreversible inhibitor but with specificity for PICK1 since it did not bind three different PDZ domains of PSD-95. Summarized, our data suggest that FP based screening assays might be a widely applicable tool in the search for small molecule inhibitors of PDZ domain interactions. PMID- 21534918 TI - Development of naturally selected and molecularly engineered intrachain and competitive FRET-aptamers and aptamer beacons. AB - Several different approaches have been taken to development of homogeneous fluorescent aptamer assays including end-labeled beacons and signaling aptamers which are intrinsically quenched by nucleotides. Two new strategies dubbed "intrachain" and "competitive" FRET-aptamer assays are summarized in this review. Intrachain and competitive FRET-aptamers can be engineered on the molecular level through a series exploratory experiments involving prior knowledge of aptamer secondary or tertiary structures and hypotheses about aptamer conformational changes. However, there is an intrinsic risk of altering aptamer affinity or specificity associated with chemical modifications of an aptamer. Natural selection methods for FRET-aptamers have also been devised to potentially obviate the chemical modification problem. The naturally selected aptamers are subjected to fluorophore (F)- and or quencher (Q)-conjugated nucleotide triphosphate (NTP) incorporation by polymerase chain reaction (PCR) with permissive polymerases such as Deep Vent exo-, but still demonstrate sensitive and specific assay performance despite modified bases, because they are ultimately selected after decoration with F and Q. This paper summarizes work in this area and presents some new examples of the engineered and naturally selected FRET-aptamers for detection of vitamin D. PMID- 21534919 TI - Supported TBD-assisted solution phase diversification of formyl-aza-heterocycles through alkylation-knoevenagel one pot sequences. AB - An efficient solution-phase parallel procedure to perform the structural diversification of some formyl-nitrogen heterocycles (A) using the reusable TBD supported base is described. The library synthesis is based in a consecutive Alkylation-Knoevenagel functionalisation that uses alkyl halides (B), Michael acceptors (C) and activated methylene compounds (D) as diversity elements. PMID- 21534920 TI - Current concepts in the management of diabetic polyneuropathy. AB - Approximately one in three people with diabetes is affected by diabetic distal symmetric sensorimotor polyneuropathy (DSPN), which represents a major health problem as it may present with excruciating neuropathic pain and is responsible for substantial morbidity, increased mortality and impaired quality of life. Neuropathic pain causes considerable interference with sleep, daily activities, and enjoyment of life. Treatment is based on four cornerstones: (1) intensive diabetes therapy and multifactorial risk intervention; (2) treatment based on pathogenetic mechanisms; (3) symptomatic treatment; and (4) avoidance of risk factors and complications. Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. From the clinical point of view, it is important to note that, based on these pathogenetic mechanisms, therapeutic approaches could be derived, some of which are currently being evaluated in clinical trials. Management of chronic painful DSPN remains a challenge for the physician and should consider the following practical rules: the appropriate and effective drug has to be tried and identified in each patient by carefully titrating the dosage based on efficacy and side effects; lack of efficacy should be judged only after 2-4 weeks of treatment using an adequate dosage. Analgesic combination therapy may be useful, and potential drug interactions have to be considered given the frequent polypharmacy in people with diabetes. Not only increased alcohol consumption but also the traditional cardiovascular risk factors such as visceral obesity, hypertension, hyperlipidemia and smoking have a role in the development and progression of diabetic neuropathy and hence need to be prevented or treated. PMID- 21534922 TI - Partially ordered sets: ranking and prediction of substances' properties. AB - There are at least two significant applications of partial order theory in chemistry: Ranking methods and substances' properties prediction. In both cases, a set of objects is endowed with a partial order relation e.g. "more polluting than", "can be obtained from", "more reactive than" etc. The couple of set and partial order relation is known in mathematics as a partially ordered set (poset). Ranking methods, such as the Hasse diagram technique, lead to a partial order where several incomparabilities (lack of order) appear between pairs of objects. This phenomenon is quite common in ranking studies, and it often is circumvented by a combination of object features leading to a total order. However, such a combination introduces subjectivities and bias in the ranking process. Here a step-by-step procedure is shown to turn incomparabilities into comparabilities taking into account all the possible bias by a linear combination of features. In such a manner, it is possible to predict how probable it is to obtain a particular total order from a given poset. Similarly, it is possible to calculate the needed bias over certain attributes to obtain a particular total order. An example application is shown where substances are ranked according to their bioconcentration factor and biodegradation potential. Another application of partial order theory to chemistry has to do with the prediction of properties for a set of substances related in a (preferably systematic) chemical fashion. A customary relation is "can be obtained from"; if such a relation is set up for a given molecular structure e.g. benzene, and all its substituted derivatives (say chlorinated ones) are considered, then the set of benzene and its chlorinated derivatives are partially ordered. Taking advantage of the poset generated, different methods can be applied to predict properties of the substances considered in the poset. Such methods include the poset-average, cluster expansion, and splinoid methods. In this paper we discuss each one of these methods, its advantages and disadvantages and we outline its applicability to estimate cooperative free energies of hemoglobins with different degree of oxygenation. PMID- 21534921 TI - Molecular docking: a powerful approach for structure-based drug discovery. AB - Molecular docking has become an increasingly important tool for drug discovery. In this review, we present a brief introduction of the available molecular docking methods, and their development and applications in drug discovery. The relevant basic theories, including sampling algorithms and scoring functions, are summarized. The differences in and performance of available docking software are also discussed. Flexible receptor molecular docking approaches, especially those including backbone flexibility in receptors, are a challenge for available docking methods. A recently developed Local Move Monte Carlo (LMMC) based approach is introduced as a potential solution to flexible receptor docking problems. Three application examples of molecular docking approaches for drug discovery are provided. PMID- 21534923 TI - Quantitative structure-activity relationships for anticancer activity of 2 phenylindoles using mathematical molecular descriptors. AB - Calculated atom pairs (APs) and a set of 369 topological indices (TIs) calculated by POLLY, Triplet, and Molconn-Z software were used to develop QSARs for anticancer activity of a group of 2-phenyl indoles. The TIs included both topostructural (TS) and topochemical (TC) indices. Results show that ridge regression using TS indices, TC indices, and atom pairs produced high-quality models for the prediction of anticancer activity of a set of 89 phenylindole derivatives. Quality of QSARs derived in this paper is comparable or superior to both CoMFA and other statistical models reported for 2-phynylindoles in the earlier published literature. Easily calculated molecular descriptors like TIs and APs used in this paper may find application in the QSAR and in silico prediction of bioactivity of new phenylindole derivatives. PMID- 21534924 TI - Chemotopology: beyond neighbourhoods. AB - We have shown in several papers the importance of using topology, particularly set-point topology, to deal with chemical questions related to the concept of similarity. The procedure developed has been called "chemotopology" and it has been applied to different chemical sets e.g. chemical elements, benzimidazoles, sterorids, amino acids and hydrides. The idea behind chemotopology is to run a hierarchical cluster analysis study on a set of objects characterised by different attributes. From this study a dendrogram is obtained, which gathers similarity neighbourhoods for the set of objects. By using a mathematical characterisation of a dendrogram it is possible to select a collection of objects' neighbourhoods which in turn become a basis for a topology. With this basis at hand different properties of subsets of objects can be calculated, all of them related to the concept of similarity e.g. closures, derived sets, boundaries, interiors and exteriors. We have also shown the chemical meaning of each one of these properties. In this manuscript, we review the foundations of the chemotopological method as well as its different applications to chemical sets. By means of examples we illustrate how the method can be used as a versatile tool for drug discovery. We also study the relationship between the topologies generated from dendrograms of a given set of objects and the dendrograms that can be obtained for particular topologies on the set of objects. PMID- 21534925 TI - On molecular graph comparison. AB - Since the last half of the nineteenth century, molecular graphs have been present in several branches of chemistry. When used for molecular structure representation, they have been compared after mapping the corresponding graphs into mathematical objects. However, direct molecular comparison of molecular graphs is a research field less explored. The goal of this mini-review is to show some distance and similarity coefficients which were proposed to directly compare molecular graphs or which could be useful to do so. PMID- 21534926 TI - Applications of graph theory, network theory, and chemotopology to structure activity relationships and characterization of metabolic processes. PMID- 21534927 TI - The reliability and validity of the French version of the Cocaine Craving Questionnaire-Brief. AB - INTRODUCTION: Cocaine has become a noticeable part of the European drug scene and is the second most commonly used illicit drug among the general population. Craving is a core issue in cocaine dependence and is strongly associated with lapse and/or relapse. However, no craving scale exists in French. The objective of our study was to assess the reliability and validity of a French language version of the 10-item Cocaine Craving Questionnaire-Brief (CCQ-Brief). METHODS: A total of 131 individuals ranging in age from 18 to 65 years were enrolled in a 12-month outpatient treatment program in 2009. The participants were seeking treatment for cocaine dependence. They completed the Mini-International Neuropsychiatric Interview (MINI) and the French version of the CCQ-Brief. At the end of the interview, a Clinical Global Impression Scale (CGIS) was completed by a clinician blind to the subject's treatment group. We evaluated the internal consistency of the French CCQ-Brief using Cronbach's alpha coefficient and the correlation of each item with the total scale using the Pearson's coefficient. We conducted an exploratory factorial analysis followed by a scree test. Only items with factor loading >0.3 were retained. The convergent validity of the French CCQ Brief was assessed using Pearson's correlation between the CCQ-Brief and the CGIS. RESULTS: The mean (SD) score of the 10-item CCQ-Brief was 3.4 (1.5). Cronbach's alpha coefficient 0.88 and remained high even when an item was deleted (ranging from 0.86 to 0.88), indicating that this tool possesses a high internal consistency. Each item exhibited a strong correlation with the total score ranging from 0.62 to 0.83. All items presented factor loadings ranged from 0.47 to 0.83. The correlation between the CCQ-Brief and the CGIS was high (r=0.49, p<0.0001), indicating a sufficient convergent validity. DISCUSSION: The French version of the CCQ-Brief is a reliable and valid instrument that can provide a comprehensive assessment of cocaine craving in treatment-seeking cocaine dependent patients. PMID- 21534928 TI - A framework for direct locating and conformational sampling of protein structural motifs. AB - A specific treatment of recurrent structural motifs that represent the local bias information has been proven to be an important ingredient in de novo protein structure predication. Significant majority of methods for local structure are based on building blocks, which still suffer from its inherent discrete nature. Instead of using building blocks, this work presents a new protocol framework for local structural motifs prediction based on the direct locating along protein sequence and probabilistic sampling in a continuous (phi, psi) space. The protein sequence was first scanned by an algorithm of sliding window with variable length of 7 to 19 residues, to match local segments to one of 82 motifs patterns in the fragment library. Identified segments were then labeled and modeled as the correlations of backbone torsion angles with mixture of bivariate cosine distributions in continuous (phi, psi) space. 3D conformations of corresponding segments were finally sampled by using a backtrack algorithm to the hidden Markov model with single output of (phi, psi). For local motifs in 50 proteins of testing set, about 62% of eight-residue segments located with high confidence value were predicted within 1.5 A of their native structures by the method. Majority of local structural motifs were identified and sampled, which indicates the proposed protocol may at least serve as the foundation to obtain better protein tertiary structure prediction. PMID- 21534929 TI - Fine tuning of protein kinase C (PKC) isoforms in cancer: shortening the distance from the laboratory to the bedside. AB - The serine/threonine protein kinase C (PKC) family was first identified as intracellular receptor(s) for the tumor promoting agents phorbol esters. Thirty years after the discovery of PKC, the role of specific PKC isoforms has been described in relationship with an altered pattern of expression in different types of cancer and a good number of small molecule inhibitors (inhibitory peptides, antisense oligonucleotides or natural compounds) targeting PKC are now available. Despite all these achievements and a huge amount of basic research studies on the biochemical regulation of PKC, there has been a delay in clinical trials with drugs targeting PKC function. This delay is easily explained taking into account the extreme biological complexity of the PKC family of isoforms and the incomplete understanding of the specific role of each PKC isozyme in different types of cancers. Some of the difficulties in developing pharmacological compounds selectively tuning the different PKCs have started to be overcome. In this review, the growing evidences of the role of the PKC isoforms alpha, betaII, delta, epsilon, zeta and iota is in promoting or counteracting tumor progression will be discussed in relationship with promising therapeutic perspectives. PMID- 21534930 TI - Interactions between proteins and platinum-containing anti-cancer drugs. AB - Cisplatin and its congeners are well-known to exert their therapeutic effects on cancer via interaction with DNA in the cell nucleus. On the other hand, the undesirable side-effects of these drugs appear to also be linked, at least to some extent, to interaction of the platinum with proteins and peptides. For other classes of anticancer drugs, interaction with proteins is in fact the primary pathway whereby therapeutically-useful effects are achieved. Here, a review is given of the known instances of interaction of cisplatin and related compounds with proteins and biologically relevant peptides, with emphasis on structural and reactivity aspects. PMID- 21534931 TI - Chemical and pharmacological significance of natural guanidines from marine invertebrates. AB - Natural Guanidines from marine invertebrates represent a group of bioactive secondary metabolites that revealed prominent pharmacological activities such as antimicrobial, antiproliferative, analgesic, and anti-coagulant properties. Acyclovir (Zovirax((r))), the first guanidine-derived pharmaceutical for the treatment of herpes infections since late 1970s, was synthesized based on a marine arabinosyl nucleoside, spongosine. Recently, ziconotide (Prialt((r))), a synthetic form of the marine-derived peptide (omega-conotoxin MVIIA) comprising a guanidine moiety, has been approved for the treatment of chronic pain. This review surveys over 130 compounds of guanidine-containing secondary metabolites from marine invertebrates with emphasis on their pharmacological significance and structure-activity relationships. PMID- 21534932 TI - Mindfulness-based stress reduction and mindfulness-based cognitive therapy: a systematic review of randomized controlled trials. AB - Fjorback LO, Arendt M, Ornbol E, Fink P, Walach H. Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy - a systematic review of randomized controlled trials. OBJECTIVE: To systematically review the evidence for MBSR and MBCT. METHOD: Systematic searches of Medline, PsycInfo and Embase were performed in October 2010. MBSR, MBCT and Mindfulness Meditation were key words. Only randomized controlled trials (RCT) using the standard MBSR/MBCT programme with a minimum of 33 participants were included. RESULTS: The search produced 72 articles, of which 21 were included. MBSR improved mental health in 11 studies compared to wait list control or treatment as usual (TAU) and was as efficacious as active control group in three studies. MBCT reduced the risk of depressive relapse in two studies compared to TAU and was equally efficacious to TAU or an active control group in two studies. Overall, studies showed medium effect sizes. Among other limitations are lack of active control group and long term follow-up in several studies. CONCLUSION: Evidence supports that MBSR improves mental health and MBCT prevents depressive relapse. Future RCTs should apply optimal design including active treatment for comparison, properly trained instructors and at least one-year follow-up. Future research should primarily tackle the question of whether mindfulness itself is a decisive ingredient by controlling against other active control conditions or true treatments. PMID- 21534933 TI - Accuracy of intraoperative gross visual assessment of myometrial invasion in endometrial cancer. AB - OBJECTIVE: To evaluate the accuracy of gross visual assessment of myometrial invasion in endometrial carcinoma. DESIGN: Prospective, descriptive study. SETTING: University hospital. POPULATION: Two hundred and fourteen consecutive patients operated between 2005 and 2008. All patients were preoperatively diagnosed with endometrial carcinoma or complex atypical hyperplasia considered by the pathologist to be at the border of highly differentiated endometrial cancer. METHODS: Intraoperative gross visual assessment of myometrial tumor invasion (<50 or >=50%), cervical tumor engagement and tumor diameter in millimeters were noted for all patients. MAIN OUTCOME MEASURES: The collected data were compared with final histopathology. RESULTS: Intraoperative gross visual assessment of myometrial tumour invasion correlated well with final histology, with an accuracy of 87%. Agreement between gross visual assessment and final histology was reached in 91% of grade 1 tumors. Additionally, we found that 98.5% of tumors with a diameter <20mm had <50% myometrial invasion, regardless of grade. CONCLUSIONS: Intraoperative gross visual assessment of myometrial tumor invasion and tumor size measurements are simple, fast and inexpensive methods that may provide important information for the surgeon to decide upon the extent of staging when other more accurate methods are not at hand. PMID- 21534934 TI - Psychiatry and the scientific fallacy. PMID- 21534935 TI - Optimizing clozapine treatment. AB - OBJECTIVE: Clozapine treatment remains the gold standard for treatment-resistant schizophrenia, but treatment with clozapine is associated with several side effects that complicate the use of the drug. This clinical overview aims to provide psychiatrists with knowledge about how to optimize clozapine treatment. Relevant strategies for reducing side-effects and increasing the likelihood of response are discussed. METHOD: Studies of clozapine available in MEDLINE were reviewed. RESULTS: A slow up-titration of clozapine is recommended in order to reach the optimal dosage of clozapine and diminish the risk of dose-dependent side-effects. Particularly, in case of partial response or non-response, the use of therapeutic drug monitoring of clozapine is recommended. Plasma levels above the therapeutic threshold of 350-420 ng/ml are necessary to determine non response to clozapine. To ease the burden of dose-dependent side-effects, dose reduction of clozapine should be tried and combination with another antipsychotic drug may facilitate further dose reduction. For most side-effects, counteracting medication exists. Augmentation with lamotrigine, antipsychotics, or electroconvulsive therapy may be beneficial in case of partial response to clozapine. CONCLUSION: Treatment with clozapine should be optimized in order to increase the rate of response and to minimize side-effects, thus diminishing the risk of discontinuation and psychotic relapse. PMID- 21534937 TI - Variation in the VWF gene in Swedish patients with type 1 von Willebrand Disease. AB - The spectrum of mutations in the von Willebrand factor (VWF) gene in a Swedish type 1 von Willebrand disease (VWD) population was investigated. To gain more knowledge about the dynamics of VWD mutations, the data were analyzed from a population genetics perspective. The VWF gene was resequenced in 54 Swedish patients diagnosed with type 1 VWD. Fifty-five variable sites were located in exons, 10 in the promoter and 38 in introns. The spectrum of mutations was similar to a European study, but included 10 new candidate mutations. The synonymous sites were evenly distributed along the coding sequence, whereas nonsynonymous sites were located into three clusters. Overall, 44% of patients had no mutations or candidate mutations and no promoter haplotype was significantly associated with disease. In 11 patients (20%), more than one mutation or candidate mutation was detected. The allelic identity for the putative disease-causing mutations was approximately 0.1, compatible with an overall disease frequency of 1%. VWF sequences for exon 28 from eight monkey species were compared with the variable positions found in our patients. Positions classified as mutations were overrepresented among sites that were fixed in all eight monkey species. No general increase of the mutation rate was found for the pseudogene region. PMID- 21534938 TI - Selection and mutation for alpha Thalassemia in nonmalarial and malarial environments. AB - alpha thalassemia is the result of the loss of one or both copies of the two human alpha globin genes. alpha thalassemia appears to be the most common monogenic disease in the world and is in high frequency where malaria is, or has been, endemic. In nonmalarial environments, alpha thalassemia is rare and its frequency can be explained by a balance of deletional mutation and purifying selection. In malarial environments, the loss of one or two copies of the four alpha globin genes in normal diploid genotypes confers resistance (lower mortality) to malaria. Fitness estimates from data from Kenyan and Papua New Guinea populations are used to predict the increase in the --alpha haplotype (with one deleted gene). The frequency of double deletions (-- haplotypes) is higher in some Asian populations than that of single deletions. In this case, heterozygotes with normal alphaalpha haplotypes are expected to have the highest fitness. Overall, this population genetic examination provides an evolutionary framework for understanding the worldwide frequency of alpha thalassemia and the deletions that cause it in both nonmalarial and malarial environments. PMID- 21534936 TI - A multinational study of mental disorders, marriage, and divorce. AB - OBJECTIVE: Estimate predictive associations of mental disorders with marriage and divorce in a cross-national sample. METHOD: Population surveys of mental disorders included assessment of age at first marriage in 19 countries (n = 46,128) and age at first divorce in a subset of 12 countries (n = 30,729). Associations between mental disorders and subsequent marriage and divorce were estimated in discrete time survival models. RESULTS: Fourteen of 18 premarital mental disorders are associated with lower likelihood of ever marrying (odds ratios ranging from 0.6 to 0.9), but these associations vary across ages of marriage. Associations between premarital mental disorders and marriage are generally null for early marriage (age 17 or younger), but negative associations come to predominate at later ages. All 18 mental disorders are positively associated with divorce (odds ratios ranging from 1.2 to 1.8). Three disorders, specific phobia, major depression, and alcohol abuse, are associated with the largest population attributable risk proportions for both marriage and divorce. CONCLUSION: This evidence adds to research demonstrating adverse effects of mental disorders on life course altering events across a diverse range of socioeconomic and cultural settings. These effects should be included in considerations of public health investments in preventing and treating mental disorders. PMID- 21534940 TI - Variance estimation for systematic designs in spatial surveys. AB - In spatial surveys for estimating the density of objects in a survey region, systematic designs will generally yield lower variance than random designs. However, estimating the systematic variance is well known to be a difficult problem. Existing methods tend to overestimate the variance, so although the variance is genuinely reduced, it is over-reported, and the gain from the more efficient design is lost. The current approaches to estimating a systematic variance for spatial surveys are to approximate the systematic design by a random design, or approximate it by a stratified design. Previous work has shown that approximation by a random design can perform very poorly, while approximation by a stratified design is an improvement but can still be severely biased in some situations. We develop a new estimator based on modeling the encounter process over space. The new "striplet" estimator has negligible bias and excellent precision in a wide range of simulation scenarios, including strip-sampling, distance-sampling, and quadrat-sampling surveys, and including populations that are highly trended or have strong aggregation of objects. We apply the new estimator to survey data for the spotted hyena (Crocuta crocuta) in the Serengeti National Park, Tanzania, and find that the reported coefficient of variation for estimated density is 20% using approximation by a random design, 17% using approximation by a stratified design, and 11% using the new striplet estimator. This large reduction in reported variance is verified by simulation. PMID- 21534939 TI - Genetic variants associated with Von Willebrand factor levels in healthy men and women identified using the HumanCVD BeadChip. AB - We have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women. The Whitehall II (WHII) study (n= 5592) and the British Women's Heart and Health Study (BWHHS) (n= 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n= 3897) and 1958 Birth Cohort (n= 5048). We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P < 10(-4) . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P= 9.7 * 10( 233) ). The lead variant in the 24 VWF SNPs was rs1063856 (P= 2.3 * 10(-20) ). SNPs at ESR1 (rs6909023) and NRG1(rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels. PMID- 21534941 TI - Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study. AB - This open-label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat shock protein 90 (HSP90) inhibitor tanespimycin (100-340 mg/m(2) )+ bortezomib (0.7-1.3 mg/m(2) ) given on days 1, 4, 8 and 11 in each 21-d cycle. Phase 2 expansion occurred at the highest tested dose of tanespimycin at 340 mg/m(2) and bortezomib at 1.3 mg/m(2) . Seventy-two patients (median age, 60 years) with relapsed or relapsed and refractory multiple myeloma (MM) were enrolled; 63 patients (89%) completed the study. Tanespimycin in combination with bortezomib was well tolerated; few patients experienced significant neutropenia, constipation and anorexia (<10%), and no patients developed severe peripheral neuropathy. Among 67 efficacy evaluable patients, there were 2 (3%) complete responses and 8 (12%) partial responses, for an objective response rate (ORR) of 27%, including 8 (12%) minimal responses. Response rates were highest among bortezomib-naive patients and proved durable in all patient subgroups, including those with bortezomib-refractory disease. Pharmacodynamic analyses indicated that tanespimycin plus bortezomib effectively inhibited the proteasome, as evidenced by decreased 20S proteasome activity, and inhibited HSP90, as reflected by increased HSP70 expression. The results of this study support additional studies of this combination approach in MM. PMID- 21534942 TI - Autoimmune cytopenia in chronic lymphocytic leukaemia: diagnosis and treatment. AB - Autoimmune cytopenia, especially autoimmune haemolytic anaemia (AIHA), appears in 5-10% of patients with chronic lymphocytic leukaemia (CLL). In these patients, the prognosis is not as poor as in those cases in which the cytopenia is due to a massive bone marrow infiltration by the disease, and their treatment requires special considerations. For these reasons, the diagnosis of autoimmune cytopenia should be entertained in any patient with CLL presenting with cytopenia. In patients with autoimmune cytopenia and CLL, treatment is as for idiopathic autoimmune cytopenia, with most patients responding to corticosteroids. For patients not responding to corticosteroids, splenectomy is a reasonable treatment choice. Monoclonal antibodies and thrombopoietin analogues have shown enough activity to support their use, especially within clinical studies, in selected cases not responding to corticosteroids and before splenectomy. In patients with resistant immune cytopenia, the most effective treatment is that of the underlying CLL. Fear of fludarabine-associated AIHA is no longer appropriate in the age of chemo-immunotherapy. Finally, prospective studies are required to better identify the optimal therapy for these patients. PMID- 21534943 TI - 'POP'! The mystery of a skeletal dysplasia vanishes thanks to exome sequencing. PMID- 21534944 TI - Phase analysis identifies compound heterozygous deletions of the PARK2 gene in patients with early-onset Parkinson disease. AB - Exon rearrangements and point mutations are common in PARK2, the most important causative gene of autosomal recessive early-onset Parkinson disease (EOPD). However, gene dosage analysis alone cannot conclusively determine the phase of exon rearrangements and the incidence of molecularly confirmed parkin-type EOPD may be underestimated. To fully characterize the mutation spectrum, we performed sequencing and gene dosage analyses of SNCA, PARK2, PINK1, and PARK7 in 114 unrelated EOPD patients with onset age <=40 years. Mutational phase of exon rearrangements was determined by reverse-transcriptase PCR (RT-PCR) and sequence analysis using a patient's own RNA. Fourteen different PARK2 mutations (3 point mutations plus 11 exon rearrangements) were identified in 18 patients, comprising 1 homozygote (0.9%), 13 compound heterozygotes (11.4%), 3 single heterozygotes (2.6%), and 1 with unknown phase (0.9%). By phase determination, more than 80% (5 of 6) of patients with apparently contiguous multi-exon deletions and 30% (5 of 18) of all PARK2 mutation carriers were additionally diagnosed as compound heterozygotes, respectively. This study shows that compound heterozygous mutations constituted a significant portion of patients with apparently contiguous multi-exon deletions. Phase determination is a prerequisite to molecular diagnosis for autosomal recessive EOPD, especially in subjects with PARK2 exon rearrangements. PMID- 21534945 TI - Molecular testing in congenital adrenal hyperplasia due to 21alpha-hydroxylase deficiency in the era of newborn screening. AB - Newborn screening (NBS) identifies the majority of classical [salt-wasting (SW) and simple-virilizing (SV)] cases of congenital adrenal hyperplasia (CAH) due to 21alpha-hydroxylase (21alpha-OHase) during the first days of life. Diagnosis of classical CAH is confirmed by follow-up serum 17-hydroxyprogesterone and/or the adrenocorticotropin stimulation test; however, neither test definitively distinguishes between the classical subtypes. After confirmation, all newborns are started on hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) treatment. While initiating fludrocortisone treatment in classical CAH patients, independent of subtype and before SW signs or symptoms occur, prevents a life-threatening SW crisis, it may later complicate distinguishing between the classical subtypes. Genotype-phenotype correlations in 21alpha-OHase deficiency are excellent; however, molecular testing is not a regular part of the diagnostic workup. Molecular testing on 39 patients (25 identified by NBS) with an already established diagnosis of CAH identified 11 SW patients (8 identified by NBS) whose mutations suggested further biochemical and clinical reassessment of their subtype. Overall, SW accounted for 57.6% of our classical CAH patients, below the generally accepted figure that >75% of classical CAH are comprised of the SW form. In the era of NBS, molecular testing is a valuable supplemental tool identifying patients who may benefit from reassessment of their salt-retaining ability. PMID- 21534947 TI - STAT signaling in Dictyostelium development. AB - Signal transducers and activators of transcription (STAT) proteins are one of the important mediators of phosphotyrosine-regulated signaling in metazoan cells. These proteins are components of JAK/STAT signal transduction pathways, which regulate immune responses, cell fate, proliferation, cell migration, and programmed cell death in multicellular organisms. The cellular slime mould, Dictyostelium discoideum, is the simplest multicellular organism using molecules homologous to STATs, Dd-STATa-d. The Dd-STATa null mutant displays delayed aggregation, no phototaxis and fails culmination. Here, the functions of Dictyostelium STATs during development and their associated signaling molecules are discussed. PMID- 21534946 TI - Novel TMPRSS3 variants in Pakistani families with autosomal recessive non syndromic hearing impairment. AB - Mutations in the TMPRSS3 gene are known to cause autosomal recessive non syndromic hearing impairment (ARNSHI). After undergoing a genome scan, 10 consanguineous Pakistani families with ARNSHI were found to have significant or suggestive evidence of linkage to the TMPRSS3 region. In order to elucidate if the TMPRSS3 gene is responsible for ARNSHI in these families, the gene was sequenced using DNA samples from these families. Six TMPRSS3 variants were found to cosegregate in 10 families. None of these variants were detected in 500 control chromosomes. Four novel variants, three of which are missense [c.310G>A (p.Glu104Lys), c.767C>T (p.Ala256Val) and c.1273T>C (p.Cys425Arg)] and one nonsense [c.310G>T (p.Glu104Stop)], were identified. The pathogenicity of novel missense variants was investigated through bioinformatics analyses. Additionally, the previously reported deletion c.208delC (p.His70ThrfsX19) was identified in one family and the known mutation c.1219T>C (p.Cys407Arg) was found in five families, which makes c.1219T>C (p.Cys407Arg) as the most common TMPRSS3 mutation within the Pakistani population. Identification of these novel variants lends support to the importance of elements within the low-density lipoprotein receptor A (LDLRA) and serine protease domains in structural stability, ligand binding and proteolytic activity for proper TMPRSS3 function within the inner ear. PMID- 21534948 TI - High prevalence of autonomous aldosterone secretion among patients with essential hypertension. AB - BACKGROUND: Previous studies based on standard endocrine testing have generally shown a low prevalence of primary aldosteronism, a form of autonomous aldosterone secretion (AAS), in hypertensive individuals. The purpose of this case-control study was to evaluate whether use of appropriately defined controls and combined testing reveal previously undetected AAS in hypertensives. MATERIALS AND METHODS: We investigated aldosterone secretion in 180 hypertensives with (n = 44) and without (n = 136) adrenal adenomas on computerized tomography (CT) and 72 matched nonhypertensive individuals with normal adrenal CT. Serum aldosterone and active renin were measured, and the aldosterone/active renin ratio was calculated before and after a modified fludrocortisone-suppression test (FST). In the latter, to eliminate any stimulatory effect of endogenous stress-induced adrenocorticotrophin hormone on aldosterone secretion, we administered 1 mg of dexamethasone on the last day of the classical FST fludrocortisone/dexamethasone suppression test (FDST). RESULTS: Using the 97.5 percentiles of serum aldosterone (74 pM L(-1)) and the aldosterone/renin ratio (32 pM L(-1) mU(-1) L(-1)) values obtained from the controls following the FDST, normal cut-off values indicative of adequate aldosterone suppression were established. Using the combination of these cut-offs, the estimated prevalence of AAS in patients with hypertension was 31%. Multiple linear regression analysis revealed a significant correlation between systolic and/or diastolic arterial blood pressure and the aldosterone value (P < 0.0001 and P < 0.01, respectively) and/or the aldosterone/renin ratio (P < 0.0001 and P < 0.01, respectively), which were obtained following the FDST. CONCLUSIONS: By applying new cut-offs obtained following modification of standard testing, AAS is quite prevalent in hypertensive individuals and correlates highly with arterial blood pressure. This may have relevance for both the aetiology of the hypertension and its optimal therapy. PMID- 21534949 TI - Rationales behind irrationality of decision making in groundwater quality management. AB - This issue paper presents how certain policies regarding management of groundwater quality lead to unexpected and undesirable results, despite being backed by seemingly reasonable assumptions. This happened in part because the so called reasonable decisions were not based on an integrative and quantitative methodology. The policies surveyed here are: (1) implementation of a program for aquifer restoration to pristine conditions followed, after failure, by leaving it to natural attenuation; (2) the "Forget About The Aquifer" (FATA) approach, while ignoring possible damage that contaminated groundwater can inflict on the other environmental systems; (3) groundwater recharge in municipal areas while neglecting the presence of contaminants in the unsaturated zone and conditions exerted by upper impervious surfaces; (4) the Soil Aquifer Treatment (SAT) practice considering aquifers to be "filters of infinite capacity"; and (5) focusing on well contamination vs. aquifer contamination to conveniently defer grappling with the problem of the aquifer as a whole. Possible reasons for the failure of these seemingly rational policies are: (1) the characteristic times of processes associated with groundwater that are usually orders of magnitude greater than the residence times of decision makers in their managerial position; (2) proliferation of improperly trained "groundwater experts" or policymakers with sectoral agendas alongside legitimate differences of opinion among groundwater scientists; (3) the neglect of the cyclic nature of natural phenomena; and (4) ignoring future long-term costs because of immediate costs. PMID- 21534950 TI - The Louisiana gulf coast: a natural laboratory for diverse groundwater studies. PMID- 21534951 TI - Postnatal growth of tracheobronchial airways of Sprague-Dawley rats. AB - Rats are widely used for the studies of pulmonary toxicology in both juveniles and adults. To facilitate such studies, investigators have developed models of lung architecture based on manual or computerized airway measurements. However, postnatal growth of conducting airways of rat lungs has never been reported. In this paper, we present conducting airway architecture statistics for male Sprague Dawley rat lungs at ages 15, 28, 40, and 81 days by analyzing CT images from airway silicon casts. Detailed branching characteristics and intersubject variance are presented. This study shows that (i) airway growth in diameter and length is not linear with age, (ii) growth of airway length is faster than that of diameter during the 15-81-day postnatal period, and (iii) asymmetry in airway diameter (ratio of major to minor daughter diameter) increases with age. PMID- 21534952 TI - Experimental demography and the vital rates of generalist and specialist insect herbivores on native and novel host plants. AB - 1. Colonization success of species when confronted with novel environments is of interest in ecological, evolutionary and conservation contexts. Such events may represent the first step for ecological diversification. They also play an important role in adaptive divergence and speciation. 2. A species that is able to do well across a range of environments has a higher plasticity than one whose success is restricted to a single or few environments. The breadth of environments in which a species can succeed is ultimately determined by the full pattern of its vital rates in each environment. 3. Examples of organisms colonizing novel environments are insect herbivores expanding their diets to novel host plants. One expectation for insect herbivores is that species with specialized diets may display less plasticity when faced with novel hosts than generalist species. 4. We examine this hypothesis for two generalist and two specialist neotropical beetles (genus Cephaloleia: Chrysomelidae) currently expanding their diets from native to novel plants of the order Zingiberales. Using an experimental approach, we estimated changes in vital rates, life-history traits and lifetime fitness for each beetle species when feeding on native or novel host plants. 5. We did not find evidence supporting more plasticity for generalists than for specialists. Instead, we found similar patterns of survival and fecundity for all herbivores. Larvae survived worse on novel hosts; adults survived at least as well or better, but reproduced less on the novel host than on natives. 6. Some of the novel host plants represent challenging environments where population growth was negative. However, in four novel plant-herbivore interactions, instantaneous population growth rates were positive. 7. Positive instantaneous population growth rates during initial colonization of novel host plants suggest that both generalist and specialist Cephaloleia beetles may be pre adapted to feed on some novel hosts. This plasticity in host use is a key factor for successful colonization of novel hosts. Future success or failure in the colonization of these novel hosts will depend on the demographic rates described in this research, natural selection and the evolutionary responses of life history traits in novel environments. PMID- 21534953 TI - Optimizing single DNA molecules manipulation by AFM. AB - Recent progress in single DNA manipulation with atomic force microscope has proved its potential in analysing genetic information at the molecular level instead of macro ensemble approach. However, current manipulation of DNA is mainly carried out by manual operations, which is labour-intensive and time consuming, thus limits the further applications in other fields. In this paper, an optimized DNA manipulation method is successfully established. An image correlation technique is introduced to realize automatic thermal drift compensation. Combined with elaborately designed tip movement control for different manipulation purposes, accurate and efficient DNA manipulations such as dissection, folding and picking are realized. The efficiency has been improved for an order of magnitude compare to manual manipulations, whereas the performance is demonstrated to be the same. This newly developed method has shed light on high-efficiency nanomanipulation of small molecules with complex structures, and thus provides the possibility of deeply understanding the intrinsic properties of single biomolecules. PMID- 21534954 TI - Crystalline ice as a cryoprotectant: theoretical calculation of cooling speed in capillary tubes. AB - It is generally assumed that vitrification of both cells and the surrounding medium provides the best preservation of ultrastructure of biological material for study by electron microscopy. At the same time it is known that the cell cytoplasm may provide substantial cryoprotection for internal cell structure even when the medium crystallizes. Thus, vitrification of the medium is not essential for good structural preservation. By contrast, a high cooling rate is an essential factor for good cryopreservation because it limits phase separation and movement of cellular components during freezing, thus preserving the native-like state. Here we present calculations of freezing rates that incorporate the effect of medium crystallization, using finite difference methods. We demonstrate that crystallization of the medium in capillary tubes may increase the cooling rate of suspended cells by a factor of 25-300 depending on the distance from the centre. We conclude that crystallization of the medium, for example due to low cryoprotectant content, may actually improve cryopreservation of some samples in a near native state. PMID- 21534955 TI - Aryl hydrocarbon receptor-dependent induction of apoptosis by 2,3,7,8 tetrachlorodibenzo-p-dioxin in cerebellar granule cells from mouse. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a prototypical environmental contaminant with neurotoxic properties that alters neurodevelopment and behavior. TCDD is a ligand of the aryl hydrocarbon receptor (AhR), which is a key signaling molecule to fully understand the toxic and carcinogenic properties of dioxin. Much effort is underway to unravel the molecular mechanisms and the signaling pathways involved in TCDD-induced neurotoxicity, and to define its molecular targets in neurons. We have used cerebellar granule cells (CGC) from wild-type (AhR+/+) and AhR-null (AhR-/-) mice to characterize the cell death that takes place in neurons after TCDD toxicity. TCDD induced cell death in CGC cultures from wild-type mice with an EC(50) of 127+/-21 nM. On the contrary, when CGC neurons from AhR-null mice were treated with TCDD no significant cell death was observed. The role of AhR in TCDD-induced death was further assessed by using the antagonists resveratrol and alpha-naphtoflavone, which readily protected against TCDD toxicity in AhR+/+ CGC cultures. AhR+/+ CGC cultures treated with TCDD showed nuclear fragmentation, DNA laddering, and increased caspase 3 activity, similarly to what was found by the use of staurosporine, a well-established inducer of apoptosis. Finally, the AhR pathway was active in CGC because TCDD could induce the expression of the target gene cytochrome P450 1A2 in AhR+/+ CGC cultures. All together these results support the hypothesis that TCDD toxicity in CGC neurons involves the AhR and that it takes place mainly through an apoptotic process. AhR could be then considered a novel target in neurotoxicity and neurodegeneration whose down-modulation could block certain xenobiotic-related adverse effects in CNS. PMID- 21534956 TI - Dopamine release from serotonergic nerve fibers is reduced in L-DOPA-induced dyskinesia. AB - L-DOPA is the most commonly used treatment for symptomatic control in patients with Parkinson's disease. Unfortunately, most patients develop severe side effects, such as dyskinesia, upon chronic l-DOPA treatment. The patophysiology of dyskinesia is unclear; however, involvement of serotonergic nerve fibers in converting l-DOPA to dopamine has been suggested. Therefore, potassium-evoked dopamine release was studied after local application of l-DOPA in the striata of normal, dopamine- and dopamine/serotonin-lesioned l-DOPA naive, and dopamine denervated chronically l-DOPA-treated dyskinetic rats using in vivo chronoamperometry. The results revealed that local l-DOPA administration into normal and intact hemisphere of dopamine-lesioned l-DOPA naive animals significantly increased the potassium-evoked dopamine release. l-DOPA application also increased the dopamine peak amplitude in the dopamine-depleted l-DOPA naive striatum, although these dopamine levels were several-folds lower than in the normal striatum, whereas no increased dopamine release was found in the dopamine/serotonin-denervated striatum. In dyskinetic animals, local l-DOPA application did not affect the dopamine release, resulting in significantly attenuated dopamine levels compared with those measured in l-DOPA naive dopamine denervated striatum. To conclude, l-DOPA is most likely converted to dopamine in serotonergic nerve fibers in the dopamine-depleted striatum, but the dopamine release is several-fold lower than in normal striatum. Furthermore, l-DOPA loading does not increase the dopamine release in dyskinetic animals as found in l-DOPA naive animals, despite similar density of serotonergic innervation. Thus, the dopamine overflow produced from the serotonergic nerve fibers appears not to be the major cause of dyskinetic behavior. PMID- 21534957 TI - Microdialysis and mass spectrometric monitoring of dopamine and enkephalins in the globus pallidus reveal reciprocal interactions that regulate movement. AB - Pallidal dopamine, GABA and the endogenous opioid peptides enkephalins have independently been shown to be important controllers of sensorimotor processes. Using in vivo microdialysis coupled to liquid chromatography-mass spectrometry and a behavioral assay, we explored the interaction between these three neurotransmitters in the rat globus pallidus. Amphetamine (3 mg/kg i.p.) evoked an increase in dopamine, GABA and methionine/leucine enkephalin. Local perfusion of the dopamine D(1) receptor antagonist SCH 23390 (100 MUM) fully prevented amphetamine stimulated enkephalin and GABA release in the globus pallidus and greatly suppressed hyperlocomotion. In contrast, the dopamine D(2) receptor antagonist raclopride (100 MUM) had only minimal effects suggesting a greater role for pallidal D(1) over D(2) receptors in the regulation of movement. Under basal conditions, opioid receptor blockade by naloxone perfusion (10 MUM) in the globus pallidus stimulated GABA and inhibited dopamine release. Amphetamine stimulated dopamine release and locomotor activation were attenuated by naloxone perfusion with no effect on GABA. These findings demonstrate a functional relationship between pallidal dopamine, GABA and enkephalin systems in the control of locomotor behavior under basal and stimulated conditions. Moreover, these findings demonstrate the usefulness of liquid chromatography-mass spectrometry as an analytical tool when coupled to in vivo microdialysis. PMID- 21534958 TI - gamma-glutamylcysteine ethyl ester protects cerebral endothelial cells during injury and decreases blood-brain barrier permeability after experimental brain trauma. AB - Oxidative stress is a pathway of injury that is common to almost all neurological conditions. Hence, methods to scavenge radicals have been extensively tested for neuroprotection. However, saving neurons alone may not be sufficient in treating CNS disease. In this study, we tested the cytoprotective actions of the glutathione precursor gamma-glutamylcysteine ethyl ester (GCEE) in brain endothelium. First, oxidative stress was induced in a human brain microvascular endothelial cell line by exposure to H(2)O(2). Addition of GCEE significantly reduced formation of reactive oxygen species, restored glutathione levels which were reduced in the presence of H(2)O(2), and decreased cell death during H(2)O(2)-mediated injury. Next, we asked whether GCEE can also protect brain endothelial cells against oxygen-glucose deprivation (OGD). As expected, OGD disrupted mitochondrial membrane potentials. GCEE was able to ameliorate these mitochondrial effects. Concomitantly, GCEE significantly decreased endothelial cell death after OGD. Lastly, our in vivo experiments using a mouse model of brain trauma show that post-trauma (10 min after controlled cortical impact) administration of GCEE by intraperitoneal injection results in a decrease in acute blood-brain barrier permeability. These data suggest that the beneficial effects of GCEE on brain endothelial cells and microvessels may contribute to its potential efficacy as a neuroprotective agent in traumatic brain injury. PMID- 21534959 TI - Dopamine-dependent ectodomain shedding and release of epidermal growth factor in developing striatum: target-derived neurotrophic signaling (Part 2). AB - Epidermal growth factor (EGF) and structurally related peptides promote neuronal survival and the development of midbrain dopaminergic neurons; however, the regulation of their production has not been fully elucidated. In this study, we found that the treatment of striatal cells with dopamine agonists enhances EGF release both in vivo and in vitro. We prepared neuron-enriched and non-neuronal cell-enriched cultures from the striatum of rat embryos and challenged those with various neurotransmitters or dopamine receptor agonists. Dopamine and a dopamine D(1) -like receptor agonist (SKF38393) triggered EGF release from neuron-enriched cultures in a dose-dependent manner. A D(2) -like agonist (quinpirole) increased EGF release only from non-neuronal cell-enriched cultures. The EGF release from striatal neurons and non-neuronal cells was concomitant with ErbB1 phosphorylation and/or with the activation of a disintegrin and metalloproteinase and matrix metalloproteinase. The EGF release from neurons was attenuated by an a disintegrin and metalloproteinase/matrix metalloproteinase inhibitor, GM6001, and a calcium ion chelator, BAPTA/AM. Transfection of cultured striatal neurons with alkaline phosphatase-tagged EGF precursor cDNA confirmed that dopamine D(1) -like receptor stimulation promoted both ectodomain shedding of the precursor and EGF release. Therefore, the activation of striatal dopamine receptors induces shedding and release of EGF to provide a retrograde neurotrophic signal to midbrain dopaminergic neurons. PMID- 21534961 TI - Stability and change self-integration for negative events: the role of listener responsiveness and elaboration. AB - Self-integration, critical to identity, is the process of connecting experiences to the self and often occurs as individuals narrate events. Elaboration (Fivush & Nelson, 2006; King & Raspin, 2004; Smyth & Pennebaker, 2008) and listener responsiveness (Pasupathi & Rich, 2005) correlate with better self-integration, but these variables are seldom disentangled. In this set of studies, we examine how individuals construct connections between the self and experience for negative events. In Study 1, 90 friendship pairs discussed a negative event. Stability self-integration, change self-integration, elaboration, and listener responsiveness were assessed independently of the narrative. Elaboration and listener responsiveness contributed independently and positively to change self integration but were unrelated to stability self-integration. Study 2 manipulated listener responsiveness and added preconversation measures of self-integration. Study 1 results were replicated, except that elaboration failed to achieve significance, and a significant interaction between initial change self integration and listener responsiveness was found. Implications are discussed. PMID- 21534962 TI - Social anxiety as a basis for friendship selection and socialization in adolescents' social networks. AB - Socially anxious children and adolescents have previously been found to have friends with similarly socially anxious, withdrawn behavioral characteristics. How peers might socialize social anxiety over time has, however, not been thoroughly investigated. We examined this in a sample of 834 youths (339 girls and 495 boys; M=14.29), followed for 3 years. We used the social network analysis software SIENA to analyze the data. The results showed that youths who were socially anxious were less popular and chose fewer friends in the network. They also tended to choose friends who were socially anxious, and over time they influenced each other into becoming more socially anxious--over and above other effects. Finally, girls' social anxiety was more influenced than boys' by their friends' social anxiety levels. The results showed the significance of looking at socially anxious youths' friendships over time and embedded in social networks. PMID- 21534960 TI - Fyn kinase regulates the association between amyloid precursor protein and Dab1 by promoting their localization to detergent-resistant membranes. AB - The adaptor protein Disabled1 (Dab1) interacts with amyloid precursor protein (APP) and decreases its pathological processing, an effect mediated by Fyn tyrosine kinase. Fyn is highly enriched in lipid rafts, a major site of pathological APP processing. To investigate the role of Fyn in the localization and phosphorylation of APP and Dab1 in lipid rafts, we isolated detergent resistant membrane (DRM) fractions from wild-type and Fyn knock-out mice. In wild type mice, all of the Fyn kinase, 17% of total APP, and 33% of total Dab1 were found in DRMs. Nearly all of the tyrosine phosphorylated forms of APP and Dab1 were in DRMs. APP and Dab1 co-precipitated both in and out of DRM fractions, indicating an association that is independent of subcellular localization. Fyn knock-out mice had decreased APP, Dab1, and tyrosine-phosphorylated Dab1 in DRMs but increased co-immunoprecipitation of DRM APP and Dab1. Expression of phosphorylation deficient APP or Dab1 constructs revealed that phosphorylation of APP increases, whereas phosphorylation of Dab1 decreases, the interaction between APP and Dab1. Consistent with these observations, Reelin treatment led to increased Dab1 phosphorylation and decreased association between APP and Dab1. Reelin also caused increased localization of APP and Dab1 to DRMs, an effect that was not seen in Fyn knock-out neurons. These findings suggest that Reelin treatment promotes the localization of APP and Dab1 to DRMs, and affects their phosphorylation by Fyn, thus regulating their interaction. PMID- 21534963 TI - Personality vulnerabilities to psychopathology: relations between trait structure and affective-cognitive processes. AB - The present research examined (a) the relations among various affective-cognitive vulnerabilities to psychopathology, (b) the relations between vulnerabilities and dispositional traits, and (c) the mediating role of vulnerabilities between dispositional traits and psychopathological symptoms. Self-report questionnaires were administered to two independent samples in Study 1 (total N=274), whereas a longitudinal experience-sampling method was employed in Study 2 (N=100). All samples consisted of college students. Results suggested that affective-cognitive vulnerabilities showed a pattern of intercorrelations consistent with a 2-factor model representing general vulnerability to internalizing and externalizing psychopathology, respectively. The vulnerabilities also revealed common and unique aspects when mapped onto the trait structure represented by the Five Factor Model. Most important, affective-cognitive vulnerabilities were found to constitute proximal-specific mechanisms that mediated between distal-broad dispositional vulnerabilities, such as Neuroticism, and different psychopathological symptoms. Our data support a model of personality psychopathology relations that benefits from an integration of both the dispositional trait and social-cognitive approaches. PMID- 21534964 TI - Mate retention tactics in Spain: personality, sex differences, and relationship status. AB - Mate retention is an important problem in romantic relationships because of mate poachers, infidelity, and the risk of outright defection. The current study (N=892) represents the first study of mate retention tactics conducted in Spain. We tested hypotheses about the effects of gender, relationship commitment status, and personality on mate retention tactics. Women and men differed in the use of resource display, appearance enhancement, intrasexual violence, and submission/self-abasement as mate retention tactics. Those in more committed relationships reported higher levels of resource display, appearance enhancement, love, and verbal signals of possession. Those in less committed relationships more often reported intentionally evoking jealousy in their partner as a mate retention tactic. Personality characteristics, particularly Neuroticism and Agreeableness, correlated in coherent ways with mate retention tactics, supporting two evolution-based hypotheses. Discussion focuses on the implications, future research directions, and interdisciplinary syntheses emerging between personality and social psychology and evolutionary psychology. PMID- 21534965 TI - Intimacy in young adults' narratives of romance and friendship predicts Eriksonian generativity: a mixed method analysis. AB - A quantitative and qualitative study tested Erikson's ego developmental hypotheses regarding the positive relationship between generativity and intimacy. At age 26, participants (N = 100) told 2 stories about "relationship-defining moments," one about a romantic partner, and another about a same-sex friend. Levels of relationship intimacy were coded from these narratives. "True love" and "true friendship" themes arose as the most prototypical, highly intimate stories. Romantic intimacy and friendship intimacy as coded from narratives each contributed uniquely to the prediction of generative concern; as intimacy in each domain increased, so did generative concern. This relationship remained statistically significant, even when controlling for gender, current romantic relationship status, subjective well-being, optimism, and depressive symptoms. Results suggest that our "relationship-defining moment" narrative task is a useful tool for examining development in emerging adulthood and that intimacy may be an important precursor to generative concern in early adulthood, consistent with Erikson's model. PMID- 21534966 TI - The lower subjective social status of neurotic individuals: multiple pathways through occupational prestige, income, and illness. AB - Subjective social status seems to predict health outcomes, above and beyond the contribution of objective status. The present hypothesis was that neuroticism predicts subjective status and does so via the influence of neuroticism on objective status (i.e., education, occupation, and income), self-perceived illness, and greater negative affect. In turn, lower subjective status would be associated with more severe self-perceived illness. Older adults (N=341) shortly after retirement completed measures of neuroticism, attainment in education, occupation, and salary, and over 2 subsequent years, they completed measures of current subjective status, self-reported illness, and current negative affect. As hypothesized, greater neuroticism was associated with lower subjective status via lower objective status and more severe self-reported illness. However, current negative affect was not associated with subjective status, and subjective status did not predict future poorer subjective health. PMID- 21534967 TI - A longitudinal analysis of self-regulation and well-being: avoidance personal goals, avoidance coping, stress generation, and subjective well-being. AB - We conducted 2 longitudinal meditational studies to test an integrative model of goals, stress and coping, and well-being. Study 1 documented avoidance personal goals as an antecedent of life stressors and life stressors as a partial mediator of the relation between avoidance goals and longitudinal change in subjective well-being (SWB). Study 2 fully replicated Study 1 and likewise validated avoidance goals as an antecedent of avoidance coping and avoidance coping as a partial mediator of the relation between avoidance goals and longitudinal change in SWB. It also showed that avoidance coping partially mediates the link between avoidance goals and life stressors and validated a sequential meditational model involving both avoidance coping and life stressors. The aforementioned results held when controlling for social desirability, basic traits, and general motivational dispositions. The findings are discussed with regard to the integration of various strands of research on self-regulation. PMID- 21534968 TI - The statistical mechanics of community assembly and species distribution. AB - * Theoretically, communities at or near their equilibrium species number resist entry of new species. Such 'biotic resistance' recently has been questioned because of successful entry of alien species into diverse natural communities. * Data on 10,409 naturalizations of 5350 plant species over 16 sites dispersed globally show exponential distributions both for species over sites and for sites over number of species shared. These exponentials signal a statistical mechanics of species distribution, assuming two conditions. First, species and sites are equivalent, either identical ('neutral') or so complex that the chance a species is in the right place at the right time is vanishingly small ('idiosyncratic'); the range of species and sites in our data disallows a neutral explanation. Secondly, the total number of naturalizations is fixed in any era by a 'regulator'. * Previous correlation of species naturalization rates with net primary productivity over time suggests that the regulator is related to productivity. * We conclude that biotic resistance is a moving ceiling, with resistance controlled by productivity. The general observation that the majority of species occur naturally at only a few sites, and only a few species occur at many sites, now has a quantitative (exponential) character, offering the study of species' distributions a previously unavailable rigor. PMID- 21534969 TI - Overexpression of PhEXPA1 increases cell size, modifies cell wall polymer composition and affects the timing of axillary meristem development in Petunia hybrida. AB - * Expansins are cell wall proteins required for cell enlargement and cell wall loosening during many developmental processes. The involvement of the Petunia hybrida expansin A1 (PhEXPA1) gene in cell expansion, the control of organ size and cell wall polysaccharide composition was investigated by overexpressing PhEXPA1 in petunia plants. * PhEXPA1 promoter activity was evaluated using a promoter-GUS assay and the protein's subcellular localization was established by expressing a PhEXPA1-GFP fusion protein. PhEXPA1 was overexpressed in transgenic plants using the cauliflower mosaic virus (CaMV) 35S promoter. Fourier transform infrared (FTIR) and chemical analysis were used for the quantitative analysis of cell wall polymers. * The GUS and GFP assays demonstrated that PhEXPA1 is present in the cell walls of expanding tissues. The constitutive overexpression of PhEXPA1 significantly affected expansin activity and organ size, leading to changes in the architecture of petunia plants by initiating premature axillary meristem outgrowth. Moreover, a significant change in cell wall polymer composition in the petal limbs of transgenic plants was observed. * These results support a role for expansins in the determination of organ shape, in lateral branching, and in the variation of cell wall polymer composition, probably reflecting a complex role in cell wall metabolism. PMID- 21534970 TI - MPK6, sphinganine and the LCB2a gene from serine palmitoyltransferase are required in the signaling pathway that mediates cell death induced by long chain bases in Arabidopsis. AB - Long chain bases (LCBs) are sphingolipid intermediates acting as second messengers in programmed cell death (PCD) in plants. Most of the molecular and cellular features of this signaling function remain unknown. We induced PCD conditions in Arabidopsis thaliana seedlings and analyzed LCB accumulation kinetics, cell ultrastructure and phenotypes in serine palmitoyltransferase (spt), mitogen-activated protein kinase (mpk), mitogen-activated protein phosphatase (mkp1) and lcb-hydroxylase (sbh) mutants. The lcb2a-1 mutant was unable to mount an effective PCD in response to fumonisin B1 (FB1), revealing that the LCB2a gene is essential for the induction of PCD. The accumulation kinetics of LCBs in wild-type (WT) and lcb2a-1 plants and reconstitution experiments with sphinganine indicated that this LCB was primarily responsible for PCD elicitation. The resistance of the null mpk6 mutant to manifest PCD on FB1 and sphinganine addition and the failure to show resistance on pathogen infection and MPK6 activation by FB1 and LCBs indicated that MPK6 mediates PCD downstream of LCBs. This work describes MPK6 as a novel transducer in the pathway leading to LCB-induced PCD in Arabidopsis, and reveals that sphinganine and the LCB2a gene are required in a PCD process that operates as one of the more effective strategies used as defense against pathogens in plants. PMID- 21534971 TI - The sucrose-regulated Arabidopsis transcription factor bZIP11 reprograms metabolism and regulates trehalose metabolism. AB - * The Arabidopsis basic region-leucine zipper transcription factor 11 (bZIP11) is known to be repressed by sucrose through a translational inhibition mechanism that requires the conserved sucrose control peptide encoded by the mRNA leader. The function of bZIP11 has been investigated in over-expression studies, and bZIP11 has been found to inhibit plant growth. The addition of sugar does not rescue the growth inhibition phenotype. Here, the function of the bZIP11 transcription factor was investigated. * The mechanism by which bZIP11 regulates growth was studied using large-scale and dedicated metabolic analysis, biochemical assays and molecular studies. * bZIP11 induction results in a reprogramming of metabolism and activation of genes involved in the metabolism of trehalose and other minor carbohydrates such as myo-inositol and raffinose. bZIP11 induction leads to reduced contents of the prominent growth regulatory molecule trehalose 6-phosphate (T6P). * The metabolic changes detected mimic in part those observed in carbon-starved plants. It is proposed that bZIP11 is a powerful regulator of carbohydrate metabolism that functions in a growth regulatory network that includes T6P and the sucrose non-fermenting-1 related protein kinase 1 (SnRK1). PMID- 21534972 TI - Lichen responses to nitrogen and phosphorus additions can be explained by the different symbiont responses. AB - * Responses to simulated nitrogen (N) deposition with or without added phosphorus (P) were investigated for three contrasting lichen species - the N-sensitive Alectoria sarmentosa, the more N-tolerant Platismatia glauca and the N(2) -fixing Lobaria pulmonaria- in a field experiment. * To examine whether nutrient limitation differed between the photobiont and the mycobiont within the lichen, the biomass responses of the respective bionts were estimated. * The lichenized algal cells were generally N-limited, because N-stimulated algal growth in all three species. The mycobiont was P-limited in one species (A. sarmentosa), but the growth response of the mycobionts was complex, as fungal growth is also dependent on a reliable carbon export from the photobiont, which may have been the reason for the decrease of the mycobiont with N addition in P. glauca. * Our findings showed that P availability was an important factor when studying effects of N deposition, as P supply can both mitigate and intensify the negative effects of N on epiphytic lichens. PMID- 21534973 TI - Rice A20/AN1 zinc-finger containing stress-associated proteins (SAP1/11) and a receptor-like cytoplasmic kinase (OsRLCK253) interact via A20 zinc-finger and confer abiotic stress tolerance in transgenic Arabidopsis plants. AB - * The inbuilt mechanisms of plant survival have been exploited for improving tolerance to abiotic stresses. Stress-associated proteins (SAPs), containing A20/AN1 zinc-finger domains, confer abiotic stress tolerance in different plants, however, their interacting partners and downstream targets remain to be identified. * In this study, we have investigated the subcellular interactions of rice SAPs and their interacting partner using yeast two-hybrid and fluorescence resonance energy transfer (FRET) approaches. Their efficacy in improving abiotic stress tolerance was analysed in transgenic Arabidopsis plants. Regulation of gene expression by genome-wide microarray in transgenics was used to identify downstream targets. * It was found that the A20 domain mediates the interaction of OsSAP1 with self, its close homolog OsSAP11 and a rice receptor-like cytoplasmic kinase, OsRLCK253. Such interactions between OsSAP1/11 and with OsRLCK253 occur at nuclear membrane, plasma membrane and in nucleus. Functionally, both OsSAP11 and OsRLCK253 could improve the water-deficit and salt stress tolerance in transgenic Arabidopsis plants via a signaling pathway affecting the expression of several common endogenous genes. * Components of a novel stress-responsive pathway have been identified. Their stress-inducible expression provided the protection against yield loss in transgenic plants, indicating the agronomic relevance of OsSAP11 and OsRLCK253 in conferring abiotic stress tolerance. PMID- 21534974 TI - A new naturally derived photosensitizer and its phototoxicity on head and neck cancer cells. AB - In our screening for photosensitizers from natural resources, 15(1) hydroxypurpurin-7-lactone ethyl methyl diester (compound 1) was isolated for the first time from an Araceae plant. To evaluate the efficacy of compound 1 as a photosensitizer for head and neck cancers, compound 1 was studied in reference to a known photosensitizer pheophorbide-a (Pha), in terms of photophysical properties, singlet oxygen generation and in in vitro experiments (intracellular uptake and phototoxicity assays) in two oral (HSC2 and HSC3) and two nasopharyngeal (HK1 and C666-1) cancer cell lines. In this study, compound 1 exhibited higher intracellular uptake over 24 h compared with Pha in both HSC3 and HK1 cells. When activated by >=4.8 J cm(-2) of light, compound 1 was slightly more potent as a photosensitizer than Pha by consistently having marginally lower IC(50) values across different cell lines. In flow cytometry experiments to study the mechanism of photoactivated cell death in HSC3, compound 1 was observed to induce more pronounced apoptosis compared with Pha, which may have been driven by the transient G(2)/M cell cycle block which was also observed. These promising results on compound 1 warrant its further investigation as a clinically useful photodynamic therapy agent for head and neck cancer. PMID- 21534975 TI - Photoprotective effects of methoxycinnamidopropyl polysilsesquioxane. AB - A new sunscreen ingredient, methoxycinnamidopropyl polysilsesquioxane (MCP-PSQ), which contains an UV-absorbing p-methoxycinnamoyl group, has been developed synthetically and evaluated using in vitro and in vivo approaches. Previous studies revealed that MCP-PSQ has a raising or boosting effect on the sun protection factor (SPF) of other sunscreen agents. In this study, we demonstrated that MCP-PSQ, an organic/inorganic hybrid compound, has photoprotective effects for human fibroblasts, and for hairless mouse and human skin. MCP-PSQ increases cell viability and suppresses the expression of p53 protein in fibroblasts after UV exposure. In addition, the numbers of sunburn cells and mast cells are reduced by topical application of MCP-PSQ on hairless mouse skin after UV irradiation. A 10% MCP-PSQ cream has higher and similar effects on SPF values for human skin compared to 5% titanium dioxide (TiO(2)) and 5% ethylhexyl methoxycinnamate (EHMC), respectively. The SPF value obtained using the MCP-PSQ cream did not drop after UV irradiation of the cream itself. However, higher dose of UV irradiation is required to guarantee the stability or photostability of the formulation. Further, there were no side effects such as erythema, edema, itch or tingling, suggesting that MCP-PSQ is a good sunscreen agent. PMID- 21534976 TI - Vitamin D status of adults from tropical Australia determined using two different laboratory assays: implications for public health messages. AB - We measured serum 25 hydroxyvitamin D [25(OH)D] levels of ambulatory adults in tropical Australia to determine whether it is appropriate to continue promoting sun-safety in this population. In August 2006 (winter), self-administered questionnaires were completed by 145 Meals-on-Wheels volunteers (49.3% male; mean age 57.8 +/- 14.7 years; 76.6% response) from Townsville, Queensland (Latitude 19(o) S). Serum 25(OH)D was analyzed using two common assays. Mean levels were 68.3 (SD +/- 18.7; range 26-142) by DiaSorin Radioimmunoassay and 83.0 (SD +/- 30.8; range 30-184) by DiaSorin Liaison(r) one. No participants were 25(OH)D deficient (<25 nmol L(-1)). Nine participants (6.2%) had 25(OH)D levels between 25 and 50 nmol L(-1) (insufficient), by both methods (seven with a BMI >= 25). Twenty-eight participants (19.3%) had one result in the insufficient range and the other in the adequate range. Thus, almost all of these free-living adults in tropical Australia had adequate vitamin D levels at the end of winter. There was poor agreement between the two 25(OH)D assays. These results suggest it is appropriate to continue promoting sun-safe messages to the ambulatory Caucasian adult population of North Queensland, which has an extremely high incidence of skin cancer. The lack of agreement between the two assays is a concern. Few doctors are aware of this measurement issue. PMID- 21534977 TI - The impact of long-term water stress on relative growth rate and morphology of needles and shoots of Metasequoia glyptostroboides seedlings: research toward identifying mechanistic models. AB - Leaf morphology in the upper canopy of trees tends to be different from that lower down. The effect of long-term water stress on leaf growth and morphology was studied in seedlings of Metasequoia glyptostroboides to understand how tree height might affect leaf morphology in larger trees. Tree height increases water stress on growing leaves through increased hydraulic resistance to water flow and increased gravitational potential, hence we assume that water stress imposed by soil dehydration will have an effect equivalent to stress induced by height. Seedlings were subjected to well-watered and two constant levels of long-term water stress treatments. Drought treatment significantly reduced final needle count, area and mass per area (leaf mass area, LMA) and increased needle density. Needles from water-stressed plants had lower maximum volumetric elastic modulus (epsilon(max)), osmotic potential at full turgor (Psi100(pi)) (and at zero turgor (Psi0(pi)) (than those from well-watered plants. Palisade and spongy mesophyll cell size and upper epidermal cell size decreased significantly in drought treatments. Needle relative growth rate, needle length and cell sizes were linear functions of the daily average water potential at the time of leaf growth (r2 0.88-0.999). We conclude that water stress alone does mimic the direction and magnitude of changes in leaf morphology observed in tall trees. The results are discussed in terms of various models for leaf growth rate. PMID- 21534978 TI - Genome-wide transcriptional changes and defence-related chemical profiling of rice in response to infestation by the rice striped stem borer Chilo suppressalis. AB - How rice defends itself against pathogen infection is well documented, but little is known about how it defends itself against herbivore attack. We measured changes in the transcriptome and chemical profile of rice when the plant is infested by the striped stem borer (SSB) Chilo suppressalis. Infestation by SSBs resulted in changes in the expression levels of 4545 rice genes; this number accounts for about 8% of the genome and is made up of 18 functional groups with broad functions. The largest group comprised genes involved in metabolism, followed by cellular transport, transcription and cellular signaling. Infestation by SSBs modulated many genes responsible for the biosynthesis of plant hormones and plant signaling. Jasmonic acid (JA), salicylic acid (SA) and ethylene were the major hormones that shaped the SSB-induced defence responses of rice. Many secondary signal transduction components, such as those involved in Ca2+ signaling and G-protein signaling, receptor and non-receptor protein kinases, and transcription factors were involved in the SSB-induced responses of rice. Photosynthesis and ATP synthesis from photophosphorylation were restricted by SSB feeding. In addition, SSB infestation induced the accumulation of defence compounds, including trypsin proteinase inhibitors (TrypPIs) and volatile organic compounds. These results demonstrate that SSB-induced defences required rice to reconfigure a wide variety of its metabolic, physiological and biochemical processes. PMID- 21534979 TI - Using the Job Demands-Resources model to investigate risk perception, safety climate and job satisfaction in safety critical organizations. AB - Using the Job Demands-Resources model (JD-R) as a theoretical framework, this study investigated the relationship between risk perception as a job demand and psychological safety climate as a job resource with regard to job satisfaction in safety critical organizations. In line with the JD-R model, it was hypothesized that high levels of risk perception is related to low job satisfaction and that a positive perception of safety climate is related to high job satisfaction. In addition, it was hypothesized that safety climate moderates the relationship between risk perception and job satisfaction. Using a sample of Norwegian offshore workers (N = 986), all three hypotheses were supported. In summary, workers who perceived high levels of risk reported lower levels of job satisfaction, whereas this effect diminished when workers perceived their safety climate as positive. Follow-up analyses revealed that this interaction was dependent on the type of risks in question. The results of this study supports the JD-R model, and provides further evidence for relationships between safety related concepts and work-related outcomes indicating that organizations should not only develop and implement sound safety procedures to reduce the effects of risks and hazards on workers, but can also enhance other areas of organizational life through a focus on safety. PMID- 21534980 TI - Social skills in women with Turner Syndrome. AB - The aim of this study was to evaluate the performance of a group of women with Turner Syndrome (TS) in interpersonal situations where several social skills were required, and to compare the results with unaffected sisters. Fifty-two TS females aged 15-35 years and 33 sisters aged 16-43 were evaluated using Del Prette Social Skills Inventory (SSI) and individual interviews. Thirty mothers to subjects and sisters answered questionnaires. It was found that TS girls' performance in SSI was as good as their sisters' and even better in meeting new people and facing unknown situations (p = 0.020). Older TS women scored better than younger ones, differently from their sisters. There were no significant correlations between total score of TS women and their age at diagnosis, time of follow-up and height z-score. Mothers reported having more problems with TS girls than with sisters. Although TS girls demonstrated having social difficulties, just a few of them spontaneously complained about interpersonal problems in the interview. Results suggest that social difficulties may not cause TS girls major problems nor make them unhappy with their social lives, and/or TS girls may not be able to perceive their own difficulties. Good performance in SSI also suggests that TS girls can identify adequate skills in presented situations and answer in a way to obtain good scores, but they may not necessarily use their skills due to other factors like anxiety and shyness. They may also have a tendency to answer SSI in a way they consider socially desirable, masking their real difficulties. PMID- 21534981 TI - Improved safety for young whole blood donors with new selection criteria for total estimated blood volume. AB - BACKGROUND: Young age, first-time donation status, and estimated blood volume (EBV) are leading determinants of syncopal complications after whole blood donation. We evaluated a multifaceted safety initiative and more restrictive selection criteria for whole blood donation by individuals younger than 19 years. STUDY DESIGN AND METHODS: Measures introduced over 2 years addressed donor education, drive environment and supervision, and new eligibility criteria for EBV of 3.5 L or more based on height, weight, and sex for individuals younger than 19 years. Presyncopal and syncopal reactions after whole blood donation during the school year in the baseline, transitional (2008), and full implementation (2009) periods were evaluated. RESULTS: Young donors (16- to 18 years-olds) gave 754,402 and 710,922 whole blood donations in the 2008 and 2009 school years accounting for 16% of the total collections in both 9-month study periods. The new selection criteria were associated with a significant reduction in the reaction rates among 16- to 18-year-olds. Sixteen-year-old donors had the greatest decrease in 2009 compared to baseline for presyncopal reactions (10.5% vs. 7.3%; odds ratio [OR], 0.67; 95% confidence interval [CI], 0.65-0.69) and syncope (43.1 vs. 37.1 per 10,000 donations; OR, 0.86; 95% CI, 0.77-0.96). Donor subgroup analysis by sex, age, and donation status demonstrated that age-related differences in reaction rates were eliminated in 2009. CONCLUSION: The safety initiative with new selection criteria for EBV led to decreased complications among donors 16 to 18 years old, such that the risk for 16-year-olds was no longer different from that observed for 19-year-olds in the analysis stratified by age, sex, and donation status. PMID- 21534982 TI - Net haemoglobin increase from reinfusion of refrigerated vs. frozen red blood cells after autologous blood transfusions. AB - BACKGROUND AND OBJECTIVES Two main blood storage procedures can be used for storing red blood cells: refrigeration and freezing. Nevertheless, the efficiency of these procedures measured as the increase in haemoglobin after reinfusion compared with baseline has never been examined. The main objective was to examine which storage procedure yielded the largest increase in circulating haemoglobin after reinfusion compared to baseline. MATERIALS AND METHODS Equal volumes of blood from 15 men were withdrawn and stored either frozen or refrigerated as packed red blood cells. Serial measures of circulating haemoglobin by carbon monoxide rebreathing provided an opportunity to monitor recovery from anaemia, as well as the net increase in circulating haemoglobin after transfusion. RESULTS The post-thaw yield of haemoglobin in the bags was 72% after refrigerated storage compared with only 52% after freezing. Nevertheless, frozen storage allowed haemoglobin to fully recover before reinfusion, while the haemoglobin was 10% lower in the refrigerated group compared with baseline. After reinfusion, the haemoglobin levels were 11.5% higher than the baseline values in the group reinfused with frozen blood, while for the refrigerated group, haemoglobin levels were only 5.2% higher than baseline. CONCLUSION The relatively larger recovery from anaemia in the frozen group during storage more than compensated for the larger loss of haemoglobin during freezing and resulted in a larger net gain in haemoglobin. Based on the average 23 g per week recovery of haemoglobin, extending refrigerated storage to 7-8 weeks may yield sufficient time for patients to fully replenish harvested haemoglobin from three bags of blood without reliance on frozen storage of RBC. PMID- 21534983 TI - In vitro quality of platelets during prolonged storage after washing with three platelet additive solutions. AB - BACKGROUND AND OBJECTIVES: Patients with anaphylactic transfusion reactions require washed platelet concentrates (PCs) for subsequent platelet (PLT) transfusions. New PLT additive solutions (PASs) contain substances that might be beneficial for the preservation of PLT function during storage. This study compares the quality of PLTs washed and stored with T-Sol, Composol or SSP+. STUDY DESIGN AND METHODS: Fifteen buffy coats were pooled and divided into three parts. PCs with 30% plasma and 70% PAS (T-Sol, Composol or SSP+) were prepared. Washing was performed on day 5 of storage. Ten PCs were prepared and washed with each PAS. In vitro variables including haemostatic function (clotting time and clot retraction) were analysed on day 5 before, directly after and up to 2 days after washing. RESULTS: Swirling was well preserved, and pH was within acceptable limits (6.4-7.4) during storage for all PASs. The PLT number was reduced by washing for all PASs, and T-Sol PCs had a further decrease during storage. PLTs in T-Sol were spontaneously more activated and had lower capacity to respond to an agonist than Composol or SSP+ PLTs. The haemostatic function was only slightly changed by washing and during postwashing storage. CONCLUSION: PLTs washed with T-Sol, Composol or SSP+ had good in vitro quality for two days after washing despite absence of glucose. PLTs in T-Sol were more affected by the washing procedure and subsequent storage than Composol or SSP+ PLTs as judged by higher spontaneous activation. PMID- 21534984 TI - A spatial regression analysis of German community characteristics associated with voluntary non-remunerated blood donor rates. AB - BACKGROUND AND OBJECTIVES: Previous studies have shown substantial geographical variation in blood donation within developed countries. To understand this issue better, we identified community characteristics associated with blood donor rates in German municipalities in an ecological analysis. MATERIALS AND METHODS: We calculated an aggregated rate of voluntary blood donors from each of 1533 municipalities in south-west Germany in 2007 from a database of the German Red Cross Blood Service. A multiple linear regression model estimated the association between the municipality-specific donor rate and several community characteristics. Finally, a spatial lag regression model was used to control for spatial autocorrelation that occurs when neighbouring units are related to each other. RESULTS: The spatial lag regression model showed that a relatively larger population, a higher percentage of inhabitants older than 30 years, a higher percentage of non-German citizens and a higher percentage of unemployed persons were associated with lower municipality-specific donor rates. Conversely, a higher donor rate was correlated with higher voter turnout, a higher percentage of inhabitants between 18 and 24 years and more frequent mobile donation sites. CONCLUSIONS: Blood donation appears to be a highly clustered regional phenomenon, suggesting the need for regionally targeted recruiting efforts and careful consideration of the value of mobile donation sites. Our model further suggests that municipalities with a decreasing percentage of 18- to 24-year-olds and an increasing percentage of older inhabitants may experience substantial declines in future blood donations. PMID- 21534985 TI - Dissociation of Pe and ERN/Ne in the conscious recognition of an error. AB - We evaluated the relationship between conscious awareness and the ERN/Ne and Pe in a digit entering task. On each trial, participants rated the accuracy of their responses on a three-point scale (incorrect, unsure, correct). The ERN/Ne was present on incorrect trials judged as incorrect. The Pe was evident on the same trials but also on correct and incorrect trials judged as unsure. We propose that the ERN/Ne occurs when there is an incorrect execution of a correct motor plan and the representation of the correct response is available for comparison with the actual response. The mismatch information that results from this comparison can be transferred to the Pe process and conscious awareness. However, the Pe process and conscious awareness do not only depend on this transfer of information from the ERN/Ne process. The Pe also occurs when there is uncertainty about the correctness of the motor plan, whether or not the plan is, in fact, correct. PMID- 21534986 TI - Volitional saccades and attentional mechanisms in schizophrenia patients and healthy control subjects. AB - Schizophrenia (SZ) patients showed increased volitional saccade latencies, suggesting deficient volitional initiation of action. Yet increased volitional saccade latencies may also result from deficits in attention shifts. To dissociate attention shifting and saccade initiation, we asked 25 SZ patients and 25 healthy subjects to make saccades toward newly appearing (onset) targets and toward the loci of disappearing (offset) targets. Similar onsets and offsets were also used as attention cues in a Posner-type manual task. As expected, onsets and offsets had similar effects on attention. In contrast, saccade latencies were considerably longer with offset compared to onset targets, reflecting additional time for volitional saccade initiation. Unexpectedly, SZ patients had normal saccade latencies. Presumably, the expected deficit was compensated by decreased fixation-related neural activity, which was induced by the disappearance of fixation stimuli. PMID- 21534987 TI - New perspectives on neurobehavioral evolution. Introduction and acknowledgments. PMID- 21534988 TI - Wally Welker and neurobehavioral evolution: an appreciation and bibliography. AB - The following review and appreciation of the pioneering work and character of Wallace I. (Wally) Welker provides a historical perspective on Welker's life-long quest for answers to fundamental questions on the relationships among brain, behavior, and evolution, and evaluates his impact upon comparative behavioral neuroscience. PMID- 21534989 TI - Evolution of the amniote pallium and the origins of mammalian neocortex. AB - Karten's neocortex hypothesis holds that many component cell populations of the sauropsid dorsal ventricular ridge (DVR) are homologous to particular cell populations in layers of auditory and visual tectofugal-recipient neocortex of mammals (i.e., temporal neocortex), as well as to some amygdaloid populations. The claustroamygdalar hypothesis, based on gene expression domains, proposes that mammalian homologues of DVR are found in the claustrum, endopiriform nuclei, and/or pallial amygdala. Because hypotheses of homology need to account for the totality of the evidence, the available data on multiple forebrain features of sauropsids and mammals are reviewed here. While some genetic data are compatible with the claustroamygdalar hypothesis, and developmental (epigenetic) data are indecisive, hodological, morphological, and topographical data favor the neocortex hypothesis and are inconsistent with the claustroamygdalar hypothesis. Detailed studies of gene signaling cascades that establish neuronal cell-type identity in DVR, tectofugal-recipient neocortex, and claustroamygdala will be needed to resolve this debate about the evolution of neocortex. PMID- 21534990 TI - Neocortex in early mammals and its subsequent variations. AB - Neocortex is an important part of the mammalian brain that is quite different from its homologue of the dorsal cortex in the reptilian brain. Whereas dorsal cortex is small, thin, and composed of a single layer of neurons, neocortex is thick and has six layers, while being variable across species in size, number of functional areas, and architectonic differentiation. Early mammals had little neocortex, with perhaps 20 areas of poor structural differentiation. Many extant mammals continue to have small brains with little neocortex, but they often have sensory specializations reflected in the organization of sensory areas in neocortex. In primates, neocortex is variously enlarged and characterized by structural and other specializations, including those of cortical networks devoted to vision and visuomotor processing. In humans, neocortex occupies 80% of the volume of the brain, where as many as 200 areas may exist. PMID- 21534991 TI - Neocortical neuron morphology in Afrotheria: comparing the rock hyrax with the African elephant. AB - The mammalian neocortex contains a great variety of neuronal types. In particular, recent studies have shown substantial morphological diversity among spiny projecting neurons in species that diverged close to the base of the mammalian radiation (e.g., monotremes, afrotherians, and xenarthrans). Here, we used a Golgi technique to examine different neuronal morphologies in an afrotherian species, the rock hyrax (Procavia capensis), and provide a comparison with the related African elephant (Loxodonta africana). Results showed that spiny neurons in the rock hyrax neocortex exhibit less morphological variation than in elephants, displaying a higher frequency of relatively "typical" pyramidal neurons. A quantitative comparison of rock hyrax pyramidal neuron morphology between frontal and visual areas, moreover, revealed greater spine density of neurons in frontal cortex, but no differences in other morphological aspects. Regional variations in pyramidal structure have also been observed in the African elephant, as well as a number of primate species. PMID- 21534992 TI - The neocortex of cetaceans: cytoarchitecture and comparison with other aquatic and terrestrial species. AB - The evolutionary process of readaptation to the aquatic environment was accompanied by extreme anatomical and physiological changes in the brain. This review discusses cortical specializations in the three major lineages of marine mammals in comparison to related terrestrial and semiaquatic species. Different groups of marine mammals adopted a wide range of strategies to cope with the challenges of aquatic living. Cetaceans and hippopotamids possess a completely agranular neocortex in contrast to phocids and sirenians; vertical modules are observed in deep layers V and VI in manatees, cetaceans, phocids, and hippopotamids, but in different cortical areas; and clustering in layer II appears in the insular cortex of hippopotamids, phocids, and cetaceans. Finally, von Economo neurons are present in cetaceans, hippopotamids, sirenians, and some phocids, with specific, yet different, cortical distributions. The interpretation of the evolutionary and functional significance of such specializations, and their relationships with the degrees of adaptation to the aquatic environment and phylogeny, remain difficult to trace, at least until comprehensive data, including representative species from all of the major mammalian families, become available. PMID- 21534994 TI - Significance of the insula for the evolution of human awareness of feelings from the body. AB - An ascending sensory pathway that underlies feelings from the body, such as cooling or toothache, terminates in the posterior insula. Considerable evidence suggests that this activity is rerepresented and integrated first in the mid insula and then in the anterior insula. Activation in the anterior insula correlates directly with subjective feelings from the body and, strikingly, with all emotional feelings. These findings appear to signify a posterior-to-anterior sequence of increasingly homeostatically efficient representations that integrate all salient neural activity, culminating in network nodes in the right and left anterior insulae that may be organized asymmetrically in an opponent fashion. The anterior insula has appropriate characteristics to support the proposal that it engenders a cinemascopic model of human awareness and subjectivity. This review presents the author's views regarding the principles of organization of this system and discusses a possible sequence for its evolution, as well as particular issues of historical interest. PMID- 21534993 TI - The von Economo neurons in the frontoinsular and anterior cingulate cortex. AB - The von Economo neurons (VENs) are large bipolar neurons located in the frontoinsular cortex (FI) and limbic anterior (LA) area in great apes and humans but not in other primates. Our stereological counts of VENs in FI and LA show them to be more numerous in humans than in apes. In humans, small numbers of VENs appear the 36th week postconception, with numbers increasing during the first 8 months after birth. There are significantly more VENs in the right hemisphere in postnatal brains; this may be related to asymmetries in the autonomic nervous system. VENs are also present in elephants and whales and may be a specialization related to very large brain size. The large size and simple dendritic structure of these projection neurons suggest that they rapidly send basic information from FI and LA to other parts of the brain, while slower neighboring pyramids send more detailed information. Selective destruction of VENs in early stages of frontotemporal dementia (FTD) implies that they are involved in empathy, social awareness, and self-control, consistent with evidence from functional imaging. PMID- 21534995 TI - The brain and behavior of the tentacled snake. AB - Tentacled snakes (Erpeton tentaculatum) are aquatic predators that feed exclusively on fish. They have a unique pair of tentacles projecting from the face and an unusual J-shaped hunting posture. These features have been the subject of speculation for over a century. In a series of behavioral studies, tentacled snakes were found to exploit fish escape responses by startling fish toward their strike. This remarkable, deceptive behavior takes advantage of the stereotyped C-start escape response of fish. For some fish approach angles, snakes predicted future fish behavior and accurately struck at their moving head. These findings suggest tentacled snakes are acting as "rare enemies"--taking advantage of prey behavior that is usually adaptive for the prey species. Anatomical and physiological analysis showed the tentacles are densely innervated by the trigeminal nerve and are sensitive mechanoreceptors that respond to water movements. Mechanosensory information from the tentacles projects to the optic tectum in approximate register with vision, providing a mechanism for integrating visual and mechanosensory cues for identifying, localizing, and capturing prey. PMID- 21534996 TI - Mammalian tactile hair: divergence from a limited distribution. AB - Mammalian species use tactile hairs to address a variety of perceptual challenges in detecting and responding appropriately to environmental stimuli. With a wide range of functional roles that range from object detection, to fine texture discrimination, to hydrodynamic trail perception, tactile hairs have been adapted for a variety of environmental niches to enhance survival through optimizing detection of somatosensory cues. Because the high level of innervation associated with tactile hairs requires a commensurately high dedication of neural resources, their distribution is restricted to specific regions of the body that encounter stimuli of interest--commonly, the face. However, several species--namely bats, naked mole-rats, hyraxes, manatees, and dugongs--are rare exceptions, with tactile hair distribution that has expanded to cover the entire body. This review examines the behavioral advantages conferred by this unusual trait, the neuroanatomical adaptations that accompany it, and how this pattern might have evolved. PMID- 21534997 TI - Manatee vibrissae: evidence for a "lateral line" function. AB - Aquatic mammals use vibrissae to detect hydrodynamic stimuli over a range from 5 to 150 Hz, similar to the range detected by lateral line systems in fishes and amphibians. Manatees possess ~5,300 vibrissae distributed over the body, innervated by ~209,000 axons. This extensive innervation devoted to vibrissae follicles is reflected in enlarged, elaborate somatosensory regions of the gracile, cuneate, and Bischoff's brain-stem nuclei, ventrobasal thalamus, and presumptive somatosensory cortex. Our preliminary psychophysical testing indicates that in Florida and Antillean manatees the Weber fraction for detection thresholds for grating textures ranges from 0.025 to 0.14. At the lower end of this range, sensitivity is comparable to human index finger thresholds. For hydrodynamic stimuli of 5-150 Hz, detection threshold levels for manatees using facial or postfacial vibrissae were substantially lower than those reported for harbor seals and similar to reports of sensitivity for the lateral line systems of some fish. Our findings suggest that the facial and postfacial vibrissae are used to detect hydrodynamic stimuli, whereas only the facial vibrissae are used for direct contact investigation. PMID- 21534998 TI - A night in the life of a rat: vibrissal mechanics and tactile exploration. AB - The rat vibrissal (whisker) system is an increasingly important model for the study of the sense of touch. This paper describes recent results obtained from high-speed videography of rat exploratory behavior and from modeling studies of vibrissal biomechanics. We review several features of vibrissal touch, including the mechanics of contact versus noncontact whisking, the coordination between head and whisker movements, and the use of information obtained from the whiskers to detect, localize, and extract the spatial properties of objects. This work highlights the idea that mechanics are critical to an understanding of sensory systems and describes some new tools to monitor the spatiotemporal patterns of whisker-object contact during natural tactile exploratory behavior. PMID- 21535000 TI - Functional implications of tactile projection patterns to the lateral hemispheres of the cerebellum of the albino rat: the legacy of Wally Welker. AB - In the late 1970s, Wally Welker and his colleagues published a series of papers describing the first high-resolution physiological maps of tactile mossy fiber projections to the granule cell layer of the rat. Over the subsequent decade, his laboratory continued to explore the implications of these results for cerebellar connectivity and function while also extending the basic mapping results to a number of additional mammalian species. In each case, the maps revealed several surprising features, including a dominance of tactile (cutaneous inputs), robust short latency responses from the sensory periphery, and a fractured patchy somatotopic organization of receptive fields. This paper summarizes the major results of these micromapping experiments and reconsiders their implications for cerebellar function in light of more recent experimental data. The paper also explores the relationship between these fundamental discoveries and Wally Welker's theory-neutral approach to experimental science. PMID- 21534999 TI - How do barrels form in somatosensory cortex? AB - The somatosensory cortex of many rodents, lagomorphs, and marsupials contains distinct cytoarchitectonic features named "barrels" that reflect the pattern of large facial whiskers on the snout. Barrels are composed of clustered thalamocortical afferents relaying sensory information from one whisker surrounded by cell-dense walls or "barrels" in layer 4 of the cortex. In many ways, barrels are a simple and relatively accessible canonical cortical column, making them a common model system for the examination of cortical development and function. Despite their experimental accessibility and popularity, we still lack a basic understanding of how and why barrels form in the first place. In this review, we will examine what is known about mechanisms of barrel development, focusing specifically on the recent literature using the molecular-genetic power of mice as a model system for examining brain development. PMID- 21535001 TI - Taking advantage of behavioral changes during development and training to assess sensory coding mechanisms. AB - The relationship between behavioral and neural performance has been explored in adult animals, but rarely during the developmental period when perceptual abilities emerge. We used these naturally occurring changes in auditory perception to evaluate underlying encoding mechanisms. Performance of juvenile and adult gerbils on an amplitude modulation (AM) detection task was compared with response properties from auditory cortex of age-matched animals. When tested with an identical behavioral procedure, juveniles display poorer AM detection thresholds than adults. Two neurometric analyses indicate that the most sensitive juvenile and adult neurons have equivalent AM thresholds. However, a pooling neurometric revealed that adult cortex encodes smaller AM depths. By each measure, neural sensitivity was superior to psychometric thresholds. However, juvenile training improved adult behavioral thresholds, such that they verged on the best sensitivity of adult neurons. Thus, periods of training may allow an animal to use the encoded information already present in cortex. PMID- 21535002 TI - Coevolution in communication senders and receivers: vocal behavior and auditory processing in multiple songbird species. AB - Communication is a strong selective pressure on brain evolution because the exchange of information between individuals is crucial for fitness-related behaviors, such as mating. Given the importance of communication, the brains of signal senders and receivers are likely to be functionally coordinated. We study vocal behavior and auditory processing in multiple species of estrildid finches with the goal of understanding how species identity and early experience interact to shape the neural systems that subserve communication. Male finches learn to produce species-specific songs, and both sexes learn to recognize songs. Our studies indicate that closely related species exhibit different auditory coding properties in the midbrain and forebrain and that early life experience of vocalizations contributes to these differences. Moreover, birds that naturally sing tonal songs can learn broadband songs from heterospecific tutors, providing an opportunity to examine the interplay between species identity and early experience in the development of vocal behavior and auditory tuning. PMID- 21535004 TI - Modeling the evolution of cortico-cerebellar systems in primates. AB - Although it is commonly accepted that brains work as functionally distributed systems in which interconnected structures work together in processing particular types of information, few studies have investigated the evolution of functionally specialized neural systems across many different lineages. MR-related research has provided in-depth information on connectivity patterns, but because of its focus on particular species, it has given only indicative clues about evolutionary patterns shaping brain organization across primates. Here, we combine depth with breadth of analysis by investigating patterns of covarying size evolution in substructures of the cortico-cerebellar system across 19 anthropoid species spanning 35 million years of divergent evolution. Results demonstrate two distinct patterns of size covariation in substructures of the cortico-cerebellar system, suggesting neural systems involving profuse cortico cerebellar connections are a major factor in explaining the evolution of anthropoid brain organization. We set out an evolutionary model of relative cortico-cerebellar expansion and provide a detailed picture of its branch specific evolutionary history suggesting the ape radiation is the clade with the strongest and most consistent evolutionary history in relative (frontal) cortico cerebellar expansion. PMID- 21535003 TI - Evolution of mirror systems: a simple mechanism for complex cognitive functions. AB - Mirror neurons (MNs) were first discovered in monkeys and subsequently in humans and birds. While MNs are deemed to play a number of high-level cognitive functions, here we propose that they serve a unitary form of sensorimotor recognition of others' behavior. We caution that this basic function should not be confounded with the higher order functions that stem from the wider cortical systems in which MNs are embedded. Depending on the species, MNs function at different levels of motor event recognition, from motor goals to fine grained movements, thus contributing to social learning and imitative phenomena. Recent studies show that MNs coding has a prospective nature, suggesting that MNs also play a role in anticipating and predicting the behavior of others during social interactions. The presence of mirroring mechanisms in subcortical structures related to visceromotor reactions and the large diffusion of imitative phenomena among animals suggest that MN systems may be more ancient and widespread than previously thought. PMID- 21535005 TI - Brains matter, bodies maybe not: the case for examining neuron numbers irrespective of body size. AB - It is usually considered a paradox that the human brain, although smaller than elephant and cetacean brains, is the most cognitively able. The concept that humans are more encephalized than all other mammals appeared in the 1970s as a solution to that paradox: humans have a brain that is much larger than expected from their body mass. Such an "excess brain mass" would provide increased cognitive abilities across species, thus explaining our cognitive superiority. However, behind the paradox lies the assumption that large mammalian brains are scaled-up versions of smaller brains, always containing more neurons than smaller ones--an assumption that we have recently shown to be invalid. Here, it is proposed that the absolute number of neurons, irrespective of brain or body size, is a better predictor of cognitive ability--in which case, the cognitive superiority of humans would come as no paradox, surprise, or exception to evolutionary rules. PMID- 21535006 TI - Can exposure limitations for well-known contact allergens be simplified? An analysis of dose-response patch test data. AB - BACKGROUND: Allergic contact dermatitis is triggered by chemicals in the environment. Primary prevention is aimed at minimizing the risk of induction, whereas secondary and tertiary prevention are aimed at reducing elicitation. OBJECTIVES: To identify the elicitation doses that will elicit an allergic reaction in 10% of allergic individuals under patch test conditions (ED(10) patch test) for different allergens, and to compare the results with those for different allergens and with animal data indicating sensitizing potency from the literature. MATERIALS AND METHODS: The literature was searched for patch test elicitation studies that fulfilled six selected criteria. The elicitation doses were calculated, and fitted dose-response curves were drawn. RESULTS: Sixteen studies with eight different allergens-methylchloroisothiazolinone/ methylisothiazolinone, formaldehyde, nickel, cobalt, chromium, isoeugenol, hydroxyiso hexyl 3-cyclohexene carboxaldehyde, and methyldibromo glutaronitrile were selected. The median ED(10) value was 0.835 ug/cm(2). The ED(10) patch test values were all within a factor of 7 from the lowest to the highest value, leaving out three outliers. No obvious patterns between the sensitization and elicitation doses for the allergens were found. CONCLUSIONS: We found a rather small variation in the ED(10) patch test between the allergens, and no clear relationship between induction potency and elicitation threshold of a range of allergens. This knowledge may stimulate thoughts on introducing a generic approach for limitations in exposure to well-known allergens. PMID- 21535007 TI - Isolated 'idiopathic' micropenis: hidden genetic defects? AB - Micropenis is defined as a stretched penile length of less than 2-2.5SD for age. Aetiologies include hypogonadotropic hypogonadism, testicular dysgenesis, defects in testosterone synthesis, androgen resistance [5alpha-reductase (5alphaR) deficiency or partial androgen insensitivity] and other rare causes like growth hormone GH deficiency. Often, the cause remains unknown. The aim of this study was to determine whether isolated micropenis with normal plasma testosterone could hide a molecular defect in the androgen pathway. Twenty-six boys with isolated micropenis were included in this study. All of them had 46,XY karyotype, normal luteinizing hormone and follicle-stimulating hormone and a normal plasma testosterone response to human chorionic gonadotropin testing. Androgen receptor (AR), 5alphaR and steroidogenic factor 1 (SF1) genes were sequenced. A mutation in the AR gene was found in two patients, and a new mutation in the SF1 gene was found in one patient who was the only one to have a low level of inhibin B (InhB). This is the first report of isolated micropenis as a revealing symptom of AR and SF1 mutations. Anti-Mullerian hormone and InhB should thus be evaluated in patients with isolated micropenis, even when plasma testosterone is in the normal range. Detection of gene mutations is helpful for diagnosis, treatment and genetic counselling for probands. PMID- 21535008 TI - Testosterone and oestradiol in concert protect seminiferous tubule maturation against inhibition by GnRH-antagonist. AB - Oestradiol enhances follicle stimulating hormone (FSH) action on seminiferous tubule maturation, but the relative involvement of oestradiol and testosterone remains unclear. This study compares the influences of oestrogen and androgen in FSH and testosterone-deficient rats. Animals were injected daily GnRH-antagonist alone (Ant) or combined with 17beta-oestradiol benzoate (EB), or testosterone propionate (TP), or both from post-natal day (pnd) 5 to 15. Hormone levels, tubule growth, cell numbers, germ cell apoptosis and proliferation, and Sertoli cell maturation were evaluated on pnd 16. Ant decreased serum FSH and testosterone levels to ~60% and ~50% of control values, respectively, and decreased tubule growth, Sertoli cell number and maturation. Germ cell number declined by apoptosis. Co-administration of EB stimulated spermatogonia proliferation and maintained FSH levels (86% of control). Tubule growth, Sertoli cell number and spermatocyte apoptosis remained normal after TP co administration, but Sertoli cell maturation, germ cell number and spermatogonia survival were reduced. Co-administration of EB with TP prevented all inhibitions. In conclusion, administration of oestradiol with testosterone, but neither one alone, protected seminiferous tubule maturation against inhibition caused by Ant induced disruption. Oestrogen was involved in stimulating germ cell proliferation and the maintenance of Sertoli cell maturation, whereas androgen affected seminiferous tubule growth and spermatocyte survival. PMID- 21535009 TI - Methylenetetrahydrofolate reductase C677T polymorphism and the risk of male infertility: a meta-analysis. AB - Several molecular epidemiological studies have been conducted to examine the association between MTHFR C677T polymorphism and male infertility susceptibility, but the results remain inconsistent. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 10 case-control studies, including 2275 cases and 1958 controls, were selected. Crude odds ratios (ORs) with 95% confidence intervals were used to assess the strength of association in the additive model, dominant model and recessive model. In the overall analysis, no significant association between the polymorphism and risk of male infertility was observed. Stratified analysis showed that significantly strong association between MTHFR C677T polymorphism and male infertility were present only in Asians (OR = 1.79 for TT vs. CC genotype; OR = 1.42 for CT/TT vs. CC genotype; OR = 1.50 for TT vs. CC/CT genotype; OR = 1.36 for T vs. C allele), but not in Caucasians. Additionally, MTHFR 677T was associated with a significant increase in the risk of azoospermia in all genetic models. No significantly increased risks of oligoasthenoteratozoospermia were found in any of the genetic models. In conclusion, this meta-analysis supports that MTHFR C677T polymorphism is capable of causing male infertility susceptibility in Asians, but not in Caucasians. PMID- 21535010 TI - Dynamics of sperm DNA fragmentation in patients carrying structurally rearranged chromosomes. AB - This investigation was conducted to assess the baseline level of sperm DNA fragmentation (SDF) in a cohort of patients presenting chromosomal rearrangements (nine reciprocal translocations and two inversions). In a separate experiment, a dynamic analysis to calculate the rate of SDF (rSDF), after a varying period of sperm storage (0 h, 1 h, 4 h, 8 h and 24 h) at 37 degrees C, was performed. Results were compared with eight fertile donors. Different experimental approaches to assess SDF, such as terminal transferase dUTP nick-end labelling (TUNEL), sperm chromatin structure assay (SCSA) and sperm chromatin dispersion test (SCDt), were used. No differences for the baseline level of SDF were found. Carriers of reorganized genomes showed statistically higher levels of SDF than did control donors (p = 0.025 for TUNEL; p = 0.022 for SCSA; p = 0.014 for SCDt). However, 54.5% (6/11) of the patients presented values similar to those of control donors. There was no significant difference in rSDF (p = 0.34). Nevertheless, the results suggest that a high variability for SDF and rSDF exists in these patients. Routine analysis of SDF and rSDF should be considered in patients presenting rearranged genomes to determine fertility status for assisted reproductive techniques (ART) purposes. PMID- 21535011 TI - Large nuclear vacuoles are indicative of abnormal chromatin packaging in human spermatozoa. AB - The aim of this investigation was to determine the presence of abnormal sperm chromatin packaging in spermatozoa with large nuclear vacuoles (LNV) selected via high magnification by analysing the pattern of chromomycin A3 (CMA3) staining. A prospective observational study was designed to analyse semen samples obtained from 66 men undergoing infertility diagnosis and treatment. The numbers of cells with normal (dull yellow staining of the sperm head/CMA3-negative) and abnormal (bright yellow fluorescence of the sperm head/CMA3-positive) chromatin packaging were determined on slides with normal and LNV spermatozoa. The presence of bright yellow fluorescence (CMA3-positive) was significantly higher (p < 0.0001) in spermatozoa with LNV than in normal spermatozoa (719/1351; 53.2% vs. 337/835; 40.3%, respectively), reflecting a higher percentage of abnormal chromatin packaging in spermatozoa with large LNV. Our data support the hypothesis that the presence of LNV reflects the presence of abnormal chromatin packaging, which may facilitate sperm DNA damage. As sperm nuclear vacuoles are evaluated more precisely at high magnifications using motile sperm organelle morphology examination (MSOME), the present results support the use of high-magnification sperm selection for intracytoplasmic sperm injection (ICSI). PMID- 21535012 TI - Identification and characterization of lactic acid bacteria isolated from rainbow trout, Oncorhynchus mykiss (Walbaum), with inhibitory activity against Lactococcus garvieae. AB - A study was conducted to evaluate the probiotic properties of endogenous rainbow trout microbiota against pathogenic Lactococcus garvieae. A total of 335 bacterial strains were isolated from rainbow trout and screened for antagonistic activity against L. garvieae using an agar spot assay. Antagonistic strains were grouped by PCR amplification of repetitive bacterial DNA elements (rep-PCR) and identified by 16S rRNA gene sequence analysis. The results revealed that the antagonistic strains belonged to the genera Lactobacillus, Lactococcus and Leuconostoc. Further probiotic characteristics, such as specific growth rate, doubling time, resistance to biological barriers, antibiotic resistance, hydrophobicity and production of antimicrobial substances, were also studied. These strains were able to survive low pH and high bile concentrations, showed good adherence characteristics and a broad spectrum of antibiotic resistance. The antagonistic efficacy was maintained after sterile filtration and was sensitive to proteinase K, indicating that proteinaceous extracellular inhibitory compounds were at least partially responsible for pathogen antagonism. Based on these results, these strains should be further studied to explore their probiotic effects in challenge experiments in vivo. This study shows clear evidence that the indigenous trout-associated microbiota may provide a defensive barrier against L. garvieae. PMID- 21535014 TI - Increased exposure to UV-B radiation during early development leads to enhanced photoprotection and improved long-term performance in Lactuca sativa. AB - Plant responses to solar UV radiation are numerous and have often been considered from a perspective of negative outcomes for plant productivity. In this study, we used two experimental approaches consisting of: (1) field-based spectrally modifying filters in addition to (2) controlled indoor exposure to UV-B, to examine the effects of UV radiation on growth and photosynthetic performance of lettuce (Lactuca sativa L.) seedlings. Various aspects of growth were affected in plants grown under a UV-inclusive environment compared to a UV-depleted environment, including reductions in leaf expansion, increases in leaf thickness and the rate of net photosynthesis. After transplantation to a uniform field environment, lettuce plants initially propagated under the UV-inclusive environment exhibited higher harvestable yields than those from a UV-depleted environment. In controlled conditions, photosynthetic rates were higher in plants grown in the presence of UV-B radiation, and relative growth of plants pre acclimatized to UV-B was also increased, in addition to higher maximum photochemical efficiency of photosystem II (PSII) (F(v) /F(m) ) following subsequent exposure to high photosynthetically active radiation (PAR) and temperature stress. Our findings are discussed within the context of sustainability in agriculture and the paradigm shift in photobiology which such beneficial responses to UV radiation could represent. PMID- 21535013 TI - Effect of amantadine on oxymorphone-induced thermal antinociception in cats. AB - This study examined the effect of amantadine, an N-methyl-d-aspartate receptor antagonist, on the thermal antinociceptive effect of oxymorphone in cats. Six adult healthy cats were used. After baseline thermal threshold determinations, oxymorphone was administered intravenously to maintain plasma oxymorphone concentrations of 10, 20, 50, 100, 200, and 400 ng/mL. In addition, amantadine, or an equivalent volume of saline, was administered intravenously to maintain a plasma amantadine concentration of 1100 ng/mL. Thermal threshold and plasma oxymorphone and amantadine concentrations were determined at each target plasma oxymorphone concentration. Effect maximum models were fitted to the oxymorphone concentration-thermal threshold data, after transformation in % maximum response. Oxymorphone increased skin temperature, thermal threshold, and thermal excursion (i.e., the difference between thermal threshold and skin temperature) in a concentration-dependent manner. No significant difference was found between the amantadine and saline treatments. Mean +/- SE oxymorphone EC(50) were 14.2 +/- 1.2 and 24.2 +/- 7.4 ng/mL in the amantadine and saline groups, respectively. These values were not significantly different. Large differences in oxymorphone EC(50) in the saline and amantadine treatment groups were observed in two cats. These results suggest that amantadine may decrease the antinociceptive dose of oxymorphone in some, but not all, cats. PMID- 21535015 TI - A maritime pine antimicrobial peptide involved in ammonium nutrition. AB - A large family of small cysteine-rich antimicrobial peptides (AMPs) is involved in the innate defence of plants against pathogens. Recently, it has been shown that AMPs may also play important roles in plant growth and development. In previous work, we have identified a gene of the AMP beta-barrelin family that was differentially regulated in the roots of maritime pine (Pinus pinaster Ait.) in response to changes in ammonium nutrition. Here, we present the molecular characterization of two AMP genes, PpAMP1 and PpAMP2, showing different molecular structure and physicochemical properties. PpAMP1 and PpAMP2 displayed different expression patterns in maritime pine seedlings and adult trees. Furthermore, our expression analyses indicate that PpAMP1 is the major form of AMP in the tree, and its relative abundance is regulated by ammonium availability. In contrast, PpAMP2 is expressed at much lower levels and it is not regulated by ammonium. To gain new insights into the function of PpAMP1, we over-expressed the recombinant protein in Escherichia coli and demonstrated that PpAMP1 strongly inhibited yeast growth, indicating that it exhibits antimicrobial activity. We have also found that PpAMP1 alters ammonium uptake, suggesting that it is involved in the regulation of ammonium ion flux into pine roots. PMID- 21535016 TI - Methylglyoxal functions as Hill oxidant and stimulates the photoreduction of O(2) at photosystem I: a symptom of plant diabetes. AB - We elucidated the metabolism of methylglyoxal (MG) in chloroplasts of higher plants. Spinach chloroplasts showed MG-dependent NADPH oxidation because of aldo keto reductase (AKR) activity. K(m) for MG and V(max) of AKR activity were 6.5 mm and 3.3 umol NADPH (mg Chl)(-1) h(-1) , respectively. Addition of MG to illuminated chloroplasts induced photochemical quenching (Qp) of Chl fluorescence, indicating that MG stimulated photosynthetic electron transport (PET). Furthermore, MG enhanced the light-dependent uptake of O(2) into chloroplasts. After illumination of chloroplasts, accumulation of H(2) O(2) was observed. K(m) for MG and V(max) of O(2) uptake were about 100 um and 200 umol O(2) (mg Chl)(-1) h(-1) , respectively. MG-dependent O(2) uptake was inhibited by 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) and 2,5-dibromo-3-methyl-6 isopropyl-p-benzoquinone (DBMIB). Under anaerobic conditions, the Qp of Chl fluorescence was suppressed. These results indicate that MG was reduced as a Hill oxidant by the photosystem I (PSI), and that O(2) was reduced to O(2) (-) by the reduced MG. In other words, MG produced in chloroplasts is preferentially reduced by PSI rather than through AKR. This triggers a type of oxidative stress that may be referred to as 'plant diabetes', because it ultimately originates from a common metabolite of the primary pathways of sugar anabolism and catabolism. PMID- 21535017 TI - Inorganic carbon acquisition in two green marine Stichococcus species. AB - The mechanism of inorganic carbon (C(i)) uptake was examined in the marine green microalgae Stichococcus cylindricus and Stichococcus minor. External carbonic anhydrase (CA) activity was not detected in either species, by potentiometric assay or by mass spectrometry. Photosynthetic characteristics of C(i) uptake indicate that both species have high apparent affinity for CO(2) with a low K(1/2) (CO(2)) of about 10 um. The O(2) evolution rates in light exceeded the spontaneous CO(2) formation rate by 2.5-fold in both species, which thus have active bicarbonate uptake. Mass spectrometric monitoring of CO(2) and O(2) fluxes showed that rates of O(2) evolution exceeded those of CO(2) depletion by about three- and twofold in S. minor and S. cylindricus, respectively, and also showed, in cells photosynthesizing at pH 8.2, a rapid depletion of CO(2) upon illumination to a CO(2) compensation concentration of 15.42 and 12.03 um in S. minor and S. cylindricus, respectively. Both species also exhibit active CO(2) uptake: addition of bovine CA at CO(2) compensation concentration caused a rapid rise in CO(2) as the CO(2) -HCO(3) (-) equilibrium was restored. Accumulation of unfixed C(i) by cells at pH 8.2 was calculated to be 84.33 mm in S. cylindricus, and 30.37 mm in S. minor to give internal accumulations of 23- and 8-fold, respectively, compared to the external C(i) concentration. PMID- 21535018 TI - Protection of calves against Haemonchus placei and Haemonchus contortus after immunization with gut membrane proteins from H. contortus. AB - A vaccine containing integral membrane glycoproteins from the intestine of Haemonchus contortus was evaluated in four groups of nine worm-free calves challenged with either 8000 H. contortus or Haemonchus placei infective larvae. Vaccinates received 50 MUg of the antigen and 1 mg QuilA adjuvant three times 21 days apart, while the controls got adjuvant alone. The calves were challenged 7 days after the last immunization and killed for worm counts 43 days later. Immunization resulted in high titre antibodies against the vaccine antigens and significant reduction in egg output and worm numbers of both challenge species, compared with control calves. It was concluded that vaccination of calves with native parasite gut membrane glycoproteins obtained from H. contortus conferred protection against both H. placei and H. contortus. PMID- 21535019 TI - Effects of immunization with the rNfa1 protein on experimental Naegleria fowleri PAM mice. AB - Free-living Naegleria fowleri causes primary amoebic meningoencephalitis (PAM) in humans and animals. To examine the effect of immunization with Nfa1 protein on experimental murine PAM because of N. fowleri, BALB/c mice were intra peritoneally or intra-nasally immunized with a recombinant Nfa1 protein. We analysed Nfa1-specific antibody and cytokine induction, and the mean survival time of infected mice. Mice immunized intra-peritoneally or intra-nasally with rNfa1 protein developed specific IgG, IgA and IgE antibodies; the IgG response was dominated by IgG1, followed by IgG2b, IgG2a and IgG3. High levels of the Th1 cytokine, IFN-gamma, and the regulatory cytokine, IL-10, were also induced. The mean survival time of mice immunized intra-peritoneally with rNfa1 protein was prolonged compared with controls, (25.0 and 15.5 days, respectively). Similarly, the mean survival time of mice immunized intra-nasally with rNfa1 protein was 24.7 days, compared with 15.0 days for controls. PMID- 21535020 TI - Reactive oxygen species-dependent necroptosis in Jurkat T cells induced by pathogenic free-living Naegleria fowleri. AB - Naegleria fowleri, a free-living amoeba, is the causative pathogen of primary amoebic meningoencephalitis in humans and experimental mice. N. fowleri is capable of destroying tissues and host cells through lytic necrosis. However, the mechanism by which N. fowleri induces host cell death is unknown. Electron microscopy indicated that incubation of Jurkat T cells with N. fowleri trophozoites induced necrotic morphology of the Jurkat T cells. N. fowleri also induced cytoskeletal protein cleavage, extensive poly (ADP-ribose) polymerase hydrolysis and lactate dehydrogenase (LDH) release. Although no activation of caspase-3 was observed in Jurkat T cells co-incubated with amoebae, intracellular reactive oxygen species (ROS) were strongly generated by NADPH oxidase (NOX). Pretreating cells with necroptosis inhibitor necrostatin-1 or NOX inhibitor diphenyleneiodonium chloride (DPI) strongly inhibited amoeba-induced ROS generation and Jurkat cell death, whereas pan-caspase inhibitor z-VAD-fmk did not. N. fowleri-derived secretory products (NfSP) strongly induced intracellular ROS generation and cell death. Necroptotic effects of NfSP were effectively inhibited by pretreating NfSP with proteinase K. Moreover, NfSP-induced LDH release and intracellular ROS accumulation were inhibited by pretreating Jurkat T cells with DPI or necrostatin-1. These results suggest that N. fowleri induces ROS-dependent necroptosis in Jurkat T cells. PMID- 21535022 TI - Potential systematic error in laboratory experiments on microbial leakage through filled root canals: an experimental study. AB - AIM: To assess the routes of bacterial leakage in a commonly used two-chamber model designed to evaluate root fillings. METHODOLOGY: Fifty-one intact human mandibular premolars with fully developed roots were used. They were left completely intact (n=23), or were accessed, instrumented and either left open (n=5) or root filled with gutta-percha and AH Plus (n=23). All teeth were sealed between two chambers using sticky wax. The apical root aspects were left uncovered. The upper chamber was seeded with Enterococcus faecalis. An enterococci-selective broth was used in the lower chamber. Leakage was assessed for 120 days and compared using survival statistics (alpha<0.05). Subsequently, roots were trans-sected, stained using a 'live' DNA stain (Syto59) and inspected using confocal laser scanning microscopy. An E. faecalis-specific RNA probe was used for fluorescence in situ hybridization (FISH). RESULTS: Leakage started to occur from day 56, with further occurrence essentially identical between root filled teeth and intact counterparts (P=0.71). All the trans-sections showed fluorescence related to Syto59 between the cementum layer and the sticky wax. Fluorescence was also observed between the root filling and the tubular dentine, whilst it was absent at the interface between root filling and sclerotic dentine. Secondary dentinal tubules, i.e. lateral branches connecting the main counterparts, contained fluorescent material. FISH revealed that Syto59 exclusively stained E. faecalis. CONCLUSIONS: The current experimental method proved to be unsuitable to compare root fillings. Histology revealed interesting observations regarding the relationship of dentine structure and bacterial leakage, which warrant further investigation. PMID- 21535021 TI - Properties and applications of calcium hydroxide in endodontics and dental traumatology. AB - Calcium hydroxide has been included within several materials and antimicrobial formulations that are used in a number of treatment modalities in endodontics. These include, inter-appointment intracanal medicaments, pulp-capping agents and root canal sealers. Calcium hydroxide formulations are also used during treatment of root perforations, root fractures and root resorption and have a role in dental traumatology, for example, following tooth avulsion and luxation injuries. The purpose of this paper is to review the properties and clinical applications of calcium hydroxide in endodontics and dental traumatology including its antibacterial activity, antifungal activity, effect on bacterial biofilms, the synergism between calcium hydroxide and other agents, its effects on the properties of dentine, the diffusion of hydroxyl ions through dentine and its toxicity. Pure calcium hydroxide paste has a high pH (approximately 12.5-12.8) and is classified chemically as a strong base. Its main actions are achieved through the ionic dissociation of Ca(2+) and OH(-) ions and their effect on vital tissues, the induction of hard-tissue deposition and the antibacterial properties. The lethal effects of calcium hydroxide on bacterial cells are probably due to protein denaturation and damage to DNA and cytoplasmic membranes. It has a wide range of antimicrobial activity against common endodontic pathogens but is less effective against Enterococcus faecalis and Candida albicans. Calcium hydroxide is also an effective anti-endotoxin agent. However, its effect on microbial biofilms is controversial. PMID- 21535023 TI - Human dental pulp cell responses to new calcium silicate-based endodontic materials. AB - AIM: To evaluate human dental pulp cell responses to radiopaque dicalcium silicate cement and white-coloured mineral trioxide aggregate (WMTA). METHODOLOGY: Flow cytometry was employed to quantify the phase percentage of pulp cell cycle. Alamar Blue was used for real-time and repeated monitoring of cell proliferation. Reverse transcription-polymerase chain reaction was performed to determine gene expression in pulp cells cultured on the cements. RESULTS: The cells cultured on the radiopaque dicalcium silicate cement had similar S and G2 phases in the cell cycle and proliferation to WMTA at all culture times. In addition, the two materials presented the same evolution with similar values in interleukin-1, inducible nitric oxide synthase, alkaline phosphatase, osteocalcin and bone sialoprotein gene expression at all culture times. CONCLUSIONS: The dental pulp cell responses to radiopaque dicalcium silicate cement were similar to those reported for WMTA in terms of cell cycle, proliferation, immunocompatibility and osteogenic differentiation. PMID- 21535024 TI - Chronic ethanol consumption in mice alters hepatocyte lipid droplet properties. AB - BACKGROUND: Hepatosteatosis is a common pathological feature of impaired hepatic metabolism following chronic alcohol consumption. Although often benign and reversible, it is widely believed that steatosis is a risk factor for development of advanced liver pathologies, including steatohepatitis and fibrosis. The hepatocyte alterations accompanying the initiation of steatosis are not yet clearly defined. METHODS: Induction of hepatosteatosis by chronic ethanol consumption was investigated using the Lieber-DeCarli (LD) high fat diet model. Effects were assessed by immunohistochemistry and blood and tissue enzymatic assays. Cell culture models were employed for mechanistic studies. RESULTS: Pair feeding mice ethanol (LD-Et) or isocaloric control (LD-Co) diets for 6 weeks progressively increased hepatocyte triglyceride accumulation in morphological, biochemical, and zonally distinct cytoplasmic lipid droplets (CLD). The LD-Et diet induced zone 2-specific triglyceride accumulation in large CLD coated with perilipin, adipophilin (ADPH), and TIP47. In LD-Co-fed mice, CLD were significantly smaller than those in LD-Et-fed mice and lacked perilipin. A direct role of perilipin in formation of large CLD was further suggested by cell culture studies showing that perilipin-coated CLD were significantly larger than those coated with ADPH or TIP47. LD-Co- and LD-Et-fed animals also differed in hepatic metabolic stress responses. In LD-Et but not LD-Co-fed mice, inductions were observed in the following: microsomal ethanol-oxidizing system [cytochrome P 4502E1 (CYP2E1)], hypoxia response pathway (hypoxia-inducible factor 1 alpha, HIF1alpha), endoplasmic reticulum stress pathway (calreticulin), and synthesis of lipid peroxidation products [4-hydroxynonenal (4-HNE)]. CYP2E1 and HIF1 alpha immunostaining localized to zone 3 and did not correlate with accumulation of large CLD. In contrast, calreticulin and 4-HNE immunostaining closely correlated with large CLD accumulation. Importantly, 4-HNE staining significantly colocalized with ADPH and perilipin on the CLD surface. CONCLUSIONS: These data suggest that ethanol contributes to macrosteatosis by both altering CLD protein composition and inducing lipid peroxide adduction of CLD-associated proteins. PMID- 21535028 TI - Ablation of peri-"mitral" flutter in a patient with congenitally corrected transposition of great vessels and situs inversus. AB - This case reports the successful ablation of a peri-"mitral" flutter in a patient with congenitally corrected transposition of the great vessels and situs inversus using an anterior mitral line. PMID- 21535025 TI - Role of snail activation in alcohol-induced iNOS-mediated disruption of intestinal epithelial cell permeability. AB - BACKGROUND: Chronic alcohol use results in many pathological effects including alcoholic liver disease (ALD). ALD pathogenesis requires endotoxemia. Our previous studies showed that increased intestinal permeability is the major cause of endotoxemia, and that this gut leakiness is dependent on alcohol stimulation of inducible nitric oxide synthase (iNOS) in both alcoholic subjects and rodent models of alcoholic steatohepatitis. The mechanism of the alcohol-induced, iNOS mediated disruption of the intestinal barrier function is not known. We have recently shown that alcohol stimulates activation of the transcription factor Snail and biomarkers of epithelial mesenchymal transition. As activated Snail disrupts tight junctional proteins, we hypothesized that activation of Snail by iNOS might be one of the key signaling pathways mediating alcohol-stimulated intestinal epithelial cell hyperpermeability. METHODS: We measured intestinal permeability in alcohol-fed C57BL/6 control and iNOS knockout (KO) mice, and measured Snail protein expression in the intestines of these mice. We then examined intestinal epithelial permeability using the Caco-2 cell model of the intestinal barrier +/- small interfering RNA (siRNA) inhibition of Snail. We assessed Snail activation by alcohol in Caco-2 cells +/- inhibition of iNOS with L-NIL or siRNA. Finally, we assessed Snail activation by alcohol +/- inhibition with siRNA for p21-activated kinase (PAK1). RESULTS: Our data show that chronic alcohol feeding promotes intestinal hyperpermeability in wild-type BL/6, but not in iNOS KO mice. Snail protein expression was increased in the intestines of alcohol-treated wild-type mice, but not in iNOS KO mice. siRNA inhibition of Snail significantly inhibited alcohol-induced hyperpermeability in Caco-2 cell monolayers. Alcohol stimulation of Snail(pS246) activation was blocked by inhibition of iNOS with L-NIL or with siRNA. siRNA inhibition of PAK1 significantly inhibited alcohol-mediated activation of Snail in Caco-2 cells. CONCLUSIONS: Our data confirmed our prior results and further demonstrated that alcohol-induced gut leakiness in rodents and intestinal epithelial cell monolayers is iNOS dependent. Our data also support a novel role for Snail activation in alcohol-induced, iNOS-mediated intestinal hyperpermeability and that PAK1 is responsible for activation of Snail at Ser246 with alcohol stimulation. Identification of these mechanisms for alcohol-induced intestinal hyperpermeability may provide new therapeutic targets for prevention and treatment of alcohol-induced leaky gut, endotoxemia, and endotoxin-associated complications of alcoholism such as ALD. PMID- 21535026 TI - Characterization of South African adolescents with alcohol use disorders but without psychiatric or polysubstance comorbidity. AB - BACKGROUND: Individuals who begin drinking during early adolescence and exhibit externalizing pathology and disinhibitory/dysregulatory tendencies are more vulnerable to developing alcohol use disorders (AUDs) in adulthood. Previous research has focused on in-treatment populations with substantial comorbid psychopathology and polysubstance use. Here, we characterize a unique sample of treatment-naive adolescents without such comorbidity to help identify vulnerable youth who may benefit from early intervention. METHODS: We compared externalizing propensity, disinhibitory characteristics, and school performance in adolescents with AUDs (but without comorbid psychopathology or other substance use; n = 70) to those of demographically matched controls (n = 70). Within the AUD group, we compared measures of substance use and the disinhibitory syndrome between boys and girls with differing severity of externalizing propensity. RESULTS: Adolescents with AUDs demonstrated more externalizing propensity and disinhibitory personality traits (impulsivity, novelty seeking, and excitement seeking), poorer self-monitoring and response inhibition, more bullying and sexual risk-taking behavior, poorer first-language performance, and greater use of alcohol, cannabis, and nicotine (p < 0.05). Within the AUD group, participants with higher externalizing propensity began drinking earlier, more frequently, and for a longer duration than those with lower externalizing symptoms (p < 0.05). Disinhibitory features (personality, cognition, and behavior) were, however, not stronger in those with higher externalizing propensity. CONCLUSIONS: We suggest that the constructs of externalizing propensity and disinhibitory syndrome are useful in characterizing treatment-naive adolescents with AUDs but without comorbid psychopathology or polysubstance use. These results support the importance of these constructs in understanding adolescent AUDs, even when the frank externalizing diagnoses of childhood (oppositional defiant disorder and conduct disorder) are excluded. PMID- 21535029 TI - Atrial fibrillation causing syncope? PMID- 21535030 TI - Atrial oversensing by an LV lead during typical flutter: the interest of electronic repositioning. AB - Occurrence of supraventricular tachycardia is a common cause of clinical impairment for patients implanted with CRT devices. We report the case of atrial activity oversensing by the left ventricular (LV) lead during typical flutter, which led to LV pacing inhibition. Temporary reprogramming of the LV detection from standard bipolar to extended bipolar and cavotricuspid isthmus ablation solved this problem. PMID- 21535031 TI - Predictors of all-cause 1-year mortality in implantable cardioverter defibrillator patients with chronic Chagas' cardiomyopathy. AB - BACKGROUND: Implantable cardioverter defibrillators (ICDs) have been used in the treatment of either sustained ventricular tachycardia or ventricular fibrillation in patients with Chagas' cardiomyopathy. This study aimed at determining mortality rate and risk factors of all-cause 1-year mortality in primary and secondary ICD patients with Chagas' cardiomyopathy. METHODS: One hundred and forty-eight Chagas' patients with ICDs were included from the Medtronic ICD Registry Latin America. All patients were followed for 1 year. RESULTS: At implant, mean age was 60.1 +/- 9.4 years and 72.9% were male. Mean left ventricular ejection fraction (LVEF) was 40.1 +/- 11%. Mean follow-up was 12 +/- 7 months. During the follow-up, 15 patients died (10.2%). Patients who died were older (64 +/-10.8 years vs 59 +/- 9.1; P = 0.04), had more atrial fibrillation (13.3% vs 3.8%; P = 0.02), had lower LVEF (33.4%+/- 9.8 vs 40.9%+/- 11.3; P = 0.01), and worse functional class (III/IV 40% vs 21.8%; P = 0.03). The multivariate analysis showed that two independent predictors of all-cause 1-year mortality remained statistically significant: age more than 65 (hazard ratio [HR] = 2.85, 95% confidence interval [CI] 1.77-3.92; P = 0.03) and LVEF less than 30% (HR = 2.68, 95% CI 1.57-3.79; P = 0.04). CONCLUSION: This analysis showed that patients older than 65 years of age and with LVEF less than 30% were independent predictors of all-cause 1-year mortality in patients with chronic Chagas' cardiomyopathy. PMID- 21535032 TI - Successful removal of a jugular implantable defibrillator lead with mechanical single-sheath technique. AB - We describe the case of a man with an implantable defibrillator and a dual-coil lead introduced via the right internal jugular vein. Due to pocket infection and lead erosion at the jugular vein, transvenous lead extraction was attempted with a mechanical single-sheath technique. The lead was completely removed without complications with culture and sensitivity results guiding an effective antibiotic therapy. PMID- 21535033 TI - Successful catheter ablation of unmappable monomorphic postinfarction ventricular tachycardia guided by a Purkinje potential. AB - We describe a case of a patient with the history of a monomorphic postinfarction ventricular tachycardia that exhibited a right bundle branch block morphology and a superior axis. Because of electrical and hemodynamic instability of arrhythmia, classical mapping techniques were not applied. An electroanatomic voltage map during sinus rhythm was performed. A Purkinje potential (PP) preceding the QRS complex was recorded at posteroseptal area of a scar. Radiofrequency energy delivery at sites where a PP was detected resulted in a successful ablation. PMID- 21535034 TI - Quality of life with atrial fibrillation: do the spouses suffer as much as the patients? AB - BACKGROUND: Atrial fibrillation (AF) can have a significant effect on quality of life (QoL). Other chronic diseases are known to not only affect the patient but to also impact the QoL of persons living with them. Scant data exist on the QoL effect of AF in spouses/significant others (SOs). METHODS: An anonymous survey regarding the perceived effect of AF on QoL was designed and distributed to both patients and spouses/SOs during an educational symposium about living with AF. Both were asked to fill out the survey independently according to how their life was affected by either their AF or their partner's AF. Questions included demographics, perceived impairment of overall QoL on a 5-point scale, as well as effect on subcategories of QoL, namely daily activity, work life, sex life, physical activity, psychological well-being, and social activity. RESULTS: Five hundred and sixty-eight subjects completed the survey of which 411 were AF patients and 129 were spouses/SOs. The perceived effect of AF on overall QoL (N = 527) was similar in patients and spouses (AF patients: mild 42.0%, moderate 26.0%, severe 32.0% vs. spouses: 44.1%, 25.2%, 31.7%; P = 0.917). This result did not change when adjusted for age and gender. There was also no significant difference between patients and spouses in the subcategories of QoL with the exception of the perceived effect on work life, which was greater in patients than spouses (P = 0.041). CONCLUSIONS: AF has a similar perceived impact on the QoL of spouses and patients. QoL improvement strategies for patients with AF should take spouses into account. PMID- 21535035 TI - Transmyocardial voyage of a temporary epicardial lead: an unusual long-term complication. AB - Although the majority of temporary epicardial leads used during cardiac surgery are removed in the perioperative period, occasionally, the wires are cut and allowed to retract into the subcutaneous tissue. Complications arising from such retained epicardial wires are rare. We present a case of transmyocardial migration of a retained epicardial wire through the right ventricular myocardium into the pulmonary artery in a patient who had undergone coronary artery bypass graft surgery 13 years ago. We describe the presentation and successful management of this case. PMID- 21535036 TI - Why did the ICD indicate "terminate" during ongoing tachycardia? PMID- 21535037 TI - Improved activation time assignment of unipolar electrograms from ischemic canine epicardium. AB - AIMS: The present study attempts to develop an objective, statistically based set of criteria for activation time determination from unipolar electrograms (U-EGMs) using a standard of activation related to biophysical theory. METHODS: A high resolution assembly of U-EGMs obtained from the epicardial surface of the canine postinfarction heart were analyzed in order to achieve the best prediction of local versus distant activation. An activation time standard (ATS) consisted of three properties: (1) propagation of activation, evidenced by a linear temporal shift of waveforms from closely spaced U-EGMs with little or no decay in amplitude; (2) cycle length-dependent changes of those propagating waveforms; and (3) evidence of electrotonic deflections, seen as nonpropagating potentials having decaying amplitude with distance. RESULTS: A number of U-EGM features were calculated and subjected to analysis by comparing their occurrence with the ATS. A discriminant function analysis incorporating multiple features (Voltage, -dV/dt and Ratio) of major U-EGM deflections improved prediction of activation time of complex fractionated EMGs from ischemic canine epicardium to 90%. CONCLUSION: A unique discriminant function based on sound biophysical principles markedly improved prediction of activation time of complex U-EGMs from ischemic canine epicardium. A computerized version of the algorithm could be developed to provide more accurate activation maps for both basic and clinical use. PMID- 21535038 TI - Systematic decrements in QTc between the first and second day of contiguous daily ECG recordings under controlled conditions. AB - BACKGROUND: Many thorough QT (TQT) studies use a baseline day and double delta analysis to account for potential diurnal variation in QTc. However, little is known about systematic changes in the QTc across contiguous days when normal volunteers are brought into a controlled inpatient environment. METHODS: Two separate crossover TQT studies included 2 days of no treatment lead-in days with ECG collection preceding periods of drug treatment . In the first study, there were two pairs of such contiguous days with 10 replicate electrocardiograms (ECGs) collected at six time points, and in the second study, there were four pairs of contiguous days with nine replicate ECGs collected at five time points. These lead-in day pairs provided the opportunity to evaluate any systematic changes across contiguous first and second days of an inpatient environment. Within-patient consistency of change across pairs of days as well as within day, diurnal variation could also be evaluated. RESULTS: Modest (4.2 ms [range 1.9-6.5 ms]) but consistent decreases (significant [P < 0.05] for all 32 comparisons) were observed (probability: <=5.4 * 10(-16)). Although group behavior with respect to QTc was consistent, individual subjects demonstrated substantial variability across pairs of days. Evidence of diurnal variation was weak and inconsistent. Magnitude of any diurnal variation was less than magnitude of change across days. CONCLUSIONS: Subjects show a systematic decrease in QTc from first day to second day of inpatient status and do not demonstrate a significant diurnal pattern. The magnitude of this systematic change is sufficient to influence QTc study interpretation. PMID- 21535039 TI - Initial results of linear duty-cycled radiofrequency for atypical flutter and atrial tachycardia. AB - BACKGROUND: Duty-cycled radiofrequency (DCRF) is increasingly used for ablation of atrial fibrillation (AF). Many patients also have atrial flutter (AFL). Recently, a linear multielectrode has been shown to create linear block at the cavotricuspid isthmus and in the left atrium (LA). OBJECTIVE: To map and ablate atypical AFL and atrial tachycardias (ATs) in the right and LA using a linear multielectrode with DCRF. METHODS: The linear multielectrode delivers DCRF at 20 45 W maximum in 1:1 unipolar/bipolar temperature-controlled mode. Target temperatures were manually titrated to 60 degrees C in the LA, if power >5W indicated adequate passive cooling. RESULTS: A total of 76 AT/AFL were targeted in 57 patients. Acute success was reached in 14/15 (93%) right AT, in 17/22 (77%) left atrial roof AFL, in 5/6 (83%) septal AFL, in 9/9 (100%) other left atrial AT, but only in 8/23 (35%) AFL from the mitral isthmus (which rose to 13/23 [57%] with additional use of irrigated radiofrequency). Nevertheless, freedom of AF/AFL 10 +/- 6 months after a single procedure was documented in 92% of right AT, 71% of roof AFL, 73% for mitral AFL, and 60% of septal or other LA AT/AFL. No char formation was noted. However, frequent induction of AF and one case of asystole occurred during delivery of DCRF in a pacemaker patient. CONCLUSION: The linear multielectrode allows mapping and ablation of atypical AFL/AT. Freedom of AF/AT was reached in 60%-92% depending on localization and number of arrhythmias. Technical modifications will improve safety and efficacy. PMID- 21535040 TI - Impact of relaxation training on patient-perceived measures of anxiety, pain, and outcomes after interventional electrophysiology procedures. AB - BACKGROUND: Electrophysiology procedures vary in invasiveness, duration, and anesthesia utilized. While complications are low and efficacy high, cases are elective and patient experiences related to anxiety, pain, and perceived outcomes are not well studied. We sought to determine if a 30-minute audio compact disc (CD) that teaches relaxation techniques and wellness perception prior to an elective procedure impacts validated measures of anxiety, pain, and procedural outcomes. METHODS: Sixty-one patients were randomly assigned to a control group (CG) (N(CG) = 31) or interventional group (IG) (N(IG) = 30). Both groups answered a baseline Hospital Anxiety and Depression Scale (HADS-A) survey consisting only of anxiety assessment questions. The IG listened to the CD the night prior to their procedure. Heart rate and blood pressure were monitored on admission and prior to the procedure. Postprocedure, both groups completed two HADS-A surveys as well as two Patient Experience Surveys (PES). There was no statistical difference in the demographics and the rate of procedural complications between the groups. The statistical significance of our data was determined using a Student's t-test and chi(2) test. RESULTS: At baseline, both groups had equal amounts of anxiety prior to their procedures (P = 0.2). The patients in the IG had lower systolic blood pressures during admission and prior the administration of analgesics in comparison to the CG. Postprocedure, results from administering the HADS-A demonstrated that the IG had 33% lower anxiety (P = 0.02) than CG patients. CONCLUSION: The implementation of basic relaxation teaching techniques prior to planned electrophysiology procedures lowers systolic blood pressure and postprocedural anxiety. PMID- 21535041 TI - Evaluation of the impact of DNA extraction methods on BAC bacterial community composition measured by denaturing gradient gel electrophoresis. AB - AIMS: The impact of DNA extraction methods on biological activated carbon (BAC) DNA yield and bacterial community was evaluated. METHODS AND RESULTS: Three different DNA extraction methods were compared: method a, method b and method c. Method c with ultrasonic pretreatment improved cell lysis efficiency (from 34% to 87%) and DNA yield [from 10.58 MUg g-1 (dry wt) of carbon to 21.42 MUg g-1 (dry wt) of carbon]. denaturing gradient gel electrophoresis profiles obtained by method c recovered the five seeded bacteria (Bacillus subtilis Strain WSO 6, Pseudomonas putida Strain WSO 7, Acinetobacter lwoffii WSO 10, Pseudomonas pertucinogena WSO 11 and Brevibacterium mcbrellneri WSO 13). CONCLUSIONS: The results showed method c with ultrasonic pretreatment was the most successful for the analysis of BAC bacterial community because it was effective in the detachment of bacteria and cell lysis, thereby resulting in good yields. SIGNIFICANCE AND IMPACT OF STUDY: These results must be taken into consideration when extracting DNA for analysing BAC bacterial community. PMID- 21535042 TI - PCR-DGGE analysis of bacterial community dynamics in kava beverages during refrigeration. AB - AIMS: Kava beverages are highly perishable even under refrigerated conditions. This study aimed to investigate the bacterial community dynamics in kava beverages during refrigeration. METHODS AND RESULTS: Four freshly made kava beverages were obtained from kava bars and stored at 4 degrees C. On days 0, 3 and 6, the aerobic plate count (APC), lactic acid bacteria (LAB) count and yeast and mould count (YMC) of the samples were determined. Meanwhile, bacterial DNA was extracted from each sample and subjected to the polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE). Moreover, species-specific PCR assays were employed to identify predominant Pseudomonas spp. involved in kava spoilage. Over the storage period, the APC, LAB count and YMC of the four kava beverages all increased, whereas their pH values decreased. The DGGE profile revealed diverse bacterial populations in the samples. LAB, such as Weissella soli, Lactobacillus spp. and Lactococcus lactis, were found in the kava beverages. Species-specific PCR assays detected Pseudomonas putida and Pseudomonas fluorescens in the samples; Ps. fluorescens became dominant during refrigeration. CONCLUSIONS: LAB and Pseudomonas may play a significant role in the spoilage of kava beverages. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides important information that may be used to extend the shelf life of kava beverages. PMID- 21535043 TI - Quorum-sensing system in Acidithiobacillus ferrooxidans involved in its resistance to Cu2+. AB - AIMS: The purpose of this study was to search for the relationship between quorum sensing (QS) and Cu2+ resistance in Acidithiobacillus ferrooxidans. METHODS AND RESULTS: Resistance to Cu2+ of A. ferrooxidans significantly decreased with the treatment dose of a synthetic QS blocker (5Z)-4-bromo-5 (bromomethylene)-2(5H)-furanone (FUR). Relative differences in expression of the QS genes afeI, afeR and Cu2+ resistance-associated genes afe0329, afe0454 were examined in the presence of Cu2+ and/or FUR compound. The expression of QS genes afeI and afeR increased significantly with 50 mmol l-1 Cu2+ in the culture, while for samples treated with both 50 mmol l-1 Cu2+ and 0.01 MUg ml-1 FUR compound, they showed little changes compared with control, and the expression of afe0329 and afe0454 genes increased slightly either. These results showed that QS system was positively related to the mechanism of Cu2+ resistance. CONCLUSIONS: QS system in A. ferrooxidans involved in its resistance to Cu2+. SIGNIFICANCE AND IMPACT OF THE STUDY: The mechanisms of Cu2+ resistance in A. ferrooxidans could be revealed on a population level rather than on a single-cell level. Our work also provides useful data for further selection of A. ferrooxidans strains with suitable Cu2+ resistance that could probably increase the bioleaching efficiency. PMID- 21535044 TI - Fermentation of lignocellulosic hydrolysate by the alternative industrial ethanol yeast Dekkera bruxellensis. AB - AIM: Testing the ability of the alternative ethanol production yeast Dekkera bruxellensis to produce ethanol from lignocellulose hydrolysate and comparing it to Saccharomyces cerevisiae. METHODS AND RESULTS: Industrial isolates of D. bruxellensis and S. cerevisiae were cultivated in small-scale batch fermentations of enzymatically hydrolysed steam exploded aspen sawdust. Different dilutions of hydrolysate were tested. None of the yeasts grew in undiluted or 1:2 diluted hydrolysate [final glucose concentration always adjusted to 40 g l-1 (0.22 mol l 1)]. This was most likely due to the presence of inhibitors such as acetate or furfural. In 1:5 hydrolysate, S. cerevisiae grew, but not D. bruxellensis, and in 1:10 hydrolysate, both yeasts grew. An external vitamin source (e.g. yeast extract) was essential for growth of D. bruxellensis in this lignocellulosic hydrolysate and strongly stimulated S. cerevisiae growth and ethanol production. Ethanol yields of 0.42 +/- 0.01 g ethanol (g glucose)-1 were observed for both yeasts in 1:10 hydrolysate. In small-scale continuous cultures with cell recirculation, with a gradual increase in the hydrolysate concentration, D. bruxellensis was able to grow in 1:5 hydrolysate. In bioreactor experiments with cell recirculation, hydrolysate contents were increased up to 1:2 hydrolysate, without significant losses in ethanol yields for both yeasts and only slight differences in viable cell counts, indicating an ability of both yeasts to adapt to toxic compounds in the hydrolysate. CONCLUSIONS: Dekkera bruxellensis and S. cerevisiae have a similar potential to ferment lignocellulose hydrolysate to ethanol and to adapt to fermentation inhibitors in the hydrolysate. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study investigating the potential of D. bruxellensis to ferment lignocellulosic hydrolysate. Its high competitiveness in industrial fermentations makes D. bruxellensis an interesting alternative for ethanol production from those substrates. PMID- 21535045 TI - Spirulina enhances the viability of Lactobacillus rhamnosus E/N after freeze drying in a protective medium of sucrose and lactulose. AB - AIMS: Response surface methodology (RSM) was used to optimize a protective medium for enhancing the viability of Lactobacillus rhamnosus E/N cells during lyophilization. METHODS AND RESULTS: Spirulina, sucrose and lactulose were selected, on the basis of a Plackett-Burman factorial design, as important protectants having the following protective effects on cell viability: 102.025, 36.885 and -34.42, respectively. A full-factorial central composite design was applied to determine optimal levels of three used agents. CONCLUSION: The optimal protective medium composition was determined to be: Spirulina 1.304% (w/v), lactulose 5.48% (w/v), and sucrose 13.04% (w/v) (Polish Patent P-393189). The predictive value of cell viability in this medium was 89.619%, and experimental viability obtained during freeze-drying was 87.5%. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, Spirulina was used for the first time as the protective agent in freeze-drying medium, significantly increasing lactobacilli viability and giving synbiotic character of the final product. PMID- 21535046 TI - Polypropylene with embedded copper metal or copper oxide nanoparticles as a novel plastic antimicrobial agent. AB - AIMS: To develop novel polypropylene composite materials with antimicrobial activity by adding different types of copper nanoparticles. METHODS AND RESULTS: Copper metal (CuP) and copper oxide nanoparticles (CuOP) were embedded in a polypropylene (PP) matrix. These composites present strong antimicrobial behaviour against E. coli that depends on the contact time between the sample and the bacteria. After just 4 h of contact, these samples are able to kill more than 95% of the bacteria. CuOP fillers are much more effective eliminating bacteria than CuP fillers, showing that the antimicrobial property further depends on the type of copper particle. Cu2+ released from the bulk of the composite is responsible for this behaviour. Moreover, PP/CuOP composites present a higher release rate than PP/CuP composites in a short time, explaining the antimicrobial tendency. CONCLUSIONS: Polypropylene composites based on copper nanoparticles can kill E. coli bacteria depending on the release rate of Cu2+ from the bulk of the material. CuOP are more effective as antimicrobial filler than CuP. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings open up novel applications of these ion-copper-delivery plastic materials based on PP with embedded copper nanoparticles with great potential as antimicrobial agents. PMID- 21535047 TI - Increasing manganese peroxidase productivity of Phanerochaete chrysosporium by optimizing carbon sources and supplementing small molecules. AB - AIMS: To overproduce manganese peroxidase (MnP) using Phanerochaete chrysosporium. Effects of carbon sources, agricultural by-products and small molecules were tested to enhance the MnP productivity. METHODS AND RESULTS: Various carbon sources and agricultural by-products were compared as the basal medium. A MnP activity of 4.7 +/- 0.31 U ml-1 was obtained using mannose as a carbon source. The enzyme productivity further reached 7.36 +/- 0.05 and 8.77 +/- 0.23 U ml-1 when the mannose medium was supplemented with cyclic adenosine monophosphate (cAMP) and S-adenosylmethionine, respectively. CONCLUSIONS: This study revealed the highest MnP productivity obtained by optimizing the carbon sources and supplementing small molecules. It can provide insight for: (i) making high quantities of enzymes by optimizing media resources and (ii) engineering the global regulatory genes in P. chrysosporium for the onsite production of MnP. SIGNIFICANCE AND IMPACT OF THE STUDY: As MnP is an important enzyme to hydrolyse lignin polymers which protects the plant cell wall from exposing of cellulose fibres, the production of the enzyme is a current demand for biofuel biotechnology. The knowledge generated from this study can help to advance the technology for stable production of MnP. PMID- 21535048 TI - Spore germination of the psychrotolerant, red meat spoiler, Clostridium frigidicarnis. AB - AIMS: To determine germination triggers of Clostridium frigidicarnis, an important spoilage bacterium of chilled vacuum-packed meat. METHODS AND RESULTS: Germination of Cl. frigidicarnis spores in the presence of a range of potential nutrient and non-nutrient germinants was tested by monitoring the fall in optical density and by phase-contrast microscopy. The amino acid L-valine induced strong germination when paired with L-lactate in sodium phosphate under anaerobic conditions. Several other amino acids promoted germination when paired with L lactate in sodium phosphate and the co-germinants NaHCO3 and L-cysteine. Heat activation, while not necessary for germination, increased the rate of germination. Spore germination was not observed when spores were incubated aerobically. CONCLUSIONS: Spores of psychrotolerant Cl. frigidicarnis germinated in the presence of L-valine in combination with L-lactate in sodium phosphate buffer under anaerobic conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: Anaerobic conditions, L-valine and L-lactate, have been identified as triggering germination in Cl. frigidicarnis, and are all present in packs of fresh, vacuum packaged, red meat. This new information adds to what is known about red meat spoilage by cold tolerant clostridia and can be used to develop intervention strategies to prevent meat spoilage. PMID- 21535049 TI - Rapid detection of Vibrio parahaemolyticus by PCR targeted to the histone-like nucleoid structure (H-NS) gene and its genetic characterization. AB - AIMS: The aim of this study was to explore a new PCR target gene for Vibrio parahaemolyticus, based on the histone-like nucleoid structure (H-NS) gene. METHODS AND RESULTS: Primers for the H-NS gene were designed for specificity to V. parahaemolyticus and incorporated into a PCR assay. The PCR assay was able to specifically detect all of the 82 V. parahaemolyticus strains tested, but did not result in amplification in the 47 other Vibrio spp. and nonVibrio spp. strains. The detection limit of the PCR assay was 0.14 pg purified genomic DNA and 1.8 * 10(5) CFU g(-1) spiked oyster samples from V. parahaemolyticus RIMD2210633. Furthermore, a multiplex PCR assay targeting the hns, tdh and trh genes was successfully developed to detect virulent V. parahaemolyticus strains. CONCLUSIONS: The H-NS-based PCR assay developed in this study was sensitive and specific, with great potential for field detection of V. parahaemolyticus in seawater or seafood samples. SIGNIFICANCE AND IMPACT OF THE STUDY: The H-NS gene was validated as a new specific marker gene in PCR assays for accurate detection and identification of V. parahaemolyticus, which has the potential to be applied in diagnostics and taxonomic studies. PMID- 21535050 TI - Deciphering the DNA repair protein, Rad23 from kuruma shrimp Marsupenaeus japonicus: full-length cDNA cloning and characterization. AB - AIMS: Lesions of DNA are removed by nucleotide excision repair (NER) process in the living systems. NER process-related host factors are believed to aid recovery steps during viral integration. Here, we report identification and characterization of a DNA repair molecule Rad23 from kuruma shrimp Marsupenaeus japonicus. METHODS AND RESULTS: The full-length cDNA of M. japonicus Rad23 gene (MjRad23) has 1149 bp coding for a putative protein of 382 amino acids with a 5' untranslated region (UTR) of 92 bp and 3' UTR region of 1116 bp. Quantitative expression analysis revealed MjRad23 is constitutively expressed in all the organs of healthy shrimp, whereas with high level in muscle tissue. Although MjRad23 expression is observed in every haemolymph samplings to post-white spot syndrome virus infection, high expression is recorded at 2 h post infection (h.p.i.). MjRad23 consists of putative functional domains including one ubiquitin domain (UBQ), two ubiquitin-associated domains (UBA) and one heat-shock chaperonin-binding motif (STI1). Multiple alignment of MjRad23 with Rad23 of other species showed highly significant identity ranging from 37 to 53%; however, high homology is observed with Rad23 of Bombyx mori (BmRad23). UBQ domain region alignment revealed maximum of 66% homology with Rad23 of Apis melifera (AmRad23). MjRad23 clustered with invertebrate sector along with insect species in evolution analysis. Three-dimensional structural analyses demonstrated the highest identity between MjRad23 and human Rad23A (hHR23A). CONCLUSIONS: The present work revealed the presence of MjRad23 gene, which is essential in DNA repair process. Further studies are required to clarify the involvement of MjRad23 in NER process. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on identification and characterization of DNA repair protein in crustaceans, which will lead to further investigation to explore the molecular mechanisms behind the NER process. PMID- 21535052 TI - Fatigue and serum carnitine levels in chronic liver disease. PMID- 21535051 TI - The incidence, predictors and management of anaemia and its association with virological response in HCV / HIV coinfected persons treated with long-term pegylated interferon alfa 2a and ribavirin. AB - BACKGROUND: The association of anaemia with outcomes in the HCV/HIV coinfected persons undergoing HCV treatment remains unclear. AIMS: To study the incidence, predictors and management of anaemia, and its association with outcomes among persons treated with pegylated interferon and weight-based ribavirin. METHODS: Retrospective analysis of a prospective controlled treatment trial of HCV/HIV coinfection. RESULTS: Among 329 subjects enrolled, 40% developed anaemia during the first 12-18 weeks of treatment (median haemoglobin decrease at week 4: 2.2 g/dL). Among 169 subjects who achieved early virological response and received therapy for 72 weeks, 55% eventually developed anaemia. However, median haemoglobin levels stayed stable after 12-18 weeks of initial therapy. Among these 169 subjects, 45% were prescribed an erythropoiesis stimulating agent (ESA), with 17% receiving it prior to a drop in haemoglobin meeting protocol definition of anaemia. Only 27% completed the study without any ribavirin dose modification. Age >40 years, lower BMI, zidovudine use and lower entry haemoglobin were significant predictors of anaemia in the multi-covariate model. Among all 329, sustained virological response (SVR) rate was similar in those with or without anaemia (23% vs. 30%; P=0.17) with no evidence of association between anaemia or ESA use and treatment response. CONCLUSIONS: Anaemia is common in HCV/HIV coinfected persons undergoing HCV treatment, and only a minority of them are able to maintain ribavirin dose. Persons with age >40 years, lower baseline haemoglobin and lower baseline BMI should be monitored carefully. Prescription of erythropoiesis stimulating agent is common, but anaemia or erythropoiesis stimulating agent use is not associated with SVR. PMID- 21535053 TI - Growth retardation in the newborn of ulcerative colitis patients can be the consequence of drug therapy. PMID- 21535054 TI - Endoscopic mucosal healing in ulcerative colitis. PMID- 21535056 TI - Transient lower oesophageal sphincter relaxation reducers--have we hit a brick wall? PMID- 21535058 TI - Do dried plums really help constipation? PMID- 21535060 TI - Prevalence of medication-related problems among patients with renal compromise in an Indian hospital. AB - WHAT IS KNOWN AND OBJECTIVE: Patients suffering from renal dysfunction often have multiple medical conditions either as a cause or as a consequence of their renal disease. These patients receive an average of 10-12 medications daily leading to complex dosing schedules and are more likely to develop medication-related problems (MRPs). The objectives of this study were to determine the nature and extent of MRPs in renally compromised patients and to explore the potential clinical significance of the MRPs. The potential for a clinical pharmacist to contribute towards resolving or preventing some of these MRPs was also explored. METHODS: A prospective study was conducted for a period of 9 months in the renal unit of Jagadguru Shri Shivaratheeshwara (JSS) Medical College Hospital, Mysore, India. Patients undergoing dialysis on outpatient basis and patients who were admitted under the care of or referred to the nephrologists for renal dysfunction from other specialties were reviewed. Patterns of the MRPs were identified using an adapted Hepler and Strand criteria. The potential clinical significance of the MRPs and the contribution of the clinical pharmacist in resolving or minimizing some of the MRPs were also explored. RESULTS AND DISCUSSION: Three hundred and twenty-seven MRPs were identified with 308 patients reviewed. The incidence of MRPs was found to be 1.06 +/- 0.85 per patient reviewed. The most common MRP identified in our study was overdose (19.3%) followed by adverse drug reactions (19.0%). Cardiovascular agents (33.6%) followed by anti-infective agents (26.3%) were the most common therapeutic classes of medication implicated in causing MRPs. Twenty-six per cent of the MRPs identified were explored to be potentially moderate or major in clinical significance. The clinical pharmacists' recommendations were accepted in 97% of the cases, which resulted in a change in therapy in 83% of the cases. WHAT IS NEW AND CONCLUSION: Medication-related problems are frequent in renally compromised patients in our patient population. The high level of acceptance of clinical pharmacist's recommendations by the nephrologists demonstrates that clinical pharmacists may help improve overall patient care in this setting. PMID- 21535061 TI - Effect of CYP3A4*1G on the fentanyl consumption for intravenous patient controlled analgesia after total abdominal hysterectomy in Chinese Han population. AB - WHAT IS KNOWN AND OBJECTIVE: Clinical investigations into postoperative intravenous patient-controlled analgesia (PCA) have indicated interindividual differences in fentanyl consumption. Cytochrome P450 3A4 (CYP3A4) is the main metabolism enzyme of fentanyl, and single nucleotide polymorphisms within the CYP3A4 gene may contribute to the variability of fentanyl analgesic efficacy. The aim of this study was to investigate whether the most common genetic variation in Chinese, CYP3A4*1G, has an impact on the fentanyl consumption for intravenous PCA in Chinese Han women undergone abdominal total hysterectomy. METHODS: A total of 79 female patients (American Society of Anesthesiologist physical status I or II) scheduled to undergo elective abdominal total hysterectomy were enrolled. All patients received combined spinal-epidural anaesthesia with bupivacaine. Intravenous fentanyl PCA was provided postoperatively for satisfactory analgesia. The doses of fentanyl consumption were recorded 2, 4, 24 and 48 h after the initiation of PCA postoperatively. Pain at rest and adverse effects were measured with rating scales. CYP3A4*1G was screened by means of direct sequencing and further confirmed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS AND DISCUSSION: Forty-six patients were GG homozygotes, 27 patients were GA heterozygotes, and six patients were AA homozygotes, respectively. The distribution of the CYP3A4*1G allele was consistent with Hardy-Weinberg equilibrium (P>0.05). At 2 and 4 h, the doses of fentanyl required for patients with GA/AA genotypes were 80.0 (45.0, 112.5) MUg and 120.0 (80, 173.8)MUg, respectively, and significantly lower than those for GG homozygotes [91.3 (80.0, 125.0) MUg and 169.0 (112.5, 226.3) MUg, respectively, P<0.05]. There was trend of decreasing fentanyl consumption at 24 and 48h in patients with GA/AA genotypes, relative to GG homozygotes, but the difference was not statistical significant (P>0.05). WHAT IS NEW AND CONCLUSIONS: CYP3A4*1G has an impact on the analgesic effect of fentanyl in Chinese Han subjects. Further validation of our results in a well-powered study would be helpful. PMID- 21535062 TI - On good and bad forms of medicalization. AB - The ongoing 'enhancement' debate pits critics of new self-shaping technologies against enthusiasts. One important thread of that debate concerns medicalization, the process whereby 'non-medical' problems become framed as 'medical' problems. In this paper I consider the charge of medicalization, which critics often level at new forms of technological self-shaping, and explain how that charge can illuminate--and obfuscate. Then, more briefly, I examine the charge of pharmacological Calvinism, which enthusiasts, in their support of technological self-shaping, often level at critics. And I suggest how that charge, too, can illuminate and obfuscate. Exploring the broad charge of medicalization and the narrower counter charge of pharmacological Calvinism leads me to conclude that, as satisfying as it can be to level one of those charges at our intellectual opponents, and as tempting as it is to lie down and rest with our favorite insight, we need to gather the energy to have a conversation about the difference between good and bad forms of medicalization. Specifically, I suggest that if we consider the 'medicalization of love,' we can see why critics of and enthusiasts about technological self-shaping should want (and in some cases have already begun) to distinguish between good and bad forms of such medicalization. PMID- 21535063 TI - Ethical concerns regarding commercialization of deep brain stimulation for obsessive compulsive disorder. AB - The United States Food and Drug Administration's recent approval of the commercial use of Deep Brain Stimulation (DBS) as a treatment for Obsessive Compulsive Disorder (OCD) will be discussed within the context of the existing USA regulatory framework. The purpose will be to illustrate the current lack of regulation and oversight of the DBS market, which has resulted in the violation of basic ethical norms. The discussion will focus on: 1) the lack of available evidence on procedural safety and efficacy, 2) the numerous conflicts of interest held by research investigators, and 3) the ambiguity of both aforementioned categories due to an inherent lack of transparency in the research. It is argued that in order to address these issues, ethical analyses of DBS for psychiatric disorders must include the role of the industry forces that have become the primary impetus for this research. As such, DBS for OCD serves as an important case example in studies of neurotechnology and innovative surgery. PMID- 21535064 TI - The place of God in synthetic biology: how will the Catholic Church respond? AB - Some religious believers may see synthetic biology as usurping God's creative role. The Catholic Church has yet to issue a formal teaching on the field (though it has issued some informal statements in response to Craig Venter's development of a 'synthetic' cell). In this paper I examine the likely reaction of the Catholic Magisterium to synthetic biology in its entirety. I begin by examining the Church's teaching role, from its own viewpoint, to set the necessary backround and context for the discussion that follows. I then describe the Church's attitude to science, and particularly to biotechnology. From this I derive a likely Catholic theology of synthetic biology. The Church's teachings on scientific and biotech research show that it is likely to have a generally positive disposition to synbio, if it and its products can be acceptably safe. Proper evaluation of, and protection against, risk will be a significant factor in determining the morality of the research. If the risks can be minimized through regulation or other means, then the Church is likely to be supportive. The Church will also critique the social and legal environment in which the research is done, evaluating issues such as the patenting of scientific discoveries and of life. PMID- 21535065 TI - Evaluating interventions in health: a reconciliatory approach. AB - Health-related Quality of Life measures have recently been attacked from two directions, both of which criticize the preference-based method of evaluating health states they typically incorporate. One attack, based on work by Daniel Kahneman and others, argues that 'experience' is a better basis for evaluation. The other, inspired by Amartya Sen, argues that 'capability' should be the guiding concept. In addition, opinion differs as to whether health evaluation measures are best derived from consultations with the general public, with patients, or with health professionals. And there is disagreement about whether these opinions should be solicited individually and aggregated, or derived instead from a process of collective deliberation. These distinctions yield a wide variety of possible approaches, with potentially differing policy implications. We consider some areas of disagreement between some of these approaches. We show that many of the perspectives seem to capture something important, such that it may be a mistake to reject any of them. Instead we suggest that some of the existing 'instruments' designed to measure HR QoLs may in fact successfully already combine these attributes, and with further refinement such instruments may be able to provide a reasonable reconciliation between the perspectives. PMID- 21535066 TI - Multiple health risk perception and information processing among African Americans and whites living in poverty. AB - We investigated the risk-information-processing behaviors of people living at or near the poverty line. Because significant gaps in health and communication exist among high- and low-income groups, increasing the information seeking and knowledge of poor individuals may help them better understand risks to their health and increase their engagement in health-protective behaviors. Most earlier studies assessed only a single health risk selected by the researcher, whereas we listed 10 health risks and allowed the respondents to identify the one that they worried about most but took little action to prevent. Using this risk, we tested one pathway inspired by the risk information seeking and processing model to examine predictors of information insufficiency and of systematic processing and extended this pathway to include health-protective action. A phone survey was conducted of African Americans and whites living in the southern United States with an annual income of <=$35,000 (N= 431). The results supported the model pathway: worry partially mediated the relationship between perceived risk and information insufficiency, which, in turn, increased systematic processing. In addition, systematic processing increased health-protective action. Compared with whites and better educated respondents, African Americans and respondents with little education had significantly higher levels of information insufficiency but higher levels of systematic processing and health-protective action. That systematic processing and knowledge influenced health behavior suggests a potential strategy for reducing health disparities. PMID- 21535067 TI - Relationship of chromatic visual-evoked potentials and the changes of foveal photoreceptor layer in central serous chorioretinopathy patients. AB - PURPOSE: To investigate the relative involvement of chromatic and achromatic visual subsystems in central serous chorioretinopathy, and to correlate the function changes with the changes of the foveal photoreceptor layer using Fourier domain optical coherence tomography (FD-OCT). METHODS: Central serous chorioretinopathy patients and control subjects were tested and compared. Equiluminant Chromatic sinusoidal gratings were presented in a pattern onset offset mode. We measured the distance between the internal limiting membrane (ILM) and the external limiting membrane (ELM) on FD-OCT images. RESULTS: Visual evoked potential mean latency was delayed significantly in central serous chorioretinopathy patients compared to controls. The visual evoked potential delay was greater for chromatic than for achromatic stimuli. Retinal thickness from ILM to ELM was associated significantly and selectively with short wavelength-sensitive (S) cone visual evoked potential latency (r = -0.40, p = 0.032). CONCLUSIONS: These results are consistent with data that indicate the loss of photoreceptors in central serous chorioretinopathy resulting in a reduced thickness of the outer nuclear layer. Additionally, they are consistent with data which indicate that the photoreceptor loss is relatively greater in cones. The S cone pathway was affected the most. PMID- 21535068 TI - A national survey of diagnostic tests reported by UK community optometrists for the detection of chronic open angle glaucoma. AB - PURPOSE: In the UK, the majority of cases of chronic open angle glaucoma are detected by community optometrists following a routine sight test. However, there is potential for variability in case finding strategies used. The aim of this study was to carry out a national web-based survey to determine current diagnostic tests used by optometrists in glaucoma case finding. METHODS: Optometrists on the Association of Optometrists (AOP) electronic database were invited to participate. The survey was open for 16 weeks between April and July 2008. RESULTS: A total of 1875 optometrists were eligible to enter the survey, of which 1264 answered the questions relating to diagnostic equipment. Respondents were asked to indicate their usual method of examining the optic nerve head. Direct ophthalmoscopy only was used by 25% with the majority (62%) using a combination of direct and slit-lamp binocular indirect methods. The vast majority of optometrists (78%) used non-contact tonometry to measure intraocular pressure, with only 16% routinely using a Goldmann or Perkins applanation tonometer. The perimeter most frequently used was either one of the Henson range of instruments (39%) or the Humphrey Field Analyser (22%). A smaller number of optometrists (<5%) had access to more specialised imaging equipment, such as HRT, GDx or OCT. CONCLUSIONS: The results of the survey demonstrate that UK optometrists are well equipped to carry out case finding for chronic open angle glaucoma, although there is a lack of standardisation with respect to equipment used. PMID- 21535069 TI - Accommodative amplitude required for sustained near work. AB - PURPOSE: Many practitioners base the prescription of near vision additions on the assertion that only one half or two-thirds of an individual's amplitude of accommodation is sustainable for a prolonged period. To better understand how much eye focus needs to be restored for presbyopic corrections to be adequate, this study investigated the robustness of the pre-presbyopic human accommodative system during a sustained and intensive near vision task. METHODS: Twenty-one pre presbyopic volunteers (aged 26.1 +/- 4.7 years) participated in the study. Binocular subjective amplitude of accommodation was measured before and after a prolonged reading exercise, using the RAF rule. During the 30 min reading task, the subject's closest comfortable eye-to-text distance and pupil size was monitored. Accommodative accuracy to 0.2, 1.0, 2.0, 3.0 and 4.0 D stimuli was determined objectively using a validated binocular open-view autorefractor immediately before, and after the reading task. RESULTS: Amplitude of accommodation (p=0.09) and accommodative accuracy (p>0.05) were statistically unchanged following the intensive near task. The mean proportion of accommodation exerted throughout the near exercise was 80.6% (range 45.3 +/- 3.7 to 96.6 +/- 4.3%), which increased as the task progressed (F=2.24, p=0.02). The mean percentage of accommodation utilised increased with subject age (r=0.517, p = 0.016). CONCLUSION: The pre-presbyopic human accommodative system is robust to fatigue during intense and prolonged near work. A greater proportion of one's amplitude of accommodation may be continuously exerted than previously suggested. PMID- 21535070 TI - Serum free cortisol as an ancillary tool in the interpretation of the low-dose 1 MUg ACTH test. AB - OBJECTIVE: Serum free cortisol, rather than serum total cortisol (TC), determines glucocorticoid activity in vivo, but how the considerable inter-subject variation in ambient serum free cortisol affects the outcome of dynamic hypothalamic pituitary-adrenal (HPA) assessment in noncritically ill subjects is unknown. DESIGN, PATIENTS AND MEASUREMENTS: We performed the low-dose 1-MUg ACTH test in 75 subjects referred for HPA evaluation. Serum TC was determined by a chemiluminescence method, and serum free cortisol was measured by the same method following equilibrium dialysis. In a subset of these patients, salivary cortisol was also measured. RESULTS: Mean fraction of free cortisol was 5.07 +/- 4.08% (+/ SD; range 1.77-10.1%). Although no correlation was seen between TC and the fraction (%) of free serum cortisol, a positive correlation existed between baseline total and free cortisol (R = 0.539 P = 0.01), as well as between peak ACTH-stimulated total and free cortisol (R = 0.619; P = 0.01). There was no correlation between baseline salivary cortisol and serum free cortisol and between peak ACTH-stimulated salivary and serum free cortisol. Using the lowest attained peak serum free cortisol in subjects whose TC response to ACTH was normal (>= 500 nM), the minimal 'pass' level for normal serum free cortisol response to 1 MUg ACTH was set at 25.0 nM. Five of the 19 subjects showing subnormal TC response to 1 MUg ACTH had normal serum free cortisol response. CONCLUSIONS: Discrepancies between the peak free and TC were noted mostly for subjects whose ACTH-stimulated TC peaked between 440 and 580 nm. At this range, the measurement of serum free cortisol allows further refinement of the assessment of borderline responses to 1-MUg ACTH. PMID- 21535071 TI - An objective scoring tool in the management of patients with pituitary apoplexy. PMID- 21535072 TI - Determinants and outcome of amiodarone-associated thyroid dysfunction. AB - OBJECTIVE: Amiodarone is frequently associated with thyroid dysfunction. Identifying predictors for amiodarone-associated thyroid dysfunction and assessing treatment outcome may aid clinicians in daily practice. METHODS: We included 303 consecutive patients with amiodarone therapy for cardiac arrhythmias (260 with atrial fibrillation and 43 with ventricular arrhythmias). Thyroid function tests were performed every 6 months. RESULTS: Mean age was 63 +/- 12 years and 66% was male. After median follow-up of 3.3 (0.1-24) years, 23 (8%) patients developed amiodarone-associated thyrotoxicosis (incidence rate 1.9 per 100 person years) and 18 (6%) hypothyroidism (incidence rate 1.1 per 100 person years). The only predictor for amiodarone-associated thyrotoxicosis was age <62 years [HR = 2.4 (95% CI 1.0-5.7), P = 0.05]. Predictors for amiodarone-associated hypothyroidism were thyroid stimulating hormone >1.4 mU/l at baseline [HR = 5.1 (95% CI 1.1-22.4), P = 0.03], left ventricular ejection fraction <45% [HR = 3.8 (95% CI 1.1-13.3), P = 0.04] and diabetes mellitus at baseline [HR = 3.3 (95% CI 1.1-10.3), P = 0.04]. Gender was not a predictor for amiodarone-associated thyroid dysfunction. Five out of 12 (42%) patients with thyrotoxicosis exhibited spontaneous normalization of thyroid function on continuation of amiodarone therapy. Mean time to normalization in the total group was 6.2 +/- 3.3 months, with no difference between continuing or discontinuing amiodarone (6.6 +/- 3.8 vs 5.8 +/- 2.8 months, P = 0.5). CONCLUSIONS: During median follow-up of 3.3 years, the incidence of amiodarone-associated thyrotoxicosis was higher compared to hypothyroidism. Only general predictors for amiodarone-associated thyroid dysfunction were observed. Discontinuation of amiodarone did not influence treatment outcome. PMID- 21535073 TI - Growth hormone is positively associated with surrogate markers of bone turnover during puberty. AB - BACKGROUND: Puberty is characterized by increases in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) and the pubertal growth spurt. Bone formation and resorption also increase, consistent with increased bone metabolism. OBJECTIVE: To determine the relationship between pubertal bone metabolism, GH and IGF-1. We hypothesized that bone turnover peaks at the time of greatest pubertal GH secretion. DESIGN AND SUBJECTS: Subjects included 86 girls and boys, 9-17 years-old (BMI 10th-90th percentiles). Because higher endogenous GH secretion is associated with a higher nadir following oral glucose, we used the GH nadir following a 2-h OGTT as indicative of GH status. Fasting serum IGF 1, aminoterminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal collagen crosslinks (CTX) were obtained. Subjects were grouped per expected timing of peak growth. Group 1: Tanner 1 girls and Tanner 1-2 boys (period preceding peak growth), Group 2: Tanner 2-3 girls and Tanner 3-4 boys (period of peak growth) and Group 3: Tanner 4-5 girls and Tanner 5 boys (period following peak growth). RESULTS: GH peaked at mid-puberty (Group 2) and IGF-1 in late puberty (Group 3). P1NP and CTX were highest in mid-puberty compared with early and late puberty (P = 0.0009 and 0.006 in girls and P = 0.005 and 0.04 in boys). GH, but not IGF-1, correlated with P1NP (r = 0.46 in both genders, P <= 0.008) and CTX (r = 0.37 and 0.38, P = 0.04 and 0.02 in girls and boys, respectively). Similarly, on regression modelling, GH (but not IGF-1) predicted both bone turnover markers in both genders. CONCLUSION: GH is strongly associated with pubertal bone metabolism, independent of systemic IGF-1 in girls and boys. PMID- 21535074 TI - Thyroid status in a large cohort of patients with mental retardation: the TOP-R (Thyroid Origin of Psychomotor Retardation) study. AB - OBJECTIVE: Abnormalities in thyroid state may affect development and function of the brain and result in mental retardation (MR). Thyroid parameters have not been systematically investigated in institutionalized MR subjects. The objective is to measure thyroid parameters in a novel cohort of 946 institutionalized subjects. DESIGN: The TOP-R (Thyroid Origin of Psychomotor Retardation) study is a cross sectional nation-wide multicentre study. PATIENTS: Subjects with unexplained MR. RESULTS: The majority of the MR subjects had thyroid parameters within the reference range used in our laboratory. Antiepileptic drugs (AEDs) use affected thyroid hormones (T4: 102.1 +/- 1.2 vs 83.9 +/- 1.2 nmol/l, P < 1 * 10(-24) ; FT4: 18.0 +/- 0.2 vs 16.1 +/- 0.2 pmol/l, P < 1 * 10(-9) ; T3: 1.72 +/- 0.02 vs 1.57 +/- 0.02 nmol/l, P < 1 * 10(-9) ; and rT3: 0.37 +/- 0.01 vs 0.27 +/- 0.01 nmol/l, P < 1 * 10(-28) in subjects without vs with AEDs). The prevalence of unrecognized primary hypothyroidism and hyperthyroidism was 5.2% and 2.8%, respectively. CONCLUSIONS: We report thyroid parameters in a cohort of institutionalized subjects with MR. Our findings substantiate the fact that AEDs affect thyroid hormone levels. Future studies will be employed to investigate genetic causes of MR related to abnormalities in thyroid hormone homeostasis. PMID- 21535075 TI - Association of plasma adiponectin levels with hearing thresholds in adults. AB - OBJECTIVE: Obesity is an independent risk factor for age-related hearing impairment. Adiponectin is one of the major adipocytokines secreted by adipose tissue. The aim of our study was to examine whether there is an association between plasma adiponectin concentrations and hearing sensitivity in adults. DESIGN AND METHODS: We recruited 954 adults aged 40-86 years, with normal or symmetrical sensorineural hearing loss and normal cognitive function. Backward stepwise multivariate linear regression was performed to assess the association between plasma adiponectin concentrations and hearing level Z-scores. Further, backward stepwise logistic regression analysis was performed to determine the risk of hearing impairment by plasma adiponectin concentration. RESULTS: Adiponectin concentrations were lower, and waist circumference (WC) was higher in subjects with Z-high in the upper 50% of Z-high. Z-high (correlation coefficient: beta = -0.02; standard error [SE] = 0.01; P = 0.003), but not Z-middle or Z-low, was significantly associated with plasma adiponectin concentrations after adjusting for WC, systemic diseases, smoking and alcohol consumption. The risk of hearing impairment for high frequencies, but not low or middle frequencies, decreased by 0.97-fold (odds ratio +/- SE = 0.97 +/- 0.02, P = 0.048, 95% confidence interval = 0.93-1.00) for every 1-unit increase in adiponectin concentration, after adjusting for age, gender, WC, systemic diseases, smoking and alcohol consumption. CONCLUSION: Plasma adiponectin may protect peripheral hearing function, particularly that related to high frequencies. Adiponectin may be a mediator of obesity-associated, age-related hearing impairment. PMID- 21535076 TI - Cytokine mRNA profile of alveolar T lymphocytes and macrophages in patients with systemic sclerosis suggests a local Tr1 response. AB - The development of an autoimmune disease like systemic sclerosis (SSc) is suspected to be driven by an activated T lymphocyte subset, expressing a cytokine profile specific to the disease. To further characterize the type of immune reaction in SSc, we searched for a broad panel of cytokine messenger ribonucleic acids (mRNAs) in T lymphocytes and monocytes/macrophages from paired samples of bronchoalveolar lavage fluid and peripheral blood in 18 patients and 16 age- and sex-matched controls. RNA from CD3(+) T lymphocytes and CD14(+) monocytes/macrophages was examined by means of the reverse transcriptase polymerase chain reaction. SSc alveolar T lymphocytes expressed a cytokine profile suggestive of a mixed Th1/Th2 reaction, showing an increased frequency of mRNA for interleukin (IL)-10, IL-6 and interferon (IFN)gamma, while IL-1beta, IFNgamma and tumour necrosis factor beta were expressed in blood T lymphocytes in a higher percentage of patients with SSc than controls. SSc alveolar T cells expressed IL-10 mRNA more often than peripheral T cells, a phenomenon not found in controls and which may point at local IL-10 activation/response in SSc lung. Transforming growth factor beta mRNA was present in all alveolar as well as peripheral blood T cell samples in patients and controls. The cytokine mRNA profile in SSc with interstitial lung disease (ILD) was similar to the profile found in SSc without ILD. Our findings point at a mixed Th1/Th2 reaction in SSc and may indicate regulatory T 1 cell activation/response in the lungs of patients with SSc. PMID- 21535077 TI - HLA class II alleles and chronic hepatitis C virus infection. AB - The aim of this study was to investigate association of human leucocyte antigens (HLA)-DRB1 and DQB1 polymorphisms with hepatitis C virus (HCV) infection and with the occurrence of severe liver fibrosis/cirrhosis in chronically infected patients. Ninety-nine white patients, from southeast Brazil, with confirmed HCV chronic infection were included in the study. Severe fibrosis/cirrhosis (METAVIR scores F3-F4) was present in 49 patients. HLA-DRB1 specificities and DRB1*11 and DQB1* alleles were determined by PCR-SSP, and their frequencies were compared between patients and a control group of 103 healthy white Brazilian individuals. The results confirmed previous reports of the association of DRB1*11 and DQB1*03 with protection from chronic HCV infection, but did not confirm their association with protection from severe fibrosis/cirrhosis. Furthermore, the results suggested that the polymorphic sites on HLA molecules responsible for protection from chronic HCV infection are encoded not only by the DRB1*1101 and DQB1*0301, as suggested in the literature, but also by other DRB1*11 and DQB1*03 alleles. Thus, we hypothesized that the common polymorphic residues shared by different DRB1*11 and/or DQB1*03 alleles might be responsible for selection of viral epitopes for presentation to CD4(+) T cells, leading to an efficient immune response against the virus. PMID- 21535078 TI - Different perforin expression in peripheral blood and prostate tissue in patients with benign prostatic hyperplasia and prostate cancer. AB - Perforin (P) is a prototypical cytotoxic molecule involved in cell-mediated immunity against various pathogens, alloantigens and particularly different tumours. The purpose of this study was to determine P expression in different lymphocyte subpopulations isolated from peripheral blood and prostate tissue of patients with benign prostatic hyperplasia (BPH) and prostate cancer (PCa) and compare it with the P expression found in the control group. Twenty subjects were recruited in each of the groups. Prostate mononuclear cells of the BPH and PCa tissues were isolated by enzymatic digestion and gradient density centrifugation, whereas peripheral blood mononuclear cells were isolated by gradient density centrifugation alone. Cells and tissue samples were labelled using monoclonal antibodies against P and different surface antigens (CD3, CD4, CD8 and CD56) and analysed by immunofluorescence and flow cytometry. Total P expression in peripheral blood lymphocytes did not differ significantly between BPH/PCa patients and control group, although the BPH and PCa tissue showed lower P expression level. A negative correlation between prostate-specific antigen levels and the overall percentage of P(+), CD3(+) CD56(-) P(+) , and CD3(-) CD56(+) P(+) cells in the prostate tissue was observed only in patients with PCa. Our findings indicate that the low frequency of P(+) lymphocytes, including T, NKT and NK cells, in the prostate tissue of patients with BPH and, particularly, PCa could be the consequence of local tissue microenvironment and one of the mechanisms involved in the pathogenesis of prostate hyperplasia following malignant alteration. PMID- 21535079 TI - What formyl peptide receptors, if any, are triggered by compound 43 and lipoxin A4? AB - In this study, we determined receptor preferences for compound 43, a nitrosylated pyrazolone derivative, and the eicosanoid lipoxin A(4) (LXA(4)), potent anti inflammatory mediators in many experimental in vivo models. Their effects have been suggested to be mediated through binding to formyl peptide receptor (FPR)2 [earlier known as formyl peptide receptor-like 1 or the lipoxin A(4) receptor (ALXR)], one of the two members of the FPR family expressed in neutrophils. Compound 43 activates all neutrophil functions investigated, whereas LXA(4) induces a unique inhibiting pathway suggested to involve beta-arrestin binding as an early signalling step, but not a transient rise in intracellular Ca(2+). We show that compound 43 can activate not only FPR2 but also FPR1, the other neutrophil receptor in the FPR family, and FPR1 is actually the preferred receptor in human neutrophils and possibly also in the murine equivalent. LXA(4) analogues from two commercial sources were used, and neither of these induced any translocation of beta-arrestin as measured in an enzyme fragment complementation assay. The conclusions drawn from these experiments are that neither compound 43 nor LXA(4) works as FPR2 agonists in neutrophils, findings of importance for a proper interpretation of results obtained with these compounds as regulators of inflammation. PMID- 21535080 TI - Analysis of properties and proinflammatory functions of cockroach allergens Per a 1.01s. AB - Cockroaches have been identified as one of the major indoor allergens inducing perennial rhinitis and asthma. Per a 1s are a group of the major allergens from American cockroach. Although Per a 1s are major allergens from American cockroach, factors contributing to the allergenicity of Per a 1s are still poorly defined. To investigate the effects of Per a 1s on the expression of PARs and the release of proinflammatory cytokines from mast cells. Per a 1.0101 and Per a 1.0104 were cloned from American cockroach and then expressed in Eschericia coli. The purified allergens were used to stimulate P815 mast cells, and the expression of protease-activated receptors (PARs) was determined by real-time RT-PCR and flow cytometry. The levels of IL-4 and IL-13 in culture media were detected with ELISA. Sera from 80 and 77.3% of cockroach allergy patients reacted to recombinant Per a (rPer a) 1.0101 and rPer a 1.0104, confirming they are major allergens. Both rPer a 1.0101 and rPer a 1.0104 had no enzymatic activity, but rPer a 1.0101 upregulated the expression of PAR-1 and PAR-2, and rPer a 1.0104 enhanced the expression of PAR-1 and PAR-4 proteins. Both recombinant allergens were able to increase the release of IL-4 and IL-13 from P815 mast cells. This is the first study aiming to investigate functions of group 1 allergens of American cockroach. rPer a 1.0101 and rPer a 1.0104 have the capacity to upregulate the expression of PARs and to enhance Th2 cytokine production in mast cells. PMID- 21535081 TI - A single-stranded DNA-cross-reactive immunogenic epitope of human homocysteine inducible endoplasmic reticulum protein. AB - The mechanism involved in generating anti-DNA antibodies (Abs) remains unclear, as DNA is poorly immunogenic. Molecular mimicry between DNA and non-DNA substances has been implicated as a possible mechanism. We previously reported that homocysteine-inducible endoplasmic reticulum protein (Herp), which is induced by endoplasmic reticulum stress, is recognized by anti-double-stranded DNA (dsDNA) IgG from patients with systemic lupus erythematosus and that immunization with Herp elicits anti-dsDNA Abs in BALB/c mice. In this study, we observed that anti-single-stranded DNA (ssDNA) Abs were also generated in Herp immunized BALB/c mice and established an anti-Herp monoclonal antibody (mAb), HT4, which specifically cross-reacted with ssDNA. The epitope of the HT4 mAb on Herp, 'EPAGSNR', was identified by screening a synthetic peptide library. The binding of the HT4 mAb to the peptide was competitively inhibited by ssDNA. Immunization of the epitope peptide elicited anti-ssDNA Abs in BALB/c mice. These results indicate that the epitope exists in a human self-protein, mimics ssDNA and shows antigenicity for anti-ssDNA Abs in normal mice. Anti-ssDNA Abs are often found in patients with drug-induced lupus erythematosus. Treatment with representative drugs that cause drug-induced lupus (chlorpromazine, procainamide and hydralazine) induced Herp expression and apoptosis in HeLa cells. These findings suggest that molecular mimicry between Herp and ssDNA is involved in anti-ssDNA Ab production in drug-induced lupus. PMID- 21535082 TI - Measuring autoantibodies against IL-17F and IL-22 in autoimmune polyendocrine syndrome type I by radioligand binding assay using fusion proteins. AB - Autoantibodies against interleukin (IL)-17A, IL-17F and IL-22 have recently been described in patients with autoimmune polyendocrine syndrome type I (APS I), and their presence is reported to be highly correlated with chronic mucocutaneous candidiasis (CMC). The aim of this study was to develop a robust high-throughput radioligand binding assays (RLBA) measuring IL-17F and IL-22 antibodies, to compare them with current enzyme-linked immunosorbent assays (ELISA) of IL-17F and IL-22 and, moreover, to correlate the presence of these antibodies with the presence of CMC. Interleukins are small molecules, which makes them difficult to express in vitro. To overcome this problem, they were fused as dimers, which proved to increase the efficiency of expression. A total of five RLBAs were developed based on IL-17F and IL-22 monomers and homo- or heterodimers. Analysing the presence of these autoantibodies in 25 Norwegian APS I patients revealed that the different RLBAs detected anti-IL-17F and anti-IL-22 with high specificity, using both homo- and heterodimers. The RLBAs based on dimer proteins are highly reproducible with low inter- and intravariation and have the advantages of high throughput and easy standardization compared to ELISA, thus proving excellent choices for the screening of IL-17F and IL-22 autoantibodies. PMID- 21535083 TI - The effect of extremely preterm birth on attachment organization in late adolescence. AB - BACKGROUND: Prior studies have examined the impact of preterm birth on the quality of the attachment relationship to the mother in infancy, but few have examined extremely preterm born infants and almost no data have been reported on prematurity and its impact on the attachment organization attained after childhood. METHODS: Thirty-nine adolescents born extremely preterm and 39 full term born control participants were assessed with the Adult Attachment Interview. RESULTS: The prematurely born showed lower scores regarding measures of attachment security and, in particular, a higher proportion of insecure dismissive patterns. This difference seemed to be clear and persistent even when controlled for intelligence and socio-economic variables. CONCLUSIONS: Because insecure attachment as well as prematurity may be considered as significant risk factors for developing psychopathology, they deserve careful attention in future research and clinical follow-ups. PMID- 21535084 TI - Psychometric properties of a motor skill checklist for 3- to 5-year-old children. AB - BACKGROUND: Early identification of children with developmental co-ordination disorder is important. Teachers may be very useful in this identification process. The objective of this study was to develop a motor skill checklist (MSC) for 3- to 5-year-old children to be completed by teachers, and to establish the psychometric properties of this new instrument. METHODS: An MSC of 28 functional items was constructed in close consideration with clinical experts and teachers. In regular schools, 366 pre-school children were rated with the MSC by their teachers (n= 111). To determine test-retest reliability, each teacher completed 4 weeks later the MSC again for one randomly selected child. In 22 classes with two teachers sharing the job, both teachers were asked to fill in the questionnaire. A subgroup of children was also tested with the Movement Assessment Battery for Children (M-ABC; n= 122). All teachers were invited to complete a questionnaire to evaluate the MSC. RESULTS: The internal consistency of the MSC was high. The test-retest reliability was good. Inter-rater reliability was adequate except in the 5-year-old children. There was a strong correlation between the checklist and the M-ABC, establishing concurrent validity. Most teachers judged the MSC as easy or rather easy to complete. CONCLUSIONS: The MSC is a reliable, valid and useful instrument to identify and assess young children with motor difficulties. PMID- 21535086 TI - Show the data, don't conceal them. PMID- 21535087 TI - Parasympathetic nervous system: A new therapeutic target in cardiovascular disease? PMID- 21535088 TI - Linking transformational leadership to nurses' extra-role performance: the mediating role of self-efficacy and work engagement. AB - AIMS: This paper is a report of a social cognitive theory-guided study about the link between supervisors' transformational leadership and staff nurses' extra role performance as mediated by nurse self-efficacy and work engagement. BACKGROUND: Past research has acknowledged the positive influence that transformational leaders have on employee (extra-role) performance. However, less is known about the psychological mechanisms that may explain the links between transformational leaders and extra-role performance, which encompasses behaviours that are not considered formal job requirements, but which facilitate the smooth functioning of the organization as a social system. METHODS: Seventeen supervisors evaluated nurses' extra-role performance, the data generating a sample consisting of 280 dyads. The nurses worked in different health services in a large Portuguese hospital and the participation rate was 76.9% for nurses and 100% for supervisors. Data were collected during 2009. A theory-driven model of the relationships between transformation leadership, self-efficacy, work engagement and nurses' extra-role performance was tested using Structural Equation Modelling. RESULTS: Data analysis revealed a full mediation model in which transformational leadership explained extra-role performance through self efficacy and work engagement. A direct relationship between transformational leadership and work engagement was also found. CONCLUSION: Nurses' supervisors with a transformational leadership style enhance different 'extra-role' performance in nurses and this increases hospital efficacy. They do so by establishing a sense of self-efficacy but also by amplifying their levels of engagement in the workplace. PMID- 21535089 TI - Examination of the utility of the promoting action on research implementation in health services framework for implementation of evidence based practice in residential aged care settings. AB - AIM: This study examined the relevance and fit of the PARiHS framework (Promoting Action on Research Implementation in Health Services) as an explanatory model for practice change in residential aged care. BACKGROUND: Translation of research knowledge into routine practice is a complex matter in health and social care environments. Examination of the environment may identify factors likely to support and hinder practice change, inform strategy development, predict and explain successful uptake of new ways of working. Frameworks to enable this have been described but none has been tested in residential aged care. METHODS: This paper reports preliminary qualitative analyses from the Encouraging Best Practice in Residential Aged Care Nutrition and Hydration project conducted in New South Wales in 2007-2009. We examined congruence with the PARiHS framework of factors staff described as influential for practice change during 29 digitally recorded and transcribed staff interviews and meetings at three facilities. FINDINGS: Unique features of the setting were flagged, with facilities simultaneously filling the roles of residents' home, staff's workplace and businesses. Participants discussed many of the same characteristics identified by the PARiHS framework, but in addition temporal dimensions of practice change were flagged. CONCLUSION: Overall factors described by staff as important for practice change in aged care settings showed good fit with those of the PARiHS framework. This framework can be recommended for use in this setting. Widespread adoption will enable cross-project and international synthesis of findings, a major step towards building a cumulative science of knowledge translation and practice change. PMID- 21535090 TI - 'Safe passage': pregnant Iranian Kurdish women's choice of childbirth method. AB - AIM: This article is a report of a grounded theory study of the influence of emotions on women's selection of a method of childbirth. BACKGROUND: There is substantial evidence to indicate that a pregnant woman's emotions play an important role in the decision-making process of selecting a child delivery method. Despite this, however, there is a notable lack of research about the relationship between pregnant women's emotions and their choice of a childbirth method in developing countries. METHODS: A qualitative study using the grounded theory approach was conducted. The data were collected from 22 Iranian Kurdish pregnant women in their third trimester using semi-structured interviews. Concurrent data collection and analysis took place between 2008 and 2009. A cumulative process of theoretical sampling and constant comparison was used to identify concepts and then expand, validate, and clarify them. FINDINGS: The substantive grounded theory that was identified from data analysis was 'safe passage'. 'Safe passage' involved five phases that were not mutually exclusive in their occurrence. The five phases of the 'safe passage' theory that were identified from the data analysis were: 'safety of baby', 'fear', 'previous experience', 'social support' and 'faith'. The goal of 'safe passage' was to achieve a healthy delivery and to ensure the health of the newborn. CONCLUSION: 'Safe passage' was a process used to determine how the emotions of pregnant Iranian Kurdish women influenced their choice of the mode of child delivery. More research is needed in this field to develop a body of knowledge beneficial to midwifery education and practice. PMID- 21535091 TI - Non-clinical interventions that increase the uptake and success of vaginal birth after caesarean section: a systematic review. AB - AIM: The aim of this study was to review non-clinical interventions that increase the uptake and/or the success rates of vaginal birth after caesarean section. BACKGROUND: Increases in rates of caesarean section are largely due to repeat caesarean section in a subsequent pregnancy. Concerns about vaginal birth after caesarean section have centred on the risk of uterine rupture. Nonetheless, efforts to increase the vaginal birth rate in these women have been made. This study reviews these in relation to non-clinical interventions. DATA SOURCES: Literature was searched up until December 2008 from five databases and a number of relevant professional websites. REVIEW METHODS: A systematic review of quantitative studies that evaluated a non-clinical intervention for increasing the uptake and/or the success of vaginal birth after caesarean section was undertaken. Only study designs that involved a comparison group were included. Further exclusions were imposed for quality using the Critical Skills Appraisal Programme. RESULTS: National guidelines influence vaginal birth after caesarean section rates, but a greater effect is seen when institutions develop local guidelines, adopt a conservative approach to caesarean section, use opinion leaders, give individualized information to women, and give feedback to obstetricians about mode of birth rates. Individual clinician characteristics may impact on the number of women choosing and succeeding in vaginal birth after caesarean section. There is inconsistent evidence that having private health insurance may be a barrier to the uptake and success of vaginal birth after caesarean section. CONCLUSION: Non-clinical factors can have a significant impact on vaginal birth after caesarean section uptake and success. PMID- 21535092 TI - Effectiveness of a health promotion programme for farmers and fishermen with type 2 diabetes in Taiwan. AB - AIMS: This paper is a report of a study examining the diabetes control and foot self-care capability in farmers and fishermen following introduction of a multi stage, multi-disciplinary team and community-based small group health promotion programme. BACKGROUND: Improving the control of diabetes is a critical issue in Taiwan because mortality rates are increasing dramatically, particularly in rural populations. METHODS: A quasi-experimental research design was deployed from January to December 2009. A total of 387 participants living in nine rural districts with previous diagnoses of type-2 diabetes were randomly selected. Three hundred and twenty-three completed the 3-stage programme, including health assessment, health promotion education and individually tailored telephone counselling and evaluation over a 1-year period. RESULTS: Most of the participants were fishermen or farmers who had <6 years of education (79%) and were elders (68.9 +/- 9.5 years). Most of the physiological variables and foot self-care capabilities showed statistically significant improvement after the programme. Furthermore, 37 participants with severe high risk of diabetic foot accepted additional referral treatments, and their peripheral nerve and vascular functions improved. CONCLUSION: The research outcomes support the value of community-based health promotion programmes in rural areas, incorporating a multidisciplinary health team and culturally competent materials to help the elder rural inhabitants with diabetes enjoy better health and quality of life. PMID- 21535093 TI - Examining and establishing translational and conceptual equivalence of survey questionnaires for a multi-ethnic, multi-language study. AB - AIM: This paper is a report of techniques used to examine and establish translational and conceptual equivalence of survey questionnaires. BACKGROUND: A major concern arose about standardization of translated survey questionnaires, when preparing to evaluate differences in acute coronary syndrome presentation in European (White), Chinese and South Asian patients. METHODS: The survey questionnaires were first translated by an accredited translation company. Between July and November 2009, materials were taken to like-speaking healthcare reviewers to ensure that the clinical meaning was appropriate. Like-speaking lay reviewers were then asked to make comment about grammar; meaning and understanding of questions; and any concerns about the suitability of graphics. A key informant from each language group reviewed all comments and worked with the investigators and the translation company to create final sets of survey questionnaires. RESULTS: Readability of the questionnaires (too complex or too basic) was the most common concern. A major discrepancy between ethnic groups arose about a graphic of 'squeezing' pain. A hand grasping a balloon was considered appropriate for European and South Asian groups, while a picture of a towel being wrung out was identified as more appropriate for the Chinese. There were no negative comments about the graphics. Soliciting key informants who were highly fluent in both English and the language under study was critical to ensure that the participants' feedback was appropriately reconciled. CONCLUSION: Traditional forward-backward translation of study materials is insufficient. Translation must be accompanied by a process whereby equivalence and acceptability are also established. PMID- 21535094 TI - Perceived racism, discrimination, and acculturation in suicidal ideation and suicide attempts among black young adults. AB - During young adulthood the suicide rate among Blacks rises dramatically and approaches that of the U.S. general population, requiring that prevention efforts include a focus on Black young adults. Although most research on suicidality among Blacks has focused on risk factors observed in the dominant culture, in this study the authors examined associations between perceived discrimination, racism, and acculturation with lifetime suicidal ideation (SI) and suicide attempt (SA) among Black young adults. Two hundred fifty Black or African American individuals aged 18-24 residing in a midsize northeastern city were recruited to participate through advertisements. Participants filled out self report questionnaires. Logistic regressions were used to examine the association of each predictor with SI and SA. Greater perceived acculturation was associated with SI in univariate and multivariate models. There were no other statistically significant results concerning the predictors of interest. The link between perceived acculturation and SI is consistent with limited available data, indicating the need for further study including the potential mechanism(s) for the association. Limitations include the cross-sectional design and reliance on subjective measures. PMID- 21535095 TI - Rate, relative risk, and method of suicide by students at 4-year colleges and universities in the United States, 2004-2005 through 2008-2009. AB - A total of 622 suicides were reported among students attending 645 distinct campuses from 2004-2005 through 2008-2009. Adjusting for gender in the population at risk of 14.9 million student-years and for the source of these data, the student suicide rate of 7.0 was significantly and substantially lower than for a matched national sample. Suicide rates by firearm were significantly and substantially lower for both female and male students. Hanging was significantly and substantially lower for male students, less prominently so for female students. It is principally the ninefold decrease in the availability of firearms on campuses (vs. homes) and secondarily other features of the campus environment that are the bases for lower student suicide rates. PMID- 21535096 TI - Prevalence and correlates of suicidal behavior among adult female victims of intimate partner violence. AB - The prevalence and correlates of suicidal threats and attempts among 662 racially and ethnically diverse adult female victims of intimate partner violence (IPV) were studied. One in five women had threatened or attempted suicide during her lifetime. They observed that multiple logistic regression results indicated that women at greater risk of severe or potentially lethal assaults as measured by the Danger Assessment and those who reported having a chronic or disabling illness were more likely to have threatened or attempted suicide. A linear association was found between age and suicide threats/attempts, with younger women having increased odds. Finally, African American IPV victims were less likely to have threatened or attempted suicide as compared to Latina victims. Study implications are discussed. PMID- 21535097 TI - Suicidal behavior and firearm access: results from the second injury control and risk survey. AB - The association between home firearms and the likelihood and nature of suicidal thoughts and plans was examined using the Second Injury Control and Risk Survey, a 2001-2003 representative telephone survey of U.S. households. Of 9,483 respondents, 7.4% reported past-year suicidal thoughts, 21.3% with a plan. Similar proportions of those with and without a home firearm reported suicidal thoughts, plans, and attempts. Among respondents with suicidal plans, the odds of reporting a plan involving a firearm were over seven times greater among those with firearms at home, compared with those without firearms at home. The results suggest people with home firearms may not be more likely to be suicidal, but when suicidal they may be more likely to plan suicide by firearm. PMID- 21535098 TI - The olsA gene mediates the synthesis of an ornithine lipid in Pseudomonas aeruginosa during growth under phosphate-limiting conditions, but is not involved in antimicrobial peptide susceptibility. AB - Pseudomonas aeruginosa responds to phosphate limitation by inducing the expression of phosphate transport systems, phosphatases, hemolysins and a DNase, many of which are important for virulence. Here we report that under phosphate limiting conditions, P. aeruginosa produces a phosphate-free ornithine lipid (OL) as the primary membrane lipid. The olsBA (PA4350-PA4351) genes were highly induced under phosphate-limiting conditions. The production and structure of the OL was confirmed by MS, revealing diagnostic fragment ions and mainly C16 : 0 and C18 : 1 dialkyl chains. It was shown that olsA is required for production of these lipids and genetic complementation of the olsA?lux mutant restored OL production. Studies in other bacteria have correlated increased resistance to antimicrobial peptides with the production of OLs. Here it was demonstrated that resistance to antimicrobial peptides increased under phosphate-limiting conditions, but OLs were not required for this increased resistance. OL production was also not required for virulence in the Caenorhabditis elegans infection model. The production of OLs is a strategy to reduce phosphate utilization in the membrane, but mutants unable to produce OLs have no observable phenotype with respect to growth, antibiotic resistance or virulence. PMID- 21535099 TI - Subtractive hybridization analysis of gastric diseases-associated Helicobacter pylori identifies peptidyl-prolyl isomerase as a potential marker for gastric cancer. AB - Helicobacter pylori, a microaerophilic Gram-negative bacterium, is known to cause chronic gastritis, peptic ulcer and gastric cancer. Genes that are present in certain isolates may determine strain-specific traits such as disease association and drug resistance. In order to understand the pathogenic mechanisms of gastric diseases, identify molecular markers of the diseases associated with H. pylori strains and provide clues for target treatment of H. pylori-related diseases, a subtracted DNA library was constructed from a gastric cancer-associated H. pylori strain and a superficial gastritis-associated H. pylori strain by suppression subtractive hybridization. The presence of gastric cancer-specific genes was identified by dot blot hybridization, DNA sequencing and PCR-based screening. Twelve gastric cancer-specific high-copy genes and nine low-copy genes were found in gastric cancer compared with the superficial gastritis strain. These genes were confirmed by PCR analysis of H. pylori isolates. Notably, peptidyl-prolyl cis-trans isomerase (PPIase) was detected positively in 11 out of 22 (50%) gastric cancer-associated H. pylori strains. In contrast, <24% of the H. pylori strains from superficial gastritis showed positive results. Given the potential role of PPIases in cell growth, apoptosis and oncogenic transformation, our results suggest that PPIase may represent a novel marker and potential therapeutic target for gastric cancer. PMID- 21535100 TI - An endophytic/pathogenic Phoma sp. from creosote bush producing biologically active volatile compounds having fuel potential. AB - A Phoma sp. was isolated and characterized as endophytic and as a pathogen of Larrea tridentata (creosote bush) growing in the desert region of southern Utah, USA. This fungus produces a unique mixture of volatile organic compounds (VOCs), including a series of sesquiterpenoids, some alcohols and several reduced naphthalene derivatives. Trans-caryophyllene, a product in the fungal VOCs, was also noted in the VOCs of this pungent plant. The gases of Phoma sp. possess antifungal properties and is markedly similar to that of a methanolic extract of the host plant. Some of the test organisms with the greatest sensitivity to the Phoma sp. VOCs were Verticillium, Ceratocystis, Cercospora and Sclerotinia while those being the least sensitive were Trichoderma, Colletotrichum and Aspergillus. We discuss the possible involvement of VOC production by the fungus and its role in the biology/ecology of the fungus/plant/environmental relationship with implications for utilization as an energy source. PMID- 21535101 TI - Magnetospirillum magneticum AMB-1 peroxiredoxins contribute to the aerotolerance and genetic stability of the genomic magnetosome island. AB - The magnetotactic bacterium Magnetospirillum magneticum AMB-1 can grow at variable oxygen concentrations, although the intracellular magnetic structures, magnetosomes, are only synthesized under microaerobic or anaerobic conditions. Three members of the peroxiredoxin family were identified in M. magneticum AMB-1. All purified recombinant proteins displayed thiol-dependent peroxidase activities. Allelic replacement mutagenesis revealed that, although the absence of the three peroxidase genes had no effect on either the growth or the formation of magnetosome under anaerobic conditions, the growth of mutants was compromised in an aerobic culture. Moreover, an accelerated loss in the genomic 'magnetosome island' (MAI) was observed in the null mutants cultured in the presence of oxygen. Taken together, these data suggest that the thiol-peroxidases identified act as key antioxidants in magnetotactic bacteria and, as a result, contribute to maintaining their capacity to synthesize magnetosome by shielding the genetic stability of the genomic MAI in adaptation to constant physiological change and stress. PMID- 21535102 TI - Relationship between periodontal status and intellectual function among community dwelling elderly persons. AB - OBJECTIVE: The aim of this study was to indicate the relationship between periodontal status and intellectual function in the elderly. BACKGROUND: Periodontal status has been shown to be related to demographic, socioeconomic, and psychological status. Intellectual function is a significant indicator of health status. Nevertheless, the relationship between periodontal status and intellectual function has not been elucidated in detail among the elderly. MATERIALS AND METHODS: A total of 152 community-dwelling elderly persons, aged 70 74 years, were enrolled in the study. Periodontal status was evaluated using the WHO Community Periodontal Index of Treatment Needs (CPITN). Intellectual function was assessed by four neuropsychological tests: Raven's Coloured Progressive Matrices (RCPM) test, the Verbal Paired Associates 1 (VerPA) task and the Visual Paired Associates 1 (VirPA) task, extracted from the Wechsler Memory Scale Revised Edition, and the Block Design subtest, extracted from the Wechsler Adult Intelligence Scales, Third Edition. Correlations between CPITN and each test were examined using Spearman rank correlation coefficients. The ordinal regression model was constructed with CPITN as the dependent variable and neuropsychological test as the principal independent variable to adjust for demographic factors, general health, lifestyle and oral health behaviour. RESULTS: Significant correlations were found between the RCPM test, the VerPA task, the Visual Paired Associates 1 and CPITN. In the ordinal regression model, CPITN was significantly related to measures of RCPM after adjusting for demographic factors, general health status, lifestyle and oral health behaviour. CONCLUSION: Intellectual function is considered a significant indicator of periodontal status among community-dwelling elderly persons. PMID- 21535103 TI - Effect of sealer coating on mechanical and physical properties of permanent soft lining materials. AB - OBJECTIVE: To evaluate the long-term effects of sealer coating on tensile bond strength and surface roughness of soft liners. BACKGROUND: Failure of the bond between resilient liners and denture base significantly compromise the dentures' longevity. In addition, surface roughness contributes to bacterial adherence on prosthetic materials, increasing the risk of oral infections. METHODS: Specimens were manufactured from four reliners [Mucopren Soft (MS), Dentuflex (DF); Soft Comfort Denso (SC) and Ufi Gel SC (USC)], distributed into 10 groups (n = 10), according to material and coating treatment. Tensile bond strength was performed after one year of ageing, while surface roughness was evaluated at 0, 1, 3, 6 and 12 ageing months. Bond strength data were submitted to two-way anova and Tukey HSD tests, while roughness data were submitted to mixed model analysis for repeated measurements (p <= 0.05). RESULTS: MS and DF without sealer coating presented the highest tensile bond strength. After coating, DF and SC presented increased tensile bond strength. No surface roughness difference was observed in the non-coated groups over time, acrylic-based reliners presented higher roughness. Among coated groups, only SC presented increased surface roughness. Acrylic-based materials presented reduced roughness at three months. CONCLUSION: Surface coating was effective for acrylic reliners in maintaining their initial properties. However, sealer coating should be re-applied every 3 months. PMID- 21535104 TI - Megacities. PMID- 21535105 TI - Social stressors associated with antepartum depressive symptoms in low-income African American women. AB - OBJECTIVES: To describe depressive symptomatology and examine the relationship between social stressors and depressive symptoms in pregnant African American women. DESIGN AND SAMPLE: Cross-sectional study of 119 women receiving care at 2 prenatal clinics in Northern California. MEASURES: Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (CES-D). Social stress variables included discrimination, trauma exposure, social conflict, and economic stress. RESULTS: In this sample, mean CES-D score was 15.88. Forty-two percent of the women had CES-D scores >= 16 (possible risk), and 23% had CES-D scores >= 23 (probable risk). There were significantly positive relationships between the social stress variables (discrimination, trauma exposure, social conflict, economic stress) and CES-D scores. Stepwise multiple regression analysis indicated that together discrimination and social conflict accounted for 36% of the variance in antepartum depressive symptoms. CONCLUSIONS: Discrimination and social conflict are considerable sources of stress that contribute to levels of antepartum depressive symptoms in African American women. While the results reinforce the importance of universal prenatal screening, comprehensive strategies are also needed to help ameliorate the impact that social stressors such as discrimination and social conflict have on the mental health of pregnant African American women. PMID- 21535106 TI - Dental insurance and dental service use by U.S. women of childbearing age. AB - OBJECTIVES: Oral health has a significant effect on health, and for women, poor oral health can lead to poor birth outcomes and can affect their child's health. Nursing interventions to improve the oral health of at-risk women have the potential to increase maternal and child systemic and oral health. The identification of women at a high risk for poor oral health is a necessary to develop and evaluate these interventions. DESIGN AND SAMPLE: This study examined the factors related to dental insurance and dental service use for women of childbearing age in the United States. A secondary analysis of the 2003-2004 National Health and Nutrition Examination Survey was completed to examine the predisposing, enabling, and need variables associated with dental insurance status and dental service use in a representative random sample of 1,071 women. RESULTS: The results showed that over 40% of women had no dental insurance. Women with less education, lower income, and dental need were significantly less likely to have dental insurance. Dental utilization by the uninsured was low and a racial/ethnic disparity was noted. CONCLUSION: A lack of dental insurance and dental service utilization is a significant concern. Nurses working with low income women should educate the population about oral health and advocate for policies to increase dental insurance coverage. PMID- 21535107 TI - Classification tree model identifies home-based service needs of Japanese long term care insurance consumers. AB - OBJECTIVES: To clarify care receivers' needs and unmet needs for home help or home nursing services during daytime and/or nighttime hours, and to identify the characteristic of elders who are most likely to need home care services. DESIGN AND SAMPLE: We used a chi-squared automatic interaction detection technique to analyze data from 92 care management researchers, who interviewed 280 caregivers. MEASURES: Demographic information, assessments of the statuses and service needs of elders. RESULTS: We found that care receivers had more unmet needs at night than during the day. Daytime home help was needed by elders who (1) lived alone or (2) lived with just one person and whose primary caregiver was not their wife. Nighttime home help was needed by those who required assistance eating, and whose primary caregiver was male. Daytime home nursing was needed by elders who (1) received medical treatment instead of day care or (2) did not receive medical treatment, but had difficulty eating. Nighttime home nursing was needed by those who had unstable illnesses and whose medical treatments continued during the night. CONCLUSIONS: Our findings may help public health nurses assess community needs in order to effectively and efficiently manage health care resources. PMID- 21535108 TI - Low-income Euro-American mothers' perceptions of health and self-care practices. AB - OBJECTIVE: Health promotion activities may decrease preventable diseases and health system overuse. This study examined how low-income Euro-American mothers described their health/wellness, self-care practices (SCP), and SCP benefits, barriers, and interpersonal influences (norms, modeling, and social support) affecting their SCP. DESIGN AND SAMPLE: This descriptive qualitative study used a convenience sample of 10 low-income, English-speaking mothers, 25-43 years old, seeking women's/children's health services at a large urban Texas health clinic. MEASURES: Data were collected via face-to-face interviews, using a standardized semistructured interview guide; data were analyzed using Miles and Huberman's qualitative research methods. RESULTS: All participants primarily described themselves positively and as mothers and workers. Most viewed health and wellness as distinct but typically included physical and emotional well-being. Mothers valued health and SCP for personal and family reasons. All identified SCP benefits. Most identified SCP barriers. Women viewed themselves as vital to family function and well-being, learned SCP primarily from parents during childhood, and described limited support for SCP. CONCLUSIONS: The results provide a better understanding of participants' self-care decision making and are useful in designing appropriate clinical health promotions. Reducing health inequities in low-income women requires further study of the underlying causes and development of effective policies and measures to address them. PMID- 21535109 TI - Lay health workers in primary and community health care for maternal and child health and the management of infectious diseases: a review synopsis. PMID- 21535110 TI - Community-based intervention packages for reducing maternal and neonatal morbidity and mortality and improving neonatal outcomes: a review synopsis. PMID- 21535111 TI - Cornerstones of public health nursing. AB - The "Cornerstones of Public Health Nursing" describe the values and beliefs that underlie the practice of Public Health Nursing, which is a synthesis of public health and nursing. The impetus for the development of the Cornerstone framework originated from the need to advocate for public health nursing programs, positions, and funding. Grounded in practice, their development engaged stakeholders from the public health nursing community at every phase. The Cornerstone framework has been used over the past decade by educators to teach public health nursing and by administrators in state and local health departments for orientation and continuing education. The Cornerstones have been nationally and internationally disseminated. This paper describes the development and dissemination of the Cornerstones framework by public health nurses in Minnesota and features exemplars from practice. PMID- 21535112 TI - Finding common ground in public health nursing education and practice. AB - Preparation of the public health nursing (PHN) workforce requires public health nurses from academia and practice to collaborate. However, a shortage of PHN clinical sites may lead to competition between schools of nursing for student placements. The Henry Street Consortium, a group of 5 baccalaureate schools of nursing and 13 local health departments in the state of Minnesota, developed a model for collaboration between PHN education and practice. This paper describes the development process--the forming, storming, norming, and performing stages- experienced by the Henry Street Consortium members. The consortium developed a set of entry-level core PHN competencies that are utilized by both education and practice. It developed menus of learning opportunities that were used to design population-based PHN clinical experiences. In addition, the consortium created a model for training and sustaining a preceptor network. The members of the Henry Street Consortium collaborated rather than competed, used consensus for decision making, and respected and accepted different points of view. This collaboration significantly impacted how schools of nursing and local health departments work together. The consortium's ability to retain its relevance, energy, and momentum for both academic and agency partners sustains the collaboration. PMID- 21535113 TI - Interactive model of client health behavior and cervical cancer screening of African-American women. AB - OBJECTIVE: Explore inductively African American women's use of Pap smear screening services and consider how well the data did or did not affirm the usefulness of the interaction model of client health behavior (IMCHB). DESIGN AND SAMPLE: The IMCHB guided this qualitative study designed to explore women's social influence and previous health care experience and their influence on the women's cognitive appraisal associated with Pap smears and cervical cancer. Interviews were conducted with 24 women, resulting in 2 groups: routine-use (n = 11) (Pap smears every 1-3 years) and non-routine-use (n = 13). MEASURES: Content analysis approach to data analysis was used, where interview data were considered in relation to elements of IMCHB. RESULTS: Analysis revealed that the IMCHB was useful for framing cervical cancer screening health behavior research. Both groups' data fit well onto the framework. The routine-use group fit the entire model, with iterative (repeat) behavior in cervical cancer screening. The non routine-use group also fit the model, but their iterative behavior in cervical cancer screening was intermittent due to negative personal influences. CONCLUSIONS: This model can provide a focus to the delivery of gynecological care based on a client's unique characteristics that can be addressed with individualized nursing interventions designed to promote positive health outcomes. PMID- 21535114 TI - Microcredit and the social determinants of health: a conceptual approach. AB - Social determinants of health, such as human behavior, environment, and socioeconomics, contribute to health disparities at the individual and population levels. The association between socioeconomics and health is established, and it is acknowledged that people with a lower socioeconomic status experience poorer health. The impetus of microcredit programs is to provide financial alternatives for low-income populations, the majority of whom are women with limited or no access to traditional lending, to start small businesses, generate income, and progress toward self-sufficiency. The income-health link within the context of microcredit has been internationally acknowledged; however, there is scarce research in this area in the United States. This article presents a review of the conceptual approach used to explore the microcredit and health link from a public health nursing perspective. Establishing conceptual foundations can enhance research focused on targeted interventions aimed at lasting change in social and health status. Exploring the link between microcredit and health can enrich research efforts and may offer innovative strategies and interventions to improve health-promoting capacity in impoverished groups. PMID- 21535115 TI - Roaming through Virginia with the public health nurse. AB - Rural health nursing has long been considered a subspecialty within public health nursing, albeit one that required the nurse to be a generalist. In the excerpts of this article, Webb (1920) shares her observations as a State Supervising Nurse for the Red Cross in Virginia while traveling in rural areas of the state with the county public health nurses. Themes evident in these excerpts include the transportation issues associated with working in remote areas, as well as nursing work in the areas of maternal and child health, communicable diseases, case finding through health inspections, and health education. Additionally, there are themes specific to rural nursing, including distance and isolation, self reliance, and development of trust among the rural population. In her 1922 book, The Evolution of Public Health Nursing, Annie M. Brainard identified many of these themes when she stated the ideal rural public health nurse needed to be a "school nurse, baby nurse, tuberculosis nurse, and a general visiting nurse", as well as tactful in dealing with "country people" who are "peculiarly independent and sensitive" (1985 edition, p. 303). PMID- 21535116 TI - Contrast echocardiography improves interobserver agreement for wall motion score index and correlation with ejection fraction. AB - BACKGROUND: The wall motion score index (WMSI) is a surrogate for left ventricular ejection fraction (LV-EF), which becomes unreliable in poor echo windows. The value of contrast LV opacification (LVO) for WMSI assessment is not well known. OBJECTIVES: We sought to compare interobserver agreement for WMSI and the correlation between the LVO-WMSI and LV-EF using two-dimensional second harmonic (SH) and LVO echocardiography. METHODS: The study comprised 100 consecutive patients (57 +/- 13 years, 85% males). Two independent physicians assessed LV segmental quality and wall motion for both the SH and LVO studies according to a 17-segment model. Systolic wall motion was defined as: normokinesia, hypokinesia (systolic inward endocardial motion <7 mm), akinesia, and dyskinesia. LV-EF was assessed from the LVO images according to the biplane modified Simpson's method. RESULTS: Of the 1,700 analyzed segments, 453 (26.6%) were poorly visualized with SH imaging, and 173 (10.2%) with LVO (P < 0.0001). The two observers agreed on segmental wall motion score in 1,299 segments (agreement 76%, Kappa 0.60) with SH imaging and in 1,491 segments (agreement 88%, Kappa 0.78) with LVO. Interobserver correlation (r(2) ) was 0.86 for the SH-WMSI and 0.93 for the LVO-WMSI. The limits-of-agreement for interobserver LVO-WMSI (mean difference -1.0%+/- 6.8%, agreement -14.6%, 12.6%) was lower than that for SH-WMSI (mean difference -2.3%+/- 10.1%, agreement -22.5, 17.9). The LVO-WMSI correlated well with LV-EF (r(2) = 0.71). LV-EF could be estimated according to the formula 1.01 - 0.32 * WMSI. CONCLUSION: Echo-contrast improves interobserver agreement for wall motion scoring and the WMSI. The LVO-imaged WMSI correlates well with LV-EF. PMID- 21535117 TI - Cardiac toxicity screening by echocardiography in healthy volunteers: a study of the effects of diurnal variation and use of a core laboratory on the reproducibility of left ventricular function measurement. AB - BACKGROUND: In investigational medicinal products testing centers (IMP), reliable methods for monitoring early signs of cardiotoxicity of a potential new drug in healthy volunteers are essential. This study examines what levels of left ventricular ejection fraction (LVEF) variance can be achieved with two dimensional echocardiography (2DE) in a core laboratory versus a site laboratory. Diurnal variability of LVEF and diastolic parameters were also reviewed. METHODS AND RESULTS: 64 healthy males, (age range 18-40 years), with optimal echo windows were recruited. Two-dimensional and tissue Doppler (TDI) echocardiography was performed by one dedicated sonographer using an Acuson Sequoia C256 machine. Heart rate and blood pressure were recorded simultaneously. Echocardiograms were performed at set time points (0, 1, 4, and 20 hours) on all subjects. The images were analyzed independently by one on-site, unblinded, sonographer reader (site lab) and one experienced off-site blinded physician over reader (core lab). The core lab showed significantly less variance in LVEF measurements than the site lab (5.5% vs. 19.9%). There was no significant diurnal variation in mean blood pressure, LVEF or E:A ratio measurements over 20 hours. CONCLUSIONS: The core lab had better reproducibility and significantly less variance in LVEF measurements by 2DE than the site lab. There was no diurnal variation in LV function measurement. PMID- 21535118 TI - The advantage of global strain compared to left ventricular ejection fraction to predict outcome after acute myocardial infarction. AB - The aim of the study was to compare the ability of global strain and left ventricular ejection fraction (LVEF) to predict outcome after acute myocardial infarction (AMI). Left ventricular (LV) function was measured using strain by Doppler and LVEF in 77 patients. Measurements were performed at admission and after 10 +/- 5 days. Outcome was measured as the combined end point of cardiac death, reinfarction and hospitalization for heart failure, unstable angina or life threatening arrhythmia. The patients were followed for 3.29 +/- 1.59 years (range 0-5.22 years) and 17 cardiac events were registered. The cutoff value of LVEF was 44% for optimal prediction of outcome. We used LVEF <= 44% vs. > 44% and the corresponding global strain value >= -15.6% vs. < -15.6% to predict cumulative event-free survival. Both methods significantly predicted cardiac combined events at admittance and after 10 days with no difference. After 10 days, however, global strain remained the only significant predictor of outcome in a multivariate logistic regression model (P < 0.0001, odds ratio 1.79). Interobserver reproducibility measured as intraclass correlation was better for global strain than for LVEF (0.92 vs. 0.71). In conclusion, the measurement of global strain in patients with AMI may predict cardiac combined events to the same extent as LVEF in the acute phase and superior to LVEF after 10 days. In addition, global strain demonstrates better interobserver reproducibility and may become an improved bedside tool to evaluate LV function as a prognostic marker after AMI. PMID- 21535119 TI - On-orbit prospective echocardiography on International Space Station crew. AB - OBJECTIVES: A prospective trial of echocardiography was conducted on six crew members onboard the International Space Station. The main objective was to determine the efficacy of remotely guided tele-echocardiography, including just in-time e-training methods and determine what is "space normal" echocardiographic data. METHODS: Each crew member operator (n = 6) had 2-hour preflight training. Baseline echocardiographic data were collected 55-167 days preflight. Similar equipment was used in each 60-minute in-flight session (mean microgravity exposure--114 days [34--190]). On-orbit ultrasound (US) operators used an e learning system within 24 hours of these sessions. Expert assistance was provided using US video downlink and two-way voice. Testing was repeated 5-16 days after landing. Separate ANOVA was used on each echocardiographic variable (n = 33). Within each ANOVA, three tests were made: (a) effect of mission phase (preflight, in-flight, postflight); (b) effect of echo technician (two technicians independently analyzed the data); (c) interaction between mission phase and technician. RESULTS: Eleven rejections of the null hypothesis (mission phase or technician or both had no effect) were found that could be considered for possible follow up. Of these, eight rejections were for significant technician effects, not space flight. Three rejections of the null hypothesis (aortic valve time velocity integral, mitral E-wave velocity, and heart rate) were attributable to space flight but determine to not be clinically significant. No rejections were due to the interaction between technician and space flight. CONCLUSION: Thus, we found no consistent clinically significant effects of long-duration space flight on echocardiographic variables of the given group of subjects. PMID- 21535120 TI - Effect of position changes on myocardial velocity in healthy subjects evaluated by tissue Doppler echocardiography. AB - OBJECTIVES: This study designed to assess the effect of different positions of head of the bed on myocardial velocity by tissue Doppler echocardiography in healthy subjects. METHODS: Thirty-nine healthy subjects (32 males/7 females, mean age 24.7 +/- 4.9 years) were studied. Tissue Doppler imaging (TDI) was performed and velocities were recorded during systole (Sm) and early (Em) and late (Am) diastole at the tricuspid annulus, septum, and mitral annulus in the four-chamber view. Measurements were performed from different positions of left lateral decubitus (0 degrees , 30 degrees , and 60 degrees ). Repeated-measures general linear models were used to assess the change in myocardial velocities. RESULTS: No significant difference between myocardial velocities was found at the mitral anulus and septal TDI recordings in the different angles of left lateral decubitus positions (P > 0.05). However, there were statistically significant difference among tricuspid anulus myocardial tissue velocities in these positions (P < 0.05). CONCLUSIONS: Tricuspid anulus myocardial tissue velocities may be significantly influenced by changing of position in healthy subjects. Effect of position changes should be considered in the assessment of these velocities. PMID- 21535121 TI - Metabolic syndrome impacts the right ventricle: true or false? AB - BACKGROUND: The impact of metabolic syndrome (MS) on the right ventricle (RV) is not clarified. The aim of this study was to evaluate the influence of MS and its components on RV structure and function. METHODS: The study included 265 subjects with MS and 118 controls adjusted by age. MS was defined by the presence of >=3 ATP-NCEP III criteria. All subjects underwent laboratory blood tests, complete two-dimensional, pulse, and tissue Doppler echocardiography. We determined the ratio of early and late diastolic tricuspid flow velocities (E/A)(t), and the ratio of early diastolic transtricuspid and septal tricuspid annuli flow velocity (E/e')(t). RV Tei index represents the sum of tricuspid isovolumic relaxation time (IVRT) and tricuspid isovolumic contraction time (IVCT) divided by RV ejection time (ET) [(IVRT + IVCT)/ET]. RESULTS: Multiple regression analysis showed that systolic blood pressure (beta = 0.104, P = 0.021), waist circumference (beta = 0.093, P = 0.033), glucose level (beta = 0.087, P = 0.045), left ventricular mass (LVmass) index (beta = 0.218, P < 0.001) and relative LV wall thickness (beta = 0.144, P = 0.034) were independently associated with the RV hypertrophy. Multivariate analysis showed that waist circumference (beta = 0.152, P = 0.013), glucose level (beta = 0.119, P = 0.039), LVmass index (beta = 0.267, P < 0.001), the relative LV wall thickness (beta = 0.184, P = 0.005), RV wall thickness (beta = 0.175, P = 0.008), and (E/e')m (beta = 0.143, P = 0.025) were independently associated with (E/e')(t). Similar results were obtained for RV Tei index. CONCLUSIONS: MS has an important role in damage of RV structure and function. Among MS criteria systolic blood pressure, waist circumference and glucose level were independently associated with RV structure and function. PMID- 21535122 TI - Risk of low-level ionizing radiation from medical imaging procedures. PMID- 21535123 TI - Attitudes and practices of healthcare providers regarding gestational diabetes: results of a survey conducted at the 2010 meeting of the International Association of Diabetes in Pregnancy Study Group (IADPSG). AB - OBJECTIVE: To investigate the attitudes and practices of healthcare providers regarding gestational diabetes mellitus and to identify differences between provider types and geographical locations. RESEARCH DESIGN AND METHODS: A survey was distributed to participants at the 2010 GDM Pasadena II: International Conference regarding management of gestational diabetes. RESULTS: Of 250 distributed surveys, there was a 60.8% (n = 152) response rate. Most responders believed it was cost beneficial to treat and screen for gestational diabetes. Approximately 2/3 accepted that the diagnosis of Type 2 diabetes could be made in pregnancy. For the diagnosis of gestational diabetes, c. 60% opted for a one-step screen while 30% opted for a two-step screen. Most responders were comfortable treating a non-pregnant woman with Type 2 diabetes. Ninety per cent of responders initiated antenatal testing at 32-34 weeks for medication-treated gestational diabetes, with a wider variation for diet-treated gestational diabetes. Obstetricians were less comfortable than other providers in treating a non pregnant woman with Type 2 diabetes, but were more likely to prescribe glyburide. Providers in the USA, compared with those from other countries, were more likely to perform a Caesarean section based on fetal weight, use glibenclamide (glyburide), initiate exercise post-delivery and less likely to check 2-h postprandial glucose levels. At least 80% of responders routinely screened for Type 2 diabetes at 6-12 weeks post-delivery. CONCLUSION: There are differences internationally and by provider types in attitudes and management regarding gestational diabetes. These findings may be useful in developing strategies for implementing the recent guidelines by the International Association of the Diabetes and Pregnancy Study Groups. PMID- 21535124 TI - Studying significance of apoptosis in mediating tolbutamide-induced teratogenesis in vitro. AB - The incidence of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus) is growing worldwide and poses a serious public health problem in a current paradigm of changing life style and food habits. Tolbutamide (sulfonylurea) is among the commonly used anti-diabetic drugs worldwide for treating type 2 diabetes and is known to cause congenital malformations in animals. In this study, the effect of tolbutamide on major organogenesis period and the possible involvement of apoptosis in mediating congenital malformations have been carried out. In the present study design, post-implantation rat embryos of day 11 were cultured for 24 h with various concentrations of tolbutamide, i.e., 10, 100, and 1000 MUg/mL cultures, respectively. The growth and developmental of each embryo was evaluated and compared with control ones for the presence of any malformations. The tolbutamide decreased all growth and developmental parameters in a concentration-dependent manner, when compared with control. However, exposure to tolbutamide at 10 MUg/mL culture did not show any significant effect on embryonic growth and development in vitro. In parallel to this, flow cytometric analysis (cell cycle and annexin V binding) and DNA fragmentation assay were carried out followed by quantitation by 3'-OH labeling of cultured rat embryos to examine the role of apoptosis in bringing about tolbutamide-induced teratogenesis. All results were found to be dose dependent and an increase in apoptosis in embryonic tissues may be related to the increased risk of congenital malformations. The outcome of the research suggested that apoptosis might be involved in mediating teratogenesis of tolbutamide in vitro. Further research is warranted to fully understand this mechanism. PMID- 21535125 TI - The association between 5-min Apgar score and mortality disappears after 24 h at the borderline of viability. AB - AIM: To quantify the relationship between 5-min Apgar scores and infant mortality for infants at the borderline of viability. METHODS: Cohort study of 7008 infants 23-25 weeks' gestation using 2002 US National Center for Health Statistics data. Using Cox proportional-hazards models, we quantified the relationship between Apgar score and infant mortality for all infants, and then infants surviving their first 24 h. Models were adjusted for gestational age, birth weight, gender, delivery method, plurality, maternal race, marital status and education. RESULTS: Within one year, 46% of infants died. Of the non-survivors, deaths within 24 h were more common among infants with Apgar scores 0-3 (83%) than among infants with Apgar scores 7-10 (13%). When including all infants and adjusting for potential confounders, each 1-point increase in Apgar score decreased the hazard of mortality by 0.82. However, after excluding infants who died within 24 h, the hazard ratio increased to 0.95; although statistically significant, the practical impact was negated. CONCLUSIONS: For 23-25 week gestation infants surviving the first 24 h, the Apgar score loses clinical significance. Clinicians should be aware of the limitations of clinical assessments in the delivery room. PMID- 21535127 TI - Can we prevent sudden cardiac death in young athletes: the debate about preparticipation sports screening. AB - All high school athletes in the United States require a preparticipation screening examination. The American Heart Association recommends a focused history and physical examination. The European Society of Cardiology recommends that all examinations include an electrocardiogram (ECG). We review the risks and costs of screening, discuss legal ramifications and analyse the ethical implications of these considerations. There are too many unknown about ECG screening to require it as routine testing for all high school athletes. CONCLUSION: Doctors must inform young athletes and their parents about the option of ECG screening and about the debate over its efficacy. Patients and parents may then choose to have an ECG or not. Mandatory universal screening is not warranted at this time. PMID- 21535126 TI - Increased perinatal intracranial pressure and brainstem dysfunction predict early puberty in boys with myelomeningocele. AB - BACKGROUND: Children with myelomeningocele (MMC) run an increased risk of developing early or precocious puberty (E/PP). AIM: To identify risk factors for E/PP in boys with MMC. METHODS: Boys born between 1970 and 1992, treated for MMC at the University Children's Hospital, Uppsala, were identified. Thirty-eight boys were eligible to be included. Medical records were examined retrospectively. Early puberty was defined as pubertal signs before the age of 10 years and 2 months. Precocious puberty was defined as the appearance of these signs before 9 years of age. Increased intracranial pressure perinatally was defined as wide sutures, bulging fontanelles and increased/increasing head circumference at birth and/or during the first week after birth. Early brainstem dysfunction was defined as severe and persistent feeding and respiratory problems before the age of 3 months despite proper control of the hydrocephalus. RESULTS: Of the 38 boys, 8 (21%) had E/PP, which was strongly associated with increased intracranial pressure perinatally and also with early brainstem dysfunction. Multivariate regression analysis showed early brainstem dysfunction to have the highest explanatory value regarding the occurrence of early puberty. CONCLUSION: Increased intracranial pressure perinatally and brainstem dysfunction early in life are strong predictors of E/PP in boys with MMC. PMID- 21535128 TI - Clinical and metabolic findings in a 6-year-old boy with a Leydig cell tumour. AB - AIM: To analyse the urinary steroid metabolome in a boy who had true precocious puberty after a Leydig cell tumour. METHOD: Case report and detailed description of clinical and metabolic findings in a 7-year-old-boy with a Leydig cell tumour. RESULTS: Before surgery, the urinary steroid metabolome showed an activation of an alternative route to gonadal androgens independent of dehydroepiandrosterone (DHEA). After surgery, the boy entered true precocious puberty. Under leuprolide acetate treatment, clinical and laboratory findings normalized. CONCLUSION: Central precocious puberty after precocious pseudopuberty may be more common than expected and should be considered in children with persistent or recurrent symptoms after initial treatment of precocious pseudopuberty. Patients with a Leydig cell tumour seem to reactivate the so-called 'back door pathway' of androgen production, which is independent of the classical route via DHEA. PMID- 21535129 TI - A case of Familial Mediterranean Fever at the Baltic Sea. PMID- 21535131 TI - Foetus-in-foetu in a 3-year-old girl. PMID- 21535132 TI - Severe Mycoplasma pneumoniae-associated mucositis treated with immunoglobulins. AB - Mycoplasma pneumoniae-associated mucositis (MPAM), previously labelled as atypical Stevens-Johnson syndrome (SJS), SJS with minimal or no skin manifestations, is a rare non-respiratory manifestation of Mycoplasma pneumoniae infection. The nineteen cases described so far in children and young adults were characterized by a high male gender prevalence (16/19) and a good response to appropriate antibiotic treatment and supportive care in the majority of patients. We describe a case of MPAM in a previously healthy girl, who improved after a 0.5 g/kg daily dose of intravenous immunoglobulins (IVIG) for four consecutive days, after traditional therapy had failed. CONCLUSION: The successful treatment with IVIG described in this report suggests that, where appropriate antibiotic and supportive therapy fails to improve the clinical course of severe MPAM, IVIG treatment is worth considering. PMID- 21535133 TI - Physiological aspects of human milk lipids and implications for infant feeding: a workshop report. AB - The biology of human milk and lactation helps understand the physiology of breastfed infants. The compositional and biological effects of human milk lipids have received considerable interest regarding their modulating effects on growth, metabolism and functions of the cardiovascular, immune and nervous system. CONCLUSION: This paper describes key aspects of a scientific workshop focused on current knowledge, unresolved questions and future research needs in the area of human milk lipids and their physiological effects in infants. PMID- 21535134 TI - Child health care uptake among low-income and immigrant families in a Swedish county. AB - AIM: To study the uptake of child health care among low-income and immigrant families in the county of Uppsala, Sweden, to investigate whether these families received extra attention as proposed in the Swedish Child Health Services (CHS) state-of-the-art consensus document from the year 2000. METHODS: Data were collected for 25,024 infants born 1998-2006 from the database of statistics of the Child Health Care Unit in Uppsala and socio-demographic indicators from Swedish national registers. Disposable income was divided into quartiles. Country of birth of the mother was categorized into four regions with two subgroups each, mothers with or without a Swedish-born partner. Analysis was conducted by Cox regression and linear regression models. RESULTS: Small differences between Swedish vs. immigrant and high vs. low-income families were detected. Low-income mothers (RR 0.78) as well as mothers born in all country of birth regions with an immigrant partner (RR 0.28-0.95) had lower rates of participation in parental groups. CONCLUSION: The CHS provided basic child health care to almost all infants including children in immigrant and low-income Swedish families. However, the results did not indicate that disadvantaged families received the extra attention proposed in the consensus document. PMID- 21535136 TI - Is multifocal electroretinography the next big thing in clinical diagnosis? PMID- 21535135 TI - Could audiovisual training be used to improve cognition in extremely low birth weight children? AB - AIM: To study whether a dyslexia remediation programme, Audilex, improves cognition in extremely low birth (ELBW) children. METHODS: Six-year-old ELBW children were allocated to a 5-week training with Audilex or playing control computer games. Before and after intervention, auditory event-related brain potentials (ERP) to sound changes were recorded and reading related skills assessed. Primary outcome was the mismatch negativity (MMN) component of ERP. Secondary outcomes were Audilex Test (ability to perform the Audilex games), the reading skills after the intervention and 2 years later. Of eligible children, 39 (54%) consented and 22 (30%) completed the protocol. RESULTS: The MMN responses to the frequency (p = 0.02) and duration deviants (p < 0.01) increased after Audilex training (n = 11), but not after control game playing (n = 11). Audilex Test performance was similar in both groups. The reading skills were similar after intervention and 2 years later; word reading score 59.7, 66.8 and 74.9 and comprehensive reading score 8.1, 8.8 and 9.4 in Audilex, Control and healthy class-mate children, respectively. CONCLUSIONS: Although all children did not complete the protocol, the results suggest that training with Audilex dyslexia programme might be beneficial for enhancing neural-level sound discrimation and possibly reading skills in ELBW children. A larger trial is warranted. PMID- 21535137 TI - Forward and backward adaptive effects in global flash multifocal electroretinogram stimulation. AB - PURPOSE: The present study investigated retinal adaptive responses in concert with the modulation of forward and backward adaptation induced by periodic global flashes using the global flash multifocal electroretinogram (mfERG). METHODS: Six normal subjects were recruited for global flash mfERG measurements, which consisted of 103 scaled hexagonal elements followed by a global flash frame. In experiments I and II, with constant luminance maintained in both local and global flash frames, the number of dark frames was independently varied and these frames were either inserted prior to or following the global flash frame to investigate the forward or backward adaptive effect of the global flash on the mfERG. In experiment III, the number of dark frames was fixed but the luminance of the global flash frame was varied with constant luminance of the focal flash. This was used to demonstrate that the adaptive effect related not to time but to variation of luminance. RESULTS: All the central, para-central and peripheral direct component amplitudes were found to be significantly influenced by variation of the number of dark frames (p < 0.01). Reducing the forward adaptive effect of the global flash enhanced the direct component response and it became steady after five dark frames were inserted following the global flash. Reducing the backward adaptive effect of the global flash also enhanced the direct component response but it started reducing after four dark frames were inserted prior to the global flash frame. These changes were different with luminance modulation of the global flash intensity with fixed dark frames, while the direct component amplitude grew approximately linearly with decreasing mean luminance of the global flash stimulation. CONCLUSION: The retina plays a major role in visual adaptation. Both forward and backward adaptive effects of the global flash on the direct component have been illustrated in this study. The results show that the forward and backward adaptive phenomena in the global flash mfERG are different and demonstrate that backward adaptation is found at the retinal level. PMID- 21535138 TI - Retinal function and morphology of severe non-proliferative diabetic retinopathy before and after retinal photocoagulation. AB - PURPOSE: The purpose of this project was to investigate the changes in macular function and macular morphology of severe non-proliferative diabetic retinopathy (NPDR), due to photocoagulation, using the multifocal electroretinogram (mfERG) and optical coherence tomography (OCT). METHODS: Thirty-five volunteers were in the control group, with one eye per person examined with the mfERG. Both the mfERG and OCT were conducted on 30 patients with diabetes who had severe NPDR before, and two, seven and 14 days after, treatment with photocoagulation. RESULTS: Compared with the control group, the P1 and N1 response densities in the patients with NPDR appeared to decrease significantly at rings 2-3 and rings 3-4, respectively, whereas no difference was seen in the implicit times. At two days after photocoagulation, the P1 and N1 response densities decreased significantly in ring 1 and they were still lower than the pre-photocoagulation values at 14 days after photocoagulation. In addition, no change was found in the implicit times before and after photocoagulation. There was no obvious difference in the macular thickness after treatment. At two days after treatment, the P1 response density in ring 1 negatively correlated with the corresponding macular thickness. CONCLUSION: The para-macular function was significantly impaired in those patients with severe NPDR and photocoagulation reduced the central macular function. Even after 14 days, the central macular function had not returned to pre-photocoagulation levels. PMID- 21535139 TI - Optical coherence tomography and multifocal electroretinogram study in human immunodeficiency virus-positive children without infectious retinitis. AB - BACKGROUND: The aim was to evaluate the macular structure and function in children with human immunodeficiency virus (HIV) disease without cytomegalovirus retinitis or visual symptoms. METHODS: Thirty-eight eyes of 19 HIV-positive children (Group A) were examined. Group B included 20 (40 eyes) age- and sex matched control subjects. Each individual underwent a complete ophthalmic examination, optical coherence tomography (OCT) scan and multifocal electroretinogram (mfERG) recording. RESULTS: In all patients, visual acuity and colour vision testing were normal. The mean foveal thickness in groups A and B was 190.28 +/- 26.58 (SD) um and 169.47 +/- 10.17 um, respectively (p = 0.0002). In Group A, the mean retinal response density of the fovea (area 1) was 19.87 +/- 10.16 nV/deg(2) and the latency was 38.56 +/- 1.18 ms. In the parafoveal area (area 2), the mean retinal response density was 10.82 +/- 2.34 nV/deg(2) and the mean latency was 36.52 +/- 1.73 ms. In the perifoveal area (area 3), the mean retinal response density was 10.83 +/- 0.90 nV/deg(2) and the mean latency was 36.36 +/- 1.90 ms. In Group B, the mean retinal response density of area 1 was 22.02 +/- 0.9 nV/deg(2) and the mean latency was 32.56 +/- 1.25 ms. In area 2, the mean retinal response density was 12.23 +/- 0.55 nV/deg(2) and the mean latency was 30.84 +/- 1.22 ms. Finally, in the perifoveal area (area 3), the mean retinal response density was 12.74 +/- 0.44 nV/deg(2) and the mean latency was 29.7 +/- 11.09 ms. The differences in amplitude and latency were statistically significant. CONCLUSION: Increased foveal thickening and significant decrease of the electrical activity of areas 1, 2 and 3 were found in HIV-positive children. These findings suggested some subclinical dysfunction of the photoreceptors and the inner retinal layers of the fovea in HIV-positive children with normal vision and without ocular disease. PMID- 21535140 TI - Use of multifocal ERG and OCT for diagnosing Stargardt's disease. PMID- 21535141 TI - Structural and functional changes after surgical treatment in foveoschisis: a case report. PMID- 21535143 TI - KB Woo (???) (1906-1991) and his family: three generations of optometry. PMID- 21535145 TI - Reintroduction as an ecosystem restoration technique. PMID- 21535146 TI - Understanding interaction effects of climate change and fire management on bird distributions through combined process and habitat models. AB - Avian conservation efforts must account for changes in vegetation composition and structure associated with climate change. We modeled vegetation change and the probability of occurrence of birds to project changes in winter bird distributions associated with climate change and fire management in the northern Chihuahuan Desert (southwestern U.S.A.). We simulated vegetation change in a process-based model (Landscape and Fire Simulator) in which anticipated climate change was associated with doubling of current atmospheric carbon dioxide over the next 50 years. We estimated the relative probability of bird occurrence on the basis of statistical models derived from field observations of birds and data on vegetation type, topography, and roads. We selected 3 focal species, Scaled Quail (Callipepla squamata), Loggerhead Shrike (Lanius ludovicianus), and Rock Wren (Salpinctes obsoletus), that had a range of probabilities of occurrence for our study area. Our simulations projected increases in relative probability of bird occurrence in shrubland and decreases in grassland and Yucca spp. and ocotillo (Fouquieria splendens) vegetation. Generally, the relative probability of occurrence of all 3 species was highest in shrubland because leaf-area index values were lower in shrubland. This high probability of occurrence likely is related to the species' use of open vegetation for foraging. Fire suppression had little effect on projected vegetation composition because as climate changed there was less fuel and burned area. Our results show that if future water limits on plant type are considered, models that incorporate spatial data may suggest how and where different species of birds may respond to vegetation changes. PMID- 21535147 TI - Relations between urban bird and plant communities and human well-being and connection to nature. AB - By 2050, 70% of the world's population will live in urban areas. In many cases urbanization reduces the richness and abundance of native species. Living in highly modified environments with fewer opportunities to interact directly with a diversity of native species may adversely affect residents' personal well-being and emotional connection to nature. We assessed the personal well-being, neighborhood well-being (a measure of a person's satisfaction with their neighborhood), and level of connection to nature of over 1000 residents in 36 residential neighborhoods in southeastern Australia. We modeled these response variables as a function of natural features of each neighborhood (e.g., species richness and abundance of birds, density of plants, and amount of vegetation cover) and demographic characteristics of surveyed residents. Vegetation cover had the strongest positive relations with personal well-being, whereas residents' level of connection to nature was weakly related to variation in species richness and abundance of birds and density of plants. Demographic characteristics such as age and level of activity explained the greatest proportion of variance in well being and connection to nature. Nevertheless, when controlling for variation in demographic characteristics (examples were provided above), neighborhood well being was positively related to a range of natural features, including species richness and abundance of birds, and vegetation cover. Demographic characteristics and how well-being was quantified strongly influenced our results, and we suggest demography and metrics of well-being must be considered when attempting to determine relations between the urban environment and human well-being. PMID- 21535148 TI - Motivations influencing the adoption of conservation easements. AB - The use of conservation easements as a conservation mechanism for private land has increased greatly in the past decade; conservation easements now protect over 15 million ha across the United States from residential and commercial development. We used a mailed survey and in-depth telephone interviews to determine factors that motivate private landowners in Iowa, Illinois, Michigan, Ohio, and Wisconsin (U.S.A.) to place conservation easements on their properties. The mailed survey asked about characteristics of landowners, their properties, and their opinions on 9 factors related to the decision to place an easement. A follow-up telephone interview was completed with 19 mail-survey participants to gain an in-depth understanding of the action and to triangulate the results with the questionnaire. Place attachment, which is a measure of personal connection to a location or property, was the greatest motivation for implementation of an easement. Results of a principal components analysis suggested contributing to the public good underlaid several of the strong motivational factors for participation. Financial reasons were the lowest ranked motivational factor; however, financial concerns may facilitate placement of an easement that would otherwise not be realized. We believe that our results may be transferable to places where land protected by easements is not dominated by traditional farming (row crops, pastures, and hay), timber harvesting, or nonextractive uses (e.g., habitat for wild animals, recreation, and protection of ecosystem services). PMID- 21535149 TI - Contrasting global trends in marine fishery status obtained from catches and from stock assessments. AB - There are differences in perception of the status of fisheries around the world that may partly stem from how data on trends in catches over time have been used. On the basis of catch trends, it has been suggested that about 70% of all stocks are overexploited due to unsustainable harvesting and 30% of all stocks have collapsed to <10% of unfished levels. Catch trends also suggest that over time an increasing number of stocks will be overexploited and collapsed. We evaluated how use of catch data affects assessment of fisheries stock status. We analyzed simulated random catch data with no trend. We examined well-studied stocks classified as collapsed on the basis of catch data to determine whether these stocks actually were collapsed. We also used stock assessments to compare stock status derived from catch data with status derived from biomass data. Status of stocks derived from catch trends was almost identical to what one would expect if catches were randomly generated with no trend. Most classifications of collapse assigned on the basis of catch data were due to taxonomic reclassification, regulatory changes in fisheries, and market changes. In our comparison of biomass data with catch trends, catch trends overestimated the percentage of overexploited and collapsed stocks. Although our biomass data were primarily from industrial fisheries in developed countries, the status of these stocks estimated from catch data was similar to the status of stocks in the rest of the world estimated from catch data. We conclude that at present 28-33% of all stocks are overexploited and 7-13% of all stocks are collapsed. Additionally, the proportion of fished stocks that are overexploited or collapsed has been fairly stable in recent years. PMID- 21535150 TI - Low-dose protamine to facilitate earlier sheath removal from the femoral artery after peripheral endovascular intervention. AB - OBJECTIVES: This study aimed to evaluate the safety of low-dose protamine administration to facilitate earlier vascular sheath removal. BACKGROUND: Vascular access complications are the most common cause of postprocedural morbidity in patients undergoing peripheral endovascular intervention (PEI). Prolonged manual compression and closure devices do not eliminate these complications. METHODS: A consecutive series of 166 patients who underwent PEI were retrospectively compared to an all-comers control group of 136 patients who did not receive protamine. The study population received an intravenous dose of protamine based upon the dose of heparin received and the length of the procedure. The arterial sheath was removed when activated clotting time was less than 220 seconds. Primary end-points included bleeding complications, comprised of groin hematomas and retroperitoneal bleeding, and vascular complications, comprised of pseudoaneurysms, access vessel thrombosis, and arteriovenous fistula formation. RESULTS: The study population on average was older than the control group (71 vs. 67 years) and had a higher incidence of hypercholesterolemia (89.8% vs. 76.5%, P = 0.002). The average dose of protamine was 1.9 +/- 0.83 mg, with a total dose of heparin of 5371 +/- 1327 units. The time until sheath removal was 8.9 +/- 8.6 minutes in the protamine group versus 188 +/- 118 minutes in the control group (P < 0.001). There were no episodes of protamine anaphylaxis or adverse reactions. The access site complication rate between the 2 groups was statistically insignificant. CONCLUSIONS: This strategy offers an inexpensive, safe, and reliable method to achieve hemostasis and facilitate earlier sheath removal in patients undergoing PEI. PMID- 21535151 TI - Do patients with drug-eluting stent thrombosis have a similar prognosis to patients presenting with st-Elevation myocardial infarction of de novo lesions? AB - BACKGROUND: Despite significant advances in stent technology and pharmacotherapy, drug-eluting stent thrombosis (DES-ST) remains a major complication of percutaneous coronary intervention (PCI) and commonly presents as ST-elevation myocardial infarction (STEMI). There are currently little data comparing the in hospital outcomes of patients presenting with STEMI due to DES-ST with those due to de novo coronary artery disease (CAD). METHODS: Our study comprised 985 consecutive patients who underwent primary PCI for STEMI, 102 of whom were diagnosed as having a definite DES-ST. The primary end-point was the in-hospital composite of death or recurrent myocardial infarction (MI). The secondary end point was the in-hospital maximum rise in creatine kinase (myocardial band [MB] fraction) and troponin I. RESULTS: The DES-ST group had a higher proportion of patients with diabetes mellitus, hypercholesterolemia, history of ischemic heart disease, coronary revascularization, and chronic renal impairment. The adjusted primary end-point was higher in the DES-ST cohort (12.7% vs. 7.4%; P = 0.05). The 2 cohorts did not differ in the secondary end-point. The independent predictors of the primary end-point were age (hazard ratio [HR]= 1.04; 95% confidence interval [CI]= 1.01 - 1.06; P = 0.005), cardiogenic shock (HR = 11.5; 95% CI = 6.38 - 20.07, P < 0.001), and lesions involving the left anterior descending coronary artery (HR = 1.8; 95% CI = 1.03 - 3.13, P = 0.04). DES-ST was not an independent predictor of the primary end-point (HR = 1.18; 95% CI = 0.53-2.63, P = 0.38). CONCLUSIONS: Patients with STEMI secondary to DES-ST have a poorer in hospital outcome than do patients in whom STEMI is due to de novo CAD. This difference may be predominantly driven by differences in the baseline characteristics between these cohorts. (J Interven Cardiol 2011;24:320-325). PMID- 21535152 TI - Reaccessing an occluded radial artery: a "proximal entry" technique. AB - Radial artery occlusion (RAO) is an infrequent but important consequence of transradial access. It prevents subsequent use of the same radial artery for coronary angiography and intervention. We describe a new "proximal entry" technique in 3 cases of RAO, which allowed successful completion of the procedures. This technique should add to the armamentarium of a radial operator allowing for reaccessing the radial artery. (J Interven Cardiol 2011;24:378-381). PMID- 21535153 TI - Xenotransplantation: from the lab to the clinic: Sunrise Symposium at the XXIII International Congress of the Transplantation Society, Vancouver, Canada, August 2010. AB - This manuscript presents a summary of the Symposium "Xenotransplantation, from the Lab to the Clinic," held at the XXIII International Congress of The Transplantation Society, August 2010. This Symposium was timely in view of recent developments in translational research in the field, and the initiation of clinical trials after a thorough review by regulatory authorities and scientific experts. Three experts presented an update on the status of preclinical research with the perspective of moving forward to clinical trials; first data from clinical trials using encapsulated porcine islet cells; and the regulatory aspects for clinical application of a xenotransplantation product. PMID- 21535154 TI - Erythropoietin, GDF15, IL6, hepcidin and testosterone levels in a large cohort of elderly individuals with anaemia of known and unknown cause. AB - Epidemiologic studies have documented an increasing frequency of anaemia in individuals 65 yrs and older. Elderly individuals with anaemia have been categorised into the following: those with chronic disease, those with iron, B12 or folate deficiency and those with anaemia of unknown aetiology (AUE). There is considerable interest and debate as to whether AUE has an inflammatory component, is caused by cytokine dysregulation affecting production or response to erythropoietin (EPO) or iron availability or represents a novel pathologic process. Here, we compare a large cohort of AUE cases with a matched, non-anaemic control group and with individuals who have anaemia of defined cause. IL-6, hepcidin, GDF15, EPO and testosterone levels were compared. IL6 and hepcidin levels did not differ significantly between AUE and control groups, indicating that inflammation or iron restriction is not central feature of anaemia in this group. GDF15 levels were significantly elevated when comparing AUE with controls and were markedly elevated in patients with renal disease. Testosterone levels were lower in men from the AUE group compared with non-anaemic controls. EPO levels in the AUE group were increased relative to controls but were inappropriately low for the degree of anaemia. Our data indicate that an impaired EPO response, in the absence of evidence for iron restriction or inflammation, is characteristic of AUE. PMID- 21535155 TI - Primary colonic lymphoma: an analysis of 74 cases with localized large-cell lymphoma. AB - BACKGROUND: Surgical resection is considered a crucial treatment in patients with primary colonic lymphoma, but combining surgery with chemotherapy has provided additional therapeutic benefits in some studies. To further explore the optimal therapeutic approach in different clinical scenarios, we reviewed cases with localized large-cell lymphoma and analyzed the factors related to the outcomes. PATIENTS AND METHODS: The 74 cases diagnosed between February 1979 and October 2010 were retrospectively reviewed for clinical features, laboratory findings, and pathological diagnosis. The outcomes were correlated with their demographics and different treatment modalities. RESULTS: Of the 74 cases, only the patients who had complete tumor resection had significantly improved progression-free survival (PFS). The patients treated with resection and chemotherapy had better overall survival (OS) and PFS than those treated with resection alone. The OS and PFS of the patients who were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy without surgery were similar to those of patients treated with CHOP and resection, but the patients treated with resection followed by cyclophosphamide, vincristine, and prednisone (COP) chemotherapy had significantly better OS and PFS than the patients treated with COP chemotherapy alone. For patients with diffuse large B-cell lymphoma (DLBCL), rituximab-based chemotherapy with or without resection had similar OS and PFS. CONCLUSIONS: We conclude that chemotherapy alone provides similar therapeutic effect compared with surgery and chemotherapy and that surgical resection can be spared if an endoscopic diagnosis could be made. PMID- 21535156 TI - Cross-sectional study of pulmonary function and MRI-derived liver and myocardial iron content in young patients with beta-thalassemia major. PMID- 21535157 TI - Melphalan 100 mg/m2 with stem cell support as first relapse treatment is safe and effective for myeloma patients with long remission after autologous stem cell transplantation. AB - INTRODUCTION: Today, a number of therapeutic options are available as the patient with myeloma relapses from initial treatment with high-dose melphalan and autologous stem cell transplantation (ASCT). For patients who experience a durable response to primary ASCT, retreatment with high-dose melphalan is recommended by many current guidelines. Yet, toxicity is an important aspect in the choice of relapse treatment, and a second ASCT in this setting could be associated with enhanced toxicity. As the goal for the treatment for relapsed myeloma should be disease control while maintaining quality of life, lower doses of melphalan might be preferable. METHODS AND OBJECTIVES: In this retrospective study, we account for the outcome of 66 patients with myeloma in first systemic relapse after ASCT, who were treated with intermediate-dose melphalan, 100 mg/m2, and stem cell support (MEL 100). The aim was to evaluate this treatment in relation to prior response duration after initial ASCT and with respect to response rate, toxicity and survival. RESULTS: The overall response rate was 62%. There was limited, mostly haematological, toxicity, and no treatment-related mortality was observed. The median progression-free survival (PFS) was 8.5 months, and the median overall survival was 24 months. Patients with time to progression of 34 months or more (n=17; >=75th percentile) after initial ASCT had a median PFS of 12.5 months after MEL 100. CONCLUSION: For patients with a long lasting response after ASCT, MEL 100 could be a therapeutic option with low toxicity and with efficacy comparable to newer immunomodulatory drugs. PMID- 21535158 TI - Xenogeneic immunosuppression of human umbilical cord mesenchymal stem cells in a major histocompatibility complex-mismatched allogeneic acute graft-versus-host disease murine model. AB - Mesenchymal stem cells (MSCs) hold great promise for treating immune disorders owing to their immunoregulatory capacity, but the mechanism remains controversial. As we show here, the mechanism of human umbilical cord mesenchymal stem cell (HUCMSC)-mediated immunosuppression involves TGF-beta and indoleamine 2,3-dioxygenase (IDO). In this study, we investigated the influence of xenogeneic HUCMSCs on acute graft-versus-host disease (aGVHD) in murine allogeneic bone marrow transplantation (BMT). In the HUCMSC-treated group, lethally irradiated DBA/2(H-2Kd) mice were adoptively transferred with expanded HUCMSCs, bone marrow (BM), and splenocytes (SCs) from C57BL/6 (H-2Kb) mice. Recipients in the control group were transferred only BM and SCs. The two groups were compared in survival, weight, histopathologic specimens, and aGVHD scoring. In the HUCMSC-treated group, 60% of the mice survived past day 30 after BMT, but in the control group, all mice died within 18 d. The mice treated with HUCMSCs exhibited light symptoms of aGVHD after day 30. The results suggest that xenogeneic HUCMSCs could alleviate aGVHD symptoms and prolong survival after allogeneic BMT. Our study suggests that in vitro expanded HUCMSCs might be used to inhibit severe aGVHD effectively in allogeneic hematopoietic cell transplantation clinically. PMID- 21535159 TI - Pathophysiology of acquired von Willebrand disease: a concise review. AB - Acquired von Willebrand disease (AVWD) is a rare, underdiagnosed hemorrhagic disorder, which is similar to congenital VWD with regard to the clinical and laboratory parameters; however, it is found in individuals with no positive family history and has no genetic basis. The etiology is varied, the commonest being hematoproliferative disorders and cardiovascular disorders. Other disorders associated with AVWD are autoimmune disorders such as systematic lupus erythematosus, hypothyroidism, and neoplasia, or it may also be drug induced. In quite a few cases, the etiology is unknown. The pathogenic mechanisms are different in different underlying disorders or they may be overlapping among these disorders. Some of the proposed mechanisms include the development of autoantibodies, selective absorption of high molecular weight von Willebrand factor (VWF) multimers, non-selective absorption of VWF, mechanical destruction of VWF under high shear stress, and increased proteolysis. This report presents a concise review of the pathophysiological mechanisms of AVWD in these various underlying conditions. PMID- 21535160 TI - Treatment of consecutive patients with chronic myeloid leukaemia in the cooperating centres from the Czech Republic and the whole of Slovakia after 2000- a report from the population-based CAMELIA Registry. AB - BACKGROUND: Most results on the treatment of chronic myeloid leukaemia (CML) with imatinib were obtained from clinical trials that may differ from the routine practice. We report the results of treatment of consecutive patients with CML at ten major centres during 2000-2008. PATIENTS AND METHODS: Data reporting was retrospective in 2000-2004 and prospective from 2005 on. A total of 661 patients [301 women and 360 men; median age 51 (range, 15-83)] with Ph+CML were registered. The median follow-up was 46.1 months (0-122.2). RESULTS: Most patients were treated with first- (379; 57.3%) or second-line (193; 29.2%) imatinib; some of the patients underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (83; 12.6%), but 6.1% were treated with other modalities [40 patients; median age 66 (range, 32-83)]. The probability of overall survival (OS) at 5 years, according to Kaplan and Meier, was 88.9%, 77.5% and 68.7% for chronic-phase patients treated with first-line imatinib, second-line imatinib and first-line AHSCT, respectively, but only 25.2% for patients receiving other modalities. The OS was dependent on the disease phase and Sokal, Hasford and European group for blood and marrow transplantation (EBMT) risk scores (P<0.001; each). Only 46.2% of deaths in patients treated with other modalities were attributable to CML. Elderly patients over 65 years achieved similar response rates and progression-free survival to the younger ones. There was a trend for inferior results of AHSCT performed after the failure of imatinib (P=0.075), probably as a result of differences in EBMT risk scores (P<0.001). CONCLUSIONS: The ability to achieve results comparable to those of previous clinical studies in our CML cohort was influenced by centralised care. Decisions not to initiate imatinib or to delay AHSCT may have a negative impact on OS, but comorbidities may limit the treatment potential of imatinib in the elderly. PMID- 21535161 TI - Outcome and risk factors for late-onset complications 24 months beyond allogeneic hematopoietic stem cell transplantation. AB - OBJECTIVES: The aim of this retrospective study was to assess the incidence of late complications occurring >=2 years after allogeneic hematopoietic stem cell transplantation (HSCT) for malignant diseases using a T-cell depletion strategy. METHODS: Between 1984 and 2004, 142 patients were eligible for the study. Total body irradiation (TBI) was carried out in 85% of the patients and T-cell depletion in 84%. RESULTS: Non-relapse mortality (NRM) was 3% (95% CI 0-11) at 10 years, and serious late events affected a substantial number of patients. The cumulative incidence (CI) of chronic graft-versus-host disease (cGvHD) was 30% (95% CI 23-40), and that of infectious complications was 17% (95% CI 11-23). Multivariate analysis showed a higher risk for late complications in patients with cGvHD (HR 1.9, 95% CI 1.2-3.2, P=0.011) and patients receiving methylprednisolone during conditioning (HR 1.9, 95% CI 1.1-3.3, P=0.019 1), patients with cGvHD also having a higher risk for NRM (HR 13.2, 95% CI 1.2-143, P=0.03), as well as those receiving steroids for >3 months (HR 40.3, 95% CI 2.3 718, P=0.02) and those receiving antithymocyte globulin (HR 9.6, 95% CI 0.8-68, P=0.024). CONCLUSIONS: A significant proportion of long-term survivors of HSCT had late complications. cGvHD remained an important risk factor for late complications despite T-cell depletion resulting in immunosuppression and infectious complications. PMID- 21535162 TI - Modern and conventional prognostic markers of chronic lymphocytic leukaemia in the everyday haematological practice. AB - OBJECTIVES: The impact of modern prognostic markers on clinical course of chronic lymphocytic leukaemia (CLL) in everyday practice has been not yet well defined, especially in large series of patients. Therefore, the goal of this study was to assess the influence of conventional as well as modern prognostic factors on overall survival (OS) and time to therapy (TTT) of patients with CLL. METHODS: We retrospectively analysed data of all patients consecutively entered into the databases of five large academic centres in the Czech Republic. The total of 1300 patients was included in the analysis. RESULTS AND CONCLUSION: Through the use of uniparametric analysis, it was determined that gender, clinical stage Rai II-IV, unmutated IgVH status, deletion 17p (for both 5% and 20% cut-off), deletion 11q, ZAP-70 positivity and high expression of CD38 had significant negative influence on OS. TTT was significantly influenced by gender, Rai stage, IgVH status, deletion 11q, deletion 17p, deletion 13q and CD38 expression. Multiparametric analysis revealed that OS was significantly influenced by gender, age, IgVH status and deletion 17p. If only patients who died of CLL were included, gender, age, Rai stage, IgVH status and deletion 17p had significant influence on OS. Based on our results, the examination of biological prognostic markers can give an insight into the possible disease evolution in daily clinical practice. Biological prognostic markers are, however, not ready (maybe except deletion 17p in younger patients) to be used for guidance of therapy at least outside of clinical trials. PMID- 21535163 TI - A study of the clinical activity of a gel combining monocaprin and doxycycline: a novel treatment for herpes labialis. AB - BACKGROUND: Current treatment of herpes labialis is usually with topical antiviral drugs and early drug administration is required for effectiveness. Monocaprin, a 1-monoglyceride of capric acid, has high microbicidal activity in vitro and efficiently inactivates herpes simplex virus. Tetracyclines are inhibitors of matrix metalloproteinases that are part of the inflammatory response and contribute to the breakdown of tissue in ulcers. The study objective was to investigate the antiviral and wound-healing effect of a hydrogel containing either monocaprin or a combination of monocaprin and a low dose of doxycycline in vivo against herpes labialis. METHODS: Subjects were divided into two groups: (i) with prodromal symptoms of herpes labialis; (ii) with a vesicle. Both groups applied the hydrogel five times a day for five days. Test formulations were: (i) hydrogel containing monocaprin and doxycycline (MCD), (ii) hydrogel containing only monocaprin and (iii) placebo hydrogel. Formulations were distributed randomly to subjects within each group. Subjects recorded treatment results in a 6-day diary and a 7-day follow-up diary. RESULTS: For the MCD group the mean time to healing was 5.5 days (prodromal) and 5.3 days (vesicles/ulceration) or significantly shorter than for the placebo groups (7.25 and 7.5 days respectively; P < 0.05). Pain relief was significantly more with MCD (combining both the prodromal and vesicle groups) than with the monocaprin and placebo groups (P = 0.0114). CONCLUSION: Combining monocaprin with low-dose doxycycline offers an effective treatment for herpes labialiss, significantly reducing time to healing and pain compared with the placebo and monocaprin alone. PMID- 21535165 TI - Adverse effects of topical photodynamic therapy. AB - BACKGROUND/PURPOSE: Topical photodynamic therapy (PDT) is increasingly used in dermatology, particularly for the treatment of superficial non-melanoma skin cancer and dysplasia. Treatment is generally considered to be well tolerated, although pain during PDT can be a limiting factor. This review explores the adverse effects of topical PDT. METHODS: A thorough search of the literature using Medline was undertaken and published data were evaluated and presented in conjunction with our own experience. RESULTS: Pain during PDT is the most commonly reported adverse effect and may prevent successful treatment delivery, although low-irradiance regimes and use of nerve blocks or cooling air can be used to reduce pain. Other acute and chronic adverse effects are reported but do not seem to be limiting factors in the use of topical PDT. To date, there is no convincing evidence for a carcinogenic effect of this treatment. CONCLUSION: Topical PDT is associated with few significant adverse effects, although methods to optimize regimes and minimize pain are required to improve the acceptability of this therapy for patients. PMID- 21535166 TI - The risk to normal and photosensitive individuals from exposure to light from compact fluorescent lamps. AB - BACKGROUND/PURPOSE: The incandescent electric light bulb has been in widespread use since the early part of the 20th century. There is now a strong move underway to improve lighting efficiency to cut carbon dioxide emissions. As a result, many countries have introduced legislation to phase out the use of incandescent bulbs, and these are largely being replaced with compact fluorescent lamps (CFLs). The rate at which CFLs are replacing the traditional bulbs has caused alarm among patients with light-sensitive skin disorders as there has been very little informed discussion regarding the safety of these new lamps for this group of patients. The purpose of the present paper is to review the available literature to assess the likely impact of CFLs on the skin of normal and photosensitive individuals. METHODS: All data sources were identified through searches of MEDLINE and a manual literature search. RESULTS: The spectrum of light emitted by CFLs is different from incandescent light. In particular, some CFLs emit short wavelength UV radiation at 253.7 nm. Most published reports show that the short wavelengths can be eliminated by the use of a double envelope. There are very little data examining directly the risk to photosensitive individuals. In one study, a patient with chronic actinic dermatitis had a severe erythematous reaction from an exposure of only 2.5min' duration. CONCLUSION: CFLs present a low level of risk to individuals of normal sensitivity but they are potentially harmful to photosensitive patients. We recommend the use of double envelope lamps, and consideration given to the adoption of a 'UV-safe' classification scheme. PMID- 21535167 TI - Diallyl sulfide protects against ultraviolet B-induced skin cancers in SKH-1 hairless mouse: analysis of early molecular events in carcinogenesis. AB - BACKGROUND: Diallyl sulfide (DAS) has been shown to have a preventive effect against various cancers. AIMS AND OBJECTIVES: We evaluated the protective effects of DAS in regression of ultraviolet B (UVB)-induced skin tumor formation in SKH-1 hairless mice and its underlying early molecular biomarkers. METHODS: We examined the efficacy of DAS in UVB light-induced skin lesion in SKH-1 hairless mice and the associated molecular events. RESULTS: Mice irradiated with UVB at 180mJ/cm(2) twice per week elicited 100% tumor incidence at 20 weeks. The topical application of DAS before UVB irradiation caused a delay in tumor appearance, multiplicity, and size. The topical application of DAS before and immediately after a single UVB irradiation (180mJ/cm(2) ) resulted in a significant decrease in UVB-induced thymine dimer-positive cells, expression of proliferative cell nuclear antigen (PCNA), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and apoptotic sunburn cells, together with an increase in p53 and p21/Cip1 positive cell population in the epidermis. Simultaneously, DAS also significantly inhibited nuclear factor-kappaB (NF-kappaB), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and nitric oxide (NO) levels. CONCLUSIONS: The protective effect of DAS against photocarcinogenesis is accompanied by the down regulation of cell-proliferative controls, involving thymine dimer, PCNA, apoptosis, transcription factors NF-kappaB, and of inflammatory responses involving COX-2, PGE2, and NO, and up-regulation of p53, p21/Cip1 to prevent DNA damage and facilitate DNA repair. PMID- 21535168 TI - The effect of 308nm excimer laser on segmental vitiligo: a retrospective study of 80 patients with segmental vitiligo. AB - BACKGROUND: Segmental vitiligo (SV), which frequently accompanies poliosis, indicating a poor prognosis that is likely resistant to treatments. OBJECTIVES: In this study, we performed a retrospective analysis to evaluate the treatment response to 308 nm excimer laser in SV patients. METHODS: A retrospective chart and photographic review was performed on 80 SV patients who had been treated with 308nm excimer laser for >3 months. RESULTS: Eighty patients with SV (mean age: 24.0 years +/- 15.3, males: 50%) were included in this study. The mean grade of repigmentation was 2.3 after 20.6 months of mean treatment duration; 23.8% of 80 patients showed grade 4, 20% showed grade 3, and 56.2% showed grade 1-2 repigmentation. However, none of them achieved complete repigmentation with excimer laser. The degree of repigmentation was positively correlated with treatment duration (r=0.315, P=0.004) and cumulative ultraviolet (UV) dosage (r=0.366, P=0.001), whereas it was negatively correlated with disease duration (r=-0.265, P=0.017). CONCLUSION: This study suggests that SV has a better repigmentation response when excimer laser is used at earlier stages of the disease and long-term use and high cumulative UV energy of the excimer laser elicit better responses. Additional treatments like surgical procedures in addition to excimer laser should be considered for complete repigmentation. PMID- 21535169 TI - Phototherapy reduces serum resistin levels in psoriasis patients. AB - This study investigated phototherapy-induced changes in certain adipokine levels in patients with psoriasis. Patients with psoriasis (n=36) were recruited and body mass index (BMI) and disease severity (Psoriasis Area and Severity Index) were recorded. Serum resistin and leptin levels before and after bath-psoralen and ultraviolet (UV) A or narrow-band UVB therapy were examined by enzyme-linked immunosorbent assay. Serum leptin levels correlated positively with BMI. Phototherapy induced no remarkable change in the leptin levels, but significantly decreased serum resistin levels from 9.02+/-8.83 to 4.86+/-3.30ng/ml. Serum resistin levels might be involved in insulin resistance and inflammation, and correlate with disease severity in patients with psoriasis. The reduction in serum resistin induced by phototherapy might be related to the clinical efficacy of this treatment for psoriasis. PMID- 21535170 TI - Seasonal cutaneous sarcoidosis: a photo-induced variant. AB - Sarcoidosis is a multisystem granulomatous disease, with cutaneous involvement in up to 35% of cases. Owing to its heterogeneous clinical presentation, sarcoidosis is often referred to as the 'great imitator' of dermatological disease. A rare variant of photosensitive cutaneous sarcoidosis has been infrequently reported in the literature. We describe an unusual case of recurrent, photo-distributed cutaneous sarcoidosis presenting only during the summer months. PMID- 21535171 TI - A single blind randomized clinical study: the efficacy of isotretinoin plus narrow band ultraviolet B in the treatment of psoriasis vulgaris. AB - In this randomized clinical trial, 39 patients with psoriasis vulgaris were randomized in two groups. Intervention group received narrow band ultraviolet B (NBUVB)+isotretinoin (0.5 mg/kg/day), control group received NBUVB+placebo. Psoriasis Area Severity Index (PASI) scoring was recorded at baseline and weeks 4, 10, and 14. Thirty-seven patients completed the study. According to recorded PASI scores the difference between efficacies of two treatments was not significant. Complete clearing was noticed in 14 and 13 patients in intervention group and controls. The mean cumulative NBUVB dose in intervention group and controls was 29.95 +/- 16.11 vs. 45.77 +/- 7.72J/cm(2) (P=0.004). Isotretinoin+NBUVB can reduce number of phototherapy sessions and cumulative NBUVB dose. PMID- 21535172 TI - Progressive macular hypomelanosis, excellent response with narrow-band ultraviolet B phototherapy. AB - Progressive macular hypomelanosis (PMH) is an acquired disorder of skin pigmentation, which is mostly under-diagnosed. It is characterized by nummular hypopigmented lesions appearing on the trunk in young persons. Several treatment options are available, although topical clindamycin and benzoyl peroxide have been used traditionally. However, good results have recently been achieved using narrow-band ultraviolet B (NBUVB) phototherapy. We present the case of a 13-year old girl with hypopigmented lesions on the trunk and limbs that had progressed over 1 year and that were diagnosed as PMH. The patient was initially treated with topical clindamycin and benzoyl peroxide. However, little improvement was seen and treatment was then started with NBUVB phototherapy. After 25 sessions, with a total cumulative dose of 18 J/cm(2) , the patient showed almost total repigmentation of the lesions. The treatment of PMH is often difficult, and very little is currently known about the treatment response in this disorder, as most reports have very small series of patients with a short disease progression time. NBUVB phototherapy has been shown to be effective, as seen in our patient, although in many cases, there is recurrence after the cessation of treatment. PMID- 21535173 TI - Treatment of giant Bowen's disease with sequential use of photodynamic therapy and imiquimod cream. AB - We present a 79-year-old man with a 2-year history of Bowen's disease. The 10 * 10 plaque was located on the right frontotemporal area. The patient was treated with two photodynamic therapy (PDT) sessions, performed 1 week apart, followed by five times per week application of imiquimod 5% cream for 6 consecutive weeks. Complete clinical and histological response was achieved 3 months after treatment was completed. The patient remains recurrence free 12 months after treatment. Cosmetic outcome was evaluated as fair because of residual erythema. Long-term follow-up is mandatory for assessment of recurrences. Further studies are needed in order to confirm the improved outcome using the combination of PDT and imiquimod cream. PMID- 21535175 TI - Allergy epidemics, solidarity and support to countries through Pediatric Allergy and Immunology. PMID- 21535176 TI - Rhinovirus-induced bronchiolitis and asthma development. AB - Human rhinovirus (HRV) and respiratory syncytial virus (RSV) are commonly associated with bronchiolitis. The breaking point in the dominance is approximately 12 months--rhinovirus dominates in the older children. Predisposition may markedly increase the prevalence of HRV bronchiolitis. Especially, low interferon responses and atopy-related factors have been associated with HRV bronchiolitis. The former has been considered as a sign of poor antiviral defense, and the latter could be associated with atopic airway inflammation in wheezing children. Although recurrent wheezing is common after both RSV and HRV bronchiolitis, HRV bronchiolitis carries a markedly higher risk of persistent wheezing until 6 years of age and for childhood asthma. This association has been independent from atopy at 7.2 (median) years of age. The increased risk of asthma in adulthood after non-RSV bronchiolitis vs. RSV bronchiolitis in infancy (at the time when PCR was not available for HRV diagnosis) offers indirect evidence for the association between HRV bronchiolitis and chronic asthma. PMID- 21535177 TI - Classification of anaphylaxis and utility of the EAACI Taskforce position paper on anaphylaxis in children. AB - Correct management and classification of anaphylaxis is mandatory. Records of emergency department (ED) visits to any of the three pediatric hospitals in Stockholm, because of reactions to foods during 2007, were identified. A retrospective analysis of clinical ED records of 371 children with 381 unique occasions of reactions to foods was performed. Symptoms/signs of reactions to foods recorded for classification of anaphylaxis were related to those presented in the EAACI Taskforce position paper on Anaphylaxis in Children (Allergy 2007; 62: 857). Forty-six different symptoms/signs of reactions to foods were retrieved. Several severe signs or symptoms from the respiratory tract and signs indicating reduced brain perfusion were not described in detail in the EAACI paper, hampering correct classification of anaphylaxis including grading of severity in our material. After modification of the EAACI classification including such signs and symptoms, we were able to classify 128 (35%) children with anaphylaxis. Seventy children (19%) did not fulfill our modified EAACI's criteria for anaphylaxis. They had been given adrenaline before or at arrival to hospital, possibly preventing anaphylaxis. Another 173 (47%) children/adolescents had neither been given adrenalin, nor fulfilled the criteria for anaphylaxis. Classification of food-induced anaphylaxis and severity grading should be built on signs and symptoms to facilitate diagnosis. The existing EAACI tool is helpful, but for Swedish children it is not quite applicable, in particular because of the lack of description of some respiratory, neurological or possible cardiovascular signs and symptoms. PMID- 21535178 TI - Extremely low prevalence of epinephrine autoinjectors in high-risk food-allergic adolescents in Dutch high schools. AB - The aim of the study was to estimate the prevalence of probable food allergy in adolescents aged 11-20 and to examine the frequency of epinephrine autoinjector (EAI) ownership among high-risk individuals. Adolescents were screened followed by a more detailed telephone questionnaire inquiring about suspected food(s), symptoms, diagnosis, and use of an EAI. The participating adolescents were classified as probably or unlikely to be food-allergic. The need for an EAI was assessed. In total, 2284 adolescents completed the screening questionnaire, of which 396 indicated food to be a problem and 168 agreed to be interviewed. Forty eight adolescents were classified as probably food-allergic, of which eight were not aware of their food allergy. Twenty-three adolescents were considered candidates for an EAI, whereas only two of them had been prescribed this medication. The calculated questionnaire-based prevalence of EAI need was 3.0% (minimal prevalence at least 1.0%), whereas the EAI ownership was 0.09%. In conclusion, we found an alarming under prescription of EAIs in school-going adolescents. PMID- 21535179 TI - Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. AB - Studies based on skin and challenge tests have shown that 12-60% of children with suspected betalactam hypersensitivity were allergic to betalactams. Responses in skin and challenge tests were studied in 1865 children with suspected betalactam allergy (i) to confirm or rule out the suspected diagnosis; (ii) to evaluate diagnostic value of immediate and non-immediate responses in skin and challenge tests; (iii) to determine frequency of betalactam allergy in those children, and (iv) to determine potential risk factors for betalactam allergy. The work-up was completed in 1431 children, of whom 227 (15.9%) were diagnosed allergic to betalactams. Betalactam hypersensitivity was diagnosed in 50 of the 162 (30.9%) children reporting immediate reactions and in 177 of the 1087 (16.7%) children reporting non-immediate reactions (p<0.001). The likelihood of betalactam hypersensitivity was also significantly higher in children reporting anaphylaxis, serum sickness-like reactions, and (potentially) severe skin reactions such as acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and drug reaction with systemic symptoms than in other children (p<0.001). Skin tests diagnosed 86% of immediate and 31.6% of non-immediate sensitizations. Cross reactivity and/or cosensitization among betalactams was diagnosed in 76% and 14.7% of the children with immediate and non-immediate hypersensitivity, respectively. The number of children diagnosed allergic to betalactams decreased with time between the reaction and the work-up, probably because the majority of children with severe and worrying reactions were referred for allergological work up more promptly than the other children. Sex, age, and atopy were not risk factors for betalactam hypersensitivity. In conclusion, we confirm in numerous children that (i) only a few children with suspected betalactam hypersensitivity are allergic to betalactams; (ii) the likelihood of betalactam allergy increases with earliness and/or severity of the reactions; (iii) although non-immediate reading skin tests (intradermal and patch tests) may diagnose non-immediate sensitizations in children with non-immediate reactions to betalactams (maculopapular rashes and potentially severe skin reactions especially), the diagnostic value of non-immediate-reading skin tests is far lower than the diagnostic value of immediate-reading skin tests, most non-immediate sensitizations to betalactams being diagnosed by means of challenge tests; (iv) cross-reactivity and/or cosensitizations among betalactams are much more frequent in children reporting immediate and/or anaphylactic reactions than in the other children; (v) age, sex and personal atopy are not significant risk factors for betalactam hypersensitivity; and (vi) the number of children with diagnosed allergy to betalactams (of the immediate-type hypersensitivity especially) decreases with time between the reaction and allergological work-up. Finally, based on our experience, we also propose a practical diagnostic approach in children with suspected betalactam hypersensitivity. PMID- 21535180 TI - IL-22 mRNA in peripheral blood mononuclear cells from allergic rhinitic and asthmatic pediatric patients. AB - T helper (T(H) )-17 lymphocytes are characterized by the expression of many regulatory cytokines, including IL-17A and IL-22, but at present no clinical data are available on the expression of these cytokines in peripheral blood mononuclear cells (PBMC) from allergic asthmatic and rhinitic (AR) children. The aim of this study was to investigate a possible relationship between IL-22 and IL 17A mRNAs and clinical parameters in seroatopic, AR, and asthmatic children. The study, conducted during the pollen season, included 18 healthy and 18 allergic (n=9 asthmatic and n=9 rhinitic) children. Serum total and specific IgE, eosinophil count, and skin prick test were performed; in addition, IL-22 and IL 17A mRNA levels were detected in PBMC from healthy and allergic subjects by quantitative real-time PCR. Despite the absence of the mRNA for the IL-17A cytokine, IL-22 expression was found in PBMC from asthmatic patients, with increased IL-22 mRNA levels in patients with chronic severe respect to those with moderate asthma. A positive correlation between IL-22 mRNA and serum total IgE levels was found in asthmatic children. In addition, higher IL-22 and IL-17A mRNA levels were detected in both AR and asymptomatic seroatopic children, compared to healthy individuals, and a correlation between IL-22 and IL17A mRNA and serum total IgE levels was demonstrated. Moreover, the mRNA level of retinoic acid related orphan receptor C, the T(H) 17 transcription factor, was found to be increased in AR but not in asthmatic patients. This study provides the first evidence that IL-22 mRNA might be expressed in chronic severe asthmatic and AR children. The expression of IL-22 and IL-17A mRNAs in asymptomatic monosensitized seroatopic children suggests a role of these cytokines in the early events involved in the development of these allergic diseases. PMID- 21535181 TI - Pediatric allergy and immunology in Turkey. AB - Allergic diseases constitute a significant health problem in Turkey. According to a recent multicenter study, which used the ISAAC questionnaire, the mean prevalence of wheezing, rhinoconjunctivitis, and eczema in 10-yr-old school children during the past year was 15.8%, 23.5%, and 8.1%, respectively. A healthcare level system, regulated by Ministry of Health, is available in Turkey. Pediatric allergists and pediatric immunologists provide patient care at the tertiary level. Currently, 48 centers deliver care for allergic and immunologic diseases in children. There are 136 pediatric and 61 adult allergists/immunologists. Although the number of allergy/clinical immunology specialists is limited, these centers are capable of delivering many of the procedures required for the proper management and diagnosis of allergy/immunology. Pediatric allergy and/or immunology is a subspecialty lasting 3 yr and follows a 4-yr pediatric specialist training. Fellow training involves gaining knowledge in basic and clinical allergy and immunology as well as the performance and interpretation of laboratory procedures in the field of allergy and clinical immunology. The Turkish National Society of Allergy and Clinical Immunology (TNSACI) was officially established in 1989 and currently has 356 members. The society organizes a national congress annually and winter schools for fellowship training as well as training courses for patients and their relatives. TNSACI also has a strong representation in European Academy of Allergy and Clinical Immunology (EAACI) and European Society for Immunodeficiencies (ESID) through its participation in the executive committee, consensus reports, and initiatives in the diagnosis of allergic and immunologic diseases of children. The 30th Congress of the EAACI is also due to be held in Istanbul, Turkey, between June 11 and 15, 2011. PMID- 21535182 TI - Detection of pulmonary complications in common variable immunodeficiency. PMID- 21535184 TI - Quality control technique to reduce the variability of longitudinal measurement of hemoglobin mass. AB - The sensitivity of the athlete blood passport to detect blood doping may be improved by the inclusion of total hemoglobin mass (Hb(mass)), but the comparability of Hb(mass) from different laboratories is unknown. To optimize detection sensitivity, the analytical variability associated with Hb(mass) measurement must be minimized. The aim of this study was to investigate the efficacy of using quality controls to minimize the variation in Hb(mass) between laboratories. Three simulated laboratories were set up in one location. Nine participants completed three carbon monoxide (CO) re-breathing tests in each laboratory. One participant completed two CO re-breathing tests in each laboratory. Simultaneously, quality controls containing Low (1-3%) and High (8 11%) concentrations of percent carboxyhemoglobin (%HbCO) were measured to compare hemoximeters in each laboratory. Linear mixed modeling was used to estimate the within-subject variation in Hb(mass), expressed as the coefficient of variation, and to estimate the effect of different laboratories. The analytic variation of Hb(mass) was 2.4% when tests were conducted in different laboratories, which reduced to 1.6% when the model accounted for between-laboratory differences. Adjustment of Hb(mass) values using quality controls achieved a comparable analytic variation of 1.7%. The majority of between-laboratory variation in Hb(mass) originated from the difference between hemoximeters, which could be eliminated using appropriate quality controls. PMID- 21535185 TI - Stimulation of muscle protein synthesis by whey and caseinate ingestion after resistance exercise in elderly individuals. AB - Sarcopenia is a well-known phenomenon in elderly individuals and resistance exercise together with sufficient amino acid (AA) availability has proved to be a counteractive implement. However, the source of AA and supplement timing require further investigation. The objective was to compare muscle protein synthesis (MPS) to intakes of whey and caseinate after heavy resistance exercise in healthy elderly individuals, and, furthermore, to compare the timing effect of caseinate intake. Twenty-four elderly men and women (mean +/- SEM; 68 +/- 1 years) were randomized to one of four groups: caseinate intake before exercise (CasPre), caseinate intake immediately after exercise (CasPost), whey intake immediately after exercise (Whey), or intake of a non-caloric control drink (Control). Muscle myofibrillar and collagen fractional synthesis rates (FSR) were measured by a primed continuous infusion of L-[1-(13) C]leucine using labeled proteins during a 6-h recovery period. No differences were observed in muscle myofibrillar and collagen FSR with Whey (0.09 +/- 0.01%/h) compared with CasPost (0.09 +/- 0.003%/h), and it did not differ between CasPre (0.10 +/- 0.01%/h) and CasPost. MPS does not differ with whey and caseinate feeding immediately after heavy resistance exercise in elderly individuals, and MPS is similar with caseinate ingestion before and after exercise. PMID- 21535186 TI - Ultrasound lung comets induced by repeated breath-hold diving, a study in underwater fishermen. AB - Pulmonary edema has been reported in breath-hold divers during fish-catching diving activity. The present study was designed to detect possible increases in extravascular lung water (EVLW) in underwater fishermen after a competition. Thirty healthy subjects were studied. They participated in two different 5-h fish catching diving competitions: one organized in the winter (10 subjects) and one organized in the autumn (20 subjects). A questionnaire was used to record underwater activity and note respiratory problems. An increase in EVLW was investigated from the detection of ultrasound lung comets (ULC) by chest ultrasonography. Complementary investigations included echocardiography and pulmonary function testing. An increase in EVLW was detected in three out of 30 underwater fishermen after the competition. No signs of cardiovascular dysfunction were found in the entire population and in divers with an increase in the ULC score. Two divers with raised ULC presented respiratory disorders such as cough or shortness of breath. Impairment in spirometric parameters was recorded in these subjects. An increase in EVLW could be observed after a fish-catching diving competition in three out of 30 underwater fishermen. In two subjects, it was related to respiratory disorders and impairment in pulmonary flow. PMID- 21535187 TI - Autonomic recovery following sprint interval exercise. AB - The autonomic nervous activity was assessed following supramaximal exercise through heart rate (HR) and blood pressure (BP) variability (HRV and BPV) and baroreflex sensitivity (BRS). The beat-to-beat HR and BP were recorded during the supine and standing states before (PRE) and at 60 (R60) and 120 min (R120) following single (one Wingate, 1W) and multiple sprint intervals (four Wingates interspersed with 4 min of light cycling, 4W). The supine low frequency (LF) component was increased (P<0.001) and the high frequency (HF) was reduced (P<0.01) at R60 (LF, 178.1 +/- 11.0; HF, 74.8 +/- 10.5) compared with PRE (LF, 140.2 +/- 7.4; HF, 110.4 +/- 7.2) after both exercises. Supine systolic BPV LF:HF was higher at R60 (4.6 +/- 1.4) compared with PRE (6.8 +/- 2.4) only after 4W (P=0.035). Supine BRS was lower (P<0.001) at R60 (6.8 +/- 1.1) than at PRE (15.3 +/- 1.8) and R120 (11.3 +/- 1.3). BRS at R120 remained lower after 4W (P=0.02). Standing BRS was less (P<0.001) at R60 (2.3 +/- 0.5) than at PRE (5.6 +/- 0.8) or R120 (3.7 +/- 0.6) and returned to PRE values only after 1W. We concluded that (a) autonomic balance is shifted to a greater sympathetic and less parasympathetic activation following both types of exercise, (b) it takes longer than 1 h to recover following supramaximal exercise and (c) the recovery is longer after 4W than 1W. PMID- 21535188 TI - Buffering capacity of human skin layers: in vitro. AB - BACKGROUND/PURPOSE: The skin possesses buffering capacity to resist acidic/alkaline aggression. Skin components contribute differently to this buffering capacity. This study investigates buffering capacity in three skin layers: intact stratum corneum (SC), epidermis and dermis. METHODS: Sodium hydroxide (NaOH) and hydrochloric acid (HCl) solutions at 0.025, 0.05 and 0.1 N were applied to skin (3.18 MUL/cm(2)). After 30 min, the skin was washed with 1 mL de-ionized water. TEWL and pH measurements were conducted at baseline (before contact with acid or base), 0, 10 and 30 min post exposure, and continued at 0, 10 and 30 min post washing. RESULTS: Data indicate that immediately following acid or base exposures, the dermis demonstrates the highest buffering capacity, while with time, intact stratum corneum predominates. CONCLUSION: These findings potentiate advanced understanding of skin's buffering capacity as related to dermatopharmacology and dermatotoxicology. PMID- 21535189 TI - Seemingly healthy skin in atopic dermatitis: observations with the use of high frequency ultrasonography, preliminary study. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic, relapsing skin disorder which is strictly determined by the epidermal barrier function. In previous studies, there is conclusive evidence that normal-looking, nonlesional skin presents meaningful barrier function defect and a sub-clinical eczematous skin reaction. AIM: The authors intended to visualize nonlesional AD skin with the use of high frequency ultrasonography to show that the normal-looking, nonlesional skin may present significant abnormalities in USG examination. METHODS: We have performed analysis with the use of high-frequency 20 MHz skin sonography in the cases of 15 AD patients of the Department of Dermatology, Medical University, Poznan, Poland. The clinical score has been evaluated on the basis of W-AZS index and EASI. The results were presented in the form of ultrasonographic images. RESULTS: High frequency ultrasonography revealed an echopoor band within nonlesional skin of six (40%) examined AD patients and in all cases within skin lesions. CONCLUSION: Our results indicate the significant role of skin ultrasonography in the complete clinical evaluation of patients with AD, which may serve as an element in selection of the most appropriate topical treatment. An echopoor band beneath the echo entry within nonlesional skin of some AD patients may reflect subclinical eczematous reaction and the readiness for the development of typical skin lesions. For this purpose, we suggest to name an intact skin in AD as seemingly healthy skin. PMID- 21535190 TI - Digestive Endoscopy. Proceedings of the Endoscopy Forum Japan 2010. Preface. PMID- 21535191 TI - The difference in the capability of delineation between convex and radial arrayed echoendoscope for pancreas and biliary tract; case reports from the standpoint of both convex and radial arrayed echoendoscope. AB - Endoscopic ultrasound (EUS) is useful in obtaining not only high-resolution images of organs and surrounding tissue but also the tissue itself for histopathological diagnosis using fine needle aspiration. Currently, there are two types of EUS available for use: radial and convex arrayed EUS. Each type of EUS has its own advantages and disadvantages. Because radial arrayed EUS can obtain 360 degree images, it is easy to see surrounding organs and vessels. In addition, a single longitudinal image of the pancreas, gallbladder and bile duct is easy to obtain. For this reason, radial arrayed EUS is highly effective in diagnostic examinations. In contrast, while scanning range of convex arrayed EUS limited to 180 degrees, it has the advantage of being able to obtain tissue samples. Additionally while using convex arrayed EUS, the upper part of the bile duct and neck of the pancreas are easily seen beyond the portal vein. It is important to understand the characteristics of each EUS in order to select the most suitable EUS technique for diagnostic assessment. PMID- 21535192 TI - Current role of radial and curved-linear arrayed EUS scopes for diagnosis of pancreatic abnormalities in Japan. AB - To elucidate the current status of radial and curved-linear arrayed endoscopic ultrasonography (EUS), the author conducted a survey using a questionnaire at different institutions to assess the following. 1. Number of EUS procedures conducted annually for pancreatic malignancies. 2. Role of radial arrayed EUS for pancreatic abnormalities. 3. Role of curved-linear arrayed EUS for pancreatic abnormalities. 4. Indication of EUS-guided fine-needle aspiration biopsy (EUS FNA) for pancreatic abnormalities. 5. Percentage of EUS-FNA among the cases carried out with EUS for pancreatic abnormalities. 6. Experience of EUS with contrast harmonic echo for pancreatic malignancies and its indications. 7. Experience of elastography on EUS for pancreatic abnormalities. In Japan, although usage of curved-linear arrayed EUS has become popular for both EUS-FNA and for screening, radial EUS is widely used for diagnosing pancreatic abnormalities. Endosonographers must understand the respective advantages and disadvantages of EUS devices and carry out EUS procedures appropriately. PMID- 21535193 TI - The role of linear array EUS for diagnosis of pancreatic malignancies in the current situation. AB - Over the last few decades, the role of endoscopic ultrasound (EUS) in the diagnosis of pancreatic malignancies has greatly increased by allowing earlier diagnosis and appropriate staging. The development of linear array EUS also allows fine needle aspiration (FNA) to be carried out under real-time EUS guidance and offers definitive diagnosis, which has fundamentally changed the diagnostic approach to pancreatic malignancies. Moreover, linear array EUS with the EUS-FNA technique has a therapeutic application that has expanded the role of this procedure in the management of pancreatic malignancies. This review will focus on the features of linear array EUS and discuss the current role of linear array EUS in the diagnosis of pancreatic malignancies. PMID- 21535194 TI - Current status of diagnostic endoscopic ultrasonography in the evaluation of pancreatic mass lesions. AB - Endoscopic ultrasonography (EUS) is currently well established as a diagnostic method for the evaluation of pancreatic mass lesions. Diagnostic EUS might be divided into two broad categories; it is an imaging method, and also a device for obtaining cytopathology and histopathology. EUS as an imaging method has seen the introduction of newer intravenous contrast agents that enable the characterization of the pancreatic masses. EUS elastography enables real-time graphical representation of differential tissue hardness within a lesion. Contrast-enhanced EUS and/or elastography provide information additional to the fundamental images, leading to more accurate diagnosis. EUS-guided fine needle aspiration (EUS-FNA) has been shown to be a highly accurate method for distinguishing benign from malignant pancreatic masses. Several investigators have reported the usefulness of EUS-FNA samples obtained from pancreatic masses for genetic analysis, e.g. p53, K-ras. Genetic analysis of EUS-FNA samples to characterize chemo-sensitivity has recently been attempted in patients with unresectable pancreatic cancers. Although further improvement of EUS technology is desired to render it an even more convenient and reliable procedure, EUS at its current level of advancement is of proven utility in the diagnosis of pancreatic masses. PMID- 21535195 TI - Role of EUS in the early detection of small pancreatic cancer. AB - The prognosis of pancreatic cancer is extremely poor as a result of the difficulty in early detection of small pancreatic cancer and the intractable nature of appropriate anti-cancer therapies. Computed tomography (CT) is generally used for initial screening, but imaging sensitivities are generally insufficient to detect small masses. Endoscopic ultrasonography (EUS), in contrast, exhibits higher sensitivity than other imaging modalities for the detection of pancreatic cancers, because of the high resolution of images. AIMS: The goal of this study was to evaluate the role of EUS in the early detection of small pancreatic cancer. METHODS: We retrospectively reviewed the Gifu University Hospital EUS database (November 2007 to October 2010), and extracted the data of patients whose aim was to confirm the presence or absence of pancreatic cancer subsequent to no tumor detection by abdominal CT. RESULTS: In a 3 year period, 132 patients underwent EUS to confirm the presence or absence of small pancreatic cancer. All patients had previously tested negative for pancreatic mass using abdominal CT, but had showed pancreatic cancer risk factors, including increased serum carcinoembryonic antigen and/or CA 19-9 (n = 106), serum amylase (n = 38), and/or mild to moderate dilation of the main pancreatic duct as determined by imaging (n = 88). EUS detected pancreatic mass in three of these patients. The masses in all three patients were minute (<=10 mm) and their presence was correlated with the detection of mild dilation of the main pancreatic duct in earlier CT scans. Increase of tumor markers was observed in two patients and hyperamylasemia and aggravation of diabetes were observed in one patient. CONCLUSIONS: EUS is strongly recommended for early detection of small pancreatic cancer in patients in whom the dilation of the main pancreatic duct was detected in previous imaging tests, with or without increase of pancreatic enzymes or tumor markers. PMID- 21535196 TI - A convex EUS is useful to diagnose vascular invasion of cancer, especially hepatic hilus cancer. AB - Endoscopic ultrasonography (EUS) has become an indispensable diagnostic procedure pairing endoscopy with transluminal high frequency ultrasonography. EUS provides images with a high resolution such that the depth of tumor invasion can be accurately determined. It also sees lesions outside of gastrointestinal tract, particularly those in pancreas, biliary system and periluminal lymph nodes. The most important limitation of EUS was lack of specificity, that is, the differentiation between benign and malignant lesions. In 1992, EUS-guided fine needle aspiration (EUS-FNA) was introduced with the sampling of a lesion in the pancreatic head using a convex EUS. Since then the indications of EUS-FNA have been expanded to include a variety of therapeutic uses. In addition, a convex EUS probe can also be used for detailed evaluation of the pancreatobiliary system, in lieu of a radial EUS. The vascular structures surrounding liver, biliary system and pancreas can be showed by a convex EUS system very clearly and easily compared with the more familiar radial EUS images. So we think a convex EUS is very useful for not only EUS-FNA but also screening and close examination for cancer with vascular invasion. PMID- 21535197 TI - Role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for diagnosis of solid pancreatic masses. AB - Since it was developed in 1992, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been widely used and has been adapted for gastrointestinal and perigastrointestinal lesions. A medical literature review to evaluate the role of EUS-FNA for diagnosis of solid pancreatic masses showed a 78 95% sensitivity, 75-100% specificity, 98-100% positive predictive value, 46-80% negative predictive value and a 78-95% accuracy. The reported complication rates of EUS-FNA for pancreatic solid masses were 0-2%, although the criteria for complications varied among the studies. Because of its high diagnostic yield and low complication rate, EUS-FNA is cost-effective and widely applicable for the diagnosis of solid pancreatic masses, and is the best initial and the preferred secondary method compared with other biopsy techniques, such as endoscopic retrograde cholangiopancreatography-guided biopsy, computed tomography/ultrasound FNA and surgery. Although EUS-FNA is 'a nearly perfected procedure,' controversy remains, such as the most suitable diameter of the needle, the appropriate number of needle passes and the necessity of on-site cytopathological evaluation. Recently investigators reported that using molecular analysis of EUS-FNA samples can achieve a higher diagnostic efficacy. Further research is encouraged to optimize the EUS-FNA procedure to reach its maximum diagnostic yield for solid pancreatic masses. PMID- 21535198 TI - Histological diagnosis by EUS-guided fine-needle aspiration biopsy in pancreatic solid masses without on-site cytopathologist: a single-center experience. AB - There are few reports on the histological diagnostic ability of endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) in a large-series of pancreatic masses. In the present study therefore we retrospectively evaluated the histological diagnostic ability of EUS-FNA in pancreatic masses without on site cytopathologist. In 355 patients with pancreatic solid masses, EUS-FNA was carried out. EUS-FNA histology showed accuracy, 90.7%; sensitivity, 89.5%; specificity, 95.6%; positive predict value, 98.8%; negative predict value, 68.8% by intention-to-treat analysis. Except for 10 with inadequate materials, EUS-FNA histology showed accuracy, 93.3%; sensitivity, 91.8%; specificity, 100%; positive predict value, 100%; negative predict value, 77.6%. The mean number of puncture was 2.88 (range 1 to 8). There was two (0.6%) procedure-related bleeding. In conclusion, diagnostic ability of EUS-FNA by histological materials was similar to previous literature on the EUS-FNA without on-site cytopathologist. PMID- 21535199 TI - The management of the pancreatic cystic neoplasm: the role of the EUS in Japan. AB - Diagnosis of cystic lesions of the pancreas is made by clinical history taking, physical examination, blood biochemical tests and diagnostic imaging, such as transabdominal ultrasound, endoscopic ultrasound (EUS), cross-sectional imaging (computed tomography and/or magnetic resonance imaging) and endoscopic retrograde cholangiopancreatography, bearing in mind the known characteristic features of the various cystic lesions that can occur in this organ. Among others, EUS, endowed with a sharp local resolving power, has been described as a highly useful examination method, because it enables concurrent fine-needle aspiration (FNA). EUS has an important role in the differential diagnosis and tumor grading (benign, premalignant or malignant) of cystic lesions. Although the differential diagnosis of cystic lesions of the pancreas based on EUS morphology is practicable to some extent, there have also been reports showing that the diagnosis might vary with the endosonographer and that the diagnostic performance of this method for tumor grading is not necessarily high. In countries overseas, differential diagnosis and tumor grading of cystic lesions of the pancreas are actively undertaken not merely by EUS morphology, but also by cyst-fluid EUS guided FNA (EUS-FNA) cytology and measurements of pancreatic enzymes and tumor markers, and importance is attached to EUS-FNA in the latest version of the American Society for Gastrointestinal Endoscopy Guideline and in the diagnostic strategies for cystic diseases of the pancreas. Meanwhile, the current Japanese consensus is that EUS-FNA is not recommended in cases of mucinous cystic lesions suspected as being intraductal papillary mucinous neoplasm or mucinous cystic neoplasm. PMID- 21535200 TI - Genetic diagnosis of pancreatic cancer using specimens obtained by EUS-FNA. AB - We review the current situation concerning molecular biological analysis in respect of pancreatic cancer, using specimens obtained by endoscopic ultrasound guided fine-needle aspiration (EUS-FNA). K-ras, p53, p16, DPC4/SMAD4, telomerase activity are used for discrimination between tumor-forming pancreatitis and pancreatic cancer. Examination of heat shock protein (HSP) 27, ribonucleotide reductase, and other factors are examined in order to test the sensitivity to Gemcitabin. Comparative genomic hybridization analysis for pancreatic cancer specimens obtained by EUS-FNA was reported to be useful for evaluate the biological characteristics of pancreatic cancer before treatment. It is expected that the genetic diagnosis using EUS-FNA specimens will not only positively contribute to improving the diagnostic performance, but it will also provide valuable information for carrying out tailor-made treatment. PMID- 21535201 TI - New techniques and future perspective of EUS for the differential diagnosis of pancreatic malignancies: contrast harmonic imaging. AB - Although endoscopic ultrasonography (EUS) has the advantage over other imaging methods in that it is possible to obtain high resolution images of the pancreas, it is limited in its ability to characterize pancreatic masses. Contrast-enhanced power Doppler ultrasonography suffers from several limitations such as blooming artifacts, poor spatial resolution, low sensitivity to slow flow and high sensitivity to motion artifacts. Recently, EUS system specific for contrast harmonic imaging has been developed. The use of this EUS system enabled us to observe images of microcirculation and parenchymal perfusion without Doppler related artifacts in the pancreas. Contrast-enhanced harmonic EUS could diagnose pancreatic carcinomas as hypovascular masses with a high sensitivity (89-96%) and specificity (64-88%). Contrast-enhanced harmonic EUS also discriminates mural nodules from mucous clots in the intraductal papillary mucinous neoplasms. PMID- 21535202 TI - Late bleeding after EUS-guided transjejunal drainage of a pancreatic pseudocyst in a Roux-en-Y patient. AB - Endoscopic ultrasonography (EUS)-guided transgastric and transduodenal drainage of a pancreatic pseudocyst (PP) has become a standard and safe procedure for nonsurgical treatment. However, there are only four reports on transjejunal drainage of PP in a patient with or without altered anatomy. Herein, we report a case of EUS-guided transjejunal PP drainage in a patient with previous Roux-en-Y reconstruction. A 58-year-old man, who had previously undergone total gastrectomy with Roux-en-Y, was admitted to another hospital because of fever, abdominal pain, nausea and vomiting. Computed tomography showed a 22 cm PP. Then, EUS guided transjejunal PP drainage was carried out. Twenty-three days after the procedure and 3 days after the patient started eating, the hematemesis was seen. Emergency endoscopy showed bleeding around a transjejunal fistula. A 6-Fr nasocystic catheter was placed into the cyst again for lavage and hemostasis as tamponade. After 1 more month, a computed tomography scan showed complete resolution of the PP with the stent still in place. PMID- 21535203 TI - EUS-FNA for pancreatic cyst lesion, today and tomorrow in the Kingdom of Thailand. AB - Unlike endoscopic retrograde cholangiopancreatography (ERCP) service, endoscopic ultrasonography (EUS) service in Thailand is at its elementary state. Currently, there are only 11 hospitals in Thailand carrying out EUS whereas there are more than 50 hospitals carrying out ERCP. This is a multicenter questionnaire survey that obtained information on EUS practice for pancreatic cysts. Of those 11 hospitals, only three hospitals provided enough number of patients with pancreatic cysts undergoing EUS. There were many differences in endosonographers opinions regarding specific information in the pancreatic cyst. In addition, the threshold to carry out and not to carry out fine needle aspiration are varies. PMID- 21535204 TI - Role of narrow band imaging for diagnosis of early-stage esophagogastric cancer: current consensus of experienced endoscopists in Asia-Pacific region. AB - In Asian countries, squamous cell carcinoma is the most common type of esophageal cancer, and the incidence of gastric cancer remains have plateaued. To synthesize current information and to illustrate its clinical benefit of narrow band imaging (NBI) for diagnosis of superficial esophageal squamous carcinoma (SESCC) and early gastric cancer (EGC), a consensus conference was held by a panel of nine experts from Asian-Pacific countries. The expert's agreement suggested importance of interpretation of both vascular architecture and surface structure of the lesions and proper processor settings for endoscopic images. Zoom endoscopy was not regarded as absolutely necessary for detection of SESCC, but magnifying observation provided valuable information for characterization of detected lesions in the esophagus and the stomach. In general, NBI is useful for detection and characterization of SESCC, whereas it is beneficial mainly for characterization of EGC. Chromoendoscopy was found to be still worthwhile in certain situations, such as determination of the extent of SESCC by Lugol's staining, or detection and delineation of EGC by indigo carmine. NBI could replace chromoendoscopy in routine examination because it is easy to use and adds much information to conventional WLI, but it cannot eliminate chromoendoscopy when we make a final diagnosis for treatment decision-making. Consequently, the benefit of NBI or magnifying NBI is specific for the organ and the purpose of the examination, thus optimum indication and usage should be understood for maximum clinical benefit. PMID- 21535205 TI - An esophageal SCC case which could be distinguished from non-neoplasia using magnifying endoscopy with NBI imaging. AB - In this case, narrow-band imaging helped to distinguish esophagitis. The case involved an 81-year-old female was being seen as an outpatient because of Gastroesophageal Reflux Disease (GERD) symptoms associated with an esophageal hiatal hernia. Endoscopy showed long reddish lesions on the posterior wall of the lower thoracic esophagus. Non-magnifying endoscopic images with white light initially suggested reflux esophagitis. Magnifying endoscopy with narrow-band imaging showed proliferation of intraepithelial papillary capillary loop-like vessels as well as irregular widening and narrowing of vessels, so the patient's condition was diagnosed as superficial esophageal cancer. Endoscopic submucosal dissection was carried out. PMID- 21535206 TI - Clinical impact of narrow-band imaging magnifying endoscopy for 'basal layer type squamous cell carcinoma' in the esophagus. AB - A 61-year-old man had received endoscopic submucosal dissection (ESD) for early gastric cancer twice. Then he had undergone annual control esophagogastroduodenoscopy using narrow-band imaging (NBI) magnifying endoscope. At the esophagogastroduodenoscopy, we were not able to detect any significant finding in the esophagus by conventional endoscopy. Switching to NBI mode, a brownish area was showed in the middle esophagus. The lesion showing the brownish area was predicted to be mucosal squamous cell carcinoma (SCC) as a result of assessment of morphologic change of intraepithelial papillary capillary loop under magnifying NBI observation. Lugol chromoendoscopy displayed the lesion as unstained area corresponding to the brownish area visualized by NBI. The ESD was performed for the lesion. Histology from ESD specimen showed SCC with minimal invasion to lamina propria at multifocal sites. The SCC was surrounded by low grade intraepithelial neoplasia. Most of the SCC showed a high degree of cytological and architectural atypia confined to the lower half of the epithelium. The type of SCC was called as 'basal layer type SCC' mainly by Japanese pathologists. We suggest that magnifying NBI endoscopy can be useful for detecting and diagnosing 'basal layer type SCC'. PMID- 21535207 TI - The usefulness of NBI magnification on diagnosis of superficial esophageal squamous cell carcinoma. AB - Reported herein is the case of a 80-year-old man who had small squamous cell carcinoma in the esophagus. The lesion was initially detected as a irregular reddish elevated and flat area depicted by non-magnified white light endoscopy and observed as a brownish area with the narrow-band imaging system (NBI). The depth of elevated and depressed area in the lesion was predicted to be LSM to MM due to Inoue's classification of morphologic change of intrapapillary capillary loop (IPCL) under magnified NBI observation. The depth of another flat area was not able to predicted by Inoue's classification, and we used Arima's classification. We predicted the depth of invasion to be MM to SM1.by this classification. Endoscopic submucosal dissection (ESD) was carried out for the lesion. As a result, the endoscopic diagnosis completely accorded with pathological diagnosis. We could diagnose correctly by adding Arima's classification to Inoue's classification. PMID- 21535208 TI - Role of narrow band imaging in Barrett's esophagus. AB - The present recommended strategy for detection of dysplasia and cancer in Barrett's esophagus is by randomly carrying out four quadrant biopsies every 2 cm. This approach is however prone to sampling error. Narrow band imaging has been routinely available for clinical use for more than half a decade now. This review will focus on the available data to date on the role of narrow band imaging in the detection and characterization of specialized intestinal metaplasia, high grade dysplasia and intramucosal cancer in Barrett's esophagus. PMID- 21535209 TI - Usefulness of magnifying narrow band imaging for assessing lateral tumor extent of early gastric cancer: a case report. AB - Narrow band imaging with magnifying endoscopy (NBI-ME) is a novel technology that enhances vascular architecture and surface structure of the superficial mucosa of the gastric cancer. We report a case in which the lateral extent of slightly elevated tumor was clearly defined based on the presence of irregular microvessel pattern and irregular microsurface pattern using NBI-ME. This lesion was diagnosed as well-differentiated adenocarcinoma confined to the mucosa because of granular/papillary surface structure containing loop-like microvessels. PMID- 21535210 TI - A case of small early gastric cancer that was successfully detected by narrow band imaging magnifying endoscopy. AB - Endoscopic diagnosis of gastric cancer is very often made by conventional white light endoscopy and/or by indigo carmine chromoendoscopy. However, with this method it is difficult to detect and demarcate a small lesion affected by inflammation or a biopsy procedure. We considered it is useful for diagnosis of such small cancers to observe a lesion with a magnifying endoscope combined with a narrow band imaging system. PMID- 21535211 TI - A case of early gastric cancer in which the degree of histological atypia was correctly predicted by magnifying endoscopy combined with narrow band imaging. AB - We herein report a case of early gastric cancer with mixed components having different grades of atypia, which was correctly predicted by magnifying endoscopy combined with narrow band imaging. A 67-year-old man had a flat elevated lesion (0-IIa) in the anterior wall of the gastric antrum. With narrow band imaging, a flat lateral extension (0-IIb), not recognized with white light imaging was seen in the anal side of the main tumor. Magnifying endoscopy combined with narrow band imaging saw a relatively regular fine network pattern of micro-vessels in the surface of the 0-IIa area. However, in the surface of the 0-IIb area, a villous structure with villi of various size and heterogeneity, micro-vessels showing tortuousity were observed. We judged the grade of atypia to be higher in the 0-IIb area than in the 0-IIa area. Histological examination of the resected specimen verified the 0-IIa area and 0-IIb area as adenoma and adenocarcinoma, respectively. PMID- 21535212 TI - Comparative evaluation of endoscopic factors from conventional colonoscopy and narrow-band imaging of colorectal lesions. AB - BACKGROUND: Narrow-band imaging (NBI) diagnosis of colorectal lesions requires further consideration and standardized classification for attaining consensus among endoscopists. OBJECTIVE: Compare vascular findings and diagnosis of colorectal lesions using various endoscopic images to assess effectiveness of NBI with magnification. METHOD: Three endoscopic factors (vascular findings; diagnosis from NBI with magnification images; and total diagnosis from all available colonoscopic images including white light endoscopy, chromoendoscopy, NBI with magnification and magnifying chromoendoscopy) for 15 colorectal lesions were evaluated by 12 expert colonoscopists (Group A), 36 endoscopists not expert in colonoscopy (Group B) and 55 individuals not medical doctors, but familiar with gastrointestinal endoscopy or other medical products (Group C). We calculated accuracy percentages for all three endoscopic factors based on responses from each group. Highest percentage for vascular finding, NBI with magnification diagnosis and total diagnosis for each lesion assumed to be opinion of each group. We compared incidence of agreement among three groups and calculated invasion depth diagnostic accuracy rate for each group. RESULTS: For vascular findings from NBI with magnification images, incidence of complete agreement among three groups was 46.7%, incidence of disagreement among three groups was 46.7% and incidence of complete disagreement among three groups was 6.7%. For diagnosis from NBI with magnification images and total diagnosis from all available endoscopic images, incidence of complete agreement, disagreement and complete disagreement were 40.0%, 60.0% and 0.0%, respectively, and 60.0%, 40.0% and 0.0%, respectively. Invasion depth diagnostic accuracy from NBI with magnification images and all available endoscopic images were 60.0% and 73.3%, respectively, in Group A; 46.7% and 66.7%, respectively, in Group B; and 46.6% and 60.0%, respectively, in Group C. CONCLUSION: Results suggest some level of educational training is required for effective application of NBI with magnification for precise diagnosis of colorectal lesions. PMID- 21535213 TI - Clinical usefulness of narrow band imaging magnifying classification for colorectal tumors based on both surface pattern and microvessel features. AB - We use the narrow band imaging (NBI) magnifying classification (Hiroshima Classification) on the basis of both their surface pattern and microvascular architecture to characterize colorectal tumors. Herein, we describe the Hiroshima Classification in detail and provide statistical data supporting its usefulness in diagnosing histologic type, whether a hyperplastic lesion, tubular adenoma, carcinoma with intramucosal to submucosal scanty invasion or carcinoma with submucosal massive invasion, and thus in selecting the appropriate treatment strategy. We also discuss the circumstances in which the Hiroshima Classification must be augmented by conventional pit pattern diagnosis. NBI magnification is easily carried out. We strongly recommend application of NBI magnification to the differential diagnosis of colorectal lesions as well as treatment decision making. PMID- 21535214 TI - Vascular pattern classification of colorectal lesions with narrow band imaging magnifying endoscopy. AB - Magnifying narrow band imaging (NBI) has enabled to observe the vascular pattern of colorectal lesions. Their broad findings have been divided into six groups according to endoscopical vascular features: normal, faint, network, dense, irregular and sparse. Most hyperplastic polyps show a faint pattern. The vascular patterns of adenomas are mainly network or dense ones. The predominant vascular patterns of cancer were irregular and sparse. Indeed, irregular pattern has found to be characteristic for protruded or flat-elevated cancer, whereas sparse pattern unique for depressed cancer. Through NBI, neoplastic lesions could be differentiated from those non-neoplastic with sensitivity of 83.5%, specificity of 98.7% and accuracy of 98.2%. It was able to distinguish between massively submucosal invasive cancers and slightly submucosal invasive cancers by using the vascular pattern with 91.0% sensitivity and 79.4% specificity. The overall accuracy was 88.3%. NBI system has showed to be a valuable technique for distinguishing neoplastic from non-neoplastic lesions, as well as massively from slightly submucosal invasive cancer. Therefore, vascular pattern analysis might be a promising tool for determining treatment selection, whether endoscopical or surgically. PMID- 21535215 TI - Sano's capillary pattern classification for narrow-band imaging of early colorectal lesions. AB - Narrow-band imaging enhances visualization of the mucosal surface structure and vascular network and helps to increase the visibility of neoplasia by improving contrast. Sano and his colleagues first reported its efficacy for endoscopic use in the gastrointestinal tract and later proposed a sequential classification of the mucosal vascular network patterns according to histopathological categories. Sano's 'capillary pattern classification' was established to facilitate diagnosis of early colorectal lesions on a step-by-step basis. This review focuses on the utility and effectiveness of Sano's capillary pattern classification when examining early colorectal lesions using narrow-band imaging. PMID- 21535216 TI - The clinical efficacy and future perspective of narrow band imaging for the diagnosis of colorectal neoplasm. AB - Growing body of evidences have shown that narrow band imaging (NBI) can be the adjunct tool of colonoscopy for real time or optical histological assessment with high accuracy and largely replaces the role of chromoendoscopy. In spite of the advantages, there are still several issues that remain to be elucidated: detectability of neoplastic lesions, diagnosis of malignant transformation, evaluation of invasion depth for cancerous lesion, morphological diagnosis and interobserver agreement. Endoscopists should be aware of the advantage, current evidence and the limitation of narrow band imaging and apply it appropriately for their clinical practice. PMID- 21535217 TI - The benefit of using narrow-band imaging systems for observation of capillary networks before determining of treatments for early colon cancer. AB - INTRODUCTION: This study examined whether magnifying endoscopy with narrow-band Imaging observation could be useful selecting the appropriate treatment for early colon cancer. PATIENTS AND METHODS: We analyzed 551 cases of colon tumors excised endoscopically or surgically, comprising 68 with large hyperplastic polyps, 25 traditional serrated adenomas, 141 tubular adenomas, 177 intramucosal cancers and 140 submucosal invasive (SM) cancers. We classified capillary network pattern into four types according to the degree of dilatation, irregularity and distribution of microcapillary features. These results were then compared with the histological findings. RESULTS: The comparison of capillary pattern and histological features showed microcapillary networks by magnifying endoscopy with narrow-band imaging observation in intramucosal lesion or SM cancer with remnant neoplastic glands at the superficial layer. CONCLUSIONS: The remaining microcapillary network was designed to maintain the architecture of neoplastic glands, even in the presence of subumucosal invasion. Consequently, loss of this network could correlate with depth of tumor invasion and histological reaction. Therefore, even if the tumor, remained of network was diagnosed to invade into SM layer, it should be checked up further examination by using magnifying endoscopy with crystal violet staining. PMID- 21535218 TI - West meets East: preliminary results of narrow band imaging with optical magnification in the diagnosis of colorectal lesions: a multicenter Australian study using the modified Sano's classification. AB - INTRODUCTION: Narrow band imaging with optical magnification (NBI-Z) enables mucosal morphology to be assessed in real time by using light with narrowed band width and magnification of up to 115*. METHODS: Colorectal lesions detected were assessed with NBI-Z. Histology was predicted using the modified Sano's classification based on capillary network patterns (cn); type I: absent cn (hyperplastic polyp), type II: cn present, surrounding mucosal glands (adenoma), type IIIa: high density cn with tortuosity and lack of uniformity (intramucosal cancer) and type IIIb: nearly avascular cn (invasive cancer). Each lesion was also graded with a confidence level (low/high). High-definition videos (mean 28.2 s; range 12-55) of each lesion assessed with NBI-Z were then taken. This was followed by polypectomy, endoscopic or surgical resection. NBI-Z diagnosis was compared with the final histopathology. To test for interobserver agreement, an endoscopist blinded to the video acquisition process/histology was invited to grade the videos. RESULTS: A total of 50 lesions (2 assessors: 100 studies), with an average size of 8.4 mm (range 3-30), in 32 patients were assessed. Twenty were hyperplastic, 25 adenomas, 2 intramucosal and 3 invasive cancers of which 19 were located in the right and 31 in the left colon. The overall accuracy of NBI-Z in predicting histology was 90%, which increased to 95% (88/93) when lesions were predicted with high confidence. The sensitivity (Sn), specificity (Sp), positive (PPV) and negative predictive values (NPV) in differentiating neoplastic from non neoplastic lesions with high confidence were 98%, 89%, 93% and 97%, respectively, while the Sn, Sp, PPV and NPV in predicting endoscopic resectability (type II, IIIa vs type I, IIIb) was 100%, 90%, 93% and 100%, respectively. The interobserver agreement between both assessors (kappa value) was substantial at 0.89. CONCLUSIONS: Using confidence levels, NBI-Z permits prediction of colorectal neoplasia with high accuracies and might allow prompt decisions to be made if a lesion should be left in situ, resected and discarded or biopsied. This approach might lead to substantial time and cost savings and could potentially reduce complications associated with polypectomy and endoscopic resections. PMID- 21535219 TI - Aim to unify the narrow band imaging (NBI) magnifying classification for colorectal tumors: current status in Japan from a summary of the consensus symposium in the 79th Annual Meeting of the Japan Gastroenterological Endoscopy Society. AB - At present, there are many narrow band imaging (NBI) magnifying observation classifications for colorectal tumor in Japan. To internationally standardize the NBI observation criteria, a simple classification system is required. When a colorectal tumor is closely observed using the recent high-resolution videocolonoscope, a pit-like pattern on the tumor can be observed to a certain degree without magnification. In the symposium we could have a consensus that we will name the pit-like pattern as 'surface pattern.' Using the NBI system, the microvessels on the tumor surface can also be recognized to a certain degree. When the NBI system is used, the structure is emphasized, and consequently, the surface pattern can be recognized easily. Recently, an international cooperative group was formed and consists of members from Japan, the USA and Europe, which is named as the Colon Tumor NBI Interest Group. This group has developed a simple category classification (NBI international colorectal endoscopic [NICE] classification), which classifies colorectal tumors into types 1-3 even by closely observing colorectal tumors using a high-resolution videocolonoscope (Validation study is now ongoing by Colon Tumor NBI Interest Group.). The key advantage of this is simplification of the NBI classification. Although the magnifying observation is the best for getting detailed NBI findings, both close observation and magnifying observation using the NICE classification might give almost similar results. Of course the NICE classification can be used more precisely with magnification. In this report we also refer the issues on NBI magnification, which should be solved as early as possible. PMID- 21535220 TI - Endoscopic findings under narrow band imaging colonoscopy in ulcerative colitis. AB - Narrow band imaging (NBI) depicts distinct intramucosal vascular network and pit pattern without any use of dye technique. It is thus suggested that NBI can be used for the assessment of severity in inflammatory bowel diseases, especially in ulcerative colitis (UC). In the active UC, NBI colonoscopy depicts friability as a black area. In the inflamed granular mucosa, crypt openings and villous structure become evident through the procedure. In the inactive UC, there are two types of mucosal vascular pattern; one being composed of deep, green vessels and superficial, black vessels, and the other lacking in superficial vessels. With used of a magnifying instrument, the mildly active mucosa can be classified into the mucosa with obvious crypt openings and that with villous structure. Mucosal vascular pattern in the inactive mucosa is shown as a honeycomb-like structure or irregular, tortuous structure under magnifying NBI observation. Furthermore, such NBI findings show close correlations with histologic findings including crypt distortion, goblet cell depletion and basal plasmacytosis. Therefore, NBI colonoscopy might be of value for the precise assessment of histologic severity in mildly active and inactive UC. PMID- 21535221 TI - Endoscopic differential diagnosis between ulcerative colitis-associated neoplasia and sporadic neoplasia in surveillance colonoscopy using narrow band imaging. AB - We investigated the efficacy of narrow band imaging, magnifying chromoendoscopy, autofluorescence imaging and photodynamic diagnosis for surveillance colonoscopy or work-up in patients with ulcerative colitis. Endoscopic differential diagnosis between sporadic neoplasia and colitis-associated dysplasia or cancer, however, is still an important issue in practice. Optimization of surveillance colonoscopy, including development of novel methods, should be addressed in the near future. PMID- 21535222 TI - Development of gastrointestinal endoscopy in Malaysia: a historical perspective with special reference to the experience at the University of Malaya Medical Centre. AB - Gastrointestinal endoscopy started in the early 1970s in Malaysia with the help of Japanese doctors. It has evolved over the past 30 years. The gastrointestinal endoscopy unit at the University of Malaya Medical Centre has been in the forefront in providing endoscopy services to patients as well as training doctors in endoscopy in the country. In recent years, trainees have included those from neighboring countries in South-East Asia. Among our most significant achievements is the organization of regular international therapeutic endoscopy workshops since 1993 where leading endoscopists from throughout the world have accepted our invitation as teaching faculty. In 2008, the World Organization of Digestive Endoscopy accorded the high distinction of Centre of Excellence to the endoscopy unit of the University of Malaya Medical Centre. PMID- 21535223 TI - Current status of direct peroral cholangioscopy. AB - Recently, several endoscopists have reported the usefulness of direct peroral video cholangioscopy for the diagnosis and therapy of bile duct lesions. Although ultra-slim pediatric or Tran nasal video endoscopes are usually used for the direct peroral video cholangioscopy, direct scope insertion without pretreatment and any assistant is considerably difficult. Based on the previous literatures, intraductal balloon catheter-assisted scope insertion might be relatively reliable method. To overcome the issue on the scope insertion, recently prototype cholangioscope that has short bending section and anchoring balloon catheter for scope replacement and insertion has been developed. In the near future, we could establish the direct peroral cholangioscopy using new developed technology. PMID- 21535224 TI - Endoscopic ultrasonography-guided drainage for tuberculous liver abscess drainage. AB - Traditionally, either surgical or percutaneous drainage is recommended for liver abscess. Recently, several endoscopists have reported the endoscopic ultrasound (EUS)-guided liver abscess drainage. Herein, we report a case of tuberculous liver abscess in which endoscopic ultrasound-guided fine needle aspiration (EUS FNA) was useful for the diagnosis and therapy. A 78-year-old woman suffered from continuous epigastric pain and fever up. Computed tomography (CT) showed a 70 mm multilocular and multiseptate cystic lesion around the head of pancreas and caudate lobe of the liver. After confirming liver abscess by EUS-FNA, EUS-guided liver abscess drainage was carried out. Finally, a 7 Fr straight stent and a 5 Fr nasocystic catheter were inserted into the cyst. Four weeks later, we found that cultured microorganism obtained using drainage catheter was Mycobacterium tuberculosis. Although he was doing well during 5 days after the procedure, CT showed the size of another abscess increased. Then, additional EUS-guided abscess drainage was carried out at the body of the stomach into the abscess of the left lobe. Two weeks later, CT showed disappearance of abscesses. Then, she discharged with the internal stent still in place. PMID- 21535225 TI - Endoscopic ultrasonography-guided fine needle aspiration biopsy in a patient with prior Billroth II gastrectomy. AB - Endoscopic ultrasonography-guided fine needle aspiration biopsy (EUS-FNA) is a safe and accurate procedure for the diagnosis of pancreatic lesions. However, in general, surgically altered anatomy excluding Billroth I gastrectomy is considered a relative contraindication to EUS-FNA. Herein, we described a successful case of EUS-FNA in a patient with prior Billroth II gastrectomy. A 78 year-old man, who had previously undergone Billroth II gastrectomy for duodenal ulcer, undertook EUS-FNA using a curved linear echoendoscope. An echoendoscope was advanced into the duodenum and EUS-FNA could be carried out using a 22-gauge needle without procedure-related adverse event. PMID- 21535226 TI - Responsive insertion technology. AB - The colonoscopic insertion technique is still one of the most difficult endoscopic procedures to master and development of a new colonoscope that is easier to insert is much awaited especially into the cecum without patient discomfort. We focused on reducing patient pain and boosting the success rate of colonoscope insertion into the cecum in complicated cases. As a result, we have successfully developed two mechanisms: "Passive Bending" and use of a "High Force Transmission insertion tube." We believe these two mechanisms when combined together will contribute to a reduction in patient discomfort and an increase in the cecal intubation rate during many difficult colonoscopies, but further evaluation is required with respect to therapeutic endoscopy effectiveness and insertion for patients with long colons. PMID- 21535227 TI - The hemorrhage caused by sporadic-type cerebral amyloid angiopathy occurs primarily in the cerebral sulci. AB - We examined a solitary hematoma in a patient with sporadic cerebral amyloid angiopathy (CAA). The hematoma affected the middle frontal sulcus, cerebral cortex (CC) and subcortical frontal white matter (sfWM). We embedded the hematoma in four paraffin blocks, each of which was cut serially into 6-um-thick sections. The first section and every 18th section from each block were subjected to Elastica-Goldner (E-G) staining, and the distribution and diameter of the ruptured blood vessels (rBVs) were examined. The rBVs were then marked on diagrams representing each E-G-stained section. The present study yielded the following important findings: (i), early- and recently ruptured Abeta-positive arteries were present mainly in the intrasulcal hematoma (ISH), rather than in the CC; (ii) many early-ruptured arteries in the ISH were larger in diameter than those in the CC; and (iii) ruptures of the cortical arteries, even near the cortical surface, did not occur so frequently and the ruptured vessels were small in size. We concluded that in patients with subcortical hematoma caused by sporadic-type CAA, successive rupturse of the meningeal vessels, mainly arteries, occur in the cerebral sulcus initially, followed by formation of an ISH and development of a fresh hemorrhagic or anemic infarct in the CC surrounding the ISH, the latter in most cases then extending into the brain parenchyma through the necrotic CC at the depth of the sulcus, finally creating a secondary hematoma in the subcortical white matter. PMID- 21535228 TI - A highly immunogenic recombinant and truncated protein of the secreted aspartic proteases family (rSap2t) of Candida albicans as a mucosal anticandidal vaccine. AB - Sap2 (secreted aspartyl proteinase2) is a member of the Sap family of Candida albicans, a human opportunistic pathogen, which acts as a virulence factor in experimental animal models of mucosal candidiasis. The C. albicans SAP2 was subcloned into vector pDS56-RBSII-6xhis, under the control of an inducible promoter to produce a truncated 6xhis-tagged, enzymatically inactive Sap2, lacking the N-terminus 76 amino acids (rSap2t). This recombinant protein was purified to homogeneity by one-step nickel-chelate affinity chromatography and used to immunize intravaginally oophorectomized estradiol-treated rats. These animals raised local anti-rSap2t immunoglobulin G (IgG) and IgA antibodies and were protected from the challenge of a highly vaginopathic strain of the fungus. Protection was possibly due to the specific antibodies as suggested by the passive transfer of immune vaginal fluid and the protective effects of passive vaccination with anti-rSap2t IgM and IgG monoclonal antibodies. Hence, this new recombinant proteinase constitutes a novel tool to investigate mechanisms of anti Candida protection at the vaginal level and as vaccination against vaginal candidiasis, a common, frequently recurrent and sometimes antimycotic-refractory infection in women. PMID- 21535229 TI - Effects of species and season on chemical composition and ruminal crude protein and organic matter degradability of some multi-purpose tree species by West African dwarf rams. AB - Seasonal chemical composition and ruminal organic matter (OM) and crude protein (CP) degradabilities were determined in four tropical multi-purpose tree species (MPTS) namely; Pterocarpus santalinoides, Grewia pubescens, Enterolobium cyclocarpum and Leucaena leucocephala. Three West African dwarf (WAD) rams fitted with permanent rumen cannula were used for the degradability trials. Foliage samples were collected four times to represent seasonal variations as follows: January--mid dry; April--late dry; July--mid rainy and October--late rainy seasons. Leaf samples were randomly collected from the trees for estimation of dry matter (DM) and chemical composition. Ruminal in sacco OM and CP degradabilities were estimated from residues in nylon bags. All samples had high CP (161-259 g/kg DM) and moderate fibre concentrations [neutral detergent fibre (without residual ash], 300-501 g/kg DM; acid detergent fibre (without residual ash), 225-409 g/kg DM and acid detergent lignin, 87-179 g/kg DM across seasons. Interaction effects of species and season on chemical composition were highly significant (p = 0.001) except for trypsin inhibitor (p = 0.614). The MPTS recorded more than 60% OM and CP degradability at 24 h, which implied that they were all highly degradable in the rumen. Their incorporation into ruminant feeding systems as dry season forage supplements is therefore recommended. PMID- 21535230 TI - Isolation, characterization and establishment of an equine retinal glial cell line: a prerequisite to investigate the physiological function of Muller cells in the retina. AB - Retinal Muller glial cells are of vital importance for maintaining a physiological environment within the retina. To this end, they provide highly specialized physiological properties to support neurons in structure, nutrition and metabolism. The purpose of this study was to isolate Muller cells from the equine retina, determine their characteristics and subsequently establish a stable equine Muller cell line (eqMC) that will provide a prerequisite for investigations on their physiological properties. Dissociated retinal cells were obtained from equine retinas by a papain digestion technique followed by trituration and a cell attachment method by which pure Muller cell cultures were achieved. Morphological examination was performed using phase-contrast microscopy, and further characterization of different subcultures was accomplished by immunocytochemistry. Cells of passage 1 showed distinct signals for glutamine synthetase and vimentin, whereas glial fibrillary acidic protein expression was almost absent. Characteristic expression patterns remained unaltered in all subcultures. Furthermore, cultured Muller cells stably expressed the microfilament alpha-smooth muscle actin, the proliferation marker Ki67 and the membrane channels Kir4.1 and aquaporin 4. The present study introduces the eqMC-7 that will facilitate studies investigating the physiological role of Muller cells within the equine retina. PMID- 21535231 TI - Effects of dietary supplementation of Chinese medicinal herbs on polymorphonuclear neutrophil immune activity and small intestinal morphology in weanling pigs. AB - The purpose of this study was to evaluate the effects of dietary Chinese medicinal herbs (CMH) supplementation composed of Panax ginseng, Dioscoreaceae opposite, Atractylodes macrocephala, Glycyrrhiza uralensis, Ziziphus jujube and Platycodon grandiflorum, on the performance, intestinal tract morphology and immune activity in weanling pigs. Two hundred and forty weaned pigs were assigned randomly to four dietary groups including the negative control (basal diet), 0.1% CMH, 0.3% CMH and 0.114% antibiotic (Chlortetracycline calcium Complex, Sulfathiazole and Procaine Penicillin G) supplementation groups for a 28-day feeding trial. Results indicated that both CMH supplementation groups had a better gain and feed/gain than control group (CT) during the first 2 weeks of the experimental period. The 0.3% CMH had a significant decrease in the diarrhoea score in first 10 days of experimental period when compared with other groups. The CMH supplementation groups had a higher villous height, increased lactobacilli counts in digesta of ileum and decreased coliform counts in colon compared with CT. The immune activities of polymorphonuclear leucocytes (PMNs), including the respiratory burst and Salmonella-killing ability, were significantly enhanced in CMH supplementation groups at day 7 of experiment period. The CMH and antibiotic supplementations increased the nutrient digestibility such as dietary dry matter, crude protein and gross energy in weanling pigs. In conclusion, the dietary CMH supplementation improved intestinal morphology and immune activities of PMNs, thus giving rise to nutrient digestibility and reduce diarrhoea frequency in weanling pigs. PMID- 21535232 TI - Supranutritional selenium level affects fatty acid composition and oxidative stability of chicken breast muscle tissue. AB - A total of 128 broilers were used to investigate the effect of selenium (Se) on fatty acid (FA) composition and oxidative stability of lipids in the breast muscle tissue. There were 4 replicates of 4 dietary treatments: T1 (basal diet with no added Se), T2 (T1 with 0.15 mg Se added per kg diet), T3 (T1 with 0.3 mg Se added per kg diet) and T4 (T1 with 3.0 mg Se added per kg diet). A yeast source was used for added Se. Breast muscle tissue was collected from two chickens per replicate pen for the determination of Se concentration by ICP-MS, FA profile by GC and lipid oxidation using thiobarbituric acid reactive substances method. Addition of supranutritional Se levels to chicken diets leads to the production of Se-enriched meat. Consumption of 100 g of breast meat from chickens fed diets supplemented with 0.15, 0.3 and 3 mg Se per kg of diet can provide 26, 41 and 220 MUg of Se, respectively. Long-chain polyunsaturated fatty acids namely C20:3n-6, C20:4n-6, C20:5n-3, C22:5n-3 and C22:6n-3 increased linearly (p = 0.047, p < 0.001, p = 0.023, p = 0.003 and p = 0.002, respectively) as the Se inclusion levels in the diets increased. At slaughter, a linear decrease in lipid oxidation (p = 0.019) was observed with Se addition, possibly attributed to the antioxidant properties of Se. Addition of supranutritional Se to chicken diets, at levels well below those causing toxicity, leads to production of Se-enriched meat, protection of health-promoting long-chain FA like C20:5n-3 and C22:6n-3 and protection of meat quality from oxidation at day 1 after slaughter. PMID- 21535233 TI - Assessment of yeast cell wall as replacements for antibiotic growth promoters in broiler diets: effects on performance, intestinal histo-morphology and humoral immune responses. AB - The study compared the effects of an antibiotic growth promoter (AGP), yeast (Saccharomyces cerevisiae) and yeast cell wall (YCW) on performance, microbiology and histo-morphology of the small intestine and humoral immune responses in Ross 308 broilers. The treatments (eight replicates/treatment, n = 12/replicate) were negative control (NC, without AGP), positive control (PC, supplemented with bacitracin methylene disalicylate, 400 mg/kg), Y and YCW (supplemented with yeast and YCW, respectively, 1000 mg/kg). Live weight at 42 days improved (p = 0.086) in the PC, Y and YCW groups. Feed conversion ratio was better (p = 0.039) in the YCW group compared with the other groups. Antibiotic growth promoter in the PC group shortened the villi in duodenum (p = 0.044). Mucosal Escherichia coli number was higher in the PC group (p < 0.001), whereas in the digesta E. coli number was lower (p = 0.001) in the PC, Y and YCW groups in relation to the NC. Mucosal Salmonella populations increased (p = 0.0001) in the PC group, whereas in the digesta, all treatments reduced the Salmonella (p = 0.0001). Following oral challenge with Salmonella pullorum, YCW increased E. coli numbers on the mucosa (p < 0.001) whereas in the digesta the Y group had lower (p < 0.0001) number of E. coli. In the digesta, Salmonella count was lower in the YCW group compared with the other treatments (p < 0.01). Yeast cell wall -treated birds exhibited better (p < 0.05) humoral immune response against Newcastle disease which was far more persistent over time than in any other treatments. It was concluded that the yeast and the yeast cell wall may have effects identical to BMD on performance of broilers and thus may constitute an effective replacement strategy in the dietary regimens for broiler chickens. PMID- 21535234 TI - Effects of alpha-lipoic acid, vitamins E and C upon the heat stress in Japanese quails. AB - Antioxidant vitamins are commonly used as colorant, preventive, sweetener, nutritive and antioxidant materials in food industry. Thus, many studies have been conducted in recent years. We have performed the present study to understand the effects of alpha-lipoic acid (ALA), vitamin C and E, added into rations of Japanese quails, on chronic heat stress. This study was carried out in five groups as: control, stress, ALA, vitamin E and vitamin C groups. Heat stress is applied to all groups except the control group. Superficial pectoral muscles tissues were used for biochemical determinations. During the research, it is found that heat stress exerted undesired effects such as increasing lipid peroxidation (LPO) level indicating oxidative stress in Japanese quails. In addition, superoxide dismutase (SOD) and catalase (CAT) enzyme activities and glutathione (GSH) amounts were studied to understand the behaviour of defence mechanism. While stress increased LPO ratio, it was determined that all antioxidant added into the ration decreases LPO significantly (p < 0.05). In addition, it was determined that all of antioxidants added into ration effectively restored SOD activity and LPO ratio which heat stress affected negatively. Interestingly, vitamin C did not adjust GSH ratio in contrast to vitamin E and ALA, where vitamin E and C did not perform any positive effect on heat stress decreased CAT activity. Finally, it can be thought that antioxidant vitamins relatively ameliorated these undesired affects caused by stress factors given. PMID- 21535235 TI - Spontaneous tolerance in kidney transplantation--an instructive, but very rare paradigm. PMID- 21535236 TI - Extenders containing dimethylformamide associated or not with glycerol are ineffective for ovine sperm cryopreservation. AB - The study aimed at testing the effectiveness of dimethylformamide, alone or combined with glycerol, as cryoprotectant for freezing ram semen. Ejaculates from nine rams were cryopreserved in Tris-based extenders, containing 5% of glycerol, association of dimethylformamide with glycerol, in four proportions achieving 5% of cryoprotectors in the media and pure dimethylformamide (2, 3, 4 and 5%) in replacement to glycerol. The samples were diluted to 100 * 10(6) sptz/ml and stored in 0.25-ml straws in liquid nitrogen. After thawing (37 degrees C for 30 s), motility was preserved better by the extender containing 5% of glycerol (p < 0.05). The extenders containing pure dimethylformamide, or more than 2% in combination with glycerol, provided sperm motilities close to zero. Plasma and acrosomal membrane integrity were preserved better (p < 0.05) in the extender containing 5% glycerol. It can be concluded that dimethylformamide, alone or combined with glycerol, has no beneficial effects on ovine semen cryopreservation. PMID- 21535237 TI - The association of the presence of seminal plasma and its components with sperm longevity in fractionated stallion ejaculates. AB - Semen jets in the stallion's ejaculate differ in both the biochemical composition of seminal plasma (SP) and in sperm concentration, forming sperm-rich fractions (HIGH) and sperm-poor fractions (LOW). This study examined (i) the association of the levels of selected components of SP [alkaline phosphatase (AP), acid phosphatase (ACP), Na(+), Cl(-), K(+), Ca, Mg and prostaglandin E(2)] with semen quality, sperm longevity and fertility; (ii) the effects of the presence of SP on sperm survival during cooled storage; (iii) the differences in the composition of SP between sperm-rich and sperm-poor ejaculatory fractions; (iv) the differences between these fractions in the effects of SP on sperm longevity. The levels of AP, ACP and Na(+) were higher in HIGH compared with LOW, whereas higher concentrations of Ca, K(+) and Mg were found in LOW than in HIGH. None of the measured components were correlated to the first cycle pregnancy rate. The presence of SP during cooled storage caused DNA degradation, but total and progressive sperm motility was not affected. Sperm-rich fractions stored with low levels of SP maintained higher level of DNA integrity compared with sperm-rich fractions in higher levels of SP, or sperm-poor fractions irrespective of the proportion of SP. The concentration of K(+) in LOW may give some indication on the maintenance of total sperm motility during cooled storage. PMID- 21535238 TI - The influence of gamete co-incubation length on the in vitro fertility and sex ratio of bovine bulls with different penetration speed. AB - The objectives of this work were to evaluate whether the sperm penetration speed is correlated to the in vitro fertility and whether adapting the gamete co incubation length to the kinetics of the bull improves in vitro fertility and affects the sex ratio. In vitro matured oocytes were co-incubated with spermatozoa from four different bulls (A-D). At various post-insemination (p.i.) times (4, 8, 12, 16 and 20 h), samples of oocytes were fixed and stained with DAPI for nuclei examination, while the remaining ones were transferred into culture to evaluate embryo development. The blastocysts produced were sexed by PCR. Two bulls (A and B) had faster kinetics than the others (C and D), as shown by the higher penetration rates recorded at 4 h p.i. (43%, 30%, 11% and 6%, respectively for bulls A, B, C and D; p<0.01). The differences in the kinetics among bulls did not reflect their in vitro fertility. The incidence of polyspermy was higher for faster penetrating bulls (36%, 24%, 16% and 4%, respectively for bulls A, B, C and D; p<0.01) and at longer co-incubation times (0%, 16%, 19%, 30% and 34%, respectively at 4, 8, 12, 16 and 20 h p.i.; p<0.01). The fertilizing ability of individual bulls may be improved by adapting the co-incubation length to their penetration speed. A sperm-oocyte co-incubation length of 8 h ensured the greatest blastocyst yields for the two faster penetrating bulls. On the contrary, 16 h co-incubation was required to increase (p<0.01) cleavage rate of the two slower bulls. Bulls with a faster kinetics did not alter the embryo sex ratio towards males. The female/male (F/M) ratios recorded were 2.1, 1.4, 1.2, 1.3 and 1.6, respectively at 4, 8, 12, 16 and 20 h p.i. PMID- 21535239 TI - Modulatory effects of bovine seminal plasma on uterine inflammatory processes. AB - In this study, a simple model to simulate a uterine environment affected by subclinical endometritis was established by culturing isolated primary bovine uterine epithelial cells (pbUEC). Co-incubation of pbUEC and polymorphonuclear (PMN) granulocytes derived from peripheral bovine blood samples, was performed before testing the cell culture supernatant for production of interleukin-8 (IL 8) via ELISA. Cytokine secretion was only detectable after co-incubation of pbUEC with PMN, whereas neither pbUEC nor PMN alone generated IL-8 in relevant chemo attractive doses. Another objective was to examine the influence of bovine seminal plasma (SP) and vesicular gland fluid (VGF) on various functional parameters of PMN including cell viability, production of reactive oxygen species and chemotaxis. Analysis of these effects was conducted by flow cytometry. Viability of PMN was determined by staining the cells with propidium iodide. Seminal plasma was added to suspensions of PMN in increasing increments and resulted in a significant increase of cell membrane damaged PMN when using SP concentrations above 0.2%. The reactive oxygen species production of PMN suspensions, stimulated with phorbol-12-myristate-13-acetate, was significantly decreased by 30% up to 90% when adding 0.06-300/00 of either SP or VGF. The PMN transmigration induced by IL-8 was diminished by 50% when 0.40/00 of either SP or VGF were added. The results of this study indicate a potential regulatory impact of SP and VGF on inflammatory processes in the bovine uterus. PMID- 21535240 TI - Laser-assisted vitrification of large equine embryos. AB - The major difficulty in providing the benefits of embryo cryopreservation for equine agriculture is the mismatch between the optimal embryo age for collection from the mare (7-8 days after ovulation was detected) and the optimal age for freezing under current methods (6.5 days after ovulation). To overcome this limitation, we tested a method to enhance penetration of cryopreservative across the capsule and trophoblast of day 7 and 8 embryos combined with rapid freezing by vitrification. Six small embryos (<300 MUm in diameter) were collected on day 6-7 after ovulation and twelve larger embryos were recovered on day 7-8. In the treatment group, replacement of blastocoelic fluid with cryopreservative solution was facilitated by a laser system used to create a small opening in the embryonic capsule and trophectoderm. All embryos were vitrified using a CryoLeaf freezing support. After recovery from freezing and embryo transfer, three of four small untreated embryos (<300 MUm in diameter, 75%) and four of nine large blastocysts in the treatment group (>300 MUm in diameter, 44%) resulted in a vesicle as detected by ultrasonography approximately one week after transfer. However, only one recipient mare was still pregnant on day 23, and she delivered a live foal. Further investigation is required to determine why most of the embryos in this experiment were lost between day 13 and day 23 of gestation. PMID- 21535241 TI - A huge ovarian cyst in a hysterectomized bitch. AB - A 11-year-old, spayed, female mixed breed-dog was presented with an abdominal mass that was detected 1 month ago. Upon abdominal palpation a large, firm, oval shaped, movable mass was found in the mid-abdominal region. Survey radiograph of the abdomen demonstrated an oval soft tissue dense mass located on the right side of the abdominal cavity. A large, heteregenous and cystic mass with solid components occupying the majority of the abdomen and a small, cystic mass with solid components caudal to the left kidney were identified by transabdominal ultrasonography. Computed tomography scans revealed bilateral ovarian masses, and a small volume of retroperitoneal fluid on the right side. A cystic, but otherwise solid mass located in the right ovary and small retained left ovary encapsulated in the ovarian bursa were excised surgically by midline laparotomy. Histopathological examination of the excised mass from the right side revealed a large cystic structure consistent with an ovarian cyst and multiple corpora lutea and follicles at different maturational stages were detected in the left ovary. The precise origin of the ovarian cyst could not be determined by morphological appearance. Immunohistochemical staining suggested a cyst of surface epithelial origin. At re-examination 6 months after the surgery, the bitch appeared healthy and the clinical findings were all normal. To our knowledge, the cyst described here is the largest reported in an incompletely ovariohysterectomized bitch. PMID- 21535242 TI - Sperm membrane functionality in the dog assessed by flow cytometry. AB - The objective assessment of sperm function increases the chances of predicting the fertilizing capacity of a fresh semen sample or diagnosing infertility problems. In this study, the available flow cytometry technique was used to determine the membrane functional capacity of canine spermatozoa. The second fractions of ejaculates from six dogs were pooled, and samples (n = 26) processed to determine the variables: sperm viability and plasma membrane integrity by Sybr 14/Pi staining; phosphatidylserine (PS) translocation by Annexin-V-FITC/PI labelling; acrosome membrane integrity by FITC-conjugated Pisum sativum agglutinin/PI labelling; and mitochondrial membrane potential (DeltaPsim) by staining with JC-1. Means for the 26 examined samples indicated that 82.66 +/- 2.8% of the viable spermatozoa showed an intact plasma membrane, 8.4 +/- 2.6% were moribund, 72.7 +/- 16% had an intact acrosome, 80.9 +/- 17% had high DeltaPsim and 8.1 +/- 11% had PS translocation with a PS translocation index of 2.1 +/- 3%. Motility was only correlated with PS translocation (R = 0.3901; p = 0.0488), and acrosome membrane integrity was correlated with PS translocation (R = -0.5816; p = 0.0018). This study provides objective physiological data on the functional capacity of canine spermatozoa. PMID- 21535243 TI - Contribution of Hfq to photooxidative stress resistance and global regulation in Rhodobacter sphaeroides. AB - The photosynthetic alphaproteobacterium Rhodobacter sphaeroides has to cope with photooxidative stress that is caused by the bacteriochlorophyll a-mediated formation of singlet oxygen ((1)O(2)). Exposure to (1)O(2) induces the alternative sigma factors RpoE and RpoH(II) which then promote transcription of photooxidative stress-related genes, including small RNAs (sRNAs). The ubiquitous RNA chaperone Hfq is well established to interact with and facilitate the base pairing of sRNAs and target mRNAs to influence mRNA stability and/or translation. Here we report on the pleiotropic phenotype of a Deltahfq mutant of R. sphaeroides, which is less pigmented, produces minicells and is more sensitive to (1)O(2). The higher (1)O(2) sensitivity of the Deltahfq mutant is paralleled by a reduced RpoE activity and a disordered induction of RpoH(II)-dependent genes. We used co-immunoprecipitation of FLAG-tagged Hfq combined with RNA-seq to identify association of at least 25 sRNAs and of mRNAs encoding cell division proteins and ribosomal proteins with Hfq. Remarkably, > 70% of the Hfq-bound sRNAs are (1)O(2) affected. Proteomics analysis of the Hfq-deficient strain revealed an impact of Hfq on amino acid transport and metabolic functions. Our data demonstrate for the first time an involvement of Hfq in regulation of photosynthesis genes and in the photooxidative stress response. PMID- 21535244 TI - New fat and new neurons: endocannabinoids control neurogenesis in obesity (Commentary on Rivera et al.). PMID- 21535245 TI - The mechanisms of the strong inhibitory modulation of long-term potentiation in the rat dentate gyrus. AB - The hippocampus is essential for the formation of certain types of memory, and synaptic plasticity such as long-term potentiation (LTP) is widely accepted as a cellular basis of hippocampus-dependent memory. Although LTP in both perforant path-dentate gyrus (DG) granule cell and CA3-CA1 pyramidal cell synapses is similarly dependent on activation of postsynaptic N-methyl-D-aspartate receptors, several reports suggest that modulation of LTP by gamma-aminobutyric acid (GABA) receptor-mediated inhibitory inputs is stronger in perforant path-DG granule cell synapses. However, little is known about how different the mechanism and physiological relevance of the GABAergic modulation of LTP induction are among different brain regions. We confirmed that the action of GABA(A) receptor antagonists on LTP was more prominent in the DG, and explored the mechanism introducing such difference by examining two types of GABA(A) receptor-mediated inhibition, i.e. synaptic and tonic inhibition. As synaptic inhibition, we compared inhibitory vs. excitatory monosynaptic responses and their summation during an LTP-inducing stimulus, and found that the balance of the summated postsynaptic currents was biased toward inhibition in the DG. As tonic inhibition, or sustained activation of extrasynaptic GABA(A) receptors by ambient GABA, we measured the change in holding currents of the postsynaptic cells induced by GABA(A) receptor antagonists, and found that the tonic inhibition was significantly stronger in the DG. Furthermore, we found that tonic inhibition was associated with LTP modulation. Our results suggest that both the larger tonic inhibition and the larger inhibitory/excitatory summation balance during conditioning are involved in the stronger inhibitory modulation of LTP in the DG. PMID- 21535246 TI - Cardiovascular responses to microinjection of noradrenaline into the medial amygdaloid nucleus of conscious rats result from alpha2-receptor activation and vasopressin release. AB - The medial amygdaloid nucleus (MeA) is involved in the modulation of physiological and behavioral processes, as well as regulation of the autonomic nervous system. Moreover, MeA electrical stimulation evokes cardiovascular responses. Thus, as noradrenergic receptors are present in this structure, the present study tested the effects of local noradrenaline (NA) microinjection into the MeA on cardiovascular responses in conscious rats. Moreover, we describe the types of adrenoceptor involved and the peripheral mechanisms involved in the cardiovascular responses. Increasing doses of NA (3, 9, 27 or 45 nmol/100 nL) microinjected into the MeA of conscious rats caused dose-related pressor and bradycardic responses. The NA cardiovascular effects were abolished by local pretreatment of the MeA with 10 nmol/100 nL of the specific alpha2-receptor antagonist RX821002, but were not affected by local pretreatment with 10 nmol/100 nL of the specific alpha1-receptor antagonist WB4101. The magnitude of pressor response evoked by NA microinjected into the MeA was potentiated by intravenous pretreatment with the ganglion blocker pentolinium (5 mg/kg), and blocked by intravenous pretreatment with the selective V1-vasopressin antagonist dTyr(CH2)5 (Me)AVP (50 MUg/kg). In conclusion, our results show that microinjection of NA into the MeA of conscious rats activates local alpha2-adrenoceptors, evoking pressor and bradycardic responses, which are mediated by vasopressin release. PMID- 21535247 TI - Gastrectomy alters emotional reactivity in rats: neurobiological mechanisms. AB - Gastrectomy (Gsx) is associated with altered emotional function and a predisposition to depression/anxiety disorders. Here we investigated the effects of Gsx on emotional reactivity in rats and explored the underlying neurobiological mechanisms. Gsx- and sham-operated rats were exposed to behavioural tests that explore anxiety- and depression-like behaviour (open field, black and white box, elevated plus maze, social interaction, forced swim) as well as memory (object recognition). The potential neurobiological mechanisms underlying these differences were explored by measuring (i) turnover of candidate neurotransmitter systems in the nucleus accumbens, (ii) hippocampal neurogenesis by BrdU labelling or by analysis of candidate genes involved in neuronal growth and (iii) changes in mRNA expression of candidate genes in dissected hippocampal and amygdala tissue. Data from individual behavioural tests as well as from multivariate analysis revealed differing emotional reactivity between Gsx- and sham-operated rats. Gsx rats showed reduced emotional reactivity in a new environment and decreased depression-like behaviour. Accumbal serotonin and dopamine turnover were both reduced in Gsx rats. Gsx also led to a memory deficit, although hippocampal neurogenesis was unaffected. Of the many candidate genes studied by real-time RT-PCR, we highlight a Gsx-associated decrease in expression of Egr-1, a transcription factor linked to neural plasticity and cognition, in the hippocampus and amygdala. Thus, Gsx induces an alteration of emotional reactivity and a memory/cognitive deficit that is associated with reduced turnover of serotonin and dopamine in the nucleus accumbens and decreased expression of Egr-1 in the hippocampus and amygdala. PMID- 21535248 TI - Maternal absence of the parathyroid hormone 2 receptor affects postnatal pup development. AB - During the lactation period, mothers have a variety of adaptive changes in brain physiology and behaviour that allow them to properly raise their pups. The exact circuitries and mechanisms responsible for these changes are not fully understood. Recent evidence suggests that the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39) and its receptor, the parathyroid hormone 2 receptor (PTH2-R), contribute to these mechanisms. To further investigate this idea, we evaluated the growth rate of pups from dams with a genetically inactivated PTH2-R (PTH2-R-KO), as well as maternal behavioural and neuroendocrine parameters. We observed that PTH2-R-KO-reared pups had a slowed growth rate. This was associated with a reduced volume of milk yielded by PTH2-R KO dams after 30-min suckling compared to wild-type (WT) dams when pups were returned after 5 h of separation. Our data suggest a reduced sensitivity of PTH2 R-KO dams to pup stimulation. We also observed a significant reduction in suckling-induced c-Fos expression in the paraventricular hypothalamic nucleus and signs of lower prolactin levels in the PTH2-R-KO dams. Our data suggest that the reduced growth rate of PTH2-R-KO-reared pups was likely the result of alterations in the milk-production pathway rather than modifications in behaviour. Although PTH2-R-KO dams showed increased anxiety in the elevated zero-maze test, no differences from WT dams in maternal behaviour were observed. Taken together, our findings suggest the involvement of the TIP39/PTH2-R system in the pathways involved in the successful development of the pups. PMID- 21535250 TI - Diagnosing isolated cardiac sarcoidosis. AB - OBJECTIVES: Cardiac sarcoidosis (CS) without clinically apparent extracardiac disease may escape detection because of the poor sensitivity of endomyocardial biopsy (EMB). We set out to analyse our experience of repeated and imaging-guided biopsies in clinically isolated CS. METHODS: We retrospectively reviewed the medical records, laboratory test results, imaging studies and pathological analyses of 74 patients with either histologically proven or clinically probable CS at our institution between January 2000 and December 2010. RESULTS: Fifty-two patients had histologically proven CS, of whom 33 (26 women) had disease that was clinically isolated to the heart. Sarcoidosis was detected in the first EMB in 10 of the 31 patients who underwent biopsy. CS was found by repeated EMBs, targeted by cardiac imaging, in seven additional patients, and 11 patients were diagnosed by sampling 18-F-fluorodeoxyglucose position emission tomography-positive mediastinal lymph nodes at mediastinoscopy. Together, the first biopsy (cardiac or mediastinal lymph node) provided the diagnosis in 34%, the second biopsy in 31% and the third in 22% of biopsied patients with isolated CS. Four (13%) of the remaining diagnosis were made after cardiac transplantation and one in a patient who did not undergo biopsy) at autopsy after sudden cardiac death. CONCLUSIONS: Cardiac sarcoidosis may present without clinically apparent disease in other organs. At least two-thirds of patients remain undiagnosed after a single EMB session. The detection rate can be improved by repeated and imaging-guided cardiac or mediastinal lymph-node biopsies. Nevertheless, false-negative biopsy results remain a problem in CS patients with no apparent extracardiac disease. PMID- 21535249 TI - Neurosteroidogenesis: insights from studies of songbirds. AB - The long-held dogma that the brain is a target of steroids produced by peripheral organs has delayed the widespread acceptance of the functional importance of neurosteroidogenesis. Comparative studies have been vital for establishing the key actions of gonadal and adrenal hormones on brain and behaviour. No doubt, studies across diverse phyla will continue to be crucial for revealing the true significance of neurosteroidogenesis to proper function of the vertebrate brain. Here, we review work carried out in our laboratory, as well as in others, highlighting advances to our understanding of brain steroid synthesis and action using songbirds as animal models. These studies show that steroidogenic transporters and enzymes are present in the songbird brain and that their expression and/or activities are subject to developmental, seasonal or short-term regulation. Our work in a songbird points to synaptic synthesis of neuroactive steroids and fast, perisynaptic membrane actions. Combined with evidence for rapid steroidal control of behaviour, these studies firmly establish a neuromodulatory role for avian neurosteroids. We hope this work will join with that of other species to embolden the acceptance of neurosteroidal signalling as a core property of vertebrate neurobiology. PMID- 21535251 TI - Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results from the MONICA/KORA Augsburg study. AB - AIMS: Oxidative stress plays a critical role in the initiation and progression of atherosclerosis. Myeloperoxidase (MPO) is a marker of oxidative stress. We prospectively investigated whether an increased serum concentration of MPO is associated with an increased risk of incident coronary heart disease (CHD). METHODS: We conducted a population-based case-cohort study in middle-aged, healthy men and women within the MONICA/KORA Augsburg studies. Serum levels of MPO were measured in 333 subjects with (cases) and 1727 without (noncases) incident CHD. Mean follow-up time was 10.8 +/- 4.6 years. RESULTS: Baseline concentrations of MPO were higher in cases compared with noncases (P <= 0.001 in men; P=0.131 in women). After adjustment for major cardiovascular risk factors, the hazard ratio (HR) with 95% confidence interval (CI) comparing the top with the two lower tertiles was 1.70 (95% CI, 1.25-2.30). After additional adjustment for markers of inflammation and endothelial dysfunction, the association was attenuated (HR 1.50; 95% CI, 1.08-2.09). There were no significant interactions of MPO with sex or increased weight on CHD risk. CONCLUSIONS: Elevated concentrations of the oxidative stress marker MPO were independently associated with increased risk of incident CHD. This finding deserves detailed evaluation in further studies. PMID- 21535252 TI - Cutaneous epitheliotropic T-cell lymphoma in the cat: a review of the literature and five new cases. AB - Cutaneous epitheliotropic T-cell lymphoma (CETL) is characterized by cutaneous infiltration of neoplastic T lymphocytes with a specific tropism for the epidermis and adnexal epithelium. This disease is reported very rarely in the cat. Clinical data were collected from an informal discussion with veterinary dermatologists through the Vetdermlist (vetderm@lists.ncsu.edu). In parallel, case archives of two European diagnostic histopathology laboratories (Institut de Pathologie et Genetique/Bio.be Gosselies, Belgium and the School of Veterinary Sciences, University of Bristol, UK) were reviewed. Fifteen cases with a good clinical description were selected, and five sets of skin biopsies were available for review. Cutaneous epitheliotropic T-cell lymphoma generally affects older cats with no apparent sex or breed predisposition. Solitary or multiple lesions were reported without predilection for any particular location. The lesions consisted of erythematous plaques or patches, scaly alopecic patches and nonhealing ulcers or nodules, which sometimes mimicked an eosinophilic plaque. Pruritus was rarely reported. No lesions affecting the oral mucosa were observed. Clinical diagnosis of CETL is more challenging in cats than in dogs. Final diagnosis must be based on histopathological examination of skin biopsy samples. The characteristic lesions of feline CETL are similar to those reported in the dog, but involvement of the adnexal glands was not observed in this series (n=5). The neoplastic T cells were generally small to medium in size. The survival time of cats with CETL seems to be more variable than that of affected dogs. Too few cases have been evaluated to permit clear recommendations to be made with respect to treatment. PMID- 21535253 TI - Microchip-associated fibrosarcoma in a cat. AB - A 9-year-old, neutered male cat was presented for a subcutaneous mass on the neck. After surgical removal of the mass, a pet identification microchip was found within the tumour. Histological examination of the mass revealed typical features of the feline postinjection sarcoma. The cat had never received injections at the tumour site; all routine vaccinations were administered in the hindlimbs. Few cases of sarcomas developing at the site of microchip application have been reported in animals, although the contributory role of vaccine administrations has not been ruled out. This is the first report of a microchip associated fibrosarcoma in a cat. Adherence to American Association of Feline Practitioners vaccination guidelines, avoiding the interscapular area, enabled confirmation of the definitive aetiology of the neoplasia. PMID- 21535254 TI - The effects of skin disease on the penetration kinetics of hydrocortisone through canine skin in vitro. AB - This study investigated the effects of allergic skin disease on the penetration kinetics of hydrocortisone through canine skin in vitro. Full-thickness lesional and nonlesional (normal) skin was removed from the dorsal lumbosacral and dorsocaudal thoracic regions, respectively, of five canine cadavers. The dogs were suspected of having flea allergy dermatitis based on their distribution and types of skin lesions. Nonlesional skin was confirmed to be histologically normal, and the histopathology of the lesional skin was consistent with allergic dermatitis. Excised skin was clipped, mounted in Franz-type diffusion cells, and the transdermal penetration of a saturated, radiolabelled hydrocortisone solution was measured over 30 h. When the penetration data for all five dogs were pooled, a restricted (or residual) maximal likelihood mixed model predicted that the permeability coefficient and pseudosteady-state flux of hydrocortisone was more than twice as great (95% confidence interval 1.55-2.71 times as great; P < 0.0001) through lesional compared with nonlesional skin. There was no significant difference in the lag time for hydrocortisone penetration through lesional compared with nonlesional skin of the dogs. This study has confirmed that the transdermal penetration of hydrocortisone may be altered, typically increased twofold, but could be as high as 10-fold, through lesional compared with nonlesional skin of dogs with suspected flea allergy dermatitis. This is likely to be affected by variables such as disease severity, concurrent infections and interindividual differences in skin characteristics. PMID- 21535255 TI - Evaluation of the bacterial microflora of the conjunctival sac of healthy dogs and dogs with atopic dermatitis. AB - The aim of this case-control study was to evaluate and compare the bacterial microflora from the conjunctival sac of dogs with atopic dermatitis and healthy dogs. Twenty-one atopic dogs without clinical and/or cytopathological signs of bacterial blepharoconjunctivitis and 21 breed-matched healthy dogs were enrolled. Under topical anaesthesia, the inferior conjunctival sac of one eye was scraped twice. Material was collected with a Kimura spatula, spread over a slide and stained with a Diff Quick((r)) -type stain (Medion Diagnostics GmbH, Dudingen, Switzerland) for cytological examination. An area of 0.5 cm(2) was examined at *1000 magnification, and the types and numbers of cells and bacteria were recorded. A bacterial swab was collected and inoculated into culture media for the growth of aerobic bacteria. Before sampling, each atopic dog was evaluated for severity of cutaneous lesions, pruritus and conjunctival inflammation. Significant differences were observed between atopic and healthy dogs for the presence of bacteria on cytology (P = 0.015), keratinized (P = 0.001) and nonkeratinized epithelial cells (P = 0.013), eosinophils (P = 0.019) and lymphocytes (P = 0.008). Bacteria were recovered from 12 atopic dogs and three healthy dogs (P = 0.004). Staphylococcus pseudintermedius was the most commonly isolated species in atopic dogs (seven of 12). In atopic dogs, no significant relation was found between conjunctival bacterial colonization (on cytology and culture) and the severity of any of the clinical parameters. This study suggests differences in conjunctival bacterial colonization and cytological features between atopic and healthy dogs. PMID- 21535256 TI - Putative Malassezia dermatitis in six goats. AB - Histopathology submissions from 28 goats with dermatological disease were identified in an archival search of pathology files. Microscopic sections of skin biopsy specimens were examined for the presence of Malassezia spp. organisms. Six cases with many Malassezia yeasts were identified histopathologically. Based on the extent of clinical disease, three cases were regarded as localized and three were generalized infections. Clinical findings included alopecia with dry seborrhoea (four cases), greasy seborrhoea (one case), and no clinical findings specific to localized Malassezia infection when concurrent bacterial infection was present (one case). Mild pruritus was reported in two cases of generalized infection. No breed predilection was apparent. Three cases were male and three were female. Malassezia dermatitis occurred in goats from 10 months to 13 years of age. Three of six cases had concurrent bacterial infection. Skin lesions resolved following topical antifungal therapy in the two goats that were treated. Histopathological findings in all cases were severe follicular and epidermal orthokeratotic hyperkeratosis with minimal epithelial change and mild superficial perivascular to interstitial nonsuppurative inflammation. Numerous budding yeasts were visible within the stratum corneum of all cases; however, Malassezia was not isolated in the three cases in which culture was attempted. Based upon these findings, the authors suggest that the diagnosis Malassezia dermatitis in goats is most likely to be made by cytological examination of skin impressions or by examination of skin biopsy samples. PMID- 21535257 TI - Epithelial migration on the canine tympanic membrane. AB - Epithelial migration (EM) is a process that serves as a self-cleaning and repair mechanism for the ear canal and tympanic membrane (TM). Epithelial migration has been evaluated in humans and several other species, but not in dogs. The objective of this study was to determine the rate and pattern of EM on the TM in clinically normal laboratory dogs. Eighteen dogs were anaesthetized, and three drops of waterproof drawing ink were placed on two sites of the pars tensa (PT) and one on the pars flaccida (PF). Images were recorded with a video otoscope and digital capture system. Each dog was evaluated and images were recorded every 6-8 days for four evaluations. Migration pattern analysis and EM rate calculation were performed with image-processing software. Descriptive statistics for EM rate (mean, SD, 95% confidence interval) were calculated for all ink-drop locations on the TM (PT1, PT2 and PF) at each time point. No significant differences in the mean EM rates were identified between right and left ears of the fox hounds breeds (beagle or fox hound), or locations PT1 and PT2. The mean overall EM rates (+/- SD) were 96.4 (+/- 43.1) and 225.4 (+/- 128.1) MUm/day for the PT and PF, respectively. All ink drops moved outwards, the majority in a radial direction, from the original location to the periphery of the TM. The ink-drop placement method used in this study can be used in future studies to determine the EM rate of the canine TM. PMID- 21535258 TI - Cortical microtubules optimize cell-wall crystallinity to drive unidirectional growth in Arabidopsis. AB - The shape of plants depends on cellulose, a biopolymer that self-assembles into crystalline, inextensible microfibrils (CMFs) upon synthesis at the plasma membrane by multi-enzyme cellulose synthase complexes (CSCs). CSCs are displaced in directions predicted by underlying parallel arrays of cortical microtubules, but CMFs remain transverse in cells that have lost the ability to expand unidirectionally as a result of disrupted microtubules. These conflicting findings suggest that microtubules are important for some physico-chemical property of cellulose that maintains wall integrity. Using X-ray diffraction, we demonstrate that abundant microtubules enable a decrease in the degree of wall crystallinity during rapid growth at high temperatures. Reduced microtubule polymer mass in the mor1-1 mutant at high temperatures is associated with failure of crystallinity to decrease and a loss of unidirectional expansion. Promotion of microtubule bundling by over-expressing the RIC1 microtubule-associated protein reduced the degree of crystallinity. Using live-cell imaging, we detected an increase in the proportion of CSCs that track in microtubule-free domains in mor1 1, and an increase in the CSC velocity. These results suggest that microtubule domains affect glucan chain crystallization during unidirectional cell expansion. Microtubule disruption had no obvious effect on the orientation of CMFs in dark grown hypocotyl cells. CMFs at the outer face of the hypocotyl epidermal cells had highly variable orientation, in contrast to the transverse CMFs on the radial and inner periclinal walls. This suggests that the outer epidermal mechanical properties are relatively isotropic, and that axial expansion is largely dependent on the inner tissue layers. PMID- 21535259 TI - Hierarchy of hormone action controlling apical hook development in Arabidopsis. AB - The apical hook develops in the upper part of the hypocotyl when seeds buried in the soil germinate, and serves to protect cotyledons and the shoot apical meristem from possible damage caused by pushing through the soil. The curvature is formed through differential cell growth that occurs at the two opposite sides of the hypocotyl, and it is established by a gradient of auxin activity and refined by the coordinated action of auxin and ethylene. Here we show that gibberellins (GAs) promote hook development through the transcriptional regulation of several genes of the ethylene and auxin pathways in Arabidopsis. The level of GA activity determines the speed of hook formation and the extent of the curvature during the formation phase independently of ethylene, probably by modulating auxin transport and response through HLS1, PIN3, and PIN7. Moreover, GAs cooperate with ethylene in preventing hook opening, in part through the induction of ethylene production mediated by ACS5/ETO2 and ACS8. PMID- 21535260 TI - Pepper asparagine synthetase 1 (CaAS1) is required for plant nitrogen assimilation and defense responses to microbial pathogens. AB - Asparagine synthetase is a key enzyme in the production of the nitrogen-rich amino acid asparagine, which is crucial to primary nitrogen metabolism. Despite its importance physiologically, the roles that asparagine synthetase plays during plant defense responses remain unknown. Here, we determined that pepper (Capsicum annuum) asparagine synthetase 1 (CaAS1) is essential for plant defense to microbial pathogens. Infection with Xanthomonas campestris pv. vesicatoria (Xcv) induced early and strong CaAS1 expression in pepper leaves and silencing of this gene resulted in enhanced susceptibility to Xcv infection. Transgenic Arabidopsis (Arabidopsis thaliana) plants that overexpressed CaAS1 exhibited enhanced resistance to Pseudomonas syringae pv. tomato DC3000 and Hyaloperonospora arabidopsidis. Increased CaAS1 expression influenced early defense responses in diseased leaves, including increased electrolyte leakage, reactive oxygen species and nitric oxide bursts. In plants, increased conversion of aspartate to asparagine appears to be associated with enhanced resistance to bacterial and oomycete pathogens. In CaAS1-silenced pepper and/or CaAS1-overexpressing Arabidopsis, CaAS1-dependent changes in asparagine levels correlated with increased susceptibility or defense responses to microbial pathogens, respectively. Linking transcriptional and targeted metabolite studies, our results suggest that CaAS1 is required for asparagine synthesis and disease resistance in plants. PMID- 21535261 TI - Cdc2: a monopotent or pluripotent CDK? AB - Cell cycle progression is controlled by both extracellular and intracellular signalling molecules. It has been generally believed that cdc2/CDK1 only control G(2)-M transition in mammalian and many other higher eukaryotic cells. Accumulating evidence shows that cdc2 not only promotes G(2)-M transition but is also capable of regulating G(1) progress and G(1)-S transition via association with multiple interphase cyclins; cdc2 activity can be inhibited by p21 and p27, two traditional G(1) CDK inhibitors. In addition, cdc2-cyclin B controls pronuclear union in interphase fertilized eggs. These data suggest that cdc2 may be a pluripotent CDK. Although mechanisms responsible for the multiple functions of cdc2 remain to be further investigated, interactions of cdc2 with pRb and with several important transcription factors may provide a clue to the pluripotent role of cdc2. PMID- 21535262 TI - A model for random genetic damage directing selection of diploid or aneuploid tumours. AB - OBJECTIVES: To test whether genetic instability may determine whether tumours become aneuploid or diploid. MATERIALS AND METHODS: We have identified genes needed for cell survival or replication by combining Affymetrix gene expression array data from 12 experimental cell lines with in silico GEO+GNF and expO databases. Specific loss of heterozygosis (LOHs), chromosomal abnormalities (called derivative chromosomes) and numbers of normal homologues were identified by SNP and SKY analyses. Random gene losses were calculated under the assumption that bi-allelic MMR gene inactivation causes a 20-fold increase in rate of gene loss. RESULTS: There were ~1.23 * 10(4) genes widely dispersed throughout the genome and possibly expressed by all cells for survival or proliferation, many of these genes performed housekeeping functions. Conservation of the genes may explain the complete haploid genomes found for 15 different cell types and derivative chromosomes selectively retained in aneuploid cancer cell lines after LOH formations, and normal homologue losses. Loss of cell survival/replication genes was calculated to be higher in colon stem cells of carriers of MMR gene mutations than carriers of APC gene mutations. CONCLUSION: Random loss of cell survival/replication genes was calculated to be low enough for colon stem cells with APC gene mutations to 'select' LOH and derivative chromosome combinations favouring tumour cell proliferation. However, cell survival/replication gene loss was calculated to be too high for colonic stem cells lacking MMR genes to survive chromosomal instability, explaining why MMR mutations only produce tumours with diploid chromosome cells. PMID- 21535263 TI - Proliferation of germ cells and somatic cells in first trimester human embryonic gonads as indicated by S and S+G2+M phase fractions. AB - OBJECTIVES: The number of germ cells and somatic cells in human embryonic and foetal gonads has previously been estimated by stereological methods, which are time- and labour-consuming with little information concerning cell proliferation. Here, we studied whether flow cytometry could be applied as an easier method, also enabling estimation of the fraction of cells in S or S+G(2)+M (SG(2) M) cell cycle phases as indicators of cell proliferation. METHODS: Cell suspensions from 35 human embryonic gonads at days 37 to 68 post-conception (pc) were immunomagnetically sorted into C-KIT positive (germ) cells and negative (somatic) cells. They were stained for DNA content and analysed by flow cytometry. S and SG(2) M fractions could be measured for 13 of the female and 20 of the male gonads. The number of cells was estimated using fluorescent reference beads. RESULTS: During the period from 37 to 68 days pc, female germ and somatic cells had a stable S and SG(2) M fractions indicating steady growth of both subpopulations, whereas they decreased in both male germ and somatic cells. The number of germ and somatic cells estimated by flow cytometry was significantly lower than in stereological estimates, suggesting loss of cells during preparation. CONCLUSIONS: Cell proliferation as indicated by S and SG(2) M fractions could be estimated specifically for primordial germ and somatic cells. Estimation of total number of germ and somatic cells was not feasible. PMID- 21535264 TI - In vitro study of enhanced osteogenesis induced by HIF-1alpha-transduced bone marrow stem cells. AB - OBJECTIVES: Hypoxia-inducible factor 1alpha (HIF-1alpha) is a pivotal regulator of hypoxic and ischaemic vascular responses that drives transcriptional activation of hundreds of genes involved in vascular reactivity, angiogenesis and arteriogenesis. Previous reports based on gene knockout technology have demonstrated that HIF-1alpha can promote osteogenesis. However, this protein is easily degraded in a normoxic state, which makes in vitro studies of HIF-1alpha induced mesenchymal stem cell (MSC) osteogenesis difficult. For better understanding of HIF-1alpha promoting osteogenesis, the role of HIF-1alpha induced MSC osteogenesis in the normoxic state has been investigated here. MATERIALS AND METHODS: HIF-1alpha was made to overexpress using a lentiviral vector, and its effects on bone marrow-derived mesenchymal stem cell (BMSC) osteogenesis were investigated. Real-time quantitative and western blotting (to assess expression levels of angiogenic and osteogenic related genes regulated by Lenti-HIF-1alpha), alkaline phosphatase (ALP) and alizarin red-S staining analyses, were performed. RESULTS: In HIF-1alpha gene-transfected BMSCs, expression levels of angiogenic, cartilaginous and osteogenic genes were all increased significantly compared to Lenti LacZ-transfected cells, at both mRNA and protein levels. ALP activity and alizarin red-S staining were significantly enhanced in HIF-1alpha transduced cells compared to control cells, on day 21. CONCLUSIONS: These results indicate that Lenti-HIF-1alpha can induce BMSC overexpression levels of angiogenic and osteogenic genes in vitro in the normoxic state. Further study will be focused on whether HIF-1alpha can also improve bone repair in vivo. PMID- 21535265 TI - Towards expansion of human hair follicle stem cells in vitro. AB - OBJECTIVES: Multipotential human hair follicle stem cells can differentiate into various cell lineages and thus are investigated here as potential autologous sources for regenerative medicine. Towards this end, we have attempted to expand these cells, directly isolated from minimal amounts of hair follicle explants, to numbers more suitable for stem-cell therapy. MATERIALS AND METHODS: Two types of human follicle stem cells, commercially available and directly isolated, were cultured using an in-house developed medium. The latter was obtained from bulge areas of hair follicles by mechanical and enzymatic dissociation, and was magnetically enriched for its CD200(+) fraction. Isolated cells were cultured for up to 4 weeks, on different supports: blank polystyrene, laminin- and Matrigel(TM) -coated surfaces. RESULTS: Two-fold expansion was found, highlighting the slow-cycling nature of these cells. Flow cytometry characterization revealed: magnetic enrichment increased the proportion of CD200(+) cells from initially 43.3% (CD200+, CD34: 25.8%; CD200+, CD34+: 17.5%) to 78.2% (CD200+, CD34: 41.5%; CD200+, CD34+: 36.7%). Enriched cells seemed to have retained and passed on their morphological and molecular phenotypes to their progeny, as isolated CD200(+) presenting cells expanded in our medium to a population with 80% of cells being CD200(+): 51.5% (CD200(+), CD34(-)) and 29.6% (CD200(+), CD34(+)). CONCLUSIONS: This study demonstrates the possibility of culturing human hair follicle stem cells without causing any significant changes to phenotypes of the cells. PMID- 21535266 TI - Insulin-like growth factor 2 enhances insulinogenic differentiation of human eyelid adipose stem cells via the insulin receptor. AB - OBJECTIVES: Previously, we have isolated stem cells (HEAC) from human eyelid adipose tissue and functionally differentiated them into insulin-secreting cells. In the present study, we examined whether insulin family members might influence insulinogenic differentiation of HEAC. MATERIALS AND METHODS: Following culture in differentiation media containing insulin family member or not, cells were examined for gene expression, protein expression and, particularly, insulin and C peptide secretion, in response to high glucose challenge. Using antibodies against the specific receptor, target receptor mediating effect of the insulin family member was investigated. RESULTS: Insulin treatment during culture had little effect on either insulin or C-peptide secretion from HEAC, against high glucose challenge after culture. However, insulin-like growth factor (IGF) 1 treatment decreased both secretions, and interestingly, IGF2 greatly increased the secretions. HEAC treated with IGF2 had strong expression of Pdx1, Isl1, Pax6 and PC1/3 genes, and distinct staining after insulin and C-peptide antibodies, and dithizone. IGF2-enhanced insulinogenic differentiation was totally blocked by antibody against insulin receptor (IR), but not by anti-IGF1 receptor (IGF1R). Differentiated HEAC expressed both IR and IGF1R genes, whereas they expressed neither IGF2 nor IGF2R genes. CONCLUSIONS: From these results, it is suggested that IGF1 might inhibit insulinogenic differentiation of HEAC, whereas IGF2 enhances differentiation, and that enhancement of IGF2 appeared to be mediated via IR. PMID- 21535267 TI - Paracrine-mediated differentiation and activation of human haematopoietic osteoclast precursor cells by skin and gingival fibroblasts. AB - OBJECTIVE: Fibroblasts appear to modulate osteoclastogenesis, but their precise role in this process remains unclear. In this work, paracrine-mediated osteoclastogenic potential of different human fibroblasts was assessed. MATERIALS AND METHODS: Fibroblast-conditioned media (CM) from foetal skin (CM1), adult skin (CM2) and adult gingiva (CM3) were used to promote osteoclastogenesis of osteoclast precursor cells. Cultures supplemented with macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) were used as controls. RESULTS: All fibroblast cultures expressed FSP-1, M-CSF and RANKL and produced osteoprotegerin (OPG); gingival fibroblasts presented lowest expression of osteoclastogenic genes and higher production of OPG. All fibroblast CM were able to induce osteoclastogenesis. CM1 showed behaviour similar to positive controls, and slightly higher osteoclastogenic potential than CM, from adult ones. Gingival fibroblasts revealed lowest osteoclastogenic ability. Presence of anti-MCSF or anti-RANKL partially inhibited osteoclastogenesis promoted by CM, although the former antibody revealed higher inhibitory response. Differences among the osteoclastogenic effect of CM were noted, mainly in expression of genes involved in differentiation and activation of osteoclast precursor cells, c-myc and c-src, and less regarding functional related parameters. CONCLUSIONS: Fibroblasts are able to induce osteoclastogenesis by paracrine mechanisms, and age and anatomical location affect this ability. Other factors produced by fibroblasts, in addition to M-CSF and RANKL, appear to contribute to observed osteoclastogenic potential. PMID- 21535268 TI - Ectopic study of tissue-engineered bone complex with enamel matrix proteins, bone marrow stromal cells in porous calcium phosphate cement scaffolds, in nude mice. AB - OBJECTIVE: This study aimed to investigate the potential of enamel matrix proteins (EMPs) on promoting osteogenic differentiation of porcine bone marrow stromal cells (pBMSCs), as well as new bone formation capabilities, in a tissue engineered bone complex scaffold of EMPs, pBMSCs and porous calcium phosphate cement (CPC). MATERIALS AND METHODS: Effects of EMPs on pBMSCs in vitro was first determined by alkaline phosphatase (ALP) activity, von Kossa staining assay and mRNA expression of ALP, bone sialoprotein (BSP) and osteocalcin (OCN) genes. Next, an ectopic new bone formation test was performed in a nude mouse model with four groups: CPC scaffold alone; CPC scaffold + EMPs; CPC scaffold + pBMSCs; and CPC scaffold + EMPs + pBMSCs, for 2 or 4 weeks. RESULTS: ALP activity, von Kossa assay and mRNA expressions of ALP, BSP and OCN genes were all significantly higher with 150 MUg/ml EMP treatment in vitro. In nude mice, new bone formation was detected only in the CPC scaffold + EMPs + pBMSCs group at 2 weeks. At 4 weeks, in the tissue-engineered construct there was significantly higher bone formation ability than other groups. CONCLUSIONS: EMPs promoted osteogenic differentiation of pBMSCs, and the tissue-engineered complex of EMPs, pBMSCs and CPC scaffold may be a valuable alternative to be used in periodontal bone tissue engineering and regeneration. PMID- 21535270 TI - Cyclin-dependent kinase inhibitor 3 (CDKN3) novel cell cycle computational network between human non-malignancy associated hepatitis/cirrhosis and hepatocellular carcinoma (HCC) transformation. AB - The relationship of cyclin-dependent kinase inhibitor 3 (CDKN3) with tumours has previously been presented in a number of publications. However, the molecular network and interpretation of CDKN3 through the cell cycle between non-malignancy associated hepatitis/cirrhosis and hepatocellular carcinoma (HCC) have remained to be elucidated. Here, we have constructed and analysed significant high expression gene CDKN3 activated and inhibited cell cycle networks from 25 HCC versus 25 non-malignancy associated hepatitis/cirrhosis patients (viral infection HCV or HBV) in GEO Dataset GSE10140-10141, by combination of a gene regulatory network inference method based on linear programming, and decomposition procedure using CapitalBio MAS 3.0 software, based on integration of public databases including Gene Ontology, KEGG, BioCarta, GenMapp, Intact, UniGene, OMIM, and others. Comparing the same and differently activated and inhibited CDKN3 networks with GO analysis, between non-malignancy associated hepatitis/cirrhosis and HCC, our results suggest a CDKN3 cell cycle network (i) with stronger DNA replication and with weaker ubiquitin-dependent protein catabolism as common characteristics in both non-malignancy associated hepatitis/cirrhosis and HCC; (ii) with more cell division and weaker mitotic G2 checkpoint in non-malignancy associated hepatitis/cirrhosis; (iii) with stronger cell cycle and weaker cytokinesis, as a result forming multinucleate cells in HCC. Thus, it is useful to identify CDKN3 cell cycle networks for comprehension of molecular mechanism between non malignancy associated hepatitis/cirrhosis and HCC transformation. PMID- 21535269 TI - Induction of apoptosis in human lymphoblastoid cells by kaempferol 3-O-beta isorhamninoside and rhamnocitrin 3-O-beta-isorhamninoside from Rhamnus alaternus L. (Rhamnaceae). AB - OBJECTIVE: Kaempferol 3-O-beta-isorhamninoside (K3O-ir) and rhamnocitrin 3-O-beta isorhamninoside (R3O-ir) from Rhamnus alaternus L leaves are investigated for their ability to induce apoptosis in human lymphoblastoid cells. We have attempted to characterize apoptotic pathway activated by these two flavonoids. MATERIAL AND METHODS: Apoptosis of the human TK6 lymphoblastoid cell line was detected by DNA fragmentation, PARP cleavage and by evaluating caspase activity. RESULTS: Apoptosis was observed after 24- and 48-h incubation of the cells with the tested compounds. DNA fragmentation was observed after treatment with flavonoids; this was confirmed by demonstration of PARP cleavage. Caspase-3 and caspase-8 activities were induced by both K3O-ir and R3O-ir flavonoids showing highest activity with compound concentration of 400 MUg/ml. CONCLUSION: We have demonstrated that K3O-ir and R3O-ir induce apoptosis in human lymphoblastoid cells by the extrinsic pathway of apoptosis. PMID- 21535271 TI - Response shift in the assessment of anxiety, depression and perceived health in urologic cancer patients: an individual perspective. AB - The assessment of quality of life in cancer patients is hampered because patients may change their frames of reference during the course of the disease. The aim of this study was to test individual differences in these response shift effects. Urologic cancer patients (n= 275) were examined during the stay in the hospital (T1), 2 weeks later (T2) and 3 months later (T3). Furthermore, at T3 they were asked to retrospectively assess their situation at T1 (then-test). The difference between this retrospective assessment and the original assessment at T1 was used to determine the response shift effect (recalibration). Anxiety (Generalized Anxiety Disorder Questionnaire-2), depression (Patient Health Questionnaire-2) and health dissatisfaction (Questionnaire on Life Satisfaction) were obtained at all points in time. The effect sizes of the mean response shift effects (recalibration) ranged between 0.26 and 0.48. Nevertheless, a large proportion of the sample showed no response shift (22-38%) or even negative response shift effects (20-30%). There were significant correlations among the response shift measures of the domains (anxiety, depression and health dissatisfaction) with coefficients between 0.29 and 0.51. The results indicate that response shift should not only be assessed on the mean score level, since it is also a dimension of individual difference. PMID- 21535272 TI - A systematic review of suicidal behaviour in old age: a gender perspective. AB - AIM: This article presents the findings of a systematic review of the literature on suicidal behaviour in old age, specifically examining gender differences. Background. Numerous studies have reported that older people are at a higher risk for suicide than other age groups in most countries. Rarely do they examine whether there are differences in suicidal behaviour among older males and females. DESIGN: Systematic review. METHODS: Electronic databases were systematically searched to identify English language reports of research about suicide and suicide attempts in old age. Studies were assessed for inclusion based on inclusion criteria. Key results concerning suicide in old age were extracted and synthesised. RESULTS: Twenty-two gender-specific studies on suicidal behaviour in old age were identified. All studies were of the quantitative type. Five factors affecting suicide by gender in old age were identified from the selected papers. CONCLUSIONS: Most findings concluded that older males had a higher risk of suicide than older females. Some findings nevertheless revealed that the risk factors for one socio-demographic group may be less relevant to others and that people operate differently in different social contexts. Further in-depth exploration on the gender-specific characteristics in old-age suicide is recommended. RELEVANCE TO CLINICAL PRACTICE: Health professionals are encouraged to increase their knowledge of the risk factors leading to suicide in old age in their local contexts and to be able to identify potential victims and render timely and appropriate intervention. They should also be ready to open up their service boundaries and develop collaborative partnerships with local agencies and the general public. PMID- 21535273 TI - The prevalence of urinary incontinence among women and men with chronic obstructive pulmonary disease in Sweden. AB - AIM: The aims of the present study were to investigate the prevalence, characteristics and status of urinary incontinence among women and men with chronic obstructive pulmonary disease in primary health care. BACKGROUND: Information on the prevalence of urinary incontinence in women and men with chronic obstructive pulmonary disease is scant. Such knowledge may be important to the development of care for patients with chronic obstructive pulmonary disease. DESIGN: A questionnaire survey. METHOD: The study included 391 women and 337 men, aged 50-75 years, with chronic obstructive pulmonary disease. A self administered, evidence-based questionnaire for incontinence was used. A response rate of 66% was obtained, of which 89.3% had spirometry-confirmed chronic obstructive pulmonary disease, and most patients had been diagnosed with moderate (Stage II) chronic obstructive pulmonary disease. RESULTS: The prevalence of urinary incontinence in women and men with chronic obstructive pulmonary disease was 49.6 and 30.3%, respectively. Women and men with urinary incontinence had a significantly higher body mass index than did women and men without urinary incontinence. The most common type of incontinence in women was stress incontinence (52.4%) and in men postmicturition dribbling (66.3%). Women with urinary incontinence had a higher presence of a symptomatic cough than did women without urinary incontinence (p < 0.001). On the whole, incontinence affected women more than men concerning experienced bothersomeness of incontinence (p < 0.001). More women than men with urinary incontinence refrained from activities (p < 0.021) and had sought help for incontinence (p < 0.012). CONCLUSION: The present results indicate that urinary incontinence content should be included in care plans for patients living with chronic obstructive pulmonary disease. In addition, the results imply that nurses and physicians working in primary health care should ask patients with chronic obstructive pulmonary disease about urinary incontinence and then offer appropriate assessment and management of it. RELEVANCE TO CLINICAL PRACTICE: In the context of primary health care, assessing and managing urinary incontinence should be included in care plans for patients living with chronic obstructive pulmonary disease. PMID- 21535274 TI - Comparison of five malnutrition screening tools in one hospital inpatient sample. AB - AIMS AND OBJECTIVES: The purpose of this study is to compare five commonly used malnutrition screening tools against an acknowledged definition of malnutrition in one hospital inpatient sample. BACKGROUND: Early identification and intervention of malnutrition in hospital patients may prevent later complications. Several screening tools have reported their diagnostic accuracy, but the criterion validity of these tools is unknown. DESIGN: A cross sectional study. METHODS: We compared quick-and easy screening tools [Malnutrition Screening Tool (MST), Short Nutritional Assessment Questionnaire (SNAQ) and Mini Nutritional Assessment Short Form (MNA-SF)] and more comprehensive malnutrition screening tools [Malnutrition Universal Screening Tool (MUST) and Nutritional Risk Screening 2002 (NRS-2002)] to an acknowledged definition of malnutrition (including low Body Mass Index and unintentional weight loss) in one sample of 275 adult hospital inpatients. Sensitivity, specificity, positive predictive value and negative predictive value were determined. A sensitivity and specificity of >= 70% was set as a prerequisite for adequate performance of a screening tool. RESULTS: According to the acknowledged definition of malnutrition 5% of patients were at moderate risk of malnutrition and 25% were at severe risk. The comprehensive malnutrition screening tools (MUST, NRS-2002) and the quick-and easy malnutrition screening tools (MST and SNAQ) showed sensitivities and specificities of >=70%. However, 47% of data were missing on the MUST questionnaire and 41% were missing on MNA-SF. The MNA-SF showed excellent sensitivity, but poor specificity for the older subpopulation. CONCLUSIONS: The quick-and-easy malnutrition screening tools (MST and SNAQ) are suitable for use in an hospital inpatient setting. They performed as well as the comprehensive malnutrition screening tools (MUST and NRS-2002) on criterion validity. However, MUST was found to be less applicable due to the high rate of missing values. The MNA-SF appeared to be not useful because of it low specificity. RELEVANCE TO CLINICAL PRACTICE: Insight in what is the most valid and practical nutritional screening tool to use in hospital practice will increase effective recognition and treatment of malnutrition. PMID- 21535275 TI - Quality of end-of-life care for non-cancer patients in a non-acute hospital. AB - AIMS AND OBJECTIVES: Few surveys have been carried out documenting the quality of life for non-cancer patients in general district hospitals reaching the final trajectory towards death. We carried out a survey of 80 patients facing the final stages of their chronic illness as well as their carers and hospital staff. BACKGROUND: With increasing life expectancy, a large majority of patients are older, where palliative care principles for patients with cancer are equally applicable. Few surveys have been carried out documenting the quality of life for non-cancer patients in general district hospitals reaching the final trajectory towards death in terms of patients' and carers' perspective, compared with the more extensive literature for patients with cancer. DESIGN: Survey. METHODS: Assessment tools include symptom check list, geriatric depression scale, Chinese Death Anxiety Inventory and the McGill Quality of Life Questionnaire for patients; SF-12 and the Chinese cost of care index for informal carers; and the Chinese Maslach Bumout and Death Anxiety Inventories for hospital staff. RESULTS: Lower-limb weakness (92.5%), fatigue (86.2%), oedema (85%), dysphagia (58.2%) and pain (48.8%) were the most common symptoms in this group of patients. The mean Chinese Caregiver Stress Index score was 45.93 (SD 6.45) (maximum score = 80). For staff, the mean SF-12 physical component score was lower than the Hong Kong population average. CONCLUSION: The findings suggest that there is room for improvement in the quality of end-of-life care. Relevance to clinical practice. Patients in the final stages of many chronic illnesses have high prevalence of symptoms comparable to those of patients with cancer. Raising awareness and improving training for all health care professionals, formulating guidelines and care pathways and incorporating quality of care as key performance indicators are measures to improve the quality of end-of-life care. PMID- 21535276 TI - Major histocompatibility complex variation in insular populations of the Egyptian vulture: inferences about the roles of genetic drift and selection. AB - Insular populations have attracted the attention of evolutionary biologists because of their morphological and ecological peculiarities with respect to their mainland counterparts. Founder effects and genetic drift are known to distribute neutral genetic variability in these demes. However, elucidating whether these evolutionary forces have also shaped adaptive variation is crucial to evaluate the real impact of reduced genetic variation in small populations. Genes of the major histocompatibility complex (MHC) are classical examples of evolutionarily relevant loci because of their well-known role in pathogen confrontation and clearance. In this study, we aim to disentangle the partial roles of genetic drift and natural selection in the spatial distribution of MHC variation in insular populations. To this end, we integrate the study of neutral (22 microsatellites and one mtDNA locus) and MHC class II variation in one mainland (Iberia) and two insular populations (Fuerteventura and Menorca) of the endangered Egyptian vulture (Neophron percnopterus). Overall, the distribution of the frequencies of individual MHC alleles (n=17 alleles from two class II B loci) does not significantly depart from neutral expectations, which indicates a prominent role for genetic drift over selection. However, our results point towards an interesting co-evolution of gene duplicates that maintains different pairs of divergent alleles in strong linkage disequilibrium on islands. We hypothesize that the co-evolution of genes may counteract the loss of genetic diversity in insular demes, maximize antigen recognition capabilities when gene diversity is reduced, and promote the co-segregation of the most efficient allele combinations to cope with local pathogen communities. PMID- 21535277 TI - Phylogeography and genetic structure of the red-legged partridge (Alectoris rufa): more evidence for refugia within the Iberian glacial refugium. AB - The Pleistocene climatic oscillations promoted the diversification in avian species during the last glacial period. The red-legged partridge (Alectoris rufa, Family Phasianidae) has a large natural distribution extending from the Mediterranean to humid temperate zones. However, the genetic structure for this species is unknown. The present study investigates the phylogeography, genetic structure and demographic history of A. rufa across its distribution, employing both mitochondrial DNA control region sequences and nuclear microsatellite loci. Our results propose that this species was greatly affected by Pleistocene glaciations. The mismatch analyses suggest that the current populations resulted from post-glacial expansion and subsequent differentiation resulting in five diagnosable genetic clusters: Southwestern, Central-eastern, Northwestern, Balearic and French and Italian. Further, we found evidence of three glacial refugia within the currently recognized Iberian glacial refugium. The intraspecific structure revealed by both maternal and biparental phylogeographic analyses was not resolved in the phylogenetic analyses. Based on all considerations, we recommended that five management units be recognized. PMID- 21535278 TI - More than meets the eye: detecting cryptic microgeographic population structure in a parasite with a complex life cycle. AB - Nonrandom recruitment of parasites among hosts can lead to genetic differentiation among hosts and mating dynamics that promote inbreeding. It has been hypothesized that strictly aquatic parasites with intermediate hosts will behave as panmictic populations among hosts because ample opportunity exists for random mixing of unrelated individuals during transmission to the definitive host. A previous allozyme study on the marine trematode Lecithochirium fusiforme did not support this hypothesis; in that, there was genetic differentiation among, and significant heterozygote deficiencies within, definitive hosts. We revisit this system and use microsatellites to obtain multilocus genotypes. Our goal was to determine whether cryptic subgroups and/or the presence of clones could account for the apparent deviation from 'panmixia'. We find strong evidence for cryptic subdivision (three genetic clusters) that causes the Wahlund effect and differentiation among definitive hosts. After accounting for these cryptic groups, we see panmictic genetic structure among definitive hosts that is consistent with the 'high mixing in aquatic habitats' hypothesis. We see evidence for cotransmission of clones in all three clusters, but this level of clonal structure did not have a major impact in causing deviations from Hardy-Weinberg equilibrium, and only affected genetic differentiation among hosts in one cluster. A cursory examination of the data may have led to incorrect conclusions about nonrandom transmission. However, it is obvious in this system that there is more than meets the eye in relation to the actual make-up of parasite populations. In general, the methods we employ will be useful for elucidating hidden patterns in other organisms where cryptic structure may be common (e.g. those with limited morphology or complex life histories). PMID- 21535280 TI - Isolation by oceanographic distance explains genetic structure for Macrocystis pyrifera in the Santa Barbara Channel. AB - Ocean currents are expected to be the predominant environmental factor influencing the dispersal of planktonic larvae or spores; yet, their characterization as predictors of marine connectivity has been hindered by a lack of understanding of how best to use oceanographic data. We used a high-resolution oceanographic model output and Lagrangian particle simulations to derive oceanographic distances (hereafter called transport times) between sites studied for Macrocystis pyrifera genetic differentiation. We build upon the classical isolation-by-distance regression model by asking how much additional variability in genetic differentiation is explained when adding transport time as predictor. We explored the extent to which gene flow is dependent upon seasonal changes in ocean circulation. Because oceanographic transport between two sites is inherently asymmetric, we also compare the explanatory power of models using the minimum or the mean transport times. Finally, we compare the direction of connectivity as estimated by the oceanographic model and genetic assignment tests. We show that the minimum transport time had higher explanatory power than the mean transport time, revealing the importance of considering asymmetry in ocean currents when modelling gene flow. Genetic assignment tests were much less effective in determining asymmetry in gene flow. Summer-derived transport times, in particular for the month of June, which had the strongest current speed, greatest asymmetry and highest spore production, resulted in the best-fit model explaining twice the variability in genetic differentiation relative to models that use geographic distance or habitat continuity. The best overall model also included habitat continuity and explained 65% of the variation in genetic differentiation among sites. PMID- 21535279 TI - Divergent transcriptional response to thermal stress by Anopheles gambiae larvae carrying alternative arrangements of inversion 2La. AB - The African malaria mosquito Anopheles gambiae is polymorphic for chromosomal inversion 2La, whose frequency strongly correlates with degree of aridity across environmental gradients. Recent physiological studies have associated 2La with resistance to desiccation in adults and thermal stress in larvae, consistent with its proposed role in aridity tolerance. However, the genetic basis of these traits remains unknown. To identify genes that could be involved in the differential response to thermal stress, we compared global gene expression profiles of heat-hardened 2La or 2L+(a) larvae at three time points, for up to eight hours following exposure to the heat stress. Treatment and control time series, replicated four times, revealed a common and massive induction of a core set of heat-shock genes regardless of 2La orientation. However, clear differences between the 2La and 2L+(a) arrangements emerged at the earliest (0.25 h) time point, in the intensity and nature of the stress response. Overall, 2La was associated with the more aggressive response: larger numbers of genes were heat responsive and up-regulated. Transcriptionally induced genes were enriched for functions related to ubiquitin-proteasomal degradation, chaperoning and energy metabolism. The more muted transcriptional response of 2L+(a) was largely repressive, including genes involved in proteolysis and energy metabolism. These results may help explain the maintenance of the 2La inversion polymorphism in An. gambiae, as the survival benefits offered by high thermal sensitivity in harsh climates could be offset by the metabolic costs of such a drastic response in more equable climates. PMID- 21535281 TI - Sleep-dependent modulation of affectively guided decision-making. AB - A question of great interest in current sleep research is whether and how sleep might facilitate complex cognitive skills such as decision-making. The Iowa Gambling Task (IGT) was used to investigate effects of sleep on affect-guided decision-making. After a brief standardized preview of the IGT that was insufficient to learn its underlying rule, participants underwent a 12-h delay containing either a normal night's sleep (Sleep group; N = 28) or continuous daytime wake (Wake group; N = 26). Following the delay, both groups performed the full IGT. To control for circadian effects, two additional groups performed both the preview and the full task either in the morning (N = 17) or the evening (N = 21). In the IGT, four decks of cards were presented. Draws from two 'advantageous decks' yielded low play-money rewards, occasional low losses and, over multiple draws, a net gain. Draws from 'disadvantageous' decks yielded high rewards, occasional high losses and, over multiple draws, a net loss. Participants were instructed to win and avoid losing as much as possible, and better performance was defined as more advantageous draws. Relative to the wake group, the sleep group showed both superior behavioral outcome (more advantageous draws) and superior rule understanding (blindly judged from statements written at task completion). Neither measure differentiated the two control groups. These results illustrate a role of sleep in optimizing decision-making, a benefit that may be brought about by changes in underlying emotional or cognitive processes. PMID- 21535282 TI - Snoring is not associated with adverse effects on blood pressure, arterial structure or function in 8-year-old children: the Childhood Asthma Prevention Study (CAPS). AB - AIMS: To study the association between childhood snoring and cardiovascular risk factors. METHODS: Cross-sectional analyses of a population-based birth cohort, who had been participants in a randomised controlled trial of interventions to prevent asthma and who were assessed at age 8 years. The presence and frequency of snoring were assessed by parent-completed questionnaire. We measured a wide range of cardiovascular function markers including non-fasting serum lipoproteins, blood pressure, high-sensitivity C-reactive protein, carotid artery intima media thickness (by ultrasound), brachial pulse wave velocity and augmentation index (by applanation tonometry). RESULTS: Of 409 children whose snoring status was assessed at age 8 years, 321 had lipid and 386 had arterial structure and function measurements. Snoring was not independently associated with blood pressure, carotid artery intima media thickness or measures of arterial stiffness (all P > 0.05). Increasing snoring frequency was independently associated with lower high-density lipoprotein cholesterol (-0.032 g/dL per step, 95% confidence interval -0.060 to -0.003), although the difference in high density lipoprotein between snorers and non-snorers was not significant (P = 0.052). An association of snoring frequency with brachial pulse wave velocity differed according to body mass index (P = 0.03) and was the reverse of that expected. CONCLUSIONS: Parentally reported snoring was not independently associated with adverse measurements of metabolic markers, vascular structure or function in 8-year-old children. Parental reports of snoring may be below the treatment threshold without additional diagnosis via sleep studies. PMID- 21535283 TI - Recognition and management of overweight and obese children: a questionnaire survey of general practitioners and parents in England. AB - AIMS: To (i) compare the views of general practitioners (GPs) and parents about the causes, consequences and management of childhood overweight/obesity; and (ii) explore the extent to which they can identify overweight/obesity in children. METHODS: A questionnaire was mailed to all GPs in one Primary Care Trust and all parents in one primary school in southern England, 2008. Information was gathered on socio-demographic background, views about causes, consequences and management of childhood overweight/obesity; judgements about the weight status of 14 images of children (seven boys, seven girls) in the Children's Body Image Scale (CBIS). Comparisons were made between GP and parents' responses using unpaired bivariate tests. RESULTS: The response rate was 33%. Differences exist between the views of GPs and parents about childhood weight management: 86.4% of parents felt GPs should be involved, compared to 73.3% of GPs (P < 0.001). Parents thought GPs should be more proactive than the GPs stated they would be. GPs were significantly more likely than parents to see a role for school nurses and dieticians. One third of respondents thought GPs lacked expertise in child weight management. Most GPs and parents correctly identified obese children from the images, but inaccuracies occurred at category margins. CONCLUSIONS: Childhood overweight/obesity is a serious public health concern, and primary care has a role to play in tackling it. GPs in England need more training in childhood overweight/obesity management. Their role needs to be clarified in the context of multiagency approaches. PMID- 21535284 TI - Paediatric biobanks: what makes them so unique? AB - Paediatric biobanks store and organise the biological material of children. They are an invaluable resource for the study of the development, health and behaviour of children. International norms for the management of adult biobanks exist, but paediatric biobanks require distinct policies to account for the needs of children, their general incapacity, and their intellectual development throughout the life of the biobank. Because of their particular nature we revisit the issues of consent, the return of research results, and privacy, and discuss how each could be modulated in the paediatric context. We recognize that such modifications entail further financial and logistical complications but maintain that it is essential that paediatric biobanks consider these issues and adapt their biobanks management policies accordingly, rather than extrapolate the current adult-based norms and jeopardise the rights of child participants. PMID- 21535285 TI - Arginine extravasation leading to skin necrosis. AB - Arginine hydrochloride is used in the evaluation of short stature and in the management of urea cycle disorders. In recent times, it has been used in the treatment of stroke-like episodes of MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes). We want to highlight the need for good intravenous access and monitoring the drip site to prevent extravasation injuries that can be caused by arginine, which is a hyperosmolar solution. PMID- 21535286 TI - Acute suppurative thyroiditis in young children. AB - We report two children with acute suppurative thyroiditis (AST). They presented with typical features of AST, which include fever, painful goiter and biochemical euthyroidism. An anatomical defect predisposed to thyroid infection, pyriform sinus fistula, was identified in one patient. Both patients responded well to surgical pus drainage and antibiotic treatment. Anatomical defects must be sought in all children with AST to perform specific surgical treatment and prevent recurrent infection. PMID- 21535287 TI - Prevalence of post-traumatic stress disorder among children and adolescents who survive road traffic crashes: a systematic review of the international literature. AB - While road traffic crashes are known to have a significant impact in terms of deaths and hospitalisations, quantifying the burden of psychological sequelae is more challenging. This systematic review critically evaluates published studies designed to estimate the prevalence of post-traumatic stress disorder among children and adolescents who have survived a road crash. Most studies have focused on injured school-aged children and adolescents, and estimate the occurrence of this condition to be between 12% and 46% in the first 4 months following crash involvement and between 13% and 25% 4-12 months following the crash. The relatively high prevalence of post-traumatic stress disorder following one of the commonest causes of injury underscores the need for greater vigilance and active management to mitigate the adverse consequences on the health and development of young crash survivors. The findings also emphasise the important role that child health professionals must play in promoting strategies that prevent road traffic crashes. PMID- 21535288 TI - Respiratory problems in children with Down syndrome. AB - Down syndrome is associated with a significant health burden, which is particularly apparent in young children who will frequently present with cardiac and respiratory problems. Respiratory presentations include problems related to structural abnormalities of the airways and lungs, glue ears, recurrent lower respiratory tract infections and obstructive sleep apnoea. These conditions are readily identifiable and able to be treated. An awareness of the breadth of respiratory problems and a plan to monitor patients with Down syndrome for their development has the potential to improve outcomes. PMID- 21535289 TI - Teenage toxins: recreational poisoning in the adolescent. AB - Adolescents are experimenting with recreational drugs on a regular basis, particularly at social gatherings such as parties, raves and mass events. A combination of reduced fluid intake, physical activity and drug-induced hyperthermia leads to complications such as heat stroke, delirium and potentially death. The clinician needs to be aware of the variety of pharmacologically active substances available in the recreational marketplace in order to diagnose and manage these patients. Recreational misadventure, because of incorrect dosage or mixing multiple substances, is a common reason for teenagers presenting to hospital with toxidromes. Death from club drug overdose is more likely to be associated with suicidal intent, related risky behaviour and trauma, as well as the inherent toxicity of the drug itself. Although many teenagers are concerned about 'drink spiking' with club drugs, the most common agent causing drink spiking incidents is ethanol. PMID- 21535290 TI - Hypoplastic left heart syndrome in context. AB - Hypoplastic left heart syndrome is a rare condition requiring major cardiac surgery during the neonatal period to sustain life, with subsequent procedures culminating in completion of the Fontan circulation - the common pathway for all 'single ventricle' conditions. Algorithms for care of these children are now well defined with predictable medium-term outcomes with the majority achieving a Fontan circulation. Hypoplastic left heart syndrome is one of a group of conditions that require complex surgery as a neonate and require a similar perioperative approach. Antenatal diagnosis is common in this patient subgroup, and there is a significant body of work that can be drawn on to inform parental choice. PMID- 21535291 TI - Immediately loaded maxillary and mandibular dental implants with fixed CAD/CAM prostheses using a flapless surgical approach: a clinical report. AB - Immediate implant loading is a viable treatment method for selected cases. One of the greatest advantages of this method is the virtual surgery, which precedes the actual clinical treatment and eliminates any need for last minute decisions. The actual surgery time is decreased, since all steps are predetermined. Additionally, no flaps have to be elevated, resulting in preservation of periimplant soft tissues, vascularization of the underlying bone, fewer postoperative complications, and minimal patient discomfort. This article presents a clinical approach made possible due to the evolution of modern scanning techniques and appropriate software. PMID- 21535292 TI - An investigation into the role of core porcelain thickness and lamination in determining the flexural strength of In-Ceram dental materials. AB - PURPOSE: A biaxial flexure test was conducted to evaluate the effect of reducing the thickness of In-Ceram core material and veneering with Vitadur alpha dentine porcelain on its flexural strength. MATERIALS AND METHODS: Four groups of 10 discs were tested; group I discs were In-Ceram discs with mean thickness of 1.58 +/- 0.08 mm, group II discs were In-Ceram discs with mean thickness of 1.0 +/- 0.11 mm, group III discs were laminated In-Ceram core porcelain/Vitadur alpha discs with a mean total thickness of 2.06 +/- 0.15 mm and core porcelain thickness of 1.0 +/- 0.11 mm; group IV discs were Vitadur alpha discs with a mean thickness of 2.08 +/- 0.16 mm. RESULTS: Mean flexural strength values decreased between groups: 436 +/- 38 MPa for group I, 352 +/- 30 MPa for group II, 237 +/- 24 MPa for group III, and 77 +/- 14 MPa for group IV. The result of ANOVA and Tukey tests indicated that the mean flexural strength of group II was significantly less than group I, indicating that thickness of the In-Ceram core provides critical flexural strength to the final product. The addition of ~ 1 mm of Vitadur alpha veneering porcelain to In-Ceram core significantly (p= 0.05) reduced the flexural strength as compared to the nonveneered In-Ceram core specimens (group II). The Vitadur alpha specimens (group IV) were significantly weaker than all the other groups. CONCLUSION: This study indicates that lamination should be avoided in areas where maximum strength is required for In Ceram all-ceramic crowns and bridges. PMID- 21535293 TI - Gyrodiniellum shiwhaense n. gen., n. sp., a new planktonic heterotrophic dinoflagellate from the coastal waters of western Korea: morphology and ribosomal DNA gene sequence. AB - The heterotrophic dinoflagellate Gyrodiniellum shiwhaense n. gen., n. sp. is described from live cells and from cells prepared for light, scanning electron, and transmission electron microscopy. Also, sequences of the small subunit (SSU) and large subunit (LSU) of rDNA have been analyzed. The episome is conical, while the hyposome is ellipsoid. Cells are covered with polygonal amphiesmal vesicles arranged in 16 horizontal rows. Unlike other Gyrodinium-like dinoflagellates, the apical end of the cell shows a loop-shaped row of five elongate amphiesmal vesicles. The cingulum is displaced by 0.3-0.5 * cell length. Cells that were feeding on the dinoflagellate Amphidinium carterae Hulburt were 9.1-21.6 MUm long and 6.6-15.7 MUm wide. Cells of G. shiwhaense contain nematocysts, trichocysts, a peduncle, and pusule systems, but they lack chloroplasts. The SSU rDNA sequence is >3% different from that of the six most closely related species: Warnowia sp. (FJ947040), Lepidodinium viride Watanabe, Suda, Inouye, Sawaguchi & Chihara, Gymnodinium aureolum (Hulburt) Hansen, Gymnodinium catenatum Graham, Nematodinium sp. (FJ947039), and Gymnodinium sp. MUCC284 (AF022196), while the LSU rDNA is 11 12% different from that of Warnowia sp., G. aureolum, and Nematodinium sp. (FJ947041). The phylogenetic trees show that the species belongs in the Gymnodinium sensu stricto clade. However, in contrast to Gymnodinium spp., cells lack nuclear envelope chambers and a nuclear fibrous connective. Unlike Polykrikos spp., cells of which possess a taeniocyst-nematocyst complex, G. shiwhaense has nematocysts but lacks taeniocysts. It differs from Paragymnodinium shiwhaense Kang, Jeong, Moestrup & Shin by possessing nematocysts with stylets and filaments. Gyrodiniellum shiwhaense n. gen., n. sp. furthermore lacks ocelloids, in contrast to Warnowia spp., Nematodinium spp., and Proterythropsis spp. Based on morphological and molecular data, we suggest that the taxon represents a new species within a new genus. PMID- 21535294 TI - Platelet-derived growth factor (PDGF)-BB produces NO-mediated relaxation and PDGF receptor beta-dependent tonic contraction in murine iliac lymph vessels. AB - We studied the effects of PDGF-BB on changes in the diameters of murine lymph vessels with or without intact endothelium. PDGF-BB induced dilation of the lymph vessels with endothelium. Pretreatment with l-NAME or removal of the endothelium caused a significant attenuation in the PDGF-BB-induced dilation. PDGF-BB also produced dose-related reduction of the diameters of the lymph vessels without endothelium. To evaluate intracellular signal transduction and Ca(2+) -dependence of the PDGF-BB-induced tonic contraction, we investigated the effects of imatinib, GW5074 (an inhibitor of Raf-1 kinase), U-73122 (an inhibitor of phospholipase C), and xestospongin C on the PDGF-BB-induced reduction responses. All of these inhibitors caused a significant attenuation in the PDGF-BB-induced reduction response that was significantly decreased by treatment with Ca(2+) free Krebs-bicarbonate solution or nifedipine. Higher concentrations of PDGF-BB produced a marked reduction of lymph vessel diameter within both high K(+) Krebs bicarbonate solution and Ca(2+) -free high K(+) Krebs solution containing 1mM EGTA. These findings suggest that PDGF-BB induced endothelium-dependent NO mediated relaxation of lymphatic smooth muscles in murine lymph vessels. PDGF receptor beta-mediated tonic contraction of the muscles through increased Ca(2+) influx through the membrane and the release of membrane-bound and intracellular Ca(2+) . PMID- 21535296 TI - Role of neuronal nitric oxide synthase in modulating microvascular and contractile function in rat skeletal muscle. AB - OBJECTIVE: This investigation tested the hypothesis that selective nNOS inhibition would lower the dynamic microvascular O2 delivery/utilization () balance (which sets the Po(2) mv) in rat skeletal muscle at rest and during contractions. METHODS: Anesthetized male Sprague-Dawley rats had their spinotrapezius muscles exposed for blood flow (radiolabeled microspheres), (direct Fick calculation), Po(2) mv (phosphorescence quenching), or exteriorized for force production measurement during electrically induced contractions (1 Hz, 6-8 V, 180 seconds) pre- and post-nNOS inhibition with 2.1MUmol/kg of the selective nNOS inhibitor SMTC. RESULTS: At rest, spinotrapezius blood flow was not different whereas SMTC reduced (?27%) resulting in an elevated precontracting baseline Po(2) mv (control: 31.2+/-1.6, SMTC: 37.1+/-2.0mmHg, p<0.05). Following contractions onset SMTC speeded the time to reach 63% of the overall Po(2) mv kinetics response (control: 22.5 +/- 1.6, SMTC: 16.9+/-1.4seconds, p<0.05). During the contracting steady-state, SMTC reduced spinotrapezius blood flow (?17%) and (?17%) such that Po(2) mv was not different (control: 22.8+/-1.6, SMTC: 22.7+/-2.1mmHg, p>0.05) which occurred despite an elevated (?~8%) muscle force production. CONCLUSIONS: These data demonstrate important physiological roles for nNOS-derived NO during contractions in healthy rat skeletal muscle and implicate maladaptations in nNOS function in pathological conditions associated with reduced NO bioavailability. PMID- 21535295 TI - Smooth muscle Ca(2+) -activated and voltage-gated K+ channels modulate conducted dilation in rat isolated small mesenteric arteries. AB - OBJECTIVE: To assess the influence of blocking smooth muscle large conductance Ca(2+) -activated K+ channels and voltage-gated K+ channels on the conducted dilation to ACh and isoproterenol. MATERIALS AND METHODS: Rat mesenteric arteries were isolated with a bifurcation, triple-cannulated, pressurized and imaged using confocal microscopy. Phenylephrine was added to the superfusate to generate tone, and agonists perfused into a sidebranch to evoke local dilation and subsequent conducted dilation into the feed artery. RESULTS: Both ACh- and isoproterenol-stimulated local and conducted dilation with similar magnitudes of decay with distance along the feed artery (2000MUm: ~15% maximum dilation). The gap junction uncoupler carbenoxolone prevented both conducted dilation and intercellular spread of dye through gap junctions. IbTx, TEA or 4-AP, blockers of large conductance Ca(2+) -activated K+ channels and voltage-gated K+ channels, did not affect conducted dilation to either agonist. A combination of either IbTx or TEA with 4-AP markedly improved the extent of conducted dilation to both agonists (2000MUm: >50% maximum dilation). The enhanced conducted dilation was reflected in the hyperpolarization to ACh (2000MUm: Control, 4+/-1 mV, n = 3; TEA with 4-AP, 14+/-3mV, n=4), and was dependent on the endothelium. CONCLUSIONS: These data show that activated BK(Ca) and K(V) -channels serve to reduce the effectiveness of conducted dilation. PMID- 21535297 TI - Apparently "BRCA-related" breast and ovarian cancer patient with germline TP53 mutation. AB - Germline TP53 gene mutations are associated with complex cancer predisposition syndrome, the Li--Fraumeni syndrome, and are not as rare as were previously thought. Currently, the identification of Li--Fraumeni syndrome is mostly based on a conformance to descriptive criteria, which recently were amended to include wider spectrum of malignancies. The presence of very young age-onset breast cancers in TP53 mutations families is a feature that overlaps with hereditary breast/ovarian cancer families with BRCA1/2 genes mutations. Peri-diagnostic germline TP53 testing results in breast cancer patients can significantly affect surgical and adjuvant radiotherapy choices. The aim of this case report is to emphasize the importance of peri-diagnostic germline TP53 molecular testing in patients with early-onset breast cancer and its effect on the management and outcome of the disease. We present the apparent BRCA1-related, although mutation negative, breast and ovarian cancer patient who subsequently was confirmed to be TP53 c.817C>T (p.R273C) mutation carrier and discuss the importance of peri diagnostic oncogenetic TP53 testing in early breast cancer cases. Histopathology and genetic modifiers (MDM2 SNP309G; TP53 R72P, PIN3) data are also addressed. PMID- 21535298 TI - Design and implementation of a near-miss reporting system at a large, academic pediatric anesthesia department. AB - BACKGROUND: Current incident reporting systems encourage retrospective reporting of morbidity and mortality and have low participation rates. A near miss is an event that did not cause patient harm, but had the potential to. By tracking and analyzing near misses, systems improvements can be targeted appropriately, and future errors may be prevented. METHODS: An electronic, web based, secure, anonymous reporting system for anesthesiologists was designed and instituted at The Children's Hospital, Denver. This portal was compared to an existing hospital incident reporting system. RESULTS: A total of 150 incidents were reported in the first 3 months of operation, compared to four entered in the same time period 1 year ago. CONCLUSION: An anesthesia-specific anonymous near-miss reporting system, which eases and facilitates data entry and can prospectively identify processes and practices that place patients at risk, was implemented at a large, academic, freestanding children's hospital. This resulted in a dramatic increase in reported events and provided data to target and drive quality and process improvement. PMID- 21535299 TI - Tips and tricks to facilitate ultrasound-guided placement of peripheral nerve catheters in children. AB - AIM: To describe an approach to facilitate ultrasound (US)-guided placement of peripheral nerve catheters in children. BACKGROUND: Continuous peripheral nerve blocks (CPNB) provide excellent surgical anesthesia and postoperative analgesia. However, catheters can be difficult to place, especially in children. METHODS: Ten US-guided peripheral nerve catheters were placed and placement difficulties encountered were recorded. Four series of 15 consecutive US-guided CPNB were then performed, adding in each series one possible solution to each of the troubles previously encountered. Finally, all maneuvers were employed in the placement of 15 US-guided CPNB in children 3-10 years old and then followed clinically. RESULTS: Initial difficulties encountered were as follows: (i) introducing the catheter, (ii) catheter tip visualization, (iii) length of catheter to be introduced, and (iv) catheter fixation and appropriate long-lasting dressing. The proposed facilitating procedure that addresses each of these difficulties is as follows: (i) three-hand technique: an assistant's hand holds the US transducer, the proceduralist anesthetist slightly withdraws and rotates the needle tip with one hand and advances the catheter with the other, (ii) needle visualization in long axis (LAX) whenever possible with catheter placed inside the needle and US guidance of spread of local anesthetic (LA) through the catheter, (iii) catheter advanced until resistance is found or up to a maximum of 5 cm, and (iv) subcutaneous tunneling of the catheter, Dermabond glue, and careful transparent dressing. All catheters in the last series were 100% effective during surgery and provided complete analgesia for >=3 days without complications. CONCLUSIONS: Continuous peripheral nerve blocks in children should be placed under US guidance in LAX whenever possible, with a three-hand technique and slightly withdrawing or rotating the needle tip to introduce the catheter, administering LA through the catheter, and performing subcutaneous tunneling and careful dressing. PMID- 21535300 TI - Minimum alveolar concentrations of sevoflurane for maintaining bispectral index below 50 in children. AB - OBJECTIVE: To determine minimum alveolar concentration (MAC) of sevoflurane for maintaining bispectral index (BIS) below 50 (MAC(BIS50) ) in children. BACKGROUND: MAC(BIS50) of sevoflurane in adults was reported to be 0.97%, which has not been elucidated in children. METHODS/MATERIALS: Twenty children, American Society of Anesthesiologists physical status I or II, aged 1-8, were induced and anesthetized with sevoflurane in oxygen. After tracheal intubation, we started maintenance of anesthesia with endtidal sevoflurane concentrations of 2.6%. The endtidal sevoflurane concentration at which BIS was measured was predetermined by the up-down method (with 0.2% as a step size). After 10 min at predetermined endtidal sevoflurane concentrations, BIS was measured for 1 min. MAC(BIS50) was determined using Dixon's up-down method and probit test. RESULT: MAC(BIS50) of sevoflurane was 2.83% (95% confidence intervals: 2.70-3.14) in children. CONCLUSIONS: MAC(BIS50) of sevoflurane in children was calculated to be three times as high as in adults. This indicates that high endtidal sevoflurane concentration is required to suppress electroencephalogram activity in children. PMID- 21535301 TI - Postoperative adverse respiratory events in preschool patients with inhaled foreign bodies: an analysis of 505 cases. AB - OBJECTIVES: To identify the risk factors associated with postoperative adverse respiratory events in preschool-aged children with inhaled foreign bodies (FBs) undergoing rigid bronchoscopy. BACKGROUND: Foreign bodies aspiration is the most common cause of admission in pediatric emergency in otolaryngology service. Performance of rigid bronchoscopy is the standard treatment for removal of FBs in children. In some cases, severe respiratory events (complete laryngospasm and pneumothorax) may cause anesthesia-related morbidity and mortality. However, the association between patient-related factors and postoperative complications in preschool-aged children with inhaled FBs undergoing rigid bronchoscopy is unclear. METHODS: We carried out a large prospective, single-institution review of anesthesia for 505 American Society of Anesthesiologists I-III preschool children aged <=7 with inhaled FBs undergoing rigid bronchoscopy. Patients with postoperative adverse respiratory events were classified into two groups: the minor events group [hemorrhage, minor desaturation, and partial laryngospasm (wheezing, stridor, and dyspnea)) and the major events group (complete laryngospasm, including major desaturation, and pneumothorax). RESULTS: The incidence of postoperative adverse respiratory events was 9.5% in preschool-aged children with inhaled FBs undergoing rigid bronchoscopy. Preoperative respiratory impairment was associated with an increased risk for the complicate (P < 0.01). Pneumothorax occurred in 4 (0.8%) patients. There was 1 (0.2%) death from severe respiratory-related complications. CONCLUSIONS: Preoperative respiratory impairment may develop the patients with FBs into postoperative adverse respiratory events. PMID- 21535302 TI - Primary ovarian twin pregnancy with one fetus progressing to term: case report and review of literature. AB - A case of primary ovarian twin pregnancy is presented. A 30-year-old woman, gravida 3 para 2, was admitted to Medical College Hospital, Jabalpur, for postdated pregnancy with intrauterine fetal demise. Ultrasonography showed a break in the continuity of the uterus suggestive of a ruptured uterus. On laparotomy, twin ovarian pregnancy was discovered. One fetus was postdated, showing signs of maceration. The bones of the other fetus were discovered in the sac, suggestive of an autolysed fetus of approximately 26 to 28 weeks of gestation. PMID- 21535303 TI - Descriptive study of blood transfusion practices in women undergoing cesarean delivery. AB - AIM: To study the blood transfusion practices in women undergoing cesarean delivery at a tertiary care centre in northern India. METHODS: This was a prospective study conducted in 1769 women who underwent cesarean section at a tertiary centre hospital from May 2008 to November 2009. A comprehensive predesigned proforma was filled in for each woman. Data related to antenatal, intrapartum and postnatal events was recorded and compared between women receiving blood transfusion during cesarean section and women not receiving blood transfusion. RESULTS: The cesarean section rate was 26% and the blood transfusion rate was 12.21%. The overall crossmatch transfusion ratio in our study was 5.46:1. After multiple regression logistic analysis factors, like placenta previa (OR 15.19, 95% CI 9.28-24.82), anemia (OR 9.93, 95% CI 5.17-19.06), blood loss >1000 mL (OR 5.97, 95% CI 4.32-8.24), abruptio (OR 4.18, 95% CI 2.02-8.62), intraoperative complications, like uterine incision extension, uterine atony, hysterectomy (OR 2.69, 95% CI 1.70-4.24), general anesthesia (2.48, 95% CI 1.70 3.61) and inadequate antenatal supervision (OR 1.59, 95% CI 1.05-2.42) were found to be significantly associated with a higher risk for blood transfusion during cesarean section. CONCLUSION: Routine crossmatching of blood for all women prior to cesarean section needs to be reviewed. Cesarean sections performed on women with high risk factors for blood transfusion can have sudden and significant blood loss and thus adequate blood arrangement prior to cesarean section is justified only in this group of women and not in all women. PMID- 21535304 TI - Maternal mental disorders and pregnancy outcomes: a clinical study in a Japanese population. AB - AIM: To assess the maternal and neonatal outcomes of pregnant women with mental disorders in Japan. MATERIAL AND METHODS: We conducted this retrospective cohort study to examine the patients who delivered at Nagoya University Hospital (2005 2009). Thereafter, the patients without any complications other than mental disorders and with several sources of psychiatric information were included in the present series, and the maternal and neonatal outcomes between patients with or without maternal mental disorders were compared. The psychiatric outcomes and the adverse effects of psychotropic drugs were also examined. RESULTS: A total of 1649 women delivered during this period, and 63 of them were complicated by maternal mental disorders. After the selection of patients for comparison purposes, women with mental disorders (n = 51) had a slightly but significantly shorter gestational age (39.2 +/- 0.2 vs 39.8 +/- 0.1 weeks, P = 0.003) and smaller birth weight (2993.0 +/- 56.7 vs 3152.4 +/- 23.6 g, P = 0.010) compared with the control group (n = 278). Intervention by psychiatrists was required for only 10 patients, and no patients required termination of pregnancy due to exacerbation of mental disorders. In schizophrenia patients who were taking atypical antipsychotics and benzodiazepine, a significant increase in maternal gestational weight gain, and a significant shorter gestational age were detected, respectively, compared with patients who were not receiving any drug treatments. CONCLUSION: A trend towards a lower birth weight and shorter gestational age was observed in Japanese women with well-controlled mental disorders, but the effect of well-controlled mental disorders on the perinatal outcome was minimal. PMID- 21535305 TI - Placental and maternal serum inhibin A in patients with preeclampsia and small for-gestational-age. AB - AIM: The purpose of this study was to determine the levels of inhibin A simultaneously in the maternal serum and placental extract in preeclampsia (PE) with or without small-for-gestational-age (SGA) and normal controls at term, and to evaluate the relationship among changes in serum and placental inhibin A according to the severity of PE and PE with or without SGA. MATERIAL AND METHODS: This study involved 40 pregnant women; normal (n = 20), and PE (n = 20), the latter of who were classified into (i) mild (n = 10) and severe PE (n = 10); (ii) PE with SGA (n = 7) and without SGA (n = 13). Inhibin A concentrations were quantified by enzyme-linked immunosorbent assay (ELISA) in the maternal serum and placental extract. Inhibin-alpha subunit in the placenta was stained by immunohistochemistry (IHC), and its intensity was graded by a semiquantitative scoring method. RESULTS: There was a positive correlation in inhibin A concentrations between the serum and placental extract (r = 0.57, P < 0.001). Both maternal serum and placental inhibin A in PE groups were significantly higher than in controls, but there was no severity-dependent increase of inhibin A when compared with mild and severe PE. There was no difference in inhibin A levels between PE with and without SGA. Moreover, the inhibin-alpha subunit was predominantly abundant in the cytoplasm of the syncytiotrophoblasts, where the PE groups showed higher staining intensity than the controls (P < 0.000). CONCLUSION: Serum inhibin A level might be a useful biomarker for diagnosis and monitoring of PE. PMID- 21535306 TI - Transvaginal cervicoisthmic cerclage using a polypropylene sling: pregnancy outcome. AB - AIM: To report pregnancy outcome following prophylactic transvaginal cervicoisthmic cerclage using a polypropylene sling in a population of high-risk pregnant women. MATERIALS AND METHODS: A retrospective study with a continuous series of 57 women presenting with prior failure of McDonald cerclage (n = 47) and/or absent portio-vaginalis of the cervix (n = 10). RESULTS: Cervicoisthmic cerclage was performed between 12 and 16 weeks of gestation (median 14 weeks' gestation). No intraoperative complication occurred. Preterm labor treated with parenteral tocolysis occurred in 14 women (24%). Cesarean delivery was systematically performed. Median gestational age at delivery was 37.2 weeks' gestation (interquartile range: 36.5-38.0). Overall neonatal survival rate was 94%. CONCLUSION: Transvaginal cervicoisthmic cerclage using a polypropylene sling may be considered as an effective alternative to the transabdominal cervicoisthmic cerclage in women presenting with previous cerclage failure. PMID- 21535307 TI - Vesicovaginal fistula following large-loop excision of the transformation zone in a chronic systemic glucocorticoid user. AB - A 42-year-old woman with a history of a large-loop excision of transformation zone for cervical intraepithelial neoplasia III four years previously visited our outpatient department for cervical intraepithelial neoplasia I that newly detected by colposcopy-directed punch biopsy. Her other medical conditions include systemic lupus erythematosus on daily prednisolone 15 mg during 19 years. After second large-loop excision of transformation zone, delayed vesicovaginal fistula was confirmed by indigo carmine leakage test, computed tomography scan, and cystoscopy. Fistula was primarily repaired with indwelling double-J catheters with anchoring omentum on suture site. PMID- 21535308 TI - Prevalence and risk of metabolic syndrome in adolescent Indian girls with polycystic ovary syndrome using the 2009 'joint interim criteria'. AB - AIM: Our objective was to study the prevalence and risk of metabolic syndrome (MS) among adolescent Indian girls with polycystic ovary syndrome (PCOS), compared to those without, as per the recent 'joint interim statement' criteria. We also aimed to compare the selected study parameters across PCOS adolescents with and without MS. MATERIAL & METHODS: Cross-sectional data of 96 adolescent girls were retrospectively analyzed applying the 2009 'joint interim criteria' for MS. Fifty-one of them were diagnosed with PCOS as per the Androgen excess society criteria 2006. The remaining 45 adolescent girls (no androgen excess manifestations and regular cycles) formed the comparison group. RESULTS: The prevalence of MS among adolescents with PCOS (60.78%; 95% CI = 50.78%, 70.78%) was significantly more compared to those without (P = 0.002). The odds ratio of MS among PCOS adolescents was 4.26 (95% CI = 1.79, 10.15). Only the mean waist circumference differed significantly between the PCOS and non-PCOS groups (P = 0.046). Interestingly, the contrast between the MS and non-MS subgroups of the PCOS adolescent sample produced significant differences in body mass index, waist circumference, blood pressure and biochemical parameters such as fasting plasma glucose, high-density lipoprotein-cholesterol and triglyceride levels. CONCLUSION: Adolescent Indian girls with PCOS were reported to have 4.26 times more chances of developing MS compared to those without. Waist circumference was found to be the cheapest and simplest significant marker of MS. The study underlines the need for routine screening of MS among adolescent girls suffering from PCOS to reduce future co-morbidities. PMID- 21535309 TI - Contralateral ovarian pregnancy after single tubal recanalisation. AB - Ovarian pregnancy accounts for less than 3% of all ectopic pregnancies. A 30-year old who had undergone right tubal reanastomosis seven months prior presented with pain abdomen and spotting. Her last menstrual period was 30 days prior. Examination revealed stable vitals, tenderness and shifting dullness per abdomen, fullness in the pouch of Douglas, a tender left adnexal mass and normal size uterus. Urine pregnancy test was positive. Culdocentesis revealed blood. A heteroechoic 3 * 3.2 * 3.1 cm left adnexal mass and free fluid were detected on ultrasound. There was no intrauterine gestational sac. On laparotomy 800 mL of hemoperitoneum was present. There was no evidence of tubal pregnancy. Left ovary had a 3 * 5 cm hemorrhagic mass. Partial ovariectomy was done and histopathology revealed ovarian pregnancy. This is the first reported case of an ovarian pregnancy occurring after tubal recanalisation. After successful tubal recanalisation procedure, altered motility of the reconstructed tube may cause expulsion of fertilized ovum into the peritoneal cavity and contralateral ovarian implantation. PMID- 21535310 TI - Severity of chorioamnionitis and neonatal outcome. AB - AIM: The aim of this study is to elucidate whether the stage of chorioamnionitis is or is not associated with the development of neonatal diseases. MATERIAL & METHODS: We reviewed the neonatal intensive care unit discharge files and placental pathology reports of 302 preterm infants. The presence of various stages of chorioamnionitis as well as absence of an association with chorioamnionitis (non-chorioamnionitis) were compared among neonatal diseases. RESULTS: Preterm infants were grouped according to three stages of chorioamnionitis or the absence of an association with chorioamnionitis. Gestational age differed significantly between these groups. Before controlling for gestational age, the chorioamnionitis stage was significantly higher among infants with chronic lung disease, retinopathy of prematurity and intraventricular hemorrhage than in infants without these diseases. On the other hand, the chorioamnionitis stage was lower in infants with respiratory distress syndrome than without. After controlling for gestational age, the stage of chorioamnionitis was significantly lower in infants with respiratory distress syndrome than in infants without respiratory distress syndrome, whereas, significant differences were not detected between the presence and absence of chronic lung disease, retinopathy of prematurity and intraventricular hemorrhage. Furthermore, gestational age was a significant risk factor for chronic lung disease, respiratory distress syndrome, retinopathy of prematurity and intraventricular hemorrhage. CONCLUSIONS: We found no significant differences in stages of chorioamnionitis between infants with and without neonatal diseases except for respiratory distress syndrome. A significant inverse relationship was observed between the stage of chorioamnionitis and development of respiratory distress syndrome. PMID- 21535311 TI - Distribution of human papillomavirus type 16 E6 and E7 gene variants in the progression of cervical dysplasia in Korean women. AB - AIM: This cross-sectional, hospital-based study examined the distribution of human papillomavirus 16 E6 and E7 gene variants in Korean women with cervical lesions of varying degrees. MATERIAL & METHODS: One hundred and forty-one Korean women (median age 43 years; range 22-65 years) with human papillomavirus 16 single infections were included. The human papillomavirus 16 E6/E7 sequences were amplified from cytology specimens. The distribution of human papillomavirus 16 variations with respect to cervical lesion was examined by the exact Mantel Haenszel linear trend test (P(trend) ) and Fisher's exact test (P). RESULTS: Human papillomavirus 16 E6 and E7 gene variants were identified in a total of 100 women (70.9%). The most prevalent human papillomavirus 16 variants were E6 Thymine178Guanine (number = 70, 49.6%) and E7 Adenine647Guanine (number = 75, 53.2%). Human papillomavirus 16 E6 Thymine178Guanine and E7 Adenine647Guanine were significantly related to the degree of cervical neoplasia (P(trend) = 0.0002, P< 0.0001; P(trend) < 0.0001, P < 0.0001, respectively). The odds ratio of human papillomavirus 16 E6 Thymine178Guanine to predict progression to cervical intraepithelial neoplasia 2-3 and invasive cancer was 2.37 (95% confidence interval 1.03-5.45) and 9.07 (95% confidence interval 2.86-28.72), respectively. The odds ratio of E7 Adenine647Guanine to predict progression to cervical intraepithelial neoplasia 2-3 and invasive cancer was 3.65 (95% confidence interval 1.16-8.51) and 9.07 (95% confidence interval 2.86-28.72), respectively. CONCLUSION: The distribution of HPV variants appears to be related to geographic difference. Human papillomavirus 16 E6 Thymine178Guanine and E7 Adenine647Guanine can be used as the candidate marker for the progression of the cervical neoplasia. PMID- 21535312 TI - Fetal nuchal translucency thickness in different cut-off points for aneuploidy screening in the south of Vietnam. AB - AIMS: The purpose of this study was to define the most suitable cut-off point for fetal nuchal translucency thickness in a screening program for aneuploidy and trisomy 21 in the south of Vietnam. MATERIAL & METHODS: Two thousand and five hundred cases of singleton pregnancies were followed prospectively from the first trimester to the delivery. The rate of aneuploidy was calculated by seeking a relationship to increased fetal nuchal translucency thickness then calculating the sensitivity and specificity of different cut-off points in thickness measurement to find the most suitable point for screening. RESULTS: The prevalence of fetal abnormality was 1.5% (95% CI 1.1-2.1), and 1.2% (95% CI 0.8 1.7) of aneuploidy cases found and the commonest was trisomy 21. A cut-off point at 2.4 mm showed the highest level of sensitivity and specificity for the detection of aneuploidy (65.5 and 95.7%) and trisomy 21 (75.0 and 95.1%), with a false-positive rate of 4.3 and 4.9%, respectively. CONCLUSION: Using a cut-off point of nuchal translucency at 2.4 mm has potential for aneuploidy and trisomy 21 screening in the south of Vietnam. PMID- 21535313 TI - Posterior placenta percreta: blood supply and possibility of recurrence. PMID- 21535314 TI - How to confirm reactive oxygen species-induced pre-eclampsia. PMID- 21535316 TI - MRG-binding protein contributes to colorectal cancer development. AB - MRGBP (MORF4-related gene-binding protein; also known as chromosome 20 open reading frame 20) encodes a subunit of the transformation/transcription domain associated protein (TRRAP)/tat-interacting protein 60 (TIP60)-containing histone acetyltransferase complex. We previously showed that MRGBP was upregulated in the majority of colorectal tumors, and the enhanced expression was associated with cell proliferation. In this study, we investigated its role in colorectal carcinogenesis and searched for genes regulated by MRGBP. Immunohistochemical staining of 22 adenomas and 47 carcinomas in the colon and rectum showed that high levels of MRGBP expression were observed more frequently in carcinomas (45%) than adenomas (5%), linking its role to malignant properties of colorectal tumors. No clinicopathological factors were associated with the levels MRGBP expression in colorectal cancer. Copy number analysis revealed that gene amplification is involved in the elevated expression. A genome-wide expression analysis identified a total of 41 genes upregulated by MRGBP. These genes were implicated in biological processes, including DNA replication, minichromosome maintenance, and cell division. Theses results suggest that MRGBP contributes to colorectal carcinogenesis through rendering advantages in cell proliferation and/or division of cancer cells. Our findings might be helpful for the identification of a specific biomarker for colorectal cancer and the development of diagnostic and/or therapeutic approaches. PMID- 21535317 TI - Coexpression of aPKClambda/iota and IL-6 in prostate cancer tissue correlates with biochemical recurrence. AB - Atypical protein kinase C lambda/iota (aPKClambda/iota) and interleukin-6 (IL-6) have been implicated in prostate cancer progression, the mechanisms of which have been demonstrated both in vitro and in vivo. However, the clinical significance of the correlation between the expressions of these factors remains to be clarified. In the present study, we report a significant correlation between aPKClambda/iota and IL-6 proteins in prostate cancer tissue by immunohistochemical staining. We evaluated the association of both proteins by analyzing clinicopathological parameters using chi-square test, Kaplan-Meier with log-rank test, and a Cox proportional hazard regression model in univariate and multivariate analyses. The results again showed that the expression of aPKClambda/iota and IL-6 correlates in prostate cancer tissue (P < 0.001). Atypical protein kinase C lambda/iota was also found to correlate with the Gleason score (P < 0.001) and with biochemical recurrence after prostatectomy (P = 0.02). Furthermore, aPKClambda/iota correlated with biochemical recurrence in a Kaplan-Meier and log-rank test (P = 0.01) and Cox analysis (P = 0.02 in the univariate analysis, P = 0.02 in the multivariate analysis). The coexpression of aPKClambda/iota and IL-6 also correlated with biochemical recurrence by Kaplan Meier and log-rank test (P = 0.005) and Cox analysis (P = 0.01 in the univariate analysis, P = 0.03 in the multivariate analysis). These results indicate a strong correlation between aPKClambda/iota and IL-6 in prostate tumors, and that the aPKClambda/iota-IL-6 axis is a reliable prognostic factor for the biochemical recurrence of this cancer. PMID- 21535318 TI - Pivotal role of epithelial cell adhesion molecule in the survival of lung cancer cells. AB - Epithelial cell adhesion molecule (EpCAM) is overexpressed in a wide variety of human cancers including lung cancer, and its contribution to increased proliferation through upregulation of cell cycle accelerators such as cyclins A and E has been well established in breast and gastric cancers. Nevertheless, very little is known about its role in supporting the survival of cancer cells. In addition, the functional role of EpCAM in the pathogenesis of lung cancer remains to be explored. In this study, we show that RNAi-mediated knockdown of EpCAM suppresses proliferation and clonogenic growth of three EpCAM-expressing lung cancer cell lines (H3255, H358, and HCC827), but does not induce cell cycle arrest in any of these. In addition, EpCAM knockdown inhibits invasion in the highly invasive H358 but not in less invasive H3255 cells in a Transwell assay. Of note, the EpCAM knockdown induces massive apoptosis in the three cell lines as well as in another EpCAM-expressing lung cancer cell line, HCC2279, but to a much lesser extent in a cdk4/hTERT immortalized normal human bronchial epithelial cell line, HBEC4, suggesting that EpCAM could be a therapeutic target for lung cancer. Finally, EpCAM knockdown partially restores contact inhibition in HCC827, in association with p27(Kip1) upregulation. These results indicate that EpCAM could contribute substantially to the pathogenesis of lung cancer, especially cancer cell survival, and suggest that EpCAM targeted therapy for lung cancer may have potential. PMID- 21535319 TI - Increasing body weight enhances prevalence and proximal extent of reflux in GERD patients 'on' and 'off' PPI therapy. AB - BACKGROUND: Increased body weight is associated with higher intragastric pressure. Proximal extent of reflux is a determinant of symptoms in patients with gastro-esophageal reflux disease (GERD). We aimed to investigate the association between body mass index (BMI) and abdominal circumference on the incidence and proximal extent of reflux. METHODS: A total of 95 patients [37 men, age 51(16-82) years] with typical and/or atypical GERD symptoms underwent 24 h impedance-pH monitoring. Forty-nine patients were studied 'off' and 46 'on' proton pump inhibitors (PPI) treatment. Reflux was classified as acid (pH < 4) or weakly acidic (pH 4-7). Proximal extent was defined as the number of reflux events reaching >=15 cm above the lower esophageal sphincter. Body mass index and abdominal circumference (cm) were assessed. KEY RESULTS: In patients 'off' PPI, there was a correlation between BMI and esophageal acid exposure (rho = 0.53, P < 0.001), volume exposure (rho = 0.48, P < 0.001), total number of reflux events (rho = 0.47, P < 0.001) and number of acid reflux events (rho = 0.49, P < 0.001). In patients 'on' PPI there was a correlation between BMI and esophageal acid exposure (rho = 0.32, P = 0.03), volume exposure (rho = 0.46, P < 0.01) and total number of reflux events (rho = 0.33, P = 0.03). Similar correlations were found between abdominal circumference and reflux. A correlation between BMI and proximal extent of reflux was present in patients 'off' PPI (rho = 0.32, P = 0.03). In patients 'on' PPI, we found a correlation between abdominal circumference and proximal extent (rho = 0.31, P = 0.03). CONCLUSIONS & INFERENCES: Body mass index and abdominal circumference may contribute to GER and its proximal extent, in patients 'on and 'off' PPI. Further studies investigating the role of weight reduction in the control of GERD symptoms are warranted. PMID- 21535320 TI - von Willebrand factor/factor VIII concentrate (Humate-P) for management of elective surgery in adults and children with von Willebrand disease. AB - von Willebrand disease (VWD) is the most common inherited bleeding disorder. Treatment guidelines recommend the use of von Willebrand factor/factor VIII (VWF/FVIII) concentrate for VWD patients with type 2 or 3 VWD undergoing surgery, and type 1 patients undergoing surgery who are unresponsive, or for whom desmopressin acetate is contraindicated. This prospective, open-label, multinational study evaluated the safety, efficacy and optimal dosing of a VWF/FVIII concentrate (Humate-P) in subjects with VWD undergoing elective surgery. Dosing was based on VWF ristocetin cofactor (VWF:RCo) and FVIII pharmacokinetic assessments performed before surgery. Pharmacokinetic assessments were completed in 33 adults and 9 children. Haemostatic efficacy was assessed on a 4-point scale (excellent, good, moderate/poor or none). Overall effective haemostasis was achieved in 32/35 subjects. Median terminal VWF:RCo half-life was 11.7 h, and median incremental in vivo recovery was 2.4 IU dL(-1) per IU kg(-1) infused. Major haemorrhage occurred after surgery in 3/35 cases despite achieving target VWF and FVIII levels. Median VWF/FVIII concentrate loading doses ranged from 42.6 IU VWF:RCo kg(-1) (oral surgery) to 61.2 IU VWF:RCo kg(-1) (major surgery), with a median of 10 (range, 2-55) doses administered per subject. Adverse events considered possibly treatment-related (n = 6) were generally mild and of short duration. The results indicate that this VWF/FVIII concentrate is safe and effective in the prevention of excessive bleeding during and after surgery in individuals with VWD. PMID- 21535321 TI - Scuba diving is possible and safe for patients with haemophilia. AB - For a long time, physical activities have been contraindicated in haemophiliacs or were restricted to few activities. Sports are nowadays advocated for haemophiliacs. Although various lists of physical activities have been proposed, scuba diving is never mentioned. Thus, with a group of haemophilic volunteers, a study was launched on whether, with strict medical follow-up, scuba diving could be allowed for patients with haemophilia. All the participants followed a training program including theory and assessment. In 6 years, a total of 517 dives were performed by 20 patients with congenital bleeding disorders. Nine were under prophylaxis for haemophilia, and nine received on-demand treatment. Two patients had type I von Willebrand's disease. Among the 20 patients, 12 made 12 153 dives, whereas six made eight dives each. No incident was noted during or after the dives. Thus, scuba diving can be authorized for PWH, if they have none of the specific medical contraindications for diving and if they have received medical training allowing them to manage their disease themselves. PMID- 21535322 TI - Liver stiffness measurements to assess progression of fibrosis in HCV-infected patients with inherited bleeding disorders. AB - Hepatitis C is a major co-morbidity in patients with inherited bleeding disorders, leading to progressive liver fibrosis and eventually cirrhosis. Liver stiffness measurement (LSM) is a non-invasive way of assessing the extent of liver fibrosis. This article describes our experience with serial LSM to assess prospectively progression of fibrosis in a cohort of patients with inherited bleeding disorders and chronic hepatitis C. A total of 84 patients underwent serial LSMs, with a median interval of 3.7 years. The change in LSM results over time was assessed. Overall, there was no significant difference between the median results of LSM 1 and LSM 2. The median result of LSM 2 was low (6.6 kPa), after a median duration of infection of 37 years. On the individual level, deterioration of LSM results of more than 2 kPa was seen in 13 patients (16%), 44 patients (52%) remained stable and 27 patients (32%) showed improvement of LSM results of more than 2 kPa. These results are comparable with those of paired liver biopsy studies. LSM appears to be a good alternative for liver biopsies in patients with hepatitis C and inherited bleeding disorders, although the interpretation of the unexpected improvement we found in some of our patients is not straightforward. LSMs will be repeated in our patient population in a few years to be able to better assess the value of serial LSM. PMID- 21535323 TI - Impact of lifestyle modification on symptomatic coronary artery disease in a haemophilia patient with inhibitors. PMID- 21535324 TI - Aspects of current management: orthopaedic surgery in haemophilia. AB - If continuous prophylaxis is not feasible due to expense or lack of venous access, we must aggressively treat major haemarthroses (including arthrocentesis) to prevent progression to synovitis, recurrent joint bleeds, and ultimately end stage osteoarthritis (haemophilic arthropathy). For the treatment of chronic haemophilic synovitis, radiosynovectomy should always be indicated as the first procedure. If, after three procedures with 6-month interval, radiosynovectomy fails, an arthroscopic synovectomy must be indicated. Between the second and fourth decades, many haemophilic patients develop joint destruction (arthropathy). At this stage possible treatments include alignment osteotomy, arthroscopic joint debridement, arthrodesis (joint fusion) and total joint arthroplasty. For the hip press-fit uncemented components (hemispherical acetabulum, flanged femoral stem, metal-to-polyethylene) are recommended whilst for the knee a posterior-stabilized (PS) cemented design is advised. Muscular problems must not be underestimated in haemophilia due to their risk of developing compartment syndromes (which will require surgical decompression) and pseudotumours (which will require surgical removal or percutaneous treatment). Regarding patients with inhibitors, the advent of APCCs and rFVIIa has made major orthopaedic surgery possible, leading to an improved quality of life for haemophilia patients. Concerning local fibrin seal, it is not always necessary to achieve haemostasis in all surgical procedures performed in persons with haemophilia. However, it could be a good adjunct therapy, mainly when a surgical field potentially will bleed more than expected (i.e. patients with inhibitors), and also in some orthopaedic procedures (mainly the surgical removal of pseudotumours). PMID- 21535325 TI - What patient, joint and isotope characteristics influence the response to radiosynovectomy in patients with haemophilia? AB - The literature describes radiosynovectomy (RS) as a good non-surgical option for reducing synovial membrane size and thus the number of haemarthrosis episodes. However, there are still many aspects concerning the beneficial effects of RS that have not been quantified. A total of 156 radiosynovectomies (RS) were performed in 104 joints corresponding to 78 haemophiliacs (yttrium-90, rhenium 186). The mean patient age was 18 years. In another study involving the same group of patients, the parameters that improved most after RS were pain and haemarthrosis, followed by the World Federation of Hemophilia clinical score, muscle strength and range of movement (ROM). Following RS, improvement was seen to be independent of patient age, haemophilia type and grade, previous haematological treatment, the presence or absence of circulating inhibitor, synovial membrane size, the type of joint (elbow, knee and ankle), previous physical activity or lack of activity, the prior presence or absence of radiographic signs of joint degeneration (arthropathy) or the isotope used. RS is effective in treating haemophilic synovitis and may require 1-3 injections (RS-1, RS-2 and RS-3) spaced 6 months apart. Following RS-1, the knee had a 3.4- and 3.2 fold greater risk of not improving in terms of pain, compared with the elbow and ankle, respectively. Regarding ROM, lesser improvement was recorded after RS-1 in cases of severe haemophilia and the ankle. In other words, severe haemophilia implies a 2.1-fold greater risk of no improvement in ROM compared with mild and moderate haemophilia. In addition, the ankle presented a 6-fold greater risk of not improving in terms of ROM compared with the elbow and knee. RS affords effective treatment of chronic haemophilic synovitis. RS is effective in all patient groups, independently of the presence of circulating inhibitor antibody, the type of joint involved, the degree of synovial membrane hypertrophy and the presence of radiographic findings of joint degeneration (arthropathy). PMID- 21535326 TI - In-patient rehabilitation in haemophilic subjects with total knee arthroplasty. AB - Total knee arthroplasty (TKA) is a major orthopaedic surgery intervention, indicated for severe haemophilic arthropathy. The aim of our study was to analyse rehabilitation outcome in haemophilic patients after TKA. A consecutive series of 21 patients (23 knees) was retrospectively evaluated. The mean age was 37 +/- 8 years (range 22-55). Physiotherapy treatment was performed twice a day for 5 days week-1, for 3 h day-1. Assessment included knee range of motion (ROM), Visual Analogue Scale (VAS) for pain evaluation, Western Ontario and McMaster University (WOMAC) Score for functional outcome, Medical Research Council Scale (MRC) for quadriceps muscle strength evaluation, incidence of adverse events and a self reported questionnaire. The patients'data were recorded before surgery (t0), at Rehabilitation Unit admission (t1), before discharge (t2) and at follow-up (t3), 11-48 months after rehabilitation. Western Ontario and McMaster University Score (ref. score: 0-96) was 56.7 +/- 12 at t0 and 6.2 +/- 6 at t3 (t3 vs. t0: P < 0.001). Visual Analogue Scale (ref. score: 0-10) decreased from 5.0 +/- 2 at t1 to 2.1 +/- 2 at t2 (t2 vs. t1: P < 0.05) and to 0.1 +/- 0 at t3 (t3 vs. t2: P < 0.05). Flexion degrees increased from 43.4 +/- 21 degrees at t1 to 80.2 +/- 15 degrees at t2 (t2 vs. t1: P < 0.001) and to 95.0 +/- 15 degrees at t3 (t3 vs t2: P < 0.05). According to MRC (ref. score: 0-5), quadriceps muscle strength increased from 2.3 +/- 0.6 at t1 to 3.6 +/- 0.5 at t2 (t2 vs. t1: P < 0.05). Adverse events were found in four patients. Patients' satisfaction on their outcome at follow-up was referred as good by 72% of patients or excellent by 28% of patients. Postsurgical intensive rehabilitation in haemophilic patients resulted effective, safe and feasible. PMID- 21535327 TI - Clinical pharmacological study of a plasma-derived factor VIIa and factor X mixture (MC710) in haemophilia patients with inhibitors--phase I trial. AB - MC710, a combined product of plasma-derived activated factor VII (FVIIa) and factor X (FX) at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In this study, pharmacokinetic (PK), pharmacodynamic (PD) parameters and safety of single doses of MC710 were investigated in 11 male haemophilia patients with inhibitors in a non-bleeding state. This was a multi-centre, open-labelled, non-randomized, active controlled crossover, dose-escalation study of five doses (20-120 MUg kg( 1) of FVIIa) with re-administration of different MC710 dosages to the same subjects. The active controls were NovoSeven (120 MUg kg(-1)) and/or FEIBA (50 and 75 U kg(-1)) which were used to compare PD parameters. The area under the curve (AUC) and maximum plasma concentration (C(max)) of MC710 active ingredients increased dose-dependently within the range of 20 and 120 MUg kg(-1). After administration of MC710, activated partial thromboplastin time (APTT) was dose dependently improved and prothrombin time (PT) was shortened to approximately 6 s at 10 min, and APTT improvement and PT shortening effects were maintained until 12 h after administration of MC710 at all doses. No serious or severe adverse event was observed after administration of MC710; furthermore, several diagnostic marker values and those changes did not indicate any signs of disseminated intravascular coagulation (DIC). These results suggest that MC710 would have haemostatic potential equal to or greater than NovoSeven and FEIBA and was be tolerable when given at doses up to 120 MUg kg(-1). PMID- 21535328 TI - Maternal malnutrition, environmental exposure during pregnancy and the risk of non-syndromic orofacial clefts. AB - OBJECTIVE: To explore the risk factors of non-syndromic orofacial clefts. SUBJECTS AND METHODS: A case-control study was conducted in China, 537 infants born with non-syndromic cleft lip with/without cleft palate, 176 infants born with cleft palate (CP), and 221 normal controls were recruited to participate in a questionnaire based study to identify risk factors related to maternal nutrition. RESULTS: Single-factor Chi-square analysis identified 12 factors as significantly related to non-syndromic orofacial clefts (P < 0.05). Multiple logistic regression showed five of these factors were associated with non syndromic orofacial clefts, male gender and maternal passive smoking during early pregnancy were risk factors for non-syndromic orofacial clefts (OR = 1.86 and 11.42; 95% CI: 2.28-2.69 and 6.87-19.00, respectively), whereas maternal weight gain during pregnancy and folic acid supplementation during early pregnancy were protective (OR = 0.15 and 0.67; 95% CI: 0.034-0.63 and 0.44-1.00, respectively). CONCLUSIONS: Our data may provide references for cleft lip and CP prevention programs, and counseling programs in China. PMID- 21535329 TI - Potential sources of Campylobacter infection on chicken farms: contamination and control of broiler-harvesting equipment, vehicles and personnel. AB - AIMS: To test the efficacy of enhanced biosecurity measures on poultry farms for reducing environmental contamination with Campylobacter during partial depopulation of broiler flocks prior to normal slaughter age. The study has also evaluated the risk of infection from live-bird transport crates that are routinely cleaned at the slaughterhouse, but may remain contaminated. METHODS AND RESULTS: On-farm sampling and Campylobacter isolation was undertaken to compare the prevalence of contamination on vehicles, equipment and catching personnel during farm visits that took place under normal or enhanced biosecurity. Campylobacters were found in almost all types of sample examined and enhanced biosecurity reduced the prevalence. However, the additional measures failed to prevent colonisation of the flocks. For transport crates, challenge trials involved exposure of broilers to commercially cleaned crates and genotyping of any campylobacters isolated. The birds were rapidly colonised with the same genotypes as those isolated from the cleaned crates. CONCLUSIONS: The enhanced biosecurity measures were insufficient to prevent flock colonisation, and the problem was exacerbated by inadequate cleaning of transport crates at the slaughterhouse. SIGNIFICANCE AND IMPACT OF THE STUDY: Current commercial practices in the United Kingdom facilitate the spread of campylobacters among broiler chicken flocks. Prevention of flock infection appears to require more stringent biosecurity than that studied here. PMID- 21535330 TI - Design of species-specific oligonucleotide probes for the detection of Bacteroides and Parabacteroides by fluorescence in situ hybridization and their application to the analysis of mouse caecal Bacteroides-Parabacteroides microbiota. AB - AIMS: To develop species-specific monitoring techniques for rapid detection of Bacteroides and Parabacteroides inhabiting the mouse intestine by fluorescence in situ hybridization. METHODS AND RESULTS: The specificity of oligonucleotide probes was evaluated by fluorescence whole-cell hybridization. Oligonucleotide probes specific for each species hybridized only with the target bacteria. Using these probes, caecal Bacteroides-Parabacteroides microbiota of conventional mice and specific pathogen-free (SPF) mice from three different breeders were analysed. It was shown that Bacteroides acidifaciens Group-1, Group-2 and Group-3 were dominant in conventional mice and SPF mice from two out of three breeders. Bacteroides vulgatus and Parabacteroides distasonis were detected in one of these two SPF breeding colonies in addition to Bact. acidifaciens. SPF mice of the remaining breeder harboured characteristic Bacteroides-Parabacteroides microbiota, consisting of Bacteroides sp. ASF519 and Bacteroides caccae. CONCLUSIONS: Bacteroides acidifaciens is the dominant and most typical species in the mouse Bacteroides-Parabacteroides microbiota. The Group-3 was identified as a novel group and revealed to occupy a major niche together with Bact. acidifaciens Group-1 and Group-2. SIGNIFICANCE AND IMPACT OF THE STUDY: The species-specific probe set developed in this study was the efficient tool for rapid detection of target bacterial groups inhabiting the mouse intestine. The results of this study provide important new information on the mouse Bacteroides-Parabacteroides community. PMID- 21535331 TI - Human heat-shock protein 60 receptor-coated paramagnetic beads show improved capture of Listeria monocytogenes in the presence of other Listeria in food. AB - AIMS: To investigate the suitability of human Hsp60, a receptor for Listeria adhesion protein (LAP), on paramagnetic beads (PMB) to capture Listeria monocytogenes from food in the presence of other Listeria to facilitate rapid and specific detection of this pathogen. METHODS AND RESULTS: Commercially available streptavidin-coated PMBs were linked with biotinylated Hsp60 (PMB-Hsp60), and the bacterial capture efficiency from pure culture and meat samples was determined. Capture rate was also compared with the monoclonal antibody (MAb)-C11E9-coated beads (PMB-C11E9) and the commercial Dynabeads anti-Listeria. Captured cells were detected and quantified by plating on selective medium, quantitative real-time PCR (qPCR) and a light-scattering sensor. Overall, all ligand-coated beads had similar capture efficiency (varied from 1.8 to 9.2%) for L. monocytogenes under the conditions employed, and the minimum cell number required to achieve such capture was 103 CFU ml-1. PMB-Hsp60 had significantly greater capture efficiency for pathogenic Listeria (P < 0.0001) than the nonpathogenic Listeria. In contrast, PMB-C11E9 and Dynabeads anti-Listeria had similar capture efficiency for both. The efficacy of all PMBs to capture L. monocytogenes in the presence of Listeria innocua from food matrices was compared. Although Dynabeads anti Listeria had the overall best capture efficiency, PMB-Hsp60 was able to selectively capture L. monocytogenes even in the presence of 10-100-fold more L. innocua cells from enriched meat samples. CONCLUSIONS: Data show that the human cell receptor, Hsp60, is suitable for the capture of pathogenic Listeria on PMB in the presence of other Listeria in food. SIGNIFICANCE AND IMPACT OF THE STUDY: As pathogen interaction with host cells is highly specific, host cell receptors could be used as alternate capture molecules on PMB to aid in specific detection of pathogens. PMID- 21535332 TI - Genetic diversity of Lactobacillus paracasei isolated from in situ human oral biofilms. AB - AIM: To determine the genetic diversity and possible origin of Lactobacillus paracasei found in the oral biofilm. METHODS AND RESULTS: Lactobacilli were isolated from a biofilm model, formed in situ prior to and during a period of exposure to 20% sucrose solution (28 days), using Rogosa Agar. The lactobacillus colonies were randomly selected (n = 222) and subcultured. The isolates were identified using pheS or rpoA gene sequence analysis. Lactobacilli identified as Lact. paracasei (n = 75) were subjected to multilocus sequencing typing (MLST) analysis by determining partial sequences of seven housekeeping genes fusA, ileS, lepA, leuS, pyrG, recA and recG. An increase recovery of lactobacilli after sucrose phase compared with nonsucrose period was observed (31 prior to and 191 following a sucrose exposure period). Seven subjects harboured Lact. paracasei and these represented 14 sequence types (ST). Comparison of the STs showed that unrelated subjects may harbour the same ST and that individuals harbour multiple STs. Three subjects harboured STs previously isolated from dairy products. CONCLUSION: The present data supports the hypothesis that oral lactobacilli may be of exogenous origin. SIGNIFICANCE AND IMPACT OF THE STUDY: The study allow us to gain insight into the genetic diversity of Lact. paracasei in oral biofilm. PMID- 21535333 TI - Detection of adeno- and lentiviral (HIV1) contaminations on laboratory surfaces as a tool for the surveillance of biosafety standards. AB - AIMS: As a biosafety laboratory, we survey the handling of adenovirus type 5 (Ad5) and HIV1-derived lentivirus in contained-use facilities in Switzerland to identify insufficiencies of the safety precautions taken by the laboratories. METHODS AND RESULTS: In the past 9 years, we took 430 swab samples from various types of surfaces in research laboratories. Samples were examined for Ad5 contaminations by real-time PCR and infectivity assay or for the presence of lentivirus (HIV1) nucleic acids by real-time (RT) PCR. Samples collected from centrifuges did not only contain Ad5 DNA more frequently but also exhibited higher numbers of Ad5 and lentiviral (HIV1) DNA copies than swabs from any other area of sampling. Five of ten samples containing infectious Ad5 particles or lentivirus (HIV1) RNA were found in samples taken from centrifuges. Ad5 contamination rates were higher in the tube holder and lower on the inner wall of the rotor chamber in centrifuges that were fitted with aerosol tight covers compared to centrifuges without covers. CONCLUSIONS: Our results allowed the comparison of hygiene standards of different laboratories and lead to the identification of centrifuges as hotspots for contaminations. SIGNIFICANCE AND IMPACT OF THE STUDY: Based on our results, we propose to use the collected data as a tool for rating future swab results. Furthermore, the amount of Ad5 and HIV1 derived lentivirus DNA could serve as an indicator of the level of good laboratory practice in contained-use laboratories handling these viral vectors. PMID- 21535334 TI - Recombinant soluble form of heparin-binding epidermal growth factor-like growth factor protein therapy drastically inhibits Fas-mediated fulminant hepatic failure: Implications in clinical application. PMID- 21535335 TI - Two SCID cases with Cernunnos-XLF deficiency successfully treated by hematopoietic stem cell transplantation. AB - SCID affects T and B cell differentiation and functions, presenting with severe opportunistic infections in the early postnatal period. It is fatal unless stem cell transplantation is performed. RS SCID forms are caused by defects in the NHEJ pathway, the enzymatic process required for the repair of DNA double-strand breaks. Cernunnos-XLF defect is one of the defects in this pathway. Here, we present two patients with Cernunnos-XLF defect, both having microcephaly, prominent growth retardation, and T-B-NK+SCID, one of whom had AHA. These patients received hematopoietic stem cells from HLA identical related donor without conditioning regimen and recovered without any complication. Now, both of the patients are well and alive seven and one yr after transplantation, respectively. A remarkable observation was the severe diarrhea that occurred in both patients soon after transplantation. PMID- 21535336 TI - Epidemiology and risk factors for late infection in solid organ transplant recipients. AB - BACKGROUND: Information concerning the risk factors and outcome of late infection (LI) after solid organ transplantation (SOT) still remains scarce. METHODS: We prospectively analyzed all patients undergoing SOT from July 2003 to March 2008, who survived the first 6 months after surgery and with a minimum 1-year follow up. Risk factors associated with the development of bacterial and cytomegalovirus (CMV) LI and survival were identified. RESULTS: Overall, 942 SOT recipients (491 kidney, 280 liver, 65 heart, and 106 double transplants) were included. During the study period 147 patients (15.6%) developed 276 episodes of LI (incidence rate, 0.43 per 1000 transplantation-days). Bacteria were the most prevalent etiology (88.0%). Primary sources of infection included urinary tract (36.9%), intra-abdominal (16.7%), and sepsis without source (13.4%). Independent risk factors for late bacterial infection were: age (hazard ratio [HR] [per year] 1.0; 95% confidence interval [CI]: 1.0-1,0), female gender (HR 1.7; 95%CI: 1.1-2.6), anti-hepatitis C virus (HCV) positive serostatus (HR 1.8; 95%CI: 1.1-3.0), chronic allograft dysfunction (HR 3.2; 95%CI: 1.7-6.1), early CMV disease (HR 2.2; 95%CI 1.2-4.1), and early bacterial infection (HR 2.5; 95%CI 1.6-3.8). The occurrence of chronic allograft dysfunction was an independent risk factor for late CMV disease (HR 6.5; 95%CI: 1.7-24.6), whereas immunosuppression based on mammalian target of rapamycin inhibitors protected against the development of late CMV disease (HR 0.3; 95%CI: 0.1-1.0). Cox model selected anti-HCV positive serostatus (adjusted HR [aHR] 2.67; 95%CI: 1.27-5.59), age (aHR [per year] 1.06; 95%CI: 1.02-1.10), and the occurrence of LI (aHR 9.12; 95%CI: 3.90-21.33) as independent factors for mortality. CONCLUSIONS: LI did not constitute an uncommon complication in our cohort, and patients at risk may benefit from close clinical monitoring. PMID- 21535337 TI - Fungemia due to Rhodotorula mucilaginosa after allogeneic hematopoietic stem cell transplantation. AB - Rhodotorula species have been increasingly recognized as emerging pathogens, particularly in immunocompromised patients. We herein report on a patient with myelodysplastic syndrome who developed fungemia due to Rhodotorula mucilaginosa after allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor. He developed severe acute graft-versus-host disease requiring high-dose steroids, and had serially been administered fluconazole and micafungin for the prophylaxis of fungal infection. Although several cases of Rhodotorula infection after HSCT have been reported, all of them were recipients of autologous HSCT, not allogeneic HSCT. A review of all the reported cases of Rhodotorula infection after HSCT revealed that all patients had received fluconazole or echinocandins before the onset of infection. The findings suggest that Rhodotorula species could be causative yeasts, particularly in patients receiving fluconazole or echinocandins, both of which are inactive against the species. PMID- 21535339 TI - Lysosomal membrane protein composition, acidic pH and sterol content are regulated via a light-dependent pathway in metazoan cells. AB - In metazoans, lysosomes are characterized by a unique tubular morphology, acidic pH, and specific membrane protein (LAMP) and lipid (cholesterol) composition as well as a soluble protein (hydrolases) composition. Here we show that perturbation to the eye-color gene, light, results in impaired lysosomal acidification, sterol accumulation, altered endosomal morphology as well as compromised lysosomal degradation. We find that Drosophila homologue of Vps41, Light, regulates the fusion of a specific subset of biosynthetic carriers containing characteristic endolysosomal membrane proteins, LAMP1, V0-ATPase and the cholesterol transport protein, NPC1, with the endolysosomal system, and is then required for the morphological progression of the multivesicular endosome. Inhibition of Light results in accumulation of biosynthetic transport intermediates that contain these membrane cargoes, whereas under similar conditions, endosomal delivery of soluble hydrolases, previously shown to be mediated by Dor, the Drosophila homologue of Vps18, is not affected. Unlike Dor, Light is recruited to endosomes in a PI3P-sensitive fashion wherein it facilitates fusion of these biosynthetic cargoes with the endosomes. Depletion of the mammalian counterpart of Light, hVps41, in a human cell line also inhibits delivery of hLAMP to endosomes, suggesting an evolutionarily conserved pathway in metazoa. PMID- 21535338 TI - Endocytosis and endosomes at the crossroads of regulating trafficking of axon outgrowth-modifying receptors. AB - In neurons, many receptors must be localized correctly to axons or dendrites for proper function. During development, receptors for nerve growth and guidance are targeted to axons and localized to growth cones where receptor activation by ligands results in promotion or inhibition of axon growth. Signaling outcomes downstream of ligand binding are determined by the location, levels and residence times of receptors on the neuronal plasma membrane. Therefore, the mechanisms controlling the trafficking of these receptors are crucial to the proper wiring of circuits. Membrane proteins accumulate on the axonal surface by multiple routes, including polarized sorting in the trans Golgi network, sorting in endosomes and removal by endocytosis. Endosomes also play important roles in the signaling pathways for both growth-promoting and -inhibiting molecules: signaling endosomes derived from endocytosis are important for signaling from growth cones to cell bodies. Growth-promoting neurotrophins and growth-inhibiting Nogo-A can use EHD4/Pincher-dependent endocytosis at the growth cone for their respective retrograde signaling. In addition to retrograde transport of endosomes, anterograde transport to axons in endosomes also occurs for several receptors, including the axon outgrowth-promoting cell adhesion molecule L1/NgCAM and TrkA. L1/NgCAM also depends on EHD4/Pincher-dependent endocytosis for its axonal polarization. In this review, we will focus on receptors whose trafficking has been reported to be modulated by the EHD4/Pincher family of endosomal regulators, namely L1/NgCAM, Trk and Nogo-A. We will first summarize the pathways underlying the axonal transport of these proteins and then discuss the potential roles of EHD4/Pincher in mediating their endocytosis. PMID- 21535340 TI - Do species' traits predict recent shifts at expanding range edges? AB - Although some organisms have moved to higher elevations and latitudes in response to recent climate change, there is little consensus regarding the capacity of different species to track rapid climate change via range shifts. Understanding species' abilities to shift ranges has important implications for assessing extinction risk and predicting future community structure. At an expanding front, colonization rates are determined jointly by rates of reproduction and dispersal. In addition, establishment of viable populations requires that individuals find suitable resources in novel habitats. Thus, species with greater dispersal ability, reproductive rate and ecological generalization should be more likely to expand into new regions under climate change. Here, we assess current evidence for the relationship between leading-edge range shifts and species' traits. We found expected relationships for several datasets, including diet breadth in North American Passeriformes and egg-laying habitat in British Odonata. However, models generally had low explanatory power. Thus, even statistically and biologically meaningful relationships are unlikely to be of predictive utility for conservation and management. Trait-based range shift forecasts face several challenges, including quantifying relevant natural history variation across large numbers of species and coupling these data with extrinsic factors such as habitat fragmentation and availability. PMID- 21535341 TI - Phylogenetic origins of local-scale diversity patterns and the causes of Amazonian megadiversity. AB - What explains the striking variation in local species richness across the globe and the remarkable diversity of rainforest sites in Amazonia? Here, we apply a novel phylogenetic approach to these questions, using treefrogs (Hylidae) as a model system. Hylids show dramatic variation in local richness globally and incredible local diversity in Amazonia. We find that variation in local richness is not explained primarily by climatic factors, rates of diversification (speciation and extinction) nor morphological variation. Instead, local richness patterns are explained predominantly by the timing of colonization of each region, and Amazonian megadiversity is linked to the long-term sympatry of multiple clades in that region. Our results also suggest intriguing interactions between clade diversification, trait evolution and the accumulation of local richness. Specifically, sympatry between clades seems to slow diversification and trait evolution, but prevents neither the accumulation of local richness over time nor the co-occurrence of similar species. PMID- 21535342 TI - Microbial metabolism in ice and brine at -5 degrees C. AB - Metabolic activity, but not growth, has been observed in ice at temperatures from -5 degrees C to -32 degrees C. To improve understanding of metabolism in ice, we simultaneously examined various aspects of metabolism ((14) C-acetate utilization, macromolecule syntheses and viability via reduction of CTC) of the glacial isolates Sporosarcina sp. B5 and Chryseobacterium sp. V3519-10 during incubation in nutrient-rich ice and brine at -5 degrees C for 50 days. Measured rates of acetate utilization and macromolecule syntheses were high in the first 20 days suggesting adjustment to the lower temperatures and higher salt concentrations of both the liquid vein network in the ice and the brine. Following this adjustment, reproductive growth of both organisms was evident in brine, and suggested for Sporosarcina sp. B5 in ice by increases in cell numbers and biomass. Chryseobacterium sp. V3519-10 cells incubated in ice remained active. These data indicate that neither low temperature nor high salt concentrations prohibit growth in ice, but some other aspect of living within ice slows growth to within the detection limits of current methodologies. These results imply that microbial growth is plausible in natural ice systems with comparable temperatures and sufficient nutrients, such as debris-rich basal ices of glaciers and ice masses. PMID- 21535343 TI - A global census of nitrogenase diversity. AB - The global diversity of nitrogen-fixing microorganisms was assessed through construction and analysis of an aligned database of 16,989 nifH sequences. We conclude that the diversity of diazotrophs is still poorly described and that many organisms remain to be discovered. Our analyses indicate that diversity is not distributed evenly across phylogenetic groups or across environments and that some of the most diverse assemblages and environments remain the most poorly characterized. The majority of OTUs were rare, falling in the long tail of the frequency distribution. The most dominant OTUs fell into either the Cyanobacteria or the alpha, beta, and gamma Proteobacteria, and five of these dominant OTUs do not have any representatives cultivated in isolation. Soils contained the greatest diversity of nifH sequences of all of the environments surveyed. Cluster III, which is dominated by nifH sequences from obligate anaerobes, was found to contain the greatest diversity of all nifH lineages and is also the group for which diversity is the least sampled. Our findings provide context for ongoing efforts to explore diazotroph diversity, indicating specific groups and environments that remain poorly characterized. PMID- 21535344 TI - The moving junction of apicomplexan parasites: a key structure for invasion. AB - Most Apicomplexa are obligate intracellular parasites and many are important pathogens of human and domestic animals. For a successful cell invasion, they rely on their own motility and on a firm anchorage to their host cell, depending on the secretion of proteins and the establishment of a structure called the moving junction (MJ). The MJ moves from the apical to the posterior end of the parasite, leading to the internalization of the parasite into a parasitophorous vacuole. Based on recent data obtained in Plasmodium and Toxoplasma, an emerging model emphasizes a cooperative role of secreted parasitic proteins in building the MJ and driving this crucial invasive process. More precisely, the parasite exports the microneme protein AMA1 to its own surface and the rhoptry neck RON2 protein as a receptor inserted into the host cell together with other RON partners. Ongoing and future research will certainly help refining the model by characterizing the molecular organization within the MJ and its interactions with both host and parasite cytoskeleton for anchoring of the complex. PMID- 21535345 TI - New approaches to the treatment of diabetic retinopathy. AB - Diabetic retinopathy (DR) is a leading cause of visual impairment in working age in industrialized countries. It is classified as non-proliferative (mild, moderate or severe) and proliferative, with diabetic macular oedema potentially developing at any of these stages. The prevalence and incidence of DR increase with diabetes duration and worsening of metabolic and blood pressure control. Current approaches to prevent and/or treat DR include optimized control of blood glucose and blood pressure and screening for early identification of high-risk, although still asymptomatic, retinal lesions. Results from recent clinical trials suggest a role for blockers of the renin-angiotensin system (angiotensin converting enzyme inhibitors and angiotensin II receptor blockers) and for fenofibrate in reducing progression and/or inducing regression of mild-to moderate non-proliferative DR. Intravitreal administration of anti-vascular endothelial growth factor (VEGF) agents was shown to reduce visual loss in more advanced stages of DR, especially in macular oedema. PMID- 21535346 TI - A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents. AB - AIMS: Combination therapy with sitagliptin and metformin has shown superior efficacy compared with metformin monotherapy. In this study, we compare two strategies: initial combination therapy with sitagliptin/metformin as a fixed dose combination (FDC) and initial metformin monotherapy, with the option to add additional antihyperglycaemic agents (AHAs) in either treatment arm during the second phase of the study in order to reach adequate glycaemic control. METHODS: We evaluated the sitagliptin and metformin FDC compared with metformin monotherapy over 44 weeks in 1250 patients with type 2 diabetes mellitus in a two part, double-blind, randomized, controlled clinical trial. The initial 18-week portion (Phase A) of this study in which additional AHAs were only allowed based on prespecified glycaemic criteria, has been previously reported. Here, we present results from the 26-week Phase B portion of the study during which double blind study medication continued; however, unlike Phase A, during Phase B investigators were unmasked to results for haemoglobin A1C (HbA1c) and fasting plasma glucose (FPG) and directed to manage glycaemic control by adding incremental AHA(s) as deemed clinically appropriate. RESULTS: There were 1250 patients randomized in the study with 965 completing Phase A and continuing in Phase B. Among patients receiving sitagliptin/metformin FDC or metformin monotherapy, 8.8% and 16.7% received additional AHA therapy, respectively. Although glycaemic therapy in both groups was to have been managed to optimize HbA1c reductions with the option for investigators to supplement with additional AHAs during Phase B, patients randomized to initial therapy with sitagliptin/metformin FDC had larger reductions of HbA1c from baseline compared with patients randomized to initial metformin monotherapy [least squares (LS) mean change: -2.3% and -1.8% (p < 0.001 for difference) for sitagliptin/metformin FDC and metformin monotherapy groups, respectively]. A significantly larger reduction in FPG from baseline was observed in the sitagliptin/metformin FDC group compared with the metformin monotherapy group (p = 0.001). Significantly more patients in the sitagliptin/metformin FDC group had an HbA1c of less than 7.0% or less than 6.5% compared with those on metformin monotherapy. Both treatment strategies were generally well tolerated, with a low and similar incidence of hypoglycaemia in both groups and lower incidences of abdominal pain and diarrhoea in the sitagliptin/metformin FDC group compared with the metformin monotherapy group. CONCLUSIONS: A strategy initially implementing combination therapy with sitagliptin/metformin FDC was superior to a strategy initially implementing metformin monotherapy, even when accounting for the later addition of supplemental AHAs. Sitagliptin/metformin FDC was generally well tolerated. PMID- 21535347 TI - Morbidity in HIV-1-infected individuals before and after the introduction of antiretroviral therapy: a longitudinal study of a population-based cohort in Uganda. AB - BACKGROUND: We compared morbidities in HIV-1-infected patients before and after the introduction of antiretroviral therapy (ART) in a rural Ugandan cohort followed from 1990 to 2008. ART was introduced in 2004. METHODS: Random-effects Poisson regression models were used to estimate incidence rates of World Health Organization (WHO) stage-defining diseases in HIV-infected individuals aged 13 years or older with known seroconversion dates, and in an age-stratified sample of HIV-negative individuals. RESULTS: The most common morbid event was bacterial pneumonia, with an incidence of 7.4/100 person-years (pyr) among 309 HIV seroconverters and 1.3/100 pyr among 348 HIV-negative participants [hazard ratio (HR) 5.64; 95% confidence interval (CI) 3.6-8.8]. Among seroconverters, the incidence of the acquisition of any WHO stage-defining disease rose from 14.4/100 pyr (95% CI 11.1-18.6) in 1990-1998 to 46.0/100 pyr (95% CI 37.7-56.0) in 1999 2003. Following the introduction of ART, the incidence among seroconverters declined to 36.4/100 pyr (95% CI 27.1-48.9) in 2004-2005 and to 28.3/100 pyr (95% CI 21.2-37.8) in 2006-2008. At the individual level, a higher rate of acquiring any WHO stage-defining disease was independently associated with lower CD4 cell count, longer duration of HIV infection and older age. In addition, individuals who had been on ART for longer than 12 months had a substantially lower rate of any WHO stage disease than those not yet on ART (adjusted HR 0.35; 95% CI 0.2 0.6). CONCLUSION: Morbidity in HIV-positive participants decreased following the introduction of ART, and this decline was more marked with increasing duration on ART. The benefits of decreased HIV-related morbidity from ART lend support to urgent efforts to ensure universal access to early diagnosis of HIV infection and to ART, especially in rural Africa. PMID- 21535348 TI - Mycosphaerella graminicola: from genomics to disease control. AB - This Mycosphaerella graminicola pathogen profile covers recent advances in the knowledge of this ascomycete fungus and of the disease it causes, septoria tritici blotch of wheat. Research on this pathogen has accelerated since publication of a previous pathogen profile in this journal in 2002. Septoria tritici blotch continues to have high economic importance and widespread global impact on wheat production. TAXONOMY: Mycosphaerella graminicola (Fuckel) J. Schrot. In Cohn (anamorph: Septoria tritici Roberge in Desmaz.). Kingdom Fungi, Phylum Ascomycota, Class Loculoascomycetes (filamentous ascomycetes), Order Dothideales, Genus Mycosphaerella, Species graminicola. HOST RANGE: Bread and durum wheat (Triticum aestivum L. and T. turgidum ssp. durum L.). Disease symptoms: Initially leaves develop a chlorotic flecking, which is followed by the development of necrotic lesions which contain brown-black pycnidia. Necrosis causes a reduction in photosynthetic capacity and therefore affects grain yield. Disease control: The disease is primarily controlled by a combination of resistant cultivars and fungicides. Rapid advances in disease control, especially in resistance breeding, are opening up new opportunities for the management of the disease. USEFUL WEBSITES: http://genome.jgi-psf.org/Mycgr3/Mycgr3.home.html. PMID- 21535349 TI - Involvement of a putative response regulator FgRrg-1 in osmotic stress response, fungicide resistance and virulence in Fusarium graminearum. AB - Response regulator (RR) proteins are core elements of the high-osmolarity glycerol (HOG) pathway, which plays an important role in the adaptation of fungi to a variety of environmental stresses. In this study, we constructed deletion mutants of two putative RR genes, FgRRG-1 and FgRRG-2, which are orthologues of Neurospora crassa RRG-1 and RRG-2, respectively. The FgRRG-1 deletion mutant (DeltaFgRrg1-6) showed increased sensitivity to osmotic stress mediated by NaCl, KCl, sorbitol or glucose, and to metal cations Li(+) , Ca(2+) and Mg(2+) . The mutant, however, was more resistant than the parent isolate to dicarboximide and phenylpyrrole fungicides. Inoculation tests showed that the mutant exhibited decreased virulence on wheat heads. Quantitative real-time polymerase chain reaction assays indicated that the expression of FgOS-2, the putative downstream gene of FgRRG-1, was decreased significantly in DeltaFgRrg1-6. All of the defects were restored by genetic complementation of DeltaFgRrg1-6 with the wild-type FgRRG-1 gene. Different from the FgRRG-1 deletion mutant, FgRRG-2 deletion mutants were morphologically indistinguishable from the wild-type progenitor in virulence and in sensitivity to the dicarboximide fungicide iprodione and osmotic stresses. These results indicate that the RR FgRrg-1 of F. graminearum is involved in the osmotic stress response, pathogenicity and sensitivity to dicarboximide and phenylpyrrole fungicides and metal cations. PMID- 21535350 TI - Long-term protection against tobacco mosaic virus induced by the marine alga oligo-sulphated-galactan Poly-Ga in tobacco plants. AB - In order to study the antiviral effect of the oligo-sulphated galactan Poly-Ga, the leaves of tobacco plants Xhanti(NN) were sprayed with water (control), with increasing concentrations of Poly-Ga, for increasing numbers of treatments or cultivated for increasing times after treatment. Control and treated plants were infected with tobacco mosaic virus (TMV) and the numbers of necrotic lesions were measured in infected leaves. The number of necrotic lesions decreased with increasing concentrations of Poly-Ga, with increasing numbers of treatments and with increasing time after treatment, indicating a long-term protection against TMV that mimicks vaccination. In addition, control Xhanti(nn) plants and plants treated with Poly-Ga and cultivated for increasing times after treatment were infected with TMV in the middle part of the plant, and the levels of TMV-capsid protein (CP) transcripts were measured in apical leaves. TMV-CP transcripts decreased in distant leaves, indicating that Poly-Ga induces systemic protection against TMV. The activities of the defence enzymes phenylalanine ammonia lyase (PAL) and lipoxygenase (LOX) and the amounts of several phenylpropanoid compounds (PPCs) were measured in control and treated plants without infection. A progressive increase in PAL activity was observed with increasing time after treatment, together with the accumulation of free and conjugated PPCs. In contrast, LOX activity remained unchanged. Interestingly, the increase in PAL activity showed a linear correlation with the decrease in necrotic lesions and the decrease in TMV-CP transcript level. Thus, Poly-Ga induced systemic and long term protection against TMV in tobacco plants that is determined, at least in part, by a sustained activation of PAL and the accumulation of PPCs with potential antiviral activity. PMID- 21535351 TI - Inactivation of Snt2, a BAH/PHD-containing transcription factor, impairs pathogenicity and increases autophagosome abundance in Fusarium oxysporum. AB - The soil-borne, asexual fungus Fusarium oxysporum f.sp. melonis (FOM) is a causal agent of muskmelon wilt disease. The current study focused on the most virulent race of FOM-race 1,2. The tagged mutant D122, generated by Agrobacterium tumefaciens-mediated transformation, caused the delayed appearance of initial wilt disease symptoms, as well as a 75% reduction in pathogenicity. D122 was impaired in the gene product homologous to the Snt2-like transcription factor of Schizosaccharomyces pombe. Involvement of snt2 in the early stage of FOM pathogenesis and its requirement for host colonization were confirmed by targeted disruption followed by quantitative reverse transcription-polymerase chain reaction analysis of snt2 expression in planta. Deltasnt2 mutants of FOM and Neurospora crassa exhibited similar morphological abnormalities, including a reduction in conidia production and biomass accumulation, slower vegetative growth and frequent hyphal septation. In N. crassa, snt-2 is required for sexual development, as Deltasnt-2 mutants were unable to produce mature perithecia. Suppressive subtraction hybridization analysis of the D122 mutant versus wild type isolate detected four genes (idi4, pdc, msf1, eEF1G) that were found previously in association with the target of rapamycin (TOR) kinase pathway. Expression of the autophagy-related idi4 and pdc genes was found to be up regulated in the Deltasnt2 FOM mutant. In N. crassa, disruption of snt-2 also conferred a significant over-expression of idi4. PMID- 21535352 TI - Identification of differentially expressed genes in a resistant versus a susceptible blueberry cultivar after infection by Colletotrichum acutatum. AB - Anthracnose fruit rot, caused by the fungus Colletotrichum acutatum, is an important disease of blueberry worldwide. The cultivar Elliott is resistant, severely restricting fungal growth and sporulation relative to the susceptible cultivar Jersey. The objectives of this research were as follows: (i) to analyse pre-penetration events in 'Elliott' and 'Jersey' at different stages of fruit development; (ii) to identify putative defence genes in 'Elliott' fruit; and (iii) to monitor the timing of the oxidative burst in both cultivars. Light microscopy revealed no differences in the pre-penetration activities of C. acutatum on the immature fruit of both cultivars. However, at fruit ripening, conidia germinated and formed appressoria more rapidly on 'Jersey' than on 'Elliott' fruit. Using suppression subtractive hybridization, 37 differentially expressed sequence tags (ESTs) were detected in 'Elliott' versus 'Jersey' upon infection. Several of the ESTs had homology to known plant defence genes, such as a class II chitinase, pathogenesis-related protein 10 (PR10) and beta-1,3 glucanase. Two putative genes involved in oxidative stress were identified: a metallothionein-like protein and monodehydroascorbate reductase. ESTs of fungal origin were also detected. Many ESTs had no homology to known genes. Using semi quantitative and quantitative reverse transcription-polymerase chain reaction (RT PCR), the expression of most of the candidate genes was detected earlier in 'Elliott' than in 'Jersey', some within 24 h post inoculation (hpi). Monitoring of the oxidative burst showed that the overall H(2) O(2) concentration was two to three times higher in 'Elliott' than in 'Jersey' at 24 hpi. The elucidation of the basis of resistance to C. acutatum in blueberry will facilitate the development of new anthracnose fruit rot-resistant cultivars. PMID- 21535353 TI - Regulators of G-protein signalling in Fusarium verticillioides mediate differential host-pathogen responses on nonviable versus viable maize kernels. AB - GBB1, a heterotrimeric G-protein beta-subunit gene, was shown to be a key regulator of fumonisin B(1) (FB(1) ) biosynthesis in the maize pathogen Fusarium verticillioides. In this study, we performed functional analyses of genes that encode putative RGS (regulators of G-protein signalling) proteins and PhLPs (phosducin-like proteins) in F. verticillioides. These proteins are known to regulate heterotrimeric G-protein activity by altering the intrinsic guanosine triphosphatase (GTPase) activity, which, in turn, influences the signalling mechanisms that control fungal growth, virulence and secondary metabolism. Our aim was to isolate and characterize gene(s) that are under the transcriptional control of GBB1, and to test the hypothesis that these genes are directly associated with FB(1) regulation and fungal development in F. verticillioides on maize kernels. We first identified eight genes (two PhLPs and six RGSs) in the F. verticillioides genome, and a subsequent transcriptional expression study revealed that three RGS genes were up-regulated in the gbb1 deletion (Deltagbb1) mutant and one RGS gene was up-regulated in the wild-type. To characterize their function, we generated knockout mutants using a homologous recombination strategy. When grown on autoclaved nonviable kernels, two mutants (DeltaflbA2 and DeltargsB) produced significantly higher levels of FB(1) compared with the wild type progenitor, suggesting that the two mutated genes are negative regulators of FB(1) biosynthesis. DeltaflbA2 also showed a severe curly conidia germination pattern, which was contradictory to that observed in the Deltagbb1 strain. Strikingly, when these mutants were grown on live maize kernels, we observed contrasting FB(1) and conidiation phenotypes in fungal mutants, which strongly suggests that these G-protein regulators have an impact on how F. verticillioides responds to host/environmental factors. Our data also provide evidence that fungal G-protein signalling is important for modulating the ethylene biosynthetic pathway in maize kernels. PMID- 21535354 TI - Identification of serine/threonine kinase and nucleotide-binding site-leucine rich repeat (NBS-LRR) genes in the fire blight resistance quantitative trait locus of apple cultivar 'Evereste'. AB - Fire blight is the most destructive bacterial disease affecting apple (Malus*domestica) worldwide. So far, no resistance gene against fire blight has been characterized in apple, despite several resistance regions having been identified. A highly efficacious resistance quantitative trait locus (QTL) was localized on linkage group 12 (LG12) of the ornamental cultivar 'Evereste'. A marker previously reported to be closely linked to this resistance was used to perform a chromosome landing. A bacterial artificial chromosome (BAC) clone of 189 kb carrying the fire blight resistance QTL was isolated and sequenced. New microsatellite markers were developed, and the genomic region containing the resistance locus was limited to 78 kb. A cluster of eight genes with homologies to already known resistance gene structures to bacterial diseases was identified and the corresponding gene transcription was verified. From this cluster, two genes were recognized in silico as the two most probable fire blight resistance genes showing homology with the Pto/Prf complex in tomato. PMID- 21535355 TI - Fungal pathogenicity genes in the age of 'omics'. AB - The identification of the fungal genes essential for disease underpins the development of disease control strategies. Improved technologies for gene identification and functional analyses, as well as a plethora of sequenced fungal genomes, have led to the characterization of hundreds of genes, denoted as pathogenicity genes, which are required by fungi to cause disease. We describe recent technologies applied to characterize the fungal genes involved in disease and focus on some genes that are likely to attract continuing research activity. PMID- 21535356 TI - Dynamic 13C/1 H NMR imaging uncovers sugar allocation in the living seed. AB - Seed growth and accumulation of storage products relies on the delivery of sucrose from the maternal to the filial tissues. The transport route is hidden inside the seed and has never been visualized in vivo. Our approach, based on high-field nuclear magnetic resonance and a custom made (13)C/(1) H double resonant coil, allows the non-invasive imaging and monitoring of sucrose allocation within the seed. The new technique visualizes the main stream of sucrose and determines its velocity during the grain filling in barley (Hordeum vulgare L.). Quantifiable dynamic images are provided, which allow observing movement of (13)C-sucrose at a sub-millimetre level of resolution. The analysis of genetically modified barley grains (Jekyll transgenic lines, seg8 and Riso13 mutants) demonstrated that sucrose release via the nucellar projection towards the endosperm provides an essential mean for the control of seed growth by maternal organism. The sucrose allocation was further determined by structural and metabolic features of endosperm. Sucrose monitoring was integrated with an in silico flux balance analysis, representing a powerful platform for non-invasive study of seed filling in crops. PMID- 21535357 TI - A synthetic gene increases TGFbeta3 accumulation by 75-fold in tobacco chloroplasts enabling rapid purification and folding into a biologically active molecule. AB - Human transforming growth factor-beta3 (TGFbeta3) is a new therapeutic protein used to reduce scarring during wound healing. The active molecule is a nonglycosylated, homodimer comprised of 13-kDa polypeptide chains linked by disulphide bonds. Expression of recombinant human TGFbeta3 in chloroplasts and its subsequent purification would provide a sustainable source of TGFbeta3 free of animal pathogens. A synthetic sequence (33% GC) containing frequent chloroplast codons raised accumulation of the 13-kDa TGFbeta3 polypeptide by 75 fold compared to the native coding region (56% GC) when expressed in tobacco chloroplasts. The 13-kDa TGFbeta3 monomer band was more intense than the RuBisCO 15-kDa small subunit on Coomassie blue-stained SDS-PAGE gels. TGFbeta3 accumulated in insoluble aggregates and was stable in leaves of different ages but was not detected in seeds. TGFbeta3 represented 12% of leaf protein and appeared as monomer, dimer and trimer bands on Western blots of SDS-PAGE gels. High yield and insolubility facilitated initial purification and refolding of the 13-kDa polypeptide into the TGFbeta3 homodimer recognized by a conformation dependent monoclonal antibody. The TGFbeta3 homodimer and trace amounts of monomer were the only bands visible on silver-stained gels following purification by hydrophobic interaction chromatography and cation exchange chromatography. N terminal sequencing and electronspray ionization mass spectrometry showed the removal of the initiator methionine and physical equivalence of the chloroplast produced homodimer to standard TGFbeta3. Functional equivalence was demonstrated by near-identical dose-response curves showing the inhibition of mink lung epithelial cell proliferation. We conclude that chloroplasts are an attractive production platform for synthesizing recombinant human TGFbeta3. PMID- 21535358 TI - Improved heterologous protein expression in the chloroplast of Chlamydomonas reinhardtii through promoter and 5' untranslated region optimization. AB - Microalgae have the potential to be a valuable biotechnological platform for the production of recombinant proteins. However, because of the complex regulatory network that tightly controls chloroplast gene expression, heterologous protein accumulation in a wild-type, photosynthetic-competent algal chloroplast remains low. High levels of heterologous protein accumulation have been achieved using the psbA promoter/5' untranslated region (UTR), but only in a psbA-deficient genetic background, because of psbA/D1-dependent auto-attenuation. Here, we examine the effect of fusing the strong 16S rRNA promoter to the 5' UTR of the psbA and atpA genes on transgene expression in the chloroplast of Chlamydomonas reinhardtii. We show that fusion of the 16S promoter had little impact on protein accumulation from the psbA 5' UTR in a psbA-deficient genetic background. Furthermore, the 16S/psbA promoter/UTR fusion was silenced in the presence of wild-type levels of D1 protein, confirming that the psbA 5' UTR is the primary target for D1-dependent auto-repression. However, fusion of the 16S promoter to the atpA 5' UTR significantly boosts mRNA levels and supports high levels of heterologous protein accumulation in photosynthetic-competent cells. The 16S/atpA promoter/UTR drove LUXCT protein accumulation to levels close to that of psbA in a psbA- background, and drove expression of a human therapeutic protein to levels only twofold lower than the psbA 5' UTR. The 16S/atpA promoter/UTR combination should have utility for heterologous protein production when expression from a photosynthetic-competent microalgal strain is required. PMID- 21535359 TI - Engineering plastid fatty acid biosynthesis to improve food quality and biofuel production in higher plants. AB - The ability to manipulate plant fatty acid biosynthesis by using new biotechnological approaches has allowed the production of transgenic plants with unusual fatty acid profile and increased oil content. This review focuses on the production of very long chain polyunsaturated fatty acids (VLCPUFAs) and the increase in oil content in plants using molecular biology tools. Evidences suggest that regular consumption of food rich in VLCPUFAs has multiple positive health benefits. Alternative sources of these nutritional fatty acids are found in cold-water fishes. However, fish stocks are in severe decline because of decades of overfishing, and also fish oils can be contaminated by the accumulation of toxic compounds. Recently, there is also an increase in oilseed use for the production of biofuels. This tendency is partly associated with the rapidly rising costs of petroleum, increased concern about the environmental impact of fossil oil and the attractive need to develop renewable sources of fuel. In contrast to this scenario, oil derived from crop plants is normally contaminant free and less environmentally aggressive. Genetic engineering of the plastid genome (plastome) offers a number of attractive advantages, including high-level foreign protein expression, marker-gene excision and transgene containment because of maternal inheritance of plastid genome in most crops. Here, we describe the possibility to improve fatty acid biosynthesis in plastids, production of new fatty acids and increase their content in plants by genetic engineering of plastid fatty acid biosynthesis via plastid transformation. PMID- 21535360 TI - Prevalence of overweight and obesity in non-institutionalized people aged 65 or over from Spain: the elderly EXERNET multi-centre study. AB - Coupled with the growth of the older population, an increase in the prevalence of overweight and obesity in this age group has occurred in the last decades. The main aims of the present study were (i) to provide an updated prevalence of overweight and obesity in a representative sample of the Spanish elderly population; (ii) to calculate the prevalence of sarcopenic obesity (SO) and (iii) to analyse the relationships between adiposity measurements and lifestyle. A cross-sectional study was carried out in a sample of 3136 persons representative of the non-institutionalized population >=65 years of age. Anthropometric measurements were obtained using standardized techniques and equipment. Overall, 84% of the population can be categorized as overweight and/or obese. The present study indicates that 67% of the Spanish elderly population has an increased percentage of fat mass and more than 56% suffer from central obesity. Moreover, SO is present in 15% of the Spanish elderly population. Finally, a strong relationship between both physically active and sedentary lifestyles and the level of adiposity was found. Prevalence of overweight and obesity among elderly people in Spain is very high and is still increasing. Lifestyle seems to be a determinant factor in the development of obesity among elderly people. PMID- 21535361 TI - The role of parents in pre-adolescent and adolescent overweight and obesity treatment: a systematic review of clinical recommendations. AB - The study aims to describe clinical recommendations (i) on the role of parents in both pre-adolescent and adolescent overweight and obesity treatment; (ii) to health professionals on how to involve parents in paediatric overweight and obesity treatment and (iii) to identify deficiencies in the associated literature. A systematic literature review was conducted in March 2010 to identify clinical practice guidelines, position or consensus statements on clinical management of paediatric overweight or obesity, developed by a national or international health professional association or government agency, and endorsed for current use. Relevant clinical recommendations in these documents were identified via a screen for the words 'parent', 'family' and synonyms. Twenty documents were included. Most documents emphasized the importance of involving parents or the family in paediatric overweight and obesity treatment with approximately a third of documents providing separate recommendations on the role of parents/family for pre-adolescents and adolescents. The documents varied markedly with regard to the presence of recommendations on parent/family involvement in the various components of lifestyle interventions or bariatric surgery. Almost half of the documents contained recommendations to health professionals regarding interactions with parents. High-quality research is needed on age-specific techniques to optimize the involvement of parents and family members in paediatric overweight and obesity treatment. PMID- 21535362 TI - Problems in identifying predictors and correlates of weight loss and maintenance: implications for weight control therapies based on behaviour change. AB - Weight management is a dynamic process, with a pre-treatment phase, a treatment (including process) phase and post-treatment maintenance, and where relapse is possible during both the treatment and maintenance. Variability in the statistical power of the studies concerned, heterogeneity in the definitions, the complexity of obesity and treatment success, the constructs and measures used to predict weight loss and maintenance, and an appreciation of who and how many people achieve it, make prediction difficult. In models of weight loss or maintenance: (i) predictors explain up to 20-30% of the variance; (ii) many predictors are the sum of several small constituent variables, each accounting for a smaller proportion of the variance; (iii) correlational or predictive relationships differ across study populations; (iv) inter-individual variability in predictors and correlates of outcomes is high and (v) most of the variance remains unexplained. Greater standardization of predictive constructs and outcome measures, in more clearly defined study populations, tracked longitudinally, is needed to better predict who sustains weight loss. Treatments need to develop a more individualized approach that is sensitive to patients' needs and individual differences, which requires measuring and predicting patterns of intra-individual behaviour variations associated weight loss and its maintenance. This information will help people shape behaviour change solutions to their own lifestyle needs. PMID- 21535363 TI - Diazotrophic microbial community of coastal microbial mats of the southern North Sea. AB - The diazotrophic community in microbial mats growing along the shore of the North Sea barrier island Schiermonnikoog (The Netherlands) was studied using microscopy, lipid biomarkers, stable carbon (delta(13) C(TOC) ) and nitrogen (delta(15) N) isotopes as well as by constructing and analyzing 16S rRNA gene libraries. Depending on their position on the littoral gradient, two types of mats were identified, which showed distinct differences regarding the structure, development and composition of the microbial community. Intertidal microbial mats showed a low species diversity with filamentous non-heterocystous Cyanobacteria providing the main mat structure. In contrast, supratidal microbial mats showed a distinct vertical zonation and a high degree of species diversity. Morphotypes of non-heterocystous Cyanobacteria were recognized as the main structural component in these mats. In addition, unicellular Cyanobacteria were frequently observed, whereas filamentous heterocystous Cyanobacteria occurred only in low numbers. Besides the apparent visual dominance of cyanobacterial morphotpyes, 16S rRNA gene libraries indicated that both microbial mat types also included members of the Proteobacteria and the Cytophaga-Flavobacterium-Bacteroides group as well as diatoms. Bulk delta(15) N isotopes of the microbial mats ranged from +6.10/00 in the lower intertidal to -1.20/00 in the supratidal zone, indicating a shift from predominantly nitrate utilization to nitrogen fixation along the littoral gradient. This conclusion was supported by the presence of heterocyst glycolipids, representing lipid biomarkers for nitrogen-fixing heterocystous Cyanobacteria, in supratidal but not in intertidal microbial mats. The availability of combined nitrogen species might thus be a key factor in controlling and regulating the distribution of the diazotrophic microbial community of Schiermonnikoog. PMID- 21535364 TI - Niche differentiation among mat-forming, sulfide-oxidizing bacteria at cold seeps of the Nile Deep Sea Fan (Eastern Mediterranean Sea). AB - Sulfidic muds of cold seeps on the Nile Deep Sea Fan (NDSF) are populated by different types of mat-forming sulfide-oxidizing bacteria. The predominant sulfide oxidizers of three different mats were identified by microscopic and phylogenetic analyses as (i) Arcobacter species producing cotton-ball-like sulfur precipitates, (ii) large filamentous sulfur bacteria including Beggiatoa species, and (iii) single, spherical Thiomargarita species. High resolution in situ microprofiles revealed different geochemical settings selecting for the different mat types. Arcobacter mats occurred where oxygen and sulfide overlapped above the seafloor in the bottom water interface. Filamentous sulfide oxidizers were associated with steep gradients of oxygen and sulfide in the sediment. A dense population of Thiomargarita was favored by temporarily changing supplies of oxygen and sulfide in the bottom water. These results indicate that the decisive factors in selecting for different mat-forming bacteria within one deep-sea province are spatial or temporal variations in energy supply. Furthermore, the occurrence of Arcobacter spp.-related 16S rRNA genes in the sediments below all three types of mats, as well as on top of brine lakes of the NDSF, indicates that this group of sulfide oxidizers can switch between different life modes depending on the geobiochemical habitat setting. PMID- 21535365 TI - Retinoblastoma-independent regulation of cell proliferation and senescence by the p53-p21 axis in lamin A /C-depleted cells. AB - The expression of A-type lamin is downregulated in several cancers, and lamin defects are the cause of several diseases including a form of accelerated aging. We report that depletion of lamin A/C expression in normal human cells leads to a dramatic downregulation of the Rb family of tumor suppressors and a defect in cell proliferation. Lamin A/C-depleted cells exhibited a flat morphology and accumulated markers of cellular senescence. This senescent phenotype was accompanied by engagement of the p53 tumor suppressor and induction of the p53 target gene p21 and was prevented by small hairpin RNAs against p53, p21, or by the oncoprotein Mdm2. The expression of E2F target genes, normally required for cell cycle progression, was downregulated after lamin A/C depletion but restored after the inactivation of p53. A similar senescence response was observed in myoblasts from a patient with a lamin A mutation causing muscular dystrophy. We thus reveal a previously unnoticed mechanism of controlling cell cycle genes expression, which depends on p53 but does not require the retinoblastoma family of tumor suppressors and that can be relevant to understand the pathogenesis of laminopathies and perhaps aging. PMID- 21535366 TI - Prescribing drugs in the 21st century. PMID- 21535367 TI - Introductory pharmacology for clinical practice. AB - The average woman will take many medications, both prescription and nonprescription, as well as herbs or other dietary supplements over the course of her lifetime. These chemicals can produce therapeutic benefits but can also cause toxic effects. Pharmacokinetics, pharmacodynamics, pharmacotherapy, adverse drug reactions, and research in pharmacology are discussed as applied to women's health. Clinicians must have a firm understanding of the basic principles of pharmacology so that they can appropriately administer medications, monitor for anticipated effects and adverse reactions, and communicate as needed with women, their families, and other health care team members. PMID- 21535368 TI - Governmental oversight of prescribing medications: history of the US Food and Drug Administration and prescriptive authority. AB - The evolution of drug regulation and awarding of prescriptive authority is a complex and sometimes convoluted process that can be confusing for health care providers. A review of the history of how drugs have been manufactured and dispensed helps explain why this process has been so laborious and complicated. Because the federal and state governments have the responsibility for protecting the public, most regulations have been passed with the intentions of ensuring consumer safety. The current system of laws and regulations is the result of many years of using the legal system to correct drug marketing that had adverse health consequences. Government oversight will continue as prescribing medications transitions to an electronic form and as health care professionals in addition to physicians seek to gain prescriptive authority. PMID- 21535369 TI - Adverse drug reactions in women's health care. AB - Adverse drug reactions (ADRs) are drug-related adverse events that occur in individuals using usual or therapeutic doses of medication. Women have a nearly 2 fold greater risk for developing ADRs than men, and they are more likely to be hospitalized secondary to an ADR. This article reviews the physiologic mechanisms of ADRs, common clinical manifestations of ADRs to medications often prescribed in women's health care, documentation and reporting of ADRs, and ADR prevention strategies. PMID- 21535370 TI - Clinicians' guide to the use of oxytocin for labor induction and augmentation. AB - Oxytocin is commonly used in obstetrics for labor induction and augmentation. Careful assessment of the individual clinical situation based on indications and contraindications is essential to enhancing safe and effective use. Counseling the woman and her partner regarding potential risks and benefits before use is necessary to promote informed consent. At least 39 weeks of gestation is required for elective labor induction. Recent research has shown that deferring elective induction until cervical readiness has been achieved without the use of pharmacologic agents can be beneficial in reducing the risk of cesarean birth associated with elective induction. A conservative physiologic oxytocin protocol for labor induction and augmentation is recommended to minimize the risk of side effects. Although treatment of excessive uterine activity related to oxytocin has not been studied prospectively, several interventions such as maternal repositioning, an intravenous fluid bolus, and discontinuation of the oxytocin infusion are beneficial in returning uterine activity to normal, based on retrospective review of oxytocin-induced tachysystole. Perinatal quality measures from the National Quality Forum and the Joint Commission can be useful in monitoring care related to induction of labor. These include elective births before 39 weeks of pregnancy and cesarean births for low-risk, first-birth mothers. PMID- 21535371 TI - A review of systemic opioids commonly used for labor pain relief. AB - Parenteral opioids for pain relief during labor have been the subject of research for many decades. Commonly used systemic opioids provide limited pain relief during labor yet are used extensively for managing labor pain. These opioids share similar pharmacologic profiles but differ in potency, pharmacokinetics, and side effects. This article reviews the pharmacokinetics, pharmacodynamics, and clinical research related to the commonly used systemic labor pain analgesics morphine, meperidine, fentanyl, remifentanil, butorphanol, and nalbuphine. PMID- 21535372 TI - Buprenorphine for the treatment of perinatal opioid dependence: pharmacology and implications for antepartum, intrapartum, and postpartum care. AB - Opioid dependence during pregnancy is associated with significant health risks for both the mother and her fetus. Opioid maintenance therapy with methadone (Dolophine) is the current standard of care, reduces medical and social risks associated with illicit drug use, and decreases rates of prematurity and low birth weight. However, treatment with methadone is frequently associated with neonatal abstinence syndrome. Buprenorphine is an alternative to methadone that preliminary data indicates is equivalent in safety and efficacy to methadone and significantly increases access to treatment. The pharmacology of buprenorphine and its implications for the care of pregnant women with opioid dependence are described. PMID- 21535373 TI - Pharmacologic management of asymptomatic bacteriuria and urinary tract infections in women. AB - Many factors influence the decision to institute treatment for the common problems of urinary tract symptoms and/or the presence of microorganisms in the urine of women. This article summarizes current evidence related to treatment choice and compares selected treatment practice guidelines. Evidence related to prevention of recurrent infection without the use of antibiotics is included. PMID- 21535374 TI - Spectrum of anxiety disorders: diagnosis and pharmacologic treatment. AB - Nearly 30% of women experience an anxiety disorder at some time during their lives, and there is increasing evidence that anxiety disorders are associated with adverse pregnancy outcomes. Despite increased media coverage regarding anxiety disorders, women are reluctant to discuss signs and symptoms of anxiety with family or health care providers. Additionally, despite ongoing research and improved educational curricula, primary care and women's health care providers find diagnosis and treatment of mental health disorders challenging. This article reviews the diagnostic features and pharmacologic treatment options for the most common anxiety disorders including generalized anxiety disorder, obsessive compulsive disorder, panic disorder, and posttraumatic stress disorder. The impact of anxiety disorders on pregnancy and guidelines for management are presented. PMID- 21535375 TI - Migraine headaches: diagnosis and management. AB - In spite of the fact that migraines are one of the major problems seen by primary care providers, almost half of people with migraines do not obtain appropriate diagnosis and/or treatment. Migraine occurs in about 18% of women, and is often aggravated by hormonal shifts occurring around women's menses, during pregnancy, and during perimenopause. Quality of life with migraines is often greatly diminished, and many women miss work days and/or are less productive with migraines. Women's health care providers are very likely to see women with poorly managed migraines, but are often not comfortable diagnosing and treating their patients with headaches. A variety of self-care treatments, acute care prescription and non-prescription headache medications, and preventive medications are available and if used by a knowledgeable provider can provide relief for many women who might not otherwise receive appropriate care. PMID- 21535377 TI - The new FDA pregnancy labeling requirements for drugs. AB - The new US Food and Drug Administration Proposed Rules for pharmaceutical products for the special population of pregnant women were published in May 2008. With these new rules in place, clinicians caring for women who are pregnant may begin to have clearer and more relevant information in the product label to guide clinical decisions regarding drug use during pregnancy. PMID- 21535376 TI - Hormonal management of the female-to-male transgender patient. AB - This article focuses on initiating and monitoring testosterone therapy for the female-to-male transgender person. For providers unfamiliar with the evaluation and treatment of the female-to-male transgender patient, this article offers an introduction to the diagnostic criteria for gender identity disorder as well as the eligibility and readiness criteria for hormonal treatment. Also included is information regarding screenings to be done before the initiation of testosterone therapy and during follow-up visits, common side effects of testosterone, and basic testosterone regimens available. PMID- 21535378 TI - Current resources for evidence-based practice, May/June 2011. PMID- 21535379 TI - Risk of mental health disorders does not increase following first trimester induced abortion. PMID- 21535380 TI - Higher rates of Chlamydia infection in low-income minority women may reflect differences in provider screening practices. PMID- 21535381 TI - Delphi study seeks consensus among expert practitioners of traditional Chinese medicine using acupuncture for treatment of hot flashes. PMID- 21535383 TI - Nutrition during pregnancy. PMID- 21535386 TI - Share with women. Depression and use of SSRI medications during pregnancy. PMID- 21535387 TI - Humoral immune response to ADAMTS13 in acquired thrombotic thrombocytopenic purpura. AB - The apparently spontaneous development of autoantibodies to ADAMTS13 in previously healthy individuals is a major cause of thrombotic thrombocytopenic purpura (TTP). Epitope mapping studies have shown that in most patients antibodies directed towards the spacer domain of ADAMTS13 are present. A single antigenic surface comprising Arg(660) , Tyr(661) and Tyr(665) that contributes to the productive binding of ADAMTS13 to unfolded von Willebrand factor is targeted by anti-spacer domain antibodies. Antibodies directed to the carboxyl-terminal CUB1-2 and TSP2-8 domains have also been observed in the plasma of patients with acquired TTP. As yet it has not been established whether this class of antibodies modulates ADAMTS13 activity. Inspection of the primary sequence of human monoclonal anti-ADAMTS13 antibodies suggests that the variable heavy chain germline gene segment VH1-69 is frequently incorporated. We suggest a model in which 'shape complementarity' between the spacer domain and residues encoded by the VH1-69 gene segment explain the preferential use of this variable heavy chain gene segment. Finally, a model is presented for the development of anti-ADAMTS13 antibodies in previously healthy individuals that incorporates the recent identification of HLA DRB1*11 as a risk factor for acquired TTP. PMID- 21535388 TI - Impact of vascular disease in predicting stroke and death in patients with atrial fibrillation: the Danish Diet, Cancer and Health cohort study. AB - BACKGROUND: The presence of vascular disease (peripheral artery disease [PAD] and/or myocardial infarction [MI]) may impact on the risk of stroke and death among patients with incident atrial fibrillation (AF). To test this hypothesis, we analyzed data from a large Danish prospective cohort, the Danish Diet, Cancer and Health (DCH) study, to assess the risk of stroke or death among those who developed AF according to concomitant presence of vascular disease. METHODS: A prospective cohort study of 57, 053 persons (27, 178 men and 29, 876 women, respectively), aged between 50 and 64 years. The risk of stroke or death for patients with vascular disease was assessed amongst 3315 patients with incident AF (mean age, 67.1years; 2130 men, 1185 women) using Cox proportional hazard models, after a median follow-up of 4.8 years. RESULTS: Of the subjects with AF, 417 (12.6%) had 'vascular disease' (PAD and/or prior MI). The risk of the primary endpoint (stroke or death) was significantly higher in patients with vascular disease at 1-year follow-up (crude hazard ratio [HR] 2.51 [1.91-3.29]), with corresponding crude HRs for PAD and MI being 3.51 (2.40-5.13), and 1.99 (1.46 2.72), respectively. For the secondary endpoints of death or stroke individually, these risk estimates were similar (crude HR 2.48 [1.89-3.26] and 1.77 [1.18 2.66], respectively). After adjustment for risk factors within the CHADS(2) score, the adjusted HR for the primary endpoint (stroke or death) in patients with vascular disease was 1.91 (1.44-2.54), which was also significant for death (1.97 [1.48-2.62]). CONCLUSION: Vascular disease (prior MI and PAD) is an independent risk factor for the primary endpoint of 'stroke or death' in patients with AF, even after adjustment for the CHADS(2) risk score, although this is driven by the impact on mortality. This reaffirms that patients with vascular disease represent a 'high-risk' population, which necessitates proactive management of all cardiovascular risk factors and effective thromboprophylaxis (i.e. oral anticoagulation), which has been shown to significantly reduce the risk of stroke and death in AF. PMID- 21535389 TI - Comparative study of commercially available procarboxypeptidase U (thrombin activatable fibrinolysis inhibitor) assays. PMID- 21535390 TI - Use and outcomes of venous thromboembolism prophylaxis after spinal fusion surgery. AB - BACKGROUND: The number of spinal fusion operations in the USA is rapidly rising, but little is known about optimal venous thromboembolism prophylaxis after spinal surgery. OBJECTIVES: To examine the use of and outcomes associated with venous thromboembolism prophylaxis after spinal fusion surgery in a cohort of 244 US hospitals. PATIENTS/METHODS: We identified all patients with a principal procedure code for spinal fusion surgery in hospitals participating in the Premier Perspective database from 2003 to 2005, and searched for receipt of pharmacologic prophylaxis (subcutaneous unfractionated heparin, low molecular weight heparin, or fondaparinux) and/or mechanical prophylaxis (compression devices and elastic stockings) within the first 7 days after surgery. We also searched for discharge diagnosis codes for venous thromboembolism and postoperative hemorrhage during the index hospitalization and within 30 days after surgery. RESULTS: Among 80,183 spinal fusions performed during the time period, cervical fusions were the most common (49.0%), followed by lumbar fusions (47.8%). Thromboembolism prophylaxis was administered to 60.6% of patients within the first week postoperatively, with the most frequent form being mechanical prophylaxis alone (47.6%). Of the 244 hospitals, 26.2% provided prophylaxis to >= 90% of their patients undergoing spinal fusion; however, 33.2% provided prophylaxis to fewer than 50% of their patients. The rate of diagnosed venous thromboembolism within 30 days after surgery was 0.45%, and the rate of postoperative hemorrhage was 1.1%. CONCLUSIONS: Substantial variation exists in the use of thromboembolism prophylaxis after spinal fusion surgery in the USA. Nevertheless, overall rates of diagnosed thromboembolism after spinal fusion appear to be low. PMID- 21535391 TI - beta(2) -Glycoprotein I: evolution, structure and function. AB - beta(2) -Glycoprotein I (beta(2) -GPI) is a protein that circulates in blood at high concentrations. The function of beta(2) -GPI has long been an enigma. More than 20 years ago, it was discovered that beta(2) -GPI is the major antigen for the circulating antibodies in the antiphospholipid syndrome. However, this knowledge has not advanced our understanding of the physiologic role of the protein. In recent years, new insights have suggested an important function of this protein in innate immunity. beta(2) -GPI was found to scavenge lipopolysaccharide and was able to clear unwanted anionic cellular remnants such as microparticles from the circulation. The function of beta(2) -GPI seems to depend on the structural conformation of the protein, and it has been established that beta(2) -GPI can exist in at least two conformations. In this review, we will highlight and summarize the current knowledge on this protein. PMID- 21535392 TI - Genetic and antibody-induced glycoprotein VI deficiency equally protects mice from mechanically and FeCl(3) -induced thrombosis. PMID- 21535393 TI - Emerging roles for factor XII in vivo. PMID- 21535394 TI - Generic versions of enoxaparin available for clinical use in Brazil are similar to the original drug. PMID- 21535395 TI - Activated protein C protects against myocardial ischemic/reperfusion injury through AMP-activated protein kinase signaling. AB - BACKGROUND: Activated protein C (APC) is a vitamin K-dependent plasma serine protease that down-regulates clotting and inflammatory pathways. It is known that APC exerts a cardioprotective effect by decreasing apoptosis of cardiomyocytes and inhibiting expression of inflammatory mediators after myocardial ischemia. OBJECTIVES: The objective of this study was to understand the mechanism of the APC-mediated cardioprotection against ischemic injury. METHODS: Cardioprotective activities of wild-type APC and two derivatives, having either dramatically reduced anticoagulant activity or lacking signaling activity, were monitored in an acute ischemia/reperfusion injury model in which the left anterior descending coronary artery (LAD) was occluded. RESULTS: APC reduced the myocardial infarct size by a mechanism that was largely independent of its anticoagulant activity. Thus, the non-anticoagulant APC-2Cys mutant, but not the non-signaling APC-E170A mutant, attenuated myocardial infarct size by EPCR and PAR-1-dependent mechanisms. Further studies revealed that APC acts directly on cardiomyocytes to stimulate the AMP-activated protein kinase (AMPK) signaling pathway. The activation of AMPK by APC ameliorated the post-ischemic cardiac dysfunction in isolated perfused mouse hearts. Moreover, both APC and APC-2Cys inhibited production of TNFalpha and IL-6 in vivo by attenuating the ischemia/reperfusion induced JNK and NF-kappaB signaling pathways. CONCLUSIONS: APC exerts a cardioprotective function in ischemic/reperfusion injury through modulation of AMPK, NF-kappaB and JNK signaling pathways. PMID- 21535397 TI - von Willebrand factor-to-ADAMTS13 ratio increases with age in a Japanese population. PMID- 21535396 TI - Glycosylation of tissue factor is not essential for its transport or functions. AB - BACKGROUND: Glycosylation plays an important role in protein function. The importance of glycosylation for tissue factor (TF) function is unclear. OBJECTIVE: The aim of the present study is to investigate the importance of TF glycosylation in transport to the cell surface and its coagulant and signaling functions. METHODS: Endothelial cells and peripheral blood mononuclear cells (PBMC) were treated with tunicamycin to inhibit N-linked glycosylation. Site specific mutagenesis of one or more potential N-linked glycosylation sites in TF was used to generate TF mutants lacking glycans. TF expression at the cell surface was determined in binding assays using (125)I-FVIIa or (125)I-TF mAb and confocal microscopy. TF coagulant activity was measured by factor (F) Xa generation assay, and TF signaling function was assessed by measuring cleavage of protease activated receptor 2 (PAR2) and activation of p44/42 MAPK. RESULTS: Tunicamycin treatment reduced TF activity at the endothelial cell surface; however, this reduction was found to be the result of decreased TF protein production in tunicamycin-treated cells. Tunicamycin treatment had no significant effect on TF activity or antigen levels in PBMC. No significant differences were observed in TF protein expression and procoagulant activity among cells transfected to express either wild-type TF or TF mutants. A fully non glycosylated TF is shown to bind FVIIa and interact with FX with the same efficiency as that of wild-type TF. Non-glycosylated TF is also capable of supporting FVIIa cleavage of PAR2 and PAR2-dependent p44/42 MAPK activation. CONCLUSIONS: Glycosylation is not essential for TF transport and coagulant or signaling functions. PMID- 21535399 TI - Cellular diversity within embryonic stem cells: pluripotent clonal sublines show distinct differentiation potential. AB - Embryonic stem cells (ESC), derived from the early inner cell mass (ICM), are constituted of theoretically homogeneous pluripotent cells. Our study was designed to test this concept using experimental approaches that allowed characterization of progenies derived from single parental mouse ESC. Flow cytometry analysis showed that a fraction of ESC submitted to neural differentiation generates progenies that escape the desired phenotype. Live imaging of individual cells demonstrated significant variations in the capacity of parental ESC to generate neurons, raising the possibility of clonal diversity among ESC. To further substantiate this hypothesis, clonal sublines from ESC were generated by limit dilution. Transcriptome analysis of undifferentiated sublines showed marked differences in gene expression despite the fact that all clones expressed pluripotency markers. Sublines showed distinct differentiation potential, both in phenotypic differentiation assays and with respect to gene expression in embryoid bodies. Clones generated from another ESC line also showed individualities in their differentiation potential, demonstrating the wider applicability of these findings. Taken together, our observations demonstrate that pluripotent ESC consist of individual cell types with distinct differentiation potentials. These findings identify novel elements for the biological understanding of ESC and provide new tools with a major potential for their future in vitro and in vivo use. PMID- 21535398 TI - NK receptors, Substance P, Ano1 expression and ultrastructural features of the muscle coat in Cav-1(-/-) mouse ileum. AB - Caveolin (Cav)-1 is an integral membrane protein of caveolae playing a crucial role in various signal transduction pathways. Caveolae represent the sites for calcium entry and storage especially in smooth muscle cells (SMC) and interstitial cells of Cajal (ICC). Cav-1(-/-) mice lack caveolae and show abnormalities in pacing and contractile activity of the small intestine. Presently, we investigated, by transmission electron microscopy (TEM) and immunohistochemistry, whether the absence of Cav-1 in Cav-1(-/-) mouse small intestine affects ICC, SMC and neuronal morphology, the expression of NK1 and NK2 receptors, and of Ano1 (also called Dog1 or TMEM16A), an essential molecule for slow wave activity in gastrointestinal muscles. ICC were also labelled with c-Kit and tachykinergic neurons with Substance P (SP). In Cav-1(-/-) mice: (i) ICC were Ano1-negative but maintained c-Kit expression, (ii) NK1 and NK2 receptor immunoreactivity was more intense and, in the SMC, mainly intracytoplasmatic, (iii) SP-immunoreactivity was significantly reduced. Under TEM: (i) ICC, SMC and telocytes lacked typical caveolae but had few and large flask-shaped vesicles we called large-sized caveolae; (ii) SMC and ICC contained an extraordinary high number of mitochondria, (iii) neurons were unchanged. To maintain intestinal motility, loss of caveolae and reduced calcium availability in Cav-1-knockout mice seem to be balanced by a highly increased number of mitochondria in ICC and SMC. Loss of Ano-1 expression, decrease of SP content and consequently overexpression of NK receptors suggest that all these molecules are Cav-1 associated proteins. PMID- 21535400 TI - Oral myiasis caused by the screwworm Cochliomyia hominivorax treated with subcutaneous ivermectin and creolin: report of six cases after trauma. AB - Human myiasis is a rare condition that is more common in regions with a warm and humid climate. The larvae involved in myiasis are voracious; they destroy healthy tissues and may cause serious haemorrhage. The condition can be life threatening. Six patients with craniofacial trauma and oral myiasis are reported. The diagnoses were made after larvae had been extracted. Treatment consisted of subcutaneous ivermectin therapy and the application of a phenol preparation (10% creolin) as a local measure for the control of larvae. After 12 (+/-1) days of hospitalization, no larvae remained in the patients' mouths and the patients were discharged. The laboratory identified the larvae as those of the fly Cochliomyia hominivorax. Healing was uneventful in the six cases presented, and no undesirable reactions were observed throughout the period of treatment. Although the usual treatment for myiasis involves surgical removal of the maggots, pharmacological therapies are emerging as effective alternatives. PMID- 21535401 TI - The art and science of managing traumatic injuries to primary teeth. AB - The selection of an appropriate treatment protocol and the rendering of treatment to children with traumatic injuries of their primary teeth are often more challenging than doing so for the permanent teeth of older individuals. This article discusses general considerations involving patient, parent, dentist, dental anatomy and occlusion that are responsible for the differences between the treatment protocols for the management of traumatic dental injuries to primary teeth and those for permanent teeth. PMID- 21535403 TI - A mandibular body fracture related to mouth-opening training in a dialysis patient. AB - A mandibular body fracture related to mouth-opening training in a dialysis patient is reported. A 61-year-old male patient had noticed pain in the right mandibular body and difficulty in mouth opening a week previously. The patient had been performing mouth-opening training for a couple of weeks. The right lower face was slightly swollen with tenderness at the right lower border of the mandible. Hypoesthesia of the right lower lip was also observed. A bone step was palpable on the alveolar ridge of the right mandible, but mobility was not marked. The mandible was atrophic in the body region with only four anterior teeth left. Panoramic X-ray examination revealed a moderately displaced fracture in the right molar region of the mandible. The patient had no severe pain or difficulty in eating using a partial denture. The patient had received dialysis for 17 years and had also been treated by warfarin and aspirin. The patient was followed up under restricted mouth opening. Osteosynthesis with bone remodeling was confirmed after 6 months by X-ray examination. No complication requiring further treatment occurred during the follow-up period. In this patient, a medically compromised condition under long-term dialysis is considered a predisposing factor, which made the atrophic mandible more susceptible to the stress related to mouth-opening training. PMID- 21535402 TI - Multidisciplinary approach to the rehabilitation of a tooth with two trauma episodes: systematic review and report of a case. AB - Studies have shown that some children and adolescents are affected only once with dental trauma, while others seem to be accident-prone and suffer from multiple dental trauma episodes. Less is known about treatment consequences related to repeated traumatic dental injuries to the same tooth and treatment guidelines are not well established. Complicated crown fractures and crown-root fractures pose difficulties for dentists to establish adequate treatment plans because these fractures require multidisciplinary knowledge and approach for a correct case planning and prognosis. The objective of this paper was to present and discuss a case of a child who sustained a second trauma to the same tooth following treatment of an earlier sustained crown fracture. The research-based background for establishment of the treatment plan is discussed. Reattachment of tooth fragment is a minimal invasive and esthetic method. Essential advantage of the reattached teeth is the fact that all the alternative methods as direct adhesive resin reconstruction, veneers and crowns can be performed in case of failure or a refracture. As a consequence of initial trauma, the tooth suffered a complicated crown fracture which was resolved by endodontic therapy and fragment reattachment. During follow-up, the child suffered a second trauma resulting in dislodgement and fracture of the reattached fragment and a crown-root fracture extending subgingivally with involvement of the biologic width. A conservative restorative option is described. After 1 year of follow-up, the clinical and radiographic findings demonstrated that the adopted clinical protocol was successful and yielded healthy periodontal tissues with no signs of periradicular pathosis. The occurrence of repeated traumatic dental injuries to teeth involving conservative management of both crown-root fracture and complicated crown fracture on the same tooth is extremely rare and a challenge for dental professionals to treat. PMID- 21535404 TI - Knowledge of elementary school teachers in Tel-Aviv, Israel, regarding emergency care of dental injuries. AB - BACKGROUND: Immediate management of traumatized teeth is often critical to the prognosis of the teeth. Most of the traumatic dental injuries occur at home, followed by school. There is a high probability that first aid would be given by lay people such as parents, teachers, or coaches. Knowledge of those people regarding emergency management of dental trauma is crucial for better prognosis. AIM: To investigate: (i) the knowledge of elementary school teachers regarding traumatic dental injuries to permanent teeth and emergency treatment, (ii) their source of information, and (iii) the demand for more education in dental trauma. MATERIALS AND METHODS: A three-part questionnaire comprised of questions regarding demographic data, attitude, and knowledge about dental injuries was distributed to teachers in 12 elementary schools in the Tel-Aviv area, Israel. RESULTS: The average knowledge score was 4.59 (in a scale of 0-10). Three individual predictors significantly improved the respondents' knowledge: being in the 35-49-year age group (P-value = 0.042), those who had children themselves (P value = 0.002) and those who had previous experience with trauma (P-value = 0.049). There was no correlation between the demand for further education in dental trauma and knowledge score. CONCLUSIONS: The knowledge regarding management of traumatic dental injuries in a group of teachers in the Tel-Aviv area is inadequate. Educational programs as well as addition to the curriculum are necessary to improve their emergency management of traumatic dental injuries and provide better protection to the students. PMID- 21535405 TI - Evaluation, using extracted human teeth, of Ricetral as a storage medium for avulsions--an in vitro study. AB - The prognosis of teeth replanted following avulsion is determined by the extra alveolar time and storage medium used. This study was undertaken to determine the efficacy of an oral rehydration solution 'Ricetral', in retaining the vitality of periodontal ligament cells when used as a storage medium for avulsed teeth prior to replantation. The study consisted of a comparative evaluation between Ricetral and two currently recommended solutions, Hank's balanced salt solution (HBSS) and milk. Thirty extracted teeth were dried for 30min and soaked in the respective storage media for 45min. The periodontal ligament cells were isolated by an enzyme treatment with collagenase and trypsin. The cells were evaluated for vitality by trypan blue staining and number of vital cells counted in a hemocytometer. Statistical analysis revealed that cell vitality was high with Ricetral and HBSS, but poor with milk. PMID- 21535406 TI - "New" techniques for more sensitive patch testing? AB - The patch test is the mainstay of diagnosis in allergic contact dermatitis. In its nearly 120-year-long history, numerous efforts to standardize several methodical aspects proved successful. The aim was always to enhance the validity and reliability of patch testing. This article reviews modifications of the basic patch test technique for enhancing test sensitivity. We expand on the recently validated strip patch test, which is a modification that involves affixing tape strips to the skin and removing them prior to patch testing. Although it was first described in 1953, we proposed the first protocol for standardized performance of the "strip patch test." The protocol was then tested in studies. As a result, test sensitivity of standardized strip patch test versus patch test was increased. The protocol produced a uniform reduction in the thickness of the stratum corneum and a good inter-rater agreement. Additionally, there was evidence of a non-specific stimulation of the inflammatory epidermal system. With regard to patient history, the standardized strip patch test showed a vastly better sensitivity than the patch test with only marginally lower specificity. As a complementary measure to patch testing diagnostic accuracy could be improved significantly by performing the standardized strip patch test. Further studies are needed on the reproducibility of the standardized strip patch test. PMID- 21535407 TI - Epsilon toxin: a fascinating pore-forming toxin. AB - Epsilon toxin (ETX) is produced by strains of Clostridium perfringens classified as type B or type D. ETX belongs to the heptameric beta-pore-forming toxins including aerolysin and Clostridium septicum alpha toxin, which are characterized by the formation of a pore through the plasma membrane of eukaryotic cells consisting in a beta-barrel of 14 amphipatic beta strands. By contrast to aerolysin and C. septicum alpha toxin, ETX is a much more potent toxin and is responsible for enterotoxemia in animals, mainly sheep. ETX induces perivascular edema in various tissues and accumulates in particular in the kidneys and brain, where it causes edema and necrotic lesions. ETX is able to pass through the blood brain barrier and stimulate the release of glutamate, which accounts for the symptoms of nervous excitation observed in animal enterotoxemia. At the cellular level, ETX causes rapid swelling followed by cell death involving necrosis. The precise mode of action of ETX remains to be determined. ETX is a powerful toxin, however, it also represents a unique tool with which to vehicle drugs into the central nervous system or target glutamatergic neurons. PMID- 21535408 TI - Crystal structure of an ascomycete fungal laccase from Thielavia arenaria--common structural features of asco-laccases. AB - Laccases are copper-containing enzymes used in various applications, such as textile bleaching. Several crystal structures of laccases from fungi and bacteria are available, but ascomycete types of fungal laccases (asco-laccases) have been rather unexplored, and to date only the crystal structure of Melanocarpus albomyces laccase (MaL) has been published. We have now solved the crystal structure of another asco-laccase, from Thielavia arenaria (TaLcc1), at 2.5 A resolution. The loops near the T1 copper, forming the substrate-binding pockets of the two asco-laccases, differ to some extent, and include the amino acid thought to be responsible for catalytic proton transfer, which is Asp in TaLcc1, and Glu in MaL. In addition, the crystal structure of TaLcc1 does not have a chloride attached to the T2 copper, as observed in the crystal structure of MaL. The unique feature of TaLcc1 and MaL as compared with other laccases structures is that, in both structures, the processed C-terminus blocks the T3 solvent channel leading towards the trinuclear centre, suggesting a common functional role for this conserved 'C-terminal plug'. We propose that the asco-laccases utilize the C-terminal carboxylic group in proton transfer processes, as has been suggested for Glu498 in the CotA laccase from Bacillus subtilis. The crystal structure of TaLcc1 also shows the formation of a similar weak homodimer, as observed for MaL, that may determine the properties of these asco-laccases at high protein concentrations. PMID- 21535409 TI - Ramiprilate inhibits functional matrix metalloproteinase activity in Crohn's disease fistulas. AB - Increased expression of matrix metalloproteinase (MMP)-2, -3 and -9 has been demonstrated in Crohn's disease fistulas, but it is unknown whether these enzymes are biologically active and represent a therapeutic target. Therefore, we investigated the proteolytic activity of MMPs in fistula tissue and examined the effect of inhibitors, including clinically available drugs that beside their main action also suppress MMPs. Fistula specimens were obtained by surgical excision from 22 patients with Crohn's disease and from 10 patients with fistulas resulting from other causes. Colonic endoscopic biopsies from six controls were also included. Total functional MMP activity was measured by a high-pressure liquid chromatography (HPLC)-based, fluorogenic MMP-substrate cleavage assay, and the specific activity of MMP-2, -3 and -9 by the MMP Biotrak Activity Assay. The MMP inhibitors comprised ethylene-diamine-tetraacetic acid (EDTA), the synthetic broad-spectrum inhibitor, GM6001, the angiotensin-converting enzyme (ACE) inhibitor, ramiprilate, and the tetracycline, doxycycline. In Crohn's disease fistulas, about 50% of the total protease activity was attributable to MMP activity. The average total MMP activity was significantly higher (about 3.5 times) in Crohn's fistulas (471 FU/MUg protein, range 49-2661) compared with non Crohn's fistulas [134 FU/MUg protein, range 0-495, (p < 0.05)] and normal colon [153 FU/MUg protein, range 77-243, (p < 0.01)]. MMP-3 activity was increased in Crohn's fistulas (1.4 ng/ml, range 0-9.83) compared with non-Crohn's fistulas, [0.32 ng/ml, range 0-2.66, (p < 0.02)]. The same applied to MMP-9 activity [0.64 ng/ml, range 0-5.66 and 0.17 ng/ml, range 0-1.1, respectively (p < 0.04)]. Ramiprilate significantly decreased the average total MMP activity level by 42% and suppressed the specific MMP-3 activity by 72%, which is comparable to the effect of GM6001 (87%). Moreover, MMP-9 activity was completely blunted by ramiprilate. Doxycycline had no effect on MMP activity. Increased functional MMP activity, notably MMP-3 and -9, is present in Crohn's fistulas and may be inhibited by ramiprilate, a widely available ACE inhibitor. PMID- 21535410 TI - In situ study of the effect of naringin, talinolol and protein-energy undernutrition on intestinal absorption of saquinavir in rats. AB - To study the potential interactions of naringin (NAR), talinolol (TAL) and protein-energy undernutrition (PEU) in the absorption process of saquinavir (SQV), perfusion experiments were performed in the small intestine of rats at different SQV concentrations. The results obtained demonstrated that SQV intestinal absorption was described by simultaneous passive diffusion (k(dif) = 3.44 hr) and saturable absorption (V(ma) = 127.31 MUM/hr; K(ma) = 10.50 MUM) together with a capacity-limited efflux (V(ms) = 270.53 MUM/hr; K(ms) = 23.44 MUM). The competitive inhibition constants of NAR on the SQV input and efflux processes were [IC50](a) = 3.98 MUM and [IC50](s) = 5.00 MUM, respectively. NAR significantly decreased (23-29%; p < 0.05) or kept unaltered the absorption rate constant (k(a) ) of SQV in function of the concentration of both compounds administered. Finally, SQV k(a) significantly increased in PEU status (around 1.8 times) when the drug was perfused either in the presence (p < 0.05) or in the absence (p < 0.01) of NAR. The variations of SQV k(a) when the antiretroviral drug is co-administered with NAR and/or TAL reinforce their interaction in the absorptive process. Malnutrition may result in altered SQV absorption, and further studies are strongly recommended to analyse the impact of this finding on the pharmacokinetic drug profile. PMID- 21535411 TI - Tacrine and bis(7)-tacrine attenuate cycloheximide-induced amnesia in mice, with attention to acute toxicity. AB - Effects of tacrine and bis(7)-tacrine (0.25-20 MUmol/kg, s.c.) on cognitive behaviour in cycloheximide (CYH)-treated mice were investigated. Cognitive behaviour was assessed by open-field test and step-through task with a 24-hr retention interval. Drugs or vehicle was given 30 min. prior to the first session. Although CYH treatment (110 mg/kg, i.p.) alone did not affect the locomotor activity of mice, CYH treatment in combination with tacrine (20 MUmol/kg) decreased the locomotor activity by 37% in the acquisition session, when compared with mice treated with CYH alone. Bis-(7) tacrine cotreatment did not produce any detectable effect on locomotor activity. During the retention trial, tacrine (5 MUmol/kg) or bis(7)-tacrine (1 MUmol/kg) enhanced the retention latency (by 3.8- or 1.4-fold, respectively) in CYH-treated mice. In both training and retention trials, CYH treatment increased the number of footshocks (by 50% and 11.3-fold, respectively). However, during the retention (but not training) trial, tacrine (5 MUmol/kg) or bis(7)-tacrine (1 MUmol/kg) decreased the footshocks (by 8.6-fold or 39%, respectively) in CYH-treated mice. Combined treatment with CYH and bis(7)-tacrine (but not tacrine) resulted in an increased mortality rate in mice. The results indicated that tacrine and bis(7)-tacrine improved the amnesia caused by CYH treatment. However, the combined treatment with bis(7)-tacrine and CYH administration caused acute toxicity. PMID- 21535412 TI - Knock-down of argonaute 2 (AGO2) induces apoptosis in myeloid leukaemia cells and inhibits siRNA-mediated silencing of transfected oncogenes in HEK-293 cells. AB - Understanding the role of oncomirs allows new insights into the development of modern therapeutic approaches for the repression of multiple oncomirs in cancer cells. At present, no suitable approach is available to repress the development of multiple oncomirs in cancer cells. Herein, we report that argonaute 2 (AGO2) could be a unique molecule to regulate the development of multiple oncomirs in cancer cells. Knock-down of AGO2 by custom-made AGO2 siRNA resulted in the induction of apoptosis in myeloid leukaemia cells (HL-60). Further investigations revealed that knock-down of AGO2 by custom-made AGO2 siRNA in HEK-293 cells resulted in silencing of the expression of target genes vascular endothelial growth factor A and histone deacetylase 2, which are known to be involved in the development of myeloid leukaemia. From these results, it can be predicted that AGO2 could regulate siRNA-mediated RNAi pathways in cancer cells. Furthermore, we investigated the possible implication of AGO2 in drug-induced apoptosis. Investigations revealed that treatment with the newly synthesized drug analogue SH-03[{(7S,7aR,13aS)-9,10-dimethoxy-3,3-dimethyl-7,7a,13,13atetrahydro-3H chromeno[3,4-b]pyrano[2,3-h]chromen-7-ol}] could induce AGO2-mediated apoptosis in myeloid leukaemia cells via intrinsic apoptotic pathways independent of Dicer. PMID- 21535415 TI - Intussusceptive angiogenesis: pillars against the blood flow. AB - Adaptation of vascular networks to functional demands needs vessel growth, vessel regression and vascular remodelling. Biomechanical forces resulting from blood flow play a key role in these processes. It is well-known that metabolic stimuli, mechanical forces and flow patterns can affect gene expression and remodelling of vascular networks in different ways. For instance, in the sprouting type of angiogenesis related to hypoxia, there is no blood flow in the rising capillary sprout. In contrast, it has been shown that an increase of wall shear stress initiates the splitting type of angiogenesis in skeletal muscle. Otherwise, during development, both sprouting and intussusception act in parallel in building the vascular network, although with differences in spatiotemporal distribution. Thereby, in addition to regulatory molecules, flow dynamics support the patterning and remodelling of the rising vascular tree. Herewith, we present an overview of angiogenic processes with respect to intussusceptive angiogenesis as related to local haemodynamics. PMID- 21535414 TI - Dishevelled C-terminus: prolyl and histidinyl motifs. AB - The phosphoprotein scaffold Dishevelled is an essential component of both Wnt signalling and of the signalsome that constitutes the supermolecular 'punctae' of assembled proteins often observed in fluorescence microscopy. The C-terminal region beyond the DEP domain displays unique and interesting character, exploited herein by careful analysis of the primary structure. Human Dishevelled-1, -2, -3 and fly Dishevelled (Dsh) sequences were downloaded and interrogated in silico. The C-terminus of Dishevelled-3 is revealed by FoldIndex((r)) to be rich in ordered structure. It displays primary sequence that is unique and divergent in important ways from vertebrate isoforms as well as from the fly Dsh. The region is amphipathic, high in prolyl content, and harbours polyprolines. Dishevelled-3 displays some regions, where the proline content is >40%. Polyprolyl sequences (2 4 residues) likely constitute important sites of interaction with other Dishevelled isoforms. Several histidine-single amino acid repeats are notable. The 637,638/647,648 repeats of Dvl3 are essential for Wnt non-canonical, but not canonical signalling. Mutagenesis reveals that the C-terminal sequence is essential for the formation of punctae, made visible by fluorescence microscopy. These Dvl3-based signalsomes are very large (25-35 MDa-MW), supermolecular complexes that display dynamic reorganization in response to Wnt stimulation. Dishevelled-3 C-terminus is rich in structure and unique motifs, worthy of detailed analysis with modern molecular tools. PMID- 21535416 TI - Exercise increases plasma levels of sphingoid base-1 phosphates in humans. AB - AIM: In recent years, blood sphingolipids attracted much attention and have been implicated in both pathophysiology and prevention of cardiovascular diseases and insulin resistance. However, factors affecting concentration and metabolism of sphingolipids in blood remain poorly recognized. We have previously found that exercise alters skeletal muscle sphingolipid metabolism. This finding prompted us to examine whether physical activity induces similar effects in blood. METHODS: Twenty healthy male patients were assigned to either untrained (UT, n = 10) or endurance trained (ET, n = 10) group. The patients performed either a 30 (UT group) or 60 (ET group) min exercise on a cycloergometer at a workload corresponding to 70% of VO(2max) . Blood samples were taken just before exercise, after 30 and 60 (ET group only) min of pedalling and following a 30-min rest. RESULTS: ET patients were characterized by higher basal plasma sphingosine-1 phosphate (S1P) concentration and decreased content of sphingosine, S1P, sphinganine-1-phosphate (SA1P) and ceramide in erythrocytes. In ET group, plasma concentrations of all measured sphingolipids remained stable both during and after exercise. On the other hand, in UT patients, the post-exercise levels of S1P and SA1P were markedly higher compared with the baseline values and this effect was accompanied by decreased erythrocyte ceramide content. CONCLUSION: It is likely that single bout of exercise and endurance training enhances production and release of S1P by erythrocytes. We speculate that exercise-induced increase in plasma S1P concentration might be one of the mechanisms underlying beneficial effects of physical activity on cardiovascular health and insulin sensitivity. PMID- 21535418 TI - Abstracts of the XXIV International Symposium on Technical Innovations in Laboratory Hematology. PMID- 21535417 TI - Local oestrogenic/androgenic balance in the cerebral vasculature. AB - Reproductive effects of sex steroids are well-known; however it is increasingly apparent that these hormones have important actions on non-reproductive tissues such as the vasculature. The latter effects can be relevant throughout the lifespan, not just limited to reproductive years, and are not necessarily restricted to one gender or the other. Our work has established that cerebral blood vessels are a non-reproductive target tissue for sex steroids. We have found that oestrogen and androgens alter vascular tone, endothelial function, oxidative stress and inflammatory responses in cerebral vessels. Often the actions of oestrogen and androgens oppose each other. Moreover, it is clear that cerebral vessels are directly targeted by sex steroids, as they express specific receptors for these hormones. Interestingly, cerebral blood vessels also express enzymes that metabolize sex steroids. These findings suggest that local synthesis of 17beta-estradiol and dihydrotestosterone can occur within the vessel wall. One of the enzymes present, aromatase, converts testosterone to 17beta-estradiol, which would alter the local balance of androgenic and oestrogenic influences. Thus cerebral vessels are affected by circulating sex hormones as well as locally synthesized sex steroids. The presence of vascular endocrine effector mechanisms has important implications for male-female differences in cerebrovascular function and disease. Moreover, the cerebral circulation is a target for gonadal hormones as well as anabolic steroids and therapeutic drugs used to manipulate sex steroid actions. The long-term consequences of these influences are yet to be determined. PMID- 21535419 TI - Clinical multicenter evaluation of a new FXa-based Antithrombin assay. AB - INTRODUCTION: The determination of functional Antithrombin is a central part of thrombophilia screening. In this multicenter study, a new FXa-based method (INNOVANCE(r) Antithrombin) was evaluated on four different analyzers. METHODS: The INNOVANCE Antithrombin method was evaluated by precision and reference interval studies and by comparing the new method with established methods through parallel measurement of samples from 249 patients and 151 apparently healthy individuals. RESULTS: The INNOVANCE Antithrombin assay demonstrated on all analyzers repeatability coefficients of variation (CVs) <= 3.2% and within-device and between-run CVs <= 6.9%. The reference intervals of all analyzers are comparable with 2.5th percentiles between 80% and 85% of normal. The INNOVANCE Antithrombin and the FIIa-based Berichrom(r) AT III (A) methods demonstrated good concordance with correlation coefficients of r = 0.908 or higher. The INNOVANCE Antithrombin method demonstrated furthermore an excellent comparability with the STA(r) Antithrombin III assay and an acceptable comparability with the Coamatic(r) LR Antithrombin assay. The patients with congenital deficiency (n = 31) were identified with all assays except for the patients carrying the P41L heparin-binding site mutation, which was only identified with the INNOVANCE Antithrombin and the STA Antithrombin III methods. CONCLUSION: The INNOVANCE Antithrombin assay has high sensitivity for Antithrombin deficiencies and is reliable, precise and suitable for routine clinical use. PMID- 21535420 TI - Bipolar disorder: from early identification to personalized treatment. PMID- 21535421 TI - Integrated genetic and genomic approach in the SingaporeTranslational and Clinical Research in Psychosis Study: an overview. AB - AIMS: Schizophrenia is a severe mental disorder with onset frequently in adolescence and followed by a chronic and disabling course. Although the exact pathophysiology of this devastating disorder has not been clearly elucidated, a large part of it has been attributed to genetic influences. This article seeks to provide an overview on what our group has embarked on--to elucidate genetic risk factors for schizophrenia within the Chinese ethnic group. METHODS: We plan to conduct an integrated approach to interrogate comprehensively the genome from different angles and in stages. The first stage involves a genome-wide association study of 1000 cases of schizophrenia-control pairs, with a follow-up replication study in another 1000 cases of schizophrenia and in 1000 controls, and combination analyses with groups from other places including China and Hong Kong. Other than the genome-wide association study, gene sequencing for purported candidate genes and copy number variation analysis will be performed. Neurocognitive intermediate phenotypes will be employed to deconstruct the complex schizophrenia phenotype in a bid to improve association findings. Promising leads from longitudinal gene and protein expression in ultra-high-risk subjects who develop psychosis and schizophrenia (in a parallel study) will be followed up as candidate genes and sequenced in the genetic analysis. Functional analysis forms the last stage of this integrated approach. CONCLUSION: This integrated genetic and genomic approach will hopefully help in further characterizing and deepening our understanding of molecular pathophysiological mechanisms underlying schizophrenia. PMID- 21535422 TI - Psychological needs of adolescents in the early phase of bipolar disorder: implications for early intervention. AB - AIM: This paper will describe the rationale for, and importance of, psychological interventions for young people early in the course of bipolar disorder. METHODS: Emerging literature in this field will be discussed in addition to describing specific clinical challenges and opportunities with this population. RESULTS: In order to be more developmentally appropriate for young people with bipolar disorder, eight aspects of clinical work which may require modification were identified. CONCLUSIONS: The evidence base for the effectiveness of psychological interventions for people diagnosed with bipolar disorder is growing. However, some aspects relating to working with adults with bipolar disorder require modification to be effective in working with young people early in the course of the disorder. PMID- 21535423 TI - Synergistic pathways to delusions: enduring vulnerabilities, proximal life stressors and maladaptive psychological coping. AB - AIM: We sought to extend findings on the vulnerability to psychosis by investigating multifactorial pathways to delusions. Risk factors assessed spanned across early acquired vulnerabilities (heredity, childhood trauma, early cannabis use), proximal life stressors (life hassles, methamphetamine use) and psychological coping (experiential avoidance). METHODS: Participants were recruited to a non-clinical sample (n = 133) or a clinical sample of psychosis patients (n = 100). RESULTS: Path analyses indicated three distinct pathways predicting vulnerability to delusions in the non-clinical sample: (i) childhood emotional trauma combined with subsequent experiences of life hassles; (ii) heredity in combination with experiential avoidance; and (iii) early cannabis use combined with proximal methamphetamine use. The first pathway was partially mediated by experiential avoidance. The model was largely replicated in the clinical sample, with childhood sexual trauma replacing emotional trauma in the model. CONCLUSION: The study demonstrated that vulnerability to delusions can be usefully predicted by a synergistic model incorporating early-acquired vulnerability factors, proximal day-to-day factors and cognitive styles. PMID- 21535424 TI - Group cognitive behavioural therapy as a treatment for negative symptoms in first episode psychosis. AB - AIM: We aimed to test the idea that there is an early critical time period during a psychotic illness when patients may be more responsive to psychological treatment attention. METHODS: We tested this hypothesis by comparing the treatment responsiveness to group cognitive behavioural therapy (CBT) of 25 first episode psychosis participants (FEP) and 15 patients with currently stable psychosis (n = 40). RESULTS: Following 12 sessions of outpatient-based group CBT, there were significant decreases in positive, depressive and anxiety symptoms, and an improvement in quality of life for both groups. However, negative symptoms only improved in the FEP group. CONCLUSION: Considering the pernicious nature of negative symptoms as well as the difficulties in treating them, this study provides some support for the concept of early intervention with CBT. PMID- 21535425 TI - Clinical efficacy of individual cognitive therapy in reducing psychiatric symptoms in people at ultra-high risk for psychosis. AB - AIM: Recently, cognitive therapy in people at ultra-high risk (UHR) for psychosis has been reported to show modest treatment benefits. The aim of this study was to assess the feasibility and efficacy of cognitive therapy in reducing psychiatric symptoms in UHR people in Korea. METHODS: We developed cognitive therapy for people at UHR for psychosis inspired by Morrison in 2004. Twenty-two UHR subjects were assigned to cognitive therapy, and 18 subjects completed the 10-session therapy. Psychopathology scores were assessed at baseline and post-treatment. RESULTS: Cognitive therapy significantly reduced the severity of psychopathology including positive, negative and depressive symptoms. The within-group effect sizes indicated large treatment benefits for these psychopathologies. CONCLUSION: These findings suggest that cognitive therapy can be administered to people at UHR for psychosis in non-western culture. PMID- 21535426 TI - Domain shuffling and module engineering of Listeria phage endolysins for enhanced lytic activity and binding affinity. AB - Bacteriophage endolysins are peptidoglycan hydrolases employed by the virus to lyse the host at the end of its multiplication phase. They have found many uses in biotechnology; not only as antimicrobials, but also for the development of novel diagnostic tools for rapid detection of pathogenic bacteria. These enzymes generally show a modular organization, consisting of N-terminal enzymatically active domains (EADs) and C-terminal cell wall-binding domains (CBDs) which specifically target the enzymes to their substrate in the bacterial cell envelope. In this work, we used individual functional modules of Listeria phage endolysins to create fusion proteins with novel and optimized properties for labelling and lysis of Listeria cells. Chimaeras consisting of individual EAD and CBD modules from PlyPSA and Ply118 endolysins with different binding specificity and catalytic activity showed swapped properties. EAD118-CBDPSA fusion proteins exhibited up to threefold higher lytic activity than the parental endolysins. Recombineering different CBD domains targeting various Listeria cell surfaces into novel heterologous tandem proteins provided them with extended recognition and binding properties, as demonstrated by fluorescent GFP-tagged CBD fusions. It was also possible to combine the binding specificities of different single CBDs in heterologous tandem CBD constructs such as CBD500-P35 and CBDP35-500, which were then able to recognize the majority of Listeria strains. Duplication of CBD500 increased the equilibrium cell wall binding affinity by approximately 50 fold, and the enzyme featuring tandem CBD modules showed increased activity at higher ionic strength. Our results demonstrate that modular engineering of endolysins is a powerful approach for the rational design and optimization of desired functional properties of these proteins. PMID- 21535427 TI - Bacteriophages and genetic mobilization in sewage and faecally polluted environments. AB - Bacteriophages are one of the most abundant entities on the planet and are present in high concentrations within humans and animals, mostly in the gut. Phages that infect intestinal bacteria are released by defecation and remain free in extra-intestinal environments, where they usually persist for longer than their bacterial hosts. Recent studies indicate that a large amount of the genetic information in bacterial genomes and in natural environments is of phage origin. In addition, metagenomic analysis reveals that a substantial number of bacterial genes are present in viral DNA in different environments. These facts support the belief that phages can play a significant role in horizontal gene transfer between bacteria. Bacteriophages are known to transfer genes by generalized and specialized transduction and indeed there are some examples of phages found in the environment carrying and transducing genes of bacterial origin. A successful transduction in the environment requires certain conditions, e.g. phage and bacterial numbers need to exceed certain threshold concentrations, the bacteria need to exist in an infection-competent physiological state, and lastly, the physical conditions in the environment (pH, temperature, etc. of the supporting matrix) have to be suitable for phage infection. All three factors are reviewed here, and the available information suggests: (i) that the number of intestinal bacteria and phages in faecally contaminated environments guarantees bacteria phage encounters, (ii) that transduction to intestinal bacteria in the environment is probable, and (iii) that transduction is more frequent than previously thought. Therefore, we suggest that phage-mediated horizontal transfer between intestinal bacteria, or between intestinal and autochthonous bacteria in extra-intestinal environments, might take place and that its relevance for the emergence of new bacterial strains and potential pathogens should not be ignored. PMID- 21535428 TI - Molecular detection of trophic links in a complex insect host-parasitoid food web. AB - Previously, host-parasitoid links have been unveiled almost exclusively by time intensive rearing, while molecular methods were used only in simple agricultural host-parasitoid systems in the form of species-specific primers. Here, we present a general method for the molecular detection of these links applied to a complex caterpillar-parasitoid food web from tropical rainforest of Papua New Guinea. We DNA barcoded hosts, parasitoids and their tissue remnants and matched the sequences to our extensive library of local species. We were thus able to match 87% of host sequences and 36% of parasitoid sequences to species and infer subfamily or family in almost all cases. Our analysis affirmed 93 hitherto unknown trophic links between 37 host species from a wide range of Lepidoptera families and 46 parasitoid species from Hymenoptera and Diptera by identifying DNA sequences for both the host and the parasitoid involved in the interaction. Molecular detection proved especially useful in cases where distinguishing host species in caterpillar stage was difficult morphologically, or when the caterpillar died during rearing. We have even detected a case of extreme parasitoid specialization in a pair of Choreutis species that do not differ in caterpillar morphology and ecology. Using the molecular approach outlined here leads to better understanding of parasitoid host specificity, opens new possibilities for rapid surveys of food web structure and allows inference of species associations not already anticipated. PMID- 21535429 TI - Usefulness of alkaline hydrogen peroxide oxidation to analyze eumelanin and pheomelanin in various tissue samples: application to chemical analysis of human hair melanins. AB - Eumelanin and pheomelanin in tissue samples can be specifically measured as the markers pyrrole-2,3,5-tricarboxylic acid (PTCA) and 4-amino-3 hydroxyphenylalanine after acidic permanganate oxidation and hydroiodic acid hydrolysis, respectively. Those degradation methods, although widely applied, are not easily performed in most laboratories. To overcome this difficulty, we developed alkaline H(2)O(2) oxidation in 1 M K(2)CO(3) that produces, in addition to the eumelanin marker PTCA, thiazole-2,4,5-tricarboxylic acid (TTCA) and thiazole-4,5-dicarboxylic acid (TDCA) as markers for pheomelanin and pyrrole-2,3 dicarboxylic acid (PDCA) as a marker for 5,6-dihydroxyindole-derived eumelanin. Those four degradation products can be easily separated by HPLC and analyzed with ultraviolet detection. The alkaline H(2)O(2) oxidation method is simple, reproducible and applicable to all pigmented tissues. Its application to characterize eumelanin and pheomelanin in human hair shows that PTCA and TTCA serve as specific markers for eumelanin and pheomelanin, respectively, although some caution is needed regarding the artificial production of TTCA from eumelanic tissue proteins. PMID- 21535430 TI - Functional foods for the fetus? PMID- 21535431 TI - Pelvic pain in pregnancy may be caused by uterosacral ligament laxity and may be associated with nocturia, urgency and abnormal bladder emptying. PMID- 21535432 TI - Balloon tamponade in atonic bleeding induces uterine contraction: attempt to quantify uterine stiffness using acoustic radiation force impulse elastography before and after balloon tamponade. PMID- 21535433 TI - Women with chromosomally normal male fetuses are at increased risk of being referred for invasive testing following first-trimester risk assessment. AB - OBJECTIVE: This study investigated the gender distribution in karyotype results from chorionic villus samples and amniocenteses performed due to an increased risk for Down syndrome based on first-trimester combined risk assessment. METHODS: All prenatal karyotypes performed from 2006-2008 due to a risk assessment above 1:300 were retrieved from the Danish Central Cytogenetic Register. The distribution of gender for all newborns was obtained from Statistics Denmark. The chi(2) test and odds ratios were used for intergroup comparison. RESULTS: We retrieved 5 157 karyotype results (54.9% male and 45.1% female karyotypes), of which 4 662 were normal. During the same period, 100 112 boys and 94 732 girls were born. Women carrying male fetuses were significantly more often referred for invasive testing than women carrying female fetuses (2.8 vs. 2.5%, p < 0.0001). However, the proportion of chromosomally normal male fetuses was significantly greater than that for female fetuses (92.0 vs. 88.4%, p < 0.0001). CONCLUSION: A significantly higher proportion of women pregnant with male fetuses compared with female fetuses had an invasive diagnostic test performed prenatally following a risk assessment for Down syndrome. PMID- 21535434 TI - Evidence regarding an effect of marine n-3 fatty acids on preterm birth: a systematic review and meta-analysis. AB - BACKGROUND: Preterm delivery remains a substantial healthcare problem, complicating 5-10% of pregnancies, and is the major cause of perinatal morbidity and mortality in the developed world. Few effective methods to prevent preterm delivery have been identified to date. OBJECTIVE: To review systematically the evidence from randomized controlled trials with respect to the hypothesis that increased consumption of marine n-3 fatty acids in pregnancy can prevent preterm birth. SETTING: Electronic searches of the following databases were performed: PubMed (1995-2009), SCOPUS including EMBASE (1995-2009), and Cochrane Library. A combination of key words and text words related to fish oil, marine n-3 fatty acids, fish consumption, preterm birth, preterm delivery, prematurity, pregnancy duration, gestational age, parturition, delivery and pregnancy were used. METHODS: A systematic review of randomized controlled trials of relevance was conducted. Three trials were included, comprising 921 women for whom data on gestational age and 1 187 women for whom data on birthweight were available. RESULTS: Overall, 46 (8.9%) of 516 women who received n-3 fatty acids gave birth before 37 completed weeks of gestation, compared with 66 (16.3%) of 405 in the control group [relative risk 0.61; 95% confidence interval (CI) 0.40-0.93; p<0.05]. Data on delivery before 34 completed weeks showed the same trend (relative risk 0.32; 95% CI 0.09-0.95). Overall, the mean birthweight was 71g higher in women who received n-3 fatty acids during pregnancy (95% CI 4.73 138.12; p<0.05). The rate of low birthweight was not statistically significantly different between the intervention and the control groups. The mean gestational age at delivery was significantly higher by 4.5 days in the intervention group supplemented with n-3 fatty acids compared with placebo (95% CI 2.3-6.8; p<0.05). CONCLUSIONS: Marine n-3 fatty acids administered in pregnancy reduce the rate of preterm birth and increase birthweight. PMID- 21535435 TI - Physical activity monitor for recording energy expenditure in pregnancy. AB - OBJECTIVE: To determine whether the energy expenditure recorded with the physical activity monitor SenseWearTM Pro(2) Armband differs from that recorded with indirect calorimetry. DESIGN: Cross-sectional comparison of measures of energy expenditure. SETTING: A convenient sample recruited from a randomized controlled trial. POPULATION: Twenty-nine pregnant women (24-43 years old). METHODS: Energy expenditure was recorded with SenseWearTM Pro(2) Armband and a portable oxygen analyzer for 90 minutes while carrying out a variety of activities of different intensities. MAIN OUTCOME MEASURES: Energy expenditure recorded with the physical activity monitor SenseWearTM Pro(2) Armband. RESULTS: Comparing energy expenditure during free-living activities, the mean differences and limits of agreements from Bland-Altman plots was -136+/-343 kJ, giving an underestimation of energy expenditure by 9%. The intraclass correlation coefficient was 0.85 (95% confidence interval 0.71-0.93; p<0.001), giving 85% of the variance explained by differences among individuals. CONCLUSIONS: SenseWearTM Pro(2) Armband is a valid measure of energy expenditure during pregnancy. PMID- 21535436 TI - Clinical relevance of the HLA system in blood transfusion. AB - HLA alloimmunization induced by pregnancy, multiple transfusions or transplantation is responsible for some of the serious complications seen in patients receiving blood and blood products. These complications are primarily the result of antibody and antigen triggering an acute immunological reaction, which in some cases can be fatal e.g. TRALI. Some adverse reactions are triggered by HLA antibodies present in the patient whereas others are initiated by antibodies or HLA reactive cells present in the transfused product. The introduction of universal leucodepletion for the prevention of vCJD transmission has resulted in a significant reduction in these reactions by eliminating the main source of alloimmunization, but residual cellular components or platelets are still able to activate the immune system and induce the development of HLA reactive antibodies or T cells. However, the use of more sensitive and specific techniques to detect HLA antibodies and antigens has not only improved the investigation of transfusion reactions and their subsequent diagnosis, but it has also facilitated the implementation of a number of measures such as the use of HLA antibody negative products to further reduce their development. PMID- 21535437 TI - Fibrinogen concentrates for bleeding trauma patients: what is the evidence? AB - INTRODUCTION: A balanced transfusion of red blood cells, fresh frozen plasma and platelets are recommended for massively bleeding trauma patients. Fibrinogen concentrates could potentially lessen or replace the need for fresh frozen plasma and/or platelet transfusions. OBJECTIVE: To provide a review of the literature covering the application of fibrinogen concentrates in trauma care. METHODS: PubMed and Cochrane database search, 'fibrinogen' and ('concentrate' or 'trauma'), not 'congenital', 10 years. RESULTS: Only four papers were identified. None were randomized controlled trials. The main conclusion of these papers was that administration of fibrinogen sometimes together with prothrombin complex concentrate might improve haemostasis in trauma patients resuscitated with synthetic colloids. CONCLUSION: Evidence for the use of fibrinogen concentrate to trauma patients with massive bleeding is lacking. Well-designed prospective, randomized, double-blinded studies evaluating the effect of fibrinogen concentrate, as the only intervention, are urgently needed. PMID- 21535438 TI - A re-evaluation of the risk of transfusion-transmitted HIV prevented by the exclusion of men who have sex with men from blood donation in England and Wales, 2005-2007. AB - BACKGROUND AND OBJECTIVES One component of the rationale for lifetime exclusion of men who have sex with men (MSM) from blood donation in the UK is the probable reduction in the risk of transfusion-transmitted HIV; this exclusion has recently been questioned. MATERIALS AND METHODS Data about HIV in blood donors and MSM were analysed to estimate the risk of infectious donations entering the blood supply under different scenarios of donor selection criteria (and donor compliance) for MSM and a heterosexual group with increased risk of HIV. RESULTS In 2005-2007, a change from lifetime exclusion of MSM to 5-year deferral or no deferral increased the point estimate of HIV risk by between 0.4% and 7.4% depending on compliance with the deferral (range -4% to 15%) and 26.5% (range 18% to 43%) respectively. A change from a 12-month deferral of the high-risk heterosexual group to lifetime exclusion reduced the estimated risk by about 7.2% (range 6% to 9%). Each point estimate was within the probable range of risk under the current criteria. CONCLUSION If prevalence is the only factor affected by a reduced deferral, then the increased risk of HIV is probably negligible. However, the impact of a change depends on compliance; if this stays the same or worsens, the risk is expected to increase because of more incident infections in MSM who donate blood. The risk of transfusion-transmitted HIV could probably be reduced further by improving compliance with any exclusion, particularly after recent risk behaviours. PMID- 21535439 TI - The safety of blood donation by elderly blood donors. AB - BACKGROUND Due to the ageing population, blood donation by the elderly is necessary to maintain blood supply. We initiated a prospective study, to assess whether there is an increased risk of donor reactions in elderly donors. STUDY DESIGN AND METHODS In this prospective study, regular donors aged from 66 to 68 and 69 to 71 years were invited to continue blood donation on mobile collection sites of the German Red Cross Blood Service West. A control group (50-52 years) was established. Admission of donors in all groups followed the German national guidelines for blood donation. Donor deferrals and all kinds of donor reactions during donation (on-site) and in the 48 h following donation (off-site) were monitored. RESULTS A total of 64 260 valid cases were entered in the study. Donor deferrals increased with age from 1.12% in the control group up to 8.74 in female donors aged 69-71 years. Adverse reactions to blood donation were rare with an overall reaction rate of 0.63% (0.05% on-site; 0.58% off-site). Off-site reactions significantly decreased with increasing age. The relative risk (RR) for adverse reactions in elderly donors compared to the control group (50-52 years) was slightly increased for on-site reactions in the 69- to 71-year-old donors (RR 1.0309; 95% CI 1.0292-1.0325). In all other comparisons, the RR for adverse reactions was distinctively lower in elderly donors (RR 0.3785 - 0.7778). CONCLUSIONS Our data confirm that elderly regular blood donors may safely continue blood donation at least to the age of 71. Based on these data, we increased the upper age limit. PMID- 21535440 TI - Factors associated with fainting: before, during and after whole blood donation. AB - BACKGROUND Whole blood (WB) donation encompasses several periods during which some donors faint. Identification of factors associated with fainting during each period should guide intervention strategies. Reducing faint reactions may reduce donor injuries and disability. METHODS Blood donation was divided into three periods: Period 1 - registration; Period 2 - phlebotomy; and Period 3 - post phlebotomy. Period 3 consists of two sub-periods (3A - on-site and 3B - off site). For each Period, stratified rates of fainting in relation to various donor and donation characteristics were calculated and multivariable logistic regression analyses to identify factors associated with fainting were conducted. Donor injuries in each period were also analysed. RESULTS Of the 956 766 donors registered in 2007, 554 534 (58%) donated WB. There were 43 fainting episodes and two injuries in Period 1 and 1520 faints and 73 injuries in Periods 2 and 3. Regression analyses showed that youth and donor first-time status are associated with fainting in all periods; but most significantly in Period 1. Small estimated blood volume is notably not a factor in Period 1 but is significant in Periods 2 and 3. The highest injury rate is seen in Period 3A (0.07 and 0.09/1000 donations) for male and female donors, respectively. CONCLUSIONS Variability in factors associated with fainting across defined periods of the donation process suggest differing underlying mechanisms and the possibility that interventions for the reactions most associated with injury during each time period can be designed. The highest rate of injury per donation occurred in ambulating donors. PMID- 21535441 TI - Caucasian facial L* shifts may communicate anti-ageing efficacy. AB - An ageing study was conducted to capture skin colour parameters in the CIELab system from Caucasians of both genders and all available adult ages. This study produced a linear correlation between L* and age for a Caucasian population between 20 and 59 years of age as follows: (L* value) = -0.13 * (Age in years) + 63.01. Previous studies have addressed age-related changes in skin colour. This work presents a novel consumer correlated quantitative linear model of skin brightness by which to communicate age-related changes. Two product assessment studies are also presented here, demonstrating the ability of anti-ageing products to deliver on objective and subjective improvements in skin brightness. It was determined to be possible to use the fundamental Caucasian L*-age correlation to describe product benefits in a novel quantitative and consumer relevant fashion, through the depiction of a 'years back' calculation. PMID- 21535442 TI - Quantitative assessment of lactate and progerin production in normal human cutaneous cells during normal ageing: effect of an Alaria esculenta extract. AB - Anti-ageing products are of a great importance in cosmetic fields. However, even if numerous strategies have been proposed to fight against skin ageing or to minimize its aesthetic impact since the beginning of the 'scientific cosmetology' era, the products basing their efficacy on the observation of pathological situations are rare. The most obvious pathology linked to the ageing of skin (notably) consists in the Hutchinson-Gilford Progeria Syndrome (HGPS), a rare disorder characterized by accelerated ageing and early death. In this disease the lamin A, a protein participating (with others lamins) in the formation of the nuclear lamina and implicated in nuclear stability, chromatin structure and gene expression, is present in a truncated version called progerin. In this study, we have examined the lactate and the progerin production of human normal cutaneous cells issued from subjects of different ages. Using a sensitive and specific progerin ELISA assay developed in house, we so provide the first quantitative demonstration of an increased progerin expression and lactate production in skin during ageing. Moreover, we have also demonstrated that in the selected experimental conditions, it was possible to down-regulate the progerin production of aged cells by using an algae extract. As this extract, an Alaria esculenta extract, could be used in cosmetic formulations, we suggest that a better understanding of the skin pathologies could be a useful tool in developing efficient active compounds, attractive for but not limited to cosmetic purposes. PMID- 21535443 TI - Topically applied KTTKS: a review. AB - Skin ageing is an irreversible process that is caused by both intrinsic and extrinsic factors. The possibility of arresting or delaying skin ageing represents a large research area and has a big potential in the cosmetics sector. Recently, the polypeptide lysine-threonine-threonine-lysine-serine (KTTKS) has attracted a lot of attention and it features in numerous up-market cosmetic products where it has become erroneously associated with the term 'pentapeptide'. In this study, we review in detail KTTKS and its major derivatives, in terms of the limited information in the literature and an appraisal of its physicochemical and theoretical skin permeation properties. There appears to be a sound in vitro basis for its action on fibroblasts due to its stimulatory effect on extracellular matrix synthesis, where the stimulatory effect of KTTKS is specific to collagen types I and III and fibronectin expression. However, there is a surprising absence of in vitro skin penetration data in the literature, and there are relatively few clinical studies using these materials. PMID- 21535444 TI - A durability study of a paracorporeal pulsatile electro-mechanical pneumatic biventricular assist device. AB - In 2002, the paracorporeal pulsatile electro-mechanical pneumatic ventricular assist device (VAD) began to be developed by the Korea Artificial Organ Center at Korea University under a Health & Medical Technology Research and Development program which finished in 2008. In vitro durability testing was conducted on the paracorporeal pulsatile pneumatic VAD to determine device durability and to evaluate device failures. The 1- and 2-year reliability of the paracorporeal pulsatile pneumatic VAD was shown to be 91.2% and 54.9%, respectively, with an 80% confidence level. Failure modes were analyzed using fault tree analysis, with customized software continuously acquiring data during the test period. After this period, 21 in vivo animal tests were done, with 14 cases of left atrium to left ventricle (LV) inflow cannulation (36Fr)/outflow grafting to descending aorta, and seven cases of apex cannulation of LV to descending aorta (12 mm). The longest postoperative day (182 days) in Korea was recently recorded in in vivo animal testing (bovine, 90 kg, male, 3.5-4.0 L/min flow rate, and 55 bpm). PMID- 21535445 TI - Liver stiffness measurement by magnetic resonance elastography is not associated with developing hepatocellular carcinoma in subjects with compensated cirrhosis. AB - BACKGROUND: Liver stiffness assessed using transient elastography is described as a potential risk factor for hepatocellular carcinoma (HCC) in cirrhosis. However, the strict assessment of hepatic parenchymal areas uninvolved with HCC has not been investigated. AIM: To determine if liver stiffness of nonmalignant hepatic parenchyma using magnetic resonance elastography (MRE) is higher in patients with HCC compared with controls. METHODS: Cases were defined by compensated cirrhosis with a Child-Turcotte-Pugh score <7 and HCC by radiological criteria or histology. Control subjects with compensated cirrhosis were frequency matched with cases by gender and disease aetiology. Overt manifestations of portal hypertension and previous therapy for liver disease or HCC were exclusion criteria. Region of interest analyses were performed on hepatic parenchyma regions distant to HCC location among cases. RESULTS: Thirty patients with HCC and 60 matched controls comprised the study cohort. The mean age for cases was 64+/-10 years (range, 45-85) with 70% being men. Major disease aetiologies were chronic viral hepatitis (57%), non-alcoholic fatty liver disease (33%) and alcohol (10%). Twenty-eight (93%) patients had solitary HCC lesions with a mean size of 5.2 cm (range, 2-14 cm). However, patients with HCC had similar liver stiffness among uninvolved areas distant to HCC lesions, when compared with controls without HCC (mean, 6.1+/-2.0 vs. 6.3+/-2.5 kPa, P=0.7). CONCLUSION: In contrast to previous studies with transient elastography, we did not observe a systematic association between liver stiffness assessed using MRE and the presence of HCC in patients with compensated cirrhosis. PMID- 21535446 TI - An alginate-antacid formulation (Gaviscon Double Action Liquid) can eliminate or displace the postprandial 'acid pocket' in symptomatic GERD patients. AB - BACKGROUND: Recently, an 'acid pocket' has been described in the proximal stomach, particularly evident postprandially in GERD patients, when heartburn is common. By creating a low density gel 'raft' that floats on top of gastric contents, alginate-antacid formulations may neutralise the 'acid pocket'. AIM: To assess the ability of a commercial high-concentration alginate-antacid formulation to neutralize and/or displace the acid pocket in GERD patients. METHODS: The 'acid pocket' was studied in ten symptomatic GERD patients. Measurements were made using concurrent stepwise pH pull-throughs, high resolution manometry and fluoroscopy in a semi-recumbent posture. Each subject was studied in three conditions: fasted, 20 min after consuming a high-fat meal and 20 min later after a 20 mL oral dose of an alginate-antacid formulation (Gaviscon Double Action Liquid, Reckitt Benckiser Healthcare, Hull, UK). The relative position of pH transition points (pH >4) to the EGJ high-pressure zone was analysed. RESULTS: Most patients (8/10) exhibited an acidified segment extending from the proximal stomach into the EGJ when fasted that persisted postprandially. Gaviscon neutralised the acidified segment in six of the eight subjects shifting the pH transition point significantly away from the EGJ. The length and pressure of the EGJ high-pressure zone were minimally affected. CONCLUSIONS: Gaviscon can eliminate or displace the 'acid pocket' in GERD patients. Considering that EGJ length was unchanged throughout, this effect was likely attributable to the alginate 'raft' displacing gastric contents away from the EGJ. These findings suggest the alginate-antacid formulation to be an appropriately targeted postprandial GERD therapy. PMID- 21535447 TI - Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease. AB - BACKGROUND: Infliximab (IFX) elicits acute severe infusion reactions in about 5% of patients with inflammatory bowel disease (IBD). AIM: To investigate the role of anti-IFX antibodies (Ab) and other risk factors. METHODS: The study included all IBD patients treated with IFX at a Danish university hospital until 2010 either continuously (IFX every 4-12 weeks) or episodically (reinitiation after >12 weeks). Anti-IFX Ab were measured using radioimmunoassay. RESULTS: Twenty five (8%) of 315 patients experienced acute severe infusion reactions. Univariate analysis showed that patients who reacted were younger at the time of diagnosis (19 vs. 26 years, P=0.013) and at first IFX infusion (28 vs. 35 years, P=0.012). Furthermore, they more often received episodic therapy (72% vs. 31%, P<0.001) and logistic regression revealed this as the only significant predictor of reactions (OR 5 [2-13]; P<0.001). IFX reinitiation after 6 months intermission further increased the risk (OR 8 [3-20], P<0.001). Most reactions (n=14, 88%) occurred at 2nd infusion in the 2nd treatment series (P=0.006). Anti-IFX IgG Ab were highly positive in 19 of 20 patients (95%) shortly after the reactions (median 84 U/mL). Anti-IFX IgG Ab measured prior to the retreatment series were negative in 7 of 11 patients tested (64%). Anti-IFX IgE Ab were negative in all patients with reactions. CONCLUSIONS: Acute severe infusion reactions were strongly associated with development of anti-IFX IgG Ab, but not with anti-IFX IgE Ab. The risk was particularly high at the 2nd infusion in retreatment series. Negative anti-IFX Ab before reinitiation did not rule out reactions. PMID- 21535448 TI - Population pharmacokinetic-pharmacodynamic analysis for sugammadex-mediated reversal of rocuronium-induced neuromuscular blockade. AB - AIMS: An integrated population pharmacokinetic-pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time. METHODS: Data (n= 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects. RESULTS: Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg(-1) 3 min after rocuronium, sugammadex 4 mg kg( 1) during deep neuromuscular blockade and sugammadex 2 mg kg(-1) during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time. CONCLUSIONS: Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min. PMID- 21535449 TI - Melatonin inhibits IL-1beta-induced monolayer permeability of human umbilical vein endothelial cells via Rac activation. AB - Melatonin is a key factor in the coordination of circadian rhythms and seasonal reproduction. Melatonin and its metabolites directly scavenge free radicals, increase the expression of antioxidant enzymes, and play a role in the anti inflammatory phase of defense responses. At present, there are no direct data available as to melatonin's possible influence on endothelial cell monolayer permeability, which is a major biological process responsible for vascular diseases. The aim of this study was to investigate the effect of melatonin on IL 1beta-induced human umbilical vein endothelial cells (HUVECs) monolayer permeability and then to test the involvement of small GTPase Rac in the melatonin-induced endothelial barrier-protective effects as well as cell contact reorganization. It was found that IL-1beta treatment increased the permeability of HUVECs monolayer, disrupted adherens junctions, and down-regulated the expression of VE-cadherin which is the main functional protein of adherens junctions. Melatonin, however, decreased dextran permeability and increased intercellular adherens junction areas reflecting an endothelial cell barrier protective response. Furthermore, melatonin dramatically improved IL-1beta induced Rac inactivation. Our results show that the barrier-protective effects of melatonin on endothelial cells are mediated by Rac activation and leads to enhancement of adherens junctions. PMID- 21535450 TI - Determination of antidermatophytic effects of non-steroidal anti-inflammatory drugs on Trichophyton mentagrophytes and Epidermophyton floccosum. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common pharmacological agents. They have three primary therapeutic properties including anti-inflammatory, anti-pyretic and analgesic effects. Seven NSAIDs were tested against two species of dermatophytes. Percentage inhibition was determined for effective agents. Diclofenac, aspirin and naproxen showed more potential to inhibit the growth of dermatophytes. Epidermophyton floccosum revealed susceptibility to more number of the tested agents than Trichophyton mentagrophytes. In conclusion, many NSAIDs may have a high potential to inhibit the growth of dermatophytes, while some of the agents belonging to this pharmaceutical group used in this study showed a potential activity on tested fungi. PMID- 21535451 TI - Antifungal susceptibilities of Cryptococcus neoformans cerebrospinal fluid isolates from AIDS patients in Kenya. AB - Poor susceptibility of Cryptococcus neoformans to fluconazole (FLC) is a matter of concern among clinicians in Africa. The emergence of resistance to FLC was recently reported in Kenya, but it is not known whether it is widespread. Thus, there is need for more antifungal drug susceptibility studies in Kenya. The aim of this study was to measure the in vitro antifungal drug susceptibilities of incident C. neoformans isolates from acquired immunodeficiency syndrome patients in Kenya. Antifungal susceptibility testing was performed in 67 C. neoformans isolates by broth microdilution method as outlined in the Clinical and Laboratory Standards Institute document M27-A3 using FLC, amphotericin B (AMB), voriconazole (VOR), ravuconazole (RAV) and flucytosine (5-FC). Isolates were grown on l canavanine glycine bromothymol blue medium for serotype identification. Six per cent of the isolates were identified as C. neoformans var. gattii serotype B or C and 94% as C. neoformans var. neoformans. All isolates tested were susceptible to AMB, VOR and RAV (100%), and high susceptibilities were seen to FLC (97%), and 5 FC (90%). Only 3% and 10% of the isolates' susceptibility to FLC and 5-FC, respectively, was dose-dependent or intermediate. These results demonstrate high susceptibilities of incident C. neoformans isolates to FLC and AMB, antifungals used for treatment of cryptococcal meningitis in Kenya. PMID- 21535452 TI - Design and use of Candida scores at the intensive care unit. AB - Invasive Candida infections are recognised as a cause of increased morbidity and mortality in intensive care patients, particularly those with recent extensive gastroabdominal surgery. Due to the difficulties of diagnosis, several authors have analysed risk factors suggestive of invasive candidiasis to identify patients at highest risk. Such patients may be potential candidates for preemptive antifungal therapy before becoming seriously ill. The extent of body site colonisation due to Candida species was recognised to be related with consequent invasive disease. The quantification of the colonisation was expressed as the Candida colonisation index. Based on the evaluation of independent risk factors predictive of invasive Candida infections, clinically relevant scores were evaluated in the last decade. Particularly, the Candida score that combines the clinical risk factors preceding surgery, total parenteral nutrition and severe sepsis with Candida multi-site colonisation can be considered a useful bedside scoring system to discern patients with mere Candida colonisation from patients with the risk of invasive candidiasis in non-neutropaenic critically ill patient population. PMID- 21535453 TI - Primary vocal cord aspergillosis and scanning electron microscopical observation of the focus of infection. PMID- 21535454 TI - Malassezia furfur fungaemia in a neonatal patient detected by lysis centrifugation blood culture method: first case reported in Italy. PMID- 21535455 TI - Voluntary exercise induces adult hippocampal neurogenesis and BDNF expression in a rodent model of fetal alcohol spectrum disorders. AB - Alcohol consumption during pregnancy can result in a myriad of health problems in the affected offspring ranging from growth deficiencies to central nervous system impairments that result in cognitive deficits. Adult hippocampal neurogenesis is thought to play a role in cognition (i.e. learning and memory) and can be modulated by extrinsic factors such as alcohol consumption and physical exercise. We examined the impact of voluntary physical exercise on adult hippocampal neurogenesis in a rat model of fetal alcohol spectrum disorders (FASD). Intragastric intubation was used to deliver ethanol to rats in a highly controlled fashion through all three trimester equivalents (i.e. throughout gestation and during the first 10 days of postnatal life). Ethanol-exposed animals and their pair-fed and ad libitum controls were left undisturbed until they reached a young adult stage at which point they had free access to a running wheel for 12 days. Prenatal and early postnatal ethanol exposure altered cell proliferation in young adult female rats and increased early neuronal maturation without affecting cell survival in the dentate gyrus (DG) of the hippocampus. Voluntary wheel running increased cell proliferation, neuronal maturation and cell survival as well as levels of brain-derived neurotrophic factor in the DG of both ethanol-exposed female rats and their pair-fed and ad libitum controls. These results indicate that the capacity of the brain to respond to exercise is not impaired in this model of FASD, highlighting the potential therapeutic value of physical exercise for this developmental disorder. PMID- 21535456 TI - Differentiable contributions of human amygdalar subregions in the computations underlying reward and avoidance learning. AB - To understand how the human amygdala contributes to associative learning, it is necessary to differentiate the contributions of its subregions. However, major limitations in the techniques used for the acquisition and analysis of functional magnetic resonance imaging (fMRI) data have hitherto precluded segregation of function with the amygdala in humans. Here, we used high-resolution fMRI in combination with a region-of-interest-based normalization method to differentiate functionally the contributions of distinct subregions within the human amygdala during two different types of instrumental conditioning: reward and avoidance learning. Through the application of a computational-model-based analysis, we found evidence for a dissociation between the contributions of the basolateral and centromedial complexes in the representation of specific computational signals during learning, with the basolateral complex contributing more to reward learning, and the centromedial complex more to avoidance learning. These results provide unique insights into the computations being implemented within fine grained amygdala circuits in the human brain. PMID- 21535457 TI - The role of locus coeruleus in the antiepileptic activity induced by vagus nerve stimulation. AB - Stimulation of the vagus nerve produces antiepileptic effects. This is used clinically to treat drug-refractory epilepsies. The mechanisms responsible for these effects depend on the activation of vagal afferents reaching the nucleus of the solitary tract. This review focuses on the neuroanatomy of the nucleus of the solitary tract and its relation with the nucleus locus coeruleus as a preferential anatomical substrate in producing antiepileptic effects. In fact, following the transient or permanent inactivation of locus coeruleus neurons, some antiepileptic effects of vagus nerve stimulation are lost. The activation of locus coeruleus per se is known to limit the spread of a seizure and the duration of a variety of seizure types. This is due to the fine chemical neuroanatomy of norepinephrine pathways that arise from the locus coeruleus, which produce widespread changes in cortical areas. These changes may be sustained by norepinephrine alone, or in combination with its co-transmitters. In addition, vagus nerve stimulation may prevent seizures by activating the serotonin containing dorsal raphe neurons. PMID- 21535458 TI - Before the cradle and beyond the grave: a lifespan/settings-based framework for health promotion. AB - AIM: To develop a unique framework which combines the concepts of settings and lifespan where they are applied to health promotion. BACKGROUND: The influential World Health Organisation's 1986 Ottawa Charter for Health Promotion supported certain settings being nominated as unique social systems for enabling specific health promotion activity. These initially included a whole raft of proposed settings ranging from the micro to macro; these at the time mainly being hospitals, communities, schools, workplaces, cities, villages, islands and the home and family. Several other settings have since also been added to the list - which now include health-promoting universities and health-promoting prisons. Most of the mentioned settings have in more recent times being acknowledged in the nursing literature. DESIGN: Discursive. METHOD: A critical examination and exploration of the existing health promotion literature related to both settings and lifespan. RESULTS: It is possible to combine the related, but hitherto unexplored, concepts of health promotion settings and lifespan. This has resulted in a useable framework to further assist practitioners with their health promotion work. CONCLUSION: What has not yet surfaced in both the nursing and the general health promotion literature is that most settings can be linked as a whole, not just by their geographical location and proximity to each other, but also to the fact that they tend to follow a linear direction that ranges across the total lifespan. RELEVANCE TO CLINICAL PRACTICE: Viewing health promotion in the way that this framework proposes further assists in locating and clarifying the often confused and contested position of health promotion in nursing. PMID- 21535459 TI - Perceived health and risk of undernutrition: a comparison of different nutritional screening results in older patients. AB - AIMS AND OBJECTIVES: To compare screening results using different nutritional screening instruments with respect to nutritional risk and associations with perceived health and health-related issues in a group of older hospital patients. BACKGROUND: The association between lower perceived health and nutritional risk in older people is widely known. It is advised to use a screening instrument to identify nutritional at-risk patients. DESIGN: A cross-sectional study design was used. METHODS: One hundred and fifty-eight older patients, in three medical hospital wards in two hospitals in southern Norway, were interviewed using a questionnaire containing questions about background variables, perceived health and health-related issues and the nutritional screening instruments Nutritional Form for the Elderly and Mini Nutritional Assessment (including Mini Nutritional Assessment-Short Form). Data were also collected regarding the screening instrument Nutrition Risk Screening 2002. All data were analysed using statistical methods. RESULTS: Many patients were at nutritional risk independent of instrument used. Nutrition Risk Screening 2002 identified fewer nutritional at risk patients than the other instruments did. Perceived ill health was significantly associated with nutritional risk using instruments specifically designed for older people. Feeling satisfied with life and lower risk of undernutrition were two important predictors for perceived good health. CONCLUSIONS: Nutritional Form for the Elderly, Mini Nutritional Assessment and Mini Nutritional Assessment-Short Form could identify approximately the same number of nutritional at-risk patients. Being at nutritional risk had a negative impact on older patients' perceived health. RELEVANCE FOR PRACTICE: Corresponding nutritional screening results can be obtained using either Nutritional Form for the Elderly or Mini Nutritional Assessment, as well as Mini Nutritional Assessment-Short Form. Instruments designed for older people should be used to screen older patients. Factors associated with nutritional risk can aid nurses in becoming aware of nutritional at-risk patients. Preventing undernutrition is important for overall health enhancement. PMID- 21535460 TI - Correlation between scanning laser polarimetry with and without enhanced corneal compensation and high-definition optical coherence tomography in normal and glaucomatous eyes. AB - PURPOSE: To assess the relationship between high-definition optical coherence tomography (HD-OCT) and scanning laser polarimetry (SLP) with variable (VCC) and enhanced (ECC) corneal compensation in measuring peripapillary retinal nerve fibre layer (RNFL) thickness in healthy eyes and those with early-to-moderate glaucomatous VF loss. METHODS: Healthy volunteers and patients with glaucoma who met the eligibility criteria were enrolled in this prospective, cross-sectional, and observational study. Subjects underwent complete ophthalmologic examination, automated perimetry, SLP-ECC, SLP-VCC and HD-OCT. SLP parameters were recalculated in 90 degrees segments (quadrants) in the calculation circle to be compared. Pearson correlation coefficients and Lin's concordance correlation coefficients were calculated. The p-values < 0.05 were considered statistically significant. RESULTS: Fifty-five normal volunteers (mean age 59.1 years) and 33 patients with glaucoma (mean age 63.8 years) were enrolled. In the glaucoma group, 18 patients (54.5%) had MD >= -6.0 dB (early glaucoma) and 15 patients (45.4%) had MD between -6.01 and -12.0 dB (moderate glaucoma). The best correlation between HD-OCT and SLP was found in the superior quadrant thickness, r = 0.74 (0.62-0.82) (p < 0.0001) with SLP-VCC and in the average thickness, r = 0.80 (0.71-0.86) (p < 0.0001) and the superior quadrant thickness r = 0.80 (0.71 0.87) (p < 0.0001) with SLP-ECC. Concordance correlation coefficients obtained for every parameter in our study between HD-OCT and SLP-VCC and between HD-OCT and SLP-ECC were poor. CONCLUSIONS: Our results suggest that HD-OCT parameters of RNFL thickness are significantly higher than SLP-VCC and SLP-ECC parameters, and therefore those thickness values are not interchangeable. The HD-OCT and SLP methods are well correlated but concordance is poor. The difference plots show a lack of agreement that changes as a proportion of the mean. PMID- 21535462 TI - Bio. Gerd B. Muller. PMID- 21535463 TI - Evolution of repeated structures along the body axis of jawed vertebrates, insights from the Scyliorhinus canicula Hox code. AB - The Hox gene family encodes homeodomain-containing transcription factors involved in the patterning of structures composed of repeated elements along the antero posterior axis of Bilateralia embryos. In vertebrate, Hox genes are thought to control the segmental identity of the rhombomeres, the branchial arches, and the somites. They are therefore thought to have played a key role in the morphological evolution of structures like the jaw, girdles, and vertebrae in gnathostomes. Thus far, our knowledge about the expression patterns of the Hox genes, the Hox code, has been mainly restricted to osteichthyans species and little is known about chondrichthyans. Recently, we identified 34 Hox genes clustered in three complexes (HoxA, HoxB, and HoxD) in the dogfish (Scyliorhinus canicula) genome suggesting that in sharks most, if not all, genes belonging to the HoxC complex are lost. To gain insights into the evolution of gnathostome Hox transcription, we present here expression patterns along the anteroposterior axis for all Hox genes known in the dogfish. A comparison of these patterns with those of osteichthyans shows that the expression patterns of the Hox genes in serially homologous compartments such as the branchial arches, the hindbrain, and the somites underwent only subtle changes during the evolution of gnathostomes. Therefore, the nested expression of Hox genes in these structures, the Hox code, is a ground plan, which predates the morphological diversification of serially homologous structures along the body axis. PMID- 21535465 TI - Finding the frame shift: digit loss, developmental variability, and the origin of the avian hand. AB - The origin of the tridactyl hand of crown birds from the pentadactyl hand of those early theropod dinosaurs lying along the avian stem has become a classic, but at times seemingly intractable, historical problem. The point in question is whether the fingers of crown birds represent digits 1-3 as predicted by generalized trends in the fossil record; or digits 2-4, as evidenced by the topology of the embryonic mesenchymal condensations from which the digits develop. The frame shift hypothesis attempted to resolve this paradox by making these signals congruent by means of a homeotic transformation in digital identity, but recently the paleontological support for this hypothesis was questioned. Here, we reassess the frame shift from a paleontological perspective by addressing what predictions a frame shift makes for skeletal morphology, whether the frame shift remains a viable explanation of the known fossil data, and where on the theropod tree the frame shift most likely occurred. Our results indicate that the frame shift remains viable, and based on the inferred pattern of digit loss, the frame shift likely occurred at a deeper position in theropod phylogeny than previously proposed. A new evolutionary model of the frame shift is described in which the early history of the frame-shifted hand is marked by an extended zone of developmental polymorphism. This model provides a new conceptual framework for the role of developmental variability in communicating broad evolutionary patterns on a taxonomically inclusive phylogenetic tree. PMID- 21535464 TI - Hepatocyte growth factor is crucial for development of the carapace in turtles. AB - Turtles are characterized by their shell, composed of a dorsal carapace and a ventral plastron. The carapace first appears as the turtle-specific carapacial ridge (CR) on the lateral aspect of the embryonic flank. Accompanying the acquisition of the shell, unlike in other amniotes, hypaxial muscles in turtle embryos appear as thin threads of fibrous tissue. To understand carapacial evolution from the perspective of muscle development, we compared the development of the muscle plate, the anlage of hypaxial muscles, between the Chinese soft shelled turtle, Pelodiscus sinensis, and chicken embryos. We found that the ventrolateral lip (VLL) of the thoracic dermomyotome of P. sinensis delaminates early and produces sparse muscle plate in the lateral body wall. Expression patterns of the regulatory genes for myotome differentiation, such as Myf5, myogenin, Pax3, and Pax7 have been conserved among amniotes, including turtles. However, in P. sinensis embryos, the gene hepatocyte growth factor (HGF), encoding a regulatory factor for delamination of the dermomyotomal VLL, was uniquely expressed in sclerotome and the lateral body wall at the interlimb level. Implantation of COS-7 cells expressing a HGF antagonist into the turtle embryo inhibited CR formation. We conclude that the de novo expression of HGF in the turtle mesoderm would have played an innovative role resulting in the acquisition of the turtle-specific body plan. PMID- 21535466 TI - Conservation and diversification of gene function during mouthpart development in Onthophagus beetles. AB - The evolutionary success of insects is in part attributable to the tremendous diversification of their mouthparts, which permitted insects to radiate into novel food niches. The developmental genetic basis of mouthpart development has been well studied in at least two insect taxa possessing derived mouthparts, the hemipteran Oncopeltus fasciatus and Drosophila. However, much less is known about the regulation of mouthpart differentiation of the presumed ancestral mandibulate type. Here we aim to extend current insights into the patterning of mandibulate mouthparts through a functional genetic analysis of three leg gap genes, homothorax (hth), dachshund (dac), and Distal-less (Dll), in the dung beetle Onthophagus taurus, a species whose mouthpart arrangement has in part retained, as well as diverged form, the ancestral mandibulate mouthpart type. We specifically include in this study a first functional genetic analysis of the adult labrum, an enigmatic mouthpart whose appendicular origin has been the subject of a long-standing debate. Our results support a functional role of all three patterning genes in the development of the labium, maxilla, as well as the labrum. In contrast, mandible development appeared to rely only on the patterning functions of hth and dac, but not Dll. Here, our results raise the possibility that evolutionary changes in the dac-patterning may have played an important role in the evolutionary transition from a short, triangular mandible adapted for chewing to the elongated, flat, and blade-like mandible of modern filter-feeding scarabaeine beetles. In general, our results contribute to a growing body of studies that suggest that basic patterning genes can contribute to morphological evolution of adult features while maintaining traditional patterning responsibilities at earlier developmental stages or in other body regions. PMID- 21535468 TI - Morphogens, nutrients, and the basis of organ scaling. AB - The regulation of organ size is a long-standing problem in animal development. Studies in this area have shown that organ-intrinsic patterning morphogens influence organ size, guiding growth in accordance with positional information. However, organ-extrinsic humoral factors such as insulin also affect organ size, synchronizing growth with nutrient levels. Proliferating cells must integrate instructions from morphogens with those from nutrition so that growth proceeds as a function of both inputs. Coordinating cell proliferation with morphogens and nutrients ensures organs scale appropriately with body size, but the basis of this coordination is unclear. Here, the problem is illustrated using the Drosophila wing--a paradigm for organ growth and size control--and a potential solution suggested. PMID- 21535467 TI - Molecular paleobiological insights into the origin of the Brachiopoda. AB - Most studies of brachiopod evolution have been based on their extensive fossil record, but molecular techniques, due to their independence from the rock record, can offer new insights into the evolution of a clade. Previous molecular phylogenetic hypotheses of brachiopod interrelationships place phoronids within the brachiopods as the sister group to the inarticulates, whereas morphological considerations suggest that Brachiopoda is a monophyletic group. Here, these hypotheses were tested with a molecular phylogenetic analysis of seven nuclear housekeeping genes combined with three ribosomal genes. The combined analysis finds brachiopods to be monophyletic, but with relatively weak support, and the craniid as the sister taxon of all other brachiopods. Phylogenetic-signal dissection suggests that the weak support is caused by the instability of the craniid, which is attracted to the phoronids. Analysis of slowly evolving sites results in a robustly supported monophyletic Brachiopoda and Inarticulata (Linguliformea+Craniiformea), which is regarded as the most likely topology for brachiopod interrelationships. The monophyly of Brachiopoda was further tested with microRNA-based phylogenetics, which are small, noncoding RNA genes whose presence and absence can be used to infer phylogenetic relationships. Two novel microRNAs were characterized supporting the monophyly of brachiopods. Congruence of the traditional molecular phylogenetic analysis, microRNAs, and morphological cladograms suggest that Brachiopoda is monophyletic with Phoronida as its likely sister group. Molecular clock analysis suggests that extant phoronids have a Paleozoic divergence despite their conservative morphology, and that the early brachiopod fossil record is robust, and is not affected by taphonomic factors relating to the late-Precambrian/early-Cambrian phosphogenic event. PMID- 21535470 TI - Salicylic acid and its function in plant immunity. AB - The small phenolic compound salicylic acid (SA) plays an important regulatory role in multiple physiological processes including plant immune response. Significant progress has been made during the past two decades in understanding the SA-mediated defense signaling network. Characterization of a number of genes functioning in SA biosynthesis, conjugation, accumulation, signaling, and crosstalk with other hormones such as jasmonic acid, ethylene, abscisic acid, auxin, gibberellic acid, cytokinin, brassinosteroid, and peptide hormones has sketched the finely tuned immune response network. Full understanding of the mechanism of plant immunity will need to take advantage of fast developing genomics tools and bioinformatics techniques. However, elucidating genetic components involved in these pathways by conventional genetics, biochemistry, and molecular biology approaches will continue to be a major task of the community. High-throughput method for SA quantification holds the potential for isolating additional mutants related to SA-mediated defense signaling. PMID- 21535469 TI - Essential functions of androgen signaling emerged through the developmental analysis of vertebrate sex characteristics. AB - Androgen-androgen receptor (AR) signaling plays key roles in the development of sex characteristics for vertebrates. The essential role of androgen-AR signaling can be analyzed by interdisciplinary approaches including molecular and evolutionary analyses. Recent evolutionally analyses of AR gene revealed that the most ancient AR appeared in cartilaginous fish, the common ancestor of all the extant, jawed vertebrates. Sexual differentiation is a remarkably complex process, which depends on the orchestration of the signaling network. Recent molecular analyses of reproductive organ development indicate the presence of putative effectors for growth factor signaling that can potentially interact with hormonal signaling. The Wnt/beta-catenin pathway is an indispensable masculinizing factor for the external genitalia development of mice. Sonic hedgehog pathway, with expression induced by androgen is involved in the copulatory organ outgrowth in teleosts. This review focuses on the interaction of androgen and growth factor pathways that promote the sexual differentiation of reproductive organs in vertebrates. PMID- 21535471 TI - A DExD/H box RNA helicase is important for K+ deprivation responses and tolerance in Arabidopsis thaliana. AB - The molecular mechanism for sensing and transducing the stress signals initiated by K(+) deprivation in plants remains unknown. Here, we found that the expression of AtHELPS, an Arabidopsis DExD/H box RNA helicase gene, was induced by low-K(+), zeatin and cold treatments, and downregulated by high-K(+) stress. To further investigate the expression pattern of AtHELPS, pAtHELPS::GUS transgenic plants were generated. Histochemical staining indicated that AtHELPS is mainly expressed in the young seedlings and vascular tissues of leaves and roots. Using both helps mutants and overexpression lines, we observed that, in the low-K(+) condition, AtHELPS affected Arabidopsis seed germination and plant weight. Interestingly, the mRNA levels of AKT1, CBL1/9 and CIPK23 in the helps mutants were much higher than in the overexpression lines under low-K(+) stress. Moreover, under low-K(+) stress, the helps mutants displayed increased K(+) influx, whereas the overexpression line of AtHELPS had a lower flux rate in the roots by the noninvasive micro-test technique. Taken together, these results provide information for the functional analysis of plant DEVH box RNA helicases, and suggest that AtHELPS, as an important negative regulator, plays a role in K(+) deprivation stress. PMID- 21535472 TI - Role of Kupffer cells in pathogenesis of sepsis-induced drug metabolizing dysfunction. AB - The present study aimed to determine the role of Kupffer cells (KCs) in cytochrome P450 (CYP) isozyme activity and the expression of its gene during polymicrobial sepsis. For ablation of KCs, rats were pretreated with gadolinium chloride (GdCl(3)) at 48 and 24 h before cecal ligation and puncture (CLP). The depletion of KCs was confirmed by measuring the mRNA level of the KC marker gene CD163. Serum aminotransferase levels and lipid peroxidation showed an increase and hepatic glutathione content showed a decrease at 24 h after CLP. These changes were prevented by GdCl(3) pretreatment. Catalytic activities of CYP1A1, 1A2 and 2E1 showed a significant reduction at 24 h after CLP but were prevented by GdCl(3). A reduction in the levels of CYP2E1 protein and CYP2B1 and CYP2E1 mRNA expression was prevented by GdCl(3). Phosphorylation of CYP1A1/1A2 markedly increased 24 h after CLP, which was prevented by GdCl(3). The increased serum level of high mobility group box 1, hepatic level of Toll-like receptors 2 and 4, and inducible nitric oxide synthase protein expression were prevented by GdCl(3). In addition, elevated serum concentrations of tumor necrosis factor-alpha and interleukin-6, and increased hepatic mRNA levels of tumor necrosis factor-alpha and interleukin-6 were decreased by depletion of KCs. Our findings suggest that ablation of KCs protects against hepatic drug-metabolizing dysfunction by modulation of the inflammatory response. PMID- 21535473 TI - Mechanisms of amyloid fibril formation--focus on domain-swapping. AB - Conformational diseases constitute a group of heterologous disorders in which a constituent host protein undergoes changes in conformation, leading to aggregation and deposition. To understand the molecular mechanisms of the process of amyloid fibril formation, numerous in vitro and in vivo studies, including model and pathologically relevant proteins, have been performed. Understanding the molecular details of these processes is of major importance to understand neurodegenerative diseases and could contribute to more effective therapies. Many models have been proposed to describe the mechanism by which proteins undergo ordered aggregation into amyloid fibrils. We classify these as: (a) templating and nucleation; (b) linear, colloid-like assembly of spherical oligomers; and (c) domain-swapping. In this review, we stress the role of domain-swapping and discuss the role of proline switches. PMID- 21535474 TI - Phosphorylation is the major mechanism regulating isocitrate lyase activity in Paracoccidioides brasiliensis yeast cells. AB - The glyoxylate cycle plays an essential role for anaplerosis of oxaloacetate during growth of microorganisms on carbon sources such as acetate or fatty acids and has been shown to contribute to virulence of several pathogens. Here, we investigated the transcriptional and post-translational regulation of the glyoxylate cycle key enzyme isocitrate lyase (PbICL) in the human pathogenic fungus Paracoccidioides brasiliensis. Although sequence analyses on fungal isocitrate lyases revealed a high phylogenetic conservation, their regulation seems to differ significantly. Closely related Aspergillus species regulate the glyoxylate cycle at the transcriptional level, whereas Pbicl was constitutively expressed in yeast cells. However, only low PbICL activity was detected when cells were grown in the presence of glucose. Two-dimensional gel analyses with subsequent antibody hybridization revealed constitutive production of PbICL, but low PbICL activity on glucose coincided with extensive protein phosphorylation. Since an in vitro dephosphorylation of PbICL from glucose grown cells strongly increased ICL activity and resembled the phosphorylation pattern of highly active acetate grown cells, post-translational modification seems the main mechanism regulating PbICL activity in yeast cells. In agreement, a transfer of yeast cells from glucose to acetate medium increased PbICL activity without requirement of de novo protein synthesis. Thus, inactivation of PbICL by phosphorylation is reversible, denoting a new strategy for the rapid adaptation to changing environmental conditions. PMID- 21535476 TI - Chromatin structure at active genes. PMID- 21535477 TI - Chromatin under mechanical stress: from single 30 nm fibers to single nucleosomes. AB - About a decade ago, the elastic properties of a single chromatin fiber and, subsequently, those of a single nucleosome started to be explored using optical and magnetic tweezers. These techniques have allowed direct measurements of several essential physical parameters of individual nucleosomes and nucleosomal arrays, including the forces responsible for the maintenance of the structure of both the chromatin fiber and the individual nucleosomes, as well as the mechanism of their unwinding under mechanical stress. Experiments on the assembly of individual chromatin fibers have illustrated the complexity of the process and the key role of certain specific components. Nevertheless a substantial disparity exists in the data reported from various experiments. Chromatin, unlike naked DNA, is a system which is extremely sensitive to environmental conditions, and studies carried out under even slightly different conditions are difficult to compare directly. In this review we summarize the available data and their impact on our knowledge of both nucleosomal structure and the dynamics of nucleosome and chromatin fiber assembly and organization. PMID- 21535478 TI - How to remain nonfolded and pliable: the linkers in modular alpha-amylases as a case study. AB - The primary structure of linkers in a new class of modular alpha-amylases constitutes a paradigm of the structural basis that allows a polypeptide to remain nonfolded, extended and pliable. Unfolding is mediated through a depletion of hydrophobic residues and an enrichment of hydrophilic residues, amongst which Ser and Thr are over-represented. An extended and flexible conformation is promoted by the sequential arrangement of Pro and Gly, which are the most abundant residues in these linkers. This is complemented by charge repulsion, charge clustering and disulfide-bridged loops. Molecular dynamics simulations suggest the existence of conformational transitions resulting from a transient and localized hydrophobic collapse, arising from the peculiar composition of the linkers. Accordingly, these linkers should not be regarded as fully disordered, but rather as possessing various discrete structural patterns allowing them to fulfill their biological function as a free energy reservoir for concerted motions between structured domains. PMID- 21535475 TI - Gram-positive bacterial superantigen outside-in signaling causes toxic shock syndrome. AB - Staphylococcus aureus and Streptococcus pyogenes (group A streptococci) are Gram positive pathogens capable of producing a variety of bacterial exotoxins known as superantigens. Superantigens interact with antigen-presenting cells (APCs) and T cells to induce T cell proliferation and massive cytokine production, which leads to fever, rash, capillary leak and subsequent hypotension, the major symptoms of toxic shock syndrome. Both S. aureus and group A streptococci colonize mucosal surfaces, including the anterior nares and vagina for S. aureus, and the oropharynx and less commonly the vagina for group A streptococci. However, due to their abilities to secrete a variety of virulence factors, the organisms can also cause illnesses from the mucosa. This review provides an updated discussion of the biochemical and structural features of one group of secreted virulence factors, the staphylococcal and group A streptococcal superantigens, and their abilities to cause toxic shock syndrome from a mucosal surface. The main focus of this review, however, is the abilities of superantigens to induce cytokines and chemokines from epithelial cells, which has been linked to a dodecapeptide region that is relatively conserved among all superantigens and is distinct from the binding sites required for interactions with APCs and T cells. This phenomenon, termed outside-in signaling, acts to recruit adaptive immune cells to the submucosa, where the superantigens can then interact with those cells to initiate the final cytokine cascades that lead to toxic shock syndrome. PMID- 21535479 TI - An evaluation of the Sebia capillarys Neonat Haemoglobin FASTTM system for routine newborn screening for sickle cell disease. AB - The West Midlands Newborn Screening Laboratory (NBSL) at Birmingham Children's Hospital (BCH), UK, screens approximately 71 000 babies per annum using the Bio Rad automated VARIANTTM nbs (Vnbs) high-pressure liquid chromatograph (HPLC). Any abnormal haemoglobins detected, including S, C, D-Punjab, E and O-Arab as directed by the NHS Sickle Cell and Thalassaemia Screening Programme (NHS Sickle Cell and Thalassaemia Screening Programme Website, http://sct.screening.nhs.uk), are then confirmed using Resolve(r) isoelectric electric focusing (IEF) kits supplied by Perkin-Elmer. The Sebia capillarys Neonat Haemoglobin FASTTM system was evaluated as a possible replacement for the first- or second-line methods used. Both the Sebia and Bio-Rad methods were compared using anonymized blood spots with known haemoglobin patterns. These results were then confirmed when necessary by IEF. The Sebia-recommended sample preparation was also modified to enable testing to be more comparable with our current processes. Percentages of haemoglobins calculated from integration of areas under the peaks were compared between the Bio-Rad Vnbs HPLC and Sebia capillarys Neonat Haemoglobin FASTTM system. Of the 347 blood spots tested by both HPLC and capillary electrophoresis, there were no significant differences. The Sebia capillarys Neonat Haemoglobin FASTTM system can be used to successfully screen newborns for sickle cell disease in blood spots collected for newborn screening with full positive sample identification and traceability. PMID- 21535480 TI - UV-tanning behavior: a problem that doesn't go away. PMID- 21535481 TI - Effects of heating temperatures and addition of reconstituted milk on the heat indicators in milk. AB - The objective of the present study was to evaluate the effect of heating temperatures and reconstituted milk on heat treatment indicators in milk by comparing the heat damage between raw milk and raw milk plus reconstituted milk (composite milk). The contents of lactulose, furosine, beta-lactoglobulin, and lactoperoxidase were determined after the heat indicators were heated to 65 to 115 degrees C for 15 s both in raw milk and composite milk. In the raw milk, the lactulose and furosine contents increased with increased heating temperature, while the beta-lactoglobulin content and lactoperoxidase activity decreased. The lactulose and furosine contents were increased after the addition of reconstituted milk. The reconstituted milk also significantly (P < 0.05) reduced the concentration of beta-lactoglobulin in the milk. Both heat treatment and an addition of reconstituted milk decreased the lactoperoxidase activity significantly (P < 0.05), and the lactoperoxidase activity was undetectable at 85 degrees C. The ratios of lactulose to furosine in pasteurized milk were higher than that in composite pasteurized milk. It is concluded that lactulose, furosine, and beta-lactoglobulin are suitable indicators of high heat pasteurization or raw milk, while lactoperoxidase may be used in monitoring mild heat pasteurization. Practical Application: Adequate heat treatment is necessary to destroy the microbes in raw milk. However, excessive heat treatment can result in inactivation of active compounds or loss of nutrients. The present study showed that the concentrations of lactulose, furosine, beta-lactoglobulin, and the activity of lactoperoxidase are sensitive to processing temperature and can serve as indicators of milk pasteurization. PMID- 21535482 TI - Effects of riboflavin photosensitization on daidzein and its photosensitized derivatives. AB - Photosensitized compounds from daidzein were studied in a riboflavin model system under visible light irradiation by high-performance liquid chromatography (HPLC). As the period of light irradiation increased, concentration of daidzein decreased significantly (P < 0.05) and new peaks of daidzein derivatives were observed and changed during photosensitization. Three new peaks from photosensitized daidzein were tentatively identified as 7-, 3', 4'-trihydroxyisoflavone (or 3' hydroxydaidzein) and 2 dimmers of daidzein by a combination of HPLC-mass spectrometry (MS) and retention times of standard compounds by HPLC. Addition of sodium azide and removal of headspace oxygen treatment affected the formation of newly formed peaks. The type I pathway of riboflavin photosensitization played more important roles than type II pathways on the formation of daidzein derivatives. Practical Application: Isoflavones are important phytochemicals found in soy foods. Generally, many foods containing soy ingredients are displayed under visible light irradiation. Also, riboflavin can be found in many foods containing vegetables. The results of this study can be used to understand the stability and changes of isoflavone aglycones in soy and soy-based foods under visible light irradiation. PMID- 21535484 TI - Glucosinolates in broccoli sprouts (Brassica oleracea var. italica) as conditioned by sulphate supply during germination. AB - Sulphur (S) fertilization is essential for primary and secondary metabolism in cruciferous foods. Deficient, suboptimal, or excessive S affects the growth and biosynthesis of secondary metabolites in adult plants. Nevertheless, there is little information regarding the influence of S fertilization on sprouts and seedlings. An experiment was set up to evaluate the effect of S fertilization, supplied as K(2)SO(4) at 0, 15, 30, and 60 mg/L, on the glucosinolate content of broccoli sprouts during the germination course of 3, 6, 9, and 12 d after sowing. Glucosinolate concentration was strongly influenced by germination, causing a rapid increase during the first 3 d after sowing, and decreasing afterwards. The S supply increased aliphatic and total glucosinolate content at the end of the monitored sprouting period. S-treated sprouts, with S(15), S(30), and S(60) at 9 and 12 d after sowing presented enhanced glucosinolate content. Overall, both germination time and S fertilization were key factors in maximizing the bioactive health-promoting phytochemicals of broccoli. Practical Application: Germination with sulphate is a simple and inexpensive way to obtain sprouts that contain much higher levels of glucosinolates (health promoting compounds), than the corresponding florets from the same seeds. PMID- 21535483 TI - Bioactivities of kernel extracts of 18 strains of maize (Zea mays). AB - Aqueous and ethanolic extracts of maize kernels from 18 varieties/strains were prepared for the evaluation of inhibitory activities toward alpha-glucosidase and scavenging activities toward nitric oxide (NO*) and superoxide (*O(2)(-)). All ethanolic extracts of maize strains tested inhibited yeast (Saccharomyces cerevisiae) alpha-glucosidase with the highest potency (49% to 54%) found for 2 purple and a yellow strains. However, inhibitory effects of maize extracts on rat intestinal alpha-glucosidase were as a whole about 10% as effective as with the yeast enzyme. Maize extracts were capable of scavenging NO* at the level of 0.25 mg/mL to extents ranging from 24% to 50% and 26% to 57%, respectively, for aqueous and ethanolic extracts. All tested aqueous extracts were also capable of scavenging *O(2)(-), with efficacies ranging from 8% to 38%, at the level of 1.5 mg/mL, whereas almost none of the ethanolic extracts scavenged *O(2)(-), except for one purple strain (approximately 10% effective). The effectiveness in the enzyme inhibition and antioxidant assays did not correlate with total phenolic and/or anthocyanin levels, nor with the nature of pigmentation among the maize strains evaluated. Practical Application: A diversity of pigmented maize strains was evaluated for biological activities related to mitigating oxidative stress and slowing down glucose absorption from the diet. Certain strains tended to be more abundant in these biological activities and have potential to be used in dietary regimes that are designed to promote human health. PMID- 21535485 TI - Effect of antibrowning agents on browning and intermediate formation in the glucose-glutamic acid model. AB - In this study, the inhibitory effects of antibrowning agents on browning and the formation of intermediates such as 3-deoxyglucosone (3-DG) and hydroxymethylfurfural (HMF) were evaluated with a glucose-glutamic acid model for soybean paste. The initial antibrowning capacity was measured in the following order: pentasodium tripolyphosphate < citric acid and oxalic acid < cysteine and glutathione < sodium sulfite. Our data showed that antibrowning agents, such as pentasodium tripolyphosphate, citric acid, and oxalic acid, were maintained antibrowning capacities during storage at both 4 and 30 degrees C, respectively. However, both cysteine and glutathione was reduced with storage time, especially in the air. A marked effect of nitrogen treatment was noted for 3 of the antibrowning agents after storage in air at 30 degrees C in the following order: sodium sulfite < cysteine < glutathione. The formation ratio of 3-DG and HMF was higher after storage at 30 degrees C than at 4 degrees C. These compounds were produced most abundantly in the presence of sodium sulfite, and the yields were not related significantly to the degree of browning. Citric acid and oxalic acid were identified as the most effective in inhibitors of browning and intermediates, even during storage in air at 30 degrees C. PMID- 21535486 TI - Identification of candidate amino acids involved in the formation of pink-red pigments in onion (Allium cepa L.) juice and separation by HPLC. AB - The formation of pink-red pigments ("pinking") by various amino acids was investigated by reacting amino acids with compounds present in onion juice. The unknown pink-red pigments were generated and separated using high-performance liquid chromatography (HPLC) and a diode array detector (DAD) in the range of 200 to 700 nm. To generate pink-red pigments, we developed several reaction systems using garlic alliinase, purified 1-propenyl-L-cysteine sulfoxide (1-PeCSO), onion thiosulfinate, natural onion juice, and 21 free amino acids. The compound 1-PeCSO was a key compound associated with pinking in the presence of both the alliinase and amino acids. Numerous naturally occurring pink-red pigments were detected and separated from pink onion juice using the HPLC-DAD system at 515 nm. Most free amino acids, with the exceptions of histidine, serine, and cysteine, formed various pink-red pigments when reacted with onion thiosulfinate. This observation indicated that onion pinking is caused not by a single pigment, but by many. Furthermore, more than one color compound could be produced from a single amino acid; this explains, in part, why there were many pink-red compound peaks in the chromatogram of discolored natural onion juice. We presumed that the complexity of the pink-red pigments was due to the involvement of more than 21 natural amino acids as well as several derivatives of the color products produced from each amino acid. We observed that the pinking process in onion juice is very similar to that of the greening process in crushed garlic, emphasizing that both thiosulfinate from flavor precursors and free amino acids are absolutely required for the discoloration. PMID- 21535487 TI - Extraction and normal-phase HPLC-fluorescence-electrospray MS characterization and quantification of procyanidins in cranberry extracts. AB - Cranberries are a major source of procyanidins, an abundant class of bioactive polyphenols found in nature. The objective of this study was to apply a protocol for extraction and normal-phase high-performance liquid chromatograph fluorescence-mass spectroscopy separation and quantification of procyanidins in cranberry extracts containing varying processing aids and/or methods of production. Cranberry extracts were best extracted using an acetone/water technique versus an acid/alkaline extraction. Procyanidins were semi-purified with C-18 and Sephadex LH-20 SPE cartridges (GE Healthcare Life Sciences, Piscataway, N.J., U.S.A.). Characterization and quantification of procyanidins up to octamers and higher molecular weight compounds, including separation of the A- and B-type dimers to tetramers was achieved. PMID- 21535488 TI - Physical performance of biodegradable films intended for antimicrobial food packaging. AB - Antimicrobial films were prepared by including enterocins to alginate, polyvinyl alcohol (PVOH), and zein films. The physical performance of the films was assessed by measuring color, microstructure (SEM), water vapor permeability (WVP), and tensile properties. All studied biopolymers showed poor WVP and limited tensile properties. PVOH showed the best performance exhibiting the lowest WVP values, higher tensile properties, and flexibility among studied biopolymers. SEM of antimicrobial films showed increased presence of voids and pores as a consequence of enterocin addition. However, changes in microstructure did not disturb WVP of films. Moreover, enterocin-containing films showed slight improvement compared to control films. Addition of enterocins to PVOH films had a plasticizing effect, by reducing its tensile strength and increasing the strain at break. The presence of enterocins had an important effect on tensile properties of zein films by significantly reducing its brittleness. Addition of enterocins, thus, proved not to disturb the physical performance of studied biopolymers. Development of new antimicrobial biodegradable packaging materials may contribute to improving food safety while reducing environmental impact derived from packaging waste. Practical Application: Development of new antimicrobial biodegradable packaging materials may contribute to improving food safety while reducing environmental impact derived from packaging waste. PMID- 21535489 TI - Magnetic resonance imaging (MRI) and relaxation spectrum analysis as methods to investigate swelling in whey protein gels. AB - Effective means for controlled delivery of nutrients and nutraceuticals are needed. Whey protein-based gels, as a model system and as a potential delivery system, exhibit pH-dependent swelling when placed in aqueous solutions. Understanding the physics that govern gel swelling is thus important when designing gel-based delivery platforms. The extent of swelling over time was monitored gravimetrically. In addition to gravimetric measurements, magnetic resonance imaging (MRI) a real-time noninvasive imaging technique that quantified changes in geometry and water content of these gels was utilized. Heat-set whey protein gels were prepared at pH 7 and swelling was monitored in aqueous solutions with pH values of 2.5, 7, and 10. Changes in dimension over time, as characterized by the number of voxels in an image, were correlated to gravimetric measurements. Excellent correlations between mass uptake and volume change (R(2)= 0.99) were obtained for the gels in aqueous solutions at pH 7 and 10, but not for gels in the aqueous solution at pH 2.5. To provide insight into the mechanisms for water uptake, nuclear magnetic resonance (NMR) relaxation times were measured in independent experiments. The relaxation spectrum for the spin-spin relaxation time (T(2)) showed the presence of 3 proton pools for pH 7 and 10 trials and 4 proton pools for pH 2.5 trials. Results demonstrate that MRI and NMR relaxation measurements provided information about swelling in whey protein gels that can constitute a new means for investigating and developing effective delivery systems for foods. PMID- 21535490 TI - Determination of a representative volume element based on the variability of mechanical properties with sample size in bread. AB - Quantitative analysis of food structure is commonly obtained by image analysis of a small portion of the material that may not be the representative of the whole sample. In order to quantify structural parameters (air cells) of 2 types of bread (bread and bagel) the concept of representative volume element (RVE) was employed. The RVE for bread, bagel, and gelatin-gel (used as control) was obtained from the relationship between sample size and the coefficient of variation, calculated from the apparent Young's modulus measured on 25 replicates. The RVE was obtained when the coefficient of variation for different sample sizes converged to a constant value. In the 2 types of bread tested, the tendency of the coefficient of variation was to decrease as the sample size increased, while in the homogeneous gelatin-gel, it remained always constant around 2.3% to 2.4%. The RVE resulted to be cubes with sides of 45 mm for bread, 20 mm for bagels, and 10 mm for gelatin-gel (smallest sample tested). The quantitative image analysis as well as visual observation demonstrated that bread presented the largest dispersion of air-cell sizes. Moreover, both the ratio of maximum air-cell area/image area and maximum air-cell height/image height were greater for bread (values of 0.05 and 0.30, respectively) than for bagels (0.03 and 0.20, respectively). Therefore, the size and the size variation of air cells present in the structure determined the size of the RVE. It was concluded that RVE is highly dependent on the heterogeneity of the structure of the types of baked products. PMID- 21535491 TI - Minimal effects of high-pressure treatment on Salmonella enterica serovar Typhimurium inoculated into peanut butter and peanut products. AB - About 1.2 billion pounds of peanut butter are consumed annually in the United States. In 2008 to 2009, an outbreak involving Salmonella Typhimurium in peanut butter led to a recall of over 3900 products by over 200 companies. More than 700 people became sick, 100 were hospitalized, and 9 people died from this outbreak. This study examines the efficacy of high-pressure processing (HPP) to decrease S. Typhimurium American Type Culture Collection (ATCC) 53647 inoculated into peanut butter and model systems. The viability of S. Typhimurium in peanut butter stored at room temperature was investigated. A culture of S. Typhimurium (6.88 log CFU/g) was inoculated into peanut butter. Following 28 d at 20 degrees C there was a 1.23-log reduction. Approximately 10(6) to 10(7) CFU/g S. Typhimurium were inoculated into 4 brands of peanut butter, 3 natural peanut butters and peanut flour slurries at 2, 5, and 10% peanut flour protein in peanut oil and in distilled water. All were treated at 600 MPa for 5 min at 45 degrees C. While significant differences were found between natural peanut butter and peanut protein mixtures, the reduction was <1.0 log. The peanut flour/oil mixtures had a 1.7, 1.6, and 1.0-log reduction from HPP (2, 5, and 10% protein, respectively) whereas peanut flour/water mixtures had a 6.7-log reduction for all protein levels. Oil had a protective effect indicating HPP may not help the microbial safety of water-in-oil food emulsions including peanut butter. Practical Application: There have been multiple outbreaks of foodborne illness involving peanut butter products. This study looks at the potential use of high-pressure processing to reduce the bacteria that may be in peanut butter. PMID- 21535492 TI - Process control of lightly salted wild and farmed Atlantic cod (Gadus morhua) by brine injection, brining, and freezing--a low field NMR study. AB - The aim of this study was to use low-field nuclear magnetic resonance (NMR) and traditional chemical methods to investigate the physical and chemical differences in wild and farmed cod processed pre- and postrigor, and how these properties were affected by brine injection, brining, and freezing. In prerigor processed farmed or wild cod, brine injections followed by brining for 2 d, with brine concentrations up to 5.5% and 4%, respectively, were not sufficient to reach a muscle salt concentration of 2% as aimed for, while wild cod processed postrigor had sufficient salt uptake after the same processing. Low-field NMR gave valuable information about the differences in the muscle structure between wild and farmed cod as well as the state of the water in the muscle during brine injection, brining, and during rigor tension. Low-field NMR is, therefore, a valuable tool that can be used to optimize the salting and storing processes of lightly salted cod products from both wild and farmed cod. For farmed cod to be used in the production of lightly salted products further research is needed. Practical Application: Optimal processing of lightly salted cod products is important to the fish industry, due to an increasing market for this product in southern Europe. Farmed cod, which is seen as a potential steady raw material source for this production, differs considerably from its wild counterparts by having other chemical and physical muscle properties, such as lower water content and lower pH. With the processing procedures used today the farmed cod can, therefore, only be used in some of the products, where wild cod is currently used as raw material. It is, therefore, important that the processing of these products is optimized with regard to these differences in the raw material. This study gives a valuable contribution to further studies about optimal combinations of brine injections, brining, and freezing of pre- and postrigor processed farmed compared to wild cod. PMID- 21535493 TI - Effect of powder and target properties on wrap around effect during coating. AB - Tapioca starch, NaCl (28, 135, and 378 MUm), corn starch, cocoa powder, soy protein isolate, cheese powder, wheat protein, modified starch, nacho cheese, and sugar were coated at 0 kV for nonelectrostatic and at 25 kV for electrostatic coating onto metal, wood, unoiled paper, oiled paper, unoiled plastic, oiled plastic, fresh bread, and dry bread. Powders and targets were allowed to naturally tribocharge, or all charge was removed before coating. Powder particle size, flowability, resistivity, and target resistivity were reported. Electrostatic coating produced the same or better wrap around, or percent side coverage as nonelectrostatic coating for every powder and target. The greatest electrostatic improvement was found when using powders that had the worst nonelectrostatic side coverage: large particle size (>135 MUm), low resistivity, and low cohesiveness, especially on targets that had high-surface resistivity (2 * 10(5) Omegam). Tribocharging had a similar effect as electrostatic coating. In both nonelectrostatic and electrostatic coating, percent side coverage increased as powder particle size decreased, cohesiveness increased, or target resistivity decreased. In electrostatic coating, percent side coverage increased as powder resistivity increased; however, in nonelectrostatic coating, as powder resistivity increased, percent side coverage increased on only oiled plastic and dry bread. Practical Application: The evenness of powder coating on food is very important for consumer acceptability, since consumers judge food from its appearance before they have a chance to taste it. If thick food targets, such as cakes, donuts, and marshmallows need to be coated, the side coverage, due to the wrap around effect, is important. Choosing powders with small particle size, high cohesiveness and high-powder resistivity, and using electrostatic coating can produce food targets coated on all sides. PMID- 21535494 TI - The effects of presalting methods from injection to pickling, on the yields of heavily salted cod (Gadus morhua). AB - The production of heavy-salted cod (Bacalao) has changed from being a single-step process (kench) salting to a multistep procedure varying between producers and countries. Presalting by injection, brining, or pickling is increasingly applied prior to pile (dry) salting. This article describes the effects of different presalting methods (injection and brining, brining only, and pickling) on yield and chemical composition of salted cod fillets, in comparison to a single-kench salting step. The procedures used influenced the weight yields and chemical composition of the products. Injection was significantly different from other methods in increasing weight yields throughout brining, dry salting, and rehydration. The yield of nitrogenous compounds tended to be lower for injected and brine-salted fillets, mainly due to higher losses of nonprotein nitrogen. Practical Application: Salting procedures for cod have changed rapidly in recent years. Injection is increasingly used as a presalting method. It has been suggested to have strong effects on weight yields of salted cod products. This article describes the effects of injection on weight yields on products in salted, rehydrated, and cooked stage. PMID- 21535495 TI - Prediction of the weight of Alaskan pollock using image analysis. AB - Determining the size and quality attributes of fish by machine vision is gaining acceptance and increasing use in the seafood industry. Objectivity, speed, and record keeping are advantages in using this method. The objective of this work was to develop the mathematical correlations to predict the weight of whole Alaskan Pollock (Theragra chalcogramma) based on its view area from a camera. One hundred and sixty whole Pollock were obtained fresh, within 2 d after catch from a Kodiak, Alaska, processing plant. The fish were first weighed, then placed in a light box equipped with a Nikon D200 digital camera. A reference square of known surface area was placed by the fish. The obtained image was analyzed to calculate the view area of each fish. The following equations were used to fit the view area (X) compared with weight (Y) data: linear, power, and 2nd-order polynomial. The power fit (Y = A . X(B)) gave the highest R(2) for the fit (0.99). The effect of fins and tail on the accuracy of the weight prediction using view area were evaluated. Removing fins and tails did not improve prediction accuracy. Machine vision can accurately predict the weight of whole Pollock. Practical Application: The weight of Alaskan Pollock can be predicted automatically by taking the image of the fish and using it in one of the correlations developed in this study. The removal of the fins or the fins and the tail did not increase the prediction accuracy of the method. Therefore, intact fish images should be used. PMID- 21535496 TI - Effect of active packaging incorporated with triclosan on bacteria adhesion. AB - Antimicrobial polyethylene and cellulose based films incorporated with triclosan were studied. The antimicrobial efficacy, the hydrophobicity, microscopic and the mechanical characteristics of the films, as well free energy of adhesion between bacteria and antimicrobial films were evaluated. It was observed that both polyethylene and cellulose based films incorporated with the antimicrobial were homogeneous. Furthermore, the addition of triclosan did not affect mechanical characteristics of the films (P > 0.05). However, triclosan incorporated into polyethylene films reduced its hydrophobicity while antimicrobial cellulose based films became more hydrophobic. The adhesion was thermodynamically favorable between tested bacteria and polyethylene films. On the other hand, the adhesion to triclosan cellulose based film was thermodynamically unfavorable to Staphylococcus aureus and Escherichia coli and favorable to Listeria innocua and Pseudomonas aeruginosa. Polyethylene and cellulose based films showed inhibitory effect against S. aureus and E. coli, being the inhibition halo higher for polyethylene films. This study improves the knowledge about antimicrobial films. PMID- 21535497 TI - Rheological properties of gelatin from silver carp skin compared to commercially available gelatins from different sources. AB - Gelatin is used as a functional ingredient in many foods, pharmaceuticals, and cosmetics as a stabilizing, thickening, and gelling agent. The rheological properties of gelatins are important in the potential functionality of gelatin. This study is designed to determine the rheological properties of gelatin extracted from the skins of silver carp (Hypophthalmichthys molitrix Valenciennes 1844). The extracted gelatin is compared with commercially available gelatins from different sources. The results indicate that the stress-strain relationship of gelatin gels remained in the linear region over a broad range of strains and stresses and gave similar elastic moduli at varying frequency, stress, and strain levels. One exception was a commercial high molecular weight fish skin gelatin that gave a lower elastic modulus indicating that its gel strength was low compared to the other gelatin samples studied. Gel strength varied between 220 and 1230 g while viscosity varied between 4.53 and 6.91 cP among the samples. Melting and gelling temperatures varied between 14.2 and 32.3 degrees C and 3.2 and 25.4 degrees C, respectively. Texture profile analysis was done at 2 deformation levels, 25% and 75%, and the results correlated well with gel strength. The correlations between hardness, cohesiveness, and gumminess and gel strength were 0.98, 0.82, and 0.99, respectively, at 25% deformation but lower at 75% deformation. The results suggest that rheological measurements might be used to quickly estimate gel strength using less material. In addition, the silver carp skin gelatin seemed to be of equal quality to some of the commercial gelatins. PMID- 21535498 TI - Glycemic responses to sweetened dried and raw cranberries in humans with type 2 diabetes. AB - This study assessed the metabolic response to sweetened dried cranberries (SDC), raw cranberries (RC), and white bread (WB) in humans with type 2 diabetes. Development of palatable cranberry preparations associated with lower glycemic responses may be useful for improving fruit consumption and glycemic control among those with diabetes. In this trial, type 2 diabetics (n= 13) received WB (57 g, 160 cal, 1 g fiber), RC (55 g, 21 cal, 1 g fiber), SDC (40 g, 138 cal, 2.1 g fiber), and SDC containing less sugar (SDC-LS, 40 g, 113 cal, 1.8 g fiber + 10 g polydextrose). Plasma glucose (mmol/L) peaked significantly at 60 min for WB, and at 30 min for RC, SDC, and SDC-LS at 9.6 +/- 0.4, 7.0 +/- 0.4, 9.6 +/- 0.5, and 8.7 +/- 0.5, respectively, WB remained significantly elevated from the other treatments at 120 min. Plasma insulin (pmol/mL) peaked at 60 min for WB and SDC and at 30 min for RC and SDC-LS at 157 +/- 15, 142 +/- 27, 61 +/- 8, and 97 +/- 11, respectively. Plasma insulin for SDC-LS was significantly lower at 60 min than either WB or SDC. Insulin area under the curve (AUC) values for RC and SDC LS were both significantly lower than WB or SDC. Phenolic content of SDC and SDC LS was determined following extraction with 80% acetone prior to high-performance liquid chromatography (HPLC) and electronspray ionization-mass spectrometry (ESI MS) and found to be rich in 5-caffeoylquinic cid, quercetin-3-galactoside, and quercetin-3-galactoside, and the proanthocyanidin dimer epicatechin. In conclusion, SDC-LS was associated with a favorable glycemic and insulinemic response in type 2 diabetics. Practical Application: This study compares phenolic content and glycemic responses among different cranberry products. The study seeks to expand the palatable and portable healthy food choices for persons with type 2 diabetes. The novel use of polydextrose as a bulking agent making possible a reduction in caloric content and potential glycemic response is also characterized in this study. PMID- 21535499 TI - Modified apple polysaccharides could induce apoptosis in colorectal cancer cells. AB - Multiple studies have pointed out that dietary components could inhibit cancer progression and metastasis, and it has been proven that many ingredients of apple have benefits for cancer prevention. We, therefore, extracted modified apple polysaccharides (MAP) from apple and hypothesized that MAP have a cancer preventive effect as do other ingredients of apple. Three human colorectal cancer cell lines: SW-1116, HT-29, and Caco-2 were exposed to different concentrations of MAP (0% to 0.1%). Inhibition of cell proliferation was measured by 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. DNA fragmentation was visualized by agarose-gel electrophoresis. The amount of apoptotic cells was assessed by flow cytometry, and protein level of caspase 3, 8, 9, Bax, and Bcl-2 was evaluated by Western blot. At the concentrations of 0.01% to 0.1%, MAP showed growth-inhibiting and apoptosis-inducing effects on cancer cells. It increased the expression of caspase 3, 8, 9, and Bax, while decreased of Bcl-2, which denoted that MAP may induce apoptosis through both the mitochondrial-mediated and death receptor-mediated apoptotic ways. These data indicate that MAP has the potential for clinical prevention and treatment for colon cancer. PMID- 21535500 TI - The protective effects of long-term oral administration of marine collagen hydrolysate from chum salmon on collagen matrix homeostasis in the chronological aged skin of Sprague-Dawley male rats. AB - To investigate the long-term effects of marine collagen hydrolysate (MCH) from Chum Salmon skin on the aberrant collagen matrix homeostasis in chronological aged skin, Sprague-Dawley male rats of 4-wk-old were orally administrated with MCH at the diet concentrations of 2.25% and 4.5% for 24 mo. Histological and biochemical analysis revealed that MCH had the potential to inhibit the collagen loss and collagen fragmentation in chronological aged skin. Based on immunohistochemistry and western blot analysis, collagen type I and III protein expression levels in MCH-treated groups significantly increased as compared with the aged control group. Furthermore, quantitative real-time polymerase chain reaction and western blot analysis showed MCH was able to increase the expressions of procollagen type I and III mRNA (COL1A2 and COL3A1) through activating Smad signaling pathway with up-regulated TGF-betaRII (TbetaRII) expression level. Meanwhile, MCH was shown to inhibit the age-related increased collagen degradation through attenuating MMP-1 expression and increasing tissue inhibitor of metalloproteinases-1 expression in a dose-dependent manner. Moreover, MCH could alleviate the oxidative stress in chronological aged skin, which was revealed from the data of superoxide dismutase activity and the thiobarbituric acid reactive substances level in skin homogenates. Therefore, MCH was demonstrated to have the protective effects on chronological skin aging due to the influence on collagen matrix homeostasis. And the antioxidative property of MCH might play an important role in the process. PMID- 21535501 TI - Activity-guided isolation and identification of radical scavenging components in Gao-Cha tea. AB - Gao-Cha is a traditional Chinese health tea made from Acer ginnala. We performed a components and radical scavenging activity analysis to identify any medicinal components in this tea. High performance thin layer chromatography (HPTLC)-1,1 Diphenyl-2-picryhydrazyl (HPTLC-DPPH) assay showed that the methanolic extract contained strong radical scavengers. Quantitative analysis revealed that the IC(50) of the extract against 1 mM DPPH was 52.7 +/- 0.6 MUg/mL. Bioactive-guided isolations led to procurement of 3 radical scavengers with IC(50)s of 17.5 +/- 2.1, 29.3 +/- 2.5, and 21.6 +/- 1.7 MUg/mL, respectively. Analysis of the high resolution-electric spray ionization-mass spectrometer and (1)H, (13)C, distortionless enhancement by polarization transfer at 135 degrees , heteronuclear quantum coherence, correlating spectroscopy coupling, and heteronuclear multiple bond coherence (HMBC) data revealed that the compounds were methyl 3, 4, 5-trihydroxybenzoate (1), quercetin-3-O-alpha-rhamnopyranoside (2), and 2,6-bis (3,4,5-trihydroxybenzoyl)-aceritol (3). Bioactive combined components analysis revealed that, apart from compounds 1, 2, and 3, the tea possibly contained radical scavengers: ginnalin A (4) and B (5), 2"-O Galloylquercitrin (6) and 3"-O-Galloyl-quercitrin (7). Compounds 2, 6, and 7 were isolated from Acer ginnala for the first time. The positions of the 2 galloyl moieties in compound 3 were unambiguously established by the HMBC spectrum for the first time. PMID- 21535502 TI - The antiallergic effect of kefir Lactobacilli. AB - This study demonstrated that oral feeding of heat-inactivated Lactobacillus (L b.) kefiranofaciens M1 from kefir grains effectively inhibited immunoglobulin (Ig) E production in response to ovalbumin (OVA) in vivo. The pattern of cytokine production by splenocyte cells revealed that the levels of cytokines produced by T helper (Th) 1 cells increased, and those of cytokines produced by Th2 cells decreased in the heat-inactivated M1 feeding group. These findings indicated that Lactobacillus kefiranofaciens M1 in the kefir played an important role in antiallergic activities. By additional analysis using flow cytometry and microarray, the mechanism of suppression of IgE production by oral feeding of the heat-inactivated M1 probably occurs because of upregulation of the expression of Cd2, Stat4, and Ifnr leading to skewing the Th1/Th2 balance toward Th1 dominance, elevation of the CD4(+)CD25(+) regulatory T (Treg) percentage, and reduction of activated CD19(+) B cells. Downregulation of complement system and components was also involved in suppression of IgE production. Practical Application: Kefir has long been considered good for health. Its health benefits include immunoregulatory effects. However, there is a lack of knowledge concerning the immunoregulatory effects induced by kefir lactic acid bacteria (LAB). Our data clearly demonstrated the antiallergic activity of kefir LAB, Lactobacillus (L b.) kefiranofaciens M1. By additional analysis using flow cytometry and microarray, the possible mechanism of suppression of IgE production by oral feeding of the heat-inactivated M1 was also elucidated. Our findings indicated that Lactobacillus kefiranofaciens M1 may have a great potential for utilization in functional food products. PMID- 21535503 TI - Natural flavone kaempferol suppresses chemokines expression in human monocyte THP 1 cells through MAPK pathways. AB - There is increasing evidence that daily intake of flavonoids reduced severity and prevalence of allergic diseases. However, the mechanism of its antiinflammatory effects in allergic diseases remains uncertain. Kaempferol, which belongs to the flavone group, is a strong antioxidant among natural flavonoids and is the essential component of many beverages and vegetables. Because chemokine is one of the key mediators in allergic inflammatory process, we investigated the effect of kaempferol on chemokines expression in monocytes. Our data demonstrated that kaempferol significantly inhibited the lipopolysaccharide (LPS)-induced production of monocyte-derived chemokine (MDC), interferon gamma-induced protein 10 (IP-10), and interleukin-8 (IL-8) in THP-1 cells. Growth-related oncogene alpha (GRO-alpha) was also suppressed at a higher concentration. We also found that kaempferol was able to suppress LPS-induced mitogen-activated protein kinase (MAPK) pathways, as well as the phosphorylation of upstream c-raf and MEK1/2. In brief, kaempferol suppressed LPS-induced T helper 1 (Th1), T helper 2 (Th2), and neutrophil-related chemokines production in monocytes might be via the MAPK pathways. PMID- 21535504 TI - Dietary ligands as determinants of iron-zinc interactions at the absorptive enterocyte. AB - Iron and zinc interact at the enterocyte and influence the absorption of one another. We have previously reported that zinc noncompetitively inhibits iron uptake in Caco-2 cells, a widely accepted model of the absorptive enterocyte. However, the determinants of this interaction, such as the effect of dietary ligands, remain uncharacterized. Dietary ligands selectively chelate iron and zinc in definite stoichiometric proportions and thus alter the bioavailability from food matrices. Here, we have used common dietary ligands, such as ascorbic acid, phytic acid, tannic acid, tartaric acid, cysteine, histidine, and methionine to characterize iron, zinc uptake individually and in combination, using Caco-2 cells. Selective chelation of zinc, using cysteine, decreased the magnitude of inhibition of iron uptake but could not reverse the inhibition. On the other hand, selective increase in iron uptake in the presence of methionine resulted in increased zinc uptake, rather than inhibition. Taken together, these in vitro results suggest that dietary ligands can modulate iron-zinc interaction and that zinc cannot competitively inhibit iron uptake. PMID- 21535505 TI - Immunizing effects of cocultures of H22 hepatocarcinoma cells and cartilage polysaccharide on murine H22 hepatocarcinoma. AB - Hepatocarcinoma is a malignant cancer, which is threatening human lives. In order to disclose the immunizing effects of the cells and cartilage polysaccharide (CHCP) on liver cancer, murine H22 hepatocarcinoma model was set up. The survival time, life span, and survival rate of the CHCP group were better than model group or other groups which was immunized with cartilage short-chain polysaccharide (CPS) only or H22 cell lysate only. A series of experiments were proceeded and the results confirmed that the humoral immunity and cellular immunity were strengthened. HE staining, TUNEL assay, and Alcian staining were used to research the mechanism of the tumor specific antigen production which may be related to the apoptosis of H22 hepatocarcinoma cells induced by CPS or some new polysaccharide compound emerged. The animal experiment testified the relationship between H22 hepatocarcinoma cell apoptosis induced by CPS and the effect of murine H22 hepatocarcinoma immunoprophylaxis. Our data demonstrated that the coculture of cartilage polysaccharide and cancer cells may serve as a novel source of antihepatocarcinoma agent that may play an important role in future liver cancer immunoprophylaxis. PMID- 21535506 TI - Isolation and characterization of barosensitive mutants of Saccharomyces cerevisiae obtained by UV mutagenesis. AB - Using UV mutagenesis, 2 high-pressure (HP) sensitive (barosensitive) mutants of Saccharomyces cerevisiae were obtained. The HP inactivation of the mutants, as well as their parent strains, followed 1st-order kinetics in the range of 175 to 250 MPa within 600 s. Both mutants showed larger 1st-order inactivation rate constant values or significant loss of viabilities, compared with their parent strains in the pressure range tested. The inactivation rate constant value of one of the mutants was comparable with that of a previously reported highly barosensitive strain, which was generated by deletion of hsp104 in a trehalose deficient strain. The activation volume values of HP inactivation reactions in the 2 mutants were apparently equivalent with those of their parent strains. This suggested that the mutation did not bring drastic volume changes of the key molecules for HP inactivation. Their auxotrophic properties, growth, and ethanol fermentation were identical in mutant and parent strains. The mutants could therefore be useful for fermentations where control by HP processing is desired. PMID- 21535507 TI - Temperature and bacterial profile of post chill poultry carcasses stored in processing combo held at room temperature. AB - Post chill whole poultry carcasses from a commercial processing plant were stored in a processing combo at room temperature (70 degrees F/21 degrees C) for 54 h to mimic the scenario of temperature abuse before further processing. Temperature data were collected in 1-min intervals and averaged each hour by 9 temperature data loggers. Two linear regressions were developed for the combo and internal breast temperature and slopes were nearly identical. Microbial data was collected by performing whole bird carcass rinses that were enumerated for aerobic plate count (APC), Enterobacteriaceae, Escherichia coli, and total coliform. Samples were collected from the chiller chute at time zero for initial bacterial counts. Carcass sampling continued once the internal breast temperature achieved 45 degrees F (7 degrees C 10 h) and continued every 2 h until the final internal breast temperature was 63 degrees F (17 degrees C 54 h). Linear regressions were developed for the first 26 h, which exhibited no statistically significant growth except for Enterobacteriaceae. A 2nd linear regression (28 to 54 h) exhibited significant growth for all analyses. Overall, APC increased from a log(10) colony forming unit (CFU)/mL count of 2.86 to 7.02, Enterobacteriaceae increased from 0.66 to 6.64, coliform increased from 0.72 to 4.81, and E. coli increased from 0.53 to 4.45. Denaturing gradient gel electrophoresis was performed to detect changes in the bacterial populations, which indicated 95% similarity within sampled groups, but the overall percent similarity among samples collected over 54 h was 8%. From the data, microbial growth demonstrates a period of 26 h for minimal growth; therefore, the product could be further processed rather than designated as waste. PMID- 21535508 TI - Use of tuf gene-based primers for the PCR detection of probiotic Bifidobacterium species and enumeration of bifidobacteria in fermented milk by cultural and quantitative real-time PCR methods. AB - Due to the increasing use of bifidobacteria in probiotic products, it is essential to establish a rapid method for the qualitative and quantitative assay of the bifidobacteria in commercial products. In this study, partial sequences of the tuf gene for 18 Bifidobacterium strains belonging to 14 species were determined. Alignment of these sequences showed that the similarities among these Bifidobacterium species were 82.24% to 99.72%. Based on these tuf gene sequences, 6 primer sets were designed for the polymerase chain reaction (PCR) assay of B. animalis subsp. animalis, B. animalis subsp. lactis, B. bifidum, B. breve, B. longum subsp. infantis, B. longum subsp. longum, and the genus of Bifidobacterium, respectively. These Bifidobacterium species are common probiotic species present in dairy and probiotic products. When each target Bifidobacterium spp. was assayed with the designed primers, PCR product with expected size was generated. In addition, for each target species, more than 70 bacterial strains other than the target species, including strains of other Bifidobacterium species, strains of Lactobacillus spp., Enterococcus spp., and other bacterial species, all generated negative results. PCR assay with primers specific to B. animalis subsp. lactis and B. longum subsp. longum confirmed the presence of these Bifidobacterium species in commercial yogurt products. In addition, for each product, enumeration of the bifidobacteria cells by culture method with BIM 25 agar and the quantitative real-time PCR showed similar cell counts. Such results indicated that within 15-d storage (4 degrees C) after manufacture, all the bifidobacteria cells originally present in yogurt products were viable and culturable during the storage. PMID- 21535510 TI - Characterization of lactic acid bacteria isolated from Italian Bella di Cerignola table olives: selection of potential multifunctional starter cultures. AB - Lactic acid bacteria (19 isolates) from Bella di Cerignola Italian table olives were investigated for their technological and probiotic properties for the selection of multifunctional starter cultures for table olives. The bacteria were first identified by phenotyping and genotyping, then characterized for the production of biogenic amines, growth at different pH, NaCl concentrations, and temperatures. The potentiality of the bacteria to have some probiotic properties (antimicrobial activity against foodborne pathogens, survival in low pH and in the presence of bile salts, ability to adhere to the mammalian cells model IPEC J2) was also investigated. Eighteen of the studied isolates were identified as Lactobacillus plantarum and one as Enterococcus faecalis. All bacteria were able to grow at a range of pH between 4.0 and 10.0 as well as in media supplemented with 2.5 to 7.5% of NaCl and 0.3% bile salts and survived in MRS broth acidified at pH 2.5; moreover, they inhibited significantly Escherichia coli O157:H7. The adhesion to IPEC-J2 cells was in general low to moderate (5.3 to 8.3%); however, 2 isolates of L. plantarum (c16 and c19) showed interesting higher adhesion values (up to 16%). Our results suggest that at least 3 isolates could be possible multifunctional starters for Bella di Cerignola olives: L. plantarum 16 and 19 for mainly their probiotic properties and L. plantarum 10 for mainly its technological characteristics. Practical Application: A functional starter is a microorganism exerting benefits on human health (probiotic) and able to guide a fermentation (starter). The main goal of this article was to select a functional starter for table olives. PMID- 21535509 TI - Preservation of chicken breast meat treated with thyme and balm essential oils. AB - The present study evaluated the effects of thyme and balm essential oils on the 3 wk storage of fresh chicken breast meat at 4 degrees C. Thyme and, to a lesser extent, balm essential oils reduced DPPH (2,2-diphenyl-1-picrylhydrazyl) radical formation in the meat (25% to 30% and 20%, respectively). Treatment with the 2 essential oils also limited lipid peroxidation and the deterioration of sarcoplasmic proteins, helping to preserve the meat even after 2 wk of storage. Thyme and balm essential oils decreased the natural microflora present in the meat; total microbial content decreased down to 50% in comparison to the control samples. In addition, a clear effect on lactic acid bacterial growth was recorded. Balm essential oil significantly limited the growth of Salmonella sp., whereas thyme essential oil effectively inhibited the growth of Escherichia coli. Our data demonstrate that these 2 essential oils effectively reduced deteriorative processes in chicken meat and extended the shelf life of this fresh product. Practical Application: The essential oils of thyme and balm can protect the chicken meat from decomposition during the storage time. PMID- 21535511 TI - Thermal and rheological properties of L-polylactide/polyethylene glycol/silicate nanocomposites films. AB - The melt rheology and thermal properties of polylactide (PLA)-based nanocomposite films that were prepared by solvent casting method with L-PLA, polyethylene glycol (PEG), and montmorillonite clay were studied. The neat PLA showed predominantly solid-like behavior (G' > G") and the complex viscosity (eta*) decreased systematically as the temperature increased from 184 to 196 degrees C. The elastic modulus (G') of PLA/clay blend showed a significant improvement in the magnitude in the melt, while clay concentration was at 6% wt or higher. At similar condition, PEG dramatically reduced dynamic modulii and complex viscosity of PLA/PEG blend as function of concentration. A nanocomposite blend of PLA/PEG/clay (74/20/6) when compared to the neat polymer and PLA/PEG blend exhibited intermediate values of elastic modulus (G') and complex viscosity (eta*) with excellent flexibility. Thermal analysis of different clay loading blends indicated that the melting temperature (T(m)) and glass transition temperature (T(g)) remained unaffected irrespective of clay concentration due to immobilization of polymer chain in the clay nanocomposite. PEG incorporation reduced the T(g) and the T(m) of the blends (PLA/PEG and PLA/PEG/clay) significantly, however, crystallinity increased in the similar condition. The transmission electron microscopy (TEM) image of nanocomposite films indicated good compatibility between PLA and PEG, whereas clay was not thoroughly distributed in the PLA matrix and remained as clusters. The percent crystallinity obtained by X-ray was significantly higher than that of differential scanning calorimeter (DSC) data for PLA. PMID- 21535512 TI - Properties of bread dough with added fiber polysaccharides and phenolic antioxidants: a review. AB - During breadmaking, different ingredients are used to ensure the development of a continuous protein network that is essential for bread quality. Interests in incorporating bioactive ingredients such as dietary fiber (DF) and phenolic antioxidants into popular foods such as bread have grown rapidly, due to the increased consumer health awareness. The added bioactive ingredients may or may not promote the protein cross-links. Appropriate cross-links among wheat proteins, fiber polysaccharides, and phenolic antioxidants could be the most critical factor for bread dough enhanced with DF and phenolic antioxidants. Such cross-links may influence the structure and properties of a bread system during baking. This article presents a brief overview of our current knowledge of the fate of the key components (wheat proteins, fibers, and phenolic antioxidants) and how they might interact during bread dough development and baking. PMID- 21535513 TI - Antioxidant enrichment and antimicrobial protection of fresh-cut fruits using their own byproducts: looking for integral exploitation. AB - Fresh-cut fruit consumption is increasing due to the rising public demand for convenience and awareness of fresh-cut fruit's health benefits. The entire tissue of fruits and vegetables is rich in bioactive compounds, such as phenolic compounds, carotenoids, and vitamins. The fresh-cut fruit industry deals with the perishable character of its products and the large percentage of byproducts, such as peels, seeds, and unused flesh that are generated by different steps of the industrial process. In most cases, the wasted byproducts can present similar or even higher contents of antioxidant and antimicrobial compounds than the final produce can. In this context, this hypothesis article finds that the antioxidant enrichment and antimicrobial protection of fresh-cut fruits, provided by the fruit's own byproducts, could be possible. PMID- 21535514 TI - Headspace volatiles along with other instrumental and sensory analyses as indices of maturation of horse mackerel miso. AB - Development of aroma-active compounds during fermentation in the preparation of fermented fish-meat paste product (fish miso) from horse mackerel meat was quantitatively determined and characterized by olfactometric and organoleptic assessments. The critical ripening time was estimated by quantitative and/or qualitative analyses of volatile compounds, peptides, amino acids, product color, and total phenolics of the fish miso matrix throughout fermentation. The results confirmed that the application of koji for the fermentation of horse mackerel meat to produce fish miso significantly reduced the fishy off odor and promoted the development of highly acceptable fish miso with a nutty, cheesy, and fruity aroma. Ethyl acetate, ethyl heptanoate, ethyl decanoate, 2-methylpropanal, 3 methylbutanal, 2,3-butanedione, dimethyl trisulfide, and 3-(methylthio) propanal were identified as key odor-active compounds in fish miso prepared from horse mackerel meat. Among the volatiles, 2-methylpropanal, 3-methylbutanal, and 2,3 butanedione were identified to serve as potential indicators of the maturation of fish miso. Amino acid content could also be a potential indicator of maturation of protein-rich, fermented products such as fish miso. In addition, surface color analysis of fish miso revealed a high correlation between sensory attributes and color components. Specifically, r and b values were considered potential indicators of maturation. Practical Application: Variability is a major drawback in fermented products such as fish miso and it requires establishing the optimum ripening time, defined as that providing the aroma attributes qualitatively and quantitatively mostly appreciated by consumers. We have carried out this work for comprehensive determination of the critical ripening time by applying several instrumental and sensory tools including quantitative and/or qualitative analysis of volatile compounds, peptides, amino acids, product color, and total phenolics of the fish miso matrix throughout the fermentation period. The outcome of the present study can be efficiently applied for detection of maturation in similar types of fermented product for large-scale production. PMID- 21535515 TI - Effect of antifungal hydroxypropyl methylcellulose-lipid edible composite coatings on Penicillium decay development and postharvest quality of cold-stored "Ortanique" mandarins. AB - Edible composite coatings based on hydroxypropyl methylcellulose (HPMC), hydrophobic components (beeswax and shellac), and food preservatives with antifungal properties were evaluated on "Ortanique" mandarins during long-term cold storage. Selected food preservatives included potassium sorbate (PS), sodium benzoate (SB), sodium propionate (SP), and their mixtures. Intact mandarins or mandarins artificially inoculated with the pathogens Penicillium digitatum and Penicillium italicum, the causal agents of citrus postharvest green (GM) and blue (BM) molds, respectively, were coated and stored up to 8 wk at 5 degrees C + 1 wk of shelf-life at 20 degrees C. HPMC-lipid coatings containing food preservatives controlled better GM than BM on Ortanique mandarins. SB- and SB + SP-based coatings reduced the incidence of GM by about 35% after 4 wk at 5 degrees C. Among all coatings, only the SB-based coating reduced the incidence of GM (about 16%) after 6 wk at 5 degrees C. All coatings significantly reduced disease severity of both GM and BM after 6 wk at 5 degrees C. Analytical and sensory fruit quality was evaluated on intact mandarins. All coatings, especially the SB + SP-based coatings, were effective to control weight loss and maintain the firmness of coated mandarins. Internal gas concentration, juice ethanol and acetaldehyde content, sensory flavor, off-flavor, and fruit appearance were not adversely affected by the application of the antifungal coatings. Further studies should focus on the modification of some physical characteristics of the coatings to improve the gloss and visual aspect of treated mandarins. PMID- 21535516 TI - Impacts of glutathione Maillard reaction products on sensory characteristics and consumer acceptability of beef soup. AB - The sensory characteristics and consumer acceptability of beef soup with added glutathione Maillard reaction products (GMRPs) were investigated to examine the effects of the GMRPs on beef-soup flavor compared to soups made with glutathione (GSH) and monosodium glutamate (MSG), a control (CON), or a control soup made with 150% beef content (CON150). The sensory characteristics of the beef soups were examined by descriptive analysis. The overall acceptabilities of the beef soups were rated by consumers. Principal component analysis was performed on descriptive data as explanatory variables with overall acceptability as a supplementary variable to observe the relationships between the descriptive data and consumer acceptability, as well as the relationships between the beef-soup samples and their sensory attributes. The samples containing GMRPs had "beef flavor" that was stronger than the CON and MSG samples, and comparable to that of the GSH sample and CON150. The GMRP samples had stronger "green onion flavor,""garlic flavor," and "boiled egg white flavor" than the other samples. The beef soup containing MSG was preferred to CON, CON150, and GSH. The samples with GMRPs were least favored because of their pronounced metallic and astringent notes. The results of this study imply the feasibility of GMRPs as a flavor enhancer since the soups containing these compounds showed more complex flavor profiles than GSH. However, future studies are required to optimize the MR conditions that produce GMRPs without undesirable characteristics. Practical Application: This study examined the practicability of the Maillard reaction products between glutathione (GSH) and glucose (GP) or fructose (FP) as a flavor enhancer by investigating the sensory characteristics and consumer acceptability evoked by them in a beef-soup system. This study helps flavor and food industry to develop a new flavor enhancer by providing practical information, such as beef flavor-enhancing effect of FP and GP compared to that by increasing beef content or adding GSH or MSG. In addition, it is expected that the outcome of this study, such as sensory attributes of and consumer responses to GSH Maillard reaction products, compliments previous studies that mostly focused on chemical analysis of Maillard reaction. PMID- 21535517 TI - Acids in combination with sodium dodecyl sulfate caused quality deterioration of fresh-cut iceberg lettuce during storage in modified atmosphere package. AB - Recent studies showed that sodium acid sulfate (SAS) and levulinic acid (LA) in combination with sodium dodecyl sulfate (SDS) was effective in inactivating human pathogens on Romaine lettuce. The present study investigated the effects of LA and SAS in combination with SDS (as compared with citric acid and chlorine) on the inactivation of E. coli O157:H7 and sensory quality of fresh-cut Iceberg lettuce in modified atmosphere packages during storage at 4 degrees C. Results showed that LA (0.5% to 3%) and SAS (0.25% to 0.75%) with 0.05% SDS caused detrimental effects on visual quality and texture of lettuce. LA- and SAS-treated samples were sensorially unacceptable due to development of sogginess and softening after 7 and 14 d storage. It appears that the combined treatments caused an increase in the respiration rate of fresh-cut lettuce as indicated by higher CO(2) and lower O(2) in modified atmosphere packages. On the positive side, the acid treatments inhibited cut edge browning of lettuce pieces developed during storage. LA (0.5%), SAS (0.25%), and citric acid (approximately 0.25%) in combination with SDS reduced population of E. coli OH157:H7 by 0.41, 0.87, and 0.58 log CFU/g, respectively, while chlorine achieved a reduction of 0.94 log CFU/g without damage to the lettuce. Therefore, compared to chlorine, LA and SAS in combination with SDS have limited commercial value for fresh-cut Iceberg lettuce due to quality deterioration during storage. PMID- 21535518 TI - Odor active compounds content in spices and their microencapsulated powders measured by SPME. AB - Within this study, main odorants of marjoram and thyme (linalool and thymol) were determined in spices and microencapsulated powders using solid-phase microextraction (SPME). Analyses were conducted on selected batches of spices before and after decontamination and on microencapsulated powders prepared for technological purposes (improvement of aroma in decontaminated spices). Conditions of SPME analyses were determined for individual compounds and matrices. Determination of total and surface contents of compounds and the percentage dependencies between encapsulated and surface aroma made it possible to identify the best powders in terms of their quality. PMID- 21535519 TI - Carotenoid composition and vitamin A value in aji (Capsicum baccatum L.) and rocoto (C. pubescens R. & P.), 2 pepper species from the Andean region. AB - The carotenoid patterns of fully ripe fruits from 12 Bolivian accessions of the Andean peppers Capsicum baccatum (aji) and C. pubescens (rocoto) were determined by high-performance liquid chromatography (HPLC)-photodiode array detector (PDA) mass spectrometry (MS). We include 2 California Wonder cultivars as C. annuum controls. A total of 16 carotenoids were identified and differences among species were mostly found at the quantitative level. Among red-fruited genotypes, capsanthin was the main carotenoid in the 3 species (25% to 50% contribution to carotenoid fraction), although ajies contained the lowest contribution of this carotenoid. In addition, the contribution of capsanthin 5,6-epoxide to total carotenoids in this species was high (11% to 27%) in comparison to rocotos and red C. annuum. Antheraxanthin and violaxanthin were, in general, the next most relevant carotenoids in the red Andean peppers (6.1% to 10.6%). Violaxanthin was the major carotenoid in yellow-/orange-fruited genotypes of the 3 species (37% to 68% total carotenoids), although yellow rocotos were characterized by lower levels (<45%). Cis-violaxanthin, antheraxanthin, and lutein were the next most relevant carotenoids in the yellow/orange Andean peppers (5% to 14%). As a whole, rocotos showed the highest contributions of provitamin A carotenoids to the carotenoid fraction. In terms of nutritional contribution, both ajies and rocotos provide a remarkable provitamin A activity, with several accessions showing a content in retinol equivalents higher than California Wonder controls. Furthermore, levels of lutein in yellow/orange ajies and rocotos were clearly higher than California Wonder pepper (>=1000 MUg.100/g). Finally, the Andean peppers, particularly red ajies, can be also considered as a noticeable source of capsanthin, the most powerful antioxidant compound among pepper carotenoids. Practical Application: Capsicum peppers are known for their content in carotenoids, although there is no information about 2 species with Andean origin: ajies and rocotos. Due to their relevance for the Andean cuisine and increasing importance in ethnic restaurants in Europe, we studied their carotenoid pattern and vitamin A contribution. PMID- 21535520 TI - Detection of target staphylococcal enterotoxin B antigen in orange juice and popular carbonated beverages using antibody-dependent antigen-capture assays. AB - There is a critical need for qualitative and quantitative methodologies that provide the rapid and accurate detection of food contaminants in complex food matrices. However, the sensitivity of the assay can be affected when antigen capture is applied to certain foods or beverages that are extremely acidic. This study was undertaken to assess the effects of orange juice and popular carbonated soft drink upon the fidelity of antibody-based antigen-capture assays and to develop simple approaches that could rescue assay performance without the introduction of additional or extensive extraction procedures. We examined the effects of orange juice and a variety of popular carbonated soft drink beverages upon a quantitative Interleukin-2 (IL-2) enzyme-linked immunosorbent assay (ELISA) assay system and a lateral flow device (LFD) adapted for the detection of staphylococcal enterotoxin B (SEB) in foods. Alterations in the performance and sensitivity of the assay were directly attributable to the food matrix, and alterations in pH were especially critical. The results demonstrate that approaches such as an alteration of pH and the use of milk as a blocking agent, either singly or in combination, will partially rescue ELISA performance. The same approaches permit lateral flow to efficiently detect antigen. Practical Application: The authors present ways to rescue an ELISA assay compromised by acidity in beverages and show that either the alteration of pH, or the use of milk as a blocking agent are not always capable of restoring the assay to its intended efficiency. However, the same methods, when employed with lateral flow technology, are rapid and extremely successful. PMID- 21535524 TI - Production of crude xylanase from Thermoascus aurantiacus CBMAI 756 aiming the baking process. AB - In recent years, the baking industry has focused its attention on substituting several chemical compounds with enzymes. Enzymes that hydrolyze nonstarch polysaccharides, such as xylanase, lead to the improvement of rheological properties of dough, loaf specific volume, and crumb firmness. The purpose of this study was to find a better solid-state fermentation substrate to produce high levels of xylanase and low levels of protease and amylase, which are enzymes involved in bread quality, from Thermoascus aurantiacus CBMAI 756. Wheat bran, corncob, and corn straw were used as energy sources. The enzyme extract of corncob showed high xylanase activity (130 U/mL) and low amylase and protease activity (<1 and 15 U/mL, respectively). This enzyme profile may be more profitable for the baking industry, because it results in a slower degradation of gluten. Our results confirm this finding, because the enzyme obtained by fermentation in corncob resulted in a gluten with a higher specific volume than all the other substrates that were tested. The crude xylanase presented maximum activity at a pH of 5, and the optimum temperature was 75 degrees C. It was stable up to 70 degrees C for an hour and at a pH range from 4 to 10. PMID- 21535525 TI - A multiplex PCR method for the identification of commercially important salmon and trout species (Oncorhynchus and Salmo) in North America. AB - The purpose of this study was to develop a species-specific multiplex polymerase chain reaction (PCR) method that allows for the detection of salmon species substitution on the commercial market. Species-specific primers and TaqMan(r) probes were developed based on a comprehensive collection of mitochondrial 5' cytochrome c oxidase subunit I (COI) deoxyribonucleic acid (DNA) "barcode" sequences. Primers and probes were combined into multiplex assays and tested for specificity against 112 reference samples representing 25 species. Sensitivity and linearity tests were conducted using 10-fold serial dilutions of target DNA (single-species samples) and DNA admixtures containing the target species at levels of 10%, 1.0%, and 0.1% mixed with a secondary species. The specificity tests showed positive signals for the target DNA in both real-time and conventional PCR systems. Nonspecific amplification in both systems was minimal; however, false positives were detected at low levels (1.2% to 8.3%) in conventional PCR. Detection levels were similar for admixtures and single-species samples based on a 30 PCR cycle cut-off, with limits of 0.25 to 2.5 ng (1% to 10%) in conventional PCR and 0.05 to 5.0 ng (0.1% to 10%) in real-time PCR. A small-scale test with food samples showed promising results, with species identification possible even in heavily processed food items. Overall, this study presents a rapid, specific, and sensitive method for salmon species identification that can be applied to mixed-species and heavily processed samples in either conventional or real-time PCR formats. PRACTICAL APPLICATION: This study provides a newly developed method for salmon and trout species identification that will assist both industry and regulatory agencies in the detection and prevention of species substitution. This multiplex PCR method allows for rapid, high-throughput species identification even in heavily processed and mixed-species samples. An inter-laboratory study is currently being carried out to assess the ability of this method to identify species in a variety of commercial salmon and trout products. PMID- 21535526 TI - Process optimization and consumer acceptability of salted ground beef patties cooked and held hot in flavored marinade. AB - Food safety is paramount for cooking hamburger. The center must reach 71 degrees C (or 68 degrees C for 15 s) to assure destruction of E. coli O157:H7 and other food pathogens. This is difficult to achieve during grilling or frying of thick burgers without overcooking the surface. Thus, the feasibility of partially or completely cooking frozen patties in liquid (93 degrees C water) together with hot holding in liquid was investigated. Initial studies demonstrated that compared to frying, liquid cooking decreased (P < 0.05) patty diameter (98 compared with 93 mm) and increased (P < 0.05) thickness (18.1 compared with 15.6 mm). Liquid cooked patties had greater weight loss (P < 0.05) immediately after cooking (29 compared with 21%), but reabsorbed moisture and were not different from fried patties after 1 h hot water holding (61 degrees C). Protein and fat content were not affected by cooking method. However, liquid cooked patties were rated lower (P < 0.05) than fried patties for appearance (5.7 compared with 7.5) and flavor (5.9 compared with 7.5). An 8-member focus group then evaluated methods to improve both appearance and flavor. Salted, grill-marked patties were preferred, and caramel coloring was needed in the marinade to obtain acceptable flavor and color during liquid cooking or hot holding. Patties with 0.75% salt that were grill-marked and then finish-cooked in hot marinade (0.75% salt, 0.3% caramel color) were rated acceptable (P < 0.05) by consumers for up to 4 h hot holding in marinade, with mean hedonic panel ratings > 7.0 (like moderately) for appearance, juiciness, flavor, and texture. PRACTICAL APPLICATION: Grill-marked and marinade-cooked ground beef patties reached a safe internal cooking temperature without overcooking the surface. Burgers cooked using this method maintained high consumer acceptability right after cooking and for up to 4 h of hot holding. Consumers and foodservice operations could use this method without specialized equipment, and instead use inexpensive and common equipment such as a soup pot or a restaurant steam table. Use of marinades (salt/caramel color or others) in this cooking and holding method provides a nearly endless culinary flavoring opportunity. PMID- 21535527 TI - Effect of high pressure pasteurization on bacterial load and bioactivity of Echinacea purpurea. AB - High hydrostatic pressure (HHP) technology was applied to organic Echinacea purpurea (E. purpurea) roots and flowers to determine the feasibility of using this technology for cold herb pasteurization, to produce microbiologically safe and shelf-stable products for the natural health products (NHPs) industry. HHP significantly (P < 0.01) reduced microbial contamination in both roots and flowers without affecting the phytochemical retention of chicoric and chlorogenic acids, and total alkamide contents. The antioxidant activity of E. purpurea methanol-derived extracts, evaluated in both chemical (2,2'-azino-bis(3 ethylbenzthiazoline-6-sulphonic acid) [ABTS] and oxygen radical absorption capacity [ORAC] assay) and in cell culture models (RAW264, 7 macrophage, H(2)O(2) induced intracellular oxidation, and lipopolysaccharide [LPS]-induced nitric oxide production), was not adversely affected by the application of HHP at both 2 and 5 min at 600 mPa. Furthermore, HHP did not affect the capacity of E. purpurea extracts to suppress nitric oxide production in LPS-activated macrophage cells. Therefore, our results show that HHP is an effective pasteurization process treatment to reduce microbial-contamination load while not adversely altering chemical and bioactive function of active constituents present in organic E. purpurea. PRACTICAL APPLICATION: Our study reports for the first time, the effectiveness of using high hydrostatic pressure (HHP) technology pressure to pasteurize E. purpurea root and flower, and the comparative retention of bioactive phytochemicals. Therefore, this technique can be used in food and natural health product industries to produce high-quality, microbiologically safe, and shelf-stable products. PMID- 21535528 TI - Evaluation of parameters that affect the 4-dimethylaminocinnamaldehyde assay for flavanols and proanthocyanidins. AB - Proanthocyanidins are widely distributed in nature and represent the most abundant flavonoids consumed in the diet. Recent attention has been given to these compounds because of their health-promoting properties toward chronic diseases. Because of their large degrees of chemical variation and stereochemistry, isolation/quantification is difficult. The 4 dimethylaminocinnamaldehyde (DMAC) spectrophotometric assay has become increasingly popular as a rapid technique to quantify the amount of proanthocyanidins present in foods and beverages; however, there is no current industry standard. In this study, several parameters affecting the DMAC reaction with catechin were examined. Effects of acid nature (hydrochloric acid [HCl] and sulfuric acid [H(2)SO(4)]) and concentration (2 to 10 N), temperature (5 to 45 degrees C), reaction time (2 to 35 min), sample water content (1 to 100%), DMAC concentration (1 to 3%), and interference of 8 different substances were evaluated. A mixture of 2% DMAC in methanol (w/v) in 6 N H(2)SO(4) (50:50 v/v) showed the highest slope in the standard curve when allowed to react for 15 to 35 min prior to analysis. For samples containing high concentrations of oligomeric proanthocyanidins, a reaction time of 20 to 35 min is recommended. The reaction of catechin with DMAC at constant room temperature (21 to 25 degrees C), with a sample water content of less than 1% was found to increase reproducibility and better assess the amount of catechin. Sample water contents higher than 1% showed significant bleaching effects on the color produced, when catechin concentrations were high (lower levels showed no significant differences). None of the substances examined in this study interfered with the assay; however, other compounds present in various food matrices may have an effect on color development. PMID- 21535529 TI - Optimization of extraction conditions of total phenolics, antioxidant activities, and anthocyanin of oregano, thyme, terebinth, and pomegranate. AB - The purpose of this study was to evaluate the total phenolic extracts and antioxidant activity and anthocyanins of varieties of the investigated plants. These plants include oregano, thyme, terebinth, and pomegranate. The optimum extraction conditions including temperature and solvent of the extraction process itself were investigated. Total phenolic and anthocyanin extracts were examined according to Folin-Ciocalteu assay and Rabino and Mancinelli method, respectively. The effect of different extracting solvents and temperatures on extracts of phenolic compounds and anthocyanins were studied. Plant samples were evaluated for their antioxidant chemical activity by 2, 2-diphenyl-1 picrylhydrazl assay, to determine their potential as a source of natural antioxidant. Results showed that all tested plants exhibited appreciable amounts of phenolic compounds. The methanolic extract (60 degrees C) of sour pomegranate peel contained the highest phenolic extract (4952.4 mg/100 g of dry weight). Terebinth green seed had the lowest phenolic extract (599.4 mg/100 g of dry weight). Anthocyanins ranged between 3.5 (terebinth red seed) and 0.2 mg/100 g of dry material (thyme). Significant effect of different extracting solvents and temperatures on total phenolics and anthocyanin extracts were found. The methanol and 60 degrees C of extraction conditions found to be the best for extracting phenolic compounds. The distilled water and 60 degrees C extraction conditions found to be the best for extracting anthocyanin. PMID- 21535530 TI - Distribution of stable free radicals among amino acids of isolated soy proteins. AB - Application of deuterium sulfide to powdered isolated soy proteins (ISP) was used to quench stable free radicals and produce a single deuterium label on amino acids where free radicals reside. The deuterium labels rendered increases of isotope ratio for the specific ions of radical-bearing amino acids. Isotope ratio measurements were achieved by gas chromatography/mass spectrometry (GC/MS) analyses after the amino acids were released by acidic hydrolysis and converted to volatile derivatives with propyl chloroformate. The isotope enrichment data showed the stable free radicals were located on Ala, Gly, Leu, Ile, Asx (Asp+Asn), Glx (Glu+Gln), and Trp but not on Val, Pro, Met, Phe, Lys, and His. Due to the low abundance of Ser, Thr, and Cys derivatives and the impossibility to accurately measure their isotope ratios, the radical bearing status for these amino acids remained undetermined even though their derivatives were positively identified from ISP hydrolysates. The relative isotope enrichment for radical bearing amino acids Ala, Gly, Leu, Ile, Asx (Asp+Asn), Glx (Glu+Gln), and Trp were 8.67%, 2.96%, 2.90%, 3.94%, 6.03%, 3.91%, and 21.48%, respectively. Isotope ratio increase for Tyr was also observed but further investigation revealed such increase was mainly from nonspecific deuterium-hydrogen exchange not free radical quenching. The results obtained from the present study provide important information for a better understanding of the mechanisms of free radical formation and stabilization in "dry" ISP. PMID- 21535531 TI - High-intensity pulsed electric fields processing parameters affecting polyphenoloxidase activity of strawberry juice. AB - High-intensity pulsed electric fields (HIPEF) were applied to strawberry juice to study the feasibility of inactivating polyphenoloxidase (PPO). Response surface methodology was used to evaluate the effect of HIPEF processing, in which total treatment time (1000 to 2000 MUs), pulse frequency (50 to 250 Hz), pulse width (1.0 to 7.0 MUs), and polarity (monopolar or bipolar) were the controlled variables at a constant electric field of 35 kV/cm. The proposed 2nd-order response functions were accurate enough to fit experimental results. Strawberry juice PPO was strongly reduced within the range of assayed conditions. HIPEF treatments were more effective in bipolar than in monopolar mode in inactivating PPO. Treatments of longer duration resulted in reductions of the enzyme activity. Moreover, it was feasible to minimize residual PPO activity (down to 2.5%) by selecting bipolar treatments at frequencies higher than 229 Hz and pulse widths between 3.23 and 4.23 MUs for a constant total treatment time of 2000 MUs. PMID- 21535532 TI - Trans fatty acids content and fatty acid profiles in the selected food products from Korea between 2005 and 2008. AB - Since a high intake of trans fatty acids (TFA) has been associated with the increased risk of developing cardiovascular disease, food regulation worldwide has been amended with respect to nutrition labeling and health claims on TFA. In the present study, the TFA levels of Korean food products were investigated to assess the regulation effect of TFA labeling. Same Korean food products within 7 different categories were purchased in years 2005 and 2008, and the contents of TFA and lipid and fatty acid composition were investigated. Lipid and TFA contents decreased in all food products manufactured in 2008. TFA levels were 0.01 to 6.88 g/100 g food in 2005, but the levels remarkably decreased to nondetectable level or up to 0.5 g TFA/100 g food in 2008. The foods from 2005 contained a various level of TFA ranging 0.6% to 44.6% of total fatty acids; however, the TFA level significantly decreased in most foods up to 3.8% from year 2008. For TFAs, trans C18:1 levels were greater than trans isomers of C18:2, and the levels in 2005 were significantly reduced in 2008 (P < 0.05). TFA levels at the sn-2 position were up to 48.3% of total fatty acids in 2005, but the level considerably decreased up to 5.4% in 2008. The considerably decreased content of TFA in 2008 suggested that food manufacturers recognized the adverse effect of TFA on human health and followed the compulsory trans fat labeling rule by Korean Food and Drug Administration (KFDA), which started December 2007. PMID- 21535533 TI - Microscopic quantification of cell integrity in raw and processed onion parenchyma cells. AB - A cell viability assessment method based computer vision analysis of the uptake of neutral red dye was used to quantify cell membrane integrity in raw and processed parenchyma cells of onion tissues. The presence of stained vacuoles was used as an indicator of tonoplast membrane integrity and photomicrographs were acquired for microscopic image analysis and cell integrity quantification. Two different image analysis methods, involving the analysis of the saturation and green components of RGB (red, green, blue) images, were compared to the conventional cell count method. Use of the saturation component of RGB images allowed for the visualization and quantification of viable and inviable cells as well as extracellular air spaces. The combination of neutral red uptake, as visualization by light field microscopy, and saturation image analysis, allowed for quantitative determination of the effects of high pressure processing on onion cell integrity. PRACTICAL APPLICATION: Preservation of vegetable tissues may involve heating or other methods that result in the loss of tissue integrity and potentially quality deterioration. In this study, we stained unprocessed and processed onion tissues with neutral red dye and then used a microscope and a computer imaging program to quantify how many cells were intact or ruptured. PMID- 21535534 TI - Influence of cell integrity on textural properties of raw, high pressure, and thermally processed onions. AB - The integrity of onion cells and its impact on tissue texture after high pressure and thermal processing was studied. The contribution of cell membranes and the pectic component of cell walls on the texture properties of onion tissue were analyzed. Neutral red (NR) staining of onion parenchyma cell vacuoles was used for the evaluation of cell membrane integrity and microscopic image analysis was used for its quantification. The content of methanol in tissue as a result of pectin methylesterase activity was used to evaluate the pectin component of the middle lamella and cell walls and the hardening effect on the tissue after processing. High pressure treatments consisted of 5-min holding times at 50, 100, 200, 300, or 600 MPa. Thermal treatments consisted of 30-min water bath exposure to 40, 50, 60, 70, or 90 degrees C. In the high pressure treatments, loss of membrane integrity commenced at 200 MPa and total loss of membrane integrity occurred at 300 MPa and above. In the thermal treatments, membrane integrity was lost between 50 and 60 degrees C. The texture of onions was influenced by the state of the membranes and texture profiles were abruptly modified once membrane integrity was lost. Hardening of the tissue corresponded with pressure and temperature PME activation and occurred after membrane integrity loss. PRACTICAL APPLICATION: The texture of vegetables is an important quality attribute that affects consumer preference. Loss of textural integrity also indicates that other biochemical reactions that affect color, flavor, and nutrient content may occur more rapidly. In this study, we analyzed changes in the texture of onions after preservation with heat and high pressure. PMID- 21535535 TI - 1H-NMR study of the impact of high pressure and thermal processing on cell membrane integrity of onions. AB - Proton nuclear magnetic resonance (1H-NMR) relaxometry was used to study the effects of high pressure and thermal processing on membrane permeability and cell compartmentalization, important components of plant tissue texture. High pressure treated onions were subjected to pressure levels from 20 to 200 MPa at 5 min hold time at initial temperatures of 5 and 20 degrees C. Thermally treated onions were exposed for 30 min at temperatures from 40 to 90 degrees C. Loss of membrane integrity was clearly shown by changes in transverse relaxation time (T(2)) of water at temperatures of 60 degrees C and above. Destabilization effects on membranes exposed to high pressure were observed at 200 MPa as indicated by T(2) measurements and cryo-scanning electron microscopy (Cryo-SEM). T(2) relaxation successfully discriminated different degrees of membrane damage based on the T(2) shift of the vacuolar component. Analyses of the average water self-diffusion coefficient indicated less restricted diffusion after membrane rupture occurred in cases of severe thermal treatments. Milder processing treatments yielded lower average diffusion coefficients than the controls. 1H-NMR proved to be an effective method for quantification of cell membrane damage in onions and allowed for the comparison of different food processes based on their impact on tissue integrity. PMID- 21535536 TI - Onion cells after high pressure and thermal processing: comparison of membrane integrity changes using different analytical methods and impact on tissue texture. AB - Two different analytical methods were evaluated for their capacity to provide quantitative information on onion cell membrane permeability and integrity after high pressure and thermal processing and to study the impact of these processing treatments on cell compartmentalization and texture quality. To determine changes in cell membrane permeability and/or integrity the methodologies utilized were: (1) measurement of a biochemical product, pyruvate, formed as a result of membrane permeabilization followed by enzymatic activity and (2) leakage of electrolytes into solution. These results were compared to previously determined methods that quantified cell viability and 1H-NMR T(2) of onions. These methods allowed for the monitoring of changes in the plasma and tonoplast membranes after high pressure or thermal processing. High pressure treatments consisted of 5 min holding times at 50, 100, 200, 300, or 600 MPa. Thermal treatments consisted of 30 min water bath exposure to 40, 50, 60, 70, or 90 degrees C. There was strong agreement between the methods in the determination of the ranges of high pressure and temperature that induce changes in the integrity of the plasma and tonoplast membranes. Membrane rupture could clearly be identified at 300 MPa and above in high pressure treatments and at 60 degrees C and above in the thermal treatments. Membrane destabilization effects could already be visualized following the 200 MPa and 50 degrees C treatments. The texture of onions was influenced by the state of the membranes and was abruptly modified once membrane integrity was lost. PRACTICAL APPLICATION: In this study, we used chemical, biochemical, and histological techniques to obtain information on cell membrane permeability and onion tissue integrity after high pressure and thermal processing. Because there was strong agreement between the various methods used, it is possible to implement something relatively simple, such as ion leakage, into routine quality assurance measurements to determine the severity of preservation methods and the shelf life of processed vegetables. PMID- 21535537 TI - Critical electric field strengths of onion tissues treated by pulsed electric fields. AB - The impact of pulsed electric fields (PEF) on cellular integrity and texture of Ranchero and Sabroso onions (Allium cepa L.) was investigated. Electrical properties, ion leakage rate, texture, and amount of enzymatically formed pyruvate were measured before and after PEF treatment for a range of applied field strengths and number of pulses. Critical electric field strengths or thresholds (E(c)) necessary to initiate membrane rupture were different because dissimilar properties were measured. Measurement of electrical characteristics was the most sensitive method and was used to detect the early stage of plasma membrane breakdown, while pyruvate formation by the enzyme alliinase was used to identify tonoplast membrane breakdown. Our results for 100-MUs pulses indicate that breakdown of the plasma membrane occurs above E(c)= 67 V/cm for 10 pulses, but breakdown of the tonoplast membrane is above either E(c)= 200 V/cm for 10 pulses or 133 V/cm for 100 pulses. This disparity in field strength suggests there may be 2 critical electrical field strengths: a lower field strength for plasma membrane breakdown and a higher field strength for tonoplast membrane breakdown. Both critical electric field strengths depended on the number of pulses applied. Application of a single pulse at an electric field up to 333 V/cm had no observable effect on any measured properties, while significant differences were observed for n>=10. The minimum electric field strength required to cause a measurable property change decreased with the number of pulses. The results also suggest that PEF treatment may be more efficient if a higher electric field strength is applied for a fewer pulses. PMID- 21535538 TI - Disintegration efficiency of pulsed electric field induced effects on onion (Allium cepa L.) tissues as a function of pulse protocol and determination of cell integrity by 1H-NMR relaxometry. AB - The influence of electrical pulse protocol parameters on cell rupture of onion tissues was investigated in order to improve fundamental understanding and to enhance the processing of plant tissues with pulsed electric fields (PEFs). The impact of PEF parameters on cell integrity of 20 mm dia, 4-mm thick disks of Don Victor onions (Allium cepa L.) was determined by ion leakage measurements. Electric field strength, pulse width, total pulse duration, and frequency effects were determined in relation to their effects on cell damage as a function of pulse protocol. Electric field strengths up to 500 V/cm increased the damage efficiency but there was no significant difference in efficiency beyond this field strength. Larger pulse widths increased the degree of tissue disintegration at a constant pulse number. Higher PEF efficiency was achieved with shorter pulse widths and a larger number of pulses at a constant total treatment time. Lower frequencies caused a greater degree of disintegration at constant number of pulses. 1H-NMR experiments were performed to determine the proton relaxation components of the PEF-treated onion samples and to obtain cell damage information nondestructively. Paramagnetic ion uptake by the onion sample was used to identify different proton relaxation components. Five different proton relaxation components were observed and changes in the 2 components representing different proton environments showed high correlations with ion leakage results (R2= 0.99), indicating that T(2) distributions can be used to obtain information about cell membrane integrity in PEF-treated samples. 1H-NMR proved to be an effective method for nondestructive quantification of cell membrane rupture in onions. PMID- 21535539 TI - Quantitative evaluation of microstructural changes and their relations with some physical characteristics of food during drying. AB - Drying is known to affect various quality attributes of a food product, especially its physical properties. However, changes of physical properties or characteristics are generally due to changes of the product microstructure. Nevertheless, not much quantitative information, as opposed to abundant qualitative information, is available to describe in detail relationships between microstructural and physical changes of food undergoing drying. The present study, thus, aimed at studying quantitative relationships between microstructural and selected physical changes of a test material, that is, carrot, undergoing hot air drying at 60 and 80 degrees C. The microstructural changes were represented quantitatively in terms of the normalized changes of the fractal dimension (DeltaFD/FD(0)) of microstructural images of the samples as well as the normalized changes of the sample average cell diameter (DeltaD/D(0)), while the physical changes of interest were shrinkage and hardness. The results showed that during an earlier period of drying DeltaFD/FD(0) as well as DeltaD/D(0) tended to increase with decreasing moisture content; deformation of the microstructures (represented either in terms of DeltaFD/FD(0) or DeltaD/D(0)) led to increased shrinkage and hardness. On the other hand, deformation of the microstructures existed, while the moisture content did not change much during the final stage of drying. The relationships between DeltaFD/FD(0) and both physical changes were quite well established; DeltaD/D(0)were also found to correlate well with the physical changes. Either DeltaFD/FD(0) or DeltaD/D(0)could thus be used as a tool to monitor the apparent physical changes (shrinkage and hardness) of a sample during drying. PRACTICAL APPLICATION: Either the normalized changes of the fractal dimension of microstructural images of a sample or the normalized changes of the sample average cell diameter can be a useful tool in monitoring the drying process by 1st assessing the product volumetric shrinkage, which can be assessed easily on-line and on a real-time basis by such techniques as image analysis, and then relating the obtained results through microstructural changes to other apparent physical changes, including the product texture. PMID- 21535540 TI - FT-NIR spectroscopy for the quality characterization of apricots (Prunus armeniaca L.). AB - The nondestructive assessment of apricot fruit quality (Bora cultivar) was carried out by means of FT-NIR reflectance spectroscopy in the wavenumber range 12000 to 4000 cm-1. Samples were harvested at four different ripening stages and scanned by a fiber optical probe immediately after harvesting and after a storage of 3 d (2 d at 4 degrees C and 1 d at 18 degrees C); the flesh firmness (FF), the soluble solids content (SSC), the acidity (A), and the titratable acidity (malic and citric acids) were then measured by destructive methods. Soft independent modeling of class analogy (SIMCA) analysis was used to classify spectra according to the ripening stage and the storage: partial least squares regression (PLS) models to predict FF, SSC, A, and the titratable acidity were also set-up for both just harvested and stored apricots. Spectral pretreatments and wavenumber selections were conducted on the basis of explorative principal component analysis (PCA). Apricot spectra were correctly classified in the right class with a mean classification rate of 87% (range: 80% to 100%). Test set validations of PLS models showed R2 values up to 0.620, 0.863, 0.842, and 0.369 for FF, SSC, A, and the titratable acidity, respectively. The best models were obtained for the SSC and A and are suitable for rough screening; a lower power prediction emerged for the other maturity indices and the relative predictive models are not recommended. PRACTICAL APPLICATION: The results of the study could be used as a tool for the assessment of the ripening stage during the harvest and the quality during the postharvest storage of apricot fruits. PMID- 21535541 TI - Microstructural characterization of multiphase chocolate using X-ray microtomography. AB - In this study, X-ray microtomography (MUCT) was used for the image analysis of the microstructure of 12 types of Italian aerated chocolate chosen to exhibit variability in terms of cocoa mass content. Appropriate quantitative 3 dimensional parameters describing the microstructure were calculated, for example, the structure thickness (ST), object structure volume ratio (OSVR), and the percentage object volume (POV). Chemical analysis was also performed to correlate the microstructural data to the chemical composition of the samples. Correlation between the MUCT parameters acquired for the pore microstructure evaluation and the chemical analysis revealed that the sugar crystals content does not influence the pore structure and content. On the other hand, it revealed that there is a strong correlation between the POV and the sugar content obtained by chemical analysis. The results from this study show that MUCT is a suitable technique for the microstructural analysis of confectionary products such as chocolates and not only does it provide an accurate analysis of the pores and microstructure but the data obtained could also be used to aid in the assessment of its composition and consistency with label specifications. PRACTICAL APPLICATION: X-ray microtomography (MUCT) is a noninvasive and nondestructive 3-D imaging technique that has several advantages over other methods, including the ability to image low-moisture materials. Given the enormous success of MUCT in medical applications, material science, chemical engineering, geology, and biology, it is not surprising that in recent years much attention has been focused on extending this imaging technique to food science as a useful technique to aid in the study of food microstructure. X-ray microtomography provides in depth information on the microstructure of the food product being tested; therefore, a better understanding of the physical structure of the product and from an engineering perspective, knowledge about the microstructure of foods can be used to identify the important processing parameters that affect the quality of a product. PMID- 21535542 TI - Effect of acid- and alkaline-aided extractions on functional and rheological properties of proteins recovered from mechanically separated turkey meat (MSTM). AB - Functional and rheological characteristics of acid- and alkali-extracted proteins from mechanically separated turkey meat (MSTM) have been investigated. Extractions were carried out at 4 pH values (2.5, 3.5, 10.5, and 11.5). The study demonstrated that alkali and acid extractions resulted in significant (P < 0.0001) decreases of cooking and water loss compared to raw MSTM; however, the cooking loss was found to be similar (P = 0.5699) among the different protein isolates. Proteins extracted at pH 10.5 showed the lowest (P = 0.0249) water loss. Emulsion and foaming properties were found to be slightly higher in alkali extracted proteins compared to those for acid extractions. The myofibrillar protein fraction showed better ability to form and stabilize emulsions compared to sarcoplasmic proteins. Myofibrillar proteins also showed better foam expansion; however, foam volume stability was similar for both myofibrillar and sarcoplasmic protein fractions. Textural characteristics (hardness, chewiness, springiness, and cohesiveness) of recovered proteins were found to be unaffected (P > 0.05) by different extraction pH. The protein extracted at pH 3.5 formed a highly viscoelastic gel network as evidenced by storage modulus (G') values, whereas the gel formed from proteins extracted at pH 10.5 was found to be the weakest. The work also revealed that acid treatments were more effective for removal of total heme pigments from MSTM. Color characteristics of protein isolates were markedly improved compared to the initial material and tended to be better when subjected to acid extractions. PRACTICAL APPLICATION: Mechanically separated meat is one of the cheapest sources of protein obtained by grinding meat and bones together and forcing the mixture through a perforated drum. The use of mechanically separated turkey meat (MSTM) for the production of further processed poultry products is limited due to its undesirable color and textural properties. Recovery of proteins from MSTM using pH shifting process will help the poultry processors to get better returns and also create opportunity to produce functional food ingredients. PMID- 21535543 TI - Porosity changes and retention of ginsenosides in North American ginseng root using different dehydration processes. AB - Air drying (AD), freeze-drying (FD), and vacuum-microwave drying (VMD) were applied to fresh North American ginseng roots to evaluate the effect of different drying techniques on pore characteristics and the subsequent recovery of ginsenoside content. FD ginseng root produced the lowest reductions in both total moisture content and water activity (P < 0.05), with no differences noted between Ontario or British Columbia ginseng. Ginseng roots from Ontario and British Columbia sources were therefore pooled to conduct the root porosity and ginsenoside measurements. Among samples, FD ginseng obtained the highest total porosity followed by VMD and AD, respectively (P < 0.05). All dehydrated samples had a porous structure with sizes that ranged from 0.002 MUm to 172 MUm, dominated by macropores (>1.5 MUm). Pore characteristics of dried ginseng root were shown to affect recovery of ginsenosides, with the general trend being an increase in total porosity resulting in an increase in total ginsenoside recovered. High performance liquid chromatography results obtained on specific ginsenosides showed that AD of ginseng root resulted in the lowest recovery of total ginsenosides, most notably, Rg1 and Rb1, followed by VMD and FD, respectively. There was no specific difference in total ginsenoside recovery from roots dried at increasing power of VMD. PMID- 21535544 TI - Ohmic heating of peaches in the wide range of frequencies (50 Hz to 1 MHz). AB - The ohmic heating (OH) rate of peaches was studied at fixed electric field strength of 60 V.cm-1, square-shaped instant reversal bipolar pulses, and frequencies varying within 50 Hz to 1 MHz. Thermal damage of tissue was evaluated from electrical admittivity. It showed that the time for half disruption (tau(T)) of tissue was required more than 10 h at temperatures below 40 degrees C. However, cellular thermal disruption occurred almost instantly (tau(T) < 1 s) at high temperatures (> 90 degrees C). Electrical conductivity sigma(o) and admittivity sigma(o)* of tissue at T(o)= 0 degrees C and their temperature coefficients (m, m*) were calculated. For freeze-thawed tissues, sigma and sigma* as well as m and m* were nearly indifferent to the frequency. However, for the intact tissue, both sigma(o), sigma(o)* and m, m* were frequency dependent. For freeze-thawed product, the power factor (P) was approximately equal to 1 and indifferent to the frequency and temperature. On the other hand, strong frequency dependence was observed for intact tissue with the minimum P approximately equal to 0.68 in the range of tens of kHz. The time required to reach a target temperature t(f) was evaluated. The t(f) increased with frequency up to the middle of the range of tens of kHz and thereafter continuously decreased. Samples exposed to the low-frequency electric field demonstrated faster electro-thermal damage rates. The textural relaxation data supported more intense damage kinetics at low-frequency OH. It has been demonstrated that a combination of high frequency OH with pasteurization at moderate temperature followed by rapid cooling minimizes texture degradation of peach tissue. PRACTICAL APPLICATION: In this study, we investigated the electric field frequency effect on the rate of OH of peaches. It was shown that the time required for reaching the target temperature is strongly dependent upon the frequency. Samples exposed to low frequency OH demonstrated higher electro-thermal damage rates. It has been shown that the combination of high-frequency OH with pasteurization at moderate temperature followed by rapid cooling minimizes texture degradation of peach tissue. Obtained results provide new information on the impact of electric field frequency on OH, which is useful for OH process design. PMID- 21535545 TI - Evaluation of antioxidant and inhibitory activities for different subclasses flavonoids on enzymes for rheumatoid arthritis. AB - Antioxidant activities of flavonoids were decreased in the order of flavonols > flavanones > flavones. Inhibitory intensities for hyaluronidase and collagenase reaction differed clearly according to flavonoid subclasses. Kaempferol, quercetin, myricetin, and rutin in flavonols inhibited hyaluronidase reaction specifically, while apigenin, luteolin, baicalin, and baicalein in flavones showed specific inhibition to collagenase reaction. In addition, the flavonoids, except baicalin and catechin, inhibited potently LPS-induced nitrite production in a dose-dependent manner, which might be mainly due to the suppression of inducible nitric oxide (NO) synthase. Quercetin and luteolin showed the strongest inhibitory activities on 15-lipoxygenase (LOX), and quercetin showed relatively potent inhibition on cyclooxygenase-1 (COX-1) reaction. Otherwise, all tested flavonoids possessed the inhibitory activity to COX-2 reaction, and especially luteolin, kaempferol, hesperetin, and naringin showed relatively the potent inhibition on COX-2 reaction. This report elucidated the anti-inflammatory activities, such as the antioxidant property, inhibition of NO production, and inhibition of inflammatory enzymes (hyaluronidase, collagenase, LOX, and COXs) of several subclass flavonoids. PMID- 21535546 TI - Effect of storage temperature and duration on the behavior of Escherichia coli O157:H7 on packaged fresh-cut salad containing romaine and iceberg lettuce. AB - This study investigated the impact of storage temperature and duration on the fate of Escherichia coli O157:H7 on commercially packaged lettuce salads, and on product quality. Fresh-cut Romaine and Iceberg lettuce salads of different commercial brands were obtained from both retail and wholesale stores. The packages were cut open at one end, the lettuce salad inoculated with E. coli O157:H7 via a fine mist spray, and resealed with or without an initial N(2) flush to match the original package atmospheric levels. The products were stored at 5 and 12 degrees C until their labeled "Best If Used By" dates, and the microbial counts and product quality were monitored periodically. The results indicate that storage at 5 degrees C allowed E. coli O157:H7 to survive, but limited its growth, whereas storage at 12 degrees C facilitated the proliferation of E. coli O157:H7. There was more than 2.0 log CFU/g increase in E. coli O157:H7 populations on lettuce when held at 12 degrees C for 3 d, followed by additional growth during the remainder of the storage period. Although there was eventually a significant decline in visual quality of lettuce held at 12 degrees C, the quality of this lettuce was still fully acceptable when E. coli O157:H7 growth reached a statistically significant level. Therefore, maintaining fresh-cut products at 5 degrees C or below is critical for reducing the food safety risks as E. coli O157:H7 grows at a rapid, temperature-dependent rate prior to significant quality deterioration. PRACTICAL APPLICATION: Specific information regarding the effect of temperature on pathogen growth on leafy greens is needed to develop science-based food safety guidelines and practices by the regulatory agencies and produce industry. Temperature control is commonly thought to promote quality of leafy greens, not safety, based at least partially on a theory that product quality deterioration precedes pathogen growth at elevated temperatures. This prevalent attitude results in temperature abuse incidents being frequently overlooked in the supply chain. This study demonstrates that human pathogens, such as E. coli O157:H7, can grow significantly on commercially packaged lettuce salads while the product's visual quality is fully acceptable. Packaged fresh-cut salads are marketed as "ready-to-eat" while lacking an effective pathogen kill step during their preparation. Thus, maintaining storage temperature at 5 degrees C or below is critical to prevent pathogen proliferation and mitigate food safety risks should pathogen contamination inadvertently occur during crop growth or postharvest fresh-cut processing. PMID- 21535547 TI - Optimizing the use of garlic oil as antimicrobial agent on fresh-cut tomato through a controlled release system. AB - Encapsulation of garlic oil (GO) in beta-cyclodextrin (beta-CD) was undertaken to generate a release system of antimicrobial volatiles and tested on microbial growth and sensory quality of fresh-cut tomato. GO volatile profile was characterized by gas chromatography mass spectrometry and to demonstrate the disadvantages of applying free GO to fresh-cut tomato, the effect of different free oil treatments (0, 50, 100, and 200 MUg/100 g) on microbial growth and sensorial quality was tested. The effect of GO capsules (0, 0.25, 0.5, and 1 g/100 g) on microbial growth and sensory quality of tomato was also investigated. Allyl disulfide was the most abundant GO compound identified. The release of volatiles from GO: beta-CD capsules (12: 88 [w/w] ratio) was evaluated at 100% relative humidity (RH). Close to 70% of GO volatiles were released from capsules when exposed to 100% RH during 5 wk. The most effective antimicrobial concentrations of free oil (100 and 200 MUg/100 g) applied to tomatoes did not present acceptable sensory quality for panelists. Tomato was affected by the highest concentration of GO capsules applied, showing the lowest microbial growth and the highest sensory quality. In this context, successful encapsulation in beta-CD could stimulate further interest in the use of GO for the control of microbial growth in fresh-cut tomato. PRACTICAL APPLICATION: The present study demonstrated that relative humidity in-package of fresh-cut tomatoes can be used as a trigger to release antimicrobial garlic oil volatiles from beta-cyclodextrin capsules, reducing microbial growth and the sensory effect of the treatment caused by the free garlic oil. In this context, successful encapsulation in beta cyclodextrin could stimulate further interest in the use of garlic oil for the control of microbial growth in fresh-cut tomatoes. PMID- 21535548 TI - Quality assessment of salted, modified atmosphere packaged rainbow trout under treatment with oregano essential oil. AB - The present study evaluated the effect of oregano essential oil (EO) on fresh salted, packaged (45%CO(2)/5%O(2)/50%N(2)) rainbow trout fillets and stored for a period of 21 d at 4 degrees C. Treatments included the following: M1 (control without added EO), M2 (EO 0.2%, v/w), and M3 (0.4%, v/w). Populations of lactic acid bacteria (LAB), H(2)S-producing bacteria (including Shewanella putrefaciens), Enterobacteriaceae, and Pseudomonas spp. reached higher final numbers in control (M1) than for M2 and M3 samples. Under treatments M2 and M3, total volatile basic nitrogen (TVBN) and trimethylamine nitrogen (TMAN) values were lower than for M1 samples, whereas lipid oxidation, as judged by determination of thiobarbituric acid values (TBA), did not occur during the refrigerated storage period. Interestingly, treatment M2 resulted in a shelf-life extension of 7 to 8 d for the fresh trout fillets, whereas treatment M3 proved unsuitable (due to strong odor) for trout fillet preservation, as determined by sensory evaluation. PRACTICAL APPLICATION: The use of an essential oil such as oregano oil in fresh fish preservation may be considered an alternative "natural" additive, enhancing the sensory characteristics and extending the shelf life of the product. PMID- 21535549 TI - Evaluation of antibacterial activity of 3-butenyl, 4-pentenyl, 2-phenylethyl, and benzyl isothiocyanate in Brassica vegetables. AB - This study investigated antibacterial activities of 4 isothiocyanates (3-butenyl, 4-phentenyl, 2-phenylethyl, and benzyl isothiocyanate) against 4 Gram-positive bacteria (Bacillus cereus, Bacillus subtilis, Listeria monocytogenes, and Staphylococcus aureus) and 7 Gram-negative bacteria (Aeromonas hydrophila, Pseudomonas aeruginosa, Salmonella choleaesuis, Salmonella enterica, Serratia marcescens, Shigella sonnei, and Vibrio parahaemolyticus) by an agar disc diffusion assay. Benzyl isothiocyanate (> 90.00 mm inhibition zone diameter at 0.1 MUL/mL) and 2-phenylethyl isothiocyanate (58.33 mm at 0.2 MUL/mL) showed large inhibition zones especially against B. cereus. Also, 3-butenyl isothiocyanate (21.67 mm at 1.0 MUL/mL) and 4-pentenyl isothiocyanate (19.67 mm at 1.0 MUL/mL) displayed potent antibacterial activity against A. hydrophila. Benzyl and 2-phenylethyl isothiocyanate indicated higher activity against most of the pathogenic bacteria than 3-butenyl and 4-pentenyl isothiocyanate, and were more effective against Gram-positive bacteria than Gram-negative bacteria. PMID- 21535550 TI - Fermentation process improvement of a Chinese traditional food: soybean residue cake. AB - Fermentation process improvement of soybean residue cake, a Chinese traditional fermented food, and its physicochemical analysis during fermentation were studied. One of the dominant strains in the fermentation was isolated and identified as Mucor racemosus Fresenius. The fermentation process was improved by subsection fermentation. The crude protein content decreased from 19.95 +/- 0.03% in the raw soybean residue to 16.85 +/- 0.10% in the fermented products, and the formaldehyde nitrogen content increased from 0.068 +/- 0.004% to 0.461 +/- 0.022% in final fermented cakes. Hardness of samples significantly (P < 0.05) increased whereas springiness, cohesiveness, and resilience significantly (P < 0.05) decreased with increasing fermentation time, respectively. Microstructure observations showed obvious change of the surface of cake samples during the fermentation process. PRACTICAL APPLICATION: During the soybean processing, it will produce plenty of by-products, and the most part of them is soybean residue. The discarded soybean residue causes economic loss. Fortunately, we can obtain nutritious and delicious fermented soybean residue cakes by fermenting soybean residue as raw material. PMID- 21535551 TI - Synergic antimicrobial activity of lysozyme, nisin, and EDTA against Listeria monocytogenes in ostrich meat patties. AB - Synergic antimicrobial activity of lysozyme (250 ppm), nisin (250 ppm), and disodium ethylenediamine tetraacetic acid (EDTA) (20 mM) against Listeria monocytogenes and meat-borne spoilage bacteria in ostrich patties packaged in air and vacuum was studied. The antimicrobial treatment decreased the L. monocytogenes population in ostrich patties below the official limit of the European Union (<2 log CFU/g). The total viable counts for the treated samples (air and vacuum) showed a reduction of 1 log cycle until to 2 d of storage; after this period the cell load increased. Moreover, the reduction of 2 log cycle for the lactic acid bacteria was observed. Enterobacteriaceae and Pseudomonas spp. were not affected by the antimicrobial treatment in both packaging atmospheres. Sensory evaluation did not differ between treated and untreated samples as regard to the color. The ostrich patties packaged in vacuum had a desirable odor during the storage time and were not affected by antimicrobial treatment. The off-odors for the patties packaged in air developed faster in the control while the odor scores for the treated samples remained above the rejection point up to the end of storage. PRACTICAL APPLICATION: Great interest is developing in food bio preservation, because of the ever-increasing needs to protect consumers' health and to valorize the naturalness and safety of food products. PMID- 21535552 TI - Use of Lactobacillus plantarum and glucose to control the fermentation of "Bella di Cerignola" table olives, a traditional variety of Apulian region (Southern Italy). AB - The purpose of this study was to evaluate the use of Lactobacillus plantarum, isolated from table olives "Bella di Cerignola," a traditional variety of Apulian region (Southern Italy), as a starter for this kind of food. We focused on the interaction of the starter with the natural occurring microflora, the quantitative/qualitative composition of yeast population, the decrease of pH, and the content of organic acids. After a preliminary characterization, 3 strains of Lb. plantarum, selected for their probiotic and technological performances, were used as a multiple-strain starter and inoculated (approximately 2%) in olives, processed according to Spanish style, brined at 8% and 10% of NaCl and added with 0.5% of glucose. The combination of the starter and glucose assured a correct fermentation course, decreasing the pH up to a safe value (4.3 to 4.5) and controlled the growth of yeasts. The concentrations of both L- and D-lactic acids increased throughout the fermentation, while citric and malic acids (both the isomers D and L) remained at low levels (0.2 to 0.4 g/L). Concerning yeast species, Candida guilliermondii was mainly isolated at the beginning (7 to 14 d), while C. famata prevailed at the end of fermentation. PRACTICAL APPLICATIONS: To the question "How to standardize and maintain quality of "Bella di Cerignola" olives (Southern Italy)" we can suggest the following answer: use Lb. plantarum and a low amount of glucose (0.5%). The result is a decrease of the pH below the safety break point. PMID- 21535553 TI - Safety and quality assessment during the ozonation of cloudy apple juice. AB - Traditionally, ozone processing within the food industry has focused on solid foods by either gaseous treatment or washing with ozonized water. However, with the FDA's approval of ozone as a direct additive to food, the potential for liquid applications has emerged. This study investigates the effect of ozone processing on microbial inactivation (E. coli ATCC 25922 and NCTC 12900) and quality parameters (color, phenolic content) of cloudy apple juice. Apple juice samples were ozonated at room temperature (20 +/- 1.5 degrees C) with a generated ozone concentration of 0.048 mg O(3) at a constant flow rate of 0.12 L/min and treatment time of 0 to 10 min. E. coli inactivation kinetics in apple juice were described quantitatively by using the Shoulder log-linear and the Weibull model. Ozone treatment of E. coli in apple juice demonstrate that a desired 5 log reduction can be achieved within 5 min. Apple juice color (L*, a*, and b*) and total phenols were significantly affected by ozone concentration and treatment time. PMID- 21535554 TI - Absence of association of autoinducer-2-based quorum sensing with heat and acid resistance of Salmonella. AB - This study used various approaches to investigate the potential association of autoinducer-2 (AI-2) presence with thermal and acid resistance of Salmonella cultures. Salmonella Thompson strains RM1987N (luxS-positive; AI-2 positive) and RM1987NLUX (luxS-negative; AI-2 negative) were exposed to 55 degrees C (6 h) in Luria-Bertani (LB) broth, while the luxS-negative S. Thompson strain and a Salmonella Typhimurium luxS-positive strain were exposed to 55 degrees C in AI-2 positive or -negative preconditioned (PC) media derived from S. Thompson and Escherichia coli O157:H7 luxS-positive and -negative strains. In addition, the luxS-negative S. Thompson strain was subjected to pH 3.5 PC media (35 degrees C, 6 h) with or without AI-2 activity, and acid-adapted or nonadapted S. Thompson strains were exposed to pH 3.0 LB broth (35 degrees C, 6 h). Surviving bacterial populations during exposure to 55 degrees C LB were not different between luxS negative and -positive S. Thompson strains. In addition, heating at 55 degrees C of the luxS-negative S. Thompson strain in AI-2-positive and -negative PC media resulted in similar (P >= 0.05) survivor counts. Furthermore, surviving cell counts of S. Typhimurium (luxS-positive) in 55 degrees C AI-2-positive PC media were not different (P >= 0.05) than those in AI-2 negative PC media. No differences in surviving cell counts of the luxS-negative S. Thompson strain was found when exposed to pH 3.5 AI-2-positive and -negative PC media. Also, survivors of acid-adapted or nonadapted cells of luxS-negative and -positive S. Thompson strains were not different following exposure to pH 3.0 LB. The results indicated that, under the conditions of this study, AI-2-based quorum sensing did not appear to be associated with heat and acid resistance of Salmonella. PMID- 21535555 TI - Molecular epidemiology of microorganisms isolated from food workers and enteral feeding of public hospitals. AB - This study aimed to compare strains of Staphylococcus aureus and E. coli isolated from food workers and enteral diet samples obtained from 2 public hospitals (H1/H2) in Goiania, Goias, Brazil, by the means of antibiogram and pulsed field gel electrophoresis (PFGE). In the H1, strains of S. aureus were present in 2 enteral diet samples and in 13 food worker swabs. Strains of E. coli were found in an enteral diet sample from H1 and in 2 enteral diet samples from H2 and in 6 food worker swabs in the H1 and in 12 food worker swabs from H2. According to the antibiogram, the 6 susceptibility profiles (A to F) of 15 S. aureus strains colonizing personnel and enteral feeding did not allow the identification of the probable source of diet contamination. All 20 E. coli strains isolated from the H1 and H2 were grouped in 4 phenotypic profiles (A to D). The phenotypes A (H1) and C (H2) showed the same profile for microorganisms isolated from handlers and diets, suggesting more phenotypic similarity among these samples. PFGE genotyping showed that S. aureus isolates from diets were related to a single strain isolated from a food worker suggesting that in this case the reason for the diet contamination may be a result of food handling. The food worker appears to be the most probable source of E. coli contamination for enteral feeding from H2. This fact emphasizes on the food workers as a risk of bacterial transmission for the diets and that the diet chain production must be controlled. PRACTICAL APPLICATION: The study emphasizes the importance of monitoring the enteral diet microbiological quality and the factors associated to its contamination. The study highlights the use of molecular biology as an instrument to correlate strains to determine the origin of the final product contamination. PMID- 21535556 TI - Antilisterial activity and consumer acceptance of irradiated chicken breast meat vacuum-infused with grape seed and green tea extracts and tartaric acid. AB - Contamination of poultry with pathogenic bacteria contributes to human foodborne disease, causes damage to industry brand names, and has a significant economic impact on the food industry in the form of both damage to industry brand names and losses associated with recalls. Irradiation is a safe and effective means of decontaminating poultry products, but the maximum dose strengths allowed negatively impact poultry sensory quality characteristics. The 1st objective of this study was to investigate the potential interactive inhibitory effects of natural antimicrobials as components of a vacuum-marination in addition to various dose levels of irradiation. Tartaric acid (TA) at 2 levels and grape seed (GS) and green tea (GT) extracts were combined, vacuum-infused into chicken breast fillets, and irradiated at 1, 2, and 3 kGy by electron beam irradiation. The 2nd objective was to use a consumer test group to evaluate TA and plant extract infusion into chicken breast fillets with and without irradiation at 2 kGy on overall impression, flavor, texture, appearance, and tenderness. The results showed that samples vacuum-infused with TA at 37.5 and 75.0 mM and irradiated at 1 kGy significantly reduced Listeria monocytogenes (L.m.) levels by 2 and 3 log CFU/g compared to the control after 12 d of refrigerated storage. Vacuum-infusion of TA at 37.5 and 75.0 mM at 2 and 3 kGy irradiation, reduced L.m. to near nondetectable levels. The addition of TA and GS and GT to chicken breast fillets with and without irradiation did not significantly impact consumer preference, tenderness, appearance, or flavor. The addition of tartaric acid and natural plant extracts to chicken marinades could contribute to the prevention of L.m. contamination. PMID- 21535557 TI - Recovery of Salmonella enterica serovars Typhimurium and Tennessee in peanut butter after electron beam exposure. AB - The effect of electron beam (e-beam) radiation on the recovery of Salmonella serotypes Tennessee (ATCC 10722) and Typhimurium (ATCC 14028) in creamy peanut butter over a 14-d storage period at 22 degrees C was studied. Each Salmonella type was independently inoculated into peanut butter and subjected to e-beam doses that ranged from 0 to 3.1 kGy, confirmed by film dosimetry. After 2-, 4-, 6 , 8-, and 14-d of storage, microbial analyses were conducted. Survivors were recovered on growth and selective media using standard spread-plating methods. Microbial counts (CFU/g) were log-converted and differences were determined by ANOVA and Tukey's Honestly Significant Differences test. When samples were not e beam-treated, there were no significant changes (P > 0.05) in microbial numbers over time. In e-beamed samples, microbial numbers decreased over time; however, reductions were not always significant. Initial recovery rates (R-rates) 2 d after e-beam treatment were significantly different for the 2 strains of Salmonella and between recovery media (P < 0.05); however, these differences did not persist for the remainder of the storage period (P > 0.05) indicating that injured cells were not able to survive in the high-fat, low-water activity peanut butter environment. R-rates for both strains of Salmonella were maintained until day 14 when there were significant reductions in Salmonella Typhimurium (P < 0.05). These results indicate that Salmonella Tennessee and Salmonella Typhimurium will survive in peanut butter when exposed to nonlethal doses of e beam irradiation. PRACTICAL APPLICATION: Electron beam (e-beam) irradiation is an alternative to thermal processing; this technique inactivates microorganisms and insects that might be present in a food by generating radiation by accelerated electrons that inactivate organisms directly because of interaction with cell components and indirectly by producing free radicals that disrupt integrity of the cell membrane. E-beam radiation will reduce the number of probable microbiological hazards that could be present while the food remains generally unaffected in texture, taste, and nutritional value. A recent study showed e-beam irradiation to be effective at reducing both Salmonella Tennessee and Typhimurium in peanut butter by one log after exposure to less than 1 kGy, highlighting the need to explore this process further. PMID- 21535558 TI - Osmosonication of blackberry juice: impact on selected pathogens, spoilage microorganisms, and main quality parameters. AB - Osmosonication combines ultrasound with nonthermal concentration. It was applied on tropical highland blackberry (Rubus adenotrichus) juice over different periods of time to assess reductions in microorganism and the impact on main quality parameters. This juice had been inoculated with Salmonella spp., Shigella sp., a lactic acid bacterium, yeasts, and molds. It was then sonicated for 5.9 to 34.1 min at 20 kHz and 0.83 W/mL. Nonthermal concentration was simulated by mixing the juice with a concentrate to obtain 650 g TSS/kg. It was then stored at -18 degrees C for up to 82 h. The lactic acid bacterium, yeasts, and molds were reduced by 1.60 to as much as 5.01 log(10) CFU/mL, whereas, for pathogens, reductions were total >=7.1 log(10) CFU/mL after 24 h of storage, even for juice not sonicated, because of low pH. Color, antioxidant capacity, anthocyanins, and ellagitannins did not change significantly during sonication treatment up to 32 min. However, an off-flavor was detected after 8 min of sonication. Nonetheless, osmosonication can be considered as an alternative to thermal processes for producing safe and high-quality concentrates. PRACTICAL APPLICATION: Osmosonication represents a potential processing alternative for producing safe and high-quality concentrated fruit juice without applying thermal treatments. Findings reported in this article can also be applied by industries when concentrating juices by classical means at relatively low temperature. It provides industries with a mathematical model specific for blackberry juice, from which different combinations of sonication time and storage time of concentrate can be chosen to achieve safety and quality goals. PMID- 21535559 TI - Behavior and enterotoxin production by coagulase negative Staphylococcus in cooked ham, reconstituted skimmed milk, and confectionery cream. AB - In this study, the behavior and enterotoxin production by 10 different coagulase negative Staphylococcus (CNS) strains inoculated in cooked ham, reconstituted skimmed milk, and confectionery cream in the presence or absence of background microbiota have been investigated. After inoculation (103 CFU/g), foods were incubated at 25, 30, and 37 degrees C and aerobic mesophilic and CNS counts were carried out at 12, 24, 48, and 72 h. Staphylococcal enterotoxins (SE) detection was performed by SET-RPLA (Oxoid, Basingstoke, U.K.) and mini-Vidas(r) (bioMerieux, La Balme les Grottes, France). CNS counts increased during incubation and approached 106 to 107 CFU/g after 12 h at 37 degrees C in the 3 foods studied. At 25 degrees C, counts reached 106 to 107 CFU/g only after 24 to 48 h. The interference of background microbiota on CNS behavior was only observed when they grew in sliced cooked ham, which presented a high initial total count (105 CFU/g). Significantly higher counts of CNS isolated from raw cow's milk in comparison with food handlers isolates were found in reconstituted milk and confectionery cream. Although CNS strains were able to produce SEA, SEB, and SED in culture media, in foods, in the presence or absence of background microbiota S. chromogenes LE0598 was the only strain able to produce SEs. Despite the scarcity of reports on CNS involvement with foodborne disease outbreaks, the results found here support the CNS growth and SE production in foods even in the presence of background microbiota and may affect food safety. PMID- 21535560 TI - Concentration and application order effects of sodium benzoate and eugenol mixtures on the growth inhibition of Saccharomyces cerevisiae and Zygosaccharomyces bailii. AB - Growth of Saccharomyces cerevisiae and Zygosaccharomyces bailii cells was monitored in the presence of sodium benzoate and eugenol alone or combined. The two antimicrobials' concentration, addition order, and timing were varied to determine and quantify any additive inhibitory effect on the yeasts. The yeast growth was also followed in the presence of ethanol, which served as solubilizer, at pertinent concentrations. The growth patterns are depicted as adjusted optical density compared with time curves. They all had sigmoid shape, described mathematically by a shifted logistic model that had an almost perfect fit to the data. The model's 3 parameters accounted for the curve's asymptote, the location of its inflection point and slope, which are rough measures of the overall growth level and its degree of suppression, the time to reach the peak growth rate and its retardation, and the overall growth rate, respectively. Maximum growth inhibition was achieved when the sodium benzoate and eugenol were administered together or alone in full dose. When each was administered alone but in 2 half dose additions, their efficacy dropped. When they were used together but added sequentially with a 24 h pause, their administration order had a noticeable effect on the treatment's efficacy, which depended on their respective concentrations. These observations are presented in a slightly modified version of the "hurdle" ideogram. They suggest that sequencing the administration of antimicrobials can be a simple tool to probe their mode of activity and quantify their efficacy. PRACTICAL APPLICATION: Reducing the amount of additives in foods is a goal pursued by many branches of the food industry. In microbial growth suppression, a promising way to accomplish such a reduction is through the administration of 2 or more antimicrobials, preferably natural, exploiting their synergism. To search for effective combinations, in respect to type and concentration, one needs an insight into their mode of activity. Sequencing their administration, as demonstrated with 2 antimicrobials and 2 common yeasts that are involved in beverage spoilage, has offered a simple way to probe into certain aspects of the effect of antimicrobial combinations on microorganisms. The presented algebraic growth model enables to quantify, separately, the growth overall suppression, its retardation, and lowering its peak rate. The proposed modified version of the "hurdles paradigm" helps to visualize the differences in the antimicrobials' general mode of activity and how it is affected by their sequencing. PMID- 21535561 TI - Dimethylamine, trimethylamine, and biogenic amine formation in high-pressure processed semidried squid (Todarodes pacificius) during refrigerated storage. AB - The quality properties of semidried squid treated with high-pressure processing (HPP) were investigated during refrigerated storage. The vacuum-packed semidried squid samples were subjected to 500 MPa for 0 min (HPP-0), 5 min (HPP-5), and 10 min (HPP-10) by using a custom-made high-pressure processor and stored at a refrigerated temperature for 28 d. The populations of indigenous psychrotrophic and mesophilic bacteria were effectively reduced by approximately 1 and 2 log CFU/g at the HPP-10 treatment, respectively. Compared to the control, the bacterial counts in HPP-treated semidried squid samples were maintained at low levels throughout the storage period. The increase in the amounts of dimethylamine (DMA) and trimethylamine (TMA) was more pronounced at the unpressurized control than at the HPP treatments. The production of biogenic amines (BAs) varied with HPP treatment during refrigerated storage. Therefore, the application of HPP may provide a significant improvement in the safety and quality of semidried squid. PMID- 21535562 TI - Prevalence and characterization of Campylobacter jejuni isolated from pasture flock poultry. AB - The growing interest in organic and natural foods warrants a greater need for information on the food safety of these products. In this study, samples were taken from 2 pasture flock farms (N = 178; feed, water, drag swabs, and insect traps), pasture flock retail carcasses (N = 48) and 1 pasture flock processing facility (N = 16) over a period of 8 mo. A total of 105 Campylobacter isolates were obtained from 53 (30%), 36 (75%), and 16 (100%) samples from the farms, retail carcasses, and processing facility, respectively. Of the 105 isolates collected, 65 were C. jejuni, 31 were C. coli, and 9 were other Campylobacter spp. Using PCR, the C. jejuni isolates were further analyzed for virulence genes involved in colonization and survival (flaA, flaC, cadF, dnaJ, racR, cbrR), invasion (virB11, ciaB, pldA), protection against harsh conditions (sodB, htrA, clpA), toxin production (cdtA, cdtB, cdtC), siderophore transport (ceuE), and ganglioside mimicry (wlaN). In addition, the short variable region of the flaA locus (flaA SVR) was sequenced to determine the genetic diversity of the C. jejuni isolates. The flaA SVR diversity indices increased along the farm to carcass continuum. PCR-based analysis indicated a low prevalence of 5 genes involved in colonization (dnaJ, ciaB, pldA, racR, virB11). The results of this survey indicate that the prevalence of Campylobacter on organic retail carcasses is similar to prevalence reports of Campylobacter on conventional retail carcasses. However, the genetic diversity of the flaA SVR genotypes increased along the farm to carcass continuum that contrasted with conventional poultry studies. PRACTICAL APPLICATION: Campylobacter jejuni is a leading cause of foodborne illness with poultry and poultry products being leading sources of infection. Free-range and pasture flock chickens are becoming more popular; however, there is an inherent biosecurity risk that can increase the prevalence of foodborne pathogens in these flocks. This study aimed to determine sources and characterize C. jejuni isolated from pasture flocks. PMID- 21535563 TI - Use of UV-C treatment to inhibit the microbial growth and maintain the quality of Yali pear. AB - The effects of UV-C radiation on microbial growth in vitro (Monilinia fruticola) and in inoculated Yali pears (Pyrus bretschneideri Rehd.) were investigated. Moreover, postharvest quality and the activities of defense and antioxidant enzymes were analyzed after the pears were exposed to UV-C irradiation at an energy level of 5 kJ m-2.The results showed that spore germination of M. fructicola was significantly inhibited by each of the 3 doses (1, 5, and 10 kJ m 2) in vitro. In the in vivo assays, lesion diameter on the fruit being inoculated before or after the UV-C treatment was both significantly lower than that on the fruit of control. Meanwhile, the activities of phenylalanine ammonia lyase, beta 1,3-glucanase, superoxide dismutase, catalase, and glutathione reductase were induced to high levels by UV-C treatment. We conclude that UV-C treatment could reduce postharvest disease by the germicidal and induced effects and maintain the quality by enhancing the antioxidant enzyme activities. PRACTICAL APPLICATION: UV C radiation has recently been proposed as a new technology to avoid chemical fungicides. However, there are few studies regarding the effect of UV-C treatment on Yali pear. In this study, we found that 5 kJ m-2 UV-C irradiation can control postharvest disease and maintain the quality of Yali pear. This method may be applied to reduce the decay of Yali pears during exporting and storage. PMID- 21535564 TI - Thermal, high pressure, and electric field processing effects on plant cell membrane integrity and relevance to fruit and vegetable quality. AB - Advanced food processing methods that accomplish inactivation of microorganisms but minimize adverse thermal exposure are of great interest to the food industry. High pressure (HP) and pulsed electric field (PEF) processing are commercially applied to produce high quality fruit and vegetable products in the United States, Europe, and Japan. Both microbial and plant cell membranes are significantly altered following exposure to heat, HP, or PEF. Our research group sought to quantify the degree of damage to plant cell membranes that occurs as a result of exposure to heat, HP, or PEF, using the same analytical methods. In order to evaluate whether new advanced processing methods are superior to traditional thermal processing methods, it is necessary to compare them. In this review, we describe the existing state of knowledge related to effects of heat, HP, and PEF on both microbial and plant cells. The importance and relevance of compartmentalization in plant cells as it relates to fruit and vegetable quality is described and various methods for quantification of plant cell membrane integrity are discussed. These include electrolyte leakage, cell viability, and proton nuclear magnetic resonance (1H-NMR). PMID- 21535565 TI - Reduction of off-flavor generation in soybean homogenates: a mathematical model. AB - The generation of off-flavors in soybean homogenates such as n-hexanal via the lipoxygenase (LOX) pathway can be a problem in the processed food industry. Previous studies have examined the effect of using soybean varieties missing one or more of the 3 LOX isozymes on n-hexanal generation. A dynamic mathematical model of the soybean LOX pathway using ordinary differential equations was constructed using parameters estimated from existing data with the aim of predicting how n-hexanal generation could be reduced. Time-course simulations of LOX-null beans were run and compared with experimental results. Model L(2), L(3), and L(12) beans were within the range relative to the wild type found experimentally, with L(13) and L(23) beans close to the experimental range. Model L(1) beans produced much more n-hexanal relative to the wild type than those in experiments. Sensitivity analysis indicates that reducing the estimated K(m) parameter for LOX isozyme 3 (L-3) would improve the fit between model predictions and experimental results found in the literature. The model also predicts that increasing L-3 or reducing L-2 levels within beans may reduce n-hexanal generation. PRACTICAL APPLICATION: This work describes the use of mathematics to attempt to quantify the enzyme-catalyzed conversions of compounds in soybean homogenates into undesirable flavors, primarily from the compound n-hexanal. The effect of different soybean genotypes and enzyme kinetic constants was also studied, leading to recommendations on which combinations might minimize off flavor levels and what further work might be carried out to substantiate these conclusions. PMID- 21535566 TI - Control of biogenic amines in food--existing and emerging approaches. AB - Biogenic amines have been reported in a variety of foods, such as fish, meat, cheese, vegetables, and wines. They are described as low molecular weight organic bases with aliphatic, aromatic, and heterocyclic structures. The most common biogenic amines found in foods are histamine, tyramine, cadaverine, 2 phenylethylamine, spermine, spermidine, putrescine, tryptamine, and agmatine. In addition octopamine and dopamine have been found in meat and meat products and fish. The formation of biogenic amines in food by the microbial decarboxylation of amino acids can result in consumers suffering allergic reactions, characterized by difficulty in breathing, itching, rash, vomiting, fever, and hypertension. Traditionally, biogenic amine formation in food has been prevented, primarily by limiting microbial growth through chilling and freezing. However, for many fishing based subsistence populations, such measures are not practical. Therefore, secondary control measures to prevent biogenic amine formation in foods or to reduce their levels once formed need to be considered as alternatives. Such approaches to limit microbial growth may include hydrostatic pressures, irradiation, controlled atmosphere packaging, or the use of food additives. Histamine may potentially be degraded by the use of bacterial amine oxidase or amine-negative bacteria. Only some will be cost-effective and practical for use in subsistence populations. PMID- 21535567 TI - Modeling the fluid dynamics in a human stomach to gain insight of food digestion. AB - During gastric digestion, food is disintegrated by a complex interaction of chemical and mechanical effects. Although the mechanisms of chemical digestion are usually characterized by using in vitro analysis, the difficulty in reproducing the stomach geometry and motility has prevented a good understanding of the local fluid dynamics of gastric contents. The goal of this study was to use computational fluid dynamics (CFD) to develop a 3-D model of the shape and motility pattern of the stomach wall during digestion, and use it to characterize the fluid dynamics of gastric contents of different viscosities. A geometrical model of an averaged-sized human stomach was created, and its motility was characterized by a series of antral-contraction waves of up to 80% relative occlusion. The flow field within the model (predicted using the software FluentTM) strongly depended on the viscosity of gastric contents. By increasing the viscosity, the formation of the 2 flow patterns commonly regarded as the main mechanisms driving digestion (i.e., the retropulsive jet-like motion and eddy structures) was significantly diminished, while a significant increase of the pressure field was predicted. These results were in good agreement with experimental data previously reported in the literature, and suggest that, contrary to the traditional idea of a rapid and complete homogenization of the meal, gastric contents associated with high viscous meals are poorly mixed. This study illustrates the capability of CFD to provide a unique insight into the fluid dynamics of the gastric contents, and points out its potential to develop a fundamental understanding and modeling of the mechanisms involved in the digestion process. PRACTICAL APPLICATION: This study illustrates the capability of computational fluid dynamic techniques to provide a unique insight into the dynamics of the gastric contents, pointing out its potential to develop a fundamental understanding and modeling of the human digestion process. PMID- 21535568 TI - Sensory properties of ginseng solutions modified by masking agents. AB - Ginseng is one of the most popular functional ingredients found in energy drink formulations. Although ginseng is known for its health benefits, ginseng is also notorious for imparting a bitter taste. Incorporating ginseng into beverages without the bitterness, while still maintaining its health benefits, is necessary for developing an acceptable product. Thus, the objectives of this study were to (1) identify effective treatments for minimizing the bitterness of ginseng in water base and model energy drink base solutions and (2) determine the sensory effects of incorporating different treatment levels to minimize the bitterness of ginseng. A series of pilot studies investigating bitterness reducing treatments were conducted, which included: congruent flavor addition, bitterness blocking agent incorporation, enzymatic modification, ingredient interaction, and complexation. Based on the results of a series of pilot studies, gamma cyclodextrin (gamma-CD) and beta-cyclodextrin (beta-CD) complexation agents were identified as having the most potential. Effectiveness of the gamma-CDs, beta CDs, and combinations of gamma- and beta-CDs were tested in 100 mL water and in 100 mL model energy drink base solutions containing 0.052 g 80% ginsenosides panax ginseng, using descriptive sensory analysis. Twelve trained panelists evaluated 42 solution treatments (3 treatments * 7 levels * 2 bases) for bitter attributes with and without nose clips. Overall, the most effective treatments were 0.09 g gamma-CDs in 100 mL of solution and 1 g beta-CDs in 100 mL solution, which both reduced the bitterness intensity of the solutions by half. Incorporation of these levels of CDs in water and model energy drink base solutions containing ginseng will aid in the development of functional beverages that are more acceptable to a wider range of consumers. PMID- 21535569 TI - Quality of ready to serve tilapia fish curry with PUFA in retortable pouches. AB - Studies on the physical, chemical, and microbiological qualities of fresh tilapia meat revealed its suitability for the preparation of ready to eat fish curry packed in retort pouches. Studies on the fatty acid profile of tilapia meat suggest fortification with polyunsaturated fatty acid (PUFA) to increase the nutritional value. Based on the commercial sterility, sensory evaluation, color, and texture profile analysis F(0) value of 6.94 and cook value of 107.24, with a total process time of 50.24 min at 116 degrees C was satisfactory for the development of tilapia fish curry in retort pouches. Thermally processed ready to eat south Indian type tilapia fish curry fortified with PUFA was developed and its keeping quality studied at ambient temperature. During storage, a slight increase in the fat content of fish meat was observed, with no significant change in the contents of moisture, protein, and ash. The thiobarbituric acid (TBA) values of fish curry significantly increased during storage. Fish curry fortified with 1% cod liver oil and fish curry without fortification (control) did not show any significant difference in the levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), during thermal processing and storage. Sensory analysis revealed that fortification of fish curry with cod liver oil had no impact on the quality. Tilapia fish curry processed at 116 degrees C and F(0) value of 7.0 (with or without fortification of cod liver oil) was fit for consumption, even after a period of 1-y storage in retort pouch. PRACTICAL APPLICATION: Tilapia is a lean variety of fish with white flesh and therefore an ideal choice as raw material for the development of ready to serve fish products such as fish curry in retort pouches for both domestic and international markets. Ready to eat thermal processed (116 degrees C and F(0) value of 7.0) south Indian type tilapia fish curry enriched with PUFA and packed in retort pouch was acceptable for consumption even after a storage period of 1 y at ambient temperature. PMID- 21535570 TI - Inclusion of blended lipid solutions as functional ingredients to alter the fatty acid profile of beef patties. AB - Beef patties formulated to contain beef fat, plant oil, and a rosemary extract to increase unsaturated fatty acid content and maintain desirable sensory attributes were compared to control beef patties formulated without plant oils. Treatment patties were formulated to a fat content of 10% or 20% by combining beef trimmings (6% fat) with 4% or 14% addition of a lipid blend. Blends contained 57% beef tallow, 0.3% rosemary extract, and 43% of high oleic safflower oil (SO), olive oil (OO), or corn oil (CO). Lipid oxidation, as measured by TBA values, of treatment patties were similar to control patties after 0 and 3 d of refrigerated (2 degrees C) storage and up to 56 d of frozen (-10 degrees C) storage. Cooked lipid blend patties having a fat content of 10% or 20% were similar to or higher than control patties for juiciness and were no different for other sensory attributes evaluated. At fat levels of 10% or 20%, oleic acid (18: 1) in cooked SO patties (46.1% and 50.3%, respectively) and OO patties (43.8% and 48.1%, respectively) was higher than the control (37.3% and 37.6%, respectively). Unsaturated to saturated fatty acid ratios at the 10% or 20% fat levels were higher in SO (1.37 and 1.60, respectively) and CO (1.40 and 1.48, respectively) patties than the control (0.97 and 0.94, respectively). Beef patties manufactured with varying lipid blends increased unsaturated fatty acid content and were similar in physical characteristics and sensory attributes of all beef patties formulated without lipid blends. PRACTICAL APPLICATION: The development of healthier beef products that will be more appealing to consumers has long been an industry goal. The authors believe that lipid blends such as the one used in this study could be used to create such products, not only in the form of beef patties, but any number of processed meat products. Because the materials and equipment used to create the lipid blends in this study are widely available, their incorporation into meat products would represent a small capital investment. This is an important factor in bringing a reasonably priced, healthier product to consumers. PMID- 21535571 TI - Relating instrumental texture, determined by variable-blade and Allo-Kramer shear attachments, to sensory analysis of rainbow trout, Oncorhynchus mykiss, fillets. AB - Texture is one of the most important quality attributes of fish fillets, and accurate assessment of variation in this attribute, as affected by storage and handling, is critical in providing consistent quality product. Trout fillets received 4 treatments: 3-d refrigeration (R3), 7-d refrigeration (R7), 3-d refrigeration followed by 30-d frozen storage (R3F30), and 7-d refrigeration followed by 30-d frozen storage (R7F30). Instrumental texture of raw and cooked fillets was determined by 3 approaches: 5-blade Allo-Kramer (AK) and variable blade (VB) attachment with 12 blades arranged in perpendicular (PER) and parallel (PAR) orientations to muscle fibers. Correlation between instrumental texture and sensory hardness, juiciness, elasticity, fatness, and coarseness was determined. Muscle pH remained constant at 6.54 to 6.64. Raw fillets lost 3.66% of their original weight after 30-d frozen storage. After cooking, weight loss further increased to 15.97%. Moisture content decreased from 69.11 to 65.02%, while fat content remained constant at 10.41%. VBPER detected differences in muscle sample strength (P= 0.0019) and demonstrated effect of shear direction reported as maximum force (g force/g sample). AKPER detected differences in energy of shear (g * mm; P= 0.0001). Fillets that received F30 treatments were less extensible. Cooking increased muscle strength and toughness. Force determined by VBPER was correlated with sensory hardness (r= 0.423, P= 0.0394) and cook loss (r= 0.412, P= 0.0450). VB attachment is accurate, valid, and less destructive in fillet texture analysis. PRACTICAL APPLICATION: A new shearing device was validated with sensory analysis. Settings and parameters obtained could be used to define fillet texture quality associated with muscle fiber orientation. PMID- 21535572 TI - Sensory characteristics and consumer acceptability of fermented soybean paste (Doenjang). AB - This study was conducted to examine the sensory profiles of fermented soybean paste (Doenjang), to understand consumers' acceptability of different types of Doenjang samples and to identify the sensory characteristics that drive consumer acceptability of Doenjang products. Descriptive analysis and consumer acceptability test were conducted for 7 different types of Doenjang samples. The samples included 2 types of Doenjang made by either traditional or commercially modified methods. For the descriptive analysis, 8 trained panelists developed and evaluated 31 descriptors. There were significant differences in all 31 attributes among the samples. Principal component analysis was also performed to summarize the sensory characteristics of the samples. In consumer testing, 200 consumers evaluated the acceptability of Doenjang samples. Significant differences in consumer acceptability were observed among the samples. The consumers preferred the Doenjang samples manufactured using a commercially modified method. In overall point of view, most consumers liked the Doenjang samples that had strong "sweet" and "MSG (monosodium glutamate)" tastes. It appears that "sweet" and "MSG" tastes are the drivers of liking for Doenjang. "Salty" taste, "meju,""traditional Korean soy sauce," and "fermented fish" odor/flavors seem to be the drivers of disliking for Doenjang. Cluster analysis identified 3 subconsumer segments sharing a common preference pattern for the 7 samples within a cluster. The results showed that each consumer cluster preferred different Doenjang samples. External preference mapping was performed to establish the relationships between the sensory attributes and consumer acceptability in each cluster. PRACTICAL APPLICATION: Consumption of the fermented soybean products is gradually expanding around the world, due to their various health benefits. Therefore, understanding sensory characteristics and consumer acceptability of Doenjang are becoming increasingly important. The intense and complex flavor characteristics of Doenjang make it difficult to obtain a comprehensive sensory profiling and drivers of liking. The finding of this study can be applied to development of a new product that has better consumer acceptability. Also this study can be a useful and effective guideline to researchers who intend to examine the sensory characteristics and consumer acceptability of fermented soybean pastes. PMID- 21535573 TI - Effect of organic poultry purchase frequency on consumer attitudes toward organic poultry meat. AB - Because of the growing consumers' interest in organic meat, consumers' (N = 976) attitude toward organic meat was evaluated. Most respondents (59%) occasionally purchased organic chicken. To determine the organic chicken consumer profile, the organic chicken consumption frequencies of different demographic groups were compared. The results show dependence on age (P= 0.039) and ethnicity (P = 0.015). Older respondents as well as respondents who identified themselves as Caucasians tended to buy organic chicken more frequently. However, many other socio-demographic factors were not correlated with organic chicken consumption: gender (P = 0.185), education (P = 0.235), household income (0.867), living with partner or not (P = 0.235), and number of children (P = 0.883). Taste was identified as the most important meat quality attribute (perceived as [very] important by 94% of the respondents). Other important meat quality criteria were: general appearance, overall health, price, nutritional value, and containing no medical residues. "Organically produced" appeared to not be that important compared with other criteria. When respondents bought organic chicken more often, the importance of most of the meat quality attributes shifted to higher levels of importance, except for the price where an adverse effect was shown. The main motivation factors to buy organic chicken were the perception that organic chicken has fewer residues (pesticides, hormones, antibiotics), is safer, and healthier. The high price for organic meats was the strongest limiting factor for organic meat purchases followed by poor availability. Approximately 41% of the non-buyers and 30% of the occasional buyers perceived organic meat as not or hardly likely to be available in their supermarket. PRACTICAL APPLICATION: This study obtained a better knowledge of consumers' attitudes and perception of organic chicken as well as the effect of various demographics on the likelihood of buying organic chicken. For marketing purposes of organic meats, it helps to know which attributes consumers perceive as important, where the consumer purchases organic chicken, and what the perceived availability of organic chicken is. Additionally, the motivation and deterrent factors are described indicating why the consumer does or does not purchase organic chicken. This information can be valuable to help promoting organic meats to the consumers. PMID- 21535574 TI - Sensory and physicochemical characterization of juices made with pomegranate and blueberries, blackberries, or raspberries. AB - The quality parameters of 1 commercial pomegranate juice mixed with 5 different concentrations of blueberry, blackberry, or raspberry juices were studied. The pH, total soluble solids content, titratable acidity, and total phenolic content were determined. To understand the aroma differences of the juices, solid phase microextraction-gas chromatography-mass spectrometry was used to determine the volatile compounds present in the mixtures. A consumer study also was carried out to relate consumer ratings to the instrumental data and to determine acceptance and possible modifications of the designed juices. Four juices received the highest scores in overall consumer liking: pomegranate/blueberry juice with 20% and 50% of blueberry, pomegranate/blackberry with 10% of blackberry, and pomegranate/raspberry with 10% of raspberry. The main characteristics in these juices were: a high maturity index (from 13.9 to 16.5), low acidity (0.79 to 1.09 g citric acid 100 per milliliter juice), and the presence of aromatic compounds typical in blueberries such as 6-methyl-5-hepten-2-one, alpha-terpineol, and E nerol. The total phenolic content was significantly higher in the pomegranate/blackberry 90%/10% sample, raising around 3500 mg gallic acid equivalents per liter, and could be a positive determinant for consumers interested in purchasing healthful products. PRACTICAL APPLICATION: The data presented in this article will help the juice industry, in the United States and elsewhere, to understand the consumer's preferences for pomegranate blended juices. Pomegranate juices have high antioxidant content, which makes these juices more desirable for the health-conscious consumer of today. PMID- 21535575 TI - Assessment of dietary intake of patulin from baby foods. AB - Patulin is a mycotoxin produced by microscopic fungi belonging to the Penicillium and Aspergillus genera, frequently detectable in moldy fruits and their derivatives fruit products. The EC Regulation 1881/06 has imposed the limit for the presence of patulin equal to 10 MUg/kg or 10 MUg/L in baby food on the basis of a PMTDI of 0.4 MUg/kg bw set by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). A total of 120 homogenized baby foods were analyzed to evaluate the exposure of baby and children to patulin through the consumption of these products. None of examined samples has shown a toxin concentration above the limit imposed by the law, however a PAT concentration equal to 9 MUg/kg was found in 22 samples, slightly below the fixed limit. The presence of patulin in marketed baby food can be regarded as a parameter indicative of the quality of raw materials used. PMID- 21535576 TI - The impact of non- and genetically modified soybean diets in aorta wall remodeling. AB - The aim of this study was to evaluate the influence of nongenetically modified soybean (non-GMS) and genetically modified soybean (GMS) meal on growth and cardiometabolic parameters in rats. Thirty male Wistar rats were divided into 3 groups (n= 10): non-GMS, GMS, and control group (CG). All animals received water and an isocaloric diet ad libitum for 455 d. Blood was drawn by cardiac puncture, and serum was separated for subsequent biochemical analyses (total cholesterol, triacylglycerols, insulin, glucose, and testosterone). The aorta was quickly harvested and fixed; the body fat mass was removed and weighed. Non-GMS and GMS had a growth index (GI) similar to CG but with a lower body weight (P < 0.05) and a lower amount of body fat mass (P < 0.05). Total cholesterol, triacylglycerol, glucose concentrations, and aortic tunics were reduced (P < 0.05) in non-GMS and GMS compared to CG. Non-GMS and GMS are able to reduced serum cholesterol, triacylglycerols, glucose, and aortic remodeling in aged rats. No differences were observed between non-GMS and GMS in all parameters. PMID- 21535577 TI - Amelioration of cadmium-induced oxidative stress, impairment in lipids and plasma lipoproteins by the combined treatment with quercetin and alpha-tocopherol in rats. AB - Cadmium (Cd) exposure results in numerous pathological consequences including oxidative stress and dyslipidemia. The present study was designed to investigate the efficacy of combined treatment with quercetin (QE) and alpha-tocopherol (AT) against Cd-induced oxidative stress and alterations in lipids and lipoproteins in the plasma and liver of rats. Oral administration of Cd (5 mg/kg bw/d) for 4 wk has shown a significant (P < 0.05) increase in thiobarbituric acid reactive substances (TBARS), lipid hydro peroxides (LOOH), total cholesterol, low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL C), free fatty acids (FFA), phospholipids (PL), triglycerides (TGs), and the activity of hydroxyl-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) in plasma with a significant (P > 0.05) reduction in the levels of reduced glutathione (GSH), high density lipoprotein cholesterol (HDL-C), and the activity of lecithin cholesterol acyl transferase (LCAT) in plasma. In addition, the levels of hepatic thiobarbituric acid reactive substances (TBARS), LOOH, conjugated dienes (CD), protein carbonyls (PC), and the activity of HMG-CoA reductase, levels of cholesterol, FFA, and TGs were significantly (P > 0.05) increased and the level of PL is significantly (P > 0.05) decreased along with the decreased activity of LCAT in the liver of Cd-treated rats. Oral supplementation with QE (50 mg/kg bw/d) and AT (50 mg/kg bw/d) for 4 wk in Cd intoxicated rats significantly (P > 0.05) has reduced the plasma levels of TBARS, LOOH, GSH, cholesterol, FFA, TGs, VLDL-C, LDL-C, and the activity of HMG-CoA and significantly (P > 0.05) has increased the activity of LCAT and the plasma levels of HDL-C. The oral supplementation also significantly (P > 0.05) has reduced the hepatic oxidative stress markers, cholesterol, TGs, FFA, and significantly (P > 0.05) has increased the LCAT activity and the PL in liver. Our results indicate that the combined treatment with QE and AT has normalized all the previously mentioned biochemical parameters in Cd-intoxicated rats than the individual treatments. The combined treatment has provided remarkable protection against Cd induced oxidative stress and alterations in lipid metabolism and, thereby, reduced the Cd-mediated cardiovascular diseases. PMID- 21535580 TI - Aroma recovery from roasted coffee by wet grinding. AB - Aroma recovery as determined by solid phase microextraction-gas chromatography mass spectrometry (SPME-GC-MS) was compared in coffees resulting from conventional grinding processes, and from wet grinding with cold and hot water. Freshly roasted coffee as well as old, completely degassed coffee was ground in order to estimate the relationship of internal carbon dioxide pressure in freshly roasted coffee with the aroma loss during grinding. The release of volatile aroma substances during grinding was found to be related to the internal carbon dioxide pressure, and wet grinding with cold water was shown to minimize losses of aroma compounds by trapping them in water. Due to the high solubility of roasted coffee in water, the use of wet-grinding equipment is limited to processes where grinding is followed by an extraction step. Combining grinding and extraction by the use of hot water for wet grinding resulted in considerable losses of aroma compounds because of the prolonged heat impact. Therefore, a more promising two step process involving cold wet grinding and subsequent hot extraction in a closed system was introduced. The yield of aroma compounds in the resulting coffee was substantially higher compared to conventionally ground coffee. PMID- 21535581 TI - Development of a rapid HPLC-UV method for simultaneous quantification of protodioscin and rutin in white and green asparagus spears. AB - Asparagus (Asparagus officinalis L.) spears are rich in bioactive compounds such as protodioscin, a saponin, and rutin, a flavonoid. Protodioscin and rutin are routinely quantified separately, and an approach permitting simultaneous measurement would significantly improve speed of analysis. We have optimized an extraction procedure and modified a method of high-performance liquid chromatography by coupling to an ultraviolet detector to simultaneously analyze protodioscin and rutin in asparagus extracts. An acidic ethanol solvent was more efficient than methanol, acetonitrile, or water in coextraction of protodioscin and rutin. Protodioscin and rutin were detected at 210 nm, with retention times of 12.6 min and 7.9 min, respectively. The method was validated by high linear correlations between 3.13 and 1000.0 MUg/mL for protodioscin (r(2)= 0.9999), and between 0.3 and 1087.5 MUg/mL for rutin (r(2)= 0.9997). The limit(s) of detection and quantification for protodioscin were 1.6 MUg/mL and 3.13 MUg/mL, respectively, and for rutin 0.2 MUg/mL and 0.3 MUg/mL, respectively. White asparagus spears and the crown of the plants were revealed to be rich sources of protodioscin and contained 2.59 to 10.4 mg/g dry weight. Green asparagus spears, particularly the upper portion, were rich in rutin and contained between 1.51 and 7.29 mg/g dry weight. PMID- 21535582 TI - Effect of enzyme activity and frozen storage on jalapeno pepper volatiles by selected ion flow tube-mass spectrometry. AB - Samples of unblanched (fresh), stannous chloride-treated, or blanched jalapeno peppers were measured for real-time generation of lipoxygenase-derived volatiles during 10 min after tissue disruption. Volatiles were also measured before and after 1.5, 2.5, 3, 6, and 9 mo of frozen storage at -15 degrees C. The concentration of all lipoxygenase-derived compounds was significantly higher in unblanched jalapeno peppers compared to enzyme inhibited peppers. The maximum concentration of (Z)-3-hexenal, (E)-2-hexenal, and hexanal was detected at about 1.2, 1.5, and 1.5 min after tissue disruption, respectively. A decrease in (Z)-3 hexenal and an increase in dimethyl sulfide and methylbutanal occurred in blanched compared to stannous chloride-treated peppers due to heat. Frozen storage resulted in no major changes in the lipoxygenase-derived volatiles of whole and pureed blanched peppers after 9 mo. However, in whole unblanched peppers a gradual decrease of (Z)-3-hexenal, (E)-2-hexenal, hexanal, hexenol, and hexanol was observed over time; whereas in pureed unblanched peppers these compounds increased, reached maximum concentration, and then decreased. Similarly, the minor volatiles 2-pentenal, 1-penten-3-one, (E)-2-heptenal, (E)-2 octenal, and (E)-2-nonenal showed an initial increase followed by a decline in both whole and pureed unblanched peppers. Tissue disruption increased generation and degradation rates during frozen storage. The compounds (E,Z)-2,6-nonadienal, n-propyl aldehyde, 2-isobutyl-3-methoxypyrazine, and a mixture of terpenes decreased in unblanched and blanched frozen samples, while nonanal and methylbutanal increased only in unblanched samples. PMID- 21535583 TI - Antioxidant and antiradical capacities in apricot (Prunus armeniaca L.) fruits: variations from genotypes, years, and analytical methods. AB - The fruit quality parameters and antioxidant capacity (ferric reducing antioxidant power, FRAP) and total phenolic content (TPC) were determined in 27 apricot cultivars and hybrids of diverse origins. Twenty one- to 35-fold variations were measured among FRAP and TPC values. Besides genotype, harvest year also contributed significantly (P<=0.05) to the variations of TPC presumably due to the climatic differences between years. A subset of genotypes (15) was also analyzed for their antiradical activities (2,2'-diphenyl-1-picrylhydrazyl, DPPH; total radical-scavenging activity, TRSA; water-soluble antioxidant capacity, ACW; and lipid-soluble antioxidant capacity, ACL), and vitamin C contents as well as color indices (CIE H degrees , L*, and chroma). The hybrid "Preventa" had outstanding FRAP (>10.4 mmol ascorbic acid/L), DPPH (74.45%), TRSA (0.002%), ACW (33587.5 nmol AA/L) and ACL (78.65 nmol Trolox/L), TPC (>2890.0 mg gallic acid/L), and vitamin C (16.17 mg/100 g FW) levels and an average carotenoid content estimated from the hue angle (66.99 degrees ). Most antioxidant and antiradical activities correlated significantly except for TRSA; the closest correlation was observed between FRAP and ACW (r=0.952). Only TRSA showed significant correlations with color indices, H degrees and chroma, suggesting TRSA measures at least a fraction of the antioxidant capacity attributable to apricot carotenoids. PMID- 21535584 TI - Effect of microbial transglutaminase on gel properties and film characteristics of gelatin from lizardfish (Saurida spp.) scales. AB - The addition of microbial transglutaminase (MTGase) generally increased the gel strength of lizardfish (Saurida spp.) scale gelatin gels (P<=0.05) with an increase in gel strength with the addition of MTGase up to 0.5% (w/v). The texture profile analysis compression tests of lizardfish scale gelatin gel with and without MTGase were studied to determine their effects on gel characteristics. MTGase added to the gels decreased the band intensity of the beta- and alpha-components with increasing concentrations of enzyme. Gel microstructures with various concentration of MTGase showed denser strands in the gels with enzyme compared with the looser stands in non-enzyme-treated gel samples. Films cast from lizardfish scale gelatin with and without 0.5% MTGase and bovine gelatin films were transparent and flexible. The lizardfish gelatin films were all slightly yellowish while the bovine gelatin films were clearer. The L value of bovine gelatin films had the highest value (P<=0.05) whereas lizardfish scale gelatin films with and without enzyme were not significantly different (P>0.05) for L, a, and b values and DeltaE. The film's mechanical properties included tensile strength (TS) and elongation at break (E) were not significantly different (P > 0.05) for E and the films of lizardfish scale gelatin showed higher TS than the films without enzyme added (P <= 0.05). The water vapor permeability of films from lizardfish scale gelatin with and without 0.5% MTGase and bovine gelatin films were 21.0 +/- 0.17, 26.3 +/- 0.79, and 25.8 +/- 0.09 g.mm/m(2).d.kPa, respectively, while the oxygen transmission rate of all 3 types of films were less than 50 cc O(2)/m(2).d. PMID- 21535585 TI - Kinetic characterization of a basic peroxidase from garlic (Allium sativum L.) cloves. AB - Peroxidases catalyze the reduction of H(2)O(2) by taking electrons from a variety of compounds from the secondary metabolism including flavonoids and lignin precursors. This work describes the purification and kinetic characterization of a basic peroxidase from garlic cloves using quercetin and p-coumaric acid, flavonoid and phenolic compounds found in garlic cloves. The high catalytic efficiency shown by this basic peroxidase in the oxidation of quercetin at acidic pH suggests good adaptation of this enzyme, involved in quercetin catabolism in the acidic physiological pH conditions of the vacuoles, where it is presumably located. Likewise, garlic peroxidase showed similar oxidation rates for hydroxycinnamyl (p-coumaric) and sinapyl-type structures, which suggests its involvement in the cross-coupling reactions that occur in the cell wall during lignification. On the other hand, the high affinity of this enzyme for H(2)O(2) would be in accordance with the oxidation of both flavonoid and phenolic compounds to regulate H(2)O(2) levels in tissues/organelles, where this peroxidase is expressed. PMID- 21535586 TI - Comparison of physical, chemical, and sensorial characteristics between U.S. imported and Northwestern Mexico retail beef. AB - To compare beef from Northwestern Mexico (NMEX) and that imported from the United States in physical-chemical (PC) and sensory traits, samples of ribeye (m. Longissimus dorsi thoracis, LDT) and knuckle (m. Vastus lateralis, VL) of Mexican (64 LDT; 51 VL) and U.S. (28 LDT; 25 VL) origin were purchased randomly from select retail stores located in 3 cities of NMEX. PC evaluation measured contents of moisture, fat and cholesterol, Warner-Bratzler shear force (WBSF), pH, CIE L*, a*, and b*, cooking loss, and normalized fatty acid profile (FAP). Trained panelists evaluated raw and cooked samples for 2 and 6 different organoleptic traits, respectively. Mexican and U.S.-imported LDT steaks did not differ (P>0.05) in PC traits. VL samples differed in L*, b*, hue*, WBSF, and fat content by country of origin (COO). The WBSF for cooked VL samples from the United States was lower (P < 0.05) and fat content was greater (P<0.05) than those for NMEX steaks. The FAP varied between muscles; Mexican LDT had a higher content of C18:0, while VL from the United States had a higher proportion of polyunsaturated fatty acids (PUFA) and a higher PUFA/Saturated ratio (P<0.05). Although sensory traits tended to be rated higher for Mexican LDT and VL steaks, no statistical differences with U.S.-imported samples were detected (P > 0.05). Results indicated that domestic and U.S. retail steaks sold in the NMEX are similar in eating quality and PC, whereas differences observed in FAP deserve further attention from a nutritional standpoint. PMID- 21535587 TI - Effect of thermal processing on the degradation, isomerization, and bioaccessibility of lycopene in tomato pulp. AB - Thermal processing affects the nutritional value of food products. The nutritional value is not only determined by the content but also by the bioaccessibility of nutrients. The present study was performed to gain detailed insight into the influence of thermal processing on the degradation, isomerization, and bioaccessibility of lycopene isomers in tomato pulp, without adding any other ingredient. The bioaccessibility, which is defined as the fraction of the nutrient that can be released from the food matrix, was measured using an in vitro method. The results demonstrated the rather high thermal stability of lycopene. Although a treatment at 140 degrees C induced isomerization, the contribution of cis-lycopene to the total lycopene content remained small. Results also confirmed that thermal processing as such can improve the in vitro bioaccessibility of lycopene in tomato pulp, but the improvement was only significant upon treatments at temperatures of 130 and 140 degrees C. At such intense process conditions, one should be aware of the negative effect on other quality and nutrient parameters. Possibilities of thermal processing as such to improve the nutritional value of tomato pulp (without the addition of other ingredients) thus looks rather limited. PMID- 21535588 TI - Fractionation, separation, and identification of antioxidative peptides in potato protein hydrolysate that enhance oxidative stability of soybean oil emulsions. AB - The objective of the study was to identify the active peptides responsible for the antioxidant activity of potato protein hydrolysate (PPH). PPH was fractionated using ammonium sulfate precipitation; the efficacy of different fractions for scavenging 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(+*)) radicals and inhibiting lipid oxidation (hexanal, TBARS) in soybean oil-in-water emulsions was investigated. Of all fractions, the fraction precipitated by 50% saturated ammonium sulfate (P50) exhibited the strongest ABTS(+*) scavenging activity and antioxidant activity. Active peptides based on the ABTS(+*) scavenging assay were isolated and purified by RP-HPLC and ultra performance liquid chromatography. Amino acid sequencing by tandem mass spectrometry identified Ser-Ser-Glu-Phe-Thr-Tyr and Ile-Tyr-Leu-Gly-Gln in P50 to be the dominant peptides that matched the sequences in metallocarboxypeptidase inhibitor and lipoxygenase 1, respectively. PMID- 21535589 TI - Effect of light and sweeteners on color in an amaretto-type liqueur. AB - Studies on the color loss in an amaretto-type liqueur under controlled light conditions showed a clear dependence of the decoloration rate on the light intensity, and complete color stability in the absence of light. The principal sweetener used in the preparation of the liqueur strongly affected the rate of color loss under irradiation, color stability being much greater for the formulations containing sucrose or no added sweetener instead of fructose 42. These differences were more pronounced in experiments conducted with chemically well-defined mixtures that contained either of the 2 azo dyes used in the coloration of the amaretto, tartrazine, and Allura Red, and various alternative sweeteners, in 28% (v/v) ethanol solution: D-fructose and, to a lesser extent, D glucose, at concentrations of 14% (w/v), were effective in bringing about photodecoloration, while no color loss was detected in the presence of sucrose, or in the absence of any added sugar. The results are interpreted in terms of a redox reaction of reducing sugars with the diarylazo compounds, the function of the light being the conversion of the azo compound from the predominant trans configuration to the cis configuration, which on geometric grounds lends itself better to a concerted, cyclical redox reaction with the reducing sugar. PMID- 21535590 TI - Effects of alpha-tocopherol on lactones in beef headspace during storage. AB - We studied the effect of alpha-tocopherol (alpha-Toc) on the production of lactones, a desirable flavor in Wagyu beef (Japanese Black Cattle), in meat headspace. Fresh beef was minced and divided into 4 groups containing different alpha-Toc levels (1.9, 2.7, 6.1, and 10.7 mg/kg) or packed with oxygen absorber. After 10 d of storage at 2 degrees C, these samples were cooked in distilled water and rendered fat was collected. The headspace of the fat was analyzed with solid-phase microextraction combined with gas chromatography-mass spectrometry. The DB-17MS capillary column led to good separation of aliphatic lactones. Oxygen was important for the development of all lactones during storage. The amounts of gamma-octalactone and gamma-nonalactone decreased linearly with increasing alpha Toc levels. The effect of alpha-Toc on delta-decalactone, delta-undecalactone, and delta-tetoradecalactone was weaker, and that on delta-hexadecalactone was ambiguous. These observations suggest that oxidation was necessary to develop the flavor of Wagyu beef, and warn that an excessive increase of alpha-Toc could reduce levels of positive flavor components, gamma-octalactone and gamma nonalactone, in the headspace of Wagyu beef. PMID- 21535591 TI - The possibility of lowering oil content of potato chips by combining atmospheric frying with postfrying vacuum application. AB - Four protocols involving the application of low pressures, either toward the end of frying or after frying, were investigated with the aim of lowering the oil content of potato chips. Protocol 1 involving frying at atmospheric pressure followed by a 3 min draining time constituted the control. Protocol 2 involved lowering of pressure to 13.33 kPa, 40 s before the end of frying, followed by draining for 3 min at the same pressure. Protocol 3 was the same as protocol 2, except that the pressure was lowered 3 s before the end of frying. Protocol 4 involved lowering the pressure to 13.33 kPa after the product was lifted from the oil and holding it at this value over the draining time of 3 min. Protocol 4 gave a product having the lowest oil content (37.12 g oil/100 g defatted dry matter), while protocol 2 gave the product with highest oil content (71.10 g oil/100 g defatted dry matter), followed by those obtained using protocols 1 and 3 (68.48 g oil/100 g defatted dry matter and 52.50 g oil/100 g defatted dry matter, respectively). Protocol 4 was further evaluated to study the effects of draining times and vacuum applied, and compared with the control. It was noted that over the modest range of pressures investigated, there was no significant effect of the vacuum applied on the oil content of the product. This study demonstrates that the oil content of potato chips can be lowered significantly by combining atmospheric frying with draining under vacuum. PMID- 21535592 TI - Study of the quality characteristics in cold-smoked salmon (Salmo salar) originating from pre- or post-rigor raw material. AB - Improved slaughtering procedures in the salmon industry have caused a delayed onset of rigor mortis and, thus, a potential for pre-rigor secondary processing. The aim of this study was to investigate the effect of rigor status at time of processing on quality traits color, texture, sensory, microbiological, in injection salted, and cold-smoked Atlantic salmon (Salmo salar). Injection of pre rigor fillets caused a significant (P<0.001) contraction (-7.9%+/- 0.9%) on the caudal-cranial axis. No significant differences in instrumental color (a*, b*, C*, or h*), texture (hardness), or sensory traits (aroma, color, taste, and texture) were observed between pre- or post-rigor processed fillets; however, post-rigor (1477 +/- 38 g) fillets had a significant (P>0.05) higher fracturability than pre-rigor fillets (1369 +/- 71 g). Pre-rigor fillets were significantly (P<0.01) lighter, L*, (39.7 +/- 1.0) than post-rigor fillets (37.8 +/- 0.8) and had significantly lower (P<0.05) aerobic plate count (APC), 1.4 +/- 0.4 log CFU/g against 2.6 +/- 0.6 log CFU/g, and psychrotrophic count (PC), 2.1 +/- 0.2 log CFU/g against 3.0 +/- 0.5 log CFU/g, than post-rigor processed fillets. This study showed that similar quality characteristics can be obtained in cold-smoked products processed either pre- or post-rigor when using suitable injection salting protocols and smoking techniques. PMID- 21535593 TI - Microencapsulated Lactobacillus rhamnosus GG powders: relationship of powder physical properties to probiotic survival during storage. AB - Freeze-dried commercial Lactobacillus rhamnosus GG (LGG) were encapsulated in an emulsion-based formulation stabilized by whey protein and resistant starch and either spray-dried or freeze-dried to produce probiotic microcapsules. There was no difference in loss of probiotics viability after spray drying or freeze drying. Particle size, morphology, moisture sorption, and water mobility of the powder microcapsules were examined. Particle size analysis and scanning electron microscopy showed that spray-dried LGG microcapsules (SDMC) were small spherical particles, whereas freeze-dried LGG microcapsules (FDMC) were larger nonspherical particles. Moisture sorption isotherms obtained using dynamic vapor sorption showed a slightly higher water uptake in spray-dried microcapsules. The effect of water mobility, as measured by nuclear magnetic resonance (NMR) spectroscopy, at various water activities (a(w) 0.32, 0.57, and 0.70) and probiotic viability during storage at 25 degrees C was also examined. Increasing the relative humidity of the environment at which the samples were stored caused an increase in water mobility and the rate of loss in viability. The viability data during storage indicated that SDMC had better storage stability compared to FDMC. Although more water was adsorbed for spray-dried than freeze-dried microcapsules, water mobility was similar for corresponding storage conditions because there was a stronger water-binding energy for spray-dried microcapsule. This possibly accounted for the improved survival of probiotics in spray-dried microcapsules. PMID- 21535594 TI - Application of the Chinese steamed bun starter dough (CSB-SD) in breadmaking. AB - The application of Chinese steamed bun starter dough (CSB-SD) in breadmaking was investigated. The activation of CSB-SD to activate the growth of lactic acid bacteria (LAB) and to increase the number of yeast, prior to making bread, was conducted by mixing CSB-SD with wheat flour and water and then incubating for 24 h. Wheat flour was then substituted by this activated CSB-SD (aCSB-SD) at 10%, 30%, and 50% (w/w) to make bread. Dough and bread properties were studied comparing to the control (without aCSB-SD). From the farinograph results, a high aCSB-SD substitution level resulted in a less stability in dough with a higher degree of softening. Extensigraph results suggested that after aging, all the substituted dough yielded a greater resistance to extension with lower extensibility values than the control. Substitutions with 30% and 50% (w/w) aCSB SD significantly increased the total CO(2) gas generation. Scanning electron microscopy SEM images of the 30% and 50% (w/w) substituted dough showed a well developed gluten matrix. The 50% (w/w) substituted breads obtained a greater risen volume, finer crumb grain, and retained more softness after 5-d storage than the control. In addition, both the 30% and 50% (w/w) substituted breads showed a slightly increased mold stability, as compared to the 0% and 10% (w/w) substituted breads. PMID- 21535595 TI - An investigation of bread-baking process in a pilot-scale electrical heating oven using computational fluid dynamics. AB - A computational fluid dynamics (CFD) model was developed for bread-baking process in a pilot-scale baking oven to find out the effect of hot air distribution and placement of bread on temperature and starch gelatinization index of bread. In this study, product (bread) simulation was carried out with different placements of bread. Simulation results were validated with experimental measurements of bread temperature. This study showed that nonuniform air flow pattern inside the oven cavity leads to uneven temperature distribution. The study with respect to placement of bread showed that baking of bread in upper trays required shorter baking time and gelatinization index compared to those in the bottom tray. The upper tray bread center reached 100 degrees C at 1200 s, whereas starch gelatinization completed within 900 s, which was the minimum baking index. Moreover, the heat penetration and starch gelatinization were higher along the sides of the bread as compared to the top and bottom portions of the bread. PMID- 21535596 TI - Calcium lactate effect on the shelf life of osmotically dehydrated guavas. AB - The effect of calcium lactate on osmodehydrated guavas in sucrose and maltose solutions was monitored during storage under passive modified atmosphere for 24 d at 5 degrees C. Sample texture and color characteristics, microbial spoilage, sensory acceptance, structural changes, and gas composition inside the packages were periodically evaluated. Calcium lactate inhibited microbial growth on guavas, with yeast and mold counts in the order of 10(2) CFU/g throughout storage. The calcium salt reduced respiration rate of guava products, showing O(2) and CO(2) concentrations around 18% and 3% inside the packages. A firming effect on fruit texture, with up to 5 and 2 times higher stress and strain at failure values and tissue structure preservation could also be attributed to calcium lactate use. However, fruits treated with calcium lactate, osmodehydrated in maltose and sucrose solutions, showed sensory acceptance scores below the acceptability limit (4.5) after 13 and 17 d of storage, respectively. PMID- 21535597 TI - Physical, mechanical, and barrier properties of carp and mammalian skin gelatin films. AB - Films of 0.11 to 0.13 mm thickness were prepared using gelatins from the skins of cultured freshwater carp species and mammalian gelatins viz., porcine and bovine skin gelatin. A comparative study was made on the physical, mechanical, and barrier properties of these films. The amino acid composition, gel strength, clarity, and gel setting point of the gelatins were also determined. Carp skin gelatins had a lower imino acid content (19.16% to 20.86%) than mammalian skin gelatins (22.91% to 23.7%). Grass carp gelatin had gel strength of 230.2 B that is comparable to the reported value for bovine skin gelatin (227.2 B). The bloom values of rohu and common carp skin gelatins were 188.6 B and 181.3 B, respectively, which were significantly lower than mammalian gelatins. Mammalian gels have significantly higher (P < 0.05) setting temperatures (23.7 to 24.2 degrees C) than carp skin gelatins. Tensile strength (TS) was lowest for films from common carp and rohu skin gelatin (490 and 497 kg/cm(2), respectively) and highest for porcine skin gelatin film. The degree of transparency (L*) was significantly higher for films from grass carp, bovine hide, and pork skin gelatin films. Carp skin gelatin films had significantly lower water vapor permeability (WVP) and oxygen permeability (OP) than mammalian skin gelatin films, which indicated that carp skin gelatin based films have superior barrier properties than mammalian skin gelatin films. PMID- 21535598 TI - A human gastric simulator (HGS) to study food digestion in human stomach. AB - The objective of this study was to develop an in vitro stomach model, the Human Gastric Simulator (HGS), for studying gastric digestion of foods. The HGS is designed in such a way as to simulate the continuous peristaltic movement of stomach walls, with similar amplitude and frequency of contraction forces as reported in vivo. The HGS mainly consists of a latex vessel, simulating the stomach chamber, and a series of rollers secured on belts that are driven by motor and pulleys to create a continuous contraction of the latex wall. It also incorporates gastric secretion, emptying systems, and temperature control that enable accurate simulation of dynamic digestion process for detailed investigation of the changes in the physical chemical properties of ingested foods. The simulated gastric contraction force demonstrates a similar pattern as in vivo stomach forces. The precise control of gastric secretion and emptying and the adjustable mechanical forces in the HGS provide a useful tool to study transformation of food constituents under simulated physiological conditions. PMID- 21535599 TI - Resistant starch modification: effects on starch properties and functionality as co-encapsulant in sodium caseinate-based fish oil microcapsules. AB - The properties of resistant starch (RS) modified by heating starch suspensions (Heat RS) or heating followed by microfluidization (Heat-MF RS) and their functionality as co-encapsulants in sodium caseinate (NaCas) based fish oil microcapsules (50%oil:25%NaCas:25%starch) were examined. RS modification reduced molecular weight and crystallinity of the starch, with the effects being more evident for Heat-MF RS. The properties of fish oil microcapsules were influenced by the starch type used (RS, Heat RS, or Heat-MF RS) in combination with NaCas. With both physical blends and heated mixtures of NaCas and starch as encapsulants, highest encapsulation efficiency but lowest oxidative stability was obtained for the microcapsules containing Heat-MF RS. Oxidative stability was independent of heat treatment applied to the mixtures of NaCas and starch and also not related to encapsulation efficiency of the freeze-dried microcapsules. The properties of the starch used in combination with NaCas were the major determinant of the oxidative stability, with lower molecular weight and decreased crystallinity providing less protection against oxidation. PMID- 21535600 TI - Antihyperlipidemic effect of sesame (Sesamum indicum L.) protein isolate in rats fed a normal and high cholesterol diet. AB - The dietary influence of sesame protein isolate (protein content 91.5%), produced from dehulled, defatted sesame meal, on blood and tissue lipid profile and lipid peroxidation has been assessed in normal and hypercholesterolemic rats. To evaluate their hypocholesterolemic and antioxidative activity in vivo, we fed 18% sesame protein isolate with or without 2% cholesterol in comparison with casein to rats for 28 d. We determined plasma total protein, total cholesterol, high density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triacylglycerol as well as susceptibility of plasma and erythrocyte membrane lipid to oxidation ex vivo. Liver tissue lipid, cholesterol, phospholipids, and lipid peroxidations were also determined. The total cholesterol, LDL-cholesterol and triacylglycerol levels were significantly reduced in the sesame protein isolate and isolate containing cholesterol group than the corresponding control casein groups. HDL-cholesterol level was also increased in sesame protein isolate (41%) and protein isolate containing cholesterol group (38%) than the corresponding control casein and casein containing cholesterol groups. There was 49% and 64% lowering of plasma lipid peroxidation as well as 36% and 56% lowering of lipoprotein oxidation susceptibility (LOS) in the 2 experimental groups (sesame protein isolate and isolate containing cholesterol group) than the corresponding control (casein and casein containing cholesterol) groups. There was significant lowering of erythrocyte membrane lipid peroxidation (68% and 63% lowering in sesame protein isolate and isolate containing cholesterol groups) and liver lipid peroxidation (61% and 76% lowering in the 2 experimental groups than the corresponding control casein groups). Therefore, our results indicate that sesame protein isolate decreases cholesterol concentration in plasma, increases HDL-cholesterol, and also decreases plasma and erythrocyte membrane lipid peroxidation with or without cholesterol fed diet in rats. PMID- 21535602 TI - Absorption of folic acid and ascorbic acid from nutrient comparable beverages. AB - One hundred percent fruit juices can help consumers increase the nutrient content of the diet since these beverages can be naturally rich in micronutrients. Micronutrient-fortified low-calorie beverages are an important alternative to those wishing to minimize their calorie intakes. However, little is known about the bioavailability of nutrients from fortified beverages relative to 100% fruit juices. The present study examined the bioavailability of ascorbic acid (AA) and folic acid (FA) in 100% orange juice (OJ) and a low-calorie beverage fortified with these nutrients. In a within-subjects, cross-over design, 12 adult men consumed a 591 mL serving of OJ, a low-calorie beverage fortified with AA and FA, and 1% low fat milk. Participants were aged 20 to 35 y, with body mass indexes between 20 and 30 kg/m(2). Blood plasma concentrations of AA and serum concentrations of FA were assayed by serial blood draws, made at 30 min intervals for 4.5 h. Blood plasma concentration of AA was significantly greater after ingestion of the fortified beverage compared to after OJ ingestion. However, the bioavailability of AA did not significantly differ from that of OJ. Analyses of FA indicated no significant difference between fortified beverage and OJ. Consumption of both vitamin containing beverages led to higher concentrations of AA and FA than the milk control. This study showed that similar levels of AA and FA bioavailability can be attained through ingestion of 100% OJ and a fortified beverage. PMID- 21535601 TI - Differential effects of sulfated triterpene glycosides, holothurin A1, and 24 dehydroechinoside A, on antimetastasic activity via regulation of the MMP-9 signal pathway. AB - Two sulfated triterpene glycosides, holothurin A(1) (HA(1)) and 24 dehydroechinoside A (DHEA), isolated from the sea cucumber Pearsonothuria graeffei, are of the holostane type with 18(20)-lactone and identical carbohydrate chains. DHEA has a side chain 23 (24)-double bond, while HA(1) has a hydroxyl group at C-21. In this study, we compared the effects of DHEA and HA(1) on metastasis in vitro and in vivo. The results show that HA(1) and DHEA treatment significantly suppressed adhesion of human hepatocellular liver carcinoma cells (HepG2) to both matrigel and human endothelial cells (ECV-304) and inhibited HepG2 cell migration and invasion in a dose-dependant manner. HA(1) and DHEA reduced tube formation of ECV-304 cells on the matrigel in vitro and attenuated neovascularization in the chick embryo using the chorioallantoic membrane (CAM) assay in vivo. Immunocytochemistry analyses revealed that both HA(1) and DHEA significantly decreased the expression of the matrix metallo proteinase-9 (MMP-9) and increased the expression level of tissue inhibitor of metalloproteinase-1 (TIMP-1), an important regulator of MMP-9 activation. Western blot analyses demonstrated that HA(1) and DHEA remarkably abolished the expression of vascular endothelial growth factor (VEGF). The expression of nuclear factor-kappa B (NF-kappaB) was significantly decreased by HA(1), while DHEA treatment had no effect on the down regulation of NF-kappaB expression. These data suggest that both DHEA and HA(1) exert significant antimetastatic activities by inhibiting MMP-9 and VEGF expression. DHEA-induced antimetastasis was more potent than HA(1). In addition, only HA(1) treatment downregulated the expression level of NF-kappaB, suggesting that the antimetastatic activity of triterpene glycosides derived from P. graeffei can be either NF-kappaB-dependent or -independent, depending on their structure. PMID- 21535603 TI - Effects of buckwheat sprouts on plasma and hepatic parameters in type 2 diabetic db/db mice. AB - We examined the effects of buckwheat sprouts (BS) (Fagopyrum esculentum Moench) on lipid and carbohydrate metabolism and on in vivo oxidative stress in type 2 diabetic mice. Mice (C57BL/KsJ-lepr(db)/lepr(db), db/db) were fed a diet containing 0%, 5%, or 10% BS based on AIN-93G for 21 d. Plasma parameters, such as total cholesterol, arteriosclerotic index, thiobarbituric acid reactive substances (TBARS), and the HbA1c concentration of whole blood in the diabetic BS fed groups were lower than those in the diabetic control (AIN-93G) group. Concentrations of hepatic parameters, such as lipids, total cholesterol, triglyceride, and TBARS levels in BS-fed groups, were lower than those in the diabetic control group. Although gene expressions of the hepatic lipid regulation enzymes such as 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) and cholesterol 7alpha-hydroxylase (CYP7A1) in diabetic BS-fed groups were higher than in the diabetic control group, the elevation of mRNA level of CYP7A1 was greater than that of HMG-CoAR. In addition, concentration of bile acids in feces was higher in the diabetic BS-fed groups than in the diabetic control group. These results suggest that BS have various in vivo activities in relation to antidiabetic effects in type 2 diabetic mice, especially for improvement in lipid metabolism. It was deduced that excretion of bile acids in feces by feeding the BS diet would contribute to the suppression of the cholesterol concentration in the plasma and liver tissues of mice. PMID- 21535604 TI - A low-calorie beverage supplemented with low-viscosity pectin reduces energy intake at a subsequent meal. AB - The addition of fiber to foods and beverages has been linked with greater satiety and reduced energy intakes at the next meal. However, measures of satiety can be influenced by the time interval between beverage consumption and the next meal. The objective of this study was to determine how the time interval between consumption and a subsequent test meal impacts the satiating power of a low calorie beverage supplemented with low-viscosity pectin fiber. Forty-two participants (20 men, 22 women) each participated in 4 study sessions. Study preloads were 2 low-calorie beverages (355 mL, 8 kcal) containing either 0 g fiber (no fiber) or 8 g low-viscosity fiber (added fiber). These preloads were consumed either 90 min before lunch or 15 min before lunch. Every 15 min, participants rated hunger, desire to eat, fullness, and thirst using 100-mm visual analogue scales. A test lunch was served and plate waste was measured. Beverages with added fiber reduced energy intakes at lunch relative to those without fiber. A short delay (15 min) between beverage consumption and a subsequent meal was associated with higher satiety ratings and reduced energy intakes, regardless of fiber content. The addition of low-viscosity pectin to low calorie beverages reduced energy intakes at the next meal, presenting a possible tool for intake regulation. A short time interval between consumption of a low calorie beverage and a meal also increased satiety and decreased food intake, reflecting the short-lived effect of volume. PMID- 21535605 TI - GC-MS determined distribution of urinary equol producers as affected by age, gender, and repeated ingestions of soymilk. AB - Status of equol excretion is likely a reflection of incidence risk of sex-hormone related diseases and deserves research attention. In this study, urine samples collected from 182 volunteers after soymilk ingestion were subjected to equol quantification using GC-MS. As categorized into male, female, and both genders and each category further classified into 6 age (year) categories, namely, <20, 21 to 30, 31 to 40, 41 to 50, >51 and overall, a trend indicating that the younger age the higher equol producer ratio was observed. For the >51 subjects, the corresponding producer ratios of males and females were 35.3% and 50.0%, respectively. Among the volunteers, 20 nonproducers were further recruited to ingest 1000 mL soymilk weekly for 16 wk and urines were analyzed bi-weekly. As resulted, 8 of 20 nonproducers were induced to become equol producers. The observed change of nonproducers to equol producers induced by repeating ingestions of soymilk is of merit from the viewpoint of healthcare. PMID- 21535606 TI - Soybean peptide lunasin suppresses in vitro and in vivo 7,12 dimethylbenz[a]anthracene-induced tumorigenesis. AB - Lunasin is a novel peptide identified in soybean and other seeds. This study evaluated the anti-tumorigenic effects of lunasin on 7,12 dimethylbenz(a)anthracene (DMBA) and 3-methylcholanthrene-treated (MCA) fibroblast NIH/3T3 cells. Lunasin significantly inhibited cell proliferation and cancerous foci formation in these 2 chemical carcinogens-treated cells. An in vivo SENCAR mouse model induced with DMBA was used to study the mammary cancer preventive properties of dietary lunasin contained in soy protein. Tumor incidence was 67% and 50%, and the tumor generation was 1.88 +/- 0.48 and 1.17 +/ 0.17, respectively, for the mice fed control diet and experimental diet obtained after AIN-93G supplementation with lunasin-enriched soy protein concentrate (containing 0.23% lunasin). However, no effects were observed in mice fed AIN-93G supplemented with soy protein concentrate (containing 0.15% lunasin). The data provided illustrate the anticancer potential of lunasin both in vitro and in vivo and supports the recommendation of soy protein as a dietary component that may aid in the prevention of mammary cancer. PMID- 21535607 TI - Hydrolysis of Chlorella by Cellulomonas sp. YJ5 cellulases and its biofunctional properties. AB - Both 10% and 20% (w/w) Chlorella suspensions were hydrolyzed by 150 to 350 U/mL of cellulases from a 3-d cultivation of Cellulomonas sp. YJ5. Higher chlorophyll, reducing sugars and soluble proteins, and lower residual insoluble solid were observed on both samples after 30-min hydrolysis by various concentrations of cellulases at 50 degrees C. Decrease in insoluble solid, increases in soluble proteins, peptides and chlorophyll contents, and microscopic observation indicated obvious lysis of cell walls occurred during 60- to 180-min hydrolysis. Significant increases in soluble proteins, peptides, Fe(2+) chelating ability, trolox equivalent antioxidation capacity (TEAC), and reducing power was obtained after 3-h hydrolysis by 150 U/mL of cellulase. These data suggested that cellulolysis technology has high application potential in Chlorella industry. PMID- 21535608 TI - Lactobacillus fermentum isolated from human colonic mucosal biopsy inhibits the growth and adhesion of enteric and foodborne pathogens. AB - A number of Lactobacillus species are used as probiotic strains in order to benefit health. We have isolated L. fermentum from human colonic mucosal biopsy samples that possess antimicrobial activities against entroinvasive and foodborne pathogens such as Escherichia coli, Salmonella paratyphi A, Shigella sonnei, Staphylococcus aureus, Enterococcus faecalis, Proteus mirabilis, Pseudomonas aeruginosa, and Vibrio sp. In addition to lactic acid, L. fermentum secretes antimicrobial proteinacious compound(s) that was found to be active even at neutral pH (pH 7.0). The compound was sensitive to heat treatment and trypsin digestion. Lactobacillus fermentum inhibited the adhesion of enteropathogens to intestinal epithelial cells in vitro. Isolated cell surface associated proteins (SAPs) from L. fermentum were sufficient for the adhesion exclusions of enteropathogenic E. coli. Our results indicate that L. fermentum produces antimicrobial compounds and SAPs to inhibit the growth and adhesion of enteropathogens, respectively. PMID- 21535609 TI - Optimization of medium constituents for epsilon-poly-L-lysine fermentation with response surface methodology. AB - epsilon-Poly-L-lysine (epsilon-PL) is a novel food biopreservative with broad antimicrobial activity. In the present study, single-factor experiments were applied to screen optimal carbon and nitrogen sources that affect the yield of a epsilon-PL-producing strain, Streptomyces violaceusniger, which was obtained in our laboratory recently. Box-Behnken design and response surface methodology (RSM) were adopted to derive a statistical model for optimizing the composition of the fermentation medium. The results showed that the main factors that affect E-PL production were glucose, carbon source; peptone, organic nitrogen source; and (NH(4))(2)SO(4), inorganic nitrogen source. The optimum fermentation medium for E-PL production of S. violaceusniger consisted of (g/L) glucose, 62.49; peptone, 5.71; (NH(4))(2)SO(4), 11.19; MgSO(4), 0.5; FeSO(4), 0.03; ZnSO(4), 0.04; KH(2)PO(4), 1.36; and Na(2)HPO(4).12H(2)O, 3.58. When cultured in the optimum medium, the epsilon-PL production was an average of 0.349 +/- 0.025 mg/mL, which was 1.75 times higher than the initial medium. PMID- 21535610 TI - Inhibition of Listeria monocytogenes by food antimicrobials applied singly and in combination. AB - Combining food antimicrobials can enhance inhibition of Listeria monocytogenes in ready-to-eat (RTE) meats. A broth dilution assay was used to compare the inhibition of L. monocytogenes resulting from exposure to nisin, acidic calcium sulfate, epsilon-poly-L-lysine, and lauric arginate ester applied singly and in combination. Minimum inhibitory concentrations (MICs) were the lowest concentrations of single antimicrobials producing inhibition following 24 h incubation at 35 degrees C. Minimum bactericidal concentrations (MBCs) were the lowest concentrations that decreased populations by >=3.0 log(10) CFU/mL. Combinations of nisin with acidic calcium sulfate, nisin with lauric arginate ester, and E-poly-L-lysine with acidic calcium sulfate were prepared using a checkerboard assay to determine optimal inhibitory combinations (OICs). Fractional inhibitory concentrations (FICs) were calculated from OICs and were used to create FIC indices (FIC(I)s) and isobolograms to classify combinations as synergistic (FIC(I) < 1.00), additive/indifferent (FIC(I)= 1.00), or antagonistic (FIC(I) > 1.00). MIC values for nisin ranged from 3.13 to 6.25 MUg/g with MBC values at 6.25 MUg/g for all strains except for Natl. Animal Disease Center (NADC) 2045. MIC values for epsilon-poly-L-lysine ranged from 6.25 to 12.50 MUg/g with MBCs from 12.50 to 25.00 MUg/g. Lauric arginate ester at 12.50 MUg/g was the MIC and MBC for all strains; 12.50 mL/L was the MIC and MBC for acidic calcium sulfate. Combining nisin with acidic calcium sulfate synergistically inhibited L. monocytogenes; nisin with lauric arginate ester produced additive-type inhibition, while epsilon-poly-L-lysine with acidic calcium sulfate produced antagonistic-type inhibition. Applying nisin along with acidic calcium sulfate should be further investigated for efficacy on RTE meat surfaces. PMID- 21535611 TI - Enumeration of fungi in fruits by the most probable number method. AB - In this study, enumeration methods for fungi in foods were evaluated using fruits that are often contaminated by fungi in the field and rot because of fungal contaminants. As the test methods, we used the standard most probable number (MPN) method with liquid medium in test tubes, which is traditionally used as the enumeration method for bacteria, and the plate-MPN method with agar plate media, in addition to the surface plating method as the traditional enumeration method for fungi. We tested 27 samples of 9 commercial domestic fruits using their surface skin. The results indicated that the standard MPN method showed slow recovery of fungi in test tubes and lower counts than the surface plating method and the plate-MPN method in almost all samples. The fungal count on the 4th d of incubation was approximately the same as on the 10th d by the surface plating method or the plate-MPN method, indicating no significant differences between the fungal counts by these 2 methods. This result indicated that the plate-MPN method had a number agreement with the traditional enumeration method. Moreover, the plate-MPN method has a little laborious without counting colonies, because fungal counts are estimated based on the number of plates with growing colonies. These advantages demonstrated that the plate-MPN method is a comparatively superior and rapid method for enumeration of fungi. PMID- 21535612 TI - Assessment of potential probiotic properties of Lactobacillus spp., Lactococcus spp., and Pediococcus spp. strains isolated from kefir. AB - In this study, the metabolic activities (in terms of quantities of the produced lactic acid, hydrogen peroxide, and exopolysaccharides) of 8 strains of Lactobacillus spp., Lactococcus spp., and Pediococcus spp., were determined. Lactic acid levels produced by strains were 8.1 to 17.4 mg/L. The L. acidophilus Z1L strain produced the maximum amount (3.18 MUg/mL) of hydrogen peroxide. The exopolysaccharides (EPS) production by the strains was ranged between 173 and 378 mg/L. The susceptibility of 7 different antibiotics against these strains was also tested. All strains were found to be sensitive to ampicillin. The tolerance of the strains to low pH, their resistance to bile salts of strains, and their abilities to autoaggregate and coaggregate with Escherichia coli ATCC 11229 were also evaluated. High EPS-producing strains showed significant autoaggregation and coaggregation ability with test bacteria (P < 0.01). A correlation also was determined between EPS production and acid-bile tolerance (P < 0.05). EPS production possibly affects or is involved in acid-bile tolerance and aggregation of Lactobacillus spp., Lactococcus spp., and Pediococcus spp. strains and supports the potential of L. acidophilus Z1L strain as new probiotic. PMID- 21535613 TI - Electrostatic sprays of food-grade acids and plant extracts are more effective than conventional sprays in decontaminating Salmonella Typhimurium on spinach. AB - About 40000 people fall victim to Salmonella infections every year in the United States. Recent occurrences of Salmonella contaminated spinach and its recalls have accelerated the need for efficient antimicrobials targeting these pathogens. Our study was aimed at evaluating the inhibitory properties of malic, tartaric, and lactic acids, and grape seed extract (GSE) alone and in combinations and their application methods against Salmonella Typhimurium-inoculated spinach using a response surface method. Fresh spinach leaves were washed, disinfected with sodium hypochlorite solution (0.04% v/v), rewashed with sterile deionized (DI) water, and inoculated with a 2nd-day culture of S. Typhimurium (7.0 log CFU/mL). Adhered S. Typhimurium population on day 0 were 7.5 log CFU/g. These were treated with individual and combinations of organic acids with GSE or DI water (control) adjusted to the same pH as that of the test solutions with both the modes of application and leaves were refrigerated at 4 degrees C. Malic acid (2%) in combination with GSE (3%) or lactic acid (3%) sprayed electrostatically showed reductions of 2.6 to 3.3 log CFU/g compared to lower log reductions (0.0 to 0.3 log CFU/g) by day 14 if sprayed conventionally. These findings indicate that malic acid in combination with GSE/lactic acid solutions applied by electrostatic spraying exhibited higher inhibition of pathogens than conventional spraying and can be used for commercial applications to enhance food safety. PMID- 21535614 TI - Effect of NaCl on the biofilm formation by foodborne pathogens. AB - This study was designed to evaluate the effect of NaCl on the biofilm formation of Listeria monocytogenes, Staphylococcus aureus, Shigella boydii, and Salmonella Typhimurium. The biofilm cells were cultured in media containing different NaCl concentrations (0% to 10%) for 10 d of incubation at 37 degrees C using a 24 well polystyrene microtiter plate, collected by swabbing methods, and enumerated using plate count method. The attachment and detachment kinetic patterns were estimated according to the modified Gompertz model. The cell surface hydrophobicity and auto-aggregation were observed at different NaCl concentrations. Most strains showed 2 distinctive phases at lower than 6% NaCl, while the numbers of adhered cells gradually increased throughout the incubation period at 4% to 10% NaCl. At 0% NaCl, the numbers of adhered L. monocytogenes, S. aureus, S. boydii, and S. Typhimurium cells rapidly increased up to 7.04, 6.47, 6.39, and 7.27 log CFU/cm(2), respectively, within 4 d of incubation. The maximum growth rate (k(A)) and specific growth rate (MU(A)) of adherent pathogenic cells were decreased with increasing NaCl concentration. Noticeable decline in the numbers of adherent cells was observed at low concentration levels of NaCl (<2%). The adherence abilities of foodborne pathogens were influenced by the physicochemical surface properties. The hydrophobicity and auto-aggregation enhanced the biofilm formation during the incubation periods. Therefore, this study could provide useful information to better understand the adhesion and detachment capability of foodborne pathogens on food contact surfaces. PMID- 21535615 TI - Carboxymethyl cellulose coating and low-dose gamma irradiation improves storage quality and shelf life of pear (Pyrus communis L., Cv. Bartlett/William). AB - Carboxymethyl cellulose (CMC) coatings alone and in combination with gamma irradiation were tested for maintaining the storage quality and extending shelf life of pear. Matured green pears were CMC coated at levels 0.25% to 1.0% w/v and gamma irradiated at 1.5 kGy. The treated fruit including control was stored under ambient (temperature 25 +/- 2 degrees C, RH 70%) and refrigerated (temperature 3 +/- 1 degrees C, RH 80%) conditions. Irradiation alone at 1.5 kGy gave 8 and 4 d extension in shelf life of pear following 45 and 60 d of refrigeration, respectively. CMC coating at 1.0% w/v was effective in giving 6 and 2 d extension in shelf life of pear following 45 and 60 d of refrigeration, respectively. All combinatory treatments delayed the decaying of pear during postrefrigerated storage, but combination of 1.0% w/v CMC and 1.5 kGy irradiation proved significantly (P<=0.05) effective in maintaining the storage quality and delaying the decaying of pear. The above combinatory treatment gave an extension of 12 and 6 d in shelf life of pear during postrefrigerated storage at 25 +/- 2 degrees C, RH 70% following 45 and 60 d of refrigeration. PMID- 21535616 TI - Characterization of butter spoiling yeasts and their inhibition by some spices. AB - This study was designed to identify the yeasts in packaged and unpackaged butters and screen antiyeast activity of spices, including marjoram (Origanum majorana L.), summer savory (Satureja hortensis L.), and black cumin (Nigella sativa L.) against the most dominant yeast species in the packaged and unpackaged butters. Mean total yeast populations were 5.40 log CFU/g in unpackaged butter samples and 2.22 log CFU/g in packaged butter samples, indicating better hygienic quality of packaged samples. Forty-nine yeast species were isolated and identified from butter samples with the most prevalent isolates belonging to genera Candida-C. kefyr, C. zeylanoides, and C. lambica-and with moderate number of isolates belonging to genera Cryptococcus, Rhodotorula, Saccharomyces, and Zygosaccharomyces. Black cumin exhibited the highest antiyeast activity against C. zeylanoides and C. lambica species, even inhibited these species, while summer savory inhibited C. kefyr. The results of this study revealed clear antimicrobial potential of black cumin against the yeast species isolated from butters. Marjoram, summer savory, and black cumin could be used as natural antimicrobial agents against spoilage yeasts in food preservation, especially in butter. PMID- 21535617 TI - A transfer of technology from engineering: use of ROC curves from signal detection theory to investigate information processing in the brain during sensory difference testing. AB - This article reviews a beneficial effect of technology transfer from Electrical Engineering to Food Sensory Science. Specifically, it reviews the recent adoption in Food Sensory Science of the receiver operating characteristic (ROC) curve, a tool that is incorporated in the theory of signal detection. Its use allows the information processing that takes place in the brain during sensory difference testing to be studied and understood. The review deals with how Signal Detection Theory, also called Thurstonian modeling, led to the adoption of a more sophisticated way of analyzing the data from sensory difference tests, by introducing the signal-to-noise ratio, d', as a fundamental measure of perceived small sensory differences. Generally, the method of computation of d' is a simple matter for some of the better known difference tests like the triangle, duo-trio and 2-AFC. However, there are occasions when these tests are not appropriate and other tests like the same-different and the A Not-A test are more suitable. Yet, for these, it is necessary to understand how the brain processes information during the test before d' can be computed. It is for this task that the ROC curve has a particular use. PMID- 21535618 TI - Effects of bagging on volatiles and polyphenols in "Wanmi" peaches during endocarp hardening and final fruit rapid growth stages. AB - Fruits of the late-ripening peach cultivar "Wanmi" were bagged at the early period of fruit endocarp hardening, and the bags were removed 1 wk before maturity harvest. The effects of bagging on volatile compounds and polyphenols were studied. Total volatiles and the sum of C(6) compounds, esters from bagged fruits were significantly lower than from nonbagged fruits from the beginning of the final rapid fruit growth stage to maturity. As the most dominant compounds of C(6) compounds and esters, the lower contents of hexanal, trans-2-hexenal, hexyl acetate, cis-3-hexenyl acetate, and trans-2-hexenyl acetate attributed to the lower content of C(6) compounds and esters in bagged fruit. gamma-Hexalactone and delta-decalactone were produced earlier in bagged fruits than in nonbagged ones, suggesting that bagging accelerates fruit maturity. Level of gamma-decalactone in bagged fruits was significantly lower than in nonbagged fruits at 159 days after full blossom (DAFB), so did delta-decalactone at 166 DAFB. Bagging did not affect chlorogenic acid and catechol contents of either fruit peel or flesh, nor did it affect contents of keracyanin or quercetin-3-rutinoside in fruit flesh during fruit development. However, keracyanin and quercetin-3-rutinoside levels were significantly reduced in bagged fruit peels before ripening compared to nonbagged fruit peels. Considering the large changes in volatiles and polyphenols, the key stage for "Wanmi" fruit maturity was between 126 DAFB and 147 DAFB, about 1 mo ahead of maturity. PMID- 21535619 TI - Impact of shelf life on content of primary and secondary metabolites in apple (Malus domestica Borkh.). AB - In this study, we evaluated the changes in apple fruit quality during shelf life. After a month of cold storage, apples of cultivars "Jonagold" and "Golden Delicious" were exposed to ambient temperatures for 21 d, with subsequent sampling every 3 or 4 d. Fruit firmness, changes in amounts of sugars, malic acid, and phenolics were observed during shelf life. Chemical analyses were done with HPLC-PDA system. An interchange between various sugars was noticed, but in general, the sum of sugars remained at the same level. The content of malic acid remained stable or dropped, resulting in sweeter fruit. Levels of phenolics were more constant in the pulp of both cultivars analyzed, while in the peel, the changes were more pronounced. In the pulp, a peak in the content of hydroxycinnamic acids and flavanols was noticed on the 2nd or 3rd sampling and afterwards, the amounts remained constant. In the peel an initial decrease of all analyzed phenolic groups was observed in both cultivars, however it was more pronounced in "Jonagold." It can be concluded that changes in primary and secondary metabolites are not the main reason for the lower quality of fruit exposed to ambient temperatures. On the other hand, fruit firmness might be the limiting factor for shelf life duration. PMID- 21535620 TI - Effects of extraction conditions on the sensory and instrumental characteristics of fish gelatin gels. AB - Fish skin gelatin has recently been of interest as a product that eliminates religious concerns (Jewish and Muslim) and could be an alternative value-added product from fish waste. Recent research has shown that extraction conditions affect gelatin quality. In this study, gelatin from Asian silver carp skin and extracted under different conditions have been studied sensory properties using descriptive analysis and time intensity testing to determine how extraction conditions affect gelatin sensory properties. Three pairs of gelatin samples were selected based on their gel strength, viscosity, and melting temperature. The impacts of different extraction conditions on instrumental methods were examined. Some functionality measurements were also done to determine how sensory measurements correlate with instrumental measurements. The gel strength varied between 60 +/- 10 g and 590 +/- 30 g while the viscosity varied between 1.9 +/- 0.0 cP and 7.4 +/- 0.2 cP. The hardness, melting and gelling temperature of the samples were well correlated with the gel strength (r > 0.90). The results indicated that the strongest correlation among all the sensory attributes was between firmness and melting temperature, which was a negative correlation ( 0.75) suggesting that the firmer the gel samples the slower they melt. The viscosity was found to be very discriminative between samples in terms of sensory properties. The functional measurements were found to be strongly correlated within themselves while the sensory measurements were less so, which might be due to the greater variability when using sensory panelists or sensory parameters simply might not be related. The firmness, melting rate, and aftertaste were those sensory attributes most successfully discriminated by the panelists. PMID- 21535621 TI - Gas chromatography/olfactometry and electronic nose analyses of retronasal aroma of espresso and correlation with sensory evaluation by an artificial neural network. AB - To develop a method for evaluating and designing the retronasal aroma of espresso, sensory evaluation data was correlated with data obtained from gas chromatography/olfactometry (GC/O, CharmAnalysisTM) and from an electronic nose system alphaFOX4000 (E-nose). The volatile compounds of various kinds of espresso (arabica coffee beans from 6 production countries: Brazil, Ethiopia, Guatemala, Colombia, Indonesia, and Tanzania; 3 roasting degrees for each country: L values, 18, 23, and 26) were collected with a retronasal aroma simulator (RAS) and examined by GC/O and E-nose. In addition, sensory descriptive analysis using a 7 point scale for RAS effluent gas was performed by 5 trained flavorists using sensory descriptors selected based on the frequency in use and coefficient of correlation. The charm values of 10 odor descriptions obtained from GC/O analysis exhibited the significant (P < 0.05) differences among both roasting degrees and origins. Also, linear discriminant analysis (LDA) on the E-nose-sensor resistances and factor analysis on the sensory evaluation scores showed that the differences of aroma characteristics among the roasting degrees were larger than those among the origins. Based on an artificial neural network (ANN) model applied to the data from GC/O analyses and sensory evaluations, the perceptual factor of the RAS aroma was predicted to be mainly affected by sweet-caramel, smoke-roast, and acidic odors. Also, 3 metal oxide semiconductor sensors (LY2/Gh, P30/1, and T40/1) of E-nose were selected for analyses of RAS aroma and correlated with the sensory descriptive scores by the ANN to support sensory evaluation. PMID- 21535622 TI - Use of species other than oak to flavor wine: an exploratory survey. AB - The concept of geographical exclusivity prompted an exploratory survey with toasted woods other than oak to flavor wine. A total of 11 woods and oak (Quercus alba) were cut into chips 20 * 10 * 2.5 mm and toasted at 200 degrees C for 2 h (light toast) or 210 degrees C for 3 h (dark). Weight losses and changes in CIE color space were monitored. The toasted chips were infused in unoaked chardonnay (5 g L(-1)) for 2 wk. Parallel infusions were done with model wine (water, ethanol, tartaric acid) adjusted to pH 3.5. Ultraviolet absorbances due to infusion were recorded on the basis that that lignin compounds and their potential pyrolysates are based on phenolic structures that absorb in the ultraviolet range. Weight losses on light and dark toasting were highly variable between species as were color changes, suggesting potential for different flavor outcomes from chemical changes. Ultraviolet absorbance curves were also highly variable showing that different species yielded different quantities of potentially flavor-active phenolic compounds in real and model wine. More absorbing matter was extracted from the light toast treatments, and light toast oak, which demonstrated the greatest weight loss on light toasting, yielded the widest range of ultraviolet-absorbing matter. In an informal sensory trial with the 24 species/toast combinations infused in chardonnay all but one wood, Cupressus macrocarpa, resulted in flavors reminiscent of oaked wines. A hedonic consumer trial with 4 species and oak compared with uninfused chardonnay showed that each of the 4 had potential as a flavorant. Thus, woods unsuited to barrel construction could provide unrealized flavor opportunities in the wine industry, and could extend to flavoring spirits. PMID- 21535623 TI - Variation in sensory profile of individual rainbow trout (Oncorhynchus mykiss) from the same production batch. AB - The variation in sensory profile of rainbow trout (Oncorhynchus mykiss), belonging to the same aquaculture production batch and handled the same way, was explored by using objective sensory profiling on heat-treated minced fillets. In addition, quality index, mechanical texture, pH, fat, and water content were measured. Different groups of fish were sampled 3 different times during a production day. The results showed significant differences in the sensory profiles of individual fish within all 3 groups as well as significant differences between the groups. Differences in mechanical texture were found between individuals in 2 of the 3 groups and between the groups. No differences were found in quality index neither between individuals nor groups. A significant negative correlation between lipid content and firm texture was observed, but in general, the chemical and physical measurements could not explain the differences in the sensory profiling or in the mechanical texture measurements. The results showed that significant differences in the sensory profiles of individual fish from the same aquaculture production batch may occur. Furthermore, the results also showed sensory differences between groups of samples taken at different times during a production day. PMID- 21535624 TI - Aroma profile and volatiles odor activity along gold cultivar pineapple flesh. AB - Physicochemical attributes, aroma profile, and odor contribution of pineapple flesh were studied for the top, middle, and bottom cross-sections cut along the central axis of Gold cultivar pineapple. Relationships between volatile and nonvolatile compounds were also studied. Aroma profile constituents were determined by headspace solid-phase microextraction at 30 degrees C, followed by gas chromatography/mass spectrometry analysis. A total of 20 volatile compounds were identified and quantified. Among them, esters were the major components which accounted for 90% of total extracted aroma. Methyl butanoate, methyl 2 methyl butanoate, and methyl hexanoate were the 3 most abundant components representing 74% of total volatiles in pineapple samples. Most odor active contributors were methyl and ethyl 2-methyl butanoate and 2,5-dimethyl 4-methoxy 3(2H)-furanone (mesifuran). Aroma profile components did not vary along the fruit, but volatile compounds content significantly varied (P < 0.05) along the fruit, from 7560 to 10910 MUg/kg, from the top to the bottom cross-sections of the fruit, respectively. In addition, most odor-active volatiles concentration increased from the top to the bottom 3rd of the fruit, concurrently with soluble solids content (SSC) and titratable acidity (TA) differences attributed to fruitlets distinct degree of ripening. Large changes in SSC/TA ratio and volatiles content throughout the fruit found through this study are likely to provoke important differences among individual fresh-cut pineapple trays, compromising consumer perception and acceptance of the product. Such finding highlighted the need to include volatiles content and SSC/TA ratio and their variability along the fruit as selection criteria for pineapples to be processed and quality assessment of the fresh-cut fruit. PMID- 21535625 TI - Consumer perception of astringency in clear acidic whey protein beverages. AB - Acidic whey protein beverages are a growing component of the functional food and beverage market. These beverages are also astringent, but astringency is an expected and desirable attribute of many beverages (red wine, tea, coffee) and may not necessarily be a negative attribute of acidic whey protein beverages. The goal of this study was to define the consumer perception of astringency in clear acidic whey protein beverages. Six focus groups (n=49) were held to gain understanding of consumer knowledge of astringency. Consumers were presented with beverages and asked to map them based on astringent mouthfeel and liking. Orthonasal thresholds for whey protein isolate (WPI) in water and flavored model beverages were determined using a 7-series ascending forced choice method. Mouthfeel/basic taste thresholds were determined for WPI in water. Acceptance tests on model beverages were conducted using consumers (n=120) with and without wearing nose clips. Consumers in focus groups were able to identify astringency in beverages. Astringency intensity was not directly related to dislike. The orthonasal threshold for WPI in water was lower (P < 0.05) than the mouthfeel/basic taste threshold of WPI in water. Consumer acceptance of beverages containing WPI was lower (P < 0.05) when consumers were not wearing nose clips compared to acceptance scores of beverages when consumers were wearing nose clips. These results suggest that flavors contributed by WPI in acidic beverages are more objectionable than the astringent mouthfeel and that both flavor and astringency should be the focus of ongoing studies to improve the palatability of these products. PMID- 21535626 TI - Measuring acceptance of milk and milk substitutes among younger and older children. AB - Appropriate nutrient-dense foods and beverages are crucial for children for proper growth and development and to develop healthful lifelong habits. This study investigated children's (ages 8 to 16 y old) perception of sensory intensity, attribute liking and overall liking of unflavored and chocolate lactose-free cow's milk and soy beverages. Products were not identified as to whether they were soy or milk. Children showed greater acceptance of lactose-free cow's milk compared to milk substitute beverages, within flavor category. No differences in acceptance emerged by ethnic group (Caucasian, African American, Hispanic), but a large difference emerged by age group. All product acceptance differences perceived by older children reoccurred among the younger children and in the same direction, but the older children used a larger range of numbers, especially at the lower end, rather than at the higher end of acceptance. The effect of age is not a simple scaling bias but may suggest a reduced criticism by younger respondents of less-acceptable products. PMID- 21535627 TI - Utilization of oryzacystatin for regulating the ripening of squid shiokara, a traditional Japanese salted and fermented seafood. AB - Shiokara is a fermented seafood composed of sliced squid mantle muscle ripened with fresh squid liver. Preliminary sensory evaluation by using the ranking test revealed that the hardness of squid muscle in shiokara was reduced within 7 d of ripening. During the process of ripening, muscle proteins were digested by proteinases present in squid liver. The degradation of paramyosin and myosin heavy chain was observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The hardness of squid mantle muscle in shiokara was reduced with the degradation of paramyosin and myosin heavy chain. This degradation was mainly caused by E-64-sensitive cysteine proteinases. To control the hardness of shiokara, we used rice seed oryzacystatin, which suppresses proteolysis by papain like cysteine proteinases. When oryzacystatin was added 4 d after the start of shiokara ripening, the muscle protein degradation stopped, without further muscle softening. These results show that oryzacystatin is useful to control the ripening of shiokara by regulating its hardness. PMID- 21535628 TI - Consumer preferences for fresh tomato at the European scale: a common segmentation on taste and firmness. AB - Although tomato flavor has not been a major goal for breeders, nowadays it becomes important as it is a subject of consumer complaint. A better knowledge of tomato consumer preferences, at the European level, should provide the basis for improvement of fruit quality and for market segmentation. In the framework of a large European project, 806 consumers from 3 countries, The Netherlands, France, and Italy, were presented with a set of 16 varieties representing the diversity of fresh tomato offer in order to evaluate their preferences. In parallel, sensory profiles were constructed by expert panels in each country. Preference maps were then constructed in each country revealing the structure of consumer preferences and allowing identification of the most important characteristics. Then a global analysis revealed that preferences were quite homogeneous across countries. This study identified the overall flavor and firmness as the most important traits for improving tomato fruit quality. It showed that consumer preferences from different European countries, with different cultures and food practices, are segmented following similar patterns when projected onto a common referential plan. Moreover, the results clearly showed that diversification of taste and texture is required to satisfy all consumers' expectations as some consumers preferred firm tomatoes, while others preferred melting ones and were more or less demanding in terms of sweetness and flavor intensity. Detailed comparisons also showed the importance of the fruit appearance in consumer preference. PMID- 21535629 TI - Physicochemical and sensory properties of fresh potato-based pasta (gnocchi). AB - This study dealt with the characterization and quality assessment of 3 kinds of potato-based pasta (gnocchi) made with steam-cooked, potato puree (water added to potato flakes), and reconstituted potatoes as main ingredients. The aim of the research was to evaluate the quality of the products in terms of physicochemical, textural, and sensory characteristics. Water content, water activity, color (L* and h degrees ), and texture (texture profile analysis [TPA] and shearing test) were evaluated on both raw and cooked samples. In addition, on the recovered cooking water the loss of solid substances was determined and on the cooked gnocchi a sensory assessment was performed. Eight sensory attributes (yellowness, hardness, gumminess, adhesiveness, potato taste, sweet taste, flour taste, and sapidity) were investigated. Statistically significant differences among products were obtained, especially concerning textural properties. In fact, sample made with reconstituted potatoes and emulsifiers resulted the hardest (8.53 +/- 1.22 N), the gummiest (2.90 +/- 0.05 N), and the "chewiest" (2.90 +/- 0.58 N) after cooking. Gnocchi made with potato puree or reconstituted potatoes significantly differed from the one produced with steam-cooked potatoes in terms of sensory properties (yellowness, hardness, flour taste, and sapidity). Pearson's correlation analysis between some textural instrumental and sensory parameters showed significant correlation coefficients (0.532 < r < 0.810). Score plot of principal component analysis (PCA) confirmed obtained results from physicochemical and sensory analyses, in terms of high discriminant capacity of colorimetric and textural characteristics. PMID- 21535630 TI - Processing of soft Hispanic cheese ("queso fresco") using thermo-sonicated milk: a study of physicochemical characteristics and storage life. AB - Queso fresco is a handmade cheese consumed in Latin America and some regions of the United States. However, deficient milk processing has affected its microbial quality and it has an extremely short shelf life and low yield. The objective of this work was to process queso fresco using thermo-sonicated milk; physicochemical parameters were evaluated, including microbial quality during storage (4 degrees C). An ultrasonic processor (UP400S, 400 W, 24 kHz, 120 MUm) was used to sonicate raw milk. Seven milk systems (500 mL each) were evaluated: 1 untreated, and 6 treated at 63 degrees C/30 min; 63 degrees C/10 min + sonication; 63 degrees C/30 min + sonication; 72 degrees C/15 s; 72 degrees C/15 s + sonication; and 72 degrees C/1 min + sonication. A conventional cheese making process was followed for all systems. The effect of sonication on milk was quite noticeable. Curdling times were reduced considerably, cheese yield (20.6%) was almost doubled, and luminosity of cheese was increased (L*). Textural properties and microstructure images matched very well. Queso fresco processed at 63 degrees C/120 MUm/30 min had the best quality. After storage for 23 d at 4 degrees C mesophilic count was just 4 log; psychrophilic count, 3.5 log; and enterobacteria count, 3 log. The pH and color remained almost constant and a minor degree of syneresis was observed at end of storage. Due to microstructural rearrangement of the milk components such as fat globules and casein micelles, cheese yield was doubled compared to the traditional handmade product. Shelf life was extended considerably and the product had higher quality. PMID- 21535631 TI - Evaluation of cleaning procedures for allergen control in a food industry environment. AB - The hygiene of chicken processing surfaces and retention of the wheat protein gliadin and of protein in general on those surfaces were compared in 15 trials after 3 increasingly rigorous cleaning steps. Eleven different chicken products with wheat derivatives as a batter were prepared on 3 processing lines in 15 production runs selected at random over 6 mo (5 runs were thus replicates). Using surface swabs, surface hygiene was monitored by adenosine triphosphate (ATP) bioluminescence, gliadin by immunoassay, and protein by the Coomassie dye method. Gliadin was monitored in 14 trials, protein in 5, and all trials were monitored by ATP bioluminescence. In a typical trial, gliadin values normalized to uncleaned values fell from 100000 arbitrary units, to 6000 after rinsing, to 30 (foam, rinse), to not detected (sanitize, rinse). Parallel ATP bioluminescence values also decreased, but crucially, the relative gliadin value was less than the relative ATP value after foam and rinse in all 14 trials, a result unchanged after sanitize and rinse. In trials comparing ATP and protein, the relative ATP values exceeded the relative protein values in 4 of 5 trials after foaming and after sanitizing. Thus, for these 11 products, ATP bioluminescence was a surrogate indicator of residual gliadin and probably of residual protein. Absolute gliadin concentration on an uncleaned processing line was also the basis of modeling the risk of cross-contamination of gliadin in follow-up product, where the line was hypothetically left uncleaned between production runs. The results show that all follow-up product could be declared "gluten-free" under proposed legislation, and suggest that some industrial cross-contamination risks are currently overestimated. PMID- 21535632 TI - Levels of 2-dodecylcyclobutanone in ground beef patties irradiated by low-energy X-ray and gamma rays. AB - Food irradiation improves food safety and maintains food quality by controlling microorganisms and extending shelf life. However, acceptance and commercial adoption of food irradiation is still low. Consumer groups such as Public Citizen and the Food and Water Watch have opposed irradiation because of the formation of 2-alkylcyclobutanones (2-ACBs) in irradiated, lipid-containing foods. The objectives of this study were to measure and to compare the level of 2 dodecylcyclobutanone (2-DCB) in ground beef irradiated by low-energy X-rays and gamma rays. Beef patties were irradiated by low-energy X-rays and gamma rays (Cs 137) at 3 targeted absorbed doses of 1.5, 3.0, and 5.0 kGy. The samples were extracted with n-hexane using a Soxhlet apparatus, and the 2-DCB concentration was determined with gas chromatography-mass spectrometry. The 2-DCB concentration increased linearly (P < 0.05) with irradiation dose for gamma-ray and low-energy X-ray irradiated patties. There was no significant difference in 2-DCB concentration between gamma-ray and low-energy X-ray irradiated patties (P > 0.05) at all targeted doses. PMID- 21535636 TI - Effect of storage conditions on the solubility and viscosity of beta-glucan extracted from bread under in vitro conditions. AB - The viscosity and solubility of beta-glucan in muffins have been shown to be reduced by certain storage conditions, though the effect of storage on bread fortified with barley beta-glucan concentrate has not been investigated. Therefore, this study investigated the effect of storage temperature and time (23 degrees C for 1, 4, and 7 d, 4 degrees C for 4, 7, and 14 d, and -20 degrees C for 1, 2, 4, and 8 wk) on the solubility and viscosity of beta-glucan upon incorporation into bread at levels corresponding to 0 or 1.5 g beta glucan/serving, with or without vital gluten addition. The firmness and moisture content of bread following each storage treatment were also evaluated. The highest moisture and lowest firmness values were found in fresh bread, though these parameters were still maintained at appreciable levels upon room temperature storage of the 1.5 g beta-glucan/serving bread with added gluten and at either room temperature or frozen storage for the 1.5 g beta-glucan/serving bread for 4 d. If it is desirable to store bread for 7 d or more, frozen storage should be utilized in order to best maintain bread moisture and firmness levels. It is recommended that beta-glucan-fortified bread be consumed fresh for greatest beta-glucan solubility and viscosity, though beta-glucan solubility of approximately 40% is still achievable upon frozen storage of the bread for up to 2 wk. It is still unclear, however, as to what extent of reductions in the solubility and viscosity of beta-glucan would lower its physiological effectiveness. PRACTICAL APPLICATION: Previous research has demonstrated that solubility and thus viscosity of beta-glucan, which is an important property associated with its health benefits can be impacted by different storage conditions applied to some bakery products, like muffins. This study demonstrates the extent of changes in the solubility and viscosity of beta-glucan incorporated into bread. Therefore, storage time and temperature should be optimized to minimize changes in beta-glucan for maintaining its efficacy for its health benefits. PMID- 21535637 TI - Comparative antioxidant activity of edible Japanese brown seaweeds. AB - Japanese edible brown seaweeds, Eisenia bicyclis (Arame), Kjellmaniella crassifolia (Gagome), Alaria crassifolia (Chigaiso), Sargassum horneri (Akamoku), and Cystoseira hakodatensis (Uganomoku) were assayed for total phenolic content (TPC), fucoxanthin content, radical scavenging activities (DPPH, peroxyl radical, ABTS, and nitric oxide), and antioxidant activity in a liposome system. Among the solvents used for extraction, methanol was the most effective to extract total phenolics (TPC) from brown seaweeds. Among 5 kinds of brown seaweeds analyzed, methanol extract from C. hakodatensis was the best source for antioxidants. The high antioxidant activity of the extract was based not only on the high content of phenolics, but on the presence of fucoxanthin. No significant correlation (P > 0.05) was observed between TPC per gram extract with DPPH radical scavenging activity of the methanol extracts. These observed discrepancy would be due to structural variations in the phenolic compounds, and different levels of fucoxanthin in the extracts. The present study also demonstrated the synergy in the antioxidant activity of the combination of brown seaweed phenolics and fucoxanthin. PMID- 21535638 TI - Validation of immunodetection (ELISA) of ricin using a biological activity assay. AB - The suitability of enzyme-linked immunosorbent assay (ELISA) for residual ricin toxicity determination was investigated in this study. Ricin was thermally treated at 80 to 90 degrees C for up to 9 min, and its residual concentration was determined by means of a commercial ELISA kit, and its bioactivity (amount of adenine released from DNA) was determined by means of a biological activity assay (BAA). Results showed that inactivation of ricin followed 1st-order kinetics. The half-life values for loss of bioactivity at 80, 85, and 90 degrees C were 1.93, 0.65, and 0.41 min, respectively. Similarly, the half-life values for reduction in ricin concentration determined by ELISA were 3.06, 0.79, and 0.43 min, respectively. The half-lives determined by both assays were only significantly different at 80 degrees C. The Z, Q(10), and Arrhenius activation energy values determined by both assays were dissimilar: 11.74 C, 7.12 and 50.1 kcal/mol, respectively, by ELISA; and 14.87 degrees C, 4.71 and 39.5 kcal/mol, respectively, by BAA. Nevertheless, our findings indicate that the 2 assays were highly correlated (R(2) = 1), and it can be concluded that ELISA would be a reliable method for detecting residual toxicity of heat-treated ricin based on fraction lost. Practical Application: The results of this study indicate that immunodetection, even though not a direct measurement of the biological activity of ricin, is suitable for determining the residual bioactivity of ricin since immunodetection and the biological activity assay used in this investigation were highly correlated. Therefore, ELISA can be used for routine assessment of residual activity or toxicity of ricin in thermally treated foods. PMID- 21535639 TI - Phytochemicals and antioxidant capacities in rice brans of different color. AB - Rice bran, a byproduct of the rice milling process, contains most of the phytochemicals. This study aimed at determining the concentrations of lipophilic, solvent-extractable (free), and cell wall-bound (bound) phytochemicals and their antioxidant capacities from brans of white, light brown, brown, purple, and red colors, and broccoli and blueberry for comparison. The concentrations of lipophilic antioxidants of vitamin E (tocopherol and tocotrienols) and gamma oryzanols were 319.67 to 443.73 and 3861.93 to 5911.12 MUg/g bran dry weight (DW), respectively, and were not associated with bran color. The total phenolic, total flavonoid, and antioxidant capacities of ORAC (oxygen radical absorbance capacity), DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging, and iron chelating in the free fraction were correlated with the intensity of bran color, while variations of these in the bound fraction were less than those in the free fraction among brans. Compounds in the bound fraction had higher antioxidant capacity of ORAC than DPPH, relative to those in the free fraction. The bound fraction of light-color brans contributed as much to its total ORAC as the free fraction. Total proanthocyanidin concentration was the highest in red rice bran, while total anthocyanin was highest in purple brans. The predominant anthocyanin was cyanidin-3-glucoside. Red and purple brans had several fold higher total phenolics and flavonoids as well as ORAC and DPPH, from both free and bound fractions, than freeze-dried blueberry and broccoli. These results indicate that rice brans are natural sources of hydrophilic and lipophilic phytochemicals for use in quality control of various food systems as well as for nutraceutical and functional food application. PMID- 21535640 TI - Influence of pulsed electric field treatments on the volatile compounds of milk in comparison with pasteurized processing. AB - Effects of pulsed electric field (PEF) treatments on the volatile profiles of milk were studied and compared with pasteurized treatment of high temperature short time (HTST) (75 degrees C, 15 s). Volatile compounds were extracted by solid-phase micro-extraction (SPME) and identified by gas chromatography/mass spectrometry (GC-MS) and gas chromatography-olfactometry (GC-O). A total of 37 volatile compounds were determined by GC-MS, and 19 volatile compounds were considered to be major contributors to the characteristic flavor of milk samples. PEF treatment resulted in an increase in aldehydes. Milk treated with PEF at 30 kV/cm showed the highest content of pentanal, hexanal, and nonanal, while heptanal and decanal contents were lower than in pasteurized milk, but higher than in raw milk. All the methyl ketones detected in PEF milk were lower than in pasteurized milk. No significant differences in acids (acetic acid, butanoic acid, hexanoic acid, octanoic acid, and decanoic acid), lactones, and alcohols were observed between pasteurized and PEF-treated samples; however, 2(5H) furanone was only detected in PEF-treated milk. Although GC-MS results showed that there were some volatile differences between pasteurized and PEF-treated milk, GC-O data showed no significant difference between the 2 samples. PMID- 21535641 TI - Chitosan-whey protein isolate composite films for encapsulation and stabilization of fish oil containing ultra pure omega-3 fatty acids. AB - Chitosan (1.5%, w/v)-whey protein isolate (WPI, 5% w/v) composite films were developed for encapsulating and stabilizing fish oil (FO) containing 93.7% eicosapentaenoic acid (EPA). Chitosan-WPI film-forming solutions (FFS) were incorporated with 1.5% or 2% FO (w/v), 2% (w/v) glycerol, Tween 80 (3 times weight of FO), and 0.5% (w/v) oregano or rosemary essential oil (EO), and cast for films at room conditions. Dried films were stored at 2 degrees C for 30 d for evaluating encapsulation efficiency (EE), lipid stability, and film functionality. Total oil contents in films from FFS incorporating 1.5% or 2% FO were 28.1% to 32.5% and 33.4% to 37.3%, respectively, and free oil contents were 13.5% to 14.7% and 15.5% to 16.3%, respectively. EE, moisture content, and water activity of the films were 47.8% to 66%, 18.7% to 24.9%, and 0.42% to 0.50%, respectively, without significant difference among differently formulated films. Increasing FO concentration from 1.5% to 2% in FFS decreased tensile strength of the films from 0.57-0.73 to 0.34-0.44 MPa, but not the film elongation. Addition of oregano EO in FFS retarded lipid oxidation of the fish oil encapsulated in the films, in which a 43% to 53% reduction in thiobarbituric acid-reactive substances value and 39% to 51% reduction in peroxide value were achieved. Chitosan-WPI composite films with incorporation of oregano essential oil could be applied as a simple and economic means for encapsulating and stabilizing fish oil for fortifying omega-3 fatty acids in various applications. PMID- 21535642 TI - Enzymatic hydrolysis of blue whiting (Micromesistius poutassou); functional and bioactive properties. AB - Functional and biochemical properties of fish protein hydrolysates (FPH) from blue whiting (BW) were studied. FPH (2.5%, 5%, 10%, and 15% degree of hydrolysis [DH]) were made from isolated proteins from headed and gutted BW with Alcalase 2.4 L. The properties of dried BW mince and protein isolate compared to 4 reference proteins (soy and milk protein) were studied: color, solubility, water holding capacity (WHC), oil-binding capacity (OBC), emulsion capacity (EC), and emulsion stability (ES). The angiotensin I-converting enzyme (ACE) inhibitory activities of the soluble fraction of BW powders were also investigated. Furthermore, the products were characterized by analyzing their chemical composition. Chemical composition, solubility, OBC, and EC of the BW powders was significantly (P < 0.05) different with different DH, while color, ES, and WHC were not significantly (P > 0.05) different. Salt content of the FPH was high (4% to 19%) and increased with increased DH. Protein solubility varied from 10% to 70% and increased with increased DH. WHC of the FPH was around 97% and was higher than that of all the reference proteins tested. OBC decreased with increased DH (from 3.5 to 2.1 g oil/g protein) and was higher than OBC of the soy and milk proteins (1.6 to 1.9 g oil/g protein). EC of FPH was similar or lower than the reference proteins. ES of FPH (60% to 90%) was similar to or lower than soy and whey proteins (60% to 98%) but higher than casein (20%). ACE inhibition activity increased as DH was increased. Practical Application: The results from this study demonstrate that a functional bioactive hydrolysate can be produced from BW, which is an underutilized fish species, and may aid the industry in better utilizing this raw material. The novelty of this research was the use of BW as a raw material where the protein has been isolated with the pH shift method. Furthermore, it was novel that bioactivity and functionality was measured in the same samples. PMID- 21535643 TI - Impact of storage on dark chocolate: texture and polymorphic changes. AB - Chocolate storage is critical to final product quality. Inadequate storage, especially with temperature fluctuations, may lead to rearrangement of triglycerides that make up the bulk of the chocolate matrix; this rearrangement may lead to fat bloom. Bloom is the main cause of quality loss in the chocolate industry. The effect of storage conditions leading to bloom formation on texture and flavor attributes by human and instrumental measures has yet to be reported. Therefore, the impact of storage conditions on the quality of dark chocolate by sensory and instrumental measurements was determined. Dark chocolate was kept under various conditions and analyzed at 0, 4, and 8 wk of storage. Ten members of a descriptive panel analyzed texture and flavor. Instrumental methods included texture analysis, color measurement, lipid polymorphism by X-ray diffraction and differential scanning calorimetry, triglyceride concentration by gas chromatography, and surface properties by atomic force microscopy. Results were treated by analysis of variance, cluster analysis, principal component analysis, and linear partial least squares regression analysis. Chocolate stored 8 wk at high temperature without fluctuations and 4 wk with fluctuations transitioned from form V to VI. Chocolates stored at high temperature with and without fluctuations were harder, more fracturable, more toothpacking, had longer melt time, were less sweet, and had less cream flavor. These samples had rougher surfaces, fewer but larger grains, and a heterogeneous surface. Overall, all stored dark chocolate experienced instrumental or perceptual changes attributed to storage condition. Chocolates stored at high temperature with and without fluctuations were most visually and texturally compromised. Practical Application: Many large chocolate companies do their own "in-house" unpublished research and smaller confectionery facilities do not have the means to conduct their own research. Therefore, this study relating sensory and instrumental data provides published evidence available for application throughout the confectionery industry. PMID- 21535644 TI - The influence of douchi starter cultures on the composition of extractive components, microbiological activity, and sensory properties of fermented fish pastes. AB - Three experiments were conducted to test the hypothesis that douchi cultures could serve as a potential starter for enhancing the quality attributes of fermented silver carp meat. In experiment 1, an active, prefermented douchi culture was incorporated into a fish paste to aid in the fish fermentation (30 d) and facilitate biochemical production of extractive flavor components (PRF). In experiment 2, a fully fermented (30 d) douchi was added to a fish paste and the mixture was fermented for 30 d (PSF). In experiment 3, a fish paste without the douchi culture was fermented for 30 d (CF). Total extracted free amino acids increased by 68.0, 68.6, and 78.8% (P < 0.05) from their initial levels to 2930, 2422, and 1573 mg/mL after 30 d of fermentation for PRF, PSF, and CF fish pastes, respectively, of which, glutamic acid, aspartic acid, alanine, lysine, and leucine were the major amino acids (>100 mg/mL). The concentrations of both formaldehyde-reactive nitrogen and ammonia nitrogen extractives increased significantly (P < 0.05) during fermentation, following the order of PRF > PSF > CF. Low amounts of biogenic amines (<25 ppm) were produced in all samples. Sensory panel evaluation showed that PRF fish pastes had desirable aroma and taste. The douchi-inoculated fermentation could be a novel technique for expanding the utilization, consumption, and the economic values of silver carp meats. Practical Application: Douchi, a fermented soybean product, is a traditional food flavoring ingredient commonly used in China, Japan, and other Asian countries. It is also used in many Chinese cuisines in the United States. On the other hand, fermented seafood made from freshwater fish such as silver carp is known to contain bioactive components believed to promote health. The findings from the present study indicated that douchi as a novel starter can be used to produce fermented silver carp fish pastes with excellent flavor and consumer acceptability. The results may be applicable to other fish species to produce similar fermentation products. PMID- 21535645 TI - Improved consistency in DNPH-mediated pyruvic acid analysis of onion juice by modifying the sample processing order. AB - Onion pungency is commonly measured on absorbency of the wine pink color that results from adding NaOH to the heated mixture of dinitrophenylhydrazine (DNPH) and onion juice. However, significant variation exists among several modifications of the original Schwimmer and Weston (SW) method. We observed differences in pyruvic acid concentrations of 20%-30% between our automated method and a batch method with manual absorbency readings. To determine the source of the differences, we examined the heating time and waiting time of the sample-DNPH mixtures and found no differences. The differences were caused by differential color degradation between the pyruvic acid standards and onion juice samples. These differences could be minimized by reading the absorbency within 1 min of NaOH addition. Using this information, we devised the one-by-one method to control the reading time at 30 s. We compared 5 different analysis methods of 40 onion samples representing 4 onion colors. The automated, high-performance liquid chromatography, and SW methods had similar results, with only about a 5% difference. However, the batch method resulted in differences of approximately 24% as compared to the automated method. The one-by-one method produced very comparable results, within 5%, to the automated method. By modifying the procedure to ensure a uniform and fast reading time, we increased the consistency between the pungency analysis methods. Therefore, fast and uniform absorbency reading time is essential for an accurate measurement of pungency in undiluted onion juice. PMID- 21535646 TI - Detection of volatile spoilage metabolites in fermented cucumbers using nontargeted, comprehensive 2-dimensional gas chromatography-time-of-flight mass spectrometry (GC*GC-TOFMS). AB - A nontargeted, comprehensive 2-dimensional gas chromatography-time-of-flight mass spectrometry (GC*GC-TOFMS) method was developed for the analysis of fermented cucumber volatiles before and after anaerobic spoilage. Volatile compounds extracted by solid-phase microextraction were separated on a polyethylene glycol 1st-dimension column and 14% cyanopropylphenyl 2nd-dimension column. Among 314 components detected in fermented cucumber brine, 199 had peak areas with coefficients of variation below 30%. Peak identifications established by mass spectral library matching were 92% accurate based on 63 authentic standards. Analysis of variance of analytes' log peak areas revealed 33 metabolites changed in concentration after spoilage (P < 0.05), including increases in acetic, propanoic, and butyric acids, n-propyl acetate, several alcohols, and a decrease in furfural. GC*GC-TOFMS with a nontargeted, semi-automated approach to data analysis made possible the separation, identification, and determination of differences in polar volatile components, facilitating the discovery of several metabolites related to fermented cucumber spoilage. Practical Application: An optimized method for the chemical analysis of volatile food components is described and applied to the profiling of volatile compounds in fermented cucumbers, resulting in the identification of 137 components, many of which are being reported for the first time in fermented cucumbers. This nontargeted GC*GC TOFMS method and inclusive data analysis platform facilitated the discovery of several metabolites that were formed or utilized during anaerobic spoilage of fermented cucumbers. Further study of these metabolites will enhance our ability to understand and potentially control the metabolism of spoilage bacteria that can degrade lactic acid under the restrictive environmental conditions present in fermented cucumbers. PMID- 21535647 TI - Characterization and antimicrobial activity of sweetpotato starch-based edible film containing origanum (Thymus capitatus) oil. AB - The objectives of this research were to characterize the mechanical and barrier properties of sweetpotato starch (SPS)-based film (SPSF) and to investigate the antimicrobial activity of SPSF containing origanum oil (OG) against foodborne pathogenic bacteria. The SPSF was fabricated with the SPS extracted from commercial sweetpotato roots. Tensile strength (TS), percent elongation at break (E), and water vapor permeability (WVP) were determined to characterize the SPSF fabricated with selected SPS concentrations, plasticizers, and the concentrations of plasticizers. The agar diffusion assay was used to determine the antimicrobial activity of SPSF containing selective concentrations of OG against Salmonella Enteritidis, Escherichia coli O157:H7, and Listeria monocytogenes. The SPSF fabricated with 2.5% SPS exhibited the greatest TS (4.58 MPa). The TS, E, and WVP of SPSF plasticized with 40% sorbitol exhibited 7.96 MPa, 77.92%, 0.212 ng m/m(2) S Pa, respectively. Therefore, the SPSF fabricated with 2.5% SPS and 40% sorbitol was determined as the optimum film. The antimicrobial activity of the SPSF containing OG increased as the concentration of OG increased. And the SPSF containing OG exhibited greater inhibitory effects against the gram-negative bacteria such as S. Enteritidis and E. coli O157:H7 than the gram-positive L. monocytogenes. The greatest antimicrobial activity was observed against S. Enteritidis when the SPSF containing 2% OG was applied, and the maximum square of zone width was 18.43 mm(2). PMID- 21535648 TI - Phytochemical composition and biological activity of 8 varieties of radish (Raphanus sativus L.) sprouts and mature taproots. AB - Radishes (Raphanus sativus L.) are members of the cruciferous vegetable family that contain many classes of biologically active phytochemicals. This study determined the phytochemical composition of the sprouts and mature taproots of 8 radish varieties. Radish sprouts contained significantly greater concentrations of glucosinolates (3.8-fold) and isothiocyanates (8.2-fold) than the mature radish taproot and also contained significantly greater concentrations of phenolics (on average 6.9-fold). The anthocyanin concentrations of the mature radish taproot were significantly greater than in the sprouts of red, pink, and purple varieties. The primary anthocyanidins present in the red and pink radish varieties were pelargonidin and delphinidin, while the primary anthocyanidin in the purple radish variety was cyanidin. Radish sprouts were between 9- and 59 fold more potent than the corresponding mature taproot at activating the antioxidant response element (ARE) in a stably transfected hepatoma cell line. The ARE activity of the radish sprouts and mature taproots was significantly correlated with the total isothiocyanate concentration of the radishes. Practical Application: Understanding the influence variety and developmental stage has on the biological activity of cruciferous vegetables provides important information for further studies examining the in vivo effects of radish treatment and foundation for providing recommendations to reduce the risk of chronic disease through dietary intervention. PMID- 21535649 TI - Effect of blending and emulsification on thermal behavior, solid fat content, and microstructure properties of palm oil-based margarine fats. AB - The ability of palm oil (PO) to crystallize as beta prime polymorph has made it an attractive option for the production of margarine fat (MF). Palm stearin (PS) expresses similar crystallization behavior and is considered one of the best substitutes of hydrogenated oils due to its capability to impart the required level of plasticity and body to the finished product. Normally, PS is blended with PO to reduce the melting point at body temperature (37 degrees C). Lipid phase, formulated by PO and PS in different ratios were subjected to an emulsification process and the following analyses were done: triacylglycerols, solid fat content (SFC), and thermal behavior. In addition, the microstructure properties, including size and number of crystals, were determined for experimental MFs (EMFs) and commercial MFs (CMFs). Results showed that blending and emulsification at PS levels over 40 wt% significantly changed the physicochemical and microstructure properties of EMF as compared to CMF, resulting in a desirable dipalmitoyl-oleoyl-glycerol content of less than 36.1%. SFC at 37 degrees C, crystal size, crystal number, crystallization, and melting enthalpies (DeltaH) were 15%, 5.37 MUm, 1425 crystal/MUm(2), 17.25 J/g, and 57.69J/g, respectively. All data reported indicate that the formation of granular crystals in MFs was dominated by high-melting triacylglycerol namely dipalmitoyl oleoyl-glycerol, while the small dose of monoacylglycerol that is used as emulsifier slowed crystallization rate. Practical Application: Most of the past studies were focused on thermal behavior of edible oils and some blends of oils and fats. The crystallization of oils and fats are well documented but there is scarce information concerning some mechanism related to crystallization and emulsification. Therefore, this study will help to gather information on the behavior of emulsifier on crystallization regime; also the dominating TAG responsible for primary granular crystal formations, as well as to determine the best level of stearin to impart the required microstructure properties and body to the finished products. PMID- 21535650 TI - Effect of partial substitution of NaCl with KCl on proteolysis of halloumi cheese. AB - The effect of substitution of NaCl with Potassium chloride (KCl) in brine solution on proteolysis of halloumi cheese was investigated. Halloumi cheeses were made and kept in 4 different brine solutions (18% w/w), including only NaCl (HA; control); 3NaCl:1KCl (w/w) (HB); 1NaCl:1KCl (w/w) (HC); 1NaCl:3KCl (w/w) (HD); and stored for 56 d at 4 degrees C. Proteolysis was assessed using water soluble nitrogen (WSN), trichloroacetic acid-soluble nitrogen (TCA-SN), phosphotungstic-soluble nitrogen (PTA-SN), urea polyacrylamide gel electrophoresis (urea-PAGE), and peptide patterns. WSN and TCA-SN contents were similar in all experimental cheeses. Peptide patterns of the pH 4.6 N fraction and urea-PAGE showed no significant difference between halloumi cheeses kept in various NaCl/KCl mixtures (HB, HC, HD) and control (HA). Sodium and potassium contents showed positive correlations with WSN and PTA-SN. There was an inverse correlation between calcium (Ca) contents and WSN and PTA-SN. Correlations between Ca and Na or K were negative at the same salt treatment. PMID- 21535651 TI - Comparative antioxidant and antiproliferative activities of red and white pitayas and their correlation with flavonoid and polyphenol content. AB - Pitaya, commonly known as dragon fruit, has generated considerable consumer interest because of its attractive color and micronutrient content. The present study investigated the total polyphenol and flavonoid content, antioxidant activity against various free radicals, and antiproliferative effect on several cancer cell lines of extracts of flesh and peel of white and red pitayas, collected from Jeju Island, Korea. The total polyphenol and flavonoid contents of 80% methanol extracts of red pitaya peel (RPP) and white pitaya peel (WPP) were approximately 3- and 5-fold higher than those of red pitaya flesh (RPF) and white pitaya flesh (WPF), respectively. Overall, the total flavonoid and polyphenol contents of these extracts were RPP>WPP>RPF>WPF and WPP>RPP>RPF>WPF, respectively. In addition, a study involving nontargeted high-performance liquid chromatography coupled with a photodiode array and electrospray ionization mass spectrometry (HPLC-PDA-ESI-MS) of different pitaya extracts indicated the presence of phenolic, hydroxycinnamic acid derivatives, flavonol glycosides, betacyanin, and its derivatives with a few unknown compounds. Separately, peel extracts of both red and white pitayas showed higher 2,2-diphenyl-1 picrylhydrazyl, hydroxyl, and alkyl radical-scavenging activity than did the corresponding flesh extracts. Both peel extracts also showed stronger antiproliferative activity against AGS and MCF-7 cancer cells than either flesh extract. There was a direct correlation between the phenolic content and antioxidant effect, but no correlation observed between antioxidant activity and antiproliferative activity. These results suggest that the peel of white and red pitaya may be a valuable ingredient in foods and may also be useful in cosmetic, nutraceutical, and pharmaceutical applications. PMID- 21535652 TI - Wild Mediterranean plants as traditional food: a valuable source of antioxidants. AB - Some wild Mediterranean plants used as traditional food are an extraordinary source of antioxidants. We tested some properties of 10 of these herbaceous plants, used in Liguria (Northwest Italy) to prepare a traditional dish known as "prebuggiun." A total of 9 of them were found to have a polyphenol content and antioxidant properties similar or better than those of red chicory and blueberry, which are, in the case of vegetables and fruits, among the richest of antioxidants. Practical Application: In this article, we reported a study on wild plants growing in the Mediterranean area. These herbs have been neglected and this study aimed to revalue these plants because they are an extraordinary source of antioxidants. The increasing demand for natural antioxidants (additives in the food industry too) justifies the search for new sources of natural antioxidants. The revaluation of these plants will be interesting for: (1) consumer health, rediscovering a vegetable source of high antioxidant power; (2) possibility of producing new commercial products, such as food supplements of high quality and low cost; (3) pharmacological applications. PMID- 21535653 TI - Edible mushroom (Flammulina velutipes) extract inhibits melanosis in Kuruma shrimp (Marsupenaeus japonicus). AB - This study compared the potential of an aqueous extract of an edible mushroom (Flammulina velutipes) to prevent melanosis in cultured Kuruma shrimp (Marsupenaeus japonicus) with other antimelanosic compounds in vivo. The mushroom extract contained 9.1 mg/mL ergothioneine (ESH). Immersion of live full-grown shrimp in a 0.5% w/v solution of mushroom extract significantly reduced PPO activity in shrimp hemolymph. In addition, expression of the prophenoloxidase (proPO) gene decreased in hemocytes, suggesting that the extract blocked the activation of the proPO cascade. Consequently, the development of melanosis in the treated shrimp was significantly suppressed during ice storage. Treatment with a 0.05% w/v solution of sodium ascorbate and 4-hexyl-1,3-benzenediol had the same effect. In vitro experiments showed that ESH effectively inhibited PPO activity and activation of the proPO cascade in hemocyte lysate supernatant. This study suggests that in vivo application of F. velutipes mushroom extract is an effective natural alternative to synthetic antimelanosic agents to inhibit postmortem melanosis in shrimp. Practical Application: The extract of an edible mushroom (F. velutipes) containing ergothioneine can be a promising natural alternative to synthetic antimelanosic agents used to prevent postharvest melanosis in shrimp and other crustaceans. Furthermore, utilization of the mushroom trimmings could also help address the growing concerns on the disposal of such agricultural wastes and instead use it into a novel purpose as a source of antimelanosic and antioxidants for food and industrial application. PMID- 21535654 TI - Luminescence spectroscopic observation of singlet oxygen formation in extra virgin olive oil as affected by irradiation light wavelengths, 1,4 diazabicyclo[2.2.2]octane, irradiation time, and oxygen bubbling. AB - A spectrofluorometer equipped with a highly sensitive near-IR InGaAs detector was used for the direct visualization of singlet oxygen emission at 1268 nm in olive oil during light irradiation with various different wavelengths. The virgin olive oil in methylene chloride (20% w/v, oxygen saturated) was irradiated at the 301, 417, 454, 483, and 668 nm, then the emission at 1268 nm, singlet oxygen dimole decaying was observed. The result showed the highest production of (1)O(2) with light irradiation at 417 nm, and followed by at 668 nm in virgin olive oil, indicating that pheophytin a and chlorophyll a were the most responsible components for the production of singlet oxygen. The UV light irradiations at the wavelength of 200, 250, and 300 nm did not induce any detectable luminescence emission at 1268 nm, but 350 nm produced weak emission at 1269 nm. The quantity of (1)O(2) produced with excitation at 350 nm was about 1/6 of that of irradiation at 417 nm. Addition of an efficient (1)O(2) quencher, 1,4 diazabicyclo[2.2.2]octane, in virgin olive oil in methylene chloride greatly decreased the luminescence emission at 1268 nm, confirming the singlet oxygen production in olive oil. Singlet oxygen production was more efficient in oxygen purged virgin olive oil than in oxygen non-purged olive oil. This represents first report on the direct observation of singlet oxygen formation in olive oil as well as in real-food system after visible light illumination. Practical Application: The present results show the positive evidence of the singlet oxygen involvement in rapid oxidative deterioration of virgin olive oil under visible light. This paper also shows the effects of different wavelength of light irradiation on the formation of singlet oxygen in olive oil. The present results would provide important information for the understanding of the mechanism involved in rapid oxidative quality deterioration of virgin olive oil under light illumination and for searching the preventive methods of deterioration of olive oil quality under light. PMID- 21535655 TI - A kinetic study on sesame cake protein hydrolysis by Alcalase. AB - In the present study, the hydrolysis of sesame cake protein was performed by Alcalase, a bacterial protease produced by Bacillus licheniformis, to investigate the reaction kinetics of sesame cake hydrolysis and to determine decay and product inhibition effects for Alcalase. The reactions were carried out for 10 min in 0.1 L of aqueous solutions containing 10, 15, 20, 25, and 30 g protein/L at various temperature and pH values. To determine decay and product inhibition effects for Alcalase, a series of inhibition experiments were conducted with the addition of various amounts of hydrolysate. The reaction kinetics was investigated by initial rate approach. The initial reaction rates were determined from the slopes of the linear models that fitted to the experimental data. The kinetic parameters, K(m) and V(max), were estimated as 41.17 g/L and 9.24 meqv/L x min. The Lineweaver-Burk plots showed that the type of inhibition for Alcalase determined as uncompetitive, and the inhibition constant, K(i), was estimated as 38.24% (hydrolysate/substrate mixture). Practical Application: Plant proteins are increasingly being used as an alternative to proteins from animal sources to perform functional roles in food formulation. Knowledge of the kinetics of the hydrolysis reaction is essential for the optimization of enzymatic protein hydrolysis and for increasing the utilization of plant proteins in food products. Therefore, in the present study, the hydrolysis of sesame cake protein was performed by Alcalase, a bacterial protease produced by B. licheniformis, to investigate the reaction kinetics of sesame cake hydrolysis and to determine decay and product inhibition effects for Alcalase. PMID- 21535656 TI - Molecular weight and structure of water soluble (1->3), (1->4)-beta-glucans affect pasting properties of oat flours. AB - Seven experimental oat lines with high (5.9% to 7.2%), medium (5.3% to 5.5%), and low (4.4%) beta-glucan concentrations were evaluated for the effects of beta glucan molecular weight (MW) and structure on viscosities of oat-flour slurries. The MW of beta-glucans was determined by size-exclusion high-performance liquid chromatography. The structural features of beta-glucans were measured by using fluorophore-assisted capillary-electrophoresis after complete hydrolysis with lichenase. The oat-slurry viscosities were measured on a Rapid Visco Analyser under 4 conditions: (1) without starch (amylolysis, removal of starch by alpha amylase); (2) without beta-glucan (removal of beta-glucan by lichenase); (3) natural action of enzymes (autolysis, in sodium buffer); and (4) inhibition of enzymes (in silver nitrate solution). Excluding one line (regression outlier), significant correlations (P < 0.05) between peak MW of beta-glucan and viscosities of oat slurries were obtained under inhibition. The ratio of degree of polymerization (DP) 3/DP4 negatively correlated with viscosity under amylolysis, autolysis, and inhibition (P < 0.05). The amount of DP >= 5 negatively correlated with pasting final viscosity after beta-glucan removal by lichenase (P < 0.05). Positive correlations (P < 0.05) between the ratio of beta (1->4)/beta-(1->3) linkages and viscosities under autolysis and inhibition were found. Overall, these findings demonstrated that the peak MW, ratio of DP3/DP4, amount of DP >= 5, and ratio of beta-(1->4)/beta-(1->3) linkages of beta-glucans impacted pasting properties of oat-flour slurries. PMID- 21535657 TI - Extraction, partial characterization, and storage stability of beta-glucosidase from propolis. AB - Extraction and assay conditions for beta-glucosidase from propolis were optimized. Highest enzyme activity was obtained in a citric acid-disodium hydrogen phosphate buffer at pH 6.0 with 2.5% insoluble polyvinylpyrrolidone at incubation temperature of 57 degrees C. beta-Glucosidase activities were found in all freshly harvested propolis while beta-glucosidase activities were scarcely present in the randomly bought propolis. Propolis was stored at -20 degrees C and 4 degrees C for 3 mo with almost no loss of beta-glucosidase activity, but at room temperature the activity decreased exponentially with the increase of storage time. These results indicated that the activity of beta-glucosidase could be a candidate for propolis-freshness index. beta-Glucosidase from propolis was capable of hydrolyzing p-nitrophenyl-beta-D-glucoside and p-nitrophenyl-beta-D galactoside, but lacked activity toward p-nitrophenyl-beta-D-glucuronide, p nitrophenyl-beta-D-cellobioside, amygdalin, cellobiose, and gentiobiose. These results were consistent with the hypothesis that flavonoid glucosides were hydrolyzed by beta-glucosidase during propolis collection and processing and provided a possible explanation for why some flavonoid biosides (that is, rutin and isorhamnetin-3-O-rutinoside) exist in propolis. Practical Application: beta Glucosidase activity was detected and partial characterization of the enzyme was determined in propolis. The enzyme activity decreased exponentially with the increase of storage time at room temperature, which suggested that the activity of beta-glucosidase could be regarded as a freshness index of propolis. The research will be useful for studying the chemical constituents of propolis. PMID- 21535658 TI - Control of lipid oxidation in extruded salmon jerky snacks. AB - A shelf-life study was conducted to evaluate the effect of antioxidants on oxidative stability of extruded jerky-style salmon snacks. Deterioration of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) due to lipid oxidation is a major concern for this healthy snack. A control jerky with no added antioxidants and 4 jerkies with antioxidants (rosemary, mixed tocopherols, tertiary butylhydroquinone, and ascorbyl palmitate) added as 0.02% of the lipid content were extruded in duplicate in a Coperion ZSK-25 twin screw extruder. Salmon jerkies from each formulation were placed in 3 mil barrier pouches, flushed with nitrogen, and stored at 35 degrees C and 75% relative humidity. Lipid oxidation was evaluated as by peroxide value and malonaldehyde content. Other chemical analyses included total fatty acid composition, lipid content, moisture, water activity, pH, and salt. Astaxanthin and CIE L*, a*, b* color were also analyzed at 4-wk intervals. Rosemary inhibited peroxide formation better than did other antioxidants at week 8; no treatment inhibited malonaldehyde levels. All jerkies had lower astaxanthin levels after 8 wk, but rosemary-treated jerky had higher pigment concentrations than did the control at weeks 4 and 8. Protection of omega-3 lipids in these extruded jerkies must be improved to offer consumers a convenient source of these healthful lipids. Practical Application: Salmon flesh can be extruded to produce a jerky that provides 410 mg of omega-3 lipids per serving. Natural antioxidants such as rosemary should be added at levels over 0.02% of the lipid content to help control lipid oxidation. Astaxanthin and CIE a* values correlated well with lipid stability and could be used to monitor quality during storage if initial values are known. PMID- 21535659 TI - Application of solid phase-microextraction (SPME) and electronic nose techniques to differentiate volatiles of sesame oils prepared with diverse roasting conditions. AB - Headspace volatiles of sesame oil (SO) from sesame seeds roasted at 9 different conditions were analyzed by a combination of solid phase microextraction (SPME) gas chromatography/mass spectrometry (GC/MS), electronic nose/metal oxide sensors (MOS), and electronic nose/MS. As roasting temperature increased from 213 to 247 degrees C, total headspace volatiles and pyrazines increased significantly (P < 0.05). Pyrazines were major volatiles in SO and furans, thiazoles, aldehydes, and alcohols were also detected. Roasting temperature was more discrimination factor than roasting time for the volatiles in SO through the principal component analysis (PCA) of SPME-GC/MS, electronic nose/MOS, and electronic nose/MS. Electronic nose/MS showed that ion fragment 52, 76, 53, and 51 amu played important roles in discriminating volatiles in SO from roasted sesame seeds, which are the major ion fragments from pyrazines, furans, and furfurals. SO roasted at 213, 230, and 247 degrees C were clearly differentiated from each other on the base of volatile distribution by SPME-GC/MS, electronic nose/MOS, and electronic nose/MS analyses. Practical Application: The results of this study are ready to apply for the discriminating samples using a combinational analysis of volatiles. Not only vegetable oils prepared from roasting process but also any food sample possessing volatiles could be targets for the SPME-GC/MS and electronic nose assays. Contents and types of pyrazines in sesame seed oil could be used as markers to track down the degree of roasting and oxidation during oil preparation. PMID- 21535660 TI - Development of volatile compounds during the manufacture of dry-cured "lacon," a Spanish traditional meat product. AB - Volatile compounds were determined throughout the manufacture of dry-cured "lacon," a traditional dry-salted, and ripened meat product made in the north west of Spain from the foreleg of the pig following a similar process to that of dry-cured ham. Volatiles were extracted by a purge-and-trap method and analyzed by gas chromatographic/mass spectrometry. One hundred and two volatile compounds were identified. In raw material, only 34 volatile compounds were found and at very low levels. The number of volatile compounds increased during processing. The substances identified belonged to several chemical classes: aldehydes (23), alcohols (9), ketones (15), hydrocarbons (37), esters (4), acids (3), furans (4), sulphur compounds (1), chloride compounds (1), and other compounds (4). Results indicated that the most abundant chemical family in flavor at the end of the manufacturing process was aldehydes, followed by hydrocarbons and ketones. Lipids were the most important precursor of flavor compounds of dry-cured "lacon." PMID- 21535661 TI - Cloud-point extraction and reversed-phase high-performance liquid chromatography for the determination of synthetic phenolic antioxidants in edible oils. AB - A cloud-point extraction (CPE) method using Triton X-114 (TX-114) nonionic surfactant was developed for the extraction and preconcentration of propyl gallate (PG), tertiary butyl hydroquinone (TBHQ), butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) from edible oils. The optimum conditions of CPE were 2.5% (v/v) TX-114, 0.5% (w/v) NaCl and 40 min equilibration time at 50 degrees C. The surfactant-rich phase was then analyzed by reversed-phase high performance liquid chromatography with ultraviolet detection at 280 nm, using a gradient mobile phase consisting of methanol and 1.5% (v/v) acetic acid. Under the studied conditions, 4 synthetic phenolic antioxidants (SPAs) were successfully separated within 24 min. The limits of detection (LOD) were 1.9 ng mL(-1) for PG, 11 ng mL(-1) for TBHQ, 2.3 ng mL(-1) for BHA, and 5.9 ng mL(-1) for BHT. Recoveries of the SPAs spiked into edible oil were in the range 81% to 88%. The CPE method was shown to be potentially useful for the preconcentration of the target analytes, with a preconcentration factor of 14. Moreover, the method is simple, has high sensitivity, consumes much less solvent than traditional methods, and is environment-friendly. Practical Application: The method established in this article uses less organic solvent to extract SPAs from edible oils; it is simple, highly sensitive and results in no pollution to the environment. PMID- 21535663 TI - Velocity and temperature field characteristics of water and air during natural convection heating in cans. AB - Presence of headspace during canning is required since an adequate amount allows forming vacuum during the process. Sealing technology may not totally eliminate all entrapped gases, and headspace might affect heat transfer. Not much attention has been given to solve this problem in computational studies, and cans, for example, were mostly assumed to be fully filled with product. Therefore, the objective of this study was to determine velocity and temperature evolution of water and air in cans during heating to evaluate the relevance of headspace in the transport mechanism. For this purpose, canned water samples with a certain headspace were used, and required governing continuity, energy, and momentum equations were solved using a finite volume approach coupled with a volume of fluid element model. Simulation results correlated well with experimental results validating faster heating effects of headspace rather than insulation effects as reported in the literature. The organized velocity motions along the air-water interface were also shown. Practical Application: Canning is a universal and economic method for processing of food products, and presence of adequate headspace is required to form vacuum during sealing of the cans. Since sealing technology may not totally eliminate the entrapped gases, mainly air, headspace might affect heating rates in cans. This study demonstrated the increased heating rates in the presence of headspace in contrast with some studies in the literature. By applying the effect of headspace, required processing time for thermally processed foods can be reduced leading to more rapid processes and lower energy consumptions. PMID- 21535662 TI - Characterization of spray-dried microalgal oil encapsulated in cross-linked sodium caseinate matrix induced by microbial transglutaminase. AB - Sodium caseinate (SC) cross-linked by microbial transglutaminase (MTGase) for encapsulating microalgal oil was investigated. Protein cross-linking was evidenced in the SDS-PAGE graph. The emulsifying properties of SC depended on the cross-linked time with MTGase. The emulsifying activity and stability indexes of SC increased with the cross-linking time of 30 to 90 min (P30 to P90), and then declined with longer cross-linked time of 180 to 420 min (P180 to P420). The P30 to P90 as wall material for microencapsulation was superior to P180 to P420 and control sample. The microcapsules prepared with P30 to P90 showed more than 97% of microencapsulation efficiency in contrast to about 90% with the P180 to P420. During storage, the microcapsules prepared with P30 to P90 exhibited higher oxidative stability as compared with other microcapsules. A sustained release of microalgal oil was observed, and core release was time dependent and affected by cross-linking degree. Results showed that the powdered microalgal oil prepared with P30 to P90 demonstrated enhanced physicochemical properties and oxidative stability. Practical Application: The novel method using cross-linked proteins as wall material induced by microbial transglutaminase in food industry for sensitive ingredients could convert microcapsules into a stable form, which would lead to its more widespread utilization as a kind of food additive. PMID- 21535664 TI - Rheology and microstructure of carrot and tomato emulsions as a result of high pressure homogenization conditions. AB - High-pressure homogenization, as a way to further mechanically disrupt plant cells and cell walls compared to conventional blending, has been applied to thermally treated and comminuted carrot and tomato material in the presence of 5% olive oil. Mixes of both vegetables in a 1:1 ratio were also included. Both the effect of homogenization pressure and the effect of multiple process cycles were studied. The different microstructures generated were linked to different rheological properties analyzed by oscillatory and steady state measurements. The results showed that while carrot tissue requires a high shear input to be disrupted into cells and cell fragments, tomato cells were broken across the cell walls already at moderate shear input, and the nature of the tomato particles changed to amorphous aggregates, probably composed of cell contents and cell wall polymers. All the plant stabilized emulsions generated were stable against creaming under centrifugation. While for tomato a low-pressure multiple cycle and a high-pressure single-cycle process led to comparable microstructures and rheological properties, carrot showed different rheological properties after these treatments linked to differences in particle morphology. Mixes of carrot and tomato showed similar rheological properties after homogenizing in a single or in a split-stream process. Practical Application: Following consumers' demand, the food industry has shown a growing interest in manufacturing products free of gums and stabilizers, which are often perceived as artificial. By tailored processing, fresh plant material could be used to structure food products in a more natural way while increasing their nutritional quality. PMID- 21535665 TI - Radiosensitization of Salmonella spp. and Listeria spp. in ready-to-eat baby spinach leaves. AB - The FDA recently approved irradiation treatment of leafy greens such as spinach up to 1 kGy; however, it is important to reduce the dose required to decontaminate the produce while maintaining its quality. Thus, the objectives of this study were: (1) to assess the radiation sensitivities of Salmonella spp. and Listeria spp. inoculated in ready-to-eat baby spinach leaves under modified atmosphere packaging (MAP) and irradiated using a 1.35-MeV Van de Graff accelerator (the leaves were irradiated both at room temperature and at -5 degrees C); and (2) to understand and optimize the synergistic effect of MAP and irradiation by studying the radiolysis of ozone formation under different temperatures, the effect of dose rate on its formation, and its decomposition. Results showed that increased concentrations of oxygen in the packaging significantly increased the radiation sensitivity of the test organisms, ranging from 7% up to 25% reduction in D(10)-values. In particular, radiosensitization could be effected (P < 0.05) by production of ozone, which increases with increasing dose-rate and oxygen concentration, and reducing temperatures. Radiosensitization was demonstrated for both microorganisms with irradiation of either fresh or frozen (-5 degrees C) baby spinach. These results suggest that low-dose (below 1 kGy) e-beam radiation under modified atmosphere packaging (100% O(2) and N(2):O(2)[1:1]) may be a viable tool for reducing microbial populations or eliminating Salmonella spp. and Listeria spp. from baby spinach. A suggested treatment to achieve a 5-log reduction of the test organisms would be irradiation at room temperature under 100% O(2) atmosphere at a dose level of 0.7 kGy. Practical Application: Decontamination of minimally processed fruits and vegetables from food-borne pathogens presents technical and economical challenges to the produce industry. Internalized microorganisms cannot be eliminated by the current procedure (water-washed or treated with 200-ppm chlorine). The only technology available commercially is ionizing radiation; however, the actual radiation dose required to inactivate pathogens is too high to be tolerated by the product without unwanted changes. This study shows a new approach in using MAP with 100% O(2), which is converted to ozone to radiosensitize pathogens while improving the shelf life of minimally processed fruits and vegetables. The process results in a high level of microorganism inactivation using lower doses than the conventional irradiation treatments. PMID- 21535666 TI - Use of ramping and equilibrium water vapor sorption methods to determine the critical relative humidity at which the glassy to rubbery transition occurs in polydextrose. AB - Recent research has demonstrated that the critical relative humidity (RHc) values, obtained using automatic water vapor sorption instruments, can be used to detect the glassy to rubbery transition. However, reported time dependency of these RHc values suggests that additional research be carried out using equilibrium water vapor sorption methods. Thus, the objectives of this study were to: (1) determine the RHc for amorphous polydextrose at various temperatures using both instrumental (Dynamic Vapor Sorption [DVS] ramping and equilibrium) and saturated salt slurry methods, and (2) compare the RHc values obtained via sorption methods to the glass transition temperature (Tg) values obtained via differential scanning calorimetry (DSC). When plotted as a "glass curve" on a state diagram, the RHc values (plotted as a function of temperature) were found to be similar to the Tg values (plotted as a function of relative humidity). Of the 3 sorption methods employed, at 25 degrees C, the saturated salt slurry exhibited the lowest RHc value (34.3%), followed by the DVS equilibrium method (41.7%), and the DVS ramping method (49.9%). The RHc DVS equilibrium method was closest to the calculated DSC Tg onset RHc value (41.6% at 25 degrees C). These water sorption methods show promise as practical tools for predicting the quality and stability attributes of amorphous materials by being able to routinely determine the location of the glassy to rubbery transition. Future research applying these sorption methods to more complex amorphous food systems is suggested. Practical Application: Despite its extreme usefulness, the Tg, a key element of the Food Polymer Science approach, remains a challenging parameter to routinely measure in amorphous food materials. Recent research has demonstrated that the RHc values can be used to detect the glassy to rubbery transition. However, reported time dependency of these RHc values suggests that additional research be carried out using equilibrium water vapor sorption methods. Therefore, in this research 2 instrumental (DVS ramping and equilibrium) methods and the traditional saturated salt slurry method were used to obtain RHc values, comparing them to DSC obtained Tg values. The water sorption methods show promise as practical tools for predicting the quality and stability attributes of amorphous materials by being able to routinely determine the location of the glassy to rubbery transition. Future research applying these sorption methods to more complex amorphous food systems is suggested. PMID- 21535667 TI - On the formulation design and rheological evaluations of pectin-based functional gels. AB - In the current study, formulation design and development of a novel pectin-based functional gel were investigated. Amidated low methoxyl pectin (ALMP), high methoxyl pectin (HMP), sorbitol, inulin, rebaudioside-A, gardenia, phloridzin, quercetin, apple flavor, and calcium chloride (as its dihydrated salt) were selected as general ingredients. Response surface methodology was applied to design different formulations and to investigate on their experimental responses. The oscillatory tests were carried out in 2 stages with ALMP, HMP, sorbitol, and inulin as the variables of the 1st stage and ALMP and calcium chloride as the variables of the 2nd stage. Results of the 1st stage indicated relatively similar behaviors throughout the frequency range applied for all of the samples studied (true gels). However, magnitudes of the 5 rheological parameters of this study (storage modulus, loss modulus, loss tangent, complex modulus, and complex viscosity) were affected by different variables (ALMP, HMP, inulin, and sorbitol concentrations). Experimental results confirmed that sorbitol could be omitted from the formula while inulin and HMP could be used at their highest levels studied. At the 2nd stage, only 2 formulas indicated a strong gel behavior and other formulas showed typical behaviors of weaker gels or those of the concentrated solutions. At the conclusion of this study, a finished gelled product formula was suggested with the application of the best levels of the ingredients. The resultant gel was found to be set rapidly with no syneresis and showed a potential to be considered as a functional gelled dessert. PMID- 21535668 TI - Production of okara and soy protein concentrates using membrane technology. AB - Microfiltration (MF) membranes with pore sizes of 200 and 450 nm and ultrafiltration (UF) membranes with molecular weight cut off of 50, 100, and 500 kDa were assessed for their ability to eliminate nonprotein substances from okara protein extract in a laboratory cross-flow membrane system. Both MF and UF improved the protein content of okara extract to a similar extent from approximately 68% to approximately 81% owing to the presence of protein in the feed leading to the formation of dynamic layer controlling the performance rather than the actual pore size of membranes. Although normalized flux in MF-450 (117 LMH/MPa) was close to UF-500 (118 LMH/MPa), the latter was selected based on higher average flux (47 LMH) offering the advantage of reduced processing time. Membrane processing of soy extract improved the protein content from 62% to 85% much closer to the target value. However, the final protein content in okara (approximately 80%) did not reach the target value (90%) owing to the greater presence of soluble fibers that were retained by the membrane. Solubility curve of membrane okara protein concentrate (MOPC) showed lower solubility than soy protein concentrate and a commercial isolate in the entire pH range. However, water absorption and fat-binding capacities of MOPC were either superior or comparable while emulsifying properties were in accordance with its solubility. The results of this study showed that okara protein concentrate (80%) could be produced using membrane technology without loss of any true proteins, thus offering value addition to okara, hitherto underutilized. Practical Application: Okara, a byproduct obtained during processing soybean for soymilk, is either underutilized or unutilized in spite of the fact that its protein quality is as good as that of soy milk and tofu. Membrane-processed protein products have been shown to possess superior functional properties compared to conventionally produced protein products. However, the potential of membrane technology has not been exploited for the recovery of okara protein. Our study showed that protein content of okara extract could be improved from approximately 68% to approximately 81% without losing any true proteins in the process. PMID- 21535669 TI - Influence of biopolymer emulsifier type on formation and stability of rice bran oil-in-water emulsions: whey protein, gum arabic, and modified starch. AB - Rice bran oil (RBO) is used in foods, cosmetics, and pharmaceuticals due to its desirable health, flavor, and functional attributes. We investigated the effects of biopolymer emulsifier type and environmental stresses on the stability of RBO emulsions. Oil-in-water emulsions (5% RBO, 10 mM citrate buffer) stabilized by whey protein isolate (WPI), gum arabic (GA), or modified starch (MS) were prepared using high-pressure homogenization. The new MS used had a higher number of octenyl succinic anhydride (OSA) groups per starch molecule than conventional MS. The droplet diameters produced by WPI and MS were considerably smaller (d < 300 nm) than those produced by GA (d > 1000 nm). The influence of pH (3 to 8), ionic strength (0 to 500 mM NaCl), and thermal treatment (30 to 90 degrees C) on the physical stability of the emulsions was examined. Extensive droplet aggregation occurred in WPI-stabilized emulsions around their isoelectric point (4 < pH < 6), at high salt (> 200 mM, pH 7), and at high temperatures (>70 degrees C, pH 7, 150 mM NaCl), which was attributed to changes in electrostatic and hydrophobic interactions between droplets. There was little effect of pH, ionic strength, and temperature on emulsions stabilized by GA or MS, which was attributed to strong steric stabilization. In summary: WPI produced small droplets at low concentrations, but they had poor stability to environmental stress; GA produced large droplets and needed high concentrations, but they had good stability to stress; new MS produced small droplets at low concentrations, with good stability to stress. Practical Application: This study showed that stable rice bran oil-in-water emulsions can be formed using biopolymer emulsifiers. These emulsions could be used to incorporate RBO into a wide range of food products. We compared the relative performance of whey protein, GA, and a new MS at forming and stabilizing the emulsions. The new OSA MS was capable of forming small stable droplets at relatively low concentrations. PMID- 21535670 TI - Optimizing irradiation treatment of shell eggs using simulation. AB - Accurate dose calculation is needed to ensure proper irradiation process control to maintain the freshness of the product. Our objective was to establish the best irradiation treatment for shell eggs taking into account their different components (shell, albumen, yolk). Computer tomography (CT) data were used to generate a 3-D geometry to simulate dose distributions within 1 egg using a radiation transport code (MCNP5). Radiation energies used for simulation were 10 MeV (high-energy) and 1.35 MeV (low-energy) for electron beam, 5 MeV for X-rays, and 1.25 MeV for a gamma-rays source such as Co-60. Low-energy (surface) e-beam simulation indicated that electrons only penetrate up to the thin albumen (0.6 cm). Because of their irregular shape, shell eggs should be irradiated from the side (rather than from top or bottom) for better dose distribution. For high energy e-beam simulation, the entire egg was irradiated and the best results were obtained when the egg was irradiated from both sides, showing a dose uniformity ratio (D(max)/D(min)) of 1.42. X- or gamma-ray source simulation from one side only, the dose uniformity ratio was 3.38 and 3.12, respectively. For surface-only irradiation, a low-energy e-beam provides a uniform dose distribution. To irradiate the entire egg, 2-sided high-energy e-beam sources are required for an efficient treatment. Unless the product rotates in front of the source, the dose uniformity ratio for X-ray or gamma ray is not adequate for shell egg treatment for pathogen decontamination purposes. Practical Application: Proper control of irradiation treatment of foods such as shell eggs is critical to ensure pathogen inactivation while maintaining product freshness. Simulation allows for accurate calculation of dose distribution within the egg to further establish the best irradiation scheme. PMID- 21535671 TI - A review of experimental and modeling techniques to determine properties of biopolymer-based nanocomposites. AB - The nonbiodegradable and nonrenewable nature of plastic packaging has led to a renewed interest in packaging materials based on bio-nanocomposites (biopolymer matrix reinforced with nanoparticles such as layered silicates). One of the reasons for unique properties of bio-nanocomposites is the difference in physics at nanoscale as compared to that at macroscale. Therefore, the effect of nanoscale on the properties of bio-nanocomposites is discussed. Properties of bio nanocomposites are governed by the extent of dispersion of nanoparticles in the biopolymer matrix and interaction between nanoparticles and the biopolymer. Selection of proper technique to determine properties of these bio-nanocomposites is very critical in assessing their performance. Experimental techniques (tensile testing, barrier property measurement, dynamic mechanical analysis, differential scanning calorimetry, thermogravimetric analysis, rheological measurement) to determine the mechanical, barrier, thermal, and rheological properties of bio nanocomposites are discussed in terms of methodology, interpretation of results, and application in studying the properties of bio-nanocomposites. Mathematical modeling plays an important role in predicting the properties of bio nanocomposites and comparing them to the measured properties. This comparison helps in better understanding the mechanism for much improved properties of bio nanocomposites. Mathematical modeling is also helpful in understanding the effects of different parameters on the properties of bio-nanocomposites. Therefore, the article describes mathematical modeling of mechanical and barrier properties of bio-nanocomposites using analytical micromechanics. PMID- 21535672 TI - Effect of blanching in water and sugar solutions on texture and microstructure of sliced carrots. AB - Thermal processing of vegetables has pronounced effects on the cell structure, often negatively affecting the final textural properties of the product. In order to study the effect of thermal processing and the protective effect of sugars on the tissue, sliced carrots were subjected to blanching treatments under different time and temperature combinations both in water and in 4% sugar solutions made of trehalose or maltose. The influence of these process conditions on mass transfer, texture, and microstructure (Cryo-scanning electron microscopy) was thus investigated. The total mass loss of all the samples blanched in water was associated to their cook value (C(100)(18)) except for the overprocessed one (90 degrees C, 10 min) that showed a total mass change significantly lower due to water uptake. The use of trehalose and maltose in the blanching solution reduced the solute loss while increasing the water loss. Microstructural analysis of the differently blanched carrots showed detachments between adjacent cell walls as well as plasmolysis phenomena as the time and temperature of the thermal treatment were increased. A protective effect of both sugars on cell structures was observed mostly in the sample treated at 90 degrees C. At macroscopic level, textural changes upon blanching were observed by a penetration test. As blanching time was increased, samples processed at 75 degrees C showed a hardness increase, while those processed at 90 degrees C showed a hardness decrease. However, both trehalose and maltose did not exert significant effects on the textural properties of blanched carrots when compared with those blanched in water. Practical Application: The results of this study could offer interesting perspectives in the optimization of the heat treatments in order to preserve the quality of semi-finished processed vegetables. Furthermore, the microstructural analysis is nowadays an important investigation tool that could contribute to a deeper understanding of both the effects of processing and ingredients on the vegetable microstructure and its relationship with the changes occurring on the quality properties at macroscopic level. PMID- 21535673 TI - Mass transfer kinetics during osmotic dehydration of pomegranate arils. AB - The mass transfer kinetics during osmotic dehydration of pomegranate arils in osmotic solution of sucrose was studied to increase palatability and shelf life of arils. The freezing of the whole pomegranate at -18 degrees C was carried out prior to osmotic dehydration to increase the permeability of the outer cellular layer of the arils. The osmotic solution concentrations used were 40, 50, 60 degrees Bx, osmotic solution temperatures were 35, 45, 55 degrees C. The fruit to solution ratio was kept 1:4 (w/w) during all the experiments and the process duration varied from 0 to 240 min. Azuara model and Peleg model were the best fitted as compared to other models for water loss and solute gain of pomegranate arils, respectively. Generalized Exponential Model had an excellent fit for water loss ratio and solute gain ratio of pomegranate arils. Effective moisture diffusivity of water as well as solute was estimated using the analytical solution of Fick's law of diffusion. For above conditions of osmotic dehydration, average effective diffusivity of water loss and solute gain varied from 2.718 * 10(-10) to 5.124 * 10(-10) m(2)/s and 1.471 * 10(-10) to 5.147 * 10(-10) m(2)/s, respectively. The final product was successfully utilized in some nutritional formulations such as ice cream and bakery products. PMID- 21535674 TI - Analysis of ingredient functionality and formulation optimization of pasta supplemented with peanut flour. AB - The working peanut pasta formulation range determined from a previous study was used to determine the effects of varying ingredient quantities and processing conditions on the pasta's quality and consumer acceptance. The variables studied were percent peanut flour substituted for durum wheat flour (30%, 40%, and 50%), amount of carrageenan (2.4%, 2.65%, and 2.9%), and drying temperature (60, 74, and 88 degrees C) on the final cooked pasta quality. Properties measured include color, texture, moisture content, and cooking loss. A home-use sensory test was conducted to determine consumer preferences and the optimum range for variables studied. Color lightness values ranged from 43.53 to 65.02, decreasing (becoming darker) with increased peanut flour level and increased drying temperature. Maximum cutting force for cooked pasta ranged from 1.59 N to 3.22 N, with higher values only for pasta dried at 88 degrees C. Moisture content ranged from 57.35% to 69.38%, and values decreased as drying temperature increased. Cooking loss ranged from 5.14% to 7.99%, increasing with higher levels of peanut flour and decreasing with higher levels of carrageenan. When prepared with 30% peanut flour and dried at 60 degrees C, the pasta was lighter in color, higher in moisture, and softer in texture than the varieties dried at higher temperatures and made with higher levels of peanut flour. Response surface analysis of consumer test data revealed that the optimum peanut pasta should contain between 35% and 45% peanut flour and should be dried between 60 and 71 degrees C; however, the pasta with 30% peanut flour was also a popular sample in the "favorite" categories. Practical Application: Most non-gluten protein fortification studies in durum wheat pasta found decreased firmness of dry and cooked pasta, increased cooking loss, increased stickiness, and darker product color when compared to traditional pasta. Partially defatted peanut flour is a versatile food ingredient and has high protein content. Since the lysine content of peanuts is higher than wheat, peanuts can be used to supplement wheat flour in food preparation. This study found by partially replacing wheat flour with peanut flour and with incorporation of hydrocolloid emulsifier, such as carrageenan or xanthan gum, dough viscosity, and pasta firmness significantly improved. Peanut pasta with high protein content and balanced amino acid profile can help support consumers with a healthy lifestyle. PMID- 21535675 TI - Ultrasonic characterization of lactose crystallization in gelatin gels. AB - Ultrasonic velocity and attenuation measurements (2.25 MHz center frequency) were used to follow bulk crystallization of lactose (43% and 46%) from gelatin (1.5% and 3%) gels at 25 degrees C, and compared to turbidity (500 nm) and isothermal calorimetric measurements. Ultrasonic velocity decreased slightly (approximately 0.5%) during crystallization while ultrasonic attenuation was low in the absence of lactose crystals and increased progressively during crystallization. The lag time before the onset of crystallization decreased and the maximum rate of increase in attenuation during crystallization increased with increasing lactose supersaturation but was not affected by gelatin concentration (P < 0.05). Similar results were seen in turbidity and isothermal calorimetric measurements. Ultrasonic attenuation measurements have the potential to measure crystallization kinetics in complex food matrices and to be applied on-line. Practical Application: Many foods contain crystals that affect their taste and texture (for example, lactose crystals can give a grainy defect in ice cream). The formation of crystals is often hard to predict so methods to measure the development of crystals inside real foods are useful. In this study, we show that as lactose crystallizes in a gelatin gel the ultrasonic attenuation--capacity to absorb sound--increases and can be related to the amount of crystals present. Ultrasound is easier to apply in real food processing than the existing methodologies. PMID- 21535676 TI - Thermal and rheological properties of breadfruit starch. AB - The thermal and rheological properties of breadfruit starch were studied using DSC and 2 different rheometers. It was found that the gelatinization temperature of starch with excess moisture content (>70%) was at approximately 75 degrees C. A new endotherm was detected at about 173 degrees C when the moisture content was lower than required for full gelatinization of the starch. A detailed examination revealed that this endotherm represented the melting of amylose-lipid complexes. Breadfruit starch paste exhibited shear-thinning fluid characteristics, and good thermal and pH stability. The setback viscosity of the breadfruit starch was lower than that of potato and corn starches. The rheological properties of the breadfruit starch paste was well described by the Herschel-Bulkley model at a shear rate of 0 to 100 s(-1), where R(2) is greater than 0.95, and it behaved like a yield-pseudoplastic fluid. Both the storage modulus and loss modulus of the paste initially increased sharply, then dropped after reaching the gelatinization peak. Breadfruit starch gel showed both flexibility and viscosity. Suspension with 6% starch content exhibited very weak gel rigidity; however, this increased significantly at starch contents above 20%. PMID- 21535677 TI - Effect of cassava starch coating on quality and shelf life of fresh-cut pineapple (Ananas comosus L. Merril cv "Perola"). AB - This research studied the influence of treatment with ascorbic acid, citric acid, and calcium lactate dipping and cassava starch edible coatings on quality parameters and shelf life of fresh-cut pineapple in slices during 12 d at 5 degrees C. After previous tests, the treatments selected for this study were samples dipped into antibrowning solution with 0.5% of ascorbic acid and 1% of citric acid, with and without 2% of calcium lactate and coated with 2% of cassava starch suspensions. Changes in weight loss, juice leakage, mechanical properties (stress at failure), color parameters (L* and H*), ascorbic acid content, sensory acceptance, and microbial growth of fruits were evaluated. Samples only treated with antibrowning agents were used as control. Edible coatings with and without calcium lactate were efficient in reducing weight loss, juice leakage, and maintaining firmness during storage. However, these samples showed more browning and the ascorbic acid content was reduced. All treatments presented good sensory acceptance (scores above 6). The determining factor of shelf life of pineapple slices was the microbial spoilage. A shelf life of 8 d was obtained for pineapple slices only treated with antibrowning agents. On the other hand, coated samples showed a reduced shelf life of 7 d and higher yeast and mold growth. Thus, although cassava starch coatings were efficient in reducing respiration rate, weight loss, and juice leakage and maintained mechanical properties, these treatments were not able to increase the shelf life of minimally processed pineapple. Practical Application: Pineapple fruit is highly appreciated for its aroma, flavor, and juiciness, but its immediate consumption is difficult. Therefore, pineapple is a potential fruit for minimal processing. However, shelf life of fresh-cut pineapple is very limited by changes in color, texture, appearance, off-flavors, and microbial growth. The use of edible coatings as gas and water vapor barrier and antibrowning agents can extend the storage time and maintain the quality of fresh-cut produce. Cassava starch and alginate coatings are alternative to preserve minimally processed pineapples without changing the quality parameters of fresh fruit. Thus, this study is useful for consumers and fresh-cut industry interested in knowing factors affecting shelf life and quality of fresh-cut pineapple. PMID- 21535678 TI - Effects of argon enriched low-oxygen atmospheres and of high-oxygen atmospheres on the kinetics of polyphenoloxidase (PPO). AB - The reported benefits of enrichment of air atmospheres with argon or oxygen for control of enzymatic browning were investigated by determining the effects of these atmospheres on PPO kinetics. Kinetics of purified apple PPO and a commercially available mushroom PPO were studied in an in vitro model system. Enrichment with argon produced greater inhibitory effects than the current industry practice of enrichment with nitrogen. Km(app) values (mM) for apple PPO in 3%O(2)/97%Ar, 3%O(2)/97%N(2), and air, were 133, 87, and 48, respectively. The data indicate that inhibition by both gases is competitive, and also support the hypothesis that the greater inhibitory effect of argon was proportional to the size of the Van der Waals radius of argon against nitrogen (1.91 A against 1.54 A). Much smaller inhibitory effects were observed in the presence of 80% O(2) (Km(app) 57 mM), and the nature of this inhibition was less clear. The results suggest that the benefits of argon enrichment may be relatively small, and may require critical enzyme, substrate, and gas levels to be successful. However, these benefits may be exploitable commercially in some fresh-cut products, and may allow less anoxic atmospheres to be used. Practical Application: Control of enzymatic browning without sulfites continues to be a challenge in some fresh-cut products. While sporadic benefits of these atmospheres in control of enzymatic browning have been reported, results have been inconsistent in commercial practice. The results suggest that the benefits of argon enrichment may be relatively small, and may require critical enzyme, substrate, and gas levels to be successful. However, these benefits may be exploitable commercially in some fresh-cut products, and allow less anoxic atmospheres to be used. PMID- 21535679 TI - Determining the critical relative humidity at which the glassy to rubbery transition occurs in polydextrose using an automatic water vapor sorption instrument. AB - Similar to an increase in temperature at constant moisture content, water vapor sorption by an amorphous glassy material at constant temperature causes the material to transition into the rubbery state. However, comparatively little research has investigated the measurement of the critical relative humidity (RHc) at which the glass transition occurs at constant temperature. Thus, the central objective of this study was to investigate the relationship between the glass transition temperature (Tg), determined using thermal methods, and the RHc obtained using an automatic water vapor sorption instrument. Dynamic dewpoint isotherms were obtained for amorphous polydextrose from 15 to 40 degrees C. RHc was determined using an optimized 2nd-derivative method; however, 2 simpler RHc determination methods were also tested as a secondary objective. No statistical difference was found between the 3 RHc methods. Differential scanning calorimetry (DSC) Tg values were determined using polydextrose equilibrated from 11.3% to 57.6% RH. Both standard DSC and modulated DSC (MDSC) methods were employed, since some of the polydextrose thermograms exhibited a physical aging peak. Thus, a tertiary objective was to compare Tg values obtained using 3 different methods (DSC first scan, DSC rescan, and MDSC), to determine which method(s) yielded the most accurate Tg values. In general, onset and midpoint DSC first scan and MDSC Tg values were similar, whereas onset and midpoint DSC rescan values were different. State diagrams of RHc and experimental temperature and Tg and %RH were compared. These state diagrams, though obtained via very different methods, showed relatively good agreement, confirming our hypothesis that water vapor sorption isotherms can be used to directly detect the glassy to rubbery transition. Practical Application: The food polymer science (FPS) approach, pioneered by Slade and Levine, is being successfully applied in the food industry for understanding, improving, and developing food processes and products. However, despite its extreme usefulness, the Tg, a key element of the FPS approach, remains a challenging parameter to routinely measure in amorphous food materials, especially complex materials. This research demonstrates that RHc values, obtained at constant temperature using an automatic water vapor sorption instrument, can be used to detect the glassy to rubbery transition and are similar to the Tg values obtained at constant %RH, especially considering the very different approaches of these 2 methods--a transition from surface adsorption to bulk absorption (water vapor sorption) versus a step change in the heat capacity (DSC thermal method). PMID- 21535680 TI - Impact of a pulsed electric field on damage of plant tissues: effects of cell size and tissue electrical conductivity. AB - Efficiency of pulsed electric field (PEF) induced permeabilization at 293 K in selected fruit and vegetable plant tissues (apple, potato, carrot, courgette, orange, and banana) at electric field strength (E) of 400 V.cm(-1), 1000 V.cm(-1) and pulse duration (t(p)) of 1000 MUs was studied experimentally. The mean cell radius () was within 30 to 60 MUm, and the ratio of electrical conductivities of the intact and damaged tissues (sigma(i)/sigma(d)) was within 0.07 to 0.79 for the studied tissues. Electroporation theory predicts higher damage for tissue with larger cells; however, the direct correlation between PEF damage efficiency and size of cell was not always observed. To explain this anomaly, a theoretical Monte Carlo model was developed and checked for parameters typical for potato tissue. The model showed a strong dependence of PEF damage efficiency and power consumption (W) on sigma(i)/sigma(d) ratio. The optimum value of electric field strength (E(opt)) was an increasing function of sigma(i)/sigma(d), and plant tissues with high sigma(i)/sigma(d) ratio (sigma(i)/sigma(d) ~ 1) required application of a rather strong field (for example, E(opt) ~ 3000 V.cm(-1) for sigma(i)/sigma(d) ~ 0.8). However, the PEF treatment at a lower field (E ~ 400 V.cm(-1)) allowed regulation of the selectivity of damage of cells in dependence of their size. A good qualitative correspondence between experimental data and simulation results were observed. PMID- 21535681 TI - Permeabilization of plant tissues by monopolar pulsed electric fields: effect of frequency. AB - Pulsed electric fields (PEF) nonthermally induce cell membrane permeabilization and thereby improve dehydration and extraction efficiencies in food plant materials. Effects of electrical field strength and number of pulses on plant tissue integrity have been studied extensively. Two previous studies on the effect of pulse frequency, however, did not provide a clear view: one study suggested no effect of frequency, while the other found a greater impact on tissue integrity at lower frequency. This study establishes the effect of pulse frequency on integrity of onion tissues. Changes in electrical characteristics, ion leakage, texture parameters, and percent weight loss were quantified for a wide range of pulse frequencies under conditions of fixed field strength and pulse number. Optical microscopy and viable-cell staining provided direct visualization of effects on individual cells. The key finding is that lower frequencies (f < 1 Hz) cause more damage to tissue integrity than higher frequencies (f = 1 to 5000 Hz). Intriguingly, the optical microscopy observations demonstrate that the speed of intracellular convective motion (that is, cytoplasmic streaming) following PEF application is strongly correlated with PEF frequency. We provide the first in situ visualization of the intracellular consequence of PEF at different frequencies in a plant tissue. We hypothesize that cytoplasmic streaming plays a significant role in moving conductive ionic species from permeabilized cells to the intercellular space between plant cells, making subsequent pulses more efficacious at sufficiently low frequencies. The results suggest that decreasing the pulse frequency in PEF may minimize the number of pulses needed to achieve a desired amount of permeabilization, thus lowering the total energy consumption. Practical Application: PEF cause pores to be formed in plant cell membranes, thereby improve moisture removal and potential extraction of desirable components. This study used in situ microscopic evaluation of onion cells, as they were pulsed with electric fields at different frequencies, to determine whether frequency was an important parameter. We illustrate that membranes were more effectively broken at lower frequencies as compared to higher frequencies. Application of this information will allow for improved design of PEF systems for more energy efficient dehydration or extraction of plant tissues. PMID- 21535683 TI - Alginate coating as carrier of oligofructose and inulin and to maintain the quality of fresh-cut apples. AB - The aim of this study was to apply an edible coating containing prebiotics such as oligofructose and inulin to fresh-cut apple wedges. An assessment of the quality, sensory, polyphenol, and volatile attributes of coated and uncoated fresh-cut apple wedges was also undertaken. Fructan analysis showed that all prebiotics remained stable over the 14-d storage period and an intake of 100 g of apple supplies 1 to 3 g of prebiotics. Browning index, firmness, acidity remained stable throughout the 14 d compared to the control while applying prebiotic coatings resulted in an increase in soluble solids. Sensory and visual assessment indicated acceptable quality of apple wedges coated with prebiotics. HPLC analysis showed that levels of polyphenolic compounds were more stable in coated apple wedges (without prebiotic inclusions) than in uncoated control apples. No difference was found between O(2) and CO(2) headspace concentration of coated and uncoated samples. Significant differences (P < 0.001) were found for headspace volatile production between the samples. Most coated samples showed lower volatile production in the headspace than uncoated samples. PMID- 21535682 TI - Bioactivity of mango flesh and peel extracts on peroxisome proliferator-activated receptor gamma [PPARgamma] activation and MCF-7 cell proliferation: fraction and fruit variability. AB - Mangos are a source of bioactive compounds with potential health promoting activity. Biological activities associated with mango fractions were assessed in cell-based assays to develop effective extraction and fractionation methodologies and to define sources of variability. Two techniques were developed for extraction and fractionation of mango fruit peel and flesh. Liquid chromatography mass spectrometry (LC-MS) was used to assess compositional differences between mango fractions in flesh extracts. Many of the extracts were effective in inhibiting the proliferation of human breast cancer cells in vitro. All fractions showed bioactivity in PPAR activation assays, but quantitative responses showed marked fruit-to-fruit variability, highlighting the need to bulk fruit prior to extraction for activity-guided fractionation of bioactive components. This study also suggests that combinations of diverse molecular components may be responsible for cell-level bioactivities from mango fractions, and that purification and activity profiling of individual components may be difficult to relate to whole fruit effects. Practical Application: Although the health benefits of fruits are strongly indicated from studies of diet and disease, it is not known what role individual fruit types can play, particularly for tropical fruits. This study shows that there is a diversity of potentially beneficial bioactivities within the flesh and peel of mango fruit, although fruit-to-fruit variation can be large. The results add to the evidence that the food approach of eating all components of fruits is likely to be more beneficial to health than consuming refined extracts, as the purification process would inevitably remove components with beneficial bioactivities. PMID- 21535684 TI - Antiobesity effects of Undaria lipid capsules prepared with scallop phospholipids. AB - Based on previous research findings, a capsule was developed containing n-3 polyunsaturated fatty acid rich scallop phospholipids (PLs) with an incorporation of brown seaweed (Undaria pinnatifida) lipids (ULs) containing fucoxanthin. The antiobesity effects of the capsules were evaluated with an animal model using 3 wk-old male KK-A(y) mice. Each group received different combinations of lipid (UL, PL, UL + PL, or UL + PL capsule) either incorporated into the diet or into drinking water. Animals were sacrificed after a 4-wk experimental feeding period, and adipose tissues and organs were dissected and weighed. Blood samples were obtained to determine plasma lipid profiles. Uncoupling protein 1 (UCP1) mRNA expression levels were determined by real-time polymerase chain reaction analysis, and UCP1 expression was determined by western blotting analysis. Treatment with either UL alone or UL + PL (capsule) through drinking water resulted in a significant reduction in body weight, compared to the control group. The total white adipose tissue weight of mice fed the UL + PL capsule in drinking water was significantly reduced. Both UCP1 and UCP1 mRNA expression in epididymal fat from mice fed the capsule were significantly higher than in the control group. These results suggest that incorporation of UL into scallop derived PL by means of capsulation may lead to an additive increase in the antiobesity properties of these bioactive lipids. PMID- 21535685 TI - Effect of oryzanol and ferulic acid on the glucose metabolism of mice fed with a high-fat diet. AB - The effects of oryzanol and ferulic acid on the glucose metabolism of high-fat fed mice were investigated. Male C57BL/6N mice were randomly divided into 4 groups: NC group fed with normal control diet; HF group fed with high-fat (17%) diet; HF-O group fed with high-fat diet supplemented with 0.5% oryzanol; and HF FA group fed with high-fat diet supplemented with 0.5% ferulic acid. All animals were allowed free access to the experimental diets and water for 7 wk. At the end of the experimental period, the HF-O and HF-FA groups exhibited significantly lower blood glucose level and glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities, and higher glycogen and insulin concentrations and glucokinase (GK) activity compared with NC and HF groups. The results of this study illustrate that both oryzanol and ferulic acid could reduce the risk of high-fat diet-induced hyperglycemia via regulation of insulin secretion and hepatic glucose-regulating enzyme activities. PMID- 21535686 TI - Adherent properties and macrophage activation ability of 3 strains of lactic acid bacteria. AB - Lactic acid bacteria (LAB) must possess probiotic properties in order to be beneficial to humans and animals. The adherent properties, the acid and bile tolerance as well as the macrophage activation ability of isolated LAB strains were investigated in this study. The adhesion was analyzed following heat, acid, trypsin, and sodium periodate treatments. Production of the cytokine tumor necrosis factor-alpha (TNF-alpha) by RAW 264.7 macrophages was also measured after stimulation with heat-killed LAB strains. The viable strains of Lactobacillus fermentum AF7, L. acidophilus GG5, and L. plantarum BB9 were able to tightly adhere to the intestinal Caco-2 cells. In addition, the GG5 strain was not affected by heating, acid, trypsin, or sodium periodate treatment. However, the adhesion of strains AF7 and BB9 was reduced significantly by heating and trypsin treatment. This result suggested the GG5 and AF7 or BB9 strains had different cell-surface adherent factors. TNF-alpha production by the RAW 264.7 macrophages was induced significantly following stimulation with heat-killed LAB at 10(8) CFU/mL in a dose-dependent fashion. In addition, macrophage activity was similar whether the treatment consisted of live probiotics, or probiotics treated with heat, acid, or trypsin. However, the activity was reduced after treating with sonication. These in vitro results showed that the LAB studied possess probiotic characteristics, such as acid or bile tolerance, adherent capability, and immune activation, and may suggest that these LAB strains retain their probiotic activity as they pass through the gastrointestinal tract. PMID- 21535687 TI - Effects of nutritional and environmental conditions on Salmonella sp. biofilm formation. AB - Biofilm formation on food industry surfaces has important health and economic consequences, since they can serve as a potential source of contamination for food products, which may lead to food spoilage or transmission of diseases. Salmonella sp. is one of the most important foodborne pathogens and several studies have led to the discovery that these bacteria are capable of adhering and forming biofilms on different surfaces. The attachment of bacterial cells is affected by several factors, including the medium in which they are grown, motility, growth phase of the cells, type and properties of the inert material, presence of organic material, temperature, pH, contact time, and so on. This investigation focused on the study and quantification of the effects of temperature (20 to 40 degrees C), pH (4.5 to 7.5), and medium composition (0.5 to 2.5 g/L of peptone) on biofilm formation by Salmonella sp. on stainless steel through surface response modeling. Results highlighted that the target strain was able to adhere on stainless steel, under all the conditions tested. To assess potential differences, the aptitude to biofilm formation (ABF), defined as the time necessary to start adhesion on the surface, was calculated by using the Gompertz equation. This parameter was modeled through a stepwise regression procedure and experimental conditions resulting in the greater ABF were growth in poor media (1.0 to 1.5 g/L of peptone), incubation temperature of about 30 degrees C, pH close to 6.0. Practical Application: The importance of this work lies in its extension of our knowledge about the effect of different environmental conditions on Salmonella adherence to stainless steel food processing equipment, as a better understanding of biofilms may provide valuable pathways for the prevention of biofilm formation. PMID- 21535688 TI - Effect of refrigerated and frozen storage on the survival of Campylobacter jejuni in cooked chicken meat breast. AB - This experimental work aimed to examine the survivability of Campylobacter jejuni in cooked chicken breast under several conditions: storage for 1, 3, and 7 d at refrigerated temperatures (4 degrees C) and for 20 d at frozen temperatures (-18 degrees C). In addition, storage at ambient temperature (26 to 28 degrees C) was involved. Chicken samples were inoculated with a mixed culture of C. jejuni strains (ATCC: 29428 and 33219) of known concentrations (50 and 500 CFU/g). Bacterial cells were recovered and enumerated using standard procedure (Preston method). Bacteria were not detected in the majority of samples stored at ambient temperature. Refrigeration reduced survivals in 95, 90, and 77.5% for samples inoculated with 500 CFU/g and kept for 1, 3, and 7 d, respectively. The maximum reduction reached 1 log(10) cycle for all refrigeration durations. It was observed that bacteria died in 17.5% of samples kept for 7 d at 4 degrees C. However, survivors in samples inoculated with 50 CFU/g were not detected in 50, 65, and 55% of samples kept for 1, 3, and 7 d, respectively. Freezing rendered survivors not detectable in 70% of samples inoculated with 50 CFU/g, while survived viable counts were reduced in 92.5% of samples inoculated with 500 CFU/g. These findings suggested that C. jejuni could be killed or just sublethally injured with or without reduction in viable counts under the investigated storage temperatures, which may indicate the ability of this bacterium to survive in chicken meat stored under refrigerated and frozen conditions. PMID- 21535689 TI - Control of Listeria monocytogenes on cold-smoked salmon using chitosan-based antimicrobial coatings and films. AB - The relatively high incidence of Listeria monocytogenes in ready-to-eat (RTE) products such as cold-smoked salmon is of serious concern. The objective of this study was to evaluate the efficacy of chitosan-based edible coatings and films incorporating 3 generally recognized as safe (GRAS) antimicrobials, sodium lactate (SL), sodium diacetate (SD), and potassium sorbate (PS), against L. monocytogenes on cold-smoked salmon. Salmon samples were surface-inoculated with a 5-strain cocktail of Listeria monocytogenes to a final concentration of 4.4 log CFU/cm(2) and then either coated with chitosan solutions or wrapped with chitosan films with or without the 3 antimicrobials. The samples were then vacuum packaged and stored at 4 degrees C for 30 d. The chitosan coatings with or without the antimicrobials consistently showed higher efficacy against L. monocytogenes than chitosan films having the same compositions. The most effective film treatments, chitosan films containing 1.2% SL/0.25% SD or 2.4% SL, achieved >= 1.3 log reductions of L. monocytogenes during the 30 d of refrigerated storage, while the most effective coating treatments, chitosan coatings containing 1.2% SL/0.25% SD or 0.15% PS/0.125% SD, achieved >= 2.8 log reductions. Practical Application: This study shows that chitosan-based edible coatings and films hold promise and can potentially assist fishery industries in their efforts to control L. monocytogenes. PMID- 21535690 TI - Changes in the composition of the bacterial flora on tray-packaged pork during chilled storage analyzed by PCR-DGGE and real-time PCR. AB - In this study, a polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) was used to investigate the changes in the composition of the bacterial population of tray-packaged pork during chilled storage. Relative quantitative real-time PCR was further used to evaluate the predominant spoilage bacteria obtained from DGGE analysis for their relative amount to the total bacteria in meat samples. DGGE analysis of the V3 and V6-V8 regions of the 16S rRNA gene showed that Pseudomonas were the predominant bacterial species at the end of the monitoring period. Real-time PCR expressed as the DeltaDeltaC(T) method showed that the average 2(-DeltaDeltaC)(T) values increased continually during the storage period from less than 0.001 at day 0 to 4.438 at the end of the monitoring, which indicated that the proportions of Pseudomonas within the total bacteria in meat samples increased. Both methods confirmed that Pseudomonas was the predominant spoilage bacteria. Practical Application: This study uses new techniques to identify bacteria in fresh retail pork and to follow changes in the bacterial population during 12 d refrigerated storage. Pseudomonads were found to increase with storage time, becoming the dominant flora after 12 d. PMID- 21535691 TI - Essential oils as biopreservatives: different methods for the technological application in lettuce leaves. AB - Investigations were carried out to assess the efficiency of 3 essential oils, clove, tea tree, and rosemary, as natural preservatives during the postharvest of lettuce leaves. The effect of different concentration (1 and 0.5 MIC) of plant essential oils applied in 3 forms (spray, immersion, and capsules) was studied on lettuce leaves. The evolution of different microbial populations was evaluated during refrigerated storage. The application forms of the biopreservatives were shown to be an important factor in determining the effectiveness of the essential oils. Clove and tea tree essential oils at 1 MIC and applied embedded in lactose capsules presented a significant inhibition on mesophilic, psicrotrophic, and coliforms populations, while rosemary in none of the 3 technological applications forms exerted inhibitory effect on all microbial populations evaluated. Essential oils (at 0.5 MIC) applied by spray, immersion, and embedded in lactose capsules exerted lower inhibitory effects, with respect to 1 MIC, on the different microbial populations present on lettuce leaves. At the end of the storage (7 d), lettuce samples treated with tea tree, clove, and rosemary (at 1 and 0.5 MIC) by spray were the only organoleptically acceptable. It is concluded that clove and tea tree essential oils can control different microbial population present in lettuce. Practical Application: The exploration of naturally occurring antimicrobials in food preservation receives increasing attention due to consumer awareness of natural food products. Biopreservatives are useful in extending the shelf life of foods, reducing or eliminating pathogenic bacteria and increasing overall quality of food products. The effectiveness of essential oil application in foods is the result of factor associations such as applications forms, concentration applied, the way of action, storage temperatures. The application methods (spray, immersion, and embedded in lactose capsules) and the concentration of essential oils have been shown to be important factors in determining the effectiveness of these biopreservatives. The oil concentrations required to produce a certain level of inhibition in actual foods could be questionable due to the organoleptic impact. However, these novel natural preservatives in combination with other factors in obstacle technologies are an alternative to control the pathogen growth minimizing undesirable changes in organoleptic characteristics. PMID- 21535692 TI - Antimicrobial activity of plant extracts against Salmonella Typhimurium, Escherichia coli O157:H7, and Listeria monocytogenes on fresh lettuce. AB - Plant extracts have been found to be effective in reducing microorganisms. This study evaluated antimicrobial activity of 12 plant extracts against Salmonella Typhimurium, Escherichia coli O157:H7, and Listeria monocytogenes by using a disk diffusion assay, and Syzygium aromaticum (clove) showed the highest inhibitory effect. To investigate the efficacy of clove extract that inactivates pathogens on lettuce, inoculated lettuce with S. Typhimurium, E. coli O157:H7, and L. monocytogenes was treated with diluted clove extracts or distilled water for 0, 1, 3, 5, and 10 min. Clove extract treatment significantly reduced populations of the 3 tested pathogens from the surface of lettuce. Practical Application: This result indicated that clove extract is a useful antimicrobial agent to reduce the microbial level of foodborne pathogens on fresh lettuce. It also might be a natural antimicrobial for reducing or replacing chemical sanitizers in food preservation. PMID- 21535693 TI - Kinetic analysis of E. coli inactivation by high hydrostatic pressure with salts. AB - Inactivation of E. coli by high hydrostatic pressure (250 to 400 MPa) with salts was investigated based on kinetic analysis. At concentrations from 0.074 to 0.145 M and from 0.240 to 0.290 M, both the absolute activation volumes and the preexponential factors were similar in KCl, NaCl, and LiCl solutions, suggesting that pressure inactivation is not salt-specific. On the other hand, in the intermediate salt-concentration range of 0.145 to 0.240 M, inactivation kinetics in the presence of the Na(+) and K(+) differed significantly from those in the presence of Li(+) (P < 0.05). In this concentration range, effect of salt stress and osmotic stress differed significantly from those in concentrations below 0.145 M or above 0.240 M. The cellular response to pressure varies with salt type and salt concentration. These novel findings provide important clues to distinguish between salt stress and osmotic stress in the inactivation of E. coli. PMID- 21535694 TI - Antimicrobial effectiveness of bioactive packaging materials from edible chitosan and casein polymers: assessment on carrot, cheese, and salami. AB - Antimicrobial packaging is one of the most promising active packaging systems for controlling spoilage and pathogenic microorganisms. In this work, the intrinsic antimicrobial properties of chitosan (CH) were combined with the excellent thermoplastic and film-forming properties of sodium caseinate (SC) to prepare SC/CH film-forming solutions and films. The antimicrobial effectiveness of SC, CH, and SC/CH coatings on the native microfloras of cheese, salami, and carrots was evaluated. In vitro assays through the test tube assay indicated that the most significant antimicrobial effect was achieved by CH and SC/CH solutions on carrot and cheese native microfloras. SC film-forming solutions did not exert antimicrobial activity on any of the native microflora studied. SC, CH, and SC/CH films stored in controlled environments showed that the retention of the antimicrobial action was observed until 5-d storage, at 65% relative humidity in both temperatures (10 degrees C and 20 degrees C). In vivo assays were also performed with SC, CH, and SC/CH applied as coatings or wrappers on the 3 food substrates. CH and SC/CH applied at both immersion and wrapper exerted a significant bactericidal action on mesophilic, psychrotrophic, and yeasts and molds counts, showing the 3 microbial populations analyzed a significant reduction (2.0 to 4.5 log CFU/g). An improvement of the bactericidal properties of the CH/SC blend respect to those of the neat CH film is reported. The ionic interaction between both macromolecules enhances its antimicrobial properties. Practical Application: The continuous consumer interest in high quality and food safety, combined with environmental concerns has stimulated the development and study of biodegradable coatings that avoid the use of synthetic materials. Among them, edible coatings, obtained from generally recognized as safe (GRAS) materials, have the potential to reduce weight loss, respiration rate, and improve food appearance and integrity. They can be used in combination with other food preservation techniques in order to extend the effectiveness of the food preservation chain. Moreover, antimicrobial films and coatings have innovated the concept of active packaging and have been developed to reduce, inhibit, or delay the growth of microorganisms on the surface of food in contact with the package. The use of antimicrobials packaging films to control the growth of microorganisms in food can have a significant impact on shelf-life extension and food safety. In addition, antimicrobial films can be prepared by the combination of inherent antimicrobial materials (that is, CH), with good film-forming protein-based ones (that is, SC). Therefore, the objective of this work is to study the performance of 2 biodegradable and edible biopolymers and their combination as natural packages for selected food products. PMID- 21535695 TI - Inactivation of Escherichia coli O157:H7 in moisture-enhanced nonintact beef by pan-broiling or roasting with various cooking appliances set at different temperatures. AB - This study evaluated inactivation of Escherichia coli O157:H7 in moisture enhanced restructured nonintact beef cooked to 65 degrees C using different cooking appliances set at different temperatures. Batches (2 kg) of coarse-ground beef (approximately 5% fat) were mixed with an 8-strain composite (100 mL) of rifampicin-resistant E. coli O157:H7 (6.4 +/- 0.1 log CFU/g) and a solution (100 mL) of sodium chloride plus sodium tripolyphosphate to yield concentrations (wt/wt) of 0.5% and 0.25%, respectively, in the final product. Beef portions of 2.54 cm thickness (15 cm dia) were prepared and were vacuum-packaged and frozen ( 20 degrees C, 42 h). Partially thawed (-2.5 +/- 1.0 degrees C) portions were pan-broiled (Presto electric skillet and Sanyo grill) or roasted (Oster toaster oven and Magic Chef kitchen oven) to 65 degrees C. The appliances were set at, and preheated before cooking to 149 or 204 degrees C (electric skillet), 149 or 218 degrees C (grill), 149 or 232 degrees C (toaster oven), and 149, 204, or 260 degrees C (kitchen oven). Temperatures of appliances and beef samples were monitored with thermocouples, and meat samples were analyzed for surviving microbial populations. In general, the higher the appliance temperature setting, the shorter the time needed to reach 65 degrees C, and the higher the edge and surface temperatures of the meat samples. Temperatures of 204 to 260 degrees C, regardless of appliance, resulted in greater (P < 0.05) pathogen reductions (3.3 to 5.5 log CFU/g) than those obtained at 149 degrees C (1.5 to 2.4 log CFU/g). The highest (P < 0.05) reduction (5.5 log CFU/g) was obtained in samples cooked in the kitchen oven set at 260 degrees C. The results should be useful to the food service industry for selection of effective nonintact beef cooking protocols, and for use in risk assessments for nonintact meat products. Practical Application: Results of this study should be useful for developing cooking recommendations to enhance the safety of nonintact beef products, and for use in risk assessments of such products. PMID- 21535696 TI - Growth inhibition of foodborne pathogens by kimchi prepared with bacteriocin producing starter culture. AB - Kimchi (starter kimchi) was prepared with Leuconostoc citreum GJ7, a bacteriocin producer, with the objective of preventing growth and/or survival of foodborne pathogens such as Escherichia coli O157:H7, Salmonella Typhi, and Staphylococcus aureus. Numbers of the pathogens inoculated to 5.41 to 5.63 log CFU/mL into the filtrate of freshly made starter kimchi remained stable for the first 12 h of incubation at 10 degrees C. Reductions of 2.69, 2.88, and 3.42 log CFU/mL were observed 48 h after inoculation with E. coli O157:H7, S. Typhi, and S. aureus, respectively. Use of the bacteriocin-producing starter culture for kimchi fermentation significantly reduced the numbers of pathogens in the filtrate. Reductions of 3.85, 4.45, and 5.19 log CFU/mL were observed 48 h after inoculation for E. coli O157:H7, S. Typhi, and S. aureus, respectively. Presumably, the antimicrobial activity came from the ingredients of kimchi such as sulfur-containing compounds, low pH (approximately pH 4.5) produced by the conversion of sugars into organic acids and the bacteriocins potentially produced by lactic acid bacteria (LAB), such as kimchicin GJ7. Together, these data suggest that addition of a starter culture capable of producing bacteriocins could serve as a strategy to protect the fermented product from delivering pathogens upon consumption and that the kimchi filtrate itself may be used as a food preservative. Practical Application: The adaptation of the starter fermentation into kimchi induced a faster die off of the pathogens as compared to natural fermentation. The in situ bateriocin-production by Leuc. citreum GJ7 in kimchi would act with antimicrobial kimchi ingredients in a synergistic manner to protect the fermented product from delivering pathogens upon consumption. PMID- 21535697 TI - Differential gene expression of E. coli O157:H7 in ground beef extract compared to tryptic soy broth. AB - E. coli O157:H7 is an important foodborne pathogen, and ground beef is a common vehicle of infection. DNA microarrays have been used for transcriptomic studies of E. coli O157:H7 using laboratory media; however, analysis of gene expression in complex matrices such as food are lacking. This study compared gene expression profiles of E. coli O157:H7 Sakai strain in raw ground beef extract (GBE) and tryptic soy broth (TSB). Total RNA was isolated from GBE and TSB after 2 h of incubation with E. coli O157:H7. Following reverse transcription (RT) of the RNA, labeled cDNA was hybridized to microarrays representing 9608 open reading frames (Operon; Genome Array-Ready Oligo Set) corresponding to 4 genomes of E. coli strains and 3 plasmids. There were 74 up-regulated (genes involved in protein and polysaccharide biosynthesis, transcription factors, membrane transport proteins, and acid shock proteins) and 54 down-regulated (encoding proteins for energy metabolism, biosynthesis of cofactors, transporters of small molecules, and transcription factors and enzymes responsible for protein degradation) genes in E. coli O157:H7 grown in GBE compared to TSB, respectively. Furthermore, compared to incubation in TSB, E. coli O157:H7 incubated in GBE for 2 h showed significantly increased survival when exposed to synthetic gastric fluid, pH 1.5. This study demonstrated that microarray analyses can be performed using complex food matrices, and gene expression of E. coli O157:H7 differs in TSB compared to GBE. The information will be useful for identification of genes that can be employed as potential targets for interventions to control E. coli O157:H7. PMID- 21535698 TI - Inappropriate use of D-values for determining biocidal activity of various antimicrobials. AB - The objective of this study was to investigate the application of established D value calculations to survival curves for various bacteria using the following antimicrobials: acidified sodium chlorite, triclosan, octanoic acid, and sodium hydroxide. D-values can be calculated in 3 ways, a linear regression, an endpoint calculation, or an average of multiple endpoint calculations. The assumption made in calculating a D-value is that the rate of kill follows 1st-order kinetics under specified treatment conditions. Each antimicrobial solution was challenged with approximately 108 CFU/mL of Staphylococcus aureus, Listeria monocytogenes, Salmonella enterica subsp. enterica, and Escherichia coli independently and in triplicate. Test systems were sampled at each of the 10 time points over a period of 7 min, neutralized, pour plated then incubated at 35 degrees C for 48 h (AOAC official method 960.09). Survival curves using the log-transformed data were calculated using regression analysis. Correlations coefficients for all linear regression analyses ranged between 0.291 and 0.982, with 6 of the 16 different treatment systems having an R2 value below 0.7. Methods used for calculating D values should lead to the same result if the survival curve in a given condition is linear. The calculated D-values were different using endpoint analysis (Stumbo method), linear regression, and average of multiple endpoints. This study demonstrates the nonlinearity of inactivation curves of antimicrobials. D-value estimations cannot be reliably used to illustrate biocidal activity in antimicrobial test systems. PMID- 21535699 TI - Analysis of caecal microbiota in rats fed with genetically modified rice by real time quantitative PCR. AB - The effect of genetically modified rice (GMR) on bacterial communities in caecal content was analyzed in a 90-d feeding rat model. A total of 12 groups of rats, which included male and female, were fed with the basal diets containing 30%, 50%, 70% GMR (B(1), B(2), B(3)) or 30%, 50%, 70% non-GMR (D(1), D(2), D(3)). The structure of intestinal microflora was estimated by real-time quantitative PCR (RQ-PCR) based on genus-specific 16s rDNA primers. SYBR Green was used for accurate detection and quantification of 6 kinds of major bacteria shared by humans and rats. According to RQ-PCR, the genome copies of Lactobacillus group from the cecum of male rats fed with 70% non-GMR was higher than those fed with 70% GMR and the relative abundance of Lactobacillus group also higher for group D. This result was in contrast with the E. coli subgroup, which was more numerous in proportion of group B, except D(2) and B(2) for male rats. The Clostridium perfringens subgroup was numerically more abundant in group D than group B of the same level, also except D(2) and B(2) for male rats. These results suggested that GMR had a complex effect on caecal microflora that may be related to the health of the host. PMID- 21535700 TI - Nano-structures of debranched potato starch obtained by isoamylolysis. AB - Starch debranching is fundamental for understanding the structure-function relationships of starch. In this paper, atomic force microscopy (AFM) was used to investigate potato starch by isoamylase [EC 3.2.1.68] debranching at nanometer scale. The hydrolysates were separated by gel-permeation chromatography and the fractions were imaged. In addition to linear structures and branches, coiled structures were revealed in the intermediate hydrolysates. It is concluded that isoamylolysis is very useful for a better understanding of starch structure property relationships. PMID- 21535701 TI - Incorporation of Mg and Ca into nanostructured Fe2O3 improves Fe solubility in dilute acid and sensory characteristics in foods. AB - Iron deficiency is one of the most common micronutrient deficiencies worldwide. Food fortification can be an effective and sustainable strategy to reduce Fe deficiency but selection of iron fortificants remains a challenge. Water-soluble compounds, for example, FeSO(4), usually demonstrate high bioavailability but they often cause unacceptable sensory changes in foods. On the other hand, poorly acid-soluble Fe compounds, for example FePO(4), may cause fewer adverse sensory changes in foods but are usually not well bioavailable since they need to be dissolved in the stomach prior to absorption. The solubility and the bioavailability of poorly acid-soluble Fe compounds can be improved by decreasing their primary particle size and thereby increasing their specific surface area. Here, Fe oxide-based nanostructured compounds with added Mg or Ca were produced by scalable flame aerosol technology. The compounds were characterized by nitrogen adsorption, X-ray diffraction, transmission electron microscopy, and Fe solubility in dilute acid. Sensory properties of the Fe-based compounds were tested in 2 highly reactive, polyphenol-rich food matrices: chocolate milk and fruit yoghurt. The Fe solubility of nanostructured Fe(2)O(3) doped with Mg or Ca was higher than that of pure Fe(2)O(3). Since good solubility in dilute acid was obtained despite the inhomogeneity of the powders, inexpensive precursors, for example Fe- and Ca-nitrates, can be used for their manufacture. Adding Mg or Ca lightened powder color, while sensory changes when added to foods were less pronounced than for FeSO(4). The combination of high Fe solubility and low reactivity in foods makes these flame-made nanostructured compounds promising for food fortification. Practical Application: The nanostructured iron-containing compounds presented here may prove useful for iron fortification of certain foods; they are highly soluble in dilute acid and likely to be well absorbed in the gut but cause less severe color changes than FeSO(4) when added to difficult to-fortify foods. PMID- 21535702 TI - First processing steps and the quality of wild and farmed fish. AB - First processing steps of fish are species-dependent and have common practices for wild and for farmed fish. Fish farming does, however, have certain advantages over traditional fisheries in that the processor can influence postmortem biochemistry and various quality parameters. This review summarizes information about the primary processing of fish based on the influence of catching, slaughtering, bleeding, gutting, washing, and filleting. Recommendations are given for the correct primary processing of fish. PMID- 21535703 TI - Canola proteins for human consumption: extraction, profile, and functional properties. AB - Canola protein isolate has been suggested as an alternative to other proteins for human food use due to a balanced amino acid profile and potential functional properties such as emulsifying, foaming, and gelling abilities. This is, therefore, a review of the studies on the utilization of canola protein in human food, comprising the extraction processes for protein isolates and fractions, the molecular character of the extracted proteins, as well as their food functional properties. A majority of studies were based on proteins extracted from the meal using alkaline solution, presumably due to its high nitrogen yield, followed by those utilizing salt extraction combined with ultrafiltration. Characteristics of canola and its predecessor rapeseed protein fractions such as nitrogen yield, molecular weight profile, isoelectric point, solubility, and thermal properties have been reported and were found to be largely related to the extraction methods. However, very little research has been carried out on the hydrophobicity and structure profiles of the protein extracts that are highly relevant to a proper understanding of food functional properties. Alkaline extracts were generally not very suitable as functional ingredients and contradictory results about many of the measured properties of canola proteins, especially their emulsification tendencies, have also been documented. Further research into improved extraction methods is recommended, as is a more systematic approach to the measurement of desired food functional properties for valid comparison between studies. PMID- 21535704 TI - Food science challenge: translating the dietary guidelines for Americans to bring about real behavior change. AB - Food scientists and nutrition scientists (dietitians and nutrition communicators) are tasked with creating strategies to more closely align the American food supply and the public's diet with the Dietary Guidelines for Americans (DGA). This paper is the result of 2 expert dialogues to address this mandate, which were held in Chicago, Illinois, and Washington, D.C., in early October 2010 between these 2 key scientific audiences. It is an objective that has largely eluded public health experts over the past several decades. This document takes the perspective of food scientists who are tasked with making positive modifications to the food supply, both in innovating and reformulating food products, to respond to both the DGA recommendations, and to consumer desires, needs, and choices. The paper is one of two to emerge from those October 2010 discussions; the other article focuses on the work of dietitians and nutrition communicators in effecting positive dietary change. PMID- 21535705 TI - The role of dietary fiber in the bioaccessibility and bioavailability of fruit and vegetable antioxidants. AB - Antioxidants are abundant compounds primarily found in fresh fruits and vegetables, and evidence for their role in the prevention of degenerative diseases is continuously emerging. However, the bioaccessibility and bioavailability of each compound differs greatly, and the most abundant antioxidants in ingested fruit are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Fruit antioxidants are commonly mixed with different macromolecules such as carbohydrates, lipids, and proteins to form a food matrix. In fruits and vegetables, carbohydrates are the major compounds found, mainly in free and conjugated forms. Dietary fiber, the indigestible cell wall component of plant material, is considered to play an important role in human diet and health. Most studies on antioxidant bioavailability are focused on foods and beverages from which antioxidants are easily released. There is evidence indicating that food microstructure affects the bioaccessibility and bioavailability of several nutrients, referring mostly to antioxidants. Nevertheless, the specific role of dietary fiber in the absorption of antioxidants has not been widely discussed. In this context, the purpose of the present review is to compile and analyze evidence relating to the association between dietary fiber and antioxidants, and the physical and chemical interactions that modulate their release from the chyme in the gastrointestinal tract. PMID- 21535706 TI - Sensory characteristics and consumer acceptability of beef stock containing glutathione Maillard reaction products prepared at various conditions. AB - The sensory characteristics and consumer acceptability of beef soup samples containing 9 types of glutathione Maillard reaction products (GMRPs) were investigated to examine the effects of the GMRPs produced under different reaction conditions on the flavor of the beef soup. The sensory characteristics of the beef stocks were examined using descriptive analysis. In consumer testing, 50 consumers evaluated the overall acceptability and flavor intensities of beef odor, salty taste, beef flavor, and seasoning flavor in the beef soup samples. It was found that the reaction conditions, including sugar type and pH, affected the sensory characteristics of the beef stock containing the GMRPs. The samples containing the GMRPs reacted at pH 7 were characterized with strong beef flavor, chestnut flavor, and cooked rice flavor. However, the GMRP reacted with xylose at pH 7 (XM7) was significantly stronger in beef-related sensory characteristics than the GMRPs reacted with glucose or fructose at pH 7 (GM7 and FM7). The samples containing the GMRPs reacted at pH 3 had strong acid-related attributes whereas the GMRPs reacted at pH 11 exhibited strong sulfur-related attributes and a bitter taste. Overall, the beef soup containing XM7, which was perceived as having a strong beef odor and flavor, was rated the highest consumer acceptability score. This suggests that XM7 has feasibility as a flavor enhancer. To elucidate its effectiveness further, it is required to apply XM7 in various food systems at varying levels and to compare its flavor enhancing effects with other flavor enhancers such as monosodium L-glutamate in future studies. Practical Application: This study characterized sensory attributes of glutathione Maillard reaction products (GMRPs) reacted under various conditions and evaluated their potential as a flavor enhancer by examining consumer acceptability of beef stock containing the GMRPs. This study showed that the GMRP reacted with xylose at pH 7 had strong 71 beef flavor and the highest consumer acceptability score. The results of this study will provide valuable information for understanding sensory aspect of flavors generated by Maillard reaction of GSH and sugars, since most studies on Maillard reaction focused on chemical reactions. Also, the outcome of this study will help flavor and food industries' efforts to develop a new flavor enhancer for use in a variety of processed food products. PMID- 21535707 TI - Refrigerated dough quality: effect of environment and genotypes of hard red spring wheat. AB - Refrigerated dough products use wheat flour as their primary ingredient, so the quality and chemical composition of the flour determine the quality of the final product. Six varieties of hard red spring wheat, grown in 3 locations in Minnesota, U.S.A., were evaluated for use in refrigerated dough products. Total arabinoxylan percentages in the flours ranged from 0.97 to 1.54. Xylanase activity of the flour was measured and ranged from 0.20 to 0.84 mU/g. An important factor in the suitability for refrigerated dough is the syruping during storage. A large amount of variability in dough syruping was observed among the varieties and locations when the extent of dough syruping was measured over a period of 10 d. The mean dough syruping on day 10 ranged from 2.05% to 14.83%. Despite the significant interaction effect of genotype and environment, 2 varieties, Glenn and Oklee, had lower dough syrup formation with greater stability across growing locations and storage days than other varieties. Practical Application: Refrigerated dough production is one of the fastest growing segments of the ready-to-use food industry. Well-formulated and processed refrigerated doughs are practical to consume and should stay fresh during extended periods of storage; thus, maintenance of dough quality during refrigeration is critical. This study was designed to perform the research on genotypic and environmental effects on variations in dough syruping during refrigeration storage of doughs from hard red spring wheats. PMID- 21535708 TI - Wheat bread enrichment with hard-to-cook bean extruded flours: nutritional and acceptance evaluation. AB - This study describes the enrichment of wheat bread with hard-to-cook black bean (BBEF) and cowpea (CEF) extruded flours. Breads containing 10% BBEF and 10% CEF presented increase of, respectively, 9% and 10% in protein content. In addition the fiber content was 2.6 higher in 10% BBEF bread and 2.2 higher in 10% CEF bread in comparison with standard bread. Despite protein and fiber increasing, the energetic value of substituted breads remained unchanged. An increase in the substitution to 15% resulted in decrease of specific volume and density of the breads. Results of sensory analysis to 10% BBEF bread presented overall appearance scores higher than standard bread and overall flavor acceptance very similar to standard. A total of 10% CEF bread presented similar appearance to those standard bread and 73% overall flavor acceptance. It is interesting to point out that distribution of 10% CEF bread overall flavor scores showed 3 distinct levels of consumer's sensibility. Practical Application: Breads enriched with extruded bean flours presented fiber and protein content improved and a very good consumer's acceptance. These results indicate that extruded bean flours constitute ingredients nutritionally and economically viable for technological application in breads elaboration, conferring improvement of nutritional characteristics without changing sensory attributes. PMID- 21535709 TI - Volatile composition of pomegranates from 9 Spanish cultivars using headspace solid phase microextraction. AB - Fruits of 9 Spanish pomegranate cultivars were analyzed for quality parameters, volatile composition, and sensory profile. Volatile compounds were extracted using headspace solid phase micro-extraction (HS-SPME) and analyzed by gas chromatography-mass spectrometry (GC-MS) and flame ionization detector (GC-FID). Twenty-one compounds were found in the headspace of fresh pomegranate juices, including aldehydes, monoterpenes, and alcohols. The most abundant compounds were hexanal, limonene, trans-2-hexenal, and cis-3-hexenol. Fruits from the cultivars Mollar Elche(ME) ME14, ME1, and ME2 presented the highest values of overall liking by the consumer panel; however, their total volatiles concentration were low compared to the other pomegranate cultivars and their color intensity was intermediate. Overall consumer liking of pomegranate juices was mainly associated with the presence of monoterpenes (alpha-terpineol); however, high aldehydes (trans-2-hexenal) concentrations were correlated with poor overall consumer liking. Fruits from sour-sweet cultivars (PTO7 and ADO4) could improve the quality of ME pomegranate juices due to their intense color, high monoterpenes concentrations, and their moderate sourness. Practical Application: The information provided in this study proves that sour-sweet pomegranate fruits can be used in the manufacturing of pomegranate juices and will improve the sensory quality and the volatile composition of this product. PMID- 21535710 TI - Roasting affects phenolic composition and antioxidative activity of hazelnuts (Corylus avellana L.). AB - The potential effect of skin removal and roasting on individual and total phenolic content, and on antioxidative potential of 6 hazelnut cultivars were investigated. HPLC-MS identification of individual phenolics confirmed the presence of 7 flavan-3-ols (catechin, epicatechin, 2 procyanidin dimers, and 3 procyanidin trimers), 3 flavonols (quercetin pentoside, quercetin-3-O-rhamnoside, and myricetin-3-O-rhamnoside), 2 hydrobenzoic acids (gallic acid, protocatechulic acid), and 1 dihydrochalcone (phloretin-2'-O-glucoside). Flavonols were only detected in whole hazelnut kernels. The content of individual phenolics, with the exception of gallic acid, was always highest in whole unroasted hazelnuts and was significantly reduced after skin removal. Similarly, total phenolic content and antioxidative potential decreased when skin was removed. Roasting had a significant negative effect on individual phenolics but not on the total phenolic content and antioxidative potential of kernels. From a health promoting phytochemical composition of hazelnuts the consumption of whole unroasted kernels with skins should be preferential to peeled kernels either roasted or unroasted. Practical Application: A significant reduction in the antioxidative potential and total phenolic content is detected after hazelnut skin removal but not after roasting, suggesting that hazelnut kernels should be consumed whole. In hazelnut skin, many phenolic compounds are located, which are not present in flesh and, therefore, the health properties of hazelnuts are strongly affected by skin removal. Thermal processing and roasting conditions used in this study had a lesser effect on the individual phenolic composition of the kernel and thus roasted and unroasted hazelnuts without skin contain comparable amounts of health promoting compounds. PMID- 21535711 TI - Influence of blanching and grinding process with hot water on beany and non-beany flavor in soymilk. AB - A total of 8 beany odor-active compounds and 4 non-beany aroma-active compounds of traditional soymilk were identified through dynamic headspace dilution analysis (DHDA) and gas chromatography-olfactometry-mass spectrometry (GC-O-MS). To eliminate the beany flavors, soymilk was processed with hot water blanching and grinding for 2, 4, 6, 8, and 10 min with a temperature between 80 and 100 degrees C. A total of 5 beany odor-active compounds and 3 non-beany aroma-active compounds of this soymilk were analyzed by headspace solid phase microextraction (HS-SPME). As a result, lipoxygenase (LOX) activity gradually decreased by hot water treatment with time, and with the decrease of Lox activity, the 5 beany odor-active compounds and 3 non-beany aroma-active compounds were significantly decreased. However, the reduction in non-beany flavor compounds was smaller than for beany odor compounds. Therefore, a balance between beany and non-beany flavors can be reached in soymilk. When the soaked soybeans were blanched and ground with hot water for 2 to 6 min, the LOX activity was between 38% and 57% of the beginning activity. For these processing times, the non-beany compounds could be largely maintained. The ratio of the total peak area of the 3 non-beany aroma compounds and 5 beany flavor compounds was between 0.07 and 0.12, and the sensory scores of the aromas were higher than that of the off-flavors. Practical Application: Beany flavors in soymilk could be reduced with hot water blanching and grinding at temperature above 80 degrees C. However, the treatment of hot water blanching affected the non-beany aromas of soymilk. A suitable blanching and grinding time is necessary to achieve a balance of soymilk flavors. PMID- 21535712 TI - Antioxidant activity, total phenolics content, anthocyanin, and color stability of isotonic model beverages colored with Andes berry (Rubus glaucus Benth) anthocyanin powder. AB - The stability of anthocyanin (ACN) freeze-dried powders from Andes berry (Rubus glaucus Benth) as affected by storage, addition of maltodextrin as a carrier agent, and illumination was evaluated in isotonic model beverages. The ethanolic ACN extract was freeze dried with and without maltodextrin DE 20. Isotonic model beverages were colored with freeze-dried ACN powder (FDA), freeze-dried ACN powder with maltodextrin (MFDA), and red nr 40. Beverages were stored in the dark and under the effect of illumination. Half life of the ACNs, changes in color, total phenolics content (TPC), and antioxidant activity were analyzed for 71 d. Addition of maltodextrin and absence of light stabilized the color of beverages and improved ACN and TPC stability during storage. The antioxidant activity of the beverages was higher when they were colored with MFDA and highly correlated with ACN content. There was no correlation between antioxidant activity and TPC. It is concluded that addition of maltodextrin DE 20 as a carrier agent during freeze-drying improves the color and stability of nutraceutical antioxidants present in Andes berry extract. This suggests a protective enclosing of ACNs within a maltodextrin matrix with a resulting powder that could serve as a supplement or additive to naturally color and to enhance the antioxidant capacity of isotonic beverages. PMID- 21535713 TI - Effect of processing and packaging conditions on quality of refrigerated potato strips. AB - Although sulfiting agents are commonly used in the fresh-cut potato industry, concerns about further regulatory restrictions on sulfite use and consumer fear of sulfite-treated foods have lead to increased research in alternative processing methods. The objective of this study was to determine processing and packaging techniques to achieve a safe and high-quality potato strips with a 4 wk minimum refrigerated shelf life. Potato strips were 1st blanched at low temperature (60 degrees C) in 0.5% CaCl(2) solution for 20 min and then 2nd blanched at high temperature (approximately 98 degrees C) in water for 5 min. Blanched strips were packaged in a near-aseptic environment or treated in-package with gaseous ozone, sodium metabisulfite (SM) solution, or FIT Fruit and Vegetable WashTM (Procter and Gamble Co., Cincinnati, Ohio, U.S.A.) and then stored at 7 +/- 1 degrees C for 28 d. No significant difference was observed in lightness of near-aseptically packaged fries, FIT-treated fries, and frozen fries; however, less color difference was determined in near-aseptically packaged fries and FIT-treated fries compared to frozen fries. Gaseous ozone treatment decreased color quality of potato strips, significantly. The highest after-frying peak force was observed in FIT-treated strips. There was no significant difference in oil absorption of refrigerated and unprocessed strips. These results indicate that either near-aseptic packaging or in-package FIT treatment are the better alternatives for blanched potato strips to extend shelf life and maintain quality. Practical Application: In this study, several processing conditions and packaging methods were evaluated to improve quality and extend shelf life of refrigerated potato strips. Results indicate that the combination of 2-step blanching and near-aseptic packaging was an effective nonchemical processing method, giving 28 d refrigerated shelf life. Similarly, FIT Fruit and Vegetable WashTM proved to be an effective chemical alternative to sulfites and avoids the allergen concern. PMID- 21535714 TI - Boar taint detection using parasitoid biosensors. AB - The off-flavor boar taint associated with the substances skatole, androstenone, and possibly indole represents a significant problem in the pig husbandry industry. Boar taint may occur in meat from uncastrated sexually mature male pigs; consumers commonly show a strong aversion to tainted meat. Consequently, there is a need for rapid methods to sort out and remove tainted carcasses at the slaughterline. We tested the ability of wasps, Microplitis croceipes to perceive and learn the 3 boar taint compounds both individually and in combination using classical conditioning paradigms. We also established the effectiveness and reliability of boar taint odor detection when wasps were used as biosensors in a contained system called the "wasp hound" using a cohort of trained wasps. We found that the wasps are able to successfully learn indole, skatole and to also detect them when presented a 1:1:1 mixture of all 3 compounds. This was shown for both a single hand-manipulated wasp bioassay and when using the "wasp hound" detector device. In contrast, the wasps showed a weak conditioned response to androstenone at the concentration tested. The estimated gas phase concentrations that the wasps perceived during training were in the range of 10 +/- 0.4 pg/s for skatole and indole, and 2 +/- 0.5 pg/s for androstenone. We conclude that use of these wasps as biosensors presents a promising method for boar taint detection and discuss future training paradigms that may improve their responses to compounds such as androstenone. Practical Application: The development of a perceptive, inexpensive, and reliable means of detecting boar taint before the product is presented to sensitive consumers. PMID- 21535715 TI - Gelation properties of spent duck meat surimi-like material produced using acid alkaline solubilization methods. AB - The gelation properties of spent duck meat surimi-like material produced using acid solubilization (ACS) or alkaline solubilization (ALS) were studied and compared with conventionally processed (CON) surimi-like material. The ACS process yielded the highest protein recovery (P < 0.05). The ALS process generated the highest lipid reduction, and the CON process yielded the lowest reduction (P < 0.05). Surimi-like material produced by the CON process had the highest gel strength, salt extractable protein (SEP), and water holding capacity (WHC), followed by materials produced via the ALS and ACS processes and untreated duck meat (P < 0.05). The material produced by the CON process also had the highest cohesiveness, hardness, and gumminess values and the lowest springiness value. Material produced by the ACS and ALS processes had higher whiteness values than untreated duck meat gels and gels produced by the CON method (P < 0.05). Surimi-like material produced using the ACS and CON processes had significantly higher myoglobin removal (P < 0.05) than that produced by the ALS method and untreated duck meat. Among all surimi-like materials, the highest Ca(2+)-ATPase activity was found in conventionally produced gels (P < 0.05). This suggests that protein oxidation was induced by acid-alkaline solubilization. The gels produced by ALS had a significantly lower (P < 0.05) total SH content than the other samples. This result showed that the acid-alkaline solubilization clearly improved gelation and color properties of spent duck and possibly applied for other high fat raw material. PMID- 21535716 TI - Acceptability of complementary foods and breads prepared from zinc-fortified cereal flours among young children and adults in Senegal. AB - We completed a series of studies to assess the acceptability of zinc-fortified, cereal-based complementary foods and zinc-fortified wheat breads. Young children and their caregivers completed acceptability tests with complementary foods fortified with iron only (60 mg iron as ferrous fumarate per kilogram cereal flour), or the same level of iron and zinc (240 mg zinc as zinc oxide per kilogram cereal flour), and the caregivers completed triangle taste tests to compare the same products. A separate group of adult participants completed acceptability tests with wheat breads fortified with iron and folic acid (15 mg iron as ferrous fumarate per kilogram flour and 1.5 mg folic acid per kilogram flour) or the same levels of iron-folic acid and 2 levels of zinc (63 mg zinc or 126 mg zinc as zinc oxide per kilogram flour). Finally, a threshold test was administered to another group of adult participants to compare nonfortified wheat bread to breads fortified with zinc in 80 mg increments ranging from 80 to 400 mg zinc as zinc oxide per kilogram flour. All products were acceptable when compared to non-zinc-fortified equivalents, and were well liked by the respective participants. For the triangle tests, caregivers were not able to detect significant differences between products. For threshold tests, adult participants detected differences in breads prepared from fortified wheat flour at 80 mg, 160 mg, and 320 mg zinc per kilogram flour, but not at 240 mg and 400 mg zinc per kilogram flour, respectively, when compared to nonfortified bread equivalents. Zinc fortification of cereal flours in the ranges of fortification that were tested does not adversely affect the acceptability of complementary foods and breads prepared from these flours. Practical Application: Fortification of staple food products is a low-cost approach to deliver additional micronutrients (including zinc) to large segments of a population. Determining the acceptability of products fortified with zinc is an important step in the development of zinc fortification programs. PMID- 21535717 TI - Retail display evaluation of steaks from select beef strip loins injected with a brine containing 1% ammonium hydroxide. Part 1: Fluid loss, oxidation, color, and microbial plate counts. AB - Select beef loin pairs (n = 10) were injected (10% pump) with brine containing either 4.5% sodium-based phosphates, (CON), or 1% ammonium hydroxide treatment (AHT). Both brines also contained 3.6% NaCl and 1% Rosemary Herbalox. Steaks cut from loins were high oxygen (80% O(2)/20% CO(2)) modified atmosphere packaged, stored 4 d at 4 degrees C in the dark to simulate transportation, and then placed in retail display for 14 d (4 degrees C). On day 0, 7, and 14 of retail display steak properties were measured. Purge from AHT steaks was higher than CON (P < 0.05). Panelists were not able to visually discriminate between AHT and CON steaks through the first 6 d of retail display. After day 6, panelists rated AHT steaks higher for muscle color, percent discoloration, and overall color. Steaks from both treatments started at day 0 retail display with similar total plate counts (P > 0.05). Microbial counts increased more rapidly for AHT steaks than CON steaks (P < 0.05). AHT and CON steaks were not different in terms of lipid oxidation through day 7 retail display. By day 14 retail display CON steaks were above the threshold for consumer perception of oxidized flavors in fresh meat. However, results also indicated the AHT and CON steaks were no longer acceptable by day 14 in terms of color, were questionable in terms of microbial load, and likely were beyond their reasonable shelf life. Based on retail display properties, results indicated 1% AHT could successfully replace 4.5% SP in a meat injection brine. Practical Application: The research in this report compares steaks that have been injected with a commercial brine formulated with SP to steaks that have been injected with a brine, where the SP in the formulation are replaced with 1% AHT. Ammonium hydroxide is an USDA-FSIS approved ingredient in brines injected into fresh meats. Successful replacement of sodium phosphate with ammonium hydroxide would allow processors to significantly reduce the sodium content of injected fresh meat. PMID- 21535718 TI - The influence of sodium on liking and consumption of salty food. AB - Excessive sodium (Na) intake has been linked to development of hypertension and related pathologies. In this study, we assessed if the sodium chloride (NaCl) concentration in a prototypical food influences the liking and intake of that food. In study 1, detection and recognition thresholds for NaCl were assessed, and perceived salt intensity and liking for hash browns of varying sodium concentrations (40 mg, 120 mg, 170 mg, and 220 mg Na/100 g) were compared in a lab setting. In study 2, detection and recognition thresholds for NaCl were assessed in a lab setting, and lunches consisting of hash browns, basic salad, and beverages were consumed freely in a dining setting on 4 separate occasions. Intake and liking ratings for hash browns were recorded after the lunch. In both studies, detection and recognition thresholds for NaCl were not associated with perceived saltiness, liking, or intake of hash browns. Liking and perceived salt taste intensity of hash browns were correlated (r = 0.547 P < 0.01), and in study 1 the 220 mg sodium hash brown was most liked (P < 0.05). In study 2, there was no association between Na concentration and liking or consumption of hash browns. In summary, liking of hash browns were influenced by whether testing was in a lab or dining room environment. In a dining room environment, large decreases (>50%) of sodium content of food were achievable with only minor decrease in liking and no effect on consumption of the food. PMID- 21535719 TI - Automatic nematode detection in cod fillets (Gadus morhua) by transillumination hyperspectral imaging. AB - Traditional quality control of cod fillets is currently made by manual inspection on candling tables. This is a time consuming and expensive operation, contributing to a significant share of the cost with cod fillet production. In this study, transillumination hyperspectral imaging was implemented as a method for automatic nematode detection in cod fillets moving on a conveyer belt, and evaluated on industrially processed cod fillets. An overall detection rate of 58% of all nematodes (N= 922), with detection rate of 71% and 46% for dark and pale nematodes, respectively, is reported. This is comparable, or better, than what is reported for manual inspection under industrial conditions. The false alarm rate was high, with 60% of the fillets reported with one or more false alarms. These results show that the method is promising, but needs further refinements to reduce the false alarm rate and increase the imaging speed from 25 to 400 mm/s. Practical Application: Manual inspection of cod fillets is a huge bottleneck for the industry, accounting for half the production cost with cod fillet processing and reducing the processing speed. Transillumination hyperspectral imaging has the potential to reduce the manual labor required for cod fillet inspection and hence reduce the cost and increase the end product quality. PMID- 21535720 TI - Quality and sensory characteristics of hard red wheat after residential storage for up to 32 y. AB - Samples of hard red wheat packaged for long-term storage, ranging in age from 0 to 32 y, were obtained from donors in residential households. All samples had been stored under nonabusive conditions (7% to 10% moisture, 13 to 27 degrees C). Selected quality parameters of the wheat (moisture, thiamin, free fatty acids, flour extraction rate, bread loaf volume, and bread firmness) and sensory properties of bread made from the stored wheat (aroma, appearance, texture, flavor, overall liking, acceptance for use as part of the regular diet, and acceptance for use in emergency situations) were evaluated. Free fatty acids increased significantly from 0.897 to 11.8 MUmol/g, and flour extraction rate decreased significantly from 76.5% to 69.9% over time. None of the other quality parameters measured (moisture, thiamin, bread loaf volume, and bread firmness) were significantly correlated with wheat storage time. Panelists who frequently or occasionally consume whole wheat bread rated all breads made from the stored wheat with hedonic scores (9-point scale) of at least 6.4 (like slightly to moderately). Consumer ratings of bread texture, flavor, and overall acceptability were negatively correlated with storage time (P < 0.001); however, at least 70% of panelists indicated that they would consume the bread as part of their regular diet even after 32 y of wheat storage, while over 97% would do so in an emergency. These data indicate that wheat maintains nutritional quality and makes acceptable bread when stored up to 32 y at 13 to 27 degrees C and 7% to 10% moisture. Practical Application: Wheat stored for the purposes of disaster relief has the potential of being stored for extremely long periods of time, which may result in undesirable changes in milling and baking quality. Therefore, we tested wheat that had been stored under residential conditions for up to 32 y to determine its functional quality and consumer acceptability. Our results indicate that wheat of low moisture (7% to 10%) packaged in sealed cans and stored for up to 32 y at or below typical room temperature retains quality and can be made into bread that is well accepted by consumers. Thus, whole wheat has good long-term storage stability and can be recommended for emergency food supplies. PMID- 21535721 TI - Retail display evaluation of steaks from select beef strip loins injected with a brine containing 1% ammonium hydroxide. Part 2: Cook yield, tenderness, and sensory attributes. AB - The impact of 2 different brines on the palatability and tenderness of select beef strip loin steaks was evaluated. Brines were differentiated by the type of alkaline agent, 4.5% sodium-based phosphate (control brine; CON) or 1% ammonium hydroxide (ammonium hydroxide treatment; AHT), incorporated into the formula. Injected steaks were placed in high oxygen (80% O(2)/20% CO(2)) MAP, stored 4 d at 4 degrees C in dark storage to simulate transportation, and then placed in retail display. Steaks were selected randomly on day 0, 7, and 14 retail display to measure pH, cook loss, shear force, and sensory characteristics. The pH for AHT steaks (pH 5.96) was slightly higher than CON steaks (pH 5.86; P < 0.05). Cook loss was lower (21%) for CON than AHT steaks (23%). There was neither a treatment nor day effect on tenderness as measured by Warner-Braztler shear force (P > 0.05). Sensory evaluation indicated that on day 0, retail display the initial juiciness, sustained juiciness, tenderness 1st impression, tenderness overall impression, and connective tissue in AHT steaks was not different from CON steaks (P > 0.05). A day effect (decrease) for those sensory parameters was observed only for sustained juiciness (P < 0.05). AHT steaks were rated higher in cooked beef flavor while CON steaks were higher in peppery and salty flavor. There was no difference in soapy and ammonia intensity between treatments. Results indicated that despite lower performance in cook loss the replacement of 4.5% sodium-based phosphate in a meat injection brine with 1% ammonium hydroxide produced a beef loin steak with comparable tenderness and palatability. Practical Application: The research in this study compares steaks that have been injected with a commercial brine formulated with sodium phosphates to steaks that have been injected with a brine where the sodium phosphate in the formulation was replaced with 1% ammonium hydroxide. Ammonium hydroxide is an USDA-FSIS approved ingredient in brines injected into fresh meats. Successful replacement of sodium phosphate with ammonium hydroxide would allow processors to significantly reduce the sodium content of injected fresh meat. PMID- 21535722 TI - Rested and stressed farmed Atlantic cod (Gadus morhua) chilled in ice or slurry and effects on quality. AB - The main objectives of this study were to investigate (1) whether rested harvest of farmed cod was better maintained by chilling with slurry rather than by traditional ice storage, (2) whether chilling with slurry would be a feasible chilling method to assure low core temperatures (<=0 degrees C) at packing of gutted fish, and (3) the effects of superchilling compared with traditional ice on selected quality parameters of cod during storage. In the experiment, seawater slurry at -2.0 +/- 0.3 degrees C was used. Anesthetized (AQUI-STM), percussion stunned, and stressed cod chilled in slurry were compared. Cod stored on ice were used as reference group. The fish were evaluated at the day of slaughter, and after 7 and 14 d of storage according to handling stress (initial muscle pH, muscle twitches, rigor mortis), core temperatures, quality index method, microbial counts, weight changes, salt and water content, water distribution, pH, adenosine triphosphate-degradation products, K-value, water-holding capacity, fillet color, and texture. Chilling cod in slurry was more rapid than chilling in ice. Prechilling (1 d) of cod in slurry before subsequent ice storage resulted in lower quality 7 d postmortem compared with both ice and continuous slurry storage. The potential advantages of superchilling became more prominent after 14 d with lower microbiological activity, better maintenance of freshness (lower total quality index scores and lower K-values) compared with fish stored on ice. A drawback with slurry-stored fish was that cloudy eyes developed earlier, in addition to weight gain and salt uptake compared to ice-stored fish. Practical Application: Chilling is an essential operation in any fish-processing plant. This manuscript addresses different applications of slurry ice in the processing and storage of Atlantic cod. Cod quality was assessed after 7 and 14 d of iced and superchilled storage. PMID- 21535723 TI - Assessment of fumonisins B1 and B2 levels in commercial maize-based food products by liquid chromatography with fluorimetric detection and postcolumn chemical derivatization. AB - The occurrence of the fumonisins B(1) and B(2) in maize-based food products marketed in Italy was examined. A simply and reliable chromatographic method with fluorimetric detection and postcolumn o-phtalaldehyde derivatization was used for a monitoring of 100 samples (8 flours, 21 corn-meal, 16 snacks, 7 maize samples, 13 gluten-free products, and 35 corn-flakes) bought in local supermarkets during the years 2008 and 2009. The presence of both fumonisins B(1) and B(2), at a concentration higher than 15 MUg/kg, was observed in all samples of corn-meal and maize-flour, in 75% of snacks, in 57% of maize samples, in 54% of gluten-free products, and in 29% of corn-flakes. A total of 7 samples including 4 corn-meals, 2 maize-flours, and 1 maize showed a value exceeding the maximum level fixed in the Regulation 1126/2007/EC; no positive sample was observed in corn-flakes, snacks, and gluten-free foods. Fumonisins contamination, on the whole range of maize-based food products analyzed, emphasizes the need of improve agricultural practices, and increase official control and monitoring studies. PMID- 21535724 TI - Evaluation of chlorine dioxide gas residues on selected food produce. AB - In recent years, the consumption of fresh fruits and vegetables has greatly increased, and so has its association with contamination of several foodborne pathogens (Listeria, Salmonella, and Escherichia coli). Hence, there is a need to investigate effective sanitizer systems for produce decontamination. Chlorine dioxide (ClO(2)), a strong oxidizing gas with broad spectrum and sanitizing properties, has previously been studied for use on selected fruits and vegetables. ClO(2) gas treatments show great potential for surface pathogen reduction; however its use from a residue safety standpoint has yet to be assessed. Thus, the objective of this study was to evaluate residues of ClO(2), chlorite, chlorate, and chloride on selected fresh produce surfaces after treatment with ClO(2) gas. A rinse procedure was used and water samples were analyzed by N, N-diethyl-p-phenylenediamine and ion chromatography method (300.0). Seven different foods--tomatoes, oranges, apples, strawberries, lettuce, alfalfa sprouts, and cantaloupe--were analyzed after ClO(2) treatment for surface residues. Very low residues were detectable for all the food products except lettuce and alfalfa sprouts, where the measured concentrations were significantly higher. Chlorine dioxide technology leaves minimal to no detectable chemical residues in several food products, thus result in no significant risks to consumers. Practical Application: Potential for chlorine dioxide gas treatments as an effective pathogen inactivation technology to produce with minimal risk for consumers. PMID- 21535725 TI - Detection of warfare agents in liquid foods using the brine shrimp lethality assay. AB - The brine shrimp lethality assay (BSLA) was used for rapid and non-specific detection of biological and chemical warfare agents at concentrations considerably below that which will cause harm to humans. Warfare agents detected include T-2 toxin, trimethylsilyl cyanide, and commercially available pesticides such as dichlorvos, diazinon, dursban, malathion, and parathion. The assay was performed by introducing 50 MUL of milk or orange juice contaminated with each analyte into vials containing 10 freshly hatched brine shrimp nauplii in seawater. This was incubated at 28 degrees C for 24 h, after which mortality was determined. Mortality was converted to probits and the LC(50) was determined for each analyte by plotting probits of mortality against analyte concentration (log(10)). Our findings were the following: (1) the lethal effects of toxins dissolved in milk were observed, with T-2 toxin being the most lethal and malathion being the least, (2) except for parathion, the dosage (based on LC(50)) of analyte in a cup of milk (200 mL) consumed by a 6-y-old (20 kg) was less than the respective published rat LD(50) values, and (3) the BSLA was only suitable for detecting toxins dissolved in orange juice if incubation time was reduced to 6 h. Our results support the application of the BSLA for routine, rapid, and non specific prescreening of liquid foods for possible sabotage by an employee or an intentional bioterrorist act. Practical Application: The findings of this study strongly indicate that the brine shrimp lethality assay can be adapted for nonspecific detection of warfare agents or toxins in food at any point during food production and distribution. PMID- 21535726 TI - Moisture-pressure combination treatments for cyanide reduction in grated cassava. AB - Several cyanide-associated health disorders have been linked with frequent consumption of mildly toxic cassava (Manihot esculenta crantz) products in individuals on a low-protein diet. Production of bread from cassava often involves application of prolonged physical pressure (pressing) to the freshly grated root for several hours. This study aimed to determine effects of pressure and wetting on grated cassava. Six treatments were applied: confining pressure for 12 h, wetting for 4 h at 25 degrees C, 2 h at 25 degrees C, 2 h at 40 degrees C, and 2 h at 50 degrees C, or each of the above followed by pressure for 12 h. Treatments released cyanide from samples in the order: 2-h wet at 50 degrees C + pressing >4-h wet at 25 degrees C + pressing = 2-h wet at 40 degrees C + pressing >2-h wet at 25 degrees C + pressing = 4-h wet at 25 degrees C >12-h pressing. Wetting for 2 h at 50 degrees C followed by pressure for 12 h reduced cyanide levels by at least 20% more than that of any other treatment. The combination of moisture and pressure enhanced the contact time between linamarin and linamarase to increase the release of hydrogen cyanide. PMID- 21535727 TI - Toxin genes profiles and toxin production ability of Bacillus cereus isolated from clinical and food samples. AB - Bacillus cereus can cause diarrheal and emetic type of food poisoning but little study has been done on the main toxins of food poisoning caused by B. cereus in Korea. The objective of this study is to characterize the toxin gene profiles and toxin-producing ability of 120 B. cereus isolates from clinical and food samples in Korea. The detection rate of nheABC, hblCDA, entFM, and cytK enterotoxin gene among all B. cereus strains was 94.2, 90.0, 65.8, and 52.5%, respectively. The ces gene encoding emetic toxin was not detected in all strains. Bacillus cereus strains carried at least 1 of the 8 enterotoxin genes were classified into 12 groups according to the presence or absence of 8 virulence genes. The 3 major patterns, I (nheABC, hblCDA, entFM, and cytK gene), II (nheABC, hblCDA and entFM gene), and VI (nheABC and hblCDA gene), accounted for 79.2% of all strains (95 out of 120 B. cereus isolates). Non-hemolytic enterotoxin (NHE) and hemolysin BL (HBL) enterotoxins were produced by 107 and 100 strains, respectively. Our finding revealed that NHE and HBL enterotoxins encoded by nhe and hbl genes were the major toxins among B. cereus tested in this study and enterotoxic type of B. cereus was predominant in Korea. PMID- 21535729 TI - Safety evaluations on ethanolic extract of red cabbage (Brassica oleracea L.) in mice. AB - The present study has carried out safety evaluations on an ethanolic extract of red cabbage (RC) leaves in terms of acute and subchronic oral toxicity tests as per Organisation for Economic Cooperation and Development (OECD) guidelines in Swiss albino mice. Single-dose administration of RC extract (1000, 2000, 3000, 4000, or 5000 mg/kg body weight) to Swiss albino mice did not manifest toxicity or any significant adverse behavioral alterations. Chronic administration of RC extract (1000, 2000, and 3000 mg/kg body weight) for 28 d also did not register any significant alterations in fluid intake, organ weights, plasma lipid profile, plasma creatine kinase-MB, lactate dehydrogenase, aspartate transaminase, alanine transaminase, creatinine, electrolytes, and calcium levels, and the total blood count showed a nonsignificant change. However, significant reduction in body weight gain, food intake, red blood cell count, and hemoglobin content along with higher alkaline phosphatase, bilirubin, and urea levels was observed in mice treated with 3000 mg/kg body weight for 28 d. Since there was no mortality up to a dose of 5000 mg/kg body weight, 50% lethal dose (LD(50)) could not be determined, and hence, it can be assumed that, LD(50) of RC extract is >5000 mg/kg. No observable adverse effect level dose of the RC extract was found to be 2000 mg/kg body weight. Hence, consumption of RC extract for various medicinal purposes is safe. Practical Application: RC is a popularly consumed foodstuff that has been ubiquitously reported to exert medicinal properties. It is mandatory to understand the highest permissible consumption limit of any food supplement to avoid toxicity. This study establishes the safe dose of RC. These results can be of relevance for the scientific fraternity as well as laymen who consume this vegetable or its phytochemical preparation. PMID- 21535728 TI - Effect of diallyl trisulfide on the pharmacokinetics of nifedipine in rats. AB - This study aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic, on the pharmacokinetics of nifedipine. Pharmacokinetic parameters of nifedipine were determined in rats following an oral gavage (3 mg/kg) or intravenous administration (0.75 mg/kg) of nifedipine with co-administration of DATS (20 mg/kg) and long-term pretreatment of DATS (20 mg/kg/d for 15 consecutive days). Compared to the control groups, higher C(max) and AUC(0-24 h) were observed for oral gavage of nifedipine after short-term and long-term pretreatment of DATS, whereas those for intravenous nifedipine were little changed. The oral bioavailabilities of nifedipine were remarkably enhanced via the concomitant use of DATS. In conclusion, DATS increased the oral exposure of nifedipine in rats likely by the modification of intestinal metabolism of nifedipine, indicating that combined use of DATS or DATS-containing supplement with nifedipine may require caution because high plasma concentrations may lead to an undesired toxicity of this agent. Practical Application: Patients suffering from cardiovascular disease should take caution in combined use of DATS or DATS rich garlic supplement with nifedipine because long-term treatment of DATS could lead high plasma concentrations of nifedipine. PMID- 21535730 TI - Influence of dietary advanced glycation end products on wound healing in nondiabetic mice. AB - The present study was to determine advanced glycation end products (AGEs) in foods from different processes, and the influence of dietary AGEs on wound healing in nondiabetic mice. AGEs mixtures were extracted from local fast foods and foods prepared in lab. A BSA-AGEs mixture made by incubating glucose with bovine serum albumin (BSA) was used as a positive control. Burns were made on the skin of mice. The results showed that foods processed by high temperatures generated higher dietary AGEs. Nonwounded mice showed no observable adverse response to high dietary AGEs. However, high dietary AGEs caused severe inflammatory responses in wounded mice. The plasma level of high mobility group box 1 (HMGB1) and its mRNA in white blood cells were found to be significantly higher in the wounded mice fed with high dietary AGEs than others. We conclude that dietary AGEs worsen inflammation and delay wound healing in nondiabetic burned mice, which might be mediated by HMGB1. PMID- 21535734 TI - Phytochemicals and antioxidant activity of fruits and leaves of paprika (Capsicum Annuum L., var. special) cultivated in Korea. AB - The phytochemical composition of carotenoids, tocopherols, free sugars, organic acids, L-ascorbic acid, capsaicinoids, and flavonoids in green and red paprika (GP and RP), and paprika leaves (PL) cultivated in Korea were analyzed. The ethanolic extracts of GP, RP, and PL were obtained with 80% ethanol, and their antioxidative activities were determined by measuring their ABTS and DPPH radical scavenging activities. RP showed the highest contents of capsanthin (58.33 +/- 3.91 mg/100 g dry weight) and L-ascorbic acid (1987.25 +/- 19.64 mg/100 g dry weight), and main compounds of PL were lutein, chlorophyll, and gamma-tocopherol (96.91 +/- 14.58, 2136.71 +/- 21.11, and 723.49 +/- 54.10 mg/100 g dry weight, respectively). RP showed the strongest antioxidant activity (IC(50) = 55.23 +/- 6.77 MUg/mL in a 2, 2'-azino-di-[3-ethylbenzthiazoline sulphonate] assay and 150.40 +/- 8.07 MUg/mL in a 2, 2-diphenyl-2-picrylhydrazyl assay), and the antioxidant activity of PL was higher than beta-carotene but lower than RP. The results indicate that the amounts of capsanthin and L-ascorbic acid in RP correlate well with antioxidant activity. PL, which has various phytochemicals such as lutein, chlorophyll, and gamma-tocopherol, might be used in nutraceuticals and pharmaceuticals for improving human health. PMID- 21535735 TI - Volatile compounds in light, medium, and dark black walnut and their influence on the sensory aromatic profile. AB - Light, medium, and dark colored kernels from 3 different cultivars (Emma K, Kwik Krop, and Sparks 127) and one wild species of black walnut were studied for their aroma volatiles. Solid-phase microextraction-gas chromatography-mass spectrometry was used to determine the aromatic compounds present in the headspace of these samples. Partial least square regression was used to correlate the instrumental aromatic data with the sensory responses, obtained in a previous study, for the same samples. Thirty-four aromatic compounds were found in the black walnut cultivars, highlighting among them the presence of 14 esters. Although more than 50% of the total concentration of volatile compounds, esters were not important compounds in determining the differences in the sensory aromatic profiles of the 3 colors of the nuts. As a general trend, the concentration of total volatile compounds was always significantly higher in light black walnuts than in the medium colored samples; medium colored samples had higher volatile content than the dark black walnuts. The presence of hexanal was related to rancid and acrid aromas and was determined to differentiate the dark black walnuts from the medium and light colored samples. PRACTICAL APPLICATION: The data presented in this article will help understand the aromatic differences between light, medium, and dark colored kernels of domestic and wild black walnut. The aromatic profile of these nuts, not studied until this moment, can be used as a model to develop flavorings and new products by the food industries. PMID- 21535736 TI - Beer volatile analysis: optimization of HS/SPME coupled to GC/MS/FID. AB - A powerful technique was developed for the identification and quantification of 9 volatile compounds of beer, using headspace solid phase micro-extraction (HS/SPME) and gas chromatograph coupled to a mass spectrometer and a flame ionization detector (GC/MS/FID). Optimized parameters included type of fiber, desorption time, and exposure time. Optimization was achieved with standard solutions of the target compounds. All samples were analyzed in triplicate. An exposure time of 45 min with PDMS fiber in the sample headspace was enough to reach equilibrium of the phases. A desorption time of 15 min in the gas chromatograph injector was enough for the fiber to desorb the target compounds. It was found that less polar compounds were more readily absorbed by the fiber (for example, isoamyl acetate) than more polar compounds (for example, acetaldehyde), under the extraction conditions, due to the nature of the fiber. Extraction conditions are important criteria to perform a good quantification of volatile compounds. Concentrations found in sampled beer, for the compounds of interest, ranged between 0.32 and 41.7 ppm. Results show that the reproducibility of the technique depends on the compounds. Esters have higher values (RSD mean value 5.05%) than higher alcohols (RSD mean value 2.5%) and aldehydes (RSD 3.7%). The simplicity of the validated methodology enables its use as a regular quality control procedure for beer flavor analysis. PRACTICAL APPLICATION: This study describes a technique successfully used to identify and quantify volatiles of interest in beer that can be used for quality control purposes under normal brewery production conditions. The technique uses a gas chromatograph coupled to a mass spectrometer with a flame ionization detector. PMID- 21535737 TI - Hot and cold water infusion aroma profiles of Hibiscus sabdariffa: fresh compared with dried. AB - Calyxes from the Roselle plant (Hibiscus sabdariffa L.) were used to prepare cold (22 degrees C for 4 h) and hot (98 degrees C for 16 min) infusions/teas from both fresh and dried forms. Aroma volatiles were extracted using static headspace SPME and analyzed using GC-MS and GC-O with 2 different columns (DB-5 and DB Wax). Totals of 28, 25, 17, and 16 volatiles were identified using GC-MS in the dried hot extract (DHE), dried cold extract (DCE), fresh hot extract (FHE), and fresh cold extract (FCE) samples, respectively. In terms of total GC-MS peak areas DHE ? DCE > FHE ? FCE. Nonanal, decanal, octanal, and 1-octen-3-ol were among the major volatiles in all 4 beverage types. Thirteen volatiles were common to all 4 teas. Furfural and 5-methyl furfural were detected only in dried hibiscus beverages whereas linalool and 2-ethyl-1-hexanol were detected only in beverages from fresh hibiscus. In terms of aroma active volatiles, 17, 16, 13, and 10 aroma active volatiles were detected for DHE, DCE, FHE, and FCE samples, respectively. The most intense aroma volatiles were 1-octen-3-one and nonanal with a group of 4 aldehydes and 3 ketones common to all samples. Dried samples contained dramatically higher levels of lipid oxidation products such as hexanal, nonanal, and decanal. In fresh hibiscus extracts, linalool (floral, citrus) and octanal (lemon, citrus) were among the highest intensity aroma compounds but linalool was not detected in any of the dried hibiscus extracts. PRACTICAL APPLICATION: Hibiscus teas/infusions are one of the highest volume specialty botanical products in international commerce. The beverage is consumed for both sensory pleasure and health attributes and is prepared a number of ways throughout the world. Although color and taste attributes have been examined, little information is known about its aroma volatiles and no other study has compared extractions from both fresh and dried as well as extraction temperature differences. This is also, apparently, the first study to identify the aroma active volatiles in hibiscus beverages using GC-olfactometry. Manufacturers and consumers will now have a better understanding of why hibiscus teas prepared in different ways from either fresh or dried forms have a different flavor quality and intensity. PMID- 21535738 TI - Preparation and mechanical properties of edible rapeseed protein films. AB - Edible films were manufactured from rapeseed oil extraction residues. To prepare rapeseed protein (RP) films, various concentrations of plasticizers and emulsifiers were incorporated into the preparation of a film-forming solution. The optimal conditions for the preparation of the RP film were 2% sorbitol/0.5% sucrose as plasticizer and 1.5% polysorbate 20 as an emulsifier. In addition, RP blend films were prepared. Gelidium corneum or gelatin was added to improve the physical properties of the RP film, and the highest tensile strength value of the films was 53.45 MPa for the 3% RP/4% gelatin film. Our results suggest that the RP-gelatin blend film is suitable for applications in food packaging. PRACTICAL APPLICATION: Edible RP films prepared in the present investigation can be applied in food packaging. PMID- 21535739 TI - Influence of the process, season, and origin on volatile composition and antioxidant activity of Juniperus phoenicea L. leaves essential oils. AB - Essential oils of Juniperus phoenicea L. leaves cultivated in 3 regions, Korbos, Matmata, and Tabarka of Tunisia were obtained by hydrodistillation (HD), steam distillation (SD), and Soxhlet (SH) extraction methods. The essential oils were analyzed and quantified by capillary gas chromatography using flame ionization detection (GC-FID) and mass spectrometry (GC-MS). The highest yield was observed in HD process (1.12%). Tabarka essential oil provided the best yield 0.79% compared to other regions. December month SD essential oil was the highest in oxygenated monoterpenes (52.7%). Nevertheless, SH essential oil showed a higher content in sesquitepenes hydrocarbons (64.5%). alpha-Terpinol (25.5%) was the main oxygenated component in Matmata juniper essential oil, extracted by SD. Moreover, the antioxidant activity of essential oils was evaluated using ABTS assays. The strongest antioxidant activity (IC(50) = 22.6 +/- 0.7 mg/L) was obtained by the Matmata (October 2007) SD essential oil. PMID- 21535740 TI - Production of L-arabinose from corn hull arabinoxylan by Arthrobacter aurescens MK5 alpha-L-arabinofuranosidase. AB - Arabinoxylans, which are comprised of a xylan backbone to which are attached glycosyl units that are primarily L-arabinofuranosyl units, are ubiquitous among plant species where it is a constituent of the cell wall. Arabinoxylan has attracted much attention as a potential biomass resource and L-arabinose has recently been reported to possess functional properties that are effective in the treatment of diabetes. Here, we report an alpha-L-arabinofuranohydrolase, isolated from the soil microbe Arthrobacter aurescens strain MK5, effective in releasing L-arabinose from corn hull arabinoxylan. When A. aurescens strain MK5 was grown in a liquid medium, corn hull arabinoxylan, which has a higher arabinose content (Ara/Xyl = 0.6) than oat spelts xylan (Ara/Xyl = 0.12), induced more efficient arabinoxylan hydrolase production. Analysis of enzyme activity in the culture broth revealed that arabinoxylan hydrolase activity was high, and alpha-L-arabinofuranosidase and beta-xylosidase activities were low. The optimum pH of the MK5 arabinoxylan hydrolase at 40 degrees C was around 7 and enzyme activity was relatively stable at an alkaline pH up to 9.5. The optimum temperature at pH 7 was around 50 degrees C and enzyme activity was stable under 50 degrees C. During the hydrolysis of corn hull arabinoxylan, only L-arabinose was released and 45.1% maximum sugar recovery was achieved. The A. aurescens MK5 enzyme was a typical arabinoxylan alpha-L-arabinofuranohydrolase and was most effective at releasing L-arabinose from corn hull arabinoxylan, which has a high arabinose content. This enzyme may have important industrial applications. PMID- 21535741 TI - Improvements in the shelf life of commercial corn dry masa flour (CMF) by reducing lipid oxidation. AB - To improve the shelf life of commercial nixtamalized corn dry masa flour (CMF), the modified atmosphere packaging (MAP) was used. Pouches (20 * 20 cm) of ethyl vinyl alcohol (EVOH) with 180 g of CMF were stored at 55 degrees C, and a(w) of 0.45; under Light and Dark conditions, antioxidants (0.02% TBHQ), Vacuum, and N(2) and CO(2), and used as treatments. Thereafter, changes in their linoleic acid (LA) concentration by GC, peroxide (PV), and anisidine values (p-A), which were monitored for 180 d. EVOH showed a significantly lower consumption of LA by autoxidation (11.7% +/- 0.2% in 117 d) than polyethylene film (70.5% +/- 0.3% in 113 d) under the same storage temperature. The elimination of oxygen by vacuum in each pouch allowed a low consumption (16.4% +/- 0.1%) of LA. PV (14.5 +/- 0.09 mEq/kg of fat), and p-A (63 +/- 0.16 mmol/kg) were low, and generated over 121 d of storage. CMF stored under MAP had 100% protection against oxidation of LA. PRACTICAL APPLICATION: A combination of Vacuum and EVOH packaging extended the shelf life of CMF to 108 d with only 10% of LA loss. For retail stores, the EVOH packaging will reduce lipid oxidation of CMF and safety related to off odors and flavors from the oxidation of tortillas will increase dramatically. PMID- 21535742 TI - Effect of myoglobin from Eastern little tuna muscle on lipid oxidation of washed Asian seabass mince at different pH conditions. AB - The effect of pH (6.0, 6.5, and 7.0) on lipid oxidation in washed Asian seabass (Lates calcarifer) mince mediated by oxymyoglobin from the dark muscle of little Eastern tuna (Euthynnus affinis) during 8 d of refrigerated storage was studied. Metmyoglobin formation and discoloration increased with increasing storage time and the changes were more pronounced at lower pH. The highest lipid oxidation and off-odor development were observed when myoglobin was incorporated in washed mince at pH 6.0. At low pH, oxidation of myoglobin took place and lipid oxidation in washed mince was enhanced. This was concomitant with the increased fishy and rancid off odor in the sample containing myoglobin, especially at pH 6.0. Washed mince containing myoglobin at pH 6.0 had 1-octen-3-ol and hexanal as the major volatile compounds. Thus, postmortem pH and myoglobin played an essential role in lipid oxidation and off odor in fish muscle during the extended storage. PRACTICAL APPLICATION: Myoglobin plays a role in the color of fish muscle. The change of myoglobin affects not only consumer acceptability, but also lipid oxidation as well as odor. The control of pH of muscle could be a potential means to lower the lipid oxidation mediated by myoglobin. As a consequence, the prime quality of fish with a negligible fishy odor could be maintained during postharvest handling or storage. PMID- 21535743 TI - Neuroprotective effect of caffeoylquinic acids from Artemisia princeps Pampanini against oxidative stress-induced toxicity in PC-12 cells. AB - Phenolics in dry Artemisia princeps Pampanini, an herbal plant traditionally consumed as food ingredients in Korea was extracted, fractionated, and quantified as well as evaluated for its neuroprotection for PC-12 cells. Whole extract had 5,852 mg gallic acid equivalents/100 g of total phenolics and 6,274 mg and 9,698 mg vitamin C equivalents/100 g of antioxidant capacities assayed by DPPH and ABTS radicals, respectively. The fraction extracted with n-butanol had the highest levels of total phenolics and antioxidant capacity than the other fractions (n hexane, chloroform, ethyl acetate, and water). Using a reversed-phase HPLC system, caffeoylquinic acid (CQA) and its derivatives such as 3-CQA, 4-CQA, 5 CQA, 1,5-diCQA, 3,4-diCQA, 3,5-diCQA, and 4,5-diCQA were isolated and quantified. The whole extract and its n-butanol fraction yielded 3,5-diCQA with the highest amount, which consisted of approximately 36.8% and 33.5%, respectively. The whole extract, the n-butanol fraction, and 3,5-diCQA showed neuroprotective effect on PC-12 cells under the insult of amyloid beta peptide in a dose-dependent manner. Treatments of the whole extract and the n-butanol fraction for PC-12 cells under oxidative stress increased approximately 1.6 and 2.4 times higher cell viability, compared with the control without treatments. For PC-12 cells treated with 3,5 diCQA, intracellular oxidative stress decreased by 51.3% and cell viability increased up to 2.8 times compared to the control with oxidative insult of amyloid beta peptide only. These results indicate that phenolics from A. princeps Pampanini alleviated the oxidative stress and enhanced the viability of PC-12 cells, suggesting that it may be applied as a dietary antineurodegenerative agent in functional foods. PMID- 21535744 TI - Physical and structural changes in liquid whole egg treated with high-intensity pulsed electric fields. AB - Liquid whole egg (LWE) is currently pasteurized through the application of heat; however, this treatment entails deleterious effects against some of the functional and technological properties of the product. In this study, the effect of high-intensity pulsed electric fields (HIPEF) processing (field strength: 19, 32, and 37 kV/cm) was compared to the traditional heat pasteurization (66 degrees C for 4.5 min). Different physical and structural characteristics of LWE, subjected or not to homogenization, were evaluated and compared, having the untreated LWE as a reference. Thermal treatment caused an increase in the viscosity of LWE, especially in nonhomogenized samples. HIPEF treatments did not modify the original color of LWE, whereas thermally treated samples developed an opaque appearance. LWE treated at 19 and 32 kV/cm exhibited a similar foaming capacity as fresh untreated egg, whereas thermal processing and PEF treatments of 37 kV/cm caused a substantial decrease in the foaming capacity of untreated liquid egg. Regarding the microstructure, the lipoprotein matrix appeared to be less affected by the HIPEF than by heat treatment if compared to the control. In addition, heat pasteurization had a significant impact on both the water-soluble protein content of the LWE samples (19.5% to 23.6% decrease) and the mechanical properties of the egg gels (up to 21.3% and 14.5% increase in hardness and cohesiveness, respectively). On the other hand, these parameters were not substantially affected in the HIPEF-treated samples. Heat-induced gels obtained from HIPEF-treated samples did not exhibit remarkable differences in the water holding capacity (WHC) with respect to heat-pasteurized samples. PRACTICAL APPLICATION: The impact of high-intensity pulsed electric fields (HIPEF) processing on technological properties of liquid-whole egg was investigated and compared to that of thermal processing. Heat treatments cause a severe impact on the foaming capacity, the water-soluble protein content, and the rheological properties of liquid egg samples, whereas HIPEF treatments better preserved the food matrix structure. Microscopic observations support these results, thus suggesting that HIPEF-processing has potential application for the preservation of liquid egg through nonthermal means. PMID- 21535745 TI - Effects of buttermilk powders on emulsification properties and acid tolerance of cream. AB - Emulsifying properties and acid tolerance are 2 of the most important characteristics of cream. The effects of the buttermilk component, especially its phospholipids, on the emulsifying properties and acid tolerance of cream were investigated in this study. Two buttermilks with differing phospholipid contents and skimmed milk were used to evaluate the effects of phospholipids on the aforementioned parameters. The mean diameter of fat globules and the cream viscosity were used as indicators of emulsifying properties. Acid tolerance was evaluated by studying the effect of citric acid on the maximum viscosity of cream. This was tested by adding 400 MUL of 10% (w/w) citric acid solution to cream every minute and simultaneously measuring pH and viscosity. In 45% and 40% fat cream systems, buttermilk, and especially that with higher phospholipid content, improved the emulsifying properties and acid tolerance of the cream. The components of buttermilk could alter the properties of the surface of fat globules, thereby altering the emulsification properties of the cream. However, neither of the tested buttermilks affected the emulsifying properties and acid tolerance of lower-fat (35% and 30%) cream systems. Emulsifying components exist in proportionately larger amounts in lower-fat creams, which could render the emulsifying properties resistant to change. The number of fat globules may also influence acid-induced changes in viscosity. The addition of phospholipids or lysophospholipids did not improve the acid tolerance of creams, a finding that may be attributable to the formation of complexes of phospholipids and protein. PRACTICAL APPLICATION: The findings presented herein demonstrate the ability to improve the acid tolerance of cream using materials derived from milk. Implementing these findings appropriately may result in a high-quality cooking cream. PMID- 21535747 TI - Monitoring of cocoa volatiles produced during roasting by selected ion flow tube mass spectrometry (SIFT-MS). AB - Selected ion flow tube-mass spectrometry (SIFT-MS) was used to measure the real time concentrations of cocoa volatiles in the headspace during roasting. Alkalized and unalkalized Don Homero and Arriba cocoa beans were roasted at 120, 150, and 170 degrees C in a rotary roaster. The concentrations of total alcohols, acids, aldehydes, esters, ketones, and alkylpyrazines increased, peaked, and decreased within the timeframe used for typical roasting. The concentrations of alkylpyrazines and Strecker aldehydes increased as the roasting temperature increased from 120 to 170 degrees C. For most of the volatile compounds, there was no significant difference between Arriba and Don Homero beans, but Arriba beans showed higher concentrations of 2-heptanone, acetone, ethyl acetate, methylbutanal, phenylacetaldehyde, and trimethylpyrazine. For unalkalized Don Homero beans (pH 5.7), the time to peak concentration decreased from 13.5 to 7.4 min for pyrazines, and from 12.7 to 7.4 min for aldehydes as the roasting temperature increased from 120 to 170 degrees C. Also, at 150 degrees C roasting, the time to peak concentration was shortened from 9 to 5.1 min for pyrazines, and from 9.1 to 5 min for aldehydes as the pH increased from 5.7 to 8.7. PRACTICAL APPLICATION: SIFT-MS allows for real-time monitoring of the key volatile compounds contributing to chocolate flavor, with minimal sample preparation, thus can be used to facilitate adjusting the roasting conditions, such as temperature and time, to optimize chocolate flavor during roasting. Real time monitoring during roasting can also be used to evaluate the flavor quality of different types of beans by comparing the concentrations of key flavor compounds. PMID- 21535746 TI - Glucose tolerance and antioxidant activity of spent brewer's yeast hydrolysate with a high content of Cyclo-His-Pro (CHP). AB - To elevate the Cyclo-His-Pro (CHP) content in yeast, the yeast hydrolysate that was obtained from enzymatic hydrolysis was subjected to various treatments. Flavourzyme-treated hydrolysate showed the highest CHP content (674.0 MUg/g) among the various proteases treatments. Ultrafiltration was selected as the best method for concentrating CHP in yeast hydrolysate, based on the yields and CHP contents. In addition, we evaluated the radical scavenge and glucose tolerance of yeast hydrolysate with a high content of CHP. Yeast hydrolysate showed intense scavenging abilities of both 1, 1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radicals. The IC(50) values of yeast hydrolysate on DPPH and ABTS radicals were 1.9 and 0.9 mg/mL, respectively. There were significant differences in glucose level between the diabetes-control and yeast hydrolysate group at 30, 60, 90, and 120 min after injection in a type 1 diabetes model (P < 0.01). Also, there were significant differences in blood glucose levels between the 2 groups at 30, 60, and 100 min after injection in the type 2 diabetes group (P < 0.05). Therefore, it is possible to use the yeast hydrolysate with high levels of CHP as an antioxidative and/or antidiabetic material for the preparation of functional foods. PRACTICAL APPLICATION: This study tried to develop a material containing a high content of CHP using yeast for possible applications of this cyclic dipeptide in the therapy of metabolic disorders. The yeast hydrolysate prepared with Flavourzyme showed a high level of CHP. The hydrolysate with a high content of CHP showed high levels of radical scavenging activities and oral glucose tolerance activity. Therefore, it is possible to use the yeast hydrolysate with high levels of CHP as an antioxidative and/or antidiabetic material for the preparation of functional foods. PMID- 21535748 TI - First investigation on ultrasound-assisted preparation of food products: sensory and physicochemical characteristics. AB - This paper presents a comparison between manufactured food products using conventional and ultrasound-assisted procedures. Three different foam-type products, chocolate Genoise, basic sponge cake, and chocolate mousse were prepared using both methods with subsequent evaluation of the samples using both sensory and physicochemical methods. Ultrasound-assisted preparations were considered superior according to the sensory analysis, and physicochemical data confirmed this finding. This approach of applying an emerging piece of equipment, with potential industrial application to assist food preparation, consists of a new technique that could be of great interest for the development of not only other food products created by molecular gastronomy but also for practical work carried out by students. PMID- 21535749 TI - Role of beta-conglycinin and glycinin subunits in the pH-shifting-induced structural and physicochemical changes of soy protein isolate. AB - Soy beta-conglycinin (7S) and glycinin (11S) were incubated up to 4 h in acidic (pH 1.5 to 3.5) or alkaline (pH 10 to 12) solutions to induce protein structural unfolding followed by refolding 1 h at pH 7.0, a process known as pH-shifting. The pH-shifting markedly increased (P < 0.05) emulsifying activity of 11S and to a lesser extent 7S; the former also produced more uniform oil droplets. The emulsifying activity improvements were accompanied by a significant rise in protein surface hydrophobicity, slight loss of the secondary structure (circular dichroism), and substantial dissociation of disulfide-linked basic and acidic 11S subunits. The findings suggested that 11S globulins of soy protein isolate (SPI) were more responsive to pH-shifting treatments than were 7S globulins, and the resulting emulsifying activity enhancements of 11S, in parallel with that of SPI, were indicative of its determinant role in the overall emulsifying properties of pH-shifting-treated SPI. PRACTICAL APPLICATION: Extreme alkaline (pH 12) and acidic (pH 1.5) medium treatments can significantly modify the structure and enhance the emulsifying properties of both beta-conglycinin and glycinin components of SPI. The functionality improvement by the pH processes is more remarkable for the glycinin protein fraction. Therefore, SPI enriched with glycinin seems to be particularly suitable for extreme acidic or alkaline processes to produce surface-active functional ingredients for food applications. PMID- 21535750 TI - Multicomponent cleaning verification of stainless steel surfaces for the removal of dairy residues using infrared microspectroscopy. AB - The application of infrared microspectroscopy (IRMS) technology, combined with multivariate analysis, was evaluated to develop sensitive and robust methods to assess cleanability of stainless steel surfaces for the removal of dairy food residues. UHT milk samples (skim, 1%, 2%, and whole) were analyzed for total nitrogen (Kjeldahl) and fat (Babcock) contents. The coupons were manually soiled with serially diluted milk samples resulting in soils ranging from 0.1 to 428.1 MUg/cm(2) for protein and 0.1 to 374.17 MUg/cm(2) for fat, and then autoclaved to simulate a heated equipment surface. Reflectance spectra were collected from stainless steel coupons by using IRMS, and multivariate analysis was used to develop calibration models based on cross-validated partial least squares regression (PLSR). Statistical analysis for the prediction of protein and fat showed a standard error of cross-validation (SECV) of 0.5 and 0.4 MUg/cm(2) for prediction of protein and fat, respectively, and correlation coefficients (rVal) > 0.99. To improve the sensitivity, swabbing and concentration steps were used prior to IRMS analysis obtaining SECV of 0.04 and 0.01 MUg/cm(2) for the prediction of protein and fat, respectively, and rVal > 0.99. The PLSR models accurately predicted the levels of protein and fat on autoclaved stainless steel coupons soiled with milk. A simple, reliable, and robust protocol based on IRMS and multivariate analysis was developed for multicomponent characterization of stainless steel surfaces that can contribute to more efficient cleaning verification with regard to contamination on surfaces of processing equipment. PRACTICAL APPLICATION: We report the application of Fourier transform infrared microspectroscopy (FTIR) for the validation of CIP cleaning efficiency that would provide a basis for better understanding of the mechanisms involved in the removal of physical soil and food residues from different types of equipment surfaces commonly utilized in the biotech, pharmaceutical, and food industries. Reliable calibration models were generated that showed the ability to predict the amounts of dairy soils on the surface of stainless steel coupons. Including a swabbing step of the coupons before infrared spectral acquisition provided improved sensitivity and reproducibility for multicomponent cleaning verification. Results from this research project would allow designing experiments to rapidly evaluate different materials and finishes, the effects of process variables, the influence of food components, and the development of reliable and robust cleaning validation protocols to ensure the safety and quality of the product. PMID- 21535751 TI - Chemical composition and antimicrobial and spasmolytic properties of Poliomintha longiflora and Lippia graveolens essential oils. AB - In the present study, we reported a comparative analysis of the chemical composition and pharmacological properties of the essential oils obtained from 2 Mexican oreganos, Poliomintha longiflora and Lippia graveolens. The gas chromatography-mass spectrometry (GC-MS) profiles of the oils showed high amounts of oxygenated monoterpenes, mainly carvacrol (%[mg/100 g dry matter]) (18.36 [459.0] in P. longiflora and 13.48 [164.7] in L. graveolens). In addition, these oils contained marked quantities of p-cymene (14.09 [352.2] and 7.46 [37.3], respectively), beta-caryophyllene oxide, beta-caryophyllene, and carvacrol acetate. Headspace analyses of the leaves of both species using different coated fibers revealed that gamma-terpinene, eucalyptol, and p-cymene were the principal light volatile components. Chromatographic fingerprints and a suitable analytical method for quantifying the main components of both essences were established using high-performance liquid chromatography (HPLC) as analytical tool. The essential oils of both species were not toxic in the acute toxicity studies in mice performed according to the Lorke procedure (DL(50) > 5000 mg/kg). The oils and the major constituents, carvacrol and p-cymene, displayed a moderate in vitro antibacterial activity, with minimum inhibitory concentration values ranging from 128 to 512 MUg/mL. In addition, these samples demonstrated a marginal antispasmodic activity in vivo and provoked a concentration-dependent inhibition of the carbachol- and histamine-induced contractions using the isolated guinea pig ileum preparation. In particular, p-cymene exerts good selective inhibitory activity on the carbachol-induced contractions (IC(50) = 9.85 MUg/mL). PRACTICAL APPLICATION: The analytical methods using GC-MS and HPLC techniques will be useful for establishing quality control as well as preclinical pharmacological and toxicological parameters of the crude drug P. longiflora, which is widely used as substitute of L. graveolens for medicinal and flavorings purposes. This overall information will be also useful for elaborating scientific and pharmacopoeic monographs of this very Mexican medicinal plant. PMID- 21535752 TI - Antibrowning and antimicrobial activities of the water-soluble extract from pine needles of Cedrus deodara. AB - The antibrowning and antimicrobial activities of the water-soluble extract from pine needles of Cedrus deodara (CDE), a traditional Chinese medicine and raw materials of pine needle tea, was investigated. Total phenols of CDE were 31.4 +/ 0.53 mg gallic acid equivalent/g, and total flavonoids were 23.1 +/- 0.79 mg rutin equivalent/g. CDE showed a strong antioxidant activity against ABTS free radicals with IC(50) (the half-inhibitory concentration) of 25.5 +/- 0.64 MUg/mL. In mushroom tyrosinase inhibitory assay, IC(50) values were 2.1 +/- 0.98 and 2.27 +/- 0.93 mg/mL for monophenolase and diphenolase, respectively. Evaluated by detecting changes of L* (indicated the darkness of sample), a* (indicated the redness of sample), and b* (indicated the yellowness of sample) values in fresh cut apple slices model, CDE showed a significant antibrowning effect when compared with ascorbic acid. In addition, it was discovered that CDE in combination with 0.5% ascorbic acid exhibited a synergistic antibrowning effect. Meanwhile, CDE was observed to show a potent antimicrobial effect on all of the tested Gram-positive and Gram-negative bacteria. In conclusion, the results of the present research suggested that pine needles of C. deodara could be used as a natural resource of antibrowning and antimicrobial agents in food preservation. PRACTICAL APPLICATION: The present study provides a theoretical basis for the potential application of pine needles of C. deodara to be used as a natural resource of antibrowning and antimicrobial agents in food industry. PMID- 21535753 TI - Effect of enzymes on strawberry volatiles during storage, at different ripeness level, in different cultivars, and during eating. AB - Strawberry samples with enzyme activity and without enzyme activity (stannous chloride added) were measured for real-time formation of lipoxygenase (LOX) derived aroma compounds after 5 min pureeing using selected ion flow tube-mass spectrometry (SIFT-MS). The concentration of (Z)-3-hexenal and (E)-2-hexenal increased immediately after blending and gradually decreased over time, while hexanal concentration increased for at least 5 min in ground strawberries. The formation of hexanal was slower than the formation of (Z)-3-hexenal and (E)-2 hexenal in the headspace of pureed strawberries. The concentration of LOX aldehydes and esters significantly increased during refrigerated storage. Damaging strawberries increased the concentration of LOX aldehydes but did not significantly affect the concentration of esters. The concentrations of many of the esters were strongly correlated to their corresponded acids and/or aldehydes. The concentration of LOX-generated aldehydes decreased during ripening, while fruity esters increased. Different varieties had different aroma profiles and esters were the greatest percentage of the volatiles. The aroma release of some of the LOX-derived aldehydes in the mouthspace in whole strawberries compared to chopped strawberries showed that these volatiles are formed in the mouth during chewing. The persistence of LOX-derived compounds was higher than esters after swallowing. The mouthspace after and before swallowing persistence ratio of esters decreased as the chain length of the acid part of the ester compounds increased in whole strawberries. PRACTICAL APPLICATION: The storage studies showed that the concentrations of fruity and fresh volatiles increased during ripening and storage while damaging only increases the fresh volatiles. The nose, mouth, and headspace information can be used in the flavor industry to improve the formula of natural strawberry flavor by considering human perception during eating. PMID- 21535754 TI - Comparison of lipid content and fatty acid composition and their distribution within seeds of 5 small grain species. AB - Barley, oats, rice, sorghum, and wheat, each with two genotypes, were sequentially abraded by an electric seed scarifier. The pearling fines (PF) and pearled kernels (PK) at each cycle were analyzed for lipid (mostly nonpolar) content and fatty acid (FA) composition. The oil content in whole or dehulled grains ranged from 2.18% of a wheat variety to 6.38% of an oat line. Compared with barley and wheat, rice, oat, and sorghum had higher relative % of C18:1 (31.60 to 36.64 compared with 12.15 to 15.61) and lower % of C18:2 (35.69 to 45.44 compared with 50.79 to 61.50). The relationship between oil content in PF and the cumulative level of surface removal essentially describes the distribution pattern of oil content within a seed. Barley, rice, and sorghum had a similar distribution pattern, characterized by a rapid rate of decreasing for the first few outer layers and then by gradual decrease to a flat value toward the inner core. In contrast, distribution within oats was characterized by a gradual reduction in oil content across the seed. The distribution of oil within wheat fell between the former 2 types. For all 10 grains, from seed surface to inner core, C16:0 and C18:0 increased, C18:1 and C18:3 decreased, and C18:2 changed slightly, providing a new reason for improved oxidative stability for pearled kernels. The differences in the changing intensity of FA composition among grain species correspond to those in oil distribution within a seed, while varietal difference in distribution patterns of content and FA composition of lipids within a species was insignificant. PRACTICAL APPLICATION: This study was the first to document fatty acid distribution across a grain seed. Results provide 2 major reasons for improved oxidative stability of pearled grains: reduced oil content and shift of fatty acids toward more saturated and less unsaturated composition. PMID- 21535755 TI - Rheological and biochemical characterization of salmon myosin as affected by constant heating rate. AB - Purified Chinook salmon myosin was studied using sodium dodecylsulfate polyacryamide gel electrophoresis and densitometric analysis to determine its purity (approximately 94%). Myosin subjected to a constant heating rate began to form aggregates at >24 degrees C as measured by turbidity at 320 nm. Conformational changes, as measured by surface hydrophobicity (S(o)), began at 18.5 degrees C and continued to increase up to 75 degrees C after which it decreased slightly. Total sulfhydryl (TSH) content remained steady from 18.5 to 50 degrees C after which point the TSH began to drop. Surface reactive sulfhydryl groups gradually increased as the temperature increased from 18.5 to 55 degrees C and then followed a similar trend as TSH decreased. Presumably disulfide bond started to be formed at around 50 to 55 degrees C. Differential scanning calorimetry showed 4 peaks, 3 endothermic (27.9, 36.0, 45.5 degrees C), and 1 exothermic (49.0 degrees C). Dynamic rheological measurements provided information concerning the gelation point of salmon myosin that was 31.1 degrees C as samples were heated at a rate of 2 degrees C/min. PMID- 21535756 TI - Isolation and characterization of lecithin from squid (Todarodes pacificus) viscera deoiled by supercritical carbon dioxide extraction. AB - Marine lecithin was isolated and characterized from squid (Todarodes pacificus) viscera residues deoiled by supercritical carbon dioxide (SC-CO(2)) extraction. SC-CO(2) extraction was carried out to extract the oil from squid viscera at different temperatures (35 to 45 degrees C) and pressures (15 to 25 MPa). The extraction yield was higher at highest temperature and pressure. The major phospholipids of squid viscera lecithin were quantified by high-performance liquid chromatography (HPLC). Phosphatidylcholine (PC; 80.5% +/- 0.7%) and phosphatidylethanolamine (PE; 13.2% +/- 0.2%) were the main phospholipids. Thin layer chromatography (TLC) was performed to purify the individual phospholipids. The fatty acid compositions of lecithin, PC and PE were analyzed by gas chromatography (GC). A significant amount of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were present in both phospholipids of PC and PE. Emulsions of lecithin in water were prepared through the use of a homogenizer. The oxidative stability of squid viscera lecithin was high in spite of its high concentration of long-chain polyunsaturated fatty acids. PRACTICAL APPLICATION: Squid viscera are discarded as a waste by fish processing industry. Since lecithin from squid viscera contains higher amounts of polyunsaturated fatty acids, it may have promising effect to use in food, pharmaceutical, and cosmetic industries. PMID- 21535757 TI - Multispectral vision for monitoring peach ripeness. AB - The main objective of this research was to develop an automatic procedure able to classify Rich Lady commercial peaches according to their ripeness stage through multispectral imaging techniques. A classification procedure was applied to the ratio images calculated as red (R, 680 nm) divided by infrared (IR, 800 nm), that is, R/IR images. Four image-based ripeness reference classes (A: unripe to D: overripe) were generated from 380 fruit images (season 1: 2006) by a nonsupervised classification method and evaluated according to reference measurements of the ripeness of the same samples: Magness-Taylor penetrometry firmness, low-mass impact firmness, reflectance at 680 nm (R680, and soluble solids content. The assignment of unknown sample images from those season 1 images (internal validation, n = 380) and of 240 images from the 2nd season (season 2: 2007) to the ripeness reference classes (external validation) was carried out by computing the minimum Euclidean distance (classification distance, C(d)) between each unknown image histogram and the average histogram of each ripeness reference class. For both validation phases, firmness values decreased and R680 increased for increasing alphabetical order of image-based class letter, reflecting the ripening process. Moreover, 70% (season 1) and 80% (season 2) of the samples below bruise susceptibility firmness were classified into class D. PRACTICAL APPLICATION: This work proposes and validates a procedure for assessing peach ripeness through spectral imaging. The control of ripeness in this fruit is crucial for ensuring its quality and the measurement of optimum peach ripeness at harvest and postharvest is a controversial issue, which needs to be balanced between a minimum ripeness, acceptable for the consumer, and a maximum ripeness, to minimize fruit losses during the postharvest process. The proposed method is nondestructive and quick, showing thus, a good perspective for its application in fresh fruit packing lines, either for peach ripeness assessment or for other fruits (providing adequate calibration). PMID- 21535759 TI - Effect of drying temperatures on starch-related functional and thermal properties of acorn flours. AB - The application of starchy flours from different origins in food systems depends greatly on information about the chemical and functional properties of such food materials. Acorns are important forestry resources in the central and southern regions of Portugal. To preserve these fruits and to optimize their use, techniques like drying are needed. The effects of different drying temperatures on starch-related functional properties of acorn flours obtained from dried fruits of Quercus rotundifolia (QR) and Quercus suber (QS) were evaluated. Flours were characterized for amylose and resistant starch (RS) contents, swelling ability, and gelatinization properties. Drying temperature mainly affected amylose content and viscoamylographic properties. Amylograms of flours from fruits dried at 60 degrees C displayed higher consistency (2102 B.U. and 1560 B.U., respectively, for QR and QS). The transition temperatures and enthalpy were less affected by drying temperature, suggesting few modifications in starch structure during drying. QR flours presented different functional properties to those obtained from QS acorn flours. The effect of drying temperatures were more evident in QR. PMID- 21535758 TI - Vacuum frying as a route to produce novel snacks with desired quality attributes according to new health trends. AB - Consumers look for products that contribute to their wellness and health, however, even health-conscious consumers are not willing to sacrifice organoleptic properties, and intense full-flavor snacks remain an important trend. The objective of this study was to examine most important quality parameters of vacuum (1.92 inHg) and atmospheric-fried carrot, potato, and apple slices to determine specific advantages of vacuum technology. Slices were fried using equivalent thermal driving forces, maintaining a constant difference between oil temperature and the boiling point of water at the working pressure (DeltaT = 60 and 80 degrees C). This resulted in frying temperatures of 160 and 180 degrees C, and 98 and 118 degrees C, for atmospheric and vacuum frying, respectively. Vacuum-fried carrot and potato chips absorbed about 50% less oil than atmospheric-fried chips, whereas vacuum-fried apple chips reduced oil absorption by 25%. Total carotenoids and ascorbic acid (AA) were greatly preserved during vacuum frying. Carrot chips vacuum fried at 98 degrees C retained about 90% of total carotenoids, whereas potato and apple slices vacuum fried at 98 degrees C, preserved around 95% of their initial AA content. Interestingly, results showed that the antioxidant capacity of chips may be related to both the presence of natural antioxidants and brown pigments developed at elevated temperatures. PRACTICAL APPLICATION: A way to reduce detrimental effects of deep-fat frying is through operating-pressure reduction, the essence behind vacuum deep-fat frying. In this way, it is possible to remove product moisture at a low temperature in a low-oxygen environment. The objective of this research was to study the effect of oil temperature reduction when vacuum frying traditional (potatoes) and nontraditional products (carrots and apples) on most important quality attributes (vitamins, color, and oil uptake). Results are promising and show that vacuum frying can be an alternative to produce nutritious and novel snacks with desired quality attributes, since vitamins and color were greatly preserved and oil absorption could be substantially reduced. PMID- 21535760 TI - Technological optimization of manufacture of probiotic whey cheese matrices. AB - In attempts to optimize their manufacture, whey cheese matrices obtained via thermal processing of whey (leading to protein precipitation) and inoculated with probiotic cultures were tested. A central composite, face-centered design was followed, so a total of 16 experiments were run using fractional addition of bovine milk to feedstock whey, homogenization time, and storage time of whey cheese as processing parameters. Probiotic whey cheese matrices were inoculated with Lactobacillus casei LAFTIL26 at 10% (v/v), whereas control whey cheese matrices were added with skim milk previously acidified with lactic acid to the same level. All whey cheeses were stored at 7 degrees C up to 14 d. Chemical and sensory analyses were carried out for all samples, as well as rheological characterization by oscillatory viscometry and textural profiling. As expected, differences were found between control and probiotic matrices: fractional addition of milk and storage time were the factors accounting for the most important effects. Estimation of the best operating parameters was via response surface analysis: milk addition at a rate of 10% to 15% (v/v), and homogenization for 5 min led to the best probiotic whey cheeses in terms of texture and organoleptic properties, whereas the best time for consumption was found to be by 9 d of storage following manufacture. PMID- 21535761 TI - Image analysis of microstructural changes in almond cotyledon as a result of processing. AB - Release of oil from nuts due to damaged cellular structures can degrade the quality of products incorporating nuts. The aim of this study was to investigate the effects of different processing conditions on microstructure of almond tissue and to quantify these changes using image processing. Spinning disk confocal fluorescence microscopy was used for imaging changes in microstructure of almonds as a function of different thermal processing of almonds. Multiple staining of Nile Red and Calcofluor White was applied to differentiate cell wall structures and oil bodies within individual almond cells without chemical fixation. An algorithm for image processing, included image preprocessing, segmentation, and determination of morphological features of segmented objects, was developed. Oil roasting processes (140 degrees C and 150 degrees C) were found to have a significant impact on microstructure of almonds when compared to the hot air roasting and blanching processes. Oil-roasted almond at 150 degrees C had a greater cellular damage due to cell wall and membrane rupture. These changes in microstructure of almonds would make them slightly more susceptible to release oil during storage. The image analysis presented allows quantitative evaluation for the effect of different processing on almond microstructure. PMID- 21535762 TI - Evaluation of microstructural properties of coffee beans by synchrotron X-ray microtomography: a methodological approach. AB - Synchrotron radiation microtomography was used as a nondestructive imaging technique to investigate the microstructural properties of green and roasted coffee beans. After image acquisition, 2D images have been reconstructed and 3D images of the beans have been then obtained. Qualitative and quantitative analysis of the images allow to fully characterize the morphological and structural features of the coffee beans. Roasting causes meaningful changes in the microstructure of the coffee bean tissue with the development in the entire bean of a porous structure with pores of different shape and size depending on the zone of the bean and cracks occurring mainly in the more external regions and between parenchyma and mucilage. The highly contrasted X-ray images have been analyzed to determine the pore size and its distribution in different regions of the coffee beans by selecting Volume-of-Interest (VoI). The use of phase-contrast hard X-rays imaging techniques represents an interesting tool of investigation of the internal structure, morphology, as well as the quality of whole coffee beans. Moreover, the high potentiality of 3D X-ray imaging and the approach used in this study could be applied in understanding the effects of roasting process conditions on the evolution of microstructural properties of the bean that may affect the stability as well the grinding and brewing performances. PRACTICAL APPLICATION: Synchrotron radiation microtomography is an elegant nondestructive imaging technique to investigate the microstructural properties of porous cellular matrices like the green and roasted coffee beans. The quantitative analysis of the resulting 2D and 3D images allows a more comprehensive and objective characterization of the sample under investigation as a whole or of extracted Volumes-of-Interest in the bean. This imaging technique could have a major role in understanding the effects of roasting process conditions on the microstructural properties of the bean. PMID- 21535763 TI - Inactivation kinetics of Vibrio vulnificus in phosphate-buffered saline at different freezing and storage temperatures and times. AB - Vibrio vulnificus (Vv) is a pathogen that can be found in raw oysters. Freezing can reduce Vv and increase the shelf life of oysters. The objective of this study was to develop predictive inactivation kinetic models for pure cultures of Vv at different frozen storage temperatures and times. Vv was diluted in phosphate buffered saline (PBS) to obtain about 10(7) CFU/mL. Samples were frozen at -10, 35, and -80 degrees C (different freezing rates), and stored at different temperatures. Survival of Vv was followed after freezing and storage at -10 degrees C (0, 3, 6, and 9 d) and at -35 and -80 degrees C (every week for 6 wk). For every treatment, time-temperature data was obtained using thermocouples in blank vials. Predictive models were developed using first-order, Weibull and Peleg inactivation kinetics. Different freezing temperatures did not significantly (alpha = 0.05) affect survival of Vv immediately after freezing. The combined effect of freezing and 1 wk frozen storage resulted in 1.5, 2.6, and 4.9 log10 reductions for samples stored at -80, -35, and -10 degrees C, respectively. Storage temperature was the critical parameter in survival of Vv. A modified Weibull model successfully predicted Vv survival during frozen storage: log10 Nt = log 10No - 1.22 - ([t/10{-1.163-0.0466T}][0.00025T(2) + 0.049325]). N(o) and N(t) are initial and time t (d) survival counts, T is frozen storage temperature, Celsius degree. PRACTICAL APPLICATION: Vibrio vulnificus can be inactivated by freezing. Models to predict survival of V. vulnificus at different freezing temperatures and times were developed. This is the first step towards the prediction of V. vulnificus related safety of frozen oysters. PMID- 21535764 TI - Behavior of flavonols and carotenoids of minimally processed kale leaves during storage in passive modified atmosphere packaging. AB - Minimally processed kale leaves were packed in passive modified atmosphere and stored at 3 conditions: 1 degrees C in the dark and 11 degrees C with or without light exposure. The products were evaluated during storage in terms of headspace gas composition, sensory attributes, flavonol, and carotenoid contents. The sensory quality decreased slightly during 17 d at 1 degrees C in the dark. At 11 degrees C, the vegetable shelf life was predicted to be 6 d in the dark and 3 d with light. Quercetin and kaempferol were stable during storage for 15 d at 1 degrees C in the absence of light. At 11 degrees C in the dark, quercetin was stable during 10 d, increasing slightly on the 8th day. Kaempferol decreased up to the 5th day but increased on the 8th day, decreasing again on the 10th day. After 5 d at 11 degrees C under light, the flavonol levels were significantly higher than those of the initial values. Neoxanthin and violaxanthin did not change significantly after 15 d at 1 degrees C in the dark. Lutein and beta carotene, however, decreased 7.1% and 11.3%, respectively. At 11 degrees C in the dark, neoxanthin, violaxanthin, lutein, and beta-carotene decreased 16.1%, 13.2%, 24.1%, and 23.7% after 10 d, respectively. At 11 degrees C under light, neoxanthin and lutein had a slight increase while violaxanthin and beta-carotene decreased 23.1% and 16.5% after 5 d. Practical Application: Passive modified atmosphere packaging together with refrigeration can extend the shelf life of minimally processed kale, retaining the health-promoting compounds, flavonols and carotenoids. Quercetin, kaempferol, neoxanthin, and violaxanthin are stable and lutein and beta-carotene slightly reduced. PMID- 21535765 TI - Bioavailability of iron and zinc from multiple micronutrient fortified beverage premixes in Caco-2 cell model. AB - Iron and zinc deficiencies are the most prevalent nutrient deficiencies worldwide. They often coexist as the dietary factors, especially phytate, which impairs iron absorption also affects zinc absorption. Therefore, suitable strategies are required to control multiple micronutrient deficiencies in populations that subsist on high-phytate foods such as the whole wheat flour based Indian bread (chapatti). The objective of the study, therefore, was to test the bioavailability of iron and zinc in 2 multiple micronutrient beverage premixes in the absence and presence of chapatti. The premix-1 contained iron, zinc, and vitamin A while premix-2 contained all micronutrients in premix-1, plus folic acid and ascorbic acid. Ferritin induction and (65)Zn uptake were assessed using coupled in vitro digestion/Caco-2 cell line model as the surrogate markers of iron and zinc bioavailability, respectively. The results show that iron bioavailability from premixes-1 and 2 was similar in the absence of chapatti. However, premix-2 showed significantly higher iron bioavailability compared to premix-1 in the presence of chapatti. In contrast, the zinc uptake was similar from both premixes-1 and 2 in the absence or presence of chapatti. These results suggest that both the premixes provide bioavailable minerals, but premix-2 appears to be promising in the presence of foods that have high phytate. PMID- 21535766 TI - Documentation of fatty acid profiles in lamb meat and lamb-based infant foods. AB - Lamb meat, when used in the weaning diet of children, is presumed to have a lower allergenicity than other forms of red meat. In children with atopic dermatitis and multiple food hypersensitivities, consumption of lamb meat has also resulted in significant clinical improvements in the severity of the eczematous lesions. Lamb meat is also of special interest in infant nutrition because it provides a somewhat unique fatty acid (FA) profile that mirrors what is thought to be optimal for neonatal growth and development. However, very little is known about how the processing of fresh meat (FM) into prepared infant foods influences its FA composition. In this study, we compared the FA profile of FM from suckling lambs with those of homogenized (HO) and lyophilized (LIO) baby foods prepared primarily with lamb meat. The results show that the content of total omega-3 polyunsaturated FAs was the highest in FM (more than 3-fold) compared to commercial baby food, due to largely higher contents of alpha-linolenic acid (1.5 fold higher), eicosapentaenoic acid (6-fold higher), and docosahexaenoic acid (10 fold higher). Furthermore, arachidonic acid was more than 6-fold higher in FM compared to LIO and HO. Results from this study suggest the possibility of enhancing the FA profile of commercial baby food based on meat by using lamb meat, but care should be taken during processing so that important FAs are not lost. PRACTICAL APPLICATION: In this article, we have documented that meat from the suckling lamb is an interesting and potentially important source of omega-3 FAs, especially some of the long-chain polyunsaturated FAs (LC-PUFAs) that are essential for optimal neonatal growth and development. These results may have special implications to the infant food industry, in that products made using meat from suckling lambs may provide not only exceptional amounts of these FAs, but also other limiting essential nutrients such as iron. This may be especially important in regions of the world, such as Italy, where use of lamb meat as a weaning food is common during infancy. PMID- 21535767 TI - Verbascosides from olive mill waste water: assessment of their bioaccessibility and intestinal uptake using an in vitro digestion/Caco-2 model system. AB - Olive mill wastewater (OMWW) is an agricultural waste material produced in high quantities in the Mediterranean basin. OMWW may be an inexpensive source of health promoting phytochemicals with potential economic value including many low molecular weight compounds such as verbascosides. While promising as antioxidants in vitro, little information is available on the potential absorption of verbascosides by humans. The main objective of the present study was to characterize the verbascoside content and potential for their bioavailability from a partially purified phenolic fraction (IP) of OMWW. The IP was obtained after ultrafiltration step at 5000 Dalton and gel filtration low-pressure chromatography (LH20) of OMWW. RP-HPLC analysis identified several soluble phenolics compounds including verbascoside and isoverbascoside as major components of OMWW fractions. The potential for bioavailability of these polyphenols was estimated by using both in vitro digestion and Caco-2 human intestinal cell models. In vitro digestive recoveries (bioaccessibility) were found to be 35.5%+/- 0.55% for verbascoside and 9.2% +/- 0.94% for isoverbascoside highlighting potential sensitivity of these phenolics to gastric and small intestinal digestive conditions. Accumulation of verbascosides by highly differentiated Caco-2 monolayers was linear between 10 and 100 MUM of verbascoside and isoverbascoside from IP extract. Uptake of verbascoside and isoverbascoside was rapid with peak accumulation occurring after 30 min with total accumulation efficiency of 0.1% and 0.2% providing intracellular levels of 130 and 80 pmol/mg cell protein for verbascoside and isoverbascoside, respectively. Combined, these data suggest that verbascosides present in OMWW are bioaccessible and provides a rationale for subsequent in vivo studies on the bioavailability and bioactivity of OMWW components. PMID- 21535768 TI - Modulation of Th1/Th2 balance by Lactobacillus strains isolated from Kimchi via stimulation of macrophage cell line J774A.1 in vitro. AB - Lactobacilli isolated from Kimchi, a Korean traditional food, were tested for their capacity to modulate the T helper (Th) 1/Th2 balance. Ovalbumin (OVA) sensitized mouse splenocytes were cultured with 26 strains of lactobacilli; the highest IL-12 induction and lowest IL-4 production were then observed in 4 strains, including Lactobacillus plantarum CJLP55, CJLP56, CJLP133, and CJLP136. These strains produced a larger amount of IL-12, which enhances differentiation and activation of Th1 cells, in macrophage cell-lines more than positive control strains L. casei KCTC 3109(T) and L. rhamnosus GG, although they also induced production of IL-10, which is a suppressor of IL-12. Indeed, CJLP133-stimulated macrophages induced production of more Th1 cytokine IFN-gamma and less Th2 cytokine IL-4 than KCTC 3109(T) and GG in co-cultivation with T cells. These findings suggest that lactobacilli from Kimchi may modulate the Th1/Th2 balance via macrophage activation in the hypersensitive reaction caused by Th2 cells. PRACTICAL APPLICATION: Allergic reactions including asthma and atopy are caused by predominance of Th2 response over Th1 response. Lactobacilli isolated from fermented foods such as yogurt, cheese, and Kimchi showed health-promoting activities. The present study indicated that several lactobacilli strains from Kimchi may reduce allergic reactions through macrophage-mediated induction of Th1 response. PMID- 21535769 TI - Ascorbic acid degradation in a model apple juice system and in apple juice during ultraviolet processing and storage. AB - Ultraviolet radiation induced degradation of ascorbic acid in a model apple juice system and in apple juice was studied using a collimated beam batch UV reactor. In the model system, ascorbic acid degradation was more rapid at higher dose levels and the reaction accelerated with increasing exposure time. Ascorbic acid degradation significantly (P < 0.05) increased as the pH was raised from 2.4 to 5.5, although no difference was observed between 2.4 and 3.3. Increasing malic acid concentration between 0.1 and 1%, increased ascorbic acid degradation (P < 0.05) although there was no difference between 0.5 and 1.0%. Solution absorbance, varied by addition of tannic acid, decreased ascorbic acid degradation with increasing concentration due to absorption of UV radiation. Fructose at levels found in apple juice significantly increased ascorbic acid degradation while glucose and sucrose did not. Factors identified that accelerate ascorbic acid degradation may at least partially explain why ascorbic acid degradation occurred more rapidly in UV-treated apple juice than in the 0.5% malic acid model system. Ascorbic acid degradation continued after UV treatments during dark storage. Storage decreases were faster at higher initial UV dose levels and higher storage temperature. PRACTICAL APPLICATION: The present study shows the effect of UV processing on ascorbic acid, a key vitamin found in many fruit juices. Process developers and researchers can use this study as a model for designing experiments to identify factors that influence the stability of vitamin C and other bioactive compounds during UV processing. PMID- 21535770 TI - Accumulation of stimulants of Toll-like receptor (TLR)-2 and TLR4 in meat products stored at 5 degrees C. AB - Recent evidence suggests that exposure to stimulants of the innate immune receptors Toll-like receptor (TLR)-2 and TLR4 may contribute to the development of atherosclerosis and insulin resistance. We showed recently that common foodsuffs can contain TLR-stimulants, and that the greatest concentrations were present in meat-based products. Using a recently developed quantitative bioassay, we here examined the kinetics of accumulation of TLR2- and TLR4-stimulants in a variety of meat products held at 5 degrees C in air or under a modified atmosphere for up to 8 d. Meat content of TLR-stimulants increased with time in each meat examined and was paralleled by growth of pseudomonads and Enterobacteriaceae, suggesting that bacterial lipopeptides and lipopolysaccharides are the likely sources of TLR2- and TLR4-stimulants, respectively. TLR-stimulants reached the highest levels (approximately 80 MUg lipopeptide-equivalents per gramme and approximately 7 MUg lipopolysaccharide equivalents per gram) in meat that was minced rather than intact, and when stored in air rather than under a modified atmosphere. TLR2- and TLR4-stimulants in meat products cooked for 1 h retained approximately 20% and approximately 40% of their bioactivity, respectively. In summary, storage conditions and microbial flora critically regulate the kinetics of TLR2- and TLR4-stimulant accumulation in meat products and these may retain biological activity after cooking. PRACTICAL APPLICATION: The novel assays presented in this work could be used to predict the potential of foodstuffs to promote inflammatory signaling in human subjects, which may be deleterious to health. These assays may also be used to monitor the historical microbial flora in food products after cooking or other forms of food processing may have rendered the original microflora nonviable. PMID- 21535771 TI - Antibacterial activities of blueberry and muscadine phenolic extracts. AB - Phenolics are one category of phyto-antimicrobials that refer to the antimicrobial substances extracted from plant sources. This study was undertaken to determine the influence of blueberry and muscadine phenolic extracts on the growths of 2 important foodborne bacterial pathogens, Salmonella Enteritidis and Listeria monocytogenes. Cells of S. Enteritidis (n = 4) or L. monocytogenes (n = 4) strains were inoculated (3 log CFU/mL) into tryptic soy broth (TSB) supplemented with 46.25 ppm of muscadine phenolics and 24 ppm of blueberry phenolics, respectively. The inoculated and un-inoculated broth with or without the supplemented phenolics were incubated at 37 degrees C for 24 h. Samples were drawn periodically, and cell populations of Salmonella and Listeria were determined on tryptic soy agar (TSA). It was observed that Salmonella was relatively more susceptible than Listeria to the phenolic extracts used in the study. The growth of Salmonella was significantly inhibited in all samples at all sampling points except for the sample that was supplemented with muscadine water extract and drawn at the 24-h sampling point. Blueberry phenolics were relatively more effective than muscadine phenolic extracts in inhibiting the growth of Salmonella. One tested strain of Listeria was more susceptible to ethanol than water phenolic extracts. The study revealed the potentials and limitations of using blueberry and muscadine phenolics to control the growths of selected Salmonella and Listeria strains. PMID- 21535772 TI - Quality of mango nectar processed by high-pressure homogenization with optimized heat treatment. AB - This work aimed to evaluate the effect of high-pressure homogenization (HPH) with heat shock on Aspergillus niger, vitamin C, and color of mango nectar. The nectar was processed at 200 MPa followed by heat shock, which was optimized by response surface methodology by using mango nectar ratio (45 to 70), heat time (10 to 20), and temperature (60 to 85 degrees C) as variables. The color of mango nectar and vitamin C retention were evaluated at the optimized treatments, that is, 200 MPa + 61.5 degrees C/20 min or 73.5 degrees C/10 min. The mathematical model indicates that heat shock time and temperature showed a positive effect in the mould inactivation, whereas increasing ratio resulted in a protective effect on A. niger. The optimized treatments did not increase the retention of vitamin C, but had positive effect for the nectar color, in particular for samples treated at 200 MPa + 61.5 degrees C/20 min. PRACTICAL APPLICATION: The results obtained in this study show that the conidia can be inactivated by applying HPH with heat shock, particularly to apply HPH as an option to pasteurize fruit nectar for industries. PMID- 21535773 TI - Kinetics and mechanism of bacterial inactivation by ultrasound waves and sonoprotective effect of milk components. AB - Inactivation of Escherichia coli and Listeria monocytogenes were investigated in buffer and milk upon treatment with ultrasound waves (USW). In addition, sonoprotective effect of milk components and ultrasound-induced changes in bacterial cells were investigated using scanning electron microscopy (SEM). Bacterial cells were added to phosphate buffer, whole milk, skim milk, or simulated milk ultrafiltrate (SMUF). To determine the sonoprotective effect of milk components, lactose (5%), casein (3%), or beta lactoglobulin (0.3%) was added to SMUF. Samples were sonicated with 24 kHz pulse USW while maintaining the system temperature between 30 to 35 degrees C. Aliquots were drawn at set times during sonication and bacteria were enumerated by surface plating appropriate dilutions on selective and nonselective media plates. Escherichia coli exhibited significantly higher D values in whole (2.43 min) and skim milk (2.41 min) than phosphate buffer (2.19 min). Listeria monocytogenes also showed higher D values in whole (9.31 min) and skim milk (8.61 min) compared to phosphate buffer (7.63 min). Data suggest that milk exerts a sonoprotective effect on these bacteria. Escherichia coli exhibited a log-linear inactivation kinetics followed by tailing whereas L. monocytogenes showed 1st-order kinetics throughout. Among the milk components tested, presence of lactose in SMUF resulted in significantly higher D values than SMUF for both organisms suggesting that lactose was exerting a protective effect on bacteria. SEM images showed that USW caused mechanical damage to the cell wall and cell membrane of bacteria leading to their inactivation. PMID- 21535774 TI - Preparation of a Lactobacillus plantarum starter culture for cucumber fermentations that can meet kosher guidelines. AB - A method is described for growth of a Lactobacillus plantarum starter culture in jars of commercially available pasteurized fresh-pack kosher dill cucumbers so that jars can be used to inoculate commercial scale cucumber fermentation tanks. A procedure is also described to transfer lactic acid bacteria from frozen storage in MRS broth into cucumber juice and commercial jars of kosher dill cucumbers so that a selected strain of lactic acid bacteria can be kosher certified for commercial fermentations in processing plants that operate under kosher certification. The strain of L. plantarum used in these experiments grew to maximum cell numbers in 4 d at 20 to 25 degrees C and then maintained viable cell numbers for 2 wk at >10(8) CFU/mL so the culture was suitable for inoculation of fermentation tanks. Refrigeration of jars of culture after they grow to maximum numbers minimizes die-off of cells sufficiently so that a pure culture can be maintained by aseptically transferring brine containing viable bacteria to a new pH-adjusted jar only once every 4 mo. PRACTICAL APPLICATION: This report describes a method to prepare a lactic acid bacteria starter culture suitable for kosher vegetable fermentations. PMID- 21535775 TI - Improved sauerkraut production with probiotic strain Lactobacillus plantarum L4 and Leuconostoc mesenteroides LMG 7954. AB - Probiotic strain Lactobacillus plantarum L4 and strain Leuconostoc mesenteroides LMG 7954 were applied for the controlled fermentation of cabbage heads. The parameters of the controlled and spontaneous fermentations, including antimicrobial effect of cabbage brines obtained at the end of both fermentations, were monitored. To check out the influence of starter culture strains, 10 randomly chosen lactic acid bacteria, isolated at the end of controlled cabbage heads fermentation were identified by API 50 CHL test, and the presence of the probiotic culture was confirmed by Pulsed Field Gel Electrophoresis. The starter cultures applied for cabbage heads fermentation allowed lowering of NaCl concentrations from 4.0% to 2.5% (w/v), considerably accelerated fermentation process by 14 d, and improved the product quality. The produced sauerkraut heads are considered probiotic product as viable probiotic cells count in final product was higher than 10(6) colony-forming units (CFU) per gram of product. PRACTICAL APPLICATION: The results of this research could be applied in the production of fermented cabbage heads with added functional (probiotic) value and with lower NaCl concentration with expected shortened fermentation time. This could not only be of economic but also of ecological importance. PMID- 21535776 TI - Characterization of a wild strain of Alicyclobacillus acidoterrestris: heat resistance and implications for tomato juice. AB - This article reports the characterization of a wild strain of Alicyclobacillus acidoterrestris and describes the implications of the heat resistance of this microorganism in tomato juice. The strain (labeled as A. acidoterrestrisgamma4) showed pH and temperature ranges for growth typical of the species (3.0 to 6.0 for the pH and 35 to 60 degrees C for the temperature); heat resistance in tomato juice was as follows: D(T) values of 40.65, 9.47, and 1.5 min (at 85, 90, and 95 degrees C, respectively) and z-value of 7 degrees C. A treatment at 70 degrees C for 15 min was found to be optimal for spore activation, whereas Malt Extract Agar, acidified to pH 4.5, showed good results for spore recovery. Concerning the implications of heat resistance of A. acidoterrestris on tomato juice, high temperatures required for spore inactivation determined a general decrease of the antioxidant activity (increase of the redox potential and reduction of the chain-breaking activity), but not the formation of brown compounds (namely, hydroxymethylfurfural), thus suggesting an effect on the secondary antioxidants (carotenoids and ascorbic acid) rather than on lycopene. PRACTICAL APPLICATION: Alicyclobacillus acidoterrestris is an emerging spore forming microorganism, capable of causing spoilage in tomato juice. Due to their high thermal resistance, spores could be used as targets for the optimization of heat processing; this article reports on the assessment of thermal resistance of a wild strain of A. acidoterrestris, then focusing on the effect of the thermal treatment necessary to inactivate spores on the quality of tomato juice. PMID- 21535777 TI - Discrimination of Alicyclobacillus strains using nitrocellulose membrane filter and attenuated total reflectance fourier transform infrared spectroscopy. AB - Alicyclobacillus spp. are thermoacidophilic, spore-forming bacteria, some of which cause spoilage in pasteurized and heat-treated apple juice products through the production of guaiacol. It would be helpful if a rapid method to detect and discriminate Alicyclobacillus strains was available. A simple and rapid sample preparation method using nitrocellulose membrane filter (NMF) and a single reflection horizontal attenuated total reflection (HATR) accessory with Fourier transform infrared (FT-IR) was developed here. Fourier transform infrared (FT-IR) spectroscopy was used and tested on 8 Alicyclobacillus strains (KF, WAC, NWN 13501, NWN-12697, NWN-12654, NWN-10682, 1016, 1101). A linear discriminant analysis (LDA) was established to discriminate Alicyclobacillus strains. The sample preparation method could successfully separated strains into different groups by principal component analysis (PCA). High identification accuracy (95%) was achieved with the LDA model. PRACTICAL APPLICATION: The method developed in the paper can be used to discriminate different Alicyclobacillus strains from each other making it possible to easily determine whether the strain of Alicyclobacillus present is associated with juice spoilage. PMID- 21535778 TI - Biofilms of Listeria monocytogenes produced at 12 degrees C either in pure culture or in co-culture with Pseudomonas aeruginosa showed reduced susceptibility to sanitizers. AB - The biofilm-forming ability of 21 Listeria monocytogenes isolates, previously pulsotyped and corresponding to 16 strains, from different origins was evaluated using the Calgary Biofilm Device, at 37 degrees C. Biofilms of 4 selected strains were also produced either on pure cultures or on co-cultures with Pseudomonas aeruginosa (PAO1), at 12 degrees C and at 37 degrees C. For these biofilms, the minimum biofilm eradication concentrations (MBECs) of 4 commercial dairy sanitizers (1 alkyl amine acetate based--T99, 2 chlorine based--T66 and DD, and 1 phosphoric acid based--BP) were determined. Listeria monocytogenes biofilms grown, either at 37 degrees C or 12 degrees C, were able to achieve similar cell densities by using different incubation periods (24 h and 7 d, respectively). In co-culture biofilms, P. aeruginosa was the dominant species, either at 37 degrees C or at 12 degrees C, representing 99% of a total biofilm population of 6 to 7 log CFU/peg. Co-culture biofilms were generally less susceptible than L. monocytogenes pure cultures. More interestingly, the biofilms produced at 12 degrees C were usually less susceptible to the sanitizers than when produced at 37 degrees C. Single or co-culture biofilms of L. monocytogenes and PAO1, particularly produced at 12 degrees C, retrieved MBEC values for agents T99 and BP that were, at times, above the maximum in-use recommended concentrations for these agents. The results presented here reinforce the importance of the temperature used for biofilm formation, when susceptibility to sanitizers is being assessed. PRACTICAL APPLICATION: Since most food plants have cold wet growth niches in production and storage areas, susceptibility testing should be performed on biofilms produced at refrigeration temperatures. Moreover, the efficiency of the sanitizers used in food industries should be performed on mixed culture biofilms, since in field conditions these will predominate. The results presented here highlight the importance of the temperature used for biofilm formation, when susceptibility to disinfectants is being assessed, as biofilms produced at lower temperature were less susceptible to sanitizers. PMID- 21535779 TI - Physical and antibacterial properties of edible films formulated with apple skin polyphenols. AB - Fruit and vegetable skins have polyphenolic compounds, terpenes, and phenols with antimicrobial and antioxidant activity. These flavoring plant essential oil components are generally regarded as safe. Edible films made from fruits or vegetables containing apple skin polyphenols have the potential to be used commercially to protect food against contamination by pathogenic bacteria. The main objective of this study was to evaluate physical properties as well as antimicrobial activities against Listeria monocytogenes, Escherichia coli O157:H7, and Salmonella enterica of apple skin polyphenols at 0% to 10% (w/w) concentrations in apple puree film-forming solutions formulated into edible films. Commercial apple skin polyphenol powder had a water activity of 0.44 and high total soluble phenolic compounds and antioxidant capacity (995.3 mg chlorogenic acid/100 g and 14.4 mg Trolox/g, respectively). Antimicrobial activities of edible film containing apple skin polyphenols were determined by the overlay method. Apple edible film with apple skin polyphenols was highly effective against L. monocytogenes. The minimum concentration need to inactive L. monocytogenes was 1.5%. However, apple skin polyphenols did not show any antimicrobial effect against E. coli O157:H7 and S. enterica even at 10% level. The presence of apple skin polyphenols reduced water vapor permeability of films. Apple skin polyphenols increased elongation of films and darkened the color of films. The results of the present study show that apple skin polyphenols can be used to prepare apple-based antimicrobial edible films with good physical properties for food applications by direct contact. PMID- 21535780 TI - Bactericidal action of binary and ternary mixtures of carvacrol, thymol, and eugenol against Listeria innocua. AB - The bactericidal effect of 3 natural agents (carvacrol, thymol, and eugenol) was evaluated as well as their binary and ternary mixtures on Listeria innocua inactivation in liquid model systems. Minimal bactericidal concentrations (MBC) of these agents were determined, and then binary and ternary mixtures were evaluated. Culture media were inoculated with L. innocua and incubated for 72 h at 35 degrees C. Turbidity of studied systems were determined every 24 h. The most effective individual antimicrobial agent was carvacrol, followed by thymol and then eugenol with MBCs of 150, 250, and 450 mg kg(-1), respectively. It was observed that the most effective binary mixture was 75 mg kg(-1) carvacrol and 62.5 mg kg(-1) thymol. Furthermore, the ternary mixture carvacrol-thymol-eugenol in concentrations of 75, 31.25, and 56.25 mg kg(-1), correspondingly, was the most effective for L. innocua inactivation. Several binary and ternary mixtures of these 3 natural antimicrobial agents worked adequately to inactivate L. innocua. PMID- 21535781 TI - Poly (DL-lactide-co-glycolide) (PLGA) nanoparticles with entrapped trans cinnamaldehyde and eugenol for antimicrobial delivery applications. AB - Eugenol and trans-cinnamaldehyde are natural compounds known to be highly effective antimicrobials; however, both are hydrophobic molecules, a limitation to their use within the food industry. The goal of this study was to synthesize spherical poly (DL-lactide-co-glycolide) (PLGA) nanoparticles with entrapped eugenol and trans-cinnamaldehyde for future antimicrobial delivery applications. The emulsion evaporation method was used to form the nanoparticles in the presence of poly (vinyl alcohol) (PVA) as a surfactant. The inclusion of antimicrobial compounds into the PLGA nanoparticles was accomplished in the organic phase. Synthesis was followed by ultrafiltration (performed to eliminate the excess of PVA and antimicrobial compound) and freeze-drying. The nanoparticles were characterized by their shape, size, entrapment efficiency, and antimicrobial efficiency. The entrapment efficiency for eugenol and trans cinnamaldehyde was approximately 98% and 92%, respectively. Controlled release experiments conducted in vitro at 37 degrees C and 100 rpm for 72 h showed an initial burst followed by a slower rate of release of the antimicrobial entrapped inside the PLGA matrix. All loaded nanoparticles formulations proved to be efficient in inhibiting growth of Salmonella spp. (Gram-negative bacterium) and Listeria spp. (Gram-positive bacterium) with concentrations ranging from 20 to 10 mg/mL. Results suggest that the application of these antimicrobial nanoparticles in food systems may be effective at inhibiting specific pathogens. PRACTICAL APPLICATION: Nanoencapsulation of lipophilic antimicrobial compounds has great potential for improving the effectiveness and efficiency of delivery in food systems. This study consisted of synthesizing PLGA nanoparticles with entrapped eugenol and trans-cinnamaldehyde. By characterizing these new delivery systems, one can understand the controlled-release mechanism and antimicrobial efficiency that provides a foundation that will enable food manufacturers to design smart food systems for future delivery applications, including packaging and processing, capable of ensuring food safety to consumers. PMID- 21535782 TI - Highly stable, edible cellulose films incorporating chitosan nanoparticles. AB - The need for biodegradable polymers for packaging has fostered the development of novel, biodegradable polymeric materials from natural sources, as an alternative to reduce amount of waste and environmental impacts. The present investigation involves the synthesis of chitosan nanoparticles-carboxymethylcellulose films, in view of their increasing areas of application in packaging industry. The entire process consists of 2-steps including chitosan nanoparticles preparation and their incorporation in carboxymethylcellulose films. Uniform and stable particles were obtained with 3 different chitosan concentrations. The morphology of chitosan nanoparticles was tested by transmission electron microscopy, revealing the nanoparticles size in the range of 80 to 110 nm. The developed film chitosan nanoparticles-carboxymethylcellulose films were characterized by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis, solubility tests, and mechanical analysis. Improvement of thermal and mechanical properties were observed in films containing nanoparticles, with the best results occurring upon addition of nanoparticles with 110 nm size in carboxymethylcellulose films. PRACTICAL APPLICATION: Carboxymethylcellulose films containing chitosan nanoparticles synthesized and characterized in this article could be a potential material for food and beverage packaging applications products due to the increase mechanical properties and high stability. The potential application of the nanocomposites prepared would be in packaging industry to extend the shelf life of products. PMID- 21535783 TI - Developing the NASA food system for long-duration missions. AB - Even though significant development has transformed the space food system over the last 5 decades to attain more appealing dietary fare for low-orbit space crews, the advances do not meet the need for crews that might travel to Mars and beyond. It is estimated that a food system for a long-duration mission must maintain organoleptic acceptability, nutritional efficacy, and safety for a 3- to 5-y period to be viable. In addition, the current mass and subsequent waste of the food system must decrease significantly to accord with the allowable volume and payload limits of the proposed future space vehicles. Failure to provide the appropriate food or to optimize resource utilization introduces the risk that an inadequate food system will hamper mission success and/or threaten crew performance. Investigators for the National Aeronautics and Space Administration (NASA) Advanced Food Technology (AFT) consider identified concerns and work to mitigate the risks to ensure that any new food system is adequate for the mission. Yet, even with carefully planned research, some technological gaps remain. NASA needs research advances to develop food that is nutrient-dense and long-lasting at ambient conditions, partial gravity cooking processes, methods to deliver prescribed nutrients over time, and food packaging that meets the mass, barrier, and processing requirements of NASA. This article provides a brief review of research in each area, details the past AFT research efforts, and describes the remaining gaps that present barriers to achieving a food system for long exploration missions. PMID- 21535784 TI - The role of oral processing in dynamic sensory perception. AB - Food oral processing is not only important for the ingestion and digestion of food, but also plays an important role in the perception of texture and flavor. This overall sensory perception is dynamic and occurs during all stages of oral processing. However, the relationships between oral operations and sensory perception are not yet fully understood. This article reviews recent progress and research findings on oral food processing, with a focus on the dynamic character of sensory perception of solid foods. The reviewed studies are discussed in terms of both physiology and food properties, and cover first bite, mastication, and swallowing. Little is known about the dynamics of texture and flavor perception during mastication and the importance on overall perception. Novel approaches use time intensity and temporal dominance techniques, and these will be valuable tools for future research on the dynamics of texture and flavor perception. PMID- 21535785 TI - Reinventing R&D in an open innovation ecosystem. AB - Today, the idea that random collisions and interactions offer solutions and business opportunities is no longer acceptable. Instead, partnerships and alignments, both downstream and upstream, are paramount for cross-fertilization and synergy. To survive, and thrive, in today's world of global innovation, alliances based on compatible differences must be sought. Innovation Partnerships and the Sharing-is-Winning model represent a paradigm shift toward accelerating co-development of sustainable innovation, with alignment of the entire value chain with consumer-centric innovations being one of its main pillars. It includes 3 levels of typical joint development: universities, research institutes, and centers; start-ups and individual inventors; a select number of key strategic suppliers. Reinventing R&D in an open innovation ecosystem and increasing success rates in an increasingly competitive marketplace require implementing significant steps--both perceived and tangible. Specific recommendations are provided for 10 major identified topics: leadership, strategy, the consumer, the value chain, internal experts and championship, metrics, IP, culture, academia, and passion. The Sharing-is-Winning model extends the scope of open innovation to sustainable and enhanced processes of co innovation. PMID- 21535786 TI - The biomimetic immunoassay based on molecularly imprinted polymer: a comprehensive review of recent progress and future prospects. AB - Immunoassay, based on a selective affinity of the biological antibody for its antigen, is one of the most usual analytical methods in food safety and environmental chemistry. However, it presents several drawbacks because of the nature of the antibody. Molecular imprinting technique, due to its high selectivity and stability, ease of preparation and low cost, has shown great potential in producing artificial antibodies in biomimetic immunoassays. This article focuses on the recent states, advantages, current problems and outlooks of molecularly imprinted radio, fluoro, enzyme-linked and chemiluminescent immunoassays, and biomimetic immunosensor, with special emphasis on the challenges in developing biomimetic enzyme-linked immunosorbent assays (BELISAs). The biomimetic immunoassay method will provide an important new analysis platform in food safety, although the sensitivity and specificity is relatively low. PRACTICAL APPLICATION: As a new simple analysis method, the biomimetic immunoassay has attractive prospect, although some limitations were existed in real-sample assay. In this critical review, some promising solutions for overcoming its drawbacks were put forward, which may promote the more quick development and extensive application of this method in food safety. PMID- 21535787 TI - Does Guinness travel well? AB - This study aimed to test the much-pronounced but poorly supported theory that "Guinness does not travel well." A total of 4 researchers from 4 different countries of origin traveled around the world for 12 mo to collect data on the enjoyment of Guinness and related factors. The main outcome was measured on a Visual Analogue Scale (VAS) from 0 (enjoyed it not at all) to 100 (enjoyed it very much). A total of 103 tastings were recorded (42 in Ireland, 61 elsewhere) in 71 different pubs spread over 33 cities and 14 countries. The enjoyment of Guinness consumed in Ireland was rated higher (74 mm VAS) than outside Ireland (57 mm; P < 0.001). This difference remained statistically significant after adjusting for researcher, pub ambience, Guinness appearance, and the sensory measures mouthfeel, flavor, and aftertaste. This study is the first to provide scientific evidence that Guinness does not travel well and that the enjoyment of Guinness (for our group of nonexpert tasters) was higher when in Ireland. Results, however, are subject to further verification because of limitations in the study design. PMID- 21535788 TI - Effect of salicylic acid treatment on postharvest quality, antioxidant activities, and free polyamines of asparagus. AB - The effects of salicylic acid (SA) on the quality and antioxidant activity of asparagus stored at 18 +/- 2 degrees C were investigated by analyzing the color, chlorophyll, shear force, and the activity of antioxidant compounds such as ascorbic acid, phenolics, flavonoids, 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity ferric reducing antioxidant power (FRAP), and polyamines (PAs). The results showed that SA improved the color and maintained the chlorophyll, phenolic, flavonoid, and ascorbic acid content of asparagus. High concentrations of SA caused a deterioration in asparagus would harm to color and had no effect on shear force within 6 d. SA induced the maximum concentration of phenolics in postharvest asparagus, promoted the increase in total flavonoids before 6 to 9 d, affected the antioxidant activity positively as indicated by the resultant increase in FRAP concentration; however, SA was only active with regard to DPPH scavenging activity within 6 d of treatment. Spermidine (Spd) is the most common form of PA in asparagus, and free putrescine (Put) contents increased over the first 3 d following harvest and then decreased. Spd and Spm concentrations evolved in a similar way and decreased during storage. Higher Spd and Spm contents in the SA pre-treatment Put was inhabited and its peaks appeared later. PMID- 21535789 TI - Effect of the gamma radiation dose rate on psychrotrophic bacteria, thiobarbituric acid reactive substances, and sensory characteristics of mechanically deboned chicken meat. AB - Frozen samples of mechanically deboned chicken meat (MDCM) with skin were irradiated with gamma radiation doses of 0.0 kGy (control) and 3 kGy at 2 different radiation dose rates: 0.32 kGy/h (3 kGy) and 4.04 kGy/h (3 kGy). Batches of irradiated and control samples were evaluated during 11 d of refrigerated (2 +/- 1 degrees C) storage for the following parameters: total psychrotrophic bacteria count, thiobarbituric acid reactive substances (TBARS), evaluation of objective color (L*, a*, and b*) and a sensory evaluation (irradiated odor, oxidized odor, pink and brown colors). No statistical difference (P > 0.05) was found amongst the TBARS values obtained for the MDCM samples irradiated with dose rates of 0.32 and 4.04 kGy/h. There was a significant increase (P < 0.05) in the psychrotrophic bacterial count as from the 7th day of refrigerated storage, for the MDCM samples irradiated at the dose rate of 4.04 kGy/h. With respect to the attribute of oxidized odor, the samples irradiated with a dose rate of 0.32 kGy/h showed a stronger intensity and were significantly different (P < 0.05) from the sample irradiated with a dose rate of 4.04 kGy/h on days 0 and 2 of refrigerated storage. Irradiation with a dose rate of 4.04 kGy/h (3 kGy) was shown to be the best condition for the processing of MDCM according to the evaluation of all the variables, under the conditions of this study. Practical Application: The results obtained for the application of different dose rates of ionizing radiation to mechanically deboned chicken meat will provide the food industry with information concerning the definition of the best processing conditions to maximize the sensory and food quality. PMID- 21535790 TI - Effects of salting processes and time on the chemical composition, textural properties, and microstructure of cooked duck egg. AB - Chemical composition, textural properties, and microstructure of cooked duck egg salted by 2 methods (coating and immersing) were determined during 4 wk of salting. As the salting time increased, moisture content increased and salt content decreased for both cooked salted egg white and yolk. Oil exudation of cooked yolk and expressible water content of cooked egg white obtained from both salting methods increased as salting proceeded (P < 0.05). After cooking, oil exudation accompanied by the solubilized pigments, especially at the outer layer of yolk, was obtained. At week 3 of salting, egg yolk from coating method had the higher egg exudation than that from immersing method. As the salting times increased, the lower hardness, springiness, gumminess, chewiness, and resilience with higher adhesiveness and cohesiveness were generally found in cooked salted egg white (P < 0.05), irrespective of salting methods. Conversely, the hardness of cooked yolk increased continuously and reached the maximum at week 2 and 2 to 3 for immersing and coating method (P < 0.05), respectively. Confocal laser scanning micrographs revealed the smaller yolk granules with more release of free lipid in salted egg after heating, compared with the fresh counterpart. As visualized by scanning electron microscope, gel of cooked salted egg white was coagulum type with larger voids. Salting methods determined oil exudation in egg yolk and texture profile of egg white gel after cooking; however, those attributes were also governed by the salting time. PRACTICAL APPLICATION: Salted duck egg can be made by 2 methods (coating and immersing) affecting the characteristic of salted egg white and yolk after cooking. Desirable cooked salted egg having the red yolk with hardness and high oil exudation could be obtained when salting was carried out for 3 and 4 wk for immersing and coating method, respectively. PMID- 21535791 TI - Role of steaming and toasting on the odor, protein characteristics of chickpea (Cicer arietinum L.) flour, and product quality. AB - Proteins play an important role in imparting functional attributes like texture and shape, which determine the sensory quality of the foods. Boondi, a deep fried product from chickpea (Cicer arietinum L.) flour dispersion, is a popular snack food in India. Chickpea dhal (splits) or flour was subjected to various processing conditions like steaming and toasting, to determine their effect on the chickpea flour protein characteristics and on the product quality. Dhal and flour subjected to different heat treatments showed differences in their odor profiles. The SDS-PAGE of sodium phosphate buffer extracts of steamed dhal or flour showed that the high molecular weight (HMW) proteins of 66 to 100 kDa that were present in the untreated dhal were found to be absent in steamed dhal extracts. However, SDS buffer extracts on SDS-PAGE of these steamed samples did not show any difference between untreated and thermally treated dhal samples. Phosphate buffer extracts of the thermally treated flours were subjected to gel filtration chromatography and the results indicated that the HMW protein fraction content decreased significantly in the treated dhal or flour samples compared to control. Boondi prepared from the thermally treated dhal samples resulted in the loss of spherical shape of boondi. Thus, the results indicate that thermal treatment of chickpea dhal and flour influence changes in protein characteristics, the sensory profile and quality of boondi. PMID- 21535792 TI - Effect of rapid thawing on the meat quality attributes of USDA select beef strip loin steaks. AB - The objective was to determine the meat quality effects of rapidly thawing beef steaks in a water bath. Frozen beef strip loins (n = 24) were cut into steaks sequentially from the rib end and identified by anatomical location (anterior, middle, posterior) within the loin. Within location, steaks were randomly assigned to conventional (C; 18 to 20 h, 4 degrees C) or rapid thawing methods. Rapid thawing methods, fast (20 min, 20 degrees C) or very fast (11 min, 39 degrees C), were conducted in a circulating water bath. The physical, thawing, cooking, color, and texture characteristics of each steak were recorded. Data were analyzed as a randomized complete block design with a 3 thawing treatments * 3 locations factorial analysis with loin as a block. No location by thawing method interaction was detected (P > 0.05) for the measured variables. Compared to C steaks, rapidly thawed steaks exhibited lower thaw drip loss (P < 0.001) and higher a* values (P < 0.001). Thawing treatment did not influence L*, b*, cook yield, or shear force. Steaks from the posterior end had higher (P < 0.001) surface to volume ratios that may have contributed to the higher thaw loss (P < 0.01), longer cooking time (P < 0.001), lower cooking yield (P < 0.001), and higher shear force (P < 0.02) compared to steaks from the anterior and middle portions of the loins. These data indicate that beef steaks taken from the entire length of the loin can be rapidly thawed in a water bath following food safety guidelines with minimal impact on meat quality. Practical Application: Freezing rate and frozen storage effects on meat quality have been well documented; however, there is comparatively little information on the meat quality effects of rapid thawing within food safety guidelines. This study demonstrates that beef strip loin steaks can be rapidly thawed in as few as 11 min without affecting texture or cooking yield, while reducing thaw drip loss. Thus, rapid thawing may enhance the apparent juiciness of steaks for consumers and provide an effective method for maintaining consistent control of experimental conditions for researchers. PMID- 21535793 TI - Fermented nondigestible fraction from common bean (Phaseolus vulgaris L.) cultivar Negro 8025 modulates HT-29 cell behavior. AB - The aim of the study was to evaluate the effect of a fermented nondigestible fraction (FNDF) of cooked bean (Phaseolus vulgaris L.) cultivar Negro 8025 on human colon adenocarcinoma HT-29 cell survival. Negro 8025 was chosen for in vitro fermentation based on comparison of chemical composition with 2 other cultivars: Azufrado Higuera and Pinto Durango. Negro 8025 had 58% total dietary fiber, 27% resistant starch, and 20 mg of (+)-catechin equivalents per gram of sample. Short-chain fatty acids (SCFAs) production and pH of the medium were measured after fermentation as indicators of colon protection through induced arrest on cell culture and apoptosis. Butyrate and pH of FNDF of Negro 8025 were higher than the control fermented raffinose extract. The FNDF inhibited HT-29 cell survival in a time- and concentration-dependent manner. The lethal concentration 50 (LC(50)) was 13.63% FNDF (equivalent to 7.36, 0.33, and 3.31 mmol of acetic, propionic, and butyric acids, respectively). DNA fragmentation, an apoptosis indicator, was detected by the TdT-mediated dUTP nick end labeling method in cells treated with the LC(50)-FNDF and a synthetic mixture of SCFAs mimicking LC(50)-FNDF. Our results suggest that common bean is a reliable source of fermentable substrates in colon, producing compounds with potential chemoprotective effect on HT-29 colon adenocarcinoma cells, so it may present an effective alternative to mitigate colon cancer development. PMID- 21535794 TI - Effect of microwave heating during alkaline-cooking of aflatoxin contaminated maize. AB - To evaluate the effectiveness of maize detoxification achieved with a modified tortilla-making process (MTMP), maize contaminated with aflatoxin B(1) (AFB(1)) and aflatoxin B(2) (AFB(2)) at levels of 22.46, 69.62, and 141.48 ng/g (AFB(1)+ AFB(2)) was processed into tortillas. Aflatoxin content was determined according to the 991.31 AOAC official method. Based on the results obtained with spiked samples (0.78 to 25 ng/g), the mean recovery was 92%, with a standard error of 1.2, and a coefficient variation value of 4.4%. The MTMP caused 68, 80, and an 84% decrease in aflatoxin content, respectively. Extract acidification (as occurs during digestion) prior to mycotoxin quantification caused some reformation of the aflatoxin structure in tortillas (up to 3%). According to these results, the MTMP seems to be safe for decontamination since a low percentage of the initial aflatoxin concentration can be reverted to the original fluorescent form upon acidification. PRACTICAL APPLICATION: The potential presence of aflatoxins in maize destined for human consumption is a serious problem to the Mexican food supply, as these toxic compounds may persist during the traditional alkaline process for tortilla elaboration. Consequently, new detoxification procedures are needed that eliminate or at least minimize the aflatoxin risk, through lowering aflatoxin concentration in maize-based products. Under these considerations, the use of MTMP is recommended, since it has definite advantages including non production of wastewater and reduced energy/time consumption. PMID- 21535795 TI - Genotoxicity evaluation of Moringa oleifera seed extract and lectin. AB - This article reports the genotoxicity assessment of an extract of M. oleifera seed powder and the water-soluble Moringa oleifera lectin (WSMoL) isolated from seeds. The lectin isolated by chitin chromatography showed hemagglutinating activity with different erythrocytes, activity in a broad pH range (4.5 to 9.5), and retention of hemagglutinating activity after being heated to 100 degrees C. Genotoxicity of the seed extract and WSMoL were assessed using the cell-free plasmid DNA as well as the Salmonella typhimurium (Ames and Kado) assays with TA97, TA98, TA100, and TA102 in the presence or absence of hepatic metabolization. Seed extract at concentration (0.2 MUg/MUL) recommended to treat water was not genotoxic by Ames, Kado, and cell-free plasmid DNA assays. S. typhimurium strains showed to be sensitive to M. oleifera extract revealing a mutagenic effect at doses higher than 0.6 MUg/MUL with hepatic metabolization. The extract at doses higher than 0.4 MUg/MUL, without hepatic metabolization, was mutagenic for TA100 and TA102. WSMoL was nonmutagenic by used assays. The use of high concentrations of the extract may pose a risk to human health and the safe use of M. oleifera seed powder to treat water for human consumption requires more study; however, the purified lectin could be an alternative for water treatment. PRACTICAL APPLICATION: The concentration 0.2 MUg/MUL of M. oleifera seed extract recommended to treat water for humans did not pose a risk to human health. The mutagenicity detected at concentrations higher than 0.4 MUg/MUL was not due to WSMoL, lectin isolated from extract. PMID- 21535796 TI - Ammonia gas permeability of meat packaging materials. AB - Meat products are packaged in polymer films designed to protect the product from exterior contaminants such as light, humidity, and harmful chemicals. Unfortunately, there is almost no data on ammonia permeability of packaging films. We investigated ammonia permeability of common meat packaging films: low density polyethylene (LDPE; 2.2 mil), multilayer polyolefin (MLP; 3 mil), and vacuum (V-PA/PE; 3 mil, 0.6 mil polyamide/2.4 mil polyethylene). The films were fabricated into 10 * 5 cm pouches and filled with 50 mL deionized water. Pouches were placed in a plexiglass enclosure in a freezer and exposed to 50, 100, 250, or 500 ppm ammonia gas for 6, 12, 24, and 48 h at -17 +/- 3 degrees C and 21 +/- 3 degrees C. At freezing temperatures, no ammonia residues were detected and no differences in pH were found in the water. At room temperature, ammonia levels and pH of the water increased significantly (P < 0.05) with increasing exposure times and ammonia concentrations. Average ammonia levels in the water were 7.77 ppm for MLP, 5.94 ppm for LDPE, and 0.89 ppm for V-PA/PE at 500 ppm exposure for 48 h at 21 +/- 3 degrees C. Average pH values were 8.64 for MLP, 8.38 for LDPE, and 7.23 for V-PA/PE (unexposed ranged from 5.49 to 6.44) at 500 ppm exposure for 48 h. The results showed that temperature influenced ammonia permeability. Meat packaging materials have low ammonia permeability and protect meat products exposed to ammonia leaks during frozen storage. PMID- 21535800 TI - Vitamin C and sugar levels as simple markers for discriminating Spanish honey sources. AB - In this work, 7 Spanish honeys with different botanical origins were studied. The honey origins were rosemary, chestnut, lavender, echium, thyme, multifloral, and honeydew. The chemical compounds determined were ascorbic acid (vitamin C), hydroxymethylfurfural, and major sugar contents (glucose and fructose). The physicochemical parameters, pH, conductivity, moisture, free acidity, and color, were also measured. Vitamin C is an important antioxidant in food, and the possibility to use it as discriminate parameter among different honeys was studied. The determination of vitamin C in honey samples was carried out by 2 different methods, volumetric and chromatographic comparing the results by both statistically. Vitamin C content was higher in thyme honeys than in the other types; however a wide dispersion in the values was found. Through a linear discriminant analysis (LDA), conductivity, glucose, fructose, and vitamin C content were the most important discriminant parameters. PRACTICAL APPLICATION: Vitamin C content in different honey sources has been determined by a simple and rapid chromatographic method (less than 3 min) in honeys from 6 botanical origins. The results together with glucose and fructose content and some physicochemical parameters have been studied in order to discriminate the botanical origin of honeys and in the future certified their quality. A statistical LDA was applied to the data, and differentiation of honey sources was possible with very good agreement. The vitamin C content found in thymus honeys was significantly higher than in other types. This fact makes vitamin C a special marker for thymus honeys that have a higher antioxidant effect than the others giving it special properties. The identification of honey sources is essential for beekeepers in order to certify honeys for consumers. PMID- 21535797 TI - Rutin inhibits oleic acid induced lipid accumulation via reducing lipogenesis and oxidative stress in hepatocarcinoma cells. AB - Excessive lipid accumulation within liver has been proposed to cause obesity, hyperlipidemia, diabetes, and fatty liver disease. Rutin, a common dietary flavonoid that is consumed in fruits, vegetables, and plant-derived beverages, has various biological functions, including antioxidant, anti-inflammatory, and anticancer effects. However, a hypolipidemic effect of rutin on fatty liver disease has not been reported. In this study, we examined the effect of rutin on reducing lipid accumulation in hepatic cells. Hepatocytes were treated with oleic acid (OA) containing with or without rutin to observe the lipid accumulation by Nile red stain. The result showed rutin suppressed OA-induced lipid accumulation and increased adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activity in hepatocytes. The expression of critical molecule involved in lipid synthesis, sterol regulatory element binding proteins-1 (SREBP-1), was attenuated in rutin-treated cells. Moreover, long-term incubation of rutin inhibited the transcriptions of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), glycerol-3-phosphate acyltransferase (GPAT), fatty acid synthase (FAS), and acetyl-coenzyme carboxylase (ACC). Besides, we also found out the antioxidative effect of rutin by increasing the expression of peroxisome proliferator-activated receptor (PPAR)-alpha and antioxidative enzymes. Taken together, our findings suggest rutin could attenuate lipid accumulation by decreasing lipogenesis and oxidative stress in hepatocyte. PMID- 21535801 TI - Production and physicochemical properties of 2-octen-1-ylsuccinic derivatives from waxy corn starch. AB - Waxy corn starch was esterified with 2-octen-1-ylsuccinic anhydride (OSA) using response surface methodology. The molecular structure and paste properties were also investigated. Results indicated that the optimum parameters for esterification were as follows: reaction period 4 h, temperature 36.7 degrees C, pH of reaction system 8.3, concentration of starch slurry 36.9%, and amount of OSA 3%. The degree of substitution was 0.0187 and the reaction efficiency was 80.6%. The ester carbonyl group in OSA starch was characterized by Fourier Transform Infrared Spectroscopy at 1723 cm(-1). Compared with native starch, OSA derivative had higher peak viscosity, better freeze-thaw stability, and decreased gelatinization temperature and digestibility by porcine pancreatic alpha-amylase. Scanning electron microscopy showed that the gels from OSA starch had less and smaller pores; however, the native starch gels changed to sponge-like structure after 4 freezing/thawing cycles. The OSA modified waxy corn starch offered a potential to be used in frozen foods. PRACTICAL APPLICATION: (a) To optimize operating conditions to achieve OSA modified waxy corn starch with a high degree of substitution; (b) to give a deeper insight into the physicochemical properties of OSA modified waxy corn starch, which offered a potential to be used in frozen foods. PMID- 21535802 TI - Comparison of fermented soybean paste (Doenjang) prepared by different methods based on profiling of volatile compounds. AB - In this study, 2 different extraction methods, namely solvent-assisted flavor evaporation (SAFE) and solid-phase microextraction (SPME), were employed to investigate the comprehensive volatile profile of Doenjang (one of Korean fermented soybean pastes) efficiently. Quantitatively, major volatiles of Doenjang isolated by SAFE were 3-methylbutanoic acid, butanoic acid, 3-hydroxy-2 methyl-4H-pyran-4-one (maltol), ethyl 2-methylbutanoate, 2-methylpropanoic acid, tetramethylpyrazine, and 4-ethyl-2-methoxyphenol, while ethanol, ethenylbenzene, ethyl benzoate, ethyl linoleate, ethyl acetate, ethyl butanoate, tetramethylpyrazine, and ethyl 2-methylpropanoate extracted by SPME. In addition, volatile profiling that applied principal component analysis to gas chromatography-mass spectrometry datasets allowed Doenjang samples that had been prepared using different traditional and commercial methods to be discriminated, and the volatile compounds that contributed to their discrimination were assigned. The major volatiles that were related to differentiation of traditional and commercial Doenjang samples were 2-pentylfuran, 4-ethylphenol, dihydro-5 methyl-2(3H)-furanone, butanoic acid, pyrazines (for example, 2-ethyl-5 methylpyrazine and 2,3-dimethylpyrazine), esters (for example, ethyl 4 methylpentanoate and diethyl succinate), maltol, dimethyl disulfide, 2- and 3 methylbutanal, hexanal, 4-vinylphenol, and ethanol. PMID- 21535803 TI - ORAChromatography and total phenolics content of peanut root extracts. AB - A large number of compounds have been reported in peanut plants. Many of these compounds are phytoalexins, which are produced by plants experiencing environmental stress and often exhibit antioxidant activity. It is difficult to determine which of the many compounds has the greatest impact on total antioxidant capacity in a mixture. The objectives of this research were to examine the oxygen-radical absorbing capacity (ORAC) value and total phenolic contents of peanut root extracts and peanut root extract fractions collected via HPLC. Peanut roots were extracted from four different cultivars (Brantley, NC-12, Phillips, and Wilson) with 70% aqueous ethanol with ultrasonic assistance. Each cultivar was sampled in duplicate. The extracts were fractionated into 18 3-min fractions by HPLC using a C-18 column. Fractions and crude extracts were freeze dried. ORAC values and total phenolic content were then determined for all fractions and crude extracts. Fractions had a significant effect on the MUM TE/mg gallic acid equivalents (GAE). ORAC values ranged from -46.89 MUM TE to 185 MUM TE in HPLC fractions. ORAChromatography can be used to focus on antioxidants in complex samples. PMID- 21535804 TI - Identification of 2-ethyl-4-methyl-3-thiazoline and 2-isopropyl-4-methyl-3 thiazoline for the first time in nature by the comprehensive analysis of sesame seed oil. AB - Toasted sesame seed oil was comprehensively analyzed. It was extracted using the SAFE (Solvent-Assisted Flavor Evaporation) technique. The extract was analyzed by GC and GC-MS on 2 phases and a total of 87 components were identified, confirmed, and are presented in this paper. The major components were methylpyrazine; 2,5 dimethylpyrazine; 2,6-dimethylpyrazine; 2-ethyl-3,6-dimethylpyrazine; furfuryl alcohol; and guaiacol. In addition, as part of this analysis, 2-ethyl-4-methyl-3 thiazoline and 2-isopropyl-4-methyl-3-thiazoline were confirmed as being present in a natural product for the first time. Their identification, confirmation, and sensory evaluation have been documented here. PMID- 21535805 TI - Antioxidant activity of commercial ready-to-drink orange juice and nectar. AB - Total antioxidant activity (TAA), total phenolic compounds (TPC), and physicochemical characteristics of ready-to-drink orange juice and nectar from the most consumed brands available in Brazil were evaluated. TPC ranged from 18.7 to 54.2 mg of gallic acid/100 mL, and TAA varied from 57.88 to 349.32 MUmol TEAC/100 mL ready-to-drink orange juice and nectar. The ascorbic acid content was the only physicochemical parameter that showed strong variation among packages and brands. Correlation of TPC with TAA showed that the higher the level of TPC the higher the TAA. Correlation of ascorbic acid content with TAA is higher for ready-to-drink orange juice than nectar. The same was found for the correlation of ascorbic acid content with TPC. The results confirm the contribution of the TPC to TAA. PMID- 21535806 TI - Characteristics and antioxidant activity of Maillard reaction products from psicose-lysine and fructose-lysine model systems. AB - D-Psicose, an epimer of D-fructose isomerized at C-3 position, is a rare ketohexose that is thought to be beneficial for obese people and diabetic patients as a noncaloric sweetener. In the present study, model Maillard reaction products were obtained from D-psicose (or D-fructose) and L-lysine heating at 120 degrees C up to 8 h with the initial pH 9.0. The changes in pH, UV-vis absorbance, and free amino groups during the reaction were detected. Moreover, the antioxidant potential of the Maillard reaction products at different intervals was investigated. Although there was almost no difference in the oxygen radical absorbance capacity, the Maillard reaction products from psicose performed better than that from fructose in the radical-scavenging activity of 2, 2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt and 1, 1, diphenyl-2-picryl-hydrazyl. The reducing power of the Maillard reaction products from psicose was also stronger than that from fructose. These results indicated that psicose played an effective role in the Maillard reaction and its Maillard reaction products could act as potential antioxidants in food industry. PMID- 21535807 TI - Changes in volatile compounds of peanut oil during the roasting process for production of aromatic roasted peanut oil. AB - The changes in volatile compounds composition of peanut oil during the roasting process of aromatic roasted peanut oil (ARPO) production were investigated. The analyses were performed by gas chromatography-mass spectrometry combined with headspace solid phase microextraction (HS-SPME/GC-MS). Among the volatiles identified in ARPO, the N-heterocyclic chemical class possessed the highest relative percentage area (RPA) 61.68%, followed by O-heterocyclic group with an RPA of 24.57%. Twenty pyrazines were considered to be the key contributors to the intense nutty/roasty flavor typical of ARPO. Compounds that increased significantly in concentration during the roasting process were mainly Maillard reaction products, as well as compounds derived from Strecker degradation and lipid peroxidation. The results clearly showed that the roasting process was necessary to obtain the typical nutty/roasty aroma of ARPO. PRACTICAL APPLICATION: ARPO is the traditional edible oil in China that possesses a characteristic strong nutty and roasty flavor that distinguishes it from other edible vegetable oils. During the production, the roasting process is the crucial factor for the formation of the typical roasted peanut aroma that plays an important role in sensory quality of peanut oil. In our investigation, not only the volatile changes of peanut oil pressed from relevant peanut seeds roasted at different roasting time were determined, but also the contributions of identified volatiles on the typical nutty/roasty flavor of ARPO were discussed. Our work clearly demonstrated the significant effect of roasting process on the typical flavor formation of ARPO. The results are valuable as scientific guidance for the roasting process that better satisfy demands of the peanut oil industries for better flavor. PMID- 21535808 TI - Evidence of cell-associated proteinases from Virgibacillus sp. SK33 isolated from fish sauce fermentation. AB - Cell-associated proteinases from Virgibacillus sp. SK33 isolated from fish sauce fermentation were extracted and characterized. Proteinases were effectively released when washed cells were incubated in 0.3 mg/mL lysozyme in 50 mM Tris maleate (pH 7) at 37 degrees C for 2 h. Major cell-associated proteinases exhibited molecular mass of 17, 32, and 65 kDa, but only a 32-kDa proteinase showed strong amidolytic activity toward Suc-Ala-Ala-Pro-Phe-AMC. Activity of all cell-associated proteinases was completely inhibited by phenylmethanesulfonyl fluoride, indicating a characteristic of serine proteinase. In addition, a 65-kDa serine proteinase was also inhibited by ethylenediaminetetraacetic acid, implying a metal-dependent characteristic. Optimum activity toward a synthetic peptide substrate was at 50 degrees C and pH 8 and 11. Proteinases with molecular mass of 17 and 32 kDa exhibited caseinolytic activity at 25% NaCl and activity based on a synthetic peptide substrate increased with NaCl concentrations up to 25%, suggesting their role in hydrolyzing proteins at high salt concentrations. This is the first report of liberated cell-associated proteinases from a moderate halophile, Virgibacillus sp. PRACTICAL APPLICATION: The cell-associated proteinases could be extracted from Virgibacillus sp. SK 33 using lysozyme. The extracted enzyme could be applied to hydrolyze food proteins at NaCl content as high as 25%. In addition, this study demonstrated that not only extracellular but also cell-associated proteinases are key factors contributing to protein degrading ability at high salt environment of Virgibacillus sp. SK 33. PMID- 21535809 TI - Authenticity of Cypriot sweet wine Commandaria using FT-IR and chemometrics. AB - FT-IR spectra of 65 sweet wines produced in Cyprus and other countries were determined, in order to study the authenticity and uniqueness of the Cypriot traditional wine "Commandaria" that is produced from sun-dried grapes. Different sample preparation methods such as freeze-drying and nitrogen-flow concentration and direct analysis were used. The spectra were obtained in transmittance mode from KBr pellets and by using the attenuated total reflectance technique, and analyzed statistically using multivariate chemometric techniques, involving principal component analysis, cluster analysis, linear and regularized discriminant analysis, and classification and regression trees. A nearly correct classification for Commandaria was achieved. Fourier Transform Infrared spectroscopy and chemometrics were able to differentiate all the types of Commandaria (nonfortified, fortified, and commercial) from various sweet wines from other countries. PRACTICAL APPLICATION: Commandaria is a traditional Cyprus product that was proven to be very popular and economically very important. There is therefore a need to determine its chemical characteristics in order to differentiate it from its competitors and thus enable Cyprus to seek the protection of the name as a regional product. A means of easily distinguishing the genuine product from others mimicking it is also of significant economic interest. PMID- 21535810 TI - Physicochemical and phytochemical properties of cold and hot water extraction from Hibiscus sabdariffa. AB - Hibiscus cold (25 degrees C) and hot (90 degrees C) water extracts were prepared in various time-temperature combinations to determine equivalent extraction conditions regarding their physicochemical and phytochemical properties. Equivalent anthocyanins concentration was obtained at 25 degrees C for 240 min and 90 degrees C for 16 min. Total phenolics were better extracted with hot water that also resulted in a higher antioxidant capacity in these extracts. Similar polyphenolic profiles were observed between fresh and dried hibiscus extracts. Hibiscus acid and 2 derivatives were found in all extracts. Hydroxybenzoic acids, caffeoylquinic acids, flavonols, and anthocyanins constituted the polyphenolic compounds identified in hibiscus extracts. Two major anthocyanins were found in both cold and hot extracts: delphynidin-3-sambubioside and cyanidin-3-sambubioside. In general, both cold and hot extractions yielded similar phytochemical properties; however, under cold extraction, color degradation was significantly lower and extraction times were 15-fold longer. PRACTICAL APPLICATION: Hibiscus beverages are prepared from fresh or dried calyces by a hot extraction and pasteurized, which can change organoleptic, nutritional, and color attributes. Nonthermal technologies such as dense phase carbon dioxide may maintain their fresh-like color, flavor, and nutrients. This research compares the physicochemical and phytochemical changes resulting from a cold and hot extraction of fresh and dried hibiscus calyces and adds to the knowledge of work done on color, quality attributes, and antioxidant capacity of unique tropical products. In addition, the research shows how these changes could lead to alternative nonthermal processes for hibiscus. PMID- 21535811 TI - Antioxidant activity and phenolic compounds in organic red wine using different winemaking techniques. AB - Wine phenolic composition depends on the grapes used to make wine and on vinification conditions. The occurrence of these biological compounds has stimulated numerous studies focused on understanding the mechanisms that influence their concentrations in wine. This article studied the effect of different vinification techniques on the antioxidant activity and on the phenolic compounds of red wine made from the variety of Monastrell grapes obtained by organic culture. To this purpose, 3 different vinification procedures were carried out: vinification after prolonged maceration, vinification with the addition of enological enzymes, and traditional vinification procedures (used as control).The results showed similar values of antioxidant activity in all 3 types of wine elaborated and found no differences in the concentrations of the different types of phenolic compounds in wine made with the 3 different methods. The evolution of antioxidant activity and phenolic compounds tested in wines during 3 mo of storage showed a similar pattern. Organic wine has acquired an important role in the economic world and its important, working in oenology to research in this field. PMID- 21535812 TI - Optimization and development of a SPE-HPLC-UV method to determine astaxanthin in Saccharina japonica. AB - An effective and accurate method including extraction, saponification, and separation was developed to determine astaxanthin (AX) in Saccharina japonica. The optimal extraction conditions with different solvents were investigated. 29.30 MUg/g of AX was extracted from dry Saccharina japonica powder by solvent. After subsequent saponification, the extracted amount of AX was increased to 37.26 MUg/g. Furthermore, 3 different ionic liquid-based silicas were prepared as sorbents for the solid phase extraction of AX from the extract. By comparing the adsorption isotherms of AX on different ionic liquid-based silicas, suitable sorbent was successfully selected and applied for separation of AX from extract. PRACTICAL APPLICATION: Astaxanthin, in 3 main forms (free, monoesters, and diesters), can be obtained from marine plants and animals. By extraction with subsequent saponification, the astaxanthin was extracted from Saccharina japonica. And then, ionic liquid-based silicas were used to separate the astaxanthin from the extract solution. This method can be widely applied for determination, or even industrial separation and purification of astaxanthin from many other algae. PMID- 21535813 TI - Influence of copigment derived from Tasmannia pepper leaf on Davidson's plum anthocyanins. AB - Davidson's plum (Davidsonia pruriens, F. Muell.), a native to Australian rainforests, large, crimson-red fruit, which superficially resembles plum, has been commercially cultivated in Australia since 1990s. The current production volume exceeds market demands therefore this study was designed to evaluate the suitability of Davidson's plum extract as a source of anthocyanin-based food colorant. The stability of the Davidson's plum extract towards heat treatment at 95 degrees C was higher than that of commercial mulberry colorant, but inferior to colorants derived from red cabbage and purple sweetpotato. An addition of a variety of phenolic acids significantly increased color intensity indicating the formation of copigmentation complexes. Commercial chlorogenic acid as well as extract from a native Australian herb rich in chlorogenic acid, Tasmannia pepper leaf (Tasmannia lanceolata, R. Br.), were both tested in model soft drink solutions subjected to light irradiation and heat treatment. In both cases, the addition of the copigment resulted in a lasting increase in color intensity. In conclusion, Davidson's plum extract can successfully be utilized as a source of natural food color. Extract from Tasmania pepper leaf can be used as a co-pigment for Davidson's plum anthocyanins. PRACTICAL APPLICATION: The color properties of an anthocyanin colorant derived from the native Australian fruit Davidson's plum are comparable to those of mulberry, which is currently applied as a food colorant in Australian food products. Utilization of Davidson's plum fruit as a source of natural color will allow the industry to increase the range of natural pigments and will create new opportunities for the emerging native food industry. PMID- 21535814 TI - Heat treatment of Brussels sprouts retains their ability to induce detoxification enzyme expression in vitro and in vivo. AB - The bioactive metabolites of glucosinolates, such as isothiocyanates, contained in cruciferous vegetables have been shown to reduce the risk of cancers through the induction of detoxification enzymes. However, cruciferous vegetables are commonly processed before consumption, significantly altering the phytochemical composition of these vegetables. Compared to freeze-dried Brussels sprouts, oven dried Brussels sprouts contain low concentrations of glucosinolates (22.14 and 0.85 MUmol/g, respectively) and isothiocyanates (3.68 and 0.15 MUmol/g, respectively). The effect of oven-dried Brussels sprouts on the expression of detoxification enzymes was evaluated in vitro and in vivo. Treatment of immortalized human hepatoma cells with the aqueous extract from oven-dried Brussels sprouts significantly increased quinone activity (0.5 and 1.5 mg/mL) and the activity of the antioxidant response element (EC50=2.39 mg/mL) and xenobiotic response element (EC50 2.92 mg/mL). C3H/HeJ mice fed a diet containing 20% oven dried Brussels sprout diets for 2 wk demonstrated significantly higher expression than animals fed a nutrient-matched control diet of CYP1A1, CYP1A2, and epoxide hydrolase in the liver and CYP1A1, CYP1A2, CYP1B1, epoxide hydrolase, UGT1A1, thioredoxin reductase, and heme oxygenase in the lungs. The low concentrations of glucosinolates and isothiocyanates in oven-dried Brussels sprouts suggest that other compounds, such as the Maillard reaction products that are produced during heating, are responsible for the induction of detoxification enzymes in vitro and in vivo. PRACTICAL APPLICATION: The manner in which cruciferous vegetables are processed prior to consumption has significant effects on what compounds people are exposed to. The presence of glucosinolates or isothiocyanates can be a good indicator of the ability of cruciferous vegetables to induce detoxification enzymes. However, the data presented here demonstrate that while heat processing of Brussels sprouts greatly reduced the concentrations of glucosinolates and isothiocyanates, their ability to induce detoxification enzymes in vitro and in vivo was retained. PMID- 21535815 TI - Structural characterization and antioxidant activities of 2 water-soluble polysaccharide fractions purified from tea (Camellia sinensis) flower. AB - The water-soluble crude polysaccharide tea flower polysaccharide (TFP), obtained from tea (Camellia sinensis) flower by boiling-water extraction and ethanol precipitation, was fractionated by Sephadex G-100 column chromatography, giving 2 polysaccharide fractions termed TFP-1 and TFP-2. The structural features of TFP-1 and TFP-2 were investigated by high-performance liquid chromatography (HPLC), gel permeation chromatography (GPC), rheometer, infrared (IR) spectra, nuclear magnetic resonance (NMR) spectroscopy, atomic force microscope (AFM), and scanning electron microscope (SEM). Results indicated that TFP-1 was composed of glucose: xylose: rhamnose: galactose=1.0:1.2:0.81:0.98 with a molecular weight of 167.5 KDa, while TFP-2 comprised glucose: xylose: rhamnose: arabinose=1.0:0.76:2.3:2.3 with a molecular weight of 10.1 KDa. The 1H NMR revealed that TFP-1 contained alpha-L-Rhap, alpha-D-Galp, alpha-D-GalpNAc, alpha D-Xylp, alpha-D-Glcp, and beta-D-Glcp residues, while TFP-2 was illustrated to have alpha-L-Rhap, alpha-L-Arap, alpha-D-Xylp, alpha-D-Glcp, and alpha-D-GlcpNAc residues. Antioxidant activities of these fractions were investigated using various in vitro assay systems compared with ascorbic acid. In conclusion, TFP-2 exhibited the higher antioxidant activities and could be explored as a novel potential antioxidant. PRACTICAL APPLICATION: At present, commonly low-grade tea is preferred to extract the tea polysaccharide, to take full advantage of tea flower resource to extract polysaccharides can greatly reduce the cost of tea products. Thus, the search for plant-derived biomaterials from this study could generate natural value-added products from underutilized tea plant waste and used as a medicinal agent against chronic health problems, such as cancers, aging, and atherosclerosis caused by reactive free radicals that produced from oxidation. PMID- 21535816 TI - Influence of various levels of flaxseed gum addition on the water-holding capacities of heat-induced porcine myofibrillar protein. AB - As a food hydrocolloid, flaxseed gum (FG) can significantly increase the water holding capacity (WHC) of food, which is important to both yield and texture of related products. The main purpose of this study is to examine the WHC increase by FG in a meat product and the mechanism of the interactions between proteins and polysaccharides when FG is added into porcine myofibrillar protein (PMP). Increasing the FG concentration caused a significant increase in WHC (P<0.001). Scanning electron micrographs (SEM) showed that WHC in the protein gel network was related to gel microstructure. Distributed analysis of the T2 relaxation revealed that addition of FG significantly decreased water mobility of porcine myofibrillar protein (PMP) (P<0.05). The Fourier transform infrared spectroscopy (FT-IR) analysis suggested that the FG adding strengthened electrostatic attraction of PMP system. Improvement of WHC in heat-induced PMP by FG is concentration dependent and achieved by a finer gel network, lower relaxation time, and stronger electrostatic attraction. PRACTICAL APPLICATION: Flaxseed gum (FG) addition significantly increased water holding capacity (WHC) of porcine myofibrillar protein (PMP). In addition, the improvement of WHC in heat-induced PMP by FG was concentration dependent and achieved by a finer gel network, lower relaxation time, and stronger electrostatic attraction. Thus, FG has potential for use in meat products. PMID- 21535817 TI - Contents of phenolics and flavonoids and antioxidant activities in skin, pulp, and seeds of miracle fruit. AB - Miracle Fruit (Synsepalum dulificum) has been studied because of its unique taste modifying properties. This study investigated contents of phenolics, flavonoids, and antioxidant activities in skin, pulp, and seeds of Miracle Fruit. The free phenolic content in skin was almost 3 times of that in pulp and 4 times of that in seeds. Skin contributed 43.96% of free phenolic compounds with 15.91% of freeze-dried solids due to its high phenolic content. As the trend observed for phenolic content, the free flavonoid content in the skin was tremendously higher than that in the seed and pulp. The skin contributed about 52% of total flavonoid with 15.91% of dried solids. On other hand, the differences in the bound phenolic contents were not so distinct among the 3 components. The free antioxidant activities in skin and pulp were comparable, and were significantly higher than that in seeds. Although the antioxidant activities in seeds was considerably lower than that in skin, 49.45% free antioxidant activity, 76.41% bound antioxidant activity, and 58.56% of total antioxidant activity were contributed by seeds due to about 66% of solid of total solids. In general, the results of antioxidant activities using sequential methods were higher than that using direct method. This study suggests that Miracle Fruit is a good source not only for flavor and color, and also antioxidant activity for functional food applications. PMID- 21535818 TI - Preparation of reactive oxygen scavenging peptides from tilapia (Oreochromis niloticus) skin gelatin: optimization using response surface methodology. AB - Gelatin extracted from tilapia skin was hydrolyzed with Properase E. Response surface methodology (RSM) was applied to optimize the hydrolysis condition (temperature [T], enzyme-to-substrate ratio [E/S], pH and reaction time [t]), to obtain the hydrolysate with the highest hydroxyl radical (*OH) scavenging activity. The optimum conditions obtained were T of 44.2 degrees C, E/S of 2.2%, pH of 9.2, and t of 3.4 h. The predicted *OH scavenging activity of the hydrolysate under the optimum conditions was 60.7%, and the actually experimental scavenging activity was 60.8%. The hydrolysate was fractionated by ultrafiltration, and 4 fractions were collected. The fraction TSGH4 (MW<2000 Da) showed the strongest *OH scavenging activity with the highest yield. Furthermore, reactive oxygen species (ROS) scavenging activities of TSGH4 with different concentrations were investigated in 5 model systems, including superoxide anion radical (*O2), *OH, hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and nitric oxide (NO*), compared with reduced glutathione (GSH). The results showed that TSGH4 significantly scavenged these ROS, and could be used as a functional ingredient in medicine and food industries. PMID- 21535819 TI - CIELAB coordinates in response to berry skin anthocyanins and their composition in Vitis. AB - Berry skin color OIV index, anthocyanin composition, and content of 78 grape cultivars were surveyed using a CIELAB system and high-performance liquid chromatography (HPLC)-mass spectrometry (MS) coupled with photodiode array detection. There were high correlations between L*, b*, and color, while a* was not a representative parameter. L* and b* values declined as berry skin color OIV became darker, and a* increased as berry skin color OIV became darker in pink and red grape cultivars only. The composition and content of anthocyanins varied widely among the cultivars. Total anthocyanins and types of anthocyanins were significantly correlated with color OIV parameters. Through multiple linear regression analysis, cyanidin derivatives had a positive effect on values of L* and b*. Delphinidin derivatives had positive effects on the value of a*. The CIELAB system gave good results for differentiation of grape berry skin color OIV. PMID- 21535820 TI - Interaction of phosphatidylcholine and alpha-tocopherol on the oxidation of sunflower oil and content changes of phosphatidylcholine and tocopherol in the emulsion under singlet oxygen. AB - Interaction of phosphatidylcholine (PC) and alpha-tocopherol (alpha-Toc) on the oxidation of oil in the emulsion consisting of sunflower oil and water under singlet oxygen at 25 degrees C was studied by determining peroxide value (PV) and conjugated dienoic acid (CDA) contents. Singlet oxygen was produced by chlorophyll b under 1700 lux. Single addition of PC or alpha-Toc decreased the values of peroxides and CDAs of oil in the emulsion via singlet oxygen quenching. PC and alpha-Toc showed simply additive interaction in decreasing the singlet oxygen oxidation of oil in the emulsion. alpha-Toc was a physical quencher of singlet oxygen in the emulsion, but PC involved chemical quenching in the antioxidant action. Chlorophyll and PC contents were decreased in the emulsion under singlet oxygen, while alpha-Toc was not. alpha-Toc protected chlorophyll and PC from degradation, and was a more important component than PC in the oil oxidation under singlet oxygen in the emulsion. PMID- 21535821 TI - Raphasatin is a more potent inducer of the detoxification enzymes than its degradation products. AB - The biological activity of cruciferous vegetables is hypothesized to be due to the metabolites of a class of phytochemicals called glucosinolates. The chemical properties of these metabolites, including isothiocyanates, determine the biological activity of these compounds and thus their effects on human health. The 2 primary radish (Raphanus sativus L.) glucosinolates, glucoraphasatin, and glucoraphenin, were isolated using solid phase extraction followed by preparative HPLC purification. In an aqueous environment, 77.6% of the maximum amount of sulforaphene produced by the metabolism of glucoraphenin was present after 24 h. Under the same conditions raphasatin, the isothiocyanate metabolite of glucoraphasatin and the oxidized counterpart of sulforaphene, was highly unstable with a half-life of less than 30 min and no raphasatin was detectable after 24 h. In HepG2 cells, raphasatin-induced quinone reductase activity and the RNA expression of several phase 1 and 2 detoxification enzymes by a significantly greater amount than the degradation products of raphasatin. Raphasatin, but not its degradation products, activated the antioxidant response element (ARE) in a stably-transfected reporter cell line. Mice fed a diet consisting of 20% freeze dried radishes for 2 wk had significantly higher liver expression of cytochrome P450 (CYP) 1A1, 1A2, quinone reductase, microsomal epoxide hydrolase, and glutathione S-transferase alpha2 than mice fed a nutritionally-matched control diet. PRACTICAL APPLICATION: Glucoraphasatin, the primary glucosinolate in radishes, is metabolized into an isothiocyanate (raphasatin) that has biological activity but is also unstable in an aqueous environment. Despite the instability of raphasatin, dietary exposure to radishes produced significant induction of detoxification enzymes. Understanding the chemical properties of raphasatin, both in terms of biological activity and instability, could help develop processing methods to retain the most activity from radishes, glucoraphasatin, and raphasatin. PMID- 21535822 TI - Oregano: chemical analysis and evaluation of its antimalarial, antioxidant, and cytotoxic activities. AB - GC-FID and GC-MS analysis of essential oil from oregano leaves (Origanum compactum) resulted in the identification of 46 compounds, representing more than 98% of the total composition. Carvacrol was the predominant compound (36.46%), followed by thymol (29.74%) and p-cymene (24.31%). Serial extractions with petroleum ether, ethyl acetate, ethanol, and water were performed on aerials parts of Origanum compactum. In these extracts, different chemical families were characterized: polyphenols (gallic acid equivalent 21.2 to 858.3 g/kg), tannins (catechin equivalent 12.4 to 510.3 g/kg), anthocyanins (cyanidin equivalent 0.38 to 5.63 mg/kg), and flavonoids (quercetin equivalent 14.5 to 54.7 g/kg). The samples (essential oil and extracts) were subjected to a screening for antioxidant (DPPH and ABTS assays) and antimalarial activities and against human breast cancer cells. The essential oil showed a higher antioxidant activity with an IC50=2+/-0.1 mg/L. Among the extracts, the aqueous extract had the highest antioxidant activity with an IC50=4.8+/-0.2 mg/L (DPPH assay). Concerning antimalarial activity, Origanum compactum essential oil and ethyl acetate extract showed the best results with an IC50 of 34 and 33 mg/mL, respectively. In addition, ethyl acetate extract (30 mg/L) and ethanol extract (56 mg/L) showed activity against human breast cancer cells (MCF7). The oregano essential oil was considered to be nontoxic. PMID- 21535823 TI - Channel catfish (Ictalurus punctatus) muscle protein isolate performance processed under different acid and alkali pH values. AB - Channel catfish (Ictalurus punctatus) muscle was subjected to 6 protein extraction and precipitation techniques using acid solubilization (pH 2.0, 2.5, and 3.0) or alkaline solubilization (pH 10.5, 11.0, 11.5) followed by precipitation at pH 5.5. The catfish protein isolate was compared with ground defatted white muscle. Alkali-processed catfish showed increased gel rigidity, gel strength, and gel flexibility compared to acid-processed catfish, which exhibited inconsistent functional performance, increasing and decreasing gel rigidity, gel strength, and gel flexibility. The gel rigidity (G') at pH 3.0 in the absence of salt had the highest G' of the acid treatments and was not significantly different from the alkaline-treated catfish muscle (P>0.05). However in the presence of added salt pH treatment it had the lowest G' and was different from alkaline treatments (P<0.05) during break force testing. These results show that pH-shift processing of channel catfish muscle provides highly functional isolates with a potentially broad range of applications. This range of applications is possible due to the modification of the textural properties of catfish muscle protein produced using different acidic or alkaline pH solubility treatments. PMID- 21535824 TI - Effect of proteolysis and calcium equilibrium on functional properties of natural cheddar cheese during ripening and the resultant processed cheese. AB - The changes in proteolysis, calcium (Ca) equilibrium, and functional properties of natural Cheddar cheeses during ripening and the resultant processed cheeses were investigated. For natural Cheddar cheeses, the majority of the changes in pH 4.6 soluble nitrogen as a percentage of total nitrogen (pH 4.6 SN/TN) and the soluble Ca content occurred in the first 90 d of ripening, and subsequently, the changes were slight. During ripening, functional properties of natural Cheddar cheeses changed, that is, hardness decreased, meltability was improved, storage modulus at 70 degrees C (G'T=70) decreased, and the maximum tan delta (TDmax) increased. Both pH 4.6 SN/TN and the soluble Ca were correlated with changes in functional properties of natural Cheddar cheeses during ripening. Kendall's partial correlation analysis indicated that pH 4.6 SN/TN was more significantly correlated with changes in hardness and TDmax. For processed cheeses manufactured from natural Cheddar cheeses with different ripening times, the soluble Ca content did not show significant difference, and the trends of changes in hardness, meltability, G'T=70, and TDmax were similar to those of natural Cheddar cheeses. Kendall's partial correlation analysis suggested that only pH 4.6 SN/TN was significantly correlated with the changes in functional properties of processed cheeses. PMID- 21535825 TI - Physical properties and microstructural changes during soaking of individual corn and quinoa breakfast flakes. AB - The importance of breakfast cereal flakes (BCF) in Western diets deserves an understanding of changes in their mechanical properties and microstructure that occur during soaking in a liquid (that is, milk or water) prior to consumption. The maximum rupture force (RF) of 2 types of breakfast flaked products (BFP)- corn flakes (CF) and quinoa flakes (QF)--were measured directly while immersed in milk with 2% of fat content (milk 2%) or distilled water for different periods of time between 5 and 300 s. Under similar soaking conditions, QF presented higher RF values than CF. Soaked flakes were freeze-dried and their cross section and surface examined by scanning electron microscopy. Three consecutive periods (fast, gradual, and slow reduction of RF) were associated with changes in the microstructure of flakes. These changes were more pronounced in distilled water than in milk 2%, probably because the fat and other solids in milk become deposited on the flakes' surface hindering liquid infiltration. Structural and textural modifications were primarily ascribable to the plasticizing effect of water that softened the carbohydrate/protein matrix, inducing partial collapse of the porous structure and eventually disintegration of the whole piece through deep cracks. PMID- 21535826 TI - Effects of protein separation conditions on the functional and thermal properties of canola protein isolates. AB - Canola meal protein isolates were prepared from defatted canola meal flour using alkaline solubilization and acid precipitation. A central composite design was used to model 2nd-order response surfaces for the protein yield and the functional properties of protein isolates. The solubilization pH and precipitation pH were used as design factors. The models showed that the protein yield and functional properties of isolates, such as water absorption and fat absorption, were sensitive to both solubilization pH and precipitation pH, whereas the emulsification was sensitive to only solubilization pH. Gel electrophoresis analysis of protein fractions gave evidence to the compositional changes between proteins isolated under different conditions. Differences in glass transition temperatures suggest that proteins tend to be more denatured when solubilized at highly alkaline conditions. These conformational and compositional changes due to different protein separation conditions have contributed to the changes in functional properties of protein isolates. PRACTICAL APPLICATION: Protein isolation conditions may be determined primarily through optimization of total protein yield. Improvements in protein functional properties may be achieved with a relatively small sacrifice in yield by altering isolation conditions. PMID- 21535827 TI - How do xanthan and hydroxypropyl methylcellulose individually affect the physicochemical properties in a model gluten-free dough? AB - To better understand the physicochemical changes imparted by hydrocolloids on gluten-free dough, 2 hydroxypropyl methylcelluloses (HPMCs) and xanthan gum were added at 2%, 3%, and 5% to rice cassava dough without the addition of alternative proteins. The formulated doughs were analyzed using thermoanalytic and rheological techniques to determine the role of water and subsequent flow behavior upon hydrocolloid addition. The baked loaves were then measured for specific loaf volume and tensile strength to determine bread quality. Thermogravimetric analysis (TGA) results revealed that hydrocolloid-added dough held water more tightly than the rice cassava control with an additional water distribution at 85 to 88 degrees C. Rheologically, the increase of elastic moduli in the low methoxy HPMC and xanthan-added dough became more pronounced with gum addition; however, both HPMC formulations had increased viscous moduli allowing the gas cells to expand without collapsing. In the bread, the final specific loaf volume increased with high methoxy HPMC (2% to 5%) and low methoxy HPMC (2%) but was depressed with increased addition of low methoxy HPMC (5%) and xanthan (3% and 5%). Crumb hardness was decreased in high methoxy HPMC loaves but was increased significantly in low methoxy HPMC (5%) and xanthan (5%) formulations. From the gums studied, it was concluded that high methoxy HPMC was the optimum hydrocolloid in the rice cassava gluten-free dough. PRACTICAL APPLICATION: Two types of hydrocolloids, xanthan gum and HPMC, were individually added to a gluten-free rice cassava formulation. Based on the thermoanalytic and rheological studies on dough, as well as the bread quality studies, high methoxy HPMC at 5% addition was determined to optimally improve the bread quality when only gum addition was considered. This study indicates the potential use of high methoxy HPMC as an additive in gluten-free bread formulations prior to considering alternative proteins. PMID- 21535829 TI - Quantification of gaping, bruising, and blood spots in salmon fillets using image analysis. AB - An image analysis method was developed to quantify the gaping, bruising, and blood spots of red salmon (Oncorhynchus nerka) fillets. Images of 15 fillets with various levels of gaping were taken either with a dSLR camera, or with a video camera. Also, the same fillets were recorded using the same camera both under regular illumination, and under polarized illumination. In either case, light at an angle was used to highlight the gapes in the flesh. An image analysis method was developed that can adaptively apply an L*threshold value to the image depending on the average color of the fillet, and quantify the resulting percent of the fillet area that has an L* value less than or equal to L*threshold. Polarized lighting changed the color by eliminating artifacts resulting from reflections. It is recommended to use polarized light for this purpose. Both cameras could be used adequately to quantify defects. The proper setting of the L*threshold value depended on the camera and on the polarized light. No correlation could be found between the average L* value of the fillets and the L*threshold value. It was possible to quantify the gaping, bruising, and blood spots on the salmon fillets using this method, which can be the first step toward the automation of this operation. PRACTICAL APPLICATION: Gaping, bruising, and blood spots can be recognized and quantified by analyzing images of salmon fillets. Polarized light is recommended to eliminate color artifacts caused by reflected light. This can be used to automate the detection of these defects. PMID- 21535828 TI - Functional properties of protein fractions of channel catfish (Ictalurus punctatus) and their effects in an emulsion system. AB - This study demonstrated the feasibility of producing soluble protein (CFSP) and insoluble protein (CFISP) fractions from catfish muscle protein. CFSP and CFISP contained 60.6% and 73.8% protein and 8.6% and 20.3% fat, respectively. Both CFSP and CFISP contained essential amino acids. Differences were observed between physicochemical properties of the 2 protein fractions, including nitrogen solubility, emulsion stability, and fat adsorption capacity. The flow and viscoelastic properties of the emulsions prepared with CFSP and CFISP were investigated using a rheometer. The power law model and the Casson model were used to determine the flow behavior index (n), consistency index (K), and yield stress. Emulsion containing CFSP (ECFSP) had a higher K value than emulsion containing CFISP (ECFISP). Both ECFSP and ECFISP emulsions exhibited pseudoplastic behavior and viscoelastic characteristics. The G' (an elastic or storage modulus) and G" (a viscous or loss modulus) values for ECFSP were higher than ECFISP. Catfish muscle tissue can be easily separated into soluble and insoluble protein powders that have desirable functional properties. PMID- 21535830 TI - Measuring and predicting head space pressure during retorting of thermally processed foods. AB - Traditional metal cans and glass jars have been the mainstay in thermally processed canned foods for more than a century, but are now sharing shelf space with increasingly popular flexible pouches and semi-rigid trays. These flexible packages lack the strength of metal cans and glass jars, and need greater control of external retort pressure during processing. Increasing internal package pressure without counter pressure causes volumetric expansion, putting excessive strain on package seals that may lead to serious container deformation and compromised seal integrity. The primary objective of this study was to measure internal pressure build-up within a rigid air-tight container (module) filled with various model food systems undergoing a retort process in which internal product temperature and pressure, along with external retort temperature and pressure, were measured and recorded at the same time. The pressure build-up in the module was compared with the external retort pressure to determine the pressure differential that would cause package distortion in the case of a flexible package system. The secondary objective was to develop mathematical models to predict these pressure profiles in response to known internal temperature and initial and boundary conditions for the case of the very simplest of model food systems (pure water and aqueous saline and sucrose solutions), followed by food systems of increasing compositional complexity (green beans in water and sweet peas in water). Results showed that error between measured and predicted pressures ranged from 2% to 4% for water, saline, and green beans, and 7% to 13% for sucrose solution and sweet peas. PRACTICAL APPLICATION: Flexible packages have limited strength, and need more accurate and closer control of retort pressure during processing. The package becomes more flexible as it heats and might expand with increasing internal pressure that may cause serious deformation or rupture if not properly controlled and/or counterbalanced with external retort pressure. This article describes methods for determining exactly what the retort pressure profile will need to be to avoid this problem during retorting, and mathematical models to predict these pressures in response to known internal temperature and initial/boundary conditions. PMID- 21535831 TI - Physicochemical, nutritional, and antimicrobial properties of wine grape (cv. Merlot) pomace extract-based films. AB - Wine grape pomace (WGP) (cv. Merlot) extract-based films were studied in terms of their physicochemical, mechanical, water barrier, nutritional, and antibacterial properties. Pomace extract (PE) was obtained by hot water extraction and had a total soluble solid of 3.6% and pH 3.65. Plant-based polysaccharides, low methoxyl pectin (LMP, 0.75% w/w), sodium alginate (SA, 0.3% w/w), or Ticafilm (TF, 2% w/w), was added into PE for film formation, respectively. Elongation at break and tensile strength were 23% and 4.04 MPa for TF-PE film, 25% and 1.12 MPa for SA-PE film, and 9.89% and 1.56 MPa for LMP-PE film. Water vapor permeability of LMP-PE and SA-PE films was 63 and 60 g mm m(-2) d(-1) kPa, respectively, lower than that of TF-PE film (70 g mm m(-2) d(-1) kPa) (P<0.05). LMP-PE film had higher water solubility, indicated by the haze percentage of water after 24 h of film immersion (52.8%) than that of TF-PE (25.7%) and SA-PE (15.9%) films, and also had higher amount of released phenolics (96.6%) than that of TF-PE (93.8%) and SA-PE (80.5%) films. PE films showed antibacterial activity against both Escherichia coli and Listeria innocua, in which approximate 5-log reductions in E. coli and 1.7- to 3.0-log reductions in L. innocua were observed at the end of 24 h incubation test compared with control. This study demonstrated the possibility of utilizing WGP extracts as natural, antimicrobial, and antioxidant promoting film-forming material for various food applications. PRACTICAL APPLICATION: WGP extract-based edible films with the addition of a small amount of commercial polysaccharides showed attractive color and comparable mechanical and water barrier properties to other edible films. The films also demonstrated their potential antioxidant and antimicrobial functions. Hence, they may be used as colorful wraps or coatings for food, pharmaceutical, or other similar applications. PMID- 21535833 TI - A simple method for weight estimation of whole herring (Clupea harengus) using planar X-ray imaging. AB - Fish weight is one of the key parameters used in commercial sorting of fresh fish. The capability of on-line and accurate estimation of the weight of each individual fish has a direct impact on profitability for the fish processors. Planar X-ray images of whole herring (n=16) were taken using a commercial medical X-ray apparatus. The integral intensity of all pixels in each image was calculated and correlated with the weight of the respective fish producing a linear relationship with a high correlation factor (R2=0.992) and a calculated mean prediction error of 2.5%. Planar X-ray imaging combined with simple image processing was successfully used to predict weight of whole herring. The technique has a potential to be used industrially for on-line weight estimation in sorting/grading systems. PMID- 21535832 TI - How micro-phase separation alters the heating rate effects on globular protein gelation. AB - This study was conducted to determine how the combination of heating rate and pH can be used to alter viscoelastic properties and microstructure of egg white protein and whey protein isolate gels. Protein solutions (1% to 7% w/v protein, pH 3.0 to 8.5) were heated using a range of heating rates (0.2 to 60 degrees C/min) to achieve a final temperature of 80 degrees C. The gelation process and viscoelastic properties of formed gels were evaluated using small strain rheology. Single phase or micro-phase separated solution conditions were determined by confocal laser scanning microscopy. In the single phase region, gels prepared by the faster heating rates had the lowest rigidity at 80 degrees C; however, a common G' was achieved after holding for 4 h at 80 degrees C . On the other hand, under micro-phase separation conditions, faster heating rates allowed phase separated particles to be frozen in the network prior to precipitation. Thus, gels produced by slower heating rates had lower rigidities than gels produced by faster heating rates. The effect of heating rate appears to depend on if the solution is under single phase or micro-phase separated conditions. PRACTICAL APPLICATION: The effect of heating rate and/or time on protein gel firmness can be explained based on protein charge. When proteins have a high net negative charge and form soluble aggregates, there is no heating rate effect and gels with equal firmness will be formed if given enough time. In contrast, when electrostatic repulsion is low, there is a competition between protein precipitation and gel formation; thus, a faster heating rate produces a firmer gel. PMID- 21535834 TI - Development of a probiotic delivery system from agrowastes, soy protein isolate, and microbial transglutaminase. AB - Probiotic delivery system was developed via the use of microbial transglutaminase (MTG) cross-linked soy protein isolate (SPI) incorporated with agrowastes such as banana peel (BE), banana pulp (BU), and pomelo rind (PR). Inoculums of Lactobacillus bulgaricus FTDC 1511 were added to the cross-linked protein matrix. The incorporation of agrowastes had significantly (P<0.05) reduced the strength, pH value, and the lightness of the SPI gel carriers, while sodium dodecyl sulfate polyacrylamide gel electrophoresis profiles revealed that the occurring cross links within the SPI gel carriers were attributed to the addition of MTG. Scanning electron microscope micrographs illustrated that SPI carriers containing agrowastes have exhibited a less-dense protein matrix. All the SPI carriers possessed maximum swelling ratio at 4 to 4.5 within 15 min in simulated gastric fluid (SGF), whereas the maximum swelling ratios of SPI/BE, SPI/BU, and SPI/PR were higher compared to that of control in simulated intestinal fluid (SIF). Additionally, SPI carriers in SGF medium did not show degradation of structure, whereas a major collapse of network was observed in SIF medium, indicating controlled-release in the intestines. The addition of agrowastes into SPI carriers led to a significantly (P<0.0001) lower release of L. bulgaricus FTDC 1511 in SGF medium and a higher release in SIF medium, compared to that of the control. SPI carriers containing agrowastes may be useful transports for living probiotic cells through the stomach prior to delivery in the lower intestines. PRACTICAL APPLICATION: Agrowastes could be utilized as a new probiotic carrier for enhanced gastrointestinal transit and during storage. This also reduces the amount of agrowastes accumulated. PMID- 21535836 TI - Efficiency of trapping methylglyoxal by phenols and phenolic acids. AB - The carbonyl stress that leads to the formation of advanced glycation end products (AGEs) has drawn much attention recently because of its micro- and macrovascular implications. During monitoring of methylglyoxal (MG), the efficiency of phenolics to directly trap MG can be demonstrated. Twenty compounds consisting of a single benzene ring structure with the addition of at least one hydroxyl group were allowed to react with MG at 37 degrees C for 1 h under physiological conditions in pH 7.4 phosphate buffer solution. Compounds composed of a benzene structure with a mono-hydroxyl substitute cannot react with MG. Among benzenediols and di-hydroxyl benzoic acids, only hydroquinone reacted with MG and showed a 13% decrease in MG. Nevertheless, high reactivity was shown for 3 benzenetriols. The percentages of MG remaining were 45%, 51%, and 36% for pyrogallol, 1,2,4-trihydroxybenzene, and 1,3,5-trihydroxybenzene, respectively. When a carboxyl group is added to the benzenetriols, steric hindrance and carbon electron charges on benzene ring are the influential factors in reactivity. Using computational chemistry calculations, a carbon electron charge of -0.24 was the minimum value for high reactivity. PMID- 21535835 TI - Attenuation of fatty liver and prevention of hypercholesterolemia by extract of Curcuma longa through regulating the expression of CYP7A1, LDL-receptor, HO-1, and HMG-CoA reductase. AB - The extract of Curcuma longa, better known as turmeric, was orally administered to experimental rats that were fed a high-cholesterol diet to investigate whether it could regulate plasma lipids and cholesterol levels and possibly improve hepatic conditions. With turmeric supplements, rats showed a significant decrease in total plasma cholesterol and low-density lipoprotein cholesterol but an increase in high-density lipoprotein cholesterol when compared with rats that were fed a high-cholesterol diet alone. Fatty liver developed in hypercholesterolemic rats with the high-cholesterol diet treatment, and this condition was markedly improved when rats were provided with turmeric supplements at 100 mg/kg or 300 mg/kg of body mass. The turmeric treatment resulted in a significant decrease in the total amount of hepatic lipid. Histological staining of liver tissues with Sudan III and hematoxylin showed that rats fed with a high cholesterol diet alone had more and larger granular fat bodies than rats having turmeric extract supplementation in their high-cholesterol diet. Reverse transcription polymerase chain reaction was used to assess the expression levels of enzymes involved in fat metabolism and cellular homeostasis in experimental rat livers. The results showed that rats fed a high-cholesterol diet supplemented with turmeric extract had a significant increase in the expression of cholesterol 7 alpha-hydroxylase, hemeoxygenase 1, and low-density lipoprotein receptors but a significant decrease in 3-hydroxy-3-methyl-glutaryl-CoA reductase level when compared with rats fed a normal or high-cholesterol diet, showing that turmeric prevents hypercholesterolemia and the formation of fatty liver by the modulation of expressions of enzymes that are important to cholesterol metabolism. PRACTICAL APPLICATION: Turmeric may be considered a functional food for regulating plasma cholesterol levels and preventing the development of fatty liver in people who frequently consume a high-cholesterol diet. PMID- 21535837 TI - Physicochemical properties of bread dough and finished bread with added pectin fiber and phenolic antioxidants. AB - Comparative studies were conducted in this paper to investigate the effects of added dietary fiber (DF) and/or phenolic antioxidants on the properties of bread dough and finished bread. Breads were developed in the absence (control bread), or presence of apple pectin and/or fruit phenolic extracts (treated breads), and subjected to quality evaluation (attributes including color, weight, and volume) and characterization of chemical and rheological properties. Chemical analyses revealed that breads with added phenolic extracts had greater antioxidant activity and higher extractable phenolic content, than control bread and the treated breads with added apple pectin(s). The measured antioxidant activity was mainly derived from the phenolics present in bread. Storage modulus G' (elasticity) and loss modulus G" (viscocity) of the treated bread dough with added pectin(s) only were higher than those of control dough. The G' or G" of the treated breads incorporated with a combination of a pectin and fruit phenolic extract depended on the type of phenolic extract (that is, apple and blackcurrant extracts behaved differently from kiwifruit extract). The G' and G" at the final baking step were higher than those of other stages, indicating an increase in cross-linking among polymeric molecules and bread particles of high molecular weight. We conclude that the added pectin and/or phenolic extract had influenced bread dough cross-linking microstructure and bread properties through being involved in the interactions with bread components such as wheat proteins during dough development and bread baking. PRACTICAL APPLICATION: Dietary fibers and phytochemicals (including phenolic antioxidants) have long been recognized as the active nutrients responsible for the health benefits of fruit and vegetables to humans. Interest in incorporating bioactive ingredients such as dietary fiber and phenolic antioxidants into popular foods like bread has grown rapidly, due to the increased consumer health awareness. The added bioactive ingredients may or may not promote the development of bread dough. This paper reports the findings associated with the properties of the functional breads enhanced with apple pectin and apple, blackcurrant, and kiwifruit phenolic extracts. Results of this paper indicate that the success of the development of such functional breads is ultimately determined by the interactions among added bioactive ingredients and other bread components. PMID- 21535838 TI - Modification of buffered peptone water for improved recovery of heat-injured Salmonella Typhimurium. AB - Rapid detection of Salmonella in foods is often limited by the high demand for the sensitivity of detection, poor physiological conditions of the target cells, and high concentration of background flora. In this study, the conditions of nonselective enrichment cultivation were modified in order to improve the quantitative detection of heat-injured Salmonella in minced meat. The effect of the modifications on the recovery was observed by means of RNA-based sandwich hybridization, which was adjusted for the quantification of Salmonella enterica 23S rRNA in crude cell extracts. The supplementation of buffered peptone water with the enzyme-controlled substrate delivery system EnBase-Flo and ferrioxamine E was shown to improve the recovery of cells in both single strain cultures and in the presence of minced meat. The presented results can be used for the development of more efficient enrichment cultivation media for faster detection of food borne Salmonella. PMID- 21535839 TI - Antimicrobial edible apple films inactivate antibiotic resistant and susceptible Campylobacter jejuni strains on chicken breast. AB - Campylobacter jejuni is the leading cause of bacterial diarrheal illness worldwide. Many strains are now becoming multidrug resistant. Apple-based edible films containing carvacrol and cinnamaldehyde were evaluated for bactericidal activity against antibiotic resistant and susceptible C. jejuni strains on chicken. Retail chicken breast samples inoculated with D28a and H2a (resistant strains) and A24a (a sensitive strain) were wrapped in apple films containing cinnamaldehyde or carvacrol at 0.5%, 1.5%, and 3% concentrations, and then incubated at 4 or 23 degrees C for 72 h. Immediately after wrapping and at 72 h, samples were plated for enumeration of viable C. jejuni. The antimicrobial films exhibited dose- and temperature-dependent bactericidal activity against all strains. Films with >=1.5% cinnamaldehyde reduced populations of all strains to below detection at 23 degrees C at 72 h. At 4 degrees C with cinnamaldehyde, reductions were variable for all strains, ranging from 0.2 to 2.5 logs and 1.8 to 6.0 logs at 1.5% and 3.0%, respectively. Films with 3% carvacrol reduced populations of A24a and H2a to below detection, and D28a by 2.4 logs at 23 degrees C and 72 h. A 0.5-log reduction was observed for both A24a and D28a, and 0.9 logs for H2a at 4 degrees C at 3% carvacrol. Reductions ranged from 1.1 to 1.9 logs and 0.4 to 1.2 logs with 1.5% and 0.5% carvacrol at 23 degrees C, respectively. The films with cinnamaldehyde were more effective than carvacrol films. Reductions at 23 degrees C were greater than those at 4 degrees C. Our results showed that antimicrobial apple films have the potential to reduce C. jejuni on chicken and therefore, the risk of campylobacteriosis. Possible mechanisms of antimicrobial effects are discussed. PRACTICAL APPLICATION: Apple antimicrobial films could potentially be used in retail food packaging to reduce C. jejuni commonly present on food. PMID- 21535840 TI - Factors of influence in the distribution of mold in the air in a wine cellar. AB - This paper studies the presence of mold in the air of a vinification and ageing wine cellar. The influence of other factors such as the time of year, the sampling point, and the activity being carried out in the cellar has been analyzed. Neither the type of activity being carried out in the cellar nor the temperature or relative humidity fluctuations throughout the year are determining factors in the presence of mold in the air. For this group of microorganisms, the design of the cellar studied is the fundamental factor. Areas with little ventilation favor high levels of relative humidity and, hence, a higher presence of mold in the air. The mold population in these areas is not very diverse, which indicates that colonization by certain types of mold that have adapted to the conditions established therein is permanent. Areas with greater air flow, constant activity, and frequent cleaning show lower mold populations in the air and of a more varied composition. PRACTICAL APPLICATION: This work shows that given the growing importance of the presence of mold in wine cellars, the design thereof should take into account suitable ventilation of all the areas and control of the relative humidity. Hence, the presence of traditional underground areas for ageing wine, which is justifiable in seasons where temperature and humidity control lead to major technical problems, should be reconsidered in the design of new wine cellars. PMID- 21535841 TI - Differentiation of lactococci from 2 Greek cheeses with protected designation of origin by phenotypic criteria and RAPD-PCR. AB - Seventy-six lactococci isolates from 2 protected designation of origin (PDO) cheeses were studied for their acidification ability, proteolytic activity, and inhibitory activities as well as their intraspecies characterization by randomly amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR). Fifty-two of them were characterized as Lactococcus lactis subsp. lactis by the SDS-PAGE of whole cell proteins. The test strains increased the amount of acid in milk from 6 to 24 h as well as the quantities of amino acids on incubation for 4 d. The majority of the isolates degraded preferentially alphas-casein. The isolates from Feta differed from those of Graviera Kritis in respect of beta-casein degradation. This fragment was either not degraded or underwent a small degradation by lactococci from Feta. A stronger intensity of acidification for the isolates from Feta and a higher casein breakdown ability for those from Graviera Kritis were also recorded. Lactococci from Feta and Graviera Kritis inhibited, preferentially, the growth of Escherichia coli O157:H7, and Yersinia enterocolitica, respectively. A high heterogeneity among the isolates according to RAPD-PCR was determined, as well as grouping of the isolates according to their source of isolation. Selected isolates from each cheese could be used as starters to make either Feta or Graviera Kritis. PMID- 21535842 TI - Application of polylactic acid coating with antimicrobials in reduction of Escherichia coli O157:H7 and Salmonella Stanley on apples. AB - Survival of Escherichia coli O157:H7 and Salmonella Stanley on apples as affected by application of polylactic acid (PLA) coating with antimicrobials was investigated. Golden Delicious apples were spot inoculated with E. coli O157:H7 or S. Stanley and spray coated with PLA solutions containing lactic acid (LA), disodium ethylenediaminetetraacetic acid (EDTA), sodium benzoate (SB), potassium sorbate (PS), or their combination (LA+EDTA, SB+LA, SB+LA+EDTA). Apples without any coating treatment served as controls. Coating treatments were allowed to dry fully, and the apples were stored at 4 degrees C for 14 d. Antimicrobial coatings reduced populations of E. coli O157:H7 and S. Stanley by up to 4 log CFU/cm2 at 1 d and 4.7 log CFU/cm2 at 14 d, compared to controls. SB+LA combination had a similar effectiveness as the SB+LA+EDTA combination against both pathogens and was more effective than other coating treatments. Without antimicrobial treatment, E. coli O157:H7 and S. Stanley were able to survive on apples stored at 4 degrees C for up to 14 d. The antimicrobial PLA coating provides an alternative intervention to reduce the pathogens on apples. PRACTICAL APPLICATION: Antimicrobial PLA coatings provide an alternative method to reduce pathogenic contaminations on fruit surface, and therefore, reduce the risk of food-borne outbreaks. PMID- 21535843 TI - The impact of high pressure and temperature on bacterial spores: inactivation mechanisms of Bacillus subtilis above 500 MPa. AB - High-pressure thermal sterilization (HPTS) is an emerging technology to produce shelf stable low acid foods. Pressures below 300 MPa can induce spore germination by triggering germination receptors. Pressures above 500 MPa could directly induce a Ca+2-dipicolinic acid (DPA) release, which triggers the cortex-lytic enzymes (CLEs). It has been argued that the activated CLEs could be inactivated under HPTS conditions. To test this claim, a wild-type strain and 2 strains of Bacillus subtilis spores lacking germinant receptors and one of 2 CLEs were treated simultaneously from 550 to 700 MPa and 37 to 80 C (slow compression) and at 60 to 80 C up to 1 GPa (fast compression). Besides, an additional heat treatment to determine the amount of germinated cells, we added TbCl3 to detect the amount of DPA released from the spore core via fluorescent measurement. After pressure treatment for 120 min at 550 MPa and 37 degrees C, no inactivation was observed for the wild-type strain. The amount of released DPA correlated to the amount of germinated spores, but always higher compared to the belonging cell count after pressure treatment. The release of DPA and the increase of heat sensitive spores confirm that the inactivation mechanism during HPTS passes through the physiological states: (1) dormancy, (2) activation, and (3) inactivation. As the intensity of treatment increased, inactivation of all spore strains also strongly increased (up to -5.7 log10), and we found only a slight increase in the inactivation of one of the CLE (sleB). Furthermore, above a certain threshold pressure, temperature became the dominant influence on germination rate. PRACTICAL APPLICATION: The continuous increase of high pressure (HP) research over the last several decades has already generated an impressive number of commercially available HP pasteurized products. Furthermore, research helped to provoke the certification of a pressure-assisted thermal sterilization process by the U.S. FDA in February 2009. However, this promising sterilization technology has not yet been applied in industrial settings. An improved understanding of spore inactivation mechanisms and the ability to calculate desired inactivation levels will help to make this technology available for pilot studies and commercialization at an industrial scale. Moreover, if the synergy between pressure and elevated temperature on the inactivation rate could be identified, clarification of the underlying inactivation mechanism during HP thermal sterilization could help to further optimize the process of this emerging technology. PMID- 21535844 TI - Survival of Escherichia coli O157:H7 in cucumber fermentation brines. AB - Bacterial pathogens have been reported on fresh cucumbers and other vegetables used for commercial fermentation. The Food and Drug Administration currently has a 5-log reduction standard for E. coli O157:H7 and other vegetative pathogens in acidified pickle products. For fermented vegetables, which are acid foods, there is little data documenting the conditions needed to kill acid resistant pathogens. To address this knowledge gap, we obtained 10 different cucumber fermentation brines at different stages of fermentation from 5 domestic commercial plants. Cucumber brines were used to represent vegetable fermentations because cabbage and other vegetables may have inhibitory compounds that may affect survival. The 5-log reduction times for E. coli O157:H7 strains in the commercial brines were found to be positively correlated with brine pH, and ranged from 3 to 24 d for pH values of 3.2 to 4.6, respectively. In a laboratory cucumber juice medium that had been previously fermented with Lactobacillus plantarum or Leuconostoc mesenteroides (pH 3.9), a 5-log reduction was achieved within 1 to 16 d depending on pH, acid concentration, and temperature. During competitive growth at 30 degrees C in the presence of L. plantarum or L. mesenteroides in cucumber juice, E. coli O157:H7 cell numbers were reduced to below the level of detection within 2 to 3 d. These data may be used to aid manufacturers of fermented vegetable products determine safe production practices based on fermentation pH and temperature. PRACTICAL APPLICATION: Disease causing strains of the bacterium E. coli may be present on fresh vegetables. Our investigation determined the time needed to kill E. coli in cucumber fermentation brines and how E. coli strains are killed in competition with naturally present lactic acid bacteria. Our results showed how brine pH and other brine conditions affected the killing of E. coli strains. These data can be used by producers of fermented vegetable products to help assure consumer safety. PMID- 21535845 TI - Effects of antimicrobial coating from catfish skin gelatin on quality and shelf life of fresh white shrimp (Penaeus vannamei). AB - The present study was conducted to evaluate the effect of fish skin gelatin-based antimicrobial coating on the shelf life of fresh white shrimp (Penaeus vannamei). Antimicrobial coating was prepared by incorporating potassium sorbate, sodium tripolyphosphate, or both ingredients in coating solution made from catfish skin gelatin. Shrimp samples were untreated, rinsed with water, or coated with the antimicrobial films, and then they were stored in ice under aerobic conditions. Samples were taken periodically and evaluated for total aerobic plate count, psychrotrophic bacteria count, near-infrared spectrum (NIR), springiness, pH value, and color measurement. The results showed that the antimicrobial coating could retard microbial growth and prolong shelf life for up to 10 d. Partial least square analysis produced an acceptable model fitting between the NIR and the changes of microbial count in shrimp samples. The springiness and pH value of shrimp muscle were not affected by the coating treatments. Color parameter a* value increased linearly for all the treatments during the whole ice-storage period. PRACTICAL APPLICATION: One of the most important technical and economic problems facing the shrimp industry is the relatively short shelf life of fresh shrimp products. Catfish skin gelatin-based antibacterial edible films/coatings provide an ideal technique to solve this problem. The shrimp industry will be the immediate beneficiary of the study, and the information provided by this research will be expended to other seafood. PMID- 21535846 TI - Antifungal effectiveness of potassium sorbate incorporated in edible coatings against spoilage molds of apples, cucumbers, and tomatoes during refrigerated storage. AB - Predominant spoilage molds of fresh apples, cucumbers, and tomatoes stored at 4 degrees C were isolated and examined for resistance to potassium sorbate (PS) incorporated in polysaccharide edible coatings. The isolated molds were Penicillium expansum, Cladosporium herbarum, and Aspergillus niger from apples. P. oxalicum and C. cucumerinum were isolated from cucumbers and P. expansium and C. fulvum from tomatoes. Guar gum edible coating incorporated with PS was the most effective mold inhibitor, significantly (P<0.05) reducing the isolated spoilage molds for 20, 15, and 20 d of storage at 4 degrees C on apples, cucumbers, and tomatoes, respectively. PS incorporated into pea starch edible coating was less effective and selectively inhibited the isolated mold species, causing significant (P<0.05) reduction in mold on apples, cucumbers, and tomatoes counts for 20, 10 to 15, and 15 to 20 d of storage at 4 degrees C, respectively. The isolated mold species exhibited different resistances to PS incorporated in the edible coatings. The greatest inhibition (2.9 log CFU/g) was obtained with C. herbarum on apples and the smallest (1.1 log CFU/g) was with P. oxalicum on cucumbers and the other isolated mold species exhibited intermediate resistance. The coatings tested, in general, inhibited molds more effectively on apples than on tomatoes and cucumbers. Addition of PS to pea starch and guar gum, edible coatings improved the antifungal activity of PS against isolated spoilage molds on apples, cucumbers, and tomatoes. PS inhibition was most effective against C. herbarum on apples and least effective against P. oxalicum on cucumbers. PMID- 21535847 TI - Chlorine stabilizer T-128 enhances efficacy of chlorine against cross contamination by E. coli O157:H7 and Salmonella in fresh-cut lettuce processing. AB - During fresh-cut produce processing, organic materials released from cut tissues can rapidly react with free chlorine in the wash solution, leading to the potential survival of foodborne bacterial pathogens, and cross-contamination when the free chlorine is depleted. A reported chlorine stabilizer, T-128, has been developed to address this problem. In this study, we evaluated the ability of T 128 to stabilize free chlorine in wash solutions in the presence of high organic loads generated by the addition of lettuce extract or soil. Under conditions used in this study, T-128 significantly (P<0.001) decreased the rate of free chlorine depletion at the presence of soil. T-128 also slightly decreased the rate of free chlorine depletion caused by the addition of lettuce extract in wash solution. Application of T-128 significantly reduced the survival of bacterial pathogens in wash solutions with high organic loads and significantly reduced the potential of cross-contamination, when contaminated and uncontaminated produce were washed together. However, T-128 did not enhance the efficacy of chlorinated wash solutions for microbial reduction on contaminated iceberg lettuce. Evaluation of several produce quality parameters, including overall visual appearance, package headspace O2 and CO2 composition, and lettuce electrolyte leakage, during 15 d of storage indicated that iceberg lettuce quality and shelf life were not negatively impacted by washing fresh-cut lettuce in chlorine solutions containing 0.1% T 128. PRACTICAL APPLICATION: Reported chlorine stabilizer is shown to enhance chlorine efficacy against potential bacterial cross-contamination in the presence of high organic loads without compromising product quality and shelf life. PMID- 21535848 TI - Dynamic predictive model for the growth of Salmonella spp. in liquid whole egg. AB - A dynamic model for the growth of Salmonella spp. in liquid whole egg (LWE) (approximately pH 7.8) under continuously varying temperature was developed. The model was validated using 2 (5 to 15 degrees C; 600 h and 10 to 40 degrees C; 52 h) sinusoidal, continuously varying temperature profiles. LWE adjusted to pH 7.8 was inoculated with approximately 2.5-3.0 log CFU/mL of Salmonella spp., and the growth data at several isothermal conditions (5, 7, 10, 15, 20, 25, 30, 35, 37, 39, 41, 43, 45, and 47 degrees C) was collected. A primary model (Baranyi model) was fitted for each temperature growth data and corresponding maximum growth rates were estimated. Pseudo-R2 values were greater than 0.97 for primary models. Modified Ratkowsky model was used to fit the secondary model. The pseudo R2 and root mean square error were 0.99 and 0.06 log CFU/mL, respectively, for the secondary model. A dynamic model for the prediction of Salmonella spp. growth under varying temperature conditions was developed using 4th-order Runge-Kutta method. The developed dynamic model was validated for 2 sinusoidal temperature profiles, 5 to 15 degrees C (for 600 h) and 10 to 40 degrees C (for 52 h) with corresponding root mean squared error values of 0.28 and 0.23 log CFU/mL, respectively, between predicted and observed Salmonella spp. populations. The developed dynamic model can be used to predict the growth of Salmonella spp. in LWE under varying temperature conditions. PRACTICAL APPLICATION: Liquid egg and egg products are widely used in food processing and in restaurant operations. These products can be contaminated with Salmonella spp. during breaking and other unit operations during processing. The raw, liquid egg products are stored under refrigeration prior to pasteurization. However, process deviations can occur such as refrigeration failure, leading to temperature fluctuations above the required temperatures as specified in the critical limits within hazard analysis and critical control point plans for the operations. The processors are required to evaluate the potential growth of Salmonella spp. in such products before the product can be used, or further processed. Dynamic predictive models are excellent tools for regulators as well as the processing plant personnel to evaluate the microbiological safety of the product under such conditions. PMID- 21535849 TI - Effects of various plasticizers and nanoclays on the mechanical properties of red algae film. AB - To manufacture red algae (RA) film, we used various plasticizers such as glycerol, sorbitol, sucrose, fructose, and polypropylene glycol (PPG), and then determined the mechanical properties of the RA films. The tensile strength (TS), elongation at break (E), and water vapor permeability (WVP) of the films containing various plasticizers ranged between 0.43 to 9.10 MPa, 10.93% to 47.17%, and 1.28 to 1.42 ng m/m2sPa, respectively. RA films containing fructose as a plasticizer had the best mechanical properties of all the films evaluated. Incorporation of nanoclay (Cloisite Na+ and 30B) improved the mechanical properties of the films. RA film with 3% Cloisite Na+ had a TS of 10.89, while RA film with 30B had a TS of 10.85 MPa; these films also had better E and WVP values than the other RA films evaluated. These results suggest that RA/nanoclay composite films are suitable for use as food packaging materials. PRACTICAL APPLICATION: Edible RE/nanoclay composite films prepared in the present investigation can be applied in food packaging. PMID- 21535850 TI - Flavonoids: precipitation kinetics and interaction with surfactant micelles. AB - Polyphenolic substances, such as flavonoids, attract considerable interest due to their ability to act as antioxidants. The vast majority of studies published deal with the nutritional, biochemical, or chemical structure aspects of these substances while few reports exist on the physico-chemical properties as well as solution behavior of the substances. In this article we report on the precipitation kinetics of naringenin, quercetin, and rutin in pure water as well as in micellar solutions of Tween 80. The methods used are dynamic and static light scattering in conjunction with cryo transmission electron microscopy. The results show that the substances precipitate rapidly in pure water. In the presence of Tween 80 micelles, however, the flavonoids can become solubilized in the micelles, which can result in solutions which are stable for days. The results suggest that the extent of solubilization is related to the chemical structure of the flavonoids. This study illustrates that precipitation kinetics and the distribution of polyphenolic substances in solutions and dispersions are factors of importance, which should be taken into account when designing investigations and interpreting results. PMID- 21535851 TI - Preparation and characterization of agar/clay nanocomposite films: the effect of clay type. AB - Agar-based nanocomposite films with different types of nanoclays, such as Cloisite Na+, Cloisite 30B, and Cloisite 20A, were prepared using a solvent casting method, and their tensile, water vapor barrier, and antimicrobial properties were tested. Tensile strength (TS), elongation at break (E), and water vapor permeability (WVP) of control agar film were 29.7+/-1.7 MPa, 45.3+/-9.6%, and (2.22+/-0.19)*10(-9) g.m/m2.s.Pa, respectively. All the film properties tested, including transmittance, tensile properties, WVP, and X-ray diffraction patterns, indicated that Cloisite Na+ was the most compatible with agar matrix. TS of the nanocomposite films prepared with 5% Cloisite Na+ increased by 18%, while WVP of the nanocomposite films decreased by 24% through nanoclay compounding. Among the agar/clay nanocomposite films tested, only agar/Cloisite 30B nanocomposite film showed a bacteriostatic function against Listeria monocytogenes. PMID- 21535852 TI - Toward better control of Salmonella contamination by taking advantage of the egg's self-defense system: a review. AB - Egg-associated salmonellosis is a major problem for food safety. It can be caused by vertical transmission (transovarian transmission) in hens and horizontal transmission though penetration. Despite a series of physical and chemical defense mechanisms naturally found in eggs, they cannot provide complete protection for them. Environmental hygiene, bacteria vectors such as birds, rodent, flies, and beetles along with feed and water contamination are the most frequently reported causes of Salmonella colonization in hens, and finally to eggs. In addition, inappropriate egg handling will cause eggs to lose their self protection ability, thus resulting in the survival and multiplication of Salmonella in an egg's contents, which contributes to the horizontal dissemination. The routes of Salmonella contamination were discussed, and the effectiveness and shortcomings of different decontamination methods were evaluated in this review. Various studies on egg storage indicated that the low temperature storage without temperature fluctuation was beneficial for the control of Salmonella. This review, based on an understanding of the stages of Salmonella transmission and an egg's self-protection mechanisms, highlights a comprehensive strategy toward Salmonella control in a process from egg production and handling to human consumption. PMID- 21535853 TI - Construction of food and water borne pathogens' dose-response curves using the expanded Fermi Solution. AB - Theoretically, the relationship between the number of pathogens that cause acute infection if settling in the gut, N, and that initially ingested, M, can be constructed from the survival probabilities at the different "stations" along the digestive tract. These probabilities are rarely known exactly, but their ranges can be estimated. If for a given N one generates estimates of M using random probabilities within these ranges, the estimates' distribution will be approximately lognormal and its cumulative (CDF) form will represent the pathogen's dose-response curve. The distribution's logarithmic mean and standard deviation can be calculated from the ranges with a formula and used to plot the curve. The method was used to generate dose-response curves of hypothetical food and waterborne pathogens and calculate their infective dose (ID) at 5%, 50%, and 95% probability. The curves were compatible with the Beta Poisson model and robust against minor perturbations in the underlying probabilities' ranges. The calculation and plotting procedure was automated and posted on the Internet as a freely downloadable interactive Wolfram Demonstration. It allows the user to generate, modify, examine, and compare dose-response curves, and to calculate their characteristics, by moving sliders on the screen. PMID- 21535854 TI - Antimicrobial activity of biodegradable polysaccharide and protein-based films containing active agents. AB - Significant interest has emerged in the introduction of food packaging materials manufactured from biodegradable polymers that have the potential to reduce the environmental impacts associated with conventional packaging materials. Current technologies in active packaging enable effective antimicrobial (AM) packaging films to be prepared from biodegradable materials that have been modified and/or blended with different compatible materials and/or plasticisers. A wide range of AM films prepared from modified biodegradable materials have the potential to be used for packaging of various food products. This review examines biodegradable polymers derived from polysaccharides and protein-based materials for their potential use in packaging systems designed for the protection of food products from microbial contamination. A comprehensive table that systematically analyses and categorizes much of the current literature in this area is included in the review. PMID- 21535855 TI - Comparison of sodium acid sulfate to citric acid to inhibit browning of fresh-cut potatoes. AB - Sodium acid sulfate (SAS) dip treatments were evaluated against a distilled water control and citric acid (CA) to compare its effectiveness in reducing enzymatic browning of raw, French-fry cut potatoes. Two separate studies were conducted with dip concentrations ranging from 0%, 1%, and 3% in experiment 1 to 0%, 2%, and 2.5% in experiment 2 to determine optimal dip concentrations. Russet Burbank potatoes were peeled, sliced, and dipped for 1 min and stored at 3 degrees C. Color, texture, fry surface pH, and microbiological analyses were conducted on days 0, 7, and 14. The 3% SAS- and CA-treated samples had significantly (p<0.0001) lower pH levels on fry surfaces than all other treatments. Both acidulants had significantly (p<=0.05) lower aerobic plate counts compared to controls in both studies by day 7. However, SAS appeared to be the most effective at the 3% level in maintaining a light fry color up to day 14 and had the highest L-values than all other treatments. The 3% SAS-treated fry slices appeared to have the least change in textural properties over storage time, having a significantly (p=0.0002) higher force value (kg force [kgf]) than the other treatments during experiment 1, without any signs of case-hardening that appeared in the control and CA-treated samples. SAS was just as comparable to CA in reducing surface fry pH and also lowering microbial counts over storage time. According to the results, SAS may be another viable acidulant to be utilized in the fresh-cut fruit and vegetable industry. PMID- 21535856 TI - Sensory properties of Californian and imported extra virgin olive oils. AB - Production and consumption of extra-virgin olive has been increasing in the United States, particularly in California. The objective of this study was to compare the sensory characteristics of 22 extra virgin olive oils (EVOO) from California, Italy, Spain, Chile, and Australia using a generic descriptive analysis. A total of 22 sensory attributes were identified and defined by the descriptive panel. With the exception of thick and citrus, all sensory attributes were significantly different among the oils. Canonical Variate Analysis (CVA) showed that California oils differed from some imported EVOOs, mainly by their absence of defects. A second analysis, of only those attributes included in the International Olive Council (IOC) official scorecard, provided a less detailed description of the samples and did not allow for a full characterization of the oils. While the IOC attributes allowed for faster classification in terms of clean versus defective EVOOs, the more comprehensive descriptive analysis provided both more information and a more refined classification of the samples. Variety and region of origin were important factors in the classification of both Californian and imported EVOOs. PRACTICAL APPLICATION: Measuring olive oil sensory quality using the IOC method-positive attributes of fruitiness, bitterness, and pungency, and defects including fusty, musty, winey, and rancid allows for the certification of oils as extra virgin but it provides limited information on the sensory characteristics of the oils. A full descriptive profile, on the other hand, provides information that can be used by producers in the processing and marketing of their oils, and is a useful tool in the education of consumers about the wide range of (positive) sensory attributes in EVOO and the various sensory styles of EVOO. PMID- 21535857 TI - Determining consumer purchase intentions: the importance of dry matter, size, and price of kiwifruit. AB - Knowledge of the relative importance of food quality attributes in determining consumer purchase intention is critical for robust assessment of economic opportunities for industry growth. The aim of this study is to demonstrate how conjoint analysis methodology that incorporates tasting of fruit can be used to collect such information. Three hundred Japanese consumers took part in research designed to measure the importance of dry matter (DM), size, and price of kiwifruit (Actinidia deliciosa "Hayward" and Actinidia chinensis "Hort16A") for purchase intention. Measurement of consumer liking for kiwifruit of different DM content was a key first step. Liking increased as DM increased and was accompanied by increased purchase likelihood/choice probability for kiwifruit. The size of kiwifruit presented to consumers varied from "small" to "extra large." Consumers liked "mid-sized" kiwifruit over "small" or "extra-large" kiwifruit. Despite these differences in liking, size was of little importance in determining purchase likelihood/choice probability for kiwifruit. Price was a very important factor in determining purchase likelihood/choice probability but was less important than DM content. As price increased, purchase likelihood/choice probability decreased. Beneath these general findings, heterogeneity existed. Some consumers placed more/less importance on the focal purchase drivers than suggested by the aggregate model. Overall, the results suggest that incentive schemes already implemented by industry should consider rewarding high-DM fruit more than fruit size. PRACTICAL APPLICATION: This research has contributed to the New Zealand kiwifruit industry gaining a better understanding of the relative importance consumers place on DM, size, and price of kiwifruit and has resulted in changes to grower incentive schemes. The research approach presented forces consumer to tradeoff attributes of kiwifruit against each other and decide on how important two key quality attributes-DM and size-are relative to each other and relative to price. The application of conjoint analysis in this article can be transferred to other fruits, food, and beverages and help guide consumer-led innovation. PMID- 21535858 TI - Effect of modified atmosphere packaging on Quality Index Method (QIM) scores of farmed gilthead seabream (Sparus aurata L.) at low and abused temperatures. AB - A Quality Index Method (QIM) scheme was developed for modified atmosphere packaging (MAP) packed gilthead seabream, and the effect of MAP gas mixtures (60% CO2 and 40% N2; 60% CO2, 30% O2, and 10% N2), temperature (2, 4, and 8 degrees C), and time of storage on QI scores was assessed. QI scores were crossed with sensory evaluation of cooked fish according to a modified Torry scheme to establish the rejection point. In order to reduce redundant parameters, a principal component analysis was applied on preliminary QIM parameters scores coming from the best performing MAP among those tested. The final QIM scheme consists of 13 parameters and a maximum demerit score of 25. The maximum storage time was found to be 13 d at 4 degrees C for MAP 60% CO2 and 40% N2. Storage at 2 degrees C do not substantially improved sensory parameters scores, while storage under temperature abuse (8 degrees C) accelerated drastically the rate of increase of QI scores and reduced the maximum storage time to 6 d. PMID- 21535859 TI - The effect of a flaxseed oil-enhanced diet on the product quality of farmed brook trout (Salvelinus fontinalis) fillets. AB - The effects of dietary modification with flaxseed oil-enhanced (Flax) feed on the product quality of brook trout fillets were examined. Trout were fed a commercial feed supplemented with fish oil (CD) or flaxseed oil (Flax) for 165 d before harvesting. Proximate composition and fatty acid profile were determined on fillets. Quality parameters of the raw fillets were examined over the storage period by measuring color (L*, a*, b*), muscle pH, and thiobarbituric acid reactive substances test. Evaluations on the cooked fillets included sensory evaluation with triangle tests and a paired preference test. There were no differences in proximate composition between the groups; however, the total omega 3 fatty acids were greater in Flax fillets (P<0.05). Diet and day were shown to interact in their effect on whiteness, pH, and lipid oxidation (P<0.05); however, linear regression did not determine that malondialdehyde concentration was associated with time in either diet type implying that lipid oxidation in the vacuum-packed fish was controlled at storage temperatures (4 degrees C). Sensory panelists were able to choose the odd sample in a replicated triangle test analyzed using the beta-binomial model, and there was preference for Flax fillets (P<0.05). Results indicate that a Flax-enhanced diet would have favorable effects on product quality of farmed brook trout. PMID- 21535860 TI - Pilot-scale technology development, nutritional and consumer assessment of whole multigrain cookies as influenced by fructan inclusion. AB - The benefits of wholegrain finger millet and sorghum were combined with that of fructan in form of fructoligosaccharide in the pilot-scale production (10 kg) of cookies. Complete nutritional analysis of the cookies was carried out to provide nutritional information to the consumers. Whole-multigrain cookies with fructan can be categorized as "High Fiber" as they suffice 21% daily value (DV) of fiber and a "Good Source" of iron as they suffice 12.8% DV of iron. A total of 300 consumers (M=110 and F=190), aged between 8 and 66 y evaluated cookies. The overall acceptability (OAA) score of 300 consumers was 8.0+/-0.58 on a 9-point hedonic scale. Females rated cookies significantly (P<0.05) higher than males in terms of flavor, texture, appearance, and OAA. Males rated cookies significantly (P<0.05) higher on color attribute than females. Encouraging response of consumers signified ample scope for viability and marketability of cookies at the commercial scale. PRACTICAL APPLICATION: Consumers are looking at snack and convenience foods to provide increased fiber in their diet and there is a tremendous interest in low-calorie and low-sugar foods. The demand of whole and multigrain products is also on the rise because of the Government's emphasis. The present study would assist in assessing feasibility of commercial production of such novel health foods. Together with this, it will ascertain the marketability and commercial viability of the product by means of the consumer preference trials. Availability of such cookies in the market would offer consumers "health" with "convenience" and "taste." PMID- 21535861 TI - Visible/near-infrared spectroscopy detects autolytic changes during storage of Atlantic salmon (Salmo salar L.). AB - Visible (VIS)/near-infrared (NIR) spectroscopy was used to investigate spectroscopic changes occurring during storage of Atlantic salmon fillets with and without bacterial growth. A storage experiment was conducted for 11 d postmortem. Bacterial growth was inhibited by soaking a group of salmon fillets in 3 mM NaN3 prior to storage, while a control group retained its normal bacterial growth. Spectra were obtained by directly applying the spectroscopic probe onto the loin part of each fillet stored under conditions accelerating degradation. Principal component analysis (PCA) was used to monitor and compare spectroscopic development of the 2 groups and the results showed that VIS/NIR spectral changes occurred in the control as well as the treated group of samples within a single day after filleting. After 2 d of storage, stored samples were distinguishable from those fresh in both groups and it was only after the microbial spoilage became pronounced (8 to 9 log colony forming unit [CFU]/g) that the spectra of the spoiled control samples could be differentiated from spectra of the treated samples with no bacterial growth. Microbial growth is therefore not the only explanation for the spectral variations prior to microbial spoilage. Nonmicrobial, autolytic changes including possible changes in the physical properties are also contributing. Our results show that VIS/NIR spectroscopy can detect autolytic changes occurring in salmon muscle during the early stage of storage, independent of microbial growth. PRACTICAL APPLICATION: Important spectroscopic changes occur even when microbial growth is not apparent. This indicates that VIS/NIR spectroscopy may be used to determine the degree of freshness before microbial spoilage becomes relevant. PMID- 21535862 TI - Use of gelatin gels as a reference material for performance evaluation of meat shear force measurements. AB - Establishing standards for meat tenderness based on Warner-Bratzler shear force (WBSF) is complicated by the lack of methods for certifying WBSF testing among texture systems or laboratories. The objective of this study was to determine the suitability of using gelatin gels as reference materials for performance testing of texture measurement systems. Three replications of 5 gels (15%, 20%, 25%, 30%, and 35% gelatin) were prepared, vacuum packaged, and stored at 4 degrees C until use. Three randomly selected strips from each gel were subjected to WBSF testing on 4 instruments (A, B, C, or D) on days 1 and 8. Additional strips from each gel were subjected to WBSF testing on instruments A and C on day 29. Regression line estimates for each set of gels were analyzed. Gel WBSF values ranged from 10 to 177 N. The WBSF by gel concentration response was highly linear (P<0.0001) for all replications, instruments, and days of analysis. R2-values across all sets of gels ranged from 0.9562 to 0.9998. On days 1 and 8, instruments A and D exhibited higher slope (P<0.0001) and lower intercept (P<0.0001) estimates than instruments B and C. Regression line parameters (slope, intercept, and R2-values) were not influenced (P>0.05) by length of gel storage (1, 8, and 29 d). Data from this study suggest that gelatin gels can be used for evaluating WBSF values from various instruments and for validating the performance of meat shear force testing. PRACTICAL APPLICATION: Validating the performance of meat shear force testing is vital to establishing meat tenderness standards. The gelatin gel standards developed in this study exhibited a highly linear, repeatable relationship with shear force and were found to be stable for at least a month. These gel standards would provide a tool for the meat industry to harmonize shear force measurements across laboratories and various texture measuring instruments. PMID- 21535863 TI - Conjoint analysis on the purchase intent for traditional fermented soy product (natto) among Japanese housewives. AB - The effect of sensory and extrinsic attributes on consumer intentions to purchase the Japanese traditional fermented soybean product natto was evaluated using conjoint analysis. Six attributes with 2 levels each were chosen and manipulated: price (high compared with low), the country of origin of the soybeans (domestic compared with imported), stickiness (strong compared with moderate), smell (rich compared with moderate), attached seasonings (attached compared with no attached seasonings), and the environmental friendliness of the packaging (high compared with low). A fractional factorial design was applied and 8 hypothetical product labels were produced. A sample of 479 Japanese housewives ranked these product labels based on their purchase intentions. Overall purchase intention was affected by country of origin, attached seasonings, and price; those attributes accounted for 81.0%, while the sensory attributes of the product accounted for 19.0% of purchase intents. In order to estimate market segments for the natto products based on consumer preference, a cluster analysis was performed. It identified 4 segments of consumers: 1 oriented to attached seasonings, another conscious of the price, and the other 2 oriented to origins. The behavioral and demographic characteristics of the respondents had a limited influence on segment membership. PRACTICAL APPLICATION: This research was conducted to understand how consumers valuate various sensory and nonsensory product attributes based on their assessment of the overall product in the case of Japanese fermented soy product (natto). The data of this research would be of great importance both in understanding consumer behavior and in designing strategies for product development. PMID- 21535864 TI - Prevalence and public health significance of aluminum residues in milk and some dairy products. AB - Sixty random samples of bulk farm milk, market milk, locally manufactured processed cheese, and milk powder were collected to be analyzed for aluminum (Al) concentration using graphite furnace atomic absorption spectrometry (GFAAS). The results were compared with provisional acceptable permissible limits (PAPLs). The maximum estimated dietary intake (MEDI) of Al for the examined samples was calculated. In addition, an experimental study was conducted to determine the possible leaching of Al from cookware in milk during boiling. The obtained results showed that Al concentration in examined bulk farm milk samples was found to be negligible. In contrast, market milk revealed higher concentration, 65.0% of the examined samples were above the PAPLs. The results revealed significant difference of Al concentration among them. The Al levels in processed cheese wrapped in Al foil were significantly higher than those found in samples packed in glass containers with a significant difference of Al concentration between them. Also, 20% of the examined milk powder samples exceeded the PAPLs (0.01 to 0.4 mg/kg). The MEDI for Al in bulk farm milk, control market milk, market milk boiled in Al cookware, market milk boiled in stainless-steel cookware, processed cheese wrapped in Al foil, processed cheese packed in glass containers, and milk powder were calculated as 3.0%, 61.0%, 63.0%, 61.0%, 428.0%, 220.0%, and 166.0% from "PTDI," respectively. The results of the experimental study showed no marked significant differences of Al concentration between market milk (control group) and those boiled in Al cookware, as well as to those boiled in stainless-steel cookware. PRACTICAL APPLICATION: The results of the present study indicate that Al level in milk kept in Al containers and dairy products packed in Al foil is beyond the permissible limits, suggesting health hazard. Therefore, all milk cans should be constructed of stainless steel, prevent the entrance of tap water into milk, and the processed cheese should be packed in glass containers and not wrapped in Al foil. Leaching of Al increased to a significant percent more during storage than during boiling, so milk should be kept in stainless steel or glass containers in the refrigerator. PMID- 21535865 TI - Antiproliferative activity of fucoidan was associated with the induction of apoptosis and autophagy in AGS human gastric cancer cells. AB - Fucoidan, a sulfated polysaccharide purified from brown algae, possesses a variety of pharmacologic effects, including antiinflammatory, antioxidant, and anticancer properties; however, the underlying action mechanisms are not completely understood. This study investigated the possible mechanisms through which fucoidan exerts its antiproliferative action in cultured AGS human gastric adenocarcinoma cells. We found that fucoidan effectively inhibits the growth of AGS cells by inducing autophagy, as well as apoptosis. Apoptosis by fucoidan treatment was associated with the downregulation of antiapoptotic Bcl-2 and Bcl xL expression, loss of mitochondrial membrane potential, activation of caspases, and concomitant degradation of poly-(ADP-ribose) polymerase protein. In addition, the morphological study indicated a characteristic finding of autophagy, such as the formation of autophagosomes in fucoidan-treated AGS cells. Furthermore, markers of autophagy, namely, the conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II and increased beclin-1 accumulation, were observed. Overall, the present data suggest that fucoidan induces apoptotic and autophagic cell death, and both apoptotic and autophagic mechanisms contribute to the fucoidan-induced AGS cell death. PMID- 21535866 TI - Mutagenicity and safety evaluation of the water extract of Camellia oleifera Abel. AB - The purpose of this study was to evaluate the mutagenicity and safety of water extract of the fruit hull of Camellia oleifera Abel (WECO), which was prepared using hot-reflux method. The oral maximum tolerated dose (MTD) of WECO was above 20 g/kg body weight both in rats and in mice, which can be regarded as virtually nontoxic. No mutagenicity was found in Ames test, mouse bone marrow cell micronucleus test and mouse sperm abnormality test. In the subacute study, the SD rats were administered orally at 0.5, 1, or 2 g/kg/BW for 30 d. There were no treatment-related toxic effects from WECO. No significant differences were found in parameters of body weight, hematology value, clinical chemistry value, and organ/body weight ratio. The level of no observed adverse effect level (NOAEL) for WECO was 2 g/kg/BW for subacute toxicity study. PRACTICAL APPLICATION: With the gradual increase in tea oil production, it was in urgent need of dealing with Camellia fruit hull, which was always discarded because of low economic benefits. Camellia fruit hull has been shown to have significant antioxidant effects including DPPH radical-scavenging ability and ferric-reducing antioxidant power (Zhang and others 2010). Toxicological evaluation of WECO provided a safety assurance of WECO for developing dietary supplements and functional foods. PMID- 21535869 TI - Reducing page count, and when language inhibits understanding the science. PMID- 21535870 TI - Luminal and basal-like breast cancer cells show increased migration induced by hypoxia, mediated by an autocrine mechanism. AB - BACKGROUND: Some breast cancer patients receiving anti-angiogenic treatment show increased metastases, possibly as a result of induced hypoxia. The effect of hypoxia on tumor cell migration was assessed in selected luminal, post-EMT and basal-like breast carcinoma cell lines. METHODS: Migration was assessed in luminal (MCF-7), post-EMT (MDA-MB-231, MDA-MB-435S), and basal-like (MDA-MB-468) human breast carcinoma cell lines under normal and oxygen-deprived conditions, using a collagen-based assay. Cell proliferation was determined, secreted cytokine and chemokine levels were measured using flow-cytometry and a bead-based immunoassay, and the hypoxic genes HIF-1alpha and CA IX were assessed using PCR. The functional effect of tumor-cell conditioned medium on the migration of neutrophil granulocytes (NG) was tested. RESULTS: Hypoxia caused increased migratory activity but not proliferation in all tumor cell lines, involving the release and autocrine action of soluble mediators. Conditioned medium (CM) from hypoxic cells induced migration in normoxic cells. Hypoxia changed the profile of released inflammatory mediators according to cell type. Interleukin-8 was produced only by post-EMT and basal-like cell lines, regardless of hypoxia. MCP-1 was produced by MDA-MB-435 and -468 cells, whereas IL-6 was present only in MDA MB-231. IL-2, TNF-alpha, and NGF production was stimulated by hypoxia in MCF-7 cells. CM from normoxic and hypoxic MDA-MB-231 and MDA-MB-435S cells and hypoxic MCF-7 cells, but not MDA-MB-468, induced NG migration. CONCLUSIONS: Hypoxia increases migration by the autocrine action of released signal substances in selected luminal and basal-like breast carcinoma cell lines which might explain why anti-angiogenic treatment can worsen clinical outcome in some patients. PMID- 21535871 TI - Formation of VEGF isoform-specific spatial distributions governing angiogenesis: computational analysis. AB - BACKGROUND: The spatial distribution of vascular endothelial growth factor A (VEGF) is an important mediator of vascular patterning. Previous experimental studies in the mouse hindbrain and retina have suggested that VEGF alternative splicing, which controls the ability of VEGF to bind to heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays a key role in controlling VEGF diffusion and gradients in tissues. Conversely, proteolysis notably by matrix metalloproteinases (MMPs), plays a critical role in pathological situations by releasing matrix-sequestered VEGF and modulating angiogenesis. However, computational models have predicted that HSPG binding alone does not affect VEGF localization or gradients at steady state. RESULTS: Using a 3D molecular-detailed reaction-diffusion model of VEGF ligand-receptor kinetics and transport, we test alternate models of VEGF transport in the extracellular environment surrounding an endothelial sprout. We show that differences in localization between VEGF isoforms, as observed experimentally in the mouse hindbrain, as well as the ability of proteases to redistribute VEGF in pathological situations, are consistent with a model where VEGF is endogenously cleared or degraded in an isoform-specific manner. We use our predictions of the VEGF distribution to quantify a tip cell's receptor binding and gradient sensing capacity. A novel prediction is that neuropilin-1, despite functioning as a coreceptor to VEGF165-VEGFR2 binding, reduces the ability of a cell to gauge the relative steepness of the VEGF distribution. Comparing our model to available in vivo vascular patterning data suggests that vascular phenotypes are most consistently predicted at short range by the soluble fraction of the VEGF distributions, or at longer range by matrix-bound VEGF detected in a filopodia dependent manner. CONCLUSIONS: Isoform-specific VEGF degradation provides a possible explanation for numerous examples of isoform specificity in VEGF patterning and examples of proteases relocation of VEGF upon release. PMID- 21535872 TI - The emergence of insecticide resistance in central Mozambique and potential threat to the successful indoor residual spraying malaria control programme. AB - BACKGROUND: Malaria vector control by indoor residual spraying was reinitiated in 2006 with DDT in Zambezia province, Mozambique. In 2007, these efforts were strengthened by the President's Malaria Initiative. This manuscript reports on the monitoring and evaluation of this programme as carried out by the Malaria Decision Support Project. METHODS: Mosquitoes were captured daily through a series of 114 window exit traps located at 19 sentinel sites, identified to species and analysed for sporozoites. Anopheles mosquitoes were collected resting indoors and tested for insecticide resistance following the standard WHO protocol. Annual cross sectional household parasite surveys were carried out to monitor the impact of the control programme on prevalence of Plasmodium falciparum in children aged 1 to 15 years. RESULTS: A total of 3,769 and 2,853 Anopheles gambiae s.l. and Anopheles funestus, respectively, were captured from window exit traps throughout the period. In 2010 resistance to the pyrethroids lambda-cyhalothrin and permethrin and the carbamate, bendiocarb was detected in An. funestus. In 2006, the sporozoite rate in An. gambiae s.s. was 4% and this reduced to 1% over 4 rounds of spraying. The sporozoite rate for An. funestus was also reduced from 2% to 0 by 2008. Of the 437 Anopheles arabiensis identified, none were infectious. Overall prevalence of P. falciparum in the sentinel sites fell from 60% to 32% between October 2006 and October 2008. CONCLUSION: Both An. gambiae s.s. and An. funestus were controlled effectively with the DDT-based IRS programme in Zambezia, reducing disease transmission and burden. However, the discovery of pyrethroid resistance in the province and Mozambique's policy change away from DDT to pyrethroids for IRS threatens the gains made here. PMID- 21535873 TI - Dynamic changes of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and natural killer T (NKT) cells in patients with acute hepatitis B infection. AB - BACKGROUND: The goal of this study is to observe changes in HBcAg-specific cytotoxic T lymphocytes (CTLs), natural killer (NK) and natural killer T (NKT) cells from peripheral blood and to relate such changes on viral clearance and liver injury in patients with acute hepatitis B (AHB). METHODS: Dynamic profiles on the frequency of HLA-A0201-restricted HBcAg18-27 pentamer complex (MHC Pentamer)-specific CTLs and lymphocyte subsets in AHB patients were analyzed in addition to liver function tests, HBV serological markers, and HBV DNA levels. ELISPOT was used to detect interferon-gamma (INF-gamma) secretion in specific CTLs stimulated with known T cell epitope peptides associated with HBV surface protein, polymerase, and core protein. RESULTS: HBV-specific CTL frequencies in AHB patients were much higher than in patients with chronic hepatitis B (CHB) (p<0.05). HBeAg and HBV DNA disappeared earlier in AHB patients with a high frequency of HBV-specific CTLs compared with those with a low frequency of HBV specific CTLs (p=0.001 and 0.024, respectively). INF-gamma spots of effector cells stimulated by Pol575-583, Env348-357, or Core18-27 epitope peptides were significantly greater in AHB patients than in CHB patients (p<0.01). CD3+CD8+ T cell numbers in AHB patients was more than observed in the healthy control group from the first to the fourth week after admission (p=0.008 and 0.01, respectively); the number of CD3+CD8+ T cells and frequency of HBcAg18-27 specific CTLs in AHB patients reached peak levels at the second week after admission. NK and NKT cell numbers were negatively correlated with the frequency of HBcAg-specific CTLs (r=-0.266, p=0.05). CONCLUSIONS: Patients with AHB possess a higher frequency of HBcAg-specific CTLs than CHB patients. The frequency of specific CTLs in AHB patients is correlated with HBeAg clearance indicating that HBV-specific CTLs play an important role in viral clearance and the self-limited process of the disease. Furthermore, NK and NKT cells are likely involved in the early, non-specific immune response to clear the virus. PMID- 21535874 TI - A deficiency of uPAR alters endothelial angiogenic function and cell morphology. AB - The angiogenic potential of a cell requires dynamic reorganization of the cytoskeletal architecture that involves the interaction of urokinase-type plasminogen activator receptor (uPAR) with the extracellular matrix. This study focuses on the effect of uPAR deficiency (uPAR-/-) on angiogenic function and associated cytoskeletal organization. Utilizing murine endothelial cells, it was observed that adhesion, migration, proliferation, and capillary tube formation were altered in uPAR-/- cells compared to wild-type (WT) cells. On a vitronectin (Vn) matrix, uPAR-/- cells acquired a "fried egg" morphology characterized by circular actin organization and lack of lamellipodia formation. The up-regulation of beta1 integrin, FAK(P-Tyr925), and paxillin (P-Tyr118), and decreased Rac1 activation, suggested increased focal adhesions, but delayed focal adhesion turnover in uPAR-/- cells. This accounted for the enhanced adhesion, but attenuated migration, on Vn. VEGF-enriched Matrigel implants from uPAR-/- mice demonstrated a lack of mature vessel formation compared to WT mice. Collectively, these results indicate that a uPAR deficiency leads to decreased angiogenic functions of endothelial cells. PMID- 21535875 TI - IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-beta1 resulting in epithelial to mesenchymal transition. AB - INTRODUCTION: TGF-beta signaling has been extensively studied in many developmental contexts, amongst which is its ability to induce epithelial to mesenchymal transitions (EMT). EMTs play crucial roles during embryonic development and have also come under intense scrutiny as a mechanism through which breast cancers progress to become metastatic. Interestingly, while the molecular hallmarks of EMT progression (loss of cell adhesion, nuclear localization of beta-catenin) are straightforward, the cellular signaling cascades that result in an EMT are numerous and diverse. Furthermore, most studies describing the biological effects of TGF-beta have been performed using high concentrations of active, soluble TGF-beta, despite the fact that TGF-beta is produced and secreted as a latent complex. METHODS: MCF-7 breast cancer cells treated with recombinant IGF-1 were assayed for metalloproteinase activity and invasiveness through a matrigel coated transwell invasion chamber. IGF-1 treatments were then followed by the addition of latent-TGF-beta1 to determine if elevated levels of IGF-1 together with latent-TGF-beta1 could cause EMT. RESULTS: Results showed that IGF-1 - a molecule known to be elevated in breast cancer is a regulator of matrix metalloproteinase activity (MMP) and the invasive potential of MCF-7 breast cancer cells. The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways. In addition, increased IGF-1, together with latent TGF-beta1 and active MMPs result in EMT. CONCLUSIONS: Taken together our data suggest a novel a link between IGF-1 levels, MMP activity, TGF beta signaling, and EMT in breast cancer cells. PMID- 21535876 TI - Depressed mood in pregnancy: prevalence and correlates in two Cape Town peri urban settlements. AB - BACKGROUND: The disability associated with depression and its impact on maternal and child health has important implications for public health policy. While the prevalence of postnatal depression is high, there are no prevalence data on antenatal depression in South Africa. The purpose of this study was to determine the prevalence and correlates of depressed mood in pregnancy in Cape Town peri urban settlements. METHODS: This study reports on baseline data collected from the Philani Mentor Mothers Project (PMMP), a community-based, cluster-randomized controlled trial on the outskirts of Cape Town, South Africa. The PMMP aims to evaluate the effectiveness of a home-based intervention for preventing and managing illnesses related to HIV, TB, alcohol use and malnutrition in pregnant mothers and their infants. Participants were 1062 pregnant women from Khayelitsha and Mfuleni, Cape Town. Measures included the Edinburgh Postnatal Depression Scale (EPDS), the Derived AUDIT-C, indices for social support with regards to partner and parents, and questions concerning socio-demographics, intimate partner violence, and the current pregnancy. Data were analysed using bivariate analyses followed by logistic regression. RESULTS: Depressed mood in pregnancy was reported by 39% of mothers. The strongest predictors of depressed mood were lack of partner support, intimate partner violence, having a household income below R2000 per month, and younger age. CONCLUSIONS: The high prevalence of depressed mood in pregnancy necessitates early screening and intervention in primary health care and antenatal settings for depression. The effectiveness and scalability of community-based interventions for maternal depression must be developed for pregnant women in peri-urban settlements. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00972699. PMID- 21535877 TI - Attenuating effect of pretreatment with Yiqifumai on lipopolysaccharide-induced intestine injury and survival rate in rat. AB - BACKGROUND: Yiqifumai is a traditional Chinese medicine compound preparation used for treatment of microcirculatory disturbance-related diseases in China. We have previous reported that pretreatment with Yiqifumai could improve the lipopolysaccharide (LPS) -induced microcirculatory disturbance in rat mesentery. The present study intended to investigate the effect of pretreatment with Yiqifumai on intestine injury and survival rate of the rats subjected to LPS challenge. METHODS: Male Wistar rats were continuously infused with LPS (5 mg kg 1 body weight h-1) via the left jugular vein for 90 min. In some rats, Yiqifumai 80 (mg/kg) was administrated through the left jugular vein 10 min before LPS infusion. The mean arterial pressure (MAP), heart rate (HR), rectal temperature (RT), respiratory rate (RR) and survival rate were measured at 24 h, 48 h and 72 h after LPS infusion. At 72 h after exposure to LPS, the intestine morphology was observed under a stereomicroscope and the immunohistochemistry staining of intestine was conducted to evaluate the expression of intercellular adhesion molecule 1 (ICAM-1) and the number of myeloperoxidase (MPO) positive cells in tissue. After observation of intestine microcirculation, blood was collected from the abdominal aorta of each animal to analyze the level of inflammatory markers in plasma, including TNF-alpha and MCP-1. RESULTS: Compared to the control, LPS infusion significantly decreased MAP and the survival rate and increased the HR, RT and RR, as well as elicited leukocyte infiltration, intestine hemorrhage, enhanced expression of ICAM-1 and raised level of inflammatory markers. All of indicators, except for the RT, were significantly attenuated by Yiqifumai, in contrast to the LPS group. CONCLUSIONS: The results demonstrated the potential of pretreatment with Yiqifumai to ameliorate rat intestine injury, inflammatory response to LPS and the decrease in survival rate caused by LPS challenge. PMID- 21535878 TI - SNPPicker: high quality tag SNP selection across multiple populations. AB - BACKGROUND: Linkage Disequilibrium (LD) bin-tagging algorithms identify a reduced set of tag SNPs that can capture the genetic variation in a population without genotyping every single SNP. However, existing tag SNP selection algorithms for designing custom genotyping panels do not take into account all platform dependent factors affecting the likelihood of a tag SNP to be successfully genotyped and many of the constraints that can be imposed by the user. RESULTS: SNPPicker optimizes the selection of tag SNPs from common bin-tagging programs to design custom genotyping panels. The application uses a multi-step search strategy in combination with a statistical model to maximize the genotyping success of the selected tag SNPs. User preference toward functional SNPs can also be taken into account as secondary criteria. SNPPicker can also optimize tag SNP selection for a panel tagging multiple populations. SNPPicker can optimize custom genotyping panels including all the assay-specific constraints of Illumina's GoldenGate and Infinium assays. CONCLUSIONS: A new application has been developed to maximize the success of custom multi-population genotyping panels. SNPPicker also takes into account user constraints including options for controlling runtime. Perl Scripts, Java source code and executables are available under an open source license for download at http://mayoresearch.mayo.edu/mayo/research/biostat/software.cfm. PMID- 21535879 TI - The research on the immuno-modulatory defect of mesenchymal stem cell from Chronic Myeloid Leukemia patients. AB - Overwhelming evidence from leukemia research has shown that the clonal population of neoplastic cells exhibits marked heterogeneity with respect to proliferation and differentiation. There are rare stem cells within the leukemic population that possess extensive proliferation and self-renewal capacity not found in the majority of the leukemic cells. These leukemic stem cells are necessary and sufficient to maintain the leukemia. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, recently CML-initiating cells beyond HSCs are also being investigated. We have previously isolated fetal liver kinase-1-positive (Flk1(+)) cells carrying the BCR/ABL fusion gene from the bone marrow of Philadelphia chromosome-positive (Ph(+)) patients with hemangioblast property. Here, we showed that CML patient-derived Flk1(+)CD31( )CD34(-) MSCs had normal morphology, phenotype and karyotype but appeared impaired in immuno-modulatory function. The capacity of patient Flk1(+)CD31( )CD34(-) MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro. CML patient-derived MSCs have impaired immuno-modulatory functions, suggesting that the dysregulation of hematopoiesis and immune response may originate from MSCs rather than HSCs. MSCs might be a potential target for developing efficacious cures for CML. PMID- 21535880 TI - Eyes wide shut--unusual two stage repair of pectus excavatum and annuloaortic ectasia in a 37 year old marfan patient: case report. AB - We report about a 37 year old male patient with a pectus excavatum. The patient was in NYHA functional class III. After performed computed tomography the symptoms were thought to be related to the severity of chest deformation. A Ravitch-procedure had been accomplished in a district hospital in 2009. The crack of a metal bar led to a reevaluation 2010, in which surprisingly the presence of an annuloaortic ectasia (root 73*74 mm) in direct neighborhood of the formerly implanted metal-bars was diagnosed. Echocardiography revealed a severe aortic valve regurgitation, the left ventricle was massively dilated presenting a reduced ejection fraction of 45%. A marfan syndrome was suspected and the patient underwent a valve sparing aortic root replacement (David procedure) in our institution with an uneventful postoperative course. A review of the literature in combination with discussion of our case suggests the application of stronger recommendations towards preoperative cardiovascular assessment in patients with pectus excavatum. PMID- 21535882 TI - Chronic typhoid infection and the risk of biliary tract cancer and stones in Shanghai, China. AB - Previous studies have shown a positive association between chronic typhoid carriage and biliary cancers. We compared serum Salmonella enterica serovar Typhi antibody titers between biliary tract cancer cases, biliary stone cases without evidence of cancer, and healthy subjects in a large population-based case-control study in Shanghai, China.Participants included 627 newly diagnosed primary biliary tract cancer patients; 1,037 biliary stone cases (774 gallbladder and 263 bile-duct) and 959 healthy subjects without a history of cancer, randomly selected from the Shanghai Resident Registry.Overall only 6/2,293 (0.26%) were Typhi positive. The prevalence of Typhi was 1/457 (0.22%), 4/977 (0.41%), and 1/859 (0.12%) among cancer cases, biliary-stone cases, and population controls, respectively.We did not find an association between Typhi and biliary cancer in Shanghai, due to the very low prevalence of chronic carriers in this population.The low seroprevalence of S. Typhi in Shanghai is unlikely to explain the high incidence of biliary cancers in this population. PMID- 21535881 TI - Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. AB - BACKGROUND: Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored. METHODS: Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies. RESULTS: There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling. CONCLUSIONS: The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT rats. PMID- 21535883 TI - Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures. AB - BACKGROUND: The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics. METHODS: Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL) analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org. RESULTS: Expression values were highly variable across strains and in many cases exhibited a high heritability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P450 transcript had a strong trans-acting eQTL (LOD 11.8) on Chr 12 at 36 +/- 1 Mb. This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR. CONCLUSIONS: Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions. PMID- 21535884 TI - Different linkages in the long and short regions of the genomes of duck enteritis virus Clone-03 and VAC strains. AB - BACKGROUND: Duck enteritis virus (DEV) is an unassigned member in the family Herpesviridae. To demonstrate further the evolutionary position of DEV in the family Herpesviridae, we have described a 42,897-bp fragment. We demonstrated novel genomic organization at one end of the long (L) region and in the entire short (S) region in the Clone-03 strain of DEV. RESULTS: A 42,897-bp fragment located downstream of the LOFR11 gene was amplified from the Clone-03 strain of DEV by using 'targeted gene walking PCR'. Twenty-two open reading frames (ORFs) were predicted and determined in the following order: 5'-LORF11-RLORF1-ORF1-ICP4 S1-S2-US1-US10-SORF3-US2-MDV091.5-like-US3-US4-US5-US6-US7-US8-ORFx-US1-S2-S1 ICP4 -3'. This was different from that of the published VAC strain, both in the linkage of the L region and S region, and in the length of the US10 and US7 proteins. The MDV091.5-like gene, ORFx gene, S1 gene and S2 gene were first observed in the DEV genome. The lengths of DEV US10 and US7 were determined to be 311 and 371 amino acids, respectively, in the Clone-03 strain of DEV, and these were different from those of other strains. The comparison of genomic organization in the fragment studied herein with those of other herpesviruses showed that DEV possesses some unique characteristics, such as the duplicated US1 at each end of the US region, and the US5, which showed no homology with those of other herpesviruses. In addition, the results of phylogenetic analysis of ORFs in the represented fragment indicated that DEV is closest to its counterparts VZV (Varicellovirus) and other avian herpesviruses. CONCLUSION: The molecular characteristics of the 42,897-bp fragment of Clone-03 have been found to be different from those of the VAC strain. The phylogenetic analysis of genes in this region showed that DEV should be a separate member of the subfamily Alphaherpesvirinae. PMID- 21535885 TI - Dynamic distribution and tissue tropism of classical swine fever virus in experimentally infected pigs. AB - BACKGROUND: Classical swine fever (CSF), caused by the Classical swine fever virus (CSFV), is an Office International des Epizooties (OIE) notifiable disease. However, we are far from fully understand the distribution, tissue tropism, pathogenesis, replication and excretion of CSFV in pigs. In this report, we investigated the dynamic distribution and tissue tropism of the virus in internal organs of the experimentally infected pigs using real-time RT-PCR and immunohistochemistry (IHC). RESULTS: A relative quantification real-time PCR was established and used to detect the virus load in internal organs of the experimentally infected pigs. The study revealed that the virus was detected in all 21 of the internal organs and blood collected from pigs at day 1 to day 8 post infections, and had an increasing virus load from day 1 to day 8 post infections. However, there was irregular distribution virus load in most internal organs over the first 2 days post infection. Blood, lymphoid tissue, pancreas and ileum usually contain the highest viral loads, while heart, duodenum and brain show relatively low viral loads. CONCLUSIONS: All the data suggest that CSFV had an increasing virus load from day 1 to day 8 post infections in experimentally infected pigs detected by real-time RT-PCR, which was in consistent with the result of the IHC staining. The data also show that CSFV was likely to reproduce in blood, lymphoid tissue, pancreas and the ileum, while unlikely to replicate in the heart, duodenum and brain. The results provide a foundation for further clarification of the pathogenic mechanism of CSFV in internal organs, and indicate that blood, lymphoid tissue, pancreas and ileum may be preferred sites of acute infection. PMID- 21535887 TI - A simple intravenous glucose tolerance test for assessment of insulin sensitivity. AB - BACKGROUND: The aim of the study was to find a simple intravenous glucose tolerance test (IVGTT) that can be used to estimate insulin sensitivity. METHODS: In 20 healthy volunteers aged between 18 and 51 years (mean, 28) comparisons were made between kinetic parameters derived from a 12-sample, 75-min IVGTT and the M(bw) (glucose uptake) obtained during a hyperinsulinemic euglycemic glucose clamp. Plasma glucose was used to calculate the volume of distribution (V(d)) and the clearance (CL) of the injected glucose bolus. The plasma insulin response was quantified by the area under the curve (AUC(ins)). Uptake of glucose during the clamp was corrected for body weight (M(bw)). RESULTS: There was a 7-fold variation in M(bw). Algorithms based on the slope of the glucose-elimination curve (CL/V(d)) in combination with AUC(ins) obtained during the IVGTT showed statistically significant correlations with M(bw), the linearity being r(2) = 0.63-0.83. The best algorithms were associated with a 25-75th prediction error ranging from -10% to +10%. Sampling could be shortened to 30-40 min without loss of linearity or precision. CONCLUSION: Simple measures of glucose and insulin kinetics during an IVGTT can predict between 2/3 and 4/5 of the insulin sensitivity. PMID- 21535886 TI - Heart-type fatty acid binding protein (H-FABP): relationship with arterial intima media thickness and role as diagnostic marker for atherosclerosis in patients with impaired glucose metabolism. AB - BACKGROUND: Heart type fatty acid binding protein (H-FABP) has been closely associated with acute coronary syndrome, cardiac abnormalities, stroke, and obstructive sleep disorder in previous studies. The aim of this study was to evaluate and compare the serum H-FABP levels and carotid artery intima-media thickness (CIMT) between patients with prediabetes and control subjects. RESEARCH DESIGN AND METHODS: We measured serum H-FABP levels in 58 prediabetic patients, 29 with impaired fasting glucose (IFG) and 29 with impaired glucose tolerance (IGT) and 28 age-, sex- and body mass index-matched control subjects using a sandwich enzyme-linked immunosorbent assay (ELISA), and in order to measure CIMT, all participants underwent high-resolution B-mode ultrasonography. RESULTS: Serum H-FABP levels were significantly elevated in pre-diabetic patients when compared with that of control subjects (IFG: 32.5 +/- 34.2 ng/dL, IGT: 45.4 +/- 45.8 ng/dL, control: 16.8 +/- 14.9 ng/dL; p = 0.011). The difference in means of H FABP levels between patients with IGT or IFG and control subjects was significant (p = 0.010 and p = 0.009, respectively). CIMT was higher in the pre-diabetic groups compared with the control group (IFG: 0.6 +/- 0.1, IGT: 0.6 +/- 0.1, control: 0.5 +/- 0.1; p < 0.001), and H-FABP level was positively correlated with CIMT (p < 0.001, rho = 0.626). CONCLUSION: Our results indicate that patients with pre-diabetes are at increased risk for cardiovascular disease. In addition, serum H-FABP levels could represent a useful marker for myocardial performance in patients with IFG and IGT. PMID- 21535888 TI - Detecting Newcastle disease virus in combination of RT-PCR with red blood cell absorption. AB - Reverse transcription-polymerase chain reaction (RT-PCR) has limited sensitivity when treating complicated samples, such as feces, waste-water in farms, and nucleic acids, protein rich tissue samples, all the factors may interfere with the sensitivity of PCR test or generate false results. In this study, we developed a sensitive RT-PCR, combination of red blood cell adsorption, for detecting Newcastle disease virus (NDV). One pair of primers which was highly homologous to three NDV pathotypes was designed according to the consensus nucleocapsid protein (NP) gene sequence. To eliminate the interfere of microbes and toxic substances, we concentrated and purified NDV from varied samples utilizing the ability of NDV binding red blood cells (RBCs). The RT-PCR coupled with red blood cell adsorption was much more sensitive in comparison with regular RT-PCR. The approach could also be used to detect other viruses with the property of hemagglutination, such as influenza viruses. PMID- 21535889 TI - Fulfillment of the premenstrual dysphoric disorder criteria confirmed using a self-rating questionnaire among Japanese women with depressive disorders. AB - BACKGROUND: Some women with depressive disorders experience severe premenstrual symptoms. However, there have been few studies in which premenstrual symptoms in women suffering from depressive disorders were assessed. In this study, we aimed to investigate premenstrual symptoms in women with depressive disorders using the premenstrual dysphoric disorder (PMDD) scale. METHODS: We administered questionnaires to 65 Japanese female outpatients who had been diagnosed with a major depressive disorder or dysthymic disorder and to 303 healthy women as control subjects. The questionnaire consisted of items on demographics and the PMDD scale, which was modified from the premenstrual symptoms screening tool (PSST) developed by Steiner et al. (Arch Womens Ment Health 2003, 6:203-209). RESULTS: Twenty-eight women (43.1%) with depressive disorder fulfilled certain items of the PMDD scale. These women are considered to have coexisting PMDD and a depressive disorder, or to have premenstrual exacerbation (PME) of a depressive disorder. On the other hand, 18 women (5.9%) in the control group were diagnosed as having PMDD. The depressive disorder group who fulfilled the PMDD criteria had more knowledge of the term premenstrual syndrome (PMS) and took more actions to attenuate premenstrual symptoms than the control group with PMDD. CONCLUSIONS: Our findings demonstrated that the occurrence of severe premenstrual symptoms is much higher in women with depressive disorders than in healthy subjects. This is partially due to this group containing women with PME, but mainly due to it containing women with PMDD. The higher percentage of PMDD suggests similarity between PMDD and other depressive disorders. Furthermore, educating healthy Japanese women and women with depressive disorders about premenstrual symptoms and evidence-based treatment for them is necessary. PMID- 21535890 TI - Insights gained from the reverse engineering of gene networks in keloid fibroblasts. AB - BACKGROUND: Keloids are protrusive claw-like scars that have a propensity to recur even after surgery, and its molecular etiology remains elusive. The goal of reverse engineering is to infer gene networks from observational data, thus providing insight into the inner workings of a cell. However, most attempts at modeling biological networks have been done using simulated data. This study aims to highlight some of the issues involved in working with experimental data, and at the same time gain some insights into the transcriptional regulatory mechanism present in keloid fibroblasts. METHODS: Microarray data from our previous study was combined with microarray data obtained from the literature as well as new microarray data generated by our group. For the physical approach, we used the fREDUCE algorithm for correlating expression values to binding motifs. For the influence approach, we compared the Bayesian algorithm BANJO with the information theoretic method ARACNE in terms of performance in recovering known influence networks obtained from the KEGG database. In addition, we also compared the performance of different normalization methods as well as different types of gene networks. RESULTS: Using the physical approach, we found consensus sequences that were active in the keloid condition, as well as some sequences that were responsive to steroids, a commonly used treatment for keloids. From the influence approach, we found that BANJO was better at recovering the gene networks compared to ARACNE and that transcriptional networks were better suited for network recovery compared to cytokine-receptor interaction networks and intracellular signaling networks. We also found that the NFKB transcriptional network that was inferred from normal fibroblast data was more accurate compared to that inferred from keloid data, suggesting a more robust network in the keloid condition. CONCLUSIONS: Consensus sequences that were found from this study are possible transcription factor binding sites and could be explored for developing future keloid treatments or for improving the efficacy of current steroid treatments. We also found that the combination of the Bayesian algorithm, RMA normalization and transcriptional networks gave the best reconstruction results and this could serve as a guide for future influence approaches dealing with experimental data. PMID- 21535891 TI - Epigenetic markers for early detection of nasopharyngeal carcinoma in a high risk population. AB - BACKGROUND: Undifferentiated nasopharyngeal carcinoma (NPC) is strongly related to Epstein-Barr virus (EBV) infection, allowing aberrant antibodies against EBV and viral DNA load as screening tools in high risk populations. Methylation analysis in the promoter of tumor suppressor genes (TSGs) may serve as a complementary marker for identifying early cases. This study determined methylation status of multiple TSGs and evaluated whether it may improve early detection. METHODS: Nasopharyngeal brushings were taken from 53 NPC patients, 22 high risk subjects and 25 healthy EBV carriers. Corresponding NPC paraffin tissue was included. DNA was bisulfite-modified preceding analysis by methylation specific PCR (MSP). Ten TSGs were studied. RESULTS: NPC paraffin and brushing DNA revealed an 81.8% concordance so that MSP analysis was done using either one of both specimens. NPC samples showed methylation for individual TSGs (DAPK1 79.2%, CDH13 77.4%, DLC1 76.9%, RASSF1A 75.5%, CADM1 69.8%, p16 66.0%, WIF1 61.2%, CHFR 58.5%, RIZ1 56.6% and RASSF2A 29.2%). High risk individuals, having elevated EBV IgA and viral load, showed high frequency of methylation of CDH13, DAPK1, DLC1 and CADM1, but low frequency of methylation of p16 and WIF1 and undetectable methylation of RASSF1A, CHFR, RIZ1 and RASSF2A. Healthy subjects showed similar patterns as high risk individuals. A combination of RASSF1A and p16 gave good discrimination between NPC and non-NPC, but best results were combined analysis of five methylation markers (RASSF1A, p16, WIF1, CHFR and RIZ1) with detection rate of 98%. CONCLUSION: Multiple marker MSP is proposed as a complementary test for NPC risk assessment in combination with EBV-based markers. PMID- 21535892 TI - Antigenic repertoire of Plasmodium vivax transmission-blocking vaccine candidates from the Indian subcontinent. AB - BACKGROUND: Genetic polymorphism is an inevitable component of a multistage infectious organism, such as the malaria parasite. By means of genetic polymorphism, parasite opts particular polymorph and reveals survival advantage. Pvs25 and pvs28 are sexual stage antigen genes, expressed at the ookinete stage inside the mosquito gut, and considered as potential transmission-blocking vaccine candidates. This study presents sequence variations in two important transmission blocking antigen genes pvs25 and pvs28 in the field isolates of P. vivax from the Indian subcontinent. METHODS: One hundred microscopically diagnosed P. vivax isolates were collected from five geographical regions of India. Pvs25 and pvs28 genes were PCR amplified and sequenced to assess sequence variation among field isolates. RESULTS: A total of 26 amino acid substitutions were observed in Pvs25 (10) and Pvs28 (16) among field isolates of P. vivax. Tandem repeat polymorphism observed in pvs28 shows 3-6 tandem repeats in the field isolates. Seven and eight novel amino acid substitutions were observed in Pvs25 and Pvs28, respectively in Indian isolates. Comparison of amino acid substitutions suggests that majority of substitutions observed in global isolates were also present in Indian subcontinent. A single haplotype was observed to be major haplotype among isolates of Delhi, Nadiad, Chennai and Panna except in isolates of Kamrup. Further, population comparison analyses suggest that P. vivax isolates inhabiting in north-eastern region (Kamrup) were distantly related with the isolates from remaining parts of the country. Majority of the amino acid substitutions observed in Indian isolates were more identical to the substitutions reported from isolates of Thailand and Bangladesh. CONCLUSION: Study uncovered many new amino acid substitutions as well as a predominance of single haplotype in Indian subcontinent except in north-eastern region of the country. The amino acid substitutions data generated in this study from different geographical regions of the Indian subcontinent could be helpful in designing a more effective anti-malarial transmission-blocking vaccine. PMID- 21535893 TI - Inhibition of full length hepatitis C virus particles of 1a genotype through small interference RNA. AB - BACKGROUND: Hepatitis C virus (HCV), a member of the Flaviviridae family of viruses, is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Currently, the only treatment available consists of a combination of Pegylated interferon alpha (INF-alpha) and ribavirin, but only half of the patients treated show a sufficient antiviral response. Thus there is a great need for the development of new treatments for HCV infections. RNA interference (RNAi) represents a new promising approach to develop effective antiviral drugs and has been extremely effective against HCV infection. RESULTS: This study was design to assess or explore the silencing effect of small interference RNAs (siRNAs) against full length HCV particles of genotype 1a. In the present study six 21-bp siRNAs were designed against different regions of HCV structural genes (Core, E1 and E2). Selected siRNAs were labeled as Csi 301, Csi 29, E1si 52, E1si 192, E2si 86 and E2si 493. Our results demonstrated that siRNAs directed against HCV core gene showed 70% reduction in viral titer in HCV infected liver cells. Moreover, siRNAs against E1 and E2 envelop genes showed a dramatic reduction in HCV viral RNA, E2si 86 exhibited 93% inhibition, while E1si 192, E2si 493 and E1si 52 showed 87%, 80%, and 66% inhibition respectively. No significant inhibition was detected in cells transfected with the negative control siRNA. CONCLUSION: Our results suggested that siRNAs targeted against HCV structural genes efficiently silence full length HCV particles and provide an effective therapeutic option against HCV infection. PMID- 21535894 TI - In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa. AB - BACKGROUND: To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. Caesalpinia pluviosa, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity. METHODS: Crude extract (CE) was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested in vitro against chloroquine-sensitive (3D7) and -resistant (S20) strains of Plasmodium falciparum and in vivo in Plasmodium chabaudi-infected mice. In vitro interaction with artesunate and the active C. pluviosa fractions was assessed, and mass spectrometry analyses were conducted. RESULTS: At non-toxic concentrations, the 100% ethanolic (F4) and 50% methanolic (F5) fractions possessed significant anti malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to m/z 303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of m/z 137 and 153. CONCLUSIONS: The findings show that the F4 fraction of C. pluviosa exhibits anti-malarial activity in vitro at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained in vivo after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4. PMID- 21535895 TI - Admission of advanced lung cancer patients to intensive care unit: a retrospective study of 76 patients. AB - BACKGROUND: Criteria for admitting patients with incurable diseases to the medical intensive care unit (MICU) remain unclear and have ethical implications. METHODS: We retrospectively evaluated MICU outcomes and identified risk factors for MICU mortality in consecutive patients with advanced lung cancer admitted to two university-hospital MICUs in France between 1996 and 2006. RESULTS: Of 76 included patients, 49 had non-small cell lung cancer (stage IIIB n = 20; stage IV n = 29). In 60 patients, MICU admission was directly related to the lung cancer (complication of cancer management, n = 30; cancer progression, n = 14; and lung cancer-induced diseases, n = 17). Mechanical ventilation was required during the MICU stay in 57 patients. Thirty-six (47.4%) patients died in the MICU. Three factors were independently associated with MICU mortality: use of vasoactive agents (odds ratio [OR] 6.81 95% confidence interval [95%CI] [1.77-26.26], p = 0.005), mechanical ventilation (OR 6.61 95%CI [1.44-30.5], p = 0.015) and thrombocytopenia (OR 5.13; 95%CI [1.17-22.5], p = 0.030). In contrast, mortality was lower in patients admitted for a complication of cancer management (OR 0.206; 95%CI [0.058-0.738], p = 0.015). Of the 27 patients who returned home, four received specific lung cancer treatment after the MICU stay. CONCLUSIONS: Patients with acute complications of treatment for advanced lung cancer may benefit from MCIU admission. Further studies are necessary to assess outcomes such as quality of life after MICU discharge. PMID- 21535897 TI - Direct interaction of FliX and FlbD is required for their regulatory activity in Caulobacter crescentus. AB - BACKGROUND: The temporal and spatial expression of late flagellar genes in Caulobacter crescentus is activated by the transcription factor FlbD and its partner trans-acting factor FliX. The physical interaction of these two proteins represents an alternative mechanism for regulating the activity of sigma54 transcription factors. This study is to characterize the interaction of the two proteins and the consequences of the interaction on their regulatory activity. RESULTS: FliX and FlbD form stable complexes, which can stand the interference of 2.65 M NaCl. The stability of FliX and FlbD was affected by the co-existence of each other. Five FliX mutants (R71A, L85K, Delta117-118, T130L, and L136K) were created by site-directed mutagenesis in conserved regions of the protein. All mutants were successfully expressed in both wild-type and DeltafliX Caulobacter strains. All but FliXL85K could rescue the motility and cell division defects of a DeltafliX mutant strain. The ability of FliX to regulate the transcription of class II and class III/IV flagellar promoters was fully diminished due to the L85K mutation. Co-immunoprecipitation experiment revealed that FliXL85K was unable to physically interact with FlbD. CONCLUSIONS: FliX interacts with FlbD and thereby directly regulates the activity of FlbD in response to flagellar assembly. Mutations in highly conserved regions of FliX could severely affect the recognition between FliX and FlbD and hence interrupt the normal progression of flagellar synthesis and other developmental events in Caulobacter. PMID- 21535896 TI - Increased expression of the chemokines CXCL1 and MIP-1alpha by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman induced status epilepticus in rats. AB - BACKGROUND: Exposure to the nerve agent soman (GD) causes neuronal cell death and impaired behavioral function dependent on the induction of status epilepticus (SE). Little is known about the maturation of this pathological process, though neuroinflammation and infiltration of neutrophils are prominent features. The purpose of this study is to quantify the regional and temporal progression of early chemotactic signals, describe the cellular expression of these factors and the relationship between expression and neutrophil infiltration in damaged brain using a rat GD seizure model. METHODS: Protein levels of 4 chemokines responsible for neutrophil infiltration and activation were quantified up to 72 hours in multiple brain regions (i.e. piriform cortex, hippocampus and thalamus) following SE onset using multiplex bead immunoassays. Chemokines with significantly increased protein levels were localized to resident brain cells (i.e. neurons, astrocytes, microglia and endothelial cells). Lastly, neutrophil infiltration into these brain regions was quantified and correlated to the expression of these chemokines. RESULTS: We observed significant concentration increases for CXCL1 and MIP-1alpha after seizure onset. CXCL1 expression originated from neurons and endothelial cells while MIP-1alpha was expressed by neurons and microglia. Lastly, the expression of these chemokines directly preceded and positively correlated with significant neutrophil infiltration in the brain. These data suggest that following GD-induced SE, a strong chemotactic response originating from various brain cells, recruits circulating neutrophils to the injured brain. CONCLUSIONS: A strong induction of neutrophil attractant chemokines occurs following GD-induced SE resulting in neutrophil influx into injured brain tissues. This process may play a key role in the progressive secondary brain pathology observed in this model though further study is warranted. PMID- 21535898 TI - Cereal based diets modulate some markers of oxidative stress and inflammation in lean and obese Zucker rats. AB - BACKGROUND: The potential of cereals with high antioxidant capacity for reducing oxidative stress and inflammation in obesity is unknown. This study investigated the impact of wheat bran, barley or a control diet (alpha-cellulose) on the development of oxidative stress and inflammation in lean and obese Zucker rats. METHODS: Seven wk old, lean and obese male Zucker rats (n = 8/group) were fed diets that contained wheat bran, barley or alpha-cellulose (control). After 3 months on these diets, systolic blood pressure was measured and plasma was analysed for glucose, insulin, lipids, oxygen radical absorbance capacity (ORAC), malondialdehyde, glutathione peroxidase and adipokine concentration (leptin, adiponectin, interleukin (IL)-1beta, IL-6, TNFalpha, plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1). Adipokine secretion rates from visceral and subcutaneous adipose tissue explants were also determined. RESULTS: Obese rats had higher body weight, systolic blood pressure and fasting blood lipids, glucose, insulin, leptin and IL-1beta in comparison to lean rats, and these measures were not reduced by consumption of wheat bran or barley based diets. Serum ORAC tended to be higher in obese rats fed wheat bran and barley in comparison to control (p = 0.06). Obese rats had higher plasma malondialdehyde (p < 0.01) and lower plasma glutathione peroxidase concentration (p < 0.01) but these levels were not affected by diet type. PAI-1 was elevated in the plasma of obese rats, and the wheat bran diet in comparison to the control group reduced PAI-1 to levels seen in the lean rats (p < 0.05). These changes in circulating PAI-1 levels could not be explained by PAI-1 secretion rates from visceral or subcutaneous adipose tissue. CONCLUSIONS: A 3-month dietary intervention was sufficient for Zucker obese rats to develop oxidative stress and systemic inflammation. Cereal-based diets with moderate and high antioxidant capacity elicited modest improvements in indices of oxidative stress and inflammation. PMID- 21535899 TI - An automated homology-based approach for identifying transposable elements. AB - BACKGROUND: Transposable elements (TEs) are mobile sequences found in nearly all eukaryotic genomes. They have the ability to move and replicate within a genome, often influencing genome evolution and gene expression. The identification of TEs is an important part of every genome project. The number of sequenced genomes is rapidly rising, and the need to identify TEs within them is also growing. The ability to do this automatically and effectively in a manner similar to the methods used for genes is of increasing importance. There exist many difficulties in identifying TEs, including their tendency to degrade over time and that many do not adhere to a conserved structure. In this work, we describe a homology based approach for the automatic identification of high-quality consensus TEs, aimed for use in the analysis of newly sequenced genomes. RESULTS: We describe a homology-based approach for the automatic identification of TEs in genomes. Our modular approach is dependent on a thorough and high-quality library of representative TEs. The implementation of the approach, named TESeeker, is BLAST based, but also makes use of the CAP3 assembly program and the ClustalW2 multiple sequence alignment tool, as well as numerous BioPerl scripts. We apply our approach to newly sequenced genomes and successfully identify consensus TEs that are up to 99% identical to manually annotated TEs. CONCLUSIONS: While TEs are known to be a major force in the evolution of genomes, the automatic identification of TEs in genomes is far from mature. In particular, there is a lack of automated homology-based approaches that produce high-quality TEs. Our approach is able to generate high-quality consensus TE sequences automatically, requiring the user to only provide a few basic parameters. This approach is intentionally modular, allowing researchers to use components separately or iteratively. Our approach is most effective for TEs with intact reading frames. The implementation, TESeeker, is available for download as a virtual appliance, while the library of representative TEs is available as a separate download. PMID- 21535900 TI - CpG oligonucleotides suppress HepG2 cells-induced Jurkat cell apoptosis via the Fas-FasL-mediated pathway. AB - OBJECTIVE: To explore the potential role of CpG motif-containing oligonucleotides (CpG-ODN) in modulating the expression of FasL in HepG2 and Fas in Jurkat cells in vitro, and to examine the effect of CpG-ODN treatment on the HepG2 cells mediated Jurkat cell apoptosis in vitro. METHODS: The expressions of FasL in HepG2 and Fas in Jurkat cells were examined by real time PCR and flow cytometry (FCM). HepG2 and Jurkat cells were co-cultured, and the frequency of apoptotic Jurkat cells and levels of activated caspase-3 were determined by FCM. RESULTS: Treatment with CpG-ODN down-regulated the expression of FasL in HepG2 cells in a dose- and time-dependent manner. In addition, treatment with CpG-ODN down regulated the Fas mRNA transcription and protein expression in Jurkat cells. Treatment of HepG2 cells or Jurkat cells with FasL-neutralizing antibody NOK-2 remarkably inhibited the HepG2-medaited Jurkat cell apoptosis. Pre-treatment of HepG2 or Jurkat cells with CpG-ODN significantly reduced the frequency of HepG2 mediated apoptotic Jurkat cells and inhibited the activation of caspase-3 in Jurkat cells in vitro. CONCLUSIONS: Our data indicated that treatment with CpG ODN inhibited the HepG2 cells-mediated Jurkat cell apoptosis by modulating the Fas/FasL pathway. Apparently, CpG-ODN treatment may be a potential therapeutic reagent for HCC. PMID- 21535901 TI - Differential expression of liver proteins between obesity-prone and obesity resistant rats in response to a high-fat diet. AB - Rodents respond to a chronic high-fat diet (HFD) in two ways: some readily become obese (obesity prone, OP) and others do not (obesity resistant, OR). Although several hypotheses have been proposed, the mechanisms underlying the inter individual susceptibility to diet-induced obesity remain to be fully defined. In the present study, two-dimensional gel electrophoresis (2-DE) combined with matrix-assisted laser desorption ionisation time-of-flight MS was carried out for identification of differentially expressed liver proteins in OP and OR rats fed a HFD, in an attempt to discover marker proteins involved in susceptibility and/or resistance to obesity in rat liver. The 2-DE analysis demonstrated that forty spots from 380 visualised spots were differentially regulated between the groups. Among these forty spots, twelve were differentially expressed proteins between OP and OR rats, reaching statistical significance. Of these, five proteins have already been linked to obesity; however, seven proteins involved in obesity susceptibility or resistance were identified for the first time in the present study. In order to validate the proteomic results and gain insight into the metabolic changes between the OP and OR groups, we further confirmed the expression pattern of some proteins of interest by Western blot analysis. Combined results of proteomic analysis with Western blot analysis revealed that reduced lipogenesis and increased fat oxidation were achieved in the livers of OR rats. In conclusion, the present proteomic study is an important advance over the previous steps required for identification of OP and OR rats, and should prove valuable in the search for the pathogenesis of obesity in humans. PMID- 21535902 TI - Dietary plant proteins and vegetable oil blends increase adiposity and plasma lipids in Atlantic salmon (Salmo salar L.). AB - In order to study whether lipid metabolism may be affected by maximum replacement of dietary fish oil and fish meal with vegetable oils (VO) and plant proteins (PP), Atlantic salmon (Salmo salar L.) smolts were fed a control diet containing fish oil and fish meal or one of three plant-based diets through the seawater production phase for 12 months. Diets were formulated to meet all known nutrient requirements. The whole-body lipid storage pattern was measured after 12 months, as well as post-absorptive plasma, VLDL and liver TAG. To further understand the effects on lipid metabolism, expression of genes encoding for proteins involved in VLDL assembly (apoB100), fatty acid uptake (FATP1, cd36, LPL and FABP3, FABP10 and FABP11) were measured in liver and visceral adipose tissue. Maximum dietary VO and PP increased visceral lipid stores, liver TAG, and plasma VLDL and TAG concentrations. Increased plasma TAG correlated with an increased expression of apoB100, indicating increased VLDL assembly in the liver of fish fed the high plant protein- and VO-based diet. Atlantic salmon fed intermediate replacement levels of VO or PP did not have increased body fat or visceral mass. Overall, the present results demonstrate an interaction between dietary lipids and protein on lipid metabolism, increasing overall adiposity and TAG in the body when fish meal and fish oil are replaced concomitantly at maximised levels of VO and PP. PMID- 21535903 TI - A diet with 35% of energy from protein leads to kidney damage in female Sprague Dawley rats. AB - High-protein (HP) diets for weight loss remain popular despite questions surrounding overall safety. In a recent study using the pig model, we showed that long-term intakes from whole proteins at 35 % energy (en %) cause moderate renal histological damage. To examine whether this observation may be species specific or more generalisable, the effect of this diet in rats was examined. Using plant and animal whole proteins, 70-d-old female Sprague-Dawley rats were randomised to either a normal-protein (NP; 15 en %) or a HP (35 en %) diet for 4, 8, 12 and 17 months. Renal function was assessed by creatinine clearance and urinary protein levels, and pathology was assessed by examination of glomerular hypertrophy, glomerulosclerosis and tubulointerstitial fibrosis. Rats consuming the HP diet had 17 % higher kidney weights (P < 0.0001), three times higher proteinuria (P < 0.0001) and 27 % higher creatinine clearance (P = 0.0012) compared with those consuming the NP diet. Consistent with this, HP-fed rats had larger glomeruli (P < 0.0001) and more glomerulosclerosis (P = 0.0003) compared with NP-fed rats. The HP diet also resulted in altered levels of free monocyte chemoattractant protein 1 (P < 0.0001). The histological changes are consistent with those observed in the pig model. In contrast to the pig model, the elevated proteinuria and creatinine clearance observed in the rat model are also usually observed with HP consumption in human subjects. These results indicate that the rat is a useful model for HP effects on the kidney and, along with previous results using the pig model, suggest that long-term intake of high levels of protein may be detrimental to renal health. PMID- 21535904 TI - Multiple cycles of repeated treatments with a Phaseolus vulgaris dry extract reduce food intake and body weight in obese rats. AB - Previous lines of experimental evidence have suggested that Phaseolus vulgaris extracts reduce food intake, body weight, lipid accumulation, hedonic properties of food, carbohydrate absorption and metabolism, and glycaemia in rats. The present study was designed to assess the effect of multiple cycles of repeated treatments with a standardised P. vulgaris dry extract on daily food intake and body weight in genetically obese Zucker fa/fa rats (Expt 1). Additionally, the study tested the effect of acute treatment with P. vulgaris dry extract on postprandial glycaemia in Zucker fa/fa rats (Expt 2). In Expt 1, P. vulgaris dry extract was administered daily, at doses of 50 and 500 mg/kg, in three 5 d treatment periods followed by three 20 d off-treatment periods. Administration of P. vulgaris dry extract resulted in dose-dependent decreases in daily food intake and body weight in each treatment phase. Reductions in food intake were of comparable magnitude in each treatment phase. In Expt 2, food-deprived rats were acutely treated with 50 and 500 mg P. vulgaris dry extract per kg immediately before access to a fixed amount of a starch-enriched chow. Treatment with P. vulgaris dry extract resulted in a dose-dependent suppression of glycaemia. These results extend previous data on the anorectic and hypoglycaemic effects of the P. vulgaris dry extract to a validated animal model of obesity. Together with data published previously in the literature, these results strengthen the hypothesis that potentially effective, novel pharmacotherapies for obesity and related disorders may originate from extracts and derivatives of P. vulgaris. PMID- 21535905 TI - Breakfast frequency inversely associated with BMI and body fatness in Hong Kong Chinese children aged 9-18 years. AB - The present study assessed the relationship between breakfast frequency and measures of obesity in Hong Kong Chinese children aged 9-18 years. A total of 11,570 children (50 % boys) underwent anthropometric measurements and completed a simple self-administered dietary behaviour questionnaire. Their parents completed a questionnaire providing demographic information. Breakfast frequency was assessed by a single question, 'How many days over the past week did you have breakfast?' Children were categorised into three groups: skippers (ate breakfast 0-2 times/week); semi-skippers (ate breakfast 3-4 times/week); non-skippers (ate breakfast 5-7 times/week), to assess all associated characteristics. Of the 3644 primary and 7926 secondary school students, 8 % (8.7 % of boys and 6.9 % of girls) and 14 % (14 % of boys and 15 % of girls), respectively, were breakfast skippers. The prevalence of obesity among breakfast skippers, semi-skippers and non-skippers was, respectively, 9.8, 10.6 and 3.8 % (P < 0.001) for primary school students and 3.9, 3.1 and 2.4 % (P < 0.001) for secondary school students. The 12 % of Hong Kong children aged 9-18 years who skipped breakfast had higher BMI, BMI z-scores and percentage of body fat (PBF) than their counterparts. The dose effects of breakfast frequency (unstandardised regression coefficient, P < 0.001) on BMI and PBF were, respectively, -0.125 kg/m2 and -0.219 % for boys and 0.165 kg/m2 and -0.353 % for girls, adjusting for physical activity per additional breakfast meal per week. Further study is recommended to elucidate whether regular breakfast consumption may have a role in the prevention of childhood obesity. PMID- 21535906 TI - Application of condoms on male clients by female sex workers in Yerevan, Armenia: prevalence and correlates. AB - This study sought to assess the prevalence of consistent condom application on male clients by female sex workers (FSWs) in Armenia and its association with demographic, psychosocial and behavioural factors. In this cross-sectional study, 120 street-based FSWs aged 20-52 completed an interviewer-administered questionnaire. The primary outcome measure was consistent application of condoms by FSWs on their male clients. A total of 21.7% of participants reported consistently applying condoms on clients. Logistic regression analysis demonstrated that higher condom use self-efficacy (Adjusted Odds Ratio, AOR=1.1; p=0.01), lower perceived condom use barriers (AOR=0.9; p=0.04) and not using douching as a method to prevent STI/HIV (AOR=4.8; p=0.04) significantly predicted consistent condom application. Higher HIV/AIDS knowledge was a marginally significant predictor of condom application (AOR=1.3; p=0.05). Future interventions should address these modifiable factors to encourage FSWs to apply condoms on clients themselves, which may reduce condom failure and exposure to HIV transmission. PMID- 21535907 TI - Foreign body aspiration and language spoken at home: 10-year review. AB - OBJECTIVE: To review foreign body aspiration cases encountered over a 10-year period in a tertiary paediatric hospital, and to assess correlation between foreign body type and language spoken at home. STUDY DESIGN AND METHOD: Retrospective chart review of all children undergoing direct laryngobronchoscopy for foreign body aspiration over a 10-year period. Age, sex, foreign body type, complications, hospital stay and home language were analysed. RESULTS: At direct laryngobronchoscopy, 132 children had foreign body aspiration (male:female ratio 1.31:1; mean age 32 months (2.67 years)). Mean hospital stay was 2.0 days. Foreign bodies most commonly comprised food matter (53/132; 40.1 per cent), followed by non-food matter (44/132; 33.33 per cent), a negative endoscopy (11/132; 8.33 per cent) and unknown composition (24/132; 18.2 per cent). Most parents spoke English (92/132, 69.7 per cent; vs non-English-speaking 40/132, 30.3 per cent), but non-English-speaking patients had disproportionately more food foreign bodies, and significantly more nut aspirations (p = 0.0065). Results constitute level 2b evidence. CONCLUSION: Patients from non-English speaking backgrounds had a significantly higher incidence of food (particularly nut) aspiration. Awareness-raising and public education is needed in relevant communities to prevent certain foods, particularly nuts, being given to children too young to chew and swallow them adequately. PMID- 21535908 TI - Characterization of olfactory stem cells. AB - There is worldwide enthusiasm for the prospect of some kind of cellular transplant therapy for repair of failing organs. The olfactory mucosa of a patient's nose is easily biopsied to provide a ready source of multipotent cells. In this article we address practical issues pertinent to using olfactory neural stem cells for tissue repair. These cells are emerging as potentially most significant candidates for human tissue repair strategies. Previously we have shown that stem cells from olfactory mucosa are multipotent. As well, we have recently published three potential clinical applications. Their expression of dopaminergic markers in vitro and in a Parkinson's rat transplant model has been demonstrated. Their conversion to chondrogenic phenotype in vitro and in vivo has also been described, as has their transplant into a rat model of cardiac infarction. Here we examine in detail the biology of the olfactory neural stem cell using the rat as our animal model cell source. We establish its presence by examining self-renewal capacity and for phenotypic acquisition in inductive circumstances. We determine its frequency within the cell population and show that our culture system selects for this putative stem cell. Our studies demonstrate that adult olfactory stem cells, when transplanted into an environmental niche different from that of their origin, are able to demonstrate multipotency by acquiring the phenotype of the resident cells. We investigate how immediate the instruction need be. We test the hypothesis that olfactory neurospheres contain stem cells whose capacity for differentiation is triggered by signals of the immediate environmental niche. Significantly, of importance to any tissue regeneration endeavor, stem cell numbers were shown to be enriched by our culture methods. This was confirmed whether measured by sphere-forming capacity or differentiation response rate. PMID- 21535909 TI - Fibrin gel improves the survival of transplanted myoblasts. AB - Duchenne muscular dystrophy (DMD) is the most frequent muscular dystrophy in children and young adults. Currently, there is no cure for the disease. The transplantation of healthy myoblasts is an experimental therapeutic strategy, since it could restore the expression of dystrophin in DMD muscles. Nevertheless, this cellular therapy is limited by immune reaction, low migration of the implanted cells, and high early cell death that could be at least partially due to anoikis. To avoid the lack of attachment of the cells to an extracellular matrix after the transplantation, which is the cause of anoikis, we tested the use of a fibrin gel for myoblast transplantation. In vitro, three concentrations of fibrinogen were compared (3, 20, and 50 mg/ml) to form a fibrin gel. A stiffer fibrin gel leads to less degradability and less proliferation of the cells. A concentration of 3 mg/ml fibrin gel enhanced the differentiation of the myoblasts earlier as a culture in monolayer. Human myoblasts were also transplanted in muscles of Rag/mdx mice in a fibrin gel or in a saline solution (control). The use of 3 mg/ml fibrin gel for cell transplantation increased not only the survival of the cells as measured after 5 days but also the number of fibers expressing dystrophin after 21 days, compared to the control. Moreover, the fibrin gel was also compared to a prosurvival cocktail. The survival of the myoblasts at 5 days was increased in both conditions compared to the control but the efficacy of the prosurvival cocktail was not significantly higher than the fibrin gel. PMID- 21535910 TI - Expression of pro- and antiapoptotic molecules of the Bcl-2 family in human islets postisolation. AB - Human islets are subjected to a number of stresses before and during their isolation that may influence their survival and engraftment after transplantation. Apoptosis is likely to be activated in response to these stresses. Apoptosis due to intrinsic stresses is regulated by pro- and antiapoptotic members of the Bcl-2 family. While the role of the Bcl-2 family in apoptosis of rodent islets is becoming increasingly understood, little is known about which of these molecules are expressed or required for apoptosis of human islets. This study investigated the expression of the Bcl-2 family of molecules in isolated human islets. RNA and protein lysates were extracted from human islets immediately postisolation. At the same time, standard quality control assays including viability staining and beta-cell content were performed on each islet preparation. Microarrays, RT-PCR, and Western blotting were performed on islet RNA and protein. The prosurvival molecules Bcl-xl and Mcl-1, but not Bcl-2, were highly expressed. The multidomain proapoptotic effector molecule Bax was expressed at higher levels than Bak. Proapoptotic BH3-only molecules were expressed at low levels, with Bid being the most abundant. The proapoptotic molecules BNIP3, BNIP3L, and Beclin-1 were all highly expressed, indicating exposure of islets to oxygen and nutrient deprivation during isolation. Our data provide a comprehensive analysis of expression levels of pro- and antiapoptotic Bcl-2 family members in isolated human islets. Knowledge of which molecules are expressed will guide future research to understand the apoptotic pathways activated during isolation or after transplantation. This is crucial for the design of methods to achieve improved transplantation outcomes. PMID- 21535911 TI - Human CD47 expression permits survival of porcine cells in immunodeficient mice that express SIRPalpha capable of binding to human CD47. AB - Signal regulatory protein alpha (SIRPalpha) is a critical immune inhibitory receptor on macrophages, and its interaction with CD47 prevents autologous phagocytosis. We have previously shown that pig CD47 does not interact with human SIRPalpha, and that human CD47 expression inhibits phagocytosis of porcine cells by human macrophages in vitro. In this study, we have investigated the potential of human CD47 expression to promote porcine cell survival in vivo. Human CD47 expressing and control porcine B-lymphoma cells were transplanted into T- and B cell-deficient nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice that express SIRPalpha capable of interacting with human CD47. Only the human CD47-expressing porcine lymphoma cells survived and were able to form tumors in NOD/SCID mice; however, both the control and human CD47-expressing porcine cells survived in macrophage-depleted NOD/SCID mice. These results indicate that transgenic expression of human CD47 may provide an effective approach to inhibiting macrophage-mediated xenograft rejection in clinical xenotransplantation. PMID- 21535912 TI - Losartan enhances the success of myoblast transplantation. AB - Duchenne muscular dystrophy is a recessive X-linked genetic disease caused by dystrophin gene mutations. Cell therapy can be a potential approach aiming to introduce a functional dystrophin in the dystrophic patient myofibers. However, this strategy produced so far limited results. Transforming growth factor-beta (TGF-beta) is a negative regulator of skeletal muscle development and is responsible for limiting myogenic regeneration. The combination of TGF-beta signaling inhibition with myoblast transplantation can be an effective therapeutic approach in dystrophin-deficient patients. Our aim was to verify whether the success of human myoblast transplantation in immunodeficient dystrophic mice is enhanced with losartan, a molecule that downregulates TGF-beta expression. In vitro, blocking TGF-beta activity with losartan increased proliferation and fusion and decreased apoptosis in human myoblasts. In vivo, human myoblasts were transplanted in mice treated with oral losartan. Immunodetection of human dystrophin in tibialis anterior cross sections 1 month posttransplantation revealed more human dystrophin-positive myofibers in these mice than in nontreated dystrophic mice. Thus, blocking the TGF-beta signal with losartan treatment improved the success of myoblast transplantation probably by increasing myoblast proliferation and fusion, decreasing macrophage activation, and changing the expression of myogenic regulator factors. PMID- 21535913 TI - Ultrashort-specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. AB - Specific immunotherapy is a well-established treatment for allergic rhinoconjunctivitis; conventional regimens are lengthy, however, reducing convenience and cost-effectiveness. This study evaluated the efficacy and safety of an ultrashort course (four doses) of the immunotherapy Grass Modified Allergen Tyrosine Adsorbate (Allergy Therapeutics, Worthing, U.K.) monophosphoryl lipid A (MATA MPL). Subjects were randomized to receive four injections of either Grass MATA MPL (n = 514; 300-2000 standardized units/injection) or placebo (n = 514) before the grass pollen season. They used electronic diaries to record allergy symptoms and medication use during the pollen season. The primary end point was the difference between the mean combined symptom and medication scores in the Grass MATA MPL and placebo groups during the 4 local peak pollen weeks. The injection course was completed by 95.3 and 97.7% of the Grass MATA MPL and placebo groups, respectively, and was well tolerated. Grass MATA MPL treatment afforded a 13.4% benefit over placebo in the 4 peak pollen weeks (p = 0.0038). The benefit in subjects with 28 complete diary entries during the 4 peak pollen weeks was 26.9% (p = 0.0031). Significant benefits over placebo were observed in subjects with severe symptoms (17.1%; p = 0.0023), in those who had a history of allergic rhinoconjunctivitis for up to 35 years (up to 37.2%; p = 0.0059) and at sites with a higher burden of disease (38.3%; p < 0.0001). The ultrashort course of Grass MATA MPL was well tolerated and provided a significant benefit over placebo in relieving allergy symptoms. PMID- 21535914 TI - Survey of respiratory therapy education program directors in the United States. AB - OBJECTIVE: As background for the American Association for Respiratory Care (AARC) third 2015 and Beyond conference, we sought information and opinions on the ability of the current respiratory therapy education infrastructure to make changes that would assure competent respiratory therapists in the envisioned healthcare future. METHODS: After pilot testing and refining the questions, we invited the directors of 435 respiratory therapy programs (based in 411 colleges) that were fully accredited or in the process of being accredited by the Commission on Accreditation for Respiratory Care as of May, 2010, to participate in the survey. RESULTS: Three-hundred forty-eight program directors (80%) provided valid survey responses. Three of the 5 competencies related to evidence based medicine and respiratory care protocols were taught less often in the associate-degree programs than in the baccalaureate-degree programs. Eighty percent of the baccalaureate-degree programs, compared to 42% of the associate degree programs, instruct students how to critique published research (P < .001). Only 34% of the associate-degree programs teach students the general meaning of statistical tests, compared to 78% of the baccalaureate-degree programs (P < .001). Ninety-four percent of the baccalaureate-degree programs, versus 81% of the associate-degree programs, teach the students to apply evidence-based medicine to clinical practice (P = .01). Teaching students how to describe healthcare and financial reimbursement systems and the need to reduce the cost of delivering respiratory care (a leadership competency identified by the second 2015 and Beyond conference) was significantly more common in the baccalaureate degree programs (72%) than in the associate-degree programs (56%) (P = .03). Other competencies showed trends toward differences, and the baccalaureate-degree programs reported higher percentages of success than the associate-degree programs. CONCLUSIONS: There are important differences between the baccalaureate degree and associate-degree programs. PMID- 21535915 TI - Age-dependent availability and functionality of bone marrow stem cells in an experimental model of acute and chronic myocardial infarction. AB - The aim of this study was to investigate the effect of aging and timing of left ventricular ischemic injury on the availability and functionality of stem cells. We studied young and aged male inbred Lewis rats that were used as donors of bone marrow mononuclear cells (BM-MNCs), divided in four experimental groups: controls, sham operated, 48 h post-myocardial infarction (MI), and 28 days post MI. In vitro studies included flow cytometry analysis, hematopoietic colony forming capacity, and invasion assays of migration capacity. BM-MNCs from these groups were transplanted in female rats after MI induction. Late engraftment was evaluated by real-time PCR of the SRY chromosome. Percentage of CD34+/CD45+(low) cells was similar among different experimental groups in young rats, but was significantly higher in aged animals (p < 0.001), particularly 28 days post-MI. KDR+/CD34+ cells were increased 48 h after MI and decreased 28 days post-MI in young animals, while they were profoundly reduced in the aged group (p < 0.001). Triple staining for CD44+/CD29+/CD71+ cells was similar in different groups of aged rats, but we observed an intense increase 48 h post-MI in young animals. Colony-forming units and cytokine-induced migration were significantly attenuated 28 days after the MI. Late engraftment in infarcted transplanted female hearts was present, but considerably heterogeneous. Finally, recovery of left ventricular systolic function in transplanted female recipients was significantly influenced by donors' BM-MNCs groups (p < 0.01). We have demonstrated that aging and timing of myocardial injury are factors that may act synergistically in determining stem cell availability and function. Such interaction should be considered when planning new cell therapy strategies for acute and chronic ischemic heart disease in the clinical arena. PMID- 21535916 TI - Pilot dietary study with normoproteic protein-redistributed plant-food diet and motor performance in patients with Parkinson's disease. AB - Although a plant-based diet can provide some benefits in Parkinson's disease (PD), no study to date has evaluated the effectiveness of a plant-food diet in the management of the disease. In this pilot study, we compared the effect of a plant-food menu (PFD) and of a omnivorous menu on motor performance of 25 PD patients, 12 in the intervention group (PDi) and 13 in the control group (PDc). After 4 weeks, the PDi group showed a significant reduction (Mann-Whitney test) in the Unified Parkinson's Disease Rating Scale, total score (47.67 vs. 74.46, P = 0.008) and sub-score III motor performances (25.42 vs. 46.46, P = 0.001), and the modified Hoehn and Yahr Staging Scale (1.96 vs. 3.15, P = 0.005). These data suggest that PFD may be useful in the management of PD patients by improving their motor performances. Additional studies are needed in order to confirm these preliminary results. PMID- 21535917 TI - Effect of magnesium chloride on psychomotor activity, emotional status, and acute behavioural responses to clonidine, d-amphetamine, arecoline, nicotine, apomorphine, and L-5-hydroxytryptophan. AB - BACKGROUND: The beneficial effects of magnesium (Mg) salts on central manifestations of Mg deficiency are well known. Mg replacement therapy can be effective to prevent some of the serious depression-like and anxiety-related behaviour sequelae of Mg deficiency. However, few experimental studies have been undertaken on Mg-deficiency-induced behavioural changes. Even fewer studies have been carried out on acute behavioural responses to clonidine, D-amphetamine, arecoline, nicotine, apomorphine, and L-5-hydroxytryptophan (HTP), which might characterize possible neuromediator changes in Mg deficiency. The effects of correcting Mg deficiency by magnesium chloride (MgCl2 . 6H2O) and the combination of this salt with vitamin B6, on the behavioural manifestations of Mg deficiency have never been described as well. OBJECTIVE: The aims of this study were: to estimate effect of MgCl2 . 6H2O alone and in combination with vitamin B6 on acute behavioural responses to agonists or blockers of the main neurotransmitter systems in CNS, psychomotor activity and emotional status of rats fed with Mg deficient diet for 49 days. In our study open field test has shown that in Mg deficient rats locomotor activity and vertical activity, number of visiting and residence time in central squares were decreased significantly. In the elevated plus maze test, the number of visiting open arms and residence time of rats were significantly less as compared with the control group. In the forced swimming test, time immobile was significantly increased by 44.29% and time of swimming was decreased by 52.79% compared to control. RESULTS: In our study Mg-deficient rats were more sensitive to d-amphetamine-induced motor stereotypes. Mg deficiency antagonized 5-hydroxytryptophan-induced head-twitch response and arecoline-induced tremor. Supplement of MgCl2 . 6H2O with vitamin B6 administered to a Mg-deficient rat increased the Mg level in plasma and erythrocytes. Furthermore, this increase was in relation to vitamin B6 given to the animal. Mg supplementation alone and in combination with pyridoxine normalized acute behavioural responses to d-amphetamine, 5-hydroxytryptophan, and arecoline in Mg deficient rats with a return to pre-deficient levels observed in the Mg sufficient group. DISCUSSION: Combination of Mg salts and pyridoxine hydrochloride can be effective at treating some behavior form of primary Mg deficiency. PMID- 21535918 TI - Dietary intake and olfactory function in patients with newly diagnosed Parkinson's disease: a case-control study. AB - OBJECTIVE: To evaluate energy and nutrient intake in newly diagnosed Parkinson's disease (PD) patients and association between olfaction and nutrient density of the diet. DESIGN: Baseline data from a prospective cohort study. SUBJECTS: Eighty seven patients and 28 age- and sex-matched controls participated in the study. METHODS: Dietary intake was assessed by using 3-day dietary records and 24-hour dietary recalls. The Brief Smell Identification Test (B-SIT) was used to test olfaction. RESULTS: Patients, compared with controls, had lower intake of polyunsaturated fatty acids (P = 0.024) and a higher intake of carbohydrates (P = 0.027) in energy percent (E%). Lower intake of protein (E%) (P = 0.045), and a low nutrient density of folate (P = 0.022), magnesium (P = 0.012), and phosphorus (P = 0.029) were associated with lower B-SIT score in both patients and controls. PD patients had a lower B-SIT score than controls (P < 0.001). CONCLUSION: The results indicate a higher relative contribution of energy from carbohydrates in PD patients. An association between low protein, folate, magnesium, and phosphorus density of the diet and olfaction was seen in the whole population. PMID- 21535919 TI - Diet-induced effects on neuronal and glial elements in the middle-aged rat hippocampus. AB - Consumption of a high-fat and/or high-cholesterol diet can have detrimental effects on the brain. In the present study, dietary treatment with saturated fats, trans fats, or cholesterol to middle-aged Fischer 344 rats resulted in alterations to serum triglyceride and cholesterol levels, organ weights, and hippocampal morphology. Previously, we demonstrated that a 10% hydrogenated coconut oil and 2% cholesterol diet resulted in worse performance on the 12-day water radial arm maze, increased cholesterol and triglyceride levels, and decreased dendritic microtubule associated protein 2 (MAP2) staining in the hippocampus. The diets administered herein were used to examine components from the previous diet and further examine their effects on hippocampal morphology. Specifically, neuronal morphology, dendritic integrity, fatty acid metabolism, microgliosis, and blood vessel structure in the hippocampus and/or adjacent structures were explored. Our results indicate alterations to peripheral and neural systems following each of the diets. PMID- 21535921 TI - Capacity for resolution of Ras-MAPK-initiated early pathogenic myocardial hypertrophy modeled in mice. AB - Activation of Ras signaling in cardiomyocytes has been linked to pathogenic myocardial hypertrophy progression and subsequent heart failure. Whether cardiomyopathy can regress once initiated needs to be established more fully. A 'tet-off' system was used to regulate expression of H-Ras-G12V in myocardium to examine whether Ras-induced pathogenic myocardial hypertrophy could resolve after removal of Ras signaling in vivo. Ras activation at weaning for 2 wk caused hypertrophy, whereas activation for 4 to 8 wk led to cardiomyopathy and heart failure. Discontinuing H-Ras-G12V transgene expression after cardiomyopathy onset led to improved survival and cardiomyopathy lesion scores, with reduced heart:body weight ratios, demonstrating the reversibility of early pathogenic hypertrophy. Activation of Ras and downstream ERK 1/2 was associated with elevated expression of proliferating cell nuclear antigen and cyclins B1 and D1, indicating cell-cycle activation and reentry. Coordinate elevation of broad spectrum cyclin-dependent kinase inhibitors (p21, p27, and p57) and Tyr15 phosphorylation of cdc2 signified the activation of cell-cycle checkpoints; absence of cell-cycle completion and cardiomyocyte replication were documented by using immunohistochemistry for mitosis and cytokinesis markers. After resolution of cardiomyopathy, cell-cycle activators and inhibitors examined returned to basal levels, a change that we interpreted as exit from the cell cycle. Cardiac cell-cycle regulation plays a role in recovery from pathogenic hypertrophy. The model we present provides a means to further explore the underlying mechanisms governing cell-cycle capacity in cardiomyocytes, as well as progression and regression of pathogenic cardiomyocyte hypertrophy. PMID- 21535922 TI - Development of a mouse model for assessing fatigue during chemotherapy. AB - Fatigue and disturbed sleep are common problems for cancer patients and affect both quality of life and compliance with treatment. Fatigue may be associated with cancer itself and with the treatment, particularly for therapies with neurotoxic side effects. To develop a model system for evaluation of chemotherapy related fatigue, we studied mice treated with either a commonly used formulation of the chemotherapeutic agent paclitaxel (paclitaxel; Taxol), which is known to have neurotoxic properties, or a nano- particle formulation of paclitaxel (nab paclitaxel; Abraxane) that is reported to have greater potency and efficacy yet fewer side effects than does paclitaxel. Mice were treated with 1 of these 2 agents (10 mg/kg IV daily for 5 consecutive days) and were monitored from 1 wk before through 4 wk after treatment. Dependent measures included running wheel activity, locomotor activity on the cage floor, core temperature, sleep patterns, CBC count, serum cytokine and chemokine concentrations, and neurologic assessment. For both drugs, mice showed the most severe perturbations of activity during the first recovery week after drug administration. Mice treated with paclitaxel showed greater neutropenia and motor deficits than did mice treated with nab-paclitaxel. However, deficits had largely resolved by 4 wk after administration of either drug. We conclude that these measures provide an assessment of chemotherapy-related fatigue that potentially can distinguish toxicity associated with different formulations of the same agent. PMID- 21535923 TI - Biometric evidence of diet-induced obesity in Lew/Crl rats. AB - Although Lew/Crl rats are central to a classic model of renal transplantation and may provide a valid system for evaluating the effect of obesity on transplantation outcomes, their response to high-fat diet has not been evaluated sufficiently. The objective of this study was to evaluate biometric and basic metabolic data of Lew/Crl rats fed a 60% kcal, lard-based, very high-fat diet (HFD) compared with those fed a 10% kcal fat control diet (CD). Rats were maintained for 17 wk; body parameters and caloric intake were monitored weekly. Biometric data were collected and calculated before and after euthanasia. Serum was evaluated for liver enzyme activity and total bilirubin, glucose, triglyceride, cholesterol, insulin, leptin, and creatinine concentrations, and urine was evaluated for protein, glucose, specific gravity, and ketones. Tissues were harvested, weighed, and evaluated histologically. Compared with CD rats, HFD rats consumed more calories and weighed more after 3 wk. After 17 wk, HFD rats had significantly increased body weight, girth, volume, epididymal fat pad weight, omental weight, and body fat. In addition, HFD rats had mild elevations in some liver enzymes and a lower serum triglyceride concentration than did CD rats. Histologic assessment and other metabolic markers of disease were not different between the 2 groups. Lew/Crl rats fed a 60% kcal HFD become obese, but they lack significant metabolic abnormalities frequently associated with obesity in other rat strains. PMID- 21535924 TI - Effects of short-term fasting in male Sprague-Dawley rats. AB - Fasting is a common procedure for animals in experiments. Although fasting may be necessary for scientific reasons, it should be minimized. In the current study, jugular-catheterized male Sprague-Dawley rats in metabolism cages were fasted for 0 to 24 h before measurement of various physiologic markers (serum chemistry, CBC analysis, serum corticosterone). When controlled for cohort, rats fasted for 6 and 16 h had significantly lower serum glucose than did nonfasted rats. Other values did not differ from controls. Only rats fasted for 24 h had elevated serum corticosterone levels. Therefore, fasting for as long as 16 h has fewer effects on rats that does fasting for 24 h. Fasting for 24 h or more therefore should receive appropriate consideration by both scientists and the IACUC in the experimental design and the animal-use protocol. PMID- 21535925 TI - Spermatogenesis in ferret testis xenografts: a new model. AB - Testis xenografting is both a promising tool to study spermatogenesis and a means to preserve the genetic information and reproductive potential of prepubertal male animals. The present study was conducted to evaluate this technique using testis tissue from domestic ferrets, an important biomedical model and a model for the conservation of small carnivore species. Fresh testis tissue from 8-wk old ferrets was implanted ectopically under the skin on the backs of castrated nude mice and subsequently evaluated for testosterone production and establishment of spermatogenesis at 10, 20, 25, and 30 wk after xenografting. A total of 40% of fresh ferret xenografts were harvested. Seminal vesicles were collected from the recipient mice and weighed as an assay for bioactive testosterone. The weights of seminal vesicles from the mice showed no significant difference from those of uncastrated, control nude mice, indicating that the xenografts were producing physiologically relevant amounts of testosterone. The ferret testis xenografts produced differentiating germ cells and sperm at the same time as did testis from age-matched control ferrets. These data demonstrate the ability of Mustelidae testicular tissue to establish spermatogenesis in nude mice after testis xenografting. PMID- 21535926 TI - Long-term evaluation of a selective retrograde coronary venous perfusion model in pigs (Sus scrofa domestica). AB - The lack of suitable target vessels remains a challenge for aortocoronary bypass grafting in end-stage coronary heart disease. This study aimed to investigate the arterialization of cardiac veins as an alternative myocardial revascularization strategy in an experimental long-term model in pigs. Selective retrograde perfusion of a coronary vein (aorta to coronary vein bypass, retrobypass) before ligation of the ramus interventricularis paraconalis (equivalent to the left anterior descending artery in humans) was performed in 20 German Landrace pigs (Sus scrofa domestica). Retroperfusion of the left anterior descending vein was performed in 10 pigs (RP+) but not in the other 10 (RP-), and the vena cordis magna was ligated (L+) in 5 pigs in each of these groups but left open (L-) in the remaining animals. Hemodynamic performance (for example, cardiac output) was significantly better in the group that underwent selective retroperfusion with proximal ligation of vena cordis magna (RP+L+; 4.1 L/min) compared with the other groups (RP+L-, 2.5 L/min; RP-L+, 2.2 L/min; RP-L-, 1.9 L/min). Long-term survival was significantly better in RP+L+ pigs (112+/-16 d) than in all other groups. Histologic follow-up studies showed significantly less necrosis in the RP+L+ group compared with all other groups. Venous retroperfusion is an effective technique to achieve long-term survival after acute occlusion of the left anterior descending artery in a pig model. In this model, proximal ligation of vena cordis magna is essential. PMID- 21535927 TI - A model of hemorrhagic shock and acute lung injury in Landrace-Large White Swine. AB - Traumatic injury is a leading cause of death worldwide for people between 5 and 44 y of age, and it accounts for 10% of all deaths. The incidence of acute lung injury, a life-threatening complication in severely injured trauma patients remains between 30% and 50%. This study describes an experimental protocol of volume-controlled hemorrhage in Landrace-Large White swine. The experimental approach simulated the clinical situation associated with hemorrhagic shock in the trauma patient while providing controlled conditions to maximize reproducibility. The duration of the protocol was 8 h and was divided into 5 distinct phases-stabilization, hemorrhage, maintenance, resuscitation, and observation-after which the swine were euthanized. Lung tissue samples were analyzed histologically. All swine survived the protocol. The hemodynamic responses accurately reflected those seen in humans, and the development of acute lung injury was consistent among all swine. This experimental protocol of hemorrhagic shock and fluid resuscitation in Landrace-Large White swine may be useful for future study of hemorrhagic shock and acute lung injury. PMID- 21535929 TI - Risk factors for dystocia in pigtailed macaques (Macaca nemestrina). AB - Dystocia (difficult labor) is an important component of the management of nonhuman primates and results in significant fetal and maternal morbidity and increased use of veterinary resources. Dystocias can arise from abnormalities of the maternal pelvis or fetus or uncoordinated uterine activity. Although risk factors for stillbirths have been established in nonhuman primates, risk factors for dystocias have not. The objective of this study was to determine maternal and fetal risk factors for dystocia in macaques. Retrospective data were collected from 83 pigtailed macaques (Macaca nemestrina) diagnosed with dystocia. The diagnosis of dystocia was made based on clinical or pathologic evidence. Maternal records of age, reproductive history, experimental history, clinical records, and fetal birth weight and any applicable fetal necropsy reports were reviewed. The gestational age of the fetus, the infant's birth weight, total previous births by the dam, and the proportions of both viable delivery (inverse effect) and surgical pregnancy interventions (direct effect) in the dam's history generated a model that maximized the experimental variance for predicting dystocia in the current pregnancy and explained 24% of the dystocia deliveries. The number of total previous births and proportion of previous cesarean sections accounted for the greatest effect. This model can identify individual dams within a colony that are at risk for dystocias and allow for changes in breeding colony management, more intense monitoring of dams at risk, or allocation of additional resources. PMID- 21535928 TI - Association of brain-type natriuretic protein and cardiac troponin I with incipient cardiovascular disease in chimpanzees (Pan troglodytes). AB - Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in chimpanzees, but its etiology and clinical presentations remain poorly understood. The disease in chimpanzees differs sufficiently from that in humans that simple extrapolation from human findings are inadequate to guide clinical diagnoses. Nevertheless, the burden of disease posed by CVD made it important to attempt to identify specific chimpanzees at risk of developing CVD to allow clinical intervention prior to clinical presentation of advanced disease. We screened 4 CVD biomarkers used in human and veterinary medicine to identify markers with prognostic value in chimpanzees. Biomarkers included complete lipid panel, C-reactive protein, brain-type natriuretic protein, and cardiac troponin I. Serum levels of brain-type natriuretic protein differed between chimpanzees with CVD and heart-healthy controls. Cardiac troponin I gave mixed results. C reactive protein and lipid panel values were not informative for cardiovascular disease, although total cholesterol, LDL-cholesterol, and triglycerides increased significantly with decade of life. Values of braintype natriuretic protein exceeding 163 mg/mL had a specificity of 90.5% for CVD, whereas levels of cardiac troponin I above the threshold of detection (0.20 ng/mL) appeared to be clinically relevant. More extensive clinical studies are recommended to validate these specific values. We conclude that brain-type natriuretic protein and possibly cardiac troponin I are useful diagnostic biomarkers for incipient CVD processes in chimpanzees. PMID- 21535930 TI - Intracardiac thrombosis and aortic dissecting aneurysms in mustached tamarins (Saguinus mystax) with cardiomyopathy. AB - Spontaneous intracardiac thrombosis is rarely reported in animals, particularly nonhuman primates. The finding of 2 cases of intracardiac thrombi in mustached tamarins (Saguinus mystax) that died as a consequence of congestive heart failure prompted us to do a retrospective study to determine the frequency of this condition. Clinical records, necropsy reports, and tissues from 60 mustached tamarins that died or were euthanized between 1996 and 2009 were reviewed. Of the 60 monkeys whose cases were reviewed, 10 (16.6%) had intracardiac thrombi, and 4 (6.6%) had dissecting aortic aneurysms. Of the 10 animals with intracardiac thrombosis, 3 had left ventricular involvement alone; 4 monkeys had thrombi only in the right ventricle, and the remaining 3 animals exhibited thrombi in both ventricles. Myocardial fibrosis and chronic renal disease were common findings in affected animals. The causes of the intracardiac thrombosis in the tamarins in the present study are not known, but the clinical signs and gross and microscopic lesions suggest that congestive heart failure secondary to cardiomyopathy is the primary contributor. In addition, the cause of the aortic dissecting aneurysms in the tamarins in this study is not known. Further studies are required to determine whether factors including aortic curvature, genetic background, or hypertension-alone or in combination-play a role. To our knowledge, the current retrospective study is the first report of intracardiac thrombosis and aortic aneurysms in mustached tamarins. PMID- 21535931 TI - Cutaneous silent period in fibromyalgia. AB - OBJECTIVES: The pathogenesis of widespread pain and increased tenderness in Fibromyalgia (FM) are still unknown. Recently, the role of central nervous system hyperexcitability is emphasized in pathogenesis of FM. The central sensitization was demonstrated with decrease in nociceptive flexion reflex (NFR) threshold in patients with FM. The NFR and cutaneous silent period (CuSP) are excitatory and inhibitory parts of the same spinal protective reflex, respectively. The aim of this study was to evaluate the changes in CuSP in FM. PATIENTS AND METHODS: Twenty-eight patients with FM and 18 healthy volunteers were subjected to the study. CuSPs on right abductor pollicis brevis muscle evoked by electrical stimulation of the right fifth digit were recorded. RESULTS: The CuSP onset latencies were significantly longer in patients with FM. There was not any significant difference in CuSP duration between patients and controls. CONCLUSION: The latency elongation of the CuSP shows that there is some delay in the development of the inhibitory part of the spinal protective reflex in patients with FM. The observed changes in CuSP of the patients with FM may suggest some abnormalities in the circuits of sensorimotor integration at spinal and supraspinal levels. The results regarding the changes observed in the CuSP in patients with FM should be confirmed by further studies. PMID- 21535932 TI - Evaluating intra-genetic variants of DJ-1 among Parkinson's disease patients of eastern India. AB - OBJECTIVES: Mutations in the DJ-1 gene have been described in autosomal recessive Parkinson's disease (PD) of European ancestry, Ashkenazi Jews, and Afro-Caribbean patients. Up to date, there is a lack of information about the prevalence of DJ-1 mutations among Indian PD patients. MATERIALS AND METHODS: In this study, we examined for DJ-1 mutations in Eastern Indian PD patients. Exons (no. 2-7) and intron boundaries of the DJ-1 gene were screened in 300 individuals (PD, 150; controls, 150) by direct sequencing. RESULTS: A total of six intronic variants (IVS4+30T>G, IVS4+45G>A, IVS4+46G>A, IVS4-98G>A, IVS5+31G>A and IVS5+69G>C) were detected including one novel intronic change (IVS5+69G>C). Clinical features of the two patients exhibiting IVS5+69G>C (novel change) were compared and both were found to have early onset PD. IVS4+30T>G, IVS4+45G>A, and IVS4+46G>A were found to be present equally both in the patient and control cohorts. We did not find any DJ-1 mutations in our study. CONCLUSION: Our results suggest that, unlike Parkin, pathogenic DJ-1 mutations seem to be restricted in certain populations and are unlikely to be of clinical importance in the eastern part of India. PMID- 21535933 TI - Granulocyte-colony stimulating factor protects memory impairment in the senescence-accelerated mouse (SAM)-P10. AB - OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with memory impairment in elderly people. At present, AD remains incurable. More and more evidences have suggested that granulocyte-colony stimulating factor (G CSF) has important non-hematopoietic neuroprotective functions in central nervous system. The present study was designed to investigate the therapeutic potential of G-CSF in the senescence-accelerated mouse prone strain (SAM-P10) mice, a mouse model of senile dementia. METHODS: Recombinant human G-CSF was administered subcutaneously in SAM-P10 mice once daily for consecutive 7 days. Morris water maze test was used to evaluate spatial memory of the mice. Immunohistochemistry analysis was done to elucidate the changes of apoptotic neurons in CA1 region of hippocampus of the mice. RESULTS: In the present study, we found that administration of recombinant G-CSF significantly protected spatial memory impairment, and decreased the number of apoptotic (caspase-3-positive) and tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-positive neurons in CA1 region of hippocampus of SAM-P10 mice, suggesting that G-CSF may protect spatial memory impairment through suppression of TRAIL-mediated apoptosis in neurons. CONCLUSIONS: These findings highlight the therapeutic potential of G-CSF in AD. PMID- 21535934 TI - Usefulness of motor-evoked potential monitoring during coil embolization of anterior choroidal artery aneurysms: technical reports. AB - OBJECTIVES: To determine whether transcranial motor-evoked potential (TCMEP) monitoring is useful for detecting blood flow insufficiency in the anterior choroidal artery (AChA) and reflects motor function during coil embolization of AChA aneurysms. METHODS: We analysed MEP findings in seven patients who underwent coil embolization for AChA aneurysms. Corkscrew electrodes positioned at C3 and C4 were used to deliver supra-maximal stimuli (230-550 V). TCMEPs were recorded from the brachioradialis, abductor pollicis brevis, anterior tibialis, and abductor hallucis muscles during all endovascular surgery procedures. RESULTS: Three of seven patients showed transient decreases in TCMEP amplitudes obtained from the lower extremities after coil insertion into the aneurysms, although digital subtraction angiography (DSA) showed no blood flow insufficiency in the AChAs. In two of these three patients, extraction of the coils resulted in recovery of TCMEP amplitudes. In the other patient, the amplitude recovered gradually during repeated TCMEP recordings. One of the three patients experienced transient hemiparesis and aphasia 3 hours after treatment. No patients experienced permanent morbidity post-operatively. DISCUSSION: Decreases in TCMEP amplitude during endovascular treatment for AChA aneurysms are likely to reflect motor dysfunction due to a subtle blood flow insufficiency in the AChA, not detectable by DSA. TCMEP monitoring is a simple and safe monitoring method during coil embolization of AChA aneurysms. PMID- 21535935 TI - Techniques of intraoperative monitoring for spinal cord function: their past, present, and future directions. AB - PURPOSE: The authors discuss the use of intraoperative monitoring of spinal cord function as an essential part of operations in which the spinal cord is at risk. Although early documented cases of intraoperative monitoring were during operations to correct spinal deformities such as scoliosis, intraoperative monitoring has also increased safety during other operations, such as tumor resection and arteriovenous malformation ablation. METHODS: The authors highlight details involved in monitoring spinal cord function intraoperatively and discuss historical, current, and future perspectives on the use of these monitoring techniques as an essential part of operations in which the spinal cord is at risk. RESULTS: Intraoperative monitoring techniques mitigate the risk of post operative deficits to the spinal cord by detecting injuries before they become permanent and while they can be reversed. CONCLUSIONS: Intraoperative spinal cord monitoring is safe, cost-effective, and valuable in reducing post-operative sensory and motor deficit. This technique should continue to be refined and its use consistently applied in any procedure where injury to the spinal cord is possible. PMID- 21535936 TI - Dexamethasone potentiated Abeta-induced learning and memory impairment in rats. AB - OBJECTIVE: To determine whether dexamethasone (DEX) could potentiate amyloid beta protein (Abeta)-induced learning and memory impairment in rats, and, if so, what the underlying mechanism is. METHODS: Morris water maze was used to investigate whether DEX could potentiate Abeta-induced learning and memory impairment in rats, and the histopathologic changes in CA1 field of hippocampus were examined under a light microscope. Immunohistochemistry was used to observe the change of the phosphorylated tau at Thr-231 in the CA1 field of hippocampus. The effects of DEX on the levels of phospho-tau and p25 induced by Abeta were analyzed by Western blot. RESULTS: The results showed that DEX could potentiate Abeta-induced learning and memory impairment and pathological damage in CA1 field of hippocampus in Sprague Dawley (SD) rats, and could enhance the increased levels of phosphorylated tau induced by Abeta(25-35) in the neuronal cell bodies in CA1 field of hippocampus of SD rats and in the protein extracts from hippocampus. Pretreatment of hippocampal neurons with DEX could up-regulate the increased levels of phosphorylated tau and p25 protein induced by Abeta(25-35) in vitro. CONCLUSIONS: These results suggest that DEX could potentiate Abeta-induced learning and memory impairment and pathological damage in CA1 field of hippocampus in SD rats, which might be related to DEX up-regulating the levels of phosphorylated tau and p25 protein induced by Abeta(25-35). Since Abeta and glucocorticoids increase with aging, DEX potentiating Abeta-induced learning and memory impairment may be one of the etiology of Alzheimer's disease. PMID- 21535937 TI - Effects of the group II mGlu receptor agonist 2R,4R-APDC on dentate gyrus cell proliferation in the adult rat brain after diffuse brain injury. AB - OBJECTIVES: Diffuse brain injury (DBI) has been shown to increase the proliferation of granule cell precursors in the adult dentate gyrus (DG). However, the mechanism by which DBI-induced cell proliferation in the DG may enhance seizure susceptibility remains largely unknown. MATERIALS AND METHODS: Using bromodeoxyuridine (BrdU) immunohistochemistry, we examined the effects of group II metabotropic glutamate receptor (mGluR) agonist, 2R,4R-4 aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), on cell proliferation in the DG after DBI. RESULTS: It has been found that 2R,4R-APDC significantly blocked DBI induced increase in the number of BrdU-positive cells in the DG, especially in hilus. In addition, double-label immunofluorescence staining showed that treatment with APDC did not affect the differentiation of newborn cells into neurons or astrocytes. Taken together, our findings indicate that the activation of mGluR system may inhibit the DBI-induced cell proliferation in the DG, but not the differentiation of newborn cells. DISCUSSION: It is suggested that 2R,4R-APDC has potential neuroprotection via inhibiting the aberrant neurogenesis induced by DBI, which is an important pathological basis of seizure or other abnormalities following DBI. PMID- 21535938 TI - Assessment of parameters influencing the blood flow velocities in cerebral arteries of the rat using ultrasonographic examination. AB - OBJECTIVES: Rat models of cerebrovascular diseases are used for a variety of human pathologies comprising ischemic stroke or subarachnoid hemorrhage. Whereas in neuro-intensive care, Doppler ultrasonographic examination of major cerebral arteries is a common diagnostic tool, only few data exist concerning the animal model. We therefore studied cerebral blood flow velocities in the rat by ultrasonographic triplex mode. METHODS: Female Wistar rats underwent a large craniectomy and baseline values for blood flow velocities were obtained by 399 examinations in 52 animals. Vessel diameters were assessed by 301 examinations in 39 animals. Finally, in 26 animals, continuous measurements of blood flow velocities were performed. For a duration of more than 30 minutes, values in the anterior trunk, the left carotid artery and the basilar artery were obtained every 60-90 seconds with simultaneous detection of heart rate. RESULTS: Blood flow velocities in the anterior part of cerebral circulation were faster than those in the posterior part and showed higher standard deviation. Flow velocities in arteries belonging to the anterior circulation changed in relation to carotid flow velocity and heart rate, whereas the velocity in the basilar artery showed much lower correlation to carotid flow velocity or heart rate. DISCUSSION: Ultrasonographic triplex mode examination of cerebral vessels offers a reproducible method to study rat cerebral blood flow velocities and vessel diameters. In combination with monitoring of systemic hemodynamic parameters, it can provide a detailed description of the vascular response to drugs, experimental stroke or subarachnoid hemorrhage. PMID- 21535939 TI - 3-n-Butylphthalide (NBP) attenuated neuronal autophagy and amyloid-beta expression in diabetic mice subjected to brain ischemia. AB - OBJECTIVE: The aim of this study was to investigate the protective effect of dl-3 n-butylphthalide (NBP) on brain damage in streptozotocin (STZ)-induced diabetic mice subjected to cerebral ischemia. METHODS: we pretreated diabetic mice with NBP orally for 4 weeks prior and 2 days after transient common carotid artery occlusion (CCAO) operation. Immunohistochemistry and transmission electron microscopy were performed to investigate the neuronal loss, astrocytes activation, amyloid-beta (Abeta) protein expression, and autophagy activation. RESULTS: The results showed that diabetes increased stroke-induced neuronal loss, astrocytes activation, Abeta generation, and autophagy activity, while NBP administration attenuated these changes. Immunofluorescence double staining of Abeta with autophagosome-specific antibody LC3 showed that most elevated Abeta(+) signal was co-localized with LC3(+) signal. CONCLUSION: Our finding suggests that NBP attenuates Abeta generation promoted by diabetes in ischemia might act through inhibiting abnormally activated neuronal autophagy. Therefore, treatment with NBP to modulate autophagy might provide a novel therapeutic strategy for diabetes by preventing ischemic brain damage and depressing the risk of post stroke dementia. PMID- 21535940 TI - The mixed human umbilical cord blood-derived mesenchymal stem cells show higher antitumor effect against C6 cells than the single in vitro. AB - OBJECTIVE: It is difficult for the treatment of neurologic tumors with current therapies, including glioma. Despite the advances in cancer therapeutics, the outcomes in these patients remain poor and, therefore, new modalities are required. Recent findings have demonstrated that human umbilical cord blood mesenchymal stem cells (UCB-MSCs) have the potential to inhibit glioma cell growth in vitro. Caspase-3 plays a critical role as an executioner of apoptosis and the level of caspase-3 expression determines the degree of apoptosis in cancer cell lines. CD133 (+) glioma displays a strong resistance to chemotherapy. Interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) are important cytokines in the generation of antitumor immunity. METHODS: UCB-MSCs were harvested by density gradient separation. Green fluorescence protein stable C6 cells were established. Cytotoxicity was detected by visual survival cell assay, and caspase-3 activity was assessed using immunohistochemistry staining and western blot. Flow cytometry was used to test CD133 positive C6 cells. The concentrations of IL-2 and IFN gamma proteins secreted from UCB-MSCs were then quantified using enzyme-linked immunosorbent assay. The cytotoxicities of IL-2 alone, IFN-gamma alone, and combination of IL-2 and IFN-gamma were compared against malignant glioma cells. RESULTS: We noted a significant cytotoxicity of UCB-MSCs for malignant glioma cells. In addition, the toxicity of mixed UCB-MSCs was significantly higher than that of single UCB-MSCs for C6 glioma cells. Capase-3 levels in UCB-MSCs treatment at an effector/target (E/T) ratio of (5+5):1 were higher than those at an E/T ratio of 10:1. On the contrary, there was no change in the protein expression of capase-3 at an E/T ratio of 0:1. Immunohistochemistry staining and western blot revealed that the expression of capase-3 was higher in mixed UCB MSCs treatment, when compared with single UCB-MSCs. We identified reductions of approximately 39 and 73% in the number of CD133 positive C6 cells treated with the single (10:1) and the mixed [(5+5):1] UCB-MSCs respectively as compared to the control group (0:1) in transwell inserts. However, the mixed UCB-MSCs secreted more immune response-related proteins (IL-2 and IFN-gamma) than the single UCB-MSCs. Combination of IL-2 and IFN-gamma might prove more cytotoxic on target cells than IL-2 alone and IFN-gamma alone. DISCUSSION: The data collected herein confirm for the first time that the mixed UCB-MSCs were shown to have more cytotoxic effects than the single UCB-MSCs through increasing the expression of caspase-3 and decreasing the expression of CD133 in C6 glioma cells. In addition, the mixed UCB-MSCs secrete more immune response-related proteins (IL-2 and IFN gamma) than the single UCB-MSCs. Combination of IL-2 and IFN-gamma was shown to have more cytotoxic effects than IL-2 alone and IFN-gamma alone. These results demonstrate that the mixed UCB-MSCs are a potential new therapeutic agent for glioma. PMID- 21535941 TI - Degenerative and inflammatory markers in the cerebrospinal fluid of multiple sclerosis patients with relapsing-remitting course of disease and after clinical isolated syndrome. AB - BACKGROUND: Literature includes evidence of initial predominance of inflammation and later development of neurodegeneration in the pathogenesis of multiple sclerosis (MS). OBJECTIVE: To search for differences in inflammatory and degenerative cerebrospinal fluid (CSF) markers between relapsing-remitting MS (RRMS) and the clinical isolated syndrome (CIS). METHODS: A total of 148 subjects were evaluated, 65 MS patients (45 RRMS and 20 CIS) and 83 controls. The evaluated parameters included albumin quotient and prealbumin, transferrin, C3 and C4 complement factors, haptoglobin, beta-2-microglobulin, orosomucoid, alpha 1-antitrypsin, apolipoprotein A-I, apolipoprotein B, cystatin C, neuron-specific enolase, tau protein, beta-amyloid, oligoclonal IgG band (OCB), and IgG quotient (QIgG). RESULTS: No differences were found in the inflammatory and degenerative CSF markers between patients with RRMS and CIS. QIgG was higher in RRMS than that in CIS but the number of OCB was higher after CIS. Cystatin C levels were significantly lower in RRMS compared to the other groups. It can be considered an indicator of the demyelination degree. Normal values of beta-amyloid were less frequent in RRMS compared to those in controls. PMID- 21535942 TI - Experimental subacute spinal cord compression: correlation of serial S100B and NSE serum measurements, histopathological changes, and outcome. AB - OBJECTIVE: To correlate serial measurements of serum S100B and neuron-specific enolase (NSE) with histopathological changes of the spinal cord and to assess their prognostic significance in a set-up of experimental spinal cord compression. METHODS: The thoracic cords of 22 rabbits were increasingly compressed and decompressed once paresis had developed. After decompression, outcome was rated as favorable or unfavorable. Following sacrifice of the animals, the cord was analyzed microscopically and morphometrically. Serum S100B and NSE were measured daily, and levels were correlated with initial degree of paresis, outcome after decompression, and histopathological changes of the cord. RESULTS: Regardless of the initial degree of paresis, animals with favorable outcome had significantly higher cell counts than animals with unfavorable outcome. The time course of S100B values following decompression was correlated with outcome. Animals with favorable outcome had either always normal levels or levels that were initially increased but normalized within 2 days. The values of animals with unfavorable outcome were elevated throughout (P<0.0001). No correlation was found between NSE levels and outcome. CONCLUSIONS: The initial degree of paresis is not a prognostic factor to predict outcome. Despite timely decompression, pronounced structural lesions of the cord may develop, resulting in an unfavorable outcome. In cases with favorable outcome, sufficient tissue is preserved to maintain function regardless of the initial extent of paresis. This different reaction of the cord may be followed indirectly with serial measurements of S100B serum levels. Thus, S100B is a reliable biochemical marker allowing for prediction of outcome. NSE does not have this prognostic significance. PMID- 21535943 TI - Comparisons of acoustic function in SCA31 and other forms of ataxias. AB - OBJECTIVE: To investigate whether acoustic impairment can be one of the characteristic extracerebellar symptoms in sporadic and hereditary ataxias including spinocerebellar ataxia type 31 (SCA31). METHODS: We investigated genotypes of dominant ataxia families, and determined a frequency of each form in our cohort of 154 families. Acoustic function in the groups of various forms of ataxia with multiple system atrophy of cerebellar predominance (MSA-C), cortical cerebellar atrophy (CCA), and hereditary ataxias including SCA31 was evaluated by using audiogram and brainstem auditory evoked potentials (BAEPs). RESULTS: Genetic analysis of dominant ataxia families revealed that a frequency of SCA31 in our cohort was fewer than that reported from other areas of Japan, indicating that SCA31 is not widely distributed throughout Japan. Results of audiogram showed no significant difference of hearing levels among ataxic groups, and those of BAEPs did not support inner ear dysfunction in SCA31 in which hearing loss had initially been suggested as one of its characteristic symptoms. CONCLUSION: This study suggests that acoustic impairment is neither specific to SCA31, MSA-C and CCA nor useful in making a differential diagnosis among them. PMID- 21535944 TI - Brain distribution and elimination of recombinant human TIMP-1 after cerebral ischemia and reperfusion in rats. AB - OBJECTIVE: To investigate recombinant human TIMP-1 ((125)I-rhTIMP-1) half-life in blood and its distribution in rat brain tissue after cerebral ischemia/reperfusion as part of a therapeutic development paradigm. METHOD: A suture model of the middle cerebral artery occlusion was used. (125)I-labeled rhTIMP-1 at 60 MUg/kg (11.23 MUCi/MUg) was administered to rats intravenously at the beginning of reperfusion. Blood and brain tissue were collected. The radioactivity was detected with a gamma counter and analyzed by autoradiography. RESULTS: The blood half-life T(1/2) of (125)I-rhTIMP-1 was 42.2 hours. Thirty minutes after (125)I-rhTIMP-1 administration, an increased accumulation of (125)I rhTIMP-1 in the ischemic hemisphere was observed. The maximum brain tissue concentration C(max) was 26.1 ng/g at 1.5 hours in the striatum and 13.9 ng/g at 5 hours in the cortex when the uptake percentage of brain tissue to blood was 6.1+/-0.4 and 6.7+/-2.1%, respectively. The cortex and striatum elimination half lives T(1/2) were 45.3 and 39.2 hours, respectively. Electrophoretic analysis of ischemic samples for (125)I-rhTIMP-1 showed a clear 28 kDa band 1.5 hours after (125)I-rhTIMP-1 administration in the cortex and striatum. The intensity of the 28 kDa band decreased after 3.0 hours of the administration. Some (125)I-rhTIMP-1 maintained its molecular integrity for 8.5 hours in ischemic striatum after reperfusion. DISCUSSION: (125)I-labeled rhTIMP-1 was distributed quickly into ischemic brain tissue and had a slow elimination in both blood and brain tissue. These results, along with other studies suggesting therapeutic benefits, will aid in the development of TIMP-1 for protecting ischemic stroke. PMID- 21535945 TI - Preliminary experience with the use of self-expanding stent as a thrombectomy device in ischemic stroke. AB - OBJECTIVES: Stent-based techniques may allow rapid arterial recanalization in acute stroke. We present our experience using a self-expanding stent to achieve transient bypass, and then as a thrombectomy device, with no permanent stent implantation, in acute stroke. MATERIAL AND METHODS: Six patients (mean age 55, range 35-71) presented with major ischemic stroke secondary to large vessel occlusion. Patients had a National Institutes of Health stroke scale score >17, no intracerebral hemorrhage or early infarction, and a poor collateral supply to the affected parenchyma. Within 6 hours of symptom onset, a stent (Solitaire; ev3 Inc., Irvine, CA, USA) was deployed across the entire occluded segment. Repeat angiogram was performed to evaluate the reconstituted flow. The balloon of the guide-catheter was inflated for proximal carotid occlusion. The partially deployed stent was slowly pulled back (mechanical thrombectomy step) under continuous aspiration. Suction was repeated to ensure the aspiration of any clot remnants. RESULTS: In all the cases, complete recanalization (Thrombolysis in Myocardial Infarction revascularization and reperfusion score of 3) was achieved in less than 60 minutes after femoral access, and a single thrombectomy attempt was sufficient to achieve clot removal. No stent was permanently implanted. Modified Rankin scores were 0-2 in all patients at a mean follow-up of 1 month. CONCLUSIONS: The presented approach allowed three desired effects: rapid endovascular revascularization, clot removal, and no need of leaving a permanent implant. In our preliminary experience this simple and rapid stent-based mechanical thrombectomy technique has had an unprecedented success rate. PMID- 21535946 TI - NR2B subunit blockade does not affect motor symptoms induced by 3-nitropropionic acid. AB - Broad-spectrum N-methyl D-aspartate (NMDA) antagonists, although proposed in therapies for several pathologies including Huntington's disease (HD), can produce dramatic side-effects. Thus, the therapeutic potential of subunit selective NMDA receptor antagonists warrants investigation. Overactivation of NMDA receptors containing the NR2B subunit plays a pathogenic role in HD, suggesting a neuroprotective potential of selective NR2B blockade. In the present study, we investigated whether the selective NR2B receptor antagonist, R-(R*,S*) alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol, could also affect motor symptoms in mice intoxicated with 3-nitropropionic acid (3-NP), a phenotypic model of HD. NR2B subunit acute blockade had no effect on spontaneous activity, HD-like symptoms (clinical scale), and sensorimotor performances (beam task) in 3-NP intoxicated mice. These results suggest that selective NR2B antagonism has no acute symptomatic effect on motor and sensorimotor impairments due to 3-NP-induced striatal injury. PMID- 21535947 TI - RE: Long-term safety of combined intracerebral delivery of free gadolinium and targeted chemotherapeutic agent PRX321 printing error. PMID- 21535948 TI - For tuberculosis elimination, Directly Observed Therapy, short course (DOTS) is essential but not sufficient. PMID- 21535949 TI - [To improve the awareness of coagulation factor inhibitors development in hemophilia patients]. PMID- 21535950 TI - [Genotype and phenotype analysis of congenital coagulator factor VII deficiency in four Chinese pedigrees]. AB - OBJECTIVE: To investigate the clinical manifestation and gene mutation in four Chinese pedigrees with the congenital coagulation factor VII deficiency. METHODS: Prothrombin time (PT), activated partial thromboplastin time, thrombin time and plasma fibrinogen were measured using STAGO STA-R automatic coagulation analyzer, and the coagulation activity of factor VII (FVII:C) was determined by a PT-based one stage method, and factor VII antigen (FVII:Ag) level by a sandwich enzyme linked immunoabsorbsent assay. All exons, exon-intron boundaries and 3',5'untranslated regions of the FVII gene from the genomic DNA of the probands and their families were amplified by PCR, and then sequenced. RESULTS: PT was significantly prolonged, and FVII:C and FVII:Ag were decreased and the following mutations were identified in the four probands: a homozygous transversion of 18041 T->G resulting in His408->Gln substitution in exon 8 in proband 1, a homozygous double nucleotide deletion, del CT (5078 - 5079) in exon 1 in proband 2, a double heterozygous of IVS6-1G->A and Gln426->stop in proband 3, and a double heterozygous of IVS6-1G->A and Arg364Gln in prohand 4. CONCLUSION: Two missense mutations, His408Gln, Arg364Gln and one nonsense, Gln426stop in the catalytic domain of FVII and one double nucleotide deletion, del CT (5078 - 5079) in exon 1 and one splicesome mutation, IVS6-1G->A in intron 6 were separately identified in four Chinese pedigrees with inherited coagulation factor VII deficiency. The Gln426stop and IVS6-1G->A were first identified in the world and the homozygous del CT (5078 - 5079) and His408Gln were first found in China. PMID- 21535951 TI - [Analysis of phenotype and genotype in three Chinese pedigrees with inherited dysfibrinogenemia]. AB - OBJECTIVE: To analyze the phenotype and genotype in three Chinese pedigrees with inherited dysfibrinogenemia. METHODS: Laboratory tests including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), reptilase time (RT), and the activities of antithrombin (AT:C), protein C (PC:C) and protein S(PS:C) were detected in three pedigrees. The activity and antigen of plasma fibrinogen (Fg) were analyzed by Clauss and immunoturbidimetry methods, respectively. The Fg of three probands was assessed by Western blot and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The sequences of all the exons and exon-intron boundaries of the three Fg genes FGA, GFB and FGG were amplified by PCR and analyzed by direct sequencing. RESULTS: Three probands had normal APTT, PT, PC:C, PS:C and AT:C, but prolonged TT and RT. The activity levels of the 3 probands's plasma Fg were reduced, but antigen levels were normal. Western blot and SDS-PAGE showed no abnormal molecular weight of Fg. The 3 heterozygous mutations of gamma Arg275His, Aalpha Pro18Leu and Aalpha Arg16Cys were identified in the 3 probands, respectively. CONCLUSION: The three probands with dysfibrinogenemia were caused by the mutations of gamma Arg275His, Aalpha Pro18Leu and Aalpha Arg16Cys, respectively. Both Aalpha Pro18Leu and Aalpha Arg16Cys were first reported in Chinese population. PMID- 21535952 TI - [Two novel mutations in one pedigree with hereditary Factor VII deficiency]. AB - OBJECTIVE: To explore the mutations of coagulation factor VII (FVII) gene in one pedigree with hereditary FVII deficiency, and to investigate the molecular mechanisms of FVII deficiency. METHODS: FVII gene mutations were analysed in the pedigree by direct DNA sequencing. The mutated DNA fragments were cloned into pMD19-T simple TA vector, and sequenced to confirm their distribution on chromosome. The plasma activity of FVII of the probands and their family members was detected with coagulation assay. The antigen of FVII were identified with ELISA. RESULTS: Three gene mutations were detected in the pedigree: A/G to C at 15386 resulting in Arg353Pro/Gln353Pro, A to T at 15274 resulting in Lys316Stop, all three mutations were heterozygotes. Three kinds of polymorphisms were identified in his father: A to G transition at position 15386 resulting in Arg353Gln, heterozygotic deletion of 2050 - 2059 cctatatcct in promoter and G to A mutation in intron 1a, the same polymorphisms were found in his grandfather. The three polymorphisms were located in the same chromosome of his father. CONCLUSION: Two mutations were found in the pedigree with hereditary FVII deficiency. One is nonsense mutation (Lys316Stop), the other is missense one (Gln353Pro). Gln353Pro and Lys316Stop might be the molecular mechanisms of FVII deficiency. The two novel mutations were reported for the first time in the literature. PMID- 21535953 TI - [Clinical study of standard dose of rituximab for the treatment of refractory primary immune thrombocytopenia]. AB - OBJECTIVE: To evaluate the efficacy and safety of rituximab on B-lymphocytes and anti-platelet glycoprotein-specific antibodies in patients with refractory primary immune thrombocytopenic (ITP). METHODS: Thirty-one ITP patients with a median age of 36 years (range 16 - 56 years) received solely intravenous rituximab at the dose of 375 mg/m(2) once weekly for consecutive 4 weeks. Lab studies included complete blood count, serum concentrations of IgG, IgM and IgA. CD3(+), CD4(+), CD8(+), CD19(+) and CD20(+) cell numbers were assayed by flow cytometry and anti-platelet glycoprotein-specific antibodies (GPIIb/IIIa, GPIb/IX) were assayed by monoclonal antibody-specific immobilisation of platelet antigens (MAIPA) prior to and following rituximab therapy. The response was evaluated according to the response criteria of international working group of ITP. RESULTS: Complete responses were achieved in 12 cases, response in 7 cases, and no response in 12 cases. Responses were sustained 2 to 28 months (median 6 months) with 4 cases relapsed. After 4 weeks of rituximab therapy, GPIIb/IIIa and GPIb/IX disappeared in responded patients, and CD 19(+)/CD20(+) cells were almost depleted in all patients. As expected, the serum concentrations of IgG, IgM, IgA, and the T cell counts were not changed after therapy. Four patients developed infusion-related reaction, 1 impaired renal function, and 3 secondary infections. CONCLUSION: Rituximab is effective and safe, and the adverse reaction is tolerable. PMID- 21535954 TI - [Relationship between factor VIII inhibitor development and polymorphisms of TNFalpha and CTLA-4 gene in Chinese Han patients with hemophilia A]. AB - OBJECTIVE: To investigate the potential association between factor VIII inhibitor development and polymorphisms of tumor necrosis factor-alpha (TNF-alpha)-308 and cytotoxic T-lymphocyte associated protein-4 gene in Chinese Han patients with hemophilia A (HA). METHODS: The single base change polymorphism in TNF-alpha and CTLA-4 gene was analyzed in 140 Chinese Han patients with hemophilia A who have been treated with plasma-derived FVIII concentrates and 108 normal controls by using PCR-restrictive fragment length polymorphism (RFLP). All of the HA patients' plasma samples were measured by modified-Nijmegen assay simultaneously. RESULTS: In HA patients, G/G genotype, G/A genotype and A/A genotype were detected in 118 (84.3%), 18 (12.8%) and 4 cases (2.9%) respectively; C/C genotype, C/T genotype and T/T genotype were detected in 108 (77.2%), 30 (21.4%) and 2 cases (1.4%) respectively. The difference in the genotype frequencies between HA patients and controls was nonsignificant (P > 0.05). Patients who were carriers of homozygotes for A allele had a higher risk of inhibitor development compared with those who were not (OR = 7.519, 95% CI = 3.168 - 17.844). Severe HA patients who were carriers of homozygotes for A allele had a higher risk of inhibitor development compared with those who were not (OR = 8.163, 95% CI = 2.521 - 26.434). There was no statistical difference in the risk of inhibitor development between the patients who were carriers or not (OR = 1.586, 95% CI = 0.729 - 3.450). CONCLUSION: TNF-alpha-308 gene polymorphism is significantly associated with inhibitor development in Chinese Han patients with severe hemophilia A. TNF-alpha gene may be a useful marker and potential modulator of the immune response to replacement therapy for hemophilia A patients. PMID- 21535955 TI - [Clinical and laboratory characteristics of hematological diseases associated with eosinophilia]. AB - OBJECTIVE: To analyze the clinical and laboratory characteristics of hematological diseases associated with eosinophilia. METHODS: Karyotype analysis was performed by direct method and/or short-time culture of bone marrow cells for R-banding. Fluorescence in situ hybridization (FISH) was performed using PDGFRalpha, PDGFRbeta and FGFR1 break-apart probes. RESULTS: The clinical and hematological findings of 44 patients were diagnosed as hematological diseases associated with eosinophilia. Abnormal karyotypes were detected in 6 cases (13.64%) with karyotyping. The efficiency of the detection of abnormal clone was markedly increased to 29.55% (13/44) with FISH techniques, including 7 cases with FIP1L1-PDGFRalpha (F/P, 15.91%), 3(6.82%) PDGFRalpha rearrangement, 2 (4.55%) aberrant PDGFRbeta gene and 1(2.27%) FGFR1 rearrangement. Patients being PDGFRalpha, PDGFRbeta or FGFR1 positive (13 cases) or negative (31 cases) showed predominant difference in clinical and laboratory features. The incidence of gut involvement, the absolute count of eosinophils in peripheral blood and the percentage of immature eosinophils in bone marrow were significantly increased in positive patients (P < 0.05). CONCLUSIONS: The hematological diseases associated with eosinophilia are characterized by unique clinical and laboratory features. Karyotyping should be a routine approach to detect the abnormal clone in these diseases. Screening for PDGFRalpha, PDGFRbeta and FGFR1 gene with FISH can provide more genetic information. PMID- 21535956 TI - [Association of miRNAs expression profiles with prognosis and relapse in childhood acute lymphoblastic leukemia]. AB - OBJECTIVE: To screen childhood ALL related microRNAs (miRNAs), analyze association of miRNAs expression profiles with prognosis and relapse in childhood acute lymphoblastic leukemia (ALL) and explore new indicator for predicting relapse and prognosis. METHODS: miRNAs expression profile was analyzed by gene chip in 49 newly diagnosed childhood ALL and 12 primary immune thrombocytopenia (ITP) cases (as control group). Abnormal expression of miRNAs was verified by qRT PCR. The correlation of miRNAs expression pattern with indicators predicting early prednisone response and relapse within a year was analyzed. RESULTS: Specific expression of miRNAs profiles associated with prednisone response and early relapse in childhood ALL was identified. Eight miRNAs (miR-18a, miR-532, miR-218, miR-625, miR-193a, miR-638, miR-550 and miR-633) could distinguish prednisone sensitive from insensitive. The early relapse of newly diagnosed patients with either high-risk or non-high-risk clinical types had some characteristics of abnormal expression of miRNAs, including miR-7, miR-216 and let-7i upregulated, while miR-486, miR-191, miR-150, miR-487 and miR-342 downregulated. CONCLUSIONS: The initial screening reveals miRNAs differentially expressed from normal in ALL suggesting the potential roles of them in leukemogenesis. MiRNAs expression signatures may be useful for predicting prognosis and relapse in childhood ALL and directing personalized treatment. PMID- 21535957 TI - [Effect of proteasome inhibitor bortezomib on proliferation, apoptosis and XIAP expression in K562 cells]. AB - OBJECTIVE: To investigate the effect of proteasome inhibitor bortezomib on proliferation, apoptosis of K562 cells and the expression of XIAP. METHODS: K562 cells were treated with bortezomib at different concentration. Cell proliferation was analyzed by WST-1 assay, cell apoptosis by flow cytometry and TUNEL, XIAP mRNA expression from 5 - 100 nmol/L by RT-PCR, and XIAP protein expression by SP immunohistochemistry. RESULTS: K562 cells were treated with bortezomib at different concentrations for 24 h respectively, the cells growth was significantly inhibited with inhibition rates from (13. 6 +/- 0. 2)% to (81. 4 +/ 0. 1)%, respectively, being markedly higher than that of control (1. 2 +/- 0. 1)% (P < 0.05). IC(50) was 24. 6 nmol/L of bortezomib treated for 24 h. When K562 cells were treated with 30 nmol/L of bortezomib for 12 - 48 h, the inhibition rates were (29. 1 +/- 0. 9)% to (59. 8 +/- 1. 2)%, respectively, the differences being statistically significant (P < 0.05) between 12 h group and 24 h group, while there was no statistical difference between 24 h, 36 h and 48 h groups. K562 cells treated with 30 nmol/L bortezomib for 24 h showed nuclear condensation, nuclear margination, nuclear fragmentation, cytoplasmic vacuoles and a large number of apoptotic body formation. The apoptotic cells rate was 83. 67% in bortezomib treated group, and 2. 33% in untreated group (P < 0.05). The expression of XIAP mRNA was decreased in a dose-dependent manner, and the expression of its protein was down-regulated. CONCLUSION: Bortezomib can inhibit the proliferation of K562 cells, and induce apoptosis by down-regulating the expression of XIAP, providing the laboratory evidence for the targeted therapy in acute leukemia. PMID- 21535958 TI - [Study on activated protein C resistance and disordered coagulation in patients with myeloproliferative neoplasms]. AB - OBJECTIVE: To study the correlation of activated protein C (APC) resistance, coagulation factors and inhibitors abnormality and JAK2V617F mutation burden in patients with myeloproliferative neoplasms (MPN). METHODS: The APC resistance was defined as the ratio of activated partial thromboplastin time (APTT) in the presence and absence of APC, i.e. APC sensitivity ratio (APCsr). Plasma protein C (PC), protein S (PS), prothrombin (FII), factor V (FV), factor VIII levels and CD11b expression on neutrophils were measured. The percentage of mutated JAK2V617F allele (V617F%) was evaluated by real time polymerase chain reaction (qRT-PCR). RESULTS: Expression of CD11b on neutrophils was significantly elevated in MPN patients compared with that of the control group. APCsr, PS and FV levels were reduced in patients with MPN. The APCsr level was decreased mainly in patients with thrombosis and JAK2V617F mutant burden higher than 75%. APCsr was not only positively correlated with PS levels but also inversely correlated with JAK2V617F allele burden in JAK2V617F mutant gene carriers. CONCLUSION: The neutrophil was activated and PS, FV level were reduced in MPN patients. The APCsr level was decreased and the occurrence of relatively acquired APC resistance was found in MPN patients with thrombosis. The APCsr is correlated with the PS level and JAK2V617F mutational furden. PMID- 21535959 TI - [Effect of hyperfibrinogenemia on coagulation time]. PMID- 21535960 TI - [Clinical and laboratory characteristics of a pedigree with May-Hegglin anomaly]. PMID- 21535961 TI - [Effect of daunorubicin and rapamycin combination on the proliferation of acute leukemia cells]. PMID- 21535962 TI - [Relationship between chronic primary immune thrombocytopenia and Helicobacter pylori (HP) infection, and eradication therapy and clinical symptom of HP]. PMID- 21535963 TI - [Investigation on the strategy of the diagnosis and treatment of primary immune thrombocytopenia in hematological doctor in our country]. PMID- 21535964 TI - [Analysis of clinical characteristics of 34 IgD-type multiple myeloma patients]. PMID- 21535965 TI - [Simplification of modified monoclonal antibody immobilization of platelet antigen assay (MAIPA) and its clinical significance]. PMID- 21535966 TI - [Progress in diagnosis and treatment of ALK positive anaplastic large cell lymphoma]. PMID- 21535967 TI - [Successful treatment of an acquired hemophilia A patient with rituximab]. PMID- 21535968 TI - [Consensus of Chinese experts on diagnosis and treatment of hemophilia]. PMID- 21535969 TI - [Consensus of Chinese experts on diagnosis and treatment of adult primary immune thrombocytopenia]. PMID- 21535971 TI - [Damage control-resuscitation and damage control-surgery]. PMID- 21535970 TI - Hysterectomy, endometrial ablation and Mirena(r) for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis. AB - OBJECTIVE: The aim of this project was to determine the clinical effectiveness and cost-effectiveness of hysterectomy, first- and second-generation endometrial ablation (EA), and Mirena(r) (Bayer Healthcare Pharmaceuticals, Pittsburgh, PA, USA) for the treatment of heavy menstrual bleeding. DESIGN: Individual patient data (IPD) meta-analysis of existing randomised controlled trials to determine the short- to medium-term effects of hysterectomy, EA and Mirena. A population based retrospective cohort study based on record linkage to investigate the long term effects of ablative techniques and hysterectomy in terms of failure rates and complications. Cost-effectiveness analysis of hysterectomy versus first- and second-generation ablative techniques and Mirena. SETTING: Data from women treated for heavy menstrual bleeding were obtained from national and international trials. Scottish national data were obtained from the Scottish Information Services Division. PARTICIPANTS: Women who were undergoing treatment for heavy menstrual bleeding were included. INTERVENTIONS: Hysterectomy, first- and second-generation EA, and Mirena. MAIN OUTCOME MEASURES: Satisfaction, recurrence of symptoms, further surgery and costs. RESULTS: Data from randomised trials indicated that at 12 months more women were dissatisfied with first generation EA than hysterectomy [odds ratio (OR): 2.46, 95% confidence interval (CI) 1.54 to 3.93; p = 0.0002), but hospital stay [WMD (weighted mean difference) 3.0 days, 95% CI 2.9 to 3.1 days; p < 0.00001] and time to resumption of normal activities (WMD 5.2 days, 95% CI 4.7 to 5.7 days; p < 0.00001) were longer for hysterectomy. Unsatisfactory outcomes associated with first- and second generation techniques were comparable [12.2% (123/1006) vs 10.6% (110/1034); OR 1.20, 95% CI 0.88 to 1.62; p = 0.2). Rates of dissatisfaction with Mirena and second-generation EA were similar [18.1% (17/94) vs 22.5% (23/102); OR 0.76, 95% CI 0.38 to 1.53; p = 0.4]. Indirect estimates suggested that hysterectomy was also preferable to second-generation EA (OR 2.32, 95% CI 1.27 to 4.24; p = 0.006) in terms of patient dissatisfaction. The evidence to suggest that hysterectomy is preferable to Mirena was weaker (OR 2.22, 95% CI 0.94 to 5.29; p = 0.07). In women treated by EA or hysterectomy and followed up for a median [interquartile range (IQR)] duration of 6.2 (2.7-10.8) and 11.6 (7.9-14.8) years, respectively, 962/11,299 (8.5%) women originally treated by EA underwent further gynaecological surgery. While the risk of adnexal surgery was similar in both groups [adjusted hazards ratio 0.80 (95% CI 0.56 to 1.15)], women who had undergone ablation were less likely to need pelvic floor repair [adjusted hazards ratio 0.62 (95% CI 0.50 to 0.77)] and tension-free vaginal tape surgery for stress urinary incontinence [adjusted hazards ratio 0.55 (95% CI 0.41 to 0.74)]. Abdominal hysterectomy led to a lower chance of pelvic floor repair surgery [hazards ratio 0.54 (95% CI 0.45 to 0.64)] than vaginal hysterectomy. The incidence of endometrial cancer following EA was 0.02%. Hysterectomy was the most cost-effective treatment. It dominated first-generation EA and, although more expensive, produced more quality adjusted life-years (QALYs) than second-generation EA and Mirena. The incremental cost-effectiveness ratios for hysterectomy compared with Mirena and hysterectomy compared with second-generation ablation were L1440 per additional QALY and L970 per additional QALY, respectively. CONCLUSIONS: Despite longer hospital stay and time to resumption of normal activities, more women were satisfied after hysterectomy than after EA. The few data available suggest that Mirena is potentially cheaper and more effective than first-generation ablation techniques, with rates of satisfaction that are similar to second-generation techniques. Owing to a paucity of trials, there is limited evidence to suggest that hysterectomy is preferable to Mirena. The risk of pelvic floor surgery is higher in women treated by hysterectomy than by ablation. Although the most cost effective strategy, hysterectomy may not be considered an initial option owing to its invasive nature and higher risk of complications. Future research should focus on evaluation of the clinical effectivesness and cost-effectiveness of the best second-generation EA technique under local anaesthetic versus Mirena and types of hysterectomy such as laparoscopic supracervical hysterectomy versus conventional hysterectomy and second-generation EA. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 21535972 TI - [Prehospital treatment of severely injured patients with focus on damage control surgery]. AB - The majority of patients undergoing damage control surgery initially receive prehospital treatment. Bleeding causes 40% of trauma deaths, half of which happen in the prehospital setting. Future research and improved treatment before hospital admission should focus on control of the bleeding, avoidance of hypothermia, minimising the time to definitive surgery, and a restrictive and goal directed therapy with regard to the intake of fluids. On occasion, lifesaving procedures could be performed during transport to the hospital. PMID- 21535973 TI - [Aspects of imaging modalities in relation to damage control surgery]. AB - The imaging modalities computed tomography (CT) and the ultrasonography (US) examination focused assessment with sonography for trauma (FAST) in relation to damage control in traumas are discussed. CT has the advantage of high sensitivity and specificity for detection of organ specific lesions. FAST ultrasound is a good screening tool for intraperitoneal bleeding, but the sensitivity and specificity is lower than by CT. We recommend FAST-US prehospitally or early in the trauma room resuscitation. Haemodynamically stable patients with relevant traumas should undergo CT. PMID- 21535974 TI - [Resuscitation and abdominal surgical aspects of damage control surgery]. AB - In multitrauma patients continuous bleeding is one of the major killers. Coagulation defects have been shown to be a primary event and to occur very early in multitrauma patients (acute traumatic coagulopathy). It is enhanced by acidosis, hypothermia and further coagulation disorders in the "bloody vicious cycle". Due to this a new resuscitation practice has been defined; damage control resuscitation, consisting of hypotensive resuscitation (restricted use of crystalloids), haemostatic resuscitation (balanced use of blood components) in combination with surgical haemostatic procedures (damage control surgery). PMID- 21535975 TI - [Orthopedic surgical aspects of damage control surgery]. AB - Damage control orthopedics (DCO) is a concept for treatment of fractures in severely injured patients. The fractures are stabilized with external fixators instead of primary definitive osteosynthesis, known as early total care (ETC). The purpose of DCO is to minimize time of surgery and bleeding and thereby minimize the "second hit". Not all patients require DCO, patients with stable vital functions can safely be treated with primary definitive osteosynthesis, DCO is, however, a safe method that can be used, when shorter time of surgery is desirable or a systemic immune response is imminent. PMID- 21535976 TI - [Anaesthesiological considerations in damage control surgery]. AB - Patients with severe traumatic injuries occasionally undergo damage control surgery. This paper highlights some of the perioperative anaesthesiological considerations. Although damage control is often used as a surgical term, it is crucial that personnel involved in the parallel resuscitation of the patient have a common understanding of the challenges that are usually present during damage control surgery. PMID- 21535977 TI - [24 hours at Johannesburg Hospital Trauma Unit]. AB - This paper describes the hectic work as a doctor at the Trauma Unit of Charlotte Maxeke Johannesburg Academic Hospital, a highly regarded and well-visited trauma unit worldwide. A trauma junior doctor is followed on a 24-hour-call through a full casualty to urgent operations and complicated postoperative management of the trauma patient. In a diary fashion the paper describes the evidence-based guidelines of management of certain trauma cases brought into the trauma unit during the 24-hour-shift. PMID- 21535978 TI - [Hyperfibrinolysis as the cause of haemorrhage and increased mortality in trauma patients]. AB - Trauma-associated coagulopathies are at times present upon arrival at the emergency department. Hyperfibrinolysis is a condition in which the natural ability to dissolve blood clots is pathologically enhanced. It is present in 2-8% of trauma patients and associated with shock and increased mortality. Hyperfibrinolysis is easily detected by thromboelastography. The condition is treated with antifibrinolytics such as tranexamic acid--whereas transfusion with blood products is inefficient. This article explores the mechanisms and diagnostics of hyperfibrinolysis in trauma patients and the relevant treatment options. PMID- 21535979 TI - [Functional haemostatic tests are fast and reliable by transfusion demanding bleeding]. AB - Viscoelastic haemostatic tests (VHT) like thrombelastography (TEG) and rotationel thrombelastometry (ROTEM) are cell-based whole blood assays, which assess the viscoelastic properties of coagulation. The focus of this narrative review is to describe the TEG/ROTEM methodology and interpretation of the TEG/ROTEM results. Current clinical applications and limitations are also discussed. It is concluded that VHT are inexpensive point of care assays that allow quick assessment of the haemostatic function and thereby allow faster and more focused interventions than traditional coagulation tests do. PMID- 21535980 TI - [Damage control surgery--a survey of a Cochrane review]. AB - Damage Control Surgery (DCS) has been the approach in dealing with multi-trauma patients for the last 15 years. In this Cochrane-review the authors seek to compare the outcome of DCS with the outcome after the conventional strategy which is often a time-consuming operation with definitive repair. However, no randomised controlled trials are found, and thus it is not possible to say whether DCS is superior to the conventional approach or not. It is not possible to perform any RCT with these patients. According to literature in general on this subject we believe, nevertheless, that the principles in DCS should be followed. PMID- 21535981 TI - Physicians' evaluation of clinical pharmacy revealed increased focus on quality improvement and cost savings. AB - INTRODUCTION: The aims of the present study were to evaluate physicians' satisfaction with medication services delivered by a clinical pharmacist (CP); to investigate and document to which extent a CP could improve the medication quality and reduce medication costs at an intensive care unit (ICU); and to explore which types of tasks the CP was asked to perform. MATERIAL AND METHODS: The project was conducted at an ICU from 1 February to 31 August 2008. The intervention consisted of certain tasks being performed by a CP. The intervention was evaluated on the basis of documentation of the intervention performed and on a questionnaire filled in by physicians at the end of the study. RESULTS: The majority of the physicians reported that the CP's intervention had raised their attention to medication costs (70%) and medication quality (76%). This physician reported impression correlated with the CP's intervention which improved medication quality and catalysed an annual estimated cost saving of at least DKK 330,000, which was achieved by targeting particular medication areas. The CP was asked to perform various medication-related tasks during the project period. Indeed, the physicians reported that they found the CP qualified to perform several medication-related tasks--and many physicians reported that they had benefitted from input regarding those tasks. CONCLUSION: The intervention occasioned positive physician feedback on clinical pharmacy services and the study shows that the CP was perceived by the physicians as a valuable professional collaborator. PMID- 21535982 TI - The influence of family structure on breakfast habits among adolescents. AB - INTRODUCTION: Regular breakfast habits are important for the health and well being of young people. The family is an important setting for developing regular breakfast habits. The objectives of the present study are to study the association between family structure and the regularity of breakfast habits among children and adolescents, and to analyse whether such potential association is modified by gender. MATERIAL AND METHODS: Data are from the Danish contribution to the international study entitled Health Behaviour in School aged Children, 2006. Participants are school children aged 11, 13 and 15 drawn from a random sample of Danish schools. The response rate was 88.8%, n = 6,269. Family structure was categorized into traditional family, single-parent family and reconstructed family. Irregular breakfast habits (IBH) were defined as having breakfast 0-1 times per week. RESULTS: Analyses of the total population show an increased, significant odds ratio (OR) of 1.56 for IBH among children from single parent families. Among children from reconstructed families, an insignificant OR of 1.27 was observed. Further, the results suggest that girls living in a reconstructed family may also have an increased risk of IBH. CONCLUSION: The breakfast habits of adolescent boys and girls are influenced by family structure. PMID- 21535983 TI - Good results in patients with defects after intraoral tumour excision using facial artery musculo-mucosal flap. AB - INTRODUCTION: The purpose of this article was to assess our experience with the facial artery musculomucosal (FAMM) flap technique for reconstruction of the oral cavity after tumour ablation. We also introduce new surgical developments for this technique. MATERIAL AND METHODS: We retrospectively examined 22 cases involving FAMM flap surgery during the period from July 2007 to December 2009, focusing on postoperative complications and flap survival. We describe a new method for closing the donor defect using the buccal fat pad, as well as a method for harvesting a broader flap than is traditionally described. RESULTS: Among the 22 cases studies, seven (32%) experienced postoperative complications. However, 57% of these cases had undergone preoperative radiotherapy. The complications we observed included problems relating to integration, partial necrosis and bleeding. There were no reported complications relating to the donor site. CONCLUSION: The FAMM flap is a suitable technique for reconstruction following tumour ablation. Our study also suggests that while preoperative radiotherapy is a contraindication for this treatment, neck dissection surgery is not. PMID- 21535984 TI - Aetiology, treatment and mortality after oesophageal perforation in Denmark. AB - INTRODUCTION: Perforation of the oesophagus into the thoracic cavity is a potentially life-threatening condition. The causes are numerous. Treatment for oesophageal perforation targets mediastinal and pleural contamination. Present knowledge about the causes of perforation and the types of treatment is poor. MATERIAL AND METHODS: A retrospective review was made between 1997 and 2005 based on extracts from the National Patient Registry. RESULTS: A total of 286 patients were diagnosed with perforation of the oesophagus (131 women and 155 men). Their average age was 60 years. A wide spectrum of causes was reported, e.g. instrumentation of the oesophagus 136 (47.6%), spontaneous rupture 89 (31.1%) or procedures otherwise related to surgical intervention 9 (3.1%). One third of the patients started conservative treatment 91 (31.9%). The majority of the patients were transferred to a thoracic surgery department for further treatment: about 25% of patients underwent surgery. The average hospitalization time was 18 days. The mortality rate was 21%. CONCLUSION: Oesophageal perforation remains a diagnostic and therapeutic challenge and the condition requires aggressive treatment. Recent consensus in early treatment with thoracotomy, debridement, irrigation and subsequent parenteral nutrition has improved survival. In this material, most perforations were iatrogenic in nature. In the 2002-2005 period, the study showed that 29% of the iatrogenic perforations were caused by the use of a rigid endoscope which is risky and whose use should therefore be restricted. It is advisable to set up national guidelines for treatment of oesophageal perforation and to centralise treatment. PMID- 21535985 TI - Status and trends in poisonings in Denmark 2007-2009. AB - INTRODUCTION: The Danish Poison Information Centre (DPIC) provides information to the public and health care professionals on acute poisonings. The DPIC received 41,000 enquiries during the first three years of its existence as an open 24h telephone service. The aim of this data register study was to classify all substance exposures, to gain knowledge of the status and trends in poisonings (toxico-surveillance) and to evaluate the development in the number of contacts. MATERIAL AND METHODS: Information and inquiries were continuously entered into a poison-centre database. A new classification system was established during the study to ensure that all agents were properly classified. A total of 41,139 calls were divided into 18 substance categories, each consisting of 3-11 subgroups. RESULTS: The number of contacts per year increased by 70% from 2007 to 2009. Three contacts per thousand individuals in the Danish population were registered in 2009. For all groups, except drugs of abuse, the data showed an increase in the actual number of exposures from 2008 to 2009. Pharmaceuticals represent one third of substance exposures, and analgesics constitute a third of these poisonings. A relative increase in contacts concerning household substances, plants and vitamins was observed. CONCLUSION: The classification gave detailed knowledge of the current poisoning status. Evaluation of subgroups showed a need for a larger number of subgroups to ensure a sufficient level of toxico surveillance. Compared to other national poison centres, we predict a doubling in enquiries during the next ten years, mainly from the public. PMID- 21535986 TI - High mortality after emergency room laparotomy in haemodynamically unstable trauma patients. AB - INTRODUCTION: Hypovolaemic shock is a major course of death in trauma patients. The mortality in patients in profound shock at the time of arrival is extremely high and we wanted to investigate the outcome of patients undergoing laparotomy at the Trauma Care Unit (TCU). MATERIAL AND METHODS: Forty-four emergency laparotomies performed at the TCU at Rigshospitalet between January 2003 and December 2009 were registered. The indication for surgical intervention was based on persisting, unstable haemodynamics and either positive findings at focused abdominal sonography in trauma (FAST) or penetrating injury. In some patients, laparotomy was performed despite a negative FAST because of ongoing instability. The patients were stratified according to their systolic blood pressure (BP). RESULTS: After 24 hours, 46% (20 patients) of the patients were alive. The survival after 30 days was 41% (18 patients). Stratifying the patients into three categories according to the systolic BP at the time of arrival (BP > 80 mmHg (n = 14), 80 mmHg >= BP > 60 mmHg (n = 10) and BP <= 60 mmHg (n = 20) revealed a 64%, 50% and 34% survival rate within the first 24 hours (p = 0.04). In the group of patients with BP <= 60 mmHg, the survival decreased to 20% after 30 days. Stratification by penetrating or blunt trauma showed no significant difference in survival (40% versus 50% survival after 30 days) (p = 0.40). However, in those patients arriving with BP <= 60 mmHg (five penetrating and 15 blunt injuries), we found that the survival rate after laparotomy was 60% and 13%, respectively. CONCLUSION: The present study shows that haemodynamically unstable patients with abdominal or suspected abdominal injuries undergoing emergency laparotomy have a high mortality, especially those with BP <= 60 mmHg. Patients with a penetrating trauma have a far better prognosis than those with a blunt trauma. PMID- 21535987 TI - Tympanotomy and sealing of the round window for treatment of sudden deafness. AB - INTRODUCTION: The objective of this study was to evaluate the effectiveness of explorative tympanotomy and sealing of the round window in patients diagnosed with sudden deafness. MATERIAL AND METHODS: A retrospective study of 22 patients presenting with sudden deafness who were treated with exploratory tympanotomy and sealing of the round window. The patients initially received conservative therapy for one month. If conservative treatment had no effect, exploratory tympanotomy and sealing of the round window was performed. RESULTS: The median pure tone average was 67 dB before surgery. Post-operatively, it was reduced to 55 dB. This is equivalent to a 12 dB (p = 0.008) improvement. Five patients improved beyond 30 dB and three patients out of 22 fulfilled the Belfast criteria for binaural hearing at the end of the observation period. Furthermore, three months after surgery, the incidence of vertigo and tinnitus had decreased from 58% to 8% and from 50% to 17%, respectively (p < 0.001 and p = 0.04). None of the patients experienced any severe or life-threatening complications. CONCLUSION: The results suggest that explorative tympanotomy and sealing of the round window may improve hearing and reduce tinnitus and vertigo after spontaneous remission has come to an end. However, randomized controlled studies are needed. PMID- 21535988 TI - Clinical findings confirm national guidelines regarding primary gastroscopy for upper gastrointestinal symptoms. AB - INTRODUCTION: This study describes unsedated transnasal oesophagogastroduodenoscopy (UT-OGD) in the office setting. Evaluation of national guidelines regarding primary endoscopy for the investigation of upper gastrointestinal (GI) symptoms was also a focus of this study. MATERIAL AND METHODS: Retrospective registration of 2,000 cases regarding demographics, symptoms, pre-endoscopic treatment, feasibility and findings. RESULTS: The proportion of males was 42%. 19% of the patients were referred due to alarm symptoms. The transnasal feasibility was 97%. Endoscopic findings: No abnormal findings (NAF) 53%, hiatal hernia 25%, oesophagitis 11%, gastric inflammation 11%, ulcer 10%, cancer 1% and others 1%. Alarm symptoms (AS) versus non-alarm symptoms (NAS): 35% of patients with AS had NAF versus 58% in the NAS group (p < 0.001). Cancer was present in 4% of the cases in the AS group versus 0.1% in the NAS group (p < 0.001). < 45 years versus >= 45 years: 69% of patients < 45 years had NAF versus 45% of patients >= 45 years (p < 0.001). Cancer was present in 0% of the cases in those < 45 years versus 1.4% in those >= 45 years (p = 0.002). CONCLUSION: UT-OGD in private practice had a higher proportion of females than similar procedures performed in hospital settings. Feasibility was high. Endoscopic findings were comparable to those reported by other studies, except for a lower prevalence of oesophagitis. Age < 45 years and absence of alarm symptoms were strong negative predictors for the presence upper GI cancer. Our data thus seem to confirm the Danish guideline regarding primary endoscopy for the investigation of upper GI symptoms. PMID- 21535989 TI - Biological aspects of altered bone remodeling in multiple myeloma and possibilities of pharmacological intervention. AB - Multiple myeloma is a fatal B cell neoplasm often resulting in focal and in some cases more diffuse destruction of bone. The bone destruction is a result of increased activity of bone resorbing cells--multinucleated osteoclasts emerging through of multiple fusions. In multiple myeloma, clonally expanding cancer cells provide a stimulatory signal for osteoclast recruitment, differentiation and excessive bone resorption. The stimulatory actions of myeloma cells are believed to be mediated via the production of cytokines and local factors or by modulating bone microenvironment in order to stimulate osteoclastic bone resorption. However, our recent study revealed potentially a novel and more intimate contribution of myeloma cells to the bone destruction. Our analysis of the bone biopsies from myeloma patients showed fully integrated malignant nuclei inside osteoclasts, which were transcriptionally active. As a result, about 30% of the osteoclasts in the bone marrow biopsies from myeloma patients were in fact osteoclast-myeloma cell hybrids. As the functional relevance of this novel cell type remained uncertain, the aim of my PhD study became to 1) strengthen the evidence of the existence of hybrid cells, 2) elucidate the functional differences between hybrid cells and non-hybrid OCs and 3) relate these findings to the pathogenesis of osteolytic disease in multiple myeloma. To this end, I developed a culture model of osteoclast-myeloma cell fusion between (pre)osteoclasts already committed to fuse and myeloma cells selected for adherence. The model was applied for testing of the bone resorptive properties of hybrid cells identified by labelling with green fluorescence. When comparing the highly fluorescent and non-fluorescent OCs on bone slices, it seemed that the frequency of highly fluorescent osteoclasts actively resorbing bone was increased as compared with non-fluorescent osteoclasts. This was assessed in two independent ways. Furthermore, these fluorescent osteoclasts appear to resorb deeper compared to non-fluorescent osteoclasts. The preliminary data that need to be confirmed suggest that formation of hybrid cells by fusion of myeloma cells with osteoclasts may result in reprogramming of the osteoclasts and contribute to the more aggressive bone resorption by osteoclasts as it is typically seen in myeloma patients. Another aspect of multiple myeloma and associated bone disease is the unmet need for novel and more efficient therapeutic regiments. Resveratrol (trans-3, 4', 5-trihydroxystilbene; RSV) is a natural compound shown to target the key players of myeloma bone disease: bone resorbing osteoclasts, bone forming osteoblasts and myeloma cells. Our in vitro study on RSV showed that it possessed this ideal triad of properties appearing and thus might be of interest as a potential drug for the treatment of multiple myeloma. RSV suppresses the growth and survival of myeloma cells, inhibits osteoclasts and stimulates the formation of osteoblasts. However, the need for high concentrations combined with low biological availability after oral administration and risk of important side effects stimulated a search for RSV derivates with the same spectrum of actions but safer and with better bioavailability. As the other task of my PhD, I screened structurally modified RSV analogues in cultures of myeloma cells, osteoblasts and osteoclasts. Compared to resveratrol, some analogues showed an up to 5,000-times increased potency to inhibit osteoclast differentiation and could still promote osteoblast maturation but they did not antagonize myeloma cells. The potency of the best-performing candidate in vitro was tested in vivo in an ovariectomy-induced model of osteoporosis, but effect on bone loss could not be detected. During my PhD, I also participated in the studies of the effect of the proteasome inhibitor - bortezomib on osteoclasts conducted at the department. Based on its potent activity in multiple myeloma, bortezomib was accepted as a front-line treatment of myeloma patients by EMEA for the European Union. In our study we assessed the effect of bortezomib on osteoclasts in cultures under the conditions that mimic the pulse-treatment regime used for myeloma patients. The pulse administration of bortezomib significantly inhibited OC activity and, moreover, significantly but transiently reduced levels of two bone resorption markers measured in serum of treated myeloma patients. In MM the clonal expansion of malignant plasma cells results in the unbalanced bone remodelling, therefore it is essential to understand the molecular mechanisms governing the actions of osteoclasts and osteoblasts. During my PhD, I was involved in the investigations of mesenchymal stem cells over-expressing delta like protein - 1(Dlk-1) previously shown to inhibit the differentiation of mesenchymal stem cells (MSC) into osteoblasts. In results, the over-expression of Dlk-1 evoked pro inflammatory phenotype in MSC suggesting the involvement of Dlk-1 in the immune response. PMID- 21535990 TI - Upper and lower airway pathology in young children with allergic- and non allergic rhinitis. AB - Allergic- and non-allergic rhinitis are very common diseases in childhood in industrialized countries. Although these conditions are widely trivialized by both parents and physicians they induce a major impact on quality of life for the affected children and a substantial drainage of health care resources. Unfortunately, diagnostic specificity is hampered by nonspecific symptom history and lack of reliable diagnostic tests which may explain why the pathology behind such diagnoses is poorly understood. Improved understanding of the pathophysiology of allergic- and non-allergic rhinitis in young children may contribute to the discovery of new mechanisms involved in pathogenesis and help direct future research to develop correctly timed preventive measures as well as adequate monitoring and treatment of children with rhinitis. Asthma is a common comorbidity in subjects with allergic rhinitis and epidemiological surveys have suggested a close connection between upper and lower airway diseases expressed as the "united airways concept". Furthermore, an association between upper and lower airway diseases also seems to exist in non-atopic individuals. Nevertheless, the nature of this association is poorly understood and there is a paucity of data objectivizing this association in young children. The aim of this thesis was to describe pathology in the upper and lower airways in young children from the COPSAC birth cohort with investigator-diagnosed allergic- and non-allergic rhinitis. Nasal congestion is a key symptom in both allergic- and non-allergic rhinitis, and eosinophilic inflammation is a hallmark of the allergic diseases. In paper I, we studied nasal eosinophilia and nasal airway patency assessed by acoustic rhinometry in children with allergic rhinitis, non-allergic rhinitis and healthy controls. Allergic rhinitis was significantly associated with nasal eosinophilia and irreversible nasal airway obstruction suggesting chronic inflammation and structural remodeling of the nasal mucosa in children already at age 6 years. Non-allergic rhinitis exhibited no change in the nasal airway patency, but some nasal eosinophilia albeit less than children with allergic rhinitis. These findings suggest different pathology in allergic- and non allergic rhinitis which may have important clinical implications for early pharmacological treatment of rhinitis in young children. In paper II, we utilized the nasal airway patency end-points derived from paper I to examine whether upper and lower airway patency are associated. Upper airway patency was assessed by acoustic rhinometry before and after intranasal alpha-agonist and lower airway patency by spirometry before and after inhaled beta2-agonist. Upper and lower airway patencies were strongly associated and independent of body size, rhinitis and asthma. The association was consistent for both baseline values and for decongested nasal airway patency and post-beta2 FEV1. Blood and nasal eosinophilia were also associated with nasal airway obstruction. This suggests generalized diminished airway dimensions as a novel susceptibility factor for concurrent symptoms of asthma and rhinitis in early childhood and supports the notion of a common pathophysiology in asthma and rhinitis. The clinical interpretation of these findings is that all children presenting either rhinitis or asthma should be considered inflamed in the entire respiratory tract. In paper III, we aimed to describe asthma and intermediary asthma end-points associated with allergic- and non-allergic rhinitis in preschool-aged children. At age 7 years, we evaluated prevalence of asthma, eczema, food sensitization, and filaggrin mutations; levels of total IgE, FeNO, and blood-eosinophils; lung function and bronchial responsiveness to cold dry air. We found that asthma was similarly associated with allergic- and non-allergic rhinitis suggesting a link between upper and lower airway diseases beyond an allergy associated inflammation. Only children with allergic rhinitis had increased bronchial responsiveness and elevated FeNO suggesting different endotypes of asthma symptoms in young children with allergic- and non-allergic rhinitis. We also found bronchial hyperresponsiveness and raised values of FeNO in children with allergic rhinitis without asthma suggesting sub-clinical bronchial inflammation and supporting the allergic disease process to involve both upper and lower airways. In conclusion, these observations objectively show marked differences in nasal pathology in young children with allergic- and non-allergic rhinitis and lend support to a close connection between upper and lower airway diseases partly from an allergy driven process, but equally from non-allergic mechanisms. PMID- 21535991 TI - Evaluation of the superselective radioligand [123I]PE2I for imaging of the dopamine transporter in SPECT. AB - Imaging of the dopamine transporter (DAT) with Single Photon Emission Computer Tomography (SPECT) has increasingly been used as a biomarker for the integrity of presynaptic dopaminergic nerve cells in patients with movement disorders. 123-I labelled N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3beta-(4-methylphenyl) nortropane, named PE2I, is a relatively new radioligand that has about 10-fold higher in vitro selectivity for the DAT than for the serotonin transporter (SERT) compared to the slightly older but very used and licensed radioligand [123I]FP CIT (DaTSCAN). Further [123I]PE2I has faster kinetics than [123I]FP-CIT. Because of its fast kinetic properties, quantification of [123I]PE2I binding to DAT is possible using kinetic or graphical analysis following bolus injection of tracer or as a combination of bolus and constant infusion. Based on preliminary bolus trials we have been able to calculate a B/I ratio of [123I]PE2I. This B/I ratio (2.7h) gave rise to steady state conditions and excellent reproducibility. Further, manual delineation of ROI directly on SPECT images performed equally well to a MRI-defined probability map based ROI delineation in terms of intrasubject variability of binding potential of DAT. Finally the in vivo SERT binding in DAT images obtained with [123I]FP-CIT was significant as compared to the [123I]PE2I image. [123I]PE2I is a super selective SPECT DAT radioligand with optimal kinetic properties for accurate quantification of the DAT availability in striatum. Apart from the more laborious B/I design it is currently to be considered the best radioligand for imaging the DAT in the human brain with SPECT. PMID- 21535992 TI - Self-management of oral anticoagulation therapy--methodological and clinical aspects. AB - Oral anticoagulation therapy (OAT) with coumarins (vitamin K-antagonists) is prescribed for both prophylactic and therapeutic use to patients at increased risk of thromboembolism. OAT has a narrow therapeutic index, and monitoring is based on the International Normalized Ratio (INR) conventionally determined on citrated plasma obtained by venepuncture. Based on the INR measurements, health care providers determine the appropriate dose of coumarins (e.g. warfarin (Marevan). Optimised management of OAT improves the quality of treatment. Patient self-management (PSM) is a new concept where the patient takes an active part in his or her own treatment. PSM in OAT implies that the patient analyses a drop of blood using a portable coagulometer (INR-monitor). The coagulometer displays the INR, which the patient uses for coumarins dosage. It is still not clarified which subset of patients (in terms of indication for OAT, age, co-morbidity etc.) that potentially will benefit from PSM, and how large this potential effect is. A precondition for a correct dosage of coumarins is a correct estimation of the INR, and the method and apparatus used for providing the INR measurements is in this context essential. The coagulometers used for PSM have not been investigated adequately in terms of precision and agreement, so this is warranted. INR has proven adequate for adjusting dosages. It is doubtful that the level of INR reflects the overall haemostatic capacity or thrombotic potential of individual patients. Measurement of continuous calibrated automated thrombin generation (CAT) and coagulation factors activities may serve as a more sensitive and global haemostatic parameter and potentially with better performance in predicting risk of complications in patients on OAT. We found that the clotting activity of coagulation factors II, VII, IX, and X and CAT exhibited no variability over a 6 week period. The activity of the coagulation factors and CAT was significantly associated with the INR, so these two tests can be used concomitantly and/or interchangeably with the INR. Approximately 50% of the total variability of the coagulation factor activities and CAT was reflected by the INR, whereas the remaining variability was within the subject (patient). Coagulation factor activities and CAT can therefore potentially be used to provide further information to the risk of bleeding and thromboembolism, since almost 50% of the variability within the subject is not displayed in the INR value. Yet it remains uncertain if this method can predict complications in individual patients on OAT. Larger clinical trials with a longer follow-up period, preferably using clinical endpoints, are needed in order to draw any firm conclusions regarding the clinical consequences. However, measurement of coagulation factor activities and CAT may improve measurement of coagulation activity in patients prescribed OAT beyond the parameters currently clinically available. The CoaguChek S and XS coagulometers used for PSM were found to have an adequate precision. Regarding the accuracy, the INR measurements tended to be lower on the coagulometers, compared with the laboratory. A large proportion of the measurements on the coagulometers deviated more than 15% from the laboratory measurements. However, only one laboratory was used for comparison and the original WHO method (gold standard) for estimating INR was not used. Furthermore, the inherent limitations of the INR have to be taken into consideration, and the results have to be viewed in this context. The accuracy of the coagulometers seems in this respect acceptable and they can be used in a clinical setting. However, external quality control is essential. In the observational studies, it was found that PSM was feasible and provides satisfactory treatment quality for various indications and in a wide range of patient age. In a randomised controlled trial, using a documented blinded composite endpoint, PSM was found to provide a treatment quality that was at least as good as that provided by conventional management. Additionally it was found, that training and implementation of PSM lead to a smaller variance in INR measurements, a higher median INR and a higher dose of coumarins compared to that obtained for conventionally managed patients. Further evidence was provided in a systematic review and meta-analysis, where it was documented, that PSM appears at least as good as and possibly better than conventional management in highly selected patients. PMID- 21535993 TI - Strontium in the bone-implant interface. AB - Total hip replacement surgery is being performed on an increasingly large part of the population and at increasingly younger age. Because we live and stay physically active longer, and since hip replacement surgery has become quite successful, the treatment is being offered to progressively more patients. Unfortunately, about 17% of hip replacement surgeries currently involve revisions. Consequently, the longevity of both the primary and revision implant is an issue and warrants further investigation. Implants undergoing early instability or even subsidence correlate with an increased risk of aseptic loosening, subsequently requiring revision. Thus, the goal is early fixation by osseointegration of the implant. For revision implants, this is an even greater challenge since an allograft is often needed during surgery to obtain immediate stability of the implant. Bone grafts are rapidly resorbed. Thus, instability of the prosthesis may develop before new bone formation is well established and can mechanically secure the prosthesis. Strontium is a dual action drug; being both bone anabolic and anti-catabolic. In the form of strontiumranelate, it is used in the treatment of osteoporosis. Strontium may potentially improve the early osseointegration and fixation of implants. This dissertation consists of three studies investigating the effect of strontium at the bone-implant interface. The questions were firstly, what is the optimal delivery method for strontium to the interface, and secondly, can strontium exercise its dual action at the interface? The studies were performed in a cementless, experimental gap model in canine. The effects of strontium were evaluated by histomorphometrical analysis of the osseointegration and mechanical push-out test of implant fixation. Different stereological methods were used for the histomorphometrical analysis of each study. The methods used were reviewed critically and found valid. Study I compared a 5% strontium-substituted hydroxyapatite (HA) coating with an HA coating after 4 weeks and 12 weeks observation time. We examined whether fixation of the implant was improved by the strontium substitution. It was found that fixation of the implant was not improved by the strontium substituted HA coating at any of the two time points. Study II compared a 5% strontium-doped HA bone graft extender with an HA bone graft extender. The bone graft extender was mixed with allograft and impacted around a titanium implant. The objective of this study was to determine whether strontium doping of the bone graft extender could protect the allograft from fast resorption and increase gap healing, leading to the improved fixation of the implant. We found that the strontium doping increased gap healing and protected the allograft, however, results of the mechanical test were inconclusive. The reason might have been that the increased gap healing had not yet reached the implant during the 4 weeks observation time, so ongrowth onto the implant was not improved. Study III investigated the effects of bioactive glass coating with a 0%, 10% or 50% strontium-substitution versus HA coating of grit-blasted titanium alloy implants. The goal was to determine whether fixation of the implant would be improved by the bioactive glass coating, and then further improved by the strontium-substitution of the coating in a dose dependent manner. Unfortunately, the bioactive glass coating failed, presumably due to aluminum contamination originating from the grit-blasting powder. The HA coated implants were superior in all parameters of osseointegration and the mechanical fixation of the implants. These studies show the importance of performing further experimental investigation. Even when investigating a known agent for use in a new application. Strontium delivered as doping of an HA bone graft extender showed potential as a dual acting agent in the interface. However, delivery methods of strontium to the bone-implant interface clearly need further investigation. PMID- 21535994 TI - Randomized controlled trials of olanzapine treatment of borderline personality disorder: two similar studies with different results. PMID- 21535995 TI - A dose comparison of olanzapine for the treatment of borderline personality disorder: a 12-week randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: To examine the efficacy and safety of olanzapine at low and moderate doses for the treatment of borderline personality disorder. METHOD: In this 12 week randomized double-blind placebo-controlled trial, 451 outpatients aged 18-65 years with DSM-IV borderline personality disorder received olanzapine 2.5 mg/d (n = 150), olanzapine 5-10 mg/d (n = 148), or placebo (n = 153). The trial was conducted from February 2004 through January 2006 at 59 community-based and academic study centers in 9 countries (United States, Italy, Poland, Romania, Turkey, Chile, Peru, Argentina, and Venezuela). The primary efficacy measure was mean change from baseline to last-observation-carried-forward endpoint on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) total score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Modified Overt Aggression Scale, the Global Assessment of Functioning, the Symptom Checklist-90-Revised, and the Sheehan Disability Scale. RESULTS: An overall mean baseline ZAN-BPD total score of 17.2 (SD = 4.9) indicated moderate symptom severity. Only treatment with olanzapine 5-10 mg/d was associated with significantly greater mean change from baseline to endpoint in ZAN-BPD total score relative to placebo (-8.5 vs -6.8, respectively; P = .010; effect size = 0.29; 95% CI, 0.06-0.52). Response rates (response indicated by >= 50% decrease from baseline in ZAN-BPD total score) were significantly higher for olanzapine 5 10 mg/d (73.6%) versus olanzapine 2.5 mg/d (60.1%; P = .018) and versus placebo (57.8%; P = .006). Time to response was also significantly shorter for patients taking olanzapine 5-10 mg/d than for placebo-treated patients (P = .028). Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, fatigue, increased appetite, and weight increase (all P values < .05). Mean weight change from baseline to endpoint was significantly greater for olanzapine-treated than for placebo treated patients (olanzapine 2.5 mg/d: 2.09 kg; olanzapine 5-10 mg/d: 3.17 kg; placebo: 0.02 kg; P < .001). The overall completion rate for the 12-week double blind treatment period was 65.2% (ie, 64.7% for olanzapine 2.5 mg/d, 69.6% for olanzapine 5-10 mg/d, and 61.4% for placebo). CONCLUSIONS: Olanzapine 5-10 mg/d showed a clinically modest advantage over placebo in the treatment of overall borderline psychopathology. This advantage in effectiveness should be weighed against the risk of adverse events (particularly weight gain), which were consistent with the known safety profile of olanzapine. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00088036. PMID- 21535997 TI - A randomized, double-blind, placebo-controlled study of light therapy for antepartum depression. AB - OBJECTIVE: Affective disorder during pregnancy is a common condition requiring careful judgment to treat the depression while minimizing risk to the fetus. Following up on promising pilot trials, we studied the efficacy of light therapy. METHOD: Twenty-seven pregnant women with nonseasonal major depressive disorder according to DSM-IV (outpatients, university polyclinic) were randomly assigned to 7,000 lux fluorescent bright white or 70 lux dim red (placebo) light administered at home in the morning upon awakening for 1 h/d in a 5-week double blind trial carried out between October 2004 and October 2008. Clinical state was monitored weekly with the 29-item Structured Interview Guide for the Hamilton Depression Rating Scale (HDRS) with Atypical Depression Supplement (SIGH-ADS). Changes of rating scale scores over time were analyzed with the general linear model. Differences from baseline of SIGH-ADS and 17-item HDRS scores at every time point were the dependent variables, time was the within-subjects factor, and treatment was the between-subjects factor. The model also included baseline score of depression and gestational age at intervention start. RESULTS: The superiority of bright light over dim light placebo was shown for both SIGH-ADS (R2 = 0.251; F(3,23) = 3.91; P < .05) and HDRS (R2 = 0.338; F(3,23) = 5.42; P < .01) when analyzing the week-by-week change from baseline, and HDRS scores showed a significant interaction of treatment with time (F(4,92) = 2.91; P < .05). Categorical analysis revealed that the response rate (HDRS >= 50% improvement) at week 5 was significantly greater for bright light (81.3%, n = 16) than for placebo light (45.5%, n = 11) (P < .05). Remission (final score <= 8) was attained by 68.6% versus 36.4%, respectively (P < .05). Expectation ratings did not differ significantly between groups. CONCLUSIONS: Bright white light treatment for 5 weeks improved depression during pregnancy significantly more than placebo dim red light. The study provides evidence that light therapy, a simple, cost-effective antidepressant modality with minimal side effects for the mother and no known risk for the unborn child, may be a useful nonpharmacologic approach in this difficult situation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01043289. PMID- 21535996 TI - Metabolic depression: a chronic depressive subtype? Findings from the InCHIANTI study of older persons. AB - OBJECTIVE: Several studies report a cross-sectional association between metabolic syndrome and depression. Possibly, metabolic syndrome promotes onset or chronicity of depression. However, such a longitudinal link has not yet been confirmed. This study examines whether metabolic syndrome or its components are associated with onset and chronicity of depression. METHOD: Secondary analyses were performed on data from 823 participants (>= 65 years of age) in the InCHIANTI study, a prospective, population-based cohort study of older persons. From 1998 to 2000, the study sample was randomly selected from the population registry of 2 sites in Italy using a multistage stratified sampling method. Baseline data collection consisted of a home interview and a medical evaluation at the study clinic. Follow-up for each participant occurred after 3 years and 6 years. Metabolic syndrome at baseline was defined as >= 3 of the following: abdominal obesity, high triglycerides, low high-density lipoprotein cholesterol, high blood pressure, and high fasting glucose. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale (CES-D) at baseline and after 3 and 6 years. Sample characteristics were compared between persons with and without depression at baseline using chi2 and t statistics. Logistic regression analyses were conducted separately in persons with and without depression at baseline to test whether metabolic syndrome at baseline could predict onset and chronicity of depression at follow-up. RESULTS: At baseline, 235 persons had metabolic syndrome, and 168 were depressed (CES-D score >= 20). Among persons not depressed at baseline, 26.0% developed depression. Higher waist circumference increased the odds of depression onset (adjusted OR per SD increase = 1.28; 95% CI, 1.05-1.56), but there was no association between other metabolic syndrome components and onset of depression. Among persons depressed at baseline, depression had a chronic character in 69.0% of persons without and 88.5% of persons with metabolic syndrome. Metabolic syndrome was associated with an almost 3-fold increase in the odds of chronicity of depression (adjusted OR = 2.66; 95% CI, 1.01-7.00), with almost every metabolic syndrome component contributing to this association. CONCLUSION: In late life, waist circumference, but not metabolic syndrome, predicted onset of depression. Depressed persons with metabolic syndrome were more likely to have persistent or recurrent depression. The latter may suggest that depression with metabolic abnormalities, which could be labeled metabolic depression, identifies a chronic subtype of depression. PMID- 21535998 TI - Bupropion sustained release added to group support for smoking cessation in schizophrenia: a new randomized trial and a meta-analysis. AB - OBJECTIVE: To clarify the efficacy and tolerability of bupropion sustained release (SR) for the treatment of cigarette smoking in people with schizophrenia. METHOD: The first study is a double-blind, placebo-controlled clinical trial with 32 outpatients from the Maryland Psychiatric Research Center. From May 2003 to July 2007, clinically stable people with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who smoked at least 10 cigarettes per day and who were interested in quitting smoking or cutting down were recruited for participation. All participated in a 9-week support group and were randomly assigned to receive 12 weeks of bupropion SR or placebo. The primary outcome measure was 4 weeks' sustained abstinence over the last 4 study weeks. Secondary outcome measures included decrease in smoking behavior and change in symptoms, neuropsychological performance, and side effects. In the second study, we performed an electronic literature search of MEDLINE in September 2008. Articles in English published between 2003 and 2008 were searched for the terms schizophrenia, bupropion SR, and smoking. Bibliographies of studies identified through the MEDLINE search were also examined. Case reports, open-label studies, crossover studies, and studies using nonstandard dosing of bupropion SR were excluded. In this way, 4 studies similar in methodology to the currently presented clinical trial were identified and the individual data combined in a meta-analysis. A random effects meta analysis using Comprehensive Meta-Analysis software was used to obtain a pooled estimate of the odds ratio for 4-week smoking abstinence between bupropion SR and placebo. RESULTS: There were no significant results on the primary or secondary smoking measures for the clinical trial, although a numeric advantage favored the bupropion SR group. There were no significant findings for secondary symptom or side effect measures and no significant change in neuropsychological performance. For the meta-analysis totaling 226 subjects, there were significant findings in favor of bupropion SR. The pooled estimate of the odds ratio for 4-week abstinence was 2.7 (95% CI, 1.3 to 5.7; P = .009), and clinically significant greater smoking reduction in the bupropion SR group, with pooled difference estimates increasing over time between groups, became statistically significant by week 5 of study medication (P < .02). CONCLUSIONS: New clinical trial data and a meta-analysis strongly support the tolerability and efficacy of bupropion SR for the treatment of cigarette smoking in people with schizophrenia TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00176449. PMID- 21535999 TI - Effects of acute hydrocortisone administration on declarative memory in patients with major depressive disorder: a placebo-controlled, double-blind crossover study. AB - OBJECTIVE: Major depressive disorder (MDD) has been associated with hypercortisolism, reduced glucocorticoid feedback sensitivity, and impaired memory function. In healthy subjects, administration of hydrocortisone impairs declarative memory. The aim of this study was to examine the effects of acute hydrocortisone administration on memory retrieval in MDD patients and healthy controls. We further tested whether the enhancing or impairing effects of hydrocortisone would prevail when it was given after encoding and when delayed retrieval was tested at a time point when glucocorticoid levels were still elevated. METHOD: In a placebo-controlled, double-blind crossover study, 44 patients with DSM-IV MDD and 51 healthy control participants received either placebo or 10 mg of hydrocortisone orally before memory testing. A word list paradigm and the Logical Memory Test from the Wechsler Memory Scale were applied. The study was conducted from April 2008 until April 2010 at sites in Bielefeld and Hamburg, Germany. RESULTS: In both memory tests, patients with MDD performed worse than controls. Healthy controls showed impaired memory performance after hydrocortisone administration compared to placebo. In contrast, hydrocortisone had no effects on memory in MDD patients. Furthermore, in healthy controls we found that administration of hydrocortisone immediately after learning did not lead to an enhanced free recall during increased cortisol levels. CONCLUSIONS: It appears that the impairing effects of hydrocortisone on memory performance are missing in patients with MDD. This might be interpreted in the context of reduced central glucocorticoid receptor functioning. PMID- 21536000 TI - A national epidemic of unintentional prescription opioid overdose deaths: how physicians can help control it. AB - Both the usage of prescription drugs such as opioid analgesics and benzodiazepines and overdoses involving them have increased dramatically in the United States since the 1990s. Patients using these drugs often have a combination of painful conditions, substance abuse, and other forms of mental illness. Psychiatrists and many primary care physicians might not be familiar with existing evidence-based guidelines for opioid prescribing or with programs designed to reduce the abuse of prescription drugs such as state prescription drug monitoring programs. Psychiatrists need to be informed regarding this problem to partner effectively with both pain specialists and primary care providers in their community. PMID- 21536001 TI - Antidepressants for major depressive disorder and dysthymic disorder in patients with comorbid alcohol use disorders: a meta-analysis of placebo-controlled randomized trials. AB - OBJECTIVE: Mood and alcohol use disorders are often co-occurring, each condition complicating the course and outcome of the other. The aim of this study was to examine the efficacy of antidepressants in patients with unipolar major depressive disorder (MDD) and/or dysthymic disorder with comorbid alcohol use disorders and to compare antidepressant and placebo response rates between depressed patients with or without comorbid alcohol use disorders. DATA SOURCES: MEDLINE/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for the acute phase treatment of MDD and/or dysthymic disorder in patients with or without alcohol use disorders. The search term placebo was cross-referenced with each of the antidepressants approved by the US, Canadian, or European Union drug regulatory agencies for the treatment of MDD and/or dysthymic disorder. STUDY SELECTION: 195 articles were found eligible for inclusion in our analysis, 11 of which focused on the treatment of MDD/dysthymic disorder in patients with comorbid alcohol use disorders. The search was limited to articles published between January 1, 1980, and March 15, 2009 (inclusive). RESULTS: We found that antidepressant therapy was more effective than placebo in patients with comorbid alcohol use disorders (risk ratio of response = 1.336; P = .021). However, this was not the case when selective serotonin reuptake inhibitor (SSRI) antidepressants were examined alone (P > .05). There was no significant difference in the relative efficacy of antidepressants (versus placebo) when comparing studies in MDD/dysthymic disorder patients with or without alcohol use disorders (P = .973). Meta-regression analyses yielded no significant differences in the risk ratio of responding to antidepressants versus placebo in trials with comorbid alcohol use disorders, whether antidepressants were used alone or adjunctively to psychotherapy, whether they were used in patients actively drinking or recently sober, or whether they were used in pure MDD or in combined MDD and dysthymic disorder populations. CONCLUSIONS: These results support the utility of certain antidepressants (tricyclics, nefazodone) in treating depression in patients with comorbid alcohol use disorders. More data on the use of newer antidepressants, including the SSRIs, for this select patient population are needed. PMID- 21536002 TI - Problematic Internet use and health in adolescents: data from a high school survey in Connecticut. AB - OBJECTIVE: This study aims to explore the prevalence and health correlates of problematic Internet use among high school students in the United States. METHOD: A cross-sectional survey with a sample size of 3,560 students was conducted among high schools in Connecticut. Demographic data, characteristics of Internet use, health measures, and risk behaviors were assessed. Chi-square and logistic regression analyses were used to study the relationship between problematic Internet use and risk behaviors as well as related gender differences. RESULTS: When problematic Internet use was diagnosed with criteria modeled after the Minnesota Impulsive Disorder Inventory that address core features of impulse control disorder (strong urge, growing tension, and attempts to cut back), the overall prevalence was about 4%, with no significant difference between genders. Problematic Internet use was more common among Asian (7.86%) and Hispanic (6.07%) students. Even though boys spent significantly more time on the Internet (16.52% of boys spent over 20 hours per week vs 12.62% of girls; P = .0001) and more frequently missed important school or social activities as a result (8.97% of boys vs 5.85% of girls; P = .0004), girls more frequently self-reported measures of excessive use of the Internet (11.81% of girls thought that they had a problem vs 8.90% of boys; P = .0048). After adjustment of sociodemographic factors, problematic Internet use was found to associate significantly with substance use (P = .0014), depression (P < .0001), and aggression (P < .0001), with largely similar patterns of associations between genders. CONCLUSIONS: Problematic Internet use may be present in about 4% of high school students in the United States. It may be associated with depression, substance use, and aggressive behaviors. High school boys, though, may have heavier Internet use and may be less self-aware of the related problems. PMID- 21536006 TI - In vitro and in vivo biological activity screening of Ru(III) complexes involving 6-benzylaminopurine derivatives with higher pro-apoptotic activity than NAMI-A. AB - A series of novel octahedral ruthenium(III) complexes involving 6 benzylaminopurine (L) derivatives as N-donor ligands has been prepared by the reaction of [(DMSO)(2)H][trans-RuCl(4)(DMSO)(2)] with the corresponding L derivative. The complexes 1-12 have the general compositions trans [RuCl(4)(DMSO)(n-Cl-LH)]?xSol (1-3), trans-[RuCl(4)(DMSO)(n-Br-LH)].xSol (4-6), trans-[RuCl(4)(DMSO)(n-OMe-LH)].xSol (7-9) and trans-[RuCl(4)(DMSO)(n-OH LH)].xSol (10-12); n=2, 3, and 4, x=0-1.5; and Sol = H(2)O, DMSO, EtOH and/or (Me)(2)CO. The complexes have been thoroughly characterized by elemental analysis, UV-visible, FTIR, Raman, and EPR spectroscopy, ES+(positive ionization electrospray) mass spectrometry, thermal analysis, cyclic voltammetry, magnetic and conductivity measurements. The X-ray molecular structure of trans [RuCl(4)(DMSO)(3-Br-LH)]?(Me)(2)CO (5) revealed the distorted octahedral coordination in the vicinity of the central atom, and also confirmed that the 3 Br-L ligand is present as the N3-protonated N7-H tautomer and is coordinated to Ru(III) through the N9 atom of the purine moiety. The tested complexes have been found to be in vitro non-cytotoxic against K562, G361, HOS and MCF7 human cancer cell lines with IC(50)>100MUM in contrast to the moderate results regarding the antiradical activity with IC(50)~10(-3)M. On the contrary, in vivo antitumor activity screening showed that the prepared Ru(III) complexes possess higher pro apoptotic activity than NAMI-A. The reduction of Ru(III) to Ru(II) and Ru(II) species formation in tumor tissues was confirmed by means of a simple method of detection and visualization of intracellular Ru(II) by fluorescence microscopy. The originality of this method is based on the preparation of a Ru(II)-bipyridine complex in situ. PMID- 21536007 TI - Molecular dynamics simulation of carboxy and deoxy human cytoglobin in solution. AB - Cytoglobin (Cgb), the fourth member of the vertebrate heme globin family, is widely expressed in mammalian tissues, and reversibly binds to CO, O(2) and other small ligands. The diverse functions of Cgb may include ligand transport, redox reactions and enzymatic catalysis. Recent studies indicate that Cgb is a potential gene medicine for fibrosis and cancer therapy. In the present work, molecular dynamics (MD) simulations were performed to investigate the functionally related structural properties and dynamic characteristics in carboxy and deoxy human Cgb. The simulation results showed that the loop regions and internal cavities were significantly affected through the binding of an exogenous ligand. The AB, GH and EF loops were found to undergo significant rearrangement and this led to distinct cavity adjustments in Xe2, Xe4 and the distal pocket. In addition, solvent accessibility and torsion angle analyses revealed an interactive distal network comprised of His(81)(E7), Leu(46)(B10) and Arg(84)(E10). The MD study of carboxy and deoxy human Cgb revealed that CO ligated Cgb modulates the protein conformation primarily by loop and cavity rearrangements rather than the heme sliding mechanism found in neuroglobin (Ngb). The significant differences between Cgb and Ngb in the loop and cavity properties are presumably linked to their various biological functions. PMID- 21536008 TI - Structural and thermodynamic characterization of the adrenodoxin-like domain of the electron-transfer protein Etp1 from Schizosaccharomyces pombe. AB - The protein Etp1 of Schizosaccharomyces pombe consists of an amino-terminal COX15 like domain and a carboxy-terminal ferredoxin-like domain, Etp1(fd), which is cleaved off after mitochondrial import. The physiological function of Etp1(fd) is supposed to lie in the participation in the assembly of iron-sulfur clusters and the synthesis of heme A. In addition, the protein was shown to be the first microbial ferredoxin being able to support electron transfer in mitochondrial steroid hydroxylating cytochrome P450 systems in vivo and in vitro, replacing thereby the native redox partner, adrenodoxin. Despite a sequence similarity of 39% and the fact that fission yeast is a mesophilic organism, thermodynamic studies revealed that Etp1(fd) has a melting temperature more than 20 degrees C higher than adrenodoxin. The three-dimensional structure of Etp1(fd) has been determined by crystallography. To the best of our knowledge it represents the first three-dimensional structure of a yeast ferredoxin. The structure-based sequence alignment of Etp1(fd) with adrenodoxin yields a rational explanation for their observed mutual exchangeability in the cytochrome P450 system. Analysis of the electron exchange with the S. pombe redox partner Arh1 revealed differences between Etp1(fd) and adrenodoxin, which might be linked to their different physiological functions in the mitochondria of mammals and yeast. PMID- 21536009 TI - A proteomic study using zebra mussels (D. polymorpha) exposed to benzo(alpha)pyrene: the role of gender and exposure concentrations. AB - It has recently been established that the use of proteomics can be a useful tool in the field of ecotoxicology. Despite the fact that the mussel Dreissena polymorpha is a valuable bioindicator for freshwater ecosystems, the application of a proteomic approach with this organism has not been deeply investigated. To this end, several zebra mussel specimens were subjected to a 7-day exposure of two different concentrations (0.1 and 2 MUg L-1) of the model pollutant benzo[alpha]pyrene (B[alpha]P). Changes in protein expression profiles were investigated in gill cytosolic fractions from control/exposed male and female mussels using 2-DE electrophoresis. B[alpha]P bioaccumulation in mussel soft tissue was also assessed to validate exposure to the selected chemical. We evaluated overall changes in expression profiles for 28 proteins in exposed mussels, 16 and 12 of which were, respectively, over- and under-expressed. Surprisingly, the comparative analysis of protein data sets showed no proteins that varied commonly between the two different B[alpha]P concentrations. Spots of interest were manually excised and analysed by MALDI-TOF/TOF mass spectrometry. The most significant proteins that were identified as altered were related to oxidative stress, signal transduction, cellular structure and metabolism. This preliminary study indicates the feasibility of a proteomic approach with the freshwater mussel D. polymorpha and provides a starting point for similar investigations. Our results confirm the need to increase the number of invertebrate proteomic studies in order to increase the following: their representation in databases and the successful identification of their most relevant proteins. Finally, additional studies investigating the role of gender and protein modulation are warranted. PMID- 21536010 TI - Fungal composition on leaves explains pollutant-mediated indirect effects on amphipod feeding. AB - The energy stored in coarse particulate organic matter, e.g. leaf litter, is released to aquatic ecosystems by breakdown processes involving microorganisms and leaf shredding invertebrates. The palatability of leaves and thus the feeding of shredders on leaf material are highly influenced by microorganisms. However, implications in the colonization of leaves by microorganisms (=conditioning) caused by chemical stressors are rarely studied. Our laboratory experiments, therefore, investigated for the first time effects of a fungicide on the conditioning process of leaf material by means of food-choice experiments using Gammarus fossarum (Crustacea: Amphipoda). Additionally, microbial analyses were conducted to facilitate the mechanistic understanding of the observed behavior. Gammarids significantly preferred control leaf discs over those conditioned in presence of the fungicide tebuconazole at concentrations of 50 and 500 MUg/L. Besides the decrease of fungal biomass with increasing fungicide concentration, also the leaf associated fungal community composition showed that species preferred by gammarids, such as Alatospora acumunata, Clavariopsis aquatica, or Flagellospora curvula, were more frequent in the control. Tetracladium marchalianum, however, which is rejected by gammarids, was abundant in all treatments suggesting an increasing importance of this species for the lower leaf palatability--as other more palatable fungal species were almost absent--in the fungicide treatments. Hence, the food-choice behavior of G. fossarum seems to be a suitable indicator for alterations in leaf associated microbial communities, especially fungal species composition, caused by chemical stressors. Finally, this or similar test systems may be a reasonable supplement to the environmental risk assessment of chemicals in order to achieve its protection goals, as on the one hand, indirect effects may occur far below concentrations known to affect gammarids directly, and on the other hand, the observed shifts in leaf associated microbial communities may have perpetuating implications in leaf shredding invertebrates. PMID- 21536011 TI - Selective uptake and biological consequences of environmentally relevant antidepressant pharmaceutical exposures on male fathead minnows. AB - Antidepressant pharmaceuticals have been reported in wastewater effluent at the nanogram to low microgram-per-liter range, and include bupropion (BUP), fluoxetine (FLX), sertraline (SER), and venlafaxine (VEN). To assess the effects of antidepressants on reproductive anatomy, physiology, and behavior, adult male fathead minnows (Pimephales promelas) were exposed for 21 days either to a single concentration of the antidepressants FLX, SER, VEN, or BUP, or to an antidepressant mixture. The data demonstrated that exposure to VEN (305 ng/L and 1104 ng/L) and SER (5.2 ng/L) resulted in mortality. Anatomical alterations were noted within the testes of fish exposed to SER and FLX, both modulators of the neurotransmitter serotonin. Additionally, FLX at 28 ng/L induced vitellogenin in male fish--a common endpoint for estrogenic endocrine disruption. Significant alterations in male secondary sex characteristics were noted with single exposures. Effects of single compound exposures neither carried over, nor became additive in the antidepressant mixtures, and reproductive behavior was not affected. Analysis of brain tissues from the exposed fish suggested increased uptake of FLX, SER and BUP and minimal uptake of VEN when compared to exposure water concentrations. Furthermore, the only metabolite detected consistently in the brain tissues was norfluoxetine. Similar trends of uptake by brain tissue were observed when fish were exposed to antidepressant mixtures. The present study demonstrates that anatomy and physiology, but not reproductive behavior, can be disrupted by exposure to environmental concentrations of some antidepressants. The observation that antidepressant uptake into fish tissues is selective may have consequences on assessing the mode-of-action and effects of these compounds in future studies. PMID- 21536012 TI - Limited toxicity of NH(x) pulses on an early and late successional tropical seagrass species: interactions with pH and light level. AB - Seagrasses have declined at a global scale due to light reduction and toxicity events, caused by eutrophication and increased sediment loading. Although several studies have tested effects of light reduction and toxicants on seagrasses, there is at present no information available on their interacting effects. In a full factorial 5-day laboratory experiment, we studied short-term interactive effects of light conditions, pH and reduced nitrogen (NH(x)) in the water layer, mimicking pulses of river discharge, on the tropical early successional species Halodule uninervis and the late successional species Thalassia hemprichii. In contrast to recent results reported for the temperate species Zostera marina, increased NH(x) supply did not affect leaf mortality or photochemical efficiency in H. uninervis and in 7 out of 8 treatments for T. hemprichii. However, both tropical species demonstrated striking differences in nitrogen accumulation, free amino acid composition and free NH3 accumulation. The increase in tissue nitrogen content was two times higher for H. uninervis than for T. hemprichii. Nitrogen stored as free amino acids (especially asparagine) only increased in H. uninervis. High pH only affected T. hemprichii, but only when not shaded, by doubling its free NH3 concentrations, concomitantly decreasing its photosynthetic efficiency. Our results indicate that the early successional H. uninervis has higher tolerance to high NH(x) loads as compared to the late successional T. hemprichii. H. uninervis was better able to avoid toxic internal NH(x) levels by further assimilating glutamine into asparagine in contrast to T. hemprichii. Moreover, both tropical species seem to cope much better with high NH(x) than the temperate Z. marina. The implications for the distribution and succession of seagrass species under high nutrient loads are discussed. PMID- 21536013 TI - Multiple target loci assembly sequencing (mTAS). AB - Here we present multiple target loci assembly sequencing (mTAS), a method for examining multiple genomic loci in a single DNA sequencing read. The key to the success of mTAS target sequencing is the uniform amplification of multiple target genomic loci into a single DNA fragment using polymerase cycling assembly (PCA). Using this strategy, we successfully collected multiloci sequence information from a single DNA sequencing run. We applied mTAS to examine 29 different sets of human genomic loci, each containing from 2 to 11 single-nucleotide polymorphisms (SNP) present at different exons. We believe mTAS can be used to reduce the cost of Sanger sequencing-based genetic analysis. PMID- 21536014 TI - The A391E mutation enhances FGFR3 activation in the absence of ligand. AB - The A391E mutation in the transmembrane domain of fibroblast growth factor receptor 3 leads to aberrant development of the cranium. It has been hypothesized that the mutant glutamic acid stabilizes the dimeric receptor due to hydrogen bonding and enhances its ligand-independent activation. We previously tested this hypothesis in lipid bilayers and showed that the mutation stabilizes the isolated transmembrane domain dimer by -1.3 degrees kcal/mol. Here we further test the hypothesis, by investigating the effect of the A391E mutation on the activation of full-length fibroblast growth factor receptor 3 in human embryonic kidney 293T cells in the absence of ligand. We find that the mutation enhances the ligand independent activation propensity of the receptor by -1.7 degrees kcal/mol. This value is consistent with the observed strength of hydrogen bonds in membranes, and supports the above hypothesis. PMID- 21536015 TI - PPAR-gamma and AMPK--advantageous targets for myocardial ischemia/reperfusion therapy. AB - Ischemic heart disease stands as the number one leading cause of death in the United States. Current interventions rely on the immediate restoration of blood flow to the ischemic area; however, this in turn may trigger a series of undesirable events that are further injurious to the myocardium, termed ischemia/reperfusion (I/R) injury. Therefore, there is a need for novel therapeutic strategies aimed at limiting the extent of myocardial injury. Yet, the molecular mechanisms responsible for I/R injury remain largely indefinable. Research efforts are currently investigating various signaling mechanisms to be used for potential targets limiting cardiac injury due to such cardiovascular events. In this review, we highlight two potential molecular targets, PPAR-gamma and AMPK, which have been extensively reported to have various cardioprotective capabilities against I/R injury. Although functionally different, the pathways these proteins mediate seem to intersect and possibly act synergistically potentiating a cardioprotective response. PMID- 21536016 TI - Tert-butyl-2(4,5-dihydrogen-4,4,5,5-tetramethyl-3-O-1H-imidazole-3-cationic-1 oxyl-2-pyrrolidine-1-carboxylic ester displays novel cytotoxicity through reactive oxygen species-mediated oxidative damage in MCF-7 and MDA-MB-231 cells. AB - The cytotoxicity of a new nitroxyl nitroxide radical, tert-butyl-2 (4,5 dihydrogen-4,4,5,5-tetramethyl-3-O-1H-imidazole-3-cationic-1-oxyl-2-pyrrolidine-1 carboxylic ester (L-NNP) was examined in MCF-7 and MDA-MB-231 cells. L-NNP treatment resulted in a significant growth inhibition in MCF-7 and MDA-MB-231 cells. Compared with control, 10, 30, and 50MUg/ml L-NNP treatments for 48h induced significant cell and nuclei swelling, and organelle distension. The marked cell death was seen in a concentration- and time-dependant manner in L-NNP treated groups. The L-NNP treated group displayed a concentration-dependant increase in DNA double strand damage compared to the control and the 1Gy gamma rays exposure groups. These results suggest that L-NNP could result in more lethal genotoxicity than 1Gy gamma-radiation. Based on mitochondrial alteration (membrane potential loss and SDH activity descend), DNA damage, an increase in MDA production, and GSH-PX inactivation, we predicate that L-NNP induces lipid oxidation and oxidative damage in MCF-7 and MDA-MB-231 cells. Since L-NNP initiated a significant increase in reactive oxygen species, which could largely be inhibited by NAC pretreatment, the overall data strongly suggest that the mechanism of cytotoxicity of L-NNP was its ability to act as a strong free radical, and significantly increase intracellular reactive oxygen species production. This led to intracellular oxidative damage, and antioxidant enzyme inactivation, resulting in cell death. We hypothesize that the greater cytotoxicity of L-NNP in MDA-MB-231 cells than in MCF-7 cells might be due to more ROS production in MDA-MB-231 cells, leading to more oxidative damage. PMID- 21536017 TI - Physical setting and natural sources of exposure to carcinogenic trace elements and radionuclides in Lahontan Valley, Nevada. AB - In Lahontan Valley, Nevada, arsenic, cobalt, tungsten, uranium, radon, and polonium-210 are carcinogens that occur naturally in sediments and groundwater. Arsenic and cobalt are principally derived from erosion of volcanic rocks in the local mountains and tungsten and uranium are derived from erosion of granitic rocks in headwater reaches of the Carson River. Radon and 210Po originate from radioactive decay of uranium in the sediments. Arsenic, aluminum, cobalt, iron, and manganese concentrations in household dust suggest it is derived from the local soils. Excess zinc and chromium in the dust are probably derived from the vacuum cleaner used to collect the dust, or household sources such as the furnace. Some samples have more than 5 times more cobalt in the dust than in the local soil, but whether the source of the excess cobalt is anthropogenic or natural cannot be determined with the available data. Cobalt concentrations are low in groundwater, but arsenic, uranium, radon, and 210Po concentrations often exceed human-health standards, and sometime greatly exceed them. Exposure to radon and its decay products in drinking water can vary significantly depending on when during the day that the water is consumed. Although the data suggests there have been no long term changes in groundwater chemistry that corresponds to the Lahontan Valley leukemia cluster, the occurrence of the very unusual leukemia cluster in an area with numerous 210Po and arsenic contaminated wells is striking, particularly in conjunction with the exceptionally high levels of urinary tungsten in Lahontan Valley residents. Additional research is needed on potential exposure pathways involving food or inhalation, and on synergistic effects of mixtures of these natural contaminants on susceptibility to development of leukemia. PMID- 21536018 TI - Protein damage from electrophiles and oxidants in lungs of mice chronically exposed to the tumor promoter butylated hydroxytoluene. AB - The food additive butylated hydroxytoluene (BHT) promotes tumorigenesis in mouse lung. Chronic BHT exposure is accompanied by pulmonary inflammation and several studies indicate that elevated levels of reactive oxygen species (ROS) are involved in its promoting activity. The link between BHT and elevated ROS involves formation of quinone methide (QM) metabolites; these electrophiles form adducts with a variety of lung proteins including several enzymes that protect cells from oxidative stress. Studies in vitro demonstrated that QM alkylation of cytoprotective enzymes is accompanied by inactivation, so an objective of the present investigation was to determine if inactivation also occurs in vivo. Two groups of mice were exposed to BHT by intraperitoneal injection, one for 10 days and the other for 24 days, and proteins from lung cytosols were examined for damage. Analysis by Western blotting demonstrated that BHT treatment caused substantial increases in protein carbonylation, nitration and adduction by 4 hydroxynonenal, confirming the occurrence of sustained oxidative and nitrosative stress over the treatment period required for tumor promotion. Effects of BHT on the activities and/or levels of a representative group of antioxidant/protective enzymes in mouse lung also were assessed; NAD(P)H:quinone reductase and glutathione reductase were unaffected, however carbonyl reductase activity decreased 50-60%. Superoxide dismutase and glutathione peroxidase activities increased 2- and 1.5-fold, respectively, and glutamate-cysteine ligase catalytic subunit expression increased 32-39% relative to untreated mice. Glutathione S transferase (GST) activity decreased 50-60% but concentrations of the predominant isoforms, GSTM1 and P1, were not affected. GSTP1 was substantially more susceptible than M1 to adduction and inhibition by treatment with BHT-QM in vitro, suggesting that lower GST activity in mice after BHT treatment is due to adduction of the P1 isoform. The results of this study provide additional insight into mechanisms of BHT-induced oxidative damage and further support a link between inflammation and tumor promotion in mouse lung. PMID- 21536019 TI - Detection of autoantibodies against Rabphilin-3A-like protein as a potential biomarker in patient's sera of colorectal cancer. AB - BACKGROUND: Rabphilin-3A-like (RPH3AL) protein functions in the regulation of hormone exocytosis, and mutations in the RPHA3L gene have been associated with tumorigenesis in colorectal cancer (CRC). We evaluated the potential use of anti RPH3AL autoantibodies as a marker for CRC detection. METHODS: Sera from 84 patients with CRC and 63 healthy controls were analysed for the presence of RPH3AL autoantibodies with a Western blotting assay. RESULTS: The frequencies of RPH3AL autoantibodies in the early stage, advanced stage and all CRC patients were 64.7%, 78.0% and 72.6%, respectively. These values are significantly higher than the frequency of RPH3AL autoantibodies in healthy controls (15.9%, P<0.001). Although the presence of RPH3AL autoantibodies did not correlate with clinical parameters, RPH3AL autoantibodies were found in 69.4% (34/49) of CRC patients who were negative for carcinoembryonic antigen. The value of the area under the receiver operating characteristic curve of RPH3AL autoantibody was 0.84, which suggests that screening for these autoantibodies could potentially be used for CRC diagnosis. CONCLUSION: Circulating RPH3AL autoantibodies are prevalent in patients with CRC, and detection of these autoantibodies might provide a novel non-invasive approach for CRC diagnosis. PMID- 21536020 TI - Characterization of a novel isolated deletion of the exon 3 within the CFTR gene: Relevance for phenotypic expression and genetic counseling. AB - OBJECTIVES: To characterize a novel deletion of exon 3 of CFTR gene and to evaluate the implications in Cystic Fibrosis (CF) care and genetic counseling. DESIGN AND METHODS: We performed a wide mutational analysis of CFTR gene, using reverse dot blot, Multiplex Ligation-dependent Probe Amplification (MLPA) assay and Real Time Quantitative PCR, in a carrier male and two CF patients with the F508del mutation. RESULTS: We found a novel isolate 538bp deletion of exon 3, described as 328del538, giving rise to a nonsense codon 60bp at the 3' end of the new coding sequence or, alternatively, a novel splice site at the breakpoints. CONCLUSIONS: The 328del538 is a rare lesion with the characteristics of a complete, but moderate, phenotypic expression. Its finding underlines the importance of improving the detection of mutations using different methods. PMID- 21536021 TI - Quantification of free serum cortisol based on equilibrium dialysis and isotope dilution-liquid chromatography-tandem mass spectrometry. AB - OBJECTIVES: Only unbound serum cortisol is bioactive and protein binding of cortisol is highly variable. Thus, the quantification of free serum cortisol (FSC) is of superior biological relevance compared to total serum cortisol quantification. Consequently, the development of automated routine tests for FSC for endocrine testing is desirable - along the lines of free thyroid hormone measurement. Since the availability of a reliable and matrix-independent method is an important tool for this goal, we have developed a highly standardised mass spectrometric FSC method. DESIGN AND METHODS: We used equilibrium dialysis (ED) to obtain a protein-free fraction from serum samples. The cortisol content of the dialysate was quantified using isotope-dilution two dimensional liquid chromatography (LCxLC-MS/MS). RESULTS: Comprehensive evaluation characterised the method as reliable and robust; using commercially available dialysis cells, convenient handling was realised. CONCLUSIONS: The method described in this article can be suggested for the implementation of a reference measurement system for FSC. PMID- 21536022 TI - Intracellular ice formation and growth in MCF-7 cancer cells. AB - Direct cell injury in cryosurgery is highly related to intracellular ice formation (IIF) during tissue freezing and thawing. Mechanistic understanding of IIF in tumor cells is critical to the development of tumor cryo-ablation protocol. In aid of a high speed CMOS camera system, the events of IIF in MCF-7 cells have been studied using cryomicroscopy. Images of 'darkening' type IIF and recrystallization are compared between cells frozen with and without ice seeding. It is found that ice seeding has significant impact on the occurrence and growth of intracellular ice. Without ice seeding, IIF is observed to occur over a very small range of temperature (~1 degrees C). The crystal dendrites are indistinguishable, which is independent of the cooling rate. Ice crystal grows much faster and covers the whole intracellular space in comparison to that with ice seeding, which ice stops growing near the cellular nucleus. Recrystallization is observed at the temperature from -13 degrees C to -9 degrees C during thawing. On the contrary, IIF occurs from -7 degrees C to -20 degrees C with ice seeding at a high subzero temperature (i.e., -2.5 degrees C). The morphology of intracellular ice frozen is greatly affected by the cooling rate, and no 'darkening' type ice formed inside cells during thawing. In addition, the intracellular ice formation is directional, which starts from the plasma membrane and grows toward the cellular nucleus with or without ice seeding. These results can be used to explain some findings of tumor cryosurgery in vivo, especially the causes of insufficient killing of tumor cells in the peripheral area near vessels. PMID- 21536023 TI - Genetic epistasis between heparan sulfate and FGF-Ras signaling controls lens development. AB - Vertebrate lens development depends on a complex network of signaling molecules to coordinate cell proliferation, migration and differentiation. In this study, we have investigated the role of heparan sulfate in lens specific signaling by generating a conditional ablation of heparan sulfate modification genes, Ndst1 and Ndst2. In this mutant, N-sulfation of heparan sulfate was disrupted after the lens induction stage, resulting in reduced lens cell proliferation, increased cell death and defective lens fiber differentiation in later lens development. The loss of Ndst function also prevented the assembly of Fgf/Fgfr complexes on the lens cell surface and disrupted ERK signaling within the lens. We further demonstrated that Ndst mutation completely inhibited the FGF1 and Fgf3 overexpression phenotypes, but Kras reactivation was sufficient to reverse the Ndst deficient lens differentiation defect. The epistatic relationship between Ndst and FGF-Ras signaling demonstrates that FGF signaling is the predominant signaling pathway controlled by Ndst in lens development. PMID- 21536024 TI - Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and anti-oxidant mechanisms. AB - Painful neuropathy, a common complication of diabetes mellitus is characterized by allodynia and hyperalgesia. Recent studies emphasized on the role of non neuronal cells, particularly microglia in the development of neuronal hypersensitivity. The purpose of the present study is to evaluate the effect of minocyline, a selective inhibitor of microglial activation to define the role of neuroimmune activation in experimental diabetic neuropathy. Cold allodynia and thermal and chemical hyperalgesia were assessed and the markers of inflammation and oxidative and nitrosative stress were estimated in streptozotocin-induced diabetic rats. Chronic administration of minocycline (40 and 80 mg/kg, i.p.) for 2 weeks started 2 weeks after diabetes induction attenuated the development of diabetic neuropathy as compared to diabetic control animals. In addition, minocyline treatment reduced the levels of interleukin-1beta and tumor necrosis factor-alpha, lipid peroxidation, nitrite and also improved antioxidant defense in spinal cords of diabetic rats as compared to diabetic control animals. In contrast, minocycline (80 mg/kg, per se) had no effect on any of these behavioral and biochemical parameters assessed in age-matched control animals. The results of the present study strongly suggest that activated microglia are involved in the development of experimental diabetic neuropathy and minocycline exerted its effect probably by inhibition of neuroimmune activation of microglia. In addition, the beneficial effects of minocycline are partly mediated by its anti inflammatory effect by reducing the levels of proinflammatory cytokines and in part by modulating oxidative and nitrosative stress in the spinal cord that might be involved in attenuating the development of behavioral hypersensitivity in diabetic rats. PMID- 21536026 TI - Hydroxysafflor yellow A protects against chronic carbon tetrachloride-induced liver fibrosis. AB - Hydroxysafflor yellow A (HSYA) was isolated from the dried flower of Carthamus tinctorius L. which was extensively used in traditional Chinese medicine to treat cirrhosis. However, the potential protective effect of HSYA in liver fibrosis is still unknown. In the present study, we investigated the effects of HSYA in rats with carbon tetrachloride (CCl4)-induced liver fibrosis. Sprague-Dawley (SD) rats were subjected to biweekly CCl4 injections over 12 weeks, while controls were given isovolumetric injections of olive oil. HSYA was given in a daily dose of 5 mg/kg by means of intraperitoneal concurrent with CCl4. Hepatic fibrosis was quantified by digital analysis of Masson's trichrome stained slides and hydroxyproline content. mRNA expression was quantified by real-time polymerase chain reaction (PCR), and protein was quantified by western blot or enzyme-linked immunosorbent assay (ELISA). CCl4 treatment induced micronodular liver fibrosis with a pronounced deposition of collagen fibers. HSYA significantly reduced liver fibrosis. HSYA down regulates alpha-smooth muscle actin (SMA), collagen alpha type I, matrix metalloproteinases (MMP)-9, and tissue inhibitors of metalloproteinases (TIMP)-1 gene expression. This was accompanied by a decreased expression of transforming growth factor (TGF)-beta1 and phosphorylation of Smad4. These results indicate that HSYA might be a promising antifibrotic agent in chronic liver disease. PMID- 21536025 TI - CL-385319 inhibits H5N1 avian influenza A virus infection by blocking viral entry. AB - CL-385319, an N-substituted piperidine, is effective in inhibiting infection of H1-, H2-, and to a lesser extent, H3-typed influenza A viruses by interfering with the fusogenic function of the viral hemagglutinin. Here we show that CL 385319 is effective in inhibiting infection of highly pathogenic H5N1 influenza A virus in Madin-Darby Canine Kidney (MDCK) cells with an IC50 of 27.03+/-2.54 MUM. This compound with low cytotoxicity (CC50=1.48+/-0.01 mM) could also inhibit entry of pseudoviruses carrying hemagglutinins from H5N1 strains that were isolated from different places at different times, while it had no inhibitory activity on the entry of VSV-G pseudotyped particles. CL385319 could not inhibit N1-typed neuraminidase activity and the adsorption of H5-typed HA to chicken erythrocytes at the concentration as high as 1 mg/ml (2.8 mM). Computer-aid molecular docking analysis suggested that CL-385319 might bind to the cavity of HA2 stem region which was known to undergo significant rearrangement during membrane fusion. Pseudoviruses with M24A mutation in HA1 or F110S mutation in HA2 were resistant to CL-385319, indicating that these two residues in the cavity region may be critical for CL-385319 bindings. These findings suggest that CL 385319 can serve as a lead for development of novel virus entry inhibitors for preventing and treating H5N1 influenza A virus infection. PMID- 21536027 TI - Scorpion (Androctonus crassicauda) venom limits growth of transformed cells (SH SY5Y and MCF-7) by cytotoxicity and cell cycle arrest. AB - The purpose of study was to examine the cytotoxic and anti-cancer properties along with addressing the plausible pathway followed by scorpion venom to reduce cell viability in SH-SY5Y and MCF-7 cells. Following exposure of cells with scorpion venom, cytotoxicity was estimated using MTT and lactate dehydrogenase assays. Apoptotic effects were measured by assessment of mitochondrial membrane potential, reactive nitrogen species, DNA fragmentation, and caspase-3 activity whereas antiproliferative effect was assayed using BrdU incorporation. Our results indicate that scorpion venom causes suppression of proliferation by arresting S-phase and induction of apoptosis through increased nitric oxide production, caspase-3 activity and depolarization of mitochondrial membrane. Induction of apoptosis and arrest of DNA synthesis are critical determinant factors for development of anti cancer drugs. These properties may lead to isolation of effective molecule(s) with potential anticancer activity from scorpion venom of Androctonus crassicauda. PMID- 21536028 TI - Migration of connective tissue-derived cells is mediated by ultra-low concentration gradient fields of EGF. AB - The directed migration of cells towards chemical stimuli incorporates simultaneous changes in both the concentration of a chemotactic agent and its concentration gradient, each of which may influence cell migratory response. In this study, we utilized a microfluidic system to examine the interactions between epidermal growth factor (EGF) concentration and EGF gradient in stimulating the chemotaxis of connective tissue-derived fibroblast cells. Cells seeded within microfluidic devices were exposed to concentration gradients established by EGF concentrations that matched or exceeded those required for maximum chemotactic responses seen in transfilter migration assays. The migration of individual cells within the device was measured optically after steady-state gradients had been experimentally established. Results illustrate that motility was maximal at EGF concentration gradients between .01- and 0.1-ng/(mL.mm) for all concentrations used. In contrast, the number of motile cells continually increased with increasing gradient steepness for all concentrations examined. Microfluidics based experiments exposed cells to minute changes in EGF concentration and gradient that were in line with the acute EGFR phosphorylation measured. Correlation of experimental data with established mathematical models illustrated that the fibroblasts studied exhibit an unreported chemosensitivity to minute changes in EGF concentration, similar to that reported for highly motile cells, such as macrophages. Our results demonstrate that shallow chemotactic gradients, while previously unexplored, are necessary to induce the rate of directed cellular migration and the number of motile cells in the connective tissue derived cells examined. PMID- 21536030 TI - Focus on molecules: ALDH1A1: from lens and corneal crystallin to stem cell marker. PMID- 21536029 TI - Subunit-specific polyclonal antibody targeting human rho1 GABA(C) receptor. AB - The GABA(C) receptor, a postsynaptic membrane receptor expressed prominently in the retina, is a ligand-gated ion channel that consists of a combination of rho subunits. We report characterization of a novel guinea pig polyclonal antibody, termed GABA(C) Ab N-14, directed against a 14-mer peptide (N-14) of the extracellular domain of the human rho1 subunit. The antibody exhibits high sensitivity for N-14 by ELISA. In Western blots, GABA(C) Ab N-14 shows reactivity with the rho1 subunit of preparations obtained from rho1 GABA(C)-expressing neuroblastoma cells, Xenopus oocytes, and mammalian retina and brain. Flow cytometry reveals a rightward shift in mean fluorescence intensity of GABA(C) expressing neuroblastoma cells probed with GABA(C) Ab N-14. Immunostaining of neuroblastoma cells and oocytes with GABA(C) Ab N-14 yields fluorescence only with GABA(C)-expressing cells. Antibody binding has no effect on GABA-elicited membrane current responses. Immunostaining of human retinal sections shows preferential staining within the inner plexiform layer. GABA(C) Ab N-14 appears well suited for investigative studies of GABA(C) rho1 subunit in retina and other neural tissues. PMID- 21536031 TI - Unilateral entorhinal denervation leads to long-lasting dendritic alterations of mouse hippocampal granule cells. AB - Following brain injury, neurons efferently connected from the lesion site are denervated and remodel their dendritic tree. Denervation-induced dendritic reorganization of granule cells was investigated in the dentate gyrus of the Thy1 GFP mouse. After mechanical transection of the perforant path, single granule cells were 3D-reconstructed at different time points post-lesion (3d, 7d, 10d, 30 d, 90 d and 180 d) and their soma size, total dendritic length, number of dendritic segments and dendritic branch orders were studied. Changes in spine densities were determined using 3D-analysis of individual dendritic segments. Following entorhinal denervation the granule cell arbor progressively atrophied until 90 d post-lesion (reduction of total dendritic length to ~50% of control). Dendritic alterations occurred selectively in the denervated outer molecular layer, where a loss of distal dendritic segments and a reduction of mean segment length were seen. At 180 d post-lesion total dendritic length partially recovered (~70% of control). This recovery appeared to be the result of a re-elongation of surviving dendrites rather than dendritic re-branching, since the number of dendritic segments did not recover. In contrast to the protracted dendritic changes, spine density changes followed a faster time course. In the denervated layer spine densities dropped to ~65% of control values and fully recovered by 30 d post-lesion. We conclude that entorhinal denervation in mouse causes protracted and long-term structural alterations of the granule cell dendritic tree. Spontaneously occurring reinnervation processes, such as the sprouting of surviving afferent fibers, are insufficient to maintain the granule cell dendritic arbor. PMID- 21536032 TI - Blockage of the channel to heme by the E87 side chain in the GAF domain of Mycobacterium tuberculosis DosS confers the unique sensitivity of DosS to oxygen. AB - Two sensor kinases, DosS and DosT, are responsible for recognition of hypoxia in Mycobacterium tuberculosis. Both proteins are structurally similar to each other, but DosS is a redox sensor while DosT binds oxygen. The primary difference between the two proteins is the channel to the heme present in their GAF domains. DosS has a channel that is blocked by E87 while DosT has an open channel. Absorption spectra of DosS mutants with an open channel show that they bind oxygen as DosT does when they are exposed to air, while DosT G85E mutant is oxidized similarly to DosS without formation of an oxy-ferrous form. This suggests that oxygen accessibility to heme is the primary factor governing the oxygen-binding properties of these proteins. PMID- 21536035 TI - Circadian rhythms. PMID- 21536034 TI - Roles of sequential ubiquitination of PCNA in DNA-damage tolerance. AB - Living organisms not only repair DNA damage induced by environmental agents and endogenous cellular metabolites, but have also developed mechanisms to survive in the presence of otherwise lethal lesions. DNA-damage tolerance (DDT) is considered such a mechanism that resumes DNA synthesis in the presence of replication-blocking lesions. Recent studies revealed that DDT in budding yeast is achieved through sequential ubiquitination of DNA polymerase processivity factor, proliferating cell nuclear antigen (PCNA). It is generally believed that monoubiquitinated PCNA promotes translesion DNA synthesis, whereas polyubiquitinated PCNA mediates an error-free mode of lesion bypass. This review will discuss how ubiquitinated PCNA modulates different means of lesion bypass. PMID- 21536033 TI - Intracellular and intercellular processes determine robustness of the circadian clock. AB - Circadian clocks are present in most organisms and provide an adaptive mechanism to coordinate physiology and behavior with predictable changes in the environment. Genetic, biochemical, and cellular experiments have identified more than a dozen component genes and a signal transduction pathway that support cell autonomous, circadian clock function. One of the hallmarks of biological clocks is their ability to reset to relevant stimuli while ignoring most others. We review recent results showing intracellular and intercellular mechanisms that convey this robust timekeeping to a variety of circadian cell types. PMID- 21536036 TI - Degradation-linked ubiquitin signal and proteasome are integral components of DNA double strand break repair: New perspectives for anti-cancer therapy. AB - Damaged DNA leads to genomic instability that causes many diseases such as cancer. Cells evolved the DNA damage response (DDR), which recognizes and efficiently repairs damaged DNA through the action of highly coordinated signalling mechanisms. Recently, a non-degradation-linked Lys(K)63-ubiquitin signal emerged as a signalling pathway essential for orchestration of the DDR after DNA double strand breaks (DSBs). How the ubiquitin-dependent proteasomal degradation system (UPS) coordinates DDR after DSBs is still poorly understood. Here, we review the evidence, suggesting the involvement of the degradation linked K48-ubiquitin signal and the proteasome at the sites of DSBs. Based on this we propose the UPS as a central element in the orchestration of the DDR at the sites of DSBs. The suggested model is also discussed in the context of anti cancer therapy. PMID- 21536037 TI - Activation of AMPK by berberine promotes adiponectin multimerization in 3T3-L1 adipocytes. AB - Adiponectin is assembled into trimer (LMW), hexamer (MMW) and high-molecular weight (HMW) multimer in adipocytes. The HMW adiponectin is more metabolically active and closely associated with peripheral insulin sensitivity. In this study, we reported that berberine, an isoquinoline alkaloid with insulin-sensitizing effect, inhibits the expression of adiponectin, but promotes the assembly of HMW adiponectin and increases the ratio of HMW to total adiponectin. Berberine activates AMPK. Knockdown of AMPKalpha1 abolishes the effect of berberine. Activation of AMPK by AICAR also increases the level of HMW adiponectin. Our study suggested that activation of AMPK by berberine promotes adiponectin multimerization. PMID- 21536038 TI - Homeoprotein Hbx4 represses the expression of the adhesion molecule DdCAD-1 governing cytokinesis and development. AB - We investigated the function of homeodomain-containing protein Hbx4 in Dictyostelium discoideum. Hbx4-overexpressing cells (Hbx4(OE)) displayed defects in growth rate and cytokinesis and showed differences in slug motility and cell type proportioning from KAx3. Furthermore, the overexpression of Hbx4 inhibited the induction of cadA, which encoded the Ca(2+)-dependent cell adhesion molecule DdCAD-1, despite expression of csaA and gpaB. The electrophoretic mobility shift assay showed that the promoter of cadA contained the Hbx4-binding site. Moreover, constitutively expressed DdCAD-1 in Hbx4(OE) rescued the defects in cytokinesis and development. These results suggest that Hbx4 modulates DdCAD-1-mediated cytokinesis and cell-type proportioning. PMID- 21536039 TI - Association of platelet-derived growth factor receptor beta accumulation with increased oxidative stress and cellular injury in sestrin 2 silenced human glioblastoma cells. AB - Sestrin 2 (SESN2) is a stress-inducible protein required for maintaining redox homeostasis. However, its mode of action remains to be clarified. In this study, we found that SESN2 is induced in human glioblastoma U87 cells following ionizing radiation (IR). SESN2 silencing not only results in increased oxidative stress but also sensitizes U87 cells to IR. Intriguingly, we found SESN2 silencing significantly increases the expression of platelet-derived growth factor receptor beta (PDGFRbeta). Using a double knockdown technique, we showed that inhibition of PDGFRbeta accumulation in SESN2-silencing cells protects the cells from the deleterious effects induced by SESN2 silencing. Taken together, we revealed that PDGFRbeta accumulation is associated with increased oxidative stress and cellular damage in SESN2 silenced human glioblastoma U87 cells. PMID- 21536040 TI - Engineering plant resistance by constructing chimeric receptors that recognize damage-associated molecular patterns (DAMPs). AB - An efficient sensing of danger and a rapid activation of the immune system are crucial for the survival of plants. Conserved pathogen/microbe-associated molecular patterns (PAMPs/MAMPs) and endogenous molecular patterns, which are present only when the tissue is infected or damaged (damage-associated molecular patterns or DAMPs), can act as danger signals and activate the plant immune response. These molecules are recognized by surface receptors that are indicated as pattern recognition receptors (PRRs). In this paper we summarize recent information on oligogalacturonides (OGs), a class of DAMPs that is released from the extracellular matrix of the plant cell during pathogen attack or wounding. We also describe the characteristics of the Arabidopsis Wall-Associated Kinase 1 (WAK1), a PRR recently identified as a receptor of OGs and discuss the use of WAK1, PRRs and chimeric receptors to engineer resistance in crop plants. PMID- 21536041 TI - Perfect timing: epigenetic regulation of the circadian clock. AB - In mammals, higher order chromatin structures are critical for downsizing the genome (packaging) so that the nucleus can be small. The adjustable density of chromatin also regulates gene expression, thus this post-genetic molecular mechanism is one of the routes by which phenotype is shaped. Phenotypes that arise without a concomitant mutation of the underlying genome are termed epigenetic phenomena. Here we discuss epigenetic phenomena from histone and DNA modification as it pertains to the dynamic regulatory processes of the circadian clock. Epigenetic phenomena certainly explain some regulatory aspects of the mammalian circadian oscillator. PMID- 21536042 TI - Potential roles for GNIH and GNRH-II in reproductive axis regulation of an opportunistically breeding songbird. AB - The ability to breed at any time of year enables opportunistically breeding species to respond to good conditions whenever they occur. We investigate the neuroendocrine basis for this relatively unusual reproductive pattern in the avian world. One proposed mechanism for year-round breeding ability is tonic activation of gonadotropin-releasing hormone-I (GnRH-I) production that is flexibly modified by gonadotropin-inhibitory hormone (GnIH) production during unfavorable conditions. GnIH could inhibit GnRH secretion from the hypothalamus and/or inhibit GnRH action on the anterior pituitary gland. We studied neuroendocrine patterns in wild Australian zebra finches (Taeniopygia guttata) sampled during a breeding period in Southern Australia, a non-breeding period in central Australia, and in juvenile males in the latter location. We asked whether patterns in immunoreactivity of three neuropeptides important for reproductive axis regulation, GnRH-I, GnRH-II and GnIH, during periods of breeding and non breeding reflect this flexibility. We found that the numbers and sizes of immunoreactive (-ir) GnRH-I cells did not vary between breeding stages and ages. Contrary to our predictions, irGnIH cell number and size, as well as the synthesis of GnIH mRNA were similar in breeding and non-breeding conditions. However, breeding males had more and larger irGnRH-II cells in the midbrain compared to non-breeding males. Hence, while changes in irGnIH cells are not associated with fluctuations in gonadotropin secretion or gonad volume, the regulation of irGnRH-II cells might represent a previously-unidentified mechanism by which reproductive flexibility can be achieved; namely via behavioral neurotransmitter actions of GnRH-II rather than through the typical sensory-CNS integration-GnRH-I route. PMID- 21536043 TI - Examining a pathway for hormone mediated maternal effects--yolk testosterone affects androgen receptor expression and endogenous testosterone production in young chicks (Gallus gallus domesticus). AB - In vertebrates maternal androgens can substantially influence developing offspring, inducing both short and long term changes in physiology and behavior, including androgen sensitive traits. However, how the effects of maternal hormones are mediated remains unknown. Two possible pathways are that maternal androgens affect parts of the hypothalamus-pituitary-gonadal axis (HPG axis) or the sensitivity to androgens by affecting androgen receptor (AR) densities within the brain. To investigate both pathways, testosterone within the physiological range or vehicle only was injected into the egg yolk of unincubated chicken eggs and AR mRNA expression in different brain nuclei as well as plasma testosterone levels were measured in two week old male and female chicks that had hatched from these eggs. Our results showed a significant sex difference in plasma testosterone levels with males showing higher levels than females. Furthermore, AR mRNA expression as well as plasma testosterone levels were significantly lower in chicks hatched from testosterone treated eggs. These results suggest a compensatory mechanism for avoiding potential detrimental effects of high testosterone levels. PMID- 21536044 TI - Diet-induced hypercholesterolemia impaired testicular steroidogenesis in mice through the renin-angiotensin system. AB - Hypercholesterolemia and low testosterone concentrations in men are associated with a high risk factor for atherosclerosis. It is known that cholesterol serves as the major precursor for the synthesis of the sex hormones. The bioactive peptides of the renin-angiotensin-system localized in the gonads play a key role in the relation between cholesterol and testosterone by modulating steroidogenesis and inhibiting testosterone production. In the present work, we evaluated the effects of diet-induced hypercholesterolemia on circulating testosterone levels and its relationship with the testicular RAS-regulating specific aminopeptidase activities in male mouse. A significant decrease in serum circulating levels of testosterone was observed after induced hypercholesterolemia. The changes found in aminopeptidase activities suggest a role of Ang III and Ang IV in the regulation of steroidogenesis. PMID- 21536045 TI - Temporal variation of vitellogenin synthesis in Ectatomma tuberculatum (Formicidae: Ectatomminae) workers. AB - Workers of the ant species Ectatomma tuberculatum (Ectatomminae) have active ovaries and lay eggs that are eaten by the queen and larvae (trophic eggs). Vitellogenins are the main proteins found in the eggs of insects and are a source of nutrients. The aim of this study was to characterize the period of vitellogenin production in workers of E. tuberculatum. The vitellogenin was identified from queen and worker eggs by SDS-PAGE. Anti-vitellogenin antibodies were obtained and used to detect this protein in the fat body and haemolymph of workers at different ages. Vitellogenin from E. tuberculatum consists of two polypeptides of 31 and 156 kDa. In the eggs of queens, the 156 kDa polypeptide is cleaved into two subunits of 36 and 123 kDa. The analysis of the haemolymph of workers showed that the secretion of vitellogenin varies with age. The secretion is initiated around the fifth day after emergence, with peak production from days 20 to 60, and stops around day 100. The variation in production is related to the different activities performed by the workers within the colony, suggesting that vitellogenin may have an important role in maintaining age polyethism. PMID- 21536046 TI - Examination of host genome for the presence of integrated fragments of Solenopsis invicta virus 1. AB - A series of oligonucleotide primer pairs covering the entire genome of Solenopsis invicta virus 1 (SINV-1) were used to probe the genome of its host, S. invicta, for integrated fragments of the viral genome. All of the oligonucleotide primer sets yielded amplicons of anticipated size from cDNA created from an RNA template from SINV-1. However, no corresponding amplification was observed when genomic DNA (from 32 colonies of S. invicta) was used as template for the PCR amplifications. Host DNA integrity was verified by amplification of an ant specific gene, SiGSTS1. The representation of fire ant colonies included both social forms, monogyne and polygyne, and those infected and uninfected with SINV 1. Furthermore, no amplification was observed from genomic DNA from ant samples collected from Argentina or the US. Thus, it appears that SINV-1 genome integration, or a portion therein, has not likely occurred within the S. invicta host genome. PMID- 21536047 TI - Crystal structure of a rigid four-spectrin-repeat fragment of the human desmoplakin plakin domain. AB - The plakin protein family serves to connect cell-cell and cell-matrix adhesion molecules to the intermediate filament cytoskeleton. Desmoplakin (DP) is an integral part of desmosomes, where it links desmosomal cadherins to the intermediate filaments. The 1056-amino-acid N-terminal region of DP contains a plakin domain common to members of the plakin family. Plakin domains contain multiple copies of spectrin repeats (SRs). We determined the crystal structure of a fragment of DP, residues 175-630, consisting of four SRs and an inserted SH3 domain. The four repeats form an elongated, rigid structure. The SH3 domain is present in a loop between two helices of an SR and interacts extensively with the preceding SR in a manner that appears to limit inter-repeat flexibility. The intimate intramolecular association of the SH3 domain with the preceding SR is also observed in plectin, another plakin protein, but not in alpha-spectrin, suggesting that the SH3 domain of plakins contributes to the stability and rigidity of this subfamily of SR-containing proteins. PMID- 21536049 TI - Prediction of GABAA receptor proteins using the concept of Chou's pseudo-amino acid composition and support vector machine. AB - The amino acid gamma-aminobutyric-acid receptors (GABA(A)Rs) belong to the ligand gated ion channels (LGICs) superfamily. GABA(A)Rs are highly diverse in the central nervous system. These channels play a key role in regulating behavior. As a result, the prediction of GABA(A)Rs from the amino acid sequence would be helpful for research on these receptors. We have developed a method to predict these proteins using the features obtained from Chou's pseudo-amino acid composition concept and support vector machine as a powerful machine learning approach. The predictor efficiency was assessed by five-fold cross-validation. This method achieved an overall accuracy and Matthew's correlation coefficient (MCC) of 94.12% and 0.88, respectively. Furthermore, to evaluate the effect and power of each feature, the minimum Redundancy and Maximum Relevance (mRMR) feature selection method was implemented. An interesting finding in this study is the presence of all six characters (hydrophobicity, hydrophilicity, side chain mass, pK1, pK2 and pI) or combination of the characters among the 5 higher ranked features (pk2 and pI, hydrophobicity and mass, pk1, hydrophilicity and mass) obtained from the mRMR feature selection method. The results show a biologically justifiable ranked attributes of pk2 and pI; hydrophobicity, hydrophilicity and mass; mass and pk1; pk2 and mass. Based on our results, using the concept of Chou's pseudo-amino acid composition and support vector machine is an effective approach for the prediction of GABA(A)Rs. PMID- 21536050 TI - Alignment-free comparison of genome sequences by a new numerical characterization. AB - In order to compare different genome sequences, an alignment-free method has proposed. First, we presented a new graphical representation of DNA sequences without degeneracy, which is conducive to intuitive comparison of sequences. Then, a new numerical characterization based on the representation was introduced to quantitatively depict the intrinsic nature of genome sequences, and considered as a 10-dimensional vector in the mathematical space. Alignment-free comparison of sequences was performed by computing the distances between vectors of the corresponding numerical characterizations, which define the evolutionary relationship. Two data sets of DNA sequences were constructed to assess the performance on sequence comparison. The results illustrate well validity of the method. The new numerical characterization provides a powerful tool for genome comparison. PMID- 21536048 TI - Different requirements for sigma Region 4 in BvgA activation of the Bordetella pertussis promoters P(fim3) and P(fhaB). AB - Bordetella pertussis BvgA is a global response regulator that activates virulence genes, including adhesin-encoding fim3 and fhaB. At the fhaB promoter, P(fhaB), a BvgA binding site lies immediately upstream of the -35 promoter element recognized by Region 4 of the sigma subunit of RNA polymerase (RNAP). We demonstrate that sigma Region 4 is required for BvgA activation of P(fhaB), a hallmark of Class II activation. In contrast, the promoter-proximal BvgA binding site at P(fim3) includes the -35 region, which is composed of a tract of cytosines that lacks specific sequence information. We demonstrate that sigma Region 4 is not required for BvgA activation at P(fim3). Nonetheless, Region 4 mutations that impair its typical interactions with core and with the -35 DNA affect P(fim3) transcription. Hydroxyl radical cleavage using RNAP with sigmaD581C-FeBABE positions Region 4 near the -35 region of P(fim3); cleavage using RNAP with alpha276C-FeBABE or alpha302C-FeBABE also positions an alpha subunit C-terminal domain within the -35 region, on a different helical face from the promoter-proximal BvgA~P dimer. Our results suggest that the -35 region of P(fim3) accommodates a BvgA~P dimer, an alpha subunit C-terminal domain, and sigma Region 4. Molecular modeling suggests how BvgA, sigma Region 4, and alpha might coexist within this DNA in a conformation that suggests a novel mechanism of activation. PMID- 21536051 TI - Modelling HIV/AIDS in the presence of an HIV testing and screening campaign. AB - Preventing and managing the HIV/AIDS epidemic in South Africa will dominate the next decade and beyond. Reduction of new HIV infections by implementing a comprehensive national HIV prevention programme at a sufficient scale to have real impact remains a priority. In this paper, a deterministic HIV/AIDS model that incorporates condom use, screening through HIV counseling and testing (HCT), regular testing and treatment as control strategies is proposed with the objective of quantifying the effectiveness of HCT in preventing new infections and predicting the long-term dynamics of the epidemic. It is found that a backward bifurcation occurs if the rate of screening is below a certain threshold, suggesting that the classical requirement for the basic reproduction number to be below unity though necessary, is not sufficient for disease control in this case. The global stabilities of the equilibria under certain conditions are determined in terms of the model reproduction number R(0). Numerical simulations are performed and the model is fitted to data on HIV prevalence in South Africa. The effects of changes in some key epidemiological parameters are investigated. Projections are made to predict the long-term dynamics of the disease. The epidemiological implications of such projections on public health planning and management are discussed. PMID- 21536052 TI - Epidemics and vaccination on weighted graphs. AB - A Reed-Frost epidemic with inhomogeneous infection probabilities on a graph with prescribed degree distribution is studied. Each edge (u,v) in the graph is equipped with two weights W((u,v)) and W((v,u)) that represent the (subjective) strength of the connection and determine the probability that u infects v in case u is infected and vice versa. Expressions for the epidemic threshold are derived for i.i.d. weights and for weights that are functions of the degrees. For i.i.d. weights, a variation of the so called acquaintance vaccination strategy is analyzed where vertices are chosen randomly and neighbors of these vertices with large edge weights are vaccinated. This strategy is shown to outperform the strategy where the neighbors are chosen randomly in the sense that the basic reproduction number is smaller for a given vaccination coverage. PMID- 21536053 TI - Dispersal, settling and layer formation. AB - Motivated by examples in developmental biology and ecology, we develop a model for convection-dominated invasion of a spatial region by initially motile agents which are able to settle permanently. The motion of the motile agents and their rate of settling are affected by the local concentration of settled agents. The model can be formulated as a nonlinear partial differential equation for the time integrated local concentration of the motile agents, from which the instantaneous density of settled agents and its long-time limit can be extracted. In the limit of zero diffusivity, the partial differential equation is of first order; for application-relevant initial and boundary-value problems, shocks arise in the time-integrated motile agent density, leading to delta-function components in the motile agent density. Furthermore, there are simple solutions for a model of successive layer formation. In addition some analytic results for a one dimensional system with non-zero diffusivity can also be obtained. A case study, both with and without diffusion, is examined numerically. Some important predictions of the model are insensitive to the specific settling law used and the model offers insight into biological processes involving layered growth or overlapping generations of colonization. PMID- 21536054 TI - Cellular mechanisms of acute decrease of glutamate release induced by raloxifene in rat cerebral cortex. AB - Raloxifene, a selective estrogen receptor modulator, has been observed to offer a neuroprotective effect in several in vitro models of neurotoxicity. An excessive release of glutamate is considered to be related to neuropathology of several neurological diseases. In this study, we investigated whether raloxifene could affect endogenous glutamate release in nerve terminals of rat cerebral cortex (synaptosomes) and explored the possible mechanism. Raloxifene exhibited a dose dependent inhibition of 4-aminopyridine (4-AP)-evoked release of glutamate, and this effect was not blocked by the estrogen receptor antagonists. The effect of raloxifene on the evoked glutamate release was prevented by the chelating extracellular Ca(2+) ions, and by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to the glutamate transporter inhibitor DL-TBOA. Raloxifene decreased the depolarization-induced increase in the cytosolic free Ca(2+) concentration ([Ca(2+)](C)), whereas it did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization. The effect of raloxifene on evoked glutamate release was prevented by blocking the Ca(v)2.2 (N type) and Ca(v)2.1 (P/Q-type) channels, but not by blocking intracellular Ca(2+) release or Na(+)/Ca(2+) exchange. In addition, the inhibitory effect of raloxifene on evoked glutamate release was abolished by the mitogen activated/extracellular signal-regulated kinase kinase (MEK) inhibitors, PD98059 and U0126. Furthermore, raloxifene significantly decreased the depolarization induced phosphorylation of mitogen-activated protein kinase/extracellular signal regulated kinase 1 and 2 (MAPK/ERK1/2) and synapsin I, the main presynaptic target of ERK. Thus, the effect of raloxifene on evoked glutamate release is linked to a decrease in [Ca(2+)](i) contributed by Ca(2+) entry through presynaptic voltage-dependent Ca(2+) channels and to the subsequent suppression of the ERK/synapsin I signaling cascade. PMID- 21536055 TI - Age-related changes in brain activation underlying single- and dual-task performance: visuomanual drawing and mental arithmetic. AB - Depending on task combination, dual-tasking can either be performed successfully or can lead to performance decrements in one or both tasks. Interference is believed to be caused by limitations in central processing, i.e. structural interference between the neural activation patterns associated with each task. In the present study, single- and dual-task effects were addressed in the context of aging. Increasing evidence from research on motor and cognitive tasks has shown that aging is associated with an expansion of brain activation and an increased BOLD-signal. This may result in increased structural interference and higher dual task interference in older adults. Functional magnetic resonance imaging was used to measure the BOLD-response in 20 old and 20 young healthy adults while performing tasks separately, or combined. Single tasks consisted of mental arithmetic cued by auditory tones, and a visuomotor task, drawing a circular shape with spatiotemporal constraints. Age-related brain activation increases were only apparent during performance of the visuomotor task. Elderly showed higher BOLD-responses in a frontoparietal network, pointing to an increased reliance on sensory feedback processing. However, no increased structural interference was found for the elderly during performance of the dual-task. Region of interest analysis involving a functional cluster within the (pre-) supplementary motor area, active during performance of both single-tasks, revealed that both groups were able to upregulate their brain activity for dual as compared to single-task performance. We assume that this allowed both groups to maintain performance under dual-task conditions, leading to minimal dual-task interference. PMID- 21536056 TI - Alcohol and nutrient intake: mechanisms of reinforcement and dependence. AB - Alcohol is not only a drug of abuse but is also a food. This combination has a significant impact on the development and consequences of alcohol abuse and dependence. Understanding the neurobiological and behavioral processes that mediate them is perhaps best approached from the perspective of ingestive behavior. Research from the Hoebel laboratory has provided innovation and leadership in understanding that feeding neuropeptides plays a significant role in alcohol intake. The research reviewed here shows that galanin and other feeding peptides increase intake and also motivate abuse and the development of dependence. In addition, the consequences of long term alcohol abuse and dependence alter nutritional systems and drinking behavior. A major challenge is understanding the role of alcohol's dual properties and feeding neuropeptide in the motivation to drink. PMID- 21536057 TI - Opioids as facilitators of feeding: can any food be rewarding? AB - Palatability is one of the most rewarding aspects of consummatory behavior. Opioids, potent facilitators of intake of sweet and fat tastants, are thought to mediate hedonics of feeding. However, the rewarding context of consumption is not limited to palatability, and gratification can be achieved through other means, e.g., eating to satisfy hunger. The current review discusses the role of opioid peptides in food intake regulation by incorporating this expanded concept of feeding reward. We present evidence that, aside from increasing sugar/fat consumption, opioids propel the intake of diets whose gustatory value is low but are nonetheless consumed under circumstances allowing feeding gratification to occur. Opioids enhance reward-driven consumption by acting within the classical reward circuitry and also by signaling reward at sites that regulate other aspects of food intake, such as satiety and aversion. We conclude that, due to the complexity of neural and functional interactions, opioids are capable of enhancing pleasure of eating any food--palatable, bland or even aversive--making any meal into a more rewarding experience, despite possible consequences. PMID- 21536058 TI - Is there a linkage between metabolism and personality in small mammals? The root vole (Microtus oeconomus) example. AB - Significant inter-individual variation in the rate of animal metabolism is a widespread phenomenon that has started to accumulate general interest. Here we follow recent calls to focus on linkage between the variation in energy metabolism and animal personality. By using wild caught root voles as a study species, we examined the relationship between the behavioral patterns (assessed in open field test) and resting metabolic rate (RMR), both of which are known to show large individual differences and intra-individual consistency in voles. Our results showed only a weak relationship between personality traits and metabolism, since the most parsimonious model (according to AICc) explaining RMR included only body mass and season as factors (explaining 84.8% of variation in RMR). However, the next two alternative models (within DeltaAICc=2) also included the personality trait reflecting proactive behaviors (PC1) in addition to body mass, sex and season (85.2 and 85.8% of RMR variance explained, respectively). In all, our study does not provide compelling support for recent ideas of close linkage between behavior and metabolism. Still, our study highlights that even in the case of wild caught individuals, when behavior and metabolism often carry effects of both intrinsic and extrinsic conditions, the potential metabolic effects of varying energetically costly behaviors cannot be neglected. PMID- 21536059 TI - Apolipoprotein E reduces food intake via PI3K/Akt signaling pathway in the hypothalamus. AB - Apolipoprotein E (apoE) is a satiation factor. While central apoE administration reduces food intake, the specific intracellular signaling mechanisms activated by apoE remain largely unknown. Using primary cultured hypothalamic neurons, we demonstrated that apoE treatment (50 nM) elicited rapid activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling cascade. Specifically, apoE induced the phosphorylation of Akt, peaking at 30 min, and the increased phosphorylation of Akt was significantly attenuated after pretreatment with LY294002 (50 MUM), an inhibitor of the PI3K signaling pathway. To determine whether the activation of PI3K by apoE is required for the ability of apoE to reduce food intake, LY294002 (1 nmol) was infused into the 3rd-cerebral ventricle before injection of an anorectic dose of apoE. Consistent with our previous report, apoE (4 MUg) exerted significant reduction of food intake in the 4-h fasted rats, compared with saline. Pretreatment with LY294002 significantly attenuated the potency of exogenous apoE to induce satiation, while the same dose of PI3K inhibitor by itself caused only a slight non-significant decrease of food intake. These results indicate that the activation of the PI3K/Akt pathway is necessary for the acute effects of apoE on food intake. PMID- 21536060 TI - Ghrelin levels are associated with hunger as measured by the Three-Factor Eating Questionnaire in healthy young adults. AB - Weight gain and appetite regulation are complex interplays between internal and external cues. Our aim was to investigate the association of eating behaviors with ghrelin taking into account lifestyle. We conducted a cross-sectional analysis in a sample of first-year university students at the Universite de Sherbrooke. We collected medical history, anthropometric measurements, vital signs, fitness index, and fasting blood samples. Questionnaires included a lifestyle questionnaire and the Three-Factor Eating Questionnaire (TFEQ) estimating dietary restraint, disinhibition and hunger. We recruited 308 participants aged 20.7+/-3.2 years and a mean BMI of 23.3+/-3.4 kg/m(2). Hunger score was significantly associated with ghrelin levels (r=0.11, P<0.05). In women, this association was independent of age, BMI, dietary and lifestyle factors (P=0.02). The association between ghrelin level and hunger score was observable in leaner individuals (r=0.28, p<0.0001) but not in heavier individuals (r=-0.08, p=0.34; stratified by BMI < vs > 22.6 kg/m(2)). Restraint (R) and disinhibition (D) were not associated with ghrelin levels. The three eating behaviors demonstrated expected correlations with lifestyle supporting the validity of the TFEQ in this cohort. In conclusion, we demonstrated that ghrelin, a biological marker, is associated with self-reported perception of hunger, independently of anthropometric measures and lifestyle. PMID- 21536061 TI - Role of GLT-1 transporter activation in prevention of cannabinoid tolerance by the beta-lactam antibiotic, ceftriaxone, in mice. AB - Recently, it has been indicated that beta lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Furthermore, these antibiotics have been shown to prevent the development of tolerance and dependence to opioids. Since cannabinoid tolerance is known to be similar to opioids, our purpose was to examine the effect of ceftriaxone on the development of tolerance to WIN 55,212-2, a cannabinoid agonist. The tail flick test, a rectal thermometer, and the ring test were used for evaluating the degree of tolerance to the analgesic, hypothermic, and cataleptic effects of WIN 55,212-2, respectively. Within one week, animals became completely tolerant to analgesic, hypothermic and cataleptic effects of WIN 55,212-2 (6mg/kg). Ceftriaxone, with its higher doses (100-200mg/kg), attenuated the development of tolerance to the analgesic and hypothermic effects of WIN 55,212-2, but had no effect on its cataleptic action. Dihydrokainic acid (10mg/kg), a GLT-1 transporter inhibitor, prevented this effect of ceftriaxone. Our results suggest that repeated treatment with ceftriaxone prevents the development of tolerance to the analgesic and hypothermic effects of cannabinoids, and GLT-1 activation appears to play a key role in this preventive effect of beta-lactam antibiotics. PMID- 21536063 TI - Roles of glutamate signaling in preclinical and/or mechanistic models of depression. AB - Accumulating evidence suggests that the glutamatergic system plays important roles in the pathophysiology and treatment of major depressive disorder (MDD). Abnormalities in the glutamatergic system are definitely observed in this disorder, and certain glutamatergic agents exhibit antidepressant effects in patients with MDD. In this review, we summarize the preclinical findings suggesting the involvement of glutamate signaling in the pathophysiology and treatment of MDD. Preclinical animal models for depression are often characterized by changes in molecules related to glutamatergic signaling. Some antidepressants exert their effects by affecting glutamatergic system components in animals. Animals with genetically modified glutamatergic function exhibit depression-like behaviors or anti-depressive behavior. In addition, several types of glutamatergic agents have shown antidepressant-like effects in preclinical models for depression. Many types of glutamate receptors (NMDA, AMPA, and metabotropic glutamate receptors) or transporters appear to be involved in the etiology of depression or in the mechanisms of action of antidepressants. These functional proteins related to glutamate signal transduction are potential targets for a new generation of antidepressants with fast-onset effects, such as the NMDA antagonist ketamine. PMID- 21536064 TI - Glutamate receptors in preclinical research on Alzheimer's disease: update on recent advances. AB - The cognitive and related symptoms of Alzheimer's disease are mainly attributable to synaptic failure. Here we review recent research on how the Alzheimer's disease amyloid beta-protein (Abeta) affects glutamate receptors and fast excitatory synaptic transmission and plasticity of that transmission. l glutamate, the main excitatory neurotransmitter in the brain, has long been implicated in causing NMDA receptor-mediated excitotoxicity leading to neurodegeneration in the late stages of the disease. However there is now extensive evidence that soluble Abeta oligomers disrupt synaptic transmission and especially synaptic plasticity via non-excitotoxic glutamatergic mechanisms. New data highlight the relatively selective involvement of certain glutamate receptor subtypes including GluN2B (NR2B) subunit-containing NMDA receptors and mGlu5 receptors. Abeta exerts direct and indirect effects on synaptic plasticity related glutamate receptor signaling and trafficking between different neuronal compartments. For example, Abeta-induced ectopic NMDA and mGlu receptor-mediated signaling coupled with caspase-3 activation may cause inhibition of long-term potentiation and facilitation of long-term depression. Intriguingly, some of the disruptive synaptic actions of Abeta have been found to be dependent on endogenous tau located in dendrites or spines. Given the role of glutamatergic transmission in regulating Abeta production and release, future therapies targeting glutamate offer the opportunity to remedy both mis-processing of Abeta and cellular mechanisms of synaptic failure in early AD. PMID- 21536065 TI - Increasing traffic on vascular routes. AB - The process of blood vessels formation and remodeling is highly regulated by a plethora of promoting and inhibiting signals that activate a large array of signaling cascades. The main molecular players of these signaling pathways are surface-localized receptors, which can transmit signals into the cytosol. Endocytosis and intracellular trafficking, by controlling protein receptor localization, distribution, and amount in space and time, can strongly impact on cell signaling outcomes. Recent work showed that, in vascular cells, integrin adhesive receptors undertake different intracellular routes, depending on their activation state, giving more complexity to the system. In addition, the endo exocytic cycle of angiogenic growth factor receptors is also essential to integrate multiple signals and coordinate different cellular events. PMID- 21536062 TI - Glutamatergic medications for the treatment of drug and behavioral addictions. AB - Historically, most pharmacological approaches to the treatment of addictive disorders have utilized either substitution-based methods (i.e., nicotine replacement or opioid maintenance) or have targeted monoaminergic or endogenous opioidergic neurotransmitter systems. However, substantial evidence has accumulated indicating that ligands acting on glutamatergic transmission are also of potential utility in the treatment of drug addiction, as well as various behavioral addictions such as pathological gambling. The purpose of this review is to summarize the pharmacological mechanisms of action and general clinical efficacy of glutamatergic medications that are currently approved or are being investigated for approval for the treatment of addictive disorders. Medications with effects on glutamatergic transmission that will be discussed include acamprosate, N-acetylcysteine, d-cycloserine, gabapentin, lamotrigine, memantine, modafinil, and topiramate. We conclude that manipulation of glutamatergic neurotransmission is a relatively young but promising avenue for the development of improved therapeutic agents for the treatment of drug and behavioral addictions. PMID- 21536066 TI - Biocompatible, biodegradable and thermo-sensitive chitosan-g-poly (N isopropylacrylamide) nanocarrier for curcumin drug delivery. AB - A nano formulation of curcumin loaded biodegradable thermoresponsive chitosan-g poly (N-isopropylacrylamide) co-polymeric nanoparticles (TRC-NPs) (150 nm) were prepared by ionic cross-linking method and characterized. The in vitro drug release was prominent at above LCST. Cytocompatibility of TRC-NPs (100-1000 MUg/ml) on an array of cell line is proved by MTT assay. The drug loaded TRC-NPs showed specific toxicity on cancer cells. The cell uptake studies were confirmed by fluorescent microscopy. Flowcytometric analysis of curcumin loaded TRC-NPs showed increased apoptosis on PC3 cells. These results indicated that TRC-NPs could be a potential nanovehicle for curcumin drug delivery. PMID- 21536067 TI - Prenatal stress in birds: pathways, effects, function and perspectives. AB - Although most work on prenatal stress has been conducted on mammalian species, birds provide useful alternative models since avian embryos develop outside the mother's body in a concealed environment, the egg, which is produced during a short time window of 4-14 days. This facilitates measurement of maternal substances provided for and manipulation of the embryo without interfering with the mother's physiology. We critically review prenatal corticosterone mediated effects in birds by reviewing both studies were females had elevated levels of plasma corticosterone during egg formation and studies applying corticosterone injections directly into the egg. A selected review of the mammalian literature is used as background. The results suggest that besides prenatal exposure to corticosterone itself, maternal corticosterone affects offspring's behaviour and physiology via alteration of other egg components. However, results are inconsistent, perhaps due to the interaction with variation in the post-natal environment, sex, age, developmental mode and details of treatment. The potential role of adaptive maternal programming has not been tested adequately and suggestions for future research are discussed. PMID- 21536068 TI - A fast solution switching system with temperature control for single cell measurements. AB - This article describes a perfusion system for biophysical single cell experiments at the physiological temperature. Our system regulates temperature of test solutions using a small heat exchanger that includes several capillaries. Water circulating inside the heat exchanger warms or cools test solutions flowing inside the capillaries. Temperature-controlled solutions are delivered directly to a single cell(s) through a multibarreled manifold that switches solutions bathing a cell in less than 1s. This solution exchange is optimal for patch clamp, single-cell microamperometry, and microfluorometry experiments. Using this system, we demonstrate that exocytosis from pancreatic beta cells and activation of TRPV1 channels are temperature sensitive. We also discuss how to measure local temperature near a single cell under investigation. PMID- 21536069 TI - Intracranial self-stimulation as a positive reinforcer to study impulsivity in a probability discounting paradigm. AB - Probability discounting is used to study risky decision-making in humans and rodents. In these paradigms, the subject chooses between a small reward that is always delivered and a large reward that is delivered with varying probabilities. Risk-taking is defined as a preference for the large, uncertain reward. The aversive consequence associated with this task involves choosing the large reward and not obtaining it. To study this form of impulsivity in rodents, food reinforcement is commonly used. Using this reinforcer, and the need to food deprive rodents to enhance task performance, may be problematic in rodent models that exhibit eating disorders, in pharmacological assessments that alter feeding, and for assessments of the neurocircuitry that is engaged by both feeding and risk-taking. We reveal here that electrical intracranial self-stimulation (ICSS) can be used as the positive reinforcer in risk assessments (i.e., probability discounting). ICSS was selected as it is rapidly acquired, the operant procedures are retained for months, and no tolerance or satiety develops to the reinforcer; thus, ICSS can be used in multiple test sessions in a repeated measures design. We developed an efficient, standardized, six phase ICSS-mediated protocol that allowed for the assessments of risk-taking in a probability discounting task. We demonstrated that the discounting behavior remained stable for several weeks. The value of this protocol is discussed in terms of practical as well as theoretical advantages of using ICSS-mediated reinforcement. PMID- 21536070 TI - Single-trial reconstruction of auditory evoked magnetic fields by means of Template Matching Pursuit. AB - We present a new paradigm for the adaptive estimation of evoked brain responses in single trials, based upon the combination of the matching pursuit (MP) algorithm and template matching, and referred to as Template Matching Pursuit (TMP). In contrast to the classical template matching with invariant single-trial morphology and to previous approaches using MP with strong similarity constraint on functions in sequential trials, this adaptive approach allows for a wide variety of waveforms, and its universality is retained by parametrizing all relevant waveforms in terms of Gabor functions. A survey of single-trial estimates obtained for 10 subjects (~4000 individual trials in total) confirms the validity of the assumption of a good approximation of single-trial waveforms. Owing to the fully parametric approach, we can easily perform also any quantitative analysis of such a huge dataset. As an example we take the trial-to trial variability of the peak amplitude and latency of the auditory M100 component. This methodology provides estimates of diversified morphologies, which makes it free from the limitations inherent to any restrictive model. This seems advantageous in the context of the ongoing debate as to the neural mechanisms of average evoked brain responses. PMID- 21536071 TI - Optimization of a real-time RT-PCR assay reveals an increase of genogroup I norovirus in the clinical setting. AB - Although norovirus has been identified as the most common cause of gastroenteritis, the majority of cases have no etiologic agent identified. In this study, we describe the optimization of a real-time RT-PCR assay for the improved detection of genogroup I norovirus in patient specimens based upon sequence data from a collection of representative clinical norovirus sequences. The redesigned assay demonstrated a 64 fold increase in sensitivity, a 2 log decrease in the limit of detection, and an 18% increase in amplification efficiency, when compared to the standard assay. The optimized test also detected GI norovirus in clinical specimens that were initially negative by the standard assay. Use of the optimized assay increased the annual positivity of GI norovirus in Iowa from 1.2% to 4.5%, indicating the prevalence of GI norovirus may be higher than previously identified. Laboratory confirmation of the etiologic agent involved in gasteroenteritis cases is essential for better understanding of the prevalence and transmission of noroviruses. PMID- 21536072 TI - Virus-like particles of Macrobrachium rosenbergii nodavirus produced in bacteria. AB - Macrobrachium rosenbergii nodavirus (MrNv) infects giant freshwater prawns and causes white tail disease (WTD). The coding region of the capsid protein of MrNv was amplified with RT-PCR and cloned into the pTrcHis2-TOPO vector. The recombinant plasmid was introduced into Escherichia coli and protein expression was induced with IPTG. SDS-PAGE showed that the recombinant protein containing the His-tag and myc epitope has a molecular mass of about 46 kDa and it was detected by the anti-His antibody in Western blotting. The protein was purified using immobilized metal affinity chromatography (IMAC) and transmission electron microscopic analysis revealed that the recombinant protein assembled into virus like particles (VLPs) with a diameter of about 30+/-3 nm. The size of the particles was confirmed by dynamic light scattering. Nucleic acids were extracted from the VLPs and treatment with nucleases showed that they were mainly RNA molecules. This is the first report describing the production of MrNv capsid protein in bacteria and its assembly into VLPs. PMID- 21536074 TI - Novel monoclonal antibodies that bind to wild and fixed rabies virus strains. AB - Ten monoclonal antibodies (MAbs) against rabies virus, including IgG3kappa, IgG2akappa, IgMkappa, and an IgG2bkappa isotype, were produced and characterized using neutralization, ELISA, immunodot-blot, and immunofluorescence assays. MAb 8D11, which recognized rabies virus glycoprotein, was found to neutralize rabies virus in vitro. When submitted to an immunofluorescence assay, seven MAbs showed different reactivity against 35 Brazilian rabies virus isolates. Three MAbs (LIA 02, 3E6, and 9C7) only failed to recognize one or two virus isolates, whereas MAb 6H8 was found to be reactive against all virus isolates tested. MAbs were also evaluated for their immunoreactivity against fixed rabies virus strains present in human and veterinary commercial vaccines. MAbs LIA 02, 6H8, and 9C7 reacted against all vaccine strains, while the remaining MAbs recognized at least 76% of vaccine strains tested. This research provides a set of MAbs with potential application for improving existing or developing new diagnostic tests and immunoassays. PMID- 21536073 TI - Modification of the Abbott RealTime assay for detection of HIV-1 plasma RNA viral loads less than one copy per milliliter. AB - Although commercial tests are approved for detection of HIV-1 plasma viral loads >= 20 copies per milliliter (ml), only one specialized research assay has been reported to detect plasma viral loads as low as 1 copy/ml. This manuscript describes a method of concentrating HIV-1 virions from up to 30 ml of plasma, which can be combined with a commercial viral load test to create a widely available, reproducible assay for quantifying plasma HIV RNA levels less than 1 copy/ml. Using this pre-analytically modified assay, samples with a known level of 0.5 copy/ml were detected in 8 of 12 replicates (mean 0.47 copy/ml; 95% confidence interval (CI) 0.14-0.81 copy/ml) and samples with a known level of 1.0 copy/ml were detected in 13 of 13 replicates (mean 1.96 copy/ml; 95% CI 1.42-2.50 copy/ml). By concentrating virus from 30 ml of plasma, HIV RNA could be measured in 16 of 19 samples (84%) from 12 of 12 subjects (mean 2.77 copy/ml; 95% CI 0.86 4.68 copy/ml). The measured viral load correlated inversely (r = -0.78; p = 0.028) with the total duration of viral suppression (viral load<40 copies/ml). PMID- 21536075 TI - Development of an antigen-capture ELISA for the detection of equine influenza virus nucleoprotein. AB - An antigen-capture enzyme-linked immunosorbent assay (AC-ELISA) was developed for the detection of the equine influenza virus (EIV), employing monoclonal and polyclonal antibodies against the A/equine/Xingjiang/2007 (H3N8) nucleoprotein (NP). Immunoglobulin G antibodies were purified and used as capture or detector antibodies. The specificity of the optimized AC-ELISA was evaluated using EIV, equine herpesvirus 1 (EHV-1), equine herpesvirus 4 (EHV-4), equine arteritis virus (EAV) and Japanese encephalitis virus (JEV), resulting in only EIV specimens yielding a strong signal. A minimal concentration of 50 ng/ml EIV protein was detected in Nonidet P40-treated virus preparations. Virus from the nasal swabs of equines infected experimentally were detected from days 3 to 7 post-infection using this AC-ELISA, with results confirmed by virus isolation and multi reverse transcription polymerase chain reaction. Both H3N8 and H7N7 EIV subtypes were AC-ELISA positive, indicating that this assay is suitable for the detection of all EIV subtypes. PMID- 21536076 TI - Use it or lose it: how neurogenesis keeps the brain fit for learning. AB - The presence of new neurons in the adult hippocampus indicates that this structure incorporates new neurons into its circuitry and uses them for some function related to learning and/or related thought processes. Their generation depends on a variety of factors ranging from age to aerobic exercise to sexual behavior to alcohol consumption. However, most of the cells will die unless the animal engages in some kind of effortful learning experience when the cells are about one week of age. If learning does occur, the new cells become incorporated into brain circuits used for learning. In turn, some processes of learning and mental activity appear to depend on their presence. In this review, we discuss the now rather extensive literature showing that new neurons are kept alive by effortful learning, a process that involves concentration in the present moment of experience over some extended period of time. As these thought processes occur, endogenous patterns of rhythmic electrophysiological activity engage the new cells with cell networks that already exist in the hippocampus and at efferent locations. Concurrent and synchronous activity provides a mechanism whereby the new neurons become integrated with the other neurons. This integration allows the present experience to become integrated with memories from the recent past in order to learn and predict when events will occur in the near future. In this way, neurogenesis and learning interact to maintain a fit brain. PMID- 21536079 TI - A novel method for the measurement of elemental selenium produced by bacterial reduction of selenite. AB - The measurement of elemental selenium (Se(0)) is needed to assess the rate and magnitude of bacteria reduction of selenite or selenate. We have developed a spectrophotometric method for the measurement Se(0) that is rapid and can be employed to measure the quantity of Se(0) produced by bacterial cultures. This method employs the use of 1M Na(2)S to convert the insoluble elemental selenium to a red-brown solution and with this method there is a direct correlation between concentration of elemental selenium and the absorption at 500nm. To demonstrate the utility of this assay, we have followed the reduction of selenite to Se(0) by Moraxella bovis, and by bacterial consortia in soil and water samples. PMID- 21536077 TI - The structural and functional connectivity of the amygdala: from normal emotion to pathological anxiety. AB - The dynamic interactions between the amygdala and the medial prefrontal cortex (mPFC) are usefully conceptualized as a circuit that both allows us to react automatically to biologically relevant predictive stimuli as well as regulate these reactions when the situation calls for it. In this review, we will begin by discussing the role of this amygdala-mPFC circuitry in the conditioning and extinction of aversive learning in animals. We will then relate these data to emotional regulation paradigms in humans. Finally, we will consider how these processes are compromised in normal and pathological anxiety. We conclude that the capacity for efficient crosstalk between the amygdala and the mPFC, which is represented as the strength of the amygdala-mPFC circuitry, is crucial to beneficial outcomes in terms of reported anxiety. PMID- 21536080 TI - Short-interval intracortical inhibition and manual dexterity in healthy aging. AB - Short-interval intracortical inhibition (SICI) acting on the first dorsal interosseus was measured using paired-pulse transcranial magnetic stimulation (interstimulus interval=2ms) in samples of young and healthy older subjects and correlated with manual dexterity measured with the Purdue Pegboard test and two isometric force-matching tasks. There was an age-related decrease in SICI and an age-related decline in all dexterity measures. The level of SICI was not correlated with any of the dexterity measures, but the appearance of atypical facilitation (rather than inhibition) in some subjects was associated with impaired pegboard performance but not force-matching performance. We conclude that SICI at rest is reduced with healthy aging but this loss of SICI does not directly contribute to the loss of dexterity; a shift in the balance of facilitatory and inhibitory processes in motor cortex to facilitation might interfere with sequenced hand movements. PMID- 21536078 TI - Role of vascular endothelial growth factor in adult hippocampal neurogenesis: implications for the pathophysiology and treatment of depression. AB - It is now well established that the adult brain has the capacity to generate new neurons throughout life. Although the functional significance of adult neurogenesis still remains to be established, increasing evidence has implicated compromised hippocampal neurogenesis as a possible contributor in the development of major depressive disorder. Antidepressants increase hippocampal neurogenesis and there is evidence in rodent models that the therapeutic efficacy of these agents is attributable, in part, to this neurogenic effect. As such, considerable interest has been directed at identifying molecular signals, including neurotrophic factors and related signaling pathways that are associated with antidepressant action and could operate as key modulators in the regulation of neurogenesis in the adult hippocampus. One interesting candidate is vascular endothelial growth factor (VEGF), which is known to possess strong neurogenic effects. In this review, we will discuss the involvement of VEGF signaling in the etiology and treatment of depression. PMID- 21536081 TI - Immobilization of Bacillus licheniformis alpha-amylase onto reactive polymer films. AB - Alpha-amylase was covalently immobilized onto maleic anhydride copolymer films preserving activity. The initial activity of the immobilized layers strongly depended on the immobilization solution, and on the physicochemical properties of the copolymer film. Higher enzyme loading (quantified by amino acid analysis using HPLC) and activity (measured by following starch hydrolysis) were attainable onto hydrophilic, highly swelling 3-D poly(ethylene-alt-maleic anhydride) (PEMA) copolymer films, while immobilization onto hydrophobic poly(octadecene-alt-maleic anhydride) (POMA) copolymer films resulted in low content enzyme layers and lower activity. No significant activity was lost upon dehydration/re-hydration or storage of enzyme containing PEMA copolymer layers in deionised water for up to 48 h. In contrast, alpha-amylase decorated POMA films suffered a significant activity loss under those conditions. The distinct behaviours may be attributed to the different intrinsic physicochemical properties of the copolymer films. The compact, hydrophobic POMA films possibly favours hydrophobic interactions between the hydrophobic moieties of the protein and the surface, which may result in conformational changes, and consequent loss of activity. Surprisingly, residual activity was found after harsh treatments of active alpha-amylase PEMA based layers revealing that immobilization onto the hydrophilic polymer films improved the stability of the enzyme. PMID- 21536082 TI - Efficient disulfide bond formation in virus-like particles. AB - Virus-like particles (VLPs) consist of a virus's outer shell but without the genome. Similar to the virus, VLPs are monodisperse nano-capsules which have a known morphology, maintain a high degree of symmetry, and can be engineered to encapsidate the desired cargo. VLPs are of great interest for vaccination, drug/gene delivery, imaging, sensing, and material science applications. Here we demonstrate the ability to control the disulfide bond formation in VLPs by directly controlling the redox potential during or after production and assembly of VLPs. The open cell-free protein synthesis environment, which has been reported to produce VLPs at yields comparable or greater than traditional in vivo technologies, was employed. Optimal conditions for disulfide bond formation were found to be VLP dependent, and a cooperative effect in the formation of such bonds was observed. PMID- 21536083 TI - Sequencing of high G+C microbial genomes using the ultrafast pyrosequencing technology. AB - Next generation pyrosequencing of high G+C content genomes still poses problems to automated sequencing and assembly processes which necessitates cost and time intensive manual work in order to finish such genomes completely. The sequencing of the high G+C actinomycete Actinoplanes sp. SE50/110 was performed with standard pyrosequencing technology (454 Life Sciences) and revealed a high number of gaps. The reasons for the introduction of gaps were analyzed on a previously known 41kb long DNA reference sequence from Actinoplanes sp. SE50/110, hosting the acarbose biosynthesis gene cluster. Mapping of the sequencing results on the reference gene cluster sequence revealed a fragmentation into 30 contiguous sequences of different lengths. The gaps between these sequences were characterized by extremely low read coverage which strongly correlated with the G+C content in the gap regions in a negative manner. Furthermore, the gap sequences contained strong stem-loop structures which hindered the amplification of these sequences during the emulsion PCR. Being significantly underrepresented or absent in the subsequent sequencing process, these sequences lead to weakly or uncovered genomic regions which forces the assembly algorithm to output multiple contiguous sequences instead of one finished genome. However, by applying a different pyrosequencing protocol, it was possible to sequence the complete acarbose biosynthesis gene cluster. The changes to the protocol include longer read length and addition of chemicals to the amplification chemistry, which reduces the self-annealing of DNA fragments during the amplification process and enables the complete reconstruction of high G+C content genomes without manual intervention. PMID- 21536084 TI - Single mutation converts mild pathotype of the Pepino mosaic virus into necrotic one. AB - Pepino mosaic virus (PepMV) is a member of the Flexiviridae family, genus Potexvirus. PepMV isolates from the same genotype differ in the symptoms they induce in Datura inoxia and Solanum lycopersicum. Necrotic isolates cause necrosis on these plants whereas mild isolates are very often asymptomatic or induce mild mosaic. Sequence analysis of the genomes of mild (PepMV-P22) and necrotic (PepMV-P19) strains revealed that they differ by several nonsynonymous mutations. Eleven mutations are located in the RdRp coding region and one mutation is placed in the TGB3 coding region. To investigate whether these mutations affect the symptom induction, both PepMV-P22 and PepMV-P19 were mutagenized. As a result we found that the genetic determinant responsible for necrosis induction was amino acid 67 of TGB3. This showed that one point mutation is sufficient to alter the virus from mild to aggressive in tomato and D. inoxia. PMID- 21536085 TI - Prior infection of pigs with a genotype 3 swine hepatitis E virus (HEV) protects against subsequent challenges with homologous and heterologous genotypes 3 and 4 human HEV. AB - Hepatitis E virus (HEV) is an important human pathogen. At least four recognized and two putative genotypes of mammalian HEV have been reported: genotypes 1 and 2 are restricted to humans whereas genotypes 3 and 4 are zoonotic. The current experimental vaccines are all based on a single strain of HEV, even though multiple genotypes of HEV are co-circulating in some countries and thus an individual may be exposed to more than one genotype. Genotypes 3 and 4 swine HEV is widespread in pigs and known to infect humans. Therefore, it is important to know if prior infection with a genotype 3 swine HEV will confer protective immunity against subsequent exposure to genotypes 3 and 4 human and swine HEV. In this study, specific-pathogen-free pigs were divided into 4 groups of 6 each. Pigs in the three treatment groups were each inoculated with a genotype 3 swine HEV, and 12 weeks later, challenged with the same genotype 3 swine HEV, a genotype 3 human HEV, and a genotype 4 human HEV, respectively. The control group was inoculated and challenged with PBS buffer. Weekly sera from all pigs were tested for HEV RNA and IgG anti-HEV, and weekly fecal samples were also tested for HEV RNA. The pigs inoculated with swine HEV became infected as evidenced by fecal virus shedding and viremia, and the majority of pigs also developed IgG anti-HEV prior to challenge at 12 weeks post-inoculation. After challenge, viremia was not detected and only two pigs challenged with swine HEV had 1-week fecal virus shedding, suggesting that prior infection with a genotype 3 swine HEV prevented pigs from developing viremia and fecal virus shedding after challenges with homologous and heterologous genotypes 3 and 4 HEV. The results from this study have important implications for future development of an effective HEV vaccine. PMID- 21536086 TI - Insights into the cellular trafficking of splice redirecting oligonucleotides complexed with chemically modified cell-penetrating peptides. AB - Conjugates of cell-penetrating peptides (CPP) and splice redirecting oligonucleotides (ON) display clinical potential as attested by in vivo experimentation in murine models of Duchenne muscular dystrophy. However, micromolar concentrations of these conjugates are required to obtain biologically relevant responses as a consequence of extensive endosomal sequestration following endocytosis. Recent work from our group has demonstrated that appending stearic acid to CPPs increases their efficiency and that the inclusion of pH titrable entities leads to further improvement. Moreover, these modified CPPs form non covalent complexes with charged ON analogs or siRNAs, which allows decreasing the concentrations of ONs by nearly one log. These modified CPPs and the parent peptides have been compared here in the same in vitro model in terms of cell uptake, trafficking and splicing redirection activity. The increased splicing redirection activity of our modified CPPs cannot be explained by differences in cell uptake but rather by their enhanced ability to escape from endocytic vesicles. Accordingly, a clear correlation between membrane destabilizing activity and splicing redirection was observed using a liposome leakage assay. Studies of cellular trafficking for the most active PF6:ON complexes indicate uptake by clathrin-mediated endocytosis using either FACS cell uptake or a splicing redirection functional assay. Acidification of intracellular vesicles and membrane potential were found important for splicing redirection but not for cell uptake. These results do confirm that the increased potency of PF6:ON complexes is not due to the use of a non endocytic route of cell internalization as proposed for some CPPs. PMID- 21536087 TI - Intravital real-time confocal laser scanning imaging of PEGylated gene vectors. PMID- 21536088 TI - The significance of mannose-binding lectin gene polymorphisms on the risk of BK virus coinfection in women with human papillomavirus-positive cervical lesions. AB - The simultaneous detection of oncogenic human papillomavirus (HPV) and BK virus (BKV) has been recently reported in cervical cancers, suggesting that these viruses may act together in the process of cell transformation; host genetic polymorphisms may also influence virus persistence/reactivation. To disclose a possible role of the gene encoding for the mannose-binding lectin, MBL2, in susceptibility to BKV infection, we analyzed functional polymorphisms in the first exon of MBL2 in women stratified for the presence/absence of BKV and affected by different grades of HPV-induced cervical precancerous lesions. All BKV-positive samples were also HPV positive (HPV 16), and all presented with high grade squamous intraepithelial lesions. The MBL2 A allele was significantly more frequent in BKV-negative patients than in BKV-positive patients. These data indicate a possible role for the A allele in conferring protection to BKV infection in high-risk HPV-positive women (odds ratio 0.40, 95% confidence interval 0.20-0.85, p = 0.01). PMID- 21536089 TI - Genetic variation at immunoglobulin kappa locus is associated with hepatitis C treatment-induced viral clearance in African Americans. AB - Host genetic factors, especially genes of the immune system, are thought to contribute to the racial differences in response rates to therapy for hepatitis C virus (HCV) infection. The aim of the present investigation was to determine whether immunoglobulin gamma heavy chain marker (GM) and kappa light chain marker (KM) -were associated with sustained viral response (SVR) in patients treated with peginterferon-alpha-2a and ribavirin. DNA samples from 319 subjects with genotype-1 HCV infections were allotyped for alleles at four GM loci: GM3/GM17, GM23+/GM23-, GM5/GM21, GM6+/GM6- and the KM locus: KM1/KM3, using molecular methods. Noncarriage of KM1 allele, i.e., KM3 homozygosity, was associated with higher SVR in African Americans (odds ratio = 2.50, 95% confidence interval = 1.12-5.60). Consistent with this finding, the HCV RNA level in KM1 noncarriers was significantly (p = 0.013) lower than in carriers of this allele. Thus, the KM3 allele may be a marker for higher SVR in African Americans. PMID- 21536090 TI - Lack of an association between interleukin-6 gene promoter polymorphisms ( 174G/C, -572G/C) and ischemic heart disease and/or ischemic stroke: a meta analysis. AB - The association between single-nucleotide polymorphisms -174G/C (rs1800795) and 572G/C (rs1800796) in the interleukin-6 (IL-6) gene promoter region and ischemic heart disease (IHD)/ischemic stroke (IS) remains controversial and ambiguous. In this study, we performed a more precise estimation of the relationship by a meta analysis based on currently available evidence from literature. To assess the effect of IL-6 polymorphisms (-174G/C, -572G/C) on IHD/IS susceptibility, a meta analysis of 30 available studies was performed through May 2010. Summary odds ratios and their 95% confidence intervals for IL-6 polymorphisms and IHD/IS were estimated using fixed- and random-effects models when appropriate. Heterogeneity and publication bias were evaluated. When available studies were pooled into the meta-analysis, there was no significant association between IL-6 polymorphisms ( 174G/C, -572G/C) and IHD/IS in any comparison model (CC vs GG, GC vs GG, dominant, and recessive models). Subgroup analyses results were consistent with the main analyses by ethnicity, ischemic types, quality score, and genotyping methods. Ethnicity (European studies) and quality score (low-quality studies) might be important sources of heterogeneity for -174G/C. However, metaregression analysis did not reveal that the foregoing characteristics could explain the tau(2) in any comparison model. We could not identify the sources of heterogeneity for -572G/C. The present meta-analysis suggests that IL-6 promoter polymorphisms (-174G/C, -572G/C) were unlikely to be associated with risk of IHD and/or IS. PMID- 21536091 TI - Genetic association study suggests a role for SP110 variants in lymph node tuberculosis but not pulmonary tuberculosis in north Indians. AB - Ethnic specificity is a key determinant in understanding the association of genetic variants with outcome of disease susceptibility. SP110, a component of the nuclear body, has been subjected to association studies with conflicting results. In this study we probed SP110 variants in pulmonary (PTB) and lymph node tuberculosis (LNTB) cases to explore their role in controlling susceptibility to Mycobacterium tuberculosis infection in north Indians. We genotyped 24 SP110 variants in over 140 north Indian tuberculosis cases and 78 ethnicity-matched controls. The SP110 gene variants were available from public databases. The cases and controls were free of any population stratification when subjected to Eigenstrat principal component analysis. Genotyping was carried out using the Sequenom MassARRAY platform. Applying exclusion criteria, 11 single nucleotide polymorphisms (SNPs) of the LNTB panel and 13 SNPs of the PTB panel passed all filters and were analyzed further. No significant association was observed between SP110 variants and PTB. Surprisingly, we discovered evidence of an association of SP110 variants with LNTB, a form of extrapulmonary tuberculosis, at 3 loci, namely, rs6436915, rs1427294, and rs1346311. When permutations analysis (n = 10,000) of allelic p values was undertaken, only rs1427294 passed the test with its p value remaining statistically significant. The C allele of rs1427294 exhibited a 5-fold risk of developing LNTB. No significant haplotypes were observed. In the pilot study presented here, our results provide evidence for the first time that SP110 may be a risk determinant locus in LNTB while confirming a doubtful role of SP110 in PTB in north Indians. In general, the results might indicate a role of SP110 variants in extrapulmonary tuberculosis rather than PTB. PMID- 21536092 TI - Gender differences in trait aggression in young adults with drug and alcohol dependence compared to the general population. AB - OBJECTIVE: Data in gender differences in aggression among alcohol and drug dependent subjects are lacking, and no published data are available about gender differences among various subtypes of substance using populations. The goal of this cross-sectional study was to investigate gender differences with regard to types of trait aggression in substance dependent young populations (age: 20-35 years) compared to the general population. METHODS: Subjects were selected from two clinical samples with a diagnosis of alcohol and drug dependence as well as from a representative sample of the general population. Trait aggression was measured by the four individual subscales of the Buss Perry Aggression Questionnaire (physical-PA, verbal aggression-VA, hostility-H and anger AN) whereas alcohol and drug use were characterized by the AUDIT and EuroADAD scales, respectively. RESULTS: Alcohol and drug dependent subjects showed higher severity on all four subscales of trait aggression compared to the general population. The male-female difference was the highest in the cannabis group. General Linear Model analysis for PA indicated a significant main effect of gender (higher PA for males, p=0.034) with no interaction between substance dependence and gender. For VA, no main effect or interaction for gender was found. Effect sizes for gender difference indicated that while males and females were similar in the control group in the severity in H and A, the level of H and AN was substantially higher in females than in males in the clinical group. These differences between the two genders reached statistical significance in the marijuana group, where female subjects showed a significantly higher severity in these two domains. CONCLUSIONS: Compared to the normal sample chronic substance use is associated with higher scores on certain factors of trait aggression, including hostility and anger, in females than in males. Our data suggest that aggression in substance dependent females is more provocable by chronic use of alcohol and drugs than in males. PMID- 21536093 TI - TaMYB4 cloned from wheat regulates lignin biosynthesis through negatively controlling the transcripts of both cinnamyl alcohol dehydrogenase and cinnamoyl CoA reductase genes. AB - The subgroup 4 of R2R3-MYB transcription factors has been proposed as repressors regulating the phenylpropanoid pathway. Here, we report a cDNA encoding a subgroup 4 R2R3-MYB factor from wheat, designated as TaMYB4. A phylogenetic analysis showed that TaMYB4 is in a subclade that is specific to monocot plants. The TaMYB4 gene was highly expressed in stem and root tissues. In vitro binding analysis in yeast cells showed TaMYB4 interacted with OsCAD2 promoter characterized by an AC-II element that has been considered as the MYB-binding site in lignin biosynthetic genes. The overexpression of TaMYB4 in transgenic tobacco led to transcriptional reduction of both cinnamyl alcohol dehydrogenase (CAD) and cinnamoyl-CoA reductase (CCR) genes involved in the lignin biosynthesis. Enzymatic assay showed reduction of CAD and CCR activities in the transgenic tobacco plants that substantially decreased the levels of total lignin but increased it's ratio of S/G. In addition, the total flavonoid content was increased in transgenic tobacco leaves, suggesting that the overexpression of TaMYB4 likely led to a redirection of the metabolic flux from the lignin pathway to the flavonoid pathway. These data suggest that TaMYB4 negatively regulates the lignin biosynthesis in wheat. PMID- 21536094 TI - The emergence of designed multiple ligands for neurodegenerative disorders. AB - The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline. PMID- 21536096 TI - Moving forward with experimental hematology. PMID- 21536095 TI - Auditory ERP components before and after transition to a first psychotic episode. AB - We investigated the course of Event Related Potentials (ERP) from prior to until shortly after a first psychotic episode in subjects at Ultra High Risk (UHR) for psychosis. N1, N2, N2b, P2 and P3 amplitudes were assessed using an auditory active oddball paradigm in 15 UHR subjects who made a transition to psychosis (UHR+T) at follow up, 23 subjects without a transition (UHR+NT) and 17 matched healthy controls at inclusion and again after approximately 18 months. Repeated measures analyses revealed no significant time effects for any of the ERP components. However, an interaction effect was found for N1 amplitudes. Post-hoc analyses showed that N1 amplitudes were smaller at follow up compared to baseline only in UHR+T subjects. P3 amplitudes showed no further reduction after psychotic onset. These findings suggest that discernable ERP components behave differently during progression from the prodromal phase to the first psychotic episode. These findings may give insight in pathophysiological mechanisms underlying the genesis of psychosis. PMID- 21536097 TI - Do elementary flux modes combine linearly at the "atomic" level?: integrating tracer-based metabolomics data and elementary flux modes. AB - The elementary flux modes (EFMs) approach is an efficient computational tool to predict novel metabolic pathways. Elucidating the physiological relevance of EFMs in a particular cellular state is still an open challenge. Different methods have been presented to carry out this task. However, these methods typically use little experimental data, exploiting methodologies where an a priori optimization function is used to deal with the indetermination underlying metabolic networks. Available "omics" data represent an opportunity to refine current methods. In this article we discuss whether (or not) metabolomics data from isotope labeling experiments (ILEs) and EFMs can be integrated into a linear system of equations. Aside from refining current approaches to infer the physiological relevance of EFMs, this question is important for the integration of metabolomics data from ILEs into metabolic networks, which generally involve non-linear relationships. As a result of our analysis, we concluded that in general the concept of EFMs needs to be redefined at the atomic level for the modeling of ILEs. For this purpose, the concept of Elementary Carbon Modes (ECMs) is introduced. PMID- 21536098 TI - Cellular and molecular actions displayed by estrone on vascular endothelium. AB - In this work we provide evidence that estrone "per se" modulates cellular endothelial growth and survival, events that play key roles in the development of vascular disease. Moreover, under oxidative stress conditions the hormone prevented apoptosis triggered by hydrogen peroxide. Although estrone did not affect E-selectin and VCAM-1 mRNAs synthesis, the hormone prevented the expression of these adhesion molecules induced by the proinflammatory agent LPS. The steroid partially attenuated leukocyte adhesion not only under basal conditions but also in the presence of LPS. Using ICI182780 compound as estrogen receptor antagonist, and PD98059 as MAPK inhibitor we obtained evidence that the mitogenic action of estrone involved the participation of ER and MAPK transduction pathway activation. The presence of estradiol impaired the effect of estrone on cell proliferation and vasoactive production. These results suggest that estrone exhibits a remarkable biological action on endothelial cells, modulating vasoactive production, proliferation, apoptosis, and cell adhesion events. PMID- 21536099 TI - Cerebral capillary endothelial cells are covered by the VEGF-expressing foot processes of astrocytes. AB - Molecules that have crucial functions in both nervous and vascular systems have attracted keen attention recently, and the name "angioneurins" has been proposed. The most striking example of angioneurins is vascular endothelial growth factor A (VEGF), which was originally identified as a key regulator of angiogenesis and has only recently been found to have important functions in the nervous system. In this study, we compared VEGF expression in the vasculature in the brain with that in the aorta and the vasculature in the kidney in mice. In larger vessels containing smooth muscle cells, VEGF was expressed by smooth muscle cells covering the lining of endothelial cells, both in and outside the brain. In cerebral capillaries lacking smooth muscle cells, endothelial cells were closely covered by VEGF-expressing foot processes of astrocytes, whereas capillaries were surrounded by VEGF-expressing processes of podocytes in the renal glomeruli. We also found that cultured cerebral microvessel endothelial cells do not express VEGF, whereas cultured cortical astrocytes do express VEGF. PMID- 21536100 TI - In vitro production of an active neurotrophic factor, neuregulin-1: qualitative comparison of different cell-free translation systems. AB - The individual biological activities of many neurotrophic factors and their variants, which are produced by alternative splicing and proteolytic processing, often remain to be characterized. Bacterial protein production combined with protein refolding and purification is a conventional procedure to obtain active neurotrophic factors; however, the procedure is time consuming and appropriate protein refolding in vitro is sometimes unpredictable. Here we examined three distinct cell-free translation systems: reticulocyte lysate, Hela cell lysate and wheat germ extract, which may allow us to produce biologically active factors in a single tube. Taking type-I neuregulin-1 beta3 as an example, we produced neuregulin-1 protein from its mRNAs flanked by Cap nucleotide and/or internal ribosome entry site (IRES) and compared the yields and biological activity of translation products from these systems. The protein yield from IRES+ mRNA was highest in the Hela cell-free system, while background translation was lowest in the wheat germ system. The biological activity of both translation products was modest or negligible, however. Neuregulin-1 protein was produced in reticulocyte lysate at yields of 19 pmol/mL (~500 ng/mL); furthermore, it was potent at phosphorylating ErbB4 receptor and able to bind to heparin sulfate. These results demonstrate that the reticulocyte lysate translation system produces active neurotrophic factors in vitro and is useful for radiolabeling or preliminary assessment of novel neurotrophic factors and their variants. PMID- 21536101 TI - Dealing with individual variability: when telling what is real depends on telling who is acting. AB - You are queuing at the bus stop, and notice that someone suddenly turns her walk into a run: typically, you assume that she wants to catch the bus and may want to tell the driver to wait. Faced with a sudden speed change, rather than considering it bizarre or unnatural, observers attach a meaning to it, and act consequently. In a social context, speed of a movement often bears as much significance as its form, and can be adapted to vehicle precise meanings. This pragmatic rule facilitates decoding of non-verbal messages from other individuals, but may not necessarily apply when observing one's own movements, for which intentions should be informative enough. Hence, the range of motion speeds labeled as 'natural' could be broader for other people's actions compared to one's own. We explored this possibility through a task in which human observers decided whether speed of a gesture had been artificially modified. A virtual hand was presented, which - unbeknownst to participants - moved according to the kinematics of either the observer, or another individual. Although a self/other distinction was never required, participants applied different criteria when dealing with self compared to other people's gestures, suggesting that the brain implicitly extracts identity information before any overt judgment is produced. Interestingly, observers were reluctant to labeling movements of another individual as artificial, in keeping with the hypothesis that large variations in movements' speed can vehicle social messages, and therefore are not regarded a priori as unnatural. PMID- 21536102 TI - Immunohistochemical localization of AMPA-type glutamate receptor subunits in the nucleus of the Edinger-Westphal in embryonic chick. AB - The Edinger-Westphal nucleus (EW) in birds is responsible for the control of pupil constriction, accommodation, and choroidal blood flow. The activation of EW neurons is mediated by the neurotransmitter glutamate, in large part through AMPA type glutamate receptors (GluRs), whose behavior varies according to the subunit composition. We investigated the developmental expression of the GluR subunits in EW of the chick (Gallus gallus) using immunohistochemistry on tissue from embryonic days 10 through 20 (E10-E20). Of the three antibodies used, one recognized the GluR1 subunit, another the GluR4 subunit, and the third recognized a sequence common to GluR2 and GluR3 subunits. No immunolabeling of EW neurons for any GluR subunits was observed prior to E12, although immunolabeling was seen in somatic oculomotor prior to E12. At E12, immunoreactivity for each of the three antibodies was in only approximately 2% of EW neurons. By E14, the abundance of GluR1+ perikarya in EW had increased to 13%, and for GluR2/3 had increased to 48%. The perikaryal abundance of the immunoreactivity for GluR1 and GluR2/3 declined to 3% and 23%, respectively, by E16. At E14, 33% of EW neurons immunolabeled for GluR4, and their frequency increased to 43% by E16, and remained at that approximate percentage through hatching. The increased expression of GluR1 and GluR4 in EW at E14 coincides with the reported onset of the expression of the calcium-binding protein parvalbumin, and the calcium currents associated with AMPA receptors formed by these two subunits may play a role in the occurrence of parvalbumin expression. PMID- 21536103 TI - Neural mechanisms of subliminal priming for traumatic episodic memory: an ERP study. AB - Event-related brain potentials (ERPs) were measured to study the electrophysiological mechanisms of subliminal priming of traumatic episodic memory. Twenty-four Chinese subjects who had experienced the great Sichuan earthquake in 2008 were classified either as normal control or as post-traumatic stress disorder (PTSD) subjects. Results showed that subliminally presented earthquake-related words elicited two significantly more positive ERP deflections (P2 and P300) than did earthquake-unrelated words between 250-300 ms and 340-400 ms post-stimulus periods for the PTSD group, but not for the control group. Dipole source analysis showed that the P2 was mainly generated in the posterior cingulate cortex (PCC), which appeared to be related to unconscious attentional resource allocation to the earthquake-related words. In addition, the P300 was found to be generated in the parahippocampal gyrus, which seemed to be related to the involuntary activation of traumatic episodic memory. These results indicated that catastrophic earthquake experiences made some subjects extremely sensitive and hyper-responsive to trauma-related information. PMID- 21536104 TI - Neuroprotective effects of tenuigenin in a SH-SY5Y cell model with 6-OHDA-induced injury. AB - Tenuigenin, an active component of Polygala tenuifolia root extracts, has been shown to provide antioxidative and anti-aging effects in Alzheimer's disease, as well as to promote proliferation and differentiation of neural progenitor cells. However, the effects of tenuigenin on Parkinson's disease remain unclear. In the present study, SH-SY5Y cells were utilized to determine the effects of tenuigenin on 6-hydroxydopamine (6-OHDA)-induced injury. Results showed that 1.0 * 10-1-10 MUM tenuigenin significantly promoted cell viability and reduced cell death. In addition, tenuigenin protected mitochondrial membrane potential (MMP) against 6 OHDA damage and significantly increased glutathione and superoxide dismutase expression. At the mRNA level, tenuigenin resulted in down-regulation of caspase 3, but up-regulation of tyrosine hydroxylase expression in 6-OHDA damaged cells. These results suggested that tenuigenin provides neuroprotection to dopaminergic neurons from 6-OHDA-induced damage. The neuroprotective mechanisms might involve antioxidative effects, maintenance of mitochondrial function, and regulation of caspase-3 and tyrosine hydroxylase expression and activity. Tenuigenin could provide a novel antioxidative strategy for Parkinson's disease. PMID- 21536105 TI - LPS elicits a much larger and broader inflammatory response than Escherichia coli infection within the hippocampus of neonatal rats. AB - An immune challenge during the neonatal period can significantly affect the development of the nervous and immune systems, such that long-term abnormalities in immune function and behavior persist into adulthood. Given that immune activation and individual cytokines have been linked to the etiology of many developmental neuropsychiatric disorders, a complete characterization of the neonatal immune response within the brain is warranted. In this study, rats were treated peripherally on postnatal day (P) 4 with either a live Escherichia coli (E. coli) infection or lipopolysaccharide (LPS), two common models of neonatal immune activation. Inflammatory gene expression was measured within the hippocampus 2 and 24h later. We determined that E. coli and LPS produce very distinct inflammatory profiles within the brain. Infection with E. coli produced a robust, yet relatively IL-1 pathway focused activation of the neonatal immune system within the brain, while LPS produced a very broad and robust immune response within the brain. This analysis also identified common inflammatory genes up-regulated by both E. coli and LPS treatment. PMID- 21536107 TI - Status epilepticus stimulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha/mitochondrial antioxidant system pathway by a nitric oxide dependent mechanism. AB - Peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1-alpha (PGC 1alpha) is a transcriptional coactivator identified as an upstream regulator of lipid catabolism, mitochondrial number and function. PGC-1alpha protects neurons against oxidative damage by inducing several members of the mitochondrial antioxidant system such as superoxide dismutase 2 (SOD2) and uncoupling protein 2 (UCP2). Its role in seizure-induced oxidative stress has not been studied. Here we showed that pilocarpine-induced status epilepticus (SE) stimulates the PGC 1alpha/mitochondrial antioxidant system signaling pathway in the rat hippocampus. Because nitric oxide (NO) is the key factor of mitochondrial biogenesis through the transcriptional induction of PGC-1alpha, we investigated whether NO is involved in activation of the PGC-1alpha/mitochondrial antioxidant system after SE. Treatment with the NO synthase (NOS) inhibitor N(G)-nitro-l-argininemethyl ester (l-NAME) attenuated the increased expression of the PGC 1alpha/mitochondrial antioxidant system after SE and enhanced oxidative stress. These results suggest that SE can induce the PGC-1alpha/mitochondrial antioxidant system signaling pathway, which may represent a protective mechanism against SE induced oxidative stress. Furthermore, NO may positively regulate the mitochondrial antioxidant system by inducing PGC-1alpha in pilocarpine-induced SE. PMID- 21536108 TI - Daily morphine injection and withdrawal disrupt 24-h wheel running and PERIOD2 expression patterns in the rat limbic forebrain. AB - Symptoms of opiate withdrawal include disturbances in circadian rhythms. We examined in male Wistar rats (n=48) the effects of a daily, mid-morning morphine injection (5-40 mg/kg, i.p.) and its withdrawal on 24-h wheel-running activity and on the expression of the clock protein, PERIOD2 (PER2), in the suprachiasmatic nucleus (SCN), oval nucleus of the bed nucleus of the stria terminalis (BNSTov), central amygdala (CEA), and dorsal striatum. Rats were killed over 2 days at 10, 22, 46, and 58 h after the last daily morphine injection at zeitgeber times (ZT) 1 or ZT13. Daily morphine injections and their withdrawal suppressed nighttime wheel running, but did not entrain any increase in activity in advance of the injection. Neither morphine injection nor its withdrawal affected PER2 expression in the SCN, whereas the normal daily peaks of PER2 in the BNSTov, CEA, and dorsal striatum were blunted both during morphine administration and its withdrawal. Treatment with a dopaminergic agonist (the D2/3 agonist, quinpirole, 1.0 mg/kg) or a noradrenergic agonist (alpha2 agonist, clonidine, 0.1 mg/kg) in morphine withdrawal did not restore normal PER2 patterns in each affected region; however, both quinpirole and clonidine themselves altered normal daily PER2 expression patterns in morphine-naive rats. These findings confirm and extend previous observations that opiates disrupt daily patterns of clock gene expression in the limbic forebrain. Furthermore, catecholaminergic drugs, which have been previously found to alleviate symptoms of opiate withdrawal, do not alleviate the effects of morphine withdrawal on PER2, but do modulate daily patterns of PER2 expression in saline controls. PMID- 21536106 TI - Regulation of cardiovascular cellular processes by S-nitrosylation. AB - BACKGROUND: Nitric oxide (NO), a highly versatile signaling molecule, exerts a broad range of regulatory influences in the cardiovascular system that extends from vasodilation to myocardial contractility, angiogenesis, inflammation, and energy metabolism. Considerable attention has been paid to deciphering the mechanisms for such diversity in signaling. S-nitrosylation of cysteine thiols is a major signaling pathway through which NO exerts its actions. An emerging concept of NO pathophysiology is that the interplay between NO and reactive oxygen species (ROS), the nitroso/redox balance, is an important regulator of cardiovascular homeostasis. SCOPE OF REVIEW: ROS react with NO, limit its bioavailability, and compete with NO for binding to the same thiol in effector molecules. The interplay between NO and ROS appears to be tightly regulated and spatially confined based on the co-localization of specific NO synthase (NOS) isoforms and oxidative enzymes in unique subcellular compartments. NOS isoforms are also in close contact with denitrosylases, leading to crucial regulation of S nitrosylation. MAJOR CONCLUSIONS: Nitroso/redox balance is an emerging regulatory pathway for multiple cells and tissues, including the cardiovascular system. Studies using relevant knockout models, isoform specific NOS inhibitors, and both in vitro and in vivo methods have provided novel insights into NO- and ROS-based signaling interactions responsible for numerous cardiovascular disorders. GENERAL SIGNIFICANCE: An integrated view of the role of nitroso/redox balance in cardiovascular pathophysiology has significant therapeutic implications. This is highlighted by human studies where pharmacologic manipulation of oxidative and nitrosative pathways exerted salutary effects in patients with advanced heart failure. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation. PMID- 21536109 TI - Cocaine enhances ST8SiaII mRNA expression and neural cell adhesion molecule polysialylation in the rat medial prefrontal cortex. AB - The present study investigated whether cocaine (COC) administration evokes changes in the mRNA and protein levels of neural cell adhesion molecule (NCAM) and polysialylated neural cell adhesion molecule (PSA-NCAM) in the medial prefrontal cortex (mPFC) of rats. NCAM/PSA-NCAM is required for neuronal structural plasticity and is constitutively expressed in the mPFC. Rats were treated with a single dose of COC (15 mg/kg, i.p.), and mRNA levels of NCAM and the polysialyltransferases ST8SiaII and ST8SiaIV, enzymes involved in polysialylation of NCAM, were measured at 3, 6 and 24 h after COC treatment. At the same time points, the protein levels of NCAM and PSA-NCAM were measured via western blotting. Acute COC injection did not affect mRNA levels of NCAM and ST8SiaIV, but it increased the mRNA level of ST8SiaII 3 h after injection. At the same time point, an increase in PSA-NCAM, but not in NCAM, protein was observed. Morphological studies of PSA-NCAM protein expression patterns (immunocytochemistry/stereology) performed 3 h after COC administration revealed an enhancement of PSA-NCAM immunostaining in perisomatic-like sites and in the length density of PSA-NCAM-positive neuropil. Double immunofluorescence staining showed that PSA-NCAM perisomatic-like sites surround excitatory neurons. We also observed that a single injection of raclopride (0.4 mg/kg) or SCH 23390 (0.5 mg/kg), D2/D3 and D1 dopamine receptors antagonists, respectively, which were ineffective when given alone, abolished the effects of COC administration on mRNA and protein expression. The data in the present study indicate that COC administration may modify constitutive synaptic plasticity in the mPFC by increasing the NCAM polysialylation in perisomatic innervations of pyramidal neurons via activation of dopamine D1 and D2/D3 receptors. PMID- 21536110 TI - Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis. AB - Pathological changes occur in areas of CNS tissue remote from inflammatory lesions in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). To determine if oxidative stress is a significant contributor to this non-inflammatory pathology, cortex tissues from mice with clinical signs of EAE were examined for evidence of inflammation and oxidative stress. Histology and gene expression analysis showed little evidence of immune/inflammatory cell invasion but reductions in natural antioxidant levels and increased protein oxidation that paralleled disease severity. Two-dimensional oxyblots and mass-spectrometry-based protein fingerprinting identified glutamine synthetase (GS) as a particular target of oxidation. Oxidation of GS was associated with reductions in enzyme activity and increased glutamate/glutamine levels. The possibility that this may cause neurodegeneration through glutamate excitotoxicity is supported by evidence of increasing cortical Ca(2+) levels in cortex extracts from animals with greater disease severity. These findings indicate that oxidative stress occurs in brain areas that are not actively undergoing inflammation in EAE and that this can lead to a neurodegenerative process due to the susceptibility of GS to oxidative inactivation. PMID- 21536111 TI - Synergistic interaction of dopamine D1 and glutamate N-methyl-D-aspartate receptors in the rat dorsal striatum controls attention. AB - The balance between corticostriatal glutamate inputs and mesostriatal dopamine afferents converging onto the same postsynaptic spines of striatal medium spiny neurons in the dorsal striatum is believed to be crucial for regulating executive functions including attention.In the present study we examined the role of dopamine D(1) and glutamate N-methyl-d-aspartate (NMDA) receptors within the medial territory of the dorsal striatum (dm-STR) of the rat during performance of a selective attention task such as the 5-choice serial reaction time (5-CSRT) task, which incorporates a variety of measures including accuracy of visual discrimination (an index of attentional functioning), omissions, premature and perseverative responses (indices of inhibitory response control) and correct response latency (decision time). Infusion of 30 ng/side of the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) in the dm-STR decreased accuracy and increased the proportion of omission but had no effect on premature or perseverative responding or correct response latency. A lower dose of 10 ng/side CPP only affected omissions. Blockade of D(1) receptors in the dm-STR by SCH23390 (50 and 100 ng/side) had no effect on accuracy but at 100 ng/side SCH23390 decreased anticipatory responding and increased the proportion of omissions. Co-infusion of SCH23390 (50 ng/side) and CPP (10 ng/side), at individually ineffective doses, potently reduced the accuracy of visual discrimination. The effects were highly selective as no changes in response control, decision time and omissions were detected. The data suggest that the synergistic interaction of D(1) and NMDA receptors on the dendritic spines of GABA neurons within the dm-STR may represent a mechanism for the control of attention. PMID- 21536112 TI - Cytotoxicity and biocompatibility evaluation of a poly(magnesium acrylate) hydrogel synthesized for drug delivery. AB - We report the synthesis and characterization as well as cytotoxicity and biocompatibility studies of a poly(magnesium acrylate) hydrogel (PAMgA) developed for drug delivery applications. Two hydrogels with different mesh sizes, large and short, were synthesized (L-C PAMgA and S-C PAMgA). The hydrogels were characterized through swelling, FT-IR and DSC. Cytotoxicity in vitro was evaluated on cell line NIH-3T3 fibroblasts via direct contact and two indirect contact methods (MTT and flow citometry). Both PAMgA hydrogels exhibited low cytotoxicity with survival rates higher than 90%. To select their administration route, biocompatibility was evaluated after intraperitoneal, subcutaneous, and oral administration to mice of both hydrogels at different dose ranges. Swelling percentages obtained were 33.3 +/- 4.2% and 166.7 +/- 8.3% for L-C PAMgA and S-C PAMgA respectively, showing a great difference in both hydrogels. Among the administration routes assayed, the hydrogels were well tolerated after oral administration of a wide dose range (10-500 mg/kg), thereby indicating that both PAMgA hydrogels are excellent candidates for oral administration due to their in vitro biocompatibility and oral non-toxicity. These results together with the fact that their synthesis is simple and inexpensive make them good candidates for the design of oral drug delivery devices. PMID- 21536113 TI - Comprehensive comparison of two new biodegradable gene carriers. AB - Safety and high transfection efficiency are the prerequisites for an ideal gene vector. Polyethylenimine (PEI), especially PEI 25k (25 kDa), is a well-known cationic gene carrier with high transfection efficiency. However, the high toxicity, depended on its molecular weight, has limited its use as a potential gene carrier. In our research, for the purpose of reducing the toxicity and increasing the transfection efficiency and further to inspect where the degradation of these biodegradable polymers take place would be more beneficial, in cytoplasm or in endocytic vesicles, two kinds of degradable polymers were synthesized. One is an acid-liable PEI derivate (PEI-GA) which was cross-linked by PEI 2k with glutadialdehyde (GA) through imine linkages and the other one (PEI TEG) was cross-linked PEI 2k with modified triethyleneglycol (TEG) through biscarbamate linkages and can be degraded at neutral environment. By the use of a series of assay methods both in vitro and in vivo, the results showed that PEI TEG was found to be biodegradable at neutral environment and exhibit high transfection ability with low toxicity, which indicated its potential as a candidate carrier for gene therapy. PMID- 21536114 TI - Functionalization of lactose as a biological carrier for bovine serum albumin by electrospraying. AB - Electrohydrodynamic atomization (EHDA) is an attractive technique to make new types of composite particles for pharmaceutical use. The aim of this work is to prove that EHDA can be successfully used to attach nano/micro-particles of protein to lactose, the commonly used excipient for pulmonary delivery, keeping all the biological properties of the protein after dissolution of the complex. Bovine serum albumin (BSA) was used as a model protein. The atomization of BSA was tested with two different solvents, dimethyl sulfoxide (DMSO) and ethanol. The process using DMSO resulted in the formation of a thin layer of protein while the tests using ethanol resulted in the formation of spherical particles with mean diameters around 700 nm. Ethanol as solvent was also used to produce a composite formed by BSA adsorbed at the surface of lactose by electrostatic forces. No denaturation or significant conformational changes of the protein were observed, although an increase in the exposition of the lactose to the jet of the solution decreases the reproducibility of the method. Due to the absence of denaturation in the model protein, this new approach can be tested for the production of new formulations for dry powders for drug delivery systems. PMID- 21536115 TI - Administration-dependent efficacy of ferrociphenol lipid nanocapsules for the treatment of intracranial 9L rat gliosarcoma. AB - The anti-tumour effect of ferrociphenol (FcdiOH)-loaded lipid nanocapsules (LNCs), with or without a DSPE-mPEG2000 coating, was evaluated on an orthotopic gliosarcoma model after administration by convection-enhanced delivery (CED) technique or by intra-carotid injection. No toxicity was observed by MRI nor by MRS in healthy rats receiving a CED injection of FcdiOH-LNCs (60MUL, 0.36mg of FcdiOH/rat) when the pH and osmolarity had been adjusted to physiological values prior to injection. At this dose, the treatment by CED with FcdiOH-LNCs significantly increased the survival time of tumour-bearing rats in comparison with an untreated group (28.5 days vs 25 days, P=0.0009) whereas DSPE-mPEG2000 FcdiOH-LNCs did not exhibit any efficacy with a median survival time of 24 days. After intra-carotid injection (400MUL, 2.4mg of FcdiOH/rat), hyperosmolar DSPE mPEG2000-FcdiOH-LNCs markedly increased the median survival time (up to 30 days, P=0.0008) as compared to the control (20%). This was strengthened by their evidenced accumulation in the tumour zone and by the measure of the fluorescent brain surface obtained on brain slides for these DiI-labelled LNCs, being 3-fold higher than for the control. These results demonstrated that, depending upon the administration route used, the characteristics of LNC suspensions had to be carefully adapted. PMID- 21536116 TI - A novel microsphere with a three-layer structure for duodenum-specific drug delivery. AB - Owing to the quick elimination of drug from duodenum and the depth of Helicobacter pylori (H. pylori) colonized in mucus, antibiotic therapy often fails in the eradication of H. pylori infection for duodenal ulcer. A novel duodenum-specific microsphere (DSM) consisting of three-layer structure was developed to enhance the drug concentration and retention time in duodenal mucus layer. Firstly a core-shell mucoadhesive microsphere was prepared with a novel emulsification/coagulation coating method by introducing drug loaded Eudragit cores into a thiolated chitosan mucoadhesive layer. Then the obtained core-shell mucoadhesive microspheres were further coated with hydroxypropyl methylcellulose acetate maleate as the pH-sensitive layer for the trigger of mucoadhesion and drug release in duodenum. From the fluorescence microscopic and scanning electron microscopic images, the three-layer structure was successfully established. The microspheres exhibited a duodenum-specific trigger performance, good mucoadhesive property and pH-dependent drug release. In vivo study performed in rats demonstrated that DSM exhibited about 3-fold augmentation of AUC and about 5-fold augmentation of C(max) for duodenal mucus drug concentration compared with free drug suspension. These results suggest that the three-layer structure microspheres may provide a promising approach for duodenum-targeting drug delivery system. PMID- 21536117 TI - Novel polymeric/lipidic hybrid systems (PLHs) for effective Cidofovir delivery: preparation, characterization and comparative in vitro study with polymeric particles and liposomes. AB - Cidofovir is an antiviral drug active as antitumoral agent a high doses against the Primary Effusion Lymphoma, a herpesvirus HHV8-associated B-cell lymphoma. A novel polymeric/lipidic hybrid system, consisting in a specific combination of biocompatible materials, capable to build a crossbred between polymeric particles and liposomes were prepared and used to stabilize and deliver the drug, unsuccessfully formulated into several types of carriers. This innovative cidofovir-delivering system has structurally been characterized in comparison to multilamellar liposomes and polymeric particles, and then tested for antitumoral efficacy against tumor cells (BCBL-1 cell line). The results demonstrated the improving of drug stability and encapsulation efficiency and suggested that polymeric/lipidic hybrid system could be promising to improve the antitumoral effect of cidofovir even at lower doses. PMID- 21536118 TI - Concentration and surface of absorption: concepts and applications to gastrointestinal patches delivery. AB - Gastrointestinal patches represent a novel multiparticulate drug delivery system able to increase the intestinal absorption of drugs with poor bioavailability. The number of patches to administer is a critical issue since it is related to the surface and drug concentration at the absorption site. The objective of this article is to evaluate the effect of the number of administered patches on the final absorption of leuprolide, a peptide chosen as model drug, assuming complete adhesion of all the devices to the intestinal membrane. The same dose of leuprolide was encapsulated into 2, 4 and 6 patches; the resulting intestinal absorption profiles were measured with the Ussing chamber ex vivo experimental setup and compared between them. The results showed that varying the number of patches, the final absorption does not present statistically significant changes, indicating that changes in concentration are balanced by change in absorption surface. These experimental findings can also be explained considering the equation that links the drug flow to surface and concentration at the absorption site, showing that the drug flow is related only to the geometry of each individual patch. PMID- 21536119 TI - Optimize nuclear localization and intra-nucleus disassociation of the exogene for facilitating transfection efficacy of the chitosan. AB - Previously, we had reported improving transfection efficiency of the chitosan plasmid DNA (CS/pDNA)complex via enhancing intracellular unpacking of the exogene by the utilization of phosphorylatable short peptide conjugated chitosan (pSP CS). In this article, we addressed a novel strategy of nucleus localization signal linked nucleic kinase substrate short peptide (NNS) modification for further optimization of the transfection efficiency. NNS, consisting of "PKKRKVREEAIKFSEEQRFRR", contained a SV40 nucleus localization signal and a potentially phosphorylatable serine residue. The short peptide could be selectively phosphorylated in the nucleus in various mammalian cells. This phosphorylatable NNS (pNNS) was conjugated to chitosan and combined with Cy3 fluorescence labeled plasmid DNA to form a pNNS-CS/pDNA complex. In vitro phosphorylation and DNA releasing assays verified that pNNS could be effectively and selectively phosphorylated by nucleic lysate, hence promoting pDNA unpacking from the complex. Thereafter, C2C12 myoblast cells were transfected. Nuclear localization of the pDNA was represented by the fluorescence in the nucleus and transfection efficiency was determined by the expression of the luciferase reporter gene, which is carried by the plasmid DNA. The results revealed that, compared with lipofactamine2000 and the previously reported pSP-CS, pNNS-CS could transport more pDNA into the nucleus and intensively augment luciferase reporter gene expression. In conclusion, nucleus localization and unpacking from the delivery vector are both critical factors in influencing exogene expression, and pNNS modification is valuable in improving transfection efficacy of the chitosan. PMID- 21536120 TI - Ion flow in cochlear hair cells and the regulation of hearing sensitivity. AB - This paper discusses how ion transport proteins in the hair cells of the mammalian cochlea work to produce a sensitive but stable hearing organ. The transport proteins in the inner and outer hair cells are summarized (including their current voltage characteristics), and the roles of these proteins in determining intracellular Ca(2+), membrane potential, and ultimately cochlear sensitivity are discussed. The paper also discusses the role of the Ca(2+) sequestration sacs in outer hair cells in the autoregulation of hair cell membrane potential and cochlear gain, and how the underdamped control of Ca(2+) within these sacs may produce the observed slow oscillations in cochlear sensitivity and otoacoustic emissions after cochlear perturbations, including perilymphatic perfusions and prolonged low-frequency tones. The relative insensitivity of cochlear gain to short-term changes in the endocochlear potential is also discussed. PMID- 21536121 TI - Adrenoceptor-mediated enhancement of interleukin-33 production by dendritic cells. AB - While noradrenaline and adrenaline suppress some aspects of immune functions, the immune enhancement via these catecholamines is not well understood. Interleukin (IL)-33, a novel member of the IL-1 family, promotes T helper type 2 (T(h)2) associated inflammations and plays a role in allergic diseases. However, the precise immune cell source and the stimulating factors for IL-33 production are less well characterized. In the present study, we examined the effects of noradrenaline and adrenaline, stress-related catecholamines, on IL-33 production by dendritic cells (DCs). Murine bone marrow-derived DCs were stimulated with lipopolysaccharide (LPS) in the presence or absence of these catecholamines. LPS alone slightly increased IL-33 production by DCs. Noradrenaline or adrenaline dramatically enhanced IL-33 mRNA expression and its protein synthesis by DCs upon LPS stimulation. The noradrenaline-induced enhancement of IL-33 production was completely blocked by beta(2)-adrenoceptor specific antagonist ICI 118,551, while beta(2)-adrenoceptor specific agonist salmeterol enhanced DC production of IL-33. Protein kinase A (PKA) specific inhibitor H89 blocked the noradrenaline-induced IL-33 production. Cyclic adenosine monophosphate (cAMP) and its analogue enhanced DC production of IL-33 upon LPS stimulation. Thus, beta(2)-adrenoceptor-mediated cAMP-PKA pathway appears to enhance DC production of IL-33. The adrenoceptor mediated enhancement of IL-33 production by DCs might be associated with the stress-related progression of T(h)2-associated disorders. PMID- 21536122 TI - Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women. AB - Low socioeconomic status (SES) may be associated with accelerated biological aging, but findings relating SES with telomere length have been inconsistent. We tested the hypotheses that shorter telomere length and telomerase activity would be related more robustly to education, an early life indicator of socioeconomic position, than to current indicators of socioeconomic circumstances. Healthy men and women aged 53-76 years from the Whitehall II epidemiological cohort provided blood samples from which telomere length was assessed in 448 and telomerase activity in 416. Educational attainment was classified into four levels, while household income and grade of employment were measured as indicators of current socioeconomic circumstances. Age, gender, blood pressure, glycated hemoglobin, high density lipoprotein cholesterol, smoking, body mass index and physical activity were included as covariates. We found that lower educational attainment was associated with shorter telomere length after controlling statistically for biological and behavioral covariates. Neither household income nor employment grade was related to telomere length. The association between telomere length and education remained significant after adjusting for current socioeconomic circumstances. In men, highest levels of telomerase activity were found in the lowest education group. We conclude that low SES defined in terms of education but not current socioeconomic circumstances is associated with shortened telomeres. Low educational attainment may be an indicator of long-term SES trajectories, and be associated with accumulated allostatic load resulting in telomere shortening. Education may also promote problem-solving skills leading to reduced biological stress responsivity, with favorable consequences for biological aging. PMID- 21536124 TI - Do interactions between stress and immune responses lead to symptom exacerbations in irritable bowel syndrome? AB - Irritable bowel syndrome (IBS) is a common, debilitating gastrointestinal (GI) disorder, with a worldwide prevalence of between 10% and 20%. This functional gut disorder is characterized by episodic exacerbations of a cluster of symptoms including abdominal pain, bloating and altered bowel habit, including diarrhea and/or constipation. Risk factors for the development of IBS include a family history of the disorder, childhood trauma and prior gastrointestinal infection. It is generally accepted that brain-gut axis dysfunction is fundamental to the development of IBS; however the underlying pathophysiological mechanisms remain elusive. Additional considerations in comprehending the chronic relapsing pattern that typifies IBS symptoms are the effects of both psychosocial and infection related stresses. Indeed, co-morbidity with mood disorders such as depression and anxiety is common in IBS. Accumulating evidence points to a role for a maladaptive stress response in the initiation, persistence and severity of IBS associated symptom flare-ups. Moreover, mechanistically, the stress-induced secretion of corticotropin-releasing factor (CRF) is known to mediate changes in GI function. Activation of the immune system also appears to be important in the generation of IBS symptoms and increasing evidence now implicates low-grade inflammation or immune activation in IBS pathophysiology. There is a growing body of research focused on understanding at a molecular, cellular and in vivo level, the relationship between the dysregulated stress response and immune system alterations (either individually or in combination) in the etiology of IBS and to the occurrence of symptoms. PMID- 21536123 TI - Prior exposure to glucocorticoids potentiates lipopolysaccharide induced mechanical allodynia and spinal neuroinflammation. AB - While stress and stress-induced glucocorticoids are classically considered immunosuppressive, they can also enhance proinflammatory responses to subsequent challenges. Corticosterone (CORT) primes rat immune cells, exacerbating pro inflammatory responses to subsequent immune challenges. Stress can also sensitize pain. One possibility is that stress primes spinal immune cells, predominantly glia, which are key mediators in pain enhancement through their release of proinflammatory cytokines. Therefore, we aimed to identify whether prior CORT sensitizes spinal cord glia such that a potentiated pro-inflammatory response occurs to later intrathecal (IT) lipopolysaccharide (LPS), thereby enhancing pain. Rats received subcutaneous CORT/vehicle 24 h before IT LPS/vehicle. Hind paw pain thresholds were measured before CORT/vehicle, before and up to 48 h after IT LPS/vehicle. In separate rats treated as above, lumbar spinal cord tissue was collected and processed for proinflammatory mediators. CORT alone had no effect on pain responses, nor on any pro-inflammatory cytokines measured. LPS induced allodynia (decreased pain threshold) lasting <4 h and elevated spinal IL 1beta and IL-6 protein. Prior CORT potentiated allodynia, lasting >24 h following LPS and potentiated spinal IL-1 and IL-6 protein. Coadministration of IL-1 receptor antagonist with LPS IT completely blocked the allodynia irrespective of whether the system was primed by CORT or not. At 24 h, TLR2, TLR4, MD2, and CD14 mRNAs were significantly elevated within the spinal cord in the CORT+LPS group compared to all other groups. Prior CORT before a direct spinal immune challenge is able to potentiate pain responses and pro-inflammatory cytokine production. PMID- 21536125 TI - Role of immunoregulatory transcription factors in differential immunomodulatory effects of tocotrienols. AB - Tocotrienols have been shown to possess antioxidant, antitumor, cardioprotective, and antiproliferative effects. This report describes novel immunomodulatory effects of tocotrienols in murine lymphocytes. gamma-Tocotrienol (GT) was more effective in suppressing concanavalin A (Con A)-induced T cell proliferation and cytokine production compared to alpha-tocotrienol (AT) when present continuously in the culture. GT inhibited T cell activation markers and costimulatory molecule. GT modulated intracellular glutathione in lymphocytes, and the suppressive effects of GT could not be abrogated by thiol or nonthiol antioxidants, indicating a poor link between anti-inflammatory properties of tocotrienols and cellular redox status. It was also observed that GT suppressed Con A-induced activation of NF-kappaB, AP-1, and NF-kappaB-dependent gene expression. Cellular uptake studies with tocotrienols showed higher accumulation of GT compared to AT. Similar immunosuppressive effects of GT were also observed when administered to mice. In contrast, transient exposure of lymphocytes to GT (4 h) resulted in higher survival and proliferation of lymphocytes in vitro and in vivo in syngeneic and allogeneic hosts. This was attributed to the ability of GT to induce NF-kappaB, AP-1, and mTOR activation in lymphocytes upon transient exposure. Our results demonstrated that antioxidants such as tocotrienols may exhibit pleiotropic effects by activating multiple mechanisms in cells. PMID- 21536126 TI - Identification of distinct c-terminal domains of the Bombyx adipokinetic hormone receptor that are essential for receptor export, phosphorylation and internalization. AB - Neuropeptides of the adipokinetic hormone (AKH) family play important roles in insect hemolymph sugar homeostasis, larval lipolysis and storage-fat mobilization. Our previous studies have shown that the adipokinetic hormone receptor (AKHR), a Gs-coupled receptor, induces intracellular cAMP accumulation, calcium mobilization and ERK1/2 phosphorylation upon agonist stimulation. However, the underlying molecular mechanisms that regulate the internalization and desensitization of AKHR remain largely unknown. In the current study we made a construct to express AKHR fused with enhanced green fluorescent protein (EGFP) at its C-terminal end to further characterize AKHR internalization. In stable AKHR-EGFP-expressing HEK-293 cells, AKHR-EGFP was mainly localized at the plasma membrane and was rapidly internalized in a dose- and time-dependent manner via the clathrin-coated pit pathway upon agonist stimulation, and internalized receptors were slowly recovered to the cell surface after the removal of AKH peptides. The results derived from RNA interference and arrestin translocation demonstrated that G protein-coupled receptor kinase 2 and 5 (GRK2/5) and beta arrestin2 were involved in receptor phosphorylation and internalization. Furthermore, experiments using deletion and site-directed mutagenesis strategies identified the three residues (Thr356, Ser359 and Thr362) responsible for GRK mediated phosphorylation and internalization and the C-terminal domain from residue-322 to residue-342 responsible for receptor export from ER. This is the first detailed investigation of the internalization and trafficking of insect G protein-coupled receptors. PMID- 21536127 TI - Transformation of cinnamic acid from trans- to cis-form raises a notable bactericidal and synergistic activity against multiple-drug resistant Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis. The long course of treatments on TB with a combination of antibiotics leads unfavorable side effects and poor patient compliance which contributes to sustaining multiple-drug resistant tuberculosis (MDR-TB). Therefore, the development of a new effective drug or synergist to reduce the prevalence of MDR TB is urgent to date. Cinnamic acid (CA) is a natural occurring phenolic compound with anti-microbial activity. Both trans- and cis-isoforms of CA exist in planta, and cis-cinnamic acid (c-CA) can be transformed from trans-cinnamic acid (t-CA) under sunlight. Due to the unavailability of c-CA, the literature regarding the biological functions of c-CA is still limited. We had previously developed a practicable method for the transformation of c-CA from t-CA and the isolation of c-CA. Using the techniques, sufficient c-CA was obtained to evaluate its antituberculosis activity against a MDR M. tuberculosis strain. Moreover, the synergistic effects of c-CA and t-CA with two first-line anti-TB antibiotics, isoniazid (INH) and rifampicin (RIF), were also determined. Although both of c-CA and t-CA decreased the viability of MDR-TB bacilli in a dose-dependent manner, the antituberculosis activity of c-CA was approximately 120-fold of t-CA. Furthermore, the c-CA exhibited higher synergistic effect with INH or RIF against tuberculosis than t-CA. The micrographs of scanning electron microscope (SEM) display that c-CA caused an injury on the out-layer of MDR-TB bacilli. The c-CA might be a potential anti-mycobacterial or synergistic agent that can be developed to against tuberculosis. PMID- 21536128 TI - Targeted gene expression in the transgenic Aedes aegypti using the binary Gal4 UAS system. AB - In this study, we report the establishment of the binary Gal4/UAS system for the yellow fever mosquito Aedes aegypti. We utilized the 1.8-kb 5' upstream region of the vitellogenin gene (Vg) to genetically engineer mosquito lines with the Vg Gal4 activator and established UAS-EGFP responder transgenic mosquito lines to evaluate the binary Gal4/UAS system. The results show that the Vg-Gal4 driver leads to a high level of tissue-, stage- and sex-specific expression of the EGFP reporter in the fat body of Vg-Gal4/UAS-EGFP hybrids after blood-meal activation. In addition, the applicability of this system to study hormonal regulation of gene expression was demonstrated in in vitro organ culture experiments in which the EGFP reporter was highly activated in isolated fat bodies of previtellogenic Vg-Gal4/UAS-EGFP females incubated in the presence of 20-hydroxyecdysone (20E). Hence, this study has opened the door for further refinement of genetic tools in mosquitoes. PMID- 21536130 TI - Thymidylate synthase expression and genotype have no major impact on the clinical outcome of colorectal cancer patients treated with 5-fluorouracil. AB - BACKGROUND AND OBJECTIVES: Thymidylate synthase (TS) expression levels appear to be related to response to 5-fluorouracil-(5-FU)-based chemotherapy in colorectal cancer (CRC) patients. Three polymorphisms have been proposed as modulators of TS expression: a tandemly repeated sequence (2R/3R) in the 5' UTR, a SNP (G>C) within the 3R allele and a 6bp deletion in the 3' UTR. To evaluate the influence of TS expression and polymorphisms on clinical outcome of 5-FU-treated patients we performed a comprehensive genetic analysis on 63 CRC patients. METHODS: TS expression levels were analyzed in normal and tumor tissues. TS coding sequence and UTR polymorphisms were investigated on DNA from normal tissue. LOH analysis was performed to determine tumor genotype. RESULTS: A difference in disease-free survival (DFS), although not statistically significant, was observed between high and low mRNA expression levels: patients with low levels showed longer DFS. The 2R2R genotype showed significantly lower expression than the 3R3R and 2R3R genotypes in normal tissue. No other TS polymorphism was associated with mRNA expression or clinical outcome. CONCLUSIONS: The results obtained in this pilot study indicate that the number of 5' UTR repeats is the major genetic determinant of TS expression. The lack of association with other polymorphisms might be partially explained by the existence of linkage disequilibrium in the TS gene. Our data support the growing evidence that TS control may require multiple mechanisms acting in close coordination with one another and suggest that TS genotyping alone in tumor samples is not sufficient to accurately predict response to 5-FU. PMID- 21536129 TI - Ethanol modulation of gene networks: implications for alcoholism. AB - Alcoholism is a complex disease caused by a confluence of environmental and genetic factors influencing multiple brain pathways to produce a variety of behavioral sequelae, including addiction. Genetic factors contribute to over 50% of the risk for alcoholism and recent evidence points to a large number of genes with small effect sizes as the likely molecular basis for this disease. Recent progress in genomics (microarrays or RNA-Seq) and genetics has led to the identification of a large number of potential candidate genes influencing ethanol behaviors or alcoholism itself. To organize this complex information, investigators have begun to focus on the contribution of gene networks, rather than individual genes, for various ethanol-induced behaviors in animal models or behavioral endophenotypes comprising alcoholism. This chapter reviews some of the methods used for constructing gene networks from genomic data and some of the recent progress made in applying such approaches to the study of the neurobiology of ethanol. We show that rapid technology development in gathering genomic data, together with sophisticated experimental design and a growing collection of analysis tools are producing novel insights for understanding the molecular basis of alcoholism and that such approaches promise new opportunities for therapeutic development. PMID- 21536131 TI - Extracellular Ca(2+) entry and mobilization of inositol trisphosphate-dependent Ca(2+) stores modulate histamine and electrical field stimulation induced contractions of the guinea-pig prostate. AB - This investigation aimed to examine the source of Ca(2+) mobilization that leads to the contractile response to either exogenously added histamine (1 MUM-1mM) or electrical field stimulation (10Hz, 0.5ms, 60V). Removal of extracellular Ca(2+) by removal of Ca(2+) from the bathing medium reduced histamine (1mM) induced responses by 34% and responses induced by electrical field stimulation by 94%. Similarly, blockade of L-type Ca(2+) channels by nifedipine (1 MUM) reduced histamine (1mM) induced responses by 43% and responses induced by electrical field stimulation by 77%. Application of cyclopiazonic acid (CPA) (10 MUM) to inhibit Ca(2+) reuptake to the sarcoplasmic reticulum enhanced both histamine induced and electrical field stimulation induced responses to a small degree, while the addition of the inosotol triphosphate (IP(3)) receptor antagonist, 2 aminophenoxyethane borane (2-APB) (100 MUM) inhibited histamine induced responses by 70% and electrical field stimulation induced responses by 57%. Ryanodine (1 MUM) did not affect contractile responses to either histamine or electrical field stimulation, either in the absence or presence of 2-APB (100 MUM). During both histamine and electrical field stimulation induced contractions, prostate smooth muscle generates IP(3) receptor mediated Ca(2+) release in conjunction with Ca(2+) entry from the extracellular environment. Ryanodine receptors on the other hand, appear not to play a role in this physiological mechanism. PMID- 21536133 TI - Editorial for the special issue of methods "Modern Analytical Ultracentrifugation". PMID- 21536134 TI - Validation of the orthogonal tilt reconstruction method with a biological test sample. AB - Electron microscopy of frozen-hydrated samples (cryo-EM) can yield high resolution structures of macromolecular complexes by accurately determining the orientation of large numbers of experimental views of the sample relative to an existing 3D model. The "initial model problem", the challenge of obtaining these orientations ab initio, remains a major bottleneck in determining the structure of novel macromolecules, chiefly those lacking internal symmetry. We previously proposed a method for the generation of initial models--orthogonal tilt reconstruction (OTR)--that bypasses limitations inherent to the other two existing methods, random conical tilt (RCT) and angular reconstitution (AR). Here we present a validation of OTR with a biological test sample whose structure was previously solved by RCT: the complex between the yeast exosome and the subunit Rrp44. We show that, as originally demonstrated with synthetic data, OTR generates initial models that do not exhibit the "missing cone" artifacts associated with RCT and show an isotropic distribution of information when compared with the known structure. This eliminates the need for further user intervention to solve these artifacts and makes OTR ideal for automation and the analysis of heterogeneous samples. With the former in mind, we propose a set of simple quantitative criteria that can be used, in combination, to select from a large set of initial reconstructions a subset that can be used as reliable references for refinement to higher resolution. PMID- 21536132 TI - Cholesterol-independent neuroprotective and neurotoxic activities of statins: perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders. AB - Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including Alzheimer disease. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. Moreover, it is becoming more apparent with additional studies that statins can have deleterious effects in preclinical studies and lack effectiveness in various recent clinical trials. This perspective paper outlines pros and cons of the use of statins in neurodegenerative disorders, with particular emphasis on Alzheimer disease. PMID- 21536135 TI - Comparison of fluorescence and light scattering based methods to assess formation and stability of protein-protein complexes. AB - Thermal shift methods such as differential scanning fluorimetry and differential static light scattering are widely used to identify stabilizing conditions for proteins that might promote crystallization. Here we report a comparison of the two methods when applied to optimization of buffer conditions for protein-protein complexes. Most of the protein complexes under study were amenable to analysis using these two techniques. Protein complexes behave towards thermal denaturation in a manner similar to single proteins, showing a more or less sharp transition consistent with a two-state model of unfolding. A comparison of the melting and aggregation temperatures for single components and the reconstituted complexes can provide additional evidence for complex formation and can be used to identify buffer conditions in which protein-protein complex formation is favored. PMID- 21536136 TI - Conformational change upon product binding to Klebsiella pneumoniae UDP-glucose dehydrogenase: a possible inhibition mechanism for the key enzyme in polymyxin resistance. AB - Cationic modification of lipid A with 4-amino-4-deoxy-L-arabinopyranose (L-Ara4N) allows the pathogen Klebsiella pneumoniae to resist the antibiotic polymyxin and other cationic antimicrobial peptides. UDP-glucose dehydrogenase (Ugd) catalyzes the NAD+-dependent twofold oxidation of UDP-glucose (UPG) to produce UDP glucuronic acid (UGA), a requisite precursor in the biosynthesis of L-Ara4N and bacterial exopolysaccharides. Here we report five crystal structures of K. pneumoniae Ugd (KpUgd) in its apo form, in complex with UPG, UPG/NADH, two UGA molecules, and finally with a C-terminal His6-tag. The UGA-complex structure differs from the others by a 14 degrees rotation of the N-terminal domain toward the C-terminal domain, and represents a closed enzyme conformation. It also reveals that the second UGA molecule binds to a pre-existing positively charged surface patch away from the active site. The enzyme is thus inactivated by moving the catalytically important residues C253, K256 and D257 from their original positions. Kinetic data also suggest that KpUgd has multiple binding sites for UPG, and that UGA is a competitive inhibitor. The conformational changes triggered by UGA binding to the allosteric site can be exploited in designing potent inhibitors. PMID- 21536137 TI - Proteopedia: a status report on the collaborative, 3D web-encyclopedia of proteins and other biomolecules. AB - Proteopedia is a collaborative, 3D web-encyclopedia of protein, nucleic acid and other biomolecule structures. Created as a means for communicating biomolecule structures to a diverse scientific audience, Proteopedia (http://www.proteopedia.org) presents structural annotation in an intuitive, interactive format and allows members of the scientific community to easily contribute their own annotations. Here, we provide a status report on Proteopedia by describing advances in the web resource since its inception three and a half years ago, focusing on features of potential direct use to the scientific community. We discuss its progress as a collaborative 3D-encyclopedia of structures as well as its use as a complement to scientific publications and PowerPoint presentations. We also describe Proteopedia's use for 3D visualization in structure-related pedagogy. PMID- 21536138 TI - Sequencing of a second interleukin-10 gene in rainbow trout Oncorhynchus mykiss and comparative investigation of the expression and modulation of the paralogues in vitro and in vivo. AB - Interleukin-10 (IL-10) is a multifaceted cytokine that is produced by and effects a variety of cell populations, including macrophages, T, B and NK cells. The gene encoding for IL-10 has been isolated in mammals, birds, amphibians and recently in fish, with only single copy identified in each species. We report here a second IL-10 gene (tIL-10b) in rainbow trout that showed 92% identity in the coding region but only 50% identity in the 5'- and 3'-UTR to the known trout IL 10 paralogue, which we have now called tIL-10a. There is a short upstream open reading frame (uORF) within the 5'-untranslated region (UTR) of tIL-10a that may inhibit its translation, whilst in tIL-10b multiple mRNA instability motifs exist in the 3'-UTR, suggesting that the two IL-10 paralogues may have different mechanisms to regulate their expression post-transcriptionally. The expression of tIL-10a is generally higher than that of tIL-10b in most of the fourteen tissues examined and in the RTS-11, RTL and RTGill cell lines. However, the expression level of tIL-10b can exceed that of tIL-10a, as seen in vivo in the ovary of healthy fish and in the gills of Yersinia ruckeri challenged fish, and in vitro in head kidney (HK) leucocytes cultured for >= 8 h. The expression of the trout IL-10 paralogues can be up-regulated by LPS and polyIC in RTS-11 cells and by LPS, polyIC, PHA, PMA, calcium ionophore (CI) and IL-21 in head kidney leucocytes, as well as by Y. ruckeri infection, and can be modulated positively or negatively by IFN-gamma. Synergistic effects on up-regulation of IL-10 expression were also seen between PHA and IL-21, as well as between PMA and CI. The expression kinetics of the IL-10 paralogues was also found to be different, suggesting that rainbow trout has evolved different pathways to regulate the expression of the two IL-10 paralogues at the transcriptional level. PMID- 21536139 TI - Gene transfection and expression in the primary culture of crayfish hemocytes. AB - Lack of efficient gene delivery and expression methods is the major obstacle for crustacean research in the cellular level. Here, we reported the construction of an expression vector with a strong promoter from shrimp white spot syndrome virus. This vector could efficiently express foreign genes in the primary culture of crayfish hemocytes with the transfection efficiency between 5 and 10% by electroporation. Our findings provide a method for in vitro gene functional study in primary crayfish cells. PMID- 21536140 TI - Identification and evaluation as a DNA vaccine candidate of a virulence associated serine protease from a pathogenic Vibrio parahaemolyticus isolate. AB - A putative serine protease gene was cloned from the genomic DNA of Vibrio parahaemolyticus FYZ8621.4. The gene consisted of 1779 base pairs and encoded a 592 amino acid protein. The gene was expressed in Escherichia coli. The expressed protease was purified by Ni-NTA His-Bind Resin column and showed a 63 kDa band on SDS-PAGE. The protease exhibited proteolytic activity on gelatin agar plate and showed maximal proteolytic activity at pH 8.0 and 37 degrees C. It hydrolyzed N alpha-benzoyl-L-tyrosine p-nitroanilide (BAPNA), but did not N-benzoyl-L-arginine ethylester (BAEE), N-benzoyl-L-tyrosine ethylester (BTEE) and N-acetyl-L-tyrosine ethylester (ATEE). Mutants at conserved residues Asp(51) (Asp(51)-Asn), His(89) (His(89)-Asp) and Ser(318) (Ser(318)-Leu, Ser(318)-Pro) lost proteolytic activities completely. The protein was confirmed to belong to serine protease. The purified serine protease was toxic to zebrafish with a LD(50) of 15.4 MUg/fish. A DNA vaccine was constructed by inserting the mutated serine protease (Ser(318)-Pro) gene into pEGFP-N1 plasmid. The pEGFP-N1/m-vps was transfected in HeLa cells. The serine protease was confirmed to be expressed by fluorescence microscopy observation and Western blotting analysis. The pEGFP-N1/m-vps was further observed to express in muscle of the injected turbot (Scophthalmus maximus) by Western blotting seven days after immunization. Efficient protection against lethal V. parahaemolyticus challenge was observed on the vaccinated turbot with pEGFP-N1/m-vps, with the highest relative percent survival (RPS) of 96.11%. Significant specific antibody responses were also observed in the turbot vaccinated with the DNA vaccine. The results indicated that the serine protease might be a potential virulence factor and could be used as an efficient vaccine candidate for the disease control caused by V. parahaemolyticus. PMID- 21536142 TI - Contribution of HLA-A/B/C/DRB1/DQB1 common haplotypes to donor search outcome in unrelated hematopoietic stem cell transplantation. AB - In unrelated hematopoietic stem cell transplantation (HSCT), the prediction of donor search outcome at the time of search initiation is of great value for the physicians to delineate the strategy of patient care. The probability of finding an unrelated donor is high for patients who carry at least 1 of the 10 most common HLA haplotypes in Caucasians. As only 10% to 20% patients respond to this criterion, here we aimed at finding additional common haplotypes to improve the prediction of a successful search. HLA broad HLA-A/B/DRB1 haplotypes that were observed with frequencies >=0.19% in patient families of European origin and that split into <=2 predominant 4-digit HLA-A/B/C/DRB1/DQB1 haplotypes were considered as common. Carriage of at least 1 of those in 168 patients of various geographic areas with no family donor was confronted to the chance of finding >=9/10 HLA matched unrelated donors. Fifty common 4-digit haplotypes were identified. A higher (P < 5 * 10(-6)) chance of finding a suitable donor was found for 55 of 170 (32%) recipients that carried at least 1 of these common haplotypes. Up to now, estimates classified patients into >=3 groups of probability with >=1 intermediate group of poor utility for the clinicians. Considering carriage of these common haplotypes together with the frequencies of alleles and of B/C and DRB1/DQB1 associations, which are carried by patient HLA haplotypes, we could classify the patients into 2 groups of probability with a 98% and 26% chance of finding a donor, respectively. Prediction of search outcome could be improved by including the 50 most common HLA haplotypes in the current approaches. PMID- 21536141 TI - Is an epigenetic switch the key to persistent extinction? AB - Many studies of learning have demonstrated that conditioned behavior can be eliminated when previously established relations between stimuli are severed. This extinction process has been extremely important for the development of learning theories and, more recently, for delineating the neurobiological mechanisms that underlie memory. A key finding from behavioral studies of extinction is that extinction eliminates behavior without eliminating the original memory; extinguished behavior often returns with time or with a return to the context in which the original learning occurred. This persistence of the original memory after extinction creates a challenge for clinical applications that use extinction as part of a treatment intervention. Consequently, a goal of recent neurobiological research on extinction is to identify potential pharmacological targets that may result in persistent extinction. Drugs that promote epigenetic changes are particularly promising because they can result in a long-term molecular signal that, combined with the appropriate behavioral treatment, can cause persistent changes in behavior induced by extinction. We will review evidence demonstrating extinction enhancements by drugs that target epigenetic mechanisms and will describe some of the challenges that epigenetic approaches face in promoting persistent suppression of memories. PMID- 21536144 TI - Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade. AB - Multiple myeloma is an incurable plasma cell malignancy. Patients who fail conventional therapy are frequently treated with hematopoietic stem cell transplantation (HSCT), which results in reduced tumor burden, but the patients subsequently relapse from sites of chemotherapy-resistant disease. Using the 5T33 murine model of myeloma and a previously successful immunotherapy regimen consisting of autologous (syngeneic) HSCT and cell-based vaccine administration, we were unable to improve survival of myeloma-bearing mice. The 5T33 tumor line, similar to malignant plasma cells from myeloma patients, expresses high levels of programmed death receptor ligand-1 (PD-L1), which binds to the inhibitory receptor, PD-1. We observed that T cells from myeloma-bearing mice express high levels of PD-1, which has also been observed in patients with multiple myeloma. These PD-1(+) T cells were exhausted and produced IL-10. Based on these observations, we combined HSCT with whole-cell vaccination and PD-L1 blockade. Inhibition of the PD-1/PD-L1 pathway with HSCT and whole-cell vaccination increased the survival of myeloma-bearing mice from 0% to 40%. These data demonstrate a role for PD-L1 in suppressing immune responses to myeloma and suggest that blockade of this pathway may enhance immunotherapy for this disease. PMID- 21536143 TI - A multicenter pilot evaluation of the National Institutes of Health chronic graft versus-host disease (cGVHD) therapeutic response measures: feasibility, interrater reliability, and minimum detectable change. AB - The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of 4 consecutive pilot trials evaluating the feasibility and estimating the interrater reliability and minimum detectable change of these response criteria. Hematology-oncology clinicians with limited experience in applying the NIH cGVHD response criteria (n = 34) participated in a 2.5-hour training session on response evaluation in cGVHD. Feasibility and interrater reliability between subspecialty cGVHD experts and this panel of clinician raters were examined in a sample of 25 children and adults with cGVHD. The minimum detectable change was calculated using the standard error of measurement. Clinicians' impressions of the brief training session, the photo atlas, and the response criteria documentation tools were generally favorable. Performing and documenting the full set of response evaluations required a median of 21 minutes (range: 12-60 minutes) per rater. The Schirmer tear test required the greatest time of any single test (median: 9 minutes). Overall, interrater agreement for skin and oral manifestations was modest; however, in the third and fourth trials, the agreement between clinicians and experts for all dimensions except movable sclerosis approached satisfactory values. In the final 2 trials, the threshold for defining change exceeding measurement error was 19% to 22% body surface area (BSA) for erythema, 18% to 26% BSA for movable sclerosis, 17% to 21% BSA for nonmovable sclerosis, and 2.1 to 2.6 points on the 15-point NIH Oral cGHVD scale. Agreement between clinician-expert pairs was moderate to substantial for the measures of functional capacity and for the gastrointestinal and global cGVHD rating scales. These results suggest that the NIH response criteria are feasible for use, and these reliability estimates are encouraging, because they were observed following a single 2.5-hour training session given at multiple transplant centers, with no opportunity for iterative training and calibration. Research is needed to evaluate inter- and intrarater reliability in larger samples, and to evaluate these response criteria as predictors of outcomes in clinical trials. PMID- 21536146 TI - Molecular characterization of a novel type II keratin gene (sseKer3) in the Senegalese sole (Solea senegalensis): Differential expression of keratin genes by salinity. AB - Keratins make up the largest subgroup of intermediate filaments and, in chordates, represent the most abundant proteins in epithelial cells. Senegalese sole (Solea senegalensis) is a commercially important flatfish in which only two type I keratin genes, sseKer1 and sseKer2, have been described. We obtained the entire cDNAs encoding for a novel type II keratin, referred to as sseKer3. Main features and sequence identities with other fish and mammalian type II keratins are described. Expression profiles during larval development and in juvenile tissues were analyzed using a real-time PCR approach. In juvenile fish, sseKer3 was strongly expressed in gills, intestine, skin and stomach. During metamorphosis climax a drop in sseKer3 expression was observed. Transcriptional regulation of sseKer3 by thyroid hormones (THs) was also evaluated. Larvae exposed to the goitrogen thiourea (TU) exhibited higher mRNA levels than untreated control. Moreover, adding exogenous T4 hormone to TU-treated larvae restored or even reduced the sseKer3 transcript levels with respect to the untreated control. The possible role of keratins in osmotic stress response was evaluated in juvenile gills exposed to three different water salinities (15, 37 and 60psu). Whereas no significant changes in sseKer2 expression were detected; sseKer1 was early (12h) up-regulated at hypo-osmotic conditions and sseKer3 was down-regulated both at low and high salinity after 24h and 48h. Their possible role is discussed. PMID- 21536145 TI - Histology and time to progression predict survival for lymphoma recurring after reduced-intensity conditioning and allogeneic hematopoietic cell transplantation. AB - Reduced-intensity conditioning (RIC) before allogeneic hematopoietic cell transplantation (HCT) is increasingly used as a potentially curative option for patients with advanced lymphoma; however, relapse remains a major challenge. Unfortunately, little data are available on outcomes, predictors of survival, and results of specific management strategies in these patients. In the present study, a total of 101 consecutive relapses occurred and were evaluated in 280 patients with lymphoma who underwent RIC HCT. Diseases included aggressive non Hodgkin lymphoma (NHL) (n = 42), indolent NHL (n = 33), and Hodgkin lymphoma (HL) (n = 26). Median time to relapse was 90 days (range, 3-1275 days), and graft versus-host disease at relapse was present in 56 patients (55%). Interventions after relapse included no therapy (n = 14), withdrawal of immunosuppression alone (n = 11), chemoradiotherapy (n = 60), and donor lymphocyte infusion/second HCT (n = 16). Overall survival (OS) was 33% (95% confidence interval [CI], 23%-44%) at 3 years after relapse and 23% (95% CI, 13%-34%) at 5 years after relapse. Both aggressive NHL (vs indolent disease; hazard ratio, 2.29; P = .008) and relapse within 1 month post-HCT (vs >6 months; hazard ratio, 3.17; P = .004) were associated with increased mortality. Estimated 3-year OS was 16% (95% CI, 5%-32%) after relapse for aggressive NHL, 40% (95% CI, 19%-61%) after relapse for indolent NHL, and 47% (95% CI, 29%-64%) after relapse for HL. The 1-year survival was 24% for patients relapsing within 1 month post-HCT, compared with 52% for those relapsing at 1-3 months, 74% for those relapsing at 3-6 months, and 77% for those relapsing at more than 6 months. We conclude that despite relapse of lymphoma after RIC HCT, some patients may experience prolonged survival, with better postrelapse outcomes occurring in patients with indolent NHL, HL, or late relapse. PMID- 21536147 TI - Phenoloxidase activity of intact and chemically modified functional unit RvH1: a from molluscan Rapana venosa hemocyanin. AB - o-Diphenol oxidase activities (o-diPO) of chemically modified functional unit RvH1-a of molluscan hemocyanin Rapana venosa were studied using L-Dopa and dopamine as substrates. With L-Dopa as substrate the native FU RvH1-a did not show any o-diPO activity. Therefore the native FU RvH1-a was converted to enzymatic active form, after treatment with SDS, trypsin, urea and different values of pH when its o-diPO activity was studied. The highest artificial induction of o-diPO activity was observed after incubation of FU with 3.0mM SDS, and RvH1-a shows both, dopamine (K(M)=6.53mM, k(cat)/K(M)=1.29) and L-Dopa (K(M)=2.0mM, k(cat)/K(M)=2.1) activity due to a more open active site of the enzyme and better access of the substrates. It was determined that the K(M) value of SDS-activated RvH1-a against dopamine is higher compared to those of hemocyanins from Helix vulgaris, Helix pomatia and native tyrosinase from Ipomoea batatas but much lower than that from Illex argentinus (ST94) tyrosinase and arthropodan hemocyanin from Carcinus aestuarii. The Km value of SDS-activated RvH1-a against L-Dopa is higher than those of hemocyanins from H. vulgaris and Cancer magister, but lower than that of the tyrosinase from Streptomyces albus. PMID- 21536148 TI - Hepatocyte growth factor-induced c-Src-phosphatidylinositol 3-kinase-AKT mammalian target of rapamycin pathway inhibits dendritic cell activation by blocking IkappaB kinase activity. AB - Hepatocyte growth factor modulates activation and antigen-presenting cell function of dendritic cells. However, the molecular basis for immunoregulation of dendritic cells by hepatocyte growth factor is undefined. In the current study, we demonstrate that hepatocyte growth factor exhibits inhibitory effect on dendritic cell activation by blocking IkappaB kinase activity and subsequent nuclear factor-kappaB activation. Inhibition of IkappaB kinase is mediated by hepatocyte growth factor-induced activation of c-Src. Proximal signaling events induced in dendritic cells by hepatocyte growth factor include a physical association of c-Src with the hepatocyte growth factor receptor c-MET and concomitant activation of c-Src. Activation of c-Src in turn establishes a complex consisting of phosphatidylinositol 3-kinase and c-MET, and promotes downstream activation of the phosphatidylinositol 3-kinase/AKT pathway and mammalian target of rapamycin. Blocking activation of c-Src, phosphatidylinositol 3-kinase and mammalian target of rapamycin prevents hepatocyte growth factor induced inhibition of IkappaB kinase, nuclear factor-kappaB and dendritic cell activation. Notably, hepatocyte growth factor-stimulated c-Src activation results in induction of phosphatidylinositol 3-kinase complexes p85alpha/p110alpha and p85alpha/p110delta, which is required for activation of mammalian target of rapamycin, and consequent inhibition of IkappaB kinase and nuclear factor-kappaB activation. Our findings, for the first time, have identified the c-Src phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway that plays a pivotal role in mediating the inhibitory effects of hepatocyte growth factor on dendritic cell activation by blocking nuclear factor-kappaB signaling. PMID- 21536149 TI - Dietary supplementation with whey protein and ginseng extract counteracts oxidative stress and DNA damage in rats fed an aflatoxin-contaminated diet. AB - Aflatoxins (AF) are among the most potent naturally occurring carcinogens and aflatoxin-B1 (AFB(1)) is classified as a group-1 carcinogen. Since the ingestion of aflatoxins-contaminated food is associated with several liver diseases, the aim of the present study was to evaluate whether AF-induced damage in rats can be counteracted by feeding with whey-protein concentrates (WPC) and Korean ginseng extract (KGE). Eighty male Sprague-Dawley rats were divided into eight equal groups and treated daily for 30 days as follows: a control group (fed an AF-free diet), a group fed ad libitum an AF-contaminated diet (2.5mg/kg diet), a group treated orally with WPC (0.5ml/rat/day), a group treated orally with KGE (20mg/kg body weight), a group treated orally with WPC+KGE, and three groups that were fed the AF-contaminated diet and were treated orally with WPC, KGE or WPC+KGE, respectively. Throughout the experimental period, animals received WPC or KGE during the consumption of their respective diet. Bone-marrow micronucleus formation, DNA fragmentation, fatty-acid synthesis (FAS) and phospholipid hydroperoxide-glutathione-peroxidase (PHGPx) mRNA expression, and oxidative stress were assayed in liver and testis. The results indicated that ingestion of aflatoxin resulted in a significant increase in micronucleated normochromatic erythrocytes (Mn-NCE) in bone marrow, DNA fragmentation, FAS mRNA expression and lipid peroxidation in both organs, and a significant decrease in micronucleated polychromatic erythrocytes/micronucleated normochromatic erythrocytes (PCE/NCE) ratio in bone marrow, PHGPx gene expression and GSH in liver and testis. Treatments with WPC and/or KGE had a significant effect on Mn-NCE or the PCE/NCE ratio in bone marrow. However, KGE or KGE+WPC increased PHGPx gene expression and GSH in testis accompanied with a significant decrease in lipid peroxidation in liver and testis and FAS-mRNA expression in liver. WPC, KGE or WPC+KGE treatments combined with exposure to an AF-contaminated diet restored all the test parameters towards control values, although they did not fully reverse the effects of the aflatoxins. It is suggested that the genotoxicity of aflatoxins can be in part prevented by dietary supplementation with WPC, KGE or their combination. PMID- 21536151 TI - Anti-TNFalpha discontinuation in rheumatoid and psoriatic arthritis: is it possible after disease remission? AB - Anti-TNFalpha blockers have rapidly become a standard treatment for rheumatoid (RA) and psoriatic arthritis (PsA) because of their acceptable safety profile and efficacy. Clinical and radiological remission may now be a realistic outcome and constitutes the best achievable state. However, clinical practice guidelines and consensus statements on the criteria of introduction, duration and cessation of treatment are under constant revision. Evidence supports that the early use of biologic DMARDs would produce rapid and sustained suppression of inflammatory disease and preserve function and joint erosions. Proof of this concept, anti TNFalpha agents would be effective in maintaining response after cessation of treatment. Conversely, when therapy with anti-TNFalpha is withdrawn, the disease rapidly returns. Remission may be defined as minimal or no clinically detectable disease activity in the presence of continuing drug treatment and a rapid control of disease activity may prevent irreversible damage and disability. The use of US PD and MRI in the early detection of disease recurrence could become necessary to prevent the relapse and direct the clinician's choice concerning a re-treatment regimen. The use of biological treatment can be for a limited period, at a time when it has the greatest opportunity to make the difference. PMID- 21536150 TI - Comparative genomics and the role of lateral gene transfer in the evolution of bovine adapted Streptococcus agalactiae. AB - In addition to causing severe invasive infections in humans, Streptococcus agalactiae, or group B Streptococcus (GBS), is also a major cause of bovine mastitis. Here we provide the first genome sequence for S. agalactiae isolated from a cow diagnosed with clinical mastitis (strain FSL S3-026). Comparison to eight S. agalactiae genomes obtained from human disease isolates revealed 183 genes specific to the bovine strain. Subsequent polymerase chain reaction (PCR) screening for the presence/absence of a subset of these loci in additional bovine and human strains revealed strong differentiation between the two groups (Fisher exact test: p<0.0001). The majority of the bovine strain-specific genes (~ 85%) clustered tightly into eight genomic islands, suggesting these genes were acquired through lateral gene transfer (LGT). This bovine GBS also contained an unusually high proportion of insertion sequences (4.3% of the total genome), suggesting frequent genomic rearrangement. Comparison to other mastitis-causing species of bacteria provided strong evidence for two cases of interspecies LGT within the shared bovine environment: bovine S. agalactiae with Streptococcus uberis (nisin U operon) and Streptococcus dysgalactiae subsp. dysgalactiae (lactose operon). We also found evidence for LGT, involving the salivaricin operon, between the bovine S. agalactiae strain and either Streptococcus pyogenes or Streptococcus salivarius. Our findings provide insight into mechanisms facilitating environmental adaptation and acquisition of potential virulence factors, while highlighting both the key role LGT has played in the recent evolution of the bovine S. agalactiae strain, and the importance of LGT among pathogens within a shared environment. PMID- 21536152 TI - Emerging role for NK cells in the pathogenesis of inflammatory arthropathies. AB - Natural killer (NK) cells are large, granular lymphocytes devoted to the defense against microbial agents and cancer cells, traditionally recognized as an important arm of the innate immunity, even if more recent data underpin a role also in the responses of acquired immunity. Several studies have led to ascertain that NK cells are involved in the pathogenesis of many immune-mediated diseases, where they may exert both protective and pathogenic roles. In particular, the CD56(bright) NK cell subset, showing immunoregulatory properties, has been found to accumulate in tissue sites of inflammation, such as the skin lesions in psoriatic patients and the synovial membrane in rheumatoid arthritis (RA) patients. In this latter disease, while data on the number of NK cells are still controversial among the different studies, more consensuses exist on the impaired activity of these cells. In another group of inflammatory arthritides, the spondyloarthropathies (SpA), the presence of peculiar allotypes of the killer cell immunoglobulin-like receptors (KIR) superfamily, coding for molecules expressed on NK cells, seems to modulate the susceptibility to this group of diseases, especially ankylosing spondylitis and psoriatic arthritis. Interestingly, in vitro studies showed that NK cells of patients with inflammatory arthropathies might produce pro-inflammatory Th1 cytokines; furthermore, they are involved in bone damage, interact and activate different cell types such as monocytes, dendritic cells and resident fibroblast-like synoviocites cells, thus creating and/or maintaining the inflammatory response. Certainly, these features encourage more research on the role of NK cells in the pathogenesis of inflammatory arthropathies, which could be essential to define potential new therapeutic strategies. PMID- 21536153 TI - Humans at high altitude: hypoxia and fetal growth. AB - High-altitude studies offer insight into the evolutionary processes and physiological mechanisms affecting the early phases of the human lifespan. Chronic hypoxia slows fetal growth and reduces the pregnancy-associated rise in uterine artery (UA) blood flow. Multigenerational vs. shorter-term high-altitude residents are protected from the altitude-associated reductions in UA flow and fetal growth. Presently unknown is whether this fetal-growth protection is due to the greater delivery or metabolism of oxygen, glucose or other substrates or to other considerations such as mechanical factors protecting fragile fetal villi, the creation of a reserve protecting against ischemia/reperfusion injury, or improved placental O(2) transfer as the result of narrowing the A-V O(2) difference and raising uterine P(v)O2. Placental growth and development appear to be normal or modified at high altitude in ways likely to benefit diffusion. Much remains to be learned concerning the effects of chronic hypoxia on embryonic development. Further research is required for identifying the fetoplacental and maternal mechanisms responsible for transforming the maternal vasculature and regulating UA blood flow and fetal growth. Genomic as well as epigenetic studies are opening new avenues of investigation that can yield insights into the basic pathways and evolutionary processes involved. PMID- 21536155 TI - Enhanced immobilization of acidic proteins in the apatite layer via electrostatic interactions in a supersaturated calcium phosphate solution. AB - Artificial materials coated with a protein-apatite composite layer have great potential in clinical applications as a third generation biomaterial. Such composite materials can be prepared by immersing a surface modified substrate into a supersaturated calcium phosphate solution (CP solution: 142 mM NaCl, 3.75 mM CaCl(2), 1.5mM K(2)HPO(4).3H(2)O, buffered at pH 7.4 at 25 degrees C with tris(hydroxymethyl)aminomethane and HCl) supplemented with a protein. In the present study proteins of various molecular weights (MW) and isoelectric points (pI) were used to form a protein-apatite composite layer on a polymeric material to determine how the molecular properties of the protein affect the efficiency of protein immobilization (i.e. the amount of immobilized protein in the apatite layer as a percentage of the total amount of protein in solution). The results indicated that the efficiency of protein immobilization did not correlate with the MW of the protein. In contrast, the efficiency of protein immobilization was strongly related to the pI of the protein. As the pI decreased the efficiency of protein immobilization increased due to the high adsorption affinity of negatively charged acidic proteins for positively charged apatite crystals and/or apatite precursors in the CP solution. Thus, the use of acidic rather than basic proteins improves the immobilization efficiency in the present coating process. PMID- 21536156 TI - Identification of virulence factors and diagnostic markers using immunosecretome of Aspergillus fumigatus. AB - Aspergillus fumigatus is a prime causative agent for various allergic and invasive aspergillosis. There has been a dramatic increase of such cases in last three decades yet the early diagnosis and virulence factor identification remains the challenge. In the present study secretome analysis of proteins isolated from the culture filtrate was done by 2D gel electrophoresis coupled with MS/MS and the immunosecretome analysis was carried out using immunoblotting of 2D transfer blots and probed with the sera of patients, immunized rabbit and mice. The identified proteins were analyzed further for homology with human proteins by BLAST search and for secretory signal by SignalP. A total of 65 protein spots from 2D gel resulted in identification of 24 different proteins along with their isoforms and out of which 15 proteins were identified as immunogenic in human. These findings may be helpful in the identification of virulence factors involved in aspergillosis and also useful as diagnostic markers. PMID- 21536157 TI - The First Neurobiology of Language Conference: NLC 2009. PMID- 21536154 TI - Characterization of an ATP-sensitive K(+) channel in rat carotid body glomus cells. AB - Carotid body glomus (CB) cells express different types of K(+) channels such as TASK, BK, and Kv channels, and hypoxia has been shown to inhibit these channels. Here we report the presence of a ~72-pS channel that has not been described previously in CB cells. In cell-attached patches with 150 mM K(+) in the pipette and bath solutions, TASK-like channels were present (~15 and ~36-pS). After formation of inside-out patches, a 72-pS channel became transiently active in ~18% of patches. The 72-pS channel was K(+)-selective, inhibited by 2-4 mM ATP and 10-100 MUM glybenclamide. The 72-pS channel was observed in CB cells isolated from newborn, 2-3 week and 10-12 week-old rats. Reverse transcriptase-PCR and immunocytochemistry showed that Kir6.1, Kir6.2, SUR1 and SUR2 were expressed in CB glomus cells as well as in non-glomus cells. Acute hypoxia (~15 mmHg O(2)) inhibited TASK-like channels but failed to activate the 72-pS channel in cell attached CB cells. K(+) channel openers (diazoxide, pinacidil, levcromakalim), sodium cyanide and removal of extracellular glucose also did not activate the 72 pS channel in the cell-attached state. The hypoxia-induced elevation of intracellular [Ca(2+)] was unchanged by glybenclamide or diazoxide. NaCN-induced increase in [Ca(2+)] was not affected by 10 MUM glybenclamide but inhibited by 100 MUM glybenclamide. Acute glucose deprivation did not elevate [Ca(2+)] in the presence or absence of glybenclamide. These results show that an ATP-sensitive K(+) channel is expressed in the plasma membrane of CB cells, but is not activated by short-term metabolic inhibition. The functional relevance of the 72 pS channel remains to be determined. PMID- 21536158 TI - Geriatric psychiatry: advances and directions. Preface. PMID- 21536159 TI - Epidemiology, assessment, and treatment of dementia. AB - The risk of developing dementia is associated with increasing age, lifestyle, and cardiovascular health. Alzheimer dementia is characterized by progressive cognitive deficits and decline in functional ability. Using history, examination, and laboratory testing, the clinician can evaluate the patient with dementia. Specific to these conditions are assessments of cognition, neuropsychiatric symptoms, and level of functioning. Managing neuropsychiatric symptoms is challenging and requires a team approach in which nonpharmacological strategies are preferred before medications are considered. Various diagnostic methods are being developed to discriminate disease from nondisease and track progression. Drug discovery is identifying novel molecules that target underlying disease mechanisms. PMID- 21536161 TI - Geriatric bipolar disorder. AB - Because the elderly are the fastest growing segment of the population, the number of older adults with bipolar disorder is increasing. Geriatric bipolar disorder is relatively rare, with an estimated lifetime prevalence of 0.5% to 1%, although approximately 4% to 17% of older patients in clinical psychiatric settings have bipolar disorder. Bipolar elders are disproportionately affected by medical burden. Given the complex nature of this disorder, comorbidity, and behavioral disturbances, various interventions may be indicated, including pharmacotherapies, electroconvulsive therapy, psychotherapies, and integrated care models. Additional research is needed to better understand the epidemiology, phenomenology, and treatment of geriatric bipolar disorder. PMID- 21536160 TI - New wine in old bottle: late-life psychosis. AB - Psychosis is common in late-life and exacts enormous costs to society, affected individuals, and their caregivers. A multitude of etiologies for late-life psychosis exist, the two most prototypical being schizophrenia and psychosis of Alzheimer disease (AD). As such, this article focuses on the nonaffective, neuropsychiatric causes of chronic psychosis in the elderly, specifically schizophrenia, delusional disorder, and the psychosis of AD and other dementias. PMID- 21536162 TI - Late-life depression: evidence-based treatment and promising new directions for research and clinical practice. AB - As the population ages, successive cohorts of older adults will experience depressive disorders. Late-life depression (LLD) carries additional risk for suicide, medical comorbidity, disability, and family caregiving burden. Although response and remission rates to pharmacotherapy and electroconvulsive therapy are comparable with those in midlife depression, relapse rates are higher, underscoring the challenge to achieve and maintain wellness. This article reviews the evidence base for LLD treatment options and provides an analysis of treatment options for difficult-to-treat LLD variants (eg, psychotic depression, vascular depression). Treatment algorithms are also reviewed based on predictors of response and promising novel treatment options. PMID- 21536163 TI - Gene-environment interactions in geriatric depression. AB - In older adults, several environmental challenges can potentially trigger the onset of an episode of major depression. Vulnerability to these challenges can be influenced by genetics. There is accumulating evidence for an interaction between stress and a serotonin transporter polymorphism, though there is also heterogeneity among studies. Other relevant genes include those encoding for the neuroendocrine stress axis, growth factors, and other monoaminergic systems. Each of these may interact with either predisposing traumas in early childhood or precipitating events later in life. PMID- 21536164 TI - Psychosocial interventions for late-life major depression: evidence-based treatments, predictors of treatment outcomes, and moderators of treatment effects. AB - This systematic review evaluates the efficacy of psychosocial interventions for the acute treatment of late-life depression and identifies predictors of treatment outcomes and moderators of treatment effects. Problem-solving therapy, cognitive behavioral therapy, and treatment initiation and participation program have supportive evidence of efficacy, pending replication. Although the data on predictors of treatment outcomes and moderators of treatment effects are preliminary, it appears that baseline anxiety and stress level, personality disorders, endogenous depression, and reduced self-rated health predict worse depression outcomes. Future research may examine the moderating effects of baseline depression severity and identify other clinical or demographic moderators. PMID- 21536166 TI - Structural neuroimaging of geriatric depression. AB - There is a large literature on the neuroanatomy of late-life depression that continues to grow with the discovery of novel structural imaging techniques along with innovative methods to analyze the images. Such advances have helped identify specific areas, characteristic lesions, and changes in the chemical composition in these regions that might be important in the pathophysiology of this complex disease. This article reviews relevant findings by each structural neuroimaging technique. When validated across many studies, such findings can serve as neuroanatomic markers that can help generate rational hypotheses for future studies to further understanding of geriatric depression. PMID- 21536165 TI - Functional neuroimaging in geriatric depression. AB - Abnormalities in specific cerebral networks likely confer vulnerability that increases the susceptibility for development of geriatric depression and affect the course of symptoms. Functional neuroimaging enables the in vivo identification of alterations in cerebral function that characterize disease vulnerability and contribute to variability in depressive symptoms and antidepressant response. Judicious use of functional neuroimaging tools can advance pathophysiologic models of geriatric depression. Furthermore, geriatric depression provides a logical context within which to study the role of specific functional abnormalities in both antidepressant response and key behavioral and cognitive abnormalities of mood disorders. PMID- 21536167 TI - Immunity, aging, and geriatric depression. AB - Inflammatory processes are likely to play a causal role in geriatric depression. Geriatric depression occurs in the context of illnesses in which inflammatory processes are part of the pathogenesis. Both aging and depression are associated with immune responses, and the connectivity among mood-regulating structures may be modulated by inflammatory responses. Geriatric depression exacerbates the symptoms of comorbid disorders. Geriatric depression often occurs in persons exposed to chronic stress, a state precipitating geriatric depression and triggering proinflammatory responses. The successful treatment of comorbid conditions that increase central nervous system inflammatory responses has general health benefits and should be part of clinical practice. PMID- 21536168 TI - Suicide in older adults. AB - This article makes the case that late-life suicide is a cause for great concern that warrants ongoing attention from researchers, health care providers, policy makers, and society at large. It reviews the evidence for factors that place older adults at risk for suicide, or protect them from it. The authors introduce the notion that suicide preventive interventions target individuals or groups at different levels of risk at different points on the developmental trajectory toward death by suicide, offering examples and recommending their strategic, combined application to create an effective, community-level response to the mounting problem of suicide in older adults. PMID- 21536170 TI - Designing personalized treatment engagement interventions for depressed older adults. AB - Despite the benefits of treatment for late-life depression, underutilization of mental health services by older adults and nonadherence to offered interventions exist. This article describes psychosocial and interactional barriers and facilitators of treatment engagement among depressed older adults served by community health care settings. The authors describe the need to engage older adults in treatment using interventions that: (1) target psychological barriers such as stigma and other negative beliefs about depression and its treatment; and (2) increase individuals' involvement in the treatment decision-making process. Personalized treatment engagement interventions designed by the authors' group for various community settings are presented. PMID- 21536171 TI - The changing face of care for venous disease. PMID- 21536169 TI - Geriatric depression in primary care. AB - Primary care settings present important opportunities for the detection and management of depression in older adults. In this article, the authors review the common barriers to effective treatment of geriatric depression, identify treatment strategies that can substantially improve the effectiveness of treatment in this setting, and highlight the opportunities for addressing health disparities in geriatric depression care. The importance of engaging and supporting family caregivers of depressed older adults and the 3 strategic areas to improve the treatment of geriatric depression in primary care are also discussed. PMID- 21536172 TI - The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. AB - The Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) have developed clinical practice guidelines for the care of patients with varicose veins of the lower limbs and pelvis. The document also includes recommendations on the management of superficial and perforating vein incompetence in patients with associated, more advanced chronic venous diseases (CVDs), including edema, skin changes, or venous ulcers. Recommendations of the Venous Guideline Committee are based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system as strong (GRADE 1) if the benefits clearly outweigh the risks, burden, and costs. The suggestions are weak (GRADE 2) if the benefits are closely balanced with risks and burden. The level of available evidence to support the evaluation or treatment can be of high (A), medium (B), or low or very low (C) quality. The key recommendations of these guidelines are: We recommend that in patients with varicose veins or more severe CVD, a complete history and detailed physical examination are complemented by duplex ultrasound scanning of the deep and superficial veins (GRADE 1A). We recommend that the CEAP classification is used for patients with CVD (GRADE 1A) and that the revised Venous Clinical Severity Score is used to assess treatment outcome (GRADE 1B). We suggest compression therapy for patients with symptomatic varicose veins (GRADE 2C) but recommend against compression therapy as the primary treatment if the patient is a candidate for saphenous vein ablation (GRADE 1B). We recommend compression therapy as the primary treatment to aid healing of venous ulceration (GRADE 1B). To decrease the recurrence of venous ulcers, we recommend ablation of the incompetent superficial veins in addition to compression therapy (GRADE 1A). For treatment of the incompetent great saphenous vein (GSV), we recommend endovenous thermal ablation (radiofrequency or laser) rather than high ligation and inversion stripping of the saphenous vein to the level of the knee (GRADE 1B). We recommend phlebectomy or sclerotherapy to treat varicose tributaries (GRADE 1B) and suggest foam sclerotherapy as an option for the treatment of the incompetent saphenous vein (GRADE 2C). We recommend against selective treatment of perforating vein incompetence in patients with simple varicose veins (CEAP class C(2); GRADE 1B), but we suggest treatment of pathologic perforating veins (outward flow duration >=500 ms, vein diameter >=3.5 mm) located underneath healed or active ulcers (CEAP class C(5)-C(6); GRADE 2B). We suggest treatment of pelvic congestion syndrome and pelvic varices with coil embolization, plugs, or transcatheter sclerotherapy, used alone or together (GRADE 2B). PMID- 21536174 TI - [Innovation for the cure of pulmonary arterial hypertension]. PMID- 21536173 TI - A systematic review and meta-analysis of the treatments of varicose veins. AB - OBJECTIVES: Several treatment options exist for varicose veins. In this review we summarize the available evidence derived from comparative studies about the relative safety and efficacy of these treatments. METHODS: We searched MEDLINE, Embase, Current Contents, Cochrane Central Register of Controlled Trials (CENTRAL) expert files, and the reference section of included articles. Eligible studies compared two or more of the available treatments (surgery, liquid or foam sclerotherapy, laser, radiofrequency ablations, or conservative therapy with compression stockings). Two independent reviewers determined study eligibility and extracted descriptive, methodologic, and outcome data. We used random-effects meta-analysis to pool relative risks (RR) and 95% confidence intervals (CI) across studies. RESULTS: We found 39 eligible studies (30 were randomized trials) enrolling 8285 participants. Surgery was associated with a nonsignificant reduction in the risk of varicose vein recurrence compared with liquid sclerotherapy (RR, 0.56; 95% CI, 0.29-1.06) and all endoluminal interventions (RR, 0.63; 95% CI, 0.37-1.07). Studies of laser and radiofrequency ablation and foam sclerotherapy demonstrated short-term effectiveness and safety. The quality of evidence presented in this review was limited by imprecision (small number of events), short-term follow-up, and indirectness (use of surrogate outcomes). CONCLUSION: Low-quality evidence supports long-term safety and efficacy of surgery for the treatment of varicose veins. Short-term studies support the efficacy of less invasive treatments, which are associated with less periprocedural disability and pain. PMID- 21536175 TI - [Echocardiography: interest and border for screening and monitoring of pulmonary arterial hypertension]. AB - Pulmonary Hypertension (PH) is a haemodynamical disorder; its definite diagnosis requires an increase of mean pulmonary arterial pressure measured by right heart catheterization (RHC). This invasive test allows to distinguish between precapillary and postcapillary PH and also to measure the vasoreactivity before starting specific therapy. Pulmonary arterial hypertension (PAH) - group 1 of PH comprises heterogeneous condition which presents identical histological findings. In the recent guidelines, task force suggests that transthoracic echocardiography (TTE) should be considered as a tool for assessment of the likely presence or absence of PH with different level of evidence. On the basis of this assessment patients can be referred for a confirmatory RHC. In addition to its role in diagnosis, TTE can be used to screen for high-risk patients population, to asses prognosis and to monitor disease stability and response to treatment. Even if TTE doesn't prove yet its major role in management of PAH patients, it is essential to include this safe and noninvasive exam in a goal oriented approach to therapy. PMID- 21536176 TI - [Magnetic resonance imaging and pulmonary hypertension: towards an improved evaluation of right heart and pulmonary circulation]. AB - In patients with pulmonary hypertension (PH), right ventricular (RV) function carries prognostic implications and this explains why RV function must be systematically evaluated at baseline and during follow-up. Cardiac Magnetic Resonance imaging (CMR) is nowadays considered the gold standard technique for non-invasively evaluating RV morphology and function. Pulmonary hemodynamics may be also successfully studied by CMR.The severity and prognosis of PH are related to a number of CMR-derived cardiac and pulmonary artery variables. The main CMR derived cardiac variables related to the severity and prognosis of PH are a lowered RV ejection fraction, paradoxical septal motion and decreased left ventricular dimension relative to RV. The main CMR-derived pulmonary artery variables related to the severity and prognosis of PH are a decreased compliance and decreased mean fl ow velocity. CMR plays a key role in the non-invasive evaluation of RV function and pulmonary hemodynamics of PH patients. It is likely that CMR will improve the rationale evaluation and survey of these patients in the near future. PMID- 21536177 TI - [Resting and exercise hemodynamics in pulmonary arterial hypertension]. AB - The normal mean pulmonary artery pressure (PAP) is 14 +/- 3 mmHg. Precapillary pulmonary hypertension is defined as a mean PAP >= 25 mmHg at rest and a pulmonary capillary wedge pressure <= 15 mmHg as assessed by right heart catheterization. When performed in experienced centers, right heart catheter procedures in patients with pulmonary hypertension are associated with low morbidity and mortality rates. Right heart catheterization remains essential for the management of pulmonary arterial hypertension (PAH) as it confirms the diagnosis, determines the type of pulmonary hypertension, its severity, its vasoreactivity as well as response to therapeutic interventions. The hemodynamic severity largely influences patients' management including the choice of initial and subsequent therapies. Hemodynamic evaluation during exercise allows a precise characterization of the true resistive properties of pulmonary vessels through the assessment of the pressure-flow relationship. The significance of isolated pulmonary hypertension during exercise remains unknown. Indeed, roughly 50% of healthy subjects > 50 years old exhibit mean PAP > 30 mmHg during mild exercise. Isolated exercise-induced increases in mean PAP > 30 mmHg during exercise is thus no longer used to define pulmonary hypertension. More complex hemodynamic parameters allow partitioning of arterial and venous vascular resistance, as well as a better characterization of pulmonary artery compliance, right ventricle function and right ventriculo-arterial coupling. The clinical relevance of these subtle markers of pulmonary vascular abnormalities remains unknown. PMID- 21536178 TI - [Novel immunopathological approaches to pulmonary arterial hypertension]. AB - Inflammation is important for the initiation and the maintenance of vascular remodeling in the most commun animal models of pulmonary hypertension (PH), and its therapeutical targeting blocks PH development in these models. In human, pulmonary vascular lesions of PH are also the source of an intense chemokine production, linked to inflammatory cell recruitment. However, arteritis is uncommon in PH patients. Of note, current PH treatments have immunomodulatory properties. In addition, some studies have shown a correlation between levels of circulating inflammatory mediators and patients' survival. The study of autoimmunity in the pathophysiology of pulmonary arterial hypertension is becoming an area of intense investigation. New immunopathological approaches to PH should allow the development of innovative treatments for this very severe condition. PMID- 21536179 TI - [Pulmonary hypertension in interstitial lung diseases: diagnostic and therapeutic approach in 2011?]. AB - Pulmonary hypertension is frequent in late-stage idiopathic pulmonary fibrosis, and is associated with a shorter survival. It should be suspected in case of dyspnea or hypoxemia disproportionate with the degree of parenchymal lung disease. It is particularly frequent in patients with the syndrome of combined pulmonary fibrosis and emphysema, and associated with a short survival (median survival less than 1 year). Pulmonary hypertension associated with chronic infiltrative lung diseases can be detected by echocardiography and must be confirmed by right-sided heart catheterization, especially to rule out post capillary pulmonary hypertension frequent in this context. Management is mainly palliative and based on supplemental nasal oxygen. Therapy specific for pulmonary arterial hypertension, poorly evaluated in pulmonary hypertension associated with infiltrative lung diseases, is occasionally proposed to patients with disproportionate pulmonary hypertension (mean PAP > 35 mmHg), with often limited efficacy, and requiring careful follow-up (risk of increased hypoxemia) and invasive evaluation. Pulmonary transplantation should be considered in the absence of contra-indication. PMID- 21536180 TI - [Systemic sclerosis associated pulmonary arterial hypertension: the pitfalls]. AB - Although pulmonary arterial hypertension (PAH) is usually considered as a late complication in limited subsets of systemic sclerosis (SSc), PAH can also occur in diffuse SSc and in early SSc. The evaluation of the velocity of the tricuspid regurgitation on echocardiography is so far the most effective screening tool for pulmonary hypertension (PH) in SSc. Nevertheless, it is not measurable in about 20% of SSc patients ; In that case, pulmonary arterial pressure can be evaluated by using the velocity of a pulmonary insufficiency and indirect signs of PH should be analyzed: pulmonary ejection time, right heart cavities dilatation and aspect of the inferior vena cava. About 10% of SSc patients with a suspected of PAH on echocardiography have post-capillary PH at right heart catheterization mainly due to left ventricular diastolic dysfunction. In some SSc patients, PAH and post-capillary PH due to left ventricular diastolic dysfunction may be associated. This can be suspected in case of post-capillary PH with a transpulmonary gradient > 12 mmHg. Lung fibrosis is another cause of PH in SSc. The distinction between PH associated to lung fibrosis from PAH is sometimes difficult, particularly in patients with a FVC between 60 and 70% of expected. Pulmonary veno-occlusive disease is a possible cause of precapillary PH in SSc. The diagnosis of pulmonary veno-occlusive disease should be discussed in each case of PAH associated ScS due to the high risk of lung edema at the introduction of specific PAH drugs. PMID- 21536181 TI - [Treatment of pulmonary arterial hypertension in 2011: what's new since the 2009 ERS/ESC guidelines?]. AB - The current treatment strategies for pulmonary arterial hypertension, outlined in the ERS/ESC guidelines published in 2009, have led to improvements in life expectancy and patient quality of life. However, a cure for the disease remains elusive. In order to improve the prognosis for patients with PAH, future research will focus on development of new therapeutic agents, identification of novel targets and studies involving combinations of existing treatments An important goal is to refine the efficacy and tolerability of agents that target NO, endothelin and prostacyclin signaling pathways. Novel targeted therapies, such as tyrosine kinase inhibitors that directly act on the abnormal proliferation of pulmonary vascular cells, are under active investigation. Finally, clinical trials evaluating combinations of treatments have shown encouraging results. PMID- 21536182 TI - Tongue movements in patients with skeletal Class III malocclusions evaluated with real-time balanced turbo field echo cine magnetic resonance imaging. AB - INTRODUCTION: The aim of this study was to evaluate the position and movements of the tongue in patients with skeletal Class III malocclusion. METHODS: Sixty-six patients (31 male, 35 female) with Class III malocclusion were divided into 3 groups according to cephalometric analysis. The first group comprised 23 patients (13 male, 10 female) with mandibular prognathism, the second group comprised 21 patients (9 male, 12 female) with maxillary retrognathism, and the third group comprised 22 patients (9 male, 13 female) with both maxillary retrognathism and mandibular prognathism. Twenty-two skeletal Class I patients (10 male, 12 female) were also included as the control group. RESULTS: Dentofacial morphology affects the position and the movements of the tongue during deglutition. Contact of the anterior portion of the tongue with the rugae area of the hard palate decreased in the Class III malocclusion groups. The posterior portion of the dorsal tongue was positioned more inferiorly, and the root of the tongue was positioned more inferiorly and anteriorly in patients with Class III malocclusion than in the control group. The tip of the tongue was also in a more anterior position in the Class III groups. When the deglutition stages were evaluated, we observed that the manner of bolus transfer was different in patients with skeletal Class III malocclusion than in those with skeletal Class I malocclusion. CONCLUSIONS: Tongue posture is affected by dentofacial structures, and adaptive changes occur in the tip, dorsum, and root of the tongue. Deglutitive tongue movements in patients with skeletal Class III malocclusion are also different from those with skeletal Class I malocclusion. PMID- 21536183 TI - Tongue movements in patients with skeletal Class II malocclusion evaluated with real-time balanced turbo field echo cine magnetic resonance imaging. AB - INTRODUCTION: The aim of this study was to evaluate the deglutitive tongue movements in patients with skeletal Class II malocclusion. METHODS: Fifty-nine patients (26 male, 33 female) with skeletal Class II relationship were divided into 3 groups according to cephalometric analysis. Group 1 (n = 19) had mandibular retrognathism, group 2 (n = 20) had maxillary prognathism, and group 3 (n = 20) had both mandibular retrognathism and maxillary prognathism. Twenty-two skeletal Class I patients (10 male, 12 female) were also included as the controls. RESULTS: In the mandibular retrusion group, the posterior portion of the dorsal tongue moved downward at stage 2 and upward at stage 3; the root of the dorsal tongue was in an inferior and anterior position at stage 2. In patients with both mandibular retrognathism and maxillary prognathism, the middle portion of the dorsal tongue was positioned superiorly at stage 3 relative to stage 1; the tongue tip was retruded at stage 3 relative to stages 1 and 2. In the control group, the middle portion of dorsal tongue was positioned superiorly at stage 3 relative to stages 1 and 2; the posterior portion of the tongue moved upward at stage 2 and downward at stage 3, and tongue-tip retrusion was observed at stage 2 relative to stage 1. Contact of the anterior portion of the tongue with the rugae area of the hard palate decreased in the Class II malocclusion groups relative to the control group. The middle portion of the dorsal tongue was positioned more superiorly in patients with Class II malocclusion during all stages of deglutition. The root of the tongue was more inferior and anterior, and the tongue tip was retruded in patients with Class II malocclusion compared with the control group. The posterior portion of the dorsal tongue was more inferiorly positioned in patients with mandibular retrusion than in the other Class II groups or the controls. In the third stage of deglutition, this portion of the tongue had a superior position in groups 2 and 3 relative to the control group. CONCLUSIONS: Dentofacial morphology affects the position and movements of the tongue during deglutition, and adaptive changes occur in the tip, dorsum, and root of the tongue. Deglutitive tongue movements in patients with a skeletal Class II relationship are different from those with a skeletal Class I relationship. PMID- 21536184 TI - Mixed longitudinal evaluation of masticatory performance in children 6 to 17 years of age. AB - INTRODUCTION: The purposes of this study were to determine (1) how masticatory performance changes with age, (2) whether masticatory performance differs between the sexes, and (3) whether patterns of masticatory performance differ among subjects with various types of malocclusion. METHODS: A total of 450 children and adolescents (244 boys, 206 girls) were assigned to 4 age cohorts (ages 6, 9, 12, and 15 years) and followed for 3 consecutive years. The subjects were selected based on having about equal numbers of boys and girls, and about equal numbers of subjects with normal occlusion and Class I and Class II malocclusions. Masticatory performance was assessed by using the artificial food CutterSil (Heraeus Kulze, South Bend, Ind). The peer assessment rating index was used to quantify the severity of the malocclusions. RESULTS: Median particle size (MPS) decreased significantly from 6 to 17 years of age. There were no statistically significant differences in MPS between the 3 occlusal groups, but there were significant sex differences, with girls having smaller MPS than boys. Multilevel analysis showed greater decreases in MPS between 6 and 9 years, and after 12 years of age, than between 9 and 12 years of age. There were no significant correlations between MPS and the weighted peer assessment rating index. MPS showed significant intercorrelations between measures of MPS obtained at years 1, 2, and 3, with correlations tending to be highest for the oldest age cohort. CONCLUSIONS: Masticatory performance improves with age, and the changes appear to be influenced by the loss of the deciduous teeth during the late mixed dentition phase of dental development. Although there are limited sex differences in masticatory performance among subjects 6 to 17 years of age, mild forms of Class I and Class II malocclusions have little or no effect on masticatory performance. PMID- 21536185 TI - True hemifacial microsomia and hemimandibular hypoplasia with condylar-coronoid collapse: diagnostic and prognostic differences. AB - INTRODUCTION: Long-term results after orthopedic or surgical treatment of hemifacial microsomia (HFM) have shown a tendency toward recurrence of the facial asymmetry. However, the literature contains a number of successful case reports that show surprising changes in the morphology of the condyles. In addition, patients with similar mandibular asymmetries, treated early with surgery, have excellent long-term follow-ups, especially those who have little or no soft tissue involvement, but only severe mandibular ramal deformities. The phenotypes of these cases are unexpectedly similar, with a consistent collapse of the condyle against the coronoid and a deep sigmoid notch. The objectives of this article were to help distinguish true HFM from this peculiar type of hemimandibular asymmetry morphologically and to quantify their differences before treatement and in the long term. METHODS: Panoramic radiographs taken at pretreatment and the long-term follow-up of 9 patients with hemimandibular hypoplasia, characterized by the collapse of the condyle against the coronoid, were compared with those of 8 patients with severe type I and type II HFM; these records were collected before and at least 10 years after distraction osteogenesis. RESULTS: Ratios and angular measurements before and after treatment differed significantly between the 2 groups. CONCLUSIONS: Perhaps these patients were misdiagnosed and actually had secondary injuries of the condyle, which have a normal functional matrix. Therefore, with growth and functional stimulation, they would tend to grow toward the original symmetry. To make a differential diagnosis between true HFM and this peculiar type of hemimandibular hypoplasia, the collaboration between not only orthodontists and surgeons, but also geneticists and dysmorphologists, is of great importance because of the different prognoses. PMID- 21536186 TI - Influence of bending mode on the mechanical properties of nickel-titanium archwires and correlation to differential scanning calorimetry measurements. AB - INTRODUCTION: Nickel-titanium orthodontic archwires are used with bonded appliances for initial leveling. However, precise bending of these archwires is difficult and can lead to changes within the crystal structure of the alloy, thus changing the mechanical properties unpredictably. The aim of this study was to evaluate different bending methods in relation to the subsequent mechanical characteristics of the alloy. MATERIALS AND METHODS: The mechanical behaviors of 3 archwires (Copper NiTi 35 degrees C [Ormco, Glendora, Calif], Neo Sentalloy F 80 [GAC International, Bohemia, NY], and Titanol Low Force [Forestadent, Pforzheim, Germany]) were investigated after heat-treatment in a dental furnace at 550-650 degrees C, treatment with an electrical current (Memory-Maker, Forestadent), and cold forming. In addition, the change in A(f) temperature was registered by means of differential scanning calorimetry. RESULTS: Heat-treatment in the dental furnace as well as with the Memory-Maker led to widely varying force levels for each product. Cold forming resulted in similar or slightly reduced force levels when compared to the original state of the wires. A(f) temperatures were in general inversely proportional to force levels. CONCLUSIONS: Archwire shape can be modified by using either chair-side technique (Memory Maker, cold forming) because the superelastic behavior of the archwires is not strongly affected. However it is important to know the specific changes in force levels induced for each individual archwire with heat-treatment. Cold forming resulted in more predictable forces for all products tested. Therefore, cold forming is recommended as a chair-side technique for the shaping of NiTi archwires. PMID- 21536187 TI - Relationship between cervical vertebral maturation and mandibular growth. AB - INTRODUCTION: The cervical vertebrae have been proposed as a method of determining biologic maturity. The purposes of this study were to establish a pattern of mandibular growth and to relate this pattern to the stages of cervical vertebral maturation. METHODS: Cephalometric radiographs, taken annually from ages 9 to 18 years, were evaluated for 90 boys from the Burlington Growth Center, Toronto, Ontario, Canada. Mandibular lengths were measured from articulare to gnathion, and incremental growth was determined. Cervical vertebral maturation stages were assessed by using a 6-stage method. Advanced, average, and delayed maturation groups were established. RESULTS: The prepubertal mandibular growth minimum velocity occurred during cervical stages 1 through 4 (P = 0.7327). Peak mandibular growth velocity occurred most frequently during stage 4 in all 3 maturation groups, with a statistical difference in the average and delayed groups (P <0.0001) and the advanced group (P = 0.0143). The average number of years spent in stage 4 was 3.79 (P <0.0001). The average amount of mandibular growth occurring during stage 4 was 9.40 mm (P <0.0001). The average amount of growth in stages 5 and 6 combined was 7.09 mm. CONCLUSIONS: Progression from cervical stages 1 through 6 does not occur annually; time spent in each stage varies depending on the stage and the maturation group. Cervical vertebral maturation stages cannot accurately identify the mandibular prepubertal growth minimum and therefore cannot predict the onset of the peak in mandibular growth. The cervical vertebral maturation stages should be used with other methods of biologic maturity assessment when considering both dentofacial orthopedic treatment and orthognathic surgery. PMID- 21536188 TI - Plaque levels of patients with fixed orthodontic appliances measured by digital plaque image analysis. AB - INTRODUCTION: A digital plaque image analysis system was developed to objectively assess dental plaque formation and coverage in patients treated with fixed orthodontic appliances. METHODS: The technique was used to assess plaque levels of 52 patients undergoing treatment with fixed appliances in the Department of Orthodontics at Johannes Gutenberg University in Mainz, Germany. RESULTS: Plaque levels ranged from 5.1% to 85.3% of the analyzed tooth areas. About 37% of the patients had plaque levels over 50% of the dentition, but only 10% exhibited plaque levels below 15% of tooth coverage. The mean plaque coverage was 41.9% +/- 18.8%. Plaque was mostly present along the gum line and around the orthodontic brackets and wires. CONCLUSIONS: The digital plaque image analysis system might provide a convenient quantitative technique to assess oral hygiene in orthodontic patients with multi-bracket appliances. Plaque coverage in orthodontic patients is extremely high and is 2 to 3 times higher than levels observed in high plaque forming adults without appliances participating in clinical studies of the digital plaque image analysis system. Improved hygiene, chemotherapeutic regimens, and compliance are necessary in these patients. PMID- 21536189 TI - What are we reading? An analysis of the orthodontic literature 1999 to 2008. AB - INTRODUCTION: The purpose of this study was to assess differences between articles published in the American Journal of Orthodontics and Dentofacial Orthopedics (AJO-DO), the Angle Orthodontist (AO), the European Journal of Orthodontics (EJO), and the Journal of Orthodontics (JO) from 1999 to 2008. METHODS: All journals were hand-searched and 4301 eligible articles were identified. A random sample of 425 articles was obtained to provide 80% power to detect a 100% increase in the number of randomized controlled trials (RCTs) at the 5% level of significance. Each article was classified according to predetermined criteria. Variations between journals were assessed using the chi(2) test or odds ratio (OR) and 95% confidence intervals (95% CI). RESULTS: The AJO-DO published 45.6% of the articles in the final sample, 27.7% were from the AO, 17.4% were from the EJO, and 9.2% were from the JO. Statistically significant differences were found between the type (P <0.001), subject (P <0.001), setting (P <0.03), and method (P <0.001) of articles published in the 4 journals. The increase in the proportion of RCTs published between 1999 and 2003 and 2004 to 2008 was not statistically significant (OR 0.64; 95% CI, 0.29, 1.43). CONCLUSIONS: Statistically significant differences were found in the publication profiles of the 4 orthodontic journals examined, but the increase in RCTs was lower than anticipated. PMID- 21536190 TI - Treatment of adult Class III malocclusions with orthodontic therapy or orthognathic surgery: receiver operating characteristic analysis. AB - INTRODUCTION: The aim of this study was to distinguish between orthodontic patients with skeletal Class III malocclusions requiring surgery and those not requiring surgery by conducting a receiver operating characteristic analysis of cephalometric variables. METHODS: We used lateral cephalometric radiographs of 80 subjects (40 nonsurgical and 40 surgical patients) with Class III malocclusions and obtain 25 cephalometric measurements using computerized cephalometry. Of these, 14 measurements showed statistically significant differences between the 2 groups. Receiver operating characteristic analysis was used to determine the ability of the 14 cephalometric measurements in distinguishing between the 2 groups. Six statistically validated and clinically relevant measurements were used to obtain the optimum discriminant effectiveness. RESULTS: For a Class III malocclusion patient with any 4 of these 6 measurement criteria, the sensitivity was 88% and the specificity was 90% in determining the need for surgical treatment: overjet, <=-4.73 mm; Wits appraisal, <=-11.18 mm; L1-MP angle, <=80.8 degrees ; Mx/Mn ratio, <=65.9%; overbite, <=-0.18 mm; and gonial angle, >=120.8 degrees . CONCLUSIONS: We selected 6 cephalometric measurements as the minimum number of discriminators required to obtain the optimum discriminant effectiveness of diagnosis between surgical and nonsurgical treatment of skeletal Class III malocclusions. PMID- 21536191 TI - Physical properties of root cementum: Part 18. The extent of root resorption after the application of light and heavy controlled rotational orthodontic forces for 4 weeks: a microcomputed tomography study. AB - INTRODUCTION: The aim of this prospective randomized clinical trial was to quantitatively measure and compare the locations, dimensions, and volume of root resorption craters in human premolars after the application of controlled light and heavy rotational orthodontic forces over a 28-day (4-week) period. METHODS: Fifteen patients requiring bilateral extraction of maxillary first premolars as part of their orthodontic treatment were recruited for this study. Each patient received a heavy (225 g) rotational force on 1 premolar and a light (25 g) rotational force on the contralateral premolar. Orthodontic rotational forces were applied over 28 days with buccal and palatal cantilever springs; 0.016-inch beta-titanium molybdenum alloys were used to apply the light force and 0.018-inch stainless steel was used for the heavy force. After the 28-day experimental period, the upper first premolars were extracted under stringent protocols to prevent root surface damage. The samples were then scanned using a microcomputed tomography (micro-CT) scan x-ray system (SkyScan 1072, Skyscan, Aartselaar, Belgium), and analyzed using convex hull algorithm (CHULL2D; University of Sydney, Sydney, Australia) software to obtain direct volumetric measurements. RESULTS: The mean volume of resorption craters was 0.42 in the light force group and 0.51 in the heavy force group (P = 0.013). When separated at the root level, the difference in volume of root resorption craters between the 2 groups was significantly different only at the midlevel (P = 0.001). Root resorption craters were consistently detected at the boundaries between the buccal and distal surfaces and the mesial and lingual surfaces. The result supports our hypothesis that positive areas develop significantly more root resorption craters at all 3 levels, as compared with minimal areas (paired t test <0.001). CONCLUSIONS: Heavy rotational forces caused more root resorption than light rotational forces and compression areas (buccal-distal and lingual-mesial surfaces in this study) showed significantly higher root resorption than other areas at all levels of the root. PMID- 21536192 TI - It's our duty! PMID- 21536193 TI - Biased look at self-ligation. PMID- 21536195 TI - Image superimposition method in tooth movement and arch dimension changes evaluation. PMID- 21536197 TI - And justice for all. PMID- 21536199 TI - Controlled, prospective trial of psychosocial function before and after mandibular advancement splint therapy. AB - INTRODUCTION: The aim of the study was to investigate psychosocial function in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS), before and after mandibular advancement splint (MAS) therapy. METHODS: In a prospective, parallel group study, changes in psychosocial scores were compared before and after MAS therapy for OSAHS. Patients from the top (MAS treated, n = 40) or bottom (conservatively treated n = 35) of a MAS waiting list rated quality of life (Short Form 36 [SF-36] Health Survey) and sleepiness (Epworth Sleepiness Scale [ESS]). Both groups' ratings at baseline were completed while on conservative therapy. RESULTS: Baseline variables did not differ between groups. At follow-up, psychosocial scores showed improvement in MAS-treated patients, with odds ratios (confidence interval) of 0.26 (0.09, 0.75) and 0.36 (0.14, 0.92) for sleepiness and energy/vitality domain, respectively. Statistically significant improvement in the median (range) sleepiness score (10 [1 to 18] to 6 [1 to 14]; P <0.001) and energy/vitality domain (18 [7 to 20] to 19 [14 to 20]; P = 0.03) were observed with MAS therapy. Reductions were detected in median apnea-hypopnea index (median [range] 16 [5.2 to 30] to 4.6 [0.8 to 17.2] events/hour; P <0.001), and oxygen desaturation index (ODI) (11 [3 to 16] to 0 [0 to 5] events/hour; P <0.001) at follow-up with MAS therapy. Similar changes were observed in the comparison group when they went on to be treated with MAS. CONCLUSIONS: This study demonstrated that treatment with MAS produced statistically and clinically significant psychosocial and cardio-respiratory improvements. PMID- 21536200 TI - Effects of sodium fluoride mouth rinses on the torsional properties of miniscrew implants. AB - INTRODUCTION: Effects of sodium fluoride (NaF) mouth rinse solutions on torsional properties of a miniscrew implant were investigated. METHODS: As-received Ti-6Al 4V miniscrew implants (AbsoAnchor [Dentos, Inc., Daigu, Korea]) were immersed in 0.1% or 0.2% NaF mouth rinse solution (pH 5.12 and 5.14, respectively) for 1 hour or 24 hours. Miniscrew implants selected as controls were not immersed. Each implant was subjected to increasing torque until fracture (n = 5 in sample groups). Mean moment and twist angle for fracture were compared using 1-way analysis of variance (ANOVA). Surfaces of implants after immersion were observed with a scanning electron microscope (SEM). Electron microprobe and micro-x-ray diffraction analyses were performed to obtain composition information about deposits on implant surfaces. RESULTS: Pits and cracks formed on the implant surfaces after immersion in both NaF mouth rinse solutions. Corrosion products, probably sodium aluminum fluoride (Na(3)AlF(6)), were observed on the implants after immersion in both NaF solutions for both time periods. There were no significant differences for mean torque (P = 0.063) and twist angle (P = 0.696) at fracture compared with control implants. CONCLUSIONS: Although titanium alloy miniscrew implants corroded slightly from immersion in 0.1% or 0.2% NaF solutions, mouth rinsing by patients with the same fluoride solution concentrations should not cause deterioration of their torsional performance. PMID- 21536201 TI - Comparison of friction force between corroded and noncorroded titanium nitride plating of metal brackets. AB - INTRODUCTION: Titanium nitride (TiN) plating is a method to prevent metal corrosion and can increase the surface smoothness. The purpose of this study was to evaluate the friction forces between the orthodontic bracket, with or without TiN plating, and stainless steel wire after it was corroded in fluoride containing solution. METHODS: In total, 540 metal brackets were divided into a control group and a TiN-coated experimental group. The electrochemical corrosion was performed in artificial saliva with 1.23% acidulated phosphate fluoride (APF) as the electrolytes. Static and kinetic friction were measured by an EZ-test machine (Shimadazu, Tokyo, Japan) with a crosshead speed of 10 mm per minute over a 5-mm stretch of stainless steel archwire. The data were analyzed by using unpaired t test and analysis of variance (ANOVA). RESULTS: Both the control and TiN-coated groups' corrosion potential was higher with 1.23% APF solution than with artificial solution (P <0.05). In brackets without corrosion, both the static and kinetic friction force between the control and TiN-coated brackets groups showed a statistically significant difference (P <0.05). In brackets with corrosion, the control group showed no statistical difference on kinetic or static friction. The TiN-coated brackets showed a statistical difference (P <0.05) on kinetic and static friction in different solutions. CONCLUSION: TiN coated metal brackets, with corrosion or without corrosion, cannot reduce the frictional force. PMID- 21536202 TI - Force levels of 23 nickel-titanium open-coil springs in compression testing. AB - INTRODUCTION: Open-coil springs are commonly used auxiliaries in fixed orthodontic appliance therapy. Space opening for impacted or heavily crowded teeth as well as distalization of molars all require specific force levels. It is the aim of the current study to present an overview of the mechanical properties of currently available nickel titanium (NiTi) closed coil springs. MATERIAL AND METHODS: Twenty-three NiTi open-coil springs were compressed by 25% and 50% of their original length at a controlled temperature of 36 degrees C. Force deflection diagrams were registered using an Instron 3344 (Instron Corp, Wilmington, De). Five samples of each coil spring were measured and evaluated for their mean force as well as their superelastic characteristics. RESULTS: Almost all coil springs showed a linear behavior in the force deflection diagram. Only a few open-coil springs (GAC light, medium, and heavy [Dentsply GAC, Bohemia, NY] and RMO 12 * 45 [Rocky Mountain Orthodontics, Denver, Colorado]) showed a superelastic behavior with a clear force plateau, also indicated by their high ratio of variance. The results of the tested open-coil springs allow the clinician to choose springs with mean forces between 0.25 N (3M Unitek light; 3M Unitek, St. Paul, Minn) and 1.3 N (GAC heavy) for a compression of 25% and 0.64 N (3M Unitek light) to 2.9 N (OrthoOrganizers 14 * 37 [OrthoOrganizers, Carlsbad, Calif], Dentaurum Rematitan strong [Dentaurum, Ispringen, Germany]) for a compression of 50%. CONCLUSIONS: Superelastic behavior was rarely observed with open-coil springs. The clinician can therefore not rely on the force range indicated without considering the amount of compression of the coil spring. PMID- 21536203 TI - Relative contributions of occlusion, maximum bite force, and chewing cycle kinematics to masticatory performance. AB - INTRODUCTION: The purpose of this study was to explore the contributions of occlusion, maximum bite force, and chewing cycle kinematics to masticatory performance. METHODS: A prospective cross-sectional study was performed on 30 subjects with Class I occlusion. Masticatory performance was measured with the test food Cuttersil (Heraeus Kulzer, South Bend, Ind) and the fractional-sieve technique. Blu-Mousse (Parkell Biomaterials, Farmingdale, NY) bite registrations were used to measure occlusal contact areas. The American Board of Orthodontics occlusal discrepancies were measured on the subjects' dental models. Maximum bite forces were recorded with a custom transducer, and 3-dimensional chewing cycle kinematics were tracked with an opto-electric computer system and Optotrak software (Northern Digital, Waterloo, Ontario, Canada). RESULTS: Masticatory performance was most closely correlated with occlusal contact area, indicating larger contact areas in subjects with better performance. Occlusal contact area and occlusal discrepancies were also related to bite force and chewing cycle kinematics. Maximum bite force was positively related with masticatory performance. CONCLUSIONS: Although masticatory performance is related, both directly and indirectly, to a number of morphologic and functional factors, it is most closely related to occlusal factors. PMID- 21536204 TI - Long-term effectiveness of canine-to-canine bonded flexible spiral wire lingual retainers. AB - INTRODUCTION: The flexible spiral wire (FSW) canine-to-canine lingual retainer bonded to all 6 anterior teeth is a frequently used type of mandibular fixed retainer. This study aimed to assess the long-term effectiveness of FSW canine-to canine lingual retainers in maintaining the alignment of the mandibular anterior teeth after orthodontic treatment. METHODS: The sample consisted of dental casts of 221 consecutively treated patients (75 girls, 146 boys) from the archives of the Department of Orthodontics and Craniofacial Biology, Radboud University Nijmegen Medical Center, The Netherlands, who received a FSW canine-to-canine lingual retainer bonded to all 6 anterior teeth after active orthodontic treatment. The casts were studied before treatment (Ts), immediately after treatment (T0), 2 years (T2), and 5 years (T5) posttreatment. RESULTS: The main irregularity index decreased significantly from 5.40 mm (SD, 3.47) at Ts to 0.07 mm (SD, 0.23) at T0. At T5, the alignment of the mandibular anterior teeth was stable in 200 patients (90.5%); in 21 patients (9.5%), a mean increase of 0.81 mm (SD, 0.47) was observed. The increase of irregularity was strongly related to the bonding failures of the retainer. In 6 patients (2.7%), unexpected posttreatment complications (torque differences of the incisors, increased buccal canine inclination) were observed. CONCLUSIONS: The FSW canine-to-canine lingual retainer is very effective in maintaining the alignment of the mandibular anterior region after active orthodontic treatment. However, regular checkups are necessary to determine bonding failures, posttreatment changes, and complications as early as possible. PMID- 21536205 TI - Mandibular lip bumper treatment and second molar eruption disturbances. AB - INTRODUCTION: Mandibular lip-bumper (LB) nonextraction treatment, usually started before complete second molar (M2) eruption, inevitably interacts with the development of the dentition. Yet, its effects on M2 eruption are still unknown. The first aim of this study was to retrospectively investigate whether LB therapy (260 patients) enhances the risk for M2 ectopic eruptions and impactions in comparison with 135 untreated subjects. The second aim was to assess, among treated patients (n = 197), the main potential determinants of M2 impaction and ectopic eruption. METHODS: M2 eruption and impaction were determined on panoramic radiographs. To assess the predictive role of M2 inclination in relation to the first molar, a panoramic radiograph suitable for this measurement before treatment was required. The data were analyzed by using software (version 8.2, SAS, Cary, NC). RESULTS: LB treatment significantly enhanced M2 impaction and ectopic eruption. Negative prognostic factors were found. An initial inclination of the M2 greater than 30 degrees was significantly associated with a higher impaction risk compared with an angulation less than 10 degrees . LB treatment duration longer than 2 years increased the risk of ectopic eruptions. CONCLUSIONS: While gaining space in the anterior arch, unwanted effects might be produced in the posterior arch. To be informed about these unplanned events is necessary to better optimize treatment. PMID- 21536206 TI - Effect of placement angle on the stability of loaded titanium microscrews: a microcomputed tomographic and biomechanical analysis. AB - INTRODUCTION: The aim of this study was to evaluate the impact of the placement angle on the stability of loaded microscrews. METHODS: Forty-eight microscrews were placed at 4 angles ( 30 degrees , 50 degrees , 70 degrees , and 90 degrees ) into the tibiae of 12 beagles, loaded with a force of 2 N immediately, and maintained for 8 weeks. Microcomputed tomography and pullout tests were used for morphometric and biomechanical analyses, respectively. RESULTS: All microcomputed tomography parameters and the peak loads at extraction of the microscrews were influenced by the placement angles of the microscrews. The higher microcomputed tomography parameters and the peak load at extraction were measured at angles from 50 degrees to 70 degrees . Oblique and vertical placement angles resulted in reduced stability of the loaded microscrews (P <0.05). CONCLUSIONS: To achieve the best stability of microscrews, a placement angle of 50 degrees to 70 degrees is advisable. PMID- 21536207 TI - Comparative evaluation of maxillary protraction with or without skeletal anchorage. AB - INTRODUCTION: The aim of this prospective clinical study was to evaluate the skeletal, dentoalveolar, and soft-tissue effects of maxillary protraction with miniplates compared with conventional facemask therapy and an untreated Class III control group. METHODS: Forty-five subjects who were in prepubertal or pubertal skeletal growth periods were included in the study and divided into 3 groups of 15 patients each. All subjects had skeletal and dental Class III malocclusions with maxillary deficiency, vertically normal growth pattern, anterior crossbite, Angle Class III molar relationship, normal or increased overbite, and retrusive nasomaxillary complex. Before maxillary protraction, rapid maxillary expansion with a bonded appliance was performed in both treatment groups. In the first group (MP+FM), consisting of 5 girls and 10 boys (mean age, 10.91 years), facemasks were applied from 2 titanium miniplates surgically placed laterally to the apertura piriformis regions of the maxilla. The second group (FM) of 7 girls and 8 boys (mean age, 10.31 years) received maxillary protraction therapy with conventional facemasks applied from hooks of the rapid maxillary expansion appliance. The third group of 8 girls and 7 boys (mean age, 10.05 years) was the untreated control group. Lateral cephalometric films were obtained at the beginning and end of treatment or observation in all groups and analyzed according to a structural superimposition method. Measurements were evaulated statistically with Wilcoxon and Kruskal-Wallis tests. RESULTS: Treatment periods were 6.78 and 9.45 months in the MP+FM and FM groups, respectively, and the observation period in the control group was 7.59 months. The differences were significant between the 3 groups (P <0.05) and the MP+FM and FM groups (P <0.001). The maxilla moved forward for 2.3 mm in the MP+FM group and 1.83 mm in the FM group with maxillary protraction. The difference was significant between 2 groups (P <0.001). The protraction rates were 0.45 mm per month in the MP+FM group and 0.24 mm per month in the FM group (P <0.001). The maxilla showed anterior rotation after facemask therapy in the FM group (P <0.01); there was no significant rotation in the MP+FM group. Posterior rotation of the mandible and increased facial height were more evident in the FM group compared with the MP+FM group (P <0.01). Both the maxilla and the mandible moved forward significantly in the control group. Protrusion and mesialization of the maxillary teeth in the FM group were eliminated in the MP+FM group. The maxillomandibular relationships and the soft-tissue profile were improved remarkably in both treatment groups. CONCLUSIONS: The undesired effects of conventional facemask therapy were reduced or eliminated with miniplate anchorage, and efficient maxillary protraction was achieved in a shorter treatment period. PMID- 21536208 TI - Effect of antibacterial monomer-containing adhesive on enamel demineralization around orthodontic brackets: an in-vivo study. AB - INTRODUCTION: The aims of this study were to evaluate the effect of an antibacterial monomer-containing self-etching adhesive in reducing enamel demineralization around orthodontic brackets in vivo and to compare it with the conventional adhesive system quantitatively. METHODS: Fourteen orthodontic patients were randomly divided into 2 equal groups; they received brackets fitted to all their teeth, bonded with either Clearfil Protect Bond (Kuraray Medical, Okayama, Japan) (experimental group) or Transbond XT (3M Unitek, Monrovia, Calif) (control group). Block randomization to obtain equal numbers in each group was used. After 30 days, all first premolars were extracted with orthodontic indications and longitudinally sectioned. Demineralization was assessed by cross sectional microhardness. Determinations were made at the bracket edge cementing limits and at occlusal and cervical points 100 and 200 MUm away from the edge. In all of these positions, 6 indentations were made at depths of 10 to 90 MUm from the enamel surface. Analysis of variance (ANOVA) and the Tukey post-hoc test were used. The statistical significance level was set at P <0.05. RESULTS: ANOVA showed statistically significant differences for adhesive type, position, depth, and their interactions (P <0.05). The multiple comparison test showed that the antibacterial monomer-containing adhesive was significantly more efficient than the conventional adhesive system, reducing enamel demineralization in almost all evaluations (P <0.05). CONCLUSIONS: The results indicated that using antibacterial monomer-containing adhesive for bonding orthodontic brackets successfully inhibited caries in vivo. This cariostatic effect was localized at the area around the brackets and was significant after 30 days. PMID- 21536209 TI - Incidence of caries lesions among patients treated with comprehensive orthodontics. AB - INTRODUCTION: Dental caries, specifically decalcified white-spot lesions (WSL), is a well-known side-effect of orthodontic treatment. The incidence of labial incipient caries lesions and its relationship with various patient and treatment variables was investigated in patients treated with comprehensive orthodontics. METHODS: Randomly selected orthodontic patient records (n = 350) were examined to determine incipient caries lesion development. Labial surfaces on pretreatment and posttreatment photographs were scored with a standardized scoring system. Independent variables were collected by chart abstraction. RESULTS: The incidence of patients who developed at least 1 new WSL during treatment was 72.9%, and this incidence was 2.3% for cavitated lesions. Treatment duration was significantly associated with new WSL development (P = 0.03). Development of WSL and cavitated lesions increased (both, P <0.00) despite increased attention to oral hygiene during treatment. Sex, age, extraction therapy, and various fluoridation sources were not associated with WSL development, but initial oral-hygiene score was moderately associated (P <0.06). CONCLUSIONS: The incidence of WSL in patients treated with comprehensive orthodontics was significantly high, and the preventive therapy provided appeared to be ineffective. This widespread problem is alarming and warrants significant attention from both patients and providers that should result in greatly increased emphasis on effective caries prevention. PMID- 21536210 TI - Clinical outcomes assessment of consecutively finished patients in a 24-month orthodontic residency: a 5-year perspective. AB - INTRODUCTION: The purpose of this study was to report on the clinical outcomes of a 24-month orthodontic residency. METHODS: One examiner scored 1019 consecutive pretreatment records and 714 consecutive posttreatment records annually over 5 years, using the American Board of Orthodontics discrepancy index and objective grading system. RESULTS: The mean discrepancy index scores were 19.63, 14.84, 12.30, 15.72, and 15.39 for years 1 through 5, respectively. The mean objective grading system scores were 31.16, 34.79, 28.55, 26.28, and 22.11 for years 1 through 5, respectively. The residents' completion rates for all cases were 58.9%, 60.5%, 82.7%, 74.4%, 78.2%, and 72.2% for years 1 through 5, respectively. CONCLUSIONS: The establishment of an annual objective outcomes assessment benefited patients by improving objective grading system scores and reduced the number of transfers between residents (increased case completion rate), thus reducing faculty time for managing many transfer patients. PMID- 21536211 TI - Placement and removal torque values of orthodontic miniscrew implants. AB - INTRODUCTION: The purpose of this study was to analyze the maximum insertion torque (MIT) and maximum removal torque (MRT) values of orthodontic miniscrews. METHODS: Two hundred eighty titanium miniscrews were placed in several sites in the maxillae and mandibles of orthodontic patients to provide skeletal anchorage. Two types of miniscrews were used: predrilling, cylindrical miniscrews, and self drilling, conical miniscrews. A force of 50 g was applied with nickel-titanium coil springs 2 weeks after placement. MIT and MRT values were assessed with a digital torque gauge. Torque values were subjected to the paired t test, Student t test, chi-square test, and 1-way analysis of variance (ANOVA) (P <0.05). RESULTS: MIT values were significantly higher for the self-drilling miniscrews (mean, 14.5 Ncm; 95% CI, 13.6-15.3) than for the predrilling miniscrews (mean, 9.2 Ncm; 95% CI, 8.6-9.9) in all implant sites. For both predrilling and self drilling miniscrews, the highest MIT values were observed at the midpalatal suture site followed by the dentoalveolar bones of the mandible and maxilla, respectively. In contrast, MRT values were significantly higher for the predrilling miniscrews (mean, 22.6 Ncm; 95% CI, 22.0-23.3) than for the self drilling miniscrews (mean, 17.6 Ncm; 95% CI, 16.8-18.4). Accordingly, the mean torque ratio of predrilling miniscrews was twice that of the self-drilling miniscrews. CONCLUSIONS: An inverse relationship between MIT and MRT values was observed. The results suggest that relatively lower MIT values were more favorable to osseointegration than higher values. PMID- 21536212 TI - Class III malocclusion with complex problems of lateral open bite and severe crowding successfully treated with miniscrew anchorage and lingual orthodontic brackets. AB - In this article, we report the successful use of miniscrews in a patient with an Angle Class III malocclusion, lateral open bite, midline deviation, and severe crowding. Simultaneously resolving such problems with conventional Class III treatment is difficult. In this case, the treatment procedure was even more challenging because the patient preferred to have lingual brackets on the maxillary teeth. As a result, miniscrews were used to facilitate significant asymmetric tooth movement in the posterior and downward directions; this contributed to the camouflage of the skeletal mandibular protrusion together with complete resolution of the severe crowding and lateral open bite. Analysis of the jaw motion showed that irregularities in chewing movement were also resolved, and a stable occlusion was achieved. Improvements in the facial profile and dental arches remained stable at the 18-month follow-up. PMID- 21536213 TI - Orthodontic treatment for a patient with hypodontia involving the maxillary lateral incisors. AB - Developmental absence of maxillary lateral incisors is not uncommon in orthodontic patients. Treatment depends on a number of factors, including skeletal pattern, type of malocclusion, overjet, and the shape and color of the canines. Management can be broadly divided into space closure, space opening or redistribution, and prosthetic replacement. The purpose of this article was to report the treatment of a girl with an Angle Class I malocclusion with missing maxillary lateral incisors and severe crowding in the mandibular labial segment. Treatment included preadjusted fixed appliances, extraction of the mandibular first premolars, and space closure of the maxillary labial segment space with the canines substituted for the maxillary lateral incisors. PMID- 21536214 TI - Orthodontic treatment of bilateral geminated maxillary permanent incisors. AB - Geminated teeth occur more frequently in the deciduous dentition than in the permanent dentition, with prevalence figures of 0.6% and 0.1%, respectively. Bilateral presentation is rare. A survey of the literature showed that the prevalence estimates for bilateral double teeth range from 0.01% to 0.04% in the deciduous dentition, and 0.05% in the permanent dentition. In this article, we report a rare case of bilateral fusion of the maxillary permanent incisors, discuss possible histogenetic mechanisms related to this anomaly, and explain the treatment management. PMID- 21536215 TI - Crohn's disease: clinical manifestations of orthodontic interest. AB - Crohn's disease is a chronic inflammation of the small intestine; it can involve other organs, such as the skin, eyes, lungs, and joints. Oral manifestations are common, especially ulcers and stomatitis, which macroscopically and histologically resemble those found in the gastrointestinal tract. However, orthodontic alterations are not yet known. This article reviews aspects related to the diagnosis of Crohn's disease and clinical considerations for an orthodontic patient. PMID- 21536216 TI - Litigation and legislation. Working for another. PMID- 21536217 TI - Adjuvant interferon: extended follow-up times needed? PMID- 21536218 TI - How does TPF improve survival over PF? PMID- 21536219 TI - How does TPF improve survival over PF? PMID- 21536222 TI - Cervical cancer: balancing obstetrical and oncological outcomes. PMID- 21536223 TI - For an operational definition of cachexia. PMID- 21536224 TI - Smart phones: new clinical tools in oncology? PMID- 21536225 TI - Treating menopausal symptoms with a tissue-selective estrogen complex. AB - Vasomotor symptoms and vulvar-vaginal atrophy are common consequences of menopause, and the only treatment approved by the US Food and Drug Administration is hormone therapy. Because both physicians and women are concerned with the tolerability and safety profile of estrogen and estrogen plus progestin treatments, alternative menopause therapies are needed. An ideal menopause treatment modality would relieve menopausal vasomotor and vulvar-vaginal symptoms, maintain bone mass, and have neutral or beneficial cardiovascular effects, without stimulating the breast or endometrium. The novel tissue selective estrogen complex (TSEC) agent was paired with a selective estrogen receptor modulator (SERM) with estrogen(s) in an attempt to achieve a more favorable clinical profile based on the blended tissue activities of its components. This article reviews the published reports from Phase III trials of TSEC, which paired bazedoxifene (BZA) and conjugated estrogens (CEs). BZA/CE alleviated menopausal symptoms and prevented postmenopausal bone loss, had an overall good safety profile with an incidence of amenorrhea and breast pain similar to that with placebo, and did not stimulate the endometrium. The largest (N = 3397) and longest (2 years) study of this TSEC containing BZA/CE demonstrated endometrial hyperplasia rates similar to that with placebo and changes in lumbar spine bone mineral density that were significantly better than that with placebo, when a minimum dose of 20 mg of BZA was used with 0.625 or 0.45 mg of CE. Subsequent smaller studies showed that BZA/CE effectively reduced the incidence and frequency of hot flushes and significantly improved signs and symptoms of vaginal atrophy. Longer term safety with regard to cardiovascular and breast effects have not been established. Given the efficacy and safety reported in these Phase III trials, the TSEC of BZA/CE may be a promising new option for the treatment of menopause. PMID- 21536226 TI - NorVold Abuse Questionnaire for men (m-NorAQ): validation of new measures of emotional, physical, and sexual abuse and abuse in health care in male patients. AB - BACKGROUND: There are far more prevalence studies on abuse of females than on males as subjects of abuse. The NorVold Abuse Questionnaire (NorAQ) measures emotional, physical, and sexual abuse, as well as abuse in health care, in women and men. OBJECTIVE: The aim of this study was to test the concurrent validity and test-retest reliability of the questions in the version of NorAQ administered to men (m-NorAQ) against the interview model. METHODS: The validation was tested in a subsample (n = 86) of a male patient sample who had filled out the m-NorAQ (N = 1667). Respondents completed m-NorAQ twice and were then interviewed. Before the interview, respondents were instructed to answer questions based on personal experience. The interview consisted of 4 open-ended questions about lifetime experiences of emotional, physical, and sexual abuse and abuse in health care. RESULTS: Results indicated that respondents in the subsample had discussed the experiences of abuse more often in both formal and informal settings than had subjects in the total patient sample. Measures of sensitivity for m-NorAQ were good to excellent (emotional abuse, 83%; physical abuse, 76%; sexual abuse, 68%; abuse in health care, 93%), as were those for specificity (emotional abuse, 72%; physical abuse, 92%; sexual abuse, 99%, abuse in health care, 90%); likelihood ratios were satisfactory (emotional abuse, 3; physical abuse, 9; sexual abuse, 46; abuse in health care, 9); and test-retest reliability measures were excellent (emotional abuse, 80%-95%; physical abuse, 77%-88%; sexual abuse, 91%-100%; abuse in health care, 84%-92%). CONCLUSION: m-NorAQ showed good to excellent concurrent validity for the different types of abuse and excellent reliability for all questions about abuse. In spite of methodological challenges, validation studies must be conducted as a minimum precaution to ensure that an instrument accurately measures abuse as intended. PMID- 21536227 TI - Stressful life events and social health factors in women using anxiolytics and antidepressants: an Italian observational study in community pharmacies. AB - BACKGROUND: In Italy, as in all of Europe, women differ from men in that they are somewhat more sensitive to the depressogenic effects of stressful life events related to their social networks and emotional sphere. Women are more likely than men to have experienced poverty, gender discrimination, and physical and sexual abuse. OBJECTIVE: The purpose of this study was to expand the knowledge about the occurrence of stressful life events in women exposed and not exposed to anxiolytics and antidepressants in a community pharmacy setting. METHODS: Women attending 100 community pharmacies in the Italian Veneto region were surveyed by pharmacists with regard to a number of general features of their current pharmacologic treatment. Women independently completed a written self-assessment questionnaire that focused on stressful life events. Unconditional logistic regression analysis was performed to investigate the association between anxiolytics and antidepressants use and potential factors, including stressful life events. RESULTS: The study population comprised 11,357 women. One or more stressful life events occurred in 90% of the women treated with anxiolytics and/or antidepressants (users [n = 3848]) and in 74% of the women not treated with these drugs (nonusers [n = 7509]) (odds ratio = 3.19; 95% CI, 2.83-3.60). On average, the life events occurred during the previous 6 months and the women considered the influence of these events on their well-being to be severe. After the unconditional logistic regression analysis, the association between anxiolytics and/or antidepressants use remained positive for most of the stressful life events studied as well as for other factors: separation/divorce, living alone or with others (family or friends), unemployment, whether currently being seen by a psychologist/psychiatrist, and treatment with drugs for the alimentary tract and metabolism, cardiovascular system, or nervous system. CONCLUSIONS: A significant association between stressful life events and anxiolytics and/or antidepressants use was observed. Further efforts are needed to increase our knowledge of the use of anxiolytics or antidepressants in relation to the occurrence of life events. PMID- 21536228 TI - Relations of adiponectin to levels of metabolic parameters and sexual hormones in elderly type 2 diabetic patients. AB - BACKGROUND: Despite the effective role of adiponectin levels in the predisposition to type 2 diabetes mellitus, the potential impact of adiponectin in manifest type 2 diabetes is less studied. OBJECTIVES: This study aimed to determine gender-specific differences regarding the relationship between adiponectin levels and metabolic parameters as well as sex hormones in elderly type 2 diabetics. METHODS: Sixty-two elderly type 2 diabetic men (mean age 60 [9] years) and 38 postmenopausal type 2 diabetic women (mean age 64 [9] years) were evaluated in a cross-sectional study. Glycemic control, lipids, sex hormones, adiponectin, and anthropometric parameters were measured in all participants. RESULTS: Serum adiponectin was higher in women than in men (P < 0.006). After controlling for age and body mass index, adiponectin concentrations showed a positive correlation with sex hormone-binding globulin and high-density lipoprotein levels (P < 0.001) and a negative correlation with glycated hemoglobin, homeostasis model assessment index for insulin resistance, glucose, C peptide, and triglyceride levels (P < 0.05) in all patients. In men, adiponectin significantly correlated with serum levels of testosterone (r = 0.420; P < 0.002). In women, negative correlations were observed between adiponectin levels and the fatty liver index (r = -0.492; P < 0.006) and gamma-glutamyltransferase (r = -0.432; P < 0.01). CONCLUSIONS: High serum adiponectin is a feature of better metabolic control and lipid profile, whereas low adiponectin levels are associated with fatty liver disease in women and low testosterone levels in men with type 2 diabetes. PMID- 21536230 TI - Demographic and clinical features of patients with fibromyalgia syndrome of different settings: a gender comparison. AB - BACKGROUND: Well-established gender differences in the clinical picture of fibromyalgia syndrome (FMS) have been suggested. However, studies on gender differences in demographic and clinical features of FMS have contradictory results. Their significance is limited by the small number of patients included and selection bias of single settings. OBJECTIVE: The purpose of this study was to compare demographic characteristics (age, family status) and clinical variables (duration of chronic pain and FMS diagnosis, tender point count, number of pain sites, and somatic and depressive symptoms) of male and female patients in different settings (general population, FMS self-help organization, and different clinical settings). METHODS: FMS was diagnosed according to survey criteria in the general population and in the self-help organization setting and by 1990 criteria of the American College of Rheumatology in the clinical settings. Tender point examination was performed according to the manual tender point survey protocol in clinical settings. Somatic and depressive symptoms were assessed by validated questionnaires. RESULTS: A total of 1023 patients (885 female, 138 male) were included in the analysis. Compared with male participants, female participants reported a longer duration of chronic widespread pain (P = 0.009) and time since FMS diagnosis (P = 0.05), and they had a higher tender point count (P = 0.04). There were no gender differences in age, family status, number of pain sites, or somatic and depressive symptoms. CONCLUSIONS: We found no relevant gender differences in the clinical picture of FMS. The assumption of well-established gender differences in the clinical picture of FMS could not be supported. PMID- 21536229 TI - Cardiovascular-renal and metabolic characterization of a rat model of polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease when PCOS first occurs and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS have not been elucidated. OBJECTIVE: This study characterized the cardiovascular-renal consequences of hyperandrogenemia in a female rat model. METHODS: Female Sprague Dawley rats (aged 4-6 weeks) were implanted with dihydrotestosterone or placebo pellets lasting 90 days. After 10 to 12 weeks, blood pressure (by radiotelemetry), renal function (glomerular filtration rate, morphology, protein, and albumin excretion), metabolic parameters (plasma insulin, glucose, leptin, cholesterol, and oral glucose tolerance test), inflammation (plasma tumor necrosis factor-alpha), oxidative stress (mRNA expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, p22(phox), p47(phox), gp91(phox), and NOX4), nitrate/nitrite excretion and mRNA expression of components of the renin-angiotensin system (angiotensinogen, angiotensin-I converting enzyme [ACE], and AT1 receptor) were determined. RESULTS: Plasma dihydrotestosterone increased 3-fold in hyperandrogenemic female (HAF) rats, whereas plasma estradiol levels did not differ compared with control females. HAF rats exhibited estrus cycle dysfunction. They also had increased food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression. CONCLUSIONS: The HAF rat is a unique model that exhibits many of the characteristics of PCOS in women and is a useful model to study the mechanisms responsible for PCOS-mediated hypertension. PMID- 21536231 TI - The Sry3 Y chromosome locus elevates blood pressure and renin-angiotensin system indexes. AB - BACKGROUND: Sex-determining region Y (Sry) is a transcription factor. Our research group has shown that there are multiple copies of Sry in Wistar-Kyoto (WKY) and spontaneous hypertensive (SHR) rats, and that they have novel functions separate from testes determination. OBJECTIVE: We hypothesized that exogenously delivered Sry3 to the normotensive WKY male kidney would activate the renin angiotensin system (RAS) and raise blood pressure (BP), based on previous in vitro studies. METHODS: Sry3 or control vector was electroporated to the left kidney of male WKY rats and the following measurements were taken: BP by telemetry, renin-angiotensin measures by radioimmunoassay, plasma and tissue catecholamines by HPLC with electrochemical detection, sodium by flame photometry, and inulin by ELISA. RESULTS: Sry3 increased BP 10 to 20 mm Hg compared with controls (P < 0.01) and produced a significant 40% decrease in urine sodium compared with controls (P < 0.05). Sry3 increased renal angiotensin II and plasma renin activity by >100% compared with controls (P < 0.01 and P < 0.05, respectively). CONCLUSION: The findings presented here confirm and extend the argument for Sry3 as one of the genes responsible for the SHR hypertensive Y chromosome phenotype and are consistent with increased tissue RAS activity due to Sry3 and increased sodium reabsorption. PMID- 21536232 TI - Perceived health in 50-year-old women and men and the correlation with risk factors, diseases, and symptoms. AB - BACKGROUND: Population-based study of a random sample of 50-year-old men and women in Gothenburg, Sweden. OBJECTIVE: To examine the determinants of perceived health and the differences between 50-year-old men and women. METHODS: Men and women born in 1953 were examined between 2003 and 2004. Participation rate was 60% among the men and 67% among the women. Questionnaires were used, including one on perceived health that was ranked on a 7-point scale from 1 (excellent) to 7 (very poor). The participants' medical histories were obtained through a questionnaire, and risk factors were measured. RESULTS: Women generally perceived their health as poorer than men. Women experienced more symptoms than men, and most symptoms were more prevalent among women than men. Poor perceived health was strongly related to number of symptoms. In multivariable analyses 5 factors were related to perceived health in both men and women: working full or part time (women OR [odds ratio] = 0.3, men OR = 0.3) and physical activity (women OR = 0.6, men OR = 0.6) had a positive effect, whereas a low level of social activities (women OR = 1.9, men OR = 1.7), still feeling tired after normal hours of sleep (women OR = 4.5, men OR = 4.0), and feeling burned out during the past 12 months (women OR = 2.3, men OR = 3.0) had a negative effect on perceived health. CONCLUSIONS: Women perceive their health as "worse" in comparison with men. Perceived health is a multifaceted condition related to social circumstances, physical activity, various symptoms, and tiredness after normal hours of sleep both in women and men. PMID- 21536233 TI - High dietary fat promotes visceral obesity and impaired endothelial function in female mice with systemic lupus erythematosus. AB - BACKGROUND: Inflammation contributes to metabolic and cardiovascular disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that predominantly affects young women. Cardiovascular disease is a major cause of mortality in patients with SLE. We recently reported that a model of SLE (female New Zealand Black/White F1 [NZBWF1] mice) developed characteristics of the metabolic syndrome. OBJECTIVES: In the present study, we tested the hypothesis that high dietary fat with SLE accelerated development of cardiovascular risk factors such as central obesity and vascular dysfunction. METHODS: Twenty-four-week-old female SLE mice (NZBWF1) were fed either a control diet (SLE, 10% kcal) or a high-fat (HF) diet (SLE + HF, 45% kcal) for a total of 14 weeks. RESULTS: Body weight was similar between SLE (42 [1] g, n = 5) and SLE + HF (45 [2] g, n = 6) mice, and weight gain was not different in the SLE + HF mice (+18.0 [3.0]%) compared with controls (+15.8 [3.6]%); food intake was not different (SLE, 2.2 [0.3] vs SLE + HF, 2.1 [0.2] g/24 hours). At the end of the experiment, 57% of the SLE + HF mice exhibited signs of albuminuria (>100 mg/dL) compared with only 20% of the control SLE mice. Endothelial-dependent relaxation in isolated carotid arteries was impaired in the SLE + HF group compared with that in the SLE group. Ovarian fat increased in SLE + HF mice (6.6 [0.5] g) compared with that in the control SLE mice (5.4 [0.1] g, P < 0.05), and liver weight decreased in SLE + HF (1.6 [0.1] g) mice compared with that in control mice (1.9 [0.1] g, P < 0.03). CONCLUSIONS: These data suggest that dietary fat accelerates renal injury and peripheral vascular dysfunction and promotes visceral obesity in a disease model with chronic inflammation. PMID- 21536234 TI - Philadelphia Chromosome Symposium: commemoration of the 50th anniversary of the discovery of the Ph chromosome. AB - This report summarizes highlights of the Philadelphia Chromosome Symposium: Past, Present and Future, held September 28, 2010, to commemorate the 50th anniversary of the discovery of the Philadelphia chromosome. The symposium sessions included presentations by investigators who made seminal contributions concerning the discovery and molecular characterization of the Ph chromosome and others who developed a highly successful therapy based on the specific molecular alteration observed in chronic myeloid leukemia. Additional presentations highlighted future opportunities for the design of molecularly targeted therapies for various types of cancer. Also included here are reminiscences connected with the discovery of the Ph chromosome by David Hungerford and Peter Nowell, the discovery that the abnormality arises from a chromosomal translocation, by Janet Rowley, and the cloning of the 9;22 translocation breakpoints by Nora Heisterkamp, John Groffen, and colleagues. PMID- 21536235 TI - Cytogenetic findings in 14 benign cartilaginous neoplasms. AB - Benign cartilaginous tumors represent a spectrum of neoplastic processes with variable clinical and pathologic presentations. These tumors are histologically characterized by the presence of chondrocytes surrounded by a cartilaginous matrix. Few studies describe karyotypic abnormalities in these benign lesions. We report a series of 14 chondromas from a single institution. Conventional cytogenetics was performed on short term cultures from all cases. Clonal chromosome aberrations were found in nine tumors. One soft tissue chondroma contained three clones with t(6;12)(q12;p11.2), t(3;7)(q13;p12), and der(2)t(2;18)(p11.2;q11.2). Three periosteal chondromas displayed random structural aberrations of chromosomes 2, 3, 6, 7, and 11 and loss of chromosome 13. Among the enchondromas, three tumors displayed chromosome losses, one contained a complex translocation involving chromosomes 12, 15, and 21 as well as an inv(2)(p21q31),t(12;15;21)(q13;q14;q22) and a separate enchondroma showed a translocation involving chromosomes 12 and 22. Our data suggest that considerable cytogenetic heterogeneity exists among benign chondromatous tumors. PMID- 21536236 TI - A cryptic deletion in 5q31.2 provides further evidence for a minimally deleted region in myelodysplastic syndromes. AB - Recurrent deletions of 5q in myeloid malignancies encompass two separate regions: deletion of 5q33, which is associated with the 5q- syndrome and haploinsufficiency of RPS14, and deletion of a more proximal locus at 5q31. We present a case with a cryptic 1.3 Mb deletion in 5q31.2 identified by array comparative genomic hybridization that places the proximal boundary of the deletion proximal and close to the candidate EGR1 gene. The patient was diagnosed initially with a myelodysplastic syndrome, with a del(20)(q11.2q13.3) as the sole abnormality identified by karyotyping. The patient progressed to acute myeloid leukemia with no change to the G-banded karyotype. The 1.3 Mb deletion on the long arm of one chromosome 5 was confirmed to have been present both at presentation with myelodysplastic syndrome and at transformation. This is an interesting case because there are few array studies identifying cryptic 5q deletions, and the study of these small deletions helps to refine the common deleted region. This case, together with previously published studies, suggests that the proximal boundary of the common deleted region may lie within the KDM3B gene. PMID- 21536237 TI - Unknown partner for USP6 and unusual SS18 rearrangement detected by fluorescence in situ hybridization in a solid aneurysmal bone cyst. AB - USP6 rearrangement is the most common genetic abnormality in primary aneurysmal bone cyst, and SS18 rearrangement has not been previously described in any type of tumor where synovial sarcoma was excluded from the differential diagnosis. We report a case of solid aneurysmal bone cyst in which fluorescence in situ hybridization (FISH) analysis indicated rearrangements of both USP6 and SS18, but histologic features were consistent with aneurysmal bone cyst throughout the lesion. Reverse-transcription polymerase chain reaction (RT-PCR) for the SS18 SSX1 and SS18-SSX2 translocations, identity testing, and SS18 FISH were performed on cytogenetic monolayer cultures and formalin-fixed paraffin-embedded (FFPE) tissue. Genomic microarray, FISH, and immunohistochemistry were performed on follow-up studies of the FFPE specimen. The karyotype was 45,X,add(X)(p11.2),add(4)(q13),add(8)(p21),-13,add(17)(p11.2),add(18)(q11.2) in all 20 cells analyzed from monolayer cultures. The karyotype showed no cytogenetically visible alterations of chromosomal regions harboring known partners for USP6. Metaphase FISH with a commercial SS18 break-apart probe showed translocation of the 5' portion of the SS18 probe to the short arm of the derivative X, as is observed in synovial sarcoma. RT-PCR showed no evidence of a SS18-SSX fusion, and immunohistochemistry was negative for TLE1, EMA, and cytokeratin AE1/3 expression. FISH on FFPE sections with a custom break-apart probe flanking USP6 showed evidence for a USP6 rearrangement throughout the tumor (25-50%). FISH on FFPE sections with a commercial SS18 break-apart FISH probe showed more variable results (0-50% split signals). There was no evidence of a SS18-USP6 fusion by FISH or RT-PCR. A molecular inversion probe array revealed a deletion encompassing the entire SS18 gene and its promoter, as well as portions of the region targeted by the commercial SS18 FISH probe. In conclusion, results obtained from commercially available FISH probes may occasionally yield misleading results. In this case, the SS18 rearrangement by FISH resulted from a complex rearrangement of 18q11.2 with a deletion of the SS18 gene. The translocation partner for USP6 remains unknown in this case. PMID- 21536238 TI - Chromosome banding analysis of cells from fine-needle aspiration biopsy samples from soft tissue and bone tumors: is it clinically meaningful? AB - Morphologic evaluation of samples from fine-needle aspiration (FNA) and core needle (CN) biopsies is an important part of the pretreatment diagnosis of bone and soft tissue tumors. Because most such tumors have characteristic, sometimes even specific, chromosomal rearrangements, ancillary genetic analyses could provide important diagnostic information. Whereas directed analyses, such as fluorescence in situ hybridization or reverse transcriptase-polymerase chain reaction, for specific genetic aberrations are well suited for the relatively small cell numbers obtained with FNA biopsies, the possibility to obtain tumor karyotypes after cell culturing has been less well studied. In the present study, karyotypes from 114 FNA biopsy samples were compared to those in corresponding surgical tumor samples; in addition, results on 31 CN samples and their corresponding tumor samples were available. Of the 138 surgical tumor samples, 88 (64%) showed clonal acquired chromosome aberrations, 42 (30%) displayed a normal karyotype, and 8 (6%) did not yield any karyotype as a result of infection or poor cell growth. The corresponding figures for the 114 FNA samples were 27 (24%), 28 (25%), and 59 (52%), and for the 31 CN samples 15 (48%), 10 (32%), and 6 (19%). The relatively low success rate, with the possible exception of primitive round cell/Ewing sarcomas (abnormal karyotype in 6 of 11 FNA samples), strongly indicates that it is not meaningful to attempt cell culturing and chromosome banding analysis on FNA biopsy sample cells in patients with suspected bone or soft tissue tumors. The use of ancillary techniques such as fluorescence in situ hybridization might improve the diagnostic value from FNA. Our preliminary data suggest that if a pretreatment karyotype is wanted, the cytogenetic analysis should be made on cells from CN samples, close to half of which showed an aberrant karyotype. PMID- 21536239 TI - Jumping translocation of chromosome 1q associated with good clinical outcome in a case of Burkitt leukemia. AB - Acquired jumping translocations (JTs) are rare secondary aberrations occurring in various hematological malignancies. In Burkitt lymphoma/leukemia (BL) chromosome 1q abnormalities such as partial or whole arm duplications/translocations are frequently associated with the disease-specific t(8;14)(q24;q32). JTs of 1q are considered to have a bad prognostic impact in BL. We report clinical, conventional and molecular cytogenetic findings of a 12-year-old boy who presented with BL. In addition to the primary aberration, t(8;14)(q24;q32), JT of 1q onto chromosomes 21 and der(14) as well as the formation of isochromosome 1q could be detected in his bone marrow sample. Despite the expected poor prognostic outcome of these aberrations, the patient has been experiencing an event free survival of 7.5 years at the time of the present report, reflecting the excellent clinical outcome of the disease. PMID- 21536240 TI - Translocation t(7;19)(q22;q13)-a recurrent chromosome aberration in pseudomyogenic hemangioendothelioma? AB - Pseudomyogenic hemangioendothelioma is a recently described morphologic entity among soft tissue tumors. It is more common in young individuals, shows a male predominance, is often multifocal and involves different tissue planes, and shows a high propensity for local recurrence. To our knowledge, no genetic characteristics of this tumor type have been presented before. Here, we describe the finding of a balanced t(7;19)(q22;q13) as the sole anomaly in three lesions from a 14-year-old girl. By means of fluorescence in situ hybridization, the breakpoints could be delineated, but reverse transcriptase-polymerase chain reaction for putative fusion genes did not reveal any fusion transcript. Interphase fluorescence in situ hybridization on sections from nine other pseudomyogenic hemangioendotheliomas indicated the presence of an unbalanced der(7)t(7;19) in one of them. Thus, the translocation between chromosomes 7 and 19 seems to be a recurrent phenomenon and is likely to be of pathogenetic significance in at least a subset of pseudomyogenic hemangioendotheliomas. PMID- 21536241 TI - Evaluating chromosomal mosaicism by array comparative genomic hybridization in hematological malignancies: the proposal of a formula. AB - Array-based comparative genomic hybridization (aCGH) has proven indispensable to the study of unbalanced constitutional and acquired chromosomal anomalies, but its sensitivity for detecting mosaicism is still not well established. On the basis of the ADM2 algorithm used for microarray image analysis with one of the most widely used oligomer-based aCGH platforms [the whole genome 244K system by Agilent Technologies (Santa Clara, CA)] we suggest a formula to infer the percentage of cells bearing a chromosome imbalance in cases with constitutional or acquired mosaicism. Three examples of acquired mosaicism in which this formula was applied are reported together with parallel fluorescence in situ hybridization (FISH) to interphase nuclei with informative probes. Although some approximation affects both the results inferred from aCGH and FISH data, the proposed formula was successful in the three patients studied. PMID- 21536242 TI - Establishment and characterization of a novel acute myeloid leukemia cell line, JIH-4, carrying a t(16;21)(p11.2;q22) and expressing the FUS-ERG fusion. AB - Human leukemia cell lines are powerful tools in the study of leukemogenesis, particularly for rare but recurrent subtypes such as acute myeloid leukemia (AML) with the t(16;21)(p11.2;q22) and FUS-ERG fusion. Four AML cell lines carrying a t(16;21)(p11.2;q22) have been described previously. We report a novel AML cell line, designated JIH-4, for which karyotypic analysis demonstrated a single abnormality, t(16;21)(p11.2;q22). The FUS-ERG fusion transcript was identified by reverse transcriptase polymerase chain reaction (RT-PCR). Neither Epstein-Barr virus nor mycoplasma was detected in JIH-4 cells. The morphology and immunoprofile of JIH-4 cells display typical features of myelogenous lineage, and short tandem-repeat PCR comparison with the donor patient's bone marrow cells confirm the cell line's authenticity. Tumor masses were found in 50% of inoculated mice 83 days after subcutaneous injection with JIH-4 cells. Our results confirm that JIH-4 cells are derived from the donor patient's leukemia cells and support using the JIH-4 cell line as a valuable tool in the study of leukemogenesis. PMID- 21536243 TI - Prostate cancer in Cowden syndrome: somatic loss and germline mutation of the PTEN gene. PMID- 21536244 TI - [Connective tissue diseases and psoriasis]. AB - Psoriasis is an autoimmune chronic inflammatory skin disease that is common in Spain. Connective tissue diseases are a heterogeneous group of conditions characterized by the abnormal function or structure of one or more of the elements that make up connective tissue. These diseases are also autoimmune in origin. In spite of the high prevalence of psoriasis in the general population, its association with a connective tissue disease such as systemic lupus erythematosus, dermatomyositis, scleroderma, or rheumatoid arthritis has only occasionally been reported. It is nevertheless important to have an understanding of such associations, given their significant clinical and therapeutic implications. The association between psoriasis and systemic lupus erythematosus is the one most often described, although the few reports available in the literature have mostly involved single cases. This review will also look at the characteristics of patients with psoriasis and dermatomyositis, mainly focusing on clinical features. The associations between psoriasis and either rheumatoid arthritis or systemic sclerosis will be examined more briefly. The review therefore aims to reflect the literature on psoriasis in association with rheumatic diseases, including coverage of etiologic, pathogenic, clinical, and therapeutic aspects. We emphasize that such cases should be managed by a multidisciplinary team in which care will usually be shared by a rheumatologist and a dermatologist. PMID- 21536245 TI - [Imiquimod in the treatment of lentigo maligna]. PMID- 21536246 TI - [Rasopathies: developmental disorders that predispose to cancer and skin manifestations]. AB - Proteins belonging to the RAS/mitogen activated protein kinase (MAPK) pathway play key roles in cell proliferation, differentiation, survival, and death. For more than 30 years now we have known that 30% of human cancers carry somatic mutations in genes encoding proteins from this pathway. Whereas somatic mutations have a high malignant potential, germline mutations are linked to developmental abnormalities that are often poorly clinically differentiated, although each is dependent upon the specific gene affected. Thus, all patients share varying degrees of mental retardation or learning difficulties, heart disease, facial dysmorphism, skin anomalies, and, in some cases, predisposition to cancer. These syndromes, known as rasopathies, include Noonan syndrome, Costello syndrome, neurofibromatosis-1, LEOPARD syndrome, cardiofaciocutaneous syndrome, and Legius syndrome. Recognizing the skin manifestations of rasopathies can facilitate diagnosis of these syndromes. PMID- 21536247 TI - Impact of preoperative renal dysfunction on long-term survival for patients undergoing aortic valve replacement. AB - BACKGROUND: The impact of the degrees of renal dysfunction (RD) after aortic valve replacement (AVR) has not been well described. The purpose of this study was to compare patients undergoing AVR with a range of renal function from normal to dialysis-dependence. METHODS: A retrospective review of 2,408 patients undergoing AVR with or without coronary artery bypass graft surgery (CABG) from January 1996 to March 2009 was performed. Glomerular filtration rate (GFR) was estimated for patients using the Modification of Diet in Renal Disease formula. Multivariable logistic and Cox regression methods were used to determine the independent association of GFR with outcomes. Adjusted odds ratios were calculated for in-hospital outcomes, and Kaplan-Meier curves were created to estimate long-term survival. RESULTS: In all, 1,512 patients (62.8%) had isolated AVR, and 896 (37.2%) underwent AVR plus CABG. Preoperative RD was common among all patients: 1,148 of 2,408 (47.7%) with mild RD (GFR 60 to 90 mL.min(-1).1.73 m(-2)), 644 of 2,408 (26.7%) moderate RD (GFR 30 to 59 mL.min(-1).1.73 m(-2)), 59 of 2,408 (2.5%) severe RD (GFR 15 to 30 mL.min(-1).1.73 m(-2)), and 114 (4.7%) with kidney failure (GFR<15) or requiring dialysis. In-hospital mortality generally rose with RD, from 2.9% for patients with no RD to 15.8% for patients with severe RD, and 17.3% for patients requiring dialysis. Patients with severe RD or preoperative dialysis were associated with significantly poorer outcomes. Adjusted long-term survival is progressively worse across levels of RD, as was postoperative length of stay (p<0.001). CONCLUSIONS: Preoperative RD is common among the AVR population and is associated with diminished long-term survival. The association between RD and worse outcomes after AVR surgery has significant clinical implications. PMID- 21536248 TI - Prevention of chylothorax complicating extensive esophageal resection by mass ligation of thoracic duct: a random control study. AB - BACKGROUND: Chylothorax after esophagectomy remains a devastating postoperative complication. Prophylactic mass ligation of the thoracic duct during the extensive resection of esophageal cancer is used to prevent the chylothorax, but there are few published data about its effect. This randomized controlled study was designed to evaluate the preventive effect of thoracic duct mass ligation on postoperative chylothorax. METHODS: Six hundred fifty-three patients undergoing transthoracic esophagectomy for cancer were randomly assigned to two groups: 328 patients received esophagectomy (preservation group) and 325 patients received thoracic duct mass ligation during esophagectomy (prevention group). The patients in whom chylothorax developed were identified and occurrence rates of chylothorax were compared between the two groups. The management and outcome of postoperative chylothorax was also recorded. RESULTS: Patients' demographic details were similar between the two groups. No major or minor intraoperative or postoperative complications related to prophylactic thoracic duct mass ligation were recorded. Chylothorax occurred in 8 patients, giving an incidence of 1.2%. In the preservation group, chylothorax occurred in 7 patients (2.1%), and in the prevention group, 1 case of chylothorax was found (0.3%). The incidence of postoperative chylothorax was significantly lower in the prevention group. Among the 8 cases of postoperative chylothorax, 6 patients made an uneventful recovery, but the other 2 patients died of complications (mortality rate, 25%). CONCLUSIONS: The technique of intraoperative thoracic duct mass ligation proved safe and effective. It minimized the risk of postoperative chylothorax in patients who underwent transthoracic esophagectomy for cancer. PMID- 21536249 TI - Standards for relations of cardiothoracic surgical organizations with industry. PMID- 21536250 TI - Allogeneic heart valve storage above the glass transition at -80 degrees C. AB - BACKGROUND: Cryopreserved allogeneic heart valves are usually stored and transported below -135 degrees C; however, such methods require expensive equipment for both storage and transportation. METHODS: In this study, vitrified porcine aortic valves were stored on either side of the cryoprotectant formulation's glass transition temperature (-119 degrees C) at -80 degrees C and 135 degrees C, using a newly formulated vitrification solution (VS83) consisting of a combination of 4.65M dimethyl sulfoxide, 4.65M formamide, and 3.30M 1,2 propanediol. Three groups of valves were studied: (1) fresh; (2) VS83-preserved, stored at -80 degrees C; and (3) VS83-preserved, stored at -135 degrees C. RESULTS: Using the VS83 cryoprotectant concentration formulation, cracking was not observed during valve storage. No ice-related events were detectable during 5 degrees C rewarming by differential scanning calorimetry. All cryopreserved tissue samples demonstrated significantly less viability than fresh samples (p<0.01). No significant viability differences were observed between the VS83 preserved groups stored at -80 degrees C and -135 degrees C. Material testing did not reveal any significant differences among the three test groups. Multiphoton imaging of VS83-preserved heart valves stored at -80 degrees C and -135 degrees C demonstrated similar collagen and elastin structures. CONCLUSIONS: These results indicate that VS83-preserved heart valves can be stored and transported at temperatures in the vicinity of -80 degrees C with retention of extracellular matrix integrity and material properties. The VS83 preservation of heart valves at -80 degrees C without the need for liquid nitrogen should result in both decreased manufacturing costs and reduced employee safety hazards. Moreover, it is anticipated that low cell viability may result in less immunogenicity in vivo. PMID- 21536251 TI - Echocardiographic predictors of left ventricular function and clinical outcomes after successful mitral valve repair: conventional two-dimensional versus speckle tracking parameters. AB - BACKGROUND: We aimed to compare conventional echocardiographic versus speckle tracking-derived parameters in predicting postoperative left ventricular (LV) dysfunction and clinical outcomes after successful mitral valve repair in patients with mitral regurgitation. METHODS: In 147 consecutive patients in sinus rhythm with severe MR, two-dimensional echocardiography and speckle-tracking imaging for global longitudinal, circumferential, and radial strains and strain rates were performed within 30 days before successful mitral valve repair. Echocardiography was repeated within 7 days in all patients, and more than 3 months after surgery in 112 patients. Clinical events were evaluated for 21+/-17 months. RESULTS: Multivariate linear regression analysis showed that preoperative LV systolic dimension (p=0.004) and volume (p=0.001) were independent determinants of immediate postoperative LV ejection fraction. Preoperative LV end systolic dimension (p=0.004), LV ejection fraction (p=0.017), and circumferential strain (p=0.029) were independent predictors of late follow-up LV ejection fraction. By Cox regression analysis, preoperative end-systolic LV dimension (hazard ratio 1.26 for every 1 mm, 95% confidence interval 1.11 to 1.44, p<0.001) was the only predictor of hospital admission for heart failure. The best cutoff values of LV end-systolic dimension (>=41 mm) and volume (>=85 mL) for predicting postoperative severe LV dysfunction (ejection fraction<0.35) identified patients at high risk for event-free survival, but those of speckle-tracking parameters did not. CONCLUSIONS: Preoperative LV remodeling parameters, such as LV end systolic dimension and volume, are superior to speckle tracking-derived deformation parameters in predicting LV dysfunction and clinical events after successful mitral valve repair in patients with severe mitral regurgitation. PMID- 21536252 TI - Predictors of acute rejection after lung transplantation. AB - BACKGROUND: Acute rejection (AR) after lung transplantation (LTx) impacts survival and quality of life. The objective of this study, therefore, was to identify risk factors for AR after LTx, focusing on donor- and recipient-specific factors, operative variables, and immunologic issues, including pretransplant panel-reactive antibody (PRA) levels, and donor-recipient human leukocyte antigen (HLA) mismatch. METHODS: From March 1996 to November 2007, 481 adults undergoing LTx had 3237 serial transbronchial biopsy specimens that were evaluated for perivascular rejection (grade A0 to A4). Longitudinal analysis was used to characterize the prevalence of rejection grade and influence of donor, recipient, technical, and immunologic variables. RESULTS: AR was highest (54%>=A1) in the first 2 months after LTx, decreased at 6 months (16%>=A1), then remained steady. Prevalence of AR at any time was dominated by donor-specific factors of young age (p<0.0001), blunt trauma (p=0.008), and nonblack race (p=0.012) and by recipient class II PRA exceeding 10% (p=0.005). AR within 2 months was associated with HLA mismatch at the DR locus (p=0.0006) and use of non-O blood-group donors (p=0.008). AR at 4 years and longer after LTx was associated with HLA mismatch at the B locus (p=0.01). CONCLUSIONS: Only a few recipient and operative factors were identified for AR after LTx. Moderately sensitized recipients identified by class II PRA exceeding 10% and those with HLA mismatches at the B and DR loci appear to be more susceptible to AR; however, such immunologic variations appear to be well controlled with current donor selection and immunosuppression protocols. The impact of donor-specific variables on AR is surprisingly strong and warrants closer inspection. PMID- 21536253 TI - Oncologic outcomes after surgical resection of subcentimeter non-small cell lung cancer. AB - BACKGROUND: The recent initiation of screening protocols and greater utilization of computed tomography has led to an increasing proportion of non-small cell lung cancer (NSCLC) patients presenting with subcentimeter stage IA tumors. The aim of this study was to compare the oncologic outcomes of lobectomy, segmentectomy, and wedge resection in patients with NSCLC tumors 1 cm or less in diameter. METHODS: Data were extracted from medical records of patients undergoing surgical resection for stage IA NSCLC and a pathologically confirmed tumor diameter measuring 1 cm or less. Primary oncologic outcomes were disease recurrence and disease-free survival. Statistical comparisons were performed using Fisher's exact test and unpaired t test. Kaplan-Meier curves were compared using the log rank test. Significance was defined as a two-tailed p value less than 0.05. RESULTS: A total of 107 patients underwent complete (R0) surgical resection for stage IA NSCLC 1 cm or less in diameter (lobectomy, 32; segmentectomy, 40; wedge, 35). Age, sex distribution, tumor size, and histology were similar between groups. There was 1 perioperative mortality in the lobectomy group (3%). At a mean follow-up of 42.5 months, overall disease recurrence was equivalent, occurring in 3 lobectomy patients (9%), 4 segmentectomy patients (10%), and 3 wedge resection patients (9%; p=0.99). Estimated 5-year disease-free survival was comparable among cohorts (lobectomy, 87%; segmentectomy, 89%; wedge, 89%; p>0.402). CONCLUSIONS: Sublobar resections are associated with oncologic outcomes that are comparable to those of lobectomy for subcentimeter stage IA NSCLC, suggesting that they may be appropriate surgical interventions in this patient cohort. The validity of these observations needs to be assessed in a prospective setting. PMID- 21536254 TI - Genomics and the new perspectives for temporomandibular disorders. AB - The field of temporomandibular disorders (TMD) is experiencing significant changes in terms of aetiology and treatment. Researchers and clinicians are becoming increasingly aware of the possibility that genetic variations may play a role in pain perception and onset of TMD. In this review, we purpose to briefly describe these allelic variants, how they may be involved in TMD pathophysiology and how they may affect TMD treatment. Studies have already pointed the association between TMD and genetic polymorphisms in the oestrogen receptor alpha, adrenergic receptor beta 2, serotonin receptor, serotonin transporter and catechol-O-methyltransferase genes, and other candidate genes continue to emerge. The main implication of these findings refers to the promising possibilities of "genome/omics-based personalised care", which consists of tailoring individual treatment based on personalised medication, depending on the individual genetic differences and early diagnosis and prognosis of the disorder, preventing acute pain conditions from becoming chronic. The following years of research shall focus on collecting and endorsing these findings if we are to provide patients in pain with efficient and successful TMD treatments. PMID- 21536255 TI - Raloxifene therapy inhibits osteoclastogenesis during the alveolar healing process in rats. AB - OBJECTIVE: To investigate the expression of OPG, RANKL and TRAP during alveolar healing process (7, 14, 21, 28 and 42 postoperative days) in ovariectomized rats treated with raloxifene or with oestrogen replacement therapy, using immunohistochemistry reaction approach. MATERIALS AND METHODS: Wistar female rats (10 weeks age) were submitted to ovariectomy surgery (OVX) or sham surgery. The female rats were divided in four groups: (1) sham; (2) OVX/O (ovariectomy and oil); (3) OVX/E2 (ovariectomy and oestrogen replacement); (4) OVX/RLX (ovariectomy and raloxifene therapy). RESULTS: It was observed high amount of OPG immunolabelling with predominance at 14 and 21 postoperative days on sham and OVX/RLX groups, respectively. At 7 postoperative days, there was no difference between the groups for TRAP protein. Otherwise, to the other periods, it was observed greater expression of TRAP and RANKL protein on OVX/O group compared to sham, OVX/E2 and OVX/RLX groups. It was also observed a discrete TRAP immunolabelling at 28 and 42 postoperative days on OVX/RLX group. CONCLUSIONS: Oestrogen deficiency induces osteoclastogenesis in the alveolar healing process. Quantitative changes in the osteoclastic activity could be prevented through the raloxifene therapy. PMID- 21536256 TI - Possible contribution of pannexin channel to ATP-induced currents in vitro in vasopressin neurons isolated from the rat supraoptic nucleus. AB - Release of arginine vasopressin (AVP) from magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) is controlled by the electrical activity of these neurons. ATP plays a crucial role in the regulation of SON MNCs by activating the purinergic P2X and P2Y receptors. Recent reports of interaction between P2X receptors and pannexin channels have provided new insights into the physiology of the central nervous system; however, the function of pannexin channels has not been assessed in AVP neurons. In the present study, we examined the possible contribution of the pannexin channel in ATP-induced responses in SON AVP neurons. We used the whole-cell patch-clamp technique in isolated rat SON MNCs that express an AVP-enhanced green fluorescent protein transgene. The ATP induced current was inhibited in a concentration-dependent manner by pannexin channel blockers carbenoxolone and mefloquine, whereas the connexin channel blockers flufenamic acid and lanthanum had no effect. Multi-cell reverse transcriptase-polymerase chain reaction experiments confirmed the existence of pannexin-1 mRNA in AVP neurons. The involvement of the ATP-activated transient receptor potential vanilloid and acid-sensing ion channels was excluded. These results suggest that pannexin channels in SON AVP neurons are involved in the regulatory mechanisms of neuronal activity. PMID- 21536257 TI - Enzymatic synthesis and surface active properties of novel hemifluorinated mannose esters. AB - The lipase-catalysed esterification of sugars with hemifluorinated acid derivatives is reported for the first time. A series of mannose modified derivatives having fluorinated chains with different length have been prepared accordingly in moderate yield. A preliminary evaluation of the surface active properties of these hemifluorinated mannose esters revealed their ability to reduce the surface tension of water much more efficiently than their aliphatic counterparts. PMID- 21536258 TI - A practical synthesis of capped 4-methylumbelliferyl hyaluronan disaccharides and tetrasaccharides as potential hyaluronidase substrates. AB - The synthesis of hyaluronan dimers and tetramers equipped with a 4 methylumbelliferyl group at the reducing end to potentially allow monitoring of hyaluronidase activities is described. The 4-OH at the non-reducing glucuronate in the presented series is either removed or methylated to prohibit transglycosylase reactions, leading to a total of four probes. PMID- 21536259 TI - Structural characterization of complex O-linked glycans from insect-derived material. AB - Although insects are among the most diverse groups of the animal kingdom and may be found in nearly all environments, one can observe an obvious lack of structural data on their glycosylation ability. Hymenoptera is the second largest of all insect orders with more than 110,000 identified species and includes the most famous examples of social insects' species such as wasps, bees and ants. In this report, the structural variety of O-glycans has been studied in two Hymenoptera species. In a previous study, we showed that major O-glycans from common wasp (Vespula germanica) salivary mucins correspond to T and Tn antigen, eventually substituted by phosphoethanolamine or phosphate groups. More detailed structural analysis performed by mass spectrometry revealed numerous minor O glycan structures bearing Gal, GlcNAc, GalNAc and Fuc residues. Thus, in order to investigate glycosylation diversity in insects, we used common wasp nest (V. germanica) and hornet nest (Vespa cabro) as starting materials. These materials were submitted to reductive beta-elimination and the released oligosaccharide alditols further fractionated by multidimensional HPLC. Tandem mass spectrometry analyses combined with NMR data revealed the presence of various families of complex O-glycans differing accordingly to both core structures and external motifs. Glycans from wasp were characterized by the presence of core types 1 and 2, Lewis X and internal Gal-Gal motifs. We also observed unusual O-glycans containing a reducing GalNAc unit directly substituted by a fucose residue. In contrast, hornet O-glycans appeared as a rather homogeneous family of core 1 type O-glycans extended by galactose oligomers. PMID- 21536260 TI - Comparative study of the cell wall composition of broccoli, carrot, and tomato: structural characterization of the extractable pectins and hemicelluloses. AB - This study delivers a comparison of the pectic and hemicellulosic cell wall polysaccharides between the commonly used vegetables broccoli (stem and florets separately), carrot, and tomato. Alcohol-insoluble residues were prepared from the plant sources and sequentially extracted with water, cyclohexane-trans-1,2 diamine tetra-acetic acid, sodium carbonate, and potassium hydroxide solutions, to obtain individual fractions, each containing polysaccharides bound to the cell wall in a specific manner. Structural characterization of the polysaccharide fractions was conducted using colorimetric and chromatographic approaches. Sugar ratios were defined to ameliorate data interpretation. These ratios allowed gaining information concerning polysaccharide structure from sugar composition data. Structural analysis of broccoli revealed organ-specific characteristics: the pectin degree of methoxylation (DM) of stem and florets differed, the sugar composition data inferred differences in polymeric composition. On the other hand, the molar mass (MM) distribution profiles of the polysaccharide fractions were virtually identical for both organs. Carrot root displayed a different MM distribution for the polysaccharides solubilized by potassium hydroxide compared to broccoli and tomato, possibly due to the high contribution of branched pectins to this otherwise hemicellulose-enriched fraction. Tomato fruit showed the pectins with the broadest range in DM, the highest MM, the greatest overall linearity and the lowest extent of branching of rhamnogalacturonan I, pointing to particularly long, linear pectins in tomato compared with the other vegetable organs studied, suggesting possible implications toward functional behavior. PMID- 21536261 TI - Elucidation of the structure and characterization of the gene cluster of the O antigen of Cronobacter sakazakii G2592, the reference strain of C. sakazakii O7 serotype. AB - The O-specific polysaccharide from the lipopolysaccharide of Cronobacter sakazakii G2592 was studied by sugar analysis along with 1D and 2D (1)H and (13)C NMR spectroscopy, and the following structure of the pentasaccharide repeating unit was established: [See figure in text]. This structure is unique among the known bacterial polysaccharide structures, which is in accord with classification of strain G2592 into a new C. sakazakii serotype, O7. It is in agreement with the O-antigen gene cluster of this strain, which was found between the housekeeping genes JUMPStart and gnd and characterized by sequencing and tentative assignment of the gene functions. PMID- 21536262 TI - Monte Carlo-based searching as a tool to study carbohydrate structure. AB - A torsion angle-based Monte Carlo searching routine was developed and applied to several carbohydrate modeling problems. The routine was developed as a Unix shell script that calls several programs, which allows it to be interfaced with multiple potential functions and various utilities for evaluating conformers. In its current form, the program operates with several versions of the MM3 and MM4 molecular mechanics programs and has a module to calculate hydrogen-hydrogen coupling constants. The routine was used to study the low-energy exo-cyclic substituents of beta-D-glucopyranose and the conformers of D-glucaramide, both of which had been previously studied with MM3 by full conformational searches. For these molecules, the program found all previously reported low-energy structures. The routine was also used to find favorable conformers of 2,3,4,5-tetra-O-acetyl N,N'-dimethyl-D-glucaramide and D-glucitol, the latter of which is believed to have many low-energy forms. Finally, the technique was used to study the inter ring conformations of beta-gentiobiose, a beta-(1->6)-linked disaccharide of D glucopyranose. The program easily found conformers in the 10 previously identified low-energy regions for this disaccharide. In 6 of the 10 local regions, the same previously identified low-energy structures were found. In the remaining four regions, the search identified structures with slightly lower energies than those previously reported. The approach should be useful for extending modeling studies on acyclic monosaccharides and possibly oligosaccharides. PMID- 21536263 TI - Using phase space reconstruction for patient independent heartbeat classification in comparison with some benchmark methods. AB - Many methods for automatic heartbeat classification have been applied and reported in literature, but relatively few of them concerned with patient independent classification because of the less significant results compared to patient dependent ones. In this work, using phase space reconstruction in order to classify five heartbeat types can fill this gap to some extent. In the first and second method, Reconstructed phase space (RPS) is modeled by the Gaussian mixture model (GMM) and bins, respectively, and then classified by classic Bayesian classifier. In the third method, RPS is directly used to train predictor time-delayed neural networks (TDNN) and classified based on minimum prediction error. All three methods highly outperform the results reported before, for patient independent heartbeat classification. The best result is achieved using GMM-Bayes method with 92.5% classification accuracy. PMID- 21536264 TI - Specialization among the specialized: auditory brainstem function is tuned in to timbre. PMID- 21536265 TI - Occupational exposure to diesel and gasoline emissions and lung cancer in Canadian men. AB - The International Agency for Research on Cancer classifies diesel exhaust as a probable human carcinogen; this decision is based largely from lung cancer evidence. Gasoline exhaust is classified as a possible carcinogen. Epidemiological studies are needed that improve upon some of the limitations of previous research with respect to the characterization of exposure, and the control for the potential confounding influence of smoking and other occupational exposures. Our objective was to investigate associations between occupational exposure to diesel and gasoline engine emissions and lung cancer. We used a case control study design that involved men 40 years of age and older at the time of interview. Analyses are based on 1681 incident cases of lung cancer and 2,053 population controls. A self-reported questionnaire elicited a lifetime occupational history, including general tasks, and information on other potential risk factors. Occupational exposures to diesel and gasoline emissions, crystalline silica, and asbestos were assigned to each job held by study subjects by industrial hygienists who were blind to case-control status. Exposure metrics for diesel and gasoline emissions that were modeled included: ever exposure, cumulative exposure, and concentration of exposure. We found a dose-response relationship between cumulative occupational exposure to diesel engine emissions and lung cancer. This association was more pronounced for the squamous and large cell subtypes with adjusted odds ratios across the three increasing tertiles of cumulative lifetime exposure relative to those with no exposure of 0.99, 1.25, and 1.32 (p=0.04) for squamous cell carcinoma, and 1.06, 1.19, 1.68 (p=0.02) for large cell carcinoma. While the association with cumulative exposure to gasoline was weakly positive, it was not statistically significant. Our findings suggest that exposure to diesel engine emissions increases the risk of lung cancer particularly for squamous and large cell carcinoma subtypes. PMID- 21536266 TI - [A 17-year-old male with left ventricular hypertrophy: He who does not know what he is searching for will not understand what he finds]. PMID- 21536267 TI - [Acute cardiomyopathy as a clinical manifestation of systemic sclerosis]. PMID- 21536268 TI - [Thyroid dysfunction in a hospital worker population: a bias?]. PMID- 21536269 TI - [Considerations on the living will document]. PMID- 21536271 TI - [Echocardiogram in heart failure: from theory to practice]. PMID- 21536272 TI - Progesterone level and progesterone/estradiol ratio on the day of human chorionic gonadotropin administration: detrimental cutoff levels and new treatment strategy? PMID- 21536273 TI - Bisphenol-A exposure alters endometrial progesterone receptor expression in the nonhuman primate. AB - OBJECTIVE: To evaluate the effect of bisphenol-A (BPA), a xenoestrogen endocrine disruptor, on endometrial P receptor (PR) expression in nonhuman primates and human cells. DESIGN: Controlled trial in primates. SETTING: University. ANIMAL(S): African green monkeys. INTERVENTION(S): After oophorectomy, BPA (50 MUg/kg/d), E(2), both, or vehicle control were administered. Estradiol and BPA were used in Ishikawa cells. MAIN OUTCOME MEASURE(S): Progesterone receptor expression using immunohistochemistry and quantitative polymerase chain reaction. RESULT(S): Progesterone receptor expression was increased in E(2)-treated primates compared with controls. Exposure to the combination of E(2) and BPA resulted in decreased PR expression compared with E(2) exposure alone. In Ishikawa cells treated with E(2), PR expression increased 5.1-fold; however, when Ishikawa cells were simultaneously treated with E(2) and BPA, PR expression was decreased to 0.6-fold that of cells treated with E(2) alone. CONCLUSION(S): Bisphenol-A alone functions as a weak estrogen. However, when administered with E(2), BPA diminishes E(2)-induced PR expression. The estrogen-like effect of BPA reported in exposed humans may be mediated by PR blockade and a resultant decrease in the estrogen inhibition normally imparted by P. Diminished PR expression may underlie previous reports linking BPA exposure to endometrial dysfunction in humans. PMID- 21536274 TI - Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment. AB - OBJECTIVE: To evaluate the degree of E2 deficiency in male congenital hypogonadotropic hypogonadism (CHH), and its response to different hormonal treatments. DESIGN: Retrospective and prospective studies. SETTING: Academic institution. PATIENT(S): Untreated or treated CHH, healthy men, untreated men with Klinefelter syndrome (KS). INTERVENTION(S): Serum sex hormone-binding globulin (SHBG) and total E2 (TE2) as well as bioavailable (BE2) and free (FE2) levels were measured and determined. MAIN OUTCOME MEASURE(S): Total, bioavailable, and free testosterone, TE2, BE2, FE2 were compared in normal men, untreated and treated CHH and in untreated KS. RESULT(S): TE2, BE2, and FE2 levels were very significantly lower in untreated patients with CHH (n=91) than in controls (n=63) and in patients with KS (n=45). The TE2 correlated positively with serum total T in patients with CHH. The TE2 also correlated very positively with serum LH in the combined population of patients with CHH and healthy men, suggesting that low E2 levels in CHH are due to severe LH-driven T deficiency. All fractions of circulating E2 were very significantly higher in patients with CHH receiving T enanthate (n=101) or the FSH-hCG combination (n=88) than in untreated patients with CHH. Contrary to dihydrotestosterone (DHT), both T enanthate and combined FSH-hCG therapy significantly and prospectively increased TE2 levels in patients with CHH. CONCLUSION(S): Contrary to KS, the male hypogonadism observed in CHH is associated with profound E2 deficiency, which can be overcome by aromatizable androgen or combined gonadotropin therapy. PMID- 21536275 TI - Defining case-control studies. PMID- 21536276 TI - Embryo culture and pH. PMID- 21536277 TI - Pitfalls in the assessment of PON1 status in clinical populations. PMID- 21536282 TI - Evaluation of sperm proteins in infertile men: a proteomic approach. AB - In this study, the sperm protein profile was compared between fertile and infertile men using 2-dimensional gel electrophoresis, liquid chromatography mass spectrometer analysis, and matrix-assisted laser desorption ionization-time-of flight-mass spectrometry. Four unique proteins, semenogelin II precursor, prolactin-induced protein, clusterin isoform 1, and prostate-specific antigen isoform 1 preproprotein, were predominantly present in the semen of healthy men; however, semenogelin II precursor and clusterin isoform 1 were not seen in the semen of infertile men, suggesting unique differences in the spermatozoa protein profiles of fertile and infertile men. PMID- 21536283 TI - Semen washing procedures do not eliminate human papilloma virus sperm infection in infertile patients. AB - OBJECTIVE: To determine the effectiveness of three sperm washing protocols for removing human papillomavirus (HPV)-infected cells from semen samples of infertile patients. DESIGN: Cross-sectional clinical study. SETTING: Andrology and microbiology sections at a university hospital. PATIENT(S): A group of 32 infertile patients positive for semen HPV, detected with polymerase chain reaction (PCR) and in-situ hybridization in sperm and exfoliated cells. INTERVENTION(S): Semen analysis and in-situ hybridization for HPV detection were performed before and after sperm washing, discontinuous Ficoll gradients, and swim-up protocols. Statistical analysis was performed with a two-tailed Student's t-test. MAIN OUTCOME MEASURE(S): Evaluation of sperm parameters and presence of HPV, performed in semen samples before and after procedures of sperm selection. RESULT(S): All native samples showed the presence of infected sperm with a mean percentage of positivity (24.7% +/- 8.9%) higher than exfoliated cells (13.8% +/- 4.3%). Fifteen samples had HPV DNA on sperm and exfoliated cells. Sperm washing centrifugation showed no changes in the number of infected samples and in the percentage of infected cells. Ficoll and swim-up protocols induced a slight reduction in the number of infected samples (30 and 26, respectively). CONCLUSION(S): This study demonstrated that conventional sperm selection rarely eliminates HPV sperm infection. More attention should be paid to the reproductive health of infected patients because, not only can HPV be transmitted, but it may also have a negative effect on development of the fetus. PMID- 21536284 TI - International Committee for Monitoring Assisted Reproductive Technology (ICMART) world report: assisted reproductive technology 2003. AB - OBJECTIVE: To analyze information on assisted reproductive technologies (ART) performed globally. DESIGN: Data on access, efficacy, and safety of ART were collected for the year 2003 from 54 countries. SETTING: National and regional ART registries globally. PATIENT(S): Patients undergoing ART globally. INTERVENTION(S): Collection and analysis of international ART registry data. MAIN OUTCOME MEASURE(S): Number of cycles performed in reporting countries and regions globally for different ART procedures with resulting pregnancy, live birth and multiple birth rates. RESULT(S): A total of 433,427 initiated cycles reported in this registry resulted in 173,424 babies born. This corresponded to a delivery rate per aspiration of 22.4% for in vitro fertilization (IVF), 23.3% for intracytoplasmic sperm injection (ICSI), and a delivery rate per transfer of 17.1% for frozen embryo transfer. Although there is wide variation among countries and regions, the overall proportion of deliveries with twins and triplets from IVF and ICSI was 24.8% and 2.0%, respectively. There were wide variations in access, and compared with the previous report (year 2002), there was a 3.9% increase in the number of reported cycles and a minor increase in the delivery rate per aspiration. There was also a marginal decline in the mean number of embryos transferred and in the rate of multiple births. CONCLUSION(S): ART access, efficacy, and safety varies greatly globally. Collection and analysis of data over time will benefit ART patients, providers, and policy makers. PMID- 21536285 TI - The impact of tracheostomy timing in patients with severe head injury: an observational cohort study. AB - STUDY DESIGN: A retrospective analysis of 66 adults with severe head injury admitted to the neurosurgical intensive care unit (ICU) who required tracheostomy. OBJECTIVE: The purpose of this cohort study was to examine the impact of the tracheostomy timing in patients with severe head injury. METHODS: Patients were included in this study if they were admitted to the neurosurgical ICU because of severe head injury and if tracheostomy was performed. The patients were classified into 2 groups: early tracheostomy (ET) and late tracheostomy (LT). The timing of tracheostomy was considered early if it was performed by day 10 of mechanical ventilation and late if it was performed after day 10. We compared the duration of mechanical ventilation, length of stay (LOS) at ICU, hospital LOS, incidence of pneumonia, duration of antibiotics use, and mortality between the ET and LT groups. RESULTS: Of the 2481 patients with severe head injury admitted to the neurosurgical ICU, 66 (2.7%) required tracheostomy; 16 of whom were in the ET group and 50 were in the LT group. The ICU LOS was significantly shorter in the ET group (p<0.001). The incidence of nosocomial pneumonia was lower in the ET group (p=0.04) and the duration of antibiotic use was significantly shorter in the ET group (p<0.001). The patients in the ET group had a lower incidence of pneumonia caused by gram-negative microorganisms (p=0.001). CONCLUSIONS: ET in patients with severe head injury might contribute to a shorter duration of ICU LOS, lower incidence of gram-negative microorganism related nosocomial pneumonia, and shorter duration of antibiotic use. PMID- 21536286 TI - MicroPPARticle in atherosclerosis: guilty or innocent by-standers? PMID- 21536287 TI - Relationships among the serum omega fatty acid levels, serum C-reactive protein levels and arterial stiffness/wave reflection in Japanese men. AB - OBJECTIVE: We examined the relationship among the serum omega-3 and omega-6 fatty acid (O3FA and O6FA) levels, serum C-reactive protein (CRP) levels, and arterial stiffness/wave reflection (AS/WR) in healthy Japanese men. METHODS: In 2206 Japanese healthy men, parameters related to the AS/WR (i.e., brachial-ankle pulse wave velocity and radial arterial pulse wave analysis) were measured. RESULTS: No significant inverse relationships were observed between the serum O3FA levels and the AS/WR-related parameters. Adjusted values of the AS/WR-related parameters and serum CRP levels were higher in the subjects with serum O6FA levels in the highest tertile than in those with serum O6FA levels in the lowest tertile. CONCLUSIONS: In healthy Japanese men with known high dietary intakes of O3FAs, the serum O3FA levels may not reflect the pathophysiological abnormalities related to AS/WR. Increased serum O6FA levels appeared to be independently associated with the unfavorable conditions related to AS/WR and inflammation. PMID- 21536288 TI - Monocyte chemotactic protein-3 induces human coronary smooth muscle cell proliferation. AB - Monocyte chemotactic protein-3 (MCP-3), also known as CCL7, belongs to the monocyte chemotactic protein (MCP) subfamily of the CC chemokines that includes MCP-1/CCL2, MCP-2/CCL8, MCP-4/CCL13, and MCP-5/CCL12. Few studies have examined the role of MCP-3 in vascular pathologies such as atherosclerosis and restenosis in which smooth muscle cell (SMC) proliferation plays an important role. In this study, we investigated the effect of MCP-3 on human coronary artery smooth muscle cell (CASMC) proliferation. MCP-3 induced concentration-dependent CASMC proliferation with the maximum stimulatory effect at 0.3 ng/mL (about 50% vs unstimulated cells) assessed by bromodeoxyuridine (BrdU) uptake and direct cell counting. Anti-MCP-3 antibody (20 ng/mL) completely inhibited cell proliferation, demonstrating the specificity of the proliferative effect of MCP-3. Moreover, the MCP-3-induced CASMC proliferation was blocked by RS 102895 (0.06-6 MUM), a specific antagonist of chemokine receptor 2 (CCR2). The mitogenic effect of MCP-3 appeared to be dependent on ERK1/2 MAPK and PI3K signaling pathway activation, as demonstrated by the reduction of MCP-3-induced CASMC proliferation observed after the treatment of cells with U0126 (1 MUM) and LY-294002 (5MUM), selective inhibitors of ERK 1/2 and PI3K activation, respectively. We found no relationship between MCP-3-induced CASMC proliferation and nuclear factor-kappaB activation. Moreover, we found that tumor necrosis factor-alpha (TNF-alpha, 30 ng/mL) and interleukin-1beta (IL-1beta, 1 ng/mL) both induced time-dependent increase of MCP 3 production by CASMCs, which was reduced by the anti-MCP-3 antibody (20 ng/mL), suggesting that the mitogenic effect of these stimuli is due, at least in part, to MCP-3. In conclusion, our results demonstrate that MCP-3 is produced by human CASMCs and directly induces CASMC proliferation in vitro, suggesting a potential role for this chemokine in vascular pathology. PMID- 21536289 TI - Effect of tensile force on the mechanical behavior of actin filaments. AB - Actin filaments are the most abundant components of the cellular cytoskeleton, and play critical roles in various cellular functions such as migration, division and shape control. In these activities, mechanical tension causes structural changes in the double-helical structure of the actin filament, which is a key modulator of cytoskeletal reorganization. This study performed large-scale molecular dynamics (MD) and steered MD simulations to quantitatively analyze the effects of tensile force on the mechanical behavior of actin filaments. The results revealed that when a tensile force of 200pN was applied to a filament consisting of 14 actin subunits, the twist angle of the filament decreased by approximately 20 degrees , corresponding to a rotation of approximately -2 degrees per subunit, representing a critical structural change in actin filaments. Based on these structural changes, the variance in filament length and twist angle was found to decrease, leading to increases in extensional and torsional stiffness. Torsional stiffness increased significantly under the tensile condition, and the ratio of filament stiffness under tensile force to that under no external force increased significantly on longer temporal scales. The results obtained from this study contribute to the understanding of mechano chemical interactions concerning actin dynamics, showing that increased tensile force in the filament prevents actin regulatory proteins from binding to the filament. PMID- 21536290 TI - Posture shifting after spinal cord injury using functional neuromuscular stimulation--a computer simulation study. AB - The ability for individuals with spinal cord injury (SCI) to affect changes in standing posture with functional neuromuscular stimulation (FNS) was explored using an anatomically inspired musculoskeletal model of the trunk, pelvis and lower extremities (LE). The model tracked trajectories for anteriorly and laterally shifting movements away from erect stance. Forces were applied to both shoulders to represent upper extremity (UE) interaction with an assistive device (e.g., a walker). The muscle excitations required to execute shifting maneuvers with UE forces <10% body-weight (BW) were determined via dynamic optimization. Nine muscle sets were examined to maximize control of shifting posture. Inclusion of the Psoas and External Obliques bilaterally resulted in the least relative UE effort (0.119, mean UE effort = 45.3N = 5.4% BW) for anterior shifting. For lateral shifting, the set including the Psoas and Latissimus Dorsi bilaterally yielded the best performance (0.025, mean UE effort = 27.8 N = 3.3% BW). However, adding the Psoas alone bilaterally competed favorably in overall best performance across both maneuvers. This study suggests suitable activation to specific muscles of the trunk and LE can enable individuals with SCI to alter their standing postures with minimal upper-body effort and subsequently increase reach and standing work volume. PMID- 21536291 TI - A novel multi-planar radiography method for three dimensional pose reconstruction of the patellofemoral and tibiofemoral joints after arthroplasty. AB - Determining the 3D pose of the patella after total knee arthroplasty is challenging. The commonly used single-plane fluoroscopy is prone to large errors in the clinically relevant mediolateral direction. A conventional fixed bi-planar setup is limited in the minimum angular distance between the imaging planes necessary for visualizing the patellar component, and requires a highly flexible setup to adjust for the subject-specific geometries. As an alternative solution, this study investigated the use of a novel multi-planar imaging setup that consists of a C-arm tracked by an external optoelectric tracking system, to acquire calibrated radiographs from multiple orientations. To determine the accuracies, a knee prosthesis was implanted on artificial bones and imaged in simulated 'Supine' and 'Weightbearing' configurations. The results were compared with measures from a coordinate measuring machine as the ground-truth reference. The weightbearing configuration was the preferred imaging direction with RMS errors of 0.48 mm and 1.32 degrees for mediolateral shift and tilt of the patella, respectively, the two most clinically relevant measures. The 'imaging accuracies' of the system, defined as the accuracies in 3D reconstruction of a cylindrical ball bearing phantom (so as to avoid the influence of the shape and orientation of the imaging object), showed an order of magnitude (11.5 times) reduction in the out-of-plane RMS errors in comparison to single-plane fluoroscopy. With this new method, complete 3D pose of the patellofemoral and tibiofemoral joints during quasi-static activities can be determined with a many fold (up to 8 times) (3.4mm) improvement in the out-of-plane accuracies compared to a conventional single-plane fluoroscopy setup. PMID- 21536292 TI - Early osteoarthritis were only detected at the nanometer scale but not at the micrometer or millimeter scale. PMID- 21536293 TI - Recent advances in electrophoretic techniques for the characterization of protein biomolecules: a poker of aces. AB - The four classical modes of electrophoresis of protein molecules (sodium dodecyl sulphate electrophoresis, SDS-PAGE, isoelectric focusing, IEF, and immobilized pH gradients, IPGs, two-dimensional maps, 2D, and capillary electrophoresis, CE) are here reviewed, with special emphasis on recent innovations. Thus, in the case of SDS-PAGE, a novel method, consisting in focusing SDS-protein micelles against a gradient of cationic charges grafted onto a polyacrylamide gel is presented. In the case of IEF, the recent decoding of the structure, polydispersity, molecular mass distribution and buffering properties of the soluble carrier ampholyte buffers are here discussed. In regard to two dimensional mapping, recent instrumentation for performing 2D maps in horizontal, large gel slabs (up to 30 cm * 40 cm) and in a radial format for the SDS dimension is here evaluated. Finally, in the case of CE, three major applications are presented: a thorough study of capillary IEF and of all experimental variables, a method of importance in screening of rDNA products; the possibility of running proteins and peptide separations in very acidic, amphoteric, isoelectric buffers in absence of any capillary coating; finally, the possibility of producing a facile, user friendly, covalent coating of the wall silanols via bonding of quaternarized piperazines endowed with an iodinated tail. In acidic, volatile buffers, such protein/peptide runs can be directly interfaced with mass spectrometry instrumentation. PMID- 21536294 TI - Utilizing a constant peak width transform for isothermal gas chromatography. AB - A computational approach to partially address the general elution problem (GEP), and better visualize, isothermal gas chromatograms is reported. The theoretical computational approach is developed and applied experimentally. We report a high speed temporally increasing boxcar summation (TIBS) transform that, when applied to the raw isothermal GC data, converts the chromatographic data from the initial time domain (in which the peak widths in isothermal GC increase as a function of their retention factors, k), to a data point based domain in which all peaks have the same peak width in terms of number of points in the final data vector, which aides in preprocessing and data analysis, while minimizing data storage size. By applying the TIBS transform, the resulting GC chromatogram (initially collected isothermally), appears with an x-axis point scale as if it were instrumentally collected using a suitable temperature program. A high speed GC isothermal separation with a test mixture containing 10 compounds had a run time of ~25 s. The peak at a retention factor k ~0.7 had a peak width of ~55 ms, while the last eluting peak at k ~89 (i.e., retention time of ~22 s) had a peak width of ~2000 ms. Application of the TIBS transform increased the peak height of the last eluting peak 45-fold, and S/N ~20-fold. All peaks in the transformed test mixture chromatogram had the width of an unretained peak, in terms of number of data points. A simulated chromatogram at unit resolution, studied using the TIBS transform, provided additional insight into the benefits of the algorithm. PMID- 21536295 TI - Counter-current chromatography: simple process and confusing terminology. AB - The origin of counter-current chromatography is briefly stated, followed by a description of the mechanism of elution of solutes, which illustrates the elegance and simplicity of the technique. The CCC retention equation can be mentally derived from three facts; that a substance with a distribution coefficient of 0 elutes at the mobile phase solvent front (one mobile phase volume); and one with a distribution coefficient of 1 elutes at the column volume of mobile phase; and solutes with higher distribution coefficients elute at additional multiples of the stationary phase volume. The pattern corresponds to the classical solute retention equation for chromatography, V(R)=V(M)+K(C)V(S), K(C) not being limited to integer values. This allows the entire pattern of solute retention to be visualized on the chromatogram. The high volume fraction of stationary phase in CCC greatly enhances resolution. A survey of the names, symbols and definitions of several widely used chromatography and liquid-liquid distribution parameters in the IUPAC Gold Book and in a recent summary in LC-GC by Majors and Carr revealed numerous conflicts in both names and definitions. These will retard accurate dissemination of CCC research unless the discordance is resolved. It is proposed that the chromatography retention parameter, K(C), be called the distribution coefficient and that a new biphasic distribution parameter, K(Delta(A)), be defined for CCC and be called the species partition ratio. The definition of V(M) should be clarified. V(H) is suggested to represent the holdup volume and V(X) is suggested for the extra-column volume. H(V) and H(L) are suggested to represent the volume and length of a theoretical plate in CCC. Definitions of the phase ratio, beta, conflict and should be clarified. PMID- 21536296 TI - Preparation of a durable superhydrophobic membrane by electrospinning poly (vinylidene fluoride) (PVDF) mixed with epoxy-siloxane modified SiO2 nanoparticles: a possible route to superhydrophobic surfaces with low water sliding angle and high water contact angle. AB - A durable superhydrophobic surface with low water sliding angle (SA) and high water contact angle (CA) was obtained by electrospinning poly (vinylidene fluoride) (PVDF) which was mixed with epoxy-siloxane modified SiO(2) nanoparticles. To increase the roughness, modified SiO(2) nanoparticles were introduced into PVDF precursor solution. Then in the electrospinning process, nano-sized SiO(2) particles irregularly inlayed (it could also be regard as self assembly) in the surface of the micro-sized PVDF mini-islands so as to form a dual-scale structure. This structure was responsible for the superhydrophobicity and self-cleaning property. In addition, epoxy-siloxane copolymer was used to modify the surface of SiO(2) nanoparticles so that the SiO(2) nanoparticles could stick to the surface of the micro-sized PVDF mini-islands. Through the underwater immersion test, the SiO(2) nanoparticles cannot be separated from PVDF easily so as to achieve the effect of durability. We chiefly explore the surface wettability and the relationship between the mass ratio of modified SiO(2) nanoparticles/PVDF and the CA, SA of electrospun mat. As the content of modified SiO(2) nanoparticles increased, the value of CA increased, ranging from 145.6 degrees to 161.2 degrees , and the water SA decreased to 2.17 degrees , apparently indicating that the membrane we fabricated has a perfect effect of superhydrophobicity. PMID- 21536297 TI - Ionic liquid crystalline phases in 3-hexadecylimidazolium bromide and binary mixtures with 1-decanol. AB - 3-Hexadecylimidazolium bromide was synthesized and characterized showing formation of thermotropic smectic liquid crystals at temperatures above its melting point from 48.5 to 150.9 degrees C. With decreasing temperature, the peak intensities in XRD patterns increase and full widths at half-maximum decrease, suggesting structural order increases with decreasing temperature. Compared with 1,2-dimethyl-3-hexadecyl-imidazolium bromide and hexafluorophosphate, the IL shows a lower melting point and less degree of chain interdigitation. The main reason is due to a more symmetrical structure and denser assembly of the IL molecules, which results in more steric resistance for the alkyl chain to interdigitate. The self-assembly behavior of the hydrophobic IL in an organic solvent was investigated showing SmA(2) lyotropic liquid crystalline phases. The first-order scattering peak shifts to lower q values with increasing IL content, which is opposite to the shift directions of the binary mixtures of the soluble imidazolium IL and water, indicating a different packing behavior of the hydrophobic IL in 1-decanol. PMID- 21536298 TI - Preparation and evaluation of magnetic carbonaceous materials for pesticide and metal removal. AB - Magnetic carbonaceous materials were produced by carbonization of a cation exchange resin loaded with ferrous or ferric iron and activation using sieved oyster shell as the activation agent. The magnetic carbonaceous material with the maximum magnetic flux density on every axis (ESS-1) was obtained from the ferric loaded resin by carbonization at 700 degrees C, followed by activation with the oyster shell at 900 degrees C, and magnetization. A separate step of carbonization and activation appears to cause more of a reduction reaction of Fe to form gamma-Fe(2)O(3). The Fe compound in the magnetic carbonaceous material was identified from the XRD pattern as mainly gamma-Fe(2)O(3). The magnetic flux density on every axis increased linearly as the amount of the oyster shell increased. Moreover, the adsorption ability of the products was evaluated for pesticides and metal ions. Both ESS-1 and a carbonaceous material obtained from the resin without ferric ion (RC) appear to have the highest adsorption ability for lead. Furthermore, the adsorption ability of ESS-1 might decrease by blockages of the pores with the loaded Fe compounds. PMID- 21536299 TI - A novel strategy to assemble colloidal gold nanoparticles at the water-air interface by the vapor of formic acid. AB - We report a novel strategy on the controlled assembly of gold nanoparticles (NPs) at the air-water interface by designing a concentration gradient of electrolytes utilizing volatile weak acidic electrolytes. Films of close-packed Au NPs can be facilely obtained by exposing citrate-protected gold colloids to the vapor of formic acid for several hours in an airtight desiccator at room temperature. Both the higher interfacial concentration of formic acid and the buffer effect of citrate solution play the key roles in the assembly. They engender a gradient distribution of hydrogen ions such that to trigger the interfacial assembly of gold NPs while preventing the bulk colloid from aggregation and coagulation. Comparative investigations have also been performed either using other volatile electrolytes like weaker acetic acid and stronger hydrochloric acid or adding an electrolyte directly into the colloids. The as-prepared films of gold NPs can serve as good substrates for surface-enhanced Raman scattering (SERS). This strategy has also been applied to the assembly of some other NPs like colloidal Pt at the air-water interface. PMID- 21536300 TI - Preparation and characterization of gold nanoparticles capped by peptide-biphenyl hybrids. AB - Gold nanoparticles were prepared using peptide-biphenyl hybrids (PBHs) as capping agents. AuNPs were characterized by different techniques including UV-Vis, TEM, EDX, FT-IR, elemental analysis, (1)H NMR and (13)C CP/MAS NMR spectroscopy. TEM analysis showed that AuNPs present diameters in the range of 1.8-3.7 nm, depending on the structure and the amount of the capping PBH used. FT-IR spectroscopy and solid-state (13)C NMR revealed that the carboxylic group of PBHs, especially in the case of the acid ligands, interacts with the gold surface (in the form of carboxylate). The results confirm that PBHs are excellent stabilizers of AuNPs, being one of the first examples on the use of peptidomimetics-gold hybrid materials. PMID- 21536301 TI - Mixed micelle formation between amino acid-based surfactants and phospholipids. AB - The mixed micelle formation in aqueous solutions between an anionic gemini surfactant derived from the amino acid cystine (C(8)Cys)(2), and the phospholipids 1,2-diheptanoyl-sn-glycero-3-phosphocholine (DHPC, a micelle forming phospholipid) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC, a vesicle-forming phospholipid) has been studied by conductivity and the results compared with the ones obtained for the mixed systems with the single-chain surfactant derived from cysteine, C(8)Cys. Phospholipid-surfactant interactions were found to be synergistic in nature and dependent on the type of phospholipid and on surfactant hydrophobicity. Regular solution theory was used to analyse the gemini surfactant-DHPC binary mixtures and the interaction parameter, beta(12), has been evaluated, as well as mixed micelle composition. The results have been interpreted in terms of the interplay between reduction of the electrostatic repulsions among the ionic head groups of the surfactants and steric hindrances arising from incorporation of the zwitterionic phospholipids in the mixed micelles. PMID- 21536302 TI - Amorphous calcium phosphate/poly(D,L-lactic acid) composite nanofibers: electrospinning preparation and biomineralization. AB - Amorphous calcium phosphate (ACP) has been recognized as an attractive biomaterial due to its bioactivity and biocompatibility. Electrospinning is a simple and low-cost way to fabricate polymer fibers. In this study, ACP nanoparticles with diameters ranging from 20 to 80 nm were synthesized using a simple precipitation method. ACP nanoparticles were hybridized with poly(D,L lactic acid) (PDLLA) to form ACP/PDLLA composite nanofibers by electrospinning, and different architectures including the nanofibrous mesh and tube consisting of ACP/PDLLA composite nanofibers were obtained and characterized. The biomineralization and cytocompatibility of as-prepared ACP/PDLLA composite nanofibers were evaluated in vitro. Osteoblast-like MG63 cells were seeded on the ACP/PDLLA composite nanofiber meshes to perform the cytocompatibility evaluation. The ACP/PDLLA composite nanofibers exhibited a fast mineralization behavior in the simulated body fluid. The attachment of MG63 cells and cytotoxicity of ACP/PDLLA composite nanofibers were also evaluated, and the experiments indicated good biocompatibility and bioactivity of ACP/PDLLA composite nanofibers. PMID- 21536303 TI - Fabrication of superhydrophobic polymethylsilsesquioxane nanostructures on cotton textiles by a solution-immersion process. AB - Superhydrophobic cotton textiles are prepared by a simple, one-step and inexpensive phase separation method under ambient conditions by which a layer of polymethylsilsesquioxane (PMSQ) nanostructures is covered onto the cellulose fibers. By changing the silane precursor concentration, PMSQ nanostructures with various shapes, morphologies and sizes were fabricated. Nanostructures were characterized using SEM, EDS, and attenuated total reflectance FTIR. The wettability of the modified cellulose surfaces was characterized with contact angle goniometry and sliding angle technique, respectively. The water contact angle of modified cotton is measured to be higher than 150 degrees , which is high enough to exhibit the lotus effect as a result of the superhydrophobicity. Tunable water-repellent properties of the fabric are also demonstrated, with sliding contact angles varying from "sticky" to "slippery" depending upon different nanostructures on the surface of the fibers. It is expected that this simple technique will accelerate the large-scale production of superhydrophobic cellulosic materials with new industrial applications. PMID- 21536304 TI - Tunable supramolecular hydrogel for in situ encapsulation and sustained release of bioactive lysozyme. AB - To develop new matrices for the entrapment and sustained release of bioactive lysozyme, a series of supramolecular hydrogels based on alpha-cyclodextrin (alpha CD) and water-soluble poly(epsilon-caprolactone)-poly(ethylene glycol) block copolymer (PCL-b-PEG) were prepared in the presence of chicken egg lysozyme. Different from commonly used polymeric microspheres and chemically crosslinked hydrogels for lysozyme encapsulation, such hydrogel matrices could be formed under mild conditions without high temperature and the use of chemical emulsifiers or crosslinkers. Their gelation rate, mechanical strength and shear viscosity as well as the release behavior for the encapsulated lysozyme could be tuned easily by the change of alpha-CD or PCL-b-PEG amount. For the encapsulated lysozyme, its conformation and biological activity could be well maintained when compared to native lysozyme. For the resultant supramolecular hydrogels, they were also confirmed to have a good biocompatibility by MTT assay using mice skin fibroblast (L929). PMID- 21536305 TI - Two dimensional self-assembly of bis-acylureas having various functional end groups. AB - We present the synthesis and morphology study of thirteen bis-acylurea molecules with various functional end groups. The bis-acylureas have two acylurea groups, NH-CO-NH-CO-, divided by a pentamethylene spacer, -(CH(2))(5)-, and two symmetric functional end groups, such as, aliphatic, benzyl, mono- and bi-thiophenyl, sulfur-containing, and propargyl (HC[triple bond]CCH(2)-) moieties. The bis acylureas were synthesized by the coupling reactions of ureas with pimeloyl chloride or pimelic acid. Upon cooling from hot isotropic solutions, the bis acylureas spontaneously form supermolecules. In the cases of aliphatic, benzyl, mono- and bi-thiophenyl functional groups, two dimensional supramolecular structures with molecularly flat surfaces were formed. Single crystal X-ray diffraction results demonstrate that each bis-acylurea molecule forms biaxial hydrogen bonds with four adjacent molecules forming a grid-like crystalline structure. Among the bis-acylureas with sulfur-containing end groups, those with sulfide (-S-) and disulfide (-SS-) moieties self-organize into two dimensional superstructures, while those with thiol (-SH) and bulky protecting group (-S trityl) precipitate with irregular shapes. The bis-acylurea with propargyl end groups form superstructures of low order possibly due to the steric effect between the rigid moieties. However, the derivatives prepared by click reactions have lamellar molecular packing similar to those of bis-acylureas forming multilayered nanosheet structures. PMID- 21536306 TI - Quality of life in adults who stutter. AB - Although persistent developmental stuttering is known to affect daily living, just how great the impact is remains unclear. Furthermore, little is known about the underlying mechanisms which lead to a diminished quality of life (QoL). The primary objective of this study is to explore to what extent QoL is impaired in adults who stutter (AWS). In addition, this study aims to identify determinants of QoL in AWS by testing relationships between stuttering severity, coping, functioning and QoL and by testing for differences in variable scores between two AWS subgroups: receiving therapy versus not receiving therapy. A total of 91 AWS filled in several questionnaires to assess their stuttering severity, daily functioning, coping style and QoL. The QoL instruments used were the Health Utility Index 3 (HUI3) and the EuroQoL EQ-5D and EQ-VAS. The results indicated that moderate to severe stuttering has a negative impact on overall quality of life; HUI3 derived QoL values varied from .91 (for mild stuttering) to .73 (for severe stuttering). The domains of functioning that were predominantly affected were the individual's speech, emotion, cognition and pain as measured by the HUI3 and daily activities and anxiety/depression as measured by the EQ-5D. AWS in the therapy group rated their stuttering as more severe and recorded more problems on the HUI3 speech domain than AWS in the non-therapy group. The EQ-VAS was the only instrument that showed a significant difference in overall QoL between groups. Finally, it was found that the relationship between stuttering severity and QoL was influenced by the individual's coping style (emotion-oriented and task oriented). These findings highlight the need for further research into stuttering in relation to QoL, and for a broader perspective on the diagnosis and treatment of stuttering, which would take into consideration quality of life and its determinants. PMID- 21536307 TI - Are children's faces really more appealing than those of adults? Testing the baby schema hypothesis beyond infancy. AB - This study examined adults' evaluations of likeability and attractiveness of children's faces from infancy to early childhood. We tested whether Lorenz's baby schema hypothesis (Zeitschrift fur Tierpsychologie (1943), Vol. 5, pp. 235-409) is applicable not only to infant faces but also to faces of children at older ages. Adult participants were asked to evaluate children's faces from early infancy to 6 years of age in terms of their likeability and attractiveness, and these judgments were compared with those of adult faces. It was revealed that adults judged faces of younger children as more likeable and attractive than faces of older children, which were in turn judged as more likeable and attractive than adult faces. However, after approximately 4.5 years of age, the baby schema no longer affected adults' judgments of children's facial likeability and attractiveness. These findings suggest that the baby schema affects adults' judgments of not only infant faces but also young children's faces. This influence beyond infancy is likely due to the fact that facial cranial growth is gradual during early childhood and certain crucial infantile facial cues remain readily available during this period. Future studies need to identify these specific cues to better understand why adults generally show positive responses to infantile faces and how such positive responses influence the establishment and maintenance of social relationships between young children and adults. PMID- 21536308 TI - Short- and long- term efficacy of cognitive behavioral therapy for DSM-IV panic disorder in patients with and without severe psychiatric comorbidity. AB - Cognitive behavioral therapy (CBT) and/or pharmacological therapy are considered to be effective in the treatment of anxiety disorders. Anxiety patients frequently suffer from comorbid psychiatric disorders such as depression or substance disorders. Ongoing substance disorders and/or severe depressive symptomatology often are the reason why patients are not treated by outpatient psychotherapy. The present study was designed to evaluate whether CBT is comparably effective both in anxiety patients with and without comorbid axis-I diagnoses. In a 5-weeks standardized inpatient CBT program for anxiety disorders at the Center of Mental Health, Ingolstadt, 48 patients with panic disorder according to DSM-IV were included. 42% of the patients suffered from panic disorder only, 58% from at least one further mental disorder, mainly from affective and/or substance disorders. The severity of symptomatology was determined using psychometric scales at admission, at discharge and at the follow up investigation. In general, therapy was highly effective. Panic symptoms as well as anxious cognitions and avoidance behavior were significantly reduced at discharge and results remained stable until the follow-up investigation. Therapy was equally effective in both groups, in patients with pure and patients with comorbid panic disorder at discharge as well as at the follow-up investigation. Thus, patients with comorbid affective or substance disorders should not be excluded from psychotherapeutic programs in future. PMID- 21536309 TI - [Chondroblastic osteosarcoma over a total hip prosthesis]. AB - Malignant transformation in the area of joint prostheses is very rare. We present the case of a woman who developed a chondroblastic osteosarcoma in the area where a total hip prosthesis had been implanted. PMID- 21536310 TI - Modulation of intestinal morphology and immunity in nile tilapia (Oreochromis niloticus) by Lactobacillus rhamnosus GG. AB - The use of lactic acid bacteria from human origins as a potential probiotic supplementation in aquaculture feed is now widely accepted. Here, we examined some of the properties and mechanisms of the action of Lactobacillus rhamnosus GG, originating from humans, on growth performance, gut mucosal immunity and humoral and cellular immune response in tilapia (Oreochromis niloticus). The results suggested that supplementation of L. rhamnosus gave an advantage in promoting the intestinal structure and the mucosal immunity of tilapia. Probiotic fish had a greater villous height in all parts of the intestines and, significantly, in the proximal and middle part. The population of intraepithelial lymphocytes was significantly higher in the probiotic group than in the control group in all parts of the intestines. The population of acidophilic granulocyte in the probiotic group was significantly higher at the proximal and distal parts when compared with the control group. The higher serum complement activity as well as the enhanced phagocytosis and killing ability of the head kidney leukocytes in the probiotic supplemented fish corresponded with the higher level of TNF alpha and IL-1 gene expression, suggesting that the induction of IL-1 and TNF alpha cytokines by L. rhamnosus served as an important regulator of gut associated immune systems. PMID- 21536311 TI - Steroid receptor mRNA expression in the ovarian follicles of cows with cystic ovarian disease. AB - Steroid receptors have been demonstrated to be important intra-ovarian regulators of follicular development and ovulatory processes. The aim of the present study was to determine the expression of steroid receptor mRNA in ovarian follicular structures from cows with cystic ovarian disease (COD) compared with ovarian structures from regularly cycling cows using reverse transcription polymerase chain reaction (RT-PCR). The cystic follicles showed a higher estrogen receptor alpha (ESR1) mRNA expression in the theca and granulosa and a lower estrogen receptor beta (ESR2) expression. The cystic follicles also showed a strong expression of androgen receptor mRNA in the granulosa. No changes were observed in total progesterone receptor mRNA, but a very significant increase in the B isoform was found in the granulosa of the cystic follicles. The findings of the current study provide evidence that an altered steroid signaling system may be present in bovine follicular cysts, and we suggest that in conditions characterized by altered ovulation, such as COD, changes in the expression of ovarian steroid receptors could play a fundamental role in the pathogeny of this disease. PMID- 21536312 TI - Development of a triplex TaqMan real-time RT-PCR assay for differential detection of wild-type and HCLV vaccine strains of classical swine fever virus and bovine viral diarrhea virus 1. AB - In this study, genomic sequences of pestiviruses available in GenBank were aligned to design three primer pairs and TaqMan probes: two targeting the NS5A region of the viral genome of classical swine fever virus (CSFV) for the differentiation of wild-type CSFV and hog cholera lapinized vaccine (HCLV) vaccine, and one targeting the 5'-untranslated region of bovine viral diarrhea virus 1 (BVDV-1). With these primers and probes, a triplex TaqMan real-time RT PCR assay was developed for differentiating wild-type CSFV, the HCLV strain, and BVDV-1. The detection limit of the assay was 4.5 TCID(50) for wild-type CSFV, 10 TCID(50) for HCLV-strain CSFV, and 3.2 TCID(50) for BVDV-1. The triplex real-time RT-PCR had at least 98% (248 samples) agreement with other RT-PCR methods. The assay provides a sensitive tool for simultaneous detection and differentiation of wild-type CSFV and HCLV from BVDV-1. PMID- 21536313 TI - Purification of household water using a novel mixture reduces diarrhoeal disease in Matlab, Bangladesh. AB - In Bangladesh, one of the main causes of waterborne diseases is related to the use of contaminated surface water. This pilot study was conducted to determine the acceptability and effectiveness of a recently developed surface water purifying mixture to prevent diarrhoeal diseases in a rural community in Bangladesh. The mixture, using a combination of alum potash, bleaching powder and lime, is added to 15 l of surface water and mixed; the water becomes suitable for drinking after 30 min. A total of 420 households from 15 villages were provided with the mixture and were taught how to use it. Episodes of diarrhoeal disease from study families were determined from hospital records of the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) in Matlab and were compared with diarrhoea episodes among 1613 control families who were not provided with the mixture. A total of 83 diarrhoeal patients were treated at Matlab Hospital from 1613 control families, but only one patient was treated for diarrhoea from among the intervention families. Among the intervention families, 73 families decided to shift from using tube well water to surface water using the mixture. The mixture could be used as a cheaper, easier and simpler point-of use water treatment strategy in Bangladesh. PMID- 21536314 TI - Sorption of emerging trace organic compounds onto wastewater sludge solids. AB - This work examined the sorption potential to wastewater primary- and activated sludge solids for 34 emerging trace organic chemicals at environmentally relevant concentrations. These compounds represent a diverse range of physical and chemical properties, such as hydrophobicity and charge state, and a diverse range of classes, including steroidal hormones, pharmaceutically-active compounds, personal care products, and household chemicals. Solid-water partitioning coefficients (K(d)) were measured where 19 chemicals did not have previously reported values. Sludge solids were inactivated by a nonchemical lyophilization and dry-heat technique, which provided similar sorption behavior for recalcitrant compounds as compared to fresh activated-sludge. Sorption behavior was similar between primary- and activated-sludge solids from the same plant and between activated-sludge solids from two nitrified processes from different wastewater treatment systems. Positively-charged pharmaceutically-active compounds, amitriptyline, clozapine, verapamil, risperidone, and hydroxyzine, had the highest sorption potential, log K(d)=2.8-3.8 as compared to the neutral and negatively-charged chemicals. Sorption potentials correlated with a compound's hydrophobicity, however the higher sorption potentials observed for positively charged compounds for a given log D(ow) indicate additional sorption mechanisms, such as electrostatic interactions, are important for these compounds. Previously published soil-based one-parameter models for predicting sorption from hydrophobicity (log K(ow)>2) can be used to predict sorption for emerging nonionic compounds to wastewater sludge solids. PMID- 21536315 TI - Factors influencing 4-fluorobenzoate degradation in biofilm cultures of Pseudomonas knackmussii B13. AB - Membrane aerated biofilm reactors (MABRs) have potential in wastewater treatment as they permit simultaneous COD minimisation, nitrification and denitrification. Here we report on the application of the MABR to the removal of fluorinated xenobiotics from wastewater, employing a Pseudomonas knackmussii monoculture to degrade the model compound 4-fluorobenzoate. Growth of biofilm in the MABR using the fluorinated compound as the sole carbon source occurred in two distinct phases, with early rapid growth (up to 0.007 h(-1)) followed by ten-fold slower growth after 200 h operation. Furthermore, the specific 4-fluorobenzoate degradation rate decreased from 1.2 g g(-1) h(-1) to 0.2 g g(-1) h(-1), indicating a diminishing effectiveness of the biofilm as thickness increased. In planktonic cultures stoichiometric conversion of substrate to the fluoride ion was observed, however in the MABR, approximately 85% of the fluorine added was recovered as fluoride, suggesting accumulation of 'fluorine' in the biofilm might account for the decreasing efficiency. This was investigated by culturing the bacterium in a tubular biofilm reactor (TBR), revealing that there was significant fluoride accumulation within the biofilm (0.25 M), which might be responsible for inhibition of 4-fluorobenzoate degradation. This contention was supported by the observation of the inhibition of biofilm accumulation on glass cover slips in the presence of 40 mM fluoride. These experiments highlight the importance of fluoride ion accumulation on biofilm performance when applied to organofluorine remediation. PMID- 21536316 TI - Ambient ammonia in terrestrial ecosystems: a comparative study in the Tennessee Valley, USA. AB - Atmospheric ammonia has been shown to degrade regional air quality and affect environmental health. In-situ measurements of ammonia are needed to determine how ambient concentrations vary in different ecosystems and the extent to which emission sources contribute to those levels. The objective of this study was to measure and compare ammonia concentrations in two Tennessee Valley (USA) ecosystems: a forested rural area and a metropolitan site adjacent to a main transportation route. Integrated samples of atmospheric ammonia were collected with annular denuder systems for ~4 weeks during the summer of 2009 in both ecosystems. Ancillary measurements of meteorological variables, such as wind direction and precipitation, were also conducted to determine any relationships with ammonia concentration. Measurements in the two ecosystems revealed ammonia concentrations that were mostly representative of background levels. Arithmetic means were 1.57+/-0.68 MUg m(-3) at the metropolitan site and 1.60+/-0.77 MUg m( 3) in the forest. The geometric mean concentrations for both sites were ~1.46 MUg m(-3). Wind direction, and to a lesser extent air temperature and precipitation, did influence measured concentrations. At the metropolitan site, ammonia concentrations were slightly higher in winds emanating from the direction of the interstate highway. Meteorological variables, such as wind direction, and physical factors, such as topography, can affect measurement of ambient ammonia concentrations, especially in ecosystems distant from strong emission sources. The 12-h integrated sampling method used in this study was unable to measure frequent changes in ambient ammonia concentrations and illustrates the need for measurements with higher temporal resolution, at least ~1-2h, in a variety of diverse ecosystems to determine the behavior of atmospheric ammonia and its environmental effects. PMID- 21536317 TI - Mercury and flooding cycles in the Tapajos River basin, Brazilian Amazon: the role of periphyton of a floating macrophyte (Paspalum repens). AB - Methylmercury (MeHg) increases mercury (Hg) toxicity and is biomagnified in the trophic chain contaminating riverine Amazon populations. Freshwater macrophyte roots are a main site of Hg methylation in different Brazilian environments. Paspalum repens periphyton was sampled in four floodplain lakes during the dry, rainy and wet seasons for measurement of total Hg (THg), MeHg, Hg methylation potentials, %C, %N, delta(13)C, delta(15)N and bacterial heterotrophic production as (3)H-leucine incorporation rate. THg concentration varied from 67 to 198 ng/g and the potential of Me(203)Hg formation was expressive (1-23%) showing that periphyton is an important matrix both in the accumulation of Hg and in MeHg production. The concentration of MeHg varied from 1 to 6 ng/g DW and was positively correlated with Me(203)Hg formation. Though methylmercury formation is mainly a bacterial process, no significant correlation was observed between the methylation potentials and bacterial production. The multiple regressions analyses suggested a negative correlation between THg and %C and %N and between methylation potential and delta(13)C. The discriminant analysis showed a significant difference in periphyton delta(15)N, delta(13)C and THg between seasons, where the rainy season presented higher delta(15)N and the wet period lighter delta(13)C, lower THg values and higher Me(203)Hg formation. This exploratory study indicates that the flooding cycle could influence the periphyton composition, mercury accumulation and methylmercury production. PMID- 21536318 TI - Taking organelles apart, putting them back together and creating new ones: lessons from the endoplasmic reticulum. AB - The endoplasmic reticulum (ER) is a highly dynamic organelle. It is composed of four subcompartments including nuclear envelope (NE), rough ER (rER), smooth ER (sER) and transitional ER (tER). The subcompartments are interconnected, can fragment and dissociate and are able to reassemble again. They coordinate with cell function by way of protein regulators in the surrounding cytosol. The activity of the many associated molecular machines of the ER as well as the fluid nature of the limiting membrane of the ER contribute extensively to the dynamics of the ER. This review examines the properties of the ER that permit its isolation and purification and the physiological conditions that permit reconstitution both in vitro and in vivo in normal and in disease conditions. PMID- 21536319 TI - The future of gynecologic oncology: are we headed for super-specialization? PMID- 21536320 TI - Predicting asthma exacerbations: peak expiratory flow revisited. PMID- 21536321 TI - Neighborhood differences in exposure and sensitization to cockroach, mouse, dust mite, cat, and dog allergens in New York City. AB - BACKGROUND: Asthma prevalence varies widely among neighborhoods within New York City. Exposure to mouse and cockroach allergens has been suggested as a cause. OBJECTIVE: To test the hypotheses that children living in high asthma prevalence neighborhoods (HAPNs) would have higher concentrations of cockroach and mouse allergens in their homes than children in low asthma prevalence neighborhoods (LAPNs), and that these exposures would be related to sensitization and asthma. METHODS: In the New York City Neighborhood Asthma and Allergy Study, a case control study of asthma, children 7 to 8 years old from HAPNs (n = 120) and LAPNs (n = 119) were recruited through the same middle-income health insurance plan. Children were classified as asthma cases (n = 128) or controls without asthma (n = 111) on the basis of reported symptoms or medication use. Allergens were measured in bed dust. RESULTS: HAPN homes had higher Bla g 2 (P = .001), Mus m 1 (P = .003), and Fel d 1 (P = .003) and lower Der f 1 (P = .001) than LAPN homes. Sensitization to indoor allergens was associated with asthma, but relevant allergens differed between LAPNs and HAPNs. Sensitization to cockroach was more common among HAPN than LAPN children (23.7% vs 10.8%; P = .011). Increasing allergen exposure was associated with increased probability of sensitization (IgE) to cockroach (P < .001), dust mite (P = .009), and cat (P = .001), but not mouse (P = .58) or dog (P = .85). CONCLUSION: These findings further demonstrate the relevance of exposure and sensitization to cockroach and mouse in an urban community and suggest that cockroach allergen exposure could contribute to the higher asthma prevalence observed in some compared with other New York City neighborhoods. PMID- 21536322 TI - Inflammation in common variable immunodeficiency is associated with a distinct CD8(+) response to cytomegalovirus. AB - BACKGROUND: Common variable immunodeficiency is the most common primary immunodeficiency. A subset of patients has debilitating inflammatory complications. OBJECTIVES: We investigated the role of cytomegalovirus (CMV), and the T-cell response targeted at this virus, in this inflammatory disease. METHODS: Phenotypic and functional assays were used to profile CMV-specific T cells in patients with common variable immunodeficiency with and without inflammatory complications. Highly sensitive immunohistochemistry was used to detect CMV antigens at sites of inflammation. RESULTS: Cytomegalovirus was significantly associated with inflammatory disease, which occurred in 31 of 43 (72%) virus-exposed patients and 8 of 31 (26%) naive patients (P = .0001). CMV pp65-NLVPMVATV epitope-specific CD8(+) T-cell frequencies were significantly elevated in inflammatory patients, but these cells did not show evidence of exhaustion, with low levels of programmed death-1 and high T-cell receptor avidity. Rather, they showed features consistent with high in vivo functionality and proliferative activity including reduced levels of the anti-inflammatory marker CD73 (1.67% of NLV(+) cells were CD73(+) vs 42.01% in noninflammatory patients; P = .004) and increased Ki-67 expression (37% vs 2% in noninflammatory patients; P < .0001). In vitro, the CMV-specific T cells showed high antigen specific proliferative potential compared with cells from noninflammatory patients. By using sensitive immunohistochemistry, we detected for the first time viral antigen at the sites of inflammation, indicative of active viral replication. CONCLUSION: Our data strongly support a direct role for CMV and a hyperreactive CMV-specific immune response in the debilitating chronic inflammatory complications of common variable immunodeficiency. PMID- 21536323 TI - Trajectories of childhood wheeze. PMID- 21536324 TI - Effect of the microstructure on the lifetime of dental ceramics. AB - OBJECTIVES: To evaluate the effect of the microstructure on the Weibull and slow crack growth (SCG) parameters and on the lifetime of three ceramics used as framework materials for fixed partial dentures (FPDs) (YZ - Vita In-Ceram YZ; IZ Vita In-Ceram Zirconia; AL - Vita In-Ceram AL) and of two veneering porcelains (VM7 and VM9). METHODS: Bar-shaped specimens were fabricated according to the manufacturer's instructions. Specimens were tested in three-point flexure in 37 degrees C artificial saliva. Weibull analysis (n=30) and a constant stress-rate test (n=10) were used to determine the Weibull modulus (m) and SCG coefficient (n), respectively. Microstructural and fractographic analyzes were performed using SEM. ANOVA and Tukey's test (alpha=0.05) were used to statistically analyze data obtained with both microstructural and fractographic analyzes. RESULTS: YZ and AL presented high crystalline content and low porosity (0.1-0.2%). YZ had the highest characteristic strength (sigma(0)) value (911MPa) followed by AL (488MPa) and IZ (423MPa). Lower sigma(0) values were observed for the porcelains (68 75MPa). Except for IZ and VM7, m values were similar among the ceramic materials. Higher n values were found for YZ (76) and AL (72), followed by IZ (54) and the veneering materials (36-44). Lifetime predictions showed that YZ was the material with the best mechanical performance. The size of the critical flaw was similar among the framework materials (34-48MUm) and among the porcelains (75-86MUm). SIGNIFICANCE: The microstructure influenced the mechanical and SCG behavior of the studied materials and, consequently, the lifetime predictions. PMID- 21536325 TI - Non-viral gene delivery nanoparticles based on poly(beta-amino esters) for treatment of glioblastoma. AB - Glioblastoma (GB) is currently characterized by low survival rates and therapies with insufficient efficacy. Here, we describe biodegradable polymers that can deliver genes to primary GB cells as well as GB tumor stem cells in vitro with low non-specific toxicity and transfection efficiencies of up to 60.6 +/- 5% in normal (10%) serum conditions. We developed polymer-DNA nanoparticles that remained more stable in normal serum and could also be stored for at least 3 months in ready-to-use form with no measurable decrease in efficacy, expanding their potential in a practical or clinical setting. A subset of polymers was identified that shows a high degree of specificity to tumor cells compared with healthy astrocytes and human neural stem cells when cultured (separately or in co culture), yielding higher transfection in GB cells while having little to no apparent effect on healthy cells. PMID- 21536326 TI - Folate-decorated nanogels for targeted therapy of ovarian cancer. AB - Nanogels are comprised of swollen polymer networks and nearly 95% water and can entrap diverse chemical and biological agents for cancer therapy with very high loading capacities. Here we use diblock copolymer poly(ethylene oxide)-b poly(methacrylic acid) (PEO-b-PMA) to form nanogels with the desired degree of cross-linking. The nanogels are further conjugated to folic acid (FA) and loaded with different types of drugs (cisplatin, doxorubicin). For the first time we demonstrate a tumor-specific delivery and superior anti-tumor effect in vivo of an anti-cancer drug using these polyelectrolyte nanogels decorated with folate targeting groups. This reinforces the use of nanogels for the therapy of ovarian and other cancers, where folate receptor (FR) is overexpressed. PMID- 21536327 TI - Comparative analysis of binding affinities to epidermal growth factor receptor of monoclonal antibodies nimotuzumab and cetuximab using different experimental animal models. AB - Although pharmaco/toxicological studies have always been conducted in pharmacologically relevant species in which the test material is pharmacologically active, the very specificity of many biopharmaceuticals could present challenges in the identification of a relevant species for pharmaco/toxicological studies. Alternative approaches may improve the predictive value of preclinical assessments of species-specific biopharmaceuticals. This could lead to improved decision-making, reduce the number of experimental animals by eliminating non-relevant studies, and decrease the time and cost involved in the drug development process. As an alternative to utilizing traditional animal models, this study investigated the activity of human EGF and the anti-EGF receptor monoclonal antibodies nimotuzumab and cetuximab using the placenta microsomal fraction of different experimental animals. Ligand-receptor binding curves were obtained from the different experimental animal models, and binding constants were calculated based on the Scatchard plots. The constants for human and monkey EGF receptor expressed on the placental extract showed a K(a)<10(-8)M, while rabbits, mice and rats showed a K(a)>10(-8)M. The K(a) values obtained from animal placentas show that Macaca fascicularis and Cercopitecus aethiops monkeys are relevant species for studying the pharmaco/toxicological properties of nimotuzumab and cetuximab. PMID- 21536328 TI - Transmitter- and hormone-activated Ca(2+) responses in adult microglia/brain macrophages in situ recorded after viral transduction of a recombinant Ca(2+) sensor. AB - In vitro studies show that microglia, the resident immune cells of the brain, express neurotransmitter and neuropeptide receptors which are linked to Ca(2+) signaling. Here we describe an approach to obtain Ca(2+) recordings from microglia in situ. We injected a retrovirus encoding a calcium sensor into the cortex of mice 2 days after stimulation of microglial proliferation by a stab wound injury. Microglial cells were identified with tomato lectin in acute slices prepared 3, 6, 21 and 42 days after the injury. The membrane current profile and the ameboid morphology indicated that microglial cells were activated at day 6 while at day 42 they resembled resting microglia. We recorded transient Ca(2+) responses to application of ATP, endothelin-1, substance P, histamine and serotonin. The fluorescence amplitude of ATP was increased only at day 6 compared to other time points, while responses to all other ligands did not vary. Only half of the microglial cells that responded to ATP also responded to endothelin 1, serotonin and histamine. Substance P, in contrast, showed a complete overlap with the ATP responding microglial population at day 6, at day 42 this population was reduced to 55%. Cultured cells were less responsive to these ligands. This study shows that in situ microglia consist of heterogeneous populations with respect to their sensitivity to neuropeptides and -transmitters. PMID- 21536329 TI - Deletion of chromosome 20q: friend or foe? PMID- 21536330 TI - Detection of temporal trends of alpha- and gamma-chlordane in Lake Erie fish communities using dynamic linear modeling. AB - Dynamic linear modeling (DLM) analysis was performed to identify the long-term temporal trends of two toxic components of the technical chlordane pesticide, alpha- and gamma-chlordane, in skinless-boneless muscle tissues of a number of sport fish species in Lake Erie. Our analysis considers the fish length as a covariate of the chlordane concentrations. The alpha-chlordane models for the coho salmon, channel catfish, rainbow trout, and common carp showed continuously decreasing trends during the entire 30+ year survey period (1976-2007). The gamma chlordane models demonstrated similar trends for the coho salmon, channel catfish, and common carp. These fish species had higher levels of alpha- and gamma-chlordane in their muscle tissues. The alpha- and gamma-chlordane levels in freshwater drum, smallmouth bass, walleye, white bass, whitefish, and yellow perch decreased until the mid-1980s and hovered at levels around the detection limits for the remaining period. The pesticide biotransformation process, the reduction of contaminant emissions to the environment, the feeding habits of the different fish species, and the food-web alterations induced by the introduction of aquatic invasive species are some of the hypotheses proposed to explain the observed temporal trends in different fish species in Lake Erie. PMID- 21536331 TI - Exposure of juvenile green frogs (Lithobates clamitans) in littoral enclosures to a glyphosate-based herbicide. AB - The majority of studies on the toxicity of glyphosate-based herbicides to amphibians have focused on larval life stages exposed in aqueous media. However, adult and juvenile amphibians may also be exposed directly or indirectly to herbicides. The potential for such exposures is of particular interest in the littoral zone surrounding wetlands as this is preferred habitat for many amphibian species. Moreover, it may be argued that potential herbicide effects on juvenile or adult amphibians could have comparatively greater influence on overall recruitment, reproductive potential and thus stability of local populations than effects on larvae. In this experiment, juvenile green frogs (Lithobates clamitans) were exposed to two concentrations (2.16 and 4.27 kg a.e./ha) of a glyphosate-based herbicide formulation (VisionMax(r)), which were based on typical application scenarios in Canadian forestry. The experimental design employed frogs inhabiting in situ enclosures established at the edge of small naturalized wetlands that were split in half using an impermeable plastic barrier. When analyzed using nominal target application rates, exposure to the glyphosate-based herbicide had no significant effect on survival, body condition, liver somatic index or the observed rate of Batrachochytrium dendrobatidis infection. However, there were marginal trends in both ANOVA analysis and post hoc regressions regarding B. dendrobatidis infection rates and liver somatic index in relation to measured exposure estimates. Results from this study highlight the importance of field research and the need to include multiple endpoints when examining potential effects of a contaminant on non-target organisms. PMID- 21536332 TI - Perfluorinated compounds in surface waters from Northern China: comparison to level of industrialization. AB - Inclusion of Perfluorooctane Sulfonate (PFOS) in the Stockholm Convention because of its exemptions, has resulted in increased annual production of PFOS-containing chemicals in China to accommodate domestic and overseas demands. Accordingly, concern about environmental contamination with perfluorinated compounds (PFCs), such as PFOS, has arisen. However, little information is available on the status and trends in the distribution, sources or risk of PFCs in aquatic environments of China. In the present study, forty two surface water samples collected from five regions with different levels of industrialization were monitored for concentrations of PFCs by use of solid phase extraction and LC/MS/MS. Mean concentrations (maximum concentration) of PFOA and PFOS, which were the dominant PFCs, were 1.2 (2.3) and 0.16 (0.52)ng/l for Guanting, 1.2 (1.8) and 0.32 (1.1)ng/l for Hohhot, 2.7 (15) and 0.93 (5.7)ng/l for Shanxi, 6.8 (12) and 2.6 (11)ng/l for Tianjin, 27 (82) and 4.7 (31)ng/l for Liaoning, respectively. The greatest concentrations of PFCs (121 ng/l), PFOA (82 ng/l) and PFOS (31 ng/l) were observed in Liaoning, which might originate from tributaries of the Liaohe River, the most polluted watershed in Northeast China. While, concentrations of PFCs in the Guanting and Hohhot regions were 3 to 20 fold less than those from Tianjin and Liaoning. This result is consistent with little contribution of PFCs being released from agricultural and non-industrial activities. The magnitudes of mass flow for PFOA and PFOS in decreasing order were: Guanting=16 years) OHCA of presumed cardiac aetiology, unwitnessed by paramedics with attempted resuscitation. Outcomes for OHCA occurring between 2003 and 2005 were compared with 2007-2009. Segmented regression analysis of interrupted time series data was performed, adjusting for known predictors, to examine changes in survival to hospital and survival to hospital discharge. RESULTS: For the pre- and post- guideline periods there were 3115 and 3248 OHCAs, respectively. Asystole increased as presenting rhythm (33-43%, p<0.001) as did median EMS response times (7.1-7.8 min, p<0.001) over the two periods. VF/VT arrests decreased (40-35.5%, p=0.001) as did bystander witnessed arrests (63-59%, p=0.002). On univariate analysis survival to hospital discharge improved between the two periods (9.4 11.8%, p=0.002) due to improved outcomes in VF/VT (19-28%, p<0.001). Segmented regression analysis of interrupted time series data showed improvement in the rate of survival to get to hospital for shockable and non-shockable rhythms [OR (95% CI)=1.54 (1.10-2.15, p=0.01) and 1.45 (1.10-2.00, p=0.02), respectively] following implementation of the guidelines however survival to hospital discharge did not improve [OR=1.07 (0.70-1.62, p=0.70) and 1.40 (0.69-2.85, p=0.40), respectively]. CONCLUSIONS: OHCA outcomes have improved since introduction of the 2005 CPR guidelines, but multivariable segmented regression analysis adjusting for pre-existing trends in survival suggests that this improvement may not be due to implementation of the 2005 resuscitation guidelines. PMID- 21536368 TI - Measuring cerebral oxygenation helps optimizing post-resuscitation therapy. PMID- 21536369 TI - Rigidification of the autolysis loop enhances Na(+) binding to thrombin. AB - Binding of Na(+) to thrombin ensures high activity toward physiological substrates and optimizes the procoagulant and prothrombotic roles of the enzyme in vivo. Under physiological conditions of pH and temperature, the binding affinity of Na(+) is weak due to large heat capacity and enthalpy changes associated with binding, and the K(d)=80 mM ensures only 64% saturation of the site at the concentration of Na(+) in the blood (140 mM). Residues controlling Na(+) binding and activation have been identified. Yet, attempts to improve the interaction of Na(+) with thrombin and possibly increase catalytic activity under physiological conditions have so far been unsuccessful. Here we report how replacement of the flexible autolysis loop of human thrombin with the homologous rigid domain of the murine enzyme results in a drastic (up to 10-fold) increase in Na(+) affinity and a significant improvement in the catalytic activity of the enzyme. Rigidification of the autolysis loop abolishes the heat capacity change associated with Na(+) binding observed in the wild-type and also increases the stability of thrombin. These findings have general relevance to protein engineering studies of clotting proteases and trypsin-like enzymes. PMID- 21536372 TI - How to tell if a new marker improves prediction. PMID- 21536370 TI - Diabetes, growth hormone-insulin-like growth factor pathways and association to benign prostatic hyperplasia. AB - Diabetes significantly increases the risk of benign prostatic hyperplasia (BPH) and low urinary tract symptoms (LUTS). The major endocrine aberration in connection with the metabolic syndrome is hyperinsulinemia. Insulin is an independent risk factor and a promoter of BPH. Insulin resistance may change the risk of BPH through several biological pathways. Hyperinsulinemia stimulates the liver to produce more insulin-like growth factor (IGF), another mitogen and an anti-apoptotic agent which binds insulin receptor/IGF receptor and stimulates prostate growth. The levels of IGFs and IGF binding proteins (IGFBPs) in prostate tissue and in blood are associated with BPH risk, with the regulation of circulating androgen and growth hormone. Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Previously, we have shown that the expression of c-Jun in the fibroblastic stroma can promote secretion of IGF-I, which stimulates prostate epithelial cell proliferation through activating specific target genes. Here, we will review the epidemiologic, clinical, and molecular findings which have evaluated the relation between diabetes and development of BPH. PMID- 21536373 TI - Alpha-tocopheryl succinate enhances doxorubicin-induced apoptosis in human gastric cancer cells via promotion of doxorubicin influx and suppression of doxorubicin efflux. AB - Doxorubicin (DOXO), a chemotherapy drug, is widely used in clinic for treating a variety of cancers. However, the treatment eventfully fails due to drug resistance and toxicity. Therefore, a combination strategy is needed to increase efficacy and reduce toxicity of DOXO. alpha-tocopheryl succinate (alpha-TOS) exhibits anticancer actions in vitro and in vivo. Here, we reported that combination of DOXO+alpha-TOS cooperatively acted to induce apoptosis in SGC-7901 cells. alpha-TOS enhanced cellular level of DOXO via promotion of DOXO influx and suppression of DOXO efflux. DOXO induced MDR1 mRNA and protein expression and alpha-TOS inhibited this event, indicating that alpha-TOS suppressed DOXO efflux via inhibition of MDR1. Furthermore, combination of DOXO+alpha-TOS induced increased levels of Fas and Bax protein expression and cleavage of caspase-8 and caspase-9, suggesting that combination treatment induced Fas/caspase-8 and Bax mediated mitochondria dependent apoptosis. Taken together, our results demonstrated that alpha-TOS enhanced DOXO anticancer efficiency via promotion of DOXO influx and suppression of MDR-1 mediated DOXO efflux. PMID- 21536374 TI - Id1 promotes lung cancer cell proliferation and tumor growth through Akt-related pathway. AB - Overexpression of Id family proteins inhibits cell differentiation and enhances cell proliferation and invasiveness. Although Id1 is the Id family member mostly linked to tumorigenesis, its role in lung cancer is unclear. An elevated Id1 expression was observed in lung cancer cell lines as well as lung cancer tissues. Id1 overexpression increased cell proliferation while Id1 knockdown decreased cell proliferation, mostly through Akt-related pathway. Nude mice study further confirmed an increased tumor growth in Id1-overexpressing cells and a decreased tumor growth in Id1-knockdowned cells. In conclusion, inactivation of Id1 may provide a novel strategy for treatment of lung cancer patients. PMID- 21536375 TI - Insulin-like growth factor-binding protein-3 suppresses tumor growth via activation of caspase-dependent apoptosis and cross-talk with NF-kappaB signaling. AB - Nuclear factor-kappaB (NF-kappaB) is constitutively activated in a variety of human cancers including prostate cancer and involved in tumorigenesis, tumor progression and chemo-resistance. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a potent tumor suppressor and is significantly suppressed in a variety of cancers. Diverse biological effects of IGFBP-3 have been reported to be both dependent and independent of the IGF/IGF-I receptor (IGF-IR) axis. The precise underlying mechanisms of IGF/IGF-IR-independent, antiproliferative actions of IGFBP-3 are yet to be elucidated. We found an inverse correlation between NF-kappaB activity and IGFBP-3 expression during prostate cancer progression using an in vitro prostate cancer progression model. Restoration of IGFBP-3 resulted in significant inhibition of constitutively elevated NF-kappaB activity in prostate cancer cells. IGFBP-3 further inhibited the expression of NF kappaB-regulated angiogenic factors such as VEGF and IL-8, and cell adhesion molecules, ICAM-1 and VCAM-1. This inhibitory action of IGFBP-3 was IGF/IGF-IR independent since IGFBP-3 mutant devoid of IGF binding affinity had a similar inhibitory effect. We identified that IGFBP-3 degrades the key NF-kappaB regulatory molecules-IkappaBalpha and p65-NF-kappaB proteins through activation of caspase-8 and -3/-7, thereby inhibiting elevated NF-kappaB activity in prostate cancer. Finally intratumoral administration of IGFBP-3 resulted in significant tumor suppression as well as sensitization of antitumor effect of doxorubicin. Our findings indicate that IGFBP-3 exerts antitumor effects via IGF independent mechanisms which involve activation of caspase-dependent apoptosis and cross-talk with NF-kappaB signaling. The use of IGFBP-3 as a cancer therapeutic with this distinctive suppression mechanism may offer alternate means to treat chemotherapy resistant tumors. PMID- 21536376 TI - Studies on degradation of reactive textile dyes solution by electrochemical method. AB - The indirect electrochemical degradation of industrial effluents has become an attractive method in recent years. This paper deals with the electrochemical degradation of Novacron Deep Red C-D (NDRCD) and Novacron Orange C-RN (NOCRN) reactive azo dyes from aqueous solution using graphite carbon electrodes. The results indicated that initial pH, current density and supporting electrolytes were played an important role in the degradation of dyes. Electrochemical behavior of reactive azo dyes has been studied with cyclic voltammetry in acidic medium using pencil graphite as working electrode. The potentials selected for the two dyes were in the range +1.0 to -0.4V and +0.5 to -0.2V, respectively. The CV, UV-Vis and chemical oxygen demand (COD) studies were selected to evaluate the degradation efficiency. The maximum colour removal efficiency of 99% and 97% and chemical oxygen demand (COD) removal efficiency of 88% and 82% could be achieved for CDRCD and COCRN, respectively at 7 g L(-1) of NaCl concentration. The LC-MS study revealed the degradation of both the dyes and confirmed that the azo groups and aromatic rings were destroyed. The results revealed the suitability of the present process for the effective degradation of dye effluents. PMID- 21536377 TI - Hybrid porous phosphate heterostructures as adsorbents of Hg(II) and Ni(II) from industrial sewage. AB - Porous phosphate heterostructures (PPH), functionalized with different ratios of aminopropyl and mercaptopropyl groups, labelled as N(x=5,25,50)-PPH and S(x=5,25,50)-PPH, respectively, were tested as adsorbents for Ni(II) and Hg(II) found in industrial sewage from electroplating processes and button battery recycling. X-ray diffraction was used to study the structures. The specific surface area of the pristine material (PPH) was 620 m(2)g(-1), whereas the specific surface areas of the modified mercaptopropyl (S(5)-PPH) and aminopropyl (N(5)-PPH) were 472 and 223 m(2)g(-1), respectively. The adsorption data were fitted to a Langmuir isotherm model. The S(5)-PPH material was saturated by 120 mmol Hg(II) per 100g of material, whereas for Ni(II) adsorption, N(25)-PPH material displayed the highest adsorption with a saturation value of 43.5 mmol per 100g. These results suggest that functionalized PPH materials may be promising toxic metal scavengers and that they may provide an alternative environmental technology. PMID- 21536378 TI - Impact of black carbon originated from fly ash and soot on the toxicity of pentachlorophenol in sediment. AB - The widely existing fly ash and soot produced during the process of combustion, which are often known as waste but also an important source of black carbon (BC) in the environment, were treated by HCl and HF solution for this study, and recorded as FC and SC, respectively. A series of experiments were carried out to investigate the toxicity of pentachlorophenol (PCP) in sediment, influence of various BCs in sediment with different contents (0%, 0.5%, 1%, 2%, 5% and 10%) on the extractability and toxicity of PCP (50mg/kg), and toxicity of various BC in sediment. The results demonstrated that the PCP exposure to wheat seed exhibited a dose-dependent behavior, and the extractability and toxicity of PCP decreased with the increasing content of BC in sediment. The PCP extractable rate was significantly (P<0.01) influenced by the higher content of BCs. Noticeably, each BC had no toxic but stimulative effect on root elongation and early seedling growth. Furthermore, it was found that the inhibitive effect on the extractability and toxicity of PCP and the stimulative effect on root elongation and early seedling growth caused by SC were more evident than FC. PMID- 21536379 TI - Temperature and irradiance influences on cadmium and zinc uptake and toxicity in a freshwater cyanobacterium, Microcystis aeruginosa. AB - Temperature and light irradiance are important factors affecting the occurrence of cyanobacterial blooms. In this study, we examined the influences of different temperatures (15, 24, and 30 degrees C) and irradiances (18, 32, and 55 MUmol photons m(-2)s(-1)) on the uptake and toxicity of cadmium (Cd) and zinc (Zn) in a freshwater cyanobacterium Microcystis aeruginosa. The subcellular distribution of Cd and Zn was analyzed. Enhanced growth rates were observed for the cyanobacterial cells incubated at higher temperature or irradiance conditions with lower metal concentrations. With increasing ambient Cd or Zn concentrations, both cellular growth rate and photosynthesis were significantly inhibited at elevated irradiance conditions. The observed increase in Cd and Zn toxicity might be attributed to the enhanced metal uptake and accumulation in Microcystis. Based on the intracellular Cd concentration, the 50% inhibition concentration (IC(50)) values were higher at the higher temperature or irradiance treatment. The subcellular distribution demonstrated that Cd in the metal rich granule (MRG) faction increased with elevated [Cd(2+)] concentration, suggesting that MRG may partially detoxify the Cd toxicity in the cyanobacterial cells. This study implied that temperature and irradiance may influence the biogeochemical cycling of metals during cyanobacterial blooming in eutrophic freshwater ecosystems. PMID- 21536380 TI - Determination of Cd, Cr, Hg and Pb in plastics from waste electrical and electronic equipment by inductively coupled plasma mass spectrometry with collision-reaction interface technology. AB - A procedure based on the use of a quadrupole inductively coupled plasma-mass spectrometer equipped with a collision-reaction interface (CRI) for control of spectral overlap interferences was developed for simultaneous determination of Cd, Cr, Hg, and Pb in plastics from waste electrical and electronic equipment (WEEE). The injection of H(2) and He (80 and 60 mL min(-1), respectively) into the sampled plasma, colliding and reacting with potentially interfering polyatomic ions, allows interference-free determination of chromium via its isotopes (52)Cr and (53)Cr that are freed from overlap due to the occurrence of (40)Ar(12)C(+), (40)Ar(12)C(1)H(+), (36)S(16)O(+) or (1)H(36)S(16)O(+). Cadmium, Hg and Pb were directly determined via their isotopes (110)Cd, (111)Cd, (112)Cd, (199)Hg, (200)Hg, (201)Hg, (202)Hg, (206)Pb, (207)Pb, and (208)Pb, without using CRI. The CRI can be quickly activated or deactivated before each analyte measurement. Limits of detection for (52)Cr were 0.04 or 0.14 MUg L(-1) with He or H(2) injected in CRI. Cadmium and Pb have LODs between 0.02 and 0.08 MUg L(-1) and Hg had 0.93-0.98 MUg L(-1), without using CRI. Analyte concentrations for samples varied from 16 to 43, 1 to 11, 4 to 12, and 5 to 13 mg kg(-1) for Cr, Cd, Hg and Pb, respectively. PMID- 21536381 TI - Immobilization of low and intermediate level of organic radioactive wastes in cement matrices. AB - The adequacy of cement-clay composite, for solidification/stabilization of organic radioactive spent liquid scintillator wastes and its resistance to frost attack were determined by a freezing/thawing (F/T) test. Frost resistance is assessed for the candidate cement-clay composite after 75 cycles of freezing and thawing by evaluating their mass durability index, compressive strength, apparent porosity, volume of open pores, water absorption, and bulk density. Infrared (IR), X-ray diffraction (XRD), differential thermal analysis (DTA), thermal gravimetric analysis (TGA) and scanning electron microscopy (SEM) were performed for the final waste form (FWF) before and after the F/T treatment to follow the changes that may take place in its microstructure during the hydration regime. The results were obtained indicate that the candidate composite exhibits acceptable resistance to freeze/thaw treatment and has adequate suitability to solidify and stabilize organic radioactive spent liquid scintillator wastes even at very exaggerating conditions (-50 degrees C and +60 degrees C). PMID- 21536382 TI - A selective optical sensor for beryllium determination based on incorporating of 1,8-dihydroxyanthrone in a poly (vinyl chloride) membrane. AB - A new optical sensor was fabricated for determination of beryllium ions. The optode membrane was prepared by incorporation of 1,8-dihydroxyanthrone and sodium tetraphenylborate (NaTPB) in a plasticized poly (vinyl chloride) membrane containing ortho-nitrophenyl octyl ether (o-NPOE) as a plasticizer. Color of the sensing membrane in contact with Be(2+) ions at pH 10.5, was changed from orange to red. The different variables affecting uptake efficiency were evaluated and optimized. Under the optimum conditions (i.e. 28.0% PVC, 60.0% o-NPOE, 8.0% 1,8 dihydroxyanthrone, 4.0% NaTPB and response time of 6 min), the proposed sensor displayed a linear range of 0.1-5 MUg mL(-1) with a detection limit of 0.03 MUg mL(-1). Also the precision (RSD%) was better than 2.9% for 7 replicate determinations of 1 MUg mL(-1) Be in various membranes. The selectivity of the probe was studied for some cations and anions. Experimental results showed that the sensor was high selective in the presence of ethylenediaminetetraacetic acid (EDTA) as a masking agent and could be used as an effective tool in analyzing the beryllium content of water samples. PMID- 21536383 TI - Enhancement of chromium uptake in tanning using oxazolidine. AB - Monocyclic and bicyclic oxazolidines were offered at three different junctures of chrome tanning process viz. prior to BCS offer, along with BCS and after basification. It was found that oxazolidine when offered after basification brought about better chromium uptake and reduction of chromium load in the wastewater. Offer of oxazolidine was also varied. Increase in offer of oxazolidine from 0.25% to 1% was found to enhance the chromium uptake and decrease the chromium load in wastewater. But the increase in uptake was not proportionate to the increase in oxazolidine offer more than 0.75%. Offer of 1% Zoldine ZA 78 (monocyclic oxazolidine) and Zoldine ZE (bicyclic oxazolidine) after basification brought about 63.4% and 73.1% enhancement in chrome content in leather compared to control where oxazolidine was not offered. The tone of the wetblue was found to be altered moderately. However this did not call for any process adjustments in wet-finishing. The oxazolidine treated leathers were found to be immensely fuller and tighter. It was found experimentally that offer of 1% of oxazolidine facilitated reduction in the offer of syntans administered for filling and grain tightening by around 46%. Oxazolidine could bring about significant reduction in cost of chemicals apart from resulting environmental benefits due to enhancement of chromium uptake during tanning. PMID- 21536384 TI - Seasonal dynamics and hosts of Amblyomma triste (Acari: Ixodidae) in Argentina. AB - The seasonal dynamics and host usage of Amblyomma triste in Argentina were analyzed. Adults of A. triste were present from early winter to mid-summer, with the peak of abundance from late winter to mid-spring (August to October). Larvae and nymphs were found from December to June, with the peak of abundance in summer. There were no differences among the biological parameters (pre-moult period of larvae and nymphs, pre-oviposition period of females, and minimum incubation period of eggs) of engorged ticks exposed to different photoperiod regimens at the laboratory, but the periods for each biological parameter obtained from ticks exposed in the field were significantly longer than those from the laboratory. Field results fit better with the data of seasonal distribution of each stage. Morphogenetic diapause was not detected, but complementary studies should test the presence of behavioral diapause. Rodents of the subfamily Sigmodontinae (Akodon azarae, Oligoryzomys flavescens, Oligoryzomys nigripes, Oxymycterus rufus and Scapteromys aquaticus) are the principal hosts for immature stages of A. triste, the caviid Cavia aperea could be another potential host for these stages, and birds are exceptional hosts for larvae and nymphs. Regarding hosts of adults in Argentina, domestic and wild large-sized mammals belonging to different orders (cattle, dog, horse, Blastocerus dichotomus and Hydrochoerus hydrochaeris) serve as hosts for adults of this tick species. In conclusion, A. triste has a life cycle of 1 year with adults feeding on large endemic and introduced mammals and immature stages using sigmodontine and caviid rodents as hosts. PMID- 21536385 TI - The role of European starlings in the spread of coccidia within concentrated animal feeding operations. AB - To investigate the relationship between European starlings and bovine coccidiosis we collected samples from European starlings, cattle feed bunks, cattle water troughs, and cattle feces within concentrated animal feeding operations (CAFOs). These samples were screened for coccidia spp. to investigate (i) the prevalence of coccidia in starlings using CAFOs; (ii) if there is a relationship between bovine coccidiosis and starling numbers; (iii) if coccidia contamination of cattle feed and water is related to the number of starlings observed on CAFOs. Coccidia belonging to the genus Eimeria were detected in cattle feces and one water sample but no Eimeria spp. were detected in European starlings or cattle feed. However, many European starling samples were positive for Isospora. Starling use of CAFOs did not appear to be associated with coccidia spp. shedding by cattle and there was no correlation between starling numbers and contamination of cattle feed and water, suggesting that starling do not contribute to the amplification and spread of Eimeria in CAFOs. PMID- 21536386 TI - Boophilus microplus cathepsin L-like (BmCL1) cysteine protease: specificity study using a peptide phage display library. AB - The tick Rhipicephalus (Boophilus) microplus is one of the most important bovine ectoparasites, a disease vector responsible for losses in meat and milk productions. A cysteine protease similar to cathepsin L, named BmCL1, was previously identified in R. microplus gut, suggesting a role of the enzyme in meal digestion. In this work, BmCL1 was successfully expressed in Pichia pastoris system, yielding 54.8 mg/L of culture and its activity was analyzed by synthetic substrates and against a R. microplus cysteine protease inhibitor, Bmcystatin. After rBmCl1 biochemical characterization it was used in a selection of a peptide phage library to determine rBmCL1 substrate preference. Obtained sequenced clones showed that rBmCL1 has preference for Leu or Arg at P(1) position. The preference for Leu at position P(1) and the activation of BmCL1 after a Leu amino acid residue suggest possible self activation. PMID- 21536387 TI - In vitro acaricidal activity of neem (Azadirachta indica) seed extracts with known azadirachtin concentrations against Rhipicephalus microplus. AB - The effect of four extracts from neem seeds (Azadirachta indica) containing 2000, 5000, 9000 and 10,000 ppm of azadirachtin A (AZA), quantified by high-performance liquid chromatography (HPLC) and diluted to 1.25%; 2.5%; 5.0%; 10.0% and 12.8% was verified by in vitro tests with engorged females and larvae of the cattle tick Rhipicephalus microplus. The results from the bioassays with the engorged females showed that the main toxic effect of the extracts was reduction of the reproductive parameters, with a sharp drop in the number of eggs laid and the hatching rate, mainly when the extracts were diluted to 10.0% and 12.8%. The product effectiveness (PE) calculations for all the solutions tested showed that the AZA solution at 10,000 ppm (N10) was the most effective. However, statistical analysis of the PE data obtained for the proportional AZA concentrations in the different diluted extracts showed significance (P<0.05) of the effects included in the model (extract dilution, principle effect (classificatory) of the assay (extract) and the interaction between the two), indicating significant variations due to the dilution, the test and the interaction between the two factors in the tests with engorged females. For solutions N2, N5, and N9, it was not possible to estimate LC(90) values in the dilution range tested. The lowest LC(50) was observed for extract N5, and although extract N10 was the only extract for which the LC(90) could be estimated within the range tested, the LC(50) was higher than for N5 and N9. These results suggest that substances other than AZA present in the extracts influenced the efficacy, especially up to a certain LC range. In the tests with larvae, no mortality was observed, indicating zero effectiveness of all the extracts tested. The results of the tests with engorged females showed that the neem extracts had acaricide activity, inhibiting egg laying and the larval hatching rate. Complementary studies are necessary to develop new methods to isolate and/or identify other substances besides AZA contained in this plant, to enable using products made from it as acaricides. PMID- 21536388 TI - Myiasis in a dog shelter in Greece: epidemiological and clinical features and therapeutic considerations. AB - The paper describes features of myiasis in a cohort of 163 dogs in an animal shelter, monitored over 3.5 years (4 fly activity seasons). Seven dogs (4 males, 3 females) were presented with myiasis; two dogs were presented twice with infestation in different areas of their body. The overall incidence rate (IR) of myiasis was 5.8 cases per 10(3) animal-months at risk, or else 0.0058 case per animal-month at risk. Six cases occurred from May to July and three from August to October, giving IRs of 7.7 per 10(3) animal-months and 3.9 per 10(3) animal months, respectively, and an IR ratio of 1.97 (P=0.35). Five cases occurred in males and four in females, giving IRs of 7.8 per 10(3) animal months and 4.3 per 10(3) animal-months, respectively, and an incidence rate ratio of 1.78 (P=0.41). Three cases were diagnosed as cutaneous myiasis of the thigh, 2 cases as myiasis of the ear canal, 2 as myiasis of the prepuce, 1 as myiasis of the toes and 1 case as myiasis of the vagina. Median time from entrance into the shelter to infestation was 5 months; it was 1m in three dogs which were injured at entrance of animal into the shelter, but longer (5-15m) in the other four dogs. Larvae were identified as 2nd or 3rd stage instars of Wohlfahrtia magnifica. Signs characteristic of local inflammation, in the affected area of the body, were recorded. Treatment included mechanical removal of larvae, cleansing of the area, administration of injectable moxidectin and a broad-spectrum antimicrobial agent. Complete recovery was achieved within 1.5 months, bar that of preputial infestations which required 2.5 months. PMID- 21536389 TI - Effects of ORP150 on appearance and function of pancreatic beta cells following acute necrotizing pancreatitis. AB - Pancreatic beta cells produce and release insulin, which decreases the blood glucose level. Endoplasmic reticulum stress caused pancreatic beta cell dysfunction and death in acute necrotizing pancreatitis (ANP). The 150kD oxygen regulated protein (ORP150) took part in the process of endoplasmic reticulum stress. This study investigated the effect of ORP150 on appearance and function of pancreatic beta cells in ANP. Acute necrotizing pancreatitis relied on retrograde infusion of 5% sodium taurocholate into the bile-pancreatic duct. The severity of ANP was estimated by serum amylase, secretory phospholipase A(2,) and pancreatic histopathology. The changes in appearance and function of pancreatic beta cells were detected by light and electron microscopy and the levels of serum glucose, insulin, and C-peptide. ORP150 expression was studied using western blot and immunohistochemisty assay. The expression of ORP150 mainly appeared on pancreatic beta cells and decreased gradually during the pathogenesis of ANP. The results of light and electron microscopy indicated pancreatic beta cell dysfunction and death, concomitant with elevation of serum glucose, insulin, and C-peptide in ANP. These results imply a probable role of ORP150 in the changes in appearance and function of pancreatic beta cells following acute necrotizing pancreatitis, through the pathway of endoplasmic reticulum stress. PMID- 21536390 TI - Morphological and molecular heterogeneity in colorectal neoplasms with K-RAS mutation. A report of two cases. AB - Approximately forty percent of colorectal cancers (CRC) are characterized by activating mutations of the K-RAS gene. Determination of K-RAS mutational status as a predictive marker for anti-EGFR therapy is usually based on the assumption of intratumoral homogeneity. We present two cases of CRC in which morphologically distinct tumor components were associated with different activating mutations of K-RAS in one patient and a mutated and a non-mutated portion in the second patient, as demonstrated by laser microdissection and consecutive molecular analyses. PMID- 21536391 TI - Relationship between pelvic organ-at-risk dose and clinical target volume in postprostatectomy patients receiving intensity-modulated radiotherapy. AB - PURPOSE: To investigate dose-volume consequences of inclusion of the seminal vesicle (SV) bed in the clinical target volume (CTV) for the rectum and bladder using biological response indices in postprostatectomy patients receiving intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: We studied 10 consecutive patients who underwent prostatectomy for prostate cancer and subsequently received adjuvant or salvage RT to the prostate fossa. The CTV to planning target volume (PTV) expansion was 7 mm, except posterior expansion, which was 5 mm. Two IMRT plans were generated for each patient, including either the prostate fossa alone or the prostate fossa with the SV bed, but identical in all other aspects. Prescription dose was 68.4 Gy in 1.8-Gy fractions prescribed to >=95% PTV. RESULTS: With inclusion of the SV bed in the treatment volume, PTV increased and correlated with PTV-bladder and PTV-rectum volume overlap (Spearman rho 0.91 and 0.86, respectively; p < 0.05). As a result, the dose delivered to the bladder and rectum was higher (p < 0.05): mean bladder dose increased from 11.3 +/- 3.5 Gy to 21.2 +/- 6.6 Gy, whereas mean rectal dose increased from 25.8 +/- 5.5 Gy to 32.3 +/- 5.5 Gy. Bladder and rectal equivalent uniform dose correlated with mean bladder and rectal dose. Inclusion of the SV bed in the treatment volume increased rectal normal tissue complication probability from 2.4% to 4.8% (p < 0.01). CONCLUSIONS: Inclusion of the SV bed in the CTV in postprostatectomy patients receiving IMRT increases bladder and rectal dose, as well as rectal normal tissue complication probability. The magnitude of PTV bladder and PTV-rectal volume overlap and subsequent bladder and rectum dose increase will be higher if larger PTV expansion margins are used. PMID- 21536392 TI - Moving toward focal therapy in prostate cancer: dual-isotope permanent seed implants as a possible solution. AB - PURPOSE: To compare the ability of single- and dual-isotope prostate seed implants to escalate biologically effective dose (BED) to foci of disease while reducing prescription dose to the prostate. METHODS AND MATERIALS: Nine plans, using 125I, 103Pd, and 131Cs alone and in combination were created retrospectively for 2 patients. Ultrasound and MRI/MRS datasets were used for treatment planning. Voxel-by-voxel BED was calculated for single- and dual isotope plans. Equivalent uniform BED (EUBED) was used to compare plans. The MRS positive planning target volumes (PTVi) were delineated along with PTV (prostate+5 mm), rectum, and urethra. Single-isotope implants, prescribed to conventional doses, were generated to achieve good PTV coverage. The PTVi were prospectively used to generate implants using mixtures of isotopes. For mixed radioisotope implants, we also explored the impact on EUBED of lowering prescription doses by 15%. RESULTS: The EUBED of PTVi in the setting of primary 125I implant increased 20-66% when 103Pd and 131Cs were used compared with 125I boost. Decreasing prescription dose by 15% in mixed-isotope implants results in a potential 10% reduction in urethral EUBED with preservation of PTV coverage while still boosting PTVi (up to 80%). When radiobiologic parameters corresponding to more-aggressive disease are assigned to foci, faster-decaying isotopes used in mixed implants have the potential to preserve the equivalent biological effect of mono-isotope implants considering less-aggressive disease distributed in the entire prostate. CONCLUSIONS: This is a hypothesis-generating study proposing a treatment paradigm that could be the middle ground between whole-gland irradiation and focal-only treatment. The use of two isotopes concurrent with decreasing the minimal peripheral dose is shown to increase EUBED of selected subvolumes while preserving the therapeutic effect at the level of the gland. PMID- 21536393 TI - Validating the RTOG-endorsed brachial plexus contouring atlas: an evaluation of reproducibility among patients treated by intensity-modulated radiotherapy for head-and-neck cancer. AB - PURPOSE: To evaluate interobserver variability for contouring the brachial plexus as an organ-at-risk (OAR) and to analyze its potential dosimetric consequences in patients treated with intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. METHODS AND MATERIALS: Using the Radiation Therapy Oncology Group (RTOG) endorsed brachial plexus contouring atlas, three radiation oncologists independently delineated the OAR on treatment planning computed-tomography (CT) axial scans from 5 representative patients undergoing IMRT to a prescribed dose of 70 Gy for head-and-neck cancer. Dose-volume histograms for the brachial plexus were calculated, and interobserver differences were quantified by comparing various dosimetric statistics. Qualitative analysis was performed by visually assessing the overlapping contours on a single beam's eye view. RESULTS: Brachial plexus volumes for the 5 patients across observers were 26 cc (18-35 cc), 25 cc (21-30 cc), 29 cc (28-32 cc), 29 cc (23-38 cc), and 29 cc (23-34 cc). On qualitative analysis, minimal variability existed except at the inferolateral portion of the OAR, where slight discrepancies were noted among the physicians. Maximum doses to the brachial plexus ranged from 71.6 to 72.6 Gy, 75.2 to 75.8 Gy, 69.1 to 71.0 Gy, 76.4 to 76.9 Gy, and 70.6 to 71.4 Gy. Respective volumes receiving doses greater than 60 Gy (V60) were 8.6 to 10.9 cc, 6.2 to 8.1 cc, 8.2 to 11.6 cc, 8.3 to 10.5 cc, and 5.6 to 9.8 cc. CONCLUSION: The RTOG-endorsed brachial plexus atlas provides a consistent set of guidelines for contouring this OAR with essentially no learning curve. Adoption of these contouring guidelines in the clinical setting is encouraged. PMID- 21536394 TI - Equine alphaherpesviruses (EHV-1 and EHV-4) differ in their efficiency to infect mononuclear cells during early steps of infection in nasal mucosal explants. AB - Equine herpesvirus type 1 (EHV-1) replicates extensively in the epithelium of the upper respiratory tract, after which it can spread throughout the body via a cell associated viremia in mononuclear leukocytes reaching the pregnant uterus and central nervous system. In a previous study, we were able to mimic the in vivo situation in an in vitro respiratory mucosal explant system. A plaquewise spread of EHV-1 was observed in the epithelial cells, whereas in the connective tissue below the basement membrane (BM), EHV-1-infected mononuclear leukocytes were noticed. Equine herpesvirus type 4 (EHV-4), a close relative of EHV-1, can also cause mild respiratory disease, but a cell-associated viremia in leukocytes is scarce and secondary symptoms are rarely observed. Based on this striking difference in pathogenicity, we aimed to evaluate how EHV-4 behaves in equine mucosal explants. Upon inoculation of equine mucosal explants with the EHV-4 strains VLS 829, EQ(1) 012 and V01-3-13, replication of EHV-4 in epithelial cells was evidenced by the presence of viral plaques in the epithelium. Interestingly, EHV-4-infected mononuclear leukocytes in the connective tissue below the BM were extremely rare and were only present for one of the three strains. The inefficient capacity of EHV-4 to infect mononuclear cells explains in part the rarity of EHV-4-induced viremia, and subsequently, the rarity of EHV-4-induced abortion or EHM. PMID- 21536395 TI - [Mortality study among veterans with dosimeter monitoring during the French nuclear tests in the Pacific]. AB - BACKGROUND: A mortality study was carried out in a cohort of veterans present on the sites of the French nuclear experiments center in the Pacific (CEP) from 1966 to 1996, and for whom external dosimeter monitoring recordings were available. METHODS: The cohort included 32,550 veterans having had at least one dosimetry recording. Current vital status was collected from the National Register of Identification of Physical People and causes of death data from the national causes of death database. Total mortality and mortality by cause were compared with mortality of the French population using standardized mortality ratios (SMR). To test the effect of a dosimeter recording higher than the threshold (0.2 mSv), i.e., no null dosimetry, the mortality of veterans was compared inside the cohort, using standardized ratios and Poisson regression models. RESULTS: The mortality analysis was performed among 26,524 men, of whom 8% had had at least one non-null dosimeter. Five thousand four hundred and ninety-two (21%) veterans died before December 31, 2008 and causes were available for nearly 97% of these deaths. Comparing the mortality between the cohort and the French population highlighted a deficit of mortality, for all causes, by cancer and for radiation induced pathologies; these results were related to the "healthy worker effect". The data showed that all causes mortality and cancer mortality of the cohort of veterans with no null dosimeter were not different from those of other veterans, but also showed an excess of hematological malignancies in this sub-population: this excess was significant in the regression model (RR=1.82; CI 95% [1.6-2.0]). CONCLUSION: Among veterans with an external dosimeter monitoring recording, presence on the sites of CEP from 1966 to 1996 does not constitute a factor of increased mortality compared with the national population. However, an increased risk was observed for mortality by hematological malignancies among veterans with no null dosimetry. This result is in line with studies on veterans present during nuclear experiments abroad. PMID- 21536396 TI - The accuracy of ultrasonography in the preoperative diagnosis of cervical lymph node metastasis in patients with papillary thyroid carcinoma: A meta-analysis. AB - BACKGROUND: Ultrasonography has been proposed to enhance preoperative assessment of cervical lymph node status in patients with papillary thyroid carcinoma (PTC). Management is most controversial for patients with a clinically negative (cN0) neck. We aimed to evaluate the diagnostic properties of ultrasonography in the detection of cervical lymph node metastasis in patients with PTC. MATERIALS AND METHODS: Studies evaluating the diagnostic accuracy of Ultrasonography in the diagnosis of cervical lymph node metastasis in patients with PTC were systematically searched for in the MEDLINE, EMBASE, Cancerlit and Cochrane Library and other database from January 1995 to November 2010. Two reviewers independently abstracted data including research design, sample size, imaging technique and technical characteristics, method of image interpretation. By patient-based and region- or node-based data analyses, we determined pooled sensitivities and specificities across studies, and constructed summary receiver operating characteristic curves, and area under summary receiver operating characteristic curves were calculated. RESULTS: The pooled patient-based sensitivity for ultrasonography was 0.72 (95% CI, 0.46-0.88), specificity was 0.98 (95% CI, 0.84-1.00), and the area under the curve (AUC) was 0.94 (95% CI, 0.92-0.0.96). The pooled region- or node-based sensitivity for ultrasonography was 0.63 (95% CI, 0.47-0.76), specificity was 0.93 (95% CI, 0.73-0.99), and the AUC was 0.81 (95% CI, 0.77-0.84). For lesion-based analysis, the subgroup of lateral compartment lymph node involvement was found to have the highest sensitivity (0.72, 95% CI 0.68-0.75) and specificity (0.97, 95% CI 0.93-0.99) among the studies (p<0.05). Study sensitivity was not correlated with the prevalence of cervical lymph node metastasis (patient-based: R(2)=0.0196, p=0.7915; region- or node-based: R(2)=0.3835, p=0.1381). CONCLUSIONS: We conclude that preoperative ultrasonography is a good technique for the preoperative lymph node staging of PTC and is helpful for detecting metastatic cervical lymph nodes at the lateral group. High-quality prospective studies regarding ultrasonography in the evaluation of cervical lymph node status in patients with PTC are still needed to be conducted. PMID- 21536397 TI - Anastomotic pseudoaneurysms after surgical reconstruction: outcomes after endovascular repair of symptomatic versus asymptomatic patients. AB - PURPOSE: To compare perioperative and follow-up outcomes of symptomatic versus asymptomatic patients following endovascular repair of anastomotic pseudoaneurysms (APAs) of the abdominal aorta and iliac arteries. METHODS: We retrospectively evaluated 17 patients (two women), with a mean age of 66.2 years (range 30-83 years). Endovascular treatment was performed in ten symptomatic, and seven asymptomatic patients electively. Data included technical success, perioperative (within 30 days) mortality and morbidity, as well as stent graft related complications, reinterventions, and survival in follow-up. RESULTS: Bifurcated (n = 13), aortomonoiliac (n = 3) endoprosthesis and one aortic cuff were implanted with a primary technical success rate of 100%. The overall in hospital mortality and morbidity rate was 11.8% and 35.3%. The mean survival was 36.5 (range 0-111) months. There was a clear trend toward a lower overall survival within hospital and at one and three years for symptomatic patients compared to asymptomatic patients. (47.7 (CI: 0-138.8) versus 52.6 (CI: 28.5 76.8) months (p = 0.274)). During follow-up, late stent graft related complications were observed in six patients (35.3%) necessitating eight endovascular reinterventions. Additional three patients with primary fistulas between the APA and the intestine were treated by late surgical revision. CONCLUSION: Endovascular therapy of APAs represents a considerable alternative to open surgical repair. Short proximal anchoring zones still pose a risk for endoleaks and unintentional overstenting of side branches with commercially available devices, but this might be overcome by use of fenestrated and branched stent grafts in elective cases. PMID- 21536398 TI - Temporal analyses of the distribution and diversity of Salmonella in natural biofilms. AB - The diversity and distribution of salmonellae in freshwater biofilms were analyzed at a fine scale (i.e. in 20 locations from a 324 cm(2) area) for two sites in San Marcos, TX. A concrete storm water overflow channel (City Park) was sampled 4 times and a concrete surface in the spring-fed headwaters of the San Marcos River (Spring Lake) 5 times between April and September 2009, and each biofilm sample analyzed by a combination of traditional enrichment methods and molecular techniques. PCR detection of the invA gene, that encodes a protein of a type III secretion system present in salmonellae, after semi-selective enrichment of salmonellae was achieved in biofilms from all 20 locations at the City Park site, with locations generally being positive 2-3 times out of 4 sampling times for a total of 59% positive samples. InvA gene fragment detection in biofilms was less frequent for the 5 sampling times and 20 locations from the Spring Lake site (18% of all samples), with 1 sampling time being entirely negative and 8 locations remaining negative throughout the study. Rep-PCR fingerprinting of 491 Salmonella isolates obtained from both sites resulted in 30 distinct profiles, with 26 and 7 profiles retrieved from City Park and Spring Lake samples, respectively, and thus with 3 profiles present at both sites, and multiple strains frequently obtained from single locations at both sites. The composition of Salmonella strains in the area analyzed changed in time with large differences between early (April, June) and late sampling times (September) within and among sites, except for one strain (S12) that was present at almost all sampling times at both sites, though often at different locations within the area analyzed. These results demonstrate the presence of salmonellae in natural biofilms and a significant micro-heterogeneity with differences in diversity and persistence of salmonellae. PMID- 21536399 TI - "Code STEMI" protocol helps in achieving reduced door-to-balloon times in patients presenting with acute ST-segment elevation myocardial infarction during off-hours. AB - BACKGROUND: Door-to-balloon (D2B) time is conceived as a crucial parameter for evaluating the quality of acute ST-segment elevation myocardial infarction (STEMI) care. Ideally, primary percutaneous intervention should be performed within 90 min of hospital arrival. OBJECTIVES: We sought to determine the impact of emergency physician-activated "Code STEMI" protocol on door-to-balloon times during off-hours. METHODS: Patients were divided into two study groups: one group consisted of 27 STEMI patients who presented during off-hours in the pre-Code STEMI period (January to December 2006) and the second group consisted of 60 STEMI patients admitted during off-hours when Code STEMI was fully operational (January 2007 to December 2008). The primary objective was to compare median D2B times in both the study groups. Secondary parameters of interest included the individual components of D2B time, peak serum troponin levels, peak creatine kinase total levels, all-cause in-hospital mortality, 6-month all-cause mortality, and 12-month all-cause mortality. RESULTS: With the implementation of "Code STEMI" protocol, the median D2B time during off-hours dropped to 77 min (interquartile range [IQR] 67-95), representing a 52-min improvement (p = 0.0001). ECG-to-catheterization laboratory time demonstrated absolute reduction of 16 min. Median peak troponin-I levels dropped from 62 ng/mL (IQR 23-142) to 25 ng/mL (IQR 7-43; p < 0.002). No statistically significant differences were perceived in all-cause mortality among the study groups. CONCLUSIONS: Implementation of "Code STEMI" protocol at our institution significantly reduced D2B times for STEMI during off-hours. PMID- 21536400 TI - The impact of emergency department overcrowding on resident education. AB - BACKGROUND: Few studies have evaluated the effect of Emergency Department (ED) overcrowding on resident education. OBJECTIVES: To determine the impact of ED overcrowding on Emergency Medicine (EM) resident education. MATERIALS AND METHODS: A prospective cross-sectional study was performed from March to May 2009. Second- and third-year EM residents, blinded to the research objective, completed a questionnaire at the end of each shift. Residents were asked to evaluate the educational quality of each shift using a 10-point Likert scale. Number of patients seen and procedures completed were recorded. Responses were divided into ED overcrowding (group O) and non-ED overcrowding (group N) groups. ED overcrowding was defined as >2 h of ambulance diversion per shift. Questionnaire responses were compared using Mann-Whitney U tests. Number of patients and procedures were compared using unpaired T-tests. RESULTS: During the study period, 125 questionnaires were completed; 54 in group O and 71 in group N. For group O, the median educational value score was 8 (interquartile range [IQR] 7-10), compared to 8 (IQR 8-10) for group N (p = 0.24). Mean number of patients seen in group O was 12.3 (95% confidence interval [CI] 11.4-13.2), compared to 13.9 (95% CI 12.7-15) in group N (p = 0.034). In group O, mean number of procedures was 0.9 (95% CI 0.6-1.2), compared to 1.3 (95% CI 1-1.6) in group N (p = 0.047). CONCLUSIONS: During overcrowding, EM residents saw fewer patients and performed fewer procedures. However, there was no significant difference in resident perception of educational value during times of overcrowding vs. non overcrowding. PMID- 21536401 TI - Analysis of radiation exposure in trauma patients at a level I trauma center. AB - BACKGROUND: Trauma patients are exposed to potentially high levels of low-dose radiation during radiologic studies. OBJECTIVES: To assess the cumulative effective dose (CED) of radiation exposure (RE) in 177 successive patients admitted to a trauma service from January 1 through February 28, 2006. RESULTS: Patients received a total of 1505 radiographs and 400 computed tomography (CT) scans in the study period. The CED was 14.56 mSv (0.97 mSv radiographs, 13.59 mSv CT scans) per patient total length of stay (LOS). CED averaged 8.66 mSv in the first hour and 11.76 mSv in the first 24 h after arrival. The most commonly performed CT scan was brain (n = 147), followed by abdomen and pelvis (n = 80), and cervical spine (n = 69). CT scans of the brain and cervical spine were the most commonly performed combined imaging tests (35%). Twelve percent of patients received no radiographs, and 15% received no CT scans. Six or more CT scans were done in 6% of patients. RE increased with longer LOS (> 6 days vs. 3-5 days vs. 1 day, p < 0.05). "Pan-scans" (a combination of CTs of the brain, cervical spine, chest, abdomen, and pelvis) were done in 13% (n = 23) of patients. There was a higher total RE from CT scans (25.09 mSv +/- 19.48 mSv vs. 4.93 mSv +/- 14.20 mSv) in patients with injury severity score (ISS) > 9 vs. <= 9 ( p < 0.0001). First hour and first 24-h RE rates from radiographs were lower in patients younger than 15 years vs. 15-45 years and older-than-45-year age cohorts (p < 0.05). CONCLUSIONS: In this study, CED was 14.56 mSv per patient. CT scans accounted for 21% of radiologic studies and 93% of CED. There was a higher CED rate in patients with ISS > 9 and longer LOS. PMID- 21536402 TI - A comparison of female and male adolescent victims of violence seen in the emergency department. AB - BACKGROUND: Violence is a leading cause of injury and death among adolescents. Reports indicate increasing incidence of violent injuries among adolescent females, but have not described characteristics of or charting completeness for these assault victims in the emergency department (ED). OBJECTIVES: To compare demographic and injury-related characteristics of assaulted urban adolescent females and males presenting to an ED; and to compare completeness of hospital coding for intentionality of females' and males' injuries. METHODS: Retrospective, cross-sectional analysis of potentially violent injuries (identified by E-codes and chart review) among urban youth presenting to a city's only level I trauma center. Demographics, injury characteristics, and chart- vs. hospital-determined intentionality were described with proportions and relative risks. RESULTS: E-code search resulted in 828 charts with injury diagnoses; 385 were determined by chart review to represent violent injuries (150 females, 235 males). Female victims had similar race, age, and socioeconomic status to males. Females' injuries were more likely to be documented as caused by a single person, by someone known to them, and at home. Females were less likely to be injured by weapons or in a public space. Females' charts were more likely to contain information about the circumstances of injury. Intentionality was equally likely to be miscoded for females and males. CONCLUSIONS: Adolescent female victims of community violence presenting to an urban ED have different assault characteristics from males. Females' charts have less missing information. A high percentage of all charts have assault intentionality miscoded, suggesting that E code-based violence surveillance in this population may not be accurate. PMID- 21536403 TI - Should the placement of carbon monoxide (CO) detectors be influenced by CO's weight relative to air? AB - BACKGROUND: Numerous states and localities have recently passed legislation mandating the installation and use of residential carbon monoxide (CO) detectors/alarms. Interestingly, there seems to be confusion about the optimal placement, if any, of CO alarms inside the home. OBJECTIVES: It was the goal of this study to demonstrate the behavior of CO in air and to help provide a data based recommendation for CO alarm placement. METHODS: CO was calculated to be slightly lighter than air. An 8-foot-tall airtight Plexiglas chamber was constructed and CO monitors placed within at the top, middle, and bottom. CO test gas (15 L, 3000 parts per million) was infused at each of the three heights in different trials and CO levels measured over time. RESULTS: Contrary to a significant amount of public opinion, CO did not layer on the floor, float at the middle of the chamber, or rise to the top. In each case, the levels of CO equalized throughout the test chamber. It took longer to equalize when CO was infused at the top of the chamber than the bottom, but levels always became identical with time. CONCLUSIONS: As would have been predicted by the Second Law of Thermodynamics, CO infused anywhere within the chamber diffused until it was of equal concentration throughout. Mixing would be even faster in the home environment, with drafts due to motion or temperature. It would be reasonable to place a residential CO alarm at any height within the room. PMID- 21536405 TI - [The surgical safety checklist reduces postoperative complications: that's true but we should now implement its use widely]. PMID- 21536404 TI - Long-term dilatation of polyester and expanded polytetrafluoroethylene tube grafts after open repair of infrarenal abdominal aortic aneurysms. AB - OBJECTIVES: Since 1995, expanded polytetrafluoroethylene (ePTFE) grafts have been implemented in open surgical repair (OSR) of abdominal aortic aneurysms (AAA) and are supposed to show less dilatation than polyester grafts. This study examined differences in graft dilatation and clinical outcome. METHODS: This single-center long-term, prospective randomized study monitored 99 consecutive patients after OSR of AAA. Implanted were 90 tube ePTFE Gore-Tex Stretch grafts, 56 tube Dacron grafts (Uni-Graft KDV, polyester, B. Braun, knitted), and 51 tube Dacron grafts (Gelseal Plus, polyester, Vascutek, triaxial knitted). Follow-up with ultrasound examination was performed at discharge, at 12 months, and at 6 years. RESULTS: Patients were a mean age of 67 years. Thirty-day mortality was 2.5% (n = 5 of 199), without significant differences among the groups. The Kaplan-Meier analysis showed 5-year survivals of 0.82 (ePTFE/Gore), 0.81 (polyester/Braun), and 0.83 (polyester/Vascutek). Mean +/- standard deviation dilatation of the midgraft segment was 1% +/- 5% (ePTFE/Gore), 10% +/- 9% (polyester/Braun), and 7% +/- 8% (polyester/Vascutek) (P <= .001) at discharge; 8% +/- 11% (ePTFE/Gore), 24% +/- 7% (polyester/Braun), and 20% +/- 13% (polyester/Vascutek; P <= .001) after 12 months; and 19% +/- 21% (ePTFE/Gore), 33% +/- 22% (polyester/Braun), and 23% +/- 19% (polyester/Vascutek; (P <= .001) after 6 years. No graft failure or rupture occurred. Graft patency was 100%. CONCLUSIONS: After a mean implantation of 6 years, the ePTFE/Gore, polyester/Braun, and polyester/Vascutek tube grafts presented with significant differences. The ePTFE grafts showed a stronger resistance against dilatation than the two types of polyester grafts. Owing to similar perioperative and postoperative courses, no advantage could be identified in any group concerning the overall outcome. Vascular implants for OSR of AAA made of ePTFE and polyester are safe, even after a long implantation time. Therefore, the choice of the suitable graft does not depend on its postimplantation dilative characteristics. The outcome is not likely to be connected with dilatation of the implanted graft, because a causal connection between graft dilatation and death cannot be made. The study does not offer a basis for the preference of one of the three graft types. Nevertheless, continuous ultrasound examinations should be performed after implantation of an aortic tube graft to identify possible problems arising from changes in the graft and the residual vascular branches over time. PMID- 21536406 TI - Extracapsular cataract removal pioneered by Sushruta. PMID- 21536407 TI - The role of vocabulary, working memory and inference making ability in reading comprehension in Down syndrome. AB - Thirteen children and young adults with Down syndrome (DS) completed tests of language and reading and their performance was compared to that of three control groups. Reading comprehension was confirmed to be a specific deficit in DS and found to be strongly correlated with underlying language skills. Although reading comprehension was more strongly related to language ability in the DS group, this was shown to be a function of more advanced word recognition rather than a characteristic of DS per se. Individuals with DS were found to have greater difficulty with inferential comprehension questions than expected given their overall comprehension ability and the reading profile associated with DS was found to be similar to that of children known as poor comprehenders. It is recommended that oral language training programs, similar to those that have been shown to improve reading comprehension in poor comprehenders, be trialed with children who have DS. PMID- 21536408 TI - Postural responses to a suprapostural visual task among children with and without developmental coordination disorder. AB - We sought to determine the effects of varying the perceptual demands of a suprapostural visual task on the postural activity of children with developmental coordination disorder (DCD), and typically developing children (TDC). Sixty-four (32 per group) children aged between 9 and 10 years participated. In a within participants design, each child performed a signal detection task at two levels of difficulty, low (LD) and high difficulty (HD). During performance of the signal detection tasks we recorded positional variability of the head and torso using a magnetic tracking system. We found that task difficulty had a greater effect on task performance among the TDC group than among children with DCD. Overall positional variability was greater the DCD group than in the TDC group. In the TDC group, positional variability was reduced during performance of the HD task, relative to sway during performance of the LD task. In the DCD group, positional variability was greater during performance of the HD task than during performance of the LD task. In children, DCD may reduce the strength of functional integration of postural activity with the demands of suprapostural visual tasks. PMID- 21536409 TI - The influence of manifest strabismus and stereoscopic vision on non-verbal abilities of visually impaired children. AB - This research was conducted in order to examine the influence of manifest strabismus and stereoscopic vision on non-verbal abilities of visually impaired children aged between 7 and 15. The sample included 55 visually impaired children from the 1st to the 6th grade of elementary schools for visually impaired children in Belgrade. RANDOT stereotest and polaroid glasses were used for the examination of stereoscopic vision, while Cover test and Hirschberg's pupils reflex test were used for the evaluation of strabismus. In the area of non-verbal abilities was evaluated visual discrimination, visuomotor integration, constructive praxia, visual memory, strategy formation, non-verbal reasoning and the representational dimension of drawings. Subtests of ACADIA test of developmental abilities were used for the evaluation of non-verbal abilities (Atkinson et al., 1972). Statistically significant relations between strabismus and constructive praxia (p=0.009), visual memory (p=0.037), strategy formation (0.040) and the quality of drawings were determined by the results analysis. According to our findings, children with divergent strabismus achieve the best results. Children with stereoscopic vision generally achieve better results in all the examined areas of non-verbal abilities, and statistically significant relations were determined in the areas of visuomotor coordination (0.002), constructive praxia (0.026) and non-verbal reasoning (0.015), which are directly connected to visuospatial abilities. Children with convergent strabismus achieve significantly lower results in the areas of constructive praxia, visual memory, strategy formation and representational dimension of drawings, and children with the lack of stereoscopic vision--in the areas of visuomotor integration, constructive praxia and non-verbal reasoning. PMID- 21536411 TI - P-values are misunderstood, but do not confound. PMID- 21536412 TI - Is there an ideal way to discontinue the ketogenic diet? AB - It is unclear what the ideal weaning speed of the ketogenic diet should be and the resultant risk of seizure worsening. A retrospective chart review was performed of children who discontinued the ketogenic diet at Johns Hopkins Hospital from January 2000 to June 2010. Speed of discontinuation was categorized into immediate (<1 week), quick (1-6 weeks), or slow (>6 weeks) rates. One hundred and eighty-three children were identified. Children with both a longer diet duration (p=0.004) and lower seizure frequency (p<0.001) were weaned more slowly by our group. There was no significant difference in the incidence of seizures worsening between discontinuation rates. However, there was an increased risk of seizures worsening in those specifically with a 50-99% seizure reduction (30% vs. 8%, p<0.0001) and for that level of seizure improvement, in those who were receiving more anticonvulsants (1.4 vs. 0.8, p=0.01). In summary, there does not appear to be an increased risk of seizure exacerbation with rapid ketogenic diet discontinuations. Those who improved 50-99% and were receiving more anticonvulsants were at the highest risk overall. Discontinuing the ketogenic diet over weeks rather than months appears safe. PMID- 21536413 TI - POMC and TP53 genetic variability and risk of basal cell carcinoma of skin: Interaction between host and genetic factors. AB - BACKGROUND: Basal cell carcinoma (BCC) of the skin is the most common neoplasm among the Caucasian population of the western world. Ultraviolet (UV) radiation induced p53 activation promotes cutaneous pigmentation by increasing transcriptional activity of pro-opiomelanocortin (POMC) in the skin. Induction of POMC/alpha-melanocyte-stimulating hormone (alpha-MSH) activates the melanocortin 1 receptor (MC1R), resulting in skin pigmentation. The tumor suppressor p53 is a key player in stress responses that preserve genomic stability, responding to a variety of insults including DNA damage, hypoxia, metabolic stress and oncogene activation. Malfunction of the p53 pathway is an almost universal hallmark of human tumors. Polymorphisms in the gene encoding p53 (TP53) alter its transcriptional activity, which in turn may influence the UV radiation-induced tanning response. OBJECTIVE: The aim of the present work is to test association between POMC and TP53 genetic variability, the possible interplay with host factors and the risk of basal cell carcinoma of skin. METHODS: We covered the variability of the two genes we used 17 tagging polymorphisms in 529 BCC cases and 532 healthy controls. We have also tested the possible interactions between the genetic variants and three known risk factors for BCC: skin complexion, sun effect and skin response to sun exposure. RESULTS: We did not observe any statistically significant association between SNPs in these two genes and BCC risk overall, nor interactions of SNPs with known BCC risk factors. However we found that, in the group of subjects with lower sun exposure, carriers of one copy of the C allele of the TP53 SNP rs12951053 had a decreased risk of BCC (OR=0.28, 95% CI 0.12-0.62, P=0.002). CONCLUSIONS: We have observed that the interplay of an environmental risk factor and one polymorphism in TP53 gene could modulate the risk of BCC. PMID- 21536414 TI - 1H and 13C solution- and solid-state NMR investigation into wax products from the Fischer-Tropsch process. AB - (1)H and (13)C solid- and solution-state NMR have been used to characterise waxes produced in the Fischer-Tropsch reaction, using Co-based catalysts either unpromoted or promoted with approximately 1 wt% of either cerium or rhenium. The aim was to measure average structural information at the submolecular level of the hydrocarbon waxes produced, along with identification of the minor products, such as oxygenates and olefins, which are typically observed in these waxes. A parameter of key interest is the average number of carbon atoms within the hydrocarbon chain (N(C)). A wax prepared using an unpromoted Co/Al(2)O(3) catalyst had N(C)~20, whilst waxes made using rhenium- or cerium-promoted Co/Al(2)O(3) catalysts were found to have N(C)~21. All three samples contained small amounts of oxygenates and alkenes. The subtle differences found in the waxes, in particular the minor species produced, demonstrate that the different promoters have different effects during the reaction, with the Re-promoted catalyst producing the fewest by-products. It is shown in (13)C solid-state NMR spectra that for that for longer chain (compared to the lengths of chain in previous studies) waxes that the lack of resolution and the complexities added by the differential cross-polarisation (CP) dynamics mean that it is difficult to accurately determine N(C) from this approach. However the N(C) determined by (13)C CP magic angle spinning NMR is broadly consistent with the more accurate solution approaches used and suggest that the wax characteristics do not change in solution. On this basis an alternative approach for determining N(C) is suggested based on (1)H solution state NMR that provides a higher degree of accuracy of the chain length as well as information on the minor constituents. PMID- 21536415 TI - Anisotropy of hyperfine interactions as a tool for interpretation of NMR spectra in magnetic materials. AB - Approach for interpretation of nuclear magnetic resonance (NMR) spectra in magnetic materials is presented, consisting in employing the anisotropy of hyperfine interaction. The anisotropic parts of hyperfine magnetic fields on (57)Fe nuclei are calculated ab initio for a model example of lithium ferrite and utilized to assign the experimental NMR spectral lines to iron sites in the crystal structure. PMID- 21536416 TI - Apatite-forming ability of bioactive poly(l-lactic acid)/grafted silica nanocomposites in simulated body fluid. AB - Bioactive PLLA/surface-grafted silica (g-SiO2) nanocomposite scaffolds were fabricated by solid-liquid phase separation method. And solid PLLA/g-SiO2 nanocomposite films were prepared by solution casting method. A series of parallel tube-like morphology and internal ladder-like structure of PLLA/g-SiO2 nanocomposite scaffolds were observed by SEM. The formation of bone-like apatite in the simulated body fluid (SBF) was characterized by XRD, IR, SEM, EDS and weight measurement. The silica incorporation favors the formation of apatite. The growth of apatite with immersion time is found on the surfaces of both the PLLA/g SiO2 nanocomposite scaffolds and the films. The potential mechanism is that silanol groups of g-SiO2 in the nanocomposites serve as nucleation sites for the formation of bone-like apatite crystals. PMID- 21536417 TI - Synthesis of a novel zwitterionic biodegradable poly (alpha,beta-L-aspartic acid) derivative with some L-histidine side-residues and its resistance to non-specific protein adsorption. AB - A novel zwitterionic polypeptide derivative, denoted as His-PAsp/PAsp, was successfully synthesized by amidation of Poly (alpha,beta-L-aspartic acid) with L histidine methyl ester. Turbidity, zeta potential and 1H NMR measurements were used to study the aggregation behaviors of His-PAsp/PAsp under different pH values. The modified polypeptide derivative composed of electro-negatively carboxylic and electro-positively imidazole residues randomly so as to bear opposite charges at pH values above or below the isoelectric point. When the zwitterionic polypeptide was coated on silicon wafer as a model substrate material, the absorption resistance of fibrinogen, a blood protein resulting in the blood coagulation cascade, on the coated surface was measured. It was found that the adsorption amount of fibrinogen on the polypeptide-coated surface depended on the dose of the polypeptide on silicon wafer. Obvious resistance of the fibrinogen adsorption on the polypeptide-coated surface was observed. Since its good biodegradability and superior anti-protein-fouling property, this pH responsive zwitterionic polypeptide is a promising candidate for surface modification in many biomedical applications, including medical implants, drug delivery carriers, and biosensors. PMID- 21536418 TI - Antimicrobial effects of quaternary phosphonium salt intercalated clay minerals on Escherichia coli and Staphylococci aureus. AB - The aim of this research was to determine the antimicrobial properties and influence factors of four clay minerals intercalated by quaternary phosphonium salt (tetradecyl tributyl phosphonium bromide, TDTB) on antimicrobial effects. Escherichia coli (E. coli) and Staphylococci aureus (S. aureus) were chosen for Minimal Inhibitory Concentration (MIC) tests to evaluate the antimicrobial activities of organ-clay minerals. The properties of organ-clay minerals were analyzed by FTIR, XRD, TEM, Z-Average and Zeta potential, and the releasing amount of TDTB into the broth was measured by ICP. The results showed that montmorillonites-TDTB inhibited the growth of E. coli and S. aureus, and the MICs were 200 +/- 20 and 80 +/- 15 mg/L, respectively. The amount of TDTB released into the broth was 3.42 +/- 0.71%. According to the properties of organ-clay mineral, it was indicated that the antimicrobial activities of organ-clay mineral were the synergic effect of the releasing amount of TDTB, Zeta potential, particle size and distribution. The organ-clay mineral with the larger releasing amount of TDTB, the higher Zeta potential, the same particle size with bacterial size and the narrower size distribution exhibited better antimicrobial activity. The present study demonstrated the properties of organ-clay minerals effected their antimicrobial activities, provided theoretically guidance to promote the antimicrobial activity of clay minerals. PMID- 21536419 TI - A nanobeads amplified QCM immunosensor for the detection of avian influenza virus H5N1. AB - As a potential pandemic threat to human health, there has been an urgent need for rapid detection of the highly pathogenic avian influenza (AI) H5N1 virus. In this study, magnetic nanobeads amplification based quartz crystal microbalance (QCM) immunosensor was developed as a new method and application for AI H5N1 virus detection. Polyclonal antibodies against AI H5N1 virus surface antigen HA (Hemagglutinin) were immobilized on the gold surface of the QCM crystal through self-assembled monolayer (SAM) of 16-mercaptohexadecanoic acid (MHDA). Target H5N1 viruses were then captured by the immobilized antibodies, resulting in a change in the frequency. Magnetic nanobeads (diameter, 30nm) coated with anti-H5 antibodies were used for further amplification of the binding reaction between antibody and antigen (virus). Both bindings of target H5N1 viruses and magnetic nanobeads onto the crystal surface were further confirmed by environmental scanning electron microscopy (ESEM). The QCM immunosensor could detect the H5N1 virus at a titer higher than 0.0128 HA unit within 2h. The nanobeads amplification resulted in much better detection signal for target virus with lower titers. The response of the antibody-antigen (virus) interaction was shown to be virus titer-dependent, and a linear correlation between the logarithmic number of H5N1 virus titers and frequency shift was found from 0.128 to 12.8 HA unit. No significant interference was observed from non-target subtypes such as AI subtypes H3N2, H2N2, and H4N8. The immunosensor was evaluated using chicken tracheal swab samples. This research demonstrated that the magnetic nanobeads amplification based QCM immunosensor has a great potential to be an alternative method for rapid, sensitive, and specific detection of AI virus H5N1 in agricultural, food, environmental and clinical samples. PMID- 21536420 TI - The enhancement of neural growth by amino-functionalization on carbon nanotubes as a neural electrode. AB - This paper reports the success of amino-functionalization on multi-walled carbon nanotubes (MWCNTs) to promote neuronal cells growth on MWCNT electrode for extracellular recording, attributed to the formation of positive charge of NH(2) molecules on their surfaces. Besides, the surface of MWCNT electrode becomes hydrophilic after amino-functionalization (AF-MWCNTs) which can enhance electrical conductivity because of lower MWCNT/electrolyte interfacial impedance and higher interfacial capacitance. Durability tests show that electrical characteristics of the MWCNTs treated by 2 wt% 1,4-diaminobutane solution (2 wt% AF-MWCNTs) can last for at least six months in air ambient. The neural recording of crayfish shows that 2 wt%-AF-MWCNTs can provide better capability on detecting action potentials of caudal photoreceptor (CPR) interneuron compared to suction glass pipette from the evidence of a higher S/N ratio (126 versus 23). The amino functionalized MWCNT electrode is feasible for long-term recording application according to the results of biocompatibility tests. As the MWCNTs were directly synthesized on Si-based substrates by catalyst-assisted thermal chemical vapor deposition (CVD) at a low temperature (400 degrees C), these self-aligned MWCNT electrodes could be friendly implemented in integrated circuits fabrications. PMID- 21536422 TI - Electrochemical aptasensor based on the dual-amplification of G-quadruplex horseradish peroxidase-mimicking DNAzyme and blocking reagent-horseradish peroxidase. AB - A simple electrochemical aptasensor for sensitive detection of thrombin was fabricated with G-quadruplex horseradish peroxidase-mimicking DNAzyme (hemin/G quadruplex system) and blocking reagent-horseradish peroxidase as dual signal amplification scheme. Gold nanoparticles (nano-Au) were firstly electrodeposited onto single wall nanotube (SWNT)-graphene modified electrode surface for the immobilization of electrochemical probe of nickel hexacyanoferrates nanoparticles (NiHCFNPs). Subsequently, another nano-Au layer was electrodeposited for further immobilization of thrombin aptamer (TBA), which later formed hemin/G-quadruplex system with hemin. Horseradish peroxidases (HRP) then served as blocking reagent to block possible remaining active sites and avoided the non-specific adsorption. In the presence of thrombin, the TBA binded to thrombin and the hemin released from the hemin/G-quadruplex electrocatalytic structure, increasing steric hindrance of the aptasensor and decomposing hemin/G-quadruplex electrocatalytic structure, which finally decreased the electrocatalytic efficiency of aptasensor toward H(2)O(2) in the presence of NiHCFNPs with a decreased electrochemical signal. On the basis of the synergistic amplifying action, a detection limit as low as 2 pM for thrombin was obtained. PMID- 21536421 TI - Urea potentiometric enzymatic biosensor based on charged biopolymers and electrodeposited polyaniline. AB - A potentiometric biosensor based on urease was developed for the quantitative determination of urea concentration in aqueous solutions for biomedical applications. The urease was either physisorbed onto an electrodeposited polyaniline film (PANI), or immobilized on a layer-by-layer film (LbL) assembled over the PANI film, that was obtained by the alternate deposition of charged polysaccharides (carboxymethylpullulan (CMP) and chitosan (CHI)). In the latter case, the urease (Urs) enzyme was either physically adsorbed or covalently grafted to the LbL film using carbodiimide coupling reaction. Potentiometric responses of the enzymatic biosensors were measured as a function of the urea concentration in aqueous solutions (from 10(-6) to 10(-1) mol L(-1) urea). Very high sensitivity and short response time were observed for the present biosensor. Moreover, a stability study showed a higher stability over time for the potentiometric response of the sensor with the enzyme-grafted LbL film, testifying for the protective nature of the polysaccharide coating and the interest of covalent grafting. PMID- 21536423 TI - Formation of G-quadruplex-hemin DNAzyme based on human telomere elongation and its application in telomerase activity detection. AB - In the present study, a chemiluminescence method for sensitive detection of human telomerase activity was developed based on the formation of G-quadruplex-hemin DNAzyme. In the presence of telomerase, the telomerase substrate (TS) primer elongated and a long single-strand DNA containing the telomere repeat units (TTAGGG)n was formed. When K(+) was introduced, the telomere repeat units could form G-quadruplex and then combined with hemin to form DNAzymes which could stimulate the generation of chemiluminescence (CL) in the presence of luminol and H(2)O(2). The amount of telomerase elongation product was controlled by the content of telomerase extracted from HeLa cells, so the amount of DNAzymes and the intensity of chemiluminescence signal were all related to the number of HeLa cells. Using this simple method, the telomerase activity extracted from 100 cultured cancer cells could be detected without the polymerase chain reaction (PCR) amplification of telomerase elongated product. PMID- 21536424 TI - Rapid on-site detection of Acidovorax avenae subsp. citrulli by gold-labeled DNA strip sensor. AB - Acidovorax avenae subsp. citrulli (AAC) is one of the most harmful diseases in cucurbit production. A rapid and sensitive DNA strip sensor was constructed based on gold nanoparticle-labeled oligonucleotide probes for the detection of AAC. Both the qualitative and semi-quantitative detections of target DNA were successfully achieved using the developed DNA strip sensor. The qualitative limit of detection (LOD) of the strip sensor was determined as 4 nM. The LOD for the semi-quantitative detection was calculated to be 0.48 nM in the range of 0-10 nM. The genomic DNA was detected directly using the DNA strip sensor without any further treatment. This DNA strip sensor is a potentially useful tool for rapid on-site DNA screening. PMID- 21536425 TI - A "turn-on" fluorescent copper biosensor based on DNA cleavage-dependent graphene quenched DNAzyme. AB - A novel and promising "turn-on" fluorescent Cu(2+) biosensor is designed based on graphene-DNAzyme catalytic beacon. Due to the essential surface and quenching properties of two-dimensional graphene, it can function as both "scaffold" and "quencher" of the Cu(2+)-dependent DNAzyme, facilitating the formation of self assembled graphene-quenched DNAzyme complex. However, Cu(2+)-induced catalytic reaction disturbs the graphene-DNAzyme conformation, which will produce internal DNA cleavage-dependent effect. In this case, the quenched fluorescence in graphene-DNAzyme is quickly recovered to a large extent in 15 min. Compared with common DNAzyme-based sensors, the presented graphene-based catalytic beacon greatly improves the signal-to-background ratio, hence increasing the sensitivity (LOD=0.365 nM). Furthermore, the controllable DNA cleavage reaction provides an original and alternative internal method to regulate the interaction between graphene and DNA relative to the previous external sequence-specific hybridization-dependent regulation, which will open new opportunities for nucleic studies and sensing applications in the future. PMID- 21536426 TI - More than a feeling: discovering, understanding, and influencing mechanosensing pathways. AB - The ability of cells to extract biophysical information from their extracellular environment and convert it to biochemical signals is known as mechanotransduction. Here we detail three passive, 'inside-out' mechanotransduction mechanisms with an emphasis on the mechanosensing pathways involved in creating these signal: Rho/ROCK, stretch-activated channels, and 'Molecular Strain Gauges.' We also examine how molecular tools have been used to perturb these pathways to better understand their interconnectivity. However, perturbing pathways may have unintended confounding effects, which must also be addressed. By discovering and understanding mechanosensitive pathways, the ability to influence them for clinical applications increases. PMID- 21536428 TI - Cytoplasmic polyadenylation and translational control. AB - Cytoplasmic polyadenylation is the process by which dormant, translationally inactive mRNAs become activated via the elongation of their poly(A) tails in the cytoplasm. This process is regulated by the conserved cytoplasmic polyadenylation element binding (CPEB) protein family. Recent studies have advanced our understanding of the molecular code that dictates the timing of CPEB-mediated poly(A) tail elongation and the extent of translational activation. In addition, evidence for CPEB-independent mechanisms has accumulated, and the breath of biological circumstances in which cytoplasmic polyadenylation plays a role has expanded. These observations underscore the versatility of CPEB as a translational regulator, and highlight the diversity of cytoplasmic polyadenylation mechanisms. PMID- 21536427 TI - mRNA localization: assembly of transport complexes and their incorporation into particles. AB - Localization of mRNAs to subcellular domains can enrich proteins at sites where they function. Coordination with translational control can ensure that the encoded proteins will not appear elsewhere, an important property for factors that control cell fate or body patterning. Here I focus on two aspects of mRNA localization. One is the question of how mRNAs that undergo directed transport by a shared mechanism are bound to the transport machinery, and why localization signals from these mRNAs have very diverse sequences. The second topic concerns the role of particles, in which localized mRNAs often appear. Recent evidence highlights the importance of such assemblies, and the possibility that close association of mRNAs confers community effects and a novel form of regulation. PMID- 21536429 TI - Function follows form: understanding brain function from a genetic perspective. PMID- 21536430 TI - Modeling anaerobic digestion of microalgae using ADM1. AB - The coupling between a microalgal pond and an anaerobic digester is a promising alternative for sustainable energy production by transforming carbon dioxide into methane using solar energy. In this paper, we demonstrate the ability of the original ADM1 model and a modified version (based on Contois kinetics for the hydrolysis steps) to represent microalgae anaerobic digestion. Simulations were compared to experimental data of an anaerobic digester fed with Chlorella vulgaris. The modified ADM1 fits adequately the data for the considered 140 day experiment encompassing a variety of influent load and flow rates. It turns out to be a reliable predictive tool for optimising the coupling of microalgae with anaerobic digestion processes. PMID- 21536431 TI - Influence of membrane fouling reducers (MFRs) on filterability of disperse mixed liquor of jet loop bioreactors. AB - The effects of membrane fouling reducers (MFRs) (the cationic polyelectrolyte (CPE) and FeCI(3)) on membrane fouling were studied in a lab-scale jet loop submerged membrane bioreactor (JL-SMBR) system. The optimum dosages of MFRs (CPE dosage=20 mg g(-1)MLSS, FeCI(3) dosage=14 mg g(-1)MLSS) were continuously fed to JL-SMBR system. The soluble and bound EPS concentrations as well as MLSS concentration in the mixed liquor of JL-SMBR were not changed substantially by the addition of MFRs. However, significant differences were observed in particle size and relative hydrophobicity. Filtration tests were performed by using different membrane types (polycarbonate (PC) and nitrocellulose mixed ester (ME)) and various pore sizes (0.45-0.22-0.1 MUm). The steady state fluxes (J(ss)) of membranes increased at all membranes after MFRs addition to JL-SMBR. The filtration results showed that MFRs addition was an effective approach in terms of improvement in filtration performance for both membrane types. PMID- 21536432 TI - Non-oxime pyrazole based inhibitors of B-Raf kinase. AB - The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor. PMID- 21536433 TI - Norcantharidin analogues with nematocidal activity in Haemonchus contortus. AB - With the major problems with resistance in parasitic nematodes of livestock to anthelmintic drugs, there is an urgent need to develop new nematocides. In the present study, we employed a targeted approach for the design of a series of norcantharidin analogues (n=54) for activity testing against the barber's pole worm (Haemonchus contortus) of small ruminants in a larval development assay (LDA) and also for toxicity testing on nine distinct human cell lines. Although none of the 54 analogues synthesized were toxic to any of these cell lines, three of them (N-octyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B2), N-decyl-7 oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B3) and 4-[(4-methyl)-3-ethyl-2 methyl-5-phenylfuran-10-oxa-4-azatricyclo[5.2.1]decane-3,5-dione (B21) reproducibly displayed 99-100% lethality to H. contortus in LDA, with LD(50s) of 25-40 MUM. The high 'hit rate' (5.6%) indicates that the approach taken here has advantages over conventional drug screening methods. A major advantage of norcantharidin analogues over some other currently available anthelmintics is that they can be produced in one to two steps in large amounts at low cost and high purity, and do not require any additional steps for the isolation of the active isomer. This positions them well for commercial development. PMID- 21536434 TI - N-hydroxy-N'-aminoguanidines as anti-cancer lead molecule: QSAR, synthesis and biological evaluation. AB - The intrinsic pharmacophore model (r(pred)(2) and r(m)(2) of 0.858 and 0.725) has been developed and used as a query to screen in-house built library based on N hydroxy-N'-aminoguanidine (HAG) analogs. The pharmacophoric modeled based HITs were synthesized and evaluated for anticancer activity and cytotoxicity. One of the compounds (15) appeared as promising lead candidate with an IC(50) value of 11 MUM yielded in HL-60 promyelocytic leukemia cells. Compound 15 reveals significantly lower cytotoxicity against HeLa and Vero cell with CC(50) values of more than 100 MUM. PMID- 21536435 TI - Synthesis and in vitro activity of N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5 amine P2X(7) antagonists. AB - Synthesis and biological evaluation of a novel class of substituted N-benzyl-1 (2,3-dichlorophenyl)-1H-tetrazol-5-amine derivatives resulted in the identification of potent P2X(7) antagonists. These compounds were assayed for activity at both the human and rat P2X(7) receptors. On the benzyl moiety, a variety of functional groups were tolerated, including both electron-withdrawing and electron-donating substituents. Ortho-substitution on the benzyl group provided the greatest potency. The ortho-substituted analogs showed approximately 2.5-fold greater potency at human compared to rat P2X(7) receptors. Compounds 12 and 38 displayed hP2X(7)pIC(50)s>7.8 with less than 2-fold difference in potency at the rP2X(7). PMID- 21536436 TI - The identification of new metallo-beta-lactamase inhibitor leads from fragment based screening. AB - The emergence of metallo-beta-lactamases (MBLs) capable of hydrolysing a broad spectrum of beta-lactam antibiotics is particularly concerning for the future treatment of bacterial infections. This work describes the discovery of lead compounds for the development of new inhibitors using a competitive colorimetric assay based on the chromogenic cephalosporin CENTA, and a 500 compound MaybridgeTM library suitable for fragment-based screening. The interactions between identified inhibitory fragments and the active site of the MBL from Klebsiella pneumoniae and Pseudomonas aeruginosa were probed by in silico docking studies. PMID- 21536437 TI - Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis. AB - A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics. PMID- 21536438 TI - Discovery of a nortropanol derivative as a potent and orally active GPR119 agonist for type 2 diabetes. AB - The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development. PMID- 21536439 TI - Chemically modified cellulose fibrous meshes for use as tissue engineering scaffolds. AB - Cellulose and sulfated cellulose fibrous meshes exhibiting robust structural and mechanical integrity in water were fabricated using a combination of electrospinning, thermal-mechanical annealing and chemical modifications. The sulfated fibrous mesh exhibited higher retention capacity for human recombinant bone morphogenetic protein-2 than the cellulose mesh, and the retained proteins remained biologically active for at least 7 days. The sulfated fibrous mesh also more readily supported the attachment and osteogenic differentiation of rat bone marrow stromal cells in the absence of osteogenic growth factors. These properties combined make the sulfated cellulose fibrous mesh a promising bone tissue engineering scaffold. PMID- 21536440 TI - The effect of foot structure on 1st metatarsophalangeal joint flexibility and hallucal loading. AB - The purpose of our study was to examine 1st metatarsophalangeal (MTP) joint motion and flexibility and plantar loads in individuals with high, normal and low arch foot structures. Asymptomatic individuals (n=61), with high, normal and low arches participated in this study. Foot structure was quantified using malleolar valgus index (MVI) and arch height index (AHI). First MTP joint flexibility was measured using a specially constructed jig. Peak pressure under the hallux, 1st and 2nd metatarsals during walking was assessed using a pedobarograph. A one-way ANOVA with Bonferroni-adjusted post hoc comparisons was used to assess between group differences in MVI, AHI, early and late 1st MTP joint flexibility in sitting and standing, peak dorsiflexion (DF), and peak pressure under the hallux, 1st and 2nd metatarsals. Stepwise linear regression was used to identify predictors of hallucal loading. Significant between-group differences were found in MVI (F(2,56)=15.4, p<0.01), 1st MTP late flexibility in sitting (F(2,57)=3.7, p=0.03), and standing (F(2,57)=3.7, p=0.03). Post hoc comparisons demonstrated that 1st MTP late flexibility in sitting was significantly higher in individuals with low arch compared to high arch structure, and that 1st MTP late flexibility in standing was significantly higher in individuals with low arch compared to normal arch structure. Stepwise regression analysis indicated that MVI and 1st MTP joint early flexibility in sitting explain about 20% of the variance in hallucal peak pressure. Our results provide objective evidence indicating that individuals with low arches show increased 1st MTP joint late flexibility compared to individuals with normal arch structure, and that hindfoot alignment and 1st MTP joint flexibility affect hallucal loading. PMID- 21536441 TI - The effect of contralateral training: Influence of unilateral isokinetic exercise on one-legged standing balance of the contralateral lower extremity in adults. AB - PURPOSE: To investigate the effects of unilateral isokinetic exercises on the one legged standing balance of the contralateral lower extremity. SUBJECTS: A volunteer sample of 32 healthy adults (12 men and 20 women) was randomized to training and control groups. METHODS: The training group received unilateral hip isokinetic exercises of the dominant leg for two weeks. Contralateral single-limb balance was measured before and after intervention, including three stability index scores of balance using Biodex Stability System: Anterior-Posterior Stability Index (APSI), Medio-lateral Stability Index (MLSI), and Overall Stability Index (OSI) scores. RESULTS: Comparison of pre-test and post-test data revealed significant improvements in APSI, MLSI, and OSI scores in the training group (p<0.05), but not in the control group. The gains of stability scores from pre- to post-test, were also significantly greater (p<0.05) in the training group than the control group. CONCLUSION: These results suggest that contralateral training with unilateral isokinetic exercises increases the one-legged standing balance of the contralateral limb following a short duration of training. PMID- 21536442 TI - Effects of obesity on the biomechanics of stair-walking in children. AB - Anthropometric characteristics, particularly body mass, are important factors in the development and progression of varus/valgus angular deformities of the knee and have long-term implications including increased risk of osteoarthritis. However, information on how excessive body weight affects the biomechanics of dynamic activities in children is limited. The purpose of this study was to test the hypothesis that during stair-walking lower extremity joint moments normalized to body mass in obese children are greater than those in normal-weight children. Eighteen obese children (10.5+/-1.5 years, 148+/-10cm, 56.6+/-8.4kg) and 17 normal-weight children (10.4+/-1.3 years, 143+/-9cm, 36.7+/-7.5kg) were recruited. A Vicon system and two AMTI force plates were used to record and analyze the kinematics and kinetics of ascending and descending stairs. Significant differences in spatio-temporal, kinematic and kinetic parameters during ascending and descending stairs between obese and normal-weight children were detected. For stair ascent, greater hip abduction moments (+23%; p=0.001) and greater knee extension moments (+20%; p=0.008) were observed. For stair descent, smaller hip extension moment (-52%; p=0.031), and greater hip flexion moments (+25%; p=0.016) and knee extension moments (+15%, p=0.008) were observed for obese subjects. To date, it is unclear if and how the body may adapt to greater joint moments in obese children. Nevertheless, these differences in joint moments may contribute to a cumulative overloading of the joint through adolescence into adulthood, and potentially result in a greater risk of developing knee and hip osteoarthritis. PMID- 21536443 TI - Inexpensive footwear decreases joint loading in elderly women with knee osteoarthritis. AB - Recent literature has highlighted that the flexibility of walking barefoot reduces overload in individuals with knee osteoarthritis (OA). As such, the aim of this study was to evaluate the effects of inexpensive, flexible, non-heeled footwear (Moleca) as compared with a modern heeled shoes and walking barefoot on the knee adduction moment (KAM) during gait in elderly women with and without knee OA. The gait of 45 elderly women between 60 and 70 years of age was evaluated. Twenty-one had knee OA graded 2 or 3 according to Kellgren and Lawrence's criteria, and 24 who had no OA comprised the control group (CG). The gait conditions were: barefoot, Moleca, and modern heeled shoes. Three dimensional kinematics and ground reaction forces were measured to calculate KAM by inverse dynamics. For both groups, the Moleca provided peak KAM and KAM impulse similar to barefoot walking. For the OA group, the Moleca reduced KAM even more as compared to the barefoot condition during midstance. On the other hand, the modern heeled shoes increased this variable in both groups. Inexpensive, flexible, and non-heeled footwear provided loading on the knee joint similar to a barefoot gait and significant overload decreases in elderly women with and without knee OA, compared to modern heeled shoes. During midstance, the Moleca also allowed greater reduction in the knee joint loads as compared to barefoot gait in elderly women with knee OA, with the further advantage of providing external foot protection during gait. PMID- 21536444 TI - The influence of heel height on utilized coefficient of friction during walking. AB - Wearing high heel shoes has been associated with an increased potential for slips and falls. The association between wearing high heels and the increased potential for slipping suggests that the friction demand while wearing high heels may be greater when compared to wearing low heel shoes. The purpose of this study was to determine if heel height affects utilized friction (uCOF) during walking. A secondary purpose of this study was to compare kinematics at the ankle, knee, and hip that may explain uCOF differences among shoes with varied heel heights. Fifteen healthy women (mean age 24.5+/-2.5yrs) participated. Subjects walked at self-selected velocity under 3 different shoe conditions that varied in heel height (low: 1.27cm, medium: 6.35cm, and high: 9.53cm). Ground reaction forces (GRFs) were recorded using a force platform (1560Hz). Kinematic data were obtained using an 8 camera motion analysis system (120Hz). Utilized friction was calculated as the ratio of resultant shear force to vertical force. One-way repeated measures ANOVAs were performed to test for differences in peak uCOF, GRFs at peak uCOF and lower extremity joint angles at peak uCOF. On average, peak uCOF was found to increase with heel height. The increased uCOF observed in high heel shoes was related to an increase in the resultant shear force and decrease in the vertical force. Our results signify the need for proper public education and increased footwear industry awareness of how high heel shoes affect slip risk. PMID- 21536446 TI - Crystal structure, docking study and structure-activity relationship of carborane containing androgen receptor antagonist 3-(12-hydroxymethyl-1,12-dicarba-closo dodecaboran-1-yl)benzonitrile. AB - A potent androgen receptor (AR) antagonist, 3-(12-hydroxymethyl-1,12 dicarba closo-dodecaboran-1-yl)benzonitrile (3a, BA341), contains a p-carborane cage as a hydrophobic pharmacophore. We elucidated the structural properties of 3a by means of single-crystal X-ray diffraction analysis and conducted a docking study of 3a with hAR LBD. The cyano group of 3a formed hydrogen bonds with Gln711 and Arg752 and the hydroxymethyl group did so with Asn705 and Thr877 in hAR LBD. The bulky p carborane cage was accommodated in the hydrophobic pocket of hAR LBD. To understand the structure-activity relationship around the hydroxymethyl group of 3a, we designed, synthesized, and evaluated the biological activities of various novel AR ligands. Since the biological activities of carbonyl compounds 8a, 8b, and 8c were similar to or weaker than those of the parent hydroxyl compounds 3a, 7a, and 7b, it seems to be necessary to have not only a hydrogen bonding acceptor, but also a hydrogen bonding donor adjacent to the hydroxymethyl group of 3a for efficient interaction with hAR LBD. PMID- 21536445 TI - Synthesis and characterization of selective dopamine D2 receptor ligands using aripiprazole as the lead compound. AB - A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D(2-like) dopamine receptors. These compounds also share structural elements with the classical D(2-like) dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7 (4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4 dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D2 receptor subtype with high affinity (K(i) values < 0.3 nM), (b) exhibit >50-fold D2 versus D3 receptor binding selectivity and (c) be partial agonists at both the D2 and D3 receptor subtype. PMID- 21536447 TI - Synthesis and in vitro evaluation of novel pro-drugs for the treatment of nephropathic cystinosis. AB - As part of our continuing work to obtain new pro-drugs for the treatment of nephropathic cystinosis, a number of glutaric and succinic acid derivatives of cystamine have been designed, synthesised and biologically evaluated in vitro. These compounds have been designed as odourless and tasteless pro-drugs which will release multiple molecules of cysteamine upon administration. All of the synthesised compounds evaluated in this study were non-cytotoxic and displayed a greater ability than cysteamine to deplete the levels of cystine in cultured fibroblasts. PMID- 21536448 TI - N4-[Alkyl-(hydroxyphosphono)phosphonate]-cytidine-new drugs covalently linking antimetabolites (5-FdU, araU or AZT) with bone-targeting bisphosphonates (alendronate or pamidronate). AB - Amino-bisphosphonates (alendronate, pamidronate) were covalently linked in a three step synthesis, with protected and triazolylated derivatives of therapeutically used nucleoside analogs (5-FdU, araC, AZT) by substitution of their triazolyl residue. From the deprotected and chromatographically purified reaction mixtures N4-[alkyl-(hydroxyphosphono) phosphonate]-cytidine combining two differently cytotoxic functions were obtained. This new family of bisphosphonates (BPs) contains as novelty an alkyl side chain with a cytotoxic nucleoside. The BPs moiety allows for a high binding to hydroxyapatite which is a prerequisite for bone targeting of the drugs. In vitro binding of 5-FdU alendronate (5-FdU-ale) to hydroxyapatite showed a sixfold increased binding of these BPs as compared to 5-FdU. Exploratory cytotoxic properties of 5-FdU-ale were tested on a panel of human tumor cell lines resulting in growth inhibition ranging between 5% and 38%. The determination of IC50-concentrations of the conjugate in Lewis lung carcinoma and murine macrophages showed an incubation time dependent growth inhibition with higher sensitivity towards the tumor cells. We assume that the antimetabolite-BPs can be cleaved into different active metabolites that may exert cytotoxic and other therapeutic effects. However, the underlying mechanisms of these promising new antimetabolite-BPs conjugates remain to be evaluated in future experiments. PMID- 21536449 TI - Design and evaluation of 3-aminopyrazolopyridinone kinase inhibitors inspired by the natural product indirubin. AB - A lead-like kinase inhibitor screening library containing new 3 aminopyrazolopyridinones and closely related compounds was designed that contained hydrogen-bond donor-acceptor motifs and substitution vectors inspired by the natural product kinase inhibitor indirubin. The solubility of the 3 aminopyrazolopyridinone scaffold was more than 1000-fold greater than that of indirubin itself, and solubility was enhanced by reduction of the proportion of lipophilic aryl substituents or the introduction of basic groups. Several components of the library showed kinase inhibitory activity. A subset of diaryl substituted analogues preferentially inhibited tyrosine kinases with low micromolar activity and good ligand efficiency, and showed cellular antiproliferative activity. The evaluation of the library shows that new, non natural compounds with relevant biological activity and improved physicochemical properties can be generated from the natural product indirubin, providing compounds that may be useful for kinase inhibitor drug discovery. PMID- 21536450 TI - Imidazolone-amide bridges and their effects on tubulin polymerization in cis locked vinylogous combretastatin-A4 analogues: synthesis and biological evaluation. AB - A series of novel combretastatin-A4 analogues in which the cis-olefinic bridge is replaced by an imidazolone-amide were synthesized, and their cytotoxicity and tubulin-polymerization inhibitory activities were evaluated. These compounds appear to be potential tubulin-polymerization inhibitors. Compounds 10, 9b and 9c, bearing 3'-NH2-4'-OCH3, 4'-CH3 and 3'-CH3-substituted 1-phenyl B-ring, confer optimal bioactivity. The binding modes of these compounds to tubulin were obtained by molecular docking, which can explain the compounds' structure activity relationship. The studies presented here provide a new structural type for the development of novel antitumor agents. PMID- 21536451 TI - Testing differences in proportions. AB - This paper is the sixth in a series of statistics articles recently published by Australian Critical Care. In this paper we explore the most commonly used statistical tests to compare groups of data at the nominal level of measurement. The chosen statistical tests are the chi-square test, chi-square test for goodness of fit, chi-square test for independence, Fisher's exact test, McNemar's test and the use of confidence intervals for proportions. Examples of how to use and interpret the tests are provided. PMID- 21536452 TI - Comorbidity and survival after early breast cancer. A review. AB - INTRODUCTION: Survival after breast cancer is determined by disease related factors such as stage at diagnosis, patient characteristics, e.g., age, and treatment. AIM: To review evidence published during the last ten years on the effect of comorbidity on survival after early breast cancer. METHODS: A search in Pubmed with keywords, breast neoplasm, comorbidity, and survival, was performed. A total of 18 studies published between 2000 and August 2010 was included in this review. RESULTS: All 18 studies demonstrated that comorbidity had a significant impact on survival after breast cancer with poorer survival among patients with one or more comorbid conditions. The effect of comorbidity persisted after adjustment for age at diagnosis and stage of disease. Older patients with comorbidity were less likely to receive therapy according to guidelines. CONCLUSION: Presence of comorbidity at diagnosis is an important prognostic factor in early breast cancer, irrespective of age and stage of disease. PMID- 21536453 TI - Cytokine profiles in localized scleroderma and relationship to clinical features. AB - Localized scleroderma (LS) is a disfiguring autoimmune disease of the skin and underlying tissue that mainly affects the pediatric population. Inflammation of the tissue leads to fibrosis and atrophy, causing physical and psychological disability that can continue throughout childhood into adulthood. Available therapies for LS have had variable effects and are associated with morbidity themselves. A better understanding of the pathophysiology of LS, especially during the active inflammatory phase, would lead to more directed and efficacious therapies. As in systemic sclerosis (SSc), the other form of scleroderma, T helper (Th) cells and their associated cytokines have been suggested to contribute significantly to the pathophysiology of LS supported by the presence of cytokines from these lineages in the sera and tissue of LS patients. It is postulated that the imbalance between Th1/Th2/Th17 cell subsets drives inflammation in the early stages of disease (Th1 and Th17 predominant) and fibrosis in the later stages of scleroderma (Th2 predominant). We review the available experimental data regarding cytokines in LS and compare them to available clinical disease severity and activity features. This provides the platform to launch further investigations into the role of select cytokines in the pathogenesis of LS and to provide directed therapeutic options in the future. PMID- 21536454 TI - Neurovirulence tests of three 17D yellow fever vaccine strains. AB - The results of tests of the neurovirulence of three yellow fever vaccine preparations of different lineages are presented. Two preparations that have been used to make vaccines of acceptable safety and efficacy gave very similar results. A third preparation from the Robert Koch Institute, designated 168-73, was proposed as a reference preparation for the mouse potency assay in 1985 by WHO, but has been more often used as a reference in the monkey neurovirulence test. In the test described here 168-73 was of lower virulence than either of the other two preparations. PMID- 21536455 TI - Improving women's preconceptional health: long-term effects of the Strong Healthy Women behavior change intervention in the central Pennsylvania Women's Health Study. AB - PURPOSE: To investigate the long-term (6- and 12-month) effects of the Strong Healthy Women intervention on health-related behaviors, weight and body mass index (BMI), and weight gain during pregnancy. Strong Healthy Women is a small group behavioral intervention for pre- and interconceptional women designed to modify key risk factors for adverse pregnancy outcomes; pretest-posttest findings from a randomized, controlled trial have been previously reported. The following questions are addressed: 1) were significant pretest-posttest changes in health related behaviors (previously reported) maintained over the 12-month follow-up period; 2) did the intervention impact weight and BMI over the 12-month follow-up period; and 3) did the intervention impact pregnancy weight gain for those who gave birth during the follow-up period? METHODS: Data are from 6- and 12-month follow-up telephone interviews of women in the original trial of the Strong Healthy Women intervention (n = 362) and from birth records for singleton births (n = 45) during the 12-month follow-up period. Repeated measures regression was used to evaluate intervention effects. MAIN FINDINGS: At the 12-month follow-up, participants in the Strong Healthy Women intervention were significantly more likely than controls to use a daily multivitamin with folic acid and to have lower weight and BMI. The intervention's effect on reading food labels for nutritional values dropped off between the 6- and 12-month follow-up. Among those who gave birth to singletons during the follow-up period, women who participated in the intervention had lower average pregnancy weight gain compared with controls. Although the intervention effect was no longer significant when controlling for pre-pregnancy obesity, the adjusted means show a trend toward lower weight gain in the intervention group. CONCLUSION: These findings provide important evidence that the Strong Healthy Women behavior change intervention is effective in modifying important risk factors for adverse pregnancy outcomes and may improve an important pregnancy outcome, weight gain during pregnancy. Because the intervention seems to help women manage their weight in the months after the intervention and during pregnancy, it may be an effective obesity prevention strategy for women before, during, and after the transition to motherhood. PMID- 21536456 TI - Blood pressure fluctuations in posterior reversible encephalopathy syndrome. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) can be a consequence of hypertensive crisis and is often associated with rapid fluctuations in blood pressure (BP). However, the role of these BP changes in the pathogenesis of PRES has not been formally studied. Our objective was to analyze the relationship between BP fluctuations and the occurrence of PRES. METHODS: We identified consecutive patients who developed PRES in the hospital and compared them with randomly selected controls matched for age, gender, and history of hypertension (HTN). Systolic BP (SBP) and diastolic BP (DBP) were collected at 2 hour intervals over a 48-hour window before the onset of PRES symptoms. A profile of changes in the values of SBP, DBP, mean arterial pressure (MAP), and pulse pressure (PP) over the 48-hour window was summarized for each individual by calculating a single number (M value) using the approach by Service et al. Comparisons of these summary numbers between the 2 groups (cases and controls) were made with the Wilcoxon signed rank test because of the smaller sample size and paired nature of the data. All tests were 2-sided, and P < .05 was considered statistically significant. RESULTS: We analyzed the BP profiles in 25 cases of PRES and 25 controls. The median age of PRES patients was 54 years (range 31-72). Fourteen of them (56%) had a history of HTN. Hypertensive encephalopathy was considered the underlying cause of PRES in 13 patients (52%). At the time of the first symptoms of PRES, the mean SBP was 182 +/- 20 mm Hg (range 218-145), DBP 95 +/- 16 mm Hg (range 134-62), MAP 124 +/- 15 (range 152-93), and PP 87 +/- 18 (range 123-46). While BP was higher in PRES cases, the severity of HTN was variable and BP fluctuations were not significantly more common than in controls (P = .38 for SBP, .79 for DBP, .25 for MAP, and .73 for PP, respectively). CONCLUSIONS: Although acute HTN is frequent in patients with PRES, BP fluctuations do not appear to be more common in hospitalized patients who develop PRES compared with controls matched for age and history of HTN. Other predisposing factors must therefore contribute to the development of PRES. PMID- 21536457 TI - Type of preadmission antidiabetic treatment and outcome among patients with ischemic stroke: a nationwide follow-up study. AB - BACKGROUND: We examined whether the preadmission use of sulfonylureas is associated with improved clinical outcome compared with other antidiabetic treatments after hospitalization with ischemic stroke. METHODS: We conducted a nationwide population-based follow-up study among all Danish patients hospitalized with ischemic stroke between 2003 and 2006 and who were registered in the Danish National Indicator Project. We obtained data on diabetes and type of antidiabetic treatment, patient characteristics, in-hospital quality of care, and mortality and readmissions by linking medical databases. We computed mortality rates and rates of readmission recurrent ischemic stroke or myocardial infarction according to type of treatment and used the Cox proportional hazards regression analysis to compute hazard ratios (HRs). RESULTS: We identified 4817 stroke patients with type 2 diabetes mellitus. We found lower 30-day mortality rates among users of metformin (adjusted HR 0.32; 95% confidence interval [CI] 0.15-0.68), insulin (adjusted HR 0.47; 95% CI 0.27-0.81), and patients without antidiabetic pharmacotherapy (adjusted HR 0.58; 95% CI 0.36-0.93) compared with users of sulfonylureas. Users of any combination had a nonstatistical significant lower 30-day mortality rate (adjusted HR 0.64; 95% CI 0.34-1.21). In contrast, we found no significant differences in 1-year mortality rate. Compared with users of sulfonylureas, users of all other types of treatment had increased risk of readmission; however, it did not reach statistical significance for all treatment groups. CONCLUSIONS: Preadmission use of sulfonylureas appeared not to be associated with an overall improved clinical outcome among type 2 diabetic patients admitted with ischemic stroke. PMID- 21536458 TI - The rubber hand illusion in a mirror. AB - In the rubber hand illusion (RHI) one's hand is hidden, and a fake hand is visible. We explored the situation in which visual information was available indirectly in a mirror. In the mirror condition, compared to the standard condition (fake hand visible directly), we found no reduction of the RHI following synchronised stimulation, as measured by crossmanual pointing and by a questionnaire. We replicated the finding with a smaller mirror that prevented visibility of the face. The RHI was eliminated when a wooden block replaced the fake hand, or when the hand belonged to another person or mannequin. We conclude that awareness of the reflection is the critical variable, despite the distant visual localisation of the hand in a mirror and the third-person perspective. Stimuli seen in a mirror activate the same response as stimuli seen in peripersonal space, through knowledge that they are near one's body. PMID- 21536459 TI - Comparative study of the quality of life between arthrodesis and total arthroplasty substitution of the ankle. AB - Our goal was to compare the health status of patients with primary and secondary arthrosis of the ankle before and after arthrodesis or total substitution arthroplasty, and to determine the improvement in quality of life and whether there is any difference between these techniques. A prospective comparative study of clinical-functional evaluation was performed using the American Orthopaedic Foot & Ankle Society (AOFAS) scale and quality of life with the short form (SF) 36 questionnaire in patients who underwent arthrodesis (16 cases) or total substitution arthroplasty of the ankle (14 cases) after 2 years (mean, 25.2 months) of follow-up after surgery, in comparison with the baseline preoperative status. In this series of comparable patients, both techniques showed a statistically significant improvement with regard to the clinical evaluation and quality of life after 2 years of follow-up; the arthrodesis group increased from mean AOFAS values of 37.12 to 45.62 (P = .055) and mean SF-36 values of 32.96 to 46.25 (P = .008), whereas in the arthroplasty group the mean values of AOFAS increased from 33 to 62 (P = .024) and SF-36 from 33.62 to 59.84 (P = .001). Nevertheless, in all cases the improvement was statistically greater in patients who underwent arthroplasty than in those who underwent arthrodesis (P = .048 for AOFAS, and P = .026 for SF-36). In conclusion, arthrodesis and arthroplasty represent good options in the surgical treatment of ankle arthrosis, providing both a significant improvement in function and in the health perception and quality of life of the patient. New-generation total ankle substitution arthroplasty provides an improvement in the quality of life and perception of general health of the patient with arthrosis of this joint, when this technique is compared with surgical fusion. PMID- 21536460 TI - Suspension and dynamic compression of the medial column using a tension band mesh plate. AB - Medial column fusion is becoming increasingly popular for flatfoot reconstruction. The authors describe a new technique for medial column arthrodesis via tension band mesh plating. Plating on the tension side would provide dynamic compression of the arthrodesis sites via weightbearing. This technique may be useful to allow patients to bear weight early in the postoperative course after flatfoot reconstruction. PMID- 21536461 TI - High-resolution 3T MR neurography of suprascapular neuropathy. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to illustrate the imaging findings on high-resolution 3T magnetic resonance neurography (MRN) in patients with suprascapular nerve (SSN) neuropathy. MATERIALS AND METHODS: From 3T MRN examinations performed for brachial plexus evaluation in 51 patients over a 3 year period, 15 patients with final diagnosis of suprascapular neuropathy were recruited. The diagnosis was confirmed by electrodiagnostic studies (EDS), clinical, and/or surgical follow-up examinations. Studies performed for the evaluation of tumor, neurofibromatosis, or known diffuse polyneuropathy were excluded. RESULTS: Two cases were excluded due to suboptimal imaging related to motion degradation and poor signal-to-noise ratio. MRN depicted asymmetric enlargement and/or abnormal T2 hyperintensity of C5 nerve root (10/13 cases), C6 nerve root (10/13 cases), both C5 and C6 nerve roots (7/13 cases), upper trunk (11/13 cases) and SSN (11/13 cases), and other brachial plexus segments involvement (4/13 cases). MR findings of denervation changes in the ipsilateral supraspinatus and infraspinatus muscles were detected in 12/13 cases. In all seven cases where contrast-enhanced images were available, MRN demonstrated enhancement of the denervated muscles but did not provide any additional information regarding the nerve abnormality. None of the MRN studies revealed a mass lesion along the course of the SSN. CONCLUSION: 3T MRN is a valuable diagnostic tool in clinically suspected cases of suprascapular neuropathy, because it can directly demonstrate the nerve abnormality, as well as secondary muscle denervation changes. The reader should be aware that brachial plexopathy may coexist in patients with clinical diagnosis of SSN neuropathy. PMID- 21536462 TI - Quantitative evaluation of hyperpolarized helium-3 magnetic resonance imaging of lung function variability in cystic fibrosis. AB - RATIONALE AND OBJECTIVES: To better understand imaging measurement precision and reproducibility and to provide guidance for measurements in individual cystic fibrosis (CF) subjects, we evaluated CF adults on two occasions 7 +/- 2 days apart using spirometry, plethysmography, and hyperpolarized helium-3 ((3)He) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Twelve CF subjects underwent spirometry, plethysmography, and (3)He MRI twice within 7 +/- 2 days, reporting (3)He ventilation defect volume (VDV) and ventilation defect percent (VDP). RESULTS: Based on measurement variability, the smallest detectable difference (SDD) for (3)He VDV and VDP was determined to be 120 mL and 2%, respectively. Although no significant difference in spirometry or plethysmography was detected after 7 days, there was a significant difference in mean (3)He VDV (130 mL +/- 250 mL, P < .0001) and VDP (3% +/- 4%, P < .0001), although baseline and 7-day measurements were highly correlated (VDV: r = .85, P = .001; VDP: r = .94, P < .0001). We estimated the sample sizes required to detect a 5%/7%/10% change in (3)He VDP as 60/15/5 subjects per group. CONCLUSION: Hyperpolarized (3)He MRI VDP measurement precision resulted in an SDD for individual CF subjects of 2%, indicating that changes greater than this can be attributed to lung functional changes and not measurement error. After 7 days, significant changes in mean (3)He VDV and VDP were detected and these changes were not reflected by changes in pulmonary function measurements. These findings demonstrate the high sensitivity and reproducibility of (3)He MRI functional imaging that permits the use of relatively small samples sizes in CF interventional studies. PMID- 21536463 TI - The feasibility of measuring phosphocreatine recovery kinetics in muscle using a single-shot (31)P RARE MRI sequence. AB - RATIONALE AND OBJECTIVES: Heterogeneity of skeletal muscle structure, composition, and perfusion results in spatial differences in oxidative function between muscles and muscle regions. The simultaneous measurement of the postexercise phosphocreatine (PCr) recovery rate across all muscles of a human limb cross-section may provide new insights into normal physiology and disease states. The objective of this work was to assess the feasibility of acquiring PCr rapid acquisition with relaxation enhancement (RARE) images with sufficient temporal and spatial resolution to accurately measure PCr recovery kinetics in a cross-section of a human limb. MATERIALS AND METHODS: One normal subject performed a finger exercise until fatigued. At cessation of exercise surface coil localized pulse-and-acquire phosphorus-31 MR spectra ((31)P- magnetic resonance spectroscopy [MRS]) of the forearm were acquired at 6 S intervals for 4 minutes. The exercise protocol was repeated 7 days later and axial PCr RARE images of the forearm were acquired following exercise with 5.6 cm(3) voxels at 6-second intervals for 4 minutes. RESULTS: The PCr recovery time constants for the PCr RARE and (31)P-MRS measurements were 91.0 and 91.1 seconds, respectively, based on a monoexponential fit. A Pearson correlation test showed that the PCr recovery data that resulted from the RARE PCr imaging were highly correlated with the data resulting from the (31)P-MRS (r = 0.91, P < .0001). DISCUSSION: Data from selected regions of RARE PCr images acquired at 6-second intervals compare well to those acquired using surface coil (31)P MR spectroscopy and can provide an accurate assessment of PCr recovery kinetics. PMID- 21536464 TI - A low tube voltage technique reduces the radiation dose at retrospective ECG gated cardiac computed tomography for anatomical and functional analyses. AB - RATIONALE AND OBJECTIVES: To investigate the effect of low-tube-voltage technique on a cardiac computed tomography (CT) for coronary arterial and cardiac functional analyses and radiation dose in slim patients. MATERIALS AND METHODS: We enrolled 80 patients (52women, 28 men; mean age, 68.7 +/- 8.9 years) undergoing retrospective electrocardiogram-gated 64-slice cardiac CT. Forty were subjected to the low (80-kV) and 40 to the standard (120-kV) tube-voltage protocol. Quantitative parameters of the coronary arteries (ie, CT attenuation, image noise, and the contrast-to-noise ratio [CNR]) were calculated, as were the effective radiation dose and the figure of merit (FOM). Each coronary artery segment was visually evaluated using a 5-point scale. Cardiac function calculated by using low-tube-voltage cardiac CT was compared with that on echocardiographs. RESULTS: CT attenuation and image noise were significantly higher at 80- than 120 kV (P < .01). CNR of the left and right coronary artery was 18.4 +/- 3.8 and 18.5 +/- 3.3, respectively, at 80 kV; these values were 19.7 +/- 2.7 and 19.8 +/- 2.8 at 120 kV; the difference was not significant. The estimated effective radiation dose was significantly lower at 80 than 120 kV (6.3 +/- 0.6 vs. 13.9 +/- 1.1 mSv, P < .01) and FOM was significantly higher at 80 than 120 kV (P < .01). At visual assessment, 99% of the coronary segments were diagnostic quality; the two protocols did not differ significantly. We observed a strong correlation and good agreement between low-tube-voltage cardiac CT and echocardiography for cardiac functional analyses. CONCLUSION: Low-tube-voltage cardiac CT significantly reduced the radiation dose by approximately 55% in slim patients while maintaining anatomical image quality and accuracy of cardiac functional analysis. PMID- 21536465 TI - Characterization and detection of physiologic lung changes before and after placement of bronchial valves using hyperpolarized helium-3 MR imaging: preliminary study. AB - RATIONALE AND OBJECTIVES: The aim of this study was to determine the efficacy of hyperpolarized (3)He (HHe) ventilation and apparent diffusion coefficient (ADC) HHe magnetic resonance imaging (MRI) in detecting changes in lung function and microstructure in emphysematous lung after bronchial valve (BV) placement. MATERIALS AND METHODS: One patient diagnosed with emphysema had nine BVs placed in upper lobe bronchi. Imaging was performed before and 6 months after BV placement. Coronal HHe ventilation MRI was used to assess volume changes in the ventilated portions of the lung. Coronal ADC HHe MRI, acquired with b value pairs of 0 and 1.6 s/cm(2) during a second 10-second breath-hold, was used to compute ADC values. RESULTS: HHe ventilation MRI revealed decreased ventilation in the treated segments of the upper lobes after BV placement. Increased ventilation in the lower lobes and two untreated segments of the left upper lobes were also observed, with an upward shift of the major fissure of the right lung. Whole-lung mean ADC decreased by 6.3% from baseline, from 0.48 +/- 0.196 to 0.45 +/- 0.176 cm(2)/s (toward healthier values) following BV placement. CONCLUSIONS: HHe ventilation MRI detected an increase in whole-lung volume and an interlobar fissure shift indicative of increased ventilation of lower relative to upper lobes. Reduced ADC values suggest increased ventilation to healthy lower lobes at the expense of more diseased, expanded alveolar spaces in the upper lobes distal to BV placement. These results suggest that this ionizing radiation-free method of examining the lungs may offer functional and structural information useful in BV intervention planning. PMID- 21536466 TI - High order diffusion tensor imaging in human glioblastoma. AB - RATIONALE AND OBJECTIVES: Diffusion tensor imaging has been used to characterize tumor heterogeneity and invasion in human glioblastoma. Recently, higher order diffusion tensors have been proposed as solutions to errors associated with diffusion tensor imaging estimates of complex microstructures. The purpose of the current study was to examine higher order diffusion characteristics in human glioblastoma prior to surgical resection using the fourth-order diffusion tensor model. MATERIALS AND METHODS: Twenty-five patients with newly diagnosed glioblastoma participated in the study. Diffusion-weighted images were collected in 21 directions. The second-order (traditional) and fourth-order diffusion tensors were calculated and compared in regions of contrast enhancement, T2 signal abnormality, and normal-appearing white matter. RESULTS: Orientation distribution functions were strikingly different between the two tensor models, particularly in regions with tumor heterogeneity and/or regions of suspected tumor invasion. Image contrast was significantly higher in fourth-order scalar measures compared to second-order scalars. Results of particular eigenvalues and scalars using the fourth-order tensor showed differences between T2 abnormal regions and contrast enhancement, whereas second-order eigenvalues and scalars did not show differences. This suggests that higher order diffusion images could potentially be more sensitive to tumor invasion. CONCLUSIONS: These results suggest that the fourth-order diffusion tensor has the ability to add value to second-order (traditional) diffusion tensor imaging in the evaluation of glioblastoma. PMID- 21536467 TI - Comments regarding 'Ultrasound Measurement of Aortic Diameter in a National Screening Programme'. PMID- 21536469 TI - Relationship of insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) gene polymorphism with the susceptibility to development of prostate cancer and influence on serum levels of IGF-I, and IGFBP-3. AB - The bioavailability of IGF-I is controlled by the binding protein, IGF binding protein-3 (IGFBP-3). In addition, IGFBP-3 is a strong anti-proliferative protein that provokes apoptosis and inhibits cell proliferation in prostate cancer. We conducted this study to investigate the association between IGFBP-3 gene polymorphism and serum levels of IGF-I and IGFBP-3 and the incidence of prostate cancer (PCa) and benign prostatic hyperplasia (BPH). DNA isolation was performed in peripheral blood samples obtained from all participants. Required areas were amplified with polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique by using proper primers belonging to this gene area. We also measured serum IGF-I and IGFBP-3 levels. The IGFBP-3 -202 A/C polymorphism genotype frequencies showed a significant difference between PCa patients and controls (chi(2)=6.27, df=2.0, P=0.026), as well as between BPH patients and controls (chi(2)=11.57, df=4.0, P=0.014). The AA genotype frequency was significantly decreased in PCa and BPH patients compared to control group and the risk of PCa and BPH occurrence of this genotype was decreased accordingly (PCa; OR=0.28, 95% CI=0.17-0.44, P=0.0001; BPH: OR=0.48, 95% CI=0.29-0.77, P=0.001). Age-adjusted mean serum IGFBP-3 concentrations were highest in the individuals with the AA genotype and diminished significantly in a stepwise manner in the presence of 1 or 2 copies of the C allele (4577 ng/ml, 3929 ng/ml and 3349 ng/ml, respectively). Patients with PCa and BPH had lower serum IGF-1 (P=0.001, and P=0.01, respectively) and IGFBP-3 levels (P=0.001, and P=0.01, respectively) compared with controls. The AA genotype at IGFBP-3 gene polymorphism is associated with reduced risks of PCa and BPH. Both IGF-I and IGFBP-3 concentrations, are associated with modified risks of PCa and BPH. PMID- 21536468 TI - Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, including dose reduction. AB - Since bone pathology is a major concern in type 1 Gaucher disease (GD1), we evaluated bone mineral density (BMD) in adults receiving velaglucerase alfa in the seminal Phase I/II and extension trial. Ten treatment-naive symptomatic patients with GD1 (four men, six women; median age 35years, range 18-62years) were included; of these, four patients were receiving bisphosphonates at enrollment. Using WHO criteria to classify the lumbar spine (LS) and femoral neck (FN) BMD T-scores, respectively, one (10%) and four (40%) patients had osteoporosis; eight (80%) and five (50%) had osteopenia; and one each (10%) was in the normal range, at baseline. By Month 69, two LS and one FN osteopenic patients normalized and one FN osteoporotic patient became osteopenic; change was seen only in patients not receiving bisphosphonates. Significant improvements in BMD Z-scores were seen at the LS by Month 24 and at the FN by Month 33 and were continuous thereafter. In linear mixed models, Z-scores were significantly lower than the reference population at baseline and improved significantly with treatment (LS and FN both P<0.01); analysis of the subgroup of patients not receiving bisphosphonates showed similar results. In conclusion, in this small cohort, velaglucerase alfa was associated with clinically meaningful and statistically significant LS and FN BMD improvements as early as Month 24 (LS) and 33 (FN), despite dose reduction and significant baseline skeletal pathology. These results suggest that velaglucerase alfa may hold promise in the management of skeletal pathology associated with GD1. PMID- 21536470 TI - Expression of Mmachc and Mmadhc during mouse organogenesis. AB - To examine whether Mmachc and Mmadhc, two genes involved in vitamin B(12) (cobalamin) metabolism, show tissue-specific expression during mouse embryogenesis, we determined their sites of expression at 11.5days post conception by in situ hybridization. There was ubiquitous expression of Mmadhc, but tissue and cell type-specific expression of Mmachc in the developing lung, heart, cardiovascular and nervous system. This suggests that during organogenesis Mmachc and Mmadhc may interact in only a subset of cells. PMID- 21536471 TI - Glycerol homeostasis and metabolism in glycerol kinase carrier mice. AB - To examine glycerol homeostasis and metabolism is essential for understanding of pathogenesis and evaluation of treatment efficacy in disorders of glycerol metabolism. In this study, we designed the intraperitoneal glycerol tolerance test (IPGlyTT) and studied glycerol tolerance in vivo using glycerol kinase (Gyk) carrier (C) and wild type (WT) mice. Serum glycerol concentrations in WT almost normalized at 90 min after injection, whereas Gyk C mice retained high serum glycerol concentrations at least until 180 min after injection. These results showed that glycerol tolerance was impaired in Gyk C mice compared to WT mice. The IPGlyTT is useful in accessing glycerol homeostasis and metabolism in animal models such as Gyk C mice and will be valuable in assessing therapeutic interventions in Gyk KO mice. PMID- 21536472 TI - Efficacy of a single dose of an otic ivermectin preparation or selamectin for the treatment of Otodectes cynotis infestation in naturally infected cats. AB - Otodectes cynotis infestation is common in kittens housed in crowded environments like animal shelters. It is unknown how rapidly O cynotis is killed within the first 72h of treatment with currently available products. Kittens >=4 weeks of age with live O cynotis in both ears (AU) were administered 0.5ml of 0.01% ivermectin otic suspension (Acarexx; Idexx Pharmaceuticals) once, AU or selamectin (Revolution; Pfizer Animal Health) once, on the skin following the manufacturer's instructions. Repeat microscopic examination was performed on individual ears based on a randomization schedule during the 72h after treatment. There was no evidence of toxicity with either drug and administration of 0.01% ivermectin significantly reduced the time to live mite-free status compared to selamectin. Both drugs have an effect against O cynotis as early as 10-12h after administration with an increasing effect over time. PMID- 21536473 TI - [Eating disorders in adults]. PMID- 21536474 TI - [Good governance: the missing link in the Spanish NHS?]. PMID- 21536475 TI - Pollen tubes and the physical world. AB - The primary goal of our previous opinion paper (Winship, L.J. et al. (2010) Trends Plant Sci. 15, 363-369) [1] was to put two models for the control of pollen tube growth on the same theoretical and biophysical footing, and to then test both for consistency with basic principles and with experimental data. Our central thesis, then and now, is that the biophysical and biochemical mechanisms that enable pollen tubes to grow and to respond to their environment evolved in a physical context constrained by known, inescapable principles. First, pressure is a scalar, not a vector quantity. Second, the water movement in and out of plant cells that generates pressure is passive, not active, and is controlled by differences in water potential. Here we respond to the issues raised by Zonia and Munnik (Trends Plant Sci. 2011; this issue) [2] in the light of new evidence concerning turgor pressure and pollen tube growth rates. PMID- 21536476 TI - Imaging and characterisation of the surface of live cells. AB - Determining the organisation of key molecules on the surface of live cells in two dimensions and how this changes during biological processes, such as signaling, is a major challenge in cell biology and requires methods with nanoscale resolution. Recent advances in fluorescence imaging both at the diffraction limit tracking single molecules and exploiting super resolution imaging have now reached a stage where they can provide fundamentally new insights. Complementary developments in scanning ion conductance microscopy also allow the cell surface to be imaged with nanoscale resolution. The challenge now is to combine the information obtained using these different methods and on different cells to obtain a coherent view of the cell surface. In the future this needs to be driven by interdisciplinary research between physical scientists and biologists. PMID- 21536477 TI - Overexpression of Rho GDP-dissociation inhibitor alpha predicts poor survival in oral squamous cell carcinoma. AB - Oral cancer has emerged as one of the fastest growing malignancies in Taiwan. However, biomarkers that reliably predict clinical outcomes have yet to be identified. This study was aimed to identify tumor-associated proteins that could be prognostic biomarkers for oral cancer. We compared the protein expression between oral squamous cell carcinoma (OSCC) tissues and adjacent non-cancerous matched tissues (NCMTs) by proteomics. We found that Rho GDP-dissociation inhibitor alpha (RhoGDIalpha) was differentially expressed in frozen cancerous samples and OSCC cell lines but not in NCMTs. Furthermore, our results indicated that RhoGDIalpha was selectively upregulated in 78 OSCC tissue sections (p<0.001), and this high expression was significantly correlated with increased tumor size (p<0.05) and poor overall survival (p<0.01). There was a trend that RhoGDIalpha expression was localized in the cytoplasm of cancer cells but was localized in the plasma membrane of NCMTs. Finally, expression of RhoGDIalpha was validated to be an independent prognostic indicator for overall survival (p<0.01). These results have identified a novel biomarker that may be useful for prediction of poor prognosis in OSCC patients. PMID- 21536478 TI - HH/GLI signalling as a new therapeutic target for patients with oral squamous cell carcinoma. AB - Aberrant activation of HH/GLI has recently been reported in multiple cancer types, yet its role in oral squamous cell carcinoma (OSCC) has not been investigated. In this study, we aimed to determine the role of HH/GLI in OSCC. Expression of GLI1 and GLI2 was examined in OSCC samples from 136 patients by immunohistochemistry and correlated with clinicopathology parameters and clinical outcomes of the patients. Two HH/GLI specific small molecule inhibitors cyclopamine and GANT61, were used to test the potential role of HH/GLI in OSCC. We found that GLI2, one of the main transcriptional activators of HH/GLI signalling, was expressed in 60 (44%) of the 136 OSCC samples and the expression was significantly associated with poor clinical outcomes. Only 44% of the patients whose tumours expressed GLI2 survived at 5years after surgery compared to 77% of those whose tumours lacked the GLI2 expression (P<0.0001). Both cyclopamine and GANT61 effectively inhibited GLI expression, slowed cell growth, promoted G1 arrest, increased apoptosis and inhibited migration of OSCC cells. Our results demonstrate that activation of HH/GLI pathway plays an important role in OSCC progression. Together with the finding that expression of GLI2 is strongly associated with a poor clinic outcome of OSCC patients, the data suggest that a subset of OSCC patients may benefit from anti-HH/GLI therapies. PMID- 21536479 TI - What does Arabidopsis natural variation teach us (and does not teach us) about adaptation in plants? AB - Sessile organisms such as plants have to develop adaptive responses to face environmental change. In Arabidopsis thaliana populations, natural variation for stress responses have been observed at different levels of integration and the genetic bases of those variations have been analysed using two strategies: classical linkage and association (LD) mapping. The strength of Arabidopsis resides in the huge amount of genomic data and molecular tools available leading to the identification of many polymorphisms responsible for phenotypic variation. Remaining limitations to clearly understand how Arabidopsis adapts to its environment, that is the complexity of the genetic architecture and the lack of ecological data, should be partially solved thanks to the development of new methods and the acquisition of new data. PMID- 21536480 TI - Living inside plants: bacterial endophytes. AB - As current research activities have focused on symbiotic or parasitic plant microbe interactions, other types of associations between plants and microorganisms are often overlooked. Endophytic bacteria colonize inner host tissues, sometimes in high numbers, without damaging the host or eliciting strong defense responses. Unlike endosymbionts they are not residing in living plant cells or surrounded by a membrane compartment. The molecular basis of endophytic interactions is still not well understood. Several traits involved in the establishment of endophytes have been elucidated. Culture-independent methods for community analysis and functional genomic as well as comparative genomic analyses will provide a better understanding of community dynamics, signaling, and functions in endophyte-plant associations. PMID- 21536481 TI - Plant pathogens as a source of diverse enzymes for lignocellulose digestion. AB - The plant cell wall is a major barrier that many plant pathogens must surmount for successful invasion of their plant hosts. Full genome sequencing of a number of plant pathogens has revealed often large, complex, and redundant enzyme systems for degradation of plant cell walls. Recent surveys have noted that plant pathogenic fungi are highly competent producers of lignocellulolytic enzymes, and their enzyme activity patterns reflect host specificity. We propose that plant pathogens may contribute to biofuel production as diverse sources of accessory enzymes for more efficient conversion of lignocellulose into fermentable sugars. PMID- 21536482 TI - Spectroscopic analysis of 2-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4 ylimino)-2-(4-nitro-phenyl) acetonitrile. AB - The optimized geometry and vibrational frequencies of 2-(2,3-dihydro-1,5-dimethyl 3-oxo-2-phenyl-1H-pyrazol-4-ylimino)-2-(4-nitro-phenyl) acetonitrile (DOPNA) were obtained by ab initio DFT/B3LYP level with complete relaxation in the potential energy surface using 6-31G and 6-311G basis sets. The Fourier-transform infrared (FT-IR) spectrum of DOPNA has been recorded in the region 4000-400 cm(-1). The harmonic vibrational frequencies were calculated and the scaled values have been compared with experimental FT-IR spectrum. The calculated frequencies are in comparable agreement with the experimental frequencies. The calculated energy span between the HOMO and the LUMO of DOPNA is 2.94 and 2.87eV by B3LYP/6-31G and B3LYP/6-311G, respectively. PMID- 21536483 TI - Fluorescent film sensor for copper ion based on an assembled monolayer of pyrene moieties. AB - We previously reported the construction of a family of fluorescent film sensors for organic copper salts by covalently coupling polycyclic aromatic hydrocarbons on epoxy-terminated self-assembled monolayers on glass plate surfaces. Here we investigate the sensing properties and mechanism of covalently coupling pyrene on a glass plate surface via a long flexible "Y" type spacer. X-ray photoelectron spectroscopy (XPS) and fluorescence spectra measurements demonstrate the covalent attachment of pyrene in our adlayer. Compared with those results obtained in the previous studies, this new film sensor did not show highly selectivity for organic copper salts, which can be attributed to the introduction of sulfonyl groups connecting the pyrene moieties and the spacers. The presence of sulfonyl units made the microenvironments of pyrene relatively hydrophilic and thus showed less screening effect for inorganic ions. The specificity and reversibility of the film sensor toward Cu (II) made it attractive for sensing applications. PMID- 21536484 TI - Syntheses, spectral, electrochemical and thermal studies of mononuclear manganese(III) complexes with ligands derived from 1,2-propanediamine and 2 hydroxy-3 or 5-methoxybenzaldehyde: self-assembled monolayer formation on nanostructure zinc oxide thin film. AB - Mononuclear Mn(III) complexes have been prepared via the Mn(II) reaction of an equimolar of Schiff-bases derived from reaction of 2-hydroxy-3 methoxybenzaldehyde or 2-hydroxy-5-methoxybenzaldehyde with 1,2-diaminopropane. Axial ligands L include: pyridine (py) and H(2)O. The resulting complexes have been characterized by FT-IR and UV-vis spectroscopy. The crystal structures of the complexes were determined and indicate that in the solid state the complex adopts a slightly distorted octahedral environment of the imine N and hydroxo O with the two axial ligands. The electrochemical reduction of these complexes at a glassy carbon electrode in acetonitrile solution indicates that the first reduction process corresponding to Mn(III)-Mn(II) is electrochemically quasi reversible. Thermal stability of these complexes was determined by TG and DTG. Layers of these complexes were formed on nanostructure zinc oxide thin film and a red shift was observed when zinc oxide thin film is modified by complex. PMID- 21536485 TI - Biosynthesis of silver nanoparticles using citrus sinensis peel extract and its antibacterial activity. AB - Biosynthesis of silver nanoparticles (AgNPs) was achieved by a novel, simple green chemistry procedure using citrus sinensis peel extract as a reducing and a capping agent. The effect of temperature on the synthesis of silver nanoparticles was carried out at room temperature (25 degrees C) and 60 degrees C. The successful formation of silver nanoparticles has been confirmed by UV-vis, FTIR, XRD, EDAX, FESEM and TEM analysis and their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa (gram-negative), and Staphylococcus aureus (gram-positive) has been studied. The results suggest that the synthesized AgNPs act as an effective antibacterial agent. PMID- 21536487 TI - Synthesis, spectral, thermal and magnetic studies of Mn(II), Ni(II) and Cu(II) complexes with some benzopyran-4-one Schiff bases. AB - The Schiff bases of N(2)O(2) dibasic ligands, H(2)La and H(2)Lb are prepared by the condensation of ethylenediamine (a) and trimethylenediamine (b) with 6-formyl 7-hydroxy-5-methoxy-2-methylbenzopyran-4-one. Also tetra basic ligands, H(4)La and H(4)Lb are prepared by the condensation of aliphatic amines (a) and (b) with 6-formyl-5,7-dihydroxy-2-methylbenzopyran-4-one. New complexes of H(4)La and H(4)Lb with metal ions Mn(II), Ni(II) and Cu(II) are synthesized, in addition Mn(II) complexes with ligands H(2)La and H(2)Lb are also synthesized. Elemental and thermal analyses, infrared, ultraviolet-visible as well as conductivity and magnetic susceptibility measurements are used to elucidate the structure of the newly prepared metal complexes. The structures of copper(II) complexes are also assigned based upon ESR spectra study. All the complexes separated with the stoichiometric ratio (1:1) (M:L) except Mn-H(4)La and Mn-H(4)Lb with (2:1) (M:L) molar ratio. In metal chelates of the type 1:1 (M:L), the Schiff bases behave as a dinegative N(2)O(2) tetradentate ligands. Moreover in 2:1 (M:L) complexes, the Schiff base molecules act as mono negative bidentate ligand and binuclear complex is then formed. The Schiff bases were assayed by the disc diffusion method for antibacterial activity against Staphylococcus aureus and Escherichia coli. The antifungal activity of the Schiff bases was also evaluated against the fungi Aspergillus flavus and Candida albicans. PMID- 21536486 TI - Platinum(IV) coordination compounds containing 5-methyl-1,2,4-triazolo[1,5 a]pyrimidin-7(4H)-one as nonleaving ligand. Molecular and cytotoxicity in vitro characterization. AB - Novel platinum(IV) coordination compounds with 5-methyl-1,2,4-triazolo[1,5 a]pyrimidin-7(4H)-one (HmtpO): cis-trans-[PtCl(2)(OH)(2)(NH(3))(HmtpO)] (1), cis trans-[PtCl(5)(HmtpO)][(CH(3))(2)NH(2)] (2) have been prepared and structurally characterized by spectroscopic methods ((1)H, IR and X-ray crystallography (2)). The X-ray results indicate that the local geometry around the platinum(IV) centre approximates a typical octahedral arrangement with nitrogen atom N3 of the HmtpO and three chloride atoms in equatorial positions. The remaining two axial positions are occupied by two chlorides. The preliminary assessment of antitumor properties of (1) was performed as an in vitro antiproliferative activity against HL-60 human acute promyelocytic leukemia and HCV29T bladder cancer. The cis-trans [PtCl(2)(OH)(2)(NH(3))(HmtpO)] (1) exhibits higher cytotoxic activity against HL 60 (IC(50)=6.4 MUM) than cisplatin. PMID- 21536488 TI - Resonance Rayleigh scattering, second-order scattering and frequency doubling scattering spectra for studying the interaction of erythrosine with Fe(phen)3(2+) and its analytical application. AB - In a weak alkaline Britton-Robinson buffer medium, erythrosine (Ery) can react with Fe(phen)(3)(2+) to form 1:1 ion-association complex, which will cause not only the changes of the absorption spectra, but also the remarkable enhancement of resonance Rayleigh scattering (RRS), second-order scattering (SOS) and frequency doubling scattering (FDS) spectra, and the appearance of new spectra of RRS, SOS and FDS. The maximum RRS, SOS and FDS wavelengths (lambda(ex)/lambda(em)) of the ion-association complex are located at 358/358 nm, 290/580 nm and 780/390 nm, respectively. The increments of scattering intensities (DeltaI) are directly proportional to the concentration of Ery in a certain range. The detection limits for Ery are 0.028 MUg mL(-1) for RRS method, 0.068 MUg mL(-1) for SOS method and 0.11 MUg mL(-1) for FDS method, respectively. Among them, the RRS method has the highest sensitivity. Based on the above researches, a new highly sensitive and simple method for the determination of Ery has been developed. In this work, the spectral characteristics of absorption, RRS, SOS and FDS spectra, the optimum conditions of the reaction and influencing factors for the RRS, SOS and FDS intensities were investigated. In addition, the reaction mechanism was discussed. PMID- 21536489 TI - Structural study of ternary iron-lead-germanate glass ceramics. AB - Glass ceramics with the composition xFe(2)O(3).(100-x)[7GeO(2).3PbO(2)] where 0<=x<=60 mol% were obtained and studied using XRD, FTIR and UV-vis spectroscopy investigations. Heat treatment of glass samples at 400 degrees C for 8 h led to the formation of alpha, gamma-PbGe(4)O(9), Pb(3)Fe(2)Ge(4)O(14) and PbO(1.44) crystalline phases. The content of these crystalline phases depends of Fe(2)O(3) concentration. FTIR spectroscopy data suggest that the lead ions have a pronounced affinity towards [GeO(5)] structural units containing non-bridging oxygens and [FeO(4)] anions producing formation of the Pb(3)Fe(2)Ge(4)O(14) crystalline phase. The introduction of low concentrations of Fe(2)O(3) into the host matrix results in the formation of new absorption UV bands between 320 and 450 nm. These bands arise from to the d-d transitions of the Fe(+3) ions. The light absorption in the range from 250 to 600 nm increases with increasing iron oxide content in matrix network, accompanied with the changes on color from white to brown yellow and darker brown. PMID- 21536490 TI - Photophysical, photochemical and BSA binding/BQ quenching properties of quaternizable coumarin containing water soluble zinc phthalocyanine complexes. AB - The non-peripherally (np-QZnPc) and peripherally (p-QZnPc) tetrakis-[7-oxo-(3-[(2 diethylaminomethyliodide)ethyl)]-4-methylcoumarin]-phthalocyaninatozinc complexes have been prepared by quaternization of non-peripherally and peripherally tetrakis[7-oxo-(3-[(2-diethylamino)ethyl)]-methylcoumarin] phthalocyaninato zinc complexes with methyliodide in dimethylsulfoxide (DMSO). The new quaternized zinc phthalocyanine complex (np-QZnPc) has been characterized by elemental analysis, MALDI-TOF, IR and UV-vis spectral data. The photophysical and photochemical properties of the peripherally and non-peripherally quaternized tetrakis-3-[(2 diethylamino)ethyl]-7-oxo-4-methylcoumarin substituted zinc phthalocyanines are reported. The effects of the position of the substituents and the aggregation of the phthalocyanine molecules on the photophysical and photochemical properties are also investigated. General trends are described for photodegradation, singlet oxygen and fluorescence quantum yields, and fluorescence lifetimes for complexes np-ZnPc/p-ZnPc in DMSO and for complexes np-QZnPc/p-QZnPc in DMSO, phosphate buffered solution (PBS) and PBS+Triton-X 100 solutions. The fluorescence of the tetra-substituted quaternized zinc phthalocyanine complexes (np-QZnPc/p-QZnPc) are effectively quenched addition of 1,4-benzoquinone (BQ) and this study also presented the ionic zinc phthalocyanine complexes strongly bind to bovine serum albumin (BSA). PMID- 21536491 TI - Determination of ethambutol by a sensitive fluorescent probe. AB - The competitive reaction between ethambutol and two fluorescent probes (i.e., berberine and palmatine) for occupancy of the cucurbit[7]uril (CB[7]) cavity was studied by spectrofluorometry. The CB[7] reacts with these probes to form stable complexes, and the fluorescence intensity of the complexes is greatly enhanced. In addition, the excitation and emission wavelengths of their complexes moved to wavelengths of 343 nm and 495 nm, respectively. However, the addition of ethambutol dramatically quenches the fluorescence intensity of the two complexes. Accordingly, a couple of new fluorescence quenching methods for the determination of ethambutol were established. The methods can be applied for quantifying ethambutol. A linear relationship between the fluorescence quenching values (DeltaF) and ethambutol concentration exists in the range of 5.0-1000.0 ng mL( 1), with a correlation coefficient (r) of 0.9997. The detection limit is 1.7 ng mL(-1). The fluorescent probe of berberine has higher sensitivity than palmatine. This paper also discusses the mechanism of fluorescence indicator probes. PMID- 21536492 TI - Using ORA to explore the relationship of nursing unit communication to patient safety and quality outcomes. AB - PURPOSE: We used ORA, a dynamic network analysis tool, to identify patient care unit communication patterns associated with patient safety and quality outcomes. Although ORA had previously had limited use in healthcare, we felt it could effectively model communication on patient care units. METHODS: Using a survey methodology, we collected communication network data from nursing staff on seven patient care units on two different days. Patient outcome data were collected via a separate survey. Results of the staff survey were used to represent the communication networks for each unit in ORA. We then used ORA's analysis capability to generate communication metrics for each unit. ORA's visualization capability was used to better understand the metrics. RESULTS: We identified communication patterns that correlated with two safety (falls and medication errors) and three quality (e.g., symptom management, complex self care, and patient satisfaction) outcome measures. Communication patterns differed substantially by shift. CONCLUSION: The results demonstrate the utility of ORA for healthcare research and the relationship of nursing unit communication patterns to patient safety and quality outcomes. PMID- 21536493 TI - Inter-individual variation in the efficient stimulation site for magnetic brainstem stimulation. AB - OBJECTIVE: To investigate inter-individual variation in the efficiency of magnetic brainstem stimulation (BST) with regard to the stimulation site. METHODS: We studied 31 healthy subjects, using a right hand muscle as a recording site. Three stimulation sites were compared: BST over the inion (inion BST), and BST over the midpoint between the inion and the right (ipsilateral BST) or left (contralateral BST) mastoid process. Five suprathreshold BSTs were performed for each stimulation site using the same stimulation intensity. The mean peak-to-peak amplitudes of motor evoked potential (MEP) were compared. The active motor threshold (AMT) and onset latency for inion BST and ipsilateral BST were also measured and compared. RESULTS: Contralateral BST did not evoke discernible MEPs in most subjects. In 21 subjects (67.7%), ipsilateral BST elicited larger MEPs than inion BST did, and AMT for ipsilateral BST was lower than or equal to the AMT for inion BST in all subjects. Ipsilateral BST elicited shorter latency in such subjects. CONCLUSIONS: The suitable stimulation site for BST differed among subjects. About two-thirds showed larger MEP to ipsilateral BST. SIGNIFICANCE: These findings might help us to find an efficient stimulation site for BST in each subject. PMID- 21536494 TI - Profile of non-volatiles in whisky with regard to superoxide dismutase activity. AB - SOD (Superoxide dismutase)-like activities of 23 kinds of single malt whisky (Scotch and Japanese) were evaluated. There was a positive correlation between SOD-like activity and the maturation age of whisky that exceeded the difference resulting from the manufacturing region. The SOD-like activity of Yamazaki 18, a typical single malt whisky in Japan, was approximately 1333 U/ml and that of non volatile components in the whisky was 388U/mg, indicating that single malt whisky generally has a very strong SOD-like activity. To elucidate their contribution to SOD-like activity, the non-volatile components of whisky (Yamazaki 18) were ultrafiltered and separated with a Diaion HP20/water-EtOH system. Elution of the fraction less than 5000 molecular weight (<5000 MW fraction) with 60% (v/v) EtOH contributed most to SOD-like activity of the whisky. As this elution contained a considerable amount of polyphenolics, the content and SOD-like specific activity of ellagic acid, gallic acid, and lyoniresinol--the main whisky polyphenolics- were evaluated. The contribution of these compounds to the SOD-like activity of whisky was approximately 15%. Polyphenolics in whisky were relatively distributed to a higher MW fraction compared to carbohydrates in whisky, and specific activity (SOD-like activity per weight) of the >10,000 MW fraction was greater than that of the <5000 MW fraction, although the content of this fraction was low. These results indicate that various polyphenolics with higher molecular weights also contribute to the SOD-like activity of whisky together with main whisky polyphenolics. PMID- 21536495 TI - Efficient hydrolytic reaction of an acetate ester with fungal lipase in a liquid liquid interface bioreactor (L-L IBR) using CaCO3-coated ballooned microsphere. AB - In a liquid-liquid interface bioreactor using a CaCO3-coated ballooned microsphere, 2-ethylhexyl acetate was efficiently hydrolyzed to 2-ethyl-1-hexanol with Absidia coerulea NBRC 4423 compared with using talc-coated or non-coated ballooned microsphere. It was assumed that CaCO3 brought about stabilization of lipase by Ca2+ and maintenance of medium pH. PMID- 21536496 TI - Examining the relationship between family meal frequency and individual dietary intake: does family cohesion play a role? AB - OBJECTIVE: To confirm previously reported associations between family meal frequency and dietary intake, and to examine family cohesion as a potential mediator of this relationship. DESIGN: Cross-sectional observational study. Data collected at baseline via questionnaire. SETTING: Randomized, controlled household weight gain prevention trial. PARTICIPANTS: Participants were 152 adults and 75 adolescents from 90 community households. VARIABLES MEASURED: Family meal frequency assessed with a single question. Perceived family cohesion measured by the Family Adaptability and Cohesion Evaluation Scale-III. Usual intake of targeted food items assessed with modified food frequency questionnaire. ANALYSIS: Hierarchical linear regression with mediation analysis. Statistical significance set at alpha-level .05. RESULTS: Family meal frequency was associated with intake of fruits and vegetables in adults, and sweets and sugar-sweetened beverages in adolescents. Family meal frequency was positively correlated with perceived family cohesion (r = 0.41, P < .01). Partial mediation by family cohesion was observed for family meal frequency and sweets intake in adolescents. CONCLUSIONS AND IMPLICATIONS: Results suggest that family cohesion is not a consistent mediator of relationship between family meal frequency and individual dietary intake. Future studies should assess additional plausible mediators of this relationship in order to better understand the effect of family meals on dietary intake. PMID- 21536498 TI - Postpartum evaluation and long term implications. AB - Hypertension, proteinuria and biochemical changes caused by pre-eclampsia may persist for several weeks and even months postpartum. Hypertension and pre eclampsia may even develop for the first time postpartum. Care in the six weeks postpartum should include management of hypertension and screening for secondary causes of hypertension including renal disease if abnormalities persist beyond six weeks. Optimal postpartum monitoring for patients with preeclampsia has not been determined, and care needs to be individualized. The postpartum period also provides a window of opportunity for planning for the next pregnancy in addition to discussing long term implications of pre-eclampsia. Increased risk for the development of premature cardiovascular disease is the most significant long term implication of pre-eclampsia. Pre-eclampsia and cardiovascular disease share a common disease pathophysiology. Women who develop pre-eclampsia have pre-existing metabolic abnormalities or may develop them later in life. Women with early onset pre-eclampsia are at the highest risk of ischemic heart disease. Women with a history of pre-eclampsia should adopt a heart healthy lifestyle and should be screened and treated for traditional cardiovascular risk factors according to locally accepted guidelines. PMID- 21536497 TI - Generation of hematopoietic humanized mice in the newborn BALB/c-Rag2null Il2rgammanull mouse model: a multivariable optimization approach. AB - Hematopoietic humanized mice generated via transplantation of human hematopoietic stem cells (hHSCs) into immunodeficient mice are a valuable tool for studying development and function of the human immune system. This study was performed to generate a protocol that improves development and quality of humanized mice in the BALB/c-Rag2(null)Il2rgamma(null) strain, testing route of injection, in vitro culture and freezing of hHSCs, types of cytokines in the culture, and co injection of lineage-depleted CD34(-) cells. Specific hHSC culturing conditions and the addition of support cells were found to increase the frequency, and human hematopoietic chimerism, of humanized mice. The optimized protocol resulted in BALB/c-Rag2(null)Il2rgamma(null) humanized mice displaying more consistent human hematopoietic and lymphoid engraftment. Thus, hematopoietic humanized mice generated on a BALB/c immunodeficient background represent a useful model to study the human immune system. PMID- 21536499 TI - Primary care doctors' management behavior with respect to epilepsy in Kerala, southern India. AB - Although a majority of persons with epilepsy in developing countries are diagnosed, treated, and followed up by primary care doctors, few efforts have been made to examine their understanding with respect to epilepsy management. Through a questionnaire survey, we gathered information about the epilepsy management behavior of 500 primary care doctors distributed across the south Indian state of Kerala. Very few of them ever had diagnosed focal seizures, and the majority of them overutilize EEGs, prescribe continuous antiepileptic drug (AED) prophylaxis for febrile convulsions, use relatively expensive AEDs often in combination and in suboptimal doses, and did not know about alternate management options for AED-resistant epilepsies. A substantial proportion of the current large treatment gap in epilepsy in developing countries could be minimized by educating the primary care physicians about the diagnosis of epileptic seizures, cost-effective AED treatment, and need-based referral for specialized care. PMID- 21536500 TI - The use of optical coherence tomography to aid in diagnosing solar maculopathy. AB - BACKGROUND: Solar maculopathy is most commonly diagnosed after the direct viewing of solar eclipses. The damage to the retina is located in the outer segments of photoreceptors and in the retinal pigmentary epithelium. It may be acceptable to use optical coherence tomography (OCT) to identify retinal damage caused by the sun. CASE REPORT: Here we describe a case of a patient who reported with a mild decrease in best-corrected visual acuities. Dilated examination found macular changes that were present in both eyes resembling solar maculopathy. OCT was utilized to aid in the diagnosis of solar maculopathy. CONCLUSIONS: With the large number of individuals who spend their time in the sun, a practitioner should consider the possible repercussions of this activity. We are all aware of the damage that the sun can cause to the skin and, as in the case of cataracts, its effects on the eye. In cases in which macular changes are noted we should consider the possibility of solar maculopathy. As is in the case presented here, OCT may be an effective means of assessing the maculopathy. PMID- 21536501 TI - Bezold-Jarisch reflex in sino-aortic denervated malnourished rats. AB - In this study we assessed the role of Bezold-Jarisch reflex (BJR) in the regulation of blood pressure (BP) of malnourished (MN) and control rats (CN) with sino-aortic denervation (SAD). Fischer rats were fed diets containing either 6% (MN) or 15% (CN) protein for 35 days after weaning. These rats underwent sham or SAD and catheterization of femoral artery and vein for BP measurements and drug injection. Phenylbiguanide (PBG 5 MUg/kg, i.v.) for activation BJR, produced bradycardia (-317+/-22 bpm for CN vs. -372+/-16 bpm for MN) and hypotension ( 57+/-4 mm Hg for CN vs. -54+/-6 mm Hg for MN. After SAD, MN rats had reduced hypotensive (-37+/-7 mm Hg for MN vs. -82+/-6 mm Hg for CN) and bradycardic ( 124+/-17 for MN vs. -414+/-20 bpm CN) responses to BJR activation. To evaluate the contribution of the parasympathetic component due to BJR for the fall in BP, methyl atropine bromide, was given between two injections of PBG (5 MUg/kg) separated by 10 min each other. Both bradycardic (-216+/-21 bpm before and -4+/-3 bpm after for CN -226+/-43 bpm before and -9+/-20 bpm after for MN) and hypotensive (-42+/-4 mm Hg before and -6+/-1 mm Hg after for CN -33+/-9 mm Hg before and -5+/-2 mm Hg after for MN) responses were abolished in CN and MN groups. These data indicate that dietary protein malnutrition changes the relation between baroreflex and BJR required for maintenance of the BP during malnourishment. PMID- 21536502 TI - Communication of information about reproductive and sexual health in cystic fibrosis. Patients, parents and caregivers' experience. AB - BACKGROUND: This review evaluated research concerning communication and information about reproductive and sexual health (RSH) in cystic fibrosis (CF). METHODS: Papers in the English language reporting RSH issues in CF, published between January 2000 and December 2010, were included. The review focused on (a) the content of information given to parents and patients, (b) the timing of information, (c) the sources of information, (d) attitudes and emotional reactions, (e) chronic illness and sexual behavior, (f) methodological and cultural considerations and (g) ethical considerations. RESULTS: Eleven papers were identified originating from Australia, the United Kingdom and Poland. Patients and parents expressed the need for up-to-date, CF-related verbal and written information, provided by the CF team and infertility specialists. Patients were often embarrassed to initiate a discussion. Health care providers expressed the need for training to counsel patients in RSH. CONCLUSION: A pro active discussion of RSH issues is proposed as a standard part of the care pathway. A list of recommendations is given to initiate this process. PMID- 21536503 TI - Cystic fibrosis newborn screening does not delay the identification of cystic fibrosis in children with negative results. AB - BACKGROUND: Several studies have demonstrated the benefit of Cystic Fibrosis Newborn Screening (CFNBS) for early diagnosis and, hence, intervention but the impact of CFNBS on those children not detected on CFNBS is not known. CFNBS may provide false reassurance that all CF has been detected and, therefore, lead to a delay in the diagnosis of children with CF which is not detected on CFNBS. The aim of this study was to determine the impact of CFNBS on the presenting features of children with CF where CF was not detected on CFNBS. METHODS: Subjects at the CFNBS center were selected if CF was identified subsequent to a negative CFNBS with subjects at the No CFNBS selected based on the absence of DeltaF508 mutations. Children presenting with features that would lead to investigation for CF independent of clinical status were excluded. Presenting features at diagnosis and pulmonary function at 6 years of age were extracted from medical records. RESULTS: Twelve children from the CFNBS site and 19 from the No CFNBS site were included in the analysis. The only significant difference between the two in features at diagnosis was lower mean weight z-scores at the No CFNBS site (-2.9 +/- 1.8) compared to the CFNBS center (-1.4 +/- 1.3, p<0.05). Age at diagnosis, presenting complaint and nutritional status did not differ by site. Growth parameters and pulmonary function at 6years of age showed no differences between sites. CONCLUSIONS: This study demonstrates that access to CFNBS does not result in delay in diagnosis or poorer outcomes in those children for whom CF was not detected on CFNBS. In addition, children with CF not detected on CFNBS present with typical features of CF and sweat chloride results that are diagnostic of CF. PMID- 21536504 TI - Ultra-performance liquid chromatography/tandem mass spectrometry for accurate quantification of global DNA methylation in human sperms. AB - Aberrant DNA methylation in human sperms has been proposed to be a possible mechanism associated with male infertility. We developed an ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for rapid, sensitive, and specific detection of global DNA methylation level in human sperms. Multiple-reaction monitoring (MRM) mode was used in MS/MS detection for accurate quantification of DNA methylation. The intra-day and inter-day precision values of this method were within 1.50-5.70%. By using 2-deoxyguanosine as an internal standard, UPLC-MS/MS method was applied for the detection of global DNA methylation levels in three cultured cell lines. DNA methyltransferases inhibitor 5-aza-2'-deoxycytidine can significantly reduce global DNA methylation levels in treated cell lines, showing the reliability of our method. We further examined global DNA methylation levels in human sperms, and found that global methylation values varied from 3.79% to 4.65%. The average global DNA methylation level of sperm samples washed only by PBS (4.03%) was relatively lower than that of sperm samples in which abnormal and dead sperm cells were removed by density gradient centrifugation (4.25%), indicating the possible aberrant DNA methylation level in abnormal sperm cells. Clinical application of UPLC-MS/MS method in global DNA methylation detection of human sperms will be useful in human sperm quality evaluation and the study of epigenetic mechanisms responsible for male infertility. PMID- 21536505 TI - An LC-MS/MS procedure for the quantification of naproxen in human plasma: development, validation, comparison with other methods, and application to a pharmacokinetic study. AB - A sensitive, precise and accurate quantitative LC-MS/MS method for the measurement of naproxen in human plasma was developed and completely validated according to current FDA and EMA guidelines. The new method employs acetonitrile protein precipitation for sample preparation and uses ketoprofen as the internal standard. Suitability of the new assay was assessed in comparison with 36 reported bioanalytical assays and the pharmacokinetic results obtained by the new method were compared to 11 reported studies in humans. The principal advantage of this LC-MS/MS method is the simultaneous achievement of high absolute recovery (90.0+/-3.6%), acceptable sensitivity (lower limit of quantitation of 0.100 MUg/mL), high inter-day precision (CV<=9.4%), high analytical recovery (between 94.4 and 103.1%), and excellent linearity over the concentration range 0.100-50.0 MUg/mL (r(2)>=0.998) combined with a short run time of only 2 min. PMID- 21536507 TI - [Ganglioneuroma as an uncommon cause of adrenal tumor]. PMID- 21536508 TI - [Carney complex]. AB - Carney complex (CNC) is an autosomal dominantly inherited syndrome characterized by spotty skin pigmentation, cardiac and cutaneous myxoma, and endocrine overactivity. Skin pigmentation includes lentigines and blue nevi. Myxomas may occur in breast, skin and heart. Cardiac myxomas may be multiple and occur in any cardiac chamber, and are more prone to recurrence. The most common endocrine gland manifestation is an ACTH-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). PPNAD may occur isolated, with no other signs of CNC. Pituitary and thyroid glands and gonads are also involved. The PRKAR1A gene, located in 17 q22-24, encodes type 1A regulatory subunit of protein kinase A. Inactivating germline mutations of this gene are found in 70% of patients with CNC. PRKAR1A is a key component of the c-AMP signaling pathway that has been implicated in endocrine tumorigenesis. Many different mutations have been reported in the PRKAR1A gene. In almost all cases the sequence change was predicted to lead to a premature stop codon and the resultant mutant mRNA was subject to nonsense-mediated mRNA decay. There is no clear genotype-phenotype correlation in patients with CNC. Genetic analysis should be performed in all CNC index cases. All affected patients should be monitored for clinical signs of CNC at least once a year. Genetic diagnosis allows for more effective preparation of more appropriate and effective therapeutic strategies and genetic counseling for patients and gene carriers, and to avoid unnecessary tests to relatives not carrying the gene. PMID- 21536506 TI - Metabolic effects of signal transduction inhibition in cancer assessed by magnetic resonance spectroscopy. AB - Despite huge efforts in development of drugs targeting oncogenic signalling, the number of such drugs entering clinical practice to date remains limited. Rational use of biomarkers for drug candidate selection and early monitoring of response to therapy may accelerate this process. Magnetic resonance spectroscopy (MRS) can be used to assess metabolic effects of drug treatment both in vivo and in vitro, and technological advances are continuously increasing the utility of this non invasive method. In this review, we summarise the use of MRS for monitoring the effect of targeted anticancer drugs, and discuss the potential role of MRS in the context of personalised cancer treatment. PMID- 21536509 TI - [Complications of bladder catheterization to obtain a urine sample in the emergency department]. AB - INTRODUCTION: Bladder catheterization (BC) is frequently performed to diagnose urinary tract infection (UTI) (the most common serious bacterial infection among young children). The purposes of this study were to evaluate performance and complications of BC to obtain a urine specimen. MATERIAL AND METHODS: This was a prospective study conducted in an urban children's hospital on patients who had a urine specimen obtained in the emergency department (ED) by BC between November 1, 2009 and December 15, 2009. Epidemiological data and the medical reasons why the BC was performed were reviewed. Finally, to determine the complications we contacted the family by telephone at least one month after the BC. RESULTS: A total of 126 BC were performed in 124 patients, 45 males (35.7%) and 81 female (64.3%). A urine sample was obtained in all cases. The median age was 7 months (5 days-35 months). Of the 126 urine cultures collected, 34 were positive (26.98%) and 1 was considered contaminated (0.8%). Escherichia coli was the most common pathogen (27, 79.41%). Fever (76.2%) was the main reason why BC was performed in children. Of the 116 patients contacted by telephone, only 5 mentioned complications: genital pain (3), unconfirmed hematuria (1) and UTI 12 days after (1). CONCLUSIONS: BC performed in ED to obtain a urine sample in non toilet trained children is effective and safe. BC is an invasive method which needs to be quality controlled. PMID- 21536510 TI - Recent advances in neonatal surgery. PMID- 21536511 TI - Finding the lateral cutaneous nerve of the thigh. PMID- 21536512 TI - Subcutaneous metastasis of a GIST tumour unresponsive to Imatinib. PMID- 21536513 TI - Allelic frequencies and statistical data obtained from 48 AIM INDEL loci in an admixed population from the Brazilian Amazon. AB - Allelic frequencies of 48 informative insert-delete (INDEL) loci were obtained from a sample set of 130 unrelated individuals living in Macapa, a city located in the northern Amazon region, in Brazil. The values of heterozygosity (H), polymorphic information content (PIC), power of discrimination (PD), power of exclusion (PE), matching probability (MP) and typical paternity index (TPI) were calculated and showed the forensic efficiency of these genetic markers. Based on the allele frequency obtained for the population of Macapa, we estimated an interethnic admixture for the three parental groups (European, Native American and African) of, respectively, 50%, 21% and 29%. Comparing these allele frequencies with those of other Brazilian populations and the parental populations, statistically significant distances were found. The interpopulation genetic distance (F(ST) coefficients) to the present database ranged from F(ST)=0.0431 (p<0.00001) between Macapa and Belem to F(ST)=0.266 (p<0.00001) between Macapa and the Native American group. PMID- 21536514 TI - Therapy for hepatic fibrosis: revisiting the preclinical models. PMID- 21536515 TI - Acute animal and human study of tensiometric pacing lead sensor based on triboelectricity. AB - Cardiac contractions bend the implanted cardiac lead body, extend and compress the lead conductors, their insulation and the inserted stylet. Magnitude of lead deflection depends on cardiac muscle contraction forces. The purpose of study was to measure the charge generated due to triboelectric effect between one of the lead conductors and the inserted stylet. The charge was measured by differential charge amplifier being connected to isolation amplifier and power supply. Sensor signal, ECG and intracardiac electrograms were acquired. Three models of custom designed leads were implanted in 8 sheep. Measurements were done in 18 patients undergoing pacemaker implantation and replacement procedures. Atrial and ventricular tensiometric signals were recorded in dual chamber and in single-lead VDD patients. Recordings in sinus rhythm at various AV intervals and in supraventricular tachycardia were done. In average, charge variation between 1 and 600 pC was measured. Tensiometric stylet could be feasible hemodynamic sensor for myocardial contraction detection. Its main advantage is that it is easily exchangeable and universal for all leads. PMID- 21536516 TI - Impact of physiological ventricular deformation on the morphology of the T-wave: a hybrid, static-dynamic approach. AB - Ventricular wall deformation is widely assumed to have an impact on the morphology of the T-wave that can be measured on the body surface. This study aims at quantifying these effects based on an in silico approach. To this end, we used a hybrid, static-dynamic approach: action potential propagation and repolarization were simulated on an electrophysiologically detailed but static 3 D heart model while the forward calculation accounted for ventricular deformation and the associated movement of the electrical sources (thus, it was dynamic). The displacement vectors that describe the ventricular motion were extracted from cinematographic and tagged MRI data using an elastic registration procedure. To probe to what extent the T-wave changes depend on the synchrony/asynchrony of mechanical relaxation and electrical repolarization, we created three electrophysiological configurations, each with a unique QT time: a setup with physiological QT time, a setup with pathologically short QT time (SQT), and pathologically long QT time (LQT), respectively. For all three electrophysiological configurations, a reduction of the T-wave amplitude was observed when the dynamic model was used for the forward calculations. The largest amplitude changes and the lowest correlation coefficients between the static and dynamic model were observed for the SQT setup, followed by the physiological QT and LQT setups. PMID- 21536517 TI - Diffuse optical multipatch technique for tissue oxygenation monitoring: clinical study in intensive care unit. AB - Diffuse optical multipatch technique is used to assess spatial variations in absorption and scattering in biological tissue, by monitoring changes in the concentration of oxyhemoglobin and deoxyhemoglobin. In our preliminary study, the temporal tracings of tissue oxygenation are measured using diffuse optical multipatch measurement and a venous occlusion test, employing normal subjects and ICU patients suffering from sepsis and heart failure. In experiments, obvious differences in tissue oxygenation signals were observed among all three groups. This paper discusses the physiological relevance of tissue oxygenation with respect to disease. PMID- 21536518 TI - Multi-pinhole SPECT calibration: influence of data noise and systematic orbit deviations. AB - The geometry of a single pinhole SPECT system with circular orbit can be uniquely determined from a measurement of three point sources, provided that at least two inter-point distances are known. In contrast, it has been shown mathematically that, for a multi-pinhole SPECT system with circular orbit, only two point sources are needed, and the knowledge of the distance between them is not required. In this paper, we report that this conclusion only holds if the motion of the camera is perfectly circular. In reality, the detector heads systematically slightly deviate from the circular orbit, which may introduce non negligible bias in the estimated parameters and degrade the reconstructed image. An analytical linear model was extended to estimate the influence of both data noise and systematic deviations on the accuracy of the calibration and on the image quality of the reconstruction. It turns out that applying the knowledge of the distances greatly reduces the reconstruction error, especially in the presence of systematic deviations. In addition, we propose that instead of using the information about the distances between the point sources, it is more straightforward to use the knowledge about the distances between the pinhole apertures during multi-pinhole calibration. The two distance-fixing approaches yield similar reconstruction accuracy. Our theoretical results are supported by reconstruction images of a Jaszczak-type phantom scan. PMID- 21536519 TI - Robust statistical label fusion through COnsensus Level, Labeler Accuracy, and Truth Estimation (COLLATE). AB - Segmentation and delineation of structures of interest in medical images is paramount to quantifying and characterizing structural, morphological, and functional correlations with clinically relevant conditions. The established gold standard for performing segmentation has been manual voxel-by-voxel labeling by a neuroanatomist expert. This process can be extremely time consuming, resource intensive and fraught with high inter-observer variability. Hence, studies involving characterizations of novel structures or appearances have been limited in scope (numbers of subjects), scale (extent of regions assessed), and statistical power. Statistical methods to fuse data sets from several different sources (e.g., multiple human observers) have been proposed to simultaneously estimate both rater performance and the ground truth labels. However, with empirical datasets, statistical fusion has been observed to result in visually inconsistent findings. So, despite the ease and elegance of a statistical approach, single observers and/or direct voting are often used in practice. Hence, rater performance is not systematically quantified and exploited during label estimation. To date, statistical fusion methods have relied on characterizations of rater performance that do not intrinsically include spatially varying models of rater performance. Herein, we present a novel, robust statistical label fusion algorithm to estimate and account for spatially varying performance. This algorithm, COnsensus Level, Labeler Accuracy and Truth Estimation (COLLATE), is based on the simple idea that some regions of an image are difficult to label (e.g., confusion regions: boundaries or low contrast areas) while other regions are intrinsically obvious (e.g., consensus regions: centers of large regions or high contrast edges). Unlike its predecessors, COLLATE estimates the consensus level of each voxel and estimates differing models of observer behavior in each region. We show that COLLATE provides significant improvement in label accuracy and rater assessment over previous fusion methods in both simulated and empirical datasets. PMID- 21536521 TI - Implementation study of an analog spiking neural network for assisting cardiac delay prediction in a cardiac resynchronization therapy device. AB - In this paper, we aim at developing an analog spiking neural network (SNN) for reinforcing the performance of conventional cardiac resynchronization therapy (CRT) devices (also called biventricular pacemakers). Targeting an alternative analog solution in 0.13- MUm CMOS technology, this paper proposes an approach to improve cardiac delay predictions in every cardiac period in order to assist the CRT device to provide real-time optimal heartbeats. The primary analog SNN architecture is proposed and its implementation is studied to fulfill the requirement of very low energy consumption. By using the Hebbian learning and reinforcement learning algorithms, the intended adaptive CRT device works with different functional modes. The simulations of both learning algorithms have been carried out, and they were shown to demonstrate the global functionalities. To improve the realism of the system, we introduce various heart behavior models (with constant/variable heart rates) that allow pathologic simulations with/without noise on the signals of the input sensors. The simulations of the global system (pacemaker models coupled with heart models) have been investigated and used to validate the analog spiking neural network implementation. PMID- 21536520 TI - Topology-based kernels with application to inference problems in Alzheimer's disease. AB - Alzheimer's disease (AD) research has recently witnessed a great deal of activity focused on developing new statistical learning tools for automated inference using imaging data. The workhorse for many of these techniques is the support vector machine (SVM) framework (or more generally kernel-based methods). Most of these require, as a first step, specification of a kernel matrix K between input examples (i.e., images). The inner product between images I(i) and I(j) in a feature space can generally be written in closed form and so it is convenient to treat K as "given." However, in certain neuroimaging applications such an assumption becomes problematic. As an example, it is rather challenging to provide a scalar measure of similarity between two instances of highly attributed data such as cortical thickness measures on cortical surfaces. Note that cortical thickness is known to be discriminative for neurological disorders, so leveraging such information in an inference framework, especially within a multi-modal method, is potentially advantageous. But despite being clinically meaningful, relatively few works have successfully exploited this measure for classification or regression. Motivated by these applications, our paper presents novel techniques to compute similarity matrices for such topologically-based attributed data. Our ideas leverage recent developments to characterize signals (e.g., cortical thickness) motivated by the persistence of their topological features, leading to a scheme for simple constructions of kernel matrices. As a proof of principle, on a dataset of 356 subjects from the Alzheimer's Disease Neuroimaging Initiative study, we report good performance on several statistical inference tasks without any feature selection, dimensionality reduction, or parameter tuning. PMID- 21536522 TI - Measuring neuromuscular control dynamics during car following with continuous haptic feedback. AB - In previous research, a driver support system that uses continuous haptic feedback on the gas pedal to inform drivers of the separation to the lead vehicle was developed. Although haptic feedback has been previously shown to be beneficial, the influence of the underlying biomechanical properties of the driver on the effectiveness of haptic feedback is largely unknown. The goal of this paper is to experimentally determine the biomechanical properties of the ankle-foot complex (i.e., the admittance) while performing a car-following task, thereby separating driver responses to visual feedback from those to designed haptic feedback. An experiment was conducted in a simplified fixed-base driving simulator, where ten participants were instructed to follow a lead vehicle, with and without the support of haptic feedback. During the experiment, the lead vehicle velocity was perturbed, and small stochastic torque perturbations were applied to the pedal. Both perturbations were separated in the frequency domain to allow the simultaneous estimation of frequency response functions of both the car-following control behavior and the biomechanical admittance. For comparison to previous experiments, the admittance was also estimated during three classical motion control tasks (resist forces, relax, and give way to forces). The main experimental hypotheses were that, first, the haptic feedback would encourage drivers to adopt a "give way to force task," resulting in larger admittance compared with other tasks and, second, drivers needed less control effort to realize the same car-following performance. Time- and frequency-domain analyses provided evidence for both hypotheses. The developed methodology allows quantification of the range of admittances that a limb can adopt during vehicle control or while performing a variety of motion control tasks. It thereby allows detailed computational driver modeling and provides valuable information on how to design and evaluate continuous haptic feedback systems. PMID- 21536523 TI - Compressed sensing with wavelet domain dependencies for coronary MRI: a retrospective study. AB - Coronary magnetic resonance imaging (MRI) is a noninvasive imaging modality for diagnosis of coronary artery disease. One of the limitations of coronary MRI is its long acquisition time due to the need of imaging with high spatial resolution and constraints on respiratory and cardiac motions. Compressed sensing (CS) has been recently utilized to accelerate image acquisition in MRI. In this paper, we develop an improved CS reconstruction method, Bayesian least squares-Gaussian scale mixture (BLS-GSM), that uses dependencies of wavelet domain coefficients to reduce the observed blurring and reconstruction artifacts in coronary MRI using traditional l(1) regularization. Images of left and right coronary MRI was acquired in 7 healthy subjects with fully-sampled k-space data. The data was retrospectively undersampled using acceleration rates of 2, 4, 6, and 8 and reconstructed using l(1) thresholding, l(1) minimization and BLS-GSM thresholding. Reconstructed right and left coronary images were compared with fully-sampled reconstructions in vessel sharpness and subjective image quality (1 4 for poor-excellent). Mean square error (MSE) was also calculated for each reconstruction. There were no significant differences between the fully sampled image score versus rate 2, 4, or 6 for BLS-GSM for both right and left coronaries (=N.S.). However, for l(1) thresholding significant differences were observed for rates higher than 2 and 4 for right and left coronaries respectively. l(1) minimization also yields images with lower scores compared to the reference for rates higher than 4 for both coronaries. These results were consistent with the quantitative vessel sharpness readings. BLS-GSM allows acceleration of coronary MRI with acceleration rates beyond what can be achieved with l(1) regularization. PMID- 21536525 TI - Implementation methodology for interoperable personal health devices with low voltage low-power constraints. AB - Traditionally, e-Health solutions were located at the point of care (PoC), while the new ubiquitous user-centered paradigm draws on standard-based personal health devices (PHDs). Such devices place strict constraints on computation and battery efficiency that encouraged the International Organization for Standardization/IEEE11073 (X73) standard for medical devices to evolve from X73PoC to X73PHD. In this context, low-voltage low-power (LV-LP) technologies meet the restrictions of X73PHD-compliant devices. Since X73PHD does not approach the software architecture, the accomplishment of an efficient design falls directly on the software developer. Therefore, computational and battery performance of such LV-LP-constrained devices can even be outperformed through an efficient X73PHD implementation design. In this context, this paper proposes a new methodology to implement X73PHD into microcontroller-based platforms with LV LP constraints. Such implementation methodology has been developed through a patterns-based approach and applied to a number of X73PHD-compliant agents (including weighing scale, blood pressure monitor, and thermometer specializations) and microprocessor architectures (8, 16, and 32 bits) as a proof of concept. As a reference, the results obtained in the weighing scale guarantee all features of X73PHD running over a microcontroller architecture based on ARM7TDMI requiring only 168 B of RAM and 2546 B of flash memory. PMID- 21536524 TI - Spatially regularized compressed sensing for high angular resolution diffusion imaging. AB - Despite the relative recency of its inception, the theory of compressive sampling (aka compressed sensing) (CS) has already revolutionized multiple areas of applied sciences, a particularly important instance of which is medical imaging. Specifically, the theory has provided a different perspective on the important problem of optimal sampling in magnetic resonance imaging (MRI), with an ever increasing body of works reporting stable and accurate reconstruction of MRI scans from the number of spectral measurements which would have been deemed unacceptably small as recently as five years ago. In this paper, the theory of CS is employed to palliate the problem of long acquisition times, which is known to be a major impediment to the clinical application of high angular resolution diffusion imaging (HARDI). Specifically, we demonstrate that a substantial reduction in data acquisition times is possible through minimization of the number of diffusion encoding gradients required for reliable reconstruction of HARDI scans. The success of such a minimization is primarily due to the availability of spherical ridgelet transformation, which excels in sparsifying HARDI signals. What makes the resulting reconstruction procedure even more accurate is a combination of the sparsity constraints in the diffusion domain with additional constraints imposed on the estimated diffusion field in the spatial domain. Accordingly, the present paper describes an original way to combine the diffusion- and spatial-domain constraints to achieve a maximal reduction in the number of diffusion measurements, while sacrificing little in terms of reconstruction accuracy. Finally, details are provided on an efficient numerical scheme which can be used to solve the aforementioned reconstruction problem by means of standard and readily available estimation tools. The paper is concluded with experimental results which support the practical value of the proposed reconstruction methodology. PMID- 21536526 TI - Store-and-feedforward adaptive gaming system for hand-finger motion tracking in telerehabilitation. AB - This paper presents a telerehabilitation system that encompasses a webcam and store-and-feedforward adaptive gaming system for tracking finger-hand movement of patients during local and remote therapy sessions. Gaming-event signals and webcam images are recorded as part of a gaming session and then forwarded to an online healthcare content management system (CMS) that separates incoming information into individual patient records. The CMS makes it possible for clinicians to log in remotely and review gathered data using online reports that are provided to help with signal and image analysis using various numerical measures and plotting functions. Signals from a 6 degree-of-freedom magnetic motion tracking system provide a basis for video-game sprite control. The MMT provides a path for motion signals between common objects manipulated by a patient and a computer game. During a therapy session, a webcam that captures images of the hand together with a number of performance metrics provides insight into the quality, efficiency, and skill of a patient. PMID- 21536527 TI - A new measure of movement symmetry in early Parkinson's disease patients using symbolic processing of inertial sensor data. AB - Movement asymmetry is one of the motor symptoms associated with Parkinson's disease (PD). Therefore, being able to detect and measure movement symmetry is important for monitoring the patient's condition. The present paper introduces a novel symbol based symmetry index calculated from inertial sensor data. The method is explained, evaluated, and compared to six other symmetry measures. These measures were used to determine the symmetry of both upper and lower limbs during walking of 11 early-to-mid-stage PD patients and 15 control subjects. The patients included in the study showed minimal motor abnormalities according to the unified Parkinson's disease rating scale (UPDRS). The symmetry indices were used to classify subjects into two different groups corresponding to PD or control. The proposed method presented high sensitivity and specificity with an area under the receiver operating characteristic (ROC) curve of 0.872, 9% greater than the second best method. The proposed method also showed an excellent intraclass correlation coefficient (ICC) of 0.949, 55% greater than the second best method. Results suggest that the proposed symmetry index is appropriate for this particular group of patients. PMID- 21536528 TI - A novel approach to dual excitation ratiometric optical mapping of cardiac action potentials with di-4-ANEPPS using pulsed LED excitation. AB - We developed a new method for ratiometric optical mapping of transmembrane potential (V(m)) in cardiac preparations stained with di-4-ANEPPS. V(m)-dependent shifts of excitation and emission spectra establish two excitation bands (<481 and >481 nm) that produce fluorescence changes of opposite polarity within a single emission band (575-620 nm). The ratio of these positive and negative fluorescence signals (excitation ratiometry) increases V(m) sensitivity and removes artifacts common to both signals. We pulsed blue (450 +/- 10 nm) and cyan (505 +/- 15 nm) light emitting diodes (LEDs) at 375 Hz in alternating phase synchronized to a camera (750 frames-per-second). Fluorescence was bandpass filtered (585 +/- 20 nm). This produced signals with upright (blue) and inverted (cyan) action potentials (APs) interleaved in sequential frames. In four whole swine hearts with motion chemically arrested, fractional fluorescence for blue, cyan, and ratio signals was 1.2 +/- 0.3%, 1.2 +/- 0.3%, and 2.4 +/- 0.6%, respectively. Signal-to-noise ratios were 4.3 +/- 1.4, 4.0 +/- 1.2, and 5.8 +/- 1.9, respectively. After washing out the electromechanical uncoupling agent, we characterized motion artifact by cross-correlating blue, cyan, and ratio signals with a signal with normal AP morphology. Ratiometry improved cross-correlation coefficients from 0.50 +/- 0.48 to 0.81 +/- 0.25, but did not cancel all motion artifacts. These findings demonstrate the feasibility of pulsed LED excitation ratiometry in myocardium. PMID- 21536529 TI - Bidomain ECG simulations using an augmented monodomain model for the cardiac source. AB - The electrocardiogram (ECG) is an essential clinical tool for the non-invasive assessment of cardiac function. Computational simulations of ECGs using bidomain models are considered the biophysically most detailed approach, but computational costs are significant. Alternatively, pseudo-bidomain formulations can be used, combining a monodomain model with an infrequent bidomain solve to obtain full extracellular potential (phi(e)) distributions and traces. However, previous attempts at such approaches did not see the expected significant decrease in compute time and did not include important effects of bath-loading on activation wavefront morphology (present in full bidomain models), representing a less accurate source term for phi(e) solution. ECG traces can also be derived from computationally cheaper phi(e) recovery techniques, whereby the time-course of phi(e) is approximated at a particular point using the monodomain transmembrane potential as source term. However, phi(e) recovery methods also assume tissue to be immersed in an unbounded conductive medium; not the case in most practical scenarios. We recently demonstrated how bath-loading effects in bidomain simulations could be replicated using an augmented monodomain model, faithfully reproducing bidomain wavefront shapes and activation patterns. Here, a computationally-efficient pseudobidomain formulation is suggested which combines the advantages of an augmented monodomain method with an infrequent bidomain solve, providing activation sequences, ECG traces and phi(e) distributions in a bounded medium surrounding the heart which closely match those of the full bidomain, but at ~ 10% the computational cost. We demonstrate the important impact of both bath-loading and a finite surrounding bath on spatiotemporal phi(e) distributions, thus demonstrating the utility of our novel pseudo-bidomain model in ECG computation with respect to previous pseudo-bidomain and phi(e) recovery approaches. PMID- 21536530 TI - Optimal rebinning of time-of-flight PET data. AB - Time-of-flight (TOF) positron emission tomography (PET) scanners offer the potential for significantly improved signal-to-noise ratio (SNR) and lesion detectability in clinical PET. However, fully 3D TOF PET image reconstruction is a challenging task due to the huge data size. One solution to this problem is to rebin TOF data into a lower dimensional format. We have recently developed Fourier rebinning methods for mapping TOF data into non-TOF formats that retain substantial SNR advantages relative to sinograms acquired without TOF information. However, mappings for rebinning into non-TOF formats are not unique and optimization of rebinning methods has not been widely investigated. In this paper we address the question of optimal rebinning in order to make full use of TOF information. We focus on FORET-3D, which approximately rebins 3D TOF data into 3D non-TOF sinogram formats without requiring a Fourier transform in the axial direction. We optimize the weighting for FORET-3D to minimize the variance, resulting in H(2)-weighted FORET-3D, which turns out to be the best linear unbiased estimator (BLUE) under reasonable approximations and furthermore the uniformly minimum variance unbiased (UMVU) estimator under Gaussian noise assumptions. This implies that any information loss due to optimal rebinning is as a result only of the approximations used in deriving the rebinning equation and developing the optimal weighting. We demonstrate using simulated and real phantom TOF data that the optimal rebinning method achieves variance reduction and contrast recovery improvement compared to nonoptimized rebinning weightings. In our preliminary study using a simplified simulation setup, the performance of the optimal rebinning method was comparable to that of fully 3D TOF MAP. PMID- 21536531 TI - Optic disk and cup segmentation from monocular color retinal images for glaucoma assessment. AB - Automatic retinal image analysis is emerging as an important screening tool for early detection of eye diseases. Glaucoma is one of the most common causes of blindness. The manual examination of optic disk (OD) is a standard procedure used for detecting glaucoma. In this paper, we present an automatic OD parameterization technique based on segmented OD and cup regions obtained from monocular retinal images. A novel OD segmentation method is proposed which integrates the local image information around each point of interest in multidimensional feature space to provide robustness against variations found in and around the OD region. We also propose a novel cup segmentation method which is based on anatomical evidence such as vessel bends at the cup boundary, considered relevant by glaucoma experts. Bends in a vessel are robustly detected using a region of support concept, which automatically selects the right scale for analysis. A multi-stage strategy is employed to derive a reliable subset of vessel bends called r-bends followed by a local spline fitting to derive the desired cup boundary. The method has been evaluated on 138 images comprising 33 normal and 105 glaucomatous images against three glaucoma experts. The obtained segmentation results show consistency in handling various geometric and photometric variations found across the dataset. The estimation error of the method for vertical cup-to-disk diameter ratio is 0.09/0.08 (mean/standard deviation) while for cup-to-disk area ratio it is 0.12/0.10. Overall, the obtained qualitative and quantitative results show effectiveness in both segmentation and subsequent OD parameterization for glaucoma assessment. PMID- 21536532 TI - On the inter-conversion between Hermite and Laguerre local image expansions. AB - The nice relationship existing among the Hermite-Gauss and the Laguerre-Gauss image expansions, whose basis functions span the same signal space, is investigated. As a result, a novel efficient method for Cartesian to polar coordinate inter-conversion, especially suited for dedicated hardware realization, is proposed. Applications to local image rotation, based on the simple steerability of the Laguerre-Gauss expansion, and to local image analysis, based on Gaussian derivatives, are considered in detail. A possible fixed-point realization of the proposed inter-conversion scheme is discussed. PMID- 21536533 TI - Computing steerable principal components of a large set of images and their rotations. AB - We present here an efficient algorithm to compute the Principal Component Analysis (PCA) of a large image set consisting of images and, for each image, the set of its uniform rotations in the plane. We do this by pointing out the block circulant structure of the covariance matrix and utilizing that structure to compute its eigenvectors. We also demonstrate the advantages of this algorithm over similar ones with numerical experiments. Although it is useful in many settings, we illustrate the specific application of the algorithm to the problem of cryo-electron microscopy. PMID- 21536534 TI - A one-layer recurrent neural network for constrained nonsmooth optimization. AB - This paper presents a novel one-layer recurrent neural network modeled by means of a differential inclusion for solving nonsmooth optimization problems, in which the number of neurons in the proposed neural network is the same as the number of decision variables of optimization problems. Compared with existing neural networks for nonsmooth optimization problems, the global convexity condition on the objective functions and constraints is relaxed, which allows the objective functions and constraints to be nonconvex. It is proven that the state variables of the proposed neural network are convergent to optimal solutions if a single design parameter in the model is larger than a derived lower bound. Numerical examples with simulation results substantiate the effectiveness and illustrate the characteristics of the proposed neural network. PMID- 21536535 TI - Cerebellarlike corrective model inference engine for manipulation tasks. AB - This paper presents how a simple cerebellumlike architecture can infer corrective models in the framework of a control task when manipulating objects that significantly affect the dynamics model of the system. The main motivation of this paper is to evaluate a simplified bio-mimetic approach in the framework of a manipulation task. More concretely, the paper focuses on how the model inference process takes place within a feedforward control loop based on the cerebellar structure and on how these internal models are built up by means of biologically plausible synaptic adaptation mechanisms. This kind of investigation may provide clues on how biology achieves accurate control of non-stiff-joint robot with low power actuators which involve controlling systems with high inertial components. This paper studies how a basic temporal-correlation kernel including long-term depression (LTD) and a constant long-term potentiation (LTP) at parallel fiber Purkinje cell synapses can effectively infer corrective models. We evaluate how this spike-timing-dependent plasticity correlates sensorimotor activity arriving through the parallel fibers with teaching signals (dependent on error estimates) arriving through the climbing fibers from the inferior olive. This paper addresses the study of how these LTD and LTP components need to be well balanced with each other to achieve accurate learning. This is of interest to evaluate the relevant role of homeostatic mechanisms in biological systems where adaptation occurs in a distributed manner. Furthermore, we illustrate how the temporal correlation kernel can also work in the presence of transmission delays in sensorimotor pathways. We use a cerebellumlike spiking neural network which stores the corrective models as well-structured weight patterns distributed among the parallel fibers to Purkinje cell connections. PMID- 21536536 TI - A wireless implantable sensor network system for in vivo monitoring of physiological signals. AB - A wireless implantable sensor network system (WISNS) is designed for in vivo monitoring physiological signals of a population of animals. WISNS can simultaneously monitor more than 15 animals, communicating three kinds of analog information among sensor nodes. Analog signals are transmitted to relay node at 800-KHz carrier by AM. Relay nodes digitalize and package them into messages, and then forward to the Wireless sensor network by Nordic RF technology (NWSN). Smaller overall dimensions (<2 cm (3)), lower power regulation, and dedicated packaging make the system suitable and compatible for implantable devices. The implantable sensor node, protocol stack of NWSN, and performance of the system are evaluated and optimized with ECG monitoring test of rats. Compared with those commercially available sensor nodes, our implantable one is leading in the weight and volume miniaturization, and our WISNS solution shows huge potential in achieving the compatibility of different animals. PMID- 21536537 TI - Assessment of nonoccupational exposure to DDT in the tropics and the north: relevance of uptake via inhalation from indoor residual spraying. AB - BACKGROUND: People who live in dwellings treated with indoor residual spraying (IRS) of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] for disease-vector control in the tropics and indigenous populations in the Arctic who consume marine mammals experience high nonoccupational exposure to DDT. Although the use of DDT in IRS is rising, the resulting nonoccupational exposure is poorly characterized. OBJECTIVES: We have provided a comparative assessment of exposure to DDT and its metabolites in the general population of the tropical and northern regions and in highly exposed populations in these regions. METHODS: We compiled > 600 average or median DDT concentrations from the peer-reviewed literature, representing > 23,000 individual measurements in humans, food, air, soil, and dust. We use Monte Carlo sampling of distributions based on these data to estimate distributions of population- and route-specific uptake. We evaluate our exposure estimates by comparing them with biomonitoring data. RESULTS: DDT concentrations are highest in people living in IRS-treated houses and lowest in the northern general population, differing by a factor of about 60. Inuits and the general population in the tropics have similar concentrations. Inhalation exposure explains most of the difference in concentration between the highly exposed and the general population in the Tropics. Calculated exposure levels are consistent with human biomonitoring data. CONCLUSIONS: Nonoccupational inhalation exposure is a relevant exposure pathway for people living in homes treated by IRS of DDT. Continued monitoring of time trends and DDE to DDT ratios in the Tropics and in the North is needed to identify a possible slowdown in concentration decline and the influence of ongoing DDT use. PMID- 21536539 TI - Lack of correlation between ERCC1 (C8092A) single nucleotide polymorphism and efficacy/toxicity of platinum based chemotherapy in Chinese patients with advanced non-small cell lung cancer. AB - PURPOSE: We investigated whether single nucleotide polymorphism of excision repair cross-complementation group 1 C8092A affected the clinical outcomes and toxicity in advanced stage non-small cell lung cancer patients receiving first line platinum based chemotherapy. MATERIAL/METHODS: A total of 300 chemotherapy treated patients were examined for C8092A genotypes in peripheral blood samples. RESULTS: Overall response rate was 33.6% and median overall survival was 13.5 months. There was no significant correlation between C8092A single nucleotide polymorphism and overall survival, tumor response or toxicity for platinum-based chemotherapy. CONCLUSIONS: Excision repair cross-complementing group 1 (ERCC1) showed controversial results in different studies that have been carried out until now. In our Chinese population there is no correlation between ERCC1 C8092A SNP and efficacy or toxicity. Ethnicity could be a possible explanation for these controversial results. PMID- 21536540 TI - Prevalence of spontaneous bacterial peritonitis in asymptomatic inpatients with decompensated liver cirrhosis - a pilot study. AB - PURPOSE: To assess the prevalence of spontaneous bacterial peritonitis (SBP) in asymptomatic patients with decompensated liver cirrhosis. MATERIAL AND METHODS: Patients (pts) with symptoms of decompensation of liver cirrhosis, ascites, and no signs indicating SBP were included to our study. Exclusion criteria include: 1/ clinical symptoms of infection, 2/ developing de novo or worsening hepatic encephalopathy, 3/ gastrointestinal bleeding within the last month, 4/ renal failure, 5/ antibiotic treatment or norfloxacin prophylaxis at admission. About 60 ml of ascitic fluid were drawn for lab examination. Pathologic assessment for atypical cells was also performed. RESULTS: 37 patients fulfilled inclusion criteria. Their mean age was 56.2 +/- 12.1. The Child-Pugh classification revealed 13 (35.1%) patients of class B and 24 (64.9%) patients of class C. The mean Model for End-Stage Liver Disease score in this group was 16.6 +/- 6.8. The mean ascitic protein content was 1.85 +/- 1.09 g/dL and mean neutrophil count 144.8 +/- 445.1/mm3. Ascitic fluid analysis revealed: signs of bacterascites in 6 of 37 (16.2%) pts; neutrocytic ascites in 1 of 37 (2.7%) pts; and 2 of 37 (5.4%) pts met criteria for SBP. C-reactive protein level was the best predictor of infection [SBP(+) 47.9 +/- 40.9 versus SBP(-) 11.7 +/- 5.1; p= 0.0005]. CONCLUSIONS: The prevalence of SBP in asymptomatic cirrhotics with ascites is low. We observed the trend towards more frequent occurrence of the infection in patients suffered from severe liver disease (Child-Pugh C group). PMID- 21536541 TI - The analgesic and antiemetic efficacy of gabapentin or ergotamine/caffeine for the treatment of postdural puncture headache. AB - PURPOSE: We investigated the analgesic and antiemetic efficacy of gabapentin or ergotamine/caffeine (Cafergot), in addition to conservative treatment consisting of bed rest and adequate fluid intake, for the treatment of postdural puncture headache (PDPH). METHODS: In this randomized, prospective, controlled study, gabapentin or Cafergot was administered to 42 adult patients suffering from PDPH. Patients were asked to record the severity of their headache and the number of vomiting episodes on a visual analogue scale (VAS) on days 1, 2, 3 and 4. The pain scale consisted of a 10 cm horizontal line marked from 0 (denoting no pain) to 10 (denoting worst possible imaginable pain) Emesis was scored as 0 = no emetic symptoms, 1 = nausea or 2 = vomiting. RESULTS: Demographic and anesthetic variables were similar between the groups. Gabapentin group had less pain, nausea and vomiting compared to the Cafergot group. No patients withdrew, gabapentin and Cafergot were well tolerated, and adverse events (somnolence, dizziness, tremor, and ataxia) did not occur. CONCLUSIONS: Gabapentin significantly reduced pain, nausea and vomiting compared to Cafergot in patients with PDPH. Lastly, we hypothesize that the gabaergic action of gabapentin, perhaps combined with other mechanisms, such as calcium channel blockade, may be responsible for its remarkable effects on PDPH. PMID- 21536542 TI - Combining in-situ proteolysis and microseed matrix screening to promote crystallization of PrPc-nanobody complexes. AB - Prion proteins (PrPs) are difficult to crystallize, probably due to their inherent flexibility. Several PrPs structures have been solved by nuclear magnetic resonance (NMR) techniques; however, only three structures were solved by X-ray crystallography. Here we combined in-situ proteolysis with automated microseed matrix screening (MMS) to crystallize two different PrP(C)-nanobody (Nb) complexes. Nanobodies are single-domain antibodies derived from heavy-chain only antibodies of camelids. Initial crystallization screening conditions using in-situ proteolysis of mouse prion (23-230) in complex with a nanobody (Nb_PrP_01) gave thin needle aggregates, which were of poor diffraction quality. Next, we used these microcrystals as nucleants for automated MMS. Good-quality crystals were obtained from mouse PrP (89-230)/Nb_PrP_01, belonged to the monoclinic space group P 1 21 1, with unit-cell parameters a = 59.13, b = 63.80, c = 69.79 A, beta = 101.96 degrees and diffracted to 2.1 A resolution using synchrotron radiation. Human PrP (90-231)/Nb_PrP_01 crystals belonged to the monoclinic space group C2, with unit-cell parameters a = 131.86, b = 45.78, c = 45.09 A, beta = 96.23 degrees and diffracted to 1.5 A resolution. This combined strategy benefits from the power of the MMS technique without suffering from the drawbacks of the in-situ proteolysis. It proved to be a successful strategy to crystallize PrP-nanobodies complexes and could be exploited for the crystallization of other difficult antigen-antibody complexes. PMID- 21536543 TI - Relevance of IgVH gene somatic hypermutation and interphase cytogenetics in lymphomatous presentation of chronic lymphocytic leukemia/small lymphocytic lymphoma. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are regarded as the same entity, with SLL restricted to tissue cases featuring no leukemic phase. In this study, the authors evaluate a group of SLL cases for cytogenetic abnormalities and IgVH gene mutational status to illicit differences between CLL and SLL. DESIGN: IgVH gene polymerase chain reaction amplification and subsequent sequencing were preformed on formalin-fixed, paraffin-embedded archival tissue of 44 patients (SLL n = 34 or CLL n = 10). Cytogenetic data, CD38, and ZAP-70 expression were also evaluated for these cases. RESULTS: The data indicate that 9/34 (26%) SLL cases have somatic hypermutation >2%, which is less than the CLL group where 40% were mutated (4/10). Cytogenetic abnormalities were seen in 58% of the SLL cases with many showing abnormalities associated with favorable to intermediate prognosis. CONCLUSION: The authors' attempt to compare CLL with SLL with regards to cytogenetic and IgVH mutational status shows no statistically significant difference. PMID- 21536545 TI - FUS-CREB3L2/L1-positive sarcomas show a specific gene expression profile with upregulation of CD24 and FOXL1. AB - PURPOSE: Low-grade fibromyxoid sarcoma (LGFMS) is typically characterized by the specific translocation t(7;16)(q33;p11) and the corresponding fusion gene FUS CREB3L2. The present study aimed to extract LGFMS-specific, and putatively FUS CREB3L2-dependent, gene expression patterns to learn more about the pathogenesis of this tumor. EXPERIMENTAL DESIGN: We carried out single nucleotide polymorphism (SNP) and global gene expression array analyses, and/or immunohistochemical (IHC) analyses on 24 LGFMS tumor biopsies. Tumor types that are important differential diagnoses to LGFMS were included as comparison in the gene and protein expression analyses. In addition, cells that stably expressed FUS-CREB3L2 were analyzed with gene expression array and the influence of FUS-CREB3L2 on gene expression was investigated in vitro. RESULTS: The SNP array analysis detected recurrent microdeletions in association with the t(7;16) chromosomal breakpoints and gain of 7q in cases with ring chromosomes. Gene expression analysis clearly distinguished LGFMS from morphologically similar tumors and MUC4 was identified as a potential diagnostic marker for LGFMS by gene expression and IHC analysis. FOXL1 was identified as the top upregulated gene in LGFMS and CD24 was upregulated in both LGFMS tumors and FUS-CREB3L2 expressing cells. FUS-CREB3L2 was capable of activating transcription from CD24 regulatory sequences in luciferase assays, suggesting an important role for the upregulation of this gene in LGFMS. CONCLUSIONS: The gene expression profile of LGFMS is distinct from that of soft tissue tumors with similar morphology. The data could be used to identify a potential diagnostic marker for LGFMS and to identify possible FUS-CREB3L2 regulated genes. PMID- 21536546 TI - IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma. AB - PURPOSE: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor alpha (IL-4Ralpha) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression. EXPERIMENTAL DESIGN: By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL 4R-mediated mitogenesis, myodifferentiation, and tumor progression. RESULTS: IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt, or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically engineered mouse model of ARMS, we have shown that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting in significant survival extension in vivo. CONCLUSIONS: Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach. PMID- 21536548 TI - Reporting the capture efficiency of a filter-based microdevice: a CTC is not a CTC unless it is CD45 negative--letter. PMID- 21536547 TI - Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice. AB - The Akt activation inhibitor triciribine and the farnesyltransferase inhibitor tipifarnib have modest to little activity in clinical trials when used as single agents. In this article, preclinical data show that the combination is more effective than single agents both in cultured cells and in vivo. Combination index data analysis shows that this combination is highly synergistic at inhibiting anchorage-dependent growth of breast cancer cells. This synergistic interaction is also observed with structurally unrelated inhibitors of Akt (MK 2206) and farnesyltransferase (FTI-2153). The triciribine/tipifarnib synergistic effects are seen with several cancer cell lines including those from breast, leukemia, multiple myeloma and lung tumors with different genetic alterations such as K-Ras, B-Raf, PI3K (phosphoinositide 3-kinase), p53 and pRb mutations, PTEN, pRB and Ink4a deletions, and ErbB receptor overexpression. Furthermore, the combination is synergistic at inhibiting anchorage-independent growth and at inducing apoptosis in breast cancer cells. The combination is also more effective at inhibiting the Akt/mTOR/S6 kinase pathway. In an ErbB2-driven breast tumor transgenic mouse model, the combination, but not single agent, treatment with triciribine and tipifarnib induces significant breast tumor regression. Our findings warrant further investigation of the combination of farnesyltransferase and Akt inhibitors. PMID- 21536550 TI - The many faces of research on face perception. AB - Face perception is fundamental to human social interaction. Many different types of important information are visible in faces and the processes and mechanisms involved in extracting this information are complex and can be highly specialized. The importance of faces has long been recognized by a wide range of scientists. Importantly, the range of perspectives and techniques that this breadth has brought to face perception research has, in recent years, led to many important advances in our understanding of face processing. The articles in this issue on face perception each review a particular arena of interest in face perception, variously focusing on (i) the social aspects of face perception (attraction, recognition and emotion), (ii) the neural mechanisms underlying face perception (using brain scanning, patient data, direct stimulation of the brain, visual adaptation and single-cell recording), and (iii) comparative aspects of face perception (comparing adult human abilities with those of chimpanzees and children). Here, we introduce the central themes of the issue and present an overview of the articles. PMID- 21536551 TI - Facial attractiveness: evolutionary based research. AB - Face preferences affect a diverse range of critical social outcomes, from mate choices and decisions about platonic relationships to hiring decisions and decisions about social exchange. Firstly, we review the facial characteristics that influence attractiveness judgements of faces (e.g. symmetry, sexually dimorphic shape cues, averageness, skin colour/texture and cues to personality) and then review several important sources of individual differences in face preferences (e.g. hormone levels and fertility, own attractiveness and personality, visual experience, familiarity and imprinting, social learning). The research relating to these issues highlights flexible, sophisticated systems that support and promote adaptive responses to faces that appear to function to maximize the benefits of both our mate choices and more general decisions about other types of social partners. PMID- 21536552 TI - Brain systems for assessing the affective value of faces. AB - Cognitive neuroscience research on facial expression recognition and face evaluation has proliferated over the past 15 years. Nevertheless, large questions remain unanswered. In this overview, we discuss the current understanding in the field, and describe what is known and what remains unknown. In S2, we describe three types of behavioural evidence that the perception of traits in neutral faces is related to the perception of facial expressions, and may rely on the same mechanisms. In S3, we discuss cortical systems for the perception of facial expressions, and argue for a partial segregation of function in the superior temporal sulcus and the fusiform gyrus. In S4, we describe the current understanding of how the brain responds to emotionally neutral faces. To resolve some of the inconsistencies in the literature, we perform a large group analysis across three different studies, and argue that one parsimonious explanation of prior findings is that faces are coded in terms of their typicality. In S5, we discuss how these two lines of research--perception of emotional expressions and face evaluation--could be integrated into a common, cognitive neuroscience framework. PMID- 21536553 TI - Stable face representations. AB - Photographs are often used to establish the identity of an individual or to verify that they are who they claim to be. Yet, recent research shows that it is surprisingly difficult to match a photo to a face. Neither humans nor machines can perform this task reliably. Although human perceivers are good at matching familiar faces, performance with unfamiliar faces is strikingly poor. The situation is no better for automatic face recognition systems. In practical settings, automatic systems have been consistently disappointing. In this review, we suggest that failure to distinguish between familiar and unfamiliar face processing has led to unrealistic expectations about face identification in applied settings. We also argue that a photograph is not necessarily a reliable indicator of facial appearance, and develop our proposal that summary statistics can provide more stable face representations. In particular, we show that image averaging stabilizes facial appearance by diluting aspects of the image that vary between snapshots of the same person. We review evidence that the resulting images can outperform photographs in both behavioural experiments and computer simulations, and outline promising directions for future research. PMID- 21536554 TI - Personality influences the neural responses to viewing facial expressions of emotion. AB - Cognitive research has long been aware of the relationship between individual differences in personality and performance on behavioural tasks. However, within the field of cognitive neuroscience, the way in which such differences manifest at a neural level has received relatively little attention. We review recent research addressing the relationship between personality traits and the neural response to viewing facial signals of emotion. In one section, we discuss work demonstrating the relationship between anxiety and the amygdala response to facial signals of threat. A second section considers research showing that individual differences in reward drive (behavioural activation system), a trait linked to aggression, influence the neural responsivity and connectivity between brain regions implicated in aggression when viewing facial signals of anger. Finally, we address recent criticisms of the correlational approach to fMRI analyses and conclude that when used appropriately, analyses examining the relationship between personality and brain activity provide a useful tool for understanding the neural basis of facial expression processing and emotion processing in general. PMID- 21536555 TI - Visual adaptation and face perception. AB - The appearance of faces can be strongly affected by the characteristics of faces viewed previously. These perceptual after-effects reflect processes of sensory adaptation that are found throughout the visual system, but which have been considered only relatively recently in the context of higher level perceptual judgements. In this review, we explore the consequences of adaptation for human face perception, and the implications of adaptation for understanding the neural coding schemes underlying the visual representation of faces. The properties of face after-effects suggest that they, in part, reflect response changes at high and possibly face-specific levels of visual processing. Yet, the form of the after-effects and the norm-based codes that they point to show many parallels with the adaptations and functional organization that are thought to underlie the encoding of perceptual attributes like colour. The nature and basis for human colour vision have been studied extensively, and we draw on ideas and principles that have been developed to account for norms and normalization in colour vision to consider potential similarities and differences in the representation and adaptation of faces. PMID- 21536557 TI - From single cells to social perception. AB - Research describing the cellular coding of faces in non-human primates often provides the underlying physiological framework for our understanding of face processing in humans. Models of face perception, explanations of perceptual after effects from viewing particular types of faces, and interpretation of human neuroimaging data rely on monkey neurophysiological data and the assumption that neurophysiological responses of humans are comparable to those recorded in the non-human primate. Here, we review studies that describe cells that preferentially respond to faces, and assess the link between the physiological characteristics of single cells and social perception. Principally, we describe cells recorded from the non-human primate, although a limited number of cells have been recorded in humans, and are included in order to appraise the validity of non-human physiological data for our understanding of human face and social perception. PMID- 21536556 TI - The neuropsychology of face perception: beyond simple dissociations and functional selectivity. AB - Face processing relies on a distributed, patchy network of cortical regions in the temporal and frontal lobes that respond disproportionately to face stimuli, other cortical regions that are not even primarily visual (such as somatosensory cortex), and subcortical structures such as the amygdala. Higher-level face perception abilities, such as judging identity, emotion and trustworthiness, appear to rely on an intact face-processing network that includes the occipital face area (OFA), whereas lower-level face categorization abilities, such as discriminating faces from objects, can be achieved without OFA, perhaps via the direct connections to the fusiform face area (FFA) from several extrastriate cortical areas. Some lesion, transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) findings argue against a strict feed forward hierarchical model of face perception, in which the OFA is the principal and common source of input for other visual and non-visual cortical regions involved in face perception, including the FFA, face-selective superior temporal sulcus and somatosensory cortex. Instead, these findings point to a more interactive model in which higher-level face perception abilities depend on the interplay between several functionally and anatomically distinct neural regions. Furthermore, the nature of these interactions may depend on the particular demands of the task. We review the lesion and TMS literature on this topic and highlight the dynamic and distributed nature of face processing. PMID- 21536560 TI - Discrete simulation of fluid dynamics: methods. PMID- 21536561 TI - Convergence of a three-dimensional quantum lattice Boltzmann scheme towards solutions of the Dirac equation. AB - We investigate the convergence properties of a three-dimensional quantum lattice Boltzmann scheme for the Dirac equation. These schemes were constructed as discretizations of the Dirac equation based on operator splitting to separate the streaming along the three coordinate axes, but their output has previously only been compared against solutions of the Schrodinger equation. The Schrodinger equation arises as the non-relativistic limit of the Dirac equation, describing solutions that vary slowly compared with the Compton frequency. We demonstrate first-order convergence towards solutions of the Dirac equation obtained by an independent numerical method based on fast Fourier transforms and matrix exponentiation. PMID- 21536562 TI - Mesh-particle interpolations on graphics processing units and multicore central processing units. AB - Particle-mesh interpolations are fundamental operations for particle-in-cell codes, as implemented in vortex methods, plasma dynamics and electrostatics simulations. In these simulations, the mesh is used to solve the field equations and the gradients of the fields are used in order to advance the particles. The time integration of particle trajectories is performed through an extensive resampling of the flow field at the particle locations. The computational performance of this resampling turns out to be limited by the memory bandwidth of the underlying computer architecture. We investigate how mesh-particle interpolation can be efficiently performed on graphics processing units (GPUs) and multicore central processing units (CPUs), and we present two implementation techniques. The single-precision results for the multicore CPU implementation show an acceleration of 45-70*, depending on system size, and an acceleration of 85-155* for the GPU implementation over an efficient single-threaded C++ implementation. In double precision, we observe a performance improvement of 30 40* for the multicore CPU implementation and 20-45* for the GPU implementation. With respect to the 16-threaded standard C++ implementation, the present CPU technique leads to a performance increase of roughly 2.8-3.7* in single precision and 1.7-2.4* in double precision, whereas the GPU technique leads to an improvement of 9* in single precision and 2.2-2.8* in double precision. PMID- 21536559 TI - The evolution of face processing in primates. AB - The ability to recognize faces is an important socio-cognitive skill that is associated with a number of cognitive specializations in humans. While numerous studies have examined the presence of these specializations in non-human primates, species where face recognition would confer distinct advantages in social situations, results have been mixed. The majority of studies in chimpanzees support homologous face-processing mechanisms with humans, but results from monkey studies appear largely dependent on the type of testing methods used. Studies that employ passive viewing paradigms, like the visual paired comparison task, report evidence of similarities between monkeys and humans, but tasks that use more stringent, operant response tasks, like the matching-to-sample task, often report species differences. Moreover, the data suggest that monkeys may be less sensitive than chimpanzees and humans to the precise spacing of facial features, in addition to the surface-based cues reflected in those features, information that is critical for the representation of individual identity. The aim of this paper is to provide a comprehensive review of the available data from face-processing tasks in non-human primates with the goal of understanding the evolution of this complex cognitive skill. PMID- 21536558 TI - Infants' knowledge of their own species. AB - Recognition of individuals at first sight is important for social species and can be achieved by attending to facial or body information. Previous research suggests that infants possess a perceptual template for evolutionarily relevant stimuli, which may include humans, dangerous animals (e.g. snakes), but not non dangerous animals. To be effective, such a mechanism should result in a systematic preference for attending to humans over non-dangerous animals. Using a preferential looking paradigm, the present studies investigated the nature of infants' early representation of humans. We show that 3.5- and six-month-old infants attend more to human beings than non-human primates (a gorilla or monkey) which are examplars of non-dangerous animals. This occurred when infants were presented with head or body information in isolation, as well as when both are presented simultaneously. This early preference for humans by 3.5 months of age suggests that there is a basic representation for humans, which includes both head and/or body information. However, neonates demonstrated a preference only for human faces over non-human primate faces, not for humans over non-human primates when the stimuli were presented with both head and body simultaneously. The results show that although neonates display a preference for human faces over others, preference for the human body only develops later, in the first few months of life. This suggests that infants have acquired some knowledge about the human body at 3.5 months of age that may have developed from their privileged experience with other humans in the first few months of life, rather than an innate ability to detect humans in their entirety. PMID- 21536563 TI - Moment isotropy and discrete rotational symmetry of two-dimensional lattice vectors. AB - We present a direct proof of a theorem linking the order of moment isotropy and degree of discrete rotational symmetry for a two-dimensional set of lattice vectors. This theorem has been proved previously based on properties of sinusoidal functions. The new proof is based instead on purely linear algebraic arguments. PMID- 21536564 TI - Involving the Navier-Stokes equations in the derivation of boundary conditions for the lattice Boltzmann method. AB - By means of the continuity equation of the incompressible Navier-Stokes equations, additional physical arguments for the derivation of a formulation of the no-slip boundary condition for the lattice Boltzmann method for straight walls at rest are obtained. This leads to a boundary condition that is second order accurate with respect to the grid spacing and conserves mass. In addition, the boundary condition is stable for relaxation frequencies close to two. PMID- 21536565 TI - Evaluation of a new solid boundary implementation in the lattice Boltzmann method for porous media considering permeability and apparent slip. AB - The accuracy of solid wall treatment in the lattice Boltzmann method (LBM) simulation of porous structures affects different hydraulic parameters including integral properties, such as permeability, or local phenomena, such as apparent slip. Based on an analysis of the advantages and disadvantages of the current methods, a new technique is introduced for exact boundary extraction from binary representation. Using this technique, the LBM model can simultaneously benefit from the advantages of existing approaches, i.e. the real micro-/nanostructure obtained with X-ray computed tomography, and a reduction in the resolution requirement. To evaluate the technique, permeability and slip length on the solid walls are investigated for a porous gas diffusion layer. The results show acceptable accuracy improvement balanced with computational costs. PMID- 21536566 TI - Matrix lattice Boltzmann reloaded. AB - The lattice Boltzmann equation was introduced about 20 years ago as a new paradigm for computational fluid dynamics. In this paper, we revisit the main formulation of the lattice Boltzmann collision integral (matrix model) and introduce a new two-parametric family of collision operators, which permits us to combine enhanced stability and accuracy of matrix models with the outstanding simplicity of the most popular single-relaxation time schemes. The option of the revised lattice Boltzmann equation is demonstrated through numerical simulations of a three-dimensional lid-driven cavity. PMID- 21536567 TI - New variational principles for locating periodic orbits of differential equations. AB - We present new methods for the determination of periodic orbits of general dynamical systems. Iterative algorithms for finding solutions by these methods, for both the exact continuum case, and for approximate discrete representations suitable for numerical implementation, are discussed. Finally, we describe our approach to the computation of unstable periodic orbits of the driven Navier Stokes equations, simulated using the lattice Boltzmann equation. PMID- 21536568 TI - Simultaneous incorporation of mass and force terms in the multi-relaxation-time framework for lattice Boltzmann schemes. AB - This paper presents an analysis of the simultaneous incorporation of force and mass source terms into the multi-relaxation-time (MRT) collision operator. MRT force incorporation was obtained through Chapman-Enskog analysis. The numerical scheme was tested on different benchmark problems, including the decay of a shear wave with different bulk and kinematic viscosities and axisymmetric flow. PMID- 21536569 TI - Higher order slip according to the linearized Boltzmann equation with general boundary conditions. AB - In the present paper, we provide an analytical expression for the first- and second-order velocity slip coefficients by means of a variational technique that applies to the integrodifferential form of the Boltzmann equation based on the true linearized collision operator and the Cercignani-Lampis scattering kernel of the gas-surface interaction. The polynomial form of the Knudsen number obtained for the Poiseuille mass flow rate and the values of the velocity slip coefficients are analysed in the frame of potential applications of the lattice Boltzmann methods in simulations of microscale flows. PMID- 21536570 TI - Efficient lattice Boltzmann algorithm for Brownian suspensions. AB - A lattice Boltzmann (LB)-based hybrid method is developed to simulate suspensions of Brownian particles. The method uses conventional LB discretization (without fluid- level fluctuations) for suspending fluid, and treats Brownian particles as point masses with a stochastic thermal noise. LB equations are used to compute the velocity perturbations induced by the particle motion. It is shown that this method correctly reproduces the short-time and long-time diffusive behaviour of a Brownian particle. Unlike the earlier hybrid methods that use thermal fluctuations in the fluid, this method correctly reproduces the temperature of the particle and does not require an empirical rescaling of the bare friction coefficient to obtain the correct diffusive behaviour. It is observed that the present method is at least twice as fast as the earlier method. This method is best suited for flows of polymers and Brownian suspensions in microfluidic devices. PMID- 21536571 TI - Viscously damped acoustic waves with the lattice Boltzmann method. AB - Acoustic wave propagation in lattice Boltzmann Bhatnagar-Gross-Krook simulations may be analysed using a linearization method. This method has been used in the past to study the propagation of waves that are viscously damped in time, and is here extended to also study waves that are viscously damped in space. Its validity is verified against simulations, and the results are compared with theoretical expressions. It is found in the infinite resolution limit k->0 that the absorption coefficients and phase differences between density and velocity waves match theoretical expressions for small values of omegatau(nu), the characteristic number for viscous acoustic damping. However, the phase velocities and amplitude ratios between the waves increase incorrectly with (omegatau(nu))(2), and agree with theory only in the inviscid limit k->0, omegatau(nu)->0. The actual behaviour of simulated plane waves in the infinite resolution limit is quantified. PMID- 21536572 TI - A local lattice Boltzmann method for multiple immiscible fluids and dense suspensions of drops. AB - The lattice Boltzmann method (LBM) for computational fluid dynamics benefits from a simple, explicit, completely local computational algorithm making it highly efficient. We extend LBM to recover hydrodynamics of multi-component immiscible fluids, while retaining a completely local, explicit and simple algorithm. Hence, no computationally expensive lattice gradients, interaction potentials or curvatures, that use information from neighbouring lattice sites, need to be calculated, which makes the method highly scalable and suitable for high performance parallel computing. The method is analytical and is shown to recover correct continuum hydrodynamic equations of motion and interfacial boundary conditions. This LBM may be further extended to situations containing a high number (O(100)) of individually immiscible drops. We make comparisons of the emergent non-Newtonian behaviour with a power-law fluid model. We anticipate our method will have a range applications in engineering, industrial and biological sciences. PMID- 21536573 TI - A lattice Boltzmann approach for solving scalar transport equations. AB - A lattice Boltzmann (LB) approach is presented for solving scalar transport equations. In addition to the standard LB for fluid flow, a second set of distribution functions is introduced for transport scalars. This LB approach fully recovers the macroscopic scalar transport equation satisfying an exact conservation law. It is numerically stable and scalar diffusivity does not have a Courant-Friedrichs-Lewy-like stability upper limit. With a sufficient lattice isotropy, numerical solutions are independent of grid orientations. A generalized boundary condition for scalars on arbitrary geometry is also realized by a precise control of surface scalar flux. Numerical results of various benchmarks are presented to demonstrate the accuracy, efficiency and robustness of the approach. PMID- 21536574 TI - Modelling thermal fluctuations in non-ideal fluids with the lattice Boltzmann method. AB - Recently, we proposed a theoretical framework to include thermal fluctuations into the Lattice Boltzmann (LB) method for non-ideal fluids. Here, we apply a variant thereof to a certain class of force-based non-ideal fluid LB models. We find that ideal-gas-like noise is an exact result of the fluctuation-dissipation theorem in the hydrodynamic regime. It is shown that satisfactory equilibration of the density and fluid momentum can be obtained in a simulation over a wide range of length scales. PMID- 21536575 TI - Chequerboard effects on spurious currents in the lattice Boltzmann equation for two-phase flows. AB - Spurious currents near an interface between different phases are a common undesirable feature of the lattice Boltzmann equation (LBE) method for two-phase systems. In this paper, we show that the spurious currents of a kinetic theory based LBE have a significant dependence on the parity of the grid number of the underlying lattice, which can be attributed to the chequerboard effect. A technique that uses a Lax-Wendroff streaming is proposed to overcome this anomaly, and its performance is verified numerically. PMID- 21536576 TI - Thermodynamic consistency in deriving lattice Boltzmann models for describing segregation in non-ideal mixtures. AB - The thermodynamic consistency of kinetic models for non-ideal mixtures in non isothermal conditions is investigated. A kinetic model is proposed that is suitable for deriving high-order lattice Boltzmann equations by an appropriate discretization of the velocity space, satisfying the Galilean invariance condition and free of spurious terms in the first moment equations. PMID- 21536577 TI - A lattice Boltzmann method for dilute polymer solutions. AB - We present a lattice Boltzmann approach for the simulation of non-Newtonian fluids. The method is illustrated for the specific case of dilute polymer solutions. With the appropriate local equilibrium distribution, phase-space dynamics on a lattice, driven by a Bhatnagar-Gross-Krook (BGK) relaxation term, leads to a solution of the Fokker-Planck equation governing the probability density of polymer configurations. Results for the bulk rheological characteristics for steady and start-up shear flow are presented, and compare favourably with those obtained using Brownian dynamics simulations. The new method is less expensive than stochastic simulation techniques, particularly in the range of small to moderate Weissenberg numbers (Wi). PMID- 21536578 TI - Rectangular lattice Boltzmann model for nonlinear convection-diffusion equations. AB - In this paper, a rectangular lattice Boltzmann model is proposed for nonlinear convection-diffusion equations (NCDEs). The model can be used to solve NCDEs with very general form by using a real/complex-valued quadric equilibrium distribution function and relaxation time. Detailed simulations on several examples are performed to validate the model. The numerical results show good agreement with the analytical solutions, and the numerical accuracy is much better than that of the models with a linear equilibrium distribution function. PMID- 21536579 TI - Smoothed particle hydrodynamics simulation of shear-induced powder migration in injection moulding. AB - We present the application of the smoothed particle hydrodynamics (SPH) discretization scheme to Phillips' model for shear-induced particle migration in concentrated suspensions. This model provides an evolution equation for the scalar mean volume fraction of idealized spherical solid particles of equal diameter which is discretized by the SPH formalism. In order to obtain a discrete evolution equation with exact conservation properties we treat in fact the occupied volume of the solid particles as the degree of freedom for the fluid particles. We present simulation results in two- and three-dimensional channel flow. The two-dimensional results serve as a verification by a comparison to analytic solutions. The three-dimensional results are used for a comparison with experimental measurements obtained from computer tomography of injection moulded ceramic microparts. We observe the best agreement of measurements with snapshots of the transient simulation for a ratio D(c)/D(eta)=0.1 of the two model parameters. PMID- 21536580 TI - Confined dynamics of a single DNA molecule. AB - The effect of a slit-like confinement on the relaxation dynamics of DNA is studied via a mesoscale model in which a bead and spring model for the polymer is coupled to a particle-based Navier-Stokes solver (multi-particle collision dynamics). The confinement is found to affect the equilibrium stretch of the chain when the bulk gyration radius is comparable to or smaller than the channel height and our data are in agreement with the (R(g,bulk)/h)(1/4) scaling of the polymer extension in the wall tangential direction. Relaxation simulation at different confinements indicates that, while the overall behaviour of the relaxation dynamics is similar for low and strong confinements, a small, but significant, slowing of the far-equilibrium relaxation is found as the confinement increases. PMID- 21536581 TI - Rotational behaviour of red blood cells in suspension: a mesoscale simulation study. AB - The nature of blood as a suspension of red blood cells makes computational haemodynamics a demanding task. Our coarse-grained blood model, which builds on a lattice Boltzmann method for soft particle suspensions, enables the study of the collective behaviour of the order of 10(6) cells in suspension. After demonstrating the viscosity measurement in Kolmogorov flow, we focus on the statistical analysis of the cell orientation and rotation in Couette flow. We quantify the average inclination with respect to the flow and the nematic order as a function of shear rate and haematocrit. We further record the distribution of rotation periods around the vorticity direction and find a pronounced peak in the vicinity of the theoretical value for free model cells, even though cell-cell interactions manifest themselves in a substantial width of the distribution. PMID- 21536582 TI - Unstable periodic orbits in the Lorenz attractor. AB - We apply a new method for the determination of periodic orbits of general dynamical systems to the Lorenz equations. The accuracy of the expectation values obtained using this approach is shown to be much larger and have better convergence properties than the more traditional approach of time averaging over a generic orbit. Finally, we discuss the relevance of the present work to the computation of unstable periodic orbits of the driven Navier-Stokes equations, which can be simulated using the lattice Boltzmann method. PMID- 21536583 TI - Endothelial shear stress from large-scale blood flow simulations. AB - We discuss the optimal evaluation of endothelial shear stress for real-life case studies based on anatomic data acquisition. The fluid dynamic simulations require smoothing of the geometric dataset to avoid major artefacts in the flow patterns, especially in the proximity of bifurcations. A systematic series of simulations at different corrugation levels shows that, below a smoothing length of about 0.5 mm, the numerical data are insensitive to further smoothing. PMID- 21536584 TI - From the Boltzmann equation to fluid mechanics on a manifold. AB - We apply the Chapman-Enskog procedure to derive hydrodynamic equations on an arbitrary surface from the Boltzmann equation on the surface. PMID- 21536585 TI - Lattice Boltzmann method for adiabatic acoustics. AB - The lattice Boltzmann method (LBM) has been proved to be a useful tool in many areas of computational fluid dynamics, including computational aero-acoustics (CAA). However, for historical reasons, its applications in CAA have been largely restricted to simulations of isothermal (Newtonian) sound waves. As the recent kinetic theory-based reformulation establishes a theoretical framework in which LBM can be extended to recover the full Navier-Stokes-Fourier (NS) equations and beyond, in this paper, we show that, at least at the low-frequency limit (sound frequency much less than molecular collision frequency), adiabatic sound waves can be accurately simulated by the LBM provided that the lattice and the distribution function ensure adequate recovery of the full NS equations. PMID- 21536586 TI - The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects {beta}-cells against stress-induced apoptosis. AB - Liver receptor homolog (LRH-1) is an orphan nuclear receptor (NR5A2) that regulates cholesterol homeostasis and cell plasticity in endodermal-derived tissues. Estrogen increases LRH-1 expression conveying cell protection and proliferation. Independently, estrogen also protects isolated human islets against cytokine-induced apoptosis. Herein, we demonstrate that LRH-1 is expressed in islets, including beta-cells, and that transcript levels are modulated by 17beta-estradiol through the estrogen receptor (ER)alpha but not ERbeta signaling pathway. Repression of LRH-1 by siRNA abrogated the protective effect conveyed by estrogen on rat islets against cytokines. Adenoviral-mediated overexpression of LRH-1 in human islets did not alter proliferation but conferred protection against cytokines and streptozotocin-induced apoptosis. Expression levels of the cell cycle genes cyclin D1 and cyclin E1 as well as the antiapoptotic gene bcl-xl were unaltered in LRH-1 expressing islets. In contrast, the steroidogenic enzymes CYP11A1 and CYP11B1 involved in glucocorticoid biosynthesis were both stimulated in transduced islets. In parallel, graded overexpression of LRH-1 dose-dependently impaired glucose-induced insulin secretion. Our results demonstrate the crucial role of the estrogen target gene nr5a2 in protecting human islets against-stressed-induced apoptosis. We postulate that this effect is mediated through increased glucocorticoid production that blunts the pro-inflammatory response of islets. PMID- 21536587 TI - HD CAG-correlated gene expression changes support a simple dominant gain of function. AB - Huntington's disease is initiated by the expression of a CAG repeat-encoded polyglutamine region in full-length huntingtin, with dominant effects that vary continuously with CAG size. The mechanism could involve a simple gain of function or a more complex gain of function coupled to a loss of function (e.g. dominant negative-graded loss of function). To distinguish these alternatives, we compared genome-wide gene expression changes correlated with CAG size across an allelic series of heterozygous CAG knock-in mouse embryonic stem (ES) cell lines (Hdh(Q20/7), Hdh(Q50/7), Hdh(Q91/7), Hdh(Q111/7)), to genes differentially expressed between Hdh(ex4/5/ex4/5) huntingtin null and wild-type (Hdh(Q7/7)) parental ES cells. The set of 73 genes whose expression varied continuously with CAG length had minimal overlap with the 754-member huntingtin-null gene set but the two were not completely unconnected. Rather, the 172 CAG length-correlated pathways and 238 huntingtin-null significant pathways clustered into 13 shared categories at the network level. A closer examination of the energy metabolism and the lipid/sterol/lipoprotein metabolism categories revealed that CAG length correlated genes and huntingtin-null-altered genes either were different members of the same pathways or were in unique, but interconnected pathways. Thus, varying the polyglutamine size in full-length huntingtin produced gene expression changes that were distinct from, but related to, the effects of lack of huntingtin. These findings support a simple gain-of-function mechanism acting through a property of the full-length huntingtin protein and point to CAG correlative approaches to discover its effects. Moreover, for therapeutic strategies based on huntingtin suppression, our data highlight processes that may be more sensitive to the disease trigger than to decreased huntingtin levels. PMID- 21536588 TI - A gender-specific association of CNV at 6p21.3 with NPC susceptibility. AB - Copy number variations (CNVs), a major source of human genetic polymorphism, have been suggested to have an important role in genetic susceptibility to common diseases such as cancer, immune diseases and neurological disorders. Nasopharyngeal carcinoma (NPC) is a multifactorial tumor closely associated with genetic background and with a male preponderance over female (3:1). Previous genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) that are associated with NPC susceptibility. Here, we sought to explore the possible association of CNVs with NPC predisposition. Utilizing genome-wide SNP-based arrays and five CNV-prediction algorithms, we identified eight regions with CNV that were significantly overrepresented in NPC patients compared with healthy controls. These CNVs included six deletions (on chromosomes 3, 6, 7, 8 and 19), and two duplications (on chromosomes 7 and 12). Among them, the CNV located at chromosome 6p21.3, with single-copy deletion of the MICA and HCP5 genes, showed the highest association with NPC. Interestingly, it was more specifically associated with an increased NPC risk among males. This gender specific association was replicated in an independent case-control sample using a self-established deletion-specific polymerase chain reaction strategy. To the best of our knowledge, this is the first study to explore the role of constitutional CNVs in NPC, using a genome-wide platform. Moreover, we identified eight novel candidate regions with CNV that merit future investigation, and our results suggest that similar to neuroblastoma and prostate cancer, genetic structural variations might contribute to NPC predisposition. PMID- 21536589 TI - FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3. AB - Ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3), binds to target gene promoters and modulates transcription by interaction with transcriptional regulators. Here, we show that ATXN3 interacts with the forkhead box O (FOXO) transcription factor FOXO4 and activates the FOXO4-dependent transcription of the manganese superoxide dismutase (SOD2) gene. Upon oxidative stress, ATXN3 and FOXO4 translocate to the nucleus, concomitantly bind to the SOD2 gene promoter and increase the expression of the antioxidant enzyme SOD2. Compared with normal ATXN3, mutant ATXN3 has a reduced capability to activate the FOXO4-mediated SOD2 expression and interferes with binding of FOXO4 to the SOD2 gene promoter. These findings are consistent with a downregulation of SOD2 in pontine brain tissue and lymphoblastoid cell (LC) lines of SCA3 patients. In response to oxidative stress, LCs from SCA3 patients show a specific impairment to upregulate SOD2 expression in correlation with a significantly increased formation of reactive oxygen species and cytotoxicity. The impairment to increase the expression of SOD2 under oxidative stress conditions is associated with a significantly reduced binding of FOXO4 to the SOD2 gene promoter in SCA3-LCs. Finally and consistent with a regulatory role of ATXN3 in SOD2 expression, knockdown of endogenous ATXN3 by RNA interference represses the expression of SOD2. These findings support that ATXN3 plays an important role in regulating the FOXO4-dependent antioxidant stress response via SOD2 and suggest that a decreased antioxidative capacity and increased susceptibility towards oxidative stress contributes to neuronal cell death in SCA3. PMID- 21536590 TI - Deficiency of alpha-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling. AB - Sarcomeric alpha-actinins (alpha-actinin-2 and -3) are a major component of the Z disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific alpha actinin-3 in ~20% of the general population. alpha-Actinin-3 deficiency is associated with decreased force generation and is detrimental to sprint and power performance in elite athletes, suggesting that alpha-actinin-3 is necessary for optimal forceful repetitive muscle contractions. Since Z-disks are the structures most vulnerable to eccentric damage, we sought to examine the effects of alpha actinin-3 deficiency on sarcomeric integrity. Actn3 knockout mouse muscle showed significantly increased force deficits following eccentric contraction at 30% stretch, suggesting that alpha-actinin-3 deficiency results in an increased susceptibility to muscle damage at the extremes of muscle performance. Microarray analyses demonstrated an increase in muscle remodeling genes, which we confirmed at the protein level. The loss of alpha-actinin-3 and up-regulation of alpha actinin-2 resulted in no significant changes to the total pool of sarcomeric alpha-actinins, suggesting that alterations in fast fiber Z-disk properties may be related to differences in functional protein interactions between alpha actinin-2 and alpha-actinin-3. In support of this, we demonstrated that the Z disk proteins, ZASP, titin and vinculin preferentially bind to alpha-actinin-2. Thus, the loss of alpha-actinin-3 changes the overall protein composition of fast fiber Z-disks and alters their elastic properties, providing a mechanistic explanation for the loss of force generation and increased susceptibility to eccentric damage in alpha-actinin-3-deficient individuals. PMID- 21536591 TI - Large human sperm vacuoles observed in motile spermatozoa under high magnification: nuclear thumbprints linked to failure of chromatin condensation. AB - BACKGROUND: An embryo's ability to grow and implant can be improved by selection of a normal spermatozoon with a vacuole-free head. However, large vacuoles in spermatozoa have yet to be fully characterized. The present study aimed to determine whether these vacuoles are of nuclear, membrane and/or acrosomal origin. METHODS: We studied 15 infertile patients with differing sperm profiles. For each sperm sample, we used high-magnification (*10 000) contrast microscopy to select and assess 30 normal 'top' spermatozoa and 30 spermatozoa with a large sperm-head vacuole (>= 25% of the head's cross-sectional area). We subsequently analysed the spermatozoa's degree of chromatin condensation (aniline blue staining), DNA fragmentation (terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labelling assay) and chromosome content (fluorescence in situ hybridization X,Y,18). Atomic force microscopy enabled us to map the plasma sperm membrane in detail. Three-dimensional deconvolution microscopy enabled us to reconstruct images of the nucleus and acrosome in 'top' and 'vacuolated' spermatozoa. RESULTS: We studied a total of 450 'top' spermatozoa and 450 vacuolated spermatozoa. The rate of non-condensed chromatin was higher for 'vacuolated' spermatozoa than for 'top' spermatozoa (36.2 +/- 1.9 versus 7.6 +/- 1.3%, respectively; P < 0.0001). 'Top' and 'vacuolated' spermatozoa did not differ significantly in terms of DNA fragmentation (0.7 +/- 0.4 versus 1.3 +/- 0.4% respectively; P = 0.25) or aneuploidy (1.1 +/- 0.5 versus 2.2 +/- 0.7% respectively; P = 0.21). The majority of aneuploid spermatozoa (9 out of 15) lacked chromatin condensation. In all vacuolated spermatozoa, the acrosome was intact, the plasma membrane was sunken but intact and the large vacuole was identified as an abnormal, 'thumbprint'-like nuclear concavity covered by acrosomal and plasmic membranes. CONCLUSIONS: The large vacuole appears to be a nuclear 'thumbprint' linked to failure of chromatin condensation. PMID- 21536592 TI - Widespread focused improvement: lessons from international health for spreading specific improvements to health services in high-income countries. AB - Patients and citizens want more and better healthcare, and want to pay less for it. One way rapidly to respond to these demands is to spread proven or promising improvements in treatments or service delivery models. However, there is little research from high-income countries about effective ways to spread these improvements. In international health there is more experience and knowledge of scale-up, more variety in research approaches used to study the subject, and fewer resources and infrastructure for scaling-up improvements across a nation. This paper draws on reviews of research and experience in international health to contribute to conceptual and empirical knowledge as well as to practical strategies. It describes and illustrates three approaches: hierarchical control, participatory adaptation and facilitated evolution. It presents lessons from international health which could be of use to those studying, choosing, planning and progressing strategies to increase the uptake of proven or promising interventions to health services in high-income countries. PMID- 21536593 TI - Comparison of masculine and feminine traits in a national sample of male and female nursing students. AB - The stereotype that male nurses are less masculine has existed for generations and spans all age groups. Several studies have investigated masculinity and femininity in nurses using the Bem Sex-Role Inventory, but the results are conflicting and inconclusive. Therefore, a nationwide survey was conducted across the United States that examined the sex-role identity of individuals who chose nursing as a career path. Twenty-eight males and 81 females from 37 states completed the survey. The males and females in the study both had higher mean scores on masculinity and femininity scales when compared with previous studies. The greatest percentage of participants were classified as androgynous, as opposed to masculine, feminine, or undifferentiated, with half of the males and nearly half of the females falling into this category. PMID- 21536594 TI - How do the sexual behaviors of foreign-born Hispanic men who have sex with men differ by relationship status? AB - High-risk sexual behaviors may result in acquisition of sexually transmitted infections including HIV. Hispanic men who have sex with men (MSM) experience a disproportionate incidence of these infections. Various risk factors, cultural aspects, and relationship factors may influence the sexual behaviors of this subgroup of MSM. The purpose of this study was to describe the sexual behaviors of a sample of foreign-born Hispanic MSM and to compare these sexual behaviors in terms of condom usage, risky sexual behaviors, avoidance of body fluids, and sexual negotiation when stratified by relationship status. Using a cross sectional, descriptive research design, a convenience sample of 135 foreign-born Hispanic MSM, the majority of whom were Cubans, was recruited and surveyed from the South Florida area. The majority of participants reported engaging in the high-risk sexual behaviors of sex without condoms, substance abuse before or during sex, anal sex, contact with body fluids, and did not negotiate safer sex behaviors. Differences in sexual behaviors when compared by relationship status were found only in terms of certain risky sexual behaviors but not in terms of condom usage, contact with body fluids, or sexual negotiation. Despite participation in a number of high-risk activities and finding few differences among those men in relationships and those not in primary relationships, factors that promote or inhibit participation in high-risk sexual behaviors among Hispanic MSM in various types of relationships need further exploration. PMID- 21536595 TI - Using canonical commonality analysis to examine the predictive quality of aging and falls efficacy on balance functioning in older adults. AB - PURPOSE: The effects of important variables measuring the psychobiological aspects of falls among older adults were considered to determine their utility in predicting balance functioning among older adults. To partition the effects of aging and falls efficacy on balance and leg strength simultaneously, canonical commonality analysis (CCA) was used. METHODS: CCA is a multivariate technique which decomposes squared semipartial correlation effect sizes into constituent, nonoverlapping segments that describe unique and common explanatory powers of predictor variables. Data from a study conducted to examine the psychobiological and aging influences on unintended falls among physically active older adults were analyzed. FINDINGS: CCA showed balance confidence as measured by the Activities-Specific Balance Confidence Scale (ABC) and age to be noteworthy predictors of balance; yet, age was determined to be more important than balance confidence when predicting balance and leg strength (i.e., balance functioning) simultaneously. In addition, results suggest that data obtained from the ABC better predicted balance functioning among active older adults as compared to the Tinetti Falls Efficacy Scale (FES), a traditional measure used to assess the construct. CONCLUSION: The ABC stands as a viable alternative to consider when assessing falls efficacy among dynamic older adults. Future research would benefit from using CCA to understand how various psychobiological constructs predict fall-related outcomes. PMID- 21536596 TI - Median arcuate ligament syndrome: a nonvascular, vascular diagnosis. AB - Median arcuate ligament syndrome (MALS) is often diagnosed when idiopathic, episodic abdominal pain is associated with dynamic compression of the proximal celiac artery by fibers of the median arcuate ligament. The character of the abdominal pain is often postprandial and associated with gradual weight loss from poor food intake, suggestive of chronic mesenteric ischemia. However, the pathognomonic imaging feature of dynamic, ostial celiac artery compression with expiration does not consistently predict clinical improvement from revascularization. Proposed but unproven pathophysiological mechanisms include neurogenic pain from compression of the splanchnic nerve plexus and intermittent ischemia from compression of the celiac artery. Alterations in blood flow and ganglion compression are both associated with delayed gastric emptying, another physiological correlate of the clinical syndrome. Published reports describe a variable response to revascularization and nerve plexus resection suggest a need for translational research to better characterize this poorly understood clinical entity. We illustrate the current gaps in our knowledge of MALS with the case of a 51-year-old woman with a 4-year history of chronic abdominal pain who responded to a combination of ganglion resection and celiac artery reconstruction. PMID- 21536598 TI - Differences between family practices in the associations of patient characteristics with health care experiences. AB - When comparing health care providers, patient experience data are usually adjusted for case-mix associations to ensure fair comparisons. Previous studies in the United States showed that case-mix associations sometimes vary across health care providers. Such variation could indicate differential provider behavior for patient subgroups, in which case current adjustment techniques might be inappropriate. To see whether this variation is also apparent in a health care system different from the U.S. system, the authors analyzed Dutch patients' experiences with family practice care. Using multilevel random slope models, the associations between age, general health status, mental health status, education, sex, and ethnicity on one hand and reported experiences on the other hand were assessed across family practices. The authors found only five significant variances between case-mix coefficients, all for outcomes related to health care professionals' conduct. These findings correspond to previous U.S. findings, suggesting that the case-mix variations reported here and previously constitute a rather robust phenomenon. PMID- 21536597 TI - Differences in repeating patterns of complex fractionated left atrial electrograms in longstanding persistent atrial fibrillation as compared with paroxysmal atrial fibrillation. AB - BACKGROUND: Complex fractionated atrial electrograms (CFAE) are morphologically more uniform in persistent longstanding as compared with paroxysmal atrial fibrillation (AF). It was hypothesized that this may result from a greater degree of repetitiveness in CFAE patterns at disparate left atrial (LA) sites in longstanding AF. METHODS AND RESULTS: CFAEs were obtained from recording sites outside the 4 pulmonary vein (PV) ostia and at a posterior and an anterior LA site during paroxysmal and longstanding persistent AF (10 patients each, 120 sequences total). To quantify repetitiveness in CFAE, the dominant frequency was measured from ensemble spectra using 8.4-second sequences, and repetitiveness was calculated by 2 novel techniques: linear prediction and Fourier reconstruction methods. Lower prediction and reconstruction errors were considered indicative of increasing repetitiveness and decreasing randomness. In patients with paroxysmal AF, CFAE pattern repetitiveness was significantly lower (randomness higher) at antral sites outside PV ostia as compared with LA free wall sites (P < 0.001). In longstanding AF, repetitiveness increased outside the PV ostia, especially outside the left superior PV ostium, and diminished at the LA free wall sites. The result was that in persistent AF, there were no significant site-specific differences in CFAE repetitiveness at the selected LA locations used in this study. Average dominant frequency magnitude was 5.32 +/- 0.29 Hz in paroxysmal AF and higher in longstanding AF, at 6.27 +/- 0.13 Hz (P < 0.001), with the frequency of local activation approaching a common upper bound for all sites. CONCLUSIONS: In paroxysmal AF, CFAE repetitiveness is low and randomness high outside the PVs, particularly the left superior PV. As evolution to persistent longstanding AF occurs, CFAE repetitiveness becomes more uniformly distributed at disparate sites, possibly signifying an increasing number of drivers from remote PVs. PMID- 21536599 TI - Excess costs attributable to postoperative complications. AB - This article estimates excess costs associated with postoperative complications among inpatients treated in Veterans Health Administration (VA) hospitals. The authors conducted an observational study on 43,822 hospitalizations involving inpatient surgery in one of 104 VA hospitals during fiscal year 2007. Hospitalization-level cost regression analyses were performed to estimate the excess cost of each of 18 unique postoperative complications. The authors used generalized linear modeling techniques to account for the heavily skewed cost distribution. Costs were measured using an activity-based cost accounting system and complications were assessed based on medical chart review conducted by the VA 'National Surgical Quality Improvement Program. The authors found excess costs associated with postoperative complications ranging from $8,338 for "superficial surgical site infection" to $29,595 for "failure to wean within 24 hours in the presence of respiratory complications." The results obtained suggest that quality improvement efforts aimed at reducing postoperative complications can contribute significantly to lowering of hospital costs. PMID- 21536600 TI - Consumer trust in sources of physician quality information. AB - Trust in the source of information about physician quality is likely to be an important factor in how consumers use that information in encounters with their doctor or in decisions about choice of provider. In this article, the authors use survey data from a nationally representative sample of 8,140 individuals with chronic illness to examine variation in consumer trust in different sources of physician quality information and how market segmentation factors explain such variation. The authors find that consumers place greater trust in physicians and hospitals relative to institutional sources and personal sources. The level of trust, however, varies considerably across consumers as a function of demographic, socioeconomic, behavioral/lifestyle factors but is not related to measures of context. These results suggest that the sources of public reports comparing physician quality may be a barrier to the use of quality data by consumers in the ways envisioned by supporters of greater quality transparency. PMID- 21536601 TI - General practitioners and clinical practice guidelines: a reexamination. AB - General practitioners' (GPs') use of clinical practice guidelines (CPGs) may be influenced by various contextual and attitudinal factors. This study examines general attitudes toward CPGs to establish profiles according to these attitudes and to determine if these profiles are associated with awareness and with use of CPGs in daily practice. The authors conducted a cross-sectional telephone survey of 1,759 French GPs and measured (a) their general attitudes toward CPGs and (b) their awareness and use in daily practice of CPGs for six specific health problems. A bivariate probit model was used with sample selection to analyze the links between GPs' general attitudes and CPG awareness/use. The authors found three GP profiles according to their opinions toward CPGs and a positive association between these profiles and CPG awareness but not use. It is important to build awareness of CPGs before GPs develop negative attitudes toward them. PMID- 21536602 TI - Access to care provided by better safety net systems for the uninsured: measuring and conceptualizing adequacy. AB - This descriptive study assesses the access to care provided by five model and diverse safety net programs that enroll uninsured adults in a coordinated system offering primary care, hospital care, prescription drugs, and most specialist services. Physician use by safety net program members was similar to insured groups. However, there was less use of hospitals in the two programs that relied on uncompensated charity care. Considering access measures commonly used in population-based surveys, the uninsured in these five communities fared no better than uninsured elsewhere. However, respondents may consider enrollment in a well structured safety net program to be equivalent to insurance. If so, population surveys may be least accurate in identifying uninsured people in the very communities that have the best safety net programs. On balance the five safety net systems profiled here meet the needs of low-income uninsured residents at a level that is roughly similar to that for people with insurance. PMID- 21536603 TI - The health insurance status of low-wage workers: the role of workplace composition and marital status. AB - Many of the provisions in the Affordable Care Act (ACA), such as tax credits and penalties for employers, vary by employer size and average wage level. Therefore, knowing the wage and firm size distribution of low-wage workers and how employer sponsored insurance (ESI) characteristics vary by these dimensions is particularly important for understanding the extent to which low-wage workers and their employers may be affected by different provisions in the ACA. To inform this issue, the authors use data from the 2006 Medical Expenditure Panel Survey Insurance Component to examine offers of coverage and cost-sharing requirements by the wage distribution and firm size dimensions of employers. They also draw on Medical Expenditure Panel Survey household-level data to describe the household circumstances of low-wage workers. The authors find that where low-wage workers are employed, who their colleagues are, and their spouses' wage levels are important factors in determining low-wage workers' access to coverage and the cost and generosity of such coverage. PMID- 21536604 TI - Access to and use of asthma health services among Latino children: the Rhode Island-Puerto Rico asthma center study. AB - This study determines asthma-related health care access and utilization patterns for Latino children of Puerto Rican and Dominican origin residing in Rhode Island (RI) and Latino children residing in Puerto Rico (Island). Data included 804 families of children with persistent asthma recruited from clinics. Island children were less likely to receive regular asthma care and care from a consistent provider and more likely to have been to the emergency department and hospitalized for asthma than RI children. Island children were 2.33 times more likely to have used the emergency department for asthma compared with RI non Latino White (NLW) children. Latino children residing in both Island and RI were less likely to have used specialty care and more likely to have had a physician visit for asthma in the past year than RI NLW children. The differences might reflect the effects of the different delivery systems on pediatric health care utilization and asthma management. PMID- 21536605 TI - Using consumer incentives to increase well-child visits among low-income children. AB - This quasi-experimental study examines the impact of Idaho's wellness incentive program, which rewards children with CHIP (Children's Health Insurance Programs) who are up-to-date with well-child visits with $30 in credits per quarter for use toward their CHIP premiums. Between baseline and the second year of implementation, the percentage of CHIP children who were up-to-date with well child visits increased by 116% (from 23% to 49%), compared with a 13% increase (from 29% to 32%) among children with Medicaid, who were not eligible for the incentive. The incentive program had a greater impact on children who were recommended to have one annual well-child visit compared with those recommended to have two to four annual visits. The program was not, however, more effective for those whose premiums were fully covered by the reward compared with those whose premiums were partially covered. This study provides encouraging evidence to states about using consumer financial incentives for increasing preventive care use. PMID- 21536606 TI - Review: relation between quality-of-care indicators for diabetes and patient outcomes: a systematic literature review. AB - The authors conducted a systematic literature review to assess whether quality indicators for diabetes care are related to patient outcomes. Twenty-four studies were included that formally tested this relationship. Quality indicators focusing on structure or processes of care were included. Descriptive analyses were conducted on the associations found, differentiating for study quality and level of analysis. Structure indicators were mostly tested in studies with weak designs, showing no associations with surrogate outcomes or mixed results. Process indicators focusing on intensification of drug treatment were significantly associated with better surrogate outcomes in three high-quality studies. Process indicators measuring numbers of tests or visits conducted showed mostly negative results in four high-quality studies on surrogate and hard outcomes. Studies performed on different levels of analysis and studies of lower quality gave similar results. For many widely used quality indicators, there is insufficient evidence that they are predictive of better patient outcomes. PMID- 21536607 TI - Pain reduction on insertion of a feeding tube in preterm infants: a randomized controlled trial. AB - BACKGROUND: Gavage feeding is required in preterm infants who cannot feed by themselves. Insertion of the feeding tube is painful, and reducing the discomfort in these patients is desirable. OBJECTIVE: The aim of this study was to assess pain and discomfort during nasal insertion of a feeding tube, and to evaluate different measures for pain relief. METHODS: We included 24 preterm infants with postmenstrual age 28 to 32 weeks' who were in stable condition. Each infant acted as his or her own control over a 3-week period during which the tube was changed 6 times. On these occasions, 6 different treatment combinations were given in randomized order: pacifier or no pacifier, combined with no fluid, sterile water, or 30% sucrose. Pain and discomfort were assessed by at least 2 independent and experienced observers using a pain assessment tool, the Premature Infant Pain Profile; score range: 0 to 21. In general, scores of 4 to 6 are interpreted as normal or no discomfort; >= 12 usually signals significant pain and distress. RESULTS: The median Premature Infant Pain Profile score during the procedure was 9 and decreased gradually toward 4 after 5 minutes. The lowest pain score was achieved by combining a pacifier with oral sucrose. Sterile water without a pacifier gave the highest score. CONCLUSIONS: Insertion of a feeding tube in preterm infants leads to a measurable degree of pain and discomfort, according to the Premature Infant Pain Profile assessment tool. Pain relief was best achieved by combining a pacifier with 30% sucrose. PMID- 21536608 TI - Young maternal age and poor child development: predictive validity from a birth cohort. AB - OBJECTIVE: We aimed to examine the ability of mother's age, and other factors measured during pregnancy (education, financial difficulties, partner status, smoking, and depression), to predict child development outcomes up to age 5 years. METHODS: Data were obtained from the Avon Longitudinal Study of Parents and Children (ALSPAC). Poor child development was defined as scoring in the worst 10% of a parent-reported ALSPAC developmental scale (ADS) at 18 months (n = 7546), the Strengths and Difficulties Questionnaire (SDQ) at 47 months (n = 8328), or teacher-reported School Entry Assessment (SEA) scores at 4 to 5 years (n = 7345). RESULTS: Only a small proportion of children with poor development had mothers aged younger than 20 years at their birth (3.3%, 6.4%, and 9.2%, for the ADS, SDQ, and SEA, respectively). A greater proportion with each measure of poor development would be identified (48.9%, 63.6%, and 74.4%, respectively) if all 6 predictors were used and a woman had at least 1 of these. Model discrimination was poor using maternal age only (area under the receiver operator characteristic curve ~ 0.5 for all 3 outcomes). This improved when all 6 predictors were included in the model (ADS: 0.56; SDQ: 0.66; SEA: 0.67). Calibration also improved with the model including all 6 predictors. CONCLUSIONS: Even if programs targeted at teen-aged mothers are successful in improving child development, they will have little impact on population levels of poor child development if young maternal age is the sole or main means of identifying eligibility for the program. PMID- 21536609 TI - Feeding of dietary botanical supplements and teas to infants in the United States. AB - OBJECTIVES: To describe the use of dietary botanical supplements and teas among infants, the characteristics of mothers who give them the specific botanical supplements and teas used, reasons for use, and sources of information. METHODS: We used data from the Infant Feeding Practices Study II, a longitudinal survey of women studied from late pregnancy through their infant's first year of life conducted by the US Food and Drug Administration and the Centers for Disease Control and Prevention between 2005 and 2007. The sample was drawn from a nationally distributed consumer opinion panel and was limited to healthy mothers with healthy term or near-term singleton infants. The final analytical sample included 2653 mothers. Statistical techniques include frequencies, chi2 tests, and ordered logit models. RESULTS: Nine percent of infants were given dietary botanical supplements or teas in their first year of life, including infants as young as 1 month. Maternal herbal use (P < .0001), longer breastfeeding (P < .0001), and being Hispanic (P = .016) were significantly associated with giving infants dietary botanical supplements or teas in the multivariate model. Many supplements and teas used were marketed and sold specifically for infants. Commonly mentioned information sources included friends or family, health professionals, and the media. CONCLUSIONS: A substantial proportion of infants in this sample was given a wide variety of supplements and teas. Because some supplements given to infants may pose health risks, health care providers need to recognize that infants under their care may be receiving supplements or teas. PMID- 21536610 TI - Symptomatic liver involvement in neonatal hereditary hemorrhagic telangiectasia. AB - High-flow hepatic vascular anomalies with arteriovenous shunting commonly manifest during the neonatal period with signs and symptoms of congestive heart failure, but to our knowledge, they have never been described in patients with hereditary hemorrhagic telangiectasia (HHT). We report here our experience with 3 patients with hepatic arteriovenous malformations (AVMs) who presented with symptoms of high-output congestive heart failure during the neonatal period and were subsequently diagnosed with HHT. Imaging showed large hypervascular lesions and multiple hepatic arteriovenous shunts that differentiated these lesions from liver hemangiomas. Transcatheter embolization was performed in all cases. One infant died of sepsis shortly after embolization; follow-up at the age of 2.5 years of the surviving infants revealed involution of the vascular lesions and no evidence of symptom recurrence. We conclude that severe symptoms related to hepatic AVMs in HHT can occur in the neonatal period and that HHT should therefore be included in the differential diagnosis of symptomatic neonatal hepatic vascular malformations. Imaging plays a key role in differentiating hepatic AVMs from hemangiomas, because the latter require additional pharmacologic treatments. Early transcatheter embolization seems to be effective, but long-term outcomes still need to be assessed. PMID- 21536611 TI - Creating flexibility in pediatric resident education. AB - INTRODUCTION: Pediatric residency programs must meet the challenge of producing graduates who are prepared to enter primary care, subspecialty fellowships or another career path. Meeting this challenge requires flexibility, which can be difficult to achieve. A program with 2 half days of continuity clinic that offers an option for residents to use 1 half day for advocacy or research projects may offer such flexibility. OBJECTIVE: To describe 1 residency program's experience with an alternative half- day continuity clinic program. METHODS: We conducted a retrospective review of resident participation, project types, scholarly products, and test scores associated with alternative half day program participation. RESULTS: Second- and third-year resident participation increased from 21% (7/33) in 2005 to 2006 to 41% (17/42) in 2008 to 2009. Forty-six residents undertook projects: 80% were research and 20% advocacy. The number of residents who presented abstracts at national meetings increased to 5 from a baseline of 4 per year. Four residents received advocacy grants. Three residents won national or regional research awards. The average score on the American Board of Pediatrics certifying examination was lower for residents in the alternative half day group, but pass rates remained high. All participants met the requirements for continuity clinic days and patient numbers. CONCLUSIONS: This unique 2 half day continuity clinic program not only enhances the education of residents entering primary care but also allows opportunities for residents anticipating careers in research or advocacy. This approach allows programmatic flexibility without creating a track system. PMID- 21536612 TI - Reproducibility of acute mountain sickness in children and adults: a prospective study. AB - OBJECTIVE: Although a history of previous acute mountain sickness (AMS) is commonly used for providing advice and recommending its prophylaxis during subsequent exposure, the intraindividual reproducibility of AMS during repeated high-altitude exposure has never been examined in a prospective controlled study. METHODS: In 27 nonacclimatized children and 29 adults, AMS was assessed during the first 48 hours after rapid ascent to 3450 m on 2 consecutive occasions 9 to 12 months apart. RESULTS: During the first exposure, 18 adults (62%) and 6 children (22%) suffered from AMS; during the second exposure, 14 adults (48%) and 4 children (15%) suffered from this problem (adults versus children, P <= .01). Most importantly, the intraindividual reproducibility of AMS was very different (P < .001) between children and adults. None of the 6 children having suffered from AMS during the first exposure suffered from AMS during the second exposure, but 4 children with no AMS during the first exposure did experience this problem during the second exposure. In contrast, 14 of the 18 adults who suffered from AMS on the first occasion also presented with this problem during the second exposure, and no new case developed in those who had not experienced AMS on the first occasion. CONCLUSIONS: In adults, a history of AMS is highly predictable of the disease on subsequent exposure, whereas in children it has no predictive value. A history of AMS should not prompt practitioners to advise against reexposure to high altitude or to prescribe drugs for its prophylaxis in children. PMID- 21536613 TI - Neonatal mortality from respiratory distress syndrome: lessons for low-resource countries. AB - Respiratory distress syndrome (RDS) is a major contributor to neonatal mortality worldwide. However, little information is available regarding rates of RDS specific mortality in low-income countries, and technologies for RDS treatment are used inconsistently in different health care settings. Our objective was to better understand the interventions that have decreased the rates of RDS-specific mortality in high-income countries over the past 60 years. We then estimated the effects on RDS-specific mortality in low-resource settings. Of the sequential introduction of technologies and therapies for RDS, widespread use of oxygen and continuous positive airway pressure were associated with the time periods that demonstrated the greatest decline in RDS-specific mortality. We argue that these 2 interventions applied widely in low-resource settings, with appropriate supportive infrastructure and general newborn care, will have the greatest impact on decreasing neonatal mortality. This historical perspective can inform policy makers for the prioritization of scarce resources to improve survival rates for newborns worldwide. PMID- 21536614 TI - Stevens-Johnson syndrome in a boy with macrolide-resistant Mycoplasma pneumoniae pneumonia. AB - Mycoplasma pneumoniae is a highly specialized parasitic bacterium that is a significant cause of community-acquired pneumonia in children. Although most such respiratory infections are mild, a minor percentage of patients require hospitalization and, occasionally, intensive treatment for respiratory failure. A variety of extrapulmonary sequelae of M pneumoniae infections have been described, including Stevens-Johnson syndrome. Macrolide resistance in M pneumoniae has developed rapidly in Asia, particularly in China, over the past decade and is now appearing in the United States. Emerging resistance to macrolides creates a therapeutic conundrum, particularly for pediatricians caring for young children in whom absolute or relative contraindications exist for the use of tetracyclines or fluoroquinolones, the 2 other main classes of drugs shown to be efficacious for M pneumoniae. We describe here the case of a child with a prolonged febrile illness associated with Stevens-Johnson-like mucocutaneous involvement who was found to have a respiratory infection with macrolide resistant M pneumoniae. PMID- 21536615 TI - Recurrent EIARF and PRES with severe renal hypouricemia by compound heterozygous SLC2A9 mutation. AB - Renal hypouricemia (RHU) is a hereditary disease that predisposes affected people to exercise-induced acute renal failure (EIARF). In most patients with RHU, the disorder is caused by loss-of-function mutations in SLC22A12 (solute carrier family 22, member 12), which encodes urate transporter 1 (URAT1). Patients with RHU without any mutations in the URAT1 gene were recently found to have a mutation in the glucose transporter 9 (GLUT9) gene (SLC2A9 [solute carrier family 2, member 9]). Central nervous system complications seem to be rare in patients with RHU with SLC22A12 mutations. Here, we report the case of a girl with severe RHU (serum urate: 5.9 MUmol/L [0.1 mg/dL]) associated with recurrent EIARF in whom the disease was caused by a compound heterozygous mutation in SLC2A9, a nonsense mutation in the paternal allele (p.G207X in exon 7), and a large duplication (c.1-2981_1204+16502) in the maternal allele detected by reverse transcription polymerase chain reaction (PCR), semiquantitative PCR, long PCR, and direct sequencing. The episodes of EIARF were complicated by posterior reversible encephalopathy syndrome (PRES), which suggested a relationship between PRES and GLUT9 or severe hypouricemia. This is the second report of mutations of both alleles of SLC2A9 that resulted in severe hypouricemia. Our findings indicate that even a nonsense mutation responsible for the heterozygous status of SLC2A9 did not cause severe hypouricemia, and they lend support to previous speculation that mutations of both SLC2A9 alleles cause severe hypouricemia. Our case shows that GLUT9, unlike URAT1, may play a specific role in exercise-induced PRES. PMID- 21536616 TI - "Remarkable improvement": sulfa drugs and pediatric meningococcal meningitis, 1937-1949. PMID- 21536617 TI - Apparent mineralocorticoid excess: time of manifestation and complications despite treatment. AB - Here we describe the case of a patient followed from birth because of a positive family history for apparent mineralocorticoid excess (AME) in an older brother. The patient, a girl, had normal serum electrolyte and blood pressure measurements in the first months after birth. Not until the age of 11 months did she develop anorexia and failure to thrive in combination with hypertension, hypokalemia, and metabolic alkalosis, which are consistent with the diagnosis of AME. This diagnosis was confirmed by mutation analysis of the HSD11B2 gene (C1228T). Treatment with amiloride and furosemide electrolyte disturbances normalized her blood pressure. At the age of 19 years she unexpectedly suffered a stroke. Additional investigations revealed no accepted risk factor for stroke. We discuss the possible underlying mechanisms for the delayed manifestation of hypertension and electrolyte disturbances in AME, propose an additional explanation for the stroke in this patient, and advise treatment with a mineralocorticoid receptor antagonist to reduce stroke risk in patients with AME. PMID- 21536619 TI - Details of laparoscopic anatomy for a radical extrafascial duodenopancreatectomy. PMID- 21536618 TI - Is frequency of shared family meals related to the nutritional health of children and adolescents? AB - OBJECTIVE: We used meta-analytic methods to examine the frequency of shared family mealtimes in relation to nutritional health in children and adolescents. The primary objective was to determine consistency and strength of effects across 17 studies that examined overweight and obese, food consumption and eating patterns, and disordered eating. METHODS: The total sample size for all studies was 182 836 children and adolescents (mean sample age: 2.8-17.3 years). Pooled odds ratios were calculated. A random-effects model was used to estimate all outcomes. RESULTS: The frequency of shared family meals is significantly related to nutritional health in children and adolescents. Children and adolescents who share family meals 3 or more times per week are more likely to be in a normal weight range and have healthier dietary and eating patterns than those who share fewer than 3 family meals together. In addition, they are less likely to engage in disordered eating. CONCLUSIONS: Educational and public health initiatives aimed at promoting shared family mealtimes may improve nutritional health of children and adolescents. Clinicians may advise their patients about the benefits of sharing 3 or more family mealtimes per week; benefits include a reduction in the odds for overweight (12%), eating unhealthy foods (20%), and disordered eating (35%) and an increase in the odds for eating healthy foods (24%). PMID- 21536620 TI - Intrathyroid adenomas in primary hyperparathyroidism: are they frequent enough to guide surgical strategy? AB - BACKGROUND: Ectopic parathyroid adenoma, including intrathyroid adenoma, is a common cause of failed parathyroid operations. The aim of this study was to evaluate the operative strategy/outcome in patients with primary hyperparathyroidism (pHPT), with special regard to intrathyroid adenomas. METHOD: The authors performed an analysis of all patients receiving operative treatment for pHPT from 2003 through 2005. The operative strategy consisted of systematic perithyroid exploration followed by extended cervical exploration in cases where the adenoma was not found initially. In cases of persistent, high intraoperative parathyroid hormone levels, hemithyroidectomy was performed on the side with higher suspicion of intrathyroid adenoma or with more extended thyroid changes. RESULTS: During the study, 115 patients received surgical treatment for sporadic pHPT. A single parathyroid adenoma (normal parathyroid position) was found in 95 patients (82.6%), ectopic single adenoma was found in 7 patients (6.1%), and double adenomas were found in 10 (8.7%) patients. Operative failure occurred in 3 cases (2.6%). In all, 4 of 7 ectopic single adenomas were intrathyroidal and were removed by hemithyroidectomy according to the authors' standard protocol. CONCLUSION: The strategy of (a) cervical exploration, (b) extended cervical exploration, and (c) hemithyroidectomy was highly successful for removing undetectable intrathyroid parathyroid adenomas during primary intervention, thereby reducing the risks associated with reintervention. PMID- 21536621 TI - Dynamics of odorant binding to thin aqueous films of rat-OBP3. AB - Uptake, retention and release of 5 selected odorants (benzaldehyde, 2 methylpyrazine, 2-isobutyl-3-methoxypyrazine, 2-isobutylthiazole, and 2,4,5 trimethylthiazole) by recombinant rat odor-binding protein 3 (rat-OBP3) were measured in a model system under nonequilibrium conditions. Gaseous odorants were introduced into a 100 mm section of a polar deactivated capillary in which aqueous rat-OBP3 films were formed to mimic the olfactory epithelium (OE), and the change in the gas-phase concentration of the outflow gas was monitored in real time using atmospheric pressure chemical ionization-mass spectrometry (APCI MS). The 5 odorants were chosen because they exhibited a broad range of dissociation constants with rat-OBP3 and because they were amenable to detection by on-line APCI-MS. All 5 odorants were quantitatively bound by rat-OBP3, which resulted in an effective concentration of the odorants in the aqueous layer (about 50 000-fold). Odorant release from the rat-OBP3-odorant complex into the gas phase showed that odorant release was governed by the dissociation constant of the complex and the flow rate of odorant-free air. When 2 odorants were introduced into the system, odorant uptake and release were influenced by the method of introduction and their relative affinities for the protein. Because rat OBP3 exhibits typical odorant-binding characteristics, the results not only provide fundamental information on the kinetics of odorant mass transfer induced by the presence of OBPs in the olfactory mucus layer but also support the possibility that vertebrate OBPs may facilitate the accumulation of odorants in the OE. PMID- 21536623 TI - Posttraumatic stress disorders in civilian orthopaedics. AB - Posttraumatic stress disorder (PTSD) is a well-characterized anxiety disorder that may occur after exposure to a traumatic event. Research is ongoing to document neuroanatomic, neuroendocrine, and genetic correlates to the behavioral phenotype. PTSD occurs in 20% to 51% of patients with musculoskeletal injury. Orthopaedic outcomes, including return to work, activities of daily living, patient perception of physical recovery, and objective physical parameters, suffer considerably in patients with PTSD. There are several ways by which treating orthopaedic surgeons can recognize at-risk patients and help prevent the development of PTSD. Should prevention prove unsuccessful, effective treatment strategies exist, as well. Research is needed to investigate whether a correlation exists between successful management of the psychiatric manifestations of PTSD and improved physical outcomes. PMID- 21536624 TI - Complications of anterior lumbar surgery. AB - The incidence of anterior lumbar surgery is increasing. Although adverse events are uncommon, several have been described. Complications can be categorized based on the time of occurrence (ie, intraoperative, postoperative), patient positioning, surgical exposure, and spinal procedure. Notable approach-related complications involve vascular, visceral, and neural structures. Abdominal complications have been reported. Clinically significant complications related to spinal decompression and reconstruction consist primarily of neurologic injuries and graft- and device-related problems. The rate of complications is higher in the setting of revision anterior surgery than with initial anterior lumbar surgery. A thorough understanding of the complications associated with anterior lumbar surgery will aid in prevention, recognition, and management of these rare problems. The assistance of a vascular, neurologic, or general surgeon may be helpful in avoiding or effectively managing complications. PMID- 21536625 TI - Autografts commonly used in anterior cruciate ligament reconstruction. AB - Anterior cruciate ligament reconstruction is among the most common orthopaedic procedures in the United States, with >200,000 performed annually. Much has been published regarding the use of autograft versus allograft. Bone-patellar tendon bone is the most frequently used autograft, but hamstring and quadriceps tendon grafts are common alternatives. Each graft has distinct advantages and disadvantages, and selection is individualized. Fixation methods vary by graft type. Fixation resulting in a construct that is too rigid may restrict knee range of motion. Donor site morbidity must be considered, as well. Autograft harvest may result in anterior knee pain, kneeling pain, anterior knee numbness, muscle weakness, and patellar fracture. Appropriate graft selection is essential to optimize outcomes. PMID- 21536626 TI - Arthroscopic management of the stiff elbow. AB - Elbow stiffness is a challenge to manage effectively. Elbow contractures commonly result from both intrinsic and extrinsic factors, causing limited motion. Recent technical advances in elbow arthroscopy have led to the development of minimally invasive procedures for the management of select cases of recalcitrant elbow stiffness. As with most arthroscopic procedures, a notable learning curve is associated with the safe, effective execution of these surgical techniques. Certain clinical scenarios require that special attention be paid to the ulnar nerve and the posterior bundle of the medial ulnar collateral ligament to improve motion safely. Arthroscopic capsular release of the elbow is effective for restoring a functional arc of motion in the short term in most patients with extrinsic contractures. PMID- 21536627 TI - Surgical management of the problematic hip in adolescent and young adult patients. AB - Surgical management of the problematic hip in adolescent and young adult patients can be challenging. In many of these patients, hip arthrosis and pain occur secondary to hip dysplasia associated with chronic instability, whether the result of prior treatment or chronic unmanaged acetabular dysplasia. Surgical techniques such as the Bernese periacetabular osteotomy are performed to correct acetabular deficiency, restore hip joint stability, and eliminate pain. Patients with previous Legg-Calve-Perthes disease or slipped capital femoral epiphysis frequently note onset of symptomatic hip arthrosis and pain in adolescence or young adulthood. Pain occurs secondary to pathologic impingement of the deformed proximal femur against the anterolateral acetabulum (ie, femoroacetabular impingement). The recent successful innovation of the transtrochanteric surgical hip dislocation approach provides complete access to the hip and offers the potential for comprehensive correction of both the often severe proximal femoral deformity and associated labral chondral disease secondary to Legg-Calve-Perthes disease and slipped capital femoral epiphysis. Restoration of more normal proximal femoral morphology results in marked improvement in functional outcome. Effective orthopaedic management requires an understanding of the mechanisms of hip disease as well as surgical expertise. PMID- 21536628 TI - Collateral ligament injuries of the thumb metacarpophalangeal joint. AB - The ulnar and radial collateral ligaments are primary stabilizers of the thumb metacarpophalangeal (MP) joint. Injury to these ligaments can lead to instability and disability. Stress testing is essential to establish the diagnosis. Complete tear is diagnosed on physical examination when the proximal phalanx of the thumb can be angulated ulnarly or radially on the metacarpal head by 30 degrees to 35 degrees with the MP joint in either zero degrees of extension or 30 degrees of flexion. Lack of a firm end point or angulation measuring >15 degrees on stress testing compared with the contralateral thumb MP joint are also indicative of complete tear. Partial ligament injuries may be managed nonsurgically, but complete tears are usually managed surgically. Various techniques are used to reattach the ligament to bone, including suture anchors and, less commonly, repair of midsubstance tears. Options for managing chronic injuries include ligament repair, ligament reconstruction with a free tendon graft, and arthrodesis of the MP joint. PMID- 21536629 TI - Diagnosis and treatment of osteochondritis dissecans. AB - This clinical practice guideline is based on a series of systematic reviews of published studies in the available literature on the diagnosis and treatment of osteochondritis dissecans of the knee. None of the 16 recommendations made by the work group is graded as strong; most are graded inconclusive; two are graded weak; and four are consensus statements. Both of the weak recommendations are related to imaging evaluation. For patients with knee symptoms, radiographs of the joint may be obtained to identify the lesion. For patients with radiographically apparent lesions, MRI may be used to further characterize the osteochondritis dissecans lesion or identify other knee pathology. PMID- 21536630 TI - AAOS Clinical Practice Guideline: diagnosis and treatment of osteochondritis dissecans. PMID- 21536631 TI - E-pearl: brachial artery embolus mimicking acute stroke. PMID- 21536632 TI - Clinical reasoning: an unexpected diagnosis in a 4-month-old infant with lethargy and H1N1 influenza. PMID- 21536633 TI - Seizures, epilepsy, and vascular malformations. PMID- 21536634 TI - Seizure risk from cavernous or arteriovenous malformations: prospective population-based study. AB - OBJECTIVES: To determine the risk of epileptic seizures due to a brain arteriovenous malformation (AVM) or cavernous malformation (CM). METHODS: In a prospective population-based study of new diagnoses of AVMs (n = 229) or CMs (n = 139) in adults in Scotland in 1999-2003, we used annual medical records surveillance, general practitioner follow-up, and patient questionnaires to quantify the risk of seizures between clinical presentation and AVM/CM treatment, last follow-up, or death. RESULTS: The 5-year risk of first-ever seizure after presentation was higher for AVMs presenting with intracranial hemorrhage or focal neurologic deficit (ICH/FND: n = 119; 23%, 95% confidence interval [CI] 9%-37%) than for incidental AVMs (n = 40; 8%, 95% CI 0%-20%), CMs presenting with ICH/FND (n = 38; 6%, 95% CI 0%-14%), or incidental CMs (n = 57; 4%, 95% CI 0%-10%). For adults who had never experienced ICH/FND, the 5-year risk of epilepsy after first ever seizure was higher for CMs (n = 23; 94%, 95% CI 84%-100%) than AVMs (n = 37; 58%, 95% CI 40%-76%; p = 0.02). Among adults who never experienced ICH/FND and presented with or developed epilepsy, there was no difference in the proportions achieving 2-year seizure freedom over 5 years between AVMs (n = 43; 45%, 95% CI 20%-70%) and CMs (n = 35; 47%, 95% CI 27%-67%). CONCLUSIONS: AVM-related ICH confers a significantly higher risk of a first-ever seizure compared to CMs or incidental AVMs. Adults with a CM have a high risk of epilepsy after a first-ever seizure but achieve seizure freedom as frequently as those with epilepsy due to an AVM. PMID- 21536635 TI - Weight gain and recurrence in idiopathic intracranial hypertension: a case control study. AB - OBJECTIVE: To determine whether weight gain is associated with recurrence in idiopathic intracranial hypertension (IIH). METHODS: Medical records of adult patients with IIH seen between 1993 and 2009 at 2 university hospitals were reviewed to identify those with and without recurrence. Patients with documented height and weight at presentation and at subsequent visits were studied. The Wilcoxon rank sum test was used to compare mean body mass index (BMI) and percent weight change between the groups of patients with recurrence and without recurrence. The signed-rank test was used for comparing BMI within groups at the various time points. RESULTS: Fifty women with IIH were included in the analyses: 26 had IIH recurrence and 24 did not. Patients with recurrence had greater BMI at the time of recurrence compared to BMI at diagnosis (p = 0.02, signed-rank test). They also demonstrated a greater degree of weight gain between initial resolution and recurrence (BMI change +2.0 kg/m(2) [-1.5 to 10.8]) compared to patients without recurrence (-0.75 kg/m(2) [-35 to 3.6], p = 0.0009, Wilcoxon rank sum test). Patients without recurrence demonstrated stable weights (0%[95% CI -9.6 to 10.1%]), while patients with recurrence demonstrated a 6% weight gain ([-3.5 to 40.2%], p = 0.005), with an average rate of BMI gain of 1.3 kg/m(2)/year vs -0.96 kg/m(2)/year in those without recurrence. CONCLUSION: Patients with IIH recurrence had significant increases in BMI compared to patients without recurrence in this cohort. Patients with resolved IIH should be advised that weight gain may be a risk factor for IIH recurrence. PMID- 21536637 TI - Midlife overweight and obesity increase late-life dementia risk: a population based twin study. AB - OBJECTIVE: The relation of overweight to dementia is controversial. We aimed to examine the association of midlife overweight and obesity with dementia, Alzheimer disease (AD), and vascular dementia (VaD) in late life, and to verify the hypothesis that genetic and early-life environmental factors contribute to the observed association. METHODS: From the Swedish Twin Registry, 8,534 twin individuals aged >=65 (mean age 74.4) were assessed to detect dementia cases (DSM IV criteria). Height and weight at midlife (mean age 43.4) were available in the Registry. Data were analyzed as follows: 1) unmatched case-control analysis for all twins using generalized estimating equation (GEE) models and 2) cotwin matched case-control approach for dementia-discordant twin pairs by conditional logistic regression taking into account lifespan vascular disorders and diabetes. RESULTS: Among all participants, dementia was diagnosed in 350 subjects, and 114 persons had questionable dementia. Overweight (body mass index [BMI] >25-30) and obesity (BMI >30) at midlife were present in 2,541 (29.8%) individuals. In fully adjusted GEE models, compared with normal BMI (20-25), overweight and obesity at midlife were related to dementia with odds ratios (ORs) (95% CIs) of 1.71 (1.30 2.25) and 3.88 (2.12-7.11), respectively. Conditional logistic regression analysis in 137 dementia-discordant twin pairs led to an attenuated midlife BMI dementia association. The difference in ORs from the GEE and the matched case control analysis was statistically significant (p = 0.019). CONCLUSIONS: Both overweight and obesity at midlife independently increase the risk of dementia, AD, and VaD. Genetic and early-life environmental factors may contribute to the midlife high adiposity-dementia association. PMID- 21536639 TI - A population-based study of neuromyelitis optica in Caucasians. AB - BACKGROUND: Epidemiologic studies have suggested different prevalence of neuromyelitis optica (NMO) in different ethnic groups. However, data on the incidence and prevalence of NMO in Caucasians are scarce. OBJECTIVE: To estimate the incidence and prevalence of NMO in a predominantly Caucasian population based on the Wingerchuk 2006 criteria. METHODS: The study was a population-based retrospective case series with longitudinal follow-up. Patients with multiple sclerosis (MS), optic neuritis (ON), acute transverse myelitis (TM), and NMO from the 4 neurology and 3 ophthalmology departments in the Region of Southern Denmark having been diagnosed between 1998 and 2008 were investigated. Patients were included based on 1) episodes of ON or TM and 2) an initial brain MRI not diagnostic for MS. An immunofluorescence assay was used to determine aquaporin-4 (AQP-4) antibodies. RESULTS: A total of 477 patients with MS, TM, or ON were evaluated: 163 fulfilled the inclusion criteria, 42 (26%) qualified for the diagnosis of NMO, 26 (62.0%) of these were AQP4 antibody positive. All except one were Caucasian, the female:male ratio was 2.8:1, and mean age at onset was 35.6 years (range 15-64 years). The clinical presentation was heterogeneous including TM, longitudinally extensive TM, ON, and brainstem syndromes. The yearly incidence rate of NMO in the population was estimated to be 0.4 per 10(5) person years (95% confidence interval [CI] 0.30-0.54) and the prevalence was 4.4 per 10(5) (95% CI 3.1-5.7). CONCLUSIONS: Despite being a rare disease, NMO is more common in a Caucasian population than earlier believed. PMID- 21536640 TI - Brodmann area 12: an historical puzzle relevant to FTLD. AB - BACKGROUND: Brodmann brain maps, assembled in 1909, are still in use, but understanding of their animal-human homology is uncertain. Furthermore, in 1909, Brodmann did not identify human area 12 (BA12), a location now important to understanding of frontotemporal lobar degeneration (FTLD). METHODS: We re examined Brodmann's areas, both animal and human, in his 1909 monograph and other literature, both historical and contemporary, and projected BA12 onto the medial surface of a fixed human brain to show its location. RESULTS: We found Brodmann did identify human BA12 in later maps (1910 and 1914), but that his brain areas, contrary to his own aims as a comparative anatomist, are now used as physiologic loci in human brain. CONCLUSION: Because of its current link with frontotemporal dementia, BA12's transition from animal (1909) to human (1910 and 1914) is not only an historical puzzle. It impacts how Brodmann's areas, based on comparative animal-human cytoarchitecture, are widely used in current research as functional loci in human brain. PMID- 21536641 TI - West syndrome associated with 14q12 duplications harboring FOXG1. PMID- 21536642 TI - Metaplastic bone in a cortical tuber of a young patient with tuberous sclerosis complex. PMID- 21536643 TI - Rotigotine-induced nail dyschromia in a patient with Parkinson disease. PMID- 21536644 TI - Diffusion tensor imaging, permanent pyramidal tract damage, and outcome in subcortical stroke. PMID- 21536645 TI - Prior antiplatelet therapy and outcome following intracerebral hemorrhage: a systematic review. PMID- 21536646 TI - Transmembrane protein 198 promotes LRP6 phosphorylation and Wnt signaling activation. AB - Wnt/beta-catenin signaling is fundamental in embryogenesis and tissue homeostasis in metazoans. Upon Wnt stimulation, cognate coreceptors LRP5 and LRP6 ([LRP5/6] low-density lipoprotein receptor-related proteins 5 and 6) are activated via phosphorylation at key residues. Although several kinases have been implicated, the LRP5/6 activation mechanism remains unclear. Here, we report that transmembrane protein 198 (TMEM198), a previously uncharacterized seven transmembrane protein, is able to specifically activate LRP6 in transducing Wnt signaling. TMEM198 associates with LRP6 and recruits casein kinase family proteins, via the cytoplasmic domain, to phosphorylate key residues important for LRP6 activation. In mammalian cells, TMEM198 is required for Wnt signaling and casein kinase 1-induced LRP6 phosphorylation. During Xenopus embryogenesis, maternal and zygotic tmem198 mRNAs are widely distributed in the ectoderm and mesoderm. TMEM198 is required for Wnt-mediated neural crest formation, antero posterior patterning, and particularly engrailed-2 expression in Xenopus embryos. Thus, our results identified TMEM198 as a membrane scaffold protein that promotes LRP6 phosphorylation and Wnt signaling activation. PMID- 21536647 TI - Forced expression of cyclin-dependent kinase 6 confers resistance of pro-B acute lymphocytic leukemia to Gleevec treatment. AB - The gene encoding c-ABL, a nonreceptor protein tyrosine kinase, is involved in a chromosomal translocation resulting in expression of a BCR-Abl fusion protein that causes most chronic myelogenous and some acute lymphocytic leukemias (CML and ALL) in humans. The Abelson murine leukemia virus (A-MuLV) expresses an alternative form of c-Abl, v-Abl, that transforms murine pro-B cells, resulting in acute leukemia and providing an experimental model for human disease. Gleevec (STI571) inhibits the Abl kinase and has shown great utility against CML and ALL in humans, although its usefulness is limited by acquired resistance. Since STI571 is active against A-MuLV-transformed cells in vitro, we performed a retroviral cDNA library screen for genes that confer resistance to apoptosis induced by STI571. We found that forced expression of Cdk6 promotes continued cell division and decreased apoptosis of leukemic cells. We then determined that the transcription factor E2A negatively regulates Cdk6 transcription in leukemic pro-B cells and that the v-Abl kinase stimulates Cdk6 expression via an extracellular signal-regulated kinase 1-dependent pathway. Finally, we show that the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor PD0332991 can act synergistically with STI571 to enhance leukemic cell death, suggesting a potential role for CDK6 inhibitors in the treatment of STI571-resistant CML or ALL. PMID- 21536649 TI - Telomerase reverse transcriptase and Wnt signaling. PMID- 21536648 TI - Mtg16/Eto2 contributes to murine T-cell development. AB - Mtg16/Eto2 is a transcriptional corepressor that is disrupted by t(16;21) in acute myeloid leukemia. Using mice lacking Mtg16, we found that Mtg16 is a critical regulator of T-cell development. Deletion of Mtg16 led to reduced thymocyte development in vivo, and after competitive bone marrow transplantation, there was a nearly complete failure of Mtg16(-/-) cells to contribute to thymocyte development. This defect was recapitulated in vitro as Mtg16(-/-) Lineage(-)/Sca1(+)/c-Kit(+) (LSK) cells of the bone marrow or DN1 cells of the thymus failed to produce CD4(+)/CD8(+) cells in response to a Notch signal. Complementation of these defects by reexpressing Mtg16 showed that 3 highly conserved domains were somewhat dispensable for T-cell development but required the capacity of Mtg16 to suppress E2A-dependent transcriptional activation and to bind to the Notch intracellular domain. Thus, Mtg16 integrates the activities of signaling pathways and nuclear factors in the establishment of T-cell fate specification. PMID- 21536650 TI - Functional cooperation between the proteins Nck and ADAP is fundamental for actin reorganization. AB - T cell antigen receptor (TCR) activation triggers profound changes in the actin cytoskeleton. In addition to controlling cellular shape and polarity, this process regulates vital T cell responses, such as T cell adhesion, motility, and proliferation. These depend on the recruitment of the signaling proteins Nck and Wiskott-Aldrich syndrome protein (WASp) to the site of TCR activation and on the functional properties of the adapter proteins linker for activation of T cells (LAT) and SH2-domain-containing leukocyte protein of 76 kDa (SLP76). We now demonstrate that Nck is necessary but insufficient for the recruitment of WASp. We show that two pathways lead to SLP76-dependent actin rearrangement. One requires the SLP76 acidic domain, crucial to association with the Nck SH2 domain, and another requires the SLP76 SH2 domain, essential for interaction with the adhesion- and degranulation-promoting adapter protein ADAP. Functional cooperation between Nck and ADAP mediates SLP76-WASp interactions and actin rearrangement. We also reveal the molecular mechanism linking ADAP to actin reorganization. PMID- 21536651 TI - Mechanistic analysis of a DNA damage-induced, PTEN-dependent size checkpoint in human cells. AB - Following DNA damage, human cells undergo arrests in the G(1) and G(2) phases of the cell cycle and a simultaneous arrest in cell size. We previously demonstrated that the cell size arrest can be uncoupled from the cell cycle arrest by mutational inactivation of the PTEN tumor suppressor gene. Here we show that the cell size checkpoint is inducible by DNA-damaging chemotherapeutic agents as well as by ionizing radiation and is effectively regulated by PTEN but not by its oncogenic counterpart, PIK3CA. Mutational analysis of PTEN and pharmacological inhibition of Akt revealed that modulation of Akt phosphorylation is unnecessary for cell size checkpoint control. To discover putative PTEN regulators and/or effectors involved in size checkpoint control, we employed a novel endogenous epitope tagging (EET) approach, which revealed that endogenous PTEN interacts at the membrane with an actin-remodeling complex that includes actin, gelsolin, and EPLIN. Pharmacological inhibition of actin remodeling in PTEN(+/+) cells recapitulated the lack of size checkpoint control seen in PTEN(-/-) cells. Taken together, these results provide further support for the existence of a DNA damage inducible size checkpoint that is regulated by a major tumor suppressor, and they provide a novel Akt-independent mechanism by which PTEN controls cell size. PMID- 21536652 TI - Semiquantitative proteomic analysis of the human spliceosome via a novel two dimensional gel electrophoresis method. AB - More than 200 proteins associate with human spliceosomes, but little is known about their relative abundances in a given spliceosomal complex. Here we describe a novel two-dimensional (2D) electrophoresis method that allows separation of high-molecular-mass proteins without in-gel precipitation and thus without loss of protein. Using this system coupled with mass spectrometry, we identified 171 proteins altogether on 2D maps of stage-specific spliceosomal complexes. By staining with a fluorescent dye with a wide linear intensity range, we could quantitate and categorize proteins as present in high, moderate, or low abundance. Affinity-purified human B, B(act), and C complexes contained 69, 63, and 72 highly/moderately abundant proteins, respectively. The recruitment and release of spliceosomal proteins were followed based on their abundances in A, B, B(act), and C spliceosomal complexes. Staining with a phospho-specific dye revealed that approximately one-third of the proteins detected in human spliceosomal complexes by 2D gel analyses are phosphorylated. The 2D gel electrophoresis system described here allows for the first time an objective view of the relative abundances of proteins present in a particular spliceosomal complex and also sheds additional light on the spliceosome's compositional dynamics and the phosphorylation status of spliceosomal proteins at specific stages of splicing. PMID- 21536653 TI - High-mobility group A2 protein modulates hTERT transcription to promote tumorigenesis. AB - The high-mobility group A2 gene (HMGA2) is one of the most frequently amplified genes in human cancers. However, functions of HMGA2 in tumorigenesis are not fully understood due to limited knowledge of its targets in tumor cells. Our study reveals a novel link between HMGA2 and the regulation of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, which offers critical insight into how HMGA2 contributes to tumorigenesis. The expression of HMGA2 modulates the expression of hTERT, resulting in cells with enhanced telomerase activities and increased telomere length. Treatment with suberoylanilide hydroxamide (SAHA), a histone deacetylase (HDAC) inhibitor, causes dose-dependent hTERT reporter activation, mimicking HMGA2 overexpression. By interacting with Sp1, HMGA2 interferes with the recruitment of HDAC2 to the hTERT proximal promoter, enhancing localized histone H3-K9 acetylation and thereby stimulating hTERT expression and telomerase activity. Moreover, HMGA2 knockdown by short hairpin HMGA2 in HepG2 cells leads to progressive telomere shortening and a concurrent decrease of steady-state hTERT mRNA levels, attenuating their ability to form colonies in soft agar. Importantly, HMGA2 partially replaces the function of hTERT during the tumorigenic transformation of normal human fibroblasts. These findings are potentially clinically relevant, because HMGA2 expression is reported to be upregulated in a number of human cancers as telomere maintenance is essential for tumorigenesis. PMID- 21536654 TI - Characterization of basigin isoforms and the inhibitory function of basigin-3 in human hepatocellular carcinoma proliferation and invasion. AB - Basigin, which has four isoforms, plays an important role in invasion of hepatocellular carcinoma (HCC). Detailed transcriptional regulation and functions of the basigin isoforms have not been reported except in the case of the predominant isoform basigin-2, which act as inducer of matrix metalloproteinases (MMPs). Here we determined that basigin-2, basigin-3, and basigin-4 were the most abundant transcript variants in human cell lines. GeneRacer PCR and luciferase reporter assays showed that basigin-3 and basigin-4 were initiated from an alternative promoter. Basigin-3 and basigin-4 were widely expressed in various normal human tissues at the mRNA level and were upregulated in HCC tissues compared to in normal tissues. Western blotting and confocal imaging showed that glycosylated basigin-3 and basigin-4 were expressed and localized to the plasma membrane. However, in cultured cell lines, only native basigin-3, and not basigin 4, was detected at protein level. Overexpression of basigin-3 inhibited HCC cell proliferation, MMP induction, and cell invasion in vitro and in vivo. Bimolecular fluorescence complementation assays and nuclear magnetic resonance (NMR) analysis indicated that basigin-3 interacted with basigin-2 to form hetero-oligomers. In conclusion, we systematically investigated the alternative splicing of basigin and found that basigin-3 could inhibit HCC proliferation and invasion, probably through interaction with basigin-2 as an endogenous inhibitor via hetero oligomerization. PMID- 21536655 TI - The Ras signaling inhibitor LOX-PP interacts with Hsp70 and c-Raf to reduce Erk activation and transformed phenotype of breast cancer cells. AB - The lysyl oxidase gene (LOX) inhibits Ras signaling in transformed fibroblasts and breast cancer cells. Its activity was mapped to the 162-amino-acid propeptide domain (LOX-PP) of the lysyl oxidase precursor protein. LOX-PP inhibits Erk signaling, motility, and tumor formation in a breast cancer xenograft model; however, its mechanism of action is largely unknown. Here, a copurification-mass spectrometry approach was taken using ectopically expressed LOX-PP in HEK293T cells and the heat shock/chaperone protein Hsp70 identified. Hsp70 interaction with LOX-PP was confirmed using coimmunoprecipitation of intracellularly and bacterially expressed and endogenous proteins. The interaction was mapped to the Hsp70 peptide-binding domain and to LOX-PP amino acids 26 to 100. LOX-PP association reduced Hsp70 chaperone activities of protein refolding and survival after heat shock. LOX-PP interacted with the Hsp70 chaperoned protein c-Raf. With the use of ectopic expression of LOX-PP wild-type and deletion proteins, small interfering RNA (siRNA) knockdown, and Lox(-/-) mouse embryo fibroblasts, LOX-PP interaction with c-Raf was shown to decrease downstream activation of MEK and NF kappaB, migration, and anchorage-independent growth and reduce its mitochondrial localization. Thus, the interaction of LOX-PP with Hsp70 and c-Raf inhibits a critical intermediate in Ras-induced MEK signaling and plays an important role in the function of this tumor suppressor. PMID- 21536656 TI - The TFIIF-like Rpc37/53 dimer lies at the center of a protein network to connect TFIIIC, Bdp1, and the RNA polymerase III active center. AB - Eukaryotic RNA polymerase III (Pol III) relies on a transcription factor TFIIF like Rpc37/53 subcomplex for promoter opening, elongation, termination, and reinitiation. By incorporating the photoreactive amino acid p-benzoyl-L phenylalanine (BPA) into Rpc37, Rpc53, and the Rpc2 subunit of Pol III, we mapped protein-protein interactions, revealing the position of Rpc37/53 within the Pol III preinitiation complex (PIC). BPA photo-cross-linking was combined with site directed hydroxyl radical probing to localize the Rpc37/53 dimerization module on the lobe/external 2 domains of Rpc2, in similarity to the binding of TFIIF on Pol II. N terminal to the dimerization domain, Rpc53 binds the Pol III-specific subunits Rpc82 and Rpc34, the Pol III stalk, and the assembly factor TFIIIC, essential for PIC formation. The C-terminal domain of Rpc37 interacts extensively with Rpc2 and Rpc34 and contains binding sites for initiation factor Bdp1. We also located the C-terminal domain of Rpc37 within the Pol III active center in the ternary elongation complex, where it likely functions in accurate termination. Our work explains how the Rpc37/53 dimer is anchored on the Pol III core and acts as a hub to integrate a protein network for initiation and termination. PMID- 21536657 TI - CPEB control of NF-kappaB nuclear localization and interleukin-6 production mediates cellular senescence. AB - CPEB is a sequence-specific translational regulatory RNA binding protein that mediates cellular senescence in primary mouse and human cells. CPEB knockout mouse embryo fibroblasts (MEFs) bypass senescence and synthesize large amounts of interleukin-6 (IL-6) and many other cytokines, which is not the case with either wild-type MEFs immortalized by prolonged culture or p53-deficient MEFs. CPEB regulates the production of IL-6 at both the translational and transcriptional levels; in CPEB-depleted cells, aberrant IL-6 transcription is mediated by improper NF-kappaB p65 phosphorylation and nuclear localization. Although IL-6 strengthens the senescence of wild-type cells, it has no effect on CPEB-deficient cells, even though they produce prodigious amounts of the cytokine. IL-6-promoted entry into senescence requires p53; CPEB knockout MEFs, however, synthesize only ~50% of the p53 of wild-type MEFs, which is insufficient to respond to IL-6. Thus, CPEB deficiency not only increases IL-6 production but also renders the cell incapable of a senescence-promoting response. PMID- 21536659 TI - A meta-analysis on alcohol drinking and gastric cancer risk. AB - BACKGROUND: Whether an association between alcohol drinking and gastric cancer risk exists is an open question. In order to provide a definite quantification of the association between alcohol drinking and gastric cancer risk, we conducted a meta-analysis of available data. PATIENTS AND METHODS: We carried out a PubMed search of articles published up to June 2010 and identified 44 case-control and 15 cohort studies, including a total of 34 557 gastric cancer cases. We derived meta-analytic estimates using random-effects models, taking into account correlation between estimates. We carried out a dose-risk analysis using nonlinear random-effects meta-regression models. RESULTS: Compared with nondrinkers, the pooled relative risk (RR) was 1.07 [95% confidence interval (CI) 1.01-1.13] for alcohol drinkers and 1.20 (95% CI 1.01-1.44) for heavy alcohol drinkers (>=4 drinks per day). The pooled estimates were apparently higher for gastric noncardia (RR for heavy drinkers=1.17, 95% CI 0.78-1.75) than for gastric cardia (RR=0.99, 95% CI 0.67-1.47) adenocarcinoma. The dose-risk model estimated a RR of 0.95 (95% CI 0.91-0.99) for 10 g/day and 1.14 (95% CI 1.08-1.21) for 50 g/day. CONCLUSIONS: This meta-analysis provides definite evidence of a lack of association between moderate alcohol drinking and gastric cancer risk. There was, however, a positive association with heavy alcohol drinking. PMID- 21536658 TI - Oncogenic tyrosine kinases target Dok-1 for ubiquitin-mediated proteasomal degradation to promote cell transformation. AB - Cellular transformation induced by oncogenic tyrosine kinases is a multistep process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinase-mediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study, we show that oncogenic tyrosine kinases, including p210(bcr-abl) and oncogenic forms of Src, downregulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinase-induced degradation. Our findings suggest that proteasome-mediated downregulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression. PMID- 21536660 TI - A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by 90Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma. AB - BACKGROUND: A prospective, single-arm, open-label, multicenter, nonrandomised phase II trial to evaluate efficacy and safety of short fludarabine, mitoxantrone, and rituximab (FMR) induction followed by radioimmunotherapy, in untreated, intermediate/high-risk follicular non-Hodgkin's lymphoma (NHL) patients. PATIENTS AND METHODS: Fifty-five patients were treated using a sequential treatment schedule of four induction cycles of FMR chemoimmunotherapy, and a subsequent consolidating single administration of (90)Y-ibritumomab tiuxetan ((90)Y-IT), 8-14 weeks later. Patients were eligible for radioimmunotherapy if at least in partial response (PR) after induction, with normal platelet and granulocyte counts and a bone marrow infiltration <= 25%. Primary study end points were response rate and hematologic toxic effects; secondary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: All the 55 patients received four induction cycles with an overall response rate of 96% (38 complete responses [CR] and 15 PR). Fifty-one patients (38 in CR and 13 in PR) received (90)Y-IT. By the end of the treatment, 49/55 patients achieved a CR. With a median follow-up of 21 months, the estimated 3-year PFS was 81% and the 3-year OS 100%. CONCLUSIONS: This study has established feasibility, tolerability, and efficacy of a regimen composed by short FMR induction with (90)Y-IT consolidation in untreated intermediate/high risk follicular NHL patients. PMID- 21536661 TI - Metastatic non-small-cell lung cancer: consensus on pathology and molecular tests, first-line, second-line, and third-line therapy: 1st ESMO Consensus Conference in Lung Cancer; Lugano 2010. AB - The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21 and 22 May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics, medical oncology, surgical oncology and radiation oncology. Before the conference, the expert panel prepared clinically relevant questions concerning five areas: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second /third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer to be addressed through discussion at the Consensus Conference. All relevant scientific literature for each question was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The consensus agreement on three of these areas: NSCLC pathology and molecular testing, the treatment of first-line, and second-line/third-line therapy in metastatic NSCLC are reported in this article. The recommendations detailed here are based on an expert consensus after careful review of published data. All participants have approved this final update. PMID- 21536663 TI - Toxicity burden score: a novel approach to summarize multiple toxic effects. AB - BACKGROUND: Toxicity data from cancer trials are summarized into a single outcome, dose-limiting toxicity (DLT), which does not account for multiple lower grade toxic effects nor differentiates between toxicity types and gradations within DLT. METHODS: Toxicity data were summarized into a toxicity burden score (TBS) using a weighted sum. The severity weights were estimated via regression using historical data. We demonstrated the method using historical data from a bortezomib trial and illustrated the advantages of defining DLT based on TBS in a simulated dose-finding trial. RESULTS: The estimated weights were 0.17, 0.40 and 0.85 for grade 1/2, grade 3 and grade 4 platelets, respectively; 0.19, 0.64, 1.03 and 2.53 for grade 1, 2, 3 and 4 neuropathy, respectively and 0.17 for each grade 3 or higher nonhematologic toxic effects unrelated to treatment. In the simulated trial, the probability of selecting doses above the maximum tolerated dose decreased when using the DLT defined based on TBS. CONCLUSIONS: TBS is a feasible approach to summarize toxicity. It includes information from the grades and types of multiple toxic effects and can be applied in all phases of drug development. Further efforts should focus on validating the method in a large prospective study before applying it in practice. PMID- 21536664 TI - Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma -data from the Czech registry. AB - BACKGROUND: Sequential therapy with tyrosine kinase inhibitors (TKIs), sunitinib and sorafenib, is a common treatment choice for patients with advanced/metastatic renal cell carcinoma (mRCC) despite lack of randomised trials. The aim of this retrospective registry-based study was to analyse the outcomes of RCC patients treated with sunitinib-sorafenib or sorafenib-sunitinib sequence. PATIENTS AND METHODS: The Czech database containing information on patients treated for mRCC using targeted agents was used as a source of data for retrospective analysis. There were 138 patients treated with sunitinib-sorafenib sequence and 122 patients treated with sorafenib-sunitinib sequence. RESULTS: Progression-free survival (PFS) was 17.7 months for patients treated with sunitinib-sorafenib sequence and 18.8 months for those receiving sorafenib followed by sunitinib (P = 0.47). Overall survival (OS) at 1 year was 83% [95% confidence interval (CI) 77% to 90%] for patients treated with sunitinib-sorafenib and 84% (95% CI 77% to 91%) for sorafenib-sunitinib patients (P = 0.99). Treatment toxic effects were predictable but a significant proportion of patients (up to 14%-25% for different lines of therapy and used TKI) switched between TKIs or discontinued TKI therapy because of toxicity. CONCLUSIONS: In contrast to most of the previously published reports, we have not observed improved PFS or OS for mRCC patients treated with the sorafenib-sunitinib sequence as compared to the sunitinib-sorafenib sequence. PMID- 21536662 TI - Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). AB - BACKGROUND: Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved. METHODS: To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case-control studies (5585 cases and 11,827 controls) participating in the International Pancreatic Cancer Case-Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models. RESULTS: Compared with abstainers and occasional drinkers (< 1 drink per day), we observed no association for light-to moderate alcohol consumption (<= 4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2-2.2 for subjects drinking >= 9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area. CONCLUSION: This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer. PMID- 21536665 TI - Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells. AB - Peroxisome proliferator-activated receptor alpha, coactivator 1alpha (PGC-1alpha) is the master regulator of mitochondrial biogenesis. PGC-1alpha expression is under the control of the transcription factor, cAMP-responsive element-binding protein (CREB). In searching for candidate transcription factors that mediate mitochondrial stress-initiated mitochondria-to-nucleus signaling in the regulation of mitochondrial biogenesis, we assessed the effect of silencing CREB regulated transcription co-activators (CRTC). CRTC isoforms are co-activators of CREB-regulated transcription by a CREB phosphorylation-independent pathway. Using cultured HepG2 cells and primary mouse hepatocytes, we determined that mitochondrial stress imposed by the complex I inhibitor rotenone elicited mitochondrial biogenesis, which was dependent on an induction of PGC-1alpha, which was inhibited by silencing PGC-1alpha. PGC-1alpha induction in response to rotenone was inhibited by silencing the expression of CRTC3, which blocked downstream mitochondria biogenesis. In contrast, silencing CRTC2 did not affect the induction of this pathway in response to rotenone. Thus, CRTC3 plays a selective role in mitochondrial biogenesis in response to rotenone. PMID- 21536667 TI - Cap-binding protein complex links pre-mRNA capping to transcription elongation and alternative splicing through positive transcription elongation factor b (P TEFb). AB - Promoter-proximal pausing of RNAPII coincides with the formation of the cap structure at the 5' end of pre-mRNA, which is bound by the cap-binding protein complex (CBC). Although the positive transcription elongation factor b (P-TEFb) stimulates the release of RNAPII from pausing and promotes transcription elongation and alternative splicing by phosphorylating the RNAPII C-terminal domain at Ser2 (S2-P RNAPII), it is unknown whether CBC facilitates these events. In this study, we report that CBC interacts with P-TEFb and transcriptionally engaged RNAPII and is globally required for optimal levels of S2-P RNAPII. Quantitative nascent RNA immunoprecipitation and ChIP experiments reveal that depletion of CBC attenuates HIV-1 Tat transactivation and impedes transcription elongation of investigated CBC-dependent endogenous genes by decreasing the levels of P-TEFb and S2-P RNAPII, leading to accumulation of RNAPII in the body of these genes. Finally, CBC is essential for the promotion of alternative splicing through facilitating P-TEFb, S2-P RNAPII, and splicing factor 2/alternative splicing factor occupancy at a splicing minigene. These findings disclose a vital role of CBC in connecting pre-mRNA capping to transcription elongation and alternative splicing via P-TEFb. PMID- 21536666 TI - Mechanisms of urokinase plasminogen activator (uPA)-mediated atherosclerosis: role of the uPA receptor and S100A8/A9 proteins. AB - Data from clinical studies, cell culture, and animal models implicate the urokinase plasminogen activator (uPA)/uPA receptor (uPAR)/plasminogen system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/uPAR/plasminogen stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage specific uPA overexpression and mice genetically deficient in uPAR to elucidate mechanisms of uPA/uPAR/plasminogen-accelerated atherosclerosis and aneurysm formation. We found that macrophage-specific uPA overexpression accelerates atherosclerosis and causes aortic root dilation in fat-fed Ldlr(-/-) mice (as we previously reported in Apoe(-/-) mice). Macrophage-expressed uPA accelerates atherosclerosis by stimulation of lesion progression rather than initiation and causes disproportionate lipid accumulation in early lesions. uPA-accelerated atherosclerosis and aortic dilation are largely, if not completely, independent of uPAR. In the absence of uPA overexpression, however, uPAR contributes modestly to both atherosclerosis and aortic dilation. Microarray studies identified S100A8 and S100A9 mRNA as the most highly up-regulated transcripts in uPA-overexpressing macrophages; up-regulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also up-regulated in the aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is up-regulated by exposure of wild-type macrophages to medium from uPA overexpressing macrophages. Macrophage microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm in a second animal model that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also reveal uPAR independence of these actions and implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. PMID- 21536668 TI - Neutral sphingomyelinase-2 mediates growth arrest by retinoic acid through modulation of ribosomal S6 kinase. AB - All-trans-retinoic acid (ATRA) induces growth arrest of many cell types. Previous studies have reported that ATRA can modulate cellular sphingolipids, but the role of sphingolipids in the ATRA response is not clear. Using MCF-7 cells as a model system, we show that ATRA stimulates an increase in ceramide levels followed by G(0)/G(1) growth arrest. Notably, induction of nSMase2 was the primary effect of ATRA on the sphingolipid network and was both time- and dose-dependent. Importantly, pretreatment with nSMase2 siRNA significantly inhibited ATRA effects on ceramide levels and growth arrest. In contrast, nSMase2 overexpression was sufficient to increase ceramide levels and induce G(0)/G(1) growth arrest of asynchronous MCF-7 cells. Surprisingly, neither ATRA stimulation nor nSMase2 overexpression had significant effects on classical cell cycle regulators such as p21/WAF1 or retinoblastoma. In contrast, ATRA suppressed phosphorylation of ribosomal S6 kinase (S6K) and its downstream targets S6 and eIF4B. Importantly, these effects were significantly inhibited by nSMase2 siRNA. Reciprocally, nSMase2 overexpression was sufficient to suppress S6K phosphorylation and signaling. Notably, neither ATRA effects nor nSMase2 effects on S6K phosphorylation required the ceramide-activated protein phosphatase PP2A, previously identified as important for S6K regulation. Finally, nSMase2 overexpression was sufficient to decrease translation as measured by methionine incorporation and analysis of polyribosome profiles. Taken together, these results implicate nSMase2 as a major component of ATRA-induced growth arrest of MCF-7 cells and identify S6K as a novel downstream target of nSMase2. PMID- 21536669 TI - Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: association with sequestosome 1/p62. AB - Proteotoxicity resulting from accumulation of damaged/unwanted proteins contributes prominently to cellular aging and neurodegeneration. Proteasomal removal of these proteins upon covalent polyubiquitination is highly regulated. Recent reports proposed a role for autophagy in clearance of diffuse ubiquitinated proteins delivered by p62/SQSTM1. Here, we compared the turnover dynamics of endogenous ubiquitinated proteins by proteasomes and autophagy by assessing the effect of their inhibitors. Autophagy inhibitors bafilomycin A1, ammonium chloride, and 3-methyladenine failed to increase ubiquitinated protein levels. The proteasome inhibitor epoxomicin raised ubiquitinated protein levels at least 3-fold higher than the lysosomotropic agent chloroquine. These trends were observed in SK-N-SH cells under serum or serum-free conditions and in WT or Atg5(-/-) mouse embryonic fibroblasts (MEFs). Notably, chloroquine considerably inhibited proteasomes in SK-N-SH cells and MEFs. In these cells, elevation of p62/SQSTM1 was greater upon proteasome inhibition than with all autophagy inhibitors tested and was reduced in Atg5(-/-) MEFs. With epoxomicin, soluble p62/SQSTM1 associated with proteasomes and p62/SQSTM1 aggregates contained inactive proteasomes, ubiquitinated proteins, and autophagosomes. Prolonged autophagy inhibition (96 h) failed to elevate ubiquitinated proteins in rat cortical neurons, although epoxomicin did. Moreover, prolonged autophagy inhibition in cortical neurons markedly increased p62/SQSTM1, supporting its degradation mainly by autophagy and not by proteasomes. In conclusion, we clearly demonstrate that pharmacologic or genetic inhibition of autophagy fails to elevate ubiquitinated proteins unless the proteasome is affected. We also provide strong evidence that p62/SQSTM1 associates with proteasomes and that autophagy degrades p62/SQSTM1. Overall, the function of p62/SQSTM1 in the proteasomal pathway and autophagy requires further elucidation. PMID- 21536670 TI - Innate immune responses of a scleractinian coral to vibriosis. AB - Scleractinian corals are the most basal eumetazoan taxon and provide the biological and physical framework for coral reefs, which are among the most diverse of all ecosystems. Over the past three decades and coincident with climate change, these phototrophic symbiotic organisms have been subject to increasingly frequent and severe diseases, which are now geographically widespread and a major threat to these ecosystems. Although coral immunity has been the subject of increasing study, the available information remains fragmentary, especially with respect to coral antimicrobial responses. In this study, we characterized damicornin from Pocillopora damicornis, the first scleractinian antimicrobial peptide (AMP) to be reported. We found that its precursor has a segmented organization comprising a signal peptide, an acidic proregion, and the C-terminal AMP. The 40-residue AMP is cationic, C-terminally amidated, and characterized by the presence of six cysteine molecules joined by three intramolecular disulfide bridges. Its cysteine array is common to another AMP and toxins from cnidarians; this suggests a common ancestor, as has been proposed for AMPs and toxins from arthropods. Damicornin was active in vitro against Gram-positive bacteria and the fungus Fusarium oxysporum. Damicornin expression was studied using a combination of immunohistochemistry, reverse phase HPLC, and quantitative RT-PCR. Our data show that damicornin is constitutively transcribed in ectodermal granular cells, where it is stored, and further released in response to nonpathogenic immune challenge. Damicornin gene expression was repressed by the coral pathogen Vibrio coralliilyticus. This is the first evidence of AMP gene repression in a host-Vibrio interaction. PMID- 21536671 TI - Molecular mechanism of activation of human Cdc7 kinase: bipartite interaction with Dbf4/activator of S phase kinase (ASK) activation subunit stimulates ATP binding and substrate recognition. AB - Cdc7 is a serine/threonine kinase conserved from yeasts to human and is known to play a key role in the regulation of initiation at each replication origin. Its catalytic function is activated via association with the activation subunit Dbf4/activator of S phase kinase (ASK). It is known that two conserved motifs of Dbf4/ASK are involved in binding to Cdc7, and both are required for maximum activation of Cdc7 kinase. Cdc7 kinases possess unique kinase insert sequences (kinase insert I-III) that are inserted at defined locations among the conserved kinase domains. However, precise mechanisms of Cdc7 kinase activation are largely unknown. We have identified two segments on Cdc7, DAM-1 (Dbf4/ASK interacting motif-1; amino acids 448-457 near the N terminus of kinase insert III) and DAM-2 (C-terminal 10-amino acid segment), that interact with motif-M and motif-C of ASK, respectively, and are essential for kinase activation by ASK. The C-terminal 143-amino acid polypeptide (432-574) containing DAM-1 and DAM-2 can interact with Dbf4/ASK. Characterization of the purified ASK-free Cdc7 and Cdc7-ASK complex shows that ATP binding of the Cdc7 catalytic subunit requires Dbf4/ASK. However, the "minimum" Cdc7, lacking the entire kinase insert II and half of kinase insert III, binds to ATP and shows autophosphorylation activity in the absence of ASK. However, ASK is still required for phosphorylation of exogenous substrates by the minimum Cdc7. These results indicate bipartite interaction between Cdc7 and Dbf4/ASK subunits facilitates ATP binding and substrate recognition by the Cdc7 kinase. PMID- 21536672 TI - Cell-surface receptor for complement component C1q (gC1qR) is a key regulator for lamellipodia formation and cancer metastasis. AB - We previously demonstrated that the receptor for the complement component C1q (gC1qR) is a lipid raft protein that is indispensable for adipogenesis and insulin signaling. Here, we provide the first report that gC1qR is an essential component of lamellipodia in human lung carcinoma A549 cells. Cell-surface gC1qR was concentrated in the lamellipodia along with CD44, monosialoganglioside, actin, and phosphorylated focal adhesion kinase in cells stimulated with insulin, IGF-1, EGF, or serum. The growth factor-induced lamellipodia formation and cell migration were significantly decreased in gC1qR-depleted cells, with a concomitant blunt activation of the focal adhesion kinase and the respective receptor tyrosine kinases. Moreover, the gC1qR-depleted cells exhibited a reduced proliferation rate in culture as well as diminished tumorigenic and metastatic activities in grafted mice. We therefore conclude that cell-surface gC1qR regulates lamellipodia formation and metastasis via receptor tyrosine kinase activation. PMID- 21536673 TI - Rescue of aberrant gating by a genetically encoded PAS (Per-Arnt-Sim) domain in several long QT syndrome mutant human ether-a-go-go-related gene potassium channels. AB - Congenital long QT syndrome 2 (LQT2) is caused by loss-of-function mutations in the human ether-a-go-go-related gene (hERG) voltage-gated potassium (K(+)) channel. hERG channels have slow deactivation kinetics that are regulated by an N terminal Per-Arnt-Sim (PAS) domain. Only a small percentage of hERG channels containing PAS domain LQT2 mutations (hERG PAS-LQT2) have been characterized in mammalian cells, so the functional effect of these mutations is unclear. We investigated 11 hERG PAS-LQT2 channels in HEK293 cells and report a diversity of functional defects. Most hERG PAS-LQT2 channels formed functional channels at the plasma membrane, as measured by whole cell patch clamp recordings and cell surface biotinylation. Mutations located on one face of the PAS domain (K28E, F29L, N33T, R56Q, and M124R) caused defective channel gating, including faster deactivation kinetics and less steady-state inactivation. Conversely, the other mutations caused no measurable differences in channel gating (G53R, H70R, and A78P) or no measurable currents (Y43C, C66G, and L86R). We used a genetically encoded hERG PAS domain (NPAS) to examine whether channel dysfunction could be corrected. We found that NPAS fully restored wild-type-like deactivation kinetics and steady-state inactivation to the hERG PAS-LQT2 channels. Additionally, NPAS rescued aberrant currents in hERG R56Q channels during a dynamic ramp voltage clamp. Thus, our results reveal a putative "gating face" in the PAS domain where mutations within this region form functional channels with altered gating properties, and we show that NPAS is a general means for rescuing aberrant gating in hERG LQT2 mutant channels and may be a potential biological therapeutic. PMID- 21536674 TI - TIN2 protein dyskeratosis congenita missense mutants are defective in association with telomerase. AB - Dyskeratosis congenita (DC) is a progressive and heterogeneous congenital disorder that affects multiple systems and is characterized by bone marrow failure and a triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. One common feature for all DC patients is abnormally short telomeres and defects in telomere biology. Most of the known DC mutations have been found to affect core components of the telomerase holoenzyme. Recently, multiple mutations in the gene encoding the telomeric protein TIN2 have been identified in DC patients with intact telomerase genes, but the molecular mechanisms underlying TIN2 mutation-mediated DC remain unknown. Here, we demonstrate that ectopic expression of TIN2 with DC missense mutations in human cells led to accelerated telomere shortening, similar to the telomere phenotypes found in DC patients. However, this telomere shortening was not accompanied by changes in total telomerase activity, localization of TIN2, or telomere end protection status. Interestingly, we found TIN2 to participate in the TPP1-dependent recruitment of telomerase activity. Furthermore, DC mutations in TIN2 led to its decreased ability to associate with TERC and telomerase activity. Taken together, our data suggest that TIN2 mutations in DC may compromise the telomere recruitment of telomerase, leading to telomere shortening and the associated pathogenesis. PMID- 21536675 TI - Switch I closure simultaneously promotes strong binding to actin and ADP in smooth muscle myosin. AB - The motor protein myosin uses energy derived from ATP hydrolysis to produce force and motion. Important conserved components (P-loop, switch I, and switch II) help propagate small conformational changes at the active site into large scale conformational changes in distal regions of the protein. Structural and biochemical studies have indicated that switch I may be directly responsible for the reciprocal opening and closing of the actin and nucleotide-binding pockets during the ATPase cycle, thereby aiding in the coordination of these important substrate-binding sites. Smooth muscle myosin has displayed the ability to simultaneously bind tightly to both actin and ADP, although it is unclear how both substrate-binding clefts could be closed if they are rigidly coupled to switch I. Here we use single tryptophan mutants of smooth muscle myosin to determine how conformational changes in switch I are correlated with structural changes in the nucleotide and actin-binding clefts in the presence of actin and ADP. Our results suggest that a closed switch I conformation in the strongly bound actomyosin-ADP complex is responsible for maintaining tight nucleotide binding despite an open nucleotide-binding pocket. This unique state is likely to be crucial for prolonged tension maintenance in smooth muscle. PMID- 21536676 TI - 15-Lipoxygenase-1-enhanced Src-Janus kinase 2-signal transducer and activator of transcription 3 stimulation and monocyte chemoattractant protein-1 expression require redox-sensitive activation of epidermal growth factor receptor in vascular wall remodeling. AB - To understand the mechanisms by which 15(S)-hydroxyeicosatetraenoic acid (15(S) HETE) activates signal transducer and activator of transcription 3 (STAT3), we studied the role of epidermal growth factor receptor (EGFR). 15(S)-HETE stimulated tyrosine phosphorylation of EGFR in a time-dependent manner in vascular smooth muscle cells (VSMCs). Interference with EGFR activation blocked 15(S)-HETE-induced Src and STAT3 tyrosine phosphorylation, monocyte chemoattractant protein-1 (MCP-1) expression and VSMC migration. 15(S)-HETE also induced tyrosine phosphorylation of Janus kinase 2 (Jak2) in VSMCs, and its inhibition substantially reduced STAT3 phosphorylation, MCP-1 expression, and VSMC migration. In addition, Src formed a complex with EGFR and Jak2, and its inhibition completely blocked Jak2 and STAT3 phosphorylation, MCP-1 expression, and VSMC migration. 15(S)-HETE induced the production of H(2)O(2) via an NADPH oxidase-dependent manner and its scavengers, N-acetyl cysteine (NAC) and catalase suppressed 15(S)-HETE-stimulated EGFR, Src, Jak2, and STAT3 phosphorylation and MCP-1 expression. Balloon injury (BI) induced EGFR, Src, Jak2, and STAT3 phosphorylation, and inhibition of these signaling molecules attenuated BI induced MCP-1 expression and smooth muscle cell migration from the medial to the luminal surface resulting in reduced neointima formation. In addition, inhibition of EGFR blocked BI-induced Src, Jak2, and STAT3 phosphorylation. Similarly, interference with Src activation suppressed BI-induced Jak2 and STAT3 phosphorylation. Furthermore, adenovirus-mediated expression of dnJak2 also blocked BI-induced STAT3 phosphorylation. Consistent with the effects of 15(S) HETE on the activation of EGFR-Src-Jak2-STAT3 signaling in VSMCs in vitro, adenovirus-mediated expression of 15-lipoxygenase 1 (15-Lox1) enhanced BI-induced EGFR, Src, Jak2, and STAT3 phosphorylation leading to enhanced MCP-1 expression in vivo. Blockade of Src or Jak2 suppressed BI-induced 15-Lox1-enhanced STAT3 phosphorylation, MCP-1 expression, and neointima formation. In addition, whereas dominant negative Src blocked BI-induced 15-Lox1-enhanced Jak2 phosphorylation, dnJak2 had no effect on Src phosphorylation. Together, these observations demonstrate for the first time that the 15-Lox1-15(S)-HETE axis activates EGFR via redox-sensitive manner, which in turn mediates Src-Jak2-STAT3-dependent MCP-1 expression leading to vascular wall remodeling. PMID- 21536677 TI - In vitro motility of liver connexin vesicles along microtubules utilizes kinesin motors. AB - Trafficking of the proteins that form gap junctions (connexins) from the site of synthesis to the junctional domain appears to require cytoskeletal delivery mechanisms. Although many cell types exhibit specific delivery of connexins to polarized cell sites, such as connexin32 (Cx32) gap junctions specifically localized to basolateral membrane domains of hepatocytes, the precise roles of actin- and tubulin-based systems remain unclear. We have observed fluorescently tagged Cx32 trafficking linearly at speeds averaging 0.25 MUm/s in a polarized hepatocyte cell line (WIF-B9), which is abolished by 50 MUM of the microtubule disrupting agent nocodazole. To explore the involvement of cytoskeletal components in the delivery of connexins, we have used a preparation of isolated Cx32-containing vesicles from rat hepatocytes and assayed their ATP-driven motility along stabilized rhodamine-labeled microtubules in vitro. These assays revealed the presence of Cx32 and kinesin motor proteins in the same vesicles. The addition of 50 MUM ATP stimulated vesicle motility along linear microtubule tracks with velocities of 0.4-0.5 MUm/s, which was inhibited with 1 mM of the kinesin inhibitor AMP-PNP (adenylyl-imidodiphosphate) and by anti-kinesin antibody but only minimally affected by 5 MUM vanadate, a dynein inhibitor, or by anti-dynein antibody. These studies provide evidence that Cx32 can be transported intracellularly along microtubules and presumably to junctional domains in cells and highlight an important role of kinesin motor proteins in microtubule dependent motility of Cx32. PMID- 21536678 TI - Activation dynamics and signaling properties of Notch3 receptor in the developing pulmonary artery. AB - Notch3 signaling is fundamental for arterial specification of systemic vascular smooth muscle cells (VSMCs). However, the developmental role and signaling properties of the Notch3 receptor in the mouse pulmonary artery remain unknown. Here, we demonstrate that Notch3 is expressed selectively in pulmonary artery VSMCs, is activated from late fetal to early postnatal life, and is required to maintain the morphological characteristics and smooth muscle gene expression profile of the pulmonary artery after birth. Using a conditional knock-out mouse model, we show that Notch3 receptor activation in VSMCs is Jagged1-dependent. In vitro VSMC lentivirus-mediated Jagged1 knockdown, confocal localization analysis, and co-culture experiments revealed that Notch3 activation is cell-autonomous and occurs through the physical engagement of Notch3 and VSMC-derived Jagged1 in the interior of the same cell. Although the current models of mammalian Notch signaling involve a two-cell system composed of a signal-receiving cell that expresses a Notch receptor on its surface and a neighboring signal-sending cell that provides membrane-bound activating ligand, our data suggest that pulmonary artery VSMC Notch3 activation is cell-autonomous. This unique mechanism of Notch activation may play an important role in the maturation of the pulmonary artery during the transition to air breathing. PMID- 21536679 TI - The Golgi protein p115 associates with gamma-tubulin and plays a role in Golgi structure and mitosis progression. AB - The Golgi apparatus is a network of polarized cisternae localized to the perinuclear region in mammalian cells. It undergoes extensive vesiculation at the onset of mitosis and its reassembly requires factors that are in part segregated via the mitotic spindle. Here we show that unlike typical Golgi markers, the Golgi-protein p115 partitioned with the spindle poles throughout mitosis. An armadillo-fold in its N terminus mediated a novel interaction between p115 and gamma-tubulin and functioned in its centrosomal targeting. Both the N- and C terminal regions of p115 were required to maintain Golgi structure. Strikingly, p115 was essential for mitotic spindle function and the resolution of the cytokinetic bridge because its depletion resulted in spindle collapse, chromosome missegregation, and failed cytokinesis. We demonstrate that p115 plays a critical role in mitosis progression, implicating it as the only known golgin to regulate both mitosis and apoptosis. PMID- 21536680 TI - Mitochondrial dysfunction in cancer cells due to aberrant mitochondrial replication. AB - Warburg effect is a hallmark of cancer manifested by continuous prevalence of glycolysis and dysregulation of oxidative metabolism. Glycolysis provides survival advantage to cancer cells. To investigate molecular mechanisms underlying the Warburg effect, we first compared oxygen consumption among hFOB osteoblasts, benign osteosarcoma cells, Saos2, and aggressive osteosarcoma cells, 143B. We demonstrate that, as both proliferation and invasiveness increase in osteosarcoma, cells utilize significantly less oxygen. We proceeded to evaluate mitochondrial morphology and function. Electron microscopy showed that in 143B cells, mitochondria are enlarged and increase in number. Quantitative PCR revealed an increase in mtDNA in 143B cells when compared with hFOB and Saos2 cells. Gene expression studies showed that mitochondrial single-strand DNA binding protein (mtSSB), a key catalyst of mitochondrial replication, was significantly up-regulated in 143B cells. In addition, increased levels of the mitochondrial respiratory complexes were accompanied by significant reduction of their activities. These changes indicate hyperactive mitochondrial replication in 143B cells. Forced overexpression of mtSSB in Saos2 cells caused an increase in mtDNA and a decrease in oxygen consumption. In contrast, knockdown of mtSSB in 143B cells was accompanied by a decrease in mtDNA, increase in oxygen consumption, and retardation of cell growth in vitro and in vivo. In summary, we have found that mitochondrial dysfunction in cancer cells correlates with abnormally increased mitochondrial replication, which according to our gain- and loss-of-function experiments, may be due to overexpression of mtSSB. Our study provides insight into mechanisms of mitochondrial dysfunction in cancer and may offer potential therapeutic targets. PMID- 21536681 TI - Activation of cytosolic phospholipase A2 downstream of the Src-phospholipase D1 (PLD1)-protein kinase C gamma (PKCgamma) signaling axis is required for hypoxia induced pathological retinal angiogenesis. AB - In view of understanding the mechanisms of retinal neovascularization, we had reported previously that vascular endothelial growth factor (VEGF)-induced pathological retinal angiogenesis requires the activation of Src-PLD1-PKCgamma signaling. In the present work, we have identified cytosolic phospholipase A(2) (cPLA(2)) as an effector molecule of Src-PLD1-PKCgamma signaling in the mediation of VEGF-induced pathological retinal angiogenesis based on the following observations. VEGF induced cPLA(2) phosphorylation in a time-dependent manner in human retinal microvascular endothelial cells (HRMVECs). VEGF also induced arachidonic acid (AA) release in a dose-, time-, and cPLA(2)-dependent manner. Depletion of cPLA(2) levels inhibited VEGF-induced HRMVEC DNA synthesis, migration, and tube formation. In addition, the exogenous addition of AA rescued VEGF-induced HRMVEC DNA synthesis, migration, and tube formation from inhibition by down-regulation of cPLA(2). Inhibition of Src, PLD1, or PKCgamma attenuated VEGF-induced cPLA(2) phosphorylation and AA release. Consistent with these findings, hypoxia induced cPLA(2) phosphorylation and activity in VEGF-Src-PLD1 PKCgamma-dependent manner in a mouse model of oxygen-induced retinopathy. In addition, siRNA-mediated down-regulation of cPLA(2) levels in the retina abrogated hypoxia-induced retinal endothelial cell proliferation and neovascularization. These observations suggest that cPLA(2)-dependent AA release is required for VEGF-induced Src-PLD1-PKCgamma-mediated pathological retinal angiogenesis. PMID- 21536682 TI - Haploid insufficiency of suppressor enhancer Lin12 1-like (SEL1L) protein predisposes mice to high fat diet-induced hyperglycemia. AB - Increasing evidence suggests that endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of type 2 diabetes mellitus. SEL1L is an ER membrane protein that is highly expressed in the pancreatic islet and acinar cells. We have recently reported that a deficiency of SEL1L causes systemic ER stress and leads to embryonic lethality in mice. Here we show that mice with one functional allele of Sel1l (Sel1l(+/-)) are more susceptible to high fat diet (HFD)-induced hyperglycemia. Sel1l(+/-) mice have a markedly reduced beta-cell mass as a result of decreased beta-cell proliferation. Consequently, Sel1l(+/-) mice are severely glucose-intolerant and exhibit significantly retarded glucose stimulated insulin secretion. Pancreatic islets from Sel1l(+/-) mice stimulated with a high concentration of glucose in vitro express significantly higher levels of unfolded protein response genes than those from wild-type control mice. Furthermore, dominant-negative interference of SEL1L function in insulinoma cell lines severely impairs, whereas overexpression of SEL1L efficiently improves protein secretion. Taken together, our results indicate that haploid insufficiency of SEL1L predispose mice to high fat diet-induced hyperglycemia. Our findings highlight a critical and previously unknown function for SEL1L in regulating adult beta-cell function and growth. PMID- 21536683 TI - Protein kinase A activity at the endoplasmic reticulum surface is responsible for augmentation of human ether-a-go-go-related gene product (HERG). AB - Human ether-a-go-go-related gene product (HERG) is a cardiac potassium channel commonly implicated in the pathogenesis of the long QT syndrome, type 2 (LQT2). LQT2 mutations typically have incomplete penetrance and affect individuals at various stages of their lives; this may mirror variations in intracellular signaling and HERG regulation. Previous work showed that sustained protein kinase A (PKA) activity augments HERG protein abundance by a mechanism that includes enhanced protein translation. To investigate the subcellular site of this regulation, we generated site-specific probes to the cytoplasmic surface of the endoplasmic reticulum (ER), the presumed locale of channel synthesis. Real-time FRET-based indicators demonstrated both cAMP and PKA activity at the ER. A PKA inhibitor targeted to the ER surface (termed p4PKIg) completely abolished PKA mediated augmentation of HERG in HEK293 cells as well as rat neonatal cardiomyocytes. Immunofluorescence co-localization, targeted FRET-based PKA biosensors, phospho-specific antibodies, and in vivo phosphorylation experiments confirmed that p4PKIg is preferentially active at the ER surface rather than the plasma membrane. Rerouting this inhibitor to the outer mitochondrial membrane diminishes its ability to block cAMP-dependent HERG induction. Our results support a model where PKA-dependent regulation of HERG synthesis occurs at the ER surface. Furthermore, reagents generated for this study provide novel experimental tools to probe compartmentalized cAMP/PKA signaling within cells. PMID- 21536684 TI - Survivin monomer plays an essential role in apoptosis regulation. AB - Survivin was initially described as an inhibitor of apoptosis and attracted growing attention as one of the most tumor-specific genes in the human genome and a promising target for cancer therapy. Lately, it has been shown that survivin is a multifunctional protein that takes part in several crucial cell processes. At first, it was supposed that survivin functions only as a homodimer, but now data indicate that many processes require monomeric survivin. Moreover, recent studies reveal a special mechanism regulating the balance between monomeric and dimeric forms of the protein. In this paper we studied the mutant form of survivin that was unable to dimerize and investigated its role in apoptosis. We showed that survivin monomer interacts with Smac/DIABLO and X-linked inhibitor of apoptosis protein (XIAP) both in vitro and in vivo. Due to this feature, it protects cells from caspase-dependent apoptosis even more efficiently than the wild-type survivin. We also identified that mutant monomeric survivin prevents apoptosis inducing factor release from the mitochondrial intermembrane space, protecting human fibrosarcoma HT1080 cells from caspase-independent apoptosis. On the other hand, our results indicate that only wild-type survivin, but not the monomer mutant form, enhances tubulin stability in cells. These findings suggest that survivin partly performs its functions as a monomer and partly as a dimer. The mechanism of dimer-monomer balance regulation may also work as a "switcher" between survivin functions and thereby explain remarkable functional diversities of this protein. PMID- 21536685 TI - Cortical actin binding protein cortactin mediates ENaC activity via Arp2/3 complex. AB - Epithelial Na(+) channel (ENaC) activity is regulated, in part, by the cortical cytoskeleton. Here we demonstrate that cortactin is highly expressed in the kidney cortex and polarized epithelial cells, and is localized to the cortical collecting duct. Coexpression of cortactin with ENaC decreases ENaC activity, as measured in patch-clamp experiments. Biotinylation experiments and single-channel analysis reveal that cortactin decreases ENaC activity via affecting channel open probability (P(o)). Knockdown of cortactin in mpkCCD(c14) principal cells results in an increase in ENaC activity and sodium reabsorption. Coimmunoprecipitation analysis shows direct interactions between cortactin and all three ENaC subunits in cultured and native cells. To address the question of what mechanism underlies the action of cortactin on ENaC activity, we assayed the effects of various mutants of cortactin. The data show that only a cortactin mutant unable to bind Arp2/3 complex does not influence ENaC activity. Furthermore, inhibitor of the Arp2/3 complex CK-0944666 precludes the effect of cortactin. Depolymerization of the actin microfilaments and inhibition of the Arp2/3 complex does not result in the loss of association between ENaC and cortactin. Thus, these results indicate that cortactin is functionally important for ENaC activity and that Arp2/3 complex is involved in this mechanism. PMID- 21536686 TI - Mode of communication, perceived level of understanding, and perceived quality of life in youth who are deaf or hard of hearing. AB - Given the important role of parent-youth communication in adolescent well-being and quality of life, we sought to examine the relationship between specific communication variables and youth perceived quality of life in general and as a deaf or hard-of-hearing (DHH) individual. A convenience sample of 230 youth (mean age = 14.1, standard deviation = 2.2; 24% used sign only, 40% speech only, and 36% sign + speech) was surveyed on communication-related issues, generic and DHH specific quality of life, and depression symptoms. Higher youth perception of their ability to understand parents' communication was significantly correlated with perceived quality of life as well as lower reported depressive symptoms and lower perceived stigma. Youth who use speech as their single mode of communication were more likely to report greater stigma associated with being DHH than youth who used both speech and sign. These findings demonstrate the importance of youths' perceptions of communication with their parents on generic and DHH-specific youth quality of life. PMID- 21536687 TI - High-throughput RNAi screening identifies a role for TNK1 in growth and survival of pancreatic cancer cells. AB - To identify novel targets in pancreatic cancer cells, we used high-throughput RNAi (HT-RNAi) to select genes that, when silenced, would decrease viability of pancreatic cancer cells. The HT-RNAi screen involved reverse transfecting the pancreatic cancer cell line BxPC3 with a siRNA library targeting 572 kinases. From replicate screens, approximately 32 kinases were designated as hits, of which 22 kinase targets were selected for confirmation and validation. One kinase identified as a hit from this screen was tyrosine kinase nonreceptor 1 (TNK1), a kinase previously identified as having tumor suppressor-like properties in embryonic stem cells. Silencing of TNK1 with siRNA showed reduced proliferation in a panel of pancreatic cancer cell lines. Furthermore, we showed that silencing of TNK1 led to increased apoptosis through a caspase-dependent pathway and that targeting TNK1 with siRNA can synergize with gemcitabine treatment. Despite previous reports that TNK1 affects Ras and NF-kappaB signaling, we did not find similar correlations with these pathways in pancreatic cancer cells. Our results suggest that TNK1 in pancreatic cancer cells does not possess the same tumor suppressor properties seen in embryonic cells but seems to be involved in growth and survival. The application of functional genomics by using HT-RNAi screens has allowed us to identify TNK1 as a growth-associated kinase in pancreatic cancer cells. PMID- 21536688 TI - TNFalpha accelerates monocyte to endothelial transdifferentiation in tumors by the induction of integrin alpha5 expression and adhesion to fibronectin. AB - Tumor-associated myeloid cells are believed to promote tumor development by stimulating tumor growth, angiogenesis, invasion, and metastasis. Tumor associated myeloid cells that coexpress endothelial and myeloid markers represent a proangiogenic subpopulation known as vascular leukocytes. Recently, we and others had shown that tumor-derived TNFalpha promotes local tumor growth and vascularity. Our data suggested that tumor growth is in part due to TNFalpha mediated increased numbers of tumor-associated vascular leukocytes (i.e., myeloid endothelial biphenotypic cells). The work detailed herein explored the mechanism by which TNFalpha mediates endothelial differentiation of myeloid cells. Our studies showed that fibronectin is a robust facilitator of endothelial differentiation of blood mononuclear cells in vitro. We have found that TNFalpha treatment of monocytes significantly increased expression of alpha(5)beta(1) integrin, a major fibronectin receptor enriched on endothelial cells, leading to a consequent fourfold increase in fibronectin adhesion. Furthermore, TNFalpha treated monocytes upregulated expression of endothelial markers, flk 1(VEGFR2/KDR) and VE-cadherin. Integrin alpha(5) subunit inhibitory antibodies blocked adhesion to fibronectin as well as consequent upregulation of flk-1 and VE-cadherin transcripts, implying a role for outside-in signaling by the alpha(5)beta(1) integrin after binding fibronectin. Finally, treatment of mouse tumors with anti-alpha(5) antibodies reduced accumulation of tumor vascular leukocytes in vivo. Our studies suggest that tumor cell-derived TNFalpha constitutes a tumor microenvironment signal that promotes differentiation of tumor-associated monocytes toward a proangiogenic/provasculogenic myeloid endothelial phenotype via upregulation of the fibronectin receptor alpha(5)beta(1). PMID- 21536689 TI - A methodological analysis of randomized clinical trials of computer-assisted therapies for psychiatric disorders: toward improved standards for an emerging field. AB - OBJECTIVE: Computer-assisted therapies offer a novel, cost-effective strategy for providing evidence-based therapies to a broad range of individuals with psychiatric disorders. However, the extent to which the growing body of randomized trials evaluating computer-assisted therapies meets current standards of methodological rigor for evidence-based interventions is not clear. METHOD: A methodological analysis of randomized clinical trials of computer-assisted therapies for adult psychiatric disorders, published between January 1990 and January 2010, was conducted. Seventy-five studies that examined computer-assisted therapies for a range of axis I disorders were evaluated using a 14-item methodological quality index. RESULTS: Results indicated marked heterogeneity in study quality. No study met all 14 basic quality standards, and three met 13 criteria. Consistent weaknesses were noted in evaluation of treatment exposure and adherence, rates of follow-up assessment, and conformity to intention-to treat principles. Studies utilizing weaker comparison conditions (e.g., wait-list controls) had poorer methodological quality scores and were more likely to report effects favoring the computer-assisted condition. CONCLUSIONS: While several well conducted studies have indicated promising results for computer-assisted therapies, this emerging field has not yet achieved a level of methodological quality equivalent to those required for other evidence-based behavioral therapies or pharmacotherapies. Adoption of more consistent standards for methodological quality in this field, with greater attention to potential adverse events, is needed before computer-assisted therapies are widely disseminated or marketed as evidence based. PMID- 21536690 TI - Toxoplasma infection and later development of schizophrenia in mothers. AB - OBJECTIVE: Several studies based on clinical samples have found an association between Toxoplasma gondii infection and schizophrenia, and a case-control study among U.S. military personnel with specimens available from both before and after diagnosis found a positive association between T. gondii immunoglobulin G (IgG) antibody level and schizophrenia. These findings have never been replicated in a prospective cohort study. The purpose of this study was to determine whether mothers infected with T. gondii have an elevated risk of schizophrenia or related disorders and whether the risk depends on IgG antibody level. METHOD: In a register-based prospective cohort study of 45,609 women born in Denmark, the level of T. gondii-specific IgG antibodies was measured in connection with childbirth between 1992 and 1995. Women were followed up from the date of delivery until 2008. RESULTS: A significant positive association between T. gondii IgG antibody level and schizophrenia spectrum disorders was found. Mothers with the highest IgG level had a relative risk of 1.73 (95% confidence interval [CI]=1.12-2.62) compared with mothers with the lowest IgG level. For schizophrenia, the relative risk was 1.68 (95% CI=0.77-3.46). When the mothers were classified according to IgG level, only those with the highest IgG levels had a significantly higher risk of schizophrenia spectrum disorders. CONCLUSIONS: Women with high levels of T. gondii-specific IgG antibodies have a significantly elevated risk of developing schizophrenia spectrum disorders. PMID- 21536691 TI - Impact of neurocognition on social and role functioning in individuals at clinical high risk for psychosis. AB - OBJECTIVE: Cognitive deficits have been well documented in schizophrenia and have been shown to impair quality of life and to compromise everyday functioning. Recent studies of adolescents and young adults at high risk for developing psychosis show that neurocognitive impairments are detectable before the onset of psychotic symptoms. However, it remains unclear how cognitive impairments affect functioning before the onset of psychosis. The authors assessed cognitive impairment in adolescents at clinical high risk for psychosis and examined its impact on social and role functioning. METHOD: A sample of 127 treatment-seeking patients at clinical high risk for psychosis and a group of 80 healthy comparison subjects were identified and recruited for research in the Recognition and Prevention Program. At baseline, participants were assessed with a comprehensive neurocognitive battery as well as measures of social and role functioning. RESULTS: Relative to healthy comparison subjects, clinical high-risk patients showed significant impairments in the domains of processing speed, verbal memory, executive function, working memory, visuospatial processing, motor speed, sustained attention, and language. Clinical high-risk patients also displayed impaired social and role functioning at baseline. Among patients with attenuated positive symptoms, processing speed was related to social and role functioning at baseline. CONCLUSIONS: These findings demonstrate that cognitive and functional impairments are detectable in patients at clinical high risk for psychosis before the onset of psychotic illness and that processing speed appears to be an important cognitive predictor of poor functioning. PMID- 21536692 TI - Combining medications to enhance depression outcomes (CO-MED): acute and long term outcomes of a single-blind randomized study. AB - OBJECTIVE: Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment. METHOD: The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder. Escitalopram (up to 20 mg/day) plus placebo, sustained-release bupropion (up to 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day) was delivered (1:1:1 ratio) by using measurement-based care. The primary outcome was remission, defined as ratings of less than 8 and less than 6 on the last two consecutive applications of the 16-item Quick Inventory of Depressive Symptomatology--Self-Report. Secondary outcomes included side effect burden, adverse events, quality of life, functioning, and attrition. RESULTS: Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 38.8% for escitalopram placebo, 38.9% for bupropion-escitalopram, and 37.7% for venlafaxine-mirtazapine, and the response rates were 51.6%-52.4%. The mean number of worsening adverse events was higher for venlafaxine-mirtazapine (5.7) than for escitalopram-placebo (4.7). At 7 months, remission rates (41.8%-46.6%), response rates (57.4%-59.4%), and most secondary outcomes were not significantly different. CONCLUSIONS: Neither medication combination outperformed monotherapy. The combination of extended-release venlafaxine plus mirtazapine may have a greater risk of adverse events. PMID- 21536693 TI - Effectiveness of switching from antipsychotic polypharmacy to monotherapy. AB - OBJECTIVE: This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy. METHOD: Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing one antipsychotic. The trial lasted 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes over time. RESULTS: Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N=48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N=40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. CONCLUSIONS: Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. These results support the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory. PMID- 21536694 TI - A case of endocrine carcinoma of the rectum. PMID- 21536695 TI - Time trends in cervical cancer screening rates in the OECD countries. PMID- 21536696 TI - Looking into the health reform crystal ball: seeing more constructive, less expensive management scenarios. PMID- 21536697 TI - Nonsuicidal self-injury as a predictor of suicidal behavior in depressed adolescents. PMID- 21536698 TI - Deep brain stimulation for treatment-resistant depression. PMID- 21536699 TI - Do antidepressants raise the risk of stroke? PMID- 21536700 TI - Should attenuated psychosis syndrome be a DSM-5 diagnosis? PMID- 21536701 TI - Happy Mother's Day, with love from the ABPN. PMID- 21536702 TI - Prescription pain medication dependence. PMID- 21536703 TI - Development of obsessive-compulsive disorder following a pineal germinoma: a case report. PMID- 21536704 TI - Alternative explanation for FMRI findings in social phobia. PMID- 21536705 TI - Impact of hypertension and body mass index on quality of life in schizophrenia. PMID- 21536706 TI - The stress of protein misfolding: from single cells to multicellular organisms. AB - Organisms survive changes in the environment by altering their rates of metabolism, growth, and reproduction. At the same time, the system must ensure the stability and functionality of its macromolecules. Fluctuations in the environment are sensed by highly conserved stress responses and homeostatic mechanisms, and of these, the heat shock response (HSR) represents an essential response to acute and chronic proteotoxic damage. However, unlike the strategies employed to maintain the integrity of the genome, protection of the proteome must be tailored to accommodate the normal flux of nonnative proteins and the differences in protein composition between cells, and among individuals. Moreover, adult cells are likely to have significant differences in the rates of synthesis and clearance that are influenced by intrinsic errors in protein expression, genetic polymorphisms, and fluctuations in physiological and environmental conditions. Here, we will address how protein homeostasis (proteostasis) is achieved at the level of the cell and organism, and how the threshold of the stress response is set to detect and combat protein misfolding. For metazoans, the requirement for coordinated function and growth imposes additional constraints on the detection, signaling, and response to misfolding, and requires that the HSR is integrated into various aspects of organismal physiology, such as lifespan. This is achieved by hierarchical regulation of heat shock factor 1 (HSF1) by the metabolic state of the cell and centralized neuronal control that could allow optimal resource allocation between cells and tissues. We will examine how protein folding quality control mechanisms in individual cells may be integrated into a multicellular level of control, and further, even custom-designed to support individual variability and impose additional constraints on evolutionary adaptation. PMID- 21536708 TI - Increased knee valgus alignment and moment during single-leg landing after overhead stroke as a potential risk factor of anterior cruciate ligament injury in badminton. AB - BACKGROUND: In badminton, knees opposite to the racket-hand side received anterior cruciate ligament (ACL) injuries during single-leg landing after overhead stroke. Most of them occurred in the backhand-side of the rear court. Comparing lower limb biomechanics during single-leg landing after overhead stroke between the forehand-side and backhand-side court may help explain the different injury rates depending on court position. HYPOTHESIS: The knee kinematics and kinetics during single-leg landing after overhead stroke following back-stepping were different between the forehand-side and backhand-side court. STUDY DESIGN: Controlled laboratory study. METHODS: Hip, knee and ankle joint kinematic and knee kinetic data were collected for 17 right-handed female college badminton players using a 3-dimensional motion analysis system. Subjects performed single left-legged landing after an overhead stroke following left and right back stepping. The kinematic and kinetic data of the left lower extremities during landing were measured and compared between left and right back-steps. RESULTS: Hip flexion and abduction and knee valgus at the initial contact, hip and knee flexion and knee valgus at the maximum knee flexion and the maximum knee valgus moment were significantly larger for the left back-step than the right back-step (p<0.05). CONCLUSION: Significant differences in joint kinematics and kinetics of the lower extremity during single-leg landing after overhead stroke were observed between different back-step directions. Increased knee valgus angle and moment following back-stepping to the backhand-side might be related to the higher incidence of ACL injury during single-leg landing after overhead stroke. PMID- 21536707 TI - Specificity of intramembrane protein-lipid interactions. AB - Our concept of biological membranes has markedly changed, from the fluid mosaic model to the current model that lipids and proteins have the ability to separate into microdomains, differing in their protein and lipid compositions. Since the breakthrough in crystallizing membrane proteins, the most powerful method to define lipid-binding sites on proteins has been X-ray and electron crystallography. More recently, chemical biology approaches have been developed to analyze protein-lipid interactions. Such methods have the advantage of providing highly specific cellular probes. With the advent of novel tools to study functions of individual lipid species in membranes together with structural analysis and simulations at the atomistic resolution, a growing number of specific protein-lipid complexes are defined and their functions explored. In the present article, we discuss the various modes of intramembrane protein-lipid interactions in cellular membranes, including examples for both annular and nonannular bound lipids. Furthermore, we will discuss possible functional roles of such specific protein-lipid interactions as well as roles of lipids as chaperones in protein folding and transport. PMID- 21536709 TI - The association between sedentary leisure and physical activity in middle-aged adults. AB - AIM: The aim of this study was to examine the association between time spent in sedentary leisure and physical activity level in mid-aged men and women. METHODS: Data were from the 2007 HABITAT study in Brisbane, Australia. A mail survey sent to 17 000 adults (40-65 years) provided 11 037 responses (68.5%), and 9121 (82.6%) were analysed. Sedentary leisure was quantified as hours/day spent sitting watching television, in home computer use, in general leisure, and overall, on a usual week and weekend day. Physical activity level (no activity, low, recommended, high, very high) included walking, moderate and vigorous activity combined into a measure of MET.min/week. Data were analysed separately for men and women using multilevel multinomial logistic regression with adjustment for sociodemographic and health variables. RESULTS: The only significant negative associations were between watching television on a week day and high activity in men (0.91; 0.83-0.98), and home computer use on a weekend day and very high activity in men (0.89; 0.81-0.98). For both men and women, there were significant positive associations between overall sedentary leisure time on a week day and very high activity (men: 1.07, 1.02-1.13; women: 1.10, 1.04-1.16), home computer use on a week day and very high activity (men: 1.11, 1.01-1.22; women: 1.15, 1.04-1.27) and general leisure on a week day and most activity levels. CONCLUSIONS: Sedentary leisure is mainly independent of physical activity and does not preclude meeting physical activity recommendations. PMID- 21536711 TI - Genetic syndromes of severe insulin resistance. AB - Insulin resistance is among the most prevalent endocrine derangements in the world, and it is closely associated with major diseases of global reach including diabetes mellitus, atherosclerosis, nonalcoholic fatty liver disease, and ovulatory dysfunction. It is most commonly found in those with obesity but may also occur in an unusually severe form in rare patients with monogenic defects. Such patients may loosely be grouped into those with primary disorders of insulin signaling and those with defects in adipose tissue development or function (lipodystrophy). The severe insulin resistance of both subgroups puts patients at risk of accelerated complications and poses severe challenges in clinical management. However, the clinical disorders produced by different genetic defects are often biochemically and clinically distinct and are associated with distinct risks of complications. This means that optimal management of affected patients should take into account the specific natural history of each condition. In clinical practice, they are often underdiagnosed, however, with low rates of identification of the underlying genetic defect, a problem compounded by confusing and overlapping nomenclature and classification. We now review recent developments in understanding of genetic forms of severe insulin resistance and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying pathophysiology. PMID- 21536710 TI - Identification of potential conserved RNA secondary structure throughout influenza A coding regions. AB - Influenza A is a negative sense RNA virus of significant public health concern. While much is understood about the life cycle of the virus, knowledge of RNA secondary structure in influenza A virus is sparse. Predictions of RNA secondary structure can focus experimental efforts. The present study analyzes coding regions of the eight viral genome segments in both the (+) and (-) sense RNA for conserved secondary structure. The predictions are based on identifying regions of unusual thermodynamic stabilities and are correlated with studies of suppression of synonymous codon usage (SSCU). The results indicate that secondary structure is favored in the (+) sense influenza RNA. Twenty regions with putative conserved RNA structure have been identified, including two previously described structured regions. Of these predictions, eight have high thermodynamic stability and SSCU, with five of these corresponding to current annotations (e.g., splice sites), while the remaining 12 are predicted by the thermodynamics alone. Secondary structures with high conservation of base-pairing are proposed within the five regions having known function. A combination of thermodynamics, amino acid and nucleotide sequence comparisons along with SSCU was essential for revealing potential secondary structures. PMID- 21536712 TI - Taxonomy for strengthening the identification of core elements for evidence-based behavioral interventions for HIV/AIDS prevention. AB - The concept of core elements was developed to denote characteristics of an intervention, such as activities or delivery methods, presumed to be responsible for the efficacy of evidence-based behavioral interventions (EBIs) for HIV/AIDS prevention. This paper describes the development of a taxonomy of core elements based on a literature review of theoretical approaches and characteristics of EBIs. Sixty-one categories of core elements were identified from the literature and grouped into three distinct domains: implementation, content and pedagogy. The taxonomy was tested by categorizing core elements from 20 HIV prevention EBIs disseminated by Centers for Disease Control and Prevention. Results indicated that core elements represented all three domains but several were difficult to operationalize due to vague language or the inclusion of numerous activities or constructs. A process is proposed to describe core elements in a method that overcomes some of these challenges. The taxonomy of core elements can be used to identify core elements of EBIs, strengthen the translation of EBIs from research to practice and guide future research seeking to identify essential core elements in prevention interventions. PMID- 21536713 TI - Hong Kong Chinese community leaders' perspectives on family health, happiness and harmony: a qualitative study. AB - This paper examines the views of Hong Kong community leaders on the underlying issues that affect family health, happiness and harmony (3Hs) in Hong Kong. Using a community reconnaissance method, a series of individual in-depth interviews with 26 leaders that represent neighbourhoods of diverse socio-economic status (SES) from June to August 2008 were conducted. Participants considered that changing family structure, economic situation and strong work ethic are the most salient factors that affect family 3Hs. The deprived comprehensive social security assistance recipients, single-parent families and migrant women were considered to be the most vulnerable groups to breakdown in family 3Hs and particularly, they lack family resources. Families from different SES have to overcome different challenges in order to achieve and sustain family 3Hs. Leaders from low SES neighbourhood were concerned more about providing tangible help such as child care facilities to improve family resources, whereas leaders from high SES neighbourhood focused more on preventive interventions such as education on relationship skills to achieve better family well-being. The findings offer insights in designing effective social marketing education campaigns and family friendly workplace policy to promote social harmony through the maintenance of 3Hs families. PMID- 21536714 TI - Relationships between the family environment and school-based obesity prevention efforts: can school programs help adolescents who are most in need? AB - Identifying factors that contribute to students' behavior and weight improvements during school-based obesity prevention interventions is critical for the development of effective programs. The current study aims to determine whether the support and resources that adolescent girls received from their families were associated with improvements in physical activity (PA), television use, dietary intake, body mass index (BMI) and body composition during participation in New Moves, a school-based intervention to prevent obesity and other weight-related problems. Adolescent girls in the intervention condition of New Moves (n = 135), and one parent of each girl, were included in the current analysis. At baseline, parents completed surveys assessing the family environment. At baseline and follow-up, 9-12 months later, girls' behaviors were self-reported, height and weight were measured by study staff and body fat was assessed using dual-energy X ray absorptiometry. Results showed few associations between family environment factors and girls' likelihood of improving behavior, BMI or body composition. These findings suggest that in general, school-based interventions offer similar opportunities for adolescent girls to improve their PA, dietary intake, and weight, regardless of family support. PMID- 21536715 TI - Cell phone usage among adolescents in Uganda: acceptability for relaying health information. AB - The increase in cell phone use has manifested a growing interest in using this technology for health promotion. The portability and 'always on' features of the cell phone, along with increasing capability for the devices to carry and transfer data suggest that they will reach more people than computers and the Internet in coming years. Self-reported quantitative survey data from 1503 secondary school students in Mbarara, Uganda collected in 2008-2009 suggest that 27% currently have cell phones and about half (51%) of all students and 61% of those who owned a cell phone believe that they would access a text messaging based HIV prevention program if it were available. Other forms of program delivery modality (e.g. Internet, religious organizations, schools) were preferred to text messaging however. We are in need of effective HIV prevention programs that can reach large audiences at low cost and are culturally relevant for the East African context. Researchers are encouraged to consider translation of effective HIV prevention programs for cell phone delivery in Africa. PMID- 21536716 TI - The rapidly changing paradigm of HIV prevention: time to strengthen social and behavioural approaches. AB - A decade after the world's leaders committed to fight the global HIV epidemic, UNAIDS notes progress in halting the spread of the virus. Access to treatment has in particular increased, with noticeable beneficial effects on HIV-related mortality. Further scaling-up treatment requires substantial human and financial resources and the continued investments that are required may further erode the limited resources for HIV prevention. Treatment can play a role in reducing the transmission of HIV, but treatment alone is not enough and cost-effective behavioural prevention approaches are available that in recent years have received less priority. HIV prevention may in the future benefit from novel biomedical approaches that are in development, including those that capitalize on the use of treatment. To date, evidence of effectiveness of biomedical prevention in real-life conditions is limited and, while they can increase prevention options, many biomedical prevention approaches will continue to rely on the behaviours of individuals and communities. These behaviors are shaped and constrained by the social, cultural, political and economic contexts that affect the vulnerability of individuals and communities. At the start of the 4(th) decade of the epidemic, it is timely to re-focus on strengthening the theory and practice of behavioural prevention of HIV. PMID- 21536717 TI - Correlates of 2009 H1N1 influenza vaccine acceptability among parents and their adolescent children. AB - School-aged children were a priority group for receipt of the pandemic (2009) H1N1 influenza vaccine. Both parental and adolescent attitudes likely influence vaccination behaviors. Data were collected from surveys distributed to middle- and high-school students and their parents in two counties in rural Georgia. Multivariable logistic regression analyses were conducted to assess correlates of parental acceptance of H1N1 influenza vaccination for their children and adolescents' acceptance of vaccination for themselves. Concordance analyses were conducted to assess agreement between parent-adolescent dyads regarding H1N1 influenza vaccine acceptance. Parental acceptance of H1N1 influenza vaccination for their children was associated with acceptance of the vaccine for themselves and feeling motivated by the H1N1 influenza pandemic to get a seasonal influenza vaccine for their child. Adolescents' acceptance was associated with receipt of a seasonal influenza vaccine in the past year, fear of getting H1N1 influenza, feeling comfortable getting the vaccine and parental acceptance of H1N1 influenza vaccine. Half (50%) of parent-adolescent pairs included both a parent and child who expressed H1N1 influenza vaccine acceptance, and 19% of pairs would not accept the vaccine. This research highlights the need for interventions that target factors associated with H1N1 influenza vaccine acceptance among both parents and adolescents. PMID- 21536718 TI - Upregulation of clusterin in prostate and DNA damage in spermatozoa from bisphenol A-treated rats and formation of DNA adducts in cultured human prostatic cells. AB - Among endocrine disruptors, the xenoestrogen bisphenol A (BPA) deserves particular attention due to widespread human exposure. Besides hormonal effects, BPA has been suspected to be involved in breast and prostate carcinogenesis, which share similar estrogen-related mechanisms. We previously demonstrated that administration of BPA to female mice results in the formation of DNA adducts and proteome alterations in the mammary tissue. Here, we evaluated the ability of BPA, given with drinking water, to induce a variety of biomarker alterations in male Sprague-Dawley rats. In addition, we investigated the formation of DNA adducts in human prostate cell lines. In BPA-treated rats, no DNA damage occurred in surrogate cells including peripheral blood lymphocytes and bone marrow erythrocytes, where no increase of single-strand DNA breaks was detectable by comet assay and the frequency of micronucleated cells was unaffected by BPA. Liver cells were positive at transferase dUTP nick end labeling assay, which detects both single-strand and double-strand breaks and early stage apoptosis. BPA upregulated clusterin expression in atrophic prostate epithelial cells and induced lipid peroxidation and DNA fragmentation in spermatozoa. Significant levels of DNA adducts were formed in prostate cell lines treated either with high dose BPA for 24 h or low-dose BPA for 2 months. The BPA-related increase of DNA adducts was more pronounced in PNT1a nontumorigenic epithelial cells than in PC3 metastatic carcinoma cells. On the whole, these experimental findings support mechanistically the hypothesis that BPA may play a role in prostate carcinogenesis and may, potentially, affect the quality of sperm. PMID- 21536719 TI - Differing evolutionary histories of WFDC8 (short-term balancing) in Europeans and SPINT4 (incomplete selective sweep) in Africans. AB - The whey acidic protein four-disulfide core (WFDC) gene cluster on human chromosome 20q13, harbors 15 small serine protease inhibitor genes with roles in innate immunity, reproduction, and regulation of endogenous proteases kallikreins. The WFDC cluster has emerged as a prime example of rapid diversification and adaptive evolution in primates. This study sought a better understanding of the evolutionary history of WFDC genes in humans and focused on exploring the adaptive selection signatures found in populations of European (Utah residents with ancestry from northern and western Europe [CEU]) and African (Yoruba from Ibadan, in Nigeria [YRI]) ancestry in a genome-wide scan for putative targets of recent adaptive selection. Our approach included resequencing coding and noncoding regions of WFDC6, EPPIN, and WFDC8 in 20 CEU and of SPINT4 in 20 YRI individuals. We generated 302 kb and 60 kb of high-quality sequence data from CEU and of YRI populations, respectively, enabling the identification of 72 single nucleotide polymorphisms. Using classic neutrality tests, empirical and haplotype-based analysis, we pinpointed WFDC8 and SPINT4 as the likely targets of short-term balancing selection in the CEU population, and recent positive selection (incomplete selective sweep) in the YRI population. Putative candidate variants targeted by selection include 44A (rs7273669A) for WFDC8, which may downregulate gene expression by abolishing the binding site of two transcription factors; and a haplotype configuration [Ser73+98A] (rs6017667A rs6032474A) for SPINT4, which may simultaneously affect protein function and gene regulation. We propose that the evolution of WFDC8 and SPINT4 has been shaped by complex selective scenarios due to the interdependence of variant fitness and ecological variables. PMID- 21536721 TI - RNA-sequence analysis of human B-cells. AB - RNA-sequencing (RNA-seq) allows quantitative measurement of expression levels of genes and their transcripts. In this study, we sequenced complementary DNA fragments of cultured human B-cells and obtained 879 million 50-bp reads comprising 44 Gb of sequence. The results allowed us to study the gene expression profile of B-cells and to determine experimental parameters for sequencing-based expression studies. We identified 20,766 genes and 67,453 of their alternatively spliced transcripts. More than 90% of the genes with multiple exons are alternatively spliced; for most genes, one isoform is predominantly expressed. We found that while chromosomes differ in gene density, the percentage of transcribed genes in each chromosome is less variable. In addition, genes involved in related biological processes are expressed at more similar levels than genes with different functions. Besides characterizing gene expression, we also used the data to investigate the effect of sequencing depth on gene expression measurements. While 100 million reads are sufficient to detect most expressed genes and transcripts, about 500 million reads are needed to measure accurately their expression levels. We provide examples in which deep sequencing is needed to determine the relative abundance of genes and their isoforms. With data from 20 individuals and about 40 million sequence reads per sample, we uncovered only 21 alternatively spliced, multi-exon genes that are not in databases; this result suggests that at this sequence coverage, we can detect most of the known genes. Results from this project are available on the UCSC Genome Browser to allow readers to study the expression and structure of genes in human B-cells. PMID- 21536720 TI - Prioritizing candidate disease genes by network-based boosting of genome-wide association data. AB - Network "guilt by association" (GBA) is a proven approach for identifying novel disease genes based on the observation that similar mutational phenotypes arise from functionally related genes. In principle, this approach could account even for nonadditive genetic interactions, which underlie the synergistic combinations of mutations often linked to complex diseases. Here, we analyze a large-scale, human gene functional interaction network (dubbed HumanNet). We show that candidate disease genes can be effectively identified by GBA in cross-validated tests using label propagation algorithms related to Google's PageRank. However, GBA has been shown to work poorly in genome-wide association studies (GWAS), where many genes are somewhat implicated, but few are known with very high certainty. Here, we resolve this by explicitly modeling the uncertainty of the associations and incorporating the uncertainty for the seed set into the GBA framework. We observe a significant boost in the power to detect validated candidate genes for Crohn's disease and type 2 diabetes by comparing our predictions to results from follow-up meta-analyses, with incorporation of the network serving to highlight the JAK-STAT pathway and associated adaptors GRB2/SHC1 in Crohn's disease and BACH2 in type 2 diabetes. Consideration of the network during GWAS thus conveys some of the benefits of enrolling more participants in the GWAS study. More generally, we demonstrate that a functional network of human genes provides a valuable statistical framework for prioritizing candidate disease genes, both for candidate gene-based and GWAS-based studies. PMID- 21536722 TI - De novo assembly and validation of planaria transcriptome by massive parallel sequencing and shotgun proteomics. AB - Freshwater planaria are a very attractive model system for stem cell biology, tissue homeostasis, and regeneration. The genome of the planarian Schmidtea mediterranea has recently been sequenced and is estimated to contain >20,000 protein-encoding genes. However, the characterization of its transcriptome is far from complete. Furthermore, not a single proteome of the entire phylum has been assayed on a genome-wide level. We devised an efficient sequencing strategy that allowed us to de novo assemble a major fraction of the S. mediterranea transcriptome. We then used independent assays and massive shotgun proteomics to validate the authenticity of transcripts. In total, our de novo assembly yielded 18,619 candidate transcripts with a mean length of 1118 nt after filtering. A total of 17,564 candidate transcripts could be mapped to 15,284 distinct loci on the current genome reference sequence. RACE confirmed complete or almost complete 5' and 3' ends for 22/24 transcripts. The frequencies of frame shifts, fusion, and fission events in the assembled transcripts were computationally estimated to be 4.2%-13%, 0%-3.7%, and 2.6%, respectively. Our shotgun proteomics produced 16,135 distinct peptides that validated 4200 transcripts (FDR <=1%). The catalog of transcripts assembled in this study, together with the identified peptides, dramatically expands and refines planarian gene annotation, demonstrated by validation of several previously unknown transcripts with stem cell-dependent expression patterns. In addition, our robust transcriptome characterization pipeline could be applied to other organisms without genome assembly. All of our data, including homology annotation, are freely available at SmedGD, the S. mediterranea genome database. PMID- 21536725 TI - Genomic contributions to Mendelian disease. PMID- 21536723 TI - Transcript amplification from single bacterium for transcriptome analysis. AB - Total transcript amplification (TTA) from single eukaryotic cells for transcriptome analysis is established, but TTA from a single prokaryotic cell presents additional challenges with much less starting material, the lack of poly(A)-tails, and the fact that the messages can be polycistronic. Here, we describe a novel method for single-bacterium TTA using a model organism, Burkholderia thailandensis, exposed to a subinhibitory concentration of the antibacterial agent, glyphosate. Utilizing a B. thailandensis microarray to assess the TTA method showed low fold-change bias (less than twofold difference and Pearson correlation coefficient R ~ 0.87-0.89) and drop-outs (4%-6% of 2842 detectable genes), compared with data obtained from the larger-scale nonamplified RNA samples. Further analysis of the microarray data suggests that B. thailandensis, when exposed to the aromatic amino acid biosynthesis inhibitor glyphosate, induces (or represses) genes to possibly recuperate and balance the intracellular amino acid pool. We validated our single-cell microarray data at the multi-cell and single-cell levels with lacZ and gfp reporter-gene fusions, respectively. Sanger sequencing of 192 clones generated from the TTA product of a single cell, with and without enrichment by elimination of rRNA and tRNA, detected only B. thailandensis sequences with no contamination. These data indicate that RNA-seq of TTA from a single cell is possible using this novel method. PMID- 21536726 TI - Classification images: A review. AB - Classification images have recently become a widely used tool in visual psychophysics. Here, I review the development of classification image methods over the past fifteen years. I provide some historical background, describing how classification images and related methods grew out of established statistical and mathematical frameworks and became common tools for studying biological systems. I describe key developments in classification image methods: use of optimal weighted sums based on the linear observer model, formulation of classification images in terms of the generalized linear model, development of statistical tests, use of priors to reduce dimensionality, methods for experiments with more than two response alternatives, a variant using multiplicative noise, and related methods for examining nonlinearities in visual processing, including second-order Volterra kernels and principal component analysis. I conclude with a selective review of how classification image methods have led to substantive findings in three representative areas of vision research, namely, spatial vision, perceptual organization, and visual search. PMID- 21536727 TI - Surface color perception and equivalent illumination models. AB - Vision provides information about the properties and identity of objects. The ease with which we perceive object properties belies the difficulty of the underlying information-processing task. In the case of object color, retinal information about object reflectance is confounded with information about the illumination as well as about the object's shape and pose. There is no obvious rule that allows transformation of the retinal image to a color representation that depends primarily on object surface reflectance. Under many circumstances, however, object color appearance is remarkably stable across scenes in which the object is viewed. Here, we review a line of experiments and theory that aim to understand how the visual system stabilizes object color appearance. Our emphasis is on models derived from explicit analysis of the computational problem of estimating the physical properties of illuminants and surfaces from the retinal image, and experiments that test these models. We argue that this approach has considerable promise for allowing generalization from simplified laboratory experiments to richer scenes that more closely approximate natural viewing. We discuss the relation between the work we review and other theoretical approaches available in the literature. PMID- 21536729 TI - Sweet DREAMs for Hippo. AB - The Hippo pathway coordinates organ size and cell proliferation. The retinoblastoma family of proteins regulates progression through the G0/G1 phase of the cell cycle. Disruption of either pathway contributes to cancer formation. Three recent studies in Genes & Development reveal how cellular proliferation is coordinated between these pathways. Here we discuss the implications of these studies and the new questions that they raise. PMID- 21536730 TI - Addicted to Myc--but why? AB - Many tumors continuously depend on the initiating oncogenes, but whether this extends to their downstream targets is unclear. In this issue of Genes & Development, Sodir and colleagues (pp. 907-916) demonstrate an essential role for endogenous Myc proteins in maintaining the tumor microenvironment, providing an unexpected molecular explanation for addiction to Myc. PMID- 21536731 TI - Of blood, bones, and ribosomes: is Swachman-Diamond syndrome a ribosomopathy? AB - Mutations in the human SBDS (Shwachman-Bodian-Diamond syndrome) gene are the most common cause of Shwachman-Diamond syndrome, an inherited bone marrow failure syndrome. In this issue of Genes & Development, Finch and colleagues (pp. 917 929) establish that SBDS functions in ribosome synthesis by promoting the recycling of eukaryotic initiation factor 6 (eIF6) in a GTP-dependent manner. This work supports the idea that a ribosomopathy may underlie this syndrome. PMID- 21536732 TI - Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman Diamond syndrome. AB - Removal of the assembly factor eukaryotic initiation factor 6 (eIF6) is critical for late cytoplasmic maturation of 60S ribosomal subunits. In mammalian cells, the current model posits that eIF6 release is triggered following phosphorylation of Ser 235 by activated protein kinase C. In contrast, genetic studies in yeast indicate a requirement for the ortholog of the SBDS (Shwachman-Bodian-Diamond syndrome) gene that is mutated in the inherited leukemia predisposition disorder Shwachman-Diamond syndrome (SDS). Here, by isolating late cytoplasmic 60S ribosomal subunits from Sbds-deleted mice, we show that SBDS and the GTPase elongation factor-like 1 (EFL1) directly catalyze eIF6 removal in mammalian cells by a mechanism that requires GTP binding and hydrolysis by EFL1 but not phosphorylation of eIF6 Ser 235. Functional analysis of disease-associated missense variants reveals that the essential role of SBDS is to tightly couple GTP hydrolysis by EFL1 on the ribosome to eIF6 release. Furthermore, complementary NMR spectroscopic studies suggest unanticipated mechanistic parallels between this late step in 60S maturation and aspects of bacterial ribosome disassembly. Our findings establish a direct role for SBDS and EFL1 in catalyzing the translational activation of ribosomes in all eukaryotes, and define SDS as a ribosomopathy caused by uncoupling GTP hydrolysis from eIF6 release. PMID- 21536733 TI - A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets. AB - Proneural genes such as Ascl1 are known to promote cell cycle exit and neuronal differentiation when expressed in neural progenitor cells. The mechanisms by which proneural genes activate neurogenesis--and, in particular, the genes that they regulate--however, are mostly unknown. We performed a genome-wide characterization of the transcriptional targets of Ascl1 in the embryonic brain and in neural stem cell cultures by location analysis and expression profiling of embryos overexpressing or mutant for Ascl1. The wide range of molecular and cellular functions represented among these targets suggests that Ascl1 directly controls the specification of neural progenitors as well as the later steps of neuronal differentiation and neurite outgrowth. Surprisingly, Ascl1 also regulates the expression of a large number of genes involved in cell cycle progression, including canonical cell cycle regulators and oncogenic transcription factors. Mutational analysis in the embryonic brain and manipulation of Ascl1 activity in neural stem cell cultures revealed that Ascl1 is indeed required for normal proliferation of neural progenitors. This study identified a novel and unexpected activity of the proneural gene Ascl1, and revealed a direct molecular link between the phase of expansion of neural progenitors and the subsequent phases of cell cycle exit and neuronal differentiation. PMID- 21536734 TI - Nuclear actin polymerization is required for transcriptional reprogramming of Oct4 by oocytes. AB - Amphibian oocytes can rapidly and efficiently reprogram the transcription of transplanted somatic nuclei. To explore the factors and mechanisms involved, we focused on nuclear actin, an especially abundant component of the oocyte's nucleus (the germinal vesicle). The existence and significance of nuclear actin has long been debated. Here, we found that nuclear actin polymerization plays an essential part in the transcriptional reactivation of the pluripotency gene Oct4 (also known as Pou5f1). We also found that an actin signaling protein, Toca-1, enhances Oct4 reactivation by regulating nuclear actin polymerization. Toca-1 overexpression has an effect on the chromatin state of transplanted nuclei, including the enhanced binding of nuclear actin to gene regulatory regions. This is the first report showing that naturally stored actin in an oocyte nucleus helps transcriptional reprogramming in a polymerization-dependent manner. PMID- 21536735 TI - MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells. AB - Chromosome-wide inactivation is an epigenetic signature of sex chromosomes. The mechanism by which the chromosome-wide domain is recognized and gene silencing is induced remains unclear. Here we identify an essential mechanism underlying the recognition of the chromosome-wide domain in the male germline. We show that mediator of DNA damage checkpoint 1 (MDC1), a binding partner of phosphorylated histone H2AX (gammaH2AX), defines the chromosome-wide domain, initiates meiotic sex chromosome inactivation (MSCI), and leads to XY body formation. Importantly, MSCI consists of two genetically separable steps. The first step is the MDC1 independent recognition of the unsynapsed axis by DNA damage response (DDR) factors such as ataxia telangiectasia and Rad3-related (ATR), TOPBP1, and gammaH2AX. The second step is the MDC1-dependent chromosome-wide spreading of DDR factors to the entire chromatin. Furthermore, we demonstrate that, in somatic cells, MDC1-dependent amplification of the gammaH2AX signal occurs following replicative stress and is associated with transcriptional silencing. We propose that a common DDR pathway underlies both MSCI and the response of somatic cells to replicative stress. These results establish that the DDR pathway centered on MDC1 triggers epigenetic silencing of sex chromosomes in germ cells. PMID- 21536736 TI - The RNA polymerase II C-terminal domain promotes splicing activation through recruitment of a U2AF65-Prp19 complex. AB - Pre-mRNA splicing is frequently coupled to transcription by RNA polymerase II (RNAPII). This coupling requires the C-terminal domain of the RNAPII largest subunit (CTD), although the underlying mechanism is poorly understood. Using a biochemical complementation assay, we previously identified an activity that stimulates CTD-dependent splicing in vitro. We purified this activity and found that it consists of a complex of two well-known splicing factors: U2AF65 and the Prp19 complex (PRP19C). We provide evidence that both U2AF65 and PRP19C are required for CTD-dependent splicing activation, that U2AF65 and PRP19C interact both in vitro and in vivo, and that this interaction is required for activation of splicing. Providing the link to the CTD, we show that U2AF65 binds directly to the phosphorylated CTD, and that this interaction results in increased recruitment of U2AF65 and PRP19C to the pre-mRNA. Our results not only provide a mechanism by which the CTD enhances splicing, but also describe unexpected interactions important for splicing and its coupling to transcription. PMID- 21536737 TI - Phosphoinositide [PI(3,5)P2] lipid-dependent regulation of the general transcriptional regulator Tup1. AB - Transcriptional activity of a gene is governed by transcriptional regulatory complexes that assemble/disassemble on the gene and control the chromatin architecture. How cytoplasmic components influence the assembly/disassembly of transcriptional regulatory complexes is poorly understood. Here we report that the budding yeast Saccharomyces cerevisiae has a chromatin architecture modulating mechanism that is dependent on the endosomal lipid PI(3,5)P(2). We identified Tup1 and Cti6 as new, highly specific PI(3,5)P(2) interactors. Tup1- which associates with multiple transcriptional regulators, including the HDAC (histone deacetylase) and SAGA complexes--plays a crucial role in determining an activated or repressed chromatin state of numerous genes, including GAL1. We show that, in the context that the Gal4 activation pathway is compromised, PI(3,5)P(2) plays an essential role in converting the Tup1-driven repressed chromatin structure into a SAGA-containing activated chromatin structure at the GAL1 promoter. Biochemical and cell biological experiments suggest that PI(3,5)P(2) recruits Cti6 and the Cyc8-Tup1 corepressor complex to the late endosomal/vacuolar membrane and mediates the assembly of a Cti6-Cyc8-Tup1 coactivator complex that functions to recruit the SAGA complex to the GAL1 promoter. Our findings provide important insights toward understanding how the chromatin architecture and epigenetic status of a gene are regulated by cytoplasmic components. PMID- 21536738 TI - Gain-of-function mutations in interleukin-7 receptor-alpha (IL7R) in childhood acute lymphoblastic leukemias. AB - Interleukin-7 receptor alpha (IL7R) is required for normal lymphoid development. Loss-of-function mutations in this gene cause autosomal recessive severe combined immune deficiency. Here, we describe somatic gain-of-function mutations in IL7R in pediatric B and T acute lymphoblastic leukemias. The mutations cause either a serine-to-cysteine substitution at amino acid 185 in the extracellular domain (4 patients) or in-frame insertions and deletions in the transmembrane domain (35 patients). In B cell precursor leukemias, the mutations were associated with the aberrant expression of cytokine receptor-like factor 2 (CRLF2), and the mutant IL 7R proteins formed a functional receptor with CRLF2 for thymic stromal lymphopoietin (TSLP). Biochemical and functional assays reveal that these IL7R mutations are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells. A cysteine, included in all but three of the mutated IL-7R alleles, is essential for the constitutive activation of the receptor. This is the first demonstration of gain-of-function mutations of IL7R. Our current and recent observations of mutations in IL7R and CRLF2, respectively suggest that the addition of cysteine to the juxtamembranous domains is a general mechanism for mutational activation of type I cytokine receptors in leukemia. PMID- 21536739 TI - Trypanosoma cruzi subverts the sphingomyelinase-mediated plasma membrane repair pathway for cell invasion. AB - Upon host cell contact, the protozoan parasite Trypanosoma cruzi triggers cytosolic Ca(2+) transients that induce exocytosis of lysosomes, a process required for cell invasion. However, the exact mechanism by which lysosomal exocytosis mediates T. cruzi internalization remains unclear. We show that host cell entry by T. cruzi mimics a process of plasma membrane injury and repair that involves Ca(2+)-dependent exocytosis of lysosomes, delivery of acid sphingomyelinase (ASM) to the outer leaflet of the plasma membrane, and a rapid form of endocytosis that internalizes membrane lesions. Host cells incubated with T. cruzi trypomastigotes are transiently wounded, show increased levels of endocytosis, and become more susceptible to infection when injured with pore forming toxins. Inhibition or depletion of lysosomal ASM, which blocks plasma membrane repair, markedly reduces the susceptibility of host cells to T. cruzi invasion. Notably, extracellular addition of sphingomyelinase stimulates host cell endocytosis, enhances T. cruzi invasion, and restores normal invasion levels in ASM-depleted cells. Ceramide, the product of sphingomyelin hydrolysis, is detected in newly formed parasitophorous vacuoles containing trypomastigotes but not in the few parasite-containing vacuoles formed in ASM-depleted cells. Thus, T. cruzi subverts the ASM-dependent ceramide-enriched endosomes that function in plasma membrane repair to infect host cells. PMID- 21536740 TI - Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero. AB - Vasculogenesis describes the process of de novo vessel formation from vascular precursor cells. Although formation of the first major vessels, such as the dorsal aorta and cardinal veins, occurs during embryonic vasculogenesis, the contribution of precursor cell populations to postnatal vessel development is not well understood. Here, we identified a novel population of postnatal vascular precursor cells in mice. These cells express the Schwann cell protein myelin protein zero (Po) and exhibit a CD45(-)CD31(-)VEcad(-)c-kit(+)CXCR4(+) surface phenotype. Po(+) vascular precursors (PVPs) are recruited into the growing vasculature, and comprise a minor population of arterial endothelial cells in adult mice. Recruitment of PVPs into growing vessels is mediated by CXCL12-CXCR4 signaling, and is enhanced during vascular expansion induced by Notch inhibition. Po-specific ablation of Flk1, a receptor for VEGF, results in branching defects and insufficient arterial patterning in the retina, as well as reduced neovascularization of tumors and ischemic tissues. Thus, in postnatal mice, although growing vessels are formed primarily by angiogenesis from preexisting vessels, a minor population of arterial endothelia may be derived from tissue resident vascular precursor cells. PMID- 21536741 TI - Langerhans cells are negative regulators of the anti-Leishmania response. AB - Migratory skin dendritic cells (DCs) are thought to play an important role in priming T cell immune responses against Leishmania major, but DC subtypes responsible for the induction of protective immunity against this pathogen are still controversial. In this study, we analyzed the role of Langerin(+) skin derived DCs in the Leishmania model using inducible in vivo cell ablation. After physiologically relevant low-dose infection with L. major (1,000 parasites), mice depleted of all Langerin(+) DCs developed significantly smaller ear lesions with decreased parasite loads and a reduced number of CD4(+) Foxp3(+) regulatory T cells (T reg cells) as compared with controls. This was accompanied by increased interferon gamma production in lymph nodes in the absence of Langerin(+) DCs. Moreover, selective depletion of Langerhans cells (LCs) demonstrated that the absence of LCs, and not Langerin(+) dermal DC, was responsible for the reduced T reg cell immigration and the enhanced Th1 response, resulting in attenuated disease. Our data reveal a unique and novel suppressive role for epidermal LCs in L. major infection by driving the expansion of T reg cells. A better understanding of the various roles of different DC subsets in cutaneous leishmaniasis will improve the development of a potent therapeutic/prophylactic vaccine. PMID- 21536742 TI - Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. AB - Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic. PMID- 21536743 TI - Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. AB - CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associated with control of acute viral infections. Considering that CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. We now demonstrate that CD4 T cell function is not extinguished as a result of viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively redirects CD4 T cell development away from the Th1 response induced during an acute infection toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral infection. PMID- 21536745 TI - Erik Sahai: getting the whole picture of metastasis. Interview by Sedwick Caitlin. PMID- 21536744 TI - Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. AB - Lymphangiogenesis plays an important role in tumor metastasis and transplant outcome. Here, we show that thrombospondin-1 (TSP-1), a multifunctional extracellular matrix protein and naturally occurring inhibitor of angiogenesis inhibits lymphangiogenesis in mice. Compared with wild-type mice, 6-mo-old TSP-1 deficient mice develop increased spontaneous corneal lymphangiogenesis. Similarly, in a model of inflammation-induced corneal neovascularization, young TSP-1-deficient mice develop exacerbated lymphangiogenesis, which can be reversed by topical application of recombinant human TSP-1. Such increased corneal lymphangiogenesis is also detected in mice lacking CD36, a receptor for TSP-1. In these mice, repopulation of corneal macrophages with predominantly WT mice via bone marrow reconstitution ameliorates their prolymphangiogenic phenotype. In vitro, exposure of WT macrophages to TSP-1 suppresses expression of lymphangiogenic factors vascular endothelial growth factor (VEGF)-C and VEGF-D, but not of a primarily hemangiogenic factor VEGF-A. Inhibition of VEGF-C is not detected in the absence or blockade of CD36. These findings suggest that TSP-1, by ligating CD36 on monocytic cells, acts as an endogenous inhibitor of lymphangiogenesis. PMID- 21536746 TI - Generating a Wnt switch: it's all about the right dosage. AB - Wnt proteins can activate different branches of the Wnt signaling pathway, raising the question of specificity. In this issue, Nalesso et al. (2011. J. Cell Biol. doi:10.1083/jcb.201011051) provide an answer to this conundrum by showing that different concentrations of Wnt ligands can elicit different intracellular responses. These findings not only provide new insights into the molecular mechanisms underlying Wnt signaling, but also indicate how Wnt gradients might contribute to tissue patterning during embryogenesis. PMID- 21536748 TI - Spatial regulation of Cdc55-PP2A by Zds1/Zds2 controls mitotic entry and mitotic exit in budding yeast. AB - Budding yeast CDC55 encodes a regulatory B subunit of the PP2A (protein phosphatase 2A), which plays important roles in mitotic entry and mitotic exit. The spatial and temporal regulation of PP2A is poorly understood, although recent studies demonstrated that the conserved proteins Zds1 and Zds2 stoichiometrically bind to Cdc55-PP2A and regulate it in a complex manner. Zds1/Zds2 promote Cdc55 PP2A function for mitotic entry, whereas Zds1/Zds2 inhibit Cdc55-PP2A function during mitotic exit. In this paper, we propose that Zds1/Zds2 primarily control Cdc55 localization. Cortical and cytoplasmic localization of Cdc55 requires Zds1/Zds2, and Cdc55 accumulates in the nucleus in the absence of Zds1/Zds2. By genetically manipulating the nucleocytoplasmic distribution of Cdc55, we showed that Cdc55 promotes mitotic entry when in the cytoplasm. On the other hand, nuclear Cdc55 prevents mitotic exit. Our analysis defines the long-sought molecular function for the zillion different screens family proteins and reveals the importance of the regulation of PP2A localization for proper mitotic progression. PMID- 21536747 TI - Regulating the transition from centriole to basal body. AB - The role of centrioles changes as a function of the cell cycle. Centrioles promote formation of spindle poles in mitosis and act as basal bodies to assemble primary cilia in interphase. Stringent regulations govern conversion between these two states. Although the molecular mechanisms have not been fully elucidated, recent findings have begun to shed light on pathways that regulate the conversion of centrioles to basal bodies and vice versa. Emerging studies also provide insights into how defects in the balance between centrosome and cilia function could promote ciliopathies and cancer. PMID- 21536749 TI - Interruption of intrachromosomal looping by CCCTC binding factor decoy proteins abrogates genomic imprinting of human insulin-like growth factor II. AB - Monoallelic expression of IGF2 is regulated by CCCTC binding factor (CTCF) binding to the imprinting control region (ICR) on the maternal allele, with subsequent formation of an intrachromosomal loop to the promoter region. The N terminal domain of CTCF interacts with SUZ12, part of the polycomb repressive complex-2 (PRC2), to silence the maternal allele. We synthesized decoy CTCF proteins, fusing the CTCF deoxyribonucleic acid-binding zinc finger domain to CpG methyltransferase Sss1 or to enhanced green fluorescent protein. In normal human fibroblasts and breast cancer MCF7 cell lines, the CTCF decoy proteins bound to the unmethylated ICR and to the IGF2 promoter region but did not interact with SUZ12. EZH2, another part of PRC2, was unable to methylate histone H3-K27 in the IGF2 promoter region, resulting in reactivation of the imprinted allele. The intrachromosomal loop between the maternal ICR and the IGF2 promoters was not observed when IGF2 imprinting was lost. CTCF epigenetically governs allelic gene expression of IGF2 by orchestrating chromatin loop structures involving PRC2. PMID- 21536750 TI - REST/NRSF governs the expression of dense-core vesicle gliosecretion in astrocytes. AB - Astrocytes are the brain nonnerve cells that are competent for gliosecretion, i.e., for expression and regulated exocytosis of clear and dense-core vesicles (DCVs). We investigated whether expression of astrocyte DCVs is governed by RE-1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), the transcription repressor that orchestrates nerve cell differentiation. Rat astrocyte cultures exhibited high levels of REST and expressed neither DCVs nor their markers (granins, peptides, and membrane proteins). Transfection of a dominant-negative construct of REST induced the appearance of DCVs filled with secretogranin 2 and neuropeptide Y (NPY) and distinct from other organelles. Total internal reflection fluorescence analysis revealed NPY-monomeric red fluorescent protein-labeled DCVs to undergo Ca(2+)-dependent exocytosis, which was largely prevented by botulinum toxin B. In the I-II layers of the human temporal brain cortex, all neurons and microglia exhibited the expected inappreciable and high levels of REST, respectively. In contrast, astrocyte REST was variable, going from inappreciable to high, and accompanied by a variable expression of DCVs. In conclusion, astrocyte DCV expression and gliosecretion are governed by REST. The variable in situ REST levels may contribute to the well known structural/functional heterogeneity of astrocytes. PMID- 21536751 TI - WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways. AB - Activation and disruption of Wnt/beta-catenin signaling both result in cartilage breakdown via unknown mechanisms. Here we show that both WNT-3A and the Wnt inhibitor DKK1 induced de-differentiation of human articular chondrocytes through simultaneous activation of beta-catenin-dependent and independent responses. WNT 3A activates both the beta-catenin-dependent canonical pathway and the Ca(2+)/CaMKII noncanonical pathways, with distinct transcriptional targets. WNT 3A promotes cell proliferation and loss of expression of the chondrocyte markers COL2A1, Aggrecan, and SOX9; however, proliferation and AXIN2 up-regulation are downstream of the canonical pathway and are rescued by DKK1, whereas the loss of differentiation markers is CaMKII dependent. Finally, we showed that in chondrocytes, the Ca(2+)/CaMKII-dependent and beta-catenin-dependent pathways are reciprocally inhibitory, thereby explaining why DKK1 can induce loss of differentiation through de-repression of the CaMKII pathway. We propose a novel model in which a single WNT can simultaneously activate different pathways with distinct and independent outcomes and with reciprocal regulation. This offers an opportunity for selective pharmacological targeting. PMID- 21536753 TI - Site-directed mutagenesis of aldehyde dehydrogenase-2 suggests three distinct pathways of nitroglycerin biotransformation. AB - To elucidate the mechanism underlying reduction of nitroglycerin (GTN) to nitric oxide (NO) by mitochondrial aldehyde dehydrogenase (ALDH2), we generated mutants of the enzyme lacking the cysteines adjacent to reactive Cys302 (C301S and C303S), the glutamate that participates as a general base in aldehyde oxidation (E268Q) or combinations of these residues. The mutants were characterized regarding acetaldehyde dehydrogenation, GTN-triggered enzyme inactivation, GTN denitration, NO formation, and soluble guanylate cyclase activation. Lack of the cysteines did not affect dehydrogenase activity but impeded GTN denitration, aggravated GTN-induced enzyme inactivation, and increased NO formation. A triple mutant lacking the cysteines and Glu268 catalyzed sustained formation of superstoichiometric amounts of NO and exhibited slower rates of inactivation. These results suggest three alternative pathways for the reaction of ALDH2 with GTN, all involving formation of a thionitrate/sulfenyl nitrite intermediate at Cys302 as the initial step. In the first pathway, which predominates in the wild type enzyme and reflects clearance-based GTN denitration, the thionitrate apparently reacts with one of the adjacent cysteine residues to yield nitrite and a protein disulfide. The predominant reaction catalyzed by the single and double cysteine mutants requires Glu268 and results in irreversible enzyme inactivation. Finally, combined lack of the cysteines and Glu268 shifts the reaction toward formation of the free NO radical, presumably through homolytic cleavage of the sulfenyl nitrite intermediate. Although the latter reaction accounts for less than 10% of total turnover of GTN metabolism catalyzed by wild-type ALDH2, it is most likely essential for vascular GTN bioactivation. PMID- 21536752 TI - Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function. AB - Although the C-terminal cytoplasmic tail of the tight junction protein occludin is heavily phosphorylated, the functional impact of most individual sites is undefined. Here, we show that inhibition of CK2-mediated occludin S408 phosphorylation elevates transepithelial resistance by reducing paracellular cation flux. This regulation requires occludin, claudin-1, claudin-2, and ZO-1. S408 dephosphorylation reduces occludin exchange, but increases exchange of ZO-1, claudin-1, and claudin-2, thereby causing the mobile fractions of these proteins to converge. Claudin-4 exchange is not affected. ZO-1 domains that mediate interactions with occludin and claudins are required for increases in claudin-2 exchange, suggesting assembly of a phosphorylation-sensitive protein complex. Consistent with this, binding of claudin-1 and claudin-2, but not claudin-4, to S408A occludin tail is increased relative to S408D. Finally, CK2 inhibition reversed IL-13-induced, claudin-2-dependent barrier loss. Thus, occludin S408 dephosphorylation regulates paracellular permeability by remodeling tight junction protein dynamic behavior and intermolecular interactions between occludin, ZO-1, and select claudins, and may have therapeutic potential in inflammation-associated barrier dysfunction. PMID- 21536754 TI - Inhibition of neuronal voltage-gated sodium channels by brilliant blue G. AB - Brilliant blue G (BBG), best known as an antagonist of P2X7 receptors, was found to inhibit voltage-gated sodium currents in N1E-115 neuroblastoma cells. Sodium currents elicited from a holding potential of -60 mV were blocked with an IC(50) of 2 MUM. Block was enhanced in a use-dependent manner at higher stimulation rates. The voltage-dependence of inactivation was shifted in the hyperpolarizing direction, and recovery from inactivation was slowed by BBG. The most dramatic effect of BBG was to slow recovery from inactivation after long depolarizations, with 3 MUM BBG increasing half-time for recovery (measured at -120 mV) from 24 to 854 ms after a 10-s step to 0 mV. These results were mimicked by a kinetic model in which BBG binds weakly to resting channels (K(d) = 170 MUM) but tightly to fast-inactivated channels (K(d) = 5 MUM) and even more tightly (K(d) = 0.2 MUM) to slow-inactivated channels. In contrast to BBG, the structurally related food coloring dye Brilliant Blue FCF had very little effect at concentrations up to 30 MUM. These results show that BBG inhibits voltage-gated sodium channels at micromolar concentrations. Although BBG inhibition of sodium channels is less potent than inhibition of P2X7 receptors, there may be significant inhibition of sodium channels at BBG concentrations achieved in spinal cord or brain during experimental treatment of spinal cord injury or Huntington's disease. Considered as a sodium channel blocker, BBG is remarkably potent, acting with more than 10 fold greater potency than lacosamide, another blocker thought to bind to slow inactivated channels. PMID- 21536755 TI - Fluorescent labeling of membrane lipid rafts. AB - INTRODUCTION: Lipid rafts are structures within the plasma membrane that have a different lipid composition than the bulk membrane, specifically being enriched in certain lipids. Lipid rafts are believed to have physiologically important functions. Commercially available kits have been developed (Invitrogen/Molecular Probes) for labeling lipid rafts using a cholera toxin subunit that has been fluorescently tagged with one of several Alexa Fluor dyes. As described in this protocol, cells are labeled while in suspension, after which they can be mounted for imaging. PMID- 21536756 TI - Labeling membranes with fluorescent cholesterols. AB - INTRODUCTION: Cholesterol, an essential component of most cellular membranes, is present in the plasma membrane and is enriched within lipid rafts. It is, however, virtually absent from the mitochondrial inner membrane, and there is little within the endoplasmic reticulum. Dehydroergosterol (DHE), a fluorescent cholesterol analog, has been found to effectively label membranes and has been used to monitor cholesterol distribution and trafficking within live cells. Other cholesterol-based probes, such as NBD (N-(7-nitrobenz-2-oxa-1,3-diazole-4-yl)) cholesterol, are commercially available (from Molecular Probes). However, cell labeling using the NBD-cholesterol analogs frequently does not show the same labeling pattern as for DHE and native cholesterol. PMID- 21536757 TI - Labeling membrane glycoproteins or glycolipids with fluorescent wheat germ agglutinin. AB - INTRODUCTION: Glycoprotein and glycolipids are found as part of the outer leaflet of cellular plasma membranes. Those glycoproteins or glycolipids that contain sialic acid and N-acetylglucosamine residues can be labeled with wheat germ agglutinin (WGA), a plant lectin that exists as a dimer (mwt ~36,000) and is normally cationic. Fluorescently labeled WGA is commercially available with fluorescein, Alexa Fluor, or rhodamine moieties. Fluorescent WGA can also be used to stain the Golgi (the trans-Golgi) in fixed cells. Fluorescently labeled concanavalin A (Con A), which selectively binds to alpha-mannopyranosyl and alpha glucopyranosyl residues, can also be used to label plasma membranes. This protocol describes the labeling of membrane glycoproteins or glycolipids with fluorescent WGA. PMID- 21536758 TI - Labeling the plasma membrane with TMA-DPH. AB - INTRODUCTION TMA-DPH (trimethylamine-diphenylhexatriene) is a fluorescent membrane probe that has classically been used to label the outer leaflet of a membrane bilayer, to label the outer leaflet of the plasma membrane in cells, and to report on membrane dynamics using the techniques of fluorescence polarization and/or fluorescence lifetime. This probe has also been used to follow exocytosis and endocytosis of labeled plasma membranes. The interaction of the aqueous environment with mitochondrial inner membrane dynamics has also been studied following the fluorescence polarization and the lifetime of TMA-DPH. This protocol describes the use of TMA-DPH to label the plasma membrane. PMID- 21536759 TI - Labeling membranes with fluorescent phosphatidylethanolamine. AB - INTRODUCTION: The phospholipid phosphatidylethanolamine (PE) can be conjugated via its head group to a number of fluorophores, including rhodamine, BODIPY (boron-dipyrromethene; 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene), and NBD (N-(7 nitrobenz-2-oxa-1,3-diazole-4-yl)). These probes can be used to label biological membranes and to study phospholipids within membranes. Rhodamine-PE, which does not readily exchange between lipid bilayers, has also been used in membrane fusion assays. Rhodamine-DHPE (lissamine rhodamine B 1,2-dihexyldecanoyl-sn glycero-3-phosphoethanolamine, triethylammonium salt) and NBD-PE have been used together in resonance energy transfer studies in membranes. This protocol describes the labeling of membranes with fluorescent PE. PMID- 21536760 TI - Two-photon uncaging microscopy. AB - INTRODUCTION: Two-photon uncaging takes advantage of the inherent optical sectioning power of two-photon excitation to generate highly localized concentration increases of neurotransmitters such as glutamate. This can be used to activate isolated clusters of receptors and, thus, produce maps of receptor densities, or activate intracellular signal transduction under these receptors, in three dimensions and in complex structures such as hippocampal brain slices. Used in combination with two-photon imaging, two-photon uncaging provides a means to study the long-term structural and functional consequences of stimulation of structures such as dendritic spines. This protocol gives an overview of the procedures used for two-photon uncaging microscopy. It includes a detailed description of the development of a microscope that enables effective two-photon release of caged neurotransmitters and provides several examples of its use in cultured and acutely isolated hippocampal neurons. PMID- 21536761 TI - Generation of replication-competent and -defective HSV vectors. AB - INTRODUCTION: Engineering effective vectors has been crucial to the efficient delivery and expression of therapeutic gene products in vivo. Among these, HSV-1 represents an excellent candidate vector for delivery to the peripheral and central nervous systems. The natural biology of HSV-1 includes the establishment of a lifelong latent state in neurons in which the viral genome persists as an episomal molecule. Genomic HSV vectors can be produced that are completely replication-defective, nontoxic, and capable of long-term transgene expression. Herpes simplex virus (HSV) vectors are constructed by using a replication deficient vector backbone (TOZ.1) for homologous recombination with a shuttle plasmid containing a cassette expressing the gene of interest inserted into the UL41 gene sequence. The TOZ.1 vector expresses a reporter gene (lacZ) in the UL41 locus, such that recombination of the transgenic cassette into the UL41 locus results in the loss of the reporter gene activity. The TOZ.1 vector also contains a unique PacI endonuclease site for digestion of parental viral DNA that substantially reduces the nonrecombinant background. Following homologous recombination of the shuttle plasmid into the PacI-digested TOZ.1 genome, the recombinants are identified as clear plaques. After three rounds of limiting dilution analysis, the structure of the recombinants can be confirmed by Southern blot or by polymerase chain reaction (PCR) analysis. PMID- 21536762 TI - Characterization of protein-DNA interactions using protein microarrays. AB - INTRODUCTION: Protein-DNA interactions (PDIs) are critical for many cellular processes. We present here a protocol for the identification of PDIs in vitro using protein microarray technology. The procedure involves double-stranding synthesized DNA oligonucleotides with a fluorescent-labeled primer, binding the labeled double-stranded DNA directly to the protein microarray, and analyzing binding of the resulting PDIs. This approach provides simultaneous identification of PDIs for thousands of proteins, and multiple carefully designed DNA probes can be tested in parallel, which enables a rapid mapping of PDIs on a proteome-wide scale. PMID- 21536763 TI - Dissection of embryonic mouse kidney, culture in vitro, and imaging of the developing organ. AB - INTRODUCTION: In this article, we outline procedures for the dissection of intact kidneys and the isolation of the ureteric bud (UB) and the metanephric mesenchyme (MM) from mouse embryos. The apparatus required for the culture of these tissues in vitro is described in detail as well as the equipment necessary for performing time-lapse imaging studies of the developing kidney. PMID- 21536764 TI - Improved protocol for efficient nonviral transfection of premature THP-1 macrophages. AB - INTRODUCTION: The human monocytic leukemia cell line THP-1 is a widely used model for investigating monocyte and macrophage biology. Successful transfection of THP 1 monocytes with subsequent phorbol 12-myristate 13-acetate (PMA)-induced differentiation into macrophages is not a trivial matter, because according to previous transfection protocols, cell viability is lost almost completely within 24 h of PMA treatment following transfection. This protocol constitutes an optimized version of a previously published protocol by our group. It describes a procedure for transfecting premature THP-1 macrophages, which subsequently can be further differentiated into mature macrophages by PMA without a loss of cell viability. Transfection of THP-1 cells with plasmids or small interfering RNA (siRNA) is achieved by electroporation using the Lonza Nucleofector technology (Basel, Switzerland). This technique allows for the efficient nonviral delivery of plasmids, DNA, RNA, or siRNA into primary cells or cell lines even if the cells are not or are only slowly proliferating. Such cells are usually rather difficult to transfect by nonviral approaches. This means that only viral approaches would be left, which are expensive and labor-intensive and require laboratories complying with the respective safety regulations. The protocol described here is an efficient and convenient alternative. PMID- 21536765 TI - Affinity purification of protein complexes. AB - INTRODUCTION: Knowledge of the composition of protein complexes provides key insights into their functions. Immunoaffinity purification provides an effective means for isolating protein complexes and elucidating their composition. Immunoisolation is achieved with antibodies directed either specifically against the proteins of interest or against tags that are coupled to the proteins of interest. This approach uses immunoaffinity purification on magnetic beads coated with antibodies for the rapid and efficient purification of protein complexes from cells or tissues. This protocol describes affinity purification of protein complexes using conjugated magnetic beads. PMID- 21536766 TI - Conjugation of magnetic beads for immunopurification of protein complexes. AB - INTRODUCTION: Knowledge of the composition of protein complexes provides key insights into their functions. Immunoaffinity purification provides an effective means for isolating protein complexes and elucidating their composition. Immunoisolation is achieved with antibodies directed either specifically against the proteins of interest or against tags that are coupled to the proteins of interest. This approach uses immunoaffinity purification on magnetic beads coated with antibodies for the rapid and efficient purification of protein complexes from cells or tissues. This protocol describes conjugation of magnetic beads with antibodies in preparation for immunopreciptation of protein complexes. PMID- 21536767 TI - Drosophila appetitive olfactory conditioning. AB - INTRODUCTION: Olfactory memory paradigms have been extensively used to study memory in Drosophila since the late 1960s, and over the intervening years, investigators have made a series of worthwhile changes and "tweaks" to the procedures. This protocol provides the reader with a detailed description of the appetitive (odor-sugar) memory assay currently used in the Waddell laboratory. We also describe the essential control assays for sensory acuity and locomotor behavior. It should be emphasized that the assays we describe work adequately in our laboratory, but are also amenable to, and may be further improved by additional adjustments. PMID- 21536768 TI - Drosophila aversive olfactory conditioning. AB - INTRODUCTION: Olfactory memory paradigms have been extensively used to study memory in Drosophila since the late 1960s, and over the intervening years investigators have made a series of worthwhile changes and "tweaks" to the procedures. This protocol provides the reader with a detailed description of the aversive (odor-shock) memory assay currently used in the Waddell laboratory. It also describes the essential control assays for sensory acuity and locomotor behavior. It should be emphasized that the assays we describe work adequately in our laboratory but are also amenable to, and may be further improved, by additional adjustments. PMID- 21536769 TI - Isolation of human capillary endothelial cells from abdominal adipose tissue. AB - INTRODUCTION: This protocol outlines a technique to isolate human capillary endothelial cells from human abdominal wall adipose tissue. The relative lack of cell-type complexity within fat tissue makes it an attractive source of endothelial cells. In addition, collaboration with a local plastic surgeon can yield significant quantities of subcutaneous adipose tissue from liposuction without the need to be on call for cadaveric or post-surgical samples. PMID- 21536770 TI - Isolation of human capillary endothelial cells using paramagnetic beads conjugated to anti-PECAM antibodies. AB - INTRODUCTION: The protocol described below outlines a technique to isolate and maintain pure populations of human capillary endothelial cells using an active selection technique that targets the platelet endothelial cell adhesion molecule (PECAM or CD31). Human abdominal wall adipose tissue is used as the source for capillary endothelial cells, which are partially purified before selection. PMID- 21536771 TI - Two-photon mapping of neural circuits. AB - INTRODUCTION: For the study of neural circuits, it would be ideal to be able to discern in a living preparation the interconnections among neurons. Working toward that aim, we have developed a method, using two-photon uncaging of glutamate in brain slices, by which we can detect neurons that are presynaptic to any particular cell. The method, described here, has single-cell resolution and can be applied systematically and quickly to test entire populations of neurons, making it possible to perform online functional analysis of connectivity. PMID- 21536772 TI - Analysis of Affymetrix ChIP-chip data using starr and R/Bioconductor. AB - INTRODUCTION: This article provides a flexible workflow for the analysis of chromatin immunoprecipitation data (ChIP-chip) that covers issues from quality control, probe sequence remapping, data preprocessing/normalization, visualization, and high-level analysis like peak finding. It emphasizes the peculiarities of single-color Affymetrix arrays, but it is flexible enough to be also amenable to other array platforms. The article is accompanied by extensive code implementing each of the analysis steps. PMID- 21536773 TI - Imaging kidney development. AB - INTRODUCTION: Development of the kidney involves interactions between several cell lineages and complex morphogenetic processes, such as branching of the ureteric bud (UB) to form the collecting duct system and condensation and differentiation of the mesenchymal progenitors to form the nephron epithelia. One of the advantages of the mouse kidney as an experimental system is that it can develop in culture, from the stage of initial branching of the UB (E11.5) for up to a week (although it achieves the size and degree of development of only an E13.5-E14.5 kidney in vivo). The availability of fluorescent proteins (FPs) has provided powerful tools for visualizing the morphogenesis of specific renal structures in organ cultures. Two categories of genetically modified mice that express FPs are useful for visualizing different cell lineages and developmental processes in these organ cultures: (1) transgenic mice that express a fluorescent reporter in the pattern of a specific gene; and (2) Cre reporter mice, which turn on an FP in cells with Cre recombinase activity (and their daughter cells), used in conjunction with cell type-specific Cre transgenic mice. Here, we describe some of the currently available Cre and FP transgenic lines that are useful for the study of kidney development. PMID- 21536774 TI - Fluorescent speckle microscopy. AB - INTRODUCTION: Fluorescent speckle microscopy (FSM) is a live imaging and quantitative measurement technique used for analyzing motion and turnover of macromolecular assemblies in vivo and in vitro. It differs from related imaging techniques such as photobleaching and photoactivation in its use of substantially lower concentrations of fluorescently labeled assembly subunits. When small numbers of labeled subunits and large numbers of unlabeled subunits become randomly incorporated together into a macromolecular structure, the random distribution of fluorophores generates nonuniform fluorescence intensity patterns that appear as distinct puncta against low background fluorescence. These puncta, called speckles, serve as fiduciary markers so that motion and turnover of the structure are visualized. Computational analysis of speckle image data transforms FSM into a powerful tool for high-resolution quantitative analysis of macromolecular assembly dynamics. Successful application of FSM depends on the ability to reliably generate and image speckles, which are characterized by their weak emission signals, and to effectively extract quantitative information through computational analysis of speckle image data, which are characterized by their stochastic fluctuations, low signal-to-noise ratios, and high spatiotemporal complexity. This article aims to provide a practical introduction to basic principles, experimental implementation, and computational data analysis of FSM. Examples are used to show the application of FSM in analyzing the dynamic organization and assembly/disassembly of cytoskeletal filament networks, an area in which FSM analysis has found great success. PMID- 21536775 TI - The preparticipation sports evaluation. PMID- 21536776 TI - Infant formulas. PMID- 21536777 TI - Addressing environmental contaminants in pediatric practice. PMID- 21536778 TI - Complementary, holistic, and integrative medicine: mind-body medicine. PMID- 21536779 TI - Just distribution of health-care resources and the neonatal ICU. PMID- 21536781 TI - Case 1: abdominal pain and coffee ground emesis in a 9-year-old boy. Case 2: vomiting, headache, and seizures in a 7-year-old boy. Case 3: primary amenorrhea in a 15-year-old girl. PMID- 21536782 TI - Sore throat and difficulty swallowing in a 9-year-old boy. PMID- 21536783 TI - Histiocytosis. PMID- 21536784 TI - Abnormal relationship between medial temporal lobe and subcortical dopamine function in people with an ultra high risk for psychosis. AB - BACKGROUND: Neuroimaging studies in humans have implicated both dysfunction of the medial temporal lobe (MTL) and the dopamine system in psychosis, but the relationship between them is unclear. We addressed this issue by measuring MTL activation and striatal dopaminergic function in individuals with an At Risk Mental State (ARMS) for psychosis, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), respectively. METHODS: Thirty-four subjects (20 ARMS and 14 Controls), matched for age, gender, digit span performance, and premorbid IQ, were scanned using fMRI, while performing a verbal encoding and recognition task, and using 18F-DOPA PET. All participants were naive to antipsychotic medication. RESULTS: ARMS subjects showed reduced MTL activation when encoding words and made more false alarm responses for Novel words than controls. The relationship between striatal dopamine function and MTL activation during both verbal encoding and verbal recognition was significantly different in ARMS subjects compared with controls. CONCLUSION: An altered relationship between MTL function and dopamine storage/synthesis capacity exists in the ARMS and may be related to psychosis vulnerability. PMID- 21536785 TI - X-ray magnetic resonance fusion to internal markers and utility in congenital heart disease catheterization. AB - BACKGROUND: X-ray magnetic resonance fusion (XMRF) allows for use of 3D data during cardiac catheterization. However, to date, technical requirements have limited the use of this modality in clinical practice. We report on a new internal-marker XMRF method that we have developed and describe how we used XMRF during cardiac catheterization in congenital heart disease. METHODS AND RESULTS: XMRF was performed in a phantom and in 23 patients presenting for cardiac catheterization who also needed cardiac MRI for clinical reasons. The registration process was performed in < 5 minutes per patient, with minimal radiation (0.004 to 0.024 mSv) and without contrast. Registration error was calculated in a phantom and in 8 patients using the maximum distance between angiographic and 3D model boundaries. In the phantom, the measured error in the anteroposterior projection had a mean of 1.15 mm (standard deviation, 0.73). The measured error in patients had a median of 2.15 mm (interquartile range, 1.65 to 2.56 mm). Internal markers included bones, airway, image artifact, calcifications, and the heart and vessel borders. The MRI data were used for road mapping in 17 of 23 (74%) cases and camera angle selection in 11 of 23 (48%) cases. CONCLUSIONS: Internal marker-based registration can be performed quickly, with minimal radiation, without the need for contrast, and with clinically acceptable accuracy using commercially available software. We have also demonstrated several potential uses for XMRF in routine clinical practice. This modality has the potential to reduce radiation exposure and improve catheterization outcomes. PMID- 21536786 TI - Marital abuse and psychological well-being among women in the southern region of Jordan. AB - PURPOSE: The purpose of this study was to examine the relationship between marital abuse and psychological well-being among women in the southern region of Jordan. DESIGN: A descriptive correlational design was used to collect data from a randomly selected sample of 915 women in the southern region of Jordan. Data collected were related to forms of marital abuse and six domains of psychological well-being. RESULTS: The analysis showed that women have moderate to high level of psychological well-being. The prevalence of ever being abused during the past 12 months ranged from 3.2% (n = 25) for being threatened with a knife to 45.1% (n = 348) for their husbands being unconcerned about them while they were sick. There were significant differences in marital abuse related to having ever had school education (chi(2) = 8.56, df = 2, p = .014). All forms of marital abuse were highly correlated (p < .01). Self-acceptance and environmental mastery domains of psychological well-being had negative and significant correlation with all forms of marital abuse (p < .01). DISCUSSION OF CONCLUSION: Health professionals in health care centers need to assess for marital abuse and its consequence on women's health. Interventions should emphasize promotion of psychological well-being and the factors that influence women empowerment. PMID- 21536787 TI - The impact of cancer on family relationships among Chinese patients. AB - This study examines the impact of cancer on family relationships among members of a Chinese cancer support group. A qualitative research design was used, including participant observation of 96 participants at group meetings over an 8-month period and in-depth interviews with seven group members. Findings indicated that family members were integral to the support group, constituting almost 40% of the participants. Patients in the group expressed concerns about family, with family members identified as having "equal suffering" when caring for patients. Notably, among both patients and family members, there was a strong emphasis on the need to conceal emotion, coupled with a focus on instrumental support in caregiving. Furthermore, patients' anxiety about "burdening" their family appeared to inflate their own experience of distress, as patients and their family carers both sought to maintain a positive front. The findings highlight the need for practitioners to focus on the entire family when designing interventions to help patients cope with cancer. More important, interventions need to be culturally sensitive that will empower patients and family members in living with the illness. PMID- 21536788 TI - Trimeric autotransporter adhesin-dependent adherence of Bartonella henselae, Bartonella quintana, and Yersinia enterocolitica to matrix components and endothelial cells under static and dynamic flow conditions. AB - Trimeric autotransporter adhesins (TAAs) are important virulence factors of Gram negative bacteria responsible for adherence to extracellular matrix (ECM) and host cells. Here, we analyzed three different TAAs (Bartonella adhesin A [BadA] of Bartonella henselae, variably expressed outer membrane proteins [Vomps] of Bartonella quintana, and Yersinia adhesin A [YadA] of Yersinia enterocolitica) for mediating bacterial adherence to ECM and endothelial cells. Using static (cell culture vials) and dynamic (capillary flow chambers) experimental settings, adherence of wild-type bacteria and of the respective TAA-negative strains was analyzed. Under static conditions, ECM adherence of B. henselae, B. quintana, and Y. enterocolitica was strongly dependent on the expression of their particular TAAs. YadA of Y. enterocolitica did not mediate bacterial binding to plasma or cellular fibronectin under either static or dynamic conditions. TAA-dependent host cell adherence appeared more significant under dynamic conditions although the total number of bound bacteria was diminished compared to the number under static conditions. Dynamic models expand the methodology to perform bacterial adherence experiments under more realistic, bloodstream-like conditions and allow dissection of the biological role of TAAs in ECM and host cell adherence under static and dynamic conditions. PMID- 21536789 TI - Anaplasma phagocytophilum infects mast cells via alpha1,3-fucosylated but not sialylated glycans and inhibits IgE-mediated cytokine production and histamine release. AB - Mast cells are sentinels for infection. Upon exposure to pathogens, they release their stores of proinflammatory cytokines, chemokines, and histamine. Mast cells are also important for the control of certain tick-borne infections. Anaplasma phagocytophilum is an obligate intracellular tick-transmitted bacterium that infects neutrophils to cause the emerging disease granulocytic anaplasmosis. A. phagocytophilum adhesion to and infection of neutrophils depend on sialylated and alpha1,3-fucosylated glycans. We investigated the hypotheses that A. phagocytophilum invades mast cells and inhibits mast cell activation. We demonstrate that A. phagocytophilum binds and/or infects murine bone marrow derived mast cells (BMMCs), murine peritoneal mast cells, and human skin-derived mast cells. A. phagocytophilum infection of BMMCs depends on alpha1,3 fucosylated, but not sialylated, glycans. A. phagocytophilum binding to and invasion of BMMCs do not elicit proinflammatory cytokine secretion. Moreover, A. phagocytophilum-infected cells are inhibited in the release of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-13, and histamine following stimulation with IgE or antigen. Thus, A. phagocytophilum mitigates mast cell activation. These findings potentially represent a novel means by which A. phagocytophilum usurps host defense mechanisms and shed light on the interplay between mast cells and vector-borne bacterial pathogens. PMID- 21536790 TI - The nasal dendritic cell-targeting Flt3 ligand as a safe adjuvant elicits effective protection against fatal pneumococcal pneumonia. AB - We have previously shown that a pneumococcal surface protein A (PspA)-based vaccine containing DNA plasmid encoding the Flt3 ligand (FL) gene (pFL) as a nasal adjuvant prevented nasal carriage of Streptococcus pneumoniae. In this study, we further investigated the safety and efficacy of this nasal vaccine for the induction of PspA-specific antibody (Ab) responses against lung infection with S. pneumoniae. C57BL/6 mice were nasally immunized with recombinant PspA/Rx1 (rPspA) plus pFL three times at weekly intervals. When dynamic translocation of pFL was initially examined, nasal pFL was taken up by nasal dendritic cells (DCs) and epithelial cells (nECs) but not in the central nervous systems, including olfactory nerve and epithelium. Of importance, nasal pFL induced FL protein synthesis with minimum levels of inflammatory cytokines in the nasal washes (NWs) and bronchoalveolar lavage fluid (BALF). NWs and BALF as well as plasma of mice given nasal rPspA plus pFL contained increased levels of rPspA-specific secretory IgA and IgG Ab responses that were correlated with elevated numbers of CD8(+) and CD11b(+) DCs and interleukin 2 (IL-2)- and IL-4-producing CD4(+) T cells in the nasal mucosa-associated lymphoid tissues (NALT) and cervical lymph nodes (CLNs). The in vivo protection by rPspA-specific Abs was evident in markedly reduced numbers of CFU in the lungs, airway secretions, and blood when mice were nasally challenged with Streptococcus pneumoniae WU2. Our findings show that nasal pFL is a safe and effective mucosal adjuvant for the enhancement of bacterial antigen (Ag) (rPspA)-specific protective immunity through DC-induced Th2-type and IL-2 cytokine responses. PMID- 21536791 TI - Enhancement of neutrophil function by interleukin-18 therapy protects burn injured mice from methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) infection is a grave concern in burn-injured patients. We investigated the efficacy of interleukin-18 (IL-18) treatment in postburn MRSA infection. Alternate-day injections of IL-18 into burn injured C57BL/6 mice significantly increased their survival after MRSA infection and after methicillin-sensitive S. aureus infection. Although IL-18 treatment of burn-injured mice augmented natural IgM production before MRSA infection and gamma interferon (IFN-gamma) production after MRSA infection, neither IgM nor IFN gamma significantly contributed to the improvement in mouse survival. IL-18 treatment increased/restored the serum tumor necrosis factor (TNF), IL-17, IL-23, granulocyte colony-stimulating factor (G-CSF), and macrophage inflammatory protein (MIP-2) levels, as well as the neutrophil count, after MRSA infection of burn-injured mice; it also improved impaired neutrophil functions, phagocytic activity, production of reactive oxygen species, and MRSA-killing activity. However, IL-18 treatment was ineffective against MRSA infection in both burn- and sham-injured neutropenic mice. Enhancement of neutrophil functions by IL-18 was also observed in vitro. Furthermore, when neutrophils from IL-18-treated burn injured mice were adoptively transferred into nontreated burn-injured mice 2 days after MRSA challenge, survival of the recipient mice increased. NOD-SCID mice that have functionally intact neutrophils and macrophages (but not T, B, or NK cells) were substantially resistant to MRSA infection. IL-18 treatment increased the survival of NOD-SCID mice after burn injury and MRSA infection. An adoptive transfer of neutrophils using NOD-SCID mice also showed a beneficial effect of IL 18-activated neutrophils, similar to that seen in C57BL/6 mice. Thus, although neutrophil functions were impaired in burn-injured mice, IL-18 therapy markedly activated neutrophil functions, thereby increasing survival from postburn MRSA infection. PMID- 21536792 TI - Fusobacterium nucleatum infection of colonic cells stimulates MUC2 mucin and tumor necrosis factor alpha. AB - The etiology of inflammatory bowel disease is not completely known, but it is influenced by the presence of normal gut microflora as well as yet-unrecognized pathogens. The anaerobic, Gram-negative bacterial species Fusobacterium nucleatum is a common resident of the human mouth and gut and varies in its pathogenic potential. In this study, we demonstrate that highly invasive F. nucleatum isolates derived from the inflamed guts of Crohn's disease patients evoked significantly greater MUC2 and tumor necrosis factor alpha (TNF-alpha) gene expression than minimally invasive strains isolated from the noninflamed gut in human colonic epithelial cells and in a rat ligated colonic loop model of infection. Only live F. nucleatum induced mucin secretion and TNF-alpha expression in direct contact with and/or during invasion of colonic cells. In rat colons, mucin secretion was augmented in response to a highly invasive F. nucleatum isolate but was unaffected by treatment with a minimally invasive strain. Taken together, these studies reveal that F. nucleatum may represent a challenging pathogen in the etiology of gut inflammatory diseases and highlight the importance of different pathotypes of candidate bacterial species in disease pathogenesis. PMID- 21536793 TI - Porphyromonas gingivalis induction of microRNA-203 expression controls suppressor of cytokine signaling 3 in gingival epithelial cells. AB - Porphyromonas gingivalis is a pathogen in severe periodontal disease. Able to exploit an intracellular lifestyle within primary gingival epithelial cells (GECs), a reservoir of P. gingivalis can persist within the gingival epithelia. This process is facilitated by manipulation of the host cell signal transduction cascades which can impact cell cycle, cell death, and cytokine responses. Using microarrays, we investigated the ability of P. gingivalis 33277 to regulate microRNA (miRNA) expression in GECs. One of several miRNAs differentially regulated by GECs in the presence of P. gingivalis was miRNA-203 (miR-203), which was upregulated 4-fold compared to uninfected controls. Differential regulation of miR-203 was confirmed by quantitative reverse transcription-PCR (qRT-PCR). Putative targets of miR-203, suppressor of cytokine signaling 3 (SOCS3) and SOCS6, were evaluated by qRT-PCR. SOCS3 and SOCS6 mRNA levels were reduced >5 fold and >2-fold, respectively, in P. gingivalis-infected GECs compared to controls. Silencing of miR-203 using a small interfering RNA construct reversed the inhibition of SOCS3 expression. A dual luciferase assay confirmed binding of miR-203 to the putative target binding site of the SOCS3 3' untranslated region. Western blot analysis demonstrated that activation of signal transducer and activator of transcription 3 (Stat3), a downstream target of SOCS, was diminished following miR-203 silencing. This study shows that induction of miRNAs by P. gingivalis can modulate important host signaling responses. PMID- 21536794 TI - Immunomodulatory and protective roles of quorum-sensing signaling molecules N acyl homoserine lactones during infection of mice with Aeromonas hydrophila. AB - Aeromonas hydrophila leads to both intestinal and extraintestinal infections in animals and humans, and the underlying mechanisms leading to mortality are largely unknown. By using a septicemic mouse model of infection, we showed that animals challenged with A. hydrophila die because of kidney and liver damage, hypoglycemia, and thrombocytopenia. Pretreatment of animals with quorum-sensing associated signaling molecules N-acyl homoserine lactones (AHLs), such as butanoyl and hexanoyl homoserine lactones (C(4)- and C(6)-HSLs), as well as N-3 oxododecanoyl (3-oxo-C(12))-HSL, prevented clinical sequelae, resulting in increased survivability of mice. Since little is known as to how different AHLs modulate the immune response during infection, we treated mice with the above AHLs prior to lethal A. hydrophila infection. When we compared results in such animals to those in controls, the treated animals exhibited a significantly reduced bacterial load in the blood and other mouse organs, as well as various levels of cytokines/chemokines. Importantly, neutrophil numbers were significantly elevated in the blood of C(6)-HSL-treated mice compared to those in animals given phosphate-buffered saline and then infected with the bacteria. These findings coincided with the fact that neutropenic animals were more susceptible to A. hydrophila infection than normal mice. Our data suggested that neutrophils quickly cleared bacteria by either phagocytosis or possibly another mechanism(s) during infection. In a parallel study, we indeed showed that other predominant immune cells inflicted during A. hydrophila infections, such as murine macrophages, when they were pretreated with AHLs, rapidly phagocytosed bacteria, whereas untreated cells phagocytosed fewer bacteria. This study is the first to report that AHL pretreatment modulates the innate immune response in mice and enhances their survivability during A. hydrophila infection. PMID- 21536795 TI - Spermidine synthase is required for virulence of Leishmania donovani. AB - Genetic lesions in the polyamine biosynthetic pathway of Leishmania donovani, the causal agent of visceral leishmaniasis, are conditionally lethal mutations that render the insect vector form of the parasite auxotrophic for polyamines. Recently, we have demonstrated that a Deltaodc L. donovani null mutant lacking ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was profoundly compromised in its ability to infect mice, indicating that ODC is essential for the infectious mammalian stage of the parasite and further validating the enzyme as a possible drug target. To assess whether other components of the polyamine biosynthetic pathway were also essential for parasite virulence, a cell line deficient in spermidine synthase (SPDSYN), the enzyme that converts putrescine to spermidine, was created by double-targeted gene replacement within a virulent L. donovani background. This Deltaspdsyn strain was auxotrophic for polyamines, required spermidine for growth in its insect vector form, and was adversely impacted in its ability to infect mice. These findings establish that SPDSYN, like ODC, is essential for maintaining a robust infection in mammals and indicate that pharmacologic inhibition of SPDSYN, and perhaps all components of the polyamine biosynthetic pathway, is a valid therapeutic strategy for the treatment of visceral and, potentially, other forms of leishmaniasis. PMID- 21536796 TI - Burkholderia cenocepacia phenotypic clonal variation during a 3.5-year colonization in the lungs of a cystic fibrosis patient. AB - Chronic lung infection is the major cause of morbidity and premature mortality in cystic fibrosis (CF) patients. Bacteria of the Burkholderia cepacia complex are the most threatening pathogens in CF, and a better understanding of how these bacteria adapt to the CF airway environment and resist the host defense mechanisms and therapeutically administered antibiotics is crucial. To provide clues to the adaptive strategies adopted by Burkholderia cenocepacia during long term colonization, we carried out a phenotypic assessment of 11 clonal variants obtained at the major Portuguese CF Center in Lisbon from sputa of the same CF patient during 3.5 years of colonization of the lungs, until the patient's death with cepacia syndrome. Phenotypic characterization included susceptibility assays against different classes of antimicrobials and characterization of cell motility, cell hydrophobicity and zeta potential, colony and cell morphology, fatty acid composition, growth under iron limitation/load conditions, exopolysaccharide production, and size of the biofilms formed. The results suggest the occurrence of clonal expansion during long-term colonization. For a number of the characteristics tested, no isolation time-dependent consistent alteration pattern could be identified. However, the values for antimicrobial susceptibility and swarming motility for the first B. cenocepacia isolate, thought to have initiated the infection, were consistently above those for the clonal variants obtained during the course of infection, and the opposite was found for the zeta potential. The adaptive strategy for long-term colonization, described here for the first time, involved the alteration of membrane fatty acid composition, in particular a reduction of the degree of fatty acid saturation, in the B. cenocepacia variants retrieved, along with the deterioration of pulmonary function and severe oxygen limitation. PMID- 21536797 TI - Iron-regulated lysis of recombinant Escherichia coli in host releases protective antigen and confers biological containment. AB - The use of a recombinant bacterial vector vaccine is an attractive vaccination strategy to induce an immune response to a carried protective antigen. The superiorities of live bacterial vectors include mimicry of a natural infection, intrinsic adjuvant properties, and the potential for administration by mucosal routes. Escherichia coli is a simple and efficient vector system for production of exogenous proteins. In addition, many strains are nonpathogenic and avirulent, making it a good candidate for use in recombinant vaccine design. In this study, we screened 23 different iron-regulated promoters in an E. coli BL21(DE3) vector and found one, P(viuB), with characteristics suitable for our use. We fused P(viuB) with lysis gene E, establishing an in vivo inducible lysis circuit. The resulting in vivo lysis circuit was introduced into a strain also carrying an IPTG (isopropyl-beta-d-thiogalactopyranoside)-inducible P(T7)-controlled protein synthesis circuit, forming a novel E. coli-based protein delivery system. The recombinant E. coli produced a large amount of antigen in vitro and could deliver the antigen into zebrafish after vaccination via injection. The strain subsequently lysed in response to the iron-limiting signal in vivo, implementing antigen release and biological containment. The gapA gene, encoding the protective antigen GAPDH (glyceraldehyde-3-phosphate dehydrogenase) from the fish pathogen Aeromonas hydrophila LSA34, was introduced into the E. coli-based protein delivery system, and the resultant recombinant vector vaccine was evaluated in turbot (Scophtalmus maximus). Over 80% of the vaccinated fish survived challenge with A. hydrophila LSA34, suggesting that the E. coli-based antigen delivery system has great potential in bacterial vector vaccine applications. PMID- 21536798 TI - SlyA is a transcriptional regulator involved in the virulence of Enterococcus faecalis. AB - Phylogenetic analysis of the crystal structure of the Enterococcus faecalis SlyA (EF_3002) transcriptional factor places it between the SlyA and MarR regulator subfamilies. Proteins of these families are often involved in the regulation of genes important for bacterial virulence and stress response. To gather evidence for the role of this putative regulator in E. faecalis biology, we dissected the genetic organization of the slyA-EF_3001 locus and constructed a slyA deletion mutant as well as complemented strains. Interestingly, compared to the wild-type parent, the DeltaslyA mutant is more virulent in an insect infection model (Galleria mellonella), exhibits increased persistence in mouse kidneys and liver, and survives better inside peritoneal macrophages. In order to identify a possible SlyA regulon, global microarray transcriptional analysis was performed. This study revealed that the slyA-EF_3001 locus appears to be autoregulated and that 117 genes were differentially regulated in the DeltaslyA mutant. In the mutant strain, 111 were underexpressed and 6 overexpressed, indicating that SlyA functions mainly as an activator of transcription. PMID- 21536799 TI - Tumor necrosis factor alpha production from CD8+ T cells mediates oviduct pathological sequelae following primary genital Chlamydia muridarum infection. AB - The immunopathogenesis of Chlamydia trachomatis-induced oviduct pathological sequelae is not well understood. Mice genetically deficient in perforin (perforin(-/-) mice) or tumor necrosis factor alpha (TNF-alpha) production (TNF alpha(-/-) mice) displayed comparable vaginal chlamydial clearance rates but significantly reduced oviduct pathology (hydrosalpinx) compared to that of wild type mice. Since both perforin and TNF-alpha are effector mechanisms of CD8(+) T cells, we evaluated the role of CD8(+) T cells during genital Chlamydia muridarum infection and oviduct sequelae. Following vaginal chlamydial challenge, (i) mice deficient in TAP I (and therefore the major histocompatibility complex [MHC] I pathway and CD8(+) T cells), (ii) wild-type mice depleted of CD8(+) T cells, and (iii) mice genetically deficient in CD8 (CD8(-/-) mice) all displayed similar levels of vaginal chlamydial clearance but significantly reduced hydrosalpinx, compared to those of wild-type C57BL/6 mice, suggesting a role for CD8(+) T cells in chlamydial pathogenesis. Repletion of CD8(-/-) mice with wild-type or perforin(-/-), but not TNF-alpha(-/-), CD8(+) T cells at the time of challenge restored hydrosalpinx to levels observed in wild-type C57BL/6 mice, suggesting that TNF-alpha production from CD8(+) T cells is important for pathogenesis. Additionally, repletion of TNF-alpha(-/-) mice with TNF-alpha(+/+) CD8(+) T cells significantly enhanced the incidence of hydrosalpinx and oviduct dilatation compared to those of TNF-alpha(-/-) mice but not to the levels found in wild-type mice, suggesting that TNF-alpha production from CD8(+) T cells and non-CD8(+) cells cooperates to induce optimal oviduct pathology following genital chlamydial infection. These results provide compelling new evidence supporting the contribution of CD8(+) T cells and TNF-alpha production to Chlamydia-induced reproductive tract sequelae. PMID- 21536800 TI - Synergistic inhibition of enterovirus 71 replication by interferon and rupintrivir. AB - BACKGROUND: Enterovirus 71 (EV71) can cause severe diseases and even lead to death in children. There is no vaccine or specific antiviral therapy to prevent or cure EV71 infection. Although interferon (IFN)-alpha has been used in the treatment of several viral infections, we found that IFN-alpha alone was ineffective in restricting EV71 replication in Vero cells. METHODS: Through a bioinformatics analysis, several cellular proteins in the IFN response pathway were identified as susceptible substrates that might be degraded by the EV71 encoded 3C protease (3C(pro)). RESULTS: Indeed, IRF9 was shown to be vulnerable to 3C(pro) cleavage, as revealed by enzyme-based and cell-based assays. Thus, the IFN-mediated antiviral mechanism compromised by the viral 3C(pro) in EV71 infected cells may be accountable, at least partially, for that IFN-alpha cannot inhibit EV71 replication. Because rupintrivir (AG7088) is known to be an effective EV71 inhibitor, we investigated the effects of the combination of rupintrivir and IFN-alpha on EV71 replication and found that they strongly synergized with each other in inhibiting EV71 replication. CONCLUSIONS: Because rupintrivir was shown to be generally tolerable in earlier clinical investigations, it is worth evaluating whether a combination of rupintrivir and IFN-alpha could be an effective treatment for EV71. PMID- 21536801 TI - CD300F blocks both MyD88 and TRIF-mediated TLR signaling through activation of Src homology region 2 domain-containing phosphatase 1. AB - CD300F is known to exhibit inhibitory activity in myeloid cells through its intracellular ITIM. To investigate the effect of CD300F stimulation on TLR signaling, the human acute monocytic leukemia cell line THP-1 was treated with CD300F-specific mAbs or two synthetic peptides that represented the ITIM-like domains of CD300F. Treatment with these agents blocked TLR2-, 3-, 4-, and 9 mediated expression of proinflammatory mediators such as IL-8 and matrix metalloproteinase-9. The luciferase reporter assay in 293T cells and Western blot analysis of THP-1 cells revealed that these inhibitory actions were effective in pathways involving MyD88 and/or TRIF of TLR signaling and associated with marked suppression of IkappaB kinase activation, phosphorylation/degradation of IkappaB, and subsequent activation of NF-kappaB. Use of specific inhibitors and immunoprecipitation analysis further indicated that the inhibitory effects were mediated by Src homology 2 domain-containing phosphatase-1, a protein tyrosine phosphatase with inhibitory activity in hematopoietic cells. These data indicate that CD300F is an active regulator of TLR-mediated macrophage activation through its association with Src homology 2 domain-containing phosphatase-1 and that the synthetic peptides can be applied for the regulation of immune responses that are induced by TLRs. PMID- 21536803 TI - Cutting edge: Identification of a motile IL-17-producing gammadelta T cell population in the dermis. AB - Dendritic epidermal T cells (DETCs) are a well-studied population of gammadelta T cells that play important roles in wound repair. In this study, we characterize a second major population of gammadelta T cells in the skin that is present in the dermis. In contrast to DETCs, these Vgamma5-negative cells are IL-7R(hi)CCR6(hi) retinoic acid-related orphan receptor gammat(+) and are precommitted to IL-17 production. Dermal gammadelta T cells fail to reconstitute following irradiation and bone marrow transplantation unless the mice also receive a transfer of neonatal thymocytes. Real-time intravital imaging of CXCR6(GFP/+) mouse skin reveals dermal gammadelta T cells migrate at ~4 MUm/min, whereas DETCs are immobile. Like their counterparts in peripheral lymph nodes, dermal gammadelta T cells rapidly produce IL-17 following exposure to IL-1beta plus IL-23. We have characterized a major population of skin gammadelta T cells and propose that these cells are a key source of IL-17 in the early hours after skin infection. PMID- 21536802 TI - Effect of MHC class I diversification on influenza epitope-specific CD8+ T cell precursor frequency and subsequent effector function. AB - Earlier studies of influenza-specific CD8(+) T cell immunodominance hierarchies indicated that expression of the H2K(k) MHC class I allele greatly diminishes responses to the H2D(b)-restriced D(b)PA(224) epitope (acid polymerase, residues 224-233 complexed with H2D(b)). The results suggested that the presence of H2K(k) during thymic differentiation led to the deletion of a prominent Vbeta7(+) subset of D(b)PA(224)-specific TCRs. The more recent definition of D(b)PA(224)-specific TCR CDR3beta repertoires in H2(b) mice provides a new baseline for looking again at this possible H2K(k) effect on D(b)PA(224)-specific TCR selection. We found that immune responses to several H2D(b)- and H2K(b)-restricted influenza epitopes were indeed diminished in H2(bxk) F(1) versus homozygous mice. In the case of D(b)PA(224), lower numbers of naive precursors were part of the explanation, though a similar decrease in those specific for the D(b)NP(366) epitope did not affect response magnitude. Changes in precursor frequency were not associated with any major loss of TCR diversity and could not fully account for the diminished D(b)PA(224)-specific response. Further functional and phenotypic characterization of influenza-specific CD8(+) T cells suggested that the expansion and differentiation of the D(b)PA(224)-specific set is impaired in the H2(bxk) F(1) environment. Thus, the D(b)PA(224) response in H2(bxk) F(1) mice is modulated by factors that affect the generation of naive epitope-specific precursors and the expansion and differentiation of these T cells during infection, rather than clonal deletion of a prominent Vbeta7(+) subset. Such findings illustrate the difficulties of predicting and defining the effects of MHC class I diversification on epitope-specific responses. PMID- 21536804 TI - B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus. AB - Systemic lupus erythematosus and its preclinical lupus-prone mouse models are autoimmune disorders involving the production of pathogenic autoantibodies. Genetic predisposition to systemic lupus erythematosus results in B cell hyperactivity, survival of self-reactive B cells, and differentiation to autoantibody-secreting plasma cells (PCs). These corrupt B cell responses are, in part, controlled by excess levels of the cytokine BAFF that normally maintains B cell homeostasis and self-tolerance through limited production. B cell maturation Ag (BCMA) is a receptor for BAFF that, under nonautoimmune conditions, is important for sustaining enduring Ab protection by mediating survival of long lived PCs but is not required for B cell maturation and homeostasis. Through analysis of two different lupus-prone mouse models deficient in BCMA, we identify BCMA as an important factor in regulating peripheral B cell expansion, differentiation, and survival. We demonstrate that a BCMA deficiency combined with the lpr mutation or the murine lupus susceptibility locus Nba2 causes dramatic B cell and PC lymphoproliferation, accelerated autoantibody production, and early lethality. This study unexpectedly reveals that BCMA works to control B cell homeostasis and self-tolerance in systemic autoimmunity. PMID- 21536805 TI - Leukotriene B4 mediates neutrophil migration induced by heme. AB - High concentrations of free heme found during hemolytic events or cell damage leads to inflammation, characterized by neutrophil recruitment and production of reactive oxygen species, through mechanisms not yet elucidated. In this study, we provide evidence that heme-induced neutrophilic inflammation depends on endogenous activity of the macrophage-derived lipid mediator leukotriene B(4) (LTB(4)). In vivo, heme-induced neutrophil recruitment into the peritoneal cavity of mice was attenuated by pretreatment with 5-lipoxygenase (5-LO) inhibitors and leukotriene B(4) receptor 1 (BLT1) receptor antagonists as well as in 5-LO knockout (5-LO(-/-)) mice. Heme administration in vivo increased peritoneal levels of LTB(4) prior to and during neutrophil recruitment. Evidence that LTB(4) was synthesized by resident macrophages, but not mast cells, included the following: 1) immuno-localization of heme-induced LTB(4) was compartmentalized exclusively within lipid bodies of resident macrophages; 2) an increase in the macrophage population enhanced heme-induced neutrophil migration; 3) depletion of resident mast cells did not affect heme-induced LTB(4) production or neutrophil influx; 4) increased levels of LTB(4) were found in heme-stimulated peritoneal cavities displaying increased macrophage numbers; and 5) in vitro, heme was able to activate directly macrophages to synthesize LTB(4). Our findings uncover a crucial role of LTB(4) in neutrophil migration induced by heme and suggest that beneficial therapeutic outcomes could be achieved by targeting the 5-LO pathway in the treatment of inflammation associated with hemolytic processes. PMID- 21536807 TI - Broadening our knowledge about diverse populations. PMID- 21536806 TI - Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3. AB - Differentiation of naive CD4 T cells into Th2 cells is accompanied by chromatin remodeling and increased expression of a set of Th2-specific genes, including those encoding Th2 cytokines. IL-4-mediated STAT6 activation induces high levels of transcription of GATA3, a master regulator of Th2 cell differentiation, and enforced expression of GATA3 induces Th2 cytokine expression. However, it remains unclear whether the expression of other Th2-specific genes is induced directly by GATA3. A genome-wide unbiased chromatin immunoprecipitation assay coupled with massive parallel sequencing analysis revealed that GATA3 bound to 1279 genes selectively in Th2 cells, and 101 genes in both Th1 and Th2 cells. Simultaneously, we identified 26 highly Th2-specific STAT6-dependent inducible genes by DNA microarray analysis-based three-step selection processes, and among them 17 genes showed GATA3 binding. We assessed dependency on GATA3 for the transcription of these 26 Th2-specific genes, and 10 genes showed increased transcription in a GATA3-dependent manner, whereas 16 genes showed no significant responses. The transcription of the 16 GATA3-nonresponding genes was clearly increased by the introduction of an active form of STAT6, STAT6VT. Therefore, although GATA3 has been recognized as a master regulator of Th2 cell differentiation, many Th2-specific genes are not regulated by GATA3 itself, but in collaboration with STAT6. PMID- 21536808 TI - Discounting the value of life. PMID- 21536809 TI - Monitoring the prenatal detection of structural fetal congenital anomalies in England and Wales: register-based study. AB - OBJECTIVE: To provide current population-based prevalence and prenatal diagnosis rates (PND) for specified major congenital anomalies in England and Wales to enable monitoring of the Fetal Anomaly Screening Programme (FASP). DESIGN: Secondary analysis of prospectively collected registry data. SETTING: Seven multiple-source, population-based congenital anomaly registers, members of the British Isles Network of Congenital Anomaly Registers (BINOCAR) in 2005 and 2006. POPULATION: 2,883 births with congenital anomalies from a total of 601,545 live and stillbirths. MAIN OUTCOME MEASURES: PND and birth prevalence of selected congenital anomaly groups/subtypes (anencephaly, spina-bifida, serious cardiac, diaphragmatic hernia, gastroschisis, exomphalos, bilateral renal agenesis, lethal/severe skeletal dysplasia, cleft lip with or without cleft palate [CL + /- P]). RESULTS: Of the selected anomaly groups, the most frequently reported were serious cardiac (14.1 per 10,000 births [95% CI 13.0-15.2]) and CL + /- P (9.7 per 10,000 births [8.9-10.5]); the least frequent were bilateral renal agenesis and lethal/severe skeletal dysplasia (< 1.5 per 10,000 births). The PND varied for different anomalies from 53.1% (95% CI 43.5-65.2) for serious cardiac anomalies to 99.6% (95% CI 97.9-100.0) for anencephaly. Least variation in PND rates was for anencephaly (range 98.9-100%) and gastroschisis (93.5-100%); greatest variation was for serious cardiac (43.5-65.2%) and lethal/severe skeletal dysplasias (50.0-100%). CONCLUSIONS: BINOCAR registers can, uniquely, provide contemporary data on PND and birth prevalence rates to enable monitoring of the ultrasound component of FASP at a national and regional level, allowing comparisons between populations to be made, planning of resources facilitated and assistance for parents making informed decisions on whether to enter the screening programme. PMID- 21536810 TI - An audiometer to monitor progressive hearing change in school-aged children. AB - OBJECTIVE: The purpose of this study was to develop a cost-effective and easy to use audiometer to monitor progressive hearing change in school-aged children. DESIGN: The hardware of the audiometer developed included a computer, an external sound blaster and a headphone. The hearing screening software was developed to control the pure tone sound level with modulability in the range of 0-45 dB HL at 1, 2, 4 and 0.5 kHz frequencies. Thirty sixth-grade children, aged 12-13 years old, were randomly divided into two groups for a hearing test in a conference room. Testing for one group was performed by a person with experience and the other group was examined by a graduate student who was not familiar with the device. After the hearing test, all children were immediately screened using a clinical diagnostic audiometer in a soundproof room by an audiologist. RESULTS: Most of the threshold dB values obtained by the audiometer in a conference room (55 ears, 93.2%) were significantly greater than those obtained by the clinical audiometer in a soundproof room. Most of the differences between these two measurements were within 5 dB (94.9%). Only 5.1% had a discrepancy within the maximum range of 10 dB. The correlation and intraclass correlation coefficients between the two measurements were 0.861 and 0.929, respectively. The results also indicated that the experience level of the screening personnel did not affect the testing. CONCLUSION: The newly developed audiometer is quite cost-effective and can be easily operated. The threshold dB values obtained by the audiometer developed in a conference room were comparable with the results of a clinical audiometer in a soundproof room. The audiometer developed could measure the hearing threshold values and, therefore, be useful in monitoring progressive hearing change in school-aged children. PMID- 21536811 TI - Avoiding inappropriate invitations to cancer screening programmes: the role of primary care. AB - OBJECTIVES: To examine current procedures for cancer screening invitation list (SIL) checking in primary care, and to make recommendations for the future use of these procedures. SETTING: Cancer screening departments/units and associated general practices across England. METHODS: 1) An analysis of the outputs of screening programme SIL checking, and accompanying practice questionnaire, for cancers of the cervix (9 screening centres, 36 general practices), breast (6 centres, 76 practices) and bowel (pilot hub, 7 practices)--supplemented by an audit of calls to screening centres to identify inappropriate invitations; 2) a national postal questionnaire survey sent to all 80 breast screening departments across England and 320 associated general practices; 3) telephone interviews with 13 NHS screening staff to obtain detailed perspectives about SIL checking procedures. RESULTS: SIL checking in primary care is undertaken by a variety of clinical and non-clinical staff. It plays a useful role in cervical screening with tangible evidence of refinements to the SIL and support from both primary care and screening centre staff. Conversely, its role in breast and bowel screening is not supported by the results of this study. Overall, there is no significant evidence of adverse effects from inappropriate invitations. CONCLUSIONS: SIL checking in primary care for cervical cancer should continue, but its use in breast and bowel cancer screening is not supported by our results. New ways of undertaking the SIL checking process to make it more accurate and less burdensome should be examined. PMID- 21536812 TI - Coverage and performance of colorectal cancer screening with the faecal occult blood test in Finland. AB - INTRODUCTION: Mortality from colorectal cancer has been shown to decrease by repeated screening using faecal occult blood (FOB) testing in randomized screening trials. This report presents coverage and performance of organized screening among the general population in Finland. METHODS: In 2004-2007, people aged 60-69 years were randomized into biennial screening and control arms. The screening test was a guaiac-based FOB test (Hemoccult) with dietary restriction and three test cards for six consecutive samples. Test positives were referred for full colonoscopy. The programme was launched in 2004 and subsequently it expanded over regions and age-cohorts. RESULTS: In 2007, the programme covered one-third of the target population and 74,592 people had been invited for screening, of them 26,866 for the second round. Uptakes for the first and second rounds, respectively, were 62% and 68% in men and 77% and 80% in women. The proportion of test positives increased from 2.4% to 2.9% from the first to the second round and the positive predictive value for cancers decreased from 7.5% to 4.3%. CONCLUSIONS: By 2007, organized colorectal cancer screening covered one third of the target population in Finland. Implementation of screening measured with response rate was successful and met the criteria for a public health programme, but performance in terms of positive predictive value needs monitoring. PMID- 21536813 TI - Pre-notification increases uptake of colorectal cancer screening in all demographic groups: a randomized controlled trial. AB - OBJECTIVES: To assess whether pre-notification is effective in increasing uptake of colorectal cancer screening for all demographic groups. SETTING: Scottish national colorectal cancer screening programme. METHODS: Males and females aged 50-74 years received a faecal occult blood test by post to complete at home. They were randomized to receive in addition: the pre-notification letter, the pre notification letter + information booklet, or the usual invitation. Overall, 59,953 subjects were included in the trial between 13/04/09 and 29/05/09 and followed to 27/11/09. Pre-notification letters were posted two weeks ahead of the screening test kit. Uptake was defined as the return of a screening test and chi squared tests compared uptake between the trial arms. Logistic regression assessed the impact of the letter and letter + booklet on uptake independently of gender, age, deprivation and screening round. RESULTS: Uptake was higher with both the letter (59.0%) and the letter + booklet (58.5%) compared with the usual invitation (53.9%, p < 0.0001). This increased uptake was seen for males, females, all age groups and all deprivation categories including least deprived females (letter 69.9%, usual invitation 66.6%) and most deprived males (42.6% vs. 36.1%), the groups with the highest and lowest levels of uptake respectively in the pilot screening rounds conducted prior to the roll out of the programme. Uptake with the pre-notification letter compared with the usual invitation was higher both unadjusted and adjusted for demographic factors (odds ratio 1.24, 95% CI 1.193-1.294). CONCLUSIONS: Pre-notification is an effective method of increasing uptake in colorectal cancer screening for both genders and all age and deprivation groups. PMID- 21536814 TI - False-positive mammographic screening: factors influencing re-attendance over a decade of screening. AB - INTRODUCTION: International studies on the effect of false-positive mammographic screening results on subsequent re-attendance at screening are inconsistent. SETTING: BreastCheck, the national breast screening programme for the Republic of Ireland, screens women two-yearly. Re-attendance for subsequent screening is approximately 90%. OBJECTIVES AND METHODS: The aim of this research was to quantify the impact of false-positive mammographic screening results on subsequent re-attendance, using the BreastCheck clinical database with a decade of screening and to determine if age group, assessment procedure, initial or subsequent screening, location of appointment for next screening round and time from recall to non-malignant diagnosis predicted re-attendance. RESULTS: From programme commencement in 2000 to the end of 2007, 13,352 screening tests resulted in assessment; 11,765 participants were aged 50-62 years and of these 9746 received false-positive results (positive predictive value 17.2%). Following a false-positive recall to assessment, re-attendance at subsequent screening differed significantly by procedure type (open biopsy 80.3%; core biopsy only 90.2%; no tissue sampling 91.4%; P < 0.0001). Re-attendance differed significantly by timing of false-positive assessment in a woman's screening history (first versus subsequent screening, 89.5% versus 93.5%, P < 0.0001) and by location of next screening appointment (screening centre 89.8% versus mobile unit 91.3%, P < 0.01). The longer the period between recall to assessment and non malignant diagnosis the less likely women were to re-attend. After logistic regression, first screening, older age, open surgical biopsy, re-invitation to screening centre and a longer period between recall and non-malignant diagnosis were significant negative predictors of re-attendance. CONCLUSION: Since April 2008 BreastCheck has employed full field digital mammography throughout the programme, with a resulting increase in recalls; re-attendance will be closely monitored. PMID- 21536815 TI - 'A mastectomy for something that wasn't even truly invasive cancer'. Women's understandings of having a mastectomy for screen-detected DCIS: a qualitative study. AB - OBJECTIVES: To explore women's understandings of having a mastectomy for screen detected ductal carcinoma in situ (DCIS). SETTING: Participants recruited throughout the United Kingdom and interviewed in their own homes by an anthropologist. METHODS: Qualitative study using semi-structured interviews and thematic analysis. Thirty-five women with screen-detected DCIS were interviewed, of whom twenty had a mastectomy. RESULTS: A qualitative thematic analysis of women's understandings of having a mastectomy for DCIS identified four key themes: understandings of routine breast screening; uncertainty about DCIS and its natural progression; uncertainty about whether a mastectomy is justified for DCIS; information gaps and treatment decisions. Women were often concerned that a mastectomy for screen-detected DCIS was a 'drastic' treatment for an asymptomatic, precancerous condition of which they had been previously unaware. Some questioned why they were treated with such urgency, even suspecting that their clinicians were responding to targets. CONCLUSION: Given the uncertainties about DCIS and its complexity, it is important that women have the information they need to make treatment decisions. Better information about the uncertainties and the rationale for using mastectomy as a treatment may help women to make better informed choices and feel more comfortable about their decisions. PMID- 21536816 TI - 'A false sense of security'? Understanding the role of the HPV vaccine on future cervical screening behaviour: a qualitative study of UK parents and girls of vaccination age. AB - OBJECTIVES: The UK Human Papillomavirus (HPV) vaccination programme was introduced in 2008 for girls aged 12-13. The vaccine offers protection against HPV types 16 and 18, which together cause about 70% of cervical cancers. Vaccinated girls will receive future invitations to the NHS Cervical Screening Programme, to prevent cancers associated with HPV types not included in the vaccine, and in case of prior infection with HPV 16 or 18. Little is known about parents' and girls' understandings of the protection offered by the vaccine, or the need for future screening. DESIGN: Qualitative interviews with twenty-six parents, and nine girls aged 12-13 who were offered HPV vaccination through a Primary Care Trust (PCT) in the South-east of England, UK. SETTING: Thirty-nine schools, and four general practices. RESULTS: Uncertainty about the level of protection offered by the HPV vaccine was evident among parents, and to a lesser extent among vaccination-aged girls. There was a lack of understanding among parents and girls that cervical screening would be required irrespective of vaccination status; some parental decisions to accept the vaccine were made on the misunderstanding that vaccination provided complete protection against cervical cancer. CONCLUSIONS: Sufficient awareness of the issues related to screening is necessary for informed decision-making about whether or not to accept the HPV vaccine. Clearer information is needed concerning the incomplete protection offered by the vaccine, and that cervical screening will still be required. Future invitations for cervical screening should stress the necessity to attend regardless of HPV vaccination status, to ensure that high levels of prevention of cervical cancer through screening are maintained. PMID- 21536817 TI - Prostate cancer screening: a survey of attitudes and practices among Finnish physicians in 1999 and 2007. AB - OBJECTIVE: To evaluate the attitudes and practices related to prostate-specific antigen (PSA) screening for prostate cancer (PC) among Finnish physicians in 1999 and 2007. MATERIALS AND METHODS: The first questionnaire survey was conducted in 1999 with a mailing to 102 urologists, 679 community physicians and 684 occupational health physicians identified from the membership files of three medical associations. The area of residence was divided into the study area of the Finnish PC screening trial and the rest of Finland. The second survey was carried out in 2007 targeting 168 urologists, 1039 community physicians and 938 occupational health physicians. RESULTS: The response proportion was 48% in 1999 and 50% in 2007. In both rounds, urologists regarded PC as a more important public health issue than other physicians. On the other hand, the non-urologists considered early diagnosis and screening more important than the urologists. PC was rated by all physicians as a less important public health problem in 2007 than in 1999. A smaller proportion of urologists found routine PSA testing indicated for asymptomatic men, compared with other physicians (40% versus 74-60% in 1999, P < 0.001 and 35% versus 44-37% in 2007, P = 0.005). The proportion of physicians reporting regular PSA screening in asymptomatic men was reduced from 1999 to 2007 (from 18% to 9%, P < 0.0001). CONCLUSION: Based on reported practices of Finnish urologists, community physicians and occupational health physicians, popularity of PSA testing declined between 1999 and 2007. Urologists found PSA testing among asymptomatic men justified less frequently than the other physicians. PMID- 21536819 TI - Colorectal cancer screening: uptake of sigmoidoscopy. PMID- 21536820 TI - Is community intervention in breast cancer screening in Brazil feasible? PMID- 21536821 TI - Recognizing the unusual: the diagnostic epiphany. PMID- 21536822 TI - A 46-year-old man with fever, ST-segment elevation. PMID- 21536823 TI - Facial swelling and ulceration with nasal destruction. PMID- 21536824 TI - Visceral angioedema due to angiotensin-converting enzyme inhibitor therapy. AB - Visceral angioedema is an uncommon but serious complication of therapy with angiotensin-converting enzyme (ACE) inhibitors. We report a case, review the literature, and discuss the incidence, features, and clinical recognition of this condition. PMID- 21536825 TI - Ulcerative colitis and an abnormal cholangiogram. PMID- 21536826 TI - Tinnitus: patients do not have to 'just live with it'. AB - Tinnitus is distressing and affects the quality of life for many patients. Because primary care physicians may be the entry point for patients seeking help for tinnitus, we urge them to acknowledge this symptom and its potential negative impact on the patient's health and quality of life. Physicians should actively listen to the patient and provide hope and encouragement, but also provide realistic expectations about the course of treatment. The patient must also understand that there may be no singular "cure" for tinnitus and that management may involve multidisciplinary assessment and treatment. PMID- 21536827 TI - Tinnitus relief: suggestions for patients. PMID- 21536828 TI - A practical guide to prostate cancer diagnosis and management. AB - Screening, diagnosis, and management of prostate cancer can be complicated, with no clear consensus about key issues. We present our approach, which reflects the guidelines of the American Urological Association (AUA). PMID- 21536829 TI - Insulin treatment for type 2 diabetes: when to start, which to use. AB - In type 2 diabetes mellitus, oral hypoglycemic agents and analogues of glucagon like peptide-1 provide adequate glycemic control early in the disease. Insulin therapy becomes necessary for those with advanced disease. Further, some experts recommend electively starting insulin therapy in early diabetes. This review addresses practical approaches to insulin therapy, particularly when it is indicated and which regimen to use. PMID- 21536831 TI - Super-resolution microscopy at a glance. PMID- 21536833 TI - DNA double-strand break repair pathway choice in Dictyostelium. AB - DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR) or non-homologous end joining (NHEJ). The mechanisms that govern whether a DSB is repaired by NHEJ or HR remain unclear. Here, we characterise DSB repair in the amoeba Dictyostelium. HR is the principal pathway responsible for resistance to DSBs during vegetative cell growth, a stage of the life cycle when cells are predominantly in G2. However, we illustrate that restriction-enzyme-mediated integration of DNA into the Dictyostelium genome is possible during this stage of the life cycle and that this is mediated by an active NHEJ pathway. We illustrate that Dclre1, a protein with similarity to the vertebrate NHEJ factor Artemis, is required for NHEJ independently of DNA termini complexity. Although vegetative dclre1(-) cells are not radiosensitive, they exhibit delayed DSB repair, further supporting a role for NHEJ during this stage of the life cycle. By contrast, cells lacking the Ku80 component of the Ku heterodimer that binds DNA ends to facilitate NHEJ exhibit no such defect and deletion of ku80 suppresses the DSB repair defect of dclre1(-) cells through increasing HR efficiency. These data illustrate a functional NHEJ pathway in vegetative Dictyostelium and the importance of Ku in regulating DSB repair choice during this phase of the life cycle. PMID- 21536834 TI - Behavioral inhibition is associated with airway hyperresponsiveness but not atopy in a monkey model of asthma. AB - OBJECTIVE: To determine whether indicators of behavioral inhibition and cortisol responses to stressful situations, obtained in infancy, were associated with asthma-related measures (atopy and airway hyperresponsiveness [AHR]) approximately 2 years later. METHODS: Measures reflecting inhibited temperament and cortisol response after a 25-hour separation from mother and relocation to a novel room were obtained for 21 rhesus monkeys (mean age, 109 days; range, 91-122 days). Inhibited temperament was measured by reduced emotionality and increased vigilance. Atopy and AHR were assessed after 2 years (age range, 19-35 months) using skin tests to common aeroallergens and inhaled methacholine challenge, respectively. RESULTS: No associations were found between atopy and either behavioral inhibition or cortisol levels (p > .56). Low emotionality was associated with AHR (r = 0.47, p = .03), and a trend was found for blunted cortisol responsiveness and AHR (r = 0.42, p = .06). CONCLUSIONS: Inhibited temperament and blunted cortisol responsiveness may be related to the development of AHR that is common to both nonatopic and atopic asthma phenotypes and may indicate risk for nonatopic asthma specifically. PMID- 21536832 TI - Endocytic adaptors--social networking at the plasma membrane. AB - Receptor-mediated endocytosis is a dynamic process that is crucial for maintaining plasma membrane composition and controlling cell-signaling pathways. A variety of entry routes have evolved to ensure that the vast array of molecules on the cell surface can be differentially internalized by endocytosis. This diversity has extended to include a growing list of endocytic adaptor proteins, which are thought to initiate the internalization process. The key function of adaptors is to select the proteins that should be removed from the cell surface. Thus, they have a central role in defining the physiology of a cell. This has made the study of adaptor proteins a very active area of research that is ripe for exciting future discoveries. Here, we review recent work on how adaptors mediate endocytosis and address the following questions: what characteristics define an endocytic adaptor protein? What roles do these proteins fulfill in addition to selecting cargo and how might adaptors function in clathrin independent endocytic pathways? Through the findings discussed in this Commentary, we hope to stimulate further characterization of known adaptors and expansion of the known repertoire by identification of new adaptors. PMID- 21536835 TI - Emotional functioning at age 7 years is associated with C-reactive protein in middle adulthood. AB - OBJECTIVE: Few have considered whether and how child emotional functioning is associated with inflammation later in life. Therefore, we evaluated whether child emotional functioning at age 7 years is associated with C-reactive protein (CRP), an indicator of systemic inflammation, in middle adulthood. METHODS: We studied adult offspring (mean age 42.2 years) of participants in the National Collaborative Perinatal Project, a national cohort of pregnant women enrolled between 1959 and 1966. Three measures of child emotional functioning were derived from psychologist ratings of child behavior at age 7 years: inappropriate self regulation (ISR), distress proneness, and behavioral inhibition. Multiple linear regression models were fit to investigate the association between childhood emotional functioning and adulthood CRP and also to evaluate potential mediators of this association. Model n's were from 400 for Model 1 to 379 for Model 4 depending on covariates included and missing data on those covariates. RESULTS: Children with high ISR and distress proneness at age 7 years had significantly higher CRP as adults (ISR: beta = 0.86; standard error [SE] = 0.28; p = .002; distress proneness: beta = 1.23; SE = 0.57; p = .03). In contrast, children with high levels of behavioral inhibition had lower CRP as adults (beta = -0.58; SE = 0.38; p = .04). Furthermore, there was evidence that associations of ISR and distress proneness with CRP may be mediated in part by adulthood body mass index (Sobel significance tests of mediation: ISR: p = .003; distress proneness: p = .07). CONCLUSIONS: Findings suggest that poor childhood emotional functioning is associated with inflammation in adulthood. These results suggest a potential childhood origin of adult inflammatory risk. PMID- 21536836 TI - Plasma nitrate levels and flow-mediated vasodilation in untreated major depression. AB - OBJECTIVE: Findings from several studies have revealed that major depression is associated with an increased cardiovascular risk. The physiopathologic mechanisms of this association remain unclear, although recently, it has been hypothesized that a decreased production of nitric oxide could be a potential contributor to vascular dysfunction in depressive patients. The objective of this study was to evaluate nitric oxide production and vascular endothelial function in treatment naive young healthy adults with a first episode of major depression. METHODS: A case-control study in 50 treatment-naive young adults with a first episode of major depression and 50 healthy control subjects was conducted. Plasma levels of nitric oxide metabolites (nitrates/nitrites) were determined using a colorimetric assay based on Griess reaction. Endothelial function was assessed by flow mediated vasodilation measurements after reactive hyperemia. RESULTS: The mean age of the depressed patients was 22.6 (standard deviation [SD], 4.6) years, whereas the controls were 23.4 (SD, 4.8) years. Sixteen men (32%) and 34 women (68%) were included in each group. The plasma nitrite/nitrate concentrations were significantly lower in depressive subjects compared with healthy controls (17.5 [SD, 4.9] MUmol/L versus 21.6 [SD, 7.0] MUmol/L, p < .001); however, flow mediated vasodilation values were similar in both groups (13.1% [SD, 4.3%] versus 12.1% [SD, 5.0%], p = .10). CONCLUSIONS: Decreased plasma concentrations of nitric oxide metabolites are not associated with vascular endothelial dysfunction in young subjects with a first episode of major depression. Reduced nitrate/nitrite levels could reflect a decreased nitric oxide production in the central nervous system of depressed subjects. Further studies are needed to confirm this hypothesis. PMID- 21536837 TI - Usual and unusual care: existing practice control groups in randomized controlled trials of behavioral interventions. AB - OBJECTIVE: To evaluate the use of existing practice control groups in randomized controlled trials of behavioral interventions and the role of extrinsic health care services in the design and conduct of behavioral trials. METHOD: Selective qualitative review. RESULTS: Extrinsic health care services, also known as nonstudy care, have important but under-recognized effects on the design and conduct of behavioral trials. Usual care, treatment-as-usual, standard of care, and other existing practice control groups pose a variety of methodological and ethical challenges, but they play a vital role in behavioral intervention research. CONCLUSIONS: This review highlights the need for a scientific consensus statement on control groups in behavioral trials. PMID- 21536839 TI - Astrocytes as regulators of synaptic function: a quest for the Ca2+ master key. AB - The emerging role of astrocytes in neural communication represents a conceptual challenge. In striking contrast to the rapid and highly space- and time constrained machinery of neuronal spike propagation and synaptic release, astroglia appear slow and imprecise. Although a large body of independent experiments documents active signal exchange between astrocytes and neurons, some genetic models have raised doubts about the major Ca2+ -dependent molecular mechanism routinely associated with release of "gliotransmitters." A limited understanding of astrocytic Ca2+ signaling and the imperfect compatibility between physiology and experimental manipulations seem to have contributed to this conceptual bottleneck. Experimental approaches providing mechanistic insights into the diverse mechanisms of intra-astrocyte Ca2+ signaling on the nanoscale are needed to understand Ca2+ -dependent astrocytic function in vivo. This review highlights limitations and potential advantages of such approaches from the current methodological perspective. PMID- 21536840 TI - Can adult neural stem cells create new brains? Plasticity in the adult mammalian neurogenic niches: realities and expectations in the era of regenerative biology. AB - Since the first experimental reports showing the persistence of neurogenic activity in the adult mammalian brain, this field of neurosciences has expanded significantly. It is now widely accepted that neural stem and precursor cells survive during adulthood and are able to respond to various endogenous and exogenous cues by altering their proliferation and differentiation activity. Nevertheless, the pathway to therapeutic applications still seems to be long. This review attempts to summarize and revisit the available data regarding the plasticity potential of adult neural stem cells and of their normal microenvironment, the neurogenic niche. Recent data have demonstrated that adult neural stem cells retain a high level of pluripotency and that adult neurogenic systems can switch the balance between neurogenesis and gliogenesis and can generate a range of cell types with an efficiency that was not initially expected. Moreover, adult neural stem and precursor cells seem to be able to self regulate their interaction with the microenvironment and even to contribute to its synthesis, altogether revealing a high level of plasticity potential. The next important step will be to elucidate the factors that limit this plasticity in vivo, and such a restrictive role for the microenvironment is discussed in more details. PMID- 21536838 TI - Dopaminergic neurotransmission in the human brain: new lessons from perturbation and imaging. AB - Dopamine plays an important role in several brain functions and is involved in the pathogenesis of several psychiatric and neurological disorders. Neuroimaging techniques such as positron emission tomography allow us to quantify dopaminergic activity in the living human brain. Combining these with brain stimulation techniques offers us the unique opportunity to tackle questions regarding region specific neurochemical activity. Such studies may aid clinicians and scientists to disentangle neural circuitries within the human brain and thereby help them to understand the underlying mechanisms of a given function in relation to brain diseases. Furthermore, it may also aid the development of alternative treatment approaches for various neurological and psychiatric conditions. PMID- 21536841 TI - Unwrapping myelination by microRNAs. AB - Myelination of axons by oligodendrocytes and Schwann cells in the central and peripheral nervous system, respectively, is essential for normal neuronal functions, and its failure results in devastating demyelinating diseases. During development, both oligodendrocyte and Schwann cell precursors undergo a temporally well-defined series of molecular and structural changes, ultimately culminating in the cessation of proliferation and the elaboration of a highly complex myelin sheath. Recent studies have demonstrated a critical role of microRNAs (miRNAs) in the progression of oligodendrocyte and Schwann cell precursors to the myelinating state-depletion of miRNAs from either cell type results in an arrest in differentiation and lack of myelination. Furthermore, these studies have begun to elucidate the dynamic regulation of miRNA expression and the complexity of miRNA-mediated gene regulation during differentiation of myelinating cells. In this review, the authors highlight the recent understanding of functional links of miRNAs to regulatory networks for central and peripheral myelination, as well as perspectives on the role of miRNAs in demyelinating diseases. PMID- 21536842 TI - Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution. AB - The heterogeneities of electrophysiological properties of cardiac tissue are the main factors that control both arrhythmia induction and maintenance. Although the local increase of extracellular potassium ([K(+)](o)) due to coronary occlusion is a well-established metabolic response to acute ischemia, the role of local [K(+)](o) heterogeneity in phase 1a arrhythmias has yet to be determined. In this work, we created local [K(+)](o) heterogeneity and investigated its role in fast pacing response and arrhythmia induction. The left marginal vein of a Langendorff perfused rabbit heart was cannulated and perfused separately with solutions containing 4, 6, 8, 10, and 12 mM of K(+). The fluorescence dye was utilized to map the voltage distribution. We tested stimulation rates, starting from 400 ms down to 120 ms, with steps of 5-50 ms. We found that local [K(+)](o) heterogeneity causes action potential (AP) alternans, 2:1 conduction block, and wave breaks. The effect of [K(+)](o) heterogeneity on electrical stability and vulnerability to arrhythmia induction was largest during regional perfusion with 10 mM of K(+). We detected three concurrent dynamics: normally propagating activation when excitation waves spread over tissue perfused with normal K(+), alternating 2:2 rhythm near the border of [K(+)](o) heterogeneity, and 2:1 aperiodicity when propagation was within the high [K(+)](o) area. [K(+)](o) elevation changed the AP duration (APD) restitution and shifted the restitution curve toward longer diastolic intervals and shorter APD. We conclude that spatial heterogeneity of the APD restitution, created with regional elevation of [K(+)](o), can lead to AP instability, 2:1 block, and reentry induction. PMID- 21536843 TI - Improved measurements of intracellular nitric oxide in intact microvessels using 4,5-diaminofluorescein diacetate. AB - 4,5-Diaminofluorescein diacetate (DAF-2 DA) has been widely used for the measurement of nitric oxide (NO) in living cells and tissues. We previously established a method that demonstrated platelet activating factor (PAF)-induced endothelial NO production in intact venules using DAF-2 DA. In previous applications, the loading dye was removed from the extracellular space before NO measurements. However, in high permeability vessels, endothelial cells quickly released the accumulated intracellular DAF-2 after the washout, which compromises the NO measurement. The objective of this study was to investigate if the presence of DAF-2 DA during NO measurements could overcome the dye retention problem and enhance the sensitivity of NO detection. Experiments were conducted in individually perfused rat venules, and endothelial NO was measured using fluorescence imaging under basal and stimulated conditions with continuous perfusion of DAF-2 DA. Continuous dye perfusion was found to promote a relatively constant endothelial dye concentration in both normal and high permeability vessels throughout the experiment. With the use of this method, the basal and stimulated NO was quantified after endothelial DAF-2 concentrations reached a steady state. Our results showed enhanced sensitivity of detecting PAF-stimulated NO compared with a previous method. We also found that the hydrolyzed intracellular DAF-2, the precursor of DAF-2 triazole, contributed significantly to the measured fluorescence and that an appropriate subtraction of non-NO dependent intracellular DAF-2 fluorescence is critical for the assessment of NO in living tissues. This method overcame the dye leakage problem, enhanced the sensitivity of NO detection, and improved NO quantification, demonstrating significant advantages over existing methodologies using DAF-2. PMID- 21536844 TI - Left ventricular systolic and diastolic function during tilt-table positioning and passive heat stress in humans. AB - The ventricular response to passive heat stress has predominantly been studied in the supine position. It is presently unclear how acute changes in venous return influence ventricular function during heat stress. To address this question, left ventricular (LV) systolic and diastolic function were studied in 17 healthy men (24.3 +/- 4.0 yr; mean +/- SD), using two-dimensional transthoracic echocardiography with Doppler ultrasound, during tilt-table positioning (supine, 30 degrees head-up tilt, and 30 degrees head-down tilt), under normothermic and passive heat stress (core temperature 0.8 +/- 0.1 degrees C above baseline) conditions. The supine heat stress LV volumetric and functional response was consistent with previous reports. Combining head-up tilt with heat stress reduced end-diastolic (25.2 +/- 4.1%) and end-systolic (65.4 +/- 10.5%) volume from baseline, whereas heart rate (37.7 +/- 2.0%), ejection fraction (9.4 +/- 2.4%), and LV elastance (37.7 +/- 3.6%) increased, and stroke volume (-28.6 +/- 9.4%) and early diastolic inflow (-17.5 +/- 6.5%) and annular tissue (-35.6 +/- 7.0%) velocities were reduced. Combining head-down tilt with heat stress restored end diastolic volume, whereas LV elastance (16.8 +/- 3.2%), ejection fraction (7.2 +/ 2.1%), and systolic annular tissue velocities (22.4 +/- 5.0%) remained elevated above baseline, and end-systolic volume was reduced (-15.3 +/- 3.9%). Stroke volume and the early and late diastolic inflow and annular tissue velocities were unchanged from baseline. This investigation extends previous work by demonstrating increased LV systolic function with heat stress, under varied levels of venous return, and highlights the preload dependency of early diastolic function during passive heat stress. PMID- 21536845 TI - Sympathetic alpha3beta2-nAChRs mediate cerebral neurogenic nitrergic vasodilation in the swine. AB - The alpha(7)-nicotinic ACh receptor (alpha(7)-nAChR) on sympathetic neurons innervating basilar arteries of pigs crossed bred between Landrace and Yorkshire (LY) is known to mediate nicotine-induced, beta-amyloid (Abeta)-sensitive nitrergic neurogenic vasodilation. Preliminary studies, however, demonstrated that nicotine-induced cerebral vasodilation in pigs crossbred among Landrace, Yorkshire, and Duroc (LYD) was insensitive to Abeta and alpha-bungarotoxin (alpha BGTX). We investigated nAChR subtype on sympathetic neurons innervating LYD basilar arteries. Nicotine-induced relaxation of porcine isolated basilar arteries was examined by tissue bath myography, inward currents on nAChR expressing oocytes by two-electrode voltage recording, and mRNA and protein expression in the superior cervical ganglion (SCG) and middle cervical ganglion (MCG) by reverse transcription PCR and Western blotting. Nicotine-induced basilar arterial relaxation was not affected by Abeta, alpha-BGTX, and alpha-conotoxin IMI (alpha(7)-nAChR antagonists), or alpha-conotoxin AuIB (alpha(3)beta(4)-nAChR antagonist) but was inhibited by tropinone and tropane (alpha(3)-containing nAChR antagonists) and alpha-conotoxin MII (selective alpha(3)beta(2)-nAChR antagonist). Nicotine-induced inward currents in alpha(3)beta(2)-nAChR-expressing oocytes were inhibited by alpha-conotoxin MII but not by alpha-BGTX, Abeta, or alpha-conotoxin AuIB. mRNAs of alpha(3)-, alpha(7)-, beta(2)-, and beta(4) subunits were expressed in both SCGs and MCGs with significantly higher mRNAs of alpha(3)-, beta(2)-, and beta(4)-subunits than that of alpha(7)-subunit. The Abeta-insensitive sympathetic alpha(3)beta(2)-nAChR mediates nicotine-induced cerebral nitrergic neurogenic vasodilation in LYD pigs. The different finding from Abeta-sensitive alpha(7)-nAChR in basilar arteries of LY pigs may offer a partial explanation for different sensitivities of individuals to Abeta in causing diminished cerebral nitrergic vasodilation in diseases involving Abeta. PMID- 21536846 TI - Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice. AB - Increased arterial stiffness and blood pressure are characteristic of humans and adult mice with reduced elastin levels caused by aging or genetic disease. Direct associations have been shown between increased arterial stiffness and hypertension in humans, but it is not known whether changes in mechanical properties or increased blood pressure occur first. Using genetically modified mice with elastin haploinsufficiency (Eln(+/-)), we investigated the temporal relationship between arterial mechanical properties and blood pressure throughout postnatal development. Our results show that some mechanical properties are maintained constant regardless of elastin amounts. The peak diameter compliance for both genotypes occurs near the physiologic pressure at each age, which acts to provide maximum pulse dampening. The stress-strain relationships are similar between genotypes and become nonlinear near the systolic pressure for each age, which serves to limit distension under high pressure. Our results also show that some mechanical properties are affected by reduced elastin levels and that these changes occur before measurable changes in blood pressure. Eln(+/-) mice have decreased aortic diameter and compliance in ex vivo tests that are significant by postnatal day 7 and increased blood pressure that is not significant until postnatal day 14. This temporal relationship suggests that targeting large arteries to increase diameter or compliance may be an effective treatment for human hypertension. PMID- 21536847 TI - Baroreceptor unloading in postural tachycardia syndrome augments peripheral chemoreceptor sensitivity and decreases central chemoreceptor sensitivity. AB - While orthostatic tachycardia is the hallmark of postural tachycardia syndrome (POTS), orthostasis also initiates increased minute ventilation (Ve) and decreased end-tidal CO(2) in many patients. We hypothesized that chemoreflex sensitivity would be increased in patients with POTS. We therefore measured chemoreceptor sensitivity in 20 POTS (16 women and 4 men) and 14 healthy controls (10 women and 4 men), 16-35 yr old by exposing them to eucapneic hyperoxia (30% O(2)), eucapneic hypoxia (10% O(2)), and hypercapnic hyperoxia (30% O(2) + 5% CO(2)) while supine and during 70 degrees head-upright tilt. Heart rate, mean arterial pressure, O(2) saturation, end-tidal CO(2), and Ve were measured. Peripheral chemoreflex sensitivity was calculated as the difference in Ve during hypoxia compared with room air divided by the change in O(2) saturation. Central chemoreflex sensitivity was determined by the difference in Ve during hypercapnia divided by the change in CO(2). POTS subjects had an increased peripheral chemoreflex sensitivity (in l.min(-1).%oxygen(-1)) in response to hypoxia (0.42 +/- 0.38 vs. 0.19 +/- 0.17) but a decreased central chemoreflex sensitivity (l.min(-1).Torr(-1)) CO(2) response (0.49 +/- 0.38 vs. 1.04 +/- 0.18) compared with controls. CO(2) sensitivity was also reduced in POTS subjects when supine. POTS patients are markedly sensitized to hypoxia when upright but desensitized to CO(2) while upright or supine. The interactions between orthostatic baroreflex unloading and altered chemoreflex sensitivities may explain the hyperventilation in POTS patients. PMID- 21536848 TI - Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats. AB - Obese Zucker rats (OZR) have elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) compared with lean Zucker rats (LZR). We examined whether altered tonic glutamatergic, angiotensinergic, or GABAergic inputs to the rostral ventrolateral medulla (RVLM) contribute to elevated SNA and MAP in OZR. Male rats (14-18 wk) were anesthetized with urethane (1.5 g/kg iv), ventilated, and paralyzed to record splanchnic SNA, heart rate (HR), and MAP. Inhibition of the RVLM by microinjections of muscimol eliminated SNA and evoked greater decreases in MAP in OZR vs. LZR (P < 0.05). Antagonism of angiotensin AT(1) receptors in RVLM with losartan yielded modest decreases in SNA and MAP in OZR but not LZR (P < 0.05). However, antagonism of ionotropic glutamate receptors in RVLM with kynurenate produced comparable decreases in SNA, HR, and MAP in OZR and LZR. Antagonism of GABA(A) receptors in RVLM with gabazine evoked smaller rises in SNA, HR, and MAP in OZR vs. LZR (P < 0.05), whereas responses to microinjections of GABA into RVLM were comparable. Inhibition of the caudal ventrolateral medulla, a major source of GABA to the RVLM, evoked attenuated rises in SNA and HR in OZR (P <0.05). Likewise, inhibition of nucleus tractus solitarius, the major excitatory input to caudal ventrolateral medulla, produced smaller rises in SNA and HR in OZR. These results suggest the elevated SNA and MAP in OZR is derived from the RVLM and that enhanced angiotensinergic activation and reduced GABAergic inhibition of the RVLM may contribute to the elevated SNA and MAP in the OZR. PMID- 21536849 TI - Mineralocorticoid receptor expression in human venous smooth muscle cells: a potential role for aldosterone signaling in vein graft arterialization. AB - Experimental studies have suggested a role for the local renin-angiotensin aldosterone system in the response to vascular injury. Clinical data support that aldosterone, via activation of the mineralocorticoid receptor (MR), is an important mediator of vascular damage in humans with cardiovascular disease. In mineralocorticoid-sensitive target tissue, aldosterone specificity for MR is conferred enzymatically by the cortisol-inactivating enzyme 11beta-hydroxysteroid dehydrogenase-2 (11betaHSD2). However, the role of MR/aldosterone signaling in the venous system has not been explored. We hypothesized that MR expression and signaling in venous smooth muscle cells contributes to the arterialization of venous conduits and the injury response in vein bypass grafts. MR immunostaining was observed in all samples of excised human peripheral vein graft lesions and in explanted experimental rabbit carotid interposition vein grafts, with minimal staining in control greater saphenous vein. We also found upregulated transcriptional expression of both MR and 11betaHSD2 in human vein graft and rabbit vein graft, whereas control greater saphenous vein expressed minimal MR and no detectable 11betaHSD2. The expression of MR and 11betaHSD2 was confirmed in cultured human saphenous venous smooth muscle cells (hSVSMCs). Using an adenovirus containing a MR response element-driven reporter gene, we demonstrate that MR in hSVSMCs is capable of mediating aldosterone-induced gene activation. The functional significance for MR signaling in hSVSMCs is supported by the aldosterone-induced increase of angiotensin II type-1 receptor gene expression that was inhibited by the MR antagonist spironolactone. The upregulation of MR and 11betaHSD2 suggests that aldosterone-mediated tissue injury plays a role in vein graft arterialization. PMID- 21536851 TI - Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms. AB - Insults during the fetal period predispose the offspring to systemic cardiovascular disease, but little is known about the pulmonary circulation and the underlying mechanisms. Maternal undernutrition during pregnancy may represent a model to investigate underlying mechanisms, because it is associated with systemic vascular dysfunction in the offspring in animals and humans. In rats, restrictive diet during pregnancy (RDP) increases oxidative stress in the placenta. Oxygen species are known to induce epigenetic alterations and may cross the placental barrier. We hypothesized that RDP in mice induces pulmonary vascular dysfunction in the offspring that is related to an epigenetic mechanism. To test this hypothesis, we assessed pulmonary vascular function and lung DNA methylation in offspring of RDP and in control mice at the end of a 2-wk exposure to hypoxia. We found that endothelium-dependent pulmonary artery vasodilation in vitro was impaired and hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in vivo were exaggerated in offspring of RDP. This pulmonary vascular dysfunction was associated with altered lung DNA methylation. Administration of the histone deacetylase inhibitors butyrate and trichostatin A to offspring of RDP normalized pulmonary DNA methylation and vascular function. Finally, administration of the nitroxide Tempol to the mother during RDP prevented vascular dysfunction and dysmethylation in the offspring. These findings demonstrate that in mice undernutrition during gestation induces pulmonary vascular dysfunction in the offspring by an epigenetic mechanism. A similar mechanism may be involved in the fetal programming of vascular dysfunction in humans. PMID- 21536850 TI - Systolic dysfunction in cardiac-specific ligand-inducible MerCreMer transgenic mice. AB - The Cre-loxP system is a useful tool to study the physiological effects of gene knockout in the heart. One limitation with using this system in the heart is the toxic effect of chronic expression of the Cre recombinase. To circumvent this limitation, a widely used inducible cardiac-specific model, Myh6-MerCreMer (Cre), using tamoxifen (TAM) to activate Cre has been developed. The current study examined cardiac function in Cre-positive C57B/J6 mice exposed to one, three, or five daily doses of a 40 mg/kg TAM to induce Cre activity specifically in the heart. Echocardiography demonstrated no statistically significant differences in systolic function (SF) at baseline as assessed by fractional shortening. In mice exposed to five injections, a significant fall in all determinants of SF was observed 6 days after TAM was initiated. However, SF returned to baseline levels 10 days after TAM initiation although the hearts exhibited significant hypertrophy. Heart weight-to-tibia length ratios were 73 +/- 3, 78.5 +/- 6, and 87.6 +/- 9 mg/cm for one, three, and five TAM injections, respectively. TAM had no effect on cardiac function or hypertrophy in Cre-negative mice. Cre-positive mice receiving five TAM injections had significant reductions in cardiac mitochondrial ATP and significant reductions in the expression of proteins important for the regulation of cardiac oxidative phosphorylation including peroxisome proliferator-activated receptor-gamma coactivator-1alpha and pyruvate dehydrogenase kinase-4. Thus inducible cardiac-specific activation of Cre recombinase caused a transient decline in SF that was dependent on the number of TAM doses and associated with significant hypertrophy and alterations in mitochondrial ATP and important proteins involved in the regulation of cardiac oxidative phosphorylation. PMID- 21536852 TI - Prostaglandins do not contribute to the nitric oxide-mediated compensatory vasodilation in hypoperfused exercising muscle. AB - We tested the hypothesis that 1) prostaglandins (PGs) contribute to compensatory vasodilation in contracting human forearm subjected to acute hypoperfusion, and 2) the combined inhibition of PGs and nitric oxide would attenuate the compensatory vasodilation more than PG inhibition alone. In separate protocols, subjects performed forearm exercise (20% of maximum) during hypoperfusion evoked by intra-arterial balloon inflation. Each trial included baseline, exercise before inflation, exercise with inflation, and exercise after deflation. Forearm blood flow (FBF; ultrasound) and local (brachial artery) and systemic arterial pressure [mean arterial pressure (MAP); Finometer] were measured. In protocol 1 (n = 8), exercise was repeated during cyclooxygenase (COX) inhibition (Ketorolac) alone and during Ketorolac-NOS inhibition [N(G)-monomethyl-l-arginine (l-NMMA)]. In protocol 2 (n = 8), exercise was repeated during l-NMMA alone and during l NMMA-Ketorolac. Forearm vascular conductance (FVC; ml.min(-1).100 mmHg(-1)) was calculated from FBF (ml/min) and local MAP (mmHg). The percent recovery in FVC during inflation was calculated as (steady-state inflation + exercise value - nadir)/[steady-state exercise (control) value - nadir] * 100. In protocol 1, COX inhibition alone did not reduce the %FVC recovery compared with the control (no drug) trial (92 +/- 11 vs. 100 +/- 10%, P = 0.83). However, combined COX-nitric oxide synthase (NOS) inhibition caused a substantial reduction in %FVC recovery (54 +/- 8%, P < 0.05 vs. Ketorolac alone). In protocol 2, the percent recovery in FVC was attenuated with NOS inhibition alone (69 +/- 9 vs. 107 +/- 10%, P < 0.01) but not attenuated further during combined NOS-COX inhibition (62 +/- 10%, P = 0.74 vs. l-NMMA alone). Our data indicate that PGs are not obligatory to the compensatory dilation observed during forearm exercise with hypoperfusion. PMID- 21536854 TI - Differential effects of diet-induced obesity on BKCa {beta}1-subunit expression and function in rat skeletal muscle arterioles and small cerebral arteries. AB - Mechanisms underlying obesity-related vascular dysfunction are unclear. This study examined the effect of diet-induced obesity on expression and function of large conductance Ca(2+)-activated potassium channel (BK(Ca)) in rat pressurized small resistance vessels with myogenic tone. Male Sprague-Dawley rats fed a cafeteria-style high fat diet (HFD; ~30% energy from fat) for 16-20 wk were ~30% heavier than controls fed standard chow (~13% fat). Obesity did not alter BK(Ca) alpha-subunit function or alpha-subunit protein or mRNA expression in vessels isolated from the cremaster muscle or middle-cerebral circulations. In contrast, BK(Ca) beta(1)-subunit protein expression and function were significantly reduced in cremaster muscle arterioles but increased in middle-cerebral arteries from obese animals. Immunohistochemistry showed alpha- and beta(1)-subunits were present exclusively in the smooth muscle of both vessels. Cremaster muscle arterioles from obese animals showed significantly increased medial thickness, and media-to-lumen ratio and pressurized arterioles showed increased myogenic tone at 30 mmHg, but not at 50-120 mmHg. Myogenic tone was not affected by obesity in middle-cerebral arteries. The BK(Ca) antagonist iberiotoxin constricted both cremaster muscle and middle-cerebral arterioles from control rats; this effect of iberiotoxin was abolished in cremaster muscle arteries only from obese rats. Diet-induced obesity has contrasting effects on BK(Ca) function in different vascular beds, through differential effects on beta(1)-subunit expression. However, these alterations in BK(Ca) function had little effect on overall myogenic tone, suggesting that the mechanisms controlling myogenic tone can be altered and compensate for altered BK(Ca) expression and function. PMID- 21536853 TI - sGC{alpha}1 mediates the negative inotropic effects of NO in cardiac myocytes independent of changes in calcium handling. AB - In the heart, nitric oxide (NO) modulates contractile function; however, the mechanisms responsible for this effect are incompletely understood. NO can elicit effects via a variety of mechanisms including S-nitrosylation and stimulation of cGMP synthesis by soluble guanylate cyclase (sGC). sGC is a heterodimer comprised of a beta(1)- and an alpha(1)- or alpha(2)-subunit. sGCalpha(1)beta(1) is the predominant isoform in the heart. To characterize the role of sGC in the regulation of cardiac contractile function by NO, we compared left ventricular cardiac myocytes (CM) isolated from adult mice deficient in the sGC alpha(1) subunit (sGCalpha(1)(-/-)) and from wild-type (WT) mice. Sarcomere shortening under basal conditions was less in sGCalpha(1)(-/-) CM than in WT CM. To activate endogenous NO synthesis from NO synthase 3, CM were incubated with the beta(3) adrenergic receptor (beta(3)-AR) agonist BRL 37344. BRL 37344 decreased cardiac contractility in WT CM but not in sGCalpha(1)(-/-) myocytes. Administration of spermine NONOate, an NO donor compound, did not affect sarcomeric shortening in CM of either genotype; however, in the presence of isoproterenol, addition of spermine NONOate reduced sarcomere shortening in WT but not in sGCalpha(1)(-/-) CM. Neither BRL 37344 nor spermine NONOate altered calcium handling in CM of either genotype. These findings suggest that sGCalpha(1) exerts a positive inotropic effect under basal conditions, as well as mediates the negative inotropic effect of beta(3)-AR signaling. Additionally, our work demonstrates that sGCalpha(1)beta(1) is required for NO to depress beta(1)/beta(2)-AR stimulated cardiac contractility and that this modulation is independent of changes in calcium handling. PMID- 21536855 TI - Comparative effects of nesiritide and nitroglycerin on renal function, and incidence of renal injury by traditional and RIFLE criteria in acute heart failure. AB - BACKGROUND: Acute renal insufficiency is associated with poorer outcomes in heart failure. Data regarding the renal effects of vasodilatory therapy in acute heart failure are inconclusive. HYPOTHESIS: Nesiritide and nitroglycerin are associated with differing effects on the incidence of acute renal injury and glomerular filtration rate changes. METHODS: A retrospective cohort study of patients hospitalized with acute congestive heart failure who received intravenous nesiritide or nitroglycerin for >=6 hours. Acute kidney injury was assessed by risk, injury, failure, loss, and end stage (RIFLE) classification (creatinine/GFR criteria) and by traditional acute rise in creatinine of 0.3 mg/dL or 25%. Secondary endpoints included change in estimated glomerular filtration rate, serum creatinine, serum blood urea nitrogen, blood pressure, and urine output. RESULTS: A total of one hundred and thirty-one patients (age 57 +/- 12 years, 67% male, left ventricular ejection fraction 38 +/- 35%, 30% ischemic) received nesiritide (N = 37) or nitroglycerin (N = 94). Diuretic regimen and doses were similar in both the groups. Mean duration of therapy was not different (nesiritide 38.6 +/- 35.7 h vs nitroglycerin 30.7 +/- 22.6 h, P = .13). No differences were detected in incidence of renal injury using either criteria (RIFLE: nesiritide 19% vs nitroglycerin 22%, P = .88; traditional: 22% vs 34%, P = .16); however, glomerular filtration rate declined (-1 +/- 18 mL/min vs -9 +/- 21 mL/min, P = .03) and blood urea nitrogen increased (-0.2 +/- 9.9 mg/dL vs 4.2 +/- 9.1 mg/dL, P = .02) to a greater degree with nitroglycerin. Nesiritide was associated with lower hourly blood pressures and a higher incidence of systolic blood pressure <80 mm Hg. CONCLUSION: The incidence of renal injury was not different between nesiritide- and nitroglycerin-treated patients with acute heart failure; however, nitroglycerin was associated with a decline in glomerular filtration rate and increase in blood urea nitrogen despite higher baseline and on treatment blood pressures. PMID- 21536856 TI - Splicing factor 2-associated protein p32 participates in ribosome biogenesis by regulating the binding of Nop52 and fibrillarin to preribosome particles. AB - Ribosome biogenesis starts with transcription of the large ribosomal RNA precursor (47S pre-rRNA), which soon combines with numerous factors to form the 90S pre-ribosome in the nucleolus. Although the subsequent separation of the pre 90S particle into pre-40S and pre-60S particles is critical for the production process of mature small and large ribosomal subunits, its molecular mechanisms remain undetermined. Here, we present evidence that p32, fibrillarin (FBL), and Nop52 play key roles in this separation step. Mass-based analyses combined with immunoblotting showed that p32 associated with 155 proteins including 31 rRNA processing factors (of which nine were components of small subunit processome, and six were those of RIX1 complex), 13 chromatin remodeling components, and six general transcription factors required for RNA polymerase III-mediated transcription. Of these, a late rRNA-processing factor Nop52 interacted directly with p32. Immunocytochemical analyses demonstrated that p32 colocalized with an early rRNA-processing factor FBL or Nop52 in the nucleolus and Cajal bodies, but was excluded from the nucleolus after actinomycin D treatment. p32 was present in the pre-ribosomal fractions prepared by cell fractionation or separated by ultracentrifugation of the nuclear extract. p32 also associated with pre-rRNAs including 47S/45S and 32S pre-rRNAs. Furthermore, knockdown of p32 with a small interfering RNA slowed the early processing from 47S/45S pre-rRNAs to 18S rRNA and 32S pre-rRNA. Finally, Nop52 was found to compete with FBL for binding to p32 probably in the nucleolus. Given the fact that FBL and Nop52 are associated with pre-ribosome particles distinctly different from each other, we suggest that p32 is a new rRNA maturation factor involved in the remodeling from pre-90S particles to pre-40S and pre-60S particles that requires the exchange of FBL for Nop52. PMID- 21536857 TI - DCIR-mediated enhancement of HIV-1 infection requires the ITIM-associated signal transduction pathway. AB - Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor expressed at high levels on dendritic cells (DCs). This surface molecule acts as an attachment factor for HIV-1 on DCs and contributes to trans- and cis-infection pathways. Moreover, DICR is induced by HIV-1 in CD4(+) T cells and promotes virus replication in this cell type. Nothing is known hitherto about the DCIR-dependent signaling, which is induced following HIV-1 ligation. First, specific pharmacologic inhibitors were tested on HIV-1 binding/entry and, second, specific antisense oligonucleotides targeted, more specifically kinases and phosphatases, were used. Our results show that SHP-1, SHP-2, Syk, and Src kinases (ie, Src, Fyn, and Hck) as well as PKC-alpha and MAP kinases (ie, Erk1/2 and p38) are all involved in the DCIR-mediated signal transduction pathway triggered by HIV-1. By mutagenesis and through the use of intracellular phosphorylated peptides, we show as well a pivotal role for the tyrosine and threonine residues of the DCIR immunoreceptor tyrosine-based inhibitory motif (ITIM). Our data suggest for the first time an involvement of ITIM domain in HIV-1-mediated signaling events and a relationship between phosphorylation events and DCIR function with respect to HIV 1 biology. PMID- 21536858 TI - Diminished metastasis in tetraspanin CD151-knockout mice. AB - Tetraspanin protein CD151 on tumor cells supports invasion and metastasis. In the present study, we show that host animal CD151 also plays a critical role. CD151 null mice showed markedly diminished experimental lung metastasis after injection of Lewis lung carcinoma or B16F10 melanoma cells. Diminished tumor cell residence in the lungs was evident 6-24 hours after injection. Consistent with an endothelial cell deficiency, isolated CD151-null mouse lung endothelial cells showed diminished support for B16F10 adhesion and transendothelial migration, diminished B16F10-induced permeability, and diminished B16F10 adhesion to extracellular matrix deposited by CD151-null mouse lung endothelial cells. However, CD151 deletion did not affect the size of metastatic foci or subcutaneous primary B16F10 tumors, tumor aggregation, tumor clearance from the blood, or tumor-induced immune cell activation and recruitment. Therefore, the effects of host CD151 on metastasis do not involve altered local tumor growth or immune surveillance. VEGF-induced endothelial cell signaling through Src and Akt was diminished in CD151-null endothelial cells. However, deficient signaling was not accompanied by reduced endothelial permeability either in vitro (monolayer permeability assay) or in vivo (VEGF-stimulated Miles assay). In summary, diminished metastasis in CD151-null host animals may be due to impaired tumor endothelial interactions, with underlying defects in mouse lung endothelial cell extracellular matrix production. PMID- 21536859 TI - ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer. AB - The Ets-related gene (ERG) is an Ets-transcription factor required for normal blood stem cell development. ERG expression is down-regulated during early T lymphopoiesis but maintained in T-acute lymphoblastic leukemia (T-ALL), where it is recognized as an independent risk factor for adverse outcome. However, it is unclear whether ERG is directly involved in the pathogenesis of T-ALL and how its expression is regulated. Here we demonstrate that transgenic expression of ERG causes T-ALL in mice and that its knockdown reduces the proliferation of human MOLT4 T-ALL cells. We further demonstrate that ERG expression in primary human T ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. This enhancer is not active in normal T cells but in transgenic mice targets expression to fetal liver c-kit(+) cells, adult bone marrow stem/progenitors and early CD4(-)CD8(-) double-negative thymic progenitors. Taken together, these data illustrate that ERG promotes T-ALL and that failure to extinguish activity of stem cell enhancers associated with regulatory transcription factors such as ERG can contribute to the development of leukemia. PMID- 21536860 TI - Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium. AB - The Lunenburg Lymphoma Biomarker Consortium (LLBC) evaluated the prognostic value of IHC biomarkers in a large series of patients with diffuse large B-cell lymphoma (DLBCL). Clinical data and tumor samples were retrieved from 12 studies from Europe and North America, with patients treated before or after the rituximab era. Using tissue microarrays from 1514 patients, IHC for BCL2, BCL6, CD5, CD10, MUM1, Ki67, and HLA-DR was performed and scored according to previously validated protocols. Optimal cut points predicting overall survival of patients treated in the rituximab era could only be determined for CD5 (P = .003) and Ki67 (P = .02), whereas such cut points for BCL2, BCL6, HLA-DR, and MUM1 could only be defined in patients not receiving rituximab. A prognostic model for patients treated in the rituximab era identified 4 risk groups using BCL2, Ki67, and International Prognostic Index (IPI) with improved discrimination of low-risk patients. Newly recognized correlations between specific biomarkers and IPI highlight the importance of carefully controlling for clinical and biologic factors in prognostic models. These data demonstrate that the IPI remains the best available index in patients with DLBCL treated with rituximab and chemotherapy. PMID- 21536861 TI - Kindlin-3 is required for the stabilization of TCR-stimulated LFA-1:ICAM-1 bonds critical for lymphocyte arrest and spreading on dendritic cells. AB - Kindlin-3 is a key lymphocyte function-associated antigen-1 (LFA-1) coactivator deleted in leukocyte adhesion deficiency-III (LAD-III). In the present study, we investigated the involvement of this adaptor in lymphocyte motility and TCR triggered arrest on ICAM-1 or on dendritic cells (DCs). Kindlin-3-null primary T cells from a LAD-III patient migrated normally on the major lymph node chemokine CCL21 and engaged in normal TCR signaling. However, TCR activation of Kindlin-3 null T lymphocytes failed to trigger the robust LFA-1-mediated T-cell spreading on ICAM-1 and ICAM-1-expressing DCs that is observed in normal lymphocytes. Kindlin-3 was also essential for cytoskeletal anchorage of the LFA-1 heterodimer and for microclustering of LFA-1 within ventral focal dots of TCR-stimulated lymphocytes spread on ICAM-1. Surprisingly, LFA-1 on Kindlin-3-null lymphocytes migrating over CCL21 acquired normal expression of an epitope associated with the conformational activation of the key headpiece domain, beta I. This activated LFA 1 was highly responsive to TCR-triggered ICAM-1-driven stop signals in normal T cells locomoting on CCL21, but not in their Kindlin-3-null T-cell counterparts. We suggest that Kindlin-3 selectively contributes to a final TCR-triggered outside-in stabilization of bonds generated between chemokine-primed LFA-1 molecules and cell-surface ICAM-1. PMID- 21536862 TI - Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice. AB - Pharmacologic induction of fetal hemoglobin (HbF) expression is an effective treatment strategy for sickle cell disease (SCD) and beta-thalassemia. Pomalidomide is a potent structural analog of thalidomide and member of a new class of immunomodulatory drugs. Recent reports demonstrated that pomalidomide reduced or eliminated transfusion requirements in certain hematologic malignancies and induced HbF ex vivo in CD34(+) progenitor cells from healthy and SCD donors. We investigated the effects of pomalidomide on erythropoiesis and hemoglobin synthesis in a transgenic mouse model of SCD. We found that 8 weeks of treatment with pomalidomide induced modest increases of HbF with similar efficacy as hydroxyurea. However, in stark contrast to hydroxyurea's myelosuppressive effects, pomalidomide augmented erythropoiesis and preserved bone marrow function. Surprisingly, combinatory therapy with both drugs failed to mitigate hydroxyurea's myelotoxic effects and caused loss of HbF induction. These findings support further evaluation of pomalidomide as a novel therapy for SCD. PMID- 21536863 TI - The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. AB - Symptomatic burden in myeloproliferative neoplasms is present in most patients and compromises quality of life. We sought to validate a broadly applicable 18 item instrument (Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF], coadministered with the Brief Fatigue Inventory) to assess symptoms of myelofibrosis, essential thrombocythemia, and polycythemia vera among prospective cohorts in the United States, Sweden, and Italy. A total of 402 MPN-SAF surveys were administered (English [25%], Italian [46%], and Swedish [28%]) in 161 patients with essential thrombocythemia, 145 patients with polycythemia vera, and 96 patients with myelofibrosis. Responses among the 3 administered languages showed great consistency after controlling for MPN subtype. Strong correlations existed between individual items and key symptomatic elements represented on both the MPN-SAF and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30. Enrolling physicians' blinded opinion of patient symptoms (6 symptoms assessed) were highly correlated with corresponding patients' responses. Serial administration of the English MPN-SAF among 53 patients showed that most MPN-SAF items are well correlated (r > 0.5, P < .001) and highly reproducible (intraclass correlation coefficient > 0.7). The MPN-SAF is a comprehensive and reliable instrument that is available in multiple languages to evaluate symptoms associated with all types of MPNs in clinical trials globally. PMID- 21536864 TI - Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. AB - The outcome of chronic myeloid leukemia (CML) has been profoundly changed by the introduction of tyrosine kinase inhibitors into therapy, but the prognosis of patients with CML is still evaluated using prognostic scores developed in the chemotherapy and interferon era. The present work describes a new prognostic score that is superior to the Sokal and Euro scores both in its prognostic ability and in its simplicity. The predictive power of the score was developed and tested on a group of patients selected from a registry of 2060 patients enrolled in studies of first-line treatment with imatinib-based regimes. The EUTOS score using the percentage of basophils and spleen size best discriminated between high-risk and low-risk groups of patients, with a positive predictive value of not reaching a CCgR of 34%. Five-year progression-free survival was significantly better in the low- than in the high-risk group (90% vs 82%, P = .006). These results were confirmed in the validation sample. The score can be used to identify CML patients with significantly lower probabilities of responding to therapy and survival, thus alerting physicians to those patients who require closer observation and early intervention. PMID- 21536865 TI - Stimulus-dependent EEG activity reflects internal updating of tactile working memory in humans. AB - Despite recent advances in uncovering the neural signature of tactile working memory processing in animals and humans, the representation of internally modified somatosensory working memory content has not been studied so far. Here, recording EEG in human participants (n = 25) performing a modified delayed match to-sample task allowed us to disambiguate internally driven memory processing from encoding-related delay activity. After presentation of two distinct vibrotactile frequencies to different index fingers, a visual cue indicated which of the two previous stimuli had to be maintained in working memory throughout a retention interval for subsequent frequency discrimination against a probe stimulus. During cued stimulus maintenance, alpha activity (8-13 Hz) over early somatosensory cortices was lateralized according to the cued tactile stimulus, even though the location of the stimuli was task irrelevant. The task-relevant memory content, in contrast, was found to be represented in right prefrontal cortex. The key finding was that the visually presented instructions triggered systematic modulations of prefrontal beta-band activity (20-25 Hz), which selectively reflected the to-be-maintained frequency of the cued tactile vibration. The results expand previous evidence for parametric representations of vibrotactile frequency in the prefrontal cortex and corroborate a central role of dynamic beta-band synchronization during active processing of an analog stimulus quantity in human working memory. In particular, our findings suggest that such processing supports not only sustained maintenance but also purposeful modification and updating of the task-relevant working memory contents. PMID- 21536866 TI - Enhanced synaptic plasticity in mice with phosphomimetic mutation of the GluA1 AMPA receptor. AB - Phosphorylation of the GluA1 subunit of AMPA receptors has been proposed to regulate receptor trafficking and synaptic transmission and plasticity. However, it remains unclear whether GluA1 phosphorylation is permissive or sufficient for enacting these functional changes. Here we investigate the role of GluA1 phosphorylation at S831 and S845 residues in the hippocampus through the analyses of GluA1 S831D/S845D phosphomimetic knock-in mice. S831D/S845D mice showed normal total and surface expression and subcellular localization of GluA1 as well as intact basal synaptic transmission. In addition, theta-burst stimulation, a protocol that was sufficient to induce robust long-term potentiation (LTP) in WT mice, resulted in LTP of similar magnitude in S831D/S845D mice. However, S831D/S845D mice showed LTP induced with 10-Hz stimulation, a protocol that is weaker than theta-burst stimulation and was not sufficient to induce LTP in WT mice. Moreover, S831D/S845D mice exhibited LTP induced with spike-timing dependent plasticity (STDP) protocol at a long pre-post interval that was subthreshold for WT mice, although a suprathreshold STDP protocol at a short pre post interval resulted in similarly robust LTP for WT and S831D/S845D mice. These results indicate that phosphorylation of GluA1 at S831 and S845 is sufficient to lower the threshold for LTP induction, increasing the probability of synaptic plasticity. PMID- 21536867 TI - Whole-genome phylogeny of Escherichia coli/Shigella group by feature frequency profiles (FFPs). AB - A whole-genome phylogeny of the Escherichia coli/Shigella group was constructed by using the feature frequency profile (FFP) method. This alignment-free approach uses the frequencies of l-mer features of whole genomes to infer phylogenic distances. We present two phylogenies that accentuate different aspects of E. coli/Shigella genomic evolution: (i) one based on the compositions of all possible features of length l = 24 (~8.4 million features), which are likely to reveal the phenetic grouping and relationship among the organisms and (ii) the other based on the compositions of core features with low frequency and low variability (~0.56 million features), which account for ~69% of all commonly shared features among 38 taxa examined and are likely to have genome-wide lineal evolutionary signal. Shigella appears as a single clade when all possible features are used without filtering of noncore features. However, results using core features show that Shigella consists of at least two distantly related subclades, implying that the subclades evolved into a single clade because of a high degree of convergence influenced by mobile genetic elements and niche adaptation. In both FFP trees, the basal group of the E. coli/Shigella phylogeny is the B2 phylogroup, which contains primarily uropathogenic strains, suggesting that the E. coli/Shigella ancestor was likely a facultative or opportunistic pathogen. The extant commensal strains diverged relatively late and appear to be the result of reductive evolution of genomes. We also identify clade distinguishing features and their associated genomic regions within each phylogroup. Such features may provide useful information for understanding evolution of the groups and for quick diagnostic identification of each phylogroup. PMID- 21536868 TI - Posttranscriptional activation of gene expression in Xenopus laevis oocytes by microRNA-protein complexes (microRNPs). AB - MicroRNA-protein complexes (microRNPs) can activate translation of target reporters and specific mRNAs in quiescent (i.e., G0) mammalian cell lines. Induced quiescent cells, like folliculated immature oocytes, have high levels of cAMP that activate protein kinase AII (PKAII) to maintain G0 and immature states. We report microRNA-mediated up-regulated expression of reporters in immature Xenopus laevis oocytes, dependent on Xenopus AGO or human AGO2 and on FXR1, as in mammalian cells. Importantly, we find that maintenance of cAMP levels and downstream PKAII signaling are required for microRNA-mediated up-regulated expression in oocytes. We identify an important, endogenous cell state regulator, Myt1 kinase, as a natural target of microRNA-mediated up-regulation in response to xlmiR16, ensuring maintenance of oocyte immaturity. Our data reveal the physiological relevance of cAMP/PKAII-controlled posttranscriptional gene expression activation by microRNAs in maintenance of the immature oocyte state. PMID- 21536869 TI - QnAs with Leroy E. Hood. Interview by Prashant Nair. PMID- 21536870 TI - Molecular evidence for a single evolutionary origin of domesticated rice. AB - Asian rice, Oryza sativa, is one of world's oldest and most important crop species. Rice is believed to have been domesticated ~9,000 y ago, although debate on its origin remains contentious. A single-origin model suggests that two main subspecies of Asian rice, indica and japonica, were domesticated from the wild rice O. rufipogon. In contrast, the multiple independent domestication model proposes that these two major rice types were domesticated separately and in different parts of the species range of wild rice. This latter view has gained much support from the observation of strong genetic differentiation between indica and japonica as well as several phylogenetic studies of rice domestication. We reexamine the evolutionary history of domesticated rice by resequencing 630 gene fragments on chromosomes 8, 10, and 12 from a diverse set of wild and domesticated rice accessions. Using patterns of SNPs, we identify 20 putative selective sweeps on these chromosomes in cultivated rice. Demographic modeling based on these SNP data and a diffusion-based approach provide the strongest support for a single domestication origin of rice. Bayesian phylogenetic analyses implementing the multispecies coalescent and using previously published phylogenetic sequence datasets also point to a single origin of Asian domesticated rice. Finally, we date the origin of domestication at ~8,200-13,500 y ago, depending on the molecular clock estimate that is used, which is consistent with known archaeological data that suggests rice was first cultivated at around this time in the Yangtze Valley of China. PMID- 21536873 TI - Combining high biodiversity with high yields in tropical agroforests. AB - Local and landscape-scale agricultural intensification is a major driver of global biodiversity loss. Controversially discussed solutions include wildlife friendly farming or combining high-intensity farming with land-sparing for nature. Here, we integrate biodiversity and crop productivity data for smallholder cacao in Indonesia to exemplify for tropical agroforests that there is little relationship between yield and biodiversity under current management, opening substantial opportunities for wildlife-friendly management. Species richness of trees, fungi, invertebrates, and vertebrates did not decrease with yield. Moderate shade, adequate labor, and input level can be combined with a complex habitat structure to provide high biodiversity as well as high yields. Although livelihood impacts are held up as a major obstacle for wildlife-friendly farming in the tropics, our results suggest that in some situations, agroforests can be designed to optimize both biodiversity and crop production benefits without adding pressure to convert natural habitat to farmland. PMID- 21536872 TI - SecB-like chaperone controls a toxin-antitoxin stress-responsive system in Mycobacterium tuberculosis. AB - A major step in the biogenesis of newly synthesized precursor proteins in bacteria is their targeting to the Sec translocon at the inner membrane. In gram negative bacteria, the chaperone SecB binds nonnative forms of precursors and specifically transfers them to the SecA motor component of the translocase, thus facilitating their export. The major human pathogen Mycobacterium tuberculosis is an unusual gram-positive bacterium with a well-defined outer membrane and outer membrane proteins. Assistance to precursor proteins by chaperones in this bacterium remains largely unexplored. Here we show that the product of the previously uncharacterized Rv1957 gene of M. tuberculosis can substitute for SecB functions in Escherichia coli and prevent preprotein aggregation in vitro. Interestingly, in M. tuberculosis, Rv1957 is clustered with a functional stress responsive higB-higA toxin-antitoxin (TA) locus of unknown function. Further in vivo experiments in E. coli and in Mycobacterium marinum strains that do not possess the TA-chaperone locus show that the severe toxicity of the toxin was entirely inhibited when the antitoxin and the chaperone were jointly expressed. We found that Rv1957 acts directly on the antitoxin by preventing its aggregation and protecting it from degradation. Taken together, our results show that the SecB-like chaperone Rv1957 specifically controls a stress-responsive TA system relevant for M. tuberculosis adaptive response. PMID- 21536871 TI - T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. AB - The glycoproteins (GP) of enveloped viruses facilitate entry into the host cell by interacting with specific cellular receptors. Despite extensive study, a cellular receptor for the deadly filoviruses Ebolavirus and Marburgvirus has yet to be identified and characterized. Here, we show that T-cell Ig and mucin domain 1 (TIM-1) binds to the receptor binding domain of the Zaire Ebola virus (EBOV) glycoprotein, and ectopic TIM-1 expression in poorly permissive cells enhances EBOV infection by 10- to 30-fold. Conversely, reduction of cell-surface expression of TIM-1 by RNAi decreased infection of highly permissive Vero cells. TIM-1 expression within the human body is broader than previously appreciated, with expression on mucosal epithelia from the trachea, cornea, and conjunctiva- tissues believed to be important during in vivo transmission of filoviruses. Recognition that TIM-1 serves as a receptor for filoviruses on these mucosal epithelial surfaces provides a mechanistic understanding of routes of entry into the human body via inhalation of aerosol particles or hand-to-eye contact. ARD5, a monoclonal antibody against the IgV domain of TIM-1, blocked EBOV binding and infection, suggesting that antibodies or small molecules directed against this cellular receptor may provide effective filovirus antivirals. PMID- 21536874 TI - Activity-dependent targeting of TRPV1 with a pore-permeating capsaicin analog. AB - The capsaicin receptor TRPV1 is the principal transduction channel for nociception. Excessive TRPV1 activation causes pathological pain. Ideal pain mangement requires selective inhibition of hyperactive pain-sensing neurons, but sparing normal nociception. We sought to determine whether it is possible to use activity-dependent TRPV1 agonists to identify nerves with excessive TRPV1 activity, as well as exploit the TRPV1 pore to deliver charged anesthetics for neuronal silencing. We synthesized a series of permanently charged capsaicinoids and found that one, cap-ET, efficaciously evoked TRPV1-dependent entry of Ca(2+) or the large cationic dye YO-PRO-1 comparably to capsaicin, but far smaller electrical currents. Cap-ET-induced YO-PRO-1 transport required permeation of both the agonist and the dye through the TRPV1 pore and could be enhanced by kinase activation or oxidative covalent modification. Moreover, cap-ET reduced capsaicin-induced currents by a voltage-dependent block of the pore. A low dose of cap-ET elicited entry of permanently charged Na(+) channel blockers to effectively suppress Na(+) currents in sensory neurons presensitized with oxidative chemicals. These results implicate therapeutic potential of these unique TRPV1 agonists exhibiting activity-dependent ion transport but of minimal pain-producing risks. PMID- 21536875 TI - Persistent predator-prey dynamics revealed by mass extinction. AB - Predator-prey interactions are thought by many researchers to define both modern ecosystems and past macroevolutionary events. In modern ecosystems, experimental removal or addition of taxa is often used to determine trophic relationships and predator identity. Both characteristics are notoriously difficult to infer in the fossil record, where evidence of predation is usually limited to damage from failed attacks, individual stomach contents, one-sided escalation, or modern analogs. As a result, the role of predation in macroevolution is often dismissed in favor of competition and abiotic factors. Here we show that the end-Devonian Hangenberg event (359 Mya) was a natural experiment in which vertebrate predators were both removed and added to an otherwise stable prey fauna, revealing specific and persistent trophic interactions. Despite apparently favorable environmental conditions, crinoids diversified only after removal of their vertebrate consumers, exhibiting predatory release on a geological time scale. In contrast, later Mississippian (359-318 Mya) camerate crinoids declined precipitously in the face of increasing predation pressure from new durophagous fishes. Camerate failure is linked to the retention of obsolete defenses or "legacy adaptations" that prevented coevolutionary escalation. Our results suggest that major crinoid evolutionary phenomena, including rapid diversification, faunal turnover, and species selection, might be linked to vertebrate predation. Thus, interactions observed in small ecosystems, such as Lotka-Volterra cycles and trophic cascades, could operate at geologic time scales and higher taxonomic ranks. Both trophic knock-on effects and retention of obsolete traits might be common in the aftermath of predator extinction. PMID- 21536876 TI - Autoregulation of an RNA polymerase II promoter by the RNA polymerase III transcription factor III C (TF(III)C) complex. AB - Extra TF(III)C (ETC) sites are chromosomal locations bound in vivo by the RNA polymerase III (Pol III) transcription factor III C (TF(III)C) complex, but are not necessarily associated with Pol III transcription. Although the location of ETC sequences are conserved in budding yeast, and similar sites are found in other organisms, their functions are largely unstudied. One such site, ETC6 in Saccharomyces cerevisiae, lies upstream of TFC6, a gene encoding a subunit of the TF(III)C complex itself. Promoter analysis shows that the ETC6 B-box sequence is involved in autoregulation of the TFC6 promoter. Mutation of ETC6 increases TFC6 mRNA levels, whereas mutation immediately upstream severely weakens promoter activity. A temperature-sensitive mutation in TFC3 that weakens DNA binding of TF(III)C also results in increased TFC6 mRNA levels; however, no increase is observed in mutants of TF(III)B or Pol III subunits, demonstrating a specific role for the TF(III)C complex in TFC6 promoter regulation. Chromatin immunoprecipitation shows an inverse relationship of TF(III)C occupancy at ETC6 versus TFC6 mRNA levels. Overexpression of TFC6 increases association of TF(III)C at ETC6 (and other loci) and results in reduced expression of a TFC6 promoter URA3 reporter gene. Both of these effects are dependent on the ETC6 B-box. These results demonstrate that the TFC6 promoter is directly regulated by the TF(III)C complex, a demonstration of an RNA polymerase II promoter being directly responsive to a core Pol III transcription factor complex. This regulation could have implications in controlling global tRNA expression levels. PMID- 21536877 TI - Cadherin-11 regulates fibroblast inflammation. AB - Fibroblasts are important participants in inflammation. Although not leukocytes, their capacity to produce cytokines, chemokines, and other inflammatory factors locally in tissues suggests that they can contribute to inflammatory diseases. For example, fibroblasts in a rheumatoid arthritis (RA) joint are a dominant source of IL-6 and RANKL in the synovium, both of which are therapeutic targets for inflammation and bone erosion. Previously, we found that fibroblasts can be targeted by mAb directed against cadherin-11 (cad-11), a mesenchymal cadherin that fibroblasts selectively express. Targeting cad-11 significantly reduced inflammation as assessed by joint swelling and clinical inflammation scores. However, the mechanism by which anti-cad-11 reduced inflammation was not known. Here, we show that cad-11 engagement induces synovial fibroblasts to secret proinflammatory cytokines including IL-6. Cad-11 engagement strongly synergized with TNF-alpha and IL-1beta in the induction of IL-6. Importantly, cad-11 activated MAP kinases and NF-kappaB for IL-6 induction. IL-6 levels in ankles of inflamed joints were reduced in cad-11 mutant mice compared to wild-type mice with inflammatory arthritis. Thus, we suggest that cad-11 modulates synovial fibroblasts to evoke inflammatory factors that may contribute to the inflammatory process in RA. PMID- 21536878 TI - Interdicting protease-activated receptor-2-driven inflammation with cell penetrating pepducins. AB - Protease-activated receptor-2 (PAR2), a cell surface receptor for trypsin-like proteases, plays a key role in a number of acute and chronic inflammatory diseases of the joints, lungs, brain, gastrointestinal tract, and vascular systems. Despite considerable effort by the pharmaceutical industry, PAR2 has proven recalcitrant to targeting by small molecule inhibitors, which have been unable to effectively prevent the interaction of the protease-generated tethered ligand with the body of the receptor. Here, we report the development of first-in class cell-penetrating lipopeptide "pepducin" antagonists of PAR2. The design of the third intracellular (i3) loop pepducins were based on a structural model of a PAR2 dimer and by mutating key pharmacophores in the receptor intracellular loops and analogous pepducins. Individual pharmacophores were identified, which controlled constitutive, agonist, and antagonist activities. This approach culminated in the identification of the P2pal-18S pepducin which completely suppressed trypsin and mast cell tryptase signaling through PAR2 in neutrophils and colon cancer cells. The PAR2 pepducin was highly efficacious in blocking PAR2 dependent inflammatory responses in mouse models. These effects were lost in PAR2 deficient and mast-cell-deficient mice, thereby validating the specificity of the pepducin in vivo. These data provide proof of concept that PAR2 pepducin antagonists may afford effective treatments of potentially debilitating inflammatory diseases and serve as a blueprint for developing highly potent and specific i3-loop-based pepducins for other G protein-coupled receptors (GPCRs). PMID- 21536879 TI - Profile of Stephen E. Plog. PMID- 21536880 TI - Influenza virus aerosol exposure and analytical system for ferrets. AB - Understanding the transmission ability of newly emerging influenza viruses is central to the development of public health preparedness and prevention strategies. Animals are used to model influenza virus infection and transmission, but the routinely used intranasal inoculation of a liquid virus suspension does not reflect natural infection. We report the development of an inoculation method that delivers an influenza virus aerosol inoculum to ferrets and the characterization of size distribution and viable virus present in aerosols shed from infected ferrets during normal breathing and sneezing. By comparing virus deposition, infectivity, virulence, and transmissibility among animals inoculated intranasally or by aerosols with a human (H3N2) or avian (H5N1) influenza virus, we demonstrate that aerosol inoculations more closely resemble a natural, airborne influenza virus infection and that viable virus is measurable in droplets and droplet nuclei exhaled by infected ferrets. These methods will provide improved risk assessment of emerging influenza viruses that pose a threat to public health. PMID- 21536882 TI - Evolution of personality differences in leadership. AB - When members of a group differ in their preferred course of action, coordination poses a challenge. Leadership offers one way to resolve this difficulty, but the evolution of leaders and followers is itself poorly understood. Existing discussions have frequently attributed leadership to differences in information or need among individuals. Here, however, we show that in an n-player, repeated coordination game, selection leads to evolutionary branching and diversification in intrinsic leadership among the members of a population even in the absence of any variation in state. When individuals interact in pairs, repeated branching is possible; when individuals interact in larger groups, the typical outcome is a single branching event leading to a dimorphism featuring extreme intrinsic leaders and followers. These personality types emerge and are maintained by frequency-dependent selection, because leaders gain by imposing their preferences on followers, but fail to coordinate effectively when interacting with other leaders. The fraction of intrinsic leaders in the population increases with the degree of conflict among group members, with both types common only at intermediate levels of conflict; when conflict is weak, most individuals are intrinsic followers, and groups achieve high levels of coordination by randomly converging on one individual's preferred option, whereas when conflict is strong, most individuals are intrinsic leaders, and coordination breaks down because members of a group are rarely willing to follow another. PMID- 21536884 TI - General rules for managing and surveying networks of pests, diseases, and endangered species. AB - The efficient management of diseases, pests, or endangered species is an important global issue faced by agencies constrained by limited resources. The management challenge is even greater when organisms are difficult to detect. We show how to prioritize management and survey effort across time and space for networks of susceptible-infected-susceptible subpopulations. We present simple and robust rules of thumb for protecting desirable, or eradicating undesirable, subpopulations connected in typical network patterns (motifs). We further demonstrate that these rules can be generalized to larger networks when motifs are combined in more complex formations. Results show that the best location to manage or survey a pest or a disease on a network is also the best location to protect or survey an endangered species. The optimal starting point in a network is the fastest motif to manage, where line, star, island, and cluster motifs range from fast to slow. Managing the most connected node at the right time and maintaining the same management direction provide advantages over previously recommended outside-in strategies. When a species or disease is not detected and our belief in persistence decreases, our results recommend shifting resources toward management or surveillance of the most connected nodes. Our analytic approximation provides guidance on how long we should manage or survey networks for hard-to-detect organisms. Our rules take into account management success, dispersal, economic cost, and imperfect detection and offer managers a practical basis for managing networks relevant to many significant environmental, biosecurity, and human health issues. PMID- 21536883 TI - Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin dependent kinase (CDK) inhibitor. AB - Cushing disease caused by adrenocorticotropin (ACTH)-secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes, hypertension, osteoporosis, central obesity, cardiovascular morbidity, and increased mortality. There is no effective pituitary targeted pharmacotherapy for Cushing disease. Here, we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene (PTTG/securin) targeted to the adenohypophyseal proopiomelanocortin (POMC) lineage, which recapitulated early features pathognomonic of corticotroph adenomas, including corticotroph expansion and partial glucocorticoid resistance. Adult Tg:Pomc-Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up-regulation, as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease. Early development of corticotroph pathologies in Tg:Pomc-Pttg embryos facilitated drug testing in vivo. We identified a pharmacologic CDK2/cyclin E inhibitor, R roscovitine (seliciclib; CYC202), which specifically reversed corticotroph expansion in live Tg:Pomc-Pttg embryos. We further validated that orally administered R-roscovitine suppresses ACTH and corticosterone levels, and also restrained tumor growth in a mouse model of ACTH-secreting pituitary adenomas. Molecular analyses in vitro and in vivo showed that R-roscovitine suppresses ACTH expression, induces corticotroph tumor cell senescence and cell cycle exit by up regulating p27, p21 and p57, and downregulates cyclin E expression. The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion. PMID- 21536885 TI - Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration. AB - The ubiquitin-proteasome pathway plays an important role in the pathogenesis of neurodegeneration, but mechanisms controlling expression of components in this pathway remain poorly understood. Nuclear factor E2-related factor 1 (Nrf1) transcription factor has been shown to regulate expression of antioxidant and cytoprotective genes. To determine the function of Nrf1 in the brain, mice with a late-stage deletion of Nrf1 in neuronal cells were generated. Loss of Nrf1 leads to impaired proteasome function and neurodegeneration. Gene expression profiling and RT-PCR analysis revealed a coordinate down-regulation of various proteasomal genes including PsmB6, which encodes a catalytic subunit of the proteasome. Transcriptional analysis and chromatin immunoprecipitation experiments demonstrated that PsmB6 is an Nrf1 target gene. These findings reveal Nrf1 as a key transcriptional regulator required for the expression of proteasomal genes in neurons and suggest that perturbations of Nrf1 function may contribute to the pathogenesis of neurodegenerative diseases. PMID- 21536886 TI - Overt attention toward oriented objects in free-viewing barn owls. AB - Visual saliency based on orientation contrast is a perceptual product attributed to the functional organization of the mammalian brain. We examined this visual phenomenon in barn owls by mounting a wireless video microcamera on the owls' heads and confronting them with visual scenes that contained one differently oriented target among similarly oriented distracters. Without being confined by any particular task, the owls looked significantly longer, more often, and earlier at the target, thus exhibiting visual search strategies so far demonstrated in similar conditions only in primates. Given the considerable differences in phylogeny and the structure of visual pathways between owls and humans, these findings suggest that orientation saliency has computational optimality in a wide variety of ecological contexts, and thus constitutes a universal building block for efficient visual information processing in general. PMID- 21536887 TI - Synchronized arousal between performers and related spectators in a fire-walking ritual. AB - Collective rituals are present in all known societies, but their function is a matter of long-standing debates. Field observations suggest that they may enhance social cohesion and that their effects are not limited to those actively performing but affect the audience as well. Here we show physiological effects of synchronized arousal in a Spanish fire-walking ritual, between active participants and related spectators, but not participants and other members of the audience. We assessed arousal by heart rate dynamics and applied nonlinear mathematical analysis to heart rate data obtained from 38 participants. We compared synchronized arousal between fire-walkers and spectators. For this comparison, we used recurrence quantification analysis on individual data and cross-recurrence quantification analysis on pairs of participants' data. These methods identified fine-grained commonalities of arousal during the 30-min ritual between fire-walkers and related spectators but not unrelated spectators. This indicates that the mediating mechanism may be informational, because participants and related observers had very different bodily behavior. This study demonstrates that a collective ritual may evoke synchronized arousal over time between active participants and bystanders. It links field observations to a physiological basis and offers a unique approach for the quantification of social effects on human physiology during real-world interactions. PMID- 21536881 TI - Contemporaneous and recent radiations of the world's major succulent plant lineages. AB - The cacti are one of the most celebrated radiations of succulent plants. There has been much speculation about their age, but progress in dating cactus origins has been hindered by the lack of fossil data for cacti or their close relatives. Using a hybrid phylogenomic approach, we estimated that the cactus lineage diverged from its closest relatives ~35 million years ago (Ma). However, major diversification events in cacti were more recent, with most species-rich clades originating in the late Miocene, ~10-5 Ma. Diversification rates of several cactus lineages rival other estimates of extremely rapid speciation in plants. Major cactus radiations were contemporaneous with those of South African ice plants and North American agaves, revealing a simultaneous diversification of several of the world's major succulent plant lineages across multiple continents. This short geological time period also harbored the majority of origins of C(4) photosynthesis and the global rise of C(4) grasslands. A global expansion of arid environments during this time could have provided new ecological opportunity for both succulent and C(4) plant syndromes. Alternatively, recent work has identified a substantial decline in atmospheric CO(2) ~15-8 Ma, which would have strongly favored C(4) evolution and expansion of C(4)-dominated grasslands. Lowered atmospheric CO(2) would also substantially exacerbate plant water stress in marginally arid environments, providing preadapted succulent plants with a sharp advantage in a broader set of ecological conditions and promoting their rapid diversification across the landscape. PMID- 21536888 TI - Unique system of photoreceptors in sea urchin tube feet. AB - Different sea urchin species show a vast variety of responses to variations in light intensity; however, despite this behavioral evidence for photosensitivity, light sensing in these animals has remained an enigma. Genome information of the recently sequenced purple sea urchin (Strongylocentrotus purpuratus) allowed us to address this question from a previously unexplored molecular perspective by localizing expression of the rhabdomeric opsin Sp-opsin4 and Sp-pax6, two genes essential for photoreceptor function and development, respectively. Using a specifically designed antibody against Sp-Opsin4 and in situ hybridization for both genes, we detected expression in two distinct groups of photoreceptor cells (PRCs) located in the animal's numerous tube feet. Specific reactivity of the Sp Opsin4 antibody with sea star optic cushions, which regulate phototaxis, suggests a similar visual function in sea urchins. Ultrastructural characterization of the sea urchin PRCs revealed them to be of a microvillar receptor type. Our data suggest that echinoderms, in contrast to chordates, deploy a microvillar, r-opsin expressing PRC type for vision, a feature that has been so far documented only in protostome animals. Surprisingly, sea urchin PRCs lack any associated screening pigment. Indeed, one of the tube foot PRC clusters may account for directional vision by being shaded through the opaque calcite skeleton. The PRC axons connect to the animal internal nervous system, suggesting an integrative function beyond local short circuits. Because juveniles display no phototaxis until skeleton completion, we suggest a model in which the entire sea urchin, deploying its skeleton as PRC screening device, functions as a huge compound eye. PMID- 21536889 TI - Unexpected patterns of fisheries collapse in the world's oceans. AB - Understanding which species are most vulnerable to human impacts is a prerequisite for designing effective conservation strategies. Surveys of terrestrial species have suggested that large-bodied species and top predators are the most at risk, and it is commonly assumed that such patterns also apply in the ocean. However, there has been no global test of this hypothesis in the sea. We analyzed two fisheries datasets (stock assessments and landings) to determine the life-history traits of species that have suffered dramatic population collapses. Contrary to expectations, our data suggest that up to twice as many fisheries for small, low trophic-level species have collapsed compared with those for large predators. These patterns contrast with those on land, suggesting fundamental differences in the ways that industrial fisheries and land conversion affect natural communities. Even temporary collapses of small, low trophic-level fishes can have ecosystem-wide impacts by reducing food supply to larger fish, seabirds, and marine mammals. PMID- 21536890 TI - Sex difference in the near-24-hour intrinsic period of the human circadian timing system. AB - The circadian rhythms of melatonin and body temperature are set to an earlier hour in women than in men, even when the women and men maintain nearly identical and consistent bedtimes and wake times. Moreover, women tend to wake up earlier than men and exhibit a greater preference for morning activities than men. Although the neurobiological mechanism underlying this sex difference in circadian alignment is unknown, multiple studies in nonhuman animals have demonstrated a sex difference in circadian period that could account for such a difference in circadian alignment between women and men. Whether a sex difference in intrinsic circadian period in humans underlies the difference in circadian alignment between men and women is unknown. We analyzed precise estimates of intrinsic circadian period collected from 157 individuals (52 women, 105 men; aged 18-74 y) studied in a month-long inpatient protocol designed to minimize confounding influences on circadian period estimation. Overall, the average intrinsic period of the melatonin and temperature rhythms in this population was very close to 24 h [24.15 +/- 0.2 h (24 h 9 min +/- 12 min)]. We further found that the intrinsic circadian period was significantly shorter in women [24.09 +/- 0.2 h (24 h 5 min +/- 12 min)] than in men [24.19 +/- 0.2 h (24 h 11 min +/- 12 min); P < 0.01] and that a significantly greater proportion of women have intrinsic circadian periods shorter than 24.0 h (35% vs. 14%; P < 0.01). The shorter average intrinsic circadian period observed in women may have implications for understanding sex differences in habitual sleep duration and insomnia prevalence. PMID- 21536891 TI - Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23~27~24 clusters. AB - MicroRNAs (miRNAs) modulate complex physiological and pathological processes by repressing expression of multiple components of cellular regulatory networks. Here we demonstrate that miRNAs encoded by the miR-23~27~24 gene clusters are enriched in endothelial cells and highly vascularized tissues. Inhibition of miR 23 and miR-27 function by locked nucleic acid-modified anti-miRNAs represses angiogenesis in vitro and postnatal retinal vascular development in vivo. Moreover, miR-23 and miR-27 are required for pathological angiogenesis in a laser induced choroidal neovascularization mouse model. MiR-23 and miR-27 enhance angiogenesis by promoting angiogenic signaling through targeting Sprouty2 and Sema6A proteins, which exert antiangiogenic activity. Manipulating miR-23/27 levels may have important therapeutic implications in neovascular age-related macular degeneration and other vascular disorders. PMID- 21536892 TI - Fossil evidence for Cretaceous escalation in angiosperm leaf vein evolution. AB - The flowering plants that dominate modern vegetation possess leaf gas exchange potentials that far exceed those of all other living or extinct plants. The great divide in maximal ability to exchange CO(2) for water between leaves of nonangiosperms and angiosperms forms the mechanistic foundation for speculation about how angiosperms drove sweeping ecological and biogeochemical change during the Cretaceous. However, there is no empirical evidence that angiosperms evolved highly photosynthetically active leaves during the Cretaceous. Using vein density (D(V)) measurements of fossil angiosperm leaves, we show that the leaf hydraulic capacities of angiosperms escalated several-fold during the Cretaceous. During the first 30 million years of angiosperm leaf evolution, angiosperm leaves exhibited uniformly low vein D(V) that overlapped the D(V) range of dominant Early Cretaceous ferns and gymnosperms. Fossil angiosperm vein densities reveal a subsequent biphasic increase in D(V). During the first mid-Cretaceous surge, angiosperm D(V) first surpassed the upper bound of D(V) limits for nonangiosperms. However, the upper limits of D(V) typical of modern megathermal rainforest trees first appear during a second wave of increased D(V) during the Cretaceous-Tertiary transition. Thus, our findings provide fossil evidence for the hypothesis that significant ecosystem change brought about by angiosperms lagged behind the Early Cretaceous taxonomic diversification of angiosperms. PMID- 21536893 TI - Astroglial networks scale synaptic activity and plasticity. AB - Astrocytes dynamically interact with neurons to regulate synaptic transmission. Although the gap junction proteins connexin 30 (Cx30) and connexin 43 (Cx43) mediate the extensive network organization of astrocytes, their role in synaptic physiology is unknown. Here we show, by inactivating Cx30 and Cx43 genes, that astroglial networks tone down hippocampal synaptic transmission in CA1 pyramidal neurons. Gap junctional networking facilitates extracellular glutamate and potassium removal during synaptic activity through modulation of astroglial clearance rate and extracellular space volume. This regulation limits neuronal excitability, release probability, and insertion of postsynaptic AMPA receptors, silencing synapses. By controlling synaptic strength, connexins play an important role in synaptic plasticity. Altogether, these results establish connexins as critical proteins for extracellular homeostasis, important for the formation of functional synapses. PMID- 21536895 TI - Emergency cell swimming. PMID- 21536894 TI - Obligate biotrophy features unraveled by the genomic analysis of rust fungi. AB - Rust fungi are some of the most devastating pathogens of crop plants. They are obligate biotrophs, which extract nutrients only from living plant tissues and cannot grow apart from their hosts. Their lifestyle has slowed the dissection of molecular mechanisms underlying host invasion and avoidance or suppression of plant innate immunity. We sequenced the 101-Mb genome of Melampsora larici populina, the causal agent of poplar leaf rust, and the 89-Mb genome of Puccinia graminis f. sp. tritici, the causal agent of wheat and barley stem rust. We then compared the 16,399 predicted proteins of M. larici-populina with the 17,773 predicted proteins of P. graminis f. sp tritici. Genomic features related to their obligate biotrophic lifestyle include expanded lineage-specific gene families, a large repertoire of effector-like small secreted proteins, impaired nitrogen and sulfur assimilation pathways, and expanded families of amino acid and oligopeptide membrane transporters. The dramatic up-regulation of transcripts coding for small secreted proteins, secreted hydrolytic enzymes, and transporters in planta suggests that they play a role in host infection and nutrient acquisition. Some of these genomic hallmarks are mirrored in the genomes of other microbial eukaryotes that have independently evolved to infect plants, indicating convergent adaptation to a biotrophic existence inside plant cells. PMID- 21536896 TI - The dominantly expressed class I molecule of the chicken MHC is explained by coevolution with the polymorphic peptide transporter (TAP) genes. AB - In most mammals, the MHC class I molecules are polymorphic and determine the specificity of peptide presentation, whereas the transporter associated with antigen presentation (TAP) heterodimers are functionally monomorphic. In chickens, there are two classical class I genes but only one is expressed at a high level, which can result in strong MHC associations with resistance to particular infectious pathogens. However, the basis for having a single dominantly expressed class I molecule has been unclear. Here we report TAP1 and TAP2 sequences from 16 chicken lines, and show that both genes have high allelic polymorphism and moderate sequence diversity, with variation in positions expected for peptide binding. We analyze peptide translocation in two MHC haplotypes, showing that chicken TAPs specify translocation at three peptide positions, matching the peptide motif of the single dominantly expressed class I molecule. These results show that coevolution between class I and TAP genes can explain the presence of a single dominantly expressed class I molecule in common chicken MHC haplotypes. Moreover, such coevolution in the primordial MHC may have been responsible for the appearance of the antigen presentation pathways at the birth of the adaptive immune system. PMID- 21536897 TI - Fluctuating and sensory-induced vasodynamics in rodent cortex extend arteriole capacity. AB - Neural activity in the brain is followed by localized changes in blood flow and volume. We address the relative change in volume for arteriole vs. venous blood within primary vibrissa cortex of awake, head-fixed mice. Two-photon laser scanning microscopy was used to measure spontaneous and sensory evoked changes in flow and volume at the level of single vessels. We find that arterioles exhibit slow (<1 Hz) spontaneous increases in their diameter, as well as pronounced dilation in response to both punctate and prolonged stimulation of the contralateral vibrissae. In contrast, venules dilate only in response to prolonged stimulation. We conclude that stimulation that occurs on the time scale of natural stimuli leads to a net increase in the reservoir of arteriole blood. Thus, a "bagpipe" model that highlights arteriole dilation should augment the current "balloon" model of venous distension in the interpretation of fMRI images. PMID- 21536898 TI - Resetting the evolution of marine reptiles at the Triassic-Jurassic boundary. AB - Ichthyosaurs were important marine predators in the Early Jurassic, and an abundant and diverse component of Mesozoic marine ecosystems. Despite their ecological importance, however, the Early Jurassic species represent a reduced remnant of their former significance in the Triassic. Ichthyosaurs passed through an evolutionary bottleneck at, or close to, the Triassic-Jurassic boundary, which reduced their diversity to as few as three or four lineages. Diversity bounced back to some extent in the aftermath of the end-Triassic mass extinction, but disparity remained at less than one-tenth of pre-extinction levels, and never recovered. The group remained at low diversity and disparity for its final 100 Myr. The end-Triassic mass extinction had a previously unsuspected profound effect in resetting the evolution of apex marine predators of the Mesozoic. PMID- 21536899 TI - Continuous neurogenesis in the adult forebrain is required for innate olfactory responses. AB - Although the functional significance of adult neurogenesis in hippocampal dependent learning and memory has been well documented, the role of such neurogenesis in olfactory activity is rather obscure. To understand the significance of adult neurogenesis in olfactory functions, we genetically ablated newly born neurons by using tamoxifen-treated Nestin-CreER(T2);neuron-specific enolase-diphtheria toxin fragment A (NSE-DTA) mice. In these mice, tamoxifen inducible Cre recombinase allows the NSE (Eno2) gene to drive DTA expression in differentiating neurons, leading to the efficient ablation of newly born neurons in the forebrain. These mutant mice were capable of discriminating odors as competently as control mice. Strikingly, although control and mutant mice frequently showed freezing behaviors to a fox scent, a predator odor, mutant mice approached this odor when they were conditioned to associate the odor with a reward, whereas control mice did not approach the odor. Furthermore, although mutant males and females showed normal social recognition behaviors to other mice of a different sex, mutant males displayed deficits in male-male aggression and male sexual behaviors toward females, whereas mutant females displayed deficits in fertility and nurturing, indicating that sex-specific activities, which are known to depend on olfaction, are impaired. These results suggest that continuous neurogenesis is required for predator avoidance and sex-specific responses that are olfaction dependent and innately programmed. PMID- 21536900 TI - Architecture, sedentism, and social complexity at Pre-Pottery Neolithic A WF16, Southern Jordan. AB - Recent excavations at Pre-Pottery Neolithic A (PPNA) WF16 in southern Jordan have revealed remarkable evidence of architectural developments in the early Neolithic. This sheds light on both special purpose structures and "domestic" settlement, allowing fresh insights into the development of increasingly sedentary communities and the social systems they supported. The development of sedentary communities is a central part of the Neolithic process in Southwest Asia. Architecture and ideas of homes and households have been important to the debate, although there has also been considerable discussion on the role of communal buildings and the organization of early sedentarizing communities since the discovery of the tower at Jericho. Recently, the focus has been on either northern Levantine PPNA sites, such as Jerf el Ahmar, or the emergence of ritual buildings in the Pre-Pottery Neolithic B of the southern Levant. Much of the debate revolves around a division between what is interpreted as domestic space, contrasted with "special purpose" buildings. Our recent evidence allows a fresh examination of the nature of early Neolithic communities. PMID- 21536902 TI - Higher categories, colimits, and the blob complex. AB - We summarize our axioms for higher categories, and describe the "blob complex." Fixing an n-category , the blob complex associates a chain complex B(*)(W;C) to any n-manifold W. The zeroth homology of this chain complex recovers the usual topological quantum field theory invariants of W. The higher homology groups should be viewed as generalizations of Hochschild homology (indeed, when W = S(1), they coincide). The blob complex has a very natural definition in terms of homotopy colimits along decompositions of the manifold W. We outline the important properties of the blob complex and sketch the proof of a generalization of Deligne's conjecture on Hochschild cohomology and the little discs operad to higher dimensions. PMID- 21536901 TI - RNA 3' processing functions of Arabidopsis FCA and FPA limit intergenic transcription. AB - The RNA-binding proteins FCA and FPA were identified based on their repression of the flowering time regulator FLC but have since been shown to have widespread roles in the Arabidopsis thaliana genome. Here, we use whole-genome tiling arrays to show that a wide spectrum of genes and transposable elements are misexpressed in the fca-9 fpa-7 (fcafpa) double mutant at two stages of seedling development. There was a significant bias for misregulated genomic segments mapping to the 3' region of genes. In addition, the double mutant misexpressed a large number of previously unannotated genomic segments corresponding to intergenic regions. We characterized a subset of these misexpressed unannotated segments and established that they resulted from extensive transcriptional read-through, use of downstream polyadenylation sites, and alternative splicing. In some cases, the transcriptional read-through significantly reduced expression of the associated genes. FCA/FPA-dependent changes in DNA methylation were found at several loci, supporting previous associations of FCA/FPA function with chromatin modifications. Our data suggest that FCA and FPA play important roles in the A. thaliana genome in RNA 3' processing and transcription termination, thus limiting intergenic transcription. PMID- 21536903 TI - Broad disorder and the allosteric mechanism of myosin II regulation by phosphorylation. AB - Double electron electron resonance EPR methods was used to measure the effects of the allosteric modulators, phosphorylation, and ATP, on the distances and distance distributions between the two regulatory light chain of myosin (RLC). Three different states of smooth muscle myosin (SMM) were studied: monomers, the short-tailed subfragment heavy meromyosin, and SMM filaments. We reconstituted myosin with nine single cysteine spin-labeled RLC. For all mutants we found a broad distribution of distances that could not be explained by spin-label rotamer diversity. For SMM and heavy meromyosin, several sites showed two heterogeneous populations in the unphosphorylated samples, whereas only one was observed after phosphorylation. The data were consistent with the presence of two coexisting heterogeneous populations of structures in the unphosphorylated samples. The two populations were attributed to an on and off state by comparing data from unphosphorylated and phosphorylated samples. Models of these two states were generated using a rigid body docking approach derived from EM [Wendt T, Taylor D, Trybus KM, Taylor K (2001) Proc Natl Acad Sci USA 98:4361-4366] (PNAS, 2001, 98:4361-4366), but our data revealed a new feature of the off-state, which is heterogeneity in the orientation of the two RLC. Our average off-state structure was very similar to the Wendt model reveal a new feature of the off state, which is heterogeneity in the orientations of the two RLC. As found previously in the EM study, our on-state structure was completely different from the off-state structure. The heads are splayed out and there is even more heterogeneity in the orientations of the two RLC. PMID- 21536904 TI - Interaction between the RNA binding domains of Ser-Arg splicing factor 1 and U1 70K snRNP protein determines early spliceosome assembly. AB - It has been widely accepted that the early spliceosome assembly begins with U1 small nuclear ribonucleoprotein (U1 snRNP) binding to the 5' splice site (5'SS), which is assisted by the Ser/Arg (SR)-rich proteins in mammalian cells. In this process, the RS domain of SR proteins is thought to directly interact with the RS motif of U1-70K, which is subject to regulation by RS domain phosphorylation. Here we report that the early spliceosome assembly event is mediated by the RNA recognition domains (RRM) of serine/arginine-rich splicing factor 1 (SRSF1), which bridges the RRM of U1-70K to pre-mRNA by using the surface opposite to the RNA binding site. Specific mutation in the RRM of SRSF1 that disrupted the RRM RRM interaction also inhibits the formation of spliceosomal E complex and splicing. We further demonstrate that the hypo-phosphorylated RS domain of SRSF1 interacts with its own RRM, thus competing with U1-70K binding, whereas the hyper phosphorylated RS domain permits the formation of a ternary complex containing ESE, an SR protein, and U1 snRNP. Therefore, phosphorylation of the RS domain in SRSF1 appears to induce a key molecular switch from intra- to intermolecular interactions, suggesting a plausible mechanism for the documented requirement for the phosphorylation/dephosphorylation cycle during pre-mRNA splicing. PMID- 21536905 TI - Assessing climate change impacts on the near-term stability of the wind energy resource over the United States. AB - The energy sector comprises approximately two-thirds of global total greenhouse gas emissions. For this and other reasons, renewable energy resources including wind power are being increasingly harnessed to provide electricity generation potential with negligible emissions of carbon dioxide. The wind energy resource is naturally a function of the climate system because the "fuel" is the incident wind speed and thus is determined by the atmospheric circulation. Some recent articles have reported historical declines in measured near-surface wind speeds, leading some to question the continued viability of the wind energy industry. Here we briefly articulate the challenges inherent in accurately quantifying and attributing historical tendencies and making robust projections of likely future wind resources. We then analyze simulations from the current generation of regional climate models and show, at least for the next 50 years, the wind resource in the regions of greatest wind energy penetration will not move beyond the historical envelope of variability. Thus this work suggests that the wind energy industry can, and will, continue to make a contribution to electricity provision in these regions for at least the next several decades. PMID- 21536906 TI - The Arabidopsis thaliana Med25 mediator subunit integrates environmental cues to control plant development. AB - Development in plants is controlled by abiotic environmental cues such as day length, light quality, temperature, drought, and salinity. These signals are sensed by a variety of systems and transmitted by different signal transduction pathways. Ultimately, these pathways are integrated to control expression of specific target genes, which encode proteins that regulate development and differentiation. The molecular mechanisms for such integration have remained elusive. We here show that a linear 130-amino-acids-long sequence in the Med25 subunit of the Arabidopsis thaliana Mediator is a common target for the drought response element binding protein 2A, zinc finger homeodomain 1, and Myb-like transcription factors which are involved in different stress response pathways. In addition, our results show that Med25 together with drought response element binding protein 2A also function in repression of PhyB-mediated light signaling and thus integrate signals from different regulatory pathways. PMID- 21536907 TI - Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex. AB - Human lysyl-tRNA synthetase is bound to the multi-tRNA synthetase complex (MSC) that maintains and regulates the aminoacylation and nuclear functions of LysRS. The p38 scaffold protein binds LysRS to the MSC and, only with the appropriate cue, mobilizes LysRS for redirection to the nucleus to interact with the microphthalmia associated transcription factor (MITF). In recent work, an (alpha(2))(2) LysRS tetramer crystallized to yield a high-resolution structure and raised the question of how LysRS is arranged (dimer or tetramer) in the MSC to interact with p38. To understand the structural organization of the LysRS-p38 complex that regulates LysRS mobilization, we investigated the complex by use of small angle X-ray scattering and hydrogen-deuterium exchange with mass spectrometry in solution. The structure revealed a surprising alpha(2)beta(1):beta(1)alpha(2) organization in which a dimeric p38 scaffold holds two LysRS alpha(2) dimers in a parallel configuration. Each of the N terminal 48 residues of p38 binds one LysRS dimer and, in so doing, brings two copies of the LysRS dimer into the MSC. The results suggest that this unique geometry, which reconfigures the LysRS tetramer from alpha(2):alpha(2) to alpha(2)beta(1):beta(1)alpha(2), is designed to control both retention and mobilization of LysRS from the MSC. PMID- 21536908 TI - Gold nanorods 3D-supercrystals as surface enhanced Raman scattering spectroscopy substrates for the rapid detection of scrambled prions. AB - Highly organized supercrystals of Au nanorods with plasmonic antennae enhancement of electrical field have made possible fast direct detection of prions in complex biological media such as serum and blood. The nearly perfect three-dimensional organization of nanorods render these systems excellent surface enhanced Raman scattering spectroscopy substrates with uniform electric field enhancement, leading to reproducibly high enhancement factor in the desirable spectral range. PMID- 21536909 TI - Quantifying the Waddington landscape and biological paths for development and differentiation. AB - We developed a theoretical framework to prove the existence and quantify the Waddington landscape as well as chreode-biological paths for development and differentiation. The cells can have states with the higher probability ones giving the different cell types. Different cell types correspond to different basins of attractions of the probability landscape. We study how the cells develop from undifferentiated cells to differentiated cells from landscape perspectives. We quantified the Waddington landscape through construction of underlying probability landscape for cell development. We show the developmental process proceeds as moving from undifferentiated to the differentiated basins of attractions. The barrier height of the basins of attractions correlates with the escape time that determines the stability of cell types. We show that the developmental process can be quantitatively described and uncovered by the biological paths on the quantified Waddington landscape from undifferentiated to the differentiated cells. We found the dynamics of the developmental process is controlled by a combination of the gradient and curl force on the landscape. The biological paths often do not follow the steepest descent path on the landscape. The landscape framework also quantifies the possibility of reverse differentiation process such as cell reprogramming from differentiated cells back to the original stem cell. We show that the biological path of reverse differentiation is irreversible and different from the one for differentiation process. We found that the developmental process described by the underlying landscape and the associated biological paths is relatively stable and robust against the influences of environmental perturbations. PMID- 21536910 TI - Slab melting versus slab dehydration in subduction-zone magmatism. AB - The second critical endpoint in the basalt-H(2)O system was directly determined by a high-pressure and high-temperature X-ray radiography technique. We found that the second critical endpoint occurs at around 3.4 GPa and 770 degrees C (corresponding to a depth of approximately 100 km in a subducting slab), which is much shallower than the previously estimated conditions. Our results indicate that the melting temperature of the subducting oceanic crust can no longer be defined beyond this critical condition and that the fluid released from subducting oceanic crust at depths greater than 100 km under volcanic arcs is supercritical fluid rather than aqueous fluid and/or hydrous melts. The position of the second critical endpoint explains why there is a limitation to the slab depth at which adakitic magmas are produced, as well as the origin of across-arc geochemical variations of trace elements in volcanic rocks in subduction zones. PMID- 21536911 TI - Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes. AB - Acetylation of histones triggers association with bromodomain-containing proteins that regulate diverse chromatin-related processes. Although acetylation of transcription factors has been appreciated for some time, the mechanistic consequences are less well understood. The hematopoietic transcription factor GATA1 is acetylated at conserved lysines that are required for its stable association with chromatin. We show that the BET family protein Brd3 binds via its first bromodomain (BD1) to GATA1 in an acetylation-dependent manner in vitro and in vivo. Mutation of a single residue in BD1 that is involved in acetyl lysine binding abrogated recruitment of Brd3 by GATA1, demonstrating that acetylation of GATA1 is essential for Brd3 association with chromatin. Notably, Brd3 is recruited by GATA1 to both active and repressed target genes in a fashion seemingly independent of histone acetylation. Anti-Brd3 ChIP followed by massively parallel sequencing in GATA1-deficient erythroid precursor cells and those that are GATA1 replete revealed that GATA1 is a major determinant of Brd3 recruitment to genomic targets within chromatin. A pharmacologic compound that occupies the acetyl-lysine binding pockets of Brd3 bromodomains disrupts the Brd3 GATA1 interaction, diminishes the chromatin occupancy of both proteins, and inhibits erythroid maturation. Together these findings provide a mechanism for GATA1 acetylation and suggest that Brd3 "reads" acetyl marks on nuclear factors to promote their stable association with chromatin. PMID- 21536912 TI - Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity. AB - Abnormally low plasma concentrations of thyroid hormones during sepsis often occur in the absence of thyroidal illness; however, the mechanisms involved in the "euthyroid sick syndrome" remain poorly understood. Here, we describe a previously unrecognized interaction between the thyroid hormone thyroxine (T(4)) and the proinflammatory cytokine macrophage migration inhibitory factor (MIF), together with its clinical relevance in sepsis. We found that in both patients with severe sepsis, and our rodent model, low plasma T(4) concentrations were inversely correlated with plasma MIF concentrations. The MIF molecule contains a hydrophobic pocket that is important for many of its proinflammatory activities. Binding of L-T(4) (or its hormonally inert isomer D-T(4)) significantly, and dose dependently, inhibited the catalytic activity of this pocket. Moreover, administration of exogenous D-T(4) significantly improved survival in mice with severe sepsis. To examine the specificity of the MIFT(4) interaction, wild-type and MIF knockout mice were subjected to the carrageenan-air pouch model of inflammation and then treated with D-T(4) or vehicle. D-T(4) significantly inhibited leukocyte infiltration in wild-type mice but not in MIF knockout mice, providing evidence that in vivo T(4) may influence MIF-mediated inflammatory responses via inhibition of its hydrophobic proinflammatory pocket. These findings demonstrate a new physiological role for T(4) as a natural inhibitor of MIF proinflammatory activity. The data may also, in part, explain the low plasma T(4) concentrations in critically ill, euthyroid patients and suggest that targeting the imbalance between MIF and T(4) may be beneficial in improving outcome from sepsis. PMID- 21536913 TI - RNA-guided complex from a bacterial immune system enhances target recognition through seed sequence interactions. AB - Prokaryotes have evolved multiple versions of an RNA-guided adaptive immune system that targets foreign nucleic acids. In each case, transcripts derived from clustered regularly interspaced short palindromic repeats (CRISPRs) are thought to selectively target invading phage and plasmids in a sequence-specific process involving a variable cassette of CRISPR-associated (cas) genes. The CRISPR locus in Pseudomonas aeruginosa (PA14) includes four cas genes that are unique to and conserved in microorganisms harboring the Csy-type (CRISPR system yersinia) immune system. Here we show that the Csy proteins (Csy1-4) assemble into a 350 kDa ribonucleoprotein complex that facilitates target recognition by enhancing sequence-specific hybridization between the CRISPR RNA and complementary target sequences. Target recognition is enthalpically driven and localized to a "seed sequence" at the 5' end of the CRISPR RNA spacer. Structural analysis of the complex by small-angle X-ray scattering and single particle electron microscopy reveals a crescent-shaped particle that bears striking resemblance to the architecture of a large CRISPR-associated complex from Escherichia coli, termed Cascade. Although similarity between these two complexes is not evident at the sequence level, their unequal subunit stoichiometry and quaternary architecture reveal conserved structural features that may be common among diverse CRISPR mediated defense systems. PMID- 21536914 TI - Diet of Paranthropus boisei in the early Pleistocene of East Africa. AB - The East African hominin Paranthropus boisei was characterized by a suite of craniodental features that have been widely interpreted as adaptations to a diet that consisted of hard objects that required powerful peak masticatory loads. These morphological adaptations represent the culmination of an evolutionary trend that began in earlier taxa such as Australopithecus afarensis, and presumably facilitated utilization of open habitats in the Plio-Pleistocene. Here, we use stable isotopes to show that P. boisei had a diet that was dominated by C(4) biomass such as grasses or sedges. Its diet included more C(4) biomass than any other hominin studied to date, including its congener Paranthropus robustus from South Africa. These results, coupled with recent evidence from dental microwear, may indicate that the remarkable craniodental morphology of this taxon represents an adaptation for processing large quantities of low quality vegetation rather than hard objects. PMID- 21536915 TI - Successful prediction of the intra- and extracellular loops of four G-protein coupled receptors. AB - We present results of the restoration of all crystallographically available intra and extracellular loops of four G-protein-coupled receptors (GPCRs): bovine rhodopsin (bRh), the turkey beta-1 adrenergic receptor (beta1Ar), and the human beta-2 adrenergic (beta2Ar) and A2A adenosine (A2Ar) receptors. We use our Protein Local Optimization Program (PLOP), which samples conformational space from first principles to build sets of loop candidates and then discriminates between them using our physics-based, all-atom energy function with implicit solvent. We also discuss a new kind of explicit membrane calculation developed for GPCR loops that interact, either in the native structure or in low-energy false-positive structures, with the membrane, and thus exist in a multiphase environment not previously incorporated in PLOP. Our results demonstrate a significant advance over previous work reported in the literature, and of particular note we are able to accurately restore the extremely long second extracellular loop (ECL2), which is also key for GPCR ligand binding. In the case of beta2Ar, accurate ECL2 restoration required seeding a small helix into the loop in the appropriate region, based on alignment with the beta1Ar ECL2 loop, and then running loop reconstruction simulations with and without the seeded helix present; simulations containing the helix attain significantly lower total energies than those without the helix, and have rmsds close to the native structure. For beta1Ar, the same protocol was used, except the alignment was done to beta2Ar. These results represent an encouraging start for the more difficult problem of accurate loop refinement for GPCR homology modeling. PMID- 21536916 TI - The hummingbird tongue is a fluid trap, not a capillary tube. AB - Hummingbird tongues pick up a liquid, calorie-dense food that cannot be grasped, a physical challenge that has long inspired the study of nectar-transport mechanics. Existing biophysical models predict optimal hummingbird foraging on the basis of equations that assume that fluid rises through the tongue in the same way as through capillary tubes. We demonstrate that the hummingbird tongue does not function like a pair of tiny, static tubes drawing up floral nectar via capillary action. Instead, we show that the tongue tip is a dynamic liquid trapping device that changes configuration and shape dramatically as it moves in and out of fluids. We also show that the tongue-fluid interactions are identical in both living and dead birds, demonstrating that this mechanism is a function of the tongue structure itself, and therefore highly efficient because no energy expenditure by the bird is required to drive the opening and closing of the trap. Our results rule out previous conclusions from capillarity-based models of nectar feeding and highlight the necessity of developing a new biophysical model for nectar intake in hummingbirds. Our findings have ramifications for the study of feeding mechanics in other nectarivorous birds, and for the understanding of the evolution of nectarivory in general. We propose a conceptual mechanical explanation for this unique fluid-trapping capacity, with far-reaching practical applications (e.g., biomimetics). PMID- 21536917 TI - Transducin-like enhancer protein 1 mediates estrogen receptor binding and transcriptional activity in breast cancer cells. AB - Estrogen receptor (ER) binds to distal enhancers within the genome and requires additional factors, such as the Forkhead protein FoxA1, for mediating chromatin interactions. We now show that the human Groucho protein, Transducin-like enhancer protein 1 (TLE1), positively assists some ER-chromatin interactions, a role that is distinct from its general role as a transcriptional repressor. We show that specific silencing of TLE1 inhibits the ability of ER to bind to a subset of ER binding sites within the genome, a phenomenon that results in perturbations in phospho-RNA Pol II recruitment. Furthermore, TLE1 is essential for effective ER-mediated cell division. We have discovered a distinct role for TLE1, as a necessary transcriptional component of the ER complex, where it facilitates ER-chromatin interactions. PMID- 21536918 TI - Whole-Teflon microfluidic chips. AB - Although microfluidics has shown exciting potential, its broad applications are significantly limited by drawbacks of the materials used to make them. In this work, we present a convenient strategy for fabricating whole-Teflon microfluidic chips with integrated valves that show outstanding inertness to various chemicals and extreme resistance against all solvents. Compared with other microfluidic materials [e.g., poly(dimethylsiloxane) (PDMS)] the whole-Teflon chip has a few more advantages, such as no absorption of small molecules, little adsorption of biomolecules onto channel walls, and no leaching of residue molecules from the material bulk into the solution in the channel. Various biological cells have been cultured in the whole-Teflon channel. Adherent cells can attach to the channel bottom, spread, and proliferate well in the channels (with similar proliferation rate to the cells in PDMS channels with the same dimensions). The moderately good gas permeability of the Teflon materials makes it suitable to culture cells inside the microchannels for a long time. PMID- 21536920 TI - Tool-marked bones from before the Oldowan change the paradigm. PMID- 21536921 TI - Photocytotoxicity of hypocrellin B (HB) was enhanced by liposomalization in vitro. AB - Hypocrellin B (HB) was encapsulated into a phosphatidylcholine liposome. Encapsulation of HB into liposomes not only improved the delivery of this photosensitizer but also increased its photodynamic efficacy compared to free HB molecules. Liposomal HB showed a higher cellular uptake than free HB as measured by confocal microscopy and was internalized into cultured HeLa cells by caveolar endocytosis, which was lipid-raft-dependent. Cell viability measurements demonstrated that liposomal HB was more phototoxic to HeLa cells than free HB as a result of the higher concentration of intracellular HB delivered by the liposomal formulation. The encapsulation of HB influenced the cell death pathway by an increased rate of necrotic cells after irradiation versus free HB, and a Type II (singlet oxygen) mechanism was responsible for the photocytotoxicity. PMID- 21536919 TI - Bispecific digoxigenin-binding antibodies for targeted payload delivery. AB - Bispecific antibodies that bind cell-surface targets as well as digoxigenin (Dig) were generated for targeted payload delivery. Targeting moieties are IgGs that bind the tumor antigens Her2, IGF1R, CD22, or LeY. A Dig-binding single-chain Fv was attached in disulfide-stabilized form to C termini of CH3 domains of targeting antibodies. Bispecific molecules were expressed in mammalian cells and purified in the same manner as unmodified IgGs. They are stable without aggregation propensity and retain binding specificity/affinity to cell-surface antigens and Dig. Digoxigeninylated payloads were generated that retain full functionality and can be complexed to bispecific antibodies in a defined 21 ratio. Payloads include small compounds (Dig-Cy5, Dig-Doxorubicin) and proteins (Dig-GFP). Complexed payloads are targeted by the bispecifics to cancer cells and because these complexes are stable in serum, they can be applied for targeted delivery. Because Dig bispecifics also effectively capture digoxigeninylated compounds under physiological conditions, separate administration of uncharged Dig bispecifics followed by application of Dig payload is sufficient to achieve antibody-mediated targeting in vitro and in vivo. PMID- 21536923 TI - FDA cGMP requirements for PET drugs. PMID- 21536928 TI - Myocardial perfusion imaging for preoperative risk stratification. AB - This review considers the changing nature of surgical risk assessment and the definition of risk; discusses the pathophysiology of perioperative myocardial infarction in relation to tests of coronary flow reserve; surveys the extensive literature on preoperative myocardial perfusion imaging (MPI) and outlines key trends; presents practical points on image interpretation; addresses the needs of special populations; compares MPI with other modalities; and integrates recommendations from practice guidelines on the effective use of MPI in the preoperative patient. PMID- 21536930 TI - Putative transport mechanism and intracellular fate of trans-1-amino-3-18F fluorocyclobutanecarboxylic acid in human prostate cancer. AB - Trans-1-amino-3-(18)F-fluorocyclobutanecarboxylic acid (anti-(18)F-FACBC) is an amino acid PET tracer that has shown promise for visualizing prostate cancer. Therefore, we aimed to clarify the anti-(18)F-FACBC transport mechanism in prostate cancer cells. We also studied the fate of anti-(18)F-FACBC after it is transported into cells. METHODS: For convenience, because of their longer half lives, (14)C compounds were used instead of (18)F-labeled tracers. Trans-1-amino 3-fluoro-1-(14)C-cyclobutanecarboxylic acid ((14)C-FACBC) uptake was examined in human prostate cancer DU145 cells with the following substrates of amino acid transporters: alpha-(methylamino) isobutyric acid (a system A-specific substrate) and 2-amino-2-norbornanecarboxylic acid (a system L-specific substrate). The messenger RNA expression of amino acid transporters in human prostate cancer specimens was analyzed by complementary DNA microarray and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Gene expression in DU145 cells was analyzed by qRT-PCR. We also examined the knockdown effect of the amino acid transporters system ASC transporter 2 (ASCT2) and sodium-coupled neutral amino acid transporter 2 (SNAT2) on (14)C-FACBC uptake. In addition, the possibility of (14)C-FACBC incorporation into proteins was examined. RESULTS: (14)C-FACBC uptake by DU145 cells was markedly decreased to approximately 20% in the absence of Na(+), compared with that in its presence, indicating that Na(+) dependent transporters are mainly responsible for the uptake of this tracer. Moreover, 2-amino-2-norbornanecarboxylic acid inhibited the transport of (14)C FACBC to the basal level in Na(+)-free buffer. In contrast, alpha-(methylamino) isobutyric acid did not inhibit (14)C-FACBC accumulation in DU145 cells. Human prostate tumor specimens and DU145 cells had similar messenger RNA expression patterns of amino acid transporter genes. Although SNAT2 and ASCT2 are 2 major amino acid transporters expressed in prostate tumor tissues and DU145 cells, ASCT2 knockdown using small interfering RNA was more effective in lowering (14)C FACBC transport than SNAT2. Almost all intracellular (14)C-FACBC was recovered from the nonprotein fraction. CONCLUSION: ASCT2, which is a Na(+)-dependent amino acid transporter, and to a lesser extent Na(+)-independent transporters play a role in the uptake of (14)C-FACBC by DU145 cells. Among the Na(+)-independent transporters, system L transporters are also involved in the transport of (14)C FACBC. Moreover, (14)C-FACBC is not incorporated into proteins in cells. These findings suggest a possible mechanism of anti-(18)F-FACBC PET for prostate cancer. PMID- 21536929 TI - A beta-camera integrated with a microfluidic chip for radioassays based on real time imaging of glycolysis in small cell populations. AB - An integrated beta-camera and microfluidic chip was developed that is capable of quantitative imaging of glycolysis radioassays using (18)F-FDG in small cell populations down to a single cell. This paper demonstrates that the integrated system enables digital control and quantitative measurements of glycolysis in B Raf(V600E)-mutated melanoma cell lines in response to specific B-Raf inhibition. METHODS: The beta-camera uses a position-sensitive avalanche photodiode to detect charged particle-emitting probes within a microfluidic chip. The integrated beta camera and microfluidic chip system was calibrated, and the linearity was measured using 4 different melanoma cell lines (M257, M202, M233, and M229). Microfluidic radioassays were performed with cell populations ranging from hundreds of cells down to a single cell. The M229 cell line has a homozygous B Raf(V600E) mutation and is highly sensitive to a B-Raf inhibitor, PLX4032. A microfluidic radioassay was performed over the course of 3 days to assess the cytotoxicity of PLX4032 on cellular (18)F-FDG uptake. RESULTS: The beta-camera is capable of imaging radioactive uptake of (18)F-FDG in microfluidic chips. (18)F FDG uptake for a single cell was measured using a radioactivity concentration of 37 MBq/mL during the radiotracer incubation period. For in vitro cytotoxicity monitoring, the beta-camera showed that exposure to 1 MUM PLX4032 for 3 days decreased the (18)F-FDG uptake per cell in highly sensitive M229 cells, compared with vehicle controls. CONCLUSION: The integrated beta-camera and microfluidic chip can provide digital control of live cell cultures and allow in vitro quantitative radioassays for multiple samples simultaneously. PMID- 21536931 TI - Radioimmunotherapy in non-Hodgkin lymphoma: opinions of nuclear medicine physicians and radiation oncologists. AB - Despite approval by the Food and Drug Administration and consistent reports of the efficacy and safety of (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, these therapies are infrequently used. This study investigates the opinions and patterns of the use of radioimmunotherapy by nuclear physicians, affiliated researchers, nuclear medicine technologists, and radiation oncologists and aims to identify possible barriers to the use of this promising therapy. METHODS: An e mail-based survey with 13 broad questions related to radioimmunotherapy was sent electronically to 13,221 Society of Nuclear Medicine members and radiation oncologists throughout the United States. RESULTS: Six hundred thirteen individuals (4.6%) responded to the electronic survey. Two hundred fifty-one responders (40.9%) had treated patients with non-Hodgkin lymphoma (NHL) with radioimmunotherapy in the last 24 mo. Of the responders, 29.5% used only (90)Y ibritumomab tiuxetan, 7.6% used only (131)I-tositumomab, and 24.9% used both radiopharmaceuticals; 37.9% did not treat NHL with radioimmunotherapy. Most responders said their patients came from university hospitals (33.9%) or private offices (25.6%), and they mainly treated in a second-line (42.9%), third-line (35.6%), or consolidation (23.5%) setting. Major concerns were that referring oncologists and hematologists wanted to treat by themselves with nonradioactive compounds (mean +/- SD, 3.418 +/- 1.49) and that (90)Y-ibritumomab tiuxetan and (131)I-tositumomab were expensive (mean +/- SD, 3.413 +/- 1.35). Of the responders and involved physicians, 40.4% and 35.2%, respectively, did not know if their institution accepted Medicare patients for radioimmunotherapy. Almost 30% (29.6%) of the responders thought radioimmunotherapy would probably grow and 38.0% thought it would grow in importance in the future. Responders who did not administer radioimmunotherapy for NHL thought it took too much time to administer radioimmunotherapy (P < 0.01) and had concerns about the dosimetry procedure (P < 0.01) and radiation safety (P < 0.01). Individuals who perceived a negative future for radioimmunotherapy had significantly more concerns about the time consuming administration process (P < 0.05) and the high cost of radioimmunotherapy (P < 0.05). Responders from academic centers had significantly fewer concerns about payment (P < 0.01), dosimetry (P < 0.01), and radiation safety (P < 0.01). CONCLUSION: Radioimmunotherapy was generally viewed positively by the surveyed population. However, limited referrals due to alternative nonradioactive therapies and logistic, educational, and economic concerns played an important role for subgroups in the perception of radioimmunotherapy for NHL. PMID- 21536932 TI - Postchemotherapy residual masses in nonseminomatous germ cell tumor patients: 18F FLT PET is unlikely to identify mature teratoma, but imaging of alphav beta3 integrin expression could. PMID- 21536933 TI - Stereotactic body radiation therapy: scope of the literature. AB - Stereotactic body radiation therapy (SBRT) is derived from the techniques of stereotactic radiosurgery used to treat lesions in the brain and spine. It combines multiple finely collimated radiation beams and stereotaxy to deliver a high dose of radiation to an extracranial target in the body in a single dose or a few fractions. This review provides a broad overview of the current state of SBRT for solid malignant tumors. Reviewers identified a total of 124 relevant studies. To our knowledge, no published comparative studies address the relative effectiveness and safety of SBRT versus other forms of external-beam radiation therapy. Stereotactic body radiation therapy seems to be widely diffused as a treatment of various types of cancer, although most studies have focused only on its use for treating thoracic tumors. Comparative studies are needed to provide evidence that the theoretical advantages of SBRT over other radiation therapies actually occur in the clinical setting; this area is currently being studied in only 1 small trial. PMID- 21536934 TI - Summaries for patients. Omalizumab therapy for patients with severe asthma. PMID- 21536935 TI - In the clinic. Celiac disease. AB - This issue provides a clinical overview of celiac disease focusing on prevention, diagnosis, treatment, practice improvement, and patient information. Readers can complete the accompanying CME quiz for 1.5 credits. Only ACP members and individual subscribers can access the electronic features of In the Clinic. Non subscribers who wish to access this issue of In the Clinic can elect "Pay for View." Subscribers can receive 1.5 category 1 CME credits by completing the CME quiz that accompanies this issue of In the Clinic. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians' Information and Education Resource) and MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing division and with assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult www.acponline.org, http://pier.acponline.org, and other resources referenced within each issue of In the Clinic. PMID- 21536937 TI - Comparison of inhaled long-acting beta-agonist and anticholinergic effectiveness in older patients with chronic obstructive pulmonary disease: a cohort study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD), a largely preventable and manageable respiratory condition, affects an estimated 12% to 20% of adults. Long-acting inhaled beta-agonists and anticholinergics have both been shown to improve COPD outcomes and are recommended for moderate to severe disease; however, little is known about their comparative effectiveness. OBJECTIVE: To compare survival in older patients with COPD who initially receive inhaled long acting beta-agonists with that of patients who receive anticholinergics. DESIGN: Population-based, retrospective cohort study. SETTING: Ontario, Canada. PATIENTS: Patients aged 66 years or older (who carry the largest burden of COPD and for whom data were available) who met a validated case definition of COPD on the basis of health administrative data and were newly prescribed an inhaled long acting beta-agonist or a long-acting anticholinergic (but not both) between 2003 and 2007. Patients were followed for up to 5.5 years. MEASUREMENTS: The primary outcome was all-cause mortality. RESULTS: A total of 46 403 patients with COPD (mean age, 77 years; 49% women) were included. Overall mortality was 38.2%. Mortality was higher in patients initially prescribed a long-acting anticholinergic than in those initially prescribed a long-acting inhaled beta agonist (adjusted hazard ratio, 1.14 [95% CI, 1.09 to 1.19]). Rates of hospitalizations and emergency department visits were also higher in those initially prescribed a long-acting anticholinergic. LIMITATION: Patients were classified as having COPD on the basis of health administrative records, which did not contain information about lung function. CONCLUSION: Older adults initially prescribed long-acting inhaled beta-agonists for the management of moderate COPD seem to have lower mortality than those initially prescribed long acting anticholinergics. Further research is needed to confirm these findings in younger patients and in a randomized, controlled trial. PRIMARY FUNDING SOURCE: Government of Ontario, Canada. PMID- 21536936 TI - Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. AB - BACKGROUND: Inhaled corticosteroids (ICS) and long-acting beta(2)-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy. OBJECTIVE: To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy. DESIGN: Prospective, multicenter, randomized, parallel-group, double-blind, placebo controlled trial. (ClinicalTrials.gov registration number: NCT00314575). SETTING: 193 investigational sites in the United States and 4 sites in Canada. PATIENTS: 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers. INTERVENTION: Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks. MEASUREMENTS: The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events. RESULTS: During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (-0.27 puff/d [CI, -0.49 to -0.04 puff/d]), and decreased mean asthma symptom score (-0.26 [CI, -0.42 to -0.10]) compared with placebo during the 48 week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively. LIMITATIONS: The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup. CONCLUSION: In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy. PRIMARY FUNDING SOURCE: Genentech and Novartis Pharmaceuticals. PMID- 21536938 TI - Effect of the Centers for Medicare & Medicaid Services policy about deep sedation on use of propofol. AB - On 11 December 2009, the Centers for Medicare & Medicaid Services issued a policy stating that deep sedation can only be administered by an anesthesiologist, a certified registered nurse anesthetist, or a trained medical doctor or a doctor of osteopathy not involved in the performance of a medical procedure. Propofol is a popular sedation agent that is usually administered by anesthesia specialists in a service termed monitored anesthesia care (MAC). Monitored anesthesia care adds substantial new fees to procedural sedation. However, available evidence shows that propofol can be used safely by non-anesthesiologists for procedural sedation. The American Society of Anesthesiologists considers that propofol implies deep sedation and should only be administered by anesthesia specialists. The Centers for Medicare & Medicaid Services policy on deep sedation can be viewed as supporting an ongoing conversion to MAC to deliver propofol for procedural sedation. However, the absence of an evidence base supporting a need for MAC to deliver propofol, combined with its high cost, suggests that alternatives to MAC to deliver propofol deserve fair and balanced evaluation. PMID- 21536939 TI - Individualized guidelines: the potential for increasing quality and reducing costs. AB - BACKGROUND: Current guidelines focus on a particular risk factor and specify criteria for categorizing persons into a small number of treatment groups. OBJECTIVE: To compare current guidelines with individualized guidelines (that use readily available characteristics from each person to calculate the risk reduction expected from treatment and to identify persons for treatment in ranked order of decreasing expected benefit), in the context of blood pressure management. DESIGN: Analysis of person-specific, longitudinal data. SETTING: The ARIC (Atherosclerosis Risk in Communities) Study. PARTICIPANTS: Persons aged 45 to 64 years without preexisting cardiovascular disease who currently do not receive antihypertensive treatment. INTERVENTION: Treatment according to the criteria of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7 guidelines); individualized guidelines, or treatment in decreasing order of expected benefit; and random care, or treatment of persons selected at random. MEASUREMENTS: Number of myocardial infarctions (MIs) and strokes and medical costs. RESULTS: Compared with treating people according to random care, individualized guidelines could prevent the same number of MIs and strokes as JNC 7 guidelines at savings that are 67% greater than using JNC 7 guidelines, or it could prevent 43% more MIs and strokes for the same cost as treatment according to JNC 7 guidelines. The superiority of individualized guidelines was not sensitive to a wide range of assumptions about costs, treatment effectiveness, level of risk for cardiovascular disease in the population, or effects on workflow. The degree of superiority was sensitive to the accuracy of the method used to rank patients and to its span (the proportion of the population for whom all of the outcomes of interest can be calculated). LIMITATIONS: Specific results apply to the effects of blood pressure management on MI and stroke in the ARIC Study population. The methods for calculating individual benefits require quantitative evidence about the relationships among risk factors, long-term outcomes, and treatment effects. CONCLUSION: Use of individualized guidelines can help to increase the quality and reduce the cost of care. PMID- 21536940 TI - Improving practice guidelines with patient-specific recommendations. PMID- 21536941 TI - A dozen eggs. PMID- 21536942 TI - Age at cancer diagnosis among persons with AIDS. PMID- 21536943 TI - Age at cancer diagnosis among persons with AIDS. PMID- 21536944 TI - Assessment of recurrence risk after unprovoked venous thromboembolism. PMID- 21536945 TI - Cross-talk between interferon-gamma and hedgehog signaling regulates adipogenesis. AB - OBJECTIVE: T cells and level of the cytokine interferon-gamma (IFN-gamma) are increased in adipose tissue in obesity. Hedgehog (Hh) signaling has been shown to potently inhibit white adipocyte differentiation. In light of recent findings in neurons that IFN-gamma and Hh signaling cross-talk, we examined their potential interaction in the context of adipogenesis. RESEARCH DESIGN AND METHODS: We used Hh reporter cells, cell lines, and primary adipocyte differentiation models to explore costimulation of IFN-gamma and Hh signaling. Genetic dissection using Ifngr1(-/-) and Stat1(-/-) mouse embryonic fibroblasts, and ultimately, anti-IFN gamma neutralization and expression profiling in obese mice and humans, respectively, were used to place the findings into the in vivo context. RESULTS: T-cell supernatants directly inhibited hedgehog signaling in reporter and 3T3-L1 cells. Intriguingly, using blocking antibodies, Ifngr1(-/-) and Stat1(-/-) cells, and simultaneous activation of Hh and IFN-gamma signaling, we showed that IFN gamma directly suppresses Hh stimulation, thus rescuing adipogenesis. We confirmed our findings using primary mouse and primary human (pre)adipocytes. Importantly, robust opposing signals for Hh and T-cell pathways in obese human adipose expression profiles and IFN-gamma depletion in mice identify the system as intact in adipose tissue in vivo. CONCLUSIONS: These results identify a novel antagonistic cross-talk between IFN-gamma and Hh signaling in white adipose tissue and demonstrate IFN-gamma as a potent inhibitor of Hh signaling. PMID- 21536946 TI - Diazoxide-unresponsive congenital hyperinsulinism in children with dominant mutations of the beta-cell sulfonylurea receptor SUR1. AB - OBJECTIVE: Congenital hyperinsulinemic hypoglycemia is a group of genetic disorders of insulin secretion most commonly associated with inactivating mutations of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (SUR1) and KCNJ11 (Kir6.2). Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with diazoxide, a channel agonist. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. We hypothesized that some medically uncontrollable cases with only one K(ATP) mutation might have dominant, diazoxide-unresponsive disease. RESEARCH DESIGN AND METHODS: Mutations of the K(ATP) genes were identified by sequencing genomic DNA. Effects of mutations on K(ATP) channel function in vitro were studied by expression in COSm6 cells. RESULTS: In 15 families with diazoxide unresponsive diffuse hyperinsulism, we found 17 patients with a monoallelic missense mutation of SUR1. Nine probands had de novo mutations, two had an affected sibling or parent, and four had an asymptomatic carrier parent. Of the 13 different mutations, 12 were novel. Expression of mutations revealed normal trafficking of channels but severely impaired responses to diazoxide or MgADP. Responses were significantly lower compared with nine SUR1 mutations associated with dominant, diazoxide-responsive hyperinsulinism. CONCLUSIONS: These results demonstrate that some dominant mutations of SUR1 can cause diazoxide-unresponsive hyperinsulinism. In vitro expression studies may be helpful in distinguishing such mutations from dominant mutations of SUR1 associated with diazoxide responsive disease. PMID- 21536947 TI - Efficient intravenous access without distress: a double-blind randomized study of midazolam and nitrous oxide in children and adolescents. AB - OBJECTIVE: To determine whether treatment with midazolam or with nitrous oxide is more efficient in facilitating intravenous (IV) access in lean and obese children and adolescents. DESIGN: A prospective, double-blind, randomized trial of 90 children and adolescents. SETTING: Astrid Lindgrens Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. Patients A total of 60 obese children and adolescents and 30 growth-retarded children and adolescents, aged 5 to 18 years, with reported anxiety and/or difficulties with IV access. INTERVENTIONS: The patients were randomly assigned to receive midazolam (dose, 0.3 mg/kg; maximum dose, 15 mg), 50% nitrous oxide, or 10% nitrous oxide. All patients received lidocaine-prilocaine. MAIN OUTCOME MEASURES: Efficiency, measured as total procedure time and number of attempts, which was defined as the number of attempts required to succeed in setting up 2 IV lines, with a successful procedure defined as 2 attempts for 2 IV lines. Secondary end points were patients' and parents' evaluations and procedure cancellations. RESULTS: Treatment with 50% nitrous oxide was the most efficient with regard to total procedure time (P < .001). An unfavorably long procedure time was observed after treatment with midazolam, especially in obese patients. An increased number of successful IV line procedures were obtained in the group of patients who received 50% nitrous oxide compared with the midazolam group and 10% nitrous oxide group (P = .04). The patients' evaluations were significantly more positive for 50% nitrous oxide than for both midazolam and 10% nitrous oxide, whereas no such difference was observed between midazolam and 10% nitrous oxide. CONCLUSIONS: Compared with treatment with midazolam, treatment with 50% nitrous oxide during IV line procedures results in a shorter total procedure time, improved rate of IV access, and a better experience for the child or adolescent. Only under rare circumstances should obese children or adolescents be treated with midazolam because of the long procedure time. TRIAL REGISTRATIONS: isrctn.org Identifier: ISRCTN33779750 and kctr.se Identifier: KCTR CT20090023. PMID- 21536948 TI - Breastfeeding of newborns by mothers carrying hepatitis B virus: a meta-analysis and systematic review. AB - OBJECTIVE: To perform a systematic review of prospective studies to confirm the role of breastfeeding in mother-to-child transmission (MTCT) of hepatitis B virus (HBV). DATA SOURCES: A database was constructed from MEDLINE, EMBASE, Cochrane Library, National Science Digital Library, and China Biological Medicine Database and through contact with experts in this field from January 1, 1990, to August 31, 2010. STUDY SELECTION: All studies were peer reviewed and met the preset inclusion standards. MAIN EXPOSURE: Breastfeeding. MAIN OUTCOME MEASURES: Data regarding HBV intrauterine infection, MTCT, maternal blood and breast milk infectiousness, infant immunoprophylaxis methods and response, and adverse events. The Mantel-Haenszel fixed-effects model was used for all analyses using odds ratios and 95% confidence intervals. RESULTS: Ten qualified studies were included. All were clinical controlled trials, involving 751 infants in the breastfeeding group and 873 infants in the nonbreastfeeding group. As indicated by infant peripheral blood hepatitis B surface antigen or HBV DNA positivity at age 6 to 12 months, the odds ratio of MTCT of HBV in the breastfeeding group compared with that in the nonbreastfeeding group was 0.86 (95% confidence interval, 0.51-1.45) (from 8 clinical controlled trials, P = .56; I(2) = 0%, P = .99). As indicated by infant peripheral blood hepatitis B surface antibody positivity at age 6 to 12 months, the odds ratio of development of hepatitis B surface antibodies in the breastfeeding group compared with that in the nonbreastfeeding group was 0.98 (95% confidence interval, 0.69-1.40) (from 8 clinical controlled trials, P = .93; I(2) = 0%, P = .99). No adverse events or complications during breastfeeding were observed. CONCLUSION: Breastfeeding after proper immunoprophylaxis did not contribute to MTCT transmission of HBV. PMID- 21536949 TI - Effects of the limited English proficiency of parents on hospital length of stay and home health care referral for their home health care-eligible children with infections. AB - OBJECTIVE: To examine the relationship of limited English proficiency of parents to hospital length of stay (LOS) and to home health care referral for their home health care eligible-children with infections. DESIGN: A retrospective cohort study. SETTING: Regional urban pediatric hospital. PARTICIPANTS: A total of 1257 children aged 0 to 18 years admitted for infection requiring prolonged antibiotic treatment during the period from January 1, 2000, to December 31, 2008. MAIN EXPOSURES: The cohort of patients were defined by primary caregivers who had to report on their English proficiency. MAIN OUTCOME MEASURES: Number of home health care referrals and LOS. RESULTS: The median LOS for the study group was 4.1 days (interquartile range, 2.6-7.2 days). Limited English proficiency was associated with longer LOS (adjusted relative LOS, 1.6 [95% confidence interval, 1.1-2.3]), indicating that patients who had caregivers with limited English proficiency stayed 60% longer, on average, than patients with English-proficient primary caregivers. Insurance status (Medicaid), absence of a primary care provider, home health care utilization, and presence of comorbidity were also associated with longer LOS. Limited English proficiency was associated with a significantly decreased number of home health care referrals (odds ratio, 0.2 [95% confidence interval, 0.04-0.8]). Patient insurance (Medicaid) and presence of any comorbidity were also significantly associated with decreased number of home health care referrals. CONCLUSIONS: Among pediatric inpatients with infections requiring long-term antibiotics, a primary caregiver with limited English proficiency was identified as an important independent risk factor for both increased LOS and decreased number of home health care referrals. PMID- 21536950 TI - Problematic internet use among US youth: a systematic review. AB - OBJECTIVE: To investigate study quality and reported prevalence among the emergent area of problematic Internet use (PIU) research conducted in populations of US adolescents and college students. DATA SOURCES: We searched PubMed, PsycINFO, and Web of Knowledge from inception to July 2010. STUDY SELECTION: Using a keyword search, we evaluated English-language PIU studies with populations of US adolescents and college students. MAIN OUTCOME MEASURES: Using a quality review tool based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, 2 reviewers independently extracted data items including study setting, subject population, instrument used, and reported prevalence. RESULTS: Search results yielded 658 articles. We identified 18 research studies that met inclusion criteria. Quality assessment of studies ranged between 14 and 29 total points of a possible 42 points; the average score was 23 (SD 5.1). Among these 18 studies, 8 reported prevalence estimates of US college student PIU; prevalence rates ranged from 0% to 26.3%. An additional 10 studies did not report prevalence. CONCLUSIONS: The evaluation of PIU remains incomplete and is hampered by methodological inconsistencies. The wide range of conceptual approaches may have impacted the reported prevalence rates. Despite the newness of this area of study, most studies in our review were published more than 3 years ago. Opportunities exist to pursue future studies adhering to recognized quality guidelines, as well as applying consistency in theoretical approach and validated instruments. PMID- 21536951 TI - Pneumococcic meningitis: complete recovery of a 6-month-old infant treated with penicillin. PMID- 21536952 TI - Sustaining excellence in pediatric care. PMID- 21536953 TI - Associations between quality of primary care and health care use among children with special health care needs. AB - OBJECTIVE: To determine whether parent-reported quality of primary care was associated with subsequent health care use for children with special health care needs. DESIGN: Secondary analysis of prospectively collected data. SETTING: The 2004-2005 and 2005-2006 Medical Expenditure Panel Survey panels. PARTICIPANTS: A total of 1591 children with special health care needs. MAIN EXPOSURES: Composite measures for family centeredness of care, timeliness of care, and realized access derived from the Consumer Assessment of Healthcare Providers and Systems survey. MAIN OUTCOME MEASURES: Rates of parent-reported emergency department visits (nonurgent and urgent) and hospitalizations. Only encounters occurring after completion of the Consumer Assessment of Healthcare Providers and Systems survey were assessed. Weighted multivariate Poisson regression analyses, yielding incident rate ratios, were used for analysis. RESULTS: Of the parents of the 1591 children included, 68.3% rated family centeredness, 51.5% rated timeliness, and 80.4% rated realized access as high quality. Low-quality family centeredness was associated with higher rates (incident rate ratio, 2.24; 95% confidence interval, 1.32-3.80) of nonurgent emergency department visits compared with corresponding rates associated with high-quality family centeredness. There were no associations between quality-of-care domains and rates of urgent emergency department visits. For privately insured children, low-quality family centeredness was associated with higher rates (incident rate ratio, 3.87; 95% confidence interval, 1.23-12.13) of hospitalizations compared with corresponding rates associated with high-quality family-centered care. For publicly insured children, no significant associations were found. CONCLUSIONS: Parent-reported, low-quality family centeredness was associated with higher rates of subsequent nonurgent emergency department visits and hospitalizations among children with special health care needs. These findings highlight family-centered care as a critical area for primary care intervention to reduce potentially preventable health care use. PMID- 21536954 TI - Variation in use of Internet-based patient portals by parents of children with chronic disease. AB - OBJECTIVES: To assess the use of Internet-based portals among families of children with chronic diseases and to describe characteristics of portal registrants and users. DESIGN: Retrospective observational study. SETTING: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, using data from September 1, 2003, through February 29, 2008. Patients/ PARTICIPANTS: Parents of children with diabetes mellitus, juvenile idiopathic arthritis, or cystic fibrosis. INTERVENTIONS: Parents of children with a chronic disease were given the opportunity to access health-related information for their children via an Internet-based portal. OUTCOME MEASURES: Percentage of families who obtained a portal account (registered), used the portal for the first time within 3 months and again 3 to 6 months after registration, number of times logged in, and session length. RESULTS: Of 1900 families, 27.9% obtained a portal account. Of those, 47.8% used the portal within 3 months of registration and 15.9% continued to use the portal 3 to 6 months after registration. Families of African American patients and of patients insured by Medicaid were less likely to obtain a portal account. More outpatient visits and having private health insurance coverage were associated with increased portal registration and use. CONCLUSIONS: Understanding the feasibility of portal use by parents is an important first step to using portals for improving self-management, patient-provider interactions, and outcomes for children with chronic diseases. Subsequent studies should address parent perceptions of the value portals add to the management of the chronic disease of their child and ways to increase that value. Barriers to using portals among racial minorities and publicly insured families should also be studied to address disparities. PMID- 21536955 TI - Putting guidelines into practice: improving documentation of pediatric asthma management using a decision-making tool. AB - OBJECTIVE: To assess improvement in documentation of asthma indicators using the Asthma Toolbox, an asthma decision-making tool developed in accord with National Asthma Education and Prevention Program guidelines. DESIGN: Retrospective medical record review using cross-sectional, independent, random samples. Reviews were conducted for 1-year periods before and after implementation and after revision reflecting 2007 guideline modifications. SETTING: Two inner-city, federally qualified health center programs providing pediatric primary care to housed and homeless populations. PARTICIPANTS: A total of 1246 patients aged 6 months to 18 years with at least 1 asthma visit to a community health center using paper records (n = 600) or a mobile medical program serving family homeless shelters using an electronic health record (EHR; n = 646). INTERVENTION: Implementation of the Asthma Toolbox incorporated into paper encounter forms and embedded in the EHR to guide providers (ie, physicians and nurse practitioners) through pediatric asthma assessment and management. MAIN OUTCOME MEASURES: Documentation of a subset of asthma severity/control measures, emergency department visits, hospitalizations, and percentage of persistent asthmatic patients prescribed controller medications. RESULTS: Documentation of each asthma indicator increased significantly after implementation (chi(2) tests; P < .001 all comparisons) for both programs. Documentation of severity/control increased from 25.5% to 77.5% in paper records and from 11.7% to 85.1% in the EHR (P < .001). Increases were sustained after Asthma Toolbox revision for all indicators. The percentage of patients with persistent/uncontrolled asthma prescribed controller medications reached 96% to 97% in both programs. CONCLUSION: Use of the Asthma Toolbox, an asthma decision-making tool, significantly increased documentation of pediatric asthma management among providers working in high-disparity, urban primary care settings. PMID- 21536956 TI - Reduction in hospital mortality over time in a hospital without a pediatric medical emergency team: limitations of before-and-after study designs. AB - OBJECTIVE: To determine whether hospital mortality has decreased over time in a hospital that has not introduced a pediatric medical emergency team (PMET). DESIGN: Retrospective observational study. SETTING: Quaternary children's hospital. PARTICIPANTS: All pediatric inpatient separations (defined as any discharge, including death) during 10 fiscal years. MAIN OUTCOME MEASURES: We searched our hospital administrative database to determine the number of pediatric inpatient separations and deaths, and we searched the hospital switchboard and pediatric intensive care databases to determine ward code and cardiopulmonary arrest rates. Relative risks (RRs) with 95% confidence intervals (CIs) and logistic regression compared results over time. RESULTS: During the periods of the 2 PMET studies showing a reduction in hospital mortality, we found a decrease in hospital mortality: for 1999-2002 vs 2002-2006, 212 deaths among 14 161 patients (1.50%) vs 219 of 26 767 (0.82%), RR, 0.55 (95% CI, 0.44-0.69); for 2000-2005 vs 2005-2007, 300 deaths among 29 497 patients (1.02%) vs 98 of 14 005 (0.70%), RR, 0.69 (95% CI, 0.55-0.86). During the periods of the 3 PMET studies showing no change in or not examining hospital mortality, we found no significant change in hospital mortality. The annual odds ratio for survival was 1.13 (95% CI, 1.09-1.16). There were no changes in ward code and cardiopulmonary arrest rates over time. CONCLUSIONS: We found a reduction in hospital mortality over time in a children's hospital without a PMET. This demonstrates the limitation of before-and-after study designs, and we hypothesize that multiple co-interventions account for the decrease in mortality. Whether a PMET could have reduced mortality further is unknown. PMID- 21536957 TI - Unit-based care teams and the frequency and quality of physician-nurse communications. AB - OBJECTIVE: To determine whether reorganizing physicians into unit-based teams in general pediatric wards is associated with greater ability to identify other care team members, increased face-to-face communication between physicians and nurses, greater perception that their patient care concerns were met, and decreased number of pages to residents. DESIGN: Prospective intervention study with data collected before and at 2 time points after implementation of unit-based teams. SETTING: General pediatric wards at an urban, tertiary care, freestanding children's hospital from April 1, 2008, through June 30, 2009. PARTICIPANTS: Pediatric residents rotating in the medical wards (n = 60) and ward-based pediatric nurses (n = 154). INTERVENTION: We reorganized resident-physician care teams to be based on specific inpatient units, with residents admitting and caring only for patients on their assigned unit. MAIN OUTCOME MEASURES: Anonymous physician and nurse self-reports of communication practices and number of pages residents received. RESULTS: In the unit-based team system, physicians were more likely to be able to identify the nurse for their patients with the most complex conditions (62.3% vs 82.8% vs 82.5%, P = .05), to report contacting (27.3% vs 64.9% vs 56.9%, P = .01) and being contacted by (7.7% vs 48.2% vs 55.2%, P = .002) that nurse in person, and to believe their patient care concerns were met (44.2% vs 82.1% vs 81.8%, P = .009). Nurses reported parallel improvements in communication patterns. The mean number of pages per day to residents decreased by 42.1% (19 vs 10 vs 11, P < .001). CONCLUSION: Unit-based teams improve the frequency and quality of multidisciplinary communication, which may create an improved climate for patient safety. PMID- 21536959 TI - Picture of the month. Ewing sarcoma. PMID- 21536958 TI - The impact of statistical choices on neonatal intensive care unit quality ratings based on nosocomial infection rates. AB - OBJECTIVE: To examine the extent to which performance assessment methods affect the percentage of neonatal intensive care units (NICUs) and very low-birth-weight (VLBW) infants included in performance assessments, the distribution of NICU performance ratings, and the level of agreement in those ratings. DESIGN: Cross sectional study based on risk-adjusted nosocomial infection rates. SETTING: NICUs belonging to the California Perinatal Quality Care Collaborative 2007-2008. PARTICIPANTS: One hundred twenty-six California NICUs and 10 487 VLBW infants. MAIN EXPOSURES: Three performance assessment choices: (1) excluding "low-volume" NICUs (those caring for <30 VLBW infants per year) vs a criterion based on confidence intervals, (2) using Bayesian vs frequentist hierarchical models, and (3) pooling data across 1 vs 2 years. MAIN OUTCOME MEASURES: Proportion of NICUs and patients included in quality assessment, distribution of ratings for NICUs, and agreement between methods using the kappa statistic. RESULTS: Depending on the methods applied, 51% to 85% of NICUs and 72% to 96% of VLBW infants were included in performance assessments, 76% to 87% of NICUs were considered "average," and the level of agreement between NICU ratings ranged from 0.23 to 0.89. CONCLUSIONS: The percentage of NICUs included in performance assessments and their ratings can shift dramatically depending on performance measurement method. Physicians, payers, and policymakers should continue to closely examine which existing performance assessment methods are most appropriate for evaluating pediatric care quality. PMID- 21536960 TI - The quality of quality research. PMID- 21536961 TI - Strategies to move beyond a problem unique to pediatrics. PMID- 21536962 TI - Understanding family experiences of care: more evidence that it makes a difference. PMID- 21536963 TI - The hazards of drawing conclusions from before-and-after studies of system-level interventions: knowing may not be enough. PMID- 21536964 TI - What is the problem with asthma care for children? PMID- 21536965 TI - Unnatural causes: social determinants of child health and well-being. PMID- 21536966 TI - Advice for patients. Decreasing unnecessary radiation exposure for children. PMID- 21536967 TI - Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis. AB - CONTEXT: Alterations in glutamatergic neurotransmission and cerebral cortical dysfunction are thought to be central to the pathophysiology of psychosis, but the relationship between these 2 factors is unclear. OBJECTIVE: To investigate the relationship between brain glutamate levels and cortical response during executive functioning in people at high risk for psychosis (ie, with an at-risk mental state [ARMS]). DESIGN: Subjects were studied using functional magnetic resonance imaging while they performed a verbal fluency task, and proton magnetic resonance spectroscopy was used to measure their brain regional glutamate levels. SETTING: Maudsley Hospital, London, England. PATIENTS AND OTHER PARTICIPANTS: A total of 41 subjects: 24 subjects with an ARMS and 17 healthy volunteers (controls). MAIN OUTCOME MEASURES: Regional brain activation (blood oxygen level dependent response); levels of glutamate in the anterior cingulate, left thalamus, and left hippocampus; and psychopathology ratings at the time of scanning. RESULTS: During the verbal fluency task, subjects with an ARMS showed greater activation than did controls in the middle frontal gyrus bilaterally. Thalamic glutamate levels were lower in the ARMS group than in control group. Within the ARMS group, thalamic glutamate levels were negatively associated with activation in the right dorsolateral prefrontal and left orbitofrontal cortex, but positively associated with activation in the right hippocampus and in the temporal cortex bilaterally. There was also a significant group difference in the relationship between cortical activation and thalamic glutamate levels, with the control group showing correlations in the opposite direction to those in the ARMS group in the prefrontal cortex and in the right hippocampus and superior temporal gyrus. CONCLUSIONS: Altered prefrontal, hippocampal, and temporal function in people with an ARMS is related to a reduction in thalamic glutamate levels, and this relationship is different from that in healthy controls. PMID- 21536968 TI - Effect of secondhand smoke on occupancy of nicotinic acetylcholine receptors in brain. AB - CONTEXT: Despite progress in tobacco control, secondhand smoke (SHS) exposure remains prevalent worldwide and is implicated in the initiation and maintenance of cigarette smoking. OBJECTIVE: To determine whether moderate SHS exposure results in brain alpha(4)beta(2)* nicotinic acetylcholine receptor (nAChR) occupancy. DESIGN, SETTING, AND PARTICIPANTS: Positron emission tomography scanning and the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (also known as 2-[(18)F]fluoro-A-85380, or 2-FA) were used to determine alpha(4)beta(2)* nAChR occupancy from SHS exposure in 24 young adult participants (11 moderately dependent cigarette smokers and 13 nonsmokers). Participants underwent two bolus-plus-continuous-infusion 2-FA positron emission tomography scanning sessions during which they sat in the passenger's seat of a car for 1 hour and either were exposed to moderate SHS or had no SHS exposure. The study took place at an academic positron emission tomography center. Main Outcome Measure Changes induced by SHS in 2-FA specific binding volume of distribution as a measure of alpha(4)beta(2)* nAChR occupancy. RESULTS: An overall multivariate analysis of variance using specific binding volume of distribution values revealed a significant main effect of condition (SHS vs control) (F(1,22) = 42.5, P < .001) but no between-group (smoker vs nonsmoker) effect. Exposure to SHS led to a mean 19% occupancy of brain alpha(4)beta(2)* nAChRs (1-sample t test, 2-tailed, P < .001). Smokers had both a mean 23% increase in craving with SHS exposure and a correlation between thalamic alpha(4)beta(2)* nAChR occupancy and craving alleviation with subsequent cigarette smoking (Spearman rho = -0.74, P = .01). CONCLUSIONS: Nicotine from SHS exposure results in substantial brain alpha(4)beta(2)* nAChR occupancy in smokers and nonsmokers. Study findings suggest that such exposure delivers a priming dose of nicotine to the brain that contributes to continued cigarette use in smokers. This study has implications for both biological research into the link between SHS exposure and cigarette use and public policy regarding the need to limit SHS exposure in cars and other enclosed spaces. PMID- 21536969 TI - Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes. AB - CONTEXT: Alcoholism is a chronic, relapsing illness in which stress and alcohol cues contribute significantly to relapse risk. Dysregulation of the hypothalamic pituitary-adrenal (HPA) axis, increased anxiety, and high alcohol craving have been documented during early alcohol recovery, but their influence on relapse risk has not been well studied. OBJECTIVES: To investigate these responses in treatment-engaged, 1-month-abstinent, recovering alcohol-dependent patients relative to matched controls (study 1) and to assess whether HPA axis function, anxiety, and craving responses are predictive of subsequent alcohol relapse and treatment outcome (study 2). DESIGN: Experimental exposure to stress, alcohol cues, and neutral, relaxing context to provoke alcohol craving, anxiety, and HPA axis responses (corticotropin and cortisol levels and cortisol to corticotropin ratio) and a prospective 90-day follow-up outcome design to assess alcohol relapse and aftercare treatment outcomes. SETTING: Inpatient treatment in a community mental health center and hospital-based research unit. PARTICIPANTS: Treatment-engaged alcohol-dependent individuals and healthy controls. MAIN OUTCOME MEASURES: Time to alcohol relapse and to heavy drinking relapse. RESULTS: Significant HPA axis dysregulation, marked by higher basal corticotropin level and lack of stress- and cue-induced corticotropin and cortisol responses, higher anxiety, and greater stress- and cue-induced alcohol craving, was seen in the alcohol-dependent patients vs the control group. Stress- and cue-induced anxiety and stress-induced alcohol craving were associated with fewer days in aftercare alcohol treatment. High provoked alcohol craving to both stress and to cues and greater neutral, relaxed-state cortisol to corticotropin ratio (adrenal sensitivity) were each predictive of shorter time to alcohol relapse. CONCLUSIONS: These results identify a significant effect of high adrenal sensitivity, anxiety, and increased stress- and cue-induced alcohol craving on subsequent alcohol relapse and treatment outcomes. Findings suggest that new treatments that decrease adrenal sensitivity, stress- and cue-induced alcohol craving, and anxiety could be beneficial in improving alcohol relapse outcomes. PMID- 21536972 TI - Arcimboldo's Vertumnus: a portrait of Rudolf II. PMID- 21536971 TI - HDACi: cellular effects, opportunities for restorative dentistry. AB - Acetylation of histone and non-histone proteins alters gene expression and induces a host of cellular effects. The acetylation process is homeostatically balanced by two groups of cellular enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HAT activity relaxes the structure of the human chromatin, rendering it transcriptionally active, thereby increasing gene expression. In contrast, HDAC activity leads to gene silencing. The enzymatic balance can be 'tipped' by histone deacetylase inhibitors (HDACi), leading to an accumulation of acetylated proteins, which subsequently modify cellular processes including stem cell differentiation, cell cycle, apoptosis, gene expression, and angiogenesis. There is a variety of natural and synthetic HDACi available, and their pleiotropic effects have contributed to diverse clinical applications, not only in cancer but also in non-cancer areas, such as chronic inflammatory disease, bone engineering, and neurodegenerative disease. Indeed, it appears that HDACi-modulated effects may differ between 'normal' and transformed cells, particularly with regard to reactive oxygen species accumulation, apoptosis, proliferation, and cell cycle arrest. The potential beneficial effects of HDACi for health, resulting from their ability to regulate global gene expression by epigenetic modification of DNA-associated proteins, also offer potential for application within restorative dentistry, where they may promote dental tissue regeneration following pulpal damage. PMID- 21536970 TI - Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. AB - CONTEXT: Polymorphisms in the gene encoding the glucocorticoid receptor (GR) regulating co-chaperone FKBP5 have been shown to alter GR sensitivity and are associated with an increased risk to develop posttraumatic stress disorder (PTSD). OBJECTIVE: To investigate interactions of the FKBP5 single-nucleotide polymorphism rs9296158 and PTSD symptoms on baseline cortisol level, low-dose dexamethasone suppression, and whole-blood gene expression. DESIGN: Association of FKBP5 genotypes and PTSD symptoms with endocrine measures and genome-wide expression profiles. SETTING: Waiting rooms of general medical and gynecological clinics of an urban hospital at Emory University. PARTICIPANTS: The 211 participants were primarily African American (90.05%) and of low socioeconomic status and had high rates of trauma and PTSD. MAIN OUTCOME MEASURES: Baseline and post-dexamethasone suppression cortisol measures and gene expression levels. RESULTS: In our endocrine study, we found that only risk allele A carriers of rs9296158 showed GR supersensitivity with PTSD; in contrast, baseline cortisol levels were decreased in PTSD only in patients with the GG genotype. Expression of 183 transcripts was significantly correlated with PTSD symptoms after multiple testing corrections. When adding FKBP5 genotype and its interaction with PTSD symptoms, expression levels of an additional 32 genes were significantly regulated by the interaction term. Within these 32 genes, previously reported PTSD candidates were identified, including FKBP5 and the IL18 and STAT pathways. Significant overrepresentation of steroid hormone transcription factor binding sites within these 32 transcripts was observed, highlighting the fact that the earlier-described genotype and PTSD-dependent differences in GR sensitivity could drive the observed gene expression pattern. Results were validated by reverse transcriptase-polymerase chain reaction and replicated in an independent sample (N = 98). CONCLUSIONS: These data suggest that the inheritance of GR sensitivity moderating FKBP5 polymorphisms can determine specific types of hypothalamic pituitary-adrenal axis dysfunction within PTSD, which are also reflected in gene expression changes of a subset of GR-responsive genes. Thus, these findings indicate that functional variants in FKBP5 are associated with biologically distinct subtypes of PTSD. PMID- 21536973 TI - Genes and environment in psychiatry: winner's curse or cure? PMID- 21536974 TI - Genetic indeterminism, the 5-HTTLPR, and the paths forward in neuropsychiatric genetics. PMID- 21536975 TI - Epidemiology of autism spectrum disorders in adults in the community in England. AB - CONTEXT: To our knowledge, there is no published information on the epidemiology of autism spectrum disorders (ASDs) in adults. If the prevalence of autism is increasing, rates in older adults would be expected to be lower than rates among younger adults. OBJECTIVE: To estimate the prevalence and characteristics of adults with ASD living in the community in England. DESIGN: A stratified, multiphase random sample was used in the third national survey of psychiatric morbidity in adults in England in 2007. Survey data were weighted to take account of study design and nonresponse so that the results were representative of the household population. SETTING: General community (ie, private households) in England. PARTICIPANTS: Adults (people 16 years or older). MAIN OUTCOME MEASURES: Autism Diagnostic Observation Schedule, Module 4 in phase 2 validated against the Autism Diagnostic Interview-Revised and Diagnostic Interview for Social and Communication Disorders in phase 3. A 20-item subset of the Autism-Spectrum Quotient self-completion questionnaire was used in phase 1 to select respondents for phase 2. Respondents also provided information on sociodemographics and their use of mental health services. RESULTS: Of 7461 adult participants who provided a complete phase 1 interview, 618 completed phase 2 diagnostic assessments. The weighted prevalence of ASD in adults was estimated to be 9.8 per 1000 (95% confidence interval, 3.0-16.5). Prevalence was not related to the respondent's age. Rates were higher in men, those without educational qualifications, and those living in rented social (government-financed) housing. There was no evidence of increased use of services for mental health problems. CONCLUSIONS: Conducting epidemiologic research on ASD in adults is feasible. The prevalence of ASD in this population is similar to that found in children. The lack of an association with age is consistent with there having been no increase in prevalence and with its causes being temporally constant. Adults with ASD living in the community are socially disadvantaged and tend to be unrecognized. PMID- 21536976 TI - Early brain overgrowth in autism associated with an increase in cortical surface area before age 2 years. AB - CONTEXT: Brain enlargement has been observed in 2-year-old children with autism, but the underlying mechanisms are unknown. OBJECTIVE: To investigate early growth trajectories in brain volume and cortical thickness. DESIGN: Longitudinal magnetic resonance imaging study. SETTING: Academic medical centers. PARTICIPANTS: Fifty-nine children with autism spectrum disorder (ASD) and 38 control children. INTERVENTION: Children were examined at approximately 2 years of age. Magnetic resonance imaging was repeated approximately 24 months later (when aged 4-5 years; 38 children with ASD; 21 controls). MAIN OUTCOME MEASURES: Cerebral gray and white matter volumes and cortical thickness. RESULTS: We observed generalized cerebral cortical enlargement in individuals with ASD at both 2 and 4 to 5 years of age. Rate of cerebral cortical growth across multiple brain regions and tissue compartments in children with ASD was parallel to that seen in the controls, indicating that there was no increase in rate of cerebral cortical growth during this interval. No cerebellar differences were observed in children with ASD. After controlling for total brain volume, a disproportionate enlargement in temporal lobe white matter was observed in the ASD group. We found no significant differences in cortical thickness but observed an increase in an estimate of surface area in the ASD group compared with controls for all cortical regions measured (temporal, frontal, and parieto-occipital lobes). CONCLUSIONS: Our longitudinal magnetic resonance imaging study found generalized cerebral cortical enlargement in children with ASD, with a disproportionate enlargement in temporal lobe white matter. There was no significant difference from controls in the rate of brain growth for this age interval, indicating that brain enlargement in ASD results from an increased rate of brain growth before age 2 years. The presence of increased cortical volume, but not cortical thickness, suggests that early brain enlargement may be associated with increased cortical surface area. Cortical surface area overgrowth in ASD may underlie brain enlargement and implicates a distinct set of pathogenic mechanisms. PMID- 21536977 TI - Common proteomic changes in the hippocampus in schizophrenia and bipolar disorder and particular evidence for involvement of cornu ammonis regions 2 and 3. AB - CONTEXT: The hippocampus is strongly implicated in schizophrenia and, to a lesser degree, bipolar disorder. Proteomic investigations of the different regions of the hippocampus may help us to clarify the basis and the disease specificity of the changes. OBJECTIVE: To determine whether schizophrenia and bipolar disorder are associated with distinct patterns of differential protein expression in specific regions of the hippocampus. DESIGN, SETTING, AND PATIENTS: A postmortem comparative proteomic study, including validation of differential expression, was performed. Midhippocampus samples from well-matched groups of 20 subjects with schizophrenia, 20 subjects with bipolar disorder, and 20 control cases from the Stanley Medical Research Institute Array Collection were analyzed. MAIN OUTCOME MEASURES: We used laser-assisted microdissection to enrich for tissue from the hippocampal regions and 2-dimensional difference gel electrophoresis to compare protein profiles. Levels of differentially expressed proteins were confirmed by enzyme-linked immunosorbent assay and Western blotting. Hippocampi from haloperidol-treated mice were used to help discriminate drug-associated from disease-associated protein changes. RESULTS: Across all hippocampal regions, 108 protein spots in schizophrenia and 165 protein spots in bipolar disorder were differentially expressed compared with controls. Sixty-one proteins were differentially expressed in both disorders. One hundred fifty-two of these proteins were identified by mass spectrometry, and they implicated a range of different processes including cytoskeletal and metabolic functions. In both disorders, cornu ammonis regions 2 and 3 were affected to a significantly greater degree than other hippocampal regions. Additionally, numerous proteins showed expression changes in more than 1 region and more than 1 disorder. Validation work confirmed changes in septin 11 and in the expression of proteins involved in clathrin-mediated endocytosis in both schizophrenia and bipolar disorder. CONCLUSIONS: Overall, similar protein changes were observed in schizophrenia and bipolar disorder and for the first time indicate that the most prominent proteomic changes occur within the hippocampus in cornu ammonis regions 2 and 3. The cytoskeletal protein septin 11 and the cellular trafficking process of clathrin-mediated endocytosis are implicated by our study. PMID- 21536978 TI - Neuroanatomical abnormalities that predate the onset of psychosis: a multicenter study. AB - CONTEXT: People experiencing possible prodromal symptoms of psychosis have a very high risk of developing the disorder, but it is not possible to predict, on the basis of their presenting clinical features, which individuals will subsequently become psychotic. Recent neuroimaging studies suggest that there are volumetric differences between individuals at ultra-high risk (UHR) for psychosis who later develop psychotic disorder and those who do not. However, the samples examined to date have been small, and the findings have been inconsistent. OBJECTIVE: To assess brain structure in individuals at UHR for psychosis in a larger and more representative sample than in previous studies by combining magnetic resonance imaging data from 5 different scanning sites. DESIGN: Case-control study. SETTING: Multisite. PARTICIPANTS: A total of 182 individuals at UHR and 167 healthy controls. Participants were observed clinically for a mean of 2 years. Forty-eight individuals (26.4%) in the UHR group developed psychosis and 134 did not. MAIN OUTCOME MEASURES: Magnetic resonance images were acquired from each participant. Group differences in gray matter volume were examined using optimized voxel-based morphometry. RESULTS: The UHR group as a whole had less gray matter volume than did controls in the frontal regions bilaterally. The UHR subgroup who later developed psychosis had less gray matter volume in the left parahippocampal cortex than did the UHR subgroup who did not. CONCLUSIONS: Individuals at high risk for psychosis show alterations in regional gray matter volume regardless of whether they subsequently develop the disorder. In the UHR population, reduced left parahippocampal volume was specifically associated with the later onset of psychosis. Alterations in this region may, thus, be crucial to the expression of illness. Identifying abnormalities that specifically predate the onset of psychosis informs the development of clinical investigations designed to predict which individuals at high risk will subsequently develop the disorder. PMID- 21536979 TI - Preinjury psychiatric status, injury severity, and postdeployment posttraumatic stress disorder. AB - CONTEXT: Physical injury has been associated with the development of posttraumatic stress disorder (PTSD). Previous studies have retrospectively examined the relationship of preinjury psychiatric status and postinjury PTSD with conflicting results, but no prospective studies regarding this subject have been conducted, to our knowledge. OBJECTIVE: To prospectively assess the relationship of predeployment psychiatric status and injury severity with postdeployment PTSD. DESIGN: Prospective, longitudinal study. SETTING: United States military personnel deployed in support of the conflicts in Iraq and Afghanistan. PARTICIPANTS: United States service member participants in the Millennium Cohort Study who completed a baseline questionnaire (from July 1, 2001, through June 30, 2003) and at least 1 follow-up questionnaire (from June 1, 2004, through February 14, 2006, and from May 15, 2007, through December 31, 2008) and who were deployed in the intervening period. Self-reported health information was used to prospectively examine the relationship between baseline psychiatric status and follow-up PTSD in injured and uninjured deployed individuals. MAIN OUTCOME MEASURES: A positive screening result using the PTSD Checklist-Civilian Version. RESULTS: Of 22 630 eligible participants, 1840 (8.1%) screened positive for PTSD at follow-up, and 183 (0.8%) sustained a deployment related physical injury that was documented in the Joint Theater Trauma Registry or the Navy-Marine Corps Combat Trauma Registry Expeditionary Medical Encounter Database. The odds of screening positive for PTSD symptoms were 2.52 (95% confidence interval, 2.01-3.16) times greater in those with 1 or more defined baseline mental health disorder and 16.1% (odds ratio, 1.16; 95% confidence interval, 1.01-1.34) greater for every 3-unit increase in the Injury Severity Score. Irrespective of injury severity, self-reported preinjury psychiatric status was significantly associated with PTSD at follow-up. CONCLUSIONS: Baseline psychiatric status and deployment-related physical injuries were associated with screening positive for postdeployment PTSD. More vulnerable members of the deployed population might be identified and benefit from interventions targeted to prevent or to ensure early identification and treatment of postdeployment PTSD. PMID- 21536980 TI - Distinguishing between major depressive disorder and obsessive-compulsive disorder in children by measuring regional cortical thickness. AB - CONTEXT: Cortical abnormalities have been noted in previous studies of major depressive disorder (MDD). OBJECTIVE: To hypothesize differences in regional cortical thickness among children with MDD, children with obsessive-compulsive disorder (OCD), and healthy controls. DESIGN: Cross-sectional study of groups. SETTING: Children's Hospital of Michigan in Detroit. PARTICIPANTS: A total of 24 psychotropic drug-naive pediatric patients with MDD (9 boys and 15 girls), 24 psychotropic drug-naive pediatric outpatients with OCD (8 boys and 16 girls), and 30 healthy controls (10 boys and 20 girls). INTERVENTION: Magnetic resonance imaging. MAIN OUTCOME MEASURE: Cortical thickness. RESULTS: In the right hemisphere of the brain, the pericalcarine gyrus was thinner in patients with MDD than in outpatients with OCD (P = .002) or healthy controls (P = .04), the postcentral gyrus was thinner in patients with MDD than in outpatients with OCD (P = .002) or healthy controls (P = .02), and the superior parietal gyrus was thinner in patients with MDD than in outpatients with OCD (P = .008) or healthy controls (P = .03). The outpatients with OCD and the healthy controls did not differ in these regions of the brain. The temporal pole was thicker in patients with MDD than in outpatients with OCD (P < .001) or healthy controls (P = .01), both of which groups did not differ in temporal pole thickness. The cuneus was thinner in patients with MDD than in outpatients with OCD (P = .008), but it did not differ from that in healthy controls. In the left hemisphere, the supramarginal gyrus was thinner in both patients with MDD (P = .04) and outpatients with OCD (P = .01) than in healthy controls, and the temporal pole was thicker in patients with MDD than in both healthy controls and outpatients with OCD (P < .001). CONCLUSIONS: To our knowledge, this is the first study to explore cortical thickness in pediatric patients with MDD. Although differences in some regions of the brain would be expected given neurobiological models of MDD, our study highlights some unexpected regions (ie, supramarginal and superior parietal gyri) that merit further investigation. These results underscore the need to expand exploration beyond the frontal-limbic circuit. PMID- 21536981 TI - Estrogen-independent activation of estrogen receptors. PMID- 21536982 TI - Rate-limiting step: can different effects of antihypertensives on central blood pressure be translated into outcomes? PMID- 21536983 TI - Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall thickness. AB - The aim of this study was to investigate the effects of the vasodilating beta blocker nebivolol and the cardioselective beta-blocker metoprolol succinate on aortic blood pressure and left ventricular wall thickness. We conducted a randomized, double-blind study on 80 hypertensive patients. The patients received either 5 mg of nebivolol or 50 to 100 mg of metoprolol succinate daily for 1 year. Their heart rate, central and brachial blood pressures, mean arterial pressure, augmentation index, carotid-femoral pulse wave velocity, and left ventricular wall thickness were measured at baseline and at the end of the study. Nebivolol and metoprolol significantly reduced heart rate, brachial blood pressure, and mean arterial pressure to the same degree. However, reductions in central systolic and diastolic blood pressures, central pulse pressure, and left ventricular wall thickness were significant only in the nebivolol group. The change in left ventricular septal wall thickness was significantly correlated with central systolic blood pressure change (r=0.41; P=0.001) and with central pulse pressure change (r=0.32; P=0.01). No significant changes in augmentation index or carotid-femoral pulse wave velocity were detected in either treatment group. This proof-of-principle study provides evidence to suggest that beta blockers with vasodilating properties may offer advantages over conventional beta blockers in antihypertensive therapy; however, this remains to be tested in a larger trial. PMID- 21536984 TI - Pulse wave analysis: what do the numbers mean? PMID- 21536985 TI - Association of blood pressure and hypertension with the risk of Parkinson disease: the National FINRISK Study. AB - Cardiovascular risk factors, such as diabetes mellitus and central obesity, have been associated with Parkinson disease (PD), but data on blood pressure and PD are lacking. We sought to examine the association of blood pressure and hypertension with the risk of PD among men and women. This study consisted of 7 surveys (1972-2002) on representative samples of the general population in Finland (National FINRISK Study). A total number of 59 540 participants (age 25 to 74 years; 51.8% women) who were free of PD and stroke at baseline were prospectively followed until December 31, 2006, to identify incident PD cases using the National Social Insurance Register database. Cox proportional hazards models were constructed to estimate the hazard ratio of PD associated with blood pressure. During a mean follow-up period of 18.8 years (SD: 10.2 years), 423 men and 371 women were ascertained to have developed PD. In women, compared with normotensive subjects (<130/80 mm Hg), the multivariable-adjusted hazard ratios of PD associated with high-normal blood pressure (130 to 139/80 to 89 mm Hg) and hypertension (>=140/90 mm Hg or use of antihypertensive agents) were 1.63 (95% CI: 1.07 to 2.47) and 1.62 (95% CI: 1.09 to 2.42). There was no significant association between blood pressure and PD risk in men. The multivariable-adjusted hazard ratios of PD associated with use of antihypertensive agents were 1.08 (95% CI: 0.79 to 1.48) in men and 1.03 (95% CI: 0.76 to 1.38) in women. This study suggests that, in women, above-optimal blood pressure, including high-normal blood pressure and hypertension, is associated with an increased risk of PD. Optimal control of blood pressure in women may reduce the incidence of PD. PMID- 21536987 TI - How to best assess blood pressure? The ongoing debate on the clinical value of blood pressure average and variability. PMID- 21536986 TI - Ethnic differences in arterial wave reflections and normative equations for augmentation index. AB - Data regarding ethnic differences in wave reflections, which markedly affect the central pressure profile, are very limited. Furthermore, because age, heart rate, and body height are strong determinants of augmentation index, relating single measurements to normative data (in which augmentation index values correspond with average population values of its determinants) is challenging. We studied subject-level data from 10 550 adults enrolled in large population-based studies. In a healthy reference sample (n=3497), we assessed ethnic differences in augmentation index (ratio of second/first systolic peaks) and generated equations for adjusted z scores, allowing for a standardized comparison between individual augmentation index measurements and the normative population mean from subjects of the same age, sex, ethnic population, body height, and heart rate. After adjustment for age, body height, heart rate, and mean arterial pressure, African blacks (women: 154%; men: 138%) and Andean Hispanics (women: 152%; men: 133%) demonstrated higher central (aortic) augmentation index values than British whites (women: 140%; men: 128%), whereas American Indians (women: 133%; men: 122%) demonstrated lower augmentation index (all P<0.0001), without significant differences between Chinese and British whites. Similar results were found for radial augmentation index. Nonlinear ethnic/sex-specific equations for z scores were successfully generated to adjust individual augmentation index values for age, body height, and heart rate. Marked ethnic differences in augmentation index exist, which may contribute to ethnic differences in hypertensive organ damage. Our study provides normative data that can be used to complement the interpretation of individual hemodynamic assessments among men and women of various ethnic populations, after removing the effect of various physiological determinants. PMID- 21536988 TI - Prolonged urocortin 2 administration in experimental heart failure: sustained hemodynamic, endocrine, and renal effects. AB - Although acute administration of urocortin 2 has beneficial actions in heart failure, the integrated hemodynamic, hormonal, and renal effects of sustained urocortin 2 treatment in this disease have not been investigated. In the current study, we administered a 4-day infusion of a vehicle control (0.9% saline; n=6) or urocortin 2 (0.75 MUg/kg per hour; n=6) to sheep with pacing-induced heart failure. Compared with time-matched controls, infusion of urocortin 2 produced rapid (30-minute) and persistent (4-day) improvements in cardiac contractility (day 4: control 905+/-73 versus urocortin 2 1424+/-158 mm Hg/s; P<0.001) and output (2.6+/-0.1 versus 3.8+/-0.3 L/min; P<0.001), together with reductions in left atrial pressure (28+/-1 versus 12+/-1 mm Hg; P<0.001) and peripheral resistance (30+/-2 versus 20+/-2 mm Hg/L per min; P<0.001). In contrast, urocortin 2-induced falls in mean arterial pressure were not established until the second day (day 4: 74+/-2 versus 72+/-2 mm Hg; P<0.05). Prolonged urocortin 2 administration was associated with sustained (days 0 to 4) declines in plasma renin activity (day 4: 1.33+/-0.27 versus 0.73+/-0.20 nmol/L per hour; P<0.001), aldosterone (970+/-383 versus 396+/-96 pmol/L; P<0.05), vasopressin (2.4+/-0.8 versus 1.3+/-0.1 pmol/L; P<0.05), endothelin 1 (7.2+/-0.7 versus 4.5+/-0.4 pmol/L; P<0.01), and atrial (269+/-27 versus 150+/-19 pmol/L; P<0.001) and B-type (65+/-9 versus 29+/-6 pmol/L; P<0.001) natriuretic peptides, as well as an acute transient rise in plasma cortisol (day 1: P<0.001). Chronic urocortin 2 also persistently augmented urinary sodium (day 4: 4-fold increase; P<0.001) and creatinine (1.4-fold; P<0.001) excretion and creatinine clearance (1.5-fold; P<0.01) compared with control. Food consumption was temporarily suppressed (P<0.05). In conclusion, 4-day urocortin 2 administration induces sustained improvements in hemodynamics and renal function, in association with inhibition of multiple vasoconstrictor/volume-retaining systems. These findings support the therapeutic potential for urocortin 2 in heart failure. PMID- 21536989 TI - Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. AB - There is currently limited data on which drug should be used to improve blood pressure (BP) control in patients with resistant hypertension. This study was designed to assess the effect of the addition of 25 mg of spironolactone on BP in patients with resistant arterial hypertension. Patients with office systolic BP >140 mm Hg or diastolic BP >90 mm Hg despite treatment with at least 3 antihypertensive drugs, including a diuretic, were enrolled in this double-blind, placebo-controlled, multicenter trial. One hundred seventeen patients were randomly assigned to receive spironolactone (n=59) or a placebo (n=58) as an add on to their antihypertensive medication, by the method of simple randomization. Analyses were done with 111 patients (55 in the spironolactone and 56 in the placebo groups). At 8 weeks, the primary end points, a difference in mean fall of BP on daytime ambulatory BP monitoring (ABPM), between the groups was -5.4 mm Hg (95%CI -10.0; -0.8) for systolic BP (P=0.024) and -1.0 mm Hg (95% CI -4.0; 2.0) for diastolic BP (P=0.358). The APBM nighttime systolic, 24-hour ABPM systolic, and office systolic BP values were significantly decreased by spironolactone (difference of -8.6, -6.6, and -6.5 mm Hg; P=0=0.011, 0.004, and 0.011 [corrected]), whereas the fall of the respective diastolic BP values was not significant (-3.0, -1.0, and -2.5 mm Hg; P=0.079, 0.405, and 0.079). The adverse events in both groups were comparable. In conclusion, spironolactone is an effective drug for lowering systolic BP in patients with resistant arterial hypertension. PMID- 21536990 TI - Autonomic-immune-vascular interaction: an emerging concept for neurogenic hypertension. PMID- 21536991 TI - Activation of estrogen receptor-alpha and of angiotensin-converting enzyme 2 suppresses ischemic brain damage in oophorectomized rats. AB - Like the angiotensin II type 1 receptor blocker, endogenous estrogen (17beta estradiol) is neuroprotective against cerebral ischemia; its effects are thought to be mediated by estrogen receptors (ERs). To verify the role of ERs and the brain renin-angiotensin system in estrogen-deficient rats with ischemia induced by middle cerebral artery occlusion, we compared rats subjected to oophorectomy (OVX(+)) with sham-oophorectomized rats (OVX(-)) and OVX(+) rats treated with 0.3 or 3.0 mg/kg of olmesartan for 2 weeks before middle cerebral artery occlusion. Independent of the blood pressure, the cortical infarct volume was larger in OVX(+) than in OVX(-) rats. It was smaller in olmesartan-pretreated OVX(+) rats. The expression of ERalpha in the peri-infarct region was correlated with the reduction of cortical infarct but not that of ERbeta or G protein-coupled estrogen receptor. Olmesartan prevented ERalpha downregulation in the cortical peri-infarct area, without affecting ERbeta or G protein-coupled estrogen receptor. Olmesartan also increased mRNA expression of angiotensin-converting enzyme 2, Bcl-2, and Bcl-xL and reduced angiotensin II and cleaved caspase 3. These effects were augmented by olmesartan and abolished by the ER inhibitor. In OVX(+) rats treated with the ERalpha agonist alone, the infarct size was decreased, and the neuroprotective genes were upregulated. These findings suggest that the transactivation of neuroprotective genes and the reduction in brain angiotensin II are ERalpha dependent and that this may augment neuroprotection together with an angiotensin II type 1 receptor blockade by olmesartan. We present the new insight that the activation of ERalpha independent of estrogen contributes at least partly to limiting cerebral ischemic damage. PMID- 21536992 TI - Angiogenic growth factors are new and essential players in the sustained relaxin vasodilatory pathway in rodents and humans. AB - Relaxin is emerging as an important vasodilator of pregnancy and is being tested for afterload reduction in acute heart failure. However, the mechanisms underlying relaxin-induced vasodilation are incompletely understood. The aims of this study were to establish a new in vitro model for relaxin-induced vasodilation and to use this approach, as well as chronically instrumented, conscious rats, to investigate the role of angiogenic growth factors in the relaxin vasodilatory pathway. Incubation of rat and mouse small renal arteries with recombinant human H2 relaxin for 3 hours in vitro attenuated myogenic constriction, which was blocked by inhibitors of gelatinases, the endothelin B receptor, and NO synthase. These findings corroborate ex vivo observations in arteries isolated from relaxin-infused nonpregnant and midterm pregnant rats, thereby validating the new experimental approach and enabling the study of human arteries. Incubation of small human subcutaneous arteries with relaxin for 3 hours in vitro also attenuated myogenic constriction through the same molecular intermediates. Vascular endothelial growth factor receptor inhibitor SU5416, 3 different vascular endothelial growth factor, and 2 different placental growth factor neutralizing antibodies prevented relaxin from attenuating myogenic constriction in rat and mouse small renal and human subcutaneous arteries. SU5416 administration also prevented relaxin-induced renal vasodilation and hyperfiltration in chronically instrumented, conscious rats. Small renal arteries isolated from these rats demonstrated increased matrix metalloproteinase 2 activity in the relaxin-infused group, which was not prevented by SU5416. We conclude that there is concordance of relaxin vasodilatory mechanisms in rats, mice, and humans, and angiogenic growth factors are novel and essential intermediates. PMID- 21536993 TI - Maximum value of home blood pressure: a novel indicator of target organ damage in hypertension. AB - The maximum office systolic blood pressure (SBP) has been shown to be a strong predictor of cardiovascular events, independently of the mean SBP level. However, the clinical implications of maximum home SBP have never been reported. We investigated the association between the maximum home SBP and target organ damage (TOD). We assessed the left ventricular mass index (LVMI) and carotid intima media thickness (IMT) using ultrasonography and the urinary albumin/creatinine ratio (UACR) as measures of TOD in 356 never-treated hypertensive subjects. Home BP was taken in triplicate in the morning and evening, respectively, for 14 consecutive days with a memory-equipped device. The maximum home SBP was defined as the maximum mean triplicate BP reading in the 14-day period for each individual and was significantly correlated with LVMI (r=0.51, P<0.001), carotid IMT (r=0.40, P<0.001), and UACR (r=0.29, P<0.001). The correlation coefficients with LVMI and carotid IMT were significantly larger for the maximum home SBP than the mean home SBP. In multivariate regression analyses, the maximum home SBP was independently associated with LVMI and carotid IMT, regardless of the mean home BP level. In the prediction of left ventricular hypertrophy and carotid atherosclerosis, the goodness-of-fit of the model was significantly improved when the maximum home SBP was added to the sum of the mean office and home BPs (P=0.002 and P<0.001, respectively). These findings indicate that assessment of the maximum home SBP, in addition to the mean home SBP, might increase the predictive value of hypertensive TOD in the heart and artery. PMID- 21536994 TI - Atrial fibrillation and death after myocardial infarction: a community study. AB - BACKGROUND: Atrial fibrillation (AF) often coexists with myocardial infarction (MI), yet its prognostic influence is disputed. Prior reports studied the relationship of AF during early hospitalization for acute MI to the risk of death and could not address the timing of AF in relation to the MI (ie, before, during, after). Furthermore, as data come mostly from clinical trials, their applicability to the community is uncertain. The aims of our study were to assess the occurrence of AF among MI patients, determine whether it has changed over time, and quantify its impact and the impact of its timing on mortality after MI. METHODS AND RESULTS: This was a community-based cohort of 3220 patients hospitalized with incident (first-ever) MI from 1983 to 2007 in Olmsted County, MN. Atrial fibrillation was identified by diagnostic codes and ECG. Outcomes were all-cause and cardiovascular death. Atrial fibrillation before MI was identified in 304 patients, and 729 developed AF after MI (218 [30%] within 2 days, 119 [16%] between 3 and 30 days, and 392 [54%] >30 days post-MI). The cumulative incidence of AF after MI at 5 years was 19% and did not change over the calendar year of MI (the incidence of AF was the same regardless of when the MI occurred). During a mean follow-up of 6.6 years, 1638 deaths occurred. AF was associated with an increased risk of death (hazard ratio [95% confidence interval] 3.77 [3.37 to 4.21]), independently of clinical characteristics at the time of MI and heart failure. This risk differed markedly according to the timing of AF, and was the greatest for AF occurring >30 days post MI (hazard ratio [95% confidence interval] 1.63 [1.37 to 1.93] for AF within 2 days, 1.81 [0.45 to 2.27] for AF between 3 and 30 days, and 2.58 [2.21 to 3.00] for AF >30 days post MI). CONCLUSIONS: In the community, AF is frequent in the setting of MI. Atrial fibrillation carries an excess risk of death, which is the highest for AF developing >30 days after MI. PMID- 21536996 TI - Indications for cardiac catheterization and intervention in pediatric cardiac disease: a scientific statement from the American Heart Association. PMID- 21536995 TI - Declining stroke and vascular event recurrence rates in secondary prevention trials over the past 50 years and consequences for current trial design. AB - BACKGROUND: It is widely supposed, but not well-demonstrated, that cumulative advances in standard care have reduced recurrent stroke and cardiovascular events in secondary prevention trials. METHODS AND RESULTS: Systematic search identified all randomized, controlled trials of medical secondary stroke prevention therapies published from 1960 to 2009. Randomized, controlled trials narrowly focused on single stroke mechanisms, including atrial fibrillation, cervical carotid stenosis, and intracranial stenosis, were excluded. From control arms of individual trials, we extracted data for baseline characteristics and annual event rates for recurrent stroke, fatal stroke, and major vascular events and analyzed trends over time. Fifty-nine randomized controlled trials were identified, enrolling 66 157 patients in control arms. Over the 5 decade periods, annual event rates declined, per decade, for recurrent stroke by 0.996% (P=0.001), fatal stroke by 0.282% (P=0.003), and major vascular events by 1.331% (P=0.001). Multiple regression analyses identified increasing antithrombotic use and lower blood pressures as major contributors to the decline in recurrent stroke. For recurrent stroke, annual rates fell from 8.71% in trials launched in the 1960s to 6.10% in the 1970s, 5.41% in the 1980s, 4.04% in the 1990s, and 4.98% in the 2000s. The sample size required for a trial to have adequate power to detect a 20% reduction in recurrent stroke increased 2.2-fold during this period. CONCLUSIONS: Recurrent stroke and vascular event rates have declined substantially over the last 5 decades, with improved blood pressure control and more frequent use of antiplatelet therapy as the leading causes. Considerably larger sample sizes are now needed to demonstrate incremental improvements in medical secondary prevention. PMID- 21536997 TI - Atrial fibrillation and death after myocardial infarction: risk marker or causal mediator? PMID- 21536998 TI - Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: the Rancho Bernardo Study. AB - BACKGROUND: Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic marker in patients with cardiovascular disease (CVD), but its prognostic value in community-dwelling adults has not been reported. We hypothesized that GDF-15 would add incremental power for prediction of mortality in a population of community-dwelling older adults without known heart disease. METHODS AND RESULTS: We measured plasma GDF-15, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein levels in 1391 Rancho Bernardo Study participants, mean age 70 years, with no history of CVD and followed them for a mean of 11 years. In models adjusted for traditional CVD risk factors, GDF-15 was a robust predictor of all-cause, cardiovascular, and noncardiovascular mortality. GDF-15 was a stronger predictor of all-cause mortality than either NT-proBNP or C-reactive protein (hazard ratio [95% confidence interval] per SD log(10) units 1.5 [1.3 to 1.8], P<0.0001 for GDF-15 versus 1.3 [1.2 to 1.5], P<0.0001 for NT-proBNP; C reactive protein was not a significant predictor). Among biomarkers considered, only GDF-15 predicted noncardiovascular death (hazard ratio 1.6 [1.4 to 2.0], P<0.0001). Growth differentiation factor-15 improved discrimination and modestly but significantly improved reclassification for all-cause and noncardiovascular mortality with borderline improvement for cardiovascular mortality; NT-proBNP significantly improved reclassification for all-cause and for cardiovascular mortality; C-reactive protein did not improve reclassification for any end point tested. Participants in the highest quartile of both GDF-15 and NT-proBNP had an increased risk of death compared with participants with only NT-proBNP elevated (hazard ratio 1.5 [1.1 to 2.0], P=0.01). CONCLUSIONS: Growth differentiation factor-15 is a strong predictor of all-cause, cardiovascular, and noncardiovascular mortality in community-dwelling older individuals, adding incremental value to traditional risk factors and to NT-proBNP and C-reactive protein levels. PMID- 21536999 TI - Plasma B-type natriuretic peptide levels and recurrent arrhythmia after successful ablation of lone atrial fibrillation. AB - BACKGROUND: Plasma B-type natriuretic peptide (BNP) is abnormally elevated in patients with lone atrial fibrillation (AF). The exact significance and prognostic implications of this elevation have yet to be determined. Little is known about BNP in lone AF patients undergoing arrhythmia ablation. We sought to determine the relationship between BNP levels and the risk of recurrent arrhythmia after ablation of lone AF. METHODS AND RESULTS: We followed up 726 patients with lone AF undergoing first-time arrhythmia ablation. All had BNP levels measured on the day of ablation with of the point-of-care Triage Meter assay (Biosite Diagnostics, San Diego, CA). At baseline, factors associated with elevated BNP levels in multivariable linear regression analysis (with log BNP being the dependent variable) were older age (beta regression coefficient for +1 year change, 0.025; P<0.0001), longer duration of AF (beta for +1-year change, 0.031; P=0.01), nonparoxysmal AF (versus paroxysmal; beta, 0.52; P<0.0001), and larger left atrial size (beta for +1-cm(2) change, 0.040; P<0.0001). The BNP levels were strongly associated with arrhythmia recurrence in univariate- (hazard ratio for +1-log-BNP change, 2.32; 95% confidence interval, 2.11 to 2.74; P<0.001) and covariate- (hazard ratio for +1-log-BNP change, 2.13; 95% confidence interval, 2.06 to 2.38; P<0.001) adjusted Cox proportional hazards analysis. The covariate-adjusted hazard ratios for recurrent arrhythmia were 1.6, 2.7, 4.3, and 5.7 for the second, third, fourth, and fifth quintiles, respectively, compared with patients in the lowest quintile (P for trend across quintiles <0.001). CONCLUSIONS: B-type natriuretic peptide levels correlate with AF burden (chronicity, altered hemodynamics, and anatomic remodeling) in patients with lone AF and are strong predictors of recurrent arrhythmia after ablation. Elevated BNP levels may reflect increased cardiac chamber wall stress and/or intrinsic atrial disease, thus increasing the risk of arrhythmia recurrence. PMID- 21537000 TI - Antenatal sildenafil treatment attenuates pulmonary hypertension in experimental congenital diaphragmatic hernia. AB - BACKGROUND: Lung hypoplasia and persistent pulmonary hypertension of the newborn limit survival in congenital diaphragmatic hernia (CDH). Unlike other diseases resulting in persistent pulmonary hypertension of the newborn, infants with CDH are refractory to inhaled nitric oxide (NO). Nitric oxide mediates pulmonary vasodilatation at birth in part via cyclic GMP production. Phosphodiesterase type 5 (PDE5) limits the effects of NO by inactivation of cyclic GMP. Because of the limited success in postnatal management of CDH, we hypothesized that antenatal PDE5 inhibition would attenuate pulmonary artery remodeling in experimental nitrofen-induced CDH. METHODS AND RESULTS: Nitrofen administered at embryonic day 9.5 to pregnant rats resulted in a 60% incidence of CDH in the offspring and recapitulated features seen in human CDH, including structural abnormalities (lung hypoplasia, decreased pulmonary vascular density, pulmonary artery remodeling, right ventricular hypertrophy), and functional abnormalities (decreased pulmonary artery relaxation in response to the NO donor 2-(N,N diethylamino)-diazenolate-2-oxide). Antenatal sildenafil administered to the pregnant rat from embryonic day 11.5 to embryonic day 20.5 crossed the placenta, increased fetal lung cyclic GMP and decreased active PDE5 expression. Antenatal sildenafil improved lung structure, increased pulmonary vessel density, reduced right ventricular hypertrophy, and improved postnatal NO donor 2-(N,N diethylamino)-diazenolate-2-oxide-induced pulmonary artery relaxation. This was associated with increased lung endothelial NO synthase and vascular endothelial growth factor protein expression. Antenatal sildenafil had no adverse effect on retinal structure/function and brain development. CONCLUSIONS: Antenatal sildenafil improves pathological features of persistent pulmonary hypertension of the newborn in experimental CDH and does not alter the development of other PDE5 expressing organs. Given the high mortality/morbidity of CDH, the potential benefit of prenatal PDE5 inhibition in improving the outcome for infants with CDH warrants further studies. PMID- 21537001 TI - Implantable cardioverter-defibrillator registry risk score models for acute procedural complications or death after implantable cardioverter-defibrillator implantation. AB - BACKGROUND: Patients undergoing implantable cardioverter-defibrillator (ICD) implantation are at risk of postprocedural complications. However, we do not have a risk stratification schema to identify patients at high and low risk of adverse events. METHODS AND RESULTS: We analyzed data from 268 701 ICD implants submitted to the ICD Registry and developed logistic regression models to identify variables most strongly associated with the risk of acute complications and/or in hospital death. Overall, 3.2% of the population experienced an adverse event. A simple risk score consisting of 10 readily available variables successfully identified patients at high and low risk of complications. The variables included in the score and assigned points included: age >= 70 years (1 point), female (2 points), New York Heart Association class III (1 point) or IV (3 points), atrial fibrillation (1 point), prior valve surgery (3 points), chronic lung disease (2 points), blood urea nitrogen >30 (2 points), reimplantation for reasons other than battery change (6 points), ICD type dual chamber (2 points) or biventricular (4 points), and nonelective ICD implant (3 points). The risk of any in-hospital complication increased from 0.6% among patients with a score of <= 5 (8.4% of the population) to 8.4% among patients with >= 19 risk points (3.9% of the population). CONCLUSIONS: A simple risk score consisting of readily available clinical variables can identify high- and low-risk subsets of patients undergoing ICD implantation. This information can guide the physician in patient selection and determining the intensity of care required post procedure. PMID- 21537002 TI - Further good news on stroke, but no time for rest. PMID- 21537003 TI - Mechanical coupling between myofibroblasts and cardiomyocytes slows electric conduction in fibrotic cell monolayers. AB - BACKGROUND: After cardiac injury, activated cardiac myofibroblasts can influence tissue electrophysiology. Because mechanical coupling through adherens junctions provides a route for intercellular communication, we tested the hypothesis that myofibroblasts exert tonic contractile forces on the cardiomyocytes and affect electric propagation via a process of mechanoelectric feedback. METHODS AND RESULTS: The role of mechanoelectric feedback was examined in transforming growth factor-beta-treated monolayers of cocultured myofibroblasts and neonatal rat ventricular cells by inhibiting myofibroblast contraction and blocking mechanosensitive channels. Untreated (control) and transforming growth factor beta-treated (fibrotic) anisotropic monolayers were optically mapped for electrophysiological comparison. Longitudinal conduction velocity, transverse conduction velocity, and normalized action potential upstroke velocity (dV/dt(max)) significantly decreased in fibrotic monolayers (14.4 +/- 0.7 cm/s [mean +/- SEM], 4.1 +/- 0.3 cm/s [n=53], and 3.1 +/- 0.2% per ms [n=14], respectively) compared with control monolayers (27.2 +/- 0.8 cm/s, 8.5 +/- 0.4 cm/s [n=40], and 4.9 +/- 0.1% per ms [n=12], respectively). Application of the excitation-contraction uncoupler blebbistatin or the mechanosensitive channel blocker gadolinium or streptomycin dramatically increased longitudinal conduction velocity, transverse conduction velocity, and dV/dt(max) in fibrotic monolayers (35.9 +/- 1.5 cm/s, 10.3 +/- 0.6 cm/s [n=17], and 4.5 +/- 0.1% per ms [n=14], respectively). Similar results were observed with connexin43-silenced cardiac myofibroblasts. Spiral-wave induction in fibrotic monolayers also decreased after the aforementioned treatments. Finally, traction force measurements of individual myofibroblasts showed a significant increase with transforming growth factor beta, a decrease with blebbistatin, and no change with mechanosensitive channel blockers. CONCLUSIONS: These observations suggest that myofibroblast-myocyte mechanical interactions develop during cardiac injury, and that cardiac conduction may be impaired as a result of increased mechanosensitive channel activation owing to tension applied to the myocyte by the myofibroblast. PMID- 21537004 TI - Acute aortic intimal layer and valvar apparatus prolapse into the left ventricle. PMID- 21537005 TI - Letter by Heling et al regarding article, "remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment?". PMID- 21537006 TI - Cellular senescence, vascular disease, and aging: part 2 of a 2-part review: clinical vascular disease in the elderly. PMID- 21537007 TI - Screening for sudden cardiac death in the young: report from a national heart, lung, and blood institute working group. PMID- 21537008 TI - Prenatal diagnosis of fetal transposition of the great arteries. PMID- 21537009 TI - Diversity and evolution of AbaR genomic resistance islands in Acinetobacter baumannii strains of European clone I. AB - To assess the diversity of AbaR genomic resistance islands in Acinetobacter baumannii European clone I (MLST clonal complex 1), we investigated 26 multidrug resistant strains of this major clone isolated from hospitals in 21 cities of 10 European countries between 1984 and 2005. Each strain harbored an AbaR structure integrated at the same position in the chromosomal ATPase gene. AbaR3, including four subtypes based on variations in class 1 integron cassettes, and AbaR10 were found in 15 and 2 strains, respectively, whereas a new, unique AbaR variant was discovered in each of the other 9 strains. These new variants, designated AbaR11 to AbaR19 (19.8 kb to 57.5 kb), seem to be truncated derivatives of AbaR3, likely resulting from the deletions of its internal parts mediated by either IS26 elements (AbaR12 to AbaR19) or homologous recombination (AbaR11). AbaR3 was detected in all 10 strains isolated in 1984 to 1991, while AbaR11 to AbaR19 were carried only by strains isolated since 1997. Our results and those from previous publications suggest that AbaR3 is the original form of AbaR in European clone I, which may have provided strains of the lineage with a selective advantage facilitating their spread in European hospitals in the 1980s or before. PMID- 21537010 TI - Induction of efflux-mediated macrolide resistance in Streptococcus pneumoniae. AB - The antimicrobial efflux system encoded by the operon mef(E)-mel on the mobile genetic element MEGA in Streptococcus pneumoniae and other Gram-positive bacteria is inducible by macrolide antibiotics and antimicrobial peptides. Induction may affect the clinical response to the use of macrolides. We developed mef(E) reporter constructs and a disk diffusion induction and resistance assay to determine the kinetics and basis of mef(E)-mel induction. Induction occurred rapidly, with a >15-fold increase in transcription within 1 h of exposure to subinhibitory concentrations of erythromycin. A spectrum of environmental conditions, including competence and nonmacrolide antibiotics with distinct cellular targets, did not induce mef(E). Using 16 different structurally defined macrolides, induction was correlated with the amino sugar attached to C-5 of the macrolide lactone ring, not with the size (e.g., 14-, 15- or 16-member) of the ring or with the presence of the neutral sugar cladinose at C-3. Macrolides with a monosaccharide attached to C-5, known to block exit of the nascent peptide from the ribosome after the incorporation of up to eight amino acids, induced mef(E) expression. Macrolides with a C-5 disaccharide, which extends the macrolide into the ribosomal exit tunnel, disrupting peptidyl transferase activity, did not induce it. The induction of mef(E) did not require macrolide efflux, but the affinity of macrolides for the ribosome determined the availability for efflux and pneumococcal susceptibility. The induction of mef(E)-mel expression by inducing macrolides appears to be based on specific interactions of the macrolide C-5 saccharide with the ribosome that alleviate transcriptional attenuation of mef(E)-mel. PMID- 21537011 TI - A promising target for treatment of multidrug-resistant bacterial infections. PMID- 21537012 TI - Adaptation and antibiotic tolerance of anaerobic Burkholderia pseudomallei. AB - The Gram-negative bacterium Burkholderia pseudomallei is the etiological agent of melioidosis and is remarkably resistant to most classes of antibacterials. Even after months of treatment with antibacterials that are relatively effective in vitro, there is a high rate of treatment failure, indicating that this pathogen alters its patterns of antibacterial susceptibility in response to cues encountered in the host. The pathology of melioidosis indicates that B. pseudomallei encounters host microenvironments that limit aerobic respiration, including the lack of oxygen found in abscesses and in the presence of nitric oxide produced by macrophages. We investigated whether B. pseudomallei could survive in a nonreplicating, oxygen-deprived state and determined if this physiological state was tolerant of conventional antibacterials. B. pseudomallei survived initial anaerobiosis, especially under moderately acidic conditions similar to those found in abscesses. Microarray expression profiling indicated a major shift in the physiological state of hypoxic B. pseudomallei, including induction of a variety of typical anaerobic-environment-responsive genes and genes that appear specific to anaerobic B. pseudomallei. Interestingly, anaerobic B. pseudomallei was unaffected by antibacterials typically used in therapy. However, it was exquisitely sensitive to drugs used against anaerobic pathogens. After several weeks of anaerobic culture, a significant loss of viability was observed. However, a stable subpopulation that maintained complete viability for at least 1 year was established. Thus, during the course of human infection, if a minor subpopulation of bacteria inhabited an oxygen-restricted environment, it might be indifferent to traditional therapy but susceptible to antibiotics frequently used to treat anaerobic infections. PMID- 21537014 TI - Azithromycin inhibits expression of the GacA-dependent small RNAs RsmY and RsmZ in Pseudomonas aeruginosa. AB - Azithromycin at clinically relevant doses does not inhibit planktonic growth of the opportunistic pathogen Pseudomonas aeruginosa but causes markedly reduced formation of biofilms and quorum-sensing-regulated extracellular virulence factors. In the Gac/Rsm signal transduction pathway, which acts upstream of the quorum-sensing machinery in P. aeruginosa, the GacA-dependent untranslated small RNAs RsmY and RsmZ are key regulatory elements. As azithromycin treatment and mutational inactivation of gacA have strikingly similar phenotypic consequences, the effect of azithromycin on rsmY and rsmZ expression was investigated. In planktonically growing cells, the antibiotic strongly inhibited the expression of both small RNA genes but did not affect the expression of the housekeeping gene proC. The azithromycin treatment resulted in reduced expression of gacA and rsmA, which are known positive regulators of rsmY and rsmZ, and of the PA0588-PA0584 gene cluster, which was discovered as a novel positive regulatory element involved in rsmY and rsmZ expression. Deletion of this cluster resulted in diminished ability of P. aeruginosa to produce pyocyanin and to swarm. The results of this study indicate that azithromycin inhibits rsmY and rsmZ transcription indirectly by lowering the expression of positive regulators of these small RNA genes. PMID- 21537013 TI - Protein binding: do we ever learn? AB - Although the influence of protein binding (PB) on antibacterial activity has been reported for many antibiotics and over many years, there is currently no standardization for pharmacodynamic models that account for the impact of protein binding of antimicrobial agents in vitro. This might explain the somewhat contradictory results obtained from different studies. Simple in vitro models which compare the MIC obtained in protein-free standard medium versus a protein rich medium are prone to methodological pitfalls and may lead to flawed conclusions. Within in vitro test systems, a range of test conditions, including source of protein, concentration of the tested antibiotic, temperature, pH, electrolytes, and supplements may influence the impact of protein binding. As new antibiotics with a high degree of protein binding are in clinical development, attention and action directed toward the optimization and standardization of testing the impact of protein binding on the activity of antibiotics in vitro become even more urgent. In addition, the quantitative relationship between the effects of protein binding in vitro and in vivo needs to be established, since the physiological conditions differ. General recommendations for testing the impact of protein binding in vitro are suggested. PMID- 21537015 TI - In vitro activity of ceftazidime-NXL104 against 396 strains of beta-lactamase producing anaerobes. AB - NXL104, a novel beta-lactamase inhibitor, was tested at a constant concentration of 4 MUg/ml in combination with ceftazidime (CAZ), with and without added metronidazole, against 396 beta-lactamase-producing strains of anaerobic bacteria. MIC(50)/MIC(90) values for Bacteroides fragilis and the B. fragilis group were 8/16 and 64/>128 MUg/ml, respectively. Although CAZ-NXL104 had limited activity against most anaerobic strains, in combination with metronidazole it shows potential for treating mixed infections involving resistant Enterobacteriaceae and anaerobes. PMID- 21537016 TI - Fate of mutation rate depends on agr locus expression during oxacillin-mediated heterogeneous-homogeneous selection in methicillin-resistant Staphylococcus aureus clinical strains. AB - Methicillin-resistant Staphylococcus aureus (MRSA) strains are characterized by a heterogeneous expression of resistance. We have previously shown in clinical oxacillin-susceptible, mecA-positive MRSA strains that selection from a very heterogeneous (HeR) to highly homogeneous (HoR) resistant phenotype was mediated by acquisition of mutations through an oxacillin-induced SOS response. In the present study, we used a spotted DNA microarray to evaluate differential gene expression during HeR-HoR selection and found increased expression of the agr two component regulatory system. We hypothesized that increased expression of agr represents a mechanistically relevant component of this process. We demonstrated that inactivation of agr during the HeR-HoR selection process results in a significant increase in mutation rate; these effects were reversed by complementing the agr mutant. Furthermore, we found that extemporal ectopic expression of agr and, more specifically, RNAII in agr-null mutant HeR cells suppressed mutation frequency and the capacity of these cells to undergo the HeR HoR selection. These findings sustain the concept that increased expression of agr during HeR-HoR selection plays a critical role in regulating the beta-lactam induced increased mutation rate in very heterogeneous MRSA strains. Moreover, they indicate that a temporally controlled increase in agr expression is required to tightly modulate SOS-mediated mutation rates, which then allows for full expression of oxacillin homogeneous resistance in very heterogeneous clinical MRSA strains. PMID- 21537017 TI - Five-minute exposure to caspofungin results in prolonged postantifungal effects and eliminates the paradoxical growth of Candida albicans. AB - We studied the impact of brief caspofungin exposures on postantifungal effects (PAFEs) and paradoxical effects for five Candida albicans isolates. In time-kill studies, caspofungin at 4* and 16* the MIC resulted in significant killing of all isolates. Caspofungin at 8 MUg/ml resulted in lower levels of killing, and paradoxical effects were evident with 4 isolates. Caspofungin exposures of 5 to 60 min caused prolonged, concentration-dependent killing that approached or exceeded the results seen with time-kill experiments and eliminated paradoxical growth. PMID- 21537018 TI - Comparison of the efficacy and safety of oritavancin front-loaded dosing regimens to daily dosing: an analysis of the SIMPLIFI trial. AB - Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients >= 18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200 mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA. PMID- 21537019 TI - Development, evaluation, and application of an in silico model for antimalarial drug treatment and failure. AB - Pharmacological mechanism-based modeling was refined and used to develop an in silico model of antimalarial drug treatment validated against clinical and field data. We used this approach to investigate key features of antimalarial drug action and effectiveness, with emphasis on the current generation of artemisinin combination therapies. We made the following conclusions. (i) The development of artemisinin tolerance and resistance will, unless checked, have an immediate, large impact on the protection afforded to its partner drug and on the likely clinical efficacy of artemisinin combination therapies. (ii) Long follow-up periods are required in clinical trials to detect all drug failures; the follow up periods of 28 days recommended by the World Health Organization are likely to miss at least 50% of drug failures, and we confirmed recent suggestions that 63 days would be a more appropriate follow-up period. (iii) Day 7 serum drug concentrations are a significant risk factor of failure, although, paradoxically, receiver operating characteristic curve analysis revealed that their predictive power is relatively poor. (iv) The pharmacokinetic properties of the partner drugs in artemisinin-containing combination therapies are the most important determinants of treatment outcome, particularly the maximum killing rate. We discuss the assumptions made in such modeling approaches and how similar approaches may be refined in future work. PMID- 21537020 TI - Identifying patients harboring extended-spectrum-beta-lactamase-producing Enterobacteriaceae on hospital admission: derivation and validation of a scoring system. AB - Increases in community-acquired infections caused by extended-spectrum-beta lactamase (ESBL)-producing Enterobacteriaceae have important implications for hospital infection control and empirical antibiotic therapy protocols. We developed and validated a tool for identifying patients harboring these organisms at hospital admission. We retrospectively analyzed chart data for 849 adult inpatients. The derivation cohort included 339 patients admitted to a large hospital in Rome during 2008, with (n = 113) or without (n = 226) culture positivity for ESBL-producing Escherichia coli, Klebsiella spp., or Proteus mirabilis within 48 h after admission. Logistic-regression-based prediction scores were calculated based on variables independently associated with the outcome. The model was validated in a second cohort (n = 510) selected with identical criteria in hospitals in Genoa and Turin during 2009. Prediction scores were based on the following six variables (reported with odds ratio for study outcome and the 95% confidence intervals in brackets): recent (<= 12 months before admission) hospitalization (5.69 [2.94 to 10.99]), transfer from another health care facility (5.61 [1.65 to 19.08]), Charlson comorbidity score >= 4 (3.80 [1.90 to 7.59]), recent (<= 3 months before admission) beta-lactam and/or fluoroquinolone treatment (3.68 [1.96 to 6.91]), recent urinary catheterization (3.52 [1.96 to 6.91]), and age >= 70 years (3.20 [1.79 to 5.70]). The model displayed good calibration and good-to-excellent discrimination in the derivation and validation sets (Hosmer-Lemshow chi(2) = 15.28 and 14.07; P = 0.17 and 0.23; areas under the receiver-operating characteristic curve, 0.83 and 0.92). It reliably identified patients likely to be harboring ESBL-producing Enterobacteriaceae at hospital admission who may need special infection control measures. Further study is needed to confirm this model's potential as a guide for prescribing empirical antibiotic therapy. PMID- 21537021 TI - Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. AB - Rifampin coadministration dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of a lopinavir-ritonavir (LPV/r) capsule formulation overcame this interaction, but a subsequent study of double doses of the tablet formulation was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-infected adults. We evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults virologically suppressed on an LPV/r regimen who were given rifampin, and the dose of the LPV/r tablet formulation was gradually increased. The steady-state pharmacokinetics of LPV/r were evaluated at baseline, a week after commencing rifampin, a week after the LPV/r dose was increased 1.5 times, and a week after the LPV/r dose was doubled. Twenty-one participants were enrolled. The median [interquartile range (IQR)] predose LPV concentrations (C(0)) were 8.1 (6.2 to 9.8) mg/liter at baseline, 1.7 (0.3 to 3.0) mg/liter after 7 days of rifampin, 5.9 (2.1 to 9.9) mg/liter with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/liter with double-dose LPV/r. There were no significant differences in the LPV area under the plasma concentration-time curve from 0 to 12 h (AUC(0 12)), C(0), C(12), maximum concentration of drug in serum (C(max)), or half-life (t(1/2)) between the baseline and double-dose LPV/r time points. Treatment was generally well tolerated, with two participants developing asymptomatic grade 3/4 transaminitis. Doubling the dose of the tablet formulation of LPV/r overcomes induction by rifampin. Less hepatotoxicity occurred in our cohort of HIV-infected participants than was reported in healthy-volunteer studies. PMID- 21537022 TI - Antimicrobial penetration and efficacy in an in vitro oral biofilm model. AB - The penetration and overall efficacy of six mouthrinse actives was evaluated by using an in vitro flow cell oral biofilm model. The technique involved preloading biofilm cells with a green fluorescent dye that leaked out as the cells were permeabilized by a treatment. The loss of green color, and of biomass, was observed by time-lapse microscopy during 60 min of treatment under continuous flow conditions. The six actives analyzed were ethanol, sodium lauryl sulfate, triclosan, chlorhexidine digluconate (CHX), cetylpyridinium chloride, and nisin. Each of these agents effected loss of green fluorescence throughout biofilm cell clusters, with faster action at the edge of a cell cluster and slower action in the cluster center. The time to reach half of the initial fluorescent intensity at the center of a cell cluster, which can be viewed as a combined penetration and biological action time, ranged from 0.6 to 19 min for the various agents. These times are much longer than the predicted penetration time based on diffusion alone, suggesting that anti-biofilm action was controlled more by the biological action time than by the penetration time of the active. None of the agents tested caused any removal of the biofilm. The extent of fluorescence loss after 1 h of exposure to an active ranged from 87 to 99.5%, with CHX being the most effective. The extent of fluorescence loss in vitro, but not penetration and action time, correlated well with the relative efficacy data from published clinical trials. PMID- 21537023 TI - Effects of altering aminoglycoside structures on bacterial resistance enzyme activities. AB - Aminoglycoside-modifying enzymes (AMEs) constitute the most prevalent mechanism of resistance to aminoglycosides by bacteria. We show that aminoglycosides can be doubly modified by the sequential actions of AMEs, with the activity of the second AME in most cases unaffected, decreased, or completely abolished. We demonstrate that the bifunctional enzyme AAC(3)-Ib/AAC(6')-Ib' can diacetylate gentamicin. Since single acetylation does not always inactivate the parent drugs completely, two modifications likely provide more-robust inactivation in vivo. PMID- 21537024 TI - The antibiotic dehydrophos is converted to a toxic pyruvate analog by peptide bond cleavage in Salmonella enterica. AB - The metabolic processing of dehydrophos, a broad-spectrum peptide antibiotic containing an unusual vinyl-phosphonate moiety, was examined by using a panel of Salmonella enterica mutants deficient in peptide uptake and catabolism. Dehydrophos bioactivity is lost in opp tpp double mutants, demonstrating a requirement for uptake via nonspecific oligopeptide permeases. Dehydrophos bioactivity is also abolished in a quadruple Salmonella mutant lacking the genes encoding peptidases A, B, D, and N, showing that hydrolysis of the peptide bond is required for activity. (31)P nuclear magnetic resonance spectroscopy was used to assess the fate of dehydrophos following in vitro digestion of the antibiotic with purified PepA. The results suggest that the initial product of peptidase processing is 1-aminovinyl-phosphonate O-methyl ester. This phosphonate analogue of dehydroalanine undergoes rearrangement to the more stable imine, followed by spontaneous hydrolysis to yield O-methyl-acetylphosphonate, a structural analogue of pyruvate. This compound is a known inhibitor of pyruvate dehydrogenase and pyruvate oxidase and is probably the active species responsible for dehydrophos bioactivity. PMID- 21537025 TI - Novel diamidines with activity against Babesia divergens in vitro and Babesia microti in vivo. AB - Dicationic diamidines, such as diminazene and pentamidine, are well-studied chemotherapeutic agents with significant activity against parasitic diseases. The in vitro activities of novel diamidine compounds against the Babesia divergens strains 1903B and 4201 were investigated. The most potent compound, a diphenyl furan, had a 50% inhibitory concentration (IC(50)) of 1.5 ng/ml. In a murine model, several test compounds were effective enough to cure mice infected with Babesia microti at a dose of 12.5 and/or 25 mg/kg of body weight given by the subcutaneous route for 4 days. The best antibabesial properties were exhibited by terphenyls, benzimidazoles, diphenyl furans, pentamidine, and pentamidine analogues. PMID- 21537026 TI - CpG oligodeoxynucleotide 2006 and miltefosine, a potential combination for treatment of experimental visceral leishmaniasis. AB - In view of the severe immunosuppression in visceral leishmaniasis (VL), a rational approach to effectively combat the parasitic scourge would be to enhance the immune status of the host. Use of CpG oligodeoxynucleotide (CpG-ODN) against leishmaniasis has previously been reported, especially as an immunomodulator and adjuvant with various immunogens. In the present study, experiments were carried out with BALB/c mice and hamsters infected with Leishmania donovani. Immunostimulating class B bacterial CpG-ODN namely, ODN-2006, was administered at various doses by the intraperitoneal (i.p.) route. The dose of CpG-ODN-2006 (1 nM/single dose) showing the most antileishmanial activity was given as free and liposomal forms with different doses of miltefosine, namely, 5 and 10 mg/kg of body weight, for 5 days in mice and hamsters, respectively. Among the various groups, mice coadministered liposomal CpG-ODN and miltefosine (5 mg/kg) showed the best inhibitory effect (97% parasite inhibition) compared with free CpG-ODN plus miltefosine and miltefosine, free CpG-ODN, and liposomal CpG-ODN given separately. Similar responses were observed in the case of hamsters, where the combination of liposomal CpG-ODN with miltefosine (10 mg/kg) gave 96% parasite inhibition. Promising antileishmanial efficacy was observed in animals treated with liposomal CpG-ODN and miltefosine. PMID- 21537027 TI - Antimicrobial resistance in urinary tract pathogens in Canada from 2007 to 2009: CANWARD surveillance study. AB - From January 2007 to December 2009, an annual Canadian national surveillance study (CANWARD) tested 2,943 urinary culture pathogens for antimicrobial susceptibilities according to Clinical and Laboratory Standards Institute guidelines. The most frequently isolated urinary pathogens were as follows (number of isolates, percentage of all isolates): Escherichia coli (1,581, 54%), enterococci (410, 14%), Klebsiella pneumoniae (274, 9%), Proteus mirabilis (122, 4%), Pseudomonas aeruginosa (100, 3%), and Staphylococcus aureus (80, 3%). The rates of susceptibility to trimethoprim-sulfamethoxazole (SXT) were 78, 86, 84, and 93%, respectively, for E. coli, K. pneumoniae, P. mirabilis, and S. aureus. The rates of susceptibility to nitrofurantoin were 96, 97, 33, and 100%, respectively, for E. coli, enterococci, K. pneumoniae, and S. aureus. The rates of susceptibility to ciprofloxacin were 81, 40, 86, 81, 66, and 41%, respectively, for E. coli, enterococci, K. pneumoniae, P. mirabilis, P. aeruginosa, and S. aureus. Statistical analysis of resistance rates (resistant plus intermediate isolates) by year for E. coli over the 3-year study period demonstrated that increased resistance rates occurred only for amoxicillin clavulanate (from 1.8 to 6.6%; P < 0.001) and for SXT (from 18.6 to 24.3%; P = 0.02). For isolates of E. coli, in a multivariate logistic regression model, hospital location was independently associated with resistance to ciprofloxacin (P = 0.026) with higher rates of resistance observed in inpatient areas (medical, surgical, and intensive care unit wards). Increased age was also associated with resistance to ciprofloxacin (P < 0.001) and with resistance to two or more commonly prescribed oral agents (amoxicillin-clavulanate, ciprofloxacin, nitrofurantoin, and SXT) (P = 0.005). We conclude that frequently prescribed empirical agents for urinary tract infections, such as SXT and ciprofloxacin, demonstrate lowered in vitro susceptibilities when tested against recent clinical isolates. PMID- 21537028 TI - In vitro susceptibility of Pythium insidiosum to macrolides and tetracycline antibiotics. AB - We describe the in vitro activity of macrolides and tetracycline antibiotics against Pythium insidiosum. The MICs were determined according to CLSI procedures (visual MIC) and by a colorimetric method [3-(4,5-dimethyl-2-thiazyl)-2,5 diphenyl-2H-tetrazolium bromide (MTT)]. The lowest geometric mean (GM) MIC (MICs in MUg/ml) (0.39 and 0.7 by visual reading and colorimetric method, respectively) and MIC ranges (0.125 to 2.0) were obtained for minocycline, while the highest MICs were shown for erythromycin (GM of 7.58 and 12.25 by visual reading and colorimetric method, respectively, and MIC ranged from 2 to 32). This significant in vitro activity makes these classes of antibiotics good candidates for experimental treatment of pythiosis. PMID- 21537029 TI - Efficacy of caspofungin in neutropenic and corticosteroid-immunosuppressed murine models of invasive pulmonary mucormycosis. AB - Caspofungin (CFG) was tested in neutropenic and corticosteroid-immunosuppressed mice challenged with a lethal sinopulmonary inoculum of Rhizopus oryzae. Compared to untreated controls, CFG administered at 1 mg/kg of body weight/day significantly improved survival (54% versus 19%; P = 0.003) and reduced median R. oryzae fungal burden by 1.5 log(10) for conidial equivalent DNA in neutropenic but not corticosteroid-immunosuppressed animals. CFG administered at 16 mg/kg/day was not significantly better than a saline control for treatment of invasive pulmonary mucormycosis (IPM) in either neutropenic or corticosteroid immunosuppressed animals. PMID- 21537030 TI - Occurrence of subacute cutaneous lupus erythematosus after treatment with systemic fluorouracil. PMID- 21537031 TI - Increased melanoma after regular sunscreen use? PMID- 21537032 TI - Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years. AB - PURPOSE: Research has documented cognitive deficits both before and after high dose treatment followed by allogeneic hematopoietic cell transplantation (HCT), with partial recovery by 1 year. This study prospectively examined the trajectory and extent of long-term cognitive dysfunction, with a focus on 1 to 5 years after treatment. PATIENTS AND METHODS: Allogeneic HCT recipients completed standardized neuropsychological tests including information processing speed (Trail Making A and Digit Symbol Substitution Test), verbal memory (Hopkins Verbal Learning Test Revised), executive function (Controlled Oral Word Association Test and Trail Making B), and motor dexterity and speed (Grooved Pegboard). Survivors (n = 92) were retested after 80 days and 1 and 5 years after transplantation. Case-matched controls (n = 66) received testing at the 5-year time point. A Global Deficit Score (GDS) summarized overall impairment. Response profiles were analyzed using linear mixed effects models. RESULTS: Survivors recovered significant cognitive function from post-transplantation (80 days) to 5 years in all tests (P < .0001) except verbal recall (P > .06). Between 1 and 5 years, verbal fluency improved (P = .0002), as did executive function (P < .01), but motor dexterity did not (P > .15), remaining below controls (P < .0001) and more than 0.5 standard deviation below population norms. In GDS, 41.5% of survivors and 19.7% of controls had mild or greater deficits (NcNemar test = 7.04, P = .007). CONCLUSION: Although neurocognitive function improved from 1 to 5 years after HCT, deficits remained for more than 40% of survivors. Risk factors, mechanisms and rehabilitation strategies need to be identified for these residual deficits. PMID- 21537033 TI - Two tales of two lymphomas. PMID- 21537034 TI - Survival outcomes after radiation therapy for stage III non-small-cell lung cancer after adoption of computed tomography-based simulation. AB - PURPOSE: Technical studies suggest that computed tomography (CT) -based simulation improves the therapeutic ratio for thoracic radiation therapy (TRT), although few studies have evaluated its use or impact on outcomes. METHODS: We used the Surveillance, Epidemiology and End Results (SEER) -Medicare linked data to identify CT-based simulation for TRT among Medicare beneficiaries diagnosed with stage III non-small-cell lung cancer (NSCLC) between 2000 and 2005. Demographic and clinical factors associated with use of CT simulation were identified, and the impact of CT simulation on survival was analyzed by using Cox models and propensity score analysis. RESULTS: The proportion of patients treated with TRT who had CT simulation increased from 2.4% in 1994 to 34.0% in 2000 to 77.6% in 2005. Of the 5,540 patients treated with TRT from 2000 to 2005, 60.1% had CT simulation. Geographic variation was seen in rates of CT simulation, with lower rates in rural areas and in the South and West compared with those in the Northeast and Midwest. Patients treated with chemotherapy were more likely to have CT simulation (65.2% v 51.2%; adjusted odds ratio, 1.67; 95% CI, 1.48 to 1.88; P < .01), although there was no significant association between use of surgery and CT simulation. Controlling for demographic and clinical characteristics, CT simulation was associated with lower risk of death (adjusted hazard ratio, 0.77; 95% CI, 0.73 to 0.82; P < .01) compared with conventional simulation. CONCLUSION: CT-based simulation has been widely, although not uniformly, adopted for the treatment of stage III NSCLC and is associated with higher survival among patients receiving TRT. PMID- 21537035 TI - Reducing time to diagnosis does not improve outcomes for women with symptomatic ovarian cancer: a report from the Australian Ovarian Cancer Study Group. AB - PURPOSE: To determine if time to diagnosis is associated with stage of disease at diagnosis or survival among women with symptomatic ovarian cancer. METHODS: A representative sample of Australian women (n = 1,463) with ovarian cancer diagnosed between 2002 and 2005 who participated in a population-based case control study were interviewed regarding the events leading to their diagnosis and were observed for mortality for 5 years. RESULTS: Of the 1,318 women (90%) who presented to a medical practitioner with symptoms, 55% presented within 1 month, 70% in less than 2 months, and 92% within 6 months of symptom onset. There were no significant differences in the time from symptom onset to first medical practitioner consultation (P = .19) or symptom onset to diagnosis (P = .64) among women with borderline, early (International Federation of Gynecology and Obstetrics [FIGO] stages I to II) or late (FIGO stages III to IV) disease. There was also no association between time to diagnosis and survival; adjusted hazard ratio for long delay (> 12 months from symptom onset to diagnosis) versus short delay (<= 1 month) was 0.94 (95% CI, 0.68 to 1.30). Women who had asymptomatic cancers diagnosed incidentally (n = 145) were younger and were more likely to have borderline or stage I disease compared with women who had symptomatic ovarian cancer. CONCLUSION: The results of this study suggest that, once ovarian cancer is symptomatic, reducing the time to diagnosis would not greatly alter stage of disease at diagnosis or survival. PMID- 21537036 TI - Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older. AB - PURPOSE: The Study of Tamoxifen and Raloxifene (STAR) demonstrated that raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer (IBC) in postmenopausal women and had lower risks of thromboembolic events, endometrial cancer, and cataracts but had a nonstatistically significant higher risk of noninvasive breast cancer. There is a need to summarize the risks and benefits of these agents. PATIENTS AND METHODS: Baseline incidence rates of IBC and other health outcomes, absent raloxifene and tamoxifen, were estimated from breast cancer chemoprevention trials; the Surveillance, Epidemiology and End Results Program; and the Women's Health Initiative. Effects of raloxifene and tamoxifen were estimated from STAR and the Breast Cancer Prevention Trial. We assigned weights to health outcomes to calculate the net benefit from raloxifene compared with placebo and tamoxifen compared with placebo. RESULTS: Risks and benefits of treatment with raloxifene or tamoxifen depend on age, race, breast cancer risk, and history of hysterectomy. Over a 5-year period, postmenopausal women with an intact uterus had a better benefit/risk index for raloxifene than for tamoxifen. For postmenopausal women without a uterus, the benefit/risk ratio was similar. The benefits and risks of raloxifene and tamoxifen are described in tables that can help identify groups of women for whom the benefits outweigh the risks. CONCLUSION: We developed a benefit/risk index to quantify benefits from chemoprevention with tamoxifen or raloxifene. This index can complement clinical evaluation in deciding whether to initiate chemoprevention and in comparing the benefits and risks of raloxifene versus tamoxifen. PMID- 21537037 TI - Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. AB - PURPOSE: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU). METHODS: On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk. RESULTS: Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P(32)), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P(32) greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation. CONCLUSION: The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P(32) and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors. PMID- 21537038 TI - Evaluation of oncology drugs at the European Medicines Agency and US Food and Drug Administration: when differences have an impact on clinical practice. AB - PURPOSE: The aims of this study were to compare the approaches of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in the evaluation and approval of new anticancer indications and to identify possible clinical implications associated with these differences. METHODS: Information on the European Union therapeutic indications for the cohort of anticancer drugs was extracted from the European Public Assessment Reports and from the FDA review reports. RESULTS: Overall, 42 anticancer drugs were approved by EMA between 1995 and 2008, corresponding to a total of 100 indications. In 47 of 100 indications, a difference was found. For 19 of these 47 indications, the difference was that one agency approved an indication, whereas the other agency did not. For the remaining 28 indications, the same indication was approved by both of the agencies and differences were evaluated through an algorithm; in 10 cases, discrepancies in therapeutic indications between EMA and FDA were considered clinically relevant. We found an overall trend that the agency that was second to give a positive approval was usually more restrictive in terms of wording of the indication compared with the agency that provided approval first. Regarding the use and robustness of available clinical data for evaluation, no clear associations could be found. CONCLUSION: Clinically relevant differences in the outcome of the EMA and FDA approval process of oncology products were found. Neither of the agencies seems to have a prevailing restrictive behavior over the other. Further efforts on harmonizing decision making between regulatory systems are needed. PMID- 21537039 TI - Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. AB - PURPOSE: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), has clinical activity in multiple tumor types. We conducted a phase II trial to assess the activity and tolerability of single-agent bevacizumab in recurrent or persistent endometrial cancer (EMC). PATIENTS AND METHODS: Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status of <= 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression or prohibitive toxicity. VEGF-A was assessed by immunohistochemistry in archival tumor and by enzyme-linked immunosorbent assay in pretreatment plasma. Primary end points were progression-free survival (PFS) at 6 months and overall response rate. RESULTS: Fifty-six patients were enrolled. Fifty-two patients were eligible and evaluable. Median age was 62 years, and prior treatment consisted of one or two regimens in 33 (63.5%) and 19 (36.5%) patients, respectively. Twenty-nine patients (55.8%) received prior radiation. Adverse events were consistent with those expected with bevacizumab treatment. No GI perforations or fistulae were seen. Seven patients (13.5%) experienced clinical responses (one complete response and six partial responses; median response duration, 6.0 months), and 21 patients (40.4%) survived progression free for at least 6 months. Median PFS and overall survival times were 4.2 and 10.5 months, respectively. Suggested associations were observed between high VEGF-A and adjusted hazard of death or tumor response when evaluated in tumor/plasma or plasma, respectively. CONCLUSION: Bevacizumab is well tolerated and active based on PFS at 6 months in recurrent or persistent EMC and warrants further investigation. PMID- 21537040 TI - Cohort study based on the seventh edition of the TNM classification for gastric cancer: proposal of a new staging system. AB - PURPOSE: We investigated the effect of the new TNM classification on gastric cancer staging. PATIENTS AND METHODS: From hospital records, information from patients with gastric cancer, who had undergone either total or partial gastrectomy for adenocarcinomas of the stomach or esophagogastric junction, was retrieved. The pathologic TNM stage was determined according to the sixth and seventh editions of the International Union Against Cancer guidelines and was based on surgical pathologic examination. RESULTS: Five hundred fifty-four patients (338 men and 216 women; median age, 68 years) had undergone partial or complete gastrectomy for intestinal (n = 209) or diffuse (n = 249) adenocarcinoma of the esophagogastric junction and stomach. Survival data and date of death were available for all patients. Patient death correlated significantly with age at diagnosis, tumor type, histologic grade, local tumor growth (T category), number of metastatic lymph nodes, lymph node ratio, lymph node status (N category), and tumor stage. No major difference was noted between the sixth and seventh editions of the TNM classification. On the basis of survival data, we revised the stage grouping system; stage I and II tumors were confined to nonmetastatic tumors, and stage III and IV tumors were confined to metastatic tumors. The Kaplan-Meier plots of this modified stage grouping showed statistically significant differences between individual stage subgroups without crossing curves and demonstrated improved survival of patients with stage II disease. CONCLUSION: The seventh edition of the TNM classification is associated with a stage migration in 60% of patients with esophagogastric and stomach cancer. This change did not improve the assessment of patient prognosis, and therefore, a revised staging system is proposed. PMID- 21537041 TI - Too-low iron doses and too many dropouts in negative iron trial? PMID- 21537042 TI - Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. AB - PURPOSE: Observational studies suggested that luteinizing hormone-releasing hormone agonists (LHRHa) might prevent premature ovarian failure resulting from adjuvant chemotherapy in premenopausal patients. We aimed to test the efficacy of ovarian function preservation with the LHRHa goserelin in patients with breast cancer. PATIENTS AND METHODS: In a prospective, randomized, open-label, controlled multicenter study, 60 patients younger than age 46 years with hormone insensitive breast cancer were allocated to receive anthracycline/cyclophosphamide (with or without taxane) -based neoadjuvant chemotherapy with or without goserelin. The first goserelin injection was administered at least 2 weeks before the first chemotherapy cycle, continuing at 3.6 mg subcutaneously every 4 weeks until the end of the last cycle. The primary objective was the reappearance of normal ovarian function, defined as two consecutive menstrual periods within 21 to 35 days at 6 months after end of chemotherapy. RESULTS: Fifty-three patients (88.3%) experienced temporary amenorrhea (93.3% with v 83.3% without goserelin). No significant difference was observed regarding the reappearance of menstruation at 6 months after chemotherapy (70.0% with v 56.7% without goserelin; difference of 13.3%; 95% CI, 10.85 to 37.45; P = .284). All but one evaluable patient reported regular menses at 2 years after chemotherapy. Time to restoration of menstruation was 6.8 months (95% CI, 5.2 to 8.4) with goserelin and 6.1 months (95% CI, 5.3 to 6.8) without goserelin (P = .304). Chemotherapy resulted in a decreased ovarian reserve measured by inhibin B and anti-Mullerian hormone during follow-up, supporting the other findings. CONCLUSION: Premenopausal patients with breast cancer receiving goserelin simultaneously with modern neoadjuvant chemotherapy did not experience statistically significantly less amenorrhea 6 months after end of chemotherapy compared with those receiving chemotherapy alone. PMID- 21537043 TI - Metastatic breast cancer in a young adult man after total-body irradiation for acute lymphoblastic leukemia. PMID- 21537044 TI - Breast cancer chemoprevention gets personal. PMID- 21537046 TI - Harnessing radiation technology to improve survival. PMID- 21537045 TI - Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. AB - PURPOSE: Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies. PATIENTS AND METHODS: We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI. RESULTS: Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression. CONCLUSION: High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression. PMID- 21537047 TI - Osteonecrosis of the jaw after zoledronic acid and denosumab treatment. PMID- 21537048 TI - Association of comorbidities with overall survival in myelodysplastic syndrome: development of a prognostic model. AB - PURPOSE: Patients with cancer often experience comorbidities that may affect their prognosis and outcome. The objective of this study was to determine the effect of comorbidities on the survival of patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: We conducted a retrospective cohort study of 600 consecutive patients with MDS who presented to MD Anderson Cancer Center from January 2002 to December 2004. The Adult Comorbidity Evaluation-27 (ACE-27) scale was used to assess comorbidities. Data on demographics, International Prognostic Scoring System (IPSS), treatment, and outcome (leukemic transformation and survival) were collected. Kaplan-Meier methods and Cox regression were used to assess survival. A prognostic model incorporating baseline comorbidities with age and IPSS was developed to predict survival. RESULTS: Overall median survival was 18.6 months. According to the ACE-27 categories, median survival was 31.8, 16.8, 15.2, and 9.7 months for those with none, mild, moderate, and severe comorbidities, respectively (P < .001). Adjusted hazard ratios were 1.3, 1.6, and 2.3 for mild, moderate, and severe comorbidities, respectively, compared with no comorbidities (P < .001). A final prognostic model including age, IPSS, and comorbidity score predicted median survival of 43.0, 23.0, and 9.0 months for lower-, intermediate-, and high-risk groups, respectively (P < .001). CONCLUSION: Comorbidities have a significant impact on the survival of patients with MDS. Patients with severe comorbidity had a 50% decrease in survival, independent of age and IPSS risk group. A comprehensive assessment of the severity of comorbidities helps predict survival in patients with MDS. PMID- 21537049 TI - Testing women with endometrial cancer to detect Lynch syndrome. AB - PURPOSE: Women with endometrial cancer as a result of Lynch syndrome may not be identified as such by Amsterdam II criteria. We estimated the costs and benefits of different testing criteria to identify Lynch syndrome in women with endometrial cancer. METHODS: We developed a Markov Monte Carlo simulation model to compare six criteria for Lynch syndrome testing for women with endometrial cancer: Amsterdam II criteria; age younger than 50 years with at least one first degree relative having a Lynch-associated cancer at any age (FDR); immunohistochemistry (IHC) triage if age younger than 50 years; IHC triage if age younger than 60 years; IHC triage at any age if 1 FDR; and IHC triage of all endometrial cancers. Net health benefit was life expectancy, and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of new colorectal cancers associated with each strategy. RESULTS: IHC triage of women with endometrial cancer having at least 1 FDR yielded a favorable ICER of $9,126 per year of life gained. This strategy would subject fewer cases to IHC but identify more mutation carriers than age thresholds of 50 or 60 years. IHC triage of all endometrial cancers could identify the most mutation carriers and prevent the most colorectal cancers but at considerable cost ($648,494 per year of life gained). CONCLUSION: IHC triage of women with endometrial cancer at any age having at least 1 FDR with a Lynch-associated cancer is a cost-effective strategy for detecting Lynch syndrome. PMID- 21537050 TI - mRNA expression signature of Gleason grade predicts lethal prostate cancer. AB - PURPOSE: Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis. PATIENTS AND METHODS: Using the complementary DNA-mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason <= 6 to those with Gleason >= 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases. RESULTS: We built a 157 gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006). CONCLUSION: Our expression signature and the genes identified may improve our understanding of the de differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment. PMID- 21537051 TI - Progression from high-grade prostatic intraepithelial neoplasia to cancer: a randomized trial of combination vitamin-E, soy, and selenium. AB - PURPOSE: High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative precursor of invasive prostate cancer (PCa). Preclinical evidence suggests vitamin E, selenium, and soy protein may prevent progression of HGPIN to PCa. This hypothesis was tested in a randomized phase III double-blind study of daily soy (40 g), vitamin E (800 U), and selenium (200 MUg) versus placebo. PATIENTS AND METHODS: Three hundred three men in 12 Canadian centers were analyzed. The main eligibility criterion was confirmed HGPIN in at least one of two biopsies within 18 months of random assignment. Treatment was administered daily for 3 years. Follow-up prostate biopsies occurred at 6, 12, 24, and 36 months postrandomization. The primary end point was time to development of invasive PCa. Kaplan-Meier plots and log-rank tests were used to compare two treatment groups for this end point. RESULTS: For all patients, the median age was 62.8 years. The median baseline prostate-specific antigen (PSA; n = 302) was 5.41 ug/L; total testosterone (n = 291) was 13.4 nmol/L. Invasive PCa developed among 26.4% of patients. The hazard ratio for the nutritional supplement to prevent PCa was 1.03 (95% CI, 0.67 to 1.60; P = .88). Gleason score distribution was similar in both groups with 83.5% of cancers graded Gleason sum of 6. Baseline age, weight, PSA, and testosterone did not predict for development of PCa. The supplement was well tolerated with flatulence reported more frequently (27% v 17%) among men receiving micronutrients. CONCLUSION: This trial does not support the hypothesis that combination vitamin E, selenium, and soy prevents progression from HGPIN to PCa. PMID- 21537052 TI - Acquired agranulocytosis and factor XI deficiency in association with thymoma. PMID- 21537053 TI - Comparing upward and speeding up. Motivational consequences of nonsocial comparison for speed-accuracy trade-offs. AB - Comparison is one of the most ubiquitous and versatile components in human information processing. Social comparisons in particular have multifaceted judgmental, affective, behavioral, and motivational consequences. Initially, the consequences of nonsocial comparisons may appear to be less complex than the consequences of social comparisons. Comparing a smaller circle with a larger circle, for example, has little motivational relevance. Across two studies, however, we demonstrated that different types of nonsocial comparisons influence the motivational underpinnings of participants' subsequent performance. Participants who were perceptually or numerically induced to compare upward (e.g., to compare a smaller stimulus with a larger stimulus) in a first task traded accuracy for speed in a subsequent unrelated performance task. Conversely, participants who had compared downward traded speed for accuracy. These trade offs are indicative of promotion- and prevention-focused motivational orientations, respectively. Comparing a geometric circle with a "superior" (e.g., larger) circle seems to yield promotion-focused strategic orientations similar to those produced by comparing oneself to a person one perceives as superior. These findings demonstrate the surprising motivational power of nonsocial comparisons. PMID- 21537054 TI - Chicken soup really is good for the soul: "comfort food" fulfills the need to belong. AB - Theories of social surrogacy and embodied cognition assume that cognitive associations with nonhuman stimuli can be affectively charged. In the current research, we examined whether the "comfort" of comfort foods comes from affective associations with relationships. Two experiments support the hypotheses that comfort foods are associated with relationships and alleviate loneliness. Experiment 1 found that the consumption of comfort foods automatically activates relationship-related concepts. Experiment 2 found that comfort foods buffer against belongingness threats in people who already have positive associations with relationships (i.e., are secure in attachment style). Implications for social surrogacy, need to belong, embodied cognition, and eating behavior are discussed. PMID- 21537055 TI - Enhancing retention through reconsolidation: negative emotional arousal following retrieval enhances later recall. AB - When information is retrieved from memory, it enters a labile state rendering it amenable to change. This process of reconsolidation may explain, in part, the benefits that are observed in later retention following retrieval of information on an initial test. We examined whether the benefits of retrieval could be modulated by an emotional event occurring after retrieval. Participants studied Swahili-English vocabulary pairs. On a subsequent cued-recall test, each retrieval was followed by a blank screen, a neutral picture, or a picture inducing negative affect. Performance on a final cued-recall test was best for items whose initial retrieval was followed by negative pictures. This outcome occurred when a negative picture was presented immediately after (Experiment 1) or 2 s after (Experiment 2) successful retrieval, but not when it was presented after restudy of the vocabulary pair (Experiment 3). Postretrieval reconsolidation via emotional processing may enhance the usual positive effects of retrieval. PMID- 21537056 TI - Cognitive capitalism: the effect of cognitive ability on wealth, as mediated through scientific achievement and economic freedom. AB - Traditional economic theories stress the relevance of political, institutional, geographic, and historical factors for economic growth. In contrast, human capital theories suggest that peoples' competences, mediated by technological progress, are the deciding factor in a nation's wealth. Using three large-scale assessments, we calculated cognitive-competence sums for the mean and for upper- and lower-level groups for 90 countries and compared the influence of each group's intellectual ability on gross domestic product. In our cross-national analyses, we applied different statistical methods (path analyses, bootstrapping) and measures developed by different research groups to various country samples and historical periods. Our results underscore the decisive relevance of cognitive ability--particularly of an intellectual class with high cognitive ability and accomplishments in science, technology, engineering, and math--for national wealth. Furthermore, this group's cognitive ability predicts the quality of economic and political institutions, which further determines the economic affluence of the nation. Cognitive resources enable the evolution of capitalism and the rise of wealth. PMID- 21537057 TI - The unanticipated interpersonal and societal consequences of choice: victim blaming and reduced support for the public good. AB - Choice makes North Americans feel more in control, free, and independent, and thus has many positive consequences for individuals' motivation and well-being. We report five studies that uncovered novel consequences of choice for public policy and interpersonal judgments. Studies 1 through 3 found that activating the concept of choice decreases support for policies promoting intergroup equality (e.g., affirmative action) and societal benefits (e.g., reducing environmental pollution), but increases support for policies promoting individual rights (e.g., legalizing drugs). Studies 4 and 5 found that activating the concept of choice increases victim blaming and decreases empathy for disadvantaged people. Study 5 found that choice does not decrease Indians' empathy for disadvantaged individuals, indicating that the social and interpersonal consequences of choice are likely culture-specific. This research suggests that the well-known positive effects of choice for individuals can be accompanied by an array of previously unexamined and potentially negative outcomes for other people and for society. PMID- 21537058 TI - Dynamic risk assessment in sexual offenders using STABLE-2000 and the STABLE 2007: an investigation of predictive and incremental validity. AB - The predictive accuracy of STABLE-2000 and STABLE-2007 was examined within a prospective research design in a German-speaking sample of 263 adult male prison released sexual offenders followed up for an average of 6.4 years. The STABLE 2007 was significantly related to all outcomes (AUC = 0.67-0.71), whereas the STABLE-2000 demonstrated only weak predictive accuracy for sexual reoffense (AUC = 0.62). Supporting the results of the construction sample, the STABLE-2007 incrementally added to the predictive accuracy of the STATIC-99 for violent and general reoffense (conviction and incarceration). Moreover, the STABLE-2007 total scores and the nominal risk/need categories made significant incremental contributions over the SORAG for predicting sexual reoffense. PMID- 21537059 TI - Biocompatibility of metal injection molded versus wrought ASTM F562 (MP35N) and ASTM F1537 (CCM) cobalt alloys. AB - We present a comparative analysis between biocompatibility test results of wrought and Metal Injection Molded (MIM) ASTM F562-02 UNS R30035 (MP35N) and F1537 UNS R31538 (CCM) alloy samples that have undergone the same generic orthopedic implant's mechanical, chemical surface pre-treatment, and a designed pre-testing sample preparation method. Because the biocompatibility properties resulting from this new MIM cobalt alloy process are not well understood, we conducted tests to evaluate cytotoxicity (in vitro), hemolysis (in vitro), toxicity effects (in vivo), tissue irritation level (in vivo), and pyrogenicity count (in vitro) on such samples. We show that our developed MIM MP35N and CCM materials and treatment processes are biocompatible, and that both the MIM and wrought samples, although somewhat different in microstructure and surface, do not show significant differences in biocompatibility. PMID- 21537060 TI - Parameter optimization for the visco-hyperelastic constitutive model of tendon using FEM. AB - Numerous constitutive models describing the mechanical properties of tendons have been proposed during the past few decades. However, few were widely used owing to the lack of implementation in the general finite element (FE) software, and very few systematic studies have been done on selecting the most appropriate parameters for these constitutive laws. In this work, the visco-hyperelastic constitutive model of the tendon implemented through the use of three-parameter Mooney-Rivlin form and sixty-four-parameter Prony series were firstly analyzed using ANSYS FE software. Afterwards, an integrated optimization scheme was developed by coupling two optimization toolboxes (OPTs) of ANSYS and MATLAB for estimating these unknown constitutive parameters of the tendon. Finally, a group of Sprague-Dawley rat tendons was used to execute experimental and numerical simulation investigation. The simulated results showed good agreement with the experimental data. An important finding revealed that too many Maxwell elements was not necessary for assuring accuracy of the model, which is often neglected in most open literatures. Thus, all these proved that the constitutive parameter optimization scheme was reliable and highly efficient. Furthermore, the approach can be extended to study other tendons or ligaments, as well as any visco hyperelastic solid materials. PMID- 21537061 TI - Oral delivery of insulin using chitosan capsules cross-linked with phytic acid. AB - Phytic acid (PA) was used as a cross-linking agent for encapsulation of insulin in a chitosan matrix for oral delivery of insulin. PA-chitosan capsules were compared with tripolyphosphate (TPP)-chitosan capsules for stable oral delivery of insulin. During 2 h incubation in simulated gastric fluid, PA-chitosan capsules prepared using pH 6, 6% PA solutions showed better stability than TPP chitosan capsules prepared using pH 7, 6% TTP solution. PA-chitosan capsules released less than 60% of their encapsulated insulin after 24 h incubation in simulated gastrointestinal fluids. TPP-chitosan capsules showed burst release and virtually the entire insulin content was released in 12 h. Both capsule types were tested in vivo via oral drug administration using diabetic mice. PA-chitosan capsules significantly decreased blood glucose levels while TPP-chitosan capsules caused a lesser reduction. The relative pharmacological bioactivity of PA chitosan capsules prepared was 6.4% while that of TPP-chitosan capsules was 1.1%. PA-chitosan capsules appeared to have good potential for use in oral delivery of insulin for sustained control of the blood glucose level. PMID- 21537062 TI - Genetic diagnosis of cancer by fuzzy-rough gene selection and the complementary hierarchical fuzzy classifier. AB - Gene expression data have extremely high dimensionality with respect to traditional classifiers which causes not to be used efficiently. In this paper a Fuzzy-Rough Gene Selection and Complementary Hierarchical Fuzzy classifier (FRGS CHF) to classify the gene expression data as a new methodology is proposed. First, some relevant genes are selected using fuzzy-rough attribute selection method. After removing redundant genes, a new complementary hierarchical fuzzy classifier is proposed. The complementary learning mechanism refers to positive and negative learning which are found in the human brain hippocampus. FRGS-CHF is made-up of two parallel hierarchical fuzzy systems; the first is trained with positive samples whilst the other is treated with negative samples. In contrast to many other methods such as statistical or neural networks, FRGS-CHF provides greater interpretability. It does not rely on the assumption of underlying data distribution. Using complementary and hierarchical approaches, the proposed method exploits the lateral inhibition between output classes and considers the problem as a multidimensional problem. Benchmarked datasets are used to demonstrate the validity and advantages of the proposed method over the other existing methods in terms of the accuracy, better transparency, time efficiency together with fewer fuzzy rules and parameters. PMID- 21537063 TI - Chondrocyte distribution and cartilage regeneration in silk fibroin sponge. AB - Chondrocytes distribution and cartilage formation in three types of fibroin sponges with different average pore sizes (40-80, 80-120 and 100-140 MUm) was measured. The image processing was performed combining two methods to identify cells automatically: extraction of local maximum luminance and multi-threshold analysis. The results showed that initial accumulation of chondrocytes localized at surface area at 3 h in the small and medium-pore groups, however, the difference in the cell distributions become equivalent until 24 h after seeding. Cartilaginous tissue was well formed in each group at 21 days, and that in the smaller pore group tend to distribute at the surface area. Spherical tissues were located at the subsurface (200-600 MUm below the surface) of the sponge in the medium- and large-pore groups at 21 days. Local cell aggregation was observed at 24 h at the same depth of the fibroin sponge as the spherical tissues observed at 21 days. These results suggest that the initial cell condensation process till 24 h after seeding play an important role in cartilage tissue formation. PMID- 21537064 TI - Dengue fever in the Indian Subcontinent: an overview. AB - The Indian Subcontinent has emerged as a scene of many mosquito-borne infectious diseases, including malaria and dengue fever. After the 1990s, the rate of malaria declined owing largely to preventive measures, but at the same time dengue fever (DF) and dengue hemorrhagic fever (DHF) were increasing in the region. Outbreaks were recorded in all countries of the Indian Subcontinent with India, Pakistan, Bangladesh and Sri Lanka on the forefront and suffering from the largest number of cases and deaths. We discuss annual cases of DF/DHF in these four countries and possible factors involved in DF outbreaks. We also discuss prevalent serotypes in this region where data suggest the emergence of DEN2 and DEN3 as the most dominant and lethal serotypes. Climate is an important factor influencing DF outbreaks, and rainfall, temperature and humidity play a pivotal role in DF outbreaks. Finally the economic impact of DF/DHF cases is discussed showing that direct and indirect economic loss due to DF/DHF reaches millions of USD each year. PMID- 21537065 TI - Comparison of virulence markers and antibiotic resistance in enterotoxigenic Escherichia coli isolated ten years apart in Tehran. AB - INTRODUCTION: Enterotoxigenic Escherichia coli (ETEC) causes diarrhoea by producing heat-labile (LT) or heat-stable (ST) enterotoxins after colonizing the small intestine by means of colonization factors (CFs). Although detection of the toxins is sufficient for verification of ETEC isolates, toxin-positive strains may be further analyzed for the presence of CFs. Antibiotics may shorten the duration of diarrhoea caused by ETEC, but the rapid emergence of resistant strains limits their usefulness. METHODOLOGY: ETEC isolates collected 10 years apart were compared for the prevalence of toxin types, CFs and antibiotic resistance. DNA/DNA hybridization with digoxigenin (DIG)-labeled probes was used for the detection of toxin types, and CF-typing was performed by DNA hybridization using DIG-labeled probes for cfaD and CS6 with slide agglutination. Disk diffusion was used to determine antibiotic resistance. The presence of class 1 integrons was detected by PCR. RESULTS: ST-positive isolates were the most prevalent among the isolates from 1988, but a significant shift towards LT-gene carriage was observed in the 1998 group. CFA/I and CFA/IV were the most common CF types within both groups. The most prevalent resistance patterns among these isolates were ACSTSXT followed by ASTSXT and ASSXT. CONCLUSION: Our study of the two groups of isolates showed that the rate of LT and ST gene carriage, as well as antibiotic resistance markers, has changed in the ten years separating the two bacterial populations. These variations show the importance of monitoring pathogenic bacteria to obtain a near realistic picture of the circulating bacterial pathogens. PMID- 21537066 TI - Prevalence and outcome of neonatal tetanus in Zaria, Northwestern Nigeria. AB - INTRODUCTION: Neonatal tetanus is a highly debilitating disease with high mortality. Global efforts at eliminating the disease in developing countries are yielding results but slower than expected. The high case fatality of neonatal tetanus remains a therapeutic challenge to physicians and requires continuous evaluation. This study aimed to determine the incidence and outcome of neonatal tetanus in Zaria, northwestern Nigeria. METHODOLOGY: A retrospective study of neonatal tetanus was conducted at the Neonatal Unit of Ahmadu Bello University Teaching Hospital, Zaria, between January 2005 and December 2009. Data generated were analyzed using the Epi Info version 3.5.1 software and statistical significance was set at p < 0.05. RESULTS: Of the 2,692 newborns admitted during the study period, 20 had tetanus, giving an overall prevalence of 0.7%. There were 14 males and 6 females (male to female ratio 2.3:1). The mean age and weight at presentation were 8.3 +/- 4.0 days and 2.7 +/- 0.3 kg, respectively. The mean incubation period was 3.2 +/- 2.0 days. Four infants (20.0%) survived, one was discharged against medical advice and 15 (75.0%) died. Factors associated with mortality were presentation at less than seven days of life, low Hendrickse score at presentation (p = 0.0005) and hypoglycaemia (p = 0.0374). CONCLUSION: The incidence and the mortality rate of neonatal tetanus appear to be lower than those previously reported by our centre for the same region. Therefore, the ongoing global efforts for disease elimination and further improvements in the quality of care should be sustained. PMID- 21537067 TI - Anemia, leukocytosis and eosinophilia in a resource-poor population with helmintho-ectoparasitic coinfection. AB - INTRODUCTION: Eosinophilia and anemia are very common hematological alterations in the tropics but population-based studies scrutinizing their value for diagnosing parasitic infections are rare. METHODOLOGY: A cross-sectional study was conducted in a rural district in northeast Brazil where parasitic infections are common. Stool and blood samples were collected and individuals were clinically examined for the presence of ectoparasites. RESULTS: In total, 874 individuals were examined. Infection with intestinal helminths occurred in 70% (95% CI 67 - 75), infestation with ectoparasites in 45% (95% CI 42 - 49) and co infection with both helminths and ectoparasites was found in 33% (95% CI 29% - 36%) of all inhabitants. Eosinophil counts ranged from 40/ul to 13.800/ul (median: 900/ul). Haemoglobin levels ranged from 4.8 g/dl to 16.8 g/dl (median: 12.5 g/dl), and anemia was present in 24% of the participants. Leukocytosis was found in 13%, eosinophilia in 74%, and hypereosinophilia in 44% of the participants. Eosinophilia was more pronounced in individuals co-infected with intestinal helminths and ectoparasites (p < 0.001) and correctly predicted parasitic infection in 87% (95% CI 84%-90.7%) of all cases. CONCLUSIONS: Eosinophilia is strongly associated with the presence of intestinal helminthiases and accentuated by co-infestation with ectoparasites. Our study confirms in a population with high prevalence of intestinal helminthiases and ectoparasites that eosinophilia can be used to accurately diagnose current parasitic infection and initiate treatment. PMID- 21537068 TI - Virological surveillance in Africa can contribute to early detection of new genetic and antigenic lineages of influenza viruses. AB - INTRODUCTION: In Africa, the burden of influenza is largely unknown since surveillance schemes exist in very few countries. The National Institute of Hygiene in Morocco implemented a sentinel network for influenza surveillance in 1996. METHODOLOGY: Epidemiological and virological surveillances were established and influenza viruses circulating in Morocco were characterised. Four practice specific indicators were collected during the 1996-1997 season and nasopharyngeal swabs were collected from patients with an influenza-like illness during a three year period (between 1996 and1998). Laboratory diagnosis was done by viral isolation. The isolates were characterized by hemagglutination- and neuraminidase inhibition assays and by sequencing the hemagglutinin gene and phylogenetic analysis. RESULTS: Among a total of 673 specimens, 107 (16%) were positive for influenza virus. Seasonal influenza strains were isolated from November to February. Antigenically, A(H1N1), A(H3N2) and B isolates were related to the vaccine strains. Genetically, one 1996/97 isolate A/Rabat/33/96 and the 1997/98 A(H3N2) isolates clustered with the new drift variant A/Sydney/5/97, a vaccine component of the 1998/99 season. CONCLUSIONS: These results indicate a seasonal circulation of influenza in Morocco concentrated between November and February. Further, the results demonstrate the importance of including the maximum number of countries in influenza surveillance to contribute to the definition of the influenza vaccine composition. PMID- 21537069 TI - Profiles of enteropathogens in asymptomatic children from indigenous communities of Merida, Venezuela. AB - INTRODUCTION: In Latin America, gastrointestinal infections represent one of the main causes of death among indigenous groups, with a mortality rate three times greater than in the general population. In this study, the carrier state of enteropathogens and the epidemiological risk factor in asymptomatic children from indigenous communities of Merida, Venezuela, were determined. METHODOLOGY: Fifty eight healthy children, 5 years of age and under, were clinically and epidemiologically evaluated. Fecal samples were tested for a range of classic enteropathogens. Antimicrobial susceptibility tests (AST) were performed by dilution methods. RESULTS: Of the specimens studied, there were 34 (58.6%) positive samples, and a single enteropathogen was detected in 22 (64.6%) of these. Associations of two and three enteropathogens were observed in 10 (29.3%) and two (5.8%) cases, respectively. Blastocystis hominis (16; 47.0%) and Salmonella spp. (15; 43.9%) were the most frequently detected enteropathogens. Carriage of enteropathogens was most frequent in children older than two years. The variety of food in the daily diet was the risk factor strongly associated with the presence of parasites and/or enteric bacteria (p = 0.024 < 0.05 and p = 0.000 < 0.05, respectively). The majority of these bacteria were susceptible to the antibiotics tested in vitro. CONCLUSION: This study shows a high prevalence of enteropathogen carriage in asymptomatic children aged five and under from indigenous communities; this result is statistically related to the consumption of food. These findings stress the need of continuous epidemiological surveillance in vulnerable populations, as an important step to prevent the morbidity and mortality due to gastrointestinal infections. PMID- 21537070 TI - Ventilator-associated pneumonia in Iranian intensive care units. AB - INTRODUCTION: Nosocomial pneumonia (NP) and ventilator associated pneumonia (VAP) occur most frequently in intensive care units (ICU). This study seeks to determine the etiological agents of NP and VAP along with their antibacterial susceptibility patterns, and to evaluate the factors contributing to patient mortality. The impact of appropriate therapy in terms of three parameters (body temperature, PaO2/FiO2 ratio and leukocyte count) was also assessed. METHODOLOGY: This study involved 836 adult patients admitted to ICUs at the Nemazee Hospital, Shiraz, Iran, over nine months during 2008 and 2009. The inclusion criterion was the commencement of infection at least 48 hours following hospital admission. Clinical parameters including core temperature, leukocyte count. and PaO2/FiO2 ratio were evaluated. Antibiotic sensitivities of the isolated bacteria to a panel of antibiotics were determined using E-test. RESULTS: Of 836 cases, only 58 (6.9 %) cases of NP were diagnosed, of which 42 (72 %) were VAP. A. baumannii, MRSA, P. aeruginosa and MSSA were the most prevalent bacteria. Significant correlations between previous antibiotic therapy (p = 0.04), use of corticosteroids (p = 0.02) and attributable mortality were found. A strong correlation between fever abatement and the ratio of PaO2/FiO2 with responses to treatment and outcomes was also evident. CONCLUSIONS: Combined treatment with meropenem/imipenem, ciprofloxacin and vancomycin seems to be appropriate and could cover all possible infective agents. To reduce mortality rate, reasonable prescription of antibiotics and corticosteroids could be effective. Furthermore, adopting a strategy to reduce body temperature and PaO2/FiO2 ratio could be beneficial in patients' outcomes. PMID- 21537071 TI - Emergence of multiple drug resistance Vibrio cholerae O1 in East Delhi. AB - INTRODUCTION: Considering the changing geographical and temporal occurrence of Vibrio cholerae, there is a continuing need to monitor the strain characteristics and antibiotic resistance patterns of this pathogen. The present study was conducted to document the changing biology of V. cholerae isolates in and around Delhi, India, and the development of antibiotic resistance. METHODOLOGY: A total of 1,424 stool samples or rectal swabs from patients with acute secretory diarrhoea admitted to Guru Teg Bahadur Hospital, Delhi, between January 2007 and December 2009 were processed using standard bacteriological methods. Strains identified as V. cholerae were further subjected to serogrouping, phage typing and antimicrobial susceptibility testing. Minimum inhibitory concentration (MIC) of gentamicin and tetracycline was determined. RESULTS: V. cholerae was isolated in 242/1,424 (17.0%) specimens. Of these, the majority were V. cholerae O1 serotype (98.3%) and serovar Ogawa. The drugs to which V. cholerae O1 isolates showed high levels of resistance were nalidixic acid, furazolidone, and cotrimoxazole throughout the study period, whereas strains were usually susceptible to chloramphenicol and cefotaxime. In 2007, there was a sudden increase of resistance to gentamicin and tetracycline, followed by a slow reversal to previous levels in subsequent years. The phage typing pattern (Basu and Mukherjee scheme) showed a dominance of phage type 2 throughout the study period. CONCLUSION: The importance of reporting all cases of V. cholerae, should be greatly emphasized, with the ultimate goal of understanding the constantly changing resistance patterns of this pathogen. PMID- 21537072 TI - Antibiotic screening of urine culture as a useful quality audit. AB - INTRODUCTION: The diagnosis of urinary tract infections includes microbiologic culture of urine to determine the etiology of the infection. However, interpretation of the results can be confounded by various factors including the accuracy of a patient's history of current antibiotic usage. METHODOLOGY: In this report, we tested urine specimens for the presence of antibiotics and compared our results to the accuracy of antibiotic data entry on the accompanying request forms. In addition, the consequences of culturing urine specimens with incomplete antibiotic history received in the laboratory were investigated. RESULTS: During the study period, 14,680 urines were obtained and tested with a modified urine antibacterial substance assay (UABA). There were (97.32%) true negative, 6 (0.04%) false-negative, 222 (1.51%) true-positive and 166 (1.13%) false-positive results. The sensitivity and specificity of this test was 97.37% and 98.85% respectively. CONCLUSION: This internal audit practice demonstrates the importance of accurately completed request forms and how this information impacts the clinical interpretation of urine culture results. PMID- 21537073 TI - Efficacy and safety of lamivudine treatment in late pregnancy with high HBV DNA: a perspective for mother and infants. AB - INTRODUCTION: Perinatal transmission - from mother to fetus - is one of the main transmission routes of chronic hepatitis B (CHB) infection. Lamivudine therapy has been reported to prevent the replication of hepatitis B virus (HBV) in pregnant women with a high viral load that can lead to perinatal transmission. METHODOLOGY: This study sought to evaluate retrospectively the efficacy and safety of lamivudine treatment in pregnant women with CHB and a high viral load. Biochemical parameters, and virological and serological responses at the 32nd and 36th week of gestation and after labor were recorded. The complications of CHB and the adverse effects of lamivudine treatment were also recorded. RESULTS: Following 8 weeks of lamivudine treatment, HBV viral load decreased to levels <= 10,000 copies/ml in five of the seven patients (71%) and in three patients (43%), HBV DNA was found to be completely negative after labor. Neither adverse effects caused by lamivudine treatment nor complications due to CHB infection were experienced by mothers or infants. CONCLUSIONS: The results of this study suggest that lamivudine therapy in highly viremic hepatitis B surface antigen (HBsAg) positive pregnant women could decrease perinatal transmission rates of HBV, and can lower the HBV viral load during labor. PMID- 21537074 TI - Anterior abdominal wall abscess caused by Streptococcus pneumoniae in a patient with self-inflicted stab injury: An unusual presentation. AB - Streptococcus pneumoniae is a major cause of community-acquired pneumonia, otitis media, paranasal sinusitis, bacteremia and meningitis, as well as osteomyelitis and occasionally peritonitis. We report the case of a 25-year-old female who had stabbed herself with a kitchen knife above the umbilicus 10 days prior to admission. Subsequently, she developed an anterior abdominal wall abscess caused by S. pneumoniae. This case is unusual as the focus was distant from the respiratory tract, the usual primary site of infection caused by this organism. Furthermore, the case assumes significance because it occurred in the absence of any typical risk factors for S. pneumoniae. PMID- 21537075 TI - Human soft tissue infection by the emerging pathogen Shewanella algae. AB - Shewanella soft tissue infections usually occur in immunocompromised patients with a preexisting cutaneous ulcer, mostly after exposure to a marine environment or contaminated water. A 35-year-old male presented with a non-healing ulcer over the distal end of his right leg but had no predisposing factors. Cultures of exudates from the wound grew Shewanella on repeated occasions. Recovery was uneventful following surgical debridement and antimicrobial therapy. Early suspicion, diagnosis, and treatment with potent antibiotics are needed to prevent any further complications resulting from infection by this emerging pathogen. PMID- 21537076 TI - Central nervous system aspergillosis in an immunocompetent patient. AB - Aspergillus sp. is a fungus that is very common in nature and may cause invasive disease with high mortality, especially in immunosuppressed patients. Here we present a case of central nervous system (CNS) aspergillosis in a previously healthy immunocompetent patient. A 23-year-old female was admitted to hospital with the complaints of headache, blurred vision, and double vision. In her cranial magnetic resonance imaging, abscess and paranchymal edema were observed in the left frontal lobe, and biopsy was performed with endoscopic nasal operation. The pathology result was consistent with aspergillus infection. It should be remembered that although CNS aspergillosis generally occurs in immunosuppressed patients, it may also rarely be diagnosed in immunocompetent individuals. PMID- 21537077 TI - Incidence of clindamycin resistance in clinical isolates of Staphylococcus aureus. PMID- 21537078 TI - Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens. AB - Apoptotic cells must be rapidly cleared, as defects in this process can lead to autoimmunity. Milk fat globule EGF factor 8 (MFG-E8) binds to apoptotic cells and facilitates their removal through interaction with phagocytes. Mice deficient in MFG-E8 develop lupus-like autoimmunity associated with accumulation of apoptotic cells in vivo. Here, we have shown that MFG-E8 controls phagocytic ingestion of cell fragments as well as their intracellular processing into MHC-antigen complexes. Older Mfge8-/- mice spontaneously developed dermatitis associated with CD8+ T cell infiltration and striking activation of effector memory CD8+ T cells. CD8+ T cell responses to both exogenous and endogenous apoptotic cell-associated antigens were enhanced in Mfge8-/- mice. MFG-E8 deficiency accelerated the onset of disease in a mouse model of autoimmune diabetes. Enhanced CD8+ T cell responses were attributed to increased cross-presentation by DCs along with increased detection of antigen-MHCI complexes. Intracellular trafficking analysis revealed that intact apoptotic cells ingested by wild-type DCs rapidly fused with lysosomes, whereas smaller fragments persisted in Mfge8-/- DC endosomal compartments for 24 hours. These observations suggest that MFG-E8 deficiency promotes immune responses to self antigens not only by delaying the clearance of dying cells but also by altering intracellular processing, leading to enhanced self-antigen presentation. PMID- 21537079 TI - CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. AB - CD73 is overexpressed in many types of human and mouse cancers and is implicated in the control of tumor progression. However, the specific contribution from tumor or host CD73 expression to tumor growth remains unknown to date. Here, we show that host CD73 promotes tumor growth in a T cell-dependent manner and that the optimal antitumor effect of CD73 blockade requires inhibiting both tumor and host CD73. Notably, enzymatic activity of CD73 on nonhematopoietic cells limited tumor-infiltrating T cells by controlling antitumor T cell homing to tumors in multiple mouse tumor models. In contrast, CD73 on hematopoietic cells (including CD4+CD25+ Tregs) inhibited systemic antitumor T cell expansion and effector functions. Thus, CD73 on hematopoietic and nonhematopoietic cells has distinct adenosinergic effects in regulating systemic and local antitumor T cell responses. Importantly, pharmacological blockade of CD73 using its selective inhibitor or an anti-CD73 mAb inhibited tumor growth and completely restored efficacy of adoptive T cell therapy in mice. These findings suggest that both tumor and host CD73 cooperatively protect tumors from incoming antitumor T cells and show the potential of targeting CD73 as a cancer immunotherapy strategy. PMID- 21537080 TI - Pivotal role of cardiomyocyte TGF-beta signaling in the murine pathological response to sustained pressure overload. AB - The cardiac pathological response to sustained pressure overload involves myocyte hypertrophy and dysfunction along with interstitial changes such as fibrosis and reduced capillary density. These changes are orchestrated by mechanical forces and factors secreted between cells. One such secreted factor is TGF-beta, which is generated by and interacts with multiple cell types. Here we have shown that TGF-beta suppression in cardiomyocytes was required to protect against maladaptive remodeling and involved noncanonical (non-Smad-related) signaling. Mouse hearts subjected to pressure overload and treated with a TGF-beta neutralizing Ab had suppressed Smad activation in the interstitium but not in myocytes, and noncanonical (TGF-beta-activated kinase 1 [TAK1]) activation remained. Although fibrosis was greatly reduced, chamber dysfunction and dilation persisted. Induced myocyte knockdown of TGF-beta type 2 receptor (TbetaR2) blocked all maladaptive responses, inhibiting myocyte and interstitial Smad and TAK1. Myocyte knockdown of TbetaR1 suppressed myocyte but not interstitial Smad, nor TAK1, modestly reducing fibrosis without improving chamber function or hypertrophy. Only TbetaR2 knockdown preserved capillary density after pressure overload, enhancing BMP7, a regulator of the endothelial-mesenchymal transition. BMP7 enhancement also was coupled to TAK1 suppression. Thus, myocyte targeting is required to modulate TGF-beta in hearts subjected to pressure overload, with noncanonical pathways predominantly affecting the maladaptive hypertrophy/dysfunction. PMID- 21537081 TI - Epicutaneous challenge of orally immunized mice redirects antigen-specific gut homing T cells to the skin. AB - Patients with atopic dermatitis (AD) often suffer from food allergy and develop flares upon skin contact with food allergens. However, it is unclear whether T cells sensitized to allergens in the gut promote this skin inflammation. To address this question, we orally immunized WT mice and mice lacking the skin homing chemokine receptor Ccr4 (Ccr4-/- mice) with OVA and then challenged them epicutaneously with antigen. Allergic skin inflammation developed in the WT mice but not in the mutants and was characterized by epidermal thickening, dermal infiltration by eosinophils and CD4+ T cells, and upregulation of Th2 cytokines. T cells purified from mesenteric lymph nodes (MLNs) of orally immunized WT mice transferred allergic skin inflammation to naive recipients cutaneously challenged with antigen, but this effect was lost in T cells purified from Ccr4-/- mice. In addition, the ability of adoptively transferred OVA-activated T cells to home to the skin following cutaneous OVA challenge was ablated in mice that lacked lymph nodes. These results indicate that cutaneous exposure to food antigens can reprogram gut-homing effector T cells in LNs to express skin-homing receptors, eliciting skin lesions upon food allergen contact in orally sensitized AD patients. PMID- 21537082 TI - A dual role for the immune response in a mouse model of inflammation-associated lung cancer. AB - Lung cancer is the leading cause of cancer death worldwide. Both principal factors known to cause lung cancer, cigarette smoke and asbestos, induce pulmonary inflammation, and pulmonary inflammation has recently been implicated in several murine models of lung cancer. To further investigate the role of inflammation in the development of lung cancer, we generated mice with combined loss of IFN-gamma and the beta-common cytokines GM-CSF and IL-3. These immunodeficient mice develop chronic pulmonary inflammation and lung tumors at a high frequency. Examination of the relationship between these tumors and their inflammatory microenvironment revealed a dual role for the immune system in tumor development. The inflammatory cytokine IL-6 promoted optimal tumor growth, yet wild-type mice rejected transplanted tumors through the induction of adaptive immunity. These findings suggest a model whereby cytokine deficiency leads to oncogenic inflammation that combines with defective antitumor immunity to promote lung tumor formation, representing a unique system for studying the role of the immune system in lung tumor development. PMID- 21537083 TI - CD8+ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung. AB - The human lung T cell compartment contains many CD8+ T cells specific for respiratory viruses, suggesting that the lung is protected from recurring respiratory infections by a resident T cell pool. The entry site for respiratory viruses is the epithelium, in which a subset of lung CD8+ T cells expressing CD103 (alphaE integrin) resides. Here, we determined the specificity and function of CD103+CD8+ T cells in protecting human lung against viral infection. Mononuclear cells were isolated from human blood and lung resection samples. Variable numbers of CD103+CD8+ T cells were retrieved from the lung tissue. Interestingly, expression of CD103 was seen only in lung CD8+ T cells specific for influenza but not in those specific for EBV or CMV. CD103+ and influenza reactive cells preferentially expressed NKG2A, an inhibitor of CD8+ T cell cytotoxic function. In contrast to CD103-CD8+ T cells, most CD103+CD8+ cells did not contain perforin or granzyme B. However, they could quickly upregulate these cytotoxic mediators when exposed to a type I IFN milieu or via contact with their specific antigen. This mechanism may provide a rapid and efficient response to influenza infection, without inducing cytotoxic damage to the delicate epithelial barrier. PMID- 21537084 TI - Transcription intermediary factor 1gamma is a tumor suppressor in mouse and human chronic myelomonocytic leukemia. AB - Transcription intermediary factor 1gamma (TIF1gamma) was suggested to play a role in erythropoiesis. However, how TIF1gamma regulates the development of different blood cell lineages and whether TIF1gamma is involved in human hematological malignancies remain to be determined. Here we have shown that TIF1gamma was a tumor suppressor in mouse and human chronic myelomonocytic leukemia (CMML). Loss of Tif1g in mouse HSCs favored the expansion of the granulo-monocytic progenitor compartment. Furthermore, Tif1g deletion induced the age-dependent appearance of a cell-autonomous myeloproliferative disorder in mice that recapitulated essential characteristics of human CMML. TIF1gamma was almost undetectable in leukemic cells of 35% of CMML patients. This downregulation was related to the hypermethylation of CpG sequences and specific histone modifications in the gene promoter. A demethylating agent restored the normal epigenetic status of the TIF1G promoter in human cells, which correlated with a reestablishment of TIF1gamma expression. Together, these results demonstrate that TIF1G is an epigenetically regulated tumor suppressor gene in hematopoietic cells and suggest that changes in TIF1gamma expression may be a biomarker of response to demethylating agents in CMML. PMID- 21537085 TI - Mouse ES and iPS cells can form similar definitive endoderm despite differences in imprinted genes. AB - The directed differentiation of iPS and ES cells into definitive endoderm (DE) would allow the derivation of otherwise inaccessible progenitors for endodermal tissues. However, a global comparison of the relative equivalency of DE derived from iPS and ES populations has not been performed. Recent reports of molecular differences between iPS and ES cells have raised uncertainty as to whether iPS cells could generate autologous endodermal lineages in vitro. Here, we show that both mouse iPS and parental ES cells exhibited highly similar in vitro capacity to undergo directed differentiation into DE progenitors. With few exceptions, both cell types displayed similar surges in gene expression of specific master transcriptional regulators and global transcriptomes that define the developmental milestones of DE differentiation. Microarray analysis showed considerable overlap between the genetic programs of DE derived from ES/iPS cells in vitro and authentic DE from mouse embryos in vivo. Intriguingly, iPS cells exhibited aberrant silencing of imprinted genes known to participate in endoderm differentiation, yet retained a robust ability to differentiate into DE. Our results show that, despite some molecular differences, iPS cells can be efficiently differentiated into DE precursors, reinforcing their potential for development of cell-based therapies for diseased endoderm-derived tissues. PMID- 21537086 TI - Are we reluctant to talk about cultural determinants? PMID- 21537087 TI - Cyclin D1 over expression as a prognostic factor in patients with tobacco-related intraoral squamous cell carcinoma. PMID- 21537088 TI - On the emergence of atypical Vibrio cholerae O1 El Tor & cholera epidemic. PMID- 21537089 TI - The need for obtaining accurate nationwide estimates of diabetes prevalence in India - rationale for a national study on diabetes. AB - According to the World Diabetes Atlas, India is projected to have around 51 million people with diabetes. However, these data are based on small sporadic studies done in some parts of the country. Even a few multi-centre studies that have been done, have several limitations. Also, marked heterogeneity between States limits the generalizability of results. Other studies done at various time periods also lack uniform methodology, do not take into consideration ethnic differences and have inadequate coverage. Thus, till date there has been no national study on the prevalence of diabetes which are truly representative of India as a whole. Moreover, the data on diabetes complications is even more scarce. Therefore, there is an urgent need for a large well-planned national study, which could provide reliable nationwide data, not only on prevalence of diabetes, but also on pre-diabetes, and the complications of diabetes in India. A study of this nature will have enormous public health impact and help policy makers to take action against diabetes in India. PMID- 21537090 TI - Correlation of cyclin D1 expression with aggressive DNA pattern in patients with tobacco-related intraoral squamous cell carcinoma. AB - BACKGROUND & OBJECTIVES: Cyclin D1 has been strongly implicated in cell proliferation particularly in the G1/S checkpoint of the cell cycle, and prognoses in human malignancies. We investigated the correlation between cyclin D1 overexpression and clinicopathological features as well as cell cycle parameters to understand its clinical significance in patients with tobacco related oral squamous cell carcinoma (OSCC). METHODS: Immunohistochemistry for cyclin D1 and DNA flowcytometry for cell cycle parameters was done on paraffin embedded tumour samples from 45 patients with OSCC RESULTS: Higher expression of cyclin D1 was observed only in 30 (66.6%) of 45 cases that correlated with advanced age (P <0.02), higher tumour stage (P<0.01), histological differentiation and lymph node metastasis (P <0.01). Analysis of nuclear DNA pattern revealed cyclin D1 immunoreactivity in tumours with aggressive DNA pattern such as aneuploidy (P<0.05) and higher S phase fraction (P<0.04). INTERPRETATION & CONCLUSIONS: Higher expression of cyclin D1 in oral cancer appears to be closely linked to cell proliferation, differentiation and lymph node invasion. Pre-operative evaluation of cyclin D1 in biopsy specimen may be useful in planning the most appropriate treatment strategies in patients with tobacco-related OSCC. PMID- 21537091 TI - Hybrid & El Tor variant biotypes of Vibrio cholerae O1 in Thailand. AB - BACKGROUND & OBJECTIVES: El Tor Vibrio cholerae O1 carrying ctxB C trait, so called El Tor variant that causes more severe symptoms than the prototype El Tor strain, first detected in Bangladesh was later shown to have emerged in India in 1992. Subsequently, similar V. cholerae strains were isolated in other countries in Asia and Africa. Thus, it was of interest to investigate the characteristics of V. cholerae O1 strains isolated chronologically (from 1986 to 2009) in Thailand. METHODS: A total of 330 V. cholerae O1 Thailand strains from hospitalized patients with cholera isolated during 1986 to 2009 were subjected to conventional biotyping i.e., susceptibility to polymyxin B, chicken erythrocyte agglutination (CCA) and Voges-Proskauer (VP) test. The presence of ctxA, ctxB, zot, ace, toxR, tcpA C , tcpA E, hlyA C and hlyA E were examined by PCR. Mismatch amplification mutation assay (MAMA) - and conventional- PCRs were used for differentiating ctxB and rstR alleles. RESULTS: All 330 strains carried the El Tor virulence gene signature. Among these, 266 strains were typical El Tor (resistant to 50 units of polymyxin B and positive for CCA and VP test) while 64 had mixed classical and El Tor phenotypes (hybrid biotype). Combined MAMA-PCR and the conventional biotyping methods revealed that 36 strains of 1986-1992 were either typical El Tor, hybrid, El Tor variant or unclassified biotype. The hybrid strains were present during 1986-2004. El Tor variant strains were found in 1992, the same year when the typical El Tor strains disappeared. All 294 strains of 1993-2009 carried ctxBC ; 237 were El Tor variant and 57 were hybrid. INTERPRETATION & CONCLUSIONS: In Thailand, hybrid V. cholerae O1 (mixed biotypes), was found since 1986. Circulating strains, however, are predominantly El Tor variant (El Tor biotype with ctxB C). PMID- 21537092 TI - Rapid situation & response assessment of diarrhoea outbreak in a coastal district following tropical cyclone AILA in India. AB - BACKGROUND & OBJECTIVES: Cyclone AILA hit Indian States on eastern coast on May 25, 2009. An investigation was conducted to examine if AILA was responsible for increased reporting of diarrhoea cases from the district of East-Medinipur in West Bengal. Identifying causative organisms for diarrhoea and assessing their antibiotic susceptibility profile were other objectives. METHODS: Rapid situation and response assessment technique was employed to triangulate primary and secondary data collected through field visits. Prescription audit was also conducted. RESULTS: Significantly increased occurrence of diarrhoea was observed in June 2009 in two subdivisions namely Haldia and Egra (OR 1.6 and 1.3 respectively; 95% CI 1.52-1.65 and 1.21-1.32 P<0.001) considering 2007 as baseline. Vibrio cholerae grew from 54 per cent of the stool samples (21/39; 17 V. cholerae O1-Ogawa and 4 non-O1-non-O139), confirming a community outbreak of cholera. Shigella flexneri 3a was isolated from 5 per cent stool specimens. Increased rate of admission in treatment centres due to diarrhoea in the whole district coincided with the formation of cyclone and showed over two-fold rise compared to the admission recorded 6 days ago. Haldia subdivision had the highest attack rate of 9 per 1000 in the month of June, 2009 whereas for the whole district it was 5 per 1000 in the same month. All the isolates of V. cholerae were resistant to ampicillin and furazolidone and sensitive to norfloxacin and azithromycin. INTERPRETATION & CONCLUSIONS: Pre-AILA changes in the environment, AILA and seasonality of diarrhoea in the study district interplayed towards increased occurrence of diarrhoea. Continuous tracking of 'seasonality of diarrhoea in the community with vulnerability assessment of potential hosts', 'antibiotic sensitivity profile of the causative microorganisms', and 'prescription practice of physicians' would help appropriate disaster management. PMID- 21537093 TI - Transient cytotoxicity of 131I beta radiation in hyperthyroid patients treated with radioactive iodine. AB - BACKGROUND & OBJECTIVES: Radioiodine ( 131 I) or radioactive iodine in low doses is used worldwide as the first line of management in the treatment of hyperthyroidism. Information is available on the extent and severity of cell damage after a high dose radioiodine ( 131 I) therapy for thyroid cancer, but information is scanty on its cellular effects, its extent and severity of cell damage after a low dose 131 I therapy. The present investigation was aimed to study the cytotoxic effects of a low dose 131 I therapy in varying doses as is normally being used in routine clinical practice in the treatment of various forms of hyperthyroidism. METHODS: Peripheral blood lymphocytes were analyzed in 32 hyperthyroid patients. All of them received 131 I in the form of sodium iodide solution orally. Blood lymphocytes were studied for the presence of chromosomal aberrations (CA) and micro nucleus (MN) using micronucleus assay. Blood samples of these patients were drawn prior to the treatment, on 7 th and 30 th days after the treatment. RESULTS: The results indicated a positive relationship between 131 I dose, CA and MN frequency. A statistically significant increase in CA and MN frequency in day 7 post- therapy and a decrease in mean levels of CA and MN on day 30 post-therapy were observed when compared to pre-therapy. INTERPRETATION & CONCLUSIONS: This study showed that the cytogenetic damage induced by 131 I in low doses i.e., less than 555MBq was minimal and reversible. Patients can be motivated to undertake this safe and easy procedure as a first line of therapy in the treatment of hyperthyroidism. PMID- 21537094 TI - A pilot study on parvovirus B19 infection in paediatric haematological malignancies. AB - BACKGROUND & OBJECTIVES: Leukaemia and lymphoma are common paediatric haematological malignancies acquiring human parvovirus B19 (B19) infection. In some studies anaemia has been found in children with acute lymphoblastic leukaemia (ALL) during maintenance therapy and rarely in lymphoma. We studied frequency of B19 infection and its implications in new onset acute leukaemia (mostly ALL) and lymphoma in children. METHODS: Seventy serum samples from 35 children (age <12 yr, 29 males) newly diagnosed with haematological malignancies (on induction therapy) were collected together with 34 controls (solid tumours). Children were examined clinically and for anti-B19 IgM antibodies by quantitative ELISA and B19 DNA by PCR (VP1-VP2) and nested-PCR (VP1 unique). Bone marrow aspirates were examined histopathologically, whenever possible. RESULTS: Of the 35 children, 22 had acute leukaemia while 13 had lymphoma. B19 infection was seen in six (17.1%) of 35 children (5 ALL, 1 NHL), two at diagnosis and four during follow up compared to none in the control. Among five B19 IgM positive ALL (n=18) children, two had B19 genome and two had giant pronormoblasts (lantern cells; but one lacked B19 DNA). Of the 70 serum samples tested, eight (11.4%) had anti-B19 IgM as two children had persistent B19 infection and one showed atypical maculopapular rashes (lower limbs) while 12 (34.3%) had anti-B19 IgG antibodies. B19 infected children had unexplained anaemia (80%), required more blood transfusions (6.6 +/- 4.8 Units vs 3.0 +/- 2.6 Units) besides induction chemotherapy was delayed (60%) and required longer duration of therapy (29.2 +/- 20 vs 6.3 +/- 7.8 days) (P<0.02). Five children (2 ALL, 2 AML, 1 NHL) died but none were infected with B19. INTERPRETATION & CONCLUSIONS: B19 infection should be considered in children with ALL as it frequently caused unexplained anaemia and delay in induction chemotherapy. PMID- 21537095 TI - Mortality in HIV infected individuals in Pune, India. AB - BACKGROUND & OBJECTIVES: With the presence of HIV epidemic for more than two decades in India, rise in the number of HIV related deaths is expected. Data on mortality in HIV infected individuals from prospective studies are scanty in India. We report here data on mortality in a systematically followed cohort of HIV infected individuals at Pune, Maharashtra, India. METHODS: A total of 457 HIV infected individuals were enrolled in a prospective study in Pune between September 2002 and November 2004. They were evaluated clinically and monitored for CD4 counts at every quarterly visit. Mortality data were collected from the records of hospital facilities provided by the study. If the death occurred outside such hospitals; relatives of the participants were requested to inform about the death. RESULTS: Median CD4 count in study participants was 218 cells/MUl (95% CI: 107-373) at baseline. The median duration of follow up was 15 months (IQR: 12, 22). Mortality was higher in antiretroviral therapy (ART) naive patients compared to those who received treatment (16.59 vs. 7.25 per 100 person years). Participants above 35 yr of age, CD4 count less than or equal to 100 cells/MUl at baseline, tuberculosis at any study time point and ART status were independently associated with high mortality [(RR=1.97; 95% CI: (1.23, 3.14), P=0.005, (RR=33.20, 95%CI (7.59, 145.29), P<0.001, (RR=2.38, 95% CI (1.38, 4.09), P= 0.002 and RR=5.60, 95% CI (3.18, 9.86), P<0.001, respectively]. Interpretation & conclusions : High mortality at advanced immunosuppression highlights the importance of early detection of HIV infection. Emphasis needs to be given at timely diagnosis and management of tuberculosis and ART initiation. It is important to create awareness about availability of free antiretroviral drugs in the government ART roll out programme. PMID- 21537096 TI - Mycobacterial heparin-binding haemagglutinin adhesion-induced interferon & antibody for detection of tuberculosis. AB - BACKGROUND & OBJECTIVES: Mycobacterial heparin-binding haemagglutinin adhesin (HBHA) plays an important role in humoral and cellular immune response and is a potential diagnostic tool for tuberculosis (TB) serodiagnosis. This study was carried out to assess the usefulness of HBHA in TB clinics for differential diagnosis of pulmonary and extra-pulmonary TB (PTB, EPTB). METHODS: In this study, 165 outpatients and 133 healthy volunteers were included to investigate the role of HBHA in TB diagnosis including the serodiagnostic tests and the interferon-gamma release assays (IGRAs). The healthy volunteers were all without BCG vaccination including 73 subjects with purified protein derivative (PPD) (-) and 60 ones with PPD (+) (that is P-B- and P+B-). Of all the 165 outpatients 77 were PTB and 88 were EPTB. HBHA protein was used for serodiagnostic tests and IGRAs in peripheral blood mononuclear cells. RESULTS: HBHA-specific antibody levels in the serum of healthy subjects were significantly different from the patients with PTB or EPTB (P<0.05). HBHA specific antibody levels in PTB patients could differentiate from EPTB with limited sensitivity (77.08%; 95%CI, 62.69 to 87.97%) and specificity (87.50%; 95%CI, 74.75 to 95.27%). IFN-gamma levels in the healthy (P+B- and P-B-) groups were significantly different (P<0.01) with a detection sensitivity of 84.8% (95%CI, 68.54 to 93.02%) and specificity of 80.7% (95%CI, 65.22 to 92.62%). The PTB and EPTB subjects showed no difference in IFN gamma production. INTERPRETATION & CONCLUSIONS: HBHA serodiagnostic test with IGRAs had the limited potential for use as auxiliary tools for the differential diagnosis of PTB and EPTB, since both methods showed low sensitivity and specificity. PMID- 21537097 TI - Efficacy of Advanced Odomos repellent cream (N, N-diethyl-benzamide) against mosquito vectors. AB - BACKGROUND & OBJECTIVES: Repellents are commonly used personal protection measures to avoid mosquito bites. In the present study, Advanced Odomos cream (12% N, N-diethyl-benzamide) was tested for its efficacy against mosquitoes in comparison to DEET (N,N-diethyl-3-methyl benzamide). METHODS: Bioassays were conducted to assess the repellency of Advanced Odomos and DEET creams against Anopheles stephensi and Aedes aegypti. Their efficacy was tested on human volunteers applied with different concentrations of test creams ranging from 1 to 12 mg/cm 2 and by exposing them to mosquitoes at hourly intervals. Field evaluation was also carried out to test the duration of protection of the test creams against Anopheles and Aedes mosquitoes during whole night and day time collections, respectively on human volunteers. Mosquito collections were done using torch light and aspirator. RESULTS: Complete (100%) protection was achieved at 10 mg/cm 2 cream formulation of Advanced Odomos (1.2 mg a.i/cm 2 ) dose against An. stephensi and 12 mg/cm 2 (1.44 mg a.i./cm 2 ) against Ae. aegypti on human baits. There was no statistically significant differences in per cent protection against mosquito bites between Advanced Odomos and DEET cream (P>0.05) in respective doses. Complete protection up to 11 h was observed against Anopheles mosquitoes during whole night collections and up to 6 h against Ae. aegypti in day time collections. No adverse reactions such as itching, irritation, vomiting, nausea, etc. were reported by the volunteers. INTERPRETATION & CONCLUSIONS: Advanced Odomos cream applied at 10 mg/cm 2 concentration provided 100% protection from Anopheles mosquitoes up to 11 h whereas about 6 h protection was recorded against Ae. aegypti. The laboratory and field trials indicate that for longer protection against Anopheles mosquitoes 10 mg/cm 2 will be appropriate and in case of Ae. aegypti more than 10 mg/cm 2 application is required for complete protection. In conclusion, the Advanced Odomos cream was comparable to the known repellent cream DEET for prolonged protection against malaria and dengue vectors. PMID- 21537098 TI - Occurrence & antibiogram of Salmonella Typhi & S. Paratyphi A isolated from Rourkela, Orissa. AB - BACKGROUND & OBJECTIVES: Almost round-the-year occurrence of Salmonella Typhi and Salmonella Paratyphi A has been noticed in Rourkela since last 13 and five years respectively. The incidence of infection along with the antibiogram of these two serotypes in this area were carried out. METHODS: The study was carried out at Ispat General Hospital, Rourkela, India, between January 2005 and December 2008 with 5340 blood samples collected from patients with suspected enteric fever and pyrexia of unknown origin. Isolation, identification and antibiogram of the causative organisms were performed according to standard bacteriological procedures. RESULTS: A total of 298 Salmonella isolates showed an overall per cent positivity of 5.58. Multidrug resistance was found in 11.96 per cent and 15.62 per cent isolates of S. Typhi and S. Paratyphi A respectively. Less than 2 per cent isolates of Salmonella showed resistance to ciprofloxacin. A resistance of 3.0 to 6.25 per cent against third generation cephalosporins was observed among the salmonella isolates. INTERPRETATION & CONCLUSION: A round-the-year occurrence of Salmonella spp. in Rourkela might have been due to the presence of a considerable number of carriers in the locality, poor sanitation in nearby slum areas, and inadequate and contaminated community water supply at times. Higher degree of susceptibility among S. Typhi isolates against various antibiotics was encouraging, but increasing trend of resistance observed among S. Paratyphi A isolates was a matter of concern. PMID- 21537100 TI - Utility of molecular studies in incontinentia pigmenti patients. AB - The diagnosis of incontinentia pigmenti (IP) is fairly easy in the presence of classical features, but can be difficult in cases with partial or non-classical features, especially in the parents. The demonstration that the disease is caused by mutations in the NEMO gene, has remarkably improved genetic counselling for this disorder. We present four families of IP in whom molecular studies established an unequivocal diagnosis in the affected daughters, and showed two mothers to be carriers, thus allowing accurate genetic counselling and prenatal diagnosis. PMID- 21537099 TI - Effect of Lactobacillus acidophilus & epidermal growth factor on experimentally induced Clostridium difficile infection. AB - BACKGROUND & OBJECTIVES: Clostridium difficile-associated disease (CDAD) remains an important nosocomial ailment. Antimicrobial therapy used for CDAD gives inconsistent results. This experimental study was planned to investigate the beneficial effects of Lactobacillus acidophilus and epidermal growth factor (EGF) for CDAD management. METHODS: Among 10 groups of BALB/c mice (6 in each), group 1 served as controls receiving no inoculum. Animals in groups 2-10 received C. difficile, those in groups 3, 6 and 9 received L. acidophilus and those in groups 4, 7 and 10 received EGF after C. difficile inoculation. Animals in groups 5-7 were pre-treated with ampicillin and those in groups 8-10 with lansoprazole prior to C. difficile. The animals were killed and investigated for colonisation by C. difficile and toxin production, myeloperoxidase (MPO) activity and histopathology. RESULTS: Colonisation by C. difficile was found to be significantly different (P<0.001) in the various groups. C. difficile toxin titres and MPO activity were significantly lower in animals given L. acidophilus and EGF after ampicillin (groups 6 and 7) and lansoprazole (groups 9 and 10). The severity of acute inflammation was also significantly less (P<0.05) in caecal and colonic segments of animals in groups 6 and 7 compared to those in group 5. Although the severity of acute inflammation was less in the caecal and colonic segment of animals in groups 9 and 10, the reduction was not significant compared to group 8. INTERPRETATION & CONCLUSIONS: Our findings showed that the administration of L. acidophilus and EGF reduced the severity of C. difficile infection in the experimental animals. PMID- 21537101 TI - New metallo-beta-lactamase: is its name after New Delhi helpful or harmful? PMID- 21537102 TI - Cardiovascular effects of noise. PMID- 21537103 TI - Cardiovascular effects of environmental noise: research in Germany. AB - Research on systematic noise effects started in Germany back in the fifties with basic experimental studies on humans. As a result, noise was classified as a non specific stressor, which could cause an ergotropic activation of the complete organism. In the light of this background research a hypothesis was proposed that long-term noise exposure could have an adverse effect on health. This hypothesis was further supported by animal studies. Since the sixties, the adverse effects of chronic road traffic noise exposure were further examined in humans with the help of epidemiological studies. More epidemiological aircraft noise studies followed in the 1970s and thereafter. The sample size was increased, relevant confounding factors were taken into account, and the exposure and health outcomes were investigated objectively and with higher quality measures. To date, more than 20 German epidemiological traffic noise studies have focused on noise induced health effects, mainly on the cardiovascular system. In particular, the newer German noise studies demonstrate a clear association between residential exposure to traffic noise (particularly night noise) and cardiovascular outcomes. Nevertheless, additional research is needed, particularly on vulnerable groups and multiple noise exposures. The epidemiological findings have still not been fully considered in German regulations, particularly for aircraft noise. The findings, however, were taken into account in national recommendations. The Federal Environment Agency recommends noise rating levels of 65 dB(A) for the day and 55 dB(A) for the night, as a short-term goal. In the medium term, noise rating levels of 60 / 50 (day, night) should be reached and noise rating levels of 55 / 45 in the long run. PMID- 21537105 TI - Cardiovascular effects of environmental noise: research in Serbia. AB - Research on the cardiovascular effects of noise in Serbia started in the year 2002, including experimental studies on humans and epidemiological studies on the adult and children population of Belgrade and Pancevo. Experimental exposure to noise [L eq = 89 dB (A)] had a hypodynamic effect, significantly lowering the cardiac index, cardiac work, and pump performance (P < 0.01). The vasoconstrictive effect of noise was shown through the significant elevation of after-load (P < 0.01). In a cross-sectional population study that was carried out on 2874 residents [1243 males and 1631 females] in Pancevo City, a significant odds ratio (adjusted for age, body mass index (BMI), and smoking habits) was found for self-reported hypertension (OR = 1.8, 95% CI = 1.0 - 2.4, P < 0.01) in men with a high level of noise annoyance compared to those with a low level of noise annoyance. In another study on 2503 residents (995 men and 1508 women) residents of Belgrade, the proportions of men with hypertension in the noisy [(L night , 8h > 45 dB (A)] and quiet areas [(L night , 8h <= 45 dB (A)] were 23.6% and 17.5%, respectively. The adjusted odds ratio (OR) for hypertension of the exposed group was 1.58 (95% CI = 1.03 - 2.42, P = 0.038), where men living in quiet streets were taken as a reference category. Associations between road traffic noise and blood pressure were also investigated in 328 preschool children in Belgrade. The systolic blood pressure was significantly higher among children from noisy residences and kindergartens, compared to children from both quiet environments (97.30 +/- 8.15 and 92.33 +/- 8.64 mmHg, respectively, P < 0.01). As a continuation of the study on preschool children, investigations were also carried out on 856 school children, aged between seven and eleven years, in Belgrade. It was found that systolic pressure was significantly higher among children from noisy schools and quiet residences, compared to children from both quiet environments (102.1 +/- 9,3 and 100.4 +/- 10.4 mmHg, respectively, P < 0.01). PMID- 21537104 TI - Cardiovascular effects of environmental noise: research in Sweden. AB - In Sweden, as in many other European countries, traffic noise is an important environmental health issue. At present, almost two million people are exposed to average noise levels exceeding the outdoor national guideline value (55 dB(A)). Despite efforts to reduce the noise burden, noise-related health effects, such as annoyance and sleep disturbances, are increasing. The scientific interest regarding more serious health effects related to the cardiovascular system is growing, and several experimental and epidemiological studies have been performed or are ongoing. Most of the studies on cardiovascular outcomes have been related to noise from road or aircraft traffic. Few studies have included railway noise. The outcomes under study include morning saliva cortisol, treatment for hypertension, self-reported hypertension, and myocardial infarction. The Swedish studies on road traffic noise support the hypothesis of an association between long-term noise exposure and cardiovascular disease. However, the magnitude of effect varies between the studies and has been shown to depend on factors such as sex, number of years at residence, and noise annoyance. Two national studies have been performed on the cardiovascular effects of aircraft noise exposure. The first one, a cross-sectional study assessing self-reported hypertension, has shown a 30% risk increase per 5 dB(A) noise increase. The second one, which to our knowledge is the first longitudinal study assessing the cumulative incidence of hypertension, found a relative risk (RR) of 1.10 (95% CI 1.01 - 1.19) per 5 dB(A) noise increase. No associations have been found between railway noise and cardiovascular diseases. The findings regarding noise-related health effects and their economic consequences should be taken into account in future noise abatement policies and community planning. PMID- 21537106 TI - Cardiovascular effects of environmental noise: research in The Netherlands. AB - The impact of environmental noise on public health, in The Netherlands, is limited: Less than 1% of the myocardial infarction cases per year are attributable to long-term exposure to road traffic noise. Furthermore, although the Dutch noise policy is not directed to prevent cardiovascular disease due to noise exposure, health does play a role in Dutch noise policy. These are the main conclusions of a systematic review of Dutch observational studies, investigating the possible impact of road traffic and aircraft noise exposure on the cardiovascular system. Since 1970, 14 Dutch studies were published investigating the possible impact of road traffic and aircraft noise exposure on the cardiovascular system. Within these studies a large variety of outcomes were investigated, ranging from blood pressure changes to cardiovascular mortality. The results of the studies were not consistent and only weak associations were found. PMID- 21537107 TI - Cardiovascular effects of environmental noise: research in the United Kingdom. AB - Although the auditory effects of noise on humans have been established, the non auditory effects are not so well established. The emerging links between noise and cardiovascular disease (CVD) have potentially important implications on public health and policy. In the United Kingdom (UK), noise from transport is a problem, where more than half of the population is exposed to more than the recommended maximum day-time noise level and just under three-quarters of the population live in areas where the recommended night-time noise level is exceeded. This review focuses on findings from studies conducted in the UK that examined environmental noise and cardiovascular disease. There were statistically no significant associations between road traffic noise and incident ischemic heart disease in the Caerphilly and Speedwell studies, but there was a suggestion of effects when modifying factors such as length of residence, room orientation, and window opening were taken into account. In a sample stratified by pre existing disease a strongly increased odds of incident ischemic heart disease for the highest annoyance category was found compared to the lowest among men without pre-existing disease (OR = 2.45, 95%1.13 - 5.31), which was not found in men with pre-existing disease. In the Hypertension and exposure to noise near airports (HYENA) study, night time aircraft noise exposure (L night ) was associated with an increased risk of hypertension, in fully adjusted analyses. A 10-dB increase in aircraft noise exposure was associated with an odds ratio of 1.14 (95%CI, 1.01 - 1.29). Aircraft noise was not consistently related to raised systolic blood pressure in children in the road traffic and aircraft noise exposure and children's cognition and health (RANCH) study. There is some evidence of an association among environmental noise exposure and hypertension and ischemic heart disease in the UK studies; further studies are required to explore gender differences, the effects of day and night time exposure, and exposure modifying factors. PMID- 21537108 TI - Cardiovascular effects of environmental noise: research in Austria. AB - Cardiovascular effects of noise rank second in terms of disability-adjusted life year (DALYs) after annoyance. Although research during the past decade has consolidated the available data base, the most recent meta-analysis still shows wide confidence intervals - indicating imprecise information for public health risk assessment. The alpine area of Tyrol in the Austrian part of the Alps has experienced a massive increase in car and heavy goods traffic (road and rail) during the last 35 years. Over the past 25 years small-, middle-, and large-sized epidemiological health surveys have been conducted - mostly within the framework of environmental health impact assessments. By design, these studies have emphasized a contextually driven environmental stress perspective, where the adverse health effects on account of noise are studied in a broader framework of environmental health, susceptibility, and coping. Furthermore, innovative exposure assessment strategies have been implemented. This article reviews the existing knowledge from these studies over time, and presents the exposure response curves, with and without interaction assessment, based on standardized re-analyses and discusses it in the light of past and current cardiovascular noise effects research. The findings support relevant moderation by age, gender, and family history in nearly all studies and suggest a strong need for consideration of non-linearity in the exposure-response analyses. On the other hand, air pollution has not played a relevant role as a moderator in the noise hypertension or the noise-angina pectoris relationship. Finally, different noise modeling procedures can introduce variations in the exposure response curves, with substantive consequences for public health risk assessment of noise exposure. PMID- 21537109 TI - Relationship between noise annoyance from road traffic noise and cardiovascular diseases: a meta-analysis. AB - Road traffic noise is an important source of noise annoyance in the community. We performed a meta-analysis to assess whether there is an association between noise annoyance from road traffic noise and cardiovascular diseases (arterial hypertension and ischemic heart disease) in adult population. The meta-analysis included studies that: a. had noise annoyance as exposure, quantified either as "annoyed versus non-annoyed" or with various scales collected by standardized questionnaires; b. arterial hypertension or ischemic heart disease as outcome; c. had included only adult population (age >18 years); d. the studies had to have as effect size odds ratios or relative risk. From the individual studies those odds ratios were selected for meta-analysis which compared most distant categories. Eight studies that fulfilled criteria published between 1992 and 2006 were included in the meta-analysis: 6 studies had a cross-sectional design, 1 study had a case-control-design and 1 study had a cohort design. Increased annoyance was significantly associated with arterial hypertension (pooled risk estimate = 1.16, 95% confidence interval 1.02-1.29) while the association with ischemic heart disease did not reach statistical significance (pooled risk estimate = 1.07, 95% confidence interval 0.99-1.14). No publication bias was evidenced. The results of this meta-analysis demonstrated the existence of a positive and significant association between noise annoyance from road traffic and the risk of arterial hypertension and a positive yet insignificant association between noise annoyance and the risk of ischemic heart disease. PMID- 21537110 TI - Macrosomia, transient neonatal hypoglycemia, and monogenic diabetes in a family with heterozygous mutation R154X of HNF4A gene. PMID- 21537111 TI - A gnome on a snail--unknown author (XVI century). [corrected] PMID- 21537112 TI - Variation in DNA damage response pathway activity: focus on intermediate phenotype instead of genetic polymorphisms. PMID- 21537113 TI - Quantifying sexual exposure to HIV within an HIV-serodiscordant relationship: development of an algorithm. AB - BACKGROUND: The risk of acquiring HIV from a single sexual contact varies enormously reflecting biological and behavioural characteristics of both infected and uninfected partners. Accurate information on HIV transmission risk is required to construct evidence-based risk reduction practices for individuals, to direct the provision of prevention strategies at the population level, and enable the definition, quantification and comparison of true exposure in individuals termed 'exposed uninfected' within clinical trials. METHODS: Following a systematic review of current literature on HIV transmission estimates, an HIV risk score was developed, incorporating weighted risk factors into a Bernoulli mathematical model, allowing quantification of overall risk of HIV acquisition within HIV-serodiscordant partnerships. RESULTS: The HIV risk score enumerates the relative risk of HIV acquisition from HIV-positive partners incorporating the type and frequency of specific sex acts, the index case HIV plasma viral load and stage of disease, and the presence of genital ulcer disease in either partner and pregnancy, HSV-2 seropositivity, and circumcision status (men only) in the HIV negative partner. CONCLUSION: Key determinants of HIV exposure risk can be incorporated into a mathematical model in order to quantify individual relative risks of HIV acquisition. Such a model can facilitate comparisons within clinical trials of exposed uninfected individuals and facilitate interventions to reduce HIV transmission. PMID- 21537115 TI - Could we - should we - calculate a risk exposure score for an HIV-negative individual in a serodiscordant couple? PMID- 21537114 TI - The hepatitis C epidemic among HIV-positive MSM: incidence estimates from 1990 to 2007. AB - BACKGROUND: Outbreaks of acute hepatitis C virus (HCV) infection among HIV infected MSM have been described since 2000. However, phylogenetic analysis suggests that the spread of HCV started around 1996. We estimated the incidence of HCV in HIV-infected MSM with well estimated dates of HIV seroconversion from 1990 to 2007. METHODS: Data from 12 cohorts within the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) Collaboration were used. HCV incidence was estimated using standard incidence methods and methods for interval censored data. We accounted for the fact that routine HCV data collection in each cohort started in different calendar years. RESULTS: Of 4724 MSM, 3014 had an HCV test result and were included. Of these, 124 (4%) had only positive HCV test results, 2798 (93%) had only negative results and 92 (3%) had both. In 1990, HCV incidence ranged from 0.9 to 2.2 per 1000 person-years, depending on the analysis strategy used. HCV incidence increased up to 1995 when it was estimated to range between 5.5 and 8.1 per 1000 person-years. From 2002 onwards, it increased substantially to values between 16.8 and 30.0 per 1000 person-years in 2005 and between 23.4 and 51.1 per 1000 person-years in 2007. CONCLUSION: Our data support phylodynamic findings that HCV incidence had already increased among HIV-infected MSM from the mid-1990s. However, the main expansion of the HCV epidemic started after 2002. Incidence estimates obtained from cohort studies may help identify changes in the spread of important infections earlier and should guide routine testing policies to minimize further disease burden. PMID- 21537116 TI - Impact of IL28B polymorphisms on response to peginterferon and ribavirin in HIV hepatitis C virus-coinfected patients with prior nonresponse or relapse. AB - IL28B polymorphisms predict treatment response in chronic hepatitis C. However, no information exists in prior treatment failures. A total of 62 HIV/hepatitis C virus (HCV) patients who completed retreatment with peginterferon-alpha/ribavirin were examined, of whom 25 (40%) had been cured. Predictors of response [odds ratio, OR (95% confidence interval, CI)] were HCV genotypes 2/3 [16.1 (2.7 90.9)], prior relapse [9.6 (1.5-62.4)] and ribavirin plasma trough concentrations at week 4 [4.9 (1.3-18.4)]. IL28B-CC only predicted response in prior nonresponders carrying HCV genotypes 1/4 [25.1 (1.9-337)]. PMID- 21537117 TI - Spontaneous resolution of HIV-associated nephropathy in an elite controller. PMID- 21537118 TI - Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. PMID- 21537120 TI - AIDS education programmes hit some targets: improving youth HIV prevention by sharing resources and better addressing community norms and concurrency. PMID- 21537121 TI - To pee or not to pee: ammonia hypothesis of hepatic encephalopathy revisited. AB - Hepatic encephalopathy is a neuropsychiatric syndrome associated with liver failure. Its aetiology has been debated for the past 100 years. Nevertheless, elevated ammonia levels are still believed to play a central role in its pathogenesis. After intestinal production, ammonia is detoxified by the liver. In liver failure, skeletal muscle and brain have been proposed to be alternative, although temporary, ammonia detoxifying organs. However, there is an increasing body of evidence that the kidney, in addition to the gut, is a pivotal organ determining systemic ammonia levels. In the last 20 years, it has been shown that the kidney can switch from an organ of systemic net ammonia production to a net ammonia excretion organ. The kidney plays a central role in the determination of ammonia levels. It is at least as important as the gut and could therefore serve as a target for new treatments for hepatic encephalopathy. PMID- 21537122 TI - Helicobacter pylori isolates from proximal and distal stomach of patients never treated and already treated show genetic variability and discordant antibiotic resistance. AB - INTRODUCTION: The treatment failure of Helicobacter pylori (H. pylori) infection may be mainly because of antibiotic resistance and the presence of a mixed infection in the same patient. AIM: To investigate the incidence of mixed infection and discordant antibiotic resistance in patients never treated and already treated. MATERIALS AND METHODS: Susceptibility test to amoxicillin, rifabutin, tinidazole, clarithromycin, levofloxacin, and moxifloxacin was conducted on H. pylori strains culture from 76 patients never treated and 72 patients already treated unsuccessfully. DNA fingerprinting was determined on H. pylori strains harboring in the same patient with a discordant resistance to the same antibiotic. RESULTS: Forty percent of patients never treated and 53% of patients already treated showed a pangastric infection. The overall resistance to amoxicillin, clarithromycin, and tinidazole was significantly higher in patients with pangastric infection in comparison with those with the infection in the antrum (P<0.05). Discordant resistance was present in 33% of patients never treated, and 21% of patients already treated. DNA fingerprinting showed substantial differences among DNA patterns suggesting a mixed infection. CONCLUSION: Culture and susceptibility test should be performed when necessary not only in the antrum but also in the fundus of patients with H. pylori infection. PMID- 21537123 TI - Serological tests for celiac disease as indicators of long-term compliance with the gluten-free diet. AB - OBJECTIVES: The efficacy of celiac disease (CD)-related antibodies in monitoring clinical outcome of patients remains unclear. Our aims were to determine dynamics of antibodies after diagnosis and to assess their performances in monitoring patients' long-term compliance with the gluten-free diet (GFD). METHODS: We prospectively estimated the performance of seven celiac disease-related antibody tests at diagnosis and at 1 year and more than 4 years after treatment initiation in 53 adults. The ability of antibodies to identify patients partially compliant to treatment was explored by the receiver operating characteristic curve analysis. The derived cut-off values ('compliance' cutoffs) were compared with cut-off values used for diagnosis ('diagnostic' cutoffs). The degree of compliance with the GFD was assessed using a standardized, multidisciplinary approach. RESULTS: Concentrations of all antibodies decreased significantly at 1 year after diagnosis. The decline continued for more than 4 years in strictly compliant patients (P<0.05-0.001). The gap between 'compliance' and 'diagnostic' cut-offs values was wider at 1 year than at more than 4 years. The predictability of partial compliance determined by the area under receiver operating characteristic curves was relevant for most tests examined at 1 year (areas ranging: 0.64-0.72) and more than 4 years (0.58-0.78). Immunoglobulin A antibodies to deamidated gliadin peptides and tissue transglutaminase had the best performance for monitoring long-term compliance. CONCLUSION: Decreased concentrations of antibodies were significantly associated with the degree of compliance with the GFD. Immunoglobulin A antibodies to deamidated gliadin peptides and tissue transglutaminase had the best and more consistent performances. The serial measurement of antibody levels seems to be more reliable in monitoring compliance than the positive/negative expression of results. PMID- 21537124 TI - Complications in colonoscopy: analysis of 7-year physician-reported adverse events. AB - INTRODUCTION: The number of malpractice claims against physicians and health institutes in Israel is increasing continuously, as in the rest of the Western world. This trend became a serious financial burden. AIM: In this study we analyzed reports of gastroenterologists on colonoscopy adverse events to the medical malpractice insurer, as well as complaint/demand for compensation from patients represented by lawyers, between 1 January 2000 and 31 December 2006. METHODS: All the reports of physicians associated with colonoscopy adverse events from health institutes covered by Madanes Insurance Group were analyzed and summarized using a specially designed questionnaire. Clinical and epidemiological details about the patients, procedures, and adverse events were coded into an excel sheet, discussed, and evaluated. RESULTS: One hundred and two cases of colonoscopy adverse events were reported. There were 48 cases of men (47.1%) and the average age was 69.9+/-12.90 years. In this period of time 252 064 colonoscopies were performed by the institutes in the sampling frame, and the number of adverse events was on average 4.0 (between 2.8 and 6.2) for 10 000 colonoscopies. The difference between the years was not statistically significant. Perforation occurred in one of 2864 procedures, bleeding in one of 29 007 procedures, and respiratory complications in one of 50 412 procedures. CONCLUSION: This is the first study in Israel based on physicians' reports of colonoscopic adverse events. The picture is optimistic, as the rate of complications is low, and the data encourage early detection and reporting. PMID- 21537125 TI - Sampling variability of transient elastography according to probe location. AB - BACKGROUND AND AIMS: Heterogeneity of fibrosis throughout the liver has been reported. However, the need for several measurements when using transient elastography was not thoroughly investigated. The aim was to find out whether measurement of liver stiffness varies according to the probe location. METHODS: Six hundred and twenty-five consecutive patients with chronic liver diseases referred for transient elastography were enrolled. All patients underwent successive liver stiffness measurements at three different sites. Representative measurements were acquisitions with a success rate greater than 60% and an interquartile range lower than 30% of the median. RESULTS: The sample included 371 eligible patients with three representative measurements. Comparing the three successive measurements categorized to fibrosis stages F0-F4, 68.2% of patients had agreement between all three sites. Discordance of one stage was noted in 28.3% of the patients, in 7% for two stages, and in 1.4% for three stages.The kappa for comparing the maximal versus the minimal results was 0.43. There was no significant difference in the characteristics of patients with discordance and patients without discordance including age, sex, waist circumference, BMI, and etiology of liver disease. The stage of fibrosis was associated with discordance between measurements (P<0.001), demonstrating low discordance rate in patients with stages F0-F1 or F4 and high discordance rate in patients with stages F2 and F3. CONCLUSION: Sampling variability according to probe location is seen in transient elastography in approximately 30% of patients. Therefore, it may be suggested to perform transient elastography from various sites to minimize the sample error. PMID- 21537127 TI - Drug-eluting bead loaded with doxorubicin versus conventional Lipiodol-based transarterial chemoembolization in the treatment of hepatocellular carcinoma: a case-control study of Asian patients. AB - OBJECTIVE: Lipiodol transcatheter arterial chemoembolization (TACE) is widely used to treat hepatocellular carcinoma (HCC). Recently, a drug-eluting bead (DEB) has been developed to enhance drug delivery to the tumor and reduce its systemic availability. The purpose of this study was to compare the efficacy and safety of intra-arterial injection of DEB loaded with doxorubicin versus conventional, Lipiodol-based TACE regimens in Asian patients with HCC. METHODS: The study was designed as a case-control, single-institution clinical trial. Twenty patients with HCC who received DEB loaded with 50 mg doxorubicin ('cases') were matched with 20 patients who had undergone conventional TACE ('controls'). The primary efficacy endpoint was tumor response at 1 month according to modified Response Evaluation Criteria in Solid Tumors. The primary safety endpoint was liver toxicity. RESULTS: The rate of objective response by modified Response Evaluation Criteria in Solid Tumors was 85% (17 of 20 patients) in the DEB arm versus 30% (six of 20 patients) in the conventional TACE arm (P=0.001). Subgroup analyses conducted in patients with large (>5 cm) or multinodular tumor confirmed significantly higher objective response rates in patients receiving DEB as compared with those treated with conventional TACE (P=0.003 and P=0.005, respectively). At the dose of 50 mg doxorubicin, there was no statistically significant difference in liver toxicity between DEB and conventional TACE (P>0.05). CONCLUSION: In Asian patients with HCC, transcatheter treatment with DEB loaded with doxorubicin offers a distinct advantage in objective tumor response rate as compared with conventional, Lipiodol-based TACE regimens. PMID- 21537126 TI - Favorable outcome of acute occupational hepatitis C in healthcare workers: a multicenter French study on 23 cases. AB - BACKGROUND: Although risk factors and useful preventive measures are largely known, specific data about the course and prognosis of acute hepatitis C among healthcare workers is lacking. AIM: To analyze the data, course, and outcome of a series of patients with occupationally transmitted acute hepatitis C in France. METHODS AND SETTING: An observational multicenter study based on two consecutive acute hepatitis C cohorts, retrospective then prospective, registered between 1993 and 2007, mostly in general hospitals. RESULTS: A cohort of 23 patients with occupationally transmitted hepatitis C virus (HCV) was set up. Occupational accident registration was done in 14 (61%) cases. They were mainly women (n=14), with a mean age of 43 years. The disease was diagnosed during surveillance after exposure in 16 patients, and nine had hyperbilirubinemia. Early treatment was applied to nine of them, with eight who sustained viral response (SVR). Fourteen underwent surveillance: spontaneous viral clearance occurred in nine of them, with two relapses. Five patients with persistent HCV RNA 12 weeks after the diagnosis were then treated, with four SVR. CONCLUSION: Information and prevention of healthcare workers concerning occupational HCV transmission need to be improved, and all blood-exposure accidents should be registered. Spontaneous viral clearance occurred in half of the patients. Antiviral treatment was highly effective, with a SVR of 86%. PMID- 21537128 TI - Risk factors for long-term prognosis in hepatocellular carcinoma after radiofrequency ablation therapy: the clinical implication of aspartate aminotransferase-platelet ratio index. AB - OBJECTIVE: Percutaneous radiofrequency ablation (RFA) is one of the first-line curative therapies for hepatocellular carcinoma (HCC), but factors affecting the prognosis remain unclear. This study aimed to evaluate the prognostic factors associated with the prognosis in patients with HCC undergoing RFA. METHODS: The study enrolled 190 treatment-naive patients with HCC (<5 cm). Factors were analyzed in terms of overall survival and recurrence. RESULTS: After a median follow-up of 30.7+/-17.5 months, 41 patients died and 149 patients were alive. Of the 112 patients who developed tumor recurrence, 61 had local recurrence and 51 had distant intrahepatic recurrence. The 5-year overall survival rate and recurrence rate were 65.5 and 73.6%, respectively. Factors associated with overall mortality were, age older than 65 years (P=0.019), aspartate aminotransferase-to-platelet ratio index (APRI) of more than 1 (P=0.015), prothrombin time international normalized ratio of more than 1.1 (P=0.013), multinodularity (P=0.024), and Child-Pugh grade B (P=0.036). Besides, multivariate analysis disclosed that APRI of more than 1 (P=0.002), multinodularity (P<0.001), and tumor size of more than 2 cm (P=0.002) predicted higher incidence of developing recurrence after RFA. Factors determining local recurrence were, age older than 65 years (P=0.030), APRI of more than 1 (P=0.003), multinodularity (P=0.019), and tumor size of more than 2 cm (P=0.015), whereas only APRI of more than 1 (P=0.013) and multinodularity (P<0.001) were independent risk factors predictive of intrahepatic distant metastasis. CONCLUSION: Both multinodularity and APRI are associated with overall survival and recurrence for patients with HCC after RFA therapy. Consequently, APRI seems to serve as a feasible marker for predicting the prognosis of patients with small HCC undergoing RFA. PMID- 21537130 TI - "The trouble with this place. . .". PMID- 21537131 TI - Health care transitions and the aging population: a framework for measuring the value of rapid rehabilitation. AB - A study was undertaken to establish a framework to measure the value of rapid rehabilitation and identify indicators to quantify effective outcomes and efficient processes as health care services are delivered to the aging population across providers, services, and settings. The rapid rehabilitation protocol serving as intervention in this research provides patients (>=65 years old) the option to transition from the acute-care hospital, early in the continuum of care, to an outpatient, skilled nursing facility operated by a division of the hospital organization. A quasi-experimental, cross-sectional, retrospective study is designed to identify and quantify the relationships present in processes and outcomes inherent in health care transitions. Statistical analysis yields unexpected relationships with limited explanatory power for the selected indicators: length of stay, cost of care, discharge delays, 30-day readmissions, falls, and patient satisfaction. However, this research finds 4 imperatives for hospital and clinical leadership: (1) increase collaboration across providers, settings, and stakeholders; (2) educate workforce to optimize risk assessment of aging population; (3) standardize critical to quality measures as scientific foundation for management of services; (4) invest in technologies to ensure the integrity, validity, and reliability of information used to draw inferences about services, risk, and performance. PMID- 21537132 TI - Electronic health record project initiation and early planning in a community health center. AB - Community health centers exist to help their constituents become proactive in addressing their own health care needs and to improve the overall well-being of the community. However, they pose a different set of challenges when implementing an electronic health record system. This article applies 2 project management principles, initiation and early planning, to the electronic health record implementation in a community health center. Issues such as planning, financial considerations, and quality improvement are discussed. PMID- 21537133 TI - The ethical leadership challenge: creating a culture of patient- and family centered care in the hospital setting. AB - The growing number of medical errors and resulting preventable deaths in hospitals presents an ethical dilemma that must be addressed by health care leaders and managers. These medical errors and deaths raise questions about safety and quality issues resulting in rising public mistrust and patient dissatisfaction. Many of these medical errors and deaths could have been avoided by including the patient and family in the care. The ethical challenge for leadership is creating a culture of patient- and family-centered care as a means to improve quality, safety, patient satisfaction, and public trust. This article addresses ways to improve safety, quality, patient satisfaction, and cost and thereby reduce medical errors and deaths by implementing a patient- and family centered care culture. The first critical step for improvement is for hospital leaders and managers to answer the ethical call to create a culture centered on patient- and family-centered care in the hospital setting. PMID- 21537134 TI - Sustainability and the health care manager: part I. AB - Given the current operating climate, organizations are coming under pressure to develop and implement sustainability programs and projects, yet few managers truly understand what is meant by sustainability and its implications for managing organizations. This article examines the concept of sustainability and provides a broader definition of the term than going "green." Using a puzzle metaphor, the authors outline and explain the different components of sustainability and provide a checklist for achieving sustainability goals. In addition, resources such as guides and tools are reviewed and offered to assist managers in gaining more insight into the challenges and complexity of sustainability. PMID- 21537135 TI - Layoffs at hospitals: a challenge for health care managers. AB - Like other organizations that are directly impacted by the state of the economy, some hospitals and other health care providers are discovering that staff reductions are realities that heretofore have been rare during recessionary periods. Consequently, health care managers are increasingly required to notify affected workers of layoff and convey to them critical information in meetings that are often fraught with anxiety and anger. Nevertheless, there are steps that the organization's managers can take to ensure that layoffs are addressed in a professional manner that maintains the trust and respect of the workforce. PMID- 21537137 TI - The laboratory workforce shortage: a managerial perspective. AB - Most clinical laboratories in the nation report severe difficulties in recruitment and retention of most types of personnel. Other important factors impacting this problem include work complexities, increased automation, and a graying workforce. As a further challenge, institutional needs for clinical laboratory personnel are expected to grow significantly in the next decade. This article examines the current situation of the clinical laboratory workforce. It analyzes the different types of personnel; the managerial, supervision, and line positions that are key for different types of laboratories; the job outlook and recent projections for different types of staff; and the current issues, trends, and challenges of the laboratory workforce. Laboratory managers need to take action with strategies suggested for overcoming these challenges. Most importantly, they need to become transformational leaders by developing effective staffing models, fostering healthy and productive work environments, and creating value with a strategic management culture and implementation of knowledge management. PMID- 21537138 TI - Depression care management: impact of implementation on health system costs. AB - This study examined the mental health care costs associated with implementation of a collaborative care management (CCM) of treatment for depression in primary care. A retrospective review of all costs was performed over a 2-year period associated with providing care to adult patients at clinical sites with CCM versus those with usual care, comparing total and mental health per member per month (PMPM) costs for 2008 and 2009 (patient population = 103,000). The mental health-PMPM costs as a percentage of total health care costs at the clinic without CCM were 4.65% in 2008 and 4.5% in 2009 (p = .085). In the clinics with CCM, there was a significant difference between the 2 years with a decrease noted in 2009 of 4.91% compared with 4.36% in 2008 (p < .0001). This study demonstrated that, on a population basis with the implementation of CCM, the metric of mental health-PMPM (using the actual costs of delivering care) suggested that an increased short-term cost of care is not always realized. Collaborative care management treatment for depression may be a more cost-efficient method of care for the population as a whole, even in the short term. PMID- 21537139 TI - Demand study for advanced dental hygiene educational degrees: part 2: assessing educational demand. AB - Currently, the debate over the addition of the midlevel provider position for dental hygienists rages on. The midlevel provider (similar to the physician's assistant) in dentistry exists in a handful of states in various forms, but is hotly contested in many other states. This is the second half of a 2-part study undertaken to add to the current body of knowledge by addressing the clinical needs changing in our population and the associated demand study for additional educational degrees for dental hygienists to address these changing needs. Part 1 addressed a literature update on oral health and systemic correlations contributing to our populations' declining health conditions, whereas part 2 illustrates the results of the demand study. It attempts to benchmark "adequate demand" and applies the stakeholder theory as its theoretical framework. PMID- 21537141 TI - Fall prevention conceptual framework. AB - Falls can have lasting psychological and physical consequences, particularly fractures and slow-healing processes, and patients may also lose confidence in walking. Injuries from falls lead to functional decline, institutionalization, higher health care costs, and decreased quality of life. The process related to the problem of patient falls in the hospital, using the nursing model developed by the theorist, Ida Jean Orlando, is explained in this article. The useful tool that provides guidance to marketers in this endeavor is Maslow's hierarchy of needs. During acute illness, individuals are greatly in need of satisfying their physiological needs. If these needs are not met, patients leave the hospital lacking a positive experience. Initial fall risk assessment is critical to plan intervention and individualize care plan. Interventions depend on the severity of fall risk factors. PMID- 21537140 TI - A comparative analysis of factors that hinder primary care physicians' and specialist physicians' ability to provide high-quality care. AB - A study was undertaken to examine factors that hinder primary care physicians' and specialist physicians' ability to provide high-quality care. The study used data collected by the Center for Studying Health System Change's 2008 Health Tracking Physician Survey. The 2008 Health Tracking Physician data set consisted of 4720 physicians belonging to the American Medical Association. Both primary care physicians and specialists rated care decisions rejected by insurance (49%, 51%), followed by patient being unable to pay for needed care (45%, 43%), and patient noncompliance with treatment recommendation (43%, 37%) as the top major problem areas in providing quality care to patients. In addition, 36% of primary care physicians and 27% of specialists reported that inadequate time with patients during visit was a major problem in providing quality care to patients. Primary care physicians reported significantly more problems associated with having adequate time with patients during office visits, ability of patients to pay for needed care, availability of qualified specialists in the area, receiving timely reports from other doctors, and patient noncompliance with treatment recommendations. On the other hand, primary care physicians reported significantly lower communication difficulties with patients due to language or cultural barriers. Care decisions rejected by insurance, patient being unable to pay for care, and patient noncompliance with treatment recommendation were the top 3 hindrances in providing quality care to patients for both physician types. For 6 of the 8 hindrance factors, there were significant differences in the level of problems identified by primary care physicians and specialist physicians. PMID- 21537142 TI - Addressing problems of employee performance. AB - Employee performance problems are essentially of 2 kinds: those that are motivational in origin and those resulting from skill deficiencies. Both kinds of problems are the province of the department manager. Performance problems differ from problems of conduct in that traditional disciplinary processes ordinarily do not apply. Rather, performance problems are addressed through educational and remedial processes. The manager has a basic responsibility in ensuring that everything reasonable is done to help each employee succeed. There are a number of steps the manager can take to address employee performance problems. PMID- 21537143 TI - Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials. AB - Clinical trials of melanoma vaccines have yielded inconclusive data on whether a positive melanoma-specific immune response predicts treatment benefit. The objective of this study was to evaluate the effect of different melanoma vaccine strategies and the association between immunologic response and survival. The authors conducted a systematic review and meta-analysis of phase II and III clinical trials of melanoma vaccine. Outcomes assessed included overall disease control, overall survival, and impact on immune response. For binary variables, proportions were reported for one-arm studies and risk ratios for controlled studies. For survival data, medians were reported for one-arm studies and hazard ratios for controlled studies. The existence and extent of heterogeneity between trials was evaluated using Cochran's Q statistic. A two-sided P value of less than 0.05 for meta-analysis results was considered statistically significant. Of 56 studies reporting data on 4375 patients, overall disease control was seen in 25.3% [95% confidence interval (CI): 20.7-30.5%] of patients. Subgroup analysis revealed that overall disease control for peptide vaccines plus interleukin-2 (IL 2) was improved compared with interleukin-2 alone (pooled risk ratio: 2.79, 95% CI: 1.62-4.80). Overall survival varied among six studies comparing vaccine with other treatments. Subgroup analysis revealed that tumor-specific immune response was associated with prolonged overall survival compared with the lack of response (pooled hazard ratio: 2.15, 95% CI: 1.88-2.44). Severe toxicity associated with vaccine treatment was uncommon. Overall, a melanoma-specific immune response predicted longer overall survival, although no evidence was found that vaccine therapy provides better overall disease control or overall survival compared with other treatments. PMID- 21537144 TI - Beclin-1 and LC3A expression in cutaneous malignant melanomas: a biphasic survival pattern for beclin-1. AB - Autophagy is an intracellular pathway for the degradation of long-lived proteins and damaged organelles. It is, in essence, a recycling process allowing cells to survive oxygen and nutrient depletion. The expression of two autophagy-related proteins, beclin 1 and light chain 3A (LC3A) was investigated in 79 nodular cutaneous melanomas. The results were correlated with histopathological factors, vascular density, and hypoxia-related proteins [hypoxia-inducible factors (HIF1alpha and HIF2alpha) and lactate dehydrogenase 5]. The reactivity of both autophagy-related proteins was uniformly cytoplasmically diffused. High beclin 1 and LC3A reactivity was related to tumor hypoxia, as this was inferred from the intense expression of HIF1alpha and lactate dehydrogenase 5, whereas low beclin 1 and LC3A expression was linked with an increased vascular density. In addition, beclin 1 was related to disease-specific survival which, however, exposed a biphasic pattern. A strong beclin 1 expression extending over a tumor area of more than 50% (high) was associated with an increased rate of early deaths, whereas a similarly strong, but less-extensive cytoplasmic reactivity (<10% tumor area; low) defined a sharp fall in the survival 5 years after surgery. Furthermore, the low beclin 1 expression was associated with high Breslow's depth, high Clark's level, and ulceration. Low LC3A expression was also related to ulceration, but not to other histopathological features nor prognosis. In multivariate analysis, beclin 1 was an independent prognostic variable. It is concluded that extensive autophagic activity is generated by tumor hypoxia and anaerobic glycolysis, whereas angiogenesis maintains low autophagic activity. Atg6/beclin 1 was proved to be capable of deciphering the prognosis in cutaneous malignant melanoma, but the matter requires further investigation. PMID- 21537145 TI - Caregiver burden and coping in early-stage Alzheimer disease. AB - This study was set out to describe caregiver-perceived burden and coping in early stage Alzheimer disease (AD). A total of 163 consecutive pairs of patients with AD and their principal caregivers were initially recruited. The caregivers completed the Caregiver Burden Inventory (CBI) and the Coping Orientations to Problems Experienced scale, and also provided sociodemographic information; the patients with AD were assessed by means of the Mini Mental State Examination and the Neuropsychiatric Inventory. Data from 126 patient-caregiver pairs were analyzed. The caregivers (mean age 56.11+/-12.37 y) were mainly women (76%); 64% were the patient's offspring; 39% lived with the patient. From the CBI data, it emerged that caregivers perceived loss of personal time (objective burden, 33%) and the feeling of missing out on opportunities (developmental burden, 25%) as their main stressors. Total CBI score was negatively correlated with Mini Mental State Examination (P=0.005). As regards coping strategies, the caregivers predominantly used problem-oriented strategies associated with a positive attitude. The use of dysfunctional strategies was predictive of caregiver burden. It is important to be aware that avoidance and dysfunctional coping strategies predispose caregivers of patients with AD to higher level of distress, whereas successful caregiving seems to be based on the use of problem-oriented strategies early in the disease when solutions are still available. PMID- 21537146 TI - Younger age at crisis following parental death in male children and adolescents is associated with higher risk for dementia at old age. AB - AIMS: To examine the association of midlife report of crisis following parental death (CFPD) during childhood and adolescence, with dementia at old age. METHODS: In 1965, 9362 male participants of the Israel Ischemic Heart Disease study were asked whether they have experienced CFPD (paternal or maternal) during the following ages: 0 to 6, 7 to 12, 13 to 18, or >18 years. Dementia was assessed over 3 decades later in 1889 survivors of the original cohort, 1652 of whom were assessed for CFPD in 1965. RESULTS: Controlling for age, the estimated odds ratios for dementia relative to individuals who reported crisis following paternal parental death (CFPD-P) at the age of 18 years and above were 3.06 (95% CI: 1.42-6.61), 2.15 (95% CI: 0.87-5.31), and 2.35 (95% CI: 1.05-5.28) for those who reported CFPD-P at the ages of 0 to 6, 7 to 12, and 13 to 18 years, respectively. Odds ratios for dementia were 0.60 (95% CI: 0.32-1.11) for participants who reported CFPD-P at ages of 18 and above compared with participants who did not report such a crisis. Similar results were obtained for the association of crisis reported following maternal parental death (CFPD-M) at different age groups and dementia. CONCLUSIONS: CFPD during childhood is associated with an increased risk for dementia in men who survived until old age. PMID- 21537147 TI - A population-based study of the quality of care in the diagnosis of large (>=5 cm) soft tissue sarcomas. AB - PURPOSE: The aim of this study was to assess preoperative biopsy utilization for patients with soft tissue sarcoma (STS) of >=5 cm in size and whether or not preoperative biopsy was associated with fewer surgical procedures to adequately treat these tumors. METHODS: We identified 899 patients from the Surveillance, Epidemiology, and End Results-Medicare database with a diagnosis of STS and who underwent surgical resection of their tumors between 1992 and 2006. We used diagnosis and procedure codes from claims data to identify which patients had a biopsy performed and the corresponding number of surgical procedures for each patient. Multivariate logistic regression analyses were carried out to assess the influence of patient, tumor, and sociodemographic characteristics on performance of biopsy and the likelihood of multiple STS operations. RESULTS: Only 40.6% of patients with tumors of >=5 cm in size underwent biopsy as part of initial management of their STS. In multivariate analysis, biopsy utilization varied significantly by sex, tumor size, grade, and geographic region. After adjusting for patient, tumor, and sociodemographic characteristics, receipt of a biopsy was the only factor significantly associated with reduced likelihood of multiple STS operations (odds ratio=0.34, 95% confidence interval, 0.24-0.49). CONCLUSION: Preoperative biopsy utilization among Medicare beneficiaries undergoing surgery for STS of >=5 cm in size is low. Performance of a biopsy for patients with soft tissue tumors of >=5 cm in size is associated with a decreased likelihood of a patient undergoing multiple surgeries for treatment of STS. PMID- 21537148 TI - Minimal residual disease is a prognostic marker for neuroblastoma with bone marrow infiltration. AB - OBJECTIVE: This pilot study focused on whether flow cytometry (FCM) detection of minimal residual disease in bone marrow (BM) could predict the outcome of patients with advanced neuroblastoma (NB). PATIENTS AND METHODS: Fifty-seven stage 4 NB patients with BM infiltration were enrolled in this study. All of them received NB-2001 protocol. BM samples were examined for tumor cell contamination by both morphology and FCM with CD45-FITC/CD81-PE/CD56-PECy5 monoclonal antibodies cocktail at diagnosis and after 4 courses of chemotherapy. RESULTS: BM samples of all patients were positive at diagnosis by FCM, and samples from 30 patients became negative after 4 courses of chemotherapy, 10 patients relapsed (33.3%) in mean 45.5 months, range 7 to 69. Another 27 patients remained positive, and 20 of them relapsed (74.1%) in mean 24.2 months, range 8 to 48. There was a statistically significant difference in event-free survival between the 2 groups (P = 0.002). CONCLUSIONS: Persistence of minimal residual disease in BM may work as a chemotherapy response marker and predict the prognosis in advanced NB. PMID- 21537150 TI - Posttreatment quality-of-life assessment in patients with head and neck cancer treated with intensity-modulated radiation therapy. AB - OBJECTIVES: To evaluate patient-reported quality-of-life (QOL) domains in patients with head and neck cancer (HNC) treated with intensity-modulated radiotherapy (IMRT); specifically time-based QOL changes compared with baseline and correlation with independent variables. METHODS: Between January 2002 and August 2006, we prospectively administered the University of Washington Quality of Life-Revised assessment to 143 patients with primary HNC treated with IMRT to investigate the impact of treatment on 12 QOL domains. We analyzed 108 patients with more than 6 months follow-up for correlation between QOL domains and independent variables. RESULTS: Patients were divided into 2 groups based on mean parotid gland dose with a 26-Gy threshold. We saw in general, an acute drop in all scores after starting treatment regardless of the degree of parotid sparing. If the parotid received a mean dose >=26 Gy, then the acute decrease was larger than if the parotid received less than 26 Gy. Higher radiation dose to the parotid resulted in significantly lower QOL scores over 9 months (pain) and often more than 2 years (chewing and taste). No significance was found between the domains and the independent variables assessed. CONCLUSIONS: Patients with HNC treated with IMRT experienced an acute decrement in QOL across many domains despite parotid sparing. Lower radiation doses to the parotid corresponded to a smaller decrease in QOL and an earlier return to baseline compared with higher doses. Self-reported QOL and functional outcomes are important determinants of patient satisfaction and should be evaluated in future studies. PMID- 21537149 TI - Consolidative radiation therapy for stage III Hodgkin lymphoma in patients who achieve complete response after ABVD chemotherapy. AB - OBJECTIVES: To examine the role of consolidation radiation therapy (RT) for patients with stage III Hodgkin lymphoma. METHODS: We retrospectively reviewed 118 patients with stage III Hodgkin lymphoma who were diagnosed and treated at the University of Texas M.D. Anderson Cancer Center from 1993 through 2006. We evaluated the influence of site and size of initial involvement and use of consolidative RT on survival and patterns of failure after complete response (CR) to ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine). RESULTS: After chemotherapy, 104 patients (88%) achieved CR; median follow-up time was 68 months (range, 8 to 190). Seventy-one patients (68%) received >=6 cycles of ABVD, and 40 patients (38.5%) received consolidative RT. Comparing patients who received RT with those who did not, the 5-year, 10-year, and 15-year overall survival (OS) rates were 98%, 80%, and 80% versus 91%, 72%, and 29%, respectively (P=0.08). Disease-free survival (DFS) rates were 94%, 81%, 65% versus 78%, 45%, and 15%, respectively (P=0.04). On multivariate analysis, the presence of initial mediastinal involvement (P=0.001) and bulky head and neck disease (P=0.001) was associated with worse DFS; mediastinal RT was associated with improved DFS (P=0.003) and OS (P=0.029). Use of >=6 cycles of ABVD was associated with improved OS (P=0.001). The pattern of failure analysis showed that most failures (23 of 28) occurred above the diaphragm. CONCLUSIONS: Consolidative RT after CR may benefit patients with initial disease above the diaphragm, whereas below-the-diaphragm disease seems to be well managed by chemotherapy alone. PMID- 21537151 TI - Effects of testosterone on renal function in salt-loaded rats. AB - INTRODUCTION: The objective of this study is to investigate the effects of androgen on renal sodium excretion and renal functional in sodium-loaded rats. METHODS: Sixty male Wistar rats aged 8 weeks were used, of which 48 underwent orchiectomy and the other 12 underwent a sham procedure. The 48 orchiectomized rats were randomly divided into 4 groups (12/group): castrated rats (Cas), testosterone-supplemented castrated rats (TC), flutamide (androgen receptor blocker)-treated castrated rats (FC) and flutamide-treated testosterone supplemented castrated rats (FTC). The 12 sham-operated rats served as controls. All 60 rats were fed with 8% NaCl chow for 8 weeks. Systemic blood pressure (BP) was recorded at 0, 4 and 8 weeks. Sodium excretion, microalbuminuria and creatinine clearance were calculated before and at the end of the experiment. Circulating levels of testosterone and angiotensin II and plasma renin activity were measured by radioimmunological method at the end of the experiment. RESULTS: BP of controls and TC was higher at 8 weeks than at baseline; BP of Cas, FC or FTC was lower than that of controls. Plasma renin activity and angiotensin concentrations were lower in Cas, FC and FTC (groups with testosterone absent or blocked) than in controls and TC (groups with testosterone intact). Cas, FC and FTC displayed less microalbuminuria, higher sodium excretion and higher creatinine clearance than control and TC. CONCLUSIONS: In salt-loaded rats, testosterone seems to activate the renin-angiotensin system, resulting in sodium retention, higher BP and renal injury. PMID- 21537152 TI - Spontaneous bilateral humeral shaft fracture due to severe renal osteodystrophia. PMID- 21537153 TI - Streptococcus pneumoniae soft tissue infections in human immunodeficiency virus. AB - Skin and soft tissue infections due to Streptococcus pneumoniae are rare. The authors report here a case of S pneumoniae cellulitis in a human immunodeficiency virus-infected patient and review the literature on pneumococcal skin and soft tissue infections in human immunodeficiency virus-infected patients. PMID- 21537154 TI - B cell activating factor gene polymorphisms in patients with risk of idiopathic thrombocytopenic purpura. AB - INTRODUCTION: B cell activating factor (BAFF) is a ligand belonging to the tumor necrosis factor family and has an important role in B cells development, survival, and immunoglobulin-production. This study was aimed to study the association between haplotypes in the 5' regulatory region of the BAFF gene and susceptibility to idiopathic thrombocytopenic purpura (ITP). METHODS: BAFF gene polymorphisms expression at positions (-871C>T, -2701 T>A and -2841T>C) of 5' regulatory region were determined with polymerase chain reaction restriction fragment length polymorphism technique in 40 chronic (ITP) patients and in 50 age and sex-matched normal volunteers as a control group. RESULTS: The difference between chronic ITP patients and control subjects as regards -871C>T polymorphism expression was highly statistically significant with higher expression of T allele in ITP patients than control group (P < 0.001). However, the other 2 polymorphisms did not show significant difference between the 2 groups. -871C>T polymorphism was associated with increased risk of chronic ITP with an odds ratio 18.857; however, the other 2 polymorphisms were not associated with an equivalent effect. CONCLUSION: -871C>T BAFF gene polymorphism expression had a significant association with chronic ITP disease. PMID- 21537155 TI - Serum angiotensin I-converting enzyme levels and the therapeutic effects of octreotide in esophageal variceal hemorrhage. AB - INTRODUCTION: The aim of this study is to investigate the relationship between serum angiotensin I-converting enzyme (ACE) levels and therapeutic effects of octreotide in the treatment of esophageal variceal hemorrhage (EVH) as a result of liver cirrhosis. METHODS: Serum ACE levels were measured by ultraviolet light colorimetric analysis in 80 cases of liver cirrhosis with EVH before and after the treatment of various doses of octreotide (25 and 50 MUg/hr treatment in 40 cases, respectively), which were compared with 20 healthy controls. RESULTS: Between the octreotide treatment groups, there were no significant differences in the Child-Pugh score, the endoscopic severity of esophageal varices and ACE levels before octreotide treatment. Pretreatment levels of serum ACE were markedly higher in patients with EVH compared with healthy controls (P < 0.001). Serum ACE levels were significantly higher before octreotide treatment than 72 hours after treatment in patients with EVH. Serum ACE after octreotide treatment declined more evidently in the 50 MUg/hr than in the 25 MUg/hr treatment group. The hemostatic rate within 6 hours after octreotide treatment was significantly higher in the 50 MUg/hr than in the 25 MUg/hr treatment group. The rebleeding rate within 72 hours after octreotide treatment was markedly lower in the 50 MUg/hr than in the 25 MUg/hr treatment group. CONCLUSIONS: Octreotide treatment in patients with EVH can result in decreased serum ACE levels, which correlated with the dose of octreotide. The decline in serum ACE levels may be involved in the mechanisms by which octreotide lowers portal vein pressure in EVH treatment. PMID- 21537156 TI - Barriers to vaccinating the elderly with H1N1 vaccine. AB - INTRODUCTION: The development of a monovalent 2009 H1N1 influenza (swine flu) vaccine for the 2009-2010 season prompted a nationwide campaign of vaccination. The authors assessed the frequency of influenza vaccine usage among 3858 elderly patients with their practice and the most common barriers to receiving vaccine. METHODS: The authors calculated the usage of seasonal and 2009 H1N1 vaccines among seniors with their university practice and surveyed a cohort of 64 patients to determine whether they had received the 2009 H1N1 vaccine and their reasons for not receiving it. RESULTS: Of the 555 elderly vaccinated with seasonal influenza vaccine, only 18% were vaccinated with 2009 H1N1 vaccine. Among the survey cohort, 72% had not received the 2009 H1N1 vaccine; 39% of them offered no reason for refusing and 22% stated they were unaware of the need for it. CONCLUSIONS: Acceptance rates of seasonal influenza vaccine among elderly were low, and a significant proportion did not receive the 2009 H1N1 vaccine because it was unclear that they should receive it. Unambiguous education of patients and physicians is needed to achieve high rates of influenza vaccination among the elderly. PMID- 21537157 TI - Carnitine deficiency increases susceptibility to bupivacaine-induced cardiotoxicity in rats. AB - BACKGROUND: Anecdotal reports suggest that carnitine deficiency increases susceptibility to bupivacaine-induced cardiotoxicity. Bupivacaine inhibits lipid based respiration in myocardial mitochondria via inhibition of acylcarnitine exchange in rats. The authors hypothesized that carnitine deficiency increases susceptibility to bupivacaine-induced asystole in rats and that acute repletion with L-carnitine reverses this effect. METHODS: Thirty male Sprague-Dawley rats were assigned to three groups. Rats assigned to the L-carnitine-deficient and L carnitine-replete groups received subcutaneous D-carnitine on the 10 d before the experiment to induce L-carnitine deficiency. Control rats received an equal volume of subcutaneous normal saline. The rats were anesthetized and mechanically ventilated. Bupivacaine was infused intravenously at a rate of 2.0 mg . kg-1 . min-1 until asystole occurred. The L-carnitine-replete group received intravenous L-carnitine 100 mg . kg-1 immediately before bupivacaine infusion. At asystole, blood was sampled to measure bupivacaine concentration. The primary outcome was time to asystole. RESULTS: L-carnitine deficiency significantly decreased survival duration (P < 0.0001). Time to bupivacaine-induced asystole decreased by 22% (P < 0.05) in the L-carnitine-deficient group (847 s [787-898]) (median [interquartile range]) compared with controls (1,082 s [969-1,427]). Intravenous administration of L-carnitine completely reversed the reduction in time to asystole. At asystole, the median plasma bupivacaine concentration in the L carnitine-deficient group was 38% (P < 0.05) less than that in control animals. Plasma bupivacaine concentration was similar in L-carnitine-replete and control animals. CONCLUSIONS: Carnitine deficiency increased sensitivity to bupivacaine induced asystole, an effect that was reversed completely by L-carnitine repletion. This study suggests that carnitine deficiency may predispose to bupivacaine-induced cardiotoxicity. L-carnitine may have a protective role against bupivacaine cardiotoxicity. PMID- 21537159 TI - Add-on rosiglitazone therapy improves plasminogen activity and high-density lipoprotein cholesterol in type 2 diabetes mellitus. AB - Rosiglitazone is an oral hypoglycaemic agent of the thiazolidinedione group. This study aimed to assess changes in the diabetic prothrombotic state via plasminogen activity and changes in surrogate markers of atherosclerotic burden via ankle brachial pressure index (ABPI) measurements after rosiglitazone was added to a pre-existing type 2 diabetes mellitus treatment regime. A nonblinded interventional study was designed. Fifty-nine patients were enrolled. Rosiglitazone-naive patients were prescribed oral rosiglitazone 4 mg daily for 10 weeks. ABPI, plasminogen activity, glycosylated haemoglobin (HbA1c) and fasting lipid profile were measured pretreatment and post-treatment. Forty-eight patients completed the study. At the end of this study, mean plasminogen activity improvement was nearly 16% (P<0.05), mean ABPI improvement was 0.01 (P=0.439), mean HbA1c reduction was 0.51% (P<0.05), mean total cholesterol (TC) increase was 0.36 mmol/l (P<0.05), mean high-density lipoprotein cholesterol (HDL-C) increase was 0.15 mmol/l (P<0.05) and mean low-density lipoprotein cholesterol increased by 0.19 mmol/l (P=0.098). Rosiglitazone significantly improved plasminogen activity. There was also significant HbA1c reduction, and rise in both TC and HDL C. Thus, rosiglitazone potentially improves the atherosclerotic burden and prothrombotic state. In future, more studies are needed to confirm the relationship between rosiglitazone, fibrinolytic system and atheromatous reduction in type 2 diabetes mellitus. PMID- 21537160 TI - Patients with deep venous thrombosis and thrombophilia risk factors have a specific prolongation of the lag time in a chromogenic thrombin generation assay. AB - The objective of the present study was to evaluate the influence of thrombophilia risk factors on variables of a chromogenic thrombin generation assay (ETP) in a setting with acute deep venous thrombosis (DVT) and non-DVT patients. In 152 outpatients suspected for DVT, the results of thrombophilia investigations were known. In all patients, thrombin generation parameters were determined and related to the presence of thrombophilia risk factors. The thrombin generation results were divided in quartiles to calculate the odds ratio, as a measure of the association with thrombophilia risk factors, corrected for age and sex. The groups with and without DVT were analysed independently. From the 152 patients, there were 108 patients with and 44 without DVT. In the DVT-positive group, lag time was significantly prolonged (21.9 versus 20.3 s; P=0.021) in patients with known thrombophilia risk factors (n=48). The odds ratio for thrombophilia risk factors was 3.7 (95% CI 1.1-12) uncorrected and 4.3 (95% CI 1.2-16) corrected for age and sex, both P values less than 0.05. No differences in ETP parameters were observed in patients without DVT with known thrombophilia risk factors (n=32). The relationship of thrombophilia risk factors with the occurrence of a prolonged lag time in the acute phase of DVT is a new finding. Increased coagulation activation may be the consequence of the thrombophilia risk factors with this observation. To unravel whether the test expresses increased consumption or increased release of anticoagulant factors may open new ways to develop diagnostic methods to add to further refinement of exclusion algorithms for DVT. PMID- 21537161 TI - Isoelectric focusing pattern of plasminogen mutants of patients with hypoplasminogenemia: correlation of in-vitro data with computer-predicted isoelectric points (pI). AB - Plasminogen (plg), the circulating proenzyme of plasmin in blood, is a polymorphic protein and most of these natural variants have been identified using isoelectric focusing (IEF) gel electrophoresis. Here, we show that a rare plg gene polymorphism 504R/W is associated with IEF phenotype A3 on the protein level. One healthy individual with homozygous plg gene polymorphism 504W studied so far exhibited low normal plg antigen and slightly decreased plg activity, suggesting that this polymorphism is associated with (mild) hypoplasminogenemia. In addition, we present the findings of IEF phenotyping of plg mutants of 26 patients with severe hypoplasminogenemia, showing one of the following four IEF patterns: A3-like, A3A-like, B-like and AB-like. In the plasma of most compound heterozygous patients, only one of the two plg mutants was detectable by IEF electrophoresis, probably due to undetectable plasma concentration of the 2nd plg mutant. In almost all cases, pI of plg mutants and variants predicted by computer modeling were in good agreement with the observed IEF band pattern. plg phenotyping by IEF in combination with molecular genetic analysis of the plg gene is a useful approach to characterize plg mutants and variants further. PMID- 21537162 TI - Activated protein C resistance as measured by residual factor V after Russell's viper venom and activated protein C treatment analyzed as a continuous variable in multiple myeloma and normal controls. AB - Increased risk of venous thromboembolism (VTE) has been described in multiple myeloma patients, particularly when exposed to immunomodulatory drugs. Epidemiological studies have shown that monoclonal gammopathy of undetermined significance (MGUS) patients also have an increased risk of VTE compared with normal individuals. Acquired activated protein C resistance (APC-R) is an independent risk factor for VTE in hematologic malignancies. We reviewed the records of patients with multiple myeloma and MGUS for APC-R by PEFAKIT APC-R test and compared them to normal individuals. We excluded from the analysis patients with a documented factor V Leiden mutation. The PEFAKIT APC-R is a plasma-based functional prothrombin assay based on ratio of patient clotting time with and without APC. Thirty-three MGUS and 93 multiple myeloma patients were compared with 39 normal individuals. Baseline characteristics from the three groups were similar in terms of age, sex, and performance status. The median APC R for multiple myeloma, MGUS, and controls were 1, 1.06, and 1.1, respectively. Multiple myeloma patients compared to normal individuals had significantly shorter APC-R (P=0.0012). No significant difference was observed between MGUS and normal individuals (P=0.17). After analyzing APC-R values and multiple coagulation parameters, a significant inverse correlation was found between APC-R and fibrinogen (P=0.0000001) and D-dimer (P=0.045) serum levels and a direct correlation with prothrombin time value (P=0.034). The Pefakit APC-R test measured as continuous variable shows a statistically significant decrease in patients with myeloma compared to normal individuals. PMID- 21537163 TI - Examining platelet-fibrin interactions during traumatic shock in a swine model using platelet contractile force and clot elastic modulus. AB - A significant proportion of severely injured patients develop early coagulopathy, characterized by abnormal clot formation, which impairs resuscitation and increases mortality. We have previously demonstrated an isolated decrease in clot strength by thrombelastography in a swine model of nonresuscitated traumatic shock. In order to more closely examine platelet-fibrin interactions in this setting, we define the observed decrease in clot strength in terms of platelet induced clot contraction and clot elastic modulus using the Hemostasis Analysis System (HAS) (Hemodyne Inc., Richmond, Virginia, USA). Whole blood was sampled for HAS measurements, metabolic measurements, cell counts, and fibrinogen concentration at baseline prior to injury and again at a predetermined level of traumatic shock defined by oxygen debt. Male swine (N=17) received femur fracture and controlled arterial hemorrhage to achieve an oxygen debt of 80 ml/kg. Platelet counts were unchanged, but fibrinogen concentration was reduced significantly during shock (167.6 vs. 66.7 mg/dl, P=0.0007). Platelet contractile force generated during clot formation did not change during shock (11.7 vs. 10.4 kdynes, P=0.41), but clot elastic modulus was dynamically altered, resulting in a lower final value (22.9 vs. 17.3 kdynes/cm, P<0.0001). In this model of traumatic shock, platelet function was preserved, whereas terminal clot elastic modulus was reduced during shock in a manner most consistent with early changes in the mechanical properties of the developing fibrin fiber network. PMID- 21537164 TI - Sleep quality in Parkinson disease: an examination of clinical variables. AB - The etiology of sleep problems in Parkinson disease (PD) is not well understood, as they may arise from the pathology of the disease or from other disease-related factors such as motor dysfunction, dopaminergic medication, and mood disturbances. The aim of this study was to investigate factors associated with sleep, including disease-related variables such as motor symptom severity, dose of medication, and mood and disease subtypes. Thirty-five nondemented patients with PD were included. Sleep was measured using 24-hour wrist actigraphy over a 7 day period, during which time participants kept a sleep diary. Subjective sleep and arousal questionnaires included the PD Sleep Scale and Epworth Sleepiness Scale. Motor symptom severity and dopaminergic medication were significantly related to measures of sleep quality. Sex differences in sleep quality were found, with men having worse sleep quality and more excessive daytime sleepiness than women. We also found that actigraphy may serve as a useful tool for identifying individuals with possible rapid eye movement behavior disorder, a sleep disorder that has important implications in early detection of PD. PMID- 21537165 TI - Clinical trials of direct thrombin and factor Xa inhibitors in atrial fibrillation. AB - PURPOSE OF REVIEW: To review the large phase 3 clinical trials that compare direct thrombin or factor Xa inhibitors with dose-adjusted warfarin in patients with atrial fibrillation who have an increased risk of stroke. RECENT FINDINGS: In large clinical trials, the oral direct thrombin inhibitor ximelagatran and the long-acting factor Xa inhibitor idraparinux were effective for reducing the risk of thromboembolic stroke, but were not marketed because of liver toxicity and excessive bleeding, respectively. In separate clinical trials, the oral direct thrombin inhibitor dabigatran etexilate and the short-acting oral factor Xa inhibitor rivaroxaban were noninferior or superior to dose-adjusted warfarin for prevention of thromboembolic stroke and systemic embolism, without increasing the risk of bleeding, and were well tolerated. Apixaban, another oral factor Xa inhibitor, is effective in reducing thromboembolic stroke compared with aspirin alone. Results of a trial comparing apixaban with dose-adjusted warfarin are awaited. SUMMARY: Dabigatran and rivaroxaban are effective, safe alternatives to dose-adjusted warfarin for reducing thromboembolic risk in patients with atrial fibrillation at high risk of stroke. PMID- 21537166 TI - Contrast-induced nephropathy: do statins offer protection? AB - PURPOSE OF REVIEW: Contrast-induced nephropathy (CIN) is a commonly occurring complication associated with the use of contrast media in radiological studies. Various clinical studies have been reported investigating the nephroprotective role of statins. In this article, we review relevant clinical studies reported in 2010. RECENT FINDINGS: An overview of these indicates that the evidence for the use of statins specifically for offering renal protection against CIN is conflicting and inconclusive. SUMMARY: Pending large, well designed, adequately powered randomized controlled trials, it can be concluded that at present there is no definite evidence for their use in preventing CIN apart from their antiatherosclerotic use. However, using the analogy of beneficial effect of statin preloading with percutaneous coronary intervention, it can be speculated that high-dose statin may be beneficial in affording nephroprotection against CIN. PMID- 21537167 TI - Maintenance of a functional hematopoietic stem cell niche through galactocerebrosidase and other enzymes. AB - PURPOSE OF REVIEW: The maintenance of a functional hematopoietic niche is critical for modulating the fate of hematopoietic stem cells (HSCs). Several enzymes were described as essential for guaranteeing niche functionality. This review summarizes the recent findings about the role of galactocerebrosidase and other enzymes involved in the maintenance of a functional HSC niche. RECENT FINDINGS: The essential role of enzymes actively involved in the maintenance of the bone marrow microenvironment, in bone remodeling, in regulating the sympathetic innervation of the niche, and in the production and relative balance of sphingolipids active in the niche has been recently highlighted. Enzymes involved in bone remodeling modify the cell-to-cell interaction between osteoblasts and HSCs. Heparanase, neutrophil elastase, and alpha-iduronidase affect the bioavailability of key cytokines and ligands within the extracellular matrix of the niche. Moreover, galactosyltransferase and galactocerebrosidase affect the function of the sympathetic nervous system and/or the balance of bioactive sphingolipids, thus influencing the SDF-1/CXCR4 axis and the proliferation of HSCs. SUMMARY: Here, we discuss the role of different enzymes directly or indirectly influencing the niche microenvironment, and we provide a comprehensive picture of their cooperative role, together with receptors, soluble factors, and the extracellular matrix, in maintaining a functional hematopoietic niche. PMID- 21537169 TI - Superoxide flashes, reactive oxygen species, and the mitochondrial permeability transition pore: potential implications for hematopoietic stem cell function. AB - PURPOSE OF REVIEW: Reactive oxygen species (ROS) have an important function in blood cell homeostasis and hematopoietic diseases. Recent discoveries concerning how ROS are generated and regulated in mitochondria via the mitochondrial permeability transition pore (mPTP) and the new phenomenon, superoxide flashes, and ROS-induced ROS release, have not been investigated in hematopoietic stem and progenitor cells, but likely have important implications for their regulation and survival. Here we relate our opinions about these potential implications. RECENT FINDINGS: The mPTP has been recently implicated in ROS generation via binding of Stat3 transcription factor to a central component of the pore. SUMMARY: The implications of this new information for hematopoiesis regulation and transplantation methodologies could prove to be important, especially as they relate to myeloid neoplasm oncogenesis and potentially new therapeutic targets. New details about ROS production suggest that techniques for bone marrow and umbilical cord blood harvest may benefit from means to downmodulate ROS. PMID- 21537168 TI - Many mechanisms mediating mobilization: an alliterative review. AB - PURPOSE OF REVIEW: Blood cell production is maintained by hematopoietic stem cells (HSCs) that reside in specialized niches within bone marrow. Treatment with granulocyte-colony stimulating factor (G-CSF) causes HSC egress from bone marrow niches and trafficking to the peripheral blood, a process termed 'mobilization'. Although the mobilization phenomenon has been known for some time and is utilized clinically to acquire HSC for transplant, the mechanisms mediating HSC release are not completely understood. We discuss recent advances and controversies in defining the mechanisms responsible for G-CSF-induced mobilization. RECENT FINDINGS: New reports define a role for resident monocytes/macrophages in maintaining niche cells, which is diminished after G-CSF treatment, suggesting a new mechanism for mobilization. Although osteoblasts have been reported to be a primary component of the HSC niche, new results suggest a unique niche composed of innervated mesenchymal stem cells. Modulating bioactive lipid signaling also facilitates mobilization, and may define a future therapeutic strategy. SUMMARY: Hematopoietic mobilization by G-CSF is primarily mediated by alterations to the bone marrow niche by both direct and indirect mechanisms, rather than directly altering HSC function. Further understanding of the processes mediating mobilization will advance our understanding on the cellular and molecular components of the HSC niche. PMID- 21537170 TI - Implementing operational research to scale-up access to antiretroviral therapy for HIV infection: lessons learned from the Cameroonian experience. AB - PURPOSE OF REVIEW: Given the lack of evidence on how to best design and implement antiretroviral therapy (ART) scaling-up policies, operational research has seen a surge in interest. There is, however, little published information on the contribution of operational research in ART programs' implementation or in improvement of associated outcomes. The article focuses therefore on how operational research may contribute to such improvements and what the key enabling factors are for its integration into program frameworks. RECENT FINDINGS: One of the most systematic operational research linked to a national ART program on the African continent was conducted in Cameroon between 2006 and 2010. Along with operational research carried out elsewhere in Africa, it helped demonstrate that a strategy of decentralizing HIV care can increase treatment coverage and improve early access to care, while maintaining good clinical outcomes. Multipartnership between local researchers, national authorities, healthcare professionals and the civil society is the key enabling factor for the relevance of operational research and the translation of its results into policy and practice. SUMMARY: In spite of a dramatic increase in access to ART during recent years in low-income countries, the fight against HIV remains a failure in terms of the goal of breaking the pandemic dynamic. Operational research is needed more than ever to face this challenge. PMID- 21537171 TI - Bone, fracture and frailty. AB - PURPOSE OF REVIEW: This review details recent findings from cohort studies that inform the prevalence, incidence and effects of antiretroviral therapy (ART) and HIV infection on low bone mineral density (BMD), osteoporosis and fractures in different populations of HIV-infected individuals. Although ART has been spectacularly effective in prevention of disease progression and improvement in survival, the effects of ART on bone health require more research. RECENT FINDINGS: Both HIV infection and ART are associated with significant bone loss in HIV-infected individuals. The clinical consequence of low BMD, fragility fractures are more common in older HIV patients, but the significance of low BMD remains unclear in younger individuals. Vitamin D deficiency is common, but the prevalence is no different to the general population, and no effect on BMD has been noted in cross-sectional studies. Frailty occurs at a prevalence of about 10% and is related to impaired immunity. SUMMARY: This review examines the contributions from recent cohort studies to the understanding of the pathogenesis of bone loss in HIV, and the complex and poorly understood relationship between the effects of HIV and that of ART on bone loss. PMID- 21537173 TI - HDL scavenger receptor class B type I and platelet function. AB - PURPOSE OF REVIEW: HDL cholesterol levels have been inversely correlated with thrombosis and HDL has been shown to mediate various antithrombotic effects. However, molecular mechanisms underlying the suppressing effect of HDL on platelet reactivity are not completely understood. The present review summarizes the recent advancements in understanding the role played by scavenger receptor class B type I (SR-BI) - an HDL receptor - in modulating platelet function and mediating platelet-HDL interactions. RECENT FINDINGS: SR-BI is expressed on platelet surface and platelets from SR-BI knockout animals are characterized by increased free-to-total cholesterol ratio, abnormal morphology, increased reactivity to strong platelets agonists, enhanced adherence to immobilized fibrinogen, and a propensity to form arterial thrombi. Crossover incubation experiments and a bone marrow transplantation approach reveal increased wild-type platelet reactivity in plasma from SR-BI mice and normal or decreased SR-BI deficient platelet reactivity in wild-type plasma. A similar functional platelet phenotype has been observed in human carriers of an SR-BI genetic variant. SR-BI ligands interfere with HDL binding to murine platelets and impede the agonist induced platelet activation as effectively as native HDL. The inhibitory effects of native HDL, moderately oxidized HDL, and SR-BI ligands are abolished in SR-BI deficient platelets but not in CD36-deficient platelets. SUMMARY: SR-BI exerts an indirect influence on platelet reactivity via maintaining normal plasma cholesterol homeostasis. In addition, SR-BI is a functional receptor for native and moderately oxidized HDL on platelets that generates an inhibitory signal for platelet activation. PMID- 21537172 TI - MSM: resurgent epidemics. AB - PURPOSE OF REVIEW: The present review discusses the recent finding on behavioral risk factors for HIV transmission from cohort studies in MSM. RECENT FINDINGS: HIV incidence among MSM has been increasing in many countries around the world. Some data support early detection and widespread use of antiretroviral treatment (ART) to decrease HIV incidence. However, suboptimal ART adherence could lead to relapse of viremia and new transmission events. Condom use for unprotected anal sex among MSM remains an important prevention tool, but use remains low in many parts of the world. Seroadaptive behaviors by MSM, such as serosorting, may also decrease condom use. However, when serosorting is practiced by MSM who receive frequent HIV testing, the risk of HIV acquisition is reduced. Serosorting and other characteristics of sexual networks, such as concurrency, may be major determinants of transmission for HIV and sexually transmitted infections among MSM. Worldwide, detailed evaluation of the factors related to rising MSM HIV incidence, as well as access to testing and care, is limited by stigma and criminalization of HIV and homosexuality. SUMMARY: Cohort studies of MSM remain an important strategy to characterize the behavioral factors that drive HIV transmission and how use of ART for prevention and treatment may affect both the risk of HIV transmission and acquisition by MSM. PMID- 21537174 TI - Profiling the regulatory lipids: another systemic way to unveil the biological mystery. AB - PURPOSE OF REVIEW: The regulatory lipids are a class of bioactive lipids which regulate various important biological processes. Profiling these regulatory lipids is an attractive method to understand the role of these metabolites. This is especially true because most of these regulatory lipids are derived from several important pharmacological targets: cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes. This review highlights the development of methods to profile these regulatory lipids and the recent publications employing these profiling methods. RECENT FINDINGS: The recent development of methods for the profiling of regulatory lipids target two different directions: to expand coverage for discovery studies (fingerprinting) and to make the quantitative method more accurate, sensitive, and faster for diagnostic or more detailed studies. Recent applications of these profiling methods including assessment of in-vivo drug engagement, pathways crosstalk, and possible mechanisms for side effects of a withdrawn anti-inflammatory drug rofecoxib are also reviewed here. SUMMARY: The profiling of regulatory lipids is a useful tool for many investigations. The breadth of coverage, throughput limits with detection, and reproducibility of quantitation are being improved. The resulting data will assist with fundamental investigation, disease biomarker discovery, drug discovery, and drug development. PMID- 21537175 TI - Metabolic and functional relevance of HDL subspecies. AB - PURPOSE OF REVIEW: Our purpose is to review recent findings highlighting the metabolic and functional diversity of HDL subspecies. RECENT FINDINGS: HDL heterogeneity - both structural and functional - is the main focus of this review. Recent work indicates that the metabolism and functionality of HDL particles differ greatly among HDL subspecies. With the introduction of new and improved methodology (e.g., proteomics), new aspects of the structural complexity and functionality of HDL have been revealed. It has been confirmed that HDL functions - including, but not limited to decreasing inflammation, apoptosis, macrophage adhesion to the endothelium and insulin resistance - are due to HDL's ability to remove cholesterol from cells (reverse cholesterol transport). A new level of HDL complexity has recently been revealed by investigating the lipid composition of HDL with gas chromatography, gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. There are about 100 different HDL associated proteins; however, there are many more lipid species potentially associated with HDL particles. SUMMARY: The most important recent findings disclose that HDL is more complex than previously thought. HDL subclasses differ in physical-chemical properties, protein and lipid composition, metabolism, physiological functions and pathophysiological significance. The staggering complexity of HDL demands significantly more investigation before we can truly begin to understand HDL metabolism and function in humans. PMID- 21537176 TI - Extracellular matrix calcification in chronic kidney disease. AB - PURPOSE OF REVIEW: Extracellular matrix (ECM) mineralization occurring in soft tissues such as blood vessels is highly prevalent in patients with chronic kidney disease. This problem is now recognized as an active and regulated process involving a complex interaction of inducers and inhibitors. This review outlines new findings on calcification at the level of the ECM, with a focus on recent studies evaluating the pathogenesis of calcification of the vasculature. RECENT FINDINGS: Mechanisms promoting vascular calcification include dysregulation of mineral metabolism, especially high levels of phosphate and calcium, release of membrane-bound matrix vesicles from vascular smooth muscle cells (VSMCs), and formation of apoptotic bodies. Subsequent changes in the phenotype of VSMCs to osteoblast-like cells follow, inducing ECM formation and attracting local factors involved in the mineralization process (similar to the process of bone formation). Along with the loss of various calcification inhibitors, there is also likely a role for elastin and elastin-degrading enzymes, sodium-phosphate co transporters, and the transmembrane protein klotho, as potential key regulators of ECM calcification. SUMMARY: Mechanisms of ECM calcification are not completely understood, although likely to be multifactorial. Increasing insight provides potential therapeutic options to reduce the burden of ectopic calcification and subsequent cardiovascular morbidity and mortality. PMID- 21537177 TI - Caenorhabditis elegans, a model organism for kidney research: from cilia to mechanosensation and longevity. AB - PURPOSE OF REVIEW: The introduction of Caenorhabditis elegans by Sydney Brenner to study 'how genes might specify the complex structures found in higher organisms' revolutionized molecular and developmental biology and pioneered a new research area to study organ development and cellular differentiation with this model organism. Here, we review the role of the nematode in renal research and discuss future perspectives for its use in molecular nephrology. RECENT FINDINGS: Although C. elegans does not possess an excretory system comparable with the mammalian kidney, various studies have demonstrated the conserved functional role of kidney disease genes in C. elegans. The finding that cystic kidney diseases can be considered ciliopathies is based to a great extent on research studying their homologues in the nematode's ciliated neurons. Moreover, proteins of the kidney filtration barrier play important roles in both correct synapse formation, mechanosensation and signal transduction in the nematode. Intriguingly, the renal cell carcinoma disease gene product von-Hippel-Lindau protein was shown to regulate lifespan in the nematode. Last but not least, the worm's excretory system itself expresses genes involved in electrolyte and osmotic homeostasis and may serve as a valuable tool to study these processes on a molecular level. SUMMARY: C. elegans has proven to be an incredibly powerful tool in studying various aspects of renal function, development and disease and will certainly continue to do so in the future. PMID- 21537178 TI - Adjuvant treatment of colon cancer: what is next? AB - PURPOSE OF REVIEW: Since 2003, fluorouracil/leucovorin plus oxaliplatin (FOLFOX) has been the standard of care in adjuvant therapy. This review reports the results of recent phase III trials which have attempted to improve upon the existing standard of care in adjuvant therapy. In addition, we examine how results of these trials have shaped our knowledge and outline directions for future research. RECENT FINDINGS: The demonstrated efficacy of adding irinotecan, bevacizumab, or cetuximab to fluorouracil-based regimens in the treatment of patients with metastatic colorectal cancer led to several multicenter phase III trials investigating the efficacy of these agents in the adjuvant setting. In the last 2 years, all of these trials have reported failures to improve patient outcomes, and the field has remained essentially static. SUMMARY: Negative results from multiple phase III trials suggest that the existing paradigm for the selection of agents to use in adjuvant trials is deeply flawed. Moving forward, we need to ensure mechanistic rationale for clinical trial design and reassess whether disease-free survival is the primary endpoint that should be used to evaluate biologic agents. Future research should be directed toward the development of prognostic and predictive markers for the development of a data driven roadmap to inform risk stratification and therapeutic decision-making. PMID- 21537179 TI - Screening for distress: a role for oncology nursing. AB - PURPOSE OF REVIEW: Interest in screening for distress in cancer patients has escalated in recent years. Despite widespread acknowledgement that screening ought to occur in daily practice, relatively few examples of successful programs exist. RECENT FINDINGS: Evidence about the need for identifying psychosocial distress is clear and there are suitable tools available to perform the screening. However, understanding about the complexities of implementing a practically sound and relevant program is still unfolding. Concerted and consistent efforts are required to achieve success in screening for distress and realize relevant outcomes. SUMMARY: This article outlines a review of recent literature on screening for distress and the role of oncology nursing. Significant developments in the field of screening for distress in cancer are highlighted and on-going controversies are described. Suggestions for future research and clinical practice are presented. PMID- 21537180 TI - Prophylaxis and treatment of dermatologic adverse events from epidermal growth factor receptor inhibitors. AB - PURPOSE OF REVIEW: As the number and uses for targeted therapies such as epidermal growth factor receptor inhibitors (EGFRIs) increase, so does the need to recognize and treat the dermatologic side-effects of these agents. Although agents such as gefitinib, erlotinib, cetuximab, lapatinib, and panitumumab have less systemic side-effects than traditional cytotoxic chemotherapy, dermatologic adverse events from EGFRIs are significantly more common. These dermatologic toxicities have previously led to reduction or cessation of therapy and recently have been shown to decrease patients' quality of life. RECENT FINDINGS: This review provides a symptom-based treatment approach to the common dermatologic adverse effects seen with the epidermal growth factor receptor antagonists: papulopustular rash, xerosis, pruritus as well as hair, nail, and mucosal changes. Each dermatologic toxicity is described; prophylaxis and treatment options, from topical to systemic, are presented based on a review of the current literature with emphasis on new clinical trials results. We also provide specific recommendations based on our practice in a specialty clinic. SUMMARY: Although the field continues to evolve, this review presents the most up-to-date information on managing dermatologic adverse effects of EGFRIs. Practitioners should find this article to be a practical resource in approaching patients on EGFRIs with dermatologic toxicities. As we learn how to optimally manage the adverse effects of these agents, we practitioners have the opportunity to increase patients' quality of life and decrease reductions or cessations of life prolonging therapy. PMID- 21537181 TI - MMP-9 and the perioperative management of LASIK surgery. AB - PURPOSE OF REVIEW: Hyperosmolarity is a central mechanism causing ocular surface inflammation and eye irritation in typical patients suffering from tear dysfunction. Tear composition in dry eyes, or dysfunctional tear syndrome, may destabilize the tear film and cause ocular surface epithelial disease. Increased activity of matrix metalloproteinases (MMPs), especially MMP-9, plays a critical role in wound healing and inflammation and is primarily responsible for the pathologic alterations to the ocular surface that leads to a dysfunctional tear state. RECENT FINDINGS: Altered corneal epithelial barrier function is the cause for ocular irritation and visual morbidity in dry eye disease. The increased MMP 9 activity in dry eyes may contribute to deranged corneal epithelial barrier function, increased corneal epithelial desquamation, and corneal surface irregularity. SUMMARY: Dry eye is one of the most common complications of photorefractive keratectomy and laser in-situ keratomileusis (LASIK). LASIK has both a neurotrophic effect on the cornea and leads to a physical change in corneal shape that results in a change in tear dynamics, leading to ocular surface desiccation. The reduction in tear function after LASIK may induce an increase in osmolarity and consequently raise the concentration of proinflammatory cytokines and MMP-9 in the tear film, which results in dry eyes and insufficient attachment between the corneal flap and the corneal bed. Appropriate diagnosis and management of dysfunctional tear syndrome may lead to less postoperative LASIK complications. PMID- 21537182 TI - New hopes and strategies for the treatment of severe ocular surface disease. AB - PURPOSE OF REVIEW: Severe ocular surface diseases (OSDs) are some of the most challenging entities facing the clinician today. This article aims to describe the recent advances and current development of ocular surface reconstruction from both basic science and clinical aspects. RECENT FINDINGS: To date, many candidate corneal epithelial stem or progenitor cell markers for culture grafts have been reported worldwide. Several groups have reported the long-term results of cultivated corneal and oral mucosal epithelial transplantation in severe OSD. In their attempt to further develop the system of ocular surface reconstruction, several groups recently reported using cells obtained from a novel origin, cell substrates, and safer culture procedures. SUMMARY: Autologous cultivated corneal limbal epithelial transplantation has been shown to be a well tolerated and promising treatment for patients with severe OSD. A newly developed transplantation technique using tissue-engineered epidermal adult stem cells, immature dental pulp stem cells, and hair follicle bulge-derived stem cells was reportedly successful for the reconstruction of corneal epithelium in an animal model of severe OSD. The recombinant human cross-linked collagen scaffold and a Food and Drug Administration-approved contact lens are also promising new techniques for successfully achieving ocular surface reconstruction. PMID- 21537183 TI - Corneal calcific band keratopathy. AB - PURPOSE OF REVIEW: Calcific band keratopathy is a chronic degenerative condition characterized by the deposition of grayish to whitish opacities in the superficial layers of the cornea. It is usually associated with chronic ocular inflammatory conditions. Various treatment modalities have been used for the management of band keratopathy including mechanical debridement, chelation, and excimer laser phototherapeutic keratectomy (PTK). This review will discuss the cause and management of calcific band keratopathy. RECENT FINDINGS: Recent use of combination treatments such as chelation, excimer laser, and amniotic membrane transplantation has renewed interest in the management of cases with band keratopathy in order to achieve faster epithelial healing and better postoperative outcomes. SUMMARY: Careful case selection is required before deciding on the surgical management plan in cases with band keratopathy. Chelation is a cost-effective and straightforward procedure. An excimer laser PTK, although costly, can provide a smooth corneal surface. Combination treatment using amniotic membrane is reserved for selected cases to enhance epithelial healing. PMID- 21537184 TI - Expanding indications for the Boston keratoprosthesis. AB - PURPOSE OF REVIEW: To review emerging indications for the Boston keratoprosthesis (KPro) and to discuss current research underway to improve clinical outcomes. RECENT FINDINGS: In addition to multiple failed corneal grafts, other ocular conditions for which the Boston KPro has been used include herpetic keratitis, aniridia, autoimmune ocular disorders, and pediatric corneal opacities. In the recent years, the KPro has been implanted for various other conditions and has also been explored as a cost-effective treatment for severe corneal diseases internationally. Cicatricial and inflammatory ocular conditions remain the most difficult cases for KPro use but studies investigating various immunomodulators and biologic materials for improved retention are ongoing. Postoperative management of glaucoma is critical for preserving the visual gains achieved with the Boston KPro. Current studies are evaluating novel devices for intraocular pressure measurement. SUMMARY: Accrued experience with the Boston KPro has demonstrated its versatility but also the difficulties that remain in postoperative management. With many studies underway to improve cost effectiveness, intra-operative and postoperative management, keratoprostheses will be made increasingly available to those countries most in need. PMID- 21537185 TI - Adenovirus advances: new diagnostic and therapeutic options. AB - PURPOSE OF REVIEW: Adenoviral infection is common, can be severe, and may cause significant morbidity. RECENT FINDINGS: Ophthalmologists and optometrists are often guilty of spreading adenovirus because it is highly contagious and has 53 serotypes with variable morphology. Adenovirus is often difficult to diagnose based on clinical appearance and, in the early stages, is associated with a red eye or superficial keratitis common to herpes and other infections. This difficulty results in the indiscriminate use of antibiotics, which are expensive and of no established value in treating a viral infection. The difficulty of accurate diagnosis also makes the use of newer proposed treatments less valuable and even potentially hazardous. SUMMARY: New diagnostic tests such as the Rapid Pathogen Screening (RPS) Adeno Detector that are practical, rapid, and inexpensive to use in the office may obviate these problems. PMID- 21537186 TI - Applications of the femtosecond laser in corneal refractive surgery. AB - PURPOSE OF REVIEW: The femtosecond laser has become a rapidly and widely adopted technology for surgeons performing refractive surgery. With the advances in femtosecond lasers, clinical outcomes and safety with their use have improved. The purpose of this review is to outline the current surgical applications of the femtosecond laser in corneal refractive surgery. RECENT FINDINGS: Many surgeons have adopted femtosecond technology for the creation of the laser in-situ keratomileusis flap secondary to its improved safety, precision and reproducibility. Other applications include astigmatic keratotomy, channel creation for the insertion of intrastromal corneal ring segments, femtosecond lenticule extraction, facilitating the insertion of corneal inlays as well as in intrastromal presbyopia correction (IntraCOR). Further novel applications continue to be developed. SUMMARY: This review outlines the recent advances and applications of the femtosecond laser in corneal refractive surgery. PMID- 21537187 TI - Refractive surgery: a treatment for and a cause of strabismus. AB - PURPOSE OF REVIEW: The purpose of this article is to review refractive surgery as a means of treatment for strabismus and as a potential cause of strabismus and binocular diplopia. RECENT FINDINGS: Numerous studies have reported that refractive surgery is effective in correcting certain types of strabismus such as accommodative and partially accommodative esotropia. Studies on the treatment of exotropia related to anisometropia have demonstrated less favorable outcomes. In patients without manifest strabismus preoperatively, recent studies have shown that strabismus and diplopia can occur after refractive surgery. Appropriate clinical testing and risk stratification are essential to determine whether a patient is at increased risk for postoperative strabismus and diplopia. SUMMARY: Refractive surgery can be useful in patients with accommodative and partially accommodative esotropia. A thorough history and clinical examination is extremely important to expose potential risk factors in all patients undergoing refractive surgery. Based on the designated risk level, more advanced testing may be warranted. PMID- 21537188 TI - LASIK interface keratitis: epidemiology, diagnosis and care. AB - PURPOSE OF REVIEW: Diffuse lamellar keratitis (DLK) is one of the more common interface complications occurs after laser in-situ keratomileusis (LASIK). The diagnosis can sometimes be challenging, as the differential diagnosis includes infectious keratitis, which requires a completely different treatment compared to DLK. This review assesses our current knowledge of the epidemiology, diagnosis and treatment of DLK. RECENT FINDINGS: DLK occurs during the immediate postoperative period, but there are also late-onset cases. Early cases can occur in outbreaks, related to exogenous factors. Late-onset cases are most often related to inciting factors. Over time, case reports and series have reported DLK onset occurring further after surgery. It is probable that additional inciting factors will also be reported over time. Visual outcomes following DLK tend to be good when the condition is diagnosed properly and treated with intensive topical or systemic steroids, possibly combined with interface irrigation. SUMMARY: DLK is a well recognized and well described complication occurring after LASIK. Associated inciting and risk factors and treatment algorithms have been described, but additional questions remain. Our knowledge and our patients will benefit from further research and development of evidence-based treatments. PMID- 21537189 TI - Cell signaling molecules as drug targets in lung cancer: an overview. AB - PURPOSE OF REVIEW: Lung being one of the vital and essential organs in the body, lung cancer is a major cause of mortality in the modern human society. Lung cancer can be broadly subdivided into nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Although NSCLC is sometimes treated with surgery, the advanced and metastatic NSCLC and SCLC usually respond better to chemotherapy and radiation. The most important targets of these chemotherapeutic agents are various intracellular signaling molecules. The primary focus of this review article is to summarize the description of various cell signaling molecules involved in lung cancer development and their regulation by chemotherapeutic agents. RECENT FINDINGS: Extensive research work in recent years has identified several cellular signaling molecules that may be intricately involved in the complexity of lung cancer. Some of these cell signaling molecules are epidermal growth factor receptors, vascular endothelial growth factor receptors, mammalian target of rapamycin, mitogen-activated protein kinase phosphatase-1, peroxisome proliferator-activated receptor-gamma, matrix metalloproteinases and receptor for advanced glycation end-products. SUMMARY: The present review will strengthen our current knowledge regarding the efficacy of the above-mentioned cell signaling molecules as potential beneficial drug targets against lung cancer. PMID- 21537191 TI - The diminishing role of surgery in pleural disease. AB - PURPOSE OF REVIEW: Pleural disease is common. Traditionally, many patients were subjected to surgery for diagnosis and treatment. Most pleural surgical procedures have not been subjected to high-quality clinical appraisal and their use is based on anecdotal series with selection bias. The evidence (or the lack) of benefits of surgery in common pleural conditions is reviewed. RECENT FINDINGS: Recent studies do not support the routine therapeutic use of surgery in patients with malignant pleural effusions, empyema or mesothelioma. Four randomized studies have failed to show significant benefits of thoracoscopic poudrage over bedside pleurodesis. Surgery as first-line therapy for empyema was studied in four randomized studies with mixed results and no consistent benefits. Cumulative evidence suggests that radical surgery in mesothelioma, especially extrapleural pneumonectomy, is not justified. Advances in imaging modalities and histopathological tools have minimized the need for surgery in the workup of pleural effusions. Complications associated with surgery are increasingly recognized. SUMMARY: Surgery has associated perioperative risks and costs, and residual pain is not uncommon. Many conventional pleural surgeries have not been assessed in randomized studies. Pulmonologists should be aware of the evidence that supports surgical interventions, or the lack of it, in order to make informed clinical decisions and optimize patient care. PMID- 21537192 TI - Prolapse surgery: which technique and when? AB - PURPOSE OF REVIEW: More answers are nowadays available about certain aspects of pelvic organ prolapse (POP) treatment. In this overview some of those aspects are addressed that were considered important and published in 2010. RECENT FINDINGS: When stress urinary incontinence (SUI) is present concomitant with POP the strategy is still to perform an additional procedure for SUI. If there is no SUI the tendency is only to correct the POP. With masked SUI no firm conclusions can be drawn.The studies that look at mesh for POP provide some careful conclusions. Absorbable biomeshes do not have many benefits over repairs without mesh in the long term. Nonresorbable mesh tends to give better results but also higher complication rates and should be applied with care.A last item is how to perform a sacrocolpopexy. Laparoscopic sacrocolpopexy is a well tolerated but time consuming and difficult procedure to treat prolapse. Comparison with other conventional techniques is lacking. Robotic surgery has the potential of enhancing the widespread introduction of laparoscopic procedures. SUMMARY: With these findings a better evidence-based choice for surgical technique can be made with regards to POP with or without SUI, the kind of mesh to use and which sacrocolpopexy technique should be chosen. PMID- 21537190 TI - Lung cancer and its association with chronic obstructive pulmonary disease: update on nexus of epigenetics. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) and lung cancer are the leading causes of morbidity and mortality worldwide. The current research is focused on identifying the common and disparate events involved in epigenetic modifications that concurrently occur during the pathogenesis of COPD and lung cancer. The purpose of this review is to describe the current knowledge and understanding of epigenetic modifications in pathogenesis of COPD and lung cancer. RECENT FINDINGS: This review provides an update on advances of how epigenetic modifications are linked to COPD and lung cancer, and their commonalities and disparities. The key epigenetic modification enzymes (e.g. DNA methyltransferases -- CpG methylation, histone acetylases/deacetylases and histone methyltransferases/demethylases) that are identified to play an important role in COPD and lung tumorigenesis and progression are described in this review. SUMMARY: Distinct DNA methyltransferases and histone modification enzymes are differentially involved in pathogenesis of lung cancer and COPD, although some of the modifications are common. Understanding the epigenetic modifications involved in pathogenesis of lung cancer or COPD with respect to common and disparate mechanisms will lead to targeting of epigenetic therapies against these disorders. PMID- 21537193 TI - An update on surgery for vesicovaginal and urethrovaginal fistulae. AB - PURPOSE OF REVIEW: This review offers a comprehensive summary of the recent publications on the treatment of vesicovaginal fistula. Most reports are related to obstetric fistula in the developing world but in the developed world fistula treatment remains a challenge. RECENT FINDINGS: The quality of the research in this field is improving. Efforts are being made to improve the classification of fistula as a prognostic tool. Surgical innovations are few in this field. Laparoscopic approaches are reported but only on a very limited amount of patients. SUMMARY: The surgical management of fistula remains a two-track item: the gigantic experience on obstetric fistula of fistula surgeons in Africa and Asia and the limited experience of some Western centres with mostly a small series of iatrogenic fistula. Advances are made in both worlds. The previously isolated fistula surgeons are now better organized and they stimulate scientific research in countries with very limited resources. The centres in the developed world explore new surgical approaches such as laparoscopy and minimally invasive treatments. PMID- 21537194 TI - The afferent system and its role in lower urinary tract dysfunction. AB - PURPOSE OF REVIEW: Lower urinary tract disorders such as overactive bladder syndrome (OABS) and interstitial cystitis/painful bladder syndrome (IC/PBS) are debilitating conditions with serious adverse effects on quality of life. Common to both OABS and IC/PBS are the sensory symptoms of urgency and frequency, implicating the afferent system in the aetiology of these disorders. Thus, understanding the role that afferent pathways play in the function of the lower urinary tract is the focus of much current research. This review aims to provide an insight into the recent advances in this field. RECENT FINDINGS: Sensory transduction in the bladder is not only mediated by direct activation of the afferents via a host of receptors and ion channels located on the afferent terminal but also may be attributed to the interplay between the urothelium and the release of urothelially derived mediators. Recent studies provide compelling evidence to support this concept and highlight the complex nature of the bladder afferent system. SUMMARY: Recent studies provide further evidence that afferent control of the bladder may be dependent on integration of excitatory and inhibitory mediators from the urothelium such as ATP and nitric oxide. A number of studies have examined the role cholinergic and adrenergic mechanisms play in bladder afferent function, and several new potential mechanisms involving the cannabinoid receptors and transient receptor potential channels have emerged as areas which warrant further investigation. A better understanding of afferent mechanisms in the bladder will hopefully lead to more effective treatments of lower urinary tract disorders. PMID- 21537195 TI - The "snowtacular". PMID- 21537196 TI - The Berlin questionnaire screens for obstructive sleep apnea in idiopathic intracranial hypertension. AB - BACKGROUND: Obstructive sleep apnea (OSA) may be associated with idiopathic intracranial hypertension (IIH), a disorder most commonly occurring in young obese women. Because polysomnography, the standard test for diagnosing OSA, is expensive and time consuming, questionnaires have been developed to identify persons with OSA. The Berlin questionnaire (BQ) reliably identifies middle-aged and older persons in the community who are at high-risk for OSA. We aimed to validate the BQ as a screening tool for OSA in IIH patients. METHODS: Patients with newly diagnosed IIH completed the BQ and then underwent diagnostic polysomnography. The BQ was scored as high or low risk for OSA, and the diagnosis of OSA was based on polysomnography findings. OSA was defined as an apnea hypopnea index of >= 5 on polysomnography. RESULTS: Thirty patients were evaluated (24 women; 15 white and 15 black; age, 16-54 years [median, 32 years]; body mass index, 27.3-51.7 kg/m2 [median, 39.8 kg/m2]). Twenty patients (66.7%) had a high-risk BQ score and 18 (60%) exhibited OSA. Fifteen of 20 (75%) with a high-risk BQ score had OSA, while 3 of 10 (30%) with a low-risk score had OSA (Fisher test, P = 0.045). The sensitivity and specificity of the BQ for OSA in IIH patients were 83% and 58%, respectively, whereas the positive predictive value was 75%. CONCLUSION: A low-risk BQ score identifies IIH patients who are unlikely to have OSA. Polysomnography should be considered in those with a high risk score. PMID- 21537197 TI - Shift work and sleep: optimizing health, safety, and performance. AB - Shift work is a fundamental component of the US workforce and an integral part of the lifestyles of a large proportion of the population. More than 22 million Americans work on shifts as part of their work life. Emerging research suggests that shift workers are at higher risk for a range of metabolic disorders and diseases (eg, obesity, cardiovascular disease, peptic ulcers, gastrointestinal problems, abnormal blood glucose levels, and metabolic syndrome). Sleep disorders associated with shift work also pose a serious public health risk, as they can impair an individual's ability to perform effectively and may lead to occupational and traffic accidents. PMID- 21537198 TI - Online medication error graphic reports: a pilot in North Carolina nursing homes. AB - OBJECTIVES: Since 2003, North Carolina nursing homes have been required by state law to report all medication errors, but the nursing homes have not had usable and timely access to their own error data. We created and pilot tested a new online graphic reporting feature to give homes practical and timely reports on their own reported errors for use in improving medication processes. METHODS: The new graphic reports feature was added to the existing online reporting system and provides immediate access to a set of tables and graphs on all submitted errors. Fifteen nursing homes were recruited to participate in a pilot test of the graphic reports. Key informant interviews were conducted to gather in-depth qualitative information on the use of the reports. RESULTS: The reports were used primarily for providing information to members of the quality assurance committee and for staff training. Sites had very few technical problems accessing or printing the reports and were able to view them on existing computer systems. Sites with significant numbers of submitted errors in the system reported greater usefulness of the graphics than sites with few errors. Staff turnover at the director of nursing position was the most common reason for low participation at some sites. CONCLUSIONS: The online graphic reports are a positive, user-friendly next step in providing information to the nursing homes to use in improving patient safety. The information is deemed by the users to be the right content, professional in appearance, and accessible to the nursing home. PMID- 21537199 TI - Developing and testing a tool to measure nurse/physician communication in the intensive care unit. AB - OBJECTIVES: The purpose of this study, conducted in 3 intensive care units (ICUs) at 1 Department of Veterans Affairs Medical Center, was to develop tools and procedures to measure nurse/physician communication in future studies. METHODS: We used mixed methods in a multistaged approach. Qualitative data came from 4 observations of patient care rounds and 8 interviews with nurses and physicians. Quantitative data came from anonymous surveys distributed to nurses in all 3 ICUs (n = 66). We administered the Safety Organizing Scale to measure nurses' self reported behaviors that enable a safety culture. Analysis of variance was the main statistical test. RESULTS: Qualitative data were used to create an observation data collection tool and a working protocol, to measure nurse/physician communication in a future study. Analysis of variance revealed significant differences between the 3 units (f = 4.57, P = 0.02). There also were significant differences on 4 of 9 items of the Safety Organizing Scale. Using mixed methods, we gained multiple perspectives that helped us to clarify and validate the context and content of communication. Quantitative analysis showed significant differences between the 3 ICUs in nurses' perceptions of a safety culture. According to qualitative analyses, nurses from the unit which reported the weakest safety culture also were the least satisfied in their communication with physicians. Qualitative analyses corroborated quantitative findings and demonstrated the importance of contextual influences on nurse/physician communication. CONCLUSIONS: Through the tools and protocol we created, more realistic strategies to promote effective communication between nurses and physicians may be developed and tested in future studies. PMID- 21537200 TI - Failed operative treatment in two cases of pseudarthrosis of the clavicle using internal fixation and bovine cancellous xenograft (Tutobone). AB - The most commonly reported technique of reconstructive surgery for congenital pseudarthrosis of the clavicle involves resection of the pseudarthrosis, insertion of autologous iliac crest bone graft and internal fixation. In an attempt to avoid the potential complications of iliac crest bone graft harvest we used bovine cancellous xenograft (Tutobone). Two cases of pseudarthrosis of the clavicle treated with resection of the pseudarthrosis, Tutobone graft and internal fixation are presented. Both cases resulted in treatment failures, which were associated with significant osteolysis and failure of incorporation of the graft material. This required removal of the loose metal work and debridement of the failed graft material. We would caution surgeons against the use of Tutobone as a graft material in the surgical management of pseudarthrosis of the clavicle. The level of evidence was level IV case series. PMID- 21537201 TI - Bilateral femoral neck fracture in a child: a 17-year follow-up. AB - A long-term follow-up of bilateral femoral neck fracture is presented. The patient sustained the injury in a road accident at the age of five. Both fractures were Delbet type III. Three days after the injury, open reduction and internal fixation were performed. A hip spica cast was applied for 8 weeks. Follow-up radiographs show uneventful healing, with no avascular necrosis of the femoral head. The initial shortening of the right proximal femur persisted. The left femur shows extensive remodeling of the femoral head toward valgus. The patient is painless and currently does some sports. PMID- 21537202 TI - A case of slipped upper femoral epiphysis in a nonambulant patient with cerebral palsy. PMID- 21537203 TI - Clinical examination is highly sensitive for detecting clinically significant spinal injuries after gunshot wounds. AB - BACKGROUND: The optimal method for spinal evaluation after penetrating trauma is currently unknown. The goal of this study was to determine the sensitivity and specificity of a standardized clinical examination for the detection of spinal injuries after penetrating trauma. METHODS: After Institutional Review Board approval, all evaluable penetrating trauma patients aged 15 years or more admitted to the Los Angeles County + University of Southern California Medical Center were prospectively evaluated for spinal pain, tenderness to palpation, deformity, and neurologic deficit. RESULTS: During the 6-month study period, 282 patients were admitted after sustaining a penetrating injury; 143 (50.7%) as a result of gunshot wound (GSW) and 139 (49.3%) as a result of stab wound (SW). None of the patients sustaining a SW had a spinal injury. Of the 112 evaluable GSW patients, 9 sustained an injury: 6 with a true-positive and 3 with a false negative clinical examination. The overall sensitivity, specificity, positive predictive value, and negative predictive value were 66.7%, 89.6%, 46.2% and 95.2%, respectively. For clinically significant injuries requiring surgical intervention, cervical or thoracolumbar spine orthosis, or cord transections, however, the sensitivity of clinical examination was 100.0%, specificity 87.5%, positive predictive value 30.8%, and negative predictive value 87.5%. CONCLUSION: Clinically significant spinal injury, although rare after SWs, is not uncommon after GSWs. A structured clinical examination of the spine in evaluable patients who have sustained a GSW is highly reliable for identifying those with clinically significant injuries. PMID- 21537204 TI - The initial anatomical severity in patients with hand injuries predicts future health-related quality of life. AB - BACKGROUND: There have been no rigorous studies exploring whether the severity of hand injury can predict health-related quality of life (HRQoL). The purpose of our study is to examine the relationship between the initial anatomic severity of hand injuries (evaluated by the Hand Injury Severity Scoring [HISS] system) and HRQoL in patients with hand injuries. METHODS: Patients with hand injuries hospitalized for surgery between 2004 and 2008 were recruited and HISS scores were calculated by a hand surgeon. One hundred seventy-three patients were interviewed for demographic information and HRQoL status. The physical and mental component summaries of HRQoL were compared with the initial HISS scores by multiple regression models. RESULTS: The greater the HISS score, the lower the score of the physical component of HRQoL. Trend tests showed a significant correlation between the physical component of HRQoL in the dominant hand injured group (p = 0.04), but not in the nondominant hand injured group (p = 0.49). With regard to age, trend tests showed a significant correlation between the physical component of HRQoL in older patients (p < 0.01) but not in younger patients (p = 0.40). For all outcomes of mental component scores, we found no significant relationship with HISS severity in neither main effects nor stratified analyses. CONCLUSIONS: HISS is able to predict the physical HRQoL with useful levels of accuracy. It is strongly recommended that surgical therapy departments provide more detailed physiotherapy programs for the high-risk groups, such as dominant hand injury and age of >=40, to improve their physical HRQoL. PMID- 21537205 TI - Incidental Findings on Routine Thoracoabdominal Computed Tomography in Blunt Trauma Patients. AB - BACKGROUND:: Thoracoabdominal MultiDetector-row Computed Tomography (MDCT) is frequently used as a diagnostic tool in trauma patients. One potential side effect of performing MDCT is the detection of incidental findings and their subsequent consequences on medical treatment. The objective was to evaluate frequency and effects of incidental findings in trauma patients. METHODS:: The reports of 1,047 consecutive blunt trauma patients (mean age, 40 years) who underwent routine contrast-enhanced thoracoabdominal MDCT were evaluated. Incidental findings were categorized by a trauma radiologist into four hierarchic categories based on their clinical consequences. We recorded additional diagnostic workup and treatment performed in conjunction with these incidental findings. RESULTS:: Of the 1,047 patients, 372 (mean age, 56 years; 61% male) had one or more incidental findings on thoracoabdominal MDCT. Complementary investigation or therapy was performed in 72 of these 372 patients; 29 of these patients required additional invasive evaluation or treatment. Nineteen patients underwent surgery due to an incidental finding. Nine patients were diagnosed with a not previously identified malignancy. CONCLUSIONS:: Routine thoracoabdominal MDCT in the evaluation of trauma patients revealed a significant number of incidental findings. Based on radiologic findings it is possible to decide whether additional follow-up or treatment is necessary. PMID- 21537209 TI - The systemic mediator-associated response test identifies patients in failed sepsis clinical trials among whom novel drugs reduce mortality. AB - BACKGROUND: Clinical trials using American College of Chest Physicians/Society of Critical Care Medicine Consensus sepsis definitions as entry criteria fail to reduce septic mortality. We hypothesized that the systemic mediator-associated response test (SMART) methodology could match sepsis therapies biologically to individual patients by relating baseline data statistically to outcomes and treatment effects. This article reports the SMART analyses of four failed sepsis investigations. METHODS: Databases from the E5 antiendotoxin antibody, North American Sepsis Trial (NORASEPT) and NORASEPT II anti-tumor necrosis factor antibody (TNFMAb), interleukin (IL)-1ra, and platelet-activation factor acetylhydrolase (PAF-AH) sepsis clinical trials were evaluated with SMART using multivariate logistic regression. From baseline data, within each study, mortality prediction models were built separately for the placebo and active drug populations. Subjects among whom each drug's effects were greatest were then identified by excluding from efficacy analysis subjects predicted by SMART to survive on placebo or to expire on active drug. Finally, prerandomization data from patients in each study were entered into SMART models, and placebo or active drug treatment effects were evaluated for parent populations and SMART cohorts. RESULTS: E5-consensus mortality: 27.4% placebo, 26.2% E5; SMART mortality: 17.1% placebo, 8.0% E5 (p < 0.01). NORASEPT-consensus mortality; 33.4% placebo, 29.5% TNFMAb; SMART mortality: 47.2% placebo, 34.7% TNFMAb (p = 0.03). IL-1ra-consensus mortality: 33.9% placebo, 29.8% IL-1ra; SMART mortality: 55.6% placebo, 34.9% IL 1ra (p < 0.001). PAF-AH-consensus mortality: 22.4% placebo, 23.9% PAF-AH; SMART mortality: 17.7% placebo, 28.9% PAF-AH (p = 0.039). CONCLUSIONS: Using prerandomization clinical trial data, SMART identifies septic patients whose host inflammatory responses can benefit from specific drugs. SMART also predicts ineffective drugs and patients whom they might harm. PMID- 21537207 TI - The impact of nontherapeutic hypothermia on outcomes after severe traumatic brain injury. AB - INTRODUCTION: In patients with isolated severe traumatic brain injury (TBI), the effect of controlled, therapeutic hypothermia on outcomes has been studied extensively. What is not well understood, however, and the purpose of this study, was to examine the impact of noninduced, nontherapeutic hypothermia on outcomes in these patients. METHODS: A retrospective review of the institutional trauma registry at the Los Angeles County + University of Southern California Medical Center was performed to identify all trauma patients admitted to the surgical intensive care unit (SICU) with isolated severe TBI from January 2000 to December 2008. Patients were classified as hypothermic (core temperature [Tc] <=35 degrees C) or normothermic (Tc >35 degrees C) based on their first Tc recorded on SICU admission. The primary outcome measure was in-hospital mortality, and secondary outcomes included SICU and hospital length of stay. RESULTS: During the study period, 1,403 patients sustaining an isolated severe TBI were admitted to the SICU. After excluding 122 patients with missing temperature data, 1,281 patients were analyzed. Hypothermia (Tc <=35 degrees C) on SICU admission was identified in 10.9% (n = 140) of the study population, with the remaining 89.1% (n = 1,141) being normothermic (Tc >35 degrees C). After adjusting for differences in baseline characteristics between the two groups, patients who were hypothermic on SICU admission were found to be significantly less likely to survive (odds ratio, 2.9; 95% confidence interval, 1.3, 6.7; p < 0.013). A penetrating mechanism of injury, Injury Severity Score >=25, and undergoing an exploratory laparotomy before admission were found to be independent risk factors for the development of hypothermia on SICU admission. CONCLUSION: For patients who have sustained isolated severe TBI, the presence of noninduced, nontherapeutic hypothermia on SICU admission is associated with a significant increase in mortality. The impact of preventative measures used to avoid the development of hypothermia and the effectiveness of measures for restoring normothermia warrant further investigation. PMID- 21537210 TI - Long-term comparison of a routine laboratory parameter-based severity score with APACHE II and SAPS II. AB - BACKGROUND: Risk score models predicting mortality have tremendous value, but because of the additional effort involved, their clinical use remains low. The aim of this study is to compare three different scores that each requires different levels of effort during admission and throughout treatment: the Acute Physiology and Chronic Health Evaluation II (APACHE II), the Simplified Acute Physiology Score II (SAPS II), and the Dense Laboratory Whole Blood Applied Risk Estimation (DELAWARE) score. Of the three, only the DELAWARE is based solely on routine laboratory parameters. METHODS: Prospective data of the three scores were collected for 268 surgical patients admitted to the intensive care unit over 1 year. The predicted hospital mortality and survival were evaluated for the first 14 days. RESULTS: With a cutoff value of 0.65, the sensitivity of the DELAWARE was 71.6%, the specificity, 92.5%, and the correct classification rate, 87.3%. The APACHE II and SAPS II showed values of 41.2%/96.8%/86.2% and 62.7%/87.1%/82.5%, respectively. The r2 value was 0.884 for the DELAWARE, 0.876/0.814 for the APACHE II and SAPS II. Hospital mortality rate was overestimated by 20% to 65% in all scores. The discriminatory ability of the APACHE II and SAPS II increased throughout the course of treatment. CONCLUSIONS: The routine laboratory-based DELAWARE provides a reliable, valid risk assessment of the surgical intensive care patient at admission. It also provides additional information without added effort or poor interobserver reliability, which leads to better data comparability. We have to state that until now the data have been collected in a single-center and their general validity is therefore limited. By the end of treatment, the SAPS II and APACHE II had increased discriminatory ability and are therefore useful as process parameters. PMID- 21537211 TI - A prospective investigation of long-term cognitive impairment and psychological distress in moderately versus severely injured trauma intensive care unit survivors without intracranial hemorrhage. AB - BACKGROUND: The primary objective was to prospectively determine the 12-month prevalence of cognitive impairment and psychologic difficulties in moderately versus severely injured adult trauma intensive care unit (TICU) survivors without intracranial hemorrhage. METHODS: We conducted a prospective cohort study in which patients were followed for 1 year after hospital discharge. A total of 173 patients from the Vanderbilt TICU who had an Injury Severity Score (ISS) of >15 (indicative of moderately severe trauma) were enrolled between July 2006 and June 2007. Patients were screened for delirium on a daily basis in the TICU by study personnel via the confusion assessment method of the ICU, and preexisting cognitive impairment was assessed through a surrogate-based evaluation using the short form of the Informant Questionnaire for Cognitive Decline in the Elderly. Of these patients, 108 were evaluated 1 year after hospital discharge with a comprehensive battery of neuropsychological tests and depression and posttraumatic stress disorder (PTSD) instruments. Cognitive impairment was defined as having two neuropsychological test scores 1.5 SD below the mean or one neuropsychological test score 2 SD below the mean. RESULTS: Fifty-nine patients (55%) demonstrated cognitive impairment at 12-month follow-up, with three of these patients (5.5%) having preexisting impairment. Clinically significant symptoms of depression and PTSD occurred in 40% and 26% of patients, respectively. No significant differences in cognitive impairment (59% vs. 50%), depressive symptoms (35% vs. 44%), and symptoms of PTSD (22% vs. 28%) were identified between moderately (ISS 15-25) and severely (ISS>25) injured TICU survivors, respectively (all p>0.05). In addition, multivariate logistic regression analysis found that moderately injured trauma patients had a similar rate of cognitive impairment when compared with those with severe injury at 12 month follow-up (p=0.25). CONCLUSION: Long-term cognitive impairment is highly prevalent in TICU survivors without intracranial hemorrhage as are psychologic difficulties. Injury severity, concussion status, and delirium duration were not risk factors for the development of neuropsychological deficits in this cohort. Individuals with moderately severe injuries seem to be as likely as their more severely injured counterparts to experience marked cognitive impairment and psychologic difficulties; thus, screening efforts should focus on this potentially overlooked patient group. PMID- 21537213 TI - Caring for an adult with a malignant primary brain tumor. PMID- 21537212 TI - Severely injured geriatric population: morbidity, mortality, and risk factors. AB - BACKGROUND: With an increasing life expectancy and more active elderly population, management of geriatric trauma patients continues to evolve. The aim was to describe the mechanism and injuries of severely injured geriatric patients and to identify risk factors associated with mortality. METHODS: The Trauma Registry at a Canadian Level I trauma center was queried for all trauma patients older than 65 years and injury severity score >15 from 2004 to 2006, resulting in a retrospective chart review of 276 patients. The data were subsequently analyzed using univariate and multivariate analysis. RESULTS: Average age was 81.5 years (mean injury severity score of 25). Most common comorbid illness was hypertension (57.3%) and most frequent mechanism of injury was falls (72.3%). The overall mortality was comparable with the US National Trauma Data Bank (26.8% vs. 32.0%, confidence interval, 0.00-0.10). Geriatric patients requiring intubation, blood transfusions, or suffering from head, C-spine, or chest trauma had an increased likelihood of death. In-hospital respiratory, gastrointestinal, or infectious complications also had higher likelihood of death. CONCLUSIONS: Falls continue to be the most frequent mechanism of injury in severely injured geriatric patients. Risk factors associated with a higher likelihood of death are identified. More research is needed to better understand this important and increasing group of trauma patients. PMID- 21537214 TI - Making a case for safe staffing. PMID- 21537227 TI - On being a foundation trust staff governor. PMID- 21537228 TI - Large bowel imaging: more than meets the eye. PMID- 21537229 TI - So you want to be ... a transplant surgeon. PMID- 21537230 TI - Crossing the pond: applying to train in the USA. PMID- 21537231 TI - What is an acute oncology service? PMID- 21537232 TI - Exercise: important for prevention and treatment of disease. PMID- 21537234 TI - Sedentary behaviour: redefining its meaning and links to chronic disease. PMID- 21537235 TI - Exercise and cancer survivorship. PMID- 21537236 TI - Exercise and the patient with chronic kidney disease. PMID- 21537237 TI - Gambling addiction: what the non-specialist needs to know. PMID- 21537238 TI - The intensive care management of common and uncommon drugs of misuse. PMID- 21537239 TI - The restless legs syndrome: is it more than that? PMID- 21537240 TI - Drug fever and DRESS syndrome. PMID- 21537241 TI - Hamilton Bailey: master surgical author. AB - A small elite of surgeons have the happy ability to be great teachers whose choice of phrase, whose ability to make difficult subjects seem easy, and whose ability to stimulate their audience or readers with enthusiasm raise them high above their peers. Many great teachers merely influence their own group of students or postgraduates. Others reach a wider audience through their writings, but only a very few can be said to have had a profound effect on the teaching of surgery throughout the world and one of these was Hamilton Bailey. This year marks the 50th anniversary of his death. PMID- 21537242 TI - Intralobar lung sequestration as a cause of unexplained recurrent chest infections. PMID- 21537243 TI - Childhood febrile convulsions and deja vu in adulthood. PMID- 21537244 TI - Redressing the brain drain. PMID- 21537246 TI - Risks of aspiration in pregnant women undergoing non-obstetric procedures: intubate or not? PMID- 21537253 TI - After the tsunami: the need to rebuild services. PMID- 21537254 TI - Mental health needs of men acknowledged for first time. PMID- 21537255 TI - Diabetic foot care: a step forward? PMID- 21537256 TI - Exploring urinary catheters: the perspectives of patients and nurses. AB - This literature review is part of a larger dissertation project that explores the lived experience of patients using long-term urinary catheters and nurses' attitudes towards urinary catheters. Systematic examination of the literature revealed six relevant primary research studies. These were critically appraised to assess their worth. Further studies were also reviewed, although these were often from neighbouring fields as relatively little research has been undertaken in this field. Findings suggest that there is a disparity between the care that nurses provide to patients with long-term catheters and the holistic care that patients need. Furthermore, nurses' decision-making skills are hampered by poor multidisciplinary documentation practices in the acute sector. It is concluded that nurses' attitudes towards urinary catheters do affect the care that patients receive. PMID- 21537257 TI - Introducing a new skin-care regimen for the incontinent patient. AB - Maintaining skin integrity and preventing skin breakdown and moisture lesions in the incontinent patient is an everyday challenge for nurses in the acute setting. The management of incontinence is often a socially or culturally prohibited topic Fletcher (2008); it is frequently attributed to ill health, the aging process or hospitalization, and often overlooked. The concept of cleansing should be commonplace, but it is complicated by the ritualism that underpins this ordinary yet fundamental aspect of patient care (Voegeli, 2010). The use of traditional methods of cleansing with soap and water in the management of skin integrity consumes significant amounts of nursing time. However, this procedure conflicts with infection control measures and predisposes the patient to further skin breakdown. This article looks at the use of an evaluation of a skin-cleansing emollient product in an elderly-care setting to provide evidence enabling an innovation that would lead to a change in practice. It highlights the importance of the implementation of a skin-care regimen as part of basic nursing care for the incontinent patient within the acute setting, and challenges ritualistic practice with evidence-based care. PMID- 21537258 TI - Use of compression hosiery in chronic oedema and lymphoedema. AB - The management of chronic oedema is a continuing partnership between patient and practitioner and accurate diagnosis and treatment planning are essential to control the condition in order to prevent complications and optimise the patient's quality of life. A paucity of funding, lack of knowledge and confidence on the part of practitioners and widely varying access to services means that many patients face barriers to gaining appropriate treatment. Nurses in many spheres will come across patients with some form of chronic oedema. The following article describes the types and causes of chronic oedema and lymphoedema and explores the use of compression hosiery as one facet in management of the condition. Patient education and the role of the practitioner are also highlighted to develop awareness of the need for adequate preparation of a patient to facilitate concordance and self-management of their condition. PMID- 21537259 TI - Essential care after an inpatient fall: National Patient Safety Agency advice. AB - John Tingle discusses a recent National Patient Safety Agency Rapid Response Report on essential care after an inpatient fall. To give the discussion a broader perspective and context he also introduces a US analysis of healthcare strategies that can be employed to reduce inpatient hospital falls. PMID- 21537260 TI - Homeostasis 5: nurses as external agents of control in breast cancer. AB - Breast cancer is caused by a homeostatic imbalance of cell division. Healthcare practitioners need to understand cellular activities to appreciate the physiological basis of health (homeostasis), the pathophysiological basis of illness and the physiological rationale of healthcare. Cells are the 'basic unit of life' (Clancy and McVicar, 2011a). This article describes normal cell division and the anatomy and physiology of the breast and, using a case study, will show how breast cancer is a homeostatic imbalance of cell division. There are analogies between the components of homeostasis and the components of the nursing (healthcare) process (Clancy and McVicar, 2011b) in the condition of breast cancer. After reading this article, nurses should be able to: understand that breast cancer is a cellular hence chemical imbalance that causes uncontrollable mitotic division of breast cells; understand how the cell cycle of cancer cells differs from that of normal cells; identify nature-nurture interactions involved in the aetiology of breast cancer; understand that when caring for people with breast cancer, health professionals including oncology nurses are acting as external agents of homeostatic control as the patient 'recovers' from breast cancer, and also to some extent when reducing signs and symptoms, hence quality of life, by providing palliative care. PMID- 21537261 TI - Missionary nurses and their role. PMID- 21537262 TI - Tackling smoking addiction in England and among NHS staff. PMID- 21537263 TI - The new EU healthcare rights directive: greater uniformity? AB - On 9th March 2011 the new EU Directive on Patients' Rights in Cross-border Healthcare was adopted. This article explores its implications for the delivery of health care in the UK. It notes that the final version of the Directive provides much greater discretion to member states to control access to resources than was suggested in early drafts of the Directive. It explores the situations in which care can be subject to prior authorization and suggests that perhaps the greatest long-term impact of the Directive will not be in patient mobility as such but rather in relation to its impact on broader standard setting across the EU. PMID- 21537264 TI - Students' perspectives on their skills acquisition and confidence. AB - AIM: To investigate students' perspectives on their skills acquisition and knowledge during the foundation year of their nursing programme, and whether this improved students' levels of competence and confidence. METHOD: Two groups of nursing students (n=140) responded to a clinical acquisition skills survey (CASS) to elicit their perceptions of clinical skills acquisition. Additionally, students' competence levels were examined, drawing comparisons with the students' objective, structured clinical examination (OSCE) results. RESULTS/FINDINGS: Students identified that the curriculum supported the acquisition of clinical skills, and clinical examination results confirmed that 95% of students were competent to pass their OSCE. CONCLUSION: Students' responses to items that related to perceived confidence and competence levels were positive. This indicates that the introduction of clinical skills teaching and assessment within a university's simulation suites augmented with structured assessment within the clinical environment improved the acquisition of clinical skills. PMID- 21537265 TI - Writing for professional publication. Part 11: writing conference abstracts. AB - Nursing and healthcare conferences range from one-day events organized by local trusts or education departments to three-day international conferences. Invitations to submit abstracts of potential presentations appear regularly in the nursing press, usually about nine months before the conference takes place. If you submit an abstract and it is accepted, you will be invited to present your paper at the conference and your abstract will be published in the conference handbook. PMID- 21537266 TI - Time for loose thinking. PMID- 21537267 TI - Stoma care nurses: collaboration is key. PMID- 21537268 TI - Peristomal skin care and the use of accessories to promote skin health. AB - Stomas are frequently encountered by nurses. Common complications include problems with the peristomal skin-the skin around the stoma. It has been reported that up to 80% of people with a stoma, who are termed ostomates, are affected. The three main types of stomas are colostomy, ileostomy and urostomy; all these come with a risk of sore peristomal skin. These stomas pass faeces or urine, which are collected in a stoma appliance that adheres to the peristomal skin. It is essential to ensure that this skin is free from breaks or soreness as this might lead to appliance leakage. This article is aimed at ward nurses and will focus on some of the stoma accessories that are used to treat, protect or 'level' peristomal skin. Accessories, such as barrier creams or films, can be used to protect skin. Filler paste, seals and convex appliances, for example, can be used to resolve creases in the skin or to treat a retracted stoma. The situations in which stoma accessories might be useful in resolving peristomal skin problems or retaining its integrity are numerous. PMID- 21537269 TI - Effective management of peristomal pyoderma gangrenosum. AB - Peristomal pyoderma gangrenosum (PPG) is a skin disorder which manifests as painful exudating, ulcerative lesions. It is generally associated with inflammatory bowel disease (IBD) when affecting patients with a stoma. Patients with PPG typically present to the stoma care nurse (SCN) in the first instance, when the discharging ulcers cause pain, prevent effective stoma appliance application and result in leakage. Anecdotal evidence suggests that clinical nurse specialist posts, such as that of the SCN, are being diluted within some trusts, with a demand for staff to work on wards to cover clinical shifts. As a consequence there is a possibility that these patients will not receive a prompt diagnosis and treatment plan. This article will examine the role of the SCN in managing the patient with PPG, including the use of effective topical treatments. The importance of early diagnosis to prevent escalation of PPG and subsequent prolonged patient discomfort-and the SCN's crucial role in this-is discussed. PMID- 21537276 TI - A professional pledge would be a boost to all. PMID- 21537277 TI - March for the alternative. PMID- 21537278 TI - Leave our nurse specialists alone! PMID- 21537279 TI - Parkinson's awareness week 2011: improve your services. PMID- 21537280 TI - Who cares for the carers? A student's experience of providing carer support and education. AB - As the incidence of dementia increases with age and people are generally living longer, the number of people requiring care will continue to rise. There are approximately 820000 people in the UK with dementia and more than 500000 carers who are not part of the health and social care workforce. These unpaid carers provide support to people with dementia, often sacrificing their own work commitments, social and family life. As part of the 'Partnerships in recovery' module studied in the third year of the pre-registration mental health nursing programme at the University of the West of Scotland, the first author (DR) chose to use a pycho-education intervention to benefit the needs of a carer and client with vascular dementia. Providing support and education increases the likelihood of both carer and client engaging in a life that is meaningful and hopeful. PMID- 21537281 TI - How healthy are our nurses? New and registered nurses compared. AB - This study examined the health behaviour of nursing staff, comparing registered and pre-registered nurses in terms of their self-reported health and lifestyle behaviour. In total, 325 pre-registered nurses and 551 registered nurses, based at the same university teaching hospital and located within an acute NHS trust, completed a self-administered health and lifestyle questionnaire survey. With the exception of smoking behaviour, registered nurses generally had a healthier lifestyle compared with pre-registered nurses. However, when examining the overall health profile of the sample, the study reveals that there is room for improvement in the health and lifestyle behaviour exhibited by both registered and pre-registered nurses. Almost half of the sample failed to meet public health recommendations for levels of physical activity, almost two-thirds did not consume five portions of fruit or vegetables daily and almost half ate foods that were high in fat and sugar content on a daily basis. These findings are alarming given the current government emphasis on the health of NHS staff and the important role that nurses play in influencing lifestyle choices among their patients. There is an urgent need to target education and support services to improve the diet and exercise habits of nursing professionals. PMID- 21537283 TI - Writing for professional publication. Part 12: summary of the series. AB - The previous articles in this series have explored the practical issues of writing for professional publication. In this final article, John Fowler, an experienced nursing lecturer and author, summarises the series and presents an overview of the practicalities of writing for publication. PMID- 21537282 TI - Homeostasis 6: nurses as external control agents in rheumatoid arthritis. AB - All disorders involve a disturbance of cellular and hence chemical function in the body. Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease that usually attacks synovial joints and surrounding ligaments, muscles and their tendons and blood vessels. This article applies the concept of health professionals operating as external agents of homeostatic control (Clancy and McVicar, 20011a; 2011b) to RA and to the care of affected patients, using a case scenario to illustrate attempts to minimize homeostatic imbalances. After reading the article, nurses should be able to understand: how the principles of homeostatic theory apply to skeletomuscular function, in particular to synovial joint function; the skeletomuscular homeostatic role in movement; and that homeostatic failure of reduced mobility, as in RA, is a result of nature-nurture interaction; that illness arises from a cellular, hence chemical, homeostatic imbalance(s) (Clancy and McVicar, 2011a; 2011b; 2011c; 2011d; 2011e). RA is considered a cellular (B-lymphocyte) hence chemical (autoantibody) imbalance that causes the homeostatic imbalances (inflammatory pain, reduced mobility, reduced activities of daily living) associated with the condition. Health professionals are able at act as external agents of homeostatic control to only a limited extent when caring for people with RA because, as with any progressive disorder, they will only be managing signs and symptoms to improve patients' quality of life. PMID- 21537284 TI - Consent and assessment of capacity to decide or refuse treatment. AB - Consent protects the right of patients to decide what happens to them. Before any medical intervention, adults must give valid consent, which must be voluntary, informed and given free of undue influence. When consent is being obtained, patients must be informed about the intervention, why it is being done and its risks; information they are given must be recorded. Every effort should be made to explain the issues in terms that the patient can understand and by providing support and aids to communicate. Consent can be expressed, where patients say they consent or put it in writing, or implied, where a healthcare professional infers from their behaviour that they consent. While different types of consent are valid, some are evidence of stronger proof in court that valid consent has been given. Competent adults have the right to refuse treatment, regardless of the reasons they give for refusal and even if the refusal will result in death; clinicians must respect their decision. In some circumstances-such as when an unconscious person is admitted as an emergency-healthcare professionals can make decisions on behalf of patients, and must do so in patients' best interests. PMID- 21537285 TI - Every nurse needs to know about learning disabilities. AB - Professor Alan Glasper says the Royal College of Nursing's position paper on learning disability nursing will remain aspirational; the number of these nurses is declining and is set to fall further. These patients present in all settings, so all nursing courses should cover meeting their needs. PMID- 21537286 TI - Care is left to unqualified staff as nurse training turns out regiments of managers. AB - Care is left to unqualified staff as nurse training turns out regiments of managers. PMID- 21537287 TI - Safety of clinical systems: health foundation finds cause for concern. AB - John Tingle discusses a report by the Health Foundation on the safety of clinical systems. This identifies the prevalence of problems, many of which have serious implications for patient safety, and the points at which they occur. Problems include missing patient information, incorrect medication dosages poor communication and missing or faulty equipment. Staff often consider system failure to be the norm; instead, they should raise problems to keep patients safer. PMID- 21537288 TI - Legal matters. PMID- 21537289 TI - Humility in nursing. PMID- 21537292 TI - A research legacy for us to build on. PMID- 21537293 TI - Predicting concordance with multilayer compression bandaging. AB - OBJECTIVE: To examine the relationship between concordance with multilayer compression bandaging and a number of client and wound characteristics, including wound severity, health status and client independence with respect to activities of daily living. METHOD: Using data gathered for a randomised controlled trial that compared two types of antimicrobial dressings on infected or critically colonised lower leg ulcers, we explored the level of concordance with compression therapy by patients with wounds that had an ankle brachial pressure index of between 0.8 and 1.2. RESULTS: A logistic regression analysis found that increased pain and wound size, older age and shallow wound depth were all significant predictors of non-concordance with multilayer compression bandaging. CONCLUSION: Although the results suggest that pain, wound size, age and wound depth are all significant predictors of non-concordance with multilayer bandaging, the generalisability of these results is limited, given that data were gathered in the context of a RCT. Further studies are required to explore the relative contribution of predictors of concordance with compression therapy, in order to help inform strategies that promote it and, thereby, optimise healing. CONFLICT OF INTEREST: None. PMID- 21537294 TI - Bacterial translocation from the gastrointestinal tract in healthy and injured rats. AB - OBJECTIVE: To study the phenomenon of asymptomatic penetration of bacteria from the gastrointestinal tract into various tissues of healthy rats and rats with skin wounds and closed fractures at different doses and with different species of bacteria. METHOD: Healthy rats and rats with full-thickness skin wounds and closed femoral fractures were given varying doses of radiolabeled bacteria (S. aureus 209P or B. subtilis 534) per os in doses of up to 1010 bacteria per 1kg of body mass. Six hours later, these animals were euthanised and, together with blood smears, tissue samples of liver, spleen, stomach, small and large intestine, lung, hypothalamus, posterior pituitary gland, epinephros and skin and muscle from the wound site were subjected to bacteriological and histological analysis. RESULTS: In total, 99 rats were used for the experiments. Viable bacteria were found to systemically penetrate into the tissues of the internal organs in 45 healthy animals, 27 rats with incisions and 27 rats with fractures. In healthy animals, viable bacteria mostly accumulated in the stomach wall, the mucous membranes of the small intestine, the mesenteric lymph nodes and in the spleen and liver. Translocation was registered in uninjured animals receiving 1x106 and more bacteria per 1kg of rat's weight and in injured rats receiving 1x104 bacteria and more. Bacteria penetrated the local tissues at both wound sites (skin wounds and fracture sites). CONCLUSION: Bacterial translocation is a protective mechanism that gives the immune system constant contact with external antigens, although it can contribute to the spreading of infection in an organism. In healthy animals, small amounts of bacteria penetrate systemically from the tract and small intestine into the tissues of the spleen and liver. During injury, translocated bacteria also appear at the focus of injury. CONFLICT OF INTEREST: None. PMID- 21537295 TI - In vitro antimicrobial efficacy of a silver alginate dressing on burn wound isolates. AB - OBJECTIVE: To test the antimicrobial effectiveness of a silver alginate dressing on opportunistic pathogens, namely meticillin-sensitive Staphylococcus aureus (MSSA) and meticillin-resistant Staphylococcus aureus (MRSA), Klebsiella spp., Enterococcus faecalis, Enterococcus faecium, Pseudomonas aeruginosa, Escherichia coli, Enterobacter sakazakii, Enterobacter cloacae, Serratia marcescens, Chryseobacterium indologenes, Proteus vulgaris and Acinetobacter baumannii. METHOD: In total, 40 microorganisms were isolated from patients attending three burn centres in the US and evaluated for their susceptibility to a silver alginate wound dressing, employing a corrected zone of inhibition assay, conducted on Mueller Hinton agar (MHA). RESULTS: The sizes of the corrected zones of inhibition varied between and within genera. For example, all Acinetobacter baumannii strains were found to be sensitive to ionic silver at pH 7, with a mean of 2.8mm, compared with 3.5mm at pH 5.5. The silver alginate dressing also demonstrated activity on all strains of Enterobacter and Escherichia coli, with susceptibility to the silver alginate dressing enhanced at pH 5.5. For Enterococcus spp. the average corrected zone of inhibition at pH 7 was 3.6mm, versus 4.9mm at pH 5.5. All strains of Pseudomonas aeruginosa were found to be sensitive to the silver alginate dressing. The average corrected zone of inhibition was 6.9mm at pH 7, compared with 8mm at pH 5.5. For MRSA and Staphylococcus aureus, it ranged from 4.5mm to 7.5mm at pH 7. When the pH was decreased to 5.5, the corrected zone of inhibition increased. CONCLUSION: This study demonstrates the activity of a silver alginate dressing on a wide range of burn isolates, including antibiotic-resistant bacteria, isolated from three different burn centres in the US. It also highlights the possible importance of pH and its potential effects on antimicrobial performance and microbial susceptibility. However, more extensive testing is required to substantiate this. CONFLICT OF INTEREST: SLP is employed by Advanced Medical Solutions Ltd. PMID- 21537296 TI - Prevention and treatment of radiodermatitis using a non-adhesive foam dressing. AB - OBJECTIVE: To validate the efficacy of a radiodermatitis management protocol (which involves preventive measures, the application of preventive creams and the use of a non-adhesive, foam dressing with a silicone contact layer) at a radiation oncology department in southern Spain. METHOD: An observational study was carried out on consecutive patients undergoing radiation therapy for sarcomas, ear nose and throat, breast, cervix and lung cancers, excluding patients with other tumours and those who stopped radiation treatment, or who died during its course. Variables that were assessed included: average healing time, general progression of the injury, degree of trauma caused by removing the dressing, convenience and comfort, patient's aesthetic perception, ease of use for health professionals, adaptability, and the length of time for which the dressing stays in place. RESULTS: 20 patients were included in the study and radiodermatitis was resolved in 100% (20/20). Optimal progression of all lesions was observed. No infections occurred, and the average total healing time ranged from one to two weeks, even during radiation therapy Patients reported a high level of satisfaction with the dressing, which scored highly in terms of convenience and comfort, atraumatic dressing, ease of use, adaptability, patients' aesthetic perception and adhesive durability. CONCLUSION: Our action protocol is effective in the prevention and treatment of radiodermatitis. We achieved optimal results in the current study, which supports the continued use of the test dressing in our department. CONFLICT OF INTEREST: None. PMID- 21537297 TI - Randomised clinical trial comparing Hydrofiber and alginate dressings post-hip replacement. AB - OBJECTIVE: To compare the performance of Hydrofiber and alginate dressings used in the treatment of primary hip arthroplasty wounds. METHOD: Patients were randomised into one of two groups, receiving either a Hydrofiber or an alginate dressing. Outcome measures, assessed by daily observations, included skin damage (erythema, blisters and skin injuries) and the dressing's ability to handle exudates. Photos of the dressing and the skin area around wounds were taken. Patients noted skin problems, discomfort at mobilisation and pain at dressing removal. RESULTS: In the alginate group, there were fewer blisters in the wound area compared with the Hydrofiber group (7% versus 18%, p=0.03). During dressing removal, fewer patients in the alginate group reported pain than patients in the Hydrofiber group (2.1% versus 15%, p=0.01) CONCLUSION: We recommend the use of both dressings following total hip arthroplasty, although the alginate would be our first choice, as we found fewer blisters when using alginate dressings as opposed to Hydrofiber dressings. CONFLICT OF INTEREST: None. PMID- 21537300 TI - Evidence debate: let's listen to both sides. PMID- 21537301 TI - A clinical evaluation of the efficacy and safety of singlet oxygen in cleansing and disinfecting stagnating wounds. AB - OBJECTIVE: This cohort study evaluated the clinical efficacy of singlet oxygen, ActiMaris (AM) a hypertonic (3%) ionised (pH 9.8) sea water solution. It was assumed that when used for wound cleansing, disinfection and the reduction of inflammation, AM would be safe and effective. METHOD: Between May 2008 and May 2009, ambulant patients presenting at one of four wound healing centres were included in the study. Patients had critically colonised and/or infected, malodorous wounds, covered with slough/fibrin or wounds showing inflammation of the periwound skin. Wounds were assessed in terms of percentage changes in fibrin, slough and granulation tissue, they were assessed clinically and high resolution digital photographs were scored by a physician who was blinded to treatment allocation. Results were compared at baseline (week 0) and following 42 days of AM treatment (week 6). RESULTS: Seventy-three patients were included in the analysis. Dressing changes were at 2-day intervals on average, and the median treatment period was 46.04 days (range: 3-197). At 42 days, 33% (n=24) of included wounds had healed, 57% (n=42) had improved and 10% (n=7) remained stagnant. Cleansing and wound disinfection with AM was effective. In 31 patients (42%) wounds had showed clinical signs and symptoms of critical colonisation and/or infection at day 0, whereas at day 42 the infection was completely eradicated. Inflammation was reduced in 60% (n=44) of cases and patients did not report pain or discomfort when using AM. CONCLUSION: The use of singlet oxygen was shown to be safe and the results of this study indicate AM to be useful for wound cleansing, disinfection, reducing inflammation and promoting wound healing. CONFLICT OF INTEREST: The centres were supplied with the study product by the sponsor. The authors have no financial interest in writing this article. PMID- 21537302 TI - Role of oxygen in wound healing: a review of evidence. AB - OBJECTIVE: To review the evidence regarding the influence of oxygen as an intrinsic factor on cutaneous wound healing. METHOD: A literature search was performed using Ovid and the Cochrane Database with the search terms: 'Wound healing', 'Oxygen', 'Collagen', 'Angiogenesis', 'Inflammation' and 'Surgical Site Infection'. Human and animal studies were included if relevant and examined for methodological quality. RESULTS: There are no meta-analyses of the use of oxygen in wound healing and only two randomised controlled trials (RCTs). Studies vary in methodological quality. The majority of the data comes from animal models. In total 1568 studies on wound healing and oxygen were found. CONCLUSION: Oxygen is vital throughout wound healing, especially in the inflammatory and proliferative phases. Research suggests that patient supplementation with oxygen could enhance bacterial killing and angiogenesis, reduce surgical site infection rates and increase wound tensile strength, facilitating improved healing. CONFLICT OF INTEREST: None. PMID- 21537303 TI - Wound healing following combined radiation and cetuximab therapy in head and neck cancer patients. AB - OBJECTIVE: This study set out to determine if cetuximab treatment increases the risk of wound healing complications when combined with radiation therapy. METHOD: We performed a retrospective chart review of head and neck cancer patients who received salvage neck dissections between 1999 and 2007, at two academic tertiary care centres. Complications from wound healing were compared between radiation and combined therapy groups. RESULTS: A total of 35 patients received radiation (n=20) or combined radiation and cetuximab therapy (n=15) prior to neck dissection. The treatment groups were similar in regard to demographic and primary tumour-related characteristics. The time between treatment and salvage neck dissection did not differ between the radiation (3.9 months) and combination treatment (3.0 months) groups (p=0.15). Wound healing complications occurred in 13% (2/15) of the patients treated with radiation and cetuximab and there were no complications in patients who received radiation alone (p=0.20). CONCLUSION: Cetuximab did not significantly increase the risk of post-surgical wound complications, although a higher absolute number of wound complications was observed in the group treated with cetuximab and radiation therapy, compared with the group treated with radiation alone. CONFLICT OF INTEREST: This work was supported by a grant from the National Institute of Health (2T32 CA091078-06). One of the authors, JAB, is an occasional consultant and honoraria for ImClone and Bristol-Meyers Squibb. PMID- 21537304 TI - Case report: doxycycline instillation used to treat a high-output lymphatic fistula secondary to needle puncture. AB - Previous reports have documented the use of doxycycline as a sclerosing agent in the treatment of recurrent pleural effusion and pneumothoracies. However, little is currently known of its use in the closure of lymphatic fistulae. This paper presents a case in which an infusion of doxycycline was used in a patient who had developed the unusual complication of a high-output lymphatic fistula, following a femoral needle puncture. As no standard of care has been established in the treatment of this problem, we embarked on a minimally-invasive course of action, using doxycycline as a sclerosing agent. We found this treatment to be effective, with no complications. PMID- 21537305 TI - Mucormycosis of the anterior chest wall presenting as a soft tissue tumour. AB - Mucormycosis is a fungal infection caused by order Mucorales in humans. It commonly affects immunocompromised individuals, usually following trauma, and is associated with high rates of mortality despite the use of modern antifungal therapy and debridement. This report describes a case of the mucormycosis that presented as a non-healing ulcer over the chest wall (an extremely rare site for this lesion) which appeared to be a soft tissue tumour. The patient was immunocompetent and had no history of trauma. Repeated biopsies suggested there were only inflammatory changes but a fungal culture confirmed Rhizopus microsporus. The ulcer was managed successfully with high doses of intravenous Amphotericin B and aggressive surgical debridement. PMID- 21537306 TI - Use of a new, flexible lipidocolloid dressing on acute and chronic wounds: results of a clinical study. AB - OBJECTIVE: To document the performance (efficacy, tolerability and acceptability) of Urgotul Flex, a new, more flexible version of the lipidocolloid dressing Urgotul, in the management of acute and chronic wounds. Efficacy was defined as the reduction in ulcer surface area after 4 weeks of treatment. METHOD: This open, non-comparative, multicentre clinical trial recruited patients from 11 centres, which included surgical, burns and rehabilitation units and paediatric, geriatric and dermatology wards. Inclusion criteria were non-infected wounds of any aetiology that were <120cm2 in size. Ulcer surface area was assessed by tracing and planimetry. Acceptability parameters were: ease of dressing application; pain at dressing change; dressing adherence to wound bed and bleeding at removal; maceration of surrounding skin; these were all assessed qualitatively. Patients were followed up for a maximum of 4 weeks, or until they healed if this occurred first. Efficacy and tolerability were assessed by the physicians on a weekly basis, and acceptability by the nursing staff at each dressing change. All of the physicians/nurses had previously participated in clinical evaluations of Urgotul using the same outcomes and assessments, and so performed a retrospective assessment of the two dressings. RESULTS: Forty-four patients from 11 investigating centres were included in the study. The mean baseline surface area at was 21cm2 and 6cm2 for the acute and chronic wounds respectively. Twenty wounds (17 acute wounds and three chronic wounds) healed. Of the remainder, the mean surface area reduction was 78% and 42% for the acute and chronic wounds respectively at the end of the 4-week treatment period. Only two local adverse events were reported, but these were not considered to be dressing related. Based on the 345 documented dressing changes, conformability of the new dressing was considered to be superior to that of Urgotul, particularly when used on acute wounds. CONCLUSION: These findings show that the efficacy and tolerability of Urgotul Flex is similar to that reported in previous observational studies on Urgotul. However, results show it is more flexible and thus more conformable, particularly when used on wounds in awkward locations, including paediatric wounds and hand surgery. CONFLICT OF INTEREST: This evaluation was sponsored by Laboratoires URGO, Chenove, France. PMID- 21537307 TI - Telemedicine in the management of patients with chronic wounds. AB - The following article presents a telemedicine system that has been introduced in southern Jutland, Denmark. Using 'low-tech' equipment, such as camera-equipped mobile phones and normal desktop computers with an internet connection, health professionals have been able to communicate and collect data in a clinical database more effectively. This system aims to improve interdisciplinary collaboration, through facilitating the interaction between health professionals and also other parties that are involved in the provision of care, such as administrative staff and local reimbursement authorities. PMID- 21537309 TI - Interim advice on silver dressings in neonatal/paediatric wound and skin care. PMID- 21537315 TI - A welcome dilemma: setting priorities for the 12th EAPC Congress. PMID- 21537314 TI - Talking about death, dying, and the end of life. PMID- 21537316 TI - Dying matters, faith matters: the role of chaplains at the end of life. PMID- 21537317 TI - Compassionate extubation in children at hospice and home. AB - OBJECTIVES: At Leeds Paediatric Intensive Care Unit (PICU), whenever possible, patients are offered the opportunity to have mechanical ventilation withdrawn at a children's hospice or in the home. The aims of this study were to examine the views of the PICU staff regarding this choice, to understand their emotional and practical considerations, and to gain insight into the perceived effect on parents. DESIGN: An anonymous open-ended questionnaire and a focus group session invited comments from the multidisciplinary staff on the palliative care service, the options for the child to die outside the PICU, and the practical and emotional effects on themselves and the parents. RESULTS: Several major themes were identified: providing an appropriate environment for death in the PICU itself, parental choice, practical issues of transferring a dying child, emotional issues, service organization, and feedback from families. Overall, the staff thought that parents benefit from the choices offered. CONCLUSIONS: The PICU seems to fit neither the 'consultative model' nor the 'integrative model' of previous literature, but rather a 'facilitative model' not previously described. PMID- 21537318 TI - Forgotten grievers: an exploration of the grief experiences of bereaved grandparents. AB - AIM: Current knowledge about bereavement has been derived mostly from the experiences of spouses, parents, and children. There is a paucity of studies on the grief of grandparents. The aims of this Irish national study were to identify and describe the bereavement experiences of grandparents following the death of a grandchild and to explore their needs and supports throughout this experience. A qualitative exploratory descriptive design was employed. METHOD: A multi-pronged sampling strategy was adopted. Seventeen people participated in in-depth interviews. The data was subjected to thematic field analysis through NVivo. RESULTS: The small body of literature generally claims that grandparents experience 'double pain', meaning that they concurrently experience feelings of loss for their grandchild and pain associated with their own child's grief. However, this study found that grandparents experience 'cumulative pain'. That is, in addition to double pain, they also experience pain from other sources. CONCLUSION: There is a need for the complexity and intensity of the grief felt by bereaved grandparents to be recognized, acknowledged, and supported by health professionals and society in general. PMID- 21537319 TI - Perspectives on spiritual care at Hospice Africa Uganda. AB - OBJECTIVE: To examine how spiritual care is perceived in an African context by recording the lived experiences of palliative care workers at Hospice Africa Uganda (HAU). METHODS: Fifteen palliative care workers with experience in providing spiritual care were interviewed and their responses were thematically analyzed. RESULTS: The participants rarely saw a distinction between religion and spirituality. Although many were comfortable dealing with religious issues emanating from the major religious traditions, including those different from their own, they were less comfortable in handling issues arising from native Ugandan traditions and culture. Beliefs such as witchcraft and cursing in particular were considered harmful and not spiritual, and several participants reported feeling uncomfortable when providing spiritual care to patients with these beliefs. The interviewees also cited difficulties such as the lack of time, resources, and available religious leaders in the community, as well as language barriers. CONCLUSION: Although the palliative care workers at HAU have views on spirituality and spiritual care that have much in common with the palliative care literature from North America and Europe, they also face more specific challenges. These include providing spiritual care in a resource-poor setting to patients undergoing severe economic hardship, and providing spiritual care to those with traditional African religious beliefs. PMID- 21537320 TI - Supporting care home residents at the end of life. AB - The English Department of Health's 2008 End of Life Care Strategy reported that 17% of deaths in England occur in care homes, with the majority of these in the 85 years and over age group. Given this, the ageing population, and the projected increase in the number of people dying, it is evident that the number of deaths in care homes is likely to increase. The research presented here seeks to consider the factors that support residents to remain in care homes towards the end of life. This study is based on four case studies of care homes in England and on interviews with external health and social care professionals who interact with these care homes. The findings indicate that three core features are fundamental to the delivery of high-quality end-of-life care in care homes: advance care planning, multidisciplinary communication and working, and provision of dignified and compassionate care. Previous research has uncovered some of these issues; this study suggests that it is the combination of these factors that makes them fundamental to meeting residents' care preferences and ensuring high-quality care. PMID- 21537321 TI - Expanding palliative care nursing education in California: the ELNEC Geriatric project. AB - In the past decade, the Robert Wood Johnson Foundation's 2002 report Means to a Better End: A Report on Dying in America Today and other studies brought attention to deficiencies in care of the dying in the USA. Palliative care's mandate is to promote a 'good death' through expert symptom management and compassionate care that addresses the psychosocial needs and dignity of persons at the end of life. The End-of-Life Nursing Education Consortium (ELNEC) Geriatric 'train-the-trainer' project was launched in 2007 to increase the knowledge and educational skills of nurses and unlicensed staff providing end-of life care for older adults in nursing homes, skilled nursing facilities, long term care, and hospices. From 2007 through 2009, 351 California-based nurses and nursing home staff attended one of four ELNEC Geriatric courses. This paper describes programme development, implementation, follow-up evaluations, and examples of participants' use of the ELNEC Geriatric curriculum. PMID- 21537322 TI - Evaluating a protocol to train hospice staff in administering individualized music. AB - The ongoing extension of the average human lifespan in most parts of the world forecasts an unprecedented number of aging adults developing Alzheimer's disease or related dementia. Behavioural and psychological symptoms of dementia, commonly referred to as agitated behaviours, are estimated to occur in over 80% of patients and are typically treated using antipsychotic medications, posing significant morbidity and mortality risks. An evidence-based protocol known as individualized music (IM) offers a non-pharmacological intervention to reduce agitation. This project, using a one-group pre-test-post-test design, was implemented by training a self-selected sample of 24 hospice professionals to use the IM protocol with dementia patients. The effectiveness of the training on increasing the participants' knowledge of and confidence in using IM was explored. Paired t-tests were employed to analyze the data and the results of the analysis were encouraging, suggesting that it is feasible to educate multidisciplinary hospice staff in implementing the IM protocol. Thus, there is potential for using IM in the palliative treatment of persons with advanced dementia. PMID- 21537323 TI - Widening the definition of palliative care. PMID- 21537324 TI - Politics and palliative care: Canada. PMID- 21537325 TI - Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy. AB - Transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP) is characterized by systemic accumulation of amyloid fibrils caused by a point mutation in the TTR gene. Despite the urgent need for alternative therapeutic strategies, the pathogenesis of FAP still remains elusive. In our study reported here, we focused on albumin, the most abundant protein in plasma, and described the role of albumin in the TTR amyloid-formation process. Patients with FAP evidenced significantly decreased serum albumin levels as the disease progressed. Biacore analysis showed that albumin had a binding affinity for TTR and exhibited higher affinity for TTR amyloid than native TTR. Albumin functioning as an antioxidant effectively suppressed TTR amyloid formation. In patients with FAP, albumin was significantly oxidized as the disease progressed. Moreover, loss of functional albumin accelerated TTR deposition in analbuminemic rats possessing a human variant TTR gene. Taken together, these results indicate that albumin may have an inhibitory role in the TTR amyloid-formation process. PMID- 21537326 TI - Nuclear factor-kappaB2/p100 promotes endometrial carcinoma cell survival under hypoxia in a HIF-1alpha independent manner. AB - Endometrial carcinoma (EC) is a common female cancer, treated mainly by surgery and adjuvant radiotherapy. Relapse following treatment is associated with increased risk of metastases. Hypoxia, a common microenvironment in solid tumors, correlates with malignant progression, rendering tumors resistant to ionizing therapy. Hence, we assessed here the immunohistochemical expression of hypoxia inducible factor-1alpha (HIF-1alpha) and members of the NF-kappaB family in 82 primary EC and 10 post-radiation recurrences of EC. Post-radiation recurrences were highly hypoxic, with a higher expression of HIF-1alpha and also RelA (p65) and p52 when compared with primary EC. We next investigated the effects of hypoxia on EC cell lines. We found that EC cell lines are highly resistant to hypoxia-induced apoptosis. We thus focused on the molecular mechanisms involved in conferring hypoxic cell death resistance. We show that in addition to the classical NF-kappaB, hypoxia activates the alternative NF-kappaB pathway. To characterize the upstream kinases involved in the activation of these pathways, we used lentiviral-mediated knockdown and mouse embryonic fibroblasts lacking IKKalpha and IKKbeta kinases. Both IKKalpha and IKKbeta kinases are required for RelA (p65) and p100 accumulation, whereas p52 processing under hypoxia is IKKalpha dependent. Furthermore, Ishikawa endometrial cell line harboring either RelA (p65) or p52 short-hairpin RNA was sensitive to hypoxia-induced cell death, indicating that, in addition to the known prosurvival role of RelA (p65) under hypoxia, alternative NF-kappaB pathway also enhances hypoxic survival of EC cells. Interestingly, although HIF-1alpha controlled classical NF-kappaB activation pathway and survival under hypoxia through RelA (p65) nuclear accumulation, the alternative pathway was HIF-1alpha independent. These findings have important clinical implications for the improvement of EC prognosis before radiotherapy. PMID- 21537327 TI - Hepatitis C virus core protein induces fibrogenic actions of hepatic stellate cells via toll-like receptor 2. AB - Hepatic stellate cells (HSCs) represent the main fibrogenic cell type accumulating extracellular matrix in the liver. Recent data suggest that hepatitis C virus (HCV) core protein may directly activate HSCs. Therefore, we examined the influence of recombinant HCV core protein on human HSCs. Primary human HSCs and the human HSC line LX-2 were stimulated with recombinant HCV proteins core and envelope 2 protein. Expression of procollagen type I alpha-1, alpha-smooth muscle actin, cysteine- and glycine-rich protein 2, glial fibrillary acidic protein, tissue growth factor beta1, matrix metalloproteinases 2 (MMP2) and 13, tissue inhibitor of metalloproteinases 1 and 2 was investigated by real time PCR. Intracellular signaling pathways of ERK1/2, p38 and, jun-amino-terminal kinase (JNK) were analyzed by western blot analysis. Recombinant HCV core protein induced upregulation of procollagen type I alpha-1, alpha-smooth muscle actin, MMP 2 and 13, tissue inhibitor of metalloproteinases 1 and 2, tissue growth factor beta1, cysteine- and glycine-rich protein 2, and glial fibrillary acidic protein mRNA expression, whereas HCV envelope 2 protein did not exert any significant effect. Blocking of toll-like receptor 2 (TLR2) with a neutralizing antibody prevented mRNA upregulation by HCV core protein confirming that the TLR2 pathway was involved. Furthermore, western blot analysis revealed HCV-induced phosphorylation of the TLR2-dependent signaling molecules ERK1/2, p38 and JNK mitogen-activated kinases. Our in vitro results demonstrate a direct effect of HCV core protein on activation of HSCs toward a profibrogenic state, which is mediated via the TLR2 pathway. Manipulating the TLR2 pathway may thus provide a new approach for antifibrotic therapies in HCV infection. PMID- 21537328 TI - Additive renoprotective effects of B2-kinin receptor blocker and PPAR-gamma agonist in uninephrectomized db/db mice. AB - We recently showed that the bradykinin B2 receptor (B2R) blocker icatibant (Icat) and the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone (Ros) exerted anti-inflammatory effects in renal tubular cells exposed to a diabetic milieu. This study aims to explore whether these effects can be translated to an experimental model of type 2 diabetic nephropathy (DN). db/db mice and their nondiabetic db/m littermates underwent sham operation or uninephrectomy (Unx) at 10 weeks and received vehicle (Veh), metformin (Met), Icat, Ros, or Icat plus Ros for 8 weeks before killing. Among the db/db group with Unx, mice that received Icat or Ros had significantly lower serum creatinine and albuminuria, which was further reduced when Icat and Ros were given in combination. These beneficial effects were not observed in the Met group that achieved similar glycemic control as Ros-treated animals. Likewise, the severity of reactive glomerular and proximal tubular hypertrophy, glomerulosclerosis, interstitial injury, cortical F4/80 and alpha-smooth muscle actin immunostaining, and CCL-2, ICAM-1 and TGF-beta overexpression were all attenuated by Icat and Ros, and these effects were enhanced when both agents were combined. Immunohistochemical staining confirmed the proximal tubular expression of CCL-2 (inflammation) and TGF-beta (fibrosis). Treatment with Icat was associated with decreased B2R, but increased, B1R expression, which was exaggerated in Unx animals. At the signaling level, Icat and Ros reduced extracellular signal regulated kinase 1/2 and STAT1 activation, respectively. Our results suggest a deleterious role of the kallikrein-kinin system in murine-accelerated DN, which can be ameliorated by the B2R blocker Icat and enhanced by the addition of Ros. This calls for further evaluation of this novel therapeutic approach in more animal models of diabetic nephropathy. PMID- 21537329 TI - Targeted intestinal epithelial deletion of the chemokine receptor CXCR4 reveals important roles for extracellular-regulated kinase-1/2 in restitution. AB - Barrier defects and/or alterations in the ability of the gut epithelium to repair itself are critical etiological mechanisms of gastrointestinal disease. Our ongoing studies indicate that the chemokine receptor CXCR4 and its cognate ligand CXCL12 regulate intestinal-epithelial barrier maturation and restitution in cell culture models. Gene-deficient mice lacking CXCR4 expression specifically by the cells of the intestinal epithelium were used to test the hypothesis that CXCR4 regulates mucosal barrier integrity in vivo. Epithelial expression of CXCR4 was assessed by RT-PCR, Southern blot, immunoblot and immunohistochemistry. In vivo wounding assays were performed by addition of 3% dextran sodium sulfate (DSS) in drinking water for 5 days. Intestinal damage and DAI scores were assessed by histological examination. Extracellular-regulated kinase (ERK) phosphorylation was assessed in vivo by immunoblot and immunofluorescence. CXCR4 knockdown cells were established using a lentiviral approach and ERK phosphorylation was assessed. Consistent with targeted roles in restitution, epithelium from patients with inflammatory bowel disease indicated that CXCR4 and CXCL12 expression was stable throughout the human colonic epithelium. Conditional CXCR4-deficient mice developed normally, with little phenotypic differences in epithelial morphology, proliferation or migration. Re-epithelialization was absent in CXCR4 conditional knockout mice following acute DSS-induced inflammation. In contrast, heterozygous CXCR4-depleted mice displayed significant improvement in epithelial ulcer healing in acute and chronic inflammation. Mucosal injury repair was correlated with ERK1/2 activity and localization along the crypt-villus axis, with heterozygous mice characterized by increased ERK1/2 activation. Lentiviral depletion of CXCR4 in IEC-6 cells similarly altered ERK1/2 activity and prevented chemokine stimulated migration. Taken together, these data indicate that chemokine receptors participate in epithelial barrier responses through coordination of the ERK1/2 signaling pathway. PMID- 21537330 TI - Cigarette smoking alters epithelial apoptosis and immune composition in murine GALT. AB - Smokers have a twofold increased risk to develop Crohn's disease (CD). However, little is known about the mechanisms through which smoking affects CD pathogenesis. Especially Crohn's ileitis is negatively influenced by smoking. Interestingly, the ileum and, more in particular, the Peyer's patches in the terminal ileum are also the sites where the first CD lesions are found. Several chemokines are implicated in the pathogenesis, among which is the CCL20-CCR6 pathway. Here, we studied the gut-associated lymphoid tissue in C57BL/6 wild-type mice and in CCR6-deficient mice after exposure to air or cigarette smoke for 24 weeks. Apoptotic index of the follicle-associated epithelium overlying the Peyer's patches was evaluated. We found that chronic smoke exposure induced apoptosis in the follicle-associated epithelium. Furthermore, immune cell numbers and differentiation along with chemokine expression were determined in Peyer's patches. Important changes in immune cell composition were observed: total dendritic cells, CD4+ T cells (including regulatory T cells) and CD8+ T cells increased significantly after smoke exposure. The CD11b+ dendritic cell subset almost doubled. Interestingly, these changes were accompanied by an upregulated mRNA expression of the chemokines CCL9 and CCL20. However, no differences in the increase of dendritic cells were observed between wild-type and CCR6-deficient mice. Our results show that cigarette smoke exposure increases apoptosis in the follicle-associated epithelium and is associated with immune cell accumulation in Peyer's patches. PMID- 21537331 TI - Antidepressants recruit new neurons to improve stress response regulation. AB - Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery. PMID- 21537332 TI - Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. AB - Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5 HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5 HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy. PMID- 21537333 TI - Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia. AB - High FLT3-ITD/wildtype (wt) load in FLT3-ITD-mutated AML has been associated with adverse impact on outcome in several studies. To clarify whether FLT3-ITD load as expressed as FLT3-ITD/wt ratio is also relevant in patients with NPM1 mutated AML, we assessed the FLT3-ITD mutation status and FLT3-ITD/wt ratio by fragment analysis in 638 NPM1mut AML (339 females; 299 males; 17.8-88.0 years), and analyzed its prognostic relevance in 355 patients. FLT3-ITD of various length and load were detected in 243/638 cases (38.1%). Median EFS (19.3 vs 9.7 months, P<0.001) and median 2-year survival rate (72.0 vs 52.7%, P=0.006) was better in FLT3wt (n=212 with available follow-up data) than FLT3-ITD (n=143). A higher FLT3 ITD/wt ratio as continuous variable was correlated with a shorter EFS (P=0.028). When patients were separated into subgroups according to the FLT3-ITD mutation load, only a FLT3-ITD/wt ratio ?0.5 conferred an independent adverse impact on EFS and OS, and retained its prognostic significance also in multivariate analysis (P=0.009 for EFS, P=0.008 for OS). In conclusion, for risk estimation in NPM1 mutated AML not only the FLT3-ITD status, but also the FLT3-ITD load has to be taken into account. These data might contribute to clinical decision making in AML. PMID- 21537334 TI - DNMT3A mutations in myeloproliferative neoplasms. PMID- 21537335 TI - Frequency and prognostic implications of JAK 1-3 aberrations in Down syndrome acute lymphoblastic and myeloid leukemia. PMID- 21537336 TI - Validity of the test-table-test for Nordic skiing for classification of paralympic sit-ski sports participants. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: To assess the interrater reliability and validity of the test-table-test (TTT) with which paralympic sports participants involved in Nordic sit-ski sports may be classified. SETTING: Movement laboratory in a rehabilitation centre, The Netherlands. METHODS: Thirty three persons with a spinal cord injury caudally to Th2, a leg amputation, poliomyelitis affecting the trunk and/or lower extremities, or cerebral palsy participated. Subjects were classified according to a classification system for Nordic skiing (that is, five subclasses between LW10 and LW12) by two raters, involving, among others, a combination of four balance tests called TTT. The validity of the TTT was investigated using a gold standard, involving balance perturbation tests on a force plate and centre of pressure (CoP) displacement measurements. RESULTS: As for the interrater reliability, Spearman's rank correlation coefficient was 0.95 (P<0.001). As regards the validity of the TTT, correlation coefficients ranging from 0.61 to 0.74 (P<0.001) were found when comparing the data with the gold standard. CONCLUSION: Interrater reliability was high in both scoring and classification. With regard to TTT validity, strong positive correlations between CoP displacement and TTT classification were found. Overall, the results of this study show that the TTT is a reliable and valid test. However, the relations between TTT and CoP displacement in the LW10 and LW10.5 subclasses found in this study are somewhat vague, which could be due to the small number of participants in these subclasses. For the LW10 and LW10.5 subclasses further refinement of the four tests within the TTT is warranted. PMID- 21537337 TI - Transdermal nitroglycerine treatment of shoulder tendinopathies in patients with spinal cord injuries. AB - STUDY DESIGN: A clinical blind study was conducted to determine the efficacy of transdermal nitroglycerine treatment on the awareness of shoulder pain. OBJECTIVE: This study aims to determine the effects of transdermal nitroglycerine on shoulder pain and on functional shoulder movement in patients with spinal cord injuries and shoulder tendinopathies. A second aim is to establish the side effects of the treatment. SETTING: Hospital "La Fe" in Valencia, Spain. METHODS: A total of 45 spinal cord injury patients, all of whom are wheelchair users with shoulder tendinopathy, were randomly divided into two groups: placebo (n=12) and experimental (n=33). The experimental group (EG) received transdermal treatment for 6 months in the form of a 1.25 mg nitroglycerine (NT) patch on the greater tubercle. A placebo patch was used with the placebo subjects. Functional shoulder movements were assessed by articular range of motion and pain, using a visual analogical scale. RESULTS: NT treatment reduced the awareness of shoulder pain and increased the functional movement and range of articular motion in the shoulders of the EG members (P<0.05). CONCLUSIONS: We conclude that transdermal NT is an efficient method for treating shoulder tendinopathies in wheelchair users with spinal cord injuries. PMID- 21537338 TI - Gait analysis following treadmill training with body weight support versus conventional physical therapy: a prospective randomized controlled single blind study. AB - STUDY DESIGN: Single-blind randomized, controlled clinical study. OBJECTIVES: To evaluate, using kinematic gait analysis, the results obtained from gait training on a treadmill with body weight support versus those obtained with conventional gait training and physiotherapy. SETTING: Thirty patients with sequelae from traumatic incomplete spinal cord injuries at least 12 months earlier; patients were able to walk and were classified according to motor function as ASIA (American Spinal Injury Association) impairment scale C or D. METHODS: Patients were divided randomly into two groups of 15 patients by the drawing of opaque envelopes: group A (weight support) and group B (conventional). After an initial assessment, both groups underwent 30 sessions of gait training. Sessions occurred twice a week, lasted for 30 min each and continued for four months. All of the patients were evaluated by a single blinded examiner using movement analysis to measure angular and linear kinematic gait parameters. Six patients (three from group A and three from group B) were excluded because they attended fewer than 85% of the training sessions. RESULTS: There were no statistically significant differences in intra-group comparisons among the spatial-temporal variables in group B. In group A, the following significant differences in the studied spatial temporal variables were observed: increases in velocity, distance, cadence, step length, swing phase and gait cycle duration, in addition to a reduction in stance phase. There were also no significant differences in intra-group comparisons among the angular variables in group B. However, group A achieved significant improvements in maximum hip extension and plantar flexion during stance. CONCLUSION: Gait training with body weight support was more effective than conventional physiotherapy for improving the spatial-temporal and kinematic gait parameters among patients with incomplete spinal cord injuries. PMID- 21537339 TI - Delayed diagnosis of vertebral osteomyelitis in a paraplegic patient. AB - STUDY DESIGN: Case report. OBJECTIVE: Vertebral osteomyelitis, usually presented with back pain and local tenderness, can pose a great challenge of early diagnosis among spinal cord injury (SCI) patients who lost sensation below the injured level. We reported a paraplegic patient who had recurrent febrile episodes after being treated as urinary tract infection initially and was discovered later to have vertebral osteomyelitis. CASE REPORT: A 41-year-old man, completely paralyzed at the T11 level and with Foley catheterization for 9 years, was re-admitted within 2 weeks for recurrent fever, turbid urine, bacteriuria and bacteremia with Escherichia coli. Spine X-ray and renal, cardiac and abdominal ultrasonography showed no definite lesions related to infection in a previous admission. Intermittently febrile episodes continued despite treatment with antibiotics for 1 week. He had no pressure sores or other wounds. Computerized tomography and magnetic resonance imaging showed lumbosacral osteomyelitis and bilateral paravertebral abscess. The patient underwent debridement of paravertebral tissue. Fever subsided soon after surgery and the patient continued antibiotics and remained free of fever at a 1-year follow-up. CONCLUSION: It can be challenging to diagnose vertebral osteomyelitis below injury levels in SCI patients. Vertebral osteomyelitis should be considered in febrile SCI patients even with known infectious foci, as classic symptoms of osteomyelitis are lacking in this population. PMID- 21537340 TI - When versatility matters: activins/inhibins as key regulators of immunity. AB - Activins and inhibins are members of the transforming growth factor-beta superfamily that have been considered crucial regulators of cell processes, such as differentiation, proliferation and apoptosis, in different cell types. Initial studies about the function of activin A in the immune system focused on the regulation of hematopoiesis in the bone marrow under homeostatic and inflammatory conditions. Recent data provide a more comprehensive understanding about the role of activins/inhibins in the immune system. Novel findings included in this review point out the important requirement of activin/inhibin signaling to maintain the balance between homeostatic and inflammatory signals that are required for the optimal development and function of immune cells. The purpose of this review is to highlight the versatile nature of activins/inhibins as key regulators of both the innate and adaptive immune responses. PMID- 21537341 TI - Bacterial lipoprotein-induced tolerance is reversed by overexpression of IRAK-1. AB - Tolerance to bacterial cell wall components including bacterial lipoprotein (BLP) represents an essential regulatory mechanism during bacterial infection. Reduced Toll-like receptor 2 (TLR2) and IL-1 receptor-associated kinase 1 (IRAK-1) expression is a characteristic of the downregulated TLR signaling pathway observed in BLP-tolerised cells. In this study, we attempted to clarify whether TLR2 and/or IRAK-1 are the key molecules responsible for BLP-induced tolerance. Transfection of HEK293 cells and THP-1 cells with the plasmid encoding TLR2 affected neither BLP tolerisation-induced NF-kappaB deactivation nor BLP tolerisation-attenuated pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) production, indicating that BLP tolerance develops despite overexpression of TLR2 in these cells. In contrast, overexpression of IRAK-1 reversed BLP-induced tolerance, as transfection of IRAK-1 expressing vector resulted in a dose-dependent NF-kappaB activation and TNF-alpha release in BLP tolerised cells. Furthermore, BLP-tolerised cells exhibited markedly repressed NF kappaB p65 phosphorylation and impaired binding of p65 to several pro inflammatory cytokine gene promoters including TNF-alpha and interleukin-6 (IL 6). Overexpression of IRAK-1 restored the nuclear transactivation of p65 at both TNF-alpha and IL-6 promoters. These results indicate a crucial role for IRAK-1 in BLP-induced tolerance, and suggest IRAK-1 as a potential target for manipulation of the TLR-mediated inflammatory response during microbial sepsis. PMID- 21537342 TI - Suppressors of cytokine signaling inhibit effector T cell responses during Mycobacterium tuberculosis infection. AB - Protective immune responses during Mycobacterium tuberculosis (M. tuberculosis) infection are regulated at multiple levels and critically dependent on the balance in the secretion of pro-inflammatory and regulatory cytokines. A key factor that governs this balance at the cellular level is suppressors of cytokine signaling (SOCS). We recently demonstrated that toll-like receptor 2 and dendritic cell (DC)-SIGNR1 differentially regulate SOCS1 expression in DCs during M. tuberculosis infection. This consecutively regulated IL-12 production and determined M. tuberculosis survival. In this study, we characterized the role of SOCS1 in regulating effector responses from CD4(+) and CD8(+) T cells during M. tuberculosis infection. Our data indicate that T cells from M. tuberculosis infected mice show increased and differential association of SOCS1 with CD3 and CD28, when compared with uninfected mice. While SOCS1 displays increased association with CD3 than CD28 in CD4(+) T cells; SOCS1 is associated more with CD28 than CD3 in CD8(+) T cells. Further, SOCS1 shows increased association with IL-12 and IL-2 receptors in both CD4(+) and CD8(+) T cells from infected mice when compared with naive mice. Silencing SOCS1 in T cells increased signal transduction from T cell receptor (TCR) and CD28 with enhanced activation of key signaling molecules and proliferation. Significantly, SOCS1-silenced T cells mediated enhanced clearance of M. tuberculosis inside macrophages. Finally, adoptive transfer of SOCS1-silenced T cells in M. tuberculosis-infected mice mediated significant reduction in M. tuberculosis loads in spleen. These results exemplify the negative role played by SOCS1 during T cell priming and effector functions during M. tuberculosis infection. PMID- 21537344 TI - New blood brothers: the GPR55 and CB2 partnership. PMID- 21537346 TI - Budget impact analysis of a new prostate cancer risk index for prostate cancer detection. AB - The objective of this study was to evaluate the budget impact of a new prostate cancer risk index for detecting prostate cancer. The index is calculated as the combination of serum prostate-specific antigen (PSA), free PSA and a precursor form p2PSA. We constructed two budget impact models using PSA cutoff values of >=2 ng ml(-1) (model #1) and >=4 ng ml(-1) (model #2) for recommending a prostate biopsy in a hypothetical health plan with 100 000 male members aged 50-75 years old. The budgetary impact on the 1-year expected total costs for prostate cancer detection was calculated. Adding the index to the current PSA prostate cancer testing strategies including the total PSA and percent free PSA, the number of detected cancer cases decreased by 20 and 5, in models #1 and #2, respectively. The savings on expected 1-year cost for prostate cancer detection were $356 647 (or $0.30 per-member-per-month (PMPM)) in model #1 and $94 219 ($0.08 PMPM) in model #2. The index produced higher cost savings in the model #1 with PSA cutoff >=2 ng ml(-1) than the model #2 with cutoff >=4 ng ml(-1) with a small short-term reduction in the number of positive tests. PMID- 21537343 TI - Proteostasis regulation at the endoplasmic reticulum: a new perturbation site for targeted cancer therapy. AB - To deal with the constant challenge of protein misfolding in the endoplasmic reticulum (ER), eukaryotic cells have evolved an ER protein quality control (ERQC) mechanism that is integrated with an adaptive stress response. The ERQC pathway is comprised of factors residing in the ER lumen that function in the identification and retention of aberrantly folded proteins, factors in the ER membrane for retrotranslocation of misfolded polypeptides, and enzymes in the cytosol that degrade retrotranslocated proteins. The integrated stress response (termed ER stress or unfolded protein response, UPR) contains several signaling branches elicited from the ER membrane, which fine-tune the rate of protein synthesis and entry into the ER to match the ER folding capacity. The fitness of the cell, particularly those bearing a high secretory burden, is critically dependent on functional integrity of the ER, which in turn relies on these stress attenuating mechanisms to maintain protein homeostasis, or proteostasis. Aberrant proteostasis can trigger cellular apoptosis, making these adaptive stress response systems attractive targets for perturbation in treatment of cell malignancies. Here, we review our current understanding of how the cell preserves ER proteostasis and discuss how we may harness the mechanistic information on this process to develop new cancer therapeutics. PMID- 21537345 TI - Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels. AB - Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation. PMID- 21537347 TI - Outcomes of extremely low risk prostate cancer following radical prostatectomy. AB - The optimal management of men with very favorable clinicopathological factors who develop biochemical recurrence (BCR) after radical prostatectomy (RP) has not been previously reported. Both local and systemic recurrences are unlikely in this cohort. This study examines their management and outcomes. Between October 2000 to March 2010, 1627 men underwent open RP by a single surgeon. In all, 448 (27.5%) met the following criteria for extremely low risk disease: preoperative PSA level <10 ng ml(-1), clinical stage T1c/T2a, Gleason score ?6, estimated cancer volume in the surgical specimen ?5% and no evidence for positive surgical margin. Undetectable PSA was defined as ?0.04 ng ml(-1). BCR was defined as PSA ?0.2 ng ml(-1) or initiation of salvage radiation therapy (SRT) for progressively rising PSA. At 54 months mean follow-up (range 3-114 months), 9 (2%) of the 448 men developed BCR. Mean time to BCR was 63 months (range 12-93) and mean PSA doubling time was 15 months (range 6-27). Six underwent SRT, two elected surveillance and one was lost to follow-up. All men undergoing SRT exhibited more than 75% reduction in pre-SRT PSA, indicating the presence of local disease recurrence. All men undergoing SRT maintained PSA levels <0.1 at last follow-up. The BCR of 2% confirmed that we selected a cohort with extremely low risk for BCR after RP. We demonstrated that men fulfilling our criteria who develop BCR all harbor local disease based on favorable response to SRT. These men should be managed with SRT if recurrence is felt to be biologically significant. PMID- 21537348 TI - The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus. AB - Many rare kidney disorders exhibit a monogenic, Mendelian pattern of inheritance. Population-based genetic studies have identified many genetic variants associated with an increased risk of developing common kidney diseases. Strongly associated variants have potential clinical uses as predictive markers and may advance our understanding of disease pathogenesis. These principles are elegantly illustrated by a region within chromosome 22q12 that has a strong association with common forms of kidney disease. Researchers had identified DNA sequence variants in this locus that were highly associated with an increased prevalence of common chronic kidney diseases in people of African ancestry. Initial research concentrated on MYH9 as the most likely candidate gene; however, population-based whole-genome analysis enabled two independent research teams to discover more strongly associated mutations in the neighboring APOL1 gene. The powerful evolutionary selection pressure of an infectious pathogen in West Africa favored the spread of APOL1 variants that protect against a lethal form of African sleeping sickness but are highly associated with an increased risk of kidney disease. We describe the data sources, process of discovery, and reasons for initial misidentification of the candidate gene, as well as the lessons that can be learned for future population genetics research. PMID- 21537349 TI - Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. AB - Many lines of evidence, ranging from in vitro experiments and pathological examinations to epidemiological studies, show that inflammation is a cardinal pathogenetic mechanism in diabetic nephropathy. Thus, modulation of inflammatory processes in the setting of diabetes mellitus is a matter of great interest for researchers today. The relationships between inflammation and the development and progression of diabetic nephropathy involve complex molecular networks and processes. This Review, therefore, focuses on key proinflammatory molecules and pathways implicated in the development and progression of diabetic nephropathy: the chemokines CCL2, CX3CL1 and CCL5 (also known as MCP-1, fractalkine and RANTES, respectively); the adhesion molecules intercellular adhesion molecule 1, vascular cell adhesion protein 1, endothelial cell-selective adhesion molecule, E selectin and alpha-actinin 4; the transcription factor nuclear factor kappaB; and the inflammatory cytokines IL-1, IL-6, IL-18 and tumor necrosis factor. Advances in the understanding of the roles that these inflammatory pathways have in the context of diabetic nephropathy will facilitate the discovery of new therapeutic targets. In the next few years, promising new therapeutic strategies based on anti-inflammatory effects could be successfully translated into clinical treatments for diabetic complications, including diabetic nephropathy. PMID- 21537350 TI - Mineral metabolism and vitamin D in chronic kidney disease--more questions than answers. AB - Patients with chronic kidney disease (CKD) are at increased risk of total and cardiovascular morbidity and mortality. The underlying pathophysiology of this association remains largely unexplained and there is currently no clear interventional pathway. Emphasis has been placed on measuring serum levels of calcium, phosphate and parathyroid hormone (PTH) to monitor disease progression, driven by the assumption that achieving values within the 'normal' range will translate into improved outcomes. Retrospective studies have provided a body of evidence that abnormal levels of mineral biomarkers, and phosphate in particular, are associated with clinical events. Disturbances in vitamin D metabolism are also likely to contribute to the pathophysiology of CKD. Designing studies that yield useful information has proved to be difficult, partly owing to conceptual and financial limitations, but also because of the tight interdependency of calcium, phosphate and PTH, and the potential impact of vitamin D on these mineral metabolites. An intervention that perturbs any one of these factors is likely to exert effects on the others, making isolation of the individual variables almost impossible. However, some therapies in current use have the potential to act as probes to answer questions relating to the association between mineral biomarkers and outcomes in CKD. PMID- 21537352 TI - Stroke: Predicting outcome after ischemic stroke-hard but achievable. PMID- 21537353 TI - Peripheral neuropathies: Establishing common clinical research standards for CIDP. PMID- 21537351 TI - Autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is an inflammatory liver disease that mainly affects females. It is characterized histologically by interface hepatitis, biochemically by increased aspartate and alanine aminotransferase levels, and serologically by the presence of autoantibodies and increased levels of immunoglobulin G. AIH affects both adults and children, and is particularly aggressive in the latter group. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. Those patients who progress to end-stage liver disease because they are unresponsive or nonadherent to treatment, and those with fulminant liver failure (encephalopathy grade II-IV) at diagnosis, require liver transplantation. Seropositivity for smooth muscle and/or antinuclear antibodies defines type 1 AIH, while positivity for liver kidney microsomal type 1 antibodies defines type 2 AIH. The primary cause of AIH is unknown; however, considerable knowledge about the mechanisms of liver damage involved has been gathered over the past 30 years, which is likely to provide the basis for specific modes of treatment and a possible cure. PMID- 21537354 TI - Multiple sclerosis: the evolving diagnostic criteria for multiple sclerosis. PMID- 21537356 TI - White matter disease: Roles of anti-MOG antibodies in demyelinating diseases. PMID- 21537355 TI - Depression and risk of developing dementia. AB - Depression is highly common throughout the life course and dementia is common in late life. Depression has been linked with dementia, and growing evidence implies that the timing of depression may be important in defining the nature of this association. In particular, earlier-life depression (or depressive symptoms) has consistently been associated with a more than twofold increase in dementia risk. By contrast, studies of late-life depression and dementia risk have been conflicting; most support an association, yet the nature of this association (for example, if depression is a prodrome or consequence of, or risk factor for dementia) remains unclear. The likely biological mechanisms linking depression to dementia include vascular disease, alterations in glucocorticoid steroid levels and hippocampal atrophy, increased deposition of amyloid-beta plaques, inflammatory changes, and deficits of nerve growth factors. Treatment strategies for depression could interfere with these pathways and alter the risk of dementia. Given the projected increase in dementia incidence in the coming decades, understanding whether treatment for depression alone, or combined with other regimens, improves cognition is of critical importance. In this Review, we summarize and analyze current evidence linking late-life and earlier-life depression and dementia, and discuss the primary underlying mechanisms and implications for treatment. PMID- 21537358 TI - Surgery: surgical quality assurance for robot-assisted prostatectomy. PMID- 21537357 TI - Neuroimmunology: Assessing the value of plasma exchange in neurology. PMID- 21537360 TI - Internet-delivered exposure-based treatment vs. stress management for irritable bowel syndrome: a randomized trial. AB - OBJECTIVES: Our research group has developed an internet-delivered cognitive behavioral treatment (ICBT) for irritable bowel syndrome (IBS). We compared ICBT with internet-delivered stress management (ISM) for IBS to assess whether the effects of ICBT are specific. METHODS: This was a randomized controlled trial, including 195 self-referred participants diagnosed with IBS. The treatment interventions lasted for 10 weeks and included an online therapist contact. The ICBT emphasized acceptance of symptoms through exposure to IBS symptoms and related negative feelings. The ICBT also included mindfulness training. The ISM emphasized symptom control through relaxation techniques, dietary adjustments, and problem-solving skills. Severity of IBS symptoms was measured with the gastrointestinal symptom rating scale-IBS version (GSRS-IBS). Credibility of the treatments and expectancy of improvement were assessed with the treatment credibility scale. The participants' perceived therapeutic alliance with their online therapist was measured with the working alliance inventory. RESULTS: At post-treatment and 6-month follow-up, 192 (99%) and 169 (87%) participants returned data, respectively. At post-treatment and 6-month follow-up, we found significant differences on the GSRS-IBS, favoring ICBT. The difference on GSRS IBS scores was 4.8 (95% confidence interval (CI): 1.2-8.4) at post-treatment and 5.9 (95% CI: 1.9-9.9) at 6-month follow-up. There were no significant differences on the treatment credibility scale or the working alliance inventory between the groups. CONCLUSIONS: Internet-delivered CBT has specific effects that cannot be attributed only to treatment credibility, expectancy of improvement, therapeutic alliance, or attention. Furthermore, a treatment based on exposure exercises specifically tailored for IBS may be a better treatment option than general stress and symptom management for IBS patients. ICBT is a promising treatment modality for IBS as it can be offered to IBS patients in much larger scale than conventional psychological treatments. PMID- 21537359 TI - Increased risks of developing anxiety and depression in young patients with Crohn's disease. AB - OBJECTIVES: Crohn's disease (CD) is associated with substantial psychosocial burden and increased risks for mental health disorders. This retrospective cohort study compared the risks of developing anxiety disorders and depression and incidences of psychotropic medication use between young CD patients and matched CD-free controls. METHODS: Medical claims, prescription drug claims, enrollment, and demographic data for patients <18 years diagnosed with CD were obtained from the MarketScan database (1 January 2000-30 June 2006). Each CD patient was matched with five CD-free controls based on exact age, sex, and months of health plan enrollment. Incidence rates and risks of developing anxiety disorders and depression and psychotropic medication use in the 6 months after the index date were compared, as were risks of developing persistent anxiety or depression (receiving medical services related to a diagnosis of anxiety or depression or psychotropic therapy for >1 year). RESULTS: After adjustment for patient characteristics, the risks of developing anxiety disorders (hazard ratio (HR) [95% confidence interval (CI);[equals;2.28 [1.65-3.17]) and depression (HR [95% CI;[equals;1.74 [1.35-2.25]) after CD diagnosis were significantly greater for the CD cohort (N=2,144) than for CD-free controls (N=10,720). Patients with CD also had greater risks of developing persistent anxiety and persistent depression (HR [95% CI;[equals;4.35 [2.22-8.50] and 2.75 [1.73-4.38], respectively). CONCLUSIONS: Compared with matched CD-free controls, young patients with CD had significantly greater risks of developing anxiety disorders and depression, were more likely to receive psychotropic treatments, and had significantly greater risks of developing persistent anxiety and depression. PMID- 21537361 TI - Response of regurgitation to proton pump inhibitor therapy in clinical trials of gastroesophageal reflux disease. AB - OBJECTIVES: The typical symptoms of gastroesophageal reflux disease (GERD) are heartburn and regurgitation. Extensive analysis has characterized heartburn and its responsiveness to proton pump inhibitor (PPI) therapy, but regurgitation has received relatively little attention. This study aimed to evaluate the response of regurgitation to PPI therapy in GERD trials. METHODS: Studies were identified by systematic searches in PubMed and Embase, as well as searching congress abstracts and the reference lists of Cochrane reviews. RESULTS: Regurgitation was not an entry criterion or the primary end point in any of the 31 clinical trials reporting the response of regurgitation to PPI treatment in GERD. The definitions of regurgitation and responsiveness varied among trials and over half used investigator assessment of response. Owing to these inconsistencies, no meta analysis was attempted. In seven placebo-controlled trials of PPI therapy, the therapeutic gain for regurgitation response averaged 17% relative to placebo and was >20% less than that observed for heartburn. Studies comparing PPIs with histamine-2 receptor antagonists or prokinetics found the comparator drug response similar to the placebo response rates seen in the placebo-controlled trials. CONCLUSIONS: The therapeutic gain with PPIs over placebo or comparator agents for the relief of regurgitation is modest, and considerably lower than for heartburn. Thus, regurgitation is likely to be an important factor for determining incomplete response to PPI treatment in GERD. Future trials would benefit from using regurgitation as a primary end point, applying an unambiguous definition of the symptom and of a positive treatment response, and using a validated patient-reported instrument for regurgitation assessment. PMID- 21537362 TI - Bisphosphonates and esophageal cancer--a pathway through the confusion. AB - Two recent papers that examined the association between oral bisphosphonates and the risk of esophageal cancer reported seemingly discrepant findings, despite both studies using data from the UK General Practice Research Database, from similar time periods. Each paper set out brief conclusions within their abstracts, generating two opposing impressions: that the risk of incident esophageal cancer is not significantly increased with bisphosphonate use, or that the risk is increased when bisphosphonates have been prescribed ten or more times, or for longer than 5 years. Of course, the latter conclusion was more widely reported in the popular press, and with patients arriving at the clinic wanting to discuss the reports, clinicians must be able to interpret the existing evidence correctly. In this article we discuss important methodological issues regarding the two observational studies, define areas of consensus and discrepancy, examine possible bias and confounding, and condense the results into a clinically useful summary. PMID- 21537363 TI - Hepatitis C-related cirrhosis with sustained prevention of hepatocellular carcinoma recurrence by long-term administration of super-low-dose peginterferon alpha 2b. AB - A 78-year-old male who experienced multiple recurrences of hepatocellular carcinoma (HCC) with hepatitis C virus (HCV)-related cirrhosis underwent transcatheter arterial chemoembolization and ablation and survived for more than 10 years. His serum HCV RNA level was 2.8 log IU/ml and the serotype of HCV was 2. He underwent long-term super-low-dose (20 MUg/week) pegylated interferon-alpha 2b therapy to prevent recurrence of HCC. He became negative for HCV RNA 2 months later, and thereafter remained negative after the discontinuation of interferon therapy, and has not experienced a recurrence of HCC for more than 20 months. PMID- 21537364 TI - Surgical treatment of coledochal cyst associated with an aberrant posterior hepatic duct: report of a case and brief literature review. AB - Choledochal cysts (CCs) are rare congenital cystic or fusiform dilatations of the biliary tree that can involve the extrahepatic and/or intrahepatic biliary tree. We report a case of huge type I CC associated with an aberrant posterior hepatic duct. A 52-year-old man presented with a 3-week history of upper right abdominal pain and jaundice and serologic sign of obstructive jaundice. Ultrasonography (US), magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography were performed with the diagnosis of CC type I according to the classification of Alonso-Lej and Todani-Watanabe. The indication for surgical resection was posed. The cyst was completely resected and the biliary tract was reconstructed with a double hepatico-jejunostomy using the same Roux limb, since during the surgical dissection a before unrecognized anatomical variation of the right biliary tree (aberrant posterior hepatic duct at VI-VII segment) was identified. The diagnosis of CC is often difficult and US and magnetic resonance cholangiopancreatography are necessary to definite biliary dilatation. Endoscopic retrograde cholangiopancreatography should be the most definitive and reliable procedure for the diagnosis and treatment of bilio pancreatic disorders. Gold standard treatment is surgery (bilio-jejunostomy) and frozen-section histology should be performed to rule out the presence of cancer. In conclusion, surgery is the gold standard for the treatment of CC type I and does not depend on the age of patients, based on a substantial lifetime risk of developing cholangiocarcinoma. Preoperative study is mandatory to assess the biliary tree morphology and to research any anatomical variation. PMID- 21537365 TI - Comments on Jo and Colleagues' Paper (2010) "Association of Subway Driver's Depressive Symptoms and Experience of Work-Related Problems". PMID- 21537366 TI - HIV aspartyl protease inhibitors as promising compounds against Candida albicans Andre Luis Souza dos Santos. AB - Cells of Candida albicans (C. albicans) can invade humans and may lead to mucosal and skin infections or to deep-seated mycoses of almost all inner organs, especially in immunocompromised patients. In this context, both the host immune status and the ability of C. albicans to modulate the expression of its virulence factors are relevant aspects that drive the candidal susceptibility or resistance; in this last case, culminating in the establishment of successful infection known as candidiasis. C. albicans possesses a potent armamentarium consisting of several virulence molecules that help the fungal cells to escape of the host immune responses. There is no doubt that the secretion of aspartyl-type proteases, designated as Saps, are one of the major virulence attributes produced by C. albicans cells, since these hydrolytic enzymes participate in a wide range of fungal physiological processes as well as in different facets of the fungal host interactions. For these reasons, Saps clearly hold promise as new potential drug targets. Corroborating this hypothesis, the introduction of new anti-human immunodeficiency virus drugs of the aspartyl protease inhibitor-type (HIV PIs) have emerged as new agents for the inhibition of Saps. The introduction of HIV PIs has revolutionized the treatment of HIV disease, reducing opportunistic infections, especially candidiasis. The attenuation of candidal infections in HIV infected individuals might not solely have resulted from improved immunological status, but also as a result of direct inhibition of C. albicans Saps. In this article, we review updates on the beneficial effects of HIV PIs against the human fungal pathogen C. albicans, focusing on the effects of these compounds on Sap activity, growth behavior, morphological architecture, cellular differentiation, fungal adhesion to animal cells and abiotic materials, modulation of virulence factors, experimental candidiasis infection, and their synergistic actions with classical antifungal agents. PMID- 21537367 TI - Anticancer actions of PPARgamma ligands: Current state and future perspectives in human lung cancer. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors and members of the nuclear receptor superfamily. Of the three PPARs identified to date (PPARgamma, PPARbeta/delta, and PPARalpha), PPARgamma has been studied the most, in part because of the availability of PPARgamma agonists (also known as PPARgamma ligands) and its significant effects on the management of several human diseases including type 2 diabetes, metabolic syndrome, cardiovascular disease and cancers. PPARgamma is expressed in many tumors including lung cancer, and its function has been linked to the process of lung cancer development, progression and metastasis. Studies performed in gynogenic and xenograft models of lung cancer showed decreased tumor growth and metastasis in animals treated with PPARgamma ligands. Furthermore, data are emerging from retrospective clinical studies that suggest a protective role for PPARgamma ligands on the incidence of lung cancer. This review summarizes the research being conducted in this area and focuses on the mechanisms and potential therapeutic effects of PPARgamma ligands as a novel anti-lung cancer treatment strategy. PMID- 21537368 TI - MicroRNA: A matter of life or death. AB - Progressive cell loss due to apoptosis is a pathological hallmark implicated in a wide spectrum of degenerative diseases such as heart disease, atherosclerotic arteries and hypertensive vessels, Alzheimer's disease and other neurodegenerative disorders. Tremendous efforts have been made to improve our understanding of the molecular mechanisms and signaling pathways involved in apoptosistic cell death. Once ignored completely or overlooked as cellular detritus, microRNAs (miRNAs) that were discovered only a decade ago, have recently taken many by surprise. The importance of miRNAs has steadily gained appreciation and miRNA biology has exploded into a massive swell of interest with enormous range and potential in almost every biological discipline because of their widespread expression and diverse functions in both animals and humans. It has been established that miRNAs are critical regulators of apoptosis of various cell types. These small molecules act by repressing the expression of either the proapoptotic or antiapoptotic genes to produce antiapoptotic or proapoptotic effects. Appealing evidence has been accumulating for the involvement of miRNAs in human diseases associated with apoptotic cell death and the potential of miRNAs as novel therapeutic targets for the treatment of the diseases. This editorial aims to convey this message and to boost up the research interest by providing a timely, comprehensive overview on regulation of apoptosis by miRNAs and a synopsis on the pathophysiologic implications of this novel regulatory network based on the currently available data in the literature. It begins with a brief introduction to apoptosis and miRNAs, followed by the description of the fundamental aspects of miRNA biogenesis and action, and the role of miRNAs in regulating apoptosis of cancer cells and cardiovascular cells. Speculations on the development of miRNAs as potential therapeutic targets are also presented. Remarks are also provided to point out the unanswered questions and to outline the new directions for the future research of the field. PMID- 21537369 TI - Plasma membrane calcium ATPase proteins as novel regulators of signal transduction pathways. AB - Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs regulate these pathways by targeting specific proteins to cellular sub-domains where the levels of intracellular free calcium are kept low by the calcium ejection properties of PMCAs. According to this model, PMCAs have been shown to interact functionally with the calcium sensitive proteins neuronal nitric oxide synthase, calmodulin-dependent serine protein kinase, calcineurin and endothelial nitric oxidase synthase. Transgenic animals with altered expression of PMCAs are being used to evaluate the physiological significance of these interactions. To date, PMCA interactions with calcium-dependent partner proteins have been demonstrated to play a crucial role in the pathophysiology of the cardiovascular system via regulation of the nitric oxide and calcineurin/nuclear factor of activated T cells pathways. This new evidence suggests that PMCAs play a more sophisticated role than the mere ejection of calcium from the cells, by acting as modulators of signaling transduction pathways. PMID- 21537371 TI - Sequential acral lentiginous melanomas of the foot. AB - A 64-year-old Japanese woman had a lightly brown-blackish pigmented macule (1.2 cm in diameter) on the left sole of her foot. She received surgical excision following a diagnosis of acral lentiginous melanoma (ALM), which was confirmed histopathologically. One month after the operation, a second melanoma lesion was noticed adjacent to the grafted site. Histopathologically, the two lesions had no continuity, but HMB-45 and cyclin D(1) double-positive cells were detected not only on aggregates of atypical melanocytes but also on single cells near the cutting edge of the first lesion. The unique occurrence of a sequential lesion of a primary melanoma might be caused by stimulated subclinical field cells during the wound healing process following the initial operation. This case warrants further investigation to establish the appropriate surgical margin of ALM lesions. PMID- 21537372 TI - Efficiency of photodynamic therapy in the treatment of diffuse facial viral warts in an immunosuppressed patient: towards a gold standard? AB - A 64-year-old man with a pulmonary transplant developed diffuse verrucae vulgares of the neck. After the failure of multiple cryotherapy treatments, 3 sessions of photodynamic therapy resulted in rapid therapeutic clinical success. This moderately painful and well-tolerated treatment is reproducible and can be very useful in treating papillomavirus infections in the immunosuppressed patient. PMID- 21537370 TI - The Role of Nutrition in Sickle Cell Disease. AB - Finding a widely available cure for sickle cell anemia (HbSS) still remains a challenge one hundred years after its discovery as a genetically inherited disease. However, growing interest in the nutritional problems of the disease has created a body of literature from researchers seeking nutritional alternatives as a means of decreasing morbidity and improving quality of life among HbSS patients. This review demonstrates that over the past 30 years the role of protein/energy deficiency in HbSS has been more clearly defined via direct measurements, leading to the concept of a relative shortage of nutrients for growth and development, despite apparently adequate dietary intakes. Although there is still a paucity of data supporting the efficacy of macronutrient supplementation, it is becoming clearer that recommended dietary allowances (RDAs) for the general population are insufficient for the sickle cell patient. A similar shortage is likely to be true for micronutrient deficiencies, including recent findings of vitamin D deficiency that may be associated with incomplete ossification and bone disease, which are well known complications of HbSS disease. We conclude that there is need for more effort and resources to be dedicated to research (including supplementation studies of larger sample size) aimed at establishing specific RDAs for HbSS patients, much like the specific RDAs developed for pregnancy and growth within the general population. PMID- 21537373 TI - Palmar-plantar erythrodysesthesia associated with chemotherapy and its treatment. AB - Palmar-plantar erythrodysesthesia (PPE), also called hand-foot syndrome, is a relatively common dermatologic toxic reaction associated with cytotoxic chemotherapy that can limit the use of such drugs. Definitive prevention and treatment strategies for PPE have not yet been established. We present a patient with recurrent ovarian cancer developing severe hand-foot syndrome after treatment with pegylated liposomal doxorubicin. A review of the relevant literature concerning pathophysiology, preventive measures and management of PPE is given. Electronic search was conducted using the Medline database for English language records. The search terms used were 'palmar-plantar erythrodysesthesia', 'hand-foot syndrome', 'pegylated liposomal doxorubicin' and 'acral erythema'. PMID- 21537374 TI - A Retroperitoneal Dedifferentiated Liposarcoma Producing Granulocyte Colony Stimulating Factor Accompanied by Spontaneous Rupture: PET/CT Imaging of a G-CSF Producing Tumor. AB - The patient was a 63-year-old man who was referred to our hospital as an emergency case with the chief complaint of abdominal pain. An abdominal CT revealed a right retroperitoneal tumor of 15 cm and retroperitoneal bleeding. After a transcatheter arterial embolization was performed, the patient was transferred to our department. There was no infective focus. The white blood cell (WBC) count (37,820/MUl, normal range <8 pg/ml) and the serum granulocyte colony stimulating factor (G-CSF) level (2,670 pg/ml, normal range <8 pg/ml) were high. Bone marrow biopsy revealed little fat, significant hyperplasia, and predominantly increased neutrophils, but no findings of bone metastasis or bone marrow involvement. A G-CSF-producing tumor was diagnosed and right nephrectomy and retroperitoneal tumorectomy were performed. However, the tumor had infiltrated into the inferior vena cava, diaphragm and abdominal wall, and only part of the tumor could be removed. In histopathological tests, hematoxylin-eosin staining showed malignant fibrous histiocytoma-like findings mixed with those for well-differentiated liposarcoma, and the case was diagnosed as dedifferentiated liposarcoma. Preoperative (18)F-FDG-PET computed tomography showed diffuse (18)F FDG uptake throughout the bone marrow and elevated uptake at the tumor site. However, since bone biopsy and bone scintigraphy indicated no bone metastasis or bone marrow involvement, we concluded that PET/CT imaging gave false-positive results in the bone marrow. This is the first report of PET/CT imaging of a G-CSF producing tumor in a urological disease. The imaging results may be useful for differential diagnosis for this tumor in patients with high WBC counts without infection. PMID- 21537375 TI - Long-term survival with primary glioblastoma multiforme: a clinical study in bulgarian patients. AB - Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with an extremely poor prognosis in spite of multimodal treatment approaches. The estimated median survival in cases with GBM is about 12-16 months. Those patients who survive =3 years after the initial diagnosis are defined as long-term survivors. In this study, we retrospectively analyze 50 consecutive cases of Bulgarian patients with newly diagnosed GBM surgically treated at our institution for a period of 1 year. Four of them survived for more than 36 months after the initial intervention. The histological re-examination revealed features typical of primary GBM in 3 of these cases, which are described in detail in the present paper. A brief review of the relevant literature is also given. PMID- 21537376 TI - Severe Dyspnea due to Pulmonary Metastasis of Renal Cell Carcinoma: Is Cytoreductive Surgery of Value? AB - Here, we present a case in which cytoreductive surgery, like left radical nephrectomy, was effective in the treatment of pulmonary metastases and para aortic metastases from renal cell carcinoma. A 28-year-old man underwent left radical nephrectomy with pulmonary metastasectomy for the diagnosis of metastatic left renal cell carcinoma. The histologic diagnosis was clear cell carcinoma G2, pT3N1M1. He subsequently underwent i.m. administration of IFN-alpha, 5 million units per day for 30 days. The nasal oxygen mask was weaned gradually, and the chest tube was removable due to cessation of the continuous production of pleural fluid. The patient was well until one year after operation. PMID- 21537377 TI - Auricular oedema and dyshidrotic eczema in a patient with acute myeloid leukaemia treated with cytarabine. AB - Cytarabine is an effective drug in the treatment of haematological malignancies. The therapy is associated with various complications. Frequencies of dermatological side-effects range from 2-72% and occur most commonly after high dose regimens. Although most cutaneous reactions are mild and resolve spontaneously within several days, they may result in an increased risk of infection and alterations in comfort. In some cases, severe life-threatening reactions have been reported. Here we describe the case of a patient with acute myeloid leukaemia, who developed severe exceptional skin toxicity in terms of auricular oedema and palmar dyshidrotic eczema after the application of low-dose cytarabine. Re-administration of the drug resulted in reduced skin toxicity during further cycles of chemotherapy. Negative epicutaneous patch-testing supported the existence of cytarabine-provoked toxicity. PMID- 21537378 TI - Varied presentation of schwannoma - a case study. AB - Schwannomas can occur anywhere in the body with unusual presentation. They are difficult to diagnose preoperatively. Fine needle aspiration biopsy does not appear to provide an accurate preoperative diagnosis. Complete excision of the mass should be the goal of surgical excision. PMID- 21537379 TI - Wernicke's Encephalopathy in Colon Cancer. AB - Wernicke's syndrome, caused by thiamine deficiency, is most commonly associated with alcoholism but can also occur in patients who are malnourished or have malabsorption of nutrients for other reasons. Since the classic triad of encephalopathy, nystagmus and ataxia occurs simultaneously in only 10-33% of cases, a high index of suspicion is needed in any patient with confusion and memory loss. In this case report, we present a 56-year-old female patient with metastatic colon cancer complicated with enterocutaneous fistula. She developed Wernicke's encephalopathy precipitated by 5-fluorouracil infusion. Replacement with thiamine rapidly reversed her neurologic symptoms and signs. PMID- 21537380 TI - Favorable clinical course of patients experiencing bevacizumab-induced proteinuria. AB - Nephrotic-range proteinuria, which denotes structural damage to the glomerular filtration barrier, occurs in 1-2% of bevacizumab-treated patients. The glomerular injury and subsequent proteinuria is probably due to a direct targeting of vascular endothelial growth factor (VEGF). We report a case series of six patients who developed a syndrome characterized by proteinuria and hypertension after starting therapy with bevacizumab and who experienced prolonged progression-free survival. Given that altered glomerular permeability appears to be a direct consequence of VEGF inhibition, we hypothesize that proteinuria may indeed correlate with drug efficacy. Optimizing safe and effective drug dosing is critical to achieve the best therapeutic impact due to limited treatment options for many life-threatening advanced cancers. Clinicians should be aware that the development of proteinuria might serve as a surrogate marker of bevacizumab antitumor efficacy and determine the appropriate criteria for withholding this effective anticancer therapy. PMID- 21537381 TI - Aplasia and agenesis of the frontal sinus in Turkish individuals: a retrospective study using dental volumetric tomography. AB - Agenesis of the paranasal sinuses is an uncommon clinical condition that appears mainly in the frontal (12%) and maxillary (5-6%) sinuses; in some populations, it appears at a higher proportion. This study investigated the prevalence of agenesis of the frontal sinuses using dental volumetric tomography (DVT) in Turkish individuals. The frontal sinuses of 410 patients were examined by DVT scans in the coronal planes for evidence of the absence of the frontal sinuses. A bilateral and unilateral absence of the frontal sinuses was seen in 0.73% and 1.22% of cases, respectively. In one case, both agenesis and aplasia of the frontal sinus was seen (0.24%). The low percentage of frontal sinus agenesis must be considered during pre-surgical planning related to the sinuses. DVT may be used as a diagnostic tool for the examination of frontal sinus aplasia. PMID- 21537382 TI - The development of molecular epidemiology to elucidate cancer risk and prognosis: a historical perspective. AB - Molecular epidemiology in cancer research grew from the field of chemical carcinogenesis and the use biomarkers for environmental exposures, with incorporation of principles from early pharmacogenetics. Over the years, molecular epidemiology has become extremely complex, with studies evaluating associations between cancer risk and prognosis and numerous markers of susceptibility, exposure and early effects, as well as epidemiologic factors. In this article, we review the field of molecular epidemiology from a historical perspective, commenting on current status of the field and future directions. PMID- 21537383 TI - Expression of sulfotransferase isoform 1A1 (SULT1A1) in breast cancer cells significantly increases 4-hydroxytamoxifen-induced apoptosis. AB - Previously, we reported a strong association of the high activity SULT1A1*1 allele and overall survival of patients receiving tamoxifen therapy, indicating that sulfation of 4-hydroxytamoxifen (4-OHT) via SULT1A1 may contribute to the therapeutic efficacy of tamoxifen treatment. In most, but not all cases, sulfation is considered to be an elimination pathway; therefore we sought to define the biological mechanism by which increased sulfation of tamoxifen could provide a therapeutic benefit. We compared the antiproliferative and apoptotic responses between MCF7-SULT1A1 expressing cells and control MCF7 pcDNA3 cells when treated with 4-OHT. We observed a greater than 30% decrease in cell proliferation in MCF7-SULT1A1 expressing cells at physiological concentrations of 4-OHT, and significant cell death in SULT1A1-expressing cells treated with 2uM 4 OHT for 48 hours compared to control cells (p<0.05). Within 24 hours of drug treatment, an 80% increase in apoptosis in SULT1A1-expressing cells was apparent when compared to similarly treated cells that did not express SULT1A1. We also observed an increase in endonuclease G, the primary endonuclease expressed in ER dependent breast cancer cells, which participates in caspaseindependent apoptosis. These data confirm that SULT1A1-mediated biotransformation of 4-OHT is important in the efficacy of 4-OHT cytotoxicity in breast tumors, and reveals a potential role for sulfated metabolites in the efficacy of tamoxifen therapy. PMID- 21537384 TI - LRP-1 variation is not associated with risk of Alzheimer's disease. AB - Alzheimer's disease (AD) is characterised by the extensive deposition of amyloid beta (Abeta) within the parenchyma and vasculature of the brain. It is hypothesised that a dysfunction in Abeta degradation and/or its removal from the brain may result in accumulation as plaques. Low density lipoprotein receptor related protein-1 (LRP-1) is a multifunctional receptor shown to be involved in cholesterol metabolism but also the removal of Abeta from the brain. Its ability to transport Abeta from the brain to the periphery has made it an attractive candidate for involvement in Alzheimer's disease (AD). We have assessed the frequencies of 9 tag- SNPs and the commonly studied synonymous SNP within exon 3 (rs1799986) in a multi-centre AD/control cohort and performed haplotype analysis. We found no evidence from a combined total of 412 controls and 1057 AD patients to support the involvement of LRP-1 variation, including the most commonly studied variant in rs1799986 in conferring genetic susceptibility to increased risk of AD. PMID- 21537385 TI - Towards a more functional concept of causality in cancer research. AB - Advances in molecular technologies challenge the different concepts of causality in biology, epidemiology and multistage mathematical models. The lack of integration of the different aspects of causality into a common framework could postpone our attempts to build a human causal model of carcinogenesis. We present here some aspects of differences in methodology, terminology and traditions between the scientific disciplines and propose a research strategy using functional analyses of the transcriptome and epigenetics to illuminate causality in complex biological systems. Overcoming the challenges of biological material collection suitable for such analyses into a prospective design, this could give unique opportunities for verification of mechanistic information from basic biological research in a human model system. The ultimate goal is to obtain a dynamic causal description of the different carcinogenesis stages. The success of this novel approach depends on the biological relationship between the gene expression of the somatic driver mutations or co-expressed genes in tumours and the gene expressions mirrored in peripheral blood along the different stages of carcinogenesis. The use of gene expression profiles and epigenetics could produce a functional concept of causality to explain the human multistage carcinogenic process. PMID- 21537386 TI - Using In silico LD clumping and meta-analysis of genome-wide datasets as a complementary tool to investigate and validate new candidate biomarkers in Alzheimer's disease. AB - Despite the recent wealth of genome-wide association studies, insufficient power may explain why much of the heritable contribution to common diseases remains hidden. As different SNP panels are genotyped by commercial chips, increasing study power through meta-analysis is made problematic. To address these power issues we suggest an approach which permits meta-analysis of candidate SNPs from multiple GWAS. By identifying correlated SNPs from different platforms (r(2)=1), using PLINK's 'clumping' method, we generated combined p-values (using Fisher's combined and random effects meta-analysis) for each clump. P-values were corrected for the number of clumps (representing the number of independent tests). We also explored to what extent commercial platforms tag HapMap SNPs within these candidate genes. To illustrate this approach, and to serve as 'proof of-principle', we used 3 late-onset Alzheimer's disease GWAS datasets to explore SNP-disease associations in 4 new candidate genes encoding cerebro-spinal fluid biomarkers for Alzheimer's disease; Fibrinogen gamma-chain (FGG), SPARC-like1 (SPARCL1), Contactin-1 (CNTN1) and Contactin-2 (CNTN2). Genes encoding current Alzheimer's biomarkers; APP (Abeta), MAPT (Tau) and APOE were also included. This method identified two SNP 'clumps'; one clump in APOE (rs4420638) and one downstream of CNTN2 (which harboured rs7523477 and rs4951168) which were significant following random effects meta-analysis (P < 0.05). The latter was linked to three conserved SNPs in the 3'-UTR of CNTN2. We cannot rule out that this result is a false positive due to the large number of statistical tests applied; nevertheless this approach is easily applied and might well have utility in future '-omics' studies. PMID- 21537388 TI - Genetic risk factors of disc degeneration among 12-14-year-old Danish children: a population study. AB - The objective of the present study was to examine the associations between eleven putative predisposing single nucleotide polymorphisms (COL9A3, COL11A2, IL1A, IL1B, IL6 and VDR) and early disc degeneration (DD). The population consisted of 12 to 14-year-old Danish children (N=352). DD was evaluated from magnetic resonance images (MRI). We analysed the association between DD and single nucleotide polymorphisms or haplotypes using logistic regression analyses. Of the 352 children studied, 73 boys and 81 girls had no MRI changes, while 30 boys and 36 girls had lumbar DD. Among girls, IL1A rs1800587 in CT/TT compared to CC resulted in OR 2.85 [1.19-6.83]. In IL6 promoter polymorphism rs1800796, the C allele was more frequent among the subjects with DD, OR 6.71 [1.71-26.3]. Of the IL6 haplotypes, GCG was associated with DD, OR 6.46 [1.61 - 26.0]. No associations were observed among boys. Our results suggest possible roles for IL1A and IL6 in early DD among girls. PMID- 21537387 TI - Implications of the angiotensin converting enzyme gene insertion/deletion polymorphism in health and disease: a snapshot review. AB - This review considers the 250+ papers concerning the association of the angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism (rs1799752) and various disease conditions published in 2009. The deletion allele occurs in approximately 55% of the population and is associated with increased activity of the ACE enzyme. It might be predicted that the D allele, therefore, might be associated with pathologies involving increased activity of the renin angiotensin system. The D allele was seen to be associated with an increased risk of hypertension, pre-eclampsia, heart failure, cerebral infarct, diabetic nephropathy, encephalopathy, asthma, severe hypoglycaemia in diabetes, gastric cancer (in Caucasians) and poor prognosis following kidney transplant. On the positive side, the D allele appears to offer protection against schizophrenia and chronic periodontitis and confers greater up-per-body strength in old age. The I allele, meanwhile, offers improved endurance/athletic performance and aerobic capacity as determined by lung function tests, although it does increase the risk of oral squamous cell carcinoma and obstructive sleep apnoea in hypertensives. PMID- 21537389 TI - A polymorphism in the glucokinase gene that raises plasma fasting glucose, rs1799884, is associated with diabetes mellitus and prostate cancer: findings from a population-based, case-control study (the ProtecT study). AB - Epidemiological studies have identified a positive association between prostate cancer and recent onset type 2 diabetes mellitus but an increasingly inverse association with greater duration of type 2 diabetes. The mecha- nisms underlying these paradoxical associations are not clear. A single nucleotide polymorphism in the glucokinase gene, rs1799884, is associated with higher circulating plasma fasting glucose and with an increased risk of type 2 diabetes. We report a case control study nested within the population-based Prostate testing for cancer and Treatment (ProtecT) study ISRCTN20141297. Men aged 50-69 years based around 9 UK cities were invited for a prostate specific antigen (PSA) test between June 2002 and November 2006. 1,551 cases and 2,993 controls were geno-typed. We observed suggestive evidence for a positive association between the AA variant rs1799884 and PSA-detected prostate cancer (OR(AA V GG)= 1.40, 95% CI= 0.95 to 2.07). There was little evidence that this effect was greater for more advanced stage/ grade cancers (OR(AA V GG)= 1.78, 95% CI= 0.99 to 3.21) versus less advanced cancers (OR(AA V GG)= 1.23, 95% CI= 0.77 to 1.94) (p for interaction = 0.33). The rs1799884 genotype was not associated with PSA concentration, suggesting that any effect on prostate cancer risk is not attributable to PSA detection bias. Our results provide suggestive evidence for a link between a genotype associated with type 2 diabetes mellitus and PSA-detected prostate cancer. We hypothesize that hyperglycaemia may be important in mediating this relationship. PMID- 21537390 TI - Length heteroplasmies in human mitochondrial DNA control regions and breast cancer risk. AB - It has been proposed that the presence of heteroplasmy in the hypervariable (HV) regions of the mitochondrial DNA (mtDNA) may be an indicator of mitochondrial genome instability, mtDNA dysfunction, and, thus, may be associated with increased cancer risk. However, whether heteroplasmy in the HV regions of mtDNA could be a risk predictor of oxidative stress-related human cancers, such as breast cancer, remains to be determined. To explore the role of heteroplasmy in the HV regions of mtDNA in breast cancer etiology, we analyzed heteroplasmy in the HV regions of mtDNA in whole blood from 103 patients with breast cancer and 103 matched control subjects. Both cases and controls displayed heteroplasmies in both of the HV1 and HV2 regions. Closer examination of the prevalence of length heteroplasmy indicated that the prevalence of heteroplasmies in both of the HV1 and HV2 regions was much higher in the cases than in the controls (HV1: 68% vs 49%, P=0.007; HV2: 46% vs 25%, P=0.002). The presence of length heteroplasmies in both of the HV1 and HV2 regions was associated with 2.18- and 2.49-folds increased risk of breast cancer, respectively, (HV1: OR=2.18, 95% CI: 1.19 - 4.00; HV2: OR=2.49, 95% CI: 1.32 - 4.69). Interestingly, we observed that the controls with length heteroplasmies in both HV1 and HV2 had statistically significantly lower copy number of mtDNA than the ones without heteroplasmies. These results suggest that the length heteroplasmy in the HV regions of mtDNA could be associated with a risk of breast cancer, perhaps through affecting the copy number of mtDNA. PMID- 21537391 TI - APOE epsilon2 and epsilon4 influence the susceptibility for Alzheimer's disease but not other dementias. AB - Apolipoprotein E (APOE) genotype was determined in a population of patients with dementia, including 735 patients with Alzheimer's disease (AD), 75 with Frontotemporal Lobar Degeneration (FTLD), 97 with Vascular Dementia (VaD) and 40 with Lewy Body Dementia (LBD), as well as in 506 age- and gender-matched controls (CON). APOE epsilon2 allele frequency was lower in patients with AD (2.8%) than in CON (6.4%, P<=0.001, OR: 0.41). Similar results were obtained comparing AD with FTLD (6.7%, P<=0.01, OR: 0.37), at difference from VaD (5.6%, P>0.05) or LBD (5.0%, P>0.05). The frequency of the APOE epsilon4 allele was increased in patients with AD (25.1%) as compared with CON (8.2%, P<=0.001, OR: 4.24), FTLD (11.3%, P<=0.001, OR: 2.67), VaD (11.8%, P<=0.001, OR: 3.02), or LBD (13.8%, P=0.048, OR: 2.07). The frequency of the epsilon4/epsilon4 genotype was increased in AD patients compared with controls (6.3 versus 0.8%, P<=0.001, OR: 8.38). The presence of the epsilon2 allele is a protective factor for AD, whereas the epsilon4 allele acts as a risk factor for the disease. Both alleles do not influence the susceptibility to FTLD, LBD and VaD. PMID- 21537392 TI - Endothelin-1 and endothelial nitric oxide polymorphisms in idiopathic pulmonary arterial hypertension. AB - Idiopathic Pulmonary arterial hypertension (IPAH) is a debilitating disease associated with very poor prognosis. The disease is characterised by endothelial dysfunction, smooth muscle proliferation and insitu thrombosis in the pulmonary artery, eventually leading to right ventricular failure. Two of the key endothelial mediators implicated in the pathogenesis of IPAH are endothelin-1 (EDN1) and nitric oxide (NO). EDN1 is a potent endogenous vasoconstrictor whereas NO is a vasodilator. In the present study screening of the EDN1 gene (EDN1) and NOS3 polymorphisms was taken up, to evaluate their association with IPAH. A significant association of EDN1 3A/4A polymorphism (+138 A; rs10478694) (OR 3.485; CI-1.254, 9.999; p=0.013) and EDN1 Lys198Asn polymorphism (G/T, rs5370) (OR-3.378, CI-1.104, 10.582; p=0.03) with IPAH was observed. Our results indicate that EDN1 polymorphisms in interaction with other genetic markers may play a significant role in individual's susceptibility to the disease and its clinical progression. PMID- 21537393 TI - The molecular genetics of sirtuins: association with human longevity and age related diseases. AB - The sirtuins are a family of proteins remarkably conserved from yeast to humans. In organisms such as yeast, worms and flies it is quite well established that the activity of sirtuins prolongs lifespan. As a result of promising findings in simple organisms, sirtuins are now investigated in higher organisms in relation to the ageing process. In mammals there are seven different sirtuin proteins each encoded by individual genes (SIRT1-7). Although sirtuins share a highly conserved catalytic domain, they differ in their biological function. Some mammalian sirtuins have been implicated in different ageing pathways and their modulation has been deemed to be beneficial in different models of age-associated diseases. Overall, sirtuins could contribute to mechanisms of human longevity and avoid or delay the onset of age-associated disorders. Here we review and discuss the potential impact of genetic variation in the sirtuin genes in relation to human longevity and age-related diseases. PMID- 21537394 TI - Genetic variation and association analyses of NEDD4 gene in Kazak Chinese patients with hypertension. AB - To analyze the association between the genetic variations of neural precursor cell expressed developmentally down-regulated 4 gene (NEDD4) and hypertension in Kazakh Chinese. The sequences of NEDD4 gene exons were sequenced in 96 Kazakh Chinese with hypertension to identify representative variations. A case-control study was conducted by genotyping the representative variations in 287 Kazakh hypertensives and 411 normotensives. Replication population was 343 Uygur hypertensives and 724 normotensives. All subjects were selected from population based cross-sectional studies of metabolic disease. Thirteen novel and 15 known single nucleotide polymorphism (SNPs) or mutations, including 6 missense mutations, were identified. Of the four representative SNPs geno-typed, only rs2303580 was association with hypertension in Kazakh (additive P/Pc=0.020/0.160) without Bonferroni's correction. The result was replicated in Uygur (additive/dominant P=0.089/0.028, Pc=0.174/0.056). By adjusting for age and BMI, the observed association would no longer be statistically significant in Kazakh (additive OR (95%CI) 1.035(0.802-1.336), but remained statistically significant in Uygur ( additive/dominant ORs (95%CI) 1.323 (1.069-1.637), 1.521(1.146 2.020)). The rs2303580 genotypes were not association with blood pressure levels in Kazakh. Although by multiple linear regression analysis and by applying Bonferroni's correction, the genotypes were significant association with diastolic blood pressure levels (AA>AG>GG) in Uygur normotensive controls (P/Pc=0.003/0.018), the direction of difference was not in accordance with the association between the qualitative hypertension phenotype and the genotype shown (G risk allele). Our data indicates that the association between the NEDD4 genetic polymorphisms and hypertension phenotype should be replicated in further studies using larger and racially diverse populations. PMID- 21537395 TI - Correlation of the 5'untranslated region (5'UTR) and non-structural 5B (NS5B) nucleotide sequences in hepatitis C virus subtyping. AB - The 5'untranslated region (5'UTR) is often targeted to detect major genotypes in hepatitis C virus (HCV) but its insufficient sequence variation limits its usefulness for differentiating HCV subtypes. Subtyping has important implications to epidemiologic studies, clinical management, and vaccine development. Analysis of the nucleotide sequence of variable regions such as the non-structural 5B (NS5B) is considered the reference method for identifying HCV subtypes. We evaluated the accuracy of subtyping of HCV genotype 1 (HCV-1) samples from the Philippines by 5'UTR sequencing as compared with the NS5B sequence. A total of 30 patients infected with HCV-1 previously confirmed by PCR-RFLP and clinically diagnosed with chronic hepatitis C were analyzed. Nucleotide sequencing of the 5'UTR showed that 15 (50%) were identified as 1a and 15 (50%) were identified as 1b. Sequence analysis of the NS5B revealed that 13 (43%) belonged to subtype 1a while 17 (57%) belonged to subtype 1b. The most predominant subtype was 1b by NS5B sequencing. The predictive value of 5'UTR sequencing to subtype 1a was 73% while for subtype 1b, predictive value was 87%. Overall concordance between 5'UTR and NS5B sequencing was 80%. NS5B sequence and phylogenetic analysis is still the reference method for identifying HCV-1a and 1b subtypes. PMID- 21537396 TI - Molecular epidemiology of infectious diseases - expanding horizons for IJMEG. PMID- 21537397 TI - Candidate pathway polymorphisms in one-carbon metabolism and risk of rectal tumor mutations. AB - We examined candidate polymorphisms in genes involved in the folate-mediated, one carbon metabolism pathway, DNMT1 1311V, MTHFD1 R134K and R653Q, MTHFR R594Q, MTR D919G, MTRR H595Y and I22M, SHMT1 L474F, SLC19A1 H27R, and TDG G199S, and associations with rectal tumor characteristics. We hypothesized that these candidate genes would influence CpG Island Methylator Phenotype and potentially KRAS2 or TP53 tumors. Data from a population-based study of 747 rectal cases (593 with tumor markers) and 956 controls were evaluated using generalized estimating equations. We observed an increased risk of TP53 tumor mutations in homozygous carriers of the MTHFD1 134K allele (0R=2.0, 95%CI 1.2-3.1, P- trend=0.02). In the presence of low folate intake, the R134K variant was associated with increased risk of CIMP+ tumors (OR=2.8, 95%CI 1.04-7.7). The MTRR I22M variant genotype was associated with a modest increased risk of TP53 mutations (OR=1.7, 95%CI 1.2-2.5, P-trend=0.001). Our findings offer limited support that polymorphisms in one carbon metabolism genes influence rectal tumor phenotype, and that folate may interact with MTHFD1 to alter CIMP+ risk. PMID- 21537399 TI - Using Fisher's method with PLINK 'LD clumped' output to compare SNP effects across Genome-wide Association Study (GWAS) datasets. AB - As the number of publically available GWAS datasets continues to grow, bioinformatic tools which enable routine manipulation of data are becoming increasingly useful. Meta-analysis using multiple GWAS datasets has become essential to elucidate novel SNP associations which may not be readily discovered in each GWAS individually due to insufficient power. Replication of GWAS findings is critical and is the 'arbiter' of genuine SNP associations. We have developed an 'LD aware' bioinformatics application which allows efficient comparison of SNP effects across multiple GWAS datasets using Fisher's combined probability test from PLINK (v1.06) 'LD clumped' output. AVAILABILITY: the application is freely available from the authors. PMID- 21537398 TI - Telomere length and variation in telomere biology genes in individuals with osteosarcoma. AB - Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents. Chromosomal aneuploidy is common in osteosarcoma cells, suggesting underlying chromosomal instability. Telomeres, located at chromosome ends, are essential for genomic stability; several studies have suggested that germline telomere length (TL) is associated with cancer risk. We hypothesized that TL and/or common genetic variation in telomere biology genes may be associated with risk of osteosarcoma. We investigated TL in peripheral blood DNA and 713 single nucleotide polymorphisms (SNPs) from 39 telomere biology genes in 98 osteosarcoma cases and 69 orthopedic controls. For the genotyping component, we added 1363 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer ScreeningTrial. Short TL was not associated with osteosarcoma risk overall (OR 1.39, P=0.67), although there was a statistically significant association in females (OR 4.35, 95% Cl 1.20-15.74, P=0.03). Genotype analyses identified seven SNPs in TERF1 significantly associated with osteosarcoma risk after Bonferroni correction by gene. These SNPs were highly linked and associated with a reduced risk of osteosarcoma (OR 0.48-0.53, P=0.0001-0.0006). We also investigated associations between TL and telomere gene SNPs in osteosarcoma cases and orthopedic controls. Several SNPs were associated with TL prior to Bonferroni correction; one SNP in NOLA2 and one in MEN1 were marginally non-significant after correction (P(adj)=0.057 and 0.066, respectively). This pilot-study suggests that females with short telomeres may be at increased risk of osteosarcoma, and that SNPs in TERF1 are inversely associated with osteosarcoma risk. PMID- 21537401 TI - Strain differences and the role of AT(1) receptor expression in anxiety. AB - This study investigated strain specific differences to the anxiolytic response to losartan focusing on genetic variation that may influence such responses. This included: AT(1) receptor sequence variation, angiotensin II receptor associated protein (ATRAP) and receptor expression between strains. Sequencing of exon 3 of AT(1a)R revealed no differences between BKW mice (n=6) and C57 and DBA(2) strains (n=3). Comparisons of AT(1) expression do show significant differences, whereby BKW mice showed the highest levels of expression and DBA(2) mice intermediate levels when compared to the C57 strain. Sequencing of sections of the Angiotensin receptor associated protein (ATRAP) identified a non-synonymous point mutation- (T/C) transversion (position 109-161) (SNP id = rs13467517) resulting in a Valine -> Alanine (V157A) amino acid change in the BKW and DBA(2) strains. Our results indicate that the previously reported strain dependent effects are not due to variation in AT(1a) receptor sequence. Differences in AT(1)gene expression levels between strains, which mirror their anxiety phenotype, are observed. This is coupled with a non-synonymous single nucleotide polymorphism in ATRAP, a negative regulator of AT(1) signalling. PMID- 21537402 TI - The pathogenicity island-like DNA segment associated with Chinese outbreak strain of Streptococcus suis serotype 2 is absent in the United States isolates. AB - To determine if the 2005 Chinese outbreak strain of Streptococcus suis is circulating in the United States, three different PCR primer-pairs derived from the nucleotide sequences surrounding and internal to the unique pathogenicity island -like DNA segment of the Chinese outbreak strain (strain 05ZYH33) were used to screen 290 swine isolates of S. suis obtained from different locations. The first primer pair amplified an approximately 1000-bp fragment from 47 (16%) of the United States isolates and the second amplified an 1800-bp fragment from 23 (8%) of the isolates. Nucleotide sequences of the amplicons shared identity with those of strain 05ZYH33. The third primer pair amplified a 716-bp amplicon from the DNA of strain 05ZYH33 only. These observations demonstrated that the PAI homologue of strain 05ZYH33 is absent in the United States isolates tested and suggested that the PCR method may be useful for active surveillance to monitor possible spread of the highly invasive strain. PMID- 21537400 TI - Polymorphisms in CTNNBL1 in relation to colorectal cancer with evolutionary implications. AB - Colorectal cancer (CRC) is a complex disease related to environmental and genetic risk factors. Several studies have shown that susceptibility to complex diseases can be mediated by ancestral alleles. Using RNAi screening, CTNNBL1 was identified as a putative regulator of the Wnt signaling pathway, which plays a key role in colorectal carcinogenesis. Recently, single nucleotide polymorphisms (SNPs) in CTNNBL1 have been associated with obesity, a known risk factor for CRC. We investigated whether genetic variation in CTNNBL1 affects susceptibility to CRC and tested for signals of recent selection. We applied a tagging SNP approach that cover all known common variation in CTNNBL1 (allele frequency >5%; r(2)>0.8). A case-control study was carried out using two well-characterized study populations: a hospital-based Czech population composed of 751 sporadic cases and 755 controls and a family/early onset-based German population (697 cases and 644 controls). Genotyping was performed using allele specific PCR based TaqMan(r) assays (Applied Biosystems, Weiterstadt, Germany). In the Czech cohort, containing sporadic cases, the ancestral alleles of three SNPs showed evidence of association with CRC: rs2344481 (OR 1.44, 95%CI 1.06-1.95, dominant model), rs2281148 (OR 0.59, 95%CI 0.36-0.96, dominant model) and rs2235460 (OR 1.38, 95%CI 1.01-1.89, AA vs. GG). The associations were less prominent in the family/early onset-based German cohort. Data derived from several databases and statistical tests consistently pointed to a likely shaping of CTNNBL1 by positive selection. Further studies are needed to identify the actual function of CTNNBL1 and to validate the association results in other populations. PMID- 21537403 TI - Detection and molecular characterization of multiple strains of Picobirnavirus causing mixed infection in a diarrhoeic child: Emergence of prototype Genogroup II-like strain in Kolkata, India. AB - BACKGROUND: Picobirnaviruses (PBVs) associated with viral gastroenteritis were reported from humans and several animal species to date. PBVs belonging to family Picobirnaviridae under proposed order Diplornavirales are small, non-enveloped, with bisegmented dsRNA genome. METHODS: PBV was detected by polyacrylamide gel electrophoresis (PAGE) and silver staining. Confirmatory RT-PCR using primer pair PicoB25 (+) and PicoB43 (-) for genogroup I PBV and PicoB23(+) and PicoB24(-) for genogroup II PBV, resulted in amplicons of 201bp and 369bp respectively. The amplicons of genogroup I PBV were cloned and sequenced; amplicon of genogroup II PBV was directly sequenced. Further, the phylogenetic relationship and genetic diversity of strains from Kolkata was compared with hitherto reported PBV strains. RESULTS: In PAGE, a faecal specimen showed three sets of PBV with large profile bisegmented genomic RNA with slight variation in migration pattern. Molecular cloning experiments confirmed that PBV/ Human/INDIA/GPBV6/2007 had mixed infection comprising four different strains of PBV genogroup I [GPBV6C1P GPBV6C4P] and one PBV genogroup II strain [GPBV6G2P]. CONCLUSION: Sequence comparison and phylogenetic analysis of gene segment 2 of GPBV6 clones (C1, C2, C3 and C4) revealed low nucleotide identities (59-63%) and distant genetic relatedness to other human and porcine genogroup I picobirnaviruses. The strain GPBV6G2P represents another PBV genogroup II strain after prototype strain 4-GA 91/USA as genogroup II PBVs have seldom been reported to date, except from Kolkata, India and Netherlands. We are reporting the first incidence of detection of multiple strain (mixed) infection of picobirnavirus [genogroups I and II] from a diarrhoeic child in a slum community of Kolkata, India. PMID- 21537404 TI - Molecular typing of Salmonella spp isolated from food handlers and animals in Nigeria. AB - A total of 61 isolates of Salmonella spp (made up of 26 clinical isolates and 20 food handler and 15 animal isolates) were typed by RAPD-PCR for the purpose of screening for epidemiologically related isolates. The RAPD -PCR typing method used comprised six primers namely 787, 797, 784, 1254, RAPD 1 and RAPD 2 but 784 and 1254 did not produce discriminatory patterns and so were dropped. From the 61 strains, RAPD fingerprinting with primers RAPD 1, 2 produced 22 and 24 fingerprint patterns respectively. RAPD fingerprinting with primers 787, 797 produced 17, 11 fingerprinting patterns respectively. Combinations of the two RAPD 1 and 2 primers increased the discrimination of Salmonella strains to 32 patterns rather than the other primers used. Primer 797 was the least discriminatory. This study showed that the RAPD 1 and 2 primers would be useful for epidemiological typing of the Salmonella spp in Nigeria. PMID- 21537405 TI - Maternal peripheral blood gene expression in early pregnancy and preeclampsia. AB - We investigated associations of early pregnancy maternal peripheral blood gene expression with preeclampsia. In a nested case control study, gene expression of peripheral blood, collected at 16weeks of gestation on average from 16 women destined to develop preeclampsia and 16 women who had normotensive pregnancies was profiled using Affymetrix GeneChip Arrays. Fold change and Student's T-test analyses were used to compare differential gene expression across the groups. Functions and functional relationships as well as common regulatory sequences of differentially expressed genes were investigated. Genes participating in abnormal placentation (e.g COL1A1), immune/inflammation response (e.g. IKBKB) and cellular development (including cell cycle) (e.g. RBI) were differentially expressed in early pregnancy peripheral blood in preeclampsia. We identified transcription factors (i.e. Sp1, MAZ and MZF1) that may account for co-expression of differentially expressed genes. Preeclampsia is associated with differential gene expression in early pregnancy peripheral blood. PMID- 21537406 TI - Gestational diabetes in Korea: incidence and risk factors of diabetes in women with previous gestational diabetes. AB - Korean women with a history of gestational diabetes mellitus (GDM) have a 3.5 times greater risk of developing postpartum diabetes than the general population. The incidence of type 2 diabetes mellitus in early postpartum is reported as 10 15% in Korean women. A prospective follow-up study on Korean women with GDM showed that approximately 40% of women with previous GDM were expected to develop diabetes within 5 years postpartum. Independent risk factors for the development of diabetes in Korean women with previous GDM are pre-pregnancy body weight, gestational age at diagnosis, antepartum hyperglycemia on oral glucose tolerance test, low insulin response to oral glucose load, and family history of diabetes. Women with postpartum diabetes have greater body mass indexes, body weight, and waist circumferences than women with normal glucose tolerance. Multiple logistic regression analysis has revealed that waist circumference is the strongest obesity index along with systolic blood pressure and that triglyceride levels are a major independent risk factor for developing diabetes. These results in Korean women with previous GDM underline the importance of postpartum testing in Korean women diagnosed with GDM, and demonstrate that impaired B-cell function, obesity, and especially visceral obesity, are associated with the development of diabetes. PMID- 21537407 TI - New perspectives on diabetic vascular complications: the loss of endogenous protective factors induced by hyperglycemia. AB - Diabetic vascular complications are among the leading causes of morbidity and mortality in diabetic patients. In the past, many studies have focused on the mechanisms of hyperglycemia-induced chronic vascular complications via the formation of toxic metabolites such as oxidative stress, advanced glycosylated end products, persistent activation of protein kinase C, and increased sorbitol concentrations. However, vascular complications result from imbalances caused by increases in systemic toxic metabolites, such as those that occur under conditions of hyperglycemia and dyslipidemia, and by reductions in endogenous protective factors such as insulin, vascular endothelial growth factor, and platelet derived growth factor. This review outlines some of the evidence supporting the importance of enhancing endogenous regenerative factors. PMID- 21537408 TI - The search for genetic risk factors of type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is caused by complex interplay between multiple genetic and environmental factors. The three major approaches used to identify the genetic susceptibility include candidate gene approach, familial linkage analysis and genome- wide association analysis. Recent advance in genome-wide association studies have greatly improved our understanding of the pathophysiology of T2DM. As of the end of 2010, there are more than 40 confirmed T2DM-associated genetic loci. Most of the T2DM susceptibility genes were implicated in decreased beta-cell function. However, these genetic variations have a modest effect and their combination only explains less than 10% of the T2DM heritability. With the advent of the next-generation sequencing technology, we will soon identify rare variants of larger effect as well as causal variants. These advances in understanding the genetics of T2DM will lead to the development of new therapeutic and preventive strategies and individualized medicine. PMID- 21537409 TI - What is the optimal monotherapy in korean drug-naive type 2 diabetic patients?: the practical evidence of antidiabetic monotherapy study. PMID- 21537410 TI - Comparison of the efficacy of glimepiride, metformin, and rosiglitazone monotherapy in korean drug-naive type 2 diabetic patients: the practical evidence of antidiabetic monotherapy study. AB - BACKGROUND: Although many anti-diabetic drugs have been used to control hyperglycemia for decades, the efficacy of commonly-used oral glucose-lowering agents in Korean type 2 diabetic patients has yet to be clearly demonstrated. METHODS: We evaluated the efficacy of glimepiride, metformin, and rosiglitazone as initial treatment for drug-naive type 2 diabetes mellitus patients in a 48 week, double-blind, randomized controlled study that included 349 Korean patients. Our primary goal was to determine the change in HbA1c levels from baseline to end point. Our secondary goal was to evaluate changes in fasting plasma glucose (FPG) levels, body weight, frequency of adverse events, and the proportion of participants achieving target HbA1c levels. RESULTS: HbA1c levels decreased from 7.8% to 6.9% in the glimepiride group (P<0.001), from 7.9% to 7.0% in the metformin group (P<0.001), and from 7.8% to 7.0% (P<0.001) in the rosiglitazone group. Glimepiride and rosiglitazone significantly increased body weight and metformin reduced body weight during the study period. Symptomatic hypoglycemia was more frequent in the glimepiride group and diarrhea was more frequent in the metformin group. CONCLUSION: The efficacy of glimepiride, metformin, and rosiglitazone as antidiabetic monotherapies in drug-naive Korean type 2 diabetic patients was similar in the three groups, with no statistical difference. This study is the first randomized controlled trial to evaluate the efficacy of commonly-used oral hypoglycemic agents in Korean type 2 diabetic patients. An additional subgroup analysis is recommended to obtain more detailed information. PMID- 21537411 TI - Exercise treadmill test in detecting asymptomatic coronary artery disease in type 2 diabetes mellitus. AB - BACKGROUND: The present study was designed to develop criteria for screening patients with type 2 diabetes mellitus (T2DM) for asymptomatic coronary artery disease (CAD). METHODS: A total of 213 patients with T2DM without typical angina or chest pain were studied between 2002 and 2007. We also evaluated 53 patients with T2DM who had reported chest discomfort using an exercise treadmill test (ETT). RESULTS: Thirty-one of the 213 asymptomatic patients had positive ETT results. We performed coronary angiography on 23 of the 31 patients with a positive ETT and found that 11 of them had significant coronary stenosis. The main differences between the patients with significant stenosis and those with a negative ETT were age (63.1+/-9.4 vs. 53.7+/-10.1 years, P=0.008) and duration of diabetes (16.0+/-7.5 vs. 5.5+/-5.7 years, P<0.001). The positive predictive value (PPV) of the ETT was calculated to be 47.8%. The PPV of the ETT increased to 87.5% in elderly patients (>=60 years) with a long duration of diabetes (>=10 years). The latter value is similar to that of patients with T2DM who presented with chest discomfort or exertional dyspnea. The PPV of the ETT in symptomatic patients was 76.9%. CONCLUSION: In the interest of cost-effectiveness, screening for asymptomatic CAD could be limited to elderly patients with a duration of diabetes >=10 years. PMID- 21537412 TI - Basal C-peptide Level as a Surrogate Marker of Subclinical Atherosclerosis in Type 2 Diabetic Patients. AB - BACKGROUND: Recent studies have revealed that C-peptide induces smooth muscle cell proliferation and causes human atherosclerotic lesions in diabetic patients. The present study was designed to examine whether the basal C-peptide levels correlate with cardiovascular risk in type 2 diabetes mellitus (T2DM) patients. METHODS: Data was obtained from 467 patients with T2DM from two institutions who were followed for four years. The medical findings of all patients were reviewed, and patients with creatinine >1.4 mg/dL, any inflammation or infection, hepatitis, or type 1 DM were excluded. The relationships between basal C-peptide and other clinical values were statistically analyzed. RESULTS: A simple correlation was found between basal C-peptide and components of metabolic syndrome (MS). Statistically basal C-peptide levels were significantly higher than the three different MS criteria used in the present study, the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program's (NCEP's), World Health Organization (WHO), and the International Diabetes Federation (IDF) criteria (NCEP-ATP III, P=0.001; IDF, P<0.001; WHO, P=0.029). The multiple regression analysis between intima-media thickness (IMT) and clinical values showed that basal C-peptide significantly correlated with IMT (P=0.043), while the analysis between the 10-year coronary heart disease risk by the United Kingdom Prospective Diabetes Study risk engine and clinical values showed that basal C-peptide did not correlate with IMT (P=0.226). CONCLUSION: Basal C-peptide is related to cardiovascular predictors (IMT) of T2DM, suggesting that basal C-peptide does provide a further indication of cardiovascular disease. PMID- 21537413 TI - A Survey on Ubiquitous Healthcare Service Demand among Diabetic Patients. AB - BACKGROUND: Advanced information technology can be used when developing diagnostic and treatment strategies to provide better care for diabetic patients. However, the levels of need and demand for the use of technological advances have not been investigated in diabetic patients. We proposed and developed an individualized, ubiquitous (U)-healthcare service using advanced information technology for more effective glucose control. Prior to our service initiation, we surveyed patient needs and other pertinent information. METHODS: During August 2009, we conducted a 34-item questionnaire survey among patients with diabetes who were older than 40 years in two certain hospitals in Korea. RESULTS: The mean age of the 228 participants was 61.2+/-9 years, and males made up 49.1% of the sample. Seventy-one percent replied that they wanted individualized healthcare service, and they also wanted their health information to be delivered through mobile devices such as a cellular phone or a personal digital assistant (40.4%). Most patients had never heard of U-healthcare services (81.1%); however, after explaining the concept, 71.1% of participants responded that they would use the service if it was provided. Despite their willingness, participants were concerned about technical difficulty in using the service (26.3%) as well as the cost of the service (29.8%). CONCLUSION: The current study suggests that more than 70% of diabetic patients are interested in using U-healthcare services. To encourage widespread use, the application program or device of U-healthcare services should be simple, easy to use and affordable while also including a policy for the protection of private information. PMID- 21537414 TI - Insulin secretion and incretin hormone concentration in women with previous gestational diabetes mellitus. AB - BACKGROUND: We examined the change in the levels of incretin hormone and effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) on insulin secretion in women with previous gestational diabetes (pGDM). METHODS: A 75-g oral glucose tolerance test (OGTT) was conducted on 34 women with pGDM. In addition, 11 women with normal glucose tolerance, matched for age, height and weight, were also tested. The insulin, GIP, GLP-1, and glucagon concentrations were measured, and their anthropometric and biochemical markers were also measured. RESULTS: Among 34 women with pGDM, 18 had normal glucose tolerance, 13 had impaired glucose tolerance (IGT) and 1 had diabetes. No significant differences were found in GLP-1 concentration between the pGDM and control group. However, a significantly high level of glucagon was present in the pGDM group at 30 minutes into the OGTT. The GIP concentration was elevated at 30 minutes and 60 minutes in the pGDM group. With the exception of the 30-minute timepoint, women with IGT had significantly high blood glucose from 0 to 120 minutes. However, there was no significant difference in insulin or GLP-1 concentration. The GIP level was significantly high from 0 to 90 minutes in patients diagnosed with IGT. CONCLUSION: GLP-1 secretion does not differ between pGDM patients and normal women. GIP was elevated, but that does not seem to induce in increase in insulin secretion. Therefore, we conclude that other factors such as heredity and environment play important roles in the development of type 2 diabetes. PMID- 21537415 TI - Decreased Expression and Induced Nucleocytoplasmic Translocation of Pancreatic and Duodenal Homeobox 1 in INS-1 Cells Exposed to High Glucose and Palmitate. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is often accompanied by increased levels of circulating fatty acid. Elevations in fatty acids and glucose for prolonged periods of time have been suggested to cause progressive dysfunction or apoptosis of pancreatic beta cells in T2DM. However, the precise mechanism of this adverse effect is not well understood. METHODS: INS-1 rat-derived insulin secreting cells were exposed to 30 mM glucose and 0.25 mM palmitate for 48 hours. RESULTS: The production of reactive oxygen species increased significantly. Pancreatic and duodenal homeobox 1 (Pdx1) expression was down-regulated, as assessed by reverse transcription-polymerase chain reaction and Western blot analyses. The promoter activities of insulin and Pdx1 were also diminished. Of note, there was nucleocytoplasmic translocation of Pdx1, which was partially prevented by treatment with an antioxidant, N-acetyl-L-cysteine. CONCLUSION: Our data suggest that prolonged exposure of beta cells to elevated levels of glucose and palmitate negatively affects Pdx1 expression via oxidative stress. PMID- 21537416 TI - Repeated gene transfection impairs the engraftment of transplanted porcine neonatal pancreatic cells. AB - BACKGROUND: Previously, we reported that neonatal porcine pancreatic cells transfected with hepatocyte growth factor (HGF) gene in an Epstein-Barr virus (EBV)-based plasmid (pEBVHGF) showed improved proliferation and differentiation compared to those of the control. In this study, we examined if pancreatic cells transfected repeatedly with pEBVHGF can be successfully grafted to control blood glucose in a diabetes mouse model. METHODS: Neonatal porcine pancreatic cells were cultured as a monolayer and were transfected with pEBVHGF every other day for a total of three transfections. The transfected pancreatic cells were re aggregated and transplanted into kidney capsules of diabetic nude mice or normal nude mice. Blood glucose level and body weight were measured every other day after transplantation. The engraftment of the transplanted cells and differentiation into beta cells were assessed using immunohistochemistry. RESULTS: Re-aggregation of the pancreatic cells before transplantation improved engraftment of the cells and facilitated neovascularization of the graft. Right before transplantation, pancreatic cells that were transfected with pEBVHGF and then re-aggregated showed ductal cell marker expression. However, ductal cells disappeared and the cells underwent fibrosis in a diabetes mouse model two to five weeks after transplantation; these mice also did not show controlled blood glucose levels. Furthermore, pancreatic cells transplanted into nude mice with normal blood glucose showed poor graft survival regardless of the type of transfected plasmid (pCEP4, pHGF, or pEBVHGF). CONCLUSION: For clinical application of transfected neonatal porcine pancreatic cells, further studies are required to develop methods of overcoming the damage for the cells caused by repeated transfection and to re-aggregate them into islet-like structures. PMID- 21537417 TI - Autoimmune hypoglycemia in a patient with characterization of insulin receptor autoantibodies. AB - BACKGROUND: Type B insulin resistance syndrome is a manifestation of autoantibodies to the insulin receptor that results in severe hyperglycemia and acanthosis nigricans. However, the mechanisms by which these autoantibodies induce hypoglycemia are largely unknown. In this paper, we report the case of patient with type B insulin resistance syndrome who presented with frequent severe fasting hypoglycemia and acanthosis nigricans. METHODS: To evaluate the mechanism of hypoglycemia, we measured the inhibition of insulin binding to erythrocytes and IM9 lymphocytes in a sample of the patient's dialyzed serum before and after immunosuppressive therapy. RESULTS: In the patient's pre treatment serum IgG, the binding of (125)I-insulin to erythrocytes was markedly inhibited in a dose-dependent manner until the cold insulin level reached 10(-9) mol/L. We also observed dose-dependent inhibition of insulin binding to IM9 lymphocytes, which reached approximately 82% inhibition and persisted even when diluted 1:20. After treatment with glucocorticoids, insulin-erythrocyte binding activity returned to between 70% and 80% of normal, while the inhibition of insulin-lymphocyte binding was reduced by 17%. CONCLUSION: We treated a patient with type B insulin resistance syndrome showing recurrent fasting hypoglycemia with steroids and azathioprine. We characterized the patient's insulin receptor antibodies by measuring the inhibition of insulin binding. PMID- 21537418 TI - Letter: a retrospective study on the efficacy of a ten-milligram dosage of atorvastatin for treatment of hypercholesterolemia in type 2 diabetes mellitus patients (korean diabetes j 2010;34:359-67). PMID- 21537419 TI - Response: a retrospective study on the efficacy of a ten-milligram dosage of atorvastatin for treatment of hypercholesterolemia in type 2 diabetes mellitus patients (korean diabetes j 2010;34:359-67). PMID- 21537420 TI - What is the purpose of launching World Journal of Diabetes? AB - The first issue of World Journal of Diabetes (WJD), whose preparatory work was initiated on September 23, 2008, is published on March 15, 2010. The WJD Editorial Board has now been established and consists of 323 distinguished experts from 38 countries. Our purpose of launching WJD is to publish peer reviewed, high-quality articles via an open-access online publishing model, thereby acting as a platform for communication between peers and the wider public, and maximizing the benefits to editorial board members, authors and readers. PMID- 21537421 TI - Systemic and metabolic effects of PDE5-inhibitor drugs. AB - Phosphodiesterase type-5 inhibitor (PDE5-i) drugs were first marketed in 1998 (sildenafil) for 'ondemand' treatment of male erectile dysfunction (ED) of any origin. They selectively inhibit intrapenile PDE5 isoenzyme which in turn increases intracellular cyclic guanosine monophosphate levels, thus resulting in prolonged relaxation of cavernosum smooth muscle cells and facilitating the erectile process. Since 2003, two new molecules (tadalafil and vardenafil) have been introduced, resulting in greater interest in these compounds and leading patients to ask for more prescriptions from their doctors. The vast use of PDE5-i in diabetic and cardiovascular ED patients led researchers to investigate their possible extra sexual effects. Several studies investigating their effects on endothelium, coronary and pulmonary circulation, inferior oesophageal sphincter and kidney functions have appeared and, finally, sildenafil was approved for the treatment of pulmonary arterial hypertension. Recent animal studies highlighted a possible interaction between chronic PDE5 inhibition and glucose homeostasis which occurs through a marked improvement of high fat diet induced insulin resistance. If this data is extended to humans, a new scenario will be opened for the chronic use of PDE5-i for sexual rehabilitation along with cardiovascular and metabolic benefits. PMID- 21537422 TI - Combination drug treatment in obese diabetic patients. AB - Drug combinations that include antiobesity drugs (such as orlistat and sibutramine) and target cardiovascular disease (CVD) risk factors may be a good approach to patients with type 2 diabetes and/or metabolic syndrome (MetS). Our group has investigated the orlistat-fenofibrate combination treatment in obese patients with MetS and the orlistat-ezetimibe and the sibutramine antihypertensive combination treatment in obese patients with hyperlipidaemia with promising results in CVD risk factor reduction. In these studies, the combination treatment significantly improved the lipid and lipoprotein profile, the carbohydrate metabolism parameters and many other variables playing a role in the atherosclerotic process. Small studies give promising results but double blind, randomized trials examining the effects of such multifactorial treatment in hard CVD endpoints in diabetic or MetS patients are missing. PMID- 21537424 TI - Effect of vildagliptin as add-on therapy to a low-dose metformin. AB - AIM: To evaluate the efficacy and safety of the addition of vildagliptin to low dose metformin and compare it to an uptitration of metformin in type 2 diabetes mellitus (T2DM) patients who have inadequate control with metformin monotherapy. METHODS: Eligible patients were randomized to receive vildagliptin 100 mg qd or metformin (500 mg qd for 2 wk and then 500 mg bid) added to open label metformin 500 mg bid for the 24 wk. The primary endpoint was baseline to endpoint hemoglobin A(1c) (HbA(1c)) change. RESULTS: The adjusted mean change from baseline in HbA(1c) at the 24th wk was -0.51% in the vildagliptin/metformin group (mean baseline HbA(1c): 7.4%) and -0.37% in the metformin monotherapy group (mean baseline HbA(1c): 7.3%). The mean difference was -0.14% with 95% Confidence Interval (-0.24%, -0.05%). As non-inferiority (margin of 0.4%) was achieved, a test for superiority was performed. This test showed statistically significant superiority of the combination over monotherapy group (P = 0.002). Gastrointestinal (GI) adverse events were significantly more frequent in the metformin group than the combination group (21.0% vs 15.4%, P = 0.032). CONCLUSION: In patients with T2DM inadequately controlled with metformin up to 1000 mg daily, the addition of vildagliptin 100 mg daily achieved larger HbA(1c) reduction with fewer GI events than with increasing the metformin dose. PMID- 21537423 TI - Diabetic retinopathy: Role of inflammation and potential therapies for anti inflammation. AB - Diabetic retinopathy is a leading cause of blindness among working-age adults. Despite many years of research, treatment options for diabetic retinopathy remain limited and with adverse effects. Discovery of new molecular entities with adequate clinical activity for diabetic retinopathy remains one of the key research priorities in ophthalmology. This review is focused on the therapeutic effects of cannabidiol (CBD), a non-psychoactive native cannabinoid, as an emerging and novel therapeutic modality in ophthalmology based on systematic studies in animal models of inflammatory retinal diseases including diabetic retinopathy - a retinal disease associated with vascular-neuroinflammation. Special emphasis is placed on novel mechanisms which may shed light on the pharmacological activity associated with CBD preclinically. These include a self defence system against inflammation and neurodegeneration mediated by inhibition of equilibrative nucleoside transporter and activation of adenosine receptor by treatment with CBD. PMID- 21537425 TI - Exacerbation of chronic inflammatory diseases by infectious agents: Fact or fiction? AB - Chronic inflammatory diseases caused by obesity represent critical public health concerns worldwide. In these diseases such as metabolic syndrome, diabetes and atherosclerosis, adipose tissue acts as an endocrine organ that releases large quantities of inflammatory mediators into circulation. Besides classically recognized effectors on the development of obesity and resultant conditions, infection has attracted attention as an enhancer of chronic inflammatory diseases. Infectious diseases have long been associated with obesity, metabolic syndrome, diabetes and atherosclerosis. However, the infectious hypothesis for chronic inflammatory diseases has been challenged by inconclusive clinical trials. Nevertheless, the large body of evidence accumulated over decades on the association of infectious diseases with obesity, diabetes and cardiovascular disease should not be disregarded. Instead, re-formulation of hypotheses of the mechanisms by which microbes affect obesity-associated diseases may be required with an emphasis on the early events in the progression of such diseases and the multifactorial nature of pathogen-host interactions. This review focuses on pathogens that directly promote obesity and on pathogens that cause chronic infections and thereby enhance metabolic diseases in obese patients. A new perspective on the interaction between infections and obesity-related diseases may improve management of chronic inflammatory diseases that rank high among global threats to human health. PMID- 21537426 TI - Surrogate markers of insulin resistance: A review. AB - Insulin resistance is a hallmark of obesity, diabetes, and cardiovascular diseases, and leads to many of the abnormalities associated with metabolic syndrome. Our understanding of insulin resistance has improved tremendously over the years, but certain aspects of its estimation still remain elusive to researchers and clinicians. The quantitative assessment of insulin sensitivity is not routinely used during biochemical investigations for diagnostic purposes, but the emerging importance of insulin resistance has led to its wider application research studies. Evaluation of a number of clinical states where insulin sensitivity is compromised calls for assessment of insulin resistance. Insulin resistance is increasingly being assessed in various disease conditions where it aids in examining their pathogenesis, etiology and consequences. The hyperinsulinemic euglycemic glucose clamp is the gold standard method for the determination of insulin sensitivity, but is impractical as it is labor- and time intensive. A number of surrogate indices have therefore been employed to simplify and improve the determination of insulin resistance. The object of this review is to highlight various aspects and methodologies for current and upcoming measures of insulin sensitivity/resistance. In-depth knowledge of these markers will help in better understanding and exploitation of the condition. PMID- 21537427 TI - Renal function in diabetic nephropathy. AB - Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. Cardiovascular and renal complications share common risk factors such as blood pressure, blood lipids, and glycemic control. Thus, chronic kidney disease may predict cardiovascular disease in the general population. The impact of diabetes on renal impairment changes with increasing age. Serum markers of glomerular filtration rate and microalbuminuria identify renal impairment in different segments of the diabetic population, indicating that serum markers as well as microalbuminuria tests should be used in screening for nephropathy in diabetic older people. The American Diabetes Association and the National Institutes of Health recommend Estimated glomerular filtration rate (eGFR) calculated from serum creatinine at least once a year in all people with diabetes for detection of kidney dysfunction. eGFR remains an independent and significant predictor after adjustment for conventional risk factors including age, sex, duration of diabetes, smoking, obesity, blood pressure, and glycemic and lipid control, as well as presence of diabetic retinopathy. Cystatin-C (Cys C) may in future be the preferred marker of diabetic nephropathy due differences in measurements of serum creatinine by various methods. The appropriate reference limit for Cys C in geriatric clinical practice must be defined by further research. Various studies have shown the importance of measurement of albuminuria, eGFR, serum creatinine and hemoglobin level to further enhance the prediction of end stage renal disease. PMID- 21537428 TI - Neurodegeneration: An early event of diabetic retinopathy. AB - Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia. However, retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination. In other words, retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR. Therefore, the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR. Elevated levels of glutamate and the overexpression of the renin- angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina. Among neuroprotective factors, pigment epithelial derived factor, somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review. Nevertheless, it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye. New strategies, based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors, are currently being tested in experimental models and in clinical pilot studies. Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research. PMID- 21537429 TI - Mediterranean diet and diabetes prevention: Myth or fact? AB - Type 2 diabetes is a major, non-communicable disease with increasing prevalence at a global level. Therefore, in order to prevent this condition action should be taken regarding the modifiable factors that influence its development - lifestyle and dietary habits. As the Mediterranean dietary pattern has beneficial effects on both human health and regarding the development and treatment of type 2 diabetes, promoting adherence to this pattern is of considerable public health importance. PMID- 21537430 TI - Molecular mechanisms of insulin resistance in type 2 diabetes mellitus. AB - Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear. It has been postulated that an increase in the intracellular concentration of fatty acid metabolites activates a serine kinase cascade, which leads to defects in insulin signaling downstream to the insulin receptor. In addition, the complex network of adipokines released from adipose tissue modulates the response of tissues to insulin. Among the many molecules involved in the intracellular processing of the signal provided by insulin, the insulin receptor substrate-2, the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest, as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo. Recently, studies have revealed that phosphoinositidedependent kinase 1 independent phosphorylation of protein kinase Cepsilon causes a reduction in insulin receptor gene expression. Additionally, it has been suggested that mitochondrial dysfunction triggers activation of several serine kinases, and weakens insulin signal transduction. Thus, in this review, the current developments in understanding the pathophysiological processes of insulin resistance in type 2 diabetes have been summarized. In addition, this study provides potential new targets for the treatment and prevention of type 2 diabetes. PMID- 21537431 TI - Metabolic effects of obesity: A review. AB - With the many recent advances in the biomedical world, vast changes are taking place in our growing knowledge of the physiological aspects of almost all the tissues and organs of the human body. One of the most prevalent topics of discussion is the question of obesity and its effect on the metabolic changes in the human body. The original classical role of adipose tissue as an energy storage organ has been greatly modified. We now know that it is an endocrine organ, producing adipokines like leptin, adiponectin, visfatin, resistin, apelin, etc, which modulate metabolic processes in the body. Since obesity is associated with an increase in the adipose tissue mass, these hormones may be expected to be produced in increased concentrations and may thus have a significant impact on the macronutrient metabolism. Further, these adipokines may interact with long term energy modulators like insulin. Even though the scientific community has started unravelling the mysteries of the close linkage between obesity, its hormones and their physiological effects, a lot still remains to be discovered. The present discussion makes an attempt to trace the basic modern day concepts of the role of obesity in various metabolic processes. PMID- 21537433 TI - Dipeptidyl peptidase-4 inhibitor for steroid-induced diabetes. AB - The addition of the dipeptidyl peptidase-4 (DDP-4) inhibitor has been reported to achieve greater improvements in glucose metabolism with fewer adverse events compared to increasing the metformin dose in type 2 diabetic patients. We present a patient with steroid-induced diabetes whose blood glucose levels were ameliorated by the use of the DPP-4 inhibitor, showing that the DPP-4 inhibitors may be an effective and safe oral anti-diabetic drug for steroid-induced diabetes. PMID- 21537432 TI - Mechanisms of developmental programming of the metabolic syndrome and related disorders. AB - There is consistent epidemiological evidence linking low birth weight, preterm birth and adverse fetal growth to an elevated risk of the metabolic syndrome (obesity, raised blood pressure, raised serum triglycerides, lowered serum high density lipoprotein cholesterol and impaired glucose tolerance or insulin resistance) and related disorders. This "fetal or developmental origins/programming of disease" concept is now well accepted but the "programming" mechanisms remain poorly understood. We reviewed the major evidence, implications and limitations of current hypotheses in interpreting developmental programming and discuss future research directions. Major current hypotheses to interpret developmental programming include: (1) thrifty phenotype; (2) postnatal accelerated or catch-up growth; (3) glucocorticoid effects; (4) epigenetic changes; (5) oxidative stress; (6) prenatal hypoxia; (7) placental dysfunction; and (8) reduced stem cell number. Some hypothetical mechanisms (2, 4 and 8) could be driven by other upstream "driver" mechanisms. There is a lack of animal studies addressing multiple mechanisms simultaneously and a lack of strong evidence linking clinical outcomes to biomarkers of the proposed programming mechanisms in humans. There are needs for (1) experimental studies addressing multiple hypothetical mechanisms simultaneously; and (2) prospective pregnancy cohort studies linking biomarkers of the proposed mechanisms to clinical outcomes or surrogate biomarker endpoints. A better understanding of the programming mechanisms is a prerequisite for developing early life interventions to arrest the increasing epidemic of the metabolic syndrome, type 2 diabetes and other related disorders. PMID- 21537434 TI - Hypothesis: Intensive insulin therapy-induced mortality is due to excessive serotonin autoinhibition and autonomic dysregulation. AB - ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES (ACCORD), THE ACTION IN DIABETES AND VASCULAR DISEASE: Preterax and Diamicron Modified Release Controlled Evaluation and the Veterans Affairs Diabetes Trial were designed to study whether older patients with type 2 diabetes mellitus could reduce the risk of heart attacks and stroke and thereby prolong their lives by maintaining their blood glucose levels at near-healthy levels but failed to demonstrate the hoped-for benefit. Why the trials failed, though, and why ACCORD saw significantly more deaths due to increased rates of cardiovascular events in the intensive therapy arm of the study are not clear. These data have now been confirmed by the results of the recently concluded NICE-SUGAR Study which again revealed that intensive glucose control increased mortality among adults in intensive care units. I propose that the negative results noted in these trials are due to altered brain serotonin concentrations and autonomic dysregulation in addition to the low-grade systemic inflammation, decreased endothelial nitric oxide and enhanced free radical generation, diminished anti-oxidant defenses and altered metabolism of essential fatty acids present in patients with type 2 diabetes. PMID- 21537435 TI - A fairy tale of modern insulin therapy in type 1 diabetes. AB - In type 1 diabetes, flexible, intensive insulin management improves not only glycemic control but also dietary freedom and treatment satisfaction. Such flexibility has been made possible with the new insulin analogues (as part of a basal-bolus regime) and is now gaining wide applicability, especially among children and adolescents. This approach requires appropriate individualized patient education. Especially for adolescents, the clinician should be able to guarantee insightful participation in direct response to their attitudes, wishes and needs. This patient-and-doctor collaboration is an ever-challenging duty and has the potential to change the future of the individual diabetic patient. PMID- 21537436 TI - Latent autoimmune diabetes in adults: A distinct but heterogeneous clinical entity. AB - Latent autoimmune diabetes in adults (LADA) accounts for 2%-12% of all cases of diabetes. Patients are typically diagnosed after 35 years of age and are often misdiagnosed as type II Diabetes Mellitus (DM). Glycemic control is initially achieved with sulfonylureas but patients eventually become insulin dependent more rapidly than with type II DM patients. Although they have a type II DM phenotype, patients have circulating beta (beta) cell autoantibodies, a hallmark of type I DM. Alternative terms that have been used to describe this condition include type 1.5 diabetes, latent type I diabetes, slowly progressive Insulin Dependent Diabetes Mellitus, or youth onset diabetes of maturity. With regards to its autoimmune basis and rapid requirement for insulin, it has been suggested that LADA is a slowly progressive form of type I DM. However, recent work has revealed genetic and immunological differences between LADA and type I DM. The heterogeneity of LADA has also led to the proposal of criteria for its diagnosis by the Immunology of Diabetes Society. Although many workers have advocated a clinically oriented approach for screening of LADA, there are no universally accepted criteria for autoantibody testing in adult onset diabetes. Following recent advances in immunomodulatory therapies in type I DM, the same strategy is being explored in LADA. This review deals with the contribution of the genetic, immunological and metabolic components involved in the pathophysiology of LADA and recent approaches in screening of this distinct but heterogeneous clinical entity. PMID- 21537439 TI - Autoimmune polyglandular syndrome type 3 complicated by mineralocorticoid responsive hyponatremia of the elderly. AB - We experienced the first case with autoimmune polyglandular syndrome type 3 (anti thyroid peroxidase antibody-positive hypothyroidism and anti-glutamic acid decarboxylase antibody-positive diabetes) complicated by mineralocorticoid responsive hyponatremia of the elderly. This case is also a rare slowly progressive insulin-dependent diabetes mellitus (SPIDDM) case, for which the patient has been treated for many years with sulfonylurea or glinide. Our observation also demonstrated that glucose metabolism in autoimmune diabetes such as SPIDDM is influenced by appetite, thyroid function and glucocorticoid effect. PMID- 21537437 TI - Pharmacological effects of lipid-lowering drugs on circulating adipokines. AB - The cardioprotective effects of lipid-lowering drugs have been primarily attributed to their effects on blood lipid metabolism. However, emerging evidence indicates that lipid-lowering drugs also modulate the synthesis and secretion of adipose tissue-secreted proteins referred to as adipokines. Adipokines influence energy homeostasis and metabolism and have also been shown to modulate the vascular inflammatory cascade. The purpose of this review will be to examine the reported effects of commonly used lipid-lowering drugs (statins, fibrates, niacin and omega-3-fatty acids) on the circulating concentrations of leptin, adiponectin, tumor necrosis-factor-alpha (TNF-alpha), Retinol binding protein 4 (RBP4) and resistin. Overall, the lipid-lowering drugs reviewed have minimal effects on leptin and resistin concentrations.Conversely, circulating adiponectin concentrations are consistently increased by each lipid-lowering drug reviewed with the greatest effects produced by niacin. Studies that have examined the effects of statins, niacin and omega-3-fatty acids on TNF-alpha demonstrate that these agents have little effect on circulating TNF-alpha concentrations. Niacin and fibrates appear to lower RBP4 but not resistin concentrations. The results of the available studies suggest that a strong relationship exists between pharmacological reductions in blood lipids and adiponectin that is not obvious for other adipokines reviewed. PMID- 21537438 TI - Risk factors for impaired glucose tolerance in obese children and adolescents. AB - AIM: To investigate which obese children have an increased risk for impaired glucose tolerance (IGT), a risk factor for later diabetes. METHODS: We studied 169 European untreated obese children and adolescents with normal glucose tolerance at baseline. Waist circumference, fasting glucose, lipids, blood pressure, pubertal stage, 2 h glucose in oral glucose tolerance test (oGTT), and HbA1c were determined at baseline and 1 year later. RESULTS: One year after baseline, 19 (11.2%) children demonstrated IGT, 4 (2.4%) children had impaired fasting glucose, no (0%) child suffered from diabetes, and 146 (86%) children still showed normal glucose tolerance. At baseline, the children with IGT and with normal glucose tolerance in a one-year follow-up did not differ significantly in respect of any analyzed parameter, apart from pubertal stage. The children developing IGT entered puberty significantly more frequently (37% vs 3%, P < 0.001). One year after baseline, the children with IGT demonstrated significantly increased waist circumference, blood pressure values, insulin and triglyceride concentrations, and insulin resistance index HOMA. The children remaining in the normal glucose tolerance status 1 year after baseline did not demonstrate any significant changes. CONCLUSION: During the study period of 1 year, more than 10% of the obese children with normal glucose tolerance converted to IGT. Repeated screening with oGTT seems meaningful in obese children entering puberty or demonstrating increased insulin resistance, waist circumference, blood pressure, or triglyceride concentrations. PMID- 21537440 TI - Contribution of animal models to the research of the causes of diabetes. AB - In most publications, animal models of diabetes have mainly been investigated for their multiple etiologies as well as for changes leading to diabetes and their genetic derivation. Aspects which seem important and need a special research endeavor are the mechanism of the causes of diabetes and the lapse into complications in different species, their molecular basis and possible arrest and prevention. A concise list and and short discussion of the intensively studied rodents is presented of spontaneous or nutritional background causing Type 2 diabetes but omitting diabetes evoked by transgenic manipulations or gene knockout techniques. PMID- 21537441 TI - Role of the renin angiotensin system in diabetic nephropathy. AB - Diabetic nephropathy has been the cause of lot of morbidity and mortality in the diabetic population. The renin angiotensin system (RAS) is considered to be involved in most of the pathological processes that result in diabetic nephropathy. This system has various subsystems which contribute to the disease pathology. One of these involves angiotensin II (Ang II) which shows increased activity during diabetic nephropathy. This causes hypertrophy of various renal cells and has a pressor effect on arteriolar smooth muscle resulting in increased vascular pressure. Ang II also induces inflammation, apoptosis, cell growth, migration and differentiation. Monocyte chemoattractant protein-1 production responsible for renal fibrosis is also regulated by RAS. Polymorphism of angiotensin converting enzyme (ACE) and Angiotensinogen has been shown to have effects on RAS. Available treatment modalities have proven effective in controlling the progression of nephropathy. Various drugs (based on antagonism of RAS) are currently in the market and others are still under trial. Amongst the approved drugs, ACE inhibitors and angiotensin receptor blockers (ARBs) are widely used in clinical practice. ARBs are shown to be superior to ACE inhibitors in terms of reducing proteinuria but the combined role of ARBs with ACE inhibitors in diabetic nephropathy is under debate. PMID- 21537442 TI - Role of bile acid sequestrants in the treatment of type 2 diabetes. AB - Cholestyramine is a first-generation bile acid sequestrant (BAS) and antihyperlipidemic agent that currently has limited use because of its relatively weak effect on lowering low density-lipoprotein (LDL)-cholesterol (C) and poor tolerability. The current first choice drugs for hyper-LDL-cholesterolemia are 3 hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) because of their strong LDL-C lowering effects and efficacy in prevention of cardiovascular disease. However, after lowering the target levels of LDL-C in very high risk patients, combination therapy with statins and other antihyperlipidemic drugs may become more important for treatment of hyper-LDL-cholesterolemia. Second generation BASs such as colesevelam and colestimide have a glucose-lowering effect and improved tolerance, which has led to re-evaluation of their utility in combination with statins or antidiabetic agents. PMID- 21537443 TI - Efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with diabetes. AB - AIM: To assess the efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with type 2 diabetes mellitus (T2DM). METHODS: This was a post hoc analysis in Korean patients, from a 24-wk, randomized, active controlled, double-blind, parallel-group, multicenter study. Eligible patients were aged between 18 and 80 years, drug naive, and had been diagnosed with T2DM [hemoglobin A(1c) (HbA(1c)): 7.5%-11.0% and fasting plasma glucose (FPG): < 270 mg/dL (< 15 mmol/L)]. Patients were randomized (1:1:1:1) to receive the vildagliptin/pioglitazone combination at 100/30 mg q.d. (high-dose) or 50/15 mg q.d. (low-dose), vildagliptin 100 mg q.d., or pioglitazone 30 mg q.d. monotherapies. The primary outcome measure was change in HbA(1c) from baseline to endpoint. RESULTS: The distribution of baseline demographic and clinical parameters was well balanced between treatment groups. The overall mean age, body mass index, HbA(1c), FPG, and duration of disease were 50.8 years, 24.6 kg/m(2), 8.6%, 10.1 mmol/L, and 2.2 years, respectively. Adjusted mean changes (+/- standard error) in HbA(1c) from baseline (~8.7%) to week 24 endpoint were -2.03% +/- 0.16% (high-dose, N = 34), -1.88% +/- 0.15% (low-dose, N = 34), -1.31% +/- 0.21% (vildagliptin, N = 36), and -1.52% +/- 0.16% (pioglitazone, N = 36). The high-dose combination therapy demonstrated greater efficacy than monotherapies [vildagliptin (P = 0.029) and pioglitazone (P = 0.027)]. Percentage of patients achieving HbA(1c) < 7% and <= 6.5% was the highest in the high-dose group (76% and 68%) followed by low-dose (58% and 47%), vildagliptin (59% and 37%), and pioglitazone (53% and 28%) groups. The overall incidence of adverse events was comparable. CONCLUSION: In Korean patients, first-line treatment with high-dose combination therapy improved glycemic control compared to pioglitazone and vildagliptin monotherapies, consistent with results published for the overall study population. PMID- 21537444 TI - Relationship between gut and sepsis: Role of ghrelin. AB - Ghrelin is a growth hormone secretagogue produced by the gut, and is expressed in the hypothalamus and other tissues as well. Ghrelin not only plays an important role in the regulation of appetite, energy balance and glucose homeostasis, but also shows anti-bacterial activity, suppresses pro-inflammatory cytokine production and restores gut barrier function. In experimental animals, ghrelin has shown significant beneficial actions in preventing mortality from sepsis. In the critically ill, corticosteroid insufficiency as a result of dysfunction of the hypothalamic-pituitary-adrenal axis is known to occur. It is therefore possible that both gut and hypothalamus play an important role in the pathogenesis of sepsis by virtue of their ability to produce ghrelin, which, in turn, could be a protective phenomenon to suppress inflammation. It remains to be seen whether ghrelin and its analogues are of benefit in treating patients with sepsis. PMID- 21537446 TI - Continuous positive airway pressure to improve insulin resistance and glucose homeostasis in sleep apnea. AB - Obstructive sleep apnea syndrome (OSAS) is a relatively common disorder in the adult population. It is associated with alterations in glucose metabolism and increases the risk for diabetes mellitus. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS. It may also have a favorable effect on insulin resistance and glucose metabolism, although relevant data is conflicting. Additional research is still needed to fully establish the effect of CPAP on glucose homeostasis. It should ascertain which patients may benefit most and how long treatment takes to induce favorable changes. Finally, patient compliance is being appreciated as a major factor influencing therapeutic outcomes, and this needs to be further examined. PMID- 21537447 TI - The launch of international journal of molecular epidemiology and genetics. PMID- 21537445 TI - Excessive 5-year weight gain predicts metabolic syndrome development in healthy middle-aged adults. AB - AIM: To quantitatively examine the impacts of an easy-to-measure parameter - weight gain - on metabolic syndrome development among middle-aged adults. METHODS: We conducted a five-year interval observational study. A total of 1384 middle-aged adults not meeting metabolic syndrome (MetS) criteria at the initial screening were included in our analysis. Baseline data such as MetS-components and lifestyle factors were collected in 2002. Body weight and MetS-components were measured in both 2002 and 2007. Participants were classified according to proximal quartiles of weight gain (WG) in percentages (%WG <= 1%, 1% < %WG <= 5%, 5% < %WG <= 10% and %WG > 10%, defined as: control, mild-WG, moderate-WG and severe-WG groups, respectively) at the end of the follow-up. Multivariate models were used to assess the association between MetS outcome and excessive WG in the total population, as well as in both genders. RESULTS: In total, 175 (12.6%) participants fulfilled MetS criteria within five years. In comparison to the control group, mild-WG adults had an insignificant risk for MetS development while adults having moderate-WG had a 3.0-fold increased risk for progression to MetS [95% confidence interval (CI), 1.8-5.1], and this risk was increased 5.4 fold (95% CI, 3.0-9.7) in subjects having severe-WG. For females having moderate- and severe-WG, the risk for developing MetS was 3.6 (95% CI, 1.03-12.4) and 5.5 (95% CI, 1.4-21.4), respectively. For males having moderate- and severe-WG, the odds ratio for MetS outcome was respectively 3.0 (95% CI, 1.6-5.5) and 5.2 (95% CI, 2.6-10.2). CONCLUSION: For early-middle-aged healthy adults with a five-year weight gain over 5%, the severity of weight gain is related to the risk for developing metabolic syndrome. PMID- 21537448 TI - Candidate variants at 6p21.33 and 6p22.1 and risk of non-small cell lung cancer in a Chinese population. AB - Chromosome 6p21.33, containing BAT3 and MSH5 genes, together with chromosome 6p22.1 were recently identified as susceptible regions for lung cancer in Caucasian populations. These findings interest us in assessing whether genetic variants in these regions also contribute to lung cancer risk in Chinese populations. We genotyped the most significant single nucleotide polymorphism (SNP) (rs9295740) reported in Caucasian populations at Chromosome 6p22.1 and one common potentially functional variant (rs2075789) located at exon 2 of MSH5 in a case-control study including 1009 histologically confirmed non-small cell lung cancer (NSCLC) cases and 1127 cancer-free controls in a Chinese population. We found that the distributions of genotypes of both SNPs between cases and controls were not significantly different (P = 0.624 for rs9295740 and P = 0.937 for rs2075789). Logistic regression analyses revealed neither of the two SNPs was significantly associated with altered risk of NSCLC in dominant or recessive genetic models. When we compared the combined variant genotypes (GA+AA) with the common homozygote GG, assuming a dominant genetic model, the adjusted ORs were 1.03 (95% CI = 0.86-1.25) for rs9295740 and 1.03 (95% CI = 0.85-1.25) for rs2075789. In addition, no significant associations were observed in subgroups stratified by age, gender, smoking status or histologic types. Our results indicate that the most significant SNP rs9295740 identified in Caucasians in 6p22.1 and the potentially functional SNP rs2075789 in 6p21.33, seem not applicable to Chinese populations as susceptible markers for lung cancer. Re sequencing and fine-mapping this region, along with extensive functional evaluations, is required. PMID- 21537450 TI - Credible genetic associations? AB - The proliferation in genetic association studies, and the recurring failure of initially promising findings to robustly replicate, demonstrates the need for stringent standards to ensure the identification of credible associations. The Human Genome Epidemiology Network has recently published intermin guideliness on evidential criteria for genetic association studies. These are reviewed, and their value and importance discussed, as well as the impact these guidelines will have on the conduct of genetic association studies. PMID- 21537449 TI - Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from Meta-analysis. AB - For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1(st), 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 "top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with alpha=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected p-value=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (p value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies. PMID- 21537451 TI - Association between CYP7A1 and the risk of proximal colon cancer in Japanese. AB - Bile acids have long been implicated in the etiology of colorectal carcinogenesis by their genotoxicity as well as cytotoxicity. Cholesterol 7-alfa-hydroxylase (CYP7A1) is the rate-limiting enzyme that converts cholesterol into cholesterol 7 alfa-hydroxycholesterol in the first step of the classical pathway of bile acid synthesis. Recently, an association between a polymorphism (-204A>C, rs3808607) in CYP7A1 and proximal colon cancer/adenoma has been reported, which was not observed with distal colon or rectal cancer/adenoma. In this case-control study, we examined the association between haplotypes of CYP7A1 and proximal or distal colon/rectal cancer risk in a Japanese population. Subjects were 96 cases of proximal colon cancer, 357 of distal colon/rectal cancer and 961 age- and sex matched non-cancer controls at Aichi Cancer Center. We examined five loci, including rs3808607, and evaluated the impact of haplotype on risk. In locus specific analyses, we saw no association with rs3808607 for any site. Haplotype analyses revealed that the TAAGG haplotype was positively associated with proximal colon cancer [confounder-adjusted odds ratio: 1.72 (95% confidence interval: 1.10-2.71), p=0.018] but not with distal colon and rectal cancer combined. This association was consistently observed in analyses stratified by potential confounders. Our results indicate that CYP7A1 plays a role in the carcinogenesis of colorectal cancer specifically in the proximal colon. Confirmation of this association in other epidemiologic studies and biological evaluation of the TAAGG haplotype are warranted. PMID- 21537452 TI - Evaluation of neprilysin sequence variation in relation to CSF beta-Amyloid levels and Alzheimer disease risk. AB - Neprilysin (NEP) is a principal peptidase involved in the degradation of beta amyloid (Abeta), and as such its encoding gene (MME) has been the target of numerous genetic association studies on Alzheimer disease. Here, in order to attempt replication of previous findings we have investigated several single nucleotide polymorphisms (SNPs) that have been claimed to be associated with AD. A key feature of the present study is the complementary investigation of both AD risk and quantitative measures of AD severity, including cerebrospinal (CSF) fluid levels of AP1-42. In contrast to the effects of APOE, none of these measures are detectably influenced by genetic polymorphism in the MME region. We thus, fail to find support for previous results suggesting that MME impacts AD. PMID- 21537453 TI - Analysis of Genome-Wide Association Study (GWAS) data looking for replicating signals in Alzheimer's disease (AD). AB - We have performed cross-platform comparisons of output from 4 GWAS in late-onset Alzheimer's disease (LOAD) - Reiman et al., 2007; Li et al., 2008; Beecham et al., 2008 and Carrasquillo et al., 2009 to search for new association signals. The aim was to reveal genes that replicated across studies and hence merit further investigation. All SNPs with p-values ranging between 5*10(-5) - 5*10(-8) from each study were assessed across the other studies (either directly or by using a perfect proxy when comparing data from different chip platforms). This revealed only a single SNP (rs929156 in the tripartite motif-containing protein 15, TRIM15, gene) that was replicating across all studies at a level approaching genome-wide significance (P = 8.77*10(-8)) and where meta-analysis of odds ratios showed a significant effect on risk (OR 1.1, 95% Cl 1.0-1.2, P = 0.03). The vast majority of data analysed failed to replicate across these GWAS. The number of replicating association signals we observed is no higher than would be expected due to chance. However, increasing the power by using additional data from larger studies may enable this approach to identify potential LOAD candidate genes for confirmatory association studies. PMID- 21537454 TI - The -590C/TIL4 single-nucleotide polymorphism as a genetic factor of atopic allergy. AB - Elevated IgE levels in individuals with asthma, allergic rhinitis, and atopic dermatitis represents a situation in that increased IL4 production seems to occur because of the genetic component of the disease. In this study, one-hundred two matched-pairs of allergic and non-allergic individuals were phenotyped for total serum IgE level using enzyme-linked immunosorbent assay (ELISA). Atopic status was defined by serum IgE concentration >=100 IU/mL The -590C/T IL4 (rs2243250) was screened by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis. An association between the IL4 -590 TT genotype and levels of IgE was confirmed in the study population (ANOVA p=0.017). Furthermore, the IL4 T allele was significantly increased in allergic (0.299) compared with non-allergic subjects (0.172) (OR=2.060, 95% 01 = 1.285-3.301, chi(2) uncorrected p=0.002) at total serum IgE cut-off of 100 IU/mL. A significant relationship between IL4 -590 TT genotype and very high IgE levels (>1000 IU/mL) (OR=3.968, 95% CI = 1.499-10.5, chi(2) uncorrected p=0.01624) was also established. The -590C/T IL4 polymorphism is a potential risk factor to and correlates with atopic allergy. PMID- 21537455 TI - Editorial board of international journal of molecular epidemiology and genetics (as of march 31, 2010). PMID- 21537456 TI - Rise and fall of anti-obesity drugs. AB - Although it is not generally a life-threatening disease, obesity is becoming a major health problem worldwide. It can be controlled by means of drugs, and, consequently, these are required to be safe as well as effective. In this paper, we summarize the fate of various drugs that have been introduced for clinical use in the treatment of obesity. Fenfluramine and dexfenfluramine were withdrawn because of heart valve damage. Sibutramine suppresses appetite and increases heart rate and blood pressure. In the Sibutramine Cardiovascular OUTcomes trial, an increase in major adverse cardiovascular events prompted its withdrawal in Europe and the United States. Rimonabant is an endocannabinoid receptor antagonist that reduces body weight and ameliorates some cardiovascular risk factors. However, adverse psychiatric side effects led to its withdrawal as well. Orlistat is approved in Europe and the United States for the treatment of obesity, but its use is limited by gastrointestinal side-effects. Ephedrine and caffeine are natural ingredients in foods and supplements that may help the person to lose weight. In the light of several failed attempts, there is a clear need to develop drugs that are effective and safe in the long term in order to successfully combat the phenomenon of obesity . PMID- 21537457 TI - New insights in diabetic foot infection. AB - Foot ulcers are common in diabetic patients, have a cumulative lifetime incidence rate as high as 25% and frequently become infected. The spread of infection to soft tissue and bone is a major causal factor for lower-limb amputation. For this reason, early diagnosis and appropriate treatment are essential, including treatment which is both local (of the foot) and systemic (metabolic), and this requires coordination by a multidisciplinary team. Optimal treatment also often involves extensive surgical debridement and management of the wound base, effective antibiotic therapy, consideration for revascularization and correction of metabolic abnormalities such as hyperglycemia. This article focuses on diagnosis and management of diabetic foot infections in the light of recently published data in order to help clinicians in identification, assessment and antibiotic therapy of diabetic foot infections. PMID- 21537458 TI - Assessing and treating insulin resistance in women with polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS) is a highly prevalent hormonal and metabolic disorder among reproductive aged women worldwide. Women with PCOS have widely varying phenotypes and seek medical care for differing reasons. In addition to concern for menstrual cycle function, ovulation, hirsutism and acne, many PCOS women have abnormal glucose metabolism. While diabetes mellitus and impaired glucose tolerance are easily diagnosed, the diagnosis of and concern for insulin resistance as a precursor disorder is underappreciated. Insulin resistance may be the first important marker of metabolic disease in PCOS women at risk for metabolic syndrome and coronary artery disease. PMID- 21537459 TI - Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms. AB - Osteoporosis, a global age-related health problem in both male and female elderly, insidiously deteriorates the microstructure of bone, particularly at trabecular sites, such as vertebrae, ribs and hips, culminating in fragility fractures, pain and disability. Although osteoporosis is normally associated with senescence and estrogen deficiency, diabetes mellitus (DM), especially type 1 DM, also contributes to and/or aggravates bone loss in osteoporotic patients. This topic highlight article focuses on DM-induced osteoporosis and DM/osteoporosis comorbidity, covering alterations in bone metabolism as well as factors regulating bone growth under diabetic conditions including, insulin, insulin-like growth factor-1 and angiogenesis. Cellular and molecular mechanisms of DM-related bone loss are also discussed. This information provides a foundation for the better understanding of diabetic complications and for development of early screening and prevention of osteoporosis in diabetic patients. PMID- 21537460 TI - Age related changes in pancreatic beta cells: A putative extra-cerebral site of Alzheimer's pathology. AB - Frequent concomitant manifestation of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has been recently demonstrated by epidemiological studies. This might be due to functional similarities between beta-cells and neurons, such as secretion on demand of highly specific molecules in a tightly controlled fashion. An additional similarity represents the age-related alteration of hyperphosphorylated tau in AD patients. Similarly, alterations have been identified in beta-cells of T2DM patients. The islet amyloid polypeptide has been associated with beta-cell apoptosis. As a consequence of increasing age, the accumulation of highly modified proteins together with decreased regenerative potential might lead to increasing rates of apoptosis. Moreover, reduction of beta-cell replication capabilities results in reduction of beta-cell mass in mammals, simultaneously with impaired glucose tolerance. The new challenge is to learn much more about age-related protein modifications. This can lead to new treatment strategies for reducing the incidence of T2DM and AD. PMID- 21537461 TI - Insulin-producing cells are bi-potential and differentiatorsprior to proliferation in early human development. AB - AIM: To investigate the differentiation and migration of endocrine cells to form the pancreatic islets of Langer-hans in early human development. METHODS: Embryonic pancreas of 6-14 wk gestation was observed using immunocytochemistry methods in early human development. RESULTS: Insulin and glucagon are expressed in the same epithelium cells in the pancreas. In addition, in-sulin-producing cells also secrete somatostatin in early human embryonic development and these insulin-pro-ducing cells also express nestin. CONCLUSION: Pancreatic duct epithelial cells that can produce insulin in early human development are pre cursors and still have the potential to differentiate other endocrine cells. These progenitors have differen-tiated before migration from primary ductal epithelium to form the pancreatic islets. PMID- 21537462 TI - Sphingosine-1-phosphate signaling in vasculogenesis and angiogenesis. AB - Blood vessels either form de novo through the process of vasculogenesis or through angiogenesis that involves the sprouting and proliferation of endothelial cells in pre-existing blood vessels. A complex interactive network of signaling cascades downstream from at least three of the nine known G-protein-coupled sphingosine-1-phosphate (S1P) receptors act as a prime effector of neovascularization that occurs in embryonic development and in association with various pathologies. This review focuses on the current knowledge of the roles of S1P signaling in vasculogenesis and angiogenesis, with particular emphasis on vascular cell adhesion and motility responses. PMID- 21537463 TI - Roles of sphingosine-1-phosphate signaling in angiogenesis. AB - Sphingosine-1-phosphate (S1P) is a blood-borne lipid mediator with pleiotropic biological activities. S1P acts via the specific cell surface G-protein-coupled receptors, S1P(1-5). S1P(1) and S1P(2) were originally identified from vascular endothelial cells (ECs) and smooth muscle cells, respectively. Emerging evidence shows that S1P plays crucial roles in the regulation of vascular functions, including vascular formation, barrier protection and vascular tone via S1P(1), S1P(2) and S1P(3). In particular, S1P regulates vascular formation through multiple mechanisms; S1P exerts both positive and negative effects on angiogenesis and vascular maturation. The positive and negative effects of S1P are mediated by S1P(1) and S1P(2), respectively. These effects of S1P(1) and S1P(2) are probably mediated by the S1P receptors expressed in multiple cell types including ECs and bone-marrow-derived cells. The receptor-subtype-specific, distinct effects of S1P favor the development of novel therapeutic tactics for antitumor angiogenesis in cancer and therapeutic angiogenesis in ischemic diseases. PMID- 21537465 TI - Localization and function of a eukaryotic-initiation-factor-2-associated 67-kDa glycoprotein. AB - AIM: To study the localization and function of a eukaryotic initiation factor 2 (eIF2alpha)-associated 67-kDa glycoprotein (p67). METHODS: Immunofluorescence staining, (35)S-Met/Cys metabolic labeling, Western blotting analysis, sucrose gradient centrifugation and high speed centrifugation were used to determine the localization of proteins in transiently transfected COS-1 cells. Transient co transfection followed by co-immunoprecipitation was used to study the interaction between p67 and double-stranded RNA (dsRNA)-dependent protein kinase (PKR). Wheat germ agglutinin agarose beads were used to absorb glycosylated proteins. In vivo(32)P-labeling followed by immunoprecipitation and Western blotting were used to measure PKR autophosphorylation, eIF2alpha phosphorylation, and p67 expression in normal and breast cancer cells. RESULTS: The image from immunofluorescence staining showed that p67 was overexpressed in the cytosol but not in the nucleus. In a sucrose gradient, approximately 30% of the overexpressed p67 was bound with ribosomes. p67 interacted with the kinase domain, but not the dsRNA-binding domains of PKR. Only the glycosylated p67 was associated with the ribosome, and p67 did not compete with PKR for ribosome binding. In breast cancer cells, there was increased autophosphorylation of PKR but no phosphorylation of eIF2alpha, compared with normal breast cells.alpha The ratio of glycosylated/deglycosylated p67 was altered in breast cancer cells. CONCLUSION: Glycosylation of p67 is required for its ribosomal association and can potentially inhibit PKR via interaction with the kinase domain of PKR. PMID- 21537464 TI - Regulation of cancer cell migration and invasion by sphingosine-1-phosphate. AB - Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that has been implicated in regulation of a number of cancer cell malignant behaviors, including cell proliferation, survival, chemotherapeutic resistance and angiogenesis. However, the effects of S1P on cancer cell migration, invasion and metastasis, are perhaps its most complex, due to the fact that, depending upon the S1P receptors that mediate its responses and the crosstalk with other signaling pathways, S1P can either positively or negatively regulate invasion. This review summarizes the effects of S1P on cancer cell invasion and the mechanisms by which it affects this important aspect of cancer cell behavior. PMID- 21537466 TI - Role of sphingosine kinase and sphingosine-1-phosphate in inflammatory arthritis. AB - The importance of sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) in inflammation has been extensively demonstrated. As an intracellular second messenger, S1P plays an important role in calcium signaling and mobilization, and cell proliferation and survival. Activation of various plasma membrane receptors, such as the formyl methionyl leucyl phenylalanine receptor, C5a receptor, and tumor necrosis factor alpha receptor, leads to a rapid increase in intracellular S1P level via SphK stimulation. SphK and S1P are implicated in various chronic autoimmune conditions such as rheumatoid arthritis, primary Sjogren's syndrome, and inflammatory bowel disease. Recent studies have demonstrated the important role of SphK and S1P in the development of arthritis by regulating the pro inflammatory responses. These novel pathways represent exciting potential therapeutic targets. PMID- 21537468 TI - Modulation of protein tyrosine phosphorylation in gastric mucosa during re epithelization processes. AB - AIM: To investigate the role of protein tyrosine phosphorylation in gastric wound formation and repair following ulceration. METHODS: Gastric lesions were induced in rats using restraint cold stress. To investigate the effect of oxidative and nitrosative cell stress on tyrosine phosphorylation during wound repair, total activity of protein tyrosine kinase (PTK), protein tyrosine phosphatase (PTP), antioxidant enzymes, nitric oxide synthase (NOS), 2',5'-oligoadenylate synthetase, hydroxyl radical and zinc levels were assayed in parallel. RESULTS: Ulcer provocation induced an immediate decrease in tyrosine kinase (40% in plasma membranes and 56% in cytosol, P < 0.05) and phosphatase activity (threefold in plasma membranes and 3.3-fold in cytosol), followed by 2.3-2.4-fold decrease (P < 0.05) in protein phosphotyrosine content in the gastric mucosa. Ulceration induced no immediate change in superoxide dismutase (SOD) activity, 30% increase (P < 0.05) in catalase activity, 2.3-fold inhibition (P < 0.05) of glutathione peroxidase, 3.3-fold increase (P < 0.05) in hydroxyl radical content, and 2.3 fold decrease (P < 0.05) in zinc level in gastric mucosa. NOS activity was three times higher in gastric mucosa cells after cold stress. Following ulceration, PTK activity increased in plasma membranes and reached a maximum on day 4 after stress (twofold increase, P < 0.05), but remained inhibited (1.6-3-fold decrease on days 3, 4 and 5, P < 0.05) in the cytosol. Tyrosine phosphatases remained inhibited both in membranes and cytosol (1.5-2.4-fold, P < 0.05). NOS activity remained increased on days 1, 2 and 3 (3.8-, 2.6-, 2.2-fold, respectively, P < 0.05). Activity of SOD increased 1.6 times (P < 0.05) days 4 and 5 after stress. Catalase activity normalized after day 2. Glutathione peroxidase activity and zinc level decreased (3.3- and 2-fold, respectively, P < 0.05) on the last day. Activity of 2',5'-oligoadenylate synthethase increased 2.8-fold (P < 0.05) at the beginning, and 1.6-2.3-fold (P < 0.05) during ulcer recuperation, and normalized on day 5, consistent with slowing of inflammation processes. CONCLUSION: These studies show diverse changes in total tyrosine kinase activity in gastric mucosa during the recovery process. Oxidative and nitrosative stress during lesion formation might lead to the observed reduction in tyrosine phosphorylation during ulceration. PMID- 21537467 TI - Role of sphingosine 1-phosphate in anti-atherogenic actions of high-density lipoprotein. AB - The reverse cholesterol transport mediated by high-density lipoprotein (HDL) is an important mechanism for maintaining body cholesterol, and hence, the crucial anti-atherogenic action of the lipoprotein. Recent studies, however, have shown that HDL exerts a variety of anti-inflammatory and anti-atherogenic actions independently of cholesterol metabolism. The present review provides an overview of the roles of sphingosine 1-phosphate (S1P)/S1P receptor and apolipoprotein A I/scavenger receptor class B type I systems in the anti-atherogenic HDL actions. In addition, the physiological significance of the existence of S1P in the HDL particles is discussed. PMID- 21537469 TI - Biocommunication and natural genome editing. AB - The biocommunicative approach investigates communication processes within and among cells, tissues, organs and organisms as sign-mediated interactions, and nucleotide sequences as code, i.e. language-like text, which follows in parallel three kinds of rules: combinatorial (syntactic), context-sensitive (pragmatic), and content-specific (semantic). Natural genome editing from a biocommunicative perspective is competent agent-driven generation and integration of meaningful nucleotide sequences into pre-existing genomic content arrangements and the ability to (re-)combine and (re-)regulate them according to context-dependent (i.e. adaptational) purposes of the host organism. PMID- 21537470 TI - CARMA3: A novel scaffold protein in regulation of NF-kappaB activation and diseases. AB - CARD recruited membrane associated protein 3 (CARMA3) is a novel scaffold protein. It belongs to the CARMA protein family, and is known to activate nuclear factor (NF)-kappaB. However, it is still unknown which receptor functions upstream of CARMA3 to trigger NF-kappaB activation. Recently, several studies have demonstrated that CARMA3 serves as an indispensable adaptor protein in NF kappaB signaling under some G protein-coupled receptors (GPCRs), such as lysophosphatidic acid (LPA) receptor and angiotensin (Ang) II receptor. Mechanistically, CARMA3 recruits its essential downstream molecules Bcl10 and MALT1 to form the CBM (CARMA3-Bcl10-MALT1) signalosome whereby it triggers NF kappaB activation. GPCRs and NF-kappaB play pivotal roles in the regulation of various cellular functions, therefore, aberrant regulation of the GPCR/NF-kappaB signaling axis leads to the development of many types of diseases, such as cancer and atherogenesis. Recently, the GPCR/CARMA3/NF-kappaB signaling axis has been confirmed in these specific diseases and it plays crucial roles in the pathogenesis of disease progression. In ovarian cancer cell lines, knockdown of CARMA3 abolishes LPA receptor-induced NF-kappaB activation, and reduces LPA induced ovarian cancer invasion. In vascular smooth cells, downregulation of CARMA3 substantially impairs Ang-II-receptor-induced NF-kappaB activation, and in vivo studies have confirmed that Bcl10-deficient mice are protected from developing Ang-II-receptor-induced atherosclerosis and aortic aneurysms. In this review, we summarize the biology of CARMA3, describe the role of the GPCR/CARMA3/NF-kappaB signaling axis in ovarian cancer and atherogenesis, and speculate about the potential roles of this signaling axis in other types of cancer and diseases. With a significant increase in the identification of LPA- and Ang-II-like ligands, such as endothelin-1, which also activates NF-kappaB via CARMA3 and contributes to the development of many diseases, CARMA3 is emerging as a novel therapeutic target for various types of cancer and other diseases. PMID- 21537471 TI - Role of sphingosine kinase localization in sphingolipid signaling. AB - The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases, and immunity, as well as other functions. The sphingosine kinases are considered signaling enzymes by producing S1P, and their activity is acutely regulated by a variety of agonists. However, these enzymes are also key players in the control of sphingolipid metabolism. A variety of sphingolipids, such as sphingosine and the ceramides, are potent signaling molecules in their own right. The role of sphingosine kinases in regulating sphingolipid metabolism is potentially a critical aspect of their signaling function. A central aspect of signaling lipids is that their hydrophobic nature constrains them to membranes. Most enzymes of sphingolipid metabolism, including the enzymes that degrade S1P, are membrane enzymes. Therefore the localization of the sphingosine kinases and S1P is likely to be important in S1P signaling. Sphingosine kinase localization affects sphingolipid signaling in several ways. Translocation of SK1 to the plasma membrane promotes extracellular secretion of S1P. SK1 and SK2 localization to specific sites appears to direct S1P to intracellular protein effectors. SK localization also determines the access of these enzymes to their substrates. This may be an important mechanism for the regulation of ceramide biosynthesis by diverting dihydrosphingosine, a precursor in the ceramide biosynthetic pathway, from the de novo production of ceramide. PMID- 21537472 TI - Suofu Qin's work on studies of cell survival signaling in cancer and epithelial cells. AB - Reactive oxygen species (ROS) encompass a variety of diverse chemical species including superoxide anions, hydrogen peroxide, hydroxyl radicals and peroxynitrite, which are mainly produced via mitochondrial oxidative metabolism, enzymatic reactions, and light-initiated lipid peroxidation. Over-production of ROS and/or decrease in the antioxidant capacity cause cells to undergo oxidative stress that damages cellular macromolecules such as proteins, lipids, and DNA. Oxidative stress is associated with ageing and the development of age-related diseases such as cancer and age-related macular degeneration. ROS activate signaling pathways that promote cell survival or lead to cell death, depending on the source and site of ROS production, the specific ROS generated, the concentration and kinetics of ROS generation, and the cell types being challenged. However, how the nature and compartmentalization of ROS contribute to the pathogenesis of individual diseases is poorly understood. Consequently, it is crucial to gain a comprehensive understanding of the molecular bases of cell oxidative stress signaling, which will then provide novel therapeutic opportunities to interfere with disease progression via targeting specific signaling pathways. Currently, Dr. Qin's work is focused on inflammatory and oxidative stress responses using the retinal pigment epithelial (RPE) cells as a model. The study of RPE cell inflammatory and oxidative stress responses has successfully led to a better understanding of RPE cell biology and identification of potential therapeutic targets. PMID- 21537473 TI - Gelatin degradation assay reveals MMP-9 inhibitors and function of O-glycosylated domain. AB - AIM: To establish a novel, sensitive and high-throughput gelatinolytic assay to define new inhibitors and compare domain deletion mutants of gelatinase B/matrix metalloproteinase (MMP)-9. METHODS: Fluorogenic Dye-quenched (DQ)TM-gelatin was used as a substrate and biochemical parameters (substrate and enzyme concentrations, DMSO solvent concentrations) were optimized to establish a high throughput assay system. Various small-sized libraries (ChemDiv, InterBioScreen and ChemBridge) of heterocyclic, drug-like substances were tested and compared with prototypic inhibitors. RESULTS: First, we designed a test system with gelatin as a natural substrate. Second, the assay was validated by selecting a novel pyrimidine-2,4,6-trione (barbiturate) inhibitor. Third, and in line with present structural data on collagenolysis, it was found that deletion of the O glycosylated region significantly decreased gelatinolytic activity (k(cat)/k(M) +/- 40% less than full-length MMP-9). CONCLUSION: The DQTM-gelatin assay is useful in high-throughput drug screening and exosite targeting. We demonstrate that flexibility between the catalytic and hemopexin domain is functionally critical for gelatinolysis. PMID- 21537475 TI - Emanuel Strehler's work on calcium pumps and calcium signaling. AB - Cells are equipped with mechanisms to control tightly the influx, efflux and resting level of free calcium (Ca(2+)). Inappropriate Ca(2+) signaling and abnormal Ca(2+) levels are involved in many clinical disorders including heart disease, Alzheimer's disease and stroke. Ca(2+) also plays a major role in cell growth, differentiation and motility; disturbances in these processes underlie cell transformation and the progression of cancer. Accordingly, research in the Strehler laboratory is focused on a better understanding of the molecular "toolkit" needed to ensure proper Ca(2+) homeostasis in the cell, as well as on the mechanisms of localized Ca(2+) signaling. A long-term focus has been on the plasma membrane calcium pumps (PMCAs), which are linked to multiple disorders including hearing loss, neurodegeneration, and heart disease. Our work over the past 20 years or more has revealed a surprising complexity of PMCA isoforms with different functional characteristics, regulation, and cellular localization. Emerging evidence shows how specific PMCAs contribute not only to setting basal intracellular Ca(2+) levels, but also to local Ca(2+) signaling and vectorial Ca(2+) transport. A second major research area revolves around the calcium sensor protein calmodulin and an enigmatic calmodulin-like protein (CALML3) that is linked to epithelial differentiation. One of the cellular targets of CALML3 is the unconventional motor protein myosin-10, which raises new questions about the role of CALML3 and myosin-10 in cell adhesion and migration in normal cell differentiation and cancer. PMID- 21537474 TI - Shuffling the cards in signal transduction: Calcium, arachidonic acid and mechanosensitivity. AB - Cell signaling is a very complex network of biochemical reactions triggered by a huge number of stimuli coming from the external medium. The function of any single signaling component depends not only on its own structure but also on its connections with other biomolecules. During prokaryotic-eukaryotic transition, the rearrangement of cell organization in terms of diffusional compartmentalization exerts a deep change in cell signaling functional potentiality. In this review I briefly introduce an intriguing ancient relationship between pathways involved in cell responses to chemical agonists (growth factors, nutrients, hormones) as well as to mechanical forces (stretch, osmotic changes). Some biomolecules (ion channels and enzymes) act as "hubs", thanks to their ability to be directly or indirectly chemically/mechanically co regulated. In particular calcium signaling machinery and arachidonic acid metabolism are very ancient networks, already present before eukaryotic appearance. A number of molecular "hubs", including phospholipase A2 and some calcium channels, appear tightly interconnected in a cross regulation leading to the cellular response to chemical and mechanical stimulations. PMID- 21537476 TI - Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action. AB - Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis. Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitin-proteasome pathway, epigenetic modulators, poly(ADP-ribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer. PMID- 21537477 TI - Plasma membrane calcium pump regulation by metabolic stress. AB - The plasma membrane Ca(2+)-ATPase (PMCA) is an ATP-driven pump that is critical for the maintenance of low resting [Ca(2+)](i) in all eukaryotic cells. Metabolic stress, either due to inhibition of mitochondrial or glycolytic metabolism, has the capacity to cause ATP depletion and thus inhibit PMCA activity. This has potentially fatal consequences, particularly for non-excitable cells in which the PMCA is the major Ca(2+) efflux pathway. This is because inhibition of the PMCA inevitably leads to cytosolic Ca(2+) overload and the consequent cell death. However, the relationship between metabolic stress, ATP depletion and inhibition of the PMCA is not as simple as one would have originally predicted. There is increasing evidence that metabolic stress can lead to the inhibition of PMCA activity independent of ATP or prior to substantial ATP depletion. In particular, there is evidence that the PMCA has its own glycolytic ATP supply that can fuel the PMCA in the face of impaired mitochondrial function. Moreover, membrane phospholipids, mitochondrial membrane potential, caspase/calpain cleavage and oxidative stress have all been implicated in metabolic stress-induced inhibition of the PMCA. The major focus of this review is to challenge the conventional view of ATP-dependent regulation of the PMCA and bring together some of the alternative or additional mechanisms by which metabolic stress impairs PMCA activity resulting in cytosolic Ca(2+) overload and cytotoxicity. PMID- 21537478 TI - Plasma membrane Ca-ATPases in the nervous system during development and ageing. AB - Calcium signaling is used by neurons to control a variety of functions, including cellular differentiation, synaptic maturation, neurotransmitter release, intracellular signaling and cell death. This review focuses on one of the most important Ca(2+) regulators in the cell, the plasma membrane Ca(2+)-ATPase (PMCA), which has a high affinity for Ca(2+) and is widely expressed in brain. The ontogeny of PMCA isoforms, linked to specific requirements of Ca(2+) during development of different brain areas, is addressed, as well as their function in the adult tissue. This is based on the high diversity of variants in the PMCA family in brain, which show particular kinetic differences possibly related to specific localizations and functions of the cell. Conversely, alterations in the activity of PMCAs could lead to changes in Ca(2+) homeostasis and, consequently, to neural dysfunction. The involvement of PMCA isoforms in certain neuropathologies and in brain ageing is also discussed. PMID- 21537479 TI - Isolation and optimization of camelid single-domain antibodies: Dirk Saerens' work on nanobodies. AB - It is well established that all camelids have unique antibodies circulating in their blood. Unlike antibodies from all other species, these special antibodies are devoid of light chains, and are composed of a heavy chain homodimer. These so called heavy-chain antibodies (HCAbs) are expressed after a V-D-J rearrangement and require dedicated constant gamma genes. An immune response is raised in these HCAbs following a classical immunization protocol. These HCAbs are easily purified from serum, and their antigen-binding fragment interacts with parts of the target that are less antigenic to conventional antibodies. The antigen binding site of the dromedary HCAb comprises one single domain, referred to as VHH or nanobody (Nb), therefore, a strategy was designed to clone the Nb repertoire of an immunized dromedary and to select the Nb with specificity for our target antigens. The monoclonal Nb is produced well in bacteria, is very stable and highly soluble, and it binds the antigen with high affinity and specificity. Currently, the recombinant Nb has been developed successfully for research purposes, as a probe in biosensors, to diagnose infections, or to treat diseases such as cancer or trypanosomiasis. PMID- 21537480 TI - Multiple implications of 3-phosphoinositide-dependent protein kinase 1 in human cancer. AB - 3-phosphoinositide-dependent protein kinase-1 (PDK1) is a central mediator of cellular signaling between phosphoinositide-3 kinase and various intracellular serine/threonine kinases, including protein kinase B, p70 ribosomal S6 kinase, serum and glucocorticoid-inducible kinase, and protein kinase C. PDK1 activates members of the AGC family of protein kinases by phosphorylating serine/threonine residues in the activation loop. Here, we review the regulatory mechanisms of PDK1 and its roles in cancer. PDK1 is activated by autophosphorylation in the activation loop and other serine residues, as well as by phosphorylation of Tyr-9 and Tyr-373/376. Src appears to recognize PDK1 following tyrosine phosphorylation. The role of heat shock protein 90 in regulating PDK1 stability and PDK1-Src complex formation are also discussed. Furthermore, we summarize the subcellular distribution of PDK1. Finally, an important role for PDK1 in cancer chemotherapy is proposed. In conclusion, a better understanding of its molecular regulatory mechanisms in various signaling pathways will help to explain how PDK1 acts as an oncogenic kinase in various cancers, and will contribute to the development of novel cancer chemotherapies. PMID- 21537481 TI - Plasma membrane calcium pumps and their emerging roles in cancer. AB - Alterations in calcium signaling and/or the expression of calcium pumps and channels are an increasingly recognized property of some cancer cells. Alterations in the expression of plasma membrane calcium ATPase (PMCA) isoforms have been reported in a variety of cancer types, including those of breast and colon, with some studies of cancer cell line differentiation identifying specific PMCA isoforms, which may be altered in some cancers. Some studies have also begun to assess levels of PMCA isoforms in clinical tumor samples and to address mechanisms of altered PMCA expression in cancers. Both increases and decreases in PMCA expression have been reported in different cancer types and in many cases these alterations are isoform specific. In this review, we provide an overview of studies investigating the expression of PMCA in cancer and discuss how both the overexpression and reduced expression of a PMCA isoform in a cancer cell could bestow a growth advantage, through augmenting responses to proliferative stimuli or reducing sensitivity to apoptosis. PMID- 21537482 TI - Important relationships between Rab and MICAL proteins in endocytic trafficking. AB - The internalization of essential nutrients, lipids and receptors is a crucial process for all eukaryotic cells. Accordingly, endocytosis is highly conserved across cell types and species. Once internalized, small cargo-containing vesicles fuse with early endosomes (also known as sorting endosomes), where they undergo segregation to distinct membrane regions and are sorted and transported on through the endocytic pathway. Although the mechanisms that regulate this sorting are still poorly understood, some receptors are directed to late endosomes and lysosomes for degradation, whereas other receptors are recycled back to the plasma membrane; either directly or through recycling endosomes. The Rab family of small GTP-binding proteins plays crucial roles in regulating these trafficking pathways. Rabs cycle from inactive GDP-bound cytoplasmic proteins to active GTP bound membrane-associated proteins, as a consequence of the activity of multiple specific GTPase-activating proteins (GAPs) and GTP exchange factors (GEFs). Once bound to GTP, Rabs interact with a multitude of effector proteins that carry out Rab-specific functions. Recent studies have shown that some of these effectors are also interaction partners for the C-terminal Eps15 homology (EHD) proteins, which are also intimately involved in endocytic regulation. A particularly interesting example of common Rab-EHD interaction partners is the MICAL-like protein, MICAL-L1. MICAL-L1 and its homolog, MICAL-L2, belong to the larger MICAL family of proteins, and both have been directly implicated in regulating endocytic recycling of cell surface receptors and junctional proteins, as well as controlling cytoskeletal rearrangement and neurite outgrowth. In this review, we summarize the functional roles of MICAL and Rab proteins, and focus on the significance of their interactions and the implications for endocytic transport. PMID- 21537483 TI - Role of platelet plasma membrane Ca-ATPase in health and disease. AB - Platelets have essential roles in both health and disease. Normal platelet function is required for hemostasis. Inhibition of platelet function in disease or by pharmacological treatment results in bleeding disorders. On the other hand, hyperactive platelets lead to heart attack and stroke. Calcium is a major second messenger in platelet activation, and elevated intracellular calcium leads to hyperactive platelets. Elevated platelet calcium has been documented in hypertension and diabetes; both conditions increase the likelihood of heart attack and stroke. Thus, proper regulation of calcium metabolism in the platelet is extremely important. Plasma membrane Ca(2+)-ATPase (PMCA) is a major player in platelet calcium metabolism since it provides the only significant route for calcium efflux. In keeping with the important role of calcium in platelet function, PMCA is a highly regulated transporter. In human platelets, PMCA is activated by Ca(2+)/calmodulin, by cAMP-dependent phosphorylation and by calpain dependent removal of the inhibitory peptide. It is inhibited by tyrosine phosphorylation and calpain-dependent proteolysis. In addition, the cellular location of PMCA is regulated by a PDZ-domain-dependent interaction with the cytoskeleton during platelet activation. Rapid regulation by phosphorylation results in changes in the rate of platelet activation, whereas calpain-dependent proteolysis and interaction with the cytoskeleton appears to regulate later events such as clot retraction. In hypertension and diabetes, PMCA expression is upregulated while activity is decreased, presumably due to tyrosine phosphorylation. Clearly, a more complete understanding of PMCA function in human platelets could result in the identification of new ways to control platelet function in disease states. PMID- 21537485 TI - Regeneration and DNA demethylation do not trigger PDX-1 expression in rat hepatocytes. AB - AIM: To explore the possibility that PDX-1 gene is reactivated as a consequence of molecular events that occur during liver regeneration. METHODS: Rat hepatocytes were maintained in DMEM-F12, 10% fetal bovine serum (FBS), penicillin/streptomycin and geneticin when applicable. Rat insulinoma RIN 1046-38 cells were maintained in M-199-10% FBS and penicillin/streptomycin. The final concentration of glucose was 11.1 mmol/L. During regeneration, lateral and medial liver lobes of adult male Wistar rats were surgically removed, with up 70% loss of liver mass. In methylation experiments, 5-aza-deoxycytidine (5-aza-dC) was used. Primer3 software was used for polymerase chain reaction (PCR). Quantitative real time PCR (qRT-PCR) was performed using SYBR Green technology; primers were designed by Beacon Designer 6 software. Western blotting and SDS-PAGE were performed according to standard procedures. Antibodies were purchased from commercial suppliers. RESULTS: We explored the possibility that liver regeneration could trigger PDX-1 expression, and hence insulin production. Twenty four hours after surgical liver removal, regeneration was active as demonstrated by the increased proliferating cell nuclear antigen; however, all the other checked genes (involved in insulin gene expression): PC-1, Ngn3, NeuroD1, Btc, PDX-1 and Ins-1, were not related to the molecular events caused by this process. The only marker detected in regenerating liver was E47: a transcription factor of the the basic helix-loop-helix family known to be expressed ubiquitously in mammalian cells. In the rat pancreas, almost all of the tested genes were expressed as shown by RT-PCR, except for Ngn3, which was silenced 2 d after birth. Therefore, the molecular events in liver regeneration are not sufficient to promote PDX-1 expression. DNA methylation is a known mechanism to achieve stable repression of gene expression in mammals: Hxk 2 gene is silenced through this mechanism in normal hepatocytes. The administration of 5-aza-dC to cultured cells is in fact able to upregulate Hxk 2 mRNA. We investigated whether PDX-1 silencing in liver cells could be exerted through methylation of CpG islands in both the promoter and the gene coding regions. The results show that the drug increased the expression level of the Hxk 2 control gene but failed to rescue the expression of PDX-1, thus DNA demethylation is not sufficient to override repression of the PDX-1 gene. CONCLUSION: During liver regeneration, PDX-1 gene is not reactivated. Demethylation does not de-repress PDX-1 gene expression. Therefore gene silencing is not achieved through this epigenetic mechanism. PMID- 21537484 TI - Plasma membrane Ca-ATPases: Targets of oxidative stress in brain aging and neurodegeneration. AB - The plasma membrane Ca(2+)-ATPase (PMCA) pumps play an important role in the maintenance of precise levels of intracellular Ca(2+) [Ca(2+)](i), essential to the functioning of neurons. In this article, we review evidence showing age related changes of the PMCAs in synaptic plasma membranes (SPMs). PMCA activity and protein levels in SPMs diminish progressively with increasing age. The PMCAs are very sensitive to oxidative stress and undergo functional and structural changes when exposed to oxidants of physiological relevance. The major signatures of oxidative modification in the PMCAs are rapid inactivation, conformational changes, aggregation, internalization from the plasma membrane and proteolytic degradation. PMCA proteolysis appears to be mediated by both calpains and caspases. The predominance of one proteolytic pathway vs the other, the ensuing pattern of PMCA degradation and its consequence on pump activity depends largely on the type of insult, its intensity and duration. Experimental reduction of PMCA expression not only alters the dynamics of cellular Ca(2+) handling but also has a myriad of downstream consequences on various aspects of cell function, indicating a broad role of these pumps. Age- and oxidation-related down regulation of the PMCAs may play an important role in compromised neuronal function in the aging brain and its several-fold increased susceptibility to neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and stroke. Therapeutic approaches that protect the PMCAs and stabilize [Ca(2+)](i) homeostasis may be capable of slowing and/or preventing neuronal degeneration. The PMCAs are therefore emerging as a new class of drug targets for therapeutic interventions in various chronic degenerative disorders. PMID- 21537486 TI - Benfang Lei's research on heme acquisition in Gram-positive pathogens and bacterial pathogenesis. AB - Benfang Lei's laboratory conducts research on pathogenesis of human pathogen Group A Streptococcus (GAS) and horse pathogen Streptococcus equi (S. equi). His current research focuses on heme acquisition in Gram-positive pathogens and molecular mechanism of GAS and S. equi pathogenesis. Heme is an important source of essential iron for bacterial pathogens. Benfang Lei and colleagues identified the first cell surface heme-binding protein in Gram-positive pathogens and the heme acquisition system in GAS, demonstrated direct heme transfer from one protein to another, demonstrated an experimental pathway of heme acquisition by the Staphylococcus aureus Isd system, elucidated the activated heme transfer mechanism, and obtained evidence for a chemical mechanism of direct axial ligand displacement during the Shp-to-HtsA heme transfer reaction. These findings have considerably contributed to the progress that has been made over recent years in understanding the heme acquisition process in Gram-positive pathogens. Pathogenesis of GAS is mediated by an abundance of extracellular proteins, and pathogenic role and functional mechanism are not known for many of these virulence factors. Lei laboratory identified a secreted protein of GAS as a CovRS regulated virulence factor that is a protective antigen and is critical for GAS spreading in the skin and systemic dissemination. These studies may lead to development of novel strategies to prevent and treat GAS infections. PMID- 21537488 TI - Lee Pedersen's work in theoretical and computational chemistry and biochemistry. AB - Nature at the lab level in biology and chemistry can be described by the application of quantum mechanics. In many cases, a reasonable approximation to quantum mechanics is classical mechanics realized through Newton's equations of motion. Dr. Pedersen began his career using quantum mechanics to describe the properties of small molecular complexes that could serve as models for biochemical systems. To describe large molecular systems required a drop-back to classical means and this led surprisingly to a major improvement in the classical treatment of electrostatics for all molecules, not just biological molecules. Recent work has involved the application of quantum mechanics for the putative active sites of enzymes to gain greater insight into the key steps in enzyme catalysis. PMID- 21537487 TI - Roles of sphingosine 1-phosphate on tumorigenesis. AB - Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with a variety of biological activities. It is generated from the conversion of ceramide to sphingosine by ceramidase and the subsequent conversion of sphingosine to S1P, which is catalyzed by sphingosine kinases. Through increasing its intracellular levels by sphingolipid metabolism and binding to its cell surface receptors, S1P regulates several physiological and pathological processes, including cell proliferation, migration, angiogenesis and autophagy. These processes are responsible for tumor growth, metastasis and invasion and promote tumor survival. Since ceramide and S1P have distinct functions in regulating in cell fate decision, the balance between the ceramide/sphingosine/S1P rheostat becomes a potent therapeutic target for cancer cells. Herein, we summarize our current understanding of S1P signaling on tumorigenesis and its potential as a target for cancer therapy. PMID- 21537489 TI - Allosteric inhibitors of plasma membrane Ca pumps: Invention and applications of caloxins. AB - Plasma membrane Ca(2+) pumps (PMCA) play a major role in Ca(2+) homeostasis and signaling by extruding cellular Ca(2+) with high affinity. PMCA isoforms are encoded by four genes which are expressed differentially in various cell types in normal and disease states. Therefore, PMCA isoform selective inhibitors would aid in delineating their role in physiology and pathophysiology. We are testing the hypothesis that extracellular domains of PMCA can be used as allosteric targets to obtain a novel class of PMCA-specific inhibitors termed caloxins. This review presents the concepts behind the invention of caloxins and our progress in this area. A section is also devoted to the applications of caloxins in literature. We anticipate that isoform-selective caloxins will aid in understanding PMCA physiology in health and disease. With strategies to develop therapeutics from bioactive peptides, caloxins may become clinically useful in cardiovascular diseases, neurological disorders, retinopathy, cancer and contraception. PMID- 21537491 TI - Minimally invasive parathyroidectomy using surgical sonography. AB - Minimally invasive parathyroidectomy is the procedure of choice for primary hyperparathyroidism due to parathyroid adenoma. Localization of the offending adenoma in minimally invasive parathyroidectomy (MIP) has been described in the literature aided by isotope, telescope or ultrasound guidance. We present a prospective study of two techniques based on surgeon experience. Thirty patients diagnosed with primary hyperparathyroidism at the Mater hospital in Dublin, Ireland were randomized to have a minimally invasive parathyroidectomy using surgical sonography (MIPUSS) or the conventional unilateral open procedure (OP) over a two year period. The age, sex and serum calcium/parathormone were comparable in both groups. There was no significant difference in complications between the two groups with temporary hypocalcemia occurring in 3 patients undergoing unilateral neck exploration and in 2 MIPUSS patients. There was one transient episode of recurrent laryngeal neuropraxia occurring in the OP group which resolved at 30 day follow-up. The incision size, operating time, hospital stay, and required post-operative analgesia were all markedly reduced in the MIPUSS group. In conclusion, MIPUSS is safe, effective and has advantages in terms of operating time, incision size and early discharge. PMID- 21537490 TI - Protease expression by microorganisms and its relevance to crucial physiological/pathological events. AB - The treatment of infections caused by fungi and trypanosomatids is difficult due to the eukaryotic nature of these microbial cells, which are similar in several biochemical and genetic aspects to host cells. Aggravating this scenario, very few antifungal and anti-trypanosomatidal agents are in clinical use and, therefore, therapy is limited by drug safety considerations and their narrow spectrum of activity, efficacy and resistance. The search for new bioactive agents against fungi and trypanosomatids has been expanded because progress in biochemistry and molecular biology has led to a better understanding of important and essential pathways in these microorganisms including nutrition, growth, proliferation, signaling, differentiation and death. In this context, proteolytic enzymes produced by these eukaryotic microorganisms are appointed and, in some cases, proven to be excellent targets for searching novel natural and/or synthetic pharmacological compounds, in order to cure or prevent invasive fungal/trypanosomatid diseases. With this task in mind, our research group and others have focused on aspartic-type proteases, since the activity of this class of hydrolytic enzymes is directly implicated in several facets of basic biological processes of both fungal and trypanosomatid cells as well as due to the participation in numerous events of interaction between these microorganisms and host structures. In the present paper, a concise revision of the beneficial effects of aspartic protease inhibitors, with emphasis on the aspartic protease inhibitors used in the anti-human immunodeficiency virus therapy, will be presented and discussed using our experience with the following microbial models: the yeast Candida albicans, the filamentous fungus Fonsecaea pedrosoi and the protozoan trypanosomatid Leishmania amazonensis. PMID- 21537492 TI - Knockdown of NPM1 by RNA interference inhibits cells proliferation and induces apoptosis in leukemic cell line. AB - Nucleophosmin (NPM1) is an abundant and ubiquitously expressed phosphoprotein that is known to influence solid tumors progression. However, little is known about the role of NPM1 in leukemia. Here, we knocked down the NPM1 expression by RNA interference to investigate the role of NPM1 in leukemic cells proliferation and apoptosis. The interference vector pNPM1-shRNA was constructed and transfected into the human leukemic K562 cell line. The expression levels of NPM1 mRNA and protein were detected by quantitative real-time PCR and Western blot, respectively. Cells proliferation potential in vitro was assessed by methyl thiazolyl tetrazolium (MTT) and colony formation assays. Flow cytometry was used to detect the distribution of cell cycle. Cellular apoptosis was reflected by the relative activities of caspase-3 and caspase-8. The results showed that the expression levels of NPM1 mRNA and protein in K562 cells were significantly reduced after pNPM1-shRNA transfection. The cells growth was significantly inhibited in a time-dependent manner and the number of colonies was significantly reduced in the pNPM1-shRNA transfected cells. Meanwhile, the percentage of cells in G1 phase in the K562/pNPM1-shRNA cells was significantly increased. In addition, there were higher relative activities of caspase-3/8 in the pNPM1-shRNA transfected cells. These results indicate that down-regulation of NPM1 expression inhibits leukemic cells proliferation, blocks cell cycle progression and induces cellular apoptosis. It may implicate a potential target for leukemia gene therapy. PMID- 21537493 TI - Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes. AB - Bitter orange (Citrus aurantium) extract is widely used in dietary supplements for weight management and sports performance. Its primary protoalkaloid is p synephrine. Most studies involving bitter orange extract and p-synephrine have used products with multiple ingredients. The current study assessed the thermogenic effects of p-synephrine alone and in conjunction with the flavonoids naringin and hesperidin in a double-blinded, randomized, placebo-controlled protocol with 10 subjects per treatment group. Resting metabolic rates (RMR), blood pressure, heart rates and a self-reported rating scale were determined at baseline and 75 min after oral ingestion of the test products in V-8 juice. A decrease of 30 kcal occurred in the placebo control relative to baseline. The group receiving p-synephrine (50 mg) alone exhibited a 65 kcal increase in RMR as compared to the placebo group. The consumption of 600 mg naringin with 50 mg p synephrine resulted in a 129 kcal increase in RMR relative to the placebo group. In the group receiving 100 mg hesperidin in addition to the 50 mg p-synephrine plus 600 mg naringin, the RMR increased by 183 kcal, an increase that was statistically significant with respect to the placebo control (p<0.02). However, consuming 1000 mg hesperidin with 50 mg p-synephrine plus 600 mg naringin resulted in a RMR that was only 79 kcal greater than the placebo group. None of the treatment groups exhibited changes in heart rate or blood pressure relative to the control group, nor there were no differences in self-reported ratings of 10 symptoms between the treatment groups and the control group. This unusual finding of a thermogenic combination of ingredients that elevated metabolic rates without corresponding elevations in blood pressure and heart-rates warrants longer term studies to assess its value as a weight control agent. PMID- 21537494 TI - Early rearing interacts with temperament and housing to influence the risk for motor stereotypy in rhesus monkeys (Macaca mulatta). AB - Laboratory and zoo housed non-human primates sometimes exhibit abnormal behaviors that are thought to reflect reduced wellbeing. Previous research attempted to identify risk factors to aid in the prevention and treatment of these behaviors, and focused on demographic (e.g. sex or age) and experience-related (e.g. single housing or nursery rearing) factors. However, not all animals that display abnormal behavior possess these risk factors and some individuals that possess a risk factor do not show behavioral abnormalities. We hypothesized that other aspects of early experience and individual characteristics might identify animals that were more likely to display one specific abnormal behavior, motor stereotypy (MS). Using logistic regression we explored the influence of early rearing (involving four different types of rearing conditions), and variation in temperament, on likelihood of displaying MS while controlling for previously identified risk factors. Analyses indicated that having a greater proportion of life lived indoors, a greater proportion of life-indoors singly-housed, and a greater number of anesthesias and blood draws significantly increased the risk of displaying MS (P < 0.001). Rearing condition failed to independently predict the display of MS; however significant interactions indicated that single housing had a greater impact on risk for indoor-reared animals versus outdoor-reared animals, and for indoor mother-reared animals versus nursery-reared animals. There were no main effects of temperament, although interactions with rearing were evident: scoring high on Gentle or Nervous was a risk factor for indoor-reared animals but not outdoor-reared animals. The final model accounted for approximately 69.3 % of the variance in the display of MS, and correctly classified 90.6% of animals. These results indicate that previously identified risk factors may impact animals differently depending on the individual's early rearing condition. These results are also the first in non-human primates to demonstrate that individual difference factors, like temperament, could be additional tools to identify animals at highest risk for motor stereotypy. PMID- 21537495 TI - Computer simulation to investigate the FRET application in DNA hybridization systems. AB - Molecular dynamics (MD) and quantum mechanics (QM) were used to investigate fluorescence resonance energy transfer (FRET) between coumarin and ethidium in two Mergny's DNA hybridization systems. By combining the transition dipoles calculated by the quantum semi-empirical method and the conformations of the FRET probes collected by MD, FRET efficiencies were derived from the Forster equation at five temperatures from 273 K to 313 K. The plotted efficiencies were compared with Mergny's experiments, and showed good agreement. The simulated orientation factor and isotropically averaged orientation factor were compared, and the results demonstrated that the assumption of isotropic orientations is invalid when FRET probes are close to each other. The first order kinetic assumptions were also used to calculate the transfer efficiencies, and the results show that this D-A FRET process approximates the first order kinetic reactions. PMID- 21537496 TI - Liquid crystalline salen manganese(III) complexes. Mesomorphic and catalytic behaviour. AB - Several salen manganese(III) complexes displaying stable columnar mesophases in a wide range of temperatures have been synthesized. In condensed phases the molecules are assembled into dimers through intermolecular manganese-oxygen interactions and the columnar structure of the mesophases consist of the stacking of supramolecular discs formed by the association of two or three dimers, depending on the number and location of alkoxy chains in the complex. The catalytic activity of the complexes in solution has been studied, and they behave as efficient homogeneous catalysts in the epoxidation of styrene with iodosylbenzene as oxidant. PMID- 21537497 TI - Formation of mixed-ligand zinc(II) complex-montmorillonite hybrids by solid-solid reactions. AB - Two luminescent hybrids, Znqb- and Znqp-montmorillonites (q = 8-hydroxyquinoline, b = 2,2'-bipyridine, p = 1,10-phenanthroline), were prepared by solid-solid reactions between Zn(II)-montmorillonite and two ligands (8-hydroxyquinoline and 2,2'-bipyridine or 1,10-phenanthroline) at room temperature. The intercalation and in situ complex formation of the two ligands into an interlayer space of Zn(II)-montmorillonite were confirmed by powder XRD, TG-DTA, as well as FT-IR, UV vis and photoluminescence spectroscopies. The emission band of Znqb montmorillonite was red-shifted compared to that of the mixture of Znq montmorillonite and Znb-montmorillonite, confirming the formation of Znqb complex in montmorillonite. The photoluminescence intensity of Znqb-montmorillonite was higher than that of Znqp-montmorillonite, indicating that 2,2'-bipyridine enhanced the emission intensity of zinc(8-hydroxyquinoline) complex in montmorillonite, while the coordination of 1,10-phenanthroline quenched the intensity of the immobilized chelate. PMID- 21537498 TI - Syntheses, transfection efficacy and cell toxicity properties of novel cholesterol-based gemini lipids having hydroxyethyl head group. AB - We have synthesized five new cholesterol based gemini cationic lipids possessing hydroxyethyl (-CH(2)CH(2)OH) function on each head group, which differ in the length of the polymethylene spacer chain. These gemini lipids are important for gene delivery processes as they possess pre-optimized molecular features, e.g., cholesterol backbone, ether linkage and a variable spacer chain between both the headgroups of the gemini lipids. Cationic liposomes were prepared from each of these lipids individually and as a mixture of individual cationic gemini lipid and 1,2-dioleoyl phosphatidylethanolamine (DOPE). Each gemini lipid based formulation induced better transfection activity than that of their monomeric counterpart. One such gemini lipid with a -(CH(2))(12)- spacer, HG-12, showed dramatic increase in the mean fluorescence intensity due to the expression of green-fluorescence protein (GFP) in the presence of 10% FBS compared to the conditions where there was no serum. Other gemini lipids retained their gene transfection efficiency without any marked decrease in the presence of serum. The only exception was seen with the gemini with a -(CH(2))(3)- spacer, HG-3, which on gene transfection in the presence of 10% FBS lost ~70% of its transfection efficiency. Overall the gemini lipid with a -(CH(2))(5)- spacer, HG-5, showed the highest transfection activity at N/P (lipid/DNA) ratio of 0.5 and lipid : DOPE molar ratio of 2. Upon comparison of the relevant parameters, e.g., %-transfected cells, the amount of DNA transfected to each cell and %-cell viability all together against Lipofectamine 2000, one of the best commercial transfecting agents, the optimized lipid formulation based on DOPE/HG-5 was found to be comparable. In terms of its ability to induce gene-transfer in the presence of serum and shelf-life DOPE/HG-5 liposome was found to be superior to its commercial counterpart. Confocal imaging analysis confirmed that in the presence of 10% serum using a Lipid : DOPE of 1 : 4 and N/P charge ratio of 0.75 with 1.2 MUg DNA per well, HG-5 is better than Lipofectamine 2000. PMID- 21537500 TI - Fabricating graphene supercapacitors: highlighting the impact of surfactants and moieties. AB - We highlight the impact of surfactants, routinely used in the fabrication of graphene, which can significantly influence the performance of supercapacitors. Through the utilisation of various graphitic forms we offer insight into the design and fabrication of graphene based supercapacitors. PMID- 21537499 TI - Manganese(II) complexes of scorpiand-like azamacrocycles as MnSOD mimics. AB - Mn(II) complexes of scorpiand-type azamacrocycles constituted by a tretrazapyridinophane core appended with an ethylamino tail including 2- or 4 quinoline functionalities show very appealing in vitro SOD activity. The observed behaviour is related to structural and electrochemical parameters. PMID- 21537501 TI - Photo-curable siloxane hybrid material fabricated by a thiol-ene reaction of sol gel synthesized oligosiloxanes. AB - The thiol-ene reaction of a sol-gel synthesized oligosiloxane thiol-ene mixture was processed through UV irradiation, resulting in transparency, high refractive index, good thermal stability and especially excellent electrical insulation materials. It provides new strong potential of the thiol-ene system for application in dielectric materials. PMID- 21537502 TI - Organic-inorganic hybrid materials starting from the novel nanoscaled bismuth oxido methacrylate cluster [Bi38O45(OMc)24(DMSO)9].2DMSO.7H2O. AB - The reaction of the basic bismuth nitrate [Bi(6)O(4)(OH)(4)](NO(3))(6).H(2)O with sodium methacrylate in DMSO gave [Bi(38)O(45)(OMc)(24)(DMSO)(9)].2DMSO.7H(2)O (OMc = O(2)CC(3)H(5)), which is highly soluble in organic solvents. By copolymerization of the bismuth oxido cluster with methyl methacrylate transparent, radiopaque organic-inorganic hybrid materials were obtained. PMID- 21537503 TI - Tris-(8-hydroxy-quinoline) aluminium/zirconium phosphate: a novel hybrid assembly with strong luminescence and prolonged lifetime. AB - A novel hybrid assembly of tris-(8-hydroxy-quinoline) aluminium intercalated into modified alpha-zirconium phosphate in aqueous media was fabricated successfully, resulting in the dramatically enhanced greenish-blue-light emission and prolonged excited-state lifetime. PMID- 21537504 TI - High mobility n-channel single-crystal field-effect transistors based on 5,7,12,14-tetrachloro-6,13-diazapentacene. AB - Heteroaromatic oligomer 5,7,12,14-tetrachloro-6,13-diazapentacene (TCDAP) was characterized and assessed as n-channel material in field-effect transistor applications. A single-crystal transistor based on TCDAP as the channel material exhibits a very high electron mobility of 3.39 cm(2) V(-1) s(-1) and an on/off ratio of ~1.08 * 10(4) respectively. PMID- 21537505 TI - Design and synthesis of new chiral phosphorus-olefin bidentate ligands and their use in the rhodium-catalyzed asymmetric addition of organoboroxines to N-sulfonyl imines. AB - Novel chiral phosphorus-olefin bidentate ligands have been synthesized in a few steps from a readily available enantiopure compound. These ligands have been applied to a rhodium-catalyzed asymmetric addition of organoboroxines to N sulfonyl aldimines, achieving high yield and enantioselectivity. PMID- 21537506 TI - Probing the crossover in CO desorption from single crystal to nanoparticulate Ru model catalysts. AB - Using model catalysts, we demonstrate that CO desorption from Ru surfaces can be switched from that typical of single crystal surfaces to one more characteristic of supported nanoparticles. First, the CO desorption behaviour from Ru nanoparticles supported on highly oriented pyrolytic graphite was studied. Both mass-selected and thermally evaporated nanoparticles were deposited. TPD spectra from the mass-selected nanoparticles exhibit a desorption peak located around 410 K with a broad shoulder extending from around 480 K to 600 K, while spectra obtained from thermally evaporated nanoparticles exhibit a single broad feature from ~350 K to ~450 K. A room temperature deposited 50 A thick Ru film displays a characteristic nanoparticle-like spectrum with a broad desorption feature at ~420 K and a shoulder extending from ~450 K to ~600 K. Subsequent annealing of this film at 900 K produced a polycrystalline morphology of flat Ru(001) terraces separated by monatomic steps. The CO desorption spectrum from this surface resembles that obtained on single crystal Ru(001) with two large desorption features located at 390 K and 450 K due to molecular desorption from terrace sites, and a much smaller peak at ~530 K due to desorption of dissociatively adsorbed CO at step sites. In a second experiment, ion sputtering was used to create surface defects on a Ru(0 1 54) single crystal surface. A gradual shift away from the desorption spectrum typical of a Ru(001) surface towards one resembling desorption from supported Ru nanoparticles was observed with increasing sputter time. PMID- 21537507 TI - The role of CN and CO ligands in the vibrational relaxation dynamics of model compounds of the [FeFe]-hydrogenase enzyme. AB - The vibrational dynamics of (MU-propanedithiolate)Fe(2)(CO)(4)(CN)(2)(2-), a model compound of the active site of the [FeFe]-hydrogenase enzyme, have been examined via ultrafast 2D-IR spectroscopy. The results indicate that the vibrational coupling between the stretching modes of the CO and CN ligands is small and restricted to certain modes but the slow growth of off-diagonal peaks is assigned to population transfer processes occurring between these modes on timescales of 30-40 ps. Analysis of the dynamics in concert with anharmonic density functional theory simulations shows that the presence of CN ligands alters the vibrational relaxation dynamics of the CO modes in comparison to all carbonyl model systems and suggests that the presence of these ligands in the enzyme may be an important feature in terms of directing the vibrational relaxation mechanism. PMID- 21537509 TI - Hierarchical self-assembly of CdTe quantum dots into hyperbranched nanobundles: suppression of biexciton Auger recombination. AB - In this paper, we report a novel nanobundle structure formed by the hierarchical self-assembly of TGA-capped CdTe quantum dots. HR-TEM confirms the polycrystalline phase of the bundle structure, and that pristine quantum dots are the building units. The steady state absorption and luminescence properties of the pristine quantum dots can be well inherited by the nanobundles. In transient state observation, carrier quenching induced by Auger recombination is found to be remarkably suppressed. Electron delocalizing to close building units is considered to be the reason. Suppression of Auger recombination may earn much more time for charge separation, which makes the novel nanobundle structures suitable for the excellent donor material in solar cell applications. PMID- 21537511 TI - N-methyl-phenacyloxycarbamidomethyl (Pocam) group: a novel thiol protecting group for solid-phase peptide synthesis and peptide condensation reactions. AB - In the so-called thioester method for the condensation of peptide segments, protecting groups for amino and thiol groups are required for chemoselective ligation. In this study, we developed a novel thiol protecting group, N-methyl phenacyloxycarbamidomethyl (Pocam). We used it for protection of cysteine side chains, and synthesized Pocam-containing peptides and peptide thioesters. These were condensed by the thioester method. After the condensation reaction, Pocam groups were cleaved by Zn/AcOH treatment. At the same time, the azido group, which was used for the protection of lysine side chains, was also converted to an amino group, demonstrating that this protecting group strategy simplified the deprotecting reaction after the peptide condensation reaction to only one step. PMID- 21537510 TI - Intermolecular radical addition to N-acylhydrazones as a stereocontrol strategy for alkaloid synthesis: formal synthesis of quinine. AB - Stereocontrolled Mn-mediated radical addition of alkyl iodides to chiral N acylhydrazones enables strategic C-C bond disconnection of chiral amines. This strategy was examined in the context of a total synthesis of quinine, generating new findings of functional group compatibility leading to a revised strategy. Completion of a formal synthesis of quinine is presented, validating the application of Mn-mediated radical addition as a useful new C-C bond construction method for alkaloid synthesis. The Mn-mediated addition generates the chiral amine substructure of quinine with complete stereocontrol. Subsequent elaboration includes two successive ring closures to forge the azabicyclo[2.2.2]octane ring system of quincorine, linked to quinine through two known reactions. PMID- 21537512 TI - Synthesis of novel molecular probes inspired by harringtonolide. AB - A novel harringtonolide-inspired scaffold containing a cycloheptatriene ring and two fused cyclopentane rings has been synthesised from simple starting materials. The scaffold, containing a similar substitution pattern and relative stereochemistry to the complex diterpenoid, has been enumerated into a small library of derivatives. One of these library members has been converted into a sub-library of substituted triazoles using copper-catalysed azide-alkyne cycloaddition (click) chemistry. The scaffold may be useful in drug discovery or in the preparation of additional molecular probes for chemical biology. PMID- 21537514 TI - Dioxazaborocanes: old adducts, new tricks. AB - Dioxazaborocanes are boronic adducts obtained by condensation of diethanolamine derivatives with boronic compounds. They were first described in the mid-1950's as a practical way to isolate a boronic adduct. Their use has for a long time been restricted to this purpose for the isolation and characterisation of either a final product or a boronic intermediate. Only recently have they been directly involved in chemical transformations in which they proved equivalent or superior to their acid counterpart. In the meantime they have also been used as protected boronic acids. We wish to show in this report that they will likely represent a fluoride-free alternative to organotrifluoroborate salts and therefore an area of intense development. PMID- 21537513 TI - Design and synthesis of pyrrolidine-containing sphingomimetics. AB - Based on the structures of natural sphingolipids, we designed heterocyclic sphingoid base mimetics in which the conformational restriction is introduced by incorporation of a pyrrolidine moiety between the 2-amino group and the C-4 carbon atom of the sphingoid base. Our synthesis features a regioselective nucleophilic ring opening of a cyclic sulfate with cyanide and subsequent manipulation of the cyanide group. During the course of synthesis, Staudinger type reductive cyclization of 1,3-azido carboxylic acid and 1,4-azido alcohol offers a direct route to the five-membered pyrrolidone and pyrrolidine products. The preliminary biological evaluation indicates that the designed pyrrolidine analog is biologically active and its cytotoxic effect is associated with the induction of apoptosis. PMID- 21537516 TI - Effect of hyperbaric oxygen therapy in rats with subtotal splenectomy preserving the inferior pole. AB - PURPOSE: To evaluate the effect of hyperbaric oxygen therapy on the survival and weight of rats submitted to subtotal splenectomy and on the viability and growth of the inferior pole. METHODS: Forty Wistar rats underwent subtotal splenectomy with preservation of the inferior pole and distributed into two groups: Group A (n=20) - not treated with hyperbaric oxygen, Group B (n=20) - treated with hyperbaric oxygen. These groups were divided into two subgroups of 10 animals each, according to the time of euthanasia, 15th and 45th days. The survival and weight of the animals were recorded. The inferior pole was measured, weighed and morphologically analyzed. RESULTS: All animals survived. The weight of the animals increased in all subgroups, but decreased on the 10th day in the subgroups treated with hyperbaric oxygen (p<0.001). The viability of the inferior pole was more evident in animals treated on the 15th day, but did not differ on the 45th day. The growth of the inferior pole has not occurred on the 15th day but on the 45th day after surgery in untreated animals (p<0.01) and treated animals (p<0.05). Vascular and cellular increase in treated animals was significantly higher than in untreated ones. CONCLUSION: Hyperbaric oxygen therapy did not affect the survival of animals but reduced their weight. It improved the viability of the inferior splenic pole, but did not interfere with their growth. PMID- 21537517 TI - Effect of the period of extrinsic mechanical compression following sclerotherapy in veins in rabbit ears. AB - PURPOSE: Research whether a post-sclerotherapy venous compression period of up to 120 hours is sufficient to avoid reperfusion in treated veins; whether there is a relationship between the inflammatory intensity in venous walls and adjacent tissue and the size of venous thrombosis; whether the intensity of the post sclerotherapy inflammation varies with the period of compression; whether there is a relationship between the presence of hemosiderin in the tissues adjacent to the sclerosing blood vessels and venous blood clots. METHODS: Twenty eight rabbits, all male, were utilized, distributed into four groups (0, 24, 72 and 120). All the animals were administered with 0.25 ml of 1% polidoconal solution and, as a control, 0.25 ml of 0.9% sodium chloride solution in the marginal dorsal vein of the right and left ears, respectively. Mechanical compression was applied to the perfused stretch of the vein, except for the animals in group 0. The period of compression varied from 0 to 120 hours in the groups. An anatomopathological examination of the section of the right and left marginal dorsal veins of all the animals was conducted. RESULTS: There was no significant difference among the various compression periods, both in terms of the degree of vein thrombosis and in the inflammatory intensity in both ears of the various groups. A positive and significant correlation was observed between the inflammatory intensity and the size of the thrombus and in the occurrence of thrombi and hemosiderin. CONCLUSIONS: A compression period of up to 120 hours is not sufficient to prevent reperfusion in sclerosing blood vessels. The intensity of tissue inflammation is related to the size of the thrombus, but not to the compression period. The presence of hemosiderin in the tissues adjacent to the vessels subjected to sclerosis is related to the presence of venous coagulation. PMID- 21537518 TI - Miniplate fixation for the repair of segmental mandibular defects filled with autogenous bone in cats. AB - PURPOSE: To evaluate the use of maxillofacial miniplate 1.5 in the repair of segmental mandibular defects filled with autogenous bone in cats. METHODS: Twelve adult cats were divided into two groups. A segmental defect of 4mm was created in one of the hemimandibles and filled with autogenous iliac crest bone graft. The operated hemimandible was fixed with a 1.5mm titanium miniplate. In group 1 (n=6), the defect was performed in the body of the mandible, behind the 1st molar. In group 2 (n=6), the defect was performed between the 4nd premolar and 1st molar, with extraction of the 1st molar. Oral alimentation was reinitiated 24 hours after surgery. Cats were euthanized at 20 weeks postoperative. RESULTS: Incorporation of the graft was suggested by the radiographs taken 20 weeks after surgery. Macroscopic examination confirmed alignment and bone union of operated hemimandibles. Histological examination showed formation of woven bone in rostral and caudal mandible/graft interfaces. The percentage of bone tissue at these areas was measured by the histometry. There was no statistically significant difference between the values of group 1(64.48 +/- 4.51) and group 2 (71.69 +/- 14.47) (Mann-Whitney's test p= 0.294). CONCLUSION: The use of miniplate 1.5 for the fixation of mandibular defects filled with autogenous bone in cats provided the main goals in the treatment of mandibular fractures: bone union, normal dental occlusion and immediate return to oral alimentation. PMID- 21537519 TI - Effects of short term fasting on the evolution of fecal peritonitis in mice. AB - PURPOSE: To investigate the effect of 72 hours food suppression on the evolution of fecal peritonitis in mice evaluating the mortality and measuring the number and size of abscesses formed into the peritoneal cavity. METHODS: Mice receiving commercial diet and water ad libitum (control group, N=35) and mice fasted during 72 h (N=35), receiving only water ad libitum, were inoculated by i.p. route, with 4uL/g body weight of a fecal suspension diluted 1:6 or 1:9 in 0.15M NaCl solution (1:6 dilution, 22 controls and 18 fasted; 1:9 dilution, 13 controls and 17 fasted). Animals were followed up until two weeks after fecal inoculation, when the survivors were euthanized for evaluation of the number and size of intra peritoneal abscesses. Mortality was evaluated by Kaplan Meyer curves. RESULTS: Mortality was significantly higher in fasted groups than in controls. However the number and size of abscesses were significantly less in fasted groups than in controls. CONCLUSION: Seventy two hours food suppression increased the susceptibility to endotoxic shock (high mortality after peritonitis induction) and the resistance to infection with fecal microorganisms (less number and size of intra-peritoneal abscesses). PMID- 21537520 TI - Effects of allopurinol and preconditioning on apoptosis due to ischemia reperfusion on a double jejunum-segment canine model. AB - PURPOSE: To investigate the duration of apoptosis caused by ischemia-reperfusion in the intestine in a new double jejunum-segment model, and to analyze the protective effects of allopurinol or ischemic preconditioning (IPC). METHODS: In Experiment I for harvesting the double jejunum-segment model after laparotomy a 30-cm-long jejunum part was selected on mongrel dogs (n=24). End-to-end anastomoses were performed at both ends and in the middle of the jejunum part, creating two equal segments. In one segment ischemia was induced by occluding the supplying vessels, the other segment served as control. Tissue samples for detecting apoptosis were taken at 30th minutes, 1st, 2nd, 4th, 6th, 8th, 12th and 24th hours of reperfusion. In Experiment II using the same model the 4-hour reperfusion time period, allopurinol (50 mg/kg) pre-treated and IPC (3 cycles of 5x1) groups (n=5 per each) were also investigated. RESULTS: In Experiment I the greatest apoptotic activity was detected at the 4th and 6th hour of reperfusion (14.2 +/- 1.31 and 16.3 +/- 1.05 per visual field at 40x magnification). In Experiment II Using the 4-hour reperfusion time period allopurinol pre-treatment increased the apoptotic activity (10.72 +/- 0.47 per 50 intestinal villi) approximately two-fold than the IPC (6.72 +/- 0.46 per 50 intestinal villi) did (p<0.05). CONCLUSIONS: Apoptotic activity has a characteristic time curve, reaching the highest values between the 4th and 6th hours after 30-minute intestinal ischemia. Ischemic preconditioning seemed to be protective against the morphological changes caused by intestinal ischemia-reperfusion. PMID- 21537521 TI - Topical hepatic hypothermia plus ischemic preconditioning: analysis of bile flow and ischemic injuries after initial reperfusion in rats. AB - PURPOSE: To evaluate the effects of the topical liver hypothermia and IPC combination against I/R injury after initial reperfusion. METHODS: In 32 Wistar rats, partial liver ischemia was induced for 90 minutes in normothermia (IN), ischemic preconditioning (IPC), 26oC topical hypothermia (H) and 26oC topical hypothermia plus IPC (H+IPC). MAP, body temperature and bile flow were recorded each 15 minutes. Plasmatic injury markers and tissue antioxidant defenses were assessed after 120 minutes of reperfusion. RESULTS: MAP and body temperature remained constant during all experiment. Bile flow returned to levels similar to controls after 45 minutes of reperfusion in the H and H+IPC groups and increased significantly in comparison to the NI and IPC groups after 105 and 120 minutes. AST and ALT increased significantly in the normothermic groups in comparison to controls. TBARS levels decreased significantly in the H+IPC group in comparison to the other groups whereas Catalase levels increased significantly in the IPC group. SOD levels were significantly higher in the H group in comparison to all groups. CONCLUSION: The induction of 26oC topical hypothermia associated or not to IPC protected the ischemic liver against ischemia/reperfusion injuries and allowed an early recovery of the hepatic function. PMID- 21537522 TI - Dexmedetomidine and S(+)-ketamine in ischemia and reperfusion injury in the rat kidney. AB - PURPOSE: To investigate blood creatinine and renal histology in rats anesthetized with S(+)-ketamine (keta) or dexmedetomidine (dex) and submitted to kidney ischemia/reperfusion injury (IRI). METHODS: Under intraperitoneal (ip) S(+) ketamine, 20 male Wistar rats were divided into two groups (n=10): maintenance with iv S(+)-ketamine or dex (keta and dex groups), and submitted to right (R) nephrectomy and left (L) renal artery clamping for 45 min. Blood creatinine was measured before ischemia (T1) and 48h after reperfusion (T2), when L nephrectomy was performed. Histological analysis was performed in all kidneys. RESULTS: Blood creatinine was significantly higher at T2 in both groups, but dex group results were lower than those of keta group. Histological changes: between groups, R kidneys did not differ; there were significant high scores for vascular dilation: keta L kidneys; for vascular congestion, tubular dilation, and necrosis: L kidneys from both groups; for tubular degeneration: keta R kidneys. CONCLUSION: S(+)-ketamine plus IRI were aggressive to rat kidneys, according to histological changes, and dexmedetomidine may have not totally protected the kidneys from these injuries, despite the better results of blood creatinine. PMID- 21537523 TI - Anesthetic recovery and hemodynamic effects of continuous thiopental infusion versus halothane for maintenance anesthesia in patients undergoing ocular surgery. AB - PURPOSE: To investigate anesthesia recovery and hemodynamic status in patients under thiopental infusion or halothane maintenance anesthesia undergoing ocular surgery. METHODS: Fifty-nine voluntary patients undergoing ocular surgery in Farabi hospital were allocated to one of two maintenance anesthesia groups: inhaled halothane, 0.8 to 1 per cent, (group I, n=37) and thiopental infusion, 10 to 12 mg/kg/hour, (group II, n=22). Hemodynamic parameters were recorded at the time of patient entrance to the operation room and at the 1, 2, 5, 10, 15, 20, 25, 30, 35, and 40 minutes following anesthesia. Anesthesia recovery variables were also compared between the two groups. RESULTS: In group I, arterial blood pressure at 10 to 40 min and heart rate at 1 and 25 min after the administration of anesthetics were significantly lower when compared with group II (W 2= 25.10, p= 0.005). Arterial oxygen saturation was similar in the two groups over the whole points of time. The time intervals between the end of surgery and beginning of the first body movements and respiratory efforts were significantly longer in group received halothane (p<0.001). CONCLUSION: Continuous infusion of thiopental can be applied effectively and safely for maintenance of anesthesia. In comparison with halothane, it is associated with lower changes of intraoperative hemodynamics and faster anesthesia recovery. PMID- 21537524 TI - Thoracotomy versus transhiatal esophageal dissection: which is the best surgical approach to short esophagus? AB - PURPOSE: To evaluate different approaches performed to obtain a more significant esophageal length. METHODS: An experimental model using 28 cadavers was conceived. Randomized groups: Group A (n=10) underwent laparotomic transhiatal approach; Group B (n=9) which differed from the first in the conduction of a wide phrenotomy and Group C (n=9) esophageal dissection was performed through a left anterolateral thoracotomy. RESULTS: Final length variations for Group A were 2.12cm and 3.29cm and for Group B 3.24 cm and 3.66cm, without and with esophageal traction, respectively. In Group C length gain observed was 3.81 cm. The mediastinal dissections conducted through the hiatus was considered the procedure that produced the better esophageal mobilization, and the association of wide phrenotomy significantly improved the results. CONCLUSION: The mediastinal dissection was the most effective to improving gain in abdominal esophagus. When toracotomy and laparotomy were compared, no significant differences were observed in the outcome. PMID- 21537525 TI - Iloprost reduces colonic injury in ischemic colitis in rats. AB - PURPOSE: Evaluate the effects of iloprost administration in the early period of ischemic colitis and the mechanism that how these effects develop. METHODS: Thirty two Wistar albino female rats with an average weight of 220g were divided into four groups of eight rats. In group 1 the rats were given iloprost and sacrificed after 24 hours and in group 2 they were sacrificed after 24 hours without any iloprost. The rats in group 3 were administrated iloprost and sacrificed after 72 hours and in group 4 they were sacrificed at 72th hour without iloprost. The differences between the groups as tissue damage, vascularization or apoptosis were assessed statistically. RESULTS: Oxidative damage and apoptosis were less pronounced and vascularization was better developed in rats that were given iloprost and sacrificed at 24th hour later in contrast to the rats that were not treated with iloprost. But there was no statistical difference among the groups at 72th hour. CONCLUSION: Iloprost inhibited leucocyte infiltration, decreased proinflammatory cytokines and enhanced angiogenesis so that the oxidative stress and inflammatory response decreased resulting in lesser tissue damage. PMID- 21537526 TI - Experimental model of traumatic ulcer in the cheek mucosa of rats. AB - PURPOSE: To establish an experimental model of traumatic ulcer in rat cheek mucosa for utilization in future alternative therapy studies. METHODS: A total of 60 adult male rats (250 - 300g) were used. Ulceration of the left cheek mucosa was provoked by abrasion using a no 15 scalpel blade. The animals were observed for 10 days, during which they were weighed and their ulcers were measured. The histological characteristics were analyzed and scored according to the ulcer phase. In the statistical analysis, a value of p<0.01 was considered a statistically significant response in all cases. RESULTS: During the five first days, the animals lost weight (Student t test, p<0.01). The ulcerated area receded linearly over time and was almost completely cicatrized after 10 days (ANOVA, Tendency posttest, p<0.0001). Groups on days 1, 2 and 3 days displayed similar results, but a decrease in scores were observed after the 4th day. CONCLUSION: The proposed cheek mucosa ulcer model in rats can be considered an efficient, low-cost, reliable, and reproducible method. PMID- 21537527 TI - The laparoscopy splenic injury repair: the use of fibrin glue in a heparinized porcine model. AB - PURPOSE: To investigate the effectiveness of fibrin glue (laparoscopic via) into promote the hemostasis of a spleen injury on a heparinized porcine model. METHODS: Eighteen Landrace porcine were submitted to laparoscopic spleen injury and randomly distributed: GHA (heparin plus adhesive), GH (heparin without adhesive) and GS (Sham - without heparin or adhesive). Ten minutes before the surgical procedures a single IV dose (200UI/kg) of heparin sodium was administrated only to groups GHA and GH. In the GHA, adhesive was applied after the mechanical injury and recorded the time until the polymerization and clot formation. RESULTS: No significant differences occurred among the groups (Fisher test) considering the weight and surgery time. The blood amount in the abdominal cavity on GH was significantly higher in comparison to the sham group and especially with the GHA (p<0.004). No significant differences were observed in the body temperature, heart rate, cardiac output, means arterial pressure, pulmonary artery pressure during the experiment. The activated partial thromboplastin time (APTT) was lower in the GHA in comparison to GH (p<0.003). CONCLUSION: The fibrin biological adhesive applied by laparoscopy is effective for hemostasis of minor spleen injury in a porcine model under the effect of anticoagulant drug. PMID- 21537528 TI - Importance to include the term superficial musculoaponeurotic system in medical subject headings and in the international anatomical nomenclature. AB - PURPOSE: To investigate the relevance of the term superficial musculoaponeurotic system (SMAS) and demonstrate that this term is important enough to be added to the MeSH database and listed in International Anatomical Nomenclature. METHODS: Terms related to SMAS were selected from original articles retrieved from the ISI Web of Science and MEDLINE (PubMed) databases. Groups of terms were created to define a search strategy with high-sensitivity and restricted to scientific periodicals devoted to plastic surgery. This study included articles between January 1996 and May 2009, whose titles, abstracts, and keywords were searched for SMAS-related terms and all occurrences were recorded. RESULTS: A total of 126 original articles were retrieved from the main periodicals related to plastic surgery in the referred databases. Of these articles, 51.6% had SMAS-related terms in the abstract only, and 25.4% had SMAS-related terms in both the title and abstract. The term 'superficial musculoaponeurotic system' was present as a keyword in 19.8% of the articles. The most frequent terms were 'SMAS' (71.4%) and superficial musculoaponeurotic system (62.7%). CONCLUSION: The term SMAS refers to a structure relevant enough to start a discussion about indexing it as a keyword and as an official term in Terminologia Anatomica: International Anatomical Terminology. PMID- 21537529 TI - Use of bipolar radiofrequency for the treatment of atrial fibrillation during cardiac surgery. AB - BACKGROUND: Atrial fibrillation with tissue ablation device through bipolar radiofrequency in conjunction with cardiac surgery has proven to be an effective method to treat this arrhythmia. OBJECTIVE: Describe the initial experience of the Instituto Nacional de Cardiologia in the surgical treatment of atrial fibrillation using bipolar radiofrequency device in patients undergoing cardiac surgery, reporting the results of postoperative follow-up of one year. METHODS: Between January 2008 and March 2009, 47 consecutive patients (36 women), with mean age of 53.7 +/- 10.6 years, with atrial fibrillation for a mean period of 34.6 months (3-192 months) underwent surgical ablation of this arrhythmia, through bipolar radiofrequency during the procedure which led to the indication of surgery. Eight of them showed intermittent atrial fibrillation and 39, continued. Eighty-one percent underwent valve surgery as the main procedure. This is a one-year postoperative retrospective, observational evaluation of clinical variables and 24-h Holter. RESULTS: Out of the 47 patients, 40 survived one year. Out of these, 33 underwent 24 h Holter, at an average interval of 401 days after the surgery. The following rhythm distribution was found: 24 (73.0%) sinus, five (15.0%) atrial fibrillation, three (9.0%) atrial Flutter and one (3.0%) junctional rhythm. Two cerebrovascular accidents were observed, one of which was associated with supraventricular arrhythmia. CONCLUSION: Surgical ablation of atrial fibrillation with bipolar radiofrequency device concomitant with cardiac surgery is an effective method for treating this arrhythmia. PMID- 21537530 TI - High blood pressure detection in adolescents by clustering overall and abdominal adiposity markers. AB - BACKGROUND: Obesity is linked to high blood pressure (HBP) in childhood. However, the role of fat as a predictor of HBP in adolescents remains unknown. OBJECTIVE: To investigate the association between general and abdominal obesity with HBP and to identify the sensitivity and specificity of these indicators to detect HBP in adolescents. METHODS: The sample was composed of 1,021 adolescents aged 10-17 years. Subjects were classified as normal, overweight/obese, according to BMI measurements, and as non-obese and with abdominal obesity, according to waist circumference (WC) measurements. Systolic (SBP) and diastolic (DBP) blood pressure were assessed using an oscillometric device. Logistic regression and ROC curves were used in the statistical analysis. RESULTS: The overall prevalence of HBP was 11.8% (13.4% in boys and 10.2% in girls). The prevalence of HBP among general overweight/obese boys and girls was 10% and 11.1%, respectively. The prevalence of HBP among boys with abdominal obesity was 28.6%. For both genders, the odds ratio (OR) for HBP was higher in abdominal obesity than in general overweight/obesity (4.09 [OR(95%CI) = 2.57-6.51]) versus 1.83 [OR(95%CI) = 1.83 4.30]). The OR for HBP was higher when general overweight/obesity and abdominal obesity were clustered (OR = 4.35 [OR(95%CI) = 2.68-7.05]), than when identified by either general overweight/obesity or abdominal obesity alone (OR = 1.32 [OR(95%CI) = 0.65-2.68]). However, both types of obesity had low predictive power in HBP detection. CONCLUSION: General and abdominal obesity were associated to HBP, however, the sensitivity and specificity of these variables to detect HBP are low in Brazilian adolescents. PMID- 21537531 TI - Method of heart rate variability threshold applied in obese and non-obese pre adolescents. AB - BACKGROUND: The detection of anaerobic threshold (AT) by heart rate variability analysis (HRVt) may mean a new way to assess the cardiorespiratory capacity (CRC) in pre-adolescents. OBJECTIVE: To test the method of HRVt to detect AT in non obese (NO), obese (O) and morbidly obese (MO) pre-adolescents in order to determine differences in their CRC. METHODS: Were studied 30 pre-adolescents, aged between 9 and 11 years, divided into three groups of ten pre-adolescents each: a) NO group - body mass index (BMI) between 5 and 85 percentiles of the chart of National Center for Chronic Disease Prevention and Health Promotion.; b) O group - BMI between 95 and 97 of the same chart; c) MO group - BMI with percentile over 97. All were submitted to an incremental protocol conducted on a treadmill, and the heart rate was recorded for the detection of the HRVt when the beat-to-beat variability (SD1), extracted from the RR intervals, reached the value of 3 ms. RESULTS: The mean values obtained at HRVt were higher for the NO group, which included: a) VO2 (ml/kg/min) NO = 27.4 +/- 9.2; O = 13.1 +/- 7.6, and MO = 11.0 +/- 1.7 b) HR (bpm): NO = 156.3 +/- 18.0, O = 141.7 +/- 11.4 and 137.7 +/- 10.4 MO; c) distance (m): NO = 1,194.9 +/- 427.7, O = 503.2 +/- 437.5 and MO = 399.9 +/- 185.1. CONCLUSION: HRVt was effective for evaluation of CRC and could be applied as an alternative method to ergoespirometry in certain situations. PMID- 21537532 TI - Analysis of mortality and hospitalization for cardiovascular diseases in Niteroi, between 1998 and 2007. AB - BACKGROUND: The reduction in mortality from cardiovascular disease has been observed in Brazil for years, attributed to a fall in risk factors, improved treatment and reduced hospital mortality. OBJECTIVE: To compare the mortality, the rate of hospitalization and hospital mortality in hospitals belonging to the Brazilian Public Health System, for ischemic heart disease (IHD), cerebrovascular diseases (CVD) and heart failure (HF), in Niteroi, between 1998 and 2007. METHODS: We used the number of deaths and hospitalizations and mortality of residents in Niteroi for Chapter IX of ICD10 and specific causes available in Datasus, in population aged 30 and older. The difference between the magnitude of the indicators was calculated for men and women taking the average of the first three year period less the average of the second three year period. RESULTS: There was drop in population mortality rates in men and women for all age groups, in three groups of causes and for Chapter IX. The falling trend of rates decreased with age. For IHD there was a decrease in hospital mortality. For CVD and HF, there was an increase. The rates of hospitalization from IHD decreased, with exception of some ranges. CONCLUSION: This study has clarified some aspects of cardiovascular morbidity and mortality in Niteroi. The reduction in population and hospital mortality from IHD indicates that there is a better approach in this condition. Increased mortality rate from cerebrovascular diseases and HF points to the need to give greater attention to the quality of hospital care for these groups of diseases. PMID- 21537533 TI - Staplers in digestive surgery: technological advancement in surgeons' own hands. PMID- 21537534 TI - TRREMS procedure (transanal repair of rectocele and rectal mucosectomy with one circular stapler): a prospective multicenter trial. AB - CONTEXT: Since anorectocele is usually associated with mucosa prolapse and/or rectal intussusceptions, it was developed a stapled surgical technique using one circular stapler. OBJECTIVE: To report the results of Transanal Repair of Rectocele and Rectal Mucosectomy with one Circular Stapler (TRREMS procedure) in the treatment of anorectocele with mucosa prolapse in a prospective multicenter trial. METHODS: It was conducted by 14 surgeons and included 75 female patients, mean aged 49.6 years, with symptoms of obstructed defecation due to grade 2 (26.7%) and grade 3 (73.3%) anorectocele associated with mucosa prolapse and/or rectal intussusception (52.0%) and an average validated Wexner constipation score of 16. All patients were evaluated by a proctological examination, cinedefecography, anal manometry and colonic transit time. The TRREMS procedure consists of the manual removal of the rectocele wall with circumferential rectal mucosectomy performed with a circular stapler. The mean follow-up time was 21 months. RESULTS: All patients presented obstructed defecation and they persisted with symptoms despite conservative treatment. The mean operative time was 42 minutes. In 13 (17.3%) patients, bleeding from the stapled line required hemostatic suture. Stapling was incomplete in 2 (2.6%). Forty-nine patients (65.3%) required 1 hospitalization day, the remainder (34.7%) 2 days. Postoperatively, 3 (4.0%) patients complained of persistent rectal pain and 7 (9.3%) developed stricture on the stapled suture subsequently treated by stricturectomy under anesthesia (n = 1), endoscopic stricturectomy with hot biopsy forceps (n = 3) and digital dilatation (n = 3). Postoperative cinedefecography showed residual grade I anorectoceles in 8 (10.6%). The mean Wexner constipation score decreased significantly from 16 to 4 (0-4: n = 68) (6: n = 6) (7: n = 1) (P<0.0001). CONCLUSION: Current trial results suggest that TRREMS procedure is a safe and effective technique for the treatment of anorectocele associated with mucosa prolapse. The stapling technique is low-cost as requires the use of a single circular stapler. PMID- 21537535 TI - Prediction of severe complications and death in superobese patients undergoing open gastric bypass with the Recife Score. AB - CONTEXT: Superobese patients who undergo gastric bypass have a greater incidence of complications. The greater incidence of comorbidity in this group leads to a higher surgical risk, and a need for special care. By analyzing the risk factors identified in the preoperative period, scoring them, constructing a score and assessing the occurrence of serious complications and death, we will have elements to identify which patients are at greater risk. OBJECTIVE: To determine the accuracy of the Recife Score for predicting serious postoperative complications and death in superobese patients who undergo Roux-en-Y gastric bypass surgery by the conventional method. METHODS: An ambidirectional study was conducted to validate the diagnostic test on 203 severely obese patients submitted to Roux-en-Y gastric bypass at the Hospital das Clinicas of the Federal University of Pernambuco, Recife, PE, Brazil, from September 1997 to May 2007. The dependent variables were major postoperative complications and death. The independent variable was the Recife Score. The data were analyzed using the Epi Info 3.5.1 program. The accuracy of the Recife Score was analyzed considering the following parameters: sensitivity, specificity, positive predictive value, negative predictive value, positive verisimilitude ratio and negative verisimilitude ratio. RESULTS: The accuracy of the Recife Score with cut-off points higher than 3 and higher than 5 to predict serious postoperative complications was, respectively, a frequency of complications of 12.3%, with a risk ratio of 2.83, sensitivity of 57.1% and specificity of 69.8%, and 12.5%, with a risk ratio of 1.88, sensitivity of 7.1% and specificity of 96.3%. The accuracy of the Recife Score with cut-off points higher than 3 and higher than 5 to predict death was, respectively, a frequency of death of 7.7%, with a risk ratio of 10.62, sensitivity of 83.3% and specificity of 69.5%, and 12.5%, with a risk ratio of 4.88, sensitivity of 16.7% and specificity of 96.5%. CONCLUSION: A Recife Score >3 prior to conventional gastric bypass presents a high level of accuracy in the prediction of serious postoperative complications and death. PMID- 21537537 TI - Achalasia in the elderly patient: a comparative study. AB - CONTEXT: Achalasia is a primary esophageal motor disorder secondary to the degeneration of ganglion cells of the inhibitory intramural myenteric plexus. It affects both sexes similarly and has two peaks of incidence, one in the 3rd to 4th decades of life and the other after 60 years of age. The effect of age on esophageal motility of patients with achalasia is not well known. Studies have shown that healthy older people, when compared to the young, have: a) a lower number of ganglion cells in the intramural myenteric plexus; b) a reduced normal relaxation of the lower esophageal sphincter; and c) a reduced esophageal peristalsis. Thus, as both age and achalasia can produce comparable degenerative changes in the intramural myenteric plexus, it is possible that advanced age could be an important factor in enhancing the clinical and manometric abnormalities commonly found in patients with achalasia. OBJECTIVES: To compare the clinical, radiological and manometric findings in young as compared to elderly (>60 years old) achalasia patients. METHODS: A retrospective study of a group of patients with untreated achalasia separated into young and elderly patients. Demographic, clinical, serology for Chagas' disease, radiological and manometric data were compared between these groups. The level of significance was P<0.05. RESULTS: The study included 105 patients, 52 young (25 M/27 F, mean age 40 years old) and 53 elderly (21 M/32 F, mean age 70 years old). The elderly group had a higher prevalence of Chagas' disease (P = 0.004) and a lower pressure of the lower esophageal sphincter [26.4 mm Hg vs 31.9 mm Hg] P = 0.001, a difference that persisted when analyzed only elderly and young patients with idiopathic achalasia. Younger patients had a higher prevalence of heartburn (P = 0.001) and chest pain (P = 0.012) than the elderly. CONCLUSION: Elderly patients with achalasia had a lower esophageal sphincter pressure than the young, even when we excluded patients with Chagas' disease but, as a group, they were less symptomatic. PMID- 21537536 TI - Evaluation of liquid ingestion after bariatric surgery. AB - CONTEXT: Bariatric surgery is an effective treatment for obesity; however, after surgery the patient may have difficulty in swallowing liquid and solid foods. OBJECTIVES: To evaluate liquid ingestion in patients who had undergone bariatric surgery. METHOD: We studied 43 volunteers with normal body mass index (BMI) (BMI: 18.5-24.9 kg/m2), 55 subjects with class III obesity (BMI: >40.0 kg/m2), and 48 subjects with bariatric surgery for treatment of class III obesity. The method chosen for evaluation was the water swallowing test. The subjects drank in triplicate 50 mL of water while being precisely timed and the number of swallows were counted. RESULTS: There was no difference between subjects with normal BMI and subjects with class III obesity. During the first 2 months after bariatric surgery the patients showed an increase in the time needed to drink the entire volume, in the number of swallows, and in the inter-swallow interval, and a decrease in the volume swallowing capacity (volume/swallowing) and swallowing flow rate (volume swallowed/second). After 2 months, the results of the swallowing measurements moved in the direction of normal values. CONCLUSION: Bariatric surgery may cause more intense alterations of liquid bolus swallowing within 2 months after the procedure, which moved to normal values after this time. PMID- 21537538 TI - Impact of prolonged 48-h wireless capsule esophageal pH monitoring on diagnosis of gastroesophageal reflux disease and evaluation of the relationship between symptoms and reflux episodes. AB - CONTEXT: Gastroesophageal reflux disease is one of the most common digestive diseases and an important cause of distress to patients. Diagnosis of this condition can require ambulatory pH monitoring. OBJECTIVES: To determine the diagnostic yield of a wireless ambulatory pH monitoring system of 48-hours, recording to diagnose daily variability of abnormal esophageal acid exposure and its symptom association. METHODS: A total of 100 consecutive patients with persistent reflux symptoms underwent wireless pH capsule placement from 2004 to 2009. The wireless pH capsule was deployed 5 cm proximal to the squamocolumnar junction after lower esophageal sphincter was manometrically determined. The pH recordings over 48-h were obtained after uploading data to a computer from the receiver that recorded pH signals from the wireless pH capsule. The following parameters were analyzed: (1) percentual time of distal esophageal acid exposure; (2) symptom association probability related to acid reflux. The results between the first and the second day were compared, and the diagnostic yield reached when the second day monitoring was included. RESULTS: Successful pH data over 48-h was obtained in 95% of patients. Nearly one quarter of patients experienced symptoms ranging from a foreign body sensation to chest pain. Forty-eight hours pH data analysis was statistically significant when compared to isolated analysis of day 1 and day 2. Study on day 2 identified seven patients (30.4%) that would be missed if only day 1 was analyzed. Three patients (18.7%) out of 16 patients with normal esophageal acid exposure on both days, showed positive symptom association probability, which generated an increase in diagnostic yield of 43.4%. CONCLUSION: Esophageal pH monitoring with wireless capsule is safe, well tolerated, does not require sedation. The extended 48-h period of study poses an increased yield to diagnose gastroesophageal reflux disease patients. PMID- 21537539 TI - Variation of the anal resting pressure induced by postexpiratory apnea effort in patients with constipation. AB - CONTEXT: Intestinal constipation--a common symptom among the general population- is more frequent in women. It may be secondary to an improper diet or organic or functional disturbances, such as dyskinesia of the pelvic floor. This is basically characterized by the absence of relaxation or paradoxical contraction of the pelvic floor and anal sphincter during evacuation. OBJECTIVE: To analyze, by manometric data, the anal pressure variation at rest, during evacuation effort by using the Valsalva maneuver and forced post-expiratory apnea in subjects with secondary constipation. METHODS: Twenty-one patients (19 females--90.4%) with a mean age of 47.5 years old (23-72) were studied. The diagnosis was performed using anorectal manometry, with a catheter containing eight channels disposed at the axial axis, measuring the proximal (1) and distal (2) portions of the anal orifice. The elevation of the pressure values in relation to the resting with the evacuation effort was present in all patients. The Agachan score was used for clinical evaluation of constipation. The variables studied were: mean anal pressure of the anal orifice for 20 seconds at rest, the effort of evacuation using Valsalva maneuver and the effort of evacuation during apnea after forced expiration, as well as the area under the curve of the manometric tracing at moments Valsalva and apnea. RESULTS: The analysis of the mean values of the anal pressure variation at rest evidenced difference between proximal and distal channels (P = 0.007), independent of the moment and tendency to differ during moments Valsalva and apnea (P = 0.06). The mean of values of the area under the manometric tracing curve showed differences between moments Valsalva and apnea (P = 0.0008), either at the proximal portion or at the distal portion of the anal orifice. CONCLUSION: The effort of evacuation associated with postexpiratory apnea, when compared with the effort associated with the Valsalva maneuver, provides lower elevation of anal pressure at rest by the parameter area under the curve. PMID- 21537540 TI - Treatment of postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome with mesalazine. AB - CONTEXT: Recent studies support the hypothesis that postinfectious irritable bowel syndrome and some irritable bowel syndrome patients display persistent signs of minor mucosal inflammation. Mesalazine has intestinal anti-inflammatory properties including cyclooxygenase and prostaglandin inhibition. The effects of mesalazine on postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome patients are still unknown. OBJECTIVE: To observe the effects of mesalazine on postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome with diarrhea patients. METHODS: Based on Rome III criteria, 61 irritable bowel syndrome with diarrhea patients (18 years old or more) were included in the evaluation. Patients were divided into two groups: postinfectious irritable bowel syndrome group, with 18 patients medicated with mesalazine 800 mg 3 times a day for 30 days; noninfective irritable bowel syndrome group, with 43 patients medicated with mesalazine 800 mg 3 times a day for 30 days. Symptom evaluations at baseline and after treatment were performed by means of a four point Likert scale including stool frequency, stool form and consistency (Bristol Stool Scale), abdominal pain and distension (maximum score: 16; minimum score: 4). RESULTS: Postinfectious irritable bowel syndrome group presented a statistically significant reduction of the total symptom score (P<0.0001). The stool frequency was significantly reduced (P<0.0001), and stool consistency, improved (P<0.0001). Abdominal pain (P<0.0001) and abdominal distension were significantly reduced (P<0.0001). Noninfective irritable bowel syndrome group presented a statistically significant reduction of total symptom score (P<0.0001). Also, the stool frequency was significantly reduced (P<0.0001) and stool consistency, improved (P<0.0001). Abdominal pain (P<0.0001) and abdominal distention were significantly reduced (P<0.0001). There was no statistical difference between postinfectious irritable bowel syndrome group and noninfective irritable bowel syndrome group on total symptom score results at 30th day of therapy with mesalazine 800 mg 3 times a day. (P = 0.13). CONCLUSION: Mesalazine reduced key symptoms of postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome with diarrhea patients. PMID- 21537541 TI - Relationship between cagA-positive Helicobacter pylori infection and risk of gastric cancer: a case control study in Porto Alegre, RS, Brazil. AB - CONTEXT: Gastric cancer is the second most common cause of cancer related death worldwide. Although Helicobacter pylori has been classified as a class I carcinogen, the presence of infection is not a factor that alone is able to lead to gastric cancer, and one of the possible explanations for this is the existence of different strains of H. pylori with different degrees of virulence. OBJECTIVES: To investigate the association between cagA-positive H. pylori and gastric cancer, using polymerase chain reaction (PCR) for the detection of this bacterial strain. METHODS: Twenty-nine patients with gastric cancer were matched by sex and age (+/- 5 years) with 58 patients without gastric cancer, submitted to upper gastrointestinal endoscopy. All patients were evaluated for the status of infection by H. pylori (through urease test, histological analysis and PCR for the genes ureA and 16SrRNA) and by cagA-positive strain (through PCR for cagA gene). RESULTS: Evaluating the presence of infection by cagA-positive H. pylori, it was verified that the rate of infection was significantly higher in the group with gastric cancer when compared with the matched controls, occurring in 62.1% and 29.3%, respectively (OR = 3.95; CI 95% 1.543-10.096). CONCLUSIONS: There is an association between cagA-positive H. pylori strain and risk of gastric cancer. PMID- 21537542 TI - Determination of strains of Helicobacter pylori and of polymorphism in the interleukin-8 gene in patients with stomach cancer. AB - CONTEXT: Gastric neoplasia is the second most common cause of death by cancer in the world and H. pylori is classified as a type I human carcinogen by the World Health Organization. However, despite the high prevalence of infection by H. pylori around the world, less than 3% of individuals carrying the bacteria develop gastric neoplasias. Such a fact indicates that evolution towards malignancy may be associated with bacterial factors in the host and the environment. OBJECTIVES: To investigate the association between polymorphism in the region promoting the IL-8 (-251) gene and the H. pylori genotype, based on the vacA alleles and the presence of the cagA gene, using clinical and histopathological data. METHODS: In a prospective study, a total of 102 patients with stomach cancer and 103 healthy volunteers were analysed. Polymorphism in interleukin 8 (-251) was determined by the PCR-restriction fragment length polymorphism reaction and sequencing. PCR was used for genotyping the vacA alleles and the cagA in the bacterial strains PCR. Gastric biopsies were histologically assessed. RESULTS: The H. pylori serology was positive for 101 (99%) of all patients analysed, and 98 (97%) of them were colonized by only one strain. In patients with monoinfection, 82 (84%) of the bacterial strains observed had the s1b/m1 genotype. The cagA gene was detected in 74 (73%) of patients infected by H. pylori. The presence of the cagA gene was demonstrated as associated with the presence of the s1b/m1 genotype of the vacA gene (P = 0.002). As for polymorphism in the interleukin 8 (-251) gene we observed that the AA (P = 0.026) and AT (P = 0.005) genotypes were most frequent in the group of patients with gastric adenocarcinoma. By comparing the different types of isolated bacterial strains with the interleukin -8 (-251) and the histopathological data we observed that carriers of the A allele (AT and AA) infected by virulent strains (m1s1 cagA+) demonstrated a greater risk of presenting a degree of inflammation (OR = 24.75 CI 95% 2.29-267.20 P = 0.004) and increased neutrophilic activity (OR = 28.71 CI 95% 2.62-314 P = 0.002) in the gastric mucosa. CONCLUSION: Our results demonstrate that the interaction between polymorphism in the interleukin -8 (-251) gene, particularly with carriers of the A allele and the infecting type of H. pylori strain (s1m1 cagA positive) performs an important function in development of gastric adenocarcinoma. PMID- 21537543 TI - Physical therapy combined with a laxative fruit drink for treatment of chagasic megacolon. AB - CONTEXT: The treatment of Chagas' disease colopathy is limited to clinical management in the initial of the process, and for patients for whom surgery is not indicated or is not possible, anti-constipation diets are used, along with judicious administration of laxatives and enemas. OBJECTIVE: To evaluate over time the effects of physical-therapy interventions combined with daily ingestion of a laxative fruit drink in the treatment of chagasic megacolon. METHOD: In a quantitative, prospective, and comparative study, 12 patients of both sexes and with a mean age of 67 +/- 12 years were clinically evaluated to receive 12 sessions of physical therapy twice a week, along with fruit drink, and were evaluated for intestinal constipation before and after treatment. RESULTS: A significant difference (P<0.0022) was observed in the constipation scores before and after 6 weeks of intervention in 91.7% of the patients, and in 72.7% after 12 months, with reduction of laxative medications, softer stools, and increased number of bowel movements. With respect to gender, age, and whether or not the patient had received surgical treatment, there was no significant difference (P>0.05). CONCLUSION: The proposed protocol is easy to implement, safe, non invasive, and low-cost, with the potential to be deployed in health care by providing benefits independent of gender, age, or whether the participant has undergone surgery, improving the condition of patients with chagasic megacolon. PMID- 21537544 TI - Clinical and nutritional status of surgical patients with and without malignant diseases: cross-sectional study. AB - CONTEXT: Malnutrition is frequently observed in inpatients with malignant diseases and may contribute to longer hospital stays. OBJECTIVE: To compare the nutritional status, lymphocyte count, hemoglobin values and length of hospital stay of patients with and without malignant diseases. METHODS: This comparative study assessed indicators of nutritional status, namely body mass index, recent weight loss, lymphocyte count, hemoglobin and length of hospital stay, of 928 surgical patients with and without malignant diseases (50.2% females and 49.8% males). The chi-square test was used to compare proportions and the Mann-Whitney test was used to compare continuous measurements between two groups. The significance level was set at 5%. RESULTS: Patients with malignant diseases had longer hospital stays (P<0.0001), furthermore, a higher percentage of patients with malignant diseases had body mass index <18.5 (P<0.0001) and experienced recent weight changes (P<0.0002). Lymphocyte count also differed statistically between the groups (P = 0.0131), which lower levels were identified among patients with malignant diseases. CONCLUSION: The lymphocyte count, hemoglobin values and weight loss are important findings of nutritional depletion in patients with malignant diseases. PMID- 21537545 TI - Research on zinc blood levels and nutritional status in adolescents with autoimmune hepatitis. AB - CONTEXT: Zinc deficiency in children and adolescents impairs their growing, development and immune system. OBJECTIVES: To verify the existence of plasma and leukocyte zinc deficiency in adolescents with autoimmune hepatitis. METHODS: The study comprised 23 patients with autoimmune hepatitis, aged 10-18 years, assisted at the Ambulatory Service of Pediatric Hepatology of the University of Campinas Teaching Hospital, Campinas, SP, Brazil, and adolescents with ages compatible with the patients' ages comprised the control group. Sample of blood in both groups was collected for the analyses of plasma zinc and leukocyte zinc by atomic absorption spectrophotometry, beyond the nutritional status was evaluated in each adolescent. The following statistical tests were used: Mann-Whitney, Spearman's correlation and interclass concordance analysis. RESULTS: The significance level adopted was 5%. The average zinc level in plasma in patients was 71.91 +/- 11.79 ug/dL and, in the control group, it was 80.74 +/- 10.92 ug/dL, showing a significant difference (P = 0.04). The leukocyte zinc level in patients was 222.33 +/- 166.13 pmol/106 cells and, in the control group, it was 226.64 +/- 217.81 pmol/106 cells; there was no statistical significance between them (P = 0.45). CONCLUSION: The evaluation of the nutritional status showed that eutrophy is prevalent in patients, and they presented a higher body fat value than the control group, with a significant difference. More research is needed with adolescents with autoimmune hepatitis regarding levels of essential micronutrients, such as zinc, because a good nutritional status can improve the prognostic of liver disease. PMID- 21537547 TI - Methionine- and choline-deficient diet induces hepatic changes characteristic of non-alcoholic steatohepatitis. AB - CONTEXT: Non-alcoholic steatohepatitis is a disease with a high incidence, difficult diagnosis, and as yet no effective treatment. So, the use of experimental models for non-alcoholic steatohepatitis induction and the study of its routes of development have been studied. OBJECTIVES: This study was designed to develop an experimental model of non-alcoholic steatohepatitis based on a methionine- and choline-deficient diet that is manufactured in Brazil so as to evaluate the liver alterations resulting from the disorder. METHODS: Thirty male C57BL6 mice divided in two groups (n = 15) were used: the experimental group fed a methionine- and choline-deficient diet manufactured by Brazilian company PragSolucoes(r), and the control group fed a normal diet, for a period of 2 weeks. The animals were then killed by exsanguination to sample blood for systemic biochemical analyses, and subsequently submitted to laparotomy with total hepatectomy and preparation of the material for histological analysis. The statistical analysis was done using the Student's t-test for independent samples, with significance level of 5%. RESULTS: The mice that received the methionine- and choline-deficient diet showed weight loss and significant increase in hepatic damage enzymes, as well as decreased systemic levels of glycemia, triglycerides, total cholesterol, HDL and VLDL. The diagnosis of non-alcoholic steatohepatitis was performed in 100% of the mice that were fed the methionine- and choline deficient diet. All non-alcoholic steatohepatitis animals showed some degree of macrovesicular steatosis, ballooning, and inflammatory process. None of the animals which were fed the control diet presented histological alterations. All non-alcoholic steatohepatitis animals showed significantly increased lipoperoxidation and antioxidant enzyme GSH activity. CONCLUSION: The low cost and easily accessible methionine- and choline-deficient diet explored in this study is highly effective in inducing steatosis and steatohepatitis in animal model, alterations that are similar to those observed in human livers. PMID- 21537546 TI - Effects of L-glutamine supplementation on the myenteric neurons from the duodenum and cecum of diabetic rats. AB - CONTEXT: Peripheral neuropathy is one of the chronic complications of diabetes mellitus and is directly related to gastrointestinal consequences of the disease. Myenteric neurons are affected in some pathological conditions such as diabetic neuropathy. The imbalance between cellular antioxidants and free radicals, leading to an increase in oxidative stress, is considered one of the main factors responsible for neuronal damages in diabetes. Drugs that reduce the oxidative stress may play a significant role in the treatment of neurological complications of diabetes mellitus. OBJECTIVE: To evaluate the effect of L-glutamine supplementation on the myenteric neurons from the cecum and duodenum of Wistar rats with streptozotocin-induced diabetes mellitus. METHODS: The animals were divided in four groups (n = 5): non-treated normoglycemics, normoglycemics treated with L-glutamine, non-treated diabetics and diabetics treated with L glutamine from the 4th day of diabetes induction on. The amino acid L-glutamine was added to their diet at 1%. Giemsa's technique was employed to stain the myenteric neurons. We determined the cell body area of 500 neurons in each group studied. The quantitative analysis was performed by sampling in an area of 16.6 mm2 in the cecum and 3.6 mm2 in the duodenum of each animal. RESULTS: After the supplementation with L-glutamine in the duodenum, we observed a preservation of neuronal density in groups normoglycemic and diabetic (P<0.05). We also observed a preservation of the cell bodies area in diabetic animals (group treated with L glutamine) (P<0.05). In the cecum, that preservation was not evident. CONCLUSION: Supplementation with L-glutamine (1%) promoted a neuroprotective effect on the myenteric neurons from the duodenum of rats, both in terms of natural aging and of diabetes mellitus. PMID- 21537548 TI - Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats. AB - CONTEXT: Methotrexate and other anticancer agents can induce intestinal mucositis, which is one of the most common limiting factor that prevent further dose escalation of the methotrexate. OBJECTIVES: To evaluate the gastric emptying and gastrointestinal transit of liquids in methotrexate-induced intestinal mucositis. METHODS: Wistar rats received methotrexate (2.5 mg/kg/day for 3 days, subcutaneously) or saline. After 1, 3 and 7 days, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage and myeloperoxidase activity (biochemical marker of granulocyte infiltration). Others rats were pre treated with methotrexate or saline, gavage-fed after 3 or 7 days with a standard test liquid meal, and sacrificed 10, 20 or 30-min later. Gastric and small intestine dye recoveries were measured by spectrophotometry. RESULTS: After 3 days of methotrexate, there was an epithelial intestinal damage in all segments, with myeloperoxidase activity increase in both in duodenum and ileum. Seven days after methotrexate, we observed a complete reversion of this intestinal damage. There was an increase in gastric dye recoveries after 10, 20, and 30-min post prandial intervals after 3 days, but not after 7 days, of methotrexate. Intestine dye recoveries were decreased in the first and second segments at 10 min, in the third at 20 min, and in the second and third at 30 min, only after 3 days of methotrexate treatment. CONCLUSION: Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats. PMID- 21537549 TI - The aerobic capacity and muscle strength are correlated in candidates for liver transplantation. AB - Liver diseases are responsible for metabolic and cardiorespiratory alterations. The objective of this paper is to correlate the maximal oxygen uptake (VO(2max)) and respiratory muscle strength and evaluating the quality of life in liver transplant candidates. Cross-sectional study consisted of 26 patients with cirrhosis who underwent maximal exercise testing, respiratory muscle strength and SF-36. There was a correlation of VO(2max) with MIP (r = 0.61) and low scores of quality of life. A correlation of VO(2max) to muscle strength and decreased quality of life in patients with liver disease. PMID- 21537550 TI - Pharmacogenetics: reality or fiction? Or are we there yet? PMID- 21537551 TI - CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes and phenytoin adverse reactions correlation. AB - OBJECTIVE: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect therapeutic outcome during treatment. The distribution of variant CYP2C9 alleles and prevalence of phenytoin adverse reactions were hereby investigated in a population of patients diagnosed with epilepsy. METHOD: Allele-specific PCR analysis was carried out in order to determine frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 100 epileptic patients. We also analyzed the frequency of phenytoin adverse reactions among those different genotypes groups. The data was presented as mean+/-standard deviation. RESULTS: The mean age at enrollment was 39.6+/-10.3 years (range, 17-72 years) and duration of epilepsy was 26.5+/-11.9 years (range 3-48 years). The mean age at epilepsy onset was 13.1+/-12.4 years (range, 1 month-62 years). Frequencies of CYP2C9*1 (84%), CYP2C9*2 (9%) and CYP2C9*3 (7%) were similar to other published reports. Phenytoin adverse reactions were usually mild and occurred in 15% patients, without correlation with the CYP2C9 polymorphism (p=0.34). CONCLUSION: Our findings indicate an overall similar distribution of the CYP2C9 alleles in a population of patients diagnosed with epilepsy in the South of Brazil, compared to other samples. This sample of phenytoin users showed no drug related adverse reactions and CYP2C9 allele type correlation. The role of CYP2C9 polymorphism influence on phenytoin adverse reaction remains to be determined since some literature evidence and our data found negative results. PMID- 21537552 TI - Prevalence of psychiatric comorbidities in temporal lobe epilepsy in a Southern Brazilian population. AB - A great prevalence of psychiatric disorders in epilepsy is well demonstrated, although most studies have used unstructured psychiatric interviews for diagnosis. Here we present a study evaluating the prevalence of psychiatric comorbidities in a cohort of Southern Brazilian patients with temporal lobe epilepsy (TLE) using a structured clinical interview. We analyzed 166 patients with TLE regarding neuropsychiatric symptoms through the Structured Clinical Interview for DSM-IV. One hundred-six patients (63.9%) presented psychiatric comorbidities. Mood disorders were observed in 80 patients (48.2%), anxiety disorders in 51 patients (30.7%), psychotic disorders in 14 (8.4%), and substance abuse in 8 patients (4.8%) respectively. Our results agree with literature data where most authors detected mental disorders in 10 to 60% of epileptic patients. This wide variation is probably attributable to different patient groups investigated and to the great variety of diagnostic methods. Structured psychiatric interviews might contribute to a better evaluation of prevalence of psychiatric comorbidities in TLE. PMID- 21537553 TI - Mortality from epilepsy: Brazil (capitals), 1980-2007. AB - OBJECTIVE: To provide data about age, gender, time and space variation by means of mortality statistics from epilepsy in Brazil. METHOD: It was used demographic and mortality data obtained from the Brazilian Ministry of Health, regarding Brazil (capitals) over the calendar years 1980-2007. For the description of the data it was used Microsoft Office Excel 2007 spreadsheet, and figuring of trends by linear regression, GraphPad Prism 5.0. RESULTS: There is a tendency to elderly mortality, and male mortality in almost age group, although regarding the relative frequency rates by age, 20-39 age strata is more representative. The mortality at home is proportionally predominant at 20-29 years of age, 47.52%. Adjusted death rates/100,000, 2007, do not show clear regional predominance. CONCLUSION: We can infer that various deaths coded as epilepsy, may be due to an acute symptomatic seizures. Sudden unexplained death in epilepsy (SUDEP) may be misdiagnosed and probably more represented at the group with more deaths at home. PMID- 21537554 TI - Clinical attention and assistance profile of patients with amyotrophic lateral sclerosis. AB - OBJECTIVE: To evaluate the functional status of amyotrophic lateral sclerosis (ALS) patients diagnosed at this institution; to analyze hospital and palliative care; to identify patients' knowledge about home care and supportive resources. METHOD: Twenty-nine patients were evaluated on the ALSFRS-R scale and two semi structured questionnaires, at the start of the study and every four months thereafter for 1 year. RESULTS: ALSFRS-R score was 30.1+/-11.5 initially and 24.4+/-10.5 at 1 year. There was an increase in use of physiotherapeutic care and adaptive aids. The primary caregivers were spouses (55.2%), parents/children/cousins (20.7%), friends (10.3%) and private nurses (3.5%); 10.3% of patients had no caregivers. Basic ALS patient care was provided by the public health system. CONCLUSION: ALS patients' multidisciplinary care was provided by UNICAMP hospital and its outpatient clinics and, in some patients, complemented by a private health plan or personal expenditure. Few ALS patients were aware of the possibility of home nursing. It is necessary to implement national and regional public home nursing in addition to multidisciplinary specialized care of ALS patients. PMID- 21537555 TI - Psychiatric disorders in myasthenia gravis. AB - OBJECTIVE: To investigate the prevalence of psychiatric disorders in patients with myasthenia gravis (MG). METHOD: Forty-one patients with MG answered to a structured psychiatric interview (MINI-Plus). RESULTS: Eleven (26.1%) patients were diagnosed with a depressive disorder and 19 (46.3%) were diagnosed with an anxiety disorder. Patients with dysthymia were older (p=0.029) and had longer disease duration (p=0.006). Patients with social phobia also had longer disease duration (p=0.039). CONCLUSION: Psychiatric disorders in MG are common, especially depressive and anxiety disorders. PMID- 21537556 TI - Restless legs syndrome and multiple sclerosis: a Brazilian multicenter study and meta-analysis of the literature. AB - OBJECTIVE: The increased prevalence of restless legs syndrome (RLS) in multiple sclerosis (MS) has recently been the subject of a few papers. The present study investigated the prevalence of RLS symptoms in MS patients and in controls in four Brazilian cities. Additionally, a systematic review and meta-analysis of the literature was carried out on the subject of RLS-MS. METHOD: MS patients and controls were investigated regarding the presence of the four typical symptoms of RLS. A questionnaire assessing RLS severity was also used for patients and controls presenting the four RLS symptoms criteria. The systematic review and meta-analysis on the subject were carried out according to the strict international criteria. RESULTS: In the present report, the RLS-MS association was confirmed as being more than fortuitous in Brazilian MS patients, in a multicenter case-control study. MS patients also presented RLS symptoms of greater severity than did the control population. A systematic review and meta analysis of the literature showed that MS patients had a fourfold higher chance of presenting RLS than did the controls. CONCLUSION: Although underlying mechanisms to explain the association RLS-MS are still a matter of discussion, there is a clear association of these two neurological conditions. PMID- 21537557 TI - Clinical and epidemiological profile of patients with multiple sclerosis in Uberaba, Minas Gerais, Brazil. AB - Multiple sclerosis (MS) is an immune-mediated disease that affects the central nervous system. Clinical presentation and prevalence vary widely around the world. OBJECTIVE: To describe the clinical and epidemiological aspects of patients with MS in Uberaba (MG). METHOD: We conducted a transversal descriptive study, with data analysis of 35 patients with MS. RESULTS: Prevalence of MS was 12.5 cases/100,000 inhabitants, with a predominance in females (71.4%) and Caucasoid (85.7%). The current average age was (43.8 ys). The most common initial symptom was sensory (40%), followed by optical neuritis (25.7%). Expanded Disability Status Scale average score was 2.4. The relapsing-remitting form was predominant (88.6%), most (74.3%) were on immunomodulatory treatment and (40%) had college education. CONCLUSION: Prevalence of MS in Uberaba (MG) is considered average in accordance to Kurtzke and Page and clinical features are consistent with most Brazilian studies. PMID- 21537558 TI - Radicular dysfunction preponderance at early phase clinical evaluation in myelitis by Schistosoma mansoni. AB - In neuroschistosomiasis, the spinal cord is the most common place of the disease. In high prevalent areas for schistosomiasis mansoni, the clinical alertness is important for an early diagnostic, in order to decrease the final neurological damage. This study provides some useful neurologic information about a series of patients with schistosomal myelitis. METHOD: The sample consisted of 13 schistosomiasis mansoni carriers examined at the moment of the diagnosis of myelitis. RESULTS: The classical triad (lumbago, weakness at the lower limbs and urinary dysfunctions) was documented in 11 (86.61%) patients. The distribution of the clinical forms was: myeloradicular in six patients (46.15%), radicular in four (30.76%) and myelitic in three (23.07%). CONCLUSION: The radicular dysfunction and their clinical associated forms were the most prominent pattern during the early phase of this disease. PMID- 21537559 TI - Migraine and cognition in children: a controlled study. AB - OBJECTIVE: Evaluate the cognitive functions of children with migraine and compare them to A control group. METHOD: 30 migraineur children and 30 control group children without migraine, age ranging from 8 to 12 years old, were subjected to a cognitive functions assessment with Wechsler Intelligence Scale for Children (WISCIII). RESULTS: Although both groups had a normal cognitive performance, children with migraine had significantly worse scores compared to the control group in the subtests of Information, Arithmetic, Vocabulary, Object Assembly and in the Indexes of Perceptual Organization, Resistance to Distraction and Processing Speed. CONCLUSION: Children with migraine had impairment in some cognitive functions such as attention, memory, information speed, and perceptual organization compared to the control group. PMID- 21537560 TI - Imipramine for vestibular dysfunction in panic disorder: a prospective case series. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and effectiveness of imipramine on the treatment of comorbid chronic dizziness and panic disorder. METHOD: Nine patients with panic disorder and agoraphobia associated with chronic dizziness underwent otoneurological screening and were treated with a 3-months course of imipramine. Anxiety levels were measured with the Hamilton Anxiety Scale (HAM-A), dizziness levels were evaluated using the Dizziness Handicap Inventory (DHI), and panic severity and treatment outcome were assessed with the Clinical Global Impression Scale (CGI). RESULTS: At the baseline 33.3% (n=3) had a bilateral peripheral deficit vestibulopathy, the mean scores for HAM-A were 27.2+/-10.4, for DHI were 51.7+/-22.7, and for CGI-S were 4.8+/-0.9. All patients had a significant reduction in their HAM-A (11.1+/-5.5, p=0.008), DHI (11.5+/-8.1, p=0.008) and CGI-I (1.8+/-0.7, p=0.011) levels after 3 months imipramine treatment (mean=72.2+/-23.2 mg/day). CONCLUSION: This study found a decrease in anxiety levels and in the impact of dizziness in the patients' quality of life after a 3-months treatment course with imipramine. PMID- 21537561 TI - Assessment of balance in mild and moderate stages of Alzheimer's disease: implications on falls and functional capacity. AB - OBJECTIVE: To analyze the correlation between balance, falls and loss of functional capacity in mild and moderate Alzheimer's disease(AD). METHOD: 40 subjects without cognitive impairment (control group) and 48 AD patients (25 mild, 23 moderate) were evaluated with the Berg Balance Scale (BBS) and the Disability Assessment for Dementia (DAD). Subjects answered a questionnaire about falls occurrence in the last twelve months. RESULTS: Moderate AD patients showed poorer balance (p=0.001) and functional capacity (p <0.0001) and it was observed a correlation between falls and balance (r= -0.613; p=0.045). CONCLUSION: There is a decline of balance related to AD which is a factor associated to the occurrence of falls, albeit not the most relevant one. The loss of functional capacity is associated with the disease's progress but not to a higher occurrence of falls. The balance impairment did not correlate with functional decline in AD patients. PMID- 21537562 TI - Implications of HAM/TSP functional incapacity in the quality of life. AB - OBJECTIVE: To identify the functional status and quality of life of HAM/TSP patients. METHOD: We evaluated prospectively 30 HAM/TSP patients (20 females) seen in the Neuroinfection Clinic of the HUGG. The functional capacity was analyzed by the functional independence measure (FIM), the expanded disability status (EDSS) scale and the Osame's motor disability score (OMDS). The quality of life was assessed by the Short-Form Health Survey 36 (SF-36)TM. RESULTS: All patients need assistance device. The FIM, OMDS and EDSS scores classified 70%, 67% and 67% of the patients as dependent, respectively. The lowest scores of the SF-36 survey were found in the domains related to the physical health (D1, D2), role-emotional functioning (D7) and social functioning (D6). CONCLUSION: Our data suggest that the HAM/TSP physical impairment has an impact in the emotional and social issues, considering the limitation in the daily activities. PMID- 21537563 TI - Neurological diagnoses in the emergency room: differences between younger and older patients. AB - Neurological diseases are prevalent in the emergency room (ER). The aim of this study was to compare the neurological diagnoses between younger and older patients evaluated in the ER of a tertiary care hospital. METHOD: Patients admitted to the ER who required neurological evaluation in the first 24 hours were separated into two groups based on age, <=50 years old and >50 years old. RESULTS: Cerebrovascular disease (59.6% vs. 21.8%, p<0.01) was most frequent in the >50 years old group. Seizures (8.1% vs. 18.6%, p<0.01) and primary headache (3.7% vs. 11.4%, p<0.01) were most frequent in the <=50 years old group. CONCLUSION: The current study demonstrated that these three neurological diagnoses represented the majority of the neurological evaluations in the ER. National guidelines for ER teams that treat these prevalent disorders must be included in clinical practice and training. PMID- 21537564 TI - Clinical experience with a novel bovine collagen dura mater substitute. AB - Dural substitutes are used to achieve watertight closure of the dura mater when adequate closure is not possible. The purpose of this study was to evaluate the efficacy and safety of a new collagen matrix dural substitute (Duradry, Technodry, Belo Horizonte MG) in the repair or expansion of cranial and spinal dura mater. METHOD: Thirty patients, operated on between March and September, 2008, were studied. Surgical records were reviewed for sex, age, location of graft, technique, and presence of fistula or infection. The patients were followed up for at least 3 months, and presence of complications, such as cerebrospinal fluid leakage, infection, aseptic meningitis hydrocephalus, pseudomeningocele, was analyzed. RESULTS: Only one patient presented cerebrospinal fluid fistula. No patients presented wound infections, hydrocephalus, pseudomenigocele, meningitis, brain abscesses or signs of toxicity related to the dural substitute. CONCLUSION: The new dural substitute used in this study is effective and safe, and the initial results are similar to those of other dural substitutes reported in the literature. PMID- 21537565 TI - A prospective study of 39 patients with trigeminal neuralgia treated with percutaneous balloon compression. AB - OBJECTIVE: Trigeminal neuralgia is the most common facial pain. It may be treated with percutaneous balloon compression (PBC), which is considered to be a safe and efficient procedure. The purpose of this study was to review our results with PBC and to assess the factors influencing the outcome. METHOD: A multivariate analysis was used to study 39 patients during a 50-month postoperative period. RESULTS: There was predominance of the female gender (54%), the right side of the face (84%) and V2V3 roots of trigeminal nerve (33%). The mean age was 62.3 years. No major complications or deaths occurred. Among all variables, postoperative hypoesthesia was the single prognostic factor capable of positively influencing the results (p=0.02). Most patients (80%) were pain-free after 50 months with a 90% satisfaction rate. CONCLUSION: PBC was a safe procedure with low morbidity, no mortality, high approval ratings, and was an important improving on patients' quality of life. PMID- 21537566 TI - Neuroendoscopic surgery for unilateral hydrocephalus due to inflammatory obstruction of the Monro foramen. AB - OBJECTIVE: Unilateral hydrocephalus (UH) is characterized by enlargement of just one lateral ventricle. In this paper, the authors will demonstrate their experiences in the neuroendoscopic management of this uncommon type of hydrocephalus. METHOD: The authors retrospectively reviewed a series of almost 800 neuroendoscopic procedures performed from September 1995 to July 2010 and selected seven adult patients with UH. Clinical and radiological charts were reviewed and analyzed. RESULTS: Six patients had intraventricular neurocysticercosis and one patient had congenital stenosis of the foramen of Monro. Headaches were the most common symptom. A septostomy restored cerebrospinal fluid circulation. During follow-up period (65.5 months, range 3 109) no patient has presented clinical recurrence as well as no severe complications have been observed. CONCLUSION: UH is a rare condition. A successful treatment can be accomplished through a neuroendoscopic approach avoiding the use of ventricular shunts. PMID- 21537567 TI - Endoscopic anatomy of the approaches to the sellar area and planum sphenoidale. AB - The productive work between otolaryngologists and neurosurgeons has resulted in the emergence of endoscopic endonasal skull base surgery. The goal of the present study is to describe the endoscopic anatomy of the endonasal approach to the sellar region and planum sphenoidale, highlighting the key points of the surgical approach and the neurovascular landmarks. METHOD: Descriptive study of the endoscopic endonasal dissection of 9 fresh cadavers with exposure of the anatomic structures. RESULTS: The endoscopic endonasal ethmoidectomy and sphenoidotomy allows an expanded access to the sellar area and planum sphenoidale. The surface anatomy of the sphenoid sinus is easily identifiable and provides safe landmarks, guiding the intracranial dissection. CONCLUSION: The endoscopic endonasal approach to the skull base by the ENT and neurosurgeon is feasible, but it requires adequate anatomical knowledge and endoscopic skills for its realization, which can be obtained by practicing in cadavers. PMID- 21537568 TI - Role of IL-4 in an experimental model of encephalitis induced by intracranial inoculation of herpes simplex virus-1 (HSV-1). AB - Herpes simplex virus-1 (HSV-1) is a pathogen that may cause severe encephalitis in humans. In this study, we aimed to investigate the role of interleukin-4 (IL 4) in a model of HSV-1 brain infection. IL-4 knockout (IL-4-/-) and wild type (WT) C57BL/6 mice were inoculated with 10(4) plaque-forming units of HSV-1 by the intracranial route. Histopathologic analysis revealed a distinct profile of infiltrating cells at 3 days post-infection (dpi). Infected WT mice presented mononuclear inflammatory cells while IL-4-/- mice developed meningoencephalitis with predominance of neutrophils. IL-4-/- mice had diminished leukocyte adhesion at 3 dpi when compared to infected WT animals in intravital microscopy study. Conversely no differences were found in cerebral levels of CXCL1, CXCL9, CCL3, CCL5 and TNF-alpha between WT and IL-4-/- infected mice. IL-4 may play a role in the recruitment of cells into central nervous system in this acute model of severe encephalitis caused by HSV-1. PMID- 21537569 TI - Advanced techniques in magnetic resonance imaging of the brain in children with ADHD. AB - Attention deficit hyperactivity disorder (ADHD) affects about 5% of school-aged child. Previous published works using different techniques of magnetic resonance imaging (MRI) have demonstrated that there may be some differences between the brain of people with and without this condition. This review aims at providing neurologists, pediatricians and psychiatrists an update on the differences between the brain of children with and without ADHD using advanced techniques of magnetic resonance imaging such as diffusion tensor imaging, brain volumetry and cortical thickness, spectroscopy and functional MRI. Data was obtained by a comprehensive, non-systematic review of medical literature. The regions with a greater number of abnormalities are splenium of the corpus callosum, cingulate gyrus, caudate nucleus, cerebellum, striatum, frontal and temporal cortices. The brain regions where abnormalities are observed in studies of diffusion tensor, volumetry, spectroscopy and cortical thickness are the same involved in neurobiological theories of ADHD coming from studies with functional magnetic resonance imaging. PMID- 21537570 TI - Sleep disorders in cerebellar ataxias. AB - Cerebellar ataxias comprise a wide range of etiologies leading to central nervous system-related motor and non-motor symptoms. Recently, a large body of evidence has demonstrated a high frequency of non-motor manifestations in cerebellar ataxias, specially in autosomal dominant spinocerebellar ataxias (SCA). Among these non-motor dysfunctions, sleep disorders have been recognized, although still under or even misdiagnosed. In this review, we highlight the main sleep disorders related to cerebellar ataxias focusing on REM sleep behavior disorder (RBD), restless legs syndrome (RLS), periodic limb movement in sleep (PLMS), excessive daytime sleepiness (EDS), insomnia and sleep apnea. PMID- 21537571 TI - Desmoplastic ganglioglioma: report of a non-infantile case. PMID- 21537572 TI - Hyperalgesia in semantic dementia. PMID- 21537573 TI - Arachnoid cysts and absence epilepsy: an evidence or a coincidence? PMID- 21537574 TI - Primary dural lymphoma: a rare subtype of primary central nervous system lymphoma (PCNSL). PMID- 21537575 TI - Ceruminous adenoma. PMID- 21537577 TI - Inaccuracies and useless debates associated with the use of secondary references. PMID- 21537580 TI - Mesenchymal stem cells in the dental tissues: perspectives for tissue regeneration. AB - In recent years, stem cell research has grown exponentially owing to the recognition that stem cell-based therapies have the potential to improve the life of patients with conditions that range from Alzheimer's disease to cardiac ischemia and regenerative medicine, like bone or tooth loss. Based on their ability to rescue and/or repair injured tissue and partially restore organ function, multiple types of stem/progenitor cells have been speculated. Growing evidence demonstrates that stem cells are primarily found in niches and that certain tissues contain more stem cells than others. Among these tissues, the dental tissues are considered a rich source of mesenchymal stem cells that are suitable for tissue engineering applications. It is known that these stem cells have the potential to differentiate into several cell types, including odontoblasts, neural progenitors, osteoblasts, chondrocytes, and adipocytes. In dentistry, stem cell biology and tissue engineering are of great interest since may provide an innovative for generation of clinical material and/or tissue regeneration. Mesenchymal stem cells were demonstrated in dental tissues, including dental pulp, periodontal ligament, dental papilla, and dental follicle. These stem cells can be isolated and grown under defined tissue culture conditions, and are potential cells for use in tissue engineering, including, dental tissue, nerves and bone regeneration. More recently, another source of stem cell has been successfully generated from human somatic cells into a pluripotent stage, the induced pluripotent stem cells (iPS cells), allowing creation of patient- and disease-specific stem cells. Collectively, the multipotency, high proliferation rates, and accessibility make the dental stem cell an attractive source of mesenchymal stem cells for tissue regeneration. This review describes new findings in the field of dental stem cell research and on their potential use in the tissue regeneration. PMID- 21537582 TI - FiltekTM Silorane and FiltekTM Supreme XT resins: tissue reaction after subcutaneous implantation in isogenic mice. AB - The aim of this study was to evaluate the tissue compatibility of a silorane based resin system (FiltekTM Silorane) and a methacrylate-based nanoparticle resin (FiltekTM Supreme XT) after implantation in the subcutaneous connective tissue of isogenic mice. One hundred and thirty five male isogenic BALB/c mice were randomly assigned to 12 experimental and 3 control groups, according to the implanted material and the experimental period of 7, 21 and 63 days. At the end of each period, the animals were killed and the tubes with the surrounding tissues were removed and processed for microscopic analysis. Samples were subjected to a descriptive and a semi-quantitative analyses using a 4-point scoring system (0-3) to evaluate the collagen fiber formation and inflammatory infiltrate. Data were statistically analyzed using the Kruskal Wallis test (alpha=0.05). The results showed that there was no significant difference between the experimental and control groups considering the three evaluation periods (p>0.05). The silorane-based and the methacrylate-based nanoparticle resins presented similar tissue response to that of the empty tube (control group) after subcutaneous implantation in isogenic mice. PMID- 21537581 TI - Effects of a novel calcium aluminate cement on the early events of the progression of osteogenic cell cultures. AB - The present study evaluated the progression of osteogenic cell cultures exposed to a novel calcium aluminate cement (CAC+) in comparison with the gold standard mineral trioxide aggregate (MTA). Cells were enzimatically isolated from newborn rat calvarial bone, plated on glass coverslips containing either CAC+ or a control MTA samples in the center, and grown under standard osteogenic conditions. Over the 10-day culture period, roundening of sample edges was clearly noticed only for MTA group. Although both cements supported osteogenic cell adhesion, spreading, and proliferation, CAC+-exposed cultures showed significantly higher values in terms of total cell number at days 3 and 7, and total protein content and alkaline phosphatase activity at day 10. The present in vitro results indicate that the exposure to CAC+ supports a higher differentiation of osteogenic cells compared with the ones exposed to MTA. Further experimental studies should consider CAC+ as a potential alternative to MTA when the repair of mineralized tissues is one of the desired outcomes in endodontic therapy. PMID- 21537583 TI - Three-year clinical performance of composite restorations placed by undergraduate dental students. AB - This retrospective study evaluated the clinical performance and the reasons for failure of anterior and posterior composite restorations placed by undergraduate dental students over a 3-year period. All cavities were restored using Prime & Bond 2.1 and TPH (Dentsply), according to the manufacturer's indications. One hundred and two patients who had received composite restorations by third and forth year undergraduate students were recalled and examined to analyze the quality of the restorations. The restorations were evaluated using the modified USPHS system. Two hundred and fifty-six composite restorations, 170 in anterior teeth and 86 in posterior teeth, were evaluated. Eighty-five percent of the restorations were considered satisfactory after 3 years. Class II and class IV restorations presented the highest prevalence of failure. Loss of the restoration and deficient marginal adaptation were the main causes of failure. No restoration failed due to secondary caries. Most restorations placed by dental students were considered satisfactory after long-term evaluation. Failure was more prevalent in larger restorations and was not associated with secondary caries. PMID- 21537584 TI - Fracture resistance of teeth subjected to internal bleaching and restored with different procedures. AB - This study evaluated the fracture resistance of teeth submitted to internal bleaching and restored with different procedures. Forty maxillary incisors were endodontically treated and assigned to 4 groups (n=10): G1- restored with composite resin (CR), G2- bleached with hydrogen peroxide (HP) and restored with CR, G3- restored with CR and fiberglass posts (CR + posts) and G4- bleached and restored with CR + posts. HP was applied in the buccal surface and pulp chamber 3 times at each one of 2 sessions with an interval of 7 days between them. Additional 10 sound incisors were subjected to fracture strength test (gold standard). The fracture strength (kN) was determined in an Instron machine. Data were analyzed by ANOVA and Tukey-Kramer test (alpha=0.05). The untreated teeth (gold standard) showed the highest (p. PMID- 21537585 TI - Microtensile bond strength test and failure analysis to assess bonding characteristics of different adhesion approaches to ground versus unground enamel. AB - This study evaluated the bonding characteristics to ground and unground enamel obtained with different strategies. For this purpose, 24 sound third-molars were bisected mesiodistally to obtain tooth halves. A flat enamel area was delimited in the tooth sections, which were randomly distributed into 8 groups (n=6), according to the enamel condition (ground and unground) and adhesive system (Adper Single Bond 2 - SB2; Adper Prompt L-Pop - PLP; Adper Prompt - AD; Clearfil SE Bond - SE). Each system was applied according manufacturers' instructions and a 6-mm-high resin composite "crown" was incrementally built up on bonded surfaces. Hourglass-shaped specimens with 0.8 mm(2) cross-section were produced. Microtensile bond strength (MUTBS) was recorded and the failure patterns were classified. Results were analyzed by two-way ANOVA and Tukey's test (alpha=0.05). There were no statistically significant differences among the MUTBS values of SB2, PLP and AD (p>0.05). SE values were significantly lower (p0.05). There was prevalence of cohesive failure within enamel, adhesive system and resin composite for SB2. The self-etch systems produced higher incidence of cohesive failures in the adhesive system. Enamel condition did not determine significant differences on bonding characteristics for the same bonding system. In conclusion, the bonding systems evaluated in this study resulted in specific MUTBS and failure patterns due to the particular interaction with enamel. PMID- 21537586 TI - Diagnosis of secondary caries in esthetic restorations: influence of the incidence vertical angle of the X-ray beam. AB - The aim of this study was to evaluate the accuracy on the diagnosis of secondary caries-like lesions simulated on esthetic restorations of different materials, changing the incidence vertical angle (IVA) of the x-ray beam. Twenty human teeth received MOD inlay preparations. In the experimental group (n=10), a round cavity was made in the floor of the proximal box to simulate the caries-like lesion. All teeth were restored with 3 composite resins (Charisma, Filtek-Z250 and TPH Spectrum) at 3 moments. Two radiographic images were acquired with 0o and 10o IVA. Ten observers evaluated the images using a 5-point confidence scale. Intra- and interobserver reliability was analyzed with the Interclass Correlation Coefficient and the diagnostic accuracy was evaluated using the area under the ROC curve (A(z)), Friedman test and Wilcoxon test (alpha=0.05). Higher accuracy values were obtained with 10o IVA (A(z)=0.66, Filtek-Z250>A(z)=0.56, TPH Spectrum) compared to 0o (A(z)=0.55, Charisma>A(z)=0.37, TPH-Spectrum), though without statistically significant difference (p>0.05). The detection of secondary caries-like lesions simulated on esthetic restorations of different materials suffered no negative influence by changing the IVA of the x-ray beam. PMID- 21537587 TI - Survival rate of sealed, refurbished and repaired defective restorations: 4-year follow-up. AB - The most common treatment in general dental practice is the replacement of restorations affected by secondary caries or marginal deficiencies. Alternative treatments to replacement of defective restorations, such as marginal sealing, refurbishment and repair, have demonstrated improvement of their clinical properties with minimal intervention. The aim of this clinical study was to estimate the median survival time (MST) of marginal sealing, repair and refurbishment of amalgam and resin-based composite restorations with localized defects as a treatment to increase the restoration longevity. A cohort of 66 patients, with 271 class I and II restorations clinically diagnosed with localized defects was longitudinally assessed. Each restoration was assigned to one of the following 5 groups: Marginal Sealing (n=48), Refurbishment (n=73), Repair (n=27), Replacement (n=42), and Untreated (n=81). Two calibrated examiners assessed the restorations at baseline and annually during 4 years, using the modified Ryge criteria: marginal adaptation, anatomic form, roughness, secondary caries and luster. Fifty-two patients with 208 restorations were assessed after 4 years; the distribution of restorations in the groups was as follows: Marginal Sealing (n=36), Refurbishment (n=63), Repair (n=21), Replacement (n=28) and Untreated (n=60). Kaplan Meier test indicated that the Sealed margins group showed the lowest MST while the Repair group showed the highest MST for restorations examined after 4 years of follow up. Defective amalgam and resin based composite restorations treated by sealing of marginal gaps, refurbishment of anatomic form, luster or roughness, and repair of secondary caries lesions, had their longevity increased. PMID- 21537588 TI - Non-nutritive sucking habits, anterior open bite and associated factors in Brazilian children aged 30-59 months. AB - The aim of the present study was to investigate the prevalence of non-nutritive sucking habits and anterior open bite as well as their main causes (associated factors) in Brazilian children aged 30-59 months. A cross-sectional study was carried out during the National Immunization Day for polio in the city of Recife in the northeastern region of Brazil. The sample was made up of 1,308 children. Data were collected from interviews with mothers or guardians as well as from clinical examinations carried out by previously trained dental students. The chi square test was used for statistical analysis at 5% significance level. The prevalence of non-nutritive sucking habits was 40%, and the habits were associated with gender (p=0.001), age (p=0.003) and feeding type (p<0.001). Anterior open bite was detected in 30.4% of children, and it was significantly associated with feeding type (p<0.001) and non-nutritive sucking habits (p<0.001). The variables found to be associated factors in the present study for the occurrence of non-nutritive sucking habits and anterior open bite emphasize the need to establish strategies that include orientation regarding health promotion based on the "common determining factors" approach. Public health policies should be adopted to encourage a longer duration of breastfeeding, thereby contributing towards reducing the prevalence of non-nutritive sucking habits and anterior open bite. PMID- 21537589 TI - Relationship between maxillary canine intra-alveolar position and maxillary incisor angulation: a cone beam computed tomography study. AB - The aims of the present study were to evaluate the angulation and inclination of permanent maxillary incisors and to correlate the results to the intra-alveolar permanent maxillary canine position during mixed dentition, using cone beam computed tomography (CBCT). The subjects were 30 children aged 7 to 10 years in the inter-transitory period of mixed dentition (permanent incisors and first molars erupted; primary canines, first and second molars erupted; and permanent canines intraosseous). The CBCT scans were obtained and, using the Dolphin Imaging((r)) software - version 11.0, 3D images were reconstructed and the measurements were performed. The angulation of the right and left lateral and central maxillary incisors was measured in relation to the sagittal plane and their inclination was measured in relation to the coronal plane. The intra alveolar height of the right and left maxillary canines was measured from the cusp tip to the axial plane. Pearson's correlation at 5% significance level showed positive correlation between the canine height and the lateral incisor angulation. It was concluded that the intra-alveolar position of the maxillary canines has a direct influence on the angulation of maxillary incisors, especially the lateral incisors. PMID- 21537590 TI - Orthodontic-surgical treatment of Class III malocclusion with mandibular asymmetry. AB - Class III skeletal malocclusion may present several etiologies, among which maxillary deficiency is the most frequent. Bone discrepancy may have an unfavorable impact on esthetics, which is frequently aggravated by the presence of accentuated facial asymmetries. This type of malocclusion is usually treated with association of Orthodontics and orthognathic surgery for correction of occlusion and facial esthetics. This report presents the treatment of a patient aged 15 years and 1 month with Class III skeletal malocclusion, having narrow maxilla, posterior open bite on the left side, anterior crossbite and unilateral posterior crossbite, accentuated negative dentoalveolar discrepancy in the maxillary arch, and maxillary and mandibular midline shift. Clinical examination also revealed maxillary hypoplasia, increased lower one third of the face, concave bone and facial profiles and facial asymmetry with mandibular deviation to the left side. The treatment was performed in three phases: presurgical orthodontic preparation, orthognathic surgery and orthodontic finishing. In reviewing the patient's final records, the major goals set at the beginning of treatment were successfully achieved, providing the patient with adequate masticatory function and pleasant facial esthetics. PMID- 21537591 TI - Dentin hypersensitivity after treatment with desensitizing agents: a randomized, double-blind, split-mouth clinical trial. AB - The aim of this study was to evaluate the efficacy of two desensitizing agents in the reduction of dentin hypersensitivity in a randomized, double-blind, split mouth clinical trial. Seventy-seven teeth from 13 patients that presented some degree of sensitivity to probing and/or air stimulation were treated with one of the following desensitizing agents: Oxa-Gel (G1), Sensi Kill (G2) and placebo gel (G3 - control). According to paired t-test, all treatments, even the placebo gel, were capable of reducing sensitivity scores for both stimuli. Analysis of data by ANOVA and Tukey's test (?=0.05) showed that the sensitivity scores were significantly lower only for Sensi Kill in comparison to the other products (Oxa Gel and placebo), when air stimulus was applied. It may be concluded that treatment with Sensi Kill presented a slightly better performance in reducing dentin hypersensitivity when compared to the other desensitizing agent. PMID- 21537592 TI - Laser phototherapy as a treatment for radiotherapy-induced oral mucositis. AB - Oral mucositis is a harmful side effect of radiotherapy (RT) on the head and neck region. There are encouraging reports on the beneficial aspects of the use of laser light on the treatment of oral mucositis. This paper reports the efficacy of laser phototherapy (LPT) on the treatment of oral mucositis in a patient undergoing RT after surgical removal of a squamous cell carcinoma with osseous invasion of the maxilla. Palatal and commissural lesions were treated with lambda660 nm, 40 mW, ?=4 mm(2), in contact mode, 5 x 2.4 J/cm(2) per point, 14.4 J/cm(2) per session. For treating the lesion on the patient's nasal mucosa, LPT (?=4 mm(2), lambda780 nm, 70 mW, 3 x 2.1 J/cm(2) per point, 6.3 J/cm(2) per session, contact mode) was used on the external area of the nose. A single dose (2.4 J/cm(2)) with the lambda660 nm laser, as described before, was applied on the entrance of each nostril. LPT was used 3 times/week during 4 weeks. Treatment results indicate that the use of LPT on oral mucositis was effective and allowed the patient to carry on the RT without interruption. However, long-term and controlled clinical trials are necessary to establish both preventive and curative protocols using LPT. PMID- 21537593 TI - Larva migrans in the oral mucosa: report of two cases. AB - Cutaneous Larva migrans is a very common disease in tropical regions. In the oral mucosa, the infection occurs in the same way as in the skin, but it is rarer. This report describes two cases of Larva migrans in the oral mucosa. The first case was in a 27-year-old woman who presented an erythematous plaque located on the buccal mucosa, extending to a posterior direction, following a linear pattern, to other areas of the mouth. After incisional biopsy of the anterior most portion of the lesion, morphological details obtained in multiple examined sections suggested Necator or Ancylostoma braziliense larvae as the cause of infection. The second case was in a 35-year-old male who presented a fusiform erythematous plaque in the palatal mucosa. This area was removed and submitted to microscopic examination under a presumptive diagnosis of "parasite migratory stomatitis". The histological characteristics were suggestive of a larva pathway. In both cases the lesion disappeared after biopsy and the patients were symptom free. PMID- 21537594 TI - Maxillary ameloblastic fibroma: a case report. AB - Ameloblastic fibroma is a relatively rare benign odontogenic tumor in which both the epithelial and ectomesenchymal components are neoplastic. An 8-year-old Caucasian boy was referred to the dentist for evaluation of failed eruption of the maxillary left first molar. The panoramic radiograph showed a well circumscribed unilocular radiolucency involving an unerupted maxillary left first permanent molar. The lesion was enucleated and the material was sent for histopathologic examination. Microscopically, it was composed by cords and islands of odontogenic epithelium in a myxoid cell-rich stroma that closely resemble the dental papilla with histopathological diagnosis of ameloblastic fibroma. After 24 months of follow-up no recurrence was observed and the maxillary left first molar erupted spontaneously through the buccal mucosa and was aligned with a fixed orthodontic appliance. This case emphasized the importance of careful differential diagnosis of intraosseous oral lesions and reported a rarity of the lesion and its atypical location. PMID- 21537595 TI - Biodiversity of the Pantanal: its magnitude, human occupation, environmental threats and challenges for conservation. PMID- 21537596 TI - Geomorphology and habitat diversity in the Pantanal. AB - The present study deals with the inter-relations in the relief which forms the Bacia do Alto Rio Paraguay (BAP) in mid-west Brazil. The overall aim is to discuss the relationship between relief forms and the biodiversity of the Pantanal. The BAP is a natural environmental system with contrasts in two of the compartments on which it is formed: the plateau, the most elevated compartment, highly transformed by human activities, and the plain which forms the Pantanal, which is more preserved and less transformed in relation to productive activities. The analysis was performed based on publications with a geomorphologic focus, examining the different relief units of the BAP and the dynamics of the revealing processes of landscape change which the Pantanal has undergone since the end of the Pleistocene. PMID- 21537597 TI - Hydrological cycle. AB - The Pantanal hydrological cycle holds an important meaning in the Alto Paraguay Basin, comprising two areas with considerably diverse conditions regarding natural and water resources: the Plateau and the Plains. From the perspective of the ecosystem function, the hydrological flow in the relationship between plateau and plains is important for the creation of reproductive and feeding niches for the regional biodiversity. In general, river declivity in the plateau is 0.6 m/km while declivity on the plains varies from 0.1 to 0.3 m/km. The environment in the plains is characteristically seasonal and is home to an exuberant and abundant diversity of species, including some animals threatened with extinction. When the flat surface meets the plains there is a diminished water flow on the riverbeds and, during the rainy season the rivers overflow their banks, flooding the lowlands. Average annual precipitation in the Basin is 1,396 mm, ranging from 800 mm to 1,600 mm, and the heaviest rainfall occurs in the plateau region. The low drainage capacity of the rivers and lakes that shape the Pantanal, coupled with the climate in the region, produce very high evaporation: approximately 60% of all the waters coming from the plateau are lost through evaporation. The Alto Paraguay Basin, including the Pantanal, while boasting an abundant availability of water resources, also has some spots with water scarcity in some sub-basins, at different times of the year. Climate conditions alone are not enough to explain the differences observed in the Paraguay River regime and some of its tributaries. The complexity of the hydrologic regime of the Paraguay River is due to the low declivity of the lands that comprise the Mato Grosso plains and plateau (50 to 30 cm/km from east to west and 3 to 1.5 cm/km from north to south) as well as the area's dimension, which remains periodically flooded with a large volume of water. PMID- 21537598 TI - Aquatic macrophyte diversity of the Pantanal wetland and upper basin. AB - This is a short review of the state of the art concerning diversity of aquatic macrophytes and the main aquatic vegetation types in the Brazilian Pantanal wetland and upper watershed. There are ca. 280 species of aquatic macrophytes on the Pantanal floodplain, with scarce endemism. On the upper watershed, Cerrado wetlands (veredas) and limestone springs have a distinct flora from the Pantanal, with twice the species richness. As a representative case of aquatic habitats influenced by river flood, some primary data are presented for the Pantanal Matogrossense National Park and associated Acurizal Preserve, analysing the floristic similarity among aquatic vegetation types. We comment on problems of conservation and observe that Panicum elephantipes Nees is one of the few natives to compete with the invasive Urochloa arrecta (Hack. ex T. Durand & Schinz) Morrone & Zuloaga. PMID- 21537599 TI - Plant diversity of the Pantanal wetland. AB - This is a review of current studies in diversity of the flora and main vegetation types in the Brazilian Pantanal. The flora of this wetland, nearly 2,000 species, constitutes a pool of elements of wide distribution and from more or less adjacent phytogeographic provinces, such as Cerrado, dry seasonal forests, Chaco, Amazonia and Atlantic Forest. The most numerous group includes wide-distribution species, mainly herbs, while the second contingent comes from the Cerrado. Endemic plants are rare, numbering only seven. The vegetation of the sedimentary floodplain is a mosaic of aquatics, floodable grasslands, riparian forests, savannas (cerrados), cerrado woodlands, dry forests, and a large area of mono dominant savannas, and pioneer woodlands. The main vegetation types are briefly described with their characteristic species, and their estimated areas are given according to the latest mapping. PMID- 21537600 TI - The floristic heterogeneity of the Pantanal and the occurrence of species with different adaptive strategies to water stress. AB - The Pantanal is characterised by a diversity of environments with areas ranging from periodic or permanent heavy flooding to areas with low flood levels, and even environments that never flood. Plant species which inhabit the floodplain are distributed in specific niches, with influence of various phytogeographic domains, including the Seasonal Semi-deciduous Forest, Amazon Rainforest, Cerrado and Chaco, as well rocky remnants, with a wide ecological span in their components. In intensely flooded areas, aquatic macrophytes are widely distributed, with their dynamics closely linked to time, depth and extent of flooding. Although the term "Pantanal" suggests a huge swamp-type wetland, water level variation during a seasonal cycle does not directly reach the root system of many plants. The landscape diversity of the Pantanal wetland is molded by the flood pulse, which interferes with the dynamics of plant communities. Therefore, the retraction and expansion of populations or communities is reflected in important ecological characteristics, considering the variety of morphological, anatomical and ecophysiological features of the species, whose phenotype is the result of a particular genotype. The present study discusses peculiar issues in the adaptation of species distributed in the Pantanal biome and underscores the importance of multidisciplinary approaches to obtain conclusive data on adaptive studies. PMID- 21537601 TI - Ethnobotany and traditional medicine of the inhabitants of the Pantanal Negro sub region and the raizeiros of Miranda and Aquidauna, Mato Grosso do Sul, Brazil. AB - A survey on the use of medical plants was carried out in the rural communities of the Rio Negro sub-region of the Pantanal and the raizeiros from Aquidauana and Miranda municipalities, Mato Grosso do Sul, Brazil, in order to recover the ethnobotanical and ethnopharmacological knowledge of these communities. Structured questionnaires were run with the residents of eight farms and 12 raizeiros. The results reveal 25 botanical families, 45 genera and 48 species of medicinal plants used, six of which are indicated for kidney disturbances, six for urinary disturbances, five for inflammation treatment, 13 for stomach aches, 10 for respiratory disturbances, four for treating sprains, four for healing wounds, four as anti-diarrheaic and one as antipyretic, among other illnesses. The main family was Asteraceae, with 12 species used. The principal preparation methods of the medicinal herbs in the Rio Negro sub-region and surrounding areas were infusion (35) and, mostly, mixed with "chimarrao" or "mate quente", traditional beverage. Nineteen exotic species are used by the raizeiros, (39.58%), which indicates a strong influence of the urban environment. The traditional pantaneiros have greater knowledge of medicinal plants than the raizeiros, and they cited only five exotic species (16.1%). PMID- 21537602 TI - Coleoptera (Insecta) as forest fragmentation indicators in the Rio Negro sub region of the Pantanal, Mato Grosso do Sul, Brazil. AB - The purpose of this study was to evaluate the integrity of two forest fragments in Rio Negro Pantanal sub-region, using coleopterans as environmental indicators. The study was carried out at Santa Emilia Farm in the Rio Negro sub-region, municipality of Aquidauana, Mato Grosso do Sul (19o 30' 18'' S and 55 degrees 36' 45'' W). Two sites were selected, locally denominated as "cordilheiras" (narrow and elongated strands of elevated soil), one with low degree of anthropic disturbance (CL) and the other, currently undergoing restoration process (TD). The sampling sites were determined using a GPS device. Ten pit-fall traps containing water and detergent were used for the specimens sampling, which were screened and identified. Abundance, richness, diversity and similarity were determined. Abundance was higher for CL (n = 277) than for TD (n = 251). The same was observed for the diversity indices, CL showed H' = 2.83 bit.individual-1 and TD = 2.48 bit.individual-1, confirming the interferences made for abundance. Specimens of ten families were captured in CL area and seven families in TD area, indicating higher richness in CL, when compared to TD. The linear correlation coefficient (p > 0.05) indicates that both areas are significantly different, showing similarity value of 66.7%. The data show that the structure and disturbance degree in the environment integrity influence the composition of beetles fauna, causing the increase of abundance, richness and diversity in anthropogenic environments undergoing the early stage of regeneration. PMID- 21537603 TI - Terrestrial and aquatic mammals of the Pantanal. AB - Different works have registered the number of mammal species within the natural habitats of the Pantanal based on currently known records, with species richness ranging from 89 to 152 of annotated occurrences. Our present list sums 174 species. However, at least three factors have to be emphasised to deal with recorded numbers: 1) to establish the ecotone limit between the floodplain (which is the Pantanal) and its neighbouring domain like the Cerrado, besides the existence of maps recently produced; 2) the lack of intensive surveys, especially on small mammals, rodents and marsupials; and 3) the constant taxonomic revision on bats, rodents and marsupials. Some species are very abundant--for example the capybara Hydrochoerus hydrochaeris and the crab-eating fox Cerdocyon thous, and some are rare, and others are still intrinsically rare--for example, the bush dog Speothos venaticus. Abundance of species is assumed to reflect ecological resources of the habitat. Local diversity and number of individuals of wild rodents and marsupials also rely on the offering of ecological resources and behavioural specialisation to microhabitat components. A large number of species interact with the type of the vegetation of the habitat, by means of habitat selection through active patterns of ecological behaviour, resulting on dependency on arboreal and forested habitats of the Pantanal. In addition, mammals respond to seasonal shrinking-and-expansion of habitats due to flooding regime of the Pantanal. The highest number of species is observed during the dry season, when there is a considerable expansion of terrestrial habitats, mainly seasonally flooded grassland. Major threats to mammal species are the loss and alteration of habitats due to human intervention, mainly deforestation, unsustainable agricultural and cattle-ranching practices, which convert the natural vegetation into pastures. The Pantanal still harbours about a dozen of species officially listened as in danger. PMID- 21537604 TI - Bat-species richness in the Pantanal floodplain and its surrounding uplands. AB - We studied the bat fauna of the Pantanal floodplain and its surrounding plateaus in Mato Grosso do Sul, Brazil, based on the scientific collection at Universidade Anhanguera-Uniderp and on the Projeto Morcegos do Pantanal data bank at UFMS, comprising 9,037 captures of 56 species recorded from 1994 to 2007. The Pantanal surveys were carried out in the Nhecolandia, Aquidauana, Miranda, and Paraguai sub-regions; the uplands surveys took place in the Maracaju, Bodoquena, and Urucum formations. Bat specimens were mist-netted over 376 nights in 35 sites, predominantly near fruiting trees, bat shelters, and forest patches. In the floodplain 46 species were recorded (n = 6,292 individuals), and 44 species were found in the uplands (n = 2,745 individuals). Six families were recorded: Phyllostomidae (30 species), Molossidae (12 species), Verpertilionidae (nine species) Noctilionidae (two species), Emballorunidae (two species) and Mormoopidae (one species). The bat fauna was predominantly composed of insectivore (32) and frugivore (15) species. The frugivorous Artibeus planirostris (n = 3,101 individuals) was the commonest species in floodplain and uplands. Other common species were Myotis nigricans (n = 762), Molossus molossus (n = 692), Noctilio albiventris (n = 681), Platyrrhinus lineatus (n = 633), Sturnira lilium (n = 461), Carollia perspicillata (n = 451), Glossophaga soricina (n = 436), Artibeus lituratus (n = 320), and Desmodus rotundus (n = 281). In the floodplain there were three insectivores among the most common species, contrasting with the uplands dominated by the frugivores. The diversity for the 35 sites assembled (H' = 2.5) is comparable to that recorded for tropical forests. The bat fauna presented here represents 34% of the Brazilian bat species, and 62% of species reported for the Upper Paraguay River Basin. Additionally, five species are reported for the first time in Mato Grosso do Sul. PMID- 21537605 TI - Introduced species in the Pantanal: implications for conservation. AB - Land use and human occupation within the natural habitats of the Pantanal have facilitated introduction of invasive species of plants and animals, including domestic species. Exotic species threaten regional biodiversity because they modify ecological community structure, alter natural habitats and affect local biodiversity. An international organisation, the International Union for Conservation of Nature (IUCN), and the Brazilian government, identify invasive species as the third most important threat to biodiversity, following habitat loss and direct effect on species. In addition, exotic species carry pathogens or may function as vectors or reservoirs for diseases that affect regional biota. PMID- 21537606 TI - A conservation agenda for the Pantanal's biodiversity. AB - The Pantanal's biodiversity constitutes a valuable natural resource, in economic, cultural, recreational, aesthetic, scientific and educational terms. The vegetation plus the seasonal productivity support a diverse and abundant fauna. Many endangered species occur in the region, and waterfowl are exceptionally abundant during the dry season. Losses of biodiversity and its associated natural habitats within the Pantanal occur as a result of unsustainable land use. Implementation of protected areas is only a part of the conservation strategy needed. We analyse biodiversity threats to the biome under seven major categories: 1) conversion of natural vegetation into pasture and agricultural crops, 2) destruction or degradation of habitat mainly due to wild fire, 3) overexploitation of species mainly by unsustainable fishing, 4) water pollution, 5) river flow modification with implantation of small hydroelectric plants, 6) unsustainable tourism, and 7) introduction of invasive exotic species. PMID- 21537607 TI - Concluding remarks: overall impacts on biodiversity and future perspectives for conservation in the Pantanal biome. AB - The Pantanal biome is characterised by seasonal flooding which determines specific ecosystem processes, with the occurrence of adapted plants and animals to the annual shrinking and expansion of habitats due to the seasonal hydrological regime. Biodiversity abundance varies during the dry and wet seasons. The Pantanal's biodiversity is a fundamental component of ecosystem services for human society, including nutrient cycling, fish production, ecotourism, carbon storage, flood control, among others, which are relevant to regional and global environmental consequences. The biome has been impacted by the conversion of natural vegetation into agricultural fields and pasture for cattle raising, with alteration and loss of natural habitats and biodiversity. Major negative impacts occur in uplands, with drastic deforestation of savanna vegetation, where main rivers feeding the Pantanal have their springs. This article discusses future needs and priorities for ecological research, in order to better understand the biome's natural system, to achieve conservation and sustainable use. PMID- 21537608 TI - Sildenafil decreases rat tracheal hyperresponsiveness to carbachol and changes canonical transient receptor potential gene expression after antigen challenge. AB - Inhibition of type-5 phosphodiesterase by sildenafil decreases capacitative Ca2+ entry mediated by transient receptor potential proteins (TRPs) in the pulmonary artery. These families of channels, especially the canonical TRP (TRPC) subfamily, may be involved in the development of bronchial hyperresponsiveness, a hallmark of asthma. In the present study, we evaluated i) the effects of sildenafil on tracheal rings of rats subjected to antigen challenge, ii) whether the extent of TRPC gene expression may be modified by antigen challenge, and iii) whether inhibition of type-5 phosphodiesterase (PDE5) may alter TRPC gene expression after antigen challenge. Sildenafil (0.1 uM to 0.6 mM) fully relaxed carbachol-induced contractions in isolated tracheal rings prepared from naive male Wistar rats (250-300 g) by activating the NO-cGMP-K+ channel pathway. Rats sensitized to antigen by intraperitoneal injections of ovalbumin were subjected to antigen challenge by ovalbumin inhalation, and their tracheal rings were used to study the effects of sildenafil, which more effectively inhibited contractions induced by either carbachol (10 uM) or extracellular Ca2+ restoration after thapsigargin (1 uM) treatment. Antigen challenge increased the expression of the TRPC1 and TRPC4 genes but not the expression of the TRPC5 and TRPC6 genes. Applied before the antigen challenge, sildenafil increased the gene expression, which was evaluated by RT-PCR, of TRPC1 and TRPC6, decreased TRPC5 expression, and was inert against TRPC4. Thus, we conclude that PDE5 inhibition is involved in the development of an airway hyperresponsive phenotype in rats after antigen challenge by altering TRPC gene expression. PMID- 21537609 TI - Effect of blocking Rac1 expression in cholangiocarcinoma QBC939 cells. AB - Cholangiocarcinomas (CCs) are malignant tumors that originate from epithelial cells lining the biliary tree and gallbladder. Ras correlative C3 creotoxin substrate 1 (Rac1), a small guanosine triphosphatase, is a critical mediator of various aspects of endothelial cell functions. The objective of the present investigation was to study the effect of blocking Rac1 expression in CCs. Seventy four extrahepatic CC (ECC) specimens and matched adjacent normal mucosa were obtained from the Department of Pathology, Inner Mongolia Medicine Hospital, between 2007 and 2009. Our results showed that the expression of Rac1 was significantly higher (53.12%) in tumor tissues than in normal tissues. Western blotting data indicated a significant reduction in Rac1-miRNA cell protein levels. Rac1-miRNA cell growth rate was significantly different at 24, 48, and 72 h after transfection. Flow cytometry analysis showed that Rac1-miRNA cells undergo apoptosis more effectively than control QBC939 cells. Blocking Rac1 expression by RNAi effectively inhibits the growth of CCs. miRNA silencing of the Rac1 gene suppresses proliferation and induces apoptosis of QBC939 cells. These results suggest that Rac1 may be a new gene therapy target for CC. Blocking Rac1 expression in CC cells induces apoptosis of these tumor cells and may thus represent a new therapeutic approach. PMID- 21537610 TI - Essential regulatory elements for NHE3 gene transcription in renal proximal tubule cells. AB - The objectives of the present study were to identify the cis-elements of the promoter absolutely required for the efficient rat NHE3 gene transcription and to locate positive and negative regulatory elements in the 5'-flanking sequence (5'FS), which might modulate the gene expression in proximal tubules, and to compare this result to those reported for intestinal cell lines. We analyzed the promoter activity of different 5'FS segments of the rat NHE3 gene, in the OKP renal proximal tubule cell line by measuring the activity of the reporter gene luciferase. Because the segment spanning the first 157 bp of 5'FS was the most active it was studied in more detail by sequential deletions, point mutations, and gel shift assays. The essential elements for gene transcription are in the region -85 to -33, where we can identify consensual binding sites for Sp1 and EGR 1, which are relevant to NHE3 gene basal transcription. Although a low level of transcription is still possible when the first 25 bp of the 5'FS are used as promoter, efficient transcription only occurs with 44 bp of 5'FS. There are negative regulatory elements in the segments spanning -1196 to -889 and -467 to 152, and positive enhancers between -889 and -479 bp of 5'FS. Transcription factors in the OKP cell nuclear extract efficiently bound to DNA elements of rat NHE3 promoter as demonstrated by gel shift assays, suggesting a high level of similarity between transcription factors of both species, including Sp1 and EGR 1. PMID- 21537611 TI - Morphometric analysis of the phrenic nerve in male and female Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). AB - Ventilatory differences between rat strains and genders have been described but the morphology of the phrenic nerve has not been investigated in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. A descriptive and morphometric study of the phrenic nerves of male (N = 8) and female (N = 9) SHR, and male (N = 5) and female (N = 6) WKY is presented. After arterial pressure and heart rate recordings, the phrenic nerves of 20-week-old animals were prepared for epoxy resin embedding and light microscopy. Morphometric analysis performed with the aid of computer software that took into consideration the fascicle area and diameter, as well as myelinated fiber profile and Schwann cell nucleus number per area. Phrenic nerves were generally larger in males than in females on both strains but larger in WKY compared to SHR for both genders. Myelinated fiber numbers (male SHR = 228 +/- 13; female SHR = 258 +/- 4; male WKY = 382 +/- 23; female WKY = 442 +/- 11 for proximal right segments) and density (N/mm2; male SHR = 7048 +/- 537; female SHR = 10355 +/- 359; male WKY = 9457 +/- 1437; female WKY = 14351 +/- 1448) for proximal right segments) were significantly larger in females of both groups and remarkably larger in WKY than SHR for both genders. Strain and gender differences in phrenic nerve myelinated fiber number are described for the first time in this experimental model of hypertension, indicating the need for thorough functional studies of this nerve in male and female SHR. PMID- 21537612 TI - Effect of gender on training-induced vascular remodeling in SHR. AB - There is accumulating evidence that physical inactivity, associated with the modern sedentary lifestyle, is a major determinant of hypertension. It represents the most important modifiable risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality for both men and women. In addition to involving sympathetic overactivity that alters hemodynamic parameters, hypertension is accompanied by several abnormalities in the skeletal muscle circulation including vessel rarefaction and increased arteriole wall-to-lumen ratio, which contribute to increased total peripheral resistance. Low-intensity aerobic training is a promising tool for the prevention, treatment and control of high blood pressure, but its efficacy may differ between men and women and between male and female animals. This review focuses on peripheral training induced adaptations that contribute to a blood pressure-lowering effect, with special attention to differential responses in male and female spontaneously hypertensive rats (SHR). Heart, diaphragm and skeletal muscle arterioles (but not kidney arterioles) undergo eutrophic outward remodeling in trained male SHR, which contributed to a reduction of peripheral resistance and to a pressure fall. In contrast, trained female SHR showed no change in arteriole wall-to-lumen ratio and no pressure fall. On the other hand, training-induced adaptive changes in capillaries and venules (increased density) were similar in male and female SHR, supporting a similar hyperemic response to exercise. PMID- 21537613 TI - Controversies and outlooks on vestibular rehabilitation. PMID- 21537614 TI - Clinical study of the oral manifestations and related factors in type 2 diabetics patients. AB - Diabetes Mellitus (DM) is reported with and associated to oral alterations, with conflicting results. The aim of this study was to identify the prevalence of oral soft tissue alterations in type 2 diabetes mellitus patients. MATERIAL AND METHODS: Socioeconomic variables, gender, heredity, capillary glucose control and local factors (prosthesis, dry mouth sensation) were analyzed in 196 diabetic and non-diabetic patients enrolled in HIPERDIA, at 41 Health units of Natal, Brazil. STUDY DESIGN: A case study. RESULTS: The last blood glucose mean was 177.0 mg/dl for diabetics and 89.46 mg/dl for non-diabetics. Mean capillary blood glucose was elevated in diabetics (215.95 mg/dl); it was 102.31 mg/dl in non-diabetics. The family history confirmed the heredity nature of the disease in 68.8% of diabetic patients (n = 66) (p < 0.001); salivary flow was 49% (n = 47) in diabetics, and 34% (n = 34) in non-diabetics. Candidiasis was present in 30.5% of diabetic patients (n=29) and 36% of non-diabetics (n=36). Both groups had lesions in the palate - 81.4% (n = 35) in diabetics, and 71.1% in non-diabetics (n = 27) (p = 0.68). CONCLUSION: The alterations are not related to diabetes and are present independently of having or not type 2 Diabetes Mellitus. PMID- 21537615 TI - Speech perception in adolescents with pre-lingual hearing impairment with cochlear implants. AB - Profound hearing loss is a disability that affects personality and when it involves teenagers before language acquisition, these bio-psychosocial conflicts can be exacerbated, requiring careful evaluation and choice of them for cochlear implant. AIM: To evaluate speech perception by adolescents with profound hearing loss, users of cochlear implants. STUDY DESIGN: Prospective. MATERIALS AND METHODS: Twenty-five individuals with severe or profound pre-lingual hearing loss who underwent cochlear implantation during adolescence, between 10 to 17 years and 11 months, who went through speech perception tests before the implant and 2 years after device activation. For comparison and analysis we used the results from tests of four choice, recognition of vowels and recognition of sentences in a closed setting and the open environment. RESULTS: The average percentage of correct answers in the four choice test before the implant was 46.9% and after 24 months of device use, this value went up to 86.1% in the vowels recognition test, the average difference was 45.13% to 83.13% and the sentences recognition test together in closed and open settings was 19.3% to 60.6% and 1.08% to 20.47% respectively. CONCLUSION: All patients, although with mixed results, achieved statistical improvement in all speech tests that were employed. PMID- 21537616 TI - Musical rhythms and their influence on P300 velocity in young females. AB - Exposure to music may be useful in the P300 retest and avoid habituation. AIM: To verify the influence of the exposure to different kinds of music in P300 in young females. STUDY DESIGN: Clinical prospective. MATERIAL AND METHOD: Forty-five women aged from 20 to 36 years were evaluated. P300 was studied before and after musical stimulation with different rhythms. Brazilian songs, international songs, and classical music melodies were selected. Each song had its velocity altered and was named as fast and slow. Subjects were divided into 2 groups exposed to music: one group was exposed to the fast version and the other to the slow version. The control group not exposed to music and was evaluated within the same time period of the others. RESULT: There were statistically significant differences when comparing P300 amplitude in the first and third stimulation with the comparison group. CONCLUSION: In the same subject, several sequential registrations of P300 caused habituation, which was not seen during exposure to music before P300 recording. Exposure to music at preset different velocities did not affect the P300 in young females. PMID- 21537617 TI - Acoustic and psychoacoustic analysis of the noise produced by the police force firearms. AB - Police officers are exposed to impact noise coming from firearms, which may cause irreversible injuries to the hearing system. AIM: To evaluate the noise exposure in shooting stands during gunfire exercises, to analyze the acoustic impact of the noise produced by the firearms and to associate it with tonal audiometry results. STUDY DESIGN: Cross-sectional. MATERIALS AND METHODS: To measure noise intensity we used a digital sound level meter, and the acoustic analysis was carried out by means of the oscillations and cochlear response curves provided by the praat software. 30 police officers were selected (27 males and 3 females). RESULTS: The peak level measured was 113.1 dB(C) from a .40 pistol and 116.8 dB(C) for a .38 revolver. The values obtained for oscillation and praat was 17.9 +/- 0.3 Barks, corresponding to the rate of 4,120 and 4,580 Hz. Audiometry indicated greater hearing loss at 4,000Hz in 86.7% of the cases. CONCLUSION: With the acoustic analysis it was possible to show cause and effect between the main areas of energy excitation of the cochlea (praat cochlear response curve) and the frequencies of low hearing acuity. PMID- 21537618 TI - Endoscopic treatment of esthesioneuroblastoma. AB - Esthesioneuroblastoma is an uncommon malignant tumor of the nasal vault. Treatment consists of craniofacial resection. As endoscopic techniques have advanced, this approach has been recommended to avoid morbidity and to reduce costs. AIM: To evaluate outcomes in patients with esthesioneuroblastoma treated by an endoscopic technique. METHODS: A prospective study of patients diagnosed with esthesioneuroblatoma and treated by an endoscopic technique. The literature over the past 20 years was reviewed for an update on the pathology. RESULTS: We present 4 patients, 3 males and 1 female, staged according to Kadish and Dulguerov. All were treated surgically with endoscopic techniques, followed by radiotherapy. One patient was also submitted to neck dissection and chemotherapy because of regional metastasis. There were no significant postoperative complications. The mean hospital stay was 3 days; one patient stayed in the ICU for 24 hours after surgery. Follow-up is recent; so far there are no recurrences. CONCLUSION: Esthesioneuroblastoma is a potentially curable malignancy. Endoscopic techniques help reduce hospital costs and decrease the morbidity. Adequate margins of healthy tissue are obtained with endoscopic resection, as with craniofacial resection. The literature suggests that outcomes after endoscopic resection are similar to those of the conventional external approach. PMID- 21537619 TI - Caudal septoplasty: efficacy of a surgical technique-preliminary report. AB - Although not being the most frequent nasal septal deviations, those of the caudal septum account for many complaints. The correction of such defects has always been the subject of much controversy, and several different operative techniques have been described. AIM: To assess the efficacy of a surgical technique for correcting caudal septal deviations. MATERIALS AND METHODS: Prospective study with preliminary reports of 10 patients who answered a standardized, specific questionnaire (the Nasal Obstruction Symptom Evaluation, or NOSE), underwent acoustic rhinometry and had their noses photographed. Caudal deviations were then corrected through a surgical technique whereby the entire deviated portion is removed and a straight cartilage segment is placed between the medial crura of the alar cartilages, through a retrograde approach, to support the nasal tip. Sixty days after all patients were reassessed. RESULTS: As for the NOSE questionnaire, mean pre-operative and post-operative scores were 82.39 and 7.39 respectively (p<0.001). Pre-operative acoustic rhinometry showed mean minimum cross-sectional area (MCA) values of 0.352 and 0.431 cm2, whereas mean post operative values were 0.657 and 0.711 cm2(p<0.0001). CONCLUSIONS: The study results prove, both subjectively (patient satisfaction as measured with a standardized questionnaire) and objectively (acoustic rhinometry findings), that the proposed technique for correction of caudal septal deviation is safe and effective. PMID- 21537620 TI - Histological analysis of autologous fascia graft implantation into the rabbit voice muscle. AB - The ideal approach for the treatment of glottal insufficiency remains a challenge for laryngologists. AIM: This experimental study assessed the histological changes and fibrosis caused by autologous fascia lata grafts into the rabbit voice muscle. STUDY DESIGN: A clinical and experimental study. METHODS: A 0.2 * 0.2 cm fragment of autologous fascia lata was grafted into the right voice muscle of 14 adult rabbits. Animals were euthanized 30 or 60 days post-procedure and histology of the excised vocal folds was carried out. RESULTS: No extensive edema, necrosis or foreign body-type reaction was observed at any time. No significant inflammatory reaction or fibrosis was seen at 30 or 60 days. CONCLUSION: The presence of fascia lata in the rabbit voice muscle had no significant influence on inflammation, and does not increase fibrosis. Rabbit voice muscle shows good tolerance to fascia lata grafting. PMID- 21537621 TI - Benign Paroxysmal Positional Vertigo: comparison of two recent international guidelines. AB - Benign Paroxysmal Positional Vertigo (BPPV) is characterized by vertigo, lasting for a few seconds and usually managed by head positioning maneuvers. To educate clinicians concerning the state-of-the art knowledge about its management, the international societies developed guidelines. AIM: the aim of this paper is to discuss, in a practical fashion, the current options available to manage BPPV. METHOD: STUDY DESIGN: non-systematic review. This study reviews two recent guidelines regarding the evaluation and treatment of BPPV. The first one was published by the American Academy of Otolaryngology Head and Neck surgery (AAO HNS) and the other by the American Academy of Neurology (AAN). The similarities were presented in different tables. RESULTS: Those guidelines presented differences regarding methods. Only the AAO-HNS guidelines recommend the Dix Hallpike test for the diagnosis of BPPV. Only canalith repositioning maneuver, Semont maneuver and vestibular rehabilitation had showed some benefit and were recommended as good treatment options. CONCLUSIONS: Both guidelines fulfilled all the aspects required for clinicians to diagnosed and manage BPPV; only the AAO HNS's guidelines were more comprehensive and of better quality. PMID- 21537622 TI - Otolaryngology and speech therapy evaluation in the assessment of oropharyngeal dysphagia: a combined protocol proposal. AB - Dysphagia is a symptom associated with an array of anatomical and functional changes which must be assessed by a multidisciplinary team to guarantee optimal evaluation and treatment, preventing potential complications. AIM: The aim of the present study is to present the combined protocol of clinical and swallowing videoendoscopy carried by ENT doctors and speech therapists in the Dysphagia Group of the ENT Department - University Hospital. MATERIALS AND METHODS: Retrospective study concerning the use of a protocol made up of patient interview and clinical examination, followed by an objective evaluation with swallowing videoendoscopy. The exam was performed in 1,332 patients from May 2001 to December 2008. There were 726 (54.50%) males and 606 (45.50%) females, between 22 days and 99 years old. RESULTS: We found: 427 (32.08%) cases of normal swallowing, 273 (20.48%) mild dysphagia, 224 (16.81%) moderate dysphagia, 373 (27.99%) severe dysphagia and 35 (2.64%) inconclusive exams. CONCLUSION: The combined protocol (Otolaryngology and Speech Therapy), is a good way to approach the dysphagic patient, helping to achieve early and safe deglutition diagnosis as far as disorder severity and treatment are concerned. PMID- 21537623 TI - Graphic angle measure as an electrocochleography evaluation parameter. AB - To improve electrocochleography's diagnostic sensitivity in Meniere's disease - new assessment methods are being studied. AIM: To determine whether or not graphic angle measurement is sensitive and specific to Meniere's disease laboratorial diagnosis and if there is an increase in the electrocochleography's sensitivity and specificity when graphic angle measurements are associated with Summating Potential-Action Potential ratio (SP/AP ratio). METHODS: Electrocochleography's was used to analyze 71 ears from 55 subjects: 41 patients with clinical diagnosis of Meniere's disease (MD group), and 14 healthy individuals as control (Group C). Graphic results were analyzed initially to obtain the SP/AP ratio; afterwards, through another program graphic angle measurements were calculated. RESULTS: Sensitivity and specificity values of angle measures, SP/AP ratio, and the association between them varied according to the cutoff point, the highest equilibrium between sensitivity and specificity was observed with the values of 166.25 for angle measurement and 27% for SP/AP relation; 62.79% / 60.71% and 74.42% / 67.86%, respectively. The association between measurements showed a sensitivity increase due to the specificity decrease; 88.37% and 50%, respectively. CONCLUSION: Angle graphic measurement is not sensitive and specific enough for the laboratorial diagnosis of MD. Angle graphic measurement and SP/AP ratio association proved to be higher in sensitivity, in detriment of exam specificity. PMID- 21537624 TI - Unilateral hearing loss: benefits and satisfaction from the use of hearing aids. AB - A unilateral hearing loss is characterized by reduced hearing in one ear. The problems caused by sensory deprivation can be minimized with the use of hearing aids (HA). AIM: To analyze the correlation between the prescribed grain and the insertion gain difference and with the results obtained regarding the benefit and satisfaction with the use of hearing aids in unilateral hearing impaired patients. MATERIALS AND METHODS: Prospective study with 15 subjects, mean age of 41.6 years, of both genders, users of hearing aids effectively. We used the International Questionnaire Results for hearing aids (International Outcome Inventory for Hearing Aids - IOI-HA), measured with a probe microphone. RESULTS: The mean values in the analyses of the IOI-HA per item were positive and higher than four points. In relation to the objective measures, the frequencies in which we obtained the gain values which were closer to the target were: 1K Hz, 2K Hz and 500 Hz, respectively. CONCLUSION: The satisfaction of individuals using hearing aid unilaterally is not completely correlated to the prescribed gain, because even if the target is not being reached in some frequencies, the individuals were pleased as to the use of their hearing aids. PMID- 21537625 TI - Evaluation of the organic and functional results of tympanoplasties through a retro-auricular approach at a medical residency unit. AB - Tympanoplasty aims at rebuilding the tympanic membrane with or without middle ear functional recovery. AIM: To evaluate the surgical results of tympanoplasties with a retro-auricular surgical approach at a medical residency unit. MATERIALS AND METHODS: Thirty-nine patients with diagnosis of simple chronic otitis media were evaluated; these patients underwent tymplanoplasty by a retro-auricular approach (underlay technique) at a medical residency unit. Patients were included in a prospective medical and audiologic investigation protocol that consisted of a clinical, otomicroscopic and audiometric evaluation. All procedures were supervised by training specialists otorrinolaringology. RESULTS: The rate of surgical success - full integration of the graft - was 95% of cases. Improvement of hearing, as demonstrated in audiometry, occurred in 72% of cases. Improvement in tinnitus was demonstrated subjectively on a visual analog scale in 69% of cases. CONCLUSION: Tympanoplasty through a retro-auricular approach is easy to perform. Full graft integration occurred in 95% of cases and was independent of factors deemed by many authors as relevant. The results - improvement of the quality of hearing and tinnitus - were significant. PMID- 21537626 TI - Mandibular range of motion in patients with idiopathic peripheral facial palsy. AB - Regarding orofacial motor assessment in facial paralysis, quantitative measurements of the face are being used to establish diagnosis, prognosis and treatment planning. AIM: To assess the prevalence of changes in mandibular range of motion in individuals with peripheral facial paralysis. MATERIALS AND METHODS: Prospective study. We had 56 volunteers, divided in two groups: G1 made up of 28 individuals with idiopathic facial paralysis (6 males and 22 females); 14 with manifestations on the right side of the face and 14 on the left side; time of onset varied between 6-12 months; G2 with 28 healthy individuals paired by age and gender to G1. In order to assess mandibular range of motion, a digital caliper was used. The following measurements were made: 1) middle line; 2) maximum oral opening; 3) lateralization to the right; 4) lateralization to the left; 5) protrusion; 6) horizontal overlap. RESULTS: Statistically significant differences between the groups were observed for maximum oral opening, lateralization to the left and protrusion. G1 presented smaller measurement values than G2. CONCLUSION: Patients with facial paralysis present significant reduction of mandibular range of motion. The results support the suggestion of incorporating functional evaluation of the temporomandibular joint to the existing facial paralysis clinical assessment protocols. PMID- 21537627 TI - Influence of gender on the vestibular evoked myogenic potential. AB - There is no consensus on the relevance of factors that influence gender differences in the behavior of muscles. Some studies have reported a relationship between muscle tension and amplitude of the vestibular evoked myogenic potential; others, that results depend on which muscles are studied or on how much load is applied. AIMS: This study aims to compare vestibular evoked myogenic potential parameters between genders in young individuals. METHODS: Eighty young adults were selected - 40 men and 40 women. Stimuli were averaged tone-bursts at 500 Hz, 90 dBHL intensity, and a 10-1000 Hz bandpass filter with amplification of 10-25 microvolts per division. The recordings were made in 80 ms windows. STUDY TYPE: An experimental and prospective study. RESULTS: No significant gender differences were found in wave latency - p = 0.19 and p = 0.50 for waves P13 and N23, respectively. No differences were found in amplitude values - p = 0.28 p = 0.40 for waves P13 and N23, respectively. CONCLUSION: There were no gender differences in latency and amplitude factors; the sternocleidomastoid muscle strain was monitored during the examination. PMID- 21537628 TI - Anatomic relation between the external branch of the superior laryngeal nerve and the thyroid gland. AB - AIM: This prospective study investigated the anatomic relations between the external branch of the superior laryngeal nerve (EBSLN), the superior thyroid artery (STA) and the thyroid gland in human cadavers. MATERIAL AND METHODS: Twenty-two human cadavers aged over 18 years old, less than 24 hours after death. RESULTS: The mean distance between the EBSLN and the superior pole of the thyroid gland was 7.68 +/-3.07 mm. A tangent to the inferior edge of the thyroid cartilage between the EBSLN and the STA measured 4.24 +/-2.67 mm. A line from the intersection of the EBSLN - related to the STA - to the superior pole of the thyroid gland measured 9.53 +/-4.65 mm. A line from the EBSLN to the midline of the most caudal point of the thyroid cartilage measured 19.70 +/-2.82 mm. A line from the RENLS to the midline on the most cranial point of the cricoid cartilage was 18.35 +/-3.66 mm. CONCLUSION: There is a variable proximity relation between the EBSLN and the superior pole of the thyroid gland; this distance ranges from 3.25 to 15.75 mm. There was no evidence of significant variation between the measures in the ethnic groups comprising the sample. PMID- 21537629 TI - Spinal accessory nerve neuropathy following neck dissection. AB - The most common complication of neck dissection is shoulder dysfunction due to manipulation of spinal accessory nerve, resulting in trapezius muscle atrophy mainly in procedures involving the posterior neck triangle. AIM: This study used electromyography to evaluate the injury to the spinal accessory nerve following neck dissection. MATERIALS AND METHODS: Prospective case series of 51 patients submitted to 60 neck dissections followed by physical therapy evaluation of shoulder dysfunction. Nerve integrity was evaluated before and after the surgery by means of surface EMG registering the electric activity of the trapezius muscle during voluntary contraction. The patients were grouped according to the type of neck dissection, presence of shoulder pain, impairment during abduction movement and hypotrophy/atrophy of the trapezius muscle. RESULTS: Action potential had median values of 54.3 microV before surgery and 11.6 microV after it (p<0.001). There was a mean decrease of 70% comparing to preoperative values. The median was 12.5 microV after dissection including level IIb, and 8.9 microV after dissection including levels IIb and V (p<0.002). CONCLUSION: Surface EMG is a sensitive and painless method for spinal accessory nerve dysfunction evaluation. The results suggest the usefulness of the trapezius muscle electromyography to confirm diagnosis and early physical therapy intervention in neuropathies of the spinal accessory nerve. PMID- 21537630 TI - Current outlook of ethics in research with human subjects. AB - In the last decades, medical care has been increasingly permeated by the concept of evidence-based-medicine, in which clinical research plays a crucial role in establishing diagnostic and treatment. Following the improvements in clinical research, we have a growing concern and understanding that some ethical issues must be respected when the subjects are human beings. Research with human subjects relies on the principles of autonomy, beneficence, no maleficence and justice. Ordinance 196/96 from the National Health Board adds to the Brazilian legislation such renowned bioethical principles. AIM: Discuss the main ethical aspects involved in research with human subjects. MATERIALS AND METHODS: Critical analysis of Ordinance 196/96 and related literature. CONCLUSION: Ordinance 196/96 rules research with human subjects; nevertheless, it requires more in-depth discussions regarding the informed consent, use of placebo, research with vulnerable populations and research in developing countries. PMID- 21537631 TI - Association between congenital nasolacrimal duct cyst and bilateral choanal atresia. PMID- 21537632 TI - Ricinus communis membrane for orbital reconstruction. PMID- 21537633 TI - Angiomyolipoma of the nasal cavity. PMID- 21537636 TI - Plagiarism in scientific publication. PMID- 21537634 TI - Simultaneous occurrence of a rare lymphoepithelial cyst and squamous cell carcinoma in the oral cavity. PMID- 21537637 TI - Comparison of the fracture torque of different Brazilian mini-implants. AB - This study evaluated fracture torque by torsion, in relation to the length and diameter of orthodontic mini-implants, to demonstrate their viability for clinical and experimental use based on the torque recommended by the manufacturers. The fractures at the moment of insertion, whose incidence in the literature is around 4%, are principally due to excessive force and the inability of the implant to resist rotational forces. Thirty orthodontic mini-implants of three commercial brands available in Brazil (Neodent 1.6 x 9 mm, Dentoflex 1.6 x 9 mm and Kopp 1.6 x 9 mm) were attached to a device made specifically for this research, leaving the mini-implants with sufficient stability. The miniimplants were submitted to torsion torque, using a digital torque wrench, until their breaking point. The values obtained with the test were submitted to analysis of variance and the Tukey test. The mean values of mini-implant ruptures were 26 N.cm for group A (Dentoflex), 25.4 N. cm for group B (Kopp) and 32.8 N.cm for group C (Neodent). From the Tukey test we could observe that the relationships between the means of the Dentoflex and Neodent groups, and between the Kopp and Neodent groups, were significant. Between the Dentoflex and Kopp groups, significance was nonexistent. All the values found in our research for fracture torque were higher than the limits recommended by the manufacturers for clinical use in orthodontics. The highest values were found in the Neodent group. PMID- 21537638 TI - Comprehensive intermaxillary tooth width proportion of Bangkok residents. AB - Proper occlusion depends on the correct width ratio between upper and lower teeth, known as Bolton's ratio. In fact, this ratio can be calculated for each pair of teeth from the central incisor to the first permanent molar. This set of ratios, known as comprehensive cumulative percentage ratios (CPRs), can be used not only to determine which tooth or teeth have a tooth width discrepancy, but can also enable the partial graphical analysis of tooth width discrepancy when there is agenesis of certain permanent teeth. Although CPRs have been calculated for Caucasians, tooth width is known to vary depending on racial origin. Therefore, a test of differences between racial groups should be carried out. If these ratios of the Caucasians and Bangkokians are significantly different, the ratio of the Bangkokians is recommended. The objective of this study was to measure tooth size disproportion for Thai patients and to calculate a corresponding set of CPRs. Thirty-seven pairs of dental models were made from a group of Bangkok residents with normal occlusion. Mesiodistal tooth width was measured for each model. The intra- and inter-examiner measurement errors were ascertained as insignificant (p > 0.05). CPRs were then calculated and compared to those derived from other studies. Ten of thirteen CPRs were significantly different from corresponding values derived from Caucasians. We conclude that tooth width ratios vary between different racial groups, and therefore that these should be calculated specifically for each patient racial group. PMID- 21537639 TI - Effect of irradiation times on the polymerization depth of contemporary fissure sealants with different opacities. AB - The aim of this study was to evaluate the depth of curing of 10 contemporary blue light-activated dental flowable materials at several opacities, influenced by different irradiation times using FT-IR spectroscopy. Fifty-five specimens (n = 5) with a 5-mm diameter and 1-mm thickness of translucent (Opallis Flow T), yellowed (Master Flow A2; Opallis Flow A2; Natural Flow A2; Fluroshield Yellowed), and opaque materials (Master Flow OA2; Natural Flow O; Opallis Flow OA3.5; Opallis Flow OP; Fluroshield White) were obtained at six curing times (10s, 20s, 30s, 40s, 50s, and 60s) using a high-intensity LED (Coltolux, ColtAne/Whaledent). The degree of conversion (DC) (%) was obtained using the Nexus 470 FTIR Spectrometer (Nicolet Instruments, USA). The FTIR-ATR spectra for uncured and cured samples were analyzed using a ZnSe crystal. The top and bottom surfaces of the cured specimens were analyzed to obtain the depth of curing. Two way ANOVA was used to analyze the data. The highest curing depth was obtained by Natural Flow OA2, while the lowest was shown by Master Flow OA2. The shortest curing time generated similar depths of cure in comparison with the most extensive for Opallis Flow A2 and Fluroshield Yellowed. Therefore, depth of curing, influenced by the irradiation time, was dependent on the materials. Using the Natural Flow OA2 opaque sealant and the 10-s curing time for Opallis Flow A2 and Fluroshield Yellowed may represent alternative approaches to sealing tooth fissures. PMID- 21537640 TI - Luxation injuries in primary teeth: a retrospective study in children assisted at an emergency service. AB - The purpose of this study was to analyze luxation injuries in children between the ages of 0 and 5 years treated at an emergency service department. A total of 1,703 records, corresponding to a period of 10 years at the Emergency Center of the Baby Clinic at Londrina State University, Brazil, were analyzed. The age, gender, etiologic factors, type of injury, injured teeth, treatment and time interval between injury and treatment were determined for each patient. Of the examined records, 409 patients met the study criteria and included a total of 679 injured teeth. Statistical analyses were carried out using the chi-square test with the level of significance set at 5%. Trauma incidence was higher in boys (57.0%) and in children less than two years of age (40.3%). Falling while walking or running was the most predominant etiologic factor (37.7%), and the most prevalent type of injury was subluxation (32.6%). Luxation injuries decreased with increasing age (p = 0.045). Treatment usually occurred within the first 1-15 days and was significantly associated with the type of trauma (p = 0.041). "Monitor only" was the treatment most frequently observed (74.0%). In conclusion, more luxation injuries were found in younger children, predominantly in boys. Falls resulting from walking or running were the etiologic factor most observed, with subluxation as the most common type of trauma. Treatment usually occurred within the first 15 days after the injury. Despite the severity of these injuries, "monitor only" was the eligible treatment. PMID- 21537641 TI - Periodontal ligament and gingival fibroblasts participate in the production of TGF-beta, interleukin (IL)-8 and IL-10. AB - The aim of this study was to quantify and compare the production of transforming growth factor beta (TGF-beta), interleukin (IL)-8 and IL-10 by human cultured periodontal ligament and gingival fibroblasts both obtained from the same donors challenged with lipopolysaccharide (LPS) from Porphyromonas gingivalis. Fibroblasts were exposed to 0.1-10 ug/mL of LPS from P. gingivalis and after 24 h the supernatants were collected and analyzed by enzyme-linked immunosorbent assay (ELISA). TGF-beta protein production was upregulated in a concentration-dependent manner, mainly in gingival fibroblasts, which was statistically significant when challenged by 10 ug/mL LPS. Additionally, at this concentration, gingival fibroblasts had almost a two-fold increase in the amount of TGF-beta when compared to periodontal ligament fibroblasts. Both periodontal ligament and gingival fibroblasts showed an increase in IL-8 production when challenged with 1 ug/mL and 10 ug/mL LPS. IL-10 production remained unaffected when challenged by any of the LPS concentrations tested in either periodontal ligament or gingival fibroblasts. Our results demonstrate that periodontal ligament and gingival fibroblasts when challenged by LPS from P. gingivalis with 24 h may play a critical role in producing TGF-beta and IL-8 but not IL-10. PMID- 21537642 TI - Evaluation of the accuracy of different transfer impression techniques for multiple implants. AB - The aim of this study was to evaluate the accuracy of three implant transfer impression techniques. Four groups (n = 5) were defined, according to the technique: TC - tapered copings without splint; SC - square copings without splint; SCS - square copings splinted with dental floss and acrylic resin, and CG (control group) - master model with four external hexagonal implants and a superstructure. Individual trays and polyether were used for the impression. All casts were checked for their fit into the master superstructure; for this, all four screws were placed in the implants. Digital photos were taken and images were analyzed using UTHSCSA ImageTool software. Statistical analyses were performed using one-way analysis of variance and Student's t test (p < 0.05). The means and standard deviation were (um): CG = 2.03 +/- 0.00, TC = 14.74 +/- 3.41, SC = 12.08 +/- 2.56, and SCS = 6.51 +/- 0.09. The control group was found to be statistically different from the TC and SC groups. Within the limitations of this study, all groups presented clinically acceptable standard gap values, and the SCS group showed no statistical difference in relation to the CG (control group), demonstrating more accuracy and fidelity to transfer implants. PMID- 21537643 TI - Effects of mouthwashes on Knoop hardness and surface roughness of dental composites after different immersion times. AB - The aim of this in vitro study was to evaluate the effect of different mouthwashes on superficial roughness and Knoop hardness of two resin composites. Eighty specimens (6 mm O and 2 mm height) were prepared and divided into eight experimental groups (n = 10) according to the resin composites (4 Seasons and Esthet X), and storage solutions (G1 - Distilled water; G2 - Colgate Plax Overnight; G3 - Colgate Plax Alcohol Free; and G4 - Colgate Plax Whitening). The initial hardness and roughness readings (T1) were measured and then the specimens were stored in 2 mL of mouthwash for 12 h (T2) and 24 h (T3). The data were analyzed with repeat-measures two-way ANOVA and Tukey's test (alpha = 5%). Regardless of the type of solution and time of exposure, there was no statistical difference for roughness between the resins (p = 0.44). G4 and G8 presented higher roughness means than G1, G3, G5 and G7, after 12 and 24 hours of immersion. For Knoop microhardness analysis, there was a significant reduction for all groups after 12 hours and 24 hours. We conclude that the mouthwashes containing hydrogen peroxide and/or alcohol decrease the microhardness of the resins tested; however, the mouthwash containing hydrogen peroxide had a higher deleterious effect on roughness. PMID- 21537644 TI - Pre-heated dual-cured resin cements: analysis of the degree of conversion and ultimate tensile strength. AB - This study evaluated the degree of conversion (DC) and ultimate tensile strength (UTS) of dual-cured resin cements heated to 50o C prior to and during polymerization. Disc- and hourglass-shaped specimens of Rely X ARC (RX) and Variolink II (VII) were obtained using addition silicon molds. The products were manipulated at 25o C or 50o C and were subjected to 3 curing conditions: light activation through a glass slide or through a pre-cured 2-mm thick resin composite disc, or they were allowed to self-cure (SC). All specimens were dark stored dry for 15 days. For DC analysis, the resin cements were placed into the mold located on the center of a horizontal diamond on the attenuated total reflectance element in the optical bench of a Fourier Transformed Infrared spectrometer. Infrared spectra (n = 6) were collected between 1680 and 1500 cm-1, and DC was calculated by standard methods using changes in ratios of aliphatic-to aromatic C=C absorption peaks from uncured and cured states. For UTS test, specimens (n = 10) were tested in tension in a universal testing machine (crosshead speed of 1 mm/min) until failure. DC and UTS data were submitted to 2 way ANOVA, followed by Tukey's test (alpha= 5%). Both products showed higher DC at 50o C than at 25o C in all curing conditions. No significant difference in UTS was noted between most light-activated groups at 25o C and those at 50o C. VII SC groups showed higher UTS at 50o C than at 25o C (p < 0.05). Increased temperature led to higher DC, but its effects on resin cement UTS depended on the curing condition. PMID- 21537645 TI - Acupuncture for the prevention of radiation-induced xerostomia in patients with head and neck cancer. AB - The aim of this study was to evaluate the effectiveness of acupuncture in minimizing the severity of radiation-induced xerostomia in patients with head and neck cancer. A total of 24 consecutive patients receiving > 5000 cGy radiotherapy (RT) involving the major salivary glands bilaterally were assigned to either the preventive acupuncture group (PA, n = 12), treated with acupuncture before and during RT, or the control group (CT, n = 12), treated with RT and not receiving acupuncture. After RT completion, clinical response was assessed in all patients by syalometry, measuring the resting (RSFR) and stimulated (SSFR) salivary flow rates, and by the visual analogue scale (VAS) regarding dry mouth-related symptoms. Statistical analyses were performed with repeated-measures using a mixed-effect modeling procedure and analysis of variance. An alpha level of 0.05 was accepted for statistical significance. Although all patients exhibited some degree of impairment in salivary gland functioning after RT, significant differences were found between the groups. Patients in the PA group showed improved salivary flow rates (RSFR, SSFR; p < 0.001) and decreased xerostomia related symptoms (VAS, p < 0.05) compared with patients in the CT group. Although PA treatment did not prevent the oral sequelae of RT completely, it significantly minimized the severity of radiation-induced xerostomia. The results suggest that acupuncture focused in a preventive approach can be a useful therapy in the management of patients with head and neck cancer undergoing RT. PMID- 21537646 TI - Fine needle aspiration biopsy in the oral cavity and head and neck region. AB - The objective of the current study was to evaluate the sensitivity, specificity and accuracy of fine needle aspiration biopsy (FNAB) of submucous nodules from the oral cavity and head and neck region as an auxiliary diagnostic tool. Fifty patients with nodule lesions in the oral cavity and the head and neck region were selected. All of them were submitted to FNAB and to either incisional or excisional biopsy. The diagnoses from the FNABs were compared with the biopsy diagnosis as the gold standard. All the cases of FNAB were analyzed by a single oral pathologist prior to the biopsy diagnosis. The results showed that the sensitivity of FNAB was 75%, its specificity was 96% and its accuracy was 58.8%. The false positive and false negative rates were 6.7% and 13.3%, respectively. The positive predictive value was 86% and the negative predictive value was 93%. The inconclusive rate was 16/50. FNAB displayed a high success rate for identifying both malignant and benign lesions, but a low accuracy for making a final diagnosis. PMID- 21537647 TI - Guidelines: necessary. . . but applicable? PMID- 21537648 TI - Is systemic sclerosis interstitial lung disease slowly progressive? PMID- 21537649 TI - Systemic sclerosis-associated interstitial pneumonia: evaluation of pulmonary function over a five-year period. AB - OBJECTIVE: To evaluate alterations in pulmonary function in patients with systemic sclerosis-associated interstitial pneumonia over a five-year period. METHODS: This was a longitudinal study involving 35 nonsmoking patients with systemic sclerosis and without a history of lung disease. At the first evaluation, performed at the time of the diagnosis of interstitial pneumonia, the patients were submitted to HRCT, spirometry, and measurement of DLCO. The patients were subdivided into two groups by the presence or absence of honeycombing on the HRCT scans. Approximately five years after the first evaluation, the patients were submitted to spirometry and measurement of DLCO only. RESULTS: Of the 35 patients, 34 were women. The mean age was 47.6 years. The mean time between the two evaluations was 60.9 months. Honeycombing was detected on the HRCT scans in 17 patients. In the sample as a whole, five years after the diagnosis, FVC, FEV1 and DLCO significantly decreased (81.3 +/- 18.2% vs. 72.1 +/- 22.2%; 79.9 +/- 17.8% vs. 72.5 +/- 20.6%; and 74.0 +/- 20.5% vs. 60.7 +/- 26.8%, respectively; p = 0.0001 for all), and the FEV1/FVC ratio significantly increased (98.5 +/- 7.2% vs. 101.9 +/- 7.8%; p = 0.008). In the same period, FVC, FEV1, and DLCO values were significantly lower in the patients with honeycombing on the HRCT scans than in those without (p = 0.0001). CONCLUSIONS: In systemic sclerosis-associated interstitial lung disease, the detection of honeycombing on HRCT is crucial to predicting accelerated worsening of pulmonary function. PMID- 21537650 TI - Implementation of community-acquired pneumonia guidelines at a public hospital in Brazil. AB - OBJECTIVE: To implement community-acquired pneumonia (CAP) guidelines at a public hospital in Brazil and to evaluate the impact of these guidelines on health care quality. METHODS: A quasi-experimental study, with a before-and-after design, involving adult patients diagnosed with CAP and hospitalized between July of 2007 and October of 2008 in the general ward of the Marilia School of Medicine Hospital das Clinicas, located in the city of Marilia, Brazil. RESULTS: During the study period, 68 patients were diagnosed with CAP: 48 before the implementation of the guidelines and 20 after their implementation. After the implementation of the guidelines, 85% of the cases were treated in accordance with the guidelines, and there was a significant increase in the use of antibiotic therapy for atypical bacteria in patients with severe CAP (6.3% vs. 75.0%; p < 0.001). Comparing the pre-implementation and post-implementation periods, we observed a trend toward a decrease in the mortality (35.4% vs. 15.0%; p = 0.09) and toward an increase in the recording of SpO2 in the medical charts of the patients (18% vs. 30%; p = 0.42). During the study period, the degree of severity was not recorded on the medical charts of most patients. In addition, the initiation of antibiotic therapy followed a pre-established schedule, regardless of the severity of the infection. CONCLUSIONS: This study showed that, although the development and implementation of CAP guidelines promoted the optimization of the treatment, there were no significant differences regarding the assessment of severity, SpO2 recording, or the initiation of antibiotic therapy. Therefore, strategies that are more effective are needed in order to modify variables related to the work of physicians and nurses. PMID- 21537651 TI - Venous thromboembolism prophylaxis in a general hospital. AB - OBJECTIVE: To evaluate the use of venous thromboembolism (VTE) prophylaxis in a general hospital. METHODS: A cross-sectional cohort study at the Hospital Nossa Senhora da Conceicao, located in the city of Porto Alegre, Brazil, involving a random sample of patients admitted between October of 2008 and February of 2009. We included patients over 18 years of age and hospitalized for more than 48 h. The exclusion criteria were anticoagulant use, pregnancy, puerperium, and a history of thromboembolic disease. The adequacy of prophylaxis was evaluated in accordance with a protocol created by the Hospital and principally based on the American College of Chest Physicians guidelines, eighth edition. RESULTS: We included 262 patients. The mean age was 59.1 +/- 16.6 years. The most common risk factors were immobilization (in 70.6%), infection (in 44.3%), cancer (in 27.5%), obesity (in 23.3%), and major surgery (in 14.1%). The risk of VTE was classified as high and moderate in 143 (54.6%) and 117 (44.7%) of the patients, respectively. Overall, 46.2% of the patients received adequate prophylaxis, 25% of those with > three risk factors for VTE and 18% of those with cancer, the differences between these last two groups and their counterparts (patients with < three risk factors and those without cancer) being statistically significant (p < 0.001 for both). CONCLUSIONS: Our data reveal that nearly all patients at our hospital were at risk for VTE, and that less than half received adequate VTE prophylaxis, which is in agreement with the literature. It is surprising that inadequate prophylaxis is more common in high-risk patients. PMID- 21537652 TI - Evaluation of the use of transbronchial biopsy in patients with clinical suspicion of interstitial lung disease. AB - OBJECTIVE: To study the clinical, radiological, and histopathological patterns of transbronchial biopsy (TBB) used in order to confirm the diagnosis in patients with clinical suspicion of interstitial lung disease (ILD) treated at a tertiary care university hospital. METHODS: We reviewed the medical records, radiology reports, and reports of transbronchial biopsies from all patients with suspected ILD who underwent TBB between January of 1999 and December of 2006 at the Hospital das Clinicas de Botucatu, located in the city of Botucatu, Brazil. RESULTS: The study included 56 patients. Of those, 11 (19.6%) had a definitive diagnosis of idiopathic pulmonary fibrosis (IPF), the rate of which was significantly higher in the patients in which ILD was a possible diagnosis in comparison with those in which ILD was the prime suspect (p = 0.011), demonstrating the contribution of TBB to the diagnostic confirmation of these diseases. The histopathological examination of the biopsies revealed that 27.3% of the patients with IPF showed a pattern of organizing pneumonia, which suggests greater disease severity. The most common histological pattern was the indeterminate pattern, reflecting the peripheral characteristic of IPF. However, the fibrosis pattern showed high specificity and high negative predictive value. For CT scan patterns suggestive of IPF, the ROC curve showed that the best relationship between sensitivity and specificity occurred when five radiological alterations were present. Honeycombing was found to be strongly suggestive of IPF (p = 0.01). CONCLUSIONS: For ILDs, chest CT should always be performed, and TBB should be used in specific situations, according to the suspicion and distribution of lesions. PMID- 21537653 TI - Symptoms of dysphagia in patients with COPD. AB - OBJECTIVE: To identify symptoms of dysphagia in individuals with COPD, based on their responses on a self-perception questionnaire. METHODS: The study comprised 35 individuals with COPD and 35 healthy individuals, matched for age and gender. The study group was assessed regarding COPD severity; sensation of dyspnea; body mass index (BMI); and symptoms of dysphagia. The control group was assessed regarding BMI and symptoms of dysphagia. RESULTS: The most common symptoms of dysphagia in the study group were pharyngeal symptoms/airway protection (p < 0.001); esophageal symptoms/history of pneumonia (p < 0.001); and nutritional symptoms (p < 0.001). Positive correlations were found between the following pairs of variables: FEV1 and BMI (r = 0.567; p < 0.001); pharyngeal symptoms/airway protection and dyspnea (r = 0.408; p = 0.015); and esophageal symptoms/history of pneumonia and pharyngeal symptoms/airway protection (r = 0.531; p = 0.001). There was a negative correlation between nutritional symptoms and BMI (r = -0.046; p < 0.008). CONCLUSIONS: Our results show that the individuals with COPD presented with symptoms of dysphagia that were associated with the pharyngeal and esophageal phases of swallowing, as well as with the mechanism of airway protection, a history of pneumonia, and nutritional symptoms. PMID- 21537655 TI - Respiratory muscle strength: comparison between primigravidae and nulligravidae. AB - OBJECTIVE: To describe and to compare MIP and MEP in primigravidae and nulligravidae in the 20-29 year age bracket and paired by age. METHODS: We included 120 primigravidae with low obstetric risk (5th-40th week of gestation) and 40 nulligravidae. All of the participants were of normal weight and none exercised regularly. All were recruited from the metropolitan area of Recife, Brazil. Measurements of MIP and MEP were obtained from RV and TLC, respectively, with a digital manometer. We used Student's t-test to compare the two groups, and we used multiple linear regression in order to determine whether group or chronological age correlated with MIP or MEP. RESULTS: In the primigravida and nulligravida groups, the mean MIP values were 88.50 +/- 16.52 cmH2O and 94.22 +/- 22.63 cmH2O, respectively, (p = 0.08), whereas the mean MEP values were 99.76 +/ 18.19 cmH2O and 98.67 +/- 20.78 cmH2O (p = 0.75). Gestational age did not correlate with MIP (r = -0.06; p = 0.49) or MEP (r = -0.11; p = 0.22). The relationship between chronological age and MIP/MEP did not differ between primigravidae and nulligravidae (angular coefficient = 0.028 and 0.453, respectively). CONCLUSIONS: Within this sample of women in the 20-29 year age bracket, the respiratory pressures of primigravidae remained stable during pregnancy and did not differ significantly from those of nulligravidae. PMID- 21537654 TI - Quality of life assessment in patients with cystic fibrosis by means of the Cystic Fibrosis Questionnaire. AB - OBJECTIVE: To assess the quality of life (QoL) of patients with cystic fibrosis (CF) followed at a university referral center for CF. METHODS: A cross-sectional study involving application of the Cystic Fibrosis Questionnaire (CFQ) and Shwachman score in CF patients between April of 2008 and June of 2009. RESULTS: The sample consisted of 75 patients. The mean age was 12.5 +/- 5.1 years (range, 6.1-26.4 years). The patients were divided into three groups by age in years: group I (< 12), II (12-14), and III (> 14). The highest and lowest CFQ scores were for the nutrition domain in group III (89.3 +/- 16.2) and the social domain in group II (59.5 +/- 22.3), respectively. Groups I and III differed significantly regarding the treatment domain (p = 0.001). Regarding Shwachman scores, there were significant differences between patients scoring < 70 and those scoring > 70 in the social (group I; p = 0.045), respiratory (group II; p = 0.053), and digestive (p = 0.042) domains. In group III, severity did not correlate with QoL. In groups I and II, patients with an FEV1 < 80% of predicted did not differ from other patients for any CFQ domain. However, in group III, values for the following domains were significantly lower in patients with an FEV1 < 80%: physical (p = 0.012); body image (p = 0.031); respiratory (p = 0.023), emotional (p = 0.041); and social role (p = 0.024). CONCLUSIONS: It is important to assess QoL in CF patients, because it can improve treatment compliance. PMID- 21537656 TI - Clinical, epidemiological, and etiological profile of inpatients with community acquired pneumonia at a general hospital in the Sumare microregion of Brazil. AB - OBJECTIVE: To analyze the clinical, etiological, and epidemiological aspects of community-acquired pneumonia (CAP) in hospitalized individuals. METHODS: We prospectively studied 66 patients (> 14 years of age) with CAP admitted to the Hospital Estadual Sumare, located in the Sumare microregion of Brazil, between October of 2005 and September of 2007. We collected data related to clinical history, physical examination, pneumonia severity index (PSI) scores, and laboratory tests (blood culture; sputum smear microscopy and culture; serology for Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila; and detection of Legionella sp. and Streptococcus pneumoniae antigens in urine). RESULTS: The mean age of patients was 53 years. Most had a low level of education, and 55.7% presented with at least one comorbidity at the time of hospitalization. The proportion of elderly people vaccinated against influenza was significantly lower among the inpatients than in the general population of the Sumare microregion (52.6% vs. > 70%). Fever was less common among the elderly patients (p < 0.05). The clinical evolution was associated with the PSI scores but not with age. The etiology was confirmed in 31 cases (50.8%) and was attributed to S. pneumoniae, principally detected by the urinary antigen test, in 21 (34.4%), followed by C. pneumoniae, in 5 (8.2%). The mortality rate was 4.9%, and 80.3% of the patients were classified as cured at discharge. CONCLUSIONS: The knowledge of the etiologic profile of CAP at the regional level favors the appropriate choice of empirical treatment, which is particularly relevant in elderly patients and in those with comorbidities. The lack of influenza vaccination in elderly patients is a risk factor for hospitalization due to CAP. PMID- 21537657 TI - Results and complications of CT-guided transthoracic fine-needle aspiration biopsy of pulmonary lesions. AB - OBJECTIVE: To analyze the cytological findings of CT-guided percutaneous fine needle aspiration biopsies of the lung, to demonstrate the diagnostic feasibility of the method in the investigation of pulmonary lesions, and to determine the complications of the procedure, evaluating its safety. METHODS: A retrospective analysis of 89 patients with various types of pulmonary lesions who underwent 97 procedures over a period of five years. The patients were divided into groups regarding the indication for the procedure: suspicion of primary lung cancer (stages IIIB or IV); suspicion of lung cancer (stages I, II, or IIIA) and clinical contraindications for surgery; suspicion of pulmonary metastasis from other organs; and pulmonary lesions with benign radiological aspect. All of the procedures were performed with 25-gauge needles and were guided by spiral CT. The final diagnosis was confirmed by surgical biopsy and clinical/oncological follow up. For the analysis of complications, the total number of procedures was considered. RESULTS: The main indication for the procedure was suspicion of advanced-stage primary lung cancer. The accuracy of the method for malignant lesions was 91.5%. The lesion was confirmed as cancer in 73% of the patients. The major complication was pneumothorax (27.8%), which required chest tube drainage in 12.4% of the procedures. CONCLUSIONS: The principal indication for CT-guided fine-needle biopsy was suspicion of primary lung cancer in patients who were not surgical candidates. The procedure has high diagnostic feasibility for malignant pulmonary diseases. The most prevalent complication was pneumothorax. However, in most cases, chest tube drainage was unnecessary. No deaths were related to the procedure. PMID- 21537658 TI - Characteristics of COPD patients admitted to the ICU of a referral hospital for respiratory diseases in Brazil. AB - OBJECTIVE: To report data regarding COPD patients admitted to the ICU of a referral hospital for respiratory diseases, including outcomes and treatment evaluation. METHODS: Study of a series of patients with respiratory failure and COPD admitted to the ICU of Nereu Ramos Hospital, located in the city of Florianopolis, Brazil, between October of 2006 and October of 2007. Data related to demographics, causes of hospitalization, pharmacological treatment, ventilatory support, length of hospital stay, in-hospital complications, ICU mortality, and 28-day mortality were obtained from the medical charts of the patients. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated. Mortality at 18 months was assessed by subsequent telephone calls. RESULTS: During the study period, 192 patients were admitted to the ICU, 24 (12.5%) of whom were diagnosed with respiratory failure and COPD. The mean length of ICU stay was 12.0 +/- 11.1 days. Noninvasive ventilation was used in 10 of the 24 patients (41.66%) and failed in 5 of those 10. Invasive mechanical ventilation (IMV) was used in a total of 15 patients (62.5%). Overall ICU mortality and 28-day mortality were 20.83% and 33.33%, respectively. However, 18 month mortality was 62.5%. CONCLUSIONS: Respiratory failure associated with COPD was responsible for 12.5% of the ICU admissions. Orotracheal intubation and IMV were necessary in 62.5% of the cases. The ICU mortality rate was in accordance with that predicted by the APACHE II scores. However, late mortality was high. PMID- 21537660 TI - Tuberculous pneumonia: a study of 59 microbiologically confirmed cases. AB - OBJECTIVE: To study the clinical, epidemiological, radiographic and endoscopic features of individuals with tuberculous pneumonia. METHODS: We evaluated 2,828 consecutive tuberculosis patients treated at a public health center between December of 2005 and February of 2007. Of those, 59 (2.1%) had pulmonary involvement consistent with fistula between a lymph node and a bronchus. RESULTS: Of the 59 patients studied, 43 (73%) were between 20 and 50 years of age, 31 (53%) were male, and 28 (47%) were Black. The most common symptoms were cough (in 100%), fever (in 88%), expectoration (in 81%), and weight loss (in 40%). Comorbidities were reported in 35 cases (59%), the most common being HIV infection (in 20%) and diabetes (in 15%). On chest X-rays, consolidation was observed, predominantly in the upper lobes (in 68%). The diagnostic confirmation (identification of AFB) was made through the sputum smear microscopy in the majority of the cases and by bronchoscopy (BAL examination or bronchial biopsy) in the remainder. Bronchial lesions were clearly indicative or suggestive of fistula in three cases and five cases, respectively. CONCLUSIONS: Tuberculous pneumonia presents as acute respiratory infection, initiating with a dry cough that is followed by fever. Chest X-rays show alveolar consolidation. In most cases, tuberculous pneumonia was accompanied by at least one comorbid condition, the most common being HIV infection, and the etiological diagnosis was made through sputum smear microscopy for AFB. Bronchoscopy findings were indicative of bronchial fistula in eight cases (13%). PMID- 21537659 TI - Compliance with tuberculosis treatment after the implementation of the directly observed treatment, short-course strategy in the city of Carapicuiba, Brazil. AB - OBJECTIVE: To determine the compliance with tuberculosis treatment among patients enrolled the tuberculosis control program in the city of Carapicuiba, Brazil, before and after the implementation of the directly observed treatment, short course (DOTS) strategy. METHODS: A retrospective historical cohort study of operational aspects based on records of attendance and treatment evolution of patients in self-administered treatment (SAT) and of those submitted to DOTS. Monthly treatment outcome tables were created, and the probability of compliance with the treatment was calculated for both groups of patients. RESULTS: A total of 360 patients with tuberculosis met the inclusion criteria: 173 (48.1%) in the SAT group; and 187 (51.9%) in the DOTS group. Treatment compliance was 6.1% higher in the DOTS group than in the SAT group. The proportion of patients completing the six months of treatment was 91.6% and 85.5% in the DOTS group and in the SAT group, respectively. CONCLUSIONS: The results of this study show that DOTS can be successfully implemented at primary health care clinics. In this population of patients, residents of a city with low incomes and a high burden of tuberculosis infection, DOTS was more effective than was SAT. PMID- 21537661 TI - Suspension laryngoscopy for the thoracic surgeon: when and how to use it. AB - Suspension laryngoscopy is one of the most common otolaryngological procedures for the diagnosis and surgical approach to the larynx. However, most thoracic surgeons are not familiar with the procedure and seldom use it. The indications for its use are similar to those for that of rigid bronchoscopy (dilatation, endoprosthesis insertion, and tumor resection). It can be performed in children and adults. Suspension laryngoscopy is an alternative when rigid bronchoscopy is unavailable and is therefore a viable option for use at smaller facilities. In this communication, we describe the technique and the applications of suspension laryngoscopy in thoracic surgery. PMID- 21537662 TI - Magnetic resonance imaging of the chest: current and new applications, with an emphasis on pulmonology. AB - The objective of the present review study was to present the principal applications of magnetic resonance imaging (MRI) of the chest, including the description of new techniques. Over the past decade, this method has evolved considerably because of the development of new equipment, including the simultaneous interconnection of phased-array multiple radiofrequency receiver coils and remote control of the table movement, in addition to faster techniques of image acquisition, such as parallel imaging and partial Fourier acquisitions, as well as the introduction of new contrast agents. All of these advances have allowed MRI to gain ground in the study of various pathologies of the chest, including lung diseases. Currently, MRI is considered the modality of choice for the evaluation of lesions in the mediastinum and in the chest wall, as well as of superior sulcus tumors. However, it can also facilitate the diagnosis of lung, pleural, and cardiac diseases, as well as of those related to the pulmonary vasculature. Pulmonary MRI angiography can be used in order to evaluate various pulmonary vascular diseases, and it has played an ever greater role in the study of thromboembolism. Because cardiac MRI allows morphological and functional assessment in the same test, it has also become part of the clinical routine in the evaluation of various cardiac diseases. Finally, the role of MRI has been extended to the identification and characterization of pulmonary nodules, the evaluation of airway diseases, and the characterization of pleural effusion. PMID- 21537663 TI - Congenital lung malformations. AB - Congenital lung malformations are rare and vary widely in their clinical presentation and severity, depending mostly on the degree of lung involvement and their location in the thoracic cavity. They can manifest at any age and can be the source of significant morbidity and mortality in infants and children. Individuals with congenital lung malformations can present with respiratory symptoms at birth or can remain asymptomatic for long periods. Recently, there has been an increase in the early diagnosis of these malformations, a change that is attributable to the routine use of prenatal ultrasound. The clinical manifestation of these malformations varies from respiratory distress in the immediate postnatal period to an incidental finding on chest X-rays. Early diagnosis and prompt treatment offer the possibility of absolutely normal lung development. The treatment of asymptomatic patients with lung malformations is controversial, because the prognosis of these diseases is unpredictable. The management of these lesions depends on the type of malformation and symptoms. Because of the risk of complications, most authors recommend resection of the lesion at the time of diagnosis. Lobectomy is the procedure of choice and yields excellent long-term results. This article describes the principal congenital lung malformations, their diagnosis, and the controversies regarding treatment. PMID- 21537664 TI - Treatment of schistosomiasis-associated pulmonary hypertension. AB - Schistosomiasis mansoni is the third most prevalent endemic parasitic disease in the world. It is estimated that over 200 million people are infected with parasites belonging to one of the Schistosoma species. Of those, 270,000 people (4.6%) suffer from pulmonary arterial hypertension, which is associated with the hepatosplenic form of the disease. This high prevalence makes schistosomiasis associated pulmonary hypertension the leading cause of pulmonary hypertension worldwide. However, no specific treatment for the pulmonary vascular component of the disease has yet been devised. We report the case of a patient with schistosomiasis-associated pulmonary hypertension who was treated satisfactorily with a phosphodiesterase-5 inhibitor (sildenafil). PMID- 21537665 TI - Hemoptysis in a patient with testicular microlithiasis and a germ cell tumor: a rare combination. PMID- 21537666 TI - Environmental assessment of an asthma education program: relationship between airborne fungi and IgE levels in children and adults. PMID- 21537668 TI - Antimicrobial resistance profiles and genetic characterisation of macrolide resistant isolates of Streptococcus agalactiae. AB - In this study, 100 clinical isolates of Streptococcus agalactiae recovered from genitourinary tract specimens of non-pregnant individuals living in Rio de Janeiro were submitted for antimicrobial susceptibility testing, detection of macrolide resistance genes and evaluation of the genetic diversity of erythromycin-resistant isolates. By agar diffusion method, all isolates were susceptible to ceftazidime, penicillin and vancomycin. Isolates were resistant to levofloxacin (1%), clindamycin (5%), erythromycin (11%) and tetracycline (83%) and were intermediated to erythromycin (4%) and tetracycline (6%). Erythromycin resistant and intermediated isolates presented the following phenotypes: M (n = 3), constitutive macrolide-lincosamide-streptogramin B (MLS B, n = 5) and inductive MLS B (n = 7). Determinants of macrolide resistance genes, erm and mef, were detected in isolates presenting MLS B and M phenotypes, respectively. Randomly amplified polymorphic DNA profiles of erythromycin-resistant isolates were clustered into two major groups of similarity. PMID- 21537670 TI - New insights into trypanosomatid U5 small nuclear ribonucleoproteins. AB - Several protozoan parasites exist in the Trypanosomatidae family, including various agents of human diseases. Multiple lines of evidence suggest that important differences are present between the translational and mRNA processing (trans splicing) systems of trypanosomatids and other eukaryotes. In this context, certain small complexes of RNA and protein, which are named small nuclear ribonucleoproteins (U snRNPs), have an essential role in pre-mRNA processing, mainly during splicing. Even though they are well defined in mammals, snRNPs are still not well characterized in trypanosomatids. This study shows that a U5-15K protein is highly conserved among various trypanosomatid species. Tandem affinity pull-down assays revealed that this protein interacts with a novel U5 102K protein, which suggests the presence of a sub-complex that is potentially involved in the assembly of U4/U6-U5 tri-snRNPs. Functional analyses showed that U5-15K is essential for cell viability and is somehow involved with the trans and cis splicing machinery. Similar tandem affinity experiments with a trypanonosomatid U5-Cwc21 protein led to the purification of four U5 snRNP specific proteins and a Sm core, suggesting U5-Cwc-21 participation in the 35S U5 snRNP particle. Of these proteins, U5-200K was molecularly characterized. U5-200K has conserved domains, such as the DEAD/DEAH box helicase and Sec63 domains and displays a strong interaction with U5 snRNA. PMID- 21537669 TI - Malaria seroprevalence in blood bank donors from endemic and non-endemic areas of Venezuela. AB - In Venezuela, a total of 363,466 malaria cases were reported between 1999-2009. Several states are experiencing malaria epidemics, increasing the risk of vector and possibly transfusion transmission. We investigated the risk of transfusion transmission in blood banks from endemic and non-endemic areas of Venezuela by examining blood donations for evidence of malaria infection. For this, commercial kits were used to detect both malaria-specific antibodies (all species) and malaria antigen (Plasmodium falciparum only) in samples from Venezuelan blood donors (n = 762). All samples were further studied by microscopy and polymerase chain reaction (PCR). The antibody results showed that P. falciparum-infected patients had a lower sample/cut-off ratio than Plasmodium vivax-infected patients. Conversely, a higher ratio for antigen was observed among all P. falciparum-infected individuals. Sensitivity and specificity were higher for malarial antigens (100 and 99.8%) than for antibodies (82.2 and 97.4%). Antibody positive donors were observed in Caracas, Ciudad Bolivar, Puerto Ayacucho and Cumana, with prevalences of 1.02, 1.60, 3.23 and 3.63%, respectively. No PCR positive samples were observed among the donors. However, our results show significant levels of seropositivity in blood donors, suggesting that more effective measures are required to ensure that transfusion transmission does not occur. PMID- 21537671 TI - Detection of rifampin-resistant genotypes in Mycobacterium tuberculosis by reverse hybridization assay. AB - We used a colorimetric reverse dot blot hybridization (CRDH) assay to detect the presence of mutations in a specific region of the rpoB gene, associated with rifampin (RIF) resistance, in a panel of 156 DNAs extracted from 103 RIF sensitive and 53 RIF-resistant cultures of Mycobacterium tuberculosis. When compared with the antimicrobial susceptibility test (AST), the sensitivity and specificity of the CRDH were 92.3% and 98.1%, respectively. When compared with sequencing, the sensitivity and specificity of the CRDH were 90.6% and 100%, respectively. To evaluate the performance of the assay directly in clinical specimens, 30 samples from tuberculosis patients were used. For these samples, the results of the CRDH were 100% consistent with the results of the AST and sequencing. These results indicate that the rate of concordance of the CRDH is high when compared to conventional methods and sequencing data. The CRDH can be successfully applied when a rapid test is required for the identification of RIF resistance in M. tuberculosis. PMID- 21537672 TI - The ability of haemolysins expressed by atypical enteropathogenic Escherichia coli to bind to extracellular matrix components. AB - Typical and atypical enteropathogenic Escherichia coli (EPEC) are considered important bacterial causes of diarrhoea. Considering the repertoire of virulence genes, atypical EPEC (aEPEC) is a heterogeneous group, harbouring genes that are found in other diarrheagenic E. coli pathotypes, such as those encoding haemolysins. Haemolysins are cytolytic toxins that lyse host cells disrupting the function of the plasma membrane. In addition, these cytolysins mediate a connection to vascular tissue and/or blood components, such as plasma and cellular fibronectin. Therefore, we investigated the haemolytic activity of 72 aEPEC isolates and determined the correlation of this phenotype with the presence of genes encoding enterohaemolysins (Ehly) and cytolysin A (ClyA). In addition, the correlation between the expression of haemolysins and the ability of these secreted proteins to adhere to extracellular matrix (ECM) components was also assessed in this study. Our findings demonstrate that a subset of aEPEC presents haemolytic activity due to the expression of Ehlys and/or ClyA and that this activity is closely related to the ability of these isolates to bind to ECM components. PMID- 21537673 TI - Schistosoma mansoni: a method for inducing resistance to praziquantel using infected Biomphalaria glabrata snails. AB - To elucidate the mechanisms of antischistosoma resistance, drug-resistant Schistosoma mansoni laboratory isolates are essential. We developed a new method for inducing resistance to praziquantel (PZQ) using successive drug treatments of Biomphalaria glabrata snails infected with S. mansoni. Infected B. glabrata were treated three times with 100 mg/kg PZQ for five consecutive days with a one-week interval between them. After the treatment, the cercariae (LE-PZQ) produced from these snails and the LE strains (susceptible) were used to infect mice. Forty five days after infection, mice were treated with 200, 400 or 800 mg/kg PZQ. Thirty days post-treatment, we observed that the mean number of worms recovered by perfusion was significantly higher in the group of mice infected with the LE PZQ isolate treated with 200 and 400 mg/kg in comparison to the LE strain with the same treatment. Moreover, there was a significant difference between the ED50 (effective dose required to kill 50% of the worms) of the LE-PZQ isolate (362 mg/kg) and the LE strain (68 mg/kg). In the in vitro assays, the worms of the LE PZQ isolate were also less susceptible to PZQ. Thus, the use of infected snails as an experimental model for development of resistance to S. mansoni is effective, fast, simple and cheap. PMID- 21537674 TI - Studying nanotoxic effects of CdTe quantum dots in Trypanosoma cruzi. AB - Semiconductor nanoparticles, such as quantum dots (QDs), were used to carry out experiments in vivo and ex vivo with Trypanosoma cruzi. However, questions have been raised regarding the nanotoxicity of QDs in living cells, microorganisms, tissues and whole animals. The objective of this paper was to conduct a QD nanotoxicity study on living T. cruzi protozoa using analytical methods. This was accomplished using in vitro experiments to test the interference of the QDs on parasite development, morphology and viability. Our results show that after 72 h, a 200 MUM cadmium telluride (CdTe) QD solution induced important morphological alterations in T. cruzi, such as DNA damage, plasma membrane blebbing and mitochondrial swelling. Flow cytometry assays showed no damage to the plasma membrane when incubated with 200 MUM CdTe QDs for up to 72 h (propidium iodide cells), giving no evidence of classical necrosis. Parasites incubated with 2 MUM CdTe QDs still proliferated after seven days. In summary, a low concentration of CdTe QDs (2 MUM) is optimal for bioimaging, whereas a high concentration (200 MUM CdTe) could be toxic to cells. Taken together, our data indicate that 2 MUM QD can be used for the successful long-term study of the parasite-vector interaction in real time. PMID- 21537676 TI - Descriptive ecology of bat flies (Diptera: Hippoboscoidea) associated with vampire bats (Chiroptera: Phyllostomidae) in the cerrado of Central Brazil. AB - We studied the ectoparasitic bat flies of three phyllostomid vampire bat species. Bats were collected monthly from April 2004-March 2005 in caves within the Cafuringa Environmental Protection Area in the Federal District of Brazil. A total of 1,259 specimens from six species in the Streblidae family were collected from 332 bats. High host affinity from the sampled bat fly species and high prevalence of bat flies confirms the primary fly-host associations (Strebla wiedemanni, Trichobius parasiticus and Trichobius furmani with Desmodus, Trichobius diaemi and Strebla diaemi with Diaemus and T. furmani with Diphylla). Male flies outnumbered females in several associations. Some of the observed associations (e.g., Strebla mirabilis with Desmodus and S. mirabilis, Trichobius uniformis and S. wiedemanni with Diphylla) were inconclusive and the causes of the associations were unclear. There are several explanations for these associations, including (i) accidental contamination during sampling, (ii) simultaneous capture of several host species in the same net or (iii) genuine, but rare, ecological associations. Although various species of vampire bats share roosts, have similar feeding habits and are close phylogenetic relatives, they generally do not share ectoparasitic streblid bat flies. T. diaemi and S. diaemi associations with Diaemus youngi have not been previously reported in this region. PMID- 21537675 TI - Correlation between koilocytes and human papillomavirus detection by PCR in oral and oropharynx squamous cell carcinoma biopsies. AB - The purpose of this study was to compare the histopathological analysis with polymerase chain reaction (PCR) methods to predict the presence of human papillomavirus (HPV) infection in oral squamous cell carcinoma biopsies. Eighty three paraffin-embedded tissue specimens from patients with oropharynx and mouth floor squamous cell carcinoma were submitted to histopathological analysis under light microscopy, specifically for the determination of the presence of koilocytes. Subsequently, DNA was purified from the same paraffin-embedded specimens and submitted to PCR. Fisher's exact test showed no statistically significant correlation between the two methods. The results suggest that the presence of koilocytes is unreliable for the detection of HPV presence in oral and oropharynx squamous cell carcinoma. PMID- 21537677 TI - The impact of the nelfinavir resistance-conferring mutation D30N on the susceptibility of HIV-1 subtype B to other protease inhibitors. AB - The human immunodeficiency virus type 1 (HIV-1) protease mutation D30N is exclusively selected by the protease inhibitor (PI) nelfinavir and confers resistance to this drug. We demonstrate that D30N increases the susceptibility to saquinavir (SQV) and amprenavir in HIV-1 subtype B isolates and that the N88D mutation in a D30N background neutralizes this effect. D30N also suppresses indinavir (IDV) resistance caused by the M46I mutation. Interestingly, in patients with viruses originally containing the D30N mutation who were treated with IDV or SQV, the virus either reversed this mutation or acquired N88D, suggesting an antagonistic effect of D30N upon exposure to these PIs. These findings can improve direct salvage drug treatment in resource limited countries where subtype B is epidemiologically important and extend the value of first and second line PIs in these populations. PMID- 21537678 TI - An experimental protocol for the establishment of dogs with long-term cellular immune reactions to Leishmania antigens. AB - Domestic dogs are considered to be the main reservoirs of zoonotic visceral leishmaniasis. In this work, we evaluated a protocol to induce Leishmania infantum/Leishmania chagasi-specific cellular and humoral immune responses in dogs, which consisted of two injections of Leishmania promastigote lysate followed by a subcutaneous inoculation of viable promastigotes. The primary objective was to establish a canine experimental model to provide positive controls for testing immune responses to Leishmania in laboratory conditions. After inoculation of viable promastigotes, specific proliferative responses of peripheral blood mononuclear cells (PBMCs) to either Leishmania lysate or recombinant proteins, the in vitro production of interferon-gamma by antigen stimulated PBMCs and a significant increase in circulating levels of anti Leishmania antibodies were observed. The immunized dogs also displayed positive delayed-type hypersensitivity reactions to Leishmania crude antigens and to purified recombinant proteins. An important finding that supports the suitability of the dogs as positive controls is that they remained healthy for the entire observation period, i.e., more than seven years after infection. Following the Leishmania antigen lysate injections, the infection of dogs by the subcutaneous route appears to induce a sustained cellular immune response, leading to an asymptomatic infection. This provides a useful model for both the selection of immunogenic Leishmania antigens and for immunobiological studies on their possible immunoprotective activities. PMID- 21537679 TI - Correlation of meta 1 expression with culture stage, cell morphology and infectivity in Leishmania (Leishmania) amazonensis promastigotes. AB - The parasitic protozoan Leishmania (Leishmania) amazonensis alternates between mammalian and insect hosts. In the insect host, the parasites proliferate as procyclic promastigotes and then differentiate into metacyclic infective forms. The meta 1 gene is preferentially expressed during metacyclogenesis. Meta 1 expression profile determination along parasite growth curves revealed that the meta 1 mRNA level peaked at the early stationary phase then decreased to an intermediate level. No correlation was observed between meta 1 expression and infectivity. Conversely, infectivity correlated with the increase of apoptotic cells in the late stationary phase. PMID- 21537680 TI - Colorimetric microwell plate reverse-hybridization assay for Mycobacterium tuberculosis detection. AB - Direct smear examination using Ziehl-Neelsen staining for pulmonary tuberculosis (PTB) diagnosis is inexpensive and easy to use, but has the major limitation of low sensitivity. Rapid molecular methods are becoming more widely available in centralized laboratories, but they depend on timely reporting of results and strict quality assurance obtainable only from costly commercial kits available in high burden nations. This study describes a pre-commercial colorimetric method, Detect-TB, for detecting Mycobacterium tuberculosis DNA in which an oligonucleotide probe is fixed onto wells of microwell plates and hybridized with biotinylated polymerase chain reaction amplification products derived from clinical samples. The probe is capable of hybridising with the IS6110 insertion element and was used to specifically recognise the M. tuberculosis complex. When combined with an improved silica-based DNA extraction method, the sensitivity of the test was 50 colony-forming units of the M. tuberculosis reference strain H37Rv. The results that were in agreement with reference detection methods were observed in 95.2% (453/476) of samples included in the analysis. Sensitivity and specificity for 301 induced sputum samples and 175 spontaneous sputum samples were 85% and 98%, and 94% and 100%, respectively. This colorimetric method showed similar specificity to that described for commercially available kits and may provide an important contribution for PTB diagnosis. PMID- 21537681 TI - Identification of candidate antigens from adult stages of Toxocara canis for the serodiagnosis of human toxocariasis. AB - In the present work, we identified adult Toxocara canis antigens through sodium dodecyl sulfate-polyacrylamide gel electrophoresis for potential use in human toxocariasis immunodiagnosis. The sensitivity and specificity of several semi purified antigens, as well as their cross-reactivity with other parasitic infections, were assessed by IgM and IgG-enzime linked immunosorbent assay. Whilst we found that the crude extract of the parasite presented limited sensitivity, specificity and high cross-reactivity against other parasites, we identified 42, 58, 68 and 97-kDa semi-purified antigens as the most promising candidates for immunodiagnosis. Moreover, the 58 and 68-kDa antigens presented the lowest IgM cross-reactivity. When tested as a combination, a mixture of the 58 and 68-kDa antigens presented 100% sensitivity and specificity, as well as minor cross-reactivity. Although the combination of the 42, 58, 68 and 97-kDa antigens presented 100% sensitivity at a dilution of 1:40, the low specificity and high cross-reactivity observed suggested a limited use for diagnostic purposes. Our data suggested that the 58 and 68-kDa antigens might be most suitable for the immunodiagnosis of human toxocariasis. PMID- 21537682 TI - Leishmania infection in humans, dogs and sandflies in a visceral leishmaniasis endemic area in Maranhao, Brazil. AB - Leishmania infection in humans, dogs and sandflies was examined in the endemic visceral leishmaniasis (VL) municipality of Raposa, state of Maranhao, Brazil. In this study, we examined Leishmania chagasi infection in the blood serum of both humans and Canis familiaris and the natural Leishmania sp. infection rate in the sandfly vector, Lutzomyia longipalpis. Enzyme-linked immunosorbent assay, indirect immunofluorescence reaction and polymerase chain reaction were performed to detect Leishmania infections in humans, dogs and sandflies, respectively. Overall, 186 out of 986 studied human beings were infected with L. chagasi parasites, representing an infection prevalence of 18.9%. An even higher infection rate was detected in dogs, where 66 (47.8%) out of 138 were infected. Among all Lu. longipalpis captured (n = 1,881), only 26.7% were females. The Leishmania infection frequency for the vector Lu. longipalpis was 1.56%. Remarkably, all infected sandflies were found in the peridomiciliary area. Furthermore, a high incidence of asymptomatic forms of VL in the human and canine populations was observed. The results of this study suggest autochthonous transmission of L. chagasi in this endemic area for visceral leishmaniasis because infection by Leishmania sp. was identified in all important elements of the transmission chain. PMID- 21537683 TI - Modulation of expression and activity of cytochrome P450s and alteration of praziquantel kinetics during murine schistosomiasis. AB - In this study, we investigated the expression and activity of liver cytochrome P450s (CYPs) and praziquantel (PZQ) kinetics in mice infected with Schistosoma mansoni. Swiss Webster (SW) mice of both genders were infected (100 cercariae) on postnatal day 10 and killed on post-infection days (PIDs) 30 or 55. Non-infected mice of the same age and sex served as controls. Regardless of mouse sex, infection depressed the activities of CYP1A [ethoxy/methoxy-resorufin-O dealkylases (EROD/MROD)], 2B9/10 [pentoxy/benzyloxy-resorufin-O-dealkylases (PROD, BROD)], 2E1 [p-nitrophenol-hydroxylase (PNPH)] and 3A11 [erythromycin N demethylase (END)] on PID 55 but not on PID 30. On PID 55, infection decreased liver CYP mRNA levels (real-time reverse transcription-polymerase chain reaction). On PID 30, whereas mRNA levels remained unaltered in males, they were depressed in females. Plasma PZQ (200 and 400 mg/kg body weight intraperitoneally) levels were measured (high-performance liquid chromatography) at different post-treatment intervals. In males and females, infection delayed the PZQ clearance on PID 55, but not on PID 30. Therefore, it can be concluded that schistosomiasis down-modulated CYP expression and activity and delayed PZQ clearance on PID 55, when a great number of parasite eggs were lodged in the liver. On PID 30, when egg-laying was initiated by the worms, no change of CYP expression and activity was found, except for a depression of CYP1A2 and 3A11 mRNAs in female mice. PMID- 21537684 TI - Polymorphism analysis of the CTLA-4 gene in paracoccidioidomycosis patients. AB - The CTLA-4 protein is expressed in activated T cells and plays an essential role in the immune response through its regulatory effect on T cell activation. Polymorphisms of the CTLA-4 gene have been correlated with autoimmune, neoplastic and infectious illnesses. This work aimed to verify possible associations between single nucleotide polymorphisms (SNPs) in CTLA-4, -318C/T in the promoter and +49A/G in exon 1 and paracoccidioidomycosis (PCM) caused by Paracoccidioides brasiliensis. For this purpose, 66 chronic form PCM patients and 76 healthy controls had their allele, genotype and haplotype frequencies determined. The genetic admixture structure of the patients and controls was evaluated to eliminate ancestral bias. The comparison of frequencies indicated no significant differences between patients and controls that could link the SNPs to PCM. Groups were admixture matched with no difference observed in population ancestry inference, indicating that the absence of association between CTLA-4 polymorphisms and PCM could not be attributed to ancestral bias. This study showed that there was no association between the CTLA-4 SNPs -318 and +49 and the resistance or susceptibility to PCM. PMID- 21537685 TI - Parvovirus B19 antibodies and correlates of infection in pregnant women attending an antenatal clinic in central Nigeria. AB - Human parvovirus B19 infection is associated with spontaneous abortion, hydrops foetalis, intrauterine foetal death, erythema infectiosum (5th disease), aplastic crisis and acute symmetric polyarthropathy. However, data concerning Nigerian patients with B19 infection have not been published yet. The purpose of this study was to establish the prevalence of B19 IgG and IgM antibodies, including correlates of infection, among pregnant women attending an antenatal clinic in Nigeria. Subsequent to clearance from an ethical committee, blood samples were collected between August-November 2008 from 273 pregnant women between the ages of 15-40 years who have given their informed consent and completed self administered questionnaires. Recombinant IgG and IgM enzyme linked immunosorbent assay kits (Demeditec Diagnostics, Germany) were used for the assays. Out of the 273 participants, 111 (40.7%) had either IgG or IgM antibodies. Out of these, 75 (27.5%) had IgG antibodies whereas 36 (13.2%) had IgM antibodies, and those aged 36-40 years had the highest prevalence of IgG antibodies. Significant determinants of infection (p < 0.05) included the receipt of a blood transfusion, occupation and the presence of a large number of children in the household. Our findings have important implications for transfusion and foeto-maternal health policy in Nigeria. Routine screening for B19 IgM antibodies and accompanying clinical management of positive cases should be made mandatory for all Nigerian blood donors and women of childbearing age. PMID- 21537686 TI - Dispersal of Triatoma infestans and other Triatominae species in the arid Chaco of Argentina: flying, walking or passive carriage? The importance of walking females. AB - The aim of this paper was to analyse the active dispersal of Triatoma infestans and the role of chickens as passive carriers of this insect in peridomestic areas of La Rioja, Argentina. To measure active dispersal, monthly catches were made on six consecutive nights for five months (in the warm season) using light traps (for flying insects) and sticky dispersal barriers (for walking insects). The nutritional and reproductive states of adults were evaluated. Over the course of the sampling period, a total of eight flying adults, six walking nymphs and 10 walking adults of the species T. infestans were captured, as well as specimens of Triatoma guasayana, Triatoma eratyrusiformis and Triatoma platensis. Our data demonstrate for the first time that females of T. infestans can disperse by walking. This may be an adaptive strategy because it allows them to move with eggs and/or with good blood reserves, which are not possible when flying. All flying and walking individuals of both genders were of an appropriate physiological state that would allow for colonisation of the target habitat. However, manual inspection of 122 chickens suggests that it is unlikely that these animals passively transport T. infestans. Finally, the dispersal activity of T. infestans was compared with other triatomines using a dispersion index. PMID- 21537687 TI - Influence of anti-filarial chemotherapy strategies on the genetic structure of Wuchereria bancrofti populations. AB - Lymphatic filarial (LF) parasites have been under anti-filarial drug pressure for more than half a century. Currently, annual mass drug administration (MDA) of diethylcarbamazine (DEC) or ivermectin in combination with albendazole (ALB) have been used globally to eliminate LF. Long-term chemotherapies exert significant pressure on the genetic structure of parasitic populations. We investigated the genetic variation among 210 Wuchereria bancrofti populations that were under three different chemotherapy strategies, namely MDA with DEC alone (group I, n = 74), MDA with DEC and ALB (group II, n = 60) and selective therapy (ST) with DEC (group III, n = 34) to understand the impact of these three drug regimens on the parasite genetic structure. Randomly amplified polymorphic DNA profiles were generated for the three groups of parasite populations; the gene diversity, gene flow and genetic distance values were determined and phylogenetic trees were constructed. Analysis of these parameters indicated that parasite populations under ST with a standard dose of DEC (group III) were genetically more diverse (0.2660) than parasite populations under MDA with DEC alone (group I, H = 0.2197) or with DEC + ALB (group II, H = 0.2317). These results indicate that the MDA may reduce the genetic diversity of W. bancrofti populations when compared to the genetic diversity of parasite populations under ST. PMID- 21537688 TI - 2D-immunoblotting analysis of Sporothrix schenckii cell wall. AB - We utilized two-dimensional gel electrophoresis and immunoblotting (2D immunoblotting) with anti-Sporothrix schenckii antibodies to identify antigenic proteins in cell wall preparations obtained from the mycelial and yeast-like morphologies of the fungus. Results showed that a 70-kDa glycoprotein (Gp70) was the major antigen detected in the cell wall of both morphologies and that a 60 kDa glycoprotein was present only in yeast-like cells. In addition to the Gp70, the wall from filament cells showed four proteins with molecular weights of 48, 55, 66 and 67 kDa, some of which exhibited several isoforms. To our knowledge, this is the first 2D-immunoblotting analysis of the S. schenckii cell wall. PMID- 21537689 TI - In vitro activity of amphotericin B cochleates against Leishmania chagasi. AB - Cochleate delivery vehicles are a novel lipid-based system with potential for delivery of amphotericin B (AmB). In this study, the efficacy of cochleates was evaluated by examining the in vitro activity of AmB cochleates (CAMB) against Leishmania chagasi in a macrophage model of infection. We demonstrate that CAMB is nontoxic to macrophages at concentrations as high as 2.5 MUg/mL, whereas the conventional formulation, AmB deoxycholate, showed high toxicity at this concentration. The in vitro activity of CAMB against L. chagasi was found to be similar to that of the reference drug AmB deoxycholate, with ED50s of 0.017 MUg/mL and 0.021 MUg/mL, respectively. Considering that L. chagasi affects organs amenable to cochleate-mediated delivery of AmB, we hypothesize that CAMB will be an effective lipid system for the treatment of visceral leishmaniasis. PMID- 21537692 TI - Transtrochanteric fractures. PMID- 21537693 TI - Pachydermoperiostosis associated with gastric neoplasia. PMID- 21537694 TI - Marked regression of tumor occupying almost the entire breast following chemotherapy. PMID- 21537695 TI - Radiotherapy and breast reconstruction after surgical treatment of breast cancer. PMID- 21537696 TI - The importance of standard operating procedures (SOPs) for clinical research centers. PMID- 21537697 TI - Any and no. PMID- 21537698 TI - Case study of supply induced demand: the case of provision of imaging scans (computed tomography and magnetic resonance) at Unimed-Manaus. AB - OBJECTIVE: To present the experience of a health plan operator (Unimed-Manaus) in Manaus, Amazonas, Brazil, with the accreditation of imaging services and the demand induced by the supply of new services (Roemer's Law). METHODS: This is a retrospective work studying a time series covering the period from January 1998 to June 2004, in which the computed tomography and the magnetic resonance imaging services were implemented as part of the services offered by that health plan operator. Statistical analysis consisted of a descriptive and an inferential part, with the latter using a mean parametric test (Student T-test and ANOVA) and the Pearson correlation test. A 5% alpha and a 95% confidence interval were adopted. RESULTS: At Unimed-Manaus, the supply of new imaging services, by itself, was identified as capable of generating an increased service demand, thus characterizing the phenomenon described by Roemer. CONCLUSION: The results underscore the need to be aware of the fact that the supply of new health services could bring about their increased use without a real demand. PMID- 21537699 TI - Information to the patient with cancer: the oncologist's view. AB - OBJECTIVE: To identify what information is provided to the patients by oncologists, assess what they take into account in the process of informing the patient, and to ascertain whom the information is provided to. METHODS: The study subjects were oncologists recruited among those registered at the Brazilian Society of Clinical Oncology - SBOC. All material was mailed to the Society, which was then forwarded to the participant oncologists. The previously stamped envelopes contained: a questionnaire, the questionnaire instructions, and the informed consent form to be signed. The data obtained was statistically treated, following a 95% confidence interval. RESULTS: 876 questionnaires were sent (total number of physicians registered at SBOC) and a 16.55% response rate was achieved. Regarding the information provided, 81% of the physicians responded they informed patients about diagnosis, treatment and prognosis; however, 73% reported that in most cases the patient is already aware of his/her disease. Nevertheless, the information is provided to the patient and his(her) family by 81% of doctors. Among the relevant aspects in the information process, the patient's gender has little influence on the information for 95% of doctors. CONCLUSION: Considering the results achieved, we conclude that in the study population, physicians are concerned about providing information according to the patient's profile. We could also notice that oncologists try to provide patients with the information they are entitled to - the truth, although they often resort to the family's assistance in providing that information. PMID- 21537700 TI - Chemical food composition: implications for atherosclerosis prevention. AB - OBJECTIVE: To compare the fatty acid and cholesterol content in food acquired in Brazil with the composition found in the most frequently used reference tables in the country. METHODS: The fatty acid and cholesterol content in 41 food items frequently used in our country and the various directions to prepare them were reviewed by using specific methodology and the information was compared to the tables adopted by Unicamp and UNIFESP. RESULTS: According to Unicamp table, the cholesterol content found in parmesan cheese was 100.7 mg/100 g, while it was 68 mg/100 g in UNIFESP table, that is, a 48% (p < 0.05), higher content in the former. This study table found a cholesterol content 31% lower (94 mg/100 g vs. 123 mg/100 g, p < 0.05) for yellow cheese. For whole milk, we found a 52% difference regarding cholesterol content, while the difference for saturated fat ranged from 1.4 g/100 g in Unicamp table to 2.130 g/100 g in our study table (p < 0.05). For some food items, no statistically significant differences were found among the tables. However, when a 1,800-calorie diet was prescribed, the discrepancies among the tables and lack of information resulted in clinically relevant differences in dietary recommendations. CONCLUSION: There are important differences in food fat content between the fatty acid and cholesterol content formally analyzed and the content shown on commonly used tables, and this can compromise our recommendations on preventing atherosclerosis. One possible explanation for the differences would be the fact that the UNIFESP table is American in origin. PMID- 21537701 TI - Risk factors for mortality in acute kidney injury. AB - OBJECTIVE: This study aims to evaluate the outcome of AKI patients caused by acute tubular necrosis admitted in clinical and surgical units of Botucatu Medical School University Hospital - UNESP. METHODS: This is a retrospective cohort study with 477 adult patients were observed from January 2001 to December 2008. AKI was defined according to serum creatinine levels as proposed by Acute Kidney Injury Network (AKIN). RESULTS: The mean age was 65.5 +/- 162 years. The majority of the patients were males (62%) older than 60 years (65.2%). Diabetes mellitus was diagnosed in 61.9%, high blood pressure in 44.4% and chronic kidney disease 21.8% of the patients. Death occurred 66% of dialysis requirement, critical care unit admission, age > 60 years and lower attendance time by nephrologists were significant and independently associated with death risk. The renal recorery among survivors was of 96.9%. CONCLUSION: This work shows that the evolution of AKI patients from clinical and surgical wards is similar to literature. However, the high mortality of the group shows the necessity of identifying risk factors for the development of AKI in these patients and training staff assistant for the early diagnosis of this syndrome. PMID- 21537702 TI - Time elapsed since the last medical visit: analysis of a statistical model applied to the case of Spanish women. AB - OBJECTIVE: This study aims at two objectives: I) to develop a model capable of predicting the statistical distribution of the variable "time elapsed since the last medical visit"; II) to empirically test the theoretical model. METHODS: To develop the theoretical model, the author will use a demonstration that is statistical in nature. In order to test the theoretical distribution, the 2006 Encuesta Nacional de Espana data regarding females will be used. RESULTS: The results found show that the distribution of the time elapsed since the last medical visit follows a Poisson distribution. This conclusion was empirically validated, and additionally, a few determinants were found that increase the likelihood that Spanish women will resort to a doctor, namely, inactivity, residence in small places and being older. CONCLUSION: The study concluded that the time elapsed since the last medical visit follows a Poisson distribution; thus, going to a medical appointment is still seen as a rare phenomenon for Spanish women. By comparing this data with our results, we found that a higher ratio of physicians to population, a higher time availability for each woman (especially in a labor inactivity setting) and strong personal relationships can lead to a higher medical visit rate, thus reducing the time elapsed since the last visit. PMID- 21537703 TI - Tobacco and alcohol use after head and neck cancer treatment: influence of the type of oncological treatment employed. AB - OBJECTIVE: To assess the cigarette smoking and alcohol intake maintenance rate in patients treated for head and neck squamous cell carcinoma and to compare the observed outcome with the type of oncological treatment employed. METHODS: One hundred and ten patients treated for high aero-digestive tract squamous cell carcinoma were included and divided into a surgical group, treated with a surgery, and a medical group, treated with chemotherapy and/or radiation. The patients were interviewed to determine whether or not they had persisted with the smoking and drinking behavior after treatment. The habit maintenance rate was compared with the treatment modality employed. The relationship between the oncological status of the patients and the cigarette smoking and alcohol intake rates found was also tested. RESULTS: Among smokers, 35% maintained the habit after treatment. The medical group had a significantly higher percentage of patients maintaining smoking compared with the surgical group (58.3% vs 25.0%; p = 0.004). Among alcohol users, 16.6% kept drinking alcoholic beverages, with a percentage also shown higher for the medical group (23.8% vs 13,3%), but with no statistically significant difference. The oncological status of patients was not related to the maintenance of the habits studied. CONCLUSION: Smoking and alcoholism maintenance rates are high after head and neck squamous cell carcinoma is treated, especially if we consider smoking in patients treated with chemotherapy and/or radiation. A more effective multidisciplinary approach is required in order to obtain better rates of tobacco and alcohol quitting, especially in patients undergoing non-surgical treatments. PMID- 21537704 TI - Breast histomorphometry of rats treated with estrogen and/or progestogen. AB - OBJECTIVE: To evaluate the breast histomorphometric changes in rats treated with estrogen and/or progestogen for a short period of time. METHODS: Forty oophorectomized rats were divided into four groups: GC, vehicle; GE, treated with estradiol benzoate (37.6 mg/animal); GP, treated with medroxyprogesterone acetate (11.2 mg/animal) and GEP, treated with estradiol benzoate (37.6 mg/animal) plus medroxyprogesterone acetate (11.28 mg/animal). In GE group, estradiol was administered subcutaneously for seven days; in GEP group, estradiol was administered once in a day for the first seven days and the progestogen over the next 23 days both subcutaneously. Twenty-four hours after the last hormone administration, the animals were killed upon deep anesthesia and the first inguinal breasts were removed, fixed in 10% formaldehyde and processed to be included in paraffin, with the sections being stained by hematoxylin-eosin. Morphology and the area occupied by mammary parenchyma were assessed, with the data undergoing analysis of variance followed by the Kruskal-Wallis test (p < 0.05). RESULTS: The control group breasts were found atrophic and, in GE and GEP group animals, typical alveoli with secretion inside are present; in progestogen treated animals (GP), alveoli formed by large cells occupying almost the entire alveolar lumen are noted. Morphometric analysis showed a larger mammary parenchyma area in hormone-treated animals (GE = GP > GEP > GC; p < 0.05). CONCLUSION: Estradiol and progestogen had a proliferative effect on mammary parenchyma. However, prior estradiol administration changes the progestogen action on rat mammary tissue. PMID- 21537705 TI - Metabolic syndrome and its components in HIV-infected individuals. AB - OBJECTIVE: To assess the prevalence of metabolic syndrome and its components in HIV infected individuals assisted in a specialized health center in a municipality in the state of Santa Catarina, Brazil. METHODS: Cross-sectional study comprising 249 individuals (130 men and 119 women), aged 18 to 73 years. Metabolic syndrome was defined according to the National Cholesterol Education Program, as recommended by the Brazilian Society of Cardiology. RESULTS: Among the individuals who participated in the study, 20.9% had metabolic syndrome - 18.5% of the men and 23.5% of the women, with no statistical association between genders. Twenty seven percent of the individuals had two components of the syndrome. Components most frequently found were those related to lipid profile (low HDL cholesterol and high triglycerides), followed by elevated waist circumference, altered blood pressure and altered fasting blood glucose. There was a significant association between gender and elevated waist-circumference. CONCLUSION: The prevalence of metabolic syndrome found in this study possibly reflects the quality of the health services delivered. We highlight the importance of investigating the presence of metabolic syndrome among HIV-infected populations, thus contributing for their survival. PMID- 21537706 TI - Stenosis of reverse great saphenous vein graft in infrainguinal arterial revascularization. AB - OBJECTIVE: The aim of this study was to evaluate the prevalence of hemodynamically significant infrainguinal bypasses stenosis using reverse great saphenous vein graft. METHODS: From March of 2008 to March of 2009, 56 infrainguinal bypasses were performed with reverse great saphenous vein graft in 56 patients. On the 30th post-operative day, 32 out of 56 patients were submitted to vascular ultrasonography. The prevalence of significant graft stenosis was determined. In addition, the diagnosis of stenosis was related to the clinical and surgical characteristics of the patients. The variables analyzed at the moment of diagnosis were the localization of the graft stenosis, the risk factors associated with stenosis and the association of vascular ultrasonography findings with ankle brachial pressure index (ABI). RESULTS: The overall prevalence of significant graft stenosis was 48.4%. Out of the total number of observed stenosis, 19.4% were considered severe, and 29% mild or moderate. There was no significant association between the presence of significant stenosis and the following variables: gender, diabetes, hypertension, smoking, hipercholesterolemia, graft diameter, site of the distal anastomosis, and graft composition. There was a weak agreement between ABI and vascular ultrasonography in detecting stenosis in general (K = 0.30; CL95% 0.232 - 0.473; p = 0.018). However, there was a substantial agreement in detecting severe stenosis (K = 0.75; CL95% 0.655 - 0.811; p = 0.0001). CONCLUSION: There was a high prevalence of stenosis on the 30th post-operative day, mostly localized in the proximal half of the vein graft. There was no significant association of stenosis with clinical and surgical factors analyzed. ABI and vascular ultrasonography had weak agreement with the diagnosis of stenosis in general and an important agreement for the diagnosis of severe stenosis. PMID- 21537707 TI - Head and neck carconogenesis: impact of MTHFD1 G1958A polymorphism. AB - OBJECTIVE: To investigate the MTHFD1 G1958A polymorphism involved in the folate metabolism as a risk for head and neck cancer, and to find the association of the polymorphism with the risk factors and clinical and histopathological characteristics. METHODS: Retrospective study investigating MTHFD1 G1958A polymorphism in 694 subjects (240 patients in the Case Group and 454 in the Control Group) by Restriction Fragment Length Polymorphism (RFLP) Analysis. Multiple logistic regression and chi-square tests were used in the statistical analysis. RESULTS: Multivariable analysis showed that smoking and age over 42 years were disease predictors (p < 0.05). MTHFD1 1958GA or AA genotypes were associated with smoking (p = 0.04) and alcoholism (p = 0.03) and were more often found in more advanced stage tumors (p = 0.04) and in patients with a shorter survival (p = 0.03). CONCLUSION: The presence of MTHFD1 G1948A polymorphism associated with smoking and alcoholism raises the head and neck cancer risk. PMID- 21537708 TI - Clinical features and outcomes in patients with diabetes mellitus undergoing coronary artery bypass graft in a reference center in southern Brazil. AB - OBJECTIVE: To describe clinical/laboratory features of patients undergoing coronary artery bypass graft (CABG) in a cardiology reference center. METHODS: Cohort study; data from patients undergoing CABG (January 2004 to February 2006, n = 717) were evaluated for clinical/laboratory features before, during and after surgery (infections, duration of hospital stay, deaths). RESULTS: Patients were 61.9 +/- 11 years old, 67.1% males, 29.6% diabetics. Intraoperatively, diabetics had a central venous catheter placed for a longer period (p < 0.001), but extracorporeal circulation, aortic clamping and total surgery times were similar to those for non-diabetics. Infection occurred in 19.1% of patients (40.1% diabetics vs. 10.3% non-diabetics, p < 0.001). The duration of hospital stay was longer for patients with diabetes vs. non-diabetic patients, but there was no difference in deaths between the two groups (p = 0.797). CONCLUSION: Patients with diabetes undergoing CABG develop more infectious diseases and stay longer in hospital than non-diabetics. PMID- 21537709 TI - Conjoined twins and legal authorization for abortion. AB - OBJECTIVE: To describe pregnancies with conjoined twins according to the request for legal termination of pregnancy. METHODS: Retrospective review of pregnancies with conjoined twins, with no possibility of extrauterine survival or postnatal surgical separation, observed at a tertiary teaching hospital, between 1998 and 2010. RESULTS: Amongst 30 cases seen during the study period, six (20.0%) couples decided to continue with the pregnancy, termination of pregnancy was not requested due to advanced gestational age (> 25 weeks) in 5 cases (16.7%). Legal authorization to terminate the pregnancy was requested in 19 (63.3%) cases: permission was granted in 12 (63.2%), denied in five (26.3%) and information was missing in two (10.5%) cases. A successful vaginal delivery was performed in 83.3% of the cases undergoing termination of pregnancy and a cesarean section was performed in all the remaining cases (p < 0.01). CONCLUSION: In pregnancies with conjoined twins and without fetal prognosis, legal termination of the pregnancy is an alternative. Moreover, a successful vaginal delivery can be performed in most cases before the third trimester, further reducing maternal risks and parental suffering. PMID- 21537711 TI - Advances in surgical treatment of colorectal liver metastases. AB - Colorectal cancer is the 3rd most common malignant neoplasm in the West. About 50% of patients develop liver metastases throughout the course of the disease. Those are responsible for at least two-thirds of deaths. Advances in surgical techniques and improvement in chemotherapy regimens have allowed offering treatment with curative intent to an increasing number of patients. This article reviews recent advances in the treatment of liver metastases, including strategies to increase resection (e.g., portal vein embolization, radiofrequency ablation, two-stage hepatectomy, conversion therapy and reverse treatment strategy) and hepatectomy in the presence of extrahepatic disease. Finally, the results of surgical treatment of liver metastases at the Hospital A.C. Camargo are briefly shown. PMID- 21537710 TI - Cancer-related fatigue: a review. AB - Cancer-related fatigue is the most prevalent cancer symptom, reported in 50%-90% of patients and severely impacts quality of life and functional capacity. The condition remains underreported and often goes untreated. Guidelines suggest screening for fatigue at the initial visit, when the diagnosis of advanced disease is made, and at each chemotherapy session, as well as the identification of treatable contributing factors such as anemia, hypothyroidism, depression and sleep disorders. Brief assessment tools such as the Brief Fatigue Inventory or the Visual Analog Scale may be appropriate in the initial scoring of fatigue severity, but the initial approach to treatment usually requires a more comprehensive assessment, education, and the determination of an individualized treatment plan. Patients with moderate or severe fatigue may benefit from both pharmacological and non-pharmacological interventions, whereas mild fatigue that does not interfere with quality of life can be treated with non-pharmacological measures alone. Non-pharmacological measures that have shown to be promising include cognitive-behavioral interventions such as energy conservation and activity management (ECAM), exercise and perhaps sleep therapy. Many other modalities may be beneficial and can be used on an individual basis, but there is insufficient evidence to promote any single treatment. Pharmacological therapies that have shown to be promising include the psycho-stimulants methylphenidate and dexmethylphenidate, modafinil (in severely fatigued patients only), and erythropoietin-stimulating agents in patients with chemotherapy-associated anemia and hemoglobin levels < 10 g/dL. Recently, our group reported impressive results with the use of the dry extract of Guarana (Paullinia cupana), with no significant side effects and at low cost, for the treatment of physical and mental cancer-related fatigue. PMID- 21537712 TI - Historical aspects of infective endocarditis. AB - Infective endocarditis was a fatal disease three generations ago. Temporal evolution of knowledge made possible important advances in diagnostic techniques, especially in echocardiography, the possibility of cardiac surgery during the active infectious process and new guidelines for antibiotic prophylaxis before interventional procedures. Nowadays, infective endocarditis is curable. In this review, we describe historical aspects of endocarditis, from Osler's observations in the 19th century to the change from a "clinically possible" to a "clinically defined" disease. PMID- 21537713 TI - Atypical glandular cells and cervical cancer: systematic review. AB - Atypical glandular cells are a common finding in cervical cytology in cervical cancer screening and its occurrence has increased in the last decades. The identification of these cells is clinically very important due to its association with cervical and endometrial dysplasic lesions and cancer. Using a systematic approach, this article reviewed studies investigating cervical lesions that are characteristic in patients previously diagnosed as having atypical glandular cells. Studies in which diagnostic investigation did not include histopathological diagnosis were excluded. A comprehensive search for available material in LILACS, SciELO, PubMed/ Medline and Old Medline databases, dated between 1966 and 2009 was performed. Articles omitted by the electronic database search were also included. Nineteen articles met the inclusion criteria and were selected. This report aims at evaluating whether atypical glandular cells, initially found in cervical cytology and subsequently identified at the histological analysis, are related to the presence of benign, pre-malignant and malignant lesions. Eleven out of 19 selected articles showed the highest correlation between atypical glandular cells with benign diseases and six with squamous pre-malignant lesions. PMID- 21537714 TI - Accreditation or accreditations? A comparative study about accreditation in France, United Kingdom and Cataluna. AB - This article analyzes the dynamics and changes in the accreditation process in three different places - France, UK and Cataluna (Spain) - based on documents about their health systems organizations, funding sources and regulations. The objective was to find out about the relevant aspects of the strategies of these countries' institutions that adapted accreditation to national circumstances in the healthcare policy arena. Although there are similarities in the basic approaches and standards used, there are different models of accreditation. Setting standards raises the question of who should define them and how they should be monitored; accreditation's methodology cannot be seen only as a voluntary process for assessing quality in healthcare or perceived as tool for certification and regulation. Interests in accreditation can be driven by a number of different forces, which depend upon the model adopted. Therefore, it can only be understood in the policy arena of each country. PMID- 21537718 TI - Principles that should guide mental health policies in low-and middle-income countries (LMICs): lessons from the Brazilian experiment. PMID- 21537719 TI - Guiding principles for the development of mental health policies in low- and middle- income countries. PMID- 21537720 TI - Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. AB - OBJECTIVE: To compare the effectiveness of intramuscular olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone as the first medication(s) used to treat patients with agitation and aggressive behavior. METHOD: One hundred fifty patients with agitation caused by psychotic or bipolar disorder were randomly assigned under double-blind conditions to receive olanzapine, ziprasidone, haloperidol plus midazolam, haloperidol plus promethazine or haloperidol alone. The Overt Agitation Severity Scale, Overt Aggression Scale and Ramsay Sedation Scale were applied within 12 hours after the first dosage. RESULTS: All medications produced a calming effect within one hour of administration, but only olanzapine and haloperidol reduced agitation by less than 10 points, and only olanzapine reduced aggression by less than four points in the first hour. After twelve hours, only patients treated with haloperidol plus midazolam had high levels of agitation and aggression and also more side effects. Ziprasidone, olanzapine and haloperidol alone had more stable results for agitation control, while ziprasidone, haloperidol plus promethazine and olanzapine had stable results for aggression control. CONCLUSION: Olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol were effective in controlling agitation and aggression caused by mental illness over 12 hours. Although all the drugs had advantages and disadvantages, haloperidol plus midazolam was associated with the worst results in all the observed parameters. PMID- 21537721 TI - Influence of specific obsessive-compulsive symptom dimensions on strategic planning in patients with obsessive-compulsive disorder. AB - OBJECTIVE: This study investigates obsessive-compulsive disorder patients in terms of strategic planning and its association with specific obsessive compulsive symptom dimensions. METHOD: We evaluated 32 obsessive-compulsive disorder patients. Strategic planning was assessed by the Rey-Osterrieth Complex Figure Test, and the obsessive-compulsive dimensions were assessed by the Dimensional Yale-Brown Obsessive-Compulsive Scale. In the statistical analyses, the level of significance was set at 5%. We employed linear regression, including age, intelligence quotient, number of comorbidities, the Yale-Brown Obsessive Compulsive Scale score, and the Dimensional Yale-Brown Obsessive-Compulsive Scale. RESULTS: The Dimensional Yale-Brown Obsessive-Compulsive Scale "worst ever" score correlated significantly with the planning score on the copy portion of the Rey-Osterrieth Complex Figure Test (r = 0.4, p = 0.04) and was the only variable to show a significant association after linear regression (beta = 0.55, t = 2.1, p = 0.04). Compulsive hoarding correlated positively with strategic planning (r = 0.44, p = 0.03). None of the remaining symptom dimensions presented any significant correlations with strategic planning. CONCLUSION: We found the severity of obsessive-compulsive symptoms to be associated with strategic planning. In addition, there was a significant positive association between the planning score on the copy portion of the Rey-Osterrieth Complex Figure Test copy score and the hoarding dimension score on the Dimensional Yale-Brown Obsessive Compulsive Scale. Our results underscore the idea that obsessive-compulsive disorder is a heterogeneous disorder and suggest that the hoarding dimension has a specific neuropsychological profile. Therefore, it is important to assess the peculiarities of each obsessive-compulsive symptom dimension. PMID- 21537722 TI - Validation of the structural coherency of the General Health Questionnaire. AB - OBJECTIVE: Investigate the structural coherency of the 60-item version of the General Health Questionnaire via exploratory and confirmatory factor analyses. METHOD: The study design is a cross-sectional survey. A random sample of 146 individuals from the city of Divinopolis-MG volunteered to participate in the present study and responded to the 60-item version of the General Health Questionnaire adapted and validated for use in Brazil. Statistics consisted of exploratory and confirmatory factor analysis. Reliability was estimated using Cronbach's alpha method. RESULTS: Alpha coefficients for all five content scales of the General Health Questionnaire were high (alpha > 0.8). For four of the five scales, a unifactorial model of constituent items provided a good fit to the data. Items comprising the fifth scale, Psychic Stress, exhibited a two correlated factor structure. A factor analysis of scores for the five scales yielded strong evidence of coherency, with all scales loading substantially on a single common factor. CONCLUSION: The General Health Questionnaire shows good psychometric coherency as evidenced by high internal consistency and unidimensionality of all but one of its constituent scales, and uniformly high loadings of all scales on a single overarching factor. These results are consistent with prior findings from the General Health Questionnaire developmental study and Brazilian adaptation studies. PMID- 21537723 TI - Validity and reliability of the Structured Clinical Interview for Mood Spectrum: Brazilian version (SCIMOODS-VB). AB - OBJECTIVE: The aim of this study was to translate the Structured Clinical Interview for Mood Spectrum into Brazilian Portuguese, measuring its reliability, validity, and defining scores for bipolar disorders. METHOD: Questionnaire was translated (into Brazilian Portuguese) and back-translated into English. Sample consisted of 47 subjects with bipolar disorder, 47 with major depressive disorder, 18 with schizophrenia and 22 controls. Inter-rater reliability was tested in 20 subjects with bipolar disorder and MDD. Internal consistency was measured using the Kuder Richardson formula. Forward stepwise discriminant analysis was performed. Scores were compared between groups; manic (M), depressive (D) and total (T) threshold scores were calculated through receiver operating characteristic (ROC) curves. RESULTS: Kuder Richardson coefficients were between 0.86 and 0.94. Intraclass correlation coefficient was 0.96 (CI 95 % 0.93-0.97). Subjects with bipolar disorder had higher M and T, and similar D scores, when compared to major depressive disorder (ANOVA, p < 0.001). The sub domains that best discriminated unipolar and bipolar subjects were manic energy and manic mood. M had the best area under the curve (0.909), and values of M equal to or greater than 30 yielded 91.5% sensitivity and 74.5% specificity. CONCLUSION: Structured Clinical Interview for Mood Spectrum has good reliability and validity. Cut-off of 30 best differentiates subjects with bipolar disorder vs. unipolar depression. A cutoff score of 30 or higher in the mania sub-domain is appropriate to help make a distinction between subjects with bipolar disorder and those with unipolar depression. PMID- 21537724 TI - [The pharmacological treatment of bipolar disorder: a systematic and critical review of the methodological aspects of modern clinical trials]. AB - OBJECTIVE: To review systematically the main clinical trials on the pharmacological treatment of bipolar disorder and to make a critical analysis of their methodological aspects. METHOD: A search in Medline, ISI and PsycINFO databases was conducted, using the following search terms: "bipolar", "randomized", "placebo" e "controlled". Randomized, double-blind, placebo controlled clinical trials on the pharmacological treatment of bipolar disorder were selected. Besides, according to our criteria, samples had to consist of at least 100 patients and experimental drug had to be used as monotherapy. RESULTS: 34 articles met our selection criteria. All drugs currently indicated for mania, bipolar depression and maintenance treatment of bipolar disorder were more effective than placebo in at least one clinical trial. However, these studies had highly selected samples, high dropout rates and low response rates. CONCLUSION: Modern clinical trials on pharmacological treatment of bipolar disorder have important methodological limitations. So, their results should be taken with caution. PMID- 21537725 TI - Pharmacological treatment of frontotemporal lobar degeneration: systematic review. AB - OBJECTIVE: To identify the therapeutic options available for treatment of cognitive and behavioral symptoms in frontotemporal lobar degeneration. METHOD: Systematic review using the descriptors "frontotemporal lobar degeneration" OR "frontotemporal dementia" OR "fronto-temporal dementia" OR "fronto-temporal degeneration" OR "Pick's disease" OR "Pick's atrophy" OR "semantic dementia" OR "progressive aphasia" AND "pharmacotherapy" OR "treatment" OR "efficacy" OR "effects" OR "management" was performed in the Medline and Lilacs databases. SELECTION CRITERIA: Quality A - randomized clinical trials. Quality B - open studies or reports of six or more cases. Quality C - reports of five or fewer cases. Two reviewers independently assessed the clinical studies. Information collected included diagnostic criteria used, sample size, duration, efficacy and tolerability measures used and results obtained. RESULTS: From the 532 studies found, 29 complied with the inclusion criteria. All studies worked with a small sample, had short duration of treatment and used non-uniform measures in evaluating efficacy and tolerability. Studies showed disparate results with respect to behavior and cognition. CONCLUSION: There is still little, and poor, evidence available for treatment of frontotemporal lobar degeneration and studies with better methodological background are needed. PMID- 21537726 TI - Sedative antidepressants and insomnia. AB - OBJECTIVE: The present review addresses the relationship between sleep and depression and how serotonergic transmission is implicated in both conditions. METHOD: Literature searches were performed in the PubMed and MedLine databases up to March 2010. The terms searched were "insomnia", "depression", "sedative antidepressants" and "serotonin". In order to pinpoint the sedative antidepressants most used to treat insomnia, 34 ISI articles, mainly reviews and placebo-controlled clinical trials, were selected from 317 articles found in our primary search. RESULTS: Sleep problems may appear months before the diagnosis of clinical depression and persist after the resolution of depression. Treatment of insomnia symptoms may improve this comorbid disease. Some antidepressant drugs can also result in insomnia or daytime sleepiness. Serotonin (5-HT) demonstrates a complex pattern with respect to sleep and wakefulness that is related to the array of 5-HT receptor subtypes involved in different physiological functions. It is now believed that 5HT2 receptor stimulation is subjacent to insomnia and changes in sleep organization related to the use of some antidepressants. CONCLUSION: Some drugs commonly prescribed for the treatment of depression may worsen insomnia and impair full recovery from depression. 5-HT2 receptor antagonists are promising drugs for treatment strategies since they can improve comorbid insomnia and depression. PMID- 21537727 TI - BDNF and episodic memory in patients with bipolar disorder. PMID- 21537728 TI - Mephentermine: rediscovering its biology and use, misuse and their implications. PMID- 21537729 TI - Quality of life and depressive symptoms in Parkinson's disease. PMID- 21537730 TI - Long-term mood disorder antedating the diagnosis of Wilson's disease. PMID- 21537731 TI - Ceiling effects in the "effectiveness of adjunctive antidepressant treatment for bipolar depression" study: was the sky the limit? PMID- 21537732 TI - [Suicide among adolescents in Brazil: public health problem?]. PMID- 21537733 TI - Brain-derived neurotrophic factor and suicidal behavior in patients with posttraumatic stress disorder. PMID- 21537735 TI - [Damage control surgery and Latin America's contributions to it]. PMID- 21537736 TI - Impact of the ACERTO project in the postoperative morbi-mortality in a university hospital. AB - OBJECTIVE: To evaluate the postoperative outcomes of patients in the Department of General Surgery, University Hospital Julio Muller, before and after implementation of the ACERTO multimodal protocol. METHODS: We conducted a retrospective study from 5974 patients' charts. We compared two periods: from January 2002 to December 2004 (before implementation of the ACERTO protocol: AA period, n = 1987) and January 2005 to December 2008 (after implementation of the protocol: DA period, n = 3987). The variables studied were length of hospital stay, blood transfusions, surgical site infections (SSI), postoperative complications and deaths. RESULTS: There was a decrease in one day in length of stay between the AA and DA period (median [range]: 4 [0-137] vs 3. [0-126] days and mode: 3 vs. 2 days, p < 0.001). During AA there was a relationship of 2.53 packs of blood products transfused per patient against 0.77 in the DA period (p <0.001). A downward trend in the number of cases of SSI was noticeable over the years (A =-153.08; AA: 7.51% vs. DA: 3.36% (p <0.001, RR = 2.23, 95 % CI:1.73 2.89). There was also a decreasing trend in operative complications (A =- 51.41, AA: 7.9% vs. DA: 6.14%, p = 0.02, RR = 1.29, 95% CI:1.03-1.60), reoperation (A =- 57.10; AA: 2.65%. vs DA: 1.19%, p <0.001, RR = 2, 22, 95% CI: 1.43 to 3.44) and deaths (A =- 62.07, 2.81 vs. 1%, 73%, p <0.01, RR = 1.63, 95% CI: 1.15 to 2.31). CONCLUSION: The introduction of the ACERTO protocol improved the surgical results, expressed as a shorter hospital stay, blood transfusion, and reduction in cases of surgical site infection, postoperative complications and deaths. PMID- 21537737 TI - Evaluation of pulmonary function in patients submitted to reduction mammaplasty. AB - OBJECTIVE: To prospectively evaluate the pulmonary function in patients undergoing reduction mammaplasty. METHODS: Twelve female patients with Gigantomastia and without medical antecedents were submitted to reduction mammaplasty at our University Hospital. The patients underwent lung function testing and arterial blood gas measurements in the preoperative and postoperative period (three to six months). The data were analyzed using the Wilcoxon test and the level of statistical significance was p <0.05. As for lung function tests,total lung capacity and residual volume were higher postoperatively (p <0.05). RESULTS: As for the arterial gases, there was no statistically significant difference. CONCLUSION: The increase in total lung capacity and residual volume may suggest a better lung function after reduction mammaplasty for Gigantomastia treatment, although not altering blood gases in healthy patients. PMID- 21537738 TI - Cytometric evaluation of abdominal subcutaneous adipocytes after percutaneous CO2 infiltration. AB - OBJECTIVE: To evaluate the effects of carbon dioxide infusion to abdominal wall adipocytes. METHODS: Fifteen volunteers were subjected to sessions of CO2 infusion for three consecutive weeks (two sessions per week with intervals of two to three days between each). The volume of carbon dioxide infused per session, at points previously marked, was always calculated on the basis of surface area to be treated, with a fixed infused volume of 250 ml/100 cm2 of treated surface. The infiltration points were marked respecting the limit of 2 cm equidistant between them. At each point 10 ml was injected per session, with a flow of 80 ml/min. Fragments were collected from subcutaneous tissue of the anterior abdominal wall before and after treatment. The number and histomorphological changes of adipocytes (mean diameter, perimeter, length, width and number of adipocytes per field of observation) were measured by computerized cytometry. The results were analyzed with paired Student t test, adopting a significance level of 5% (p <0.05). RESULTS: There was a significant reduction in the number of adipocytes in the abdominal wall, as well as the area, diameter, perimeter, length and width of the adipocytes, after the infusion of CO2 (p = 0.0001). CONCLUSION: The percutaneous infiltration of CO2 reduces the population of adipocytes of the anterior abdominal wall and modifies their morphology. PMID- 21537739 TI - Using the Prolene Hernia System (PHS) for inguinal hernia repair. AB - OBJECTIVE: To assess immediate postoperative and late complications in patients with inguinal hernia undergoing surgical correction by Gilbert technique, using the Prolene Hernia System (HPS). METHODS: We surveyed all patients undergoing inguinal hernia repair with PHS mesh at The Sao Lucas Hospital--PUCRS, from January 2001 to october 2006. Information was retrospectively collected through telephone calls and chart review. The protocol for data collection included epidemiological aspects, as well as immediate and late complications. RESULTS: ninety-six patients were enrolled. We identified six (6.25%) complications in different patients, none of which resulting in death. Two patients (2.08%) had seroma; hematoma was identified in one patient (1.04%); one patient (1.04%) had wound infection. Two patients (2.08%) had scrotal edema. After a mean follow up of 49.25 months (range 16 to 86.12) two patients (2.08%) had chronic pain and one patient (1.04%) had hernia recurrence twenty-six months after surgery. CONCLUSION: The repair of inguinal hernia with PHS is a safe, effective and reproducible method, with low complication and recurrence rates or long term symptoms. PMID- 21537740 TI - Veress needle insertion into the left hypochondrium for creation of pneumoperitoneum: diagnostic value of tests to determine the position of the needle in unselected patients. AB - OBJECTIVE: To assess the effectiveness of the Veress needle puncture in the left hypochondrium and the accuracy of the tests described for the intraperitoneal correct positioning of the tip of the Veress needle in an unselected population. METHODS: Ninetyone patients consecutively scheduled for Videolaparoscopy had the abdominal wall punctured in the left hypochondrium. There were no exclusion criteria. The patients received general anesthesia and mechanical ventilation according to the protocol. After puncturing five tests were used to confirm the positioning of the needle tip within the peritoneal cavity: aspiration test--AT; resistance to infusion--Pres; recovery of the infused fluid--Prec, dripping test- DT, and test of initial intraperitoneal pressure--IIPP. The test results were compared with results from literature for groups with defined exclusion criteria. The results were used for calculating sensitivity (S) specificity (E), positive predictive value (PPV) and negative predictive value (NPV). Inferential statistical methods were used to analyze the findings. RESULTS: There were 13 failures. AT had E = 100% and NPV 100%. Pres had S = 100%, E = 0; PPV = 85.71%; NPV does not apply. Prec: S = 100%, E = 53.84%, PPV = 92.85%, NPV = 100%. DT: S = 100%, E = 61.53%, PPV = 93.97% NPV 100%. In IIPP, S, E, PPV and NPV were 100%. CONCLUSION: The puncture in the left hypochondrium is effective and the performed tests guide the surgeon regardless of sex, BMI, or previous laparotomy. PMID- 21537741 TI - Influence of the inversion of the portal/splenic vein diameter in the results of the surgical treatment of schistossomotic portal hypertension. AB - OBJECTIVE: To evaluate the morbidity and mortality in surgical treatment of schistosomal portal hypertension in patients with inversion of the Portal/Splenic Vein diameter ratio. METHODS: We conducted a retrospective cross-sectional study of patients undergoing surgical treatment of portal hypertension in the period between September 1993 and January 2004. The study population was divided into two groups: a) Inversion--splenic vein diameter greater than or equal to portal vein's--and b) control group (portal vein diameter greater than the splenic vein's). Statistical comparisons used the Student t test for averages difference, chi-square test for proportions difference and Fisher's exact test for small samples. RESULTS: 169 patients were analyzed, with follow-up averaging 23.6 months. Twenty-one patients (12.4%) had splenic vein caliber greater of equal than the portal vein's (Inversion--study group). The mean preoperative diameter of the portal and splenic veins were respectively 1.49 and 1.14 cm in the control group, and 0.98 versus 1.07 cm in the inversion group. The portal vein diameter was significantly higher in the control group when compared to the inversion group (p <0.05). Varices in the gastric fundus were found in 33.3% of the inversion group and in 38.5% of patients in the control group. Postoperative rebleeding occurred in 23.1% of patients in the inversion group and in 13.4% of the control group ones (p > 0.05). In the postoperative evaluation with Doppler ultrasonography of portal vessels, no cases of portal vein thrombosis were observed in the inversion group, whilst in the control group portal thrombosis was identified in 16.9% of the patients (p <0.05). Death occurred in one (4.8%) individual from the inversion group; mortality was 4.1% in the control group (p>0.05). The mean serum level of platelets was significantly lower (65,950/mm2) in the inversion group than in the controls (106,647/mm2) (p<0.05). CONCLUSION: The results suggest that the reversal of portal/splenic vein caliber ratio does not represent a contraindication to surgical treatment of schistosomal portal hypertension. PMID- 21537742 TI - Abdominal wall endometrioma. AB - OBJECTIVE: To report the authors' experience with the clinical manifestations and surgical treatment of abdominal wall endometriomas. METHODS: A retrospective analysis of patients operated for abdominal wall endometrioma was carried out, with emphasis on age, symptoms, previous cesarean, relation of symptoms with the menstrual cycle, physical examinations and additional surgical treatment, postoperative course and histopathological results of specimens. RESULTS: Fourteen patients were operated during the study period, aged between 28 and 40 years. The presence of a local mass and pain that worsened during menstruation were the main complaints. Ultrasound and Computerized Tomography examinations were important in the precise location of the disease. Surgical excision was wide, involving the tumor and affected tissues. The patients progressed satisfactorily and histopathology confirmed the diagnosis of abdominal wall endometrioma in all cases. CONCLUSION: There was a clear relationship between cesarean section and abdominal wall endometrioma. Ultrasound studies and CT scans helped to plan the surgical approach, allowing resection of the tumor and all adjacent affected tissues. PMID- 21537743 TI - Ethyl-2-cyanoacrylate as a sealant after partial cecum resection in rattus norvegicus albinus. AB - OBJECTIVE: To evaluate the use of ethyl-2-cyanoacrylate in the treatment of an injury caused in a partially excluded segment of the mouse gut: the cecum. METHODS: We used 45 male Wistar rats, divided into three equal groups; in all there was performed a partial resection of the cecum. The groups were designated as Group 1: the lesion was treated with application of ethyl-2-cyanoacrylate, Group 2: suture and application of ethyl-2-cyanoacrylate, Group 3: purse-string suture. The animals were monitored postoperatively and half of each group was necropsied 14 days after the procedure, the remaining on the 28th. They were subjected to macroscopic evaluation, had cecal samples collected for histological examination and the findings were submitted to statistical analysis. RESULTS: Weight gain after the experiment was different among groups (p=0.028). The presence of microabscesses was higher at 28 days postoperatively in group 2 when compared to group 3 (p=0.003). The collagen deposition on the 28th postoperative day was greater in group 1 (p=0.036) and intensity of inflammation at the 14th postoperative day was greater in group 1 (p=0.045). In the other parameters there was no statistical difference. CONCLUSION: The use of ethyl-2-cyanoacrylate was effective in the treatment of cecal stump exclusion of rats as for macroscopic and microscopic findings and postoperative outcome. PMID- 21537744 TI - Effect of oral supplementation of vitamin C on intestinal anastomotic resistance. AB - OBJECTIVE: To compare the resistance of anastomosed and intact jejunal segments of rats submitted to administration of vitamin C in different postoperative periods. METHODS: Fifty Wistar rats underwent enterotomy followed by end-to-end anastomosis of the jejunal segment, 10 cm from the duodenojejunal flexure. The animals were divided into two groups (n = 25): Group I--control; Group II- administration of oral vitamin C 100 mg/kg. We evaluated the bursting pressures of the anastomotic and the intact jejunal segments in the third, fifth, seventh, 21st and 28th postoperative days. RESULTS: The rats that received vitamin C had higher anastomotic bursting pressure in the fifth, seventh and 28th postoperative days. The same happened with the bursting pressures of intact jejunal segments. CONCLUSION: Vitamin C increased the resistance of jejunal anastomoses in rats, both in the immediate and in late postoperative periods. In addition, the final resistance of intact jejunal segments of rats under administration of vitamin C was significantly higher than in the control group. PMID- 21537745 TI - [Management of chronic pain after inguinal hernioplasty]. AB - Chronic groin pain after herniorrhaphy is a concern, as approximately 10% of patients undergoing inguinal hernia repair have symptoms, which often limit physical ability. The etiopathogenesis is related to periostitis pubis (somatic pain) and more often to nerve injury (neuropathic pain). It is clinically important to distinguish between these two types of pain because treatment can be different. The physician should establish a routine diagnosis and treatment, and most patients will need surgical approach. Prevention of this condition is of great importance and can lead to a lower incidence of the syndrome. Some measures are key, such as how to avoid application of stitches or clips to the pubis periosteum, using the prosthesis carefully and identifying the nerves in the groin. This last measure is certainly the most important in the prevention of chronic pain and involves thorough knowledge of anatomy and the use of refined technique. PMID- 21537746 TI - [Neck skin collision tumor]. AB - The collision or mixed tumor is a malignant neoplasm of the skin related to sun exposure and incidence rates of up to 1.5%. It displays a distinctive clinical behavior in relation to other malignancies of the skin and the histological diagnosis, characterized by the collision between a basal cell carcinoma and squamous cell carcinoma, i.e., two malignancies with distinct histologies and sharp interface between them. The case reported was of a male, 73-year-old patient, with two cervical lesions progressively growing in recent months. The chosen treatment was surgery. Histological examination showed the presence of squamous cell carcinoma adjacent to basal cell carcinoma. These tumors preferentially occur in light-skinned men in the fifth or sixth decades of life. Their most common location is in the head and neck, especially in the central part of the face. The differential diagnosis of basal-squamous carcinoma is defined by distinct histological criteria, since both tumors have similar clinical behavior. Local recurrence rates vary from 12% to 45%, whereas regional ones are of approximately 7.5%. The main prognostic factors are gender, surgical margins, perineural infiltration and lymph node status. The treatment of choice is resection, radiotherapy being indicated as adjuvant or to inoperable lesions. Local recurrence is the main limiting factor in disease-free survival, with poor results. PMID- 21537747 TI - [The class and the classroom: a space-time of knowledge production]. AB - The teacher/student relationship is considered to be cultural, but it is also pedagogical, as it is established by means of the knowledge intentionally taught and learned. In this scene, the teaching activity must, necessarily, include moments of reflection and criticism, during which the meaning and the teaching methods must be brought about by presenting the student with one's own perspective, while at the same time learning from him, as well as moments in which both will experience and exchange this "magic" event called "classroom". This essay presents methods and techniques which make it possible to turn these moments into opportunities for knowledge building. PMID- 21537748 TI - [Traumatic lung hernia]. AB - Traumatic lung herniation is an unusual clinical problem. We present a case of a large left post-traumatic lung hernia on the left, anterior, second intercostal space following blunt chest trauma. An important factor in the etiology of these lesions is the relative lack of muscular support of the anterior part of the chest. This report describes the diagnosis and management of a post-traumatic lung hernia. PMID- 21537749 TI - [Gastrointestinal stromal tumor (GIST): case report]. AB - The authors report a case of a male patient in his forties with progressive abdominal pain associated with weight loss, dyspnea, and edema of the inferior limbs, culminating in a surgical acute abdomen. A segmental enterectomy containing a lesion of about 10 cm in diameter was performed. It was later confirmed, by means of immuno-histochemistry, as being a Gastrointestinal Stromal Tumor of high biological aggressiveness. Etiology, diagnosis, classification, prognosis and therapeutic with Imatinib Mesylate-STI-571 (Glivec(r)-Novartis) are hence discussed. PMID- 21537750 TI - Potential immunological markers for diagnosis and therapeutic assessment of toxocariasis. AB - In human toxocariasis, there are few approaches using immunological markers for diagnosis and therapeutic assessment. An immunoblot (IB) assay using excretory secretory Toxocara canis antigen was standardized for monitoring IgG, IgE and IgA antibodies in 27 children with toxocariasis (23 visceral, three mixed visceral and ocular, and one ocular form) for 22-116 months after chemotherapy. IB sensitivity was 100% for IgG antibodies to bands of molecular weight 29-38, 48 54, 95-116, 121-162, >205 kDa, 80.8% for IgE to 29-38, 48-54, 95-121, > 205 kDa, and 65.4% for IgA to 29-38, 48-54, 81-93 kDa. Candidates for diagnostic markers should be IgG antibodies to bands of low molecular weight (29-38 and 48-54 kDa). One group of patients presented the same antibody reactivity to all bands throughout the follow-up study; in the other group, antibodies decayed partially or completely to some or all bands, but these changes were not correlated with time after chemotherapy. Candidates for monitoring patients after chemotherapy may be IgG antibodies to > 205 kDa fractions, IgA to 29-38, 48-54, 81-93 kDa and IgE to 95-121 kDa. Further identification of antigen epitopes related to these markers will allow the development of sensitive and specific immunoassays for the diagnosis and therapeutic assessment of toxocariasis. PMID- 21537752 TI - Protective and risk factors for toxocariasis in children from two different social classes of Brazil. AB - The aim of this study was to analyze the prevalence of Toxocara spp. antibodies in children from two different socioeconomic classes in the Presidente Prudente municipality, Sao Paulo State, Brazil, and the protective and risk factors associated with toxocariasis. One hundred and twenty-six middle-class (MC) and 126 disadvantaged children (DC) were included in this study. Anti-Toxocara ELISA test was performed in order to evaluate seroprevalence. A survey was applied to the children's guardians/parents in order to analyze the protective and risk factors. The overall prevalence was 11.1%, and of 9.5% (12/126) and 12.7% (16/126) for MC and DC subgroups, respectively. Toxocara seropositivity was inversely proportional to the family income. A high household income was considered a protective factor for toxocariasis in the total population and in both MC and DC subgroups. Being a girl was considered a protective factor for the total population and for both subgroups. Whilst being an owner of cat was a risk factor for children belonging to the total and for both MC and DC subgroups, having dog was considered as a risk factor for only the MC. Epidemiologic protective/factor risks can be distinct depending on the strata of the same population. Thus, it is relevant to evaluate these factors independently for different socioeconomic classes in order to design future investigations and programs for preventing the infection of human beings by Toxocara spp. and other geohelminths. PMID- 21537753 TI - Immunization status of residents in pediatrics at the Federal University of Sao Paulo, Brazil. AB - Vaccination of health care workers is an efficient way to reduce the risk of occupational infection and to prevent nosocomial transmission to vulnerable patients. Despite this, achieving high immunization rates among those professionals is a challenge. We assessed the immunization status of Residents in Pediatrics at the Federal University of Sao Paulo from June to December 2008. Their immunization records were checked and evaluated according to the Brazilian Immunization Schedule for health care workers. Considering all required vaccines, only 3.1% of the 64 Residents were up-to-date with their immunizations. Influenza was the vaccine with the lowest uptake (3.1%) and measles and rubella were diseases with the highest evidence of immunity (62.5% each). Only 37.5% of Residents had received three hepatitis B vaccine doses with a subsequent serology confirming seroconversion. Moreover, the vast majority of Residents in Pediatrics who were not up-to-date were unaware of the fact. Both medical schools and Pediatric Residence programs should not only offer information but also check vaccination records in an effort to keep their healthcare workers' vaccinations up-to-date. PMID- 21537754 TI - Assessment of physical impairments in leprosy patients: a comparison between the world health organization (who) disability grade and the Eye-Hand-Foot score. AB - This cross-sectional study assessed the grade of physical impairments in 61 individuals with leprosy receiving multidrug therapy (MDT) under the Brazilian Unified Health System (SUS), and residing in Campina Grande, Paraiba State, Brazil. Impairments were assessed using the disability grade (DG) standardized by the WHO, and the EHF score (Eye-Hand-Foot sum of impairment scores). Impairments were detected in 25 (41%) of the subjects. A total of 14 (23%) patients scored DG 1, while 11 (18%) were assigned DG 2. The EHF score ranged from 1 to 10 points in the group of patients with physical impairments, with a mean score of 3.6 points. The majority of individuals with impairments were affected in at least two sites. We conclude that the EHF score showed overlapping impairments in the segments examined and may be more appropriate than the DG classification system for describing the degree of physical impairment of leprosy patients. PMID- 21537755 TI - Evaluation of glycoprotein B genotypes and load of CMV infecting blood leukocytes on prognosis of AIDS patients. AB - BACKGROUND: Cytomegalovirus (CMV) remains an important pathogen to immunocompromised patients even in the era of HAART. The present study aimed at evaluating the influence of CMV viral load and its gB genotypes on AIDS patients' outcome. METHODS: Blood samples of 101 AIDS patients were collected and tested for HIV load, CD4 - cell count and opportunistic pathogens, including CMV. Semi nested PCRs were run to detect CMV genome and in the positive samples, gB genotyping and CMV load were established using enzymatic restriction and real time PCR, respectively. All patients were clinically followed for four years. RESULTS: In thirty patients (31%) CMV was detected and all fatal cases (n = 5) occurred in this group of patients (p = 0.007), but only two patients had CMV disease (1.9%). However, viral load was not statistically associated with any analyzed parameter. The most frequently observed CMV genotype was gB2 (45.16%) followed by gB3 (35.48%). gB2 genotype was more frequently found in patients with CD4-cell counts under 200 cells/mm3 (p = 0.0017), and almost all fatal cases (80%) had gB2 genotype. CONCLUSIONS: Our study suggests that CMV and its polymorphisms in biologically relevant genes, such as the gB encoding ORF, may still influence the prognosis and outcome of AIDS patients. The gB2 genotype was associated to patient's bad outcome. PMID- 21537756 TI - Cutaneous sporotrichosis treatment with potassium iodide: a 24 year experience in Sao Paulo State, Brazil. AB - BACKGROUND: Sporotrichosis is a subacute or chronic disease caused by a dimorphic fungus, Sporothrix schenckii. The first and most traditional treatment is potassium iodide in satured solution (SSKI) used by DE BEURMANN in 1907. For its effectiveness, it is still used for cutaneous sporotrichosis. OBJECTIVE: To evaluate the treatment of cutaneous sporotrichosis with SSKI in relation to clinical cure, side effects, length of treatment and reactivation. METHODS: We conducted a retrospective analysis of medical records over a 24-year period (1981 2005). Patients of all ages who were treated in the hospital's division of dermatology were included in the study providing that they had a positive culture of S. schenckii. Satured solution of potassium iodide (3 to 6g per day) was the treatment prescribed. For children, half of the dose was prescribed. RESULTS: The lymphocutaneous disease was prevalent, the cure rate was 94.7%, side effects were described in 5.5% of the cases, mean length of treatment was 3.5 months and possible reactivation was observed in 11.1%. CONCLUSION: SSKI is an effective drug, with many side effects, but with low frequency. Resolution was for maximum six months of treatment. SSKI has been found to be a very effective drug in this retrospective study of culture-proven cases of cutaneous and lymphocutaneous sporotrichosis. It should be used as first drug of choice especially in resource limited settings. PMID- 21537757 TI - Dermatophytoses in domesticated animals. AB - Dermatophytes are among the most frequent causes of ringworm infections in domesticated animals. They are known to serve as reservoirs of the zoophilic dermatophytes and these infections have important zoonotic implication. In Nigeria and probably West Africa, there are not many studies on the incidence of dermatophytosis in domesticated animals. In the current study, 538 domesticated animals with clinically suggestive lesions were investigated for dermatophytes. Identification of dermatophyte species was performed by macro- and micro morphological examination of colonies and by biochemical methods. In the cases of isolates that had atypical morphology and/or biochemical test results, the rDNA internal transcribed spacer region 2 (ITS 2) sequencing was performed. Out of this number, 214 (39.8%) were found to be colonized by a variety of ten species of dermatophytes. M. canis was the most frequently isolated species (37.4%), followed by T. mentagrophytes (22.9%) and T. verrucosum (15.9%). M. persicolor and T. gallinae were jointly the least species isolated with a frequency of 0.55% respectively. The recovery of dermatophyte isolates previously shown to be common etiological agents of dermatophytosis especially from children in the same region suggests that animal to human transmission may be common. Possible implications and recommendations are discussed. PMID- 21537758 TI - Efficacy of Euphorbia hirta latex as plant derived molluscicides against freshwater snails. AB - The toxic effect of binary and tertiary combinations of Euphorbia hirta Linn latex powder with other plant molluscicidal compounds, were evaluated against the freshwater snails Lymnaea (Radix) acuminata and Indoplanorbis exustus in pond. These combinations showed significant time and dose dependent effect against both the snails. These compounds at higher doses were also lethal to freshwater fish Channa punctatus (Bloch) (Channidae {Ophicephalidae}), which shares the habitat with these snails, but the LC90 (24h) doses of snails have no apparent killing properties in fish populations when treated in mixed population of snails and fish. PMID- 21537759 TI - TNF-alpha production and apoptosis in hepatocytes after Listeria monocytogenes and Salmonella Typhimurium invasion. AB - Invasion of hepatocytes by Listeria monocytogenes (LM) and Salmonella Typhimurium (ST) can stimulate tumor necrosis factor alpha (TNF-alpha) release and induce apoptosis. In this study, we compared the behavior of hepatocytes invaded by three L. monocytogenes serotypes (LM-4a, LM-4b and LM-1/2a) and by ST to understand which bacterium is more effective in the infectious process. We quantified TNF-alpha release by ELISA, apoptosis rates by annexin V (early apoptosis) and TUNEL (late apoptosis) techniques. The cell morphology was studied too. TNF-alpha release rate was highest in ST-invaded hepatocytes. ST and LM-1/2a induced the highest apoptosis production rates evaluated by TUNEL. LM-4b produced the highest apoptosis rate measured by annexin. Invaded hepatocytes presented various morphological alterations. Overall, LM-4b and LM-1/2a proved to be the most efficient at cell invasion, although ST adapted faster to the environment and induced earlier hepatocyte TNF-alpha release. PMID- 21537760 TI - Refractory pemphigus vulgaris associated with herpes infection: case report and review. AB - BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune disease characterized by blistering of the skin and mucosa, which develops due to the interaction between predisposing genetic and environmental factors. Infections caused by members of the Herpesviridae family have been suggested as a possible triggering factor for PV. OBJECTIVE AND METHODS: In this report, we investigate the presence of herpesviruses in refractory lesions on the right upper eyelid. The lesion has persisted despite the treatment with corticosteroids. Polymerase chain reaction (PCR) and DNA sequence analysis have been used to detect the DNA of HSV 1/2, VZV, EBV, CMV, HHV-6, HHV-7, and HHV-8. RESULTS: The sample collected from the right upper eyelid has tested positive for HSV 1/2. Sequence analysis has confirmed the PCR results and allowed the identification of the HSV strain as belonging to type 1. After treatment with acyclovir, the lesion of the right upper eyelid has cleared and not relapsed. CONCLUSION: When patients present PV lesions which are refractory to corticosteroid therapy, herpetic infection should be considered. PMID- 21537761 TI - Large gastroenteritis outbreak due to norovirus GII in Sao Paulo, Brazil, summer 2010. PMID- 21537762 TI - [Diarrheal disease: a recurring problem in public health]. PMID- 21537763 TI - [Public presentation of the updated version and historical review of Revista Peruana de Medicina Experimental y Salud Publica]. PMID- 21537764 TI - [Frequency and pathotypes of diarrheagenic Escherichia coli in Peruvian children with and without diarrhea]. AB - INTRODUCTION; Diarrheagenic E. coli (DEC) are a major cause of diarrhea in children in developing countries. However, they are not part of routine diagnosis in clinical laboratories. OBJECTIVES: To determine the DEC prevalence in Peruvian children and to describe the genetic variability of these strains. MATERIALS AND METHODS: A total of 8 003 E. coli strains previously isolated from eight different studies of diarrhea in children, mainly from peri-urban areas of Lima, were analyzed. Diagnosis of DEC was done with Multiplex real-time PCR using genes for each of the 6 DEC groups. Conventional PCR was performed for the detection of additional virulence genes. RESULTS: Globally, the mean prevalence in diarrhea samples (n=4,243) was: enteroaggregative E. coli (EAEC) 9.9%, enteropathogenic E. coli (EPEC) 8.5%, enterotoxigenic E. coli (ETEC) 6.9%, diffusely adherent E. coli (DAEC) 4.8%, Shiga toxin-producing E. coli (STEC) 0.8% and enteroinvasive E. coli (EIEC) 0.6%. The relative frequency of each pathogen varies according to the age and the type of study. The main pathotypes in control samples (n=3,760) were EPEC (10.9%) and EAEC (10.4%). An important variability in the virulence genes frequency and molecular resistance mechanisms for each pathotype was found, without differences between diarrhea and control groups. CONCLUSIONS: DEC are a major cause of diarrhea in Peruvian children. These pathogens are highly heterogeneous. Additional studies are required to determine the prevalence in rural areas of Peru and in severe diarrhea cases. PMID- 21537765 TI - [Adhesion patterns in diffusely adherent Escherichia coli (DAEC) strains isolated from children with and without diarrhea]. AB - INTRODUCTION: Diffusely adherent E. coli (DAEC) is the sixth recognized group of diarrheagenic E. coli. However, its association with diarrhea remains controversial. Variability in the adherence patterns of clinical strains is unknown. OBJECTIVES: To compare the adherence patterns between strains isolated from children with and without diarrhea. MATERIALS AND METHODS: A total of 31 DAEC strains were analyzed, 25 from children with diarrhea and 6 from asymptomatic (control) children, isolated from a cohort study of children under one year of age in the southern districts of Lima. DAEC were identified by PCR (daaD gene). The pattern and adherence score in HEp-2 cell culture were evaluated, Actin polimerization was determined by fluorescence actin staining (FAS) and motility was evaluated by conventional microbiology methods. RESULTS: Diffuse adherence pattern was found in 88% of diarrhea samples and in the total of control strains. The number of bacteria adhered per cell was significantly lower in diarrhea samples (p<0.05). However, actin polymerization was greater in diarrhea samples (60% vs. 17%). Motility test was positive in 60% of the diarrhea samples and in all control samples. CONCLUSIONS: Our findings suggest a difference between adherence patterns, actin polymerization and motility between DAEC strains corresponding to diarrhea and control groups. The significance of these results must be confirmed with a bigger number of strains and determining the presence of virulence genes in the strains. PMID- 21537766 TI - [Validation of the clock drawing test - Manos' version - as a screening test for detection of dementia in older persons of Lima, Peru]. AB - INTRODUCTION: The clock drawing test (PDR-M) - Manos' version - is a brief cognitive assessment tool for dementia detection. Objectives. To assess the validity and reliability of the PDR-M to discriminate between patients with dementia and healthy control subjects. MATERIALS AND METHODS: We evaluated subjects over 65 years of age, excluding those with severe concomitant diseases and those with hearing or visual impairment. We obtained demographic data and performed the PDR-M and Mini Mental State Examination (MMSE). Subjects of the dementia group were also submitted to clinical, laboratory and neuropsychological evaluations as well as computed tomography scanning. Sensitivity and specificity of the PDR-M were calculated as well as the area under the ROC curve. RESULTS: We evaluated 210 individuals, 103 with confirmed diagnosis of dementia and 107 healthy controls with similar age and sex in both groups, but a higher educational level in the control group. Setting a cutoff point of 7, a sensitivity of 99.0% and a specificity of 83.5% were found. When comparing the areas under the ROC curves of the PDR-M and MMSE we found no statistically significant difference. CONCLUSIONS: The PDR-M is a brief and reliable instrument for the detection of dementia in the urban population of Lima, Peru. PMID- 21537767 TI - [Health-related quality of life among urban and rural to urban migrant populations in Lima, Peru]. AB - OBJECTIVES: To explore if there is a difference in the perception and self reported quality of life between rural-to-urban migrants and urban groups. MATERIALS AND METHODS: Cross-sectional study, secondary analysis of the PERU MIGRANT study (PEru's Rural to Urban MIGRANTs Study). WHOQOL-Brief survey' s global scores and per specific domains obtained in the survey were compared using Kruskall-Wallis' test and assessing size effect. RESULTS: A total of 307 subjects (62.2% migrants, 57% female, means age 47 years-old) were surveyed. Compared with the urban group, migrants reported lower quality of life both on the global scores as well as in psychological health and the living environment domains. Migrants reported a higher score on the physical health?s domain. CONCLUSIONS: The impact of rural-to-urban migration on quality of life suggests a differential effect within its specific domains. PMID- 21537768 TI - [Comparison between gastric biopsies without fixation for 24 hours and conventional biopsy for the diagnosis of Helicobacter pylori in a reference hospital in Peru]. AB - OBJECTIVES: To compare gastric biopsies immediately fixed with 10% formalin with biopsies fixed after 24 hours for the detection of Helicobacter pylori (Hp) in a reference hospital in Peru. MATERIALS AND METHODS: A diagnostic test study on gastric biopsies from 72 patients attending the Gastroenterology service of hospital Essalud Alberto Sabogal in Callao was performed. Samples from each patient were divided into two glass jars, one of which was fixed immediately with 10% formalin and the other was fixed after 24 hours. Both groups of samples were processed with the conventional technique of paraffin embedding and staining with hematoxylin-eosin. RESULTS: Hp was found in 56.9% of the group of biopsies which were immediately fixed and in 79.2% of the group of biopsies fixed after 24 hours, showing statistical difference (p <0.001). CONCLUSIONS: There is an increased frequency of diagnosis of Hp in the samples that were fixed after 24 hours, which may suggest that this would act as a biological culture for Hp, which would facilitate its diagnosis. PMID- 21537769 TI - [Differences between observed and estimated by hematocrit hemoglobin and its relevance in the diagnosis of anemia among coastal population in Venezuela: analysis of the second national study of human growth and development (SENACREDH)]. AB - OBJECTIVES: To evaluate the differences between the observed hemoglobin levels and those estimated based on hematocrit in the context of the 2nd National Study of Human Growth and Development of the Venezuelan Population (SENACREDH). MATERIALS AND METHODS: 6,004 individuals were chosen by a probabilistic multistage cluster sampling representing 7,286,781 inhabitants from North Central Coastal area (Vargas, Carabobo, Capital District, Aragua and Miranda). Means of observed and estimated hemoglobin (hematocrit/3) were compared, using t test for related samples and linear regression. RESULTS: Mean difference between the values of observed and estimated hemoglobin was -0.3446 +/-0.0002 (p<0.001); significantly overestimating the hemoglobin values. Regression models of hemoglobin on hematocrit showed an r2=0,87. In order to correct the estimation, we propose a new formula for calculating hemoglobin based on haematocrit values: estimated hemoglobin=(Haematocrit/3.135)+ 0.257. CONCLUSIONS: There is an overestimation of hemoglobin levels from hematocrit levels and therefore an underestimation of the prevalence of anemia; however, a high positive correlation between them was found, allowing modeling for achieving a better estimation of the hemoglobin from the hematocrit value. PMID- 21537770 TI - [Predictive factors of alcohol use problems among patients visiting an emergency room]. AB - OBJECTIVES: To assess the predictive effect of key individual-level characteristics to identify cases of alcohol use problems among patients visiting an emergency room. MATERIALS AND METHODS: The study sample was composed of 371 people attending an emergency room in a public hospital in Lima, Peru, during a period of seven complete days in January, 2005. For data gathering, we used a questionnaire for demographic information, the SIDUC/CICAD for recent use (i.e., in the last 6 hours) of psychoactive substances before arriving to the emergency room, and the AUDIT, to identify alcohol use problems in the last year. Univariate and multivariate logistic regression models were used to estimate the predictive effect of age, sex, area of attention in the emergency room, presence of physical injuries and recent use of alcohol. RESULTS: The odds of being a case of alcohol use problem for males is 26 times the odds of having that problem for females (p-value<0,001). Stratified analysis by sex and adjusted by age and area of attention in the emergency room, showed that males who had recent use of alcohol were more likely of having alcohol use problems as compared to those who did not have recent alcohol use (OR=5.2; 95% CI: 2.4 - 11.5; p<0,001), while for females such an association did not exist. CONCLUSIONS: These results support screening initiatives for those males who have recent alcohol use before arriving to an emergency room in order to identify cases of alcohol-related problems and refer them for an appropriate counseling or medical treatment. PMID- 21537771 TI - [Correlation and concordance between the national test of medicine (ENAM) and the grade point average (GPA): analysis of the peruvian experience in the period 2007 - 2009]. AB - OBJECTIVES: To evaluate the correlation and concordance between the 'Peruvian National Exam of Medicine' (ENAM) and the Mean Grade Point Average (GPA) in recently graduated medical students in the period 2007 to 2009. MATERIALS AND METHODS: We carried out a secondary data analysis, using the records of the physicians applying to the Rural and Urban Marginal Service in Health of Peru (SERUMS) processes for the years 2008 to 2010. We extracted from these registers, the grades obtained in the ENAM and GPA. We performed a descriptive analysis using medians and 1st and 3rd quartiles (q1/q3); we calculated the correlation between both scores using the Spearman correlation coefficient, additionally, we conducted a lineal regression analysis, and the concordance was measured using the Bland and Altman coefficient. RESULTS: A total of 6 117 physicians were included, the overall median for the GPA was 13.4 (12.7/14.2) and for the ENAM was 11.6 (10.2/13.0).Of the total assessed, 36.8% failed the TEST. We observed an increase in annual median of ENAM scores, with the consequent decrease in the difference between both grades. The correlation between ENAM and PPU is direct and moderate (0.582), independent from the year, type of university management (Public or Private) and location. However, the concordance between both ratings is regular, with a global coefficient of 0.272 (CI 95%: 0.260 to 0.284). CONCLUSIONS: Independently of the year, location or type of university management, there is a moderate correlation between the ENAM and the PPU; however, there is only a regular concordance between both grades. PMID- 21537772 TI - [Circulation of a different lineage of dengue virus serotype 2 American / Asian genotype in the Peruvian Amazon, 2010]. AB - Our objective was to determine the genotype of the dengue virus type 2 (DENV-2) that circulated in the Amazon region of Peru between November 2010 and January 2011. We analyzed eight samples collected during dengue surveillance activities in the cities of Iquitos, Yurimaguas, Trujillo, Tarapoto and Lima between November 2010 and January 2011 that were sent to Insitituto Nacional de Salud. The viruses were isolated in C6/36 HT cell line. Viral RNA was extracted and the serotype (RT - PCR multiplex) and genotype (RT-Nested PCR of the region E/NS1) were determined. Finally, the E/ NS1 amplicons were sequenced and analyzed by phylogeny. The phylogenetic analysis revealed the introduction of a different lineage which entered in Peru by the end of 2010. These isolates found in Iquitos and other cities in Peru are closely related to DENV-2 isolates that circulated in Brazil during 2007 and 2008, associated with severe dengue cases and deaths. In conclusion, we detected the introduction of a different lineage of DENV-2 America / Asia genotype in Peru that could be associated with the presence of more severe cases. PMID- 21537773 TI - [Clinical characteristics of patients admitted to hospital "Cesar Garayar Garcia", Iquitos during the dengue epidemic, January-February 2011]. AB - We conducted a clinical description of confirmed dengue cases admitted to the Hospital " Cesar Garayar Garcia" in Iquitos from January 25 to February 5, 2011. According to current WHO classification, major warning signs leading to hospitalization were: abdominal pain (28/28) and persistent vomiting (15/28), the causes of severity were: hypotension (9 / 13), severe bleeding (6 / 13) and plasma extravasation with respiratory distress (4 / 13). The median patient age was 22 years, however, 8 / 13 patients classified as severe dengue were under 16 years. In conclusion, unlike previous epidemics, we found a high involvement of young people and severity in the clinical presentation predominating a high frequency of shock (hypotension) and vascular leakage, which could be related to the circulation of an emerging variant DENV-2 which is more virulent. PMID- 21537774 TI - [Association of cardiovascular autonomic neuropathy and prolonged QT interval with cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus]. AB - In order to evaluate the relationship between cardiovascular autonomic neuropathy and corrected QT interval (QTc) with cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus, we followed up for 5 years 67 patients attending the outpatient Endocrinology Service. 82% completed follow-up and cardiovascular events occurred in 16 patients. We found that long QTc interval was the only variable significantly associated with cardiovascular morbidity and mortality in the multiple logistic regression analysis (RR: 13.56, 95% CI: 2.01 91.36) (p = 0.0074). PMID- 21537775 TI - [Malocclusions in children and adolescents from villages and native communities in the Ucayali Amazon region in Peru]. AB - We conducted a cross-sectional descriptive study to assess the prevalence of malocclusions in children and adolescents aged 2 to 18 years of villages and native communities of the Ucayali jungle of Peru. We assessed the presence of malocclusions using Angle's classification and orthodontic changes. We evaluated 201 individuals, 106 (52.7%) were women, most of them (54.7%) had between 6 and 12 years. The prevalence of malocclusions was 85.6%, the most prevalent according to Angle's classification was class I (59.6%). Orthodontic alterations were present in 67.2% of cases. The most frequent were dental crowding (28.4%), anterior crossbite (17.4%), exaggerated overjet (8.5%), excessive overbite (5.0%) and anterior open bite (5.0%). We found a high prevalence of malocclusion and orthodontic changes in the evaluated native communities, highlighting the need to implement preventive programs to improve the oral health of these neglected populations. PMID- 21537776 TI - [Hemoglobin and testosterone: importance on high altitude acclimatization and adaptation]. AB - The different types of response mechanisms that the organism uses when exposed to hypoxia include accommodation, acclimatization and adaptation. Accommodation is the initial response to acute exposure to high altitude hypoxia and is characterized by an increase in ventilation and heart rate. Acclimatization is observed in individuals temporarily exposed to high altitude, and to some extent, it enables them to tolerate the high altitudes. In this phase, erythropoiesis is increased, resulting in higher hemoglobin and hematocrit levels to improve oxygen delivery capacity. Adaptation is the process of natural acclimatization where genetical variations and acclimatization play a role in allowing subjects to live without any difficulties at high altitudes. Testosterone is a hormone that regulates erythropoiesis and ventilation and could be associated to the processes of acclimatization and adaptation to high altitude. Excessive erythrocytosis, which leads to chronic mountain sickness, is caused by low arterial oxygen saturation, ventilatory inefficiency and reduced ventilatory response to hypoxia. Testosterone increases during acute exposure to high altitude and also in natives at high altitude with excessive erythrocytosis. Results of current research allow us to conclude that increase in serum testosterone and hemoglobin is adequate for acclimatization, as they improve oxygen transport, but not for high altitude adaptation, since high serum testosterone levels are associated to excessive erythrocytosis. PMID- 21537778 TI - [Environmental drivers of emergence and spreading of Vibrio epidemics in South America]. AB - Vibrio cholerae and V. parahaemolyticus are the two Vibrio species with a major impact on human health. Diseases caused by both pathogens are acquiring increasing relevance due to their expansion at global scale. In this paper, we resume the ecological aspects associated with the arrival and spreading of infections caused by V. parahaemolyticus and V. cholerae in Peru from a South American perspective. Moreover, we discuss the similarities in the emergence in Peru of cholera cases in 1991 and V. parahaemolyticus infections in 1997. These constituted exceptional experiments to evaluate the relationships between the Vibrio epidemics and changes in the environment. The epidemic radiations of V. cholerae and V. parahaemolyticus constitute to clear examples supporting the oceanic dispersion of pathogenic vibrios and have enabled the identification of El Nino events as a potential mechanism for the spreading of diseases through the ocean. PMID- 21537777 TI - [Vertical transmission of HTLV-1 in Peru]. AB - Human type 1 T-cell lymphotropic virus (HTLV-1) infection has been described in many areas of the world, including Caribbean countries, Japan, Africa, Oceania and South America. In this review we define the endemicity of HTLV-1 in the country proposing four epidemiological criteria. Then we discuss the core subject of the review, which is the vertical transmission of HTLV-1. This mechanism is one of the main forms of transmission in our country. Within the development of this particular topic, we present an estimated rate of vertical transmission and the risk factors associated to vertical transmission based on an exhaustive review of the national and international literature. This review pretend to provide a first approach to the vertical transmission of HTLV-1, an aspect poorly studied in our country. PMID- 21537779 TI - [Challenges and problems in the microbiological diagnosis in diarrhea]. AB - Clinical microbiology laboratories in Peru have the task to diagnose the infectious agents present in the clinical samples, for this, they have different tools available; their use depends on having material and human resources. The microbiological laboratory can perform simple and complex tests, depending on the level, the geographical location and the available resources. We mention the problems found with the available laboratory procedures and their potential diagnostic aid. We emphasize the need of having standardised procedures, the continuous education and training of the staff, and the importance of the laboratory network led by the Instituto Nacional de Salud. PMID- 21537780 TI - [Campylobacter and campylobacteriosis: a view from South America]. AB - The thermotolerant species of Campylobacter have become very important in public health, especially as agents of infectious diarrhea in human beings. In this brief revision we present part of the available information generated in South America about epidemiological, clinical and bacteriological aspects of campylobacteriosis and we identify some differences between the observed and documented campylobacteriosis in South America compared to those described in industrialized countries. PMID- 21537781 TI - [Experiences in the epidemiological surveillance of foodborne pathogens by pulsed field gel electrophoresis (PFGE) in Peru]. AB - Foodborne diseases and other enteric infections often occur as outbreaks and cause morbidity and mortality all over the world. In Peru, they represent a serious public health problem, and are caused by a great variety of infectious agents. For epidemiological research, a wide array of typification methods are used. One of the most important tools for the molecular subtyping of bacterial pathogens is the Pulsed Field Gel Electrophoresis (PFGE), which is a highly precise method that allows the discrimination between different bacterial isolates which are epidemiologically related. The Instituto Nacional de Salud del Peru (INS) is part of the WHO Global Foodborne Infections Network (WHO-GFN) and of the PulseNet Latin American and Caribbean Net (PN-AL & C), with whom it shares the genetic profiles of the isolated pathogenic strains, so that it is possible to compare de genotypes of similar strains found in different countries and to identify the occurrence of epidemic outbreaks in the region, strengthening the regional system of epidemiological surveillance and generating a rapid, coordinated response between the countries. We present the two last years experience including the advances in the use of these strategic tools that have allowed us to characterize genotype patterns implicated in foodborne diseases from isolates recovered in the laboratory network of Peru. PMID- 21537782 TI - [Historical report: first isolation of Vibrio cholera serogroup O1 biovar El Tor serovar Inaba during the cholerae epidemic in Peru - 1991]. AB - 20 years ago, a new diarrheal disease was introduced in Peru and the Enteropathogens Reference Laboratory of the Instituto Nacional de Salud had an outstanding role in the isolation and rapid and timely identification of Vibrio cholerae. Cholera had not been seen before, but during the last week of January 1991 an outbreak of acute diarrhea was detected, presenting intense dehydration and some deaths. The epidemic affected, in the beginning, many locations of the peruvian coast. Some working teams of the General Office of Epidemiology and of the Instituto Nacional de Salud obtained fecal samples from patients with acute diarrhea coming from the cities of Chancay, Chimbote, Piura and some hospitals in Lima. The collected samples were transported on Cary and Blair media and processed in the National Reference Laboratory of Enteropathogens (LANARE) of the Instituto Nacional de Salud. Vibrio cholerae serogroup 01 biovar El Tor serovar Inaba was isolated from all the samples, it was sensible to tetracyclines and other antibiotics. This research confirmed the first outbreak of cholera in Peru. PMID- 21537783 TI - [Neonatal dengue in Peru: a case report]. AB - We present the case of a full-term female newborn, whose mother died seven days postpartum from multi-organ failure due to severe dengue confirmed by NS1 antigen detection and positive IgM. The newborn did not have any complication, but at the fourth day of life she developed fever, jaundice, signs of plasma leakage, thrombocytopenia, hepatomegaly, ascitis, and others signs of systemic inflammation response syndrome. She fully recovered with supportive treatment. The RT-PCR test of a peripheral blood sample revealed a positive result for the dengue virus serotype 2, confirming the first case of neonatal dengue reported in Peru. PMID- 21537784 TI - [Fulminant myocarditis and acute gastroenteritis due to Coxsackie virus B6]. AB - We present the case of a young woman who suffered cardiogenic due to by Coxsackie virus B6. The patient attended a private clinic with an acute gastroenteritis and after one hour of receiving hydratation,she developed hypotension and shock, severe hypoxemia and bilateral lung infiltrate. The patient entered the Intensive Care Unit, where she received hemodynamic support. Due to the clinical picture and cardiac enzymes increase, a cardiac failure was suspected and the echocardiographic findings suggested "myocarditis". The evolution was successful and Coxsackie B6 virus infection diagnosis was made during the follow up by increase of the levels of antibodies for virus Coxsackie B6. PMID- 21537785 TI - [Oscar Grados Bazalar (1929 - 2008)]. PMID- 21537786 TI - [Etiologic agents of diarrhea: bacteria and parasites of importance in children and adults]. PMID- 21537787 TI - [Levels of CD4 cell counts in hospitalized patients with diagnosis of dengue in hospital "Cesar Garayar Garcia", Iquitos]. PMID- 21537788 TI - [Impact of the dengue epidemic due to a new lineage of DENV-2 American/ Asian genotype in the health services demand in hospital "Cesar Garayar Garcia", Iquitos]. PMID- 21537789 TI - [Strongyloides spp. larvae in lettuces obtained in markets of Lima]. PMID- 21537790 TI - [Need for a consensus in the diagnosis of human toxocariasis: implications for the Latin American public health]. PMID- 21537791 TI - [Vertical or circumstantial transmission?]. PMID- 21537792 TI - [Using Twitter to promote continuous education and health research in Peru]. PMID- 21537793 TI - [Climate change, rainfall, society and disasters in Latin America: relations and needs]. PMID- 21537794 TI - Dynamic behavior of sylvatic yellow fever in Brazil (1954-2008). AB - INTRODUCTION: Sylvatic yellow fever (SYF) is enzootic in Brazil, causing periodic outbreaks in humans living near forest borders or in rural areas. In this study, the cycling patterns of this arbovirosis were analyzed. METHODS: Spectral Fourier analysis was used to capture the periodicity patterns of SYF in time series. RESULTS: SYF outbreaks have not increased in frequency, only in the number of cases. There are two dominant cycles in SYF outbreaks, a seven year cycle for the central-western region and a 14 year cycle for the northern region. Most of the variance was concentrated in the central-western region and dominated the entire endemic region. CONCLUSIONS: The seven year cycle is predominant in the endemic region of the disease due the greater contribution of variance in the central western region; however, it was possible identify a 14 cycle that governs SYF outbreaks in the northern region. No periodicities were identified for the remaining geographical regions. PMID- 21537795 TI - Aedes aegypti and Aedes albopictus (Diptera: Culicidae): coexistence and susceptibility to temephos, in municipalities with occurrence of dengue and differentiated characteristics of urbanization. AB - INTRODUCTION: The aim of the present study was to verify the coexistence between Aedes aegypti and Aedes albopictus populations in municipalities of the States of Parana and Santa Catarina with different urbanization profiles where dengue occurs and evaluate their susceptibility to the organophosphate temephos. METHODS: The number of eggs per ovitrap were counted and incubated for hatching to identify the species. Data analysis of the populations was conducted to determine randomness and aggregation, using the variance-to-mean ratio (index of dispersion). Susceptibility to temephos was evaluated by estimation of the resistance ratios RR50 and RR95. Aedes aegypti samples were compared with the population Rockefeller and Aedes albopictus samples were compared with a population from the State of Santa Catarina and with the Rockefeller population. RESULTS: Coexistence between Aedes aegypti and Aedes albopictus and the aggregation of their eggs were observed at all the sites analyzed in the State of Parana. CONCLUSIONS: All the Aedes aegypti populations from the State of Parana showed alteration in susceptibility status to the organophosphate temephos, revealing incipient resistance. Similarly, all the Aedes albopictus populations (States of Parana and Santa Catarina) presented survival when exposed to the organophosphate temephos. PMID- 21537796 TI - Ultrastructural study on the morphological changes to male worms of Schistosoma mansoni after in vitro exposure to allicin. AB - INTRODUCTION: Garlic has a wide range of actions, including antibacterial, antiviral, antifungal, antiprotozoal and anthelmintic actions. This antiparasitic activity has been attributed to allicin, which is the main constituent of garlic. The present study aimed to investigate the in vitro activity of allicin on the tegument of adult Schistosoma mansoni worms using scanning electron microscopy. METHODS: Swiss Webster mice were infected with S. mansoni cercariae (100 per mouse) and sacrificed 50 days later to acquire the adult worms. These worms were collected by perfusion and placed in RPMI medium 1,640 at 37 degrees C before transferring to RPMI media containing 0 (control), 5, 10, 15 and 20mg/mL of allicin, where they were incubated for 2h. The worms were fixed in 2.5% glutaraldehyde solution, washed twice, post-fixed in osmium tetroxide, washed twice and then dehydrated with ascending grades of ethanol. The samples were air dried, mounted on stubs, gold coated in an ion sputtering unit and viewed using a scanning electron microscope. RESULTS: A concentration of 5mg/mL caused wrinkling in the tegument; a concentration of 10mg/mL resulted in changes to tubercles and loss or modification of spines. With 15 and 20mg/mL increasing damage to the tegument could be seen, such as vesicle formation and the presence of ulcers. CONCLUSIONS: These findings demonstrate the effect of allicin on adult S. mansoni worms and indicate that most of the changes occur at concentrations greater than that normally indicated for treatment. PMID- 21537797 TI - Diagnosis of human herpesvirus 6B primary infection by polymerase chain reaction in young children with exanthematic disease. AB - INTRODUCTION: Exanthem subitum is a classical rash disease of early childhood caused by human herpesvirus 6B (HHV-6B). However, the rash is frequently misdiagnosed as that of either measles or rubella. METHODS: In this study, a nested multiplex polymerase chain reaction (PCR) was used to diagnose HHV-6B primary infection, differentiate it from infections caused by HHV-6A and compare it to antibody avidity tests. The samples were separated into case group and control group according to the results of the indirect immunofluorescence assay (IFA) technique. RESULTS: From the saliva samples analyzed, HHV-6A DNA was detected in 3.2% of the case group and in 2.6% of the control group. Regarding HHV-6B, PCR detected viral DNA in 4.8% of the case group and in 1.3% of the control group. Among the serum samples studied, a frequency of 1.7% was determined for HHV-6A in the case group and 1.2% in the control group. PCR did not detect HHV-6B DNA in serum samples. The sensitivity and specificity of the PCR technique ranged from 0% to 4.8% and 97.5% to 100%, respectively, compared to IFA. CONCLUSIONS: The PCR technique was not suitable for diagnosing primary infection by HHV-6B in children with exanthematic disease and should not substitute the IFA. PMID- 21537798 TI - Prevalence of intestinal parasites in preschool children in the region of Uberlandia, State of Minas Gerais, Brazil. AB - INTRODUCTION: Children are an important high-risk group for helminth and protozoa infections. Daycare centers are environments where children have proven to be more susceptible to acquiring intestinal parasites. Thus, the purpose of this study was to verify the prevalence of intestinal parasites in children who attended the two daycare centers maintained by the local government of Uberlandia, State of Minas Gerais, Brazil. METHODS: Fecal samples were collected from 133 children (73 children at the Public Preschool for Early Childhood Education, PPECE A, and 60 at the PPECE B) following identification according to sex and age and agreement to participate by parents or guardians who signed the free, informed consent form. The samples were examined by the Lutz method. RESULTS: Coproparasitological tests performed on 133 children showed that 29.3% of them were parasitized for enteroparasites or commensals, 6.7% of the children presented polyparasitism. Among the protozoa, Giardia lamblia were the most prevalent and Hymenolepis nana were the most frequent among the helminths. CONCLUSIONS: Thus, analysis of the results showed that intestinal parasites still represent a public health problem, especially among children and in areas where the socioeconomic and educational conditions are less favorable. PMID- 21537799 TI - An outbreak of influenza among physicians during the first wave of Mexico City's 2009 H1N1 epidemic. PMID- 21537800 TI - [Scorpion sting and its relationship with child chronic kidney disease]. PMID- 21537801 TI - Prevalence and socioeconomic correlates of unintented pregnancy among women in rural Bangladesh. AB - OBJECTIVE: This paper examines the prevalence and socioeconomic correlates of unintended pregnancy among rural women in Bangladesh. MATERIAL AND METHODS: The study used data from the 2007 Bangladesh Demographic and Health Survey. Chi square tests and binary logistic regression were performed using the data set. RESULTS: Overall, 30.0% of the most recent births were unplanned. Both bivariate and multivariate analyses confirm that age, ever use of contraceptive method, religion and wealth index were important determinants of unintended pregnancy. Pregnancy order appeared as the most single determinant of unplanned pregnancy. Women with fourth or higher order pregnancies were at higher risk (OR=4.31, 95%CI; 4.31-6.56) of unintended pregnancy than those who experienced pregnancy for the first time. CONCLUSION: Unintended pregnancy is common in rural Bangladesh. Intervention programs regarding reproductive health and services should be undertaken. Awareness should be created to continue the use of modern contraceptive methods to avoid unintended pregnancy. PMID- 21537802 TI - Fall-related injuries among youth under 20 years old who were treated in Nicaraguan emergency departments, 2004. AB - OBJECTIVE: To describe the circumstances of fall-related injuries among youth 0 19 years treated in emergency departments in Nicaragua; to estimate the incidence rates (IR) of falls; and, to identify areas for prevention efforts. MATERIAL AND METHODS: All patients <20 years who were residents of Managua, Leon, Jinotepe, and Ciudad Sandino (6593) were selected for analysis. Data were collected with the 2004 Injury Surveillance System. RESULTS: In 2004, the IR of falls for youth <20 years old was 104.2 incidents per 10000 persons. The IR for male youth was twice that of female youth. Overall, trees (23.3%) and beds (15.2%) were the main objects involved in falls. Fractures were the leading injuries sustained. CONCLUSIONS: This study identifies three areas that can be addressed: furniture, recreation, and physical environment. Interventions that may be most useful for caregivers and adolescents include changes in the home environment and recreation play areas, as well as educational programs. PMID- 21537803 TI - Racism and mental health among university students in Mexico City. AB - OBJECTIVE: To assess whether differences exist in experiences of discrimination, perceptions of physical attractiveness, socioeconomic position, and mental health according to student's skin color. MATERIALS AND METHODS: The population included students from a public university in Mexico City. The following three groups were created based on skin color: white, light brown, and brown. By means of regression models, we evaluated whether differences in mental health according to skin color could be due to experiences of discrimination, perceptions of physical attractiveness, and/or socioeconomic position. RESULTS: Students with brown skin had lower levels of self-esteem and vitality and higher levels of fatigue and alcohol consumption. These differences were explained by more frequent experiences of discrimination and because students with brown skin perceived themselves as less attractive. CONCLUSIONS: This is one of the first studies to document the possible effects of racism on mental health among the urban population. Verification of these findings in representative samples is required. PMID- 21537804 TI - [Parental aptitude to prevent child sexual abuse after a participatory education intervention]. AB - OBJECTIVE: To evaluate the aptitude of parents regarding the educational impact of equity education for children to prevent child sexual abuse using participatory strategies. MATERIAL AND METHODS: Quasi-experimental design. Ninety two parents with children in preschool were included in the study. The parents were given a course using participatory educational strategies for one hour daily over a period of 20 days. Prior to the course, a group of experts in child education and sexology prepared a questionnaire with 20 sentences. A Wilcoxon test was used to compare intergroup differences RESULTS: We found statistically significant differences in the parents' responses before and after the educational intervention, with a median (range) of 10(2-12)/18(6-20), p<0.01. CONCLUSIONS: A significant change in aptitude was noted when parents attended classes using a participatory strategy to learn about the impact of educational equity for the prevention of child sexual abuse. Thus, it is imperative to continue evaluating different educational strategies. PMID- 21537805 TI - [Targeted treatment of Aedes aegypti at localities with high risk for dengue transmission, Morelos, Mexico]. AB - OBJECTIVE: To determine the relative importance of Aedes aegyti breeding sites for potential targeted dengue control interventions in Morelos. MATERIAL AND METHODS: Cross-sectional entomological surveys were conducted and collection of Ae. aegypti pupae was taken from all water-holding containers in Cuautla, Jojutla and Tlaquiltenango during dry (1,713 households) and rainy (1,677) seasons in 2008. Relative importance of different types of breeding sites was determined by the contribution (%) to total pupae production within each locality. RESULTS: In Cuautla most pupae during the dry season were found in wash basins (48.5%), tanks and buckets/pots (15% each); during the rainy season, diverse small items (21.3%), buckets/pots (19.3%) and plant pots (12.9%) were more productive. In Jojutla and Tlaquiltenango, 97% of all pupae was found in plant pots during the dry season; during the rainy season diverse small items (26.3%), washing/cooking utensils (13.9%), buckets/pots (12.9%) and plant pots (12.7%) were significant. CONCLUSION: Prevention and control of the dengue vector should be based on this kind of evidence to target the most productive breeding-sites. PMID- 21537806 TI - Scale for assessing the quality of Mexican adults' mealtime habits. AB - OBJECTIVE: To construct a scale for assessing the quality of mealtime habits in a sample of urban Mexican adults, computing the contribution of a set of advisable and unadvisable mealtime habits. MATERIAL AND METHODS: We performed an exploratory factor analysis among 7 472 adults participating in the baseline assessment of the Health Workers Cohort Study, to assess the mealtime habits quality. Likelihood ratio test for difference of two probabilities and test for the difference of two means were used to identify differences between low and high categories of the Mealtime Habits Quality Scale (MHQS) across variables of interest. RESULTS: Participants with the top quality of mealtime habits showed lower rates of overweight, obesity, abdominal obesity, and elevated body fat. They were also more adherent to a prudent dietary pattern than a western dietary pattern, and consumed more fruits and vegetables. CONCLUSIONS: Anthropometric and dietary variables differed across MHQS categories. However, further validation of the scale, and assessment of their ability to predict weight gain or related diseases are needed, using prospective and intervention studies. PMID- 21537807 TI - [Interventions involving parents in order to impact adolescent sexual behavior]. AB - OBJECTIVE: To examine the effects of educational interventions that incorporate parent participation to modify adolescent sexual behavior. MATERIAL AND METHODS: We conducted a systematic search of 5 electronic databases for articles published between 2002 and 2009 that evaluated educational interventions involving parents. RESULTS: Nineteen articles evaluated 15 interventions that met all the criteria for inclusion. They found a significant increase in adolescents' intentions to postpone sexual intercourse and use contraceptives, a reduction in self-reported sexual relations and an increase in condom use. Positive results were also found for individual protective factors such as knowledge and attitude, and family factors such as parent-child communication, perception of rules, monitoring/supervision by parents and family support. CONCLUSION: Educational interventions that include parents support healthy sexual behavior among adolescents. Parental participation can be included in any intervention aimed at adolescents. PMID- 21537808 TI - [Francisco Xavier Balmis and the vaccine network, a pioneering example of vaccination implementation]. AB - The first organised global immunization campaign was undertaken in America and the Philippines by the 'Royal Philanthropic Expedition of the Vaccine' (1803 1810). The work of Balmis as director of the Expedition and Salvany, his Assistant Director, not only included vaccinating children but also the development of an organised model for its application. The model was based on a network of centres created to protect and transport the vaccine fluids in good condition until they reached their vaccination sites and how to conduct a census of vaccinated people. In order to improve vaccine acceptability, local health workers were incorporated and the press was used to disseminate news. The strategy developed served as an antecedent that, two hundred years later, is unquestionably similar to health planning models such as Pineault and Daveluy, used in modern vaccination campaigns. PMID- 21537818 TI - Positive effect of modified Goeckerman regimen on quality of life and psychosocial distress in moderate and severe psoriasis. AB - Psoriasis is a chronic inflammatory skin disease with a profound effect on quality of life and psychosocial stress. The relationship between clinical improvement and psycho-social impact after treatment is complex. The objective of this study was to compare changes in quality of life and psychosocial distress, and overall cost-effectiveness, in patients with psoriasis receiving the modified Goeckerman regimen (UV irradiation and coal tar) with those receiving conventional treatment. Patients with moderate/severe psoriasis receiving the Goeckerman regimen were followed from admission to discharge. Clinical severity, was evaluated weekly using the Psoriasis Area and Severity Index (PASI). Psoriasis Disability Index (PDI) and Hospital Anxiety and Depression Scale (HADS) questionnaires were applied at admission and one month after discharge. Thirty six patients with psoriasis receiving conventional treatment and 48 patients receiving the Goeckerman regimen were recruited to the study. The mean PASI score in the Goeckerman group decreased from 27.1 to 6.9 and PDI scores decreased from 25.3 to 13.8. HADS scores for anxiety and depression decreased significantly from 9.8 to 6.3 and 9.1 to 6.8, respectively. In comparison with conventional therapy, the modified Goeckerman regime showed similar clinical efficacy, with additional benefits in improving overall quality of life and psychosocial distress in patients with moderate/severe psoriasis, and more cost-effectiveness. PMID- 21537819 TI - Primary cutaneous B-cell lymphoma: subtypes, treatment and outcome of 10 cases. PMID- 21537820 TI - Successful use of mizoribine in a patient with sarcoidosis and cutaneous vasculitis. PMID- 21537821 TI - Hair shaft abnormalities in localized autosomal recessive hypotrichosis 2 and a review of other non-syndromic human alopecias. PMID- 21537822 TI - Oral lesions in four cases of subacute cutaneous lupus erythematosus. AB - Patients with subacute cutaneous lupus erythematosus (SCLE) present with intense photosensitivity. Clinical patterns comprise papulosquamous or annular lesions on sun-exposed areas; although the face is usually spared. Intraoral lesions have not been reported in most case series of SCLE, but are well-documented in other forms of lupus erythematosus. This study included four female patients diagnosed with SCLE, who presented with specific oral involvement consisting of palatal patches (three cases), buccal mucosal patches (one case), gingival keratotic erythema (one case), and lip lesions (one case). All patients presented with exuberant facial lesions, a condition not often observed in SCLE. Our findings suggest that oral involvement in SCLE may not be as rare as once thought, and that patients with intense facial lesions are at particular risk of developing oral lesions. PMID- 21537823 TI - Atypical fibrous histiocytoma of the skin with necrobiotic granuloma-like features. PMID- 21537824 TI - Eruptive keloids associated with breast cancer: a paraneoplastic phenomenon? PMID- 21537825 TI - Primary cutaneous mantle cell lymphoma. PMID- 21537826 TI - Positive effect of low-dose imatinib mesylate in a patient with nephrogenic systemic fibrosis. PMID- 21537827 TI - Concomitant manifestation of pili annulati and alopecia areata: coincidental rather than true association. AB - The autosomal dominantly inherited hair disorder pili annulati is characterized by alternating light and dark bands of the hair shaft. Concomitant manifestation of pili annulati with alopecia areata has been reported previously on several occasions. However, no systematic evaluation of patients manifesting both diseases has been performed. We studied the simultaneous or sequential occurrence of pili annulati and alopecia areata in individuals diagnosed in different European academic dermatology units. We included 162 Caucasian individuals from 14 extended families, comprising 76 affected and 86 unaffected family members. Statistical analysis showed that the frequency of alopecia areata among patients with pili annulati was higher than within the general population. Five of our patients with pili annulati have gone through severe episodes of alopecia areata. We cannot rule out that the currently unknown genetic defect underlying pili annulati might also confer an increased risk for the development of a more pronounced manifestation of alopecia areata. Based on the current data, and considering the low number within individual families of patients affected by both diseases, however, a direct association between pili annulati and alopecia areata seems unlikely. PMID- 21537828 TI - NADPH oxidase-dependent formation of reactive oxygen species contributes to angiotensin II-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells. AB - The objective of the present study was to investigate the role of NADPH oxidase dependent formation of reactive oxygen species (ROS) in the angiotensin II (Ang II)-induced epithelial-mesenchymal transition (EMT) and in the accumulation of extracellular matrix (ECM) in rat peritoneal mesothelial cells (RPMCs). Primary cultured RPMCs were incubated with serum-free media for 24 h in order to arrest and synchronize cell growth. The cells were treated with Ang II (10-7 M) up to 48 h. Cells were pretreated with an Ang II type I receptor antagonist (losartan, 10 5 M), or an inhibitor of NADPH, oxidase diphenyleneiodonium (DPI) (10-5 M), for 1 h before addition of Ang II. The dichlorofluorescein (DCF)-sensitive cellular ROS were measured by fluorometric assay and confocal microscopy. RT-PCR was employed to detect the mRNA expression for the NADPH oxidase subunit p47phox, plasminogen activator inhibitor-1 (PAI-1), alpha-smooth muscle actin (alpha-SMA) and E cadherin. PAI-1, alpha-SMA and p47phox protein expression were examined by Western blot analysis. Ang II significantly induced the production of intracellular ROS. DPI and losartan inhibited Ang II-induced ROS generation by 86.8% and 77.4% (p<0.05), respectively. Ang II significantly stimulated NADPH oxidase subunit p47phox mRNA and protein expression in RPMCs. Both losartan and DPI inhibited Ang II-induced up-regulation of p47phox mRNA by 37.3% and 67.8% (p<0.05), respectively. Ang II also stimulated alpha-SMA mRNA and protein expression and down-regulated E-cadherin mRNA expression in RPMCs. This effect was suppressed by both losartan and DPI. Ang II significantly up-regulated PAI-1 mRNA and protein expression and these were significantly suppressed by both losartan and DPI. In conclusion, NADPH oxidase-dependent formation of ROS mediates Ang II dependent EMT and accumulation of ECM in rat peritoneal mesothelial cells. NADPH oxidase may represent a potential therapeutic target in the management of peritoneal fibrosis. PMID- 21537829 TI - Dynamin-related protein 1 is implicated in endoplasmic reticulum stress-induced pancreatic beta-cell apoptosis. AB - Pancreatic beta-cell dysfunction is a critical component in the pathogenesis of diabetes. Endoplasmic reticulum (ER) stress is one of the factors that induces pancreatic beta-cell dysfunction, but the underlying mechanisms have not been well elucidated. In this study, we report that a mitochondrial fission modulator, dynamin-related protein 1 (DRP-1), plays an important role in ER stress-induced beta-cell apoptosis. Induction of DRP-1 expression significantly promoted ER stress-induced apoptosis in the DRP-1 WT (DRP-1 wild- type) inducible beta-cell line, but not in the DRP-1 K38A (a dominant negative mutant of DRP-1) inducible beta-cell line. We further demonstrated that the mitochondrial membrane potential decreased, and that cytochrome c release, caspase-3 activation and generation of reactive oxygen species (ROS) were enhanced by induction of DRP-1 WT, but prevented by DRP-1 K38A in pancreatic beta-cells under ER stress conditions. These results indicate that DRP-1 mediates ER stress-induced pancreatic beta-cell apoptosis. PMID- 21537830 TI - GATA binding protein 3 overexpression and suppression significantly contribute to the regulation of allergic skin inflammation. AB - GATA binding protein 3 (GATA3) is a key molecule regulating the balance in the ratio of type 1 helper T (Th1) cells to type 2 helper T (Th2) cells, which is thought to be indicative of the pathogenesis of allergic diseases such as asthma and atopic dermatitis. The aim of this study was to investigate the role of GATA3 in allergic skin inflammation. Transgenic (Tg) mice overexpressing human GATA3 (hGATA3) were produced by the microinjection of pCMV/hGATA3 constructs into fertilized mouse eggs. The hGATA3 gene was successfully expressed at the protein level in the lymph node and thymus of CMV/hGATA3 transfected cells and Tg mice. CMV/hGATA3 Tg mice showed a significant increase in the allergic skin inflammation response such as ear thickness, draining auricular lymph node (aLN) weight, epidermal thickness, inflammatory cell number and Th2 immunoglobulin (Ig) concentration compared to wild-type (WT) mice after phthalic anhydride (PA) treatment. Furthermore, the secretion of Th2 type cytokines was increased by PA treatment in CMV/hGATA3 Tg mice, while the secretion of Th1 type cytokine was suppressed under the same conditions. However, the increased levels of Th2 type cytokines in CMV/hGATA3 Tg mice were almost recovered by the down-regulation of GATA3 expression with D-pinitol treatment. Therefore, these findings suggest that GATA3 could be considered as a potential target regulating the mechanism responsible for the differences in allergic skin inflammation. PMID- 21537831 TI - Effect of glucosamine, a therapeutic agent for osteoarthritis, on osteoblastic cell differentiation. AB - Osteoarthritis (OA) is characterized by qualitative and quantitative changes in the architecture and composition of all the joint structures. Glucosamine (GlcN) has been used to treat OA in humans, because GlcN is present in the cartilage tissues as a component of glycosaminoglycans, and exhibits the symptom-modifying effect on OA by normalizing cartilage metabolism. On the other hand, the pathological change of subchondral bone is associated with the initiation and progression of cartilage damage in OA. However, the effect of GlcN on bone metabolism remains unsolved. In the present study, we determined the effect of GlcN on bone metabolism (osteoblastic cell differentiation) using mouse osteoblastic MC3T3-E1 cells by evaluating the expression of early (type I collagen and alkaline phosphatase), middle (osteopontin) and late (osteocalcin and mineralization) stage differentiation markers, and further compared its effects to those of N-acetyl-D-glucosamine (GlcNAc), a derivative of GlcN. The results indicated that the mineralization of mature osteoblasts was increased by treatment with GlcN and GlcNAc. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR) analyses revealed that GlcN and GlcNAc substantially increased the expression of a middle stage marker and a late stage marker, although they did not essentially affect the expression of early stage markers. In addition, GlcN and GlcNAc suppressed the expression of receptor activator of NF-kappaB ligand (RANKL), a key factor involved in the osteoclastic cell differentiation and activation. Together these observations suggest that both GlcN and GlcNAc may have a potential not only to induce osteoblastic cell differentiation especially at middle-late stages, but also to suppress the osteoclastic cell differentiation, thereby possibly increasing bone matrix deposition and decreasing bone resorption, and eventually modulating bone metabolism in OA. PMID- 21537832 TI - DcR3-TL1A signalling inhibits cytokine-induced proliferation of rheumatoid synovial fibroblasts. AB - Decoy receptor 3 (DcR3), a member of the tumour necrosis factor receptor (TNFR) superfamily, lacks the transmembrane domain of conventional TNFRs in order to be a secreted protein. DcR3 competitively binds and inhibits members of the TNF family, including Fas ligand (FasL), LIGHT and TL1A. We previously reported that TNFalpha-induced DcR3 overexpression in rheumatoid synovial fibroblasts (RA-FLS) protects the cells from Fas-induced apoptosis and that DcR3 induces VLA-4 expression in THP-1 macrophages to inhibit cycloheximide-induced apoptosis. Meanwhile, recent studies have suggested that DcR3 acting as a ligand directly induces the differentiation of macrophages to osteoclasts. Therefore, in the present study, we analyzed the direct effects of DcR3 as a ligand in RA-FLS. The experiments showed that DcR3 binds to TL1A expressed in RA-FLS resulting in the negative regulation of cell proliferation induced by inflammatory cytokines. DcR3 TL1A signalling may be involved in the pathogenesis of rheumatoid arthritis (RA). PMID- 21537833 TI - Knockdown of prion protein (PrP) by RNA interference weakens the protective activity of wild-type PrP against copper ion and antagonizes the cytotoxicity of fCJD-associated PrP mutants in cultured cells. AB - Development of the pathogenesis of transmissible spongiform encephalopathies (TSEs) requires the presence of both the normal host prion protein (PrPC) and the abnormal pathological proteinase-K resistant isoform (PrPSc). Reduction of PrPC levels has been shown to extend survival time after prion infection. In this report, based on analysis of the known sequences of human PrP, we constructed two small interfering RNA (siRNA) duplexes targeting the segments of amino acids (aa) 108-114 (Ri2) and aa 171-177 (Ri3). Western blot analysis results revealed that these PrP-specific siRNAs could effectively knock down the levels of either endogenous PrP in human neuroblastoma SHSY-5Y cells or recombinant PrP transfected with the plasmid expressing the full-length human PrP in human embryonic kidney (HEK) 293T cells. Meanwhile, the two siRNAs also showed a significant effect on the reduction of the expression of the PrP-PG9 and PrP-PG12 familial Creutzfeldt-Jakob disease (CJD)-associated PrP mutants with four and seven extra octarepeats, in the cells transfected with the respective expression plasmids. MTT tests identified that knockdown of wild-type PrP by Ri2 and Ri3 did not change the cell growth capacities, but significantly decreased the cell resistances against the challenge of Cu2+. Co-expression of Ri2 and Ri3 partially antagonized the cytotoxicity caused by expressing PrP-PG9 and PrP-PG12 in the two cell lines. Moreover, the rescuing effectiveness of PrP siRNAs was time-related, with the more efficient antagonism of the cytotoxicity of fCJD-associated PrP mutants occurring at the early stages after transfection. The data shown here provide useful clues for seeking potential therapeutic tools for prion diseases. PMID- 21537834 TI - Endothelin-1 does not impair insulin-induced angiogenesis in vitro. AB - Endothelin-1 (ET-1) modulates several vascular functions and plays an important role in the pathogenesis of insulin resistance. However, its role in the pathogenesis of impaired angiogenesis observed under insulin resistance conditions is not known. In the present study, we addressed this issue by analyzing the effect of ET-1 in human umbilical vein endothelial cells (HUVEC) on i) insulin-induced phosphorylation of two protein kinases involved in angiogenesis, Akt and ERK1/2, and on ii) insulin-induced angiogenesis in two in vitro models, those of Matrigel and of fibroblast/endothelial co-culture. Both insulin (100 ng/ml) and ET-1 (10 nmol/l) dose-dependently increased the phosphorylation of Akt and ERK1/2. Pre-treatment with ET-1 did not suppress the insulin-induced Akt and ERK1/2 phosphorylation. In the two in vitro models of angiogenesis, ET-1 did not inhibit insulin-induced angiogenesis. From these data we conclude that in vitro, at the times and at the concentrations examined, ET-1 does not impair insulin-induced angiogenesis. PMID- 21537835 TI - Human umbilical cord blood-derived mesenchymal stem cells improve glucose homeostasis in rats with liver cirrhosis. AB - Disturbance of glucose metabolism is a common feature in liver cirrhosis which is associated with insulin resistance and is an established risk factor for disease progression and survival in patients with chronic liver diseases. We investigated whether umbilical cord blood-derived mesenchymal stem cells (HMSCs) have an effect on the expression of molecules responsible for glucose utilization and hepatic gluconeogenesis, focusing on the insulin signaling pathway in rats with liver cirrhosis. Rats received a dose of CCl4 (100 ul/100 g 4:1 in corn oil) thrice-weekly. HMSCs were infused at 4 weeks after induction of liver cirrhosis by CCl4. Infusion of HMSCs improved insulin resistance which was associated with increased glucose levels and decreased insulin sensitivity in CCl4-induced cirrhotic rats. HMSCs increased activities in the proximal part of the insulin signaling cascade, as evidenced by increased expression of key enzymes such as phosphatidylinositol-3-kinase (PI 3-kinase), protein kinase B (PKB), protein kinase C-zeta (PKC-zeta), and the decrease of glycogen synthase kinase 3 (GSK-3) compared to CCl4-induced liver cirrhotic rats. We also observed that glucose-6 phosphatase (G-6-P) and phosphoenolpyruvate kinase (PEPCK), two hepatic enzymes involved in gluconeogenesis were strongly decreased over 40-50% after infusion of HMSCs. Taken together, our results showed that HMSCs could improve insulin resistance in CCl4-induced liver cirrhosis, thereby contributing to glucose homeostasis. PMID- 21537836 TI - Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-kappaB and PI3K/Akt signaling pathways. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells with little or no adverse effects on normal cells. TRAIL is relatively safe for clinical applications. However, TRAIL resistance is widely found in cancer cells leading to limitations in utilizing TRAIL as a therapeutic agent for cancer treatment. Recently, artesunate, an effective and safe anti-malarial drug, was also described as a promising candidate for cancer therapy. It would be of importance to determine whether combination treatment of TRAIL together with artesunate could overcome drug resistance of tumors. Here, we demonstrate the first evidence that artesunate effectively enhances TRAIL-mediated cytotoxicity by suppressing pro-survival proteins, such as survivin, XIAP and Bcl-XL. Upon treatment with artesunate, the levels of survival proteins were strongly suppressed in HeLa cells. The down regulation of these survival proteins could be regulated by repressing activation of NF-kappaB and Akt. Artesunate also inhibited TRAIL-induced transcriptional activity of NF-kappaB. In addition, this substance significantly enhanced both extrinsic and intrinsic apoptosis, which were induced by TRAIL. Taken together, the results of the present study suggest that artesunate exhibits an ability to overcome TRAIL resistance and combination treatment of TRAIL together with artesunate may be an effective strategy for cancer therapy. PMID- 21537837 TI - FBXO31 determines poor prognosis in esophageal squamous cell carcinoma. AB - Cyclin D1 plays important roles in esophageal squamous cell carcinoma (ESCC) cases by amplification of the 11q13.3 locus. FBXO31 is a subunit of the SCF ubiquitin ligase, which targets cyclin D1 for degradation. In this study, we clarified the clinical significance of FBXO31 and characterized the association between cyclin D1 and FBXO31 in ESCC cases. Total RNA was extracted from tumor tissues obtained from 68 ESCC patients who underwent surgical resection. FBXO31 expression levels were determined by quantitative RT-PCR, and both FBXO31 and cyclin D1 protein expression and localization were evaluated by immunohistochemistry (IHC). Furthermore, using CGH and gene expression array data of another subset, we validated the association between cyclin D1 genomic amplification and FBXO31 expression levels. Higher FBXO31 expression levels significantly correlated with depth of tumor invasion and clinical stage (P<0.05). In addition, the FBXO31 high expression group showed a significantly poorer prognosis than the low expression group (P<0.001). Multivariate analysis indicated that FBXO31 expression was an independent prognostic factor [relative risk (RR): 1.79, confidence interval (CI): 1.14-3.01, P=0.01]. Using IHC, concordant expression was observed between cyclin D1 and FBXO31 in the nucleus and cytoplasm, respectively. CGH array indicated that cases having cyclin D1 with increased copy number were significantly associated with elevated FBXO31 expression levels (P<0.05). FBXO31 could be a novel and robust prognostic marker for ESCC. PMID- 21537839 TI - Endosialin is expressed in high grade and advanced sarcomas: evidence from clinical specimens and preclinical modeling. AB - We previously surveyed the expression of endosialin/ CD248/TEM-1 by immunohistochemistry in human clinical specimens of sarcomas and documented expression in tumor cells, stromal cells and vasculature. In the present study, we completed a retrospective analysis of the diagnostic reports available for these same samples in order to identify high-grade and metastatic disease. Our results show that endosialin can be detected in advanced disease. We screened human sarcoma cell lines in vitro for endosialin expression and developed preclinical human xenograft models of disseminated sarcoma. We found that 22 out of 42 human sarcoma cell lines were positive for endosialin with a positive correlation between mRNA and protein levels. When implanted in vivo, endosialin was expressed at all sites of dissemination. These data provide clinical and preclinical evidence that endosialin can be detected in advanced sarcoma. These results demonstrate for the first time that endosialin is a suitable therapeutic target for poor prognosis and advanced disease. PMID- 21537838 TI - FLT-PET may not be a reliable indicator of therapeutic response in p53-null malignancy. AB - FDG (18F-deoxy-glucose) is the current gold standard for PET imaging. FLT (3' deoxy-3'-(18F-fluorothymidine), a PET imaging marker of proliferation, has been proposed as an alternative to FDG for the assessment of therapeutic response. We examined the therapeutic predictive value of FLT-PET and FDG-PET using CALU-6, a human, p53-null, non-small cell lung cancer cell line with comparison of combined targeted therapy, TRAIL and sorafenib, versus combined conventional chemotherapy, docetaxel and cisplatin. CALU-6 tumor-bearing nu/nu mice (n=46) were evaluated in 3 therapeutic trials measuring FLT and FDG prediction of tumor response at 72 h following initiation of daily combination therapy with targeted agents, TRAIL (200 ug i.v.) and sorafenib (30 mg/kg i.p.) and compared to conventional chemotherapeutics cisplatin (3 mg/kg i.p.) and docetaxel (7.5 mg/kg i.p.). PET imaging response was compared to morphological and histological indicators of therapeutic response, including decreased vascularity (in vivo AngioSense imaging and anti-CD31 staining), slowed tumor growth (caliper measurements), decreased cellular proliferation (Ki-67 staining) and increased apoptosis (TUNEL staining). Decreases in tumor accumulation of FLT (FLTMAX -30%, p=0.03) at 72 h post treatment were observed in response to TRAIL and sorafenib combination therapy resulting in smaller, less vascular, more apoptotic tumors. No similar reduction in tumor accumulation of FLT (FLTMAX -2%, p=0.67) was observed 72 h following initiation of cisplatin and docetaxel combination therapy, despite histological and morphological evidence of drug response. In contrast, tumor imaging with FDG did demonstrate a decrease in accumulation in both treatment groups, -21% (p=0.30) in response to cisplatin/docetaxel and -8% (p=0.59) in response to TRAIL/sorafenib, but did not reach statistical significance. FLT, but not FDG, is predictive of therapeutic response to the targeted regimen TRAIL/sorafenib. However, FLT-PET may not predict therapeutic response to DNA damaging agents in p53-null tumors, likely due to loss of cell cycle control of thymidine kinase 1 (TK1). Thus, tumor imaging response by FLT may be limited in human tumors without functional p53. PMID- 21537840 TI - Methylation-related mutations in the BRCA1 promoter in peripheral blood cells from cancer-free women. AB - Early-onset breast cancer is one of the most common malignancies and causes of death among young women, and its incidence is increasing. In the present study, we aimed to investigate the epigenetic modifications of the breast cancer type 1 susceptibility gene (BRCA1) in breast tissues and blood cells derived from women with breast cancer and women without breast cancer. BRCA1 promoter methylation was examined by methylation-specific PCR in 47 breast cancer tissues and in peripheral blood cells derived from 7 breast cancer patients and 73 healthy women. Subsequently, the methylation status of the BRCA1 promoter was confirmed and analyzed at high resolution by sodium bisulfite genomic sequencing. BRCA1 promoter methylation was detected in 13 primary sporadic breast cancer tissues (27.3%) and in 2 blood cell samples derived from breast cancer patients (28.5%). A strong association (p-value, 0.0038) was found between BRCA1 methylation and young age (<= 40 years) at diagnosis. The BRCA1 promoter was also methylated in blood cells from 8 women without breast cancer (10.9%) and 2 breast cancer patients (28%). The methylation pattern of the BRCA1 promoter CpG island was similar in the blood cells from healthy women as well as in women with breast cancer. Moreover, we report for the first time, the observation of methylation related mutations leading to the formation of non-CpG methylation, as well as the formation of novel methylated CpG sites in the 5' regulatory region of the BRCA1 gene in the peripheral blood cells from cancer-free women. These results suggest the possible implication of BRCA1 promoter methylation in the early onset of breast cancer and propose the use of this epigenetic modification as a powerful molecular marker for detecting women potentially predisposed to cancer. PMID- 21537841 TI - Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer. AB - Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that is in clinical development for the treatment of solid tumours. This preclinical study examined the inhibition of two key signalling pathways (VEGFR-2, EGFR) at drug concentrations similar to those achieved in the clinic, and their contribution to direct and indirect antitumour effects of vandetanib. For in vitro studies, receptor phosphorylation was assessed by Western blotting and ELISA, cell proliferation was assessed using a cell viability endpoint, and effects on cell cycle determined using flow cytometry. For in vivo studies, Western blotting, ELISA and immunohistochemistry (IHC) were used to assess receptor phosphorylation. Cell culture experiments demonstrated that anti-proliferative effects of vandetanib resulted from inhibition of either EGFR or VEGFR-2 signalling in endothelial cells, but were associated with inhibition of EGFR signalling in tumour cells. Vandetanib inhibited both EGFR and VEGFR-2 signalling in normal lung tissue and in tumour xenografts. In a lung cancer model expressing an activating EGFR mutation, the activity of vandetanib was similar to that of a highly selective EGFR inhibitor (gefitinib), and markedly greater than that of a highly selective VEGFR inhibitor (vatalanib). These data suggest that at the plasma exposures achieved in the clinic, vandetanib will significantly inhibit both VEGFR-2 and EGFR signalling, and that both inhibition of angiogenesis and direct inhibition of tumour cell growth can contribute to treatment response. PMID- 21537842 TI - Urothelial cancer cell response to combination therapy of gemcitabine and TRAIL. AB - High-risk superficial urothelial carcinoma of the bladder (UCB) is commonly treated with intravesical bacillus Calmette-Guerin (BCG), but with significant side effects. We recently showed that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibited high therapeutic potential against UCB cells and with only limited toxic effects in normal cells. However, many cancer cells are refractory to TRAIL during monotherapy. Therefore, our experimental aim was to develop combinatorial approaches with other pro- apoptotic agents to reactivate apoptosis in resistant phenotypes. We demonstrate that UCB cells varied in their response to TRAIL, and the effect was caspase dependent (reduced or abrogated by pre-incubation of cells with caspase-inhibitor peptides). In contrast wortmannin, a PI3K/Akt inhibitor, enhanced the TRAIL effect. Furthermore, combination therapy of TRAIL with low dose gemcitabine markedly enhanced UCB cell response (except in the TRAIL-resistant HT1376 cell line). The enhanced response was both time- and concentration-dependent and asymptotic at gemcitabine concentration >1 umol/l. To define the mechanisms underlying gemcitabine-augmented TRAIL action, we evaluated the expression of several proteins regulating the apoptotic pathway. Gemcitabine-augmented TRAIL effect was associated with inhibition of the Bcl-2 protein (intrinsic signalling) along with activation of the caspase (extrinsic) cascade. The combined maximal stimulation of both the intrinsic and extrinsic signalling pathways also appeared to overcome the survival (PI3K/Akt) pathway as evident by the lack of response to wortmannin. Our semisolid multicellular-spheroid model showed that TRAIL and gemcitabine selectively caused UCB cells to undergo apoptosis without affecting normal cells, and both appeared to penetrate deeply enough to allow for combination intravesical therapy. PMID- 21537843 TI - Monoamine carboxylate transporters are involved in BI-1-associated cancer metastasis in HT1080 colon fibrosarcoma cells. AB - The overexpression of BI-1 induces an acidic extracellular pH due to alterations of mitochondrial function, leading to cancer metastasis through anaerobic glucose metabolism. In this study, ion transporters such as sodium hydrogen exchangers (NHE) and monoamine carboxylate transporters (MCTs) were studied in BI-1 overexpressing HT1080 cells (BI-1 cells). The extracellular pH became acidic as culture time of BI-1 cells increased, while intracellular pH stayed relatively stable at pH 7.2. The expression of MCTs increased in BI-1 cells as culture time passed. 5-(N-ethyl-N-isopropyl) amiloride or dimethylamiloride, NHE inhibitor, abrogated the elevated MCT expression, indicating that MCT followed NHE activation. An MCT inhibitor, lonidamine, regulated the acidification of extracellular pH, also inhibiting both increased cancer cell migration and infiltration and MMP2/9 activity. The inhibition of either NHE or MCT affected the intracellular pH, leading to a severely acidic intracellular pH and cell death. In BI-1 cells, the activation of ion transporters such as NHE or MCT may offer a survival strategy against metabolism-associated acidic stresses. These findings suggest that BI-1 can lead cancer invasion and metastasis by inducing extracellular environment acidic. PMID- 21537844 TI - Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer. AB - The broccoli isothiocyanate, sulforaphane (SFN), was recently identified as being capable of eliminating highly therapy-resistant pancreatic carcinoma (PC) cells without inducing toxic side effects. While SFN has been shown to stimulate autophagy or 'self-eating', it is unclear whether this catabolic process is a pro or anti-tumorigenic response. To investigate the role of autophagy in SFN induced cell death, established PC cell lines were treated with SFN, and the induction of autophagy was evaluated by detecting the abundance of autophagic vesicles by electron microscopy, the increase in converted LC3-II by Western blot analysis and the autophagosome puncta of GFP-LC3 by immunofluorescence. SFN induced autophagy was suppressed by the autophagy inhibitor chloroquine, while the autophagy inducer rapamycin did not further enhance autophagy in PC cells. Importantly, neither modulator altered SFN cytotoxicity, suggesting that SFN induced autophagy and cell death act independently of each other. In contrast, the antioxidant N-acetyl-cysteine sustained cell viability and prevented autophagy induction after SFN exposure, indicating that both signaling pathways depend on reactive oxygen species (ROS). Our studies provide a valuable new mechanistic insight into the SFN-induced elimination of PC cells and suggest that an SFN-enriched diet potentially enhances ROS-releasing chemotherapeutic agents. PMID- 21537845 TI - RhoC protein stimulates migration of gastric cancer cells through interaction with scaffold protein IQGAP1. AB - The scaffold protein IQGAP1 is closely related to certain Rho GTPases. Research has revealed that IQGAP1 acts as an effector of Cdc42 and Rac1 in the regulation of cell activity such as proliferation and migration. However, whether IQGAP1 is associated with RhoC, another important Rho GTPase, is unclear. Previous results from our laboratory indicated that IQGAP1 and RhoC are highly expressed in gastric cancer tissues and cells. This study was designed to investigate the possible interaction between IQGAP1 and RhoC in the regulation of the migration of cancer cells. The expression of IQGAP1 and RhoC in gastric cancer tissues and cell lines was detected by Western blotting. siRNAs targeting IQGAP1 or RhoC were transfected into gastric cancer cells to knock down the expression of the proteins. Adenoviral constructs encoding full length IQGAP1, the C-terminal fragment of IQGAP1, and the constitutively active RhoC gene were used to infect gastric cancer cells to increase the expression of the proteins. The migratory activity of a gastric cancer cell line was measured by a transwell migration assay. Western blotting revealed that the IQGAP1 and RhoC proteins were highly expressed in gastric cancer tissues and cells. Spearman's rank correlation analysis indicated that the increases in the expression of IQGAP1 and RhoC were closely correlated. The transwell migration assay revealed that both IQGAP1 and RhoC stimulated the migration activity of the gastric cancer cell line AGS. The knockdown of IQGAP1 expression by siRNA blocked the migration-stimulating activity of RhoC, while the knockdown of RhoC expression had no effect on the migration-stimulatory activity of IQGAP1. Co-IP results showed that RhoC and IQGAP1 bound to each other. These results reveal a previously unrecognized interaction between IQGAP1 and RhoC, and demonstrate that IQGAP1 is a downstream effector of RhoC in the regulation of the migration activity of gastric cancer cells. PMID- 21537846 TI - Natural plant extract tubeimoside I induces cytotoxicity via the mitochondrial pathway in human normal liver cells. AB - Tubeimoside I (TBMS I) is a natural compound extracted from Bolbostemma paniculatum (Maxim.) Franquet (Cucurbitaceae), a traditional Chinese herbal medicine widely used for the treatment of inflammation. Recently, it has been suggested that TBMS I may be a potent anticancer agent for a variety of human cancers. However, TBMS I is known to distribute preferentially in the liver, and thus may harm normal liver cells if it is delivered systemically for cancer treatment. This safety concern warrants careful evaluation of the hepatotoxicity of TBMS I to normal liver cells, which to date has not been carried out. Here, we report the cytotoxic effects of TBMS I on one type of normal liver cells (L-02 cells), and the associated molecular events as underlying mechanisms. Cultured human normal liver L-02 cells were treated with TBMS I at concentrations of 0, 15 and 30 uM for 24, 48 and 72 h, respectively. Subsequently, the cell survival rate was evaluated by the MTT dye method, and several key molecular events associated with apoptosis were assayed, including mitochondrial depolarization, release of cytochrome c (cyt-c), activation of caspases, and the balance between Bax and Bcl 2 protein expression. Our results indicate that TBMS I inhibited the proliferation of L-02 cells in a dose- and time-dependent manner. The TBMS I induced growth inhibition of L-02 cells was accompanied by the collapse of mitochondrial membrane potential, release of cyt-c from the mitochondria to the cytosol, activation of caspase-9 and -3, decrease of anti-apoptotic protein Bcl-2 levels and increase of the pro-apoptotic protein Bax levels, all indicative of apoptosis through the mitochondrial pathway. Taken together, these results confirm that TBMS I has a significant apoptotic effect on normal liver L-02 cells, which may be significant to its clinical applications. PMID- 21537847 TI - Management of meningeal neoplasms: meningiomas and hemangiopericytomas. AB - OPINION STATEMENT: Meningiomas are the most frequently diagnosed primary brain tumor accounting for nearly one third of all primary brain and central nervous system tumors reported in the United States. According to the 2007 World Health Organization classification scheme, Grade I meningiomas are benign, Grade II defines atypical lesions, while Grade III meningiomas are anaplastic or frankly malignant tumors. Not surprisingly, Grade II and III meningiomas usually follow a more aggressive course and confer a worse prognosis. The diagnosis of meningioma is confirmed by pathologic examination and improvements in imaging help to better define when observation versus intervention is appropriate. Surgical resection, when possible, is the mainstay of treatment. When complete resection is not possible, stereotactic radiosurgery (SRS) can result in disease stabilization. Chemotherapy has yet to result in reproducible long-term disease free or overall survival benefits. Biologic agents remain under investigation. Hemangiopericytomas are rare dural based sarcomas. These tumors are known for their aggressiveness, high recurrence rates and their proclivity to metastasize to extracranial locations. Gross total resection when feasible remains the treatment of choice. PMID- 21537848 TI - Support vector machine based diagnostic system for breast cancer using swarm intelligence. AB - Breast cancer is becoming a leading cause of death among women in the whole world, meanwhile, it is confirmed that the early detection and accurate diagnosis of this disease can ensure a long survival of the patients. In this paper, a swarm intelligence technique based support vector machine classifier (PSO_SVM) is proposed for breast cancer diagnosis. In the proposed PSO-SVM, the issue of model selection and feature selection in SVM is simultaneously solved under particle swarm (PSO optimization) framework. A weighted function is adopted to design the objective function of PSO, which takes into account the average accuracy rates of SVM (ACC), the number of support vectors (SVs) and the selected features simultaneously. Furthermore, time varying acceleration coefficients (TVAC) and inertia weight (TVIW) are employed to efficiently control the local and global search in PSO algorithm. The effectiveness of PSO-SVM has been rigorously evaluated against the Wisconsin Breast Cancer Dataset (WBCD), which is commonly used among researchers who use machine learning methods for breast cancer diagnosis. The proposed system is compared with the grid search method with feature selection by F-score. The experimental results demonstrate that the proposed approach not only obtains much more appropriate model parameters and discriminative feature subset, but also needs smaller set of SVs for training, giving high predictive accuracy. In addition, Compared to the existing methods in previous studies, the proposed system can also be regarded as a promising success with the excellent classification accuracy of 99.3% via 10-fold cross validation (CV) analysis. Moreover, a combination of five informative features is identified, which might provide important insights to the nature of the breast cancer disease and give an important clue for the physicians to take a closer attention. We believe the promising result can ensure that the physicians make very accurate diagnostic decision in clinical breast cancer diagnosis. PMID- 21537849 TI - Federated querying architecture with clinical & translational health IT application. AB - We present a software architecture that federates data from multiple heterogeneous health informatics data sources owned by multiple organizations. The architecture builds upon state-of-the-art open-source Java and XML frameworks in innovative ways. It consists of (a) federated query engine, which manages federated queries and result set aggregation via a patient identification service; and (b) data source facades, which translate the physical data models into a common model on-the-fly and handle large result set streaming. System modules are connected via reusable Apache Camel integration routes and deployed to an OSGi enterprise service bus. We present an application of our architecture that allows users to construct queries via the i2b2 web front-end, and federates patient data from the University of Utah Enterprise Data Warehouse and the Utah Population database. Our system can be easily adopted, extended and integrated with existing SOA Healthcare and HL7 frameworks such as i2b2 and caGrid. PMID- 21537850 TI - SeDeLo: using semantics and description logics to support aided clinical diagnosis. AB - Automated medical diagnosis systems based on knowledge-oriented descriptions have gained momentum with the emergence of semantic descriptions. The objective of this paper is to propose a normalized design that solves some of the problems which have been detected by authors in previous tools. The authors bring together two different technologies to develop a new clinical decision support system: description logics aimed at developing inference systems to improve decision support for the prevention, treatment and management of illness and semantic technologies. Because of its new design, the system is capable of obtaining improved diagnostics compared with previous efforts. However, this evaluation is more focused in the computational performance, giving as result that description logics is a good solution with small data sets. In this paper, we provide a well structured ontology for automated diagnosis in the medical field and a three-fold formalization based on Description Logics with the use of Semantic Web technologies. PMID- 21537852 TI - A new Watermarking System based on Discrete Cosine Transform (DCT) in color biometric images. AB - This paper recommend a biometric color images hiding approach An Watermarking System based on Discrete Cosine Transform (DCT), which is used to protect the security and integrity of transmitted biometric color images. Watermarking is a very important hiding information (audio, video, color image, gray image) technique. It is commonly used on digital objects together with the developing technology in the last few years. One of the common methods used for hiding information on image files is DCT method which used in the frequency domain. In this study, DCT methods in order to embed watermark data into face images, without corrupting their features. PMID- 21537851 TI - Data mining in healthcare and biomedicine: a survey of the literature. AB - As a new concept that emerged in the middle of 1990's, data mining can help researchers gain both novel and deep insights and can facilitate unprecedented understanding of large biomedical datasets. Data mining can uncover new biomedical and healthcare knowledge for clinical and administrative decision making as well as generate scientific hypotheses from large experimental data, clinical databases, and/or biomedical literature. This review first introduces data mining in general (e.g., the background, definition, and process of data mining), discusses the major differences between statistics and data mining and then speaks to the uniqueness of data mining in the biomedical and healthcare fields. A brief summarization of various data mining algorithms used for classification, clustering, and association as well as their respective advantages and drawbacks is also presented. Suggested guidelines on how to use data mining algorithms in each area of classification, clustering, and association are offered along with three examples of how data mining has been used in the healthcare industry. Given the successful application of data mining by health related organizations that has helped to predict health insurance fraud and under-diagnosed patients, and identify and classify at-risk people in terms of health with the goal of reducing healthcare cost, we introduce how data mining technologies (in each area of classification, clustering, and association) have been used for a multitude of purposes, including research in the biomedical and healthcare fields. A discussion of the technologies available to enable the prediction of healthcare costs (including length of hospital stay), disease diagnosis and prognosis, and the discovery of hidden biomedical and healthcare patterns from related databases is offered along with a discussion of the use of data mining to discover such relationships as those between health conditions and a disease, relationships among diseases, and relationships among drugs. The article concludes with a discussion of the problems that hamper the clinical use of data mining by health professionals. PMID- 21537853 TI - Integration of RFID and web service for assisted living. AB - The number of people over 65 years old throughout most stable and prosperous countries in the world is increasing. Availability of their care in their own homes is imperative because of the economic reasons and their choices where to live (World Health Organization, Definition of an older or elderly person. http://www.who.int/healthinfo/survey/ageingdefnolder/en/ ; EQUIP-European Framework for Qualifications in Home Care Services for Older People, http://www.equip-project.com ; Salonen, 2009). "Recent advancement in wireless communications and electronics has enabled the development of low-cost sensor networks. The sensor networks can be utilized in various application areas." (Akyildiz, et al. 2002) These two statements show that there is a great promise in wireless technology and utilizing it in assisted living might be very beneficial to the elderly people. In this paper, we propose software architecture called Location Windows Service (LWS) which integrates the Radio Frequency Identification (RFID) technology and the web service to build an assisted living system for elderly people at home. This architecture monitors the location of elderly people without interfering in their daily activities. Location information messages that are generated as the elderly move from room to room indicate that the elderly person is fit and healthy and going about their normal life. The communication must be timely enough to follow elderly people as they move from room to room without missing a location. Unacknowledged publishing, subscription filtering and short location change messages are also included in this software model to reduce the network traffic in large homes. We propose some defense schemes being applied to the network environment of the assisted living system to prevent any external attacks. PMID- 21537854 TI - Data capture of transdermal glucose monitoring through computerized appliance based virtual remote sensing and alert systems. AB - Monitoring of blood glucose levels is important to persons with diabetes or pre diabetic, abnormal glucose indications. Such individuals must determine when insulin is needed to reduce glucose levels in their bodies, or when additional glucose must be administered to raise levels. A conventional technique used by many diabetics to personally monitor their glucose level includes the periodic drawing of blood, the application of blood to a test strip, and determination of blood glucose level using calorimetric, electrochemical, or photometric detection. This technique does not permit continuous or automatic monitoring of levels in the body, but typically must be performed manually, and on a periodic basis. Unfortunately, checking consistency varies widely among individuals, where wide variation of high or low levels of glucose or other analytes may have detrimental effects. The ongoing capture of data through continuous and/or automatic in vivo monitoring of analyte levels, and its inclusion with a user friendly computer interface, is now possible using a subcutaneous implanted sensor. Such devices are small and comfortable when used, allowing a wide range of life activities. In this technology review we propose one promising model using a combination of emerging, systems-based technologies in non-invasive analyte monitoring, as integrated within household-based health monitoring using home appliances. PMID- 21537855 TI - Integrating computerized primitives and annotated video patterns: a proposed model for autism diagnosis and research. AB - The use of computerized, digital video as a means for interactive data capture has been suggested as an alternative to direct observation of behavior. The appeal of observational measures is that they are presumed to be less vulnerable to potential biases from informants, such as parents or teachers, and permit more individualized assessment that may be lost with the use of rating scales. As a potential tool for long-term, automated observation and analysis. In this technology review we propose one promising model for the integration of computerized primitives recognition and annotated video patterns as an approach to large-scale autism diagnosis and research. PMID- 21537856 TI - Peritoneal dialysis in an ageing population: a 10-year experience. AB - BACKGROUND: Chronic kidney disease (CKD) is becoming increasingly prevalent and there are increasing numbers of older patients with advanced CKD. Peritoneal dialysis (PD) is a potential treatment. This study aims to compare PD outcomes in age-defined populations in the largest PD centre in the Republic of Ireland over 10 years. METHODS: We retrospectively identified all adult patients, over the age of 50 years, who commenced PD as their first modality of renal replacement therapy (RRT) between 1 January 1998 and 31 December 2008 at our institution. Primary outcome was patient survival; secondary outcomes were technique failure, peritonitis-free survival, transplantation and hospitalisations. RESULTS: One hundred and forty-eight patients with a mean age of 63 years were included. Twenty-two patients were on assisted PD, the majority of whom were aged 70 years or over (P = 0.001). There were no differences in patient survival or technique failure by age group, Charlson Co-Morbidity Index (CCI), modified-CCI or adjusted CCI. Renal transplantation occurred predominantly in younger patients (P = 0.001) with lower m-CCI (P = 0.001) and a-CCI (P = 0.002) who performed PD independently (P = 0.004). Older patients required longer hospital stays to initiate PD (P = 0.004). Assisted PD was not associated with an increase in early complications or technique failure but death rates were higher (P = 0.002). CONCLUSION: This study shows PD to be an acceptable modality of renal replacement therapy in elderly patients, with no observed differences in survival, technique survival or complication rates. Co-morbidities appear to play a stronger role in predicting survival than age alone. Assisted PD is a viable option in those unable to undergo PD independently. PMID- 21537857 TI - Lansoprazole-induced acute allergic interstitial nephritis in a renal transplant recipient: a case report. AB - Drug-induced interstitial nephritis is one of the causes of graft dysfunction in renal transplant recipients. Although commonly implicated as a cause of drug induced interstitial nephritis in the general population, proton pump inhibitor induced interstitial nephritis has not yet been reported in renal transplant recipients. Trimethoprim-sulfamethoxazole is responsible for most cases of interstitial nephritis in this population. Here, we describe the first case of proton pump inhibitor-related interstitial nephritis in a renal transplant recipient. PMID- 21537858 TI - Effects of pulsed electromagnetic fields on benign prostate hyperplasia. AB - INTRODUCTION: Benign prostate hyperplasia (BPH) has been treated with various types of electromagnetic radiation methods such as transurethral needle ablation (TUNA), interstitial laser therapy (ILC), holmium laser resection (HoLRP). In the present study, the effects of a noninvasive method based on the exposure of patients with BPH to a pulsative EM Field at radiofrequencies have been investigated. MATERIALS AND METHODS: Twenty patients with BPH, aging 68-78 years old (y.o), were enrolled in the study. Patients were randomly divided into two groups: the treatment group (10 patients, 74.0 +/- 5.7 y.o) treated with the alpha-blocker Alfusosin, 10 mg/24 h for at least 4 weeks, and the electromagnetic group (10 patients, 73.7 +/- 6.3 y.o) exposed for 2 weeks in a very short wave duration, pulsed electromagnetic field at radiofrequencies generated by an ion magnetic inductor, for 30 min daily, 5 consecutive days per week. Patients of both groups were evaluated before and after drug and EMF treatment by values of total PSA and prostatic PSA fraction, acid phosphate, U/S estimation of prostate volume and urine residue, urodynamic estimation of urine flow rate, and International Prostate Symptom Score (IPSS). RESULTS: There was a statistically significant decrease before and after treatment of IPSS (P < 0.02), U/S prostate volume (P < 0.05), and urine residue (P < 0.05), as well as of mean urine flow rate (P < 0.05) in patients of the electromagnetic group, in contrast to the treatment group who had only improved IPSS (P < 0.05). There was also a significant improvement in clinical symptoms in patients of the electromagnetic group. Follow-up of the patients of this group for one year revealed that results obtained by EMFs treatment are still remaining. CONCLUSION: Pulsed electromagnetic field at radiofrequencies may benefit patients with benign prostate hyperplasia treated by a non-invasive method. PMID- 21537859 TI - How do we know when a lymph node dissection is adequate? PMID- 21537860 TI - F18-FDG PET/CT and differentiated thyroid carcinoma: a critical and still debated issue. PMID- 21537861 TI - Survival factors in patients with recurrence after curative resection of esophageal squamous cell carcinomas. AB - BACKGROUND: Approximately half of patients who undergo curative resection for esophageal cancers develop recurrence postoperatively. The factors affecting survival after such recurrence remain largely unknown. METHODS: To investigate factors affecting survival after recurrence in patients who had undergone curative resection for esophageal cancer, we retrospectively reviewed data for 461 patients who underwent curative esophagectomy with or without preoperative therapy for esophageal squamous cell carcinoma from January 1996 to December 2007. The correlations between several clinicopathological factors and survival after recurrence were examined. RESULTS: Recurrence occurred in 196 of 461 patients (42.5%), with a median survival time after recurrence of 8.2 months. Multivariate analysis identified advanced tumor stage, preoperative chemoradiotherapy (CRT), number of recurrent tumors, and the presence of recurrence at the local site and liver as associated with shortened survival after recurrence. The analysis also indicated that treatment of the recurrence prolonged survival regardless of the treatment type. Although the pattern of recurrence did not significantly differ according to type of preoperative therapy, patients who underwent preoperative CRT were less often treated with radiotherapy for recurrence. Patients with multiple recurrent tumors less often received radiotherapy or surgery than those with a solitary recurrence. Chemotherapy for recurrence was not associated with either preoperative therapy or the number of recurrences. CONCLUSIONS: Our retrospective study showed that multiple recurrent tumors and preoperative CRT limit the available treatment for recurrence and thereby are associated with poor prognosis. Vigorous treatment for recurrence can extend survival after recurrence in patients who undergo esophagectomy. PMID- 21537862 TI - Surgery in retroperitoneal soft tissue sarcoma: a call for a consensus between Europe and North America. PMID- 21537864 TI - Normal PTH levels in primary hyperparathyroidism: still the same disease? AB - PURPOSE: Previous studies have suggested that primary hyperparathyroidism (pHPT) with only normal parathyroid hormone (PTH) levels is a milder, less symptomatic form of pHPT. This study investigates symptoms, laboratory values, imaging, and outcomes of sporadic pHPT patients with normal PTH values. METHODS: We reviewed our prospectively collected database of 861 patients with sporadic pHPT who underwent parathyroidectomy between December 1999 and June 2010. Patients with only normal PTH values for 6 months before surgery were compared to a randomized control group of sporadic pHPT patients with elevated PTH, matched 1:2 for age and gender. RESULTS: Fifty-eight (7%) patients had only normal PTH values within 6 months of surgery. The mean PTH was 55.1 pg/ml in the normal PTH group and 151.3 pg/ml in the control group (n=116). There was no difference in preoperative calcium values, subjective symptoms, bone health, or the frequency of single gland disease (SGD; 88% vs. 91%) between the two groups, but the normal PTH group had higher preoperative vitamin D values (30.8 vs. 21.4 ng/ml; P<0.001), smaller adenomas (405 vs. 978 mg, P<0.001), and more frequently underwent bilateral neck exploration (57% vs. 49%). There was a trend toward lower sensitivity of preoperative imaging in the normal PTH group. CONCLUSIONS: Patients with pHPT and either elevated or normal PTH levels present with similar symptoms and calcium levels. The majority of patients with normal PTH have SGD, although adenomas are smaller. This may explain why patients with normal PTH values have less sensitive imaging and more frequently require four-gland exploration. PMID- 21537863 TI - Presence of pancreatic intraepithelial neoplasia in the pancreatic transection margin does not influence outcome in patients with R0 resected pancreatic cancer. AB - BACKGROUND: Margin status is one of the strongest prognosticators after resection of pancreatic ductal adenocarcinoma (PDAC). The clinical significance of pancreatic intraepithelial neoplasia (PanIN) at a surgical margin has not been established. METHODS: A total of 208 patients who underwent R0 resection for PDAC between 2004 and 2008 were selected. Intraoperative frozen section slides containing the final pancreatic parenchymal transection margin were evaluated for presence or absence, number, and grade of PanINs. Data were compared to clinicopathologic factors, including patient survival. RESULTS: PanIN lesions were present in margins in 107 of 208 patients (51.4%). Median number of PanINs per pancreatic resection margin was 1 (range, 1-11). A total of 72 patients had PanIN-1 (34.6%), 44 had PanIN-2 (21.1%), and 16 had PanIN-3 (7.2%) at their margin. Overall median survival was 17.9 (95% confidence interval, 14-21.9) months. Neither the presence nor absence of PanIN nor histological grade had any significant correlation with important clinicopathologic characteristics. There were no significant survival differences between patients with or without PanIN lesions at the resection margin or among patients with PanIN-3 (carcinoma in situ) versus lower PanIN grades. However, patients with R1 resection had a significantly worse outcome compared with patients without invasive cancer at a margin irrespective of the presence of PanIN (P=0.02). CONCLUSIONS: The presence of PanINs at a resection margin does not affect survival in patients who undergo R0 resection for PDAC. These results have significant clinical implications for surgeons, because no additional resection seems to be indicated when intraoperative frozen sections reveal even high-grade PanIN lesions. PMID- 21537865 TI - Molecular imaging of proliferation and glucose utilization: utility for monitoring response and prognosis after neoadjuvant therapy in locally advanced gastric cancer. AB - BACKGROUND: Metabolic imaging of gastric cancer is limited due to the 30% of primary tumors that are not (18)F-fluorodeoxyglucose (FDG) avid. In contrast, the proliferation marker (18)F-fluorothymidine (FLT) has been shown to visualize also non-FDG-avid gastric tumors. In this study we tested whether FLT-positron emission tomography (PET) can improve the predictive potential of molecular imaging for assessing response to neoadjuvant therapy in gastric cancer compared with FDG-PET. METHODS: 45 patients with gastric cancer underwent FDG- and FLT-PET before and 2 weeks after initiation of chemotherapy. FDG/FLT-PET findings and Ki67 immunohistochemistry were correlated with clinical and histopathological response and survival. RESULTS: 14 patients had non-FDG-avid tumors, whereas all tumors could be visualized by FLT-PET. No significant association of clinical or histopathological response with any of the analyzed metabolic parameters [initial standardized uptake value (SUV), SUV after 2 weeks, change of SUV for FDG/FLT] was found. Univariate Cox regression analysis for Ki67 and metabolic parameters revealed significant prognostic impact for survival only for FLT SUV(mean) day 14 (p=0.048) and Ki67 (p=0.006). Multivariate Cox regression analysis (including clinical response, Lauren type, ypN category, and FLT SUV(mean) day 14) revealed Lauren type and FLT SUV(mean) day 14 as the only significant prognostic factors (p=0.006, p=0.002). CONCLUSIONS: FLT uptake 2 weeks after initiation of therapy was shown to be the only imaging parameter with significant prognostic impact. Neither FLT-PET nor FDG-PET were correlated with histopathological or clinical response. However, these data must be interpreted with caution due to the single center trial study design, relatively short follow-up, poor response rates, and unfavorable prognosis. PMID- 21537866 TI - Retroperitoneal sarcoma: is it time to change the surgical policy? AB - BACKGROUND: Complete tumor resection is the mainstay of treatment for retroperitoneal sarcoma (RPS), but the size and quality of surgical margins for radical resection in RPS are unknown. They are believed to be pushing tumors, but recently, aggressive surgical policies leading to multivisceral resection have seemed to suggest better local control compared with simple tumor resection. We analyzed a single-institution series of RPS to provide information useful to surgical decision-making. METHODS: From 1996 to 2008, 77 patients referred to our institution underwent surgery for primary RPS. Thirty tumors were classified as liposarcoma, and 20 as leiomyosarcoma. Potential prognostic factors were tested retrospectively. Number and pathologic status of resected organs were assessed. RESULTS: 151 organs were resected. Ninety-two were involved by the tumor (60.9%). Liposarcoma involved 48 of 77 organs resected for this histotype (62.3%). Infiltrative pattern was observed in 39/92 organs, and expansive pattern in 53/92 viscera. The infiltrative pattern was more often observed in leiomyosarcoma and non-lipogenic tumors. The expansive pattern was more often observed in liposarcoma. Psoas was the organ most often involved by infiltrative pattern (12/14); the kidney was the organ most often involved by expansive pattern (19/28). 80% of patients had at least one viscera infiltrated by the tumor. CONCLUSIONS: This series, in which an aggressive surgical policy was adopted along with extensive pathologic sampling, shows that RPS has a high rate of viscera infiltration. This growth pattern is characteristic of well differentiated liposarcoma too. These pathologic data should be considered when planning surgical strategy. PMID- 21537867 TI - Therapeutic surgical management of palpable melanoma groin metastases: superficial or combined superficial and deep groin lymph node dissection. AB - BACKGROUND: Management of patients with clinically detectable lymph node metastasis to the groin is by ilioinguinal or combined superficial and deep groin dissection (CGD) according to most literature, but in practice superficial groin dissection (SGD) only is still performed in some centers. The aim of this study is to evaluate the experience in CGD versus SGD patients in our center. METHODS: Between 1991 and 2009, 121 therapeutic CGD and 48 SGD were performed in 169 melanoma patients with palpable groin metastases at our institute. Median follow up was 20 and, for survivors, 45 months. RESULTS: In this heterogeneous group of patients, overall (OS) and disease-free survival, local control rates, and morbidity rates were not significantly different between CGD and SGD patients. However, CGD patients had a trend towards more chronic lymphedema. Superficial lymph node ratio, the number of positive superficial lymph nodes, and the presence of deep nodes were prognostic factors for survival. CGD patients with involved deep lymph nodes (24.8%) had estimated 5-year OS of 12% compared with 40% with no involved deep lymph nodes (p=0.001). Preoperative computed tomography (CT) scan had high negative predictive value of 91% for detection of pelvic nodal involvement. CONCLUSIONS: This study demonstrated that survival and local control do not differ for patients with palpable groin metastases treated by CGD or SGD. Patients without pathological iliac nodes on CT might safely undergo SGD, while CGD might be reserved for patients with multiple positive nodes on SGD and/or positive deep nodes on CT scan. PMID- 21537869 TI - Personalizing thyroid cancer care: are we there yet? PMID- 21537868 TI - Clinical significance of pre- to post-chemoradiotherapy s-CEA reduction ratio in rectal cancer patients treated with preoperative chemoradiotherapy and curative resection. AB - PURPOSE: To evaluate the clinical significance of a reduction in serum carcinoembryonic antigen (s-CEA) concentration ratio from before to after preoperative chemoradiotherapy (CRT) in terms of recurrence and prognostic factors in rectal cancer patients. METHODS: We retrospectively evaluated 333 rectal cancer patients who received preoperative CRT followed by surgery with curative intent between January 2000 and December 2006. Patients were divided into three groups: those with pre-CRT s-CEA<=6 ng/mL (group 1), those with pre CRT s-CEA>6 mg/mL and post-CRT s-CEA>=70% lower than pre-CRT s-CEA (group 2), and those with pre-CRT s-CEA>6 mg/mL and post-CRT s-CEA<70% lower or higher than pre CRT s-CEA (group 3). RESULTS: The 5-year disease-free survival rate was similar in group 1 (76.0%) and group 2 (66.0%), but significantly lower in group 3 (39.5%) (p<0.001). Multivariate analysis showed that CEA group 3, ypT stage, ypN stage, and type of surgery were independent prognostic factors for disease-free survival. CONCLUSIONS: The reduction ratio of pre- to post-CRT s-CEA concentration may be an independent prognostic factor for disease-free survival following preoperative CRT and surgery in rectal cancer patients with initial s CEA>6 ng/mL. PMID- 21537870 TI - Axillary failure in patients treated with MammoSite accelerated partial breast irradiation. AB - BACKGROUND: The risk of axillary failure (AF) after accelerated partial breast irradiation (APBI) using MammoSite brachytherapy is unknown and has been source of concern as the axillary region is not treated with this technique. We aimed to determine the rate of AF in patients treated with APBI and identify factors associated with its occurrence. METHODS: Data from the American Society of Breast Surgeons MammoSite Registry Trial were reviewed and patients with AF were identified. Clinical, pathologic and treatment-related variables were analyzed to determine which factors were associated with AF. RESULTS: A total of 1440 patients underwent MammoSite APBI. A total of 1449 cases were treated (9 patients received bilateral treatment), 1255 cases (87%) of invasive breast cancer and 194 cases (13%) of ductal carcinoma in situ (DCIS). The median length of follow-up was 59 months. There were 10 patients who had an AF. Of these, 9 patients had an initial diagnosis of invasive cancer and 1 had an initial diagnosis of DCIS. The 5-year actuarial rate of AF was 0.79%. The only independent risk factor for AF identified by multivariate analysis was the presence of high-grade disease (P=.008). The 5-year overall survival rate in patients with an AF was 77.8% (there was 1 death related to breast cancer). CONCLUSIONS: The rate of AF after MammoSite APBI is low and appears to be similar to that achieved with whole breast irradiation. PMID- 21537871 TI - MicroRNA signature distinguishes the degree of aggressiveness of papillary thyroid carcinoma. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) has relatively indolent behavior, although some tumors recur and disseminate to distant sites. The aggressive biological behavior of PTC is difficult to predict. MicroRNAs (miRNAs) are dysregulated in various tumors types, and some of them serve as markers of poor prognosis. In this study, we evaluated miRNA expression as a marker of more aggressive behavior in PTC. METHODS: miRNA array was used to identify a subset of differentially expressed miRNAs between aggressive and nonaggressive PTC. These miRNAs were further validated by real-time RT-PCR in a cohort of 17 PTC with local tumor recurrence or distant metastases and 15 PTC with no extrathyroidal dissemination and correlated with BRAF, RAS, and RET/PTC mutations and MET expression. RESULTS: The miRNA array identified miR-146b, miR-221, miR-222, miR 155, miR-31 upregulation and miR-1, miR-34b, miR-130b, miR-138 downregulation in aggressive compared with nonaggressive PTC. Significant miRNA deregulation was confirmed in the validation cohort, with upregulation of miR-146b and miR-222 and downregulation of miR-34b and miR-130b seen in aggressive PTC. Among BRAF positive tumors, miR-146b showed strong association with aggressive PTC. MET was identified as a potential target gene for 2 downregulated miRNAs (miR-34b and miR 1), and significantly higher level of MET expression was observed in aggressive PTC. CONCLUSIONS: We demonstrate that miR-146b, miR-222, miR-34b, miR-130b are differentially expressed in aggressive compared with nonaggressive PTC. Among BRAF-positive tumors, overexpression of miR-146b was associated with aggressive behavior, suggesting that it may further refine the prognostic importance of BRAF. PMID- 21537872 TI - FDG-PET parameters as prognostic factor in esophageal cancer patients: a review. AB - BACKGROUND: (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been used extensively to explore whether FDG Uptake can be used to provide prognostic information for esophageal cancer patients. The aim of the present review is to evaluate the literature available to date concerning the potential prognostic value of FDG uptake in esophageal cancer patients, in terms of absolute pretreatment values and of decrease in FDG uptake during or after neoadjuvant therapy. METHODS: A computer-aided search of the English language literature concerning esophageal cancer and standardized uptake values was performed. This search focused on clinical studies evaluating the prognostic value of FDG uptake as an absolute value or the decrease in FDG uptake and using overall mortality and/or disease-related mortality as an end point. RESULTS: In total, 31 studies met the predefined criteria. Two main groups were identified based on the tested prognostic parameter: (1) FDG uptake and (2) decrease in FDG uptake. Most studies showed that pretreatment FDG uptake and postneoadjuvant treatment FDG uptake, as absolute values, are predictors for survival in univariate analysis. Moreover, early decrease in FDG uptake during neoadjuvant therapy is predictive for response and survival in most studies described. However, late decrease in FDG uptake after completion of neoadjuvant therapy was predictive for pathological response and survival in only 2 of 6 studies. CONCLUSIONS: Measuring decrease in FDG uptake early during neoadjuvant therapy is most appealing, moreover because the observed range of values expressed as relative decrease to discriminate responding from nonresponding patients is very small. At present inter-institutional comparison of results is difficult because several different normalization factors for FDG uptake are in use. Therefore, more research focusing on standardization of protocols and inter-institutional differences should be performed, before a PET-guided algorithm can be universally advocated. PMID- 21537873 TI - Prognostic value of computed tomography for monitoring pulmonary metastases in soft tissue sarcoma patients after surgical management: a retrospective cohort study. AB - BACKGROUND: The lung is the most common site of metastases in patients with a soft tissue sarcoma. However, surveillance protocol for pulmonary metastasis after surgical management has not been proved. The goal of this retrospective study was to evaluate the prognostic value of computed tomography of the chest in soft tissue sarcoma patients after surgery. METHODS: A retrospective study was performed on 176 patients who were followed up with chest computed tomographic (CT) scan or plain chest radiographs for pulmonary metastasis monitoring after surgery. Ninety-six patients were followed up with plain chest radiographs and 80 patients with chest CT scan. Mean duration of follow-up was 55.8 months. The Kaplan-Meier method and the log-rank test were used to calculate overall survival rates and survival rate difference between chest CT and plain radiograph cohorts. RESULTS: The overall 5- and 10-year survival rates of 176 patients were 75.6% and 70.3%, respectively. The 5-year survival estimates of 96 patients who were included in the plain radiograph cohort and 80 patients in the chest CT cohort were 74.2% and 76.6%, respectively (P=0.70). Fifty-four patients (30.7%) had pulmonary metastasis. Of the 54 patients, 26 belonged to the plain radiograph cohort and 28 patients belonged to the chest CT cohort. Pulmonary metastasis of chest CT cohort had the tendencies of unilaterality, a smaller number of patients, and management with metastasectomy other than palliative management. The 2- and 4-year survival ratess after detection of pulmonary metastasis were 20.1% and 0% in the plain radiograph cohort and 47.4% and 31.6% in the chest CT cohort (P<0.05). CONCLUSION: Serial monitoring with chest CT could give rise to early detection of pulmonary metastases, chance for metastasectomy, and eventually survival advantage. PMID- 21537874 TI - Impact of the 21-gene recurrence score assay compared with standard clinicopathologic guidelines in adjuvant therapy selection for node-negative, estrogen receptor-positive breast cancer. AB - BACKGROUND: The development of multigene assays has proved useful in the clinical management of early-stage breast cancer. The 21-gene recurrence score (RS) assay has been shown to quantify risk of distant recurrence and predict chemotherapy benefit in node-negative and node-positive, estrogen-receptor (ER)-positive breast cancer patients. Small, single-institution series have shown that, compared with standard clinicopathologic criteria, use of RS significantly affects adjuvant chemotherapy recommendations. METHODS: We performed a retrospective review of RS use and its effect on chemotherapy recommendations in node-negative, ER-positive breast cancer patients at a tertiary care teaching hospital. Patient and tumor characteristics and adjuvant treatment information were obtained on 183 patients with RS results between January 2004 and October 2009. Risk categories were assigned based on the RS and on standard clinicopathologic criteria according to guidelines from NCCN, St. Gallen, and Adjuvant!. RESULTS: A total of 14 patients were excluded for negative ER status (n=2), insufficient data (n=4), inclusion in TAILORx trial (n=7), and recurrent breast cancer (n=1), leaving 169 patients in the cohort. RS use increased 3-fold over the study period (from 18% in 2004 to 50% in 2009). Tumor grade, ER status, and PR status were significantly correlated with RS category. Overall concordance between RS and NCCN, St. Gallen, and Adjuvant! was 10, 48, and 50%, respectively. Depending on the guideline used for comparison, adjuvant therapy recommendations changed with the addition of the RS in 27-74% of cases. CONCLUSIONS: RS use is increasing, and the assay significantly reduced adjuvant chemotherapy utilization in node-negative, ER -positive breast cancer patients. PMID- 21537875 TI - Intact nanoparticulate indomethacin in fast-dissolving carrier particles by combined wet milling and aerosol flow reactor methods. AB - PURPOSE: Drug development is often hindered by a drug's low dissolution rate. We present a method to increase dissolution rate of a drug powder by producing crystalline nanoparticles that are dispersed in carrier microparticles. METHODS: Indomethacin crystals of a few hundred nanometers are prepared by media milling using poloxamer 188 as a stabilizer. Nanoparticles are embedded into microparticles with a mannitol matrix and an L-leucine coating layer using an aerosol flow reactor method. RESULTS: Microparticles stabilize the primary nanoparticles in an intact crystalline form and release them when re-dispersed in aqueous medium. Secondary microparticle structure dissolves rapidly, resulting in a fast release and dissolution of indomethacin. In this manner, it is possible to change the surface layer of the particles from the one needed for nanoparticle production to one more suitable for process formulation of pharmaceuticals for, e.g., tablet or pulmonary products. CONCLUSIONS: Particle assemblies where nano sized crystalline drug domains are embedded in solid microparticles are presented. The present work is a promising approach towards a "nanos-in-micros" concept as a tool for pharmaceutical nanoparticle processing. PMID- 21537876 TI - Combination of hyaluronic acid hydrogel scaffold and PLGA microspheres for supporting survival of neural stem cells. AB - PURPOSE: To develop a biomaterial composite for promoting proliferation and migration of neural stem cells (NSCs), as well as angiogenesis on the materials, to rescue central nervous system (CNS) injuries. METHODS: A delivery system was constructed based on cross-linked hyaluronic acid (HA) hydrogels, containing embedded BDNF and VEGF-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres for controlled delivery and support for NSCs in the CNS. The surface morphologies were evaluated by SEM and AFM, mechanical property was investigated by rheological tests, and release kinetics were performed by ELISA. Bioactivity of released BDNF and VEGF was assessed by neuron and endothelial cell culture, respectively. Compatibility with NSCs was studied by immunofluorescent staining. RESULTS: Release kinetics showed the delivery of BDNF and VEGF from PLGA microspheres and HA hydrogel composite were sustainable and stable, releasing ~20 30% within 150 h. The bioactivities preserved well to promote survival and growth of the cells. Evaluation of structure and mechanical properties showed the hydrogel composite possessed an elastic scaffold structure. Biocompatibility assay showed NSCs adhered and proliferated well on the hydrogel. CONCLUSIONS: Our created HA hydrogel/PLGA microsphere systems have a good potential for controlled delivery of varied biofactors and supporting NSCs for brain repair and implantation. PMID- 21537877 TI - 3-D image pre-processing algorithms for improved automated tracing of neuronal arbors. AB - The accuracy and reliability of automated neurite tracing systems is ultimately limited by image quality as reflected in the signal-to-noise ratio, contrast, and image variability. This paper describes a novel combination of image processing methods that operate on images of neurites captured by confocal and widefield microscopy, and produce synthetic images that are better suited to automated tracing. The algorithms are based on the curvelet transform (for denoising curvilinear structures and local orientation estimation), perceptual grouping by scalar voting (for elimination of non-tubular structures and improvement of neurite continuity while preserving branch points), adaptive focus detection, and depth estimation (for handling widefield images without deconvolution). The proposed methods are fast, and capable of handling large images. Their ability to handle images of unlimited size derives from automated tiling of large images along the lateral dimension, and processing of 3-D images one optical slice at a time. Their speed derives in part from the fact that the core computations are formulated in terms of the Fast Fourier Transform (FFT), and in part from parallel computation on multi-core computers. The methods are simple to apply to new images since they require very few adjustable parameters, all of which are intuitive. Examples of pre-processing DIADEM Challenge images are used to illustrate improved automated tracing resulting from our pre-processing methods. PMID- 21537878 TI - Automated reconstruction of neural tissue and the role of large-scale simulation. PMID- 21537880 TI - Taurine in adipocytes prevents insulin-mediated H2O2 generation and activates Pka and lipolysis. AB - Among many actions assigned to taurine (Tau), the most abundant amino acid in numerous mammalian tissues, it prevents high-fat diet-induced obesity with increasing resting energy expenditure. To sustain this Tau action, the goal of the present study was to explore the acute effects of Tau on baseline and on adrenaline, insulin and their second messengers to modulate lipolysis in white adipose tissue (WAT) cells from rat epididymis. The Tau effects in this topic were compared with those recorded with Gly, Cys and Met. Tau on its own did not modify baseline lipolysis. Tau raised isoproterenol- and dibutyryl-cAMP (Bt2cAMP) activated glycerol release. Gly diminished Bt2cAMP-activated glycerol release, and Cys and Met had no effect. Cyclic AMP-dependent activation of protein kinase A (PKA) in cell-free extracts decreased slightly by Gly and was unaltered by Cys, Met, and Tau. PKA catalytic activity in cell-free extracts was stimulated by Tau and unchanged by Cys, Gly and Met. Gly and Tau effects on PKA disappeared when these amino acids were withdrawn by gel filtration. Insulin-mediated NADPH oxidase (NOX) raises H2O2 pool, which promotes PKA subunit oxidation, and precludes its cAMP activation; thus, lipolysis is diminished. Tau, but not Cys, Gly and Met, inhibited, by as much as 70%, insulin-mediated H2O2 pool increase. These data suggested that Tau raised lipolysis in adipocytes by two mechanisms: stimulating cAMP-dependent PKA catalytic activity and favoring PKA activation by cAMP as a consequence of lowering the H2O2 pool. PMID- 21537881 TI - Low amino acids affect expression of 11beta-HSD2 in BeWo cells through leptin activated JAK-STAT and MAPK pathways. AB - Maternal protein restriction diminishes placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity and causes fetal growth restriction in mammals. However, it is unknown whether such effect was caused directly by nutrient deficiency, or indirectly through the mediation of maternal hormones. In the present study, a human placental cell line (BeWo) was cultured in F12K as control and F12 as low amino acids (LAA) media for 48 h to investigate the effects of amino acids deficiency on 11beta-HSD2 expression and activity. Despite a significant up-regulation of 11beta-HSD2 mRNA expression in LAA cells, 11beta HSD2 activity and protein content were decreased by 38 and 54%, respectively (P<0.05), indicating a mechanism of post-transcriptional regulation. Among 5 miRNAs targeting 11beta-HSD2, miR-498 was expressed significantly higher in LAA cells. Leptin concentration was significantly lower (P<0.01) in LAA medium. The mRNA expression of both isoforms of leptin receptor was significantly higher in LAA cells, although no difference was detected at protein level. To further clarify whether leptin is involved in mediating the effect of LAA on 11beta-HSD2 activity, leptin was supplemented to LAA medium, whereas three specific inhibitors of leptin signaling pathways, WP1066 for JAK-STAT, PD98059 for MAPK and LY294002 for PI3K, respectively were added to control medium. Leptin restored the diminished 11beta-HSD2 activity in LAA cells, whereas WP1066 (5 nM) and PD98059 (50 nM) significantly decreased 11beta-HSD2 activity in control cells. In conclusion, the present results indicate that LAA diminishes 11beta-HSD2 expression and activity in BeWo cells through leptin-activated JAK-STAT and MAPK pathways. PMID- 21537882 TI - Interstitial pneumonitis induced by bicalutamide given for prostate cancer. AB - We describe interstitial pneumonitis induced by bicalutamide prescribed to treat prostate cancer. A 78-year-old man with severe lower paralysis and a bladder/rectal disorder was referred to our hospital. Prostate-specific antigen was elevated to 1418 ng/mL at that time and magnetic resonance imaging revealed multiple bone metastases. A rectal examination revealed hard nodules in the bilateral lobes of the prostate. We diagnosed prostate cancer without a biopsy, and then maximally blockaded androgens by castration and bicalutamide administration. Eight months later, he was admitted to a local hospital with breathing difficulties, and a computed tomography scan revealed interstitial pneumonitis. A physician concluded that the cause of the interstitial pneumonitis was bicalutamide, which was immediately withdrawn and replaced with prednisolone. The patient recovered over a period of 3 months. Bicalutamide-induced interstitial pneumonitis is quite rare. However, adverse reactions to maximal androgen blockade therapy should be considered and appropriate treatment for interstitial pneumonitis should be promptly initiated, as this condition is reversible. PMID- 21537883 TI - Anatomical study of the external carotid artery and its branches for administration of superselective intra-arterial chemotherapy via the superficial temporal artery. AB - BACKGROUND: The branching patterns of the external carotid artery vary among individuals, and consideration of the proximity of nerves is important during catheter insertion in superselective intra-arterial infusion via the superficial temporal artery. We aimed to evaluate the anatomy of the external carotid artery and its surrounding nerves for safe and accurate administration of superselective intra-arterial chemotherapy via the superficial temporal artery. METHODS: We analyzed the external carotid artery and its branches morphometrically in 28 Japanese cadavers (56 sides). RESULTS: Vascular tortuosity in the preauricular region of the catheter insertion site was observed in 42.9% of the sides; the main trunk of the external carotid artery was excessively tortuous in 25.0% of the sides, primarily in the preparotid region. Faciolingual and superior thyrolingual trunks were observed in 28.6 and 1.8% of the sides, respectively. The superior thyroid, lingual, facial, occipital, and maxillary arteries branched from the external carotid artery above the carotid bifurcation in 41.1% of the sides. The mean distance between the insertion site and maxillary artery was 39.5 mm, indicating the extent of catheter insertion. The auriculotemporal nerve was observed near the superficial temporal artery in the preauricular region in 44.6% of the sides; however, the clearly identifiable nerves in the exposed area were difficult to avoid. CONCLUSION: Because of the branching variations observed in individuals and sides, preoperative angiography is extremely important for avoiding complications. PMID- 21537885 TI - Primary lung cancer in never smokers. PMID- 21537884 TI - Surrogacy of tumor response and progression-free survival for overall survival in metastatic breast cancer resistant to both anthracyclines and taxanes. AB - BACKGROUND: In breast cancer, the validity of surrogate endpoints for overall survival (OS) is a matter of controversy. METHODS: In order to generate a hypothesis, we evaluated whether tumor response or progression-free survival (PFS) could be valid surrogates for OS in patients with metastatic breast cancer. Data from 30 patients were available from a phase II study of trastuzumab and capecitabine in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer resistant to both anthracyclines and taxanes. The proportional hazards (PH) model was applied to evaluate the relationship between OS and tumor response or PFS. In addition, to explore prognostic factors influencing OS or post-progression survival, the PH model with a stepwise regression procedure was applied. RESULTS: The relationship between tumor response and PFS was highly significant (P = 0.0036); however, there was no significant relationship between tumor response and OS or between PFS and OS. In the multivariate analysis, the sum of the longest diameter of target lesions (P = 0.0011), neutrophil count (P = 0.0033), and creatinine (P = 0.0085) were statistically significantly associated with OS. CONCLUSION: We generated a hypothesis that neither PFS nor tumor response were valid as surrogate endpoints for OS, at least in the phase II trial for metastatic breast cancer resistant to both anthracyclines and taxanes. We also found that the sum of the longest diameter of target lesions, neutrophil count, and creatinine were prognostic factors for OS. PMID- 21537886 TI - Safety and pharmacokinetic study of nab-paclitaxel plus carboplatin in chemotherapy-naive patients with advanced non-small cell lung cancer. AB - BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a Cremophor EL-free formulation of paclitaxel newly designed to avoid solvent-related toxicities. We have evaluated the safety, tolerability, pharmacokinetics, and tumor response profile of weekly nab-paclitaxel (100 mg/m(2)) infusion together with administration of carboplatin at an area under the curve (AUC) of 6 every 3 weeks in Japanese patients with advanced non-small cell lung cancer (NSCLC). METHODS: Nab-paclitaxel (100 mg/m(2)) was administered without steroid or antihistamine premedication as a 30-min intravenous infusion once a week in combination with carboplatin at an AUC of 6 on day 1 of repeated 21-day cycles. The pharmacokinetics of both drugs were analyzed, and both adverse events and treatment response were monitored. RESULTS: Eighteen patients were enrolled in the study. The most frequent treatment-related toxicities of grade 3 or 4 were neutropenia (67%), leukopenia (50%), and anemia (22%). No severe hypersensitivity reactions were observed despite the lack of premedication, and no unexpected or new toxicities were detected. Pharmacokinetics analysis did not reveal any substantial drug-drug interactions. Seven partial responses were observed among the 18 evaluable patients, yielding a treatment response rate of 38.9%. CONCLUSIONS: The combination of nab-paclitaxel (100 mg/m(2)) administered weekly and carboplatin at an AUC of 6 every 3 weeks was well tolerated in Japanese patients with advanced NSCLC. This combination therapy also showed promising antitumor activity and was not associated with relevant pharmacokinetic interactions. PMID- 21537887 TI - Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells. AB - Cancer stem cells (CSC) are chemoresistant and implicated in tumor recurrence, metastasis and high patient mortality; thus substances impairing CSC activity, could be invaluable as novel cancer therapeutics. We previously showed that CAPE (caffeic acid phenethyl ester), a component of propolis, a honeybee product, inhibits growth of MDA-MB-231 (MDA-231) cells, mdr gene expression, NF-kappaB, EGFR, and VEGF. We hypothesized that CAPE also acts by interfering with CSC mediated effects. We isolated breast CSC (bCSC) from MDA-231 cells, a model of human triple-negative breast cancer, and mouse xenografts. bCSC grow as mammospheres (MMS) and when dissociated into single cells, form MMS again, a sign of self-renewal. bCSC exhibited the characteristic CD44(+)/CD24(-/low) phenotype and generated progenitors in the presence of serum, a CSC trait responsible for regenerating tumor mass. CAPE caused dose-dependent bCSC self-renewal inhibition and progenitor formation. Clonal growth on soft agar was inhibited dose dependently, but apoptosis was not induced as determined by Annexin-V/PI assay. Instead, bCSC were noted to significantly progress from a quiescent cell cycle state in G0/G1 (82%), S phase (12%) to a cycling state with an increase in S phase (41%) and subsequent decrease in G0/G1 (54%). Treatment of bCSC with CAPE (4.5-days) decreased CD44 levels by 95%, while another cell population containing 10-100-fold lower CD44 content concurrently increased. Results suggest that CAPE causes pronounced changes in bCSC characteristics manifested by inhibition of self renewal, progenitor formation, clonal growth in soft agar, and concurrent significant decrease in CD44 content, all signs of decreased malignancy potential. PMID- 21537889 TI - Evaluation of the TRA ECETOC model for inhalation workplace exposure to different organic solvents for selected process categories. AB - OBJECTIVE: The aim of this work is to describe the operation principle of the TRA ECETOC model developed using the descriptor system, and the utilization of that model for assessment of inhalation exposures to different organic solvents for selected process categories identifying a given application. METHOD: Measurement results were available for toluene, ethyl acetate and acetone in workplace atmosphere in Poland. The following process categories have been postulated: (1) Paints and lacquers factory: use in closed, continuous process with occasional controlled exposure; (2) Shoe factory: roller or brush application of glues; (3) Refinery: use in closed process, no likelihood of exposure. The next step was to calculate the workplace concentration at chosen process categories by applying the TRA ECETOC model. RESULTS: The selected categories do not precisely describe the studied applications. Very high concentration values of acetone were measured in the shoe factory, mean 443 ppm. The concentration obtained with the aid of the model is underestimated, ranging from 25.47 to 254.7 ppm, for the case with and without activation of the local exhaust ventilation (LEV), respectively. Estimated concentration at a level corresponding to that of the measured concentration would be possible if the process category involving spraying, e.g., PROC 7 was considered. For toluene and ethyl acetate, the measured concentrations are within the predicted ranges determined with the use of the model when we assume the concentration predicted with active ventilation for the beginning, and the concentration predicted with inactive ventilation for the end of the range. CONCLUSIONS: Model TRA ECETOC can be easily used to assess inhalation exposure at workplace. It has numerous advantages, its structure is clear, requires few data, is available free of charge. Selection of appropriate process categories related to the uses identified is guarantee of successful exposure assessment. PMID- 21537890 TI - Asbestos in Poland: occupational health problems. AB - The presentation addresses current problems of health risk and health effects associated with exposure to asbestos, including data on historical exposure and on currently valid occupational exposure limits. The quantity and types of the raw material used for the production of various asbestos products have also been discussed in relation to the particular types of asbestos-induced occupational diseases. The authors describe the medical care system for former asbestos workers and those currently exposed during removal of asbestos-containing products. The national system for medical certification of occupational asbestos related diseases and the compensation procedure have been outlined as well. According to the parliamentary Act of 1997, importing, manufacture and sale of asbestos and asbestos-containing materials are prohibited in Poland. Thus, the assessment of asbestos exposure and the monitoring of health conditions of workers at asbestos-processing plants have become irrelevant. However, the delayed health effects attributable to past exposure continue to be the matter of concern for public health. Likewise, the environmental pollution from asbestos waste landfills in the vicinity of asbestos-processing plants (where high levels of asbestos fibre in ambient air have been recorded) will continue to be a serious public health problem. Presently, two programmes aimed at minimising the adverse effects of asbestos on population health are underway. One of them is the governmental programme for "Elimination of asbestos and asbestos-containing products used in Poland, 2002-2032". The programme was updated in 2009 to cover the workers contracted to perform demolition works and provide protective covers to asbestos waste landfills. This will be the exposed group who need prophylactic health care. The other is a programme of prophylactic examinations for former asbestos workers and is referred to as the AMIANTUS programme. Both programmes have been briefly described. PMID- 21537891 TI - Oxidative lime pretreatment of Alamo switchgrass. AB - Previous studies have shown that oxidative lime pretreatment is an effective delignification method that improves the enzymatic digestibility of many biomass feedstocks. The purpose of this work is to determine the recommended oxidative lime pretreatment conditions (reaction temperature, time, pressure, and lime loading) for Alamo switchgrass (Panicum virgatum). Enzymatic hydrolysis of glucan and xylan was used to determine the performance of the 52 studied pretreatment conditions. The recommended condition (110 degrees C, 6.89 bar O(2), 240 min, 0.248 g Ca(OH)(2)/g biomass) achieved glucan and xylan overall yields (grams of sugar hydrolyzed/100 g sugar in raw biomass, 15 filter paper units (FPU)/g raw glucan) of 85.9 and 52.2, respectively. In addition, some glucan oligomers (2.6 g glucan recovered/100 g glucan in raw biomass) and significant levels of xylan oligomers (26.0 g xylan recovered/100 g xylan in raw biomass) were recovered from the pretreatment liquor. Combining a decrystallization technique (ball milling) with oxidative lime pretreatment further improved the overall glucan yield to 90.0 (7 FPU/g raw glucan). PMID- 21537892 TI - Engineering a metabolic pathway for isobutanol biosynthesis in Bacillus subtilis. AB - Isobutanol can be biosynthesized via alpha-ketoisovalerate catalyzed by heterologous keto acid decarboxylase (KDC) and alcohol dehydrogenase (ADH). In this work, isobutanol biosynthesis pathway was designed in Bacillus subtilis, a notable solvent-tolerant host. In order to do that, a plasmid pPKA expressing KDC and ADH under the control of a B. subtilis strong promoter P(43) was constructed. Isobutanol was detected in the products of the recombinant B. subtilis harboring pPKA plasmid, whereas none was detected by the wild-type strain. Effects of the medium ingredients such as glucose concentration and valine addition, and operating parameters such as initial pH, inoculation volume, and medium work volume on isobutanol production were also investigated. Isobutanol production reached to the maximum of 0.607 g/L after 35-h cultivation under the conditions: glucose concentration of 3%, valine addition of 2%, initial pH of 7.0, inoculum of 1%, and work volume of 50 mL/250 mL. Though the isobutanol production by the recombinant was low, it was the first successful attempt to produce isobutanol in engineered B. subtilis, and the results showed its great potential as an isobutanol-producing cell factory. PMID- 21537893 TI - Turnover of carbohydrate-rich vegetal matter during microaerobic composting and after amendment in soil. AB - We propose that microaerobic composting (MC) can be used to decompose vegetal matter with a short turnover time and large carbon (C) recycling potential. We used a novel method for measuring the degree of fragmentation of water-insoluble acid-soluble (WIAS) polysaccharides as a proxy in tracking their relative degree of degradation (i.e., fragmentation endpoint index). Oak leaves and food scrap processed by MC reached a fragmentation end point within 2 weeks. After amending the MC products into soil, the half-life of the polysaccharide residues was ~6-7 times longer (~100-110 days) than that measured during MC. The main products given up during MC were volatile organic acids (VOAs), alcohols and soluble carbohydrates in the compost tea, and CO(2). These products accounted for about 2% of the initial carbon in the feedstock. Very small amounts of VOAs, particularly butyric acid, were formed in the amended soil. Based on a residence time of materials in fermentors of 2 weeks, a ~100-m(3) capacity MC facility could process 2,000-4,000 metric tons of vegetable matter amended in ten hectares of arable land per year. PMID- 21537894 TI - The relation between maternal ADHD symptoms & improvement in child behavior following brief behavioral parent training is mediated by change in negative parenting. AB - This study examined the extent to which maternal attention-deficit/hyperactivity disorder (ADHD) symptoms predict improvement in child behavior following brief behavioral parent training. Change in parenting was examined as a potential mediator of the negative relationship between maternal ADHD symptoms and improvement in child behavior. Seventy mothers of 6-10 year old children with ADHD underwent a comprehensive assessment of adult ADHD prior to participating in an abbreviated parent training program. Before and after treatment, parenting was assessed via maternal reports and observations and child disruptive behavior was measured via maternal report. Controlling for pre-treatment levels, maternal ADHD symptomatology predicted post-treatment child disruptive behavior problems. The relation between maternal ADHD symptomatology and improvement in child behavior was mediated by change in observed maternal negative parenting. This study replicated findings linking maternal ADHD symptoms with attenuated child improvement following parent training, and is the first to demonstrate that negative parenting at least partially explains this relationship. Innovative approaches combining evidence-based treatment for adult ADHD with parent training may therefore be necessary for families in which both the mother and child have ADHD. Larger-scale studies using a full evidence-based parent training program are needed to replicate these findings. PMID- 21537895 TI - Prospective relations among fearful temperament, protective parenting, and social withdrawal: the role of maternal accuracy in a moderated mediation framework. AB - Early social withdrawal and protective parenting predict a host of negative outcomes, warranting examination of their development. Mothers' accurate anticipation of their toddlers' fearfulness may facilitate transactional relations between toddler fearful temperament and protective parenting, leading to these outcomes. Currently, we followed 93 toddlers (42 female; on average 24.76 months) and their mothers (9% underrepresented racial/ethnic backgrounds) over 3 years. We gathered laboratory observation of fearful temperament, maternal protective behavior, and maternal accuracy during toddlerhood and a multi-method assessment of children's social withdrawal and mothers' self-reported protective behavior at kindergarten entry. When mothers displayed higher accuracy, toddler fearful temperament significantly related to concurrent maternal protective behavior and indirectly predicted kindergarten social withdrawal and maternal protective behavior. These results highlight the important role of maternal accuracy in linking fearful temperament and protective parenting, which predict further social withdrawal and protection, and point to toddlerhood for efforts of prevention of anxiety-spectrum outcomes. PMID- 21537896 TI - Hostile intent attributions and relational aggression: the moderating roles of emotional sensitivity, gender, and victimization. AB - The current study adopts a relational vulnerability model to examine the association between hostile attribution bias and relational aggression. Specifically, the relational vulnerability model implicates the interactive effects of a number of relational risk factors in the development of relational aggression. A sample of 635 3rd, 4th, and 5th grade students (50.2% females) completed a self-report measure assessing hostile attribution bias and emotional distress for relational provocations. Peer nominations and teacher reports of relational aggression and relational victimization were also collected. Results supported the relational vulnerability model for girls only. Specifically, hostile attribution bias was associated with relational aggression only when relational victimization and emotional distress were also high. Implications for future research and clinical practice are discussed. PMID- 21537897 TI - Prevention of stroke following transient ischemic attack. AB - Transient ischemic attacks (TIAs) are common neurologic events characterized by stroke-like symptoms that completely resolve. They were previously thought to be benign but research over the past decade has revealed the high risk of further neurologic and cardiac events following TIA. With the knowledge of prognosis following TIA, the need for more urgent diagnostic workup and treatment has become clear, and several tools for identifying patients at the highest risk have been developed. In this review, we discuss appropriate diagnostic testing, acute management, and long-term management for preventing stroke after TIA, current research in progress, as well as areas of need for future research. PMID- 21537898 TI - Was Herodotus correct? PMID- 21537899 TI - Unintended pregnancy and perinatal depression trajectories in low-income, high risk Hispanic immigrants. AB - Perinatal depression is a prevalent and detrimental condition. Determining modifiable factors associated with it would identify opportunities for prevention. This paper: 1) identifies depressive symptom trajectories and heterogeneity in those trajectories during pregnancy through the first-year postpartum, and 2) examines the association between unintended pregnancy and depressive symptoms. Depressive symptoms (BDI-II) were collected from low-income Hispanic immigrants (n=215) five times from early pregnancy to 12-months postpartum. The sample was at high-risk for perinatal depression and recruited from two prenatal care settings. Growth mixture modeling (GMM) was used to identify distinct trajectories of depressive symptoms over the perinatal period. Multinomial logistic regression was then conducted to examine the association between unintended pregnancy (reported at baseline) and the depression trajectory patterns. Three distinct trajectory patterns of depressive symptoms were identified: high during pregnancy, but low postpartum ("Pregnancy High": 9.8%); borderline during pregnancy, with a postpartum increase ("Postpartum High": 10.2%); and low throughout pregnancy and postpartum ("Perinatal Low": 80.0%). Unintended pregnancy was not associated with the "Pregnancy High" pattern, but was associated with a marginally significant nearly four fold increase in risk of the "Postpartum High" pattern in depressive symptoms (RRR=3.95, p<0.10). Family planning is a potential strategy for the prevention of postpartum depression. Women who report unintended pregnancies during prenatal care must be educated of their increased risk, even if they do not exhibit antenatal depressive symptoms. Routine depression screening should occur postpartum, and referral to culturally appropriate treatment should follow positive screening results. PMID- 21537900 TI - Ecosystem, location, and climate effects on foliar secondary metabolites of lodgepole pine populations from central British Columbia. AB - Lodgepole pines, Pinus contorta Douglas ex Louden var. latifolia Engelm. ex S. Watson, are encountering increased abiotic stress and pest activity due to recent increases in temperature and changes in precipitation throughout their range. This tree species counters these threats by producing secondary metabolites, including phenolics and terpenoids. We examined foliar levels of lignin, soluble phenolics, monoterpenoids, sesquiterpenoids, and diterpenoids in 12 stands in British Columbia, Canada. We used these data to assess associations among foliar secondary metabolite levels and ecosystem, geographic, and climatic variables. Regressions were also performed to observe which combinations of variables best explained secondary metabolite variance. Stands of P. c. latifolia in the Coastal Western Hemlock and Interior Cedar/Hemlock biogeoclimatic zones had consistently greater foliar levels of almost all measured secondary metabolites than did other stands. Lignin was present in greater amounts in Boreal White/Black Spruce ecosystem (i.e., northern) stands than in southern stands, suggesting a role for this metabolite in pine survival in the boreal forest. Attempts to develop regression models with geographic and climatic variables to explain foliar secondary metabolite levels resulted in multiple models with similar predictive capability. Since foliar secondary metabolite levels appeared to vary most between stand ecosystem types and not as much due to geographic and climatic variables, metabolic profiles appeared best matched to the stress levels within local environments. It is unknown if differences in secondary metabolite levels are the result of genetic adaptation or phenotypic plasticity, but results from this and other studies suggest that both are important. These results are interpreted in light of ongoing efforts to assist in the migration of certain populations of P. c. latifolia northward in an effort to counter predicted effects of climate change. PMID- 21537901 TI - Near-infrared imaging spectroscopy as a tool to discriminate two cryptic Tetramorium ant species. AB - Correct species identification is a precondition for many ecological studies. Morphologically highly similar, i.e., cryptic, species are an important component of biodiversity but particularly difficult to discriminate and therefore understudied ecologically. To find new methods for their rapid identification, thus, is important. The cuticle's chemical signature of insects often is unique for species. Near-infrared spectroscopy (NIRS) can capture such signatures. Imaging NIRS facilitates precise positioning of the measurement area on biological objects and high-resolution spatial capturing. Here, we tested the applicability of imaging NIRS to the discrimination of cryptic species by using the ants Tetramorium caespitum and T. impurum. The classification success of Partial Least Squares Regression was 98.8%. Principal Component Analysis grouped spectra of some T. impurum individuals with T. caespitum. Combined with molecular genetic and morphological evidence, this result enabled us to pose testable hypotheses about the biology of these species. We conclude that discrimination of T. caespitum and T. impurum with imaging NIRS is possible, promising that imaging NIRS could become a time- and cost-efficient tool for the reliable discrimination of cryptic species. This and the direct facilitation of potential biological insight beyond species identification underscore the value of imaging NIRS to ecology. PMID- 21537902 TI - Distinguishing defensive characteristics in the phloem of ash species resistant and susceptible to emerald ash borer. AB - We examined the extent to which three Fraxinus cultivars and a wild population that vary in their resistance to Emerald Ash Borer (EAB) could be differentiated on the basis of a suite of constitutive chemical defense traits in phloem extracts. The EAB-resistant Manchurian ash (F. mandshurica, cv. Mancana) was characterized by having a rapid rate of wound browning, a high soluble protein concentration, low trypsin inhibitor activities, and intermediate levels of peroxidase activity and total soluble phenolic concentration. The EAB-susceptible white ash (F. americana, cv. Autumn Purple) was characterized by a slow wound browning rate and low levels of peroxidase activity and total soluble phenolic concentrations. An EAB-susceptible green ash cultivar (F. pennsylvanica, cv. Patmore) and a wild accession were similar to each other on the basis of several chemical defense traits, and were characterized by high activities of peroxidase and trypsin inhibitor, a high total soluble phenolic concentration, and an intermediate rate of wound browning. Lignin concentration and polyphenol oxidase activities did not differentiate resistant and susceptible species. Of 33 phenolic compounds separated by HPLC and meeting a minimum criterion for analysis, nine were unique to Manchurian ash, five were shared among all species, and four were found in North American ashes and not in the Manchurian ash. Principal components analysis revealed clear separations between Manchurian, white, and green ashes on the basis of all phenolics, as well as clear separations on the basis of quantities of phenolics that all species shared. Variation in some of these constitutive chemical defense traits may contribute to variation in resistance to EAB in these species. PMID- 21537903 TI - Moringa oleifera pod inhibits inflammatory mediator production by lipopolysaccharide-stimulated RAW 264.7 murine macrophage cell lines. AB - Pro-inflammatory mediators produced during inflammatory response have been demonstrated to initiate and aggravate pathological development of several chronic diseases. Plant bioactive constituents have been reported to exert anti inflammatory activities. Various parts of Moringa oleifera have long been used as habitual diets and traditional remedy along the tropical region. Anti inflammatory activity of boiled M. oleifera pod extract was assessed by measuring pro-inflammatory mediator expression in the lipopolysaccharide-induced murine RAW264.7 macrophage cells. Prior treatment with 31-250 MUg/mL M. oleifera extract for 1 h inhibited elevation of mRNA and protein level of interleukine-6, tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenease-2, induced by lipopolysaccharide for 24 h in a dose-dependent manner. The suppressive effect was mediated partly by inhibiting phosphorylation of inhibitor kappa B protein and mitogen-activated protein kinases. These results indicate that the anti-inflammatory activity from bioactive compounds present in the M. oleifera pod constituents may contribute to ameliorate the pathogenesis of inflammatory-associated chronic diseases. PMID- 21537905 TI - Natural compounds as inflammation inhibitors. PMID- 21537904 TI - The role of inflammation and COX-derived prostanoids in the effects of bradykinin on isolated rat aorta and urinary bladder. AB - Bradykinin, a vasoactive peptide, increases during inflammation and induces the formation of prostaglandins through specific receptor activation. Two types of receptors mediate the biological effects of bradykinin, B(1) and B(2) receptors. Although B(2) receptors are present in most tissues, B(1) receptors are expressed after inflammatory stimuli or tissue injury. Bradykinin has a high affinity for B(2) and a low affinity for B(1) receptors, whereas the opposite occurs for des Arg(9)-bradykinin. Recently, it has been reported that nonsteroidal anti inflammatory drugs have different inhibitory activities on cyclooxygenase isozymes, COX-1, COX-2, and COX-3. In the present study, we have investigated the contributions of different COX isozyme inhibitions and inflammation on bradykinin induced effects of isolated rat aorta and urinary bladder smooth muscle contractions. Male Sprague-Dawley rats weighing 200-250 g were used in the study. The vasodilatory responses to bradykinin (1 nM-1 MUM) were studied on isolated rat aorta rings contracted with norepinephrine (0.1 MUM) following incubation with dipyrone (100, 700, and 2,000 MUM). The relaxant responses of dipyrone (100, 700, and 2,000 MUM) were also compared on the isolated rat urinary bladder contracted with bradykinin (n = 8). A bacterial lipopolysaccharide was used for the induction of inflammation (n = 8). The levels of PGE(2), PGF(1alpha), TXB(2), nitric oxide synthase (NOS), IL-10, and TNF-alpha were all determined in both the plasma and the perfusate of the aorta preparations (n = 5). The vasodilatory activities of bradykinin and des-Arg9-bradykinin were significantly increased upon the inhibition of COX-3 (dipyrone at 100 MUM). These effects disappeared in the inflamed group. PGE(2), PGF1alpha, and TXB(2) were significantly high, but NOS activity was low in the aorta perfusate after the inhibition of COX-3. Dipyrone showed the relaxant activity of the urinary bladder contracted with bradykinin. The vasodilatory activity of des-Arg(9)-bradykinin was in the inflamed group but not in the non-inflamed group. Bradykinin did not contract urinary bladder in inflamed group. The results suggest that COX-induced products may play an important role in the bradykinin-induced rat aortic smooth muscle relaxations. PMID- 21537906 TI - How reliable is the manual correction of the autoscoring of a level IV sleep study (ApneaLinkTM) by an observer without experience in polysomnography? AB - OBJECTIVE: This study aims to compare the manual correction of the automatic analysis of ApneaLinkTM between a skilled observer in the interpretation of sleep studies and a subject trained only in the scoring of ApneaLinkTM device. METHODS: Ninety-six subjects performed the ApneaLinkTM and polysomnography (PSG) simultaneously in the sleep laboratory. Two blind observers, who were independent from the results of the PSG, performed first the automatic scoring and then the hand correction from the ApneaLinkTM device. The scorers of ApneaLinkTM represented two physicians with different levels of training (scorer A: 20 years of experience in reading polysomnography plus 3 years of experience in the interpretation of ApneaLinkTM, scorer B: 1 year of experience in the analysis of ApneaLinkTM). The interobserver agreement was assessed with the intraclass correlation coefficient (ICC) and kappa statistics. The diagnostic accuracy of the manual analysis ApneaLinkTM device was evaluated by the area under the receiver operator curve (AUC-ROC). RESULTS: Ninety patients were included (69 men; mean age, 49.6; median RDI, 13.9; median BMI, 29.3 Kg/m(2)). The ICC between the manual apnea/hypopnea index from ApneaLinkTM and the respiratory disturbance index of the PSG for each observer was similar (scorer A, 0.902; CI 95% 0.80 0.95; vs. scorer B, 0.904; CI 95% 0.86-0.94; p = 0.9). The agreement between the observers on the presence or absence of obstructive sleep apnea syndrome (OSAS) was very good (kappa, 0.83; CI 95% 0.69-0.98). The AUC-ROC was similar between the observers (scorer A, 0.88; CI 95% 0.78-0.98; scorer B, 0.83; CI 95% 0.71 0.95; p = 0.5). CONCLUSIONS: The non-expert observer showed a very good agreement with the expert observer on the results of the manual correction of the ApneaLinkTM autoscoring. Both observers had similar diagnostic accuracy to identify subjects with OSAS when compared with PSG. PMID- 21537907 TI - Correlations of sleep disorders with severity of obstructive airway disease in mustard gas-injured patients. AB - INTRODUCTION: Mustard gas has serious adverse effects on several organs and functions in humans. In this study, we analyzed potential correlations between obstructive airway disease and sleep disorders in Iranian mustard gas-injured patients. METHODS: We enrolled 30 male mustard gas-injured veterans and civilians from the Chemical Warfare Exposure Clinic at Baqiyatallah Hospital, Tehran. All the subjects underwent comprehensive polysomnographic and spirometric evaluations for diagnosis of sleep disorders. Patients were categorized into three groups according to the severity of their obstructive airway disease based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria: group 1 (GOLD I and II), group 2 (GOLD III), and group 3 (GOLD IV). RESULTS: Patients with less severe obstructive airway disease had significantly higher rate of hypopnea (p = 0.05) and AHI (p = 0.05). The number of REM events was significantly higher in patients with less severe airway disease (p = 0.028). Stage 1 sleep among patients with higher FEV1 significantly constituted a higher proportion of sleep, and stage 4 sleep was significantly longer in patients with higher DLCO (p = 0.043, both). CONCLUSION: We found that sleep parameters in SM-exposed patients have some relations with spirometric parameters. Future studies with large patient populations are needed for confirmation of our results, and therapeutic interventions are needed to evaluate endeavors we can do to enhance health and quality of life in our mustard gas-injured population. PMID- 21537908 TI - Seizure management in the setting of hepatic disease. AB - OPINION STATEMENT: In the past 20 years, many antiepileptic drugs (AEDs) have been marketed that are not significantly metabolized by the liver, but some patients still require the use of older and more metabolically complex AEDs for optimal seizure control, and current economic and insurance-coverage limitations have forced many patients to switch to less expensive agents, which are often the older AEDs. For the patient with hepatic disease, it is clearly preferable to use medications with little potential to exacerbate their condition. In my practice, I try to use agents with simpler metabolism, especially for patients with multiple medical problems. Doing this can mean using AEDs in monotherapy that are FDA-approved only for adjunctive use. I also find that older agents and hepatically metabolized AEDs can be the most appropriate for particular patients. Selection of the optimal seizure medication requires consideration of multiple factors, only one of which is the impact on liver function. I routinely obtain an executive laboratory panel at least yearly for even the healthiest of patients, to reassure both the patient and myself that the metabolism of their AED regimen is not significantly affected. Occasionally, a change or abnormality in liver function is identified. Certainly hepatic disease can make epilepsy management more difficult, and communication between the neurologist and the other treating physicians is a necessity, although the neurologist and the hepatologist may have differing opinions on how to respond to worsening liver function. Concern about potential liver damage by AEDs may prompt unnecessary discontinuation, sometimes with disastrous consequences for seizure control. Overly complex AED regimens can cause underlying liver problems to worsen. Clinical observation and judgment must complement the data derived from laboratory parameters. Worsening hepatic disease can also result in encephalopathic states that worsen or mimic seizures. The EEG can often be helpful in differentiating these conditions and is crucial in determining appropriate epilepsy therapy. PMID- 21537909 TI - Role of pGlu-serpinin, a novel chromogranin A-derived peptide in inhibition of cell death. AB - Chromogranin A (CgA) is a member of the granin family of molecules found in secretory granules of endocrine and neuro-endocrine cells. Here, we have identified a new 23-mer CgA-derived peptide secreted from pituitary AtT-20 cells, which we named pyroGlu-serpinin (pGlu-serpinin). LC-MS studies of peptides in conditioned medium of AtT-20 cells indicate that pGlu-serpinin is derived from initial processing of mouse CgA at paired basic residues, Arg461-Arg462 and Arg433-Arg434, to yield a previously described 26 amino acid peptide, serpinin. Three amino acids are then cleaved from the N terminus of serpinin, yielding a peptide with an N-terminal glutamine, which is then subsequently pyroglutaminated. Immunocytochemistry showed co-localization of pGlu-serpinin with adrenocorticotropic hormone in secretory granules of AtT-20 cells, and it was released in an activity-dependent manner. Functional studies demonstrated that pGlu-serpinin was able to prevent radical oxygen species (hydrogen peroxide) induced cell death of AtT-20 cells and cultured rat cerebral cortical neurons at a concentration of 1 and 10 nM, respectively. These data indicate that pGlu serpinin has anti-apoptotic effects that may be important in neuroprotection of central nervous system neurons and pituitary cells. Furthermore, pGlu-serpinin added to the media of AtT-20 cells up-regulated the transcription of the serine protease inhibitor, protease nexin-1 (PN-1) mRNA. pGlu-serpinin's ability to increase levels of PN-1, a potent inhibitor of plasmin released during inflammatory processes causing cell death, may play a role in protecting cells under adverse pathophysiological conditions. PMID- 21537910 TI - Virological and molecular characterization of Kaposi's sarcoma-associated herpesvirus strains from Xinjiang, China. AB - Kaposi's sarcoma (KS) is a highly and abnormally vascularized tumor-like lesion affecting the skin. KS-associated herpesvirus (KSHV/HHV-8) is etiologically linked to all epidemiological forms of KS. However, clinical phenotypes show considerable discrepancy, indicating the presence of virological and molecular characteristics of KSHV that influence its pathogenesis. We investigated the molecular virological features of KSHV strains from Xinjiang, where KSHV infection is endemic and there is a high incidence of KS. Phylogenetic characterization based on the VR1 region of the KSHV K1 gene for 21 classical and AIDS-KS specimens revealed the Eurasian KSHV genotypes C (n = 18) and A (n = 3), with subtypes A5, C6, and C7 identified for the first time in China. The distribution was closely associated with their unique ethnic origin and evolution. The KSHV viral load in AIDS-KS was substantially lower than in classic KS (p = 0.05), as quantified by real-time fluorescent quantitative polymerase chain reaction (PCR). The results reveal the general consistency of the biological and pathological properties of local KS with others, but characteristics associated with unique ethnicity evolution still remain. PMID- 21537911 TI - Dried blood spot UHPLC-MS/MS analysis of oseltamivir and oseltamivircarboxylate- a validated assay for the clinic. AB - The neuraminidase inhibitor oseltamivir (Tamiflu(r)) is currently the first-line therapy for patients with influenza virus infection. Common analysis of the prodrug and its active metabolite oseltamivircarboxylate is determined via extraction from plasma. Compared with these assays, dried blood spot (DBS) analysis provides several advantages, including a minimum sample volume required for the measurement of drugs in whole blood. Samples can easily be obtained via a simple, non-invasive finger or heel prick. Mainly, these characteristics make DBS an ideal tool for pediatrics and to measure multiple time points such as those needed in therapeutic drug monitoring or pharmacokinetic studies. Additionally, DBS sample preparation, stability, and storage are usually most convenient. In the present work, we developed and fully validated a DBS assay for the simultaneous determination of oseltamivir and oseltamivircarboxylate concentrations in human whole blood. We demonstrate the simplicity of DBS sample preparation, and a fast, accurate and reproducible analysis using ultra high performance liquid chromatography coupled to a triple quadrupole mass spectrometer. A thorough validation on the basis of the most recent FDA guidelines for bioanalytical method validation showed that the method is selective, precise, and accurate (<=15% RSD), and sensitive over the relevant clinical range of 5-1,500 ng/mL for oseltamivir and 20-1,500 ng/mL for the oseltamivircarboxylate metabolite. As a proof of concept, oseltamivir and oseltamivircarboxylate levels were determined in DBS obtained from healthy volunteers who received a single oral dose of Tamiflu(r). PMID- 21537912 TI - Development of a modified grating coupler in application to geosciences. AB - A grating coupler system has been developed to measure refractive index gradients with high spatial (6.7 MUm) and temporal (milliseconds) resolution. The system was applied to two-phase model systems consisting of water and non-aqueous pollution liquids. Refractive index gradients at the interfaces between the aqueous and organic phase of 1-butanol, hexane, and 1-heptanol were monitored under steady-state conditions. The temporal resolution was utilized in diffusion experiments with glycerol and sodium chloride in water, where the formation of a concentration gradient was studied. In a further application, the grating coupler system was modified to monitor low-level concentrations of aqueous pollution profiles as are caused by bacterial degradation in the aqueous phase. Toluene was selected as contaminant. The sensor sensitivity was improved by coating the sensor with the pre-concentrating polymers polydimethylsiloxane and Teflon((r)) AF-2400. With the grating coupler setup, a multi-purpose instrument was created to measure high-resolution refractive index gradients with high temporal and spatial resolution in different fields of application. The new sensor system can be used to measure absolute refractive indices by covering parts of the sensing area with cover media of known refractive index. Coatings can be used for sensitivity improvement by pre-concentrating the sample, for selectivity by utilizing filtering properties of the coating, and as calibration standard for absolute refractive index measurements. PMID- 21537913 TI - Monitoring of the non-steroid anti-inflammatory drug indomethacin: development of immunochemical methods for its purification and detection. AB - The present research focused on the development of an immunoassay and an immunochemical sol-gel-based immunoaffinity purification (IAP) method for purification and detection of the non-steroid anti-inflammatory drug (NSAID) indomethacin (IMT). A polyclonal antibody (Ab) for IMT was generated, and two sensitive microplate assays for the detection of IMT were developed (termed OV and HRP formats), based on the enzyme-linked immunosorbent assay (ELISA) method. The limits of detection of the assays were 15 +/- 1.25 ng mL(-1) (n = 50) and 12 +/- 0.17 ng mL(-1) (n = 4) for the OVA and HRP formats, respectively. The Abs exhibited slight cross-reactivity with other NSAIDs. The Abs were also used to develop a sol-gel-based IAP method for clean-up and concentration of IMT. Several sol-gel formats with various amounts of antibodies were examined; the best and most reproducible format was at a TMOS:HCl molar ratio of 1:6 in which 120 MUL of IMT Abs was entrapped. The binding capacity under these conditions was ca. 100 to 250 ng of IMT with very low non-specific binding (less than 5% of the applied amount). The sol-gel IAP method, combined with solid-phase extraction, successfully eliminated serum interference to a degree that enabled analysis of spiked serum samples by ELISA. The method was also found to be fully compatible with subsequent chemical analytical methods, such as liquid chromatography followed by mass spectrometry. The approaches developed in this study form a basis for analysis of IMT in biological samples in order to monitor their pharmacokinetic properties, and may be further used to study population exposure to IMT, and to monitor the occurrence of IMT contamination in water samples. PMID- 21537914 TI - Can the provenance of the conflict minerals columbite and tantalite be ascertained by laser-induced breakdown spectroscopy? AB - Conflict minerals is a term applied to ores mined in conditions of armed conflict and human rights abuse. Niobium and tantalum are two rare metals whose primary natural occurrence is in the complex oxide minerals columbite and tantalite, the ore of which is commonly referred to as coltan. The illicit export of coltan ore from the Democratic Republic of the Congo is thought to be responsible for financing the ongoing civil conflicts in this region. Determining the chemical composition of an ore is one of the means of ascertaining its provenance. Laser induced breakdown spectroscopy (LIBS) offers a means of rapidly distinguishing different geographic sources for a mineral because the LIBS plasma emission spectrum provides the complete chemical composition (i.e., "chemical fingerprint") of any material in real time. To test this idea for columbite tantalite, three sample sets were analyzed. Partial least squares discriminant analysis (PLSDA) allows correct sample-level geographic discrimination at a success rate exceeding 90%. PMID- 21537915 TI - Determination of 19 volatile organic compounds in wastewater effluents from different treatments by purge and trap followed by gas-chromatography coupled to mass spectrometry. AB - A rapid and simple methodology based on purge and trap with gas-chromatography coupled to triple quadrupole mass spectrometry has been developed for the analysis of 19 volatile organic compounds (VOCs) in wastewater (WW) effluents from four different treatments. The determination was carried out in the raw WW effluents, which were not submitted to any pre-treatment (e.g., filtration). A matrix effect study was also performed, concluding that solvent calibration was adequate to quantify VOCs in WW effluent samples containing a variety of suspended particulate matter. Adequate validation parameters were obtained with recovery values in the range 73-124% and precision values lower than 24%. Limits of quantification were established at 0.1 MUg L(-1) for all VOCs. The proposed method was applied to the analysis of WW samples, detecting chloroform and toluene at concentrations ranging from 0.1 to 4.80 MUg L(-1). PMID- 21537916 TI - Imaging the cellular uptake of tiopronin-modified gold nanoparticles. AB - Well-dispersed gold nanoparticles (NP) coated with tiopronin were synthesized by X-ray irradiation without reducing agents. High-resolution transmission electron microscopy shows that the average core diameters of the NPs can be systematically controlled by adjusting the tiopronin to Au mole ratio in the reaction. Three methods were used to study the NP uptake by cells: quantitative measurements by inductively coupled plasma mass spectrometry, direct imaging with high lateral resolution transmission electron microscopy and transmission X-ray microscopy. The results confirmed that the NP internalization mostly occurred via endocytosis and concerned the cytoplasm. The particles, in spite of their small sizes, were not found to arrive inside the cell nuclei. The synthesis without reducing agents and solvents increased the biocompatibility as required for potential applications in analysis and biomedicine in general. PMID- 21537917 TI - Raman spectroscopic grading of astrocytoma tissues: using soft reference information. AB - Gliomas are the most frequent primary brain tumours. During neurosurgical treatment, locating the exact tumour border is often difficult. This study assesses grading of astrocytomas based on Raman spectroscopy for a future application in intra-surgical guidance. Our predictive classification models distinguish the surgically relevant classes "normal tissue" and "low" and "high grade astrocytoma" in Raman maps of moist bulk samples (80 patients) acquired with a fibre-optic probe. We introduce partial class memberships as a strategy to utilize borderline cases for classification. Borderline cases supply the most valuable training and test data for our application. They are (a) examples of the sought boundary and (b) the cases for which new diagnostics are needed. Besides, the number of suitable training samples increases considerably: soft logistic regression (LR) utilizes 85% more spectra and 50% more patients than linear discriminant analysis (LDA). The predictive soft LR models achieve ca. 85, 67 and 84% (normal, low and high grade) sensitivity and specificity. We discuss the different heuristics of LR and LDA in the light of borderline samples. While we focus on prediction, the spectroscopic interpretation of the predictive models agrees with previous descriptive studies. Unsaturated lipids are used to differentiate between normal and tumour tissues, while the total lipid content prominently contributes to the determination of the tumour grade. The high wavenumber region above 2,800 cm(-1) alone did not allow successful grading. We give a proof of concept for Raman spectroscopic grading of moist astrocytoma tissues and propose to include borderline samples into classifier training and testing. PMID- 21537918 TI - Substance P conjugated to CdTe quantum dots triggers cytosolic calcium concentration oscillations and induces quantum dots internalization in the pancreatic carcinoma cell line AR4-2J. AB - Highly fluorescent CdTe quantum dots (QDs) stabilized by 3-mercaptopropionic acid were prepared by an aqueous solution approach and used as a fluorescent label to link substance P (SP) in studying the interaction of SP with NK-1 receptor, which was expressed on the AR4-2J cell line. Nonspecific adsorptions of CdTe QDs on the AR4-2J cell membrane were observed, whereas the QD-SP conjugates successfully crossed the cell membrane and entered the cytosol. SP is a neurotransmitter, and neurotransmitter-induced calcium concentration oscillation is a common phenomenon in diverse cells especially of secretory type. Cytosolic calcium concentration responses were studied in the AR4-2J cell line during stimulation with SP and QD SP conjugates. The oscillations triggered by SP and QD-SP conjugates were dose dependent and very similar. Such QD-SP conjugates readily internalized into the cytosol as would be expected of an active NK-1 ligand. Therefore QD-SP conjugates could be used successfully to study ligand and NK-1 receptor interactions in live cells. Our research may provide a meaningful reference for congener research. PMID- 21537919 TI - Telomere and 45S rDNA sequences are structurally linked on the chromosomes in Chrysanthemum segetum L. AB - Some reports have shown that nucleolar organizer regions are located at the telomeric region and have a structural connection with telomeres at the cellular level in many organisms. In this study, we found that all 45S ribosomal DNA (rDNA) signals were located at telomeric regions on the chromosomes in Chrysanthemum segetum L., and the 45S rDNA showed distinct signal patterns on different metaphase chromosome spreads. The bicolor fluorescence in situ hybridization experiment on the extended fibers revealed that telomere repeats were structurally connected with or interspersed into rDNA sequences. The close cytological structure relation between rDNA and telomere sequences led us to use PCR with combinations of the telomere primer and the rDNA primer to obtain some fragments, which were flanked by different rDNA and telomere primer sequences. One representative clone CHS2 contains closely connected rDNA and telomere sequences, suggesting that the telomere sequence invaded into the conserved rDNA sequence. In addition, the sequences of some PCR clones were flanked by the single telomeric primer sequence or the rDNA primer sequence. These results suggested that homologous recombination occurred between tandem repeat units of rDNA sequences or telomere repeats at the chromosome terminus. PMID- 21537921 TI - Tolvaptan for heart failure patients with volume overload. PMID- 21537920 TI - Effect of guided tissue regeneration on the outcome of surgical endodontic treatment of through-and-through lesions: a retrospective study at 4-year follow up. AB - PURPOSE: The main purpose of this retrospective cohort study was to evaluate the 4-year success rate of endodontic surgery in combination with a collagen resorbable membrane for the treatment of through-and-through periradicular lesions. MATERIALS AND METHODS: Patients with one or more teeth with a through and-through periradicular lesion in need of endodontic surgery were treated. A clinical and radiographic evaluation was performed at 3, 6, 12, 24, 36, and 48 months. The outcome was categorized at 1 and 4-year follow-up as success, failure, and doubtful depending on clinical signs and symptoms and radiographic evaluation. Fisher's exact test was used to evaluate differences between successful and failed cases (P < 0.05). RESULTS: Forty-three teeth in 33 patients were radiographically and clinically evaluated after 4 years. Thirty-eight teeth were classified as success, 4 teeth as failure, and 1 tooth as doubtful. No statistically significant differences were found in results related to tooth type, tooth location, and presence of post. CONCLUSIONS: The association of endodontic surgery and guided tissue regeneration for the treatment of through and-through periapical lesions leads to excellent outcomes up to 4 years. Standardized criteria are needed to determine the treatment outcome. PMID- 21537922 TI - Correlation between arsenic concentration in fish and human scalp hair of people living in arsenic-contaminated and noncontaminated areas of Pakistan. AB - The effects of arsenic (As) toxicity due to frequent consumption of arsenic contaminated fish was estimated by the analysis of scalp hair of adult males, living near arsenic-contaminated area of Pakistan. For comparison purposes, scalp hair samples were also collected from the inhabitants of Hyderabad city consuming fish species with low levels of As, collected from Indus River. Concentration of As in scalp hair samples was analyzed by using hydride generation atomic absorption spectrometry (HG AAS), after microwave-assisted acid digestion. The accuracy of the As measurement was tested simultaneously analyzing certified reference material. The concentration of As in muscle tissues of fish species were found in the range of 2.11 to 14.1 MUg/g and 1.92 to 12.2 MUg/g, collected from arsenic-contaminated and noncontaminated areas, respectively. Exposed subjects had significantly elevated levels of As in scalp hair samples (0.72-4.94 MUg/g) as compared with referent subjects (0.21-1.484 MUg/g; p < 0.01). The As levels in scalp hair was positively correlated with As levels in fish. PMID- 21537923 TI - Melatonin prevents oxidative stress in ovariectomized rats treated with aluminium. AB - This study is designed to determine the simultaneous effect of aluminium (Al) and melatonin (Mel) treatment in intact and ovariectomized (Ovx) female rats on oxidative stress and their inter-organ relationship in the kidney and liver. Al treated rats received an intra-peritoneal injection of solution of aluminium lactate (0.575 mg Al/100 g of body weight, three times a week), during 12 weeks. Mel groups received intra-peritoneal injections of melatonin at a dose of 10 mg/kg/day, 5 days/week, during 12 weeks. The results of this study showed that Al treatment in female rats modifies homeostasis of glutathione and the antioxidant capacity of the rat liver and kidney. The alteration of glutathione homeostasis and oxidative status was not associated with an increased lipid peroxidation in both organs with the exception of the increase observed in the liver of Ovx rats. Al also induced modifications in the activity of some enzymes related to the glutathione cycle: GSH-Px in the liver and kidney and glutathione reductase only in the kidney. Al exposure decreased CAT activity in both the kidney and liver of intact and Ovx groups. The administration of Mel in the intact and castrated females treated with Al seems to reduce oxidative changes in the liver and kidney of intact and Ovx rats. PMID- 21537924 TI - Identification of high-risk group and therapeutic options in children with liver abscess. AB - The outcome of children with liver abscess (LA) depends upon prompt diagnosis and intervention. We evaluated the etiology, clinical profile, various interventional modalities of management and outcome of children with LA. A total of 39 hospitalized children (mean age 7.2 +/- 3.9 years) with radiologically proven LA were analyzed. Parenteral antibiotics, percutaneous drainage (PD) or open surgical drainage (OSD) was done as required. Cases with ruptured or impending rupture of LA, upper gastrointestinal bleed, jaundice, pleural effusion or consolidation were labeled as "high risk" cases. Triad of fever, pain and hepatomegaly was the most common presentation. Single abscess was present in 66.7% and right lobe was involved in 69.2% of cases. Majority of LA were pyogenic (PLA, 25/39). Amebic liver abscess (ALA) and PLA had similar clinical and laboratory profile except that multiloculated abscess on ultrasonography was a feature of PLA (12/25 vs. 0/11; p = 0.006). Cases with ALA settled significantly more often with antibiotics alone (5/11 vs. 3/25; p = 0.04) than PLA and none required surgery (0/11 vs. 7/25; p = 0.03). Subjects with "high-risk" LA (n - 26) had significantly larger abscesses, more polymorphonuclear leucocytosis (74 +/- 15% vs. 61 +/- 13%; p = 0.01) in peripheral blood and need of drainage (24/26 vs. 7/13; p = 0.03) than patients with average-risk LA. Based on the results, 38/39 children recovered, with complete abscess resolution in 28, over 48 +/- 63.8 days. In conclusion, ALA, although similar in presentation, are uniloculated, and patients with ALA recover more often without drainage than patients with PLA. Patients with "high risk" LA are more common and have a good outcome with drainage. PD, being safe, efficacious and less invasive than OSD, should be the preferred drainage procedure. PMID- 21537925 TI - Interval between onset of symptoms and diagnosis of medulloblastoma in children: distribution and determinants in a population-based study. AB - Hospital-based studies have reported long delays in the diagnosis of paediatric brain tumours. Our objective was to describe the duration between onset of symptoms and diagnosis of medulloblastoma in children and study their clinical determinants in a population-based study. This retrospective cohort study included all paediatric medulloblastoma from a region of France from 1990 to 2005. The median interval from symptom onset until diagnosis for these 166 patients was 65 days and did not decrease during the study period. The most frequent manifestations were: vomiting (88%), headaches (79%), psychomotor regression (60% of children under 3 years), psychological symptoms (27%), strabismus (26%), and asthenia (25%). For one third of the children under 3 years, the diagnosis was made only after life-threatening signs of intracranial hypertension appeared. The prediagnosis interval was significantly longer (median 91 vs. 60 days, p = 0.001) in children with psychological symptoms (27%). Causes for intervals that exceeded the median (65 days) included inconsistent (25%) or late (36%) combination of headaches and vomiting, a period of spontaneous symptom remission (14%-20%), no (24%) or late (57%) neurological signs, psychological symptoms (35%), and a normal neurological examination (27%). Time to medulloblastoma diagnosis in children remains fairly long, despite advances in imaging. Primary-care physicians must be suspicious not only of suggestive neurological signs, but also of non-specific symptoms that persist or are multiple. A meticulous neurological examination and cerebral imaging for such patients might facilitate earlier diagnosis. PMID- 21537926 TI - PFAPA syndrome in siblings. Is there a genetic background? AB - "PFAPA syndrome" is an autoinflammatory entity composed of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. There have been many reports of children with the disease, but only occasionally have been described in siblings, and no specific genetic mutation has been determined yet. Corticosteroids are the mainstay in the treatment of the acute attacks. The role of surgery in long-term follow-up (tonsillectomy with or without adenoidectomy) is controversial. We report two brothers affected with the syndrome, in whom corticosteroids as the only treatment led to an improvement. A genetic work-up was performed, making very unlikely other possible syndromes of recurrent fever. CONCLUSION: PFAPA syndrome is the most common recurrent periodic fever disorder described in childhood. Its genetic background has not been elucidated yet. Our contribution with two siblings affected with PFAPA syndrome further support the genetic basis for the entity. PMID- 21537927 TI - Maximal isokinetic and isometric muscle strength of major muscle groups related to age, body mass, height, and sex in 178 healthy subjects. AB - The main objective of this study was to establish normative values for maximal concentric isokinetic strength and maximal isometric strength of all major muscle groups in healthy subjects applying sex, age, height, and body mass-adjusted statistical models. One hundred and seventy-eight (178) (93 male and 85 female) healthy non-athletic Danish volunteers aged 15-83 years were recruited. Eighteen test protocols for each sex were applied to determine isokinetic and isometric muscle strength at knee, ankle, hip, shoulder, elbow, and wrist using a dynamometer (Biodex System 3 PRO). Multiple linear regressions were performed with maximal muscle strength (peak torque) as dependent variable and age, height, and body mass as independent variables. Muscle strength significantly related to age in 24, to height in 13 and to body mass in 27 out of the 36 models. In gender specific analyses, the variables age, height and body mass accounted for 25% (20 29) (95% confidence interval) of the variation (r (2)) in strength for men and 31% (25-38) for women. The r (2) was similar for the isokinetic models and the isometric models [31% (22-40) vs. 28% (23-34)]. Age, height, and body mass related to strength in most muscle groups and gender-specific models with estimated prediction intervals were established for maximal strength of major muscle groups. PMID- 21537928 TI - Self-paced intermittent-sprint performance and pacing strategies following respective pre-cooling and heating. AB - This study examined the effects of pre-exercise cooling and heating on neuromuscular function, pacing and intermittent-sprint performance in the heat. Ten male, team sport athletes completed three randomized, counterbalanced conditions including a thermo-neutral environment (CONT), whole body submersion in an ice bath (ICE) and passive heating in a hot environment (HEAT) before 50 min of intermittent-sprint exercise (ISE) in the heat (31 + 1 degrees C). Exercise involved repeated 15 m maximal sprints and self-paced exercise of varying intensities. Performance was measured by sprint times and distance covered during self-paced exercise. Maximal isometric contractions were performed to determine the maximal voluntary torque (MVT), activation (VA) and contractile properties. Physiological measures included heart rate (HR), core (T (core)) and skin (T (skin)) temperatures, capillary blood and perceptual ratings. Mean sprint times were slower during ICE compared to HEAT (P < 0.05). Total distance covered was not different between conditions, but less distance was covered during HEAT in 31-40 min compared to CONT, and 41-50 min compared to ICE (P < 0.05). MVT was reduced post-exercise compared to post-intervention in CONT and HEAT. VA was reduced post-intervention in HEAT compared to CONT and ICE, and post-exercise compared to ICE (P < 0.05). HR, T (core) and T (skin) during exercise were lower in ICE compared to CONT and HEAT (P < 0.05). Sprint times and distance covered were not affected by ICE and HEAT conditions compared to CONT. However, initial sprint performance was slowed by pre-cooling, with improvements following passive heating possibly due to altered contractile properties. Conversely, pre-cooling improved exercise intensities, whilst HEAT resulted in greater declines in muscle recruitment and ensuing distance covered. PMID- 21537929 TI - Adaptation of the respiratory controller contributes to the attenuation of exercise hyperpnea in endurance-trained athletes. AB - We have reported that minute ventilation [[Formula: see text]] and end-tidal CO(2) tension [[Formula: see text]] are determined by the interaction between central controller and peripheral plant properties. During exercise, the controller curve shifts upward with unchanged central chemoreflex threshold to compensate for the plant curve shift accompanying increased metabolism. This effectively stabilizes [Formula: see text] within the normal range at the expense of exercise hyperpnea. In the present study, we investigated how endurance trained athletes reduce this exercise hyperpnea. Nine exercise-trained and seven untrained healthy males were studied. To characterize the controller, we induced hypercapnia by changing the inspiratory CO(2) fraction with a background of hyperoxia and measured the linear [Formula: see text] relation [[Formula: see text]]. To characterize the plant, we instructed the subjects to alter [Formula: see text] voluntarily and measured the hyperbolic [Formula: see text] relation ([Formula: see text]). We characterized these relations both at rest and during light exercise. Regular exercise training did not affect the characteristics of either controller or plant at rest. Exercise stimulus increased the controller gain (S) both in untrained and trained subjects. On the other hand, the [Formula: see text]-intercept (B) during exercise was greater in trained than in untrained subjects, indicating that exercise-induced upward shift of the controller property was less in trained than in untrained subjects. The results suggest that the additive exercise drive to breathe was less in trained subjects, without necessarily a change in central chemoreflex threshold. The hyperbolic plant property shifted rightward and upward during exercise as predicted by increased metabolism, with little difference between two groups. The [Formula: see text] during exercise in trained subjects was 21% lower than that in untrained subjects (P < 0.01). These results indicate that an adaptation of the controller, but not that of plant, contributes to the attenuation of exercise hyperpnea at an iso metabolic rate in trained subjects. However, whether training induces changes in neural drive originating from the central nervous system, afferents from the working limbs, or afferents from the heart, which is additive to the chemoreflex drive to breathe, cannot be determined from these results. PMID- 21537930 TI - Melanoma-associated retinopathy associated with intranasal melanoma. AB - PURPOSE: To present a case of melanoma-associated retinopathy (MAR) associated with an intranasal melanoma. CASE REPORT: A 77-year-old Japanese man visited us complaining of night blindness, blurred vision, and color vision difficulties in both eyes. His best-corrected visual acuity was 0.7 in the right and 1.0 in the left eyes. The rod response of the electroretinogram (ERG) was abolished, and the maximum response had a negative waveform. The a-wave of the single-flash cone response was square shaped, and the b-wave was delayed. The ON-response of the long-flash cone ERG was absent, but the OFF-response was preserved. A severe loss of retinal sensitivity was detected by static perimetry. Positron emission tomography showed no abnormal signs. Six months after the initial examination, an intranasal tumor was detected and surgically removed. The final diagnosis based on histopathology was malignant melanoma. CONCLUSION: Our case demonstrates that MAR can be associated with an intranasal mucosal melanoma. Thus, in cases where the primary lesion cannot be identified in patients with MAR-like symptoms and signs, we recommend that preferential sites of mucosal melanomas be examined. PMID- 21537932 TI - A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families. AB - The RAD51C gene has been recently proposed as a high-penetrance breast and ovarian cancer gene. However, early replication studies have failed to confirm the finding. Thus, further studies in larger cohorts should be conducted in order to clarify the role of RAD51C as a cancer susceptibility gene. Here, we describe a high-resolution melting analysis (HRMA)-based method developed for presequence screening of RAD51C sequence variants. We have screened RAD51C sequence variants by HRMA in 492 breast cancer patients with family history of breast and/or ovarian cancer that were previously tested negative for BRCA1/2. All variants were confirmed by direct sequencing. We have detected 12 different RAD51C germ line sequence variants, including eight transitions, two transversion, and two indels (insA, and delT). All these variants generated melting profiles which differ from wild type homozygous controls. Interestingly, we have identified one clearly pathogenic mutation (c.774delT) in the subset of 101 breast and ovarian cancer families, supporting that RAD51C is a human breast and ovarian cancer susceptibility gene. PMID- 21537931 TI - Molecular pathogenesis of core binding factor leukemia: current knowledge and future prospects. AB - Core binding factor (CBF) acute myeloid leukemia (AML) is the most common cytogenetic subtype of AML, defined by the presence of t(8;21) or inv(16)/t(16;16). The chromosomal aberrations create AML1-ETO and CBFbeta-MYH11 fusion genes that disrupt the functions of CBF, an essential transcription factor in hematopoiesis. Despite the relatively good outcome of patients with CBF-AML, only approximately half of the patients are cured with current therapy, indicating the need for improved therapeutic strategies. In this review, we summarize current knowledge regarding altered transcriptional regulation, aberrant signaling pathways, and cooperating genetic events in CBF leukemia, and discuss challenges ahead for translating these findings into the clinic. PMID- 21537933 TI - Well-done meat intake and meat-derived mutagen exposures in relation to breast cancer risk: the Nashville Breast Health Study. AB - Previous studies of the association of meat intake and meat-derived mutagen exposure with breast cancer risk have produced inconsistent results. We evaluated this association in a population-based case-control study of incident breast cancer conducted in Nashville, Tennessee, United States, including 2,386 breast cancer cases and 1,703 healthy women controls. Telephone interviews were conducted to obtain information related to meat intake including amount, cooking methods, and doneness levels, as well as other known or hypothesized risk factors for breast cancer. Unconditional logistic regression was used to derive odds ratios (ORs) after adjusting for potential confounders. High intake of red meat was associated with a significantly elevated risk of breast cancer (P-trend < 0.001). The association was particularly strong for high intake of well-done red meat (P-trend < 0.001), with an adjusted OR of 1.5 (95% CI = 1.3-1.9) for the highest versus the lowest quartile. Associations between red meat and breast cancer risk were slightly stronger for postmenopausal women than for premenopausal women. Meat-derived mutagens such as 2-amino-3,8 dimethylimidazo[4,5-f]quinoxaline and 2-amino-3,4,8-trimethylimidazo[4,5 f]quinoxaline, were significantly associated with increased breast cancer risk among postmenopausal women only (P-trend = 0.002 and 0.003, respectively). The results from this study provide strong support for the hypotheses that high red meat intake and meat-derived mutagen exposure may be associated with an increase in breast cancer risk. PMID- 21537934 TI - Need for clarification of data in the recent meta-analysis about RAD51 135G>C polymorphism and breast cancer risk. PMID- 21537935 TI - Effects of music therapy on pain among female breast cancer patients after radical mastectomy: results from a randomized controlled trial. AB - Music therapy has been used in multiple health care settings to reduce patient pain, anxiety, and stress. However, few available studies have investigated its effect on pain among breast cancer patients after radical mastectomy. The aim of this study was to explore the effects of music therapy on pain reduction in patients with breast cancer after radical mastectomy. This randomized controlled trial was conducted at the Surgical Department of Oncology Center, First Affiliated Hospital of Xi'an Jiaotong University from March to November 2009. A total of 120 breast cancer patients who received Personal Controlled Analgesia (PCA) following surgery (mastectomy) were randomly allocated to two groups, an intervention group and a control group (60 patients in each group). The intervention group accepted music therapy from the first day after radical mastectomy to the third admission to hospital for chemotherapy in addition to the routine nursing care, while the control group received only routine nursing care. Pain scores were measured at baseline and three post-tests using the General Questionnaire and Chinese version of Short-Form of McGill Pain Questionnaire. The primary endpoint was the change in the Pain Rating Index (PRI-total) score from baseline. Music therapy was found to reduce the PRI-total score in the intervention group significantly compared with the control group with a mean difference (95% CI) of -2.38 (-2.80, -1.95), -2.41 (-2.85, -1.96), and -1.87 ( 2.33, -1.42) for the 1st, 2nd, and 3rd post-tests, respectively. Similar results were found for Visual Analogue Scale (VAS) and Present Pain Intensity (PPI) scores. The findings of the study provide some evidence that music therapy has both short- and long-term positive effects on alleviating pain in breast cancer patients following radical mastectomy. PMID- 21537936 TI - Second events following ductal carcinoma in situ of the breast: a register-based cohort study. AB - The incidence of ductal carcinoma in situ (DCIS) of the breast has increased in recent decades, particularly, in counties offering mammography screening. The aims of the present study are to examine factors that may predict subsequent breast malignancy amongst patients with DCIS, and to compare the incidence of the subsequent malignancy and mortality with that of the general population. This population-based study includes all primary cases of pure DCIS diagnosed in Norway in the period 1993 to 2007 (N = 3167). The patients were followed to subsequent malignancy (DCIS or invasive cancer) or death. Risk estimates within 10 years of follow-up were calculated using Kaplan-Meier methods adjusting for competing risks, Cox regression models and Standard Incidence and Mortality Ratios. Patients with DCIS had a 11.2% risk of being diagnosed with a subsequent breast malignancy within 10 years (9.4% for invasive cancer), implying that they were five times as likely to be diagnosed with breast malignancy as the general female population in Norway. The risk was dependent on the treatment of the DCIS; patients treated with mastectomy and breast-conserving treatment had a 3.8 and 9.8% risk of ipsilateral invasive cancer within 10 years, respectively. Breast cancer mortality was 2.5% within 10 years of follow-up, a fourfold risk compared with the general population. Patients with DCIS have an increased risk of both subsequent breast malignancy and breast cancer death compared with women in the general population. Our results support previous knowledge of DCIS as a heterogeneous disease. PMID- 21537937 TI - "There is no dose-response relationship in psychopharmacotherapy" vs "pharmacotherapy in psychiatry is based on ligand-receptor interaction": a unifying hypothesis and the need for plasma concentration based clinical trials. PMID- 21537938 TI - Characterization of the acute effects of alcohol on asymmetry of inferior frontal cortex activity during a Go/No-Go task using functional near-infrared spectroscopy. AB - RATIONALE: Successful response inhibition is associated with right-lateralized inferior frontal cortex (IFC) activity, and alcohol impairs this inhibitory control, thereby enhancing false-alarm responses in the Go/No-Go task. However, the neural correlates of effect of alcohol on response inhibition remain unclear. OBJECTIVE: This study characterized the acute effects of alcohol on IFC activity during Go/No-Go tasks using near-infrared spectroscopy (NIRS). METHODS: Thirty two subjects visited our laboratory twice: once for alcohol intake and once for placebo intake. On each visit, subjects performed Go/No-Go tasks immediately before and 10 min after intake of the alcohol or placebo. NIRS was used to evaluate IFC activity measured during Go/No-Go tasks. RESULTS: Alcohol significantly enhanced false-alarm responses in No-Go trials. NIRS analysis showed that IFC activity was greater in the right hemisphere than in the left hemisphere prior to alcohol or placebo intake. This right hemispheric superiority was eliminated in response to alcohol but not in response to placebo. Correlation analysis showed that subjects with right-lateralized IFC activity made fewer false-alarm responses in No-Go trials and that alcohol-induced inhibition of hemispheric IFC asymmetry resulted in higher false-alarm rates. CONCLUSION: These findings suggest that the right IFC may mediate the acute effects of alcohol on inhibitory control. When the alcohol impairs the right IFC activity, subjects cannot inhibit the pre-potent responses for No-Go trials, resulting in enhanced false-alarm responses. Thus, this study successfully demonstrated the neural correlates of the alcohol effect in the right IFC activity during inhibitory control processes. PMID- 21537939 TI - One-trial behavioral sensitization in preweanling rats: differential effects of cocaine, methamphetamine, methylphenidate, and D-amphetamine. AB - RATIONALE: Preweanling rats exhibit robust one-trial cocaine-induced behavioral sensitization; however, it is uncertain whether other psychostimulants can also induce sensitization in young rats using the one-trial procedure. OBJECTIVE: The purpose of this study was to determine whether methamphetamine, methylphenidate, and D: -amphetamine are capable of inducing one-trial locomotor sensitization in preweanling rats. METHODS: In a series of four experiments, rats were pretreated with cocaine (30 mg/kg), methamphetamine (2-12 mg/kg), methylphenidate (5-20 mg/kg), or amphetamine (5 mg/kg) before being placed in a novel activity chamber or the home cage on PD 19. Rats were then challenged with the same psychostimulant (20 mg/kg cocaine, 1-8 mg/kg methamphetamine, 2.5-7.5 mg/kg methylphenidate, or 1-2 mg/kg amphetamine) on PD 21, with distance traveled being measured for 180 min. In a separate experiment, rats were pretreated with methamphetamine on PD 16-19 and challenged with methamphetamine on PD 21. RESULTS: Only cocaine, but not various dose combinations of other psychostimulants, was able to produce one-trial behavioral sensitization in preweanling rats. Context-dependent locomotor sensitization was also evident if rats were pretreated with methamphetamine on PD 16-19 and tested on PD 21. CONCLUSIONS: It is uncertain why only cocaine was able to induce one-trial locomotor sensitization in preweanling rats, but it is possible that: (a) the neural circuitry mediating sensitization differs according to psychostimulant, (b) cocaine is more readily associated with environmental contexts than other psychostimulants, or (c) affinity and pharmacokinetic factors may underlie cocaine's ability to induce one-trial behavioral sensitization in preweanling rats. PMID- 21537940 TI - Dipyridamole monotherapy in schizophrenia: pilot of a novel treatment approach by modulation of purinergic signaling. AB - BACKGROUND: Emerging data indicate the neuromodulator adenosine may play a role in the therapeutics of schizophrenia. Adenosine A(2A) receptor stimulation exerts a functional antagonism at postsynaptic D(2) receptors. Data from animal models relevant to schizophrenia support a therapeutic effect of modulating adenosinergic transmission in the ventral striatum. One previous clinical trial showed superiority of adjunctive dipyridamole, an adenosine reuptake inhibitor, compared to placebo in ameliorating positive symptoms in schizophrenia patients. OBJECTIVES: The aim of this study was to examine the effects of dipyridamole monotherapy of 200 mg/day on positive and negative symptoms, with the goal of determining dosing for future adjunctive studies in schizophrenia. METHODS: Twenty symptomatic schizophrenia participants were randomized to a 6-week double blind trial comparing olanzapine (20 mg/day) to dipyridamole monotherapy (200 mg/day). Thirteen participants completed the treatment phase (eight on dipyridamole; five on olanzapine). RESULTS: The olanzapine group showed a trend (p = 0.08) for superiority on BPRS total scores (mean +/- SD: total BPRS score decreasing from 36.8 +/- 2.3 at week 1, to 33.2 +/- 5.5 at the end of the study). The mean total BPRS scores decreased from 36.4 +/- 5.3 to 34.0 +/- 7.7 in the dipyridamole group. CONCLUSIONS: Although these pilot data do not support a significant antipsychotic effect of dipyridamole monotherapy, the results provide some evidence for examining dipyridamole (200 mg/day) as adjunct to symptomatic antipsychotic-treated schizophrenia patients. PMID- 21537941 TI - Hippocampal CA1 region shows differential regulation of gene expression in mice displaying extremes in behavioral sensitization to amphetamine: relevance for psychosis susceptibility? AB - RATIONALE: Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences in vulnerability for psychosis are reflected in differential sensitivity for psychostimulants such as amphetamine. We hypothesize that the same genes and pathways underlying behavioral sensitization in mice are also involved in the vulnerability to psychosis. OBJECTIVES: The aim of the current study was to investigate which genes and pathways may contribute to behavioral sensitization in different dopaminergic output areas in the mouse brain. METHODS: We took advantage of the naturally occurring difference in psychostimulant sensitivity in DBA/2 mice and selected animals displaying extremes in behavioral sensitization to amphetamine. Subsequently, the dopamine output areas, prefrontal cortex, nucleus accumbens, and cornu ammonis 1 (CA1) area of the hippocampus, were isolated by laser microdissection and subjected to DNA microarray analysis 1 h after a challenge dose of amphetamine. RESULTS: A large number of genes with differential expression between high and low responders were identified, with no overlap between brain regions. Validation of these gene expression changes with real-time quantitative polymerase chain reaction demonstrated that the most robust and reproducible effects on gene expression were in the CA1 region of the hippocampus. Interestingly, many of the validated genes in CA1 are members of the cAMP response element (CRE) family and targets of the glucocorticoid receptor (GR) and myocyte enhancer factor 2 (Mef2) transcription factors. CONCLUSION: We hypothesize that CRE, Mef2, and GR signaling form a transcription regulating network, which underlies differential amphetamine sensitivity, and therefore, may play an important role in susceptibility to psychosis. PMID- 21537942 TI - Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice. AB - RATIONALE: A number of cancer chemotherapeutic agents have been associated with a loss of memory in breast cancer patients although little is known of the causality of this effect. OBJECTIVES: To assess the potential cognitive effects of repeated exposure to chemotherapeutic agents, we administered the selective estrogen receptor modulator tamoxifen or the antimetabolite chemotherapy, methotrexate, and 5-fluorouracil, alone and in combination to mice and tested them in a learning and memory assay. METHODS: Swiss-Webster male mice were injected with saline, 32 mg/kg tamoxifen, 3.2 or 32 mg/kg methotrexate, 75 mg/kg 5-fluorouracil, 3.2 or 32 mg/kg methotrexate in combination with 75 mg/kg 5 fluorouracil once per week for 3 weeks. On days 23 and 24, mice were tested for acquisition and retention of a nose-poke response in a learning procedure called autoshaping. In addition, the acute effects of tamoxifen were assessed in additional mice in a similar procedure. RESULTS: The chemotherapeutic agents alone and in combination reduced body weight relative to saline treatment over the course of 4 weeks. Repeated treatment with tamoxifen produced both acquisition and retention effects relative to the saline-treated group although acute tamoxifen was without effect except at a behaviorally toxic dose. Repeated treatment with methotrexate in combination with 5-fluorouracil produced effects on retention, but the magnitude of these changes depended on the methotrexate dose. CONCLUSIONS: These data demonstrate that repeated administration of tamoxifen or certain combination of methotrexate and 5-fluorouracil may produce deficits in the acquisition or retention of learned responses which suggest potential strategies for prevention or remediation might be considered in vulnerable patient populations. PMID- 21537944 TI - Anxiogenic behaviour induced by 17alpha-ethynylestradiol in male guppies (Poecilia reticulata). AB - Behaviour studies are used in toxicology research as they are excellent tools to measure physiological end-points caused by exogenous chemicals. In mammals both reproductive and non-reproductive behaviours have been used for a long period of time, whereas in teleost fishes non-reproductive behaviours have received little attention compared to reproductive behaviours. Recent advances in measuring stress related behaviours in zebrafish have provided additional tools to understand behaviour toxicology in fish. One species with well documented reproductive behaviour disturbed by different toxicants is the guppy, which is better suited than zebrafish for reproductive behaviour studies and therefore might be a better model organism for comparative behaviour studies in fish toxicology. Here we report new applications for non-reproductive behaviours in guppy and test these behaviours on males treated with the endocrine disruptor 17alpha-ethynylestradiol at environmentally relevant concentrations. 17alpha ethynylestradiol increased freezing and bottom-dwelling when fish were placed in a non-familiar aquarium, but did not significantly affect shoaling behaviour. These results are similar to the anxiogenic behaviours seen in rats treated perinatally with 17alpha-ethynylestradiol and add more concern to the impacts of endocrine disruptors on aquatic wildlife. PMID- 21537945 TI - Additional value of FDG PET/CT to contrast-enhanced CT in the differentiation between benign and malignant intraductal papillary mucinous neoplasms of the pancreas with mural nodules. AB - OBJECTIVES: This study aimed at determining the additional value of FDG PET/CT to contrast-enhanced CT in the differentiation between benign and malignant intraductal papillary mucinous neoplasms (IPMNs) of the pancreas with mural nodules. METHODS: This retrospective review of medical records was approved by our institutional review board. The preoperative PET/CT images of 16 non-diabetic patients with surgically proven IPMN, where mural nodules of 3 mm or larger were shown by preoperative contrast-enhanced CT, were retrospectively evaluated. The 16 patients were divided into two groups: 7 patients with benign IPMN [adenoma (n = 1) and borderline tumor (n = 6)] and 9 patients with malignant IPMN [carcinoma in situ (CIS) (n = 8) and invasive carcinoma (n = 1)]. Nuclear medicine physician blinded to the pathologic assessment of malignancy of IPMN set a spherical volume of interest (VOI) over the mural nodules on PET/CT images and recorded the peak standardized uptake value (SUV(max)) in the VOI, referring the contrast-enhanced CT images. Statistical differences in the size of mural nodule, the diameter of main pancreatic duct (MPD), and SUV(max) of the tumors between benign IPMNs and malignant IPMNs were compared using the Mann-Whitney U test. Statistical significance was set at p < 0.05. Additionally, the diagnostic accuracy of FDG PET for the detection of malignancy was calculated. RESULTS: The SUV(max) of the malignant IPMNs with mural nodules of 3 mm or larger was higher than that of benign IPMNs (2.7 +/- 0.6 vs. 1.9 +/- 0.3, p < 0.01). Meanwhile, there was no significant difference in mural nodule diameter and MPD diameter between the two groups. FDG PET/CT showed an excellent diagnostic accuracy for the differentiation between malignant and benign IPMNs with mural nodules: the sensitivity, specificity, PPV, NPV, and accuracy in malignant IPMN with mural nodule of FDG PET/CT were 77.8, 100, 100, 77.8, and 87.5 for the cutoff value of 2.3; and 100, 57.1, 75.0, 100, and 81.3 for the cutoff value of 2.0, respectively. CONCLUSIONS: The result of this study indicates that FDG PET/CT can provide additional information for the differentiation between benign and malignant IPMNs of the pancreas with mural nodules. PMID- 21537946 TI - Novel proteins from the calcifying shell matrix of the Pacific oyster Crassostrea gigas. AB - The shell of the Pacific oyster Crassostrea gigas is composed of more than 99% CaCO3 and of around 0.5% of occluded organic matrix. According to classical views, this matrix is supposed to regulate the shell mineral deposition. In this study, we developed one of the first proteomic approaches applied to mollusk shell in order to characterise the calcifying matrix proteins. The insoluble organic matrix, purified after demineralisation of the shell powder, was digested with trypsin enzyme, and separated on nano-LC, prior to nanospray quadrupole/time of-flight analysis. MS/MS spectra were searched against the above 220,000 EST sequences available in the public database for Crassostrea. Using this approach, we were able to identify partial or full-length sequence transcripts that encode eight novel shell matrix proteins. PMID- 21537947 TI - Energy budget for the cultured, zooxanthellate octocoral Sinularia flexibilis. AB - The zooxanthellate octocoral Sinularia flexibilis is a producer of potential pharmaceutically important metabolites such as antimicrobial and cytotoxic substances. Controlled rearing of the coral, as an alternative for commercial exploitation of these compounds, requires the study of species-specific growth requirements. In this study, phototrophic vs. heterotrophic daily energy demands of S. flexibilis was investigated through light and Artemia feeding trials in the laboratory. Rate of photosynthetic oxygen by zooxanthellae in light (~200 MUmol quanta m-2 s-1) was measured for the coral colonies with and without feeding on Artemia nauplii. Respiratory oxygen was measured in the dark, again with and without Artemia nauplii. Photosynthesis-irradiance curve at light intensities of 0, 50, 100, 200, and 400 MUmol quanta m-2 s-1 showed an increase in photosynthetic oxygen production up to a light intensity between 100 and 200 MUmol quanta m-2 s-1. The photosynthesis to respiration ratio (P/R > 1) confirmed phototrophy of S. flexibilis. Both fed and non-fed colonies in the light showed high carbon contribution by zooxanthellae to animal (host) respiration values of 111-127%. Carbon energy equivalents allocated to the coral growth averaged 6-12% of total photosynthesis energy (mg C g-1 buoyant weight day-1 and about 0.02% of the total daily radiant energy. "Light utilization efficiency (epsilon)" estimated an average epsilon value of 75% 12 h-1 for coral practical energetics. This study shows that besides a fundamental role of phototrophy vs. heterotrophy in daily energy budget of S. flexibilis, an efficient fraction of irradiance is converted to useable energy. PMID- 21537950 TI - ATXN-2 CAG repeat expansions are interrupted in ALS patients. AB - It has recently been suggested that short expansions of CAG repeat in the gene ATXN-2 causing SCA2 (spinocerebellar ataxia type 2) are associated with an increased risk of amyotrophic lateral sclerosis (ALS) in the populations of the USA and northern Europe. In this study, we investigated the role of ATXN-2 in Italian patients clinically diagnosed with ALS and characterized the molecular structure of ATXN-2 expansions. We assessed the size of the CAG repeat in ATXN-2 exon 1 in 232 Italian ALS patients and 395 matched controls. ATXN-2 expanded alleles containing > 30 repeats have been observed in seven sporadic ALS patients (3.0%), while being absent in the controls (p = 0.00089). Four out of the seven patients had an ATXN-2 allele in the intermediate-fully pathological range: one with 32 repeats, 2 with 33 repeats and 1 with 37 repeats, accounting for 1.7% of the ALS cohort. Sequencing of expanded (> 32) alleles showed that they were all interrupted with at least one CAA triplet. ATXN-2 alleles with the same length and structure have been reported in SCA2 patients with parkinsonism or in familial and sporadic Parkinson. Conversely, the phenotype of the present patients was typically ALS with no signs or symptoms of ataxia or parkinsonism. In conclusion, the findings of ATXN-2 expansions in pure ALS cases suggest that ALS may be a third phenotype (alongside ataxia/parkinsonism and pure Parkinson) associated with ATXN-2 interrupted alleles. PMID- 21537949 TI - Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders. AB - Next-generation sequencing and genome-wide association studies represent powerful tools to identify genetic variants that confer disease risk within populations. On their own, however, they cannot provide insight into how these variants contribute to individual risk for diseases that exhibit complex inheritance, or alternatively confer health in a given individual. Even in the case of well characterized variants that confer a significant disease risk, more healthy individuals carry the variant, with no apparent ill effect, than those who manifest disease. Access to low-cost genome sequence data promises to provide an unprecedentedly detailed view of the nature of the hereditary component of complex diseases, but requires the large-scale comparison of sequence data from individuals with and without disease to deliver a clinical calibration. The provision of informatics support remains problematic as there are currently no means to interpret the data generated. Here, we initiate this process, a prerequisite for such a study, by narrowing the focus from an entire genome to that of a single biological system. To this end, we examine the 'Hemostaseome,' and more specifically focus on DNA sequence changes pertaining to those human genes known to impact upon hemostasis and thrombosis that can be analyzed coordinately, and on an individual basis, to interrogate how specific combinations of variants act to confer disease predisposition. As a first step, we delineate known members of the Hemostaseome and explore the nature of the genetic variants that may cause disease in individuals whose hemostatic balance has become shifted toward either a prothrombotic or anticoagulant phenotype. PMID- 21537948 TI - RNAi: a potential new class of therapeutic for human genetic disease. AB - Dominant negative genetic disorders, in which a mutant allele of a gene causes disease in the presence of a second, normal copy, have been challenging since there is no cure and treatments are only to alleviate the symptoms. Current therapies involving pharmacological and biological drugs are not suitable to target mutant genes selectively due to structural indifference of the normal variant of their targets from the disease-causing mutant ones. In instances when the target contains single nucleotide polymorphism (SNP), whether it is an enzyme or structural or receptor protein are not ideal for treatment using conventional drugs due to their lack of selectivity. Therefore, there is a need to develop new approaches to accelerate targeting these previously inaccessible targets by classical therapeutics. Although there is a cooling trend by the pharmaceutical industry for the potential of RNA interference (RNAi), RNAi and other RNA targeting drugs (antisense, ribozyme, etc.) still hold their promise as the only drugs that provide an opportunity to target genes with SNP mutations found in dominant negative disorders, genes specific to pathogenic tumor cells, and genes that are critical for mediating the pathology of various other diseases. Because of its exquisite specificity and potency, RNAi has attracted a considerable interest as a new class of therapeutic for genetic diseases including amyotrophic lateral sclerosis, Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), spinocerebellar ataxia, dominant muscular dystrophies, and cancer. In this review, progress and challenges in developing RNAi therapeutics for genetic diseases will be discussed. PMID- 21537951 TI - Beyond structural genomics: computational approaches for the identification of ligand binding sites in protein structures. AB - Structural genomics projects have revealed structures for a large number of proteins of unknown function. Understanding the interactions between these proteins and their ligands would provide an initial step in their functional characterization. Binding site identification methods are a fast and cost effective way to facilitate the characterization of functionally important protein regions. In this review we describe our recently developed methods for binding site identification in the context of existing methods. The advantage of energy-based approaches is emphasized, since they provide flexibility in the identification and characterization of different types of binding sites. PMID- 21537952 TI - Relative cost effectiveness of the SPHERE intervention in selected patient subgroups with existing coronary heart disease. AB - Heterogeneity exists within the patient population with coronary heart disease and the cost effectiveness of treatment may vary across subgroups within the overall population. This study compares the cost effectiveness of a secondary prevention intervention for a combined patient population relative to three selected subgroups: patients aged over 70 years; patients with a diagnosis other than angina only (that is, patients with a history of myocardial infarction, coronary artery bypass graft and/or percutaneous transluminal coronary angioplasty); and patients with diabetes. The results for the general population have been published elsewhere, but ongoing budget constraints require consideration of the appropriateness of targeting resources to patient subgroups. We adopt a probabilistic model to combine within trial and beyond trial impacts of treatment to estimate the lifetime health care costs and quality-adjusted life years of two primary care-based secondary prevention strategies: SPHERE Intervention--tailored practice and patient care plans and Control--standardised usual care. In all cases, the intervention was associated with mean cost savings and mean QALYs gains, when compared to the control, though statistical significance was never achieved. However, the probability of the intervention being cost effective was higher than 85% in all analyses across a range of potential cost-effectiveness threshold values. There is no compelling statistical evidence to support the targeting of specific subgroups across the general population. However, if affordability constraints are binding, the results do allow a tentative ranking of priorities based on the probabilistic subgroup analysis. PMID- 21537953 TI - Successful surgical intervention for the management of endocarditis due to multidrug resistant Candida parapsilosis: case report and literature review. AB - Candida parapsilosis is an uncommon cause of invasive endocarditis. This pathogen induces severe complications and carries a high mortality rate. We describe a case of C. parapsilosis endocarditis in a 54-year-old man with a history of HIV and Hepatitis C infection who previously underwent prosthetic valve replacement due to bacterial endocarditis. The patient presented with prolonged febrile episodes and fungemia with repeat blood cultures positive for C. parapsilosis. The patient failed multiple regimens of antifungal therapy and the C. parapsilosis isolate progressively acquired resistance to a number of drugs. Due to the multidrug resistant nature of the isolate, replacement of the infected valve was required to resolve his fungemia, and the patient remained asymptomatic for two years. This case is unusual due to the multidrug resistant nature of the isolate requiring both combined medical and surgical intervention. A review of published reports indicates that endocarditis due to C. parapsilosis responds well to a combination of medical and surgical interventions; the latter is particularly suitable for immunocompromised hosts. PMID- 21537954 TI - Analysis of arsenic metabolites in HepG2 and AS3MT-transfected cells. AB - It has been suggested that arsenic (+3 oxidation state) methyltransferase (AS3MT) plays a critical role in methylation of arsenic, and that arsenic-glutathione conjugate is a substrate for AS3MT-catalyzed methylation of arsenic. However, the mechanism of arsenic methylation in cells is not fully understood. Here, we have constructed T-REx-CHO-hAS3MTtr cells that transiently overexpress human AS3MT in response to tetracycline. The decreases in cell viability after exposure to sodium arsenite were greater in tetracycline-treated cells (tet(+) cells) than in untreated cells (tet(-) cells). Concentration of total cellular arsenic was significantly higher in tet(+) cells than in tet(-) cells. Speciation analyses of arsenic metabolites in whole cell lysates and cell culture medium were performed using both HepG2 cells and T-REx-CHO-hAS3MTtr cells. Speciation analyses of arsenic metabolites in lysates of T-REx-CHO-hAS3MTtr cells revealed that dimethylated arsenicals were the predominant arsenic metabolites in tet(+) cells, while methylated metabolites were not found in tet(-) cells. In contrast, less amount of methylated arsenic metabolites were found in the HepG2 cell lysates, and monomethylated trivalent arsenicals were the predominant methylated arsenic metabolites. Arsenate was found in the culture medium after 24 h culture with arsenite. A larger amount of arsenate was found in the culture medium of tet(+) or tet(-) cells compared to HepG2 cells. These findings indicated that AS3MT expression enhanced the cytotoxic effect of arsenite in tet(+) cells because these cells accumulated more arsenic metabolites than did the tet(-) cells, and accordingly, the tet(+) cells were more susceptible to arsenic than were the tet( ) cells. Oxidation--reduction of arsenic may be implicated in the toxic effects of arsenite. PMID- 21537955 TI - The in vitro MN assay in 2011: origin and fate, biological significance, protocols, high throughput methodologies and toxicological relevance. AB - Micronuclei (MN) are small, extranuclear bodies that arise in dividing cells from acentric chromosome/chromatid fragments or whole chromosomes/chromatids lagging behind in anaphase and are not included in the daughter nuclei at telophase. The mechanisms of MN formation are well understood; their possible postmitotic fate is less evident. The MN assay allows detection of both aneugens and clastogens, shows simplicity of scoring, is widely applicable in different cell types, is internationally validated, has potential for automation and is predictive for cancer. The cytokinesis-block micronucleus assay (CBMN) allows assessment of nucleoplasmic bridges, nuclear buds, cell division inhibition, necrosis and apoptosis and in combination with FISH using centromeric probes, the mechanistic origin of the MN. Therefore, the CBMN test can be considered as a "cytome" assay covering chromosome instability, mitotic dysfunction, cell proliferation and cell death. The toxicological relevance of the MN test is strong: it covers several endpoints, its sensitivity is high, its predictivity for in vivo genotoxicity requires adequate selection of cell lines, its statistical power is increased by the recently available high throughput methodologies, it might become a possible candidate for replacing in vivo testing, it allows good extrapolation for potential limits of exposure or thresholds and it is traceable in experimental in vitro and in vivo systems. Implementation of in vitro MN assays in the test battery for hazard and risk assessment of potential mutagens/carcinogens is therefore fully justified. PMID- 21537956 TI - Current role of pharmacogenomics in cardiovascular medicine. AB - OPINION STATEMENT: Pharmacogenomics holds the promise of transforming patient care by allowing providers to tailor therapy to each individual patient based on his or her genetic information. Although no established pharmacogenomic applications in cardiovascular medicine yet exist, there are at least three emerging applications that may ultimately become routine clinical practice; these are related to warfarin, clopidogrel, and statins. Of the three, warfarin pharmacogenomics has been the most rigorously evaluated to date, with several clinical trials either completed or underway. Clopidogrel pharmacogenomics has a growing body of supporting scientific evidence and warrants evaluation in prospective clinical trials. Statin pharmacogenomics remains the least developed application, with controversy surrounding a widely marketed genetic test whose validity has been questioned by recent evidence. Providers are advised to take a "wait and see" approach to pharmacogenomics at the present time, with the expectation that it will be a few years before any cardiovascular pharmacogenomic application is unequivocally proven to be both cost-effective as well as of clinical benefit. PMID- 21537958 TI - Computational study of the electronic structures, UV-Vis spectra and static second-order nonlinear optical susceptibilities of macrocyclic thiophene derivatives. AB - Using thiophene (which has a moderate resonance energy) as a spacer rather than benzene permits better pi-electron delocalization and leads to a large nonlinear optical response. Thus, the nonlinear optical coefficients of a series of macrocyclic thiophene derivatives (C[3T_DA](n) with C(n) symmetry) were studied, and their electronic structures, UV-Vis spectra and static second-order nonlinear optical susceptibilities (beta(0)) were computed. The calculated results showed that DeltaE(H-L) increased and the UV-Vis spectrum redshifted as the number of C[3T_DA] units increased (one C[3T_DA] unit consists of trithiophene and diacetylene). The value of beta(0) calculated by either the ZINDO-SOS or the FF method showed the same trend: the absolute value of beta(0) increased as the number of units increased. The value of beta(0) predicted by ZINDO-SOS was an order of magnitude larger than that predicted by the FF method. However, the results suggest that macrocyclic thiophene compounds potentially exhibit large static second-order nonlinear optical susceptibilities. PMID- 21537959 TI - Quantum chemical investigation of the thermal pyrolysis reactions of the carboxylic group in a brown coal model. AB - Different reaction pathways of the carboxylic group in a brown coal model were investigated by applying density function quantum chemical theory, examining the possible cross-linking and decomposition reactions between the hydrogen bonded carboxylic group-carboxylic group and the carboxylic group-hydroxyl group during the thermal pyrolysis process. The results show that bimolecular dehydration and decarboxylation of hydrogen bonded carboxylic groups have distinctly lower activation barriers and therefore, proceed preferentially at low temperature. The esterification reaction between the hydrogen bonded carboxylic group and hydroxyl group, together with unimolecular decarboxylation of isolated single carboxylic groups were also possible at moderate temperature. Aryl-aryl coupling is thought to occur via radical pyrolysis and recombination at relatively high temperature. PMID- 21537957 TI - Molecular dynamics simulation and density functional theory studies on the active pocket for the binding of paclitaxel to tubulin. AB - Paclitaxel (PTX) is used to treat various cancers, but it also causes serious side effects and resistance. To better design similar compounds with less toxicity and more activity against drug-resistant tumors, it is important to clearly understand the PTX-binding pocket formed by the key residues of active sites on beta-tubulin. Using a docking method, molecular dynamics (MD) simulation and density functional theory (DFT), we identified some residues (such as Arg278, Asp26, Asp226, Glu22, Glu27, His229, Arg369, Lys218, Ser277 and Thr276) on beta tubulin that are the active sites responsible for interaction with PTX. Another two residues, Leu371 and Gly279, also likely serve as active sites. Most of these sites contact with the "southern hemisphere" of PTX; only one key residue interacts with the "northern hemisphere" of PTX. These key residues can be divided into four groups, which serve as active compositions in the formation of an active pocket for PTX binding to beta-tubulin. This active binding pocket enables a very strong interaction (the strength is predicted to be in the range of -327.8 to -365.7 kJ mol(-1)) between beta-tubulin and PTX, with various orientated conformations. This strong interaction means that PTX possesses a high level of activity against cancer cells, a result that is in good agreement with the clinical mechanism of PTX. The described PTX pocket and key active residues will be applied to probe the mechanism of tumor cells resistant to PTX, and to design novel analogs with superior properties. PMID- 21537960 TI - Study of the betulin molecule in a water environment; ab initio and molecular simulation calculations. AB - Ab initio and molecular simulation methods were used in calculations of the neutral individual betulin molecule, and molecular simulations were used to optimize the betulin molecule immersed in various amounts of water. Individual betulin was optimized in different force fields to find the one exhibiting best agreement with ab initio calculations obtained in the Gaussian03 program. Dihedral torsions of active groups of betulin were determined for both procedures, and related calculated structures were compared successfully. The selected force field was used for subsequent optimization of betulin in a water environment, and a conformational search was performed using quench molecular dynamics. The total energies of betulin and its interactions in water bulk were calculated, and the influence of water on betulin structure was investigated. PMID- 21537961 TI - Triethanolammonium acetate as a multifunctional ionic liquid in the palladium catalyzed green Heck reaction. AB - An efficient green Heck reaction protocol was performed using a triethanolammonium acetate ionic liquid-palladium(II) catalytic system. The ionic liquid used acts as a reaction medium, base, precatalyst-precursor, and mobile support for the active Pd species. Our experimental investigation indicates that performing the Heck reaction in ionic liquid is superior to the same procedure carried out in triethanolamine. The mechanism of the reaction of triethanolammonium acetate with PdCl(2) was examined using density functional theory (M06 method). It was found that two Pd(II) complexes are formed, one of which acts further as a precatalyst yielding catalytically active Pd(0) complex. The calculated activation energies are in agreement with our experimental findings. PMID- 21537962 TI - Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome. AB - Visceral hypersensitivity is currently considered a key pathophysiological mechanism involved in pain perception in large subgroups of patients with functional gastrointestinal disorders, including irritable bowel syndrome (IBS). In IBS, visceral hypersensitivity has been described in 20%-90% of patients. The contribution of the central nervous system and psychological factors to visceral hypersensitivity in patients with IBS may be significant, although still debated. Peripheral factors have gained increasing attention following the recognition that infectious enteritis may trigger the development of persistent IBS symptoms, and the identification of mucosal immune, neural, endocrine, microbiological, and intestinal permeability abnormalities. Growing evidence suggests that these factors play an important role in pain transmission from the periphery to the brain via sensory nerve pathways in large subsets of patients with IBS. In this review, we will report on recent data on mechanisms involved in visceral hypersensitivity in IBS, with particular attention paid to peripheral mechanisms. PMID- 21537963 TI - Recent advances in functional anorectal disorders. AB - Defecatory disorders are a common cause of chronic constipation and should be managed by biofeedback-guided pelvic floor retraining. While anorectal tests are necessary to diagnose defecatory disorders, recent studies highlight the utility of a careful digital rectal examination. While obstetric anal injury can cause fecal incontinence (FI), diarrhea is a more important risk factor for FI among women in the community, who typically develop FI after age 40. Initial management of fecal incontinence should focus on bowel disturbances. Pelvic floor retraining with biofeedback therapy is beneficial for patients who do not respond to bowel management. Sacral nerve stimulation should be considered in patients who do not respond to conservative therapy. PMID- 21537964 TI - Current trends in critical care nutrition. AB - Nutrition in the intensive care setting is a vital part of patient care, and may even be referred to as "nutritional therapy". Current nutritional practices have progressed a lot over the past few years, and draw from a large body of accumulating evidence. Yet, as with other trends in critical care, there are a lot of variations in the way nutrition is approached between institutions, as well as between individual physicians. This review attempts to look at some of these differences and provide recommendations based upon the available literature. PMID- 21537965 TI - Does habituation depend on cortical inhibition? Results of an rTMS study in healthy subjects. AB - Habituation, i.e. the decremental response to repeated sensorial stimulation, is studied in humans through evoked potential stimulation. Mechanisms underlying habituation are not yet cleared, even if inhibitory circuits are supposed to play an important role. Light deprivation (LD) increases visual cortical excitability likely through down-regulation of GABA circuits. We previously found that high frequency repetitive transcranial magnetic stimulation (hf-rTMS) can revert these facilitatory effects likely restoring the activity of inhibitory circuits. Here, we studied the effects of LD and rTMS on habituation of visual evoked potentials (VEPs). The hypothesis was that if the inhibitory circuits have a role in habituation, then LD that downregulates GABA circuits, should impair habituation that in turn should be restored by hf-rTMS. Fifteen healthy subjects underwent VEPs recording in baseline (without LD), in LD alone (without rTMS), in LD and 1 Hz rTMS and in LD and 10 Hz rTMS. Habituation observed in baseline (without LD) was significantly impaired after LD; 10 Hz but not 1 Hz rTMS was able to restore normal habituation phenomena. VEPs habituation is impaired by LD but it could be restored if hf-rTMS is given during LD. As LD acts reducing GABA circuits activity and hf-rTMS likely upregulates such circuits, these data give support to the hypothesis that cortical inhibition can play a relevant role in mechanisms underlying habituation. PMID- 21537966 TI - Correlation between cortical plasticity, motor learning and BDNF genotype in healthy subjects. AB - There is good evidence that synaptic plasticity in human motor cortex is involved in behavioural motor learning; in addition, it is now possible to probe mechanisms of synaptic plasticity using a variety of transcranial brain stimulation protocols. Interactions between these protocols suggest that they both utilise common mechanisms. The aim of the present experiments was to test how well responsiveness to brain-stimulation protocols and behavioural motor learning correlate with each other in a sample of 21 healthy volunteers. We also examined whether any of these measures were influenced by the presence of a Val66Met polymorphism in the BDNF gene since this is another factor that has been suggested to be able to predict response to tests of synaptic plasticity. In 3 different experimental sessions, volunteers underwent 5-Hz rTMS, intermittent theta-burst stimulation (iTBS) and a motor learning task. Blood samples were collected from each subject for BDNF genotyping. As expected, both 5-Hz rTMS and iTBS significantly facilitated MEPs. Similarly, as expected, kinematic variables of finger movement significantly improved during the motor learning task. Although there was a significant correlation between the effect of iTBS and 5-Hz rTMS, there was no relationship in each subject between the amount of TMS-induced plasticity and the increase in kinematic variables during motor learning. Val66Val and Val66Met carriers did not differ in their response to any of the protocols. The present results emphasise that although some TMS measures of cortical plasticity may correlate with each other, they may not always relate directly to measures of behavioural learning. Similarly, presence of the Val66Met BDNF polymorphism also does not reliably predict responsiveness in small groups of individuals. Individual success in behavioural learning is unlikely to be closely related to any single measure of synaptic plasticity. PMID- 21537967 TI - Two stages and three components of the postural preparation to action. AB - Previous studies of postural preparation to action/perturbation have primarily focused on anticipatory postural adjustments (APAs), the changes in muscle activation levels resulting in the production of net forces and moments of force. We hypothesized that postural preparation to action consists of two stages: (1) Early postural adjustments (EPAs), seen a few hundred ms prior to an expected external perturbation and (2) APAs seen about 100 ms prior to the perturbation. We also hypothesized that each stage consists of three components, anticipatory synergy adjustments seen as changes in covariation of the magnitudes of commands to muscle groups (M-modes), changes in averaged across trials levels of muscle activation, and mechanical effects such as shifts of the center of pressure. Nine healthy participants were subjected to external perturbations created by a swinging pendulum while standing in a semi-squatting posture. Electrical activity of twelve trunk and leg muscles and displacements of the center of pressure were recorded and analyzed. Principal component analysis was used to identify four M modes within the space of muscle activations using indices of integrated muscle activation. This analysis was performed twice, over two phases, 400-700 ms prior to the perturbation and over 200 ms just prior to the perturbation. Similar robust results were obtained using the data from both phases. An index of a multi M-mode synergy stabilizing the center of pressure displacement was computed using the framework of the uncontrolled manifold hypothesis. The results showed high synergy indices during quiet stance. Each of the two stages started with a drop in the synergy index followed by a change in the averaged across trials activation levels in postural muscles. There was a very long electromechanical delay during the early postural adjustments and a much shorter delay during the APAs. Overall, the results support our main hypothesis on the two stages and three components of the postural preparation to action/perturbation. This is the first study to document anticipatory synergy adjustments in whole-body tasks. We interpret the results within the referent configuration hypothesis (an extension of the equilibrium-point hypothesis): The early postural adjustment is based primarily on changes in the coactivation command, while the APAs involve changes in the reciprocal command. The results fit an earlier hypothesis that whole-body movements are controlled by a neuromotor hierarchy where each level involves a few-to-many mappings organized to stabilize its overall output. PMID- 21537968 TI - Modulation of the motor system during visual and auditory language processing. AB - Studies of embodied cognition have demonstrated the engagement of the motor system when people process action-related words and concepts. However, research using transcranial magnetic stimulation (TMS) to examine linguistic modulation in primary motor cortex has produced inconsistent results. Some studies report that action words produce an increase in corticospinal excitability; others, a decrease. Given the differences in methodology and modality, we re-examined this issue, comparing conditions in which participants either read or listened to the same set of action words. In separate blocks of trials, participants were presented with lists of words in the visual and auditory modality, and a TMS pulse was applied over left motor cortex, either 150 or 300 ms after the word onset. Motor evoked potentials (MEPs) elicited were larger following the presentation of action words compared with control words. However, this effect was only observed when the words were presented visually; no changes in MEPs were found when the words were presented auditorily. A review of the TMS literature on action word processing reveals a similar modality effect on corticospinal excitability. We discuss different hypotheses that might account for this differential modulation of action semantics by vision and audition. PMID- 21537969 TI - Readiness-to-change cluster profiles among adults with mental illness who were homeless participating in a life skills intervention. AB - This longitudinal study examined differences in intervention outcomes based on readiness-to-change cluster profiles among 73 adults with a mental illness at risk for homelessness participating in a manualized life skills intervention. Intervention topics included money management, food management, safe community participation, and room- and self-care. Life skill knowledge and readiness-to change, measured using the University of Rhode Island Change Assessment, was examined at baseline, post-intervention, and 3-6 months later. Two scoring patterns emerged for readiness-to-change at each time point: Pre-Engaged and Engaged. Participants who were Engaged at the time of assessment scored significantly better than Pre-Engaged on post-intervention life skill testing, however group identification changed over time. Baseline readiness-to-change did not predict future performance or attrition, and therefore may not provide accurate indication of client investment for future learning or participation. Further investigation is needed to determine what factors contribute to Engaged membership. PMID- 21537970 TI - Distribution of micafungin in the tissue fluids of patients with invasive fungal infections. AB - The distribution of micafungin (MCFG) in tissue fluids, such as cerebrospinal fluid (CSF), pleural effusions, ascites, and wound tissue fluids, was examined in seven patients with invasive fungal infections. MCFG (100-300 mg) was administered once daily over a 1-h intravenous infusion. Blood and tissue fluid samples were collected from 1 to 24 h after infusion. Although two patients had similar MCFG concentrations in their plasma, the concentrations in the CSF differed between these two patients. The concentration in the CSF of one patient was much higher than the MIC(90) for Candida albicans, Candida glabrata, and Aspergillus fumigatus, whereas the MCFG concentration in the CSF of the other patient was comparable to the MIC(90). By contrast, MCFG concentrations in pleural effusions, ascites, and wound tissue fluids were above the MIC(90). These results suggest that intravenous MCFG may be effective to treat invasive fungal infections that invade the organs and tissues. PMID- 21537971 TI - Extracorporeal membrane oxygenation and swine flu. PMID- 21537972 TI - Development of a miniaturized mass-flow meter for an axial flow blood pump based on computational analysis. AB - In order to monitor the condition of patients with implantable left ventricular assist systems (LVAS), it is important to measure pump flow rate continuously and noninvasively. However, it is difficult to measure the pump flow rate, especially in an implantable axial flow blood pump, because the power consumption has neither linearity nor uniqueness with regard to the pump flow rate. In this study, a miniaturized mass-flow meter for discharged patients with an implantable axial blood pump was developed on the basis of computational analysis, and was evaluated in in-vitro tests. The mass-flow meter makes use of centrifugal force produced by the mass-flow rate around a curved cannula. An optimized design was investigated by use of computational fluid dynamics (CFD) analysis. On the basis of the computational analysis, a miniaturized mass-flow meter made of titanium alloy was developed. A strain gauge was adopted as a sensor element. The first strain gauge, attached to the curved area, measured both static pressure and centrifugal force. The second strain gauge, attached to the straight area, measured static pressure. By subtracting the output of the second strain gauge from the output of the first strain gauge, the mass-flow rate was determined. In in-vitro tests using a model circulation loop, the mass-flow meter was compared with a conventional flow meter. Measurement error was less than +/-0.5 L/min and average time delay was 0.14 s. We confirmed that the miniaturized mass-flow meter could accurately measure the mass-flow rate continuously and noninvasively. PMID- 21537973 TI - The usefulness of a grading system for complications resulting from pancreatic resections: a single center experience. AB - The aim of this study was to test the usefulness of the Clavien-Dindo classification after pancreatic resection. In 183 patients who underwent pancreatic resections, complications were classified according to Clavien-Dindo classification and each grade was evaluated regarding the length of the postoperative stay and was compared to the most important complications. Sixty four (35.0%) patients had no complications; out of the 119 (65.0%) patients with complications, grade I, was 9.3%; grade II, 35.5%; grade III, 9.3%; grade IV, 7.7% and grade V, 3.3%. The postoperative pancreatic fistula rate was 29.1%, postpancreatectomy hemorrhage, 35% and delayed gastric emptying, 11.5%. There was a progressive increase in the length of hospitalization from patients with no complications to those having grade IV (P < 0.001). Postoperative pancreatic fistula, postpancreatectomy hemorrhage and delayed gastric empty rates significantly increased from Clavien-Dindo grade I to grade IV; only postoperative pancreatic fistula and postpancreatectomy hemorrhage severity significantly increased from grade I to grade IV (both P < 0.001). The Clavien Dindo classification is an objective, simple, and reliable way of reporting all complications following pancreatic resections and it allows to recognize appropriately all the most important complications after pancreatic resection, and the severity of postoperative pancreatic fistula and postpancreatectomy hemorrhage. PMID- 21537974 TI - Bowel obstruction after cardiac surgery due to diaphragmatic unrecognised hernia. AB - Diaphragmatic hernia is a very rare occurrence after cardiac surgery without complications. We report a case of a 66-year-old male who underwent double aortocoronary bypass surgery, mitral and tricuspidal annuloplasty developed bowel obstruction 5 months after the operation. X-ray demonstrated small bowel loops in the left side of the chest. A laparoscopy was performed, but during the reduction of the hernia, patient suffered bradycardia because of adhesions between bowel and pericardical sac. Operation was interrupted and patient was transferred to our hospital where a cardiac surgery unit is present. No hemodynamic or respiratory deterioration was observed. Thoracic abdominal entero-CT, transthoracical echocardiography were performed. Patient underwent second surgery in cooperation with the cardial surgical team. Sternotomy was carried out. Hernial content was drawn onto the abdomen, diaphragmatic defect was closed with a direct suture. Mini-laparotomy was performed to exclude that the herniated small bowel did not have ischaemic suffering. No morbidity was observed in the post-operative course. This case illustrates the importance of an accurate pre operative diagnosis in order to obtain information on relationship between loops of bowel and mediastinal organs. If sternotomy is required, surgical team must be supported by a cardiac surgical team. PMID- 21537975 TI - Validation of navigation assisted cup placement in total hip arthroplasty. AB - PURPOSE: Computer navigation has the potential to provide precise intraoperative knowledge to the surgeon. Previous studies with navigation have confirmed its function for improved component position but few studies have reported the accuracy and precision of navigation system in clinical use. With this study we propose to evaluate the efficacy of navigation in guiding cup placement. METHODS: Fifty-six patients undergoing primary total hip arthroplasty were prospectively included in this study. Stryker imageless navigation system which is accurate to 0.5 degrees was used in all cases. Intraoperative data was collected for the acetabular component position using navigation for the freehand cup placement and the final cup placement done using navigation. Postoperative evaluation of component position was done with computed tomography (CT) and the deviation from intraoperative freehand and navigation values were calculated. RESULTS: The mean inclination of the freehand reading was 39.5 degrees (range, 20 degrees -58 degrees ), mean version of freehand reading was 10.7 degrees (-6 degrees - 27 degrees ), and the mean navigation reading was 43.2 degrees (37 degrees -49 degrees ) for inclination and 13.0 degrees (-8 degrees - 24 degrees ) for version. On postoperative CT scan analysis the mean inclination was 45.3 degrees (34 degrees -56 degrees ) and mean version was 15.1 degrees (4 degrees -25 degrees ). The deviation of the freehand inclination from the post operative CT scan reading was 11.4 degrees (1 degrees -30 degrees ) and the version deviated by a mean of 10.8 degrees (2 degrees -26 degrees ). The deviation of the navigation reading from the CT scan reading had a mean of 5.3 degrees (1 degrees -13 degrees ) for inclination and 5.6 degrees (1 degrees -17 degrees ) for version. CONCLUSION: The accuracy of the navigation system over conventional freehand cup placement is validated by this study. PMID- 21537976 TI - Recurrence of axial malalignment after surgical correction in congenital femoral deficiency and fibular hemimelia. AB - PURPOSE: Recurrent genu valgum deformity complicates treatment of congenital femoral deficiencies (CFD) and fibular hemimelia (FH). We analysed factors influencing recurrence. METHODS: Patients who underwent limb lengthening or deformity correction for CFD and/or FH were reviewed. Radiographs after surgery and after a minimum of a further six months were analysed. Change in parameters of mechanical axis deviation per month (? MAD/month) and of angle per month were calculated. These parameters were tested against cofactors patient age, baseline MAD, type of CFD and FH, severity of ball-and-socket joints, ankle-joint stiffness, absence of cruciate ligaments and resection of the fibular anlage. RESULTS: Recurrent valgus deformity was found in 23 of the 42 limbs included with a mean change of MAD of 23.4 mm (5-60 mm). There was no significant difference between patients with ? MAD/month <0.5 mm versus >1 mm regarding MAD in the first radiograph and patient age. CFD cases Pappas types VII and VIII showed a ? MAD/month of 1.6 mm, whereas milder cases of Pappas IX showed a ? MAD/month of 0.8. Mild FH (type Ia) showed a mean ? MAD/month of 0.39 mm, whereas mean ? MAD/month for FH type Ib/II was 0.72 mm. In FH type II cases, mean ? MAD/month was 0.79 mm after resection of the fibular anlage compared with 1.98 mm in those without resection. CONCLUSIONS: Recurrence in FH and CFD was not dependent on patient age but partly on FH and CFD type. Limbs with more severe ball-and-socket knee joints showed more recurrence. Overcorrection depending deformity type should be performed. PMID- 21537977 TI - The composition of upstream open reading frames (uORF) in four genes from Trypanosoma cruzi typical strains. AB - Upstream open reading frames (uORF) are small open reading frames located in the 5' untranslated region (5' utr) of a mature mRNA. We analysed in four strains representing the Trypanosoma cruzi groups Tc I, Tc II, Tc IV and Tc VI the uORF present in 5' utr sequences of four genes: P-type H+-ATPase 1, DEAD/H RNA helicase, casein kinase 1.1 and ferredoxin-NADP+ reductase. A segment in the 5' utr at each of these genes encompassing one or more uORF was PCR amplified and sequenced. An analysis of these sequences reveals that the uORF in T. cruzi show minor variations; however, these nucleotide substitutions mirror the divergence of T. cruzi strains into major groups. PMID- 21537978 TI - Cloning and characterization of the autophagy-related gene 6 from the hard tick, Haemaphysalis longicornis. AB - Autophagy is the intracellular protein degradation process which is induced by starvation. Ticks have a unique tolerance for starvation, and it is possible that this tolerance is associated with their longevity. Previously, we isolated the homologues of four autophagy-related (ATG) genes in the hard tick, Haemaphysalis longicornis, suggesting that autophagy appeared to play an important role in tolerance for starvation as well as the development of ticks. In this study, the homologue of ATG6 was isolated from H. longicornis (HlATG6). HlATG6 mRNA expression was higher in the egg and unfed larval stages than in other stages and upregulated in ovaries during the blood-feeding period. Moreover, HlATG6 knockdowned ticks laid a few and poorly developed eggs that were white brown in color and not well surface-coated with wax. However, the expression of vitellogenin (Vg)-2, HlVg-2, in the fat body of HlATG6-knockdowned ticks was significantly upregulated. In addition, hemolymph had a deep brown color in HlATG6-knockdowned ticks on day 21 after engorgement and drop-off, indicating that the Vgs synthesized by the fat body and midgut are retained and accumulated in the hemolymph of HlATG6-knockdowned ticks, probably due to the downregulation of the Vg uptake capability of oocytes. Interestingly, HlATG6 knockdown provided non-significant influences on the expression of the Vg receptor (HlVgR) at oocytes, suggesting a non-significant depression of VgR-mediated endocytosis in the oocytes of HlATG6-knockdowned ticks. Therefore, it was interpreted that the repression of Vg uptake in the oocytes of HlATG6-knockdowned ticks may be involved in endocytic processes other than the receptor recognition of Vgs in oocytes. PMID- 21537979 TI - First confirmed report of outbreak of malignant ovine theileriosis among goats in Sudan. AB - An outbreak of malignant ovine theileriosis among goats was confirmed and documented. In this outbreak, 16 out of 22 (72.7%) goats died within 4 days showing clinical signs of malignant ovine theileriosis as well as in the postmortem findings. The goats were reared in a mixed flock with sheep in Atbara Town, Northern Sudan. The infection was detected microscopically and confirmed serologically by IFA test and molecularly by PCR technique using specific primer for Theileria lestoquardi. Hyalomma anatolicum was the most prevalent (dominant) tick species found in the farm. It is recommended to undertake future research on the role of goats on the epidemiology of malignant ovine theileriosis. PMID- 21537981 TI - Morphological descriptions for the identification of Hypopygiopsis tumrasvini Kurahashi (Diptera: Calliphoridae). AB - This article presents morphological descriptions of larvae and adults of Hypopygiopsis tumrasvini Kurahashi (Diptera: Calliphoridae), a blow fly species that may be of forensic importance. Both second and third instar larvae are illustrated, with emphasis placed on important characteristic features used for larval identification, such as the cephalopharyngeal skeleton, anterior and posterior spiracles, and dorsal spines between the prothorax and mesothorax. Eight to 11 papillae were found on each anterior spiracle arranged in a single row. The dorsal spines between the prothorax and mesothorax were arranged in sets of posteriorly projecting acuminate spines with darkly pigmented tips. The posterior spiracles each bear three prominent and separated long, slender spiracular slits encircled by a dark, thick peritreme that is complete ventromedially around a button. Prominent inner projection of peritreme is seen between the middle and lower spiracular slits. A previously published key for differentiating third instar larvae of flies of possible forensic importance in Thailand is updated to include this additional species. Some characteristic features of males and females of the species are also provided. PMID- 21537980 TI - Synergy of the antiretroviral protease inhibitor indinavir and chloroquine against malaria parasites in vitro and in vivo. AB - Many malaria-endemic areas are also associated with high rates of human immunodeficiency virus (HIV) infection. An understanding of the chemotherapeutic interactions that occur during malaria and HIV co-infections is important. Our previous studies have demonstrated that some antiretroviral protease inhibitors are effective in inhibiting Plasmodium falciparum growth in vitro. Currently, studies examining the interactions between antiretroviral protease inhibitors and antimalarial drugs are being conducted, but the data are limited. In this study, we examined the synergistic interactions between the antiretroviral protease inhibitor indinavir and chloroquine (CQ) in chloroquine-resistant and chloroquine sensitive malaria parasites in vitro and in vivo. In vitro, by using modified fixed-ratio isobologram method, fractional inhibitory concentrations index (FICI) was calculated to indicate the interaction between the two drugs. The results demonstrated that indinavir interacted synergistically with chloroquine against both chloroquine-sensitive P. falciparum clone 3D7 (mean FICI 0.784) and multidrug-resistant P. falciparum clone Dd2 (mean FICI 0.599). In vivo drug interactions were measured using a 4-day suppressive test in a rodent malaria model infected with Plasmodium chabaudi. We observed that indinavir enhanced the antimalarial activity of chloroquine against both the chloroquine-sensitive line P. chabaudi ASS and the chloroquine-resistant line P. chabaudi ASCQ. More importantly, chloroquine had a 100% clearance of asexual parasites when used in combination with indinavir at an appropriate dose ratio (10 mg/kg CQ + 1.8 g/kg indinavir) where there was no obvious toxicity. We conclude from this study that the combination of indinavir and chloroquine may become a novel antimalarial drug regimen. PMID- 21537982 TI - Scanning electron microscopy and morphometrics of nymph and larva of the tick Hyalomma impressum (Acari: Ixodidae). AB - Nymphs and larvae of ixodid ticks play an important role on the distribution of ticks and transmission of pathogens. They almost infest small mammals and birds which either move from place to place as rodents or migrate across different countries as migratory birds. The morphological descriptions of nymph and larva of the tick Hyalomma impressum were firstly studied in details by scanning electron microscopy and morphometric analysis. The distinguished characters of H. impressum nymph are as follows: dorsal idiosoma (excluding scutum) with 26-27 pairs of setae, posterior margin of scutum is narrowly rounded, posterolateral margins of scutum is straight, cervical grooves on the scutum extend to the midlength, coxa I with two large spurs, coxae (II-IV) with one small spur for each, spiracle is an egg shape with a numerous pores, palpus does not project beyond the hypostome, with nine setae dorsally and six setae ventrally, hypostome has cylindrical shape, dental formula 2/2, teeth number per file is eight in the outer file and seven in the inner file, basis capitulum has triangular shape without setae dorsally and tetragonal shape with three pairs of setae ventrally. The distinctive characters of H. impressum larva are as follows: idiosoma with 13 pairs of setae for each dorsal (including scutal setae) and ventral (excluding coxal setae), scutum with cervical grooves is narrow and shallow extending about one third of the scutal length, posterior margin of scutum is broadly rounded, posterolateral margins of scutum is straight, fold-like indistinctive spurs on coxae II and III, palpus with eight setae dorsally, three setae ventrally and one seta apically, hypostome with dental formula 2/2, teeth number per file (excluding small basal and apical teeth) is seven in the outer file and six in the inner file, basis capitulum without setae dorsally and with three pairs of setae ventrally. PMID- 21537983 TI - Review of research on hookworms (Uncinaria lucasi Stiles, 1901) in northern fur seals (Callorhinus ursinus Linnaeus, 1758). AB - The objective of this article is to review knowledge on the hookworm Uncinaria lucasi Stiles, 1901 in northern fur seals, Callorhinus ursinus Linnaeus, 1758. Emphasis is placed on research on this host-parasite system in the Pribilof Islands, AK, USA where the bulk of the studies has been performed. PMID- 21537984 TI - Rapid detection of Opisthorchis viverrini and Strongyloides stercoralis in human fecal samples using a duplex real-time PCR and melting curve analysis. AB - Human opisthorchiasis caused by the liver fluke Opisthorchis viverrini is an endemic disease in Southeast Asian countries including the Lao People's Democratic Republic, Cambodia, Vietnam, and Thailand. Infection with the soil transmitted roundworm Strongyloides stercoralis is an important problem worldwide. In some areas, both parasitic infections are reported as co infections. A duplex real-time fluorescence resonance energy transfer (FRET) PCR merged with melting curve analysis was developed for the rapid detection of O. viverrini and S. stercoralis in human fecal samples. Duplex real-time FRET PCR is based on fluorescence melting curve analysis of a hybrid of amplicons generated from two genera of DNA elements: the 162 bp pOV-A6 DNA sequence specific to O. viverrini and the 244 bp 18S rRNA sequence specific to S. stercoralis, and two pairs of specific fluorophore-labeled probes. Both O. viverrini and S. stercoralis can be differentially detected in infected human fecal samples by this process through their different fluorescence channels and melting temperatures. Detection limit of the method was as little as two O. viverrini eggs and four S. stercoralis larvae in 100 mg of fecal sample. The assay could distinguish the DNA of both parasites from the DNA of negative fecal samples and fecal samples with other parasite materials, as well as from the DNA of human leukocytes and other control parasites. The technique showed 100% sensitivity and specificity. The introduced duplex real-time FRET PCR can reduce labor time and reagent costs and is not prone to carry over contamination. The method is important for simultaneous detection especially in areas where both parasites overlap incidence and is useful as the screening tool in the returning travelers and immigrants to industrialized countries where number of samples in the diagnostic units will become increasing. PMID- 21537985 TI - In vivo anthelmintic activity of chelidonine from Chelidonium majus L. against Dactylogyrus intermedius in Carassius auratus. AB - Dactylogyrus intermedius is one of the most common and serious cause of parasitic diseases of freshwater fish in aquaculture, and can cause morbidity and high mortality in most species of freshwater fish worldwide. To attempt controlling this parasite and explore novel potential antiparasitic agents, the present study was designed to ascertain the anthelmintic activity of Chelidonium majus L. whole plant and to isolate and characterize the active constituents against D. intermedius. The ethanol extract from C. majus whole plant showed significant anthelmintic activity against D. intermedius [EC(50) (median effective concentration) value = 71.5 mg L(-1)] and therefore subjected to further isolation and purification using various chromatographic techniques. A quaternary benzo[c]phenanthridine alkaloid exhibited significant activity against D. intermedius was obtained and identified as chelidonine. In vivo anthelmintic efficacy tests exhibited that chelidonine was 100% effective against D. intermedius at a concentration of 0.9 mg L(-1), with EC(50) value of 0.48 mg L( 1) after 48 h of exposure, which is more effective than the positive control, mebendazole (EC(50) value = 1.3 mg L(-1)). In addition, the 48-h median lethal concentration (LC(50)) for chelidonine against the host (Carassius auratus) was 4.54 mg L(-1). The resulting therapeutic index for chelidonine was 9.46. These results provided evidence that chelidonine might be potential sources of new antiparasitic drugs for the control of Dactylogyrus. PMID- 21537986 TI - Improved detection of canine Angiostrongylus vasorum infection using real-time PCR and indirect ELISA. AB - This study reports the development of a real-time PCR assay and an indirect ELISA to improve on current detection of canine Angiostrongylus vasorum infection. A highly specific fluorescent probe-based, real-time PCR assay was developed to target the A. vasorum second internal transcribed spacer region and detected DNA in EDTA blood, lung tissue, broncho-alveolar larvage fluid, endotracheal mucus, pharyngeal swabs and faecal samples. PCR was fast (~1 h), highly efficient when using EDTA blood samples, consistently detected a single molecule of parasite DNA and did not amplify DNA from other parasitic nematodes or definitive host species. An indirect ELISA was also developed using the soluble protein fraction from adult A. vasorum worms. Some cross-reactive antigen recognition was observed when tested against sera from dogs infected with Crenosoma vulpis (n = 8), Toxocara canis (n = 5) and Dirofilaria immitis (n = 5). This was largely overcome by setting the cut-off for a positive result at an appropriately high level. Field evaluation of the real-time PCR and ELISA was conducted by testing sera and EDTA blood from dogs with suspected A. vasorum infection (n = 148) and compared with the Baermann's larval migration test in faeces. Thirty-one dogs were positive by at least one test. Of these, 20 (65%) were detected by the Baermann method, 18 (58%) by blood PCR, 24 (77%) by ELISA and 28 (90%) by blood PCR and ELISA together. Combined testing using real-time PCR and ELISA therefore improved the detection rate of A. vasorum infection and holds promise for improved clinical diagnosis and epidemiological investigation. PMID- 21537987 TI - Biolarvicidal compound gymnemagenol isolated from leaf extract of miracle fruit plant, Gymnema sylvestre (Retz) Schult against malaria and filariasis vectors. AB - Owing to the fact that the application of synthetic larvicide has envenomed the surroundings as well as non-target organisms, natural products of plant origin with insecticidal properties have been tried as an indigenous method for the control of a variety of insect pests and vectors in the recent past. Insecticides of plant origin have been extensively used on agricultural pests and, to a very limited extent, against insect vectors of public health importance, which deserve careful and thorough screening. The use of plant extracts for insect control has several appealing features as these are generally more biodegradable, less hazardous and a rich storehouse of chemicals of diverse biological activities. Moreover, herbal sources give a lead for discovering new insecticides. Therefore, biologically active plant materials have attracted considerable interest in mosquito control study in recent times. The crude leaf extracts of Gymnema sylvestre (Retz) Schult (Asclepiadaceae) and purified gymnemagenol compound were studied against the early fourth-instar larvae of Anopheles subpictus Grassi and Culex quinquefasciatus Say (Diptera: Culicidae). In the present study, bioassay guided fractionation of petroleum ether leaf extract of G. sylvestre led to the separation and identification of gymnemagenol as a potential new antiparasitic compound. Phytochemical analysis of G. sylvestre leaves revealed the presence of active constituents such as carbohydrates, saponins, phytosterols, phenols, flavonoids and tannins. However, cardiac glycosides and phlobatannins are absent in the plant extracts. Quantitative analysis results suggested that saponin (5%) was present in a high concentration followed by tannins (1.0%). The 50 g powder was loaded on silica gel column and eluted with chloroform-methanol-water as eluents. From that, 16 mg pure saponin compound was isolated and analysed by thin layer chromatography using chloroform and methanol as the solvent systems. The structure of the purified triterpenoid fraction was established from infrared (IR), ultraviolet (UV), (1)H nuclear magnetic resonance (NMR), (13)C NMR and mass spectral data. The carbon skeleton of the compound was obtained by (13)C NMR spectroscopy. The chemical shift assignments obtained for gymnemagenol from (1)H NMR correspond to the molecular formula C(30)H(50)O(4). The compound was identified as 3beta, 16beta, 28, 29-tetrahydroxyolean-12-ene (gymnemagenol sapogenin). Parasite larvae were exposed to varying concentrations of purified compound gymnemagenol for 24 h. The results suggested that the larval mortality effects of the compound were 28%, 69%, 100% and 31%, 63%, 100% at 6, 12 and 24 h against A. subpictus and C. quinquefasciatus, respectively. In the present study, the per cent mortality were 100, 86, 67, 36, 21 and 100, 78, 59, 38 and 19 observed in the concentrations of 1,000, 500, 250, 125 and 62.75 ppm against the fourth-instar larvae of A. subpitcus and C. quinquefasciatus, respectively. The purified compound gymnemagenol was tested in concentrations of 80, 40, 20, 10 and 5 ppm, and the per cent mortality were 100, 72, 53, 30 and 15 against A. subpitcus and 100, 89, 61, 42 and 30 against C. quinquefasciatus, respectively. The larvicidal crude leaf extract of G. sylvestre showed the highest mortality in the concentration of 1,000 ppm against the larvae of A. subpictus (LC(50) = 166.28 ppm, r (2) = 0.807) and against the larvae of C. quinquefasciatus (LC(50) = 186.55 ppm, r (2) = 0.884), respectively. The maximum efficacy was observed in gymnemagenol compound with LC(50) and r (2) values against the larvae of A. subpictus (22.99 ppm, 0.922) and against C. quinquefasciatus (15.92 ppm, 0.854), respectively. The control (distilled water) showed nil mortality in the concurrent assay. PMID- 21537989 TI - Larvicidal efficacy of Jatropha curcas and bacterial insecticide, Bacillus thuringiensis, against lymphatic filarial vector, Culex quinquefasciatus Say (Diptera: Culicidae). AB - The present study explored the effects of Jatropha curcas leaf extract and Bacillus thuringiensis israelensis larvicidal activity against the lymphatic filarial vector, Culex quinquefasciatus. Wights were selected for investigating the larvicidal potential against the first to fourth instar larvae of the laboratory-reared mosquito species, C. quinquefasciatus Say, in which the major lymphatic filariasis was used. The medicinal plants were collected from the area around Bharathiar University, Coimbatore. The dried plant materials were powdered by an electric blender. From the powder, 100 g of the plant materials was extracted with 300 ml of organic solvents of methanol for 8 h, using a Soxhlet apparatus, and filtered. The crude plant extracts were evaporated to dryness in a rotary vacuum evaporator. The plant extract showed larvicidal effects after 24 h of exposure; however, the highest larval mortality was found in the leaf extract of methanol J. curcas against the first to fourth instar larvae of values LC(50) = 1.200%, 1.290%, 1.358%, and 1.448% and LC(90) = 2.094%, 2.323%, 2.444%, and 2.544% and B. thuringiensis israelensis against the first to fourth instar larvae of values LC(50) = 9.332%, 9.832%, 10.212%, 10.622% and LC(90) = 15.225%, 15.508%, 15.887%, and 15.986% larvae of C. quinquefasciatus, respectively. No mortality was observed in the control. These results suggest methanol extracts of J. curcas and B. thuringiensis israelensis have potential to be used as an ideal eco-friendly approach for the control of the major lymphatic filarial vector, C. quinquefasciatus. PMID- 21537990 TI - Isolation and identification of Legionella and their host amoebae from weak alkaline carbonate spring water using a culture method combined with PCR. AB - Legionella were detected with the direct DNA extraction method, Legionella culture method, and free-living amoebae (FLA) culture method from weak alkaline carbonate spring water in Taiwan. Moreover, we also investigated the existence of Acanthamoeba, Hartmannella, and Naegleria, ubiquitous FLA in aquatic environments, to identify the correlations between existing Legionella. This study reports detecting Legionella in 15 of the 51 weak alkaline carbonate spring water samples (29.4%). This work also found five of the 51 samples (9.8%) analyzed by the direct DNA extraction method, three of the 51 (5.9%) samples analyzed by the Legionella culture method, and 11 of the 51 samples (21.6%) evaluated using the FLA culture method to be positive for Legionella. The most frequently identified Legionella species was the Legionella-like amoebal pathogen (n=5), followed by unidentified Legionella spp. (n=4), and Legionella pneumophila (n=4), Legionella fairfieldensis (n=3), and then Legionella rubrilucens (n=2). Legionella waltersii was detected once. The occurrence of Acanthamoeba, Hartmannella, and Naegleria were 5.9% (3/51), 52.9% (27/51), and 5.9% (3/51), respectively. All Hartmannella isolates were identified as Hartmannella vermiformis, and Naegleria isolates were all identified as Naegleria australiensis. The three Acanthamoeba isolates were identified as one Acanthamoeba polyphaga and two Acanthamoeba jacobsi. H. vermiformis (40.7%) were Legionella hosts, including all of the amoebae-resistant Legionella detected in the present study. Therefore, the important correlations between Legionella and H. vermiformis require further clarification. The combined results of this survey confirm that Legionella and FLA are ubiquitous in weak alkaline carbonate spring water in Taiwan. PMID- 21537988 TI - Toxocara canis larvae reinfecting BALB/c mice exhibit accelerated speed of migration to the host CNS. AB - Using a small animal imaging system, migratory activity of Toxocara canis larvae stained by carboxyfluorescein succinimidyl ester (CFSE) was observed post primary infection (PPI) and post reinfection (PR) of BALB/c mice. Each infection was performed with 1,000 larvae per mouse. Primary infections were performed with labeled larvae, while for challenge infections the reinfecting larvae were stained by CFSE. The worm burden in mouse organs was determined during a period from 6 h to 21 days and 4 months PPI and PR. In comparison with primary infections that led to the first larvae appearance in the brain after 60 h, greatly accelerated migration of the parasites administered 3 weeks PPI to the CNS and eyes of challenged mice was noted-in both organs the larvae appeared 6 h PR. In all challenged mice, reinfecting larvae prevailed in the resident parasite population. Preliminary experiments with Toxocara cati larvae also revealed early brain involvement in primarily infected mice. Staining of T. canis larvae by CFSE had no effect on the development of a humoral antibody response against T. canis excretory-secretory antigens. In ELISA, elevated levels of specific IgG and IgG1 were noted on day 14 PPI and the levels of antibodies increased till the end of experiment. Reinfection induced an increase in the levels of both antibodies. In terms of optical density, IgG1 antibodies gave higher values in all sera examined. In ELISA for IgG antibodies, an increase in the avidity index of around 50% was detected 1 month PPI; higher-avidity antibodies were also detected in sera of reinfected animals. PMID- 21537991 TI - Biochemical profile of Biomphalaria glabrata (Mollusca: Gastropoda) after infection by Echinostoma paraensei (Trematoda: Echinostomatidae). AB - The effect of infection by Echinostoma paraensei on the activity of the enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the concentration of total proteins, uric acid and urea in the hemolymph of Biomphalaria glabrata were investigated after exposure to five or 50 miracidia. The biochemical concentrations were measured weekly until the end of the fourth week after exposure. There was a significant decrease in the concentrations of total proteins in the snails exposed both to five and 50 miracidia, as well as an increase in the nitrogenous products of excretion, ALT and AST activities. The higher ALT activity in the hemolymph of the snails after infection with 50 miracidia suggests highest energetic requirement in these snails in relation to snails exposed to five miracidia. The results also suggest an increase in the use of total proteins, since there was increased formation of nitrogenous catabolites, in conformity with an increase in the aminotransferase activities, frequently associated with tissue damages. This can be explained by damage due to penetration by the miracidia and subsequent development of intramolluscan sporocysts and rediae. PMID- 21537992 TI - Genetic counseling in the adult with congenital heart disease: what is the role? AB - New discoveries using high-resolution methods for detecting genetic aberrations indicate that the genetic contribution to congenital heart disease has been significantly underestimated in the past. DNA diagnostics have become more accessible and genetic test results are increasingly being used to guide clinical management. Adult congenital heart disease specialists seeking to counsel adults with congenital heart disease about the genetic aspects of their condition face the challenge of keeping abreast of new genetic techniques and discoveries. The emphasis of this review is on the genetic basis of structural cardiovascular defects. A framework for identifying adult congenital heart disease patients most likely to benefit from genetic testing is suggested, along with a summary of current techniques for genetic testing. The clinical and ethical challenges associated with genetic counseling are highlighted. Finally, emerging technologies and future directions in genetics and adult congenital heart disease are discussed. PMID- 21537993 TI - Quantity and activation of myofiber-associated satellite cells in a mouse model of amyotrophic lateral sclerosis. PMID- 21537996 TI - Amino acid sequence analysis and identification of mutations in the NS gene of 2009 influenza A (H1N1) isolates from Kenya. AB - Although the important role of the nonstructural (NS) gene of influenza A virus in virulence and replication is well-established, the knowledge about the extent of variation in the NS gene of 2009 influenza A (H1N1) viruses in Kenya and Africa is scanty. This study analysed the NS gene of 31 isolates from Kenya in order to obtain a more detailed knowledge about the genetic variation of NS gene of 2009 influenza A (H1N1) isolates from Kenya. A comparison with the vaccine strain and viruses isolated elsewhere in Africa was also made. The amino acid sequences of the non-structural protein, NS1 of the viruses from this study and the vaccine strain revealed 18 differences. Conversely, the nuclear export protein (NEP) of the isolates in this study had 11 differences from the vaccine strain. Analysis of the NS1 protein showed only one fixed amino acid change I123V which is one of the characteristics of clade 7 viruses. In the NEP, the amino acid at position 77 was the most mutable with 9 (39%) of all mutations seen in this protein. A mutation A115T which is a characteristic of clade 5 viruses was noted in the isolates from Lagos, Nigeria. The study shows a substantial number of mutations in the NS gene that has not been reported elsewhere and gives a glimpse of the evolution of this gene in the region. PMID- 21537994 TI - Current challenges for the advancement of neural stem cell biology and transplantation research. AB - Transplantation of neural stem cells (NSC) is hoped to become a promising primary or secondary therapy for the treatment of various neurodegenerative disorders of the central nervous system (CNS), as demonstrated by multiple pre-clinical animal studies in which functional recovery has already been demonstrated. However, for NSC therapy to be successful, the first challenge will be to define a transplantable cell population. In the first part of this review, we will briefly discuss the main features of ex vivo culture and characterisation of NSC. Next, NSC grafting itself may not only result in the regeneration of lost tissue, but more importantly has the potential to improve functional outcome through many bystander mechanisms. In the second part of this review, we will briefly discuss several pre-clinical studies that contributed to a better understanding of the therapeutic potential of NSC grafts in vivo. However, while many pre-clinical animal studies mainly report on the clinical benefit of NSC grafting, little is known about the actual in vivo fate of grafted NSC. Therefore, the third part of this review will focus on non-invasive imaging techniques for monitoring cellular grafts in the brain under in vivo conditions. Finally, as NSC transplantation research has evolved during the past decade, it has become clear that the host micro-environment itself, either in healthy or injured condition, is an important player in defining success of NSC grafting. The final part of this review will focus on the host environmental influence on survival, migration and differentiation of grafted NSC. PMID- 21537995 TI - LIF-dependent signaling: new pieces in the Lego. AB - LIF, a member of the IL6 family of cytokine, displays pleiotropic effects on various cell types and organs. Its critical role in stem cell models (e.g.: murine ES, human mesenchymal cells) and its essential non redundant function during the implantation process of embryos, in eutherian mammals, put this cytokine at the core of many studies aiming to understand its mechanisms of action, which could benefit to medical applications. In addition, its conservation upon evolution raised the challenging question concerning the function of LIF in species in which there is no implantation. We present the recent knowledge about the established and potential functions of LIF in different stem cell models, (embryonic, hematopoietic, mesenchymal, muscle, neural stem cells and iPSC). We will also discuss EVO-DEVO aspects of this multifaceted cytokine. PMID- 21537997 TI - Molecular characterization of the complete genomes of two new field isolates of Cowpea chlorotic mottle virus, and their phylogenetic analysis. AB - Cowpea chlorotic mottle virus (CCMV, family Bromoviridae) is found worldwide and has been used as a model virus for a long time, but no data is available about the genetic diversity of field isolates. Recently, two new field isolates (Car1 and Car2) of CCMV obtained from cowpea showed distinct phenotypic symptoms when inoculated to cowpea. CCMV-Car1 induced severe mosaic and interveinal chlorosis, while CCMV-Car2 produced mild mottling and leaf rolling. Both isolates produced asymptomatic infection in Nicotiana benthamiana. The complete genome of both isolates was amplified by reverse transcription-polymerase chain reaction using specific primers against the CCMV sequences available in the GenBank database, cloned and sequenced. Both nucleotide and amino acid sequences were compared between the newly sequenced CCMV isolates and the three previously characterized CCMV strains (T, M1, and R). Phylogenetic analysis of the RNA 1 sequence showed that CCMV-Car1 was in a separate branch from the rest of the CCMV isolates while CCMV-Car2 grouped together with CCMV-R. On the basis of RNA 2 and RNA 3 sequences, two major groupings were obtained. One group included CCMV-Car1 and CCMV-Car2 isolates while the other contained CCMV-T, CCMV-M1, and CCMV-R strains. Recombination programs detected a potential recombination event in the RNA 1 sequence of CCMV-Car2 isolate but not in RNA 2 and RNA 3 sequences. The results showed that both mutations and recombination have played an important role in the genetic diversity of these two new isolates of CCMV. PMID- 21537998 TI - Effects of benzalkonium chloride on the ocular surface of the rabbit. AB - PURPOSE: To evaluate the effects of benzalkonium chloride (BAK) on the ocular surface in rabbits. METHODS: Eighteen white rabbits were divided into three groups. Topical administration of eye drops was performed four times a day for 14 days; 0.01% BAK for group I, 0.1% BAK for group II, and phosphate-buffered saline (PBS) for the control group. Schirmer test and Rose Bengal staining were carried out and conjunctival impression cytology was performed in both the upper and lower bulbar conjunctiva on days 0, 7, and 14. After day 14, both the upper and lower conjunctiva were evaluated by light and electron microscopy. Immunofluorescence staining was also performed for the detection of mucin 5AC. RESULTS: A decrease in the goblet cell density (GCD) and histopathological changes were more prominent in the BAK-treated groups compared to the control group (P < 0.05). Moreover, these changes were more noticeable in group II than in group I (P < 0.05). The decrease in the GCD and histopathological changes were statistically more significant in the lower conjunctiva than in the upper conjunctiva in the BAK-treated groups (P < 0.05). CONCLUSION: BAK caused damage to the ocular surface in a gravity-dependent manner. The adverse effects of BAK were more severe in the lower conjunctiva than in the upper conjunctiva. PMID- 21537999 TI - Buccal mucosal graft for hydroxyapatite orbital implant exposure. PMID- 21538000 TI - Expression profiles of cytokines and chemokines in vitreous fluid in diabetic retinopathy and central retinal vein occlusion. AB - PURPOSE: The involvement of cytokines and chemokines in vitreous fluid is important in the development and progression of diabetic retinopathy (DR) and central retinal vein occlusion (CRVO). In this study, the concentrations of cytokines and chemokines in the vitreous fluid of eyes with DR and CRVO were measured and compared. METHODS: We studied 76 eyes with proliferative DR and diabetic macular edema (DR group), 10 eyes with CRVO (CRVO group), and 23 eyes with an epiretinal membrane and macular hole (control group), among a series of 160 eyes from which vitreous fluid samples were collected during vitrectomy. The vitreous fluid samples were collected by suction with a vitreous cutter at the initial stage of vitrectomy. Twenty-seven different cytokines and chemokines were measured simultaneously using an array system (Bio-Plex((r))) with beads combined with antibodies (Bio-Rad), as follows: interleukin (IL)-1beta, IL-1 receptor agonist, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL 17, eotaxin, basic fibroblast growth factor, granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-gamma, interferon-inducible 10-kDa protein (IP-10), monocytochemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1alpha), MIP-1beta, platelet-derived growth factor (PDGF)-BB, regulated upon activation, normal T cell expressed and secreted, tumor necrosis factor alpha (TNF-alpha), and vascular endothelial growth factor (VEGF). RESULTS: Compared to the control group, the levels of IL-6, IL-8, IL-10, IL-13, IP-10, MCP-1, MIP 1beta, PDGF and VEGF in the vitreous fluid were significantly higher in the DR group, while the levels of IL-1beta, IL-2, IL-5, IL-8, IL-9, IL-10, IL-12, IL-13, eotaxin, G-CSF, IFN-gamma, IP-10, MCP-1, MIP-1beta, TNF-alpha and VEGF were significantly higher in the CRVO group. Compared to the DR group, IL-2, IL-9, IL 12, MCP-1 and IFN-gamma were significantly elevated in the CRVO group. Multivariate regression analysis revealed that among 6 factors correlated to VEGF in the DR group, IL-10 and IL-13 were more positively correlated and PDGF was most inversely correlated to VEGF. CONCLUSION: In addition to inflammatory cytokines and neurotrophic factors such as VEGF, anti-inflammatory cytokines such as IL-10 and IL-13 may be involved more in the pathogenesis of DR and CRVO than in other diseases; cytokines and chemokines may also be correlated to VEGF in the vitreous fluid. It is also suggested that the inflammatory reaction may be more activate in CRVO than in DR. PMID- 21538001 TI - Intravitreal intrusion of an intrascleral MIRAgel buckling implant. PMID- 21538002 TI - Glaucomatous eye macular ganglion cell complex thickness and its relation to temporal circumpapillary retinal nerve fiber layer thickness. AB - PURPOSE: To clarify the correlation between temporal circumpapillary retinal nerve fiber layer (RNFL) thickness and macular ganglion cell complex (mGCC) thickness in glaucomatous eyes. METHODS: Seventy-seven eyes of 77 subjects were categorized as normal, early glaucoma and moderate-to-advanced (moderate) glaucoma. After the circumpapillary RNFL thickness and mGCC thickness were measured, the temporal mean RNFL and mean mGCC were compared within the three groups. The study also investigated whether there was any correlation between the temporal RNFL and mGCC thicknesses. RESULTS: In the glaucoma groups, significant thinning of the temporal RNFL and mGCC thicknesses was noted. With the exception of the papillomacular bundle (r = -0.078), correlations were seen in each of the early glaucoma mGCC and temporal RNFL sectors (r = 0.38-0.753). Correlations were also noted for the mGCC and all temporal RNFL sectors in the moderate glaucoma group (r = 0.425-0.809). CONCLUSIONS: From the early stage of glaucoma, similar decreases of the mGCC and RNFL occured, and a high correlation existed between the two. Therefore, like RNFL, mGCC can potentially be used to detect the early stages of glaucoma. However, in early glaucoma eyes, the papillomacular bundle of the RNFL may be spared, even though mGCC thinning is present. PMID- 21538003 TI - Vitreous inflammatory factors in macular edema with central retinal vein occlusion. AB - PURPOSE: To investigate the correlation of soluble intercellular adhesion molecule 1 (sICAM-1) and vascular endothelial growth factor (VEGF) with macular edema in patients with central retinal vein occlusion (CRVO). METHODS: Twenty nine patients who had CRVO with macular edema and 16 patients with non-ischemic ocular diseases (control group) participated. Retinal ischemia was evaluated by measuring the area of capillary non-perfusion with fluorescein angiography and the public domain Scion Image program. Macular edema was examined by optical coherence tomography. Vitreous samples were obtained during pars plana vitrectomy. VEGF and sICAM-1 levels in vitreous fluid and plasma were determined by enzyme-linked immunosorbent assay. RESULTS: The median vitreous levels of VEGF and sICAM-1 were significantly higher in the CRVO patients than in the control group [366 vs. 15.6 pg/ml (P < 0.001) and 20.5 vs. 5.0 ng/ml (P < 0.001), respectively]. Vitreous levels of both VEGF and sICAM-1 were also significantly higher in the CRVO patients who had retinal ischemia than in those without ischemia (P < 0.001 and P = 0.011, respectively). Vitreous levels of VEGF and sICAM-1 were also significantly correlated with the severity of macular edema (P = 0.004 and P = 0.012, respectively). CONCLUSIONS: VEGF and sICAM-1 may both increase vascular permeability in CRVO patients with macular edema, with sICAM-1 acting together with and/or via VEGF. PMID- 21538004 TI - Influence of three-dimensional image viewing on visual function. AB - PURPOSE: A three-dimensional (3D) image viewing experiment was performed using a new 3D scenography system. The influence on visual function was investigated both in adults and in children employing both objective and subjective methods. METHODS: The subjects were 21 healthy adults (mean age +/- standard deviation: 42.1 +/- 10.0 years) and 21 healthy children (7.8 +/- 1.5 years). The 3D image viewing time was set at 90 min for adults and 60 min for children, and the visual function was objectively evaluated using an accommodative microfluctuation analysis system both before and after 3D image viewing. In addition, subjective symptoms were surveyed employing a questionnaire both before and after viewing in the adult group to subjectively evaluate the visual function. RESULTS: No significant difference was noted in accommodative microfluctuation between the before and after viewing in either the adult or child group, nor was there a significant difference in subjective symptoms in the adult group based on the questionnaire. However, accommodative microfluctuation tended to increase after viewing in some subjects. CONCLUSIONS: Under the conditions of this study, 3D image viewing did not influence visual function, or only very slightly influenced it, if at all, but there are many unknown problems, requiring further surveys using 3D image viewing. PMID- 21538005 TI - Characteristics of age-related macular degeneration in patients with diabetic retinopathy. AB - PURPOSE: The purpose of this study was to determine the clinical characteristics of age-related macular degeneration (AMD) in patients with diabetic retinopathy (DR). METHODS: Retrospective, consecutive case series. Twenty-six eyes of 25 Japanese patients were studied. All patients were diagnosed as having exudative AMD with DR. Patients with no apparent DR, dry AMD, neovascular maculopathy associated with high myopia, and age <50 years were excluded. The clinical characteristics of AMD in patients with DR, e.g., gender, age, stage of DR, and type of AMD were evaluated. RESULTS: In the 26 eyes, 2 eyes (7.7%) were classified as mild nonproliferative DR (NPDR), 7 (27.0%) with moderate NPDR, 16 (61.5%) with severe NPDR and 1 eye (3.8%) with PDR. Of the 26 eyes with exudative AMD, 21 eyes (80.8%) were classified as neovascular AMD, 4 (15.4%) as polypoidal choroidal vasculopathy and 1 eye (3.8%) as a retinal angiomatous proliferation. Among the eyes with neovascular AMD, 9 eyes (42.9%) were classified as predominantly classic choroidal neovascularization (CNV). CONCLUSIONS: There is a predominance of men, neovascular AMD and predominantly classic CNV in Japanese AMD patients with DR. The exudative AMD in patients with DR may have different clinical characteristics from those without DR. PMID- 21538006 TI - Self-reported oral hygiene habits and periodontal symptoms among postpartum women. AB - PURPOSE: The purpose of this study is to describe oral hygiene practices and periodontal symptoms among postpartum women and to assess whether self-reported periodontal symptoms are correlated with a clinical diagnosis of periodontal disease. METHODS: A self-administered questionnaire was developed to assess socio demographic information, oral hygiene habits and frequency of dental visits among a group of 409 postpartum women. Additional questions included information on self-reported periodontal symptoms. Pregnancy information was obtained from medical charts. RESULTS: 99.3% of the participants brushed their teeth every day; 46.2 and 53.8% reported teeth brushing once a day or more, respectively. Periodontal disease was present in 61.4% of women. Patients with gum swelling and tooth mobility were almost twice as likely to have a periodontal disease (OR 1.7, CI 95% 0.9-2.8 and OR 1.7, CI 95%: 0.8-3.5, respectively). No associations were found between periodontal disease, gum swelling PTB and/or LBW. CONCLUSIONS: Maternal clinical periodontal disease at delivery was related with self-perceived gum swelling and tooth mobility. Dentists and prenatal medical care providers may have the opportunity to target pregnant women that might be at higher risk for periodontal disease by asking whether they have tooth mobility and/or swollen gums. PMID- 21538007 TI - Combination of biochemical markers in predicting pre-term delivery. AB - PURPOSE: The aim of this study was to evaluate the predictive performances of some biochemical markers in predicting pre-term delivery in asymptomatic women. METHODS: We included 491 asymptomatic women at 24 weeks' gestation, who underwent the endocervical phosphorylated insulin-like growth factor binding protein (phIGFBP-1) test, cervico-vaginal interleukins 6 (IL-6) and 8 (IL-8), and serum C reactive protein (CRP). A receiver-operating characteristics (ROC) curve was used to determine the most useful cut off point. A multivariate logistic regression model was used in order to analyze the combination of significant predictive variables for pre-term delivery following univariate analysis. RESULTS: ROC curves indicated that 33 MUg/l was the optimal cut off value for phIGFBP-1 test, 21.3 ng/l for IL-6, 324 ng/l for IL-8, and 8.42 mg/l for CRP in predicting pre term delivery. The univariate logistic regression analyses revealed an odds ratio of 3.04 for phIGFBP-1 test, 4.82 for IL-6, and 3.08 for CRP. The multivariate analysis of phIGFBP-1 test, IL-6, and CRP showed that they were independent variables and therefore useful in combination for predicting pre-term delivery. CONCLUSIONS: The phIGFBP-1 test, the cervico-vaginal IL-6, and the serum CRP are independent variables that can be used together to predict pre-term delivery in asymptomatic women. PMID- 21538008 TI - Lymphadenectomy as a prognostic marker in uterine non-endometrioid carcinoma. AB - INTRODUCTION: A pelvic lymphadenectomy with or without para-aortic lymphadenectomy is performed during surgery for endometrial cancer at least in high-risk patients for recurrence or progression. The question of whether pelvic and/or para-aortic lymphadenectomy improves survival rates of high-risk patients with uterine non-endometrioid carcinoma is still unclear. Therefore, the aim of this study was to evaluate the outcome of patients with uterine non-endometrioid cancer, with regard to the performance of a lymphadenectomy in a well characterized cohort population. MATERIALS AND METHODS: The prognostic value of a performed lymphadenectomy was examined in 55 patients with a histological diagnosis of a uterine non-endometrioid carcinoma. A performed lymphadenectomy was analyzed with respect to the surgical and pathological stage and characteristics. RESULTS: Of the 55 patients with an uterine non-endometrioid carcinoma, 38 (69.1%) and 2 (3.6%) patients were diagnosed in FIGO stage I and II, respectively, while 14 (25.5%) patients had FIGO stage III and 1 patient (1.8%) presented with metastatic disease (FIGO IV). 16 patients (29.1%) demonstrated a myometrial invasion of more than 50%, while a cervical and ovarian involvement could be observed in 7 (12.7%) and 9 (16.4%) cases, respectively. Pelvic and/or para-aortic lymph node sampling was performed for 42 patients (76.4%) while 7 patients (12.7%) demonstrated lymph node metastasis. Univariate survival analysis demonstrated no differences in progression-free survival, cause specific survival or overall survival for a performed lymphadenectomy. Regression analysis led to a model containing only the FIGO surgical stage as an independent term that was predictive of progression-free survival, cause-specific survival and overall survival. DISCUSSION: Although a performed lymphadenectomy did not have any positive benefit in the survival of patients with uterine non endometrioid carcinomas in this study, it might provide important prognostic information with a subsequent adjuvant treatment. However, these results remain to be confirmed in further larger and prospective studies. PMID- 21538009 TI - Presence of HPV DNA in placenta and cervix of pregnant Mexican women. AB - PURPOSE: To identify the presence of HPV DNA in cervical as well as in placental tissue of pregnant Mexican women and to determine which type is more frequent. METHODS: In a cross-sectional study, 56 placental samples were obtained from 72 pregnant women. HPV DNA was extracted and amplified with polymerase chain reaction using a consensus primer and then identified by type using RsaI endonuclease. The main outcome measures were placenta with/without HPV relation and HPV types in placenta. RESULTS: HPV DNA was identified in 75% of cervical tissue samples and 47.2% of placental tissue samples. Type 18 was the most frequently identified HPV type. CONCLUSIONS: There was a higher frequency of HPV DNA found in the cervix of Mexican women during pregnancy than reported in the previous studies. Its identification in full-term placental tissue has no relation to the type of delivery in childbirth. PMID- 21538010 TI - Ehlers Danlos Syndrome Type IV and pregnancy. AB - INTRODUCTION: A case report is presented of a 23-year-old patient who was diagnosed with Ehlers Danlos syndrome (EDS) Type IV (vascular type) in the 23rd week of her second pregnancy. EDS Type IV has one of the highest mortality rates for pregnant women of any condition with significant morbidity if the mother survives. DISCUSSION: Current literature is presented and supports the necessity for close monitoring of mother and child in a specialist unit with involvement of a multi-disciplinary team. There is no agreed consensus on the mode or timing of delivery but recent literature is supportive of delivery by caesarean section at 32 weeks. CONCLUSION: This case report demonstrates a successful outcome for both mother and child with a planned delivery at 34 weeks by caesarean section and emphasises the importance of strategic planning for complicated deliveries and the effectiveness of good communication networks. Patients with EDS Type IV should be counselled about the potential risks for both themselves and the child to enable them to make informed decisions about their obstetric care. PMID- 21538011 TI - BMMB: past and future. PMID- 21538012 TI - Role of collagen content and cross-linking in large pulmonary arterial stiffening after chronic hypoxia. AB - Chronic hypoxic pulmonary hypertension (HPH) is associated with large pulmonary artery (PA) stiffening, which is correlated with collagen accumulation. However, the mechanisms by which collagen contributes to PA stiffening remain largely unexplored. Moreover, HPH may alter mechanical properties other than stiffness, such as pulse damping capacity, which also affects ventricular workload but is rarely quantified. We hypothesized that collagen content and cross-linking differentially regulate the stiffness and damping capacity of large PAs during HPH progression. The hypothesis was tested with transgenic mice that synthesize collagen type I resistant to collagenase degradation (Col1a1(R/R)). These mice and littermate controls (Col1a1(+/+)) were exposed to hypoxia for 10 days; some were treated with beta-aminopropionitrile (BAPN), which prevents new cross-link formation. Isolated PA dynamic mechanical tests were performed, and collagen content and cross-linking were measured. In Col1a1(+/+) mice, HPH increased both collagen content and cross-linking, and BAPN treatment prevented these increases. Similar trends were observed in Col1a1(R/R) mice except that collagen content further increased with BAPN treatment. Mechanical tests showed that in Col1a1(+/+) mice, HPH increased PA stiffness and damping capacity, and these increases were impeded by BAPN treatment. In Col1a1(R/R) mice, HPH led to a smaller but significant increase in PA stiffness and a decrease in damping capacity. These mechanical changes were not affected by BAPN treatment. Vessel specific correlations for each strain showed that the stiffness and damping capacity were correlated with the total content rather than cross-linking of collagen. Our results suggest that collagen total content is critical to extralobar PA stiffening during HPH. PMID- 21538013 TI - The management of patients with primary chronic anal fissure: a position paper. AB - Anal fissure is one of the most common and painful proctologic diseases. Its treatment has long been discussed and several different therapeutic options have been proposed. In the last decades, the understanding of its pathophysiology has led to a progressive reduction of invasive and potentially invalidating treatments in favor of conservative treatment based on anal sphincter muscle relaxation. Despite some systematic reviews and an American position statement, there is ongoing debate about the best treatment for anal fissure. This review is aimed at identifying the best treatment option drawing on evidence-based medicine and on the expert advice of 6 colorectal surgeons with extensive experience in this field in order to produce an Italian position statement for anal fissures. While there is little chance of a cure with conservative behavioral therapy, medical treatment with calcium channel blockers, diltiazem and nifepidine or glyceryl trinitrate, had a considerable success rate ranging from 50 to 90%. Use of 0.4% glyceryl trinitrate in standardized fashion seems to have the best results despite a higher percentage of headache, while the use of botulinum toxin had inconsistent results. Nonresponding patients should undergo lateral internal sphincterotomy. The risk of incontinence after this procedure seems to have been overemphasized in the past. Only a carefully selected group of patients, without anal hypertonia, could benefit from anoplasty. PMID- 21538014 TI - The relationship between etiology, symptom severity and indications of surgery in cases of anal incontinence: a 25-year analysis of 1,046 patients at a tertiary coloproctology practice. AB - BACKGROUND: The etiology of anal incontinence (AI) is often multifactorial. There is little data on the relationship between the etiology of AI, symptom severity, and the need for surgery. The aim of our study was to investigate this association in a large number of unselected patients with AI referred to a tertiary specialist coloproctological practice. METHODS: Patients with AI seen at our unit between 1983 and 2008 were analyzed. The main etiologies were categorized as congenital, traumatic, neurologic, idiopathic, post-operative, post-obstetric, secondary to rectal prolapse, or inflammatory bowel disease. The severity of AI was graded using the validated Pescatori incontinence scale. RESULTS: Overall, 1,046 patients were studied. The AI score was higher in patients with congenital (4.7 +/- 1.1), traumatic (4.6 +/- 1.4), and neurological (4.4 +/- 1.2) incontinence. Surgical treatment was indicated in 214 cases (20.5%). Patients with AI related to trauma and congenital anomalies required surgery in 43.5 and 31.4% of cases, respectively, a percentage significantly higher than that for patients with other etiologies (P = 0.002). Prolapse-related AI usually responded to correction of the prolapse. CONCLUSIONS: Patients with congenital, traumatic, and neurological AI tend to have greater symptom severity. Traumatic, rectal prolapse-related, and congenital AI cases more often require surgery. PMID- 21538015 TI - Modeling lipid accumulation in oleaginous fungi in chemostat cultures: I. Development and validation of a chemostat model for Umbelopsis isabellina. AB - Lipid-accumulating fungi may be able to produce biodiesel precursors from agricultural wastes. As a first step in understanding and evaluating their potential, a mathematical model was developed to describe growth, lipid accumulation and substrate consumption of the oleaginous fungus Umbelopsis isabellina (also known as Mortierella isabellina) in submerged chemostat cultures. Key points of the model are: (1) if the C-source supply rate is limited, maintenance has a higher priority than growth, which has a higher priority than lipid production; (2) the maximum specific lipid production rate of the fungus is independent of the actual specific growth rate. Model parameters were obtained from chemostat cultures of U. isabellina grown on mineral media with glucose and NH(4) (+). The model describes the results of chemostat cultures well for D > 0.04 h(-1), but it has not been validated for lower dilution rates because of practical problems with the filamentous fungus. Further validation using literature data for oleaginous yeasts is described in part II of this paper. Our model shows that not only the C/N-ratio of the feed, but also the dilution rate highly influences the lipid yield in chemostat cultures. PMID- 21538016 TI - Disease-specific knowledge, coping, and adherence in patients with inflammatory bowel disease. AB - BACKGROUND: Little is known about the effects of disease-related education and knowledge in individuals with inflammatory bowel disease (IBD). The limited available research on this topic suggests there may be potential benefits to disease-related patient education. We hypothesized that individuals with greater IBD knowledge would have more coping strategies and higher medication adherence. METHODS: A total of 111 adults with IBD residing in the United States were recruited online by convenience sampling from IBD support group forums. IBD knowledge, coping, and medication adherence were assessed using standardized questionnaires. Data on seventeen clinico-demographic variables were also collected. A Pearson correlation was conducted to examine the relationship between IBD knowledge and use of coping strategies and also between IBD knowledge and medication adherence. Multivariate regression and one-way ANOVA tests were used to assess the continuous and categorical clinico-demographic variables, respectively, for potential confounding. RESULTS: A significant positive association was found between greater IBD knowledge and active coping scores (r = 0.189, P = 0.024), instrumental support scores (r = 0.160, P = 0.047), planning scores (r = 0.159, P = 0.048), and emotional support scores (r = 0.159, P = 0.048). A relationship between knowledge and adherence score was not found. Significant relationships were found between four clinico-demographic variables and coping. CONCLUSION: Greater IBD knowledge appears to be associated with the use of more adaptive coping strategies in patients with IBD, suggesting that providing disease-related patient education may enhance coping in this population. Future studies should explore the utility of formal disease-related patient education in improving these and other outcomes. PMID- 21538017 TI - Evaluation of modified Estimation of Physiologic Ability and Surgical Stress in gastric carcinoma surgery. AB - BACKGROUND: We recently modified our prediction scoring system "Estimation of Physiologic Ability and Surgical Stress" and have designated the current version mE-PASS. This scoring system has been designed to obtain predicted postoperative mortality rates before surgery and this study was performed to assess its usefulness in elective surgery for gastric carcinoma. METHODS: We investigated seven variables for mE-PASS and evaluated the postoperative course in 3,449 patients who underwent elective surgery for gastric carcinoma in Japan between August 20, 1987 and April 9, 2007, in order to quantify the predicted in-hospital mortality rates (R). The calibration and discrimination power of R were assessed using the Hosmer-Lemeshow test and the area under the receiver operating characteristic curve (AUC), respectively. The ratios of observed-to-estimated mortality rates (OE ratios) were quantified as a measure of quality. RESULTS: The overall postoperative morbidity and mortality rates were 19.0 and 2.0%, respectively. R demonstrated good power in calibration (chi(2) value, 12.5; df 8; P = 0.89) as well as discrimination (AUC, 95% confidence intervals: 0.80, 0.75 0.85). The OE ratios between hospitals ranged from 0.44 to 1.8. Overall, the OE ratios seemed to improve with time (OE ratio, 95% confidence intervals: 1.3, 0.73 2.4 for the early period between 1987 and 2000; 1.0, 0.59-1.7 for the middle period between 2001 and 2004; and 0.65, 0.36-1.2 for the late period between 2005 and 2007). CONCLUSION: Based on these findings, mE-PASS might be useful for medical decision-making and for assessing the quality of care in elective surgery for gastric carcinoma. PMID- 21538018 TI - A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer. AB - BACKGROUND: Accumulating evidence suggests that the tumor suppressor gene Kruppel like factor 6 (KLF6) and its dominant-negative splice form KLF6-SV1 play important roles in both the development and progression of cancer. However, the role of KLF6-SV1 in gastric cancer remains largely unknown. METHODS: KLF6-SV1 expression was detected in various human gastric cancer cell lines and gastric cancer patient samples by reverse transcriptase polymerase chain reaction (RT PCR) and Western blotting. Small interfering RNA (siRNA) was used to inhibit KLF6 SV1 expression in BGC-823 and SGC-7901 cell lines. The effects of downregulation of KLF6-SV1 by siRNA on cell proliferation, migration, invasion, and tumor growth were examined in vitro and in vivo. RESULTS: Overexpression of KLF6-SV1 was detected in tumor samples from gastric cancer patients, and in various differentiated gastric cancer cell lines. In vitro downregulation of KLF6-SV1 by siRNA inhibited BGC-823 and SGC-7901 cell proliferation, anchorage-independent growth, migration, and invasion through the altered expression of Ki-67, vascular endothelial growth factor (VEGF), E-cadherin, and matrix metalloproteinase (MMP) 9. Also, KLF6-SV1 silencing promoted caspase-dependent apoptosis of BGC-823 and SGC-7901 cells via the regulation of phosphatidylinositol 3-OH kinase (PI3K)/Akt activity and Bcl-2-related protein expression. In vivo animal studies showed that KLF6-SV1 siRNA significantly inhibited the tumorigenicity of BGC-823 and SGC-7901 cells. Gene therapy with polyethylenimine/si-SV1 intratumoral injection also resulted in the suppression of tumor growth and prolonged animal survival in an established xenograft tumor model. CONCLUSION: These data demonstrate that KLF6 SV1 is an important regulator of the growth, migration, invasion, and survival of gastric cancer cells, and downregulation of KLF6-SV1 by siRNA may offer a new potential gene therapy approach for gastric cancer. PMID- 21538019 TI - Value of sentinel lymph node mapping using a blue dye-only method in gastric cancer: a single-center experience from North-East Hungary. AB - BACKGROUND: Forty percent of patients with gastric cancer have unnecessarily extended lymph node dissections with higher rates of morbidity and mortality than those in non-extended procedures. Successful sentinel lymph node (SLN) mapping may help to reduce the number of extended lymphadenectomies. METHODS: SLN mapping was investigated by a blue dye-only method in patients with gastric cancer. The first cohort of patients (n = 16) were marked submucosally by an endoscopist and in the second cohort of patients (n = 23) a subserosal injection was performed by the surgeon. RESULTS: Thirty-nine patients, all Caucasians, underwent gastric resection or total gastrectomy with SLN biopsy using patent blue-dye mapping and modified D2 lymphadenectomy. The mapping procedure and the lymphadenectomy were supervised by the same surgeon. A total of 770 lymph nodes were removed and examined. The mean number of blue nodes was 4.3 per patient. In 22/23 cases at least one SLN showed tumor involvement. The sensitivity of SLN mapping was 95.7%, the false-negative rate was 4.3%, and the specificity was 100%. The negative predictive value was 93.8% and the positive predictive value was 100%. In cases of T1 and T2 tumors the sensitivity was 100%. We found the two marking methods (submucosal vs. subserosal) to be equivalent and there was no side-effect of the blue-dye mapping. CONCLUSIONS: Our results suggest that SLN mapping with blue dye alone represents a safe procedure that seems to be adaptable for non-obese patients undergoing open surgery for gastric cancer in the Eastern European region. The procedure has high sensitivity and specificity, especially in cases of T1 and T2 tumors. PMID- 21538020 TI - ENU-induced missense mutation in the C-propeptide coding region of Col2a1 creates a mouse model of platyspondylic lethal skeletal dysplasia, Torrance type. AB - The COL2A1 gene encodes the alpha1(II) chain of the homotrimeric type II collagen, the most abundant protein in cartilage. In humans, COL2A1 mutations create many clinical phenotypes collectively termed type II collagenopathies; however, the genetic basis of the phenotypic diversity is not well elucidated. Therefore, animal models corresponding to multiple type II collagenopathies are required. In this study we identified a novel Col2a1 missense mutation- c.44406A>C (p.D1469A)--produced by large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis in a mouse line. This mutation was located in the C-propeptide coding region of Col2a1 and in the positions corresponding to a human COL2A1 mutation responsible for platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T). The phenotype was inherited as a semidominant trait. The heterozygotes were mildly but significantly smaller than wild-type mice. The homozygotes exhibited lethal skeletal dysplasias, including extremely short limbs, severe spondylar dysplasia, severe pelvic hypoplasia, and brachydactyly. As expected, these skeletal defects in the homozygotes were similar to those in PLSD-T patients. The secretion of the mutant proteins into the extracellular space was disrupted, accompanied by abnormally expanded rough endoplasmic reticulum (ER) and upregulation of ER stress-related genes, such as Grp94 and Chop, in chondrocytes. These findings suggested that the accumulation of mutant type II collagen in the ER and subsequent induction of ER stress are involved, at least in part in the PLSD-T-like phenotypes of the mutants. This mutant should serve as a good model for studying PLSD-T pathogenesis and the mechanisms that create the great diversity of type II collagenopathies. PMID- 21538021 TI - Surveillance of patients affected by Peutz-Jeghers syndrome: diagnostic value of MR enterography in prone and supine position. AB - INTRODUCTION: Peutz-Jeghers syndrome (PJS) is a familial polyposis syndrome characterized by multiple hamartomatous polyps throughout the gastrointestinal tract. The aim of our study was to retrospectively determine the diagnostic value of MR enterography (MRE), performed in supine and prone position, in the detection of small bowel polyps in PJ patients. MATERIALS AND METHODS: We retrospectively reviewed MRE examinations of 8 PJS patients who underwent MRE, pushed-double-ballon enteroscopy, laparoscopic endoscopy or surgery, within 3 months. Polietilenglicole was orally administered before the examination. True FISP and HASTE sequences were acquired in supine and prone position; 3D VIBE Gd enhanced sequences in prone position only. RESULTS: Concordance between MRE and endoscopy was 72.6% for polyps <15 mm, 93% for polyps >15 mm. In supine and prone position concordance with endoscopy for polyps <15 mm was 63% and 66.8%, respectively. In the detection of smaller polyps the difference between supine position only and supine plus prone position was statistically significant (P < 0.027). DISCUSSION: MRE performed by combining prone and supine position was accurate in the detection of PJS polyps, with 93% concordance with enteroscopy for larger and more risky polyps. MRE offers a promising and non invasive alternative to capsule endoscopy, suggesting the possibility of an effective yearly surveillance in PJ patients. PMID- 21538022 TI - Does the left superior longitudinal fascicle subserve language semantics? A brain electrostimulation study. AB - Recent diffusion tensor imaging (DTI) tractography studies indicate that the supramarginal gyrus (SMG) represents a relay between frontal and temporal language sites. Some authors postulate that pathways connecting SMG to the posterior temporal lobe, i.e., the posterior part of the superior longitudinal fascicle (SLF) subserve semantic aspects of language. However, DTI provides only anatomic but not functional data. Therefore, it is impossible to conclude. Interestingly, intra-operative electrical mapping of cortical and subcortical language structures during tumor surgery is recognized as a reliable technique in functional neuroanatomy research. We mapped the underlying white matter of the SMG, especially the SLF, in 11 patients who underwent awake surgery for a glioma involving the left inferior parietal lobule. Using direct electrostimulation, we investigated the exact role of the SLF in language. Our findings indicate that the white matter under the inferior parietal lobule is highly involved in the dorsal phonological system. First, the SMG, connected to the ventral premotor cortex by horizontal fibers of the SLF, subserves articulatory processing, as demonstrated by dysarthria elicited by stimulation. Second, long arcuate fibers, found deeper in the white matter, subserve phonological processing, as supported by phonemic paraphasia induced by electrostimulation. Third, the most important result is that no semantic disturbances were elicited by stimulating the SLF, including its posterior part. Furthermore, no semantic disorders occurred postoperatively. Subcortical brain mapping by direct electrical stimulation does not provide arguments for a possible role of the left SLF in language semantic processing. PMID- 21538023 TI - Concept mapping with South Asian immigrant women: barriers to mammography and solutions. AB - Despite benefits of screening mammography, many South Asian (SA) immigrant women in Canada remain under screened. We aimed to elicit their experiences and beliefs about barriers to mammography and possible solutions. SA immigrant women aged 50 years or over were eligible if they never had a mammogram or had one more than 3 years ago. We employed the participatory mixed-method approach of Concept Mapping. Sixty women participated with a mean age of 58 years. Participants brainstormed 150 items which were consolidated into 67 items. After sorting and rating, cluster analysis revealed eight clusters of barriers on knowledge, fear, language and transportation, access to mammogram center, access to doctor, beliefs and practices, self-care, and family dependence. Participants discussed possible solutions, and emphasized out-reach models to address knowledge gaps and issues of language and transportation. One example was a community-based shuttle bus to screening centres, hosted by trained co-ethnic workers. The results are discussed to enhance the socio-cultural sensitivity of breast screening programs. PMID- 21538024 TI - The survivin -31 snp in human colorectal cancer correlates with survivin splice variant expression and improved overall survival. AB - BACKGROUND: Survivin is involved in the regulation of cell division and survival, two key processes in cancer. The majority of studies on survivin in colorectal cancer (CRC) have focused on protein expression and less is known about the expression of survivin splicing variants or survivin gene polymorphisms in CRC. In the present study, the mRNA levels of the five known isoforms of survivin as well as survivin protein were assessed in matched normal and neoplastic colorectal tissue. Moreover, the 9386 C/T and -31 G/C polymorphisms were investigated. METHODS: Quantitative RT-PCR was used to assess mRNA levels in fresh/frozen tissue samples. Protein levels were immunohistochemically evaluated on formalin-fixed paraffin-embedded tissue sections. Individuals were genotyped using real time PCR. RESULTS: Expression of all 5 survivin splice variants as well as survivin protein was elevated in colorectal carcinomas compared to normal tissue. Specific splice variant expression differentially correlated with clinicopathological parameters. Furthermore, both snps correlated with splice variant levels or their ratios in colorectal carcinomas while the -31 G/C snp may be related to CRC development and improved overall survival. CONCLUSION: Our results support a role of survivin in colorectal carcinogenesis while the -31 G/C snp may constitute a marker of survival. PMID- 21538025 TI - Rapid quantification of myocardial fibrosis: a new macro-based automated analysis. AB - BACKGROUND: Fibrosis is associated with various cardiac pathologies and dysfunction. Current quantification methods are time-consuming and laborious. We describe a semi-automated quantification technique for myocardial fibrosis and validated this using traditional methods. METHODS: Pulmonary Hypertension (PH) was induced in adult Wistar rats by subcutaneous monocrotaline (MCT) injection(40 mg/kg). Cryosections of myocardial tissue (5 MUm) of PH rats (n = 9) and controls (n = 9) were stained using Picrosirius red and scanned with a digital microscopic MIRAX slide scanner. From these sections 21 images were taken randomly of each heart. Using ImageJ software a macro for automated image analysis of the amount of fibrosis was developed. For comparison, fibrosis was quantified using traditional polarisation microscopy. Both methods were correlated and validated against stereology as the gold standard. Furthermore, the method was tested in paraffin-embedded human tissues. RESULTS: Automated analysis showed a significant increase of fibrosis in PH hearts vs. control. Automated analysis correlated with traditional polarisation and stereology analysis (r(2) = 0.92 and r(2) = 0.95 respectively). In human heart, lungs, kidney, and liver, a similar correlation with stereology (r(2) = 0.91) was observed. Time required for automated analysis was 22% and 33% of the time needed for stereology and polarisation analysis respectively. CONCLUSION: Automated quantification of fibrosis is feasible, objective, and time-efficient. PMID- 21538026 TI - Glioblastomas with oligodendroglial component-common origin of the different histological parts and genetic subclassification. AB - BACKGROUND: Glioblastomas are the most common and most malignant brain tumors in adults. A small subgroup of glioblastomas contains areas with histological features of oligodendroglial differentiation (GBMO). Our objective was to genetically characterize the oligodendroglial and the astrocytic parts of GBMOs and correlate morphologic and genetic features with clinical data. METHODS: The oligodendroglial and the "classic" glioblastoma parts of 13 GBMO were analyzed separately by interphase fluoreszence in situ hybridization (FISH) on paraffin sections using a custom probe set (regions 1p, 1q, 7q, 10q, 17p, 19q, cen18, 21q) and by comparative genomic hybridization (CGH) of microdissected paraffin embedded tumor tissue. RESULTS: We identified four distinct genetic subtypes in 13 GBMOs: an "astrocytic" subtype (9/13) characterized by +7/-10; an "oligodendroglial" subtype with -1p/-19q (1/13); an "intermediate" subtype showing +7/-1p (1/13), and an "other" subtype having none of the former aberrations typical for gliomas (2/13). The different histological tumor parts of GBMO revealed common genetic changes in all tumors and showed additional aberrations specific for each part. CONCLUSION: Our findings demonstrate the monoclonal origin of GBMO followed by the development of the astrocytic and oligodendroglial components. The diagnostic determination of the genetic signatures may allow for a better prognostication of the patients. PMID- 21538027 TI - Inhibition of IGF-1R-dependent PI3K activation sensitizes colon cancer cells specifically to DR5-mediated apoptosis but not to rhTRAIL. AB - BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) initiates apoptosis in tumor cells upon binding to its cognate agonistic receptors, death receptors 4 and 5 (DR4 and DR5). The activity of the insulin like growth factor 1 (IGF-1) survival pathway is often increased in cancer, influencing both cell proliferation and apoptosis. We hypothesized that inhibiting the IGF-1 receptor (IGF-1R) using NVP-AEW541, a small molecular weight tyrosine kinase inhibitor of the IGF-1R, could increase death receptor (DR) mediated apoptosis in colon cancer cells. METHODS: The analyses were performed by caspase assay, flow cytometry, Western blotting, immunoprecipitation and fluorescent microscopy. RESULTS: Preincubation with NVP-AEW541 surprisingly decreased apoptosis induced by recombinant human TRAIL (rhTRAIL) or an agonistic DR4 antibody while sensitivity to an agonistic DR5 antibody was increased. NVP AEW541 could inhibit IGF-1-induced activation of the phosphatidylinositol 3 kinase (PI3K) pathway. The effects of the PI3K inhibitor LY294002 on TRAIL induced apoptosis were similar to those of NVP-AEW541, further supporting a role for IGF-1R-mediated activation of PI3K. We show that PI3K inhibition enhances DR5 mediated caspase 8 processing but also lowers DR4 membrane expression and DR4 mediated caspase 8 processing. Inhibition of PI3K reduced rhTRAIL sensitivity independently of the cell line preference for either DR4- or DR5-mediated apoptosis signaling. CONCLUSIONS: Our study indicates that individual effects on DR4 and DR5 apoptosis signaling should be taken into consideration when combining DR-ligands with PI3K inhibition. PMID- 21538028 TI - EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1. AB - BACKGROUND: Epstein-Barr virus (EBV)-associated gastric carcinomas (GC) constitute a distinct clinicopathological entity of gastric cancer. In order to determine underlying distinct aberrant promoter methylation we tested cardiac and non-cardiac GC with regard to the presence of EBV. METHODS: One hundred GC were tested by RNA- in situ hybridization for the presence of EBV by EBV-encoded small RNA (EBER). Aberrant promoter methylation was investigated by methylation specific real-time PCR for p16, p14, APC and hMLH1. P16 protein expression was assessed by immunohistochemistry. RESULTS: In our selected study cohort, EBER transcripts were detected in 19.6% (18/92) of GC. EBV-positive GC revealed significantly more often gene hypermethylation of p16, p14 and APC (p < 0.0001, p < 0.0001, and p = 0.02, respectively) than EBV-negative GC. The majority of GC with p16 hypermethylation showed a p16 protein loss (22/28). In contrast, no correlation between the presence of EBV and hMLH1 hypermethylation was found (p = 0.7). EBV-positive GC showed a trend towards non-cardiac location (p = 0.06) and lower stages (I/II) according to the WHO (p = 0.05). CONCLUSIONS: Hypermethylation of tumor suppressor genes is significantly more frequent in EBV associated GC compared to EBV-negative GC. Our data add new insights to the role of EBV in gastric carcinogenesis and underline that EBV associated GC comprise a distinct molecular-pathologic as well as a distinct clinicopathological entity of GC. PMID- 21538029 TI - Efficacy of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan. AB - BACKGROUND: It is still not known which patients with chronic hepatitis C who failed to respond to previous pegylated interferon (Peg-IFN) plus ribavirin therapy can benefit from re-treatment. METHODS: Seventy-four patients (HCV genotype 1, n = 56, genotype 2, n = 18) were re-treated with Peg-IFN plus ribavirin. RESULTS: On re-treatment, the sustained virologic response (SVR) rate was 41% for genotype 1 and 56% for genotype 2. With genotype 1, the factors associated with an SVR were previous treatment response and the serum hepatitis C virus (HCV) RNA level at the start of re-treatment. Patients with a >= 2-log decrease in HCV RNA at week 12 (partial early virologic response, p-EVR) in previous treatment had significantly higher SVR rates than those without these decreases (p < 0.001); no patient without a p-EVR in the previous treatment attained an SVR with re-treatment (0/16). All patients with <5 log(10) IU/ml of HCV RNA at the start of re-treatment attained an SVR (6/6), while only 33% (15/45) of those patients with >= 5 log(10) IU/ml of HCV RNA attained an SVR (p < 0.01). Among the patients with relapse in the previous treatment, those who attained an SVR on re-treatment required a longer duration of re-treatment than the duration of the previous treatment (re-treatment, 63.8 +/- 13.0 weeks vs. previous treatment, 53.9 +/- 13.5 weeks, p = 0.01). CONCLUSIONS: Re-treatment of genotype 1 patients should be limited to patients with a p-EVR in the previous treatment and a low HCV RNA level at the start of re-treatment. In re-treatment with Peg-IFN plus ribavirin, longer treatment duration can contribute to increasing the anti-viral effect. PMID- 21538030 TI - Treatment of non-erosive reflux disease with a proton pump inhibitor in Chinese patients: a randomized controlled trial. AB - BACKGROUND: Evidence suggests that rates of gastroesophageal reflux disease are increasing in the Asia-Pacific region, where patients tend to have predominantly non-erosive reflux disease as opposed to erosive (reflux) esophagitis. At present, data for the responsiveness of non-erosive reflux disease to proton pump inhibition are scant. We aimed to study esomeprazole for the treatment of non erosive reflux disease in Chinese patients. METHODS: Patients with a clinical diagnosis of gastroesophageal reflux, and a locally validated reflux index, the Chinese GerdQ, of equal to or greater than 12 were recruited and randomized to receive esomeprazole 20 mg daily or placebo for 8 weeks. Reflux index scores, quality of life (SF-36), and the hospital anxiety and depression (HAD) scale and symptom relief were evaluated before, during, and after treatment. RESULTS: A total of 175 patients were randomized. Patients in the esomeprazole group (n = 85) demonstrated statistically significant reductions in their GerdQ index, from 19.45 to 15.37 and to 14.32 (p = 0.013, p = 0.005) at weeks 4 and 8, respectively. Compared to placebo at week 8, 57.1% of patients on esomeprazole found that their symptoms had resolved or were acceptable compared with 37.2% in the placebo group (p = 0.001). There were no statistically significant differences in overall quality-of-life measures or the HAD scale related to treatment. CONCLUSIONS: This study suggests that esomeprazole is efficacious in treating Chinese patients with non-erosive reflux disease. PMID- 21538031 TI - Late-life anxiety disorders: a review. AB - Anxiety disorders are a major clinical problem in late life; estimated prevalence rates vary from 6% to 10%, and the disease impact is considerable and equal to that of depression. However, anxiety disorders often remain undetected and untreated in older adults. This discrepancy may be accounted for by a combination of patient variables (eg, a lack of help-seeking behavior and long duration of illness) and variables related to current clinical practice (eg, a lack of knowledge regarding late-life anxiety and ageism). Because anxiety disorders usually have an age at onset earlier in life, patients and mental health professionals may be inclined to attribute the anxiety and avoidance symptoms to personality factors instead of a treatable syndrome. Comorbidity with other psychiatric disorders, such as depressive disorder, may complicate the appropriate diagnosis. Identification may be further obscured because the phenomenology of anxiety disorders in older adults tends to differ from the phenomenology in younger adults. Randomized controlled trials have yielded support for the effectiveness of cognitive-behavioral therapy and serotonergic antidepressants. However, both treatments seem hampered by relatively high dropout rates, and the available data are based primarily on a relatively healthy, well-educated, and "young" older population. The dissemination of knowledge regarding late-life anxiety disorders is vital, as evidence-based treatments are available but are still rarely implemented. PMID- 21538032 TI - Perceived ugliness: an update on treatment-relevant aspects of body dysmorphic disorder. AB - Despite increased awareness of body dysmorphic disorder (BDD) during the past two decades, it is still a relatively unknown and understudied disorder. Its hallmark is a preoccupation with perceived defects or flaws in one's own appearance, often tied to the face (eg, nose, skin). BDD sufferers often think about their appearance "flaws" for up to several hours daily and frequently engage in ritualistic behaviors such as mirror checking, hair combing, comparing, asking for reassurance, makeup application, or skin picking. Furthermore, avoidance behaviors such as mirror avoidance or the avoidance of social activities are also common. In this paper, we provide an overview of BDD's unique symptomatology, its prevalence, and the comorbidities associated with it. A further aim is to provide an overview of effective treatments and possible obstacles and barriers to seeking or adhering to appropriate mental health care. PMID- 21538033 TI - Selective mutism: an update and suggestions for future research. AB - Speculation continues regarding the accurate classification of selective mutism and potential etiologic factors. Current research has shed some light on several factors that may predispose some children to this disorder, but conclusions are difficult to draw due to reliance on subjective measures, few comparison groups, and/or limited theoretical grounding. This article provides an update on recent efforts to elucidate the etiologic pathways of selective mutism and on the current debate regarding its strong overlap with anxiety disorders, most notably social phobia. An additional attempt is made to examine findings based on a developmental perspective that accounts for multiple pathways, context, and the developmental stage of the child. Emotion regulation theory is offered as a potential factor in why some children may be more vulnerable to the etiologic factors described. Suggestions for future research are offered based on this integration of information. PMID- 21538034 TI - Awareness and knowledge of child abuse amongst physicians - a descriptive study by a sample of rural Austria. AB - This study with a selected sample of physicians was conducted to assess their awareness and knowledge of child abuse. Two thirds (66.7%) of all participants confirmed contact with obviously abused children in the course of their professional life, whereas 87.3% did not report any prior education or training in that field. In relation to general practitioners, pediatricians had significantly more contacts with abused children (p = 0.021) and more prior education (p = 0.012). Results indicate that physicians in rural regions of Austria possess basic knowledge. Better training and further specialization is needed to facilitate diagnosing, enhance reporting, strengthen cooperation with experts and reduce fears when handling abuse victims. Austria is a rich country with excellent health care and competitive research structures. However, child abuse research in Austria still has to fill gaps in order to keep up with international developments. PMID- 21538035 TI - Recruitment of patients with type 2 diabetes for target group specific exercise programs at an Outpatient Department of a Medical University: A factor analysis. AB - We aimed to evaluate if an outpatient department is a suitable place to recruit people who suffer from Diabetes Mellitus for exercise programs. Therefore, a survey was conducted at the outpatient department of Endocrinology and Metabolism of the Medical University of Vienna. All in all, 104 persons (44 women, 60 men; age: 62.38 +/- 13.69 years) were included in the study. We evaluated their interest in exercise programs, which consisted of cardiovascular exercise, strength- and flexibility-training and were offered in the 10th and 13th districts of Vienna. Almost half of the interviewed patients (43%) were interested in exercise programs and eventually almost one quarter (23%) participated in the program. Crucial factors were young age (p = 0.034) and a good economic situation (p = 0.046), which positively affected the participation in the exercise program. We could also detect gender-specific health awareness, as more women than men were interested and finally took part in the courses (3 of 10 women vs. 1 of 10 men, p = 0.023). Our results show that an outpatient department is a suitable place to recruit diabetic patients for exercise programs. However, the limited number of high-quality exercise programs might have decreased the number of participants, as the courses were only offered in two districts. Due to that, the majority of the interviewed persons could not be offered these programs in the vicinity of their places of residence. To promote health awareness and to cover the demand of exercise courses, more high-quality facilities and more focused health care provider services are needed. PMID- 21538036 TI - Perioperative and follow-up results in chronic pancreatitis patients after pancreatic resection. AB - BACKGROUND/AIM: Surgical therapy for chronic pancreatitis is reserved for patients with intractable abdominal pain, complications of the disease, or suspected underlying carcinoma. Pancreatic resection can be performed safety with good postoperative results. METHODS: Between January 1996 and December 2009, the findings for 90 consecutive patients suffering from chronic pancreatitis were analyzed in prospective trial. Short-term results - postoperative complications were investigated 30 days after surgery. Long-term follow-up results, including quality of life (QoL) assessment using visual analog scale of pain (VAS), Karnofsky performance scale (KPS), and EORTC Quality of Life Questionnaire (QoL C30) were carried out. The influence of postoperative complications on long-term quality of life was documented. RESULTS: The overall mortality rate and morbidity rate were 3.3% (3 patients) and 27.7% (25 patients), respectively. Surgically related morbidity rate was 21.1% (19 patients). Long-term follow-up was investigated in 65 patients (72%). The median pain score decreased using VAS from 8 to 1 and using KPS increased from 50 to 100 (p < 0.0001). During the follow-up, the median global QoL improved by 100%. Apart from the cognitive functioning, the physical status, working ability, and emotional and social functioning all improved significantly (p < 0.0001). The presence of postoperative complications had no significant influence on long-term quality of life. CONCLUSION: Surgery for patients with chronic pancreatitis can be performed safely with minimal morbidity and very good long-term results. PMID- 21538037 TI - Significance of herpesvirus 6 in BAL fluid of hematology patients with acute respiratory failure. AB - PURPOSE: Human herpesvirus 6 (HHV6) is an emerging cause of interstitial pneumonia in immunocompromised hosts. However, the clinical significance of a positive PCR test for HHV6 in respiratory samples from patients with hematological malignancies remains unclear. METHODS: We retrospectively studied the features and outcomes of 29 critically ill hematology patients with acute respiratory failure and lung pulmonary infiltrates visible on a chest radiograph, who tested positive for a qualitative PCR for HHV6 in bronchoalveolar lavage fluid. RESULTS: Of the 29 patients, 18 (62%) were stem cell transplant recipients and 11 (38%) had received chemotherapy. All patients had a fever. Clinical manifestations consistent with extra-pulmonary HHV6 disease were noted in 17 (59%) patients. One or more co-pathogens were found in 25 (86%) patients. The four remaining patients diagnosed with HHV6 pneumonia and subsequently recovered with foscarnet therapy. Antiviral therapy was also given to seven patients with co-infections, of whom two ultimately died. CONCLUSIONS: In most cases, HHV6 recovered from BAL fluid is a co-pathogen whose clinical relevance remains undetermined. However, in some cases, HHV6 is the only pathogen, along with disseminated systemic viral disease, and the patient is likely to benefit from foscarnet therapy. PMID- 21538038 TI - Seronegative visceral leishmaniasis with relapsing and fatal course following rituximab treatment. AB - Both the presentation and clinical course of visceral leishmaniasis (VL) may be atypical in immunosuppressed subjects, often resulting in delayed diagnosis and treatment. We describe a case of VL characterized by negative serologic testing, a relapsing course, and a fatal outcome 2 years after the patient had been successfully treated for non-Hodgkin's lymphoma with rituximab. Diagnosis of VL may be further delayed or even missed in patients treated with drugs that interfere with specific antibody production unless specific diagnostic methods, such as bone marrow examination and parasite DNA amplification/detection, are routinely employed. PMID- 21538039 TI - Palliative care and end-of-life issues in patients treated with left ventricular assist devices as destination therapy. AB - Left ventricular assist devices as destination therapy (DT) improve quality of life for many patients with advanced heart failure. However, DT can be associated with risks such as infection, bleeding, and stroke, and may impose psychosocial strain on patients and caregivers. Furthermore, patients treated with DT eventually will die with their device in place whether death is related to the device or not. In response to these concerns, palliative medicine consultation has been suggested with standard DT care to improve focus on quality of life, symptom management, and end-of-life planning. This article reviews key issues associated with caring for patients with DT, including psychosocial, quality-of life, caregiving, and ethical issues, and discusses end-of-life management of patients with DT, including practical considerations, but moreover, review topics regarding communication, symptom management, and provision of appropriate comfort care. PMID- 21538040 TI - Neuroradiological viewpoint on the diagnostics of space-occupying brain lesions. AB - Conventional magnetic resonance (MR) imaging of space-occupying lesions may answer most of the questions concerning the diagnosis and subsequent treatment strategies if patient age, clinical and paraclinical findings are considered as well. However, crucial and relevant differential diagnoses require additional MR methods, such as diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI) and magnetic resonance spectroscopy (MRS). In necrotic ring-enhancing lesions DWI may detect inflammatory processes, whereas characteristics of the peritumoral area may help to distinguish between metastases and glioblastomas. In solid tumors DWI, PWI and MRS may also aid the differentiation between low-grade gliomas and malignant tumors, such as gliomas WHO (World Health Organization) grade III and IV and lymphomas. This review briefly explains special MR methods with respect to brain tumors and illustrates the diagnostic pathways necessary for supplying a reliable diagnosis as well as optimal pre-operative imaging of space-occupying brain lesions. PMID- 21538041 TI - Can we overcome the effect of conflicts in rendering palliative care? An introduction to the Middle Eastern Cancer Consortium (MECC). AB - The Middle East has been experiencing an ongoing political conflict for the past several decades. This situation has been characterized by hostility often leading to violence of all sources. At times, such a conflict led to the outbreak of a military war, which was followed by an enmity between religious, ethnic, cultural, and national populations. In such environmental situations, palliative care professionals often confront major challenges including bias, mistrust, and mutual suspicion between patients and their treating clinicians. In order to overcome such obstacles, while rendering palliative care services, all professionals involved need careful planning and execution of their treatment plans. The latter is however possible, and sometimes successful even across lines of conflict, thereby promoting understanding, mutual respect, and tolerance between the involved communities and individuals. PMID- 21538042 TI - Chlamydia trachomatis infection during pregnancy associated with preterm delivery: a population-based prospective cohort study. AB - Chlamydia trachomatis infection is the most prevalent bacterial sexually transmitted infection and may influence pregnancy outcome. This study was conducted to assess the effect of chlamydial infection during pregnancy on premature delivery and birthweight. Pregnant women attending a participating midwifery practice or antenatal clinic between February 2003 and January 2005 were eligible for the study. From 4,055 women self-administered questionnaires and urine samples, tested by PCR, were analysed for C. trachomatis infection. Pregnancy outcomes were obtained from midwives and hospital registries. Gestational ages and birthweights were analysed for 3,913 newborns. The C. trachomatis prevalence was 3.9%, but varied by age and socio-economic background. Chlamydial infection was, after adjustment for potential confounders, associated with preterm delivery before 32 weeks (OR 4.35 [95% CI 1.3, 15.2]) and 35 weeks gestation (OR 2.66 [95% CI 1.1, 6.5]), but not with low birthweight. Of all deliveries before 32 weeks and 35 weeks gestation 14.9% [95% CI 4.5, 39.5] and 7.4% [95% CI 2.5, 20.1] was attributable to C. trachomatis infection. Chlamydia trachomatis infection contributes significantly to early premature delivery and should be considered a public health problem, especially in young women and others at increased risk of C. trachomatis infection. PMID- 21538043 TI - Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. AB - Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and arthritis (CINCA) syndrome is the most severe clinical phenotype in the spectrum of cryopyrin- (NLRP3/NALP3) associated periodic syndromes (CAPS). The study of patients with NOMID/CINCA has been instrumental in characterizing the extent of organ-specific inflammatory manifestations and damage that can occur with chronic interleukin (IL)-1beta overproduction. Mutations in CIAS1/NLRP3 lead to constitutive activation of the "NLRP3 inflammasome," an intracellular platform that processes and secretes increased amounts of IL-1beta. The pivotal role of IL-1beta in NOMID/CINCA has been demonstrated in several clinical studies using IL-1--blocking agents that lead to rapid resolution of the inflammatory disease manifestations. NOMID/CINCA is a monogenic autoinflammatory syndrome; and the discovery of the role of IL-1 in NOMID has led to the exploration in the role of IL-1 in other disorders including gout and Type II diabetes. The inflammation in NOMID/CINCA is continuous with intermittent flares, and organ manifestations encompus the central nervous system, eye, inner ear, and bones. This review discusses updates on the pathogenesis of NOMID/CAPS, emerging long term-outcome data regarding IL-1- blocking agents that have influenced our considerations for optimal treatment, and a monitoring approach tailored to the patient's disease severity and organ manifestations. PMID- 21538044 TI - Nursing's role in cancer pain management. AB - Nurses have advanced practice, research, and education in the field of cancer pain management. This paper highlights the contributions nurses have made to pain science and practice through literature published in the past 3 years. Work accomplished by nurses is examined in the areas of pain assessment, pain management, intervention-based research, evidence-based practice, patient education, and palliative care. Nurses serve as advocates for empowering patients to engage in self-management of their pain, and offer education and support to patients and families at their most vulnerable times. Nurse researchers have been at the forefront of work to develop and test new instruments and approaches to measure pain, elucidate pain experiences through quantitative and qualitative methodologies, and gauge the quality of pain care for patients and its impact on their caregivers. This research has uncovered many patient, health care professional, and systemic barriers to effective pain control, and has offered feasible solutions to overcoming these barriers. PMID- 21538045 TI - Lymphomas and metastases of the extra-ocular musculature. AB - INTRODUCTION: The involvement of extra-ocular muscles in malignant diseases has been described only sporadically. The purpose of this study was to estimate the prevalence of orbital muscle lymphoma and metastases and to analyse their radiological findings. METHODS: In the time period from January 2000 to January 2010, 11 patients with extra-ocular muscle malignancies (EOMM) were retrospectively identified in the radiological database of our institution. There were four women and seven men with a median age of 58 years (range, 47 to 72 years). In three patients non-Hodgkin lymphoma (NHL), in seven cases intramuscular metastases of solid tumours and in one patient plasmacytoma of orbital muscles were diagnosed. In all, magnetic resonance imaging (MRI) was performed on 11 patients using a 1.5-T MRI scanner (Magnetom Vision Sonata Upgrade, Siemens, Germany). The diagnosis of EOMM was confirmed histopathologically by muscle biopsy in all cases. RESULTS: The prevalence of orbital muscle involvement in plasmacytoma was 0.3%, in NHL 0.4% and in carcinomas 0.1%. Clinically, EOMM presented as painless proptosis and motility disturbance. Medial and lateral rectus muscles were involved in most patients. On T2-weighted images, the lesions were isointense or mixed iso-to-hyperintense in comparison to the unaffected musculature. On T1-weighted images, all tumours were homogeneously isointense. After intravenous administration of contrast medium, most lesions showed moderate heterogeneous enhancement. CONCLUSION: Lymphomas and metastases are rare lesions of the extra-ocular musculature with a prevalence below 0.5%. Their radiological and clinical signs are non-specific and include painless muscle enlargement or masses. They should be considered in the differential diagnosis of diseases of extra-ocular muscles. PMID- 21538046 TI - Alteration of brain viscoelasticity after shunt treatment in normal pressure hydrocephalus. AB - INTRODUCTION: Normal pressure hydrocephalus (NPH) represents a chronic neurological disorder with increasing incidence. The symptoms of NPH may be relieved by surgically implanting a ventriculoperitoneal shunt to drain excess cerebrospinal fluid. However, the pathogenesis of NPH is not yet fully elucidated, and the clinical response of shunt treatment is hard to predict. According to current theories of NPH, altered mechanical properties of brain tissue seem to play an important role. Magnetic resonance elastography (MRE) is a unique method for measuring in vivo brain mechanics. METHODS: In this study cerebral MRE was applied to test the viscoelastic properties of the brain in 20 patients with primary (N = 14) and secondary (N = 6) NPH prior and after (91 +/- 16 days) shunt placement. Viscoelastic parameters were derived from the complex modulus according to the rheological springpot model. This model provided two independent parameters MU and alpha, related to the inherent rigidity and topology of the mechanical network of brain tissue. RESULTS: The viscoelastic parameters MU and alpha were found to be decreased with -25% and -10%, respectively, compared to age-matched controls (P < 0.001). Interestingly, alpha increased after shunt placement (P < 0.001) to almost normal values whereas MU remained symptomatically low. CONCLUSION: The results indicate the fundamental role of altered viscoelastic properties of brain tissue during disease progression and tissue repair in NPH. Clinical improvement in NPH is associated with an increasing complexity of the mechanical network whose inherent strength, however, remains degraded. PMID- 21538047 TI - Mammillotegmental tract in the human brain: diffusion tensor tractography study. AB - INTRODUCTION: Several animal studies have been conducted for the identification of the mammillotegmental tract (MTT); however, no study has been reported in the human brain. METHODS: In the current study, using diffusion tensor tractography (DTT), we attempted to identify the MTT in the human brain. We recruited 31 healthy volunteers for this study. Diffusion tensor images were acquired using 1.5 T, and the MTT was obtained using a probabilistic tractography method based on a multi-fiber model. Values of fractional anisotropy, mean diffusivity, and tract volume of the MTT were measured. RESULTS: MTTs of all subjects, which originated from the mammillary body, ascended posteriorly to the bicommissural level along the third ventricle and then turned caudally and terminated at the tegmentum of the midbrain. No significant differences were observed in terms of fractional anisotropy, mean diffusivity, and tract volume according to hemisphere and sex (P < 0.05). Using DTT, we identified the MTT in the human brain. CONCLUSION: We believe that the methodology and results of this study would be helpful in research on the MTT in the human brain. PMID- 21538048 TI - Establishment of fibrillin-deficient osteoprogenitor cell lines identifies molecular abnormalities associated with extracellular matrix perturbation of osteogenic differentiation. AB - Fibrillin-1 and fibrillin-2 are structural components of the extracellular matrix which are also involved in modulating local TGFbeta and BMP bioavailability. Loss of fibrillin-1 or fibrillin-2 is associated with perturbed osteoblast maturation principally as the result of unbalanced TGFbeta and BMP signaling. Here, we demonstrated that stable expression of small hairpin RNAs against fibrillin 1(Fbn1) or fibrillin-2 (Fbn2) transcripts in the clonal osteoprogenitor cell line Kusa-A1 led to the same phenotypic and molecular manifestations as germline Fbn1- or Fbn2-null mutations in primary calvarial osteoblast cultures. Proof-of-concept experiments are also presented showing that Fbn1- or Fbn2-silenced Kusa-A1 cell lines are suitable models to identify candidate determinants of osteogenesis which are under the control of extracellular microfibrils. Specific findings included: the inference of a potential role for fibrillin-1-mediated cell-matrix interactions in regulating Kusa-A1 proliferation; the possibility of fibrillin-2 involvement in modulating the activity of transcription factor Runx2 by restricting microRNA expression and/or processing; and the suggestion that fibrillin-1 and fibrillin-2 influence Notch signaling indirectly by differentially regulating BMP signaling. Collectively, the data reiterated the notion that fibrillin-1 and fibrillin-2 exert opposite effects on osteoblast differentiation through the discrete modulation of a broad network of interacting signaling molecules. PMID- 21538049 TI - Metabolic effects of contraceptive steroids. AB - Estrogen and progestins have been used by millions of women as effective combined contraceptives. The safety of hormonal contraceptives has been documented by years of follow-up and serious adverse events that may be related to their use are rare in the young population exposed to these agents. The balance between the benefits and the risks of contraceptive steroids is generally positive in particular when comparing to the risks of pregnancy and especially in women with risk factors. The metabolic changes induced by the synthetic steroids used in contraception, such as lipoprotein changes, insulin response to glucose, and coagulation factors have been considered as potential markers of cardiovascular and venous risk. Observations of these effects have led to modifications of the composition of hormonal contraceptive in order to minimize these changes and hence potentially decrease the risks. The synthetic estrogen Ethinyl-Estradiol (EE) exerts a stronger effect that natural estradiol (E2) on hepatic metabolism including estrogen-dependent markers such as liver proteins. This stronger hepatic impact of EE has been related to its 17alpha-ethinyl group which prevents the inactivation of the molecule and results in a more pronounced hepatic effect of EE as compared to estradiol. Due to its strong activity, administering EE via a non-oral route does not prevent its impact on liver proteins. In order to circumvent the metabolic changes induced by EE, newer products using more natural compounds such as estradiol (E2) and estradiol valerate (E2V) have been introduced. The synthetic progestins used for contraception are structurally related either to testosterone (T) (estranes and gonanes) or to progesterone (pregnanes and 19-norpregnanes). Several new progestins have been designed to bind more specifically to the progesterone receptor and to minimize side-effects related to androgenic, estrogenic or glucocorticoid receptor interactions. Dienogest (DNG), and drospirenone (DRSP) and the 19-norpregnanes including Nestorone(r) (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG) have been combined with estrogen either EE or E2 or estradiol valerate (E2V). Risks and benefits of the newer progestins used in contraception depend upon the type of molecular structure, the type and dose of estrogen associated in a combination and the route of administration. The lower metabolic impact of estradiol-based combinations may result in an improved safety profile, but large surveillance studies are warranted to confirm this plausible hypothesis. So far, the contraindications and warnings for use of current COCs also apply to the estradiol-based COCs. PMID- 21538050 TI - Toxic megacolon from sexually transmitted Shigella sonnei infection. PMID- 21538051 TI - Transumbilical laparoscopic-assisted appendectomy for children and adults. PMID- 21538052 TI - Cecal volvulus: a rare complication of colonoscopy. PMID- 21538053 TI - Dynamic MRI defecography vs. entero-colpo-cysto-defecography in the evaluation of midline pelvic floor hernias in female pelvic floor disorders. AB - PURPOSE: The aim of this study was to compare the diagnostic efficacy of dynamic MR defecography (MR-D) with entero-colpo-cysto-defecography (ECCD) in the assessment of midline pelvic floor hernias (MPH) in female pelvic floor disorders. METHODS: From August 2004 to August 2010, 3,006 female patients who required ECCD for the evaluation of pelvic floor disorders were enrolled in this study. All the 1,160 patients with ECCD findings of MPH were asked to undergo MR D; 1,142 accepted to undergo MR-D and constituted the object of analysis. This study was approved by the Institutional Ethical Committee. All the patients gave their written informed consent to take part in the study. RESULTS: Overall, the prevalence of MPH at ECCD was higher if compared with that at MR-D. Concerning the hernia content, there were significantly more enteroceles and sigmoidoceles on ECCD than on MR-D, whereas, in relation to the hernia development modalities, the prevalence of elytroceles, edroceles, and Douglas' hernias at ECCD was significantly higher than that at MR-D. In spite of a 100% specificity, the sensibility of MR-D in the detection of an omentocele, sigmoidocele, and enterocele was, respectively, 95%, 82%, and 65%, showing an inferior diagnostic capacity if compared with that of ECCD. CONCLUSION: MR-D shows lower sensitivity than ECCD in the detection of MPH development. The less-invasive MR-D may have a role in a better evaluation of the entire pelvic anatomy and pelvic organ interaction especially in patients with multicompartmental defects, planned for surgery. PMID- 21538054 TI - Polymorphisms of caspase 8 and caspase 9 gene and colorectal cancer susceptibility and prognosis. AB - PURPOSE: Caspase-8 (CASP8) and caspase-9 (CASP9) play crucial roles in regulating apoptosis, and their functional polymorphisms may alter cancer risk. Our aim was to investigate the association between CASP8 and CASP9 gene polymorphisms and colorectal cancer (CRC) susceptibility. METHODS: A case-control study at 402 CRC patients and 480 healthy controls was undertaken in order to investigate the association between the genotype and allelic frequencies of CASP8 -652 6N ins/del and CASP9 -1263 A>G polymorphisms and the CRC susceptibility. The polymerase chain reaction (PCR) restriction fragment length polymorphism method was used and the incidence of polymorphisms on messenger RNA (mRNA) expression levels was detected by quantitative reverse-transcriptase PCR in CRC tissues. RESULTS: No statistical significant association was observed between CASP8 -652 6N ins/del polymorphism frequencies and CRC susceptibility. CASP9 -1263 G allele was observed to be significant associated with reduced risk of CRC. Homozygotes for the -1263 GG CASP9 genotype, and hetrozygotes for the -1263 AG genotype expressed 6.64- and 3.69-fold higher mRNA levels of Caspase-9, respectively compared to the -1263 AA genotype cases. No significant association was observed between CASP9 1263 A>G polymorphism and tumor characteristics. The CASP9 -1263 GG genotype was associated with increased overall survival in CRC patients. CONCLUSION: The CASP9 -1263 A>G polymorphism was observed to play a protective role in CRC predisposition, while the CASP9 -1263 GG genotype may confer a better prognosis at CRC patients. PMID- 21538055 TI - beta-catenin and Her2/neu expression in rectal cancer: association with histomorphological response to neoadjuvant therapy and prognosis. AB - BACKGROUND: Neoadjuvant treatment strategies have been developed to improve survival of patients with advanced rectal cancer. Since mainly patients with major histopathological response benefit from this therapy, predictive and prognostic markers are needed. We examined the association of beta-catenin and Her2/neu protein expression with histopathologic response to neoadjuvant radiochemotherapy and prognosis in patients with locally advanced rectal cancer. METHODS: Fifty-four patients (33 male; 21 female; median age 60.4 years) with locally advanced rectal cancer were included in this study. All patients received a neoadjuvant radiochemotherapy (50.4 Gy, 5-FU) followed by surgical resection. Histomorphologic regression was evaluated by Dworak and Cologne staging system. Major response was defined by Dworak classification when resected specimens contained less than 50% vital tumor cells (n = 14) and by Cologne grading system when resected specimens contained less than 10% vital tumor cells (n = 15). Intratumoral beta-catenin (nuclear/membranous) and Her2/neu (cytoplasmatic/membranous) expression was determined by immunohistochemistry in pre- and post-therapeutic specimens and correlated with clinicopathologic parameters. RESULTS: A significant association was detected between pre therapeutic membranous beta-catenin levels and response: patients with a lower beta-catenin protein expression showed significantly more often a major response compared with patients having high intratumoral protein levels (p = 0.011). In addition, patients with a higher Her2/neu protein expression showed a significant survival benefit compared with patients having low intratumoral protein levels (5 year survival rate: 81% vs. low 41%; p = 0.023). CONCLUSIONS: The pre-therapeutic beta-catenin and Her2/neu protein expression seem to be valuable predictive and prognostic markers in the multimodality treatment of advanced rectal cancer. PMID- 21538056 TI - Early postoperative CEA level is a better prognostic indicator than is preoperative CEA level in predicting prognosis of patients with curable colorectal cancer. AB - PURPOSE: Carcinoembryonic antigen (CEA) measurements performed preoperatively and during the early postoperative period were examined prospectively to assess their prognostic value for colorectal cancer (CRC) patients receiving curative surgery. METHODS: Between 2000 and 2004, 1,361 patients with CRC who underwent curative surgery at the Taipei Veterans General Hospital were enrolled prospectively. CEA was measured prior to surgery and during the third or fourth postoperative week. The endpoint was length of postoperative disease-free survival, and prognostic importance was determined using the log-rank test and Cox regression hazard model. RESULTS: Six hundred (44.1%) CRC patients had high CEA concentrations preoperatively, and 188 (13.8%) patients retained high values postoperatively. Within the median follow-up period of 61 (6-108) months, CRC recurred in 313 patients. By univariate analysis TNM staging, tumor differentiation, lymphovascular invasion, preoperative CEA concentration, and postoperative CEA concentration affected the outcome. By multivariate analysis, the prognostic importance of postoperative CEA was retained (95% CI, 1.73-3.01; HR = 2.28) but that of preoperative CEA was lost (95% CI, 0.82-1.33; HR = 1.05). CRC recurred earlier in patients with high postoperative CEA concentrations; metastasis to the liver was common (72.3%) among patients in this group. CONCLUSIONS: Early postoperative CEA concentration is an independent prognostic factor for CRC. Patients with high postoperative CEA values should receive aggressive follow-up examinations for early relapse of CRC, with special attention paid to recurrence at the liver. PMID- 21538057 TI - Meta-analysis of associations between polymorphisms in the promoter regions of matrix metalloproteinases and the risk of colorectal cancer. AB - PURPOSE: Matrix metalloproteinases (MMPs) play important roles in pathogenesis and development of cancer. Recently, lots of studies showed that there were associations between polymorphisms in the promoter regions of MMPs and risk of colorectal cancer; however, the results remained inconclusive. To clarify these associations, we conducted a meta-analysis. METHODS: We conducted a computerized literature search in the database of PubMed, Embase, ISI Web of Knowledge, and Medline (from January 2000 to July 2010). Overall and subgroup analysis based on the ethnicity of study population was carried out. Odds ratio (OR) and 95% confidence interval (95%CI) were used to evaluate these associations. Statistical analysis was performed with software Review Manager (version 5.0). RESULTS: There were 12 studies involving five polymorphic sites in four MMP genes. For MMP1 ( 1607), 2G polymorphism increased the risk of colorectal cancer under dominant and recessive models (dominant, OR = 1.23, 95%CI 1.01-1.49; recessive, OR = 1.52, 95%CI 1.30-1.77). For MMP3 (-1612), 6A/6A genotype increased this risk under the recessive model (OR = 1.33, 95%CI 1.04-1.70); however, this association was lost under the dominant model. For MMP2 -1306 C>T, MMP3 -1171 5A>6A, and MMP9 -1562 C>T, there was no association between these polymorphisms and the risk of colorectal cancer under the dominant and recessive models. CONCLUSIONS: Polymorphisms of MMP1 (-1607) and MMP3 (-1612) increased the risk of colorectal cancer; these two polymorphic sites could be used as markers for early diagnosis of colorectal cancer. However, for MMP2 (-1306), MMP3 (-1171), and MMP9 (-1562), further studies with large sample size should be carried out. PMID- 21538058 TI - Structural stability and unfolding transition of beta-glucosidases: a comparative investigation on isozymes from a thermo-tolerant yeast. AB - The folding of proteins in the milieu of the cellular environment involves various interactions among the residues of the polypeptide chain and the microenvironment where it resides. These interactions are responsible for stabilizing the protein molecule, and disruption of the same provides information about the stability of the molecule. beta-Glucosidase isozymes, despite having high homology in their primary and tertiary designs, show deviations in their properties such as unfolding, refolding, and stability. In a comparative study on two large cell-wall-bound isozymes, beta-glucosidase I (BGLI) and beta glucosidase II (BGLII) from a thermo-tolerant yeast, Pichia etchellsii, we have investigated guanidine hydrochloride (GdnHCl)-induced, alkali-induced, and thermal-unfolding transitions using CD and fluorescence spectroscopy and high sensitivity differential scanning calorimetry. Using spectral parameters (MRE 222 nm) to monitor the conformational transitions of the GdnHCl-induced unfolding phenomenon, it was observed that the midpoints of unfolding, apparent C (m), occurred at 1.2 M +/- 0.05 and 0.8 M +/- 0.03 GdnHCl, respectively, for BGLI and BGLII. The alkali-induced unfolding process indicated that BGLI showed a mid transition point at pH 11 +/- 0.17, while for BGLII it was at pH 10 +/- 0.40, further indicating BGLI to be more stable to alkali denaturation than BGLII. In the case of thermal unfolding, the midpoint of transition was observed at 63 +/- 0.12 degrees C for BGLI and at 58 +/- 0.55 degrees C for BGLII. Analysis by high sensitivity differential scanning calorimeter supported the unfolding data in which BGLI showed higher melting temperature, T (m), (56.07 degrees C +/- 0.34) than BGLII (54.02 degrees C +/- 0.36). Our results clearly indicate that BGLI is structurally more rigid and stable than BGLII. PMID- 21538059 TI - The transient catalytically competent coenzyme allocation into the active site of Anabaena ferredoxin NADP+ -reductase. AB - Ferredoxin-NADP(+) reductase (FNR) catalyses the electron transfer from ferredoxin to NADP(+) via its flavin FAD cofactor. A molecular dynamics theoretical approach is applied here to visualise the transient catalytically competent interaction of Anabaena FNR with its coenzyme, NADP(+). The particular role of some of the residues identified as key in binding and accommodating the 2'P-AMP moiety of the coenzyme is confirmed in molecular terms. Simulations also indicate that the architecture of the active site precisely contributes to the orientation of the N5 of the FAD isoalloxazine ring and the C4 of the coenzyme nicotinamide ring in the conformation of the catalytically competent hydride transfer complex and, therefore, contributes to the efficiency of the process. In particular, the side chain of the C-terminal Y303 in Anabaena FNR appears key to providing the optimum geometry by reducing the stacking probability between the isoalloxazine and nicotinamide rings, thus providing the required co-linearity and distance among the N5 of the flavin cofactor, the C4 of the coenzyme nicotinamide and the hydride that has to be transferred between them. All these factors are highly related to the reaction efficiency, mechanism and reversibility of the process. PMID- 21538060 TI - Low-density lipoprotein cholesterol suppresses apoptosis in human multiple myeloma cells. AB - Multiple myeloma (MM) is an incurable disease accompanied by low plasma levels of low-density lipoprotein cholesterol (LDL-c). The significance of altered cholesterol metabolism in the pathophysiology of MM remains elusive. Although it has been hypothesized that myeloma cells depend on exogenous cholesterol for its survival, the role of LDL-c on myeloma cells has not been elucidated. To evaluate the impact of exogenous LDL-c on cell viability, three human myeloma cell lines (RPMI-8226, NCI-H929, and U-266B1) were grown in the presence or absence of lipoproteins. Cell viability was markedly reduced in the absence of lipoproteins in sera. However, exogenous LDL-c improved cell viability. We showed that reduced cell viability was associated with increased levels of cleaved caspase-3, whereas proliferation rate remained unchanged. Interestingly, exogenous LDL-c counteracted apoptosis in human myeloma cell lines and primary cultures of human myeloma cells. Thus, our results demonstrated that LDL-c is an important anti apoptotic factor for myeloma cells and begin to explain the hypocholesterolemia observed in patients with MM. PMID- 21538062 TI - Parvovirus B19 infection-related acute hepatitis after rituximab-containing regimen for treatment of diffuse large B-cell lymphoma. PMID- 21538061 TI - Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS). AB - The inhibition of histone deacetylase (HDAC) can induce differentiation, growth arrest, and apoptosis in cancer cells. This phase II multicenter study was undertaken to estimate the efficacy of belinostat, a potent inhibitor of both class I and class II HDAC enzymes, for the treatment of myelodysplastic syndrome (MDS). Adults with MDS and <=2 prior therapies were treated with belinostat 1,000 mg/m(2) IV on days 1-5 of a 21-day cycle. The primary endpoint was a proportion of confirmed responses during the first 12 weeks of treatment. Responding patients could receive additional cycles until disease progression or unacceptable toxicity. Twenty-one patients were enrolled, and all were evaluable. Patients were a median 13.4 months from diagnosis, and 14 patients (67%) had less than 5% bone marrow blasts. Seventeen patients (81%) were transfusion dependent. Prior therapy included azacytidine (n = 7) and chemotherapy (n = 8). The patients were treated with a median of four cycles (range, 1-8) of belinostat. There was one confirmed response-hematologic improvement in neutrophils-for an overall response rate of 5% (95% CI, 0.2-23). Median overall survival was 17.9 months. Grades 3-4 toxicities considered at least to be possibly related to belinostat were: neutropenia (n = 10), thrombocytopenia (n = 9), anemia (n = 5), fatigue (n = 2), febrile neutropenia (n = 1), headache (n = 1), and QTc prolongation (n = 1). Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual. PMID- 21538063 TI - Fragment length analysis screening for detection of CEBPA mutations in intermediate-risk karyotype acute myeloid leukemia. AB - During last years, molecular markers have been increased as prognostic factors routinely screened in acute myeloid leukemia (AML). Recently, an increasing interest has been reported in introducing to clinical practice screening for mutations in the CCAAT/enhancer-binding protein alpha (CEBPA) gene in AML, as it seems to be a good prognostic factor. However, there is no reliable established method for assessing CEBPA mutations during the diagnostic work-up of AMLs. We describe here a straightforward and reliable fragment analysis method based in PCR capillary electrophoresis (PCR-CE) for screening of CEBPA mutations; moreover, we present the results obtained in 151 intermediate-risk karyotype AML patients (aged 16-80 years). The method gave a specificity of 100% and sensitivity of 93% with a lower detection limit of 1-5% for CEBPA mutations. The series found 19 mutations and four polymorphisms in 12 patients, seven of whom (58%) presented two mutations. The overall frequency of CEBPA mutations in AML was 8% (n = 12). CEBPA mutations showed no coincidence with FLT3-ITD or NPM1 mutations. CEBPA mutation predicted better disease-free survival in the group of patients without FLT3-ITD, NPM, or both genes mutated (HR 3.6, IC 95%; 1.0-13.2, p = 0.05) and better overall survival in patients younger than 65 of this group without molecular markers (HR 4.0, IC 95%; 1.0-17.4, p = 0.05). In conclusion, the fragment analysis method based in PCR-CE is a rapid, specific, and sensitive method for CEBPA mutation screening and our results confirm that CEBPA mutations can identify a subgroup of patients with favorable prognosis in AML with intermediate-risk karyotype. PMID- 21538064 TI - Contralateral cerebral hemodynamic changes after unilateral direct revascularization in patients with moyamoya disease. AB - Direct revascularization has been used successfully to prevent strokes by improving regional cerebral blood flow (rCBF) to the affected hemisphere faster in patients with moyamoya disease (MMD). Since most literatures have focused on the rCBF changes of operative hemisphere, we evaluated the hemodynamics of nonoperative side by xenon-enhanced computed tomography (Xe-CT) and acetazolamide challenge test in patients with MMD during a short time follow-up. Fifteen MMD patients with unilateral ischemic presentations who received direct revascularization on the symptomatic hemispheres with complete hemodynamic evaluations by Xe-CT and acetazolamide challenge test were enrolled. Hemodynamic evaluations were performed 1, 3, and 6 months, postoperatively. The postoperative rCBF and cerebral vascular reserve (CVR) were recorded and correlated with clinical outcome. Angiography was performed if the patient had neurological deterioration or deficits. The average follow-up time was 8.5+/-3.5 months. Three months after the ipsilateral direct revascularization, the CVR of nonoperative hemispheres (25.8+/-8.1%) began to decrease significantly (P=0.003). Six months later, the rCBF showed a downward trend in nonoperative hemispheres (47.4+/-8.0 ml.100 g(-1) min(-1)) than the preoperative status, but the difference was not significant (P=0.053). Three patients presented with decreased rCBF and impaired CVR in the nonoperative hemispheres. Among them, two patients were symptomatic. Unilateral direct revascularization in symptomatic hemisphere for MMD patient could induce CVR impaired in primary asymptomatic hemisphere during the short term after the surgery. Therefore, critical follow-up, especially the hemodynamic follow-up in the asymptomatic hemispheres should be performed in patients with MMD. PMID- 21538065 TI - Cardiac magnetic resonance imaging for the diagnosis of patients presenting with chest pain, raised troponin, and unobstructed coronary arteries. AB - To evaluate the incremental diagnostic and prognostic value of cardiac magnetic resonance (CMR) in patients with chest pain, raised troponin and unobstructed coronary arteries, and to compare subsequent event rates between diagnostic groups. 130 patients (mean age: 54 +/- 17) presenting with troponin-positive acute chest pain and unobstructed coronary arteries were included. All patients were managed according to European Society of Cardiology guidelines, including echocardiography, and had CMR within 6.2 +/- 5.3 days of presentation. During follow-up, major adverse cardiovascular events (MACE) were recorded. CMR provided a diagnosis in 100 of 130 patients (76.9%), with the remaining 30 (23.1%) having a normal examination. CMR diagnosed 37 (28.5%) acute myocardial infarctions, 34 (26.1%) myocarditis, 28 (21.5%) apical ballooning syndromes and 1 (0.8%) hypertrophic cardiomyopathy. When a single diagnosis was suspected by the referring physician, CMR validated this diagnosis in 32 patients (76.2%). CMR provided a formal diagnosis in 61 patients (69.3%) in which the clinical diagnosis was uncertain between at least two possibilities. CMR corrected a wrong diagnosis in 10 patients (7.7%). CMR-suggested diagnosis led to a modification of therapy in 42 patients (32.3%). Median follow-up was 34 months (interquartile range 24-49) in 124 patients. Sixteen patients (12.9%) experienced MACE. MACE rate was not different between patients with a conclusive CMR and normal CMR. In patients with acute troponin-positive chest pain and unobstructed coronary arteries, early CMR has important diagnostic and therapeutic implications. However its association with occurrence of MACE during mid term follow-up was not obvious. PMID- 21538066 TI - Cardiovascular sources of systemic embolism: detection and characterization using multidetector CT and MR imaging. AB - The purpose of this article is to provide a current review of multidetector CT (MDCT) and MRI findings and imaging protocols for the cardiovascular diseases that can precipitate systemic embolism. These conditions include intracardiac thrombus or tumors, paradoxical embolism through right-to-left shunts, and diseases of the thoracic aorta. MDCT and MRI may be helpful for detection of these conditions. Familiarity with the pathogenesis and CT and MRI appearance of these conditions is important as their detection may have a major impact on patient management. PMID- 21538068 TI - Effect of aging on the shape and position of the eyebrow in an Indian population. AB - BACKGROUND: The eyebrow is one of the most important structures of the face from an aesthetic point of view. As age increases, the brow changes its shape and position. This age-related change decreases the vitality, youth, and expression associated with the aesthetically ideal face. This article describes changes in eyebrow position in Indian women with aging. METHODS: This study recruited 80 female subjects for each of the required age ranges (20-30 years and 50-60 years) from the staff and outpatient settings at a tertiary care center in central India. Women who had any condition that could affect the measurements were excluded from the study. Standardized digital photographs in frontal view were captured with the forehead and eyebrows in a maximally relaxed position and with the eyes open. Eyebrow position was determined by measuring from a reference horizontal plane drawn between the medial canthi to vertical points on the upper brow margin at the medial canthus, pupil, and lateral canthus. The result was statistically analyzed. RESULTS: With aging, the least rise was seen in the lateral segment, which was not statistically significant. This difference was statistically significant at the medial and midbrow positions (p < 0.05). In the younger group, the lateral brow position was significantly higher than the midbrow (p < 0.05). In contrast, the older group showed a nonsignificant difference in the position of the midbrow and the lateral brow. The mean horizontal distance of the brow apex from the midpoint of the pupil for young women was 15.2 mm. CONCLUSION: The study results imply that the brow does not drop in women with age. It is recommended that in most instances, the lateral brow should be preferentially elevated, whereas the medial brow should undergo minimal or no elevation. Most patients require brow reshaping by restoration of the brow apex lateral to the level of the outer corneal limbus. By comparing eyebrow shape and position in both young and mature women, this study provides objective data that can be used to plan forehead-rejuvenating procedures in Indian women. PMID- 21538069 TI - Beneficial effect of cigarette smoking cessation on fibrin clot properties. AB - To examine the associations between cigarette smoking and preferable clot properties. Plasma fibrin clots from 21 randomly selected current smokers (n = 7), former smokers (n = 7) and non-smokers (n = 7) were analyzed, using scanning electron microscopy (SEM). With the use of the turbidimetric clotting and lysis assay in plasma, the maximum absorbance (MaxAbs(C), MaxAbs(L)) was measured and lysis time (Lys(50%)) was calculated. Smoking cessation significantly influenced fibrin fiber branching and density. Median fiber diameter was not changed. Lys(50%) was the highest in current smokers and was reduced in former smokers to the non-smoker level (2120 +/- 385 versus 1771 +/- 122 and 1724 +/- 272 s; P = 0.04). Smoking cessation improves fibrin clot architecture which results in the lesser resistance to lysis. PMID- 21538070 TI - Effect of hypercapnia on intracellular pH regulation in a rainbow trout hepatoma cell line, RTH 149. AB - Fish exposed to elevated water CO(2) experience a rapid increase in blood CO(2) levels (hypercapnia), resulting in acidification of both intra- and extra cellular compartments. While the mechanisms associated with extracellular pH regulation have been well explored, much less is known about intracellular pH (pH(i)) regulation. There is great interest in developing non-animal models for research. One such model is the rainbow trout hepatoma cell line (RTH 149), which has been used to study a wide range of topics; however, no studies have investigated its potential use in pH(i) regulation. Employing the pH-sensitive fluoroprobe BCECF, the present study examined pH(i) regulation in RTH 149 under normocapnia and during extracellular acidification induced by either elevated CO(2) or 1 M HCl. During exposure to hypercapnia, RTH 149 cells were acidified without recovery as long as the elevated CO(2) was maintained. In addition, rates of pH(i) recovery from NH(4)Cl-induced acidosis were significantly lower in cells exposed to hypercapnia or HCl compared to that in normocapnic cells, indicating that elevated CO(2) indirectly impeded pH(i) recovery through a reduction in pH(e) and/or pH(i). Moreover, pH(i) regulation in RTH 149 was EIPA-sensitive, suggesting that an NHE may be involved. Overall, RTH 149 may have the potential for identifying transporters likely to play a role in pH(i) regulation in fish. However, it should not be used as a complete replacement for in vivo studies, especially to quantify acid-base regulatory ability at whole animal level, since RTH 149 appeared to have enhanced pH(i) recovery rates relative to primary hepatocytes. PMID- 21538071 TI - Development and characterization of transgenic mouse models for conditional gene knockout in the blood-brain and blood-CSF barriers. AB - For many CNS acting drugs, penetration into the central nervous system (CNS) is limited by the blood-CNS-barriers. In an effort to quantitate the role of the protein components that make up the blood-CNS-barriers, we created transgenic mice that allow conditional gene knockout using Cre/loxP technology. We targeted the expression of Cre-recombinase to the choroid plexus (the blood-cerebral spinal fluid barrier) using the lymphotropic papovavirus control region (LPVcr) and to brain endothelium (the blood-brain-barrier) using the proximal promoter region of the human von Willebrand Factor gene (hVWF-f). We verified that LPVcr restricts expression to the choroid plexus in adult mice by using the LPVcr to drive n-LacZ expression in transgenic mice. The LPV-Cre and hVWF-Cre plasmids were then constructed and tested for Cre-recombinase function in vitro, and subsequently used to create transgenic mice. The resulting transgenic mice were characterized for cell-type specific Cre-mediated endonuclease activity by crossing them with transgenic mice containing a loxP-flanked-LacZ/EGFP dual reporter gene Z/EG. The dual Cre-Z/EG transgenic offspring were evaluated for the location of EGFP mRNA expression by reverse transcriptase PCR and for protein expression by immunohistochemistry. Immunohistochemistry for EGFP verified expression in the target cells, and no ectopic expression outside of the expected cell types. The LPV-Cre.0607 transgenic line expressed functional Cre only in the choroid plexus and hVWF-Cre.1304 line in brain endothelium. PMID- 21538073 TI - An unusual glycoform of human salivary mucin MG2. AB - Since in a previous study we encountered a subject with an unusual split MG2 banding pattern, the aim of this study was to investigate the molecular basis of this observation. Submandibular/sublingual secretion was collected under resting and stimulated conditions and examined on Western blots probed with anti-MG2 antibodies or on gels stained with periodic acid-Schiff reagent. Genomic DNA was isolated and the N-, tandem repeat (TR), and C-terminal regions of MUC7 were amplified by PCR since MG2 is known to display a genetic polymorphism. Although the typical appearance of MG2 on blots and gels is a single 180 kDa band, salivary secretions from the subject exhibited doublet immunoreactive bands of approximately 180 and 125 kDa. Additionally, under resting conditions the 180 kDa band was predominant whereas upon stimulation the 125 kDa band became predominant. Genomic DNA analysis showed that MUC7 in the individual with split MG2 bands was not truncated and that the MUC7 genotype in this individual was (6/6) where both alleles encoded six TRs. The MG2 split banding pattern observed in this subject was not derived from proteolytic degradation of this salivary mucin in whole saliva or from genetic polymorphism. The expression of two isoforms of MG2 could in principle improve or reduce the activity of this key component of the oral host defense system. PMID- 21538072 TI - Metagenomic analysis of the peri-implant and periodontal microflora in patients with clinical signs of gingivitis or mucositis. AB - The long-term success of osseointegrated oral implants is endangered by inflammation of peri-implant hard and soft tissues caused by bacterial biofilms that may have been initiated by bacterial transmission from the adjacent dentition. The present study aimed to compare the bacterial communities at inflamed implant and tooth sites by broad-range PCR techniques to evaluate the etiological processes of peri-implant and periodontal diseases and potential future therapeutic strategies. Eighteen samples of peri-implant and periodontal microflora were collected from nine partially edentulous patients with implant retained crowns or bridges revealing clinical signs of gingivitis or mucositis. The clinical parameters plaque index (PI), probing depth (PD), and bleeding on probing were recorded. Amplified fragments of bacterial 16S rRNA genes were separated by use of single-strand conformation polymorphism analysis, and sequences were determined to identify the predominant bacterial genera. The clinical parameters PI and PD were significantly different at implants (PI = 0.4 +/- 0.7, PD = 3.1 +/- 0.6 mm) compared with teeth (PI = 1.8 +/- 0.8, PD = 2.5 +/- 0.2 mm). A total of 20 different genera were found at the inflamed tooth and implant sites. The microbial diversity of the microflora surrounding the remaining dentition (12.0 +/- 3.8) was significantly higher (p = 0.01) than the diversity of the peri-implant microflora at implant-retained crowns or bridges (6.3 +/- 2.3). Within the limitations of the present study, the microbial diversity of the investigated implants and teeth with clinical signs of mucositis or gingivitis exhibits substantial differences, demonstrating that transmission of the complete bacterial microflora from teeth to implants could be excluded. Furthermore, broad-range molecular biological detection methods specify bacterial genera and species in the peri-implant and periodontal microflora which were not in the focus of research interests so far. PMID- 21538074 TI - Long-term oral appliance therapy in obstructive sleep apnea syndrome: a controlled study on temporomandibular side effects. AB - The objective of this study was to assess variations in the occurrence of temporomandibular disorders (TMDs) and the risk of developing pain and function impairment of the temporomandibular complex in obstructive sleep apnea syndrome (OSAS) patients treated with either an oral appliance (mandibular advancement device) or continuous positive airway pressure (CPAP) in a 2-year follow-up study. In addition, we assessed the relationship between the mean mandibular protrusion and the frequency of wearing the appliance during follow-up with the occurrence of pain and function impairment of the temporomandibular complex. Fifty-one patients were randomized to oral appliance therapy and 52 patients to CPAP therapy. TMDs (diagnosed according to the Axis I Research Diagnostic Criteria for TMD), pain intensity and disability and mandibular function impairment were recorded at baseline, after 2 months, 1 year and 2 years of therapy. Only in the initial period of treatment the occurrence of pain-related TMDs was considerably higher (24%) in the oral appliance group compared to CPAP (6%). Oral appliance therapy furthermore resulted in more temporomandibular pain compared to CPAP (odds ratio 2.33, 95% confidence interval (1.22-4.43)). However, there were no limitations in mandibular function in both groups during the (entire) follow-up period. Although generally not serious and of transient nature, oral appliance therapy results in more pain-related TMDs in the initial period of use compared with CPAP therapy. Oral appliance therapy is associated with increased pain in the temporomandibular complex in the initial period of use. Because of the transient nature, this pain is not a reason to contra indicate an oral appliance in OSAS patients. Moreover, TMDs and the risk of developing pain and function impairment of the temporomandibular complex appear limited with long-term oral appliance use. PMID- 21538075 TI - The challenge of asthma in minority populations. AB - The burden and disparity of asthma in race/ethnic minorities present a significant challenge. In this review, we will evaluate data on asthma epidemiology in minorities, examine potential reasons for asthma disparities, and discuss strategies of intervention and culturally sensitive care. PMID- 21538076 TI - The differential diagnosis of familial lentiginosis syndromes. AB - Cutaneous markers of systemic disease are vital for clinicians to recognize. This chapter outlines familial lentiginosis syndromes that include Peutz-Jeghers syndrome, Carney Complex, the PTEN hamartomatous syndromes, and LEOPARD/Noonan syndrome. The inheritance of these syndromes is autosomal dominant; they also share characteristic skin findings that offer a clue to their recognition and treatment. We will discuss the clinical presentation of these disorders, with a focus on the dermatological manifestations, and will provide an update on the molecular mechanisms involved. Recognition of cutaneous markers associated with these rare familial cancer syndromes provides the opportunity to pursue early surveillance for malignancies, as well as genetic counseling. PMID- 21538077 TI - Low penetrance hereditary retinoblastoma in a family: what should we consider in the genetic counselling process and follow up? AB - Hereditary retinoblastoma (Rb) is a high penetrance autosomal dominant disease showing not only an increased risk of suffering bilateral Rb but also other second neoplasms. However, some families show a low-penetrance phenotype with reduced expressivity and incomplete penetrance of the retinoblastoma gene (RB1). Given the lack of specific guidelines for the follow-up of adult patients with hereditary Rb, the authors present a case report of a family with a low penetrance phenotype and review the recommended surveillance in this setting, stressing the difficulties found in the genetic counselling process and follow up. Thus, since patients are at an increased risk, lifelong regular medical surveillance to detect any second malignancy at a stage that can be cured is required. In addition, avoidance of DNA-damaging agents and genetic testing should be considered for a throughout management of these families. PMID- 21538078 TI - A cost-effectiveness analysis of prophylactic surgery versus gynecologic surveillance for women from hereditary non-polyposis colorectal cancer (HNPCC) Families. AB - Women at risk for Lynch Syndrome/HNPCC have an increased lifetime risk of endometrial and ovarian cancer. This study investigates the cost-effectiveness of prophylactic surgery versus surveillance in women with Lynch Syndrome. A decision analytic model was designed incorporating key clinical decisions and existing probabilities, costs, and outcomes from the literature. Clinical forum where risk reducing surgery and surveillance were considered. A theoretical population of women with Lynch Syndrome at age 30 was used for the analysis. A decision analytic model was designed comparing the health outcomes of prophylactic hysterectomy with bilateral salpingo-oophorectomy at age 30 versus annual gynecologic screening versus annual gynecologic exam. The literature was searched for probabilities of different health outcomes, results of screening modalities, and costs of cancer diagnosis and treatment. Cost-effectiveness expressed in dollars per discounted life-years. Risk-reducing surgery is the least expensive option, costing $23,422 per patient for 25.71 quality-adjusted life-years (QALYs). Annual screening costs $68,392 for 25.17 QALYs; and annual examination without screening costs $100,484 for 24.60 QALYs. Further, because risk-reducing surgery leads to both the lowest costs and the highest number of QALYs, it is a dominant strategy. Risk-reducing surgery is the most cost-effective option from a societal healthcare cost perspective. PMID- 21538079 TI - [2,4-(13)C]beta-hydroxybutyrate metabolism in astrocytes and C6 glioblastoma cells. AB - This study was undertaken to determine if the ketogenic diet could be useful for glioblastoma patients. The hypothesis tested was whether glioblastoma cells can metabolize ketone bodies. Cerebellar astrocytes and C6 glioblastoma cells were incubated in glutamine and serum free medium containing [2,4-(13)C]beta hydroxybutyrate (BHB) with and without glucose. Furthermore, C6 cells were incubated with [1-(13)C]glucose in the presence and absence of BHB. Cell extracts were analyzed by mass spectrometry and media by (1)H magnetic resonance spectroscopy and HPLC. Using [2,4-(13)C]BHB and [1-(13)C]glucose it could be shown that C6 cells, in analogy to astrocytes, had efficient mitochondrial activity, evidenced by (13)C labeling of glutamate, glutamine and aspartate. However, in the presence of glucose, astrocytes were able to produce and release glutamine, whereas this was not accomplished by the C6 cells, suggesting lack of anaplerosis in the latter. We hypothesize that glioblastoma cells kill neurons by not supplying the necessary glutamine, and by releasing glutamate. PMID- 21538080 TI - Oxidative damage to RNA and expression patterns of MTH1 in the hippocampi of senescence-accelerated SAMP8 mice and Alzheimer's disease patients. AB - Mammalian MTH1 protein, a MutT-related protein, catalyzes the hydrolysis of 8-oxo 7,8-dihydroguanosine triphosphate (8-oxoGTP) to monophosphate, thereby preventing incorporation of 8-oxo-7,8-dihydroguanine (8-oxoguanine) into RNA. In this study, we applied immunohistochemistry to follow the expression of MTH1 and the amount of 8-oxoguanine in RNA during aging. There were increased amounts of 8-oxoguanine in RNA in the CAl and CA3 subregions of hippocampi of 8- and 12-month-old SAMP8 mice, which exhibited early aging syndromes and declining learning and memory abilities compared to those of age-matched control SAMR1 mice. The expression levels of MTH1 in the hippocampi of 8- and 12-month-old SAMP8 mice were significantly lower than those of control mice. Therefore, in this mouse model, age-related accumulation of 8-oxoguanine in RNA is correlated with decreased expression of MTH1. Increased amounts of 8-oxoguanine in the RNA, and decreased expression of MTH1 were also observed in the hippocampi of patients suffering from Alzheimer's disease. These results suggest that MTH1 deficiency might be a causative factor for aging and age-related disorders. PMID- 21538081 TI - HIV testing behaviors among female sex workers in Southwest China. AB - Despite the recognized importance of HIV testing in prevention, care and treatment, HIV testing remains low in China. Millions of female sex workers (FSW) play a critical role in China's escalating HIV epidemic. Limited data are available regarding HIV testing behavior among this at-risk population. This study, based on a cross-sectional survey of 1,022 FSW recruited from communities in Southwest China, attempted to address the literature gap. Our data revealed that 48% of FSW ever took HIV testing; older age, less education, working in higher-income commercial sex venues and better HIV knowledge were associated with HIV testing. Those who never took HIV testing were more likely to engage in high risk behaviors including inconsistent condom use with clients and stable partners. A number of psychological and structural barriers to testing were also reported. We call for culturally appropriate interventions to reduce HIV risks and promote HIV testing for vulnerable FSW in China. PMID- 21538082 TI - Social network characteristics and HIV vulnerability among transgender persons in San Salvador: identifying opportunities for HIV prevention strategies. AB - The purpose of this study is to improve understanding of HIV vulnerability and opportunities for HIV prevention within the social networks of male-to-female transgender persons in San Salvador, El Salvador. We compare HIV prevalence and behavioral data from a sample of gay-identified men who have sex with men (MSM) (n = 279), heterosexual or bisexual identified MSM (n = 229) and transgender persons (n = 67) recruited using Respondent Driven Sampling. Transgender persons consistently reported higher rates of HIV risk behavior than the rest of the study population and were significantly more likely to be involved in sex work. While transgender persons reported the highest rates of exposure to HIV educational activities they had the lowest levels of HIV-related knowledge. Transgender respondents' social networks were homophilous and efficient at recruiting other transgender persons. Findings suggest that transgender social networks could provide an effective and culturally relevant opportunity for HIV prevention efforts in this vulnerable population. PMID- 21538083 TI - AIDS conspiracy beliefs and unsafe sex in Cape Town. AB - This paper uses multivariate logistic regressions to explore: (1) potential socio economic, cultural, psychological and political determinants of AIDS conspiracy beliefs among young adults in Cape Town; and (2) whether these beliefs matter for unsafe sex. Membership of a religious organisation reduced the odds of believing AIDS origin conspiracy theories by more than a third, whereas serious psychological distress more than doubled it and belief in witchcraft tripled the odds among Africans. Political factors mattered, but in ways that differed by gender. Tertiary education and relatively high household income reduced the odds of believing AIDS conspiracies for African women (but not men) and trust in President Mbeki's health minister (relative to her successor) increased the odds sevenfold for African men (but not women). Never having heard of the Treatment Action Campaign (TAC), the pro-science activist group that opposed Mbeki on AIDS, tripled the odds of believing AIDS conspiracies for African women (but not men). Controlling for demographic, attitudinal and relationship variables, the odds of using a condom were halved amongst female African AIDS conspiracy believers, whereas for African men, never having heard of TAC and holding AIDS denialist beliefs were the key determinants of unsafe sex. PMID- 21538084 TI - Strategies to retain participants in a long-term HIV prevention randomized controlled trial: lessons from the MINTS-II study. AB - Achieving satisfactory retention in online HIV prevention trials typically has proven difficult, particularly over extended timeframes. The overall aim of this study was to assess factors associated with retention in the Men's INTernet Study II (MINTS-II), a randomized controlled trial of a sexual risk reduction intervention for men who have sex with men. Participants were recruited via e mails and banner advertisements in December, 2007 to participate in the MINTS-II Sexpulse intervention and followed over a 12-month period. Retention across the treatment and control arms was 85.2% at 12 months. Factors associated with higher retention included: randomization to the control arm, previous participation in a study by the research team, e-mail and telephone reminders to complete a survey once it was available online, and fewer e-mail contacts between surveys. The results provide evidence that achieving satisfactory retention is possible in online HIV prevention trials, and suggest best practices for maximizing retention. PMID- 21538085 TI - Density of drinking establishments and HIV prevalence in a migrant town in Namibia. AB - Given the established link between alcohol consumption and risk taking behavior, it is plausible that neighborhoods with higher density of drinking establishments will be associated with increased prevalence of HIV. We conducted an ecological study comparing neighborhoods in Luderitz, Namibia, to evaluate this relationship. We observed increased prevalence of HIV comparing high densities of registered and unregistered shebeens, bars, and total number of drinking establishments, as compared with low densities, were associated with increased prevalence of HIV (PR = 3.02, 95% CI: 2.04-4.47; PR = 1.71, 95% CI: 1.42-2.07; PR = 1.55, 95% CI: 1.19-2.02). Our observation of increased prevalence associated with higher densities of drinking establishment's merits consideration. PMID- 21538086 TI - Concurrent sexual partnerships among urban African American high-risk women with main sex partners. AB - To determine correlates of concurrent sexual partnerships among high-risk low income urban African American women, survey responses of 337 women who had main sexual partners for over 6 months and reported high-risk behaviors were analyzed; 142 of these women also reported other sexual partnerships within the past 90 days. Unadjusted analyses showed that concurrency was significantly associated with relationship status, sexual debut, forced sex, incarceration of self and partners, depression, drug use, known or suspected partner nonmonogamy, and partner drug use. Age of sexual debut, relationship status, and indicators of problem drug use remained significantly associated with concurrency when controlling for individual factors, and only indicators of problem drug use and known or suspected partner nonmonogamy remained significantly associated with concurrency when also controlling for partner characteristics. Our results suggest the presence of extensive sexual networks within this population and document the need for interventions that address drug abuse and partnership instability. Moreover, the strong association between concurrency and perceptions of partners' nonmonogamy suggest the need for intervention to target men and women in this core group. PMID- 21538087 TI - HIV prevention and transmission myths among heterosexually active adults in low income areas of South Florida. AB - Misconceptions about HIV transmission and prevention may inhibit individuals' accurate assessment of their level of risk. We used venue-based sampling to conduct a cross-sectional study of heterosexually active adults (N = 1,221) within areas exhibiting high poverty and HIV/AIDS rates in Miami-Dade and Broward counties in 2007. Two logistic regression analyses identified correlates of holding inaccurate beliefs about HIV transmission and prevention. Belief in incorrect HIV prevention methods (27.2%) and modes of transmission (38.5%) was common. Having at least one incorrect prevention belief was associated with being Hispanic compared to white (non-Hispanic), being depressed, and not knowing one's HIV status. Having at least one incorrect transmission belief was associated with being younger, heavy alcohol use, being depressed, not having seen a physician in the past 12 months, and not knowing one's HIV status. Among low-income heterosexuals, HIV prevention and transmission myths are widespread. Debunking them could have HIV prevention value. PMID- 21538089 TI - [Surgical therapy in Graves' orbitopathy]. AB - Surgical therapy of Graves' orbitopathy comprises orbital decompression as well as strabismus and lid surgery. The former is primarily carried out during active disease, the latter during inactive disease. Orbital decompression abates increased intraorbital pressure and is thus applicable against dysthyroid optic neuropathy and also reduces exophthalmos. The choice of a specific procedure depends mainly on the experience of the respective center. In this article, the pterional transcranial, transnasal transethmoidal, transconjunctival and swinging eyelid approaches are presented. Eye muscle recession relieves the abnormal tension of fibrotic muscles and thus corrects diplopia. Compared to normal strabismus surgery, the dose-response relationship is increased. Lid lengthening surgery is applied to counter upper or lower lid retraction. If several of these operations are necessary the order is chosen in such a way that downstream procedures cannot change specific results of upstream operations. PMID- 21538088 TI - A brief assessment of learning for orphaned and abandoned children in low and middle income countries. AB - Assessment of children's learning and performance in low and middle income countries has been critiqued as lacking a gold standard, an appropriate norm reference group, and demonstrated applicability of assessment tasks to the context. This study was designed to examine the performance of three nonverbal and one adapted verbal measure of children's problem solving, memory, motivation, and attention across five culturally diverse sites. The goal was to evaluate the tests as indicators of individual differences affected by life events and care circumstances for vulnerable children. We conclude that the measures can be successfully employed with fidelity in non-standard settings in LMICs, and are associated with child age and educational experience across the settings. The tests can be useful in evaluating variability in vulnerable child outcomes. PMID- 21538090 TI - [Clinical and neuroradiological diagnostics in Graves' orbitopathy]. AB - Early diagnosis of Graves' orbitopathy (GO) is important for a timely treatment of the disease. The diagnosis is based on clinical as well as radiological findings. Detailed assessment and follow-up mainly rely on standardized clinical examinations which register symptoms and signs including inflammation, upper lid retraction, exophthalmos, eye muscle involvement and diplopia, corneal involvement, raised intraocular pressure and optic nerve involvement, the latter representing a particular challenge. Each case of GO is classified in terms of severity and activity allowing suitable therapeutic strategies to be derived. PMID- 21538091 TI - Drug discovery using very large numbers of patents: general strategy with extensive use of match and edit operations. AB - A patent data base of 6.7 million compounds generated by a very high performance computer (Blue Gene) requires new techniques for exploitation when extensive use of chemical similarity is involved. Such exploitation includes the taxonomic classification of chemical themes, and data mining to assess mutual information between themes and companies. Importantly, we also launch candidates that evolve by "natural selection" as failure of partial match against the patent data base and their ability to bind to the protein target appropriately, by simulation on Blue Gene. An unusual feature of our method is that algorithms and workflows rely on dynamic interaction between match-and-edit instructions, which in practice are regular expressions. Similarity testing by these uses SMILES strings and, less frequently, graph or connectivity representations. Examining how this performs in high throughput, we note that chemical similarity and novelty are human concepts that largely have meaning by utility in specific contexts. For some purposes, mutual information involving chemical themes might be a better concept. PMID- 21538092 TI - Caregiver burden in chronic mental illness: the role of patient and caregiver characteristics. AB - The aim of the present study is to identify the relative contribution of patient and caregiver characteristics in a sample of primary carers of patients with chronic mental disorders living in the community. As carers were recruited from caregiver organizations, mainly mothers of an adult child suffering from schizophrenia participated in the study (n = 102). Within a comprehensive transactional stress model, burden was assessed with respect to objective and subjective burden, cognitive-emotional well-being, psychological distress and subjective quality of life. Primary stressors include illness-related characteristics of the patient, and a number of personal dispositions and resources of the caregivers were included as potential moderating variables. Multiple regression analyses were separately calculated for each dimension of burden. Interaction of carers' expressed emotion and external locus of control with the patient's problem with family communication as well as perceived social support was most predictive for objective and subjective burden, whereas carers' neuroticism appeared as the most relevant predictor of their well-being, psychological distress and subjective quality of life. Among the patients' variables, regular employment contributed significantly to reduce carers' distress and enhance their well-being. As the sample was recruited from caregiver organizations, a selection bias has to be taken into account. To reduce caregiver burden, especially mothers' burden, the patients' occupational abilities should be strongly enhanced at an early stage. Family interventions should improve dysfunctional interactions, enhance the carers' social activities and focus more intensely on the carers' own dispositions. PMID- 21538093 TI - Neurobiology of plant parasitic nematodes. AB - The regulatory constraints imposed on use of chemical control agents in agriculture are rendering crops increasingly vulnerable to plant parasitic nematodes. Thus, it is important that new control strategies which meet requirements for low toxicity to non-target species, vertebrates and the environment are pursued. This would be greatly facilitated by an improved understanding of the physiology and pharmacology of these nematodes, but to date, these microscopic species of the Phylum Nematoda have attracted little attention in this regard. In this review, the current information available for neurotransmitters and neuromodulator in the plant parasitic nematodes is discussed in the context of the more extensive literature for other species in the phylum, most notably Caenorhabditis elegans and Ascaris suum. Areas of commonality and distinctiveness in terms of neurotransmitter profile and function between these species are highlighted with a view to improving understanding of to what extent, and with what level of confidence, this information may be extrapolated to the plant parasitic nematodes. PMID- 21538094 TI - Agreement between web-based and paper versions of a socio-demographic questionnaire in the NutriNet-Sante study. AB - OBJECTIVES: Web-based studies nowadays raise a major interest as they can improve all steps involved in observational studies. Our objective was to compare the web based version of the NutriNet-Sante self-administered socio-demographic and economic questionnaire with the traditional paper version. METHODS: Both versions of the questionnaire were sent to 170 volunteers and filled in by 147 of them (either paper first, n = 76, or web-based first, n = 71). Agreement between versions was assessed by intraclass correlations (ICC) and kappas. RESULTS: Agreement between both versions was high, with ICC and kappas ranging between 0.81-1.00 and 0.76-1.00, respectively, similarly across groups of administration order, age, gender and self-estimated web knowledge in general. The web-based version was the one preferred by 93.7% of the subjects and enabled to avoid 553 missing values (2.00% of the total entries), 24 inconsistent data (0.09%), 8 aberrant data (0.03%), 472 data entry errors (0.85%) and to save 2,800 (US $4,072) when sent to 170 subjects. CONCLUSION: The web-based socio-demographic and economic questionnaire provided information of similar-to-superior quality compared to the traditional paper version, with substantial logistic and cost advantages. PMID- 21538095 TI - Septate endophyte colonization and host responses of grasses and forbs native to a tallgrass prairie. AB - Native tallgrass prairies support distinct dark septate endophyte (DSE) communities exemplified by Periconia macrospinosa and Microdochium sp. that were recently identified as common root symbionts in this system. Since these DSE fungi were repeatedly isolated from grasses and forbs, we aimed to test their abilities to colonize different hosts. One Microdochium and three Periconia strains were screened for colonization and growth responses using five native grasses and six forbs in an in vitro system. Previously published data for an additional grass (Andropogon gerardii) were included and reanalyzed. Presence of indicative inter- and intracellular structures (melanized hyphae, microsclerotia, and chlamydospores) demonstrated that all plant species were colonized by the DSE isolates albeit to varying degrees. Microscopic observations suggested that, compared to forbs, grasses were colonized to a greater degree in vitro. Host biomass responses varied among the host species. In broad comparisons, more grass species than forbs tended to respond positively to colonization, whereas more forb species tended to be non-responsive. Based on the suspected differences in the levels of colonization, we predicted that tallgrass prairie grasses would support greater DSE colonization than forbs in the field. A survey of field collected roots from 15 native species supported this hypothesis. Our study supports the "broad host range" of DSE fungi, although the differences in the rates of colonization in the laboratory and in the field suggest a greater compatibility between grasses and DSE fungi. Furthermore, host responses to DSE range from mutualism to parasitism, suggesting a genotype-level interplay between the fungi and their hosts that determines the outcome of this symbiosis. PMID- 21538096 TI - Graft fixation alternatives in anterior cruciate ligament reconstruction. AB - Reconstruction of the anterior cruciate ligament is a frequently performed procedure that has had outstanding results. Outcomes are dependent upon an early postoperative physical therapy program that stresses early motion. Early rehabilitation demands rigid intraoperative mechanical fixation of the graft since therapy begins before biologic incorporation of the graft in the bone tunnels. Regardless of the graft substitute chosen, many methods of fixation are available. The best fixation technique depends on several factors, including graft choice and surgeon comfort. The figures are not documented in this paper. We review current methods available for graft fixation in anterior cruciate ligament surgery. PMID- 21538097 TI - Fatigue in advanced cancer patients attending an outpatient palliative radiotherapy clinic as screened by the Edmonton Symptom Assessment System. AB - INTRODUCTION: Advanced cancer patients present with a variety of physical and psychological symptoms. Fatigue is one such symptom which reduces overall quality of life and is difficult to manage. The purpose of this study was to report the presence, severity, and correlating factors of fatigue in advanced cancer patients attending an outpatient palliative radiotherapy clinic. MATERIALS/METHODS: Patients referred to the Rapid Response Radiotherapy Program between January 1999 and October 2009 completed the Edmonton Symptom Assessment System (ESAS) prior to consultation. Demographic information including age, Karnofsky Performance Status (KPS), gender, and primary cancer sites were collected. Ordinal logistic regression analysis was conducted to determine relationships between demographic information, other ESAS items, and levels of fatigue. Multivariate ordinal logistic regression analysis was used to determine the most significant predictors of fatigue. A p value of <0.05 was considered statistically significant. RESULTS: A total of 1,397 patients completed the ESAS prior to consultation. Median age was 68 years (range, 21-95), median KPS was 60 (range, 10-100), and slightly more males completed the ESAS (53.0%). Common primary cancers were of the lung (35.8%), breast (20.7%), and prostate (17.7%). Only 179 (12.8%) patients reported no fatigue; the majority of patients reported moderate (31.8%) or severe (34.4%) fatigue. A low KPS (p < 0.0001), being female (p = 0.0056), or being referred for bone metastases (p = 0.0185) significantly correlated with higher levels of fatigue. Patients with a genitourinary primary cancer (p = 0.0078) and/or referred for malignant spinal cord compression (p = 0.0004) reported less fatigue. All other ESAS items were significantly related to fatigue. The most significant predictors of fatigue were pain (p < 0.0001, odds ratio (OR) = 1.07), nausea (p = 0.0010, OR = 1.10), depression (p < 0.0001, OR = 1.10), drowsiness (p < 0.0001, OR = 1.33), dyspnea (p = 0.0003, OR = 1.08), and overall well-being (p < 0.0001, OR = 1.19). CONCLUSION: Moderate fatigue was reported in over 66% of our advanced cancer patients prior to radiotherapy. Since radiotherapy inherently causes fatigue, proactive and multidisciplinary management is required for these patients. Similar rates of fatigue severity, in lengthier, fatigue-specific tools, suggest that the ESAS may be a good tool for screening the advanced cancer population. PMID- 21538098 TI - Age and androgen-deprivation therapy on exercise outcomes in men with prostate cancer. AB - PURPOSE: The purpose of this study is to examine the effects of age (<= 65 years or >65 years) and androgen-deprivation therapy (ADT, presence or absence) as factors that may predict changes in body composition and fitness following a 24 week exercise program in prostate cancer patients. METHODS: One hundred twenty one men were randomly allocated to either: (1) aerobic exercise (AE), (2) resistance exercise (RE), or (3) usual care (UC). Body composition was assessed by DXA. Aerobic fitness was assessed through a maximal treadmill test. Muscular strength was assessed by leg extension and bench press using the eight-repetition maximum test. Responses were compared between younger (<= 65 years) and older (> 65 years) patients with or without ADT. RESULTS: There did not appear to be an interaction between age and ADT on body composition or fitness, nor were there any significant changes in body composition for participants <= 65 years. In participants aged >65 years, lean mass decreased in AE (p = 0.013) and UC (p = 0.006), but was preserved in RE. In participants receiving ADT, there was a decrease in lean mass in AE (p = 0.003) and UC (p < 0.001) but not in RE. The non ADT group did not show any changes in body composition but did show improvements in muscular fitness following resistance training (p < 0.001). CONCLUSION: Changes in body composition and physical fitness following a 24-week exercise program in men with prostate cancer are not influenced by age and/or ADT. Resistance training appears to attenuate the age-related decrease in lean mass and increase in body fat in older patients with prostate cancer and those receiving ADT. PMID- 21538099 TI - EORTC QLQ-C15-PAL quality of life scores in patients with advanced cancer referred for palliative radiotherapy. AB - PURPOSE: Symptom control and improved quality of life (QOL) are primary goals of treatment in palliative oncology. The present study assessed and compared patient demographics, baseline Karnofsky Performance Status (KPS) and QOL using the QLQ C15-PAL questionnaire prior to palliative radiotherapy (RT) for bone, brain, or lung disease. Few studies have used this questionnaire, an abbreviated version that was developed by the European Organization for Research and Treatment of Cancer specifically for patients with advanced cancer to decrease the burden of completing the longer, more time-consuming QLQ-C30. METHODS: Patients referred to an outpatient palliative RT clinic completed QLQ-C15-PAL questionnaires prior to palliative RT for bone, brain, or lung cancer sites. The associations between baseline QLQ-C15-PAL functional/symptom scales, patient demographics, and clinical variables including KPS were explored. RESULTS: When data from all 369 patients were analyzed, higher KPS scores correlated significantly with better overall QOL and higher physical and emotional functioning. The QLQ-C15-PAL provided more detailed information regarding how symptom burden varied depending on disease site. Patients with bone metastases had worse QLQ-C15-PAL scores for pain, while those with brain and lung disease had worse scores for fatigue. Other health-related QOL scores measured by the QLQ-C15-PAL varied as a function of age and gender. CONCLUSION: As the QLQ-C15-PAL provides detailed and often critical information regarding symptom burden, it may eventually be recognized as a universal core questionnaire to assess QOL in this patient population with advanced cancer while relieving the survey burden. PMID- 21538100 TI - Isolation of a citrus promoter specific for reproductive organs and its functional analysis in isolated juice sacs and tomato. AB - While searching for genes expressed in acid lemon but not in acidless lime pulp, we isolated clone Cl111 which showed the following expression phenotypes: (1) while it was expressed in the ovaries in both varieties, its mRNA was detected only in the pulp of the acid fruit, (2) no or very low expression of the gene was detected in vegetative organs. These expression patterns suggested that Cl111 is an ovary- and pulp-specific gene. The ability of ~2-kb fragments upstream of the transcription start site of the lemon and lime genes to confer reporter-gene activity was investigated by transient expression in isolated juice vesicles of both varieties. Whereas Cl111 promoter from lemon showed faint activity in lemon and lime juice vesicles, no activity was evident with the lime promoter. The activities of the 2-kb fragments and their delimited fragments were further investigated in tomato. The results indicated that the promoters were active in a manner similar to that in acid lemon and acidless lime: the lemon promoter generated activity in the fruit endocarp, analogous to citrus fruit pulp. The delimitation analyses identified an expression-conferring region which, in the lemon promoter, contained a sequence homologous to a fruit-specific element of the melon cucumisin gene. Another region, which reduced promoter activity, contained an I-Box-like sequence, identified as a fruit-specific negative element. Taken together, Cl111 promoter was confirmed to be pulp- and flower specific. Differences in the expression of Cl111 between the two varieties could be attributable to changes in the gene promoter region. PMID- 21538101 TI - Inducibility of three salinity/abscisic acid-regulated promoters in transgenic rice with gusA reporter gene. AB - The present study evaluates the pattern of stress inducibility of one natural promoter (from rice Rab16A) and two synthetically designed promoters, viz., 4X ABRE (abscisic acid-responsive element, having four tandem repeats of ABRE) and 2X ABRC (abscisic acid-responsive complex, having two tandem repeats of ABRE and two copies of coupling elements), in response to varying concentrations of NaCl and abscisic acid (ABA). Each promoter, independently linked to gusA (that encodes beta glucuronidase, GUS), was introduced into rice (cv. Khitish) through particle bombardment. The T(2) progenies showed integration of gusA in their genome. The accumulation of gusA transcript, driven by each promoter in T(2) transgenics, increased with increasing salt/ABA concentration, with ABA being the better activator of each promoter. Induction in GUS expression, driven by different promoters, was noted on exogenous salt/ABA treatments in a concentration-dependent manner. The maximum induction was observed with 2X ABRC promoter. All the three promoters could drive stress-inducible GUS expression in both vegetative and floral organs. However, prominent GUS expression was noted in the whole seed (both embryo and aleurone layer of endosperm) only by 2X ABRC, whereas it was localized only in the embryo for the other two promoters. Thus, our observation characterizes three efficient salinity/ABA-inducible promoters that have the potentiality in crop biotechnology to drive transgene expression for stress tolerance, whenever abiotic stress is encountered. PMID- 21538102 TI - A tyrosine decarboxylase catalyzes the initial reaction of the salidroside biosynthesis pathway in Rhodiola sachalinensis. AB - Salidroside, the 8-O-beta-D-glucoside of tyrosol, is the main bioactive component of Rhodiola species and is found mainly in the plant roots. It is well known that glucosylation of tyrosol is the final step in the biosynthesis of salidroside; however, the biosynthetic pathway of tyrosol and its regulation are less well understood. A summary of the results of related studies revealed that the precursor of tyrosol might be tyramine, which is synthesized from tyrosine. In this study, a cDNA clone encoding tyrosine decarboxylase (TyrDC) was isolated from Rhodiola sachalinensis A. Bor using rapid amplification of cDNA ends. The resulting cDNA was designated RsTyrDC. RNA gel-blot analysis revealed that the predominant sites of expression in plants are the roots and high levels of transcripts are also found in callus tissue culture. Functional analysis revealed that tyrosine was best substrate of recombinant RsTyrDC. The over-expression of the sense-RsTyrDC resulted in a marked increase of tyrosol and salidroside content, but the levels of tyrosol and salidroside were 274 and 412%, respectively, lower in the antisense-RsTyrDC transformed lines than those in the controls. The data presented here provide in vitro and in vivo evidence that the RsTyrDC can regulate the tyrosol and salidroside biosynthesis, and the RsTyrDC is most likely to have an important function in the initial reaction of the salidroside biosynthesis pathway in R. sachalinensis. PMID- 21538103 TI - Fine mapping of a male sterility gene MS-cd1 in Brassica oleracea. AB - A dominant male sterility (DGMS) line 79-399-3, developed from a spontaneous mutation in Brassica oleracea var. capitata, has been widely used in production of hybrid cultivars in China. In this line, male sterility is controlled by a dominant gene Ms-cd1. In the present study, fine mapping of Ms-cd1 was conducted by screening a segregating population Ms79-07 with 2,028 individuals developed by four times backcrossing using a male sterile Brassica oleracea var. italica line harboring Ms-cd1 as donor and Brassica oleracea var. alboglabra as the recipient. Bulked segregation analysis (BSA) was performed for the BC(4) population Ms79-07 using 26,417 SRAP primer SRAPs and 1,300 SSRs regarding of male sterility and fertility. A high-resolution map surrounding Ms-cd1 was constructed with 14 SRAPs and one SSR. The SSR marker 8C0909 was closely linked to the MS-cd1 gene with a distance of 2.06 cM. Fourteen SRAPs closely linked to the target gene were identified; the closest ones on each side were 0.18 cM and 2.16 cM from Ms-cd1. Three of these SRAPs were successfully converted to dominant SCAR markers with a distance to the Ms-cd1 gene of 0.18, 0.39 and 4.23 cM, respectively. BLAST analysis with these SCAR marker sequences identified a collinear genomic region about 600 kb in scaffold 000010 on chromosomeA10 in B. rapa and on chromosome 5 in A. thaliana. These results provide additional information for map-based cloning of the Ms-cd1 gene and will be helpful for marker-assisted selection (MAS). PMID- 21538104 TI - Towards new horizons in brain PET. PMID- 21538106 TI - Deep sequencing of voodoo lily (Amorphophallus konjac): an approach to identify relevant genes involved in the synthesis of the hemicellulose glucomannan. AB - A Roche 454 cDNA deep sequencing experiment was performed on a developing corm of Amorphophallus konjac--also known as voodoo lily. The dominant storage polymer in the corm of this plant is the polysaccharide glucomannan, a hemicellulose known to exist in the cell walls of higher plants and a major component of plant biomass derived from softwoods. A total of 246 mega base pairs of sequence data was obtained from which 4,513 distinct contigs were assembled. Within this voodoo lily expressed sequence tag collection genes representing the carbohydrate related pathway of glucomannan biosynthesis were identified, including sucrose metabolism, nucleotide sugar conversion pathways for the formation of activated precursors as well as a putative glucomannan synthase. In vivo expression of the putative glucomannan synthase and subsequent in vitro activity assays unambiguously demonstrate that the enzyme has indeed glucomannan mannosyl- and glucosyl transferase activities. Based on the expressed sequence tag analysis hitherto unknown pathways for the synthesis of GDP-glucose, a necessary precursor for glucomannan biosynthesis, could be proposed. Moreover, the results highlight transcriptional bottlenecks for the synthesis of this hemicellulose. PMID- 21538107 TI - Highly efficient production of anti-HER2 scFv antibody variant for targeting breast cancer cells. AB - The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor overexpressed in 30% of human breast cancers. One of the mechanisms by which tumor cell proliferation can be inhibited consists in hampering HER2 dimerization by targeting its extracellular domain with specific antibodies. In recent clinical practice, a valuable alternative to entire IgGs resides in the use of smaller molecules, such as single-chain variable fragments (scFv), developed for selective molecular targeting. In this paper, we report on the production and purification of a soluble anti-HER2 scFv antibody secreted by Pichia pastoris. The gene encoding scFv800E6 with an additional 6* His-tag at the 3'-end was inserted into the expression vector pPICZalpha and transformed in P. pastoris. The highest expression level was obtained in presence of 0.5% methanol and 0.8% glycerol in the culture medium after 48 h of induction. The use of P. pastoris proved very valuable as an expression system, allowing the isolation of 10 mg/L of highly purified antibody, remarkably higher than previously reported data. The functionality of purified anti-HER2 scFv was assessed by cytofluorimetry and immunofluorescence on HER2-positive MCF7 breast cancer cells, showing good affinity and high selectivity for the target membrane receptor. These findings confirm that P. pastoris is a suitable host for high level expression of antibody fragments and highlight the potential role of scFv800E6 in diagnostic and therapeutic application. PMID- 21538105 TI - Diversity and spatial distribution of prokaryotic communities along a sediment vertical profile of a deep-sea mud volcano. AB - We investigated the top 30-cm sediment prokaryotic community structure in 5-cm spatial resolution, at an active site of the Amsterdam mud volcano, East Mediterranean Sea, based on the 16S rRNA gene diversity. A total of 339 and 526 sequences were retrieved, corresponding to 25 and 213 unique (>=98% similarity) phylotypes of Archaea and Bacteria, respectively, in all depths. The Shannon Wiener diversity index H was higher for Bacteria (1.92-4.03) than for Archaea (0.99-1.91) and varied differently between the two groups. Archaea were dominated by anaerobic methanotrophs ANME-1, -2 and -3 groups and were related to phylotypes involved in anaerobic oxidation of methane from similar habitats. The much more complex Bacteria community consisted of 20 phylogenetic groups at the phylum/candidate division level. Proteobacteria, in particular delta Proteobacteria, was the dominant group. In most sediment layers, the dominant phylotypes of both the Archaea and Bacteria communities were found in neighbouring layers, suggesting some overlap in species richness. The similarity of certain prokaryotic communities was also depicted by using four different similarity indices. The direct comparison of the retrieved phylotypes with those from the Kazan mud volcano of the same field revealed that 40.0% of the Archaea and 16.9% of the Bacteria phylotypes are common between the two systems. The majority of these phylotypes are closely related to phylotypes originating from other mud volcanoes, implying a degree of endemicity in these systems. PMID- 21538108 TI - Functional analysis of the response regulator DegU in Bacillus megaterium DSM319 and comparative secretome analysis of degSU mutants. AB - We functionally analysed the two-component regulatory system DegSU (historically SacU) in Bacillus megaterium DSM319 by generating a genetic knock out as well as a sacU32 mutation. The latter--known to cause a hypersecretion phenotype in Bacillus subtilis--had no influence on extracellular protease and amylase activity in B. megaterium. Since the B. megaterium DegU complemented a Bacillus licheniformis ?degSU mutant, functionality of the protein was proven. Expression of the sacB encoded levansucrase was found to be dependent on DegSU in B. megaterium. Consistently, the fusion of the sacB promoter to gfp revealed a strong increase in GFP-expression in the sacU32 strain. On 2 D-gels of the secretome, a large number of intracellular proteins was seen. The culture medium contained only 42 secreted proteins which can be assigned to polypeptides involved in the metabolism of the cell wall, polypeptides with proteolytic activities and those with unknown functions. Though overall protease activity matches with the wild type, two proteolytic enzymes (Vpr and YwaD) are missing in the secretome of the ?degSU strain, while other degradative enzymes are not affected. In line with such findings, no increase of proteolytic or other degradative enzymes was seen in the sacU32 mutant. Thus, compared to B. subtilis and B. licheniformis, the number of extracellular proteins influenced by DegSU is surprisingly low in B. megaterium, a feature, probably advantageous as to the use of the sacU32 mutant for production of secreted proteins. PMID- 21538109 TI - Bacterial abl-like genes: production of the archaeal osmolyte N(epsilon)-acetyl beta-lysine by homologous overexpression of the yodP-kamA genes in Bacillus subtilis. AB - Nepsilon-acetyl-beta-lysine is an archaeal compatible solute whose synthesis is mediated by the sequential reactions of the lysine-2,3-aminomutase AblA and the acetyltransferase AblB. alpha-Lysine serves as the precursor and is converted by AblA to beta-lysine, and AblB then acetylates this intermediate to N(epsilon) acetyl-beta-lysine. The biochemical and biophysical properties of N(epsilon) acetyl-beta-lysine have so far not been studied intensively due to restrictions in the supply of this compound. A search for ablAB-like genes in the genomes of members of the family Bacillaceae revealed the yodP-kamA genes that encode a AblA related lysine-2,3-aminomutase and AblB-related putative acetyltransferase. In Bacillus subtilis, the yodP-kamA genes are part of a transcriptional unit (yodT yodS-yodR-yodQ-yodP-kamA) whose expression is upregulated during sporulation and controlled by the mother-cell-specific transcription factor SigE. N(epsilon) acetyl-beta-lysine was not detectable in vegetatively growing or osmotically stressed B. subtilis cells, and the deletion of the yodT-yodS-yodR-yodQ-yodP-kamA region had no noticeable effects on growth in rich or minimal media or osmotic stress resistance. However, when we expressed the yodP-kamA genes outside their natural genetic context from an isopropyl beta-D-1-thiogalactopyranoside inducible promoter on a plasmid in B. subtilis, the recombinant strain synthesized considerable amounts (0.28 MUmol/mg protein) of N(epsilon)-acetyl beta-lysine. The data reported here thus open the bottleneck for the large-scale production of N(epsilon)-acetyl-beta-lysine to investigate its properties as a compatible solute. PMID- 21538110 TI - Reversible immobilization of glucoamylase onto magnetic carbon nanotubes functionalized with dendrimer. AB - Magnetic carbon nanotubes (MCNTs) with necklace-like nanostructures was prepared via hydrothermal method, and hyperbranched poly(amidoamine) (PAMAM) was grafted on the surface of MCNTs on the basis of the Michael addition of methyl acrylate and the amidation of the resulting ester with a large excess of ethylenediamine (EDA), which could achieve generational growth under such uniform stepwise reactions. The terminal -NH(2) groups from the dendritic PAMAM were reacted with differently functionalized groups to form functionalized MCNTs. Subsequently, enzyme was immobilized on the functionalized MCNTs through adsorption, covalent bond, and metal-ion affinity interactions. The immobilization of glucoamylase, hereby chosen as model enzyme, onto the differently functionalized MCNTs is further demonstrated and assessed based on its activity, thermal stability, as well as reusability. Besides ease in recovery by magnetic separation, the immobilized glucoamylase on functionalized MCNTs offers superior stability and reusability, without compromising the substrate specificity of free glucoamylase. Furthermore, the results indicate that the metal-chelate dendrimer offers an efficient route to immobilize enzymes via metal-ion affinity interactions. The applicability of the regenerated supports in the current study is relevant for the conjugation of other enzymes beyond glucoamylase. PMID- 21538112 TI - Newly generated interspecific wine yeast hybrids introduce flavour and aroma diversity to wines. AB - Increasingly, winemakers are looking for ways to introduce aroma and flavour diversity to their wines as a means of improving style and increasing product differentiation. While currently available commercial yeast strains produce consistently sound fermentations, there are indications that sensory complexity and improved palate structure are obtained when other species of yeast are active during fermentation. In this study, we explore a strategy to increase the impact of non-Saccharomyces cerevisiae inputs without the risks associated with spontaneous fermentations, through generating interspecific hybrids between a S. cerevisiae wine strain and a second species. For our experiments, we used rare mating to produce hybrids between S. cerevisiae and other closely related yeast of the Saccharomyces sensu stricto complex. These hybrid yeast strains display desirable properties of both parents and produce wines with concentrations of aromatic fermentation products that are different to what is found in wine made using the commercial wine yeast parent. Our results demonstrate, for the first time, that the introduction of genetic material from a non-S. cerevisiae parent into a wine yeast background can impact favourably on the wine flavour and aroma profile of a commercial S. cerevisiae wine yeast. PMID- 21538113 TI - "Biofilmology": a multidisciplinary review of the study of microbial biofilms. AB - The observation of biofilm formation is not a new phenomenon. The prevalence and significance of biofilm and aggregate formation in various processes have encouraged extensive research in this field for more than 40 years. In this review, we highlight techniques from different disciplines that have been used to successfully describe the extracellular, surface and intracellular elements that are predominant in understanding biofilm formation. To reduce the complexities involved in studying biofilms, researchers in the past have generally taken a parts-based, disciplinary specific approach to understand the different components of biofilms in isolation from one another. Recently, a few studies have looked into combining the different techniques to achieve a more holistic understanding of biofilms, yet this approach is still in its infancy. In order to attain a global understanding of the processes involved in the formation of biofilms and to formulate effective biofilm control strategies, researchers in the next decade should recognise that the study of biofilms, i.e. biofilmology, has evolved into a discipline in its own right and that mutual cooperation between the various disciplines towards a multidisciplinary research vision is vital in this field. PMID- 21538114 TI - Microbial community succession in a bioreactor modeling a souring low-temperature oil reservoir subjected to nitrate injection. AB - Injection of up-flow packed-bed bioreactors with excess volatile fatty acids and limiting concentrations of nitrate and sulfate gave complete reduction of nitrate from 0 to 5.5 cm and complete or near-complete reduction of sulfate from 3.2 to 11.5 cm along the bioreactor flow path. Most of the biomass (85%) and most of the genes for nitrate reduction (narG, 96%; napA, 99%) and for sulfate reduction (dsrB, 91%) were present near the inlet (0-5.5 cm) of the 37-cm-long bioreactor. Microbial community analysis by a combination of denaturing gradient gel electrophoresis and pyrosequencing of 16S rRNA amplicons indicated that nitrate reducing Arcobacter and Pseudomonas species were located from 0 to 3.2 cm and throughout, respectively. Desulfobulbus species were the main sulfate reducers present and acetotrophic methanogens of the genus Methanosaeta predominated at 20 37 cm. Overall, the results indicated a succession of microbial communities along the bioreactor flow path. In the absence of nitrate, the sulfate reduction zone moved nearer to the bioreactor inlet. The sulfide concentration in the bioreactor effluent was temporarily lowered after nitrate injection was re-started. Hence, the bioreactor sulfide output could be disrupted by pulsed, not by constant nitrate injection, as demonstrated also previously in a low-temperature oil field. PMID- 21538111 TI - A diverse bacterial community in an anoxic quinoline-degrading bioreactor determined by using pyrosequencing and clone library analysis. AB - There is a concern of whether the structure and diversity of a microbial community can be effectively revealed by short-length pyrosequencing reads. In this study, we performed a microbial community analysis on a sample from a high efficiency denitrifying quinoline-degrading bioreactor and compared the results generated by pyrosequencing with those generated by clone library technology. By both technologies, 16S rRNA gene analysis indicated that the bacteria in the sample were closely related to, for example, Proteobacteria, Actinobacteria, and Bacteroidetes. The sequences belonging to Rhodococcus were the most predominant, and Pseudomonas, Sphingomonas, Acidovorax, and Zoogloea were also abundant. Both methods revealed a similar overall bacterial community structure. However, the 622 pyrosequencing reads of the hypervariable V3 region of the 16S rRNA gene revealed much higher bacterial diversity than the 130 sequences from the full length 16S rRNA gene clone library. The 92 operational taxonomic unit (OTUs) detected using pyrosequencing belonged to 45 families, whereas the 37 OTUs found in the clone library belonged to 25 families. Most sequences obtained from the clone library had equivalents in the pyrosequencing reads. However, 64 OTUs detected by pyrosequencing were not represented in the clone library. Our results demonstrate that pyrosequencing of the V3 region of the 16S rRNA gene is not only a powerful tool for discovering low-abundance bacterial populations but is also reliable for dissecting the bacterial community structure in a wastewater environment. PMID- 21538115 TI - Enhanced production of GDP-L-fucose by overexpression of NADPH regenerator in recombinant Escherichia coli. AB - Biosynthesis of guanosine 5'-diphosphate-L-fucose (GDP-L-fucose) requires NADPH as a reducing cofactor. In this study, endogenous NADPH regenerating enzymes such as glucose-6-phosphate dehydrogenase (G6PDH), isocitrate dehydrogenase (Icd), and NADP(+)-dependent malate dehydrogenase (MaeB) were overexpressed to increase GDP L-fucose production in recombinant Escherichia coli. The effects of overexpression of each NADPH regenerating enzyme on GDP-L-fucose production were investigated in a series of batch and fed-batch fermentations. Batch fermentations showed that overexpression of G6PDH was the most effective for GDP L-fucose production. However, GDP-L-fucose production was not enhanced by overexpression of G6PDH in the glucose-limited fed-batch fermentation. Hence, a glucose feeding strategy was optimized to enhance GDP-L-fucose production. Fed batch fermentation with a pH-stat feeding mode for sufficient supply of glucose significantly enhanced GDP-L-fucose production compared with glucose-limited fed batch fermentation. A maximum GDP-L-fucose concentration of 235.2 +/- 3.3 mg l( 1), corresponding to a 21% enhancement in the GDP-L-fucose production compared with the control strain overexpressing GDP-L-fucose biosynthetic enzymes only, was achieved in the pH-stat fed-batch fermentation of the recombinant E. coli overexpressing G6PDH. It was concluded that sufficient glucose supply and efficient NADPH regeneration are crucial for NADPH-dependent GDP-L-fucose production in recombinant E. coli. PMID- 21538116 TI - Spontaneous bacterial cell lysis and biofilm formation in the colon of the Cape Dune mole-rat and the laboratory rabbit. AB - A wide range of techniques, including high-throughput DNA sequencing methods, have been applied to the evaluation of the normal intestinal flora. However, the inability to grow many of those species in culture imposes substantial constraints on the techniques used to evaluate this important community. The presence of biofilms in the normal gut adds further complexity to the issue. In this study, a flow cytometric analysis was used to separate intact bacterial cells, cell debris, and other particulate matter based on bacteria-specific staining and particle size. In addition, an analysis of biofilm formation using fluorescent light microscopy was conducted. Using these approaches, the ratio of bacterial cell debris to intact bacterial cells as a measure of spontaneous lysis of bacterial cells in the gut of the Cape dune mole-rat (Bathyergus suillus) and the laboratory rabbit (Oryctolagus cuniculus) was examined, and the degree of biofilm formation was semi-quantitatively assessed. The results suggest that the degree of spontaneous cell lysis was greater in the appendix than in the cecum in both the mole-rat and the rabbit. Further, the results point toward extensive epithelial-associated biofilm formation in the proximal mole-rat and rabbit large bowel, although the biofilms may be less structured than those found in laboratory rodents and in humans. PMID- 21538117 TI - The neurobiology of erythropoietin. PMID- 21538118 TI - Abeta oligomer-induced synapse degeneration in Alzheimer's disease. AB - Abeta oligomers cause a collection of molecular events associated with memory loss in Alzheimer's disease, centering on disrupting the maintenance of synapse structure and function. In this brief review of the synaptotoxic effects of Abeta oligomers, we focus on the neuronal properties governing oligomer targeting and toxicity-especially with respect to binding sites and mechanisms of binding. We also discuss ways in which mechanistic insights from other diseases offer clues in the pursuit of the molecular basis of Alzheimer's disease. PMID- 21538119 TI - Role of acetylcholinesterase on the structure and function of cholinergic synapses: insights gained from studies on knockout mice. AB - Electrophysiological and ultrastructural studies were performed on phrenic nerve hemidiaphragm preparations isolated from wild-type and acetylcholinesterase (AChE) knockout (KO) mice to determine the compensatory mechanisms manifested by the neuromuscular junction to excess acetylcholine (ACh). The diaphragm was selected since it is the primary muscle of respiration, and it must adapt to allow for survival of the organism in the absence of AChE. Nerve-elicited muscle contractions, miniature endplate potentials (MEPPs) and evoked endplate potentials (EPPs) were recorded by conventional electrophysiological techniques from phrenic nerve-hemidiaphragm preparations isolated from 1.5- to 2-month-old wild-type (AChE(+/+)) or AChE KO (AChE(-/-)) mice. These recordings were chosen to provide a comprehensive assessment of functional alterations of the diaphragm muscle resulting from the absence of AChE. Tension measurements from AChE(-/-) mice revealed that the amplitude of twitch tensions was potentiated, but tetanic tensions underwent a use-dependent decline at frequencies below 70 Hz and above 100 Hz. MEPPs recorded from hemidiaphragms of AChE(-/-) mice showed a reduction in frequency and a prolongation in decay (37%) but no change in amplitude compared to values observed in age-matched wild-type littermates. In contrast, MEPPs recorded from hemidiaphragms of wild-type mice that were exposed for 30 min to the selective AChE inhibitor 5-bis(4-allyldimethyl-ammoniumphenyl)pentane-3 one (BW284C51) exhibited a pronounced increase in amplitude (42%) and a more marked prolongation in decay (76%). The difference between MEPP amplitudes and decays in AChE(-/-) hemidiaphragms and in wild-type hemidiaphragms treated with BW284C51 represents effective adaptation by the former to a high ACh environment. Electron microscopic examination revealed that diaphragm muscles of AChE(-/-) mice had smaller nerve terminals and diminished pre- and post-synaptic surface contacts relative to neuromuscular junctions of AChE(+/+) mice. The morphological changes are suggested to account, in part, for the ability of muscle from AChE(-/ ) mice to function in the complete absence of AChE. PMID- 21538120 TI - Dissimilarity in vulnerability: self-reported symptoms among children with experiences of intimate partner violence. AB - Children with experiences of intimate partner violence (IPV) are at risk. Not all children, however, display symptoms, and differences connected to gender and age have been demonstrated. In this exploratory study, children's own reports of symptoms were used. The 41 recruited children, between 7 and 19 years old, were entered into a group program specially directed toward children with experiences of IPV. These children reported experiencing more symptoms overall when compared with non-exposed children. The relationship to the abuser and children's symptoms related differently for boys and for girls. Girls who had continued contact with the abusive father described more mental health problems than did other girls exposed to IPV and more than did boys with continued contact. Among children with experiences of custody disputes or other judicial processes, age rather than gender was connected to differences in self-reported symptoms. Younger children with experiences of judicial processes reported more mental health problems than did those with no experience. PMID- 21538121 TI - Identifying patterns of early risk for mental health and academic problems in adolescence: a longitudinal study of urban youth. AB - This investigation examined profiles of individual, academic, and social risks in elementary school, and their association with mental health and academic difficulties in adolescence. Latent profile analyses of data from 574 urban youth revealed three risk classes. Children with the "well-adjusted" class had assets in the academic and social domains, low aggressive behavior, and low depressive symptoms in elementary school, and low rates of academic and mental health problems in adolescence. Children in the "behavior-academic-peer risk" class, characterized by high aggressive behavior, low academic achievement, and low peer acceptance, had conduct problems, academic difficulties, and increased mental health service use in adolescence. Children with the "academic-peer risk" class also had academic and peer problems but they were less aggressive and had higher depressive symptoms than the "behavior-academic-peer risk" class in the first grade; the "academic-peer risk" class had depression, conduct problems, academic difficulties, and increased mental health service use during adolescence. No differences were found between the risk classes with respect to adolescent outcomes. PMID- 21538122 TI - Aberrant activation-induced cytidine deaminase expression is associated with mucosal intestinalization in the early stage of gastric cancer. AB - Although Helicobacter pylori is a risk factor for gastric cancer (GC), its detailed carcinogenesis remains unclear. Recently, aberrant expression of activation-induced cytidine deaminase (AID) was demonstrated in gastric epithelium with H. pylori infection and seems to cause the accumulation of mutation. This investigation aims to elucidate whether or not AID expression plays an important role in the carcinogenesis of early GC. We examined the correlation between immunohistochemical AID expression and histological characteristics, including pre-existing chronic gastritis and cellular mucin phenotype in 138 cases of intramucosal GC. Furthermore, we investigated the relationship between AID, p53 protein, and beta-catenin. The low degree of polymorphonuclear neutrophil activity, and the high degree of glandular atrophy and intestinal metaplasia were significantly correlated with the high levels of AID expression in non-neoplastic mucosa (P = 0.007, P <= 0.001, and P = 0.003). With regard to mucin phenotype of carcinoma, the intestinal phenotype tended to have the higher AID expression levels (P = 0.052). AID showed close correlations with Cdx2 and nuclear staining of beta-catenin (P = 0.003, P = 0.034). As for p53 protein, no correlation was found with AID expression. Our findings suggest that aberrant AID expression is correlated with persistent inflammatory condition induced by H. pylori infection and may contribute to the development of GC through an inflammatory condition and intestinalization. PMID- 21538123 TI - Differential expression of MYC in H. pylori-related intestinal and diffuse gastric tumors. AB - Evidence suggests that the carcinogenic process guided by Helicobacter pylori is related to the expression of cell cycle and apoptosis proteins as BCL-2, BAX, and MYC. However, the literature is conflicting regarding the expression frequency in the histological subtypes and did not consider cagA gene presence. To investigate the expression of these proteins considering the histological subtypes of gastric cancer associated with H. pylori (cagA), a total of 89 cases were used. H. pylori infection and cagA status were determined by PCR. Immunodetection was performed for MYC, BCL-2, and BAX proteins. H. pylori was found in 95.5% of the patients, among them, 65.8% were cagA(+). Nuclear MYC was detected in 36.4%, BAX in 55.7%, while BCl-2 in just 5%. Nuclear MYC staining was significantly lower in the intestinal than diffuse subtype (p = 0.008) and was related with the presence of H. pylori cagA(+). Additionally, most of the few cases cytoplasmic MYC positive were in the intestinal subtype. In diffuse tumors, although most nuclear MYC positive cases were cagA(+), it was not significant. No difference was observed between BCL-2 or BAX expression considering the presence of cagA gene in the histological subtypes. It seems that MYC could be relevant for the diffuse tumorigenic pathway associated with H. pylori and possibly influenced by the presence of cagA gene, while in intestinal tumors, the tumorigenic pathway does not occur through the MYC expression. PMID- 21538125 TI - Retraction: Erratum to: Greater occipital nerve block in chronic migraine. PMID- 21538124 TI - High CD10 expression in lymph node metastases from surgically treated prostate cancer independently predicts early death. AB - Patients with nodal positive prostate cancers are an important cohort with poorly defined risk factors. CD10 is a cell surface metallopeptidase that has been suggested to play a role in prostate cancer progression. CD10 expression was evaluated in 119 nodal positive prostate cancer patients using tissue microarrays constructed from primary tumors and lymph node metastases. All patients underwent radical prostatectomy and standardized extended lymphadenectomy. They had no neoadjuvant therapy and received deferred androgen deprivation. In the primary tumor, high CD10 expression was significantly associated with earlier death from disease when compared with low CD10 expression (5-year survival 73.7% vs. 91.8%; p = 0.043). In the metastases, a high CD10 expression was significantly associated with larger total size of metastases (median 11.4 vs. 6.5 mm; p = 0.015), earlier death of disease (5-year survival 71.5% vs. 87.3%; p = 0.017), and death of any cause (5-year survival 70.0% vs. 87.2%; p = 0.001) when compared with low CD10 expression. CD10 expression in the metastases added independent prognostic information for overall survival (p = 0.029) after adjustment for Gleason score of the primary tumor, nodal tumor burden, and resection margins. In conclusion, a high CD10 expression in prostate cancer predicts early death. This information is inherent in the primary tumors and in the lymph node metastases and might help to personalize patient management. PMID- 21538126 TI - The Lombrosian prejudice in medicine. The case of epilepsy. Epileptic psychosis. Epilepsy and aggressiveness. AB - In the nineteenth century, epilepsy became subject of experimental research. Lombroso established a relationship between epilepsy and criminality believing in the existence of epileptoid traits and atavism. He tried to demonstrate the common origin of epilepsy, criminality, and genius; factors deteriorating the CNS would act upon centers, which control behavior and ethics. This impairment would cause a lack of control on the lower nervous centers, reducing restraints of instincts and criminal behavior. He described developmental frontal cortex lesions in epileptic patients (today Taylor's dysplasia) and these observations supported the erroneous conviction of a relationship between criminality and epilepsy. Neurological, behavioral, and criminological sciences analyzed Lombroso's doctrine, whereas it was controversial that epileptic patients should be prone to violent actions and aggressive behavior. Today, there is an international panel of experts on epilepsy, which suggests five relevant criteria to determine if a crime committed with aggressiveness could result from epileptic seizures. PMID- 21538127 TI - Absence of MRI soft tissue abnormalities in severe spinal cord injury in children: case-based update. AB - INTRODUCTION: Occult spinal cord injury should be suspected based not only on the mechanism of trauma but also on the age of the patient. The pediatric spine has unique biomechanical and anatomical properties that must be considered carefully when evaluating spinal cord trauma. For instance, the hypermobility and elasticity of the spinal column in children often lead to self-reducing injuries that can mask spinal cord injury. CASE ILLUSTRATION: We present the case of a 22 month-old male patient who was found to have ligamentous injury detected by magnetic resonance imaging (MRI) in the upper cervical spine but missed by MRI in the lower thoracic spine. Furthermore, there was no spinal cord injury in the upper cervical spine, but indeed a serious insult in the thoracic region. Since the advent of MRI, spinal cord injury without radiographic abnormality (SCIWORA) has become increasingly rare but not altogether extinct. CONCLUSIONS: We present a noteworthy example of the inadequacy of MRI in revealing SCIWORA, a term that is antiquated as we combine the latest imaging techniques with a better understanding of the biomechanics of trauma and spine injury. Based on the literature and our case illustration, we believe that the biomechanics of the pediatric spine must be considered when children who may have sustained a SCIWORA are examined. PMID- 21538128 TI - The value of intraoperative neurophysiological monitoring in tethered cord surgery. AB - PURPOSE: The value of intraoperative neurophysiological monitoring (IONM) with surgical detethering in dysraphic patients has been questioned. A retrospective analysis of our series of 65 patients is presented with special focus on technical set-up and outcome. METHODS: All patients were diagnosed with a tethered cord (TC) due to spinal dysraphism. A high-risk group (HRG) was determined consisting of 40 patients with a lipomyelomeningocele and/or a split cord malformation sometimes in combination with a tight filum terminale. The surgical procedure was a detethering operation in all cases performed by a single surgeon during a 9-year period (1999-2008). A standard set-up of IONM was used in all patients consisting of motor-evoked potentials (MEP) evoked by transcranial electrical stimulation (TES) and electrical nerve root stimulation. In young patients, conditioning stimulation was applied in order to improve absent or weak MEPs. RESULTS: IONM responses could be obtained in all patients. Postoperative deterioration of symptoms was found in two patients of whom one patient belonged to the HRG. Mean maximal follow-up of all 65 patients was 4.6 years (median 4.1 years). Long-term deterioration of symptoms was found in 6 of 65 patients with a mean follow-up of 5 years (median 5.3 years). CONCLUSION: The use of IONM is feasible in all TC patients. The identification of functional nervous structures and continuous guarding of the integrity of sacral motor roots by IONM may contribute to the safety of surgical detethering. PMID- 21538129 TI - Idiopathic intracranial hypertension in children: visual outcome and risk of recurrence. AB - PURPOSE: Idiopathic intracranial hypertension (IIH) is a disorder associated with increased intracranial pressure without evidence of a space-occupying lesion and with normal cerebrospinal fluid constituents. The disease is rare in the pediatric population. In this study, we assessed the visual outcome of children with IIH and the risk of recurrence. METHODS: This single-center observational retrospective cohort study included 90 children younger than 18 years of age who satisfied the modified Dandy criteria for the diagnosis of IIH. Upon follow-up, the treatment was discontinued when patients were free of symptoms such as headaches, transient visual obscurations or tinnitus, and when examination revealed no evidence of papilledema. The main outcome measures were visual acuity and visual field outcomes as well as risk of recurrence. RESULTS: The mean follow up was 30.65 months (range 1.15-172.6 months, standard deviation 27.47 months). Special grading scales were devised for visual acuity and visual field scores. The mean visual acuity score improved from 4.7 +/- 0.62 to 4.87 +/- 0.44 (p = 0.003).The mean visual field score improved from 3.41 +/- 0.8 to 3.52 +/- 0.75 (p = 0.21). The recurrence rate was 23.7%, and the risk of recurrence was highest within the first 18 months after diagnosis of IIH. CONCLUSIONS: These study results suggest that pediatric patients with IIH have a favorable visual outcome in terms of both visual acuity and visual field. If there is any recurrence, it is most likely to occur during the first 18 months after diagnosis. PMID- 21538130 TI - Pediatric low-grade glioma survivors experience high quality of life. AB - PURPOSE: The purpose of this study was to determine pediatric low-grade glioma survivors' quality of life and late morbidity including motor, sensory, and cognitive deficits. METHODS: We surveyed 49 survivors and their parents (KINDL questionnaire). RESULTS: Despite tumor and treatment-associated morbidity, survivors (25 boys and 24 girls, median age at diagnosis 7.8 years), but not their parents, rated their total quality of life higher than their peers. Although all survivors had some late morbidity, half of them were able to conduct their daily lives without restriction. CONCLUSION: These results reflect survivors' effective coping mechanisms and underscore the difficulties of assessing quality of life in pediatric populations. PMID- 21538131 TI - The relationship between basal cisterns on CT and time-linked intracranial pressure in paediatric head injury. AB - PURPOSE: Although intracranial pressure (ICP) monitoring is a cornerstone of care for severe traumatic brain injury (TBI), the indications for ICP monitoring in children are unclear. Often, decisions are based on head computed tomography (CT) scan characteristics. Arguably, the patency of the basal cisterns is the most commonly used of these signs. Although raised ICP is more likely with obliterated basal cisterns, the implications of open cisterns are less clear. We examined the association between the status of perimesencephalic cisterns and time-linked ICP values in paediatric severe TBI. METHODS: ICP data linked to individual head CT scans were reviewed. Basal cisterns were classified as open or closed by blinded reviewers. For the initial CT scan, we examined ICP values for the first 6 h after monitor insertion. For follow-up scans, we examined ICP values 3 h before and after scanning. Mean ICP and any episode of ICP >= 20 mmHg during this period were recorded. RESULTS: Data from 104 patients were examined. Basal cisterns were patent in 51.72% of scans, effaced in 34.48% and obliterated in 13.79%. Even when cisterns were open, more than 40% of scans had at least one episode of ICP >= 20 mmHg, and 14% of scans had a mean ICP >= 20 mmHg. The specificity of open cisterns in predicting ICP < 20 mmHg was poor (57.9%). Age-related data were worse. CONCLUSION: Children with severe TBI frequently may have open basal cisterns on head CT despite increased ICP. Open cisterns should not discourage ICP monitoring. PMID- 21538132 TI - Relationship between CO(2) at a rural site and integral measures of atmospheric stagnation, recirculation, and ventilation. AB - Integral quantities, wind run, S, and recirculation factor, R, useful for describing air flow, are calculated and combined with CO(2) mixing ratios. Meteorological observations were obtained from a RASS sodar and CO(2) mixing ratios from a continuous analyzer installed at a rural site in the upper Spanish plateau. The measuring campaign spread over 3 years and two approaches were followed. The first approach considered integral quantities on a daily basis and two classifications of air flow, to date scarcely used. The first classification distinguished among stagnation, recirculation, and ventilation, the second considering synoptic, meso-, and local scales. Moreover, 52.94% of daily values handled in this paper corresponded to ventilation and 49.70% to synoptic scale. The main goal of this approach is the subsequent link between the two classifications: the synoptic scale was associated with ventilation, mesoscale with recirculation and local scale partially with recirculation. CO(2) observations were distributed in air flow groups following these classifications and mesoscale processes were satisfactorily described since noticeable evidence of transport from nearby cities was observed. In the second approach, S and R pairs were used and CO(2) mixing ratios were distributed following percent intervals of ventilation, calculated by binning these pairs. The main goal of the second approach is to consider only three groups of mixing ratios. In the first group, with high ventilation, mixing ratios were low. With intermediate ventilation, mixing ratios were medium, and with low ventilation mixing ratios were high. A contrast of 21 ppm between the third and first groups was obtained at the 95th percentile. Finally, the second group provided a contrast of 3 ppm between north and south directions and also between east and west attributed to transport from nearby cities. PMID- 21538134 TI - Physiological correlates of emotion-regulation during prolonged cycling performance. AB - We proposed that experiencing unpleasant emotions during performance represents unsuccessful emotion-regulatory efforts, and that such effort concurrently tax physiological resources. We used data from 2-h cycling trials (N = 28) at a power output equivalent to lactate threshold. Emotions were calculated before and during cycling with ongoing assessments of ventilation, respiratory quotient, heart rate, and oxygen uptake. Emotion data indicated significant changes over time with all participants reporting decreases in vigour and increases in fatigue, with 14 cases of concurrent increases in anger, depression, and tension. After grouping participants into positive and negative emotion groups, a time x unpleasant emotion group ANOVA indicated a significant interaction effect for changes in ventilation (F (6,21) = 3.09, P = .03, Partial Eta(2) = .47) over time, with no significant difference in other physiological variables or perceived exertion. Among athletes reporting negative emotions, ventilation increased during the middle section, whereas among athletes reporting positive emotions, ventilation increased shortly before completion. Findings suggest that regulating negative emotion is an effortful process taxing physiological substrates. PMID- 21538133 TI - An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties. AB - The concept of drug-likeness has been widely applied in combinatorial chemistry as an approach to reduce attrition in drug discovery and development. Meanwhile, bicyclic privileged structures with versatile binding properties have emerged as ideal source of core scaffolds for the design and synthesis of combinatorial libraries. For the purpose of better assisting the design of bicyclic privileged structure-based combinatorial libraries, we conducted an integrated drug-likeness study on compounds of these scaffolds. Distributions of physicochemical properties (PCPs) were analyzed and in silico prediction models were built. Our results showed that there exist much difference between the drug-like ranges (DLRs) of bicyclic privileged structures and that of others, which have significant impact on compound selection. The DLRs for bicyclic privileged structures were defined as 260 <= MW <= 524; 0.9 <= ALogP <= 5.4; 2 <= Hacc <= 8; Hdon <= 3; 21.0 <= PSA <= 128.6; 6.3 <= FPSA <= 34.2; 1 <= RotB <= 10; 2 <= Nr <= 5; 1 <= Nc <= 7; SA <= 4. Two accurate and easy to understand in silico prediction models, Caco-2 permeability model and metabolic stability classification model, had been built to guide drug candidate optimization. In these models, hydrogen-bond donor and rotatable bond showed major impact on the permeability of compounds, while lipophilicity, flexibility, degree of branching and the existence of some functional groups determined the fate of a drug in metabolic process. Suggestions on structural modification toward higher permeability and metabolic stability were given according to the in silico models. PMID- 21538135 TI - Cache protection strategies of a non-social food-caching corvid, Clark's nutcracker (Nucifraga columbiana). AB - Clark's nutcrackers (Nucifraga columbiana), a non-social corvid, cache much of their food in order to survive periods of resource uncertainty. These caches are at risk as they are subject to pilferage from other animals including conspecifics. Potentially, nutcrackers can ensure the safety of these caches by keeping track of whether they have been observed making a cache and subsequently engage in cache protection strategies-strategies that have been shown by other members of the corvid family (e.g., scrub-jays and ravens). Behaviors including creating more caches, eating a higher proportion of seeds, and re-caching existing compromised sites have been shown in laboratory settings with social corvids and have provided preliminary evidence of the complex cognitive abilities of corvids. In the present study, Clark's nutcrackers are shown to engage in similar cache protection behaviors when observed by a conspecific. Furthermore, we show that these behaviors are a result of social, rather than associative, cues. PMID- 21538137 TI - Isolation of a novel C18-Delta9 polyunsaturated fatty acid specific elongase gene from DHA-producing Isochrysis galbana H29 and its use for the reconstitution of the alternative Delta8 pathway in Saccharomyces cerevisiae. AB - A novel gene (IgASE2) encoding a C18-Delta9 polyunsaturated fatty acids specific (C18-Delta9-PUFAs-specific) elongase was isolated and characterized from DHA-rich microalga, Isochrysis galbana H29. The IgASE2 gene was 1,653 bp in length, contained a 786 bp ORF encoding a protein of 261 amino acids that shared 87% identity with Delta9 elongase, IgASE1, and possessed a 44 bp 5'-untranslated region (5'-UTR) and a 823 bp 3'-untranslated region (3'-UTR). IgASE2, by its heterologous expression in Saccharomyces cerevisiae, elongated linoleic acid (LA, 18:2n-6) and alpha-linolenic (ALA, 18:3n-3) to eicosadienoic acid (EDA, 20:2n-6) and eicosatrienoic acid (ETrA, 20:3n-3), respectively. The conversions of LA to EDA and ALA to ETrA were 57.6 and 56.1%, respectively. Co-expression of this elongase with Delta8 desaturase required for the synthesis of C20-polyunsaturated fatty acids resulted in the accumulation of dihomo-gamma-linolenic acid (20:3n-6) from LA and eicosatetraenoic acid (20:4n-6) from ALA. These results demonstrated that IgASE2 exhibited C18-Delta9-PUFAs-specific elongase activity and the alternative Delta8 pathway was reconstituted. PMID- 21538136 TI - Population genetics of the cytoplasm and the units of selection on mitochondrial DNA in Drosophila melanogaster. AB - Biological variation exists across a nested set of hierarchical levels from nucleotides within genes to populations within species to lineages within the tree of life. How selection acts across this hierarchy is a long-standing question in evolutionary biology. Recent studies have suggested that genome size is influenced largely by the balance of selection, mutation and drift in lineages with different population sizes. Here we use population cage and maternal transmission experiments to identify the relative strength of selection at an individual and cytoplasmic level. No significant trends were observed in the frequency of large (L) and small (S) mtDNAs across 14 generations in population cages. In all replicate cages, new length variants were observed in heteroplasmic states indicating that spontaneous length mutations occurred in these experimental populations. Heteroplasmic flies carrying L genomes were more frequent than those carrying S genomes suggesting an asymmetric mutation dynamic from larger to smaller mtDNAs. Mother-offspring transmission of heteroplasmy showed that the L mtDNA increased in frequency within flies both between and within generations despite sampling drift of the same intensity as occurred in population cages. These results suggest that selection for mtDNA size is stronger at the cytoplasmic than at the organismal level. The fixation of novel mtDNAs within and between species requires a transient intracellular heteroplasmic stage. The balance of population genetic forces at the cytoplasmic and individual levels governs the units of selection on mtDNA, and has implications for evolutionary inference as well as for the effects of mtDNA mutations on fitness, disease and aging. PMID- 21538138 TI - Enhancement of flavone levels through overexpression of chalcone isomerase in hairy root cultures of Scutellaria baicalensis. AB - A complementary DNA (cDNA) encoding Scutellaria baicalensis chalcone isomerase (SbCHI) was isolated using rapid amplification of cDNA ends polymerase chain reaction. After the treatment of wounding or methyl jasmonate, SbCHI transcripts were increased in S. baicalensis cell suspensions. SbCHI-overexpressed and SbCH silenced transgenic hairy root lines were established by using an Agrobacterium rhizogenes-mediated system. SbCHI-overexpressed hairy root lines not only enhanced SbCHI gene expression but also produced more flavones (i.e., baicalin, baicalein, and wogonin) than the control hairy root line. In contrast, SbCHI silenced hairy root lines reduced SbCHI transcripts and flavone production compared to those of the control hairy roots. In addition, the amount of wogonin in all hairy root cultures was increased compared to that of wild-type roots of S. baicalensis. Finally, this study showed the importance of CHI in flavone biosynthesis and the efficiency of metabolic engineering in S. baicalensis hairy roots. PMID- 21538140 TI - Statistical-mechanical measure of stochastic spiking coherence in a population of inhibitory subthreshold neurons. AB - By varying the noise intensity, we study stochastic spiking coherence (i.e., collective coherence between noise-induced neural spikings) in an inhibitory population of subthreshold neurons (which cannot fire spontaneously without noise). This stochastic spiking coherence may be well visualized in the raster plot of neural spikes. For a coherent case, partially-occupied "stripes" (composed of spikes and indicating collective coherence) are formed in the raster plot. This partial occupation occurs due to "stochastic spike skipping" which is well shown in the multi-peaked interspike interval histogram. The main purpose of our work is to quantitatively measure the degree of stochastic spiking coherence seen in the raster plot. We introduce a new spike-based coherence measure M ( s ) by considering the occupation pattern and the pacing pattern of spikes in the stripes. In particular, the pacing degree between spikes is determined in a statistical-mechanical way by quantifying the average contribution of (microscopic) individual spikes to the (macroscopic) ensemble-averaged global potential. This "statistical-mechanical" measure M ( s ) is in contrast to the conventional measures such as the "thermodynamic" order parameter (which concerns the time-averaged fluctuations of the macroscopic global potential), the "microscopic" correlation-based measure (based on the cross-correlation between the microscopic individual potentials), and the measures of precise spike timing (based on the peri-stimulus time histogram). In terms of M ( s ), we quantitatively characterize the stochastic spiking coherence, and find that M ( s ) reflects the degree of collective spiking coherence seen in the raster plot very well. Hence, the "statistical-mechanical" spike-based measure M ( s ) may be used usefully to quantify the degree of stochastic spiking coherence in a statistical-mechanical way. PMID- 21538139 TI - A 5-formyltetrahydrofolate cycloligase paralog from all domains of life: comparative genomic and experimental evidence for a cryptic role in thiamin metabolism. AB - A paralog (here termed COG0212) of the ATP-dependent folate salvage enzyme 5 formyltetrahydrofolate cycloligase (5-FCL) occurs in all domains of life and, although typically annotated as 5-FCL in pro- and eukaryotic genomes, is of unknown function. COG0212 is similar in overall structure to 5-FCL, particularly in the substrate binding region, and has distant similarity to other kinases. The Arabidopsis thaliana COG0212 protein was shown to be targeted to chloroplasts and to be required for embryo viability. Comparative genomic analysis revealed that a high proportion (19%) of archaeal and bacterial COG0212 genes are clustered on the chromosome with various genes implicated in thiamin metabolism or transport but showed no such association between COG0212 and folate metabolism. Consistent with the bioinformatic evidence for a role in thiamin metabolism, ablating COG0212 in the archaeon Haloferax volcanii caused accumulation of thiamin monophosphate. Biochemical and functional complementation tests of several known and hypothetical thiamin-related activities (involving thiamin, its breakdown products, and their phosphates) were, however, negative. Also consistent with the bioinformatic evidence, the COG0212 proteins from A. thaliana and prokaryote sources lacked 5-FCL activity in vitro and did not complement the growth defect or the characteristic 5-formyltetrahydrofolate accumulation of a 5-FCL-deficient (DeltaygfA) Escherichia coli strain. We therefore propose (a) that COG0212 has an unrecognized yet sometimes crucial role in thiamin metabolism, most probably in salvage or detoxification, and (b) that is not a 5-FCL and should no longer be so annotated. PMID- 21538141 TI - Stochastic amplification of calcium-activated potassium currents in Ca2+ microdomains. AB - Small conductance (SK) calcium-activated potassium channels are found in many tissues throughout the body and open in response to elevations in intracellular calcium. In hippocampal neurons, SK channels are spatially co-localized with L Type calcium channels. Due to the restriction of calcium transients into microdomains, only a limited number of L-Type Ca(2+) channels can activate SK and, thus, stochastic gating becomes relevant. Using a stochastic model with calcium microdomains, we predict that intracellular Ca(2+) fluctuations resulting from Ca(2+) channel gating can increase SK2 subthreshold activity by 1-2 orders of magnitude. This effectively reduces the value of the Hill coefficient. To explain the underlying mechanism, we show how short, high-amplitude calcium pulses associated with stochastic gating of calcium channels are much more effective at activating SK2 channels than the steady calcium signal produced by a deterministic simulation. This stochastic amplification results from two factors: first, a supralinear rise in the SK2 channel's steady-state activation curve at low calcium levels and, second, a momentary reduction in the channel's time constant during the calcium pulse, causing the channel to approach its steady state activation value much faster than it decays. Stochastic amplification can potentially explain subthreshold SK2 activation in unified models of both sub- and suprathreshold regimes. Furthermore, we expect it to be a general phenomenon relevant to many proteins that are activated nonlinearly by stochastic ligand release. PMID- 21538143 TI - Low-power 808-nm laser irradiation inhibits cell proliferation of a human-derived glioblastoma cell line in vitro. AB - It has been reported that low-power laser irradiation (LLI) can modulate various biological processes including cell proliferation. Some reports suggest that LLI interferes with the cell cycle and inhibits cell proliferation, while others suggest that LLI has a stimulatory effect. Mechanisms underlying the effects of LLI remain unclear. Since the effects of LLI on cancer cells are not well understood, with the aim of developing an LLI therapy for malignant glioblastoma, we investigated the effects of LLI on the cell proliferation of the human-derived glioblastoma cell line A-172. Glioblastoma cell cultures were irradiated with a diode laser at a wavelength of 808 nm and the effects on cell viability and proliferation were examined. Cell counting at 24 and 48 h after irradiation showed that LLI (at 18, 36 and 54 J/cm(2)) suppressed proliferation of A-172 cells in a fluence-dependent manner (irradiation for 20, 40 and 60 min). A reduction in the number of viable cells was also demonstrated by a fluorescent marker for viable cells, calcein acetoxymethylester (calcein-AM). The reduction in cell viability was not associated with morphological changes in the cells or with necrotic cell death as demonstrated by propidium iodide staining. LLI also had little effect on cell proliferation as shown by 5-bromo-2'-deoxyuridine staining. We discuss possible mechanisms underlying the suppressive effect of 808 nm LLI on the viability of human-derived glioblastoma A-172 cells. PMID- 21538144 TI - Metformin pharmacokinetics in nondiabetic pregnant women with polycystic ovary syndrome. AB - BACKGROUND: The use of metformin throughout gestation by pregnant women with polycystic ovary syndrome (PCOS) significantly reduces the number of first trimester spontaneous abortions and the rate of occurrence of gestational diabetes. OBJECTIVE: The objective of this study was to investigate the pharmacokinetics and the placental transfer of metformin in pregnant women with PCOS. PATIENTS AND METHODS: Eight pregnant women with PCOS taking 850 mg metformin every 12 h during the third trimester of pregnancy were evaluated. Maternal blood samples were collected at steady state during the dose interval (0 12 h). Maternal and umbilical cord blood samples were also obtained at delivery. Metformin plasma concentrations were analyzed by high-performance liquid chromatography, and pharmacokinetic parameters were determined using a non compartmental model. Data are reported as median and minimum and maximum values. RESULTS: Metformin pharmacokinetic parameters were: t(1/2), 3.8 (2.8-5.4) h; t(max), 2.0 (0.5-3.0) h; C(max), 1.4 (0.5-2.1) mg/L; C(mean), 0.5 (0.2-0.9) mg/L; AUC(0-12), 6.4 (1.1-9.2) mg h/L; Cl/f, 105 (60-274) L/h; Vd/f, 551 (385-1173) L; median fluctuation, 89 (79-95)%. Umbilical/maternal metformin plasma concentration ratios were 0.7 (0.4-1.3). CONCLUSION: Metformin oral clearance (Cl/f) had increased in our patients relative to nonpregnant healthy volunteers or diabetic patients. Therefore, lower plasma metformin concentrations were observed for nondiabetic pregnant women with PCOS. Future studies should be conducted to demonstrate the therapeutic efficacy of metformin during pregnancy. Caution is warranted as umbilical/maternal metformin plasma concentrations ratios of around 0.7 require metformin dosage adjustment. PMID- 21538145 TI - One-year prospective follow-up of pharmacological treatment in children with attention-deficit/hyperactivity disorder. AB - OBJECTIVES: To delineate the safety and tolerability profile of methylphenidate and atomoxetine in children and adolescents with attention deficit hyperactivity disorder (ADHD) monitored for more than 1 year. DESIGN: A cohort study analyzing data from the national ADHD register on patients from the Lombardy Region treated with MPH or atomoxetine. PARTICIPANTS: A total of 229 children (median age 11 years, range 6-17), enrolled in 15 regional centers between June 2007 and May 2010. RESULTS: The prevalence rate of pharmacological treatment for ADHD was 0.23%, whereas the estimated ADHD prevalence in the population was 0.95%. In total, 73.8% of patients had been treated with atomoxetine (10-90 mg daily) or MPH (10-75 mg daily); 22% of patients also received an additional psychotropic drug. Of the treated children, 26.9% discontinued the drug prior to 1 year of treatment, mostly because of adverse effects (28.6%). No new or unexpected adverse events (rate 39.2%) were encountered. Decreased appetite, headache, and unstable mood were the leading events. The most severe events occurred in two boys: one experienced absence seizures for the first time with MPH, the other experienced hallucinations with atomoxetine. Therapy was discontinued in ten male patients (7.7%) because of adverse events. All patients with adverse effects recovered well. CONCLUSIONS: A very low rate of ADHD prevalence was estimated in Italian children compared to that reported in other countries. Although the medications for ADHD are generally well tolerated, with only mild or minor adverse effects in most cases, their rational use can only be guaranteed by disseminating and monitoring evidence-based practices and by monitoring the safety and efficacy of treatments in both the short and long terms with appropriate tools and approaches. PMID- 21538146 TI - Buprenorphine versus methadone in pregnant opioid-dependent women: a prospective multicenter study. AB - PATIENTS AND METHODS: In order to investigate the effects of exposure to buprenorphine compared with methadone during pregnancy, a prospective multicenter study was conducted in collaboration with maternity hospitals, maintenance therapy centers, and general practitioners involved in addiction care. Ninety pregnant women exposed to buprenorphine and 45 to metadone were selected for the study. RESULTS: During pregnancy, some women were exposed to illicit agents: cannabis (42% in the buprenorphine group vs. 58% in the methadone-treated group), heroin (17% vs. 44%), or cocaine (3% vs. 11%). Pregnancies ended in 85 vs. 40 live births, one vs. two stillbirths, two vs. one spontaneous abortion, two vs. one voluntary termination, and one vs. one medical termination in the buprenorphine and the methadone groups, respectively. Newborns had a birth weight of 2,892 +/- 506 g (buprenorphine) vs. 2,731 +/- 634 g (methadone) and a body length of 47.6 +/- 2.5 cm vs. 47.1 +/- 3 cm. 18.8% vs. 10% of newborns were delivered before 37 weeks of amenorrhea. Neonatal withdrawal syndrome occurred more frequently in the methadone group (62.5% vs. 41.2, p = 0.03). After adjustment for heroin exposure in late pregnancy, rates of neonatal withdrawal were no longer different between the methadone and buprenorphine groups. Twenty one babies (84%) in the methadone group and 20 (57%) in the buprenorphine group (p = 0.03) required opiate treatment. CONCLUSIONS: We did not observe more frequent malformations or cases of withdrawal syndrome in the buprenorphine group than in the methadone-treated group. Buprenorphine appears to be as safe as the currently approved substitute methadone considered to date as the reference treatment for pregnant opioid-dependent women. PMID- 21538147 TI - Inhibitory activity of cinnamon bark species and their combination effect with acarbose against intestinal alpha-glucosidase and pancreatic alpha-amylase. AB - Inhibition of alpha-glucosidase and pancreatic alpha-amylase is one of the therapeutic approaches for delaying carbohydrate digestion, resulting in reduced postprandial glucose. The aim of this study was to evaluate the phytochemical analysis and the inhibitory effect of various cinnamon bark species against intestinal alpha-glucosidase and pancreatic alpha-amylase. The results showed that the content of total phenolic, flavonoid, and condensed tannin ranged from 0.17 to 0.21 g gallic acid equivalent/g extract, from 48.85 to 65.52 mg quercetin equivalent/g extract, and from 0.12 to 0.15 g catechin equivalent/g extract, respectively. The HPLC fingerprints of each cinnamon species were established. Among cinnamon species, Thai cinnamon extract was the most potent inhibitor against the intestinal maltase with the IC(50) values of 0.58 +/- 0.01 mg/ml. The findings also showed that Ceylon cinnamon was the most effective intestinal sucrase and pancreatic alpha-amylase inhibitor with the IC(50) values of 0.42 +/- 0.02 and 1.23 +/- 0.02 mg/ml, respectively. In addition, cinnamon extracts produced additive inhibition against intestinal alpha-glucosidase and pancreatic alpha-amylase when combined with acarbose. These results suggest that cinnamon bark extracts may be potentially useful for the control of postprandial glucose in diabetic patients through inhibition of intestinal alpha-glucosidase and pancreatic alpha-amylase. PMID- 21538148 TI - Rho-mediated activation of PI(4)P5K and lipid second messengers is necessary for promotion of angiogenesis by Semaphorin 4D. AB - Phosphatidylinositol 4-phosphate 5-kinase (PI(4)P5K) is a type I lipid kinase that generates the lipid second messenger phospholipid phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) and functions downstream of RhoA in actin organization. It is known to play an essential role in neurite remodeling, yielding a phenotype identical to that seen in cells treated with Semaphorin 4D (Sema4D), a protein that regulates proliferation, adhesion and migration in many different cell types. Plexin-B1, the receptor for Sema4D, activates RhoA in order to generate a pro-angiogenic signal in endothelial cells. Therefore, we looked in human umbilical vein endothelial cells (HUVEC) to determine if Plexin-B1 exerted control over the cytoskeleton by regulation of PI(4)P5K activity. Here we demonstrate the Rho/Rho Kinase (ROK)-dependent generation of PI(4,5)P(2) upon treatment of HUVEC with Sema4D, as well as co-localization of PI(4)P5Kalpha with Plexin-B1. Formation of PI(4,5)P(2) was necessary for cytoskeletal polymerization, as expression of the phosphatase synaptojanin blocked this effect. We noted phosphorylation and activation of PLCgamma and an increase in intracellular calcium upon treatment of HUVEC with Sema4D, responses that were necessary for a pro-angiogenic phenotype observed in vitro. Taken together, these results suggest that Plexin-B1 promotes angiogenesis in endothelial cells by signaling through PI(4)P5Kalpha and generating lipid second messengers. PMID- 21538149 TI - Parastomal hernia incarceration due to migrated intragastric balloon. AB - The temporary placement of intragastric balloons is a common method to achieve rapid weight loss before planned metabolic surgery. We report the case of a 48 year-old morbidly obese patient. Ten years ago the patient underwent emergency sigmoidectomy with creation of a double-barreled ileostomy for perforated diverticulitis. Over time he developed a giant parastomal hernia. For preoperative weight reduction before planned restoration of intestinal continuity, an intragastric balloon was inserted 3 years ago. The patient was admitted to our emergency department with peritonism and a septic shock. After computed tomography showing small bowel ileus, laparotomy was performed, revealing marked ischemia of incarcerated small and large intestine. Only postoperatively was the intragastric balloon found in the resected small bowel, causing a mechanical ileus with consecutive incarceration of the bowel. We review the literature on complications due to the migration of intragastric balloons. This clinical case gives a fair warning of the possible deleterious outcome of intragastric balloons, especially in hernia patients. PMID- 21538150 TI - A nationwide study on readmission, morbidity, and mortality after umbilical and epigastric hernia repair. AB - BACKGROUND: Repair for umbilical and epigastric hernia is a minor and common surgical procedure. Early outcomes are not well documented. METHODS: All patients >=18 years operated on for umbilical or epigastric hernia in Denmark during a 2 year period (2005-2006) were analysed according to hospital stay, risk of readmission, complications, and mortality <30 days after operation. Patients with acute operations and patients having an umbilical and epigastric hernia repair secondary to other surgical procedures were excluded. Results were based on data from the National Patient Registry. RESULTS: A total 3,431 operations (open repairs 3,165; laparoscopic repairs 266) in 3,383 patients were performed. The median hospital stay was 0 day (range 0-61 days) (open 0 day; laparoscopic 1 day); 75% stayed in hospital for 0 days, 20% for 1 day and 5% > 1 day. Readmissions occurred in 5.3% of cases (open 4.9%; laparoscopic 10.5%). In the majority of patients readmissions were due to wound-related problems (haematoma, bleeding and/or infection) (46%), seroma (19%), or pain (7%). At 30 days, complications and mortality occurred in 4.1% (open 3.7%; laparoscopic 8.2%) and 0.1% (open 0.1%; laparoscopic 0.4%), respectively. CONCLUSION: This first prospective nationwide study on elective umbilical and epigastric hernia repair found low morbidity and mortality but a high readmission rate mostly because of wound problems, seroma formation, or pain. Future research should focus on early outcomes in terms of wound problems, seroma formation, and pain after umbilical and epigastric hernia repair. PMID- 21538151 TI - First laparoscopic totally extraperitoneal repair of Laugier's hernia: a case report. AB - An atypical femoral hernia developing through the lacunar ligament is called Laugier's hernia. Preoperative diagnosis of these atypical hernias is very difficult because of their rarity and similar clinical appearance to conventional femoral hernias. A 52-year-old female presented with right groin swelling. During laparoscopic totally extraperitoneal (TEP) inguinal hernia repair, a hernia sac through an opening in the lacunar ligament was diagnosed and repaired with mesh covering the inguinal floor. The surgeon should be alert to the possibility of an atypical femoral hernia when examining patients with inguinal hernias. A laparoscopic approach should be chosen instead of a conventional approach for the treatment of femoral hernias because of its high diagnostic and therapeutic capacity for all types of femoral hernia, including Laugier's. PMID- 21538152 TI - Stress overload: a new approach to the assessment of stress. AB - The link between stress and health has not received strong empirical support, possibly due to problems in the stress measures used. Here, the first wholly empirical development of a new "Stress Overload Scale" is described. A pool of 150 items was formed to reflect "overload", a common denominator in stress theories. Then, the results of five sequenced studies, conducted in heterogeneous community samples, were used to pare the item pool. Exploratory (n = 431) and confirmatory (n = 433) analyses revealed two factors (Event Load and Personal Vulnerability) corresponding to theoretical constructs; only the best factor markers were submitted to further construct validity (n = 310) and reliability tests (n = 342). The 24 strongest items were selected for the SOS, which demonstrated criterion validity in predicting who (n = 285) would become sick following a common stressor. The SOS is (1) psychometrically strong, especially in its validity relative to popular measures; (2) appropriate to community research, due to its brevity and fit to a broad demographic spectrum; (3) unique in its ability to cross-section individuals into risk categories. It should prove useful to community psychologists in determining etiology, diagnosing risk for pathology, and evaluating the efficacy of interventions. PMID- 21538153 TI - Targeting apoptosis for optical imaging of infection. AB - PURPOSE: Infection is ubiquitous and a major cause of morbidity and mortality. The most reliable method for localizing infection requires radiolabeling autologous white blood cells ex vivo. A compound that can be injected directly into a patient and can selectively image infectious foci will eliminate the drawbacks. The resolution of infection is associated with neutrophil apoptosis and necrosis presenting phosphatidylserine (PS) on the neutrophil outer leaflet. Targeting PS with intravenous administration of a PS-specific, near-infrared (NIR) fluorophore will permit localization of infectious foci by optical imaging. METHODS: Bacterial infection and sterile inflammation were induced in separate groups (n = 5) of mice. PS was targeted with a NIR fluorophore, PSVue((r))794 (2.7 pmol). Imaging was performed (ex = 730 nm, em = 830 nm) using Kodak Multispectral FX-Pro system. The contralateral normal thigh served as an individualized control. Confocal microscopy of normal and apoptotic neutrophils and bacteria confirmed PS specificity. RESULTS: Lesions, with a 10-s image acquisition, were unequivocally visible at 5 min post-injection. At 3 h post injection, the lesion to background intensity ratios in the foci of infection (6.6 +/- 0.2) were greater than those in inflammation (3.2 +/- 0.5). Image fusions confirmed anatomical locations of the lesions. Confocal microscopy determined the fluorophore specificity for PS. CONCLUSIONS: Targeting PS presented on the outer leaflet of apoptotic or necrotic neutrophils as well as gram-positive microorganism with PS-specific NIR fluorophore provides a sensitive means of imaging infection. Literature indicates that NIR fluorophores can be detected 7-14 cm deep in tissue. This observation together with the excellent results and the continued development of versatile imaging devices could make optical imaging a simple, specific, and rapid modality for imaging infection. PMID- 21538154 TI - In vivo photoactivation without "light": use of Cherenkov radiation to overcome the penetration limit of light. AB - PURPOSE: The poor tissue penetration of visible light has been a major barrier for optical imaging, photoactivatable conversions, and photodynamic therapy for in vivo targets with depths beyond 10 mm. In this report, as a proof-of-concept, we demonstrated that a positron emission tomography (PET) radiotracer, 2-deoxy-2 [(18)F]fluoro-D-glucose ((18)FDG), could be used as an alternative light source for photoactivation. PROCEDURES: We utilized (18)FDG, which is a metabolic activity-based PET probe, as a source of light to photoactivate caged luciferin in a breast cancer animal model expressing luciferase. RESULTS: Bioluminescence produced from luciferin allowed for the real-time monitoring of Cherenkov radiation-promoted uncaging of the substrate. CONCLUSION: The proposed method may provide a very important option for in vivo photoactivation, in particular for activation of photosensitizers for photodynamic therapy and eventually for combining radioisotope therapy and photodynamic therapy. PMID- 21538155 TI - Detection of altered collagen fiber alignment in the cervical facet capsule after whiplash-like joint retraction. AB - The cervical facet joint has been identified as the source of pain in patients with whiplash-associated disorders, but most clinical studies report no radiographic evidence of tissue injury in these disorders. The goal of this study was to utilize quantitative polarized light imaging to assess the potential for altered collagen fiber alignment in human cadaveric cervical facet capsule specimens (n = 8) during and after a joint retraction simulating whiplash exposure. Although no evidence of ligament damage was detected during whiplash like retraction, mechanical and microstructural changes were identified after loading. Retraction produced significant decreases in ligament stiffness (p = 0.0186) and increases in laxity (p = 0.0065). In addition, image analysis indicated that 21.1 +/- 17.1% of the capsule sustained principal strains that were unrecovered immediately after retraction. Altered collagen fiber alignment was detected in 32.7 +/- 22.9% of the capsule after retraction. The capsule regions with unrecovered strain and altered fiber alignment after retraction were significantly co-localized with each other (p < 0.0001), suggesting the altered mechanical function may relate to a change in the tissue's fiber organization. The identification of altered fiber alignment in this ligament following retraction without any tears implicates the whiplash kinematic as a potential cause of microstructural damage that is not detectable using standard clinical imaging techniques. PMID- 21538156 TI - Noninvasive ventilation for patients with acute respiratory distress syndrome. PMID- 21538157 TI - Upper GI endoscopy in elderly patients: predictive factors of relevant endoscopic findings. AB - Elderly patients are at increased risk for peptic ulcer and cancer. Predictive factors of relevant endoscopic findings at upper endoscopy in the elderly are unknown. This was a post hoc analysis of a nationwide, endoscopic study. A total of 3,147 elderly patients were selected. Demographic, clinical, and endoscopic data were systematically collected. Relevant findings and new diagnoses of peptic ulcer and malignancy were computed. Both univariate and multivariate analyses were performed. A total of 1,559 (49.5%), 213 (6.8%), 93 (3%) relevant findings, peptic ulcers, and malignancies were detected. Peptic ulcers and malignancies were more frequent in >85-year-old patients (OR 3.1, 95% CI = 2.0-4.7, p = 0.001). The presence of dysphagia (OR = 5.15), weight loss (OR = 4.77), persistent vomiting (OR = 3.68), anaemia (OR = 1.83), and male gender (OR = 1.9) were significantly associated with a malignancy, whilst overt bleeding (OR = 6.66), NSAIDs use (OR = 2.23), and epigastric pain (OR = 1.90) were associated with the presence of peptic ulcer. Peptic ulcer or malignancies were detected in 10% of elderly patients, supporting the use of endoscopy in this age group. Very elderly patients appear to be at higher risk of such lesions. PMID- 21538158 TI - Automatic scoring of virtual mastoidectomies using expert examples. AB - PURPOSE: Automatic scoring of resident performance on a virtual mastoidectomy simulation system is needed to achieve consistent and efficient evaluations. By not requiring immediate expert intervention, the system provides a completely objective assessment of performance as well as a self-driven user assessment mechanism. METHODS: An iconic temporal bone with surgically important regions defined into a fully partitioned segmented dataset was created. Comparisons between expert-drilled bones and student-drilled bones were computed based on gradations with both Euclidean and Earth Mover's Distance. Using the features derived from these comparisons, a decision tree was constructed. This decision tree was used to determine scores of resident surgical performance. The algorithm was applied on multiple expert comparison bones and the scores averaged to provide reliability metric. RESULTS: The reliability metrics for the multi-grade scoring system are better in some cases than previously reported binary classification metrics. The two scoring methods given provide a trade-off between accuracy and speed. CONCLUSIONS: Comparison of virtually drilled bones with expert examples on a voxel level provides sufficient information to score them and provide several specific quality metrics. By merging scores from different expert examples, two related metrics were developed; one is slightly faster and less accurate, while a second is more accurate but takes more processing time. PMID- 21538159 TI - Calibrated segmentation of CBCT and CT images for digitization of dental prostheses. AB - PURPOSE: State of the art computer aided implant planning procedures typically use a surgical template to transfer the digital 3D planning to the operating room. This surgical template can be generated based on an acrylic copy of the patient's removable prosthesis--the so-called radiographic guide--which is digitized using a CBCT or CT scanner. Since the same accurate fit between the surgical template and the patient as with the radiographic guide and the patient should be ensured, a procedure to accurately digitize this guide is needed. METHODS: A procedure is created to accurately digitize radiographic guides based on a calibrated segmentation. Therefore, two steps have to be executed. First, during a calibration step a calibration object is CBCT or CT scanned and a calibration algorithm which results in an optimal threshold value is executed. Next the guide is CBCT or CT scanned and a 3D model is created using the obtained optimal threshold. To validate our method, we compared a high accuracy laser scanned copy of the guide with the generated 3D model by creating a distance map between both models. RESULTS: The procedure was performed for different CBCT and CT scanners, and the digitization error for each scanner was defined. The 90th percentile error measured on average 0.15 mm, which was always less than the applied voxel size for all CBCT and CT test scans. CONCLUSIONS: The calibration procedure evaluated in this study solves the known problem of digitizing a radiographic guide based on non-standardized gray value CBCT images. The procedure can easily be executed by a clinician and allows an accurate digitization of a radiographic guide using a CBCT or CT scanner. Starting from this digitization, an accurate surgical template can be made which has a good fit on the patient's remaining teeth and surrounding soft tissues. PMID- 21538160 TI - Sox4 mediates Tbx3 transcriptional regulation of the gap junction protein Cx43. AB - Tbx3, a T-box transcription factor, regulates key steps in development of the heart and other organ systems. Here, we identify Sox4 as an interacting partner of Tbx3. Pull-down and nuclear retention assays verify this interaction and in situ hybridization reveals Tbx3 and Sox4 to co-localize extensively in the embryo including the atrioventricular and outflow tract cushion mesenchyme and a small area of interventricular myocardium. Tbx3, SOX4, and SOX2 ChIP data, identify a region in intron 1 of Gja1 bound by all tree proteins and subsequent ChIP experiments verify that this sequence is bound, in vivo, in the developing heart. In a luciferase reporter assay, this element displays a synergistic antagonistic response to co-transfection of Tbx3 and Sox4 and in vivo, in zebrafish, drives expression of a reporter in the heart, confirming its function as a cardiac enhancer. Mechanistically, we postulate that Sox4 is a mediator of Tbx3 transcriptional activity. PMID- 21538162 TI - [Cardiac syncope : diagnosis and therapy]. AB - The second most frequent category of syncope is cardiac syncope. In contrast to syncope of noncardiac causes, the 1-year mortality of patients presenting with cardiac syncope without treatment is as high as 33%. Therefore, immediate diagnosis and treatment are necessary. Bradyarrhythmias or tachyarrhythmias are the most common causes of cardiac syncope. In many cases, an initial evaluation including history, physical examination, and electrocardiogram identifies the cause of syncope, so that specific treatment can be initiated immediately. In the remainder of cases, implantable loop recorders are useful to identify arrhythmias, while the presence or absence of structural cardiac disease is diagnosed by echocardiography. Syncope due to arrhythmias is typically treated with implantation of a pacemaker or an implantable cardioverter-defibrillator; treatment of syncope of other cardiac causes requires therapy of the underlying heart disease. PMID- 21538161 TI - Axonal commissures in the central nervous system: how to cross the midline? AB - Organisms with bilateral symmetry elaborate patterns of neuronal projections connecting both sides of the central nervous system at all levels of the neuraxis. During development, these so-called commissural projections navigate across the midline to innervate their contralateral targets. Commissural axon pathfinding has been extensively studied over the past years and turns out to be a highly complex process, implicating modulation of axon responsiveness to the various guidance cues that instruct axon trajectories towards, within and away from the midline. Understanding the molecular mechanisms allowing these switches of response to take place at the appropriate time and place is a major challenge for current research. Recent work characterized several instructive processes controlling the spatial and temporal fine-tuning of the guidance molecular machinery. These findings illustrate the molecular strategies by which commissural axons modulate their sensitivity to guidance cues during midline crossing and show that regulation at both transcriptional and post transcriptional levels are crucial for commissural axon guidance. PMID- 21538163 TI - Diazoxide inhibits aortic endothelial cell apoptosis in diabetic rats via activation of ERK. AB - Endothelial cell (EC) survival is critical in the maintenance of endothelial function as well as in the regulation of angiogenesis and vessel integrity since endothelial dysfunction is the initial lesion of atherosclerosis. The goal of this study was to examine the effect of diazoxide, a mitochondrial ATP-sensitive K(+)(mito K(ATP)) channel opener, on aorta ECs apoptosis and its potential mechanism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats at prediabetic stage. Diazoxide (25 mg kg(-1) day(-1)) was administered intraperitoneally from age 8 weeks to age 30 weeks. Thoracic aorta and cultured thoracic aortic ECs were used. The thickening of thoracic aortic wall and apoptosis of ECs were markedly increased in OLETF rats early from the age of 16 weeks, at the impaired glucose tolerance stage, compared with Long-Evans Tokushima Otsuka rats, in conjunction with intimal hyperplasia and perivascular fibrosis. In contrast, diazoxide treatment inhibited these changes. Further study strongly demonstrated that extracellular signal-regulated kinases (ERKs) are key regulatory proteins in protecting ECs from apoptosis. Diazoxide could significantly enhance phosphorylation of ERK via opening mito K(ATP) channels. This role was reversed by both 5-hydroxydecanoate, selectively closing mito K(ATP) channels, and PD 98509, MEK inhibitors. The present studies demonstrate that diazoxide prevents the onset and development of macrovascular disease in OLETF rats by inhibiting apoptosis directly via phosphorylated ERK increase in aorta ECs. Our findings establish the basis for the therapeutic potential of diazoxide in atherosclerotic disease. PMID- 21538164 TI - Vitamin D receptor gene BsmI, FokI, ApaI, TaqI polymorphisms and bone mineral density in a group of Turkish type 1 diabetic patients. AB - Previous studies have suggested an influence of vitamin D receptor alleles on bone metabolism and on susceptibility to type 1 diabetes mellitus in different ethnic populations. We aimed to investigate the distribution of vitamin D receptor (VDR) alleles in relation to biochemical bone turnover parameters and bone densitometry measurements in a group of Turkish type 1 diabetic patients. One hundred and seventeen patients (M/F 57/60, 27.6 +/- 7.3 y duration of diabetes 8.1 +/- 6.3 y) and 134 healthy controls (M/F 61/73, 26.2 +/- 5.3 y) were included in the study. Bone mineral density (BMD) was evaluated by dual-energy X ray absorptiometry (DEXA). The vitamin D receptor gene (VDR) polymorphisms FokI, Bsm1, Apa1, and Taq1 were examined using a PCR-based restriction analysis. Serum levels of calcium, phosphor osteocalcin, intact parathyroid hormone, and C telopeptide were measured. Vitamin D receptor Bsm1 Fok1, Apa1, and Taq1 genotype distributions were not different between patient with diabetes and control groups. BMD was 0.77 +/- 0.2 g/cm(2) vs. 0.97 +/- 0.2 g/cm(2) (P = 0.0001) for the femur, 1.0 +/- 0.1 g/cm(2) vs. 1.13 +/- 0.1 g/cm(2) (P = 0.001) for type 1 diabetic patients and controls. Bone turnover markers were significantly lower in type 1 diabetic group. BMD measurements and bone metabolic markers were not different between the genotypes in either the patient with diabetes or the controls. The VDR gene polymorphisms, Bsm1, Fok 1, Apa1, and Taq1 showed no influence on bone metabolism in our group of type 1 diabetic patients. PMID- 21538165 TI - Severe transient left ventricular dysfunction induced by thyrotoxicosis. AB - We report on a 44-year-old woman presenting with chest pain and dyspnoea without previous stress-related events. By means of echocardiography severe left ventricular dysfunction and wall motion abnormalities resembling stress-induced cardiomyopathy (Tako Tsubo) were seen. Laboratory investigation revealed thyrotoxicosis and elevated cardiac markers. Six days after starting medical treatment, complete restoration of the left ventricular function was observed. The transient left ventricular dysfunction was induced by thyrotoxicosis resembling stress-induced cardiomyopathy that resolved completely after medical treatment. PMID- 21538166 TI - Disparities in enrollment and use of an electronic patient portal. AB - BACKGROUND: With emphasis on the meaningful use of electronic health records, patient portals are likely to become increasingly important. Little is known about patient enrollment in, and use of, patient portals after explicit invitation from providers. OBJECTIVES: To examine enrollment in, and use of, an electronic patient portal by race/ethnicity, gender and age. DESIGN: Observational, cross sectional study. PARTICIPANTS: Patients with attending physicians seen at one urban, academic primary care practice between May 2008 and October 2009 who received electronic orders inviting their participation in an electronic patient portal. MAIN MEASURES: (a) Enrollment in the patient portal, (b) Solicitation of provider advice among enrollees, (c) Requests for medication refills among enrollees. KEY RESULTS: Overall, 69% of 7,088 patients enrolled in the patient portal. All minority patients were significantly less likely to enroll than whites: 55% blacks, 64% Latinos and 66% Asians compared with 74% whites (chi-square p < 0.05 for all pairwise comparisons). These disparities persisted in adjusted analyses, although differences for Asians were no longer significant. In addition, the oldest patients were less likely to enroll than the youngest (adjusted OR 0.79, 95% CI 0.65-0.97). Although there were no racial/ethnic disparities in use of the patient portal among enrollees, we found differences by age and gender. The youngest patients were significantly less likely to solicit provider advice or request medication refills than any other age group in unadjusted and adjusted analyses. Similarly, male patients were less likely to solicit provider advice than women in all analyses. CONCLUSION: Large racial/ethnic disparities were seen in enrollment in our patient portal. Among enrollees, use of the portal was similar by race/ethnicity, but not by age or gender. Future efforts to expand use of the patient portal need to address potential mechanisms for these disparities to ensure this technology is accessible to diverse patient populations. PMID- 21538167 TI - Electronic medical records and improving the quality of the screening process. PMID- 21538169 TI - Staphylococcus lugdunensis native tricuspid valve endocarditis: a case report and review of literature. AB - Coagulase negative staphylococci are skin commensals and are generally disregarded as contaminants in clinical specimens. Repeated isolation of coagulase negative staphylococci in blood cultures should warrant a species identification to recognize unusually virulent organisms that demand aggressive treatment, such as Staphylococcus lugdunensis. Staphylococcus lugdunensis is known to cause a wide variety of infections, including a predominant left-sided endocarditis. We report a rare case of native tricuspid valve Staphylococcus lugdunensis endocarditis in a non-intravenous drug user and include a brief literature review. PMID- 21538168 TI - Bariatric surgery: a systematic review of the clinical and economic evidence. AB - CONTEXT: Use of bariatric surgery for severe obesity has increased dramatically. OBJECTIVE: To systematically review 1. the clinical efficacy and safety, 2. cost effectiveness of bariatric surgery, and 3. the association between number of surgeries performed (surgical volume) and outcomes. DATA SOURCES: MEDLINE (from 1950), EMBASE (from 1980), CENTRAL, EconLit, EURON EED, Harvard Center for Risk Analysis, trial registries and HTA websites were searched to January 2011. STUDY SELECTION: 1. Randomized controlled trials (RCTs) and 2. cost-utility and cost minimisation studies comparing a contemporary bariatric surgery (i.e., adjustable gastric banding, Roux-en-Y gastric bypass, sleeve gastrectomy) to another contemporary surgical comparator or a non-surgical treatment or 3. Any study reporting the association between surgical volume and outcome. DATA EXTRACTION: Outcomes included changes in weight and obesity-related comorbidity, quality of life and mortality, surgical complications, resource utilization, and incremental cost-utility. RESULTS: RCT data evaluating mortality and obesity-related comorbidity endpoints were lacking. A small RCT of 16 patients reported that adjustable gastric banding reduced weight by 27% (p < 0.01) compared to diet treated controls over 40 weeks. Six small RCTs reported comparisons of commonly used, contemporary procedures. Gastric banding reduced weight to a lower extent than gastric bypass and sleeve gastrectomy and resulted in shorter operating times, fewer serious complications, lower weight loss efficacy, and more frequent reoperations compared to gastric bypass. Sleeve gastrectomy and gastric bypass reduced weight to a similar extent. A 2-year RCT in 50 adolescents reported that gastric banding substantially reduced weight compared to lifestyle modification (35 kg vs. 3 kg; p <0.001). Based on findings of 14 observational studies, higher volume centers and surgeons had lower mortality and complication rates. Surgery resulted in long-term incremental cost-utility ratios of $ <1.000-$40,000 (2009 USD) per quality-adjusted-life-year compared with non-surgical treatment. CONCLUSIONS: Contemporary bariatric surgery appears to result in sustained weight reduction with acceptable costs but rigorous, longer-term (>=5 year) data are needed and a paucity of RCT data on mortality and obesity related comorbidity is evident. Procedure-specific variations in efficacy and risks exist and require further study to clarify the specific indications for and advantages of different procedures. PMID- 21538170 TI - Radiation pneumonitis. PMID- 21538171 TI - Parental sleep concerns in autism spectrum disorders: variations from childhood to adolescence. AB - Sleep problems of adolescents and older children with Autism Spectrum Disorder (ASD) were compared to toddlers and young children in 1,859 children. Sleep was measured with the Children's Sleep Habits Questionnaire. Total sleep problems were significant across all age groups, however the factors contributing to these problems differed. Adolescents and older children had more problems with delayed sleep onset, shorter sleep duration, and daytime sleepiness; while younger children had more bedtime resistance, sleep anxiety, parasomnias, and night wakings. The results suggest that sleep problems persist through adolescence in ASD with differences in types of problems experienced and emphasize the need for clinicians to address sleep behaviors not only in young children with ASD but throughout the age span. PMID- 21538172 TI - IQ predicts biological motion perception in autism spectrum disorders. AB - Biological motion is easily perceived by neurotypical observers when encoded in point-light displays. Some but not all relevant research shows significant deficits in biological motion perception among those with ASD, especially with respect to emotional displays. We tested adults with and without ASD on the perception of masked biological motion and the perception of direction from coherent and scrambled biological motion. Within the autism spectrum group, there was a large and statistically significant relationship between IQ and the ability to perceive directionality in masked biological motion. There were no group differences in sensitivity to biological motion or the ability to identify the direction of motion. Possible explanations are discussed, including the possible use of compensatory strategies in high IQ ASD. PMID- 21538173 TI - Changes in the administrative prevalence of autism spectrum disorders: contribution of special education and health from 2002-2008. AB - This study examined changes in the administrative prevalence of autism spectrum disorders (ASD) in Utah children from 2002 to 2008 by record source (school and health), age (four, six, and eight), and special education classification. Prevalence increased 100% with 1 in 77 children aged eight identified with ASD by 2008. Across study years and age groups rates were higher when health and school data were combined with a greater proportion of cases ascertained from health. The proportion of children with both a health ASD diagnosis and a special education autism classification did not significantly change. Most children with an ASD health diagnosis did not have an autism special education classification. Findings highlight the growing health and educational impact of ASD. PMID- 21538174 TI - Deep breathing improves blunted baroreflex sensitivity even after 30 years of type 1 diabetes. AB - AIMS/HYPOTHESES: Cardiovascular autonomic neuropathy is associated with increased morbidity in patients with type 1 diabetes. Although it is conventionally considered to be an organic, irreversible disorder, we previously demonstrated in patients with short-duration type 1 diabetes that reduced baroreflex sensitivity (BRS) could be corrected by slow, deep breathing, indicating a functional component to the disorder. We have now tested whether autonomic abnormalities in long-term diabetes progress to a stage that cannot be modified by functional manoeuvres, indicating a switch towards predominantly organic dysfunction. METHODS: We studied 117 patients with a short duration (8.9 +/- 0.1 years) and 37 patients with a long duration (33.7 +/- 0.5 years) of type 1 diabetes, 73 healthy controls and 12 heart-transplanted participants (surgical heart denervation). An autonomic score was calculated from autonomic function tests. Spectral analysis of heart rate and blood pressure variability, and BRS, were obtained from recordings during normal (15 breaths per min) and slow, deep (six breaths per min) controlled breathing. RESULTS: BRS was reduced in all patients, but more in patients with a long duration of diabetes or with increasing autonomic involvement, although the effect of duration disappeared after adjustment for age. Slow breathing increased the BRS to the level of the control participants at a normal rate of breathing (15 per min) in all patients except those with an abnormal autonomic score. CONCLUSIONS/INTERPRETATION: Patients with type 1 diabetes have a blunted BRS that in the majority of patients can be restored by slow breathing, irrespective of disease duration. Even after a long duration of diabetes, the abnormal BRS is at least in part of functional origin. PMID- 21538175 TI - Susceptibility to diet-induced obesity and glucose intolerance in the APP (SWE)/PSEN1 (A246E) mouse model of Alzheimer's disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein. AB - AIMS/HYPOTHESIS: Obesity is a major risk factor for development of insulin resistance, a proximal cause of type 2 diabetes and is also associated with an increased relative risk of Alzheimer's disease. We therefore investigated the susceptibility of transgenic mice carrying human mutated transgenes for amyloid precursor protein (APP (SWE)) and presenilin 1 (PSEN1 (A246E)) (APP/PSEN1), or PSEN1 (A246E) alone, which are well-characterised animal models of Alzheimer's disease, to develop obesity, glucose intolerance and insulin resistance, and whether this was age- and/or diet-dependent. METHODS: We analysed the effects of age and/or diet on body weight of wild-type, PSEN1 and APP/PSEN1 mice. We also analysed the effects of diet on glucose homeostasis and insulin signalling in these mice. RESULTS: While there were no body weight differences between 16-17- and 20-21-month-old PSEN1 mice, APP/PSEN1 mice and their wild-type controls on standard, low-fat, chow diet, the APP/PSEN1 mice still exhibited impaired glucose homeostasis, as investigated by glucose tolerance tests. This was associated with increased brain protein tyrosine phosphatase 1B protein levels in APP/PSEN1 mice. Interestingly, short-term high-fat diet (HFD) feeding of wild-type, PSEN1 and APP/PSEN1 mice for a period of 8 weeks led to higher body weight gain in APP/PSEN1 than in PSEN1 mice and wild-type controls. In addition, HFD-feeding caused fasting hyperglycaemia and worsening of glucose maintenance in PSEN1 mice, the former being further exacerbated in APP/PSEN1 mice. The mechanism(s) behind this glucose intolerance in PSEN1 and APP/PSEN1 mice appeared to involve increased levels of brain retinol-binding protein 4 and basal phosphorylation of S6 ribosomal protein, and decreased insulin-stimulated phosphorylation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 in the brain. CONCLUSIONS/INTERPRETATION: Our results indicate that Alzheimer's disease increases susceptibility to body weight gain induced by HFD, and to the associated glucose intolerance and insulin resistance. PMID- 21538176 TI - Examination of the efficacy and safety of intraoperative gastroscopic testing of the gastrojejunal anastomosis in laparoscopic Roux Y gastric bypass surgery. AB - The laparoscopic Roux Y gastric bypass (LRYGB) is one of the most often performed bariatric surgical intervention. Intraoperative gastroscopy (IOG) seems to be reliable to decrease the leakage rate of gastrojejunal anastomosis (GJA) and of gastric pouch (GP). Our aim was to test the efficacy and the safety of this method. Two hundred fifty-two LRYGB operations were performed in our institution between 1 January 2008 and 1 January 2010. IOG is routinely made to test the integrity of GJA and of GP. Patients' dates were retrospectively analysed. The intragastric pressure developed during gastroscopy in humans was measured and compared with pressure values led to destruction (positive air test) of the GJA and/or GP in animal models (hybrid pigs). Stomach and bowel wall samples from the test animals without pressure strain, with pressure strain developed at gastroscopy in humans and with pressure strains led to destruction of GJA and/or GP were histologically examined. IOG resulted in six of our cases (2.3%) positive air test. There was no anastomosis insufficiency in postoperative period. Mean pressure during IOG was 32 mmHg, mean time of examination was 3.8 min and mean maximal pressure was 43 mmHg in humans. The mean pressure leading to positive air test in pigs was 150 mmHg. We could not detect any microscopical difference between stomach and jejunum samples without pressure strain and after pressure strain developed in humans during the gastroscopy. We conclude that intraoperative gastroscopy is an effective and safe method to test the integrity of GJA and GP in LRYGB surgery. PMID- 21538177 TI - Reducing cost of surgery by avoiding complications: the model of robotic Roux-en Y gastric bypass. AB - BACKGROUND: Robotic surgery is a complex technology offering technical advantages over conventional methods. Still, clinical outcomes and financial issues have been subjects of debate. Several studies have demonstrated higher costs for robotic surgery when compared to laparoscopy or open surgery. However, other studies showed fewer costly anastomotic complications after robotic Roux-en-Y gastric bypass (RYGBP) when compared to laparoscopy. METHODS: We collected data for our gastric bypass patients who underwent open, laparoscopic, or robotic surgery from June 1997 to July 2010. Demographic data, BMI, complications, mortality, intensive care unit stay, hospitalization, and operating room (OR) costs were analyzed and a cost projection completed. Sensitivity analyses were performed for varied leak rates during laparoscopy, number of robotic cases per month, number of additional staplers during robotic surgery, and varied OR times for robotic cases. RESULTS: Nine-hundred ninety patients underwent gastric bypass surgery at the University Hospital Geneva from June 1997 to July 2010. There were 524 open, 323 laparoscopic, and 143 robotic cases. Significantly fewer anastomotic complications occurred after open and robotic RYGBP when compared to laparoscopy. OR material costs were slightly less for robotic surgery (USD 5,427) than for laparoscopy (USD 5,494), but more than for the open procedure (USD 2,251). Overall, robotic gastric bypass (USD 19,363) was cheaper when compared to laparoscopy (USD 21,697) and open surgery (USD 23,000). CONCLUSIONS: Robotic RYGBP can be cost effective due to balancing greater robotic overhead costs with the savings associated with avoiding stapler use and costly anastomotic complications. PMID- 21538178 TI - HIV/AIDS disparity between African-American and Caucasian men who have sex with men: intervention strategies for the black church. AB - This manuscript examines the HIV/AIDS health disparity among African-American (AA) men who have sex with men (MSM) as compared to non-Hispanic White (NHW) MSM, and proposes faith-based intervention strategies as a means of reducing the disparity. Effective faith-based HIV/AIDS intervention programs to encompass AA MSM must include community-based participatory research; engage the faith community through data sharing; specifically target and equip church leaders in addition to laity; involve effective collaboration and compromise between public health practitioners and faith leaders; emphasize spirituality and compassion; utilize popular opinion leaders; and be intergenerational. PMID- 21538179 TI - Effect of age on dual-task performance in children and adults. AB - Age effects on dual-task costs were examined in healthy adults (Exp. 1) and in typically developing children (Exp. 2). In both experiments, individual differences in performance on the single-task components were titrated so that any age differences in dual-task costs could not be attributed to differences in single-task performance. Dual-task costs were found, but there were no age related differences in these costs in older relative to younger adults, in 7-year old relative to 9-year-old children, or across all four age groups. The results from these experiments suggest that previously reported age differences in dual task costs, in both healthy ageing and child development, may be due to a failure to adequately equate single-task difficulty. PMID- 21538180 TI - On domain differences in categorization and context variety. AB - Membership in many natural categories is considered all-or-none, while membership in most artifact categories is found to be graded. We introduce an alternative for the prevailing view that this domain difference in categorization results from representational differences. The context variety account posits that an item's gradedness reflects the variety of contexts it appears in. Items that feature in a variety of contexts are assumed to be more likely to elicit a graded categorization response, since the suggested target category only provides one of many solutions to the question of the item's identity. We review earlier work that suggested a domain difference in context variety, with artifactual items appearing in a greater variety of contexts than natural ones. The context variety domain difference is established in two separate experiments but is shown not to explain the domain difference in categorization. A selection of artifactual and natural items, for which the domain difference in context variety is reversed, is presented for categorization in a third experiment. This selection, too, fails to provide evidence for the context variety account of categorization differences. The domain difference in categorization is shown to be robust against this manipulation. Context variety appears to have no bearing on categorization, so the context variety account is not a sustainable alternative to accounts that posit representational differences between natural and artifact categories. PMID- 21538181 TI - Contrast ultrasound and targeted microbubbles: diagnostic and therapeutic applications for angiogenesis. AB - Angiogenesis represents the formation of new capillaries from existing vasculature, and as such plays a critical role in the response to ischemia in the setting of chronic coronary artery and peripheral vascular disease. Recent technological advances in non-invasive imaging modalities now allow the molecular imaging of angiogenesis. One such technique is contrast-enhanced ultrasound using microbubbles targeted against molecular markers of the angiogenic process. The ability to non-invasively image the angiogenic process would be useful in risk stratifying patients with arterial occlusive disease and would aid in the evaluation of new therapies to promote angiogenesis in ischemic cardiac and skeletal muscle. Furthermore, ultrasound technologies have also been developed that allow targeted angiogenic gene therapy using high-power ultrasound and DNA bearing microbubbles. This review will focus specifically on recent advances in (1) contrast-enhanced ultrasound molecular imaging techniques for the evaluation of angiogenesis and (2) ultrasound-mediated gene delivery for therapeutic angiogenesis, techniques that have potential for translation to clinical practice. PMID- 21538182 TI - Imaging cardiac stem cell therapy: translations to human clinical studies. AB - Stem cell therapy promises to open exciting new options in the treatment of cardiovascular diseases. Although feasible and clinically safe, the in vivo behavior and integration of stem cell transplants still remain largely unknown. Thus, the development of innovative non-invasive imaging techniques capable of effectively tracking such therapy in vivo is vital for a more in-depth investigation into future clinical applications. Such imaging modalities will not only generate further insight into the mechanisms behind stem cell-based therapy, but also address some major concerns associated with translational cardiovascular stem cell therapy. In the present review, we summarize the principles underlying three major stem cell tracking methods: (1) radioactive labeling for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, (2) iron particle labeling for magnetic resonance imaging (MRI), and (3) reporter gene labeling for bioluminescence, fluorescence, MRI, SPECT, and PET imaging. We then discuss recent clinical studies that have utilized these modalities to gain biological insights into stem cell fate. PMID- 21538183 TI - Aging-induced collateral dysfunction: impaired responsiveness of collaterals and susceptibility to apoptosis via dysfunctional eNOS signaling. AB - Despite positive animal studies, clinical angiogenesis trials have been disappointing, possibly due to risk factors present in humans but usually unexplored in animals. We recently demonstrated aging causes impaired collateral remodeling and collateral dropout; here, we investigate potential mechanisms responsible for these findings. Four-, 10-, and 18-month-C57BL/6J mice were subjected to femoral artery ligation; flow was measured using laser Doppler perfusion imaging. Endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS were measured in calf muscle. Apoptosis was assessed in endothelial (EC) and smooth muscle (SMC) cells isolated from young and old mice. Angiogenesis was measured using a Matrigel plug assay. Lethally irradiated young and old mice received bone marrow cells (BMC) from either young or old donors and were subjected to femoral artery ligation (FAL). BMC mobilization and homing were assessed. Flow recovery was impaired and less eNOS and phosphorylated eNOS was present in older vs. young mice (p < 0.001 and p = 0.015, respectively). ECs and SMCs from older mice were more sensitive to an apoptotic stimulus, but were rescued by NO-enhancing drugs. In older mice, angiogenesis (Matrigel plug assay) was impaired, as was mobilization and homing of BM progenitor cells following FAL. Although both mobilization and homing improved when older mice received BMC transplantation from young donors, flow recovery failed to improve. Aging impairs BMC mobilization and homing, collateral responsiveness to angiogenic stimuli, and increases EC and SMC susceptibility to apoptosis via dysfunctional eNOS signaling. The latter could contribute to impaired remodeling and collateral dropout. These finding identify potential obstacles to therapeutic interventions in elderly patients. PMID- 21538184 TI - Adenosine reduces cell surface expression of toll-like receptor 4 and inflammation in response to lipopolysaccharide and matrix products. AB - Recent evidence suggests that Toll-like receptor 4 (TLR4) is not only involved in innate immunity but is also an important mediator of adverse left ventricular remodeling and heart failure following acute myocardial infarction (MI). TLR4 is activated by lipopolysaccharide (LPS) but also by products of matrix degradation such as hyaluronic acid and heparan sulfate. Although cardioprotective properties of adenosine (Ado) have been extensively studied, its potential to interfere with TLR4 activation is unknown. We observed that TLR4 pathway is activated in white blood cells from MI patients. TLR4 mRNA expression correlated with troponin T levels (R (2) = 0.75; P = 0.01) but not with levels of white blood cells and C reactive protein. Ado downregulated TLR4 expression at the surface of human macrophages (-50%, P < 0.05). Tumor necrosis factor-alpha production induced by the TLR4 ligands LPS, hyaluronic acid, and heparan sulfate was potently inhibited by Ado (-75% for LPS, P < 0.005). This effect was reproduced by the A2A Ado receptor agonist CGS21680 and the non-selective agonist NECA and was inhibited by the A2A antagonist SCH58261 and the A2A/A2B antagonist ZM241,385. In contrast, Ado induced a 3-fold increase of TLR4 mRNA expression (P = 0.008), revealing the existence of a feedback mechanism to compensate for the loss of TLR4 expression at the cell surface. In conclusion, the TLR4 pathway is activated after MI and correlates with infarct severity but not with the extent of inflammation. Reduction of TLR4 expression by Ado may therefore represent an important strategy to limit remodeling post-MI. PMID- 21538185 TI - Constitutive HIF-1alpha expression blunts the beneficial effects of cardiosphere derived cell therapy in the heart by altering paracrine factor balance. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) expression promotes angiogenesis and can influence stem cell engraftment. We investigated the effect of stable over expression of constitutively active HIF-1alpha on cardiosphere-derived cell (CDC) engraftment and left ventricular function. CDCs were transduced with a lentivirus expressing a constitutively active mutant of human HIF-1alpha (LVHIF-1alpha). Two million male rat CDCs were injected into the infarct following ligation of the mid-LAD in female syngeneic rats. Left ventricular ejection fraction (EF) and circumferential strain were measured by echocardiography at 1 and 4 weeks post-MI in the following groups: PBS group (n = 7), CELL group (n = 7), and CELL-HIF group (n = 7). HIF-1alpha, VEGF, endothelin-1 expression, and CDC engraftment were measured by quantitative PCR. At 30 days, EF was unchanged in the CELL-HIF group (p = NS), increased in the CELL group (p = 0.025), and decreased in the PBS group (p = 0.021), but engraftment was similar (2.4% +/- 3.3% vs 1.7% +/- 0.8%, p = NS). Mean circumferential strain of the infarcted region was unchanged in the CELL-HIF group, but improved in the CELL group (p = 0.02). Endothelin-1 and VEGF expression were higher in HIF-CDCs exposed to hypoxia, compared with non transduced CDCs. HIF-1alpha expression in CDCs blunted the beneficial functional effects of CDC transplantation, suggesting that paracrine factor balance may play an important role in cardiac regeneration. PMID- 21538186 TI - Patterns of lymph node metastases in papillary thyroid carcinoma: results from consecutive bilateral cervical lymph node dissection. AB - BACKGROUND: In patients with papillary thyroid carcinoma (PTC), the appropriate extent of lymph node dissection has not yet been established due to lack of accurate patterns of lymph node metastases (LNM). The aim of this study was to clarify the LNM pattern in PTC patients based on our institution's experience with a consistent technique of bilateral neck dissection, and to consider the rational extent of lymph node dissection. METHODS: Between 1990 and 1999, 152 consecutive patients with PTC who underwent curative total thyroidectomy and bilateral neck dissection as initial treatment were analyzed. The patterns of LNM according to clinicopathological classification were analyzed using the lymph node ratio (LNR; number of metastatic lymph nodes/number of dissected nodes) and frequency (FLNM; number of patients with LNM/number of dissected patients) in cervical compartments. RESULTS: Regardless of clinicopathological classification, LNR in the central compartment was consistently higher than in other compartments, and FLNM in the ipsilateral lateral compartment was consistently higher than in other compartments except for multifocal tumors. The LNR and FLNM in the contralateral lateral compartment were significantly higher in advanced (>=T3) cases than in cases with smaller tumors (T1) and were comparable to those in the ipsilateral lateral compartment in advanced (>=T3) cases. CONCLUSIONS: The pattern of LNR provided a better reflection of the patterns of LNM. In terms of the LNR, central neck dissection is the basic extent of lymph node dissection for all clinically apparent PTC. In advanced patients, it is also advisable to include bilateral lateral neck dissection. PMID- 21538187 TI - Comparison of the prognostic value of tumour- and patient-related factors in patients undergoing potentially curative resection of oesophageal cancer. AB - BACKGROUND: Evidence is increasing that elevated systemic inflammation is associated with poor survival in patients with oesophageal carcinoma. However, it is not yet established if any specific component of systemic inflammatory response is a better predictor of cancer survival. The aim of the present study was to compare the predictive value of selected markers of systemic inflammation in patients who undergo surgical resection of oesophageal cancer. METHODS: One hundred twelve patients who underwent potentially curative resection for oesophageal carcinoma, including type I and type II tumours of the gastro oesophageal junction (Siewert and Stein in Dis Esophagus 9:173-182, 1996), between 1996 and 2008 were included in the study. Patients had laboratory measurement of white cells, neutrophils, lymphocytes, platelet counts, albumin, and C-reactive protein. Glasgow Prognostic Score (mGPS), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and metastatic lymph node ratio (LNR) were calculated. RESULTS: On multivariate analysis, only the LNR (HR 2.87, 95% CI 1.99-4.15, p < 0.001) and the mGPS (HR 4.31, 95% CI 2.20-8.45, p < 0.001) were independently associated with cancer-specific survival in oesophageal cancer. An elevated mGPS was associated with high white cell count (p < 0.05) and poorer survival (p = 0.001). CONCLUSION: The present study indicates that the mGPS, an acute-phase protein-based prognostic score, better predicts cancer survival compared with the cellular components of systemic inflammation in patients with oesophageal carcinoma. PMID- 21538189 TI - Liver allografts from hepatitis C virus-positive donors may be transplanted with good outcome. PMID- 21538190 TI - Rural high north: a high rate of fatal injury and prehospital death. AB - BACKGROUND: Finnmark County is the northernmost county in Norway. For several decades, the rate of mortality after injury in this sparsely inhabited region has remained above the national average. Following documentation of this discrepancy for the period 1991-1995, improvements to the trauma system were implemented. The present study aims to assess whether trauma-related mortality rates have subsequently improved. METHODS: All injury-associated fatalities in Finnmark from 1995-2004 were identified retrospectively from the National Registry of Death and reviewed. Low-energy trauma in elderly individuals and poisonings were excluded. RESULTS: A total of 453 cases of trauma-related death occurred during the study period, and 327 of those met the inclusion criteria. Information was retrievable for 266 cases. The majority of deaths (86%) occurred in the prehospital phase. The main causes of death were suicide (33%) and road traffic accidents (21%). Drowning and snowmobile injuries accounted for an unexpectedly high proportion (12 and 8%, respectively). The time of death did not show trimodal distribution. Compared to the previous study period, there was a significant overall decline in injury-related mortality, yet there was no change in place of death, mechanism of injury, or time from injury until death. CONCLUSIONS: Changes in injury-related mortality cannot be linked to improvements in the trauma system. There was no change in the epidemiological patterns of injury. The high rate of on-scene mortality indicates that any major improvement in the number of injury-related deaths lies in targeted prevention. PMID- 21538191 TI - Comparison of a novel technique of the microlaparoscopic pyloromyotomy to circumbilical and Weber-Ramstedt approaches. AB - INTRODUCTION: The aim of this retrospective comparative study was to compare the surgical results and outcomes of the newly inaugurated approach of microlaparoscopic pyloromyotomy with open techniques. METHODS: The surgical charts of 110 infants (85 boys and 25 girls, ages ranging from 10 to 98 (average 28) days) undergoing pyloromyotomy microlaparoscopically (28), through the circumbilical approach (56), or via the right upper quadrant access (26) were reviewed. The variables were compared between the three surgical approach groups, and the statistical analysis was performed. RESULTS: There was a significant difference between Bianchi and microlaparoscopy in terms of operation time (average 38.5 vs. 20.5 min, p < 0.0001) and time to full enteral feed (average 48 vs. 32 h, p = 0.001). There was no significant difference in postoperative length of stay (75 vs. 82 h, p = 0.12). The operative time for the surgeons experienced in microlaparoscopy was in average of 14 min (range, from 9 to 18 min). When comparing the Weber-Ramstedt procedure and microlaparoscopy, microlaparoscopy required significantly less operative time (50 vs. 20 min, p < 0.0001), a shorter time to full enteral feed (70 vs. 32 h, p < 0.001), and a shorter postoperative length of stay (90 vs. 82 h, p = 0.04). There were no cases of mucosal perforation or incomplete pyloromyotomy. CONCLUSION: Despite the small sample size included in the present study, it seems that microlaparoscopic pyloromyotomy is safe and feasible with the lowest rate of complications and the shortest operative time. The Bianchi approach is a good alternative to achieve a small scar without laparoscopy. PMID- 21538192 TI - Can laparoscopic pancreaticoduodenectomy be safely implemented? AB - INTRODUCTION: The implementation of laparoscopic pancreaticoduodenectomy (LPD) has been appropriately met with apprehension, and concerns exist regarding outcomes early in a program's experience. We reviewed our early experience and outcomes of LPD. METHODS: A retrospective review of patients undergoing LPD was compared to a matched cohort of open pancreaticoduodenectomy (OPD) patients. The endpoints are as follows: age, gender, ASA score, BMI, operative time, estimated blood loss, perioperative transfusion requirement, intensive care unit stay, margin status, lymph node count, 90 day morbidity and mortality, length of stay, and adjuvant therapy treatment. RESULTS: Fourteen patients underwent an attempted LPD. The median operative time was 456 min (interquartile range (IQR), 109.5), median estimated blood loss was 300 ml (IQR, 225), and 29% of the patients required a perioperative blood transfusion. A conversion was necessary in two patients (14%). A malignancy was present in 12 patients. The mean tumor size was 2.2 cm (standard deviation (SD), 1.1), the mean lymph node count was 18.5 (SD 6.2), and an R0 resection was achieved in all 12 cases. Clavien grade I/II complications occurred in 42% of the patients, and Clavien grade III/IV complications occurred in three (20%). There was one late postoperative death. The median length of stay was 8 days. Compared to OPD, LPD took longer to perform, but no differences were noted with respect to blood loss, morbidity, mortality, R0 resection rate, and LN harvest. CONCLUSIONS: LPD can be implemented in a high-volume pancreatic surgery center with acceptable oncologic and patient outcomes. PMID- 21538193 TI - Looking ahead: the SSAT strategic plan for the next decade. AB - The Society for Surgery of the Alimentary Tract's (SSAT) mission is to advance the science and practice of surgery in the treatment of digestive disease. An essential core value of the SSAT is multidisciplinary collaboration with both its sister societies in the Digestive Disease Week (DDW) Council and other surgical societies in Gastrointestinal Surgery. In order to achieve the society's goals, the strategic plan rests on the society's values of interdisciplinary collaboration, scholarship, education, and discovery. The strategic plan also creates a meritocracy system to foster the development of future leaders for both the SSAT and the broader house of surgery. In the short term, this plan will: Re organize committee structure and reporting responsibilities; Clarify committee goals and deliverables; Facilitate member participation in the committees and governance of the society; Enhance member services by utilizing enhanced communication strategies; Accelerate efforts to meet the Maintenance of Certification needs of the membership; Re-focus the SSAT's energy on Quality and Outcome Assessment of GI surgery; Clarify and standardize the methodology for allocating funds for new projects. Over the course of the next few years, the SSAT will: Develop a financial model that increases revenue to support the expanded tasks the society intends to undertake; Play an active role in developing the evolving training paradigms for gastrointestinal surgeons through the continuum from residency, fellowship, and early mentored practice; Continue to support development of surgeon scientists through Career Development Award; Enhance relationship with the SSAT Foundation; Continue to improve the experience of members attending DDW; Develop surgeons interested in public policy to be leaders at a national level. The strategic plan is ambitious, and the current leadership realizes that all the tasks and objectives cannot be accomplished in 1 year. There is much to do in order to keep the SSAT the premier professional society for gastrointestinal surgery. Changes in the external environment may require modifications of the priorities or the plan itself in the coming years. Implicit in this plan is the need for annual review by the Board of Trustees at the May Board Meeting so that modifications can be made as the world around us changes. PMID- 21538194 TI - An abdominal mass. AB - BACKGROUND: A 93-year-old woman, with life-threatening comorbidities, was admitted to our hospital for fever, nausea, vomiting, and a large and tender abdominal mass. The CT scan showed a gallbladder empyema with a large stone inside. RESULTS: Having considered the age of the patient and the presence of life-threatening comorbidities, we decided to drain percutaneously the gallbladder under US guidance. After drainage, the patient showed immediate relief from pain and she made a fast and full recovery. CONCLUSION: Percutaneous drainage of gallbladder empyema is an effective procedure and a good alternative for patients unfit to undergo surgery due to severe comorbidities. PMID- 21538195 TI - Wool characteristics in the third generation of Arkharmerino * Ghezel and Arkharmerino * Moghani crossbreed sheep. AB - This investigation was conducted to evaluate the comparative productive performances and effect of some environmental factors on wool characteristics of Arkharmerino * Ghezel (Ar * Gh) and Arkharmerino * Moghani (Ar * Mo) crossbreed sheep. The mid-side fleece samples taken from animals during 2 years (2007-2008) were analyzed. Each sample was measured for average fiber diameter, fiber diameter variability, staple length, proportion of medullated fiber, proportion of kemp, and comfort factor. The comparative values for these fleece characteristics in F(3) generation Ar * Gh were 28.78 +/- 0.48 MUm, 36.84 +/- 1.16%, 11.94 +/- 0.35 cm, 7.07 +/- 0.93%, 1.02 +/- 0.23%, and 68.93%, respectively; while those traits were 29.79 +/- 0.43 MUm, 41.86 +/- 1.16%, 11.96 +/- 0.37 cm, 8.13 +/- 1.06%, 2.71 +/- 0.45%, and 63.33 +/- 3.66% for Ar * Mo, respectively. The effects of genotype, sex, birth type, and year of birth were analyzed. Genotype had a significant (P < 0.01) effect on average fiber diameter and proportion of kemp, and Ar * Gh crossbreeds had lower diameter with less proportion of kemp. The two differences in fiber characteristics that were attributable to sex were fiber diameter variability and proportion of medullated fiber, and females had higher measure than males for both traits. Statistical analysis showed that crossbreeding with Arkharmerino generally had positive effects on the fleece favored to be used in the hand woven authentic carpet production. PMID- 21538196 TI - Computed tomography-guided gamma knife stereotactic radiosurgery for trigeminal neuralgia. AB - BACKGROUND: Gamma knife stereotactic radiosurgery (GKSR) is an effective minimally invasive option for the treatment of medically refractory trigeminal neuralgia (TN). Optimal targeting of the retrogasserian trigeminal nerve target requires thin-slice, high-definition stereotactic magnetic resonance imaging (MRI). The purpose of this study was to evaluate management outcomes in TN patients ineligible for MRI and who instead underwent GKSR using computed tomography (CT). METHODS: The authors reviewed their experience with CT-guided GKSR in 21 patients (median age: 75 years) with idiopathic TN. Contraindications to MRI included implanted pacemakers (n = 16), aneurysm clips (n = 2), cochlea implants (n = 1), metallic vascular stents (n = 1) or severe obesity (weight of 163 kg, n = 1). Contrast-enhanced CT at 1- or 1.25-mm intervals was acquired in all patients. One patient also underwent CT cisternography. The median target dose for GKSR was 80 Gy. The median follow-up was 35 months after GKSR. Treatment outcomes were compared to 459 patients who underwent MRI-guided GKSR for TN at our institute in the same time interval. RESULTS: Targeting of the trigeminal nerve guided by CT scan was feasible in all patients. Stereotactic frame titanium pin-related artifacts that interfered with full visualization of the trigeminal nerve were found in one patient who had the ipsilateral posterior pin placed near the inion. After GKSR, 90% of patients achieved initial pain relief that was adequate or better, with or without medication (Barrow Neurological Institute pain scores I-IIIb). Median time to pain relief was 2.6 weeks. Pain relief was maintained in 81% at 1 year, 66% at 2 years, and 46% at 5 years. Eight (42%) of 19 patients who achieved initial pain relief reported some recurrent pain at a median of 18 months after GKSR. Some degree of facial sensory dysfunction occurred in 19% of patients within 24 months of GKSR. These results are comparable to those of patients who had MRI-guided GKSR. CONCLUSIONS: CT-guided GKSR provides a similar rate of pain relief as MRI-guided radiosurgery. The posterior pins should be placed at least 1 cm away from the inion to reduce pin and frame-related artifacts on the targeting CT scan. This study indicates that GKSR using CT targeting is appropriate for patients with medically refractory TN who are unsuitable for MRI. PMID- 21538197 TI - Case report: pseudotendon formation after a type III flexor digitorum profundus avulsion. AB - BACKGROUND: Avulsion of the flexor digitorum profundus tendon is a common injury to the hand that virtually always requires surgical repair for restoration of normal finger function. CASE DESCRIPTION: We report a case of a Type III flexor digitorum profundus tendon avulsion in which the patient refused surgery yet attained nearly full active ROM and an excellent functional result via the formation of a pseudotendon, as observed on MRI obtained 2.5 years after the initial injury. LITERATURE REVIEW: There are no reported cases of restoration of normal finger function after pseudotendon formation in a flexor digitorum profundus tendon avulsion injury. PURPOSES AND CLINICAL RELEVANCE: This case shows the potential for pseudotendon to not only form but have adequate tensile strength to restore function in certain types of flexor tendon injuries. PMID- 21538199 TI - Benefits on quality of life concomitant to metabolic improvement in intervention program for prevention of diabetes mellitus. AB - OBJECTIVE: To evaluate whether an interdisciplinary intervention program on lifestyle results in better quality of life (QoL) and lower frequencies of depression and binge eating disorder (BED) in individuals at risk for type 2 diabetes mellitus. METHODS: A total of 177 individuals (32.2% men, age 55.4 +/- 12.5 years) at risk for diabetes were allocated to a 9-month traditional (TI) or intensive interdisciplinary intervention (II) on dietary habits and physical activity including psychoeducative groups. They were submitted to questionnaires and clinical and laboratory examinations. Predictors of non-adherence were analyzed by logistic regression. RESULTS: Only individuals submitted to II had blood pressure and plasma glucose levels reduced. Frequencies of depression reduced in both interventions but of BED only in II (28.0-4.0%, P < 0.001). Increments in the scores of SF-36 domains (physical functioning: 11.1 +/- 14.0 vs. 5.3 +/- 13.0, role-emotional: 20.4 +/- 40.2 vs. 6.2 +/- 43.8, P = 0.05) were greater in the II than in TI, respectively. Changes in SF-36 correlated with decreases in anthropometry, blood pressure and glucose levels, depression and BED scores. Male gender was independently associated with non-adherence to the II. CONCLUSIONS: In addition to metabolic benefits, an interdisciplinary approach may induce desirable extrametabolic effects, favoring the control of psychiatric disorders and improving the QoL of individuals at risk for diabetes. PMID- 21538200 TI - The organization of room geometry and object layout geometry in human memory. AB - Research with humans and with nonhuman species has suggested a special role of room geometry in spatial memory functioning. In two experiments, participants learned the configuration of a room with four corners, along with the configuration of four objects within the room, while standing in a fixed position at the room's periphery. The configurations were either rectangular (Experiment 1) or irregular (Experiment 2). Room geometry was not recalled better than object layout geometry, and memories for both configurations were orientation dependent. These results suggest that room geometry and object layout geometry are represented similarly in human memory, at least in situations that promote long term learning of object locations. There were also some differences between corners and objects in orientation dependence, suggesting that the two sources of information are represented in similar but separate spatial reference systems. [corrected] PMID- 21538201 TI - The diagnosticity of individual data for model selection: comparing signal detection models of recognition memory. AB - We tested whether the unequal-variance signal-detection (UVSD) and dual-process signal-detection (DPSD) models of recognition memory mimic the behavior of each other when applied to individual data. Replicating previous results, there was no mimicry for an analysis that fit each individual, summed the goodness-of-fit values over individuals, and compared the two sums (i.e., a single model selection). However, when the models were compared separately for each individual (i.e., multiple model selections), mimicry was substantial. To quantify the diagnosticity of the individual data, we used mimicry to calculate the probability of making a model selection error for each individual. For nondiagnostic data (high model selection error), the results were compatible with equal-variance signal-detection theory. Although neither model was justified in this situation, a forced-choice between the UVSD and DPSD models favored the DPSD model for being less flexible. For diagnostic data (low model selection error), the UVSD model was selected more often. PMID- 21538202 TI - Evidence of fixed capacity in visual object categorization. AB - How is visual object perception limited by divided attention? Whereas some theories have proposed that it is not limited at all (unlimited capacity), others have proposed that divided attention introduces restrictive capacity limitations or serial processing (fixed capacity). We addressed this question using a task in which observers searched for instances of particular object categories, such as a moose or squirrel. We applied an extended simultaneous-sequential paradigm to test the fixed-capacity and unlimited-capacity models (Experiment 1). The results were consistent with fixed capacity and rejected unlimited capacity. We ascertained that these results were due to attention, and not to sensory interactions such as crowding, by repeating the experiment using a cuing paradigm with physically identical displays (Experiment 2). The results from both experiments were consistent with theories of object perception that have fixed capacity, and they rejected theories with unlimited capacity. Both serial and parallel models with fixed capacity remain viable alternatives. PMID- 21538203 TI - Head for the hills: the influence of environmental slant on spatial memory organization. AB - Environmental slant is known to improve navigation performance in humans and other animals. Successful navigation relies on accurate spatial orientation and accurate spatial memory retrieval. The role of environmental slant in spatial orientation has been established, but its role in spatial memory organization is unclear. Two experiments using immersive virtual reality explored the influence of environmental slant on reference frame selection during spatial learning. Participants studied object locations on a sloped surface. When no additional environmental cues were present (Experiment 1), spatial memory retrieval was best from the studied perspective aligned with the direction of slope. When the direction of slope was placed in competition with the axis of the surrounding room (Experiment 2), spatial memory retrieval was best from the initially studied perspective. The latter finding contrasts with the results of research showing that pigeons preferentially rely on environmental slant over room shape. The findings are discussed in the context of spatial memory theory. PMID- 21538204 TI - Combination of extracorporeal membrane oxygenation and high-frequency oscillatory ventilation saved a child with severe ARDS after pulmonary resection. AB - We report a case in which a 2-year-old girl who underwent a right middle and lower lung lobectomy for congenital cystic adenomatoid malformation suffered massive bleeding and developed acute respiratory distress syndrome (ARDS) during the operation. She was ventilated with a high level of F(I)O(2) (0.75-1.0), PEEP (10-20 cmH(2)O), and PIP (33-55 cmH(2)O) to maintain SPO(2) (>90%). Following transfer to the ICU, continuous hemodialysis was introduced to reduce excessive blood volume. However, pulmonary oxygenation did not improve, and marked subcutaneous emphysema occurred on postoperative day 3 (POD 3). We introduced venovenous (V-V) extracorporeal membrane oxygenation (ECMO) to rest the lung, and V-V ECMO was changed to right and left atrial ECMO because of unsatisfactory oxygen support on POD 23. A CT scan showed almost the entire lung had collapsed, even though we had administered diuretics, steroids, nitric oxide, sivelestat, and surfactant for ARDS. We applied high-frequency oscillatory ventilation (HFOV) with a mean airway pressure of 20 cmH(2)O, frequency of 9.2 Hz, and amplitude of 38 cmH(2)O on POD 45. The collapsed lung was then gradually recruited, and pulmonary oxygenation improved (P/F ratio = 434). ECMO was successfully weaned on POD 88. The patient required a tracheostomy, but she was able to function without a ventilator on POD 142. Although HFOV has failed to show a mortality benefit in ARDS patients, the unique lung recruitment by HFOV can be a useful therapeutic option for severe ARDS patients in combination with sufficient lung rest produced by ECMO. PMID- 21538205 TI - Epidemiologic survey: reference ranges of serum insulin-like growth factor 1 levels in Caucasian adult population with immunoradiometric assay. AB - Gender, age adjusted, population based reference ranges are necessary to use insulin-like growth factor 1 (IGF-1) as a diagnostic marker or for therapeutic monitoring in growth hormone (GH) related diseases. The aim of the present study was to describe the serum IGF-1 distribution and to calculate age and gender specific reference values for Caucasian adult population. A representative sample of 1002 male and 1039 female, totally 2041 participants aged above 18 years old was examined. The subjects suffering from diabetes mellitus, renal diseases, liver diseases, cancer, or diseases of pituitary gland were excluded by medical history, physical examination, and laboratory tests. The subjects were not using any drug that could affect IGF-1 levels. Body mass index (BMI)>30 or<18 kg/m2 were excluded. Serum IGF-1 concentrations were determined by immunoradiometric assay (IRMA). Serum IGF-1 concentrations were declined with age in both males and females after the age of 18. Males had significantly higher serum IGF-1 levels than females in the age groups 18-24, 50-69 (P<0.05), but not in others (P>0.05). The present study established age and gender specific reference ranges for serum IGF-1 levels calculated for Caucasian adult population with IRMA that could be used in medical practice. PMID- 21538206 TI - Biology of Leipothrix dipsacivagus (Acari: Eriophyidae), a candidate for biological control of invasive teasels (Dipsacus spp.). AB - The present study describes key aspects of the biology of Leipothrix dipsacivagus, an eriophyid mite that is under study as a biological control candidate of Dipsacus fullonum and D. laciniatus (Dipsacaceae). Preliminary host specificity tests have shown that it can develop and reproduce only on Dipsacus spp. (teasels). Studies were conducted in a laboratory at 26 +/- 2(o)C with 16 h of light per day. Mites for the stock colony were collected from D. laciniatus in Klokotnitsa, Bulgaria and reared on rosettes of D. laciniatus in the laboratory. Unfertilized L. dipsacivagus females reared in isolation from the juvenile stage produced male offspring only, while progeny of fertilized females were of both sexes, suggesting arrhenotokous parthenogenesis with haplodiploid sex determination. Experiments were designed to compare male progeny from fertilized females to males from unfertilized females and to compare males and females from fertilized females. Male progeny of virgin mothers had significantly longer durations of active immature stages and total egg-to-adult period than male progeny of fertilized females. Female progeny had significantly longer durations of egg incubation, active immature stages and egg-to-adult period than male progeny from fertilized mothers. Adult longevity was significantly greater in females than in males. Fertilized females produced significantly more eggs per day and overall than virgin females. The results of this study suggest that fertilization status of L. dipsacivagus females can affect both their own fecundity and the development of their male progeny. PMID- 21538207 TI - The impact of lumbar scoliosis on pain, function and health-related quality of life in postmenopausal women. AB - The impact of adult scoliosis on pain, function and health-related quality of life (QOL) has not been clearly defined. A population-based study using widely applied screening tools could better reflect the impact of adult scoliosis. In this study, a visual analog pain scale assessment (VAS) for lumbar and leg pain, an Oswestry disability index (ODI) and a standard version of the Medical Outcome Study Short Form-36 (SF-36) questionnaire were sent by mail to 261 women of age 50 years and older, consecutively evaluated with dual-energy radiograph absorptiometry (DXA) scan images. 138 patients (32 with lumbar curves 10 degrees or bigger) returned the questionnaires. Differences in lumbar VAS, leg VAS, ODI and SF-36 values between groups of patients with curves <10 degrees , 10 degrees 19 degrees and >=20 degrees were evaluated. Correlation analyses of the Cobb angle, age and body mass index (BMI) with VAS, ODI and SF-36 values, and multivariate regression analysis were performed. Patients with curves <10 degrees , 10 degrees -19 degrees and >=20 degrees had no significant differences in lumbar or leg VAS, ODI or SF-36 values. ODI values correlated with age and BMI; SF-36 values correlated with BMI only; lumbar and leg VAS values did not correlate with lumbar curvature, age or BMI. Regression disclosed that Cobb angle values did not influence ODI, SF-36 or VAS values. In postmenopausal women with mild and moderate lumbar curves, Cobb angle had no influence on pain, function and QOL; age and BMI had small effect. PMID- 21538208 TI - In vivo biostability of polymeric spine implants: retrieval analyses from a United States investigational device exemption study. AB - The Dynesys System for stabilizing the lumbar spine was first surgically implanted in Europe in 1994. In 2003, a prospective, randomized, investigational device exemption clinical trial of the system for non-fusion dynamic stabilization began. Polycarbonate urethane (PCU) and polyethylene terephthalate (PET) components explanted from four patients who had participated in the study were analyzed for biostability. Components had been implanted 9-19 months. The explanted components were visually inspected and digitally photographed. Scanning electron microscopy was used to analyze the surface of the spacers. The chemical and molecular properties of the retrieved spacers and cords were quantitatively compared with lot-matched, shelf-aged, components that had not been implanted using attenuated total reflection Fourier transform infrared (FTIR) and gel permeation chromatography (GPC). FTIR analyses suggested that the explanted spacers exhibited slight surface chemical changes but were chemically unchanged below the surface and in the center. New peaks that could be attributed to biodegradation of PCU were not observed. The spectral analyses for the cords revealed that the PET cords were chemically unchanged at both the surface and the interior. Peaks associated with the PET biodegradation were not detected. GPC results did not identify changes to the distributions of molecular weights that might be attributed to biodegradation of either PCU spacers or PET cords. The explanted condition of the retrieved components demonstrated the biostability of both PCU spacers and PET cords that had been in vivo for up to 19 months. PMID- 21538209 TI - Glycosidic bond cleavage is not required for phytosteryl glycoside-induced reduction of cholesterol absorption in mice. AB - Phytosteryl glycosides occur in natural foods but little is known about their metabolism and bioactivity. Purified acylated steryl glycosides (ASG) were compared with phytosteryl esters (PSE) in mice. Animals on a phytosterol-free diet received ASG or PSE by gavage in purified soybean oil along with tracers cholesterol-d(7) and sitostanol-d(4). In a three-day fecal recovery study, ASG reduced cholesterol absorption efficiency by 45 +/- 6% compared with 40 +/- 6% observed with PSE. Four hours after gavage, plasma and liver cholesterol-d(7) levels were reduced 86% or more when ASG was present. Liver total phytosterols were unchanged after ASG administration but were significantly increased after PSE. After ASG treatment both ASG and deacylated steryl glycosides (SG) were found in the gut mucosa and lumen. ASG was quantitatively recovered from stool samples as SG. These results demonstrate that ASG reduces cholesterol absorption in mice as efficiently as PSE while having little systemic absorption itself. Cleavage of the glycosidic linkage is not required for biological activity of ASG. Phytosteryl glycosides should be included in measurements of bioactive phytosterols. PMID- 21538210 TI - Identification of diacylglycerol acyltransferase inhibitors from Rosa centifolia petals. AB - Diacylglycerol acyltransferase (DGAT) catalyzes the final step of triacylglycerol (TAG) synthesis, and is considered as a potential target to control hypertriglyceridemia or other metabolic disorders. In this study, we found that the extract of rose petals suppressed TAG synthesis in cultured cells, and that the extract showed DGAT inhibitory action in a dose-dependent manner. Fractionation of the rose extract revealed that the DGAT inhibitory substances in the extract were ellagitannins; among them rugosin B, and D, and eusupinin A inhibited DGAT activity by 96, 82, and 84% respectively, at 10 MUM. These substances did not inhibit the activities of other hepatic microsomal enzymes, glucose-6-phosphatase and HMG-CoA reductase, or pancreatic lipase, suggesting that ellagitannins inhibit DGAT preferentially. In an oral fat load test using mice, postprandial plasma TAG increase was suppressed by rose extract; TAG levels 2 h after the fat load were significantly lower in mice administered a fat emulsion containing rose extract than in control mice (446.3 +/- 33.1 vs 345.3 +/ 25.0 mg/dL, control vs rose extract group; P < 0.05). These results suggest that rose ellagitannins or rose extract could be beneficial in controlling lipid metabolism and used to improve metabolic disorders. PMID- 21538211 TI - Organ donation after cardiac death: donor and recipient outcomes after the first three years of the Ontario experience. AB - PURPOSE: The aim of this study was to explore donor and recipient outcomes from organ donation after cardiac death (DCD) in Ontario and to examine the impact of DCD on deceased donation rates in Ontario since its implementation. METHODS: Donor data were obtained from the Trillium Gift of Life Network (TGLN) TOTAL database from June 1, 2006 until May 31, 2009. All DCDs were tracked, including unsuccessful DCD attempts during that time. For the first 36 months after DCD implementation, all Ontario solid organ transplant programs that utilized organs from DCD provided clinical outcome data at one year. Total DCD activity until December 1, 2010 was also tracked. In addition, we compared organ donation and DCD rates across all Canadian jurisdictions and the USA. RESULTS: For the first 36 months of DCD activity in Ontario, June 1, 2006 to May 31, 2009, there were 67 successful DCDs out of 87 attempted DCDs in 18 Ontario hospitals, resulting in 128 kidney, 41 liver, and 21 lung transplants. The one-year kidney patient and death-censored allograft survivals were 96 and 97%, respectively. Mean (SD) creatinine at 12 months was 150 (108) MUmol.L(-1). In 26 (20%) extended criteria donors (ECD-DCD), the one-year creatinine was 206 (158) MUmol.L(-1) vs 137 (80) MUmol.L(-1) in 102 standard criteria donors (SCD-DCD) (P = 0.002). The one-year liver and lung allograft survivals were 78% and 70%, respectively. Since its implementation four and a half years ago, DCD has accounted for 10.9% of deceased donor activity in Ontario. In 2009, Ontario had a record number of organ donors. Of the 221 deceased donors, 37 (17%) donors were DCD. By December 1, 2010 there were 121 DCD Ontario donors resulting in > 300 solid organ transplants and accounting for 90% of all DCD activity in the country. CONCLUSION: The rapid update of DCD in Ontario can be attributed to strong proponents in the critical care and transplantation communities with continued support from Trillium Gift of Life Network (TGLN). Ontario is the only province to demonstrate growth in deceased donor rates over the last decade (25% over the last four years), which can be attributed primarily to the success of its DCD activity. PMID- 21538212 TI - Effect of experimental temperature on the permeation of model diffusants across porcine buccal mucosa. AB - The influence of experimental temperature on the permeability of model diffusants across porcine buccal mucosa was investigated in vitro. The permeability increased significantly as the experimental temperature was increased in increments of approximately 7 degrees C. It was observed that the apparent permeability and temperature were related by an exponential relationship that conformed to the Arrhenius equation. Diffusants with higher lipophilicities- buspirone and bupivacaine--had lower activation energies for diffusion when compared to hydrophilic diffusants--antipyrine and caffeine. The activation energy for diffusion of the model diffusants decreased linearly with increasing distribution coefficients across porcine buccal mucosa. The results suggested that the buccal mucosa acts as a stronger barrier to the diffusion of hydrophilic diffusants than the lipophilic ones. The log-linear relationship between permeability and temperature indicates that temperature should be carefully controlled in diffusion experiments. These results also point to the possibility of developing heat-generating buccal delivery devices, especially for hydrophobic diffusants. PMID- 21538213 TI - Evaluation of the membrane permeability (PAMPA and skin) of benzimidazoles with potential cannabinoid activity and their relation with the Biopharmaceutics Classification System (BCS). AB - The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying these molecules as very permeable, independent of their thermodynamic solubility, if and only if these have a Log P(oct) value <3.0. In contrast, transdermal permeability is conditioned on the solubility of the molecule so that it can only serve as a model for classifying the permeability of molecules that possess high solubility (class I: high solubility, high permeability; class III: high solubility, low permeability). PMID- 21538214 TI - Development of biotechnology products in pre-filled syringes: technical considerations and approaches. AB - A monoclonal antibody (mAb) product development case study is presented to address some of the issues faced during developing a pre-filled syringe (PFS) product for a biotherapeutic. In particular, issues involving incompatibility with silicone oil and a stability-based approach for selection of PFS barrel and tip cap components have been discussed. Silicone spiking studies followed by exposure to agitation stress or accelerated temperature conditions were used to check for incompatibilities of the mAb with silicone oil, a necessary product contact material in PFS. In addition, screening studies to compare various closure materials as well as syringe barrel processing methods were used to select the optimum closure materials as well as the correct syringe processing method. Results indicate that the model mAb formulation used was sensitive to high levels of silicone oil especially under accelerated temperature conditions resulting in formation of protein-silicone particles in the solution for samples that were spiked with the silicone oil. Agitation stress did not have any significant impact on the quality attributes tested. Samples stored in syringe barrels that were processed with sprayed-on silicone had higher levels of subvisible particles as compared to those that were processed with the baked-on process. The tip cap comparability study resulted in one tip cap material having superior compatibility among the three that were tested. The quality attribute that was most impacted by the tip cap materials was mAb oxidation. An approach for evaluation of primary packaging components during the development of pre filled syringe presentations for biotechnology-based compounds has been highlighted. PMID- 21538215 TI - Endoscopic submucosal dissection combined with the placement of biodegradable stents for recurrent esophageal cancer after chemoradiotherapy. AB - We report a case of a patient with esophageal squamous cell carcinoma who presented with obstruction of the esophagus. On endoscopy, a central ulcerating lesion was found spreading to the anterior wall of the middle esophagus. Four courses of chemoradiation therapy successfully produced a complete response for 3 years. A recurrence occurred which consisted of a morphologically flat lesion that occupied the entire circumference of the esophagus. Endoscopic submucosal dissection removed all lesions en bloc. To prevent a post-procedure mucosal defect of the circumference of the esophagus, biodegradable poly-l-lactic acid monofilaments esophageal stents were placed on the same day. One month later, the patient reported a feeling of obstruction. An endoscopic examination revealed food stuck in the stents, this was removed, and balloon dilatation provided good passage which has been maintained for 7 months. PMID- 21538217 TI - Photo-degradation study of CdTe nanocrystals by fluorescence measurement. AB - The photo-degradation of green-, yellow-, orange- and red-emitting CdTe nanocrystals (NCs) in sol-gel SiO(2) films was investigated quantitatively by measuring the PL efficiency as a function of the irradiation intensity. The degradation behaviors of the NCs depended strongly on the particle size and the surface state. Green- and yellow-emitting CdTe NCs exhibited a red-shifted PL peak wavelength and decreased PL efficiency after irradiation. In contrast, the PL peak wavelength of red-emitting CdTe NCs remained unchange and their PL efficiency increased. Furthermore, the degraded degree of green-emitting NCs depended linearly on the irradiation intensity [Formula: see text], whereas hat of red-emitting NCs showed a quadratic dependence [Formula: see text] at room temperature. This is ascribed to the different surface state of green- and red emitting CdTe NCs. PMID- 21538216 TI - Resistance to the translation initiation inhibitor silvestrol is mediated by ABCB1/P-glycoprotein overexpression in acute lymphoblastic leukemia cells. AB - Protein synthesis is a powerful therapeutic target in leukemias and other cancers, but few pharmacologically viable agents are available that affect this process directly. The plant-derived agent silvestrol specifically inhibits translation initiation by interfering with eIF4A/mRNA assembly with eIF4F. Silvestrol has potent in vitro and in vivo activity in multiple cancer models including acute lymphoblastic leukemia (ALL) and is under pre-clinical development by the US National Cancer Institute, but no information is available about potential mechanisms of resistance. In a separate report, we showed that intraperitoneal silvestrol is approximately 100% bioavailable systemically, although oral doses were only 1% bioavailable despite an apparent lack of metabolism. To explore mechanisms of silvestrol resistance and the possible role of efflux transporters in silvestrol disposition, we characterized multi-drug resistance transporter expression and function in a silvestrol-resistant ALL cell line generated via culture of the 697 ALL cell line in gradually increasing silvestrol concentrations. This resistant cell line, 697-R, shows significant upregulation of ABCB1 mRNA and P-glycoprotein (Pgp) as well as cross-resistance to known Pgp substrates vincristine and romidepsin. Furthermore, 697-R cells readily efflux the fluorescent Pgp substrate rhodamine 123. This effect is prevented by Pgp inhibitors verapamil and cyclosporin A, as well as siRNA to ABCB1, with concomitant re-sensitization to silvestrol. Together, these data indicate that silvestrol is a substrate of Pgp, a potential obstacle that must be considered in the development of silvestrol for oral delivery or targeting to tumors protected by Pgp overexpression. PMID- 21538218 TI - Additive effects of low-level laser therapy with exercise on subacromial syndrome: a randomised, double-blind, controlled trial. AB - The subacromial syndrome is the most common source of shoulder pain. The mainstays of conservative treatment are non-steroidal anti-inflammatory drugs and exercise therapy. Recently, low-level laser therapy (LLLT) has been popularized in the treatment of various musculoskeletal disorders. The aim of this study is to evaluate the additive effects of LLLT with exercise in comparison with exercise therapy alone in treatment of the subacromial syndrome. We conducted a randomised clinical study of 80 patients who presented to clinic with subacromial syndrome (rotator cuff and biceps tendinitis). Patients were randomly allocated into two groups. In group I (n = 40), patients were given laser treatment (pulsed infrared laser) and exercise therapy for ten sessions during a period of 2 weeks. In group II (n = 40), placebo laser and the same exercise therapy were given for the same period. Patients were evaluated for the pain with visual analogue scale (VAS) and shoulder range of motion (ROM) in an active and passive movement of flexion, abduction and external rotation before and after treatment. In both groups, significant post-treatment improvements were achieved in all parameters (P = 0.00). In comparison between the two groups, a significant improvement was noted in all movements in group I (P = 0.00). Also, there was a substantial difference between the groups in VAS scores (P = 0.00) which showed significant pain reduction in group I. This study indicates that LLLT combined exercise is more effective than exercise therapy alone in relieving pain and in improving the shoulder ROM in patients with subacromial syndrome. PMID- 21538222 TI - Molecular mobility in biodegradable poly(epsilon-caprolactone)/poly(hydroxyethyl acrylate) networks. AB - Poly(epsilon-caprolactone)/poly(hydroxyethyl acrylate) networks have been investigated by thermally stimulated depolarization currents (TSDC) and differential scanning calorimetry (DSC). The introduction of hydrophilic units (HEA) in the system aiming at tailoring the hydrophilicity of the system results in a series of copolymer networks with microphase separation into hydrophobic/hydrophilic domains. Polycaprolactone (PCL) crystallization is prevented by the topological constraints HEA units imposed in such heterogeneous domains. Moreover, the mobility of the amorphous PCL chains is enhanced as revealed by the main relaxation process which becomes faster. The glass transition of PHEA-rich domains shifts to lower temperatures, as the total amount of PCL in the copolymer increases, due to the presence of PCL units within the same region. The behaviour of the copolymer networks swollen with different content of water has been investigated to analyze the interaction between water molecules and hydrophobic/hydrophilic domains and provide further insights into the molecular structure of the system. PMID- 21538223 TI - Marine pyrroloiminoquinone alkaloids. AB - Recent reports on the synthetic studies of marine pyrroloiminoquinone alakloids and their analogs are reviewed. PMID- 21538224 TI - The individualisation of a dog bite mark: a case study highlighting the bite mark analysis, with emphasis on differences between dog and human bite marks. AB - A person who keeps or controls a dog in his own interest is liable "without fault" should that dog cause harm to any person. By owning a dog, man welcomes into his home a beast that preserves much of its primordial self, and is capable of inflicting a fatal bite wound. The courts may require the forensic expert to identify which specific dog caused the damage or fatal bite in an effort to establish the owner/controller of the animal. Very little has been published on the individualisation of dog bite marks, the procedures to be followed when confronted with usable bite marks and the range of analysis techniques available. The authors advocate a multidisciplinary approach, and utilise a case study to demonstrate the protocol to be followed when analysing a dog bite mark. The paper also highlights differences between human and dog inflicted bites. The authors warn against over interpretation of poor quality bite marks and a final conclusion of absolute certainty. PMID- 21538225 TI - Database of post-mortem rectal cooling cases under strictly controlled conditions: a useful tool in death time estimation. AB - The most common method used in determining the estimated time since death in the early post-mortem phase is back-calculation based on rectal temperature decrease. Cooling experiments are essential for model generation and validation. Post mortem temperature models are necessary to perform back-calculations. Thus far, cooling experiments have not been performed under controlled environmental conditions. The present study provides data on 84 post-mortem cooling experiments under strictly controlled environmental conditions. For a period of 5 years, starting in 2003, deceased persons with a known time of death and known environmental conditions at the death scene were transferred to a climatic chamber for the process of body cooling. The environmental temperature was programmed to the death scene temperature and kept constant throughout the process of body cooling. Rectal and ambient temperatures were measured every minute. Relevant case-specific information was summarized in a FileMaker database. The database serves as a reference tool for the comparison of real cases in forensic routine and to check the plausibility of model-derived estimates. PMID- 21538226 TI - Kinetic degradation of the pollutant guaiacol by dark Fenton and solar photo Fenton processes. AB - This work is first intended to optimize the experimental conditions for the maximum degradation of guaiacol (2-methoxyphenol) by Fenton's reagent, and second, to improve the process efficiency through the use of solar radiation. Guaiacol is considered as a model compound of pulp and paper mill effluent. The experiments were carried out in a laboratory-scale reactor subjected or not to solar radiation. Hydrogen peroxide solution was continuously introduced into the reactor at a constant flow rate. The kinetics of organic matter decay was evaluated by means of the chemical oxygen demand (COD) and the absorbance measurements. The experimental results showed that the Fenton and solar photo Fenton systems lead successfully to 90% elimination of COD and absorbance at 604 nm from a guaiacol solution under particular experimental conditions. The COD removal always obeyed a pseudo-first-order kinetics. The effect of pH, temperature, H(2)O(2) dosing rate, initial concentration of Fe(2+), and initial COD was investigated using the Fenton process. The solar photo-Fenton system needed less time and consequently less quantity of H(2)O(2). Under the optimum experimental conditions, the solar photo-Fenton process needs a dose of H(2)O(2) 40% lower than that used in the Fenton process to remove 90% of COD. PMID- 21538227 TI - Evaluation of the optimal strategy for ex situ bioremediation of diesel oil contaminated soil. AB - PURPOSE: Bioaugmentation and biostimulation have been widely applied in the remediation of oil contamination. However, ambiguous results have been reported. It is important to reveal the controlling factors on the field for optimal selection of remediation strategy. In this study, an integrated field landfarming technique was carried out to assess the relative effectiveness of five biological approaches on diesel degradation. The limiting factors during the degradation process were discussed. METHOD: A total of five treatments were tested, including conventional landfarming, nutrient enhancement (NE), biosurfactant addition (BS), bioaugmentation (BA), and combination of bioaugmentation and biosurfactant addition (BAS). The consortium consisted of four diesel-degrading bacteria strains. Rhamnolipid was used as the biosurfactant. The diesel concentration, bacterial population, evolution of CO(2), and bacterial community in the soil were periodically measured. RESULTS: The best overall degradation efficiency was achieved by BAS treatment (90 +/- 2%), followed by BA (86 +/- 2%), NE (84 +/- 3%), BS (78 +/- 3%), and conventional landfarming (68 +/- 3%). In the early stage, the total petroleum hydrocarbon was degraded 10 times faster than the degradation rates measured during the period from day 30 to 100. At the later stage, the degradation rates were similar among treatments. In the conventional landfarming, contaminated soil contained bacteria ready for diesel degradation. CONCLUSION: The availability of hydrocarbon was likely the limiting factor in the beginning of the degradation process. At the later stage, the degradation was likely limited by desorption and mass transfer of hydrocarbon in the soil matrix. PMID- 21538228 TI - Developmental expression of heat shock proteins 60, 70, 90, and A2 in rabbit testis. AB - Currently, no reports exist concerning the expression patterns and developmental changes of heat shock proteins (HSPs) in the reproductive system of the male rabbit. In the present study, the testes of rabbits were collected at post-natal months 1, 2, 3, 4, 5, and 40. HSP60, HSC70, HSP90, and HSPA2 were detected by both Western blot and immunohistochemical methods. The expression levels of HSP60 and HSC70 showed no apparent change during the developmental progress. HSP90 increased at the second month; prior to the third month, HSPA2 was expressed at a low level. Immunohistochemistry localized HSP60 in the cytoplasm of all of the cell types in the testis and in the apical pole of the spermatids. The distribution pattern of HSC70 and HSP90 was similar, both being mainly located in the spermatids of stage VII-VIII and in the cytoplasm of the spermatogonium. HSPA2 staining was mainly observed in the cytoplasm of pachytene spermatocytes and spermatids in testes of 3-, 4-, 5-, and 40-month-old rabbits. These results provide a basic reference point for studying the functions of HSPs in the male rabbit reproductive system and should be beneficial for the future determination of the mechanisms of heat shock on male rabbit fertility. PMID- 21538230 TI - Reversible increases in cortical diffusion-weighted MR signal in a patient with Sturge-Weber syndrome and subacute hemiplegia. PMID- 21538229 TI - Dietary immunomodulatory factors in the development of immune tolerance. AB - Emerging evidence suggests that exposures during pregnancy and the early postnatal period can modify gene expression and disease propensity. Diet is a major environmental exposure, and dietary factors, including polyunsaturated fatty acids, probiotics, oligosaccharides, antioxidants, folate, and other vitamins, have effects on immune function. Some also have been implicated in reduced risk of allergy in observational studies. Intervention trials with polyunsaturated fatty acids, probiotics, and oligosaccharides suggest preliminary but as-of-yet-unconfirmed benefits. Food allergen avoidance during pregnancy, lactation, or infancy has provided no consistent evidence in allergy prevention and is no longer recommended. Rather, there is now a focus on food allergens in tolerance induction. Specific nutrients can induce changes in gene expression during early development and have been implicated in potentially heritable "epigenetic" changes in disease predisposition. Collectively, these observations emphasize that early exposures may modify tolerance development and that further research on these exposures should remain a priority. PMID- 21538231 TI - Evaluation of contributing factors to restless legs syndrome in migraine patients. AB - Recent studies have provided evidence for a positive association between migraine and restless legs syndrome (RLS), although the exact mechanisms and contributing factors remain unclear. A cross-sectional, case-control study was conducted, including patients with migraine (n = 262) and headache-free control subjects (n = 163). Migraine was diagnosed according to International Classification of Headache Disorders II criteria. RLS diagnosis was made based on four essential criteria as described by the International Restless Legs Syndrome Study Group. All patients completed the Migraine Disability Assessment (MIDAS) questionnaire, Beck Depression Inventory (BDI)-II scores, Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS). A total of 210 blood samples were collected to correlate various parameters with RLS. RLS frequency was significantly greater in patients with migraine than in controls (13.7 vs. 1.8%). Migraine patients with RLS had high scores for MIDAS, BDI-II, PSQI, and ESS compared with those without RLS. In addition, migraine patients with RLS had a high rate of smoking and RLS family history, as well as increased levels of serum phosphorus and urea nitrogen compared with those without RLS. However, there was no difference in serum iron and ferritin levels between the groups. In migraine patients, logistic regression analysis revealed that positive RLS family history, BDI-II, ESS, and serum phosphorus levels were significant RLS predictors. Our study confirmed a positive association between RLS and migraine. RLS comorbidity in migraine patients was associated with insomnia, daytime sleepiness, depressive symptoms, headache-related disability, and increased serum phosphorus levels. These findings may provide a better understanding of RLS pathogenesis in migraine. PMID- 21538232 TI - Peripartum angiopathy with simultaneous sinus venous thrombosis, cervical artery dissection and cerebral arterial vasoconstriction. PMID- 21538233 TI - Tinospora cordifolia attenuates oxidative stress and distorted carbohydrate metabolism in experimentally induced type 2 diabetes in rats. AB - Diabetes is a chronic metabolic disorder affecting a vast number of people worldwide. Oxidative stress is the causative agent amplifying diabetic complications in various organs by generating noxious amount of free radicals. A huge interest always exists in exploring nutraceuticals from plant materials to replace synthetic drugs in order to overcome their adverse effects and also for economic reasons. The anti-diabetic efficiency of a medicinal plant, Tinospora cordifolia (TC) was studied in experimentally induced type 2 diabetes in Sprague Dawley rats. Diabetes was induced by a combination of high fat diet (HFD) for a period of 10 weeks followed by intraperitoneal injection of streptozotocin (STZ, 35 mg/kg of body weight). Oral treatment of TC (100 and 200 mg/kg body weight) for 14 days regulated blood glucose, provoked insulin secretion and also suppressed oxidative stress marker, thiobarbituric acid reactive substances (TBARS), formation and restored cellular defence anti-oxidant markers including superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH), in liver. Treatment with TC (100 and 200 mg/kg) also inhibited glucose 6 phosphatase and fructose 1,6-diphosphatase (p < 0.001); and restored glycogen content in liver (p < 0.005), which was also studied by histopathological staining with periodic acid-Schiff stain. In conclusion, the traditional plant Tinospora cordifolia mediates its anti-diabetic potential through mitigating oxidative stress, promoting insulin secretion and also by inhibiting gluconeogenesis and glycogenolysis, thereby regulating blood glucose. PMID- 21538234 TI - Diagnostic accuracy of NT-proBNP ratio (BNP-R) for early diagnosis of tachycardia mediated cardiomyopathy: a pilot study. AB - BACKGROUND: When heart failure and tachycardia occur simultaneously, a useful diagnostic tool for early discrimination of patients with benign tachycardia mediated cardiomyopathy (TMC) versus major structural heart disease (MSHD) is not available. Such a tool is required to prevent unnecessary and wearing diagnostics in patients with reversible TMC. Moreover, it could lead to early additional diagnostics and therapeutic approaches in patients with MSHD. METHODS: A total of 387 consecutive patients with supraventricular arrhythmia underwent assessment at a single center. Of these patients, 40 fulfilled the inclusion criteria with a resting heart rate >=100 bpm and an impaired left ventricular ejection fraction <40%. In all patients, successful electrical cardioversion was performed. At baseline, day 1 and weekly for 4 weeks, levels of NT-proBNP and echocardiographic parameters were evaluated. An NT-proBNP ratio (BNP-R) was calculated as a quotient of baseline NT-proBNP/follow-up NT-proBNP. After 4 weeks, cardiac catheterization was performed to identify patients with a final diagnosis of TMC versus MSHD. RESULTS: Initial NT-proBNP concentrations were elevated and consecutively decreased after cardioversion in all patients. Multivariate regression and ROC analysis revealed that BNP-R discriminated between patients with TMC versus MSHD independent and superior to all other variables. The area under the ROC curve for BNP-R to detect TMC was 0.90 (95% CI 0.79-1.00; p < 0.001) after 1 week and 0.995 (95% CI 0.99-1.00; p < 0.0001) after 4 weeks. One week after cardioversion already, a BNP-R cutoff >=2.3 was useful for TMC diagnosis indicated by an accuracy of 90%, sensitivity of 84% and specificity of 95%. CONCLUSION: BNP-R was found to be highly accurate for the early diagnosis of TMC. PMID- 21538235 TI - Candida albicans, a major human fungal pathogen. AB - Candida albicans is the most common human fungal pathogen (Beck-Sague and Jarvis, 1993). It is normally a harmless commensal organism. However, it is a opportunistic pathogen for some immunologically weak and immunocompromised people. It is responsible for painful mucosal infections such as the vaginitis in women and oral-pharangeal thrush in AIDS patients. In certain groups of vulnerable patients it causes severe, life-threatening bloodstream infections and it causes severe, life-threatening bloodstream infections and subsequent infections in the internal organs. There are various fascinating features of the C. albicans life cycle and biology that have made the pathogen the subject of extensive research, including its ability to grow in unicellular yeast, pseudohyphal, and hyphal forms (Fig. 1A); its ability to switch between different but stable phenotypic states, and the way that it retains the ability to mate but apparently loses the ability to go through meiosis to complete the sexual cycle. This research has been greatly facilitated by the derivation of the complete C. albicans genome sequence (Braun et al., 2005), the development of a variety of molecular tools for gene manipulation, and a store of underpinning knowledge of cell biology borrowed from the distantly related model yeast Saccharomyces cerevisiae (Berman and Sudbery, 2002; Noble and Johnson, 2007). This review will provide a brief overview of the importance of C. albicans as a public health issue, the experimental tools developed to study its fascinating biology, and some examples of how these have been applied. PMID- 21538236 TI - Isolation and characterization of a family VII esterase derived from alluvial soil metagenomic library. AB - A novel esterase gene, estDL30, was isolated from an alluvial metagenomic library using function-driven screening. estDL30 consisted of 1,524 nucleotides and encoded a 507-amino acid protein. Sequence analysis revealed that EstDL30 is similar to many type B carboxylesterases, containing a G-E-S-A-G pentapeptide with a catalytic Ser residue. Phylogenetic analysis suggested that EstDL30 belongs to the family VII lipases, together with esterases from Bacillus subtilis (P37967), Streptomyces coelicolor A3(2) (CAA22794), and Arthrobacter oxydans (Q01470). Purified EstDL30 showed its highest catalytic efficiency toward p nitrophenyl butyrate, with a k (cat) of 2293 s(-1) and k (cat)/K (m) of 176.4 s( 1)mM(-1); however, little activity was detected when the acyl chain length exceeded C(8). Biochemical characterization of EstDL30 revealed that it is an alkaline esterase that possesses maximal activity at pH 8 and 40 degrees C. The effects of denaturants and divalent cations were also investigated. EstDL30 tolerated well the presence of methanol and Tween 20. Its activity was strongly inhibited by 1 mM Cu(2+) and Zn(2+), but stimulated by Fe(2+). The unique properties of EstDL30, its high activity under alkaline conditions and stability in the presence of organic solvents, may render it applicable to organic synthesis. PMID- 21538237 TI - Correlations of fecal bacterial communities with age and living region for the elderly living in Bama, Guangxi, China. AB - Bama County (Guangxi, China) is famous for its longevous population. In this study, intestinal microflora of 17 healthy elderly subjects of different ages and from different regions (rural and urban) in Bama, were analyzed by denaturing gradient gel electrophoresis (DGGE). Significant effects of age and living region on the whole intestinal bacterial communities were observed by redundancy analysis (RDA). A total of 11 bacterial strains that were correlated with age and living region were identified using a t-value biplot combined with band sequencing. Four bacterial strains were correlated with both age and living region of the elderly in Bama. Two Bacteroides strains and one Ruminococcaceae strain were abundant in the rural, younger elderly; conversely, one Desulfovibrio strain was high in the urban, older elderly. Another Bacteroidetes strain was only correlated with the participant's age, and its abundance increased with the age of the elderly. The richness of one Clostridium sordellii strain, which was only correlated with the elderly living region, was high in the urban elderly. The study also found five other novel bacterial strains that were correlated with the age or living region of the elderly in Bama. These results expand our understanding of age- and region-effects on the intestinal microflora of the elderly and raise the possibility of developing probiotics originating from centenarians. PMID- 21538238 TI - Inhibitory effect of Lactobacillus reuteri on periodontopathic and cariogenic bacteria. AB - The interaction between Lactobacillus reuteri, a probiotic bacterium, and oral pathogenic bacteria have not been studied adequately. This study examined the effects of L. reuteri on the proliferation of periodontopathic bacteria including Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Porphyromonas gingivalis, and Tannerella forsythia, and on the formation of Streptococcus mutans biofilms. Human-derived L. reuteri strains (KCTC 3594 and KCTC 3678) and rat-derived L. reuteri KCTC 3679 were used. All strains exhibited significant inhibitory effects on the growth of periodontopathic bacteria and the formation of S. mutans biofilms. These antibacterial activities of L. reuteri were attributed to the production of organic acids, hydrogen peroxide, and a bacteriocin-like compound. Reuterin, an antimicrobial factor, was produced only by L. reuteri KCTC 3594. In addition, L. reuteri inhibited the production of methyl mercaptan by F. nucleatum and P. gingivalis. Overall, these results suggest that L. reuteri may be useful as a probiotic agent for improving oral health. PMID- 21538239 TI - Screening-level assays for potentially human-infectious environmental Legionella spp. AB - In spite of the fact that various Legionella species are isolated from nonclinical water settings, there is no standard method to determine whether environmental legionellae may be infectious to humans. Here we provide a screening-level approach based on an in vivo murine (A/J mouse) model and three in vitro proliferation assays using Acanthamoeba polyphaga, and THP-1 human and J774 murine macrophage cell lines to identify potentially human-infectious legionellae. As an initial demonstration the infectivity potential of three clinical (Legionella pneumophila, L, longbeacheae, and L. micdadei) and three environmental (L. dumoffii, L. maceachernii, and L. sainthelensi) legionellae were evaluated. A/J mice were intranasally infected and by 6 h post infection (p.L), there were significant bacterial titers in the lungs. L. pneumophila, L. dumoffii, and L. micdadei densities were higher than L. longbeacheae, L. maceacherni, and L. sainthelensi at 24 h p.i. However, only L. pneumophila and L. micdadei persisted in the lungs after 48 h, indicating that the other isolates were rapidly cleared. Results from the in vitro assays showed that only L. pneumophila significantly multiplied within A. polyphaga, THP-1 and J774 cells after 72 h, but lysis of any of the in vitro hosts also flagged the strains for potential concern (e.g. L. dumoffii and L. micdadei). The results demonstrate the value of using multiple approaches to assess the potential level of pathogenicity of Legionella strains isolated from different environmental matrices. PMID- 21538240 TI - Physiological and metabolic responses for hexadecane degradation in Acinetobacter oleivorans DR1. AB - The hexadecane degradation of Acinetobacter oleivorans DR1 was evaluated with changes in temperature and ionic salt contents. Hexadecane degradation of strain DR1 was reduced markedly by the presence of sodium chloride (but not potassium chloride). High temperature (37 degrees C) was also shown to inhibit the motility, biofilm formation, and hexadecane biodegradation. The biofilm formation of strain DR1 on the oil-water interface might prove to be a critical physiological feature for the degradation of hexadecane. The positive relationship between biofilm formation and hexadecane degradation could be observed at 30 degrees C, but not at low temperatures (25 degrees C). Alterations in cell hydrophobicity and EPS production by temperature and salts were not correlated with biofilm formation and hexadecane degradation. Our proteomic analyses have demonstrated that metabolic changes through the glyoxylate pathway are important for efficient degradation of hexadecane. Proteins involved in fatty acid metabolism, gluconeogenesis, and oxidative stress defense proteins appear to be highly expressed during biodegradation of hexadecane. These results suggested that biofilm formation and oxidative stress defense are important physiological responses for hexadecane degradation along with metabolic switch to glyoxylate pathway in strain DR1. PMID- 21538241 TI - The effect of lipid supplements on ruminal bacteria in continuous culture fermenters varies with the fatty acid composition. AB - A single flow continuous culture fermenter system was used in this study to investigate the influence of dietary lipid supplements varying in their fatty acid content on the DNA concentration of selected rumen bacteria. Four continuous culture fermenters were used in a 4 * 4 Latin square design with four periods of 10 d each. Treatment diets were fed at 45 g/d (DM basis) in three equal portions during the day. The diets were: 1) control (CON), 2) control with animal fat source (SAT), 3) control with soybean oil (SBO), and 4) control with fish oil (FO). Lipid supplements were added at 3% of diet DM. The concentrations of total volatile fatty acids and acetate were not affected (P>0.05) by lipid supplements. Concentrations of propionate, iso-butyrate, valerate and iso-valerate were highest (P<0.05) with the FO diet compared with the other treatment diets. The concentration of til C18:l (vaccenic acid, VA) in effluents increased (P<0.05) with SBO and FO diets and was highest with the SBO diet. The concentrations of C18:0 in effluents were lowest (P<0.05) for the FO diet compared with the other treatment diets. Concentrations of DNA for Anaerovibrio lipolytica, and Butyrivibrio proteoclasticus in fermenters were similar (P>0.05) for all diets. The DNA concentrations of Butyrivibrio fibrisolvens and Ruminococcus albus in fermenters were lowest (P<0.05) with the FO diet but were similar (P>0.05) among the other treatment diets. Selenomonas ruminantium DNA concentration in fermenters was highest (P<0.05) with the FO diet. In conclusion, SBO had no effect on bacterial DNA concentrations tested in this study and the VA accumulation in the rumen observed on the FO diet may be due in part to FO influence on B. fibrisolvens, R. albus, and S. ruminantium. PMID- 21538242 TI - Seasonal abundance and distribution of Vibrio species in the treated effluent of wastewater treatment facilities in suburban and urban communities of Eastern Cape Province, South Africa. AB - We assessed the seasonal abundance and distribution of Vibrio species as well as some selected environmental parameters in the treated effluents of two wastewater treatment plants (WWTP), one each located in a suburban and urban community of Eastern Cape Province, South Africa. Vibrio population density ranged from 2.1 * 10(5) to 4.36 * 10(4) CFU/ml in the suburban community and from 2.80 * 10(5) to 1.80 * 10(5) CFU/ml in the urban community. Vibrio species associated with 180 MU, 60 MU, and 20 MU plankton sizes were observed at densities of 0-136 * 10(3) CFU/ml, 0-8.40 * 10(2) CFU/ml, and 0-6.80 * 10(2) CFU/ml, respectively at the suburban community's WWTP. In the urban community, observed densities of culturable Vibrio were 0-2.80 * 10(2) CFU/ml (180 MU), 0-6.60 * 10(2) CFU/ml (60 MUm), and 0-1.80 * 10(3) CFU/ml (20 MUm). The abundance of free-living Vibrio species ranged from 0 to 1.0 * 10(2) and 1.0 * 10(3) CFU/ml in the suburban and urban communities' WWTPs, respectively. Molecular confirmation of the presumptive Vibrio isolates revealed the presence of V. fluvialis (41.38%), V. vulnificus (34.48%), and V. parahaemolyticus (24.14%) in the suburban community effluents. In the urban community molecular confirmation revealed that the same species were present at slightly different percentages, V. fluvialis (40%), V. vulnificus (36%), and V. parahaemolyticus (24%). There was no significant correlation between Vibrio abundance and season, either as free-living or plankton-associated entities, but Vibrio species abundance was positively correlated with temperature (r=0.565; p<0.01), salinity, and dissolved oxygen (p<0.05). Turbidity and pH showed significant seasonal variation (p<0.05) across the seasons in both locations. This study underscores the potential of WWTPs to be sources of Vibrio pathogens in the watershed of suburban and urban communities in South Africa. PMID- 21538243 TI - Oceanicoccus sagamiensis gen. nov., sp. nov., a gammaproteobacterium isolated from sea water of Sagami Bay in Japan. AB - A gram-negative, motile, coccoid- and amorphous-shaped, non-pigmented chemoheterotrophic bacterium, designated strain PZ-5(T), was isolated from sea water of Sagami Bay in Japan and subjected to a polyphasic taxonomic study. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the novel isolate could be affiliated with the class Gammaproteobacteria. Strain PZ-5(T) showed below 93.9% similarity with validly published bacteria and demonstrated the highest sequence similarity to Dasania marina KOPRI 20902(T) (93.9%). Strain PZ-5(T) formed a monophyletic group with D. marina KOPRI 20902(T). The DNA G+C content of strain PZ-5(T) was 49.8 mol%. The major isoprenoid quinone was Q-8 and predominant cellular fatty acids were C(15:0) ISO 20H (19%), C(16:1) omega7c (17.4%), C(17;1) omega8c (16.2%), C(11:0) 3OH (7.5%), and C(15:1) omega8c (6.5%). Based on evidence from a polyphasic taxonomical study, it was concluded that the strain should be classified as representing a new genus and species of the class Gammaproteobacteria, for which the name Oceanicoccus sagamiensis gen. nov., sp. nov., (type strain PZ-5(T) =NBRC 107125(T) =KCTC 23278(T)) is proposed. PMID- 21538244 TI - Sphingomonas jejuensis sp. nov., isolated from marine sponge Hymeniacidon flavia. AB - A Gram-negative, non-motile, rod shaped, and orange-pigmented chemoheterotrophic bacterium, strain MS-31(T) was isolated from the marine sponge Hymeniacidon flavia, collected from near Jeju Island, Korea. The Strain MS-31(T) was subjected to a polyphasic taxonomic study. The phylogenetic analysis based on the 16S rRNA gene sequences revealed that the novel isolate could be affiliated within the genus Sphingomonas. The strain MS-31(T) showed 95.6% of 16S rRNA gene sequence similarity with the most closely related species Sphingomonas koreensis JSS26(T). The DNA G+C content of the strain MS-31(T) was 69.4 mol%. The major isoprenoid quinone was ubiqunone 10 and predominant cellular fatty acids were summed feature 7 (comprising C(18:1) omega7c, C(18:1) Omega9t and/or C(18:1) omegal2t, 39.7%), C(16:0) (16.3%), C(14:0) 2OH (15.9%) and summed feature 3 (comprising C(16:1) omega7c and/or C(15:0) iso 2OH, 11.7%). The polar lipids were sphingoglycolipid, phosphatidyletha-nolamine, phosphatidylglycerol, diphosphatidylglycerol and unidentified glycolipid. Based on the evidence from the polyphasic taxonomic study, the strain should be classified as a new species of the genus Sphingomonas. As a result, the name Sphingomonas jejuensis sp. nov. (type strain MS-31(T) =KCTC 23321(T) =NBRC 107775(T)) is proposed. PMID- 21538245 TI - Acinetobacter baumannii biofilms: variations among strains and correlations with other cell properties. AB - Acinetobacter baumannii is an opportunistic pathogen that causes serious infections in humans by colonizing and persisting on surfaces normally found in hospital settings. The capacity of this pathogen to persist in these settings could be due to its ability to form biofilms on inanimate surfaces. This report shows that although the ATCC 19606(T) type strain and 8 different clinical isolates form biofilms, there are significant variations in the cell density and microscopic structures of these cell aggregates, with 3 of the isolates forming pellicles floating on the surface of stagnant broth cultures. PCR indicated that, like ATCC 19606(T), all 8 clinical isolates harbor all the genetic components of the CsuA/BABCDE chaperone-usher pili assembly system, which is needed for biofilm formation on plastic. Pili detection in cells of all strains examined supports the presence and function of a pilus assembly system. However, only one of them produced the putative ATCC 19606(T) CsuA/B pilin subunit protein. Hydrophobicity tests and motility assays also showed significant variations among all tested strains and did not result in direct correlations between the biofilm phenotype and cell properties that could affect biofilm formation on abiotic surfaces. This lack of correlation among these 3 phenotypes may reflect some of the variations already reported with this pathogen, which may pose a challenge in the treatment of the infections this pathogen causes in humans using biofilm formation on abiotic surfaces as a target. PMID- 21538246 TI - Identification of S-nitrosylation of proteins of Helicobacter pylori in response to nitric oxide stress. AB - Innate and adaptive immune responses are activated in humans when Helicobacter pylori invades the gastric mucosa. Nitric oxide (NO) and reactive nitrogen species are important immune effectors, which can exert their functions through oxidation and S-nitrosylation of proteins. S-nitrosoglutathione and sodium nitroprus-side were used as NO donors and H. pylori cells were incubated with these compounds to analyze the inhibitory effect of NO. The suppressing effect of NO on H. pylori has been shown in vitro. Furthermore, the proteins modified by S nitrosylation in H. pylori were identified through the biotin switch method in association with matrix-assisted laser desorption ionization/time-of-flight tandem mass spectrometry (MALDI-TOF-MS/MS). Five S-nitrosylated proteins identified were a chaperone and heat-shock protein (GroEL), alkyl hydroperoxide reductase (TsaA), urease alpha subunit (UreA), HP0721, and HP0129. Importantly, S nitrosylation of TsaA and UreA were confirmed using purified recombinant proteins. Considering the importance of these enzymes in antioxidant defenses, adherence, and colonization, NO may exert its antibacterial actions by targeting enzymes through S-nitrosylation. Identification of protein S-nitrosylation may contribute to an understanding of the antibacterial actions of NO. Our findings provide an insight into potential targets for the development of novel therapeutic agents against H. pylori infection. PMID- 21538247 TI - A Thermostable phytase from Neosartorya spinosa BCC 41923 and its expression in Pichia pastoris. AB - A phytase gene was cloned from Neosartorya spinosa BCC 41923. The gene was 1,455 bp in size, and the mature protein contained a polypeptide of 439 amino acids. The deduced amino acid sequence contains the consensus motif (RHGXRXP) which is conserved among phytases and acid phosphatases. Five possible disulfide bonds and seven potential N-glycosylation sites have been predicted. The gene was expressed in Pichia pastoris KM71 as an extracellular enzyme. The purified enzyme had specific activity of 30.95 U/mg at 37 degrees C and 38.62 U/mg at 42 degrees C. Molecular weight of the deglycosylated recombinant phytase, determined by SDS PAGE, was approximately 52 kDa. The optimum pH and temperature for activity were pH 5.5 and 50 degrees C. The residual phytase activity remained over 80% of initial activity after the enzyme was stored in pH 3.0 to 7.0 for 1 h, and at 60% of initial activity after heating at 90 degrees C for 20 min. The enzyme exhibited broad substrate specificity, with phytic acid as the most preferred substrate. Its K (m) and V (max) for sodium phytate were 1.39 mM and 434.78 U/mg, respectively. The enzyme was highly resistant to most metal ions tested, including Fe(2+), Fe(3+), and Al(3+). When incubated with pepsin at a pepsin/phytase ratio of 0.02 (U/U) at 37 degrees C for 2 h, 92% of its initial activity was retained. However, the enzyme was very sensitive to trypsin, as 5% of its initial activity was recovered after treating with trypsin at a trypsin/phytase ratio of 0.01 (U/U). PMID- 21538248 TI - Transcriptional control of genes involved in yeast phospholipid biosynthesis. AB - Phospholipid biosynthetic genes encode enzymes responsible for phospholipid biosynthesis. They are coordinately regulated by the availability of phospholipid precursors through the inositol-sensitive upstream activating sequence (UAS(INO)). However, not all phospholipid genes are UAS(INO)-containing genes and not all UAS(INO)-containing genes have the same response to the phospholipid precursors. Therefore, the transcriptional regulation of phospholipid genes in response to the availability of phospholipid precursors is still unclear. Here, 22 out of 47 phospholipid biosynthetic genes were identified as UAS(INO) containing genes, including EKI1, EPT1, INM1, IPK2, KCS1, PAH1, and PIK1 which have never been reported before. We also showed, using qRT-PCR technique, that 12 UAS(INO)-containing genes are down-regulated by 100 MUM inositol in the wild type cells and up-regulated by 100 MUM inositol in the ino2Delta cells. Therefore, it is possible that these genes are transcriptionally regulated by the UAS(INO) through the negative response of Ino2p to inositol. One other UAS(INO)-containing gene might be regulated by the positive response of Ino2p to 100 MUM inositol. Surprisingly, we found 9 UAS(INO)-containing genes are not dependent on the response of Ino2p to 100 MUM inositol, indicating that they may be regulated by other pathway. Furthermore, we identified 9 and 3 non-UAS(INO)-containing genes that are possibly regulated by the negative and positive response of Ino2p to 100 MUM inositol, respectively. Therefore, these observations provide insight into the understanding of the co-regulated phospholipid biosynthetic genes expression. PMID- 21538249 TI - Genome sequence analysis of H5N1 influenza a virus isolated from a Vietnamese in 2007. AB - Highly pathogenic H5N1 avian influenza A virus (AIV) crossed the species barrier and caused a number of deaths in humans in Vietnam and 14 other countries. Since the last report of human H5N1 infection in November 2005, the first documented H5N1 human infection was reported in June 2007 in Vietnam and was followed by 7 more cases, including 5 fatalities. In this study, we isolated and analyzed the full length of the H5N1 genome from a sample from the first patient in 2007. Phylogenetic analysis of eight genomic segments of the H5N1 virus strain (A/Vietnam/HN/2007, VNH07) revealed that this strain appears to be of genotype V and contains the HA gene, which is classified into clade 2.3.4. The deduced amino acid sequence of the HA protein has a typical affinity sequence for alpha2,3 linkage (SAalpha2,3-Gal) receptors and typical multibasic cleavage sequences. Compared with other H5N1 isolates, VNH07 showed that the possible reassortments for the NA and NP segments occurred between A/goose/Guangxi/3017/2005-like isolates (2.3.2) and A/human/Zhejiang/16/2006-like isolates (2.3.4). PMID- 21538250 TI - Molecular characterization reveals involvement of altered El Tor biotype Vibrio cholerae O1 strains in cholera outbreak at Hyderabad, India. AB - Thirty-four Vibrio cholerae isolates collected from a cholera outbreak in Hyderabad, South India were found to belong to serogroup Ol biotype El Tor serotype Ogawa. The genotype of all the isolates was confirmed by PCR assays. All the isolates were found PCR positive for ctxAB, ompW, rflOl, rtxC, and tcpA genes. All the isolates but one harboured rstR ( El Tor ) allele. However, one isolate carried both rstR ( EL Tor ) as well as rstR ( Classical ) alleles. Cholera toxin (ctxB) genotyping of the isolates confirmed the presence of altered cholera toxin B of classical biotype in all the isolates. All the isolates except VCH35 harboured an RS1-CTX prophage array on the large chromosome. The isolate VCH35 contained a tandem repeat of classical CTX prophage on the small chromosome. The clonal relationship among the V. cholerae isolates as carried out by enterobacterial repetitive intergenic consensus sequences PCR, BOX PCR and randomly amplified polymorphic DNA, uniformly showed a genetic relationship among the outbreak isolates. The results of this study suggest that altered El Tor biotype V. cholerae with the classical cholera toxin gene are involved in cholera outbreaks in India. PMID- 21538251 TI - Identification of PhoB binding sites of the yibD and ytfK promoter regions in Escherichia coli. AB - By using a lacZ operon fusion genomic library of the Escherichia coli 0157:H7 Sakai, we identified phosphate-starvation-inducible (psi) promoters located upstream of the yibD and ytfK genes. They have been previously proposed to belong to the phosphate regulon (pho regulon) by Beak and Lee (2006), based on the DNA array and in vivo transcriptional experiments. However, the direct interaction of these promoters with the activator protein of the pho regulon, PhoB, has not been determined. We determined the binding regions of PhoB in these promoter regions by DNase I footprinting. Both regions contained two pho boxes similar to the consensus sequence for PhoB binding. PMID- 21538252 TI - Pontibacter salisaro sp. nov., isolated from a clay tablet solar saltern in Korea. AB - A Gram-negative, aerobic, rod-shaped, and red-pigmented bacterial strain, HMC5104(T), was isolated from a solar saltern, found in Jeungdo, Republic of Korea (34 degrees 59'47"N 126 degrees 10'02"E). The major fatty acids were summed feature 4 (comprising iso-C(17:1) I and/or anteiso-C(17:1) B; 37.2%), iso-C(15:0) (20.4%), and iso-C(17.0) 30H (15.3%). The DNA G+C content was 46.0 mol%. The major isoprenoid quinone was menaquinone-7 (MK-7). A phylogenetic tree based on 16S rRNA gene sequences showed that strain HMC5104(T) formed a lineage within the genus Pontibacter, and was closely related to Pontibacter korlensis (95.9%), P. roseus (94.9%), and P. actiniarum (94.3%). Similarities to all other Pontibacter species were between 95.9-93.9%. On the basis of the evidence presented in this study, strain HMC5104(T) represents a novel species of the genus Pontibacter, for which the name Pontibacter salisaro sp. nov. is proposed. The type strain is HMC5104(T) (=KCTC 22712(T) = NBRC 105731(T)). PMID- 21538253 TI - The Helicobacter pylori Ferric Uptake Regulator (Fur) is essential for growth under sodium chloride stress. AB - Epidemiological data and animal models indicate that Helicobacter pylori and dietary NaCl have a synergistic ill effect on gastric maladies. Here we show that the Ferric Uptake Regulator (Fur), which is a crucial regulatory factor required for H. pylori colonization, is essential for growth in the presence of high NaCl concentrations. Moreover, we demonstrate that the transcriptional response induced by sodium chloride stress exhibits similarities to that seen under iron depletion. PMID- 21538254 TI - Kaposi's sarcoma-associated herpesvirus infection of endothelial progenitor cells impairs angiogenic activity in vitro. AB - A recent study reported that endothelial progenitor cells (EPCs0 are one of the reservoirs of Kaposi's sarcoma associated herpesvirus (KSHV). Although EPCs are closely linked to angiogenesis and vasculogenesis, little is known about the angiogenic potential of KSHV in EPCs. In this study, we used EPCs isolated from human umbilical cord blood to show that early infection by KSHV in vitro impaired the neovascularization of EPCs in matrigel. Our results suggest that KSHV may disrupt the angiogenic potential of EPCs and that the disseminated infection of KSHV could be associated with EPC dysfunction. PMID- 21538255 TI - Improved antibiotic resistance gene cassette for marker exchange mutagenesis in Ralstonia solanacearum and Burkholderia species. AB - Marker exchange mutagenesis is a fundamental approach to understanding gene function at a molecular level in bacteria. New plasmids carrying a kanamycin resistance gene or a trimethoprim resistance gene were constructed to provide antibiotic resistance cassettes for marker exchange mutagenesis in Ralstonia solanacearum and many antibiotic-resistant Burkholderia spp. Insertion sequences present in the flanking sequences of the antibiotic resistance cassette were removed to prevent aberrant gene replacement and polar mutation during mutagenesis in wild-type bacteria. Plasmids provided in this study would be convenient for use in gene cassettes for gene replacement in other Gram-negative bacteria. PMID- 21538256 TI - Diversity analysis of Burkholderia cepacia complex in the water bodies of West Lake, Hangzhou, China. AB - A survey of Burkholderia cepacia complex (Bcc) species was conducted in water bodies of West Lake in China. A total of 670 bacterial isolates were recovered on selective media. Out of them, 39.6% (265 isolates) were assigned to the following species: Burkholderia multivorans, Burkholderia cenocepacia recA lineage IIIA, IIIB, Burkholderia stabilis, Burkholderia vietnamiensis, and Burkholderia seminalis while B. cenocepacia is documented as a dominant Bcc species in water of West Lake. In addition, all Bcc isolates tested were PCR negative for the cblA and esmR transmissibility marker genes except B. cenocepacia IIIB A8 which was positive for esmR genelater. The present study raises great concerns on the role of West Lake as a "reservoir" for potential Bcc pathogenic strains. PMID- 21538257 TI - Development of Porphyromonas gingivalis-specific quantitative real-time PCR primers based on the nucleotide sequence of rpoB. AB - Species-specific quantitative real-time PCR (qPCR) primers were developed for the detection of Porphyromonas gingivalis. These primers, Pg-F/Pg-R, were designed based on the nucleotide sequences of RNA polymerase beta-subunit gene (rpoB). Species-specific amplicons were obtained from the tested P. gingivalis strains but not in any of the other strains (46 strains of 46 species). The qPCR primers could detect as little as 4 fg of P. gingivalis chromosomal DNA. These findings suggest that these qPCR primers are suitable for applications in epidemiological studies. PMID- 21538258 TI - Development of a high-throughput screening method for recombinant Escherichia coli with intracellular dextransucrase activity. AB - To efficiently engineer intracellular dextransucrase (DSase) expression in Escherichia coli, a high-throughput screening method was developed based on the polymer-forming activity of the enzyme. Recombinant E. coli containing the Leuconostoc citreum DSase (LcDS) gene was grown on Luria-Bertani agar plates, containing 2% sucrose, at 37 degrees C for 8 h. The plates were then evenly overlaid with 0.6% soft agar, containing 1.2 mg/ml D-cycloserine, and incubated at 30 degrees C to allow gradual cell disruption until a dextran polymer grew through the overlaid layer. A significant correlation between dextran size and enzyme activity was established and applied for screening truncated mutants with LcDS activity. PMID- 21538259 TI - A simple and reliable method for obtaining Entomosporium monoconidial isolates. AB - Monoconidial isolates of Entomosporium mespili were successfully cultured using a simple isolation procedure. A detailed description of the steps required for isolating E. mespili is provided. The characteristic pattern of conidial germination and growth on potato dextrose agar is also described. The process that was successful in obtaining pure isolates involved collecting material in the morning, picking a glistening white mass of conidia under dissecting microscope magnification, depositing a mass of conidia onto a drop of water on a glass slide, streaking the conidial mass onto potato dextrose agar, incubating the plate for 48 h, and transferring the characteristic fan-shaped colonies to fresh medium. PMID- 21538262 TI - [Standardized examination and research advancement of circumferential resection margin in patients with middle-lower rectal cancer]. AB - The introduction of total mesorectal excision and the use of neoadjuvant therapy has led to improved prognosis of rectal cancer. Circumferential resection margin(CRM) is one of the main prognostic factors. Positive CRM is associated with adverse prognosis. It is of clinical significance to clarify different patterns of CRM involvement, the exact definitions, and associated factors. TME quality assessment and accurate determination of CRM involvement are crucial in the pathologic examination of rectal cancer. Extended abdominoperineal resection during which the levator muscles are resected en bloc with the anus and lower rectum may be superior than conventional abdominoperineal resection (APR) in terms of obtaining a negative CRM. PMID- 21538263 TI - [Analysis of risk factors associated with lymph node metastasis and prognosis of T1-2 colorectal cancer]. AB - OBJECTIVE: To investigate factors associated with lymph node metastasis and prognosis in patients with T1-2 colorectal cancer. METHODS: Patients with pT1-2 colorectal cancer between January 1999 to January 2005 were included. Chi-square test and multivariable logistic analysis were performed to evaluate risk factors associated with lymph node metastasis. Survival outcomes were analyzed using Kaplan-Meier and Cox regression model. RESULTS: Tumor location and depth of invasion were independent risk factors for lymph node metastasis(P<0.01 and P<0.05). Gender, age, tumor gross pattern, tumor differentiation, carcinoembryonic antigen level, and tumor diameter were not associated with lymph node metastasis. Lymph node metastasis and distant metastasis on postoperative follow-up were independent risk factors for survival(P<0.05 and P<0.01). CONCLUSION: Factors associated with lymph node metastasis in pT1-2 colorectal cancer do not affect the survival. However, lymph node metastasis and distant metastasis are predictive for survival. PMID- 21538264 TI - [Impact of number of retrieved lymph nodes and lymph node ratio on the prognosis in patients with stage II and III colorectal cancer]. AB - OBJECTIVE: To discuss the impact of number of retrieved lymph nodes and lymph node ratio(LNR) on the prognosis in patients with stage II and III colorectal cancer. METHODS: Clinicopathological data of 507 patients with stage II and III colorectal cancer were analyzed retrospectively. Follow-up was available in all the patients. RESULTS: The total number of retrieved lymph nodes was 5801, of which 1122 had metastasis. There was a positive correlation between metastatic lymph nodes and retrieved lymph nodes(r=0.171, P<0.01). In stage II colorectal cancer there was a significant difference in 5-year survival rate between patients with more than 12 lymph nodes retrieved and those with less than 12 lymph nodes retrieved(P<0.01). LNR also affected the 5-year survival rate of patients with stage II and III colorectal cancer(P<0.05). In patients with similar LNR, the 5-year survival rate differed significantly among different regions of lymph node metastasis(P<0.05). LNR influenced the prognosis independent of the number of lymph nodes retrieved. CONCLUSIONS: The number of retrieved lymph nodes is a prognostic factor for stage II and III colorectal cancer. More than 12 lymph nodes should be retrieved for better staging and prognosis. LNR is also a prognostic factor in stage II and III colorectal cancer. Regions of lymph nodes metastasis should be considered when evaluating the prognosis of patients using LNR. PMID- 21538265 TI - [Associated risk factors of peritoneal metastasis in colorectal cancer]. AB - OBJECTIVE: To investigate risk factors associated with peritoneal metastasis in colorectal cancer. METHODS: Clinicopathological data of 873 patients with colorectal cancer treated at the Nanfang Hospital of Southern Medical University from January 2003 to December 2008 were retrospectively analyzed. The associations between peritoneal metastasis and clinicopathological factors were evaluated by univariate analysis including independent-samples t test and chi(2) test, and multivariable logistic regression analysis. RESULTS: Univariate analysis showed that age(P=0.032), tumor size(P=0.001), tumor differentiation(P=0.008), depth of bowel wall invasion(P=0.000), lymph node metastasis(P=0.000), serum carcinoembryonic antigen (CEA) level(P=0.003), and serum carbohydrate antigen 19-9(CA19-9) level(P=0.009) were associated with peritoneal metastasis. On multivariable logistic regression analysis, depth of bowel wall invasion, lymph node metastasis, serum CEA level and CA19-9 level remained as significant risk factors(all P<0.05). CONCLUSION: Depth of bowel wall invasion, lymph node metastasis, serum CEA level, and CA19-9 level are risk factors for peritoneal metastasis in colorectal cancer. PMID- 21538266 TI - [Value of modified APACHE II score in predicting postoperative complications in patients with acute obstructing colorectal carcinoma]. AB - OBJECTIVE: To evaluate the value of modified acute physiologic and chronic health score (APACHE II score) in predicting postoperative complications in patients with acute obstructing colorectal carcinoma. METHODS: Postoperative complications in 92 patients with acute obstructing colorectal carcinoma were evaluated by APACHE II score and modified APACHE II score (severe organ dysfunction and immune damage in chronic health indicators were replaced by the duration and degree of obstruction, which were considered as the severity of intestinal obstruction). The sensitivity, specificity, and Youden index were compared with regard to complication prediction. Receiver operating characteristic curves were plotted to calculate area under the curve(AUC). RESULTS: Twenty-five patients developed postoperative complications including 3 deaths. The APACHE-II score(13.72+/ 4.24), modified APACHE II score (19.28+/-4.92), intestinal obstruction severity score (5.56+/-2.20) were significantly higher in patients with complications than those in patients without complications (10.58+/-3.44, 14.69+/-3.73, 4.10+/-1.52, all P<0.01). The sensitivity, specificity, accuracy, Youden index, and AUC were 0.640, 0.940, 0.859, 0.580, and 0.839 for the modified APACHE-II score with 20 being the optimal cut-off point, respectively, and were 0.560, 0.896, 0.804, 0.456, and 0.784 for APACHE-II (14 was the optimal cut-off point), respectively. CONCLUSION: The modified APACHE-II score system with the intestinal obstruction severity score is a better prediction method for the occurrence of postoperative complications in patients with acute obstructing colorectal carcinoma. PMID- 21538267 TI - [Metabolic disturbance and insulin resistance in patients with colorectal cancer]. AB - OBJECTIVE: To investigate whether insulin resistance exists in patients with colorectal cancer and its clinical significance. METHODS: A total of 135 patients with colorectal cancer were included as the study group, and 120 healthy subjects were included as the control group. Height, weight, and blood pressure were recorded. Fasting plasma glucose, triglycerides, high-density lipoprotein cholesterol (HDL-C), and insulin were measured. Insulin resistance index(lnHOMA IR) was calculated. RESULTS: The lnHOMA-IR was 0.84+/-0.38 in the study group and 0.42+/-0.08 in the control group(P<0.05). The incidence of metabolic syndrome was 34.1%(46/135) in the study group and 22.5%(27/120) in the control group(P<0.05). Insulin resistance index did not differ between the groups according to metabolic syndrome(0.98+/-0.41 vs. 0.74+/-0.22, P>0.05). There were no significant associations between insulin resistance index and tumor differentiation, depth of invasion, lymph node metastasis, distant metastasis, and TNM staging(P>0.05). CONCLUSION: Insulin resistance exists in colorectal cancer patients, and it is possibly associated with metabolic syndrome and the tumor. PMID- 21538268 TI - [Clinical study of perineural invasion in patients with rectal cancer]. AB - OBJECTIVE: To investigate the clinical significance of perineural invasion(PNI) in rectal cancer. METHODS: Clinical data of 204 patients undergoing resection of low rectal cancer from January 2003 to January 2005 at the First People's Hospital of Chenzhou were analyzed retrospectively. Paraffin sections of surgical specimens from all the patients who underwent resection of low rectal cancer were stained with HE. PNI-positive was defined as infiltration of carcinoma cell into the perineurium or neural fascia. The association of PNI with clinicopathologic features and prognosis of rectal cancer was analyzed. RESULTS: PNI was positive in 31.9%(65/204) of the patients. The tumor size, depth of invasion, lymph node metastasis, TNM stage, tumor growth pattern, histologic grade, tumor resection were significantly associated with PNI. The overall survival time of the PNI positive patients was shorter than that of the PNI-negative patients[(43.8+/-1.5) months vs.(57.2+/-1.5) months, P<0.01]. Furthermore, the overall survival time of the PNI-positive stage II( patients was shorter than that of the stage III( patients [(46.5+/-3.2) months vs. (55.7+/-1.2) months, P<0.05]. CONCLUSION: PNI can be used as one of the indicators to predict the prognosis of patients with rectal cancer. PMID- 21538269 TI - [Comparative study of oncologic outcomes after multivisceral resection for stage IIC colorectal cancer between inflammatory and malignant adhesion]. AB - OBJECTIVE: To evaluate the differences in oncologic outcomes between inflammatory adhesion and malignant adhesion in patients with stage IIC colorectal cancer after multivisceral resection(MVR). METHODS: A retrospective review was undertaken of 287 patients who underwent MVR for stage IIC CRC, 120 patients for stage IIB, and 140 patients for IIIA. Patients were divided into two groups: inflammatory adhesion(IA) and malignant invasion(MI). RESULTS: There were 153 patients with colon cancer and 135 patients with rectal cancer in the stage IIC group. The overall survival was significantly lower in the MI group at 5 years(38.5% vs. 59.4%, P<0.05). Stage IIC patients with IA had similar survival rate to the patients with stage IIB CRC. Compared to the MA group, patients with stage IIIA CRC showed significant differences in 5 years overall survival rate. Univariate analysis showed that differentiation, adhesion pattern, and complication were significant prognostic factors for patients with colon cancer, while pathological characteristics, adhesion pattern, and differentiation were significant for rectal cancer. CONCLUSIONS: MI is an adverse prognostic factor for patients with stage IIC CRC. T4 should be further classified according to the adhesion pattern. PMID- 21538270 TI - [Impact of nutritional status on postoperative outcomes for patients with colorectal cancer]. AB - OBJECTIVE: To evaluate the impact of nutritional status on postoperative outcomes for patients with colorectal cancer. METHODS: Data of 289 colorectal cancer patients from the Affiliated Hospital of Putian Medical College between January 2006 and December 2009 were collected prospectively. Nutritional status was evaluated according to Reilly Nutrition Risk Score(Reilly NRS) and Nutrition Risk Screening 2002(NRS-2002). RESULTS: The postoperative mortality was 3.5%(10/289) and the complication rate was 29.4%(82/297). Patients were stratified into those at nutrition risk(n=89) and those not at risk(n=200) according to Reilly NRS and the two groups were similar in mortality rate(5.6% vs. 2.5%, P>0.05) and complication rate(36.1% vs. 26.5%, P>0.05). When stratified using NRS-2002, patients at nutritional risk(n=105) had a similar mortality rate (5.7% vs. 2.2%, P>0.05) but a higher complication rate(38.4% vs. 24.4%, P<0.05). NRS-2002 remained as an significant predictor of postoperative complications(P=0.007, OR=3.14, 95% CI:1.63-6.29) on multivariable logistic regression analysis. CONCLUSION: As a nutritional evaluation tool, NRS-2002 may predict postoperative complication for colorectal cancer. PMID- 21538271 TI - [Significance of aquaporin-1 and aquaporin-3 expression in colorectal carcinoma]. AB - OBJECTIVE: To investigate the significance of aquaporin-1(AQP-1) and aquaporin 3(AQP-3) in the development of colorectal carcinoma. METHODS: The expression of AQP-1 and AQP-3 was investigated using immunohistochemical staining with Streptavidin Peroxidase in tissues from colorectal adenoma (CRA, n=25), colorectal cancer (CRC, n=50), and adjacent mucosa (CRT, n=50). RESULTS: The positive rate of AQP-1 was 64%(32/50) in CRC, significantly higher than that in CRT (38%, 19/50) and CRA(32%, 8/25)(P<0.05). The expression of AQP-1 was associated with depth of invasion and lymph node metastasis in CRC patients(P<0.05). The positive rate of AQP-3 was 56% in CRT, 44% in CRA, and 52% in CRC. There were no significant differences (P>0.05). The expression of AQP-3 was associated with age, tumor diameter, and depth of invasion (P<0.05). No significant correlation between the expression of AQP-1 and AQP-3 in CRC was shown by Spearman correlation analysis(P>0.05). CONCLUSIONS: AQP-1 expression is increased in CRC while the expression of AQP-3 is not. There is no correlation between the expression of AQP-1 and AQP-3 in CRC. PMID- 21538272 TI - [MicroRNA-221 controls CDKN1C/P57 expression in human colorectal carcinoma]. AB - OBJECTIVE: To investigate the expression of microRNA-221 (miR-221) and CDKN1C/P57 in colorectal carcinoma (CRC) and adjacent non-cancerous tissues. The effect of miR-221-specific inhibitor on cell proliferation and apoptosis in CRC cells was also assessed. METHODS: The expression of miR-221 was detected by real-time RT PCR. CDKN1C/P57 mRNA and corresponding protein expression pattern were detected by semi-quantitative RT-PCR and Western-blot. The specific 2'-methoxy-modified RNA oligonucleotide of miR-221(miRNA inhibitor,anti-miR-221) was designed, synthesized and transfected into Caco2 cell by liposome. Finally, the status of CRC cell proliferation and apoptosis were detected by MTT assay and flow cytometry. RESULTS: The expression of miR-221 was significantly up-regulated in CRC tissues as compared to the adjacent non-cancerous tissues(2.041+/-1.401 vs. 0.806+/-0.341, P<0.01). There was no significant difference in CDKN1C/P57 mRNA expression between CRC and non-cancerous tissues, whereas CDKN1C/P57 protein markedly decreased in CRC (3.019+/-1.708 vs. 0.972+/-0.316, P<0.01). miR-221 specific inhibitor significantly enhanced CDKN1C/P57 protein expression, inhibited proliferation of CRC cells and induced apoptosis of CRC cells(P<0.01). CONCLUSIONS: miR-221 inhibits CDKN1C/P57 expression by post-transcriptional gene silencing to promote CRC development and progression. miR-221-specific inhibitor potentially inhibits the growth of CRC cells. Therefore, it may be a new target for the biologic therapy for CRC. PMID- 21538274 TI - Desperate times. AB - Medicaid is crushing the state budget. A lingering recession that swelled enrollment, a state budget shortfall that could top $27 billion, and the fact that health system reform will require significant expansion of Medicaid combined to create urgency about improving Medicaid's efficiency and effectiveness in this year's legislative session. Some health policy experts believe Medicaid simply is unsustainable in its current form. PMID- 21538273 TI - [Association of hypoxia-inducible factor 1alpha expression with microlymphatic vessel density and lymph node micrometastasis in rectal cancer]. AB - OBJECTIVE: To explore the association of the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) with microlymphatic vessel density(MLVD) and lymph node micro-metastasis in rectal cancer. METHODS: The experimental group consisted of 40 middle-low rectal cancer specimens pathologically confirmed at the First Affiliated Hospital of Anhui Medical University between 2000 and 2003. Forty samples of normal tissues taken from the corresponding area around the cancer were used as the control group. Immunohistochemistry was used to detect HIF 1alpha expression and MLVD in both the tumor tissues and the adjacent normal tissues. Lymph node micrometastasis was ascertained using immunohistochemical staining with CK20. RESULTS: In rectal cancer tissues, the HIF-1alpha expression was 77 386+/-14 911 and MLVD was 7.3+/-0.7, significantly higher than those in normal adjacent tissues(33 092+/-5877 and 0.3+/-0.2, both P<0.01). The HIF-1alpha expression was positively correlated with MLVD in rectal cancer(r=0.781, P<0.01). Thirty-one patients had no lymph nodes metastasis and 10 had micrometastasis. The HIF-1alpha expression and MLVD in specimens with lymph node micrometastasis was significantly higher than that in those without lymph node micrometastasis(P<0.05). CONCLUSION: HIF-1alpha and MLVD play important roles in the development of rectal cancer,which may promote lymphatic micrometastasis in rectal cancer. PMID- 21538275 TI - Doctor 911. AB - The Texas Medical Association has helped many physicians realize a happy ending to their legal nightmares. When the association believes a physician member has been unfairly scrutinized or mistreated by public and private organizations, it can devote resources, assistance, and expertise to advocate on the physician's behalf. TMA also has resources available to physicians who suspect their billing and coding practices may need some revision or who simply want to make sure they're on track. PMID- 21538276 TI - Finding a home. AB - A Blue Cross and Blue Shield of Texas (BCBSTX) pilot program seeks to measure how effective a patient-centered medical home can be at improving quality and controlling health care costs. The program couples what some are calling "aggressive care coordination" by participating physicians with extensive feedback from BCBSTX on several quality and patient satisfaction measures. Practices get a per-patient-per-month care management fee and share in whatever savings are achieved if they hit the cost and quality benchmarks. PMID- 21538277 TI - Moms too young. AB - Many efforts throughout Texas strive to connect teen mothers with vital resources. Many physicians work in state and local programs to promote effective, proven interventions for preventing pregnancy in adolescents. In the legislature, the Texas Medical Association endorses the agenda of the San Antonio-based Healthy Futures Alliance, a community coalition to reduce teen and unplanned pregnancy. PMID- 21538278 TI - At the end of the beginning. Foreword. PMID- 21538279 TI - Understanding the host genetics of chronic hepatitis B and C. AB - The outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are heterogeneous, ranging from an asymptomatic self-limiting infection to cirrhosis and hepatocellular carcinoma. Several viral environmental and demographic variables have been identified as determinants of disease outcome, but these fail to explain a large proportion of the variability. Evidence from twin studies suggests that the host genetic background is an important contributor to disease outcome. Identification of genes that influence the outcome of infection has been attempted using a wide spectrum of approaches including candidate gene disease association studies, genome-wide scanning in affected sibling pairs and most recently genome-wide association studies. We summarize the main findings from a large number of studies in this review. Many studies have focused on the MHC loci from which several reproducible disease associations have been identified. More recently, genome-wide association studies have identified an important locus within the IL-28 - Il-29 region on chromosome 29, which appears to be a major determinant of the treatment response in patients infected with HCV and also a determinant of spontaneous resolution of infection. Translation of the genetic architecture of chronic viral hepatitis into therapeutic opportunities has been slow to proceed. One clinical trial and one drug development program have been based on genetic discoveries. The use of IL-28B genotyping to predict the response to pegylated interferon and ribavirin may also find its way into clinical practice. Indeed, stratification of clinical trial populations based on IL-28B genotype is already considered mandatory. PMID- 21538281 TI - Progress in the genetics of primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that has a prevalence of 1 in 1000 women over the age of 40. Treatment is presently limited to ursodeoxycholic acid, a hydrophilic bile acid that has nonspecific, choleretic, effects in cholestatic liver disease. PBC has strong autoimmune features, including highly specific loss of tolerance to a ubiquitous mitochondrial antigen. Both environmental and genetic factors are considered important in the pathogenesis of disease. Prior to the advent of genome-wide association studies, only class II human leucocyte antigen (HLA) loci (HLA DRB1*08, *11, and *13) had been reproducibly shown to associate with disease. Non HLA loci were suggested for several genes (e.g., CTLA-4, MDR3), but often inconclusively replicated. With the application of genome-wide technology, HLA was confirmed as the strongest association and many other risk loci have been identified, with equivalent effect size to HLA, including IL12A, IL12RB2, STAT4, IRF5-TNPO3, 17q12.21, MMEL1, SPIB, and CTLA-4. These collectively support an important role for innate and adaptive immunity in development of disease. Further insights are predicted as studies with larger cohorts are assembled, and different approaches are taken to further discover common and uncommon gene variants associated with disease. Disease subphenotypes such as response to therapy, clinical progression, and symptoms remain additional areas for further dedicated studies, and in which different genetic risk factors may be relevant. Identification of risk loci associated with disease has the potential to aid development of rational, disease-specific, therapies in the future. PMID- 21538280 TI - Genetics of alcoholic and nonalcoholic fatty liver disease. AB - Excess alcohol consumption with consequent alcoholic liver disease (ALD) and metabolic syndrome-related nonalcoholic fatty liver disease (NAFLD) are recognized as the most common causes of liver dysfunction worldwide. However, although the majority of heavy drinkers and individuals with obesity/insulin resistance will develop steatosis, only a minority progress to steatohepatitis, fibrosis, and cirrhosis. Both ALD and NAFLD are best considered complex disease traits where subtle interpatient genetic variations and environment interact to produce disease phenotype and determine disease progression. A decade after the sequencing of the human genome, the development of technologies to support the comprehensive study of genomic variation has begun to provide new insights into the modifier genes that contribute to this interpatient variation. Here we review the current status of the field with particular focus on advances from recent genome-wide association studies and their translation into a better mechanistic understanding of pathogenesis. PMID- 21538282 TI - Dissecting the genetic heterogeneity of gallbladder stone formation. AB - Gallstone disease affects almost 20% of individuals in Westernized countries. As its incidence in the developing countries is rising considerably, currently, it is the second most common gastroenterological condition worldwide. Gallstone formation is driven by an interaction between genetic and environmental risk factors. Previous studies have demonstrated that the genetic background accounts for ~25% of the total disease risk. Linkage and case-control studies of candidate genes and recent genome-wide studies have identified multiple lithogenic genes, in particular the hepatocanalicular cholesterol transporter ABCG5/G8 and the bilirubin conjugating enzyme UGT1A1, as major genetic determinants of gallstones in humans. In this review, we summarize the recent findings related to the genetics of cholelithiasis, update the "inventory" of human lithogenic genes, and relate the genetic studies to the pathobiologic background of the disease. In closing, future applications of genetic testing for gallstone carriers and asymptomatic family members are addressed. PMID- 21538283 TI - Genetics of hepatobiliary carcinogenesis. AB - Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are two leading causes of cancer death in the world. Liver carcinogenesis is driven by genetic alterations in combination with viral and environmental factors. beta-catenin and P53 mutations represent the two main genetic alterations described in HCC, and P53 and KRAS mutations in CC, but rare genetic alterations could be particularly valuable if they constitute drug-able targets (such as PIK3CA or EGFR mutations). Recent progress using global genomic analysis has highlighted the marked genetic heterogeneity of this disease and this approach has also been used to assess prognosis or refine the diagnosis. The validation of sorafenib as the first targeted therapy useful in HCC has opened up new prospects for biotherapy in this cancer. In the future, mapping of genetic alterations will be essential to adapt treatment to HCC and CC biology. PMID- 21538284 TI - Deciphering the genetic predisposition to primary sclerosing cholangitis. AB - Genetic variants within the major histocompatibility complex (MHC) on chromosome 6 have been shown to confer risk for primary sclerosing cholangitis (PSC) ~30 years ago. However, robust genetic associations outside this genetic region have been difficult to establish. By genome-wide association analysis, a surprising large overlap of genetic risk loci outside of the MHC with prototypical autoimmune diseases has been recognized. In this article, we review the present knowledge of susceptibility loci in PSC, by assessing the robustness of the findings and speculating on potential mechanistic roles of predicted risk genes in PSC pathogenesis. We suggest a model where the primary insult is likely to resemble the tissue injury in most autoimmune conditions. Functional insight into risk pathways could offer novel therapeutic opportunities, and we speculate on specific opportunities that may arise based on current knowledge. PMID- 21538285 TI - Genetic modifiers of liver injury in hereditary liver disease. AB - The genetic background of patients with liver diseases modulates hepatic injury, with some individuals being predisposed to better defenses and regenerative capacity. In this review, we focus our description of this phenomenon on inherited disorders affecting the liver, with a particular emphasis on Wilson disease (WD), genetic hemochromatosis, and alpha-1 anti-trypsin disease (A1-AT). Wide variations in the clinical phenotype of WD may in part be related to the mutations of the ATP7B genotype, though modifier genes and environmental factors also likely play an important role. There is also a significant variability in the expression of iron overload in patients with genetic hemochromatosis that are homozygous for the C282Y mutation. Homozygosity for the A1-ATZ mutation is generally required for the development of liver disease in A1-AT although there is increasing evidence for modifier effects from a heterozygous genotype in other liver diseases. PMID- 21538286 TI - Genomics in the post-GWAS era. AB - The field of genomics has entered a new era in which the ability to identify genetic variants that impact complex human traits and disease in an unbiased fashion using genome-wide approaches is widely accessible. To date, the workhorse of these efforts has been the genome-wide association study (GWAS), which has quickly moved from novel to routine, and has provided key insights into aspects of the underlying allelic architecture of complex traits. The main lesson learned from the early GWAS efforts is that though many disease-associated variants are often discovered, most have only a minor effect on disease, and in total explain only a small amount of the apparent heritability. Here we provide a brief overview of the genetic variation classes that may harbor the heritability missing from GWAS, and touch on approaches that will be leveraged in the coming years as genomics-and by extension medicine-becomes increasingly personalized. PMID- 21538287 TI - Adult polyglucosan body disease: a rare presentation with chronic liver disease and ground-glass hepatocellular inclusions. AB - Liver involvement in genetic and metabolic disorders may result in intrahepatic accumulation of specific precursors or byproducts, which have distinctive features on light microscopy. The "polyglucosan disorders" are diseases in which polyglucosan (abnormal glycogen with decreased branching) is formed and deposited in various tissues because of decreased or absent glycogen branching enzyme activity. These disorders include Lafora disease (myoclonus epilepsy) and type IV glycogen storage disease. Polyglucosan deposits in both conditions result in ground-glass hepatocellular inclusions resembling those seen in chronic hepatitis B virus infection. In the present report, we describe a case of the rare, adulthood form of glycogen branching enzyme deficiency, adult polyglucosan body disease (APBD), in which abnormal serum liver tests prompted a liver biopsy. The pathologic findings of periportal ground-glass hepatocellular inclusions, mild chronic portal inflammation, and periportal fibrosis are not well described in APBD, but resemble the chronic changes that have been reported in Lafora disease. The differential diagnosis of ground-glass hepatocytes and the genetic basis of APBD are discussed. PMID- 21538288 TI - [Hypertension due to aortic coarctation--a missed clinical diagnosis]. AB - HISTORY AND FINDINGS: A 30-year-old woman presented to our emergency department with severe headaches, dizziness and uncontrolled hypertension. She had arterial hypertension and a known heart murmur since adolescence. Previous medical work up did not reveal any cause for secondary hypertension. Recently her blood pressure had been difficult to control. A systolic murmur as well as absent inguinal and feet pulses were notable at the physical examination. INVESTIGATIONS: When performing doppler ultrasound the closing pressures of the dorsalis pedis arteries were only 70 mm Hg compared to a blood pressure reading of 160 mm Hg on the upper arms. Thoracic magnetic resonance imaging showed subtotal aortic coarctation causing the differences in blood pressures. Echocardiography and cardiac catheterization additionally revealed a moderately stenosed bicuspid aortic valve, the pressure gradient across the coarctation was 30 mm Hg. THERAPY AND COURSE: Despite the severity of the coarctation an interventional approach was favoured instead of a classical operative therapy. Balloon dilatation with stent implantation was performed without complications. Since the intervention blood pressure have remained normotensive, the coarctation gradient being markedly reduced. CONCLUSIONS: In young patients with arterial hypertension, as well as in cases of severe and refractory hypertension, causes of secondary hypertension must be looked for and excluded. Especially when hypertension occurs in adolescence, aortic coarctation should be taken into account, in addition to renal or endocrine causes. A thorough physical examination with cardiac auscultation and checking of all peripheral pulses is the crucial step to the diagnosis. PMID- 21538289 TI - Abnormal fast activity before the onset of West syndrome. AB - In our sequential EEG study performed on 68 infants with various pre- and perinatal brain insults, we found peculiar abnormal fast activity (AFAs) in 12 patients. 9 of the 12 patients with AFAs later developed West syndrome (WS) compared with only 3 of the 56 patients without AFAs (p<0.001, chi(2) test). We analyzed these AFAs using EEG topography, and compared them with ictal fast activity (IFA) corresponding to tonic spasms observed later in the same patients after they had developed WS. We also investigated the clinical and EEG features in these patients. AFAs were first observed commonly at 4-5 months of CA, before the onset of WS. AFA topographic maps revealed posterior predominance in 11 of the 12 patients; IFA maps also showed posterior predominance but were more widely distributed. We propose that, though AFAs and IFAs are different, they share certain aspects of their pathophysiology, and that the maturational process of the occipital cortex plays an important role in the shared aspects. Since AFAs are observed before the onset of WS, they can be considered a sign that WS is imminent. PMID- 21538290 TI - Effects of long-acting release octreotide on glucose homeostasis in acromegaly patients after trans-sphenoidal surgery. AB - The present study was aimed to investigate glucose homeostasis and insulin secretion in acromegalic patients during octreotide-long acting release (LAR) therapy and designed as an observational prospective study. 18 acromegalic patients who had undergone trans-sphenoidal surgery with active disease were included. All patients were treated with octreotide-LAR injection for 1 year. These patients received oral glucose tolerance test (OGTT) before, 21 days after, and 1 year after octreotide-LAR treatment. Primary outcomes were changes in glucose levels and insulin secretion during an OGTT. We also determined the differences between subjects with normalized and uncontrolled IGF-1 levels. Of the 18 patients treated with octreotide-LAR for 1 year, 89% achieved fasting GH levels <2.5 MUg/l, 85% reached the nadir GH concentration <1 MUg/l, and 61% achieved normal age- and sex-matched IGF-1 values. 21 days after one dose of octreotide-LAR injection, insulin response during OGTT significantly decreased, and the Matsuda index increased significantly. One year after octreotide-LAR therapy, most parameters of glucose homeostasis returned to baseline levels. However, insulin response during OGTT at 30 and 60 min, and the insulinogenic index were still significantly decreased. Compared with the IGF-1-normalized group, the IGF-1 uncontrolled group had the same fasting GH and nadir GH levels and a higher insulin AUC and total insulin secretion. During octreotide-LAR treatment, the early-phase insulin response to OGTT is reduced and plasma glucose levels remained normal in most patients. The IGF-1 uncontrolled group had the same fasting GH and nadir GH levels during OGTT, but had better glucose homeostasis. PMID- 21538291 TI - Complete endovascular occlusion of a cranial dural fistula using a venous "to the point" approach. AB - BACKGROUND AND OBJECT: Cranial dural arteriovenous fistulas are commonly treated using an endovascular method. In comparison to intracerebral arteriovenous malformations, it is important to reach the venous part of these malformations to maintain a complete occlusion. Therefore, often the venous side is totally occluded using coils and/or glue. PATIENT AND METHODS: We describe a patient with an initially Type IIab (Cognard classification) left occipital cranial fistula. The patient suffered from an intense pulsate tinnitus. Therefore, the first embolization was performed using an approach via the dilated left middle meningeal artery using Onyx. The shunt of the fistula was reduced significantly but total occlusion was impossible. Therefore, the venous approach was used. Over a guiding catheter in the sigmoid sinus, the venous side of the fistula could be reached with a microcatheter. This part of the fistula was then completely occluded using coated and bare coils, without occluding the adjacent sinus. Control angiography of all previous feeders showed a complete occlusion of the fistula (used classification: Cognard). RESULTS: The fistula was entirely occluded. The patient's outcome was excellent. The patient did not develop any symptoms and no complication occurred due to the treatment. CONCLUSIONS: Direct occlusion of the venous part of an arteriovenous cranial fistula can be an option before an occlusion of the sinus has to be performed. This approach can lead to reduction of risk during the endovascular procedure and risk reduction in long term follow-up. PMID- 21538292 TI - Transorbital penetrating skull-base injuries: two severe cases with wooden branches and review of the literature. PMID- 21538295 TI - [FBI]. PMID- 21538294 TI - [Adherence to the H1N1 vaccination recommendation in patients with Crohn's disease or ulcerative colitis]. AB - BACKGROUND AND OBJECTIVE: In September 2009, the German "Standing Committee for Vaccination" (STIKO) recommended the H1N1 influenza vaccination to all patients with chronic diseases. We investigated the adherence to this recommendation in patients with the inflammatory bowel diseases (IBD) Crohn's disease or ulcerative colitis. Special attention was paid to arguments for vaccination refusal. METHODS: In an explorative multicenter study we asked adult patients to answer a questionnaire about their participation in the H1N1 vaccination campaign, their arguments for and against this vaccination and disease specific parameters. RESULTS: Out of 1389 participating patients, 226 (16 %) received the H1N1 vaccination. Among patients who were vaccinated against the seasonal flu as well as patients who were treated with anti-TNF-treatment and members of the German Crohn's and Colitis Association, the participation rates were significantly higher (32 %, 26 %, 25 %, respectively). The main argument against the H1N1 vaccination was fear of side effects (59 %). However, 77 % of all vaccinated patients judged the vaccine as very well tolerated. The non-adherence to general vaccination recommendations against tetanus and seasonal flu was also high (25 % and 66 %, respectively). CONCLUSION: Only a minority of patients with Crohn's disease or ulcerative colitis had adhered to the official recommendation concerning vaccination against H1N1. In order to reach higher acceptance, further vaccination campaigns must focus on the safety of the recommended vaccine. PMID- 21538296 TI - [Do behavioural problems existing at referral become worse in subsequent years? A study of young persons referred to the outpatient unit of the mental health service]. AB - BACKGROUND: Although young persons with severe and complex emotional and behavioural problems are often referred to the outpatient unit of the mental health service, little information is available about whether these problems increase over the years. This information is urgently needed in order to ensure that the mental health service provides adequate care. AIM: To obtain more insight into any increase in young persons' emotional and behavioural problems that may occur over a period of six years following referral to an outpatient unit of the mental health service. METHOD: The nature, severity and complexity of the emotional and behavioural problems of 123 young persons (1999) and of 149 young persons (2005) at the time of the referral - as rated by their parents on the basis of the Child Behavior Checklist (CBCL) - were assessed; the young persons' records were also checked for background characteristics. RESULTS: Compared to 1999, the year 2005 saw a slight decrease in the severity of the problems existing at referral; social problems also declined significantly compared to 1999. Problems identified in the 2005 group often seemed less complex than in 1999. The severity of delinquent behaviour as measured on the Delinquent Behaviour Scale seems to have risen in the 12 to 18 age group in 2005, whereas the severity declined in the 4 to 11-year olds. CONCLUSION: Emotional and behavioural problems as reported by the parents at the time their children were referred to the mental health service do not increase. PMID- 21538297 TI - [Obsessive compulsive disorder with tics: a new subtype?]. AB - BACKGROUND: Obsessive compulsive disorder (OCD) is a heterogeneous disorder. With the help of phenomenological research, attempts are being made to create more homogeneous subtypes. AIM: To search the literature in order to compare the symptoms of OCD patients with tics and without tics, and thereby determine whether OCD with tics can be distinguished clinically from OCD without tics. METHOD: Search terms were used in conjunction with PubMed and Psychinfo in order to locate studies in which OCD patients without tics were compared with OCD patients with tics. RESULTS: In the 26 studies found in our search 872 OCD patients out of a total of 2801 OCD patients (i.e. 31%) had a comorbid tic disorder. OCD patients with tics displayed similarities and differences at symptom level. OCD patients with tics were associated with male gender and early age of onset. Tic-like symptoms such as touching, twitching, repeating, symmetry behavior and rubbing were seen more frequently in OCD patients with tics. OCD patients without tics more often displayed contamination obsessions and engaged in compulsive washing. On the other hand, the obsessions of patients with tics and without tics were very similar. The goal-directedness of compulsions differed between OCD patients with tics and those without tics. By analogy with 'the premonitory urges' that often precede tics, OCD patients with tics more often reported 'just-right' perceptions prior to their compulsions. OCD patients without tics more often reported anxiety prior to their compulsions. Compulsions seemed to be aimed at reducing tension and feelings of anxiety. CONCLUSION: On the basis of the clinical symptoms OCD with tics does seem to be a subtype of OCD. However further research is needed into the aetiology, effective treatment and the course of the disorder before OCD with tics can be accepted conclusively as a subtype of OCD. PMID- 21538298 TI - [Rating scales for assessing catatonia; which ones are the best?]. AB - BACKGROUND: Despite increasing scientific and clinical interest in catatonia, there is still no precise definition of this psychiatric disorder. AIM: To study the relevant literature and review systematically the various rating scales that have been developed for assessing catatonia in clinical practice. METHOD: Several searches were performed using Medline, the latest one in August 2010. RESULTS Seven catatonia rating scales were retrieved and studied: the Modified Rogers Scale, the Rogers Catatonia Scale, the Bush-Francis Catatonia Rating Scale (BFCRS), the Northoff Catatonia Rating Scale (NCRS), the Braunig Catatonia Scale (BCRS), the Bush-Francis Catatonia Scale- Revised version and the Kanner Scale. CONCLUSION: Several scales are suitable for assessing catatonia in clinical practice. The BFCRS, the NCRS and the BCRS are reliable scales for use in various clinical populations in which catatonia is prevalent. For routine use in clinical practice, the scale of choice is the BFCRS because it is well-founded, reliable and easy to administer. PMID- 21538299 TI - [Aripiprazole-induced parkinsonism in a 64-year-old female patient diagnosed with bipolar disorder]. AB - A 64-year-old female patient, diagnosed with bipolar disorder, developed parkinsonism 18 days after aripiprazole had been initiated. Twenty-six days after the patient had stopped taking aripiprazole the parkinson syndrome disappeared completely. Aripiprazole is usually associated with a low incidence of extrapyramidal symptoms. So far, little is known about the pathophysiology of parkinsonism and the possible role of aripiprazole. The case-study includes some hypotheses and recommendations. PMID- 21538300 TI - [Developmental coordination disorder in a child with ADHD; is DCD a DSM-IV diagnosis that is not recognised by child psychiatry?]. AB - A five-year-old boy received treatment for attention deficit hyperactivity disorder (ADHD). In connection with his motor problems he was referred to a rehabilitation centre specialising in the study and treatment of developmental coordination disorder (DCD). When treating a patient with ADHD, doctors should ask regularly about the patient's motor functioning and, if necessary, arrange a referral. In the first instance a young patient should be referred to a paediatric physiotherapist or, if the problems are complex, referral should be to a paediatric rehabilitation doctor. A combination of ADHD and DCD has a poorer prognosis than ADHD alone. PMID- 21538301 TI - Growing and analyzing biofilms in flow chambers. AB - This unit describes the setup of flow chamber systems for the study of microbial biofilms, and methods for the analysis of structural biofilm formation. Use of flow chambers allows direct microscopic investigation of biofilm formation. The biofilms in flow chambers develop under hydrodynamic conditions, and the environment can be carefully controlled and easily changed. The protocols in this unit include construction of the flow chamber and the bubble trap, assembly and sterilization of the flow chamber system, inoculation of the flow chambers, running of the system, image capture and analysis, and disassembly and cleaning of the system. In addition, embedding and fluorescent in situ hybridization of flow chamber-grown biofilms are addressed. PMID- 21538302 TI - Production of Myxoma virus gateway entry and expression libraries and validation of viral protein expression. AB - Invitrogen's Gateway technology is a recombination-based cloning method that allows for rapid transfer of numerous open reading frames (ORFs) into multiple plasmid vectors, making it useful for diverse high-throughput applications. Gateway technology has been utilized to create an ORF library for Myxoma virus (MYXV), a member of the Poxviridae family of DNA viruses. MYXV is the prototype virus for the genus Leporipoxvirus, and is pathogenic only in European rabbits. MYXV replicates exclusively in the host cell cytoplasm, and its genome encodes 171 ORFs. A number of these ORFs encode proteins that interfere with or modulate host defense mechanisms, particularly the inflammatory responses. Furthermore, MYXV is able to productively infect a variety of human cancer cell lines and is being developed as an oncolytic virus for treating human cancers. MYXV is therefore an excellent model for studying poxvirus biology, pathogenesis, and host tropism, and a good candidate for ORFeome development. PMID- 21538303 TI - Coronaviruses: propagation, quantification, storage, and construction of recombinant mouse hepatitis virus. AB - The focus of this protocol is mouse hepatitis virus (MHV), with occasional references to other coronaviruses. Many of these protocols can be easily adapted to other coronaviruses. Protocols for propagating MHV in DBT and 17CL-1 cells; the storage and titration of viral stocks; purification of MHV on sucrose gradients; and the generation of recombinant viruses by a cDNA assembly method and by targeted recombination will be presented. Protocols are also included for the propagation of DBT, 17CL-1, and L2 cells used for growing and titrating MHV, and for the growth of BHK-R cells and FCWF cells. The latter two cell lines are used for regenerating infectious MHV by an in vitro cDNA assembly protocol and by a targeted recombination protocol, respectively, allowing reverse genetic manipulation of these viruses. An additional protocol for the maintenance of the large plasmids used for generating recombinant MHVs will also be presented. PMID- 21538304 TI - Whole-body imaging of infection using fluorescence. AB - Optical imaging is emerging as a powerful tool to study physiological, neurological, oncological, cell biological, molecular, developmental, immunological, and infectious processes. This unit describes the use of fluorescent reporters for biological organisms, components, or events. We describe the application of fluorescence imaging to examination of infectious processes, in particular subcutaneous and pulmonary bacterial infections, but the same approaches are applicable to nearly any infectious route. The strategies described use mycobacterial infections as an example, but nearly identical systems can be used for Pseudomonas, Legionella, Salmonella, Escherichia, Borrelia, and Staphylococus, suggesting that the approaches are generally applicable to nearly any infectious agent. Two strategies for fluorescence imaging are described: the first method uses reporter enzyme fluorescence (REF), and the second uses fluorescent proteins for fluorescence imaging. Methods are described in detail to facilitate successful application of these emerging technologies to nearly any experimental system. PMID- 21538305 TI - Whole-body imaging of infection using bioluminescence. AB - Bioluminescence imaging is a powerful technique to visualize and monitor biological processes in numerous systems. This unit describes two strategies for bioluminescence imaging that can be used to study bacterial infection in mice. One method is to express a luciferase gene in the bacteria; the second method is to use bacteria that express both a luciferase and beta-lactamase along with a substrate containing caged luciferin, which is released by beta-lactamase hydrolysis and reacts with luciferase to generate light. For both strategies, bioluminescent signals are imaged using an IVIS live animal imaging system (Caliper Life Sciences). The bioluminescence images are analyzed to localize bioluminescent bacteria, quantify signal, and determine the wavelengths of the signals produced. The correlation of bacterial numbers with signal intensity in vivo can be determined, allowing a quantitative measure of bacterial numbers in mice in real time. Methods are described in detail to facilitate successful application of these emerging technologies in nearly any experimental system. PMID- 21538308 TI - The end of rheumatoid factor as we know it? PMID- 21538309 TI - B cell tolerance: putting the horse before the cart. PMID- 21538310 TI - Lupus T cells switched on by DNA hypomethylation via microRNA? PMID- 21538311 TI - Toward a data-driven evaluation of the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis: is it sensible to look at levels of rheumatoid factor? AB - OBJECTIVE: Recently, new classification criteria for rheumatoid arthritis (RA) have been devised by methodology that used first a quantitative approach (data from databases), then a qualitative approach (consensus; based on paper patients), and finally a common sense-based approach (evaluation of the former phases). Now the individual items that make up these criteria are being evaluated. This study was undertaken to analyze the item "autoantibodies," in particular rheumatoid factor (RF) level. METHODS: Three separate cohorts comprising a total of 972 patients with undifferentiated arthritis were studied for RA development (according to the 1987 American College of Rheumatology criteria) and arthritis persistence. The positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios (LRs) were compared between different levels of RF and the presence of anti-citrullinated protein antibody (ACPA). A similar comparison was made in 686 RA patients for the rate of joint destruction and achievement of sustained disease-modifying antirheumatic drug-free remission during 7 years of followup. The variation in RF levels obtained by different measurement methods in the same RF-positive sera was explored. RESULTS: Compared to high RF levels, presence of ACPA had a better balance between positive LR and negative LR and between PPV and NPV for RA development. The additive value of ACPA assessment after testing for RF level was higher than vice versa. The association between high RF level and RA severity was not as strong as that between ACPA antibodies and RA severity. The RF level obtained by different methods in the same patients' sera varied considerably. CONCLUSION: Our findings indicate that determination of RF level is subject to large variation; high RF level has limited additive prognostic value compared to ACPA positivity. Thus, omitting RF level and using RF presence, ACPA presence, and ACPA level may improve the 2010 criteria for RA. PMID- 21538312 TI - A detailed comparative study of high-resolution ultrasound and micro-computed tomography for detection of arthritic bone erosions. AB - OBJECTIVE: To test whether bony lesions appearing on ultrasound (US) imaging are cortical breaks detectable by micro-computed tomography (micro-CT). METHODS: Twenty-six subjects (14 with rheumatoid arthritis, 6 with psoriatic arthritis, and 6 healthy controls) were assessed for bone erosions at the radial, palmar, and dorsal regions of the second metacarpophalangeal (MCP) joint and the palmar and dorsal regions of the third and fourth MCP joints. All patients underwent US and, for validation of the results, micro-CT scanning. The prevalence and severity of bone erosions as determined by US and by micro-CT were recorded and compared. RESULTS: Overall there was a good correlation between the severity of erosions as assessed by US and by micro-CT (r = 0.463, P < 0.0001). False negative results (US negative/micro-CT positive) were obtained in only 9.9% of the joint regions and were mostly due to small erosive lesions at the dorsal sides of the MCP joints. False-positive results (US positive/micro-CT negative) were more frequent (28.6%) and were primarily based on vascular bone channels at the palmar sides of the MCP joints as well pseudo-erosions created by osteophytes. CONCLUSION: These data show that the majority of bone lesions appearing on US are indeed bone erosions with a cortical break. The sensitivity of US for detecting bone erosions was high and there was a good correlation between the severity of bone erosions as assessed by US and as assessed by micro CT. Specificity of US for bone erosions was substantially lower, suggesting that smaller lesions seen on US do not always represent breaks in the cortical bone surface. PMID- 21538313 TI - Inflammation-independent defective early B cell tolerance checkpoints in rheumatoid arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) patients who have never received treatment for RA have been found to have defective early B cell tolerance checkpoints, resulting in impaired removal of developing autoreactive B cells. However, it is unclear whether these defects in B cell tolerance checkpoints are a primary aspect of the disease or are the result of ongoing inflammatory processes in these patients. The aim of this study was to assess the impact of standard immunosuppressive treatments, methotrexate and anti-tumor necrosis factor alpha (anti-TNFalpha) agents, on early B cell tolerance checkpoints in RA patients. METHODS: Blood samples were obtained from RA patients before and after treatment with methotrexate and/or anti-TNFalpha agents. B cells were tested pre- and posttherapy for reactivity of recombinant antibodies cloned from single B cells, which allowed us to determine the evolution of the frequency of autoreactive clones in the mature naive B cell compartment in RA patients before and after treatment. B cells from healthy donors were used as controls. RESULTS: Posttreatment frequencies of autoreactive mature naive B cells were elevated in the blood of RA patients. Nevertheless, the frequencies after treatment remained similar to those observed in the same patients before treatment. CONCLUSION: Despite the achievement of clinical improvement in RA patients following treatment with methotrexate and/or anti-TNFalpha agents, these therapies did not correct the accumulation of peripheral autoreactive mature naive B cells in these patients, suggesting that inflammation is not responsible for the defective early B cell tolerance checkpoints in RA. PMID- 21538314 TI - Safety and efficacy of anti-tumor necrosis factor alpha therapy in ten patients with recent-onset refractory reactive arthritis. AB - OBJECTIVE: There are few treatments for reactive arthritis (ReA). Since concentrations of tumor necrosis factor alpha (TNFalpha) are high in the serum and joints of patients with persistent ReA, this cytokine could be targeted in patients who do not respond to nonsteroidal antiinflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). We under-took this study to investigate the safety and efficacy of TNF antagonists in patients with recent onset and refractory ReA. METHODS: All French rheumatology and internal medicine practitioners registered on the Club Rhumatisme et Inflammation web site were asked to report on patients with ReA (defined by the criteria of the Third International Workshop on Reactive Arthritis) who had received anti-TNF therapy within the 12 months following the triggering infection. Tolerance and efficacy were retrospectively assessed using a standardized questionnaire. RESULTS: Ten patients with ReA previously refractory to NSAIDs and DMARDs, for which there was clinical and microbiologic evidence of a triggering bacterial infection, received anti-TNF therapy within a median of 6 months (range 2-12 months) between the beginning of ReA and the initiation of the treatment. The median followup was 20.6 months (range 6-50 months). We observed no severe adverse event and no infection related to the bacterium that triggered the ReA. Anti-TNF therapy was rapidly effective in 9 patients (90%), as shown by the rapid effect on a visual analog scale pain score, tender joint count, swollen joint count, and extraarticular manifestations, and by the corticosteroid-sparing effect. CONCLUSION: Anti-TNF therapy appears to be a safe and effective treatment of rheumatic and extraarticular manifestations in patients with recent-onset and refractory ReA, with a corticosteroid-sparing effect. Thus, TNFalpha could be a relevant target for ReA therapy. PMID- 21538315 TI - Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. AB - OBJECTIVE: We previously reported that human synovium contains cells that, after culture expansion, display properties of mesenchymal stem cells (MSCs). The objective of this study was to identify MSCs in native synovium in vivo. METHODS: To identify stem cells in the synovium in vivo, a double nucleoside analog cell labeling scheme was used in a mouse model of joint-surface injury. For labeling of slow-cycling cells, mice received iododeoxyuridine (IdU) for 30 days, followed by a 40-day washout period. For labeling of cells that proliferate after injury, mice underwent knee surgery to produce an articular cartilage defect and received chlorodeoxyuridine (CIdU) for 4 days, starting at multiple time points after surgery. Unoperated and sham-operated joints served as controls. Knee joint paraffin sections were analyzed by double and triple immunostaining to detect nucleoside analogs, conventional MSC markers, and chondrocyte-lineage markers. RESULTS: Long-term-retaining, slow-cycling IdU-positive cells were detected in the synovium. At 4 days and 8 days after injury, there was marked proliferation of IdU-positive cells, which costained for CIdU. IdU-positive cells were nonhematopoietic, nonendothelial stromal cells, were distinct from pericytes, and stained positive for MSC markers. MSCs were phenotypically heterogeneous and located in topographically distinct niches in the lining layer and the subsynovial tissue. Twelve days after injury, double nucleoside-labeled cells within synovium were embedded in cartilage-specific metachromatic extracellular matrix and costained positive for the chondrocyte-lineage markers Sox9 and type II collagen. CONCLUSION: Our findings provide the first evidence of the existence of resident MSCs in the knee joint synovium that undergo proliferation and chondrogenic differentiation following injury in vivo. PMID- 21538316 TI - Monosodium urate monohydrate crystal-recruited noninflammatory monocytes differentiate into M1-like proinflammatory macrophages in a peritoneal murine model of gout. AB - OBJECTIVE: To profile monosodium urate monohydrate (MSU) crystal-recruited monocyte inflammatory function during the course of in vivo differentiation, in a murine model of peritoneal MSU crystal-induced inflammation. METHODS: C57BL/6J mice were injected intraperitoneally with MSU crystals, and the peritoneal cells were harvested at different time points. The MSU crystal-recruited monocyte/macrophage population was analyzed for the expression of differentiation and activation markers, cytokine production following MSU crystal restimulation ex vivo and in vivo, expression of NLRP3-associated proteins (ASC, caspase 1) and pro-interleukin-1beta (proIL-1beta), and phagocytic capacity. RESULTS: Monocytes recruited 8 hours after MSU crystal stimulation (F4/80(low) Gr-1(int) 7/4+) exhibited poor phagocytic capacity, expressed low levels of proIL-1beta, and failed to produce proinflammatory cytokines in response to MSU crystal restimulation. In the absence of MSU crystal restimulation, differentiating monocytes produced low levels of transforming growth factor beta1 ex vivo, and this was abrogated following MSU crystal restimulation. Over time these cells developed a proinflammatory phenotype in vivo, characterized by the production of IL-1beta, tumor necrosis factor alpha, IL-6, CCL2 (monocyte chemotactic protein 1), and CXCL1 (cytokine-induced neutrophil chemoattractant) following ex vivo MSU crystal restimulation, and leading to IL-1beta production and cell infiltration following MSU crystal rechallenge in vivo. Proinflammatory function was associated with differentiation toward a macrophage phenotype (F4/80(high) Gr-1 7/4-), an increase in phagocytic capacity, and an increase in the expression of proIL-1beta. CONCLUSION: MSU crystal-recruited monocytes differentiate into proinflammatory M1-like macrophages in vivo. This proinflammatory macrophage phenotype is likely to play a key role in perpetuating inflammation in gouty arthritis in the presence of ongoing deposition of fresh MSU crystals. PMID- 21538317 TI - Increased inflammatory cytokine expression in the vastus lateralis of patients with knee osteoarthritis. AB - OBJECTIVE: Increased inflammation and pain are inseparable parts of knee osteoarthritis (OA) that may lead to disuse of the affected limb. The aim of this study was to examine the effects of knee OA on inflammation- and atrophy-related genes and proteins in the vastus lateralis muscle of patients with knee OA. METHODS: Nineteen patients with knee OA and 14 asymptomatic control subjects matched for age and body mass index underwent strength measurements and a muscle biopsy. Muscle was analyzed for the total cellular protein of inflammatory kinases (p65 NF-kappaB, JNK1/2, STAT-3, and suppressor of cytokine signaling 3 [SOCS-3]) and inflammatory intracellular molecules (interleukin-6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1], tumor necrosis factor alpha [TNFalpha], IL-1beta, and atrogin-1). RESULTS: Knee OA resulted in greater levels of IL-6 protein (34%; P = 0.002). The levels of inflammatory kinases, including STAT-3 (187%; P = 0.002), p65 NF-kappaB (156%; P = 0.002), and JNK1 (179%; P = 0.027), were also elevated. Furthermore, elevated expression of gene transcripts encoding MCP-1 (28%; P = 0.023), TNFalpha (85%; P < 0.001), and SOCS-3 (38%; P = 0.055) was observed in patients with knee OA compared with control subjects. Patients with knee OA had reduced muscle strength compared with control subjects (mean +/- SEM 84.7 +/- 8.7 versus 143.1 +/- 20.8 Nm; P = 0.005). Negative correlations were observed between muscle strength and MCP-1 protein abundance (r = -0.37 [P = 0.042]) and the gene expression of TNFalpha and atrogin-1 messenger RNA (r = -0.46 [P = 0.012] and r = -0.36 [P = 0.040], respectively). CONCLUSION: Gene expression and the protein abundance of numerous muscle markers of inflammation and atrophy were elevated in patients with knee OA, and the increase in muscle inflammation was associated with a reduction in muscle strength. Given the role inflammation markers may play in muscle strength and atrophy, further studies are needed to investigate the effect of exercise intervention on skeletal muscle inflammation. PMID- 21538318 TI - Clinical image: Development of miliary tuberculosis following one intraarticular injection of etanercept. PMID- 21538319 TI - MicroRNA-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. AB - OBJECTIVE: To identify microRNA genes with abnormal expression in the CD4+ T cells of patients with systemic lupus erythematosus (SLE) and to determine the role of microRNA-126 (miR-126) in the etiology of SLE. METHODS: MicroRNA expression patterns in CD4+ T cells from patients with SLE and healthy control subjects were analyzed by microRNA microarray and stem loop quantitative polymerase chain reaction (qPCR). Luciferase reporter gene assays were performed to identify miR-126 targets. Dnmt1, CD11a, and CD70 messenger RNA and protein levels were determined by real-time qPCR, Western blotting, and flow cytometry. CD11a, CD70, and EGFL7 promoter methylation levels were detected by bisulfite sequencing. IgG levels in T cell-B cell cocultures were determined by enzyme linked immunosorbent assay. RESULTS: The expression of 11 microRNA was significantly increased or decreased in CD4+ T cells from patients with SLE relative to that in CD4+ T cells from control subjects. Among these, miR-126 was up-regulated, and its degree of overexpression was inversely correlated with Dnmt1 protein levels. We demonstrated that miR-126 directly inhibits Dnmt1 translation via interaction with its 3'-untranslated region, and that overexpression of miR-126 in CD4+ T cells can significantly reduce Dnmt1 protein levels. The overexpression of miR-126 in CD4+ T cells from healthy donors caused the demethylation and up-regulation of genes encoding CD11a and CD70, thereby causing T cell and B cell hyperactivity. The inhibition of miR-126 in CD4+ T cells from patients with SLE had the opposite effects. Expression of the miR-126 host gene EGFL7 was also up-regulated in CD4+ T cells from patients with SLE, possibly in a hypomethylation-dependent manner. CONCLUSION: Our data suggest that miR-126 regulates DNA methylation in CD4+ T cells and contributes to T cell autoreactivity in SLE by directly targeting Dnmt1. PMID- 21538320 TI - Systemic sclerosis is an independent risk factor for increased coronary artery calcium deposition. AB - OBJECTIVE: Endothelial dysfunction and inflammation are pathogenic mechanisms common to systemic sclerosis (SSc) and atherosclerosis. This study was undertaken to examine the relationship between coronary atherosclerosis, as assessed by the coronary artery calcium score (CACS), and conventional cardiovascular and disease specific risk factors in SSc patients. METHODS: The CACS was measured by computed tomography, and cardiovascular risk factors were examined in SSc patients and compared with controls matched for age, sex, and glycemic status. Disease activity score, antiphospholipid antibodies, high-sensitivity C-reactive protein level, and erythrocyte sedimentation rate were measured in SSc patients. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. RESULTS: We recruited 53 SSc patients (50 women and 3 men) and 106 controls. The patients had a mean +/- SD age of 53.1 +/- 12.9 years and a median disease duration of 9 years. Compared to controls, SSc patients had significantly lower low-density lipoprotein (LDL) cholesterol levels (P = 0.001), high-density lipoprotein cholesterol levels (P = 0.01), diastolic blood pressure, waist circumference, and body mass index and were more likely to be receiving vasodilators (all P < 0.001). There was a significantly higher proportion of SSc patients among subjects with more severe coronary calcification (CACS >= 101) compared to those with lesser severity (CACS <100) (56.5% versus 29.4%; P = 0.01). Multiple logistic regression analysis revealed SSc to be an independent determinant for a CACS >= 101 (OR 10.89 [95% CI 2.21-53.75], P = 0.003) together with age and LDL cholesterol level after adjustment for other cardiovascular risk factors. Among disease-specific factors, only disease duration (OR 1.14 [95% CI 1.02-1.27], P = 0.02) was independently associated with more severe coronary calcification (CACS >= 101). CONCLUSION: Our findings indicate that SSc is an independent risk factor for coronary calcification, in addition to the conventional risk factors for coronary atherosclerosis, such as age and hypertension. PMID- 21538321 TI - Genetic determinants in hepatitis C virus-associated mixed cryoglobulinemia: role of polymorphic variants of BAFF promoter and Fcgamma receptors. AB - OBJECTIVE: Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)-related immune complex disorder. Only some HCV-infected patients develop MC, which suggests that the genetic background of the host plays a key role. This study was undertaken to evaluate the contribution of host genetic factors in the pathogenesis of HCV-associated MC (HCV-MC) by analyzing allelic variants of low affinity Fcgamma receptor (FcgammaR) genes and BAFF promoter. METHODS: FcgammaR polymorphisms (FCGR2A 131 R/H, FCGR2B 232 I/T, FCGR3A 176 V/F, and FCGR3B NA1/NA2) and BAFF promoter polymorphism -871 C/T were analyzed in 102 patients with HCV-MC and 108 patients with HCV without MC, using polymerase chain reaction based techniques. RESULTS: A higher prevalence of -871 T/T homozygosity (31% versus 16%; P = 0.001) and a greater frequency of T alleles of the BAFF promoter (80% versus 57%; P = 0.004) were found in the HCV-MC group than in the HCV group. A significant increase in serum BAFF concentration was significantly associated with the higher frequency of the T allele in HCV-MC (mean +/- SD 4.12 +/- 1.29 versus 2.09 +/- 0.81 ng/ml; P < 0.0005). The distribution of the FcgammaR genotypes was not significantly different. In the 21 HCV-MC patients treated with rituximab, the response was strictly related to F allele homozygosity (significantly reduced in 5 of 5 patients with the FCGR3A F/F genotype versus 4 of 16 with V/V or V/F; P < 0.0005). CONCLUSION: These results indicate the importance of host genetic background in the development of HCV-MC, suggesting that mechanisms enhancing Ig production and B cell survival may play a relevant role. Genetic FcgammaR variants seem to be crucial to the effectiveness of rituximab therapy. PMID- 21538322 TI - Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. AB - OBJECTIVE: The current treatment options for systemic-onset juvenile idiopathic arthritis (JIA) are methotrexate, steroids, and biologic agents. This study was undertaken to evaluate the safety of the orally active histone deacetylase inhibitor givinostat (ITF2357) and its ability to affect the disease. METHODS: Givinostat was administered orally, for up to 12 weeks at a dosage of 1.5 mg/kg/day, to 17 patients with systemic-onset JIA who had had active disease for >=1 month. Disease activity was clinically assessed using the American College of Rheumatology Pediatric 30 (ACR Pedi 30), ACR Pedi 50, or ACR Pedi 70 criteria for improvement and a systemic feature score. The primary goal was safety and the primary efficacy end point was the number of patients completing 12 weeks of treatment who were responders. RESULTS: Givinostat was safe and well tolerated, with adverse events (AEs) being mild or moderate, of short duration, and self limited. The 17 patients from the intent-to-treat population reported a total of 44 AEs, and the 9 patients in the per-protocol population reported a total of 25. Six AEs in 3 patients (nausea, vomiting, and fatigue) were related to the study drug, but each resolved spontaneously and no patient was withdrawn from the study due to drug-related AEs. In the per-protocol population at week 4, the improvement as measured by the ACR Pedi 30, ACR Pedi 50, and ACR Pedi 70, respectively, was 77.8%, 55.6%, and 22.2%, and this increased further to 77.8%, 77.8%, and 66.7% at week 12. The most consistent finding was the reduction in the number of joints with active disease or with limited range of motion. CONCLUSION: After 12 weeks, givinostat exhibited significant therapeutic benefit in patients with systemic-onset JIA, particularly with regard to the arthritic component of the disease, and showed an excellent safety profile. PMID- 21538323 TI - Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. AB - OBJECTIVE: To gain insight into the molecular bases of genetically unexplained periodic fever syndromes (PFS) by screening NLRP12, a gene in which only a nonsense and a splice site mutation have so far been identified, and to assess the functional consequences of the identified missense variation. METHODS: NLRP12 was screened for mutations by direct sequencing. Functional assays were performed in HEK 293T cells stably expressing the proapoptotic protein ASC and procaspase 1, in order to determine the effects of normal and mutated NLRP12 proteins on speck formation, caspase 1 signaling, and NF-kappaB activation. RESULTS: A heterozygous NLRP12 missense mutation involving a CpG site (c.1054C>T; p.Arg352Cys) was identified in exon 3, which encodes the nucleotide-binding site (NBS) of the protein, in 2 patients from different countries and carrying different NLRP12 haplotypes. The mutation, which does not alter the inhibitory effect of NLRP12 on NF-kappaB activation, increases speck formation and activates caspase 1 signaling. To define this new class of PFS, we propose the term NLRP12 associated disorders (NLRP12AD). CONCLUSION: Given the rarity of known NLRP12 associated disorders, the identification of this NLRP12 molecular defect contributes to the delineation of the clinical spectrum associated with mutations in this gene and highlights the importance of screening NLRP12 in patients presenting with unexplained PFS. This study also demonstrates, by means of functional assays, the deleterious effect of this recurrent missense mutation; the gain of function for speck formation and caspase 1 signaling associated with this NBS mutation is consistent with the inflammatory phenotype of PFS. PMID- 21538324 TI - 17beta-estradiol induces CD40 expression in dendritic cells via MAPK signaling pathways in a minichromosome maintenance protein 6-dependent manner. AB - OBJECTIVE: The human immune system exhibits sexual dimorphism in autoimmune diseases such as systemic lupus erythematosus (SLE). Female sex hormones, including 17beta-estradiol, are strongly implicated in the gender bias in SLE. CD40 is a costimulatory molecule and plays a crucial role in modulating the immune response of effector cells. We have previously shown that 17beta-estradiol up-regulated CD40 expression and altered minichromosome maintenance protein 6 (MCM6) gene expression in dendritic cells (DCs). The mechanism of the correlation between CD40 and MCM6 in the presence of 17beta-estradiol remains unknown. This study was undertaken to elucidate this mechanism and to explain the role of MCM6 in the gender bias in SLE. METHODS: Bone marrow-derived DCs transfected with small interfering RNA (siRNA) for MCM6 were treated with 17beta-estradiol in the absence or presence of CpG. The expression levels of costimulatory molecules, activity of MAPKs, and levels of MCM6 protein were measured. Moreover, the functions of DCs, including proliferation, apoptosis, endocytosis, and cytokine production, were analyzed. In addition, levels of messenger RNA for MCM6 were detected in DCs purified from SLE patients. RESULTS: Regardless of the presence or absence of CpG, 17beta-estradiol induced CD40 expression via the activation of p38 and JNK, but not ERK. The activation of p38 and JNK enhanced MCM6 expression, which then induced CD40 expression. Suppression of MCM6 in DCs abolished the up regulation of 17beta-estradiol-induced CD40 expression. Importantly, MCM6 expression was significantly increased in SLE patients compared with healthy controls. CONCLUSION: Our findings indicate that 17beta-estradiol induces CD40 expression in DCs via p38 and JNK MAPKs in an MCM6-dependent manner. MCM6 may be a critical mediator of sex-based differences in autoimmune disease. PMID- 21538325 TI - Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice. AB - OBJECTIVE: To investigate whether the enhancement of joint lymphangiogenesis by injection of vascular endothelial growth factor C (VEGF-C) adeno-associated virus (AAV) into the affected joints has therapeutic efficacy in chronic inflammatory arthritis in mice. METHODS: Tumor necrosis factor-transgenic (TNF-Tg) mice were used as a model of chronic inflammatory arthritis. Human VEGF-C was cloned into an AAV expression vector to generate AAV-VEGF-C. The joints of TNF-Tg mice were injected with AAV-VEGF-C or AAV-luciferase (AAV-Luc) as a control. During the 4 months following injection, magnetic resonance imaging of the joints and lymphatic imaging were performed to assess changes in synovial volume and lymph flow from the joint tissues to local draining lymph nodes. Joint inflammation, bone erosion, and cartilage loss were examined by histologic analyses. Lymphatic vessel formation was assessed using immunohistochemistry. RESULTS: Intraarticular administration of AAV-VEGF-C virus significantly attenuated the increase in synovial volume and increased lymphatic vessel number in the joint sections, as compared with that in control AAV-Luc-injected joints, during the 4-month period. This was accompanied by a reduction in the area of inflammation, bone erosion, cartilage loss, and osteoclast numbers. Lymph flow from the joints to local draining lymph nodes was slower in TNF-Tg mice than in wild-type littermates, and was significantly improved with AAV-VEGF-C treatment. CONCLUSION: Intraarticular injection of AAV-VEGF-C increased lymphangiogenesis and improved lymphatic drainage from the inflamed joints of mice, resulting in attenuation of joint tissue damage. Thus, improvement of joint lymphatic function by local administration of lymphatic growth factors represents a new therapeutic approach for chronic inflammatory arthritis. PMID- 21538326 TI - Contributions of angiogenesis to inflammation, joint damage, and pain in a rat model of osteoarthritis. AB - OBJECTIVE: To determine the contributions of angiogenesis to inflammation, joint damage, and pain behavior in a rat meniscal transection model of osteoarthritis (OA). METHODS: OA was induced in male Lewis rats (n=8 per group) by meniscal transection. Animals were orally dosed with dexamethasone (0.1 mg/kg/day), indomethacin (2 mg/kg/day), or the specific angiogenesis inhibitor PPI-2458 (5 mg/kg every other day). Controls consisted of naive and vehicle-treated rats. Synovial inflammation was measured as the macrophage fractional area (expressed as the percentage), thickness of the synovial lining, and joint swelling. Synovial angiogenesis was measured using the endothelial cell proliferation index and vascular density. Channels positive for vessels at the osteochondral junction were assessed (osteochondral angiogenesis). Medial tibial plateaus were assessed for chondropathy, osteophytosis, and channels crossing the osteochondral junction. Pain behavior was measured as weight-bearing asymmetry. RESULTS: Dexamethasone and indomethacin each reduced pain behavior, synovial inflammation, and synovial angiogenesis 35 days after meniscal transection. Dexamethasone reduced, but indomethacin had no significant effect on, the total joint damage score. PPI-2458 treatment reduced synovial and osteochondral angiogenesis, synovial inflammation, joint damage, and pain behavior. CONCLUSION: Our findings indicate that synovial inflammation and joint damage are closely associated with pain behavior in the meniscal transection model of OA. Inhibition of angiogenesis may reduce pain behavior both by reducing synovitis and by preventing structural change. Targeting angiogenesis could therefore prove useful in reducing pain and structural damage in OA. PMID- 21538327 TI - Systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease: impact of pulmonary arterial hypertension therapies. AB - OBJECTIVE: Precapillary pulmonary hypertension (PH) is an important cause of death in patients with systemic sclerosis (SSc). It can occur in isolation (pulmonary arterial hypertension [PAH]) or in association with interstitial lung disease (ILD). Importantly, the outcomes and efficacy of PAH therapies in patients with SSc-related PH complicating ILD (PH-ILD) remain unknown. This study was undertaken to evaluate our experience with PH-ILD with regard to the efficacy and safety of PAH therapies in this patient cohort. METHODS: We conducted a retrospective analysis of consecutive SSc patients from 2 large referral centers who had PH-ILD confirmed by right-sided heart catheterization and who received targeted PAH therapies. World Health Organization (WHO) functional class, 6 minute walk distance, and hemodynamic parameters were assessed at baseline and after a mean +/- SD of 7.7 +/- 6.2 months of treatment for PAH. Kaplan-Meier and Cox proportional hazards models were used to analyze survival and to identify prognostic factors. RESULTS: Seventy patients were included in the study. No significant changes were observed in WHO functional class, 6-minute walk distance, or hemodynamic parameters after therapy. The 1-, 2-, and 3-year survival estimates were 71%, 39%, and 21%, respectively. In the multivariate model, worsening oxygenation during followup and reduced renal function were the only significant risk factors for death. CONCLUSION: This study represents the largest series to date in which the impact of PAH therapies in SSc-related PH-ILD was examined. In this cohort, PAH therapies were associated with no clear benefits. Deterioration in oxygenation was an important determinant of long-term survival. Prospective clinical trials focusing on this group of patients are warranted. PMID- 21538328 TI - Physical activity is associated with magnetic resonance imaging-based knee cartilage T2 measurements in asymptomatic subjects with and those without osteoarthritis risk factors. AB - OBJECTIVE: To evaluate the association of exercise and knee-bending activities with magnetic resonance imaging (MRI)-based knee cartilage T2 relaxation times and morphologic abnormalities in asymptomatic subjects from the Osteoarthritis Initiative, with or without osteoarthritis (OA) risk factors. METHODS: We studied 128 subjects with knee OA risk factors and 33 normal control subjects ages 45-55 years, with a body mass index of 18-27 kg/m(2) and no knee pain. Subjects were categorized according to exercise level, using the leisure activity component of the Physical Activity Scale for the Elderly, and by self-reported frequent knee bending activities. Two radiologists graded the cartilage of the right knee on MR images, using the Whole-Organ MRI Score (WORMS). Cartilage was segmented, and compartment-specific T2 values were calculated. Differences between the exercise groups and knee-bending groups were determined using multiple linear and logistic regression models. RESULTS: Among subjects with risk factors for knee OA, light exercisers had lower T2 values compared with sedentary and moderate/strenuous exercisers. When the sexes were analyzed separately, female moderate/strenuous exercisers had higher T2 values compared with sedentary individuals and light exercisers. Subjects without risk factors displayed no significant differences in T2 values according to exercise level. However, frequent knee-bending activities were associated with higher T2 values in both subjects with OA risk factors and those without OA risk factors and with more severe cartilage lesions in the group with risk factors. CONCLUSION: In subjects at risk of knee OA, light exercise was associated with low T2 values, whereas moderate/strenuous exercise in women was associated with high T2 values. Higher T2 values and WORMS grades were also observed in frequent knee-benders, suggesting greater cartilage degeneration in these individuals. PMID- 21538329 TI - Peptide-glycosaminoglycan cluster formation involving cell penetrating peptides. AB - Glycosaminoglycans (GAGs) affect the efficiency of cellular uptake of a wide range of cell penetrating peptides (CPPs). GAGs have been proposed to cluster with CPPs at the cell surface before uptake but little is known about the formation or stability of CPP-GAG clusters. Here we apply a combination of heparin affinity chromatography, dynamic light scattering, and fluorescence spectroscopy to characterize the formation, stability, and size of the clusters formed between CPPs and heparin. Under conditions similar to those used in cell uptake experiments the CPP, penetratin (Antp), was observed to form significantly more stable clusters with heparin than the CPP TAT, despite TAT showing a comparable affinity for heparin. This difference in cluster stability may explain the origins of the preferred cell uptake pathways followed by Antp and TAT, and may be an important parameter for optimizing the efficiency of designed CPP delivery vectors. PMID- 21538330 TI - An evaluation of Poisson-Boltzmann electrostatic free energy calculations through comparison with experimental mutagenesis data. AB - For systems involving highly and oppositely charged proteins, electrostatic forces dominate association and contribute to biomolecular complex stability. Using experimental or theoretical alanine-scanning mutagenesis, it is possible to elucidate the contribution of individual ionizable amino acids to protein association. We evaluated our electrostatic free energy calculations by comparing calculated and experimental data for alanine mutants of five protein complexes. We calculated Poisson-Boltzmann electrostatic free energies based on a thermodynamic cycle, which incorporates association in a reference (Coulombic) and solvated (solution) state, as well as solvation effects. We observe that Coulombic and solvation free energy values correlate with experimental data in highly and oppositely charged systems, but not in systems comprised of similarly charged proteins. We also observe that correlation between solution and experimental free energies is dependent on dielectric coefficient selection for the protein interior. Free energy correlations improve as protein dielectric coefficient increases, suggesting that the protein interior experiences moderate dielectric screening, despite being shielded from solvent. We propose that higher dielectric coefficients may be necessary to more accurately predict protein protein association. Additionally, our data suggest that Coulombic potential calculations alone may be sufficient to predict relative binding of protein mutants. PMID- 21538331 TI - Characterization of secondary amide peptide bond isomerization: thermodynamics and kinetics from 2D NMR spectroscopy. AB - Secondary amide cis peptide bonds are of even lower abundance than the cis tertiary amide bonds of prolines, yet they are of biochemical importance. Using 2D NMR exchange spectroscopy (EXSY) we investigated the formation of cis peptide bonds in several oligopeptides: Ac-G-G-G-NH(2) , Ac-I-G-G-NH(2) , Ac-I-G-G-N NH(2) and its cyclic form: I-G-G-N in dimethylsulfoxide (DMSO). From the NMR studies, using the amide protons as monitors, an occurrence of 0.13-0.23% of cis bonds was obtained at 296 K. The rate constants for the trans to cis conversion determined from 2D EXSY spectroscopy were 4-9 * 10(-3) s(-1) . Multiple minor conformations were detected for most peptide bonds. From their thermodynamic and kinetic properties the cis isomers are distinguished from minor trans isomers that appear because of an adjacent cis peptide bond. Solvent and sequence effects were investigated utilizing N-methylacetamide (NMA) and various peptides, which revealed a unique enthalpy profile in DMSO. The cyclization of a tetrapeptide resulted in greatly lowered cis populations and slower isomerization rates compared to its linear counterpart, further highlighting the impact of structural constraints. PMID- 21538332 TI - Spatiotemporal modeling and analysis of transient gene delivery. AB - A quantitative and mechanistic understanding of intracellular transport processes in eukaryotic cells during transient transfection is an important prerequisite for the systematic and specific optimization of transient gene expression procedures for pharmaceutic and industrial protein production. There is evidence that intracellular transport processes during gene delivery and their regulation may have significant influence on the transfection efficiency. This contribution describes a compartmented, spatiotemporally resolved and stochastic modeling approach that describes intracellular transport processes responsible for gene delivery during transient transfection. It enables a detailed prediction and analysis and identification of potential bottlenecks. This model is currently being adapted to a model cell line, HEK293s. The simulated results are compared with experimental quantitative polymerase chain reaction (qPCR) data and confocal imaging data obtained with transfected and stained HEK293 cells. Global parameter estimation is performed to qPCR data based on two different novel plasmid constructs in order to identify candidates for plasmid-specific transport parameter variations. The influence of the specific property of HEK293 cells to grow in clusters is investigated and the impact of active microtubule transport depending on cell morphology and clustering is examined. A general sensitivity analysis allows for the identification of the sensitive parameters. PMID- 21538333 TI - Microprinted feeder cells guide embryonic stem cell fate. AB - We introduce a non-contact approach to microprint multiple types of feeder cells in a microarray format using immiscible aqueous solutions of two biopolymers. Droplets of cell suspension in the denser aqueous phase are printed on a substrate residing within a bath of the immersion aqueous phase. Due to their affinity to the denser phase, cells remain localized within the drops and adhere to regions of the substrate underneath the drops. We show the utility of this technology for creating duplex heterocellular stem cell niches by printing two different support cell types on a gel surface and overlaying them with mouse embryonic stem cells (mESCs). As desired, the type of printed support cell spatially direct the fate of overlaid mESCs. Interestingly, we found that interspaced mESCs colonies on differentiation-inducing feeder cells show enhanced neuronal differentiation and give rise to dense networks of neurons. This cell printing technology provides unprecedented capabilities to efficiently identify the role of various feeder cells in guiding the fate of stem cells. PMID- 21538334 TI - A mechanistic understanding of production instability in CHO cell lines expressing recombinant monoclonal antibodies. AB - One of the most significant problems in industrial bioprocessing of recombinant proteins using engineered mammalian cells is the phenomenon of cell line instability, where a production cell line suffers a loss of specific productivity (qP). This phenomenon occurs with unpredictable kinetics and has been widely observed in Chinese hamster ovary (CHO) cell lines and with all commonly used gene expression systems. The underlying causes (both genetic and physiological) and the precise molecular mechanisms underpinning cell line instability have yet to be fully elucidated, although recombinant gene silencing and loss of recombinant gene copies have been shown to cause qP loss. In this work we have investigated the molecular mechanisms underpinning qP instability over long-term sub-culture in CHO cell lines producing recombinant IgG1 and IgG2 monoclonal antibodies (Mab's). We demonstrate that production instability derives from two primary mechanisms: (i) epigenetic--methylation-induced transcriptional silencing of the CMV promoter driving Mab gene transcription and (ii) genetic--progressive loss of recombinant Mab gene copies in a proliferating CHO cell population. We suggest that qP decline resulting from loss of recombinant genes is a consequence of the inherent genetic instability of recombinant CHO cell lines. PMID- 21538335 TI - Aptamer-based downstream processing of his-tagged proteins utilizing magnetic beads. AB - Aptamers are synthetic nucleic acid-based high affinity ligands that are able to capture their corresponding target via molecular recognition. Here, aptamer-based affinity purification for His-tagged proteins was developed. Two different aptamers directed against the His-tag were immobilized on magnetic beads covalently. The resulting aptamer-modified magnetic beads were characterized and successfully applied for purification of different His-tagged proteins from complex E. coli cell lysates. Purification effects comparable to conventional immobilized metal affinity chromatography were achieved in one single purification step. Moreover, we have investigated the possibility to regenerate and reuse the aptamer-modified magnetic beads and have shown their long-term stability over a period of 6 months. PMID- 21538336 TI - Recombinant human gelatin substitute with photoreactive properties for cell culture and tissue engineering. AB - The human recombinant collagen I alpha1 chain monomer (rh-gelatin) was modified by the incorporation of an azidophenyl group to prepare photoreactive human gelatin (Az-rh-gelatin), with approximately 90% of the lysine residues conjugated with azidobenzoic acid. Slight changes in conformation (circular dichroism spectra) and thermal properties (gelation and melting points) were noticed after modification. Ultraviolet (UV) irradiation could immobilize the Az-rh-gelatin on polymer surfaces, such as polystyrene and polytetrafluoroethylene. Az-rh-gelatin was stably retained on the polymer surfaces, while unmodified gelatin was mostly lost by brief washing. Human mesenchymal cells grew more efficiently on the immobilized surface than on the coated surface. The immobilized Az-rh-gelatin on the polymer surfaces was able to capture engineered growth factors with collagen affinity, and the bound growth factors stimulated the growth of cells dose dependently. It was also possible to immobilize Az-rh-gelatin in micropatterns (stripe, grid, and so on) using photomasks, and the cells grew according to the patterns. These results suggest that the photoreactive human gelatin, in combination with collagen-binding growth factors, will be clinically useful for surface modification of synthetic materials for cell culture systems and tissue engineering. PMID- 21538337 TI - Clonal analysis of the proliferation potential of human bone marrow mesenchymal stem cells as a function of potency. AB - Human mesenchymal stem cells (MSCs) from bone marrow are a heterogeneous ensemble of progenitors and lineage-committed cells, with a broad range of regenerative properties. Ex vivo expansion to produce sufficient quantities of MSCs is essential for most therapeutic applications. The present study resolves the relationship between proliferation potential of MSCs and their potency. Clonal analysis generated single-cell derived colonies of MSCs that were classified according to their trilineage potential to exhibit adipo- (A), chondro- (C), and osteogenesis (O) as a measure of potency. Multipotent OAC clones were highly proliferative with colony-forming efficiencies that ranged from 35% to 90%; whereas, O clones formed colonies with an efficiency of 5% or less (P < 0.01). Similar trends were evident during ex vivo expansion: for example, the median specific growth rate was 0.8 day(-1) (20 h doubling time) for cultures inoculated with OAC clones and was 5-fold less for inocula of O clones (P < 0.01). OA and OC clones had similar proliferation potentials. More than 75% of cells in subconfluent cultures inoculated with O clones stained positive for senescence-associated beta-galactosidase activity vs. less than 10% for OAC clones (P < 0.001). Apoptotic cells were in the minority for all potency groups. Preliminary data generated during clonal analysis suggest that osteogenic potential of MSCs to produce mineralized matrix is a function of potency, as well. These results are discussed in the context of the preparation of efficacious MSC therapies by ex vivo expansion. PMID- 21538338 TI - Cell-mediated deposition of porous silica on bacterial biofilms. AB - Living hybrid materials that respond dynamically to their surrounding environment have important applications in bioreactors. Silica based sol-gels represent appealing matrix materials as they form a mesoporous biocompatible glass lattice that allows for nutrient diffusion while firmly encapsulating living cells. Despite progress in sol-gel cellular encapsulation technologies, current techniques typically form bulk materials and are unable to generate regular silica membranes over complex geometries for large-scale applications. We have developed a novel biomimetic encapsulation technique whereby endogenous extracellular matrix molecules facilitate formation of a cell surface specific biomineral layer. In this study, monoculture Pseudomonas aeruginosa and Nitrosomonas europaea biofilms are exposed to silica precursors under different acid conditions. Scanning electron microscopy (SEM) imaging and electron dispersive X-ray (EDX) elemental analysis revealed the presence of a thin silica layer covering the biofilm surface. Cell survival was confirmed 30 min, 30 days, and 90 days after encapsulation using confocal imaging with a membrane integrity assay and physiological flux measurements of oxygen, glucose, and NH 4+. No statistical difference in viability, oxygen flux, or substrate flux was observed after encapsulation in silica glass. Shear induced biofilm detachment was assessed using a particle counter. Encapsulation significantly reduced detachment rate of the biofilms for over 30 days. The results of this study indicate that the thin regular silica membrane permits the diffusion of nutrients and cellular products, supporting continued cellular viability after biomineralization. This technique offers a means of controllably encapsulating biofilms over large surfaces and complex geometries. The generic deposition mechanism employed to form the silica matrix can be translated to a wide range of biological material and represents a platform encapsulation technology. PMID- 21538339 TI - Synergistic capture of Clostridium botulinum type A neurotoxin by scFv antibodies to novel epitopes. AB - A non-immune library of human single chain fragment variable (scFv) antibodies displayed on Saccharomyces cerevisiae was screened for binding to the Clostridium botulinum neurotoxin serotype A binding domain [BoNT/A (Hc)] with the goal of identifying scFv to novel epitopes. To do this, an antibody-mediated labeling strategy was used in which antigen-binding yeast clones were selected after labeling with previously characterized monoclonal antibodies (MAbs) specific to the Hc. Twenty unique scFv clones were isolated that bound Hc. Of these, 3 also bound to full-length BoNT/A toxin complex with affinities ranging from 5 to 48 nM. Epitope binning showed that the three unique clones recognized at least two epitopes distinct from one another as well as from the detection MAbs. After production in E. coli, scFv were coupled to magnetic particles and tested for their ability to capture BoNT/A holotoxin using an Endopep-MS assay. In this assay, toxin captured by scFv coated magnetic particles was detected by incubation of the complex with a peptide containing a BoNT/A-specific cleavage sequence. Mass spectrometry was used to detect the ratio of intact peptide to cleavage products as evidence for toxin capture. When tested individually, each of the scFv showed a weak positive Endopep-MS result. However, when the particles were coated with all three scFv simultaneously, they exhibited significantly higher Endopep-MS activity, consistent with synergistic binding. These results demonstrate novel approaches toward the isolation and characterization of scFv antibodies specific to unlabeled antigens. They also provide evidence that distinct scFv antibodies can work synergistically to increase the efficiency of antigen capture onto a solid support. PMID- 21538340 TI - Impact of single-port cholecystectomy on postoperative pain. AB - BACKGROUND: This study compared postoperative pain following four-port laparoscopic cholecystectomy (LC) and single-port cholecystectomy (SPC). METHOD: This prospective, quasi-randomized, single-centre trial focusing on postoperative pain included 49 patients undergoing elective surgery with either a conventional LC, or SPC using a surgical glove port. Postoperative pain was evaluated using a visual analogue scale (VAS) and postoperative analgesic use as primary outcome measures. Total duration of operation, length of hospital stay, blood test results on the day after surgery and total port cost were secondary outcome measures. RESULTS: Twenty-five LCs and 24 SPCs were undertaken. The VAS score on day 1 after surgery was significantly less in the SPC group than in the LC group: median (range) 24 (12-38) versus 45 (33-57) mm (P = 0.002). Significantly fewer patients in the SPC group required analgesia (9 of 24 versus 19 of 25 in the LC group; P = 0.007). There were no significant differences in total duration of operation, length of hospital stay, and blood test results on the day after surgery. CONCLUSION: Single-port surgery using a surgical glove port reduces postoperative pain compared with conventional LC. PMID- 21538341 TI - Effect of O2:CO2 ratio on the primary metabolism of Chlamydomonas reinhardtii. AB - High oxygen:carbon dioxide ratios may have a negative effect on growth and productivity of microalgae. To investigate the effect of O2 and CO2 concentrations and the ratio between these on the metabolism of Chlamydomonas reinhardtii we performed turbidostat experiments at different O2:CO2 ratios. These experiments showed that elevated O2 concentrations and the corresponding increase in the ratio of O2:CO2 common in photobioreactors led to a reduction of growth and biomass yield on light with 20-30%. This is most probably related to the oxygenase activity of Rubisco and the resulting process of photorespiration. Using metabolic flux modeling with measured rates for each experiment we were able to quantify the ratio of the oxygenase reaction to the carboxylase reaction of Rubisco and could demonstrate that photorespiration indeed can cause the reduction in biomass yield on light. The calculated ratio of the oxygenase reaction to the carboxylase reaction was 16.6% and 20.5% for air with 2% CO2 and 1% CO2, respectively. Thus photorespiration has a significant impact on the biomass yield on light already at conditions common in photobioreactors (air with 2% CO2). PMID- 21538342 TI - Prevalence of complementary medicine use in a phase 1 clinical trials program: the MD Anderson Cancer Center Experience. AB - BACKGROUND: A key end point of early cancer clinical trials is the assessment of toxicities and their possible association with new experimental drugs. Therefore, the concurrent use of complementary and alternative medicine (CAM) in patients with advanced malignancies seen in a dedicated phase 1 clinic was evaluated. METHODS: An investigator-designed survey was anonymously completed by patients seen in the phase 1 clinic. Pharmacologic CAM included any oral, topical, or intravenous agent, including vitamins, dietary supplements, and herbal products. Nonpharmacologic CAM included prayer, meditation, hypnosis, massage, and acupuncture. RESULTS: Of the 404 patients approached about completing the CAM survey, 394 (98%) agreed to respond, and 309 (78%) surveys were returned. Of those 309 patients, 162 (52%) used 1 or more CAM. Of the 162 CAM users, 77% utilized pharmacologic CAM, 71% used nonpharmacologic CAM, and 48% used both modalities. The most frequent CAM used were vitamins (70%), prayer (57%), and herbal products (26%). CAM utilization was not significantly associated with race, age, level of education, employment, or income level but was used more by women than men (P < .01). There was no statistically significant association between the use of CAM and quality of life as perceived by patients. Of the CAM users, 43% of patients had been using CAM for >5 years. Only 5% reported having side effects from using CAM, whereas 23% did not fully disclose their CAM use to their physicians. CONCLUSIONS: CAM usage is common in patients with advanced malignancies seen in a phase 1 clinic. PMID- 21538343 TI - Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. AB - BACKGROUND: The phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway plays a critical role in the pathogenesis of hepatocellular carcinoma (HCC). We performed a single-arm, phase 1/2 study of everolimus in patients with advanced HCC. METHODS: Patients with histologically confirmed measurable advanced HCC, 0-2 prior regimens, and adequate hematologic, hepatic, and renal functions received everolimus at 5 mg/day or 10 mg/day orally (6 weeks/cycle). The primary end points were determination of a safe dosage of everolimus (phase 1) and progression-free survival (PFS) at 24 weeks (phase 2). RESULTS: Twenty-eight patients were enrolled and evaluable for efficacy and toxicity. No dose-limiting toxicities were observed at the 5 mg/day (n = 3) or 10 mg/day (n = 6) dosage level in phase 1. Twenty-five patients received everolimus at 10 mg/day. Grade 3 4 adverse events included lymphopenia (n = 3), aspartate transaminase (n = 3), hyponatremia (n = 2), and 1 patient each with anemia, alanine transaminase, hyperglycemia, proteinuria, rash, and hypoxia. One patient (4%) had partial response (95% confidence interval [CI], 0.9%-19.6%). The median PFS and overall survival were 3.8 months (95% CI, 2.1-4.6) and 8.4 months (95% CI, 3.9-21.1), respectively. The estimated PFS rate at 24 weeks was 28.6% (95% CI, 7.9%-49.3%). CONCLUSION: Everolimus was well tolerated in patients with advanced HCC, and 10 mg/day was defined as the phase 2 dosage. Although the study did not proceed to the second stage of phase 2, preliminary antitumor activity was observed with everolimus in patients with advanced HCC, most of whom had prior systemic treatment. PMID- 21538344 TI - Clinical course of adult patients with ependymoma: results of the Adult Ependymoma Outcomes Project. AB - BACKGROUND: Ependymomas are a rare tumor in adults, and there are limited reports of the clinical course, treatment, and current health status of patients. METHODS: Patients with ependymoma completed an online survey regarding their diagnosis, treatment course, and current health status. Descriptive statistics were used to report the characteristics and degree of symptom severity. Correlations between demographic and clinical characteristics were explored with univariate analysis. RESULTS: One hundred eighteen adults participated, and there were more women (n = 68) than men (n = 50). The median age was 48 years (range, 22-77 years). Fifty-nine participants (48%) reported that they had not been able to work since their diagnosis, and 31% reported receiving disability benefits. Patients who had been treated for spine tumors had symptoms longer than those who had been treated for brain lesions (chi-square statistic, 7.294; P = .026), and the majority had 3 symptoms before diagnosis. Most patients reported undergoing complete resection (brain lesions, 62%; spine tumors, 58%), and patients with spine tumors were less likely to have received additional treatment (chi-square statistic, 9.687; P = .008). The majority had not had a recurrence and reported consulting a neurosurgeon for surveillance. Despite having stable disease and not receiving active treatment, most patients described moderate to severe symptoms, including fatigue (44%), numbness/tingling (39%), pain (36%), and disturbed sleep (34%) overall. Brain lesions were associated with altered vision (25%), difficulty concentrating (25%), weakness (19%), irritability (19%), difficulty speaking (19%), and understanding (17%); and spine lesions were associated with extremity weakness (55%), sexual dysfunction (48%), radiating pain (37%), and change in bowel pattern (35%). CONCLUSIONS: Treatment for adult patients with ependymoma is not standardized. Despite the low recurrence rate, patients reported significant symptoms and disability. PMID- 21538345 TI - Subsets of human CD4(+) regulatory T cells express the peripheral homing receptor CXCR3. AB - Regulatory T cells (Tregs) migrate into peripheral sites of inflammation such as allografts undergoing rejection, where they serve to suppress the immune response. In this study, we find that ~30-40% of human CD25(hi) FOXP3(+) CD4(+) Tregs express the peripheral CXC chemokine receptor 3 (CXCR3) and that this subset has potent immunoregulatory properties. Consistently, we observed that proliferative responses as well as IFN-gamma production were significantly higher using CXCR3-depleted versus undepleted responders in the mixed lymphocyte reaction, as well as following mitogen-dependent activation of T cells. Using microfluidics, we also found that CXCR3 was functional on CXCR3(pos) Tregs, in as much as chemotaxis and directional persistence towards interferon-gamma-inducible protein of 10 kDa (IP-10) was significantly greater for CXCR3(pos) than CXCR3(neg) Tregs. Following activation, CXCR3-expressing CD4(+) Tregs were maintained in vitro in cell culture in the presence of the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and we detected higher numbers of circulating CXCR3(+) FOXP3(+) T cells in adult and pediatric recipients of renal transplants who were treated with mTOR-inhibitor immunosuppressive therapy. Collectively, these results demonstrate that the peripheral homing receptor CXCR3 is expressed on subset(s) of circulating human Tregs and suggest a role for CXCR3 in their recruitment into peripheral sites of inflammation. PMID- 21538346 TI - Generation of a Listeria vaccine strain by enhanced caspase-1 activation. AB - The immunostimulatory properties conferred by vaccine adjuvants require caspase-1 for processing of IL-1beta and IL-18. Caspase-1 is activated in response to a breach of the cytosolic compartment by microbes and the process is initiated by intracellular pattern recognition receptors within inflammasomes. Listeria monocytogenes is detected in the cytosol by the NLRC4, NLRP3 and AIM2 inflammasomes. NLRC4 is activated by flagellin, and L. monocytogenes evades NLRC4 by repressing flagellin expression. We generated an L. monocytogenes strain that was forced to express flagellin in the host cell cytosol. This strain hyperactivated caspase-1 and was preferentially cleared via NLRC4 detection in an IL-1beta/IL-18 independent manner. We also created a strain of L. monocytogenes with forced expression of another NLRC4 agonist, PrgJ, from the Type III secretion system of Salmonella typhimurium. Forced expression of flagellin or PrgJ resulted in attenuation, yet both strains conferred protective immunity in mice against lethal challenge with L. monocytogenes. This work is the first demonstration of specific targeting of the caspase-1 activation pathway to generate a safe and potent L. monocytogenes-based vaccine. Moreover, the attenuated strains with embedded flagellin or PrgJ adjuvants represent attractive vectors for vaccines aimed at eliciting T-cell responses. PMID- 21538347 TI - Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity. AB - In the last two decades, anti-cancer vaccines have yielded disappointing clinical results despite the fact that high numbers of self/tumor-specific T cells can be elicited in immunized patients. Understanding the reasons behind this lack of efficacy is critical in order to design better treatment regimes. Recombinant lentivectors (rLVs) have been successfully used to induce antigen-specific T cells to foreign or mutated tumor antigens. Here, we show that rLV expressing a murine nonmutated self/tumor antigen efficiently primes large numbers of self/tumor-specific CD8(+) T cells. In spite of the large number of tumor specific T cells, however, no anti-tumor activity could be measured in a therapeutic setting, in mice vaccinated with rLV. Accumulating evidence shows that, in the presence of malignancies, inhibition of T-cell activity may predominate overstimulation. Analysis of tumor-infiltrating lymphocytes revealed that specific anti-tumor CD8(+) T cells fail to produce cytokines and express high levels of inhibitory receptors such as programmed death (PD)-1. Association of active immunization with chemotherapy or antibodies that block inhibitory pathways often leads to better anti-tumor effects. We show here that combining rLV vaccination with either cyclophosphamide or PD-1 and PD-L1 blocking antibodies enhances rLV vaccination efficacy and improves anti-tumor immunity. PMID- 21538348 TI - Adiponectin is a negative regulator of antigen-activated T cells. AB - Adiponectin (APN), a cytokine constitutively produced in fat tissue, has been shown to exert anti-inflammatory effects in various disease models. While the influence of APN on monocytic cells has been extensively studied in vitro, little is known about its role in T cells. In this study, we show that while <10% of human peripheral blood T cells express adiponectin receptors (AdipoRs) on their surface, most T cells store AdipoRs in intracellular compartments. AdipoRs colocalized with immune regulatory molecules CTLA-4 and TIRC7 within clathrin coated vesicles. After stimulation, the expression of adiponectin receptor 1 (AdipoR1) and AdipoR2 was upregulated on the surface of antigen-specific T cells, as determined by tetramer or CD137 staining, and AdipoR1 and AdipoR2 coexpressed with CTLA-4. Addition of APN resulted in a significant diminution of antigen specific T-cell expansion. Mechanistically, APN enhanced apoptosis and inhibited proliferation of antigen-specific T-cell lines. Further, APN directly inhibited cytokine production in response to antigen stimulation. In line with the in vitro data, APN-deficient (knockout, KO) mice had higher frequencies of CD137(+) T cells upon Coxsackie B virus infection. Altogether, our data suggest that APN is a novel negative T-cell regulator. In contrast to the CTLA-4 ligand B7 only expressed on APCs, APN is abundant in human plasma. PMID- 21538349 TI - The adjuvant effect of TLR agonists on CD4(+) effector T cells is under the indirect control of regulatory T cells. AB - TLR agonists have been suggested to directly impact Tregs, thereby enhancing or reversing their suppressive function. Here, in order to select TLR agonists leading to potent effector T-cell responses, while minimizing Treg inhibitory function, we used a model antigen, covalently linked to an inert delivery system, combined with a large panel of TLR agonists, for the immunization of mice with an attenuated/depleted or intact Treg subset. We observed that the negative modulation of effector CD4(+) T cells exerted by Tregs cannot be circumvented, whatever the TLR agonist used as adjuvant. To better understand the impact of TLR agonists on Tregs, we investigated (i) the TLR expression profile of highly purified CD4(+) Foxp3(+) Tregs, at steady state or subsequent to in vivo activation by TLR agonists and (ii) the Treg phenotype after in vivo and in vitro activation by TLR agonists. Our results demonstrate that TLR agonists, as single signal inducers, are not able to directly activate Tregs. The phenotypic Treg activation observed in vivo, following TLR administration, does not result from cross-talk with conventional T cells but is rather a consequence of the interaction with other immune cell type(s). PMID- 21538350 TI - Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. AB - Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition and reduced patient survival. As vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data showed that WFA had weak cytotoxic and apoptotic activity at concentrations less than or equal to 500 nM, but retained potent anti-invasive activity at these low doses. Imaging of breast cancer cell lines revealed that WFA induces perinuclear vimentin accumulation followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2 MUM in plasma with a half-life of 1.36 hr following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation. PMID- 21538352 TI - PDZ adaptors: their regulation of epithelial transporters and involvement in human diseases. AB - Homeostasis in the body is at least partially maintained by mechanisms that control membrane permeability, and thereby serve to control the uptake of essential substances (e.g., nutrients) and the efflux of unwanted substances (e.g., xenobiotics and metabolites) in epithelial cells. Various transporters play fundamental roles in such bidirectional transport, but little is known about how they are organized on plasma membranes. Protein-protein interactions may play a key role: several transporters in epithelial cells interact with the so-called adaptor proteins, which are membrane anchored and interact with both transporters and other membranous proteins. Although most of the evidences for transporter adaptor interaction has been obtained in vitro, recent studies suggest that adaptor-mediated transporter regulation does occur in vivo and could be relevant to human diseases. Thus, protein-protein interaction is not only associated with the formation of macromolecular complexes but is also involved in various cellular events, and may provide transporters with additional functionality by forming transporter networks on plasma membranes. Interactions between xenobiotic transporters and PSD95/Dlg/ZO1 (PDZ) adaptors were previously reviewed by Kato and Tsuji (2006. Eur J Pharm Sci 27:487-500); the present review focuses on the latest findings about PDZ adaptors as regulators of transporter networks and their potential role in human diseases. PMID- 21538351 TI - NKG2A is a marker for acquisition of regulatory function by human CD8+ T cells activated with anti-CD3 antibody. AB - Treatment with anti-CD3 mAb modulates immune responses that cause type 1 diabetes and other diseases. CD8+ Tregs can be induced in vitro and in vivo by mAb. However, 1/3 of patients do not respond to drug therapy and in an equal proportion, anti-CD3 mAb does not induce Tregs in vitro. The acquisition of CD8+ Treg activity is a function of the CD8+ cells and not the targets in the assay. To identify markers to differentiate responses of CD8+ Tregs, we analyzed genes differentially expressed in CD8+ T cells of non-responders compared with responders, and found that an inhibitory receptor NKG2A (CD159a) was highly expressed in cells from all non-responders tested. Application of a mAb agonistic to NKG2A during in vitro CD8+ Treg induction by anti-CD3 prevented induction of CD8+ Tregs. CD8+ T cells that are TNFR2+ but NKG2A- are the most potently induced Tregs. The level of NKG2A expression on resting CD8+ T cells inversely correlated with acquisition of regulatory function when activated. We suggest that the induction of human CD8+ Tregs by anti-CD3 mAb is controlled by a negative signaling through NKG2A, and that NKG2A may serve as a negative marker of human CD8+ Tregs. PMID- 21538353 TI - Update on the pharmacokinetics and redox properties of protein-bound uremic toxins. AB - Protein-bound uremic toxins, such as indoxyl sulfate, 3-carboxy-4-methyl-5-propyl 2-furanpropanoic acid, p-cresyl sulfate, hippuric acid, and indoleacetic acid, have been the subjects of extensive investigations. In this review, we summarized the recent works providing the new insight on the pharmacokinetics and redox properties of these uremic toxins. They have a common characteristic of being difficult to remove by conventional dialysis because they all bind tightly to serum albumin. They are transported via organic anion transporters to various tissues, and accumulate not only in the kidney but also in other tissues including vascular endothelial cells, smooth muscle cells, osteoblasts, and the central nervous system. Accumulated uremic toxins alter nonrenal drug clearance. Intracellular accumulated uremic toxins have been linked to the induction of oxidative stress and the stimulation of proinflammatory cytokines through the production of reactive oxygen species, which play a role in the progression of chronic kidney disease and the development of complications. Unfortunately, despite the massive amount of information on the undesirable effects of uremic toxins, methods for improving the detoxification of these toxins appear to be lacking. PMID- 21538354 TI - Functional characterization of rat plasma membrane monoamine transporter in the blood-brain and blood-cerebrospinal fluid barriers. AB - This study investigated the expression and functional roles of rat plasma membrane monoamine transporter (rPMAT) in the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier by using in vitro brain barrier model cells (TR BBB13 and TR-CSFB3 cells) and multiple in vivo experimental techniques. Quantitative reverse transcription-polymerase chain reaction analysis showed relatively high expression of rPMAT mRNA in TR-BBB13 and TR-CSFB3 cells. 1-Methyl 4-phenylpyridinium (MPP(+) ) was transported into rPMAT-expressing cells in a sodium-independent manner. [(3) H]MPP(+) was taken up concentration dependently by TR-BBB13 and TR-CSFB3 cells with K(m) values similar to that of rPMAT expressing cells. [(3) H]MPP(+) transports into these cells were markedly inhibited by serotonin, dopamine, and cationic drugs. rPMAT small interfering RNA (siRNA) significantly suppressed the [(3) H]MPP(+) uptake by TR-BBB13 cells. Intracerebrally injected [(3) H]MPP(+) was eliminated from the brain parenchymal region, whereas brain [(3) H]MPP(+) uptake did not increase with time during in situ brain perfusion, suggesting that the brain-to-blood transport across the BBB predominates over the blood-to-brain transport. Brain microdialysis studies revealed that the elimination across the BBB was significantly decreased by coperfusion of unlabelled MPP(+) , serotonin, or dopamine. [(3) H]MPP(+) was also eliminated from the CSF. These findings suggest that PMAT in brain barriers functions as the brain-to-blood transporter to regulate brain concentrations of organic cations including monoamines and cationic neurotoxins. PMID- 21538355 TI - A comprehensive study demonstrating that p-glycoprotein function is directly affected by changes in pH: implications for intestinal pH and effects on drug absorption. AB - The purpose of this study was to investigate whether changes in the pH of the gastrointestinal tract can directly affect P-glycoprotein (P-gp) function. The effect of changes in extracellular pH on P-gp functionality was examined by testing colchicine (a nonionizable P-gp substrate) in bidirectional Caco-2 and MDR1-Madine Darby canine kidney (MDCK) cell permeability assays, in which the pH of the apical and basolateral chambers was varied. Reduction of the pH from 7.4 to 5.0 and 4.5 markedly increased the apical-to-basolateral flux of colchicine and reduced the basolateral-to-apical flux. The efflux ratio for colchicine was reduced to 1.2 at pH 4.5, compared with values greater than 20 that were measured in the pH range of 5.5-7.4. A similar result was obtained when MDR1-MDCK cells were used in the bidirectional permeability studies. Other nonionizable P-gp substrates (digoxin, dexamethasone, paclitaxel, and etoposide) responded to acidic pH (4.5) in a manner similar to colchicine. Reduced P-gp ATPase activity is a reason for the diminished P-gp function observed at pH 4.5. PMID- 21538356 TI - Long-term survival after esophagectomy for early esophageal squamous cell carcinoma in Linxian, China. AB - BACKGROUND AND OBJECTIVES: Linxian in Henan Province, China, has among the highest rates of esophageal cancer worldwide. Little is known about long-term survival after esophagectomy for early neoplastic lesions found during early detection screening. A long-term survival analysis was performed for 315 patients from Linxian who received esophagectomy for early esophageal squamous cell carcinoma (ESCC). METHODS: Cases that received esophagectomy for early ESCC were age- and gender-matched with two healthy controls, and Kaplan-Meier survival analyses were performed for both groups. RESULTS: Ten-year survival was 77% for cases and 64% for controls, and this difference was not statistically significant (P = 0.33). There were no significant differences in survival based on age or gender (P > 0.05). Cases with ESCC in situ had significantly better survival than cases with invasive ESCC (P = 0.035). CONCLUSIONS: Survival of cases who received esophagectomy for early ESCC was not significantly different from survival of age and gender-matched controls. Early intervention probably improved survival rates for these patients who otherwise would most likely have developed advanced esophageal carcinoma. Early screening and intervention are highly relevant in areas with a high risk of esophageal cancer such as Linxian, China. PMID- 21538357 TI - Prognostic impact of dihydropyrimidine dehydrogenase expression on pancreatic adenocarcinoma patients treated with S-1-based adjuvant chemotherapy after surgical resection. AB - BACKGROUND AND OBJECTIVES: The aim of this study is to investigate the prognostic value of intratumoral expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT) in patients treated with S-1-based chemotherapy after surgical resection for pancreatic adenocarcinoma. METHODS: Intratumoral TS, DPD, and OPRT expression was investigated in 106 patients with resected pancreatic adenocarcinoma by immunohistochemistry. Associations between clinicopathological factors, including intratumoral TS, DPD, and OPRT expression, and survival were evaluated by univariate and multivariate analyses. RESULTS: Of 106 patients, 72 had received S 1-based adjuvant chemotherapy (S-1(+) group), and 34 had not (S-1(-) group). High TS, DPD, and OPRT expression was observed in 64%, 37%, and 66% of patients, respectively. Among S-1(+) group patients, survival was significantly better for patients with low DPD expression than for patients with high DPD expression (P = 0.022). Intratumoral DPD expression was the only independent prognostic factor for patients treated with S-1-based adjuvant chemotherapy by multivariate analysis (P = 0.037). Intratumoral TS and OPRT expression did not appear to influence survival. CONCLUSIONS: Intratumoral DPD expression may be a relevant predictive marker of survival benefit associated with S-1-based adjuvant chemotherapy for pancreatic adenocarcinoma. PMID- 21538358 TI - Type II radical hysterectomy and adjuvant therapy for pelvic lymph node metastasis with stage IB-IIB cervical carcinoma: a retrospective study of 288 patients. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate type II radical hysterectomy with or without adjuvant therapy as a treatment for patients with pelvic lymph node metastasis (PLNM) and stage IB-IIB cervical carcinoma. METHODS: A total of 288 patients with stage IB-IIB cervical carcinoma and confirmed PLNM who underwent a type II radical hysterectomy between 1995 and 2005 were retrospectively evaluated. RESULTS: The 5-year overall survival (OS) rate for this cohort was 65.6%, and independent prognostic factors identified for PLNM patients included a non-squamous cell histological subtype and parametrial involvement. Survival differences between patients that received or did not receive adjuvant treatment were also evaluated, and the 5-year OS and DFS rates for patients who did not receive adjuvant therapy (47 and 41.4%, respectively) were much lower than the rates for patients who did receive adjuvant therapies (67.7 and 59.4%, respectively). However, these differences were not statistically significant (OS, P = 0.057; DFS, P = 0.080). CONCLUSIONS: Type II radical hysterectomy, in combination with adjuvant therapies, is an efficient treatment for PLNM patients with stage IB-IIB cervical cancer. PMID- 21538359 TI - MDR1 (multidrug resistence 1) can regulate GCS (glucosylceramide synthase) in breast cancer cells. AB - BACKGROUND AND OBJECTIVES: Besides MDR1/P-glycoprotein (MDR1/P-gp), glucosylceramide synthase (GCS), an enzyme, which transfers UDP-glucose to ceramide to form glucosylceramide was also related with multidrug resistance (MDR) in breast cancer. Although many research showed that GCS could affect mdr1 in cancer cells, nobody knows that whether mdr1 can affect GCS in breast cancer. Our study aims to verify that. METHODS: A plasmid with multidrug resistence 1(mdr1) cDNA was transfected into the sensitive breast cancer cell line MCF-7, while an RNA interference (RNAi) vector targeted mdr1 was transfected into the MDR cell line MCF-7/ADM. Then RT-PCR, Western blot, MTT, and flow cytometry were used to assess the expression and function of mdr1 and GCS. RESULT: The data displayed that up-regulation of mdr1 could increase the expression of GCS, while the RNAi-expression plasmids could decrease that. Meantime, the changes of ceramide are opposed to that of GCS and are the same to the alteration of apoptosis rate. CONCLUSIONS: Our results demonstrate that MDR1 could increase cellular apoptosis by regulating the expression of GCS in breast cancer cells. PMID- 21538360 TI - Prognostic significance of distribution of lymph node metastasis in advanced mid or low rectal cancer. AB - BACKGROUND: Few studies have focused on distribution of lymph node metastasis. The aim of this study is to evaluate the prognostic significance of the location of involved lymph nodes in patients with advanced mid or low rectal cancer. METHODS: We defined proximal lymph node involvement (PLNp) as superior rectal and inferior mesenteric lymph node metastasis along the trunks of the supplying vessel, and mesorectal lymph node involvement (MLNp) as lymph node metastasis located within the mesorectum. RESULTS: PLNp was identified in 67 patients (8.4%) of total 797 patients. Age <60 years (P=0.02), poorly differentiated/mucinous histologic type (P=0.011), and positive perineural invasion (P<0.001) were risk factors of PLNp in patients with node positive rectal cancer. Patients with PLNp had poorer oncologic outcomes than those without PLNp in terms of overall survival (P<0.001). For patients with node-positive rectal cancer, there was significant difference in the overall survival rate between PLNp and MLNp groups, regardless of N stage (P=0.025 for N1, P=0.009 for N2). CONCLUSIONS: Our results suggest that PLNp is associated with adverse oncologic outcomes and has prognostic significance in patients with node positive mid or low rectal cancer. PMID- 21538361 TI - Less false-negative sentinel node procedures in melanoma patients with experience and proper collaboration. AB - BACKGROUND AND OBJECTIVES: The aims of the study were to determine the percentage of false-negative sentinel node procedures in melanoma patients, to investigate the time cohort of these recurrences, whether a learning phase was involved and to search for causes of the failures. METHODS: Between December 1993 and December 2008, 708 melanoma patients underwent a sentinel node biopsy. The procedure was considered false-negative if a recurrence developed in the basin from which a tumor-free sentinel node had been removed. Of all false-negative cases, the pre operative images, operative report and pathology slides were reviewed. RESULTS: Sentinel node biopsy was positive in 164 (23%) of the patients and false-negative in 10 (1.4%), which results in a false-negative rate of 5.7%. Five of the 10 failures occurred in the first year after the sentinel node biopsy was introduced. Causes for these false-negative procedures could be attributed once to the nuclear medicine physician, once to the surgeon and twice to the pathologist. CONCLUSION: The sentinel node procedure failed to identify involvement in 5.7% of the patients with lymph node metastases. Half of the false negative biopsies took place in the first year after the procedure was introduced, illustrating the existence of a learning period. PMID- 21538362 TI - Treatment of borderline cases for curative resection of biliary tract cancer. AB - BACKGROUND AND AIM: To dissect the high rate of non-curative resection associated with biliary tract cancer, we compared the outcome of non-curative resection with that of inoperable cancer in patients referred for surgery. METHODS: We retrospectively analyzed 447 patients with biliary tract cancer who were referred to our hospital between 1970 and 2008. We compared the background and overall survival (OS) rates accordingly to surgery (curative resection, non-curative resection, or no surgery "inoperable") and alternative therapies (chemotherapy and/or radiotherapy). RESULTS: The 3-year OS rate was 19% for the non-curative resection group (n=72) and 2% for the inoperable group (n=135, P<0.0001). Among the inoperable cases, the 3-year OS rate for patient who received chemotherapy, including gemcitabine (GEM), was 18% (n=18), which was similar to that of patients of the non-curative resection who were treated with GEM (P=0.7379). There were no significant differences in survival between non-curative resection without GEM and inoperable cases with GEM-based chemotherapy. CONCLUSION: Our results indicate that the prognosis of patients who undergo non-curative surgery is better than those with inoperable cancer, but similar to those who receive chemotherapy including GEM. PMID- 21538363 TI - Is genetic signature enough? PMID- 21538364 TI - Volatile flavours in raw egg yolk of hens fed on different diets. AB - BACKGROUND: Recent studies have suggested that the composition of lipophilic components of egg yolk is influenced by the feed. The aim of the present study was to isolate volatile flavours from egg yolk after different feeding trials using solvent extraction and thin layer high-vacuum distillation. The resulting aroma extract was analysed by various gas chromatographic techniques. Chickens were either fed with laying meal, laying meal plus cabbage and onion or laying meal plus rapeseed oil or held in free-range. RESULTS: The predominating odour impressions were described as onion-like. Comparing all analytical and sensory data of the flavour extracts, there were minimal differences among the respective samples. Free-range eggs contained fewer volatile compounds than the other samples, whereas rapeseed oil supplementation caused an enrichment of sulfur compounds. CONCLUSION: While data from gas chromatography/flame ionisation detection, gas chromatography/mass spectrometry and gas chromatography/olfactometry were less conclusive, the results from sulfur specific analysis using gas chromatography/flame photometric detection showed a considerable effect. However, because of the low abundance of sulfur compounds in the yolk, these differences are not expected to be perceivable by the consumer. PMID- 21538365 TI - Are stomatal responses the key to understanding the cost of fungal disease resistance in plants? AB - Preventing disease in cereal crops is important for maintaining productivity and as the availability and efficacy of chemical control becomes reduced the emphasis on breeding for disease resistance increases. However, there is evidence that disease resistance may be physiologically costly to the plant and we ask if understanding stomatal responses to fungal attack is the key to minimising reductions in growth associated with disease resistance. PMID- 21538366 TI - Soil compaction: a review of past and present techniques for investigating effects on root growth. AB - Soil compaction has been known to affect root growth for millennia. Root growth in natural soils is complex and soil compaction induces several stresses which may interact simultaneously, including increased soil strength, decreased aeration and reduced hydraulic conductivity. Yet, moderate soil compaction offers some benefits to growing roots by increasing root-soil contact so they can extract adequate resources. Until now, improving our understanding of the specific responses of roots to below-ground stimuli has been difficult. However, the advent of new technologies and practices, including X-ray computed tomography, to provide non-destructive, three-dimensional images of root systems throughout the plant's lifecycle now allows the responses of roots encountering changes in their physical, chemical or biotic environment to be established directly and non-invasively. Previous destructive methods, such as root washing, were incapable of identifying and characterising fine root architectural characteristics as these are inextricably linked to the composition of the soil matrix. X-ray computed tomography coupled with genetic approaches will provide a more comprehensive appreciation of the effect of soil compaction on root growth, and the knowledge required to generate improvements in plant breeding programmes and crop husbandry. PMID- 21538367 TI - Phase solubility studies and stability of cholesterol/beta-cyclodextrin inclusion complexes. AB - BACKGROUND: Cyclodextrins (CDs) are able to enhance the solubility, stability and bioavailability of several bioactive hydrophobic compounds by complex formation. They can also be used for removal of undesired components (such as cholesterol, off-flavors or bitter components) present in foods. Although many patents account for the use of cyclodextrins for removal of cholesterol from dairy foods, there is no available information on the effect of water on encapsulation efficiency and on the stability of sterols in CDs. The aim of this work was to study the inclusion properties and the factors affecting the encapsulation and stability of cholesterol in beta-cyclodextrin (BCD). The optimum encapsulation conditions (ligand-CD molar ratio, stirring time and temperature), and stability of the complexes as a function of storage time and water content were analyzed. RESULTS: Phase solubility study pointed out the formation of 1:1 stoichiometric complexes between cholesterol and beta-cyclodextrin, which was influenced by temperature variations. The process was shown to be exothermic and energetically favored. The presence of cholesterol greatly modified the BCD water sorption curves, being the amount of adsorbed water smaller in the combined systems. The principal 'driving force' for complex formation is the substitution of the high-enthalpy water molecules by an appropriate hydrophobic ligand. The freeze-dried complexes probed to be stable at different storage conditions. CONCLUSION: The phase solubility and stability data obtained could be essential for selecting the most suitable conditions when CDs are employed either for removing cholesterol or to incorporate functional ingredients (i.e. sitosterol) in the development of innovative food products. PMID- 21538368 TI - Partial dehydration and cryopreservation of Citrus seeds. AB - BACKGROUND: Three categories of seed storage behavior are generally recognized among plant species: orthodox, intermediate and recalcitrant. Intermediate seeds cannot be stored in liquid nitrogen (LN) without a previous partial dehydration process. The water content (WC) of the seeds at the moment of immersion in LN must be regarded as the most critical factor in cryopreservation. The purpose of this study was to investigate the basis of the optimal hydration status for cryopreservation of Citrus seeds: C. sinensis (sweet orange), C. paradisi (grapefruit), C. reticulata (mandarin) in LN. RESULTS: To study the tolerance to dehydration and LN exposure, seeds were desiccated by equilibration at relative humidities between 11 and 95%. Sorption isotherms were determined and modeled; lipid content of the seeds was measured. Seed desiccation sensitivity was quantified by the quantal response model. Differential scanning calorimetry (DSC) thermograms were determined on cotyledon tissue at different moisture contents to measure ice melting enthalpies and unfrozen WC. Samples of total seed lipid extract were also analyzed by DSC to identify lipid transitions in the thermograms. CONCLUSIONS: The limit of hydration for LN Citrus seeds treatment corresponded to the unfrozen WC in the tissue, confirming that seed survival strictly depended on avoidance of intracellular ice formation. PMID- 21538369 TI - Effect of natural biostimulants on yield and nutritional quality: an example of sweet yellow pepper (Capsicum annuum L.) plants. AB - BACKGROUND: Modifications in growing techniques can affect the yield and nutritional quality of various cultivated plant species. Owing to its high nutritional value, pepper (Capsicum annuum L.) was used in this study as a model plant to investigate the effect of natural biostimulants on yield and fruit quality parameters under conditions of reduced fertilisation. RESULTS: A positive influence of biostimulant treatment on yield parameters was observed. The overall increase in the pigment content of leaves after biostimulant application agreed well with the higher total and commercial yields of treated pepper cultivars compared with their controls. The results showed that natural biostimulants had a positive effect on the vitamin C and total phenolic contents in pepper fruits during the hot summer season. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2' azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) antioxidant activities were also significantly higher (P < 0.05) in treated plants and correlated strongly with all measured quality parameters except total phenolic content. CONCLUSION: Generally, biostimulants improved the antioxidant activity, vitamin C and phenolic contents in fruits as well as the pigment content in leaves of treated compared with non-treated pepper plants grown hydroponically. Thus the application of biostimulants could be considered as a good production strategy for obtaining high yields of nutritionally valuable vegetables with lower impact on the environment. PMID- 21538370 TI - Postharvest evaluation of soilless-grown table grape during storage in modified atmosphere. AB - BACKGROUND: Soilless growth systems, developed mainly for vegetables and ornamental crops, have also been used recently as an alternative to soil culture for table grape in order to achieve optimal production performance. In this study, sensory, physical and chemical parameters were analysed in table grapes obtained from soil and soilless growth systems at harvest and during storage in air or modified atmosphere. RESULTS: At harvest, soilless-grown berries were 30% firmer than those grown in soil. Moreover, they showed 60% higher antioxidant activity and total phenol content than soil-grown fruits. Modified atmosphere storage resulted in a better quality of table grapes compared with those stored in air. Furthermore, soilless growth was more suitable than soil growth for preserving visual quality and controlling rachis browning and weight loss. CONCLUSION: Since the soilless system produces berries that are cleaner and of higher quality than those grown in soil, the implementation of soilless growth for the production of health-promoting and convenience fruits is suggested. PMID- 21538371 TI - Ultrasound-assisted generation of ACE-inhibitory peptides from casein hydrolyzed with nanoencapsulated protease. AB - BACKGROUND: Bioactive peptides generated from milk proteins are eminent ingredients for functional foods and nutraceuticals. Amongst several approaches to release these peptides, hydrolysis of milk proteins with proteolytic enzymes is a promising choice. It is, however, required to inactivate the enzyme after a predetermined time, which leads to impurity of the final product. Immobilization of enzyme molecules can overcome this problem as it simplifies enzyme separation from the reaction mixture. A fungal protease from Aspergillus oryzea was encapsulated within nanoparticles yielded via silicification of polyamidoamine dendrimer template generation 0. It was used to hydrolyze the dominant milk protein (casein) in the absence or presence of sonication. The production of angiotensin converting enzyme (ACE)-inhibitory peptides was monitored during hydrolysis. RESULTS: Sonication did not affect maximum ACE-inhibitory activity but shortened the process sixfold. Ultrafiltration permeate of the centrifugal supernatant of casein solution hydrolyzed during sonication inhibited ACE activity as efficiently as the supernatant obtained from it. CONCLUSION: The protease from Aspergillus oryzea encapsulated within nanospheres is suitable for generation of ACE-inhibitory peptides from casein. The nanoncapsulation procedure is simple, rapid and efficient. This may enable the industrial production of functional products from milk. PMID- 21538372 TI - A sensitivity-improved enzyme-linked immunosorbent assay for fenvalerate: a new approach for hapten synthesis and application to tea samples. AB - BACKGROUND: Fenvalerate has been widely used for the control of many common pests, but residues of this pesticide have been found in some agricultural crops. China is a large exporter of tea products; thus monitoring of pesticide residues in tea products has become increasingly important. In this study, a method of competitive direct enzyme-linked immunosorbent assay (CD-ELISA) for the rapid detection of fenvalerate in tea sample was developed. RESULTS: A polyclonal antibody against fenvalerate (FEN) was produced by the hapten with the characteristic moiety of fenvalerate. After acidification, the hapten was synthesized from 2-(4-chloro-phenyl)-3-methyl-butyric acid and aminocaproic acid methyl ester. The CD-ELISA method developed has a high sensitivity of detection: 9 ug L(-1) for IC(50) and 0.5 ug L(-1) for IC(15) . Fenvalerate was treated with 0.5 mmol L(-1) NaOH-methanol solution to improve its solubility by isomerization. In the tea sample, the detection limit of fenvalerate was 0.16 mg L(-1) . A recovery rate of 76.67-91.43% was obtained from spiked tea. The reliability of the CD-ELISA method is better in comparison with the gas chromatographic method (R(2) = 0.9968). CONCLUSION: In this study, a simple and efficient immunoassay method was developed. It is preferable for the rapid determination of fenvalerate residues in tea samples. PMID- 21538373 TI - [ Editorial: Pharmazie in unserer Zeit 3/2011]. PMID- 21538374 TI - Sonographic appearance of a schwannoma mimicking an axillary lymphadenopathy. AB - Schwannomas are benign nerve sheath tumors derived from Schwann cells and are the most common type of peripheral nerve tumor. Schwannomas occur mainly in the extremities, trunk, and head and are rarely manifested in the axilla. Although various solid tumors can develop in the axilla, only a few cases of schwannoma in the axillary cavity have been reported. Herein, we describe the sonographic appearance of a schwannoma arising from the brachial plexus in the axilla. PMID- 21538375 TI - Sonographic diagnosis of gastric duplication cyst communicating with the gastric lumen. AB - Gastric duplication cysts are rare congenital anomalies, which account for about 7% of all enteric duplications. We report the sonographic findings of a rare case of gastric duplication cyst, communicating with the gastric lumen in a 30-year old woman. PMID- 21538376 TI - Prolapsed simple ureterocele: evaluation by transvaginal voiding sono urethrography. AB - Prolapsed ureterocele is a rare complication that may present with acute bladder outlet obstruction, generally in female infants. We present a case of prolapsed simple ureterocele in an adult woman, evaluated by transvaginal micturating sono urethrography. High-frequency transvaginal sonography of the urethra performed during micturation revealed the relationship of the ureterocele with the urethral wall. PMID- 21538377 TI - Prenatal two- and three-dimensional imaging in two cases of severe penoscrotal hypospadias. AB - We present the prenatal two- and three-dimensional (3D) ultrasound (US) findings in two cases of severe penoscrotal hypospadias. 3D sonography was used for better definition of ambiguous genitalia. The images were compared with postnatal clinical features. Despite hypospadias being the most common urogenital anomaly of male neonates, the diagnosis is often missed before birth. Performing prenatal ultrasound should include the study of genitals, not only determining the sex. PMID- 21538378 TI - First-trimester septated cystic hygroma and cavum velum interpositum cyst. AB - First-trimester septated cystic hygroma, frequently noted during general obstetric first-trimester screening, is strongly associated with fetal aneuploidy and structural anomalies and is considered an ominous finding. We present the case of a fetus with a first-trimester septated cystic hygroma and cavum velum interpositum cyst. PMID- 21538379 TI - Neuroanatomy of childhood disruptive behavior disorders. AB - Our aims were to (1) examine possible neuroanatomical abnormalities associated with the Disruptive Behavior Disorders (DBDs) as a group and (2) assess neuroanatomical anomalies specific to each DBD (i.e., conduct disorder [CD] and oppositional defiant disorder). Cortical thickness analysis and voxel-based morphometry were analyzed in 47 8-year-old boys (22 DBDs with and without CD and/or ODD and 25 healthy controls) from Magnetic Resonance Imaging brain scans. DBD symptoms were assessed using the Dominic-R. In DBD subjects relative to controls, we found (1) a decreased overall mean cortical thickness; (2) thinning of the cingulate, prefrontal and insular cortices; and (3) decreased gray matter density (GMd) in the same brain regions. We also found that scores on the Dominic R were negatively correlated with GMd in the prefrontal and precuneus/superior temporal regions. There was a subdiagnostic main effect for CD, related to thinning of the middle/medial frontal, and for ODD in the left rectal/orbitofrontal. Findings suggest that thinning and decreased GMd of the insula disorganizes prefrontal circuits, diminishing the inhibitory influence of the prefrontal cortex on anger, aggression, cruelty, and impulsivity, and increasing a person's likelihood of aggressive behavior. These findings have implications for pathophysiologic models of the DBDs, their diagnostic classification system, and for designing more effective intervention programs. PMID- 21538380 TI - Modifying clopidogrel maintenance doses according to vasodilator-stimulated phosphoprotein phosphorylation index improves clinical outcome in patients with clopidogrel resistance. AB - BACKGROUND: Despite dual antiplatelet therapy, the rate of major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) remains high. Ex vivo tests of clopidogrel resistance can predict MACE after PCI. The purpose of this study is to evaluate the clinical impact of adjusting phosphorylation analysis in patients with clopidogrel resistance undergoing PCI. HYPOTHESIS: We hypothesized that VASP-guided clopidogrel maintenance doses, compared to fixed doses, improved clinical outcome. METHODS: This monocentric, prospective, randomized study was performed on 306 patients undergoing PCI. Patients were randomized to a control group (n = 156) and to a vasodilator stimulated phosphoprotein (VASP)-guided group (n = 150). In the VASP-guided group, patients received adjusted maintenance doses of clopidogrel to obtain platelet reactivity index (PRI) of <50% during 1 year after PCI. The primary endpoint was the rate of MACE. The secondary endpoints were major and minor bleeding. RESULTS: All patients completed the PCI procedure and 298 patients completed follow-up. The control and VASP-guided groups had similar demographic, clinical, and angiographic characteristics. In the VASP-guided group, PRI was significantly decreased (from 72.1% +/- 11.4% to 27.7% +/- 8.4%; P = 0.001) in 128 patients (87.1% of all participants). During the 1-year follow-up, 14 MACEs were recorded in the VASP-guided group and 30 MACEs were recorded in the control group (9.3% vs 20.4%, respectively; P = 0.008). There was no difference in the rate of major and minor bleeding in the VASP-guided group compared with the control group (12.9% vs 16.6%; P = 0.06). CONCLUSIONS: Modifying clopidogrel maintenance doses according to platelet reactivity monitoring decreases the rate of MACE after PCI without increasing bleeding in patients with clopidogrel resistance during 1-year follow-up. PMID- 21538381 TI - Simultaneous drug-eluting and bare-metal stent implantation: long-term clinical outcome and findings of clinically indicated coronary angiography. AB - BACKGROUND: Simultaneous drug-eluting stent (DES) and bare-metal stent (BMS) implantation is occasionally employed in clinical practice, but its long-term clinical and angiographic outcome is not clear. HYPOTHESIS: We aimed to describe the long-term clinical outcome and the findings of clinically indicated coronary angiography in patients subjected to simultaneous DES and BMS implantation ("hybrid stenting"). METHODS: We identified 236 patients (mean age 62.9 +/- 11.4 years, 76.7% men) who had undergone percutaneous coronary intervention with at least 1 DES and 1 BMS. At a median follow-up of 42 months (range, 6-89 months) available in 222 patients, 13 (5.9%) patients died from cardiac causes, 13 (5.9%) experienced nonfatal acute myocardial infarction, and 24 (10.8%) experienced unstable angina. Clinically indicated repeat coronary angiography was performed in 64 patients (28.8%). RESULTS: Thirty-one patients (14%) had target lesion revascularization (TLR). The DES demonstrated lower TLR rates (15.9% vs 36.9%, P = 0.002) and lower late loss (0.44 +/- 0.5 mm vs 0.68 +/- 0.7 mm, P = 0.009) compared with BMS. Use of DES was independently associated with lower risk for binary restenosis (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.19 0.89, P = 0.03) and TLR (HR: 0.26, 95% CI: 0.12-0.54, P<0.001). CONCLUSIONS: Although a hybrid stenting strategy demonstrates a reasonable long-term prognosis even in high-risk patients, DES have a better angiographic outcome compared with BMS under the influence of common patient-related restenosis risk factors. PMID- 21538382 TI - Evaluation of trimetazidine in angina pectoris by echocardiography and radionuclide angiography: a meta-analysis of randomized, controlled trials. AB - BACKGROUND: The objective of this meta-analysis was to evaluate the efficacy of the metabolic agent trimetazidine (TMZ) as monotherapy in the treatment of stable angina pectoris, from echocardiography and radionuclide angiography data. HYPOTHESIS: Treatment with TMZ proved to be as effective as other first-line antianginal agents for coronary patients, and it provided additional efficacy in combination with hemodynamic agents. METHODS: A search of the literature published between 1965 and 2008 was performed on the MEDLINE and EMBASE databases. Only randomized, controlled trials were included in this meta analysis. Patients had to be treated for at least 2 weeks with data on the following 4 parameters at baseline and at the end of the treatment period: left ventricular ejection fraction (LVEF), LV end-diastolic volume (LVEDV), LV end systolic volume (LVESV), and wall motion score index (WMSI). The quality of the trials was assessed by the Jadad score. RESULTS: Eleven clinical studies meeting our criteria were analyzed. Results showed that TMZ significantly improved LVEF, with a mean increase of 6.88% (95% confidence interval [CI]: 5.50-8.25), and significantly reduced LVESV by 11.58 mL (95% CI: 5.79-17.37) and WMSI by 0.23 (95% CI: 0.07-0.38). Changes in LVEDV were variable. In both the long term and the short term, TMZ can improve LV function. The efficacy was unchanged in patients with diabetes mellitus. CONCLUSIONS: This meta-analysis confirmed the efficacy of TMZ monotherapy in improving LV function compared with placebo. PMID- 21538383 TI - Long-term outcomes of sirolimus-eluting stents vs. paclitaxel-eluting stents in unprotected left main coronary artery bifurcation lesions. AB - BACKGROUND: The treatment of unprotected left main coronary artery (uLMCA) bifurcation lesions remains challenging. HYPOTHESIS: We hypothesized that the type of drug-eluting stent would correlate with clinical outcomes for the treatment of uLMCA bifurcation lesions. METHODS: One hundred fifteen patients who underwent stent implantation using a provisional T-stenting technique with sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES) for uLMCA bifurcation lesions were enrolled. A major adverse cardiac event (MACE) was defined as a composite of cardiac death, myocardial infarction, or target lesion revascularization. RESULTS: Ninety-four patients were treated with SES and 21 patients with PES. Baseline characteristics were similar between the 2 groups. Angiographic follow-up was performed in 99 (86%) patients. Late loss in the LMCA to the left anterior descending coronary artery was significantly lower in the SES group than in the PES group (0.28 +/- 0.54 mm vs 1.03 +/- 0.45 mm, P<0.001). One case of stent thrombosis occurred in the SES group. During follow-up with a median of 712 days, the SES group had a lower MACE compared with the PES group (10.6% vs. 28.6%, P = 0.032). Cox proportional hazards models including age, sex, diabetes, acute coronary syndrome, true bifurcation, stenting strategy, and type of drug-eluting stent used (SES vs. PES) demonstrated that stent type was the only predictor of MACE (hazard ratio of PES vs SES: 3.88, 95% confidence interval: 1.29-11.67, P = 0.016). CONCLUSIONS: According to the results of the present study, SES may be associated with more favorable outcomes than PES for stenting of uLMCA bifurcation, which should be further studied by larger trials. PMID- 21538384 TI - Ratio of right to left ventricular ejection: a pilot study using Doppler to detect interventricular dyssynchrony. AB - BACKGROUND: Chronic pulmonary hypertension (cPH) is known to delay maximal right ventricular (RV) deformation, causing mechanical dyssynchrony, which previously has been identified only through the use of myocardial tissue Doppler imaging. However, alterations between RV and left ventricular (LV) ejection should be easily identified during routine echocardiographic examinations. HYPOTHESIS: We hypothesized that assessment of differences in ejection fraction between left and right ventricles would be detected using pulsed Doppler. METHODS: Standard echo and Doppler data were collected from 30 patients without PH (mean age, 53 +/- 7 y; mean pulmonary artery systolic pressure [PASP], 31 +/- 5 mm Hg) and from 40 patients with cPH (mean age, 53 +/- 13 y, P not significant; mean PASP, 82 +/- 24 mm Hg, P<0.00001). Temporal differences in the ejection of both ventricles were measured as the ratio of total duration of RV to LV outflow tract (RVOT and LVOT) pulsed Doppler signals. RESULTS: A ratio (<0.99) of RVOT to LVOT total duration of ejection was found not only to be the best Doppler parameter to identify an abnormal pulmonary artery systolic pressure, with a 90% sensitivity and 100% specificity (area under the curve 0.958, P = 0.0001), but also identified differences in the temporal ejection between the 2 ventricles, or dyssynchrony, as a result of cPH. CONCLUSIONS: The ratio of pulsed Doppler RV to LV total duration of ejection is easily obtainable and appears useful in identifying the presence of interventricular dyssynchrony in cPH patients. A prospective study is now required to determine if this Doppler ratio can identify minute changes in the ejection of both ventricles as a result of changes in disease status or response to PH therapy. PMID- 21538385 TI - Aortic and coronary artery dissection during percutaneous coronary intervention: a case report and review article. AB - Coronary artery dissection is an uncommon but potentially serious complication in percutaneous coronary interventions. We treated a 53-year-old female patient with right coronary spasm, which was misdiagnosed as a coronary lesion. The coronary spasm resolved with nitrate administration, but proximal coronary dissection developed during angiography. It progressed anterograde and led to inferior myocardial infarction and severe hemodynamic instability due to right coronary artery occlusion. Percutaneous intervention failed, and it was determined that coronary dissection progressed retrograde, across the truncus of the aorta. Ascending aortic grafting and coronary bypass surgery were performed. The patient recovered and was discharged after 10 days. Close cardiothoracic observation is mandatory in patient evaluation and management. PMID- 21538386 TI - Assessment of systolic and diastolic function in asymptomatic subjects using ambulatory monitoring with acoustic cardiography. AB - BACKGROUND: Adequately recording diastolic heart sounds and systolic time intervals over longer periods is difficult. Thus, information on the circadian variation of these parameters in an ambulatory population is lacking. Moreover, age-related changes in the prevalence of diastolic heart sounds and measurements of systolic time intervals in an asymptomatic population have not been studied in continuous recordings. HYPOTHESIS: Diastolic heart sounds and systolic time intervals will have age and circadian variations that reflect known changes in cardiac function due to aging and circadian rhythms. METHODS: We studied 128 asymptomatic subjects wearing an ambulatory monitor with acoustic cardiography. The recording spanned a mean duration of 14 hours, including sleep. Data were analyzed for the presence of third (S3) and fourth (S4) heart sounds and for systolic time intervals. RESULTS: In these asymptomatic subjects, S3 was significantly more prevalent in those age <40 years than in those age >40 years, and significantly more pronounced during sleep in the younger group. Also, S4 was significantly more prevalent in those age >40 years and significantly more pronounced during sleep in those age >40 years. In contrast, time intervals reflecting systolic function showed less circadian variation and less worsening with age. CONCLUSIONS: The nocturnal increase of S4 in the elderly reflects diastolic impairment-likely a result of changes in diastolic filling patterns with increasing age. An S3 after the age of 40 is a relatively uncommon finding and therefore should be a specific sign of cardiac disease. Continuous monitoring of diastolic heart sounds and systolic time intervals is possible using acoustic cardiography. PMID- 21538387 TI - Seasonal variation in heart failure hospitalization. AB - BACKGROUND: A seasonal variation has been reported for occurrence of acute cardiovascular events, such as myocardial infarction, sudden death, and rupture/dissection of aortic aneurysms. HYPOTHESIS: The aim of this study was to determine whether a seasonal variation exists for heart failure (HF) hospitalization. METHODS: The study included all cases of HF admissions to Ferrara Hospital between January 2002 and December 2009. The sample was divided into subgroups by gender, age, cardiovascular risk factors, patients' outcome, and order of ICD-9 codes (first diagnosis, accessory diagnosis). On the basis of date of admission, cases have been analyzed for seasonal variation and annual frequency. For seasonal analysis, monthly cases were categorized into four 3 month intervals by seasons. Moreover, monthly admissions have been also adjusted for number of days, and the average number of admissions per month has been used. RESULTS: The database included 15,954 patients with the ICD-9-CM codes of HF (420 429). Hospital admissions for HF were most frequent in winter (28.4%) and least in summer (20.4%). Chronobiological analysis yielded a significant peak in January for total cases and all subgroups considered. No differences were found for subgroups by gender, age, fatal cases, presence of hypertension and diabetes mellitus, patients' outcome, and order of ICD-9 codes (first diagnosis, accessory diagnosis). CONCLUSIONS: A seasonal periodicity for HF hospitalization was demonstrated, with a peak in winter months, independent of gender, age, major cardiovascular risk factor, and patients' outcome. These data could be useful for practitioners to improve causative prevention measures, therapeutic management, and educational strategies. PMID- 21538388 TI - Ranolazine for the treatment of heart failure with preserved ejection fraction: background, aims, and design of the RALI-DHF study. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF), formerly referred to as diastolic heart failure (DHF), accounts for >50% of all HF patients. So far, there has been no specific treatment for impaired left ventricular (LV) relaxation. Data from in vitro and animal studies indicate that ranolazine improves diastolic function by inhibiting the late sodium current. HYPOTHESIS: RAnoLazIne for the Treatment of Diastolic Heart Failure (RALI-DHF) is a prospective, single-center, randomized, double-blind, placebo-controlled proof of-concept study to determine if ranolazine compared with placebo will be more effective in improving diastolic function in patients with HFpEF. METHODS: Twenty patients with HFpEF (EF >= 50% and ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity [E/E'] >15 or N-terminal pro-type brain natriuretic peptide >220 pg/mL) will be randomized to receive ranolazine or placebo in a 1.5:1 ratio during their catheterization if the LV end-diastolic pressure is >=18 mm Hg and the time constant of relaxation (tau) is >=50 ms. Treatment will consist of intravenous infusion of study drug (or placebo) for 24 hours, followed by oral treatment for a total of 14 days. ENDPOINTS: The study will include the following exploratory endpoints: (1) change from baseline to 30 minutes from initiation of intravenous study drug administration during cardiac catheterization hemodynamic parameters at both resting and paced (120 beats per minute) conditions: tau, LV end-diastolic pressure, and dP/dt(min) .; and (2) change from baseline to day 14 in E/E', maximal oxygen consumption, and N-terminal pro-type brain natriuretic peptide. CONCLUSIONS: The RALI-DHF study is designed as a translational study to bridge the gap between basic science and therapeutics and to determine if ranolazine, compared with placebo, will be more effective in improving diastolic function in patients with HFpEF. PMID- 21538389 TI - Drug-eluting stents vs. intracoronary brachytherapy for in-stent restenosis: a meta-analysis. AB - BACKGROUND: It has been reported that drug-eluting stents (DES) were superior to intracoronary brachytherapy (ICBT) in patients with in-stent restenosis (ISR). However, it is unknown whether there might be differences between DES and ICBT in terms of efficacy and safety in large sample size and long-term follow-up. HYPOTHESIS: The aim of this study was to determine whether DES implantation remains favorable in large sample size and long-term follow-up when compared with ICBT among patients with ISR. METHODS: We conducted a search in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials without language restrictions. A meta-analysis of 1942 cases from 12 controlled trials of DES vs ICBT for ISR was performed. RESULTS: Drug-eluting stents were significantly more effective in reducing target-vessel revascularization (TVR) (odds ratio [OR]: 0.44, 95% confidence interval [CI]: 0.23-0.81, P = 0.009) and binary restenosis (OR: 0.34, 95% CI: 0.26-0.46, P<0.00001) compared with ICBT at midterm follow-up. There were no significant differences between DES and ICBT in cardiac death, myocardial infarction (MI), and late stent thrombosis at midterm follow-up. A statistical significance has been found between the 2 groups in TVR (OR: 0.61, 95% CI: 0.43-0.86, P = 0.005) at long-term follow-up. There were no significant differences in cardiac death and MI between the 2 groups at long-term follow-up. CONCLUSIONS: These findings provide evidence that DES is superior to ICBT for the treatment of ISR in TVR and binary restenosis reduction, but not in cardiac death, MI, and late stent thrombosis reduction. (c) 2011 Wiley Periodicals, Inc. Yong-Guang Lu, MD, and Yan-Mei Chen, MD, contributed equally to this work. The authors have no funding, financial relationships, or conflicts of interest to disclose. PMID- 21538390 TI - Insulin resistance, inflammation, and vascular disease in nondiabetic predialysis chronic kidney disease patients. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with high cardiovascular morbidity and mortality, which is not fully explained by traditional risk factors; hence, the interest in nontraditional risk factors such as inflammation and insulin resistance (IR). Though IR is shown in nondiabetic CKD, its association with vascular disease and inflammation in this population is unknown, and is what this study aims to investigate. HYPOTHESIS: IR and inflammation are related to vascular disease in nondiabetic predialysis CKD patients. METHODS: We studied carotid-artery intima-media thickness (IMT) and endothelial function (brachial artery flow mediated dilation [FMD]) in 35 nondiabetic predialysis patients with stage 3-5 CKD and 35 age- and gender-matched controls. Insulin resistance was measured using the homeostasis model assessment for insulin resistance score (HOMA-IR), inflammation by high-sensitivity CRP (hsCRP), and their relationship with FMD and IMT. RESULTS: Patients with CKD showed reduced FMD (3.34 +/- 2.14% vs. 5.27 +/- 1.78%, P<0.001) and increased IMT (0.78 +/- 0.22 mm vs. 0.64 +/- 0.16 mm, P = 0.003) compared with controls. The CKD patients had a higher HOMA-IR (2.20 +/- 1.08 vs. 1.13 +/- 0.64, P<0.001) and hsCRP (3.25 +/- 5.47 mg/L vs. 1.10 +/- 1.85 mg/L [median +/- interquartile range], P = 0.02). In the study population, HOMA-IR was directly related to hsCRP. After adjusting for traditional risk factors, high HOMA-IR and hsCRP were significantly related to decreased FMD (adjusted beta = -0.44, 95% confidence interval [CI]: -1.55 to 0.08, P = 0.003 and adjusted beta = -0.51, 95% CI: -0.51 to -0.15, P = 0.001) and increased IMT (adjusted beta = 0.62, 95% CI: 0.54-1.90, P = 0.001 and adjusted beta = 0.43, 95% CI: 0.08-0.57, P = 0.011), respectively. CONCLUSIONS: Subjects with systemic inflammation were more insulin-resistant, and in nondiabetic predialysis CKD, IR and systemic inflammation were independently associated with endothelial dysfunction and atherosclerosis. PMID- 21538391 TI - Repeat percutaneous balloon mitral valvotomy vs. mitral valve replacement in patients with restenosis after previous balloon mitral valvotomy and unfavorable valve characteristics. AB - BACKGROUND: Symptomatic mitral restenosis develops in up to 21% of patients after percutaneous balloon mitral valvotomy (PBMV), and most of these patients undergo mitral valve replacement (MVR). HYPOTHESIS: Repeating PBMV (re-PBMV) might be an effective and less-invasive treatment for these patients. METHODS: Forty-seven patients with post-PBMV mitral restenosis and unfavorable valve characteristics were assigned either to re-PBMV (25 cases; mean age 40.7 +/- 11 y, 76% female) or MVR (22 cases; mean age 47 +/- 10 y, 69% female) at 51 +/- 33 months after the prior PBMV. The mean follow-up was 41 +/- 32 months and 63 +/- 30 months for the re-PBMV and MVR groups, respectively. RESULTS: The 2 groups were homogenous in preoperative variables such as gender, echocardiographic findings, and valve characteristics. Patients in the MVR group were older, with a higher mean New York Heart Association functional class, mean mitral valve area, mitral regurgitation grade, and right ventricular systolic pressure (P = 0.03), and more commonly were in AF. There were 3 in-hospital deaths (all in the MVR group) and 4 during follow-up (3 in the MVR group and 1 in the re-PBMV group). Ten-year survival was significantly higher in re-PBMV vs MVR (96% vs. 72.7%, P<0.05), but event-free survival was similar (52% vs. 50%, P = 1.0) due to high reintervention in the re-PBMV group (48% vs. 18.1%, P = 0.02). CONCLUSIONS: In a population with predominantly unfavorable characteristics for PBMV, short- and long-term outcomes are both reasonable after re-PBMV with less mortality but requiring more reinterventions compared with MVR. PMID- 21538392 TI - Melphalan-induced supraventricular tachycardia: incidence and risk factors. AB - BACKGROUND: Cardiotoxicity of aggressive chemotherapeutic regimens includes cardiomyopathy and arrhythmias. Although cardiomyopathy is a well-recognized entity, arrhythmias are poorly studied. HYPOTHESIS: Certain chemotherapeutic regimes are associated with supraventricular arrhythmias, particularly atrial fibrillation. METHODS: We retrospectively reviewed the data on patients who received hematopoietic stem cell transplant (bone marrow transplant; BMT) from 1998 to 2005 and developed supraventricular tachycardia (SVT) during the same hospital admission. The Fisher chi2 test and the Student t test were used for comparison of categorical and continuous variables, respectively. RESULTS: During the period of 1998-2005, there were 1221 BMTs, 62 (5.1%) of which were complicated by SVT. Melphalan-based regimens demonstrated a significantly higher rate of SVT than any other chemotherapy. Out of 438 patients who received melphalan, 48 (11%) developed atrial fibrillation (n = 35) or SVT (n = 13) during the same hospital admission, and 390 did not. Patients with SVT were older, had higher baseline creatinine, larger size of the left atrium, and more cardiac comorbidities. Incidence of SVT was associated with greater length of stay (24.9 +/- 8.9 d vs 19.6 +/- 5.8 days, P<0.0001), even after adjustment for comorbidities. CONCLUSIONS: Supraventricular tachycardia, mostly atrial fibrillation, complicates about 5% of chemotherapeutic treatments used with BMT. Melphalan is the most arrhythmogenic agent, and is associated with SVT in 11% of patients. Development of SVT results in about a 4-day increase in the length of hospital stay. PMID- 21538393 TI - Nanostructural investigation of frontalis sling biomaterial surfaces. AB - This study examined the nanostructural surface of three frontalis sling biomaterials: autogenous fascia lata, preserved fascia lata and silicone rod. The morphological characteristics of the sling biomaterial surfaces were examined qualitatively and quantitatively by scanning electron microscopy and atomic force microscopy, respectively. The autogenous fascia lata showed well-arranged nanostructures of parallel fascia collagen fibrils with clear 67 nm axial periodicity, whereas the preserved fascia lata showed tangled nanostructures of damaged collagen fibril bundles. The silicone rod showed a substantial amount of debris with some scratches and the smoothest roughness compared with the other sling biomaterials, followed by preserved fascia lata. Autogenous fascia lata showed the highest surface roughness. The association between the roughness and cell adhesion suggests that the nanostructure of autogenous fascia lata biomaterials is the best for frontalis sling and that of the silicone rod biomaterials is the worst. PMID- 21538394 TI - Ultrastructural investigation of intact orbital implant surfaces using atomic force microscopy. AB - This study examined the surface nanostructures of three orbital implants: nonporous poly(methyl methacrylate) (PMMA), porous aluminum oxide and porous polyethylene. The morphological characteristics of the orbital implants surfaces were observed by atomic force microscopy (AFM). The AFM topography, phase shift and deflection images of the intact implant samples were obtained. The surface of the nonporous PMMA implant showed severe scratches and debris. The surface of the aluminum oxide implant showed a porous structure with varying densities and sizes. The PMMA implant showed nodule nanostructures, 215.56 +/- 52.34 nm in size, and the aluminum oxide implant showed crystal structures, 730.22 +/- 341.02 nm in size. The nonporous PMMA implant showed the lowest roughness compared with other implant biomaterials, followed by the porous aluminum oxide implant. The porous polyethylene implant showed the highest roughness and severe surface irregularities. Overall, the surface roughness of orbital implants might be associated with the rate of complications and cell adhesion. PMID- 21538395 TI - CEC separation of ofloxacin enantiomers using imprinted microparticles prepared in molecular crowding conditions. AB - Molecular crowding is a new concept to obtain molecularly imprinted polymers (MIPs) with greater capacity and selectivity, which could shift the equilibrium of a print molecule reacting with functional monomers in the direction of complex formation side. In this work, molecular crowding agent was first applied to the preparation of MIPs microparticles by precipitation polymerization. A new system of molecular crowding surrounding was developed, composed of polystyrene and tetrahydrofuran, in the presence of the template (S)-ofloxacin. Partial filling capillary electrochromatography (CEC) was utilized to evaluate imprinting effect of the resulting microparticles by chiral separations of ofloxacin. Some important parameters in the preparation, i.e. template to monomer ratio, influence of cross-linking monomers and functional monomer composition on the CEC separation of MIP microparticles were investigated. Baseline separation of ofloxacin (R(s) =1.53) was obtained under optimized conditions and the highest theory plate of the later eluent (S)-ofloxacin was 5400. The textural and morphological parameters for imprinted particles, such as Brunauer-Emmett-Teller surface areas, pore volumes and pore size distributions have also been determined. Compared to the MIP microparticle prepared by conventional precipitation polymerization, the (S)-ofloxacin-imprinted particles formed under molecular crowding conditions showed higher selectivity (alpha=1.09) and separation efficiency (<25 min) in the CEC mode. PMID- 21538396 TI - Cationic poly(amidoamine) dendrimers as additives for capillary electroseparation and detection of proteins. AB - We examine the influence of cationic poly(amidoamine) (PAMAM) dendrimers on capillary electroseparation-UV analysis of proteins. PAMAMs adsorbing to the capillary surface suppressed the wall-adsorption of proteins; meanwhile, PAMAMs added to the buffer exhibited selectivity toward proteins. Presence of 3 x 10-4 g/mL PAMAM generation one (G 1.0) in 30 mM phosphate, at pH 2.6, rendered significant enhancement in separation efficiency; the merged peaks of myoglobin and trypsin inhibitor were separated. Moreover, the protein-dendrimer interactions changed the inherent UV absorbance profiles of proteins. UV-Vis study showed that the absorbance of cytochrome C and transferrin increased at the detection wavelength of 214 nm; their detection sensitivity enhanced by 2.44 and 2.01-folds, respectively, with addition of 5 x 10-4 g/mL PAMAM G 1.0. PMID- 21538397 TI - Thirty years of capillary electrophoresis in food analysis laboratories: potential applications. AB - CE has generated considerable interest in the research community since instruments were introduced by different trading companies in the 1990s. Nowadays, CE is popular due to its simplicity, speed, highly efficient separations and minimal solvent and reagent consumption; it can also be included as a useful technique in the nanotechnology field and it covers a wide range of specific applications in different fields (chemical, pharmaceutical, genetic, clinical, food and environmental). CE has been very well evaluated in research laboratories for several years, and different new approaches to improve sensitivity (one of the main drawbacks of CE) and robustness have been proposed. However, this technique is still not well accepted in routine laboratories for food analysis. Researching in data bases, it is easy to find several electrophoretic methods to determine different groups of analytes and sometimes they are compared in terms of sensitivity, selectivity, precision and applicability with other separation techniques. Although these papers frequently prove the potential of this methodology in spiked samples, it is not common to find a discussion of the well-known complexity of the matrices to extract analytes from the sample and/or to study the interferences in the target analytes. Summarizing, the majority of CE scientific papers focus primarily on the effects upon the separation of the analytes while ignoring their behavior if these analytes are presented in real samples. PMID- 21538398 TI - Experimental study of dielectrophoresis and liquid dielectrophoresis mechanisms for particle capture in a droplet. AB - This work presents a microfluidic system that can transport, concentrate, and capture particles in a controllable droplet. Dielectrophoresis (DEP), a phenomenon in which a force is exerted on a dielectric particle when it is subjected to a non-uniform electric field, is used to manipulate particles. Liquid dielectrophoresis (LDEP), a phenomenon in which a liquid moves toward regions of high electric field strength under a non-uniform electric field, is used to manipulate the fluid. In this study, a mechanism of droplet creation presented in a previous work that uses DEP and LDEP is improved. A driving electrode with a DEP gap is used to prevent beads from getting stuck at the interface between air and liquid, which is actuated with an AC signal of 200 V(pp) at a frequency of 100 kHz. DEP theory is used to calculate the DEP force in the liquid, and LDEP theory is used to analyze the influence of the DEP gap. The increment of the actuation voltage due to the electrode with a DEP gap is calculated. A set of microwell electrodes is used to capture a bead using DEP force, which is actuated with an AC signal of 20 V(pp) at a frequency of 5 MHz. A simulation is carried out to investigate the dimensions of the DEP gap and microwell electrodes. Experiments are performed to demonstrate the creation of a 100-nL droplet and the capture of individual 10-MUm polystyrene latex beads in the droplet. PMID- 21538399 TI - Electrophoretic and zymographic characterization of proteins isolated by various extraction methods from ejaculated and capacitated boar sperms. AB - The presented work focuses on electrophoretic and zymographic characterization of boar sperm proteins isolated by various extraction methods and on comparison of the protein profiles obtained from ejaculated and in vitro capacitated spermatozoa. Sperm proteins of ejaculated and in vitro capacitated boar sperms were isolated with the following agents: 1% v/v Triton X-100, 1% v/v Triton X 114, 2% v/v acetic acid, 1% m/v sodium dodecyl sulphate (SDS), 30 mM N-octyl-beta D-glucopyranoside (OBG), rehydration buffer (RHB) for isoelectric focusing and finally by the freezing-thawing approach. The extracts were characterized in terms of 1-DE, 2-DE protein profiles, 1-DE glycoprotein staining and proteinase and hyaluronidase substrate zymographic profiles. The results have shown quantitative and qualitative differences in 1-DE protein and glycoprotein profiles with respect to the employed isolation approach. These differences were seen even more clearly in 2-DE protein profiles, where it was possible to distinguish the presence/absence, changes in relative abundance and pI/M(r) shifts of various protein spots. Proteinase and hyaluronidase zymograms supported the prediction that various isolation protocols result in various profiles of enzymatically active molecules. PMID- 21538400 TI - Some possibilities of an analysis of complex samples by a mass spectrometry with a sample pretreatment by an offline coupled preparative capillary isotachophoresis. AB - This work deals with an analysis of biologically important compounds in complex matrices using preparative isotachophoresis (pITP) in column coupling configuration as a sample pretreatment technique followed by a direct infusion mass spectrometry with nano-electrospray ionization (DI-nESI-MS). Busereline was chosen as a model analyte, and urine was chosen as an example of complex matrix. In pITP experiments, sodium cation (10 mmol/L concentration) was used as a leading ion and beta-alanine as terminating ion (20 mmol/L concentration). The fractions, obtained by pITP pre-separation with the assistance of the mixture of discrete spacers, were finally analyzed by DI-nESI-MS. It was shown that pITP performed before DI-nESI-MS analysis can significantly simplify complex matrix, and, due to its concentration power, pITP can consequently decrease the concentration limit of detection. The concentration of buserelin in the urine samples analyzed by pITP-DI-nESI-MS was 10 MUg/L (reflecting at a 8.10-9 mol/L concentration) in our work but from the ion intensities obtained in MS as well as MS/MS analyses, it is clear that this concentration level could be several orders of magnitude lower for reliable detection and identification of buserelin in urine analyzed using pITP with DI-nESI-MS detection. PMID- 21538401 TI - An easy preparative gel electrophoretic method for targeted depletion of hemoglobin in erythrocyte cytosolic samples. AB - Hemoglobin (Hb) approximately constitutes 98% of the protein composition of a red blood cell (RBC), thus masking the remaining 2% which has still to be discovered completely due to the difficulty in its analysis. Here, we proposed a large-scale native gel electrophoresis that effectively tackles this limitation through a novel sample preparation strategy able to concentrate low-abundance species by removing Hb by means of electrophoretic instruments. Clear native PAGE was performed in a gel electrophoresis tube where the run was intermittently interrupted and different fractions were recovered in liquid phase into a collection chamber placed at the end of the tube. In this way, fractions containing multi-protein complexes with different molecular weights were collected in the native form by a simple elution. Red fraction containing Hb multi-protein complexes can be excluded from subsequent analyses, or rather be analyzed separately, reducing therefore the dynamic range of erythrocyte cytosolic protein concentrations and increasing the number of protein identifications. In particular, 838 protein spots in total were detected when fractions were analyzed by 2-D IEF-SDS-PAGE. This depletion method is inexpensive, simple to perform, reproducible and makes it possible to process large amounts of sample (up to 150 mg), thus making it suitable for in-depth proteome investigations. Furthermore, this strategy has the potential to be applied both to native and denatured proteomes of different biological samples. PMID- 21538402 TI - Peptide fractionation by acid pH SDS-free electrophoresis. AB - SDS-free polyacrylamide gel electrophoresis is an effective alternative approach to peptide fractionation. Here we describe a discontinuous buffer system at acid pH that improves the separation of acidic peptides from tryptic digestion. MOPS and chloride act as trailing and leading ions, respectively, in this system, while histidine operates as counterion and buffers all solutions. In these electrophoretic conditions, peptides with pI below 5.5 migrate with low overall electrophoretic mobilities but high differences from one another, which allows for their efficient resolution. In silico analysis of several proteomes shows that the acid pH system allows a peptide simplification of 2.5-fold with respect to the total peptide mixture, and still a proteome coverage of about 95% is achievable. A straightforward method with a protocol including proteomic studies was achieved for SDS-PAGE of proteins, enzyme treatment and further peptide fractionation by SDS-free acid PAGE. PMID- 21538403 TI - Electro-osmotic flow in polygonal ducts. AB - The paper presents semi-analytical solutions to electro-osmotic (EO) flow through polygonal ducts under the Debye-Huckel approximation. Analytical series solutions assisted with numerical collocations are found to yield very fast convergence. The solutions have practical applications as the pores of EO membranes are mostly hexagonal, stacked densely in a beehive-like matrix. In addition, we develop simple asymptotic approximations that would be applicable to all EO tube flows of small as well as large dimensionless electrokinetic width. This facilitates investigation of analytical structures of general EO flows in all shapes of tubes, including the present geometries. In particular, for thick electrical double layers, the flow rate of EO is related to the corresponding viscous Poiseuille flow rate, while for thin electrical double layers, the flow rate is shown to be characterized by the cross-sectional area and the perimeter length of the tubes. PMID- 21538404 TI - Electron localization and delocalization indices for solids. AB - The electron localization and delocalization indices obtained by the integration of exchange-correlation part of pair density over chemically meaningful regions of space, e.g., QTAIM atoms are valuable tools for the bonding analysis in molecular systems. However, among periodic systems only few simplest models were analyzed with this approach until now. This contribution reports implementation and evaluation of the localization and delocalization indices on the basis of solid state DFT calculations. A comparison with the results of simple analytical model of Ponec was made. In addition, a small set of compounds with ionic (NaCl), covalent (diamond, graphite), and metallic (Na, Cu) bonding interactions was characterized using this method. Typical features of different types of bonding were discussed using the delocalization indices. PMID- 21538405 TI - Assessment of exposure to intermediate frequency electric fields and contact currents from a plasma ball. AB - While electric fields at intermediate frequencies are not widely utilized for industrial technologies, surprisingly, certain toys emit the highest electric fields found in our living environment. These toys, plasma balls, are devices that use high voltage to create ionized light discharges. In this study, we assessed exposure to electric fields and contact/induced current from a recreational plasma ball device. The electric field strength was measured as a function of distance from the device, and the contact/induced current was measured with a current clamp in different exposure situations with point or grasping contact. The characteristic spectra of the electric field and contact current were measured, and both the multiple frequency rule and weighting of the spectra were applied according to the International Commission on Non-Ionizing Radiation Protection (ICNIRP) 1998 and 2010 guidelines. The results indicate that the recommended reference levels for the general public are exceeded at distances <1.2 m, and that the contact currents in the hand may be twice higher than recommended by the general public guidelines. PMID- 21538406 TI - Phthalate esters modulate the differentiation and maturation of mouse peripheral blood mononuclear cell-derived dendritic cells. AB - Phthalate esters, such as di-(2-ethylhexyl) phthalate (DEHP), are widespread environmental contaminants. Previously, we have observed that DEHP exacerbates dermatitis elicited by mite antigen in NC/Nga mice. Also, DEHP enhances the functions of bone marrow-derived dendritic cells (DCs) in vitro. The present study sought to investigate whether phthalate esters affect peripheral blood mononuclear cell (PBMC)-derived DCs of NC/Nga mice. First, we studied the time course of DC generation from PBMCs and the dose dependency of granulocyte macrophage colony-stimulating factor and interleukin-4, and then determined the conditions under which DC differentiation and maturation are moderately induced from PBMCs. Under the conditions determined above, DEHP at 10 MU m significantly inhibited the expression of DC differentiation and maturation markers, such as CD11c, CD40, CD80, CD86 and CD205, whereas mono-(2-ethylhexyl) phthalate, a metabolite of DEHP, did not. Furthermore, the effects of DEHP on PBMC-derived DCs were partially rescued by treatment with ICI 182,780, an estrogen receptor antagonist. Taken together, these results suggest that DEHP can modulate the differentiation and maturation of mouse PBMC-derived DCs at least partially through activation of the estrogen receptor under our experimental conditions. PMID- 21538407 TI - Effect of fluorescent whitening agent on the transcription of cell damage-related genes in zebrafish embryos. AB - 7-Diethylamino-4-methylcoumarin (DEMC) is a fluorescent whitening agent (FWAs). There have been some studies on DEMC's protective effects against biological activity but there are few papers about the in vivo toxicity of DEMC. In this study, we used wild-type zebrafish embryos 3 days post fertilization (dpf). Test solutions with DEMC concentrations were negative control (without vehicle), 0 (with vehicle, 0.01% v/v ethanol), 0.25, 0.5, 0.75, 1.0, 1.25, 1.5 and 2 ppm. Embryos and larvae were counted for survival rate and hatching rate. Heart rates were also counted at 2.5 and 3.0 dpf. At 3.0 dpf, quantitative RT-PCR was performed with some samples (0, 0.25, 0.75 and 1.25 ppm) to determine the toxic effect to DEMC by detecting the expression levels of toxic-responsive genes. We used 11 genes, which included oxidative stress-related genes [sod(Mn), sod(Cu,Zn) and hsp70], mitochondrial metabolism-related genes (coxI, pyc, cyt and cyclinG1) and apoptosis-related genes (c-jun, bcl2, bax and p53). High-concentration DEMC treated groups showed significant different survival rate, hatching rate and heart rate compared with low-concentration DEMC-treated groups. The LC50 of this chemical, 0.959 ppm, was calculated. We also confirmed that some genes in the DEMC exposure groups showed significantly up-regulations in expression levels compared with control groups. We concluded that the fluorescence agent, DEMC, has possible developmental toxicities and alteration effect of gene expression, which are related to oxidative stress, mitochondrial metabolism and apoptosis in zebrafish embryos. PMID- 21538408 TI - A safety study of a B-class CpG ODN in Sprague-Dawley rats. AB - Oligodeoxynucleotides containing CpG motifs (CpG ODNs) are potent immune activators and are being tested as anti-tumor, antimicrobial agents and as adjuvants in vaccines. Little has been reported, however, about the systematic and comprehensive safety evaluation on repeated CpG ODN administration. To investigate the safety profile of a newly developed CpG ODN, CpG 684, we conducted a 28-day repeated dose toxicity study in rats, at dose levels of 5, 20 and 150 ug CpG 684 per rat. No abnormalities in clinical observations, growth, urinalysis and bone marrow cell counts were found in CpG 684 treated rats. CpG 684 was proved biologically active, capable of up-regulating the expressions of CD40 and CD86 molecules. The monocyte numbers were increased at the dose levels of 20 and 150 ug per rat. The spleen weights were increased in female rats at the dose level of 150 ug per rat. Microscopically, 5, 20 and 150 ug per rat CpG 684 caused local inflammatory cell infiltration and hyperplasia of fibrous tissue at injection sites; the treatment of 5 and 150 ug per rat CpG 684 induced enhanced inflammatory reaction in inguinal lymphoid tissue, and the dose of 150 ug per rat induced cell hyperplasia in white pulp of spleen and white pulp expansion. CpG 684 at 150 ug per rat led to decreases in peripheral lymphocyte, serum globulin, glucose, alkaline phosphatase and K+ levels in female rats, and induced the decrease in serum albumin and total protein in rats of both sexes. The data from this study will provide an important reference for developing CpG 684 as an adjuvant for vaccines of human use. PMID- 21538409 TI - Juvenile rats do not exhibit elevated sensitivity to acrylamide toxicity after oral administration for 12 weeks. AB - Acrylamide (AA), a neurotoxic, testicular toxic, genotoxic and carcinogenic chemical, has been reported to be formed in processed food, and sensitivity to AA intoxication in childhood is a concern. In the present study, to clarify the general toxicological profile of AA in juvenile rats, subchronic toxicity was evaluated in F344 rats administered AA in the drinking water at 0 (control), 10, 20 and 40 ppm, presented to the dams (three per group) immediately after the birth of their litters, through lactation (3 weeks), and directly to the offspring in their drinking water after weaning for a further 9 weeks (12 weeks total). Treatment with AA caused a decrease in body weights in 20 and 40 ppm F(1) females, compared with the controls. Average AA intake throughout the treatment period for the 10, 20 and 40 ppm groups after weaning was equivalent to 1.0, 2.1 and 4.4 mg kg(-1) body weight per day, respectively, in males and 1.2, 2.5 and 4.9 mg kg(-1) body weight per day, respectively, in females. No toxicologically significant organ weight changes were observed. AA-induced histopathological changes were limited to focal degeneration and necrosis of the seminiferous epithelium in the testes and desquamated epithelium in the ducts of epididymides, noted only in 40 ppm males. Taken together with previous reports, juvenile rats are not necessarily more susceptible to AA-induced toxicity as compared with young adults. PMID- 21538410 TI - Protective effect of apocynin on antimycin A-induced cell damage in osteoblastic MC3T3-E1 cells. AB - Apocynin is a naturally occurring methoxy-substituted catechol, experimentally used as an inhibitor of NADPH-oxidase. In the present study, we investigated the protective effects of apocynin on antimycin A (AMA)-induced toxicicy in osteoblastic MC3T3-E1 cells. Exposure of MC3T3-E1 cells to AMA caused significant cell viability loss, as well as mitochondrial membrane potential (MMP) dissipation, complex IV inactivation, ATP loss, intracellular calcium ([Ca2+]i) elevation and oxidative stress. Pretreatment with apocynin prior to AMA exposure significantly reduced AMA-induced cell damage by preventing MMP dissipation, complex IV inactivation, ATP loss, [Ca2+]i elevation and oxidative stress. These results suggest that apocynin has a protective effect against AMA-induced cell damage by its antioxidant effects and the attenuation of mitochondrial dysfunction. Apocynin also induced the activation of PI3K (phosphoinositide 3 kinase), Akt (protein kinase B) and CREB (cAMP-response element-binding protein) inhibited by AMA. All these data indicate that apocynin may reduce or prevent osteoblasts degeneration in osteoporosis or other degenerative disorders. PMID- 21538411 TI - 'The effect of micronutrients on superoxide dismutase in senescent fibroblasts'. AB - The specific activities of zinc/copper (Zn/Cu)-superoxide dismutase (SOD-1) and manganese (Mn)-superoxide dismutase (SOD-2) were assayed in young passage 5 fibroblasts and in serially subcultured cells that were characterized as senescent at passages 15-35. SOD-1 and SOD-2 activities did not significantly change in senescent and young cells cultured in either routine medium [minimum essential medium 1 (MEM1)], or in Zn, Cu and Mn supplemented medium (MEM2) containing normal human plasma levels of the cations. SOD-1 and SOD-2 activities, however, underwent parallel progressive significant activity increases in senescent passage 20 and 25 cells, which peaked in value in passage 30 and 35 cells subcultured in supplemented medium (MEM3) containing triple human plasma levels of the cations. Concurrently, superoxide radical generation rates underwent progressive significant increases in senescent passage 15-25 cells, which peaked in value in passage 30 and 35 cells subcultured in MEM1 or MEM2. These rates, however, were significantly lowered in senescent cells subcultured in MEM3. We infer that it was only possible to significantly stimulate SOD-1 and SOD-2 activities in senescent MEM3 cultured cells enabling them to combat oxidative stress. PMID- 21538412 TI - Genome-wide approaches to the study of adaptive gene expression evolution: systematic studies of evolutionary adaptations involving gene expression will allow many fundamental questions in evolutionary biology to be addressed. AB - The role of gene expression in evolutionary adaptation has been a subject of debate for over 40 years. cis-regulation of transcription has been proposed to be the primary source of morphological novelty in evolution, though this is based on only a handful of examples. Recently the first genome-wide studies of gene expression adaptation have been published, giving us an initial global view of this process. Systematic studies such as these will allow a number of key questions currently facing the field of gene expression evolution to be addressed. PMID- 21538414 TI - Characterization of stem cells and cancer cells on the basis of gene expression profile stability, plasticity, and robustness: dynamical systems theory of gene expressions under cell-cell interaction explains mutational robustness of differentiated cells and suggests how cancer cells emerge. AB - Here I present and discuss a model that, among other things, appears able to describe the dynamics of cancer cell origin from the perspective of stable and unstable gene expression profiles. In identifying such aberrant gene expression profiles as lying outside the normal stable states attracted through development and normal cell differentiation, the hypothesis explains why cancer cells accumulate mutations, to which they are not robust, and why these mutations create a new stable state far from the normal gene expression profile space. Such cells are in strong contrast with normal cell types that appeared as an attractor state in the gene expression dynamical system under cell-cell interaction and achieved robustness to noise through evolution, which in turn also conferred robustness to mutation. In complex gene regulation networks, other aberrant cellular states lacking such high robustness are expected to remain, which would correspond to cancer cells. PMID- 21538413 TI - Pairing phosphoinositides with calcium ions in endolysosomal dynamics: phosphoinositides control the direction and specificity of membrane trafficking by regulating the activity of calcium channels in the endolysosomes. AB - The direction and specificity of endolysosomal membrane trafficking is tightly regulated by various cytosolic and membrane-bound factors, including soluble NSF attachment protein receptors (SNAREs), Rab GTPases, and phosphoinositides. Another trafficking regulatory factor is juxta-organellar Ca(2+) , which is hypothesized to be released from the lumen of endolysosomes and to be present at higher concentrations near fusion/fission sites. The recent identification and characterization of several Ca(2+) channel proteins from endolysosomal membranes has provided a unique opportunity to examine the roles of Ca(2+) and Ca(2+) channels in the membrane trafficking of endolysosomes. SNAREs, Rab GTPases, and phosphoinositides have been reported to regulate plasma membrane ion channels, thereby suggesting that these trafficking regulators may also modulate endolysosomal dynamics by controlling Ca(2+) flux across endolysosomal membranes. In this paper, we discuss the roles of phosphoinositides, Ca(2+) , and potential interactions between endolysosomal Ca(2+) channels and phosphoinositides in endolysosomal dynamics. PMID- 21538415 TI - In scientific publishing at the article level, effort matters more than journal impact factors: hard work and co-authors overshadow journal venue in acquiring citations. PMID- 21538416 TI - Comment on "Does constructive neutral evolution play an important role in the origin of cellular complexity?" DOI 10.1002/bies.201100010. PMID- 21538417 TI - Evaluation of polysaccharide-based chiral stationary phases in quality control of (S)-mirtazapine. AB - High-performance liquid chromatographic methods were developed for separation of the enantiomers of mirtazapine and its four process-related substances. The direct separations were achieved on chiral stationary phases containing amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD-H), cellulose tris(3,5 dimethylphenylcarbamate) (Chiralcel OD-H) and cellulose tris(4-methylbenzoate) (Chiralcel OJ-H ). The experimental data were utilized to discuss the effects of the mobile phase composition, the nature of the alcoholic modifier and the specific structural features of the analytes on retention and separation. The elution sequence was determined under the optimized separation conditions. PMID- 21538418 TI - Evaluation of microwave-assisted extraction for aristolochic acid from Aristolochiae Fructus by chromatographic analysis coupled with nephrotoxicity studies. AB - In this paper, a microwave-assisted extraction (MAE) method was established for aristolochic acid-I from Aristolochiae Fructus, and the advantage of MAE was evaluated by chromatographic analysis coupled with nephrotoxicity studies. The experimental parameters of MAE for aristolochic acid-I in Aristolochiae Fructus were investigated and MAE was compared with Soxhlet extraction and ultrasound assisted extraction in terms of extraction yields and extraction conditions. Under the optimum conditions, MAE could provide higher extraction yields of aristolochic acid-I (1.10 mg/g) than ultrasound-assisted extraction (0.82 mg/g) and Soxhlet extraction (0.95 mg/g), in addition to using less solvent and having a shorter extraction time. Furthermore, the nephrotoxicities of the extracts of Aristolochiae Fructus from different extraction procedures were investigated in Sprague-Dawley rats. The results of nephrotoxicity studies of, for example, general conditions, biochemistry parameters and histopathology examination showed no significantly differences in the nephrotoxicity levels of the extracts from MAE and that from Soxhlet extraction. These results indicated that MAE technique is a simple, rapid and effective extraction method, and the microwave irradiation during MAE procedure did not have any influence on the nephrotoxicity of Aristolochiae Fructus compared with Soxhlet extraction. PMID- 21538420 TI - HDAC inhibitor MS-275 attenuates the inflammatory reaction in rat experimental autoimmune prostatitis. AB - BACKGROUND: Experimental autoimmune prostatitis (EAP) is an autoimmune inflammatory disease of male sex accessory glands and is characterized by a cellular and humoral prostate-specific autoimmune response. EAP shares important clinical and immunological features with human chronic prostatitis and chronic pelvic pain syndrome. MS-275, a potent histone deacetylase inhibitor, has promising anti-inflammatory activities and might be a new agent in the therapy of prostate inflammation. METHODS: EAP rats were treated with MS-275 (5 mg/kg, i.p.) once daily. Using immunohistochemistry and PCR assay, we determined immune cellular responses and infiltration into the prostate glands, and changes of mRNA levels of representative inflammatory molecules in prostate tissue. Changes in Foxp3(+) CD4(+) cell populations of lymph nodes and peripheral blood were analyzed by flow cytometry. Additionally, direct anti-inflammatory effects of MS 275 were investigated in vitro with a macrophage cell line. RESULTS: MS-275 treatment significantly reduced the local accumulation of immune cells and mRNA levels of representative pro-inflammatory molecules in prostate tissue. Furthermore, MS-275 treatment increased percentage of Foxp3(+) CD4(+) Treg cells in lymph nodes and their proportion to CD4(+) cells in peripheral blood, and induced a relative increase of ED2(+) macrophage numbers in EAP prostate. Additional in vitro study showed that MS-275 induced a switch of macrophages from classic M1 to anti-inflammatory M2 phenotype. CONCLUSIONS: In summary, our data demonstrated that MS-275 could effectively suppress inflammatory reaction in EAP, through suppressing immune cells and pro-inflammatory molecules, and inducing anti-inflammatory immune cells and molecules, which may suggest MS-275 as a potential candidate for treatment of inflammatory prostatitis. PMID- 21538419 TI - Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion. AB - BACKGROUND: Signal transducer and activator of transcription 3 (Stat3) is an oncogenic transcriptional factor that plays a critical role in carcinogenesis and cancer progression and is a potential therapeutic target. Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified previously as a novel inhibitor of survivin that selectively kills prostate cancer cells over "normal" prostate epithelial cells. METHODS: DU145, C4 2B, and LNCaP cells were treated with sanguinarine. The phosphorylation status of Stat3 and related proteins were measured with Western blots. Activation of transcription by Stat3 was measured with luciferase reporter assay. The effect of sanguinarine on anchorage-independent growth was examined with soft agar assay, and on cell migration and invasion of DU145 cells were measured with scratch assay and invasion assay, respectively. RESULTS: In this study, we identified sanguinarine as a potent inhibitor of Stat3 activation which was able to suppress prostate cancer growth, migration, and invasion. Sanguinarine inhibits constitutive as well as IL6-induced phosphorylation of Stat3 at both Tyr705 and Ser727 in prostate cancer cells. The inhibition of Stat3 phosphorylation by sanguinarine correlates with reduction of Janus-activated Kinase 2 (Jak2) and Src phosphorylation. Sanguinarine downregulates the expression of Stat3-mediated genes such as c-myc and survivin and inhibits the Stat3 responsive element luciferase reporter activity. Sanguinarine inhibits the anchorage-independent growth of DU145 and LN-S17 cells expressing constitutively activated Stat3. Migration and invasion abilities of DU145 cells were also inhibited by sanguinarine in a manner similar to the dominant negative form of Stat3. CONCLUSIONS: These data demonstrate that sanguinarine is a potent Stat3 inhibitor and it could be developed as a therapeutic agent for prostate cancer with constitutive activation of Stat3. PMID- 21538421 TI - TP53INP1 overexpression in prostate cancer correlates with poor prognostic factors and is predictive of biological cancer relapse. AB - BACKGROUND: Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a proapoptotic protein involved in cell stress response. Whereas there is an overexpression of TP53INP1 in numerous tissues submitted to stress agents, TP53INP1 is down-expressed in stomach, pancreatic, and inflammation-mediated colic carcinomas. In medullary thyroid carcinomas, TP53INP1 overexpression correlates with poor prognosis. TP53INP1 expression has never been reported in Prostate Cancer (PC). Our aim was to investigate variations of TP53INP1 expression and their correlation to clinicopathological parameters in PC. METHODS: Quantitative measurements of immunohistochemical expression of TP53INP1 using high-throughput densitometry, assessed on digitized microscopic tissue micro-array images, were correlated with clinicopathological parameters in 91 human PC. Treatment of LNCaP tumor cells in vitro with cytokines and with TP53INP1 antisense oligonucleotide (ASO) was also analyzed. RESULTS: In normal prostate tissues, TP53INP1 is only expressed in prostate basal cells. There is a de novo TP53INP1 expression in prostate luminal cells in inflammatory prostate tissues, high grade PIN lesions and in PC. Stimulation of LNCaP cells with inflammatory cytokines enhances the level of TP53INP1 mRNA. In PC, TP53INP1 overexpression correlates with high Gleason grade, unfavorable D'Amico score and lymph node invasion, and is an independent factor of biological cancer relapse. Moreover, treatment of LNCaP cells with a TP53INP1 ASO down-regulates TP53INP1 protein level, inhibits proliferation, and induces apoptosis. CONCLUSION: TP53INP1 overexpression in PC seems to be a worse prognostic factor, particularly predictive of biological cancer relapse. Results in vitro suggest that TP53INP1 could be considered as a relevant target for potential specific therapy. PMID- 21538422 TI - Imaging prostate cancer lymph node metastases with a multimodality contrast agent. AB - BACKGROUND: Methods to detect lymph node (LN) metastases in prostate cancer (PCa) are limited. Pelvic LN dissection is commonly performed during prostatectomy, but often followed by morbid complications. More refined methods for detecting LN invasion are needed. METHODS: We developed a dual-labeled targeting agent having a near-infrared (NIR) fluorophore for intraoperative guidance, and a conventional radiotracer for detection of LN metastasis. Nu/Nu mice were orthotopically implanted with DsRed-expressing human PCa (PC3) cells. Antibody (Ab) specific for epithelial cell adhesion molecule was conjugated to DOTA, IRDye 800CW, and radiolabeled with (64) Cu. Dual-labeled Ab was administered intravenously at 10 12 weeks post-implantation, and positron emission tomography/computed tomography (PET/CT) and fluorescence imaging were performed within 18-24 hr. RESULTS: Metastasis to lumbar LNs was detected by DsRed fluorescence imaging, as well as pathology, in 75% of mice having pathology-confirmed primary prostate tumors. These metastases were also detected by NIR fluorescence imaging. In some cases, metastases to sciatic, medial, renal, and axillary nodes were also detected. For all LNs examined, no significant differences were found between the percentages of metastases detected by NIR imaging (63%) and uPET/CT (64%) (P = 0.93), or between those detected by DsRed imaging (25%) and pathological examination (19%) (P = 0.12). CONCLUSION: This study demonstrates that a multimodality contrast agent is useful for early detection of metastatic disease, and has applications for intraoperative PCa treatment. Further agent optimization is necessary to enhance specificity, and provide validation for prostate and other LN metastasizing epithelial cancers. PMID- 21538423 TI - Early onset prostate cancer has a significant genetic component. AB - BACKGROUND: Prostate cancer (PCa) affects more than 190,000 men each year with ~10% of men diagnosed at <=55 years, that is, early onset (EO) PCa. Based on historical findings for other cancers, EO PCa likely reflects a stronger underlying genetic etiology. METHODS: We evaluated the association between EO PCa and previously identified single nucleotide polymorphisms (SNPs) in 754 Caucasian cases from the Michigan Prostate Cancer Genetics Project (mean 49.8 years at diagnosis), 2,713 Caucasian controls from Illumina's iControlDB database and 1,163 PCa cases diagnosed at >55 years from the Cancer Genetic Markers of Susceptibility Study (CGEMS). RESULTS: Significant associations existed for 13 of 14 SNPs (rs9364554 on 6q25, rs10486567 on 7p15, rs6465657 on 7q21, rs6983267 on 8q24, rs1447295 on 8q24, rs1571801 on 9q33, rs10993994 on 10q11, rs4962416 on 10q26, rs7931342 on 11q13, rs4430796 on 17q12, rs1859962 on 17q24.3, rs2735839 on 19q13, and rs5945619 on Xp11.22, but not rs2660753 on 3p12). EO PCa cases had a significantly greater cumulative number of risk alleles (mean 12.4) than iControlDB controls (mean 11.2; P = 2.1 * 10(-33)) or CGEMS cases (mean 11.9; P = 1.7 * 10(-5)). Notably, EO PCa cases had a higher frequency of the risk allele than CGEMS cases at 11 of 13 associated SNPs, with significant differences for five SNPs. EO PCa cases diagnosed at <50 (mean 12.8) also had significantly more risk alleles than those diagnosed at 50-55 years (mean 12.1; P = 0.0003). CONCLUSIONS: These results demonstrate the potential for identifying PCa associated genetic variants by focusing on the subgroup of men diagnosed with EO disease. PMID- 21538424 TI - Comparison of incidentally detected prostate cancer with screen-detected prostate cancer treated by prostatectomy. AB - BACKGROUND: The prostate may often harbor a prostate cancer (PC) which will not cause morbidity if left untreated. Screening for PC leads to increased detection of these insignificant cancers. Objective of this study is to compare PC detected by PSA screening at subsequent screening rounds and treated by radical prostatectomy (RP) with PC incidentally found in cystoprostatectomy specimens. METHODS: Radical prostatectomy specimens of 617 screen-detected PC were compared with 123 PC identified in cystoprostatectomy specimens. Surgical specimens were systematically examined and stage, grade, tumor volume were recorded. Next, we classified PC as clinically significant or insignificant (i.e., tumor volume <0.5 cm(3), absence of Gleason pattern 4/5, organ confined). Pathological features of incidentally detected PC were compared with PC detected in subsequent screening rounds and with screen-detected T1c PC. RESULTS: Screen-detected PC overall were more often multifocal, larger in volume, more advanced in tumor stage and of higher grade, while the frequency of insignificant PC was lower as compared to those in cystoprostatectomy specimens. This effect became more pronounced during subsequent screening rounds. Screen-detected T1c PC were also more often multifocal (73% vs. 37%) in average fivefold larger (0.85 cm(3) vs. 0.16 cm(3)), less often organ confined (81% vs. 94%), and less frequently clinically insignificant (33% vs. 81%). CONCLUSIONS: Screen-detected (T1c) PC treated with RP shows more aggressive features than incidentally found PC. This PSA screening related selection seems to be mainly driven by tumor volume and-in later screening rounds-by the preferential treatment by prostatectomy of more aggressive PC. PMID- 21538425 TI - Alternol exerts prostate-selective antitumor effects through modulations of the AMPK signaling pathway. AB - BACKGROUND: Alternol is an original compound purified from the fermentation products of Alternaria alternata var. monosporus, a microorganism from the bark of the yew tree. It has been reported that Alternol can inhibit proliferation of mouse leukemia cells and human gastric carcinoma cells, the aim of this study was to investigate the effects of Alternol on prostate cancer cells in comparison to prostate cells. METHODS: The MTT assay was utilized to assess cell viability. Cell cycle was analyzed by flow cytometry with propidium iodide staining. Protein expression levels were examined by Western blotting. RESULTS: Alternol treatment resulted in a significant decrease in the viability of prostate cancer cells but had lesser effects on prostate cells. Alternol inhibited AMP-activated protein kinase (AMPK) phosphorylation in prostate cancer C4-2 cells but stimulated AMPK phosphorylation in prostate RWPE-1 cells. Inhibition of p27 phosphorylation was observed in C4-2 cells whereas a promotion of p27 phosphorylation was seen in RWPE-1 cells. Alternol treatment resulted in a profound increase in the LC3II/LC3I protein ratio in RWPE-1 cells but not in C4-2 cells. A dose-dependent down-regulation of Bcl-2 protein was detected in C4-2 cells but not in RWPE-1 cells. Pretreatment of cells with Compound C (AMPK inhibitor) before Alternol treatment abolished the selective antitumor effect of Alternol. CONCLUSIONS: These results reveal for the first time that Alternol exerts a selective antitumor effect on prostate cancer cells when compared with RWPE-1 prostate epithelial cells. In addition, the AMPK signaling pathway is responsible for the selective antitumor effects of Alternol. PMID- 21538426 TI - Characteristics of baseline PSA and PSA velocity in young men without prostate cancer: Racial differences. AB - BACKGROUND: Baseline prostate specific antigen (PSA) and PSA velocity used to stratify subsequent prostate cancer risk in young men may not directly applicable to all populations. We sought to compare the baseline PSA and PSA velocity among ethnic groups. PATIENTS AND METHODS: Chinese, African-American (AA), and Caucasian-American (CA) men aged <=50 years old without prostate cancer were used to identify baseline PSA and PSA velocity. The differences of baseline PSA and PSA velocity between races were assessed. The important cutoffs of baseline PSA and PSA velocity were used to stratify patients among races. RESULTS: Four thousand two hundred six Chinese, 997 AA, and 2,030 CA were included. The rates of baseline PSA of >=1.0, >=2.5, and >=4.0 ng/ml was 24.4%, 4.2%, and 2.1% in Chinese, 30.7%, 5.2%, and 1.8% in AA, 29.7%, 5.3%, and 2.8% in CA, respectively. The rates of PSA velocity of >=0.35, >=0.75, and >=1.0 ng/ml/year was 6.0%, 3.1%, and 2.6% in Chinese, 5.3%, 2.3%, and 1.7% in AA, 5.4%, 3.5%, and 3.3% in CA, respectively. Chinese had a lower baseline PSA and higher PSA velocity as compared to AA and CA. Baseline PSA and PSA velocity in AA had no statistical differences as compared to CA. CONCLUSIONS: The distributions of baseline PSA and PSA velocity in young men among Chinese, AA, and CA races are different. These characteristics shall be taken into account when using these variables to stratify risk of prostate cancer in young men. PMID- 21538427 TI - Risk-adjusted incidence rates for prostate cancer in the United States. AB - BACKGROUND: Risk-adjusted incidence rates (RAIRs) are population-based cancer incidence rates that reflect those who have never had the cancer but are at risk of developing it. This study compares RAIRS with conventionally reported incidence rates for prostate cancer. METHODS: A retrospective cohort design was used, based on data from the Surveillance, Epidemiology, and End Results (SEER) registries, with focus on white and black malignant prostate cancer cases in the years 2000-2007. RAIRs use only the first primary cancer and adjust for cancer prevalence in order to obtain a better population-based measure of cancer risk. RESULTS: Conventionally reported prostate cancer incidence rates underestimate risk for white males by from 0.1% in the age group 40-49 to 20.1% in the age group 80 years and older. In black males, conventional rates underestimate risk by 0.2% in the age group 30-39 to 26.4% in the age group 80 years and older. Trends in RAIRs from 2000 to 2007 increased in the age group 30-49 (17.0% for whites and 14.8% for blacks), decreased in the age group 50-69 (-4.5% for whites and -5.9% for blacks), and decreased in the age group 70 and older (-15.8% for whites and -26.5% for blacks). Trends in RAIRs were similar or less pronounced than trends in conventional rates. The estimated number of cases in the United States in 2007 based on RAIRS was 9.0% greater for whites and 11.3% greater for blacks than when based on conventional rates. CONCLUSION: Prostate cancer incidence rates that include second and later prostate cancer primaries and adjust for prevalence better reflect cancer burden, whereas, prostate cancer incidence rates that only include the first diagnosed case and adjust for prevalence better reflect cancer risk. PMID- 21538428 TI - Lymphatic spread of nodal metastases in high-risk prostate cancer: The ascending pathway from the pelvis to the retroperitoneum. AB - BACKGROUND: The aim of this study was to map the nodal metastases distribution in patients with high-risk prostate cancer (PCa) treated with extended pelvic lymph node dissection (ePLND) and retroperitoneal lymph node dissection (rLND) at the time of radical prostatectomy (RP). MATERIALS AND METHODS: This prospective mapping study included 19 patients with high-risk PCa (sharing at least two out of the three following parameters: PSA >20 ng/ml, cT3, biopsy Gleason score >=8). All patients were treated with RP, ePLND (removal of the obturator, hypogastric, external iliac, presacral, and common iliac lymph nodes) and rLND (removal of para-aortal/para-caval and inter-aorto-caval lymph nodes) by a single surgeon. All patients signed an informed consent highlighting the absence of clinical data supporting the benefit of this surgical approach. RESULTS: Overall, 18 out of 19 patients (94.7%) had pelvic lymph node invasion. The most commonly affected pelvic nodal landing site was obturator (88.8%), followed by external iliac (83.3%), common iliac (77%), hypogastric (44.4%), and presacral (33.3%). Moreover, 14 (77.8%) patients also had involvement of retroperitoneal lymph nodes. Only patients with positive common iliac lymph nodes having at least five positive lower pelvic lymph nodes (n = 14), also had invariably positive retroperitoneal lymph nodes. No patients with negative common iliac lymph nodes had positive retroperitoneal lymph nodes. CONCLUSIONS: PCa lymphatic spread ascends from the pelvis up to the retroperitoneum invariably through common iliac lymph nodes. PCa lymphatic spread can be divided in two main levels: pelvic and common iliac plus retroperitoneal lymph nodes. PMID- 21538429 TI - Comment on a systematic review of randomized trials of peginterferon alpha-2a versus peginterferon alpha-2b in chronic hepatitis C. PMID- 21538430 TI - Dietary supplementation with methyl donor groups could prevent nonalcoholic fatty liver. PMID- 21538431 TI - Inflammation does not always kill hepatocytes during liver damage. PMID- 21538432 TI - Neutralization of lipopolysaccharide effects in liver diseases, the quest for the Holy Grail. PMID- 21538433 TI - Electrostatic modifications of the human leukocyte antigen DR P9 peptide-binding pocket in primary sclerosing cholangitis: back to the future with human leukocyte antigen DRbeta. PMID- 21538434 TI - Hepatitis C virus-infected women have a higher risk of advanced fibrosis and graft loss after liver transplantation than men. AB - In natural history studies of hepatitis C virus (HCV) infection, women have a lower risk of disease progression to cirrhosis. Whether female sex influences outcomes of HCV in the posttransplantation setting is unknown. All patients transplanted for HCV-related liver disease from 2002-2007 at five United States transplantation centers were included. The primary outcome was development of advanced disease, defined as biopsy-proven bridging fibrosis or cirrhosis. Secondary outcomes included death, graft loss, and graft loss with advanced recurrent disease. A total of 1,264 patients were followed for a median of 3 years (interquartile range, 1.8-4.7), 304 (24%) of whom were women. The cumulative rate of advanced disease at 3 years was 38% for women and 33% for men (P=0.31), but after adjustment for recipient age, donor age, donor anti-HCV positivity, posttransplantation HCV treatment, cytomegalovirus infection and center, female sex was an independent predictor of advanced recurrent disease (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.02-1.70; P=0.04). Among women, older donor age and treated acute rejection were the primary predictors of advanced disease. The unadjusted cumulative 3-year rates of patient and graft survival were numerically lower in women (75% and 74%, respectively) than men (80% and 78%, respectively), and in multivariable analyses, female sex was an independent predictor for death (HR, 1.30; 95% CI, 1.01-1.67; P=0.04) and graft loss (HR, 1.31; 95% CI, 1.02-1.67; P=0.03). CONCLUSION: Female sex represents an underrecognized risk factor for advanced recurrent HCV disease and graft loss. Further studies are needed to determine whether modification of donor factors, immunosuppression, and posttransplantation therapeutics can equalize HCV-specific outcomes in women and men. PMID- 21538435 TI - The ethics of placebo treatment for patients with acute exacerbation of chronic hepatitis B. PMID- 21538436 TI - Hepatic organic anion transporting polypeptide transporter and thyroid hormone receptor interplay determines cholesterol and glucose homeostasis. AB - The role of organic anion transporting polypeptides (OATPs), particularly the members of OATP1B subfamily, in hepatocellular handling of endogenous and exogenous compounds is an important and emerging area of research. Using a mouse model lacking Slco1b2, the murine ortholog of the OATP1B subfamily, we have demonstrated previously that genetic ablation causes reduced hepatic clearance capacity for substrates. In this study, we focused on the physiological function of the hepatic OATP1B transporters. First, we studied the influence of the Oatp1b2 deletion on bile acid (BA) metabolism, showing that lack of the transporter results in a significantly reduced expression of Cyp7a1, the key enzyme of BA synthesis, resulting in elevated cholesterol levels after high dietary fat challenge. Furthermore, Slco1b2-/- mice exhibited delayed clearance after oral glucose challenge resulting from reduced hepatic glucose uptake. In addition to increased hepatic glycogen content, Slco1b2-/- mice exhibited reduced glucose output after pyruvate challenge. This is in accordance with reduced hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK) in knockout mice. We show that this phenotype is due to the loss of liver-specific Oatp1b2-mediated hepatocellular thyroid hormone entry, which then leads to reduced transcriptional activation of target genes of hepatic thyroid hormone receptor (TR), including Cyp7a1 and Pepck but also Dio1 and Glut2. Importantly, we assessed human relevance using a cohort of archived human livers in which OATP1B1 expression was noted to be highly associated with TR target genes, especially for glucose facilitating transporter 2 (GLUT2). Furthermore, GLUT2 expression was significantly decreased in livers harboring a common genetic polymorphism in SLCO1B1. CONCLUSION: Our findings reveal that OATP1B-mediated hepatic thyroid hormone entry is a key determinant of cholesterol and glucose homeostasis. PMID- 21538438 TI - Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: a vicious circle of clinical significance? AB - Insulin resistance (IR) is common in chronic hepatitis C (CHC) and associates with reduced virological response to pegylated-interferon (PEG-IFN)/ribavirin therapy, but the underlying mechanisms are still unclear. We have previously shown that, in CHC patients, insulin plasma levels are inversely related to antiviral effect induced by PEG-IFN. Therefore, we investigated the in vitro effect of insulin on interferon alpha (IFN-alpha) intracellular signaling as well as that of IFN-alpha on insulin signaling. HepG2 cells, preincubated with or without insulin, were stimulated with IFN-alpha2b and messenger RNA (mRNA) and protein expression of IFN-stimulated genes (ISGs) were measured at different timepoints. The role of intracellular suppressors of cytokine signaling 3 (SOCS3) was evaluated with the small interfering RNA (siRNA) strategy. To assess the effect of IFN-alpha on insulin signaling, HepG2 were preincubated with or without IFN before addition of insulin and cells were then analyzed for IRS-1 and for Akt/PKB Ser473 phosphorylation. Insulin (100 and 1000 nM) significantly reduced in a dose-dependent fashion IFN-induced gene expression of PKR (P=0.017 and P=0.0017, respectively), MxA (P=0.0103 and P=0.00186), and 2'-5' oligoadenylatesynthetase 1 (OAS-1) (P=0.002 and P=0.006). Insulin also reduced IFN-alpha-induced PKR protein expression. Although insulin was confirmed to increase SOCS3 expression, siRNA SOCS3 did not restore ISG expression after insulin treatment. IFN-alpha was found to reduce, in a dose-dependent fashion, IRS-1 gene expression as well as Akt/PKB Ser473 phosphorylation induced by insulin. CONCLUSION: These results provide evidence of reciprocal interference between insulin and IFN-alpha signaling in liver cells. These findings may contribute to understand the role of insulin in CHC: IR might be favored by endogenous cytokines including IFN-alpha, and the resulting hyperinsulinemia then reduces the antiviral response to exogenous IFN in a vicious circle of clinical significance. PMID- 21538437 TI - Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production. AB - Phosphatidylcholine transfer protein (PC-TP, synonym StARD2) is a highly specific intracellular lipid binding protein that is enriched in liver. Coding region polymorphisms in both humans and mice appear to confer protection against measures of insulin resistance. The current study was designed to test the hypotheses that Pctp-/- mice are protected against diet-induced increases in hepatic glucose production and that small molecule inhibition of PC-TP recapitulates this phenotype. Pctp-/- and wildtype mice were subjected to high fat feeding and rates of hepatic glucose production and glucose clearance were quantified by hyperinsulinemic euglycemic clamp studies and pyruvate tolerance tests. These studies revealed that high-fat diet-induced increases in hepatic glucose production were markedly attenuated in Pctp-/- mice. Small molecule inhibitors of PC-TP were synthesized and their potencies, as well as mechanism of inhibition, were characterized in vitro. An optimized inhibitor was administered to high-fat-fed mice and used to explore effects on insulin signaling in cell culture systems. Small molecule inhibitors bound PC-TP, displaced phosphatidylcholines from the lipid binding site, and increased the thermal stability of the protein. Administration of the optimized inhibitor to wildtype mice attenuated hepatic glucose production associated with high-fat feeding, but had no activity in Pctp-/- mice. Indicative of a mechanism for reducing glucose intolerance that is distinct from commonly utilized insulin-sensitizing agents, the inhibitor promoted insulin-independent phosphorylation of key insulin signaling molecules. CONCLUSION: These findings suggest PC-TP inhibition as a novel therapeutic strategy in the management of hepatic insulin resistance. PMID- 21538439 TI - Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. AB - Liver fibrogenesis is a process tightly controlled by endogenous anti- and pro fibrogenic factors. Interferon gamma (IFNgamma) is a potent antifibrogenic cytokine in vitro and might therefore represent a powerful therapeutic entity. However, its poor pharmacokinetics and adverse effects, due to the presence of IFNgamma receptors on nearly all cells, prevented its clinical application so far. We hypothesized that delivery of IFNgamma specifically to the disease inducing cells and concurrently avoiding its binding to nontarget cells might increase therapeutic efficacy and avoid side effects. We conjugated IFNgamma to a cyclic peptide recognizing the platelet-derived growth factor beta receptor (PDGFbetaR) which is strongly up-regulated on activated hepatic stellate cells (HSC), the key effector cells responsible for hepatic fibrogenesis. The IFNgamma conjugates were analyzed in vitro for PDGFbetaR-specific binding and biological effects and in vivo in acute (early) and chronic (progressive and established) carbon-tetrachloride-induced liver fibrosis in mice. The targeted-IFNgamma construct showed PDGFbetaR-specific binding to fibroblasts and HSC and inhibited their activation in vitro. In vivo, the targeted-IFNgamma construct attenuated local HSC activation in an acute liver injury model. In the established liver fibrosis model, it not only strongly inhibited fibrogenesis but also induced fibrolysis. In contrast, nontargeted IFNgamma was ineffective in both models. Moreover, in contrast to unmodified IFNgamma, our engineered targeted-IFNgamma did not induce IFNgamma-related side effects such as systemic inflammation, hyperthermia, elevated plasma triglyceride levels, and neurotropic effects. CONCLUSION: This study presents a novel HSC-targeted engineered-IFNgamma, which in contrast to systemic IFNgamma, blocked liver fibrogenesis and is devoid of side effects, by specifically acting on the key pathogenic cells within the liver. PMID- 21538440 TI - Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. AB - Incidence rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have increased in the United States. Metabolic syndrome is recognized as a risk factor for HCC and a postulated one for ICC. The magnitude of risk, however, has not been investigated on a population level in the United States. We therefore examined the association between metabolic syndrome and the development of these cancers. All persons diagnosed with HCC and ICC between 1993 and 2005 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. For comparison, a 5% sample of individuals residing in the same regions as the SEER registries of the cases was selected. The prevalence of metabolic syndrome as defined by the U.S. National Cholesterol Education Program Adult Treatment Panel III criteria, and other risk factors for HCC (hepatitis B virus, hepatitis C virus, alcoholic liver disease, liver cirrhosis, biliary cirrhosis, hemochromatosis, Wilson's disease) and ICC (biliary cirrhosis, cholangitis, cholelithiasis, choledochal cysts, hepatitis B virus, hepatitis C virus, alcoholic liver disease, cirrhosis, inflammatory bowel disease) were compared among persons who developed cancer and those who did not. Logistic regression was used to calculate odds ratios and 95% confidence intervals. The inclusion criteria were met by 3649 HCC cases, 743 ICC cases, and 195,953 comparison persons. Metabolic syndrome was significantly more common among persons who developed HCC (37.1%) and ICC (29.7%) than the comparison group (17.1%, P<0.0001). In adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio=2.13; 95% confidence interval=1.96-2.31, P<0.0001) and ICC (odds ratio=1.56; 95% confidence interval=1.32-1.83, P<0.0001). CONCLUSION: Metabolic syndrome is a significant risk factor for development of HCC and ICC in the general U.S. population. PMID- 21538441 TI - Activating transcription factor 6 plays protective and pathological roles in steatosis due to endoplasmic reticulum stress in zebrafish. AB - Many etiologies of fatty liver disease (FLD) are associated with the hyperactivation of one of the three pathways composing the unfolded protein response (UPR), which is a harbinger of endoplasmic reticulum (ER) stress. The UPR is mediated by pathways initiated by PRKR-like endoplasmic reticulum kinase, inositol-requiring 1A/X box binding protein 1, and activating transcription factor 6 (ATF6), and each of these pathways has been implicated to have a protective or pathological role in FLD. We used zebrafish with FLD and hepatic ER stress to explore the relationship between Atf6 and steatosis. A mutation of the foie gras (foigr) gene caused FLD and hepatic ER stress. The prolonged treatment of wild-type larvae with tunicamycin (TN), which caused chronic ER stress, phenocopied foigr. In contrast, acute exposure to a high dose of TN robustly activated the UPR but was less effective at inducing steatosis. The sterol regulatory element binding protein transcription factors were not required for steatosis in any of these models. Instead, depleting larvae of active Atf6 either through a membrane-bound transcription factor peptidase site 1 mutation or an atf6 morpholino injection protected them against steatosis caused by chronic ER stress, but exacerbated steatosis caused by acute TN treatment. CONCLUSION: ER stress causes FLD. A loss of Atf6 prevents steatosis caused by chronic ER stress but can also potentiate steatosis caused by acute ER stress. This demonstrates that Atf6 can play both protective and pathological roles in FLD. PMID- 21538442 TI - Contributions of new hepatocyte lineages to liver growth, maintenance, and regeneration in mice. AB - The contributions that de novo differentiation of new hepatocyte lineages makes to normal liver physiology are unknown. In this study, a system that uniquely marks cells during a finite period following primary activation of a serum albumin gene promoter/enhancer-driven Cre recombinase (albCre) transgene was used to investigate birthrates of new hepatocyte lineages from albumin (Alb)-naive precursors in mice. Elapsed time was measured with a two-color fluorescent marker gene that converts from expressing tandem dimer Tomato (tdT; a red fluorescent protein) to expressing green fluorescent protein (GFP) following primary exposure to Cre. The accumulation of GFP and the decay of tdT each contributed to a regular fluorescence transition, which was calibrated in vivo. In normal adults, this system revealed that a steady-state level of 0.076% of all hepatocytes had differentiated within the previous 4 days from albCre-naive cell lineages. In comparison with resting adult livers, the relative abundance of these newborn hepatocytes was elevated 3.7-fold in the growing livers of juveniles and 8.6-fold during liver regeneration after partial hepatectomy in adults. CONCLUSION: Newborn hepatocyte lineages arising from Alb-naive cells contribute to liver maintenance under normal conditions. Hepatocyte lineage birthrates can vary in response to the liver's physiological status. PMID- 21538443 TI - Hypoxia-inducible transcription factor 2alpha promotes steatohepatitis through augmenting lipid accumulation, inflammation, and fibrosis. AB - Oxygen dynamics in the liver is a central signaling mediator controlling hepatic homeostasis, and dysregulation of cellular oxygen is associated with liver injury. Moreover, the transcription factor relaying changes in cellular oxygen levels, hypoxia-inducible factor (HIF), is critical in liver metabolism, and sustained increase in HIF signaling can lead to spontaneous steatosis, inflammation, and liver tumorigenesis. However, the direct responses and genetic networks regulated by HIFs in the liver are unclear. To help define the HIF signal-transduction pathway, an animal model of HIF overexpression was generated and characterized. In this model, overexpression was achieved by Von Hippel Lindau (Vhl) disruption in a liver-specific temporal fashion. Acute disruption of Vhl induced hepatic lipid accumulation in an HIF-2alpha-dependent manner. In addition, HIF-2alpha activation rapidly increased liver inflammation and fibrosis, demonstrating that steatosis and inflammation are primary responses of the liver to hypoxia. To identify downstream effectors, a global microarray expression analysis was performed using livers lacking Vhl for 24 hours and 2 weeks, revealing a time-dependent effect of HIF on gene expression. Increase in genes involved in fatty acid synthesis were followed by an increase in fatty acid uptake-associated genes, and an inhibition of fatty acid beta-oxidation. A rapid increase in proinflammatory cytokines and fibrogenic gene expression was also observed. In vivo chromatin immunoprecipitation assays revealed novel direct targets of HIF signaling that may contribute to hypoxia-mediated steatosis and inflammation. CONCLUSION: These data suggest that HIF-2alpha is a critical mediator in the progression from clinically manageable steatosis to more severe steatohepatitis and liver cancer, and may be a potential therapeutic target. PMID- 21538445 TI - Improving agricultural injury surveillance: a comparison of incidence and type of injury event among three data sources. AB - BACKGROUND: Agriculture ranks as one of the most hazardous industries in the nation. Ongoing injury surveillance is key to identifying and preventing major sources of injury. OBJECTIVE: The objective of this study was to compare the total number and types of injuries identified from community reporting versus two newly available medical data systems. These new systems are important because they are less time consuming and expensive to maintain. METHOD: Farm injury case records from 2007 were collected for 10 NY counties from the following sources: ambulance reports, hospital data, and community surveillance data. RESULTS: For the 107 ambulance report cases, horses (35%), tractors (15%), and livestock (10%) were the three leading injury sources. For the 261 hospital cases, the leading sources were hand tools (24%), farmstead machinery (23%), and buildings/structures/surfaces (22%). Tractor injuries (37%) were the most common source of injuries identified by the 44 community surveillance cases. Struck by object was the most frequent injury event type for hospital and surveillance data (34%, 30%). Falls were the highest category for ambulance reports (36%) and were also common for hospital data (29%). Nine of the 11 fatal cases were found through community surveillance. CONCLUSION: Ambulance reports and hospital data contribute a large number of additional farm injury cases to existing surveillance data. From these cases, horse injuries, falls, and hand tool injuries appear to play a larger role in farm injuries. Future research should explore how to best use these electronic resources for agricultural injury surveillance. PMID- 21538444 TI - In vivo adaptation of hepatitis C virus in chimpanzees for efficient virus production and evasion of apoptosis. AB - Hepatitis C virus (HCV) employs various strategies to establish persistent infection that can cause chronic liver disease. Our previous study showed that both the original patient serum from which the HCV JFH-1 strain was isolated and the cell culture-generated JFH-1 virus (JFH-1cc) established infection in chimpanzees, and that infected JFH-1 strains accumulated mutations after passage through chimpanzees. The aim of this study was to compare the in vitro characteristics of JFH-1 strains emerged in each chimpanzee at early and late stages of infection, as it could provide an insight into the phenomenon of viral persistence. We generated full-genome JFH-1 constructs with the mutations detected in patient serum-infected (JFH-1/S1 and S2) and JFH-1cc-infected (JFH 1/C) chimpanzees, and assessed their effect on replication, infectious virus production, and regulation of apoptosis in cell culture. The extracellular HCV core antigen secreted from JFH-1/S1-, S2-, and C-transfected HuH-7 cells was 2.5, 8.9, and 2.1 times higher than that from JFH-1 wild-type (JFH-1/wt) transfected cells, respectively. Single cycle virus production assay with a CD81-negative cell line revealed that the strain JFH-1/S2, isolated from the patient serum infected chimpanzee at a later time point of infection, showed lower replication and higher capacity to assemble infectious virus particles. This strain also showed productive infection in human hepatocyte-transplanted mice. Furthermore, the cells harboring this strain displayed lower susceptibility to the apoptosis induced by tumor necrosis factor alpha or Fas ligand compared with the cells replicating JFH-1/wt. CONCLUSION: The ability of lower replication, higher virus production, and less susceptibility to cytokine-induced apoptosis may be important for prolonged infection in vivo. Such control of viral functions by specific mutations may be a key strategy for establishing persistent infection. PMID- 21538446 TI - Occupational asbestos exposure as a risk factor for laryngeal carcinoma in a population-based case-control study from Germany. AB - BACKGROUND: As several studies have identified asbestos exposure as an independent occupational risk factor for laryngeal cancer, the aim of our study was to confirm this association. METHODS: In a population-based case-control study on laryngeal cancer in South-West Germany occupational exposures and other risk factors were obtained by face-to-face interviews using a detailed standardized questionnaire covering the complete individual working history, supplemented by job-specific questionnaires (JSQ) especially for selected jobs known to entail exposure to asbestos. Detailed exposure information was collected over a wide range of asbestos related jobs and branches and analyzed using different modeling strategies. RESULTS: Seventy-three (28.4%) cases and 158 (20.5%) controls reported any exposure to asbestos. Elevated risk estimates for asbestos exposure were found. However, those became substantially reduced after adjustment for smoking and alcohol. CONCLUSION: Moderately elevated risks for laryngeal cancer after exposure to asbestos were confirmed. Difficulties in the collection of adequate exposure data were demonstrated. PMID- 21538447 TI - Social play behavior in infant Sichuan snub-nosed monkeys (Rhinopithecus roxellana) in Qinling Mountains, China. AB - We describe the development of social play behavior and assess factors influencing the development of play in infant Sichuan snub-nosed monkeys (Rhinopithecus roxellana). Infant snub-nosed monkeys began to exhibit social play at 3 months of age, when they spent an average 0.89% of time engaging in this behavior (range: 0.7-1.12%). At 6 months of age, there was a significant increase in the proportion of time spent in social play, averaging 9.78% of observation time (range: 4.92-17.08%). However, from 7 to 9 months of age during the winter, social play decreased gradually before rising again from 10 months of age in the spring. Play behavior in infant snub-nosed monkeys is influenced by environmental temperature. Males were observed to play more than females, although further data on this are required. Social rank did not influence the social play of wild Sichuan snub-nosed monkey infants. PMID- 21538448 TI - Validation of a cortisol enzyme immunoassay and characterization of salivary cortisol circadian rhythm in chimpanzees (Pan troglodytes). AB - Monitoring concentrations of stress hormones is an important tool for behavioral research and conservation for animals both in the wild and captivity. Glucocorticoids can be measured in mammals as an indicator of stress by analyzing blood, feces, urine, hair, feathers, or saliva. The advantages of using saliva for measuring cortisol concentrations are three-fold: it is minimally invasive, multiple samples can be collected from the same individual in a short timeframe, and cortisol has a relatively short response time in saliva as compared with other materials. The purpose of this study was to: (1) conduct an adrenocorticotropic hormone (ACTH) challenge as a physiological validation for an enzyme immunoassay to measure salivary cortisol in chimpanzees and (2) characterize the circadian rhythm of salivary cortisol in chimpanzees. We determined that salivary cortisol concentrations peaked 45 min following the ACTH challenge, which is similar to humans. Also, salivary cortisol concentrations peaked early in the morning and decreased throughout the day. We recommend that saliva collection may be the most effective method of measuring stress reactivity and has the potential to complement behavioral, cognitive, physiological, and welfare studies. PMID- 21538449 TI - Meta-analysis and sensitivity analysis for multi-arm trials with selection bias. AB - Multi-arm trials meta-analysis is a methodology used in combining evidence based on a synthesis of different types of comparisons from all possible similar studies and to draw inferences about the effectiveness of multiple compared treatments. Studies with statistically significant results are potentially more likely to be submitted and selected than studies with non-significant results; this leads to false-positive results. In meta-analysis, combining only the identified selected studies uncritically may lead to an incorrect, usually over optimistic conclusion. This problem is known asbiselection bias. In this paper, we first define a random-effect meta-analysis model for multi-arm trials by allowing for heterogeneity among studies. This general model is based on a normal approximation for empirical log-odds ratio. We then address the problem of publication bias by using a sensitivity analysis and by defining a selection model to the available data of a meta-analysis. This method allows for different amounts of selection bias and helps to investigate how sensitive the main interest parameter is when compared with the estimates of the standard model. Throughout the paper, we use binary data from Antiplatelet therapy in maintaining vascular patency of patients to illustrate the methods. PMID- 21538450 TI - Exploring the benefits of adaptive sequential designs in time-to-event endpoint settings. AB - Sequential analysis is frequently employed to address ethical and financial issues in clinical trials. Sequential analysis may be performed using standard group sequential designs, or, more recently, with adaptive designs that use estimates of treatment effect to modify the maximal statistical information to be collected. In the general setting in which statistical information and clinical trial costs are functions of the number of subjects used, it has yet to be established whether there is any major efficiency advantage to adaptive designs over traditional group sequential designs. In survival analysis, however, statistical information (and hence efficiency) is most closely related to the observed number of events, while trial costs still depend on the number of patients accrued. As the number of subjects may dominate the cost of a trial, an adaptive design that specifies a reduced maximal possible sample size when an extreme treatment effect has been observed may allow early termination of accrual and therefore a more cost-efficient trial. We investigate and compare the tradeoffs between efficiency (as measured by average number of observed events required), power, and cost (a function of the number of subjects accrued and length of observation) for standard group sequential methods and an adaptive design that allows for early termination of accrual. We find that when certain trial design parameters are constrained, an adaptive approach to terminating subject accrual may improve upon the cost efficiency of a group sequential clinical trial investigating time-to-event endpoints. However, when the spectrum of group sequential designs considered is broadened, the advantage of the adaptive designs is less clear. PMID- 21538451 TI - Test non-inferiority (and equivalence) based on the odds ratio under a simple crossover trial. AB - For testing the non-inferiority (or equivalence) of a generic drug to a standard drug, the odds ratio (OR) of patient response rates has been recommended to measure the relative treatment efficacy. On the basis of a random effects logistic regression model, we develop asymptotic test procedures for testing non inferiority and equivalence with respect to the OR of patient response rates under a simple crossover design. We further derive exact test procedures, which are especially useful for the situations in which the number of patients in a crossover trial is small. We address sample size calculation for testing non inferiority and equivalence based on the asymptotic test procedures proposed here. We also discuss estimation of the OR of patient response rates for both the treatment and period effects. Finally, we include two examples, one comparing two solution aerosols in treating asthma, and the other one studying two inhalation devices for asthmatics, to illustrate the use of the proposed test procedures and estimators. PMID- 21538452 TI - Time-dependent ROC analysis under diverse censoring patterns. AB - In biomedical studies, statistical approaches based on the Receiver Operating Characteristic (ROC) analysis have been extensively used in the evaluation of classification performance of markers and construction of classifiers. In this article, we investigate time-dependent ROC approaches for censored survival data. While most existing studies have been focused on uncensored and right-censored data, insufficient attention has been paid to other censoring schemes. This study advances from existing studies by investigating more diverse censoring schemes and developing ROC measurements under such censoring. Both estimation and inference are investigated. We conduct simulation and find satisfactory performance of the proposed approaches. We apply the proposed approaches to two real data sets, compare the prognostic power of markers, and investigate whether their linear combinations have better prognostic performance. We also explore graphical tools that can assist diagnostics and efficiently monitor the classification performance. PMID- 21538453 TI - Modified robust variance estimator for generalized estimating equations with improved small-sample performance. AB - Generalized estimating equations (GEE (Biometrika 1986; 73(1):13-22) is a general statistical method to fit marginal models for correlated or clustered responses, and it uses a robust sandwich estimator to estimate the variance-covariance matrix of the regression coefficient estimates. While this sandwich estimator is robust to the misspecification of the correlation structure of the responses, its finite sample performance deteriorates as the number of clusters or observations per cluster decreases. To address this limitation, Pan (Biometrika 2001; 88(3):901-906) and Mancl and DeRouen (Biometrics 2001; 57(1):126-134) investigated two modifications to the original sandwich variance estimator. Motivated by the ideas underlying these two modifications, we propose a novel robust variance estimator that combines the strengths of these estimators. Our theoretical and numerical results show that the proposed estimator attains better efficiency and achieves better finite sample performance compared with existing estimators. In particular, when the sample size or cluster size is small, our proposed estimator exhibits lower bias and the resulting confidence intervals for GEE estimates achieve better coverage rates performance. We illustrate the proposed method using data from a dental study. PMID- 21538454 TI - Experimental field study of problem-solving using tools in free-ranging capuchins (Sapajus nigritus, formerly Cebus nigritus). AB - Some populations of capuchins are reported to use tools to solve foraging problems in the wild. In most cases, this involves the act of pounding and digging. The use of probing tools by wild capuchins is considerably less common. Here we report on the results of an experimental field study conducted in southern Brazil designed to examine the ability of wild black-horned capuchins (Sapajus nigritus) to use a wooden dowel as a lever or a probe to obtain an embedded food reward. A group of eight capuchins was presented with two experimental platforms, each housing a clear Plexiglas box containing two bananas on a shelf and four inserted dowels. Depending on the conditions of the experiment, the capuchins were required either to pull (Condition I) or push (Conditions II and III) the dowels, in order to dislodge the food reward from the shelf so that it could be manually retrieved. In Condition I, four individuals spontaneously solved the foraging problem by pulling the dowels in 25% (72/291) of visits. In Conditions II and III, however, no capuchin successfully pushed the dowels forward to obtain the food reward. During these latter two experimental conditions, the capuchins continued to pull the dowels (41/151 or 27% of visits), even though this behavior did not result in foraging success. The results of these field experiments are consistent with an identical study conducted on wild Cebus capucinus in Costa Rica, and suggest that when using an external object as a probe to solve a foraging problem, individual capuchins were able to rapidly learn an association between the tool and the food reward, but failed to understand exactly how the tool functioned in accomplishing the task. The results also suggest that once a capuchin learned to solve this tool-mediated foraging problem, the individual persisted in using the same solution even in the face of repeated failure (slow rate of learning extinction). PMID- 21538455 TI - Hidden Markov models for zero-inflated Poisson counts with an application to substance use. AB - Paradigms for substance abuse cue-reactivity research involve pharmacological or stressful stimulation designed to elicit stress and craving responses in cocaine dependent subjects. It is unclear as to whether stress induced from participation in such studies increases drug-seeking behavior. We propose a 2-state Hidden Markov model to model the number of cocaine abuses per week before and after participation in a stress-and cue-reactivity study. The hypothesized latent state corresponds to 'high' or 'low' use. To account for a preponderance of zeros, we assume a zero-inflated Poisson model for the count data. Transition probabilities depend on the prior week's state, fixed demographic variables, and time-varying covariates. We adopt a Bayesian approach to model fitting, and use the conditional predictive ordinate statistic to demonstrate that the zero-inflated Poisson hidden Markov model outperforms other models for longitudinal count data. PMID- 21538456 TI - Differentiation of neural stem cells influences their chemotactic responses to vascular endothelial growth factor. AB - Although much effort has been devoted to the delineation of factors involved in the migration of neural stem/progenitor cells (NSCs), the relationship between the chemotactic response and the differentiation status of these cells remains elusive. In the present study, we found that NSCs in varying differentiation states possess different chemotactic responses to vascular endothelial growth factor (VEGF): first, the number of chemotaxing NSCs and the optimal concentrations of VEGF that induced the peak migration vary greatly; second, time lapse video analysis shows that NSCs at certain differentiation states migrate more efficiently toward VEGF, although the migration speed remains unchanged irrespective of cell states; third, the phosphorylation status of Akt, ERK1/2, SAPK/JNK, and p38MAPK is closely related to the differentiation levels of NSCs subjected to VEGF; and, finally, although inhibition of ERK1/2 signaling significantly attenuates VEGF-stimulated transfilter migration of both undifferentiated and differentiating NSCs, NSCs show normal chemotactic response after treatment with inhibitors of SAPK/JNK or p38MAPK. Meanwhile, interference with PI3K/Akt signaling prevents only NSCs of 12 hr differentiation, but not NSCs of 1 day or 3 days differentiation, from migrating in response to VEGF. Moreover, blocking of PI3K/Akt or MAPK signaling impairs the migration efficiency and/or speed, the extent of which depends on the cell differentiation status. Collectively, these results demonstrate that differentiation of NSCs influences their chemotactic responses to VEGF: NSCs in varying differentiation states have different migratory capacities, thereby shedding light on optimization of the therapeutic potential of NSCs to be employed for neural regeneration after injury. PMID- 21538457 TI - Amlodipine and atorvastatin exert protective and additive effects via antiapoptotic and antiautophagic mechanisms after transient middle cerebral artery occlusion in Zucker metabolic syndrome rats. AB - We examined the neuroprotective effects amlodipine and/or atorvastatin in metabolic syndrome (MetS) Zucker fatty rats against transient (90 min) middle cerebral artery occlusion (MCAO). The rats were pretreated with vehicle, amlodipine, atorvastatin, or amlodipine plus atorvastatin for 28 days, and 24 hr after transient MCAO the infarct size was assessed via hematoxylin and eosin staining, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and microtubule-associated protein 1 light chain 3 (LC3) expression were examined by immunohistochemistry to evaluate apoptosis and autophagy, respectively. Compared with the vehicle group, rats treated with amlodipine or atorvastatin alone showed a significant decrease in infarct volume (P < 0.01), which was further decreased in the amlodipine plus atorvastatin group (P < 0.001). Compared with the vehicle group, the numbers of TUNEL- and LC3 positive cells were markedly reduced by amlodipine or atorvastatin alone (P < 0.01) and further decreased by amlodipine plus atorvastatin (P < 0.001). The number of apoptotic TUNEL/autophagic LC3 double-positive cells was also significantly decreased with amlodipine or atorvastatin alone compared with vehicle (P < 0.01) and was further decreased by amlodipine plus atorvastatin (P < 0.001). These data suggest additive neuroprotective effects of combination amlodipine and atorvastatin treatment after acute ischemic stroke in MetS model Zucker rats. These effects are mediated, at least in part, via antiapoptotic and antiautophagic mechanisms. Further studies are now needed to expand these preliminary results to understand fully the mechanisms involved in the protective effects of amlodipine and atorvastatin against ischemic stroke. PMID- 21538458 TI - Applications of mass spectrometry to metabolomics and metabonomics: detection of biomarkers of aging and of age-related diseases. AB - Every 5 years or so new technologies, or new combinations of old ones, seemingly burst onto the science scene and are then sought after until they reach the point of becoming commonplace. Advances in mass spectrometry instrumentation, coupled with the establishment of standardized chemical fragmentation libraries, increased computing power, novel data-analysis algorithms, new scientific applications, and commercial prospects have made mass spectrometry-based metabolomics the latest sought-after technology. This methodology affords the ability to dynamically catalogue and quantify, in parallel, femtomole quantities of cellular metabolites. The study of aging, and the diseases that accompany it, has accelerated significantly in the last decade. Mutant genes that alter the rate of aging have been found that increase lifespan by up to 10-fold in some model organisms, and substantial progress has been made in understanding fundamental alterations that occur at both the mRNA and protein level in tissues of aging organisms. The application of metabolomics to aging research is still relatively new, but has already added significant insight into the aging process. In this review we summarize these findings. We have targeted our manuscript to two audiences: mass spectrometrists interested in applying their technical knowledge to unanswered questions in the aging field, and gerontologists interested in expanding their knowledge of both mass spectrometry and the most recent advances in aging-related metabolomics. PMID- 21538459 TI - Activation and modulation of human alpha4beta2 nicotinic acetylcholine receptors by the neonicotinoids clothianidin and imidacloprid. AB - Neonicotinoids are synthetic, nicotine-derived insecticides used for agricultural and household pest control. Though highly effective at activating insect nicotinic receptors, many neonicotinoids are also capable of directly activating and/or modulating the activation of vertebrate nicotinic receptors. In this study, we have investigated the actions of the neonicotinoids clothianidin (CTD) and imidacloprid (IMI) on human neuronal alpha4beta2 nicotinic acetylcholine receptors. The data demonstrate that the compounds are weak agonists of the human receptors with relative peak currents of 1-4% of the response to 1 mM acetylcholine (ACh). Coapplication of IMI strongly inhibited currents elicited by ACh. From Schild plot analysis, we estimate that the affinity of IMI for the human alpha4beta2 receptor is 18 MUM. The application of low concentrations of CTD potentiated responses to low concentrations of ACh, suggesting that receptors occupied by one ACh and one CTD molecule have a higher gating efficacy than receptors with one ACh bound. Interestingly, subunit stoichiometry affected inhibition by CTD, with (alpha4)(2) (beta2)(3) receptors significantly more strongly inhibited than the (alpha4)(3) (beta2)(2) receptors. PMID- 21538460 TI - Bone marrow mononuclear cells migrate to the demyelinated sciatic nerve and transdifferentiate into Schwann cells after nerve injury: attempt at a peripheral nervous system intrinsic repair mechanism. AB - In the present work, we analyzed whether endogenous and/or transplanted bone marrow mononuclear cells (BMMC) migrate spontaneously to the crushed sciatic nerve and whether they transdifferentiate into Schwann cells (SC) in order to help repair the damaged tissue. We also studied both the immunohistochemical evolution of myelin proteins MBP and P(0) and the myelin composition of both the proximal and distal stumps of the crushed sciatic nerve to determine the demyelination-remyelination period. Immunohistochemical analysis of crushed animals showed that the degeneration process consists of loss of nerve fiber integrity accompanied by degradation of myelin basic proteins MBP and P(0) , which is anticipated by protein cluster formation. The remyelination process appears as a recovery in nerve fiber structure as well as in MBP and P(0) immunoreactivity; results obtained studying isolated myelin from the crushed sciatic nerve show a strong correlation between them. As opposed to demyelination, axonal damage is observed for a short period of time and takes place mostly in the crush area and the segments adjacent to the lesion. Evidence of spontaneous migration of endogenous or intravascularly transplanted BMMC (CD34(+) and vimentin(+) ) is found during the demyelination period exclusively to the injured sciatic nerve. Once migration takes place, transdifferentiation to SC is observed. Such migration and transdifferentiation processes might be inferred to constitute a spontaneous repair mechanism after nerve injury. PMID- 21538461 TI - Potassium-induced structural changes of the endoplasmic reticulum in pyramidal neurons in murine organotypic hippocampal slices. AB - The endoplasmic reticulum (ER) structure is of central importance for the regulation of cellular anabolism, stress response, and signal transduction. Generally continuous, the ER can temporarily undergo dramatic structural rearrangements resulting in a fragmented appearance. In this study we assess the dynamic nature of ER fission in pyramidal neurons in organotypic hippocampal slice cultures stimulated by depolarizing concentration of potassium (50 mM). The slices were obtained from transgenic mice expressing fluorescent ER-targeted DsRed2 protein. We employed live tissue confocal microscopy imaging with fluorescence recovery after photobleaching (FRAP) to monitor the extent of structural rearrangements of the ER. In control slices, the ER structure was continuous. Potassium stimulation resulted in extensive fragmentation (fission), whereas return to basal potassium levels (2.5 mM) led to ER fusion and normalization of ER structure. This ER fission/fusion could be repeated several times in the same neuron, demonstrating the reversibility of the process. Blockade of the N-methyl-D-aspartate receptor (NMDAR) with the antagonist D-AP5 or removal of extracellular Ca(2+) prevented depolarization-induced ER fission. ER fission is sensitive to temperature, and decreasing temperature from 35 degrees C to 30 degrees C augments fission, implying that the altering of ER continuity may be a protective response against damage. We conclude that events that generate membrane depolarisation in brain tissue lead to the release of endogenous glutamate that may regulate neuronal ER continuity. The rapid and reversible NMDAR-mediated changes in ER structure reflect an adaptive, innate property of the ER for synaptic activation as well as response to tissue stress, injury, and disease. PMID- 21538462 TI - Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia. AB - The molecular basis of schizophrenia is poorly understood; however, different brain regions are believed to play distinct roles in disease symptomology. We have studied gene expression in the superior temporal cortex (Brodmann area 22; BA22), which may play a role in positive pathophysiology, and compared our results with data from the anterior prefrontal cortex (BA10), which shows evidence for a role in negative symptoms. Genome-wide mRNA expression was determined in the BA22 region in 23 schizophrenics and 19 controls and compared with a BA10 data set from the same subjects. After adjustments for confounding sources of variation, we carried out GeneGO pathway enrichment analysis in each region. Significant differences were seen in age-related transcriptional changes between the BA22 and the BA10 regions, 21.8% and 41.4% of disease-associated transcripts showing age association, respectively. After removing age associated changes from our data, we saw the highest enrichment in processes mediating cell adhesion, synaptic contact, cytoskeletal remodelling, and apoptosis in the BA22 region. For the BA10 region, we observed the strongest changes in reproductive signalling, tissue remodelling, and cell differentiation. Further exploratory analysis also identified potentially disease-relevant processes that were undetected in our more stringent primary analysis, including autophagy in the BA22 region and the amyloid process in the BA10 region. Collectively, our analysis suggests disruption of many common pathways and processes underpinning synaptic plasticity in both regions in schizophrenia, whereas individual regions emphasize changes in certain pathways that may help to highlight pathway-specific therapeutic opportunities to treat negative or positive symptoms of the disease. PMID- 21538463 TI - SKF83959 suppresses excitatory synaptic transmission in rat hippocampus via a dopamine receptor-independent mechanism. AB - Dopamine (DA) profoundly modulates excitatory synaptic transmission and synaptic plasticity in the brain. In the present study the effects of SKF83959, the selective agonist of phosphatidylinositol (PI)-linked D(1) -like receptor, on the excitatory synaptic transmission were investigated in rat hippocampus. SKF83959 (10-100 MUM) reversibly suppressed the field excitatory postsynaptic potential (fEPSP) elicited by stimulating the Schaffer's collateral-commissural fibers in CA1 area of hippocampal slices. However, the inhibition was not blocked by the D(1) receptor antagonist SCH23390, the D(2) receptor antagonist raclopride, the 5 HT(2A/2C) receptor antagonist mesulergine, or the alpha(1) -adrenoceptor antagonist prazosin. In addition, SKF83959 inhibited the afferent volley and significantly reduced the paired-pulse facilitation ratios. In dissociated hippocampal CA1 pyramidal neurons, SKF83959 had no detectable effect on glutamate induced currents but potently inhibited voltage-activated Na(+) current (IC50 value = 26.9 +/- 1.0 MUM), which was not blocked by SCH23390 or by intracellular dialysis of GDP-beta-S. These results demonstrate that SKF83959 suppressed the excitatory synaptic transmission in hippocampal CA1 area, which was independent of D(1) -like receptor. The mechanism underlying the effect could be mainly inhibition of Na(+) channel in the afferent fibers. The suppression of excitatory synaptic transmission and the Na(+) channel by SKF83959 may contribute to its therapeutic benefits in Parkinson's disease. PMID- 21538464 TI - Altered oxidative stress profile in the cortex of mice fed an enriched branched chain amino acids diet: possible link with amyotrophic lateral sclerosis? AB - Branched-chain amino acids (BCAAs), valine, isoleucine, and leucine, are widely used among athletes as dietary integrators. Although the occurrence of untoward effects of BCCA supplementation, with particular regard to neurological disturbances, cannot be excluded, no specific studies have been performed so far. The aim of this work was to evaluate the effects of a diet enriched in BCAAs on the expression of oxidative stress pathway genes in the brain of C57Bl/6J mice. Animals were fed a standard or a BCAA diet for 95 days starting from postnatal day 21 until sacrifice. BCAA treatment, at doses comparable to human usage, significantly down-regulated the expression of some antioxidant genes, while up regulating the expression of some oxygen transporters. In conclusion, it appears that BCAAs administered by diet could alter some specific oxidative stress pathways in the brain. Caution should thus be exercised in the widespread use of BCAAs as dietary integrators in sports practice. PMID- 21538465 TI - Dendritic EGFP-STIM1 activation after type I metabotropic glutamate and muscarinic acetylcholine receptor stimulation in hippocampal neuron. AB - Several signaling pathways in neurons engage the endoplasmic reticulum (ER) calcium store by triggering calcium release. After release, ER calcium levels must be restored. In many non-neuronal cell types, this is mediated by store operated calcium entry (SOCE), a cellular homeostatic mechanism that activates specialized store-operated calcium channels (SOC). Although much evidence supports the existence of SOCE in neurons, its importance has been difficult to determine because of the abundance of calcium channels expressed and the lack of SOC-specific pharmacological agents. We have explored the function of the SOCE inducing protein STIM1 in neurons. In EGFP-STIM1-expressing hippocampal neurons, the sarco- and endoplasmic reticulum calcium ATPase (SERCA) inhibitor thapsigargin caused rapid aggregation (i.e., activation) of STIM1 in soma and dendrites. Upon STIM1 activation by thapsigargin, a dramatic reduction in STIM1 mobility was detected by fluorescence recovery after photobleaching (FRAP). By triggering release of ER calcium with 3,5-dihydroxyphenylglycine (DHPG) or carbachol (Cch), agonists of type I metabotropic glutamate receptors (mGluR) and muscarinic acetylcholine receptors (mAChR), respectively, STIM1 was activated, and calcium entry (likely to represent SOCE) occurred in dendrites. It is therefore possible that neuronal SOCE is activated by physiological stimuli, some of which may alter the postsynaptic calcium signaling properties. PMID- 21538466 TI - Down-regulation of Kir4.1 in the cerebral cortex of rats with liver failure and in cultured astrocytes treated with glutamine: Implications for astrocytic dysfunction in hepatic encephalopathy. AB - Brain edema in acute hepatic encephalopathy (HE) is due mainly to swelling of astrocytes. Efflux of potassium is implicated in the prevention of glial swelling under hypoosmotic conditions. We investigated whether pathogenic factors of HE, glutamine (Gln) and/or ammonia, induce alterations in the expression of glial potassium channels (Kir4.1, Kir2.1) and Na(+) -K(+) -2Cl(-) cotransporter-1 (NKCC1) in rat cerebral cortex and cultured rat cortical astrocytes and whether these alterations have consequences for potassium efflux and astrocytic swelling. Thioacetamide-induced acute liver failure in rats resulted in significant decreases in the Kir4.1 mRNA and protein contents of cerebral cortex, whereas expression of Kir2.1 and NKCC1 remained unaltered. Incubation of primary cortical astrocytes for 72 hr in the presence of Gln (5 mM), but not of ammonia (5 mM or 10 mM), induced a decrease in the levels of Kir4.1 mRNA and protein. Similarly to incubation with Gln, reduction of Kir4.1 mRNA expression by RNA interference caused swelling of astrocytes as shown by confocal imaging followed by 3D computational analysis. Gln reduced the astrocytic uptake of D-[(3) H]aspartate, but, in contrast to the earlier reported effect of ammonia, this reduction was not accompanied by decreased expression of the astrocytic glutamate transporter GLT-1 mRNA. Both Gln and ammonia decreased hypoosmolarity-induced (86) Rb efflux from the cells, but the effect was more pronounced with Gln. The results indicate that down-regulation of Kir4.1 may mediate distinct aspects of Gln-induced astrocytic dysfunction in HE. PMID- 21538467 TI - Tin protoporphyrin provides protection following cerebral hypoxia-ischemia: involvement of alternative pathways. AB - The contribution of heme oxygenase (HO)-linked pathways to neurodegeneration following cerebral hypoxia-ischemia (HI) remains unclear. We investigated whether HO modulators affected HI-induced brain damage and explored potential mechanisms involved. HI was induced in 26-day-old male Wistar rats by left common carotid artery ligation, followed by exposure to a humidified atmosphere of 8% oxygen for 1 hr. Tin protoporphyrin (SnPP; an HO inhibitor), ferriprotoporphyrin (FePP; an HO inducer), or saline was administered intraperitoneally once daily from 1 day prior to HI until sacrifice at 3 days post-HI. SnPP reduced (P < 0.05) infarct volume compared with saline-treated animals, but FePP had no effect on brain injury. SnPP did not significantly inhibit HO activity at 3 days post-HI, but SnPP increased (P < 0.001) total nitric oxide synthase (NOS) activity compared with HI + saline. Both inducible NOS and cyclooxygenase activities were attenuated (P < 0.05) by SnPP, whereas mitochondrial complex I and V activities were augmented (P < 0.05) by SnPP. SnPP had no effect on NMDA receptor currents. Overall, like other HO inhibitors, SnPP produced many nonselective effects, such as attenuation of inflammatory enzymes and increased mitochondrial respiratory function, which were associated with a protective response 3 days post-HI. PMID- 21538468 TI - Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. AB - There is limited data on the impact of treatment interruptions due to nonadherence in patients with chronic phase chronic myeloid leukemia (CP-CML) treated with Imatinib. We looked at factors (including adherence to therapy) affecting the outcome in a large cohort of patients with CP-CML. All the 516 patients received Imatinib free-of-cost through a company sponsored scheme, which mandated regular three monthly visits for drug procurement. Data regarding the disease characteristics, adherence to treatment and outcomes, were obtained from patients records. Unwarranted interruption of treatment for more than 1 week was defined as nonadherence. With a median follow-up of 39 months, the estimated 5 year event free survival (EFS) was 70.8% (95%, CI = 63.3-78.3). Nearly one-third of the patients (29.6%) were found to be nonadherent at some point during their treatment. On univariate analysis, the factors adversely affecting the EFS were prolonged symptom duration before diagnosis, treatment with hydroxyurea for more than 1 month before start of Imatinib, and nonadherence to therapy. Only nonadherence was significant in multivariate analysis (HR1.6; P = 0.048). The 5 year EFS in adherent and nonadherent patients was 76.7% and 59.8% respectively (P = 0.011, log rank test). Nonadherent patients were less likely to achieve complete cytogenetic responses (26% versus 44%; P = 0.004; chi(2) test) at any point. A significant proportion of patients with CP-CML have drug interruptions due to nonadherence during therapy and this compromises the EFS. Adherence to therapy must be included as an important evaluation parameter in all future studies of CML. PMID- 21538469 TI - Prolonged disease-free survival and overall survival with CVP alternating with fludarabine in advanced follicular lymphoma. PMID- 21538470 TI - Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. AB - The second generation BCR/ABL kinase inhibitor nilotinib is increasingly used for the treatment of imatinib-resistant chronic myeloid leukemia (CML). So far, nilotinib is considered a well-tolerated drug with little if any side effects, although an increase in the fasting glucose level has been reported. We examined a series of 24 consecutive CML patients treated with nilotinib in our center for the development of non-hematologic adverse events. Three of these 24 CML patients developed a rapidly progressive peripheral arterial occlusive disease (PAOD) during treatment with nilotinib. In all three cases, PAOD required repeated angioplasty and/or multiple surgeries within a few months. No PAOD was known before nilotinib-therapy in these patients, although all three had received imatinib. In two patients, pre-existing risk factors predisposing for PAOD were known, and one of them had developed diabetes mellitus during nilotinib. In the other 21 patients treated with nilotinib in our center, one less severe PAOD, one myocardial infarction, one spinal infarction, one subdural hematoma, and one sudden death of unknown etiology were recorded. In summary, treatment with nilotinib may be associated with an increased risk of vascular adverse events, including PAOD development. In a subgroup of patients, these events are severe or even life-threatening. Although the exact mechanisms remain unknown, we recommend screening for pre-existing PAOD and for vascular risk factors such as diabetes mellitus in all patients before starting nilotinib and in the follow up during nilotinib-therapy. PMID- 21538471 TI - The sexual segment of Hemidactylus turcicus and the evolution of sexual segment location in squamata. AB - The kidneys of the Mediterranean Gecko, Hemidactylus turcicus (Gekkonidae), were investigated using light and electron microscopy with the primary focus placed on morphology of the sexual segment of the kidney. The nephrons of male H. turcicus are composed of five distinct regions: 1) a renal corpuscle and glomerulus, 2) a proximal convoluted tubule, 3) an intermediate segment, 4) a distal convoluted tubule, and 5) the sexual segment of the kidney/collecting duct. Female H. turcicus is similar but lack a sexual segment of the kidney. The sexual segment of the kidney is hypertrophied during the months of March through August, which corroborates previous reports of reproductive activity. During inactive months, the sexual segment of the kidney is nondiscernable from the collecting ducts. The sexual segment consists of tall columnar epithelial cells with basally positioned nuclei. Perinuclear Golgi complexes and rough endoplasmic reticulum are present. Secretory granules, which fill the apices of the epithelial cells, are electron dense and released into the lumen by a merocrine secretory process. Narrow intercellular canaliculi separate each epithelial cell and are sealed by tight junctions at the luminal aspect. Basally, leukoctyes are observed within the intercellular canaliculi and outside the basal lamina. Mast cells can be found just outside the basal lamina in close association with renal capillaries. The sexual segment of the kidney of H. turcicus is similar to that of three unrelated lizards for which ultrastructure was investigated with secretion mode being the major difference Also, H. turcicus is similar to most other lizards in that complete regression occurs during reproductive inactivity, but differs in this trait from the skink, Scincella lateralis, and most snakes which display a hypertrophied sexual segment of the kidney throughout the entire year. Although some unique similarities appear during the optimization, no direct patterns or directions are observed, and only the molecular based phylogeny resolves the ancestral condition of the Squamata as the sexual segment of the kidney being observed in the distal convoluted tubule, collecting duct, and ureter. PMID- 21538472 TI - The gut of the juvenile African lungfish Protopterus annectens: a light and scanning electron microscope study. AB - We describe the microstructure of the alimentary canal of the juvenile lungfish Protopterus annectens. Following the oesophagus, the gut is formed by a long segment that extends down to the pyloric valve. This segment, classically named stomach, is lined by a transitional epithelium but lacks all characteristics of the vertebrate stomach. It has been defined here as the intestinal vestibule. The spiral valve is divided into a first large chamber, which contains mucosal ridges, and a second smooth portion. The entire spiral valve is lined with a pseudostratified columnar epithelium that contains approximately six cell types: enterocytes, goblet cells, ciliated cells, leukocytes, dark pigment cells, and vascular cells. Enterocytes and goblet cells show a high number of cytoplasmic vacuoles. The number and size of the vacuoles, and the number of ciliated cells, decreases from the anterior toward the posterior end, suggesting that most of the digestive processes take place in the anterior part of the spiral valve. The epithelium overlies a lamina propria in the first large chamber and a vascular plexus in the smooth portion. The cloaca has a thick muscular wall covered by a transitional epithelium. An extensive lymphatic system formed by capillaries and lymphatic micropumps is present along the entire wall of the alimentary canal. PMID- 21538473 TI - Ultrastructure of the sexually dimorphic basitarsal glands of leg I in manaosbiid harvestmen (Opiliones, Laniatores). AB - Chemical communication is an important aspect of arthropod biology especially for those arthropods with limited abilities to detect visual and acoustic signals. Sexually dimorphic glands are often associated with the production of pheromones, which play a role in reproductive processes. In the family Manaosbiidae (Opiliones: Laniatores), males exhibit an enlarged, swollen, often fused, and spindle-like basitarsus on leg I. In this study, we provide a novel description of the morphology and ultrastructure of the glandular structures found in the proximal swollen tarsomeres of the male manaosbiid Rhopalocranaus albilineatus Roewer, 1932 and compare the external leg I morphology with that of two other manaosbiid harvestmen (Barrona williamsi Goodnight and Goodnight, 1942 and Cranellus montgomeryi Goodnight and Goodnight, 1947). The two proximal tarsomeres of the male R. albilineatus leg I contain two large, paired, acinar glands consisting of many glandular cells. Cells empty their secretory products into a large, branched epicuticular duct, which exits the leg via a pore on the ventral region. Thus, a total of four glandular structures are present within the two swollen tarsomeres and each possesses a conducting canal and pore. Finally, we discuss possible roles of these basitarsal glands in manaosbiid reproductive biology based on the present understanding of sexually dimorphic glands in other terrestrial arthropods (i.e., insects and spiders). PMID- 21538474 TI - Deciphering morphological variation in the braincase of caecilian amphibians (Gymnophiona). AB - High levels of morphological homoplasy have hindered progress in understanding morphological evolution within gymnophione lissamphibians. Stemming from the hypothesis that the braincase has the potential to yield phylogenetic information, the braincases of 27 species (23 genera) of gymnophione amphibians were examined using high-resolution micro-computed tomography and histologically prepared specimens. Morphology of the brain and its relationship to features of the braincase is described, and it is shown that eight different patterns exist in the distribution of foramina in the antotic region. The distribution of variants is congruent with molecule-based phylogeny. Additionally, all variants are shown to correspond directly to stages along developmental continua, suggesting that the evolutionary truncation of development in the antotic region at various stages has driven the evolution of morphology in this region. Attempts to correlate the observed morphology with proxies of putative heterochronic events (including those attributable to burrowing, life history, and size) fail to explain the distribution of morphology if each proxy is considered separately. Thus, it is concluded that either currently unrecognized causes of heterochrony or combinations thereof have influenced morphology in different lineages independently. These data identify clades whose morphology can now be reconsidered in light of previously unrecognized heterochronic events, thereby providing a foundation for future analyses of the evolution of morphology within Gymnophiona as a whole. Most significantly, these data confirm, for the first time in a lissamphibian group, that the braincase can preserve important phylogenetic information that is otherwise obscured in regions of the skull that experience strong influences from functional constraints. PMID- 21538475 TI - Testicular degeneration during spermatogenesis in the blue shark, Prionace glauca: nonconformity with expression as seen in the diametric testes of other carcharhinids. AB - The elasmobranch testis consists of spherical spermatocysts, each housing a single germ cell stage and its own clone of Sertoli cells. Because of the simple diametrical arrangement of cysts in maturational order, the testes of Squalus acanthias, Scyliorhinus canicula, and Prionace glauca are classified as the diametric shark testis type. The aim of this study was to document histologically the spermatocyst composition in the blue shark stage-by-stage and to establish whether the diametric testis type confers any uniformity regarding the expression of spermatogenesis in all sharks with this testis type. Analysis of the testes of blue sharks breeding in summer revealed extensive cyst degeneration of various forms and degrees, cyst shrinkage, and cyst disorganization with or without evidence of cell death, initially at the spermatogonia-spermatocyte transition but predominantly in spermatocyte and spermatid cysts. Animals could be grouped into two categories based on the major degenerative phenomena observed, namely those with extensive multinucleate cell (MNC) formation, and those with pronounced vacuolation in cysts. A major finding was the significant (P < 0.001) predominance of MNC formation and vacuolation in late-stage spermatogonial cysts in the respective categories of sharks. Spermatocyte cysts showed varying degrees of germ cell depletion, with or without evidence of degeneration. Normal-looking, but clearly subnormal-sized primary and secondary spermatocyte cysts with no evidence of degeneration were significantly the dominant spermatocyte cyst types in both categories. It is proposed that these subnormal-sized spermatocyte cysts could proceed into spermiogenesis. Because neighboring spermatid cysts lacked ordered bundling of spermatid heads (disorganized), a morphology significantly correlated with the vacuolation category of sharks, these results suggest that further progression into spermiogenesis was halted in such cysts. Thus, testicular degeneration in the diametric testis type is species specific in quantity and quality. PMID- 21538476 TI - Caspase-2 deficiency protects mice from diabetes-induced marrow adiposity. AB - Type I (T1) diabetes is an autoimmune and metabolic disease associated with bone loss. Bone formation and density are decreased in T1-diabetic mice. Correspondingly, the number of TUNEL positive, dying osteoblasts increases in bones of T1-diabetic mice. Moreover, two known mediators of osteoblast death, TNFalpha and ROS, are increased in T1-diabetic bone. TNFalpha and oxidative stress are known to activate caspase-2, a factor involved in the extrinsic apoptotic pathway. Therefore, we investigated the requirement of caspase-2 for diabetes-induced osteoblast death and bone loss. Diabetes was induced in 16-week old C57BL/6 caspase-2 deficient mice and their wild type littermates and markers of osteoblast death, bone formation and resorption, and marrow adiposity were examined. Despite its involvement in extrinsic cell death, deficiency of caspase 2 did not prevent or reduce diabetes-induced osteoblast death as evidenced by a twofold increase in TUNEL positive osteoblasts in both mouse genotypes. Similarly, deficiency of caspase-2 did not prevent T1-diabetes induced bone loss in trabecular bone (BV/TV decreased by 30 and 50%, respectively) and cortical bone (decreased cortical thickness and area with increased marrow area). Interestingly, at this age, differences in bone parameters were not seen between genotypes. However, caspase-2 deficiency attenuated diabetes-induced bone marrow adiposity and adipocyte gene expression. Taken together, our data suggest that caspase-2 deficiency may play a role in promoting marrow adiposity under stress or disease conditions, but it is not required for T1-diabetes induced bone loss. PMID- 21538477 TI - Apoptotic osteocytes regulate osteoclast precursor recruitment and differentiation in vitro. AB - Fatigue loading causes a spatial distribution of osteocyte apoptosis co-localized with bone resorption spaces peaking around microdamage sites. Since osteocytes have been shown to regulate osteoclast formation and activity, we hypothesize that osteocyte apoptosis regulates osteoclastogenesis. In this study, we used serum-starvation to mimic reduced nutrient transport in microdamaged bone and induce apoptosis in MLO-Y4 osteocyte-like cells; conditioned medium was used to apply soluble factors released by apoptotic osteocytes (aOCY) to healthy non apoptotic MLO-Y4 cells. Osteoclast precursor (RAW264.7 monocyte) migration and differentiation were assessed in the presence of conditioned media (CM) from: (A) aOCY, (B) osteocytes treated with apoptosis conditioned medium (i.e., healthy osteocytes in the presence of apoptosis cues; apoptosis CM-treated osteocytes (atOCY)), and (C) osteocytes treated with non-apoptosis conditioned medium (i.e., healthy osteocytes in the absence of apoptosis cues; non-apoptosis CM-treated osteocytes (natOCY)). Receptor activator for nuclear factor-kappaB ligand (RANKL), macrophage colony stimulating factor (M-CSF), vascular endothelial growth factor (VEGF) and osteoprotegerin (OPG) mRNA, and protein expression were measured. Our findings indicate that soluble factors released by aOCY and atOCY promoted osteoclast precursor migration (up to 64% and 24% increase, respectively) and osteoclast formation (up to 450% and 265% increase, respectively). Osteoclast size increased up to 233% in the presence of aOCY and atOCY CM. Recruitment, formation and size were unaltered by natOCY. RANKL mRNA and protein expression were upregulated only in aOCY, while M-CSF and VEGF increased in atOCY. Addition of RANKL-blocking antibody abolished aOCY-induced osteoclast precursor migration and osteoclast formation. VEGF and M-CSF blocking antibodies abolished atOCY-induced osteoclastogenesis. These findings suggest that aOCY directly and indirectly (through atOCY) initiate targeted bone resorption by regulating osteoclast precursor recruitment and differentiation. PMID- 21538478 TI - Morphology of the gas bladder in bumblebee catfishes (Siluriformes, Pseudopimelodidae). AB - The gross morphology of the gas bladder is described and compared for representatives of all valid genera of Pseudopimelodidae (Siluriformes). Cephalosilurus albomarginatus and species of Batrochoglanis, and Microglanis have the most basic form: a large, cordiform gas bladder with a simple internal T shaped septum. Cephalosilurus apurensis, C. fowleri, and C. nigricauda also have a large, cordiform gas bladder, but they have well-developed trabeculae associated with the internal T-shaped septum, and a pair of well-developed constrictor muscles inserted on the external wall; the latter feature is present in most species of Pimelodidae, but absent in all other catfishes. The monotypic Lophiosilurus alexandri also has well-developed constrictor muscles, and its gas bladder is moderately sized. The species of Pseudopimelodus and Cruciglanis have a diminutive gas bladder partially divided into two lateral sacs without internal communication, and lack constrictor muscles. The parapophysis of the fourth vertebra is a wide and long shelf connected to the dorsal surface of the gas bladder in most pseudopimelodid genera. However, in the species of Pseudopimelodus and Cruciglanis the parapophysis of the fourth vertebra is shorter and has its anterior ramus folded back, partially covering the gas bladder anteroventrally; and the tympanic opening is smaller than in species of the other genera. Five phylogenetic characters are proposed based on the morphology of the gas bladder and associated structures in species of Pseudopimelodidae, and the evolution of those characters in the family is discussed. J. Morphol., 2011. (c) 2011 Wiley-Liss, Inc. PMID- 21538479 TI - Microarray profiling of monocytic differentiation reveals miRNA-mRNA intrinsic correlation. AB - MiRNAs (microRNAs) are small non-coding RNAs involved in mammalian gene expression of cellular processes including differentiation, apoptosis and cancer development. Both specific miRNAs and mRNAs have been identified during monocytic differentiation, but their interactions have not been fully characterized. Here we report that by genome-wide microarray analysis for U937 monocytic differentiation induced by TPA, a large number of miRNAs and mRNAs were differentially expressed, and by bioinformatics analysis could demonstrate that their functional pathway patterns overlap strongly. While expected negative correlation between the expression levels of miRNAs and their target mRNAs was seen, several positive correlations between miRNAs and host mRNAs were also observed, such as C13orf25/miR17, MCM7/miR93, and MGC14376/miR22. These microarray data were verified by quantitative RT-PCR, and the TPA-induced differentiation of U937 cells was confirmed by flow cytometric analysis. Our study suggests an intrinsic correlation between miRNAs and mRNAs underlying their interactions which would provide new insights for defining the mechanisms occurring during monocytic differentiation. PMID- 21538480 TI - Analgesic-antitumor peptide inhibits proliferation and migration of SHG-44 human malignant glioma cells. AB - Malignant gliomas, the most common subtype of primary brain tumors, are characterized by high proliferation, great invasion, and neurological destruction and considered to be the deadliest of human cancers. Analgesic-antitumor peptide (AGAP), one of scorpion toxic polypeptides, has been shown to have antitumor activity. Here, we show that recombinant AGAP (rAGAP) not only inhibits the proliferation of gliomas cell SHG-44 and rat glioma cell C6, but also suppresses the migration of SHG-44 cells during wound healing. To explain these phenomena, we find that rAGAP leads to cell cycle of SHG-44 arrested in G1 phase accompanied by suppressing G1 cell cycle regulatory proteins CDK2, CDK6, and p-RB by means of the down-regulated protein expression of p-AKT. Meanwhile, rAGAP significantly decreases the production of NF-kappaB, BCL-2, p-p38, p-c-Jun, and p-Erk1/2 and further suppresses the activation of VEGF and MMP-9 in SHG-44 cells. These findings suggest rAGAP inhibit proliferation and migration of SHG-44 cells by arresting cell cycle and interfering p-AKT, NF-kappaB, BCL-2, and MAPK signaling pathways. PMID- 21538481 TI - Matrix metalloproteinase-1 induces cleavage of exogenous alphaB-crystallin transduced by a cell-penetrating peptide. AB - Cell-penetrating peptides (CPPs), including TAT-CPP, have been used to deliver exogenous proteins into living cells. Although a number of proteins fused to TAT CPP can be delivered into various cells, little is known about the proteolytic cleavage of TAT-fusion proteins in cells. In this study, we demonstrate that a small heat shock protein (sHSP), alphaB-crystallin (alphaB-crystallin), delivered by TAT-CPP is susceptible to proteolytic cleavage by matrix metalloproteinase-1 (MMP-1) in cardiac myoblast H9c2 cells. Recombinant TAT-alphaB-crystallin was efficiently transduced into H9c2 cells. For a few hours following protein transduction, generation of a 14-kDa fragment, a cleavage band of TAT-alphaB crystallin, increased in a time-dependent manner. This fragment was observed only in detergent-insoluble fractions. Interestingly, treatment with MMP inhibitors blocked the cleavage of TAT-alphaB-crystallin. In test tubes, recombinant MMP-1 processed TAT-alphaB-crystallin to generate the major cleavage fragment 14-kDa, as observed in the cells treated with TAT-alphaB-crystallin. The N-terminal sequences of the 14-kDa fragment were identified as Leu-Arg-Ala-Pro-Ser-Trp-Phe, indicating that this fragment is generated by cleavage at Phe54-Leu55 of alphaB crystallin. The MMP-1-selective inhibitor abolished the production of 14-kDa fragments in cells. In addition, the cleaved fragment of TAT-alphaB-crystallin was significantly reduced in cells transfected with MMP-1 siRNA. Moreover, the enzymatic activity of MMP-1 was markedly increased in TAT-alphaB-crystallin treated cells. TAT-alphaB-crystallin has a cytoprotective effect on H9c2 cells under hypoxic insult, moreover, MMP-1-selective inhibitor treatment led to even increased cell viability. These results suggest that MMP-1 is responsible for proteolytic cleavage of TAT-alphaB-crystallin during its intracellular transduction in H9c2 cells. PMID- 21538482 TI - Evidence that the kinase-truncated c-Src regulates NF-kappaB signaling by targeting NEMO. AB - The tyrosine kinase c-Src and transcription factor NF-kappaB are considered crucial components required for normal osteoclastogenesis. Genetic ablation of either pathway leads to detrimental osteopetrotic phenotypes in mice. Similarly, obstruction of either pathway halts osteoclastogenesis and lessens various forms of bone loss. It has been shown previously that mice expressing a kinase domain truncated c-Src, termed Src251, develop severe osteopetrosis owing to increased osteoclast apoptosis. It was further suggested that this phenomenon is associated with reduced Akt kinase activity. However, the precise mechanism underlying the osteoclast inhibitory effect of Src251 remains obscure. C-Src associates with TRAF6-p62 interacting with receptor activator of NF-kappaB (RANK) distal region and the complex facilitate activation of RANK down stream signal transduction cascades including NF-kappaB. Given this proximity between c-Src and NF-kappaB signaling in osteoclasts, we surmised that inhibition of osteoclastogenesis by Src251 may be achieved through inhibition of NF-kappaB signaling. We have demonstrated recently that NEMO, the regulatory subunit of the IKK complex, is crucial for osteoclastogenesis and interacts with c-Src in osteoclast progenitors. Transfection studies, in which we employed various forms of c-Src and NEMO, revealed that the dominant negative form of c-Src, namely Src251, mediates degradation of NEMO thus halting NF-kappaB signaling. Furthermore, degradation of NEMO requires its intact zinc finger domain which is located at the ubiquitination domain. This process also requires appropriate cellular localization of Src251, since deletion of its myristoylation domain ablates its degradation capacity. Buttressing these findings, the expression of NEMO and NF kappaB signaling were significantly reduced in monocytes collected from Src251 transgenic mice. PMID- 21538483 TI - Induction of autophagy by dimethyl cardamonin is associated with proliferative arrest in human colorectal carcinoma HCT116 and LOVO cells. AB - Dimethyl cardamonin (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone; DMC) is a naturally occurring chalcone, and it is the major compound isolated from the leaves of Syzygium samarangense (Blume) Merr. & L.M. Perry (Myrtaceae). Experiments were conducted to determine the effects of DMC on cell proliferation, cell-cycle distribution, and programmed cell death in cultures of human colorectal carcinoma HCT116 and LOVO cells. Results showed that DMC inhibited HCT116 and LOVO cell proliferation and induced G(2) /M cell cycle arrest, which was associated with the conversion of microtubule associated protein light chain 3 (LC3)-I-LC3-II, an autophagosome marker, and the incorporation of monodansylcadaverine (MDC), a marker for the acidic compartment of autolysosomes or acidic vesicular organelles. The treatment of HCT116 and LOVO cells using a combination of DMC with an autophagy inhibitor, such as 3-methyladenine (3-MA), beclin 1 siRNA, or atg5 siRNA, suppressed the effect of DMC-mediated anti proliferation. These results imply that DMC can suppress colorectal carcinoma HCT116 and LOVO cell proliferation through a G(2) /M phase cell-cycle delay, and can induce autophagy, the hallmark of Type II programmed cell death (PCD). Taken together, our results suggest that DMC may be an effective chemotherapeutic agent for HCT116 and LOVO colorectal carcinoma cells. PMID- 21538484 TI - Altered expression levels of miRNAs in serum as sensitive biomarkers for early diagnosis of traumatic injury. AB - MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides in length which regulate gene expression negatively and play important roles in many pathological processes. It has been demonstrated that circulating miRNAs hold promise to serve as practicable molecular markers for diverse physiological and pathological conditions. In this investigation, we chose partial hepatectomy (PH) as traumatic injury model. There were significantly differential expression of miRNAs in rat serum post-traumatic injury (21 miRNAs were more than twofold up regulated). Especially, the expression of miR-9 showed the highest up-regulated (>70-fold), and it possessed the characteristics of biomarker that was more sensitive than aspartate aminotransferase and alanine aminotransferase and C reactive protein for traumatic liver injury. There was also a prominent increase in the expression levels of miR-9 in different brain areas after traumatic injury. Our data suggest that serum miR-9 may serve as promising biomarker for traumatic injury with high sensitivity. Furthermore, these findings may help to elucidate the complex network which mediates stress response to traumatic injury. PMID- 21538485 TI - Calcium and magnesium enhance arsenate rhizotoxicity and uptake in Triticum aestivum. AB - Cations such as calcium (Ca) and magnesium (Mg) alleviate toxicities of cationic toxicants and increase those of anionic toxicants such as arsenic (As) present as arsenate under aerobic conditions. Increasing evidence exists that these phenomena are related to the outer surface electrical potential (psi 0 degrees ) of the root cell plasma membrane (PM). Short-term (48-h) nutrient culture experiments with wheat (Triticum aestivum L.) seedlings investigated Ca and Mg effects on arsenate rhizotoxicity and uptake. Increased Ca and Mg in solution from 0.2 to 3.5 mM equally reduced the negativity of psi 0 degrees from -45 to 15 mV. This increased arsenate activity at the PM surface from 0.3 to 0.9 uM at the same bulk concentration of 2.0 uM NaH(2) AsO(4) consequently increased arsenate uptake and rhizotoxicity. However, increased Mg was more effective than Ca in enhancing As uptake by roots, especially with the activity of As in the range of 0.5 to 1.5 uM in the bulk medium. This was explained by a modified electrostatic uptake model which indicated a mechanism other than through an effect on psi 0 degrees . Subcellular fractionation of roots indicated that > 95% of As was associated with cellular debris and heat-stable protein (HSP). The results of the present study show that Ca and Mg reduce the negativity of psi 0 degrees , increasing arsenate uptake and rhizotoxicity, and suggest that Mg is more efficient than Ca in enhancing the uptake of As due, in large part, to inducing greater As binding by peptides in the HSP fraction. PMID- 21538486 TI - Extended biotic ligand model for prediction of mixture toxicity of Cd and Pb using single metal toxicity data. AB - The combined toxic effects of Cd and Pb in the presence of different concentrations of Ca(2+) were predicted using the biotic ligand model (BLM), with the parameters derived from the Cd-only and Pb-only toxicity data. The BLM-based toxic unit (TU) approach and the proposed BLM-based f(mix) approach were used for prediction. The predicted mixture toxic effects using the BLM-based f(mix) approach were closer to the observed mixture effects (root mean square error [RMSE] = 9.7 at 25 mM Ca(2+) ) than that using the BLM-based TU approach (RMSE = 25.6 at 25 mM Ca(2+) ). This can be attributed to the fact that the BLM-based TU approach only considers the competition between Ca(2+) and Cd or Pb, whereas the BLM-based f(mix) approach considers both the competition between Cd and Pb and the competition between Ca(2+) and Cd or Pb for biotic ligand sites. In addition, the parameters derived from the Cd-only and Pb-only solutions in the presence of the background Ca(2+) concentration (0.025 mM) could be used to predict the mixture toxic effects at higher Ca(2+) concentrations. The BLM-based f(mix) approach proposed in the current study suggests a new way of predicting the Cd-Pb mixture toxicity from the single metal toxicity data by adopting the f(mix) values. PMID- 21538487 TI - Toxicity of metals to roots of cowpea in relation to their binding strength. AB - Metal phytotoxicity is important in both environmental and agricultural systems. A solution culture study examined the toxicity of 26 metals to roots of cowpea (Vigna unguiculata (L.) Walp.); new data were collected for 15 metals and published data for 11 metals. Metal toxicity, calculated as causing a 50% reduction in root elongation rate, was determined based on either the measured concentration in the bulk solution (EC50(b)) or the calculated activity at the outer surface of the plasma membrane (EA50(0) degrees ). The EC50(b) values ranged from 0.007 uM for Tl to 98,000 uM for K, with the order of rhizotoxicity to cowpea, from most to least toxic, being Tl = Ag > Cu > Hg = Ni = Ga = Ru = In > Sc = Cd = Gd = La = Co = Cs = Pb > Zn = Al = H > Mn > Ba = Sr > Li > Mg > Ca = Na > K. The EA50(0) degrees values suggest that the binding of metals to hard ligands is an important, general, nonspecific mechanism of toxicity, a hypothesis supported by the similar toxicity symptoms to roots of cowpea by many metals. However, additional mechanisms, such as strong binding to soft ligands, substantially increase rhizotoxicity of some metals, especially Tl, Ag, and Cs. Besides direct toxic effects, osmotic effects or reduced activity of Ca(2+) at the outer surface of the root plasma membrane (and resultant Ca deficiency) may decrease short-term root growth. PMID- 21538488 TI - Genomic investigation of year-long and multigenerational exposures of fathead minnow to the munitions compound RDX. AB - We assessed the impacts of exposure to an environmentally representative concentration (0.83 mg/L) of the explosive cyclotrimethylenetrinitramine (RDX) on fathead minnows (Pimephales promelas) in one-year and multigenerational bioassays. In the one-year bioassay, impacts were assessed by statistical comparisons of females from breeding groups reared in control or RDX-exposure conditions. The RDX had no significant effect on gonadosomatic index or condition factor assayed at 1 d and at one, three, six, nine, and 12 months. The liver somatic index was significantly increased versus controls only at the 12-month timepoint. RDX had no significant effect on live-prey capture rates, egg production, or fertilization. RDX caused minimal differential-transcript expression with no consistent discernable effect on gene-functional categories for either brain or liver tissues in the one-year exposure. In the multigenerational assay, the effects of acute (96 h) exposure to RDX were compared in fish reared to the F(2) generation in either control or RDX-exposure conditions. Enrichment of gene functions including neuroexcitatory glutamate metabolism, sensory signaling, and neurological development were observed comparing control-reared and RDX-reared fish. Our results indicated that exposure to RDX at a concentration representing the highest levels observed in the environment (0.83 mg/L) had limited impacts on genomic, individual, and population-level endpoints in fathead minnows in a one-year exposure. However, multigenerational exposures altered transcript expression related to neural development and function. Environ. PMID- 21538489 TI - Assessment of indirect pesticide effects on worm-eating warbler populations in a managed forest ecosystem. AB - Ecological risk assessments rarely evaluate indirect pesticide effects. Pesticides causing no direct mortality in wildlife can still reduce prey availability, resulting in a lower reproductive rate or poor juvenile condition. Few studies have examined these consequences at the population level. We use a four-year data set from a forest ecosystem in which Bacillus thuringiensis kurstaki (Btk) was applied to control gypsy moths (Lymantria dispar L.). Lower worm-eating warbler (Helmitheros vermivorus) productivity on Btk plots contributed to an intrinsic growth rate <1. Altered provisioning behavior by adults led to lower nestling mass in Btk-treated plots, and simulations of reduced juvenile survival expected as a result further reduced population growth rate. The present study explored different spatial representations of treated areas, using a two-patch matrix model incorporating dispersal. Minimal migration from areas with increasing subpopulations could compensate for detrimental reductions in reproductive success and juvenile survival within treated subpopulations. We also simulated population dynamics with different proportions of treated areas to inform management strategies in similar systems. Nontoxic insecticides are capable of impacting nontarget populations with consistent, long term use and should be evaluated based on the spatial connectivity representative of habitat availability and the time period appropriate for risk assessment of pesticide effects in wildlife populations. PMID- 21538490 TI - Understanding solution-state noncovalent interactions between xenobiotics and natural organic matter using 19F/1H heteronuclear saturation transfer difference nuclear magnetic resonance spectroscopy. AB - A combination of forward and reverse heteronuclear ((19)F/(1)H) saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopic techniques were applied to characterize the noncovalent interactions between perfluorinated aromatic xenobiotics and dissolved humic acid. These NMR techniques produce detailed molecular-level descriptions of weak noncovalent associations between components in complex environmental mixtures, allowing the mechanisms underlying these interactions to be explored; (19)F observed heteronuclear STD (H-STD) is used to describe the average molecular orientation of the xenobiotics during their interactions with humic acid, whereas (1)H observed reverse-heteronuclear STD (RH-STD) is used to both identify and quantify preferences exhibited by xenobiotics for interactions at different types of humic acid moieties. First, by using H-STD, it is shown that selected aromatic organofluorides orient with their nonfluorine functional groups (OH, NH(2), and COOH) directed away from humic acid during the interactions, suggesting that these functional groups are not specifically involved. Second, the RH-STD experiment is shown to be sensitive to subtle differences in preferred interaction sites in humic acid and is used here to demonstrate preferential interactions at aromatic humic acid sites for selected aromatic xenobiotics, C(10)F(7)OH, and C(6)F(4)X(2), (where X = F, OH, NH(2), NO(2), or COOH), that can be predicted from the electrostatic potential density maps of the xenobiotic. PMID- 21538491 TI - Sorption of PBDE in low-density polyethylene film: implications for bioavailability of BDE-209. AB - The coefficients of partitioning (K(pew) ) between low-density polyethylene (LDPE) film (50-um thickness) and water for 23 polybrominated diphenyl ether (PBDE) congeners were determined based on a regression analysis of sorption kinetics over an extended exposure period (up to 365 d). A curvilinear relationship between log K(pew) and log K(OW) (octanol-water partition coefficient) was obtained for the target BDE congeners with the turning point at log K(OW) approximately 8. Previously obtained dietary uptake efficiencies of BDE congeners in common carp (Cyprinus carpio) were also found to relate curvilinearly to log K(OW) . In addition, field-measured relative abundances of BDE-209 compiled from previous investigations conducted in the Pearl River Delta of South China were significantly (p < 0.001) higher in abiotic samples (n = 79 from 11 matrices) than in biotic samples (n = 73 from 12 matrices), suggesting the likelihood for reduced bioavailability of BDE-209 in certain biota. Finally, a molecular-scale analysis indicated that the curvilinear relationship between log K(pew) and log K(OW) can be attributed to the energy barrier that a molecule has to overcome as it attempts to diffuse into the LDPE structure, which can become significant for larger molecules. Similarly, the reduced bioavailability of BDE-209 in many biological species can be regarded as a reflection of the magnitude of molecular interactions between cell membranes and BDE-209. PMID- 21538492 TI - Intercomparison and applicability of some dynamic and equilibrium approaches to determine methylated mercury species in pore water. AB - To assess adequately the impact of methylmercury (MeHg) on sensitive wetland ecosystems, accurate measurements of MeHg in pore water are required. In the present study, the feasibility of three methods for porewater sampling was investigated with respect to MeHg in sediments and rice paddy fields. The performance of dialysis samplers (peepers), sediment core sectioning followed by porewater separation by centrifugation (core), and the thin film diffusive samplers (DGT) were evaluated. These methods were intercompared in field experiments at two sites in Guizhou province, SW China disparately impacted by mercury pollution. All the methods report that the concentrations of MeHg in the soils of the Gouxi (GX) rice paddy near Wanshan were much higher than that in the sediment of the Hongjiadu Reservoir (HR), which is located within the Wujiang River basin. The three methods also report different MeHg profiles at the same site. However, these methods exhibit different temporal and spatial resolution scales, due to the differing operations involved with the sampling methods, may also reflect different states of MeHg in pore water. This corresponds to MeHg derived from diffusive flux, equilibrium concentration, and bulk concentration in pore water detected by DGT, peeper, and sediment core, respectively. The advantages and limits of the three methods are also presented. PMID- 21538493 TI - Desorption of pyrethroids from suspended solids. AB - Pyrethroid insecticides have been widely detected in sediments at concentrations that can cause toxicity to aquatic organisms. Desorption rates play an important role in determining the bioavailability of hydrophobic organic compounds, such as pyrethroids, because these compounds are more likely to be sorbed to solids in the environment, and times to reach sorptive equilibrium can be long. In the present study, sequential Tenax desorption experiments were performed with three sorbents, three aging times, and four pyrethroids. A biphasic rate model was fit to the desorption data with r(2) > 0.99, and the rapid and slow compartment desorption rate constants and compartment fractions are reported. Suspended solids from irrigation runoff water collected from a field that had been sprayed with permethrin 1 d before were used in the experiments to compare desorption rates for field-applied pyrethroids with those for laboratory-spiked materials. Suspended solids were used in desorption experiments because suspended solids can be a key source of hydrophobic compounds in surface waters. The rapid desorption rate parameters of field-applied permethrin were not statistically different from those of laboratory spiked permethrin, indicating that desorption of the spiked pyrethroids is comparable to desorption of the pyrethroids added and aged in the field. Sorbent characteristics had the greatest effect on desorption rate parameters; as organic carbon content of the solids increased, the rapid desorption fractions and rapid desorption rate constants both decreased. The desorption rate constant of the slow compartment for sediment containing permethrin aged for 28 d was significantly different compared to aging for 1 d and 7 d, whereas desorption in the rapid and slow compartments did not differ between these treatments. PMID- 21538494 TI - Editorial comment re: Killinger et al. "Secondary changes in bowel function after successful treatment of voiding symptoms with neuromodulation". PMID- 21538495 TI - Women's experience with severe overactive bladder symptoms and treatment: insight revealed from patient focus groups. AB - AIMS: Research has focused on treatment of overactive bladder (OAB) symptoms in women with the goal of cure. The objective of this study was to assess women's perceptions of their OAB symptoms, treatment experience, and outcomes by conducting patient focus groups. METHODS: Women seen in our academic center female urology referral clinics were identified by ICD-9 codes for OAB symptoms and recruited to participate in one of five focus groups, totaling 33 patients. Non-clinician moderators conducted the focus group sessions incorporating topics related to patients' perceptions of OAB symptoms, treatments, and outcomes. Data analysis was performed using grounded theory methodology. RESULTS: Qualitative analysis yielded several preliminary themes: impact of OAB on quality of life, strategies to control wetness, medications and side effects, and triggers. The majority of focus group participants reported only a partial response to medication and other physician-recommended treatments for OAB. Therefore, they developed self-reliant personalized strategies to improve their quality of life. These strategies included fluid restriction, preventive toileting, and, most importantly, the use of incontinence pads. CONCLUSIONS: The majority of the women who participated in the focus groups reported only a partial response to medical and other treatments for OAB. As a result, they developed personalized self management strategies to improve their quality of life. Although most studies addressing the treatment of OAB aim at curing the condition, such a strategy may be unrealistic. Applying a chronic care model that uses a patient-centered symptom-management approach to OAB may optimize patient outcomes and improve quality of life. PMID- 21538496 TI - Patient-perceived outcomes of the AdVance sling up to 40 months post procedure. AB - AIMS: The objective of this study was to determine patient-perceived outcomes of the AdVance sling over 40 months and to determine if results were durable over time. METHODS: This study represents a retrospective chart review of a single surgeon's experience with the AdVance sling paired with a follow-up 5 question telephone survey performed in April 2010. The telephone survey consisted of 2 validated questions pertaining to patient satisfaction (the PGI-I and the PGI-S) along with 3 additional questions pertaining to number of pads per day (PPD) used, additional therapies tried, and whether or not the patient would recommend the procedure to a friend. Ordinal and non-normally distributed variables were analyzed via rank order correlation (Spearman's rho) and the association between the number of pads per day used at the time of telephone survey and progressing time since sling procedure was plotted with linear regression analysis. RESULTS: The surgeon performed a total of 44 AdVance sling procedures from 2006 to April 2011. 42 charts were available for review and 36 (85.7%) patients were reached via telephone. Average patient age was 63.64 years and average time in months since sling procedure was 18.76. Average number of PPD used was 2.11 preoperatively, 0.38 at the one month post-operative visit, and 1.67 at time of the telephone survey. Additionally, advancing time since sling operation correlated with higher numbers of PPD. 34/36 patients would recommend the procedure to a friend. CONCLUSION: Despite patient satisfaction with the sling procedure, our data show that patients were using an increasing number of PPD as time from sling procedure advanced. This is important information for patients and physicians to consider when choosing this procedure. PMID- 21538497 TI - Short-term test-retest reproducibility of urethral pressure profilometry in women with urodynamic stress incontinence with and without detrusor overactivity. AB - AIMS: To determine and compare reproducibility of urethral pressure profilometry (UPP) in women with urodynamic stress incontinence (USI) alone or together with detrusor overactivity (DO). METHODS: Women were recruited from a urodynamic clinic diagnosed with USI using dual channel cystometry. UPP was performed with the technique described by Hilton and Stanton [Hilton P, Stanton SL. Br J Obstet Gynaecol 90:919-33,1983]. Different urethral function parameters were obtained. Two weeks later the tests were repeated. The precision and bias of the tests were measured using the Bland and Altman method [Bland JM, Altman DG. Lancet 1:307 10,1986]. The coefficient of variation (CV) value allowed direct comparison of repeatability of each test, with a lower value indicating less variation. RESULTS: Thirty-one women completed both visits. Fourteen women had USI, the other 17 diagnosed with USI with DO at the end of two visits. There was no significant difference between visits for all the parameters for all women recruited. The most reproducible parameter was functional urethral length and maximum urethral pressure as demonstrated by lowest CV. The women with USI group had more reproducible UPP parameters than those with mixed USI and DO in all parameters apart from pressure transmission ratio in Quartiles 2, 3, and 4. However, there was no significant difference between the two diagnostic groups. CONCLUSIONS: Tests of urethral function in urethral pressure profilometry are shown to have poor reproducibility in women with USI, but limit of agreement may be acceptable in some of the tests. The with-in subject CV appears to be higher in women with mixed USI and DO compared to USI only. PMID- 21538498 TI - Urinary incontinence: an under-recognized risk factor for falls among elderly dementia patients. AB - AIMS: Elderly people with dementia are at increased risk of falls and intervention trials to prevent falls have failed to demonstrate clinical effectiveness in this population. This study evaluates the role of urinary incontinence as a fall risk factor in older patients with dementia, with the aim of developing relevant intervention strategies. METHODS: Elderly patients with dementia visiting our center were recruited. All subjects underwent a Comprehensive Geriatric Assessment (CGA), and patients were divided into two groups (fall and non-fall) according to their history of falls in the past year. Components of the CGA, including physical function, mental function, depressive symptoms, incontinence, and nutritional status, were evaluated according to fall history. RESULTS: Overall, 159 patients with dementia (mean age 77.3 +/- 9.0 years, 59.1% male) participated. Fifty-four patients (34.0%) had experienced falls in the past year. Among all subjects, 50.3% were diagnosed with mild dementia, 37.7% with moderate dementia, and 12.0% with severe dementia according to an established Clinical Dementia Rating scale. Subjects in the fall group displayed poorer physical function, balance, depressive mood, nutritional status, urinary incontinence, and had an increased prevalence of polypharmacy. However, multivariate analysis revealed urinary incontinence as the only independent risk factor for falls (OR = 4.9 +/- 2.2, 95% CI: 2.0-12.0, P < 0.001). CONCLUSIONS: Urinary incontinence is a previously unidentified risk factor for falls among elderly dementia patients. An interventional study with the focus of urinary incontinence could improve the effectiveness of fall prevention among these patients. PMID- 21538499 TI - Predictor of de novo urinary incontinence following holmium laser enucleation of the prostate. AB - AIMS: To investigate the incidence of de novo urinary incontinence (UI) after holmium laser enucleation of the prostate (HoLEP) for benign prostatic hyperplasia and to determine predictors of postoperative de novo UI. METHODS: A total of 204 men who underwent HoLEP and in whom 12-month follow-up data on UI were available were included in this study. The efficacy of HoLEP was assessed at 1-, 3-, 6-, and 12-month postoperatively using the International Prostate Symptom Score (IPSS) and with uroflowmetry. The presence or absence of UI was recorded at each follow-up visit. All definitions of UI corresponded to recommendations of the International Continence Society. RESULTS: The mean preoperative total prostate and transition zone volumes were 53.3 (range 20-162) g and 27.2 (range 4 107) g, respectively. The mean enucleated weight was 23.0 (range 3.0-82.3) g. The IPSS and uroflowmetry showed that all micturition parameters improved significantly starting at 1-month postoperatively. After HoLEP, 29 patients (16.2%) had de novo UI, most of which resolved within 1-6 months; 11 had stress UI, 12 had urgency UI, and the remaining 6 had mixed UI. On logistic regression analysis, bladder mucosal injury during morcellation and maximum urethral closure pressure on baseline urodynamics were the independent predictors of de novo UI after surgery. CONCLUSIONS: Our data suggest that HoLEP is effective in improving micturition, but de novo postoperative UI occurred in some patients although usually transient. Surgeons should be careful to not injure the bladder mucosa during morcellation. PMID- 21538500 TI - Reproducibility of urodynamic filling sensation at weekly interval in healthy volunteers and in women with detrusor overactivity. AB - AIMS: To evaluate the reproducibility of bladder sensation during standardized filling cystometry in female volunteers and overactive bladder (OAB) patients, repeated with weekly interval. METHODS: We recruited 13 female nulliparous volunteers (age 21-47) and 17 female patients with OAB between (age 18-72). They participated in three investigation periods, each separated by 7 days to assess reproducibility of sensation related to standardized cystometry. Subjects were asked to report all sensations they felt during bladder filling. RESULTS: The previously described pattern of sensation was reported during bladder filling in all. Consecutive sensations corresponded to statistically higher bladder volumes. Volumes, at which different sensations of bladder filling were reported, were significantly higher in controls than in OAB patients [first sensation of filling (FSF) P = 0.003, first desire to void (FDV) P < 0.0001, and strong desire to void (SDV) P < 0.0001]. The sensation/volume ratios were significantly higher in patients with OAB than in the healthy volunteers: FSF occurred at mean 46% and FDV at mean 73% of SDV in OAB patients, compared to 36% and 64% in healthy volunteers. Sensations proved highly reproducible when determined with weekly interval. CONCLUSIONS: Our data demonstrate that cystometric filling sensation determined in a standardized way with weekly interval is highly reproducible in healthy and in OAB patients. This finding has, in our opinion, clinical importance as it shows that the technique is reliable both for a sensory evaluation of the LUT as to study influence of treatment aimed at changing this sensation. PMID- 21538501 TI - Non-invasive monitoring of glucocorticoid metabolites in brown hyaena (Hyaena brunnea) feces. AB - The brown hyaena (Hyaena brunnea) is the least known of the large predators of southern Africa. The current IUCN status of the brown hyaena is "Near Threatened", and there are conservation concerns related to a general lack of biological knowledge of the species. For instance, a better knowledge of the responses to environmental and social stressors would improve our abilities to sustainably manage brown hyaena populations in both captive and free-ranging environments. We conducted adrenocorticotrophic hormone (ACTH) challenges in one female and one male adult brown hyaena at Lion Park Zoo, South Africa, to validate measurements of glucocorticoid metabolites (GCM) in brown hyaena feces via an enzyme immunoassay (EIA). We also measured gastrointestinal transit times (GIT times) and the GCM degradation in feces left in ambient temperature for up to 32 hr to more reliably assess the use of this assay as a tool for non-invasive glucocorticoid measurements. Intramuscular injections of synthetic ACTH yielded GCM levels of 388% (female) and 2,682% (male) above baseline with peak increases occurring 25- to 40-hr after injection. The time delay of fecal GCM excretion approximately corresponded with food transit time in the brown hyaenas. Fecal GCM levels declined significantly over time since defecation. Our results provided a good validation that fecal GCMs accurately reflect circulating glucocorticoid stress hormones in brown hyaenas, but we highlight that samples have to be frozen immediately after defecation to avoid bias in the measurements as a result of bacterial degredation. PMID- 21538502 TI - An alternate and reversible method for flight restraint of cranes. AB - Flight restraint is important for zoos, safaris, and breeding centers for large birds. Currently used techniques for flight restraint include both surgical and non-surgical approaches. Surgical approaches usually cause permanent change to or removal of tendon, patagial membrane, or wing bones, and can cause pain and inflammation. Non-surgical approaches such as clipping or trimming feathers often alter the bird's appearance, and can damage growing blood feathers in fledglings or cause joint stiffness. We observed microstructure of primary feathers of the red-crowned crane (Grus japonensis) and found that the width of barbs is a determinative factor influencing vane stiffness and geometric parameters. We hypothesized that partial longitudinal excision of barbs on the ventral surface of the primary feathers would reduce the stiffness of the vane and render the feathers unable to support the crane's body weight during flight. Furthermore, we hypothesized that this modification of barbs would also change the aerodynamic performance of feathers such that they could not generate sufficient lift and thrust during flapping to enable the bird to fly. We tested this hypothesis on a red-crowned crane that had normal flight capability by excising the ventral margin of barbs on all 10 primaries on the left wing. The bird was unable to take off until the modified feathers were replaced by new ones. Removal of barbs proved to be a simple, non-invasive, low-cost and reversible method for flight restraint. It is potentially applicable to other large birds with similar structural characteristics of primary feathers. PMID- 21538503 TI - Reproduction of varanid lizards (Reptilia: Squamata: Varanidae) at the Bronx Zoo. AB - Captivity provides many opportunities for studying the reproductive biology of varanid lizards (Family: Varanidae; genus: Varanus). This article presents reproductive data for 12 varanid species maintained in captivity at the Bronx Zoo between 1977 and 2010. Five species, V. prasinus, V. beccarii, V. melinus, V. mertensi, and V. ornatus have successfully reproduced at the zoo, for which clutch, incubation, and hatchling data are presented, and compared with previously published values. Clutch, incubation, and hatchling measurements typically fell within the known ranges for each species, or represent minor range extensions. V. mertensi was the only species that reproduced seasonally (chi(2) = 9.061, P = 0.029). Five species multiclutched; individual V. mertensi and V. prasinus females produced as many as four clutches per year. The shortest intervals between successive clutches observed for V. kordensis (61 days), V. melinus (77 days), V. mertensi (51 days), and V. prasinus (68 days) represent the shortest known values for each species. Relative clutch mass (RCM) ranged from 0.187 to 0.437. A mean RCM of 0.370 +/- 0.092 for V. prasinus is substantially higher than previously published values for the species. These results illustrate that when maintained under favorable conditions in captivity, some varanids are capable of remarkably high fecundities, rapid reproductive turnover rates, and sizeable maternal investments. Periodicals, Inc. PMID- 21538504 TI - Semen characteristics and artificial insemination in rockhopper penguins (Eudyptes chrysocome chrysocome). AB - This work was performed as part of a multi-year study to determine the cause of the low fertility in captive rockhopper penguins (Eudyptes chrysocome chrysocome) and attempt to increase the fertility through artificial insemination (AI). Semen collection and characterization was performed on 14 male rockhopper penguins. The samples were evaluated for volume, sperm concentration, and sperm quality (motility, forward motility, viability, and morphology). There was a large variation between individuals and between collections for each individual. Mean volume of ejaculate was 0.24 ml. Mean concentration was 47.09 * 10(6) sperm/ml. Mean number of sperm per collection was 6.57 * 10(6). The mean motility was 49.4%. Mean forward motility was 1.7. Mean percentage of living sperm was 88.9%. Mean percentage of sperm with normal morphology was 69.4%. AI was performed on a total of 10 females using pooled semen samples. The birds were also allowed to naturally mate. Ten eggs were laid and three fertile eggs were produced, one of them hatched but died within 24 hr. Paternity testing was performed using 12 microsatellite loci, but unfortunately due to insufficient variability, the paternity of the chick and two embryos could not be determined. PMID- 21538505 TI - Suckling behavior and its development in two Yangtze finless porpoise calves in captivity. AB - We focally observed the suckling behavior of two Yangtze finless porpoise calves, C05 and C07, in captivity. Between 15 and 730 days postpartum of C05 and between birth and 30 days postpartum of C07, 286.3 (1.9 +/- 0.4 hr/day (mean +/- standard deviation), n = 148 days) and 18.3 hr (2.0 +/- 0.5 hr/day, n = 9 days) of video footage were recorded, in which 429 and 111 suckling events were observed, respectively. We found that the calves made their initial suckling attempts after repeated stroking of the mother's body with their rostrums. The suckling duration was 4.4 +/- 1.8 sec and 4.8 +/- 2.4 sec, respectively. Before suckling, the calves swam under the mother's genital region (99.1% of number of event, respectively). During suckling, the mother generally turned sideways to facilitate the calves' suckling (80.7 and 76.6%, respectively). The calves almost equally used the two mammary slits [52.2% (left) and 47.8% (right), and 44.1% (left) and 55.9% (right), respectively]. The frequency and proportion of time C05 spent suckling continuously decreased to zero by 483 days postpartum. The two variables for C07 increased following birth, to a peak at 16 days postpartum, and then decreased continuously until 30 days postpartum. We discuss the possible implications of these observations for the management and conservation of this endangered cetacean. PMID- 21538506 TI - Overuse of training increases mechanoreceptors in supraspinatus tendon of rats SHR. AB - The presence of mechanoreceptors in tendon after overuse activities can be a further step to learn about tendinopathy and overuse. Studies of tendons mechanoreceptors in rats are rare. We studied 12 isogenic spontaneous hypertensive rats (SHR), which underwent an overuse protocol consisting of an hour per daily session of treadmill running at a speed of 17 m/min, 5 times/week for 4 months. Supraspinatus tendons were evaluated with immunohistochemistry using S100 protein antibodies and histological protocol. Supraspinatus tendons at the end of 4 months of overuse protocol had a high number of media mechanoreceptors (4.3) than controls (0.6). The overexpression of S100 protein antibody in overuse activities maybe could represent a adaptative effort to tendon before the tear. PMID- 21538507 TI - Pectoralis major tendon rupture: a biomechanical analysis of repair techniques. AB - Rupture of the insertion of the pectoralis major muscle to the proximal humerus is becoming a common injury. Repair of these ruptures increases patient satisfaction, strength, and cosmesis, and shortens return to competitive sports. Several repair techniques have been described, but recently many surgeons are using suture anchors. The traditional repair technique uses transosseous sutures, but no study has biomechanically compared the strength of these two repair techniques in human cadavers. Twelve fresh-frozen human shoulder specimens were dissected. The pectoralis major tendon insertion was cut from the bone and repaired using one of the two repair techniques: specimens were randomly assigned to transosseous trough with suture tied over bone versus four suture anchors. The fixation constructs were pulled to failure at 4 mm/s on a materials testing system. The mean ultimate failure load of the transosseous repairs was 611 N and the mean ultimate failure load of the suture anchor repair was 620 N. The mean stiffness of the transosseous repair was 32 and 28 N/mm for the suture anchor group. We found no statistically significant difference between these two repair techniques. PMID- 21538509 TI - Are polymorphisms of molecules involved in bone healing correlated to aseptic femoral and tibial shaft non-unions? AB - Fracture healing is a well-organized process between several molecules and mediators. As known from other diseases, genetic polymorphisms may exhibit different expression patterns in these mediators. Concerning fracture healing, this may lead to an extended healing process or non-union. We investigated the incidence of polymorphisms in patients with aseptic non-unions after femoral and tibial shaft fractures as compared to patients with uneventful healing. Exclusion criteria were smoking, diabetes, bilateral fractures, systemic corticoid therapy, and septic non-unions. Analysis of allele frequencies and genotype distribution of various mediators were carried out following PCR. Clinical parameters such as injury severity and in-hospital were analyzed. Fifty patients following non-union (group NU) were enrolled, the control group consisted of 44 patients (group H). A significant association of a PDGF haplotype and non-unions following fracture could be observed. There was a significantly increased in-hospital time and amount of surgical procedures in group NU. Polymorphisms within the PDGF gene seem to be a genetic risk factor for the development of non-unions of the lower extremity following fracture. The early identification of high risk patients could result in an adapted therapeutical strategy and might contribute to a significant decrease of posttraumatic non-unions. PMID- 21538508 TI - PI3Kgamma deletion reduces variability in the in vivo osteolytic response induced by orthopaedic wear particles. AB - Orthopedic wear particles activate a number of intracellular signaling pathways associated with inflammation in macrophages and we have previously shown that the phosphoinositol-3-kinase (PI3K)/Akt pathway is one of the signal transduction pathways that mediates the in vitro activation of macrophages by orthopedic wear particles. Since PI3Kgamma is primarily responsible for PI3K activity during inflammation, we hypothesized that PI3Kgamma mediates particle-induced osteolysis in vivo. Our results do not strongly support the hypothesis that PI3Kgamma regulates the overall amount of particle-induced osteolysis in the murine calvarial model. However, our results strongly support the conclusion that variability in the amount of particle-induced osteolysis between individual mice is reduced in the PI3Kgamma(-/-) mice. These results suggest that PI3Kgamma contributes to osteolysis to different degrees in individual mice and that the mice, and patients, that are most susceptible to osteolysis may be so, in part, due to an increased contribution from PI3Kgamma. PMID- 21538510 TI - Role of trabecular microarchitecture in the formation, accumulation, and morphology of microdamage in human cancellous bone. AB - Alterations in microdamage morphology and accumulation are typically attributed to impaired remodeling, but may also result from changes in microdamage initiation and propagation. Such alterations are relevant for cancellous bone with high metabolic activity and numerous bone quality changes. This study investigates the role of trabecular microarchitecture on morphology and accumulation of microdamage in human cancellous bone. Trabecular bone cores from donors of varying ages and bone volume fraction (BV/TV) were separated into high and low BV/TV groups. Samples were subjected to no load or uniaxial compression to 0.6% (pre-yield) or 1.1% (post-yield) strain. Microdamage was stained with lead uranyl acetate and specimens were imaged via microcomputed tomography to quantify microdamage and determine its morphology in three-dimensions (3D). Donors with high BV/TV had greater post-yield strain and were tougher than low BV/TV donors. High BV/TV bone had less microdamage than low BV/TV bone under post but not pre-yield loading. Microdamage under both loading conditions showed significant correlations with microarchitecture and BV/TV, but the key predictor was structure model index (SMI). As SMI increased (more trabecular rods), microdamage morphology became crack-like. Thus, low BV/TV and increased SMI have strong influences on microdamage accumulation in bone through altered initiation. PMID- 21538511 TI - A clinician's guide to X-linked hypophosphatemia. AB - X-linked hypophosphatemia (XLH) is the prototypic disorder of renal phosphate wasting, and the most common form of heritable rickets. Physicians, patients, and support groups have all expressed concerns about the dearth of information about this disease and the lack of treatment guidelines, which frequently lead to missed diagnoses or mismanagement. This perspective addresses the recommendation by conferees for the dissemination of concise and accessible treatment guidelines for clinicians arising from the Advances in Rare Bone Diseases Scientific Conference held at the NIH in October 2008. We briefly review the clinical and pathophysiologic features of the disorder and offer this guide in response to the conference recommendation, based on our collective accumulated experience in the management of this complex disorder. PMID- 21538512 TI - Additional clinical observations on psychiatric disorders in adult-onset focal dystonia: a case control study. PMID- 21538514 TI - Where are the somatosensory evoked potentials recorded from DBS leads implanted in the human pedunculopontine tegmental nucleus generated? PMID- 21538513 TI - Circulating osteogenic cells: implications for injury, repair, and regeneration. AB - The aim of this review is to provide a critical reading of recent literature pertaining to the presence of circulating, fluid-phase osteoblastic cells and their possible contribution to bone formation. We have termed this group of cells collectively as circulating osteogenic precursor (COP) cells. We present evidence for their existence, methods used for their isolation and identification, possible physiological and pathophysiological roles, cellular origins, and possible mechanisms for their migration to target tissues. PMID- 21538515 TI - A randomized, double-blind trial of transcranial electrostimulation in early Parkinson's disease. AB - We studied the effects of noninvasive transcranial electrical stimulation on the motor and psychological symptoms of early Parkinson's disease. Twenty-three subjects were treated with 10 days of placebo versus active treatment and then followed for 14 weeks. Baseline off medication Unified Parkinson's Disease Rating Scale parts I-III was 29.4 +/- 10.0. The primary end point, Unified Parkinson's Disease Rating Scale in week 2 following treatment, reduced by 5.3 +/- 9.7 for those in active treatment and 7.7 +/- 4.8 for those receiving placebo (not significant). Similarly, no significant differences were seen in the Hamilton Anxiety Scale, Geriatric Depression Scale, and Epworth Sleepiness Scale over the duration of the study. The treatment was well tolerated without device-related adverse events. Despite the negative study, nonpharmacological approaches should continue to be pursued in Parkinson's disease, as they are generally well received by patients. PMID- 21538517 TI - A familial case of sleep rhythmic movement disorder persistent into adulthood; approach to pathophysiology. PMID- 21538518 TI - Long-term management issues in restless legs syndrome. AB - Restless legs syndrome is a neurologic movement and sleep disorder with lifelong symptoms causing considerable morbidity. Several short-term and some long-term open-label and double-blind clinical trials have demonstrated the efficacy and safety of dopaminergic treatment in restless legs syndrome. Long-term treatment, however, is associated with the emergence of vexing long-term side effects that pose a challenge for physicians. These long-term complications can be broadly categorized as disease-related (impact on sleep and acute exacerbation of restless legs syndrome symptoms), and medication issues (augmentation, sleep attacks, impulse control disorders, addiction and dependence, site reaction, occasionally sleep apnea, fibrotic complications, and weight gain). PMID- 21538519 TI - The economic impact of cognitive impairment in Parkinson's disease. AB - BACKGROUND: We investigated to what extent cognitive impairment and dementia were related to the direct medical and nonmedical costs in Parkinson's disease. METHODS: Sixty-one patients with Parkinson's disease from a population-based cohort were assessed for motor and cognitive symptoms in 1993, 1997, and 2001. Data on use of health care and social services were collected. RESULTS: The costs of patients with dementia were 3.3 times higher (?34,980) than those of nondemented patients (?10,626) per year of survival. Institutional care was the largest cost factor, representing 67% of the costs. Cognitive functioning predicted direct costs by 29.4%. Cognitive decline was associated with increased costs, even in nondemented subjects. CONCLUSIONS: Our findings suggest that dementia has a substantial impact on direct costs in Parkinson's disease, mainly due to high costs for institutional care. In addition, there were indications that even patients with mild cognitive impairment have higher nonmedical costs. PMID- 21538520 TI - Cardiac autonomic denervation in Parkinson's disease is linked to REM sleep behavior disorder. AB - BACKGROUND: Recent studies have suggested a close connection between autonomic dysfunction and rapid eye movement sleep behavior disorder, which differs in nature from other early-stage markers of Parkinson's disease. In this study we examined the relationship between rapid eye movement sleep behavior disorder and autonomic dysfunction in Parkinson's disease as measured by cardiac beat-to-beat variability. METHODS: In 53 patients with Parkinson's disease and 36 controls, electrocardiographic trace from a polysomnogram was assessed for measures of beat to-beat RR variability including RR-standard deviation and frequency domains (low and high-frequency components). Results were compared between patients with Parkinson's disease and controls, and between patients with Parkinson's disease with and without rapid eye movement sleep behavior disorder. RESULTS: On numerous cardiac autonomic measures, patients with Parkinson's disease showed clear abnormalities compared with controls. However, these abnormalities were confined only to those patients with associated rapid eye movement sleep behavior; those without were not different than controls. CONCLUSIONS: As with other clinical autonomic variables, cardiac autonomic denervation is predominantly associated not with Parkinson's disease itself, but with the presence of rapid eye movement sleep behavior disorder. PMID- 21538521 TI - Immediate versus delayed electrical stimulation boosts botulinum toxin effect: A pilot study. PMID- 21538522 TI - THAP1 mutations are infrequent in spasmodic dysphonia. PMID- 21538523 TI - Successful deep brain stimulation in a case of posttraumatic tremor and hemiparkinsonism. PMID- 21538524 TI - A randomized, double-blind, placebo-controlled trial of levetiracetam for dyskinesia in Parkinson's disease. AB - BACKGROUND: This randomized double blind, placebo-controlled crossover study investigated the antidyskinetic effects of levetiracetam in Parkinson's disease. METHODS: Sixteen participants with levodopa-induced dyskinesia were enrolled. Hourly videotaped dyskinesia assessments scored by the Goetz method and hourly Unified Parkinson's Disease Rating Scale motor subscale scoring were conducted on 1 day at the end of each treatment period. RESULTS: Dyskinesia was slightly less on placebo (P = .26). Patient diary records also showed less dyskinesia on placebo (P = .10). Parkinsonism was a little worse on levetiracetam, at borderline statistical significance (P = .05). CONCLUSIONS: Levetiracetam was well tolerated at doses up to 2000 mg per day, but we did not detect any antidyskinetic properties. PMID- 21538526 TI - Disappearance of essential tremor after stroke: which fiber of cerebellar loops is involved in posterior limb of the internal capsule? PMID- 21538525 TI - Reward processing abnormalities in Parkinson's disease. AB - The primary motor cortex is important for motor learning and response selection, functions that require information on the expected and actual outcomes of behavior. Therefore, it should receive signals related to reward. Pathways from reward centers to motor cortex exist in primates. Previously, we showed that gamma aminobutyric acid-A-mediated inhibition in the motor cortex, measured by paired transcranial magnetic stimulation, changes with expectation and uncertainty of money rewards generated by a slot machine simulation. We examined the role of dopamine in this phenomenon by testing 13 mildly affected patients with Parkinson's disease, off and on dopaminergic medications, and 13 healthy, age-matched controls. Consistent with a dopaminergic mechanism, reward expectation or predictability modulated the response to paired transcranial magnetic stimulation in controls, but not in unmedicated patients. A single dose of pramipexole restored this effect of reward, mainly by increasing the paired transcranial magnetic stimulation response amplitude during low expectation. Levodopa produced no such effect. Both pramipexole and levodopa increased risk taking behavior on the Iowa Gambling Task. However, pramipexole increased risk taking behavior more in patients showing lower paired transcranial magnetic stimulation response amplitude during low expectation. These results provide evidence that modulation of motor cortex inhibition by reward is mediated by dopamine signaling and that the physiological state of the motor cortex changes with risk-taking tendency in patients on pramipexole. The cortical response to reward expectation may represent an endophenotype for risk-taking behavior in patients on agonist treatment. PMID- 21538527 TI - Factors contributing to institutionalization in patients with Huntington's disease. AB - The objective of this study was to determine which factors are predictive of institutionalization in Huntington's disease. Seven hundred and ninety-nine subjects with 4313 examinations from the Baltimore Huntington's Disease Center were included in the data set; 88 of these patients with an average follow-up time of 9.2 years went from living at home to being institutionalized while being observed in our clinic. We examined demographic, genetic, and clinical variables for a relationship with institutionalization using linear regressions, a Cox proportional hazards model, and chi2 or t tests in certain cases. In our linear models, scores on the Quantified Neurologic Examination (R2=0.203, P<.001), Huntington's disease Activities of Daily Living Scale (R2=0.259, P<.001), and Motor Impairment Score (R2=0.173, P<.001) were found to have the strongest correlation with time until institutionalization. In addition, CAG repeat length (R2=0.248, P<.001) was significantly associated with disease duration at institutionalization, when controlling for age at onset. In the Cox proportional hazards model, scores on the Activities of Daily Living Scale, Mini-Mental State Examination, Quantified Neurologic Examination, and Motor Impairment Score all significantly predicted placement in long-term care. Finally, institutionalized patients were shown to have a higher CAG number and a lower level of educational attainment than patients who avoided institutionalization for at least 15 years after disease onset. Neurologic findings, functional capacity, cognitive impairment, and CAG repeat length are all likely determinants of institutionalization. In contrast with other dementing conditions like Parkinson's and Alzheimer's, psychiatric symptoms were not shown to predict institutionalization in Huntington's disease. This may illustrate the especially debilitating nature of the movement disorder of Huntington's disease in comparison with the other dementias. PMID- 21538528 TI - Deep brain stimulation for Gilles de la Tourette syndrome: a case series targeting subregions of the globus pallidus internus. AB - Deep brain stimulation remains an experimental treatment for patients with Gilles de la Tourette syndrome. Currently, a major controversial issue is the choice of brain target that leads to optimal patient outcomes within a presumed network of basal ganglia and cortical pathways involved in tic pathogenesis. This report describes our experience with patients with severe refractory Gilles de la Tourette syndrome treated with globus pallidus internus deep brain stimulation. Five patients were selected for surgery, 2 targeting the posteroventral globus pallidus internus and 2 targeting the anteromedial region. The remaining patient was first targeted on the posterolateral region, but after 18 months the electrodes were relocated in the anteromedial area. Tics were clinically assessed in all patients pre- and postoperatively using the Modified Rush Video protocol and the Yale Global Tic Severity Scale. Obsessive-compulsive behaviors were quantified with the Yale-Brown Obsessive Compulsive Scale. The Gilles de la Tourette Syndrome-Quality of Life Scale was also completed. All patients experienced improvements in tic severity but to variable extents. More convincing improvements were seen in patients with electrodes sited in the anteromedial region of the globus pallidus internus than in those with posterolateral implants. Mean reduction in the Modified Rush Video Rating scale for each group was 54% and 37%, respectively. Our open-label limited experience supports the use of the anteromedial globus pallidus internus as a promising target for future planned randomized double-blind trials of deep brain stimulation for patients with Gilles de la Tourette syndrome. PMID- 21538529 TI - The LRRK2 R1441C mutation is more frequent than G2019S in Parkinson's disease patients from southern Italy. AB - BACKGROUND: Mutations in the leucine-rich repeat kinase 2 gene are the most frequent cause of familial and sporadic Parkinson's disease, and G2019S is the most common leucine-rich repeat kinase 2 mutation across several Mediterranean countries. METHODS: One hundred ninety-two patients with Parkinson's disease from Campania, a region in southern Italy, were screened for R1441C/H/G and G2019S by direct sequencing and SfcI digestion. RESULTS: Among 192 patients with Parkinson's disease (mean age+/-SD, 63.9+/-11.8 years; disease onset, 54.0+/-12.5 years; family history for Parkinson's disease or tremor, 45%), 8 carried a heterozygous R1441C mutation, whereas only 1 had the G2019S mutation. All R1441C patients originate from the province of Naples and share the same haplotype, suggesting a founder effect. CONCLUSIONS: G2019S is not ubiquitously the most common leucine-rich repeat kinase 2 mutation; in Campania R1441C is more frequent. Region-specific mutation prevalence data should be taken into account for a sensitive and cost-effective molecular diagnosis and counseling of patients with Parkinson's disease. PMID- 21538531 TI - The modified bradykinesia rating scale for Parkinson's disease: reliability and comparison with kinematic measures. AB - Bradykinesia encompasses slowness, decreased movement amplitude, and dysrhythmia. Unified Parkinson's Disease Rating Scale-based bradykinesia-related items require that clinicians condense abnormalities in speed, amplitude, fatiguing, hesitations, and arrests into a single score. The objective of this study was to evaluate the reliability of a modified bradykinesia rating scale, which separately assesses speed, amplitude, and rhythm and its correlation with kinematic measures from motion sensors. Fifty patients with Parkinson's disease performed Unified Parkinson's Disease Rating Scale-directed finger tapping, hand grasping, and pronation-supination while wearing motion sensors. Videos were rated blindly and independently by 4 clinicians. The modified bradykinesia rating scale and Unified Parkinson's Disease Rating Scale demonstrated similar inter- and intrarater reliability. Raters placed greater weight on amplitude than on speed or rhythm when assigning a Unified Parkinson's Disease Rating Scale score. Modified bradykinesia rating scale scores for speed, amplitude, and rhythm correlated highly with quantitative kinematic variables. The modified bradykinesia rating scale separately captures bradykinesia components with interrater and intrarater reliability similar to that of the Unified Parkinson's Disease Rating Scale. Kinematic sensors can accurately quantify speed, amplitude, and rhythm to aid in the development and evaluation of novel therapies in Parkinson's disease. PMID- 21538532 TI - Serum urate and probability of dopaminergic deficit in early "Parkinson's disease". AB - The objective of this study was to investigate whether higher levels of urate, an antioxidant linked to a lower likelihood of developing Parkinson's disease, is also a predictor of having a dopamine transporter brain scan without evidence of dopaminergic deficit. In a cross-sectional study of 797 mildly affected, untreated parkinsonian subjects diagnosed with early Parkinson's disease in the Parkinson Research Examination of CEP-1347 Trial, we investigated the relationship at baseline between serum urate and striatal dopamine transporter density, determined by single-photon emission computed tomography of iodine-123 labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane uptake. A scan without evidence of dopaminergic deficit was defined as lowest putamen iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane > 80% age-expected putamen dopamine transporter density. The odds of having a scan without evidence of dopaminergic deficit rose across increasing quintiles of urate level, with an age and sex-adjusted odds ratio of 3.2 comparing the highest to the lowest urate quintile (95% confidence interval, 1.5-7.2; P for trend = .0003), and remained significant after adjusting for potential confounding factors. The association was significant in men but not women, regardless of whether common or sex specific quintiles of urate were used. Higher levels of urate were associated with a greater likelihood of a scan without evidence of dopaminergic deficit among subjects with early untreated parkinsonism in the Parkinson Research Examination of CEP-1347 Trial. The findings support the diagnostic utility of urate in combination with other determinants. PMID- 21538530 TI - Genetic LRRK2 models of Parkinson's disease: Dissecting the pathogenic pathway and exploring clinical applications. AB - Dominantly inherited mutations in leucine-rich repeat kinase 2 are the most common cause of familial Parkinson's disease. Understanding leucine-rich repeat kinase 2 biology and pathophysiology is central to the elucidation of Parkinson's disease etiology and development of disease intervention. Recently, a number of genetic mouse models of leucine-rich repeat kinase 2 have been reported utilizing different genetic approaches. Some similarities in Parkinson's disease-related pathology emerge in these genetic models despite lack of substantial neuropathology and clinical syndromes of Parkinson's disease. The systematic characterization of these models has begun to shed light on leucine-rich repeat kinase 2 biology and pathophysiology and is expected to offer the identification and validation of drug targets. In this review, we summarize the progress of genetic leucine-rich repeat kinase 2 mouse models and discuss their utility in understanding much needed knowledge regarding early-stage (presymptomatic) disease progression, identifying drug targets, and exploring the potential to aid compound screening focused on inhibitors of kinase activity of leucine-rich repeat kinase 2. PMID- 21538533 TI - 'Keeping your brain active': the activities of people aged 50-65 years. AB - OBJECTIVE: The paper aims to construct a baseline of knowledge about current activities, attitudes and motivations of a sample of people aged 50-65 years in relation to 'keeping one's brain active', with a particular focus on activities suggested in the literature and in popular parlance to have positive effects. METHODS: An online survey of people aged 50-65 years concerning their activities and motivations in relation to 'keeping one's brain active' was conducted with a sample of people employed in Scotland and in two online discussion forums. The survey ascertained respondents' background demographic data, data on health and lifestyle factors, activities they engaged in and reasons for engagement, including any concerns about dementia and experience of dementia. The achieved sample of 402 responses was representative of the general population on most counts, although the sample included more better-educated people and more smokers. RESULTS: Dementia prevention was a motivating factor for 21% of the respondents. More women and more of those living alone reported this motivation. It was linked with experience of dementia and future fears of developing the condition. New 'brain-training' technologies were used by younger people in higher socio-economic groups, and dementia prevention was cited as a motivation. CONCLUSION: The findings indicate that dementia prevention motivates activities perceived to keep the brain active, despite there being a virtual absence of scientific evidence showing that the desired effects will follow. Given the existence of evidence suggesting that other activities, particularly physical exercise, may be more important and the possibility that stress itself may promote the development of dementia, further research is urgently needed. PMID- 21538534 TI - Ageing in people with autistic spectrum disorder. AB - BACKGROUND: Although autism in children and in adults attracts attention with respect to clinical and research needs, autism in the older individuals has not been considered to any degree. We review the evidence for urgently addressing the question of ageing in people with autistic spectrum disorder (ASD), focusing on those with disability. METHODS: Perspectives are reviewed in relation to demographics, experiences of relatives or carers, anticipated residential care needs, requirement for specifically designed cognitive assessment tools and importance of initiating new brain ageing research initiatives in this area. RESULTS: With escalating numbers of ASD individuals with disability reaching old age, provision of care is the paramount issue that is only beginning to be addressed in a few European communities and in the USA. How ageing affects cognition in such individuals as they reach an age no longer consistent with parental care is unknown, lacking any published evidence, and there is a clear need to design cognitive and behavioural assessment tools appropriate to ageing in ASD individuals with disability, as was the case with respect to dementia as a whole. Although there is a growing body of evidence on pathological, imaging, neuropharmacological and other key brain abnormalities in ASD, these are, to date, confined to children and young (only rarely to middle aged) adults. CONCLUSIONS: The need for new initiatives in research into ageing in ASD is urgent. Apart from a growing care crisis, the prospect of understanding brain ageing in this population may bring potential rewards beyond immediate clinical need given the precedent of Down syndrome. PMID- 21538535 TI - Prevalence and risk factors of depressive symptoms in latest life--results of the Leipzig Longitudinal Study of the Aged (LEILA 75+). AB - INTRODUCTION: Because the oldest old will be the fastest-growing age group in the future and information about epidemiology of depressive symptoms in latest life is scarce, the present study aims at determining the age-specific and gender specific prevalence rates and risk factors of depressive symptoms in latest life. METHODS: As part of the Leipzig Longitudinal Study of the Aged (LEILA 75+), a population-based sample of 1,006 individuals aged 75 years and older were interviewed on socio-demographic, clinical and psychometric variables. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (cut-off score >=16); mild cognitive impairment (MCI) was diagnosed according to criteria of the International Working Group on MCI. Factors associated with depressive symptoms were determined with multiple logistic regression models. RESULTS: Of the overall sample, 38.2% (95% confidence interval, CI 35.2-41.2) were classified as depressed. In the full multivariate model, the following variables were significantly associated with depressive symptoms: divorced or widowed marital status, low educational level, poor self rated health status, functional impairment, multi-domain MCI, stressful life events and poor social network. All variables but MCI remained significant correlates of depressive symptoms in the parsimonious model. DISCUSSION: Because depressive symptoms are common in oldest age and associated with broad categories of risk factors, latest-life depression represents an important public health issue. Employment of comprehensive geriatric assessment to ascertain depressive symptoms and its concomitants could help to improve treatment success. PMID- 21538536 TI - Person-centred care and job satisfaction of caregivers in nursing homes: a systematic review of the impact of different forms of person-centred care on various dimensions of job satisfaction. AB - OBJECTIVE: The positive effects of person-centred care on older clients have been demonstrated. However, relatively little is known about the effect that giving person-centred care has on caregivers. This literature review examines the job satisfaction of caregivers who deliver person-centred care in nursing homes. DESIGN: The research questions are: Do the various forms of person-centred care affect job satisfaction differently? Which particular dimensions of job satisfaction have been evaluated in studies on person-centred care, and does their sensitivity to person-centred care differ? Using the search engines Pubmed, Cinahl, Psychinfo and Embase up to August 2010, 46 efficacy studies were found, seven of which satisfied our criteria. RESULTS: Emotion-oriented care, snoezelen, and small-scale care most often show positive effects on job satisfaction. Person centred care has been shown to have positive effects on general job satisfaction, job demands at psychogeriatric wards, emotional exhaustion and personal accomplishment. CONCLUSIONS: Taking into account the fair-to-moderate quality of the studies included, it is concluded that there are limited indications that person-centred care has a positive effect on a number of dimensions of caregivers' job satisfaction. Further study is required to expand and to support these tentative conclusions. PMID- 21538537 TI - Tolerability of extended-release quetiapine fumarate compared with immediate release quetiapine fumarate in older patients with Alzheimer's disease with symptoms of psychosis and/or agitation: a randomised, double-blind, parallel group study. AB - OBJECTIVE: The objective of this study was to assess the safety and tolerability of extended-release quetiapine fumarate (quetiapine XR) compared with quetiapine immediate-release (quetiapine IR) in older patients with Alzheimer's disease with symptoms of psychosis and/or agitation. METHODS: This was a 6-week, double-blind, double-dummy, randomised study. Of the 109 patients screened, 100 were randomised to receive quetiapine XR (n = 68) or quetiapine IR (n = 32), at doses of 50 and 25 mg/day, respectively. Treatment was escalated to 100 mg/day by Day 4. At Day 8, a flexible-dose (50-300 mg/day) period began when dose adjustment was made at the investigator's discretion. The primary variable was incidence and type of adverse events (AEs). Secondary variables included efficacy and other safety assessments. RESULTS: Mean daily doses were 143.6 and 142.0 mg in the quetiapine XR and quetiapine IR groups, respectively. Ninety patients completed the study; only one withdrew (in the quetiapine XR group) because of an AE. Laboratory evaluations identified severe neutropaenia (one patient), mild neutropaenia (three patients) and eosinophilia (five patients); however, these were not reported, as AEs and confounding factors, such as patient age, concomitant illness and medication, made it difficult to determine any relationship to quetiapine treatment. Numerical improvements from baseline were seen across both treatment groups in Neuropsychiatric Inventory frequency * severity total, Neuropsychiatric Inventory-Nursing Home version, Cohen-Mansfield Agitation Inventory, Clinical Global Impression-Severity of Illness and Clinical Global Impression-Improvement scores. CONCLUSION: Quetiapine XR dosed up to 300 mg/day was generally well tolerated, with a similar profile to that of quetiapine IR. PMID- 21538538 TI - Prevalence and correlates of depressive symptoms in Chinese older adults: a population-based study. AB - OBJECTIVE: In China, the rapid socioeconomic transition and the consequential traditional culture change had significant influences on Chinese older-adult depression. In the present study, the prevalence, the potential risk, and the protective factors of depression in the Chinese older population were investigated. METHODS: A cross-sectional survey was conducted with a nationwide representative Chinese sample of 4945 older adults; the Center for Epidemiologic Studies Depression Scale (CES-D) was used as the measurement tool for depressive symptoms. Demographic and other self-reported related factors were taken into consideration. RESULTS: The prevalence of self-reported depressive symptoms (CES D >= 16) in the total study population was 39.86% (pre-old: 39.95%, young-old: 39.84%, old-old: 39.65%, oldest-old: 45.19%); CES-D score was significantly higher in the oldest-old group than in the three younger groups. Furthermore, multiple regression analysis indicated that age itself was not an effective predictor for depressive symptoms, whereas family support and health status explained most of the variation. CONCLUSIONS: The present study found a higher prevalence of depression in the Chinese older population compared with those reported two decades ago. Family support and health status were the most significant protective factors for depression in Chinese older adults. Traditional Chinese culture, which values family significantly and contributed to the previously reported lower prevalence rate, changed dramatically, which may explain the current higher prevalence. In addition to the deterioration of family support, the worsening of health status is another significant factor. PMID- 21538539 TI - Discharge diagnosis and comorbidity profile in hospitalized older patients with dementia. AB - OBJECTIVES: The aim of this study was to investigate the principal discharge diagnosis and related comorbidity in hospitalized older patients affected by dementia. METHODS: Data from 51,838 consecutive computerized discharge records of the St. Anna University Hospital (Ferrara, Italy) were analyzed. Records included only subjects aged >=60 years. Number of admissions, length of stay in hospital, primary and secondary discharge diagnosis (by ICD-9-CM code), number of procedures, and possible death were evaluated. RESULTS: Demented patients represented 8.6% of the sample (4466 individuals) and were older and more likely to be female patients compared with controls (47,372 individuals); they were characterized by higher number of admissions to hospital, instrumental clinical investigations, secondary diagnoses, and mortality rate. Among the primary diagnoses, a higher prevalence of cerebrovascular disease, pneumonia, and hip fracture was observed in demented patients. Furthermore, pulmonary embolism, renal failure, septicemia, and urinary infections were frequently reported in demented patients, but not in controls. As regards secondary diagnoses, dementia was associated with an increased risk of delirium, muscular atrophy and immobilization, dehydration, cystitis, and pressure ulcers, whereas the risk for other conditions, including cancer, was reduced. CONCLUSIONS: Among older patients, dementia was associated with higher rate of admissions to hospital and mortality. Discharge diagnoses were sensibly different according to the presence of dementia; in particular, a greater load and a different kind of comorbidity were observed in demented patients. On the whole, our data suggest that the adequate management of demented outpatients might help to reduce hospitalization. PMID- 21538540 TI - Posttraumatic stress disorder in older adults: an overview of characteristics and treatment approaches. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is a common and disabling condition following a traumatic event. Despite its high prevalence rates, relatively little is known about the manifestation and course of the disorder in older adults. Moreover, there has been little evaluation of the efficacy of psychotherapeutic treatment approaches for older patients. DESIGN: This overview aims to summarize available data on the prevalence and symptoms of late-life PTSD and to review the current treatment approaches for older adults. RESULTS: The course and severity of PTSD symptoms in older adults depend on the time the trauma occurred (early versus late life). In the case of acute traumatization, lower prevalence rates and symptom severities are generally observed in older than in younger populations. In the case of early-life traumatization, a decline in PTSD symptom severity can be observed over the life course. Research on treatment approaches has produced promising results, indicating that disorder specific interventions (i.e., trauma confrontation and cognitive restructuring) can be effectively combined with an age-specific narrative life-review approach. CONCLUSION: Given the limited empirical evidence, caution is warranted in generalizing the reported findings. Nevertheless, it is possible to draw a number of conclusions concerning the characteristics and treatment of PTSD in older adults. Further research is needed to better understand the various presentations of PTSD in late life and to validate and improve the effectiveness of available treatment approaches. PMID- 21538541 TI - Association of saliva 3-methoxy-4-hydroxyphenylglycol levels and a later depressive state in older subjects living in a rural community: 3-year follow-up study. AB - OBJECTIVE: The aim of the study was to examine the association of saliva levels of 3-methoxy-4-hydroxyphenylglycol (sMHPG) with a later depressive state in older people living in a rural community. METHODS: Baseline sMHPG levels were measured in 214 older subjects followed by completion of the Beck Depression Inventory (BDI) from 2004 to 2006 (time A). The same cohort underwent BDI again from 2007 to 2009 (time B). RESULTS: One hundred forty-four subjects (44 men, 100 women) were reassessed by the BDI. Baseline sMHPG levels in men with a BDI score of <=9 at time A and a BDI score of >=10 at time B were significantly higher than those in men with a BDI score of <=9 at times A and B. In men, there was a significant correlation between baseline sMHPG levels and BDI score at time B (r = 0.40, p = 0.007) but not at time A (r = 0.29, p = 0.06). This association was not significant in women. CONCLUSION: These data indicate that high sMHPG levels at time A could be associated with a later depressive state in older men living in a community. PMID- 21538542 TI - Improving taxonomy-based protein fold recognition by using global and local features. AB - Fold recognition from amino acid sequences plays an important role in identifying protein structures and functions. The taxonomy-based method, which classifies a query protein into one of the known folds, has been shown very promising for protein fold recognition. However, extracting a set of highly discriminative features from amino acid sequences remains a challenging problem. To address this problem, we developed a new taxonomy-based protein fold recognition method called TAXFOLD. It extensively exploits the sequence evolution information from PSI BLAST profiles and the secondary structure information from PSIPRED profiles. A comprehensive set of 137 features is constructed, which allows for the depiction of both global and local characteristics of PSI-BLAST and PSIPRED profiles. We tested TAXFOLD on four datasets and compared it with several major existing taxonomic methods for fold recognition. Its recognition accuracies range from 79.6 to 90% for 27, 95, and 194 folds, achieving an average 6.9% improvement over the best available taxonomic method. Further test on the Lindahl benchmark dataset shows that TAXFOLD is comparable with the best conventional template based threading method at the SCOP fold level. These experimental results demonstrate that the proposed set of features is highly beneficial to protein fold recognition. PMID- 21538543 TI - Crystal structure of Sulfolobus tokodaii Sua5 complexed with L-threonine and AMPPNP. AB - The hypermodified nucleoside N(6)-threonylcarbamoyladenosine resides at position 37 of tRNA molecules bearing U at position 36 and maintains translational fidelity in the three kingdoms of life. The N(6)-threonylcarbamoyl moiety is composed of L-threonine and bicarbonate, and its synthesis was genetically shown to require YrdC/Sua5. YrdC/Sua5 binds to tRNA and ATP. In this study, we analyzed the L-threonine-binding mode of Sua5 from the archaeon Sulfolobus tokodaii. Isothermal titration calorimetry measurements revealed that S. tokodaii Sua5 binds L-threonine more strongly than L-serine and glycine. The Kd values of Sua5 for L-threonine and L-serine are 9.3 MUM and 2.6 mM, respectively. We determined the crystal structure of S. tokodaii Sua5, complexed with AMPPNP and L-threonine, at 1.8 A resolution. The L-threonine is bound next to AMPPNP in the same pocket of the N-terminal domain. Thr118 and two water molecules form hydrogen bonds with AMPPNP in a unique manner for adenine-specific recognition. The carboxyl group and the side-chain hydroxyl and methyl groups of L-threonine are buried deep in the pocket, whereas the amino group faces AMPPNP. The L-threonine is located in a suitable position to react together with ATP for the synthesis of N(6) threonylcarbamoyladenosine. PMID- 21538544 TI - Distinguishing two groups of flavin reductases by analyzing the protonation state of an active site carboxylic acid. AB - Flavin-containing reductases are involved in a wide variety of physiological reactions such as photosynthesis, nitric oxide synthesis, and detoxification of foreign compounds, including therapeutic drugs. Ferredoxin-NADP(H)-reductase (FNR) is the prototypical enzyme of this family. The fold of this protein is highly conserved and occurs as one domain of several multidomain enzymes such as the members of the diflavin reductase family. The enzymes of this family have emerged as fusion of a FNR and a flavodoxin. Although the active sites of these enzymes are very similar, different enzymes function in opposite directions, that is, some reduce oxidized nicotinamide adenine dinucleotide phosphate (NADP(+)) and some oxidize reduced nicotinamide adenine dinucleotide phosphate (NADPH). In this work, we analyze the protonation behavior of titratable residues of these enzymes through electrostatic calculations. We find that a highly conserved carboxylic acid in the active site shows a different titration behavior in different flavin reductases. This residue is deprotonated in flavin reductases present in plastids, but protonated in bacterial counterparts and in diflavin reductases. The protonation state of the carboxylic acid may also influence substrate binding. The physiological substrate for plastidic enzymes is NADP(+), but it is NADPH for the other mentioned reductases. In this article, we discuss the relevance of the environment of this residue for its protonation and its importance in catalysis. Our results allow to reinterpret and explain experimental data. PMID- 21538545 TI - Conformational dynamics of L-lysine, L-arginine, L-ornithine binding protein reveals ligand-dependent plasticity. AB - The molecular basis of multiple ligand binding affinity for amino acids in periplasmic binding proteins (PBPs) and in the homologous domain for class C G protein coupled receptors is an unsolved question. Here, using unrestrained molecular dynamic simulations, we studied the ligand binding mechanism present in the L-lysine, L-arginine, L-ornithine binding protein. We developed an analysis based on dihedral angles for the description of the conformational changes upon ligand binding. This analysis has an excellent correlation with each of the two main movements described by principal component analysis (PCA) and it's more convenient than RMSD measurements to describe the differences in the conformational ensembles observed. Furthermore, an analysis of hydrogen bonds showed specific interactions for each ligand studied as well as the ligand interaction with the aromatic residues Tyr-14 and Phe-52. Using uncharged histidine tautomers, these interactions are not observed. On the basis of these results, we propose a model in which hydrogen bond interactions place the ligand in the correct orientation to induce a cation-pi interaction with Tyr-14 and Phe 52 thereby stabilizing the closed state. Our results also show that this protein adopts slightly different closed conformations to make available specific hydrogen bond interactions for each ligand thus, allowing a single mechanism to attain multiple ligand specificity. These results shed light on the experimental evidence for ligand-dependent conformational plasticity not explained by the previous crystallographic data. PMID- 21538546 TI - Solution structure of the protein lipocalin 12 from rat epididymis. PMID- 21538547 TI - Crystal structure of a metal-dependent phosphoesterase (YP_910028.1) from Bifidobacterium adolescentis: Computational prediction and experimental validation of phosphoesterase activity. AB - The crystal structures of an unliganded and adenosine 5'-monophosphate (AMP) bound, metal-dependent phosphoesterase (YP_910028.1) from Bifidobacterium adolescentis are reported at 2.4 and 1.94 A, respectively. Functional characterization of this enzyme was guided by computational analysis and then confirmed by experiment. The structure consists of a polymerase and histidinol phosphatase (PHP, Pfam: PF02811) domain with a second domain (residues 105-178) inserted in the middle of the PHP sequence. The insert domain functions in binding AMP, but the precise function and substrate specificity of this domain are unknown. Initial bioinformatics analyses yielded multiple potential functional leads, with most of them suggesting DNA polymerase or DNA replication activity. Phylogenetic analysis indicated a potential DNA polymerase function that was somewhat supported by global structural comparisons identifying the closest structural match to the alpha subunit of DNA polymerase III. However, several other functional predictions, including phosphoesterase, could not be excluded. Theoretical microscopic anomalous titration curve shapes, a computational method for the prediction of active sites from protein 3D structures, identified potential reactive residues in YP_910028.1. Further analysis of the predicted active site and local comparison with its closest structure matches strongly suggested phosphoesterase activity, which was confirmed experimentally. Primer extension assays on both normal and mismatched DNA show neither extension nor degradation and provide evidence that YP_910028.1 has neither DNA polymerase activity nor DNA-proofreading activity. These results suggest that many of the sequence neighbors previously annotated as having DNA polymerase activity may actually be misannotated. PMID- 21538548 TI - Structural characterization of the mitomycin 7-O-methyltransferase. AB - Mitomycins are quinone-containing antibiotics, widely used as antitumor drugs in chemotherapy. Mitomycin-7-O-methyltransferase (MmcR), a key tailoring enzyme involved in the biosynthesis of mitomycin in Streptomyces lavendulae, catalyzes the 7-O-methylation of both C9beta- and C9alpha-configured 7-hydroxymitomycins. We have determined the crystal structures of the MmcR-S-adenosylhomocysteine (SAH) binary complex and MmcR-SAH-mitomycin A (MMA) ternary complex at resolutions of 1.9and 2.3 A, respectively. The study revealed MmcR to adopt a common S-adenosyl-L-methionine-dependent O-methyltransferase fold and the presence of a structurally conserved active site general acid-base pair is consistent with a proton-assisted methyltransfer common to most methyltransferases. Given the importance of C7 alkylation to modulate mitomycin redox potential, this study may also present a template toward the future engineering of catalysts to generate uniquely bioactive mitomycins. PMID- 21538549 TI - Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: a positron emission tomography study in Papio anubis. AB - [11 C] P943 is a recently developed PET radiotracer for serotonin 5-HT1B receptors. We characterized a number of its in vivo pharmacokinetic properties, including the evaluation of its two stereo-isomers, saturability of specific binding, selectivity for 5-HT1B and 5-HT1D receptors, and vulnerability to pharmacologically induced increases in endogenous 5-HT levels. Six isoflurane anesthetized baboons were scanned with [11 C] P943 at baseline, and following various pharmacological manipulations. The interventions included the administration of pharmacological doses of P943, SB-616234-S (a 5-HT1B selective antagonist), SB-714786 (a 5-HT1D selective antagonist), as well as the administration of 5-HT releasing agents (fenfluramine, amphetamine) and 5-HT reuptake inhibitor (citalopram). [11 C] P943 was observed to bind saturably and specifically to 5-HT1B receptors and to be sensitive to all three challenges known to alter 5-HT levels in the proximity of receptors. [11 C] P943 shows promise as a tracer to image serotonin function in healthy subjects as well as subjects with psychiatric or neurologic conditions. PMID- 21538550 TI - Enhancement of histone acetylation in midbrain of mice with ethanol physical dependence and its withdrawal. PMID- 21538551 TI - Growth hormone increases neural cell adhesion polysialylation state in the dentate gyrus of gamma-irradiated rats. PMID- 21538552 TI - Motor activity affects dopaminergic and noradrenergic systems of the dorsal horn of the rat lumbar spinal cord. AB - Dopamine (DA) and noradrenaline (NA) modulate responses to nociceptive stimuli, within the dorsal horn of the spinal cord. Both neurotransmitters may play a role in supraspinal regulation in response to proprioceptive afferences to the dorsal horn. However, direct evidence of changes in neurotransmitter release within the dorsal horn due to non-noxious stimuli is lacking. The present study was designed to determine, whether non-nociceptive exercise produces changes in release of DA and NA within the dorsal horn, and whether these changes are associated with long lasting inhibition after the exercise stops. Microdialysis probes, implanted in layers 2-5 of Rexed, in combination with high-performance liquid chromatography coupled to electrochemical detection (HPLC-EC) were used to measure concentrations of DA and NA metabolite (MHPG) in lumbar spinal cords of rats. Microdialysate was sampled before, during, and after a treadmill exercise of one hour. Results indicate that DA and NA releases are inhibited during non nociceptive motor activity. At rest, DA concentration was 204 +/- 10.5 pg/10 MUl and was significantly decreased during exercise to -11.4% (P <= 0.05). Greater decrease occurred after 30 min of exercise and was of -31.4% (P <= 0.05). Similarly, MHPG was significantly decreased of -18% during exercise (P <= 0.05). When exercise stopped, both systems showed long-lasting inhibition. Exercise post release lasted 30 min for DA and 90 min for MHPG. MHPG greatest decrease of 47.8% occurred 30 min after stopping the exercise (P <= 0.001). Thus, DA and NA systems seem to respond to exercise-induced proprioceptive afferent stimuli to the dorsal horn. PMID- 21538553 TI - Effects of potential dietary inhibitors of endogenous DNA damage on mutagenesis and lipid peroxidation in lacZ mice. AB - The effects of a nine month administration of dietary: (1) 3H-1,2-dithiole-3 thione (D3T), (2) N-acetylcysteine (NAC), (3) antioxidant vitamin mix, (vitamin C+E), (4) free radical scavenger, amifostine, and (5) calorie restriction, (CR), on mutagenesis and lipid peroxidation in lung, kidney, spleen and liver of lacZ transgenic mice were examined. These agents/diets were chosen because they might inhibit certain proposed mechanisms of endogenous damage to DNA. The agents were added to a high fat, reduced antioxidant AIN-76 diet, to better approximate a Western style diet than the conventional AIN-76 diet. As the lacZ gene is not expressed, mutations in that gene are neutral, and simply accumulate over time. The mutant fractions in control mice increased about 50-100%. Most of the agents inhibited to various extents the age-related increase in mutagenesis in lung, kidney, and/or spleen, but no inhibition was observed in liver. There was no significant effect of age on lipid peroxidation levels in controls, possibly reflecting steady state turnover of lipid peroxidation products. Almost all of the treatments except D3T inhibited lipid peroxidation in most organs to different degrees. The vitamin C+E mix was the most effective at inhibiting lipid peroxidation, but a single most effective inhibitor of mutagenesis could not be discerned. Some associations were observed between the reduction in lipid peroxidation and the inhibition of mutagenesis. The results are consistent with a partial role for oxidative stress in the age-related increase in mutagenesis. These observations may have implications for chemoprevention of carcinogenesis. PMID- 21538554 TI - Recombinant human immunodeficiency virus-1 transactivator of transcription1-86 allosterically modulates dopamine transporter activity. PMID- 21538555 TI - Malathion and fenvalerate induce micronuclei in mouse bone marrow cells. AB - Health effects of pesticides are a major public health concern. In this study, the genotoxic effects of two commonly-used pesticides, malathion, and fenvalerate, were investigated in mice in vivo. Induction of micronuclei in bone marrow cells was used as the test parameter following exposure to 2.5, 5 or 10 mg/kg malathion by intraperitoneal (i.p.) or per oral (p.o.) exposure. Exposure by both routes was found to cause a significant increase in micronucleated polychromatic erythrocytes (PCEs) in a dose-dependent manner (r = 0.9769; P < 0.05). The highest dose (10 mg/kg) induced significant (P < 0.05) cytotoxicity. In contrast, fenvalerate caused an increase in micronucleated PCEs only at higher doses (10 and 20 mg/kg) via i.p. injection, and was not associated with cytotoxicity. A significant dose-response correlation was not observed in the dose ranges tested for fenvalerate (r = 0.8704; P > 0.05). The results suggest that technical grade malathion is a genotoxic agent. In contrast, technical grade fenvalerate appears to be a potent genotoxic agent, but this observation should be confirmed with further investigation(s). PMID- 21538557 TI - Analysis of genomic instability in the offspring of fathers exposed to low doses of ionizing radiation. AB - Transgenerational genomic instability was studied in nonirradiated children born from fathers who were irradiated with low doses of ionizing radiation while working as clean-up workers at the Chernobyl Nuclear Power Plant (liquidators) and nonirradiated mothers from nuclear families. Aberrant cell frequencies (ACFs), chromosomal type aberration frequencies, and chromatid break frequencies (CBFs) in the lymphocytes of fathers-liquidators, and their children were significantly higher when compared with the control group (P < 0.05). Individual ACFs, aberration frequencies, and CBFs were independent of the time between irradiation of the father and conception of the child (1 month to 18 years). Chromosomes were categorized into seven groups (A through G). Analysis of aberrant chromosomes within these groups showed no differences in the average frequency of aberrant chromosomes between children and fathers-liquidators. However, significant differences were observed in the average frequency of aberrant chromosomes in groups A, B, and C between children and mothers in the families of liquidators. These results suggest that low doses of radiation induce genomic instability in fathers. Moreover, low radiation doses might be responsible for individual peculiarities in transgenerational genomic instability in children (as a consequence of response to primary DNA damage). Thus, genomic instability may contribute to increased morbidity over the lifetime of these children. PMID- 21538556 TI - Genetic toxicology in the 21st century: reflections and future directions. AB - A symposium at the 40th anniversary of the Environmental Mutagen Society, held from October 24-28, 2009 in St. Louis, MO, surveyed the current status and future directions of genetic toxicology. This article summarizes the presentations and provides a perspective on the future. An abbreviated history is presented, highlighting the current standard battery of genotoxicity assays and persistent challenges. Application of computational toxicology to safety testing within a regulatory setting is discussed as a means for reducing the need for animal testing and human clinical trials, and current approaches and applications of in silico genotoxicity screening approaches across the pharmaceutical industry were surveyed and are reported here. The expanded use of toxicogenomics to illuminate mechanisms and bridge genotoxicity and carcinogenicity, and new public efforts to use high-throughput screening technologies to address lack of toxicity evaluation for the backlog of thousands of industrial chemicals in the environment are detailed. The Tox21 project involves coordinated efforts of four U.S. Government regulatory/research entities to use new and innovative assays to characterize key steps in toxicity pathways, including genotoxic and nongenotoxic mechanisms for carcinogenesis. Progress to date, highlighting preliminary test results from the National Toxicology Program is summarized. Finally, an overview is presented of ToxCastTM, a related research program of the U.S. Environmental Protection Agency, using a broad array of high throughput and high content technologies for toxicity profiling of environmental chemicals, and computational toxicology modeling. Progress and challenges, including the pressing need to incorporate metabolic activation capability, are summarized. PMID- 21538558 TI - Fenthion and terbufos induce DNA damage, the expression of tumor-related genes, and apoptosis in HEPG2 cells. AB - This study investigates the effects of fenthion and terbufos, two organophosphorous pesticides, on DNA damage, tumor-related gene expression, and apoptosis in HepG2 cells. We found that exposure to concentrations ranging from 50 to 200 MUM of fenthion and terbufos for 2 hr caused significant death in HepG2 cells. Both compounds induced DNA damage in a concentration-dependent manner as measured using the alkaline comet assay. Tumor-related genes (jun, myc, and fos) and apoptosis-related genes (socs3, tnfaip3, ppp1r15a, and nr4a1) were up regulated by both compounds. Finally, both compounds induced apoptosis. The results demonstrate that both terbufos and fenthion induce DNA damage and should be considered potentially hazardous to humans. PMID- 21538559 TI - Characterization of environmental chemicals with potential for DNA damage using isogenic DNA repair-deficient chicken DT40 cell lines. AB - Included among the quantitative high throughput screens (qHTS) conducted in support of the US Tox21 program are those being evaluated for the detection of genotoxic compounds. One such screen is based on the induction of increased cytotoxicity in seven isogenic chicken DT40 cell lines deficient in DNA repair pathways compared to the parental DNA repair-proficient cell line. To characterize the utility of this approach for detecting genotoxic compounds and identifying the type(s) of DNA damage induced, we evaluated nine of 42 compounds identified as positive for differential cytotoxicity in qHTS (actinomycin D, adriamycin, alachlor, benzotrichloride, diglycidyl resorcinol ether, lovastatin, melphalan, trans-1,4-dichloro-2-butene, tris(2,3-epoxypropyl)isocyanurate) and one non-cytotoxic genotoxic compound (2-aminothiamine) for (1) clastogenicity in mutant and wild-type cells; (2) the comparative induction of gammaH2AX positive foci by melphalan; (3) the extent to which a 72-hr exposure duration increased assay sensitivity or specificity; (4) the use of 10 additional DT40 DNA repair deficient cell lines to better analyze the type(s) of DNA damage induced; and (5) the involvement of reactive oxygen species in the induction of DNA damage. All compounds but lovastatin and 2-aminothiamine were more clastogenic in at least one DNA repair-deficient cell line than the wild-type cells. The differential responses across the various DNA repair-deficient cell lines provided information on the type(s) of DNA damage induced. The results demonstrate the utility of this DT40 screen for detecting genotoxic compounds, for characterizing the nature of the DNA damage, and potentially for analyzing mechanisms of mutagenesis. PMID- 21538560 TI - Deletion of oligodendrocyte Cx32 and astrocyte Cx43 causes white matter vacuolation, astrocyte loss and early mortality. AB - CNS glia exhibit a variety of gap junctional interactions: between neighboring astrocytes, between neighboring oligodendrocytes, between astrocytes and oligodendrocytes, and as 'reflexive' structures between layers of myelin in oligodendrocytes. Together, these junctions are thought to form a network facilitating absorption and removal of extracellular K(+) released during neuronal activity. In mice, loss of the two major oligodendrocyte connexins causes severe demyelination and early mortality, while loss of the two major astrocyte connexins causes mild dysmyelination and sensorimotor impairment, suggesting that reflexive and/or oligo-oligo coupling may be more important for the maintenance of myelin than other forms. To further explore the functional relationships between glial connexins, we generated double knockout mice lacking one oligodendrocyte and one astrocyte connexin. Cx32-Cx43 dKO animals develop white matter vacuolation without obvious ultrastructural abnormalities in myelin. Progressive loss of astrocytes but not oligodendrocytes or microglia accompanies sensorimotor impairment, seizure activity and early mortality at around 16 weeks of age. Our data reveal an unexpected role for connexins in the survival of white matter astrocytes, requiring the expression of particular isoforms in both oligodendrocytes and astrocytes. PMID- 21538562 TI - Differential and cooperative actions of Olig1 and Olig2 transcription factors on immature proliferating cells after contusive spinal cord injury. AB - Spontaneous remyelination after spinal cord injury (SCI) is limited probably due to inadequate signaling to generate sufficient OLs from progenitor cells. The present study tested a hypothesis that introduction of olig genes, critical regulators of OL development, into immature proliferating cells could increase oligodendrogenesis after contusive SCI in adult rats. Recombinant retroviruses encoding Olig1 and Olig2 transcription factors, separately or in combination, with green fluorescent protein (GFP) were injected into the injured spinal cord. Unexpectedly, introduction of Olig2-GFP retroviruses led to a marked hyperplasia of GFP+ cells at 1 week, and soft agar colony forming assay of isolated GFP+ cells confirmed Olig2-induced tumorous transformation. In contrast, Olig1 did not alter the number of GFP+ cells. Simultaneous expression of Olig1 and Olig2 (Olig1/2) led to a marked increase in the number of GFP+ cells without tumor formation. The proportion of GFP+ cells with OL progenitor markers was increased by Olig1/2. Moreover, Olig1/2 robustly increased the proportion of mature OLs and expression of myelin related proteins, while Olig1 alone exhibited only modest effects. Olig1/2 upregulated Sox10, which drives terminal OL differentiation, implicating Sox 10 as a mediator of Olig1/2 effects on the maturation. Finally, injection of Olig1/2 retroviruses significantly improved a quality of hindpaws locomotion and increased the total number of OLs after SCI. Activation of both Olig1 and Olig2 may be beneficial by both increasing the progenitor cell proliferation and enhancing OL differentiation in the injured spinal cord. PMID- 21538563 TI - Morphogenesis of the human palma arch using three-dimensional geometric modeling. AB - The hand goes through complex morphological modifications during embryogenesis. The goal of this study was to use geometric modeling to study the morphometric modifications of the palmar arch. Five embryos were used for the study (sizes: 15, 17, 23, 30, and 44 mm). After digitalization of histologic sections (Sony DXC 930P 3CCD camera, Leica Qwin) and segmentation of the metacarpal cartilaginous matrices (Winsurf 4.3 software), geometric modeling and calculations were performed using MSC.Patran 2005r2 software. Correlations (r > 0.99) were found between embryo size and metacarpal volume, metacarpal surface, and the surface of the modeled palmar arch. The growth of the palmar arch is nonhomothetic. Significant reduction (P = 0.05) in the divergence of the 2nd, 3rd, 4th, and 5th metacarpals was observed. Deepening of the palmar arch is correlated with embryo size and age (r > 0.99). Geometric modeling allows 3D rendering of histologic sections and thus quantitative description of the morphogenesis. The results of this study support the hypothesis that opposition of the thumb in correlation with deepening of the palmar arch appears early in embryological development. It constitutes a specific morphological characteristic that appears very early in the human phylum. The fact that the human thumb is naturally in opposition in the resting position is a consequence of this morphogenesis. The thumb's resting position has received little attention in clinical settings and should be considered as the reference position for biomechanical analysis of the thumb column. PMID- 21538564 TI - Shape variation of the neural arch in the thoracic and lumbar spine: characterization and relationship with the vertebral body shape. AB - Quantifying the human vertebral geometry is important for accurate medical procedures. We aimed to characterize the neural arch (NA) shape at T1-L5. All T1 L5 dry vertebrae (N = 4,080) of 240 individuals were measured and analyzed by age, gender, and ethnicity. A 3D digitizer was used to measure the dimensions of the spinous (SP) and transverse (TP) processes, vertebral canal (VC), laminae, and isthmus. Most parameters were independent of age and ethnicity, yet greater in males than in females. Isthmus length increases from T1 (9.8 mm) to T12 (19.87 mm) and decreases from T12 to L5 (9.68 mm) with right > left in the thorax and oppositely in the lumbar region. The SP is longer than its thickness both decreasing in the upper thorax (by ca. 4mm), increasing in the lower thoracic and upper lumbar vertebrae (by 7 mm for length and ca. 14.5 mm for thickness) and decreasing again along the lower lumbar vertebrae (both by 8 mm). The TP length decreases at T1-T12 (by 13 mm) and increases at L1-L5 with left > right at T1-L5 (P < 0.003). The laminar length decreases from T1 (8.72 mm) through T5 (4.76 mm) and increases toward L5 (8.4 mm) with right > left at T1-L5 (P < 0.003). The VC is oval-shaped at T1 and T11-L5 (width > length), rounded-shape at T2 and T10 (width = length), and inverted oval-shaped at T3-T9 (length > width). In conclusion, the NA is systematically asymmetrical and dynamic in shape along the thoracic and lumbar spine. The inter-relationship with the vertebral body and articular facets is discussed. PMID- 21538561 TI - Drosophila melanogaster as a model system for human brain cancers. AB - Glioblastomas (GBM), the most common primary brain tumors, infiltrate the brain, grow rapidly, and are refractory to current therapies. Signature genetic lesions in glioblastomas include mutation of the epidermal growth factor receptor tyrosine kinase (EGFR) receptor tyrosine kinase and activating mutations in components of the PI-3 kinase (PI3K) pathway. Despite years of study, how these pathways specifically regulate glial pathogenesis is unclear. To address the genetic and cellular origins of this disease, a novel Drosophila GBM model has been developed in which glial progenitor cells give rise to proliferative and invasive neoplastic cells that create transplantable tumors in response to constitutive co-activation of the EGFR-Ras and PI3K pathways. Standing with a rich literature demonstrating the direct relevance of Drosophila to studies on human cancer, neurological disease, and neurodevelopment, this model represents a robust cell-type specific Drosophila neurological disease model in which malignant cells are created by mutations in genetic pathways thought to be driving forces in a homologous human disease. Using lineage analysis and cell type specific markers, neoplastic glial cells were found to originate from committed glial progenitor cells, rather than from multipotent neuroblasts. Genetic analyses demonstrated that EGFR-Ras and PI3K induce fly glial neoplasia through activation of a combinatorial genetic network composed, in part, of other genetic pathways also commonly mutated in human glioblastomas. In the future, large-scale forward genetic screens with this model may reveal new insights into the origins and treatments of human glioblastoma. PMID- 21538565 TI - Early fetal development of the intermediate tendon of the human digastricus and omohyoideus muscles: a critical difference in histogenesis. AB - The digastricus and omohyoideus muscles are known to carry two muscle bellies connected by an intermediate tendon. However, according to our histological observations of 22 fetuses (7-20 weeks of gestation), the mode of formation of the intermediate tendon was critically different between these two muscles. At 7 9 weeks, the posterior belly of the digastricus carried a definite intramuscular tendon continuous with a long descending tendon. The stylohyoideus, external carotid artery and hypoglossal nerve appeared to impede attachment of the tendon to the Reichert or hyoid cartilage. The digastricus anterior belly did not contain any intramuscular tendon, but desmin-positive muscle fibers consistently surrounded a bulb-like mesenchymal condensation at the caudal free end of the digastricus posterior tendon. Thus, most parts of the digastricus tendon were apparently derived from the posterior belly. In contrast, the omohyoideus always possessed a single long muscle belly until 15 weeks. The intermediate tendon first appeared at 15 weeks as a short plate-like connective structure along the medial margin of the muscle. Vimentin immunoreactivity suggested the presence of mechanical stress along the plate-like tissue, possibly due to bending of the long muscle. Muscle fibers were replaced by collagen fibers to form an intermediate tendon by 20 weeks. PMID- 21538566 TI - Swelling around a child's knee. AB - Swellings around the paediatric knee have a large differential diagnosis, although the majority can be diagnosed clinically. Some swellings merit further investigation by Magnetic Resonance Imaging (MRI). PMID- 21538567 TI - Synostosis of the joint between the body and greater cornu of the human hyoid bone. AB - The structure of the joint between the body and the greater cornu in the human hyoid bone was examined histologically in 259 cadavers (16-98 years). Joints were classified into three grades based on histological observations. Grade I showed fibrocartilage without degenerative change in the marginal region of the joint. Grade II showed prominent calcification or ossification on the outer margin of the joint without fusion. Grade III showed bony fusion. Histological changes with age were revealed by a comparison of the prevalences of these three grades among individuals of three age groups: young adult (16-39 years), middle aged (40-69 years), and elderly (70+ years). The frequency of hyoid bones with diarthrodial structure of this joint was compared between the age groups. The mean age of subjects with each grade of histological changes was calculated. Results show that, with age, the proportion of Grade I decreased significantly (P < 0.05) and that of Grade III increased significantly. Joints with diarthrodial structure decreased significantly with age relative to all subjects (P < 0.05). Clefts with necrotic tissue were observed in cartilage along with progressive calcification. The mean age of subjects with the histological changes was significantly higher than that of individuals without such changes (P < 0.05). Calcification and ossification of joints were induced with age from fibrous tissue and cartilage on the outer margin of a joint. The authors suggest that the age changes in the joint between the body and greater cornu of the hyoid bone may affect the mobility of this joint and may be related to masticatory and swallowing functions. PMID- 21538568 TI - Origins and distribution of nerves to the female urinary bladder: new anatomical findings in the sex differences. AB - The development of nerve-sparing procedures is important in preventing bladder dysfunction following radical hysterectomy. In this study, we dissected 14 halves of 7 female pelvises (age range: 46-86 years; mean age: 74 years) to examine the origins, courses, and distributions of nerve branches to the bladder in females in detail, and 6 halves of 3 male pelvises (age range: 71-85 years, mean age: 78 years) to compare with the female specimens. Nerve branches to the bladder originated mainly from the inferior hypogastric plexus, but independent direct branches running along the ureter from the hypogastric nerve were also distributed particularly to the trigone in all female specimens. We classified these independent branches into four types according to their relationship to the ureter. In males the numbers of the independent branches were small and they were difficult to find. The present observations indicate that nerve distribution patterns to the bladder differ between females and males. In nerve sparing procedures for radical hysterectomy, the area between the ureter and the hypogastric nerve is important. PMID- 21538569 TI - Anomalous peroneus (fibularis) longus muscle: An atypical insertion and incomplete distal tendon. PMID- 21538570 TI - Dissecting the accessory soleus muscle: a literature review, cadaveric study, and imaging study. AB - The accessory soleus muscle (ASM) has been an unusual anatomical variant since its first recordings in Guy's Hospital Reports of the early nineteenth century. Individuals with an ASM may present with symptoms of pain and/or swelling and were often misdiagnosed as soft-tissue tumors such as hemangioma, sarcoma, or lipoma. The aim of our study was threefold: (1) to review the cadaveric and clinical literature to determine the reported prevalence of ASM; (2) to conduct a cadaveric study investigating the prevalence and attachment sites of the ASM; (3) to conduct a retrospective analysis of magnetic resonance imaging (MRI) of patients presenting with ankle symptoms to determine prevalence and attachment sites of the ASM. Our findings demonstrated that the prevalence of the muscle (3%) was as stated in the literature (0.7-5.5%), but with males more likely to possess unilateral ASM and females more likely to possess bilateral ASM. Three common attachment types were reported in the literature: (i) a distal attachment to the medial aspect of the calcaneus by a separate tendon (26.1% of ASM subjects), (ii) a distal tendinous attachment to the calcaneal tendon (3.5%), and (iii) a distal fleshy attachment to the medial surface of the calcaneus (4.3%), with the remaining 66.1% of ASM subjects from previous studies with unidentified attachment types. Our cadaveric specimens were found to possess each attachment type, whereas imaging patients all possessed distal attachments to the medial calcaneus via a separate tendon. Furthermore, a rare cadaveric specimen with two distal attachments was also found. We believe it is important to recognize the prevalence of this condition and be aware of its morphology in order to understand its clinical presentation, accurately diagnose the condition, and pursue effective forms of management. PMID- 21538571 TI - Asymmetric anionic polymerization of 2,7-bis(4-t-butylphenyl)fluoren-9-ylmethyl methacrylate and photoinduced structural transition of the obtained polymer. AB - 2,7-Bis(4-t-butylphenyl)fluoren-9-ylmethyl methacrylate (BBPFMMA) was synthesized as a new candidate of a bulky monomer suitable for asymmetric anionic polymerization (IUPAC nomenclature: asymmetric helix-chirogenic polymerization) leading to a preferred-handed helical, optically active polymer. The new monomer was polymerized using the complex of 9-fluorenyllithium and (S)-(+)-1-(2 pyrrolidinylmethyl)pyrrolidine in toluene at -78 degrees C. As opposed to the original intention to obtain a polymethacrylate, the monomer seemed to undergo structural transition (decomposition) giving 2,7-bis(4-t butylphenyl)dibenzofulvene and the obtained polymer was most probably a terpolymer of BBPFMMA, 2,7-bis(4-t-butylphenyl)dibenzofulvene, and methacrylic acid. The obtained polymer showed circular dichroism (CD) spectra, indicating that chirality had been introduced to the copolymer chain during the course of polymerization. On photo irradiation, the polymer underwent a structural transition involving a remarkable decrease in apparent molecular weight measured by size-exclusion chromatography (SEC) and changes in FT-IR spectral patterns. However, the CD spectrum of the polymer was not obviously altered by irradiation, indicating that polymer chirality is not affected by light. PMID- 21538572 TI - Asymmetric polymerizations of chiral 4-benzyl-2-ethynyloxazoline with rhodium catalyst and chiroptical properties of the polymers. AB - Optically active 4-alkyl-2-ethynyloxazoline derivatives (BnEOx) were polymerized with rhodium catalysts. The polymerization in toluene produced polymer with the highest absolute values of specific rotation ([alpha](D) = -77.3 degrees ). The yields, molecular weights, and specific rotations of poly(BnEOx)s were influenced by polymerization conditions. The copolymerization with phenylacetylene (PA) was effective to increase the molecular weight of the copolymer. It is interesting to note that the copolymers exhibited positive specific rotations ([alpha](D) = +4.7 degrees to +62.5 degrees ) despite the fact that [alpha](D) s of BnEOx and the homopolymer are negative sign. The chiroptical properties were investigated by the chiral/achiral copolymerization of BnEOx with PA. The copolymerizations of BnEOx with PA gave copolymers containing higher order structure such as one handed helical conformation. Furthermore, induced Cotton effects were observed in the pi-pi* transition region of conjugated main chain depending a complex of these polymers with zinc triflate salt in tetrahydrofuran solution, indicating the formation of chiral supramolecular aggregates. PMID- 21538573 TI - Direct asymmetric N-specific reaction of nitrosobenzene with aldehydes catalyzed by a chiral primary amine-based organocatalyst. AB - Nitroso compounds have two reactive nitrogen and oxygen atoms. It is interesting and important to perform a nitrogen or oxygen selective reaction with interesting substrates. These atom specific reactions are crucial to specifically synthesis of specific compounds. An enantioselective N-specific reaction of nitrosobenzene with unmodified aldehydes was successfully achieved catalyzed first by a variety of primary amine-based organocatalysts with higher yield and enantioselectivity. The bulkier substituted groups of the organocatalyst and two hydrogen bonds from the organocatalyst and the oxygen atom of nitrosobenzene make the reaction preferentially N-specific and predominantly afford R products. PMID- 21538575 TI - Experimental and theoretical studies of vacuum-ultraviolet electronic circular dichroism of hydroxy acids in aqueous solution. AB - The electronic circular dichroism (ECD) spectra of three L-hydroxy acids (L lactic acid, (+)-(S)-2-hydroxy-3-methylbutyric acid, and (-)-(S)-2 hydroxyisocaproic acid) were measured down to 160 nm in aqueous solution using a vacuum-ultraviolet ECD spectrophotometer. To assign the two positive peaks around 210 and 175 nm and the one negative peak around 190 nm in the observed spectra, the ECD spectrum of L-lactic acid was calculated using time-dependent density functional theory (DFT) for the optimized structures by DFT and a continuum model. The observed ECD spectrum was successfully reproduced as the average spectrum for four optimized structures with seven water molecules that localized around the COO(-) and OH groups of L-lactic acid. The positive peak around 210 nm and the negative peak around 185 nm in the calculated spectrum were attributable to the npi* transition of the carboxyl group, with the latter peak also being influenced by the pipi* transition of the carboxyl group; however, the positive peak around 165 nm involved unassignable higher energy transitions. The comparison of the calculated ECD spectra for L-lactic acid and L-alanine revealed that the network with loose hydrogen bonding around the COO(-) and OH groups is responsible for the flexible conformation of hydroxy acids and complicated side chain dependence of ECD spectra relative to amino acids. PMID- 21538574 TI - Interaction of cyclooxygenase-2 promoter polymorphisms with Helicobacter pylori infection and risk of gastric cancer. AB - Overexpression of cyclooxygenase (COX)-2 has been implicated in the development of cancer. This study aimed to evaluate the relationship between genetic variants in COX-2 promoter interacting with Helicobacter pylori and the susceptibility to gastric cancer (GC). Three COX-2 polymorphisms -1290A>G (rs689465), -1195G>A (rs689466), and -765G>C (rs20417) were genotyped in 323 GC patients and 944 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression model. In GC patients, the ORs were 2.33 (95% CI = 1.50-3.63) and 2.70 (95% CI = 1.68-4.33) for -1195AA and -765CG genotype carriers, respectively. Haplotype analysis showed all -1195A allele-containing haplotypes, except G(-1290)-A(-1195)-G(-765), were associated with increased risk for GC, compared with the A(-1290)-G(-1195)-G(-765) haplotype. Moreover, significant multiplicative and additive interactions were observed between H. pylori infection and all these three polymorphisms, and H. pylori-infected subjects carrying the variant allele of -1290A>G, -1195G>A, or -765G>C had increased risk of GC compared with non-H. pylori-infected subjects with wild-type allele (OR = 4.10, 95% CI = 1.90-8.83; OR = 3.46, 95% CI = 1.31-9.11; and OR = 3.32, 95% = 1.27-8.73, respectively). Our results suggested that the COX-2 promoter polymorphisms were associated with increased risk of GC, especially interacting with H. pylori infection. PMID- 21538576 TI - Neocarzinostatin as a probe for DNA protection activity--molecular interaction with caffeine. AB - Neocarzinostatin (NCS), a potent mutagen and carcinogen, consists of an enediyne prodrug and a protein carrier. It has a unique double role in that it intercalates into DNA and imposes radical-mediated damage after thiol activation. Here we employed NCS as a probe to examine the DNA-protection capability of caffeine, one of common dietary phytochemicals with potential cancer chemopreventive activity. NCS at the nanomolar concentration range could induce significant single- and double-strand lesions in DNA, but up to 75 +/- 5% of such lesions were found to be efficiently inhibited by caffeine. The percentage of inhibition was caffeine-concentration dependent, but was not sensitive to the DNA lesion types. The well-characterized activation reactions of NCS allowed us to explore the effect of caffeine on the enediyne-generated radicals. Postactivation analyses by chromatographic and mass spectroscopic methods identified a caffeine quenched enediyne-radical adduct, but the yield was too small to fully account for the large inhibition effect on DNA lesions. The affinity between NCS chromophore and DNA was characterized by a fluorescence-based kinetic method. The drug-DNA intercalation was hampered by caffeine, and the caffeine-induced increases in DNA-drug dissociation constant was caffeine-concentration dependent, suggesting importance of binding affinity in the protection mechanism. Caffeine has been shown to be both an effective free radical scavenger and an intercalation inhibitor. Our results demonstrated that caffeine ingeniously protected DNA against the enediyne-induced damages mainly by inhibiting DNA intercalation beforehand. The direct scavenging of the DNA-bound NCS free radicals by caffeine played only a minor role. PMID- 21538577 TI - Focal adhesion kinase is required for KSHV vGPCR signaling. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma, an angiogenic and inflammatory endothelial cell (EC) tumor that is common in areas of high KSHV prevalence. KSHV encodes a pro-angiogenic viral chemokine receptor (vGPCR) that promotes EC growth in vitro and KS-like tumors in mouse models. vGPCR is therefore considered a viral oncogene that plays a crucial role in the pathobiology of KS. In this study, we show that focal adhesion kinase (FAK) becomes activated upon vGPCR expression in primary ECs and that FAK is required for vGPCR-mediated activation of ERK1/2, NFkappaB, AP-1, and vGPCR induced migration and inhibition of anoikis. FAK is crucial to cell motility and tumor invasiveness and is a potential therapeutic target in various malignancies. Our data show that via vGPCR, KSHV has evolved a way to constitutively activate FAK signaling. PMID- 21538578 TI - Genetic polymorphisms in APE1 are associated with renal cell carcinoma risk in a Chinese population. AB - Apurinic/apyrimidinic endonuclease 1 (APE1) is a DNA repair protein, which plays important roles in the base excision repair (BER) pathway. Genetic variations of APE1 have been shown to influence an individual's susceptibility to carcinogenesis. We hypothesized the genetic polymorphisms of APE1 are associated with the risk of renal cell carcinoma (RCC). In a case-control study of 612 RCC patients and 632 age and sex matched healthy controls, we genotyped two APE1 functional polymorphisms (-656 T>G, rs1760944 and 1349 T>G, rs1130409) and assessed their associations with risk of RCC. We found that, compared with 1349 TT/TG genotypes, the variant genotype 1349 GG had a significantly increased RCC risk [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.10-1.95], particularly among subgroups of BMI > 23 kg/m(2) (OR = 1.54, 95% CI = 1.06-2.22), male (OR = 1.70, 95% CI = 1.17-2.46), never smokers (OR = 1.56, 95% CI = 1.11 2.21), light smokers (OR = 2.01, 95%CI = 1.02-3.95), and drinkers (OR = 2.00, 95% CI = 1.13-3.54). Furthermore, the polymorphism was significantly associated with risk of developing localized stage RCC. No altered RCC risk was associated with the -656 T>G polymorphism, but we found individuals who were homozygous for both risk alleles of the two SNPs had a 2.17-fold increased risk for RCC, compared to individuals with 0 risk alleles. Our results suggest that polymorphisms of APE1 may confer susceptibility to RCC. PMID- 21538580 TI - Apigenin, a chemopreventive bioflavonoid, induces AMP-activated protein kinase activation in human keratinocytes. AB - AMP-activated protein kinase (AMPK) is a cellular energy sensor that is conserved in eukaryotes. Although AMPK is traditionally thought to play a major role in the regulation of cellular lipid and protein metabolism, recent discoveries reveal that AMPK inhibits mammalian target of rapamycin (mTOR) signaling and connects with several tumor suppressors such as liver kinase B1 (LKB1), p53, and tuberous sclerosis complex 2 (TSC2), indicating that AMPK may be a potential target for cancer prevention and treatment. For the first time, we demonstrated that apigenin, a naturally occurring nonmutagenic flavonoid, induced AMPK activation in human keratinocytes (both cultured HaCaT cell line and primary normal human epidermal keratinocytes). Through experiments with over-expression of constitutively active Akt and knockdown of LKB1 expression by siRNAs, we further found that the activation of AMPK by apigenin was not dependent on its inhibition of Akt, and was independent of the activation of upstream kinase LKB1. Instead, another upstream kinase of AMPK, calcium/calmodulin-dependent protein kinase kinase-beta (CaMKKbeta), was required for apigenin-induced AMPK activation. We have demonstrated that knockdown of CaMKKbeta expression by siRNA or inhibition of CaMKKbeta activity by either CaMKK inhibitor STO-609 or BAPTA-AM (1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester; a chelator of intracellular Ca(2+)) prevented apigenin-induced AMPK activation. Apigenin induced AMPK activation inhibited mTOR signaling and further induced autophagy in human keratinocytes. These results suggest that one of the mechanisms by which apigenin exerts its chemopreventive action may be through activation of AMPK and induction of autophagy in human keratinocytes. PMID- 21538581 TI - Association of a common genetic variant in prostate stem-cell antigen with gastric cancer susceptibility in a Korean population. AB - A recent genome wide association study (GWAS) indentified a significant association between rs2294008 (C > T) polymorphism in prostate stem-cell antigen (PSCA) and increased risk of gastric cancer in Japanese and Korean populations. The aim of this study was to determine whether rs2294008 polymorphism is associated with risk of gastric cancer in a Korean population. We conducted a large-scale case-control study of 3,245 gastric cancer patients and 1,700 controls. The frequencies of the CC, CT, and TT genotypes of rs2294008 polymorphism were 17.8%, 49.9%, and 32.3% in the gastric cancer patients; and 24.4%, 48.1%, and 27.5% in the controls, respectively. We found that the CT and TT genotypes were associated with a significantly increased risk of gastric cancer (OR(CT) = 1.50, 95% confidence intervals, 95% CI: 1.28-1.76; OR(TT) = 1.71, 95% CI: 1.43-2.04), compared with the CC genotype. Further, stratified by tumor location and histological type, the effect of the rs2294008 T allele was larger in cardia (OR(TT) = 2.62, 95% CI = 1.42-4.85) than non-cardia (OR(TT) = 1.67, 95% CI = 1.40-2.00), in diffuse-type (OR(TT) = 2.00, 95% CI: 1.55-2.59) than in intestinal-type (OR(TT) = 1.51, 95% CI: 1.22-1.86). Our study showed that rs2294008 in the PSCA gene was associated with increased risks of gastric cancer in a Korean population, suggests that rs2294008 might play an important role in gastric carcinogenesis. PMID- 21538583 TI - Multilevel data storage memory devices based on the controlled capacitive coupling of trapped electrons. PMID- 21538579 TI - Protective role of cathepsin L in mouse skin carcinogenesis. AB - Lysosomal cysteine protease cathepsin L (CTSL) is believed to play a role in tumor progression and is considered a marker for clinically invasive tumors. Studies from our laboratory using the classical mouse skin carcinogenesis model, with 7,12-dimethyl-benz[a]anthracene (DMBA) for initiation and 12-O tetradecanoylphorbol-13-acetate (TPA) for promotion, showed that expression of CTSL is increased in papillomas and squamous cell carcinomas (SCC). We also carried out carcinogenesis studies using Ctsl-deficient nackt (nkt) mutant mice on three different inbred backgrounds. Unexpectedly, the multiplicity of papillomas was significantly higher in Ctsl-deficient than in wild-type mice on two unrelated backgrounds. Topical applications of TPA or DMBA alone to the skin of nkt/nkt mice did not induce papillomas, and there was no increase in spontaneous tumors in nkt/nkt mice on any of the three inbred backgrounds. Reduced epidermal cell proliferation in Ctsl-deficient nkt/nkt mice after TPA treatment suggested that they are not more sensitive than wild-type mice to TPA promotion. We also showed that deficiency of CTSL delays terminal differentiation of keratinocytes, and we propose that decreased elimination of initiated cells is at least partially responsible for the increased papilloma formation in the nackt model. PMID- 21538585 TI - The direct writing of plasmonic gold nanostructures by electron-beam-induced deposition. PMID- 21538586 TI - Atomically resolved mapping of polarization and electric fields across ferroelectric/oxide interfaces by Z-contrast imaging. PMID- 21538587 TI - Rational molecular design of stimulus-responsive supramolecular hydrogels based on dipeptides. PMID- 21538588 TI - Stretchable inorganic-semiconductor electronic systems. PMID- 21538589 TI - Highly efficient orange and white organic light-emitting diodes based on new orange iridium complexes. PMID- 21538590 TI - Tunneling negative differential resistance in a flexible active composite. PMID- 21538591 TI - Superhydrophobic tracks for low-friction, guided transport of water droplets. PMID- 21538592 TI - Painting by numbers: nanoparticle-based colorants in the post-empirical age. AB - The visual appearance of the artificial world is largely governed by films or composites containing particles with at least one dimension smaller than a micron. Over the past century and a half, the optical properties of such materials have been scrutinized and a broad range of colorant products, based mostly on empirical microstructural improvements, developed. With the advent of advanced synthetic approaches capable of tailoring particle shape, size and composition on the nanoscale, the question of what is the optimum particle for a certain optical property can no longer be answered solely by experimentation. Instead, new and improved computational approaches are required to invert the structure-function relationship. This progress report reviews the development in our understanding of this relationship and indicates recent examples of how theoretical design is taking an ever increasingly important role in the search for enhanced or multifunctional colorants. PMID- 21538593 TI - Ultrahigh strength and stiffness in cross-linked hierarchical carbon nanotube bundles. PMID- 21538594 TI - Smooth nanowire/polymer composite transparent electrodes. PMID- 21538595 TI - Application of the protection/deprotection strategy to the science of porous materials. PMID- 21538596 TI - Porous silicon microcavities based photonic barcodes. PMID- 21538597 TI - Underwater oil capture by a three-dimensional network architectured organosilane surface. PMID- 21538600 TI - Functionalization of mesoporous carbon with superbasic MgO nanoparticles for the efficient synthesis of sulfinamides. AB - Highly basic MgO nanoparticles with different sizes have been successfully immobilized over mesoporous carbon with different pore diameters by a simple wet impregnation method. The prepared catalysts have been characterized by various sophisticated techniques, such as XRD, nitrogen adsorption, electron energy loss spectroscopy, high-resolution TEM, X-ray photoelectron spectroscopy, and the temperature-programmed desorption of CO(2). XRD results reveal that the mesostructure of the support is retained even after the huge loading of MgO nanoparticles inside the mesochannels of the support. It is also demonstrated that the particle size and dispersion of the MgO nanoparticles on the support can be finely controlled by the simple adjustment of the textural parameters of the supports. Among the support materials studied, mesoporous carbon with the largest pore diameter and large pore volume offered highly crystalline small-size cubic phase MgO nanoparticles with a high dispersion. The basicity of the MgO-supported mesoporous carbons can also be controlled by simply changing the loading of the MgO and the pore diameter of the support. These materials have been employed as heterogeneous catalysts for the first time in the selective synthesis of sulfinamides. Among the catalysts investigated, the support with the large pore diameter and high loading of MgO showed the highest activity with an excellent yield of sulfinamides. The catalyst also showed much higher activity than the pristine MgO nanoparticles. The effects of the reaction parameters, including the solvents and reaction temperature, and textural parameters of the supports in the activity of the catalyst have also been demonstrated. Most importantly, the catalyst was found to be highly stable, showing excellent activity even after the third cycle of reaction. PMID- 21538601 TI - Hierarchical self-assembly of amphiphilic peptide dendrons: evolution of diverse chiral nanostructures through hydrogel formation over a wide pH range. AB - An amphiphilic dendron containing three dendrite L-glutamic acid units and a long alkyl chain was synthesized by a convergent method. It was found that the dendron could form hydrogels over a wide pH range from 2 to 13. Moreover, accompanying the pH change, the compounds self-assembled into various chiral structures: from helical nanotube, helical nanotube with a string of beads, and coiled superhelix to dendrite nanostructures, such as pine, feather, etc. A series of characterizations based on TEM observations, X-ray diffraction and FTIR spectroscopic measurements revealed that the dendron formed a bilayer first and then hierarchically self-assembled into various chiral nanostructures. The four carboxylic acid groups and three amide groups played an important role in the self-assembly. The interaction between the multiamide groups stabilized the bilayer structures, whereas the ionization degree of the carboxylic acids was responsible for the formation of various chiral structures. The work presented a hydrogel system with wide pH adaptability and showed the regulation on chiral structures by simple pH variations. PMID- 21538602 TI - Going full circle: phase-transition thermodynamics of ionic liquids. AB - We present the full enthalpic phase transition cycle for ionic liquids (ILs) as examples of non-classical salts. The cycle was closed for the lattice, solvation, dissociation, and vaporization enthalpies of 30 different ILs, relying on as much experimental data as was available. High-quality dissociation enthalpies were calculated at the G3 MP2 level. From the cycle, we could establish, for the first time, the lattice and solvation enthalpies of ILs with imidazolium ions. For vaporization, lattice, and dissociation enthalpies, we also developed new prediction methods in the course of our investigations. Here, as only single-ion values need to be calculated and the tedious optimization of an ion pair can be circumvented, the computational time is short. For the vaporization enthalpy, a very simple approach was found, using a surface term and the calculated enthalpic correction to the total gas-phase energy. For the lattice enthalpy, the most important constituent proved to be the calculated conductor-like screening model (COSMO) solvation enthalpy in the ideal electric conductor. A similar model was developed for the dissociation enthalpy. According to our assessment, the typical error of the lattice enthalpy would be 9.4 kJ mol(-1), which is less than half the deviation we get when using the (optimized) Kapustinskii equation or the recent volume-based thermodynamics (VBT) theory. In contrast, the non-optimized VBT formula gives lattice enthalpies 20 to 140 kJ mol(-1) lower than the ones we assessed in the cycle, because of the insufficient description of dispersive interactions. Our findings show that quantum-chemical calculations can greatly improve the VBT approaches, which were parameterized for simple, inorganic salts with ideally point-shaped charges. In conclusion, we suggest the term "augmented VBT", or "aVBT", to describe this kind of theoretical approach. PMID- 21538603 TI - Increasing the isomerisation kinetics of azo dyes by chemical bonding to liquid crystalline polymers. AB - It is well known that the proper substitution of the azobenzene core allows tuning the thermal cis-to-trans isomerisation kinetics of azo dyes. The thermal isomerisation process of nitro-substituted azobenzenes is accelerated up to 13 times with respect to that in the common isotropic solvents when they are doped in nematic low molar mass liquid crystals. This kinetic acceleration is even stronger when these azo dyes are covalently linked to a nematic siloxane polymer. In this environment, the isomerisation process is accelerated more than 10(3) times. This effect is presented herein for the first time. The possible application of the networks obtained as possible photo-actuators has been also considered. PMID- 21538604 TI - On the mechanism of irreversible carbon dioxide binding with a frustrated lewis pair: solvent-assisted frustration and transition-state entropic encouragement. AB - The mechanism of irreversible carbon dioxide binding with a Lewis pair Mes(3)P:AlCl(3) (Mes=2,4,6-C(6)H(2)Me(3)) is computationally investigated to reveal that the steric congestion is not the driving force for the activation of CO(2). Instead, we find that the specific solute-solvent interaction between the Lewis acid and a bromobenzene molecule lowers the effective binding energy of the Lewis pair. This solvation effect affects the reaction in a similar manner to the steric encumbering of conventional frustrated Lewis pairs. Additionally, the transition state toward the CO(2) binding becomes extraordinarily flexible upon solvation. This flexibility encourages the adduct formation entropically and thus lowers the free-energy barrier of the reaction. We conclude that this combination of energy-barrier lowering through solvent-assisted frustration and the entropic encouragement generates a feasible activation route for CO(2) under mild conditions. PMID- 21538605 TI - Controlling the duality of the mechanism in liquid-phase oxidation of benzyl alcohol catalysed by supported Au-Pd nanoparticles. AB - In the solvent-free oxidation of benzyl alcohol to benzaldehyde using supported gold-palladium nanoparticles as catalysts, two pathways have been identified as the sources of the principal product, benzaldehyde. One is the direct catalytic oxidation of benzyl alcohol to benzaldehyde by O(2), whereas the second is the disproportionation of two molecules of benzyl alcohol to give equal amounts of benzaldehyde and toluene. Herein we report that by changing the metal oxide used to support the metal-nanoparticles catalyst from titania or niobium oxide to magnesium oxide or zinc oxide, it is possible to switch off the disproportionation reaction and thereby completely stop the toluene formation. It has been observed that the presence of O(2) increases the turnover number of this disproportionation reaction as compared to reactions in a helium atmosphere, implying that there are two catalytic pathways leading to toluene. PMID- 21538606 TI - Molecular recognition at the active site of catechol-O-methyltransferase (COMT): adenine replacements in bisubstrate inhibitors. AB - L-Dopa, the standard therapeutic for Parkinson's disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbruggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N methyladenine, and 6-methylpurine, displayed nanomolar IC(50) values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and Mg(2+) confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group. PMID- 21538607 TI - Selective CO2 adsorption by a triazacyclononane-bridged microporous metal-organic framework. AB - Metal-organic frameworks constructed by self-assembly of metal ions and organic linkers have recently been of great interest in the preparation of porous hybrid materials with a wide variety of functions. Despite much research in this area and the large choice of building blocks used to fine-tune pore size and structure, it remains a challenge to synthesise frameworks composed of polyamines to tailor the porosity and adsorption properties for CO(2). Herein, we describe a rigid and microporous three-dimensional metal-organic framework with the formula [Zn(2)(L)(H(2)O)]Cl (L=1,4,7-tris(4-carboxybenzyl)-1,4,7-triazacyclononane) synthesised in a one-pot solvothermal reaction between zinc ions and a flexible cyclic polyaminocarboxylate. We have demonstrated, for the first time, that a porous rigid framework can be obtained by starting from a flexible amine building block. Sorption measurements revealed that the material exhibited a high surface area (135 m(2) g(-1)) and was the best compromise between capacity and selectivity for CO(2) over CO, CH(4), N(2) and O(2); as such it is a promising new selective adsorbent for CO(2) capture. PMID- 21538608 TI - High-throughput and time-resolved energy-dispersive X-ray diffraction (EDXRD) study of the formation of CAU-1-(OH)2: microwave and conventional heating. AB - Aluminium dihydroxyterephthalate [Al(8)(OH)(4)(OCH(3))(8)(BDC(OH)(2))(6)]?x H(2)O (denoted CAU-1-(OH)(2)) was synthesized under solvothermal conditions and characterized by X-ray powder diffraction, IR spectroscopy, sorption measurements, as well as thermogravimetric and elemental analysis. CAU-1-(OH)(2) is isoreticular to CAU-1 and its pores are lined with OH groups. It is stable under ambient conditions and in water, and it exhibits permanent porosity and two types of cavities with effective diameters of approximately 1 and 0.45 nm. The crystallization of CAU-1-(OH)(2) was studied by in situ energy-dispersive X-ray diffraction (EDXRD) experiments in the 120-145 degrees C temperature range. Two heating methods-conventional and microwave-were investigated. The latter leads to shorter induction periods as well as shorter reaction times. Whereas CAU-1 (OH)(2) is formed at all investigated temperatures using conventional heating, it is only observed below 130 degrees C using microwave heating. The calculation of the activation energy of the crystallization of CAU-1-(OH)(2) exhibits similar values for microwave and conventional synthesis. PMID- 21538609 TI - Molecular implementation of sequential and reversible logic through photochromic energy transfer switching. AB - Photochromic spiropyrans modified with fluorophores were investigated as molecular platforms for the achievement of fluorescence switching through modulation of energy transfer. The dyads were designed in such a way that energy transfer is only observed for the open forms of the photochrome (merocyanine and protonated merocyanine), whereas the closed spiropyran is inactive as an energy acceptor. This was made possible through a deliberate choice of fluorophores (4 amino-1,8-naphthalimide, dansyl, and perylene) that produce zero spectral overlap with the spiro form and considerable overlap for the merocyanine forms. From the Forster theory, energy transfer is predicted to be highly efficient and in some cases of 100% efficiency. The combined switching by photonic (light of lambda>530 nm) and chemical (base) inputs enabled the creation of a sequential logic device, which is the basic element of a keypad lock. Furthermore, in combination with an anthracene-based acidochromic fluorescence switch, a reversible logic device was designed. This enables the unambiguous coding of different input combinations through multicolour fluorescence signalling. All devices can be conveniently reset to their initial states and repeatedly cycled. PMID- 21538610 TI - Calix[2]-m-benzo[4]phyrin with aggregation-induced enhanced-emission characteristics: application as a HgII chemosensor. PMID- 21538611 TI - Controllable nanocarving of anatase TiO2 single crystals with reactive {001} facets. PMID- 21538612 TI - Copper-catalyzed oxidative arylation of heteroarenes under mild conditions using dioxygen as the sole oxidant. PMID- 21538613 TI - Assembly of DNA triangles mediated by perylene bisimide caps. AB - Perylene bisimides (PBI) have been synthetically incorporated as caps onto a Y shaped DNA triple strand. These PBI caps serve as "sticky" ends in the spontaneous assembly of larger DNA ensembles, linking the triangular DNA through stacking interactions. This, in turn, yields a hypsochromic shift in the absorption and a red shift in the fluorescence as characteristic optical readouts. This assembly occurs spontaneously without any enzymatic ligation process and without the use of overhanging DNA as sticky ends. Instead, dimerizations of the PBI chromophores in the assembly are controlled by the DNA as a structural scaffold. Thereby, the PBI-driven assembly is fully reversible. Due to the fact that PBI dimerization does not occur in the single strand, the aggregates can be destroyed by thermal dehybridization of the DNA scaffold and reassembled by reannealing of the DNA construct. In view of the fact that PBI forms stable radical anions, the presented DNA architectures are not only interesting optical biomaterials, but are also promising materials for molecular electronics with DNA. PMID- 21538614 TI - Heteroleptic ruthenium sensitizers that contain an ancillary bipyridine ligand tethered with hydrocarbon chains for efficient dye-sensitized solar cells. AB - New heteroleptic ruthenium complexes have been synthesized and used as the sensitizers for dye-sensitized solar cells (DSSCs). The ancillary bipyridine ligand contains rigid aromatic segments (fluorene-, carbazole-, or dithieno[3,2 b:2',3'-d]pyrrole-substituted bipyridine) tethered with a hydrophobic hexyl substituent. The conjugated aromatic segment results in significant bathochromic shift and hyperchromic effects in these complexes compared with Z907 (cis [RuLL'(NCS)(2)]; L=4,4'-dicarboxylic acid-2,2'-bipyridine, L'=4,4'-dinonyl-2,2'- bipyridine). The long hydrocarbon chains help to suppress the dark current if appropriately disposed. DSSCs that use these complexes exhibit very impressive conversion efficiencies (5.94 to 6.91 %) that surpass that of Z907-based (6.36 %) DSSCs and are comparable with that of N719-based standard cells (7.13 %; N719=cis di(thiocyanato)bis(2,2'-bipyridyl-4,4'-dicarboxylato)ruthenium(II) bis(tetrabutylammonium)) fabricated and measured under similar conditions (active area: 0.5*0.5 cm(2); AM 1.5 sunlight). PMID- 21538615 TI - Towards a fully synthetic MUC1-based anticancer vaccine: efficient conjugation of glycopeptides with mono-, di-, and tetravalent lipopeptides using click chemistry. AB - The membrane-bound tumor-associated glycoprotein MUC1 is aberrantly glycosylated in cancer cells compared with normal cells, and is therefore considered an attractive target for cancer immunotherapy. However, tumor-associated glycopeptides from MUC1 do not elicit a sufficiently robust immune response. Therefore, antitumor vaccines were developed, which consist of MUC1 glycopeptides as the B epitopes and immune-stimulating toll-like receptor 2 (TLR 2) lipopeptide ligands. These fully synthetic vaccine candidates were prepared by solid-phase synthesis of the MUC1 glycopeptides. The Pam(3) Cys lipopeptide, also synthesized on solid-phase, was C-terminally coupled to oligovalent lysine cores, which N terminally incorporate O-propargyl oligoethylene glycol acyl side chains. The MUC1 glycopeptides and lipopeptide lysine constructs were then conjugated by click chemistry to give oligovalent synthetic vaccines. Oligovalent glycopeptide lipopeptide conjugates are considered more immunogenic than their monovalent analogues. PMID- 21538616 TI - Enantiocontrolled synthesis of beta-branched alpha-amino acids by using Cu(I) catalyzed 1,4-addition of glycine imines to beta-substituted gem-diactivated olefins. PMID- 21538617 TI - Nickel-catalyzed cyclizations of enoates and chiral allenes: an approach to domoic acid. PMID- 21538618 TI - Enantioselective intramolecular crossed Rauhut-Currier reactions through cooperative nucleophilic activation and hydrogen-bonding catalysis: scope and mechanistic insight. AB - A highly efficient and enantioselective intramolecular crossed Rauhut-Currier (RC) reaction of nitroolefins with tethered enonates has been developed through cooperative nucleophilic activation and a hydrogen-bonding catalytic strategy (<=98% ee and 98% yield). The reaction features simple experimental procedures and is completely chemoselective and atom-economic in character. The potential synthetic applications have been demonstrated by the conversion of the RC reaction products into biologically and pharmaceutically valuable compounds with highly diastereoselectivity. In addition, computational investigations were employed to support the proposed mechanism and to obtain a good understanding of the origin of the stereoselectivity in RC reactions. PMID- 21538619 TI - A multicatalyst system for the one-pot desymmetrization/oxidation of meso-1,2 alkane diols. PMID- 21538620 TI - Enabling bifunctionality and hemilability of N-heteroaryl NHC complexes. PMID- 21538621 TI - Molecular structures of THF-solvated alkali-metal 2,2,6,6-tetramethylpiperidides finally revealed: X-ray crystallographic, DFT, and NMR (including DOSY) spectroscopic studies. AB - The often studied THF solvates of the utility alkali-metal amides lithium and sodium 2,2,6,6-tetramethylpiperidide are shown to exist in the solid state as asymmetric cyclic dimers containing a central M(2)N(2) ring and one molecule of donor per metal to give a distorted trigonal planar metal coordination. DFT studies support these structures and confirm the asymmetry in the ring. In C(6)D(12) solution, the lithium amide displays a concentration-dependent equilibrium between a solvated and unsolvated species which have been shown by diffusion-ordered NMR spectroscopy (DOSY) to be a dimer and larger oligomer, respectively. A third species, a solvated monomer, is also present in very low concentration, as proven by spiking the NMR sample with THF. In contrast, the sodium amide displays a far simpler C(6)D(12) solution chemistry, consistent with the solid-state dimeric arrangement but with labile THF ligands. PMID- 21538622 TI - Efficient copper-catalyzed synthesis of poly-N-heterocycles containing amino acid residues. AB - An efficient copper-catalyzed method has been developed for the synthesis of poly N-heterocycles containing amino acid residues. The protocol uses readily available 2-halobenzamides containing amino acids and their methyl esters, substituted phenylacetonitriles, and malononitrile as the starting materials and the reactions were performed well under mild conditions. The method should provide a novel and useful strategy for synthesis of N-heterocyclic compounds. PMID- 21538623 TI - Assessment of extracts from mistletoe (Viscum album) for herb-drug interaction by inhibition and induction of cytochrome P450 activities. AB - Three commercially available extracts from mistletoe (Viscum album L.) grown on ash tree (abnobaVISCUM((r)) Fraxini 20 mg), on fir (abnobaVISCUM((r)) Abietis 20 mg), and on pine (abnobaVISCUM((r)) Pini 20 mg) were tested in vitro for their potential to interfere with the major drug metabolizing cytochromes P450 by hepatocyte viability, by inhibition of cytochromes P450 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4, and by the induction of cytochromes P450 1A2, 2B6, 2C9, 2E1 and 3A4. As the three extracts are produced from mistletoe plants belonging to three different subspecies of Viscum album L. they have explicit differences in the content and spectrum of various active ingredients, e.g. mistletoe specific lectins. Cytotoxic effects on liver cells were observed for abnobaVISCUM((r)) Fraxini with a high lectin content with an EC(50) value of 2.56 ug/mL, for abnobaVISCUM((r)) Abietis with a moderate lectin content with an EC(50) value of 5.79 ug/mL and for abnobaVISCUM((r)) Pini with a low lectin content with an EC(50) value of 30.86 ug/mL. The induction of cytochromes P450 was tested on human liver cells from three donors. Inhibition of cytochromes P450 was carried out on human liver microsomes. No or minor induction and inhibition was observed for all three extracts. The data indicate no or minor potential for herb-drug interactions by interference with cytochromes P450 by any of the three mistletoe extracts. PMID- 21538624 TI - Tanshinone IIa alleviates the biochemical changes associated with hypoxic ischemic brain damage in a rat model. AB - This study aimed to investigate the effects of Tanshinone IIa (TanIIa) on the biochemical changes associated with hypoxic ischemic brain damage (HIBD) in a rat model. Neonatal SD rats were randomized into normal control, HIBD and TanIIa + HIBD groups. At different time points after HIBD, TanIIa was given at 1 ug/g. The intracellular free calcium concentration and the expression of phospho-NR1 S897 was determined. The intracellular free calcium concentration in the HIBD group was significantly increased. The induction of intracellular free calcium concentration in the TanIIa + HIBD group was less than that in the HIBD group. Large amounts of phospho-NR1 S897 positive cells were distributed in the cortex in the normal control group; the number of phospho-NR1 S897 positive cells in the ipsilateral cortex was dramatically decreased at 24 h after HIBD. Both the number of phospho-NR1 S897 positive cells and the FITC fluorescent density in the HIBD + TanIIa group were less than those in the normal control group at every time point after HIBD, but more than those in the HIBD group. TanIIa alleviated the down regulation of phospho-NR1 S897 and the elevated intracellular free calcium concentration in the cerebral cortex in the HIBD model. TanIIa could exert a neuroprotective effect through affecting NMDA receptor expression, inhibiting calcium transportation and decreasing the intracellular free calcium concentration. PMID- 21538625 TI - Aged red garlic extract reduces cigarette smoke extract-induced cell death in human bronchial smooth muscle cells by increasing intracellular glutathione levels. AB - Increasing antioxidant capacity has been proposed as a promising strategy to prevent cigarette smoke-induced lung diseases. This study tested whether garlic extracts prevented cigarette smoke extract (CSE)-induced cell death in human bronchial smooth muscle cells (HBSMCs). Garlic extracts were prepared from fresh raw garlic (FRG), aged black garlic (ABG) and aged red garlic (ARG). Treatment of HBSMCs with 10% CSE induced cell death accompanied by activation of caspase. Of the garlic extracts, treatment with ARG extract reduced CSE-induced cell death. The combination of ARG extract with CSE attenuated the CSE-induced reduction in glutathione (GSH) content, generation of reactive oxygen species (ROS) and induction of heme oxygenase-1 expression compared with CSE treatment without ARG extract. Furthermore, the combination of L-BSO, a GSH synthesis inhibitor, with ARG and CSE extracts failed to increase the intracellular GSH content and cell viability. Taken together, these results demonstrate that ARG extract reduces CSE induced cell death by increasing GSH content and reducing ROS generation in HBSMCs. PMID- 21538626 TI - Shikonin derivatives protect immune organs from damage and promote immune responses in vivo in tumour-bearing mice. AB - Shikonin, a major component of Lithospermum erythrorhizon and Arnebia euchroma, exhibits antiinflammatory, immunomodulatory and antitumour activities. Although many recent studies have focused on the antitumour effects of shikonin, the exact mechanisms underlying its antitumour and immunomodulatory effects in tumour bearing mice remain unclear. The aim of the present study was to investigate the antitumour and immunomodulatory effects of shikonin derivatives (ShD) in tumour bearing mice. Swiss mice inoculated with hepatoma HepA(22) or sarcoma 180 (S(180)) cells were treated with ShD or 5-fluorouracil (5Fu). Survival time, immune organs, natural killer cell activity, lymphocytes, lymphocyte transformation and interleukin (IL)-2 production were analysed. ShD significantly prolonged the survival (median survival time prolonged by >7 days) of tumour bearing mice in a dose-dependent manner, inhibited the growth of transplantable neoplasms (inhibitory rate, > 33%), and recovered (at [ShD] = 2.5 mg/kg/day) or increased (at [ShD] > 5 mg/kg/day) the number of CD3- and CD19-positive cells. ShD also played a role in protecting the immune organs from damage and reversed or enhanced immune responses, as noted by the nearly normal thymic structure; enlarged splenic corpuscles; and improved natural killer cell activity, lymphocyte transformation and IL-2 production in ShD-treated mice. ShD reduced the tumour load of tumour-bearing mice and protected the immune organs against tumour-induced damage and immune function impairment. PMID- 21538627 TI - Mutagenicity and oral toxicity studies of Terminalia chebula. AB - The fruit of Terminalia chebula Retz. (T. chebula), which is a member of the Combfreetaceae family, is used widely in Asian countries as a traditional folk medicine, and its extract has been reported to be an anticancer, antidiabetic and anticaries agent. In our previous study, chebulic acid isolated from T. chebula extract was confirmed to show antioxidant activity and protective action against endothelial cell dysfunction. In order to support the safety-in-use of the ethyl acetate (EtOAc)-soluble portion of a T. chebula ethanol extract containing 29.4% chebulic acid content, the prepared portion was tested in an in vitro mutagenicity assay, and a single- and 14-day repeated dose oral toxicity study. In the bacterial mutation assay, up to 5000 ug/mL concentration of the EtOAc soluble portion, the numbers of colonies did not increase whether with or without metabolic activation. In the oral toxicity study, the single oral dose of the extract at 2000 mg/kg did not produce mortality or abnormal lesions in the internal organs of rats. The results of a 14-day orally repeated dose showed that the EtOAc-soluble portion of T. chebula ethanol extracts gave no adverse effects at dosages of 2000 mg/kg in rats in the study. PMID- 21538628 TI - Effects of ginseng rhizome and ginsenoside Ro on testosterone 5alpha-reductase and hair re-growth in testosterone-treated mice. AB - This research program on the novel functions of Panax ginseng C. A. Meyer focused on the effects of ginseng rhizome on hair re-growth in androgenetic alopecia. Extracts of red ginseng rhizome showed greater dose-dependent inhibitory effects against testosterone 5alpha-reductase (5alphaR) when compared with extracts of the main root. Ginsenoside Ro, the predominant ginsenoside in the rhizome, and ginsenoside Rg(3), a unique ginsenoside in red ginseng, showed inhibitory activity against 5alphaR with IC(50) values of 259.4 and 86.1 um, respectively. The rhizome of P. japonicus, which contains larger amounts of ginsenoside Ro, also inhibited 5alphaR. Topical administration of extracts of red ginseng rhizomes (2 mg/mouse) and ginsenoside Ro (0.2 mg/mouse) to shaved skin inhibited hair re-growth suppression after shaving in the testosterone-treated C57BL/6 mice. These results suggest that red ginseng rhizomes containing both oleanane- and dammarane-type ginsenosides are a promising raw material for cosmetic use. This is the first report that ginsenoside Ro enhances in vivo hair re-growth based on their inhibitory activity against 5alphaR in the androgenetic alopecia model. PMID- 21538629 TI - Icariin induces the expression of toll-like receptor 9 in ana-1 murine macrophages. AB - Icariin is the major pharmacologically active compound of Herba epimedii which has been used as a tonic, aphrodisiac and an antirheumatic in traditional Chinese medicine. This study analysed the effect of icariin on the expression of Toll like receptor 9 (TLR9) which plays an important role in regulation of the innate immune response. Stimulation of Ana-1 murine macrophages with icariin induced a significant dose-dependent expression of TLR9, and its mRNA expression which increased from 3 h post-treatment was approximately five-fold that of DMSO treated cells. Several molecules, such as myeloid differentiation factor 88, tumor necrosis factor-alpha and interleukin 6, which are involved in the TLR9 downstream signaling pathway, were also significantly up-regulated in response to icariin stimulation. Our findings demonstrated that icariin is able to induce the expression of TLR9. PMID- 21538630 TI - The mechanism of sesame oil in ameliorating experimental autoimmune encephalomyelitis in C57BL/6 mice. AB - Experimental autoimmune encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). The study investigated the effectiveness of treatment with sesame oil on the development of EAE. EAE was induced in 8 week old C57BL/6 mice with an emulsion of MOG35-55. Therapy with sesame oil (4 mL/kg/day as oral gavage) was started on day 3 before the immunization. IFN-gamma and IL-10 production from cultured spleen supernatants were determined by the ELISA method. The results showed that daily oral gavage of sesame oil significantly reduced the clinical symptoms of EAE in C57BL/6 mice. In addition, sesame oil-treated mice displayed a significantly delayed disease onset. Mononuclear cells isolated from spleen of sesame oil-treated mice showed a significant decrease in the production of IFN gamma compared with control mice (p = 0.001). IL-10 production was also enhanced in splenic mononuclear cells in sesame oil-treated mice. The ratio of IFN-gamma to IL-10 in sesame oil-treated EAE mice was significantly less than in non treated EAE mice (p = 0.01). This report indicates that sesame oil therapy protected mice from developing EAE by reducing IFN-gamma secretion. Thus, sesame oil treatment may be effective in MS patients by immunomodulating the Th1 immune response. PMID- 21538631 TI - MR-visible lipids and the tumor microenvironment. AB - MR-visible lipids or mobile lipids are defined as lipids that are observable using proton MRS in cells and tissues. These MR-visible lipids are composed of triglycerides and cholesterol esters that accumulate in neutral lipid droplets, where their MR visibility is conferred as a result of the increased molecular motion available in this unique physical environment. This review discusses the factors that lead to the biogenesis of MR-visible lipids in cancer cells and in other cell types, such as immune cells and fibroblasts. We focus on the accumulations of mobile lipids that are inducible in cultured cells by a number of stresses, including culture conditions, and in response to activating stimuli or apoptotic cell death induced by anticancer drugs. This is compared with animal tumor models, where increases in mobile lipids are observed in response to chemo- and radiotherapy, and to human tumors, where mobile lipids are observed predominantly in high-grade brain tumors and in regions of necrosis. Conducive conditions for mobile lipid formation in the tumor microenvironment are discussed, including low pH, oxygen availability and the presence of inflammatory cells. It is concluded that MR-visible lipids appear in cancer cells and human tumors as a stress response. Mobile lipids stored as neutral lipid droplets may play a role in the detoxification of the cell or act as an alternative energy source, especially in cancer cells, which often grow in ischemic/hypoxic environments. The role of MR-visible lipids in cancer diagnosis and the assessment of the treatment response in both animal models of cancer and human brain tumors is also discussed. Although technical limitations exist in the accurate detection of intratumoral mobile lipids, early increases in mobile lipids after therapeutic interventions may be useful as a potential biomarker for the assessment of treatment response in cancer. PMID- 21538633 TI - Ursodeoxycholic acid treatment of hepatic steatosis: a (13)C NMR metabolic study. AB - Ursodeoxycholic acid (UDCA) is commonly used for the treatment of hepatobiliary disorders. In this study, we tested whether a 4-week treatment with this bile acid (12-15 mg/kg/day) could improve hepatic fatty acid oxidation in obese Zucker rats - a model for nonalcoholic fatty liver disease and steatosis. After 24 h of fasting, livers were perfused with physiological concentrations of [U-(13) C]nonesterified fatty acids and [3-(13) C]lactate/[3-(13) C]pyruvate. Steatosis was associated with abundant intracellular glucose, lactate, alanine and methionine, and low concentrations of choline and betaine. Steatotic livers also showed the highest output of glucose and lactate. Glucose and glycolytic products were mostly unlabeled, indicating active glycogenolysis and glycolysis after 24 h of fasting. UDCA treatment resulted in a general amelioration of liver metabolic abnormalities with a decrease in intracellular glucose and lactate, as well as their output. Hepatic betaine and methionine were also normalized after UDCA treatment, suggesting the amelioration of anti-oxidative defenses. Choline levels were not affected by the bile acid, which may indicate a deficient synthesis of very-low-density lipoproteins. The percentage contribution of [U-(13) C]nonesterified fatty acids to acetyl-coenzyme A entering the tricarboxylic acid (TCA) cycle was significantly lower in livers from Zucker obese rats relative to control rats: 23.1 +/- 4.9% versus 44.1 +/- 2.7% (p < 0.01). UDCA treatment did not alter significantly fatty acid oxidation in control rats, but improved significantly oxidation in Zucker obese rats to 46.0 +/- 6.1% (p > 0.05), comparable with control group values. The TCA cycle activity subsequent to fatty acid oxidation was reduced in steatotic livers and improved when UDCA was administered (0.24 +/- 0.04 versus 0.37 +/- 0.05, p = 0.05). We further suggest that the mechanism of action of UDCA is either related to the activity of the farnesoid receptor, or to the amelioration of the anti-oxidative defenses and cell nicotinamide adenine dinucleotide (NAD(+) /NADH) ratio, favoring TCA cycle activity and beta-oxidation. PMID- 21538634 TI - Specific identification of iron oxide-labeled stem cells using magnetic field hyperthermia and MR thermometry. AB - Cell-based therapies represent important novel strategies for the improved treatment of various diseases. To monitor the progress of therapy and cell migration, noninvasive imaging methods are needed. MRI represents such a modality, allowing, for example, for the tracking of cells labeled with superparamagnetic iron oxide nanoparticles. Unfortunately, the labeled cells cannot always be identified nonambiguously in the MR images. In this article, we present the combination of two different types of MR experiment to identify iron oxide-labeled cells nonambiguously. The labeled cells appear as hypointense spots on standard T(2)*-weighted MR images. Furthermore, they can be heated magnetically and subsequently identified by MR thermometry as a result of their heat dissipation. Other hypointense regions in the MR images are not heated and do not show heat dissipation. A proof-of-principle study was successfully performed in vitro and in vivo. The positive identification of the iron oxide labeled cells was demonstrated in collagen type I hydrogel phantoms and in living mice with high spatial and temporal accuracy. The motion of the in vitro samples was corrected in order to improve the specificity of the identification of labeled cells. Therefore, this method possesses the potential for cell tracking without prior knowledge about the cells, and thus allows the noninvasive monitoring of cell-based therapies, as long as the cells contain a sufficient amount of iron oxide for detection in MR thermometry and imaging. PMID- 21538635 TI - Hyperpolarized 129Xe lung MRI in spontaneously breathing mice with respiratory gated fast imaging and its application to pulmonary functional imaging. AB - In the present study, a balanced steady-state free precession pulse sequence combined with compressed sensing was applied to hyperpolarized (129) Xe lung imaging in spontaneously breathing mice. With the aid of fast imaging techniques, the temporal resolution was markedly improved in the resulting images. Using these protocols and respiratory gating, (129) Xe lung images in end-inspiratory and end-expiratory phases were obtained successfully. The application of these techniques for pulmonary functional imaging made it possible to simultaneously evaluate regional ventilation and gas exchange in the same animal. A comparative study between healthy and elastase-induced mouse models of emphysema showed abnormal ventilation as well as gas exchange in elastase-treated mice. PMID- 21538636 TI - Using spatial prior knowledge in the spectral fitting of MRS images. AB - We propose a Bayesian smoothness prior in the spectral fitting of MRS images which can be used in addition to commonly employed prior knowledge. By combining a frequency-domain model for the free induction decay with a Gaussian Markov random field prior, a new optimization objective is derived that encourages smooth parameter maps. Using a particular parameterization of the prior, smooth damping, frequency and phase maps can be obtained whilst preserving sharp spatial features in the amplitude map. A Monte Carlo study based on two sets of simulated data demonstrates that the variance of the estimated parameter maps can be reduced considerably, even below the Cramer-Rao lower bound, when using spatial prior knowledge. Long-TE (1)H MRSI at 1.5 T of a patient with a brain tumor shows that the use of the spatial prior resolves the overlapping peaks of choline and creatine when a single voxel method fails to do so. Improved and detailed metabolic maps can be derived from high-spatial-resolution, short-TE (1)H MRSI at 3 T. Finally, the evaluation of four series of long-TE brain MRSI data with various signal-to-noise ratios shows the general benefit of the proposed approach. PMID- 21538632 TI - Assessment of therapeutic response and treatment planning for brain tumors using metabolic and physiological MRI. AB - MRI is routinely used for diagnosis, treatment planning and assessment of response to therapy for patients with glioma. Gliomas are spatially heterogeneous and infiltrative lesions that are quite variable in terms of their response to therapy. Patients classified as having low-grade histology have a median overall survival of 7 years or more, but need to be monitored carefully to make sure that their tumor does not upgrade to a more malignant phenotype. Patients with the most aggressive grade IV histology have a median overall survival of 12-15 months and often undergo multiple surgeries and adjuvant therapies in an attempt to control their disease. Despite improvements in the spatial resolution and sensitivity of anatomic images, there remain considerable ambiguities in the interpretation of changes in the size of the gadolinium-enhancing lesion on T(1) weighted images as a measure of treatment response, and in differentiating between treatment effects and infiltrating tumor within the larger T(2) lesion. The planning of focal therapies, such as surgery, radiation and targeted drug delivery, as well as a more reliable assessment of the response to therapy, would benefit considerably from the integration of metabolic and physiological imaging techniques into routine clinical MR examinations. Advanced methods that have been shown to provide valuable data for patients with glioma are diffusion, perfusion and spectroscopic imaging. Multiparametric examinations that include the acquisition of such data are able to assess tumor cellularity, hypoxia, disruption of normal tissue architecture, changes in vascular density and vessel permeability, in addition to the standard measures of changes in the volume of enhancing and nonenhancing anatomic lesions. This is particularly critical for the interpretation of the results of Phase I and Phase II clinical trials of novel therapies, which are increasingly including agents that are designed to have anti-angiogenic and anti-proliferative properties as opposed to having a direct effect on tumor cell viability. PMID- 21538637 TI - Quantitative assessment of central nervous system disorder induced by prenatal X ray exposure using diffusion and manganese-enhanced MRI. AB - Prenatal radiation exposure induces various central nervous system (CNS) disorders depending on the dose, affected region and gestation period. The goal of this study was to assess noninvasively a CNS development disorder induced by prenatal X-ray exposure using quantitative manganese-enhanced MRI (MEMRI) as well as apparent diffusion coefficient (ADC) and transverse relaxation time (T(2)) maps in comparison with immunohistological staining. The changes in DeltaR(1) (increase in the longitudinal relaxation rate (R(1)) from before and after MnCl(2) administration.) induced by the Mn(2+) contrast agent were evaluated in the CNS of normal and prenatally irradiated rats. ADC and T(2) were also compared with the histological results obtained using hematoxylin and eosin (to estimate cell density), activated caspase-3 (apoptotic cells) and glial fibrillary acidic protein (proliferation of astrocytes/astroglia). We found the following: (i) the decreased Mn(2+) uptake (indicated by a smaller DeltaR(1)) for radiation-exposed rats was predominantly correlated with a decrease in cell viability (apoptotic cytopathogenicity) and CNS cell density after prenatal radiation exposure; (ii) the longer T(2) and ADC were associated with a decrease in CNS cell density and apoptotic alteration after radiation exposure. In addition to the slight proliferation of astroglia (+58%), there was a substantial decrease in cell density (-78%) and an excessive increase in apoptotic cells (+613%) in our prenatal radiation exposure model. The results suggest that MEMRI in the prenatal X-ray exposure model predominantly reflected the decrease in cell density and viability rather than the proliferation of astroglia. In conclusion, quantitative MEMRI with ADC/T(2) mapping provides objective information for the in vivo assessment of cellular level alterations by prenatal radiation exposure, and has the potential to be used as a standard approach for the evaluation of the cellular damage of radiotherapy. PMID- 21538638 TI - Parahydrogen-induced polarization (PHIP) hyperpolarized MR receptor imaging in vivo: a pilot study of 13C imaging of atheroma in mice. AB - MR techniques using hyperpolarized (13)C have successfully produced examples of angiography and intermediary metabolic imaging, but, to date, no receptor imaging has been attempted. The goal of this study was to synthesize and evaluate a novel hyperpolarizable molecule, 2,2,3,3-tetrafluoropropyl 1-(13)C-propionate-d(2,3,3) (TFPP), for the detection of atheromatous plaques in vivo. TFPP binds to lipid bilayers and its use in hyperpolarized MR could prove to be a major step towards receptor imaging. The precursor, 2,2,3,3-tetrafluoropropyl 1-(13)C-acrylate d(2,3,3) (TFPA), binds to 1,2-dimyristoylphosphatidylcholine lipid bilayers with a 1.6-ppm chemical shift in the (19)F MR spectrum. This molecule was designed to be hyperpolarized through the addition of parahydrogen to the (13)C-acrylate moiety by parahydrogen-induced polarization. TFPA was hyperpolarized to TFPP to an extent similar to that of the hydroxyethylacrylate to hydroxyethylpropionate transition: 17 +/- 4% for TFPP versus 20% for hydroxyethylpropionate; T(1) relaxation times (45 +/- 2 s versus 55 +/- 2 s) were comparable and the hyperpolarized properties of TFPP were characterized. Hydroxyethylacrylate, like TFPA, has a chemical structure with an acrylate moiety, but does not contain the lipid-binding tetrafluoropropyl functional group. Hyperpolarized TFPP binds to the lipid bilayer, appearing as a second, chemically shifted (13)C hyperpolarized MR signal with a further reduction in the longitudinal relaxation time (T(1) = 21 +/- 1 s). In aortas harvested from low-density lipoprotein receptor knock-out mice fed with a high-fat diet for 9 months, and in which atheroma is deposited in the aorta and heart, TFPP showed greater binding to lipid on the intimal surface than in control mice fed a normal diet. When TFPP was hyperpolarized and administered in vivo to atheromatous mice in a pilot study, increased binding was observed on the endocardial surface of the intact heart compared with normally fed controls. Hyperpolarized TFPP has bio-sensing specificity for lipid, coupled with a 42,000-fold sensitivity gain in the MR signal at 4.7 T. Binding of TFPP with lipids results in the formation of a characteristic second peak in MRS. TFPP therefore has the potential to act as an in vivo molecular probe for atheromatous plaque imaging and may serve as a model of receptor-targeted bio-imaging with enhanced MR sensitivity. PMID- 21538639 TI - Quantification of in vivo metabolic kinetics of hyperpolarized pyruvate in rat kidneys using dynamic 13C MRSI. AB - With signal-to-noise ratio enhancements on the order of 10,000-fold, hyperpolarized MRSI of metabolically active substrates allows the study of both the injected substrate and downstream metabolic products in vivo. Although hyperpolarized [1-(13)C]pyruvate, in particular, has been used to demonstrate metabolic activities in various animal models, robust quantification and metabolic modeling remain important areas of investigation. Enzyme saturation effects are routinely seen with commonly used doses of hyperpolarized [1 (13)C]pyruvate; however, most metrics proposed to date, including metabolite ratios, time-to-peak of metabolic products and single exchange rate constants, fail to capture these saturation effects. In addition, the widely used small-flip angle excitation approach does not correctly model the inflow of fresh downstream metabolites generated proximal to the target slice, which is often a significant factor in vivo. In this work, we developed an efficient quantification framework employing a spiral-based dynamic spectroscopic imaging approach. The approach overcomes the aforementioned limitations and demonstrates that the in vivo (13)C labeling of lactate and alanine after a bolus injection of [1-(13)C]pyruvate is well approximated by saturatable kinetics, which can be mathematically modeled using a Michaelis-Menten-like formulation, with the resulting estimated apparent maximal reaction velocity V(max) and apparent Michaelis constant K(M) being unbiased with respect to critical experimental parameters, including the substrate dose, bolus shape and duration. Although the proposed saturatable model has a similar mathematical formulation to the original Michaelis-Menten kinetics, it is conceptually different. In this study, we focus on the (13)C labeling of lactate and alanine and do not differentiate the labeling mechanism (net flux or isotopic exchange) or the respective contribution of various factors (organ perfusion rate, substrate transport kinetics, enzyme activities and the size of the unlabeled lactate and alanine pools) to the labeling process. PMID- 21538640 TI - Quantification of 5'-deoxy-5'-methylthioadenosine in heat-treated natural rubber latex serum. AB - INTRODUCTION: 5'-Deoxy-5'-methylthioadenosine (MTA) is one of the biologically active components found in natural rubber latex (NRL) serum, a common waste product from rubber plantations. In this study the contents of MTA in heat treated NRL serum were measured in order to assess the potential of the serum as an alternative source of MTA. OBJECTIVE: To devise an HPLC/UV-based quantitative analytical protocol for the determination of MTA, and to determine the effect of heat treatment on the content of MTA in NRL serum from various sources. METHODOLOGY: An HPLC/UV-based determination of MTA using an acidic eluant was devised and validated. In the heat treatment, the effect of refluxing times on MTA liberation was evaluated. RESULTS: The quantification protocol was validated with satisfying linearity, limits of detection and quantitation, precisions for peak areas and recovery percentages from intra- and inter-day operations. The amounts of MTA in the NRL sera from various sources increased with heat treatment to yield 5-12 MUg MTA/mL of serum. CONCLUSION: The devised protocol was found to be satisfyingly applicable to the routine determination of MTA in NRL serum. The effect of heat treatment on the content of MTA also indicated another possible use for NRL serum, normally discarded in vast amounts by the rubber industry, as an alternative source of MTA. PMID- 21538641 TI - Decreased fetal cardiac performance in the first trimester correlates with hyperglycemia in pregestational maternal diabetes. AB - OBJECTIVE: In-vitro animal studies suggest that high glucose levels impair fetal cardiac function early in gestation. We aimed to study whether evidence of first trimester myocardial dysfunction can be detected in fetuses of women with pregestational diabetes mellitus. METHODS: Women with diabetes mellitus underwent fetal echocardiography at 11-14 weeks' gestational age. In fetuses with normal anatomy, the cardiac preload, diastolic function, global myocardial performance and placental afterload were studied by Doppler of the ductus venosus (DV), mitral and tricuspid early/atrial (E/A) ratios, left and right ventricular myocardial performance index (MPI) and umbilical artery (UA) Doppler, respectively. Cases were matched for gestational age and UA and DV Doppler with controls that had no diabetes mellitus. RESULTS: Sixty-three singleton diabetic pregnancies were matched with 63 controls. Mean gestational age at enrollment was 12.6 (range, 11.1-13.6) weeks. Diabetic mothers had moderate to poor glycemic control (median (range) glycosylated hemoglobin A1 (HbA1c), 7.5 (5.1-12.7)%, and the HbA1c level was >= 7% in 37 (59%)). Fetuses of diabetic mothers exhibited worse measures of diastolic dysfunction: the isovolumetric relaxation time (IRT) was significantly prolonged (left ventricle: 36.9 +/- 7.4 ms vs. 45.8 +/- 6.8 ms; right ventricle: 35.6 +/- 8 ms vs. 46.4 +/- 7.3 ms, P < 0.0001 for both). The mitral E/A ratio was lower in diabetics (0.55 +/- 0.06 vs. 0.51 +/- 0.08, P = 0.03), and the global myocardial performance was lower in both ventricles (left ventricle MPI: 0.5 +/- 0.08; right ventricle MPI: 0.52 +/- 0.08, P = 0.03 and P < 0.0001, respectively). This lower global myocardial performance was caused by a prolonged myocardial relaxation time, which was most marked in diabetics with an HbA1c of >= 7% (P < 0.001 vs. controls for both ventricles). There were no significant correlations between cardiac Doppler parameters and DV, UA indices and fetal heart rate (P > 0.05 for all). CONCLUSIONS: Fetuses of poorly controlled diabetic mothers demonstrate significant differences in first trimester diastolic myocardial function compared with non-diabetic controls. The decrease in myocardial performance is more marked with increasing HbA1c and appears to be independent of preload and afterload. The ability to document these cardiac functional changes this early in pregnancy opens potential new avenues to understand the consequences of maternal glycemic status. PMID- 21538642 TI - Prediction of intrauterine fetal death in small-for-gestational-age fetuses: impact of including ultrasound biometry in customized models. AB - OBJECTIVE: Customized growth charts derived from maternal demographic characteristics alone have been shown to improve the prediction of pregnancy complications compared to population growth curves. We sought to estimate the impact of adding ultrasound biometric parameters to the customized chart for the prediction of intrauterine fetal death (IUFD). METHODS: A retrospective cohort study was undertaken using an ultrasound database including singleton pregnancies followed between 16 and 20 weeks' gestation. After exclusion of preterm births, congenital anomalies, multifetal pregnancies and stillbirths (excluded only from derivation samples), we identified 59 016 births, divided into derivation (34 832) and validation (24 184) samples. Coefficients for significant physiological and pathological variables affecting fetal growth were derived using backward stepwise multiple regression (Cust-chart). The same process was repeated including second-trimester biometric parameters: biparietal diameter, head circumference, femur length and abdominal circumference in the regression models (Cust-plus-USS-chart). The association between small-for-gestational age < 10(th) centile (SGA) pregnancies, defined using the two customized charts or our population-based growth chart (Pop-chart) and IUFD, were compared. Statistical analyses including OR, 95% CI and screening accuracy using each chart were performed. RESULTS: The derived coefficients for fetal growth are comparable to those of previously published series. Of 24 184 pregnancies in the validation sample, IUFD was seen in 169 (0.7%). The pregnancies identified as SGA were: 2482 (10.26%), 2499 (10.33%) and 2634 (10.89%) using the Cust-chart, Cust-plus-USS chart and Pop-chart, respectively. The OR (95% CI) for the association between SGA defined by the three charts and IUFD was: 7.0 (4.5-11), 6.5 (4.2-10.2) and 2.4 (1.6-3.6) according to the Cust-chart, Cust-plus-USS-chart and Pop-chart, respectively. Screening efficiency for IUFD using both customized charts was similar, with both demonstrating a higher sensitivity compared with the Pop chart. CONCLUSIONS: Customized charts are more efficient in identifying pregnancies at risk for IUFD compared with population-based charts. However, adding second-trimester ultrasound biometric parameters to the customized model does not improve the prediction of IUFD compared with using maternal characteristics only. PMID- 21538643 TI - Early-stage cervical cancer: agreement between ultrasound and histopathological findings with regard to tumor size and extent of local disease. AB - OBJECTIVES: To determine the agreement between ultrasound and histological examination of the cervix in patients with early stage cervical cancer with regard to tumor size and local extent of the disease. METHODS: Eighteen patients with histologically proven cervical cancer Stage IB1-IIA according to traditional clinical staging (FIGO 1988) who were scheduled for radical surgery underwent a standardized transvaginal ultrasound examination. The maximum tumor length, anteroposterior tumor diameter, tumor width, tumor area, depth of cervical stroma invasion, and the minimal thickness of tumor-free cervical stroma on sagittal and transverse planes through the cervix were measured, and the local extent of the disease within the parametria and vagina were evaluated. The surgical specimens were examined using a specifically devised method of histopathological examination. The results of the ultrasound and histopathological examinations were compared. RESULTS: Limits of agreement were wide and the intraclass correlation coefficient (ICC) was low (0.51-0.58) for three of the four measurements taken to represent the minimal depth of tumor-free cervical stroma, i.e. the results of the measurements taken posteriorly and laterally. However, the limits of agreement were narrower and the ICC values were higher (0.74-0.92) for the depth of cervical stroma invasion and for the tumor size measurements. Histological examination revealed parametrial cancer infiltration in four patients, which was detected during ultrasound examination, with no false positive results. CONCLUSIONS: Transvaginal sonography is acceptably accurate for evaluation of tumor size and depth of cervical stroma invasion in clinical practice. PMID- 21538644 TI - Revisiting the Ramachandran plot from a new angle. AB - The pioneering work of Ramachandran and colleagues emphasized the dominance of steric constraints in specifying the structure of polypeptides. The ubiquitous Ramachandran plot of backbone dihedral angles (phi and psi) defined the allowed regions of conformational space. These predictions were subsequently confirmed in proteins of known structure. Ramachandran and colleagues also investigated the influence of the backbone angle tau on the distribution of allowed phi/psi combinations. The "bridge region" (phi <= 0 degrees and -20 degrees <= psi <= 40 degrees ) was predicted to be particularly sensitive to the value of tau. Here we present an analysis of the distribution of phi/psi angles in 850 non homologous proteins whose structures are known to a resolution of 1.7 A or less and sidechain B-factor less than 30 A2. We show that the distribution of phi/psi angles for all 87,000 residues in these proteins shows the same dependence on tau as predicted by Ramachandran and colleagues. Our results are important because they make clear that steric constraints alone are sufficient to explain the backbone dihedral angle distributions observed in proteins. Contrary to recent suggestions, no additional energetic contributions, such as hydrogen bonding, need be invoked. PMID- 21538645 TI - Specificity of HCPTP variants toward EphA2 tyrosines by quantitative selected reaction monitoring. AB - EphA2 receptor tyrosine kinase and the human cytoplasmic protein tyrosine phosphatase (HCPTP) are overexpressed in a number of epithelial cancers. Overexpressed EphA2 in these cancers shows a significant decrease in phosphotyrosine content which results in suppression of receptor signaling and endocytosis and an increase in metastatic potential. The decreased phosphotyrosine content of EphA2 has been associated with decreased contact with its ligand, ephrin A1 and dephosphorylation by HCPTP. Potential specificity of the two HCPTP variants for tyrosines on EphA2 has not been investigated. We have used a mass spectrometry assay to measure relative rates of dephosphorylation for the two HCPTP variants at phosphotyrosine sites associated with control of the EphA2 kinase activity or interaction with downstream targets. Our results suggest that although both variants dephosphorylate the EphA2 receptor, the rate and specificity of dephosphorylation for specific tyrosines are different for HCPTP-A and HCPTP-B. The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates. This difference in preference for dephosphorylation sites on EphA2 not only illuminates the different roles of the two variants of the phosphatase in EphA2 signaling, but also explains why both HCPTP variants are highly conserved in most mammals. PMID- 21538646 TI - Polytellurophenes. AB - Will polytellurophenes bridge the gap between conjugated polymer and inorganic solid-state semiconductors? Polytellurophenes are a virtually unexplored class of conjugated polymer. In this paper, the synthetic methodologies that have been used to prepare polytellurophenes are chronicled. The properties of the resulting polymers are discussed and their potential for use as electronic materials is evaluated. It is far too early to know if these materials will lead to a useful class of thin-film semiconductors, however some key challenges associated with their synthesis and implementation are outlined. These challenges will need to be addressed as the conjugated polymer research community begins to utilize this area of the periodic table. PMID- 21538647 TI - X-ray structural studies of quinone reductase 2 nanomolar range inhibitors. AB - Quinone reductase 2 (QR2) is one of two members comprising the mammalian quinone reductase family of enzymes responsible for performing FAD mediated reductions of quinone substrates. In contrast to quinone reductase 1 (QR1) which uses NAD(P)H as its co-substrate, QR2 utilizes a rare group of hydride donors, N-methyl or N ribosyl nicotinamide. Several studies have linked QR2 to the generation of quinone free radicals, several neuronal degenerative diseases, and cancer. QR2 has been also identified as the third melatonin receptor (MT3) through in cellulo and in vitro inhibition of QR2 by traditional MT3 ligands, and through recent X ray structures of human QR2 (hQR2) in complex with melatonin and 2-iodomelatonin. Several MT3 specific ligands have been developed that exhibit both potent in cellulo inhibition of hQR2 nanomolar, affinity for MT3. The potency of these ligands suggest their use as molecular probes for hQR2. However, no definitive correlation between traditionally obtained MT3 ligand affinity and hQR2 inhibition exists limiting our understanding of how these ligands are accommodated in the hQR2 active site. To obtain a clearer relationship between the structures of developed MT3 ligands and their inhibitory properties, in cellulo and in vitro IC50 values were determined for a representative set of MT3 ligands (MCA-NAT, 2-I-MCANAT, prazosin, S26695, S32797, and S29434). Furthermore, X-ray structures for each of these ligands in complex with hQR2 were determined allowing for a structural evaluation of the binding modes of these ligands in relation to the potency of MT3 ligands. PMID- 21538649 TI - Modeling the effects of weaning age on length of female reproductive period: implications for the evolution of human life history. AB - OBJECTIVES: Human life history is unique among primates. Despite our extended lifespan, the length of the female reproductive period is shorter in humans than in our closest living relatives, chimpanzees. Here, we investigate whether this difference could be explained by another unique aspect of human life history-a young weaning age. METHODS: Age-dependent female fertility is modeled with the Brass polynomial. We model female reproductive period length as single locus with multiple alleles. Selection acts on the length of the female reproductive period in an evolutionary agent-based simulation. We quantify the effect of weaning age on the optimal length of the female reproductive period under a range of adult mortality rates. RESULTS: Females sacrifice a smaller proportion of their reproductive potential due to nursing by weaning their offspring at younger ages. As a consequence, the optimal length of the female reproductive period decreases as weaning age decreases, even when adult mortality is low. CONCLUSIONS: Natural selection will favor mutations or strategies that can decrease weaning age without incurring fitness costs. In the presence of younger weaning ages, selection favors a shorter female reproductive period. To the extent that allocare can decrease weaning age without decreasing fitness, its ubiquity in human societies and near absence in other primate societies may explain why women have a shorter reproductive period. Furthermore, allocare may have provided human ancestors with an avenue to decreased weaning age-and, ultimately, a shorter female reproductive period-that was unavailable to their hominoid contemporaries. PMID- 21538648 TI - Nutrition in transition: dietary patterns of rural Amazonian women during a period of economic change. AB - OBJECTIVES: The goal of this study was to understand the relationship between economic change (wage labor, retirement, and the Bolsa Familia program) and dietary patterns in the rural Amazon and to determine the extent to which these changes followed the pattern of the nutrition transition. METHODS: The study was longitudinal. The weighed-inventory method and economic interviews were used to collect data on dietary intake and household economics in a sample of 30 and 52 women in 2002 and 2009, respectively. Twenty of the women participated in both years and make-up the longitudinal sub-sample. Comparative statistics were used to identify changes in dietary patterns over time and multiple linear regressions were used to explore the relationship between economics, subsistence strategies, and diet. RESULTS: There was a significant decline in kcal (P < 0.01) and carbohydrate (P < 0.01) but no change in protein intake over time in both the larger and smaller, longitudinal subsample. The percent of energy, carbohydrate, protein, and fat purchased increased in the larger and longitudinal samples (P <= 0.02) and there was an increase in refined carbohydrate and processed, fatty-meat consumption over time. The abandonment of manioc gardens was associated with increased dependence on purchased food (P = 0.03) while receipt of the Bolsa Familia was associated with increased protein intake and adequacy (P = 0.02). CONCLUSIONS: The dietary changes observed are only in partial agreement with predictions of the nutrition transition literature. The relationship between the economic and diet changes was shaped by the local context which should be considered when implementing CCT programs, like the Bolsa Familia. PMID- 21538650 TI - Physical activity in an indigenous Ecuadorian forager-horticulturalist population as measured using accelerometry. AB - OBJECTIVE: Minimal information on physical activity is available for non-Western populations undergoing the transition to a market economy. This is unfortunate given the importance of these data for understanding health issues such as the global obesity epidemic. We consider the utility of using accelerometry technology to examine activity patterns and energy use regulation among indigenous Shuar, an Ecuadorian forager-horticulturalist population undergoing economic and lifestyle change. We investigate sex differences in Shuar activity patterns and the effects of reproductive status on activity. Finally, we discuss the potential of accelerometry use in human biology research. METHODS: Physical activity levels were measured using Actical accelerometers in 49 indigenous Shuar adults (23 males, 26 females) from a rural Ecuadorian community. Female participants were in various reproductive states including pregnant, lactating, and nonpregnant/nonlactating. RESULTS: Activity counts (AC), activity energy expenditure (AEE), and physical activity levels (PAL) were significantly higher (P < 0.05) in males than females. Significant differences in energy expenditure were found among pregnant or lactating females and males with pregnant or lactating partners (P < 0.001). Males with pregnant or lactating partners also had significantly higher activity levels than did other men (P < 0.01). CONCLUSIONS: Shuar activity levels are relatively low compared to other non Western populations. Despite increasing market integration, pregnant and lactating females seem to be adopting a strategy noted in other subsistence populations where male participation in subsistence activities increases to compensate for their partners' elevated reproductive costs. Despite certain limitations, use of accelerometry in human biology research shows promise. PMID- 21538651 TI - Lowland origin women raised at high altitude are not protected against lower uteroplacental O2 delivery during pregnancy or reduced birth weight. AB - OBJECTIVE: Maternal physiologic responses to pregnancy promoting fetal oxygen and nutrient delivery are important determinants of reproductive success. Incomplete physiologic compensation for reduced oxygen availability at high altitude (>=2,500 m) compromises fetal growth. Populations of highland (e.g., Andeans, Tibetans) compared with lowland origin groups (e.g., Europeans, Han Chinese) are protected from this altitude-associated decrease in birth weight; here we sought to determine whether maternal development at high altitude-rather than highland ancestry-contributed to the protection of birth weight and uterine artery (UA) blood flow during pregnancy. METHODS: In women of lowland ancestry who were either raised at high altitude in La Paz, Bolivia (3,600-4,100 m) ("lifelong," n = 18) or who had migrated there as adults ("newcomers," n = 40) we compared maternal O(2) transport during pregnancy and their infant's birth weight. RESULTS: Pregnancy raised maternal ventilation and arterial O(2) saturation equally, with the result that arterial O(2) content was similarly maintained at nonpregnant levels despite a fall in hemoglobin. UA blood flow and uteroplacental O(2) delivery were lower in lifelong than newcomer residents (main effect). Birth weight was similar in lifelong residents versus newcomers (2,948 +/- 93 vs. 3,090 +/- 70 gm), with both having values below those of a subset of eight high altitude residents who descended to deliver at low altitude (3,418 +/- 133 gm, P < 0.05). CONCLUSION: Lifelong compared with newcomer high-altitude residents have lower uteroplacental O(2) delivery and similar infant birth weights, suggesting that developmental factors are likely not responsible for the protective effect of highland ancestry. PMID- 21538652 TI - Caregiving, gender, and nutritional status in Nyanza Province, Kenya: grandmothers gain, grandfathers lose. AB - Based on anecdotal and qualitative reports, a general assumption is that caregiving negatively impacts grandparents in Africa. OBJECTIVES: The purpose of this article is to determine how caregiving and gender impact nutritional status over four waves of data from Luo elders. METHODS: Luo elders, aged 60 and over (age 73.6 +/- 7.9) were sampled. Participant recruitment was rolling and included 287 Luo grandparents in 2005, 396 in 2006, 389 in 2007, and 390 in 2009. A total of 689 elders participated in at least 1 year. Standard anthropometric measures were used to determine nutritional status. Impact of caregiving was examined using structural equation models. RESULTS: Caregiving positively associated with nutritional status among women. This main effect was mediated by caregiving intensity, which also positively associated with nutritional status. Among men, caregiving negatively associated with nutritional status, although caregiving intensity did not significantly associate with most anthropometric measures. Socioeconomic status (SES) positively associated with five of nine anthropometric measures in women and all measures in men. Several measures indicated that both men and women became larger over time but few of the variables tested predicted growth. CONCLUSIONS: The beneficial impact on grandmothers might indicate a coping strategy. These results indicated that researchers should shift away from comparing caregivers to noncaregivers and instead look at the multiple factors which may make some families resilient and others at risk. Human biologists can contribute to this literature by examining the ecological and cultural contexts under which caregiving represents a burden with physiological repercussions. PMID- 21538653 TI - Clinical trial design in non-invasive brain stimulation psychiatric research. AB - Major depressive disorder (MDD) trials - investigating either non-pharmacological or pharmacological interventions - have shown mixed results. Many reasons explain this heterogeneity, but one that stands out is the trial design due to specific challenges in the field. We aimed therefore to review the methodology of non invasive brain stimulation (NIBS) trials and provide a framework to improve clinical trial design. We performed a systematic review for randomized, controlled MDD trials whose intervention was transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) in MEDLINE and other databases from April 2002 to April 2008. We created an unstructured checklist based on CONSORT guidelines to extract items such as power analysis, sham method, blinding assessment, allocation concealment, operational criteria used for MDD, definition of refractory depression and primary study hypotheses. Thirty-one studies were included. We found that the main methodological issues can be divided in to three groups: (1) issues related to phase II/small trials, (2) issues related to MDD trials and, (3) specific issues of NIBS studies. Taken together, they can threaten study validity and lead to inconclusive results. Feasible solutions include: estimating the sample size a priori; measuring the degree of refractoriness of the subjects; specifying the primary hypothesis and statistical tests; controlling predictor variables through stratification randomization methods or using strict eligibility criteria; adjusting the study design to the target population; using adaptive designs and exploring NIBS efficacy employing biological markers. In conclusion, our study summarizes the main methodological issues of NIBS trials and proposes a number of alternatives to manage them. PMID- 21538654 TI - Validation of a 4-item Negative Symptom Assessment (NSA-4): a short, practical clinical tool for the assessment of negative symptoms in schizophrenia. AB - The 16-item Negative Symptom Assessment (NSA-16) scale is a validated tool for evaluating negative symptoms of schizophrenia. The psychometric properties and predictive power of a four-item version (NSA-4) were compared with the NSA-16. Baseline data from 561 patients with predominant negative symptoms of schizophrenia who participated in two identically designed clinical trials were evaluated. Ordered logistic regression analysis of ratings using NSA-4 and NSA-16 were compared with ratings using several other standard tools to determine predictive validity and construct validity. Internal consistency and test--retest reliability were also analyzed. NSA-16 and NSA-4 scores were both predictive of scores on the NSA global rating (odds ratio = 0.83-0.86) and the Clinical Global Impressions--Severity scale (odds ratio = 0.91-0.93). NSA-16 and NSA-4 showed high correlation with each other (Pearson r = 0.85), similar high correlation with other measures of negative symptoms (demonstrating convergent validity), and lesser correlations with measures of other forms of psychopathology (demonstrating divergent validity). NSA-16 and NSA-4 both showed acceptable internal consistency (Cronbach alpha, 0.85 and 0.64, respectively) and test- retest reliability (intraclass correlation coefficient, 0.87 and 0.82). This study demonstrates that NSA-4 offers accuracy comparable to the NSA-16 in rating negative symptoms in patients with schizophrenia. PMID- 21538655 TI - Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stress-induced amnesia. AB - We have studied the effects of spatial learning and predator stress-induced amnesia on the expression of calcium/calmodulin-dependent protein kinase II (CaMKII), brain-derived neurotrophic factor (BDNF) and calcineurin in the hippocampus, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adult male rats were given a single training session in the radial-arm water maze (RAWM) composed of 12 trials followed by a 30-min delay period, during which rats were either returned to their home cages or given inescapable exposure to a cat. Immediately following the 30-min delay period, the rats were given a single test trial in the RAWM to assess their memory for the hidden platform location. Under control (no stress) conditions, rats exhibited intact spatial memory and an increase in phosphorylated CaMKII (p-CaMKII), total CaMKII, and BDNF in dorsal CA1. Under stress conditions, rats exhibited impaired spatial memory and a suppression of all measured markers of molecular plasticity in dorsal CA1. The molecular profiles observed in the BLA, mPFC, and ventral CA1 were markedly different from those observed in dorsal CA1. Stress exposure increased p-CaMKII in the BLA, decreased p-CaMKII in the mPFC, and had no effect on any of the markers of molecular plasticity in ventral CA1. These findings provide novel observations regarding rapidly induced changes in the expression of molecular plasticity in response to spatial learning, predator exposure, and stress-induced amnesia in brainregions involved in different aspects of memory processing. PMID- 21538656 TI - A study of hippocampal structure-function relations along the septo-temporal axis. AB - This study examined structural-functional differences along the septo-temporal axis of hippocampus using radial-maze tasks that involved two different memory processes [reference memory (RM) and working memory (WM)], and the use of two kinds of information (spatial vs. nonspatial cue learning). In addition, retention of the nonspatial cue task was tested nine weeks following completion of acquisition, and the rats then underwent discrimination reversal training. Ibotenic acid lesions limited to either the dorsal pole, intermediate area, or ventral pole had minimal effects on acquisition of the complex place and cue discrimination tasks. The one exception was that rats with lesions confined to the dorsal third of hippocampus made more WM errors on the spatial task (but not the cue task) early in training. Selective lesions of the three hippocampal regions had no effects on either long-term retention or reversal of the nonspatial cue discrimination task. In contrast, rats that had all of the hippocampus removed were severely impaired in learning the spatial task, making many RM and WM errors, whereas on the nonspatial cue task, the impairment was limited to WM errors. Further analysis of the WM errors made in acquisition showed that rats with complete lesions were significantly more likely on both the spatial and nonspatial cue tasks to reenter arms that had been baited and visited on that trial compared to arms that had not been baited. A similar pattern of errors emerged for complete hippocampal lesioned rats during reversal discrimination. This pattern of errors suggests that in addition to an impairment in handling spatial information, complete removal of hippocampus also interferes with the ability to inhibit responding to cues that signal reward under some conditions but not under others. The finding that selective lesions limited to the intermediate zone of the hippocampus produce no impairment in either WM ("rapid place learning") or RM in our radial maze tasks serve to limit the generality of the conclusion of Bast et al. (Bast et al. (2009) PLos Biol 7:730 746) that the intermediate area is needed for behavioral performance based on rapid learning about spatial cues. PMID- 21538657 TI - Role of estrogen receptor alpha and beta expression and signaling on cognitive function during aging. AB - This review presents evidence for the idea that the expression of estrogen receptor alpha and beta (ERalpha and ERbeta) interacts with the level of estradiol (E2) to influence the etiology of age-related cognitive decline and responsiveness to E2 treatments. There is a nonmonotonic dose response curve for E2 influences on behavior and transcription. Evidence is mounting to indicate that the dose response curve is shifted according to the relative expression of ERalpha and ERbeta. Recent work characterizing age-related changes in the expression of ERalpha and ERbeta in the hippocampus, as well as studies using mutant mice, and viral mediated delivery of estrogen receptors indicate that an age-related shift in ERalpha/ERbeta expression, combined with declining gonadal E2 can impact transcription, cell signaling, neuroprotection, and neuronal growth. Finally, the role of ERalpha/ERbeta on rapid E2 signaling and synaptogenesis as it relates to hippocampal aging is discussed. PMID- 21538658 TI - Target-specific output patterns are predicted by the distribution of regular spiking and bursting pyramidal neurons in the subiculum. AB - Pyramidal neurons in the subiculum project to a variety of cortical and subcortical areas in the brain to convey information processed in the hippocampus. Previous studies have shown that two groups of subicular pyramidal neurons--regular-spiking and bursting neurons--are distributed in an organized fashion along the proximal-distal axis, with more regular-spiking neurons close to CA1 (proximal) and more bursting neurons close to presubiculum (distal). Anatomically, neurons projecting to some targets are located more proximally along this axis, while others are located more distally. However, the relationship between the firing properties and the targets of subicular pyramidal neurons is not known. To study this relationship, we used in vivo injections of retrogradely transported fluorescent beads into each of nine different regions and conducted whole-cell current-clamp recordings from the bead-containing subicular neurons in acute brain slices. We found that subicular projections to each area were composed of a mixture of regular-spiking and bursting neurons. Neurons projecting to amygdala, lateral entorhinal cortex, nucleus accumbens, and medial/ventral orbitofrontal cortex were located primarily in the proximal subiculum and consisted mostly of regular-spiking neurons (~80%). By contrast, neurons projecting to medial EC, presubiculum, retrosplenial cortex, and ventromedial hypothalamus were located primarily in the distal subiculum and consisted mostly of bursting neurons (~80%). Neurons projecting to a thalamic nucleus were located in the middle portion of subiculum, and their probability of bursting was close to 50%. Thus, the fraction of bursting neurons projecting to each target region was consistent with the known distribution of regular-spiking and bursting neurons along the proximal-distal axis of the subiculum. Variation in the distribution of regular-spiking and bursting neurons suggests that different types of information are conveyed from the subiculum to its various targets. PMID- 21538660 TI - Human hippocampal theta oscillations and the formation of episodic memories. AB - The importance of the hippocampal theta oscillation (4-8 Hz) to memory formation has been well-established through studies in animals, prompting researchers to propose comprehensive theories of memory and learning that rely on theta oscillations for integrating information in the hippocampus and neocortex. Yet, empirical evidence for the importance of 4-8 Hz hippocampal theta oscillations to memory formation in humans is equivocal at best. To clarify this apparent interspecies discrepancy, we recorded intracranial EEG (iEEG) data from 237 hippocampal electrodes in 33 neurosurgical patients as they performed an episodic memory task. We identified two distinct patterns of hippocampal oscillations, at ~3 and ~8 Hz, which are at the edges of the traditional 4-8 Hz human theta band. The 3 Hz "slow-theta" oscillation exhibited higher power during successful memory encoding and was functionally linked to gamma oscillations, but similar patterns were not present for the 8 Hz "fast-theta" oscillation. For episodic memory, slow theta oscillations in the human hippocampus appear to be analogous to the memory related theta oscillations observed in animals. Both fast-theta and slow-theta oscillations exhibit evidence of phase synchrony with oscillations in the temporal cortex. We discuss our findings in the context of recent research on the electrophysiology of human memory and spatial navigation, and explore the implications of this result for theories of cortico-hippocampal communication. PMID- 21538659 TI - Greater running speeds result in altered hippocampal phase sequence dynamics. AB - Hebb (1949) described a "phase sequence" to be the sequential activation of sets of cell assemblies. Within the hippocampus, cell assemblies have been described as groups of coactive neurons whose place fields overlap. Membership of assemblies in a phase sequence changes systematically as a rat travels through an environment, serving to accelerate the temporal order that place fields are encountered during a single theta cycle. This sweeping forward of network activity ("look ahead"), results in locations in front of the animal being transiently represented. In this experiment, a population vector-based reconstruction method was used to capture the look ahead and reveals that the composition of the phase sequence changes with velocity, such that more cell assemblies are active within a theta cycle at higher running speeds. These results are consistent with hypotheses suggesting that hippocampal networks generate short time scale predictions of future events to optimize behavior. PMID- 21538661 TI - 5-HT(1A) and 5-HT(7) receptors differently modulate AMPA receptor-mediated hippocampal synaptic transmission. AB - We have studied the effects of 5-HT(1A) and 5-HT(7) serotonin receptor activation in hippocampal CA3-CA1 synaptic transmission using patch clamp on mouse brain slices. Application of either 5-HT or 8-OH DPAT, a mixed 5-HT(1A)/5-HT(7) receptor agonist, inhibited AMPA receptor-mediated excitatory post synaptic currents (EPSCs); this effect was mimicked by the 5-HT(1A) receptor agonist 8-OH PIPAT and blocked by the 5-HT(1A) antagonist NAN-190. 8-OH DPAT increased paired pulse facilitation and reduced the frequency of mEPSCs, indicating a presynaptic reduction of glutamate release probability. In another group of neurons, 8-OH DPAT enhanced EPSC amplitude but did not alter paired-pulse facilitation, suggesting a postsynaptic action; this effect persisted in the presence of NAN 190 and was blocked by the 5-HT(7) receptor antagonist SB-269970. To confirm that EPSC enhancement was mediated by 5-HT(7) receptors, we used the compound LP-44, which is considered a selective 5-HT(7) agonist. However, LP-44 reduced EPSC amplitude in most cells and instead increased EPSC amplitude in a subset of neurons, similarly to 8-OH DPAT. These effects were respectively antagonized by NAN-190 and by SB-269970, indicating that under our experimental condition LP-44 behaved as a mixed agonist. 8-OH DPAT also modulated the current evoked by exogenously applied AMPA, inducing either a reduction or an increase of amplitude in distinct neurons; these effects were respectively blocked by 5-HT(1A) and 5 HT(7) receptor antagonists, indicating that both receptors exert a postsynaptic action. Our results show that 5-HT(1A) receptors inhibit CA3-CA1 synaptic transmission acting both pre- and postsynaptically, whereas 5-HT(7) receptors enhance CA3-CA1 synaptic transmission acting exclusively at a postsynaptic site. We suggest that a selective pharmacological targeting of either subtype may be envisaged in pathological loss of hippocampal-dependent cognitive functions. In this respect, we underline the need for new selective agonists of 5-HT(7) receptors. PMID- 21538662 TI - Influence of vestibular input on spatial and nonspatial memory and on hippocampal NMDA receptors. AB - It has recently been shown that a lack of vestibular sensory information decreases spatial memory performance and induces biochemical changes in the hippocampus in rodents. After vestibular neurectomy, patients display spatial memory deficit and hippocampal atrophy. Our objectives were to explore: (a) spatial (Y maze, radial-arm maze), and non-spatial (object recognition) memory performance, (b) modulation of NMDA receptors within the hippocampus using radioligand binding, and (c) hippocampal atrophy, using MRI, in a rat model of bilateral labyrinthectomy realized in two operations. Chemical vestibular lesions (VLs) were induced in 24 animals by transtympanic injections of sodium arsanilate (30 mg/0.1 ml/ear), one side being lesioned 3 weeks after the other. The control group received transtympanic saline solution (0.1 ml/ear) (n = 24). Spatial memory performance (Y maze and radial maze) decreased after VL. Conversely, non spatial memory performance (object recognition) was not affected by VL. No hippocampal atrophy was observed with MRI, but density of NMDA receptors were increased in the hippocampus after VL. These findings show that the lack of vestibular information induced specific deficits in spatial memory. Additionally, quantitative autoradiographic data suggest the involvement of the glutamatergic system in spatial memory processes related to vestibular information. When studying spatial memory performances in the presence of vestibular syndrome, two step labyrinthectomy is a suitable procedure for distinguishing between the roles of the specific components of vestibular input loss and those of impaired locomotor activity. PMID- 21538663 TI - HCMV gets a Sat-Nav too. PMID- 21538664 TI - The potential role of self-sampling for high-risk human papillomavirus detection in cervical cancer screening. AB - High-risk human papillomavirus (hr-HPV) detection will become an important tool in the screening for cervical cancer. Self-sampling is an inexpensive and well accepted method for HPV detection that will increase participation of nonresponders in current screening programs. Even more, because self-collected samples are as good as physician-collected samples for HPV detection, self sampling might be a suitable method for future primary cervical cancer screening. PMID- 21538665 TI - How to control an infectious bead string: nucleosome-based regulation and targeting of herpesvirus chromatin. AB - Herpesvirus infections of humans can cause a broad variety of symptoms ranging from mild afflictions to life-threatening disease. During infection, the large double-stranded DNA genomes of all herpesviruses are transcribed, replicated and encapsidated in the host cell nucleus, where DNA is typically structured and manoeuvred through nucleosomes. Nucleosomes individually assemble DNA around core histone octamers to form 'beads-on-a-string' chromatin fibres. Herpesviruses have responded to the advantages and challenges of chromatin formation in biologically unique ways. Although herpesvirus DNA is devoid of histones within nucleocapsids, nuclear viral genomes most likely form irregularly arranged or unstable nucleosomes during productive infection, and regular nucleosomal arrays resembling host cell chromatin in latently infected cells. Besides variations in nucleosome density, herpesvirus chromatin 'bead strings' undergo dynamic changes in histone composition and modification during the different stages of productive replication, latent infection and reactivation from latency, raising the likely possibility that epigenetic processes may dictate, at least in part, the outcome of infection and ensuing pathogenesis. Here, we summarise and discuss several new and important aspects regarding the nucleosome-based mechanisms that regulate herpesvirus chromatin structure and function in infected cells. Special emphasis is given to processes of histone deposition, histone variant exchange and covalent histone modification in relation to the transcription from the viral genome during productive and latent infections by human cytomegalovirus and herpes simplex virus type 1. We also present an overview on emerging histone directed antiviral strategies that may be developed into 'epigenetic therapies' to improve current prevention and treatment options targeting herpesvirus infection and disease. PMID- 21538666 TI - Viruses as key regulators of angiogenesis. AB - Angiogenesis is an important physiological process that is controlled by a precise balance of growth and inhibitory factors in healthy tissues. However, environmental and genetic factors may disturb this delicate balance, resulting in the development of angiogenic diseases, tumour growth and metastasis. During the past decades, extensive research has led to the identification and characterization of genes, proteins and signalling pathways that are involved in neovascularization. Moreover, increasing evidence indicates that viruses may also regulate angiogenesis either directly, by (i) producing viral chemokines, growth factors and/or receptors or (ii) activating blood vessels as a consequence of endothelial cell tropism, or indirectly, by (iii) modulating the activity of cellular proteins and/or (iv) inducing a local or systemic inflammatory response, thereby creating an angiogenic microenvironment. As such, viruses may modulate several signal transduction pathways involved in angiogenesis leading to changes in endothelial cell proliferation, migration, adhesion, vascular permeability and/or protease production. Here, we will review different mechanisms that may be applied by viruses to deregulate the angiogenic balance in healthy tissues and/or increase the angiogenic potential of tumours. PMID- 21538667 TI - Viruses and the fuel sensor: the emerging link between AMPK and virus replication. AB - Adenosine 5' monophosphate-activated protein kinase (AMPK) is conserved in all eukaryotic cells and functions as the key regulator of cellular metabolism by responding to the energy status of the cell. It is activated by an increase in the AMP : ATP ratio and then attempts to redress the balance by upregulating catabolic processes, whilst concomitantly inhibiting anabolic processes. Despite its critical importance in the functioning of eukaryotic cells, there has been a paucity of studies investigating the potential for dysregulation of AMPK by viruses. Recently, however, there have been a number of reports that have begun to address this gap in our knowledge. In this article, we will review this emerging field, outlining how a variety of viruses have been shown to either stimulate or inhibit AMPK activity. We will also document the effects of these perturbations on the biology of virus infection, in particular with regard to the ability of viruses to persist or cause cytopathogenesis. PMID- 21538668 TI - The use of knockout mice to test the specificity of antibodies for cannabinoid receptors. PMID- 21538669 TI - Obesity and interpersonal problems: an analysis with the interpersonal circumplex. AB - This study examines the interpersonal problems profiles of obese individuals by cluster analysing the interpersonal problems circumplex scores of participants. The Inventory of Interpersonal Problems-Short Circumplex (IIP-32) was completed by 368 treatment-seeking obese individuals. These data were cluster analysed, and groups of obese subjects defined by varying interpersonal problems were compared with regard to psychological distress, self-esteem, body dissatisfaction, quality of life and binge behaviours. Cluster analyses of the IIP-32 resulted in four clusters, which occupied two quadrants of the interpersonal circumplex. Several differences in body mass index, psychological distress, quality of life and body dissatisfaction emerged across the four interpersonal groups. Although obese individuals reported elevated interpersonal distress, these subjects are not homogeneous with regard to interpersonal problems. Psychiatric co-morbidity and psychological distress may explain these interpersonal differences. These findings underscore the importance for clinicians to assess carefully patients' interpersonal functioning, especially with respect to treatment-seeking obese patients. KEY PRACTITIONER MESSAGE: Research has not consistently specified the types of interpersonal problems most frequently experienced by treatment-seeking obese individuals. Most obese individuals share a friendly-dominant interpersonal style. This research supports the importance of measuring and targeting interpersonal variables in the design and evaluation of obesity treatment programmes. PMID- 21538670 TI - Near real-time vaccine safety surveillance with partially accrued data. AB - PURPOSE: The Vaccine Safety Datalink (VSD) Project conducts near real-time vaccine safety surveillance using sequential analytic methods. Timely surveillance is critical in identifying potential safety problems and preventing additional exposure before most vaccines are administered. For vaccines that are administered during a short period, such as influenza vaccines, timeliness can be improved by undertaking analyses while risk windows following vaccination are ongoing and by accommodating predictable and unpredictable data accrual delays. We describe practical solutions to these challenges, which were adopted by the VSD Project during pandemic and seasonal influenza vaccine safety surveillance in 2009/2010. METHODS: Adjustments were made to two sequential analytic approaches. The Poisson-based approach compared the number of pre-defined adverse events observed following vaccination with the number expected using historical data. The expected number was adjusted for the proportion of the risk window elapsed and the proportion of inpatient data estimated to have accrued. The binomial based approach used a self-controlled design, comparing the observed numbers of events in risk versus comparison windows. Events were included in analysis only if they occurred during a week that had already passed for both windows. RESULTS: Analyzing data before risk windows fully elapsed improved the timeliness of safety surveillance. Adjustments for data accrual lags were tailored to each data source and avoided biasing analyses away from detecting a potential safety problem, particularly early during surveillance. CONCLUSIONS: The timeliness of vaccine and drug safety surveillance can be improved by properly accounting for partially elapsed windows and data accrual delays. PMID- 21538671 TI - Longitudinal monitoring of the safety of drugs by using a web-based system: the case of pregabalin. AB - PURPOSE: Information about the time course of adverse drug reactions (ADRs) is often lacking. If this information would be available, it could help increase patient's adherence to drugs when experiencing an ADR. The aim of this study was to demonstrate how a web-based intensive monitoring system using the patient as a source of information can be used to gather longitudinal safety data of a drug. In this study, pregabalin was used as an example. METHODS: First-time users of pregabalin were approached in Dutch pharmacies between 1 August 2006 and 31 January 2008. After online registration, patients received questionnaires by email 2 weeks, 6 weeks, 3 months and 6 months after the start of the drug use. Data on patient characteristics, drug use and ADRs were collected and analysed. RESULTS: A total of 1373 patients registered for the pregabalin study. Of these patients, 1051 (76.5%) filled in at least one questionnaire. On an aggregated level, the ADR profile remained relatively stable over time. Incidence densities showed that the five most frequently reported reactions occurred early in the treatment. Initially, the majority of the patients did not undertake any action when experiencing an ADR. Recovery did not seem to be completely dependent of drug cessation. CONCLUSIONS: With web-based intensive monitoring, it is possible to study the time course of ADRs. This method can be a valuable addition to pharmacovigilance because it can generate other types of information as compared with spontaneous reporting and other intensive monitoring methodologies. PMID- 21538672 TI - Variation in initiating secondary prevention after myocardial infarction by hospitals and physicians, 1997 through 2004. AB - PURPOSE: Myocardial infarction (MI) survivors benefit from receiving secondary prevention, including beta-blockers, angiotensin-blocking agents, and statins, as recommended by guidelines. Compliance with these guidelines is suboptimal. We sought to describe the initiation of secondary prevention in MI survivors, and to describe the variation in initiation by discharging the hospital, the physician, and the physician "responsible" for secondary prevention prescribing decisions in British Columbia in 1997-2004. METHODS: We assembled a cohort of 28,613 patients discharged alive from the hospital after their first MI and were not readmitted within 30 days. Physicians responsible for prescribing post-MI secondary prevention medications were identified as the physicians prescribing the greatest number of cardiac medications (post-discharge cardiac prescribers). We used multilevel logistic regression to assess the variation in drug initiation at discharging hospital, discharging physician, and post-discharge cardiac prescriber levels, which were adjusted for patient and provider characteristics during the study period. RESULTS: Beta-blockers initiation increased from 56 to 71% over the 8-year study period; angiotensin-converting enzyme/angiotensin II receptor blocker initiation increased from 37 to 70%, and statin initiation increased from 22 to 66% (0-28% for high-potency statins). The probability for initiating an average patient with the study drugs varied widely in age-sex adjusted models at the hospital and physician levels. Further adjustment did not meaningfully change findings. The variation was largest for statins. The maximum between-provider variance was found for high-potency statins in 2003-2004 at the post-discharge cardiac prescriber level. CONCLUSIONS: Study-drug initiation is increasing among MI survivors, but the variation in initiation is wide between discharging hospitals and physicians. PMID- 21538673 TI - Exposure to CYP3A4-inducing and CYP3A4-non-inducing antiepileptic agents and the risk of fractures. AB - PURPOSE: To evaluate whether exposure to Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)-inducing antiepileptics increases fracture risk compared to CYP3A4-non-inducing antiepileptics. METHODS: We performed a retrospective cohort study of initiators of antiepileptic agents using a UK medical record database (The Health Improvement Network) from 1995 to 2007. We considered an antiepileptic user an initiator if he or she had not received a prescription for an antiepileptic agent within the first year after entry in the database. Proportional hazards regression was used to calculate hazard ratios for fracture during long-term (>= 6 months) exposure to CYP3A4 inducing versus CYP3A4 non inducing antiepileptics. RESULTS: We identified 4077 initiators of CYP3A4 inducing antiepileptics and 6433 initiators of CYP3A4-non-inducing antiepileptics with at least 6 months of antiepileptic exposure. During 6006 person-years exposed to CYP3A4-inducing antiepileptics, 118 fractures were identified for an incidence rate of 1.96 (95% confidence interval (CI): 1.63-2.35) fractures per 100 person-years. During 7184 person-years exposed to CYP3A4-non-inducing antiepileptics, 127 fractures were identified, for an incidence rate of 1.77 (95% CI: 1.47-2.10) fractures per 100 person-years. The adjusted hazard ratio for CYP3A4-inducing antiepileptic versus CYP3A4-non-inducing antiepileptic was 1.21 (95% CI: 0.93-1.56). No duration-response relationship was evident. CONCLUSIONS: Our results do not support the hypothesis that CYP3A4 induction by antiepileptic agents increases the fracture risk. Further research will be needed to evaluate whether mechanisms other than CYP3A4 induction might explain some of the elevated risk of fractures associated with long-term use of antiepileptic agents. PMID- 21538674 TI - Off-label prescribing patterns of antidepressants in children and adolescents. AB - PURPOSE: To understand the extent of off-label prescribing among pediatrics, the study assesses the prescribing patterns of antidepressants in ambulatory settings. METHODS: A cross-sectional analysis was conducted using the National Ambulatory Medical Care Survey from 2000 to 2006. The prevalence of off-label prescribing of antidepressants was estimated, and predictive factors were evaluated. PARTICIPANTS: Children and adolescents aged 6-18 years to private physicians' offices. MAIN OUTCOME MEASURES: Prevalence of antidepressant prescriptions including FDA and non-FDA-approved indications, types of antidepressants prescribed, and factors associated with off-label prescribing. RESULTS: Our study population made 18 646 visits to private physicians' offices, representing about 667 million weighted visits during the study period. The mean age of the patients was 12.2 years (SD = 3.7), and majority of the visits were made by White people (73.1%). Of all visits, 3.7% (95%CI: 3.2%-4.2%) were associated with antidepressants. The most prevalent form of antidepressants prescribed were selective serotonin reuptake inhibitors (63.7%). Only 9.2% of the visits were associated with FDA-approved indications. Visits made to pediatricians (adjusted OR = 2.4; 95%CI: 1.1-5.1), family physicians, and other offices (adjusted OR = 1.9; 95%CI: 1.2-3.1) were more likely to be associated with off-label prescribing as compared with visits to a psychiatrist's office. CONCLUSIONS: The study observed a very high prevalence of off-label antidepressant prescribing patterns among children and adolescents in US ambulatory care settings. Coordinated efforts should be placed to evaluate the potential reasons and ramifications of antidepressant off-label prescribing to guard patients' safety. PMID- 21538675 TI - Benefit-risk assessment: to quantify or not to quantify, that is the question. PMID- 21538676 TI - Intended and unintended consequences of a proposed national tax on sugar sweetened beverages to combat the U.S. obesity problem. AB - Monthly data derived from the Nielsen Homescan Panel for calendar years 1998 through 2003 are used to estimate the effects of a proposed tax on sugar sweetened beverages (SSBs). Most arguments in describing the ramifications of a tax fail to consider demand interrelationships among various beverages. To circumvent this shortcoming we employ a variation of Quadratic Almost Ideal Demand System (QUAIDS) model. The consumption of isotonics, regular soft drinks and fruit drinks, the set of SSBs, is negatively impacted by the proposed tax, while the consumption of fruit juices, low-fat milk, coffee, and tea is positively affected. Diversion ratios are provided identifying where the volumes of the SSBs are directed as a result of the tax policy. The reduction in the body weight as a result of a 20% tax on SSBs is estimated to be between 1.54 and 2.55 lb per year. However, not considering demand interrelationships would result in higher weight loss. Unequivocally, it is necessary to consider interrelationships among non-alcoholic beverages in assessing the effect of the tax. PMID- 21538677 TI - Quality of life of younger breast cancer survivors: persistence of problems and sense of well-being. AB - OBJECTIVE: Ten years after diagnosis, women diagnosed with breast cancer at age 50 or younger were assessed to determine whether quality of life (QOL) problems found at five years persisted. We predicted that QOL in the physical and social domains would be poorer, but improvements would be found in the psychological domain. METHODS: We re-interviewed 312 women, who had been interviewed at their five year anniversary and remained cancer free, on their QOL in three domains (physical, social, and psychological). Comparisons between their 5- and 10-year reports were performed using paired t-tests for numeric variables and McNemar's test for categorical variables. Multiple regression analysis was used to model change from 5 to 10 years in each QOL domain, given the level of QOL at 5 years. RESULTS: The women's mean age was 55, 60% were college graduates, 79% had a partner, and 27% were non-Euro-American. Ten years after diagnosis they reported poorer general health (p<0.0001) and physical well-being (p = 0.001), less sexual activity (p = 0.009), and more chronic conditions (p<0.0001) than at 5 years. Relationships were found between: (1) the number of chronic conditions at 5 years and decreased physical, social, and psychological well-being at 10 years; and (2) a smaller social network at 5 years and poorer social functioning at 10 years. CONCLUSIONS: Certain aspects of both physical and social QOL worsened over time. The remaining question is whether these changes can be attributed to the late effects of treatment or to normal effects of aging. PMID- 21538679 TI - Fear of movement in cancer survivors: validation of the modified Tampa scale of kinesiophobia-fatigue. AB - OBJECTIVE: To date, there is no validated questionnaire to assess fear of movement in cancer survivors. We aim to validate the modified Tampa scale of kinesiophobia-fatigue (TSK-F) in Dutch cancer survivors participating in a rehabilitation programme. We first select the optimal model for cancer survivors. Subsequently, stability, internal consistency, and construct validity of the optimal model is tested. METHODS: A sample of 658 cancer survivors participating in a rehabilitation programme was included. Out of nine models derived in chronic pain and chronic fatigue patients, the optimal model of the TSK-F was selected in a calibration sample (n1 = 329) using confirmatory factor analysis. Stability of the derived optimal model was confirmed in a validation sample (n2 = 329). Internal consistency and construct validity were assessed in the full sample. RESULTS: The 11-item two-factor model of the TSK-F was the best-fitting model for cancer survivors and it seemed to be invariant for sex and cancer diagnosis. Internal consistency of the model was acceptable (Cronbach's alpha between 0.62 and 0.74). Construct validity was illustrated by significant associations between TSK-F total and TSK-F somatic focus with perceived global health status (EORTC QOL-C30) and fatigue (FACT-F) (p<0.001). CONCLUSIONS: The adjusted 11-item TSK-F consisting of two subscales 'somatic focus' and 'activity avoidance' seems to be a robust and valid tool in measuring fear of movement in cancer survivors with an acceptable internal consistency. Further psychometric testing of the TSK-F in cancer survivors is recommended. In the future, TSK-F scores may be used to customise rehabilitation programmes in cancer survivors. PMID- 21538678 TI - Initial evaluation of an Internet intervention to improve the sleep of cancer survivors with insomnia. AB - OBJECTIVE: Insomnia is a common complaint among cancer survivors. Fortunately, cognitive-behavioral therapy for insomnia (CBT-I) has been shown to be an effective treatment in this population. However, it is rarely implemented given its limited availability. To address this barrier, we examined the ability of an easily accessible online CBT-I program to improve insomnia symptoms in cancer survivors. METHODS: Twenty-eight cancer survivors with insomnia were randomly assigned to either an Internet insomnia intervention (n = 14) or to a waitlist control group (n = 14). The online program, Sleep Healthy Using The Internet, delivers the primary components of CBT-I (sleep restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse prevention). Pre- and post assessment data were collected via online questionnaires and daily sleep diaries. RESULTS: Participants in the Internet group showed significant improvements at post-assessment compared with those in the control group in overall insomnia severity (F(1,26) = 22.8; p<0.001), sleep efficiency (F(1,24) = 11.45; P = 0.002), sleep onset latency (F(1,24) = 5.18; P = 0.03), soundness of sleep (F(1,24) = 9.34; P = 0.005), restored feeling upon awakening (F(1,24) = 11.95; P = 0.002), and general fatigue (F(1,26) = 13.88; P = 0.001). Although other group * time interactions were not significant, overall adjusted effect sizes for all sleep variables as well as for fatigue, depression, anxiety, and quality of life ranged from small to large. CONCLUSIONS: CBT-I delivered through an interactive, individually tailored Internet intervention may be a viable treatment option for cancer survivors experiencing insomnia. PMID- 21538680 TI - Moderators and long-term effectiveness of cognitive behaviour therapy for fatigue during cancer treatment. AB - OBJECTIVE: A randomised controlled trial (RCT) demonstrated that cognitive behaviour therapy (CBT) for fatigue during curative cancer treatment was effective shortly after cancer treatment. This study aimed to identify which patient characteristics predict fatigue improvement after CBT. In addition, the long-term effectiveness was investigated. METHODS: Patients with various malignancies participated in the RCT (n = 210). Participants were assessed before cancer treatment (T1), postintervention (T2), which was at least 2 months after cancer treatment, and after 1-year follow-up (T3). Monthly fatigue assessments were completed between T2 and T3. A regression analysis with interactions was performed to determine if domains of quality of life (EORTC-QLQ-C30) functioning (Health Survey Short Form-36) or psychological distress (Symptom Checklist-90) moderated the effect of CBT on fatigue. Analyses of covariance were used to study the long-term effectiveness of CBT. RESULTS: Fatigue at T2 was predicted by a significant interaction between self-reported cognitive functioning and CBT. No interactions were found between other domains of quality of life, functioning, psychological distress and CBT. At T3, no significant difference on fatigue was found between CBT and usual care. Exploratory analyses showed that the difference nearly reached significance until 7 months postintervention. CONCLUSIONS: Patients who experienced more concentration and memory problems at T1 benefited more from CBT for fatigue and are indicators. After a year of follow-up, the effect of CBT for fatigue was no longer observed, and the effect on fatigue seemed to be diminished 7 months postintervention. The implication is that CBT for fatigue should be offered to patients with cancer with the highest chance to benefit. PMID- 21538681 TI - Clinical validation of the EORTC QLQ-OG25 questionnaire for the evaluation of health-related quality of life in Mexican patients with esophagogastric cancers. AB - BACKGROUND: Quality of life questionnaires (QLQ) QLQ-STO22 and QLQ-OES18 are currently available to measure Health-related quality of life (HRQL) in patients with Esophageal (EC) or Gastric cancer (GC). The QLQ-OG25 integrates questions from both questionnaires to be useful for EC, Esophagogastric junction carcinoma (EGJC), and GC. Our aim was to validate the Mexican-Spanish version. PATIENTS AND METHODS: The translation procedure followed European Organization for Research and Treatment of Cancer (EORTC) guidelines. QLQ-C30 and QLQ-OG25 instruments were completed by patients with EC, EGJC, and GC. Patients were divided into three groups: (1) palliative treatment; (2) treatment with curative intent, and (3) survivors. Reliability and validity tests were performed. RESULTS: One-hundred sixty-three patients were included: 62 women and 101 men (mean age, 54.9 years; range, 22-82 years). Sixty-nine, seventy-three, and twenty-one patients were allocated into groups 1, 2, and 3, respectively. Questionnaire compliance rates were high and were well accepted. Group 3 patients reported better functional HRQL scores and lower symptom scores than patients in groups 2 and 1. Scales in the QLQ-C30 and QLQ-OG25 distinguished among other clinically distinct groups of patients. Cronbach's alpha coefficients of all multi-item scales of the QLQ-OG25 instrument were >0.7 (range, 0.7-0.83). Multitrait scaling analysis demonstrated good convergent and discriminant validity, even adjusting by location. Test retest scores were consistent. CONCLUSION: The Mexican-Spanish version of the EORTC QLQ-OG25 questionnaire is reliable and valid for HRQL measurement in patients with esophagogastric cancer and can be used in clinical trials in the Mexican community. PMID- 21538682 TI - Lowfat, a mammalian Lix1 homologue, regulates leg size and growth under the Dachsous/Fat signaling pathway during tissue regeneration. AB - In the cricket Gryllus bimaculatus, missing distal parts of amputated legs are regenerated from blastemas based on positional information. The Dachsous/Fat (Ds/Ft) signaling pathway regulates blastema cell proliferation and positional information along the longitudinal axis during leg regeneration. Herein, we show that the Gryllus homologue of Lowfat (Gb'Lft), which modulates Ds/Ft signaling in Drosophila, is involved in leg regeneration. Gb'lft is expressed in regenerating legs, and RNAi against Gb'lft (Gb'lft(RNAi)) suppressed blastema cell hyperproliferation caused by Gb'ft(RNAi) or Gb'ds(RNAi) but enhanced that caused by Gb'kibra(RNAi) or Gb'warts(RNAi). In Gb'lft(RNAi) nymphs, missing parts of amputated legs were regenerated, but the length of the regenerated legs was shortened depending on the position of the amputation. Both normal and reversed intercalary regeneration occurred in Gb'lft(RNAi) nymphs, suggesting that Gb'Lft is involved in blastema cell proliferation and longitudinal leg regeneration under the Ds/Ft signaling pathway, but it is not required for intercalary regeneration. PMID- 21538683 TI - Gsx transcription factors repress Iroquois gene expression. AB - We have previously shown that the Gsx family homeobox gene Gsh2 is part of the regulatory network specifying dorsoventral pattern of primary neurons in the developing amphibian embryo. Here, we investigate the role of Gsx transcription factors in regulating the transcription of Iroquois family homeobox genes in the amphibian neural plate. Iroquois genes are key regulators of neural patterning and their expression is coincident with that of the Gsx genes during open neural plate stages. We show that Gsx proteins repress Iroquois expression in the embryo and conversely, inhibition of Gsx activity with either antisense morpholino oligos or an anti-morphic Gsx protein up-regulates Iroquois expression. These data indicate that Gsx factors act as negative regulators of Iroquois gene expression in the amphibian neural plate and support a model in which the Gsx proteins promote neuronal differentiation by repressing the expression of known inhibitors of neuronal differentiation such as Iro3. PMID- 21538684 TI - ET3/Ednrb2 signaling is critically involved in regulating melanophore migration in Xenopus. AB - Melanoblasts are derived from neural crest cells (NCCs) and are the only NCCs that migrate through the dorsolateral pathway. However, how melanoblasts evolved to migrate through a pathway different from other NCCs is still unclear, because little is known about common molecular mechanisms of melanoblast migration that are conserved between species. Endothelin receptor B2 (Ednrb2) is required for avian melanoblasts to enter the dorsolateral pathway. Here, we show that Endothelin-3 (ET3)/Ednrb2 signaling is also required for melanoblast migration in Xenopus laevis, although they migrate through the ventral pathway. In Xenopus, Ednrb2 is expressed by melanoblasts from pre-migration stages and ET3 is expressed around their destinations, suggesting that ET3/Ednrb2 signaling may determine melanophore localization. Furthermore, melanoblast migration is interrupted by aberrant ET3/Ednrb2 signaling in vivo and their invasive ability is enhanced by ET3 in vitro. Our results suggest that ET3/Ednrb2 signaling is required for melanoblast migration in Ednrb2 gene-conserved animals. PMID- 21538686 TI - A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related symphalangism spectrum disorder (NOG-SSD). AB - The NOG gene encodes noggin, a secreted polypeptide that is important for regulating multiple signaling pathways during human development, particularly in cartilage and bone. The hallmark of NOG-related syndromes is proximal symphalangism, defined by abnormal fusion of the proximal interphalangeal joints of the hands and feet. Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia. The variable clinical presentations led to the designation of five different autosomal dominant syndromes, all subsequently found to have resulted from NOG mutations. These include (1) proximal symphalangism; (2) multiple synostoses syndrome 1; (3) stapes ankylosis with broad thumbs and toes; (4) tarsal-carpal coalition syndrome; and (5) brachydactyly type B2. Herein, we review the phenotypic features associated with mutations in the NOG gene, demonstrating the overlapping characteristics of these syndromes. Due to the variable phenotypic spectrum within families and among families with the same mutation, we propose a unifying term, NOG-related symphalangism spectrum disorder (NOG-SSD), to aid in the clinical recognition and evaluation of all affected individuals with these phenotypes. These NOG gene variants are available in a new locus-specific database (https://NOG.lovd.nl). PMID- 21538687 TI - Feedback of individual genetic results to research participants: in favor of a qualified disclosure policy. AB - This article discusses whether and when researchers have a moral obligation to feedback individual genetic research results. This unsettled debate has rapidly gained in urgency in view of the emergence of biobanks and the advances in next generation sequencing technology, which has the potential to generate unequalled amounts of genetic data. This implies that the generation of many known and unknown genetic variants in individual participants of genetics/genomics research as intentionally or collaterally obtained byproducts is unavoidable. As we conclude that valid reasons exist to adopt a duty to return genetic research results, a qualified disclosure policy is proposed. This policy contains a standard default package, possibly supplemented with (one or more of) three additional packages. Whereas the default package, containing life-saving information of immediate clinical utility, should be offered routinely and mandatory to all research participants, offering (one of) the three additional packages is context-specific. Such a qualified disclosure policy in our opinion best balances the potential benefits of disclosure with the potential risks for research participants and the harms of unduly hindering biomedical research. We appeal to the genetics community to make a joint effort to further refine the packages and set thresholds for result selection. PMID- 21538685 TI - Myocyte proliferation in the developing heart. AB - Regulation of organ growth is critical during embryogenesis. At the cellular level, mechanisms controlling the size of individual embryonic organs include cell proliferation, differentiation, migration, and attrition through cell death. All these mechanisms play a role in cardiac morphogenesis, but experimental studies have shown that the major determinant of cardiac size during prenatal development is myocyte proliferation. As this proliferative capacity becomes severely restricted after birth, the number of cell divisions that occur during embryogenesis limits the growth potential of the postnatal heart. We summarize here current knowledge concerning regional control of myocyte proliferation as related to cardiac morphogenesis and dysmorphogenesis. There are significant spatial and temporal differences in rates of cell division, peaking during the preseptation period and then gradually decreasing toward birth. Analysis of regional rates of proliferation helps to explain the mechanics of ventricular septation, chamber morphogenesis, and the development of the cardiac conduction system. Proliferation rates are influenced by hemodynamic loading, and transduced by autocrine and paracrine signaling by means of growth factors. Understanding the biological response of the developing heart to such factors and physical forces will further our progress in engineering artificial myocardial tissues for heart repair and designing optimal treatment strategies for congenital heart disease. PMID- 21538688 TI - Functional analysis of LDLR promoter and 5' UTR mutations in subjects with clinical diagnosis of familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is a dominant disorder due to mutations in the LDLR gene. Several mutations in the LDLR promoter are associated with FH. Screening of 3,705 Spanish FH patients identified 10 variants in the promoter and 5' UTR. Here, we analyse the functionality of six newly identified LDLR variants. Mutations located in the LDLR promoter regulatory elements R2 and R3 (c.-155_ 150delACCCCinsTTCTGCAAACTCCTCCC, c.-136C>G, c.-140C>G, and c.-140C>T) resulted in 6 to 15% residual activity in reporter expression experiments and changes in nuclear protein binding affinity compared to wild type. No reduction was observed when cells were transfected with c.-208T, c.-88A, and c.-36G mutant fragments. Our results indicate that mutations localized in R2 and R3 are associated with hypercholesterolemia, whereas mutations outside the LDLR response elements are not a cause of FH. This data emphasizes the importance of functional analysis of variants in the LDLR promoter to determine their association with the FH phenotype. PMID- 21538689 TI - Birt Hogg-Dube syndrome-associated FLCN mutations disrupt protein stability. AB - Germline mutations in the FLCN gene cause Birt-Hogg-Dube syndrome, familial spontaneous pneumothorax, or apparently nonsyndromic inherited RCC. The vast majority of reported FLCN mutations are predicted to result in a truncated/absent gene product and so infrequent missense and inframe-deletion (IFD) FLCN mutations might indicate critical functional domains. To investigate this hypothesis we (1) undertook an in silico evolutionary analysis of the FLCN sequence and (2) investigated in vitro the functional effects of naturally occurring FLCN missense/IFD mutations. The folliculin protein sequence evolved more slowly and was under stronger purifying selection than the average gene, most notably at a region between codons 100 and 230. Pathogenic missense and IFD FLCN mutations that impaired folliculin tumor suppressor function significantly disrupted the stability of the FLCN gene product but two missense substitutions initially considered to be putative mutations did not impair protein stability, growth suppression activity, or intracellular localization of folliculin. These findings are consistent with the distribution of FLCN mutations throughout the coding sequence, and suggest that multiple protein domains contribute to folliculin stability and tumor suppressor activity. In vitro assessment of protein stability and tumor suppressor activity provides a practical strategy for assessing the pathogenicity of potential FLCN mutations. PMID- 21538691 TI - SEM-EDS technique employed in evaluating the aggregation behaviors of amphiphilic ABC-type triblock copolymers in mixed solvents with tuned polarities. AB - In this paper, a scanning electron microscopy-energy dispersive spectroscopy (SEM EDS) technique has been developed for evaluating the aggregation structure of amphiphilic fluorinated ABC-type triblock copolymers MeOPEO(16)-PSt(220) PFHEA(22) in mixed solvents with different polarities. The polarities of mixed solvents can be tuned by changing volume ratios of toluene, anhydrous ethanol, and distilled water, which leads to the changes in morphology and size of self assembled colloidal particles of the copolymers in the system. The aggregation behaviors of the copolymers are revealed by SEM, transmission electron microscopy (TEM), and corresponding SEM-EDS techniques. The variations in concentrations of O and F elements over the thickness of copolymers particles give direct evidence for a better understanding of the arrangement of each block segment of copolymers in solution. And the technique can also help to explain the aggregation structure of micro- or nanomaterial with shell-core structure. Microsc. Res. Tech., 2011. (c) 2011 Wiley Periodicals, Inc. PMID- 21538690 TI - Deficiency in DNA mismatch repair increases the rate of telomere shortening in normal human cells. AB - DNA mismatch repair (MMR) is essential for genome stability and inheritance of a mutated MMR gene, most frequently MSH2 or MLH1, results in cancer predisposition known as Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC). Tumors that arise through MMR deficiency show instability at simple tandem repeat loci (STRs) throughout the genome, known as microsatellite instability (MSI). The STR instability is dominated by errors that accumulate during replication in the absence of effective MMR. In this study we show that there is a high level of instability within telomeric DNA with a tendency toward deletions in tumor derived MMR defective cell lines. We downregulated MSH2 expression in a normal fibroblast cell line and isolated four clones, with differing levels of MSH2 depletion. The telomere-shortening rate was measured at the Xp/Yp, 12q, and 17p telomeres in the MSH2 depleted and three control clones. Interestingly the mean telomere-shortening rate in the clones with MSH2 depletion was significantly greater than in the control clones. This is the first demonstration that MSH2 deficiency alone can lead to accelerated telomere shortening in normal human cells. PMID- 21538692 TI - Characterization of a novel transcript of the EHMT1 gene reveals important diagnostic implications for Kleefstra syndrome. AB - The core phenotype of Kleefstra syndrome (KS) is characterized by intellectual disability, childhood hypotonia, and a characteristic facial appearance. This can be caused by either submicroscopic 9q34 deletions or loss of function mutations of the EHMT1 gene. Remarkably, in three patients with a clinical suspicion of KS, molecular cytogenetic analysis revealed an interstitial 9q34 microdeletion proximal to the coding region of the EHMT1 gene based on the NM_ 024757.3 transcript. Because we found a mono-allelic EHMT1 transcript suggestive for haploinsufficiency of EHMT1 in two of these patients tested, we hypothesized that a deletion of regulatory elements or so far unknown coding sequences in the 5' region of the EHMT1 gene, might result in a phenotype compatible with KS. We further characterized the molecular content of deletions proximal to the transcript NM_ 024757.3 and confirmed presence of a novel predicted open reading frame comprising 27 coding exons (NM_ 024757.4). Further analysis showed that all three deletions included the presumed novel first exon of the EHMT1 gene. Subsequent testing of 75 individuals without previously detectable EHMT1 aberrations showed one additional case with a deletion comprising only this 5' part of the gene. These results have important implications for the genetic screening of KS and for studies of the functional significance of EHMT1. PMID- 21538693 TI - Morphological and mineral analysis of dental enamel after erosive challenge in gastric juice and orange juice. AB - This study evaluated and compared in vitro the morphology and mineral composition of dental enamel after erosive challenge in gastric juice and orange juice. Human enamel specimens were submitted to erosive challenge using gastric juice (from endoscopy exam) (n = 10), and orange juice (commercially-available) (n = 10), as follows: 5 min in 3 mL of demineralization solution, rinse with distilled water, and store in artificial saliva for 3 h. This cycle was repeated four times a day for 14 days. Calcium (Ca) loss after acid exposure was determined by atomic emission spectroscopy. The presence of carbonate (CO) and phosphate (PO) in the specimens was evaluated before and after the erosive challenge by FT-Raman spectroscopy. Data were tested using t-tests (P < 0.05). Morphology of enamel was observed in scanning electron microscopy (SEM). The mean loss of Ca was: 12.74 +/ 3.33 mg/L Ca (gastric juice) and 7.07 +/- 1.44 mg/L Ca (orange juice). The analysis by atomic emission spectroscopy showed statistically significant difference between erosive potential of juices (P = 0.0003). FT-Raman spectroscopy found no statistically significant difference in the ratio CO/PO after the erosive challenge. The CO/PO ratios values before and after the challenge were: 0.16/0.17 (gastric juice) (P = 0.37) and 0.18/0.14 (orange juice) (P = 0.16). Qualitative analysis by SEM showed intense alterations of enamel surface. The gastric juice caused more changes in morphology and mineral composition of dental enamel than orange juice. The atomic emission spectroscopy showed to be more suitable to analyze small mineral loss after erosive challenge than FT-Raman. PMID- 21538694 TI - Surface treatment of glass fiber and carbon fiber posts: SEM characterization. AB - Morphology, etching patterns, surface modification, and characterization of 2 different fiber posts: Gfp, Glass fiber post; and Cfp, carbon fiber were investigated by SEM analysis, after different surface treatments. Thirty fiber posts, being 15 Gfp and 15 Cfp were divided into a 5 surface treatments (n = 3): C-alcohol 70% (control); HF 4%-immersion in 4% hydrofluoric acid for 1min; H(3) PO(4) 37%-immersion in 37% phosphoric acid for 30s; H(2) O(2) 10%-immersion in 10% hydrogen peroxide for 20 min; H(2) O(2) 24%-immersion in 24% hydrogen peroxide for 10 min. Morphology, etching patterns, surface modification and surface characterization were acessed by SEM analysis. SEM evaluation revealed that the post surface morphology was modified following all treatment when compared with a control group, for both type of reinforced posts. HF seems to penetrate around the fibers of Gfp and promoted surface alterations. The Cfp surface seems to be inert to treatment with HF 4%. Dissolution of epoxy resin and exposure of the superficial fiber was observed in both post groups, regardless the type of reinforcing fiber, H(2) O(2) in both concentrations. Relative smooth surface area was produced by H(3) PO(4) 37% treatment, but with similar features to untreated group. Surface treatment of fiber post is a determinant factor on micromechanical entanglement to resin composite core. Post treatment with hydrogen peroxide resulted strength of carbon and glass/epoxy resin fiber posts to resin composite core. PMID- 21538695 TI - Nitric oxide averts hypoxia-induced damage during reoxygenation in rat heart. AB - Nitric oxide (NO), synthesized by the hemoproteins NO synthases (NOS), is known to play important roles in physiological and pathological conditions in the heart, including hypoxia/reoxygenation (H/R). This work investigates the role that endogenous NO plays in the cardiac H/R-induced injury. A follow-up study was conducted in Wistar rats subjected to 30 min of hypoxia, with or without prior treatment using the nonselective NOS inhibitor L-NAME (1.5 mM). The rats were studied at 0 h, 12 h, and 5 days of reoxygenation, analysing parameters of cell, and tissue damage (lipid peroxidation, apoptosis, and protein nitration), as well as in situ NOS activity and NO production (NOx). The results showed that after L NAME administration, in situ NOS activity was almost completely eliminated in all the experimental groups, and consequently, NOx levels fell. Contrarily, the lipid peroxidation level and the percentage of apoptotic cells rose throughout the reoxygenation period. These results reveal that NOS inhibition exacerbates the peroxidative and apoptotic damage observed before the treatment with L-NAME in the hypoxic heart, pointing to a cardioprotective role of NOS-derived NO against H/R-induced injury. These findings could open the possibility of future studies to design new therapies for H/R-dysfunctions based on NO-pharmacology. PMID- 21538696 TI - Characterization of human ovarian teratoma hair by using AFM, FT-IR, and Raman spectroscopy. AB - The structural, physical, and chemical properties of hair taken from an ovarian teratoma (teratoma hair) was first examined by atomic force microscopy (AFM), Fourier transform infrared (FT-IR), and Raman spectroscopy. The similarities and differences between the teratoma hair and scalp hair were also investigated. Teratoma hair showed a similar morphology and chemical composition to scalp hair. Teratoma hair was covered with a cuticle in the same manner as scalp hair and showed the same amide bonding modes as scalp hair according to FT-IR and Raman spectroscopy. On the other hand, teratoma hair showed different physical properties and cysteic acid bands from scalp hair: the surface was rougher and the adhesive force was lower than the scalp hair. The cystine oxides modes did not change with the position unlike scalp hair. These differences can be understood by environmental effects not by the intrinsic properties of the teratoma hair. PMID- 21538697 TI - Comparative study of hydrophilic and hydrophobic ionic liquids for observing cultured human cells by scanning electron microscopy. AB - An ionic liquid (IL) is a salt that remains in the liquid state at room temperature. It does not vaporize under vacuum and imparts electrical conductivity to samples for observation by scanning electron microscopy (SEM). Recently, the usefulness of ILs has been widely recognized. In our previous study, one of the ILs 1-ethyl-3-methylimidazolium tetrafluoroborate (EtMelm(+) BF(4)(-)) was used for SEM analysis of biological samples. In comparison with the conventional method, samples prepared using EtMelm(+) BF(4)(-) provided more detailed SEM images of the cell ultrastructure, enabling the observation of protrusions. In addition, the IL treatment is a less time consuming and simple method that does not include dehydration, drying, and conductivity treatments, which are an essential parts of the conventional method. In this study, we compared the usefulness of four hydrophobic and three hydrophilic ILs for SEM to observe fixed cultured human A549 cells. All ILs worked well to prevent "charge up" effect for SEM observation. However, the hydrophilic ILs tended to provide clearer images than the hydrophobic ILs. We concluded that various ILs can be used for SEM sample preparation and their application to a wide range of fields is anticipated in future. PMID- 21538698 TI - Morphometric analysis of human sciatic nerve perineurial collagen type IV content. AB - OBJECTIVES: Aging is the process which unavoidably alters structure and function of the basal membranes in humans. Though, collagen type IV presents the most prominent component of the basal membranes, we estimated its presence in the perineurium of the human sciatic nerve samples during the aging process. MATERIALS AND METHODS: Material was 12 sciatic nerve samples, obtained from cadavers whose age ranged from 36 to 84 years. Cadavers were classified into three age groups: first which age ranged from 35 to 54 years, second which age ranged from 55 to 74 years and third which included cases older than 75 years. Tissue slices were further stained by labeled streptavidin-biotin method with collagen type IV monoclonal antibody and analyzed with light microscope under 100* lens magnification with oil immersion. Digital images of sciatic nerve perineurium were further processed and analyzed with ImageJ software. RESULTS: Our results showed that there is statistically significant increase of perineurial area, perimeter, collagen type IV area, and collagen type IV area per perineurial perimeter unit in the third age group. These parameters also increased in the second age group, but this increase was not significant. Multiple regression analysis showed that beside fascicular size, age more significantly predict perineurial collagen type IV content. CONCLUSIONS: Results of morphometric and statistical analysis pointed to the conclusion that there is significant increase of sciatic nerve perineurial thickness during the aging process. This increase might represent the consequence of perineurial collagen type IV deposition with aging. PMID- 21538699 TI - Assembly modes of dragonfly wings. AB - The assembly modes of dragonfly wings are observed through FEG-ESEM. Different from airplane wings, dragonfly wings are found to be assembled through smooth transition mode and global package mode. First, at the vein/membrane conjunctive site, the membrane is divided into upper and lower portions from the center layer and transited smoothly to the vein. Then the two portions pack the vein around and form the outer surface of the vein. Second, at the vein/spike conjunctive site, the vein and spike are connected smoothly into a triplet. Last, at the vein/membrane/spike conjunctive site, the membrane (i.e., the outer layer of the vein) transits smoothly to the spike, packs it around, and forms its outer layer. In short, the membrane looks like a closed coat packing the wing as a whole. The smooth transition mode and the global package mode are universal assembly modes in dragonfly wings. They provide us the references for better understanding of the functions of dragonfly wings and the bionic manufactures of the wings of flights with mini sizes. PMID- 21538701 TI - MRT letter: Real time and in situ imaging the reversible evolution of ethanol vapor condensed on mica surface. AB - The reversible adsorption and desorption of ethanol vapor on mica surface at ambient temperature were investigated in situ with time-evolution by Vibrating Scanning Polarization Force Microscopy (VSPFM). At temperature 20 degrees C and relative humidity 20%, ethanol vapor condensed and formed clusters on the freshly cleaved mica. These clusters expanded to a network structure and later formed a full film shown by continuous VSPFM imaging. The film broke into pieces and desorbed completely if in unsaturated condition. The film showed different apparent heights when different biases were used in VSPFM study, indicated polarized orientation of the ethanol molecules on the mica surface. It is a process of hours for the clusters or network structures to form a film on mica, which demonstrated that vapor ethanol molecule is not so easy to precipitate on mica as ethanol molecule in liquid stage. PMID- 21538700 TI - Predicting functional motor potential in chronic stroke patients using diffusion tensor imaging. AB - Electrophysiological and neuroimaging studies suggest that the integrity of ipsilesional and inter-hemispheric motor circuits is important for motor recovery after stroke. However, the extent to which each of these tracts contributes to the variance in outcome remains unclear. We examined whether diffusion tensor imaging (DTI)-derived measures of corticospinal and transcallosal tracts predict motor improvement in an experimental neurorehabilitation trial. 15 chronic stroke patients received bihemispheric transcranial direct current stimulation and simultaneous physical/occupational therapy for five consecutive days. Motor impairment was assessed prior to and after the intervention. At baseline, the patients underwent DTI; probabilistic fiber tracking was used to reconstruct the pyramidal tract (PT), alternate descending motor fibers (aMF), and transcallosal fibers connecting primary motor cortices (M1-M1). Ipsilesional corticospinal tracts (PT, aMF) and M1-M1 showed significantly decreased fractional anisotropy (FA) and increased directional diffusivities when compared to age-matched healthy controls. Partial correlations revealed that greater gains in motor function were related to higher FA values and lower directional diffusivities of transcallosal and ipsilesional corticospinal tracts. M1-M1 diffusivity had the greatest predictive value. An additional slice-by-slice analysis of FA values along the corticospinal tracts demonstrated that the more the ipsilesional FA profiles of patients resembled those of healthy controls, the greater their functional improvement. In conclusion, our study shows that DTI-derived measures can be used to predict functional potential for subsequent motor recovery in chronic stroke patients. Diffusivity parameters of individual tracts and tract combinations may help in assessing a patient's individual recovery potential and in determining optimal neurorehabilitative interventions. PMID- 21538703 TI - Longitudinal gray matter changes in multiple sclerosis--differential scanner and overall disease-related effects. AB - Voxel-based morphometry (VBM) has been used repeatedly in single-center studies to investigate regional gray matter (GM) atrophy in multiple sclerosis (MS). In multi-center trials, across-scanner variations might interfere with the detection of disease-specific structural abnormalities, thereby potentially limiting the use of VBM. Here we evaluated longitudinally inter-site differences and inter site comparability of regional GM in MS using VBM. Baseline and follow up 3D T1 weighted magnetic resonance imaging (MRI) data of 248 relapsing-remitting (RR) MS patients, recruited in two clinical centers, (center1/2: n = 129/119; mean age 42.6 +/- 10.7/43.3 +/- 9.3; male:female 33:96/44:75; median disease duration 150 [72-222]/116 [60-156]) were acquired on two different 1.5T MR scanners. GM volume changes between baseline and year 2 while controlling for age, gender, disease duration, and global GM volume were analyzed. The main effect of time on regional GM volume was larger in data of center two as compared to center one in most of the brain regions. Differential effects of GM volume reductions occurred in a number of GM regions of both hemispheres, in particular in the fronto-temporal and limbic cortex (cluster P corrected <0.05). Overall disease-related effects were found bilaterally in the cerebellum, uncus, inferior orbital gyrus, paracentral lobule, precuneus, inferior parietal lobule, and medial frontal gyrus (cluster P corrected <0.05). The differential effects were smaller as compared to the overall effects in these regions. These results suggest that the effects of different scanners on longitudinal GM volume differences were rather small and thus allow pooling of MR data and subsequent combined image analysis. PMID- 21538704 TI - The modulatory influence of a predictive cue on the auditory steady-state response. AB - Whether attention exerts its impact already on primary sensory levels is still a matter of debate. Particularly in the auditory domain the amount of empirical evidence is scarce. Recently noninvasive and invasive studies have shown attentional modulations of the auditory Steady-State Response (aSSR). This evoked oscillatory brain response is of importance to the issue, because the main generators have been shown to be located in primary auditory cortex. So far, the issue whether the aSSR is sensitive to the predictive value of a cue preceding a target has not been investigated. Participants in the present study had to indicate on which ear the faster amplitude modulated (AM) sound of a compound sound (42 and 19 Hz AM frequencies) was presented. A preceding auditory cue was either informative (75%) or uninformative (50%) with regards to the location of the target. Behaviorally we could confirm that typical attentional modulations of performance were present in case of a preceding informative cue. With regards to the aSSR we found differences between the informative and uninformative condition only when the cue/target combination was presented to the right ear. Source analysis indicated this difference to be generated by a reduced 42 Hz aSSR in right primary auditory cortex. Our and previous data by others show a default tendency of "40 Hz" AM sounds to be processed by the right auditory cortex. We interpret our results as active suppression of this automatic response pattern, when attention needs to be allocated to right ear input. PMID- 21538702 TI - Attention-related networks in Alzheimer's disease: a resting functional MRI study. AB - In addition to memory deficits, attentional impairment is a common manifestation of Alzheimer's disease (AD). The present study examines the abnormalities of attention-related functional networks in AD using resting functional MRI (fMRI) technique and evaluates the sensitivity and specificity of these networks as potential biomarkers compared with the default mode network (DMN). Group independent component analysis (Group ICA) was applied to fMRI data from 15 AD patients and 16 normal healthy elderly controls (NC) to derive the dorsal attention network (DAN) and the ventral attention network (VAN) which are respectively responsible for the endogenous attention orienting ("top-down") process and the exogenous attention re-orienting ("bottom-up") process. Receiver operating characteristic (ROC) curve analysis was performed for activity in core regions within each of these networks. Functional connectivity analysis revealed disrupted DAN and preserved (less impaired) VAN in AD patients compared with NC, which might indicate impairment of a "top-down" and intact "bottom-up" attentional processing mechanisms in AD. ROC curve analysis suggested that activity in the left intraparietal sulcus and left frontal eye field from DAN as well as the posterior cingulate cortex from the DMN could serve as sensitive and specific biomarkers distinguishing AD from NC. PMID- 21538705 TI - Age-related changes in visually evoked electrical brain activity. AB - Whereas much is known about the degenerative effects of aging on cortical tissue, less is known about how aging affects visually evoked electrical activity, and at what latencies. We compared visual processing in elderly and young controls using a visual masking paradigm, which is particularly sensitive to detect temporal processing deficits, while recording EEG. The results show that, on average, elderly have weaker visual evoked potentials than controls, and that elderly show a distinct scalp potential topography (microstate) at around 150 ms after stimulus onset. This microstate occurred irrespective of the visual stimulus presented. Electrical source imaging showed that the changes in the scalp potential resulted from decreased activity in lateral occipital cortex and increases in fronto-parietal areas. We saw, however, no evidence that increased fronto-parietal activity enhanced performance on the discrimination task, and no evidence that it compensated for decreased posterior activity. Our results show qualitatively different patterns of visual evoked potentials (VEPs) in the elderly, and demonstrate that increased fronto-parietal activity arises during visual processing in the elderly already between 150 and 200 ms after stimulus onset. The microstate associated with these changes is a potential diagnostic tool to detect age-related cortical changes. PMID- 21538706 TI - Silver-induced conformational changes of polypeptides: a CD study. AB - The role of silver ions in various pathologies, as well as their effect on peptide conformation and properties are less understood. Consequently, we synthesized several peptides with various residues in their sequence to investigate silver-induced conformational changes at various pH values by Circular Dichroism spectroscopy. Uniquely, the glycine-based, histidine containing peptide showed a severe change from a random coil and beta-turn conformation to large alpha-helices during silver binding. When comparing the effect of silver ions on the conformation of bradykinin a similar tendency was found. Besides, silver ions reduced the amyloid-beta peptide tendency to aggregation. Our results suggest a specific and protective role for silver ions in brain pathologies, which is related to their high affinity toward physiologically and pharmacologically active peptides. Fourier transform infrared spectroscopy studies as well as the mass spectrometric ones support our conclusions. PMID- 21538708 TI - A new FcepsilonRI receptor-mimetic peptide (PepE) that blocks IgE binding to its high affinity receptor and prevents mediator release from RBL 2H3 cells. AB - We have recently reported on a class of IgE-binding peptides designed based on the crystallographic structure of the high affinity FcepsilonRI. Peptides contain receptor key residues located within the two distinct binding sites for IgE and selectively bind IgE with an affinity ranging between 6 and 60 uM. We have here designed and characterized a new molecule containing the receptor loops C'-E and B-C and an optimized linker for joining them made of a Lys side chain and a beta Ala. This new peptide shows an increased affinity (around 30 times) compared to the parent loop C'-E + B-C previously described, while retaining the same two site mechanism of binding and the same selectivity. It also blocks the binding of IgE to the cell-anchored receptor and efficiently prevents histamine release from mast cells. These properties make the peptide a useful scaffold for the development of new anti-allergic drugs. PMID- 21538707 TI - Conformational constraints in angiotensin IV to probe the role of Tyr2, Pro5 and Phe6. AB - The aromatic amino acids Tyr and Phe in angiotensin IV (Ang IV) were conformationally constrained by the use of beta-Me substituted analogs, or cyclic constrained analogs. None of these modifications was allowed for Tyr1, while only e-beta-MePhe6 substitution resulted in an AngIV analog with high IRAP potency and selectivity versus AP-N or the AT1 receptor. This indicates an important role of the orientation of the Phe6 for inducing selectivity. Pro5 replacement with 2 aminocyclopentanecarboxylic acid maintained IRAP potency and abolished AT1 affinity. These results confirm the importance of conformational constrained amino acids to generate selectivity in bioactive peptides. PMID- 21538709 TI - A defensin-like antimicrobial peptide from the venoms of spider, Ornithoctonus hainana. AB - The defensin-like antimicrobial peptides have been characterized from various other arthropods including insects, scorpions, and ticks. But no natural spider defensin-like antimicrobial peptides have ever been isolated from spiders, except couple of cDNA and DNA sequences of five spider species revealed by previous genomic study. In this work, a defensin-like antimicrobial peptide named Oh defensin was purified and characterized from the venoms of the spider, Ornithoctonus hainana. Oh-defensin is composed of 52 amino acid (aa) residues including six Cys residues that possibly form three disulfide bridges. Its aa sequence is MLCKLSMFGAVLGV PACAIDCLPMGKTGGSCEGGVCGCRKLTFKILWDKKFG. By BLAST search, Oh-defensin showed significant sequence similarity to other arthropod antimicrobial peptides of the defensin family. Oh-defensin exerted potent antimicrobial activities against tested microorganisms including Gram-positive bacteria, Gram-negative bacteria, and fungi. The cDNA encoding Oh-defensin precursor was also cloned from the cDNA library of O. hainana. PMID- 21538710 TI - Vaccinating the inflammatory bowel disease patient: deficiencies in gastroenterologists knowledge. AB - BACKGROUND: Current therapy for inflammatory bowel disease (IBD) patients often involves agents that suppress the immune system, placing patients at an increased risk for developing infections, of which several are potentially vaccine preventable. Many IBD patients are not being vaccinated appropriately. The aims of this study were to assess gastroenterologist's knowledge regarding vaccinating the IBD patient, eliciting the barriers that prevent vaccinations, and defining the gastroenterologist's role in vaccinations. METHODS: One thousand gastroenterologists, randomly selected from the membership of the American College of Gastroenterology, were asked to complete a 19 question electronic survey regarding the suitable vaccines for the immunocompetent and immunosuppressed IBD patient and the barriers to recommending the vaccines. The perceived role of the gastroenterologist versus the primary care physician (PCP) was also assessed. RESULTS: In all, 108 responses were analyzed; 68 (62%) gastroenterologists managed 40+ IBD patients, with 65 (52%) asking their patients about immunization history most or all of the time. The majority believed that the PCP should determine which vaccinations to give (64%) and to administer the vaccines (83%). Overall, 66%-88% of gastroenterologists correctly recommended the inactivated vaccines for their IBD patients not on immunosuppressive therapies while 20%-30% incorrectly recommended administering the live vaccines to their immunosuppressed patients. CONCLUSIONS: Gastroenterologist knowledge of the appropriate immunizations to recommend to the IBD patient is poor and may be the primary reason why the majority of gastroenterologists believe that the PCP should be responsible for vaccinations. Educational programs on vaccinations directed to gastroenterologists who prescribe immunosuppressive agents are needed. PMID- 21538711 TI - Manifestations of small bowel disease in pediatric Crohn's disease on magnetic resonance enterography. AB - BACKGROUND: We report the manifestations of Crohn's disease (CD) observed on magnetic resonance enterography (MRE) in a pediatric population at the time of CD diagnosis. METHODS: MRE of 95 consecutive pediatric patients with inflammatory bowel disease (IBD) examined in 2006-2009 were retrospectively analyzed, with documentation of findings based on type and location of the small bowel (SB) disease. RESULTS: In all, 51 were boys and 44 girls. 54 had CD, 31 non-CD IBD, and 10 no IBD. The most common site of SB involvement in CD was the terminal ileum seen in 29 (53.7%) patients, followed by ileum in 10 (18.5%) and jejunum in 9 (16.7%) patients. Solitary jejunal inflammation (3.7%), SB stenoses (1.9%), fistula formation (0.95%), and abscess (0.95%) were much less common. Perienteric lymphadenopathy was seen in 30 (55.6%) patients and fatty proliferation in 9 (16.7%). The most common manifestation of SB inflammation was increased contrast enhancement of bowel wall (93.5%), thickening of the bowel wall (90.3%), and derangement of bowel shape with saccular formations (25.8%). CONCLUSIONS: MRE in the pediatric population often demonstrates increased contrast uptake, bowel wall thickening, and perienteral lymphadenopathy in CD. More chronic small bowel changes seen commonly in adults and solitary jejunal involvements are less commonly seen. PMID- 21538712 TI - Molecular modeling study of the opioid receptor interactions with series of cyclic deltorphin analogues. AB - In this study, ten tetra- and heptapeptide analogues of deltorphin containing the urea bridges between residues 2 and 4 have been docked into the delta- and u opioid receptors to explain their different biological activities. The important factors explaining particular ligand activity such as free energy of binding, conformation of the ligand, its location inside the binding pocket as well as the number and strength of the receptor-ligand interactions have been discussed. Several different binding modes for investigated ligands have been proposed. It appears that the binding site is not identical even for very similar ligands. Results of this study help to explain the differences in biological activity of the deltorphin analogues, their interaction with the opioid receptors at the molecular level and support designing a new generation of potent opioid drugs with improved selectivity. PMID- 21538713 TI - Successful infliximab treatment in a patient with Takayasu arteritis associated with ulcerative colitis or migration does not override genetics. PMID- 21538714 TI - Antimouse CD52 monoclonal antibody inhibits established spontaneous colitis in IL 10-deficient mice. PMID- 21538715 TI - Rare complication of ulcerative colitis: aseptic nasal septal abscess. PMID- 21538716 TI - Development of colonic inflammatory activity after colostomy in patients with exclusively skin perineal Crohn's disease. PMID- 21538717 TI - New pathogenic paradigms in inflammatory bowel disease. AB - Recent progresses in basic science have opened new pathogenic scenarios in inflammatory bowel disease. The T helper cell type (Th)1/Th2 paradigm has been outdated thanks to the advances in understanding the function of Th17 cells. Innate immunity, nonimmune cells, and defective tolerogenic mechanisms play a no less crucial role than do adaptive immunity, immune cells, and hyperactivation of effector mechanisms. These new paradigms, together with the no longer "static" but "dynamic" vision of intestinal inflammation, highlight new possible therapeutic targets in inflammatory bowel disease. PMID- 21538718 TI - Cesarean section and the risk of pediatric Crohn's disease. AB - BACKGROUND: Crohn's disease (CD) could involve an inappropriate immune response against normal bowel flora. Disrupted or atypical patterns of microbial bowel colonization may impair development of homeostasis between gut flora and the immune system. Perinatal microbial exposures may be particularly important in stimulating intestinal immune recognition. As birth by cesarean section is thought to represent an atypical pattern of early bowel colonization, we examined its association with pediatric CD. METHODS: Some 1536 patients diagnosed with pediatric CD and 15,439 controls matched by delivery unit, week of birth, sex, and born between 1973 and 2006 were identified through Swedish registers. The association of birth by cesarean section with pediatric CD was examined using conditional logistic regression, with stratification by sex and adjustment for parental socioeconomic index and maternal infections during pregnancy. RESULTS: Birth by cesarean section is associated with a modestly increased risk for pediatric CD among boys (odds ratio [OR] = 1.25, 95% confidence interval [CI] 1.01-1.54) but not girls, (OR = 0.99, 95% CI 0.76-1.29) and elective cesarean section is associated with a modest increased risk for the entire population (OR = 1.36, 95% CI 1.02-1.80). CONCLUSIONS: This study does not suggest that the delivery procedure should be altered, but the findings may be of etiological significance in CD, indicating a potential role for perinatal exposures associated with delivery mode. Although the sex difference may have arisen by chance, the modestly increased CD risk for boys delivered by cesarean section is consistent with sex-specific differences in susceptibility to some exposures. PMID- 21538719 TI - Vulval Crohn's disease: a tertiary center experience of 23 patients. PMID- 21538720 TI - Ulcerative colitis after anesthesia with desflurane and sevoflurane. PMID- 21538721 TI - Cyclosporine in the management of severe ulcerative colitis while breast-feeding. PMID- 21538722 TI - Patient preference in choosing biological therapy in Crohn's disease. PMID- 21538724 TI - Anxiety symptoms among adolescents in Japan and England: their relationship with self-construals and social support. AB - BACKGROUND: Most of our knowledge about anxiety in adolescents has come from studies conducted in Western countries. Little is known about the extent to which these results can be generalized to those who live in other cultures. The main aim of this study was to compare the frequency and correlates of anxiety symptoms among adolescents in Japan and England. METHOD: A total of 689 adolescents (338 from England and 351 from Japan), aged 12-17 years, took part in this research. They completed a set of questionnaires which were used to measure DSM-IV anxiety disorder symptoms, general difficulties and positive attributes, self-construals, and social support. RESULTS: Adolescents in England reported significantly higher levels of anxiety symptoms than adolescents in Japan. In both countries, independent self-construal was negatively associated with anxiety symptoms, while interdependent self-construal was positively associated with anxiety. However, the magnitude of this relationship was stronger for independent self-construal than the interdependent self-construal. Path analysis showed that the effect of interdependent self-construal seemed to be weaker in Japan than in England. CONCLUSION: Future studies need to explore the effects of cultural context and environmental experiences such as the role of parenting styles that account for the higher levels of anxiety in English compared with Japanese adolescents. PMID- 21538725 TI - Dietary intake of omega-3 fatty acids and risk of depressive symptoms in adolescents. AB - BACKGROUND: Previous randomized controlled trials have demonstrated that omega-3 polyunsaturated fatty acids (n-3 PUFA) are beneficial in reducing symptoms of depression. However, there is limited evidence regarding the influence of dietary n-3 PUFA intake on mood in adolescents drawn from population studies. OBJECTIVE: In the present investigation, we examined the relationship between dietary n-3 PUFA intake on depression symptomatology in a large prospective pregnancy cohort followed for 17 years. METHODS: Adolescents enrolled in the Western Australian Pregnancy Cohort (Raine) Study completed a Food Frequency Questionnaire to assess dietary fatty acid intake, as well as other dietary factors at age 14 and a fasting blood sample was taken. Participants also completed the Beck Depression Inventory for Youth (BDI-Y) at age 14 (N = 1,407) and at age 17 (N = 995). RESULTS: An inverse relationship was observed between intake of both saturated fat and of n-3 PUFA at age 14 and BDI-Y scores at both 14 and 17 years of age. However, after adjusting for energy (kJ) intake and other lifestyle confounders, the relationships were no longer significant. CONCLUSIONS: Associations previously reported between n3 PUFA and depressive symptoms may be due to collinearity with other dietary and lifestyle factors. PMID- 21538723 TI - Affect intensity and lability: the role of posttraumatic stress disorder symptoms in borderline personality disorder. AB - BACKGROUND: Emotion dysregulation is likely a core psychological process underlying the heterogeneity of presentations in borderline personality disorder (BPD) and is associated with BPD symptom severity. Emotion dysregulation has also been independently associated with posttraumatic stress disorder (PTSD), a disorder that has been found to co-occur with BPD in 30.2% of cases in a nationally representative sample. However, relatively little is known about the specific relationships between emotion dysregulation and PTSD among those diagnosed with BPD. The purpose of this study was to evaluate relationships between PTSD symptom severity and negative affect intensity and affective lability among individuals with BPD. METHOD: Participants were 67 individuals diagnosed with BPD (79% women; M(age) = 38, SD = 10), who reported one or more DSM-IV PTSD Criterion A events. RESULTS: Hierarchical multiple regression analyses indicated that when examined concurrently with BPD symptom severity, PTSD symptom severity, but not BPD symptom severity, was related to negative affect intensity and affective lability. Re-experiencing symptoms uniquely predicted affective lability, and hyperarousal symptoms uniquely predicted negative affect intensity, lending additional support to emerging literature linking re-experiencing and hyperarousal symptoms with emotion dysregulation. CONCLUSIONS: PTSD symptom severity among individuals with a BPD diagnosis is related to elevations in emotion dysregulation. It is important to evaluate whether early treatment of PTSD symptoms provided concurrently with BPD treatment leads to enhanced improvements in emotion regulation among individuals with co occurring PTSD and BPD. PMID- 21538726 TI - Major depressive disorder in a family study of obsessive-compulsive disorder with pediatric probands. AB - OBJECTIVE: This study examined the comorbidity of obsessive-compulsive disorder (OCD) with major depressive disorder (MDD) in a family study of OCD with pediatric probands. METHOD: This study assessed the lifetime prevalence of MDD in 141 first-degree relatives (FDR) and 452 second-degree relatives (SDR) of pediatric probands with OCD and healthy controls, and identified variables associated with MDD in case FDR. All available FDR were directly interviewed blind to proband status; parents were also interviewed to assess the family psychiatric history of FDR and SDR. Best-estimate diagnoses were made using all sources of information. Data were analyzed with logistic regression and robust Cox regression models. RESULTS: Lifetime MDD prevalence was significantly higher in case than in control FDR (30.4 versus 15.4%). Lifetime MDD prevalence was significantly higher in FDR of case probands with MDD than in FDR of case probands without MDD or control FDR (46.3 versus 19.7 versus 15.4%, respectively). MDD in case FDR was significantly associated with MDD in case probands and with age and OCD in those relatives. Lifetime MDD prevalence was similar in case and control SDR. However, lifetime MDD prevalence was significantly higher in SDR of case probands with MDD than in SDR of case probands without MDD or control SDR (31.9 versus 16.8 versus 15.4%, respectively). CONCLUSIONS: MDD prevalence was significantly higher in both FDR and SDR of case probands with MDD than in relatives of case probands without MDD or control relatives, suggesting that pediatric OCD comorbid with MDD is a complex familial syndrome. PMID- 21538728 TI - Prophylactic role of D-Saccharic acid-1,4-lactone in tertiary butyl hydroperoxide induced cytotoxicity and cell death of murine hepatocytes via mitochondria dependent pathways. AB - D-Saccharic acid 1,4-lactone (DSL) is a derivative of D-glucaric acid. It is a beta-glucuronidase inhibitor and possesses anticarcinogenic, detoxifying, and antioxidant properties. In the present study, the protective effects of DSL were investigated against tertiary butyl hydroperoxide (TBHP) induced cytotoxicity and cell death in vitro using murine hepatocytes. Exposure of TBHP caused a reduction in cell viability, enhanced the membrane leakage, and disturbed the intracellular antioxidant machineries in murine hepatocytes. Investigating the signaling mechanism of TBHP-induced cellular pathophysiology and protective action of DSL, we found that TBHP exposure disrupted mitochondrial membrane potential, facilitated cytochrome c release in the cytosol, and led to apoptotic cell death via mitochondria-dependent pathways. DSL counteracted these changes and maintained normalcy in hepatocytes. Combining, results suggest that DSL possesses the ability to ameliorate TBHP-induced oxidative insult, cytotoxicity, and apoptotic cell death probably due to its antioxidant activity and functioning via mitochondria-dependent pathways. PMID- 21538729 TI - Nitroxides: applications in synthesis and in polymer chemistry. AB - This Review describes the application of nitroxides to synthesis and polymer chemistry. The synthesis and physical properties of nitroxides are discussed first. The largest section focuses on their application as stoichiometric and catalytic oxidants in organic synthesis. The oxidation of alcohols and carbanions, as well as oxidative C-C bond-forming reactions are presented along with other typical oxidative transformations. A section is also dedicated to the extensive use of nitroxides as trapping reagents for C-centered radicals in radical chemistry. Alkoxyamines derived from nitroxides are shown to be highly useful precursors of C-centered radicals in synthesis and also in polymer chemistry. The last section discusses the basics of nitroxide-mediated radical polymerization (NMP) and also highlights new developments in the synthesis of complex polymer architectures. PMID- 21538727 TI - Constitutive activation of nuclear factor-E2-related factor 2 induces biotransformation enzyme and transporter expression in livers of mice with hepatocyte-specific deletion of Kelch-like ECH-associated protein 1. AB - Chemicals that activate nuclear factor-E2-related factor 2 (Nrf2) often increase multidrug-resistance-associated protein (Mrp) expression in liver. Hepatocyte specific deletion of Kelch-like ECH-associated protein 1 (Keap1) activates Nrf2. Use of hepatocyte-specific Keap1 deletion represents a nonpharmacological method to determine whether constitutive Nrf2 activation upregulates liver transporter expression in vivo. The mRNA, protein expression, and localization of several biotransformation and transporters were determined in livers of wild-type and hepatocyte-specific Keap1-null mice. Sulfotransferase 2a1/2, NADP(H):quinone oxidoreductase 1, cytochrome P450 2b10, 3a11, and glutamate-cysteine ligase catalytic subunit expression were increased in livers of Keap1-null mice. Organic anion-transporting polypeptide 1a1 expression was nearly abolished, as compared to that detected in livers of wild-type mice. By contrast, Mrp 1-5 mRNA and protein levels were increased in Keap1-null mouse livers, with Mrp4 expression being more than 15-fold higher than wild types. In summary, Nrf2 has a significant role in affecting Oatp and Mrp expressions. PMID- 21538730 TI - From the surface to volume: concepts for the next generation of optical holographic data-storage materials. AB - Optical data storage has had a major impact on daily life since its introduction to the market in 1982. Compact discs (CDs), digital versatile discs (DVDs), and Blu-ray discs (BDs) are universal data-storage formats with the advantage that the reading and writing of the digital data does not require contact and is therefore wear-free. These formats allow convenient and fast data access, high transfer rates, and electricity-free data storage with low overall archiving costs. The driving force for development in this area is the constant need for increased data-storage capacity and transfer rate. The use of holographic principles for optical data storage is an elegant way to increase the storage capacity and the transfer rate, because by this technique the data can be stored in the volume of the storage material and, moreover, it can be optically processed in parallel. This Review describes the fundamental requirements for holographic data-storage materials and compares the general concepts for the materials used. An overview of the performance of current read-write devices shows how far holographic data storage has already been developed. PMID- 21538731 TI - Oral, direct thrombin and factor Xa inhibitors: the replacement for warfarin, leeches, and pig intestines? AB - To prevent thromboses after surgery, patients have until now had to inject themselves daily with heparin. For stroke prophylaxis in atrial fibrillation, patients take vitamin K antagonists of the coumarin type, which have a narrow therapeutic window and whose dosage must be regularly monitored. In order to improve the standard of therapy in thromboembolic diseases such as deep-vein thrombosis, pulmonary embolism, and stroke in atrial fibrillation, intensive research has been carried out over the last decade in the search for new, orally active thrombin and factor Xa inhibitors. A number of these compounds are already on the market or are in advanced clinical development; they could revolutionize the anticoagulant market. PMID- 21538732 TI - Binding of filamentous actin and winding into fibrillar aggregates by the polyphenolic C-glucosidic ellagitannin vescalagin. PMID- 21538733 TI - Aromatic rings in chemical and biological recognition: energetics and structures. AB - This review describes a multidimensional treatment of molecular recognition phenomena involving aromatic rings in chemical and biological systems. It summarizes new results reported since the appearance of an earlier review in 2003 in host-guest chemistry, biological affinity assays and biostructural analysis, data base mining in the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB), and advanced computational studies. Topics addressed are arene-arene, perfluoroarene-arene, S???aromatic, cation-pi, and anion-pi interactions, as well as hydrogen bonding to pi systems. The generated knowledge benefits, in particular, structure-based hit-to-lead development and lead optimization both in the pharmaceutical and in the crop protection industry. It equally facilitates the development of new advanced materials and supramolecular systems, and should inspire further utilization of interactions with aromatic rings to control the stereochemical outcome of synthetic transformations. PMID- 21538734 TI - Nonenzymatic dynamic kinetic resolution of alpha-(arylthio)- and alpha (alkylthio)alkanoic acids. PMID- 21538735 TI - An exo- and enantioselective 1,3-dipolar cycloaddition of azomethine ylides with alkylidene malonates catalyzed by a N,O-ligand/Cu(OAc)2-derived chiral complex. PMID- 21538736 TI - Size-complementary rotaxane cross-linking for the stabilization and degradation of a supramolecular network. PMID- 21538737 TI - A bifunctional mechanism for ethene dimerization: catalysis by rhodium complexes on zeolite HY in the absence of halides. PMID- 21538738 TI - Copper-catalyzed 1,4-addition of organoboronates to alkylidene cyanoacetates: mechanistic insight and application to asymmetric catalysis. PMID- 21538739 TI - Making and breaking peptide bonds: protein engineering using sortase. AB - Sortases are a class of bacterial enzymes that possess transpeptidase activity. It is their ability to site-specifically break a peptide bond and then reform a new bond with an incoming nucleophile that makes sortase an attractive tool for protein engineering. This technique has been adopted for a range of applications, from chemistry-based to cell biology and technology. In this Minireview we provide a brief overview of the biology of sortase enzymes and current applications in protein engineering. We identify areas that lend themselves to further innovation and that suggest new applications. PMID- 21538740 TI - Efficient gold(I)-catalyzed direct intramolecular hydroalkylation of unactivated alkenes with alpha-ketones. PMID- 21538741 TI - Efficient and selective gas-phase monomethylation versus N-H bond activation of ammonia by "bare" Zn(CH3)+: atomic zinc as a leaving group in an SN2 reaction. PMID- 21538742 TI - Cascade formation of isoxazoles: facile base-mediated rearrangement of substituted oxetanes. PMID- 21538743 TI - Accelerated NMR spectroscopy by using compressed sensing. PMID- 21538744 TI - Stable N-heterocyclic carbene complexes of hypermetallyl germanium(II) and tin(II) compounds. PMID- 21538745 TI - Cinchona alkaloid amide catalyzed enantioselective formal [2+2] cycloadditions of allenoates and imines: synthesis of 2,4-disubstituted azetidines. PMID- 21538746 TI - CO2-responsive polymeric vesicles that breathe. PMID- 21538747 TI - Asymmetric organocatalytic 1,6-conjugate addition of aldehydes to dienic sulfones. PMID- 21538748 TI - Direct observation of time-resolved polymorphic states in the self-assembly of end-capped heptapeptides. PMID- 21538749 TI - Experimental evidence of phosphine oxide generation in solution and trapping by ruthenium complexes. PMID- 21538750 TI - Tracing the hydrogen source of hydrocarbons formed by vanadium nitrogenase. PMID- 21538751 TI - Ultrafast microscopy of microfluidics: compressed sensing and remote detection. PMID- 21538752 TI - A practical strategy for the structural diversification of aliphatic scaffolds through the palladium-catalyzed picolinamide-directed remote functionalization of unactivated C(sp3)-H bonds. PMID- 21538753 TI - Nitrogen directs multiple radical additions to the 9,9'-bi-1-aza(C60 I(h))[5,6]fullerene: X-ray structure of 6,9,12,15,18-C59N(CF3)5. PMID- 21538755 TI - Asymmetric neutral amination of nitroolefins catalyzed by chiral bifunctional ammonium salts in water-rich biphasic solvent. PMID- 21538757 TI - Transport of free and peptide-bound glycated amino acids: synthesis, transepithelial flux at Caco-2 cell monolayers, and interaction with apical membrane transport proteins. AB - In glycation reactions, the side chains of protein-bound nucleophilic amino acids such as lysine and arginine are post-translationally modified to a variety of derivatives also known as Maillard reaction products (MRPs). Considerable amounts of MRPs are taken up in food. Here we have studied the interactions of free and dipeptide-bound MRPs with intestinal transport systems. Free and dipeptide-bound derivatives of N(6)-(1-fructosyl)lysine (FL), N(6)-(carboxymethyl)lysine (CML), N(6)-(1-carboxyethyl)lysine (CEL), formyline, argpyrimidine, and methylglyoxal derived hydroimidazolone 1 (MG-H1) were synthesized. The inhibition of L [(3)H]lysine and [(14) C]glycylsarcosine uptakes was measured in Caco-2 cells which express the H(+)/peptide transporter PEPT1 and lysine transport system(s). Glycated amino acids always displayed lower affinities than their unmodified analogues towards the L-[(3)H]lysine transporter(s). In contrast, all glycated dipeptides except Ala-FL were medium- to high-affinity inhibitors of [(14)C]Gly Sar uptake. The transepithelial flux of the derivatives across Caco-2 cell monolayers was determined. Free amino acids and intact peptides derived from CML and CEL were translocated to very small extents. Application of peptide-bound MRPs, however, led to elevation (up to 80-fold) of the net flux and intracellular accumulation of glycated amino acids, which were hydrolyzed from the dipeptides inside the cells. We conclude 1) that free MRPs are not substrates for the intestinal lysine transporter(s), and 2) that dietary MRPs are absorbed into intestinal cells in the form of dipeptides, most likely by the peptide transporter PEPT1. After hydrolysis, hydrophobic glycated amino acids such as pyrraline, formyline, maltosine, and argpyrimidine undergo basolateral efflux, most likely by simple diffusion down their concentration gradients. PMID- 21538758 TI - Activity-based profiling of retaining beta-glucosidases: a comparative study. AB - Activity-based protein profiling (ABPP) is a versatile strategy to report on enzyme activity in vitro, in situ, and in vivo. The development and use of ABPP tools and techniques has met with considerable success in monitoring physiological processes involving esterases and proteases. Activity-based profiling of glycosidases, on the other hand, has proven more difficult, and to date no broad-spectrum glycosidase activity-based probes (ABPs) have been reported. In a comparative study, we investigated both 2-deoxy-2-fluoroglycosides and cyclitol epoxides for their utility as a starting point towards retaining beta-glucosidase ABP. We also investigated the merits of direct labeling and two step bio-orthogonal labeling in reporting on glucosidase activity under various conditions. Our results demonstrate that 1) in general cyclitol epoxides are the superior glucosidase ABPs, 2) that direct labeling is the more efficient approach but it hinges on the ability of the glucosidase to be accommodated in the active site of the reporter (BODIPY) entity, and 3) that two-step bio-orthogonal labeling can be achieved on isolated enzymes but translating this protocol to cell extracts requires more investigation. PMID- 21538759 TI - Myricetin: a naturally occurring regulator of metal-induced amyloid-beta aggregation and neurotoxicity. PMID- 21538760 TI - Click Peptide concept: o-acyl isopeptide of islet amyloid polypeptide as a nonaggregative precursor molecule. AB - The O-acyl isopeptide (1) of islet amyloid polypeptide (IAPP), which contains an ester moiety at both Ala8-Thr9 and Ser19-Ser20, was prepared by sequential segment condensation based on the O-acyl isopeptide method. Isopeptide 1 possessed nonaggregative properties, retaining its random coil structure under the acidic conditions; this suggests that the insertion of the O-acyl isopeptide structures in IAPP suppressed aggregation of the molecule. As a result of the rapid O-to-N acyl shift of 1 under neutral pH, in situ-formed IAPP adopted a random-coil structure at the start of the experiment, and then underwent conformational change to alpha-helix/beta-sheet mixed structures as well as aggregation. The click peptide strategy with the nonaggregative precursor molecule 1 could be a useful experimental tool to identify the functions of IAPP, by overcoming the handling difficulties that arise from IAPP's intense and uncontrollable self-assembling nature. PMID- 21538761 TI - Gene regulation system with an artificial RNA switch operating in human cells. PMID- 21538762 TI - Exploration of biarsenical chemistry--challenges in protein research. AB - The fluorescent modification of proteins (with genetically encoded low-molecular mass fluorophores, affinity probes, or other chemically active species) is extraordinarily useful for monitoring and controlling protein functions in vitro, as well as in cell cultures and tissues. The large sizes of some fluorescent tags, such as fluorescent proteins, often perturb normal activity and localization of the protein of interest, as well as other effects. Of the many fluorescent-labeling strategies applied to in vitro and in vivo studies, one is very promising. This requires a very short (6- to 12-residue), appropriately spaced, tetracysteine sequence (-CCXXCC-); this is either placed at a protein terminus, within flexible loops, or incorporated into secondary structure elements. Proteins that contain the tetracysteine motif become highly fluorescent upon labeling with a nonluminescent biarsenical probe, and form very stable covalent complexes. We focus on the development, growth, and multiple applications of this protein research methodology, both in vitro and in vivo. Its application is not limited to intact-cell protein visualization; it has tremendous potential in other protein research disciplines, such as protein purification and activity control, electron microscopy imaging of cells or tissue, protein-protein interaction studies, protein stability, and aggregation studies. PMID- 21538763 TI - Feglymycin is an inhibitor of the enzymes MurA and MurC of the peptidoglycan biosynthesis pathway. PMID- 21538764 TI - Identification and characterization of new inhibitors of fungal homoserine kinase. PMID- 21538765 TI - Probing the functionalization of gold surfaces and protein adsorption by PM IRRAS. AB - The control of morphology and coating of metal surfaces is essential for a number of organic electronic devices including photovoltaic cells and sensors. In this study, we monitor the functionalization of gold surfaces with 11 mercaptoundecanoic acid (MUA, HS(CH(2) )(10) CO(2) H) and cysteamine, aiming at passivating the surfaces for application in surface plasmon resonance (SPR) biosensors. Using polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS), cyclic voltammetry, atomic force microscopy and quartz crystal microbalance, we observed a time-dependent organization process of the adsorbed MUA monolayer with alkyl chains perpendicular to the gold surface. Such optimized condition for surface passivation was obtained with a systematic search for experimental parameters leading to the lowest electrochemical signal of the functionalized gold electrode. The ability to build supramolecular architectures was also confirmed by detecting with PM-IRRAS the adsorption of streptavidin on the MUA-functionalized gold. As the approaches used for surface functionalization and its verification with PM-IRRAS are generic, one may now envisage monitoring the fabrication of tailored electrodes for a variety of applications. PMID- 21538766 TI - Wrapping bacteria in graphene. PMID- 21538767 TI - Optimal transseptal puncture location for robot-assisted left atrial catheter ablation. AB - BACKGROUND: The preferred method of treatment for atrial fibrillation (AF) is by catheter ablation, in which a catheter is guided into the left atrium through a transseptal puncture. However, the transseptal puncture constrains the catheter, thereby limiting its manoeuvrability and increasing the difficulty in reaching various locations in the left atrium. In this paper, we address the problem of choosing the optimal transseptal puncture location for performing cardiac ablation to obtain maximum manoeuvrability of the catheter. METHODS: We have employed an optimization algorithm to maximize the global isotropy index (GII) to evaluate the optimal transseptal puncture location. As part of this algorithm, a novel kinematic model for the catheter has been developed, based on a continuum robot model. Pre-operative MR/CT images of the heart are segmented using the open source image-guided therapy software, 3D Slicer, to obtain models of the left atrium and septal wall. These models are input to the optimization algorithm to evaluate the optimal transseptal puncture location. RESULTS: The continuum robot model accurately describes the kinematics of the catheter. Simulation and experimental results for the optimal transseptal puncture location are presented in this paper. The optimization algorithm generates discrete points on the septal wall for which the dexterity of the catheter in the left atrium is maximum, corresponding to a GII of 0.4362. CONCLUSION: We have developed an optimization algorithm based on the GII to evaluate the optimal position of the transseptal puncture for left atrial cardiac ablation. PMID- 21538768 TI - How to build patient-specific synthetic abdominal anatomies. An innovative approach from physical toward hybrid surgical simulators. AB - BACKGROUND: According to literature evidence, simulation is of the utmost importance for training and innovative surgical strategies assessment. At present commercial physical simulators are limited to single or only a few anatomical structures and these are often just standard anatomies. METHODS: This paper describes a strategy to produce patient-specific abdominal silicone organs with realistic shapes and colors, starting from radiological images. Synthetic organs can be assembled in a complex physical simulator or, if paired with electromagnetic sensors, in a hybrid environment (mixed reality) to quantify deformations caused by surgical action. RESULTS: A physical trunk phantom with liver, gallbladder, pancreas and a sensorized stomach has been developed. It is coupled with consistent radiological images and a 3D model of the entire upper abdomen. The simulator has been evaluated in quantitative and qualitative terms to quantify its accuracy and utility, respectively. CONCLUSIONS: This simulator can be used in the field of abdominal surgery to train students and as a testing environment to assess and validate innovative surgical technologies. PMID- 21538769 TI - Force feedback in a piezoelectric linear actuator for neurosurgery. AB - BACKGROUND: Force feedback in robotic minimally invasive surgery allows the human operator to manipulate tissues as if his/her hands were in contact with the patient organs. A force sensor mounted on the probe raises problems with sterilization of the overall surgical tool. Also, the use of off-axis gauges introduces a moment that increases the friction force on the bearing, which can easily mask off the signal, given the small force to be measured. METHODS: This work aims at designing and testing two methods for estimating the resistance to the advancement (force) experienced by a standard probe for brain biopsies within a brain-like material. The further goal is to provide a neurosurgeon using a master-slave tele-operated driver with direct feedback on the tissue mechanical characteristics. Two possible sensing methods, in-axis strain gauge force sensor and position-position error (control-based method), were implemented and tested, both aimed at device miniaturization. The analysis carried out was aimed at fulfilment of the psychophysics requirements for force detection and delay tolerance, also taking into account safety, which is directly related to the last two issues. Controller parameters definition is addressed and consideration is given to development of the device with integration of a haptic interface. RESULTS: Results show better performance of the control-based method (RMSE < 0.1 N), which is also best for reliability, sterilizability, and material dimensions for the application addressed. CONCLUSIONS: The control-based method developed for force estimation is compatible with the neurosurgical application and is also capable of measuring tissue resistance without any additional sensors. Force feedback in minimally invasive surgery allows the human operator to manipulate tissues as if his/her hands were in contact with the patient organs. PMID- 21538770 TI - Intravascular catheter navigation using path planning and virtual visual feedback for oral cancer treatment. AB - BACKGROUND: It is tedious and difficult to position a flexible catheter in a target vessel branch within complicated-shaped vessels owing to the lack of real time visual feedback. Digital subtraction angiography and fluoroscopic guidance are currently used for catheter placement. METHODS: The proposed method employs an electromagnetic (EM) tracking system to track a sensor-attached catheter. Vessel centerlines are extracted from the CT angiography image, based on which a navigational information tree is built to facilitate catheter manipulation. A virtual endoscopy technique is adopted to generate virtual intravascular video as visual feedback. Unscented Kalman filtering based image registration is performed to align the EM tracker frame with the anatomical atlas and to envision the target registration error. RESULTS: Preliminary experimental results showed the feasibility and effectiveness of the new method, with navigation accuracy of 1.80 +/- 0.85 mm. CONCLUSIONS: The proposed method can provide continuous virtual visual feedback to facilitate catheter placement and has the potential for clinical use, with significant reduction in X-ray radiation exposure and doses of contrast agents. PMID- 21538771 TI - Development of a robotic FD-CT-guided navigation system for needle placement preliminary accuracy tests. AB - BACKGROUND: A needle placement system using a serial robot arm for manipulation of biopsy and/or treatment needles is introduced. A method for fast calibration of the robot and the preliminary accuracy tests of the robotic system are presented. METHODS: The setup consists of a DLR/KUKA Light Weight Robot III especially designed for safe human/robot interaction mounted on a mobile platform, a robot-driven angiographic C-arm system and a navigation system. RESULTS: Calibration of the robot with the navigation system has a residual error of 0.23 mm (rms) with a standard deviation of +/- 0.1 mm. Needle targeting accuracy with different trajectories was 1.2 mm (rms) with a standard deviation of +/- 0.4 mm. CONCLUSIONS: Robot absolute positioning accuracy was reduced to the navigation camera accuracy. The approach includes control strategies that may be very useful for interventional applications. PMID- 21538772 TI - Visual servoing for a US-guided therapeutic HIFU system by coagulated lesion tracking: a phantom study. AB - BACKGROUND: Applying ultrasound (US)-guided high-intensity focused ultrasound (HIFU) therapy for kidney tumours is currently very difficult, due to the unclearly observed tumour area and renal motion induced by human respiration. In this research, we propose new methods by which to track the indistinct tumour area and to compensate the respiratory tumour motion for US-guided HIFU treatment. METHODS: For tracking indistinct tumour areas, we detect the US speckle change created by HIFU irradiation. In other words, HIFU thermal ablation can coagulate tissue in the tumour area and an intraoperatively created coagulated lesion (CL) is used as a spatial landmark for US visual tracking. Specifically, the condensation algorithm was applied to robust and real-time CL speckle pattern tracking in the sequence of US images. Moreover, biplanar US imaging was used to locate the three-dimensional position of the CL, and a three actuator system drives the end-effector to compensate for the motion. Finally, we tested the proposed method by using a newly devised phantom model that enables both visual tracking and a thermal response by HIFU irradiation. RESULTS: In the experiment, after generation of the CL in the phantom kidney, the end-effector successfully synchronized with the phantom motion, which was modelled by the captured motion data for the human kidney. The accuracy of the motion compensation was evaluated by the error between the end-effector and the respiratory motion, the RMS error of which was approximately 2 mm. CONCLUSION: This research shows that a HIFU-induced CL provides a very good landmark for target motion tracking. By using the CL tracking method, target motion compensation can be realized in the US-guided robotic HIFU system. PMID- 21538773 TI - Kinematic fundamentals of a biomechatronic laparoscopy system. AB - BACKGROUND: Optical assistance in laparoscopic surgery is essential for an optimal procedure. Unlike conventional surgery, it requires new systems to reduce spatial location time, navigation and cleanliness without compromising surgical quality. This article shows the kinematic analysis of a new bio-mechatronic design to assist laparoscopic visual perspective in real time, either during training or in surgery. METHODS: The bio-mechatronic system is analyzed in order to get the kinematic model of the system. RESULTS: The set of kinematic equations for the bio-mechatronic system are presented here. The system has been tested functionally in several surgical procedures successfully. CONCLUSION: The analysis shows the workspace under postural conditions of navigation in real time, where it is possible to get visually self assistance during training or specific surgeries. The new bio-mechatronic system has been tested in training with inanimate and biological models, in veterinary surgery and pediatrics, with the appropriate consent and respecting the Treaty of Helsinki. PMID- 21538774 TI - A novel haptic robotic viscogram for characterizing the viscoelastic behaviour of breast tissue in clinical examinations. AB - BACKGROUND: This paper presents a novel tactile sensing robot designed to characterize the viscoelastic behaviour of breast tissue during clinical breast examination (CBE). The robot, named the 'robotic tactile breast mass identifier' (Robo-Tac-BMI), mainly consists of an indentation probe controlled by a robotic system and a visualization interface to manipulate the end-effector. Major high order mechanical parameters are extracted to characterize the viscoelastic behaviour of the tissue in order to certify mass detection and judge the mass type. By fusing the measurements over both breasts, the probe can generalize a mechanical image to visualize the viscoelastic distribution within the internal tissue. The viscoelastic properties provide additional and objective information to facilitate the surgeon's task in the decision-making process. METHODS: A new computational method is presented for characterizing mass existence in a real breast model. The effect of the strain rate on the mechanical properties is considered to study the viscoelastic behaviour of different mass types. A creative method is proposed to find the optimum strain rate for different mass positions and consistencies, which improves nodule detection. The computational results would be used as the basis for the design and set-up of the Robo-Tac-BMI. Clinical tests with statistical analyses were performed on 161 cases, using the Robo-Tac-BMI. RESULTS: The results include analysis of two high-order mechanical properties. Robo-Tac-BMI's capability of nodule detection and differentiation between benign and malignant mass types are investigated. The results were validated by 'gold standard' tests. CONCLUSION: The results show that Robo-Tac BMI has the potential to provide high-order mechanical parameters, unlike the conventional screening modality carried out by the surgeon, which is not inclusive or quantitative and lacks effectiveness and documentation. The nodule detection ability of this device is confirmed statistically in clinical breast examinations. Differentiation between different mass types is reported as the preliminary result of Robo-Tac-BMI utilization. PMID- 21538775 TI - Advanced glycation end products downregulate glucokinase in mice. AB - BACKGROUND: Glucokinase, the enzyme that catalyses the conversion of glucose to G 6-P, plays a key role in glucose metabolism. AGEs are implicated in diabetic complications. A previous study reported that AGEs decreased beta-cell function through inhibition of cytochrome c oxidase and adenosine triphosphate synthesis. This study investigated the effects of AGEs on glucokinase and islet function. METHODS: Six-month-old male C57BL6 mice were divided into bovine serum albumin (BSA) and AGE-BSA groups. BSA (200 ug/g) and AGE-BSA (60 U/g) were administered intraperitoneally twice daily. After 2 weeks, serum AGE levels were measured, oral glucose tolerance test was performed, and insulin levels during the oral glucose tolerance test were determined. Glucokinase protein expression level and activity were measured in pancreatic islets. RESULTS: We observed that the normal mice (C57/BL6) treated for 2 weeks with AGE-BSA showed impaired glucose tolerance and decrease in acute insulin release. Glucokinase activity in islets from the AGE-BSA-treated mice was significantly inhibited and accompanied by blunted response of islets to high glucose stimulation. Moreover, in vitro experiments showed that glucokinase protein expression was decreased, its activity was inhibited, and islet function was decreased. GKA partially restored glucokinase activity and islet function caused by AGEs. CONCLUSIONS: We concluded that AGEs inhibited glucokinase activity, leading to islet dysfunction in mouse pancreatic islets. PMID- 21538776 TI - The relationship between serum ferritin and metabolic syndrome in healthy Korean men. AB - BACKGROUND AND OBJECTIVE: Elevated serum ferritin levels have been reported to be associated with several metabolic disorders. We investigated the relationship between serum ferritin level and metabolic syndrome and its components in healthy Korean men. METHODS: In this cross-sectional study, serum ferritin level and metabolic syndrome and its components were measured from 18 581 men from January to December in 2008. The presence of metabolic syndrome was determined according to the most recent consensus report of the National Cholesterol Education Program's Third Adult Treatment Panel. Logistic regression models were applied to examine the relationship between the serum ferritin level and the metabolic syndrome and its components. RESULTS: After adjusting for clinical covariates, the odds ratio and 95% confidence intervals of metabolic syndrome with respect to Q2, Q3 and Q4 were 1.34 (1.14-1.57), 1.49 (1.24-1.70) and 1.99 (1.70-2.33), respectively (p for trend < 0.001). The multivariable-adjusted model also showed a significantly graded relationship between individual components of metabolic syndrome and the quartile groups of serum ferritin. CONCLUSIONS: In this study, elevated ferritin concentration is independently associated with metabolic syndrome and its components among healthy Korean men. PMID- 21538777 TI - Reduction in insulin sensitivity following administration of the clinically used low-dose pressor, norepinephrine. AB - BACKGROUND: Hyperglycaemia in acutely ill patients is well described and correcting this hyperglycaemia improves outcomes. It has been generally attributed to endogenous factors, specifically decreased secretion of insulin or increased secretion of anti-insulin hormones, and cytokines, or both. Norepinephrine is the most commonly used vasopressor in critically ill patients. When titrated, it has anecdotally been found to cause wide swings in blood glucose levels. We tested the hypothesis that norepinephrine, a plausible exogenous, iatrogenic cause of hyperglycaemia, causes resistance to insulin action with the hyperinsulinaemic-euglycaemic clamp method. METHODS: Hyperinsulinaemic-euglycaemic (about 100 mg dL(-1) ) clamps were performed before and during infusion of norepinephrine, in doses of 110 ng kg(-1) min(-1) , which raised mean arterial pressure from 82 +/- 7 to 94 +/- 8 mmHg (p < 0.01) in 11 healthy adults. RESULTS: The glucose infusion rate required to maintain euglycaemia during the clamps, a marker of whole-body insulin sensitivity, decreased from 11.2 +/- 3.7 mg kg(-1) min(-1) at baseline to 9.0 +/- 2.6 mg kg( 1) min(-1) (p = 0.015) during the norepinephrine infusion. Steady-state insulin and C-peptide levels did not significantly change. Cortisol levels showed diurnal variation in the beginning and were also different at steady state. CONCLUSIONS: Infusion of pressor doses of norepinephrine causes resistance to insulin action in humans. PMID- 21538778 TI - Perforation of the descending thoracic aorta during transcatheter aortic valve implantation (TAVI): an unexpected and dramatic procedural complication. AB - Transcatheter aortic valve implantation (TAVI) has become an established technique for the treatment of aortic stenosis in patients who cannot undergo surgery. Although TAVI is obviously less invasive than open surgical repair, it is not free of complications. We report a case of unexplained refractory shock during transfemoral TAVI with subsequent autopsy demonstrating a 1-cm large perforation of the descending thoracic aorta as the cause of death. To the best of our knowledge, this is the first case ever reported. PMID- 21538779 TI - Ischemic hepatitis secondary to hepatic artery steal in a patient with celiac artery stenosis and severe postural hypotension. AB - Ischemic hepatitis, also known as hypoxic hepatitis or shock liver is defined as an acute, transient elevation of aminotransferase levels in the absence of any known causes. The pathogenesis is multifactorial. Many studies have suggested systemic hypotension as a major contributor to the pathogenesis of ischemic hepatitis but that alone is not enough to cause it. Celiac artery stenosis does not commonly cause clinically significant hepatic ischemia because of its rich collaterals. We present a case of a 78-year-old male with a background of severe orthostatic hypotension, who presented with elevation of liver enzymes due to hepatic artery steal precipitated by celiac artery stenosis. Clinical investigations showed elevated transaminases and unremarkable CT scan. Invasive celiac artery angiography showed a critical ostial lesion and it was stented. The liver enzymes peaked the day following stenting and normalized over the next 9 days. This confirmed clinically significant hepatic artery steal due to an ostial celiac artery stenosis. Relieving the celiac artery stenosis normalized the liver enzymes confirming the interdependence of the two components of this rare syndrome. Our report is the only report to our knowledge where classic hepatic artery steal and shock liver was demonstrated due to the rare combination of severe orthostatic hypotension and celiac artery ostial stenosis. PMID- 21538780 TI - Vascular hemostasis bandage compared to standard manual compression after cardiac catheterization in children. AB - BACKGROUND: Femoral venous and arterial approaches are the commonly used to obtain vascular access for pediatric cardiac catheterization. Hemostasis after catheter removal is usually obtained by manual compression. However, this technique is time consuming and at times painful. Although several closure devices are available for adults, they are not widely applicable in children. OBJECTIVES: To evaluate the safety and efficacy of a microporous polysaccharide hemospheres hemostasis (MPH) bandage compared to manual compression. METHODS: Prospective randomized study, involving 112 children after cardiac catheterization. One group received the MPH bandage, another manual compression. Compression time was predetermined by the size of sheath plus one minute. Success was defined as no bleeding or hematoma formation. If bleeding continued, compression was continued as needed and time to hemostasis recorded. Informed consent was obtained prior to randomization. Group comparisons were performed with a Student's t, Pearson's Chi Square, and Fisher's exact test as appropriate. RESULTS: Fewer children required a compression time of >15 min (P = 0.006) and more had a shorter time to hemostasis (P = 0.003) in the MPH group for venous access control. Time to hemostasis was also shorter in the MPH (P = 0.048) in arterial access cases, but the number of children requiring a compression time >15 min was the same. Complications including hematoma formation in each group were similar. CONCLUSIONS: The MPH bandage allows a shorter time to achieve hemostasis compared to manual compression. This improves turnaround time and laboratory efficiency. PMID- 21538781 TI - Arterial duct stenting in low-weight newborns with duct-dependent pulmonary circulation. AB - OBJECTIVES: To evaluate feasibility and results of arterial duct (AD) stenting in low-weight newborns with congenital heart disease and duct-dependent pulmonary circulation (CHD-DPC). BACKGROUND: AD stenting is nowadays considered a cost effective alternative to surgical shunt in CHD-DPC. This option might be even more advisable in low-weight neonates (<2.5 kg), who are at higher surgical risk and in whom stent redilation might adapt shunt magnitude to patient's growth. METHODS: Between April 2003 and September 2010, 76 neonates with CHD-DPC underwent AD stenting at our institution, as lower-risk palliation with respect to surgical shunt. Procedural and follow-up data of the 15 low-weight newborns (2.0 +/- 0.3 kg, median 2.2) (group I) were compared with the remaining normal weight newborns (3.5 +/- 0.7 kg, median 3.2) (group II). RESULTS: Feasibility, complication rate, and need for surgical shunt did not significantly differ between groups. Global X-ray exposure was significantly higher in the low-weight group (82 +/- 108 vs. 30 +/- 33 Gray/cm(2) , P < 0.002), which maybe due to a longer angiographic presenting work-up. In-hospital mortality rate was 14.3% (vs. 1.9% in the group II, P = NS), although none of the fatalities was procedure related. During follow-up, five patients (35.7% vs. 15.7% in the group II, P = NS) underwent stent redilation before surgical repair. At control angiography, the Nakata and McGoon indexes had significantly increased (P < 0.05 for both comparisons), without any significant difference with the group II (162 +/- 52% vs. 144 +/- 158% and 40 +/- 17% vs. 42 +/- 38%, P = NS). CONCLUSIONS: AD stenting is also feasible and effective in low-weight newborns with CHD-DPC, supporting the spontaneous improvement process or promoting a significant pulmonary artery growth. PMID- 21538782 TI - Coronary artery fistula: an unusual cause of chest pain in a young adult. AB - Coronary artery fistula, usually congenital in origin, is an abnormal communication between a coronary artery and a cardiac chamber or great vessel [coronary sinus, pulmonary artery, pulmonary vein, or super vena cava (SVC)]. A coronary fistula can produce high-output heart failure from volume overload and/or myocardial ischemia from coronary steal phenomenon. A 35-year-old man was found to have a large fistula from the left circumflex coronary artery to the SVC right atrium junction, an extremely rare anomaly. This patient developed right ventricular dysfunction and chest pain due to myocardial ischemia in the left circumflex coronary artery distribution for several months before evaluation. Because of the large size of the fistula, surgical ligation was chosen instead of coil embolization to close the fistula. The patient was free of chest pain postprocedure. Coronary artery fistulas, though rare, should be considered in the differential diagnosis when a young patient presents with chest pain and/or heart failure. PMID- 21538783 TI - Comparison of pharmacokinetics of the limus-eluting stents in Japanese patients. AB - OBJECTIVES: The aim of this study was to compare the pharmacokinetics of the four limus-eluting stents used in Japanese patients. BACKGROUND: There are presently no reports comparing human pharmacokinetics among drug-eluting stents (DESs). METHODS: We retrospectively analyzed data from pharmacokinetic studies of patients implanted with an 18-mm DES: Cypher stent (sirolimus, n = 10), Endeavor stent (zotarolimus, n = 7), Xience V stent (everolimus, n = 6), and Nobori stent (biolimus A9, n = 10), in multicenter trials of Japan. Total drug doses of the Cypher stent, Endeavor stent, Xience V stent, and Nobori stent were 150, 180, 88, and 293 MUg, respectively. Drug concentrations were measured in serial whole blood samples after implantation and the pharmacokinetics were analyzed. RESULTS: Mean peak drug levels were 0.86 ng mL(-1) for Cypher, 1.80 ng mL(-1) for Endeavor, 0.50 ng mL(-1) for Xience V, and 0.09 ng mL(-1) for Nobori. After adjustment for the loaded dose, mean peak drug levels of the Cypher and Xience V stents were similar (0.0057 ng mL(-1) MUg(-1) each) while the Endeavor (0.0100 ng mL(-1) MUg(-1)) was higher, and the Nobori (0.0003 ng mL(-1) MUg(-1)) was lower, compared with the Cypher and Xience V stents. The other pharmacokinetic parameters of four DESs differed according to characteristics of the coated drug. The systemic exposure of biolimus A9 was much lower than that of the other DESs studied. CONCLUSIONS: In Japanese patients, systemic exposure was low, regardless of the type of limus drug eluted from the stents; but specific pharmacokinetic activities were varied according to the drug characteristics, concentration, and DES design. PMID- 21538784 TI - Percutaneous management of inferior epigastric artery injury after cardiac catheterization. AB - Inferior epigastric artery injury after cardiac catheterization and percutaneous coronary intervention is sporadically reported in the literature, yet it is a serious complication that can lead to life-threatening retroperitoneal hemorrhage and poor clinical outcomes after percutaneous coronary intervention. We present two cases of inferior epigastric artery injury from inadvertent puncture during cardiac catheterization and a discussion in the management and prevention of this potentially fatal complication. PMID- 21538785 TI - Vascular interventions in young patients undergoing transvenous pacemaker revision. AB - AIMS: Transvenous lead implantation for pacemaker (PM) or implantable cardioverter defibrillators systems in children and young patients with congenital heart disease is widely practiced. With longer implantation times, the risk for vascular occlusion increases. Transvenous angioplasty may be used to maintain venous patency for system revision in the future. Retrospective analysis of the interventional techniques employed in our young patients undergoing PM revision may identify its clinical benefit. METHODS AND RESULTS: Between May 2005 and August 2010, 28 procedures to maintain central venous patency were performed in 24 patients. Median age was 14.3 years (range, 3.6-29.5 years). The median lead age at time of intervention was 6.8 years (range, 8 days-21.5 years). Balloon dilation of the stenotic vessels was performed with and without prior lead removal. Revascularization with stent implantation was successfully attempted in all clinically relevant obstructions. All PM systems retained full function or were upgraded as planned. There were no major complications and acute surgical referral was not required. CONCLUSION: Angioplasty techniques may be used to maintain and increase the longevity of transvenous pacing pathways in young patients. PMID- 21538786 TI - Early- and mid-term outcomes of transcatheter aortic valve implantation in patients with logistic EuroSCORE less than 20%: a comparative analysis between different risk strata. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an emerging alternative to medical therapy reserved to a limited population with severe aortic stenosis. The European consensus document recommended TAVI for prohibitive risk patients not eligible for conventional surgery (prohibitive risk defined as expected mortality >= 20% calculated with the Logistic EuroScore (LES) in association with clinical judgment). To date, there is lack of clarity on data about outcomes of TAVI in lower risk patients. We sought to evaluate the outcomes of patients undergoing TAVI with LES >= 20% in comparison with patients with LES < 20%. METHOD: Of 165 patients who underwent TAVI using the 18-French Medtronic CoreValve (N = 153) and the Sapien EdwardsTM (N = 12) at our Institution between June 2007 and September 2010, we identified those with LES < 20%, with prosthesis implantation (n = 84), and reported on their clinical outcome compared with patients with LES >= 20% (n = 78). The primary endpoint was the incidence of overall death and major adverse cerebrovascular and cardiac events (MACCE) at 30 day and midterm follow-up stratifying patients by clinical characteristics. RESULTS: At 30-day, a significant higher incidence of MACCE (20.8% vs. 6.0%, odds ratio [OR] 4.08 95% confidence interval [CI] 1.42-11.74, P = 0.009) and death (15.6% vs. 2.4%, OR 7.45 95% CI 1.61-34.48, P = 0.010) was reported in the LES >= 20% group as compared with the LES < 20% group, respectively. The 12-month MACCE rates was (27.1% vs. 11.4%, hazard ratio [HR] 2.47 95% CI 0.93-6.63, P = 0. 071) for LES >= 20% and LES < 20% patients, respectively (mortality rates was 25.7% vs. 6.8% HR 4.21 95% CI 1.24-14.30, P = 0.021). CONCLUSION: This study tends to suggest that current mortality reported after TAVI could be significantly affected by the very-high risk profile of the population which currently undergoes this procedure, making comparison with surgical series rather unreliable. PMID- 21538787 TI - Large calibre arterial access device closure for percutaneous aortic valve interventions: use of the Prostar system in 118 cases. AB - BACKGROUND: Percutaneous aortic valve treatments, balloon aortic valvuloplasty (BAV) and transcatheter aortic valve implantation (TAVI), are effective ways to treat patients with symptomatic aortic stenosis when open surgical repair is not feasible or considered too high risk. Large bore vascular access is required, and successful management of this arterial access is key to overall procedural success. We report outcomes and complications using the Prostar vascular closure device following BAV and TAVI. METHODS: During the period under consideration, 54 patients underwent BAV and 64 patients underwent TAVI (n = 118). Procedural data and outcomes were collected prospectively on a dedicated database. RESULTS: Patients were aged 80 +/- 6.9 years (BAV) and 80.8 +/- 6.1 years (TAVI) and 46.2% (BAV) and 46.8% (TAVI) were male, respectively. Primary success (hemostasis achieved immediately after deployment of the Prostar system on the table and persisting for a minimum of 24 hr in the absence of major or minor bleeding complications) was achieved in 94.4% (n = 54) of the patients undergoing BAV and 92.2% (n = 64) of the patients undergoing TAVI, respectively. The combined success rate was 93.3%. Major bleeding (see definitions section) was seen in 1.9% of cases in the BAV group and 4.7% of cases in the TAVI group. Minor bleeding (see definitions section) was seen in 3.7% of cases in the BAV group and 3.1% of cases in the TAVI group. CONCLUSIONS: Use of the Prostar vascular closure system to achieve hemostasis following percutaneous aortic valve interventions is associated with a high primary success rate and acceptable level of bleeding complications. PMID- 21538788 TI - Aspiration thrombectomy for acute foot and hand ischemia. AB - Acute thromboembolic occlusion of the arteries of the extremities is a potentially fatal vascular emergency that requires an early diagnosis and rapid restoration of blood flow. Selective thrombolysis or surgical treatment has been used, but such procedures are sometimes difficult because of the advanced clinical stage of the embolus and the high risk of thromboembolysis therapy. Herein, we describe the clinical utility of aspiration thrombectomy for acute foot and hand ischemia. PMID- 21538789 TI - Serial intravascular ultrasound analysis comparing double kissing and classical crush stenting for coronary bifurcation lesions. AB - BACKGROUND: Compared with the classical crush, double kissing (DK) crush improved outcomes in patients with coronary bifurcation lesions. However, there is no serial intravascular ultrasound (IVUS) comparisons between these two techniques. OBJECTIVES: This study aimed to analyze the mechanisms of the two crush stenting techniques using serial IVUS imaging. METHODS: A total of 54 patients with IVUS images at baseline, post-stenting and eight-month follow-up were classified into classical (n = 16) and DK (n = 38) groups. All patients underwent final kissing balloon inflation (FKBI). Unsatisfactory kissing (KUS) was defined as the presence of wrist or >20% stenosis during FKBI at the side branch (SB) ostium. The vessels at bifurcation lesions were divided into the proximal main vessel (MV) stent, the crushed segment, the distal MV stent, the SB ostium and the SB stent body. RESULTS: KUS and incomplete crushing were commonly observed in the classical group (62.5%, 81.3%), compared with DK group (18.0%, 39.5%, P < 0.001 and P = 0.004). The post-stenting stent symmetry in the classical group was 71.85 +/- 7.69% relative to 85.93 +/- 6.09% in DK group (P = 0.022), resulting in significant differences in neointimal hyperplasia (NIH, 1.60 +/- 0.21 mm(2) vs. 0.85 +/- 0.23 mm(2) , P = 0.005), late lumen loss (1.31 +/- 0.81 mm(2) vs. 0.55 +/- 0.70 mm(2) , P = 0.013), and minimal lumen area (MLA, 3.57 +/- 1.52 mm(2) vs. 4.52 +/- 1.40 mm(2,) P = 0.042) at the SB ostium between two groups. KUS was positively correlated with the incomplete crush and was the only predictor of in stent-restenosis (ISR) at the SB ostium. CONCLUSION: DK crush was associated with improved quality of the FKBI and larger MLA. KUS predicted the occurrence of ISR. PMID- 21538790 TI - Contemporary approaches to saphenous vein graft interventions: a survey of 275 interventional cardiologists. AB - BACKGROUND: We sought to examine contemporary practice patterns of saphenous vein graft (SVG) interventions. METHODS: A link to a 10-item online questionnaire was completed in June 2009 by 275 (7%) of 3,771 US interventional cardiologists surveyed. RESULTS: Sixty-five percent of the respondents use an embolic protection device (EPD) in >75% of SVG interventions. The main reason for not using an EPD was "anatomic difficulties" (55%), followed by device complexity (20%). Filter-based EPDs were the most widely available, well known, and commonly used EPDs, whereas the Guardwire (Medtronic Vascular) was the least commonly used EPD. The main factors underlying EPD selection were lesion location (83%), familiarity with devices (72%), and SVG diameter (64%). Factors that could increase EPD use included availability of simpler to use devices (63%), and more studies demonstrating benefit from EPD use (37%). Compared with interventionalists who used EPDs in most cases (>75%), those who utilized EPDs less frequently were less likely to be familiar with each EPD and had less EPDs available for use. Many interventionalists (84%) administer intragraft vasodilators during SVG interventions, prefer drug-eluting stents (63%) and administer >12 months antiplatelet therapy poststent implantation. CONCLUSIONS: During SVG interventions (1) "anatomic difficulties" are the most common reason for not utilizing an EPD; (2) filter-based EPDs are most commonly used; (3) lesion location is the most important factor for EPD selection; (4) availability of simpler to use devices could increase EPD use; and (5) intragraft vasodilators, drug-eluting stents and prolonged antiplatelet therapy are commonly utilized. PMID- 21538791 TI - Transcatheter valve in valve implantation for failed mitral and tricuspid bioprosthesis. AB - OBJECTIVE: We report our experience with the transapical transcatheter "Valve in valve" implantation (T-VIV) in patients with a failed mitral or tricuspid bioprosthesis; we briefly review the pertinent literature, and discuss some technical aspects of this procedure. BACKGROUND: Redo valve surgery for failure of a mitral or tricuspid bioprosthesis might become extremely challenging, both because of the patients' condition, which is frequently poor, and for the technical aspects of the operation itself, that can be very demanding. T-VIV has been widely employed with good results for the treatment of aortic bioprosthesis failure, and could represent an attractive option in this setting. METHODS: Four patients with multiple comorbidities (age: 63-83 years; logistic Euroscore: 37.2 81.5) underwent T-VIV at our institution for failure of a mitral [3] or tricuspid [1] bioprosthesis. A 26 mm Sapien valve was used in all cases. All the mitral procedures were performed via a transapical approach. The tricuspid procedure was performed via a transjugular approach. RESULTS: The first mitral procedure was complicated by the splaying of the xenograft stents and embolization of the valve. The procedure was converted to conventional surgery, and the patient died on postoperative day 1. In the subsequent procedures, the valve was positioned more atrially, and was fixed to the malfunctioning xenograft sewing ring. All subsequent procedures were successful, all patients were discharged home and were alive and well at follow-up. CONCLUSIONS: The results of T-VIV procedure in the mitral position have been suboptimal, and four of the sixteen patients reported to date died. However, all patients were extremely diseased, and some of the reported failures were related to amendable technical factors relative to the surgical access or to the valve deployment technique. With increasing experience, this procedure might become indicated as an alternative to conventional surgery in selected patients, encouraging increased use of bioprosthesis, and marking a pivotal change in the management of valvular disease. PMID- 21538792 TI - Online naphazoline quality control by micellar-enhanced spectrofluorimetry. AB - The aim of this study was to develop a method for online spectrofluorimetric quality control of naphazoline (NPZ) in pharmaceuticals and raw drugs. A combination of a flow-injection analysis (FIA) system with micellar-enhanced fluorescence detection is presented as a powerful alternative for the rapid and sensitive analysis of naphazoline. Since NPZ shows low native fluorescence, the use of an anionic surfactant, such as sodium dodecyl sulphate (SDS), provides a considerable enhancement of fluorescence intensity and the nature of the technique allows a possible and easy adaptation to a FIA system. Using lambda(exc) = 280 nm and lambda(em) = 326 nm, a good linear relationship (LOL) was obtained in the range 0.003-10 ug mL(-1) with a detection limit (LOD) of 3 * 10(-4) ug mL(-1) (s/n = 3). Parameters related to the nature of the analytical signal and to the FIA manifold were optimized. Satisfactory recoveries were obtained in the analysis of commercial pharmaceutical formulations. The proposed method is simple, accurate and allows for high-speed sampling and considerably shorter analysis times. In addition, it requires inexpensive equipment and reagents and has easy operational conditions and no side effects, thus avoiding environmental pollution through toxic waste. PMID- 21538793 TI - Integration of dual source computed tomography with magnetic navigation system for percutaneous coronary intervention: a feasibility study. AB - OBJECTIVES: To investigate the feasibility of integration of the dual source computed tomography (DSCT) and magnetic navigation system (MNS) to guide percutaneous coronary intervention (PCI). BACKGROUND: MNS has proven to be feasible for yielding high rates of procedural success for PCI. DSCT coronary angiography (DSCT-CA) may provide a roadmap of a target vessel and serve as a reference route for MNS. Combination of these two technologies might decrease the contrast use, fluoroscopy exposure, and be beneficial to the intervention of the totally occluded lesions. METHODS: Twenty-five patients with positive results of DSCT-CA and indications for PCI were included. CT images were transferred to MNS, and target vessels were extracted and registered to X-ray system as a roadmap. RESULTS: DSCT-CA and MNS-assisted PCIs were successfully performed in 25 of the 26 target vessels (96.2%), with the mean guidewire crossing time of 100.0 (25-75% inter-quartile ranges (IQR): 70.7-157.8) sec, mean total radiation dosage of 268.1 (IQR: 150.5-527.0) MUGym(2) , or 42.0 (IQR: 23.0-70.0) mGy, respectively. The contrast usage for guidewire positioning was 0 (IQR: 0-3.0) ml for the successfully crossed lesions. Both of the two totally occluded lesions in this study were successfully crossed with guidewires under the guidance of the DSCT-CA derived roadmap. CONCLUSION: Integration of DSCT with MNS for PCI is feasible. This integration of advanced modalities might decrease contrast usage, lower fluoroscopy exposure for guidewire positioning, and might also play a role in totally occluded lesions. PMID- 21538794 TI - Study of the interaction between ofloxacin and human serum albumin by spectroscopic methods. AB - The binding of ofloxacin (OFLX) to human serum albumin (HSA) was investigated by fluorescence and circular dichroism (CD) techniques. The binding parameters have been evaluated by a fluorescence quenching method. Competitive binding measurements were performed in the presence of warfarin and ibuprofen and suggest binding to the warfarin site I of HSA. The distance r between donor (HSA) and acceptor (OFLX) was estimated according to the Forster's theory of non radiatiative energy transfer. CD spectra revealed that the binding of OFLX to HSA induced conformational changes in HSA. Molecular docking was performed and shows that for the lowest energy complex OFLX is located in site I of HSA, which correlate to the competitive binding experiments. PMID- 21538795 TI - Metabolic self-organization of bioluminescent Escherichia coli. AB - A possible reason for the complexity of the signals produced by bioluminescent biosensors might be self-organization of the cells. In order to verify this possibility, bioluminescence images of cultures of lux gene reporter Escherichia coli were recorded for several hours after being placed into 8-10 mm diameter cylindrical containers. It was found that luminous cells distribute near the three-phase contact line, forming irregular azimuthal waves. As we show, space time plots of quasi-one-dimensional bioluminescence measured along the contact line can be simulated by reaction-diffusion-chemotaxis equations, in which the reaction term for the cells is a logistic (autocatalytic) growth function. It was found that the growth rate of the luminous cells (~0.02 s(-1)) is >100 times higher than the growth rate of E. coli. We provide an explanation for this result by assuming that E. coli exhibits considerable respiratory flexibility (the ability of oxygen-induced switching from one metabolic pathway to another). According to the simple two-state model presented here, the number of oxic (luminous) cells grows at the expense of anoxic (dark) cells, whereas the total number of (oxic and anoxic) cells remains unchanged. It is conjectured that the corresponding reaction-diffusion-chemotaxis model for bioluminescence pattern formation can be considered as a model for the energy-taxis and metabolic self organization in the population of the metabolically flexible bacteria under hypoxic conditions. PMID- 21538796 TI - Benchmark study on glyphosate-resistant cropping systems in the United States. Part 5: Effects of glyphosate-based weed management programs on farm-level profitability. AB - BACKGROUND: Glyphosate-resistant (GR) crops have changed the way growers manage weeds and implement control strategies. Since the introduction of GR crops, growers in many instances have relied on glyphosate almost exclusively to control a broad spectrum of weeds. This over-reliance on glyphosate has resulted in the evolution of glyphosate resistance in some weed species. Growers and scientists are concerned about the sustainability of GR crops and glyphosate. When a grower is making decisions about weed control strategies, economic costs and benefits of the program are primary criteria for selection and implementation. Studies across six states were initiated in 2006 to compare the economics of using a weed resistance best management practice (BMP) system with a grower's standard production system. RESULTS: Resistance BMP systems recommended by university scientists were more costly but provided similar yields and economic returns. Rotation of GR crops resulted in a higher net return (maize and soybean) compared with continuous GR crop (cotton or soybean) or rotating a GR crop with a non-GR crop (maize). CONCLUSION: Growers can implement weed resistance BMP systems with the confidence that their net returns will be equivalent in the short run, and, in the long term, resistance BMP systems will prevent or delay the evolution of GR weeds in their fields, resulting in substantial savings. PMID- 21538797 TI - Soil microbial degradation of neonicotinoid insecticides imidacloprid, acetamiprid, thiacloprid and imidaclothiz and its effect on the persistence of bioefficacy against horsebean aphid Aphis craccivora Koch after soil application. AB - BACKGROUND: The neonicotinoids imidacloprid, imidaclothiz, acetamiprid and thiacloprid consist of similar structural substituents but differ considerably with respect to soil use. Therefore, the effects of soil microbial activity on the degradation and bioefficacy persistence of the four neonicotinoids were evaluated. RESULTS: In unsterilised soils, 94.0% of acetamiprid and 98.8% of thiacloprid were degraded within 15 days, while only 22.5% of imidacloprid and 25.1% of imidaclothiz were degraded over a longer period of 25 days. In contrast, in sterilised soils, the degradation rates of acetamiprid and thiacloprid were respectively only 21.4% and 27.6%, whereas the degradation rates of imidaclothiz and imidacloprid were respectively 9.0% and almost 0% within 25 days. The degradation products of imidacloprid and imidaclothiz were identified as olefin, nitroso or guanidine metabolites, the degradation product of thiacloprid was identified as an amide metabolite and no degradation product of acetamiprid was detected. A bioefficacy assay revealed that the bioefficacy and persistence of imidacloprid, imidaclothiz, acetamiprid and thiacloprid against horsebean aphid A. craccivora were related to their degradation rate and the bioefficacy of their degradation products in soil. CONCLUSION: Soil microbial activity played a key role in the bioefficacy persistence of neonicotinoid insecticides and therefore significantly affected their technical profile after soil application. PMID- 21538798 TI - Insecticide resistance in field populations of Asian citrus psyllid in Florida. AB - BACKGROUND: Asian citrus psyllid (ACP), Diaphorina citri, is a major pest of citrus because it vectors the putative causal agent of huanglongbing disease. Insecticides are currently the basis of psyllid management programs, and the number of annual insecticide applications has increased significantly. In this paper, a series of investigations of insecticide resistance among field populations of adult and immature ACP in Florida is described. RESULTS: In 2009, the highest level of resistance for adult ACP, as compared with the laboratory susceptible (LS) population, was found with imidacloprid with an LD(50) resistance ratio (RR(50) ) of 35 in one population. This was followed by chlorpyriphos (RR(50) = 17.9, 13.3, 11.8 and 6.9), thiamethoxam (RR(50) = 15 and 13), malathion (RR(50) = 5.4 and 5.0) and fenpropathrin (RR(50) = 4.8). In 2010, mortality of adults from all five sites sampled was lower than with the LS population at three diagnostic concentrations of each insecticide tested. Among nymph populations, indications of resistance were observed with carbaryl (RR(50) = 2.9), chlorpyriphos (RR(50) = 3.2), imidacloprid (RR(50) = 2.3 and 3.9) and spinetoram (RR(50) = 4.8 and 5.9). General esterase, glutathione S-transferase and monooxygenase levels were also elevated in field-collected adult and nymph ACP as compared with the LS population. CONCLUSION: The present results suggest that varying levels of insecticide susceptibility exist in ACP populations across the citrus-growing areas of Florida. Increased levels of detoxifying enzymes in these populations may partially explain these differences. The present results indicate that insecticide resistance may become an emerging problem for ACP control if effective resistance management is not practiced. PMID- 21538799 TI - F2 screening for resistance to pyramided Bacillus thuringiensis maize in Louisiana and Mississippi populations of Diatraea saccharalis (Lepidoptera: Crambidae). AB - BACKGROUND: In the mid-southern region of the United States, sugarcane borer, Diatraea saccharalis (F.), is a major target pest of transgenic maize expressing Bacillus thuringiensis (Bt) proteins. Novel transgenic maize technologies containing two or more pyramided Bt genes for controlling lepidopteran pests have recently become commercially available. Insect resistance management (IRM) is an important issue in the sustainable use of Bt crop technologies. The objective of this study was to determine the frequency of resistance alleles in field populations of D. saccharalis to the new pyramided Bt maize technologies. RESULTS: A total of 382 F(2) family lines derived from 735 feral larvae/pupae of D. saccharalis collected from six locations in Louisiana and Mississippi during 2008 and 2009 were screened for resistance to three new Bt maize technologies: MON 89034, GenuityTM VT Triple ProTM and SmartStaxTM. None of the 382 F(2) isoline families survived on the Bt maize leaf tissue for >= 12 days in the F(2) screen. The joint frequency for two- or three-gene resistance models with 95% probability in these populations was estimated to be < 0.0063 to MON 89034 and < 0.003 to VT Triple ProTM and SmartStaxTM. CONCLUSION: These results suggest that the resistance allele frequency in D. saccharalis to the three pyramided Bt maize technologies is low in the mid-southern region of the United States, which should meet the rare resistance assumption of the currently used IRM strategy for Bt maize. PMID- 21538800 TI - Development of semiochemical attractants for monitoring bean seed beetle, Bruchus rufimanus. AB - BACKGROUND: Bruchus rufimanus is a serious pest of field beans. The objective here was to develop a semiochemical-baited trapping system to facilitate monitoring of the pest. RESULTS: Volatile compounds that were electrophysiologically active with the antennae of B. rufimanus females were identified from headspace samples of Vicia faba flowers and from male B. rufimanus. Selected headspace samples and synthetic compounds were tested in olfactometer bioassays. The semiochemicals were then formulated in lures for traps and evaluated in a field trapping experiment. Cone traps baited with a three-component blend of floral volatiles, releasing (R)-linalool (17.7 mg day( 1)), cinnamyl alcohol (0.4 mg day(-1)) and cinnamaldehyde (0.77 mg day(-1)), caught significantly more of both sexes of B. rufimanus than unbaited control traps. A male volatile, 1-undecene, was EAG active with female antennae. It was attractive to females in an olfactometer, indicating that it is a sex pheromone. However, in the field it only enhanced trap catches if it was released together with the floral volatiles. CONCLUSION: The blends of semiochemicals identified were shown to be attractive in cone traps under field conditions. The prototype trapping system developed could be used as a monitoring tool to determine infestation levels of B. rufimanus in bean fields. PMID- 21538801 TI - Cross-resistance of horseweed (Conyza canadensis) populations with three different ALS mutations. AB - BACKGROUND: Horseweed is a weed commonly found in agronomic crops, waste areas and roadsides. Resistance to ALS-inhibiting herbicides in horseweed was first reported in 1993 in a population from Israel. Resistance to ALS-inhibiting herbicides in horseweed is now widespread, but, as of now, the resistance mechanism has not been reported. RESULTS: Two of three populations evaluated (P116 and P13) were found to be uniform for resistance (>98% of individuals survived 8.8 g AI ha(-1) of cloransulam), whereas a third population, P525, contained about 85% resistant individuals. Cross-resistance to cloransulam, chlorimuron, imazethapyr and bispyribac was observed in the P116 population. P525 and P13 were both sensitive to imazethapyr but resistant to chlorimuron, imazethapyr and bispyribac. Enzyme activity assays indicated that resistance in P13 was due to an altered target site. Southern blot analysis indicated that the ALS target site is encoded by a single copy gene. Overlapping ALS gene regions were amplified and sequenced from each population. Amino acid substitutions of Ser for Pro at position 197 (P197S) was detected from P13, Ala for Pro (P197A) was identified from P525 and substitution of Glu for Asp (D376E) at position 376 was found in P116. Molecular markers were developed to differentiate between wild type and resistant codons at positions 197 and 376 of horseweed ALS. CONCLUSION: Resistance to ALS-inhibiting herbicides in horseweed is conferred by target-site mutations that have also been identified in other weed species. Identification of the mutations within horseweed ALS gene sequence enables molecular assays for rapid detection and resistance diagnosis. PMID- 21538802 TI - Gene amplification and insecticide resistance. AB - Pesticide resistance in arthropods has been shown to evolve by two main mechanisms, the enhanced production of metabolic enzymes, which bind to and/or detoxify the pesticide, and mutation of the target protein, which makes it less sensitive to the pesticide. One route that leads to enhanced metabolism is the duplication or amplification of the structural gene(s) encoding the detoxifying enzyme, and this has now been described for the three main families (esterases, glutathione S-transferases and cytochrome P450 monooxygenases) implicated in resistance. More recently, a direct or indirect role for gene duplication or amplification has been described for target-site resistance in several arthropod species. This mini-review summarises the involvement of gene duplication/amplification in the insecticide/acaricide resistance of insect and mite pests and highlights recent developments in this area in relation to P450 mediated and target-site resistance. PMID- 21538803 TI - Efficacy of Beauveria bassiana against the red imported fire ant, Solenopsis invicta (Hymenoptera: Formicidae), in Taiwan. AB - BACKGROUND: Combining biological control and chemical control could be used for controlling red imported fire ant (RIFA), Solenopsis invicta, more effectively. Beauveria bassiana F256, a local strain from Taiwan, was evaluated for its efficacy in the control of S. invicta under both laboratory and field conditions. RESULTS: The efficacies of different doses of B. bassiana (Bb) using direct application and bait formulation methods were compared. The number of RIFA workers killed by the direct application of Bb or by bait were significantly higher than those of the control, with different rates of efficacy under laboratory conditions. Under field conditions, the direct application of Bb into RIFA mounds was more efficient in inactivating the mounds than the bait application. CONCLUSION: It was shown that B. bassiana is able to control S. invicta under both laboratory and field conditions and can be used as a biocontrol agent against RIFA in Taiwan. PMID- 21538804 TI - BMPR-II is dispensable for formation of the limb skeleton. AB - Initiation of BMP signaling is dependent upon activation of Type I BMP receptor by constitutively active Type II BMP receptor. Three Type II BMP receptors have been identified; Acvr2a and Acvr2b serve as receptors for BMPs and for activin like ligands whereas BMPR-II functions only as a BMP receptor. As BMP signaling is required for endochondral ossification and loss of either Acvr2a or Acvr2b is not associated with deficits in limb development, we hypothesized that BMPR-II would be essential for BMP signaling during skeletogenesis. We removed BMPR-II from early limb mesoderm by crossing BMPR-II floxed mice with those carrying the Prx1-Cre transgene. Mice lacking limb expression of BMPR-II have normal skeletons that could not be distinguished from control littermates. From these data, we conclude that BMPR-II is not required for endochondral ossification in the limb where loss of BMPR-II may be compensated by BMP utilization of Acvr2a and Acvr2b. PMID- 21538805 TI - Evaluating sex-pheromone- and kairomone-based lures for attracting codling moth adults in mating disruption versus conventionally managed apple orchards in Pennsylvania. AB - BACKGROUND: Effectiveness of different types of commercial sex-pheromone- and kairomone-based lures for attracting codling moth adults may vary under different pest management practices. The attractiveness of four types of codling moth (CM) lures (CM L2 Long-Life((r)), CM 10X Megalure((r)), Pherocon CM DA((r)) and Pherocon CM-DA Combo((r))) was evaluated in commercial apple orchards either treated with sex pheromone mating disruption (MD) or only conventional insecticides (non-MD) in Adams County, Pennsylvania, in 2006 and 2007. RESULTS: CM DA Combo lure was most effective in terms of mean seasonal weekly moth capture as well as mean cumulative moth capture in MD orchards. In both years, the CM L2 lure was as attractive to adult moths as the CM DA Combo lure in non-MD orchards. The CM DA and CM 10X lures caught significantly fewer moths in both MD and non-MD orchards compared with the CM DA Combo lure. CONCLUSIONS: ON the basis of mean seasonal weekly moth capture as well as mean cumulative moth capture, the CM DA Combo and CM L2 lures were found to be significantly more effective for monitoring CM adults in both MD and non-MD orchards. In contrast, the CM DA and CM 10X lures were not as effective in either type of orchard. PMID- 21538806 TI - Epigenetics in C. elegans: facts and challenges. AB - Epigenetics is defined as the study of heritable changes in gene expression that are not accompanied by changes in the DNA sequence. Epigenetic mechanisms include histone post-translational modifications, histone variant incorporation, non coding RNAs, and nucleosome remodeling and exchange. In addition, the functional compartmentalization of the nucleus also contributes to epigenetic regulation of gene expression. Studies on the molecular mechanisms underlying epigenetic phenomena and their biological function have relied on various model systems, including yeast, plants, flies, and cultured mammalian cells. Here we will expose the reader to the current understanding of epigenetic regulation in the roundworm C. elegans. We will review recent models of nuclear organization and its impact on gene expression, the biological role of enzymes modifying core histones, and the function of chromatin-associated factors, with special emphasis on Polycomb (PcG) and Trithorax (Trx-G) group proteins. We will discuss how the C. elegans model has provided novel insight into mechanisms of epigenetic regulation as well as suggest directions for future research. PMID- 21538807 TI - Generation of a tamoxifen inducible SMN mouse for temporal SMN replacement. AB - Proximal spinal muscular atrophy (SMA) is caused by low levels of the SMN protein, encoded by the Survival Motor Neuron genes (SMN1 and SMN2). Mouse models of SMA can be rescued by increased SMN expression, but the timing of SMN replacement for complete rescue is unknown. Studies in zebrafish predict restoration of SMN function during embryogenesis may be important for axonal pathfinding, while the mouse models and normal human disease progression suggest that post-natal treatment may be sufficient for amelioration of disease. To evaluate the timing for SMN replacement, we have generated a stably integrated Cre-inducible SMN mouse in which expression of full-length SMN2 occurs after tamoxifen administration. Our temporally inducible SMN transgene is able to express SMN in embryonic, neonatal, and weanling mice and as such can be utilized in severe and mild SMA mouse models to identify the therapeutic window for SMN replacement. PMID- 21538808 TI - Uncoupling of retinoic acid signaling from tailbud development before termination of body axis extension. AB - During the early stages of body axis extension, retinoic acid (RA) synthesized in somites by Raldh2 represses caudal fibroblast growth factor (FGF) signaling to limit the tailbud progenitor zone. Excessive RA down-regulates Fgf8 and triggers premature termination of body axis extension, suggesting that endogenous RA may function in normal termination of body axis extension. Here, we demonstrate that Raldh2-/- mouse embryos undergo normal down-regulation of tailbud Fgf8 expression and termination of body axis extension in the absence of RA. Interestingly, Raldh2 expression in wild-type tail somites and tailbud from E10.5 onwards does not result in RA activity monitored by retinoic acid response element (RARE) lacZ. Treatment of wild-type tailbuds with physiological levels of RA or retinaldehyde induces RARE-lacZ activity, validating the sensitivity of RARE-lacZ and demonstrating that deficient RA synthesis in wild-type tail somites and tailbud is due to a lack of retinaldehyde synthesis. These studies demonstrate an early uncoupling of RA signaling from mouse tailbud development and show that termination of body axis extension occurs in the absence of RA signaling. PMID- 21538809 TI - An inducible transgenic Cre mouse line for the study of hippocampal development and adult neurogenesis. AB - The hippocampus is crucial for higher brain functions, such as learning, memory, and emotion. Many diseases like epilepsy and Down's syndrome are associated with abnormalities in early hippocampal development. In addition, adult dentate neurogenesis is thought to be defective in several classes of psychiatric disorders. However, the mechanisms regulating hippocampal development and adult neurogenesis remain unclear. One of the limitations to studying these processes is the scarcity of available specific mouse tools. Here, we report an inducible transgenic Cre mouse line, Frizzled 9-CreERTM, in which tamoxifen administration induces Cre recombinant. Our data show that Cre is expressed in the developing hippocampal primordium, confined to the granule cell layer at P20 and further limited to the subgranular zone in the adult dentate gyrus. Cre recombinase shows very high activity in all of these regions. Thus, this transgenic line will be a powerful tool in understanding the mechanisms of hippocampal development, adult neurogenesis, and associated diseases. PMID- 21538810 TI - Getting to the heart of planar cell polarity signaling. AB - The genes that underpin normal heart development, and which can be disrupted to result in congenital structural malformations, are rapidly being uncovered. However, the specific cellular processes that lie downstream of these genetic cascades, accurately shaping tissues and complex structures within the heart, remain relatively unclear. The noncanonical Wnt planar cell polarity (PCP) signaling pathway is known to have a role in embryonic morphogenesis and as such is an important candidate pathway to carry out these roles in heart development. The pathway regulates the polarization of cells in a variety of contexts, allowing cells to change shape and position and to "know" their orientation within a mass of tissue. PCP signaling has also been shown recently to regulate the cellular position of the primary cilium. This organelle is known to be crucial for the establishment of left-right patterning in the early embryo and may also act as a signaling antenna for other developmental and regulatory pathways. It is not surprising that recent studies have also linked PCP to left right patterning. In this review, we will examine the current evidence suggesting that PCP signaling has a central role in cardiac development and malformation. PMID- 21538811 TI - In vivo labeling of zebrafish motor neurons using an mnx1 enhancer and Gal4/UAS. AB - The zebrafish spinal cord primary motor neurons are commonly used as an experimental model to study the molecular mechanisms that regulate axonal pathfinding and neuromuscular junction formation, and for the modeling of human neurodegenerative disorders. This study characterized a 125-bp mnx1 enhancer to direct gene expression in spinal cord motor neurons. A promoter containing three copies of the 125-bp mnx1 enhancer was generated in a Tol2 vector and used to drive enhanced green fluorescent protein (EGFP) expression either directly or in combination with the Gal4/UAS transcriptional activation system. Both methods induced protein expression for up to 5 days after fertilization, allowing the observation of the dendritic tree and axonal arborization of single motor neurons within a somitic segment in fixed and live animals. The use of the 125-bp mnx1 promoter for transient transgenic expression or for the generation of stable transgenic fish lines will facilitate the study of motor neuron development and neurodegenerative processes. PMID- 21538813 TI - Molecular and developmental mechanisms of congenital heart valve disease. AB - Congenital heart disease occurs in approximately 1% of all live births and includes structural abnormalities of the heart valves. However, this statistic underestimates congenital valve lesions, such as bicuspic aortic valve (BAV) and mitral valve prolapse (MVP), that typically become apparent later in life as progressive valve dysfunction and disease. At present, the standard treatment for valve disease is replacement, and approximately 95,000 surgical procedures are performed each year in the United States. The most common forms of congenital valve disease include abnormal valve cusp morphogenesis, as in the case of BAV, or defects in extracellular matrix (ECM) organization and homeostasis, as occurs in MVP. The etiology of these common valve diseases is largely unknown. However, the study of murine and avian model systems, along with human genetic linkage studies, have led to the identification of genes and regulatory processes that contribute to valve structural malformations and disease. This review focuses on the current understanding and therapeutic implications of molecular regulatory pathways that control valve development and contribute to valve disease. PMID- 21538815 TI - TGFbeta signaling and congenital heart disease: Insights from mouse studies. AB - Transforming growth factor beta (TGFbeta) regulates one of the major signaling pathways that control tissue morphogenesis. In vitro experiments using heart explants indicated the importance of this signaling pathway for the generation of cushion mesenchymal cells, which ultimately contribute to the valves and septa of the mature heart. Recent advances in mouse genetics have enabled in vivo investigation into the roles of individual ligands, receptors, and coreceptors of this pathway, including investigation of the tissue specificity of these roles in heart development. This work has revealed that (1) cushion mesenchyme can form in the absence of TGFbeta signaling, although mesenchymal cell numbers may be misregulated; (2) TGFbeta signaling is essential for correct remodeling of the cushions, particularly those of the outflow tract; (3) TGFbeta signaling also has a role in ensuring accurate remodeling of the pharyngeal arch arteries to form the mature aortic arch; and (4) mesenchymal cells derived from the epicardium require TGFbeta signaling to promote their differentiation to vascular smooth muscle cells to support the coronary arteries. In addition, a mouse genetics approach has also been used to investigate the disease pathogenesis of Loeys Dietz syndrome, a familial autosomal dominant human disorder characterized by a dilated aortic root, and associated with mutations in the two TGFbeta signaling receptor genes, TGFBR1 and TGFBR2. Further important insights are likely as this exciting work progresses. PMID- 21538814 TI - The emerging genetic landscape underlying cardiac conduction system function. AB - Proper function of an organized Cardiac Conduction System (CCS) is vital to the survival of metazoans ranging from fly to man. The routine use of non-invasive electrocardiogram measures in the diagnosis and monitoring of cardiovascular health has established a trove of reliable CCS functional data in both normal and diseased cardiac states. Recent combination of echocardiogram (ECG) data with genome-wide association studies has identified genomic regions implicated in ECG variability which impact CCS function. In this study, we review the substantial recent progress in this area, highlighting the identification of novel loci, confirming the importance of previously implicated loci in CCS function, and exploring potential links between genes with important roles in developmental processes and variation in function of the CCS. PMID- 21538812 TI - Xenopus: An emerging model for studying congenital heart disease. AB - Congenital heart defects affect nearly 1% of all newborns and are a significant cause of infant death. Clinical studies have identified a number of congenital heart syndromes associated with mutations in genes that are involved in the complex process of cardiogenesis. The African clawed frog, Xenopus, has been instrumental in studies of vertebrate heart development and provides a valuable tool to investigate the molecular mechanisms underlying human congenital heart diseases. In this review, we discuss the methodologies that make Xenopus an ideal model system to investigate heart development and disease. We also outline congenital heart conditions linked to cardiac genes that have been well studied in Xenopus and describe some emerging technologies that will further aid in the study of these complex syndromes. PMID- 21538816 TI - Diabetic embryopathy: a role for the epigenome? AB - Embryonic development under adverse conditions, such as maternal diabetes or obesity during pregnancy, constitutes a major risk factor for birth defects, as well as for long-term health consequences and disease susceptibility in the offspring. While contributions from epigenetic changes have been invoked previously to explain the long-term changes in terms of developmental programming, we here review how maternal metabolism may directly affect the embryonic epigenome in relationship to teratogenic processes. We consider four epigenetic modalities--DNA methylation, non-coding RNA, transcription factors, and histone modifications--and their contribution to epigenetic memory, and discuss how epigenomic changes may mediate the altered control of embryonic gene expression brought about by maternal diabetes. In combination, the epigenomic modalities serve to define transcription-permissive domains of the genome, resulting in distinct epigenomic landscapes in different developmental cell types. We evaluate experimental approaches to characterize the epigenome in adverse pregnancy conditions, highlighting the role of next-generation sequencing on the technological side, while emphasizing the necessity to study defined cell populations in terms of biologic impact. Finally, we outline the challenges in moving from findings that correlate epigenomics to developmental phenotypes to scenarios that establish teratogenic causality. PMID- 21538817 TI - Facial suture synostosis of newborn Fgfr1(P250R/+) and Fgfr2(S252W/+) mouse models of Pfeiffer and Apert syndromes. AB - Apert and Pfeiffer syndromes are hereditary forms of craniosynostosis characterized by midfacial hypoplasia and malformations of the limbs and skull. A serious consequence of midfacial hypoplasia in these syndromes is respiratory compromise due to airway obstruction. In this study, we have evaluated Fgfr1(P250R/+) and Fgfr2(S252W/+) mouse models of these human conditions to study the pathogenesis of midfacial hypoplasia. Our histologic and micro-CT evaluation revealed premature synostosis of the premaxillary-maxillary, nasal-frontal, and maxillary-palatine sutures of the face and dysplasia of the premaxilla, maxilla, and palatine bones. These midfacial abnormalities were detected in the absence of premature ossification of the cranial base at postnatal day 0. Our results indicate that midfacial hypoplasia is not secondary to premature cranial base ossification but rather primary synostosis of facial sutures. Birth Defects Research (Part A), 2011. PMID- 21538819 TI - A double abdominal aorta with a double inferior vena cava: a human congenital vascular patterning defect. AB - BACKGROUND: Developmental abnormalities of the abdominal aorta are exceedingly rare, and the molecular mechanisms underlying these defects are unknown. CASE: We present computed angiographic findings of a 64-year-old female with long-standing hypertension having an abdominal double aorta accompanied by a double inferior vena cava. The abdominal aorta bifurcated into two lumens just caudal to the diaphragm at the level of the 12th thoracic vertebra. The dorsal abdominal aortic trunk supplied several lumbar arteries, the inferior mesenteric artery, and both iliac arteries. The ventral abdominal aortic trunk supplied the celiac artery, both renal arteries, and the superior mesenteric artery. CONCLUSION: We propose that a defect in the development of the aortic vascular smooth muscle is a possible mechanism for this rare anomaly based on our current understanding of the formation of the aorta during early embryonic development. PMID- 21538820 TI - Nephroblastoma: does the decrease in tumor volume under preoperative chemotherapy predict the lymph nodes status at surgery? AB - BACKGROUND: Partial nephrectomy (NSS) for unilateral nephroblastoma may be beneficial, although in case of regional lymph node (LN) involvement, radiotherapy counteracts the functional benefit of NSS. The aim is to verify whether decrease of tumor volume under preoperative chemotherapy implies clearance of regional LN. PROCEDURE: SIOP 9301 (1993-2001) collected 1,450 localized nephroblastoma patients of whom 1,360 (93%) had sufficiently available data and were retrospectively reviewed. RESULTS: Histologic subtypes were classically distributed. Patients were divided in those with tumor positive LN (76, 5.5%) and those with tumor negative LN (1,284, 94.5%) at surgery. In the LN(+) group, the tumor volume changed from a median of 554 (318-772) to 192 (63 458) ml = 67% (27-88%) during preoperative ChT. In the LN(-) group-377 (200-612) to 130 (44-294) ml = 62% (28-83%) (NS). Increase of tumor volume was observed in 16% of patients with LN(+), and 11% of those with LN(-) (NS); ranges are interquartile. Initial tumor volume was significantly larger in the LN(+) patients (P = 0.00091) but not different (NS) at surgery; patients with initial tumor volume under 318 ml had the regional LN involved significantly less frequently (P = 0.00751). CONCLUSIONS: Change in tumor volume under preoperative chemotherapy is not a predictor for LN status at surgery, although larger initial volume is associated with a higher risk of LN invasion. The decrease of tumor volume is not a good criterion for the safety of NSS. The low rate of LN(+) (5.5%) indicates that this risk is low. PMID- 21538818 TI - What chick and mouse models have taught us about the role of the endocardium in congenital heart disease. AB - Specific cell and tissue interactions drive the formation and function of the vertebrate cardiovascular system. Although much attention has been focused on the muscular components of the developing heart, the endocardium plays a key role in the formation of a functioning heart. Endocardial cells exhibit heterogeneity that allows them to participate in events such as the formation of the valves, septation of the outflow tract, and trabeculation. Here we review, the contributions of the endocardium to cardiovascular development and outline useful approaches developed in the chick and mouse that have revealed endocardial cell heterogeneity, the signaling molecules that direct endocardial cell behavior, and how these insights have contributed to our understanding of cardiovascular development and disease. PMID- 21538821 TI - Initial testing (Stage 1) of AT13387, an HSP90 inhibitor, by the pediatric preclinical testing program. AB - AT13387, a non-geldanamycin inhibitor of heat-shock protein 90 (HSP90), was tested against the PPTP in vitro panel (1.0 nM to 10 uM) and against the PPTP in vivo panels (40 or 60 mg/kg) administered orally twice weekly. In vitro AT13387 showed a median EC(50) value of 41 nM and exhibited activity consistent with a cytotoxic effect. In vivo AT13387 induced significant differences in EFS distribution compared to controls in 17% evaluable solid tumor xenografts, but in none of the ALL xenografts. No objective tumor responses were observed. In vivo AT13387 demonstrated only modest single agent activity. PMID- 21538822 TI - Tandem stem cell rescue as consolidation therapy for high-risk neuroblastoma. AB - BACKGROUND: Despite aggressive treatment for high-risk neuroblastoma (NB), event free survival (EFS) remains <40%. In single arm studies, intensifying therapy with high-dose chemotherapy and tandem autologous stem cell rescue (HDC/SCR) improved outcome. We retrospectively describe our institutional experience in using HDC/SCR for patients with high-risk NB, focusing on outcome and acute toxicities. METHODS: Eighty-four patients with high-risk NB at Children's Healthcare of Atlanta treated over a 12-year time period underwent HDC/SCR as part of upfront therapy; 28 patients received a single HDC/SCR and 56 patients received tandem HDC/SCR. The two groups were compared in terms of EFS, overall survival (OS), and acute transplant related toxicities. RESULTS: Patients who received tandem HDC/SCR had a significantly improved EFS compared with patients who received a single HDC/SCR (4-year EFS 59.3 +/- 6.7% vs. 26.8 +/- 9.2%, P=0.01). Similarly, the 4-year OS was improved in patients receiving tandem HDC/SCR, though this did not reach statistical significance (70.6 +/- 9.2% vs. 44.7+/-11.2%, P=0.06). Multivariate regression confirmed the prognostic role of the treatment group. None of the patients who underwent a single HDC/SCR developed veno-occlusive disease (VOD), while 17% of patients who underwent tandem HDC/SCR developed mild-to-severe VOD. Rates of other transplant-related acute toxicities were similar. CONCLUSION: Tandem HDC/SCR for patients with high risk NB seems to improve survival without significant increases in acute toxicities. This needs to be validated in randomized prospective trials. PMID- 21538823 TI - Bi-allelic deletions within 13q14 and transient trisomy 21 with absence of GATA1s in pediatric acute megakaryoblastic leukemia. AB - Oligonucleotide array comparative genomic hybridization, karyotype and fluorescence in situ hybridization analyses were employed to delineate the cytogenetic abnormalities in a case of pediatric acute megakaryoblastic leukemia. Here we present a unique genetic profile that includes bi-allelic deletions within 13q14, where the retinoblastoma tumor suppressor gene (RB1) resides, as well as isolated trisomy 21 without a concomitant mutation in the hematopoietic transcription factor GATA1s and translocation (17;22), that does not involve the megakaryoblastic leukemia 1 (MKL1) gene located on chromosome 22. Alteration of the RB1 gene is most likely the critical leukemogenic event in this patient. PMID- 21538825 TI - Sirolimus for refractory vascular anomalies. PMID- 21538824 TI - Combination testing of cediranib (AZD2171) against childhood cancer models by the pediatric preclinical testing program. AB - BACKGROUND: Cediranib (AZD2171) is a potent small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors. Cediranib has demonstrated single agent activity in several adult cancers and is being studied in combination with standard cytotoxic agents in multiple disease settings. PROCEDURES: Cediranib was tested in vivo against six childhood tumor xenograft models (four sarcomas, one glioblastoma, one neuroblastoma) alone or combined with cyclophosphamide (two models), vincristine (three models) or cisplatin (one model), each administered at its maximum tolerated dose, or rapamycin (six models). RESULTS: The combination of cediranib with standard cytotoxic agents was superior to the cytotoxic agent used alone for a single xenograft (one of the three xenografts evaluated for the vincristine-cediranib combination). The cediranib cyclophosphamide combination was inferior to single agent cyclophosphamide in time to event for both models studied and was significantly inferior for one of the models. Cediranib combined with rapamycin was superior to each of the agents used alone in two of the six models and was determined to be additive or supra additive with rapamycin in four models, although the effects were not large. CONCLUSIONS: Cediranib combined with cytotoxic chemotherapy agents demonstrated little or no benefit (and in one case was significantly inferior) compared to chemotherapy alone for the six pediatric cancer xenografts studied. By contrast, the combination of cediranib with rapamycin was additive or supra-additive in four of the six models in terms of prolongation of time to event, though tumor regressions were not observed for this combination. PMID- 21538826 TI - Student award winner in the undergraduate's degree category for the Society for Biomaterials 35th Annual Meeting, Orlando, Florida, April 13-16, 2011. Neurite growth in PEG gels: effect of mechanical stiffness and laminin concentration. AB - Within a 3D environment, the chemical and mechanical properties of a scaffold can significantly influence nerve behavior. How these properties influence with nerve cells is important for optimizing neurite extension within a scaffold. The purpose of this study was to investigate the effect of low concentration poly(ethylene glycol) (PEG) with added laminin on 3D growth of dissociated dorsal root ganglia. Because of its high affinity for neurite adhesion and ability to promote extension, laminin was conjugated to the PEG chain, as well as mixed in the gel, at various concentrations to provide chemical cues. Gel stiffness, as determined by G*, significantly decreased with decreasing PEG concentration and with increasing laminin conjugate. Extension within the gels increased as the concentration of laminin increased with no difference between how laminin was presented (mixed or conjugated) to the cells. For example, in 3% PEG, extension increased from 92.29 +/- 5.27 MUm to 146.35 +/- 13.12 MUm as laminin conjugate concentration increased from plain to 100 MUg/ml. Results indicated that the chemical properties of the scaffold influenced neurite growth more than the mechanical properties as laminin concentration had a greater impact on growth than the stiffness of the gel over the range studied. Neurite length as a function of scaffold stiffness and adhesion properties was also characterized and demonstrated a positive linear relationship between rate of neurite extension and laminin concentration. This study further demonstrates the importance of characterizing interactions between cell behavior and the chemical and mechanical environment. PMID- 21538827 TI - Controlled and sustained gene delivery from injectable, porous PLGA scaffolds. AB - Biodegradable poly(lactic-co-glycolic acid) (PLGA) scaffolds are widely used for the delivery of therapeutic molecules such as plasmid DNA (pDNA) and growth factors. However, many of these scaffolds must be implanted, and it would be beneficial to develop PGLA systems that can be injected in a minimally invasive manner. In this study, we present an injectable, porous PLGA scaffold that solidifies in situ for controlled gene delivery. Micro-scale porosity was engineered into the system to facilitate cell migration, proliferation and extracellular matrix elaboration. Relatively rapid release of pDNA was achieved through simple mixing into the polymer solution prior to scaffold solidification, whereas sustained release was achieved by incorporating pDNA-laden PLGA microspheres into the polymer solution. Sustained pDNA release was obtained for over 70 days. When the released pDNA was complexed with PEI and used to transfect HEK293 cells, substantial gene transfection was achieved from all time points, demonstrating that the pDNA was bioactive for the entire time course of the study. These in situ forming porous scaffolds for pDNA delivery are easy to prepare and can be injected without invasive surgery. Importantly, localized delivery of bioactive pDNA can be achieved for short to prolonged time periods, and small changes in the system composition permit facile tailoring of release profiles. In the future, this system may be used to control host cell regenerative responses by, for example, inducing cellular migration into the porous scaffold architecture via release of pDNA encoding for chemokines or pro angiogenic molecules. PMID- 21538828 TI - Poly(DL-lactic acid) film surface modification with heparin for improving hemocompatibility of blood-contacting bioresorbable devices. AB - This work describes a simple method to immobilize heparin by covalent bonding to the surface of poly(lactic acid) film with the aim of showing improved hemocompatibility. Carboxyl groups present in heparin molecules were activated by reaction with N-hydroxy-succinimide and allowed to react with free amino groups created at the surface of poly(DL-lactic acid) films by controlled aminolysis. Contact angle measurements and XPS analysis confirmed the binding. Quantification was determined by radioactivity using heparin labeled with tritium. The surface exhibited anti factor Xa activity, thus confirming the presence of bounded heparin that kept some biological activity. Finally platelets adhesion showed less platelet adhesion on heparin modified films as well as preserved morphology. PMID- 21538829 TI - Synthesis, characterizations and biocompatibility of alternating block polyurethanes based on P3/4HB and PPG-PEG-PPG. AB - Block copolymers with exactly controlled structures, that is, alternating block polyurethanes based on poly(3-hydroxybutyrate-co-4-hydroxybutrate) (P3/4HB-diol) and poly (propylene glycol)-poly(ethylene glycol)-poly(propylene glycol) (PPG-PEG PPG) were synthesized by solution polymerization via specifically selective coupling reaction between terminal hydroxyl P3/4HB segment and isocyanate group end-capped PPG-PEG-PPG segment, using 1,6-hexamethylene diisocyanate (HDI) as end capped agent. The chemical structure, molecular weight and distribution were systematically characterized by nuclear magnetic resonance spectrum (1H NMR), Fourier transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC). The thermal property was investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis. The hydrophilicity was studied by static contact angle of H2O and CH2I2. DSC revealed that the PU3/4HB-alt-PPG-PEG-PPG exhibited a distinct change from amorphous to 30% crystallinity degree, T(g) from -25 to -50 degrees C, T(m) from 110 to 145 degrees C. The polyurethanes were more hydrophilic (water contact angle centers around 80 degrees ) than the raw PHA materials. The platelet adhesion assay showed that the obtained polyurethanes had a lower platelet adhesion than the raw materials and the amount of platelet adhesion could be controlled by varying the segmental length of P3/4HB-diol. This could be explained by the inclusion of PPG-PEG-PPG between the P3/4HB segments, improving the hemocompatibility of P3/4HB. The cell culture assay revealed that the obtained polyurethanes were cell inert and unfavorable for the attachment of mouse fibroblast cell line L929 and rabbit blood vessel smooth muscle cells (RaSMCs). This suggests that these polyurethanes would be promising candidates as hemocompatibility and tissue-inert materials. PMID- 21538830 TI - Bioaccumulation data from laboratory and field studies: are they comparable? AB - Once they are released into the environment, a number of chemicals are known to bioaccumulate in organisms, sometimes to concentrations that may threaten the individual or their predators. However, use of physical or chemical properties or results from laboratory bioaccumulation tests to predict concentrations sometimes found in wild organisms remains a challenge. How well laboratory studies and field measurements agree or disagree, and the cause of any discrepancies, is a subject of great interest and discussion from both a scientific and a regulatory perspective. A workshop sponsored by the ILSI Health and Environmental Sciences Institute, US Environmental Protection Agency, and the Society of Environmental Toxicology and Chemistry assembled scientists from academia, industry, and government to compare and contrast laboratory and field bioaccumulation data. The results of this workshop are summarized in a series of 5 articles published in this issue of Integrated Environmental Assessment and Management. The articles describe: 1) a weight-of-evidence approach that uses fugacity ratios to bring field measurements into the assessment of biomagnification potential for legacy chemicals; 2) a detailed comparison between laboratory and field data for the most commonly measured bioaccumulation endpoint, the biota-sediment accumulation factor; 3) a study that identifies and quantifies the differences between laboratory and field metrics of bioaccumulation for aquatic and terrestrial organisms; and 4) 2 reports on trophic magnification factors: the 1st addresses how trophic magnification factors are determined and interpreted and the 2nd describes how they could be used in regulatory assessments. Collectively, these articles present the workshop participants' current understanding and assessment of bioaccumulation science and make a number of recommendations on how to improve the collection and interpretation of bioaccumulation data. PMID- 21538831 TI - Lead exposure and poisoning of songbirds using the Coeur d'Alene River Basin, Idaho, USA. AB - Previous studies have found widespread Pb poisoning of waterfowl in the Coeur d'Alene River Basin in northern Idaho, USA, which has been contaminated by mining and smelting activities. We studied the exposure of ground-feeding songbirds to Pb, sampling 204 American robins (Turdus migratorius), song sparrows (Melospiza melodia), and Swainson's thrushes (Catharus ustulatus) throughout the basin. These songbirds had mean blood Pb concentrations (mg/kg, dry weight) of less than 0.19 at a reference area (25 mg Pb/kg soil), 1.09 at moderately contaminated sites (170 to 1300 mg Pb/kg soil), and 2.06 at highly contaminated sites (2000 to 5000 mg Pb/kg soil). Based on guidelines for evaluating blood Pb in birds, 6% of robins from the highly contaminated sites had background concentrations, 24% were subclinically poisoned, 52% were clinically poisoned, and 18% were severely clinically poisoned with Pb. Blood Pb concentrations were lower in song sparrows than in robins and lowest in Swainson's thrushes. More than half of the robins and song sparrows from all contaminated sites and more than half of the Swainson's thrushes from highly contaminated sites showed at least 50% inhibition of the activity of the enzyme delta-aminolevulinic acid dehydratase (ALAD), commonly used as a measure of exposure to Pb. The highest hepatic Pb concentration of 61 mg/kg (dry weight) was detected in a song sparrow. Using Al as a marker for soil in songbird ingesta, we estimated average soil ingestion rates as 20% in robins, 17% in song sparrows, and 0.7% in Swainson's thrushes. Soil Pb in ingesta accounted for almost all of the songbirds' exposure to Pb. Based on these results, it is recommended that ecological risk assessments of ground-feeding songbirds at contaminated sites include soil ingestion as a pathway of exposure to Pb. PMID- 21538832 TI - Influence of drought and total phosphorus on diel pH in wadeable streams: implications for ecological risk assessment of ionizable contaminants. AB - Climatological influences on site-specific ecohydrology are particularly germane in semiarid regions where instream flows are strongly influenced by effluent discharges. Because many traditional and emerging aquatic contaminants, such as pharmaceuticals, are ionizable, we examined diel surface water pH patterns (i.e., change in pH over a 24-h period) at 23 wadeable streams in central Texas, USA, representing a gradient of nutrient enrichment during consecutive summers of 2006 and 2007. The years of our study were characterized by decidedly different instream flows, which likely affected production:respiration dynamics and led to distinctions in diel pH patterns between 2006 and 2007. Site-specific ambient water quality criteria for NH(3) and the aquatic toxicity of the model weak base pharmaceutical sertraline were predicted using continuous water quality monitoring data from the sites. Drought conditions of 2006 significantly increased (p<0.05) diel pH changes compared to high instream flows of 2007,and the magnitude of diel pH variability was most pronounced at nutrient-enriched sites in 2006. Differences in diel pH change patterns between 2006 and 2007 affected predictions of the environmental fate and effects for model weak base pharmaceuticals and NH(3). Overall, site-specific diel pH was more variable at some sites than the difference in mean surface water pH between the 2 summers. Diel pH variability affected regulatory criteria, because 20% of the study sites in 2006 experienced greater than 5-fold differences in National Ambient Water Quality Criteria for NH(3) over 24-h periods. Our study emphasizes the potential uncertainty that diel pH variability may introduce in site-specific assessments and provides recommendations for environmental assessment of ionizable contaminants. PMID- 21538833 TI - Xplicit, a novel approach in probabilistic spatiotemporally explicit exposure and risk assessment for plant protection products. AB - The quantification of risk (the likelihood and extent of adverse effects) is a prerequisite in regulatory decision making for plant protection products and is the goal of the Xplicit project. In its present development stage, realism is increased in the exposure assessment (EA), first by using real-world data on, e.g., landscape factors affecting exposure, and second, by taking the variability of key factors into account. Spatial and temporal variability is explicitly addressed. Scale dependencies are taken into account, which allows for risk quantification at different scales, for example, at landscape scale, an overall picture of the potential exposure of nontarget organisms can be derived (e.g., for all off-crop habitats in a given landscape); at local scale, exposure might be relevant to assess recovery and recolonization potential; intermediate scales might best refer to population level and hence might be relevant for risk management decisions (e.g., individual off-crop habitats). The Xplicit approach is designed to comply with a central paradigm of probabilistic approaches, namely, that each individual case that is derived from the variability functions employed should represent a potential real-world case. This is mainly achieved by operating in a spatiotemporally explicit fashion. Landscape factors affecting the local exposure of habitats of nontarget species (i.e., receptors) are derived from geodatabases. Variability in time is resolved by operating at discrete time steps, with the probability of events (e.g., application) or conditions (e.g., wind conditions) defined in probability density functions (PDFs). The propagation of variability of parameters into variability of exposure and risk is done using a Monte Carlo approach. Among the outcomes are expectancy values on the realistic worst-case exposure (predicted environmental concentration [PEC]), the probability p that the PEC exceeds the ecologically acceptable concentration (EAC) for a given fraction of habitats, and risk curves. The outcome can be calculated at any ecologically meaningful organization level of receptors. An example application of Xplicit is shown for a hypothetical risk assessment for nontarget arthropods (NTAs), demonstrating how the risk quantification can be improved compared with the standard deterministic approach. PMID- 21538834 TI - Development and evaluation of a dynamic model that projects population biomarkers of methylmercury exposure from local fish consumption. AB - A dynamic model was developed to project Hg concentrations in common biomarkers of exposure in response to changes in Hg concentrations in predatory fish from local waters. The model predicts biomarkers in susceptible populations for intake rates representing the mean, 90th, 95th, and 99 th percentiles of populations of interest. The biomarkers the model calculates are blood methylmercury, total hair Hg, and fetal blood methylmercury. Decision makers can use the model to determine the degree of reduction in fish tissue Hg levels necessary to protect the health of susceptible populations. Biomarker output was calibrated with literature sources. Output was then compared to additional literature sources to evaluate model function. Projected biomarkers were not different from literature sources. The model can be used as a tool to understand the impact of local fish consumption on susceptible populations. PMID- 21538835 TI - Use of trophic magnification factors and related measures to characterize bioaccumulation potential of chemicals. AB - Recent technical workgroups have concluded that trophic magnification factors (TMFs) are useful in characterizing the bioaccumulation potential of a chemical, because TMFs provide a holistic measure of biomagnification in food webs. The objectives of this article are to provide a critical analysis of the application of TMFs for regulatory screening for bioaccumulation potential, and to discuss alternative methods for supplementing TMFs and assessing biomagnification in cases where insufficient data are available to determine TMFs. The general scientific consensus is that chemicals are considered bioaccumulative if they exhibit a TMF > 1. However, comparison of study-derived TMF estimates to this threshold value should be based on statistical analyses such that variability is quantified and false positive and false negative errors in classification of bioaccumulation potential are minimized. An example regulatory decision-making framework is presented to illustrate the use of statistical power analyses to minimize assessment errors. Suggestions for considering TMF study designs and TMFs obtained from multiple studies are also provided. Alternative bioaccumulation metrics are reviewed for augmenting TMFs and for substituting in situations in which field data for deriving TMFs are unavailable. Field-derived, trophic level-normalized biomagnification factors (BMF(TL) s), biota-sediment accumulation factors (BSAF(TL) s), and bioaccumulation factors (BAF(TL) s) are recommended if data are available, because these measures are most closely related to the biomagnification processes characterized by TMFs. Field- and laboratory-derived BAFs and bioconcentration factors are generally less accurate in predicting biomagnification. However, bioconcentration factors and BAFs remain useful for characterizing bioaccumulation as a result of the transfer of chemicals from abiotic environmental compartments to lower trophic levels. Modeling that incorporates available laboratory and field data should also be considered for augmenting assessments of bioaccumulation potential. Modeling can provide a TMF-focused assessment for new or unreleased chemicals in the absence of field data by estimating TMF values and theoretical relationships between physical-chemical properties and TMF values (quantitative structure-activity relationships). An illustration of the use of physicochemical properties for estimating TMFs is provided. Overall, TMFs provide valuable information regarding bioaccumulation potential and should be incorporated into regulatory decision making following the suggestions outlined in this article. PMID- 21538836 TI - Explaining differences between bioaccumulation measurements in laboratory and field data through use of a probabilistic modeling approach. AB - In the regulatory context, bioaccumulation assessment is often hampered by substantial data uncertainty as well as by the poorly understood differences often observed between results from laboratory and field bioaccumulation studies. Bioaccumulation is a complex, multifaceted process, which calls for accurate error analysis. Yet, attempts to quantify and compare propagation of error in bioaccumulation metrics across species and chemicals are rare. Here, we quantitatively assessed the combined influence of physicochemical, physiological, ecological, and environmental parameters known to affect bioaccumulation for 4 species and 2 chemicals, to assess whether uncertainty in these factors can explain the observed differences among laboratory and field studies. The organisms evaluated in simulations including mayfly larvae, deposit-feeding polychaetes, yellow perch, and little owl represented a range of ecological conditions and biotransformation capacity. The chemicals, pyrene and the polychlorinated biphenyl congener PCB-153, represented medium and highly hydrophobic chemicals with different susceptibilities to biotransformation. An existing state of the art probabilistic bioaccumulation model was improved by accounting for bioavailability and absorption efficiency limitations, due to the presence of black carbon in sediment, and was used for probabilistic modeling of variability and propagation of error. Results showed that at lower trophic levels (mayfly and polychaete), variability in bioaccumulation was mainly driven by sediment exposure, sediment composition and chemical partitioning to sediment components, which was in turn dominated by the influence of black carbon. At higher trophic levels (yellow perch and the little owl), food web structure (i.e., diet composition and abundance) and chemical concentration in the diet became more important particularly for the most persistent compound, PCB-153. These results suggest that variation in bioaccumulation assessment is reduced most by improved identification of food sources as well as by accounting for the chemical bioavailability in food components. Improvements in the accuracy of aqueous exposure appear to be less relevant when applied to moderate to highly hydrophobic compounds, because this route contributes only marginally to total uptake. The determination of chemical bioavailability and the increase in understanding and qualifying the role of sediment components (black carbon, labile organic matter, and the like) on chemical absorption efficiencies has been identified as a key next steps. PMID- 21538837 TI - Comparing laboratory- and field-measured biota-sediment accumulation factors. AB - Standardized laboratory protocols for measuring the accumulation of chemicals from sediments are used in assessing new and existing chemicals, evaluating navigational dredging materials, and establishing site-specific biota-sediment accumulation factors (BSAFs) for contaminated sediment sites. The BSAFs resulting from the testing protocols provide insight into the behavior and risks associated with individual chemicals. In addition to laboratory measurement, BSAFs can also be calculated from field data, including samples from studies using in situ exposure chambers and caging studies. The objective of this report is to compare and evaluate paired laboratory and field measurement of BSAFs and to evaluate the extent of their agreement. The peer-reviewed literature was searched for studies that conducted laboratory and field measurements of chemical bioaccumulation using the same or taxonomically related organisms. In addition, numerous Superfund and contaminated sediment site study reports were examined for relevant data. A limited number of studies were identified with paired laboratory and field measurements of BSAFs. BSAF comparisons were made between field-collected oligochaetes and the laboratory test organism Lumbriculus variegatus and field collected bivalves and the laboratory test organisms Macoma nasuta and Corbicula fluminea. Our analysis suggests that laboratory BSAFs for the oligochaete L. variegatus are typically within a factor of 2 of the BSAFs for field-collected oligochaetes. Bivalve study results also suggest that laboratory BSAFs can provide reasonable estimates of field BSAF values if certain precautions are taken, such as ensuring that steady-state values are compared and that extrapolation among bivalve species is conducted with caution. PMID- 21538839 TI - ASD is an incorrect abbreviation for autism spectrum disorders. PMID- 21538838 TI - Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment. AB - Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome. PMID- 21538840 TI - Analysis of neurogranin (NRGN) in schizophrenia. AB - A recent study reported a genome-wide significant association between schizophrenia and rs12807809-a SNP located approximately 3 kbp upstream of the neurogranin gene (NRGN). We sought to determine if (a) NRGN contains common exonic variants or variants affecting expression (eQTLs) that could account for the association with rs12807809 and (b) there exist rare non-synonymous highly penetrant variants that could potentially confer high risk of schizophrenia. We sequenced all four exons of NRGN in a screening set of 14 individuals but found no novel common polymorphisms. We additionally sequenced the coding exons in up to 1,113 individuals (699 cases) but this revealed only a singleton-coding variant in exon 2 (G246T leading to Gly-55 -> Val amino acid change) in which prediction of function analysis suggested is likely to be benign. Finally, analysis of a brain expression dataset of at least 130 individuals did not identify any eQTLs that were correlated with associated SNP rs12807809 following correction for multiple testing. PMID- 21538841 TI - Cellometer vision as an alternative to flow cytometry for cell cycle analysis, mitochondrial potential, and immunophenotyping. AB - Cell phenotyping and cell cycle analysis are two commonly used assays in both clinical diagnosis and biomedical research. Cell phenotyping by identifying different biomarkers is essential for the diagnosis of hematologic malignancy, sub-classifying diseases, monitoring response to treatment, predicting prognosis, detecting rare cell populations and residual malignant cells. Cell cycle analysis distinguishes cells in different phases of cell cycle and is often used to determine the cellular response to drugs and biological stimulations. These assays have been traditionally carried out by sensitive fluorescence detection methods such as flow cytometry and laser scanning cytometry for fluorescence based cell population analysis. However, these instruments remain relatively expensive, large in size, and require a considerable amount of maintenance, which may not be feasible for smaller research groups that do not have access to these equipments or field clinics that require quick diagnostic results on site. Recently, a small portable imaging cytometry system (Cellometer Vision) has been developed by Nexcelom Bioscience LLC (Lawrence, MA) for automated cell concentration and viability measurement using bright-field and fluorescent imaging methods. Here we report new applications of the Cellometer imaging cytometry for fluorescence-based cell population analysis and compared them with conventional flow cytometry. Cell population analysis assays such as immunophenotyping, cell cycle, and mitochondrial membrane potential detection methods have not yet been reported for the Cellometer Vision system. Using this imaging cytometry method for fluorescence-based assays that are typically done by flow cytometry offers a quick, simple, and inexpensive alternative method for biomedical research, which may be beneficial for smaller research laboratories and clinics. PMID- 21538842 TI - Biomimetic deposition of calcium phosphate minerals on the surface of partially demineralized dentine modified with phosphorylated chitosan. AB - The aim of this study is to remineralize partially demineralized dentine sections using phosphorylated chitosan (P-chi) based on mimicking the nucleating role of the phosphorylated noncollagenous proteins in the biomineralization of dentine. The surface of partially demineralized dentine sections, mainly composed of type I collagen, were modified by covalent immobilization of P-chi on the collagen surface. The dentine sections were subsequently put into remineralizing solution for remineralization, and then the remineralizing effect was investigated. The remineralization effect of this methodology was compared with that of fluoride. Moreover, the influence of surface properties of samples on remineralizing effect was investigated. The experimental results indicated that the effect of fluoride on remineralization of dentine was limited when residual crystals were lacking on the surface of partially demineralized dentine, whereas the covalent immobilization of P-chi can significantly induce deposition of calcium phosphate minerals on the surface of the partially demineralized dentine. This biomimetic methodology resulted in favorable surface properties (i.e., highly negative charge and low interfacial free energy between substrate and remineralizing medium) for crystal nucleation. Thus, P-chi can facilitate surface remineralization of dentine and thereby could find application in the minimally invasive management of dentine caries and dentine hypersensitivity. PMID- 21538843 TI - Molecular architecture of muscles in an acoel and its evolutionary implications. AB - We have characterized the homologs of an actin, a troponin I, and a tropomyosin gene in the acoel Symsagittifera roscoffensis. These genes are expressed in muscles and most likely coexpressed in at least a subset of them. In addition, and for the first time for Acoela, we have produced a species-specific muscular marker, an antibody against the tropomyosin protein. We have followed tropomyosin gene and protein expression during postembryonic development and during the posterior regeneration of amputated adults, showing that preexisting muscle fibers contribute to the wound closure. The three genes characterized in this study interact in the striated muscles of vertebrates and invertebrates, where troponin I and tropomyosin are key regulators of the contraction of the sarcomere. S. roscoffensis and all other acoels so far described have only smooth muscles, but the molecular architecture of these is the same as that of striated fibers of other bilaterians. Given the proposed basal position of acoels within the Bilateria, we suggest that sarcomeric muscles arose from a smooth muscle type, which had the molecular repertoire of striated musculature already in place. We discuss this model in a broad comparative perspective. PMID- 21538844 TI - Preparation and characterization of shellac-coated anthocyanin pectin beads as dietary colonic delivery system. AB - SCOPE: Anthocyanins are connected with various biological activities. A promising way to enhance the availability of anthocyanins for in situ effects in the lower intestine is colon-specific delivery. METHODS AND RESULTS: Shellac and shellac/hydroxypropyl methylcellulose (HPMC) coated anthocyanin amidated pectin beads as dietary colonic delivery systems were successfully prepared by ionotropic gelation and fluid bed Wurster coating with aqueous shellac solution. Release characteristics, studied in vitro and ex vivo using simulated gastric fluid (SGF), ileostomy fluid and colostomy fluid (CF) revealed a retardation of anthocyanins during simulated passage of stomach and ileum as well as the desired release of pigments in the colon. Coating level was identified as an important parameter. By addition of 5 or 15% of the water-soluble polysaccharide HPMC to the shellac film, resistance in SGF was increased due to the plasticizer properties of the polymer. Incorporation of 15% HPMC (w/w based on shellac) into the shellac film additionally led to increased anthocyanin diffusivity and complete release as well as degradation of the formulation in CF. CONCLUSION: In the used in vitro and ex vivo model system mimicking the human intestinal transit, the potential of shellac and shellac/HPMC coated anthocyanin amidated pectin beads as dietary colon targeting systems was demonstrated. PMID- 21538845 TI - Synergism between resveratrol and other phytochemicals: implications for obesity and osteoporosis. AB - Resveratrol, a phytoalexin, has gained much attention recently due to its effects on sirtuins. While the anti-cancer properties of resveratrol have been extensively investigated, the anti-adipogenic and osteogenic effects of resveratrol are also gaining considerable interest. The finding that resveratrol supplementation mimics caloric restriction prompted researchers to study the effects of resveratrol on lipid metabolism. Mesenchymal stem cells are the precursors for both adipocytes and osteoblasts. In the aging population, differentiation to adipocytes dominates over the differentiation to osteoblasts in bone marrow, contributing to the increased tendency for fractures to occur in the elderly. Thus, an inverse relationship exists between adipocytes and osteoblasts in the bone marrow. Resveratrol acts on several molecular targets in adipocytes and osteoblasts leading to a decrease in adipocyte number and size and an increase in osteogenesis. Furthermore, resveratrol in combination with genistein and quercetin synergistically decreased adipogenesis in murine and human adipocytes. A recent in vivo study showed that phytochemicals including resveratrol in combination with vitamin D prevented weight gain and bone loss in a postmenopausal rat model. Therefore, combinations of resveratrol with other phytochemicals may lead to potential novel potent therapies for both obesity and osteoporosis. PMID- 21538846 TI - Cancer chemoprevention with green tea catechins by targeting receptor tyrosine kinases. AB - Recent studies indicate that receptor tyrosine kinases (RTKs), which play important roles in cell proliferation, are one of the possible targets of green tea catechins (GTCs) in cancer cell growth inhibition. (-)-Epigallocatechin-3 gallate (EGCG), the major catechin in green tea, inhibits cell proliferation and induces apoptosis in various types of cancer cells, including colorectal cancer and hepatocellular carcinoma cells, by blocking the activation of the epidermal growth factor receptor (EGFR) family of RTKs. EGCG inhibits the activation of insulin-like growth factor-1 receptor (IGF-1R) and VEGFR2, the other members of the RTK family, and this effect is also associated with the anticancer and chemopreventive properties of this agent. EGCG suppresses the activation of EGFR in part by altering membrane lipid organization and causing the subsequent inhibition of the dimerization and activation of this receptor. Preliminary trials have shown that GTCs successfully prevent the development and progression of precancerous lesions, such as colorectal adenomas, without causing severe adverse effects. The present report reviews evidence indicating that GTCs exert anticancer and chemopreventive effects by inhibiting the activation of specific RTKs, especially EGFR, IGF-1R, and VEGFR2, and concludes that targeting RTKs and their related signaling pathways by using tea catechins could be a promising strategy for the prevention of human cancers. PMID- 21538847 TI - Flavanols from green tea and phenolic acids from coffee: critical quantitative evaluation of the pharmacokinetic data in humans after consumption of single doses of beverages. AB - Coffee contains a complex mixture of chlorogenic acids, which are mainly ferulic and caffeic acids ester-linked to quinic acid. Green tea contains flavanols, mainly (-)-epigallocatechin gallate (EGCG), (-)-epigallocatechin (EGC) and (-) epicatechin (EC). For healthy humans, we identified seven studies on green tea in liquid form and five on coffee beverage reporting single-dose plasma pharmacokinetics. Weighted averages, based on the number of subjects, and elimination of outliers, allowed estimation of some pharmacokinetic parameters. After consumption of an "average" cup of green tea containing 112 mg of (-) epigallocatechin gallate, 51 mg of EGC and 15 mg of EC in 200 mL, the predicted C(max) values (total free and sulfate/glucuronide conjugates) in plasma are 125, 181 and 76 nM, respectively, together with 94 nM methyl-EGC and 51 nM methyl-EC (standard deviation <20%). After consumption of an "average" cup of coffee (160 mg total chlorogenic acids (0.46 mmol)/200 mL), predicted C(max) values of caffeic, ferulic, isoferulic, dihydrocaffeic and dihydroferulic acids are 114, 96, 50, 384 and 594 nM, respectively (too few studies to calculate standard deviation). Most studies report a very low amount of intact chlorogenic acids in plasma, with one exception. More studies on absorption of chlorogenic acids from coffee are required, including dose-response studies. PMID- 21538848 TI - Green tea and prevention of esophageal and lung cancers. AB - Green tea contains high concentrations of tea polyphenols that have shown inhibitory effects against the development, progress, and growth of carcinogen induced tumors in animal models at different organ sites, including the esophagus and lung. Green tea polyphenols also have shown to suppress cell proliferation and induce apoptosis. Besides antioxidative property, green tea polyphenols have pro-oxidative activities under certain conditions and modulate phase II metabolic enzymes that can enhance the detoxification pathway of environmental toxicants and carcinogens. Although epidemiological studies have provided inconclusive results on the effect of green tea consumption against the development of esophageal and lung cancers in humans overall, the inverse association between green tea intake and risk of esophageal cancer risk is more consistently observed in studies with adequate control for potential confounders. Epidemiological studies also have demonstrated an inverse, albeit moderate, association between green tea consumption and lung cancer, especially in non-smokers. This article reviews data on the cancer-preventive activities of green tea extract and green tea polyphenols and possible mechanisms against the esophageal and lung carcinogenesis in experimental animals, and summarizes the current knowledge from epidemiological studies on the relationship between green tea consumption and esophageal and lung cancer risk in humans. PMID- 21538849 TI - Body composition and hormonal effects following exposure to mycotoxin deoxynivalenol in the high-fat diet-induced obese mouse. AB - SCOPE: To characterize the effects of ingesting the common foodborne mycotoxin deoxynivalenol (DON) on body weight and composition in the high-fat (HF) diet induced obese mice, a model of human obesity. METHODS AND RESULTS: Female B6C3F1 mice were initially fed HF diets containing 45% kcal (HF45) or 60% kcal (HF60) as fat for 94 days to induce obesity. Half of each group was either continued on unamended HF diets or fed HF diets containing 10 mg/kg DON (DON-HF45 or DON-HF60) for another 54 days. Additional control mice were fed a low-fat (LF) diet containing 10% kcal as fat for the entire 148-day period. DON induced rapid decreases in body weights and fat mass, which stabilized to those of the LF control within 11 days. These effects corresponded closely to a robust transient decrease in food consumption. While lean body mass did not decline in DON-fed groups, further increases were suppressed. DON exposure reduced plasma insulin, leptin, insulin-like growth factor 1, and insulin-like growth factor acid labile subunit as well as increased hypothalamic mRNA level of the orexigenic agouti related protein. CONCLUSION: DON-mediated effects on body weight, fat mass, food intake, and hormonal levels in obese mice were consistent with a state of chronic energy restriction. PMID- 21538851 TI - Adverse effects of concentrated green tea extracts. AB - A myriad of health claims are being made in favor of the consumption of green tea. However, mostly due to the easy availability and greater than ever popularity of highly concentrated green tea extracts, sometimes combined with an attitude of more-is-better, certain health risks of green tea consumption have begun to emerge. Among such risks are the possibility of liver damage, the potential to interact with prescription drugs to alter their therapeutic efficacy, and the chance to cause harm when combined with other highly popular herbal remedies. This review will summarize documented examples of adverse effects of green tea in humans, and will discuss risks of copious consumption of highly concentrated green tea extracts as indicated by studies in animals. While there is no intention to minimize any of the scientifically established benefits of the use of green tea, the purpose of this review is to focus primarily on the potential for adverse effects and raise awareness of the rare, yet under appreciated risks. PMID- 21538850 TI - The role of antioxidant versus pro-oxidant effects of green tea polyphenols in cancer prevention. AB - Consumption of green tea (Camellia sinensis) may provide protection against chronic diseases, including cancer. Green tea polyphenols are believed to be responsible for this cancer preventive effect, and the antioxidant activity of the green tea polyphenols has been implicated as a potential mechanism. This hypothesis has been difficult to study in vivo due to metabolism of these compounds and poor understanding of the redox environment in vivo. Green tea polyphenols can be direct antioxidants by scavenging reactive oxygen species or chelating transition metals as has been demonstrated in vitro. Alternatively, they may act indirectly by upregulating phase II antioxidant enzymes. Evidence of this latter effect has been observed in vivo, yet more work is required to determine under which conditions these mechanisms occur. Green tea polyphenols can also be potent pro-oxidants, both in vitro and in vivo, leading to the formation of hydrogen peroxide, the hydroxyl radical, and superoxide anion. The potential role of these pro-oxidant effects in the cancer preventive activity of green tea is not well understood. The evidence for not only the antioxidant, but also pro-oxidant, properties of green tea is discussed in the present review. PMID- 21538853 TI - Interaction of hydroxycinnamic acids and their conjugates with organic anion transporters and ATP-binding cassette transporters. AB - SCOPE: Hydroxycinnamic acids are abundant antioxidants in our diet. In humans, hydroxycinnamic acids are metabolized to form sulfates and glucuronides, with the majority recovered in urine. METHODS AND RESULTS: We assessed the potential roles of organic anion transporters (OATs) and ATP-binding cassette (ABC) transporters in the renal uptake and efflux of hydroxycinnamic acid conjugates. Uptake studies using OAT1 (SLC22A6)-, OAT2 (SLC22A7)-, and OAT3 (SLC22A8)-expressing 293H embryonic kidney cells showed that OAT1 and OAT3, but not OAT2, accepted hydroxycinnamic acid conjugates as substrates. OAT1 and OAT3 mediated the basolateral uptake of hydroxycinnamic acid sulfates and glucuronide conjugates, respectively. Hydroxycinnamic acid sulfates are substrates of OAT4 and were capable of trans-stimulating 5-carboxyfluorescein uptake mediated by OAT4. On the other hand, hydroxycinnamic acid conjugates are not substrates for the ABC transporters, multidrug resistance protein 2 (MRP2/ABCC2) or breast cancer resistance protein (BCRP/ABCG2), demonstrated by the inability to alter ATPase activity. Cis-inhibition studies with OATs and MRPs revealed that hydroxycinnamic acid conjugates have limited impact on the transport of model substrates significantly at physiological concentrations. CONCLUSION: Concerted action of OAT1, OAT3, and OAT4 is involved in the elimination of hydroxycinnamic acid conjugates into urine, whereas MRP2 and breast cancer resistance protein are not involved in the disposition of these conjugates. PMID- 21538852 TI - Chemopreventive effects of tea in prostate cancer: green tea versus black tea. AB - The polyphenol compositions of green tea (GT) and black tea (BT) are very different due to post-harvest processing. GT contains higher concentrations of monomeric polyphenols, which affect numerous intracellular signaling pathways involved in prostate cancer (CaP) development. BT polymers, on the other hand, are poorly absorbed and are converted to phenolic acids by the colonic microflora. Therefore, after consumption of GT, higher concentrations of polyphenols are found in the circulation, whereas after BT consumption the phenolic acid levels in the circulation are higher. The majority of in vitro cell culture, in vivo animal, and clinical intervention studies examine the effects of extracts of GT or purified (-)-epigallocatechin-3-gallate (EGCG) on prostate carcinogenesis. These studies provide strong evidence supporting a chemopreventive effect of GT, but results from epidemiological studies of GT consumption are mixed. While the evidence for a chemopreventive effect of BT is much weaker than the body of evidence with regard to GT, there are several animal BT intervention studies demonstrating inhibition of CaP growth. This article will review in detail the available epidemiological and human clinical studies, as well as animal and basic mechanistic studies on GT and BT supporting a chemopreventive role in CaP. PMID- 21538854 TI - Curcumin reduces pulmonary tumorigenesis in vascular endothelial growth factor (VEGF)-overexpressing transgenic mice. AB - SCOPE: We investigated the inhibition of pulmonary tumor formation through treatment with curcumin in transgenic mice. METHODS AND RESULTS: In this study, a strain of transgenic mice carrying human vascular endothelial growth factor A165 (hVEGF-A165) gene to induce pulmonary tumor was used as an in vivo cancer therapy model. We found that curcumin significantly reduced hVEGF-A165 overexpression to normal, specifically in Clara cells of the lungs of transgenic mice, and suppressed the formation of tumors. In addition, we demonstrated a relationship between curcumin treatment and the expression of VEGF, EGFR, ERK2, and Cyclin A at the transcriptional and translational levels. We also noticed a reduction of Cyclin A and Cyclin B after curcumin treatment that had an effect on the cell cycle. Curcumin-induced inhibition of Cyclin A and Cyclin B likely results in decreased progression through S and G2/M phases. These results demonstrated that the expression of proteins involved in the S to M phase transition in transgenic mice is suppressed by curcumin. CONCLUSION: A Data suggest that a blockade of the cell cycle may be a critical mechanism for the observed effects on vasculogenesis and angiogenesis following treatment with curcumin. PMID- 21538856 TI - Mechanistic issues concerning cancer prevention by tea catechins. AB - The cancer preventive activities of tea (Camellia sinensis, Theaceae) have been demonstrated in animal models for cancers at different organ sites and suggested by some epidemiological studies. Many mechanisms for cancer prevention have been proposed based on studies in cell lines, which demonstrated the modulation of signal transduction and metabolic pathways by (-)-epigallocatechin-3-gallate (EGCG), the most abundant and active polyphenol in green tea. These molecular events may result in cellular changes, such as enhancement of apoptosis, suppression of cell proliferation, and inhibition of angiogenesis. Nevertheless, it is not known whether these are the molecular mechanisms of inhibition of carcinogenesis in animals and humans. This article discusses the key issues involved in extrapolating results from cell line studies to mechanistic information in vivo and in translating animal studies to human cancer prevention. PMID- 21538855 TI - Green tea and breast cancer. AB - The identification of modifiable lifestyle factors that could reduce the risk of breast cancer is a research priority. Despite the enormous chemopreventive potential of green tea and compelling evidence from animal studies, its role in breast cancer development in humans is still unclear. Part of the uncertainty is related to the relatively small number of epidemiological studies on green tea and breast cancer and that the overall results from case-control studies and prospective cohort studies are discordant. In addition, the mechanisms by which green tea intake may influence risk of breast cancer in humans remain not well studied. We review the human studies that have evaluated the relationship between green tea intake and four biomarkers (sex steroid hormones, mammographic density, insulin-like growth factor, adiponectin) that are believed to be important in breast cancer development. Results from these biomarker studies are also inconclusive. Limitations of observational studies and areas of further investigations are discussed. PMID- 21538857 TI - Hypocholesterolemic and hypoglycemic effects of enzymatically modified carbohydrates from rice in high-fat-fed C57BL/6J mice. AB - SCOPE: Enzymatically modified rice starch (ERS) synthesized with 4-alpha glucanotransferase has a longer structure than rice starch, which could delay digestion, similar to dietary fiber. We investigated the effects of ERS on glucose and lipid metabolism with mice fed a high-fat diet containing ERS (HFD ERS). METHOD AND RESULTS: Four weeks of ERS feeding showed hypoglycemic effects with a significant reduction in fasting glucose (46%), insulin (57%), and leptin (83%) levels; improved glucose tolerance (20% in AUC of oral glucose tolerance test); and increased adiponectin concentrations (+27%) compared to the HFD group. Notably, phosphorylation of AMP kinase (AMPK) was markedly induced in the HFD-ERS livers compared to HFD livers. Additionally, ERS significantly reduced total cholesterol concentrations with induction of fecal bile acid excretion (+21%, P<0.05) in the HFD-ERS group compared to the HFD group. The mRNA and protein expressions of hepatic LDL receptors were significantly induced. However, cholesterol 7 alpha-hydroxylase (CYP7A1) expression was downregulated possibly due to induction of intestinal farnesoid X receptor (FXR; +2.4-fold, p<0.05) and fibroblast growth factor-15 (FGF-15; +2.2-fold, p<0.01). CONCLUSION: Our data suggest that ERS feeding may have hypoglycemic and hypocholesterolemic effects via a mechanism similar to that of dietary fiber. PMID- 21538858 TI - The role of the concept of "history of safe use" in the safety assessment of novel foods and novel food ingredients. Opinion of the Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG). AB - The Council of the European Union has proposed a revision on the EU regulation on novel foods and novel food ingredients concerning safety assessment of traditional foods from non-EU countries and their introduction onto the EU market. The proposal stipulates that such foods may be placed on the EU market if their history of safe use in the country of origin is appropriately documented. The present statement of the SKLM gives an overview on current discussions on practical implementation of the "history of safe use" concept as well as examples of its application. The SKLM, in principle, agrees with these concepts, underscores, however, in connection with convincing evidence for a "history of safe use" the need for a range of additional information to achieve a comprehensive risk assessment. In the opinion of the SKLM such information must comprise compositional data as well as experience on adverse effects. A list of questions considered essential is presented. The following opinion was adopted on December 23rd 2010. PMID- 21538861 TI - Tuning the mechanical properties of composites from elastomeric to rigid thermoplastic by controlled addition of carbon nanotubes. AB - A commercial thermoplastic polyurethane is identified for which the addition of nanotubes dramatically improves its mechanical properties. Increasing the nanotube content from 0% to 40% results in an increase in modulus, Y, (0.4-2.2 GPa) and stress at 3% strain, sigma(epsilon = 3%) , (10-50 MPa), no significant change in ultimate tensile strength, sigma(B) , (~50 MPa) and decreases in strain at break, epsilon(B) , (555-3%) and toughness, T, (177-1 MJ m(-3) ). This variation in properties spans the range from compliant and ductile, like an elastomer, at low mass fractions to stiff and brittle, like a rigid thermoplastic, at high nanotube content. For mid-range nanotube contents (~15%) the material behaves like a rigid thermoplastic with large ductility: Y = 1.5 GPa, sigma(epsilon = 3%) = 36 MPa, sigma(B) = 55 MPa, epsilon(B) = 100% and T = 50 MJ m(-3) . Analysis suggests that soft polyurethane segments are immobilized by adsorption onto the nanotubes, resulting in large changes in mechanical properties. PMID- 21538862 TI - Targeted cell-cell interactions by DNA nanoscaffold-templated multivalent bispecific aptamers. AB - Cell-cell interactions are essential for multicellular organisms, playing important roles in their development, function, and immunity. Herein a bottom-up strategy to construct self-assembled DNA nanostructures is reported, consisting of multivalent, bispecific, cell-targeting aptamers to specifically induce cell cell interactions. Various DNA nanoscaffolds are rationally designed to assemble aptamers with different valencies and flexibilities, and their cellular binding capabilities are tested. Multivalent aptamers, assembled on more rigid scaffolds, display higher binding activities. Further, multivalent bispecific aptamer fusion molecules are constructed based on this configuration, and successfully link two types of cells. Using cell-targeting aptamers, the presented strategy eliminates the need to chemically modify cell surfaces and offers excellent cell specificity, binding efficiency, and stability. This proof-of-concept study establishes that multivalent bispecific aptamers linked on DNA-nanoscaffolds can mediate cellular engagement, which could lead to their use in directing or guiding cell-cell interactions in many biological events. PMID- 21538863 TI - DNA-templated silver nanoparticles as a platform for highly sensitive and selective fluorescence turn-on detection of dopamine. PMID- 21538864 TI - Nanostructuring polymeric materials by templating strategies. AB - This contribution summarizes efforts in designing, assembling/synthesizing, and structurally and functionally characterizing nanostructured materials using anodized aluminum oxide (AAO) as a thin-film template. Optical waveguide spectroscopy, using a nanoporous template as the guiding structure, is a particularly powerful analytical tool. The layer-by-layer approach for the fabrication of multilayer assemblies is shown to allow the fabrication of nanotube arrays. In addition to using dendrimers as building blocks, semiconducting nanomaterial (e.g., quantum dot) hybrid architectures with very interesting photophysical properties can be assembled. These can be employed, for example, in biosensing applications. Other strategies for using the AAO layers as templates include the growth of polymeric nanorod arrays from different functional monomers, which, after the dissolution of the template, are still able to guide light. This opens up novel concepts for integrated optics platforms with nanostructured materials. PMID- 21538865 TI - Forster resonance energy transfer in quantum dot-dye-loaded zeolite L nanoassemblies. PMID- 21538866 TI - Tuning stamp surface energy for soft lithography of polar molecules to fabricate bioactive small-molecule microarrays. AB - Soft-lithography-based techniques are widely used to fabricate microarrays. Here, the use of microcontact insertion printing is described, a soft-lithography method specifically developed for patterning at the dilute scales necessary for highly selective biorecognition. By carefully tuning the polar surface energy of polymeric stamps, problems associated with patterning hydrophilic tether molecules inserted into hydrophilic host self-assembled monolayers (SAMs) are surmounted. Both prefunctionalized tethers and on-chip functionalization of SAMs patterned by microcontact insertion printing enable the fabrication of small molecule microarrays. Substrates patterned with the neurotransmitter precursor 5 hydroxytryptophan selectively capture a number of different types of membrane associated receptor proteins, which are native binding partners evolved to recognize free serotonin. These advances provide new avenues for chemically patterning small molecules and fabricating small molecule microarrays with highly specific molecular recognition capabilities. PMID- 21538867 TI - Micro-/nano-engineered cellular responses for soft tissue engineering and biomedical applications. AB - The development of biomedical devices and reconstruction of functional ex vivo tissues often requires the need to fabricate biomimetic surfaces with features of sub-micrometer precision. This can be achieved with the advancements in micro /nano-engineering techniques, allowing researchers to manipulate a plethora of cellular behaviors at the cell-biomaterial interface. Systematic studies conducted on these 2D engineered surfaces have unraveled numerous novel findings that can potentially be integrated as part of the design consideration for future 2D and 3D biomaterials and will no doubt greatly benefit tissue engineering. In this review, recent developments detailing the use of micro-/nano-engineering techniques to direct cellular orientation and function pertinent to soft tissue engineering will be highlighted. Particularly, this article aims to provide valuable insights into distinctive cell interactions and reactions to controlled surfaces, which can be exploited to understand the mechanisms of cell growth on micro-/nano-engineered interfaces, and to harness this knowledge to optimize the performance of 3D artificial soft tissue grafts and biomedical applications. PMID- 21538868 TI - Synthesis of Ag(2) S-Ag nanoprisms and their use as DNA hybridization probes. AB - A simple synthetic route to prepare Ag(2) S-Ag nanoprisms consists of the facile addition of Na(2) S to a solution of triangular Ag nanoprisms. The resulting Ag(2) S-Ag nanoparticles are more stable in solution than the original Ag nanoprisms, and two surface plasmon resonance (SPR) bands of the original Ag nanoprisms still remain. In addition, the SPR bands of the Ag(2) S-Ag nanoprisms are tunable over a wide range. The Ag(2) S-Ag nanoprisms can be directly bioconjugated via well-established stable Ag(2) S surface chemistry with readily available sulfur coupling agents. The nanoprisms are used in the hybridization of functionalized oligonucleotides, and show promise as probes for future biosensing applications. PMID- 21538869 TI - Age-dependent changes in microscale stiffness and mechanoresponses of cells. AB - Cellular ageing can lead to altered cell mechanical properties and is known to affect many fundamental physiological cell functions. To reveal age-dependent changes in cell mechanical properties and in active mechanoresponses, the stiffness of human fibroblasts from differently aged donors was determined, as well as the cell's reaction to periodic mechanical deformation of the culture substrate, and the two parameters were correlated. A comparison of the average Young's moduli revealed that cells from young donors (<25 years) are considerably stiffer than cells from older donors (>30 years). The reduced stiffness of cells from the older donor group corresponds to the measured decrease of actin in these cells. Remarkably, cells from the older donor group show a significantly faster reorganization response to periodic uniaxial tensile strain than cells from the young donor group. The impact of a reduced amount of actin on cell stiffness and cell reorganization kinetics is further confirmed by experiments where the amount of cellular actin in cells from the young donor group was decreased by transient siRNA knockdown of the actin gene. These cells show a reduced stiffness and enhanced reorganization speed, and in this way mimic the properties and behavior of cells from the older donor group. These results demonstrate that mechanical properties of human fibroblasts depend on the donor's age, which in turn may affect the cells' active responses to mechanical stimulations. PMID- 21538870 TI - Universal scaling of the charge transport in large-area molecular junctions. AB - Charge transport through alkanes and para-phenylene oligomers is investigated in large-area molecular junctions. The molecules are self-assembled in a monolayer and contacted with a top electrode consisting of poly(3,4-ethylenedioxythiophene) poly(4-styrenesulfonic acid) (PEDOT:PSS). The complete set of J(V,T) characteristics of both saturated and pi-conjugated molecules can be described quantitatively by a single equation with only two fit parameters. The derived parameters, in combination with a variation of the bulk conductivity of PEDOT:PSS, demonstrate that the absolute junction resistance is factorized with that of PEDOT:PSS. PMID- 21538871 TI - Chitosan-functionalized graphene oxide as a nanocarrier for drug and gene delivery. AB - The covalent functionalization of graphene oxide (GO) with chitosan (CS) is successfully accomplished via a facile amidation process. The CS-grafted GO (GO CS) sheets consist of about 64 wt.% CS, which imparts them with a good aqueous solubility and biocompatibility. Additionally, the physicochemical properties of GO-CS are studied. As a novel nanocarrier, GO-CS is applied to load a water insoluble anticancer drug, camptothecin (CPT), via pi-pi stacking and hydrophobic interactions. It is demonstrated that GO-CS possesses a superior loading capacity for CPT, and the GO-CS-CPT complexes show remarkably high cytotoxicity in HepG2 and HeLa cell lines compared to the pure drug. At the same time, GO-CS is also able to condense plasmid DNA into stable, nanosized complexes, and the resulting GO-CS/pDNA nanoparticles exhibit reasonable transfection efficiency in HeLa cells at certain nitrogen/phosphate ratios. Therefore, the GO-CS nanocarrier is able to load and deliver both anticancer drugs and genes. PMID- 21538872 TI - Receptor-mediated cellular uptake of nanoparticles: a switchable delivery system. PMID- 21538873 TI - Complementary-like graphene logic gates controlled by electrostatic doping. PMID- 21538874 TI - Experimental design applied to the analysis of volatile compounds in apple juice by headspace solid-phase microextraction. AB - A simple and fast method based on solid-phase microextraction (SPME) followed by fast gas chromatography (Fast GC) has been developed for the analysis of volatile compounds in Asturian apple juices employed in the cider production. Three different fiber coatings have been checked (PDMS, PDMS-DVB and CAR-PDMS) and PDMS DVB has been presented to be the most suitable one. Experimental design has been employed in the optimization of extraction factors and robustness assessment. The use of Fast GC allowed the separation of 14 compounds (esters, aldehydes and alcohols) in approximately 4 min, clearly reducing the analysis time when compared to conventional GC. Good linearity, recoveries and repeatability of the solid-phase microextraction were obtained with r(2) values, recoveries and relative standard deviations ranging from 0.9822 to 0.9998, 83.2 to 109.8% and 0.5 to 11.7%, respectively, using standard solution. PMID- 21538875 TI - Deviation from van't Hoff dependence in RP-LC induced by tautomeric interconversion observed for four compounds. AB - The most encountered situations in reversed-phase liquid chromatography for temperature dependence of retention are those obeying the linear equation known as the van't Hoff plot. When studying compounds that are involved in structural modifications, it is likely that the temperature dependences of their retention factors do not follow this rule. It is the aim of this paper to report some particular cases when compounds involved in tautomeric interconversion have a different retention behavior with temperature: a deviation from the linearity of ln k on 1/T, or, in certain temperature ranges, temperature increase leading to a retention increase. Examples of compounds exhibiting deviation from the van't Hoff temperature dependence are piroxicam, drotaverine, vincamine, and epivincamine. A simple thermodynamic model relying on tautomeric equilibria in mobile phase is proposed for these compounds, which gives a polynomial dependence between ln k and 1/T. PMID- 21538876 TI - Mixed aqueous solutions as dilution media in the determination of residual solvents by static headspace gas chromatography. AB - Static headspace (HS) sampling has been commonly used to test for volatile organic chemicals, usually referred to as residual solvents (RS) in pharmaceuticals. If the sample is not soluble in water, organic solvents are used. However, these seriously reduce the sensitivity in the determination of some RS. Here, mixed aqueous dilution media (a mixture of water and an organic solvent like dimethyl formamide, dimethyl sulfoxide or dimethyl acetamide) were studied as alternative media for static HS-gas chromatographic analysis. Although it has been known that mixed aqueous dilution media can often improve sensitivity for many RS, this study used a systematic approach to investigate phase volumes and the organic content in the HS sampling media. Reference solutions using 18 different class 1, 2 and 3 RS were evaluated. The effect of salt addition was also studied in this work. A significant increase in the peak area was observed for all RS using mixed aqueous dilution media, when compared with organic solvents alone. Matrix effects related to the mixed aqueous dilution media were also investigated and reported. Repeatability and linearity obtained with mixed aqueous dilution media were found to be similar to those observed with pure organic solvents. PMID- 21538877 TI - Validated dispersive liquid-liquid microextraction for analysis of organophosphorous pesticides in water. AB - Dispersive liquid-liquid microextraction (DLLME) combined with gas chromatography and mass spectrometry (GC-MS) was applied to the determination of six organophosphorous pesticides (OPPs) in water samples. The analytes included in this study were prophos, diazinon, chlorpyrifos methyl, methyl parathion, fenchlorphos and chlorpyrifos. Several extraction and dispersion solvents were tested for dispersive liquid-liquid microextraction of these analytes and the best results were obtained using chloroform as extraction solvent and 2-propanol as dispersion solvent. Calibration curves of the analytes in water samples were constructed in the concentration range from 100 to 1100 ng/L for prophos, diazinon and methyl parathion and in the range from 100 to 1000 ng/L for chlorpyrifos methyl, fenchlorphos and chlorpyrifos. Limits of detection (LODs) were in the range of 1.5-9.1 ng/L and limits of quantification (LOQs) were in the range of 5.1-30.3 ng/L, below the maximum admissible level for drinking water. Relative standard deviations (RSDs) were between 6.5 and 10.1% in the concentration range of 100-1000 ng/L. The relative recoveries (%RRs) of tap, well and irrigation water samples fortified at 800 ng/L were in the range of 46.1 129.4%, with a larger matrix effect being detected in tap water. PMID- 21538878 TI - Determination of trace biogenic amines with 1,3,5,7-tetramethyl-8-(N hydroxysuccinimidyl butyric ester)-difluoroboradiaza-s-indacene derivatization using high-performance liquid chromatography and fluorescence detection. AB - A reversed-phase high-performance liquid chromatographic method based on chemical derivatization with fluorescence detection has been developed for analyzing biogenic amines in food and environmental samples. A BODIPY-based fluorescent reagent, 1,3,5,7-tetramethyl-8-(N-hydroxysuccinimidyl butyric ester) difluoroboradiaza-s-indacene (TMBB-Su), was employed for the derivatization of these biogenic amines at 20 degrees C for 20 min in pH 7.20 borate buffer after careful investigation of the derivatization conditions including reagent concentration, buffer solution, reaction temperature and reaction time. Separation of biogenic amines with gradient elution was conducted on a C8 column with methanol-tetrahydrofuran-water as mobile phase. The detection limits were obtained in the range from 0.1 to 0.2 nM (signal-to-noise=3). This procedure has been validated using practical samples. The study results demonstrated a potential of employing high-performance liquid chromatography (HPLC) with 1,3,5,7 tetramethyl-8-(N-hydroxysuccinimidyl butyric ester)-difluoroboradiaza-s-indacene labeling as a tool for quantitative analysis of biogenic amines involved in various matrices. PMID- 21538879 TI - Proteomic analysis of Singapore grouper iridovirus envelope proteins and characterization of a novel envelope protein VP088. AB - Singapore grouper iridovirus (SGIV) is an enveloped virus causing heavy economic losses to marine fish culture. The envelope fractions of SGIV were separated from the purified virions by Triton X-100 treatment, and subjected to 1-DE-MALDI TOF/TOF-MS/MS and LC-MALDI-TOF/TOF-MS/MS analysis. A total of 19 virus-encoded envelope proteins were identified in this study and 73.7% (13/17) of them were predicted to be membrane proteins. Three viral envelope proteins were uniquely identified by 1-DE-MALDI, whereas another ten proteins were identified only by LC MALDI, with six proteins identified by both workflows. VP088 was chosen as a representative of proteomic identification and characterized further. VP088 was predicted to be a viral transmembrane envelope protein which contains two RGD (Arg-Gly-Asp) motifs, three transmembrane domains, and five N-glycosylation sites. VP088 gene transcript was first detected at 12 h p.i. and reached the peak at 48 h p.i. Combined with the drug inhibition assay, VP088 gene was identified as a late (L) gene. Recombinant VP088 (rVP088) was expressed in Escherichia coli, and the specific antiserum against rVP088 was raised. VP088 was proved to be a viral envelope protein by Western blot and immunoelectron microscopy (IEM). Furthermore, rVP088 can bind to a 94 kDa host cell membrane protein, suggesting that VP088 might function as an attaching protein. Neutralization assay also suggested that VP088 is involved in SGIV infection. This study will lead to a better understanding of molecular mechanisms of the iridoviral pathogenesis and virus-host interactions. PMID- 21538881 TI - Transcriptional and proteomic profiling of flatfish (Solea senegalensis) spermatogenesis. AB - The Senegalese sole (Solea senegalensis) is a marine flatfish of high economic value and a target species for aquaculture. The efforts to reproduce this species in captivity have been hampered by the fact that farmed males (F1) often show lower sperm production and fertilization capacity than wild-type males (F0). Our knowledge on spermatogenesis is however limited to a few studies. In a previous work, we identified by 2-D DIGE several potential protein markers in testis for the poor reproductive performance of F1 males. Therefore, the objectives of the present study were, first, to investigate changes in genes and proteins expressed in the testis throughout spermatogenesis in F0 males by using a combination of transcriptomic and proteomic approaches and, second, to further compare the testis proteome between late spermatogenic stages of F0 and F1 fish to identify potential indicators of hampered reproductive performance in F1 fish. We identified approximately 400 genes and 49 proteins that are differentially expressed during the progression of spermatogenesis and that participate in processes such as transcriptional activation, the ubiquitin-proteasome system, sperm maturation and motility or cytoskeletal remodeling. Interestingly, a number of these proteins differed in abundance between F0 and F1 fish, pointing toward alterations in cytoskeleton, sperm motility, the ubiquitin-proteasome system and the redox state during spermiogenesis as possible causes for the decreased fertility of F1 fish. PMID- 21538880 TI - Proteomic characterization of the major arthropod associates of the carnivorous pitcher plant Sarracenia purpurea. AB - The array of biomolecules generated by a functioning ecosystem represents both a potential resource for sustainable harvest and a potential indicator of ecosystem health and function. The cupped leaves of the carnivorous pitcher plant, Sarracenia purpurea, harbor a dynamic food web of aquatic invertebrates in a fully functional miniature ecosystem. The energetic base of this food web consists of insect prey, which is shredded by aquatic invertebrates and decomposed by microbes. Biomolecules and metabolites produced by this food web are actively exchanged with the photosynthesizing plant. In this report, we provide the first proteomic characterization of the sacrophagid fly (Fletcherimyia fletcheri), the pitcher plant mosquito (Wyeomyia smithii), and the pitcher-plant midge (Metriocnemus knabi). These three arthropods act as predators, filter feeders, and shredders at distinct trophic levels within the S. purpurea food web. More than 50 proteins from each species were identified, ten of which were predominantly or uniquely found in one species. Furthermore, 19 peptides unique to one of the three species were identified using an assembled database of 100 metazoan myosin heavy chain orthologs. These molecular signatures may be useful in species monitoring within heterogeneous ecosystem biomass and may also serve as indicators of ecosystem state. PMID- 21538882 TI - Glycoproteomics analysis to identify a glycoform on haptoglobin associated with lung cancer. AB - Glycosylation is a common protein modification that is of interest in current cancer research because altered carbohydrate moieties are often found during cancer progress. A search for biomarkers in human lung cancer serum samples using glycoproteomic approaches identified fucosylated haptoglobin (Hp) significantly increased in serum of each subtype of lung cancer compared to normal donors. In addition, MS provided evidence of an increase of Hp fucosylation; the glycan structure was determined to be an alpha 2,6-linked tri-sialylated triantennary glycan containing alpha1,3-linked fucose attached to the four-linked position of the three-arm mannose of N-linked core pentasaccharide. These preliminary findings suggest that the specific glycoform of Hp may be useful as a marker to monitor lung cancer progression. PMID- 21538883 TI - Immunodepletion of albumin and immunoglobulin G from bovine plasma. AB - Current MS-based proteomics has facilitated the identification of large numbers of proteins from complex mixtures. The bovine plasma proteome has the potential to provide a wealth of information concerning the biological state of an animal. However, during MS-based experiments, higher abundance proteins such as albumin and immunoglobulin G (IgG) can hinder the identification of potentially important proteins that are present in much lower abundance. While a variety of readily available technologies exist for the depletion of multiple high-abundance proteins from human, mouse and rat samples, there are few available for bovine. In this study, we report the depletion of >97% of albumin and >92% of IgG from bovine plasma. PMID- 21538884 TI - Mass spectrometric analysis of GABAA receptor subtypes and phosphorylations from mouse hippocampus. AB - The brain GABA(A) receptor (GABA(A) R) is a key element of signaling and neural transmission in health and disease. Recently, complete sequence analysis of the recombinant GABA(A) R has been reported, separation and mass spectrometrical (MS) characterisation from tissue, however, has not been published so far. Hippocampi were homogenised, put on a sucrose gradient 10-69% and the layer from 10 to 20% was used for extraction of membrane proteins by a solution of Triton X-100, 1.5 M aminocaproic acid in the presence of 0.3 M Bis-Tris. This mixture was subsequently loaded onto blue native PAGE (BN-PAGE) with subsequent analysis on denaturing gel systems. Spots from the 3-DE electrophoretic run were stained with Colloidal Coomassie Brilliant Blue, and spots with an apparent molecular weight between 40 and 60 kDa were picked and in-gel digested with trypsin, chymotrypsin and subtilisin. The resulting peptides were analysed by nano-LC-ESI-MS/MS (ion trap) and protein identification was carried out using MASCOT searches. In addition, known GABA(A) R-specific MS information taken from own previous studies was used for searches of GABA(A) R subunits. beta-1, beta-2 and beta-3, theta and rho-1 subunits were detected and six novel phosphorylation sites were observed and verified by phosphatase treatment. The method used herein enables identification of several GABA(A) R subunits from mouse hippocampus along with phosphorylations of beta-1 (T227, Y230), beta-2 (Y215, T439) and beta-3 (T282, S406) subunits. The procedure forms the basis for GABA(A) R studies at the protein chemical rather than at the immunochemical level in health and disease. PMID- 21538885 TI - A posteriori quality control for the curation and reuse of public proteomics data. AB - Proteomics is a rapidly expanding field encompassing a multitude of complex techniques and data types. To date much effort has been devoted to achieving the highest possible coverage of proteomes with the aim to inform future developments in basic biology as well as in clinical settings. As a result, growing amounts of data have been deposited in publicly available proteomics databases. These data are in turn increasingly reused for orthogonal downstream purposes such as data mining and machine learning. These downstream uses however, need ways to a posteriori validate whether a particular data set is suitable for the envisioned purpose. Furthermore, the (semi-)automatic curation of repository data is dependent on analyses that can highlight misannotation and edge conditions for data sets. Such curation is an important prerequisite for efficient proteomics data reuse in the life sciences in general. We therefore present here a selection of quality control metrics and approaches for the a posteriori detection of potential issues encountered in typical proteomics data sets. We illustrate our metrics by relying on publicly available data from the Proteomics Identifications Database (PRIDE), and simultaneously show the usefulness of the large body of PRIDE data as a means to derive empirical background distributions for relevant metrics. PMID- 21538886 TI - Characterizing the proteome of the human dorsolateral prefrontal cortex by shotgun mass spectrometry. AB - The studies of neuropsychiatric disorders would be facilitated by enhanced knowledge of the dorsolateral prefrontal cortex (DLPFC) proteome. To construct a data set of human DLPFC proteins, protein extracts were prepared from 12 postmortem brains focussing on the DLPFC region (Brodmann area 9) and analyzed using a combined gel electrophoresis and shotgun mass spectrometry approach, featuring data-independent label-free nanoflow liquid chromatography mass spectrometry (nLC-MS(E)). The detected mass/time features were aligned and annotated using the results from ProteinLynx Global Server. The resulting data set comprised 488 unique and accurately identified proteins, with stringent identification by a minimum of two distinct peptides detected at least in >75% of samples. These proteins were involved predominantly in cytoskeletal architecture, metabolism, transcription/translation, and synaptic function. Combination of this data set with that obtained by our previous characterization of the same brain region results in a total of 755 unique proteins, making this the most comprehensive analysis of this important brain region to date. PMID- 21538889 TI - Editorial: Biotechnology Journal - a progress report. PMID- 21538892 TI - Meeting report: International Conference on Cellular and Molecular Bioengineering (ICCMB). PMID- 21538893 TI - Pseudomonas fluorescens-mediated biocontrolin the post-genomic era: from lap to lab to land. PMID- 21538894 TI - Nrf2-mediated induction of phase 2 detoxifying enzymes by glyceollins derived from soybean exposed to Aspergillus sojae. AB - Numerous antioxidants have been reported to cause transcriptional activation of several antioxidant enzymes through binding antioxidant-response element on their promoter region. We, therefore, attempted to examine whether glyceollins, which share common structural features with many phase 2 enzyme inducers and antioxidant activity, could induce detoxifying/antioxidant enzymes. Glyceollins induced NAD(P)H:quinone oxidoreductase activity in a dose-dependent manner in both mouse hepatoma Hepa1c1c7 and its mutant BPRc1 cells. The compounds also increased the expression of some representative antioxidant enzymes, such as heme oxygenase 1,gamma-glutamylcysteine synthase, and glutathione reductase, by promoting nuclear translocation of the NF-E2-related factor-2 (Nrf2). Furthermore, phosphorylation of Akt and antioxidant response element-mediated reporter gene expression were enhanced by glyceollins but suppressed by LY294002, an inhibitor of phosphoinositide 3-kinases (PI3K). This suggests that glyceollins may cause Nrf2-mediated phase 2 enzyme induction through activation of the PI3K signaling pathway as well as interaction with Keap1. Our molecular docking simulations also suggest that the glyceollin isomers tightly bind into the binding pocket around Cys151, preventing Nrf2 from docking to Keap1. In conclusion, the current data suggest that glyceollins induced phase 2 detoxifying enzymes likely through promoting nuclear translocation of Nrf2, which is known to be regulated by phosphorylation of Nrf2 and/or disrupting Keap1-Nrf2 complex formation. PMID- 21538895 TI - Recombinant dengue virus type 3 envelope domain III protein from Escherichia coli. AB - Dengue is a public health problem of global significance for which there is neither an effective antiviral therapy nor a preventive vaccine. The envelope protein of dengue virus is the major antigen to elicit neutralizing antibody response and protective immunity in hosts. Optimization of culture media was carried out for enhanced production of recombinant dengue virus type 3 envelope domain III (rDen 3 EDIII) protein in E. coli. Further, batch and fed-batch cultivation process were also developed in optimized medium. After fed-batch cultivation, the dry cell weight was about 22.80 g/L of culture. The rDen 3 EDIII protein was purified using immobilized metal affinity chromatography. This process produced ~649 mg of purified rDen 3 EDIII protein per liter of culture. The purity of the protein was determined by SDS-PAGE analysis and the reactivity was checked by Western blotting as well as ELISA. These results show that the purified protein may be used for the dengue diagnosis or further prophylactic studies for dengue infection. PMID- 21538897 TI - Prediction of the aggregation propensity of proteins from the primary sequence: aggregation properties of proteomes. AB - In the cell, protein folding into stable globular conformations is in competition with aggregation into non-functional and usually toxic structures, since the biophysical properties that promote folding also tend to favor intermolecular contacts, leading to the formation of beta-sheet-enriched insoluble assemblies. The formation of protein deposits is linked to at least 20 different human disorders, ranging from dementia to diabetes. Furthermore, protein deposition inside cells represents a major obstacle for the biotechnological production of polypeptides. Importantly, the aggregation behavior of polypeptides appears to be strongly influenced by the intrinsic properties encoded in their sequences and specifically by the presence of selective short regions with high aggregation propensity. This allows computational methods to be used to analyze the aggregation properties of proteins without the previous requirement for structural information. Applications range from the identification of individual amyloidogenic regions in disease-linked polypeptides to the analysis of the aggregation properties of complete proteomes. Herein, we review these theoretical approaches and illustrate how they have become important and useful tools in understanding the molecular mechanisms underlying protein aggregation. PMID- 21538898 TI - Sensitive high-throughput screening for the detection of reducing sugars. AB - The exploitation of renewable resources for the production of biofuels relies on efficient processes for the enzymatic hydrolysis of lignocellulosic materials. The development of enzymes and strains for these processes requires reliable and fast activity-based screening assays. Additionally, these assays are also required to operate on the microscale and on the high-throughput level. Herein, we report the development of a highly sensitive reducing-sugar assay in a 96-well microplate screening format. The assay is based on the formation of osazones from reducing sugars and para-hydroxybenzoic acid hydrazide. By using this sensitive assay, the enzyme loads and conversion times during lignocellulose hydrolysis can be reduced, thus allowing higher throughput. The assay is about five times more sensitive than the widely applied dinitrosalicylic acid based assay and can reliably detect reducing sugars down to 10 MUM. The assay-specific variation over one microplate was determined for three different lignocellulolytic enzymes and ranges from 2 to 8%. Furthermore, the assay was combined with a microscale cultivation procedure for the activity-based screening of Pichia pastoris strains expressing functional Thermomyces lanuginosus xylanase A, Trichoderma reesei beta mannanase, or T. reesei cellobiohydrolase 2. PMID- 21538896 TI - Birth, life and death of nascent polypeptide chains. AB - The journey of nascent polypeptides from synthesis at the peptidyl transferase center of the ribosome ("birth") to full function ("maturity") involves multiple interactions, constraints, modifications and folding events. Each step of this journey impacts the ultimate expression level and functional capacity of the translated protein. It has become clear that the kinetics of protein translation is predominantly modulated by synonymous codon usage along the mRNA, and that this provides an active mechanism for coordinating the synthesis, maturation and folding of nascent polypeptides. Multiple quality control systems ensure that proteins achieve their native, functional form. Unproductive co-translational folding intermediates that arise during protein synthesis may undergo enhanced interaction with components of these systems, such as chaperones, and/or be subjects of co-translational degradation ("death"). This review provides an overview of our current understanding of the complex co-translational events that accompany the synthesis, maturation, folding and degradation of nascent polypeptide chains. PMID- 21538899 TI - The aggregation properties of Escherichia coli proteins associated with their cellular abundance. AB - Proteins are key players in most cellular processes. Therefore, their abundances are thought to be tightly regulated at the gene-expression level. Recent studies indicate, however, that steady-state cellular-protein concentrations correlate better across species than the levels of the corresponding mRNAs; this supports the existence of selective forces to maintain precise cellular-protein concentrations and homeostasis, even if gene-expression levels diverge. One of these forces might be the avoidance of protein aggregation because, in the cell, the folding of proteins into functional conformations might be in competition with anomalous aggregation into non-functional and usually toxic structures in a concentration-dependent manner. The data in the present work provide support for this hypothesis because, in E. coli, the experimental solubility of proteins correlates better with the cellular abundance than with the gene-expression levels. We found that the divergence between protein and mRNAs levels is low for high-abundance proteins. This suggests that because abundant proteins are at higher risk of aggregation, cellular concentrations need to be stringently regulated by gene expression. PMID- 21538901 TI - Singapore National Institute of Chemistry--helping Singapore punch above its weight. PMID- 21538904 TI - Palladium-catalyzed allyl cross-coupling reactions with in situ generated organoindium reagents. AB - Inter- and intramolecular palladium-catalyzed allyl cross-coupling reactions, using allylindium generated in situ from allyl halides and indium, is demonstrated. Allylindium compounds may be effective nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions. A variety of allyl halides, such as allyl iodide, allyl bromide, crotyl bromide, prenyl bromide, geranyl bromide, and 3-bromocyclohexene afforded the allylic cross-coupling products in good to excellent yields. Stereochemistry of the double bond is retained in the allylic cross-coupling reactions. Electrophilic cross-coupling partners, such as aryl and vinyl halides, dibromoolefin, alkynyl iodide, and aryl and vinyl triflates participate in these reactions. The presence of various substituents, such as n-butyl, ketal, acetyl, ethoxycarbonyl, nitrile, N phenylamido, nitro, and chloride groups on the aromatic ring of electrophilic coupling partners showed little effect on the efficiency of the reactions. The present conditions work equally well for not only intermolecular but also intramolecular palladium-catalyzed cross-coupling reactions. These methods provide an efficient synthetic method for the introduction of an allyl group, which can be easily further functionalized to afford an sp(2)- and sp-hybridized carbon. The present method complements existing synthetic methods as a result of advantageous features such as easy preparation and handling, thermal stability, high reactivity and selectivity, operational simplicity, and low toxicity of allylindium reagents. PMID- 21538900 TI - Mapping the catechol binding site in dopamine D1 receptors: synthesis and evaluation of two parallel series of bicyclic dopamine analogues. AB - A novel class of isochroman dopamine analogues, originally reported by Abbott Laboratories, have >100-fold selectivity for D1-like over D2-like receptors. We synthesized a parallel series of chroman compounds and showed that repositioning the oxygen atom in the heterocyclic ring decreases potency and confers D2-like receptor selectivity to these compounds. In silico modeling supports the hypothesis that the altered pharmacology for the chroman series is due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxy group of the catechol moiety. This interaction realigns the catechol hydroxy groups and disrupts key interactions between these ligands and critical serine residues in TM5 of the D1-like receptors. This hypothesis was tested by the synthesis and pharmacological evaluation of a parallel series of carbocyclic compounds. Our results suggest that if the potential for intramolecular hydrogen bonding is removed, D1-like receptor potency and selectivity are restored. PMID- 21538905 TI - Cooperative activation of alkyne and thioamide functionalities; direct catalytic asymmetric conjugate addition of terminal alkynes to alpha,beta-unsaturated thioamides. AB - A detailed study of the direct catalytic asymmetric conjugate addition of terminal alkynes to alpha,beta-unsaturated thioamides is described. A soft Lewis acid/hard Bronsted base cooperative catalyst, comprising [Cu(CH(3)CN)(4)]PF(6), bisphosphine ligand, and Li(OC(6)H(4)-p-OMe) simultaneously activated both substrates to compensate for the low reactivity of copper alkynylide. A series of control experiments revealed that the intermediate copper-thioamide enolate functioned as a Bronsted base to generate copper alkynylide from the terminal alkyne, thus driving the catalytic cycle through an efficient proton transfer between substrates. These findings led to the identification of a more convenient catalyst using potassium hexamethyldisilazane (KHMDS) as the Bronsted base, which was particularly effective for the reaction of silylacetylenes. Divergent transformation of the thioamide functionality and a concise enantioselective synthesis of a GPR40 receptor agonist AMG-837 highlighted the synthetic utility of the present catalysis. PMID- 21538906 TI - Nanoscale effects on the stability of the lambda-Ti3O5 polymorph. AB - The nanocrystalline valency-delocalized lambda-phase of the binary oxide Ti(3)O(5) has recently emerged as a promising phase-change material that exhibits rapid photo-reversible optical and resistance changes at ambient temperature. Nanoscaling caused the monoclinic-lambda to monoclinic charge-ordered beta-phase structural instability to shift to considerably lower temperatures compared to the bulk material, and led to a broad thermal hysteresis. The structural transformation was accompanied by a large change in volume and large lattice relaxations, which imply the presence of strong electron-phonon coupling. We attribute the suppression of the phase transition to the enhanced surface energy on the nanoscale. PMID- 21538907 TI - UV photolysis of ClOOCl and the ozone hole. AB - The photochemistry of the ClO dimer (ClOOCl) plays a central role in the catalytic destruction of polar stratospheric ozone. In spite of decades of intense investigations, some of its laboratory photochemical data had not reached the desired accuracy to allow a reliable simulation of the stratospheric ozone loss until recently. Inevitable impurities in ClOOCl samples have obstructed conventional measurements. In particular, an absorption measurement of ClOOCl in 2007, which gave much lower cross sections than previous studies, implied that the formation of the ozone hole cannot be explained with current chemical models. Scientists have wondered whether the model is insufficient or the data is erroneous. Efforts aiming to resolve this controversy are reviewed in this paper, which emphasizes newly developed experiments to determine two critical photochemical properties of ClOOCl--its absorption cross section and product branching ratio--including the first reported product branching ratio at 351.8 nm photolysis. PMID- 21538908 TI - The one hundred and fifty year history of the Department of Chemistry, the University of Tokyo. PMID- 21538910 TI - Urinary proteomics analysis for renal injury in hypertensive disorders of pregnancy with iTRAQ labeling and LC-MS/MS. AB - PURPOSE: As a noninvasive examination, urinary proteomics is a very useful tool to identify renal disease. The purpose of the present study was to find differential proteins among women with preeclampsia, gestational hypertension and normal pregnancy, and to screen potential biomarkers for the early diagnosis of preeclampsia. EXPERIMENTAL DESIGN: Urinary proteins were identified by iTRAQ labeling coupled with 2-D LC-MS/MS. The bioinformatics analysis was performed with the Metacore software and the International Protein Index (IPI) and the Gene Ontology (GO) Database. The differentially expressed proteins were verified by ELISA. RESULTS: 362 nonredundant proteins were identified, 113 of which were expressed differentially between preeclampsia and normal pregnant group and 31 differential proteins among three groups. These differential proteins were associated with biological processes of blood coagulation, cell adhesion and differentiation, immune response and cytoskeleton development, etc. They interacted with each other in the network. The urinary angiotensinogen (AGT) was downregulated, which was consistent with the ELISA validation results. CONCLUSIONS AND CLINICAL RELEVANCE: The present study found a multitude of differential proteins that might provide a clue for investigating the mechanism of proteinuria development in preeclampsia. Low urinary angiotensinogen levels were useful for identifying preeclampsia. PMID- 21538911 TI - Vascular proteomics and the discovery process of clinical biomarkers: The case of TWEAK. AB - In the last years, big efforts are devoted to the search of novel biomarkers. Proteomic approaches in healthy and pathological samples may help us to discern differential protein expression patterns. These identified proteins include potential culprits in pathological pathways and/or clinical biomarkers to identify individuals at risk. However, extensively validation must be carried out before their implementation into the clinical practice. Biomarkers need to discriminate between health and disease, detect preclinical disease stages, have impact on survival prediction, and add predictive value beyond traditional risk factors and global risk algorithms. Now, we summarize the data of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), a new cardiovascular biomarker identified by proteomic analysis. Decreased sTWEAK concentrations have been shown in patients with carotid atherosclerosis, coronary artery disease, congestive heart failure, peripheral artery disease, or chronic kidney disease (CKD). sTWEAK predicted adverse outcomes in patients with heart failure, myocardial infarction, and CKD. Finally, different drug regimens were able to modify sTWEAK plasma levels in patients with CKD. Although sTWEAK seems so far to fulfill the requisites in the development of a new biomarker, more large-scale studies are warranted to consolidate its usefulness. PMID- 21538912 TI - Differential glomerular proteome analysis of two murine nephropathy models at onset of albuminuria. AB - PURPOSE: Early stages of various entities of progressive kidney diseases are commonly characterized by development of glomerular hypertrophy and albuminuria. The purpose of the present study was to identify protein biomarker candidates for these glomerular alterations. EXPERIMENTAL DESIGN: Quantitative differences in the glomerular proteomes of two unrelated murine nephropathy models in the defined stage of glomerular hypertrophy at onset of albuminuria were identified by 2-D DIGE and MALDI-TOF/TOF analysis. Investigated mouse models were (I): transgenic (tg) mice expressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn) ), a model of diabetes mellitus associated nephropathy and (II): growth hormone (GH)-tg mice, an established model of progressive glomerulosclerosis. RESULTS: In GIPR(dn) -tg mice, nine differentially abundant glomerular proteins were unambiguously identified, and eight in GH-tg mice (each versus controls). Four proteins (Annexin A4, Dihydropyrimidinase-related protein 2, Myosin regulatory light chain 2, Tropomyosin 1) displayed a congeneric differential glomerular abundance in both models, thus representing a common differential protein expression profile of glomerular hypertrophy at onset of albuminuria. The glomerular presence of these proteins was also detected in specimen of human focal and segmental glomerulosclerosis and diabetic nephropathy. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings suggest a pathogenetic relevance of the identified proteins in early stages of chronic kidney diseases and their potential use as diagnostic markers. PMID- 21538913 TI - Proteomic analysis of urinary upper gastrointestinal cancer markers. AB - PURPOSE: We have investigated the use of human urine as a non-invasive medium to screen for molecular biomarkers of carcinomas of the upper gastrointestinal (uGI) tract using SELDI-TOF-MS. EXPERIMENTAL DESIGN: A total of 120 urine specimens from 60 control and 60 uGI cancer patients were analysed to establish a potential biomarker fingerprint for the weak cation exchanger CM10 chip surface, which was validated by blind testing using a further 59 samples from 33 control and 26 uGI cancer patients. RESULTS: Using Biomarker Pattern software, we established a model with a sensitivity of 98% and specificity of 95% for the learning sample set, and a sensitivity of 96% and specificity of 72% for the validation data set. Model variable importance included six peptides with m/z of 10,230, 10,436, 10,574, 10,311, 10,467, and 10,118 of which the 10, 230 molecular species was the main decider (sensitivity 86% and specificity 80%). Initial protein database searching identified 10,230 as S100-A6, 10,436 as S100-P, 10,467 as S100-A9, and 10,574 as S100-A12 of which S100-A6 and S100-A9 were confirmed by Western blotting. CONCLUSIONS AND CLINICAL RELEVANCE: We have demonstrated that SELDI-TOF MS as a screening tool is a rapid and valid methodology in the search for urinary cancer biomarkers, and is potentially useful in defining and consolidating biomarker patterns for uGI cancer screening. PMID- 21538914 TI - Is the time ripe for kidney tissue proteomics? AB - In this viewpoint article, the importance of renal tissue proteomics in health and disease is explored. The analysis of the urinary proteome and the potential clinical application of these findings are progressing. However, additional benefit would be gained from a detailed parallel exploration of the proteome of the renal parenchyma, both in models and clinical samples. With this aim, we will briefly summarize the existing literature, compare the findings and propose future tasks. Special emphasis is placed on the importance of studying specific cellular compartments and cell types within the kidney. Recent technical advances are also discussed. It is anticipated that the combination of such technologies, especially proteomic analysis of material extracted by laser capture microdissection from paraffin embedded tissue or direct mass spectrometrical tissue imaging, will revolutionize the field. PMID- 21538915 TI - New pathway for qualification of novel methodologies in the European Medicines Agency. AB - The European Medicines Agency (EMA) qualification process is a new, voluntary, scientific pathway leading to either a Committee for Medicinal Products for Human Use (CHMP) opinion or a Scientific Advice on innovative methods or drug development tools: (i) CHMP Qualification Opinion on the acceptability of a specific use of the proposed method, based on the assessment of submitted data and (ii) CHMP Qualification Advice on future protocols and methods for further method development towards qualification, based on the evaluation of the scientific rationale and on preliminary data submitted. The qualification procedure was established as a response to the drug development bottlenecks and inefficiencies, but also to the availability of new methodologies, not yet integrated in the drug development and clinical management paradigm. The qualification process addresses innovative methods developed by consortia, networks, public/private partnerships, learned societies or pharmaceutical industry. It is expected to facilitate communication between the scientific community and the regulators and to address challenges with the development and use of medicines. In this article, we will present an overview of the process and the up to now scientific advice working party (SAWP) experience. PMID- 21538916 TI - Proteomics in chronic kidney disease: The issues clinical nephrologists need an answer for. AB - A growing number of patients are recognised to have chronic kidney disease (CKD). However, only a minority will progress to end-stage renal disease requiring dialysis or transplantation. Currently available diagnostic and staging tools frequently fail to identify those at higher risk of progression or death. Furthermore within specific disease entities there are shortcomings in the prediction of the need for therapeutic interventions or the response to different forms of therapy. Kidney and urine proteomic biomarkers are considered as promising diagnostic tools to predict CKD progression early in diabetic nephropathy, facilitating timely and selective intervention that may reduce the related health-care expenditures. However, independent groups have not validated these findings and the technique is not currently available for routine clinical care. Furthermore, there are gaps in our understanding of predictors of progression or need for therapy in non-diabetic CKD. Presumably, a combination of tissue and urine biomarkers will be more informative than individual markers. This review identifies clinical questions in need of an answer, summarises current information on proteomic biomarkers and CKD, and describes the European Kidney and Urine Proteomics initiative that has been launched to carry out a clinical study aimed at identifying urinary proteomic biomarkers distinguishing between fast and slow progressors among patients with biopsy-proven primary glomerulopathies. PMID- 21538917 TI - Ionic liquid-based synthesis--a low-temperature route to nanophosphates. PMID- 21538918 TI - Microbes as electrochemical CO2 conversion catalysts. PMID- 21538919 TI - Inclusion bodies in loggerhead erythrocytes are associated with unstable hemoglobin and resemble human Heinz bodies. AB - The aim of this study was to clarify the role of the erythrocyte inclusions found during the hematological screening of loggerhead population of the Mediterranean Sea. We studied the erythrocyte inclusions in blood specimens collected from six juvenile and nine adult specimens of the loggerhead turtle, Caretta caretta, from the Adriatic and Tyrrhenian Seas. Our study indicates that the percentage of mature erythrocytes containing inclusions ranged from 3 to 82%. Each erythrocyte contained only one round inclusion body. Inclusion bodies stained with May Grunwald-Giemsa show that their cytochemical and ultrastructure characteristics are identical to those of human Heinz bodies. Because Heinz bodies originate from the precipitation of unstable hemoglobin (Hb) and cause globular osmotic resistance to increase, we analyzed loggerhead Hb using electrophoresis and high performance liquid chromatography to detect and quantitate Hb fractions. We also tested the resistance of Hb to alkaline pH, heat, isopropanol denaturation, and globular osmosis. Our hemogram results excluded the occurrence of any infection, which could be associated with an inclusion body, in all the specimens. Negative Feulgen staining indicated that the inclusion bodies are not derived from DNA fragmentation. We hypothesize that amino acid substitutions could explain why loggerhead Hb precipitates under normal physiologic conditions, forming Heinz bodies. The identification of inclusion bodies in loggerhead erythrocytes allow us to better understand the haematological characteristics and the physiology of these ancient reptiles, thus aiding efforts to conserve such an endangered species. PMID- 21538920 TI - Diagnosis of subclinical and clinical acute T-cell-mediated rejection in renal transplant patients by urinary proteome analysis. AB - PURPOSE: Noninvasive diagnosis of acute renal allograft rejection may be advantageous compared with the allograft biopsy. EXPERIMENTAL DESIGN: In this study, a multi-marker classification model for rejection was defined on a training set of 39 allograft patients by statistical comparison of capillary electrophoresis mass spectrometry (CE-MS) peptide spectra in urine samples from 16 cases with subclinical acute T-cell-mediated tubulointerstitial rejection and 23 nonrejection controls. RESULTS: Application of the rejection model to a blinded validation set (n=64) resulted in an AUC value of 0.91 (95% CI: 0.82 0.97, p=0.0001). In total, 16 out of 18 subclinical and 10 out of 10 clinical rejections (BANFF grades Ia/Ib), and 28 out of 36 controls without rejection were correctly classified. Acute tubular injury in the biopsies or concomitant urinary tract infection did not interfere with CE-MS-based diagnosis. Sequence information of identified altered collagen alpha(I) and alpha (III) chain fragments in rejection samples suggested an involvement of matrix metalloproteinase-8 (MMP-8). Biopsy stainings revealed matrix metalloproteinase-8 exclusively in neutrophils located within peritubular capillaries and sparsely, in the tubulointerstitium during rejection. CONCLUSIONS AND CLINICAL RELEVANCE: The established marker set contains peptides related to tubulointerstitial infiltration seen in acute rejection. The set of urinary peptide markers will be used for early diagnosis of acute kidney allograft rejection marker in a multicenter phase III prospective study. PMID- 21538921 TI - Long-range signaling systems controlling glial migration in the Drosophila eye. AB - The Drosophila compound eye comprises about 750 individual ommatidia arranged into an almost crystalline array. The eye is not needed for viability and thus served as a favorite model organ to decipher many signaling systems controlling diverse aspects such as cell fate allocation or cell-cycle control. Here, we review that the Drosophila eye can also serve to study the interaction between neurons and glial cells. In the Drosophila eye, all glial cells originate from the brain lobes and need to migrate onto the larval eye disc as neurogenesis is initiated during the third instar stage. Although we do have a relatively good understanding of the sequential progression of neurogenesis in the eye disc, we are still at the beginning in our dissection of the molecular pathways orchestrating the coordinated development of neurons and glial cells. PMID- 21538922 TI - Visual circuit assembly in Drosophila. AB - Both insect and vertebrate visual circuits are organized into orderly arrays of columnar and layered synaptic units that correspond to the array of photoreceptors in the eye. Recent genetic studies in Drosophila have yielded insights into the molecular and cellular mechanisms that pattern the layers and columns and establish specific connections within the synaptic units. A sequence of inductive events and complex cellular interactions coordinates the assembly of visual circuits. Photoreceptor-derived ligands, such as hedgehog and Jelly-Belly, induce target development and expression of specific adhesion molecules, which in turn serve as guidance cues for photoreceptor axons. Afferents are directed to specific layers by adhesive afferent-target interactions mediated by leucine-rich repeat proteins and cadherins, which are restricted spatially and/or modulated dynamically. Afferents are restricted to their topographically appropriate columns by repulsive interactions between afferents and by autocrine activin signaling. Finally, Dscam-mediated repulsive interactions between target neuron dendrites ensure appropriate combinations of postsynaptic elements at synapses. Essentially, all these Drosophila molecules have vertebrate homologs, some of which are known to carry out analogous functions. Thus, the studies of Drosophila visual circuit development would shed light on neural circuit assembly in general. PMID- 21538923 TI - The role of Pax6 in forebrain development. AB - Pax6 encodes a highly conserved transcriptional regulator with two DNA-binding motifs, a paired domain and a paired-like homeodomain. Humans carrying PAX6 loss of-function mutations suffer from abnormal development of the eyes (congenital aniridia) and brain. Small eye mice carrying Pax6 loss-of-function mutations provide a good model for these human conditions. Their analysis has demonstrated the critical importance of this transcription factor in multiple cell types and at several key stages of forebrain development. In the forebrain, Pax6 is critical for the establishment of the pallial-subpallial boundary, which separates dorsal (future cerebral cortex) and ventral (future striatum) telencephalic regions. Levels of Pax6 expression are critically important for cortical progenitor proliferation and its presence in a rostro-lateral(high) to caudo-medial(low) gradient in the cortex is necessary to establish rostro-lateral identities. Furthermore, axon guidance is disrupted in Pax6-/- mutants: the majority of thalamocortical axons fail to enter the ventral telencephalon and those that do are unable to innervate their cortical targets. The extent to which the effects of Pax6 later in development are secondary to its effects in early patterning and proliferation remains largely unknown. This is likely to be clarified by future studies on the molecular mechanisms of action of Pax6 and, in particular, the identification of its downstream target genes. Such studies should also help generate an increasingly coherent understanding of how this pleiotropic transcription factor becomes involved in so many facets of neural development. PMID- 21538924 TI - Reviewing the morphology of the jaw-closing musculature in squirrels, rats, and guinea pigs with contrast-enhanced microCT. AB - Rodents are defined by their unique masticatory apparatus and are frequently separated into three nonmonophyletic groups--sciuromorphs, hystricomorphs, and myomorphs--based on the morphology of their masticatory muscles. Despite several comprehensive dissections in previous work, inconsistencies persist as to the exact morphology of the rodent jaw-closing musculature, particularly, the masseter. Here, we review the literature and document for the first time the muscle architecture noninvasively and in 3D by using iodine-enhanced microCT. Observations and measurements were recorded with reference to images of three individuals, each belonging to one of the three muscle morphotypes (squirrel, guinea pig, and rat). Results revealed an enlarged superficial masseter muscle in the guinea pig compared with the rat and squirrel, but a reduced deep masseter (possibly indicating reduced efficiency at the incisors). The deep masseter had expanded forward to take an origin on the rostrum and was also separated into anterior and posterior parts in the rat and squirrel. The zygomaticomandibularis muscle was split into anterior and posterior parts in all the three specimens by the masseteric nerve, and in the rat and guinea pig had an additional rostral expansion through the infraorbital foramen. The temporalis muscle was found to be considerably larger in the rat, and its separation into anterior and posterior parts was only evident in the rat and squirrel. The pterygoid muscles were broadly similar in all three specimens, although the internal pterygoid was somewhat enlarged in the guinea pig implying greater lateral movement of the mandible during chewing in this species. PMID- 21538925 TI - Three-dimensional structure of the nasal passageway of a hagfish and its implications for olfaction. AB - From high-resolution (65 MUm) data acquired by magnetic resonance imaging, we have reconstructed the nasal passageway of a single adult hagfish specimen (probably Eptatretus stoutii). We have used this reconstruction to investigate how the anatomy and morphometry of the nasal passageway influence the olfactory ability of the hagfish. We found that the long, broad section of the passageway preceding the nasal chamber will delay the response to an odor by 1-2 s. Diffusion of odorant to the olfactory epithelium, on which the olfactory sensitivity of an animal depends, will be favored by the relatively large surface area of the olfactory epithelium (~140 mm(2) ) and a modest expansion in the nasal chamber. Oscillating flow (0.3-0.4 Hz) within the narrow (65-130 MUm) sensory channels of the nasal chamber is laminar (Reynolds number ~ 5) and quasi steady (Womersley number generally less than one). Distribution of flow over the olfactory epithelium may be aided by: (a) a narrowing before the nasal chamber; (b) partial blockage of the nasal passageway by a protrusion on the central olfactory lamella; and (c) the inward inclination of the olfactory lamellae. PMID- 21538926 TI - Computer three-dimensional anatomical reconstruction of the human sinus node and a novel paranodal area. AB - We have previously shown in rabbit that the pacemaker of the heart (the sinus node) is widespread and matches the wide distribution of the leading pacemaker site within the right atrium. There is, however, uncertainty about the precise location of the pacemaker in human heart, and its spatial relationships with the surrounding right atrial muscle. Therefore, the aim of the current study was to investigate the distribution of the sinus node tissue in a series of healthy human hearts and, for one of the hearts to construct a computer three-dimensional anatomical model of the sinus node, including the likely orientation of myocytes. A combination of experimental techniques--diffusion tensor magnetic resonance imaging (DT-MRI), histology, immunohistochemistry, image processing and computer modelling--was used. Our data show that the sinus node was larger than in previous studies and, most importantly, we identified a previously unknown area running alongside the sinus node (the "paranodal area"), which is even more extensive than the sinus node. This area possesses properties of both nodal and atrial tissues and may have a role in pacemaking. For example, it could explain the wide spread distribution of the leading pacemaker site in human right atrium, a phenomenon known as the wandering pacemaker observed in clinics. In summary, a novel 3D anatomical reconstruction presents a new picture of the distribution of nodal cells within the human right atrium. PMID- 21538927 TI - Anatomical boundary of the tympanic membrane pars flaccida of the Meriones unguiculatus (Mongolian gerbil). AB - The pars flaccida of the Meriones unguiculatus (Mongolian gerbil) was in previous studies shown to bulge almost spherically when pressurized, a behavior suggesting that it is suspended by a fixed circular boundary. The question arises whether this "functional" boundary is based on an underlying circular anatomical boundary, an important issue for modeling the middle-ear mechanics. In this article, the boundaries of the Mongolian gerbil pars flaccida were visualized in situ with otomicroscopy and in slides with light microscopy and by micro-CT radiology. For the major part of its circumference, the pars flaccida was found to be suspended by rigid bone, that is, the tympanic legs. The remaining boundary is made up of the terminal portion of the handle of the malleus and the soft tissue of the terminal arches. The attachment to these structures is simple and uncomplicated, and the geometry is regular and symmetric: deviating by only 3.5% from a perfect circular shape. The findings justify the use of a fixed circular boundary as a good approximation for the modeling of pars flaccida deformation in the Mongolian gerbil. PMID- 21538928 TI - Contribution of the proinflammatory cytokine IL-18 in the formation of human nasal polyps. AB - Nasal polyposis is a chronic inflammatory disease of the nasal mucosa. The etiology and the mechanisms of formation of nasal polyps are still not clear. Interleukin (IL)-18 is a novel proinflammatory cytokine that plays important roles in regulating immune inflammatory responses. However, the presence of IL-18 in human nasal mucosa and its roles in the inflammatory process of nasal polyps has not been studied yet. In this study, it was the first time to investigate the expression of IL-18 in human nasal mucosa and nasal polyps, and its potential function in the formation of nasal polyps. Surgical samples were analyzed by Western blot and immunohistochemistry to evaluate the expression and location of IL-18, and its correlated cytokines, IL-4, and IFN-gamma. Furthermore, the airway epithelial cell line, A549, was used to investigate the mutual regulation of IFN gamma, IL-4, and IL-18. IFN-gamma, IL-4, and IL-18 were all highly expressed in the epithelial cells, submucosal glands, and infiltrating inflammatory cells in the nasal polyp tissues, comparing with the control samples. Especially, the expression of IL-18 was upregulated significantly in nasal polyp tissues compared with control tissues. In addition, IL-18 was expressed in A549 cells in response to lipopolysaccharide and IL-4. Our data suggest that nasal epithelial cells are involved in the pathogenesis of nasal polyps formation and potentially via the secretion of IL-18, which is likely to play important roles in the formation of nasal polyps. PMID- 21538929 TI - Early fetal development of the human cochlea. AB - The cochlear scalas are differentiated from a single tube with a lining by the tall epithelium, that is, the cochlear duct. However, we have no information about the mechanism involved in the formation of the scalas. We evaluated histological sections taken from 20 fetuses: eight each at 8--9 weeks [early stage; 28--45 mm crown-rump length (CRL)] and 11--12 weeks (middle stage; 52--74 mm CRL), and four at 14--15 weeks (late stage; 90--110 mm CRL) of gestation. In four of eight early-stage and in all eight middle-stage specimens, we observed irregular perilymphatic spaces and their fusion; these spaces tended to be larger in the future scala tympani than in the future scala vestibuli. The cochlear duct epithelium was positive for cytokeratin 19 in contrast to the other parts of the cochlea. The tectorial membrane appeared in two of eight middle-stage and all four late-stage specimens. After 16 weeks, mesothelial lining of the scala may follow the development of aquaporin-positive thin blood vessels along the scala wall. Notably, gap formation of the cochlear duct epithelium at a site facing the scala tympani consistently occurred before the development of S100 protein negative organ of Corti. This gap is likely to correspond to a site occupied finally by Hensen's cells. All these steps likely started in the basal coil and extended to the apical side of the cochlea. These findings suggest that leakage through the epithelial gap of endolymph, with a high concentration of potassium ions, causes mesenchymal cell death, leading to the coalescence of vacuoles containing low potassium perilymph. PMID- 21538930 TI - Comparative ultrastructural analysis of mitochondria in the CA1 and CA3 hippocampal pyramidal cells following global ischemia in Mongolian gerbils. AB - Post-ischemic injury of the hippocampus unrolls at different levels and has both functional and structural implications. The deficiency in neuron energy metabolism is an initiating factor. We performed transmission electron microscopic (TEM) comparative analysis of mitochondria in excitatory spine synapses in CA1 stratum radiatum and CA3 hippocampal areas after 5 min of global cerebral ischemia in Mongolian gerbils, 4 and 7 days after reperfusion. Electron microscopy and unbiased morphometric methods were used to evaluate synaptic plasticity, and the number and size of mitochondria in synaptic terminals. We compared the morphological organization of mitochondria in presynaptic terminals between CA1 and CA3 areas in control and post-ischemic condition according to the following morphometric parameters: mitochondrial volume fraction, mitochondrial frequency in CA1 and CA3 terminals, mean number of mitochondria per presynaptic terminal, frequency of damaged mitochondria in terminals, and density of presynaptic terminals. Our ultrastructural study revealed statistically significant differences in morphometric parameters between CA1 and CA3 areas in control conditions, as well as in post-ischemic conditions. Also, we found temporal differences in measured parameters obtained 4 and 7 days after reperfusion. This study showed significant morphological differences in the organization of mitochondria in excitatory spine synapses between CA1 and CA3 areas, which corresponded with already known differences in functionality and sensitivity to the ischemic insult. Our conclusion is that revealed post-ischemic changes in mitochondrial distribution in presynaptic CA1 and CA3 terminals could be an indicator of hippocampal metabolic dysfunction and synaptic plasticity. PMID- 21538931 TI - A morphological analysis on the osteocytic lacunar canalicular system in bone surrounding dental implants. AB - Osseointegration is the most preferable interface of dental implants and newly formed bone. However, the cavity preparation for dental implants often gives rise to empty lacunae or pyknotic osteocytes in bone surrounding the dental implant. This study aimed to examine the chronological alternation of osteocytes in the bone surrounding the titanium implants using a rat model. The distribution of the osteocytic lacunar canalicular system (OLCS) in bone around the titanium implants was examined by silver impregnation according to Bodian's staining. We also performed double staining for alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), as well as immunohistochemistry for fibroblast growth factor (FGF) 23--a regulator for the serum concentration of phosphorus--and sclerostin, which has been shown to inhibit osteoblastic activities. Newly formed bone and the injured bone at the early stage exhibited an irregularly distributed OLCS and a few osteocytes positive for sclerostin or FGF23, therefore indicating immature bone. Osteocytes in the surrounding bone from Day 20 to Month 2 came to reveal an intense immunoreactivity for sclerostin. Later on, the physiological bone remodeling gradually replaced such immature bone into a compact profile bearing a regularly arranged OLCS. As the bone was remodeled, FGF23 immunoreactivity became more intense, but sclerostin became less so in the well arranged OLCS. In summary, it seems likely that OLCS in the bone surrounding the dental implants is damaged by cavity formation, but later gradually recovers as bone remodeling takes place, ultimately inducing mature bone. PMID- 21538932 TI - Protective effect of extract of Astragalus on learning and memory impairments and neurons' apoptosis induced by glucocorticoids in 12-month-old male mice. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. Stress-level glucocorticoids are correlated with dementia progression in patients with AD. In this study, 12 month male mice were chronically treated with stress-level dexamethasone (DEX, 5 mg/kg) and extract of Astragalus (EA, 10, 20, and 40 mg/kg) or Ginsenoside Rg1 (Rg1, 6.5 mg/kg) for 21 days. We investigated the protective effect of EA against DEX injury in mice and its action mechanism. Our results indicate that DEX can induce learning and memory impairments and neuronal cell apoptosis. The mRNA levels of caspase-3 are selectively increased after DEX administration. The results of immunohistochemistry demonstrate that caspase-3 and cytochrome c in hippocampus (CA1, CA3) and neocortex are significantly increased. Furthermore, DEX treatment increased the activity of caspase-9 and caspase-3. Treatment groups with EA (20 and 40 mg/kg) or Rg1 (6.5 mg/kg) significantly improve learning and memory, downregulate the mRNA level of caspase-3, decrease expression of caspase 3 and cytochrome c in hippocampus (CA1, CA3) and neocortex, and inhibit activity of caspase-9 and caspase-3. The present findings highlight a possible mechanism by which stress level of DEX accelerates learning and memory impairments and increases neuronal apoptosis and the potential neuronal protection of EA. PMID- 21538933 TI - 5-Nitro-2-(3-phenylpropylamino) benzoic acid induced drug resistance to cisplatin in human erythroleukemia cell lines. AB - Mechanisms of cisplatin resistance in cancer cells are not fully understood. Here, we showed a critical role for the chloride channel-3 (ClC-3) in cisplatin resistance in human erythroleukemia K562 and RK562 cells. We found that a chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) could protect cells from cisplatin-induced apoptosis. NPPB treatment decreased the mRNA and the protein expression of Bax/Bcl-2, decreased the protein expressions of cytochrome C and caspase-3, and increased the mRNA expressions of cyclin D1 and ClC-3 in cells treated with cisplatin. The caspase-3 activity was decreased significantly and the rate of cell apoptosis was decreased. NPPB treatment increased CIC-3 expression, which could increase acidification of intracellular compartments, and increased sequestration of cisplatin, inducing decreased effective drug concentrations, and subsequently cell death. Collectively, our data indicate that NPPB can induce drug resistance to cisplatin by upregulating the expression of CIC-3. NPPB-induced CIC-3 expression facilitates acidification of sequestrated cisplatin, and plays an important role in preventing cisplatin-induced apoptosis in human erythroleukemia K562 and RK562 cells. PMID- 21538934 TI - Distribution of nitrergic neurons in the dorsal root ganglia of the bottlenose dolphin (Tursiops truncatus). AB - Dorsal root ganglia (DRGs) contain the cell bodies of primary afferent neurons that transmit sensory information from the periphery into the spinal cord. Distinct populations of DRG neurons have been characterized by a variety of different immunohistochemical markers. A subpopulation of ganglionic neurons containing neuronal nitric oxide synthase (nNOS), an enzyme known to generate nitric oxide, has been detected in a number of mammalian species. Despite previous studies, no information is known on the presence and exact distribution of nNOS-immunoreactive neurons in the DRGs of the bottlenose dolphin. In this investigation, immunoperoxidase for nNOS was used to determine the distribution and the perikaryal size of nitrergic neurons in the DRGs of this species. Double immunofluorescence protocol was used to determine the percentage of nNOS immunoreactive (IR) neurons over the total primary afferent neurons. In addition, double immunostaining was used to verify whether there was colocalization of nNOS with substance P (SP). In all DRGs, a subpopulation of small- and medium-sized neurons (about 9%) exhibited nNOS immunoreactivity. Data analysis revealed that the majority of nNOS-IR neurons (81.3%) expressed SP. The density of nNOS immunoreactive and nNOS/SP-double immunopositive cells was relatively constant throughout the ganglia. However, as observed in others mammals, the number of nitrergic neurons decreased in the caudalmost DRGs. Our results, in conjunction with previous observations, suggest that nNOS-IR neurons may be involved in the afferent transmission of visceral and nociceptive information as well as in the regulation of the vascular tone. PMID- 21538935 TI - Epithelial membrane protein 1 inhibits human spinal chondrocyte differentiation. AB - The molecular mechanisms underlying human spinal chondrocyte differentiation remain unclear. We recently demonstrated that epithelial membrane protein 1 (EMP1) is highly expressed in degenerative intervertebral discs. EMP1 is involved in the differentiation of multiple cell types, including progenitor/pre-B cells, neurons, and podocytes. Therefore, we hypothesize that EMP1 may participate in the differentiation of spinal chondrocytes. We cultured chondrocytes from human nucleus pulposus. Through lentivirus-mediated knockdown and overexpression of EMP1, we find that EMP1 promotes cell proliferation and survival, alters cell morphology and cell cycle, reduces cell condensation, and inhibits cell hypertrophy and the expression of chondrocyte maturation markers such as collagen X, aggrecan, sex-determining region Y (SRY)-box 9, and runt-related transcription factor 2. We also show that EMP1 is not expressed in the ossification center of vertebrae but is highly expressed in the nucleus pulposus and growth plate, where chondrocytes are immature and endochondral ossification has not occurred. These results suggest that EMP1 inhibits human spinal chondrocyte differentiation. PMID- 21538936 TI - Role of peg and socket junctions in stretch coupling in intestinal smooth muscle. PMID- 21538937 TI - Vertebral anomaly in fossil sea cows (Mammalia, Sirenia). AB - Four incompletely preserved caudal vertebrae lacking the neural arches of two fossil sirenian individuals of Halitherium schinzii (Oligocene) from the Rhine area in Germany and northern Belgium reveal osteological alterations. The caudal vertebrae possess a transverse process with growth retardation. This asymmetry indicates that the affected transverse processes are less developed than their counterparts and, consequently, deviate from the norm. Computed tomography (CT) scans reveal osteosclerotic patterns, a morphological feature that characterizes sea cows and supports the nonpathological state of the vertebrae. Additionally, no indications of vertebral fractures or any other occurrences due to external factors are present. This is the oldest documentation of such an anomaly in any sirenian and is interpreted here as hypoplasia, the underdevelopment of an organ or parts of it that might cause a functional deficiency. PMID- 21538938 TI - "Digit anatomy": a new technique for learning anatomy using motor memory. AB - Gestural motions of the hands and fingers are powerful tools for expressing meanings and concepts, and the nervous system has the capacity to retain multiple long-term motor memories, especially including movements of the hands. We developed many sets of successive movements of both hands, referred to as "digit anatomy," and made students practice the movements which express (1) the aortic arch, subclavian, and thoracoacromial arteries and their branches, (2) the celiac trunk, superior mesenteric artery and their branches, and formation of the portal vein, (3) the heart and the coronary arteries, and (4) the brachial, lumbar, and sacral plexuses. A feedback survey showed that digit anatomy was helpful for the students not only in memorizing anatomical structures but also in understanding their functions. Out of 40 students, 34 of them who learned anatomy with the help of digit anatomy were "very satisfied" or "generally satisfied" with this new teaching method. Digit anatomy that was used to express the aortic arch, subclavian, and thoracoacromial arteries and their branches was more helpful than those representing other structures. Although the movements of digit anatomy are expected to be remembered longer than the exact meaning of each movement, invoking the motor memory of the movement may help to make relearning of the same information easier and faster in the future. PMID- 21538939 TI - Anatomy as the backbone of an integrated first year medical curriculum: design and implementation. AB - Morehouse School of Medicine chose to restructure its first year medical curriculum in 2005. The anatomy faculty had prior experience in integrating courses, stemming from the successful integration of individual anatomical sciences courses into a single course called Human Morphology. The integration process was expanded to include the other first year basic science courses (Biochemistry, Physiology, and Neurobiology) as we progressed toward an integrated curriculum. A team, consisting of the course directors, a curriculum coordinator, and the Associate Dean for Educational and Faculty Affairs, was assembled to build the new curriculum. For the initial phase, the original course titles were retained but the lecture order was reorganized around the Human Morphology topic sequence. The material from all four courses was organized into four sequential units. Other curricular changes included placing laboratories and lectures more consistently in the daily routine, reducing lecture time from 120 to 90 minute blocks, eliminating unnecessary duplication of content, and increasing the amount of independent study time. Examinations were constructed to include questions from all courses on a single test, reducing the number of examination days in each block from three to one. The entire restructuring process took two years to complete, and the revised curriculum was implemented for the students entering in 2007. The outcomes of the restructured curriculum include a reduction in the number of contact hours by 28%, higher or equivalent subject examination average scores, enhanced student satisfaction, and a first year curriculum team better prepared to move forward with future integration. PMID- 21538941 TI - Overcoming in vivo barriers to targeted nanodelivery. AB - Nanoparticles have been investigated as promising nanocarriers for delivery of imaging and therapeutic agents for several decades, but have met with limited success. Although enormous progress in the fields of nanotechnology and nanoscience has been achieved, basic discoveries have not yet translated into effective targeted therapies. Nanoparticles can potentially improve the pharmacokinetics and pharmacodynamics of drugs; however, the complexity of in vivo systems imposes multiple barriers that severely inhibit efficiency and have to be overcome to fully exploit the theoretical potential of nanoparticles. Here, we address two major challenges to effective systemic nanodelivery. Both limited penetration across the vascular endothelium and uptake by the reticuloendothelial system (RES) substantially impede effectiveness of nanoparticle delivery into tissues. Although the design of nanoparticles with extended circulation half-life is essential, it is not sufficient for effective penetration of nanoparticles across the formidable barrier formed by the vascular endothelium. Current nanodelivery systems rely on passive transvascular exchange and tissue accumulation. They require high dosages to create large concentration gradients that drive nanoparticles passively across the blood-tissue interface. However, passive accumulation has resulted in only a fractional dosage of nanoparticles penetrating into target tissue. This inevitably diminishes therapeutic efficacy and aggravates potential side effects. Although there are multiple ways to augment passive delivery, active delivery of targeted nanoparticles across the vascular endothelium could significantly increase the therapeutic index and decrease side effects of nanoparticle-based drug delivery systems. Use of active transendothelial transport pathways, such as caveolae, may provide an effective solution to both target and deliver nanoparticles. PMID- 21538940 TI - MAOA, DBH, and SLC6A4 variants in CHARGE: a case-control study of autism spectrum disorders. AB - Genetic factors are established to contribute to the development of autism. We examined three loci, serotonin transporter (SLC6A4), dopamine beta-hydroxylase (DBH), and the variable number of tandem repeat promoter of the monoamine oxidase A (MAOA) for association with autism in participants from the Childhood Autism Risks from Genetics and the Environment (CHARGE ) Study, the first large-scale population-based case-control investigation of both environmental and genetic contributions to autism risk. Among male children enrolled in the CHARGE study we tested associations between each of the three polymorphisms and autism (AU) (n = 119), or a combined group of autism and other autism spectrum disorders (AU+ASD, which includes an additional n = 53) as compared with typically developing controls (TD, n = 137). The case-control association analysis showed neither SLC6A4 nor DBH to be statistically significantly associated with AU or ASD. However, the male children carrying 4 tandem repeats in the promoter region of the MAOA gene showed a two-fold higher risk of AU (or AU+ASD) than those carrying allele 3, adjusted for confounders (OR = 2.02, 95% CI = 1.12, 3.65, P = 0.02 for AU vs. TD, and OR = 2.05, 95% CI = 1.19, 3.53, P = 0.01 for ASD vs. TD). In addition, children of mothers homozygous for the 4 tandem repeat allele showed at least a three-fold higher risk of AU (or AU+ASD) than those with mothers homozygous for allele 3 (OR = 3.07, 95% CI = 1.19, 7.91, P = 0.02 for AU vs. TD, and OR = 3.26, 95% CI = 1.35, 7.89, P = 0.009 for AU+ASD vs. TD). These results suggest a potential role of the functional MAOA promoter alleles in the male child, the mother, or both in ASD. PMID- 21538943 TI - Guidelines for European workplace drug testing in oral fluid. AB - Over the past decade, oral fluid has established itself as a robust testing matrix for monitoring drug use or misuse. Commercially available collection devices provide opportunities to collect and test oral fluid by the roadside and near-patient testing with both clinical and criminal justice applications. One of the main advantages of oral fluid relates to the collection of the matrix which is non-invasive, simple, and can be carried out under direct observation making it ideal for workplace drug testing. Laboratories offering legally defensible oral fluid workplace drug testing must adhere to national and international quality standards (ISO/IEC 17025); however, these standards do not address issues specific to oral fluid testing. The European Workplace Drug Testing Society (EWDTS) recognizes the importance of providing best practice guidelines to organizations offering testing and those choosing to use oral fluid drug testing to test their employees. The aim of this paper is to present the EWDTS guidelines for oral fluid workplace drug testing. PMID- 21538942 TI - Spectophotometric methods for determination of cefdinir in pharmaceutical formulations via derivatization with 1,2-naphthoquinone-4-sulfonate and 4-chloro 7-nitrobenzo-2-oxa-1, 3-diazole. AB - Two new simple, sensitive, accurate, and precise spectrophotometric methods have been developed and validated for the determination of cefdinir (CFD) in bulk drug and in its pharmaceutical formulations. The first method was based on the reaction of CFD with 1, 2- napthaquinone-4- sulfonic acid sodium (NQS) in an alkaline medium (pH 11) to form an orange-coloured product that was measured at 490 nm. The second method depends on hydrolysis of CFD using 0.5 M NaOH at 100 degrees C and subsequent reaction of the formed sulfide ions with 4-chloro-7 nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) to form a yellow-coloured chromogen measured at 390 nm. Different variables affecting the reactions of CFD with both NQS and NBD-Cl (e.g. NaOH concentration, hydrolysis time, NQS or NBD-Cl concentration and diluting solvent) were studied and optimized. Under optimum conditions, good linear relationships with good correlation coefficients (0.9990 0.9999) were found in the range of 10-80 and 5.0-30 ug ml(-1) for NQS and NBD-Cl, respectively. The limits of assay detection and quantitation ranged from 1.097 and 0.280 and 3.656 and 0.934 ug ml(-1) for NQS and NBD-Cl, respectively. The accuracy and precision of the proposed methods were satisfactory. The proposed method is simple, rapid, precise and convenient and was successfully applied for analysis of CFD in its pharmaceutical formulations and the recovery percentages ranged from 99.25 to 100.20%. PMID- 21538944 TI - Investigations on changes in 13C/12C ratios of endogenous urinary steroids after pregnenolone administration. AB - For the detection of possible misuse of naturally occurring anabolic androgenic steroids like testosterone (T), anti-doping laboratories use a combination of two techniques. One is molecular steroid profiling to evaluate urinary steroid concentrations and normal diagnostic ratios. The other is isotope ratio mass spectrometry (IRMS), in which the 13C/12C ratios of target analytes like T are compared to the 13C/12C ratios of endogenous reference compounds (ERCs). The 13C/12C of the most commonly used ERC, pregnanediol (5beta-pregnane 3alpha,20alpha-diol, PD), can be influenced by administration of pregnenolone (3beta-hydroxy-pregn-5-en-20-one, PREG). Therefore PREG administration bears the potential to circumvent IRMS testing for doping control samples. In order to investigate the influence of PREG on PD and on other urinary excreted steroids, administration studies with oral and transdermal application of PREG were carried out. The influence of PREG administration on concentrations and 13C/12C ratios of all investigated target analytes was negligible. Only PD and 5beta-pregnan-3alpha ol-20-one (3aP) showed significant depletion in both their glucuronidated and sulfated steroids. The results suggest that appropriate alternative ERCs are: 11beta-hydroxy-androsterone/etiocholanolone, 5beta-pregnane-3alpha,17,20alpha triol, pregn-5-ene-3beta,17,20alpha-triol and cholesterol. Due to its properties to disguise the misuse of anabolic steroids by influencing the 13C/12C ratio of PD, PREG should be considered to be added to the World Anti-Doping Agency (WADA) list of prohibited substances as a masking agent. PMID- 21538945 TI - Subjective effects in humans following administration of party pill drugs BZP and TFMPP alone and in combination. AB - The use of piperazine derivatives, colloquially named 'party pills', has been escalating in New Zealand and worldwide since their introduction in the 1990s. Benzylpiperazine (BZP) is often used alone, or can be combined with trifluoromethylphenylpiperazine (TFMPP). Taken together as an oral dose, they have been reported to produce effects similar to 3, 4 methylenedioxymethamphetamine (MDMA). While the pharmacokinetic data have recently been published, little research has been conducted on the subjective effects of these piperazines on humans. This paper outlines the subjective effects observed following oral doses of BZP (200 mg) and TFMPP (60 mg) alone, or in combination (100/30 mg) compared to placebo. Participants were asked to comment on the subjective effects of each drug using three subjective rating scales-the Addiction Center Research Inventory (ARCI), the Profile of Mood States (POMS), and the Visual Analog Scales (VAS)-before and approximately 120 min after a single dose. BZP showed significant dexamphetamine-like stimulant effects, inducing euphoria, sociability, and drug liking, whereas TFMPP induced fewer stimulant-like effects and increased anxiety, via its serotonergic effects. The combination of BZP and TFMPP induced similar subjective effects, along with well characterized dexamphetamine- and MDMA-like effects. These subjective data allow for obvious comparisons to be made between party pill drugs and other commonly known stimulants. However, despite estimates of over 20 million doses sold in New Zealand alone and increasing seizures by the Drug Enforcement Administration in the USA, there are no published cases of dependence worldwide. The long-term effects of regular party pill use are also unknown, and create the potential for future research. PMID- 21538946 TI - Health-related quality of life of US adults with arthritis: analysis of data from the behavioral risk factor surveillance system, 2003, 2005, and 2007. AB - OBJECTIVE: To describe the health-related quality of life (HRQOL) of persons with and without arthritis in the 50 US states and the District of Columbia, and to determine correlates of poor HRQOL in persons with arthritis. METHODS: Data from the Behavioral Risk Factor Surveillance System were used. Descriptive analyses were age standardized and multivariate analyses used logistic regression. RESULTS: Of persons ages >=18 years with arthritis, 27% reported fair/poor health, compared to 12% without arthritis. The mean numbers of physically unhealthy, mentally unhealthy, and activity-limited days for persons with arthritis exceeded those for persons without arthritis. In regression analyses, black non-Hispanics reported better HRQOL than white non-Hispanics, especially in the >=14 versus 0 days comparisons. Yet no difference existed in self-reported health status between these two groups. Having a low family income and being unable to work were both strongly associated with poor HRQOL. Being physically active was associated with better HRQOL. Binge drinking was associated with poor HRQOL for some measures, but was associated with better self-reported health. Cost being a barrier to care and having diabetes mellitus were strongly associated with worse HRQOL. CONCLUSION: Adults from the US with arthritis had worse HRQOL than those without. Physical health and mental health were both affected by arthritis; therefore, efforts to alleviate the arthritis burden should address both domains. Given the current and projected high prevalence of arthritis, we face a significant burden of poor HRQOL. Increasing physical activity, reducing comorbidities, and increasing access to health care could improve the HRQOL of persons with arthritis. PMID- 21538947 TI - Male urethral Pap smears and peniscopy examination and polymerase chain reaction human papillomavirus correlation. AB - The aims of this study were to determine HPV in a male population and its correlation with penile gross inspection and urethral pap smears. Fifty male volunteers were included in the study; all of them were sexual partners of women with evidence of HPV-related cervical diseases. Urethral Pap smear features and polymerase chain reaction (PCR; HPV detection) of urethral samples were correlated. Statistical analyses were conducted to identify variables associated with high and low-risk HPV types. Mean age of participants was 33.14 +/- 1.52 (range, 23-50 years), and the mean age for those with high risk HPV was 32.12 +/- 6.66 and 34.08 +/- 6.58 for subjects with low-risk HPV (P = 0.820). Penile gross inspection revealed 19 (38%) cases with no lesions, papules in balanoprepusial furrol/sulcus in 23 (46%) cases, papilla in 23 (46%) cases, urethral lesions in 22 (44%) cases, penile body plaques in 22 (44%) cases, melanoses in 11 (22%) cases, sebaceous cysts on scrotum in 10 (20%) cases, and molting of the glands in 28 (56%) cases. Cytopathologic analysis revealed koilocytes in 24 (48%) cases. Dyskeratosis was observed in 24 (48%) cases. A bacterial background was found in 27 (54%) cases, and inflammatory cells were found in 27 (54%) cases. Twenty-six (52%) cases showed cytological features suggestive of Gardnerella Vaginalis. Twenty-four (48%) cases were high-risk HPV, and 26 (52%) were low-risk HPV (P = 0.037) as assessed by PCR-based detection. There was a statistically significant difference between koilocytes and bacterial background with high-risk human papillomavirus (P = 0.001). Abnormal colposcopy examination detected lesions were sampled for cytology by Pap smears. PMID- 21538948 TI - Diagnostic value of liquid-based (Liqui-PREP) preparations and interobserver reproducibility in fine needle aspiration cytology of the nodular thyroid lesions. AB - The aim of this study is to define the diagnostic role of Liqui-Prep (LP) technique for the diagnosis of thyroid lesions and to assess interobserver variabilities. In all, 98 thyroid FNA (fine needle aspiration) cytology samples from 83 patients for preoperative evaluation of thyroid nodules, prepared by the LP, were examined. The LP slides were independently evaluated by three pathologists and they were classified into the five categories according to the Bethesda system. The histopathologic diagnoses were grouped as follows: benign, follicular neoplasm, and malignant. Agreements between LP and histopathologic diagnoses were investigated using kappa values. Marginal homogenity and kappa tests were used for statistical analysis for the evaluation of the agreement between the pathologists and the interobserver variability of the thyroid aspiration cytology results. The presence of nucleoli, nuclear grooving, overlapping, intranuclear inclusion, and nuclear irregularity were recorded and scored on each case based on LP slide review. Concurrences between LP and the histologic diagnoses for the three pathologists were almost perfect (k = 0.798; k = 0.826; k = 0.880). When the observers were paired there was no significant difference from the diagnostic point of view. Interobserver agreement among the three pathologists was moderate. Initially diagnostic difficulties may occur because of the inadequate experience of the pathologists concerning the evaluation of the cytologic changes associated with this new technique. Liqui Prep technique is useful for the cytologic diagnosis of the thyroid nodules. The nuclear irregularity was the most essential feature for the differentiation of malignant lesions from follicular neoplasm by the LP method. PMID- 21538949 TI - Esophageal tuberculosis: EUS FNA diagnosis of uncommon presentation as a cystic lesion. PMID- 21538950 TI - Fine needle aspiration of vagal paraganglioma: an interesting clinical presentation. PMID- 21538951 TI - Prostatic adenocarcinoma metastatic to axillary lymph node diagnosed by fine needle aspiration biopsy. PMID- 21538953 TI - Fine-needle aspiration cytology of orbital meningiomas. AB - Meningiomas are benign tumors derived from arachnoid cells. Most commonly they arise within the cranial cavity, but they may arise extracranially in various anatomic sites. We present four cases of orbital meningiomas diagnosed on fine needle aspiration cytology (FNAC) and confirmed on histopathology. All the cases are presented with orbital mass. FNAC smears showed classical whorling and syncytial pattern of cells, with round to oval nucleus, inconspicuous nucleoli and one each case showed intranuclear inclusion and psammoma bodies. FNAC diagnosis of such lesions is difficult, because cytological features may mimic other soft tissue lesions located in orbital region. Awareness of this entity and its cytological appearance is important to allow correct diagnosis. PMID- 21538952 TI - The usefulness of S100P, mesothelin, fascin, prostate stem cell antigen, and 14-3 3 sigma in diagnosing pancreatic adenocarcinoma in cytological specimens obtained by endoscopic ultrasound guided fine-needle aspiration. AB - Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the pancreas is an efficient and minimally invasive procedure for the diagnosis and staging of pancreatic adenocarcinoma. Because of some limitations of EUS-FNA in diagnosis of well-differentiated or early stage cancers, the purpose of this study is to assess the added benefit of immunohistochemistry. We studied five proteins overexpressed in pancreatic adenocarcinoma, namely, prostate stem cell antigen, fascin, 14-3-3 sigma, mesothelin and S100P utilizing immunohistochemistry on paraffin sections from cellblocks obtained by EUS-FNA. Sixty-two cases of EUS-FNA of the pancreas that had follow-up histological and/or clinical diagnosis and sufficient material in cell blocks were included. Using histological diagnosis and/or clinical outcome as the reference standard, EUS-FNA shows the highest sensitivity (95%) and specificity (91%) and is superior to any marker in this study. Among five antibodies, S100P reveals the best diagnostic characters showing 90% of sensitivity and 67% of specificity. Fascin shows high specificity (92%) but low sensitivity (38%). Mesothelin has a moderate sensitivity (74%) and low specificity (33%), PSCA and 14-3-3 show high sensitivity but zero specificity. S100P and mesothelin were useful in nine indeterminate cases. S100P correctly predicted six of seven cancers and one of one without cancer and mesothelin correctly diagnosed five of seven cancers and one of two noncancers in this group. EUS-FNA cytomorphology is superior to any of the immunohistochemical markers used in this study. Use of S100P and mesothelin in cytologically borderline cases can increase the diagnostic accuracy in this group. PMID- 21538954 TI - (Cyto)pathology and sequencing: Next (or last) generation? PMID- 21538955 TI - Mullerianosis of the urinary bladder: report of a case with diagnosis suggested in urine cytology and review of literature. AB - Mullerianosis of the urinary bladder is a rare entity characterized by the presence of an admixture of at least two types of mullerian tissue in the muscularis propria of the bladder. We report a case of mullerianosis of the urinary bladder in a 28-year-old nulliparous woman with no history of pelvic surgery or endometriosis, and the diagnosis of mullerianosis was suggested initially in urine cytopathology report. In this study, previously reported cases of mullerianosis of urinary bladder are reviewed, and differential diagnosis of endometrial-like cells in the urine has been discussed. Fewer than 20 cases of mullerianosis of the urinary bladder have been reported in the literature, and only one of these cases had cytological description in a urine specimen. Most of patients were of reproductive age ranging from 28 to 53 years and had no previous history of pelvic surgery or Cesarean section. The clinical presentations frequently were abdominal/pelvic pain and dysuria/hematuria, which may or may not be associated with menstruation. Radiologic study revealed polypoid, mass-like lesion ranging from 1 to 4.5 cm in size, predominantly involving the dome or posterior wall of the bladder. Histological sections showed two or more of the three related benign mullerian glandular epithelial proliferations-endometriosis, endosalpingiosis, and endocervicosis. Most of the patients have good prognosis with medical management. PMID- 21538957 TI - Follow-up evaluation of radiation-induced DNA damage in CSF disseminated high grade glioma using phospho-histone H2AX antibody. AB - Cytological examination of cerebrospinal fluid (CSF) is used not only for the diagnosis of spinal disease, but also to assess the postoperative effect of treatment. We experienced a case of high-grade glioma in disseminated CSF, and retrospectively examined the clinical, pathological and cytological features. We further investigated radiation-induced DNA damage in glioma cells using phospho Histone H2AX antibody. A five-year-old boy received a clinical diagnosis of optic nerve glioma, and was followed-up for three months after chemotherapy. Magnetic resonance imaging was repeated, revealing abnormalities in other brain areas. The pathological diagnosis was anaplastic astrocytoma. CSF dissemination was detected, and increases in the number and mitosis of tumor cells were observed in CSF cytology. After radiotherapy the tumor cells in CSF decreased markedly. On cytomorphologic and immunocytochemical evaluation post-irradiation, tumor cells showed vacuolation of both the nucleus and cytoplasm, degeneration of nuclear chromatin, and alteration of the phospho-Histone H2AX expression, compared with tumor cells before the irradiation. CSF cytology is an effective means of evaluating DNA damage in tumor cells after irradiation, and may be useful in assessing the therapeutic response. PMID- 21538956 TI - Patterns of papillary thyroid carcinoma cells analyzed in fine-needle aspiration smears may reveal changes in tumor cell behavior. AB - Fine-needle aspiration (FNA) cytology is widely used to examine thyroid lesions. However, its diagnostic accuracy is limited by the narrow choice of cytopathologic markers indicative of invasive/metastatic powers of a tumor. The aim of this study was to identify features that may serve as such indicators. We have examined FNA smears of 50 histologically proven papillary thyroid carcinoma (PTC) cases applying computer-assisted morphometry to assess patterns formed by PTC cells. Cytokeratine (CK) 8 immunocytochemistry was used to verify the epithelial origin of cells under study. All analyzed smears contained blood, histiocyte-like cells and CK8-positive follicular cells occurring both as single cells and in monolayer cell sheets. In 60% of cases we revealed cell sheets displaying two distinct cell patterns. The first one (pattern R) consisted of moderately pleomorphic, rather regularly arranged cells having an amphophilic cytoplasm. The second one (pattern I) was formed by highly pleomorphic cells with a basophilic cytoplasm. Patterns R and I were clearly different in cell size and shape as well as in nuclear size and shape. These patterns were never observed within the same cell sheet indicating that they may be formed by different subclones of tumor cells. Thus, it can be concluded that PTC frequently displays two definitely different cell patterns. We think that these patterns have a potential to serve as indicators for early events of an invasive/metastatic process. It remains to be seen whether the simultaneous occurrence of these patterns is a PTC-specific feature. PMID- 21538958 TI - Isolated leishmanial lymphadenopathy - a rare type of leishmaniasis in India: a case report. AB - A patient presented with isolated, soft to firm, inguinal swelling since childhood clinically thought to be a benign lipomatous lesion. Fine-needle aspiration of the swelling revealed amastigote form of Leishmania donovani in a background of reactive lymphoid hyperplasia. Excision of the swelling resulted in reversal of positive Aldehyde test. Isolated leishmanial lymphadenopathy in an immunocompetent person, is a rare manifestation of leishmaniasis in India. The possible role of transplacental transmission is discussed. PMID- 21538959 TI - Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of mediastinal lymph nodes: experience from region with high prevalence of tuberculosis. AB - Utility of EUS-FNA in diagnosing granulomatous lesions of mediastinum in regions with high prevalence of tuberculosis has not yet been evaluated. In the present study, utility and limitations of EUS-FNA of mediastinal lesions from a tertiary care center with high prevalence of tuberculosis were studied. All cases where EUS-FNA had been performed to diagnose mediastinal lymphadenopathy from January 2006 to December 2008 were retrieved from the files of cytopathology laboratory. These were reviewed by the cytopathologist. Two hundred and eighty one EUS-FNA aspirates from 269 patients were evaluated. Satisfactory aspirates were available in 259 cases. A cytological diagnosis of granulomatous lymphadenitis was rendered in 206 cases. Of these, tuberculosis could be established as an etiology in 76 cases and sarcoidosis in 7 cases only. In remaining 123 cases the etiology of granulomatous lymphadenitis could not be established and clinical correlation was suggested. Malignancies were diagnosed or suspected in 24 and 5 cases, respectively. The study highlights that the dilemma of tuberculosis versus sarcoidosis persists in regions with high prevalence of tuberculosis. However, EUS-FNA is useful in diagnosing unsuspected malignancies and confirming the presence of granulomatous lymphadenitis. PMID- 21538960 TI - Talc crystals in pleurodesis-associated talc granuloma. PMID- 21538961 TI - Chronic organizing retroperitoneal abscess caused by Klebsiella oxytoca masquerading as sarcoma: recognition by Diff-Quik stain on FNA material. PMID- 21538962 TI - Molluscum contagiosum of the cervix. PMID- 21538963 TI - Group consensus review minimizes the diagnosis of "follicular lesion of undetermined significance" and improves cytohistologic concordance. AB - We conducted a group consensus review of thyroid aspirates that were previously interpreted as "atypia of undetermined significance/follicular lesion of undetermined significance" (AUS/FLUS) and followed by surgical interventions. The study aimed to investigate if consensus review would minimize the diagnosis of AUS/FLUS with an optimal interobserver agreement and also promote a better cytohistologic concordance. A group of reviewers who were blinded to the corresponding histologic findings simultaneously evaluated a total of 50 aspirates at a multiheaded light microscope. Using the Bethesda System for Reporting Thyroid Cytopathology as a guideline, a consensus interpretation was reached upon review of each aspirate. Interobserver agreement was calculated and recorded. The cytohistologic correlation was then performed between the consensus interpretation and the corresponding histologic diagnosis. The consensus review reclassified 26 (52%) aspirates as non-neoplasia/benign, 10 (20%) as follicular neoplasm/suspicious for a follicular neoplasm, 1 (2%) as papillary thyroid carcinoma, and 2 (4%) as nondiagnostic. Eleven (22%) aspirates remained AUS/FLUS. The interobserver agreement across the five diagnostic categories ranged from 71.6% to 100% with an average level of 88.8%. Cytohistologic concordance was achieved in 24 of 26 (92.3%) and 9 of 11 (81.8%) aspirates that were reclassified as non-neoplasia/benign and neoplasia/malignancy, respectively. A diagnostic accuracy of 89.2% (33/37) was obtained in reclassified cases. In conclusion, the group consensus review minimized AUS/FLUS, offered an optimal level of interobserver agreement, and most importantly, promoted excellent cytohistologic concordance in reclassified cases and, therefore, could play a substantial role in the future in reducing reaspiration and/or unnecessary surgeries. PMID- 21538964 TI - Smear patterns and spectrum of premalignant and malignant cervical epithelial lesions in postmenopausal Indian women: a hospital-based study. AB - Cervical cancer is one of the leading causes of morbidity and mortality among women but can be prevented through simple cost-effective measures, such as creating awareness, and regular screening with the Pap smear, both in the premenopausal and postmenopausal age group. This study was carried out to study the cervical smear patterns and type of cervical epithelial lesions in a group of postmenopausal Indian females and the relationship with clinical profile of patients. Pap smears were taken from 320 postmenopausal Indian females and meticulously screened. Lesions were classified according to type of postmenopausal pattern. 120 smears showed varying degrees of premalignant and malignant changes, which were classified using the Bethesda system. The findings were correlated with duration of menopause, parity, and duration of sexual activity and significance was derived. Histopathological correlation was conducted in those cases where biopsies were available. It was found that as the age of the patients increased, the incidence of low-grade and high-grade squamous intraepithelial lesions and carcinoma also increased with the relationship being statistically significant. The occurrence of these lesions also showed an association with increasing parity and period of sexual activity. Thus, it can be concluded that it is important to create widespread awareness about the necessity of regular screening, including the postmenopausal period. Conventional cytology or the Pap smear is a cost-effective and efficient method for screening of patients but requires training and experience to minimize errors. It is suitable for developing regions where costlier techniques are not in routine use. PMID- 21538965 TI - Fine-needle aspiration cytology of low-grade adenosquamous carcinoma of the breast. PMID- 21538966 TI - The triage efficacy of fine needle aspiration biopsy for follicular variant of papillary thyroid carcinoma using the Bethesda reporting guidelines. AB - Diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC) by ultrasound-guided fine-needle aspiration (FNA) is challenging. In this retrospective review, we evaluated triage efficacy (i.e., potential for triggering surgical intervention) in 44 archived FNA biopsies of surgically confirmed FVPTC obtained between December 2006 and December 2008. We compared the original FNA diagnoses with reclassified diagnoses based on 2007 National Cancer Institute (NCI)/Bethesda recommendations, and reviewed FNA cytologic features. Original FNA diagnoses included colloid nodule (7%, 3/44), atypical follicular cells (5%, 2/44), follicular lesion (11%, 5/44), follicular neoplasm (16%, 7/44), suspicious for malignancy/PTC (27%, 12/44), and papillary thyroid carcinoma (34%, 15/44). Reclassified diagnoses included indeterminate (5%, 2/44), colloid nodule (7%, 3/44), atypical cells of undetermined significance [ACUS] (7%, 3/44), Hurthle cell neoplasm (2%, 1/44), follicular neoplasm (7%, 3/44), suspicious for malignancy/PTC (25%, 11/44), and PTC (48%, 21/44). Triage efficacy was 77% (34/44) for original diagnoses versus 82% (36/44) for reclassified FNA diagnoses. We frequently observed cytologic features of PTC, such as nuclear grooves and fine chromatin; conversely, intranuclear inclusions, though present in 77% cases, were scant. Our review findings suggest that lack of characteristic cytologic features of PTC,coexistence with other thyroid lesions, and small tumor size arethe major obstacles to FNA diagnosis of FVPTC. Reclassification of thyroid FNA diagnoses does not significantly improve triage efficacy. Furthermore, FNA diagnoses of follicular neoplasm and suspicious for malignancy are valuable in patients with FVPTC because they trigger triage toward surgical intervention. PMID- 21538967 TI - Bilateral hilar lymphadenopathy due to Chlamydia pneumoniae infection. AB - We here report a 5-year-old boy who presented with cough and bilateral hilar lymphadenopathy with a family history of sarcoidosis. The laboratory investigations did not confirm this diagnosis. The child was serologically proven to have Chlamydia pneumoniae infection. He responded well to a course of erythromycin resulting in complete resolution of his symptoms and the presenting radiographic findings on his initial chest X-ray. Pediatr. Pulmonol. 2011; 46:1038-1040. (c) 2011 Wiley-Liss, Inc. PMID- 21538968 TI - Cardiopulmonary function and oxygen delivery during total liquid ventilation. AB - INTRODUCTION: Total liquid ventilation (TLV) with perfluorocarbons has shown to improve cardiopulmonary function in the injured and immature lung; however there remains controversy over the normal lung. Hemodynamic effects of TLV in the normal lung currently remain undetermined. This study compared changes in cardiopulmonary and circulatory function caused by either liquid or gas tidal volume ventilation. METHODS: In a prospective, controlled study, 12 non-injured anesthetized, adult New Zealand rabbits were primarily conventionally gas ventilated (CGV). After instrumentation for continuous recording of arterial (AP), central venous (CVP), left artrial (LAP), pulmonary arterial pressures (PAP), and cardiac output (CO) animals were randomized into (1) CGV group and (2) TLV group. In the TLV group partial liquid ventilation was initiated with instillation of perfluoroctylbromide (12 ml/kg). After 15 min, TLV was established for 3 hr applying a volume-controlled, pressure-limited, time-cycled ventilation mode using a double-piston configured TLV. Controls (CGV) remained gas-ventilated throughout the experiment. RESULTS: During TLV, heart rate, CO, PAP, MAP, CVP, and LAP as well as derived hemodynamic variables, arterial and mixed venous blood gases, oxygen delivery, PVR, and SVR did not differ significantly compared to CGV. CONCLUSIONS: Liquid tidal volumes suitable for long-term TLV in non-injured rabbits do not significantly impair CO, blood pressure, and oxygen dynamics when compared to CGV. PMID- 21538969 TI - Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome. AB - An unavoidable outcome of cystic fibrosis newborn screening (CF NBS) programs is the detection of infants with an indeterminate diagnosis. The United States CF Foundation recently proposed the term cystic fibrosis transmembrane conductance regulator related metabolic syndrome (CRMS) to describe infants with elevated immunoreactive trypsinogen (IRT) on NBS who do not meet diagnostic criteria for CF. The objective of this study was to describe the clinical outcomes of infants with CRMS identified through an IRT/DNA algorithm. We reviewed the records of all infants with CRMS diagnosed at our CF Center from 2002 to 2010. We identified 12 infants, and compared them to 27 infants diagnosed with CF by NBS. Compared to CF patients, CRMS patients were more likely to be pancreatic sufficient as assessed by fecal elastase measurement (100% vs. 8%, P < 0.01). Their weight for age percentile was normal from birth. A positive oropharyngeal (OP) culture for Pseudomonas aeruginosa (Pa) was found in 25% of CRMS patients. One patient with the F508del/R117H/7T genotype was reassigned the diagnosis of CF after he had a positive OP culture for Pa, and his follow up sweat Cl at 1 year of life was 73 mmol/L. CF patients were more likely to receive oral antibiotics and be hospitalized for pulmonary symptoms. Our results indicate that CRMS patients can develop signs of CF disease, but have a milder clinical course than CF infants. Close initial monitoring of these patients is warranted. Pediatr. Pulmonol. 2011; 46:1079-1084. (c) 2011 Wiley Periodicals, Inc. PMID- 21538970 TI - Passive multivariable temperature and conductivity RFID sensors for single-use biopharmaceutical manufacturing components. AB - Single-use biopharmaceutical manufacturing requires monitoring of critical manufacturing parameters. We have developed an approach for passive radio frequency identification (RFID)-based sensing that converts ubiquitous passive 13.56 MHz RFID tags into inductively coupled sensors. We combine several measured parameters from the resonant sensor antenna with multivariate data analysis and deliver unique capability of multiparameter sensing and rejection of environmental interferences with a single sensor. We demonstrate here the integration of these RFID sensors into single-use biopharmaceutical manufacturing components. We have tested these sensors for over 500 h for measurements of temperature and solution conductivity with the accuracy of 0.1 degrees C (32-48 degrees C range) and accuracy of 0.3-2.9 mS/cm (0.5-230 mS/cm range). We further demonstrate simultaneous temperature and conductivity measurements with an individual RFID sensor with the accuracy of 0.2 degrees C (5-60 degrees C range) and accuracy of 0.9 mS/cm (0.5-183 mS/cm range). Developed RFID sensors provide several important features previously unavailable from other single-use sensing technologies such as the same sensor platform for measurements of physical, chemical, and biological parameters; multi-parameter monitoring with individual sensors; and simultaneous digital identification. PMID- 21538971 TI - Efficient suspension bioreactor expansion of murine embryonic stem cells on microcarriers in serum-free medium. AB - Large numbers of cells will be required for successful embryonic stem cell (ESC) based cellular therapies or drug discovery, thus raising the need to develop scaled-up bioprocesses for production of ESCs and their derived progeny. Traditionally, ESCs have been propagated in adherent cultures in static flasks on fibroblasts layers in serum-containing medium. Direct translation of two dimensional flatbed cultures to large-scale production of the quantities of cells required for therapy simply by increasing the number of dishes or flasks is not practical or economical. Here, we describe successful scaled-up production of ESCs on microcarriers in a stirred culture system in a serum-free medium. Cells expanded on CultiSpher S, Cytodex 3, and Collagen microcarriers showed superior cell-fold expansions of 439, 193, and 68, respectively, without excessive agglomeration, compared with 27 in static culture. In addition, the ESCs maintained their pluripotency after long-term culture (28 days) in serum-free medium. This is the first time mESCs have been cultured on microcarriers without prior exposure to serum and/or fibroblasts, while also eliminating the excessive agglomeration plaguing earlier studies. These protocols provide an economical, practical, serum-free means for expanding ESCs in a stirred suspension bioprocess. PMID- 21538972 TI - Alkaline peroxide assisted wet air oxidation pretreatment approach to enhance enzymatic convertibility of rice husk. AB - Pretreatment of rice husk by alkaline peroxide assisted wet air oxidation (APAWAO) approach was investigated with the aim to enhance the enzymatic convertibility of cellulose in pretreated rice husk. Rice husk was presoaked overnight in 1% (w/v) H(2)O(2) solution (pH adjusted to 11.5 using NaOH) (equivalent to 16.67 g H(2)O(2) and 3.63 g NaOH per 100 g dry, untreated rice husk) at room temperature, followed by wet air oxidation (WAO). APAWAO pretreatment resulted in solubilization of 67 wt % of hemicellulose and 88 wt % of lignin initially present in raw rice husk. Some amount of oligomeric glucose (~8.3 g/L) was also observed in the APAWAO liquid fraction. APAWAO pretreatment resulted in 13-fold increase in the amount of glucose that could be obtained from otherwise untreated rice husk. Up to 86 wt % of cellulose in the pretreated rice husk (solid fraction) could be converted into glucose within 24 hours, yielding over 21 g glucose per 100 g original rice husk. Scanning electron microscopy was performed to visualize changes in biomass structure following the APAWAO pretreatment. Enzymatic cellulose convertibility of the pretreated slurry at high dry matter loadings was also investigated. PMID- 21538973 TI - Recombinant monomeric CD40 ligand for delivering polymer particles to dendritic cells. AB - Dendritic cells (DCs) are considered the most efficient antigen-presenting cells and are therefore ideal targets for in vivo delivery of antigen for vaccines. We are investigating the strategy of using CD40 ligand (CD40L) as a targeting moiety because this protein has the potential to not only target DCs, but also stimulate cell maturation, leading to more potent immune responses. We have shown that a recombinant, monomeric CD40 ligand fusion protein conjugated to polystyrene micro and nanoparticles led to significantly enhanced uptake by DCs in vitro. This enhancement was observed for particles of both sizes and in both a murine DC cell line and primary DCs. The uptake appeared to be specifically mediated by CD40L binding to CD40 expressed on DCs. Enhanced uptake of nanoparticles in draining lymph nodes of mice was not observed, however, 48 hours after subcutaneous injection. These findings suggest that CD40 ligand may be a potentially useful targeting moiety for delivery of particulate vaccines to DCs, and that further optimization of both CD40L and the polymer carriers is necessary to achieve efficacy in vivo. PMID- 21538974 TI - Development and implementation of a perfusion-based high cell density cell banking process. AB - A perfusion-based high cell density (HD) cell banking process has been developed that offers substantial advantages in time savings and simplification of upstream unit operations. HD cell banking provides the means to reduce the time required for culture inoculum expansion and scale-up by eliminating the need for multiple small to intermediate scale shake flask-based operations saving up to 9 days of operation during large-scale inoculum expansion. HD perfusion cultures were developed and optimized in a disposable Wave bioreactor system. Through optimization of perfusion rate, rocking speed and aeration rate, the perfusion system supported peak cell densities of >20 * 10(6) cells/mL while maintaining high cell viability (>= 90%). The cells were frozen at HD (90-100 * 10(6) viable cells/mL) in 5-mL CryoTube vials. HD cell banks were demonstrated to enable direct inoculation of culture into a Wave bioreactor in the inoculum expansion train thus eliminating the need for intermediate shake flask expansion unit operations. The simplicity of the disposable perfusion system and high quality of the cell banks resulted in the successful implementation in a 2000 L scale manufacturing facility. PMID- 21538975 TI - Integrated use of ultra scale-down and financial modeling to identify optimal conditions for the precipitation and centrifugal recovery of milk proteins. AB - This article investigates the integrated application of ultra scale-down (USD) techniques and economic modeling as a means for identifying optimal bioprocess operating conditions. The benefits of the approach are illustrated for the recovery of lactoperoxidase (LPO) from bovine milk. In the process, milk is skimmed to deplete its lipid content, before being subjected to low pH incubation with acetic acid in order to precipitate the primary impurity (casein). Following removal of the solids by disk stack centrifugation, pH adjustment and filtration, cation exchange chromatography is used as a positive mode column step to bind the LPO before it is polished and freeze dried. An economic model of this process was used to identify where greatest product loss occurs and hence where the largest opportunity cost was being incurred. Scale-down analysis was used to characterize the influence of the critical steps, identified as precipitation and centrifugation, upon LPO recovery. A mathematical model was used to relate the centrifuge feed flowrate and discharge interval to the supernatant yield, and it was shown that increasing the centrifugal solids residence time achieved superior solids de-watering and so higher product yield, although this also increased the overall processing time. To resolve this conflict, scale-down data were used again in conjunction with an economic model to determine the most suitable conditions that maximized annual profit and minimized operating costs. The results demonstrate the power of combining USD data with models of economic and process performance in order to establish the best overall operating strategies for biopharmaceutical manufacture. PMID- 21538976 TI - Enhancing hypericin production of Hypericum perforatum cell suspension culture by ozone exposure. AB - Accumulation of secondary metabolites is one of the common reactions of plants to ozone exposure in nature. To investigate the effect of ozone on the production of desired compounds of plant cell cultures, we assayed hypericin production of Hypericum perforatum suspension cell cultures treated with different doses of ozone at different culture phases. The results show that hypericin contents of the cells treated with 60 to 180 nL L(-1) ozone are significantly higher than those of the control, showing that ozone exposure may stimulate hypericin synthesis. Hypericin production of the cells treated with ozone at exponential phase is higher than that of lag and stationary phase, which suggests that exponential phase cell cultures are more responsive to ozone exposure than lag and stationary phase cells. The highest hypericin production is obtained by the cells exposed to 90 nL L(-1) ozone at late exponential phase for 3 h, being about fourfold of the control. PMID- 21538977 TI - The subcellular location of antigen expressed by adenoviral vectors modifies adaptive immunity but not dependency on cross-presenting dendritic cells. AB - Adenoviral (Ad) vaccine vectors can generate protective immunity to various pathogens in animal studies. However, recent failures in clinical vaccine trials have underscored the need for a better understanding of how mucosal immune responses to Ad-encoded vaccine Ags are generated in vivo. In this study, we addressed whether directing Ad-encoded ovalbumin (OVA) to different subcellular compartments influences the generation of OVA-specific acquired immunity and the APCs required following i.n. immunization of mice. We show that both secreted and membrane-anchored OVA activate CD4(+) T cells, induce cytotoxic CD8(+) T lymphocytes (CTLs) and generate serum IgG. Additionally, vaginal IgG is induced when OVA is expressed at these subcellular locations, but only the secreted form generates a significant IgA response in the lungs. On the contrary, intracellular expression of OVA efficiently expands CD8(+) T cells but fails to activate CD4(+) T cells, results in poor CTL activity, and does not generate Abs. Finally, we show that regardless of the subcellular localization of OVA, conventional DCs (cDCs) are required for the activation of T cells. However, the direct transduction of conventional DCs is not essential. These findings have important implications for the improvement of Ad vector design and vaccine-induced mucosal immunity. PMID- 21538978 TI - Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material. AB - Necrosis is a characteristic feature of advanced solid tumors. Released necrotic factors, also referred to as damage associated molecular patterns (DAMPs), are known to critically impact the tumor microenvironment by enhancing angiogenesis or influencing the immune response. We have recently shown that DAMPs can act as chemoattractants and activators of granulocytes. We demonstrate that necrotic material from both normal and tumor cells promotes proliferation and trafficking of human mesenchymal stem cells (MSCs). We characterize the protein high mobility group box 1 (HMGB1) as a crucial member of DAMPs within necrotic material. In addition, we show that DAMPs interfere with expression of indoleamine 2, 3 dioxygenase (IDO) in MSCs. The biological activity of necrotic material toward MSCs is abolished once these DAMPs are oxidized. MSCs found within tumor tissue can act as immunoregulatory cells and are able to promote tumor metastasis, thus playing a crucial role within the tumor microenvironment. Here, we reveal DAMPs to be crucial factors in the setting of MSC biology within the tumor microenvironment. The tumor microenvironment is characterized by reducing and hypoxic conditions that protect DAMPs from oxidation. Based on our results, oxidizing conditions should be considered for therapeutic approaches that target the tumor microenvironment. PMID- 21538979 TI - Structural insights into the binding of hepatitis B virus core peptide to HLA-A2 alleles: towards designing better vaccines. AB - Binding of specific antigenic peptides with human leukocyte antigen (HLA) molecules is a prerequisite for the initiation of T-cell responses and structural information about the peptide-HLA complex is essential for the detailed understanding of such interactions. HLA-A2 is the most prevalent HLA allele globally but aside from A*02:01 there is a significant lack of crystal structures, particularly for alleles that occur in high frequencies among Asian populations. Here, we report three HLA-A2 structures with the immunodominant hepatitis B core antigen 18-27 (HBcAg18-27) epitope, namely A*02:03, A*02:06, and A*02:07 at resolutions of 2.16, 1.70, and 1.75 A respectively. This comparative analysis reveals that minor polymorphic residue changes between different HLA alleles can induce significant alterations in the major histocompatibility complex-peptide interface, and introduce conformational changes in the p3-p8 peptide region. Circular dichroism analysis demonstrated the HLA-A2-peptide complexes to have a hierarchy of thermostability and binding affinity in the order of A*02:06>A*02:07>A*02:01>A*02:03. Our findings provide structural insights into the varied HLA-A2 allele binding of the hepatitis B core antigen 18 27 epitope and the data suggest that chemical modifications of the peptide side chains could be a promising strategy to modulate and improve HLA-A2-peptide binding affinity for vaccine design. PMID- 21538980 TI - Genotyping of single nucleotide polymorphism in gamma-glutamyl hydrolase gene by capillary electrophoresis. AB - The gamma-glutamyl hydrolase (GGH) gene plays an important role in methotrexate (MTX) metabolism, ensuring that MTX polyglutamates (MTX-(Glu)(n)) could be converted back into MTX. Accumulation of MTX-(Glu)(n) is a problem in MTX therapy. SNP 452 C>T has been reported to associate with lower catalytic activity and higher accumulation of long-chain MTX-(Glu)(n) in patients treated with higher doses of MTX treatment. We propose and establish a simple and effective CE method for detecting SNP in GGH gene. The DNA samples after amplification were analyzed by SSCP-CE method. The CE conditions were generated by using 1* TBE buffer containing 1.5% w/v hydroxypropyl methyl cellulose under reverse polarity at 25 degrees C. This method was applied to detect genotyping of acute lymphoblastic leukemia patients receiving MTX treatment. The results were confirmed by DNA sequencing with good agreement. Concentrations of MTX-(Glu)(n) in whole blood were analyzed by on-line stacking CE method. MTX-(Glu)(n) levels and genotypes in GGH gene of acute lymphoblastic leukemia patients were evaluated. The SSCP-CE method was found to be feasible for SNP screening in the GGH gene. PMID- 21538981 TI - Use of multiple reaction monitoring for multiplex analysis of colorectal cancer associated proteins in human feces. AB - Colorectal cancer (CRC) is the second most common cause of cancer-related deaths worldwide with an annual incidence of almost a million cases and an annual mortality around 500,000. The fecal occult blood test is currently the first line method for CRC screening, but has unacceptably low sensitivity and specificity. Improved screening tests are therefore urgently required for early-stage CRC screening when therapy is most likely to be effective. We describe a discovery based proteomics hypothesis using orthogonal multi-dimensional fractionation (1-D SDS-PAGE, RP-HPLC, size exclusion chromatography) to mine deep into the fecal proteome for the initial discovery process, which generated a library containing 108 human fecal proteins with the associated peptide and MS/MS data. These data were then used to develop and optimize a multiplex multiple reaction monitoring assay for 40 non-redundant human proteins present in the feces. To show proof of principal for clinical analysis, multiplex screening of these 40 proteins was carried out on fecal samples from eight CRC patient and seven normal volunteers. We identified 24 proteins consistently found in all samples and nine proteins found only in the CRC patients, showing the potential of this approach for the analysis of potential CRC biomarkers. Absolute quantitation using C-terminal isotopically labeled synthetic peptides corresponding to hemoglobin and carcinoembryonic antigen 5 was also performed. PMID- 21538982 TI - Electrokinetic transport through nanochannels. AB - This article presents a numerical study of the electrokinetic transport phenomena (electroosmosis and electrophoresis) in a three-dimensional nanochannel with a circular cross-section. Due to the nanometer dimensions, the Boltzmann distribution of the ions is not valid in the nanochannels. Therefore, the conventional theories of electrokinetic flow through the microchannels such as Poisson-Boltzmann equation and Helmholtz-Smoluchowski slip velocity approach are no longer applicable. In the current study, a set of coupled partial differential equations including Poisson-Nernst-Plank equation, Navier-Stokes, and continuity equations is solved to find the electric potential field, ionic concentration field, and the velocity field in the three-dimensional nanochannel. The effects of surface electric charge and the radius of nanochannel on the electric potential, liquid flow, and ionic transport are investigated. Unlike the microchannels, the electric potential field, ionic concentration field, and velocity field are strongly size-dependent in nanochannels. The electric potential gradient along the nanochannel also depends on the surface electric charge of the nanochannel. More counter ions than the coions are transported through the nanochannel. The ionic concentration enrichment at the entrance and the exit of the nanochannel is completely evident from the simulation results. The study also shows that the flow velocity in the nanochannel is higher when the surface electric charge is stronger or the radius of the nanochannel is larger. PMID- 21538983 TI - Electrophoretic detection of genetic variability among Schistosoma japonicum isolates by sequence-related amplified polymorphism. AB - In the present study, sequence-related amplification polymorphism (SRAP) was utilized to study the genetic variability among Schistosoma japonicum isolates from different provinces in China, using Schistosoma mansoni from Puerto Rico for comparison. Five out of ten tested SRAP primer combinations displayed significant polymorphisms among S. japonicum isolates from China, namely ME2/EM1, ME4/EM1, ME4/EM6, ME5/EM4 and ME5/EM5. Analysis of the 61 S. japonicum samples from China with five SRAP primer combinations identified a total of 83 reproducible polymorphic fragments. The number of fragments using each primer combination ranged from 14 to 19, with an average of 16 polymorphic bands per primer pair, and the size of fragment ranged approximately from 100 to 1000 bp. Representative specific SRAP fragments were excised from the gels, and confirmed by PCR amplification of genomic DNA using primers designed and based on the sequences of these SRAP fragments. Based on SRAP profiles, unweighted pair-group method with arithmetic averages (UPGMA) dendrogram was constructed. UPGMA clustering algorithm categorized S. japonicum isolates from China into nine clades and two lineages (representing the mountainous and lake/marshland regions). These results indicate the usefulness of the SRAP technique for revealing genetic variability among S. japonicum isolates from China, and the SRAP technique should be applicable to other living organisms. PMID- 21538984 TI - A flexible genome-wide bootstrap method that accounts for ranking and threshold selection bias in GWAS interpretation and replication study design. AB - The phenomenon known as the winner's curse is a form of selection bias that affects estimates of genetic association. In genome-wide association studies (GWAS) the bias is exacerbated by the use of stringent selection thresholds and ranking over hundreds of thousands of single nucleotide polymorphisms (SNPs). We develop an improved multi-locus bootstrap point estimate and confidence interval, which accounts for both ranking- and threshold-selection bias in the presence of genome-wide SNP linkage disequilibrium structure. The bootstrap method easily adapts to various study designs and alternative test statistics as well as complex SNP selection criteria. The latter is demonstrated by our application to the Wellcome Trust Case Control Consortium findings, in which the selection criterion was the minimum of the p-values for the additive and genotypic genetic effect models. In contrast, existing likelihood-based bias-reduced estimators account for the selection criterion applied to an SNP as if it were the only one tested, and so are more simple computationally, but do not address ranking across SNPs. Our simulation studies show that the bootstrap bias-reduced estimates are usually closer to the true genetic effect than the likelihood estimates and are less variable with a narrower confidence interval. Replication study sample size requirements computed from the bootstrap bias-reduced estimates are adequate 75 90 per cent of the time compared to 53-60 per cent of the time for the likelihood method. The bootstrap methods are implemented in a user-friendly package able to provide point and interval estimation for both binary and quantitative phenotypes in large-scale GWAS. PMID- 21538985 TI - Discrete-time semi-Markov modeling of human papillomavirus persistence. AB - Multi-state modeling is often employed to describe the progression of a disease process. In epidemiological studies of certain diseases, the disease state is typically only observed at periodic clinical visits, producing incomplete longitudinal data. In this paper we consider fitting semi-Markov models to estimate the persistence of human papillomavirus (HPV) type-specific infection in studies where the status of HPV type(s) is assessed periodically. Simulation study results are presented indicating that the semi-Markov estimator is more accurate than an estimator currently used in the HPV literature. The methods are illustrated using data from the HIV Epidemiology Research Study. PMID- 21538986 TI - Alternative methods for testing treatment effects on the basis of multiple outcomes: simulation and case study. AB - In clinical trials multiple outcomes are often used to assess treatment interventions. This paper presents an evaluation of likelihood-based methods for jointly testing treatment effects in clinical trials with multiple continuous outcomes. Specifically, we compare the power of joint tests of treatment effects obtained from joint models for the multiple outcomes with univariate tests based on modeling the outcomes separately. We also consider the power and bias of tests when data are missing, a common feature of many trials, especially in psychiatry. Our results suggest that joint tests capitalize on the correlation of multiple outcomes and are more powerful than standard univariate methods, especially when outcomes are missing completely at random. When outcomes are missing at random, test procedures based on correctly specified joint models are unbiased, while standard univariate procedures are not. Results of a simulation study are reported, and the methods are illustrated in an example from the Clinical Antipsychotic Trials of Intervention Effectiveness for schizophrenia. PMID- 21538987 TI - Nanoparticle-enabled selective electrodeposition. PMID- 21538988 TI - Transparent, thermally stable and mechanically robust superhydrophobic surfaces made from porous silica capsules. PMID- 21538989 TI - TiO2 anatase nanoparticle networks: synthesis, structure, and electrochemical performance. AB - Nanocrystalline anatase TiO(2) materials with different specific surface areas and pore size distributions are prepared via sol-gel and miniemulsion routes in the presence of surfactants. The samples are characterized by X-ray diffraction, nitrogen sorption, transmission electron microscopy, and electrochemical measurements. The materials show a pure anatase phase with average crystallite size of about 10 nm. The nitrogen sorption analysis reveals specific surface areas ranging from 25 to 150 m(2) g(-1) . It is demonstrated that the electrochemical performance of this material strongly depends on morphology. The mesoporous TiO(2) samples exhibit excellent high rate capabilities and good cycling stability. PMID- 21538990 TI - Graphene growth via carburization of stainless steel and application in energy storage. AB - A modified version of the carburization process, a widely established technique used in the steel industry for case hardening of components, is used for the growth of graphene on stainless steel. Controlled growth of high-quality single- and few-layered graphene on stainless steel (SS) foils through a liquid-phase chemical vapor deposition (CVD) technique is reported. Reversible Li intercalation in these graphene-on-SS structures is demonstrated, where graphene and SS act as electrode and current collector, respectively, providing very good electrical contact. Direct growth of an active electrode material, such as graphene, on current-collector substrates makes this a feasible and efficient process for developing thin-film battery devices. PMID- 21538991 TI - An insight into the mechanism of CEC separation of template analogues on a norepinephrine-imprinted monolith. AB - A monolith molecularly imprinted polymer (MIP) column was prepared from template (-)-norepinephrine, functional monomer (itaconic acid), and a cross-linker (either ethylene glycol dimethacrylate or divinylbenzene) in porogen N,N dimethylformamide. Understanding the molecular recognition of a template using an MIP seems feasible. However, it is hard to explain the recognition properties of their analogues on an MIP. The separation mechanism was investigated with the addition of charged surfactants, native and derivatised beta-cyclodextrin (beta CD), achiral crown ether, etc. to determine the retention behaviour of the template analogues. The addition of organic modifiers and the adjustment of separation conditions were used to manipulate the selectivity. No chiral recognition was observed under most of the test conditions except the experiment with the charged beta-CD on the divinylbenzene-MIP column. The different experimental conditions led to differences in the mobilities of the analytes and resulted in remarkable enantiomeric separation of the template. We confirmed the presence of mixed-mode selectivity of the stationary phase based on hydrogen bonding, hydroelectric and hydrophobic interactions, and the electrophoretic mode. PMID- 21538992 TI - Online coupling of molecularly imprinted solid-phase extraction to HPLC for determination of trace tetracycline antibiotic residues in egg samples. AB - An automated system has been developed for the determination of trace tetracycline antibiotics (TCs) in egg samples, based on online molecularly imprinted solid-phase extraction (MISPE) coupling with high-performance liquid chromatography (HPLC). Oxytetracycline and chlortetracycline were chosen as mixed templates to synthesize highly selective molecularly imprinted polymers for online extraction. Under the optimal online MISPE-HPLC condition, 10 mL egg samples were injected into the MISPE column and then the matrix was washed out. By rotating the switching valve, TCs were transferred to the analytical column and then separated by HPLC. Because sample pretreatment and chromatographic separation were carried out simultaneously, the whole analytical time (18 min) was significantly shortened compared with conventional offline techniques. The detection limits ranged from 0.8 to 1.3 ng/g. The enhancement factors were in the range of 159-410. The spiked recoveries of TCs in real egg samples ranged from 91.6 to 107.6% and the relative standard deviations (RSDs) were not higher than 4.0%. PMID- 21538993 TI - Modelling by partial least squares the relationship between the HPLC mobile phases and analytes on phenyl column. AB - Twenty-five descriptors and 61 structurally different analytes have been used on a partial least squares (PLS) to latent structure technique in order to study chromatographically their interaction mechanism on a phenyl column. According to the model, 240 different retention times of the analytes, expressed as Y variable (log k), at different % MeOH mobile-phase concentrations have been correlated with their theoretical most important structural or molecular descriptors. The goodness-of-fit was estimated by the coefficient of multiple determinations r(2) (0.919), and the root mean square error of estimation (RMSEE=0.1283) values with a predictive ability (Q(2)) of 0.901. The model was further validated using cross validation (CV), validated by 20 response permutations r(2) (0.0, 0.0146), Q(2) (0.0, -0.136) and validated by external prediction. The contribution of certain mechanism interactions between the analytes, the mobile phase and the column, proportional or counterbalancing is also studied. Trying to evaluate the influence on Y of every variable in a PLS model, VIP (variables importance in the projection) plot provides evidence that lipophilicity (expressed as Log D, Log P), polarizability, refractivity and the eluting power of the mobile phase are dominant in the retention mechanism on a phenyl column. PMID- 21538994 TI - Preinvasive colorectal lesion transcriptomes correlate with endoscopic morphology (polypoid vs. nonpolypoid). AB - Improved colonoscopy is revealing precancerous lesions that were frequently missed in the past, and ~30% of those detected today have nonpolypoid morphologies ranging from slightly raised to depressed. To characterize these lesions molecularly, we assessed transcription of 23,768 genes in 42 precancerous lesions (25 slightly elevated nonpolypoid and 17 pedunculated polypoid), each with corresponding samples of normal mucosa. Nonpolypoid versus polypoid morphology explained most gene expression variance among samples; histology, size, and degree of dysplasia were also linked to specific patterns. Expression changes in polypoid lesions frequently affected cell-cycling pathways, whereas cell-survival dysregulation predominated in nonpolypoid lesions. The latter also displayed fewer and less dramatic expression changes than polypoid lesions. Paradigmatic of this trend was progressive loss through the normal > nonpolypoid > polypoid > cancer sequence of TMIGD1 mRNA and protein. This finding, along with TMIGD1 protein expression patterns in tissues and cell lines, suggests that TMIGD1 might be associated with intestinal-cell differentiation. We conclude that molecular dysregulation in slightly elevated, nonpolypoid, precancerous colorectal lesions may be somewhat less severe than that observed in classic adenomatous polyps. PMID- 21538995 TI - IL-28A (IFN-lambda2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease. AB - IL-28 (IFN-lambda) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL-28 cytokine family members were found to be profoundly down-regulated in allergic asthma. We now reveal a novel role of IL-28 cytokines in inducing type 1 immunity and protection from allergic airway disease. Treatment of wild-type mice with recombinant or adenovirally expressed IL-28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN-gamma. Moreover, abrogation of endogenous IL-28 cytokine function in IL-28Ralpha(-/-) mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL-28A immunoregulatory activity was its capacity to modulate lung CD11c(+) dendritic cell (DC) function to down-regulate OX40L, up-regulate IL-12p70 and promote Th1 differentiation. Consistently, IL-28A-mediated protection was absent in IFN-gamma(-/-) mice or after IL-12 neutralization and could be adoptively transferred by IL-28A-treated CD11c(+) cells. These data demonstrate a critical role of IL-28 cytokines in controlling T cell responses in vivo through the modulation of lung CD11c(+) DC function in experimental allergic asthma. PMID- 21538996 TI - Observations of cardiac beating behaviors of wild-type and mutant Drosophilae with optical coherence tomography. AB - Time-resolved optical coherence tomography (OCT) scanning images of wild-type and mutant fruit flies (Drosophila melanogaster), illustrating the heartbeat patterns for evaluating their cardiac functions, are demonstrated. Based on the heartbeat patterns, the beat rate and the relative phase between the first two heart segments can be evaluated. The OCT scanning results of mutant flies with impaired proteasome function in cardiac muscles show irregular heartbeat patterns and systematically decreased average beat rates, when compared with the regular patterns of ~4.97 beats/s in average beat rate of the wild-type. In both wild type and proteasome mutant flies, the beatings at different locations in the same heart segment are essentially synchronized. However, between different heart segments, although the beating in the second segment shows a lag in phase behind that of the first segment in a wild-type, in a proteasome mutant, the beating in the second segment becomes significantly leading that of the first segment. Besides the comparison between the wild-type and proteasomal mutant flies, the influences of using different methods for immobilizing flies during OCT scanning on the heart functions are demonstrated. PMID- 21538997 TI - Trafficking of drug candidates relevant for sports drug testing: detection of non approved therapeutics categorized as anabolic and gene doping agents in products distributed via the Internet. AB - Identifying the use of non-approved drugs by cheating athletes has been a great challenge for doping control laboratories. This is due to the additional complexities associated with identifying relatively unknown and uncharacterized compounds and their metabolites as opposed to known and well-studied therapeutics. In 2010, the prohibited drug candidates and gene doping substances AICAR and GW1516, together with the selective androgen receptor modulator (SARM) MK-2866 were obtained by the Cologne Doping Control Laboratory from Internet suppliers and their structure, quantity, and formulation elucidated. All three compounds proved authentic as determined by liquid chromatography-high resolution/high accuracy (tandem) mass spectrometry and comparison to reference material. While AICAR was provided as a colourless powder in 100 mg aliquots, GW1516 was obtained as an orange/yellow suspension in water/glycerol (150 mg/ml), and MK-2866 (25 mg/ml) was shipped dissolved in polyethylene glycol (PEG) 300. In all cases, the quantified amounts were considerably lower than indicated on the label. The substances were delivered via courier, with packaging identifying them as containing 'amino acids' and 'green tea extract', arguably to circumvent customs control. Although all of the substances were declared 'for research only', their potential misuse in illicit performance-enhancement cannot be excluded; moreover sports drug testing authorities should be aware of the facile availability of black market copies of these drug candidates. PMID- 21538998 TI - Determination of 6-mercaptopurine in the presence of uric acid using modified multiwall carbon nanotubes-TiO2 as a voltammetric sensor. AB - In this work, a multiwall carbon nanotubes modified electrode (prepared by incorporating TiO(2) nanoparticles with p-aminophenol as a mediator) was used as voltammetric sensor for the determination of 6-mercaptopurine (6-MP) in the presence of uric acid (UA). The voltammograms of 6-MP and UA in a mixture can be separated from each other by differential pulse voltammetry with a potential difference of 380 mV at a scan rate of 10 mV s(-1). These conditions are sufficient to allow for the determination of 6-MP and UA both individually and simultaneously. The electrocatalytic currents increase linearly with 6-MP concentration in the ranges of 0.09-350 umol L(-1) (two linear segments with different slopes). The detection limit for 6-MP was 0.065 umol L(-1) . The RSD% for 1.0 and 15.0 umol L(-1) 6-MP were 0.7%, and 1.2%, respectively. The kinetic parameters of the system were determined using electrochemical approaches. The method was successfully applied for the determination of 6-MP in drug sample, and 6-MP plus UA in urine samples. PMID- 21538999 TI - Determination of pethidine hydrochloride using potentiometric coated graphite and carbon paste electrodes. AB - A new approach for lowering the detection limit of a pethidine ion-selective electrode is presented. A coated graphite (CGE) and carbon paste (CPE) electrodes for pethidine ions based on pethidine-phosphotungstate (PD-PT) as ion-pair complex are described. The sensors exhibit a Nernstian slope of 58.1 and 54.2 mVdecade(-1) for pethidine ion over a wide concentration range from 2.6 * 10(-7) to 1.0 * 10(-2) M and 2.1 * 10(-6) to 1.0 * 10(-2) M with a detection limit of 1.8 * 10(-7) M and 7.3 * 10(-7) M for pethidine coated graphite (PD-CGE) and pethidine carbon paste electrode (PD-CPE), respectively. These sensors exhibited a fast response time (about 5-8 s) and good stability. The standard electrode potentials, E(o) , were determined at different temperatures and used to calculate the isothermal temperature coefficient (dE(o) /dT) of the PD-CGE and PD CPE, which was 0.0062 and 0.0071 V/ degrees C, respectively. Selectivity coefficients, determined by matched potential method (MPM) and separate solution method (SSM), showed high selectivity for pethidine hydrochloride (PDCl) over a large number of inorganic cations, organic cations, sugars, urine components, and some common drug excipients. The sensors were applied for determination of PDCl in ampoule and in spiked urine samples using potentiometric determination, standard addition and the calibration curve methods. The results obtained were satisfactory with excellent percentage recovery comparable and sometimes better than those obtained by other routine methods for the assay. PMID- 21539000 TI - Prediction of polar surface area of drug molecules: a QSPR approach. AB - A quantitative structure-property relationship (QSPR) study based on an artificial neural network (ANN) was carried out for the prediction of the microemulsion liquid chromatography polar surface area (PSA) of a set of 32 drug compounds. The genetic algorithm-kernel partial least squares (GA-KPLS) method was used as a variable selection tool. A KPLS method was used to select the best descriptors and the selected descriptors were used as input neurons in neural network model. For choosing the best predictive model from among comparable models, square correlation coefficient Q(2) for the whole set calculated based on leave-group-out predicted values of the training set and model-derived predicted values for the test set compounds is suggested to be a good criterion. Finally, to improve the results, structure-property relationships were followed by nonlinear approach using artificial neural networks and consequently better results were obtained. Also this demonstrates the advantages of ANN. PMID- 21539001 TI - Single and mixed chemically modified carbon paste ion-selective electrodes for determination of ketotifen fumarate. AB - New modified carbon paste electrodes for determination of ketotifen fumarate in its pure and pharmaceutical preparations were constructed. The used modifiers are ketotifen phosphotungestate (Keto(3) PT), and ketotifen tetraphenylborate (Keto TPB). Single and mixed ion-associate electrodes were prepared. Both Keto-TPB and mixed (Keto-TPB and Keto(3) PT) electrodes have a linearity range of 1.00 * 10( 5) -1.00 * 10(-2) mol L(-1) . The slopes were 58.30 and 54.20 mV/decade for Keto TPB and mixed chemically modified carbon paste electrodes (CMCPE), respectively. The limits of detection were 1.42 * 10(-6) and 1.00 * 10(-5) mol L(-1) for Keto TPB and mixed CMCPEs, respectively. The potential variation due to pH change is considered acceptable in the pH ranges 4.44-9.11 and 2.50-9.00 for Keto-TPB and mixed ion-exchanger CMCPE, respectively. The response time was <=10 s for both electrodes. Selectivity coefficients values towards different inorganic cations, sugars, and amino acids reflect high selectivity of the prepared electrodes. Potentiometric titrations and standard addition methods were applied for the determination of ketotifen ion in its pure samples and pharmaceutical formulations (Zaditen tablet and syrup) using proposed electrodes. The electrodes were also tested in flow injection analysis (FIA). The results obtained from both methods were statistically treated by F- and t-tests. The carbon paste electrodes have the advantages of being more easily prepared and longer life span compared to the plastic membrane electrodes previously reported. PMID- 21539002 TI - Dynamics of GABArho2 receptors in retinal bipolar neurons and cerebellar astrocytes. AB - Gamma-aminobutyric acid (GABA)rho receptors are selectively targeted to the axon terminals of the retinal bipolar neurons. The traffic of a green fluorescent protein-tagged GABArho2 was examined in retinal bipolar neurons and cerebellar astrocytes. In bipolar neurons, time-lapse laser confocal microscopy revealed that the fluorescence emitted by GABArho2-green fluorescent protein accumulates first, in clusters, in the soma and is then distributed along the axon in at least two populations: one that remains relatively immobile and a second population of smaller clusters that moved constantly to and from the axon end. In astrocytes, the fluorescent clusters were relatively immobile and located mainly in the soma. PMID- 21539004 TI - Retraction. An innovative noninvasive respiratory stress test indicates significant coronary artery disease. PMID- 21539005 TI - Frontiers in membrane and membrane protein biophysics. Proceedings of a symposium and Festschrift to honor Stephen H White on his 70th birthday. August 19-20, 2010. Irvine, California, USA. PMID- 21539003 TI - Hippocampal volume is related to body mass index in Alzheimer's disease. AB - Obesity is associated with lower brain volumes in early Alzheimer's disease, but its effects on hippocampal volumes are unclear, as weight loss is also associated with Alzheimer's disease. To address this question, we applied an automated hippocampal mapping method to brain MRI scans for 162 patients with Alzheimer's disease. We hypothesized that obesity, measured by body mass index, would be associated with lower hippocampal volumes in mildly affected patients. Statistical maps showed a selective pattern of hippocampal volume differences that were significantly associated with body mass index. Associations were detected in the anterior hippocampus, and confirmed by permutation testing. Cardiovascular risk factors, such as high body mass index, may promote additional neurodegenerative changes, and should therefore be considered in epidemiological studies and clinical trials. PMID- 21539006 TI - Introducing insulin into diabetes management: transition strategies for older adults. AB - Many older adults with type 2 diabetes require insulin to supplement or replace oral hypoglycemic control. Overtime, the addition of this more intensive therapy is needed to preserve beta cell function or prevent macrovascular sequelae. This is the result of the natural progression of diabetes and not a failure on the part of the patient. Clinicians must evaluate many factors in an attempt to individualize a safe optimal glycemic level for older adults. Considerations should include when insulin should be initiated, the type of insulin and regimen, and a safe individualized target goal while preventing hypoglycemia. Important in this decision are the patients comorbid condition, functional and cognitive status, social environment, financial ability, and life expectancy. The risks and benefits of more stringent glycemic control must be considered in the context of treatment options, priorities, and quality-of-life issues for both the patient and family. PMID- 21539007 TI - UK moves to ensure "access to unlicensed herbal medicines". PMID- 21539008 TI - Native American health left out in the cold. PMID- 21539009 TI - 17th-century childbirth: "exquisite torment and infinite grace". PMID- 21539010 TI - The legacies of Francis Galton. PMID- 21539011 TI - Response to vitamin D supplementation during Antarctic winter is related to BMI, and supplementation can mitigate Epstein-Barr Virus Reactivation. AB - Maintaining vitamin D status without sunlight exposure is difficult without supplementation. This study was designed to better understand interrelationships between periodic vitamin D supplementation and immune function in Antarctic workers. The effect of 2 oral dosing regimens of vitamin D supplementation on vitamin D status and markers of immune function was evaluated in people in Antarctica with no UV light exposure for 6 mo. Participants were given a 2000-IU (50 MUg) daily (n = 15) or 10,000-IU (250 MUg) weekly (n = 14) vitamin D supplement for 6 mo during a winter in Antarctica. Biological samples were collected at baseline and at 3 and 6 mo. Vitamin D intake, markers of vitamin D and bone metabolism, and latent virus reactivation were determined. After 6 mo, the serum 25-hydroxyvitamin D concentration (mean +/- SD) increased from 56 +/- 17 to 79 +/- 16 nmol/L and from 52 +/- 10 to 69 +/- 9 nmol/L in the 2000-IU/d and 10,000-IU/wk groups, respectively (main effect over time, P < 0.001). Participants with a greater BMI (participant BMI range = 19-43 g/m2) had a smaller increase in 25-hydroxyvitamin D after 6-mo supplementation (P < 0.05). Participants with high serum cortisol and higher serum 25-hydroxyvitamin D were less likely to shed Epstein-Barr virus in saliva (P < 0.05). The doses given raised vitamin D status in participants not exposed to sunlight for 6 mo, and the efficacy was influenced by baseline vitamin D status and BMI. The data also provide evidence that vitamin D, interacting with stress, can reduce risk of latent virus reactivation during the winter in Antarctica. PMID- 21539012 TI - Will the Affordable Care Act make health insurance affordable? AB - Using a budget-based approach to measuring affordability, this issue brief explores whether the subsidies available through the Affordable Care Act are enough to make health insurance affordable for low-income families. Drawing from the Consumer Expenditure Survey, the authors assess how much "room" people have in their budget, after paying for other necessities, to pay for health care needs. The results show that an overwhelming majority of households have room in their budgets for the necessities, health insurance premiums, and moderate levels of out-of-pocket costs established by the Affordable Care Act. Fewer than 10 percent of families above the federal poverty level do not have the resources to pay for premiums and typical out-of-pocket costs, even with the subsidies provided by the health reform law. Affordability remains a concern for some families with high out-of-pocket spending, suggesting that this is the major risk to insurance affordability. PMID- 21539013 TI - Three nurses take the lead on change. PMID- 21539015 TI - Gifts bring a little bit of cheer. PMID- 21539014 TI - Surgical scheduling: taking an important role to the next level. PMID- 21539016 TI - What would a new constitution mean? PMID- 21539017 TI - Private health sector good for patients. PMID- 21539018 TI - Sexual health of gay men and other men who have sex with men. Proceedings of the HIV/STD Prevention Plus Conference. April 2010. Boston, Massachusetts, USA. PMID- 21539019 TI - Direct measurement of electron transfer distance decay constants of single redox proteins by electrochemical tunneling spectroscopy. AB - We present a method to measure directly and at the single-molecule level the distance decay constant that characterizes the rate of electron transfer (ET) in redox proteins. Using an electrochemical tunneling microscope under bipotentiostatic control, we obtained current-distance spectroscopic recordings of individual redox proteins confined within a nanometric tunneling gap at a well defined molecular orientation. The tunneling current decays exponentially, and the corresponding decay constant (beta) strongly supports a two-step tunneling ET mechanism. Statistical analysis of decay constant measurements reveals differences between the reduced and oxidized states that may be relevant to the control of ET rates in enzymes and biological electron transport chains. PMID- 21539020 TI - Menstruation matters: introduction to representations of the menstrual cycle. PMID- 21539021 TI - Anthropological fantasies in the debate over cycle-stopping contraception. PMID- 21539022 TI - "Not done yet?!" Women discuss the "end" of menopause. PMID- 21539023 TI - The egg, sperm, and beyond: gendered assumptions in gynecology textbooks. PMID- 21539024 TI - I, being born woman and suppressed. PMID- 21539025 TI - Between classical and popular: the book of tea and the popularization of tea drinking culture in the Tang China. PMID- 21539026 TI - Ethos groceries and countercultural appetites: consuming memory in Whole Foods' brand utopia. PMID- 21539027 TI - China's new-age small farms and their vertical integration: agribusiness or co ops? AB - The future of Chinese agriculture lies not with large mechanized farms but with small capital-labor dual intensifying family farms for livestock-poultry-fish raising and vegetable-fruit cultivation. Chinese food consumption patterns have been changing from the old 8:1:1 pattern of 8 parts grain, 1 part meat, and 1 part vegetables to a 4:3:3 pattern, with a corresponding transformation in agricultural structure. Small family-farming is better suited for the new-age agriculture, including organic farming, than large-scale mechanized farming, because of the intensive, incremental, and variegated hand labor involved, not readily open to economies of scale, though compatible with economies of scope. It is also better suited to the realities of severe population pressure on land. But it requires vertical integration from cultivation to processing to marketing, albeit without horizontal integration for farming. It is against such a background that co-ops have arisen spontaneously for integrating small farms with processing and marketing. The Chinese government, however, has been supporting aggressively capitalistic agribusinesses as the preferred mode of vertical integration. At present, Chinese agriculture is poised at a crossroads, with the future organizational mode for vertical integration as yet uncertain. PMID- 21539028 TI - HIV discharge planning: from correctional setting to community care in Mississippi. PMID- 21539029 TI - Documenting symptoms for use in potential disability claims. PMID- 21539030 TI - An unusual case: malignant fibrous histiocytoma in HIV. PMID- 21539031 TI - Treatment. HAART may increase risk of stroke in HIV-infected. PMID- 21539032 TI - Research. HIV-infected have more pregnancies, more complications. PMID- 21539033 TI - Study reveals irreversible rapid aging of 'helper' T-cells. PMID- 21539034 TI - Therapy. Direct purchasers may proceed with claims against Abbott. PMID- 21539035 TI - SSI. HIV-positive mother of 3 not motivated to work, says ALJ. PMID- 21539036 TI - Evidence is mounting that HIV infection accelerates aging process. Clinicians need to emphasize wellness. PMID- 21539037 TI - Computerized HIV intervention is effective. It takes nothing away from MD time. PMID- 21539038 TI - Same-sex teen behavior much higher than thought. Numbers almost doubled from prior studies. PMID- 21539039 TI - Hospitals, EDs miss many HIV-infected individuals. Study calls for routine HIV testing. PMID- 21539040 TI - HIV increase in black men not a surveillance artifact. Increased testing does not account for case surge. PMID- 21539042 TI - FDA notifications. DHHS panel releases new ART guidelines. PMID- 21539041 TI - FDA notifications. FDA approves new atazanavir labeling. PMID- 21539043 TI - FDA notifications. Fixed dose ART approved by FDA. PMID- 21539044 TI - Food masquerade. AB - Radishes cut to look like roses, watermelons carved into fruit baskets, apples made into swans, cakes frosted to look like dolls-when did this game of food masquerade start and how? This essay speculates about food's on-going history of disguise, of pretending to be what it's not. From the Renaissance courtier's delight in confections disguised as beasts, birds, and other fancies to our present day fascination with Japanese bento lunch boxes, food masquerade would seem to be a fanciful part of the history of food.Food masquerade injects some levity into our growing seriousness about food, our suspicion that most supermarket food is riddled with toxins and bad karma. It proposes that eating food should be fun. Food masquerade also gets to the very heart of artistic visual representation: the magical transformation of paint, clay or wood into an image of something else. It is a synecdoche for art itself. PMID- 21539045 TI - Mealtime at a Tibetan monastery. AB - With assistance from lay volunteers and using a giant stove, Tibetan monks at Longen monastery in rural Qinghai province China prepare and serve meals for several hundred of their peers during the summer retreat. In the past, rugged geography and the isolation of this monastery above 13,000 feet gave reasons for the monks to eat local meat since other foodstuffs were unavailable in an area unable to support agriculture beyond herding animals, chiefly yaks and cows. However, closer contact with the outside has allowed the monks to adopt a vegetarian diet, but one that still uses local resources such as yoghurt and wild sweet potatoes. PMID- 21539046 TI - The cultural politics of eating in Shenzhen. AB - Throughout the 1980s and early 1990s, construction in Shenzhen symbolized both the transformation of Chinese socialism and the concomitant integration of Chinese society into global capitalist networks. This article tells the story of Shenzhen from the perspective of this first generation of immigrants, the so called Old Shenzheners, who use nostalgia about food to define, debate, and ultimately retreat from conversations about what Shenzhen culture was and what it ought to be. Their food nostalgia is part of a larger cultural tradition of Chinese alimentary politics and has allowed Shenzheners to indigenize capitalist globalization to make the city their own. Old Shenzheners' food nostalgia represents an important moment in the Chinese transition to a post socialist political economy, redefining what it means to be both Chinese and global in a post-cold war world order. PMID- 21539048 TI - Upgrading the local: Belgian cuisine in global waves. AB - This essay touches upon questions about the use of food as an identity marker, the nature of local food, and the influence of foreign food. Since 1830, Belgium witnessed two international food waves that alternated with two local food waves, both opposing as well as using each other's characteristics. In this process, local food was continuously redefined. Belgium reveals a relationship between local and foreign food both in the sense of incorporation and exclusion. Foreign food always influenced local cooking and eating. The opposition between the "self" and the "other" is at times strongly upheld: local food is labeled as "our," "authentic," "national," or "regional" (the "self") to make the difference with "their," "artificial," or "international" (the "other"). This classification of foodways as national/regional is used to forge sentiments of belonging, especially in Belgium where strong separatist political feelings lead to intense regional reactions. PMID- 21539047 TI - On the tomato trail: in search of ancestral roots. AB - A profile of Roger Chetelat, the director of the C.M. Rick Tomato Genetics Resource Center at the University of California, Davis. Chetelat maintains one of the largest collections of tomato seeds in the world. Many of those seeds come from wild tomato species that Chetelat and his associates collect on field research trips to the dry coastal areas of Chile, Peru, and Ecuador. Wild tomatoes are tough, versatile organisms that have evolved resistance to virtually all common tomato diseases and pests and stubbornly tolerate extreme environmental conditions. Some boast extraordinarily high levels of sugars, beta carotene, vitamin C, lycopene, and antioxidants. Chetelat has dedicated his career to finding and preserving these genetic riches. Modern cultivated tomatoes are a frail, inbred lot. They all trace their origins to a single, wild tomato plant that underwent a random mutation sometime in prehistory. Because of this genetic fluke, that plant's fruits were plump, juicy, and many, many times larger than the output of its progenitors. Offspring from that tomato were taken away from the Andes and domesticated in what is present-day Mexico, becoming severed from their wild ancestors and the vast pool of genetic diversity that tomatoes had evolved over the millennia. Botanists call this a "bottleneck." It leaves subsequent generations susceptible to disease and unable to adjust to rapid climate changes. The stored wild seeds at the Rick Center enable plant breeders to re-incorporate desirable wild traits into new tomato varieties, literally reconnecting them to their ancestral roots, ensuring that this vast reservoir of genetic diversity will be available when it is needed. PMID- 21539049 TI - The tomato queen of San Joaquin. AB - The life of Tillie Lewis exemplifies key moments in American food history from the rise of the canning industry to wartime rations to the craze for diet food. Her biography was consciously manipulated and fashioned through the years to make it a quintessential rags-to-riches story. Nonetheless, her accomplishments stand out, marking her as a brilliantly successful woman in an industry dominated by men. PMID- 21539050 TI - Food porn. AB - Since the term first appeared, food porn has typically referred to watching others cook on television or gazing at unattainable dishes in glossy magazines without actually cooking oneself. This forum seeks to revisit this notion of food porn that is mostly taken for granted in both popular and scholarly literature. It offers a brief perspective of the appearance and use of the term food porn to examine how it came to be a term used mostly by commentators rather than by people actively engaged in the world of cooking. Practitioners (chefs and a food television producer) and academics address whether or not food porn exists, what shape it might take, what purpose it might serve, and/or what usefulness it might have, showing that these contentious issues are more complex than the ease with which the term is used might let on. PMID- 21539051 TI - Jean-Baptiste Labat and the buccaneer barbecue in seventeenth-century Martinique. AB - If, as the sociologist Pierre L. van den Berghe has suggested, cuisine is a significant expression of man's sociability, one might say that the seventeenth century missionary Jean-Baptiste Labat was the single most social animal in the Caribbean islands in the 1690s. Although his primary responsibility on the island of Martinique was to serve the island's multiethnic population as a spiritual leader, le pere Labat's memoirs chronicle the diverse culinary experiences of the missionary as he literally eats his way around the island, learning to prepare such delicacies as cocoa confit, roasted manatee, lizard en brochette, and parakeet en daube. Positing his unbridled interest in the culinary arts as a mark of his "obedience" to the duties assigned him as missionary, Labat's taxonomy of island delicacies and exotic tastes no doubt titillated the curiosity of his mainland readers while nevertheless grounding itself strongly in the values of order, authenticity, and industry so essential to Labat's apostolic mission. This article focuses on two "buccaneer barbecues" as examples of gastronomical experiences through which Labat was able to construct and negotiate new social, cultural, and symbolic meanings, exploring identity politics through the frame of the culinary arts in seventeenth-century Martinique. PMID- 21539052 TI - Conviviality in Catalonia. AB - Food, essential to social interaction everywhere, has particular importance in the regeneration of this rural community in Catalonia. The misery of the Civil War in Spain was followed by three decades of rural depopulation and economic decline, but a gradual return to the countryside since the 1980s has encouraged the revival of villages like Mieres. Food and drink play a fundamental role in the fiestas, fairs, and other celebrations that pack the public calendar, creating and sustaining social interaction and rebuilding a sense of community. PMID- 21539053 TI - Like your labels? AB - The descriptive "conventions" used on food labels are always evolving. Today, however, the changes are so complicated (partly driven by legislation requiring disclosures about environmental impacts, health issues, and geographical provenance) that these labels more often baffle buyers than enlighten them. In a light-handed manner, the article points to how sometimes reading label language can be like deciphering runes-and how if we are familiar with the technical terms, we can find a literal meaning, but still not see the implications. The article could be ten times longer because food labels vary according to cultures but all food-exporting cultures now take advantage of our short attention-span when faced with these texts. The question is whether less is more-and if so, in this contest for our attention, what "contestant" is voted off. PMID- 21539054 TI - Culinary nationalism. AB - Culinary consciousness raisers, cooking texts often serve as vehicles of national identification. From Pampille (Marthe Allard Daudet) and her cookbook, Les Bons Plats de France, in 1913 to the international culinary competitions of today such as the Bocuse d'or, culinary distinction promotes national interests. In contrast to the strident nationalism of the early twentieth century, culinary nationalism today operates in an increasingly globalized world. National culinary distinction defines the nation and sells its products in a highly competitive international arena. A recent culinary text, the South Korean film Le Grand Chef [Sik Gaek ] (2007), illustrates the phenomenon, subsuming national culinary promotion in a mega culinary competition, all in the service of Korean culinary achievement. PMID- 21539055 TI - Silver lining: building a shared Sudanese identity through food. AB - The displaced of Sudan, due to both decades of civil war and natural disasters, are disproportionately female and many are responsible for dependents. For those settling in the capital, Khartoum, their livelihood depends on carving out ways to earn money in an urban area that is experiencing tremendous growth from the millions of recent arrivals. When confronted with the immediate need to provide for their families, women turn to a skill universally expected of them: cooking. Therefore, Khartoum is home to a thriving micro-economy of food vendors. By selling these dishes in the capital, they broaden the culinary horizons of the city while preserving their own food traditions. Their growing numbers provide an opportunity for regional foodways to gain wider introduction, adaptation, and, finally, adoption. These same vendors also facilitate a nascent sense of a shared Sudanese identity and nationalism. For established Khartoum urbanites, the definition of Sudanese food (and, by extension, what it means to be Sudanese) expands as street-vendor fare moves to restaurants and becomes more widely available throughout the city. As urban Sudanese overcome their preconceptions and discover a taste for regional cuisines, meals function as unofficial diplomacy during this turbulent time in Sudan's history. PMID- 21539056 TI - The color of hay: the peasants of Maramures. PMID- 21539057 TI - Discovering terroir in the world of chocolate. AB - The author investigates the applicability of the word "terroir" to chocolate. As a Master of Wine, wine journalist, and wine educator, the author has tried to understand how "terroir," the environmental and human factors associated with growing vines and making wine, impacts the flavor of wine. Comparing and contrasting viticulture and winemaking to cacao farming and chocolate manufacture, the author analyzes to what degree terroir could be a concept that informs chocolate appreciation. He notes that the great distances between cacao farms and factories encourage the perception of cacao and chocolate as commodities. He observes that the varietal and origin nomenclature of cacao can be at worst misleading and generally lacks clarity and precision. He shows how the many steps that transform cacao into chocolate threaten the expression of terroir in the final product. Yet he acknowledges that there could be a basis for use of the word in the world of cacao and chocolate. PMID- 21539058 TI - "Guinomi". AB - In the West, pottery is usually deemed "craft" rather than "art" and has long existed near the bottom of the aesthetic hierarchy. In Japan, to the contrary, pottery is among the most highly regarded forms of art, in great part due to its role in the Zen-inspired Tea ceremony. Because the Tea ceremony effectively creates a link between several art forms (landscape, architecture, poetry, calligraphy, pottery, cuisine), a profound and highly codified symbolic system has developed that articulates all art forms, all the while celebrating the chance effects of the heat of the kiln and the cycles of nature. This complex aesthetic system has a radical impact on formal Japanese cuisine, which is of startling complexity and symbolic profundity. PMID- 21539059 TI - [A rare cause of lower gastrointestinal bleeding]. PMID- 21539060 TI - [Twenty six-year-old man with abdominal pain and bloating]. PMID- 21539061 TI - [Systematic review: Epidemiology of gastroesophageal reflux disease in Latin America]. PMID- 21539062 TI - [Cesar Roux]. PMID- 21539063 TI - [Colorectal cancer screening at Clinica Alemana, Santiago de Chile]. AB - INTRODUCTION: Colorectal cancer (CRC) incidence is rapidly increasing. It has been demonstrated that it can be prevented and cured when the diagnosis is made in early stages. OBJECTIVE: For this reason it is necessary to apply a screening program in asymptomatic patients. METHOD: Since 2003, we conducted a CRC screening plan called "Mes del Colon" at Clinica Alemana Santiago. A press and local diffusion campaign was designed. Open to the community CRC talks were scheduled. An ad hoc database was designed. An informed consent was available. Patients older than 50 years and high risk patients were included. Total colonoscopy and a medical interview after the procedure were included in the plan with favorable economic conditions. RESULTS: Since 2003, 1158 patients were included The 1.8% of them were excluded because of incomplete data or because they did not meet the inclusion criteria. The 54% of patients were women. Mean age was 58.4 years old and mean body mass index 25.5 kg/m2. Polipoid lesions were seen in 45% of the patients. Six (1%) of them were adenocarcinomas, 291 (57%) adenomas (98% tubular adenomas), 189 (37%) hyperplastic polyps and 25 (5%) miscellaneous lesions. In this series, the necessary number to investigate for 1 adenoma was 3.9. CONCLUSIONS: CRC prevention campaigns are needed due to the continuous increase of the incidence in our country. The detection of precursor or early lesions that are longstanding before becoming advanced cancer allows its treatment avoiding progression. PMID- 21539064 TI - [Surveillance colonoscopy before scheduled: is it worthwhile?]. AB - OBJECTIVE: To determine de incidence of colonic polyps in colonoscopies performed before scheduled and to identifY the clinical and endoscopic features that predicted this finding. METHODS: All patients who underwent at least two complete colonoscopies less than three years apart were retrospectively identified in our computerized database. We excluded patients with high risk of colonic neoplasm requiring a new colonoscopy in less than three years. We analyzed the incidence of polyps before the first and third year after the first study, and the clinical and endoscopic features related to this finding by means of multivariate logistic regression. RESULTS: 378 paired colonoscopies fulfilled criteria, 129 were performed less than one year apart (group 1), and 249 less than three years apart (group 2). Regarding surveillance colonoscopies, 19% of patients presented adenomas and 1.5% high grade dysplasia (HGD) in group 1, and 21% presented adenomas and 2% HGD in group 2. In group 1 fair preparation (P = 0.03), and prolonged colonoscopy (P = 0.02) on the first study were independent predictors to find any polyp on the second study before scheduled. In group 2 fair cleansing (P = 0.04), history of sessile polyps (P = 0.01) and 3 or more polyps in the first study (P = 0.01) were independent predictors to find any polyp, while more than 5 polyps in the first study predicate adenomas. CONCLUSION: During the first year incident polyps related to difficult procedures (missed polyps?) while at 3 years the history of previous polyps was also important. PMID- 21539065 TI - [Role of antibodies in celiac disease after one year of treatment to predict the adherence to gluten-free diet]. AB - INTRODUCTION: The celiac disease (CD) is characterized by a permanent sensitivity to gluten. The treatment for this disease is the life-long strict compliance with a gluten-free diet (GFD). The average of compliance with GFD ranges between 15% and 80%. Antibodies' role in the follow up of these patients regarding the adherence to the GFD is not well established. Objective. To determine the relationship between the antibodies for CD and the adherence to the GFD in patients with over a year of treatment. MATERIAL AND METHODS: Patients with CD with a minimum of one year of GFD were prospectively included They were asked to complete a self-survey regarding to the compliance to GFD and the level of adherence was determined: low (no compliance or more than 2 gluten intakes per week), medium (1 or 2 gluten intakes per week or 2 or 3 gluten intakes per month), or high (1 gluten intake per month or less than 3 intakes per year). The follow up was performed by their general practitioners. From one year of GFD onwards, the results of the available antibodies at the time of the last follow up were assessed: antigliadine IgA (AGA) and IgG (AGG), anti-endomysium IgA (EMA) and IgG (EMG), anti-transglutaminase (ATG), and deaminated peptides of gliadine IgA and IgG, considering them as positive or negative. Through an univariate analysis, the above-mentioned antibodies were correlated (independent variables) in order to identify predicting factors of high and low adherence to the GFD (dependent variables). RESULTS: Ninety patients were analyzed, age 43.6 +/- 15.3 years old, 89% women, 58% classic celiacs. The average time of GFD was 7.9 years and 63% had been on a GFD for over 3 years. A 71% of patients (95% CI 69%-80%) showed high adherence to the GFD, and a 67% (95% CI 2%-13%) showed low adherence. GFD of less than 3 years was a determining factor for low adherence [relative risk (RR) 2.41 (95% CI 1.2-2.89)]. The predictive antibodies for GFD high adherence were: (1) negative EMA [RR 1.27 (95% CI 1.03-1.54)], (2) negative ATG [RR 1.62 (95% CI 1.12-2.47)], and (3) all negative requested ones [RR 1.60 (95% CI 1.17-2.18)]. The predictive antibodies for GFD low adherence were: (1) positive AGA [RR 15.5 (95% CI 2.29-105)], (2) positive EMA [RR 10.2 (95% CI 2.19 47.7)], (3) positive ATG [RR 9.63 (95% CI 1.53-63.4)], and 4) all negative requested ones [RR 0.11 (95% CI 0.018-0.71)]. CONCLUSION: After one year of treatment, the negativity of EMA or ATG antibodies had a significant correlation with the high adherence to GFD and the positivity of AGA, EMA or ATG antibodies had a significant correlation with a low adherence. PMID- 21539066 TI - [Surgical results of type III and IV hiatal hernia with left thoracotomy]. AB - OBJECTIVE: The goal of the study is to report the short- and long-term outcome of a left approach in the management of type III and IV hiatal hernia. METHODS: We have retrospectively reviewed all the records of patients treated for type III and IV hiatal hernia with a left transthoracic approach. All the patients were evaluated before and after the surgery on clinical presentation, symptoms and functional assessment. We have specifically focused the evaluation on surgical results, mortality, morbidity and long term functional assessment. RESULTS: Sixty five patients were included in this study. Type III hiatal hernia (86%) were majority compared to type IV(14%). Surgical techniques included Nissen fundoplication (37%), Collis Nissen elongation gastroplasty (20%) and Belsey-Mark IV (15%). Morbidity was low and there was no hospital mortality. Mean follow-up was 42 months. Long-term reassessment demonstrated a significant improvement of symptoms. Erosive esophagitis persisted in one patient (P < 0.001). Pressure at the level of lower esophageal sphincter was normal in all patients. 24-hours pH metry was normal in 92% of patients. Anti-acid medication was reduced significantly (P < 0.001). CONCLUSION: Obesity, short esophagus, massive hiatal hernia, associated oesophageal diseases or previous failed surgery constituted the indications of choice for transthoracic approach. This procedure gives satisfactory functional and anatomical long term results with healing of mucosal damage. PMID- 21539067 TI - [Isolation of fetal liver oval cells in physiologic conditions form their natural niche]. AB - The liver is characterized by a remarkable ability to proliferate and self-renew. In the situation of mild or moderate liver damage, hepatocytes carry out regeneration. Nevertheless, when liver damage is far too much extensive and the number of residual mature hepatocytes is not enough to accomplish regeneration, or likewise when mature hepatocyte proliferation is inhibited, hepatic regeneration depends on the activation of liver stem cells that give rise to oval cells. The population of liver stem cells is scant in normal liver. It is considered that in fetal liver this population is just over 1% of the cells. For this reason, it is necessary to isolate and enrich them for their study. With this goal several models of hepatic damage that permit the isolation of oval cells af ter the induction of massive hepatic injure have been developed. Here we present a simple methodology that allows the isolation of oval cells from rat fetal liver without prior induction of liver damage. The use of oval cell 2 (OC2) and oval cell 3 (OC3) antigens as molecular markers allowed the highly precise characterization of this cell population. Furthermore, the in vitro culture in presence of HGF yielded a substantial enrichment of the oval cell population. PMID- 21539068 TI - [Esophageal tuberculosis: case report and review of the literature]. AB - The esophageal tuberculosis is the rarest form of this infection in the gastrointestinal tract, corresponding to 0.15% of the cases. This pathology is unusual even in countries with high prevalence of tuberculosis. Its clinical presentation could be easily confused with the one of esophageal carcinoma. The diagnosis is reached by demonstrating in a sample of the mucosa the presence of caseating granulomas or by finding the Mycobacterium tuberculosis in a sample of tissue. In the present case report 73-year-old male with dysphagia, weight loss and fever is presented. At the endoscopy an ulcerated lesion of 5 centimeters in the lower third of the esophagus that compromises 50% of the circumference is observed. In the chest x-ray there are bilateral lung infiltrates confirmed by the CT scan. A baciloscopy is done and the result is positive. At the histological analysis giant cells are found and there is evidence of tuberculous bacillus. The patient develops an intestinal obstruction secondary to chagasic megacolon. He presents a massive hemoptisis and die. The aim of this presentation is to comment a pathology rarely reported in the literature and enhance the importance of considering it according to the clinical context. PMID- 21539069 TI - [Laryngeal and lung tuberculosis: a case presentation]. AB - Tuberculosis continues to be one of the principal problems in worldwide public health. In Uruguay there are around 650 cases being reported each year. Laryngeal tuberculosis is a disease not frequently encoutered and is normally diagnosed by the otorhinolaryngologist since dysphonia is the main symptom in most cases. We report one case diagnosed in the Endoscopy Service of the Hospital de Clinicas. The patient was derived from a medical clinic due to atypical gastroesophageal reflux symptoms with unfavourable evolution under proton pump inhibitor treatment. PMID- 21539070 TI - [Systematic review: Epidemiology of gastroesophageal reflux disease in Latin America]. AB - The prevalence of gastroesophageal reflux disease (GERD) is 10% to 20% in Europe and North America, and about 5% in Asia. This systematic review aimed to quantify the prevalence and incidence of GERD in Latin America, and to determine the potential risk factors and co-morbidities. Systematic literature searches were conducted in PubMed, Embase and the Scientific Electronic Library On-line. No language restrictions were imposed. Eight studies were identified that reported on the prevalence of heartburn and/or regurgitation in Latin America. The prevalence of heartburn and/or regurgitation was 11.9% to 31.3% in the five studies that reported on at least weekly symptoms, and 25% to 35% in the three studies that did not report on symptom frequency. GERD symptoms were associated with obesity and respiratory diseases. No population-based studies on the incidence of GERD or the prevalence of reflux esophagitis were identified. However, four studies investigated the prevalence of reflux esophagitis in patients referred for upper gastrointestinal endoscopy, reporting it to be 35% to 47% in patients referred because of GERD symptoms and 13% in patients referred for any indication. The reported prevalence of GERD in Latin America is similar to estimates obtained in previous studies from Europe and North America, and higher than those obtained from Asia. The association of GERD symptoms with specific comorbidities warrants further investigation and should inform patient management. PMID- 21539071 TI - [Colorectal cancer: epidemiology and primary profilaxis]. PMID- 21539072 TI - [AIR 1/2011: reminder for those who long for a future]. AB - The main themes proposed in this issue, are commented on: education and care as a research project; the need of a continuous dialogue with the patient; drug surveillance as a way of thinking of patients as subjects and not objects of observation; the challenge of caregivers, as an area where the language of research needs to be confronted on with the language of life. PMID- 21539073 TI - [Venus study: a research and education project on nurses and drug surveillance]. AB - INTRODUCTION: Adverse events (AE) are a relevant problem with major health consequences for both patients and health system in different countries. AIMS: To estimate and describe the AE and Adverse Drug Reactions (ADRs) detected by nurses in hospital during an observation time of six months. METHODS: The observational study involved 174 nurses and 36 head nurses. Nurses recorded for each patient: health condition, unexpected AE, administered drugs, and suspected ADR. Nurses were also requested to send ADR reports to the Italian Pharmacovigilance System. RESULTS: Data were collected from 4608 patients. Nurses identified AE in 2458 patients and observed 6647 different events, mostly psychiatric (800 cases). Female, elderly, and 0-1 years old patients, number of administered drugs, and poor health conditions were all risk factors for adverse events (p < 0.01). Nurses identified 160 patients with ADRs (3.5% of observed patients). CONCLUSIONS: Nurses have shown a good observational skill for AE, but low ability to detect ADRs probably due to lack of knowledge on drugs and ADR. For this reason a continuing education is essential. PMID- 21539074 TI - [Effectiveness of a nurse-led educational intervention for patients admitted for acute coronary syndrome]. AB - OBJECTIVE: To assess the effectiveness of a nurse-led class with phone follow-up, to help patients achieve lifestyle changes after an acute coronary syndrome (ACS). METHODS: Each patient < or = 75 years, admitted to a intensive cardiac care unit (ICCU) for ACS from September 2003 to December 2004, who attended the education class (case) was matched with two patients paired for age, sex and admission time, admitted for ACS to ICCUs in the other hospitals in the same area (controls). One year later the two groups were blindly interviewed on the phone, using a structured questionnaire about their lifestyles. RESULTS: One-hundred nineteen cases and 238 controls were phoned and 84% cases and 61% controls completed the interview. Cases reported a more correct lifestyle: they ate > or = 4 portions/day of fruit or vegetables (55% vs. 36%, p = 0.003) and > or = 2 portions/week of fish (48% vs. 32%, p = 0.010), reported > or = 30 min/day of physical activity (67% vs. 59%, p = 0.262) and stopped smoking (82% vs. 71% of previous smokers, p = 0.264). CONCLUSION: An educational intervention led by cardiology nurses, with a group meeting and personal phone follow-up, improved lifestyle habits one year after an ACS. PMID- 21539075 TI - [The degree of coincidence between the needs of cancer patients and the answers in the statutes of associations and dedicated health services]. AB - AIMS: The research took place in the northern area of Emilia Romagna, and aimed at investigating the needs expressed by cancer patients and those included in the goals of health services and associations dedicated to cancer disease. METHOD: The study involved 22 cancer patients (12 females and 10 males, mean age 55.36 +/ 10.7) through a semi-structured interview. Twenty-five Organizational Regulations and 17 Health Card Services of institutions dedicated to cancer disease were also analyzed. RESULTS: The basic needs of cancer patients are rarely economic, legal, material and more often medical and psychological (e.g. psychological support, medical care and equal treatment, continuity of care in hospital and at home and information about diagnosis and treatment). The health services focus on the fulfillment of the needs of self-determination, dignity and respect for people, information on diagnosis and treatments, and of psychological support. The associations provide help through activities geared towards ensuring socialization opportunities (need for aggregation and company), support patients and their family and aim to be a connection in the continuity of care between hospital and home. CONCLUSIONS: While the aims of health services and associations are oriented to respond to many basic needs, some remain still unmet and others are not adequately considered (eg. need to return to daily lives). The offer, aimed to fulfill these need, could be enhanced through a network of synergistic partnerships between health services, citizenship and associations. PMID- 21539076 TI - [Phlebitis associated to intravenous/infusional therapy]. AB - Phlebitis is a common problem associated to intravenous therapies, it may cause pain, sepsis and increased duration of hospitalization. Several factors can increase the risk of phlebitis. The literature review addresses the mechanisms of chemical phlebitis, the characteristics of drugs likely to cause a phlebitis and the main measures to be adopted for prevention and treatment. PMID- 21539077 TI - [Patients reported adverse drug reactions: what's happening in Europe]. AB - This contribution in based on a report that describes the European situation regarding patient reported Adverse Drug reactions (DPR) and analyzes the literature on the topic. In 7 European countries DPRs are accepted, and used for decision making. Patients reports in general are more vivid that those of health care workers and report information that professional reporters can never be expected to provide. Moreover, DPRs are reliable and comparable to those of professional reporters. PMID- 21539078 TI - [Family caregivers--waiting for visibility]. AB - A course with the family caregivers of patients with Alzheimer disease, multiple sclerosis, Parkinson disease and other chronic severe illnesses was the occasion for reflecting on caregivers and educational needs. The usual uneven relationship of teachers (doctors and nurses) and learners (usually caregivers) was paralleled and the dialogue and the exchange of experiences was conducted at the same level. The course, aimed at providing practical help (teach caregivers how to care for their relative) but also at promoting a reflection on the caregiving experience, was held in two editions with the participation of more than 100 caregivers. PMID- 21539079 TI - [The language of modern national morphology: sustainable development or crisis?]. PMID- 21539080 TI - [Microtubule-associated proteins as markers of nerve cell differentiation and functional status]. AB - This paper is aimed at the characterization of beta-III-tubulin, MAP2 and doublecortin, the proteins which participate in the organization, stabilization and function of the microtubules of nerve cell cytoskeleton. Due to the structural and functional features, these proteins may be regarded as differentiation markers, associated with neurogenesis and as the indicators of nerve cell functional status under normal and pathological conditions. The data presented show that these proteins perform important structural and transport functions in nerve cells and are essential for some neurospecific intracellular processes. However, current knowledge of the functional role of these proteins in nerve cells is insufficient and requires significant supplementation indispensable for unequivocal interpretation of the studies results. PMID- 21539081 TI - [Peculiarities of cortico-cortical ipsilateral connections of the primary, secondary and tertiary sensomotor zones of cat cerebral cortex]. AB - Relative distribution of the efferent association fibers of the primary motor--MI (area 4y), secondary--SMII (2pri) and tertiary--SMIII (area 5) sensomotor zones of cerebral cortex were studied in 30 cats using Nauta-Gigax method. The projection of insignificant number of associative fibers to the primary cortical sensory zone--CI (area 1,2, 3a, 3b) was demonstrated. Massive bilateral connections of MI with SMII (2pri) and SMIII (area 5) were shown. It was suggested that the restoration of the motor functions after local destruction of CMI, CMII and CMIII is due to the demonstrated multiple horizontal associative connections between the functional units of the mentioned sensomotor centers. PMID- 21539082 TI - [Morpho-functional and hodological peculiarities of ascending dopaminergic system of Rhodeus sericeus (Cyprinidae)]. AB - Using the methods of tyrosine hydroxylase (TH) immunohistochemistry combined with nerve fiber labeling with carbocyanin dye DiI (1,1',dioctadecyl-3,3;3',3' tetramethylindocarbocyanine perchlorate), the distribution of catecholaminergic (CE) neurons and their ascending projections to the basal telencephalon were studied in adult Amur cypriniform fish Rhodeus sericeus. Highly specialized complex of CE neurons was demonstrated in diencephalon. Six populations of TH immunopositive neurons were detected in the area of posterior tuberculum, two of them were double-labeled, indicating the presence of dopaminergic projections to the ventral portion of the telencephalon (striatum). In the posteriotuberal area, two populations of CE cells were identified (small round neurons and large pear shaped cells) which probably could correspond to the populations of sensomotor and limbic cells in mammals. PMID- 21539083 TI - [Serotonin- and nitroxidergic neurons of rat medulla oblongata]. AB - The purpose of the present work was topochemical mapping of serotonin- and nitroxidergic neurons in medulla oblongata of 12 Wistar rats in eight nuclei envolved in so-called "bulbar vasomotor to the center". It was found that a portion of serotoninergic neurons lying in a projection of the investigated nuclei, was equal, on the average, to 12-15%, and those in the nuclei of posterior raphe group increased up to 31-43%. Nitroxidergic neurons were distributed more uniformly, and their portion in different nuclei varied from 19 to 49%. 2-6% of neurons were located between the nuclei, and between the nuclei and conducting pathways; these cells presumably carry out integration functions in hemodynamics regulation. PMID- 21539084 TI - [Ultrastructure of the caudal mesenteric ganglion neurons during early development in kittens]. AB - Electron microscopy was used to study the peculiarities of the development of nervous elements in the sympathetic caudal mesenteric ganglion (CMG) in the cat from the moment of birth until the end of the second month of life. The discordance in the rate of maturation of both neurons and their endings was observed. In newborn kittens, mature neurons, glial cells and synapses were observed together with many immature ones. In 14-day-old animals, the proportion of immature neurons decreased, while destruction of neurons was observed more frequently in this age. In CMG of the animals of all the age groups, axodendritic synapses were found most frequently and axosomatic synapses were observed more rarely. Finally, the ultrastructure of CMG in kittens become comparable to that of adult animals at the age of 60 days. PMID- 21539085 TI - [Changes of the tissues and of regional lymph nodes in rats with chronic inflammatory process treated with interleukin-2]. AB - The structure of Wistar rat subcutaneous adipose tissue and axillary (regional) lymph nodes (LN) was studied by the methods of light microscopy after the subcutaneous implantation of the fragments of silicone mammary implant in the area of right scapula in animals treated with interleukin-2 (IL-2). Subcutaneous implantation of sterile silicone plates to rats was found to induce chronic granulomatous inflammatory process with the formation of connective tissue capsule. Implants placement to rats treated with IL-2 resulted in the formation of a thicker capsule with the signs of sclerosis, fibrosis and hyialinosis; all the capsular structures were heavily infiltrated with macrophages, which contained phagocytozed silicone fragments. After the introduction of silicone implants, the volume of the capsule and connective tissue in the regional LN progressively increased, while after IL-2 treatment the intensity of sclerotic processes was significantly decreased. The relative area of lymphoid nodules without the germinal centers in LN sections was increased 1 month following the induction of chronic inflammatory process in rats treated with IL-2, but by 6 months the proportion of nodules both with or without germinal centers become less, as compared to the initial data. PMID- 21539086 TI - [Morphological peculiarities of mesenteric lymph nodes in hypokinesia modeling]. AB - Using histological methods, qualitative and quantitative changes in cell composition were studied in mesenteric lymph nodes in 20 male Wistar rats after experimental 30 days-long hypokinesia, and in 10 rats 1 month following the cessation of mobility restriction. Hypokinesia was found to result in massive destruction of lymphoid cells in the structural organ zones, suppression of lymphocytopoiesis, reduction in plasma cell and macrophage numbers, indicating the dampening of the immune reactions, however the full restoration of the cytoarchitectonics in the structural zones of lymph nodes did not take part 30 days following the cessation of hypokinesia. PMID- 21539087 TI - [Morpho-functional characteristic of oral mucosal epithelium after treatment with a cytostatic drug]. AB - The effect of cytostatic drug cyclophosphamide (CY) on lingual epithelium was studied in 90 female mice using histological, morphometric, quantitative histochemical and immunohistochemical methods. CY (400 mg/kg) was injected intraperitoneally three times with a 48 h interval. Material was obtained 2 days after injections and 10-20 days after their discontinuation. CY treatment was shown to result in the damage of both surface epithelium of the tongue and the epithelium of minor lingual salivary glands. Damage to the surface epithelium was more pronounced on the ventral surface of the tongue and was associated mainly with the disturbances of its proliferation. Changes were less severe on the dorsal surface and were seen as the disturbances of epithelial differentiation and desquamation. Glandular epithelium was damaged to a lesser extent than the surface one, with serocytes being more sensitive to the cytotoxic injury than mucocytes. After cytostatic drug discontinuation, the tendency for the normalization of the epithelial characteristics was noted. Most persistent changes in the surface epithelium were found on the dorsal surface of the tongue and in the glandular epithelium--in the serous secretory portions of the salivary glands. PMID- 21539088 TI - [Buccal epithelium reactivity in children]. AB - The purpose of this study was the analysis of the buccal smears from 200 healthy children and children with chronic tonsillitis and chicken pox. The smears were stained using Pappenheim's method. The peculiarity of buccal mucosa cytograms of children of different ages was the significant increase in mature forms of the cells (presence of differentiation stage 5 and 6 cells) in adolescents. They also had a lower area of epitheliocytes at all the stages of differentiation and of their nuclei. In chronic tonsillitis and chicken pox, the complex of cytological changes was detected, that included the increase of the leukocyte number, changes in the proportions of epitheliocytes in cell population, augmentation of inflammation-destruction and destruction indexes. PMID- 21539089 TI - [The rodlet cells of some species of freshwater and marine bony fishes of orders Cypriniformes and Perciformes]. AB - The fine structure of rodlet cells from pronephros of Cobitis taenia (L.), mesonephros of Tinca tinca (L.), Rutilus rutilus (L.), Stizostedion volgense (Gmelin), Stizostedion lucioperca (L.), Perca fluviatilis (L.), Trachurus mediterraneus (Staindachner) and Diplodus annularis (L.) was studied. In the organs examined, cells at developmental stages III, IV and V were detected. It is shown, that the rodlet cells have the structural organization similar to that described in different organs of fish studied earlier, which was independent on the species habitat. The typical features of the rodlet cells are the presence of large granules with the rod-like core. A portion of the cells had a broad fibrillar sheath. Secretory product was released according to the apocrine type. Interspecies differences were found between the morphometric parameters of the cells and theirs subcellular structures. PMID- 21539090 TI - [Morphological characteristics of the urinary bladder glandular apparatus at different stages of postnatal ontogenesis]. AB - Total preparations of the urinary bladder wall obtained from 130 corpses of humans of both sexes and various ages, who died by chance cause, were examined with the macro-microscopical method. Morphometry was used to study the structural characteristics of the glands of this organ in the different parts of its wall (proximal, medial and distal thirds of the urinary bladder). The diversity of the appearance of the glands was noted; the greatest variability of glandular shape variants was detected at the age of 22-35 years. The glandular apparatus of the urinary bladder was found to attain its maximum development at the age of 22-35 years, thereafter it undergoes the involutive changes. Proximo-distal gradient of the change of shape of the glands was detected along the urinary bladder, this gradient was independent on age and gender. Age-associated changes of the total numbers of glands and of their density (relative numbers) in the walls of the urinary bladder, as well as the regional peculiarities of these parameters, were described for the first time. Gender-related differences in the structure of the urinary bladder glands were found only in the reproductive period. They were demonstrated as the larger gland dimensions in females of this age as compared to those of males. PMID- 21539091 TI - [Age-related changes of the epidermis of men's scalp]. AB - Histological, morphometric and immunocytochemical methods were used to study the autopsy samples of the interfollicular epidermis in the temporal region of scalp of male individuals aged from 7 months to 75 years. Monoclonal antibodies against Ki-67, involucrin and p53 were applied to evaluate the proliferative pool in the epidermis, the thickness of the layer of the cells which started the terminal differentiation, and the fraction of the apoptotic cells. Epidermis in children was thin; it had a low content of Ki-67- and p53-positive cells and small thickness of involucrin-positive cell layer. The highest proliferative activity and maximal thickness of the epidermis were detected at the age of 19-21 years. Thereafter the epidermis thinning was observed, together with the progressive decrease of keratinocyte proliferative activity and an increase of the fraction of p53-positive cells. Absolute thickness of the involucrin-positive cellular layer remained practically constant at different ages, while its proportion in the total epidermal thickness uncreased. PMID- 21539092 TI - [Reparative osteogenesis after transplantation of bone marrow multipotent stromal cells cultivated at various oxygen concentrations]. AB - Comparative histological and morphometric methods were used to study the bone callus (BC) in rats 14 and 30 days after the experimental fibula fracture. Animals were infused with cell preparations of multipotent bone marrow stromal cells--BMSC (also known as multipotent mesenchymal stromal cells) in the site of injury immediately after the fracture. BMSC were cultivated in vitro under normoxic (20% O2) and hypoxic (5% O2) conditions. 14 days after the fracture, in rats that received no BMSC (control group) and in animals injected with BMSC, newly formed BC contained fibrous tissue, cartilage and reticulofibrous bone tissue (RFBT). The portion of BC, occupied by RFBT was significantly greater in rats that received BMSC grown at 5% O2, than in the other experimental groups. Thickening index of BC at day 14 was 1.3 and 1.4 times higher in animals treated with BMSC grown at 5% and 20% O2 (p < 0.05) than in rats that received no BMSC. At day 30, BC was histologically more mature in rats that received BMSC infusion than in the control group, while the restoration of the initial bone thickness was also more effective in these animals. Thus, the results of this study demonstrated that the infusion of allogeneic BMSC, expanded in vitro at different oxygen concentrations, into the site of fracture improved osteocartilaginous fragment and BC formation and bone size restoration in rats with fibula fracture. PMID- 21539093 TI - [Osteocytic bone remodeling: history of the problem, morphological markers]. AB - On the basis of the authors' own results and the analysis of the literature, the morphological markers of resorptive and synthetic phases of osteocytic bone remodeling under physiological conditions, are discussed. Their application by different authors is considered taking into account the history of the research of the osteocyte role in bone matrix metabolism (synthesis and resorption). Currently, there arose an urgent need for the quantitative assessment of osteocyte remodeling by combining routine histological methods of the osseous tissue study with the possibilities of modern image analysis systems. PMID- 21539094 TI - [The outstanding date in the history of surgery, anatomy and pedagogy (on the celebration of bicentenary of N.I. Pirogov's birth in the Military Medical Academy)]. PMID- 21539095 TI - [Ultrasonographic visualization of ciliary pars plana cysts]. AB - On a basis of detailed analysis of ultrasound biomicroscopy (UBM) scanograms of 617 patients (823 eyes) ciliary pars plana cysts were found in 8.9% (55 patients, 66 eyes). The main types of ciliary pars plana cyst were revealed: solitary isolated and multiple (isolated and confluent). The results of the study confirmed topographic and morphologic correlation of ciliary pars plana cysts and peripheral retinoschisis. Authors demonstrated the value of UBM for visualization not ciliary pars plana cysts only but oral and peripheral retinal degenerative changes as well, that can lead to retinoschisis and retinal detachment. PMID- 21539096 TI - [Ocular and orbital blood flow in apparently healthy adults]. AB - Doppler measurements of ocular and orbital blood flow at rest were studied using duplex ultrasonography in 30 apparently healthy adult volunteers. The following linear and calculated Doppler measurements were estimated at rest: blood flow in ophthalmic artery (OA), central retinal artery (CRA), posterior ciliary arteries, central retinal vein and superior ophthalmic vein (SOV). In 10 patients Doppler measurements of blood flow in OA, CRA SOV were estimated 5 times by 2 observers with different level of skills in ultrasonographic ophthalmologic examination. Statistic analysis showed strong correlation of linear and calculated measurements in OA, CRA and venous blood flow velocity. A number of Doppler measurements with the most significant inter- and intraobserver variation were revealed. Measurements with high reproducibility were determined. Thus, a unique technique should be performed in estimation of Doppler measurements of blood flow in ocular and orbital vessels. The velocities in the main arteries (OA, CRA) and veins (SOV) were showed to have significant strong interobserver correlation. The highest reproducibility and accuracy was revealed for maximal systolic velocity in OA and CRA and maximal velocity for cardiac cycle in SOV. PMID- 21539097 TI - [Value of complex ultrasonography in children with concomitant strabismus]. AB - 28 children with concomitant strabismus were examined using complex ultrasonography. Thickness of horizontal recti muscles was estimated in convergent and divergent strabismus. The blood flow in central retinal artery was estimated in patients with concomitant strabismus. PMID- 21539098 TI - [Specifics of interactions of mono- and binocular mechanisms of spatial perception in cecutient children]. AB - Interactions of mono- and binocular mechanisms of spatial perception were estimated using stereokinetic test proposed by L.N. Mogilev in 117 children with low vision and 317 healthy children aged 5-18 years old. Cecutient and healthy children had similar values of steriokinetic illusion in monocular visual conditions, while in binocular visual conditions the results were significantly different. It was shown that in children with low vision there is no increase in contribution of binocular mechanisms with aging. The mean value of coefficient K characterizing this contribution in healthy group was positive and increased from preschool age till adolescence. The mean value of coefficient K in cecutient children was negative or near zero. It is revealed that visual impairment may influence the development of mono- and binocular mechanisms of spatial perception and their interaction. PMID- 21539099 TI - [Anterior and posterior chambers interrelation in patients with glaucoma associated with myopia]. AB - In examination of patients with glaucoma associated with high myopia (6.5 - 10.0 dpt) aged 18-32 years old we used ultrasound biomicroscopy and gonioscopy. The main group was subdivided into 3 smaller groups: the 1st one (12 eyes) contained patients with pretrabecular angle block, 2nd (18 eyes--with trabecular angle block, 3rd (7 eyes)--with partial posterior chamber block and iris root prolapse. 27 emmetropic patients with POAG and 10 myopic eyes with normal IOP served as controls. Comparative analysis showed that one of the most significant factors of POAG pathogenesis in high myopic eyes is congenital and acquired changes in anterior and posterior chambers interrelation. PMID- 21539100 TI - [Specifics of surgically created draining zone in children with glaucoma after intraoperative mitomycin C according to ultrasonographic data]. AB - The results of ultrasound biomicroscopy of draining zone created by filtering procedures in children with glaucoma after intraoperative mitomycin C (MMC) are represented. 149 eyes of 129 children with glaucoma after surgery with and without MMC were studied. In 68 cases we created limbal-based conjunctival flap and in 81--fornix-based. Comparative analysis did not reveal influence of MMC on scleral and internal surgical zones. Significant difference after surgery with MMC consisted in forming of cystic bleb in 20.8% when limbal-based conjunctival flap was created. It was showed that fornix-based conjunctival flap not only prevents forming of "mitomycin" cystic bleb but maintains positive effects of citostatic medications as well. PMID- 21539101 TI - [Rationale for implant insertion after enucleation of eyes with uveal melanoma]. AB - Results of retrospective analysis of medical charts of 328 patients after enucleation due to uveal melanoma (UM) are represented. Our study showed that recurrent tumor occurs in 2.44% cases. The main reasons of recurrence are scleral invasion or tumor damage during surgery. After enucleation due to juxtapapillary UM recurrence is rare and occurs after long-term follow-up. Thus after enucleation due to UM implant insertion is possible in case of scleral integrity and absence of macroscopically apparent tumor extension beyond sclera. PMID- 21539102 TI - [Our experience of biomaterial use for lamellar keratoplasty]. AB - The results of use of biomaterial Alloplant (BMA) for lamellar keratoplasty (LKP) were analyzed. The most part of patients had ocular burns (40.2%), i.e. the most severe damage. Combined variants of BMA for LKP with other alloplants were studied. The most often used combination was alloplant for LKP with alloplant for conjunctiva reconstruction and allotendinous threads (24.5%), this combination let to cover extensive corneal and conjunctival defects. Significant improvement of visual acuity in 241 patients after long-term follow-up was achieved. The complications of LKP with BMA transplantation are discussed. PMID- 21539103 TI - [Collagen implant in refractory glaucoma surgery]. AB - The problem of surgical treatment of refractory glaucoma (RG) in patients with corneal disease is studied. Glaucoma prior to penetrating keratoplasty is a significant risk factor for postkeratoplastic glaucoma that results in graft failure. The main tendency of RG surgery is implantation of draining devices. The aim of our study was to evaluate the efficacy of glaucoma surgery with collagen implant in patients with RG associated with severe corneal disease. 42 operations were analyzed. This operation technique let us achieve persistent hipotensive effect and corneal improvement. The insertion of collagen implant is absolutely safe in terms of corneal graft survival and it prevents scaring in surgery zone. PMID- 21539104 TI - [Results of 10-year use of complex treatment of choroidal melanoma stage T2 with brachytherapy and transpupillary thermotherapy]. AB - We studied the results of complex treatment of choroidal melanoma (CM) using Ru 106+Rh- 106 brachytherapy (BT) combined with transpupillary thermotherapy (TTT). 70 patients (70 eyes) with CM prominence ranged from 2.5 till 10.8 mm (mean 6.5+0.24 mm) were enrolled into the study. Follow-up was 6-120 months, median 47 months. TTT (810 microm) was carried out 24-48 hours later ophthalmic applicator suturing. Absolute or partial regression was achieved in 69 patients (99%) from 6.4+0.24 mm till 2.4+1.9 mm. In 1 case treatment was not effective. In 1 patient enucleation was performed due to secondary glaucoma. Dissemination with liver metastases was observed in 3 patients. Kaplan-Meier analysis showed 5 year eye preservation as high as 99%, absence of metastases--94%, survival rate without recurrence--91%, total efficacy (patients without negative results)--89%. Thus complex treatment (BT + TTT) of CM compared with monotherapy BT showed to have better local outcomes (including eye preservation) and it does not reduce survival rate even in patients with stage T2 (less than 10 mm). PMID- 21539105 TI - [Choroidal melanoma stage T2 higher than 6.0 mm: organ-preserving treatment with brachytherapy and transpupillary thermotherapy vs enucleation? Survival analysis]. AB - The aim of the study was to compare survival rates of patients with stage T2 choroidal melanoma (CM) with prominence more than 6.0 mm after eye-preserving treatment using Ru-106 brachytherapy (BT) combined with transpupillary thermotherapy (TTT) and after primary enucleation. The main group included patients treated with BT alone or combined with simultaneous TTT. Patients with CM after primary enucleation served as control. The groups were standardized in terms of age (p = 0.063), mean prominence (p > 0.149), mean maximal base diameter (p > 0.85), number of unfavorable localized tumors (juxtapapillary and ciliochoroidal) (p = 0.246), follow-up duration (p > 0.23). Kaplan-Meier analysis showed 5 year level of metastasing after eye-preserving treatment as high as 16%, after enucleation--13% (p > 0.96). Eye-preserving treatment using BT combined with TTT in patients with CM with prominence less than 10.0 mm (T2N0M0) allows to preserve eye as an organ and to save some degree of useful visual acuity. This treatment strategy can be considered an appropriate option. PMID- 21539106 TI - [Long-term results of secondary glaucoma surgical treatment]. AB - The efficacy of combined hypotensive surgery in patients with secondary glaucoma was studied. The main group included 30 patients who underwent deep sclerectomy with angle dilatation, 50 patients after sinusotrabeculectomy served as controls. The results were evaluated in 3 years. Visual acuity reduced by 0.04 compared with early postoperative results in the main group and by 0.1 in control group. In the main group the summarized visual field reduced by 14-15 degrees, in control group--30.5 degrees. IOP rise in the main group was 2 mm Hg, while in control--6.0 mm Hg. Deep sclerectomy with angle dilatation in secondary glaucoma compared with conventional surgery showed to be more effective in terms of stable hypotensive effect, more natural long-term hydrodynamics and prolonged visual functions preservation. PMID- 21539107 TI - [Method of implant insertion in anophthalmic socket]. AB - The method of extraocular muscles fixation is presented, it consist in direct fixation to alloplant according to their physiological attachment to ensure stump movement after enucleation. A total of 54 patients aged 26-82 years were treated. Primary enucleation was performed in 46 patients and 8 patients were previously treated with brachytherapy. Surgery was performed under general anesthesia using microsurgical technique. After alloplant was fixed to the anterior surface of tenon's capsule a running suture was put horizontally and conjunctival suture had vertical orientation. A pressure dressing was applied for 2-3 days. Generally there were no technical difficulties, but in patients after brachytherapy separation of muscles and tenon's capsule was complicated because of scarring in the site of previous radiation. PMID- 21539108 TI - [The potential of reflexotherapy for patients with acquired myopia]. AB - Efficacy of reflexotherapy for patients with acquired myopia is analyzed. Guidelines for different reflexotherapy techniques and their combinations are presented. The best results were obtained when treated with complex technique that included biomaterial "Alloplant" pharmacopuncture. PMID- 21539109 TI - [On a problem of syphilitic damage of the eye]. AB - Clinical features and epidemiology of syphilitic damage of the eye in Smolensk region was studied in 1996-2008 period. 32 medical charts of patients with ophthalmosyphilis were analyzed. Ophthalmosyphilis is usually registered in patients with secondary syphilis with disease duration more than 6 months (56.3%) and in patients with late neurosyphilis (40.6%). The diagnosis was established in 24.5+4.8 (from 14 till 34) days after clinical presentation. Clinical forms of ophthalmosyphilis included bilateral uveitis (15.6%), optic neuritis (15.8%), iridocyclitis (12.5%) and choreoretinitis (12.5%). Complications of ophthalmosyphilis included optic nerve atrophy developed in 6.2%, cataract--6.2% and glaucoma--3.1%. In epidemiologically unfavorable situation caution should be taken by ophthalmologists in terms of syphilitic infection, appropriate laboratory tests should be considered. PMID- 21539110 TI - [Glaucoma treatment during pregnancy and lactation]. AB - 4 cases of glaucoma during pregnancy and lactation are represented to study individual treatment approach in situations like these. Clinical characteristic of medications used and other treatment options are described. PMID- 21539111 TI - [Stimulate the right things in health care]. PMID- 21539112 TI - [Who loves HSAN and the National Board of Health and Welfare?]. PMID- 21539113 TI - [2- or 3-dose pcV in upper respiratory infection. How often? How much? How long?]. PMID- 21539114 TI - [Flavonols, cocoa and chocolate affect the cardiovascular system. But still too early to prescribe chocolate as treatment]. PMID- 21539115 TI - [Ciliopathy--cause of several peculiar syndromes]. PMID- 21539116 TI - [FRAX--model for 10-year fracture risk assessment. Support in the treatment of osteoporosis, according to preliminary Swedish guidelines]. PMID- 21539117 TI - [Shorter waiting time in emergency departments with physicians in the triage team. Comparison of standard and emergency physician triage]. PMID- 21539118 TI - [Critical questions are missing in the inspection of the national quality registries]. PMID- 21539119 TI - [Disulfiram can be effective, but monitored treatment is required]. PMID- 21539120 TI - [70 years with penicillin in clinical use]. PMID- 21539121 TI - [Vaccine against pandemic influenza A(H1N1)--effect and safety]. PMID- 21539122 TI - [Free-radical oxidation and antioxidant protection by experimental cholestasis]. PMID- 21539123 TI - [Laparoscopic evacuation of the foreign body from the abdominal cavity]. PMID- 21539124 TI - [Treatment of metachrone tumors of five localizations]. PMID- 21539125 TI - [The methods of left liver lobe volume gain in surgical hepatology]. PMID- 21539126 TI - [Methods of the duodenal stump closure]. PMID- 21539127 TI - [Protocols of the Moscow surgical society sessions]. PMID- 21539128 TI - New Zealand should have mandatory fortification of bread with folic acid: no. PMID- 21539129 TI - [Obesity treatment without knowledge--focus without general view]. PMID- 21539130 TI - [How to protect acutely ill, unconscious patients in connection with drug trials?]. PMID- 21539131 TI - [Toe tourniquet syndrome]. PMID- 21539132 TI - New Zealand general practice should adopt population-based screening for attention deficit hyperactivity disorder (ADHD): no. PMID- 21539133 TI - [Recent progress in hepatology]. PMID- 21539134 TI - Low host specificity in the Kudoidae (Myxosporea: Multivalvulida) including seventeen new host records for Kudoa thalassomi. AB - Kudoid parasites are known to infect a large variety of fish. A significant proportion of Kudoa species have relatively low host specificity, with a single species able to infect multiple host species representing various host families even from different host orders. Since DNA sequences have been associated with myxosporean species characterisations, it has become far easier to determine host range of new species and validate host records from earlier descriptions. This study investigated the host specificity of a kudoid parasite, Kudoa thalassomi Adlard, Bryant, Whipps et Kent, 2005, from the Great Barrier Reef in Australia using DNA sequence analysis and morphology. The results revealed the host specificity to be broad, with K. thalassomi identified in 18 different fish species representing six different fish families. This study also compares current genetic information from different host isolates of Kudoa Meglitsch, 1947 to their host ranges recorded in existing literature. From this analysis, only half of the Kudoa species with multiple host records (27 Kudoa species) have half or more isolates that are genetically characterised, and thus specifically identified with a high confidence, from their known hosts. Only five kudoid species have genetically characterised isolates from all of their recorded hosts. PMID- 21539135 TI - Lamellodiscus (Monogenea: Diplectanidae) parasites of Dentex macrophthalmus (Teleostei: Sparidae) from the North Atlantic coast of Africa, with a redescription of L. dentexi Aljoshkina, 1984, and description of three new species. AB - Lamellodiscus dentexi Aljoshkina, 1984, a gill parasite of Dentex macrophthalmus (Bloch), is redescribed based on new material from the northwest coast of Africa (Senegal and Morocco). Three new species of Lamellodiscus Johnston et Tiegs, 1922 from D. macrophthalmus are described, Lamellodiscus toguebayei sp. n., L. vicinus sp. n., and L. triacies sp. n., all belonging to the "ignoratus" group. They can be distinguished from all other species of this group by the size and shape of male copulatory organ and sclerotised parts of the haptor. Considering the peculiar morphology of the male copulatory organ (long and thin tube) we propose to put together L. dentexi, L. virgula Euzet et Oliver, 1967 and L. obeliae Oliver, 1973 to form the "elongatus" type within the "elegans" group. PMID- 21539136 TI - Infection dynamics of the monogenean parasite Gyrodactylus gasterostei on sympatric and allopatric populations of the three-spined stickleback Gasterosteus aculeatus. AB - Parasites with high host specificity maximally depend on their hosts, which should increase the likelihood of coevolution. However, coevolution requires reciprocal selection exerted by the host and the parasite, and thus a considerable level of parasite virulence. In species of the monogenean ectoparasite genus Gyrodactylus consecutive generations are confronted with a single host, which may constrain the evolution of virulence. Transmission, which is often important in the ecology of Gyrodactylus species, may have the opposite effect, but may also lead to the avoidance of coevolutionary arms races. We investigated the potential outcome of coevolution between Gyrodactylus gasterostei Glaser, 1974 and its host, the three-spined stickleback (Gasterosteus aculeatus L.) by determining the strength of genotype by genotype (GxG) interactions on two levels: within and between sympatric and allopatric host populations. To do so, we compared the parasite's infection dynamics on laboratory-reared sympatric (Belgian) and allopatric (German) hosts. We found that a parasite line successfully infected a range of sympatric host genotypes (represented by families), while it failed to establish on allopatric hosts. Phylogeographic studies suggest that neutral genetic divergence between the host populations cannot explain this dramatic difference. Provided that this result can be generalised towards other parasite lines, we conclude that coevolution in this host-parasite system is more likely to lead to local adaptation on the population level than to GxG interactions within populations. PMID- 21539137 TI - Acanthocolpidae (Digenea) of marine fishes off New Caledonia, with the descriptions of two new species. AB - The following acanthocolpid species are reported from New Caledonia. Acaenodera nautili sp. n. from Conger cinereus Ruppel differs from other Acaenodera species in details of the body-spination, the sucker-ratio and the bipartite seminal vesicle; Stephanostomum murielae sp. n. from Carangoides hedlandensis (Whitley) differs from most species of Stephanostomum in the average of 36 circum-oral spines, the circum-oral spine rows with a ventral hiatus and the anterior extent of the vitellarium being > 10% of the hindbody length from ventral sucker. The species is distinguished from the three other species with these characters in a detailed review. The other species reported are: Stephanostomum aaravi Bray et Cribb, 2003 from Lethrinus miniatus and L. rubrioperculatus; Stephanostomum ditrematis (Yamaguti, 1939) from Gnathanodon speciosus; Stephanostomum japonocasum Durio et Manter, 1969 from Cephalopholis urodeta, Epinephelus areolatus, E. chlorostigma, E. maculatus, E. retouti, Lethrinus miniatus and Variola louti; Stephanostomum uku Yamaguti, 1970 and Pleorchis uku Yamaguti, 1970 from Aprion virescens. PMID- 21539138 TI - Morphological and molecular study of Microphallus primas (Digenea: Microphallidae) metacercaria, infecting the shore crab Carcinus maenas from northern Portugal. AB - The present study describes the anatomy and surface topography of the metacercaria of Microphallusprimas (Jagerskiold, 1909) infecting the shore crab Carcinus maenas (L.) in Aveiro estuary, northern Portugal. The metacercaria species identification resulted from the combined use of morphological and molecular data, particularly the 28S rDNA gene. The metacercariae encysted preferentially in the host's hepatopancreas and also in the gonads. Isolated cysts were present in two distinct forms, spherical and oval, and were shown to be the identical species by the internal transcribed spacer 1 (ITS1) sequence. Chemically excysted metacercariae were studied by light (LM) and scanning electron microscopy (SEM). Their specific characteristics observed include the particular aspect of the vesiculo-prostatic pouch surrounded by a very thin membrane, the presence of a prominent muscular papilla, and an obvious metraterm. The dorsal and ventral tegumental surfaces of the metacercaria were densely packed with similar squamous spines, which decreased in number and size towards the hindbody. The edges of the posterior and ventral face of the body were coated with numerous microvilli, whose function remains unknown. In order to identify the species of metacercariae, we compared a 28S partial rDNA sequence of the two forms of cysts with the same 28S partial region of M. primas available in GenBank. With this comparison, we determined that the sequences had a 100% similarity and therefore belonged to the same species, i.e., M. primas. PMID- 21539139 TI - Three new species of Spiniloculus (Cestoda: Tetraphyllidea) from Chiloscyllium punctatum (Elasmobranchii: Orectolobiformes) off Borneo with clarification of the identity of the type of the genus. AB - The type species (Spiniloculus mavensis Southwell, 1925) of the previously monotypic tetraphyllidean genus Spiniloculus Southwell, 1925 is redescribed from the type material from Moreton Bay, Australia. As a consequence the identity of this species is definitively resolved. Three new species in the genus, all collected from Chiloscyllium punctatum Muller et Henle (brownbanded bambooshark), in Borneo, are described. Spiniloculus calhouni sp. n. conspicuously differs from all three of its congeners in its possession of post-poral testes. Spiniloculus fylerae sp. n. and Spiniloculus paigeae sp. n. differ from their two other congeners in that they are relatively small worms (4-6.5 and 2.2-5 mm in total length, respectively) with fewer than 30 proglottids. They can be distinguished from one another in that, while the vitelline follicles are interrupted at the level of its ovary in S. fylerae, this is not the case in S. paigeae. Furthermore, whereas the cirrus sac of the former species is pyriform, it is elongate-oval in the latter species. This brings the total number of species in the genus to four, and lends support to the suggestion that the original identity of the type host of S. mavensis as Mustelus sp. was in error. This work also extends the range of the genus to include the island of Borneo. A key to the species of Spiniloculus is provided. Morphological data generated here, using both light and scanning electron microscopy, support the suggested close affinities between Spiniloculus and Yorkeria Southwell, 1927, both of which parasitize bamboosharks. PMID- 21539140 TI - Spermiogenesis and ultrastructure of the spermatozoon of the trypanorhynch cestode Aporhynchus menezesi (Aporhynchidae), a parasite of the velvet belly lanternshark Etmopterus spinax (Elasmobranchii: Etmopteridae). AB - Spermiogenesis and the ultrastructural organisation of the spermatozoon of the trypanorhynch cestode Aporhynchus menezesi Noever, Caira, Kuchta et Desjardins, 2010 are described by means of transmission electron microscopy. Type I spermiogenesis of A. menezesi starts with the formation of a differentiation zone containing two centrioles separated by an intercentriolar body constituted by five electron-dense plates. Each centriole gives rise to a free flagellum, which grows at an angle of 90 degrees in relation to a median cytoplasmic process. The nucleus and cortical microtubules elongate along the spermatid body. Later, both flagella rotate and fuse with the median cytoplasmic process. At the final stage of spermiogenesis, the young spermatozoon is detached from the residual cytoplasm by a narrowing of the ring of arched membranes. The mature spermatozoon is a long and filiform cell, tapered at both ends, lacking mitochondria. It is characterized by the presence of two axonemes of the 9+'1' trepaxonematan pattern, the absence of crested bodies, the presence of parallel cortical microtubules and nucleus. This pattern corresponds to the type I spermatozoon of the eucestodes. The anterior extremity of the spermatozoon is characterized by the presence of an arc-like row of up to seven parallel cortical microtubules that partially surrounds the first axoneme. These anterior cortical microtubules are thicker than the posterior microtubules and, consequently, the sperm cell of A. menezesi exhibits two types of cortical microtubules. Another interesting aspect is the presence of alpha-glycogen rosettes. This spermatological pattern is similar to that observed in the spathebothriidean and diphyllobothriidean cestodes. PMID- 21539141 TI - Antineoplastic effects of simvastatin in experimental breast cancer. AB - BACKGROUNDS: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have proven therapeutic and preventive effects on cardiovascular diseases. Preclinical evidence demonstrates tumor-suppressive effects of statins in several human neoplasias, including breast cancer. MATERIALS AND METHODS: In this study, antineoplastic effects of simvastatin in chemoprevention of N-methyl-N nitrosourea-induced mammary carcinogenesis in female rats were evaluated. The drug was dietary administered at two concentrations--18 mg/kg (SIMVA 18) and 180 mg/kg (SIMVA 180). RESULTS: Basic parameters of experimental carcinogenesis after long-term simvastatin treatment in animals were assessed. In the SIMVA 180 group, simvastatin significantly suppressed tumour frequency by 80.5% and tumour incidence by 58.5% in comparison to the controls. Higher dose simvastatin non significantly decreased the mean tumor volume by 23.5%, as well as non significantly lengthened the latency period by 14.5 days compared to the control animals. Simvastatin, administered at a lower dose did not change parameters of mammary carcinogenesis in comparison to the control group. Simvastatin in both treated groups significantly decreased serum levels of triacylglycerols and VLDL cholesterol in comparison to the control animals. Compared to the controls, a significant increase in food intake by the animals was recorded in the SIMVA 18 and SIMVA 180 groups. No significant differences in the final body weight gain between the simvastatin-administered and the control group were found. CONCLUSION: This study represents the first report of simvastatin use in experimental mammary carcinogenesis in vivo. PMID- 21539142 TI - Smoking: a preventable cause of rheumatoid arthritis. PMID- 21539143 TI - Which patients with renal colic should be referred? AB - Around 1-2 people per thousand present with an acute episode of pain caused by renal stones each year. Renal colic is classically sudden in onset, unilateral, and radiates from loin to groin. Renal pelvic or upper ureteric stones usually cause more flank pain and tenderness while lower ureteric stones cause pain radiating towards the ipsilateral testicle or labia. Other common symptoms include nausea and vomiting, haematuria and irritative LUTS. A febrile patient with renal colic requires immediate hospital admission. Symptoms suggestive of renal colic along with a positive dipstick for haematuria have a reported sensitivity of 84% and specificity of 99% but it is important to consider other differential diagnoses. An NSAID is preferred over an opiate drug as an initial analgesic choice as the NSAID can help reduce ureteric spasm. Diclofenac has the best evidence base for this class of analgesic. About 90% of stones will pass spontaneously and thus it is often appropriate to manage renal colic at home. Patients with signs of peritonitis, systemic infection, septic shock as well as those whose diagnosis is unclear should be referred urgently to hospital. Patients who are systemically unwell with renal stones are more likely to have an infected and obstructed urinary tract system that needs urgent imaging and possible drainage. All patients who are managed at home should have renal tract imaging within a week by fast track referral to radiology or as an urgent urology outpatient referral as per local guidelines to rule out an obstructed urinary system. Patients with recurrent stones should be advised to maintain a copious fluid intake (>2 L/day) to reduce the concentration of the urine. A reduction in salt intake (ideally <2g/day) and animal protein in the diet can help to reduce stone formation. PMID- 21539145 TI - Treatment of neurasthenia by hypnotism and suggestion. 1911. PMID- 21539144 TI - Managing patients on dialysis in the community. AB - In an average GP practice there will be one or two patients currently on renal replacement therapy (RRT) and a larger number with progressive chronic kidney disease who will reach end stage renal disease (ESRD). The options for RRT are kidney transplantation, haemodialysis (HD) or peritoneal dialysis (PD). For many patients with ESRD, treatment at home allows greater flexibility and independence than can be facilitated by inpatient HD. PD can be broadly categorised into two types: continuous ambulatory peritoneal dialysis and automated peritoneal dialysis. Each PD patient has a personalised prescription depending on their body mass, residual renal function and the physical properties of their peritoneal membrane. On average patients can have four years of successful PD before needing to switch to an altemative mode of RRT. In home haemodialysis (HHD), the entire process is initiated and managed by the patient at home. HHD is an option for any motivated patient who can learn the necessary skills to manage their own HD and deal with the potential complications. The strongest clinical argument for choosing HHD is the ability to provide longer and more regular HD sessions. Daily HD results in an improvement in BP control, solute clearance and anaemia management, and thus confers a significant survival benefit to patients. PMID- 21539146 TI - GPs have key role in detecting familial hypercholesterolaemia. AB - Currently the vast majority of people with familial hypercholesterolaemia (FH) in the U.K. remain undiagnosed, probably 85% of the predicted 120,000 cases. FH is a common inherited disorder of lipid metabolism causing high levels of LDL cholesterol which leads to early CHD. It has an autosomal dominant pattern of inheritance so siblings and children of a patient with FH will have a 50% chance of inheriting the condition. FH is present in the heterozygous form in 1 in 500 of the population. The homozygous form is very rare, affecting 1 in 1,000,000. Around half of men with FH, if untreated, will have developed clinically evident CHD by the age of 55 years, and approximately one third of women by the age of 60. A significant reduction in the mortality and morbidity of the disease can be achieved through changes in lifestyle and the use of statins to lower cholesterol. NICE recommends that clinical management of FH patients should primarily be carried out in lipid clinics. When cascade testing from lipid clinics is underway, GPs will be approached by relatives who have been identified as being at 50% risk of having FH, because they have an affected first-degree relative with the disorder. They will then need to take a blood sample for cholesterol measurement, and often will also be asked to provide a sample for DNA testing. A preliminary investigation in the surgery of a family member would involve a full lipid profile to calculate LDL cholesterol. If this is not elevated in an adult, cut-off value 4.9 mmol/L, FH is highly unlikely. Even if an FH patient is young, currently does not have CHD and may have no other CHD risk factors, the Framingham risk charts should not be used. These individuals are at increased CHD risk which warrants treatment with statins. The vascular health check screening programme recommends that where a total cholesterol of > 7.5 mmol/L is found FH should be considered. PMID- 21539148 TI - Cancer and the general practitioner. 1911. PMID- 21539147 TI - Pregnancy related conditions. PMID- 21539149 TI - What do you mean my results are 'normal'? PMID- 21539150 TI - A new beta-naphthalenecarboxylic acid biglycoside from Chirita longgangensis var. hongyao. AB - To investigate the chemical constituents in the stems of Chirita longgangensis var. hongyao, methanol extract of the stems was subjected to column chromatography with various chromatographic techniques. One new beta naphthalenecarboxylic acid biglycoside, 1, 4-dihydroxy-2-naphthalenecarboxylic acid methyl ester-4-O-alpha-L-rhamnopyranosyl-(1-->6)-beta-D-glucopyranoside (1) was isolated, along with two known compounds: isotaxiresinol 4-O-methyl ether (2) and (R)-7-hydroxy-alpha-dunnione (3). Compound 2 was first obtained from Chirita genus and compound 3 was isolated from this plant for the first time. All structures were elucidated on the basis of spectral and chemical evidence, and the NMR spectroscopic data of compound 2 was published for the first time. PMID- 21539151 TI - Characterization of diterpenoids in the bark of Pseudolarix kaempferi by HPLC ESI/MSn. AB - Fragmentation behavior of diterpenoids was investigated by ESI/MSn and the qualitative analysis of diterpenoids in the bark of Pseudolarix kaempferi was performed using high-performance liquid chromatography/ multi-stage mass spectrometry (HPLC-ESI/MSn). The characteristic fragmentation behaviors of the diterpenoids are the cleavages of the lactone ring and C4-O bond. Furthermore, the eliminations of substituent groups at C-18, C-7 and C-8 can also be observed in the MS" (n = 3-4) spectra. For C-4 acetoxy subsititued diterpenoids, [M+Na 60]+ and [M-H-104] are the base peaks of MS2 spectra in the positive and negative ionization modes, respectively. For C-4 hydroxyl subsititued diterpenoids, [M+Na 44]+ and [M-H-62] are the base peaks of MS2 in the positive and negative ionization modes, respectively. For C-18 glucosylated or esterized diterpenoids, [M+Na-44]+ is the base peak of MS2 spectra in positive ionization mode. These fragmentation rules were successfully exploited in the identification of diterpenoids in methanol/water (6:4) extract of P. kaempferi by LC-MS in positive ionization mode. A total of 9 diterpenoids were identified or tentatively characterized, and one of them is reported here for the first time. The described method could be utilized for the sensitive and rapid qualitative analysis of P. kaempferi. PMID- 21539152 TI - Modulating drug loading and release profile of beta-cyclodextrin polymers by means of cross-linked degree. AB - The purpose of the present study is to use beta-cyclodextrin polymers (beta-CDP) with different cross-linked degree (CLD) to form inclusion complexes with ibuprofen and examine the effects of structural and compositional factors of beta CDP on its drug loading and release behaviors. A series of beta-CDP with different CLD were synthesized and characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and 13C NMR spectrum. The beta-CDP was systemically characterized for the relation between the CLD of beta-CDP and the drug loading and release as well. The results of FT-IR and 13C NMR showed that similar peak shaped vibration of beta-CDP and beta-CD implies that the polymer keeps the original characteristic structure of beta-CD. The CLD of the beta-CDP played a critical role in the drug loading and release, increasing the CLD resulted in reduction of drug loading, but increase in drug release. PMID- 21539153 TI - Virtual Valley Forge: a revolutionary hospital concept. PMID- 21539154 TI - The Fort Campbell High Interest Program. PMID- 21539155 TI - The use of human umbilical cord blood for wound healing, burns, and brain injury in combat zones. PMID- 21539156 TI - The injured brain: TBI, mTBI, the immune system, and infection: connecting the dots. AB - Traumatic brain injury or stroke causes profound suppression of the cellular immune system and short- and long-term psychological sequelae. Infection is also a common result and is likely caused by bacterial translocation from the gut. Both the bacterial translocation from the gut and the ensuing pneumonia and sepsis are ameliorated by adoptive immune therapy. Huge health care costs are incurred by brain trauma and its sequelae in our soldiers, athletes, and general population. Diffusion tensor imaging and adoptive immune therapy should become standards of care to follow the injured brain serially as it heals and as the immune suppression and infections are overcome. Brain infrastructure healing is retarded by a suppressed immune system, and the blood-brain barrier's response to trauma offers opportunity for adoptive immune therapy to enhance microglial directed neuronal repair and maintenance. PMID- 21539157 TI - Posttraumatic stress disorder and metabolic syndrome: retrospective study of repatriated prisoners of war. AB - OBJECTIVE: We conducted a retrospective study of metabolic data for Vietnam-era repatriated prisoners of war (RPWs) and a comparison group to determine if metabolic syndrome (MbS) was more common in those individuals with clinically diagnosed, current or lifetime posttraumatic stress disorder (PTSD) as suggested in a recent report. METHODS: The metabolic data of our patients nearest the time of psychiatric evaluation (1998-2004) for PTSD were analyzed using both an analysis of variance and logistic regression. RESULTS: Although we found elevated triglyceride levels (40 mg/dl higher) in RPWs with PTSD who met MbS criteria, overall the prevalence of MbS was the same in RPWs with and without PTSD and comparison group. Moreover, current PTSD symptom severity did not increase the likelihood of MbS. CONCLUSIONS: Our results from these repatriates who actively participate in a 37-year medical follow up program do not support the conclusion that MbS occurs more commonly in individuals with current PTSD. PMID- 21539158 TI - Clinical quality management in the combat zone: the good, the bad, and the unintended consequences. AB - Clinical quality management (CQM) is a fixture of modern U.S. healthcare to include fixed military medical treatment facilities. CQM is now being applied to the battlefield. In a related fashion, standards of care have been proposed in the context of combat medicine. The overall goal is to improve the medical care of casualties. Despite good intentions, the concepts and execution of CQM and standards of care are neither well-described in the literature nor established in official military doctrine and regulation. This has resulted in variable and haphazard applications that range from the positive and supportive to the negative and counterproductive. This article outlines the use of CQM in combat operations and asserts that a deliberate analysis of the benefits and risks is needed before its continued use. Future directions should focus on the impact of CQM on mission, doctrine, training, staffing, and unit organization. Rigorous adherence to evidence of effectiveness is essential before applying CQM in the combat zone. PMID- 21539159 TI - Unmet health services needs experienced by Puerto Rican OEF/OIF veterans and families post deployment. AB - OBJECTIVE: This study examined perceptions of unmet health services needs among native Puerto Rican Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) Veterans and family members (FMs) post deployment. METHODS: Investigators used qualitative methods to collect and analyze data from 8 veterans and 8 FMs (N = 16). All participants were native-born residents of Puerto Rico. Investigators conducted single, in-depth interviews with participants. They conducted 13/16 interviews in Spanish. Puerto Rican-Spanish speakers transcribed audio-taped interviews verbatim and then translated them into English for coding. RESULTS: Veterans' unmet needs included psychological evaluations, mental health services, support groups, medical evaluations, and pain treatment. Denial and stigma emerged as factors that deter Veterans from seeking mental health treatment. The need for family support groups also emerged from the data. CONCLUSIONS: Native Puerto Rican Veterans and FMs identified several gaps in health services. Findings suggest the need for studies comparing the health services needs of Puerto Rican versus mainland OEF/OIF Veterans and families. PMID- 21539160 TI - Psychological well-being of Canadian Forces officer candidates: the unique roles of hardiness and personality. AB - Previous research has found that individual characteristics play an important role in psychological wellbeing and perception of stress. Although the Five Factor Model of personality has been found to consistently predict psychological well-being in the general population and among military personnel, hardiness has also been found to be a predictor of well-being. This study examined the unique role of hardiness, above that of personality, in the well-being and stress perceptions of Canadian Forces officer candidates undergoing basic training. The results of the study were consistent with those of previous research, suggesting that military hardiness is an important predictor of well-being and stress perceptions. Furthermore, hardiness was related to all domains of psychological well-being and training perceptions when the Five Factor Model of personality was statistically controlled. These findings demonstrate that hardiness and personality constitute 2 different constructs, both of which have significant contributions to well-being. PMID- 21539161 TI - Socio-cultural factors that foster use and abuse of alcohol among a sample of enlisted personnel at four Navy and Marine Corps installations. AB - Rates of heavy drinking are consistently higher among U.S. military personnel than among civilians, particularly among young male personnel. In addressing drinking in the military, more information is needed on contextual factors influencing drinking to better understand the conditions that lead to or facilitate drinking. Results from 15 focus groups conducted with enlisted personnel at 2 Navy and 2 Marine Corps installations as part of formative research for an alcohol abuse prevention trial are reported in this article. The study explored the "drinking climate" of each installation in terms of shared attitudes and recognized norms regarding alcohol use and installation personnel's general understanding of policies concerning alcohol consumption. Analysis revealed several contextual factors that add to our understanding of drinking behaviors. PMID- 21539162 TI - Psychosocial screening in children with wartime-deployed parents. AB - Children of U.S. military families are exposed to unique challenges and stressors directly related to their parents' wartime deployments, potentially placing them at higher risk for psychosocial disruption. The objective of this study was to investigate the effects of parental wartime military deployment on psychosocial symptoms as measured by parent and youth self-report on the Pediatric Symptom Checklist. During annual physicals at a large military pediatric clinic, parents (216) and youth (198) were surveyed about emotional and behavioral difficulties and the current status of parental deployment. Parents reported more child psychosocial symptoms, and youth self reported more psychosocial symptoms if there was a currently deployed parent. Youth self-reports may be another way to identify psychosocial symptoms in at-risk military youth. These findings accentuate the importance of training providers who care for military youth to recognize and respond to their unique needs during parental deployment. PMID- 21539163 TI - How well do the Framingham risk factors correlate with diagnoses of ischemic heart disease and cerebrovascular disease in a military beneficiary cohort? AB - We sought to determine how well the Framingham prediction rules correlate with ischemic heart disease and cerebrovascular disease in a military beneficiary cohort by examining demographic and International Classification of Diseases, Ninth Revision codes from electronic medical records between 2001 and 2008. This sample (n = 163,627) included people averaged at 52 years of age (range 18-108); slightly more than half were male (55%), 21% were African-American, and 59% were Caucasian. Fifteen percent of beneficiaries had ischemic heart disease and 3.4% had cerebrovascular disease. The Framingham model fits our data well; all Framingham risk factors were associated with increased likelihood of ischemic heart disease and all Framingham risk factors except gender increased cerebrovascular disease prevalence. Age was the strongest correlate for both ischemic heart disease and cerebrovascular disease (> 60 years old; ischemic heart disease relative risk, 3.9; 95% confidence interval, 3.7-4.0; cardiovascular disease relative risk, 3.9; 95% confidence interval, 3.6-4.2) followed by hyperlipidemia and hypertension. We conclude that military clinicians can risk stratify military beneficiaries using the Framingham risk model. PMID- 21539164 TI - An uncommon cause of chest pain in the deployed soldier. AB - Chest pain is a common complaint at medical treatment facilities during combat operations. The initial evaluation focuses on potentially life-threatening conditions (acute coronary syndrome, aortic dissection, pulmonary embolus), in addition to pericarditis and benign musculoskeletal conditions such as costochondritis. Pulmonary arteriovenous malformation is a rare condition, but an important diagnostic consideration in soldiers who present with chest pain and/or hypoxia and in whom other life-threatening conditions, such as cardiovascular disasters and pulmonary embolus, are excluded. We present the case of a male soldier deployed to Operation Iraqi Freedom, who was air-evacuated back to Washington, DC, for definitive care. We present his case and a review of the relevant literatures on the diagnosis and treatment of patients with pulmonary arteriovenous malformations. PMID- 21539165 TI - Females have a greater incidence of stress fractures than males in both military and athletic populations: a systemic review. AB - OBJECTIVE: The purpose of this study was to review incidence of stress fractures in military and athlete populations and identify factors explaining causes and differences in the incidence among genders. METHODS: Searches were conducted using several major databases. The studies were included if they were original studies including both male and female subjects and their aim was to identify incidence rates and risk factors contributing to the development of stress fractures. Of several thousand studies, 11 focusing on military populations and 10 on athletes are discussed. RESULTS: In both populations, females had higher incidence of stress fractures, with incidence of approximately 3% and approximately 9.2% for males and females, respectively, in military populations and approximately 6.5% and approximately 9.7%, respectively, in athletes. CONCLUSIONS: Factors possibly explaining why females are more susceptible to stress fractures include bone anatomy, lower aerobic capacity, smaller muscle, and poor diet. However, both female recruits and athletes with normal weight and bone health are less likely to develop stress fractures, showing that gender is less important than the overall physical shape/condition. PMID- 21539166 TI - Predicting success in the tactical air combat party training pipeline. AB - OBJECTIVES: To develop a statistical model that predicts the likelihood of success or failure of military training candidates using tests administered before initial skill training as inputs. METHODS: Data were acquired from candidates before the start of U.S. Air Force Tactical Air Control Party training, including (1) demographic, (2) psychological composition evaluated using Emotional Quotient Inventory, (3) physical performance capability, (4) a physical activity questionnaire, and (5) salivary fatigue biomarker index. A total of 126 candidates were tracked until they either passed or failed the training, and a total of 55 variables were used as inputs for creation of the model. RESULTS: Clustering analysis of the data revealed that only 4 of 55 variables were useful for predicting success or failure. The variables in the order of their importance are as follows: run time, number of miles run per week in the last year, level of salivary fatigue biomarker, and height. CONCLUSIONS: The results suggest that simple testing methods can identify candidates at high risk of failure. PMID- 21539167 TI - Anthropometric characteristics of feet of soldiers in the New Zealand Army. AB - Lower limb and lower back injuries are prevalent within the New Zealand (NZ) Army: independently collected data shows these to be most prevalent, with on average 10% of military personnel affected by such an injury at any time. To improve the quality and appropriateness of footwear, it is essential that normative foot anthropometric data is collected from NZ Army personnel. NZ Army personnel (n = 807) were included in this study; data on foot length, circumference, width, and arch heights were collected. It was found that the NZ Army personnel had notable differences in feet anthropometry compared to an exemplary model for the NZ general population, specifically in terms of arch height. It was also found that a substantial proportion (approximately 50%) of personnel tested could not be provided with a boot that fit (mainly Maori and Pacific Island soldiers) because of a limited width range of the currently issued boot. PMID- 21539168 TI - Descriptive epidemiology of 153 diving injuries with rebreathers among French military divers from 1979 to 2009. AB - INTRODUCTION: Rebreathers are routinely used by military divers, which lead to specific diving injuries. At present, there are no published epidemiologic data in this field of study. METHODS: Diving disorders with rebreathers used in the French army were retrospectively analyzed since 1979 using military and medical reports. RESULTS: One hundred and fifty-three accidents have been reported, with an estimated incidence rate of 1 event per 3,500 to 4,000 dives. Gas toxicities were the main disorders (68%). Loss of consciousness was present in 54 cases, but only 3 lethal drowning were recorded. Decompression sicknesses (13%) were exclusively observed using 30 and 40% nitrox mixtures for depth greater than 35 msw. Eleven cases of immersion pulmonary edema were also noted. CONCLUSION: Gas toxicities are frequently encountered by French military divers using rebreathers, but the very low incidence of fatalities over 30 years can be explained by the strict application of safety diving procedures. PMID- 21539169 TI - Acute water intoxication during military urine drug screening. AB - Random mandatory urine drug screening is a routine practice in the military. The pressure to produce a urine specimen creates a temptation to consume large volumes of water, putting those individuals at risk of acute water intoxication. This occurs when the amount of water consumed exceeds the kidney's ability to excrete it, resulting in hyponatremia owing to excess amount of water compared to serum solutes. The acute drop in serum osmolality leads to cerebral edema, causing headaches, confusion, seizures, and death. There has been increasing awareness of the danger of overhydration among performance athletes, but dangers in other groups can be underappreciated. We present the case of a 37-year-old male Air Force officer who developed acute water intoxication during urine drug screening. Our case demonstrates the need for a clear Air Force policy for mandatory drug testing to minimize the risk of developing this potentially fatal condition. PMID- 21539170 TI - Accuracy of user-friendly blood typing kits tested under simulated military field conditions. AB - Rapid user-friendly ABO-Rh blood typing kits (Eldon Home Kit 2511, ABO-Rh Combination Blood Typing Experiment Kit) were evaluated to determine their accuracy when used under simulated military field conditions and after long-term storage at various temperatures and humidities. Rates of positive tests between control groups, experimental groups, and industry standards were measured and analyzed using the Fisher's exact chi-square method to identify significant differences (p < or = 0.05). When Eldon Home Kits 2511 were used in various operational conditions, the results were comparable to those obtained with the control group and with the industry standard. The performance of the ABO-Rh Combination Blood Typing Experiment Kit was adversely affected by prolonged storage in temperatures above 37 degrees C. The diagnostic performance of commercial blood typing kits varies according to product and environmental storage conditions. PMID- 21539171 TI - Self-reported tinnitus and ototoxic exposures among deployed Australian Defence Force personnel. AB - The objective of this study was to investigate the effect of chemical and environmental exposures during deployment on tinnitus among Australian Defence Force personnel previously deployed to Bougainville and East Timor. Participants were asked to self-report recent occurrence and severity of "ringing in the ears," and identify any chemical and environmental exposures during their deployment. Self-reported exposure to loud noises, heavy metals, intense smoke, engine exhaust, solvents and degreasing agents, and chemical spills increased the risk of self-assessed moderate or severe tinnitus. Daily exposure to 4 or more ototoxic factors was associated with 2- to 4-fold increase in the risk. In addition to loud noises, chemical exposures may also play a role in the development of tinnitus among Australian Defence Force personnel serving overseas. PMID- 21539172 TI - Management of a laterally luxated upper incisor caused by the hit of a rifle stock. AB - Lateral luxation is the displacement of the tooth in a direction other than axial, which is accompanied by comminution or fracture of the alveolar socket. Lateral luxation is one of the most prevalent dental injuries among the general population, resulting in up to 27% of all dental wounds. All physical activities have an associated risk of orofacial injuries due to falls, collisions, and contact with hard surfaces. Just like any other training activities, military training exercises present a significant risk of dental traumas, which comprise 2% to 8% of all military dental emergencies. The aim of this report was to present a case of a dental lateral luxation caused by the hit of a rifle stock during close combat training. The tooth was extruded from its bony lock, temporarily filled with a calcium hydroxide-based paste, replaced into its original anatomic position, and secured with Ivy loop wirings. The permanent endodontic treatment was performed 4 weeks after repositioning. At the end of the 8-months follow-up, the tooth was asymptomatic and any pathological alterations were absent. PMID- 21539173 TI - A case of combat-related scorpion envenomation in Afghanistan. AB - We report a case of scorpion envenomation occurring during combat in Tagab district, province of Kapisa, Afghanistan. A French soldier was stung by a yellow scorpion (suspected Androctonus australis) and sustained systemic envenomation with hemodynamic and neurological manifestations. We discuss the clinical features, prevention, and management of a scorpion sting. PMID- 21539174 TI - Non-cirrhotic hepatocellular carcinoma in a young active duty male. AB - A 22-year-old Airman was presented to the clinic with new onset abdominal pain, which revealed to be well-differentiated hepatocellular carcinoma. Hepatocellular carcinoma in a young patient with no cirrhosis or fibrosis is a relatively rare diagnosis with possible relationship to exercise supplement use. With the high incidence of supplement use in the military population, caution and further investigation into supplement use with correlation to the incidence of liver cancers may be warranted. PMID- 21539175 TI - Emergency canine surgery in a deployed forward surgical team: a case report. AB - INTRODUCTION: Forward surgical teams (FSTs) perform a variety of non-doctrinal functions. During their deployment to Afghanistan, the 541st FST (Airborne) performed emergency surgery on a German shepherd military working dog (MWD). METHODS: Retrospective examination of a case of veterinary surgery in a deployed FST. RESULTS: A 5 1/2-year-old German shepherd MWD presented with extreme lethargy, tachycardia, excessive drooling, and a firm, distended abdomen. These conditions resulted from gastric dilatation with volvulus. Since evacuation to a veterinarian was untenable, emergency laparotomy was performed in the FST. The gastric dilatation with volvulus was treated by detorsion and gastropexy, and the canine patient fully recovered. CONCLUSION: Canine surgery can be safely performed in an FST. Based on the number of MWDs deployed throughout the theater, FSTs may be called upon to care for them in the absence of available veterinary care. PMID- 21539176 TI - Rationing human life: health care reform and people with disabilities. AB - Peter Singer has proposed health care rationing that includes an invidious discrimination against people with disabilities. Unfortunately, Congress has codified the potential for such discrimination in the 2010 Patient Protection and Affordable Care Act. But why should any public official have the discretion to treat the lives of people with disabilities as of "lower value" than the lives of anyone else. There must be a comprehensive limitation in the law against the misuse of comparative clinical effectiveness research to support the rationing of human life. PMID- 21539177 TI - The good, the bad, and the ugly: how the due process clause may limit comprehensive health care reform. AB - This article examines atopic which has receivedlittle attention from the media or other scholarly publications: The due process concerns that arise when engaging in comprehensive federal health care reform and regulation. First, the article provides a background discussion detailing the factors necessitating health care reform in the United States. Second, it analyzes whether a constitutionally protected right to make personal health care decisions exists under the Fifth and Fourteenth Amendments' Due Process Clauses. Finally, the article analyzes the susceptibility of government-sponsored health care-specifically proposals which include a public option-to due process challenges and makes suggestions to avoid any potential fundamental rights violations. PMID- 21539178 TI - Other people's lives: reflections on medicine, ethics, and euthanasia. Part two: medicine versus euthanasia. PMID- 21539179 TI - Linkage of a RAPD marker with powdery mildew resistance. AB - The aim of this study was to investigate the inheritance of powdery mildew disease and to tag it with a DNA marker to utilize for the marker-assisted selection (MAS) breeding program. The powdery mildew resistant genotype Fallon(er) and susceptible genotype 11760-3ER were selected from 177 genotypes by heavy infestation of germplasm with Erysiphe pisi through artificial inoculation. The F1 plants of the cross Fallon/11760-3 indicated the dominance of the susceptible allele, while F2 plants segregated in 3 : 1 ratio (susceptible : resistant) that fit for goodness of fitness by chi2 (P > 0.07), indicating monogenic recessive inheritance for powdery mildew resistance in Pisum sativum. A novel RAPD marker OPB18 (5'-CCACAGCAGT-3') was linked to the er-1 gene with 83% probability with a LOD score of 4.13, and was located at a distance of 11.2 cM from the er-1 gene. PMID- 21539180 TI - Study of genetic variation in sesame (Sesamum indicum L.) using agro morphological traits and ISSR markers. AB - This research was conducted to study the genetic variation among eighteen genotypes of sesame (Sesamum indicum L.) collected from various agro-climatic regions of Iran along with six exotic genotypes from the Asian countries using both agro-morphological and ISSR marker traits. The results showed significant differences among genotypes for all agro-morphological traits and a relatively high genetic coefficient of variation observed for number of fruiting branches per plant, capsules per plant, plant height and seed yield per plant. Cluster analysis based on these traits grouped the genotypes into five separate clusters. Larger inter- than intra cluster distances implies the presence of higher genetic variability between the genotypes of different groups. Genotypes of two clusters with a good amount of genetic divergence and desirable agronomic traits were detected as promising genotypes for hybridization programs. The 13 ISSR primers chosen for molecular analysis revealed 170 bands, of which 130 (76.47%) were polymorphic. The generated dendrogram based on ISSR profiles divided the genotypes into seven groups. A principal coordinate analysis confirmed the results of clustering. The agro-morphological traits and ISSR markers reflected different aspects of genetic variation among the genotypes as revealed by a non significant cophenetic correlation in the Mantel test. Therefore the complementary application of both types of information is recommended to maximize the efficiency of sesame breeding programs. The discordance among diversity patterns and geographical distribution of genotypes found in this investigation implies that the parental lines for hybridization should be selected based on genetic diversity rather than the geographical distribution. PMID- 21539181 TI - Y chromosome--a tool in infertility studies of Latvian population. AB - Human Y chromosome is used as a tool in male infertility and population genetic studies. The aims of this research were to analyse the prevalence of Y chromosome microdeletions among infertile Latvian men, and to identify possible lineages of Y chromosome that may be at increased risk of developing infertility. A study encompassed 105 infertile men with different spermatogenic disturbances. Deletions on Y chromosome were detected in 5 out of 105 (approximately 5%) cases analysed in this study. Three of them carried deletion in AZFc region and two individuals had AZFa + b + c deletion. Study of Y chromosome haplogroups showed that N3a1 and R1a1 lineages were found less frequently in the infertile male group compared to ethnic Latvian group, however K* cluster was predominantly found in infertile male Y chromosomes. CONCLUSIONS: 1) Our study advocates running Y chromosome microdeletion analyses only in cases of severe form of infertility; 2) Y chromosome haplogroup analysis showed statistically significant tendencies that some haplogroups are more common in ethnic male group, but others are more common in infertile males. PMID- 21539182 TI - Morphogenetic variability and handedness in Montenegro and Serbia. AB - This study tries to establish correlations between the types of handedness and several morpho-physiological characteristics, controlled by one or a small number of genes with alternative dominant recessive manifestation. The population genetic homozygosity degree study includes the analysis of the presence, distribution and individual traits combination in left-handed and right-handed persons. It was conducted at three localities in two states, Serbia (SRB) and Montenegro (MNE). Our hypothesis is that a possible genetic load due to increased recessive homozygosity, being a potential population-genetic parameter of left handedness manifestation, may cause some change in other morpho-physiological characters. The average proportion of 23 studied homozygously-recessive characters (HRC's) was similar among observed left-handed individuals in the studied localities. It varied from 10.5 +/- 0.4 in Serbia to 10.7 +/- 0.3 in MNE. The differences were somewhat bigger among right-handed persons, varying from 8.7 +/- 0.3 in MNE to 9.1 +/- 0.3 HRC's in Serbia. However, in all localities the average homozygosity was significantly higher among left-handed school children. The number of HRC's among 400 individuals varied from 2 to 16 among right-handed and from 4 to 19 among left-handed persons. There were no differences in scholar scores between left-handed and right-handed children, although small differences were found between two state samples. PMID- 21539183 TI - Study of the HLA class II allele polymorphism and phylogenetic analysis in Vojvodina population. AB - The polymorphism at the HLA DRB1 and DQB1 loci in the population of Vojvodina was studied by PCR-SSP method. A total of 13 DRB1 and 5 DQB1 specificities displaying population-specific frequency distribution pattern were described. The most frequent HLA Class II alleles in Vojvodina population were: HLA-DRB1*11 (af = 0.30), -DRB1*04 (af = 0.28), -DRB1*07(af = 0.21), -DRB1*13 and -DRB1*16 (af = 0.18), -DQB1*03 (af = 0.64), -DQB1*05 (af = 0.39) and -DQB1*02 (af = 0.35). The haplotypes with high frequencies (> or = 0.02) included HLA DRB1*11 DQB1*03 (0.0825), DRB1*04DQB1*03 (0.0725), DRB1*07DQB1*02 (0.0475). The allele DRB1*07 showed the strongest association with DQB1*02 (delta = 0.0261, chi2 = 4.437) and DRB1*13 allele with DQB1*06 (delta = 0.0222, chi2 = 4.247). The allelic frequencies and populations distance dendrogram revealed the closest relationship of Vojvodina population with Hungarians, Croat, and Greeks which can be the result of turbulent migration within this region and admixture with neighbour populations during the history. PMID- 21539184 TI - Gastrointestinal passage of Bacillus cereus. PMID- 21539185 TI - Conjugated linoleic acid and conjugated linolenic acid production by bifidobacteria. PMID- 21539186 TI - The ethylene biosynthesis in Jonagold apple during ripening, storage and shelf life--a modelling appraoch. PMID- 21539187 TI - Construction of data-driven models to predict the occurrence of planktonic species in the North Sea. PMID- 21539188 TI - Modelling nitrous oxide emissions from a Sharon reactor. PMID- 21539189 TI - Increasing the cost-efficiency of membrane bioreactors by advanced process control. PMID- 21539190 TI - Investigating kernel structures for shear and Ca-induced activated sludge aggregation using a population balance model with an inverse problem methodology. PMID- 21539191 TI - An approach to represent realistic particles of bulk assembly in three dimensional-DEM simulations and applications. PMID- 21539192 TI - Modelling greenhouse temperature and humidity in order to develop an energy saving model-based control strategy. PMID- 21539193 TI - Parameterization of a stochastic cellular automaton describing a chemical reaction. PMID- 21539194 TI - Search for new alternatives in the battle against histomonosis in turkeys. PMID- 21539195 TI - Detrimental shifts in microbial communities from inflammatory bowel disease patients upon selective pressures. PMID- 21539196 TI - IFABP expression as diagnostic tool for integrity of epithelium. PMID- 21539197 TI - Single-cell level decision-making between growth and dormancy. PMID- 21539198 TI - Anaerobic oxidation of methane in a simulated cold seep ecosystem. PMID- 21539199 TI - Identification of key-genes from the sophorolipid biosynthetic pathway of Candida bombicola opens a new route to increased biosurfactant yields. PMID- 21539200 TI - Transcriptomic analysis of phenanthrene degrading Sphingomonas biofilms exposed to environmentally relevant solute and matric stresses. PMID- 21539201 TI - Biogenic silver nanoparticles for disinfection of viral contaminated water. PMID- 21539202 TI - Antibacterial properties of biogenic silver stabilised on lactobacillus cell walls. PMID- 21539203 TI - Opportunities and challenges for molecular farming in Flanders. PMID- 21539204 TI - Consumer attitudes towards beef and beef technologies. PMID- 21539205 TI - Consumer perception and behaviour related to food labelling. PMID- 21539206 TI - Detection of hazelnut in food by PCR. PMID- 21539207 TI - Development of competitive ELISA for the soybean protein detection in processed foods. PMID- 21539208 TI - Bacterial modulation of the fasting induced adipose factor (FIAF) in an intestinal cell line model: a potential host-microbe crosstalk related to obesity. PMID- 21539209 TI - Furan formation in baby food model system via lipid oxidation and sugar degradation. PMID- 21539210 TI - Isolation and applications of milk fat globule membrane material: isolation from buttermilk and butter serum. PMID- 21539211 TI - Formation of semicarbazide upon hypochlorous acid treatment of nitrogen containing compounds. PMID- 21539212 TI - A microbial assessment scheme of the cooked chilled food production. PMID- 21539213 TI - High-throughput screening in search of broad applicable, small molecule inhibitors of salmonella biofilm formation. PMID- 21539214 TI - Plant species composition and vegetation structure of Angetu forest, southeastern Ethiopia. PMID- 21539215 TI - Prediction of the botanical composition of grass-clover mixtures by near infrared reflectance spectroscopy. PMID- 21539216 TI - Silicon-induced brown spot resistance in rice (Oryza sativa L.). PMID- 21539217 TI - Direct and indirect impacts of hemiparasitic plants on community structure and biogeochemical cycling in semi-natural grasslands. PMID- 21539218 TI - Using long-term monitoring data to detect changes in macroinvertebrate species composition in the harbour of Ghent (Belgium). PMID- 21539219 TI - Sustainable carbon neutral methane oxidation in anaerobic effluents through a partnership of methane oxidizing communities and microalgae. PMID- 21539220 TI - Quantification of greenhouse gas emissions from municipal wastewater treatment plants: a case study. PMID- 21539221 TI - Performance and greenhouse gas emissions from an industrial nitrogen removal plant: trade-off between water and air quality? PMID- 21539222 TI - Oland is feasible to treat sewage-like nitrogen concentrations at low hydraulic residence time. PMID- 21539224 TI - The antioxidant capacity of leek (Allium ampeloprasum var. porrum). PMID- 21539223 TI - Dehalogenation of trichloroethylene in microbial electrolysis cells with biogenic palladium nanoparticles. PMID- 21539225 TI - Effect of atomisation air pressure on solids concentration in a fluidised-bed coater. PMID- 21539226 TI - Application of a mechanistic UV/hydrogen peroxide model at full-scale: sensitivity analysis, calibration and performance evaluation. PMID- 21539227 TI - Palladium nanoparticles produced by fermentatively grown bacteria as catalyst for diatrizoate removal with biogenic hydrogen. PMID- 21539228 TI - Assessment of skinfold thickness as a factor related to chronic progressive lymphoedema in Belgian draught horses. PMID- 21539229 TI - Cell surface properties determine persistence of Pseudomonas aeruginosa. PMID- 21539230 TI - Reverse engineering of synaptic plasticity in the hippocampus. PMID- 21539231 TI - Comparison between different techniques to measure plant water uptake. PMID- 21539232 TI - Environmental factors affecting the prevalence of insect bite hypersensitivity in Belgian warmblood horses in Vlaanderen. PMID- 21539233 TI - Computational estimation of soybean oil adulteration in Nepalese mustard seed oil based on fatty acid composition. PMID- 21539234 TI - Morphological variation of plant architecture in red clover (Trifoliumpra tense). PMID- 21539235 TI - Novel insights in the acceptor specificity of cellodextrin phosphorylase. PMID- 21539236 TI - The presence and in vivo expression levels of virulence genes in vibrios belonging to the Harveyi clade in relation to virulence towards gnotobiotic brine shrimp. PMID- 21539237 TI - Transcriptional control of the general stress response in Rhizobium etli. PMID- 21539238 TI - Elucidating the structure-function relationship of a bacterial GTPase in DNA replication through random mutagenesis. PMID- 21539239 TI - Alarmone-dependent regulators in Rhizobium etli. PMID- 21539240 TI - Biofilm based bioremediation strategies for the treatment of pesticide waste streams. PMID- 21539241 TI - A systems biology approach to browning in apple: proteomics. PMID- 21539242 TI - Emamectin benzoate (Affirm). a modern insecticide for the control of lepidoptera larvae on fruits, grapes and vegetables crops. AB - Emamectin benzoate (Affirm) is a novel insecticide with potent efficacy against many specie of lepidoptera which are damaging fruits and leaves of agricultural crops. The active ingredient belongs to the naturally derived chemical group of avermectine, causing paralysis of lepidoptera larvae due to the activation of chloride channel at nerves level. Affirm is acting mainly through ingestion, due to its mode of action and fast activity, it is effective at very low rates and on all instars stages. It has been developed for the use on pomefruits, stonefruits, grapes and a broda range of vegetables crops at a rate range of 1.5 to 3 g ai/100L. The product shows translaminar activity and rapid degradation on leaf surface; therefore the active ingredient breaks down in a very short time to sublethal doses for most beneficials organisms living on the vegetation. The short rentry time, generally 24 hours for beneficials and impollinators, makes Affirm compatible for IPM programme in orchards and greenhouses. Also the residue profile is very favourable, leading to a very low maximum residue level and short preharvest interval in all edible crops. PMID- 21539243 TI - Integrated management of phytoplasma diseases in pome fruit: an overview of efficacy results of IPM insecticides against pear Psylla (Cacopsylla pyri). AB - Phytoplasmas are plant pathogenic mollicutes that cause devastating diseases in various crops worldwide. The closely related pome fruit tree phytoplasmas Candidatus Phytoplasma mali and Candidatus Phytoplasma pyri are the causal agents of apple proliferation and pear decline, respectively. They can be transmitted from tree to tree by Psyllidae. As pear suckers (Cacopsylla pyri) are widely considered to be the most important pest in pear orchards, a good control of this insect vector is a key element for limiting the natural spread of pear decline. Efficient control relies on a perfect tuning of treatment schedules, taking into account efficacies of (at preferably) low-impact insecticides and side (repellent)-effects of alternative products (e.g. kaolin, mineral oils and fungicides), the optimal positioning of these crop protection agents, and the best possible presence of beneficial predators. The department of Zoology of the pcfruit vzw research institute (Belgium) has a long tradition of executing insecticide field trials according to EPPO guidelines. Here, we present an overview of the results of a selection of IPM-compatible insecticides (abamectin, spirotetramat, thiacloprid, spinosad, spirodiclofen), tested in efficacy trials against pear Psylla on different life stages during the last decade. Based on these results and monitoring data of pest and beneficial biology, we additionally propose optimal pear Psylla control schedules which allow to reduce the number of (phytoplasma harbouring) psyllids in integrated systems to a minimum. PMID- 21539244 TI - The influence of humidity on the effect of Steinernema feltiae against diapausing codling moth larvae (Cydia pomonella L.) (Lepidoptera: Tortricidae). AB - Codling moth (CM) is a serious and global pest of pome fruit. It overwinters in cryptic habitats as cocooned diapausing larvae. Field trials with the entomopathogenic nematode Steinernema feltiae (Rhabditida: Steinernematidae) report control of diapausing CM of up to 70%, but results are variable. The objective of this study was to define environmental conditions favouring the performance of the nematodes. Cocooned larvae were more susceptible than non cocooned larvae. S. feltiae was unable to infect CM at a water activity (aw values) < or = 0.9. Mortality of cocooned larvae was reported at lower aw-values than of non-cocooned larvae. Exposure time and impact of external relative humidity (RH) was studied. Mortality of cocooned larvae did not further increase after half an hour of exposure, whereas the mortality increased with increasing exposure time in non-cocooned larvae. LC50 and LC90 considerably decreased with increasing RH. The influence of the relative humidity was less pronounced when surpassing 80% than the effect of the volume of applied water. When S. feltiae was formulated in a surfactant-polymer-formulation (SPF), mortality significantly increased when compared to application in water. PMID- 21539245 TI - The pathogenicity of Beauveria bassiana: what happens after an endophytic phase in plants? AB - The banana weevil Cosmopolites sordidus (Germar) (Coleoptera: Curculionidae) is a serious constraint to banana (Musa spp.) production throughout the world. The entomopathogenic fungus Beauveria bassiana (Balsamo) Vuillemin (Ascomycota: Hypocreales) offers a potential weevil management option, but conventional delivery mechanisms have limited its success. As an endophyte, however, B. bassiana can be efficiently delivered to banana planting materials for the potential management of C. sordidus. However, entomopathogens can change morphology and efficacy against their target host when successively sub-cultured on artificial media or when exposed to certain physical and chemical environmental conditions. Whether such changes occur in B. bassiana after an endophytic phase inside a banana plant remains unknown. The primary aim of our study was to evaluate the viability, growth, sporulation and pathogenicity of endophytic B. bassiana. To attain this, two sets of experiments, namely morphological characterization and larval bioassays, were conducted under laboratory conditions. In these experiments, growth and pathogenicity of the wild type B. bassiana strain G41, obtained originally from banana farms, was compared with the endophytic B. bassiana strain G41, re-isolated from the rhizome of B. bassiana-inoculated banana plants at one month post-inoculation. Morphological characterization, conidial germination, colony growth and sporulation rate was assessed on SDAY media while pathogenicity was determined 15 days after immersing the larvae of C. sordidus in different conidial doses. No differences were observed in colony appearance and growth rate between the endophytic and wild type strain. Percentage conidial germination for the endophytic strain (91.4 94.0%) was higher than for the wild-type (86.6-89.7%). LD50 equated 1.76 x 10(5) and 0.71 x 10(5) conidia/ml for the wild-type and endophytic B. bassiana strains, respectively, but did not differ between strains. Our study demonstrated that, after an endophytic phase inside the banana plant, B. bassiana retains it morphology and pathogenicity against the banana weevil larvae; and thus can offer protection against the damaging larvae feeding inside the rhizome. PMID- 21539246 TI - Nomuraea rileyi: a plausible fungi selectively controlling lepidopteron, Paraponyx stratiotata L. damaging queen palm (Livistona rotundifolia L.). AB - Queen Palm (Livistona rotundifolia) is cultivated extensively for both local and foreign ornamental markets with the desired characteristics of even and ever green, pest and disease free healthy palm and quality leaves. The root borer, Paraponyx stratiotata (Lepidoptera) is recently encountered on young palm roots and damaging them within. They emerged as a new pest on L. rotundifolia grown in all the area. Different entomopathogens were evaluated and determined the potential of Nomuroea rileyi selectively due to its greater infective ability. Field collected root borer larvae were reared and N. rileyi was evaluated both in vitro and in net house conditions. Treatments comprising Beauveria bassiana, Metarhizium anisopliae, Trichoderma sp., N. rileyi, a standard check with 3% Carbofuran and water as a control were evaluated in potted seedlings (3 months old) of queen palms. Among the entomopathogens tested, N. rileyi was found more effective and recorded the best of 61% mortality. Subsequent experiment had been conducted with commercial bio-products alone or in combination with local isolates as treatments; N. rileyi, B. bassiana, M. anisopliae, B. bassiana + M. anisopliae, N. rileyi + M. anisopliae, N. rileyi+ B. bassiana, and water as a control were evaluated. Among these treatments N. rileyi was alone more effective than in combination with or other entomopathogens alone. In vitro study revealed LD50 of N. rileyi as best spore load of 1 x 10(8) spores/ml compare to other treatments. This proves the potential of N. rileyi on P. stratiotata. The application of N. rileyi had claimed not only to reduce the incidence of root damage but also to sustain the growth and vigor of the L. rotundifolia to most fit for exporting. PMID- 21539247 TI - Mass rearing of the pink corn borer, Sesamia cretica Led. (Lepidoptera: Noctuidae) larvae, on semi artificial diets. AB - The effect of two different semi-artificial diets (S.A.D1 and S.A.D2) as well as a natural corn diet on the biology and bionomics of the pink stem borer, Sesamia cretica was studied under laboratory conditions. The insect was successfully mass reared for ten successive generations at the conditions of 27 +/- 2 C degrees and 60-80% R.H. In addition, a photoperiod of 0:24 (L:D) for larvae and 12:12 (L:D) in concern to the other stages, respectively. ALong the ten successive generations, there were no significant differences between the larval periods for both the artificial diets. The S.A.D2 induced the shortest (24.0 days) larval period compared with the natural diet (27.5 days) and S.A.D1 (31.5 days). Rearing larvae on the natural diets revealed a pupal period of 11.0 days, while it was 10.0 days and 8.5 days for the artificial diets (S.A.D1) and in (S.A.D2), in respect. Moth longevity (pre-oviposition, oviposition and post-oviposition periods), to a certain extent, was affected by the larval diets. The maximal moth longevity (13.0 days) was observed for larva reared on corn plants (4, 8 and 1 days). On the other hand, the shortest period (10.5 days) of moth longevity was noticed in SAD2 (1, 9 and 0.5 days). S.A.D1 showed 11.0 days moth longevity (3,7 and 1 days). The longest oviposition period (9.0 days) was recorded in the artificial diet S.A.D2, while it was only 7.0 days in the artificial diet S.A.D1 compared with 8.0 days in case of the natural diet. The number of deposited eggs increased with the progress of the 10 successive generations (G1:G10) from 150 to 265 and from 384 eggs to 564 eggs / female for the S.A.D1 and S.A.D2, in sequence. The highest mean number of deposited eggs per female (564) was for the derived females from larvae fed on the artificial diet in G10 of S.A.D2. The rate of the deposited eggs in S.A.D2 was gradually increased (from 9.70 to 61.14% increase) more than those reared on the natural diet throughout the ten generations. The highest significant percent hatchability (92.69%) has been resulted from the artificial diet SAD2. But, it has been decreased to 85.59% in the artificial diet S.A.D1 in comparison to 65.71% in the natural diet. In addition, the significant shortest total generation period was 44.0 days resulted from the artificial diet S.A.D2, while it was 53.5 and 54.0 days for corn plants and the artificial diet S.A.D1, consequently. In short, results indicated that the S.A.D2 could be considered as a suitable artificial diet for a feasible mass rearing of the pink corn borer, Sesamia cretica led. The S.A.D2 showed the shortest larval, pupal and life span for the generation periods. Moreover, it induced the longest oviposition period and the highest mean number of deposited eggs per female and the highest significant percent of eggs hatchability/fertility. The utilization of this artificial diet (S.A.D2) would supply the researchers with high-quality insects in adequate numbers, at specified times and specific stages of development for the bioassay, toxicological and biological studies. PMID- 21539248 TI - The influence of weather and geographical conditions on flight dynamics of WCR adults. AB - Since the appearance of western corn rootworm (Diabrotica virgifera virgifera Le Conte) (Coleoptera: Chrysometidae) in Romania, many researchers have been made, in more or less success. In this study we try to clarify the ecology of the species in order to predict its evolution and its potential area of distribution. In Romania, this species was signalled for the first time in 1996, in western part of country neighbouring with Hungary. This region is an important area for maize production for seed and silage. Together, the climatic conditions, altitude and their influence on species behaviour and distribution have become more apparent. Their habitat and survival strategies are strongly dependent on local weather patents and altitude. In order to investigate the potential impact of weather and altitude on pest populations, a clear understanding of the nature and characterization of pest is required. In general, most pest species are influenced by warm, rainfall and altitude. Taking into consideration our data from the years 2008 and 2009, we can emphasize a very serious influence of air temperature, rainfall and altitude on WCR flight dynamics in adults. Dry and warm conditions generally lead to increasing of insects' number. Our data shown positive correlations between air temperature (daily mean) and adults number captured on pheromone traps (daily mean), but the there are limits from which these become negative. The same trend was recorded in previous research period (2004-2006). The rainfall is an important factor that influences adults' dynamics in maize fields. Excessive rainfall leads to adults' number decreasing. Our daily observations showed a decreasing number of beetles while rainfall increases. Regarding the altitude, we observed a decreasing number of WCR adults at once the attitude increase. For capture of adults we used pheromone traps, in 3 replications (T1, T2 and T3) at difference altitude where maize was grown. Significant relationship of WCR flight dynamic with weather and geographical conditions were found. Activities were carried out under the PN-II-ID-PCE-2007 1/RO project. PMID- 21539249 TI - Study on weevil pests of oilseed rape at Keszthely, Hungary. AB - One of the most important pests of rape in early spring are weevils (Ceutorhynchus spp.). The aim of our studies was to identify the occurring weevil species and to study their emergence, swarming, mating and damage. Our observations were performed on an experimental plot at Keszthely (Hungary, Zala County) in early spring of four consecutive years. Following species were collected and identified: Ceutorhynchus pallidactylus MARSHAM, Ceutorhynchus obstrictus MARSHAM, Ceutorhynchus napi GYLLENHAL, Ceutorhynchus pleurostigma MARSHAM. The obvious dominance of C. pallidactylus and C. obstrictus was detected. Their frequency of occurrence was 88-90% among the identified adults. We found that C. obstrictus was the last species to settle. Complete developmental period was 68 +/- 7 days in case of C. pallidactylus and 70 +/- 7 days in case of C. obstrictus. Average number of eggs laid by one female was 176 +/- 23 in case of C. obstrictus and 21 +/- 6 in case of C. pallidactylus. PMID- 21539250 TI - Population dynamics of caterpillars on three cover crops before sowing cotton in Mato Grosso (Brazil). AB - Direct seeding mulch-based cropping systems under a preliminary cover crop such as millet are common in some areas of Brazil. Lepidopteran pests that damage cotton, soybean and maize crops can proliferate on cover crops, so preventive chemical treatments are necessary. Very little data is available on these pests on cover crops. This paper presents the dynamics of Spodoptera frugiperda, S. eridania, Mocis latipes and Diatraea saccharalis caterpillars monitored at Primavera do Leste, Mato Grosso state (Brazil) during the of 2005/2006 and 2006/2007 cropping seasons on four cover crops, i.e. finger millet (Eleusine coracana), pearl millet (Pennisetum glaucum), sorghum (Sorghum bicolor) and ruzigrass (Brachiaria ruziziensis). The pests were visually counted on plants within a 1 m2 transect (wooden frame). Caterpillars were reared to facilitate identification of collected species and parasitoids. Many S. frugiperda caterpillars were observed on millet in 2005, with a maximum of 37 caterpillars/m2. On sorghum, we found 30 caterpillars/m2, or 0.83 caterpillars/plant. The Diatraea borer attacked sorghum later than the other pests. M. latipes was also observed on millet. The millet cover crop had to be dried for at least 1 month before direct drilling the main cotton crop in order to impede S. frugiperda infestations on cotton plantlets, thus avoiding the need for substantial resowing. The comparative methodological aspects are discussed. PMID- 21539251 TI - Evaluation of the efficacy and selectivity of Oberon (Spiromesifen) for the control of Tetranychus urticae on strawberry. AB - A study was performed in the period June to July 2009 by Bioagritest test facility according to EPPO guidelines and Principles of Good Experimental Practice (GEP), in the campaign of Tursi (MT), southern Italy, in order to evaluate the efficacy and selectivity of Spiromesifen on strawberry for the control of Tetranyichus urticae. Two different dosages of OBERON (a.i. Spiromesifen)--45 and 60 ml/hl--were compared with a unique dosage of two commercial formulates: VERTIMEC (a.i. Abamectine, Syngenta Crop Protection), 60 ml/hl, and MAGISTER (a.i. Fenazaquin, Dow AgroSciences), 60 ml/hl. The study has achieved the purpose of evaluating/measuring with a single application the activity of Spiromesifen (Oberon) to control T. urticae on strawberry and its selectivity on phytoseiids. All the treatments differed significantly from the checks and showed high ability to control mites, on all stages of the population. About selectivity on phytoseiids, only Spiromesifen (at both doses) has demonstrated a good selectivity, while Abamectine (in part) and Fenazaquin (totally), have limited the population of the predator. The study confirmed the usefulness, indeed the need for the new compounds, to get confirmation of their selectivity against the useful entomofauna. The experiment has allowed to demonstrate the suitability of Spiromesifen to be included in strategies for strawberry integrated pest management. PMID- 21539252 TI - Evaluation of the efficacy of Oberon (Spiromesifen), to contain infestations of mites and whiteflies on Capsicum annuum L. AB - Following the EPPO guidelines and Principles of Good Experimental Practice (GEP), an experiment was realised in autumn 2008 for evaluating the efficacy of Oberon applied by foliar treatments to contain infestations of mites and whiteflies on Capsicum annuum L.. Two different dosages of OBERON (a.i. Spiromesifen)--45 and 60 g/hl--were compared with a unique dosage of two commercial formulates: VERTIMEC (a.i. Abamectine, Syngenta Crop Protection), 60 g/hl, and MAGISTER (a.i. Fenazaquin, Dow AgroSciences), 110 g/hl. Oberon resulted very effective in the control of phytopathogenic mites at both doses of 45 and 60 g/hl. Its effectiveness demonstrated to be remarkable for approximately one month after application. By contrast, Vertimec and Magister have proven their effectiveness for a much lower period of time (about the first 15 days post application). About the efficacy against whiteflies, even 36 days after the foliar application Oberon showed a strong containment of the populations of aleurodides. There were no phenomena of phytotoxicity nor on leaves nor on flowers and fruits, in none of the treatments. About the phytotoxicity on the useful entomofauna, the assessments made on the different treatments have highlighted the lack of harmful effects on predators and on parasitoids of insects and mites. PMID- 21539253 TI - Efficacy of some oils and chemical compounds on Insignorthezia insignis (Browne) (Hemiptera: Ortheziidae) infesting Lantana camara in Alexandria, Egypt. AB - Field and laboratory experiments were conducted in March, 2008 in El-Nouzha garden, Alexandria governorate. Pre-and post treatment inspections of the insects were examined and recorded before and after (2,4,8, and 12 weeks). Spraying was applied to evaluate the efficiency of the tested compounds, [Mineral oils (KZ oil and Star oil); IGRs (Chlorfluazuron, lufenuron and pyriproxyfen); Neem oil; emamectin benzoate and thiamethoxam]. Percentages of reduction were calculated. The ensign scale insects Insignorthezia insignis (Browne) were collected from treated Lantana camara shrubs to investigate the effect of the tested chemicals on Aspartate transferase (AST), Alanine transferase (ALT) and Alkaline phosphatase (ALPK) of the insect enzymes activities. From the obtained results, it could be concluded that the tested materials gave good results for controlling both adult and immature stages of the ensign scale insect Insignorthezia insignis (Browne) that infested Lantana camara shrubs, through affecting enzymes activities of the assigned insect pest. PMID- 21539254 TI - Effect of an oxadiazine, indoxacarb, on the biochemical composition of ovaries in the German cockroach. AB - Conventional insecticides have been widely used to control cockroaches but these insects have developed resistance to several compounds. Safer insecticides with a low toxicity such as oxadiazine have been advanced: indoxacarb (30% WG) is designated to be a reduced-risk insecticide and is considered as an organophosphate replacement. Insecticidal activity occurs via blockage of the sodium channels in the insect nervous system. In a first series of experiments, the toxicity of different concentrations (15, 20, 25 and 30 ppm) administrated by topical application to newly emerged adults was studied on the German cockroach Blattella germanica, and the LC50 and LT50 values were determined. In a second series of experiments, the compound was applied at its LC50 and LC90 over a period of 6 days, and the effects on the biochemical composition of ovaries (proteins, carbohydrates and lipids) during the adult life (2, 4 and 6 days) were examined. PMID- 21539255 TI - Side-effects of glyphosate on the life parameters of Eriopis connexa (Coleoptera: Coccinelidae) in Argentina. AB - In Argentina, transgenic soybean crop (Roundup Ready, RR) has undergone a major expansion over the last 15 years, with the consequent increase of glyphosate applications, a broad-spectrum and post emergence herbicide. Soybean crops are inhabited by several arthropods. Eriopis connexa Germar (Coleoptera: Coccinelidae) is a predator associated to soybean soft-bodies pest and have a Neotropical distribution. Nowadays, it is being considered a potentially biological control agent in South America. The objectives of this work were to evaluate the side-effects of glyphosate on larvae (third instar) and adults of this predator. Commercial compound and the maximum registered concentrations for field use were employed: GlifoGlex 48 (48% glyphosate, 192 mg a.i./litre, Gleba Argentina S.A.). The exposure was by ingestion through the treated prey (Rophalosiphum padi) or by drinking treated water during 48 h for treatment of the adult. The herbicide solutions were prepared using distilled water as solvent. The bioassays were carried out in the laboratory under controlled conditions: 23 +/- 0.5 degrees C, 75 +/- 5% RH and 16:8 (L:D) of photoperiod. Development time, weight of pupae, adult emergence, pre-oviposition period, fecundity and fertility were evaluated as endpoints. Larvae from glyphosate treatment molted earlier than controls. In addition, the weight of pupae, longevity, fecundity and fertility were drastically reduced in treated organisms. The reductions were more drastic when the treatments were performed at the third larval stage than as adult. The reproduction capacity of the predator was the most affected parameter and could be related to a hormonal disruption by glyphosate in the treated organisms. This work can confirm the deleterious effects of this herbicide on beneficial organisms. Also, it agrees with prior studies carried out on other predators associated to soybean pest, such as Chrysoperla externa (Neuroptera: Chrysopidae) and Alpaida veniliae (Araneae: Araneidae). PMID- 21539256 TI - Compatibility of a Melia azedarach extract with Eriopis connexa (Coleoptera: Coccinellidae). AB - The integrated pest management (IPM) premises claim for a joint use of beneficial organisms (parasitoids and predators) and selective pesticides. Botanical pesticides are being considered as selective pesticides. During the last 20 years of the 20th century, the plant family Meliaceae was identified as a promising source of compounds with insect-control properties. The Chinaberry tree, Melia azedarach L., is a deciduous tree native to Persia, India, and China, but has been cultivated in many countries including Africa, Australia, and the Americas. It is a source of tetranortriterpenoid compounds called meliatoxins, which have similar structures and insecticidal activities compared to azadirachtin. Eriopis connexa Germar (Coleoptera: Coccinelidae) is a native predator from the Neotropical Region. It is a beneficial organism associated to several agro ecosystems, feeding on soft-bodies pest such as aphids, whiteflies and thrips. In horticultural crops, it has been observed to feed on worldwide important pest such as Bemisia tabaci Gennadius (Heteroptera: Aleyrodeidae) and Myzus persicae L. (Heteroptera: Aphididae), both of them considered as virus vectors. The objectives of this work were to evaluate the side-effects of M. azaderach (Meliaceas) extract on eggs, larvae and adults of Eriopis connexa. Extracts from unripe fruits (1%, w/w, obtained by the CEPROCOR, Cordoba-Argentina) were employed for ecotoxicological bioassays. The exposure method was by immersion for eggs and by ingestion of drinking water for adults. The botanical extract solutions were prepared using distilled water as solvent and a tensioactive (Tween 20) for topical application. The bioassays were carried out in the laboratory under controlled conditions: 23 +/- 0.5 degrees C temperature, 75 +/- 5% RH and 16:8 (L:D) photoperiod. Hatching, development time, adult emergence, pre-oviposition period, fecundity and fertility were evaluated as endpoints. No detrimental effects were observed in treated organisms irrespective of the exposure way and development stage. According to these preliminary results, M. azaderach fruit extracts can be compatible with E. connexa for pest control. However, future studies should be addressed to conclude about its toxicity on beneficial organisms. PMID- 21539257 TI - Efficacy of five volatile oils and their mixtures against the soft scale insect, Saissetia coffeae (Walker) (Hemiptera: Coccidae) infesting the Sago palm, Cycas revoluta in Alexandria, Egypt. AB - Five tested plant volatile oils and their mixtures were evaluated for controlling the coccid, Saissetia coffeae (Walker) on growing Sago palms Cycas revoluta in Antoniades public gardens, Alexandria, Egypt. The tested volatile oils at concentration rates of 0.5, 1 and 1.5% (v/v) were: Camphor 20%, Dill 20%, Rose 30%, Peppermint 20% and Clove 30% (v/v). Their mixtures were : Camphor/Peppermint, Camphor/Rose at a rate of 1:1, Camphor/Rose/Peppermint at 1:1:2 rate and Camphor/Rose/Dill at 2:1:1 rate. The results, as a general mean of residual reduction percent for the whole inspection intervals of the test lasted 2 days up to 9 days post treatment, indicated that the superior volatile oils in reducing the insect were both Camphor and Rose, followed by Dill, Peppermint and the least efficient one was the Clove oil. The evaluated mixtures of the volatile oils showed that each of Camphor/Rose/Peppermint, Camphor/Rose and Camphor/Peppermint mixtures attained a higher rank of efficiency against that of the assigned soft scale insect. PMID- 21539258 TI - Efficacy of Curcuma aeruginosa rhizome and Adhatoda vasica plant extracts, on red spider mite, Tetranychus urticae in Livistona rotundifolia. AB - Queen palm, Livistona rotundifolia foliage contributes greatly in export industry. Red spider mite (RSM) (Tetranychus urticae) infests on the foliage and reduces its affordable market quality. T. urticae is found in dry environment and is one of the phytophagous mite belongs to family Tetranychidae. Different chemicals such as 80% sulphur + Diazinon @ (50g+12ml/10L) are recommended against red spider mite, but these have lesser effect on this tiny mite. Since these chemicals are not environment friendly, Green Farms Ltd., in Sri Lanka prefers to use biological agents for mite management. Extracts of Curcuma aeruginosa rhizome and Adhatoda vasica plant parts were studied separately causing mortality on T. urticae. Field experiments were conducted to study the efficacy of C. aruginosa extract for controlling RSM on L. rotundifolia leaves. Curcuma aruginosa was tested at concentrations of 2, 5, 10, 15, 20 and 25 g/L and a control with equal amount of water. C aruginosa extracts of different concentrations were treated six times at five days interval on the palms separately. Living spider mites and eggs were pre-counted in marked leaves before applying C. aruginosa extracts. Next count was taken a day prior to next spraying. The result revealed that all the concentrations except 2 g/L were found to be effective compared to control. However there was no difference between the concentrations from 5 to 25 g/L. Hence C. aruginosa rhizome extract at its lowest concentration of 5 g/L is equally effective for the control of RSM on L. rotundifolia leaves. In another experiment extracts of Adhatoda vasica bark, leaves, and flower and water as control were applied thrice with three days interval. Pre treatment counting of living spider mites and eggs were taken in marked leaves. Post count was taken a day prior to next spraying. Third and forth counting were done after three days and four weeks from final spraying respectively. The results revealed that bark, flowers were found to be more effective compared to control. Flowers and bark were the best and hence there is no need of third sprayings as almost all the spider mites population were eradicated after second spraying. Flower extraction showed best performance until three months since final spraying. Flower and bark extracts showed higher acaricidal property and leaf showed moderate acaricidal property. PMID- 21539259 TI - Impact of Alpinia galanga rhizome extract on Bactrocera dorsalis population. AB - The Bactrocera dorsalis (Hendel) is one of the most economically damaging pests and generally is controlled by insecticides. This research was done by evaluate the impact of rhizomes of Alpinia galanga extract on population of B. dorsalis. The rhizome of A. galanga was extracted by Soxhlet's apparatus using hexane, dichloromethane, ethyl acetate and 95% ethanol as separated solvent system. Various concentrations of all crude extracts were trailed by Topical spray application with adult B. dorsalis, completely randomized designs, 5 replicates. The results showed hexane crude extract gave the highest control efficiency to adult B. dorsalis which the 24 hours-LC50 values was 4,866.06 +/- 184.52 ppm (hexane), 24,156.66 +/- 880.33 ppm (dichloromethane), 16,744.73 +/- 641.27 ppm (ethyl acetate) and 6,337.54 +/- 145.42 ppm (95% ethanol). Thus, this extract may an alternative way for control this insect pest in the future. PMID- 21539261 TI - Integrated pest management strategies to sustain corn productivity. AB - The study was conducted to evaluate the economics and effectiveness of Trichogramma and earwigs in the suppression of corn borer and identify other corn pest associated during vegetative stage using light trapping. A Randomized Complete Block Design was used in laying out the experiments with five treatments as follows: Treatment 1-Control, Treatment 2-Trichogramma, Treatment 3-Earwigs, Treatment 4-Light Trapping and Treatment 5-Trichogramma + earwigs. Based on the analysis of variance it revealed highly significant variations among treatments with regards to number of parasitized and unparasitized egg mass of corn borer at 35 and 45 days after planting. In like manner, the damage assessment done by corn borer differed significantly at 35 and 45 days after planting. With regards to weight of green corn grains per sampling area, a highly significant differences was observed among the treatment means. The combination of Trichogramma and Earwigs showed high effectively in the field by exhibiting the highest computed yield per hectare and higher return of investment per peso invested. PMID- 21539260 TI - Toxicity of ethyl acetate extract from Jatropha gossypifolia senescent leaves against Spodoptera exigua Hubner (Lepidoptera: Noctuidae) and Meteorus pulchricornis (Hymenoptera: Braconidae). AB - This study explored the insecticidal effects of Thai botanical, senescent leaf Jatropha gossypifolia extracts on second instar Spodoptera exigua larvae by the dipping method and topical sprayer method. The leaf crude extract was extracted using Soxhlet apparatus with ethyl acetate as solvent. The leaf crude extracts showed insecticidal activity with a LC50 of 6182 ppm at 24 hours after treatment. In addition, this research was observed its toxicity to worm parasitoid, Meteorus pulchricornis by contact method. The result shows 60 percent mortality of this parasitoid species at dose up to 40,000 ppm. Thus, Jatropha gossypifolia leaf crude extracts can be as alternative IPM control tool for Spodoptera exigua which friendly to benefit insect such as Meteorus pulchricornis. PMID- 21539262 TI - The effectivenes of Trichotim in control of Cydia pomonella L. in western Romania. AB - In the last years a significant attack increasing of codling moth was observed in the western part of Romania. In order to reduce the population of this pests a bioproduct was used named Trichotim based on entomophagous insect Trichogramma sp. Trichotim is a Romanian product certified in year 2000 with the purpose to control the pests present in various cultures such us cabbage, vineyards and fruits plantations. The study was expanded over two years (2008 and 2009), in a super intensive apple orchard of Didactical Experimental Station part of University of Agricultural Sciences Timisoara. In order to control the codling moth, the product Trichotim was used three times correlated to pest biology (two releasing of Trichogramma wasps in the time of first generation and one release in the time of second generation of the pest), releasing 300.000 wasps/ha in total, where 250.000 wasps in first generation time of the codling moth respectively 50.000 wasps in the time of second generation of the pest. The releasing of entomophagous species Trichogramma succeeded at two days after maximal flight values of Cydia pomonella L. The flight curves was realized based on pheromonal traps ATRAPOM placed in tree canopy in stage BBCH 69 (end of flowering, all petals fallen). In order to assess the efficacy of Trichotim the observation was conducted 14 days before fruit harvesting. In the plots where 300.000 wasps were released, the fruits were attacked in percent of 12,33% (efficacy 87,67%) in year 2008 and respectively 14,66% (efficacy 85,33%) in 2009. In untreated plots (control) the fruits were attacked in percent of 23% in 2008 respectively 27,33% in 2009. PMID- 21539263 TI - Population genetics of Eldana saccharina Walker (Lepidoptera: Pyralidae) and the implications for management using biocontrol. AB - The African sugarcane stalk borer, Eldona saccharina Walker (Lepidoptera: Pyralidae), is widely distributed throughout sub-Saharan Africa and is an important insect pest of maize and sugarcane. The insect shows significant variation in behaviour, host plant and natural enemy guild in different regions. Several attempts to redistribute the natural enemies of E. saccharina from West Africa to South Africa were unsuccessful. The significant behavioural, host plant and natural enemy variations as well as failures of biocontrol attempts evoked a hypothesis of genetic diversification. To evaluate this hypothesis a molecular analysis was conducted on geographically isolated populations of E. saccharina from East, North, South and West Africa, using the cytochrome c oxidase subunit I (COI) region of the mitochondrial genome. The results revealed that E. saccharina populations are separated into four major units corresponding to the West Africa, Rift Valley, South/East Africa and southern African populations. Mitochondrial DNA divergence among the four populations ranged from 1% to 4.98%. To examine the impact of the observed genetic variation on the fertility of inter-population crosses, a mating experiment was conducted between the Rift valley and South African population to produce an F1 generation, and these were backcrossed with the South African parent population. Fertility of eggs produced by the F1/parent population cross was significantly reduced when compared to fertility of the "true" South African line, and the F1/F1 cross. The contributions of the observed genetic differences and inter population incompatibility for the failure of previous biocontrol attempts are discussed and recommendations on future biocontrol practices are given. PMID- 21539264 TI - Gamma radiation consequences on desert locust Schistocerca gregaria (Forsk.) digestive system. AB - Schistocera gregaria (Forsk.) (Orthoptera, Acrididae) remains a major insect pest in Africa, more particularly in the Sahelian zone. Present control methods are only partially efficient. In a previous study, we tested the potentiality of a sterile insect technique (SIT). Males of S. gregaria appeared to be much radiosensitive as already a dose of 3 Gy limited their survival. Gamma-radiations are known to damages the epithelial tissue of midgut, which affects the alimentation in insects. In this work, we show how digestive system of S. gregaria males is affected when submitted to a dose of 4 gamma rays. Nutrition is affected as males stop feeding soon after irradiation and progressively lose weight. Histological analyses on the midgut showed important epithelium damages. The regenerative cells by which the epithelial cells are replaced were damaged on the first days following irradiation. Consequently, regenerative cells are unable to divide and replace the normal loss of midgut cell. After nine days, the entire midgut epithelium was destroyed and only longitudinal muscles layer remained intact. This indicates that low radiation doses should be used if SIT will be applied. PMID- 21539265 TI - Attraction of Heterorhabditis sp. toward synthetic (E)-beta-cariophyllene, a plant SOS signal emitted by maize on feeding by larvae of Diabrotica virgifera virgifera. AB - Most plants, when damaged by herbivore insects, synthesize and release various chemicals as indirect defence mechanism that attract parasitic or predatory insects that are natural enemies of the herbivores. When attacked by Western Corn Rootworms, the roots of many maize plant varieties emit (E)-beta-caryophyllene that attracts the neighbouring entomopathogenic nematodes to kill the feeding pest. Through plant genetics and biotechnology it was possible to manipulate this volatile compound in order to increase the effectiveness of entomopathogenic nematodes in reducing the damage of the pest. In order to further use this strategy to improve the effectiveness of Heterorhabditis bacteriophora by selective breeding, we invesa tigated the applicability of the strategy in different standard laboratory bioassays using three different sand and agar plate assays. The synthetic form of (E)-beta-caryophyllene and H. megidis (the strain, which in previous investigation, showed significant attraction to caryophyllene) were used in the study. In all bioassays no significant difference was observed in attraction of nematodes between the caryophyllene treatments and the controls. The results contradict results of previous investigations done by other investigators (Rasmann et al., 2005). Future investigations for the genetic improvement of the host finding ability of entomopathogenic nematodes can therefore not target attraction to caryophyllene. PMID- 21539266 TI - A new approach to identify species in Xiphinema americanum sensu lato. AB - Four putative species belonging to the X. americanum group are known to transmit American nepoviruses and these nematodes and viruses are listed in European quarantine legislation. Identification of species in this group is therefore of particular importance for phytosanitary purposes, but is problematic because of the similar morphology of the putative species. As part of the Synthesys project BE-TAF 1769, eight collaborative institutions contributed material to Fera for study. Video technology allowed the best records of type material and in conjunction with photographic images created a 'virtual' collection of images that relies less on the deteriorating quality of museum specimens. Revised definitions of lip region and tail shape are considered to be the most stable characters for differentiation. Position of the amphidial aperture, development of the odontostyle collar and some established morphometric characters are considered of limited use although they retain value for latter stages of identification. PMID- 21539267 TI - Arbuscular mycorrhizae induced defense against root-knot nematode early infection. PMID- 21539268 TI - Effect of different potting systems; inoculation time; nematode density and sources of cereal cyst nematode (Heterodera filipjevi) on juvenile penetration into wheat root system. AB - Investigations were designed to optimize testing systems for screening wheat breeding lines for resistance to Heterodera filipjevi. The effects of: 1) plant potting systems 2) inoculum level and time of inoculation 3) and type of inoculum of H. filipjevi on detection accuracy were examined in growth chamber experiments in Turkey. The rate of nematode penetration in the highly susceptible variety Bezostaya was used as the base measurement of efficacy. The results showed that the highest level of penetration coupled with high level of germination was obtained in plastic tubes (13 cm long x 3 cm in diam.) when compared to both small flower pots (400 cm3) and smaller plastic tubes (10.2 cm long x 0.8 cm in diam.). The highest rate of nematode penetration into wheat root system was obtained by inoculating the seedlings with 1000 J2 per plant. However, inoculation with 200 J2 at sowing or 200 J2 at sowing plus an additional 200 J2 after germination improved percent penetration when compared to inoculation with 600 or 1000 J2/plant at sowing. The test on the optimum form of inoculum showed that inoculating the seedling with J2's gave the highest rate of nematode penetration over inoculum with eggs or cysts. The results of these experiments demonstrated that screening wheat for resistance can be optimized by raising the seedlings in plastic tubes and inoculating them with 400 J2. PMID- 21539269 TI - Response of six strawberry (Fragaria x ananassa Duch.) cultivars to the root lesion nematode (Pratylenchus penetrans Filipjev and Schurmanns Stekhoven). AB - In the Philippines, strawberry is grown only in Benguet Province because of its unique climatic conditions. It has been a lucrative source of income for Benguet farmers and adds to the revenue of Benguet Province. The root lesion nematode, Pratylenchus penetrans is an economically important pest of strawberry in the area. It can cause substantial losses to strawberry growers, both by reducing vegetative plant growth and by reducing strawberry yields. The nematode has a very wide host range and hence, is not readily controlled by crop rotation. An alternative approach which growers may wish to consider trying is planting of strawberry varieties which are either resistant or tolerant to this nematode. The relative susceptibility/tolerance of six strawberry cultivars to the root lesion nematode, P. penetrans was evaluated under greenhouse and field conditions. Inoculation of 500 nematodes/pot did not significantly affect the fresh top weight, fresh root weight, and yield of strawberry cultivars Festival, Whitney, Winterdawn, Earlibrite, and Camarosa. The said cultivars had significantly higher number of nematodes recovered from the roots. On the other hand, the highest strawberry yield was recorded in cv Sweet Charlie, however, this was significantly reduced by nematode inoculation .Surprisingly, the number of nematodes recovered from the roots of this cultivar was significantly the lowest among the cultivars tested. Results of the field experiment showed that strawberry cv Sweet Charlie gave the highest marketable yield which was significantly different from the rest of the cultivars tested. This was followed by Festival, and Earlibrite. On the other hand, Camarosa and Whitney gave significantly lower yield than the above cultivars but significantly higher than Winterdawn. In terms of nematodes recovered from the roots, the highest was noted in Whitney, followed by Sweet Charlie and Earlibrite. The lowest was obtained from Camarosa, followed by Festival and Winterdawn. Based on the results of the greenhouse experiment, Festival, Whitney, Winterdawn, Earlibrite and Camarosa can be considered tolerant while Sweet Charlie was slightly susceptible to P. penetrans. However, based on the field trial, Sweet Charlie, Festival and Earlibrite were tolerant while Whitney, Camarosa and Winterdawn were slightly susceptible. PMID- 21539270 TI - Management of root knot nematode, Meloidogyne incognita in cucumber (Cucumis sativus) using silicon. AB - Silicon (Si) has been reported to effectively manage some pests and diseases of plants. This study was conducted to determine the effect of Si concentration, mode, and frequency of application in managing Meloidogyne incognita in cucumber. A susceptible cultivar of cucumber (cv. Cyclone) was planted in pots containing heat-sterilized soil. Three weeks after planting, the plants were inoculated with 1,000 juveniles/ pot. Uninoculated plants were provided to serve as control. Three concentrations of Si in the form of sodium metasilicate was applied on the leaves and roots alone and also on both the leaves and roots. Application was done once during the growing period and weekly until seven days before harvest. Leaf and root application of Si was found to significantly increase (p = 0.0029) the fresh top weight of inoculated and uninoculated plants. On the other hand, inoculation of root-knot nematode significantly increased the fresh root weight of cucumber which could be due to enlargement of roots or formation of galls. Interestingly, the inoculated plants gave significantly higher marketable yield than uninoculated ones. Application of Si at the rate of 200 ppm significantly increased the marketable yield compared to the higher rate of Si (400 ppm). At 200 ppm, one application of Si both on the leaves and roots significantly reduced the number of galls in inoculated plants. This was comparable to the same concentration applied continuously on the roots and at higher concentration (400 ppm) applied continuously on the leaves and on the roots. On the other hand, single root application of Si at the rate of 400 ppm gave the lowest number of eggmasses, however, it was comparable to the same Si concentration applied singly on the leaves and applied continuously both on the leaves and roots. These treatments, however, were at par with continuous application of the lower rate of Si (200 ppm) on the leaves and both leaves and roots. PMID- 21539271 TI - Intraspecific variability of Steinernema feltiae strains from Cemoro Lawang, eastern Java, Indonesia. AB - Four strains of Steinernema feltiae from Eastern Java, Indonesia were characterized based on morphometric, morphological and molecular data. In addition, their virulence against last instar Tenebrio molitor and heat tolerance was tested. Infective juvenile have a mean body length ranging from 749 to 792 microm. The maximum sequence difference among the four strains was 7 bp (8.8%) in the ITS and 2 bp (0.3%) in D2D3 regions of the rDNA. All the strains are not reproductively isolated and can reproduce with European strain S. feltiae Owiplant. The lowest LC50 was observed for strain SCM (373) and the highest for S. feltiae strain Owiplant (458) IJs/40 T. molitor. All four strains showed relatively better mean heat tolerance when compared with S. feltiae Owiplant, both in adapted and non-adapted heat tolerance experiments. PMID- 21539272 TI - Navigating rough waters. PMID- 21539273 TI - Home care & hospice legislative priorities 2011: making the case for patients' & agencies' needs. PMID- 21539274 TI - The way forward for information technology in long-term and post-acute care. PMID- 21539275 TI - 'From the start consider the finish': a recipe for promoting excellent end-of life care. PMID- 21539276 TI - The home care agency of the future: empathy, innovation, execution. PMID- 21539277 TI - Serving in the dark. PMID- 21539278 TI - The winds of change: using the power of the Internet. PMID- 21539280 TI - Home care is the answer. PMID- 21539279 TI - Alzheimer's disease: a virtual tsunami for the country--an amazing opportunity for home care. PMID- 21539281 TI - Coroners and death certification law reform: the Coroners and Justice Act 2009 and its aftermath. AB - After considering various different options for half a decade, the last Government legislated in 2009 to reform the England and Wales coroner and death certification systems. The Coroners and Justice Act 2009 provides for the creation of a new Chief Coroner post to lead the jurisdiction and for local medical examiners to oversee a new death certification scheme applicable equally to burial and cremation cases. In October 2010 the new Government announced that it judges the main coroner reform to be unaffordable, will not proceed with it and plans to repeal the provisions. It intends to implement the new death certification arrangements, which is welcome. The decision to abort the main coroner reform in spite of longstanding and widespread recognition of the need for major change is deplorable though in line with other failures over the last century to properly modernise this neglected service. PMID- 21539282 TI - Therapeutic misadventure. AB - Therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease. Within the National Health Service there were over 86,000 reported adverse incidents in 2007. In the USA medication errors have been rated as the fourth highest cause of death. Unfortunately one of the greatest contributors to iatrogenic injury is human error. The potential types of misadventure are infinite. Medication errors are a major part of this, being responsible for over 70% of cases that cause serious harm. However, many medication errors caused by slips, lapses, technical errors and mistakes are preventable; intentional violations of safe operating procedures are not. While medication errors were tolerated by society in the past, the readiness to institute criminal proceedings against health-care professionals has increased greatly in the UK over the last decade. The medication process consists of writing prescriptions, dispensing the product, administering it and monitoring its effects. Prescription errors arise owing to incomplete information, lack of appropriate labelling, environmental factors and human blunders. Even with a perfect prescription the right medication must be dispensed and appropriately labelled. Dispensing errors are not uncommon and may be compounded by non clinical considerations. Administration of a drug by injection is one of the most dangerous aspects of the medication process, especially in inexperienced hands. The final component of medication supply is monitoring the effect of the medication. With short courses of medication such monitoring is easy, but with long-term medication, particularly with potent drugs where the margin between efficacy and toxicity is small, active procedures may be required to ensure toxicity does not ensue. Despite the endeavour of health-care professions to stick to the rule of 'first, do no harm', in reality this is difficult to achieve all of the time. When errors occur the natural thoughts of wanting to blame an individual at the sharp end (active error) should be tempered. Identifying and correcting system (latent) errors will, in the end, provide a safer health-care system. PMID- 21539283 TI - Law of 22 April 2005 on patients' rights and the end of life in France: setting the boundaries of euthanasia, with regard to current legislation in other European countries. AB - The term 'euthanasia' is not clearly defined. Euthanasia is evoked in many aspects of terminal care: interruption of curative treatment at the end of life, palliative care or the act of deliberately provoking death through compassion. A law on 'patients' rights and the end of life', promulgated in France on 22 April 2005, led to changes in the French Code of Public Health. In this work, we have first outlined the key provisions of this law and the changes it has brought, then we have compared current legislation on the subject throughout Europe, where a rapid overview of current practice in terminal patient care revealed four different types of legislation: the first authorizes euthanasia (in the sense of provoking death, if this choice is medically justified), the second legalizes 'assisted suicide', the third, which is sometimes referred to as 'passive euthanasia', consists of the non-administration of life-sustaining treatment and, finally, the fourth prohibits euthanasia in any form whatsoever. In the last section, we have attempted to clarify the as yet indistinct notion of 'euthanasia' in order to determine whether the conception of terminal care in the Law of 22 April 2005 was consistent with that put forward by the philosopher Francis Bacon, who claimed that, 'The physician's role is to relieve pain, not only when such relief can lead to healing, but also when it can proffer a calm and trouble-free death, thus putting an end to the suffering and the agony of death' (modern adaptation of the original quote). PMID- 21539284 TI - Traditional male circumcision-related fatalities in the Mthatha area of South Africa. AB - Traditional male circumcision is still widely practised by the Xhosa population throughout South Africa. Male circumcision is carried out mainly during summer and winter seasons. This is a retrospective record review of the male circumcision-related fatalities at Mthatha General Hospital during 2005 and 2006. The purpose of this study is to highlight the problem of circumcision-related deaths in the Mthatha area of South Africa. Twenty-five deaths related to traditional circumcisions were recorded over the period. The common causes of deaths were septicaemia (9 patients; 36%), pneumonia (5; 20%), dehydration (3; 12%), assault (3; 12%), thromboembolism (2; 8%), gangrene (2; 8%) and congestive heart failure (1; 4%). All fatalities were among black Africans with a median age of 17.56 (SD = 2.56) years. In seven deaths (28%) the young men came from the Libode District. The youngest victim was 12 years old. Most of the deaths (13; 52%) occurred in July 2006. The mortality associated with traditional male circumcision in the Mthatha area of South Africa is alarming. PMID- 21539285 TI - Age and gender variations in trend of road traffic fatalities in Manipal, India. AB - BACKGROUND: The incidence of road traffic fatalities has been increasing at an alarming rate and is a global cause for concern. AIMS: To assess the age- and gender-based variations in the pattern of road traffic fatalities in Manipal, southern India and to provide an epidemiological profile of the population at risk. SETTINGS AND DESIGN: Registry-based retrospective research on road traffic fatalities in Manipal, extending from 1994 to 2009, was conducted at the Department of Forensic Medicine, Kasturba Medical College, Manipal. MATERIAL AND METHODS: The data were collected from the autopsy files and information furnished by the police in the inquest papers. Road traffic fatalities were analysed, keeping the gender and age of the victim as co-variables. RESULTS AND CONCLUSIONS: Road traffic fatalities constituted the majority of autopsied cases (38.6%) and unnatural deaths (37.8%). Percentage share of road traffic fatalities with regard to unnatural deaths in Manipal did not show a definite trend during the last 16 years. Male preponderance was quite evident, male-female ratio being 7.2:1. Male mortality pattern peaked during the third decade followed by a gradual decline, whereas the mortality pattern among women was almost uniform from second to seventh decade. Overall, people in their third decade were most prone to road traffic fatalities (26.9%), a trend similar to that of male mortalities. The overall pattern of road traffic fatalities was quite similar to those in other parts of India and the world. The global problem with regard to road traffic fatalities remains the same irrespective of the difference in topography and demography of the region. PMID- 21539286 TI - Fusion in the hyoid bone: usefulness and implications. AB - Increasing age induces fusion in the hyoid bone. The present study was conducted to assess the usefulness of fusion in the hyoid bone in age estimation. A total of 130 excised hyoid bones from dead bodies belonging to the age group of 4-70 years were studied. The mean age of unilateral and bilateral fusion in males was 39.39 and 41.77 years, respectively. The mean age of unilateral and bilateral fusion in females was 37.5 and 45 years, respectively. Fusion was not seen in ages below 20 years. Non-fusion has been found even after the age of 60 years. Although there was significant association between fusion in the hyoid bone and advancing age, it cannot be considered a good indicator for estimating age. With a high degree of variation in the age of fusion, the hyoid bone needs to be studied along with other determinants for estimating age. Fusion in the hyoid bone is not related to the sex of the victim and there is no tendency towards early fusion on the left side compared with the right side. If the victim of pressure on the neck is aged over 38 years, the clinicians and forensic experts should expect fractured hyoids. If a fractured hyoid bone is not found even in the elderly, pressure on the neck cannot be ruled out. PMID- 21539287 TI - Matching profiles of masked perpetrators: a pilot study. AB - Seventeen male volunteers were photographed laterally with and without a tight fitting balaclava. We then matched these photographs in blind trials. The matches were performed in two separate trials: as side-by-side comparisons, and by using superimposition. In both trials we graded the matches as good, possible and no fit. We found a very high true identification rate of 94% using superimposition, i.e. whether a match judged as good was in fact the correct match. The correct exclusion rate was also high, 94%, when using superimposition, i.e. when no match was found this was in fact correct. However, even though we were often correct in judging the best fit, we often had several possible matches for each case, which means that comparing profiles is not very selective. As such, using superimposition to compare the profile of a masked perpetrator with lateral photos of one or more suspects may indicate the possible matches, and perhaps even the best match, which may be helpful in police investigations, but it would not carry enough weight to be used as evidence per se. This study only focused on the profile. Future studies will use surface laser scans to analyse congruence between masked and unmasked subjects using the whole head. PMID- 21539288 TI - Appraisal by Year Six French medical students of the teaching of forensic medicine and health law. AB - Legal medicine is a cross-sectional specialty in which medico-legal situations very frequently combine with routine medical practice. A total of 132 students in the last year of the second cycle of medical studies (Year 6) replied anonymously and voluntarily to a questionnaire corresponding to the topics in the curriculum for the national ranking examination: law relating to death and the dying, examination of assault victims, medical malpractice liability rules, writing death certificates, respect of medical confidentiality and the principles of medical deontology. The most frequently cited activities of the forensic physician were autopsy (87.9%), writing certificates (75.8%) and consultations with victims of violence (60.6%). Students did not often come into contact with a medico-legal situation during Years 2-6 of medical studies. Assiduity in attending lectures was low. Students preferred the standard textbooks available in specialized bookshops. They were severe in their appraisal of their own competence at the end of the second cycle, and did not feel ready to examine a corpse (95.5%) or to examine victims of assault (92.4%). Knowledge of the law and of the risks of medical practice was felt to be inadequate by 60.5% of students, and of the writing of a medical certificate by 56.8%. Training medical students in this field is a major challenge in view of the limited number of teaching hours and the need to acquire increasingly specialized knowledge. Complementary initiatives appear to be necessary, such as partnership with other clinical specialties which are frequently confronted with medico-legal situations. PMID- 21539289 TI - Virtual autopsy with multidetector computed tomography of three cases of charred bodies. AB - Herein, we report a comparison of multidetector computed tomography (MDCT) and autopsy in the evaluation of three cases of charred human bodies. Interestingly, MDCT identified several findings useful for forensic purposes, including traumatic injuries not related to the fire, relevant vital reaction signs and detection of foreign bodies. Our results, in addition to data gathered in previous studies, indicate that MDCT is an excellent tool for imaging in postmortem investigations and that it has great potential for the forensic documentation and examination of charred bodies. PMID- 21539290 TI - Implications of a new case law on the Deprivation of Liberty Safeguards. AB - The Deprivation of Liberty Safeguards (DOLS), introduced into the Mental Capacity Act 2005 (MCA), were implemented in April 2009. Recent case law established several principles: the Mental Health Act (MHA) has primacy over the MCA and it is not appropriate for professionals to pick and choose which Act to use; the eligibility assessors for DOLS need to consider whether a hospital would detain the patient under the MHA. The eligibility assessors for DOLS need to apply a 'but for' test, whereby consideration would need to be given to the need for detention in hospital if it were not for the physical illness, and if the only reason for detention in hospital was the need for treatment of the physical disorder then detention under DOLS would be appropriate. This judgement clarifies that individuals with mental disorders who only require treatment in hospital for physical disorders should be detained under DOLS. The implications of this judgement are discussed in this paper. PMID- 21539291 TI - Identity of victims from fragmented and decomposed remnants by DNA profiling in a case of serial killings. AB - A 28-year-old man, Surinder Koli, from a Nithari village adjoining Delhi, India committed serial murder. This case was of paramount importance in medico-legal investigations, as it was a landmark case of a serial killer reported from India. The skeletal remains (627 pieces) including skull/skull portions (19) were recovered from the nearby sewer drain, sump and the backyard of the house in which this man was residing. In addition, soft tissues (51) were also recovered from the same sewer drain. The victims were killed over a two-year period. The establishment of identity of the victims was crucial to prove the case in the court of law as well as for the claimants. Nineteen sets were prepared by radiology/anatomical examination from the exhibits recovered. DNA profiling confirmed the correctness of these sets and also short tandem repeat typing of nuclear DNA successfully identified eight individuals. Both DNA profiling and radiography/anatomical examination played an important role in solving this complicated case. PMID- 21539292 TI - A homicide by suspension. AB - Hanging is one of the commonest medico-legal entities that a forensic pathologist may come across and is almost always a suicide. We report a case of homicide by hanging, masquerading as a sudden death, where a 32-year-old man was hanged by his wife, helped by her boyfriend, who nearly escaped from the grip of the law. The autopsy findings were almost in keeping with that of a suicidal suspension except for the small contusion in the inner aspect of the lower lip and multiple abrasions in the lower part of the legs, which were due to the struggle and terminal asphyxial movements. Furthermore, the victim was under the influence of alcohol, which is usually expected in a case of this nature. PMID- 21539294 TI - Adsorbate-localized versus substrate-mediated excitation mechanisms for generation of coherent Cs-Cu stretching vibration at Cu(111). AB - Coherent Cs-Cu stretching vibration at a Cu(111) surface covered with a full monolayer of Cs is observed by using time-resolved second harmonic generation spectroscopy, and its generation mechanisms and dynamics are simulated theoretically. While the irradiation with ultrafast pulses at both 400 and 800 nm generate the coherent Cs-Cu stretching vibration at a frequency of 1.8 THz (60 cm(-1)), they lead to two distinctively different features: the initial phase and the pump fluence dependence of the initial amplitude of coherent oscillation. At 400 nm excitation, the coherent oscillation is nearly cosine-like with respect to the pump pulse and the initial amplitude increases linearly with pump fluence. In contrast, at 800 nm excitation, the coherent oscillation is sine-like and the amplitude is saturated at high fluence. These features are successfully simulated by assuming that the coherent vibration is generated by two different electronic transitions: substrate d-band excitation at 400 nm and the quasi-resonant excitation between adsorbate-localized bands at 800 nm, i.e., possibly from an alkali-induced quantum well state to an unoccupied state originating in Cs 5d bands or the third image potential state. PMID- 21539293 TI - An uncommon case of hypersexual behaviour with frotteurism. AB - Frotteurism is an aberrant behaviour wherein the person tends to rub or bring about physical contact between his genitals and an unrelated female to derive sexual pleasure. Our report describes an atypical case of hypersexual behaviour presenting in the form of masturbation with features of frotteurism and unipolar depression. The paper discusses the differential diagnosis and management of hypersexual behaviour. PMID- 21539295 TI - Immunoassay for phenylurea herbicides: application of molecular modeling and quantitative structure-activity relationship analysis on an antigen-antibody interaction study. AB - An indirect competitive enzyme-linked immunosorbent assay (icELISA) for 12 phenylurea herbicides (PUHs) was established with the half-maximum inhibition concentration (IC(50)) of 1.7-920.7 MUg L(-1). A method of computer-aided molecular modeling was established in quantitative structure-activity relationship (QSAR) studies to obtain a deeper insight into the PUHs' antibody interactions on how and which molecular properties of the analytes quantitatively affect the antibody recognition. A two-dimensional (2D)-QSAR model based on the Hansch equation and a hologram QSAR (HQSAR) model were constructed, and both showed highly predictive abilities with cross-validation q(2) values of 0.820 and 0.752, respectively. It was revealed that the most important impact factor of the antibody recognition was the PUHs' hydrophobicity (log P), which provided a quadratic correlation to the antibody recognition. Hapten-carrier linking groups were less exposed to antibodies during immunization; thus, groups of the analytes in the same position were generally considered to be less contributive to antibody recognition during immunoassay. But the results of substructure-level analysis showed that these groups played an important role in the antigen antibody interaction. In addition, the frontier-orbital energy parameter E(LUMO) was also demonstrated as a related determinant for this reaction. In short, the result demonstrated that the hydrophobicity and the lowest unoccupied molecular orbital energy (E(LUMO)) of PUH molecules were mainly responsible for antibody recognition. PMID- 21539296 TI - A universal method for detection of amyloidogenic misfolded proteins. AB - Diseases associated with the misfolding of endogenous proteins, such as Alzheimer's disease and type II diabetes, are becoming increasingly prevalent. The pathophysiology of these diseases is not totally understood, but mounting evidence suggests that the misfolded protein aggregates themselves may be toxic to cells and serve as key mediators of cell death. As such, an assay that can detect aggregates in a sensitive and selective fashion could provide the basis for early detection of disease, before cellular damage occurs. Here we report the evolution of a reagent that can selectively capture diverse misfolded proteins by interacting with a common supramolecular feature of protein aggregates. By coupling this enrichment tool with protein specific immunoassays, diverse misfolded proteins and sub-femtomole amounts of oligomeric aggregates can be detected in complex biological matrices. We anticipate that this near-universal approach for quantitative misfolded protein detection will become a useful research tool for better understanding amyloidogenic protein pathology as well as serve as the basis for early detection of misfolded protein diseases. PMID- 21539297 TI - Symmetrically substituted nido-carboranylphthalocyanines: facile synthesis, characterization, and solution properties. Evidence for intra- and intermolecular H+/K+ exchange. AB - The direct, non ex post synthesis of a novel phthalocyanine decorated with eight thiohexyl-nido-carborane functions, nido-[H(2)MCHESPc]K(8), where the anionic polyhedra are in the form of K(+) salt, is reported and discussed. The solution properties of this compound, including the unprecedented exchange between the pyrrolic protons and the peripheral alkali-metal ions, are also analyzed. PMID- 21539298 TI - New semiconducting coordination polymers from zinc sulfide clusters and chains. AB - Two new semiconducting zinc coordination polymers, Zn(8)S(SPh)(14)(bpy) (1) and Zn(2)(SPh)(4)(bpy) (2), have been synthesized by a dual-ligand approach. Single crystal structural analyses indicate that compound 1 has a helical-chain structure with P1 clusters bridging with bipyridyl (bpy) ligands and compound 2 possesses a layered structure with zinc sulfide chains cross-linked with bpy ligands. The diffuse-reflectance spectra reveal that the band gaps of the two compounds are 2.41 eV for 1 and 2.56 eV for 2. PMID- 21539299 TI - Gd(III)[15-metallacrown-5] recognition of chiral alpha-amino acid analogues. AB - Chiral Ln(III)[15-metallacrown-5] complexes with phenyl side chains have been shown to encapsulate aromatic carboxylates reversibly in their hydrophobic cavities. Given the importance of selective guest binding for applications of supramolecular containers in synthesis, separations, and materials design, the affinity of Gd(III)[15-metallacrown(Cu(II), L-pheHA)-5] hosts for a series of chiral carboxylate guests with varying substitutions on the alpha-carbon (phenylalanine, N-acetyl-phenylalanine, phenyllactate, mandelate, methoxyphenylacetate) has been investigated. Differential binding of S- and R phenylalanine was revealed by X-ray crystallography, as the S-enantiomer exclusively forms associative hydrogen bonds with oxygen atoms in the metallacrown ring. Selective guest binding in solution was assessed with isothermal titration calorimetry, which measures the sequential guest binding in the hydrophobic cavity first and the hydrophilic face of the host, and a cyclic voltammetry assay, which quantifies guest binding strength in the hydrophobic cavity of the host exclusively. In solution, the Gd(III)[15-metallacrown(Cu(II), L-pheHA)-5] hydrophobic cavity exhibits modest chiral selectivity for enantiomers of phenylalanine (K(S)/K(R) = 2.4) and mandelate (K(S)/K(R) = 1.22). Weak binding constants of ~100 M(-1) were measured for neutral and -1 charged carboxylates with hydrophilic functional groups (ammonium, N-acetyl, methyl ether). Weaker binding relative to the unsubstituted guests is attributed to unfavorable interactions between the hydrophilic functionalities of the guest and the hydrophobic cavity of the host. In contrast, binding constants greater than 2000 M(-1) were measured for alpha-hydroxy analogues phenyllactate and mandelate. The significantly increased affinity likely arises from the guests being bound as a 2 anion upon metal-assisted deprotonation in the Gd(III)[15-metallacrown(Cu(II), l-pheHA)-5] cavity. It is established that guest binding affinity in the hydrophobic cavity of the host follows the general trend of neutral zwitterion < monoanion < dianion, with hydrophilic functional groups decreasing the binding affinity. These results have broad implications for the development of metallacrowns as supramolecular catalysts or in chiral separations. PMID- 21539300 TI - neo-Clerodane diterpenoids from Ajuga bracteosa. AB - Different neo-clerodane diterpenoids were isolated from a dichloromethane extract of Ajuga bracteosa depending on the isolation procedure used, owing to the labile nature of these tetrahydrofurofuran derivatives. Under "hydroxyl-free" purification conditions, both clerodin- and dihydroclerodin-type diterpenes were obtained [four new compounds, ajubractins A-D (1-4), along with clerodin (5), 3 epi-caryoptin (6), ajugapitin (7), 14,15-dihydroclerodin (8), 3-epi-14,15 dihydrocaryoptin (9), ivain II (10), and 14,15-dihydroajugapitin (11)]. When methanol-water mixtures were used for a C18 reversed-phase prepurification procedure and for semipreparative HPLC, the new ajubractin E (12) was also isolated along with 3 and 8-11, as previously, but 7 was the only tetrahydrofurofuran derivative obtained. Epimeric (15R and 15S) mixtures were obtained instead of 14-hydro-15-hydroxyclerodin derivatives [15-hydroxyajubractin C (13), 14-hydro-15-hydroxyajugachin A (14), and 14-hydro-15-hydroxyajugapitin (15)], along with 15-epi-lupulin B (16). The structures of the new compounds were elucidated by NMR and MS data analysis and by comparison with values previously reported. Antifeedant activity against Spodoptera littoralis larvae was evaluated for the compounds obtained. PMID- 21539301 TI - Cryptocaryols A-H, alpha-pyrone-containing 1,3-polyols from Cryptocarya sp. implicated in stabilizing the tumor suppressor Pdcd4. AB - A high-throughput cell-based reporter assay designed to identify small-molecule stabilizers of the tumor suppressor Pdcd4 was used to screen extracts in the NCI Natural Products Repository. Bioassay-guided fractionation of an extract from a Papua New Guinea collection of the tropical tree Cryptocarya sp. provided a series of new 5,6-dihydro-alpha-pyrone-containing 1,3-polyols (1-8), named cryptocaryols A-H. Their structures were assigned from a combination of NMR, MS, and CD studies in conjunction with NMR database comparisons. Compounds 1-8 were found to rescue Pdcd4 from TPA-induced degradation with EC50 concentrations that ranged from 1.3 to 4.9 MUM. PMID- 21539302 TI - Pickering emulsions: wetting and colloidal stability of hairy particles--a self consistent field theory. AB - The assembly of sterically stabilized colloids at liquid-liquid interfaces is studied with the self-consistent field (SCF) theory using the discretization scheme that was developed by Scheutjens, Fleer, and co-workers. The model is based on a poly(methyl methacrylate) (pMMA) particle with poly(isobutylene) (pIB) grafted to the surface. The stabilizing groups on the particle surface have a significant effect on the interfacial assembly and, therefore, also on the formation and properties of Pickering emulsions. The wetting behavior of the particle is altered by the presence of the stabilizing groups, which affects the equilibrium position of the particles at the interface. The stabilizing groups can also lead to an activation barrier before interfacial adsorption, analogous to the steric repulsion between two particles. These effects are numerically solved with the SCF theory. It is commonly known that flocculating conditions enhance the interfacial adsorption and yield stable Pickering emulsions, which is confirmed in this work. Additionally, it is concluded that those conditions are not an absolute requirement. There is a window of stabilizer concentrations Gamma(pIB), 2.2-3.3 mg/m(2) pIB, that shows both partial wetting and colloidal stability. The activation barrier for interfacial assembly is 140-550 k(B)T and is an order of magnitude higher than the colloidal stability. The difference can be attributed to the unfavorable interaction of pIB with water and a difference in geometry (plate-sphere vs sphere-sphere). This study demonstrates the interplay and provides a quantitative comparison between the wetting behavior and the colloidal stability, and it gives a better understanding of the colloidal assembly at soft interfaces and formation of Pickering emulsions in general. PMID- 21539304 TI - Mechanistic toxicodynamic model for receptor-mediated toxicity of diazoxon, the active metabolite of diazinon, in Daphnia magna. AB - The organothiophosphate diazinon inhibits the target site acetylcholinesterase only after activation to its metabolite diazoxon. Commonly, the toxicity of xenobiotics toward aquatic organisms is expressed as a function of the external concentration and the resulting effect on the individual level after fixed exposure times. This approach does not account for the time dependency of internal processes such as uptake, metabolism, and interaction of the toxicant with the target site. Here, we develop a mechanistic toxicodynamic model for Daphnia magna and diazoxon, which accounts for the inhibition of the internal target site acetylcholinesterase and its link to the observable effect, immobilization, and mortality. The model was parametrized by experiments performed in vitro with the active metabolite diazoxon on enzyme extracts and in vivo with the parent compound diazinon. The mechanism of acetylcholinesterase inhibition was shown to occur irreversibly in two steps via formation of a reversible enzyme-inhibitor complex. The corresponding kinetic parameters revealed a very high sensitivity of acetylcholinesterase from D. magna toward diazoxon, which corresponds well with the high toxicity of diazinon toward this species. Recovery of enzyme activity but no recovery from immobilization was observed after in vivo exposure to diazinon. The toxicodynamic model combining all in vitro and in vivo parameters was successfully applied to describe the time course of immobilization in dependence of acetylcholinesterase activity during exposure to diazinon. The threshold value for enzyme activity below which immobilization set in amounted to 40% of the control activity. Furthermore, the model enabled the prediction of the time-dependent diazoxon concentration directly present at the target site. PMID- 21539303 TI - Bioorthogonal labeling of 5-hydroxymethylcytosine in genomic DNA and diazirine based DNA photo-cross-linking probes. AB - DNA is not merely a combination of four genetic codes, namely A, T, C, and G. It also contains minor modifications that play crucial roles throughout biology. For example, the fifth DNA base, 5-methylcytosine (5-mC), which accounts for ~1% of all the nucleotides in mammalian genomic DNA, is a vital epigenetic mark. It impacts a broad range of biological functions, from development to cancer. Recently, an oxidized form of 5-methylcytosine, 5-hydroxymethylcytosine (5-hmC), was found to constitute the sixth base in the mammalian genome; it was believed to be another crucial epigenetic mark. Unfortunately, further study of this newly discovered DNA base modification has been hampered by inadequate detection and sequencing methods, because current techniques fail to differentiate 5-hmC from 5 mC. The immediate challenge, therefore, is to develop robust methods for ascertaining the positions of 5-hmC within the mammalian genome. In this Account, we describe our development of the first bioorthogonal, selective labeling of 5 hmC to specifically address this challenge. We utilize beta-glucosyltransferase (betaGT) to transfer an azide-modified glucose onto 5-hmC in genomic DNA. The azide moiety enables further bioorthogonal click chemistry to install a biotin group, which allows for detection, affinity enrichment, and, most importantly, deep sequencing of the 5-hmC-containing DNA. With this highly effective and selective method, we revealed the first genome-wide distribution of 5-hmC in the mouse genome and began to shed further light on the biology of 5-hmC. The strategy lays the foundation for developing high-throughput, single-base resolution sequencing methods for 5-hmC in mammalian genomes in the future. DNA and RNA are not static inside cells. They interact with protein and other DNA and RNA in fundamental biological processes such as replication, transcription, translation, and DNA and RNA modification and repair. The ability to investigate these interactions will also be enhanced by developing and utilizing bioorthogonal probes. We have chosen the photoreactive diazirine photophore as a bioorthogonal moiety to develop nucleic acid probes. The small size and unique photo-cross-linking activity of diazirine enabled us to develop a series of novel cross-linking probes to streamline the study of protein-nucleic acid and nucleic acid-nucleic acid interactions. In the second half of this Account, we highlight a few examples of these probes. PMID- 21539305 TI - New C15-substituted active vitamin D3. AB - C15-Substituted 1alpha,25-dihydroxyvitamin D(3) analogs were synthesized for the first time to investigate the effects of the modified CD-ring on biological activity concerning the agonistic positioning of helix-3 and helix-12 of the vitamin D receptor (VDR). X-ray cocrystallographic analysis proved that 0.6 A shifts of the CD-ring and shrinking of the side chain were necessary to maintain the position of the 25-hydroxy group for proper interaction with helix-12. The 15 hydroxy-16-ene derivative showed higher binding affinity for hVDR than the natural hormone. PMID- 21539306 TI - Treatment of pharmaceuticals and diagnostic agents using zero-valent iron- kinetic studies and assessment of transformation products assay. AB - This research examined whether treatment with zero-valent iron in the presence of oxygen is a suitable process for the degradation of pharmaceuticals (antibiotics, cytostatic drugs) and diagnostic agents. It was shown that the concentration of all selected compounds was decreased efficiently by treatment with iron. The compounds exhibited a pseudo-first-order decay with a linear dependence on ln(c/c(0)) on time. The observed reaction rate strongly depended on pH, the amount of added iron, and the stirring speed. The influence of temperature on the reaction rate was small. Comparison of detected transformation products with those obtained after catalytic hydrogenation and treatment with Fenton's reagent revealed that reductive and oxidative processes are responsible for the transformations observed. PMID- 21539307 TI - Identification of tetrabromobisphenol A diallyl ether as an emerging neurotoxicant in environmental samples by bioassay-directed fractionation and HPLC-APCI-MS/MS. AB - Brominated flame retardants (BFRs) have been widely used as additives in products to reduce their flammability. Recent findings suggested that some BFRs exhibit neurotoxicity and thus might pose a threat to human health. In this work, a neurotoxicity assay-directed analysis was developed, combining sample cleanup, fractionation, chemical identification, and bioassay. Viability of primary cultured cerebellar granule neurons (CGNs) was used to evaluate the neurotoxicity of extracts or separated fractions from environmental samples. Tetrabromobisphenol A diallyl ether (TBBPA DAE) was identified as the causative toxicant in sediment samples collected from a river near a brominated flame retardant (BFR) manufacturing plant in South China. Liquid chromatography atmospheric pressure chemical ionization tandem mass spectrometry (LC-APCI-MS/MS) was optimized to determine TBBPA DAE levels in the potent fractions and to confirm TBBPA DAE as the key neurotoxicant. On the basis of comparison with the structure of other TBBPA derivatives, the 1-propenyl group in TBBPA DAE appears to be the cause for the neurotoxic potency. The levels of TBBPA DAE in samples along the river were found at up to 49 ng/L for river water, 10,183 ng/g dry weight (dw) in surface sediments, and 42 ng/g dw in soils. According to the distribution of TBBPA DAE in the environmental samples, the manufacturing plant was identified as the release source of TBBPA DAE. To our knowledge, this study is the first to demonstrate potential neurotoxicity induced by TBBPA DAE in real environmental samples. PMID- 21539308 TI - On the synthesis of conformationally modified peptides through isonitrile chemistry: implications for dealing with polypeptide aggregation. AB - A method for introducing a dimethyleneoxy constraint joining the N atoms of two consecutive amino acids in the context of a polypeptide has been developed. This constraint can profoundly affect the tendency of a polypeptide to suffer aggregation and desolubilization, and it can be readily removed under mild conditions. PMID- 21539309 TI - LocaPep: localization of epitopes on protein surfaces using peptides from phage display libraries. AB - The use of peptides from a phage display library selected by binding to a given antibody is a widespread technique to probe epitopes of antigenic proteins. However, the identification of interaction sites mimicked by these peptides on the antigen surface is a difficult task. LocaPep is a computer program developed to localize epitopes using a new clusters algorithm that focuses on protein surface properties. The program is constructed with the aim of providing a flexible computational tool for predicting the location of epitopes on protein structures. As a first set of testing results, the localization of epitope regions in eight different antigenic proteins for which experimental data on their antibody interactions exist is correctly identified by LocaPep. These results represent a disparate sample of biologically different systems. The program is freely available at http://atenea.montes.upm.es. PMID- 21539310 TI - Labeling substrates of protein arginine methyltransferase with engineered enzymes and matched S-adenosyl-L-methionine analogues. AB - Elucidating physiological and pathogenic functions of protein methyltransferases (PMTs) relies on knowing their substrate profiles. S-adenosyl-L-methionine (SAM) is the sole methyl-donor cofactor of PMTs. Recently, SAM analogues have emerged as novel small-molecule tools to efficiently label PMT substrates. Here we reported the development of a clickable SAM analogue cofactor, 4-propargyloxy-but 2-enyl SAM, and its implementation to label substrates of human protein arginine methyltransferase 1 (PRMT1). In the system, the SAM analogue cofactor, coupled with matched PRMT1 mutants rather than native PRMT1, was shown to label PRMT1 substrates. The transferable 4-propargyloxy-but-2-enyl moiety of the SAM analogue further allowed corresponding modified substrates to be characterized through a subsequent click chemical ligation with an azido-based probe. The SAM analogue, in combination with a rational protein-engineering approach, thus shows potential to label and identify PMT targets in the context of a complex cellular mixture. PMID- 21539311 TI - Effect of glycans and the glycophosphatidylinositol anchor on strain dependent conformations of scrapie prion protein: improved purifications and infrared spectra. AB - Mammalian prion diseases involve conversion of normal prion protein, PrP(C), to a pathological aggregated state (PrP(res)). The three-dimensional structure of PrP(res) is not known, but infrared (IR) spectroscopy has indicated high, strain dependent beta-sheet content. PrP(res) molecules usually contain a glycophosphatidylinositol (GPI) anchor and large Asn-linked glycans, which can also vary with strain. Using IR spectroscopy, we tested the conformational effects of these post-translational modifications by comparing wild-type PrP(res) with GPI- and glycan-deficient PrP(res) produced in GPI-anchorless PrP transgenic mice. These analyses required the development of substantially improved purification protocols. Spectra of both types of PrP(res) revealed conformational differences between the 22L, ME7, and Chandler (RML) murine scrapie strains, most notably in bands attributed to beta-sheets. These PrP(res) spectra were also distinct from those of the hamster 263K scrapie strain. Spectra of wild-type and anchorless 22L PrP(res) were nearly indistinguishable. With ME7 PrP(res), modest differences between the wild-type and anchorless spectra were detected, notably an ~2 cm(-1) shift in an apparent beta-sheet band. Collectively, the data provide evidence that the glycans and anchor do not grossly affect the strain-specific secondary structures of PrP(res), at least relative to the differences observed between strains, but can subtly affect turns and certain beta-sheet components. Recently reported H-D exchange analyses of anchorless PrP(res) preparations strongly suggested the presence of strain-dependent, solvent-inaccessible beta core structures throughout most of the C-terminal half of PrP(res) molecules, with no remaining alpha-helix. Our IR data provide evidence that similar core structures also comprise wild-type PrP(res). PMID- 21539312 TI - Potent, selective, and orally available benzoisothiazolone phosphomannose isomerase inhibitors as probes for congenital disorder of glycosylation Ia. AB - We report the discovery and validation of a series of benzoisothiazolones as potent inhibitors of phosphomannose isomerase (PMI), an enzyme that converts mannose-6-phosphate (Man-6-P) into fructose-6-phosphate (Fru-6-P) and, more importantly, competes with phosphomannomutase 2 (PMM2) for Man-6-P, diverting this substrate from critical protein glycosylation events. In congenital disorder of glycosylation type Ia, PMM2 activity is compromised; thus, PMI inhibition is a potential strategy for the development of therapeutics. High-throughput screening (HTS) and subsequent chemical optimization led to the identification of a novel class of benzoisothiazolones as potent PMI inhibitors having little or no PMM2 inhibition. Two complementary synthetic routes were developed, enabling the critical structural requirements for activity to be determined, and the compounds were subsequently profiled in biochemical and cellular assays to assess efficacy. The most promising compounds were also profiled for bioavailability parameters, including metabolic stability, plasma stability, and permeability. The pharmacokinetic profile of a representative of this series (compound 19; ML089) was also assessed, demonstrating the potential of this series for in vivo efficacy when dosed orally in disease models. PMID- 21539313 TI - Hydrogen-bonding catalysis and inhibition by simple solvents in the stereoselective kinetic epoxide-opening spirocyclization of glycal epoxides to form spiroketals. AB - Mechanistic investigations of a MeOH-induced kinetic epoxide-opening spirocyclization of glycal epoxides have revealed dramatic, specific roles for simple solvents in hydrogen-bonding catalysis of this reaction to form spiroketal products stereoselectively with inversion of configuration at the anomeric carbon. A series of electronically tuned C1-aryl glycal epoxides was used to study the mechanism of this reaction based on differential reaction rates and inherent preferences for S(N)2 versus S(N)1 reaction manifolds. Hammett analysis of reaction kinetics with these substrates is consistent with an S(N)2 or S(N)2 like mechanism (rho = -1.3 vs rho = -5.1 for corresponding S(N)1 reactions of these substrates). Notably, the spirocyclization reaction is second-order dependent on MeOH, and the glycal ring oxygen is required for second-order MeOH catalysis. However, acetone cosolvent is a first-order inhibitor of the reaction. A transition state consistent with the experimental data is proposed in which one equivalent of MeOH activates the epoxide electrophile via a hydrogen bond while a second equivalent of MeOH chelates the side-chain nucleophile and glycal ring oxygen. A paradoxical previous observation that decreased MeOH concentration leads to increased competing intermolecular methyl glycoside formation is resolved by the finding that this side reaction is only first-order dependent on MeOH. This study highlights the unusual abilities of simple solvents to act as hydrogen-bonding catalysts and inhibitors in epoxide-opening reactions, providing both stereoselectivity and discrimination between competing reaction manifolds. This spirocyclization reaction provides efficient, stereocontrolled access to spiroketals that are key structural motifs in natural products. PMID- 21539314 TI - Scalable synthesis of cortistatin A and related structures. AB - Full details are provided for an improved synthesis of cortistatin A and related structures as well as the underlying logic and evolution of strategy. The highly functionalized cortistatin A-ring embedded with a key heteroadamantane was synthesized by a simple and scalable five-step sequence. A chemoselective, tandem geminal dihalogenation of an unactivated methyl group, a reductive fragmentation/trapping/elimination of a bromocyclopropane, and a facile chemoselective etherification reaction afforded the cortistatin A core, dubbed "cortistatinone". A selective Delta(16)-alkene reduction with Raney Ni provided cortistatin A. With this scalable and practical route, copious quantities of cortistatinone, Delta(16)-cortistatin A (the equipotent direct precursor to cortistatin A), and its related analogues were prepared for further biological studies. PMID- 21539315 TI - Antineoplastic agents. 590. X-ray crystal structure of dolastatin 16 and syntheses of the dolamethylleuine and dolaphenvaline units. AB - Three advances necessary to bring dolastatin 16 (1) into full-scale preclinical development as an anticancer drug have been accomplished. The X-ray crystal structure of dolastatin 16 has been solved, which allowed stereoselective syntheses of its two new amino acid units, dolamethylleuine (Dml) and dolaphenvaline (Dpv), to be completed. The X-ray crystal structures of synthetic Z-Dml and TFA-Dpv have also been completed. PMID- 21539316 TI - Aluminum, gallium, and indium hydrazides and the generation of oligonuclear element-nitrogen cages: molecular intermediates on the way to element nitrides. AB - Organoelement aluminum, gallium, and indium hydrazides, [R(2)ENHN(H)R'](2) (E = Al, Ga, In), are easily available from the corresponding trialkylelement compounds, ER(3), and hydrazines, H(2)NN(H)R', via elimination of the respective hydrocarbons. Their diverse molecular structures are derived from four-, five-, or six-membered element-nitrogen heterocycles. Their stepwise thermolysis under carefully controlled conditions was shown to proceed along one of several different well-defined routes. Cleavage of the N-N bonds afforded aluminum or gallium imides, [REN(H)](n), with up to eight metal atoms in a single molecule, while preservation of the N-N bonds led to interesting cages in which intact N-N bonds of formally dianionic hydrazinediides bridge the metal atoms via their two adjacent donor atoms. Further thermolysis yielded the amorphous element nitrides via the gradual degradation of the hydrazinediide groups. Several intermediates have been isolated and provided insight in the course of these reactions. A particularly interesting compound was one that features a hydrazinetetraide unit, [N-N](4-), that is stabilized by coordination to six gallium atoms. PMID- 21539317 TI - Verrucamides A-D, antibacterial cyclopeptides from Myrothecium verrucaria. AB - Four new cyclic tetradecapeptides, verrucamides A-D (1-4), have been isolated from the solid-substrate fermentation culture of the ascomycete fungus Myrothecium verrucaria. The structures of these compounds, each featuring six N methylated amino acid residues, were elucidated primarily by NMR and MS methods. The absolute configurations of 1-4 were assigned by application of Marfey's method on their acid hydrolysates. Compounds 1-4 showed antimicrobial activity against the Gram-positive bacterium Staphylococcus aureus. PMID- 21539319 TI - New insights into the structure of PAMAM dendrimer/gold nanoparticle nanocomposites. AB - In this work, we have employed a suite of complementary analytical techniques to shed light on the nanocomposite structures formed during gold nanoparticles (AuNPs) synthesis in the presence of poly(amidoamine) (PAMAM) dendrimers. Nanocomposites of AuNPs and either fourth or eighth generation amine-terminated PAMAM dendrimers (G4 or G8) were prepared. The size distributions of AuNPs and the nanocomposites were determined by transmission electron microscopy. Atomic force microscopy phase imaging and neutral impact collision ion scattering spectroscopy (NICISS) were utilized for the first time to investigate and compare nanocomposite structures formed from G4 and G8. Our results suggest that G4 stabilized the AuNP by capping the AuNP particle surface but that a certain fraction of the gold surface was still barely covered. In contrast, the metal nanoparticle surface was completely covered by G8. In addition, NICISS results provided evidence that nanocomposites deformed when being deposited directly onto a substrate. PMID- 21539318 TI - Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide-oligospermine conjugates. AB - Oligonucleotides and their derivatives are a proven chemical strategy for modulating gene expression. However, their negative charge remains a challenge for delivery and target recognition inside cells. Here we show that oligonucleotide-oligospermine conjugates (Zip nucleic acids or ZNAs) can help overcome these shortcomings by serving as effective antisense and antigene agents. Conjugates containing DNA and locked nucleic acid (LNA) oligonucleotides are active, and oligospermine conjugation facilitates carrier-free cell uptake at nanomolar concentrations. Conjugates targeting the CAG triplet repeat within huntingtin (HTT) mRNA selectively inhibit expression of the mutant huntingtin protein. Conjugates targeting the promoter of the progesterone receptor (PR) function as antigene agents to block PR expression. These observations support further investigation of ZNA conjugates as gene silencing agents. PMID- 21539320 TI - Facile one-pot synthesis and morphological control of asymmetric superparamagnetic composite nanoparticles. AB - A one-pot colloidal reaction strategy was developed to synthesize asymmetric magnetic composite particles (AMCPs) with high anisotropy and magnetic content. The asymmetricity was established by having two portions of the particle composed of both polystyrene and silica, among which the latter was conjugated with magnetite nanoparticles. Phase separation was found to be critical in developing the asymmetric structure between the inorganic and polymer components during miniemulsion polymerization and the sol-gel reaction. Morphological control of the magnetic composite particles was achieved in a straightforward fashion by adjusting the processing parameters. These asymmetric nanomaterials with superparamagnetic and amphiphilic properties will have significant potential in biomedical applications. PMID- 21539321 TI - How linear is "linear" polyaniline? AB - The structure of emeraldine salt and emeraldine bases with different molar weight and their behavior in electrochemical doping was studied by different spectroscopic and spectroelectrochemical techniques. By Fourier transform infrared (FTIR) spectroscopy, the branching of the polymer chain at tri- and tetrasubstituted benzene rings as well as the presence of small amounts of phenazine units are shown. The branching of the polymer chains increases with the increasing of the molar weight of emeraldines. The optical transitions in protonated and unprotonated emeraldine were studied by ultraviolet-visible near infrared (UV-vis NIR) spectroscopy. By comparison of the electron spin resonance (ESR) spectra of emeraldine in protic solvents and acidic solutions, the emeraldine bases are shown to be to some extent protonated. Applying in situ ESR UV-vis NIR spectroelectrochemistry, the charged states in emeraldines upon p doping were investigated considering the influence of the nonideal "linear" polymer structures. The initial stage of oxidation of the emeraldine base and salt consists of the different charged states. The phenazine units in the polymer chains stabilize the charged states in the emeraldines upon p-doping. PMID- 21539322 TI - Comment on "The interaction of 5-(alkoxy)naphthalen-1-amine with bovine serum albumin and its effect on the conformation of protein". PMID- 21539324 TI - Effects of ions on ligand binding to pyruvate kinase: mapping the binding site with infrared spectroscopy. AB - The effects of mono- and divalent ions (Li(+), K(+), Na(+), Cs(+), Mg(2+), Ca(2+), Mn(2+), Zn(2+)) on the binding of phosphoenolpyruvate (PEP) to rabbit muscle pyruvate kinase (PK) were studied by attenuated total reflection infrared spectroscopy in combination with a dialysis accessory. The experiments assessed the structural change of the protein as well as the binding mode of PEP. They indicated that a signal at 1638 cm(-1) assigned to a beta sheet was perturbed differently with Na(+) as compared to the other monovalent ions. Otherwise, we obtained similar conformational changes in the presence of different monovalent cations, and therefore, it seems unlikely that the ion effects on activity are due to an ion effect on the structure of the PEP:PK complex. With different divalent cations, a particularly large conformational change was observed with Mn(2+) and attributed to a more closed conformation of the complex. The absorption of bound PEP was also detected. The antisymmetric stretching vibration of the carboxylate group of bound PEP indicates a more homogeneous binding mode for Mn(2+) compared to the other divalent ions. The symmetric stretching vibration depends on both monovalent and divalent ions, indicating that the dihedral angle O-C(1)-C(2)-O is affected by the ions in the catalytic site. Little change in the bond strengths of PEP is observed, indicating that the PEP:PK complex does not adopt a reactive conformation. PMID- 21539325 TI - A single amino acid limits the substrate specificity of Thermus thermophilus uridine-cytidine kinase to cytidine. AB - The salvage pathways of nucleotide biosynthesis are more diverse and are less well understood as compared with de novo pathways. Uridine-cytidine kinase (UCK) is the rate-limiting enzyme in the pyrimidine-nucleotide salvage pathway. In this study, we have characterized a UCK homologue of Thermus thermophilus HB8 (ttCK) biochemically and structurally. Unlike other UCKs, ttCK had substrate specificity toward only cytidine and showed no inhibition by UTP, suggesting uridine does not bind to ttCK as substrate. Structural analysis revealed that the histidine residue located near the functional group at position 4 of cytidine or uridine in most UCKs is substituted with tyrosine, Tyr93, in ttCK. Replacement of Tyr93 by histidine or glutamine endowed ttCK with phosphorylation activity toward uridine. These results suggested that a single amino acid residue, Tyr93, gives cytidine limited specificity to ttCK. However, replacement of Tyr93 by Phe or Leu did not change the substrate specificity of ttCK. Therefore, we conclude that a residue at this position is essential for the recognition of uridine by UCK. In addition, thymidine phosphorylase from T. thermophilus HB8 was equally active with thymidine and uridine, which indicates that this protein is the sole enzyme metabolizing uridine in T. Thermophilus HB8. On the basis of these results, we discuss the pyrimidine-salvage pathway in T. thermophilus HB8. PMID- 21539326 TI - Mechanism of the palladium-catalyzed addition of arylboronic acids to enones: a computational study. AB - The palladium(II)-catalyzed addition of arylboronic acids to beta,beta disubstituted enones has been investigated with the BP86 density functional. The results show that the mechanism requires three steps: transmetalation, alkene insertion, and protonation. The alkene insertion is the rate-determining step. For unactivated alkenes, the Heck-type beta-hydride elimination is more favored than protonation. PMID- 21539328 TI - Reversible hydrogen bond network dynamics: molecular dynamics simulations of calix[4]arene-catenanes. AB - We present detailed molecular dynamics (MD) simulations of mechanically interlocked calix[4]arene-catenanes under external force. Single-molecule force spectroscopy experiments revealed that the separation of dimers with two aliphatic loops results in reversible hydrogen bond breakage through an intermediate in a triple-well potential, while the tetra-loop species separates in a one-step manner (Janke, M.; et al. Nat. Nanotechnol. 2009, 4, 225). MD simulations show that calix[4]arenes interlocked by four loops (1) display a complete restructuring of the hydrogen bond network under mechanical force. All hydrogen bonds of the closed structure open, and new ones are formed in the extended structure. For small loading rates, we found reversible rejoining of the hydrogen bond network, while the rebinding ability diminishes with increasing pulling velocity, demonstrating the feasibility of MD simulations to capture also rebinding dynamics. Calix[4]arene dimers with two longer loops (2) under external force display more intricate physics because the elongation proceeds in a two step transition from a compact structure to an open one, in which complete dissociation into calix[4]arene monomers is only prevented by the mechanical locking of the loops. We present a detailed analysis of hydrogen bond breakage and show that the transition from the closed to the intermediate structure is very similar to the transition from the closed to the open structure in the tetra loop case. The stability of the intermediate is explained in terms of the closed hydrogen bonds, which are only broken when the transition to the open structure is enforced. PMID- 21539329 TI - Role of anionic micellar template on the morphology, solid-state ordering, and unusual conductivity trend in poly(aniline-co-pyrrole) nanomaterials. AB - Here, we report three structurally different anionic amphiphilic dopant micellar templates for the development of poly(aniline-co-pyrrole) copolymer nanomaterials and investigating the role of dopant on the morphology, solid-state ordering, and unusual bulk conductivity trend in conducting nanostructures. All three amphiphilic dopants possessed identical azobenzene sulfonic acid as polar head but vary in their hydrophobic alkyl tails. Dynamic light scattering analysis confirmed the formation of 4.3 and 100 nm micelles by the single tail and double tail amphiphiles in water, respectively. Upon adding aniline or pyrrole (or mixture of both), the dopant micelles produce a thick white emulsion containing micrometer size larger aggregates, which template for nanomaterial. The copolymer nanomaterials were synthesized by varying the amount of aniline and pyrrole in the feed from 0 to 100 mol % under identical emulsion polymerization routes. Electron microscopic analysis (SEM and TEM) revealed that the morphology of the copolymer nanomaterials transformed from nanofiber to nanospheres via nanorods upon increasing the composition of pyrrole in the feed. Four probe bulk conductivities of the nanomaterials, which were produced on the basis of single tail dopant (or no tail dopant), showed unusual nonlinear trend over the pyrrole composition. Because all three copolymers series showed similar morphology evolution, the influence of morphology transformation on the unusual trend in the bulk conductivities was ruled out. The percent crystallinity of the samples obtained from WXRD spectra provides direct evidence that the bulk conductivity of the copolymer conducting nanomaterials is primarily influenced by their three dimensional solid-state ordering rather than other factors such as morphology transformation. The structure of the dopant plays major roles in arranging the polymer-dopant complexes in highly ordered forms, which contribute to their bulk conductivity behaviors in the solid state. PMID- 21539330 TI - Electronic structure of cofactor-substrate reactant complex involved in the methyl transfer reaction catalyzed by cobalamin-dependent methionine synthase. AB - Complete active space self-consistent field (CASSCF) computations followed by the second-order perturbation theory have been applied to investigate the electronic properties of a structural mimic of the reactant complex formed in the catalytic cycle of cobalamin-dependent methionine synthase (MetH). Two different structural models have been employed to analyze the reaction complex between methylcobalamin (MeCbl) and homocysteine (Hcy). The first model, referred to as the small model (SM), is based on a truncated corrin ring with inner conjugated macrocycle only and has symmetry constrain with respect to methylthiolate. The second is based on a full corrin ring, i.e., [Co(III)(corrin)]-Me(+)...(-)S-CH(3), without the side chains (which were replaced by hydrogen atoms) and referred to as the large model (LM). The active space chosen for both models includes all essential orbitals participating in the methyl transfer reaction. Although the CASSCF calculations are much more demanding for the LM (due to the structural complexity) than the SM, the results are fully consistent. The energetic of ionic and diradical states have been examined as a function of the C...S distance between the methyl group of MeCbl and the sulfur of the thiolate substrate for both models. The most important finding of the present work is the energetic variation of ionic and diradical states as a function of C...S distance. The two states cross each other at a C...S distance of 4.0 A, i.e., for a distance shorter than ~4.0 A, the ionic state is energetically the lowest electronic state, while the diradical state becomes the lowest state at longer distances. However, the potential energy surface of the ionic state shows greater sensitivity with respect to the C...S distance than that of the diradical one. The former can be associated with S(N)2 type displacement, where the cleavage of the Co-C bond would be heterolytic, while the latter can be associated with an electron transfer (ET), where the cleavage is homolytic. Finally, the importance of this finding is briefly discussed in the context of MeCbl-dependent enzymatic catalysis. PMID- 21539331 TI - Electrophoresis of a charge-regulated sphere normal to an air-water interface. AB - The electrophoresis of a charge-regulated sphere normal to an air-water interface is investigated theoretically. The charge-regulated surface considered here is the generalization of conventional constant surface potential and constant surface charge density situations and models excellently well biocolloids or particles coated with a thin film of polyelectrolytes. The thickness of the double layer surrounding the particle can be arbitrary. A pseudospectral method based on Chebyshev polynomials is employed to solve the governing electrokinetic equations. We found, among other things, that the electric potential on the particle surface is the most dominant factor in the determination of the eventual particle electrophoretic mobility. The larger the number of dissociated functional groups on the particle surface (N(s)), the higher the absolute surface potential of the particle and hence the larger the magnitude of the mobility. Moreover, the electric potential on the particle surface depends on both the concentration of dissociated hydrogen ions, [H(+)](0), and the concentration of electrolytes, kappaa, in the solution. If [H(+)](0) and/or kappaa are small, the bulk condition is advantageous to the dissociation reaction, yielding a higher surface density (higher surface potential) and hence a higher mobility. The air water interface retards the particle motion in general, especially when the double layer is thick enough to touch the interface. Up to around 60%, reduction of the mobility is observed for some situation. The boundary effect disappears as the double layer gets very thin. This is mainly due to the buildup of the electric potential at the interface right in front of the particle, which in turn generates a repulsive electrostatic force. Comparison with a solid planar wall is carried out to highlight the fundamental nature of the air-water interface, such as the unique phenomenon of the electric potential buildup mentioned above. PMID- 21539332 TI - Electrochemical and spectroscopic study of pyranine fluorescent probe: role of intermediates in pyranine oxidation. AB - 8-Hydroxy-1,3,6-pyrenetrisulfonic acid (pyranine) is a hydrophilic pyrene derivative, highly reactive toward free radicals, that has been widely used in methodologies for the evaluation of antioxidant capability and the monitoring of free-radical polymer processes. In this work, we studied and characterized the electrochemical oxidation of pyranine by cyclic voltammetry, chronocoulometry, and spectroelectrochemical techniques. The electrochemical oxidation of pyranine leads to the formation of a pyranine free radical (PyO*) that is easily detectable by spectroelectrochemistry measurements. This oxidation process takes place through a CEC (chemical-electrochemical-chemical) mechanism where the chemical step previous to the oxidation corresponds to an acid-base equilibrium. A reversible diffusion-controlled electron-transfer process observed at high pH suggests that the charge-transfer process is followed by a chemical step associated with secondary PyO* dimerization-disproportionation chemical reactions. Surprisingly, pyranine oxidation mediated by peroxyl radicals showed a change in the stoichiometry of the reaction at pH values close to the pK(a) of pyranine. This behavior was attributed to the different reactivities of the ionized (PyO(-)) and the nonionized (PyOH) phenolic forms of pyranine for peroxyl radicals, affecting the role of secondary reactions at different pH values and, therefore, the measured stoichiometry. PMID- 21539333 TI - Characterization and quantification of RNA post-transcriptional modifications using stable isotope labeling of RNA in conjunction with mass spectrometry analysis. AB - Mass spectrometry has emerged as an increasingly powerful tool for the identification and characterization of nucleic acids, in particular RNA post transcriptional modifications. High mass accuracy instrumentation is often required to discriminate between compositional isomers of oligonucleotides. We have used stable isotope labeling ((15)N) of E. coli RNA in conjunction with mass spectrometry analysis of the combined heavy- and light-labeled RNA for the identification and quantification of oligoribonucleotides and post transcriptional modifications. The number of nitrogen atoms in the oligoribonucleotide and fragment ions can readily be determined using this approach, enabling the discrimination between potential compositional isomers without the requirement of high mass accuracy mass spectrometers. In addition, the identification of specific fragment ions in both the unlabeled and labeled oligoribonucleotides can be used to gain further confidence in the assignment of RNA post-transcriptional modifications. Using this approach we have identified a range of post-transcriptional modifications of E. coli 16S rRNA. Furthermore, this method facilitates the rapid and accurate quantification of oligoribonucleotides, including cyclic phosphate intermediates and missed cleavages often generated from RNase digestions. PMID- 21539334 TI - Self-templating synthesis of SnO2-carbon hybrid hollow spheres for superior reversible lithium ion storage. AB - This paper reports a novel self-templating methodology for the formation of SnO(2)-carbon hybrid hollow spheres by using Sn spheres as sacrificing templates. The time-sequenced structural evolution of the templates indicates that the nanoscale Kirkendall effect plays a critical role in the transformation from Sn spheres to the hybrid hollow spheres. Moreover, the as-synthesized SnO(2)-carbon hybrid hollow spheres have been applied as anode materials for lithium-ion batteries, which exhibit a much higher initial Coulombic efficiency and better cycling performance than pure SnO(2) hollow spheres. PMID- 21539335 TI - Development of submillisecond time-resolved mass spectrometry using desorption electrospray ionization. AB - Reaction kinetics studied by mass spectrometry (MS) has previously been limited to millisecond time resolution. This paper presents the development of a submillisecond time-resolved mass spectrometric method for fast reaction kinetic study, based on the capability of desorption electrospray ionization (DESI) for direct and fast ionization of a high-speed liquid jet stream. The principle underlying this methodology is that two reactant solutions undergo rapid mixing to produce a free liquid jet which is ionized by DESI at different positions corresponding to different reaction times. Due to the high velocity of the liquid jet, high time resolution can be achieved. In this study, the fast reduction reaction of 2, 6-dichlorophenolindophenol (DCIP) and L-ascorbic acid (L-AA) was chosen as an example to demonstrate this concept, and the reaction rate constant was successfully measured with an unprecedented time resolution of 300 MUs. The good agreement of the measured value of (116 +/- 3) s(-1) with that measured by the stopped-flow optical method (105 +/- 2) s(-1) validates the feasibility of such a DESI-MS approach. Unlike classical spectroscopic techniques that require either chromophoric substrates or labeling, MS is a general detector with high chemical specificity. Therefore, this time-resolved DESI-MS method should find wide applications in fast (bio)chemical reaction investigations. PMID- 21539336 TI - Facile determination of double bond position in unsaturated fatty acids and esters by low temperature plasma ionization mass spectrometry. AB - Unsaturated fatty acids and esters can be oxidized in situ during ionization using a low temperature plasma (LTP) probe. The discharge generates ozone from air that reacts with and cleaves olefins. The molecular ions of the resulting acid/ester oxidation products are present in the full scan mass spectra and are confirmed by exact mass measurements. The fragmentation information can be used to assign double bond positions. We have successfully applied this strategy to a range of mono-/polyunsaturated fatty acids and fatty acid methyl/ethyl esters to assign their double bond locations. The procedure allows rapid and direct identification of double bond positions in situ at atmospheric pressure without sample preparation prior to mass spectrometric analysis. Microbial fatty acid ethyl ester (FAEE) mixtures from complex bacterial samples were directly analyzed by this method. Structural confirmation of their diagnostic ions by using exact mass measurements and tandem mass spectrometry confirms double bond positions in unsaturated bacterial FAEEs. PMID- 21539338 TI - On the distribution functions of depletion interactions. AB - Molecular dynamics computer simulations were performed on model colloidal binary mixtures of two large and many small soft repulsive spheres. Depletion forces arise between the two large spheres, as a function of their distance, because of the nonadditivity of the volume they exclude to the small spheres. The probability distribution functions of both longitudinal and transverse component of the total force exerted by the small particles were calculated and generally turned out non-Gaussian. The distributions of the collective forces were analyzed in terms of the distribution of the force that a single small sphere exerts on a large sphere and of the number of the surrounding small spheres. The reconstructed function matches well the corresponding exact distribution. Residual correlation among small particles, combined with a relatively small number of neighbors, slows the approach to the Gaussian limit. In our fully repulsive model, the direct force between a large and a small sphere is a monotonic function of their distance. On these bases, we propose and successfully test an approach that relates the probability distribution function of the depletion forces to the large-sphere-small-sphere radial distribution function. This approach can be extended to experimental data of radial distribution function, thus allowing for an estimate of depletion force fluctuations in real colloidal mixtures. PMID- 21539339 TI - Ab initio reaction rate constants computed using semiclassical transition-state theory: HO + H2 -> H2O + H and isotopologues. AB - A new algorithm [Nguyen, T. L.; Stanton, J. F.; Barker, J. R. Chem. Phys. Lett. 2010, 9, 499] for the semiclassical transition-state theory (SCTST) formulated by W. H. Miller and co-workers is used to compute rate constants for the isotopologues of the title reaction, with no empirical adjustments. The SCTST and relevant results from second-order vibrational perturbation theory (VPT2) are summarized. VPT2 is used at the CCSD(T) level of electronic structure theory to compute the anharmonicities of the fully coupled vibrational modes (including the reaction coordinate) of the transition structure. The anharmonicities are used in SCTST to compute the rate constants over the temperature range from 200 to 2500 K. The computed rate constants are compared to experimental data and theoretical calculations from the literature. The SCTST results for absolute rate constants and for both primary and secondary isotope effects are in excellent agreement with the experimental data for this reaction over the entire temperature range. The sensitivity of SCTST to various parameters is investigated by using a set of simplified models. The results show that multidimensional tunneling along the curved reaction path is important at low temperatures and the anharmonic coupling among the vibrational modes is important at high temperatures. The theoretical kinetics data are also presented as fitted empirical algebraic expressions. PMID- 21539337 TI - Identification of arginine residues in peptides by 2D-IR echo spectroscopy. AB - The CN stretching vibrations of the guanidyl group in the arginine dipeptide side chain are examined by two-dimensional infrared spectroscopy. In D(2)O, the spectra display two distinct diagonal peaks. These nearly degenerate modes undergo ultrafast energy transfer. The energy-transfer rate was determined directly from the 2D-IR spectra to be 1/2.1 ps(-1). The cross peaks in 2D-IR arising from the energy transfer provide a definitive identification of arginine in larger proteins. An example of arginine in the transmembrane protein M2, found in influenza viruses, is given. PMID- 21539340 TI - Lipid membranes with a majority of cholesterol: applications to the ocular lens and aquaporin 0. AB - Using molecular dynamics (MD) simulations, we studied the structure and dynamics of two dimyristoylphosphatidylcholine (DMPC):cholesterol bilayers at concentrations representative of the ocular lens (ratios of 1:1 and 1:2). These MD simulations agree well with experimental deuterium order parameters and bilayer peak-to-peak distances. Although it is known that the average surface area per lipid rapidly decreases from low to moderate levels of cholesterol, our simulations indicate that there is a relatively small change in the average lipid area from 50 to 66.7% cholesterol (40.5 +/- 0.2 and 39.5 +/- 0.1 A(2)/lipid, respectively). Radial distribution functions for the hydroxyl group on cholesterol indicate the formation of cholesterol-only nanoscale domains for the membrane with 66.7% cholesterol but a uniform distribution of cholesterol and DMPC for the membrane with 50% cholesterol. These small domains form a single shell of hexagonally packed cholesterols that are interconnected in a web-like structure of cholesterol. Calculations of internal DMPC dynamics show that the relaxation times for carbon-hydrogen reorientation of choline decrease with an increase in cholesterol, but the main body (carbonyl-glycerol to C11) is independent of cholesterol concentration. MD simulations of the aquaporin 0 tetramer show stabilization in its interactions with lipid membranes containing cholesterol by forming ring-ring stacking between surface aromatic residues of the protein and the rings of cholesterol. Moreover, there is an increase in hydrogen bonds with longer lifetimes in a mixed bilayer of DMPC and cholesterol. PMID- 21539341 TI - Insights into the interaction of discodermolide and docetaxel with tubulin. Mapping the binding sites of microtubule-stabilizing agents by using an integrated NMR and computational approach. AB - The binding interactions of two antitumor agents that target the paclitaxel site, docetaxel and discodermolide, to unassembled alpha/beta-tubulin heterodimers and microtubules have been studied using biochemical and NMR techniques. The use of discodermolide as a water-soluble paclitaxel biomimetic and extensive NMR experiments allowed the detection of binding of microtubule-stabilizing agents to unassembled tubulin alpha/beta-heterodimers. The bioactive 3D structures of docetaxel and discodermolide bound to alpha/beta-heterodimers were elucidated and compared to those bound to microtubules, where subtle changes in the conformations of docetaxel in its different bound states were evident. Moreover, the combination of experimental TR-NOE and STD NMR data with CORCEMA-ST calculations indicate that docetaxel and discodermolide target an additional binding site at the pore of the microtubules, which is different from the internal binding site at the lumen previously determined by electron crystallography. Binding to this pore site can then be considered as the first ligand-protein recognition event that takes place in advance of the drug internalization process and interaction with the lumen of the microtubules. PMID- 21539342 TI - Nanoparticle-controlled aggregation of colloidal tetrapods. AB - Tetrapods are among the most promising building blocks for nanoscale self assembly, offering various desirable features. Whereas these particles can be fabricated with remarkable precision, comparatively less is known about their aggregation behavior. Employing a novel, powerful simulation method, we demonstrate that charged nanoparticles offer considerable control over the assembly of tip-functionalized tetrapods. Extending these findings to tetrapods confined to a gas/liquid interface, we show that regular structures can be achieved even without functionalization. PMID- 21539343 TI - Electron distribution in partially reduced mixed metal oxide systems: infrared spectroscopy of CemVnOo(+) gas-phase clusters. AB - Vibrational predissociation spectra of rare-gas-tagged [(CeO(2))(VO(2))(1-2)](+) and [(Ce(2)O(3))(VO(2))](+) clusters are measured in the 400-1200 cm(-1) region. Density functional theory (DFT) is used to determine the geometric and electronic structure of low-energy isomers of the partially reduced clusters. Comparison of experimental and simulated spectra provides evidence for the larger stability of Ce(+3)/V(+5) compared to that of Ce(+4)/V(+4), which confirms that the exceptionally high reducibility of Ce(+4) accounts for the promoting role of ceria in supported vanadium oxide catalysts. PMID- 21539344 TI - A computational study of the mechanisms of the photoisomerization reactions of monocyclic and bicyclic olefins. AB - The mechanisms of the photochemical isomerization reactions were investigated theoretically using a model system of cyclohexene (1), cycloheptene (2), norbornene (3), and two bicyclic olefins (4 and 5) using the CASSCF (six electron/six-orbital active space) and MP2-CAS methods with the 6-311(d,p) basis set. The structures of the conical intersections, which play a decisive role in such photoisomerizations, were obtained. The intermediates and transition structures of the ground state were also calculated to assist in providing a qualitative explanation of the reaction pathways. Two photoreaction pathways were examined in the present work. The first can produce a photoproduct with an extra ring. The other can yield a photoproduct with a smaller ring with an external double bond. Both pathways involve cyclic carbene intermediates. Also, our model investigations suggest that both reaction pathways follow a similar photochemical pattern as follows: reactant -> Franck-Condon region -> conical intersection -> cyclic carbene intermediate -> transition state -> photoproduct. Moreover, these two reaction pathways can compete with each other since the energetics of their conical intersection points are quite similar. Our present theoretical results agree with the available experimental observations. PMID- 21539345 TI - (R)-3,5-diCF3-SYNPHOS and (R)-p-CF3-SYNPHOS, electron-poor diphosphines for efficient room temperature Rh-catalyzed asymmetric conjugate addition of arylboronic acids. AB - Two new atropisomeric electron-poor chiral diphosphine ligand analogues of SYNPHOS were prepared, and their electronic properties are described. These two ligands afforded high performance for the Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to alpha,beta-unsaturated carbonyl compounds at room temperature. PMID- 21539346 TI - Synergistic effect of graphene oxide/MWCNT films in laser desorption/ionization mass spectrometry of small molecules and tissue imaging. AB - Matrix-assisted laser desorption/ionization mass spectrometry has been considered an important tool for various biochemical analyses and proteomics research. Although addition of conventional matrix efficiently supports laser desorption/ionization of analytes with minimal fragmentation, it often results in high background interference and misinterpretation of the spatial distribution of biomolecules especially in low-mass regions. Here, we show design, systematic characterization, and application of graphene oxide/multiwalled carbon nanotube based films fabricated on solid substrates as a new matrix-free laser desorption/ionization platform. We demonstrate that the graphene oxide/multiwalled carbon nanotube double layer provides many advantages as a laser desorption/ionization substrate, such as efficient desorption/ionization of analytes with minimum fragmentation, high salt tolerance, no sweet-spots for mass signal, excellent durability against mechanical and photoagitation and prolonged exposure to ambient conditions, and applicability to tissue imaging mass spectrometry. This platform will be widely used as an important tool for mass spectrometry-based biochemical analyses because of its outstanding performance, long-term stability, and cost effectiveness. PMID- 21539347 TI - ssDNA aptamer-based column for simultaneous removal of nanogram per liter level of illicit and analgesic pharmaceuticals in drinking water. AB - Aptamers are a new class of single-stranded DNA/RNA molecules selected from synthetic nucleic acid libraries for molecular recognition. Our group reports a novel aptamer column for the removal of trace (ng/L) pharmaceuticals in drinking water. In this study, cocaine and diclofenac were chosen as model molecules to test the aptamer column which presented high removal capacity, selectivity, and stability. The removal of pharmaceuticals was as high as 88-95%. The data of adsorption were fitted with Langmuir isotherm and a pseudo-second-order kinetic model. A thermodynamic experiment proved the adsorption processes were exothermic in spontaneity. The kinetics of aptamer was composed of three steps: activation, binding, and hybridization. The first step was the rate-controlling step. The adsorption system was divided into three parts: kinetic, mixed, and thermodynamic zones from 0% to 100% binding fraction of aptamer. Furthermore, the aptamer column was reusable and achieved strong removal efficiency from 4 to 30 degrees C at normal cation ion concentration (5-100 mg/L) for multipollutants without cross effects and secondary pollution. This work indicates that aptamer, as a new sorbent, can be used in the removal of persistent organic pollutants, biological toxins, and pathogenic bacteria from surface, drinking, and ground water. PMID- 21539348 TI - Mechanism for OH-initiated degradation of 2,3,7,8-tetrachlorinated dibenzo-p dioxins in the presence of O2 and NO/H2O. AB - The atmospheric oxidation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TeCDD) is investigated theoretically by high-accuracy molecular orbital calculation. The study shows that the OH radical can easily be added to the C atom adjacent to the O atom in dioxin ring to form OH radical adduct. The 2,3,7,8-TeCDD-OH adduct can immediately react with O(2) to form the 2,3,7,8-TeCDD-OH-O(2) adduct which can react with NO or H(2)O to complete the decomposition process. The degradation mechanism varies with the addition position of O(2) and the O-abstraction by NO. The OH radical can be reproduced through the H-abstraction of H(2)O and initiate a new round of degradation. The direct dynamic calculation is performed, and the rate constants is calculated over a temperature range of 200-1200 K, using the canonical variational transition state theory with small-curvature tunneling effect. The four-parameter formula of rate constants with the temperature is fitted and the lifetimes of the reaction species in the troposphere are estimated according to the rate constants, which is helpful for the atmospheric model study on the formation and degradation of dioxin. PMID- 21539350 TI - Dynamic wetting and spreading characteristics of a liquid droplet impinging on hydrophobic textured surfaces. AB - We report on the wetting dynamics of a 4.3 MUL deionized (DI) water droplet impinging on microtextured aluminum (Al 6061) surfaces, including microhole arrays (hole diameter 125 MUm and hole depth 125 MUm) fabricated using a conventional microcomputer numerically controlled (MU-CNC) milling machine. This study examines the influence of the texture area fraction phi(s) and drop impact velocity on the spreading characteristics from the measurement of the apparent equilibrium contact angle, dynamic contact angle, and maximum spreading diameter. We found that for textured surfaces the measured apparent contact angle (CA) takes on values of up to 125.83 degrees , compared to a CA of approximately 80.59 degrees for a nontextured bare surface, and that the spreading factor decreases with the increased texture area fraction because of increased hydrophobicity, partial penetration of the liquid, and viscous dissipation. In particular, on the basis of the model of Ukiwe and Kwok (Ukiwe, C.; Kwok, D. Y. Langmuir 2005, 21, 666), we suggest a modified equation for predicting the maximum spreading factor by considering various texturing effects and wetting states. Compared with predictions by using earlier published models, the present model shows better agreement with experimental measurements of the maximum spreading factor. PMID- 21539349 TI - Dissolution of technetium(IV) oxide by natural and synthetic organic ligands under both reducing and oxidizing conditions. AB - Technetium-99 (Tc) in nuclear waste is a significant environmental concern due to its long half-life and high mobility in the subsurface. Reductive precipitation of technetium(IV) oxides [TcO(2)(s)] is an effective means of immobilizing Tc, thereby impeding its migration in groundwater. However, technetium(IV) oxides are subject to dissolution by oxidants and/or complexing agents. In this study we ascertain the effects of a synthetic organic ligand, ethylenediaminetetraacetate (EDTA), and two natural humic isolates on the dissolution and solubility of technetium(IV) oxides. Pure synthetic technetium(IV) oxide (0.23 mM) was used in batch experiments to determine dissolution kinetics at pH ~6 under both reducing and oxidizing conditions. All organic ligands were found to enhance the dissolution of technetium(IV) oxides, increasing their solubility from ~10(-8) M (without ligands) to 4 * 10(-7) M under strictly anoxic conditions. Reduced Tc(IV) was also found to reoxidize rapidly under oxic conditions, with an observed oxidative dissolution rate approximately an order of magnitude higher than that of ligand-promoted dissolution under reducing conditions. Significantly, oxidative dissolution was inhibited by EDTA but enhanced by humic acid compared to experiments without any complexing agents. The redox functional properties of humics, capable of facilitating intramolecular electron transfer, may account for this increased oxidation rate under oxic conditions. Our results highlight the importance of complex interactions for the stability and mobility of Tc and thus for the long-term fate of Tc in contaminated environments. PMID- 21539351 TI - Anisotropic wet etched silicon substrates for reoriented and selective growth of ZnO nanowires and enhanced hydrophobicity. AB - Herein we report the fabrication of ZnO nanowires on anisotropic wet etched silicon substrates by selective hydrothermal growth. <100> oriented silicon wafers were first patterned by anisotropic wet etch with a KOH solution, resulting in V-shaped stripes of different periods. Then, a thin layer of gold was deposited and annealed to promote the hydrothermal growth of ZnO nanowires. It was found that the growth rate of ZnO nanowires on <111> surfaces was much higher than that on <100> surfaces. As a first application of such micro- and nanostructured surfaces, we show enhanced wetting properties by measuring the contact angle of water droplets on the samples obtained under different patterning and growth conditions. Our results also demonstrated the possibility of tuning the contact angle of the sample in the range between 115 degrees and 155 degrees , by changing either the pattern of the silicon template or the hydrothermal growth conditions. PMID- 21539353 TI - Syntheses of group 7 metal carbonyl complexes with a stable N-heterocyclic chlorosilylene. AB - Two structurally characterized manganese [L(2)Mn(CO)(4)](+)[Mn(CO)(5)](-) (1) and rhenium [L(3)Re(CO)(3)](+)[ReCO)(5)](-) (2) silylene complexes were prepared in one pot syntheses by reacting 1 equivalent of Mn(2)(CO)(10) with 2 equivalents of stable N-heterocyclic chlorosilylene L {L = PhC(NtBu)(2)SiCl} and 1 equivalent of Re(2)(CO)(10) with 3 equivalents of L in toluene at room temperature. Both complexes 1 and 2 were characterized by single-crystal X-ray structural analysis, NMR and IR spectroscopy, EI-MS spectrometry, and elemental analysis. PMID- 21539354 TI - Investigation of porous Ni-based metal-organic frameworks containing paddle-wheel type inorganic building units via high-throughput methods. AB - In the search of Ni based metal-organic frameworks (MOFs) containing paddle-wheel type building units, three chemical systems Ni(2+)/H(n)L/base/solvent with H(n)L = H(3)BTC (1,3,5-benzenetricarboxylic acid), H(3)BTB (4,4',4'',-benzene-1,3,5 triyl-tris(benzoic acid)), and H(2)BDC (terephthalic acid) were investigated using high-throughput (HT) methods. In addition to the conventional heating, for the first time HT microwave assisted synthesis of MOFs was carried out. Six new compounds were discovered, and their fields of formation were established. In the first system, H(3)BTC was employed and a comprehensive HT-screening of compositional and process parameters was conducted. The synthesis condition for the Ni paddle-wheel unit was determined and two compounds [Ni(3)(BTC)(2)(Me(2)NH)(3)].(DMF)(4)(H(2)O)(4) (1a) and [Ni(6)(BTC)(2)(DMF)(6)(HCOO)(6)] (1b) were discovered (Me(2)NH = dimethylamine, DMF = dimethylformamide). In the second system, the use of the extended tritopic linker H(3)BTB and the synthesis conditions for the paddle-wheel units led to the porous MOF, [Ni(3)(BTB)(2)(2-MeIm)(1.5)(H(2)O)(1.5)].(DMF)(9)(H(2)O)(6.5) (2), (2 MeIm = 2-methylimidazole). This compound shows a selective adsorption of H(2)O and H(2) with a strong hysteresis. In the third system, H(2)BDC was used, and the base (DABCO) was incorporated as a bridging ligand into all structures. Thus, two pillared layered porous MOFs [Ni(2)(BDC)(2)(DABCO)].(DMF)(4)(H(2)O)(1.5) (3a) and [Ni(2)(BDC)(2)(DABCO)].(DMF)(4)(H(2)O)(4) (3b) as well as a layered compound [Ni(BDC)(DABCO)].(DMF)(1.5)(H(2)O)(2) (3c) were isolated. The 3a and 3b polymorphs of the [Ni(2)(BDC)(2)(DABCO)] framework can be selectively synthesized. The combination of microwave assisted heating, low overall concentration, stirring of the reaction mixtures, and an excess of DABCO yields a highly crystalline pure phase of 3b. The fields of formation of all compounds were established, and scale-up was successfully performed for 1b, 2, 3a, 3b, and 3c. All compounds were structurally characterized. In addition to IR, elemental and TG analyses, gas and vapor sorption experiments were carried out. PMID- 21539355 TI - Unsymmetrical 1lambda3-1,2,4,6-thiatriazinyls with aryl and trifluoromethyl substituents: synthesis, crystal structures, EPR spectroscopy, and voltammetry. AB - A general synthetic route to 3-trifluoromethyl-5-aryl-1lambda(3)-1,2,4,6 thiatriazinyl radicals was developed. X-ray structures were obtained for all five neutral radicals and show that they exist in the solid state as cofacial dimers linked by S...S contacts. X-ray structures were also obtained for two of the precursor chlorothiatriazines along with several aryl N-imidoylamidines, p methoxybenzamidine, and N-chlorosulfonyl-N,N'-benzamidine. Cyclic voltammetric studies were performed on the [R(2)C(2)N(3)S](*) radicals in CH(3)CN and CH(2)Cl(2) with [(n)Bu(4)N][PF(6)] as the supporting electrolyte under vacuum conditions in an all-glass electrochemical cell. The results provide quasi reversible formal potentials for the [R(2)C(2)N(3)S](-/0) process in the range of -0.61 to -0.47 V, irreversible peak potentials for the [R(2)C(2)N(3)S](0/+) process from 0.59 to 0.91 V at lower concentrations, and the appearance of a second, reversible oxidation process from 0.69 to 0.94 V at higher concentrations (versus the Fc(0/+) couple; Fc = ferrocene). This behavior was indicative of monomer-dimer equilibrium in solution, as ascertained from digital models of the voltammograms. There is a small but measurable trend in both the oxidation and reduction potentials with varying remote aryl substituents. EPR spectra were obtained for all five neutral radicals in CH(2)Cl(2) solutions, which confirm the concentration of the unpaired electron density on the heterocyclic core. Trends were also seen in the hyperfine splitting constants a(N) with varying remote aryl substituents. Calculations were performed for all three oxidation states of the [R(2)C(2)N(3)S](-/*/+) monomeric rings; the resulting theoretical redox energies correlate well with solution phase voltammetric data. PMID- 21539356 TI - Chemical and physical changes in milk protein concentrate (MPC80) powder during storage. AB - The solubility and chemical changes due to the Maillard reaction were investigated in milk protein concentrate powder containing 80% protein (MPC80) during storage at temperatures and relative humidities in the ranges of 25-40 degrees C and 44-84%, respectively. The Maillard reaction was studied by measuring furosine (a product of lactosylated protein after digestion with acid) and free hydroxymethylfurfural (HMF) contents by HPLC and L*, a*, b* values with a color-meter. Furosine, free HMF, and browning in MPC80 increased during storage, whereas the solubility decreased. The correlation between the Maillard reaction and solubility loss was explored in modified MPC80 to which glucose was added to enhance the rate of the Maillard reaction. More furosine and brown pigments were observed in the glucose-containing MPC80 than in MPC80 with added lactose. The opposite trend occurred for solubility, suggesting that the Maillard reaction may be a cause of solubility loss in MPC powder. PMID- 21539357 TI - Synthesis and characterization of a series of model complexes of the active site of [Fe]-hydrogenase (Hmd). AB - A series of Fe complexes were synthesized and characterized as small molecule mimics for the active site of [Fe]-hydrogenase (Hmd). The collection includes both structurally new compounds and analogues of previously reported models. These complexes contain the essential ligands of the enzyme, namely, acyl, CO, pyridone, and sulfur ligands. They serve as IR and Mossbauer spectroscopic models for the Fe center in [Fe]-hydrogenase. The field-dependent Mossbauer study of representative model complexes shows that the sign and absolute value of the quadrupole splitting are sensitive to the change in the ligand environment of the Fe center. PMID- 21539358 TI - Aqueous colloidal mesoporous nanoparticles with ethenylene-bridged silsesquioxane frameworks. AB - Aqueous colloidal mesoporous nanoparticles with ethenylene-bridged silsesquioxane frameworks with a uniform diameter of ~20 nm were prepared from bis(triethoxysilyl)ethenylene in a basic aqueous solution containing cationic surfactants. The nanoparticles, which had higher hydrolysis resistance under aqueous conditions, showed lower hemolytic activity toward bovine red blood cells than colloidal mesoporous silica nanoparticles. PMID- 21539359 TI - Temperature dependence of the crystal structure and g-values of trans diaquabis(methoxyacetato)copper(II): evidence for a thermal equilibrium between complexes with tetragonally elongated and compressed geometries. AB - The crystal structures of trans-diaquabis(methoxyacetato)copper(II) and the isostructural nickel(II) complex have been determined over a wide temperature range. In conjunction with the reported behavior of the g-values, the structural data suggest that the copper(II) compound exhibits a thermal equilibrium between three structural forms, two having orthorhombically distorted, tetragonally elongated geometries but with the long and intermediate bonds to different atoms, and the third with a tetragonally compressed geometry. This is apparently the first reported example of a copper(II) complex undergoing an equilibrium between tetragonally elongated and compressed forms. The optical spectrum of single crystals of the copper(II) compound is used to obtain metal-ligand bonding parameters which yield the g-values of the compressed form of the complex and hence the proportions of the complex in each structural form at every temperature. When combined with estimates of the Jahn-Teller distortions of the different forms, the latter produce excellent agreement with the observed temperature dependence of the bond lengths. The behavior of an infrared combination band is consistent with such a thermal equilibrium, as is the temperature dependence of the thermal ellipsoid parameters and the XAFS. The potential surfaces of the different forms of the copper(II) complex have been calculated by a model based upon Jahn-Teller coupling. It is suggested that cooperative effects may cause the development of the population of tetragonally compressed complexes, and the crystal packing is consistent with this hypothesis, though the present model may oversimplify the diversity of structural forms present at high temperature. PMID- 21539360 TI - The membrane interface dictates different anchor roles for "inner pair" and "outer pair" tryptophan indole rings in gramicidin A channels. AB - We investigated the effects of substituting two of the four tryptophans (the "inner pair" Trp(9) and Trp(11) or the "outer pair" Trp(13) and Trp(15)) in gramicidin A (gA) channels. The conformational preferences of the doubly substituted gA analogues were assessed using circular dichroism spectroscopy and size-exclusion chromatography, which show that the inner tryptophans 9 and 11 are critical for the gA's conformational preference in lipid bilayer membranes. [Phe(13,15)]gA largely retains the single-stranded helical channel structure, whereas [Phe(9,11)]gA exists primarily as double-stranded conformers. Within this context, the (2)H NMR spectra from labeled tryptophans were used to examine the changes in average indole ring orientations, induced by the Phe substitutions and by the shift in conformational preference. Using a method for deuterium labeling of already synthesized gAs, we introduced deuterium selectively onto positions C2 and C5 of the remaining tryptophan indole rings in the substituted gA analogues for solid-state (2)H NMR spectroscopy. The (least possible) changes in orientation and overall motion of each indole ring were estimated from the experimental spectra. Regardless of the mixture of backbone folds, the indole ring orientations observed in the analogues are similar to those found previously for gA channels. Both Phe-substituted analogues form single-stranded channels, as judged from the formation of heterodimeric channels with the native gA. [Phe(13,15)]gA channels have Na(+) currents that are ~50% and lifetimes that are ~80% of those of native gA channels. The double-stranded conformer(s) of [Phe(9,11)]gA do not form detectable channels. The minor single-stranded population of [Phe(9,11)]gA forms channels with Na(+) currents that are ~25% and single-channel lifetimes that are ~300% of those of native gA channels. Our results suggest that Trp(9) and Trp(11), when "reaching" for the interface, tend to drive both monomer folding (to "open" a channel) and dimer dissociation (to "close" a channel). Furthermore, the dipoles of Trp(9) and Trp(11) are relatively more important for the single-channel conductance than are the dipoles of Trp(13) and Trp(15). PMID- 21539362 TI - On the structural and electronic properties of [Zn2(4,4'-bipyridine)(mes)4]n- (n=0-2), a homologous series of bimetallic complexes bridged by neutral, anionic, and dianionic 4,4'-bipyridine. AB - Addition of 1 equiv of potassium metal to a tetrahydrofuran (THF) solution of Zn(2)(4,4'-bipyridine)(mes)(4) (1; mes =2,4,6-Me(3)C(6)H(2)) in the presence of 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) yielded the radical anionic species [Zn(2)(4,4'-bipyridine)(mes)(4)](*-), which was characterized by single crystal X-ray diffraction in [K(18-crown-6)(THF)(2)][Zn(2)(4,4' bipyridine)(mes)(4)] (2). A similar reaction employing 2 equiv of alkali metal afforded the related complex [K(18-crown-6)](2)[Zn(2)(4,4'-bipyridine)(mes)(4)] (3). The [Zn(2)(4,4'-bipyridine)(mes)(4)](n-) (n = 0-2) moieties present in 1-3 are largely isostructural, yet exhibit significant structural variations which arise because of differences in their electronic structure. These species represent a homologous series of complexes in which the ligand exists in three distinct oxidation states. Structural data, spectroscopic measurements, and density functional theory (DFT) calculations are consistent with the assignment of 1, 2, and 3 as complexes of the neutral, radical anionic, and dianionic 4,4' bipyridyl ligand, respectively. To the best of our knowledge, species 2 and 3 are the first crystallographically characterized transition metal complexes of the 4,4'-bipyridyl radical and dianion. PMID- 21539361 TI - Rhodopsin in nanodiscs has native membrane-like photointermediates. AB - Time-dependent studies of membrane protein function are hindered by extensive light scattering that impedes application of fast optical absorbance methods. Detergent solubilization reduces light scattering but strongly perturbs rhodopsin activation kinetics. Nanodiscs may be a better alternative if they can be shown to be free from the serious kinetic perturbations associated with detergent solubilization. To resolve this, we monitored absorbance changes due to photointermediates formed on the microsecond to hundred millisecond time scale after excitation of bovine rhodopsin nanodiscs and compared them to photointermediates that form in hypotonically washed native membranes as well as to those that form in lauryl maltoside suspensions at 15 and 30 degrees C over a pH range from 6.5 to 8.7. Time-resolved difference spectra were collected from 300 to 700 nm at a series of time delays after photoexcitation and globally fit to a sum of time-decaying exponential terms, and the photointermediates present were determined from the spectral coefficients of the exponential terms. At the temperatures and pHs studied, photointermediates formed after photoexcitation of rhodopsin in nanodiscs are extremely similar to those that form in native membrane, in particular displaying the normal forward shift of the Meta I(480) ? Meta II equilibrium with increased temperature and reduced pH which occurs in native membrane but which is not observed in lauryl maltoside detergent suspensions. These results were obtained using the amount of rhodopsin in nanodiscs which is required for optical experiments with rhodopsin mutants. This work demonstrates that late, physiologically important rhodopsin photointermediates can be characterized in nanodiscs, which provide the superior optical properties of detergent without perturbing the activation sequence. PMID- 21539363 TI - Photoswitchable nanoprobes offer unlimited brightness in frequency-domain imaging. AB - A single probe has limited brightness in time-domain imaging and such limitation frequently renders individual molecules undetectable in the presence of interference or complex cellular structures. However, a single photoswitchable probe produces a signal, which can be separated from interference or noise using photoswitching-enabled Fourier transformation (PFT). As a result, the light modulated probes can be made super bright in the frequency domain simply by acquiring more cycles in the time domain. PMID- 21539364 TI - Tightening of active site interactions en route to the transition state revealed by single-atom substitution in the guanosine-binding site of the Tetrahymena group I ribozyme. AB - Protein enzymes establish intricate networks of interactions to bind and position substrates and catalytic groups within active sites, enabling stabilization of the chemical transition state. Crystal structures of several RNA enzymes also suggest extensive interaction networks, despite RNA's structural limitations, but there is little information on the functional and the energetic properties of these inferred networks. We used double mutant cycles and presteady-state kinetic analyses to probe the putative interaction between the exocyclic amino group of the guanosine nucleophile and the N7 atom of residue G264 of the Tetrahymena group I ribozyme. As expected, the results supported the presence of this interaction, but remarkably, the energetic penalty for introducing a CH group at the 7-position of residue G264 accumulates as the reaction proceeds toward the chemical transition state to a total of 6.2 kcal/mol. Functional tests of neighboring interactions revealed that the presence of the CH group compromises multiple contacts within the interaction network that encompass the reactive elements, apparently forcing the nucleophile to bind and attack from an altered, suboptimal orientation. The energetic consequences of this indirect disruption of neighboring interactions as the reaction proceeds demonstrate that linkage between binding interactions and catalysis hinges critically on the precise structural integrity of a network of interacting groups. PMID- 21539366 TI - Oxygen reduction to water mediated by a dirhodium hydrido-chloride complex. AB - The two-electron mixed-valence dirhodium complex Rh(2)(0,II)(tfepma)(2)(CN(t)Bu)(2)Cl(2) (tfepma = CH(3)N[P(OCH(2)CF(3))(2)](2)) reacts with HCl to furnish two isomeric dirhodium hydrido-chloride complexes, Rh(2)(II,II)(tfepma)(2)(CN(t)Bu)(2)Cl(3)H. In the presence of HCl, the hydride complex effects the reduction of 0.5 equiv of O(2) to 1 equiv of H(2)O, generating Rh(2)(II,II)(tfepma)(2)(CN(t)Bu)(2)Cl(4), which can be prepared independently by chlorine oxidation of the Rh(2)(0,II) precursor. The starting Rh(2)(0,II) complex is regenerated photochemically to close an oxygen-to-water reduction photocycle. PMID- 21539365 TI - Photosensitizer drug delivery via an optical fiber. AB - An optical fiber has been developed with a maneuverable mini-probe tip that sparges O(2) gas and photodetaches pheophorbide (sensitizer) molecules. Singlet oxygen is produced at the probe tip surface which reacts with an alkene spacer group releasing sensitizer upon fragmentation of a dioxetane intermediate. Optimal sensitizer photorelease occurred when the probe tip was loaded with 60 nmol sensitizer, where crowding of the pheophorbide molecules and self-quenching were kept to a minimum. The fiber optic tip delivered pheophorbide molecules and singlet oxygen to discrete locations. The 60 nmol sensitizer was delivered into petrolatum; however, sensitizer release was less efficient in toluene-d(8) (3.6 nmol) where most had remained adsorbed on the probe tip, even after the covalent alkene spacer bond had been broken. The results open the door to a new area of fiber optic-guided sensitizer delivery for the potential photodynamic therapy of hypoxic structures requiring cytotoxic control. PMID- 21539367 TI - Enantioselective bromoaminocyclization using amino-thiocarbamate catalysts. AB - A facile and efficient enantioselective bromoaminocyclization of unsaturated sulfonamides has been developed using an amino-thiocarbamate catalyst. A range of enantioenriched pyrrolidines were prepared with up to 99% yield and 99% ee. The corresponding lactams could be obtained through oxidation of the pyrrolidines. PMID- 21539368 TI - The directive of the protein: how does cytochrome P450 select the mechanism of dopamine formation? AB - Dopamine can be generated from tyramine via arene hydroxylation catalyzed by a cytochrome P450 enzyme (CYP2D6). Our quantum mechanical/molecular mechanical (QM/MM) results reveal the decisive impact of the protein in selecting the 'best' reaction mechanism. Instead of the traditional Meisenheimer-complex mechanism, the study reveals a mechanism involving an initial hydrogen atom transfer from the phenolic hydroxyl group of the tyramine to the iron-oxo of the compound I (Cpd I), followed by a ring-pi radical rebound that eventually leads to dopamine by keto-enol rearrangement. This mechanism is not viable in the gas phase since the O-H bond activation by Cpd I is endothermic and the process does not form a stable intermediate. By contrast, the in-protein reaction has a low barrier and is exothermic. It is shown that the local electric field of the protein environment serves as a template that stabilizes the intermediate of the H abstraction step and thereby mediates the catalysis of dopamine formation at a lower energy cost. Furthermore, it is shown that external electric fields can either catalyze or inhibit the process depending on their directionality. PMID- 21539369 TI - 4D scanning ultrafast electron microscopy: visualization of materials surface dynamics. AB - The continuous electron beam of conventional scanning electron microscopes (SEM) limits the temporal resolution required for the study of ultrafast dynamics of materials surfaces. Here, we report the development of scanning ultrafast electron microscopy (S-UEM) as a time-resolved method with resolutions in both space and time. The approach is demonstrated in the investigation of the dynamics of semiconducting and metallic materials visualized using secondary-electron images and backscattering electron diffraction patterns. For probing, the electron packet was photogenerated from the sharp field-emitter tip of the microscope with a very low number of electrons in order to suppress space-charge repulsion between electrons and reach the ultrashort temporal resolution, an improvement of orders of magnitude when compared to the traditional beam-blanking method. Moreover, the spatial resolution of SEM is maintained, thus enabling spatiotemporal visualization of surface dynamics following the initiation of change by femtosecond heating or excitation. We discuss capabilities and potential applications of S-UEM in materials and biological science. PMID- 21539370 TI - Heterogeneous reactions of alkylamines with ammonium sulfate and ammonium bisulfate. AB - The heterogeneous reactions between alkylamines and ammonium salts (ammonium sulfate and ammonium bisulfate) have been studied using a low-pressure fast flow reactor coupled to an ion drift-chemical ionization mass spectrometer (ID-CIMS) at 293 +/- 2 K. The uptake of three alkylamines, i.e., monomethylamine, dimethylamine, and trimethylamine, on ammonium sulfate shows a displacement reaction of ammonium by aminium, evidenced by the release of ammonia monitored using protonated acetone dimer as the reagent ion. For the three alkylamines, the initial uptake coefficients (gamma(0)) range from 2.6 * 10(-2) to 3.4 * 10(-2) and the steady-state uptake coefficients (gamma(ss)) range from 6.0 * 10(-3) to 2.3 * 10(-4) and decrease as the number of methyl groups on the alkylamine increases. A different reaction mechanism is observed for the uptake of the three alkylamines on ammonium bisulfate, which is featured by an acid-base reaction (neutralization) with irreversible alkylamine loss and no ammonia generation and occurs at a rate limited by diffusion of gaseous alkylamines to the ammonium bisulfate surface. Our results reveal that the reactions between alkylamines and ammonium salts contribute to particle growth and alter the composition of ammonium sulfate and bisulfate aerosols in the atmosphere. PMID- 21539371 TI - Catalytic mechanism of RNA backbone cleavage by ribonuclease H from quantum mechanics/molecular mechanics simulations. AB - We use quantum mechanics/molecular mechanics simulations to study the cleavage of the ribonucleic acid (RNA) backbone catalyzed by ribonuclease H. This protein is a prototypical member of a large family of enzymes that use two-metal catalysis to process nucleic acids. By combining Hamiltonian replica exchange with a finite temperature string method, we calculate the free energy surface underlying the RNA-cleavage reaction and characterize its mechanism. We find that the reaction proceeds in two steps. In a first step, catalyzed primarily by magnesium ion A and its ligands, a water molecule attacks the scissile phosphate. Consistent with thiol-substitution experiments, a water proton is transferred to the downstream phosphate group. The transient phosphorane formed as a result of this nucleophilic attack decays by breaking the bond between the phosphate and the ribose oxygen. In the resulting intermediate, the dissociated but unprotonated leaving group forms an alkoxide coordinated to magnesium ion B. In a second step, the reaction is completed by protonation of the leaving group, with a neutral Asp132 as a likely proton donor. The overall reaction barrier of ~15 kcal mol( 1), encountered in the first step, together with the cost of protonating Asp132, is consistent with the slow measured rate of ~1-100/min. The two-step mechanism is also consistent with the bell-shaped pH dependence of the reaction rate. The nonmonotonic relative motion of the magnesium ions along the reaction pathway agrees with X-ray crystal structures. Proton-transfer reactions and changes in the metal ion coordination emerge as central factors in the RNA-cleavage reaction. PMID- 21539372 TI - pi-Electron manipulation of the 5,6-dihydroxyindole/quinone system by 3 alkynylation: mild acid-mediated entry to (cross)-conjugated scaffolds and paradigms for medium-tunable chromophores. AB - 5,6-Dihydroxyindole-based systems engender increasing interest for the design and implementation of new functional aromatic scaffolds and eumelanin-like materials with tailored absorption and electronic properties. However, studies aimed at elucidating the influence of external pi-conjugating groups on the redox properties and acid-induced reactivity of these highly oxidizable indolic platforms are lacking. We report herein the synthesis (as acetyl derivatives) and chemical/quantum chemical characterization of the first pi-extended 5,6 dihydroxyindole derivatives, 3-ethynyl-5,6-dihydroxyindole (1) and 3,3'-(1,2 ethynediyl)bis-5,6-dihydroxyindole (2), in order to understand whether and how beta extension of the enamine-like pyrrole sector affects the absorption properties, redox behavior, and protonation equilibria at both the o-diphenol and quinone levels. Oxidation of 1 and 2 proceeded smoothly to generate dark insoluble materials with eumelanin-like UV properties. On exposure to phosphate buffer at pH 3, 1 was rapidly converted to 3-acetyl-5,6-dihydroxyindole (5) and, in the presence of 5,6-dihydroxyindole, to the cross-conjugated 3,3' ethenylidenebis-5,6-dihydroxyindole (6). DFT calculations on 1 and 2 and their quinones in their pristine states and after protonation provided a mechanistic frame to rationalize the unusual acid-mediated chemistry of 1 and disclosed 2 quinone as the prototype of a novel class of medium-dependent chromophores. The ethynyl(ene) structural motif is thus proposed as the key to new tunable pi electron extended 5,6-dihydroxyindole/5,6-indolequinone paradigms for the rational design of alkyne-containing hybrid eumelanin-type polymers. PMID- 21539373 TI - Laser fabrication of large-scale nanoparticle arrays for sensing applications. AB - A novel method for high-speed fabrication of large scale periodic arrays of nanoparticles (diameters 40-200 nm) is developed. This method is based on a combination of nanosphere lithography and laser-induced transfer. Fabricated spherical nanoparticles are partially embedded into a polymer substrate. They are arranged into a hexagonal array and can be used for sensing applications. An optical sensor with the sensitivity of 365 nm/RIU and the figure of merit of 21.5 in the visible spectral range is demonstrated. PMID- 21539374 TI - Spontaneous growth and phase transformation of highly conductive nickel germanide nanowires. AB - We report the synthesis, phase transformation, and electrical property measurement of single-crystal NiGe and epsilon-Ni(5)Ge(3) nanowires (NWs). NiGe NWs were spontaneously synthesized by chemical vapor deposition of GeH(4) onto a porous Ni substrate without the use of intentional catalysts. The as-grown NWs of the orthorhombic NiGe phase were transformed to the hexagonal epsilon-Ni(5)Ge(3) phase by thermal annealing induced Ni enrichment. This controllable conversion of germanide phases is desirable for phase-dependent property study and applications, and the observation of novel metastable epsilon-Ni(5)Ge(3) phase suggests the importance of kinetic factors in such nanophase transformations. Electrical studies reveal that NiGe NWs are highly conductive, with an average resistivity of 35 +/- 15 MUOmega.cm, while the resistivity of epsilon-Ni(5)Ge(3) NWs is more than 4 times that of the NiGe phase. NWs of nickel germanides, particularly NiGe, would be useful building blocks for germanium-based nanoelectronic devices. PMID- 21539375 TI - Conductance of single cobalt chalcogenide cluster junctions. AB - Understanding the electrical properties of semiconducting quantum dot devices have been limited due to the variability of their size/composition and the chemistry of ligand/electrode binding. Furthermore, to probe their electrical conduction properties and its dependence on ligand/electrode binding, measurements must be carried out at the single dot/cluster level. Herein we report scanning tunneling microscope based break junction measurements of cobalt chalcogenide clusters with Te, Se and S to probe the conductance properties. Our measured conductance trends show that the Co-Te based clusters have the highest conductance while the Co-S clusters the lowest. These trends are in very good agreement with cyclic voltammetry measurements of the first oxidation potentials and with density functional theory calculations of their HOMO-LUMO gaps. PMID- 21539376 TI - Understanding pore rearrangement during mild to hard transition in bilayered porous anodic alumina membranes. AB - We present a systematic study about the influence of the main anodization parameters (i.e., anodization voltage ramp and hard anodization voltage) on the pore rearrangement in nanoporous anodic alumina during mild to hard anodization regime transition. To cover the ranges between mild and hard regimes, the anodization parameters were each set to three levels (i.e., 0.5, 1.0, and 2.0 V s(-1) for the anodization voltage ramp and 80, 110, and 140 V for the hard anodization voltage). To the best of our knowledge, this is the first rigorous study about this phenomenon, which is quantified indirectly by means of a nickel electrodeposition. It is found that pore rearrangement takes place in a relatively random manner. Large areas of pores remain blocked when the anodization regime changes from mild to hard and, under certain anodization conditions, a pore branching takes place based on the self-ordering mechanism at work during anodization. Furthermore, it is statistically demonstrated by means of a design of experiments strategy that the effect of the anodization voltage ramp on the pore rearrangement is practically negligible in contrast to the hard anodization voltage effect. It is expected that this study gives a better understanding of structural changes in nanoporous anodic alumina when anodization is switched from mild to hard regime. Furthermore, the resulting nanostructures could be used to develop a wide range of nanodevices (e.g., waveguides, 1D photonic crystals, Fabry-Perot interferometers, hybrid mosaic arrays of nanowires). PMID- 21539377 TI - Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a go-go related gene (hERG) profile. AB - We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929). PMID- 21539378 TI - Characterization and source apportionment of water-soluble organic matter in atmospheric fine particles (PM2.5) with high-resolution aerosol mass spectrometry and GC-MS. AB - Water-soluble organic matter (WSOM) in fine particles (PM(2.5)) collected at one rural and three urban sites from the Southeastern Aerosol Research and Characterization network were characterized with a High-Resolution Time-of-Flight Aerosol Mass Spectrometer (HR-ToF-AMS). These samples were also analyzed for a suite of molecular markers by Gas Chromatography-Mass Spectrometry (GC-MS) to assist in the interpretation of WSOM sources. The HR-ToF-AMS measurements allow a direct determination of the organic mass-to-carbon ratios (average +/- 1sigma = 1.93 +/- 0.12) and hence the quantification of WSOM on the same filters used to close the aerosol mass budget. WSOM constitutes a major fraction of total PM(2.5) mass (26-42%) and organic mass (50-90%) at all sites. The concentrations of WSOM are substantially higher in summer, mainly due to enhanced production of biogenic secondary organic aerosol (SOA). WSOM is composed mainly of oxygenated species with average oxygen-to-carbon (O/C) ratio of 0.56 (+/- 0.08). Positive matrix factorization (PMF) of the high resolution mass spectra of WSOM identifies a less oxidized component (denoted as lOOA, O/C = 0.50) associated with biogenic SOA and a more oxidized component (denoted as mOOA, O/C = 0.60) associated with WSOM contributed by wood combustion. On average, lOOA accounts for 75 (+/- 13) % of WSOM in summer while mOOA accounts for 78 (+/- 21) % in winter, suggesting that WSOM in the southeastern U.S. is primarily contributed by SOA production from biogenic species in summer and by wood burning emissions in winter. This work also demonstrates the utility of HR-ToF-AMS for investigating the bulk chemical composition of WSOM as well as for evaluating its source contributions. PMID- 21539379 TI - Ultrathin zirconium disulfide nanodiscs. AB - We present a colloidal route for the synthesis of ultrathin ZrS(2) (UT-ZrS(2)) nanodiscs that are ~1.6 nm thick and consist of approximately two unit cells of S Zr-S. The lateral size of the discs can be tuned to 20, 35, or 60 nm while their thickness is kept constant. Under the appropriate conditions, these individual discs can self-assemble into face-to-face-stacked structures containing multiple discs. Because the S-Zr-S layers within individual discs are held together by weak van der Waals interactions, each UT-ZrS(2) disc provides spaces that can serve as host sites for intercalation. When we tested UT-ZrS(2) discs as anodic materials for Li(+) intercalation, they showed excellent nanoscale size effects, enhancing the discharge capacity by 230% and greatly improving the stability in comparison with bulk ZrS(2). The nanoscale size effect was especially prominent for their performance in fast charging/discharging cycles, where an 88% average recovery of reversible capacity was observed for UT-ZrS(2) discs with a lateral diameter of 20 nm. The nanoscale thickness and lateral size of UT-ZrS(2) discs are critical for fast and reliable intercalation cycling because those dimensions both increase the surface area and provide open edges that enhance the diffusion kinetics for guest molecules. PMID- 21539380 TI - Phase diagram and dynamics of the liquid crystal isopentylcyanobiphenyl (5*CB). AB - From measurements of the specific volume as a function of temperature and pressure, the phase diagram for the liquid crystal forming isopentylcyanobiphenyl (5*CB) was determined. There are a number of phases (isotropic liquid, glass, cholesteric, and crystalline), and we show that the phase boundaries differ from previous reports, reflecting the slow crystallization kinetics of the system. Using dielectric spectroscopy at ambient and elevated pressure, we identify the relaxation processes in the isotropic and cholesteric phases. From application of density scaling to the dynamics, we obtain scaling exponents, which were found to vary with the type of motion. Moreover, unlike previous results for many other liquid crystals, the scaling exponent for the isotropic state differs from the thermodynamic potential parameter, and hence the relaxation time along the clearing line varies significantly with pressure. The distinctive properties of 5*CB reflect the very different volume dependences of the thermodynamics and the dynamics. PMID- 21539381 TI - Density functional theory study of conformation-dependent properties of neutral and radical cationic L-tyrosine and L-tryptophan. AB - Conformation-dependent properties of L-tyrosine and L-tryptophan in neutral and radical cations were studied by using the density functional theory (DFT) with a new density functional M05-2X. The results are compared with those obtained by using the conventional DFT (B3LYP). Results obtained by both types of DFT were in qualitative accord, including the existence of two conformational subgroups and their subgroup-dependent adiabatic ionization energy and hydrogen bonding. On the other hand, quantitative differences were found between the two DFT methods as well: the M05-2X method successfully reproduced experimental adiabatic ionization energy, whereas the B3LYP functional consistently yielded significantly lower values by 0.2-0.3 eV. More importantly, natural bond orbital (NBO) analysis for cationic conformers showed that all conformers of L-tyrosine and L-tryptophan undergo charge localization upon ionization regardless of the presence of intramolecular hydrogen bonding, unlike the case of L-phenylalanine that was treated earlier by other studies. Different degrees of charge localization among all three aromatic amino acids are explained by employing a simple model in which the aromatic amino acid is assumed to consist of two submoieties of distinct cationic core: the backbone and aromatic side chain. The difference in adiabatic ionization energy between these two submoieties is found to govern the degree of charge localization. PMID- 21539382 TI - Solution processable indoloquinoxaline derivatives containing bulky polyaromatic hydrocarbons: synthesis, optical spectra, and electroluminescence. AB - New hybrid materials featuring the dipolar fragment 6H-indolo[2,3-b]quinoxaline attached to the bulkier polyaromatic hydrocarbons such as fluoranthene, triphenylene, or polyphenylated benzene have been synthesized by a two-step procedure involving Sonogashira and Diels-Alder reactions. They were characterized by absorption, emission, electrochemical, thermal, and theoretical investigations. The electronic properties of the compounds were dominated by the 6H-indolo[2,3-b]quinoxaline chromophore, and the incorporation of polyaromatic hydrocarbons reduces the chances of nonradiative deactivation processes associated with the excited state and improves the emission properties. The compounds displayed cyan emission with moderate quantum efficiency when excited at the absorption maximum. All of the compounds exhibited an irreversible reduction process corresponding to the addition of electron at the quinoxaline segment. They showed moderate thermal stability and glass transition temperature greater than 100 degrees C. The presence of rigid 6H-indolo[2,3-b]quinoxaline and bulkier polyaromatic hydrocarbon segments enhances the thermal stability and glass transition temperature significantly. Finally, the dyes were successfully applied as an electron-transporting and emitting layer in multilayered organic light-emitting diodes comprising a N,N'-bis(l-naphthyl)-N,N'-diphenyl-1,1' biphenyl-4,4'-diamine hole-transporting layer. The cyan emitting devices were characterized by moderate device performance parameters. PMID- 21539383 TI - Novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells. AB - Nrf2-mediated activation of antioxidant response element is a central part of molecular mechanisms governing the protective function of phase II detoxification and antioxidant enzymes against carcinogenesis, oxidative stress, and inflammation. Nrf2 is sequestered in the cytoplasm by its repressor, Keap1. We have designed and synthesized novel chalcone derivatives as Nrf2 activators. The potency of these compounds was measured by the expression of Nrf2 dependent antioxidant genes GCLM, NQO1, and HO1 in human lung epithelial cells, while the cytotoxicity was analyzed using MTT assay. In vivo potency of identified lead compounds to activate Nrf2 was evaluated using a mouse model. Our studies showed 2-trifluoromethyl-2'-methoxychalone (2b) to be a potent activator of Nrf2, both in vitro and in mice. Additional experiments showed that the activation of Nrf2 by this compound is independent of reactive oxygen species or redox changes. We have discussed a quantitative structure-activity relationship and proposed a possible mechanism of Nrf2 activation. PMID- 21539384 TI - Manipulating micellar environments for enhancing transition metal-catalyzed cross couplings in water at room temperature. AB - The remarkable effects of added salts on the properties of aqueous micelles derived from the amphiphile PTS are described. Most notably, Heck reactions run in the presence of NaCl lead to couplings on aryl bromides in water at room temperature. Olefin cross- and ring-closing metathesis reactions run in the presence of small amounts of pH-lowering KHSO(4) are also accelerated, another phenomenon that does not apply to typical processes in organic media. These salt effects allow, in general, for synthetically valuable C-C bond-forming processes to be conducted under environmentally benign conditions. Recycling of the surfactant is also demonstrated. PMID- 21539385 TI - Growth of Ge nanofilms using electrochemical atomic layer deposition, with a "bait and switch" surface-limited reaction. AB - Ge nanofilms were deposited from aqueous solutions using the electrochemical analog of atomic layer deposition (ALD). Direct electrodeposition of Ge from an aqueous solution is self-limited to a few monolayers, depending on the pH. This report describes an E-ALD process for the growth of Ge films from aqueous solutions. The E-ALD cycle involved inducing a Ge atomic layer to deposit on a Te atomic layer formed on Ge, via underpotential deposition (UPD). The Te atomic layer was then reductively stripped from the deposit, leaving the Ge and completing the cycle. The Te atomic layer was bait for Ge deposition, after which the Te was switched out, reduced to a soluble telluride, leaving the Ge (one "bait and switch" cycle). Deposit thickness was a linear function of the number of cycles. Raman spectra indicated formation of an amorphous Ge film, consistent with the absence of a XRD pattern. Films were more stable and homogeneous when formed on Cu substrates, than on Au, due to a larger hydrogen overpotential, and the corresponding lower tendency to form bubbles. PMID- 21539386 TI - Chemoselective and enantioselective oxidation of indoles employing aspartyl peptide catalysts. AB - Catalytic enantioselective indole oxidation is a process of particular relevance to the chemistry of complex alkaloids, as it has been implicated in their biosynthesis. In the context of synthetic methodology, catalytic enantioselective indole oxidation allows a rapid and biomimetic entry into several classes of alkaloid natural products. Despite this potentially high utility in the total synthesis, reports of catalytic enantioselective indole oxidation remain sparse. Here we report a highly chemoselective catalytic system for the indole oxidation that delivers 3-hydroxy-indolenines with good chemical yields and moderate to high levels of enantio- and diastereoselectivity (up to 95:5 er and up to 92:8 dr). These results represent, to our knowledge, the most selective values yet reported in the literature for catalytic asymmetric indole oxidation. Furthermore, the utility of enantioenriched hydroxy-indolenines in stereospecific rearrangements is demonstrated. PMID- 21539387 TI - Localized in situ polymerization on graphene surfaces for stabilized graphene dispersions. AB - We demonstrate a novel in situ polymerization technique to develop localized polymer coatings on the surface of dispersed pristine graphene sheets. Graphene sheets show great promise as strong, conductive fillers in polymer nanocomposites; however, difficulties in dispersion quality and interfacial strength between filler and matrix have been a persistent problem for graphene based nanocomposites, particularly for pristine graphene. With this in mind, a physisorbed polymer layer is used to stabilize graphene sheets in solution. To create this protective layer, we formed an organic microenvironment around dispersed graphene sheets in surfactant solutions, and created a nylon 6, 10 or nylon 6, 6 coating via interfacial polymerization. Technique lies at the intersection of emulsion and admicellar polymerization; a similar technique was originally developed to protect luminescent properties of carbon nanotubes in solution. These coated graphene dispersions are aggregation-resistant and may be reversibly redispersed in water even after freeze-drying. The coated graphene holds promise for a number of applications, including multifunctional graphene polymer nanocomposites. PMID- 21539388 TI - Solid-supported 2'-O-glycoconjugation of oligonucleotides by azidation and click reactions. AB - 2'-O-[(2-Bromoethoxy)methyl]cytidine and 2'-O-[(2-azidoethoxy)methyl]cytidine have been prepared and introduced as appropriately protected 3'-phosphoramidite (1) and 3'-(H-phosphonate) (2) building blocks, respectively, into 2'-O-methyl oligoribonucleotides. The support-bound oligonucleotides were subjected to two consecutive conjugations with alkynyl-functionalized monosaccharides. The first saccharide was introduced by a Cu(I) promoted click reaction with 2 and the second by azidation of the 2-bromoethoxy group of 1 followed by the click reaction. The influence of the 2'-glycoconjugations on hybridization with DNA and 2'-O-methyl RNA targets was studied. Two saccharide units within a 15-mer oligonucleotide had a barely noticeable effect on the duplex stability, while introduction of a third one moderately decreased the melting temperature. PMID- 21539389 TI - Well-controlled cationic water-soluble phospholipid polymer-DNA nanocomplexes for gene delivery. AB - The facile synthesis of biocompatible and nontoxic gene delivery vectors has been the focus of research in recent years due to the high potential in treating genetic diseases. 2-Methacryloxyethyl phosphorylcholine (MPC) copolymers were recently studied for their ability to produce nontoxic and biocompatible materials. The synthesis of well-defined and water-soluble MPC polymer based cationic vectors for gene delivery purposes was therefore attractive, due to the potential excellent biocompatibility of the resulting copolymers. Herein, cationic MPC copolymers of varying architectures (block versus random) were produced by the reversible addition--fragmentation chain transfer (RAFT) polymerization technique. The copolymers produced were evaluated for their gene delivery efficacy in the presence and absence of serum. It was found that copolymer architectures and molecular weights do affect their gene delivery efficacy. The statistical copolymers produced larger particles, and showed poor gene transfection efficiency as compared to the diblock copolymers. The diblock copolymers served as efficient gene delivery vectors, in both the presence and absence of serum in vitro. To the best of our knowledge, this is the first report where the effect of architecture of MPC based copolymer on gene delivery efficacy has been studied. PMID- 21539390 TI - Design, synthesis, and evaluation of 2-diethanolamino-4,8-diheptamethyleneimino-2 (N-aminoethyl-N-ethanolamino)-6-(N,N-diethanolamino)pyrimido[5,4-d]pyrimidine fluorescein conjugate (8MDP-fluor), as a novel equilibrative nucleoside transporter probe. AB - Nucleoside transporters are integral membrane glycoproteins that play critical roles in physiological nucleoside and nucleobase fluxes, and influence the efficacy of many nucleoside chemotherapy drugs. Fluorescent reporter ligands/substrates have been shown to be useful in the analysis of nucleoside transporter (NT) protein expression and discovery of new NT inhibitors. In this study, we have developed a novel dipyridamole (DP)-based equilibrative nucleoside transporter 1 (ENT1) fluorescent probe. The potent ENT1 and ENT2 inhibitor analogue of dipyridamole, 2,6-bis(diethanolamino)-4,8 diheptamethyleneiminopyrimido[5,4-d]pyrimidine (4, 8MDP), was modified to replace one beta-hydroxyethyl group of the amino substituent at the 2-position with a beta-aminoethyl group and then conjugated through the amino group to 6 (fluorescein-5-carboxamido)hexanoyl moiety to obtain a new fluorescent molecule, 2-diethanolamino-4,8-diheptamethyleneimino-2-(N-aminoethyl-N-ethanolamino)-6-(N,N diethanolamino)pyrimido[5,4-d]pyrimidine-fluorescein conjugate, designated 8MDP fluorescein (8MDP-fluor, 6). The binding affinities of 8MDP-fluor at ENT1 and ENT2 are reflected by the uridine uptake inhibitory K(i) values of 52.1 nM and 285 nM, respectively. 8MDP-fluor was successfully demonstrated to be a flow cytometric probe for ENT1 comparable to the nitrobenzylmercaptopurine riboside (NBMPR) analogue ENT1 fluorescent probe SAENTA-X8-fluorescein (SAENTA-fluor, 1). This is the first reported dipyridamole-based ENT1 fluorescent probe, which adds a novel tool for probing ENT1, and possibly ENT2. PMID- 21539391 TI - Strain-promoted "click" chemistry for terminal labeling of DNA. AB - 1,3-Dipolar [3 + 2] cycloaddition between azides and alkynes--an archetypal "click" chemistry--has been used increasingly for the functionalization of nucleic acids. Copper(I)-catalyzed 1,3-dipolar cycloaddition reactions between alkyne-tagged DNA molecules and azides work well, but they require optimization of multiple reagents, and Cu ions are known to mediate DNA cleavage. For many applications, it would be preferable to eliminate the Cu(I) catalyst from these reactions. Here, we describe the solid-phase synthesis and characterization of 5' dibenzocyclooctyne (DIBO)-modified oligonucleotides, using a new DIBO phosphoramidite, which react with azides via copper-free, strain-promoted alkyne azide cycloaddition (SPAAC). We found that the DIBO group not only survived the standard acidic and oxidative reactions of solid-phase oligonucleotide synthesis (SPOS), but that it also survived the thermal cycling and standard conditions of the polymerase chain reaction (PCR). As a result, PCR with DIBO-modified primers yielded "clickable" amplicons that could be tagged with azide-modified fluorophores or immobilized on azide-modified surfaces. Given its simplicity, SPAAC on DNA could streamline the bioconjugate chemistry of nucleic acids in a number of modern biotechnologies. PMID- 21539392 TI - GPCR ligand dendrimer (GLiDe) conjugates: adenosine receptor interactions of a series of multivalent xanthine antagonists. AB - Previously, G protein-coupled receptor (GPCR) agonists were tethered from polyamidoamine (PAMAM) dendrimers to provide high receptor affinity and selectivity. Here, we prepared GPCR ligand--dendrimer (GLiDe) conjugates from a potent adenosine receptor (AR) antagonist; such agents are of interest for treating Parkinson's disease, asthma, and other conditions. Xanthine amine congener (XAC) was appended with an alkyne group on an extended C8 substituent for coupling by Cu(I)-catalyzed click chemistry to azide-derivatized G4 (fourth generation) PAMAM dendrimers to form triazoles. These conjugates also contained triazole-linked PEG groups (8 or 22 moieties per 64 terminal positions) for increasing water-solubility and optionally prosthetic groups for spectroscopic characterization and affinity labeling. Human AR binding affinity increased progressively with the degree of xanthine substitution to reach K(i) values in the nanomolar range. The order of affinity of each conjugate was hA(2A)AR > hA(3)AR > hA(1)AR, while the corresponding monomer was ranked hA(2A)AR > hA(1)AR >= hA(3)AR. The antagonist activity of the most potent conjugate 14 (34 xanthines per dendrimer) was examined at the G(i)-coupled A(1)AR. Conjugate 14 at 100 nM right-shifted the AR agonist concentration--response curve in a cyclic AMP functional assay in a parallel manner, but at 10 nM (lower than its K(i) value), it significantly suppressed the maximal agonist effect in calcium mobilization. This is the first systematic probing of a potent AR antagonist tethered on a dendrimer and its activity as a function of variable loading. PMID- 21539394 TI - Turnagainolides A and B, cyclic depsipeptides produced in culture by a Bacillus sp.: isolation, structure elucidation, and synthesis. AB - Two new cyclic depsipeptides, turnagainolides A (1) and B (2), have been isolated from laboratory cultures of a marine isolate of Bacillus sp. The structures of 1 and 2, which are simply epimers at the site of macrolactonization, were elucidated by analysis of NMR data and chemical degradation. A total synthesis of the turnagainolides confirmed their structures. Turnagainolide B (2) showed activity in a SHIP1 activation assay. PMID- 21539393 TI - Acid-degradable cationic dextran particles for the delivery of siRNA therapeutics. AB - We report a new acid-sensitive, biocompatible, and biodegradable microparticulate delivery system, spermine modified acetalated-dextran (Spermine-Ac-DEX), which can be used to efficiently encapsulate siRNA. These particles demonstrated efficient gene knockdown in HeLa-luc cells with minimal toxicity. This knockdown was comparable to that obtained using Lipofectamine, a commercially available transfection reagent generally limited to in vitro use due to its high toxicity. PMID- 21539395 TI - Extraction of proteins with low fluoride level from Antarctic krill (Euphausia superba) and their composition analysis. AB - The extraction of proteins with low fluoride level (LFP) from Antarctic krill (Euphausia superba) was investigated in this work. The optimal conditions for protein solubilization were determined to be pH 11.5 and 4 degrees C. The proteins were solubilized two times; a water/krill ratio (mL/g) of 6 and a time of 30 min were used for the first step, whereas the second used a water/krill residue ratio (mL/g) of 3 and a time of 30 min. The optimum pH for protein precipitation was 4.6. A LFP with fluoride content of 9.86 mg/kg (dry weight) was finally obtained through a fluoride removal program. The protein yield of LFP was 52.68%. Composition analysis of LFP indicated it was composed of 66.96% of crude proteins (dry weight) and 33.01% of total lipids (dry weight),, and all nine essential amino acids were in sufficient amounts to meet FAO/WHO/UNU requirements for adults and infants. In addition, LFP could be taken as a good source of EPA and DHA for consideration of use as a food item for human consumption. PMID- 21539396 TI - Interactions of halichondrin B and eribulin with tubulin. AB - Compounds that modulate microtubule dynamics include highly effective anticancer drugs, leading to continuing efforts to identify new agents and improve the activity of established ones. Here, we demonstrate that [(3)H]-labeled halichondrin B (HB), a complex, sponge-derived natural product, is bound to and dissociated from tubulin rapidly at one binding site per alphabeta-heterodimer, with an apparent K(d) of 0.31 MUM. We found no HB-induced aggregation of tubulin by high-performance liquid chromatography, even following column equilibration with HB. Binding of [(3)H]HB was competitively inhibited by a newly approved clinical agent, the truncated HB analogue eribulin (apparent K(i), 0.80 MUM) and noncompetitively by dolastatin 10 and vincristine (apparent K(i)'s, 0.35 and 5.4 MUM, respectively). Our earlier studies demonstrated that HB inhibits nucleotide exchange on beta-tubulin, and this, together with the results presented here, indicated the HB site is located on beta-tubulin. Using molecular dynamics simulations, we determined complementary conformations of HB and beta-tubulin that delineated in atomic detail binding interactions of HB with only beta tubulin, with no involvement of the alpha-subunit in the binding interaction. Moreover, the HB model served as a template for an eribulin binding model that furthered our understanding of the properties of eribulin as a drug. Overall, these results established a mechanistic basis for the antimitotic activity of the halichondrin class of compounds. PMID- 21539397 TI - High-pressure in situ 129Xe NMR spectroscopy and computer simulations of breathing transitions in the metal-organic framework Ni2(2,6-ndc)2(dabco) (DUT 8(Ni)). AB - Recently, we have described the metal-organic framework Ni(2)(2,6-ndc)(2)(dabco), denoted as DUT-8(Ni) (1) (DUT = Dresden University of Technology, 2,6-ndc = 2,6 naphthalenedicarboxylate, dabco = 1,4-diazabicyclo[2.2.2]octane). Upon adsorption of molecules such as nitrogen and xenon, this material exhibits a pronounced gate pressure effect which is accompanied by a large change of the specific volume. Here, we describe the use of high-pressure in situ (129)Xe NMR spectroscopy, i.e., the NMR spectroscopic measurements of xenon adsorption/desorption isotherms and isobars, to characterize this effect. It appears that the pore system of DUT 8(Ni) takes up xenon until a liquid-like state is reached. Deeper insight into the interactions between the host DUT-8(Ni) and the guest atom xenon is gained from ab initio molecular dynamics (MD) simulations. van der Waals interactions are included for the first time in these calculations on a metal-organic framework compound. MD simulations allow the identification of preferred adsorption sites for xenon as well as insight into the breathing effect at a molecular scale. Grand canonical Monte Carlo (GCMC) simulations have been performed in order to simulate adsorption isotherms. Furthermore, the favorable influence of a sample pretreatment using solvent exchange and drying with supercritical CO(2) as well as the influence of repeated pore opening/closure processes, i.e., the "aging behavior" of the compound, can be visualized by (129)Xe NMR spectroscopy. PMID- 21539398 TI - DNP by thermal mixing under optimized conditions yields >60,000-fold enhancement of 89Y NMR signal. AB - Hyperpolarized (89)Y complexes are attractive NMR spectroscopy and MR imaging probes due to the exceptionally long spin-lattice relaxation time (T(1) ~ 10 min) of the (89)Y nucleus. However, in vivo imaging of (89)Y has not yet been realized because of the low NMR signal enhancement levels previously achieved for this ultra low-gamma(n) nucleus. Here, we report liquid-state (89)Y NMR signal enhancements over 60,000 times the thermal signal at 298 K in a 9.4 T magnet, achieved after the dynamic nuclear polarization (DNP) of Y(III) complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) samples at 3.35 T and 1.4 K. The (89)Y DNP was shown to proceed by thermal mixing and the liquid state (89)Y NMR signal enhancement was maximized by (i) establishing the optimal microwave irradiation frequency, (ii) optimizing the glassing matrix, (iii) choosing a radical with negligible inhomogeneous line broadening contribution to the ESR linewidth, and (iv) addition of an electron T(1e) relaxation agent. The highest enhancements were achieved using a trityl OX063 radical combined with a gadolinium relaxation agent in water-glycerol matrix. Co-polarization of (89)YDOTA and sodium [1-(13)C]pyruvate showed that both (89)Y and (13)C nuclear species acquired the same spin temperature, consistent with thermal mixing theory of DNP. This methodology may be applicable for the optimization of DNP of other low-gamma(n) nuclei. PMID- 21539399 TI - Polydopamine/liposome coatings and their interaction with myoblast cells. AB - Surface-mediated drug delivery is a recent concept, where active surface coatings are employed to deliver therapeutic cargo to cells. Herein, we explore the potential of liposomes embedded in polydopamine (PDA) coatings to serve as drug deposits stored on planar substrates. We quantify the PDA growth rate on glass by XPS and show that PDA coatings support myoblast adherence and proliferation. Further, PDA capping layers were deposited on glass substrates precoated with poly(L-lysine) and zwitterionic liposomes. Already thin PDA capping layers render liposome coated surfaces cell adhesive. We experimentally show for the first time, the internalization of a model hydrophobic cargo, that is, fluorescent lipids embedded within the lipid bilayer of liposomes by the cells from the surface. This is evident from the fluorescence exhibited by the cells grown on PDA coatings containing fluorescently labeled liposomes, with the highest fluorescent intensity found in the close proximity of the cell nuclei. The cargo uptake efficiency depends on the thickness of the PDA capping layer and the cell residence time on the coated substrates. Taken together, we demonstrate the first step toward the establishment of a versatile approach using liposomal drug deposits in polymer thin films for surface-mediated drug delivery. PMID- 21539400 TI - Effect of interfacial structure on the transistor properties: probing the role of surface modification of gate dielectrics with self-assembled monolayer using organic single-crystal field-effect transistors. AB - Single-crystal field-effect transistors based on 2,3-dimethylpentacene have been used to probe the effect of surface modification of the insulating dielectric SiO(2) layer on the transistor characteristics. Self-assembled monolayers (SAMs) of different chain lengths and functional groups were used to systematically modify the structure and property of the semiconductor/dielectric interface. The charge carrier mobility as a function of SAM used for surface modification was analyzed. The character of the terminal functional group, as well as the mechanic treatment (rubbing) of the monolayer, much influences the carrier mobility. Introduction of a polar end group (donor or acceptor type) decreases the mobility compared to a nonpolar end group. Prerubbing of the monolayer serves to increase the charge carrier mobility by a factor of 2-4-fold. The results are interpreted in terms of the orderliness of the monolayer which affects the contact at the monolayer/semiconductor interface, which in turn affects the trapping sites' density or the smoothness of the potential surface that the carriers experience while transporting along the interface. PMID- 21539401 TI - Nanowires assembled SnO2 nanopolyhedrons with enhanced gas sensing properties. AB - Self-assembly of one-dimensional nanoscale building blocks into functional 2-D or 3-D complex superstructures has stimulated a great deal of interest. We report the synthesis and characterization of nanopolyhedrons assembled from ultrathin SnO(2) nanowires based on the sodium dodecyl sulfate (SDS)-assisted hydrothermal process. As-synthesized SnO(2) nanopolyhedrons have uniform diameters around 300 nm and are self-assembled by numerous ultrathin SnO(2) nanowires with diameters of 5-10 nm. The growth mechanism was also studied by investigating the samples synthesized at different reaction time. Thin films of the assembled SnO(2) nanopolyhedrons were configured as high performance sensors to detect methanol, ethanol, and acetone, which exhibited 1 ppm sensitivity, very fast response and recovery times (several seconds for different gases with concentrations of 1-200 ppm) to all the target gases and highly selective detection to acetone. PMID- 21539402 TI - Method for patterning various nanomaterials: electrochemical deposition of patterned Ni thin films and their utilization as a strippable mask. AB - We report an interesting approach for preparing micropatternings of nanomaterials, such as carbon nanotubes and TiO(2) nanoparticles. In the method, exfoliation of electrodeposited Ni thin films was the key process. After patterning indium thin oxide (ITO) plates with an insulating photoresist by conventional photolithography, Ni was electrodeposited on only the exposed ITO areas. The resulting substrates were evenly covered with nanomaterials by a drop cast method. By exfoliating the electrodeposited Ni thin films from the substrates, patterned nanomaterial films were formed. PMID- 21539403 TI - Intranasal versus oral administration of lisdexamfetamine dimesylate: a randomized, open-label, two-period, crossover, single-dose, single-centre pharmacokinetic study in healthy adult men. AB - BACKGROUND AND OBJECTIVE: Data on pharmacokinetic parameters of the prodrug stimulant lisdexamfetamine dimesylate via alternate routes of administration are limited. The pharmacokinetics of d-amphetamine derived from lisdexamfetamine dimesylate after single oral (PO) versus intranasal (IN) administration of lisdexamfetamine dimesylate were compared. METHODS: In this randomized, two period, crossover study, healthy men without a history of substance abuse were administered single PO or IN (radiolabelled with <=100 MUCi (99m)Tc diethylenetriamine-pentaacetic acid and confirmed by scintigraphy) lisdexamfetamine dimesylate 50 mg >=7 days apart. Serial blood samples were drawn to measure d-amphetamine and intact lisdexamfetamine at 0 (pre-dose), 15, 30 and 45 minutes and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post dose for PO administration and at 0 (pre-dose), 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for IN administration. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Eighteen subjects were enrolled and completed the study. The mean +/- SD maximum observed plasma concentration (C(max)) and area under the plasma concentration time curve from time zero to time of last measurable concentration (AUC(last)) of d-amphetamine following PO administration of lisdexamfetamine dimesylate were 37.6 +/- 4.54 ng/mL and 719.1 +/- 157.05 ng . h/mL, respectively; after IN administration, these parameters were 35.9 +/- 6.49 ng/mL and 690.5 +/- 157.05 ng . h/mL, respectively. PO and IN administration demonstrated similar median time to reach C(max) (t(max)) for d-amphetamine: 5 hours for PO administration versus 4 hours for IN administration. Mean +/- SD elimination half-life (t(1/2)) values were also similar for PO (11.6 +/- 2.8 hours) and IN (11.3 +/- 1.8 hours) lisdexamfetamine dimesylate. TEAEs after PO and IN administration were reported by 27.8% of subjects (5/18) and 38.9% of subjects (7/18), respectively; all AEs were mild or moderate in severity, and TEAEs such as anorexia, dry mouth, headache and nausea were consistent with known amphetamine effects. CONCLUSION: IN administration of lisdexamfetamine dimesylate resulted in d-amphetamine plasma concentrations and systemic exposure to d-amphetamine comparable to those seen with PO administration. Subject variability for d-amphetamine pharmacokinetic parameters was low. Both PO and IN lisdexamfetamine dimesylate demonstrated a tolerability profile similar to that of other long-acting stimulants. PMID- 21539404 TI - Relationship between clotting activity and phosphatidylserine expression on erythrocyte membranes in polycythemia vera patients with the JAK2 V617F mutation. AB - INTRODUCTION: Polycythemia vera (PV) accompanies the clinical course of thrombosis. Phosphatidylserine (PS) expression on the plasma membrane has been known to be one of place where the coagulation system activates. We studied the relationship between clotting factor activity and PS expression on the erythrocyte membrane in patients with erythrocytosis. METHODS: The coagulation test and PS expression in 23 patients with erythrocytosis were measured. PS expression was determined indirectly by measuring annexin V binding to erythrocytes using fluorescence activated cell sorter analysis (FACS). RESULTS: The activity of clotting factors (II, V, VII, VIII, von Willebrand factor, IX, X) was significantly lower in PV than in the mutation-negative erythrocytosis. There was a significant correlation between reduced activity of clotting factors such as V, X, and IX and increased PS expression of the erythrocyte membrane. CONCLUSION: Increased expression of PS on the erythrocyte membrane may reduce the activities of clotting factors in PV patients with JAK2 V617F mutation. PMID- 21539405 TI - Foreshadowing the present--the legacies of Theodor Reik: Editor's introduction. PMID- 21539406 TI - Masochism: passionate pain and erotized triumph. PMID- 21539407 TI - Ruined by success, but rescued by failure: Theodor Reik and the creative impact of social masochism. PMID- 21539408 TI - Listening with a third ear, a second heart, and a sixth sense: standing on the shoulders of Theodor Reik. PMID- 21539409 TI - Theodor Reik's listening with the third ear and the role of self-analysis in contemporary psychoanalytic thinking. PMID- 21539410 TI - The sexual couple: a psychoanalytic exploration. AB - Even an originally revolutionary movement like psychoanalysis can become conservative and can take refuge, at last, in reactionary acquiescence. Many revolutionary minds, fighters of yesterday, are tired and now rest their cause on dogmas and preconceived ideas. The progress of science does not tolerate such refuge. The shape of psychoanalysis around the year 2000 of our era will be very different from the concept of the New York Psychoanalytical Society of 1945. No prophetic gift is needed to predict that it will be much more occupied with the total human personality than with the sexual components. The picture of psychoanalysis in the year 2000 will, I am sure, be nearer to that which neo psychoanalysis sketches then to that of libido theory. It will be recognized then that the crude sex-drive cannot have the power attributed to it by Freud and that early mixtures of sexual and non-sexual urges are clearly to be observed in those very phenomena which impress us as "purely" sexual." (Reik, 1945). PMID- 21539411 TI - Reik's confession: construction or interpretation. PMID- 21539412 TI - Reminiscences of a good man. PMID- 21539414 TI - Increased expression of the transient receptor potential melastatin 7 channel is critically involved in lipopolysaccharide-induced reactive oxygen species mediated neuronal death. AB - AIMS: To assess the mechanisms involved in lipopolysaccharide (LPS)-induced neuronal cell death, we examined the cellular consequences of LPS exposure in differentiated PC12 neurons and primary hippocampal neurons. RESULTS: Our data show that LPS is able to induce PC12 neuronal cell death without the participation of glial cells. Neuronal cell death was mediated by an increase in cellular reactive oxygen species (ROS) levels. Considering the prevalent role of specific ion channels in mediating the deleterious effect of ROS, we assessed their contribution to this process. Neurons exposed to LPS showed a significant intracellular Ca(2+) overload, and nonselective cationic channel blockers inhibited LPS-induced neuronal death. In particular, we observed that both LPS and hydrogen peroxide exposure strongly increased the expression of the transient receptor protein melastatin 7 (TRPM7), which is an ion channel directly implicated in neuronal cell death. Further, both LPS-induced TRPM7 overexpression and LPS-induced neuronal cell death were decreased with dithiothreitol, dipheniliodonium, and apocynin. Finally, knockdown of TRPM7 expression using small interference RNA technology protected primary hippocampal neurons and differentiated PC12 neurons from the LPS challenge. INNOVATION: This is the first report showing that TRPM7 is a key protein involved in neuronal death after LPS challenge. CONCLUSION: We conclude that LPS promotes an abnormal ROS-dependent TRPM7 overexpression, which plays a crucial role in pathologic events, thus leading to neuronal dysfunction and death. PMID- 21539415 TI - Effects of invertebrate iridescent virus 6 in Phyllophaga vandinei and its potential as a biocontrol delivery system. AB - Invertebrate iridescent virus 6 (IIV6) was determined to cause infection in Phyllophaga vandinei Smyth (Coleoptera: Scarabaeidae) through a range of modes of transmissions. This is the first evidence of IIV6 infection in P. vandinei that caused both patent and sub-lethal infections in larvae and adults. Mortality rates were determined to be ~30% when virus inoculum was injected into larvae or adults. Adults injected with virus showed dramatically altered behavior; injected beetles were not observed feeding or mating compared with adults injected with buffer or adults that were not injected. Tissue collected from infected adults resulted in infection when injected into healthy adults, as confirmed with PCR. PCR also confirmed that frass of infected larvae and adults contained virus, and when reconstituted frass from infected individuals was injected into healthy adults or larvae they become infected. Healthy adults could be infected by coming into contact with soil or plant material that had been exposed to infected adults as much as two weeks prior to introduction of nonvirus exposed adults. Although relatively low mortality resulted when adults or larvae were injected with the virus, the demonstration of horizontal transmission, potentially through frass of infected individuals, identifies a mode of transmission that may be exploited as a potential management tool to reduce P. vandinei. PMID- 21539416 TI - The presence of conspecific decoys enhances the attractiveness of an NaCl resource to the yellow-spined locust, Ceracris kiangsu. AB - Adults of the yellow-spined bamboo locust, Ceracris kiangsu Tsai (Orthoptera: Oedipodidae), aggregate and gnaw at human urine-contaminated materials, a phenomenon termed puddling. Several urine-borne chemicals, including NaCl, are known to stimulate adult C. kiangsu to consume filter paper. Because in nature C. kiangsu adults may use cues to locate puddling resources, we tested the influence of conspecific decoys (dried C. kiangsu) on foraging and consumption of 3% NaCl treated filter paper. In a two-choice test experiment in the laboratory, female adults showed no preference for filter papers (not treated with NaCl) with or without decoys. In contrast, C. kiangsu females consumed significantly more NaCl treated filter paper on which conspecific decoys were attached than those without decoys in both the laboratory and in a bamboo forest. When the bait was changed to 3% NaCl plus the insecticide bisultap, significantly more C. kiangsu were killed in the bamboo forest when decoys were present, however the results were not significant when the experiment was done in the laboratory. Hence, moving towards conspecifics seems to facilitate NaCl resource foraging in C. kiangsu, suggesting that the presence of conspecifics promotes feeding on puddling resources. PMID- 21539417 TI - Effects of the insect growth regulator, novaluron on immature alfalfa leafcutting bees, Megachile rotundata. AB - Alfalfa leafcutting bees, Megachile rotundata F. (Hymenoptera: Megachilidae), are the most common pollinators of alfalfa in the Pacific Northwest. Reports from users of M. rotundata in Idaho, Utah and Colorado have indicated exceptionally poor bee return from fields treated with novaluron to control Lygus spp. Our goal was to evaluate novaluron toxicity to immature M. rotundata using two different possible mechanisms of exposure. One goal was to assess immature mortality via treating nectar-pollen provisions and adults with novaluron. Immature M. rotundata mortality in all novaluron provision dosing treatments was significantly higher than the water or blank controls, providing evidence that novaluron is toxic to progeny in nest cells. The mean cumulative frequency showed that more eggs and 1st-2nd instars died compared to older instars. Female M. rotundata nested similarly in field cages during the field cage experiment; however, there was greater immature mortality in cages where females were fed sugar-water + novaluron compared to sugar-water only. Although females provided adequate provisions, there was a low percentage of egg hatch and larval development when females ingested novaluron before mating and nesting. Novaluron was also present in egg provision of bees collecting resources from novaluron sprayed plants. At least 84% of progeny died when the females were allowed to mate and nest 24 hours after a novaluron application. Novaluron could be contributing to poor bee return in alfalfa grown for seed. Timely insecticide applications to suppress Lygus spp. is an important consideration to improve ongoing bee health. PMID- 21539418 TI - Variation within and between Frankliniella thrips species in host plant utilization. AB - Anthophilous flower thrips in the genus Frankliniella (Thysanoptera: Thripidae) exploit ephemeral plant resources and therefore must be capable of successfully locating appropriate hosts on a repeated basis, yet little is known of interspecific and intraspecific variation in responses to host plant type and nutritional quality. Field trials were conducted over two seasons to determine if the abundance of males and females of three common Frankliniella species, F. occidentalis (Pergande), F. tritici (Fitch) and F. bispinosa (Morgan), their larvae, and a key predator, Orius insidiosus (Say) (Hemiptera: Anthocoridae) were affected by host plant type and plant nutritional quality. Two host plants, pepper, Capsicum annuum L. (Solanales: Solanaceae) and tomato, Solanum lycopersicum L. that vary in suitability for these species were examined, and their nutritional quality was manipulated by applying three levels of nitrogen fertilization (101 kg/ha, 202 kg/ha, 404 kg/ha). F. occidentalis females were more abundant in pepper than in tomato, but males did not show a differential response. Both sexes of F. tritici and F. bispinosa were more abundant in tomato than in pepper. Larval thrips were more abundant in pepper than in tomato. Likewise, O. insidiosus females and nymphs were more abundant in pepper than in tomato. Only F. occidentalis females showed a distinct response to nitrogen fertilization, with abundance increasing with fertilization. These results show that host plant utilization patterns vary among Frankliniella spp. and should not be generalized from results of the intensively studied F. occidentalis. Given the different pest status of these species and their differential abundance in pepper and tomato, it is critical that scouting programs include species identifications for proper management. PMID- 21539419 TI - Proboscis morphology and its relationship to feeding habits in noctuid moths. AB - This study describes proboscis morphology and identifies morphometric differences among five species of noctuid moths with different feeding habits (fruit versus nectar-feeding). Morphological and morphometric parameters were analyzed using scanning electron microscopy and light microscopy. Measurements included: galea height in ten sites from base to tip, total proboscis length, and length of the distal region that contains large sensilla styloconica and / or tearing hooks and erectible barbs. Both morphometric and morphological differences were identified among species within and between feeding guilds, and these results are discussed in light of the feeding habits of each species. PMID- 21539420 TI - Principal components of electroencephalographic spectrum as markers of opponent processes underlying ultradian sleep cycles. AB - Sleep-wake regulation involves reciprocal interactions between sleep- and wake promoting processes that inhibit one another. To uncover the signatures of the opponent processes underlying ultradian sleep cycles, principal component analysis was performed on the sets of 16 single-Hz log-transformed electroencephalographic (EEG) power densities (1-16 Hz frequency range). Data were collected during unrestricted night sleep followed by 9 20-min naps (14 women aged 17-55 yrs) and during 12 20-min naps after either restriction or deprivation of sleep (9 males and 9 males, respectively, aged 18-22 yrs). It was found that any subset of power spectra could be reduced to the invariant four principal component structure. The time courses of scores on these four components might be interpreted as the spectral EEG markers of the kinetics of two pairs of opponent chronoregulatory processes. In a sequence of ultradian sleep cycles, the 1st and 2nd components represent the alternations between competing drives for sleep and wakefulness, respectively, whereas the 3rd and 4th components reflect the alternations between light and deep sleep, respectively. The results suggest that principal component structuring of EEG spectrum can be employed for derivation of the parameters of the quantitative models conceptualizing the three major aspects of sleep-wake regulation-homeostatic, circadian, and ultradian processes. PMID- 21539421 TI - Does lighting manipulation during incubation affect hatching rhythms and early development of sole? AB - Light plays a key role in the development of biological rhythms in fish. Previous research on Senegal sole has revealed that both spawning rhythms and larval development are strongly influenced by lighting conditions. However, hatching rhythms and the effect of light during incubation are as yet unexplored. Therefore, the aim of this study was to investigate the impact of the light spectrum and photoperiod on Solea senegalensis eggs and larvae until day 7 post hatching (dph). To this end, eggs were collected immediately after spawning during the night and exposed to continuous light (LL), continuous darkness (DD), or light-dark (LD) 12L:12D cycles of white light (LD(W)), blue light (LD(B); lambda(peak) = 463 nm), or red light (LD(R); lambda(peak) = 685 nm). Eggs exposed to LD(B) had the highest hatching rate (94.5% +/- 1.9%), whereas LD(R) and DD showed the lowest hatching rate (54.4% +/- 3.9% and 48.4% +/- 4.2%, respectively). Under LD conditions, the hatching rhythm peaked by the end of the dark phase, but was advanced in LD(B) (zeitgeber time 8 [ZT8]; ZT0 representing the onset of darkness) in relation to LD(W) and LD(R) (ZT11). Under DD conditions, the same rhythm persisted, although with lower amplitude, whereas under LL the hatching rhythm split into two peaks (ZT8 and ZT13). From dph 4 onwards, larvae under LD(B) showed the best growth and quickest development (advanced eye pigmentation, mouth opening, and pectoral fins), whereas larvae under LD(R) and DD had the poorest performance. These results reveal that developmental rhythms at the egg stage are tightly controlled by light characteristics, underlining the importance of reproducing their natural underwater photoenvironment (LD cycles of blue wavelengths) during incubation and early larvae development of fish. PMID- 21539422 TI - Field chronobiology of a molluscan bivalve: how the moon and sun cycles interact to drive oyster activity rhythms. AB - The present study reports new insights into the complexity of environmental drivers in aquatic animals. The focus of this study was to determine the main forces that drive mollusc bivalve behavior in situ. To answer this question, the authors continuously studied the valve movements of permanently immersed oysters, Crassostrea gigas, during a 1-year-long in situ study. Valve behavior was monitored with a specially build valvometer, which allows continuously recording of up to 16 bivalves at high frequency (10 Hz). The results highlight a strong relationship between the rhythms of valve behavior and the complex association of the sun-earth-moon orbital positions. Permanently immersed C. gigas follows a robust and strong behavior primarily driven by the tidal cycle. The intensity of this tidal driving force is modulated by the neap-spring tides (i.e., synodic moon cycle), which themselves depend of the earth-moon distance (i.e., anomalistic moon cycle). Light is a significant driver of the oysters' biological rhythm, although its power is limited by the tides, which remain the predominant driver. More globally, depending where in the world the bivalves reside, the results suggest their biological rhythms should vary according to the relative importance of the solar cycle and different lunar cycles associated with tide generation. These results highlight the high plasticity of these oysters to adapt to their changing environment. PMID- 21539423 TI - Influence of time of day on propofol pharmacokinetics and pharmacodynamics in rabbits. AB - This study evaluates the administration time-of-day effects on propofol pharmacokinetics and sedative response in rabbits. Nine rabbits were sedated with 5 mg/kg propofol at three local clock times: 10:00, 16:00, and 22:00 h. Each rabbit served as its own control by being given a single infusion at the three different times of day on three separate occasions. Ten arterial blood samples were collected during each clock-time experiment for propofol assay. A two compartment model was used to describe propofol pharmacokinetics, and the pedal withdrawal reflex was used as the sedation pharmacodynamic response. The categorical data comprising the presence or absence of pedal withdrawal reflex was described by a logistic model. The typical volume of the central compartment equaled 7.67 L and depended on rabbit body weight. The elimination rate constant depended on drug administration time; it was lowest at 10:00 h, highest at 16:00 h, and intermediate at 22:00 h. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment, with the rate constant for the distribution to the effector compartment equal to 0.335 min(-1). Drug concentration had a large effect on the probability of anesthesia. The degree of anesthesia was largest at 10:00 h, lowest at 16:00 h, and intermediate at 22:00 h. In summary, both the pharmacokinetics and pharmacodynamics of propofol in rabbits depended on administration time. The developed population approach may be used to assess chronopharmacokinetics and chronopharmacodynamics of medications in animals and humans. PMID- 21539424 TI - Assessment of circadian rhythms of both skin temperature and motor activity in infants during the first 6 months of life. AB - The authors developed a method useful for home measurement of temperature, activity, and sleep rhythms in infants under normal-living conditions during their first 6 mos of life. In addition, parametric and nonparametric tests for assessing circadian system maturation in these infants were compared. Anthropometric parameters plus ankle skin temperature and activity were evaluated in 10 infants by means of two data loggers, Termochron iButton (DS1291H, Maxim Integrated Products, Sunnyvale, CA) for temperature and HOBO Pendant G (Hobo Pendant G Acceleration, UA-004-64, Onset Computer Corporation, Bourne, MA) for motor activity, located in special baby socks specifically designed for the study. Skin temperature and motor activity were recorded over 3 consecutive days at 15 days, 1, 3, and 6 mos of age. Circadian rhythms of skin temperature and motor activity appeared at 3 mos in most babies. Mean skin temperature decreased significantly by 3 mos of life relative to previous measurements (p = .0001), whereas mean activity continued to increase during the first 6 mos. For most of the parameters analyzed, statistically significant changes occurred at 3-6 mos relative to 0.5-1 mo of age. Major differences were found using nonparametric tests. Intradaily variability in motor activity decreased significantly at 6 mos of age relative to previous measurements, and followed a similar trend for temperature; interdaily stability increased significantly at 6 mos of age relative to previous measurements for both variables; relative amplitude increased significantly at 6 mos for temperature and at 3 mos for activity, both with respect to previous measurements. A high degree of correlation was found between chronobiological parametric and nonparametric tests for mean and mesor and also for relative amplitude versus the cosinor-derived amplitude. However, the correlation between parametric and nonparametric equivalent indices (acrophase and midpoint of M5, interdaily stability and Rayleigh test, or intradaily variability and P(1)/P(ultradian)) despite being significant, was lower for both temperature and activity. The circadian function index (CFI index), based on the integrated variable temperature-activity, increased gradually with age and was statistically significant at 6 mos of age. At 6 mos, 90% of the infants' rest period coincided with the standard sleep period of their parents, defined from 23:00 to 07:00 h (dichotomic index I < O; when I < O = 100%, there is a complete coincidence between infant nocturnal rest period and the standard rest period), whereas at 15 days of life the coincidence was only 75%. The combination of thermometry and actimetry using data loggers placed in infants' socks is a reliable method for assessing both variables and also sleep rhythms in infants under ambulatory conditions, with minimal disturbance. Using this methodological approach, circadian rhythms of skin temperature and motor activity appeared by 3 mos in most babies. Nonparametric tests provided more reliable information than cosinor analysis for circadian rhythm assessment in infants. PMID- 21539425 TI - Eveningness, sleep patterns, daytime functioning, and quality of life in Israeli adolescents. AB - The purpose of the study was to assess the relationships between eveningness, sleep patterns, measures of daytime functioning, i.e., sleepiness, sleep problem behaviors, and depressed mood, and quality of life (QOL) in young Israeli adolescents. A cross-sectional survey was performed in urban and rural middle schools in Northern Israel. Participants were 470 eighth and ninth grade middle school students (14 +/- 0.8 yrs of age) in the normative school system. Students completed the modified School Sleep Habits Survey (SSHS) and Pediatric Quality of Life Inventory Short Form, assessing six subscales of physical, emotional, social, school performance, and psychosocial functioning, plus an addition generated total score. During weekdays and weekends, evening types went to bed later, their sleep latency was longer, their wake-up time was later, and their sleep duration was shorter than intermediate and morning types. Evening types exhibited more sleep problem behaviors, sleepiness, depressed mood, and lower QOL compared to intermediate and morning types. Based on the regression model, sleepiness, sleep-problem behaviors, and depressed mood were the variables most strongly associated with QOL, followed by morning-evening preference, weekday sleep duration, and weekend sleep latency. This study is the first to assess QOL in normative, healthy adolescents and to demonstrate strong associations between morning-evening preference and QOL. These findings enhance the need to identify young individuals with an evening preference, and to be aware of the characteristics and manifestations of the evening chronotype on daytime and nighttime behaviors in adolescence. PMID- 21539426 TI - Diurnal variation in heart rate variability before and after maximal exercise testing. AB - As heart-rate variability (HRV) is under evaluation in clinical applications, the authors sought to better define the interdependent impact of age, maximal exercise, and diurnal variation under physiologic conditions. The authors evaluated the diurnal changes in HRV 24-h pre- and post-maximal aerobic exercise testing to exhaustion in young (19-25 yrs, n = 12) and middle-aged (40-55 yrs, n = 12) adults. Subjects wore a portable 5-lead electrocardiogram holter for 48 h (24 h prior to and following a maximal aerobic capacity test). Time-, frequency-, time-frequency-, and scale-invariant-domain measures of HRV were computed from RR interval data analyzed using a 5-min window size and a 2.5-min step size, resulting in a different set of outputs every 2.5 min. Results were averaged (mean +/- SE) over four prespecified time periods during the morning, afternoon, evening, and night on Day 1 and Day 2. Diurnal changes in HRV in young and middle aged adults were compared using a two-way, repeated-measures analysis of variance (ANOVA). Young adults demonstrated higher HRV compared to middle-aged adults during periods of wakefulness and sleep prior to maximal exercise stress testing (i.e., high-frequency power during Day 1: young adults: morning 1862 +/- 496 ms(2), afternoon 1797 +/- 384 ms(2), evening 1908 +/- 431 ms(2), and night 3202 +/- 728 ms(2); middle-aged adults: morning 341 +/- 53 ms(2), afternoon 405 +/- 68 ms(2), evening 469 +/- 80 ms(2), and night 836 +/- 136 ms(2)) (p < .05). Exercise resulted in reductions in HRV such that multiple measures of HRV were not significantly different between age groups during the afternoon and evening periods. All measures of HRV demonstrated between-group differences overnight on Day 2 (p < .05). Young adults are associated with higher baseline HRV during the daytime. Sleep increases variability equally and proportionally to daytime variability. Given the higher baseline awake HRV and equal rise in HRV during sleep, the change in HRV from sleep to morning with exercise is greater in younger subjects. These physiologic results have clinical significance in understanding the pathophysiology of altered variability in ill patients. PMID- 21539427 TI - Unraveling seasonality in population averages: an examination of seasonal variation in glucose levels in diabetes patients using a large population-based data set. AB - It has been shown that the population average blood glucose level of diabetes patients shows seasonal variation, with higher levels in the winter than summer. However, seasonality in the population averages could be due to a tendency in the individual to seasonal variation, or alternatively due to occasional high winter readings (spiking), with different individuals showing this increase in different winters. A method was developed to rule out spiking as the dominant pattern underlying the seasonal variation in the population averages. Three years of data from three community-serving laboratories in Israel were retrieved. Diabetes patients (N = 3243) with a blood glucose result every winter and summer over the study period were selected. For each individual, the following were calculated: seasonal average glucose for all winters and summers over the period of study (2006-2009), winter-summer difference for each adjacent winter-summer pair, and average of these five differences, an index of the degree of spikiness in the pattern of the six seasonal levels, and number of times out of five that each winter-summer difference was positive. Seasonal population averages were examined. The distribution of the individual's differences between adjacent seasons (winter minus summer) was examined and compared between subgroups. Seasonal population averages were reexamined in groups divided according to the index of the degree of spikiness in the individual's glucose pattern over the series of seasons. Seasonal population averages showed higher winter than summer levels. The overall median winter-summer difference on the individual level was 8 mg/dL (0.4 mmol/L). In 16.9% (95% confidence interval [CI]: 15.6-18.2%) of the population, all five winter-summer differences were positive versus 3.6% (95% CI: 3.0-4.2%) where all five winter-summer differences were negative. Seasonal variation in the population averages was not attenuated in the group having the lowest spikiness index; comparison of the distributions of the winter-summer differences in the high-, medium-, and low-spikiness groups showed no significant difference (p = .213). Therefore, seasonality in the population average blood glucose in diabetes patients is not just the result of occasional high measurements in different individuals in different winters, but presumably reflects a general periodic tendency in individuals for winter glucose levels to be higher than summer levels. PMID- 21539428 TI - Working on Sundays-effects on safety, health, and work-life balance. AB - Several attributes of the work schedule can increase the risk of occupational injuries and accidents, health impairments, and reduced social participation. Although previous studies mainly focused on the effects of shiftwork and long working hours on employee health and safety, there is little evidence of a potential negative impact of working Sundays on the incidence of occupational accidents, health impairments, and work-life balance. A representative sample of employed workers in 31 member and associated states of the European Union (n = 23,934) served as the database for a cross-sectional analysis. The sample was collected via face-to-face interviews in the year 2005. The association of the risks of occupational accidents, health impairments, and decreases in work-life balance with working Sundays was calculated using logistic regression models, controlling for potential confounders, such as shiftwork, workload, and demographic characteristics. The results indicated that working one or more Sundays/month was associated with increase both in the risk of reporting one or more health impairments (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.06-1.29) and poorer work-life balance (OR: 1.15, 95% CI: 1.02-1.28). These effects remained after controlling for potentially confounding factors, such as other work schedule attributes, intensity of physical and mental workload, and individual characteristics. Furthermore, working Sundays was also related to increased risk of occupational accidents within the last year (OR: 1.34, 95% CI: 1.03-1.73). Controlling again for individual, workload, and working-time characteristics, a significant association with accident risk, however, remained only in work sectors with low a priori risk of occupational accidents (OR: 1.40, 95% CI: 1.02-1.91), although the increased risk could be observed for both medium and high a priori risk sectors working Sundays (without controlling for additional confounders). The results thus indicate that the detrimental effects of working Sundays on safety, health, and social well-being should be taken into account when designing work schedules. The potential hazards to employees' safety, health, and work-life balance, in particular, should be considered in discussions concerning extending work on Sundays in certain sectors, e.g., retail. PMID- 21539429 TI - Role of patient chronotype on circadian pattern of myocardial infarction: a pilot study. AB - Population-based studies indicate the risk of acute myocardial infarction (AMI) is greatest in the morning, during the initial hours of diurnal activity. The aim of this pilot study was to determine whether chronotype, i.e., morningness and eveningness, impacts AMI onset time. The sample comprised 63 morning- and 40 evening-type patients who were classified by the Horne-Ostberg Morningness Eveningness Questionnaire (MEQ) in the hospital after experiencing the AMI. The average wake-up and bed times of morning types were ~2 h earlier than evening types. Although the lag in time between waking up from nighttime sleep and AMI onset during the day did not differ between the two chronotypes, the actual clock hour time of the peak in the 24-h AMI pattern did. The peak in AMI of morning types occurred between 06:01 and 12:00 h and that of the evening types between 12:01 and 18:00 h. Although the results of this small sample pilot study suggest one's chronotype influences the clock time of AMI onset, larger scale studies, which also include assessment of 24-h patterning of events in neither types, must be conducted before concluding the potential influence of chronotype on the timing of AMI onset. PMID- 21539430 TI - Light pollution ? light pollution? PMID- 21539432 TI - Xanthomonas campestris diffusible factor is 3-hydroxybenzoic acid and is associated with xanthomonadin biosynthesis, cell viability, antioxidant activity, and systemic invasion. AB - Xanthomonas campestris pv. campestris produces a membrane-bound yellow pigment called xanthomonadin. A diffusible factor (DF) has been reported to regulate xanthomonadin biosynthesis. In this study, DF was purified from bacterial culture supernatants using a combination of solvent extraction, flash chromatography, and high-performance liquid chromatography. Mass spectrometry and nuclear magnetic resonance analyses resolved the DF chemical structure as 3-hydroxybenzoic acid (3 HBA), which was further confirmed by synthetic 3-HBA. Significantly, bioassay and in silico analysis suggest that DF production is widely conserved in a range of bacterial species. Analysis of DF derivatives established the hydroxyl group and its position as the key structural features for the role of DF in xanthomonadin biosynthesis. In addition, we showed that DF is also associated with bacterial survival, H2O2 resistance, and systemic invasion. Furthermore, evidence was also presented that DF and diffusible signaling factor have overlapping functions in modulation of bacterial survival, H2O2 resistance, and virulence. Utilization of different mechanisms to modulate similar virulence traits may provide X. campestris pv. campestris with plasticity in response to various environmental cues. PMID- 21539433 TI - Horizontal gene transfer in nematodes: a catalyst for plant parasitism? AB - The origin of plant parasitism within the phylum Nematoda is intriguing. The ability to parasitize plants has originated independently at least three times during nematode evolution and, as more molecular data has emerged, it has become clear that multiple instances of horizontal gene transfer (HGT) from bacteria and fungi have played a crucial role in the nematode's adaptation to this new lifestyle. The first reported HGT cases in plant-parasitic nematodes were genes encoding plant cell wall-degrading enzymes. Other putative examples of HGT were subsequently described, including genes that may be involved in the modulation of the plant's defense system, the establishment of a nematode feeding site, and the synthesis or processing of nutrients. Although, in many cases, it is difficult to pinpoint the donor organism, candidate donors are usually soil dwelling and are either plant-pathogenic or plant-associated microorganisms, hence occupying the same ecological niche as the nematodes. The exact mechanisms of transfer are unknown, although close contacts with donor microorganisms, such as symbiotic or trophic interactions, are a possibility. The widespread occurrence of horizontally transferred genes in evolutionarily independent plant-parasitic nematode lineages suggests that HGT may be a prerequisite for successful plant parasitism in nematodes. PMID- 21539434 TI - An autoactive mutant of the M flax rust resistance protein has a preference for binding ATP, whereas wild-type M protein binds ADP. AB - Resistance (R) proteins are key regulators of the plant innate immune system and are capable of pathogen detection and activation of the hypersensitive cell death immune response. To understand the molecular mechanism of R protein activation, we undertook a phenotypic and biochemical study of the flax nucleotide binding (NB)-ARC leucine-rich repeat protein, M. Using Agrobacterium-mediated transient expression in flax cotyledons, site-directed mutations of key residues within the P-loop, kinase 2, and MHD motifs within the NB-ARC domain of M were shown to affect R protein function. When purified using a yeast expression system and assayed for ATP and ADP, these mutated proteins exhibited marked differences in the quantity and identity of the bound nucleotide. ADP was bound to recombinant wild-type M protein, while the nonfunctional P-loop mutant did not have any nucleotides bound. In contrast, ATP was bound to an autoactive M protein mutated in the highly conserved MHD motif. These data provide direct evidence supporting a model of R protein function in which the "off" R protein binds ADP and activation of R protein defense signaling involves the exchange of ADP for ATP. PMID- 21539435 TI - Aripiprazole associated hyponatraemia. PMID- 21539436 TI - Testosterone replacement therapy and cardiovascular risk factors modification. AB - Hypogonadism in males is associated with increased atherosclerotic disease. Physiologically, testosterone appears to have both positive and negative effects on the cardiovascular system. Testosterone decreases angina and may improve the cardiac healing response after myocardial infarction. Testosterone enhances function in males with heart failure (HF). Testosterone causes water retention and oedema is common in older persons. Oedema should not be used to diagnose HF in older persons. Studies in older persons with HF and frailty have shown a non statistically lower mortality rate compared to those receiving placebo. PMID- 21539437 TI - Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments. AB - Pseudobulbar affect (PBA) consists of uncontrollable outbursts of laughter or crying inappropriate to the patient's external circumstances and incongruent with the patient's internal emotional state. Recent data suggest disruption of cortico pontine-cerebellar circuits, reducing the threshold for motor expression of emotion. Disruption of the microcircuitry of the cerebellum itself may likewise impair its ability to act as a gate-control for emotional expression. Current evidence also suggests that serotonergic and glutamatergic neurotransmission play key roles. Although antidepressants have shown benefit, the supportive clinical data have often derived from small numbers of patients and unvalidated measures of PBA severity. Dextromethorphan/quinidine, the first FDA-approved PBA medication, is a novel therapy with antiglutamatergic actions. As life expectancy lengthens and the neurologic settings of PBA become more common, the need for treatment can be expected to increase. PMID- 21539438 TI - Isolation and characterization of resistance gene analogues from Psilanthus species that represent wild relatives of cultivated coffee endemic to India. AB - Biotic or abiotic stress can cause considerable damage to crop plants that can be managed by building disease resistance in the cultivated gene pool through breeding for disease resistance genes (R-genes). R-genes, conferring resistance to diverse pathogens or pests share a high level of similarity at the DNA and protein levels in different plant species. This property of R-genes has been successfully employed to isolate putative resistance gene analogues (RGAs) using a PCR-based approach from new plant sources. Using a similar approach, in the present study, we have successfully amplified putative RGAs having nucleotide binding-site leucine-rich repeats (NBS-LRR-type RGAs) from seven different sources: two cultivated coffee species (Coffea arabica L. and Coffea canephora Pierre ex. A. Froehner), four related taxa endemic to India (wild tree coffee species: Psilanthus bengalensis (Roem. & Schuttles) J.-F. Leroy, Psilanthus khasiana , Psilanthus travencorensis (Wight & Arn.) J.-F. Leroy, Psilanthus weightiana (Wall. ex Wight & Arn.) J.-F. Leroy), and a cDNA pool originally prepared from light- and drought-stressed Coffea arabica L. leaves. The total PCR amplicons obtained using NBS-LRR-specific primers from each source were cloned and transformed to construct seven independent libraries, from which 434 randomly picked clones were sequenced. In silico analysis of the sequenced clones revealed 27 sequences that contained characteristic RGA motifs, of which 24 had complete uninterrupted open reading frames. Comparisons of these with published RGAs showed several of these to be novel RGA sequences. Interestingly, most of such novel RGAs belonged to the related wild Psilanthus species. The data thus suggest the potential of the secondary gene pool as possible untapped donors of resistance genes to the present day cultivated species of coffee. PMID- 21539441 TI - Gnom(Cmp): a quantitative approach for comparative analysis of closely related genomes of bacterial pathogens. AB - Comparative genome analysis is a powerful approach to understanding the biology of infectious bacterial pathogens. In this study, a quantitative approach, referred to as Gnom(Cmp), was developed to study the microevolution of bacterial pathogens. Although much more time-consuming than existing tools, this procedure provides a much higher resolution. Gnom(Cmp) accomplishes this by establishing genome-wide heterogeneity genotypes, which are then quantified and comparatively analyzed. The heterogeneity genotypes are defined as chromosomal base positions that have multiple variants within particular genomes, resulted from DNA duplications and subsequent mutations. To prove the concept, the procedure was applied on the genomes of 15 Staphylococcus aureus strains, focusing extensively on two pairs of hVISA/VISA strains. hVISA refers to heteroresistant vancomycin intermediate S. aureus strains and VISA is their VISA mutants. hVISA/VISA displays some remarkable properties. hVISA is susceptible to vancomycin, but VISA mutants emerge soon after a short period of vancomycin therapy, therefore making the pathogen a great model organism for fast-evolving bacterial pathogens. The analysis indicated that Gnom(Cmp) could reveal variants within the genomes, which can be analyzed within the global genome context. Gnom(Cmp) discovered evolutionary hotspots and their dynamics among many closely related, even isogenic genomes. The analysis thus allows the exploration of the molecular mechanisms behind hVISA/VISA evolution, providing a working hypotheses for experimental testing and validation. PMID- 21539442 TI - Quantitative evolution of transposable and satellite DNA sequences in Picea species. AB - Clones containing tandemly arranged repeats belonging to two distinct sequence families, (i) PAG004P22F (2F) and PAG004E03C (3C) or (ii) Ty3/gypsy- (8R; PAG004B08R) and Ty1/copia-like sequences (9R; PAG007F19R), were selected from a randomly sheared total genomic DNA library of Picea abies . The inserts were used as probes in dot-blot hybridizations to genomic DNA of P. abies, Picea orientalis , Picea pungens , and Picea pungens var. glauca. All these entities are diploid and share the same chromosome number (2n = 24), but the genome sizes differ largely. The redundancy (copy number per 1C DNA) of sequences related to each probe varied greatly between the genomes. No significant correlation was found between the genome size and the copy number of sequences in any family. The quantitative ratios varied greatly (in each genome) between the two families of satellite DNA, between the sequences that represented copia or gypsy retrotransposons, and between tandemly arranged sequences and retroelements as a whole, suggesting that there is no common factor that controls the quantitative evolution of repeats belonging to different sequence families during speciation in Picea. PMID- 21539443 TI - Effect of an oral glucose load on PTH, 250HD3, calcium, and phosphorus homeostasis in postmenopausal women. AB - INTRODUCTION. Previous studies particularly in children and neonates have shown that serum calcium declines and parathyroid hormone (PTH) rises during an oral glucose load. However, there is not a general agreement in this regard. This study was carried out to evaluate the effects of an oral glucose load on calcium and phosphorus homeostasis in postmenopausal women along with serum insulin, PTH, and 250HD3 changes. PATIENTS AND METHODS. After an overnight fasting, an oral glucose tolerance test was performed in 50 postmenopausal women; and glucose, insulin, PTH, and D3 were measured at baseline and every 30 min during the 2 hours of the test. RESULTS. Serum glucose and insulin increased as expected and reached their peak values at 60 and 90 min, respectively. PTH and phosphorus decreased significantly and the maximum decline was observed at 30 and 120 min after glucose load (p < 0.0001), respectively. Serum calcium, magnesium, and D3 levels showed no significant changes at any time measured. Serum PTH values had a significant negative correlation with glucose and insulin values (p = 0.026 and p = 0.031, respectively). Serum D3 also correlated negatively with glucose (p = 0.002). CONCLUSION. Our study shows that an oral glucose load induced hyperglycemia/hyperinsulinemia promotes a significant decline in serum PTH and phosphorus levels without changes in calcium or 250HD3 in postmenopausal women. PMID- 21539444 TI - Serum high molecular weight adiponectin correlates with arterial stiffness in community-dwelling persons. AB - INTRODUCTION. Serum high molecular weight (HMW) adiponectin, an adipocytokine, which is a protein secreted specifically by adipose tissue, improves insulin sensitivity and plays an important role in the development of metabolic syndrome and cardiovascular disease (CVD). Pulse wave velocity (PWV) is a noninvasive method of measuring arterial stiffness for the assessment of CVD in high-risk populations. We investigated whether serum HMW adiponectin is independently associated with arterial stiffness when evaluated using PWV. METHODS. We randomly recruited 99 men aged 69 +/- 9 (mean +/- standard deviation) years and 170 women aged 68 +/- 7 years during their annual health examination in a single community. Peripheral arterial stiffness was evaluated by mean PWV determined at three points: from the heart to the carotid artery, to the brachial artery, and to the ankle. RESULTS AND CONCLUSIONS. Age-adjusted PWV in all sites other than the heart to the carotid artery decreased progressively with increased serum HMW adiponectin. Age-adjusted mean PWV significantly decreased from the lowest to the highest serum HMW adiponectin group. Multiple linear regression analyses for mean PWV revealed that decreased serum HMW adiponectin levels were significantly associated with increased mean PWV as well as age, BMI, SBP, DBP, prevalence of antihypertensive medication, and eGFR. Inclusion of serum HMW adiponectin into the model further increased the coefficient of determination (R(2)). Multivariate adjusted mean PWV was significantly lowest in the highest serum HMW adiponectin group. PMID- 21539445 TI - Serum gamma-glutamyl transferase within its normal concentration range is related to the presence of impaired fasting glucose and diabetes among Japanese community dwelling persons. AB - INTRODUCTION. Serum gamma-glutamyl transferase (GGT) activity changes in response to oxidative stress. Little data are available on the association between serum GGT and the prevalence of impaired fasting glucose (IFG) and diabetes among Japanese community-dwelling persons. METHODS. We recruited 871 men, aged 61 +/- 14 (range, 20-89) years, and 1,139 women, aged 63 +/- 12 (range, 21-88) years during their annual health examination from a single community. We performed a cross-sectional study to examine whether serum GGT was associated with IFG and diabetes. RESULTS AND CONCLUSIONS. The levels of most confounding characteristics varied with increasing GGT activity. The prevalence of IFG and diabetes was significantly and linearly associated with increasing quartiles of serum GGT. After adjustment for sex, age, smoking status, drinking status, low-density lipoprotein cholesterol, uric acid, estimated glomerular filtration rate, and alanine aminotransferase, the odds ratio (OR) [95% confidence interval (CI)] for IFG compared with the participants with lowest quartile of serum GGT was 1.91 (1.31-2.78) for second quartiles, 2.41 (1.63-3.57) for third quartiles, and 3.24 (2.03-5.17) for highest quartiles. The multivariate-adjusted OR (95% CI) for diabetes was 1.91 (1.18-3.09) for second quartiles, 2.15 (1.30-3.54) for third quartiles, and 3.79 (2.11-6.82) for highest quartiles. Furthermore, the multivariate-adjusted ORs for IFG were also associated with increasing levels of serum GGT within subgroups of age, body mass index, drinking status, serum high molecular-weight adiponectin levels, insulin resistance, and the presence of antihypertensive/antilipidemic medication. These results suggested that higher serum GGT within normal concentration range was significantly associated with IFG and diabetes in the general population. PMID- 21539446 TI - Low-Intensity swimming training after weaning improves glucose and lipid homeostasis in MSG hypothalamic obese mice. AB - Low-intensity swimming training, started at an early age, was undertaken to observe glycemic control in hypothalamic obese mice produced by neonatal monosodium l-glutamate (MSG) treatment. Although swimming exercises by weaning pups inhibited hypothalamic obesity onset and recovered sympathoadrenal axis activity, this event was not observed when exercise training is applied to young adult mice. However, the mechanisms producing this improved metabolism are still not fully understood. Current work verifies whether, besides reducing fat tissue accumulation, low-intensity swimming in MSG-weaned mice also improves glycemic control. Although MSG and control mice swam for 15 min/day, 3 days a week, from the weaning stage up to 90 days old, sedentary MSG and normal mice did not exercise at all. After 14 h of fasting, animals were killed at 90 days of age. Retroperitonial fat accumulation was measured to estimate obesity. Fasting blood glucose and insulin concentrations were also measured. Mice were also submitted to ipGTT. MSG obese mice showed fasting hyperglycemia, hyperinsulinemia, and glucose intolerance and insulin resistance. However, the exercise was able to block MSG treatment effects. Higher total cholesterol and triglycerides observed in MSG mice were normalized by exercise after weaning. Exercised MSG animals had higher HDLc than the sedentary group. Data suggest that early exercise training maintains normoglycemia, insulin tissue sensitivity, and normal lipid profile in mice programmed to develop metabolic syndrome. PMID- 21539448 TI - A novel agonistic anti-human death receptor 5 monoclonal antibody with tumoricidal activity induces caspase- and mitochondrial-dependent apoptosis in human leukemia Jurkat cells. AB - An agonistic antibody against TNF-related apoptosis-inducing ligand death receptor 5 (DR5) is a practicable candidate drug for antitumor therapy. In this study, a novel murine anti-human DR5 monoclonal antibody, mDRA-6(IgG1-kappa), has been generated. This study aimed to explore the caspase-dependent and mitochondrial mechanisms of mDRA-6 in inducing apoptosis in human leukemia Jurkat cells. The apoptotic effects of mDRA-6 on Jurkat cells, which express DR5 on the cell surface, were detected by flow cytometry and western blot after exposure to different doses of mDRA-6 and at fixed doses of mDRA-6 at different times. It was demonstrated that mDRA-6 can induce Jurkat cell apoptosis via caspase- and mitochondrial-dependent pathways. These results indicate that the novel antibody mDRA-6 against DR5 has an antitumor function and may provide a new reagent for tumor therapy. PMID- 21539449 TI - Knockdown of osteopontin chemosensitizes MDA-MB-231 cells to cyclophosphamide by enhancing apoptosis through activating p38 MAPK pathway. AB - Cyclophosphamide (CTX) is a commonly used chemotherapeutic agent for breast cancer. However, chemoresistance remains a common clinical problem. Osteopontin (OPN) has been shown to induce chemoresistance by inhibiting apoptosis; p38 MAPK pathway has been reported to be involved in chemotherapy-induced apoptosis. Thus, this study investigated whether OPN knockdown would chemosensitize MDA-MB-231 cells to CTX by enhancing apoptosis through activating p38 MAPK pathway. MDA-MB 231 cells were transfected with OPN stable siRNA plasmid, and it was found that OPN knockdown chemosensitized MDA-MB-231 cells to CTX, which is dependent on p38 MAPK pathway activation. Moreover, results showed that each of OPN knockdown and CTX could induce apoptosis through activating p38 MAPK pathway and that OPN knockdown and CTX could induce enhanced apoptosis through activating p38 MAPK pathway synergistically. Therefore, this study concludes that OPN knockdown chemosensitizes MDA-MB-231 cells to CTX by enhancing apoptosis through activating p38 MAPK pathway. PMID- 21539450 TI - Inhibition effect of siRNA-downregulated UHRF1 on breast cancer growth. AB - The UHRF1 gene plays important roles in both cell proliferation through its NIRF_N domains, a PHD domain, an SRA domain, and a RING domain, and multidrug resistance in breast cancer treatment. In this work, a short-hairpin RNA (shRNA) lentiviral system was introduced in two human breast cancer cell lines (MDA-MB 231 and MCF-7) to downregulate the expression of UHRF1 and study the specific inhibition of UHRF1 in breast cancer growth. The effect of UHRF1-shRNA on breast cancer cell proliferation was examined using methylthiazoletetrazolium, bromodeoxyuridine, and colony formation assays. The proliferative potential of the UHRF1-shRNA-treated cells showed a remarkable decrease. Moreover, the downregulation of UHRF1 in both breast cancer cell lines significantly inhibited the colony formation capacity. Results suggested that the inhibition of UHRF1 via an RNA interference lentiviral system may provide an effective way for breast cancer therapy. PMID- 21539451 TI - Influence of short polyglutamine tracts and p160 coactivators on the transactivation of the androgen receptor. AB - The androgen receptor (AR) acting as a transcription factor plays a pivotal role in the occurrence and progression of prostate cancer (CaP). Several AR-related factors or modulators have been reported to influence AR activity. Whether and how these factors cooperatively modulate the AR activity has not been well defined. In the present study, the combined effect of p160 coactivators, short CAG length (encoding a short polyQ tract), and AR mutations on AR transactivation in a yeast system was evaluated. It was found that the short polyQ tract can upregulate the transactivation of the wild-type (WT) AR and partial-function (PF) AR mutants in response to a physiological level (10(-9) M) of dihydrotestosterone. Addition of a p160 coactivator (SRC-1 or TIF2) to the above systems resulted in a significant increase in the ligand-stimulated transactivation. Although the androgen antagonist bicalutamide could suppress the activity of androgen-activated WT or PF ARs, it was unable to do so for gain-of function AR mutants. A combination of the short polyQ tract and coactivator TIF2 acted cooperatively on the WT AR and PF AR mutants to enhance their transactivation in response to either a low level of dihydrotestosterone (10(-10) M) or adrenal dehydroepiandrosterone. Taken together, this finding suggests that the modulated AR activity may involve early in the carcinogenesis of CaP. Additionally, these data support the concept that a given CaP in which the AR activity is modulated by multiple AR modulators may progress more readily to castrate resistance. PMID- 21539452 TI - CpG oligodeoxynucleotide 1826 enhances the Lewis lung cancer response to radiotherapy in murine tumor. AB - CpG oligodeoxynucleotides (ODNs) are synthetic DNA sequences containing unmethylated cytosine-guanine motifs with potent immune modulatory effects. Via Toll-like receptor 9 agonists of dendritic cells and B cells, CpG ODNs induce cytokines, activate natural killer cells, and elicit vigorous T-cell responses that lead to significant antitumor effects. On the basis of these properties of CpG ODNs, a previous study has tested that they could enhance tumor response to single-dose radiotherapy. The present study extended this finding to the fractionated radiotherapy of the Lewis lung cancer and assessed the ability of CpG ODN 1826 to increase the immune function of mice and the effect of CpG ODN 1826 on the apoptosis of Lewis lung cancer. First, tumor growth delay was observed, and the enhancement ratio of CpG ODN 1826 was found to be 2.4; decreased tumor weight was found after combined treatments with CpG ODN 1826 and X-ray radiation compared with either treatment alone (P < 0.01). Second, enhanced cell apoptotic index was found after combined treatments with CpG ODN 1826 and X ray radiation compared with either treatment alone (p < 0.01). Increased tumor necrosis factor-alpha and decreased interleukin-10 concentration in serum and enhanced spleen exponent were observed after combined treatments with CpG ODN 1826 and X-ray radiation compared with X-ray radiation treatment alone (p < 0.01). Results suggest that CpG-ODN1826 can increase the radiosensitivity of Lewis lung cancer, which may be associated with stimulation of immune system and enhanced cell apoptosis. PMID- 21539453 TI - Autophagic and apoptotic response to sonodynamic therapy induced cell damage in leukemia l1210 cells in vitro. AB - PURPOSE: The present study was initiated to study the autophagic and apoptotic response to sonodynamic therapy (SDT) in murine leukemia L1210 cells in vitro. METHODS: L1210 cells were examined after 6 hours of incubation following SDT induction with ultrasound at a frequency of 1.1 MHz and an intensity of 3 W/cm(2) in the presence of 1 MUg/mL protoporphyrin IX. Apoptosis rate and cell survival rate were assessed through double fluorescent staining with Annexin V-PE and 7 amino-actinomycin D as determined by flow cytometry. Transmission electron microscope and fluorescence microscope were used to identify the formation of acidic vesicular organelles (autophagic vacuoles) during autophagy. Western blots were used to examine the processing of light chain 3 (LC3)-I to LC3-II and Atg5 expression levels. RESULTS: This study showed that SDT treatment reduced the numbers of viable cells to 30.17% and enhanced the apoptotic cells to 19.37% (p < 0.05 compare with control). Additionally, autophagic vacuoles formation clearly occurred after SDT and simultaneously accompanied by obvious LC3 processing and increased Atg5 expression levels. CONCLUSIONS: In L1210 cells, both apoptosis and autophagy were involved in cell damage induced by SDT treatment at the experimental conditions. PMID- 21539454 TI - The enhancement of radiosensitivity in human esophageal carcinoma cells by thalidomide and its potential mechanism. AB - To investigate the effects of thalidomide on the radiosensitivity of human esophageal cancer cells (TE1 cells) and the potential mechanism underlying these effects. The effects of thalidomide on proliferation of TE1 cells were determined by Methyl thiazolyl tetrazolium assay. The multitarget click model was used to delineate the survival curve using a colony-forming assay, and the radiosensitivity was determined after TE1 cells were treated by thalidomide and/or X-ray radiation. The cell cycle was detected using flow cytometry. Our results are as follows: thalidomide alone suppressed the proliferation of TE1 cells in a dose- and time-dependent manner. The suppressive effects were enhanced by prolonged duration or elevated concentration of thalidomide. However, thalidomide did not affect the cell cycle of TE1 cells. The expression of vascular endothelial growth factor (VEGF) mRNA and protein was suppressed after treatment with thalidomide alone in a dose-dependent manner. Synergistic suppressive effects on VEGF expression were observed after administration of thalidomide and X-ray exposure. In conclusion, thalidomide was able to enhance the radiosensitivity of TE1 cells in vitro, which could be closely related to its suppressive effects on the expression of VEGF in TE1 cells, but had no obvious effects on the cell cycle. PMID- 21539455 TI - The tolerance and therapeutic efficacy of rhenium-188 hydroxyethylidene diphosphonate in advanced cancer patients with painful osseous metastases. AB - PURPOSE: This study evaluated the tolerance and therapeutic efficacy of rhenium 188 hydroxyethylidene diphosphonate ((188)Re-HEDP) in patients with different types of advanced cancer suffering from bone pain caused by osseous metastases. METHODS: Sixty-four patients received a single injection of escalating doses of (188)Re-HEDP with various dosages. Vital signs were observed before and after treatment for 8 weeks; adverse effects and rebound pain were recorded within 8 weeks after injection. Blood counts, biochemical parameters, and electrocardiogram were also measured over a period of 8 weeks. Clinical follow-up studies including the bone pain score and the Karnofsky performance score were performed. Pain response was scored by a four-point pain-rating scale as complete, marked, mild, and no response. RESULTS: No adverse effects or clinically significant changes in vital signs, electrocardiograms, and biochemical parameters in patients were observed, and there was no statistical change in alkaline phosphate levels in patients before or after treatment. The overall nadir of thrombopenia was at week 4, leucopoenia at week 3, and anemia at week 8. At week 8, the mean level of platelets and leukocytes returned to baseline levels. The pain score descended from 8.11 to 7.74 on the day of therapy, with a nadir of 4.89 at week 4, and up to 6.67 at week 8 after therapy (p < 0.05). The Karnofsky performance score continually increased from 74.81 before therapy to 82.31 at 8 weeks (p > 0.05 Pain palliation was reported by 73.33% of patients, with a mean duration of 6.85 weeks and a mean start time of 4.05 days. Of the specific tumor types, pain relief was achieved in 84.62% of patients with prostate cancer, 78.57% with breast cancer, 62.50% with lung cancer, and 55.56% with liver cancer. CONCLUSIONS: (188)Re-HEDP is a useful radiopharmaceutical agent for improving bone pain in patients with advanced cancer with painful bone metastases. PMID- 21539456 TI - Synthesis of nanosilver using a vitamin C derivative and studies on radiation protection. AB - Silver nanoparticles were prepared from silver nitrate using a vitamin C derivative, 6-palmitoyl ascorbic acid-2-glucoside (PAsAG), via a sonochemical experiment. The resultant golden yellow solution that contained silver nanoparticle-PAsAG complex (SN-PAsAG) of about 5 nm particle sizes was explored for its potential to offer protection to DNA from gamma-radiation-induced damages. The presence of SN-PAsAG during irradiation inhibited the disappearance of covalently closed circular (ccc) form of plasmid pBR322 with a dose modifying factor of 1.78. SN-PAsAG protected cellular DNA from radiation-induced damage as evident from comet assay study on mouse spleen cells, irradiated ex vivo. When orally administered with SN-PAsAG at 1 hour prior to whole-body radiation exposure, cellular DNA was found protected from radiation-induced strand breaks in various tissues (spleen cells, bone marrow cells, and blood leucocytes) of animals. Also, SN-PAsAG could enhance the rate of repair of cellular DNA in blood leucocytes and bone marrow cells when administered immediately after radiation exposure. The studies, under in vitro, ex vivo, and in vivo radiation exposure conditions, showed effective radiation protection. PMID- 21539457 TI - Glycine cleavage enzyme complex: molecular cloning and expression of the H protein cDNA from cultured human skin fibroblasts. AB - The human H-protein is one of four essential components (H-, L-, P-, and T proteins) of the mammalian glycine cleavage enzyme complex and its function is involved in the pathogenesis and diagnosis of glycine encephalopathy. A transcript corresponding to the glycine cleavage H-protein functional gene was isolated from cultured human skin fibroblasts along with a transcript for a putative processed pseudogene on chromosome 2q33.3. Sequence analysis of the fibroblast H-protein functional gene transcript showed complete identity to that reported from human liver. The H-protein cDNA was subsequently cloned with a hexahistidine affinity tag in the Pichia pastoris plasmid vector pPICZalphaA and recombined into the yeast genome downstream of the alcohol oxidase promoter for methanol-induced expression. The recombinant H-protein was secreted into the culture medium and purified to homogeneity using a one-step nickel nitrilotriacetic acid resin column. Approximately 4 mg of homogeneous H-protein was obtained from 1 L of culture medium. Since the attachment of a lipoic acid prosthetic group is required for H-protein function, we have expressed and purified E. coli lipoate protein ligase and succeeded in lipoylating H-protein, converting the apo-H-protein to the functional holo-H-protein. A lipoamide dehydrogenase assay was performed to confirm that the apo-H-protein was inactive, whereas the holo-H-protein was approximately 2.3-fold more active than free lipoic acid as a hydrogen donor in driving the reaction. The availability of copious amounts of human recombinant H-protein by using Pichia pastoris expression and affinity purification will facilitate the elucidation of the structure and function of the H-protein and its relationship to the P-, T-, and L proteins in the glycine cleavage enzyme complex. In view of the fact that there is no detectable glycine cleavage enzyme activity in human skin fibroblasts, we speculate that a plausible function of the H-protein is to interact with the L protein, which is also part of the l-ketoglutarate dehydrogenase complex present in fibroblasts. PMID- 21539458 TI - B-type natriuretic peptide blood levels identify patients with non-ST elevation acute coronary syndromes at high risk for complications during intravenous beta blocker infusion. AB - BACKGROUND: We hypothesized that measurement of B-type natriuretic peptide could identify patients with non-ST elevation acute coronary syndromes at high risk for complications during beta-blocker (esmolol) infusion. METHODS: We reviewed the records of 340 consecutive patients admitted with a non-ST elevation acute coronary syndrome. Seventy three (47 males, aged 62 +/- 14 years) received esmolol up to a maximum dose of 300 MUg/ kg/min until the symptoms were relieved or an adverse event occurred. RESULTS: The median infusion rate at steady state was 175 MUg/kg/min (median infusion time 18 h). Infusion was halted in 14 patients. The frequency of drug discontinuation increased across admission BNP quartiles. BNP > 141 pg/ml at admission had a 95% predictive value for subsequent withdrawal of esmolol. The presence of BNP > 141 pg/ml in combination with systolic blood pressure < 130 mmHg and left ventricular ejection fraction < 50% identified a group of patients at high risk for drug interruption (interruption frequency = 83%, 95% CI: 55-95%). CONCLUSIONS: In conclusion, BNP measurement in combination with systolic blood pressure and 2D echocardiography may identify patients with non-ST elevation acute coronary syndromes at high risk for adverse events during esmolol infusion. PMID- 21539459 TI - Selective autoretroperfusion preserves myocardial function during coronary artery ligation in swine. AB - BACKGROUND: External pumps have been previously used to minimize edema and hemorrhage caused by coronary retroperfusion. The objective of this study was to use a pump-less approach (selective autoretroperfusion, SARP) to preserve myocardial function after acute coronary artery ligation. METHODS: In five experimental pigs, the LAD artery was ligated distal to the first diagonal and retroperfusion was instituted for three hours from a brachiocephalic artery at 50 mmHg pressure through an adjustable occluder on the cannula. In eight control pigs, the LAD artery was ligated distal to the second diagonal for the same duration with no SARP. RESULTS: ECG showed more prominent S-T segment elevation in the untreated control group despite the more distal ligation. The degree of myocardial contraction was significantly attenuated in the control group but was largely preserved in the SARP treated group. The myocytes were well preserved in the SARP group with no rupture of venous microvessels. Myocyte edema and disruption was observed in the control group with only mild extracellular edema in the SARP treated group. CONCLUSION: SARP preserved myocardial function with no damage to the myocyte and venules during three hours of acute LAD ligation. PMID- 21539460 TI - The dangers of detrimental coping in emergency medical services. AB - BACKGROUND: To manage the untoward effects of exposure to personally disturbing incidents (PDIs), fire/emergency medical services (EMS) professionals use a variety of coping methods. Some detrimental coping patterns have been steeped in the tradition of emergency services. OBJECTIVE: To examine the effectiveness of various coping methods utilized by fire/EMS professionals for mitigating the negative effects of exposure to PDIs. METHODS: To differentiate a relationship between the demographic data, traumatic stress, exposure to personally disturbing incidents, and coping methods of fire/EMS professionals, three questionnaires were utilized: a background/demographic questionnaire (BDQ), the 28-item General Health Questionnaire (GHQ-28), and the Ways of Coping Questionnaire (WOC). Descriptive and correlational analyses were used to evaluate the level of traumatic stress symptomatology associated with personally disturbing incidents and describe the relationship between the psychological health of fire/EMS professionals and coping methods. RESULTS: One hundred eighty fire/EMS professionals were surveyed. This study identified the subjective stress associated with five PDIs and pinpointed five detrimental coping methods of fire/EMS personnel that were predictors for increasing traumatic stress symptomatology. CONCLUSION: A significant relationship has been established between the dangers of detrimental coping methods and traumatic stress in fire/EMS professionals. Five detrimental coping methods have been correlated with traumatic stress. Three optimal coping methods offer promise in managing the untoward effects of PDIs. PMID- 21539461 TI - Expert witness qualifications and ethical guidelines for emergency medical services litigation: resource document for the National Association of EMS Physicians position statement. AB - The clinical provision of medical care by emergency medical services (EMS) providers in the out-of-hospital environment and the operation of EMS systems to provide that care are unique in the medical arena. There is a substantive difference in the experience of individuals who provide medical care in the out of-hospital setting and the experience of those who provide similar care in the hospital or other clinical settings. Furthermore, physicians who provide medical direction for EMS personnel have a clinical and oversight relationship with EMS personnel. This relationship uniquely qualifies EMS medical directors to provide expert opinions related to care provided by nonphysician EMS personnel. Physicians without specific EMS oversight experience are not uniformly qualified to provide expert opinion regarding the provision of EMS. This resource document reviews the current issues in expert witness testimony in cases involving EMS as these issues relate to the unique qualifications of the expert witness, the standard of care, and the ethical expectations. PMID- 21539463 TI - Remembering a friend, mentor, and scholar: Dr A Norman Cranin. PMID- 21539464 TI - Is implant dentistry a restorative discipline with a surgical component? A change of definition is proposed. PMID- 21539466 TI - Sporulation and survival of Toxoplasma gondii oocysts in different types of commercial cat litter. AB - Toxoplasma gondii oocysts are environmentally resistant and can survive outdoors for many months in dry and cold climates. In the present study, sporulation and survival of T. gondii oocysts was studied in different types of cat litters commercially available in the United States. Oocysts sporulated within 2-3 days in all types of cat litters and occasionally remained viable for 14 days. Results indicate that cat litter should be changed daily to prevent sporulation and infectivity to people. PMID- 21539467 TI - Acetylsalicylate reduces endothelial and platelet-derived microparticles in patients with coronary artery disease. AB - Previous studies suggest that endothelial progenitor cells (EPCs) contribute to vascular repair processes. In contrast, circulating microparticles (MPs) are reported to be part of a process that is damaging to vascular cells. Numerous studies suggest that the "balance" between EPCs and MPs is important for the integrity of vascular cells and preservation of endothelial function. In the present study, we assess the impact of acetylsalicylate (ASA) - which is, beside statins and physical exercise, a third basic column in the preventive therapy of coronary artery disease (CAD) - on EPCs and MPs in patients with CAD. We investigated the effect of treatment (8 weeks) with ASA (100 mg/d) on endothelial function (flow-mediated vasodilation, FMD), number of circulating EPCs, and endothelial- and platelet-derived microparticles (eMP, pMP) in 15 male patients (age 59.5 +/- 12.3 years) with CAD but nonsignificant stenosis. The number of pMPs and eMPs decreased by 62.7% (p < 0.05) and 28.4% (p < 0.05), respectively. The number of circulating EPCs (VEGFR2(+)CD34(+)), expressed as 0/00 of circulating polymorphonuclear leukocytes, remained unchanged. Despite the reduced number of pMPs and eMPs in response to the ASA therapy, the FMD responses and the maximal dilator effects of nitroglycerin were unaffected. In a control experiment, patients (n = 6) treated with the selective COX-2 inhibitor etoricoxib (90 mg/day) for 8 weeks showed no changes in the number of pMPs, eMPs, and EPCs and in FMD. We report on a novel effect of ASA treatment on the number of circulating endothelial- and platelet-derived microparticles in patients with cardiovascular disease. The mechanism remains elusive, and appears not to be associated with the COX-2 pathway. PMID- 21539468 TI - The short-term consumption of a moderately high-fat diet alters nitric oxide bioavailability in lean female Zucker rats. AB - To determine whether short-term consumption of a moderately high-fat diet (MHFD) affects nitric oxide (NO) production, the concentration of stable NO metabolites (NOx) in urine and plasma of rats fed a MHFD (15.6 %g fat) or control diet (4.5 %g fat) was measured weekly for 4 weeks. Plasma and urine NOx levels were significantly depressed in the MHFD group by week 1 and remained so for the duration of the study. Decreased NO bioavailability may result from a decrease in NO production or the scavenging of NO by reactive oxygen species (ROS). Because endothelial NOS (eNOS) is the major contributor to NO production and circulating levels of NOx, eNOS expression was measured in several tissues. At week 1, there was a MHFD-associated decrease in eNOS expression in the liver. Subsequently, eNOS expression declined in the heart and kidney medulla of MHFD-fed rats at weeks 3 and 4, respectively. The expression of eNOS in the kidney cortex and adipose tissue did not change. These results suggest that a MHFD alters eNOS expression in a time-dependent and tissue-specific manner. In the liver, NOS activity and tissue levels of NOx and nitrotyrosine were measured. Nitrotyrosine levels were used as an indirect measure of the NO scavenged by ROS. There was a decrease in NOS activity, suggesting that the low levels of hepatic NOx were due, in part, to a decrease in NO production. In addition, there was a dramatic increase in nitrotyrosine formation, suggesting that the decline in hepatic NOx was also due to an increased interaction of NO with ROS. Tyrosine nitration commonly has detrimental effects on proteins. The decrease in NO and increase in protein nitration could potentially have adverse effects on tissue function. PMID- 21539469 TI - Augmentation of cellular immune response by Ipomoea obscura and Ipobscurine alkaloid attenuates tumor growth in mice. AB - The immune status of the host plays a crucial role in controling the process of carcinogenesis. General or selective activation of various immunocompetent cells and their secretory function to maintain a healthy immune status may help in cancer prophylaxis, as well as therapy. The present study focused on the effect of Ipomoea obscura and Ipobscurine on cell-mediated immune response. In this study we evaluated the effect of I. obscura and an indole alkaloid fraction from I. obscura on effector mechanisms of cell-mediated immune response by analyzing cytotoxic T lymphocyte (CTL) activity, natural killer (NK) cell activity, antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent complement-mediated cytotoxicity (ACC). The effect of I. obscura and Ipobscurine on interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) levels was also analyzed. In the in vitro and in vivo systems, I. obscura and Ipobscurine treatment augmented cell-mediated immune response by enhancing the killing activity of CTL and NK cells from splenocytes in normal as well as tumor-bearing mice. ADCC and ACC were also enhanced significantly in both normal and tumor bearing animals after drug administration, compared with untreated control. Administration of I. obscura and Ipobscurine significantly enhanced the production of IL-2 and IFN-gamma in normal as well as tumor-bearing animals. This study reveals that both I. obscura and Ipobscurine have the potential to augment immune response through the enhanced secretion of IL-2 and IFN-gamma by T cells and thereby inhibit tumor growth and as an alternative medicine for cancer treatment. PMID- 21539470 TI - Orchidectomy attenuates impaired endothelial effects of a high-salt diet in Sprague-Dawley rats. AB - The effect of sex hormones on vascular reactivity is considered one of the underlying factors contributing to gender differences in cardiovascular functions and diseases. Experiments were designed to investigate the role of androgens in salt-induced hypertension by assessing the relaxation response of isolated aortic rings to acetylcholine and sodium nitroprusside in the presence or absence of l nitroarginine methyl ester in Sprague-Dawley rats. The rats were either orchidectomized or sham-operated, with or without testosterone replacement, and were placed on a normal or high-salt diet for 6 weeks. The results indicate a significant increase (p < 0.001) in the mean arterial blood pressure of rats on the high-salt diet, when compared with control or orchidectomized rats. Orchidectomy elicited a reduction in mean arterial blood pressure (p < 0.01), while testosterone replacement normalized mean arterial blood pressure to values seen in intact rats on the high-salt diet. The high-salt diet reduced the relaxation response to acetylcholine both in the presence and absence of inhibition of endothelial nitric oxide synthase with l-nitroarginine methyl ester. Bilateral orchidectomy attenuated the impaired endothelial function induced by the high-salt diet in rats, but this was reversed by concomitant administration of testosterone, suggesting a role for androgens in enhancing long term vascular smooth muscle tone and hence maintenance of high blood pressure in salt-induced hypertension. PMID- 21539471 TI - Craniofacial phenotype in the branchio-oculo-facial syndrome: four case reports. AB - Branchio-oculo-facial syndrome represents a craniofacial disorder in which affected patients may develop a wide range of distinctive features that include cleft lip and/or palate, cervical aplastic skin defect, malformed pinna, and ocular anomalies. This study reports four new cases confirmed by the identification of mutations in the TFAP2A gene and describes in detail the findings in the craniofacial region. The four cases included two familial and two sporadic, and three have been followed since the birth. Two out of the four cases showed atypical features. One patient presented brainstem immaturity with dysregulation of sympathetic and parasympathetic systems, which have so far not been described in the literature and were associated with anxiety, panic attacks, and tiredness. Another patient had as an additional feature a hypoplastic thumb with distal implantation. PMID- 21539472 TI - Current state of vocationally oriented medical rehabilitation--a German perspective. AB - The aim of this paper is to outline a current trend in inpatient medical rehabilitation in Germany, i.e. vocationally oriented medical rehabilitation (VOMR). Since employment-related demands and challenges pose a potential source of strain regarding employees' health and work ability, rehabilitative treatment in Germany is increasingly geared towards including work-related issues in diagnostics and therapy. To date, German rehabilitation research and practice have focussed primarily on the development of screening instruments for identifying vocational problems, interface management and inter-sectoral cooperation and the specification and standardisation of vocationally oriented interventions and programmes (e.g. work hardening, group interventions). Further developments in VOMR should examine the varying needs of patients for work related interventions as well as the neglect of specific subgroups of patients (e.g. long-term unemployed) and topics (e.g. interference between work and other life domains). PMID- 21539473 TI - Low molecular weight inhibitors of Prolyl Oligopeptidase: a review of compounds patented from 2003 to 2010. AB - INTRODUCTION: Prolyl Oligopeptidase (POP) is a serine peptidase that cleaves post proline bonds in short peptides. Besides the direct hydrolytic regulation function over peptides, neuropeptides and peptide hormones, POP is probably involved in the regulation of the inositol pathway and participates in protein protein interactions. Experimental data show that POP inhibitors have neuroprotective, anti-amnesic and cognition-enhancing properties. These compounds are considered therapeutic agents of interest for the treatment of cognitive deficits related to neuropsychiatric and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Recent findings pointed to the involvement of POP in angiogenesis, although the exact mechanism is still under study. AREAS COVERED: This review comprises patents and patent applications involving POP inhibitors patented between 2003 and 2010, classified as peptidomimetics, heteroaryl ketones and alkaloids. The binding processes and the mechanisms of inhibition of these inhibitors are also discussed, together with their in vivo effects. EXPERT OPINION: The major part of the repertory of POP inhibitors derived from systematical modification of the canonical compound benzyloxycarbonyl-prolyl-prolinal (ZPP). Nevertheless, only two of them have progressed into the clinical trials. One possible reason for this failure is the lack of studies concerning pharmacodynamics, pharmacokinetics and toxicity, together with the absence of suitable animal models. Moreover, POP is still not a well-defined therapeutic target. Further studies are required for the elucidation of the biological role of POP and to validate the therapeutic action of inhibitors in cognitive processes. In contrast, the involvement of POP in protein protein interactions together with the recent evidences in angiogenesis opens alternative approaches to the traditional active site-directed inhibitors, as well as new therapeutic applications. PMID- 21539474 TI - Driveline infections in patients supported with a HeartMate II: incidence, aetiology and outcome. AB - OBJECTIVES: To investigate the incidence and outcome of driveline infections in patients supported with a continuous flow left ventricular assist device (HeartMate II (HMII)) and to study the microbiological aetiology. DESIGN: Retrospective analysis of 31 patients who received an implantation of a HMII. Follow-up was from implantation to either device explantation, death or closure of the study. Clinical signs of infections were divided into superficial, deep or systemic and compared to culture and gram stain, the clinical course and infectious parameters. RESULTS: The incidence of driveline infections was 1.65 episodes per patient per year. Staphylococcus aureus and Escherichia coli were the most common bacterial aetiology. More than two weeks of treatment was required in 81% of the patients. In terms of detecting superficial driveline infections, leucocyte count demonstrated a sensitivity of 27% and C-reactive protein (CRP) a sensitivity of 28%. In 22 cases of driveline infections plasma pro-calcitonin was found to be normal. CONCLUSION: Driveline infections are common in HMII recipients but primarily remain superficial and are reasonably easy to manage. Infectious agents mostly originate from the skin and gastrointestinal tract. Blood biomarkers did not appear to be helpful in detecting driveline infections. PMID- 21539475 TI - Multiple-dose chronic inhalation toxicity study of size-separated kaolin refractory ceramic fiber in male Fischer 344 rats. AB - Abstract Refractory ceramic fibers (RCF) are man-made vitreous fibers used primarily in industrial high-temperature applications, especially for insulation of furnaces and kilns. Because of their increasing use and potential for human exposure an in an effort to define the dose-response, as a follow up to a maximum tolerated dose [30 mg/m(3)] study in rats (Mast et al., 1995), a multiple dose chronic toxicity/carcinogenicity inhalation study was conducted in Fischer 344 (F344) rats. Four groups of 140 weanling male F344 rats were exposed via noseonly inhalation to either HEPA-filtered air (chamber controls) or 3, 9, or 16 mg/m(3)(approximately 36, 91, and 162 fibers/cm(3)) of kaolin-based "size selected" RCF fibers (approximately 1 um in diameter and approximately 20 um in length) for 6 h/day, 5 days/wk for 24 mo. They were then held unexposed until approximately 20% survival and sacrificed (30 mo). Croups of 3-6 animals were sacrificed at 3, 6, 12, 18, and 24 mo to follow the progression of pulmonary lesions and to determine fiber lung burdens. Additional groups of 3-6 rats were removed from exposure at 3, 6, 12, and 18 mo and were held until sacrificed at 24 mo (recovery groups) for similar determinations. A dose-related increase in fiber lung burden was observed. Lung burdens at 24 mo ranged from 5.6 * 10(4) to 27.8 * 10(4) fibers/mg dry lung tissue. Significant increases in lung weights and lung to body weight ratios were seen in the high-dose group. Treatment-related lesions were restricted to the lungs. To some extent, all doses of RCF resulted in minimal to mild macrophage infiltration, bronchiolization of proximal alveoli, and microgranuloma formation by 12 mo of exposure. Interstitial fibrosis was observed at 12 mo in the 9 and 16 mg/m(3) groups but not in the low-dose group at any time point. A minimal amount of focal pleural fibrosis was first observed at 12 mo in the 9 and 76 mg/m(3) dose groups and progressed to a mild severity in the high-dose group by the end of the study. The incidence of pulmonary neoplasm's was well within the range typically reported in the male F344 rat. Neoplasm's (bronchoalveolar adenomas and carcinomas) were observed in all groups 10 mg/m(3) (air control), 1 of 129 (0.8%); 3 mg/m(3), 2 of 123 (1.6%); 9 mg/m(3), 5 of 127 (3.9%); 16 mg/m(3), 2 of 124 (1.6%)]. A single pleural mesothelioma was observed in an animal exposed to 9 mg/m(3) of kaolin RCF. The results of this study suggest that the dose response for primary lung neoplasms is steep, while that for mesothelioma may not be. PMID- 21539476 TI - Studies on the chronic toxicity (inhalation) of four types of refractory ceramic fiber in male Fischer 344 rats. AB - Abstract Refractory ceramic fibers (RCF) are man-made vitreous fibers used primarily in industrial high-temperature applications, especially for insulation of furnaces and kilns. Because of their increasing use and potential for human exposure, a chronic toxicity/carcinogenicity inhalation study was conducted in Fischer 344 (F344) rats. Five groups of 140 weanling male F344 rats were exposed via noseonly inhalation to either HEPA-filtered air (chamber controls) or 30 mg/m(3) (approximately 220 fibers/cm(3)) of three types [kaolin-based, high purity, and aluminum zirconia silica (AZS)] of "size-selected" RCF fibers (approximately 1u in diameter and approximately 20 um in length) and an "after service" heat-treated (2400 degrees F for 24 h) kaolin-based fiber for 6 h/day, 5 days/wk for 24 mo. They were then held unexposed until approximately 20% survival and then sacrificed at 30 mo. A positive control group of 80 F344 rats was exposed to 10 mg/m(3) chrysotile asbestos. Croups of 3-6 animals were sacrificed at 3, 6, 9, 12, 15, 18, and 24 mo to follow the progression of lesions and to determine fiber lung burdens. Additional groups of 3 rats were removed from exposure at 3, 6, 9, 12, and 18 mo and were held until sacrificed at 24 mo (recovery groups) for similar determinations. Lung burdens increased rapidly for all RCFs, appearing to plateau by about 12 mo. By 24 mo, lung burdens ranged from 2.6 to 9.6 * 10(5) fiberslmg of dry lung tissue for the RCFs tested. Treatment related lesions were restricted to the lungs. To some extent all types of RCF resulted in macrophage infiltration, bronchiolization of proximal alveoli, and microgranuloma formation by 3 mo of exposure. Interstitial fibrosis was observed at 6 mo for all types of RCF, except the "after-service" fiber where fibrosis was not seen until 12 mo. The lesions progressed in severity until 12-15 mo, after which they plateaued. A minimal amount of focal pleural fibrosis was first observed at 9 mo and progressed to a mild severity by the end of the study. Fxposure-related pulmonary neoplasms (bronchoalveolar adenomas and carcinomas combined) were observed with all 4 types of RCF [kaolin, 16 of 123 (13%); AZS, 9 of 121 (7.4%); high-purity, 19 of 121 (15.7%); and "after-service,"4 of 118 (3.4%)], compared to 2 of 120 (1.5%) in the untreated air controls. Pleural mesotheliomas were observed in two kaolin, three AZS, two high-purity, and one "after-service" exposed rats. A comparable but slightly greater amount of fibrosis was observed in the lungs of the positive (chrysotile asbestos) controls. The incidence of bronchoalveolar neoplasms in the chrysotile exposed rats was 13 of 69 (18.8%), and a mesothelioma occurred in 1 (1.4%) animal. The results of this study showed that the four types of RCF studied had carcinogenic activity in rats at the maximum tolerated dose. PMID- 21539477 TI - The impact of serum homocysteine on intima-media thickness in normotensive, white coat and sustained hypertensive adolescents. AB - BACKGROUND AND PURPOSE: In recent decades, elevated levels of homocysteine (Hcy) have been found to be associated with an increased risk of vascular events. Additionally, in some case-control studies, hyperhomocysteinaemia has been found to be related to higher intima-media thickness (IMT), but the results are inconclusive. Therefore, in the present study we intended to assess the relationship between serum levels of Hcy and IMT in normotensive and hypertensive adolescents. PATIENTS AND METHODS: 59 normotensive 47 white coat hypertensive and 73 sustained hypertensive adolescents were included in our study. IMT of the common carotid arteries was measured by B-mode ultrasonography. Plasma NOx as well as homocysteine levels were measured in all cases. The relationship between IMT and Hcy and NOx were assessed by a pooled analysis. Additionally, serum levels of Hcy and NOx were compared between normotensives and hypertensive subgroups. RESULTS: IMT was elevated in hypertensive adolescents (means +/- SD: 0.055 +/- 0.01 cm) compared with normotensives (0.048 +/- 0.008 cm, p < 0.01). Higher serum concentrations of homocysteine were measured in hypertensive teenagers (11.9 +/- 7.25 umol/l for hypertensive and 9.85 +/- 3.12 umol/l for normotensives respectively, p < 0.01). In contrast to this, serum NOx was lower in patients (28.8 +/- 14.9 umol/l) compared with controls (38.8 +/- 7.6 umol/l, p < 0.01). The pooling of homocysteine and IMT data of hypertensive and normotensive adolescents revealed a significant positive relationship between the two parameters (r = 0.43, p < 0.001). CONCLUSIONS: We conclude that elevated serum levels of homocysteine may play a role in increased IMT in adolescent hypertension. PMID- 21539478 TI - Regulation and roles of neuronal diacylglycerol kinases: a lipid perspective. AB - Diacylglycerol kinases (DGKs) are a class of enzymes that catalyze the ATP dependent conversion of diacylglycerol (DAG) to phosphatidic acid (PtdOH), resulting in the coordinate regulation of these two lipid second messengers. This regulation is particularly important in the nervous system where it is now well established that DAG and PtdOH serve very important roles in modulating a variety of neurological functions. There are currently 10 identified mammalian DGKs, organized into five classes or "Types" based upon similarities in their primary sequences. A number of studies have identified eight of these isoforms in various regions of the mammalian central nervous system (CNS): DGK-alpha, DGK-beta, DGK gamma, DGK-eta, DGK-zeta, DGK-iota, DGK-epsilon, and DGK-theta. Further studies have provided compelling evidence supporting roles for these enzymes in neuronal spine density, myelination, synaptic activity, neuronal plasticity, epileptogenesis and neurotransmitter release. The physiological regulation of these enzymes is less clear. Like all interfacial enzymes, DGKs metabolize their hydrophobic substrate (DAG) at a membrane-aqueous interface. Therefore, these enzymes can be regulated by alterations in their subcellular localization, enzymatic activity, and/or membrane association. In this review, we summarize what is currently understood about the localization and regulation of the neuronal DGKs in the mammalian CNS. PMID- 21539479 TI - Molecular mechanisms of drug resistance in tyrosine kinases cAbl and cKit. AB - The inhibition of protein kinases has gained general acceptance as an effective approach to treat a wide range of cancers. However, in many cases, prolonged administration of kinase inhibitors often leads to acquired resistance, and the therapeutic effect is subsequently diminished. The wealth of recent studies using biochemical, kinetic, and structural approaches have revealed the molecular basis for the clinically observed resistance. In this review, we highlight several of the most common molecular mechanisms that lead to acquired resistance to kinase inhibitors observed with the cAbl (cellular form of the Abelson leukemia virus tyrosine kinase) and the type III receptor tyrosine kinase cKit, including a newly identified mechanism resulting from accelerated kinase activation caused by mutations in the activation loop. Strategies to overcome the loss of drug sensitivity that represents a challenge currently facing the field and the emerging approaches to circumvent resistance are discussed. PMID- 21539481 TI - Pharmacologic approaches to the prevention of intraoperative awareness. PMID- 21539480 TI - Living in a box or call of the wild? Revisiting lifetime inactivity and sarcopenia. AB - SIGNIFICANCE: The accepted effects of aging in mammalian skeletal muscle are progressive atrophy and weakening, or sarcopenia. Canonical hallmarks of aging in skeletal muscle include a reduction in muscle fiber cross-sectional area, a loss in muscle fibers through apoptosis and denervation, and infiltration of connective tissue or fibrosis. Emerging thought suggests that pro-inflammatory signaling and oxidative stress may contribute to sarcopenia. CRITICAL ISSUES: Unfortunately, most of the mammalian models used to examine and understand sarcopenia are confounded by the pervasive influence of prolonged physical inactivity. Further, the potential for underlying metabolic disorder and chronic disease (e.g., type II diabetes and cardiovascular disease) may accelerate skeletal muscle wasting. Because physical inactivity may share elevated pro inflammatory (tumor necrosis factor-alpha and inducible nitric oxide synthase) and insufficient stress response (insulin-like growth factor-1 [IGF-1], heat shock protein 25 [HSP25], NAD-dependent deacetylase sirtuin-3 [SIRT-3], and peroxisome proliferator-activated receptor-gamma coactivator 1[PGC-1alpha]) signaling with aging and chronic disease, it is critical to distinguish true aging from chronic inactivity or underlying disease. Conversely, the efficacy of exercise and caloric restrictive interventions against sarcopenia in aging populations appears highly effective when (a) conducted across the lifespan, or (b) at higher intensities when commenced in middle age or later. RECENT ADVANCES: While the prospective mechanisms by which exercise or daily activity provide have not been elucidated, upregulation of HSPs, PGC-1alpha, and IGF-1 may ameliorate inflammatory signaling, apoptosis, and sarcopenia. Limited data indicate that the aging phenotype exhibited by mammals living in their natural habitat (Weddell seal and shrews) express limited apoptosis and fiber atrophy, whereas significant collagen accumulation remains. In addition, aging shrews displayed a remarkable ability to upregulate antioxidant enzymes (copper, zinc isoform of superoxide dismutase, manganese isoform of superoxide dismutase, catalase, and glutathione peroxidase). FUTURE DIRECTIONS: It is possible that in healthy populations requiring daily activity to thrive, fibrosis and weakness, more than atrophy, may be the predominant phenotype of muscle aging until senescence. Elucidating the molecular mechanisms by which lifetime inactivity contributes to sarcopenia and chronic disease will be critical in managing the quality of life and health costs associated with our aging population. PMID- 21539482 TI - Is migraine a predictor for identifying patients at risk of stroke? PMID- 21539483 TI - Do we need novel radiologic response criteria for brain tumor immunotherapy? PMID- 21539485 TI - An update on epilepsy. AB - The understanding of seizures and epilepsy as a disease has accelerated to reflect advances in the understanding of the interplay of seizures and epilepsy on neurophysiology, neuroplasticity, sleep, neuropsychology, behavior and social functioning of the individual, which interact with and can be affected by an individual's quality of life, educational development and occupational success. Updates in the treatment of status epilepticus, epilepsy in children and adults (particularly women), and psychogenic nonepileptic seizures/attacks have been announced. There is increasing emphasis on untangling the interactive forces of new antiepileptic medications from epilepsy/seizures on the neurophysiological, neuropsychologic and psychiatric/behavioral functioning of individuals with epilepsy. The role of GABA in the pathophysiology of seizures and status epilepticus has led to novel therapy proposals. Neurostimulation technologies and neurosurgical procedures have improved the clinical outcomes of patients with epilepsy, and have led to important advances in understanding the neuropathophysiology of epilepsy/seizures and brain plasticity. For example, neurostimulation allows long-term in vivo electroneurophysiological recordings of specific brain regions that has not been previously possible in humans. The 64th Annual Meeting of the American Epilepsy Society and the 3rd Biennial North American Regional Epilepsy Congress provided state-of-the-art updates to scientific and clinical practice issues in the treatment of epilepsy. PMID- 21539486 TI - Management of suspected Alzheimer's disease patients by specialist physicians at the first visit in Spain: First Consultation Study. AB - OBJECTIVE: To assess the management of suspected Alzheimer's disease (AD) patients at the first visit by Spanish specialist physicians. MATERIALS & METHODS: Epidemiological, cross-sectional and multicenter study. A total of 200 specialists (neurologists, psychiatrists and geriatricians) from hospitals and specialized centers across Spain included a total of 1851 patients of both sexes older than 18 years suspected to be suffering from AD. Data of clinical and demographic characteristics, methods of diagnosis, treatments and follow-up were collected in one visit. RESULTS: The mean age of the population was 75.2 +/- 7.9 years. The most frequent symptoms were difficulty in performing familiar tasks (76.7%), memory loss (76.0%) and misplacing items (72.7%). The assessment of suspected AD subjects included: neurological examination (walk apraxia [10.8%] and extrapyramidal signs [10.7%]), evaluation of cognition (mean of the Mini Mental State Examination score was 19.9 +/- 5.2 [mild AD]), function and behavior, and supplementary diagnostic tests (blood test [90%] and computerized axial tomography [66.8%]). In total, 69.5% of the patients were diagnosed with AD according to Spanish Society of Neurology criteria. Principal treatment was cholinesterase inhibitors (87.8%). The mean time for follow-up visit: 4 +/- 2.4 months; with the same physician (95.5%), neurologist (68.2%), psychiatrist (19%) and geriatrician (11.7%). CONCLUSIONS: Several possible areas are amenable to improvement by means of reducing the time to diagnosis, increasing the number of patients treated with nonpharmacological therapy, and providing more information on the benefits of treatment, care and providing the best therapeutic options available. In this study, almost half of the patients took 1-3 years to visit a physician after appearance of the first symptoms. Significant differences were observed between the medical specialty and treatments provided; nevertheless, the majority of physicians used cholinesterase inhibitors (87.8%) as the principal treatment. PMID- 21539488 TI - Diet and Alzheimer's disease risk factors or prevention: the current evidence. AB - Preventing or postponing the onset of Alzheimer's disease (AD) and delaying or slowing its progression would lead to a consequent improvement of health status and quality of life in older age. Elevated saturated fatty acids could have negative effects on age-related cognitive decline and mild cognitive impairment (MCI). Furthermore, at present, epidemiological evidence suggests a possible association between fish consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA; in particular, n-3 PUFA) and a reduced risk of cognitive decline and dementia. Poorer cognitive function and an increased risk of vascular dementia (VaD) were found to be associated with a lower consumption of milk or dairy products. However, the consumption of whole-fat dairy products may be associated with cognitive decline in the elderly. Light-to-moderate alcohol use may be associated with a reduced risk of incident dementia and AD, while for VaD, cognitive decline and predementia syndromes, the current evidence is only suggestive of a protective effect. The limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supports a protective role of these macronutrients against cognitive decline, dementia and AD. Only recently, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline, although the Mediterranean diet (MeDi) combines several foods, micro- and macro-nutrients already separately proposed as potential protective factors against dementia and predementia syndromes. In fact, recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from MCI to AD, reduced risk of AD and a decreased all-cause mortality in AD patients. These findings suggested that adherence to the MeDi may affect not only the risk of AD, but also of predementia syndromes and their progression to overt dementia. Based on the current evidence concerning these factors, no definitive dietary recommendations are possible. However, following dietary advice for lowering the risk of cardiovascular and metabolic disorders, high levels of consumption of fats from fish, vegetable oils, nonstarchy vegetables, low glycemic index fruits and a diet low in foods with added sugars and with moderate wine intake should be encouraged. Hopefully this will open new opportunities for the prevention and management of dementia and AD. PMID- 21539487 TI - Loss of motor function in preclinical Alzheimer's disease. AB - Accumulating evidence suggests that Alzheimer's disease (AD) has a long preclinical phase, during which time its characteristic pathology accumulates and patient function declines, but symptoms are insufficient to warrant a clinical diagnosis of dementia. There have been increasing reports of noncognitive symptoms, including loss of motor function, reported to be associated with incident AD. To understand the link between motor function and preclinical AD, this article examines: our understanding of motor function and its clinical assessment in cohort studies; the relationship of motor function and loss of cognition in older persons; risk factors for cognitive and motor decline; and the relation of post-mortem indices of AD and motor function prior to death. Together, these data suggest that age-related cognitive and motor decline may share a common causation. Furthermore, individuals with a clinical diagnosis of AD may represent the 'tip of the iceberg', since AD pathology may also account for a substantial proportion of cognitive and motor dysfunction currently considered 'normal aging' in older persons without dementia. Thus, AD may have a much larger impact on the health and wellbeing of our aging population. PMID- 21539489 TI - The use of ketamine in complex regional pain syndrome: possible mechanisms. AB - Complex regional pain syndrome is a neuropathic pain syndrome that is characterized by: severe pain beyond the area of injury; autonomic dysregulation; neurogenic edema; movement disorder; and atrophy and dystrophy. Ketamine is an open-channel NMDA blocker that only acts on those receptors whose Mg(2+) block has been lifted. It is effective in the treatment of the syndrome when standard treatments have failed. Different protocols are utilized depending on the severity of illness. There have been no serious ketamine-induced complications from these protocols, owing to careful psychological screening and the liberal use of midazolam and lorazepam to counter any psychomimetic effects and clonidine to block possible 'Olney's' lesions. PMID- 21539490 TI - Transcutaneous electrical nerve stimulation for the management of painful conditions: focus on neuropathic pain. AB - The management of neuropathic pain is challenging, with medication being the first-line treatment. Transcutaneous electrical nerve stimulation (TENS) is an inexpensive, noninvasive, self-administered technique that is used as an adjunct to medication. Clinical experience suggests that TENS is beneficial providing it is administered at a sufficiently strong intensity, close to the site of pain. At present, there are too few randomized controlled trials on TENS for neuropathic pain to judge effectiveness. The findings of systematic reviews of TENS for other pain syndromes are inconclusive because trials have a low fidelity associated with inadequate TENS technique and infrequent treatments of insufficient duration. The use of electrode arrays to spatially target stimulation more precisely may improve the efficacy of TENS in the future. PMID- 21539491 TI - Pediatric procedural sedation and analgesia outside the operating room: anticipating, avoiding and managing complications. AB - In the new millennium, there has been a huge surge in the numbers of procedures performed under sedation in pediatric patients outside the operating room. Traditionally, these were performed by anesthesiologists. Increasingly, other specialists, such as emergency room physicians, pediatricians and radiologists, are involved in the management of procedural sedations under elective or emergency situations. Professional organizations such as the American Society of Anesthesiologists, American Academy of Pediatrics, Joint Commission on Accreditation of Healthcare Organizations and other organizations are working continuously to make procedural sedation for children safe, economical and tailored to the needs of the child and the diagnostic/therapeutic procedure being performed. Multi-institutional databases have been set up to investigate the complications related to procedural sedation and lessons are being learned from the analysis of these data. This article reviews these data and describes strategies to prevent and manage common adverse events following procedural sedation in children outside the operating room. PMID- 21539493 TI - Cross-cultural adaptation, reliability and validity of the Persian version of the Modified Falls Efficacy Scale. AB - PURPOSE: To translate the Swedish version of the Falls Efficacy Scale (FES), the FES(S), into Persian, and to determine reliability and validity of the scale to be used for Persian speaking elderly people. METHOD: The 'forward-backward' procedure was applied to translate the FES(S) into Persian. A methodological study was then carried out to determine the psychometric properties of the Persian version of the scale. Eighty-one community-dwelling elderly persons (>=65 years) were included. RESULTS: Both reliability and validity of the Persian FES(S) were found to be acceptable (Cronbach's alpha= 0.75, interclass correlation coefficients = 0.99, p < 0.001 and standard errors of measurements = 1.82). Low to moderate negative correlations of the total score of the scale with the age of the participants and number of falls in the past year were shown. There were also low to moderate correlations between the Persian FES(S) score and the Mini-Mental State Examination score, duration of walks and physical fitness. The participants who took a daily walk, felt healthy, reported no general tiredness and who had had no fall during the past year rated their self-efficacy higher than did their peers. CONCLUSIONS: The present study verified that the Persian FES(S) is a culturally relevant, valid and reliable tool for measuring self-perceived confidence in Iranian older adults. PMID- 21539494 TI - Fate of bone marrow stromal cells in a syngenic model of bone formation. AB - Bone marrow stromal cells (BMSCs) have been demonstrated to induce bone formation when associated to osteoconductive biomaterials and implanted in vivo. Nevertheless, their role in bone reconstruction is not fully understood and rare studies have been conducted to follow their destiny after implantation in syngenic models. The aim of the present work was to use sensitive and quantitative methods to track donor and recipient cells after implantation of BMSCs in a syngenic model of ectopic bone formation. Using polymerase chain reaction (PCR) amplification of the Sex determining Region Y (Sry) gene and in situ hybridization of the Y chromosome in parallel to histological analysis, we have quantified within the implants the survival of the donor cells and the colonization by the recipient cells. The putative migration of the BMSCs in peripheral organs was also analyzed. We show here that grafted cells do not survive more than 3 weeks after implantation and might migrate in peripheral lymphoid organs. These cells are responsible for the attraction of host cells within the implants, leading to the centripetal colonization of the biomaterial by new bone. PMID- 21539495 TI - Ophiostoma mitovirus 3a , ascorbic acid, glutathione, and photoperiod affect the development of stromata and apothecia by Sclerotinia homoeocarpa. AB - Hypovirulence in Sclerotinia homoeocarpa is associated with infection by Ophiostoma mitovirus 3a (OMV3a). OMV3a is also present in asymptomatic isolates, with growth and virulence comparable to that of virus-free isolates. Hypovirulent isolates have impaired mitochondrial function resulting in increased activity of the alternative oxidase pathway, which is implicated in the reduction of reactive oxygen species in other fungi. In this study, hypovirulent, asymptomatic, and virus-free isolates were grown on potato dextrose agar amended with ascorbic acid or glutathione and were incubated under various photoperiods to determine the importance of reactive oxygen species, light, and OMV3a infection for differentiation of stromata and apothecia by S. homoeocarpa. Hypovirulent isolates did not form stromata or apothecia. Glutathione and darkness reduced stromata size and apothecia production by virulent and asymptomatic isolates. Apothecia formed under several different photoperiods, and ascorbic acid increased apothecia production. Ascospores were not detected in these apothecia. The results suggest that hypovirulence, light, and the superoxide radical are important factors in the formation of stromata and apothecia by S. homoeocarpa isolates. This is the first report of sterile apothecia production by North American isolates of S. homoeocarpa and provides a starting point for attempts to produce fertile apothecia. PMID- 21539496 TI - In vitro degradation of the moss Hylocomium splendens by three pleosporalean fungi. AB - Three darkly pigmented species of conidial fungi of the family Pleosporaceae isolated from plants colonizing the Saskatchewan Glacier forefield were examined for potential roles in the degradation of moss gametophytes. Curvularia inaequalis and Ulocladium atrum isolated from bryophytes Ditrichum flexicaule and Tortella tortuosa , respectively, and Chalastospora gossypii from Saxifraga oppositifolia were inoculated onto autoclaved gametophytes of the moss Hylocomium splendens. All three species of fungi caused mass losses of the moss gametophytes. In vitro enzymatic tests revealed that all three fungi degraded cellulose, while none degraded insoluble polyphenols. When this material was examined by scanning electron microscopy, it was evident that the fungi had eroded the outer wall layer of the moss leaf cells to some extent but not the inner layer containing more lignin-like compounds. Once the outer wall layer was removed, the cells easily disarticulated. It is proposed that accumulations of these phenolics-rich leaf fragments subsequently ameliorate the rooting environment for vascular plants and have the potential to support the growth of basidiomycetes and other fungi, potentially mycorrhizal with pioneer vascular plants. PMID- 21539498 TI - Flt3 ligand synergizes with granulocyte-colony-stimulating factor in bone marrow mobilization to improve functional outcome after spinal cord injury in the rat. AB - BACKGROUND AIMS: The effect of granulocyte-colony-stimulating factor (G-CSF) and/or the cytokine fms-like thyrosin kinase 3 (Flt3) ligand on functional outcome and tissue regeneration was studied in a rat model of spinal cord injury (SCI). METHODS: Rats with a balloon-induced compression lesion were injected with G-CSF and/or Flt3 ligand to mobilize bone marrow cells. Behavioral tests (Basso Beattie-Bresnahan and plantar test), blood counts, morphometric evaluation of the white and gray matter, and histology were performed 5 weeks after SCI. RESULTS: The mobilization of bone marrow cells by G-CSF, Flt3 ligand and their combination improved the motor and sensory performance of rats with SCI, reduced glial scarring, increased axonal sprouting and spared white and gray matter in the lesion. The best results were obtained with a combination of G-CSF and Flt3. G CSF alone or in combination with Flt3 ligand significantly increased the number of white blood cells, but not red blood cells or hemoglobin content, during and after the time-course of bone marrow stimulation. The combination of factors led to infiltration of the lesion by CD11b(+) cells. CONCLUSIONS: The observed improvement in behavioral and morphologic parameters and tissue regeneration in animals with SCI treated with a combination of both factors could be associated with a prolonged time-course of mobilization of bone marrow cells. The intravenous administration of G-CSF and/or Flt3 ligand represents a safe and effective treatment modality for SCI. PMID- 21539497 TI - Expansion of T cells targeting multiple antigens of cytomegalovirus, Epstein-Barr virus and adenovirus to provide broad antiviral specificity after stem cell transplantation. AB - BACKGROUND AIMS: Hematopoietic stem cell transplant (HSCT) is the treatment of choice for a proportion of patients with hematologic malignancies as well as for non-malignant diseases. However, viral infections, particularly Epstein-Barr virus (EBV), cytomegalovirus (CMV) and adenovirus (Ad), remain problematic after transplant despite the use of antiviral drugs. We have shown that cytotoxic T lymphocytes (CTL) generated against CMV-pp65, EBV and Ad antigens in a single culture are capable of controlling infections with all three viruses after HSCT. Although pp65-specific CTL have proved efficacious for the control of CMV infection, several reports highlight the importance of targeting additional CMV antigens. METHODS: To expand multivirus-specific T cells with activity against both CMV-pp65 and CMV-IE-1, peripheral blood mononuclear cells (PBMC) were transduced with the adenoviral vector (Ad5f35-IE-1-I-pp65). After 9-12 days the CTL were restimulated with autologous EBV-transformed B cells transduced with the same Ad vector. RESULTS: After 18 days in culture nine CTL lines expanded from less than 1.5 * 10(7) PBMC to a mean of 6.1 * 10(7) T cells that recognized CMV antigens pp65 [median 273 spot-forming cells (SFC), range 47-995] and IE-1 (median 154 SFC, range 11-505), the Ad antigens hexon (median 153 SFC, range 26 465) and penton (median 37 SFC, range 1-353), as well as EBV lymphoblastoid cell lines (median 55 SFC, range 9-301). Importantly, the T cells recognized at least two antigens per virus and lysed virus peptide-pulsed targets. CONCLUSIONS: CTL that target at least two antigens each of CMV, EBV and Ad should have clinical benefit with broad coverage of all three viruses and enhanced control of CMV infections compared with current protocols. PMID- 21539499 TI - TILling head and neck cancer for cell therapy. PMID- 21539500 TI - Nosocomial Klebsiella pneumoniae bacteraemia in adult cancer patients- characteristics of neutropenic and non-neutropenic patients. AB - BACKGROUND: Neoplastic diseases are common in patients with nosocomial Klebsiella pneumoniae bacteraemia. This study investigated the clinical characteristics of neutropenic and non-neutropenic adult cancer patients with nosocomial K. pneumoniae bacteraemia. METHODS: Adult cancer patients with K. pneumoniae bacteraemia were retrospectively analyzed at a medical centre in northern Taiwan over a 3-y period. We compared clinical characteristics of cancer patients with nosocomial K. pneumoniae bacteraemia between neutropenic and non-neutropenic groups and identified risk factors for 14-day mortality. RESULTS: Of the 189 patients recruited, 49 (26%) had neutropenia. Haematological malignancies, advanced cancer stage, chemotherapy treatment within 1 month and unknown origin of bacteraemia were predominant among patients with neutropenia. Patients without neutropenia tended to be older, tended to have solid tumours and tended to have bacteraemia of biliary origin. The overall 14-day mortality rate was 25.4%. There was no significant difference in 14-day mortality rate between patients with neutropenia (24.5%) and those without neutropenia (25.7%) (p = 0.808). The duration and severity of neutropenia, administration of inadequate empirical antibiotics and presence of extended-spectrum beta-lactamase-producing strains were not risk factors for mortality due to nosocomial K. pneumoniae. Multivariate analysis showed that septic shock was the only independent risk factor for mortality. CONCLUSIONS: Nosocomial bacteraemia due to K. pneumoniae in patients with malignancies had heterogeneous characteristics between neutropenic and non neutropenic groups. Cancer patients in both groups have a poor prognosis. More attention should be paid to cancer patients with nosocomial bacteraemia due to K. pneumoniae despite treatment with adequate antibiotics. PMID- 21539501 TI - An IRT validation of the Affective Self Rating Scale. AB - BACKGROUND: The Affective Self Rating Scale (AS-18) is intended for the use in bipolar outpatients. It includes subscales for the rating of depressive and manic type symptoms. It has previously been validated using methods from Classical Test Theory. AIMS: The aim of this study was to evaluate the psychometric properties of the AS-18 when used at an outpatient clinic for patients with bipolar disorder at routine visits, and to analyze the potential for improvement of the scale. METHODS: 231 patients with mainly bipolar I disorder doing ratings on routine visits at an affective disorder outpatient clinic were included. Ratings were analyzed using the Mokken non-parametric and the Rasch parametric model statistical methods. RESULTS: In the Mokken analysis, both subscales of the AS-18 showed a strong ability to rank respondents according to their total score and all items contributed adequately to the measurement. In the Rasch model, there were no indications of disturbing influence from secondary dimensions in the subscales. The depression subscale had the capacity reliably to separate the sample in at most three levels and the mania subscale in two levels. The limited capacity to separate respondents can mainly be explained by a lack of items reflecting lower levels of depressive and manic symptoms. CONCLUSIONS: AS-18 has good basic psychometric properties for use of rating of symptoms in bipolar I patients at routine visits, but there is also room for improvement. Item Response Theory (IRT) methods are suitable tools for evaluation and construction of rating scales. PMID- 21539502 TI - A simplified intrathymic injection technique for mice. AB - Intrathymic injection is a common technique used for research concerning immunotolerance induction, gene therapy and T cell development in mice. Traditionally used protocols involve major surgery that exposes the thoracic cavity, which results in injury to the mice and increased risk of poor recovery and postsurgical complications such as infection. We introduce a simplified intrathymic injection technique that does not expose the thoracic cavity and virtually eliminates pain, distress and postoperative complications while maintaining high injection efficiency. The technique is suitable for both adult and neonatal mice. PMID- 21539503 TI - Comparative analysis of Candida biofilm quantitation assays. AB - Candida grows on devices producing treatment resistant biofilms. A key tool for the study of biofilms includes an accurate assessment of viable cell growth. This study systematically tested seven techniques, among which the XTT assay provided the most reproducible, accurate, and efficient method for the quantitative estimation of C. albicans biofilms. PMID- 21539504 TI - First isolation of the anamorph of Kazachstania heterogenica from a fatal infection in a primate host. AB - We describe the isolation of the anamorph of the ascomycetous yeast Kazachstania heterogenica from a fatal infection in a 2 year, 9-month-old female white-handed gibbon (Hylobates lar). The yeast was observed in histological sections (lung and intestine) and co-isolated with the bacterium Escherichia coli from different internal organs. This is the first report of the recovery of this yeast from a fatal infection in a primate host. PMID- 21539505 TI - Curcumin acts synergistically with fluconazole to sensitize a clinical isolate of Candida albicans showing a MDR phenotype. AB - The primary objective of this work was to evaluate the capability of curcumin, a natural compound found in the Curcuma longa plant, to sensitize a clinical isolate of Candida albicans, which was found to have a high resistance to fluconazole. In addition, we assessed whether the resistance of this isolate was the result of the existence of efflux pumps, which could confer a multiple drug resistance phenotype. To evaluate azole resistance, we used the Clinical Laboratory Standard Institute (CLSI) MIC assays procedures with minor modifications. For evaluation of synergistic interaction of curcumin and fluconazole, checkerboard experiments were employed. Nile red and Rhodamine 6G accumulation assays were used to evaluate efflux pump activity. Curcumin was found to have a great capability to inhibit fluconazole resistance of the isolate of C. albicans. It was capable of restoring its sensitivity to this azole when used at 11 MUM. Analysis with different azoles and the two indicated dyes showed that an efflux pump could be acting and contributing to the resistance of this isolate to fluconazole. The results suggest that a major facilitator superfamily (MFS) transporter might be involved in this process. PMID- 21539506 TI - Epidemiology of endemic systemic fungal infections in Latin America. AB - Although endemic mycoses are a frequent health problem in Latin American countries, clinical and epidemiological data remain scarce and fragmentary. These mycoses have a significant impact on public health, and early diagnosis and appropriate treatment remain important. The target population for endemic disease in Latin America is mostly represented by low-income rural workers with limited access to a public or private health system. Unfortunately, diagnostic tools are not widely available in medical centers in Latin America; consequently, by the time patients are diagnosed with fungal infection, many are already severely ill. Among immunocompromised patients, endemic mycoses usually behave as opportunistic infections causing disseminated rather than localized disease. This paper reviews the epidemiology of the most clinically significant endemic mycoses in Latin America: paracoccidioidomycosis, histoplasmosis, and coccidioidomycosis. The burdens of disease, typically affected populations, and clinical outcomes also are discussed. PMID- 21539507 TI - Therapeutic and toxicologic studies in a murine model of invasive pulmonary aspergillosis. AB - Invasive pulmonary aspergillosis remains problematic in immunocompromised patient populations. We studied potential therapeutic options in a murine model of pulmonary aspergillosis in triamcinolone-suppressed DBA/2 mice infected intranasally with conidia from Aspergillus fumigatus. Mice were treated with liposomal-amphotericin B (AmBi; AmBisome), lipid-complexed amphotericin B (ABLC; Abelcet), voriconazole (VCZ), micafungin (MICA), caspofungin (CAS) or deoxycholate amphotericin B (AMBd) given alone or in combination. Monotherapy with AmBi, ABLC, AMBd, CAS or MICA had activity in prolonging survival; however, only AMBd or CAS reduced fungal burden in the lungs and kidneys. Combinations of AmBi plus CAS or MICA prolonged survival, but were not better than monotherapy. VCZ was ineffective and AMBd plus CAS showed a possible antagonism. AmBi or ABLC at higher dosages, or loading-doses of AmBi resulted in reduced survival. Histopathology showed increased incidence of serious renal and mild hepatic toxicity in triamcinolone-treated mice given an amphotericin B regimen compared to no or only triamcinolone (minimal renal changes occurred with CAS or VCZ with or without triamcinolone); suggestive of combined toxicity of triamcinolone and the amphotericin B in AmBi or ABLC. Infected treated mice showed progressive pulmonary disease including abscesses, angioinvasion and abundant intralesional fungi. High loading-doses of AmBi were associated with nephrosis and damage to other tissues. No monotherapy or combination regimen showed superiority for the treatment of pulmonary aspergillosis in corticosteroid suppressed mice and the potential for combined drug toxicity was enhanced in these mice. High dosages of lipid-formulated amphotericin B also proved unsatisfactory. Additional studies are needed to evaluate improved treatment. PMID- 21539508 TI - Metabolic networks: beyond the graph. AB - Drugs are devised to enter into the metabolism of an organism in order to produce a desired effect. From the chemical point of view, cellular metabolism is constituted by a complex network of reactions transforming metabolites one in each other. Knowledge on the structure of this network could help to develop novel methods for drug design, and to comprehend the root of known unexpected side effects. Many large-scale studies on the structure of metabolic networks have been developed following models based on different kinds of graphs as the fundamental image of the reaction network. Graphs models, however, comport wrong assumptions regarding the structure of reaction networks that may lead into wrong conclusions if they are not taken into account. In this article we critically review some graph-theoretical approaches to the analysis of centrality, vulnerability and modularity of metabolic networks, analyzing their limitations in estimating these key network properties, consider some proposals explicit or implicitly based on directed hypergraphs regarding their ability to overcome these issues, and review some recent implementation improvements that make the application of these models in increasingly large networks a viable option. PMID- 21539509 TI - A recent update on the role of ghrelin in glucose homeostasis. AB - Recent evidence highlights an important role of ghrelin in glucose homeostasis. In this review we provide a detailed summary of recent advances in this field. We describe the effects of ghrelin on all aspects of glucose homeostasis including glucose-stimulated insulin secretion, hepatic glucose production and insulin stimulated glucose disposal in the peripheral tissues. The existing evidence suggests ghrelin primarily inhibits insulin release from the pancreas and we highlight an important mechanism involving AMPK-UCP2 ATP-stimulated potassium channels and intracellular calcium regulation. Ghrelin increases hepatic glucose production and prevents glucose disposal in muscle and adipose tissues, which collectively leads to hyperglycemia and impaired glucose tolerance. We discuss the important role ghrelin plays in glucose homeostasis during different metabolic states. During severe calorie restriction, ghrelin increases blood glucose concentrations in order to maintain glucose homeostasis. In diet-induced obesity, ghrelin exacerbates hyperglycemia and promotes a diabetic phenotype. PMID- 21539510 TI - Novel inflammatory biomarkers in diseases: new hopes for diagnosis and therapy. PMID- 21539511 TI - Inflammation and immunology of the vitreoretinal compartment. AB - The immune system protects organisms against environmental and endogenous pathogens. By complex mechanisms, it regulates the homeostasis of inflammatory processes and tissue repair mechanisms. In the retina, these pathways can result in an irreversible tissue scar, which is related to malfunction and loss of function. In the aging retina, inflammation plays a major role and causes adverse effects. Several ophthalmological diseases contain aspects of maladjusted inflammatory processes. This review summarizes the general function of the immune system and its regulatory mechanisms in the vitreoretinal compartment. Next to non-pathological inflammatory processes, the review presents aspects of inflammation in the aging retina, AMD, glaucoma, uveitis and diabetic retinopathy. A better understanding of the complex immunology of the eye and inflammation of the vitreoretinal compartment may guide us towards more effective therapies for these very prevalent eye conditions. PMID- 21539512 TI - Lipoprotein-associated phospholipase A2: how effective as a risk marker of cardiovascular disease and as a therapeutic target? AB - Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been studied extensively in terms of biology, pathophysiology, diagnostic and prognostic values. Lp-PLA2 is an enzyme produced in atherosclerotic plaque by inflammatory cells, linked to LDL, HDL and VLDL. The binding of Lp-PLA2 to a specific lipoprotein fraction renders it more atherogenic. Increasing evidence has demonstrated Lp-PLA2 as a novel "ideal" marker for CVD as of its high specificity for vascular inflammation and low biologic variability. Thus, determination of Lp-PLA2 in individuals may provide clinically relevant information about their future risk of CVD events. In addition, Lp-PLA2 has been considered as a therapeutic target, which has been acted upon indirectly (lipid lowering medications) and directly (Lp-PLA2 antagonists such as darapladib) in pharmacologic therapies. This review will provide an overview on biochemistry, biology, proatherogenic, proinflammatory and proapoptotic effects of Lp-PLA2. Clinical utility and its validity as an independent CVD biomarker as well as a diagnostic biomarker to be detected in the very early stages of atherosclerosis will be also discussed. Moreover, the role of Lp-PLA2 as a pharmacologic therapeutic target is another theme of this review. PMID- 21539513 TI - Pentraxins: CRP and PTX3 and cardiovascular disease. AB - The pentraxins, C-reactive protein (CRP), serum amyloid P (SAP) and pentraxin3 (PTX3) are useful biomarkers for cardiovascular disease (CVD), particularly ischemic heart disease and heart failure, and are deeply involved in the pathogenesis of CVD linked to inflammation and innate immunity. Circulating elevated pentraxins, especially CRP and PTX3 levels can provide prognostic information for a variety of clinical settings and facilitate the diagnosis of CVD. Changes in these levels over time are also important indicators of pharmacological therapy, and may indicate the mechanisms by which pentraxins directly or indirectly affect the pathophysiology of CVD in an experimental setting. Here, we discuss major relevant findings associated with the clinical implications of CRP and PTX3 and their role in CVD. PMID- 21539514 TI - The clinical utility of kidney injury molecule 1 in the prediction, diagnosis and prognosis of acute kidney injury: a systematic review. AB - OBJECTIVE: This systematic review evaluates the clinical utility of a novel biomarker kidney injury molecule 1 (Kim-1) in the prediction, diagnosis and prognosis of acute kidney injury (AKI). METHODS: We searched literature in electronic databases from January 2002 to December 2009 by the key words "kidney injury molecule 1" or "Kim-1" and "acute kidney injury" or "acute renal failure". Studies were eligible for inclusion if they were primary studies published in English, in which Kim-1 was measured for the purpose of prediction, diagnosis or prognosis of AKI in patients. RESULTS: Eight articles met the selection criteria for inclusion in the study. Compared to non AKI patients, Kim-1 increased significantly (at least p<0.05) in AKI patients by 2 hours after cardiac surgery. In the prediction of AKI in patients within 24 hours of cardiac surgery, the sensitivity of Kim-1 ranged from 92% to 100% and AUC between 0.78 and 0.91. Kim-1 increased significantly (at least p<0.05) in AKI established patients, especially in patients with acute tubular necrosis (ATN). The AUC of Kim-1 in the diagnosis of AKI was from 0.9 to 0.95. However, Kim-1 showed weak association with the need of renal replacement therapy and death of AKI patient. CONCLUSIONS: Kim-1 is a potential novel urinary biomarker in the early detection of AKI within 24 hours after kidney insult. It might be especially beneficial in the diagnosis of ischemic ATN. PMID- 21539515 TI - Neutrophil gelatinase-associated lipocalin (NGAL) as a new biomarker for non- acute kidney injury (AKI) diseases. AB - Neutrophil gelatinase-associated lipocalin, or NGAL, an acute phase protein, is part of the lipocalin family. NGAL is highly induced in inflammatory conditions and ischemia, and is a critical component of innate immunity to bacterial infection. Recently, NGAL has been proven as an emerging biomarker for predicting acute kidney injury (AKI). Meanwhile, numerous studies have also demonstrated that NGAL may be a potential biomarker for the diagnosis, prediction, prevention, and prognosis of non--AKI diseases such as chronic kidney diseases, vascular disorders, cancer, preeclampsia, and allergies. This article systematically reviews the clinical utilities of NGAL as a new biomarker for non--AKI diseases. PMID- 21539516 TI - Heat shock proteins protect against ischemia and inflammation through multiple mechanisms. AB - After heat shock or other metabolic stress, heat shock proteins (Hsps) are expressed at high levels in all tissues and cells. The highly inducible 70 kDa heat shock protein (Hsp70) is associated with improved post-ischemic myocardial contractile recovery. Similarly, the small 27 kDa heat shock protein (Hsp27), that is abundant in muscle, is also linked with improved myocardial function after ischemic injury. Various Hsps have pro-survival functions that include chaperone, anti-apoptotic and/or anti-inflammatory activity. In this review we will summarize our understanding of myocardial protection and present evidence for protection having time dependent aspects that appear to be stimulus dependent. PMID- 21539517 TI - Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia. AB - The aim of the present study was to investigate the relationship between circulating PCSK9 (proprotein convertase subtilisin kexin type 9) and FCHL (familial combined hyperlipidaemia) and, when positive, to determine the strength of its heritability. Plasma PCSK9 levels were measured in FCHL patients (n=45), NL (normolipidaemic) relatives (n=139) and their spouses (n=72). In addition, 11 FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. PCSK9 levels were higher in FCHL patients compared with NL relatives and spouses: 96.1 compared with 78.7 and 82.0 ng/ml (P=0.004 and P=0.002 respectively). PCSK9 was significantly associated with both TAG (triacylglycerol) and apolipoprotein B levels (P<0.001). The latter relationship was accounted for by LDL (low-density lipoprotein)-apolipoprotein B (r=0.31, P=0.02), not by VLDL (very-low-density lipoprotein)-apolipoprotein B (r=0.09, P=0.49) in a subgroup of subjects (n=59). Heritability calculations for PCSK9 using SOLAR and FCOR software yielded estimates of 67-84% respectively (P<0.0001). PCSK9 increased from 122 to 150 ng/ml in 11 FCHL patients treated with atorvastatin (40 mg) once daily for 8 weeks (P=0.018). In conclusion, plasma PCSK9 is a heritable trait associated with both FCHL diagnostic hallmarks. These results, combined with the significant rise in PCSK9 levels after statin therapy, warrant further studies in order to unravel the exact role of PCSK9 in the pathogenesis and treatment of this highly prevalent genetic dyslipidaemia. PMID- 21539518 TI - Wnt5a controls neurite development in olfactory bulb interneurons. AB - Neurons born in the postnatal SVZ (subventricular zone) must migrate a great distance before becoming mature interneurons of the OB (olfactory bulb). During migration immature OB neurons maintain an immature morphology until they reach their destination. While the morphological development of these cells must be tightly regulated, the cellular pathways responsible are still largely unknown. Our results show that the non-canonical Wnt pathway induced by Wnt5a is important for the morphological development of OB interneurons both in vitro and in vivo. Additionally, we demonstrate that non-canonical Wnt signalling works in opposition to canonical Wnt signalling in neural precursors from the SVZ in vitro. This represents a novel role for Wnt5a in the development of OB interneurons and suggests that canonical and non-canonical Wnt pathways dynamically oppose each other in the regulation of dendrite maturation. PMID- 21539519 TI - Tissue- and paralogue-specific functions of acyl-CoA-binding proteins in lipid metabolism in Caenorhabditis elegans. AB - ACBP (acyl-CoA-binding protein) is a small primarily cytosolic protein that binds acyl-CoA esters with high specificity and affinity. ACBP has been identified in all eukaryotic species, indicating that it performs a basal cellular function. However, differential tissue expression and the existence of several ACBP paralogues in many eukaryotic species indicate that these proteins serve distinct functions. The nematode Caenorhabditis elegans expresses seven ACBPs: four basal forms and three ACBP domain proteins. We find that each of these paralogues is capable of complementing the growth of ACBP-deficient yeast cells, and that they exhibit distinct temporal and tissue expression patterns in C. elegans. We have obtained loss-of-function mutants for six of these forms. All single mutants display relatively subtle phenotypes; however, we find that functional loss of ACBP-1 leads to reduced triacylglycerol (triglyceride) levels and aberrant lipid droplet morphology and number in the intestine. We also show that worms lacking ACBP-2 show a severe decrease in the beta-oxidation of unsaturated fatty acids. A quadruple mutant, lacking all basal ACBPs, is slightly developmentally delayed, displays abnormal intestinal lipid storage, and increased beta-oxidation. Collectively, the present results suggest that each of the ACBP paralogues serves a distinct function in C. elegans. PMID- 21539520 TI - Translation initiation factors and active sites of protein synthesis co-localize at the leading edge of migrating fibroblasts. AB - Cell migration is a highly controlled essential cellular process, often dysregulated in tumour cells, dynamically controlled by the architecture of the cell. Studies involving cellular fractionation and microarray profiling have previously identified functionally distinct mRNA populations specific to cellular organelles and architectural compartments. However, the interaction between the translational machinery itself and cellular structures is relatively unexplored. To help understand the role for the compartmentalization and localized protein synthesis in cell migration, we have used scanning confocal microscopy, immunofluorescence and a novel ribopuromycylation method to visualize translating ribosomes. In the present study we show that eIFs (eukaryotic initiation factors) localize to the leading edge of migrating MRC5 fibroblasts in a process dependent on TGN (trans-Golgi network) to plasma membrane vesicle transport. We show that eIF4E and eIF4GI are associated with the Golgi apparatus and membrane microdomains, and that a proportion of these proteins co-localize to sites of active translation at the leading edge of migrating cells. PMID- 21539521 TI - Noninvasive measurement of fetal augmentation index by fetal aortic diameter pulse and flow velocity waveforms. AB - OBJECTIVE: To study fetal systemic arterial stiffness in normal fetuses and compromised fetuses who had umbilical placental insufficiency (UPI). DESIGN: Prospective study. SETTING: University departments. SAMPLE: A total of 118 normal fetuses (21-40 weeks) and 55 fetuses (UPI group) with evidence of potential compromise (high umbilical artery pulsatility index). METHODS: A new real-time noninvasive measurement system based on a combined Doppler ultrasound and echo tracking system was used as a measure of aortic/systemic arterial stiffness. The augmentation index (AI) of the fetal thoracic descending aorta was measured by using simultaneous measurements of diameter pulse and flow velocity waveforms. MAIN OUTCOME MEASURE: Augmentation index as a measure of stiffness. RESULTS: In normal fetuses, successful measurements for obtaining the AI were achieved in 103 of 118 fetuses. In the normal group, the AI, as well as placental resistance, decreased during the second trimester; in contrast, an increase in the AI was observed during the third trimester. Using the AI values from the normal group, the UPI group was divided into two subgroups: 29 fetuses with a normal AI and 26 fetuses with a high AI. The clinical outcome was significantly worse in the latter subgroup compared with the normal subgroup. CONCLUSIONS: The increase of afterload caused by a high umbilical placental resistance was associated with a decrease of aortic distensibility in the compromised fetuses, suggesting an alteration of aortic wall structure. PMID- 21539522 TI - Screening and outcome of chromosomal abnormalities other than trisomy 21 in Northern Finland. AB - OBJECTIVE: To examine the performance of first-trimester combined screening after adding the specific algorithms for trisomies 18 and 13 in the Down syndrome screening program for chromosomal abnormalities other than trisomy 21 and to determine the outcomes of such pregnancies. DESIGN: A retrospective study. SETTING: Oulu University Hospital, Finland. POPULATION: Pregnant women (n=56 076) participating voluntarily in first-trimester combined Down syndrome screening in Northern and Eastern Finland during the study period 1 June 2002 to 31 December 2008. METHODS: The data of all known cases of chromosomal abnormalities other than trisomy 21 were collected. MAIN OUTCOME MEASURES: Risk algorithms for trisomies 21, 18 and 13 were used for the calculation of patient-specific risks for certain chromosomal abnormalities. Algorithms were based on maternal age, crown-rump length, nuchal translucency, and measurement of free beta-human chorionic gonadotrophin and pregnancy-associated plasma protein-A. Detection rates and false-positive rates were calculated. RESULTS: A total of 27 cases of trisomy 18, 11 cases of trisomy 13 and 30 cases of other chromosomal abnormalities were analyzed. The algorithm for Down syndrome detected 55.6% of trisomy 18 cases, 36.4% of trisomy 13 cases and 60.0% of other chromosomal abnormalities. When specific risk algorithms were added, the detection rates improved for trisomy 18 (74.0%) and for trisomy 13 (54.5%), with only a slight increase of the false-positive rate of 0.2%. The detection rate for other chromosomal abnormalities did not improve. CONCLUSIONS: Adding the trisomy 18 algorithm to the Down screening program resulted in the detection of five additional trisomy 18 cases. PMID- 21539523 TI - Oral health considerations in older women receiving oral bisphosphonate therapy. AB - Recent reports of bisphosphonate-related osteonecrosis of the jaw (BRONJ) have increased awareness of oral health in patients receiving osteoporosis therapy. This study describes the demographic, oral health, and clinical characteristics of a contemporary population of women aged 50 and older undergoing oral bisphosphonate treatment who returned a mailed questionnaire pertaining to dental symptoms. The study, as previously reported, was conducted within Kaiser Permanente Northern California, a large, integrated healthcare delivery system. The cohort included 7,909 women with bisphosphonate exposure of at least 1 year, with a subset of 923 women reporting dental symptoms who underwent clinical examination. Overall, the average age was 71 +/- 9; 70% were white, and 74% had at least some college education. Nearly two-thirds had received oral bisphosphonate therapy for 3 or more years. Most reported daily tooth brushing, 85% had had a dental examination in the past year, 22% reported denture use, and 6% reported moderate to severe periodontal disease. Oral healthcare patterns varied according to age and race and ethnicity. Five hundred seven (6.4%) women reported a tooth extraction in the prior year, of whom two developed BRONJ (0.4%). Tori or exostoses were found in 28% of examined participants with dental symptoms; these were predominantly in the lingual mandible and palate, with palatal BRONJ occurring in 1.6% of symptomatic participants with palatal tori. In summary, among older women with bisphosphonate exposure, oral health varied according to patient characteristics, and BRONJ occurred more frequently after tooth extraction or on palatal tori. These data support efforts to optimize oral health and to identify risk factors for BRONJ in older individuals receiving bisphosphonate drugs. PMID- 21539524 TI - Decision-making and outcomes of feeding tube insertion: a five-state study. AB - OBJECTIVES: To examine family member's perceptions of decision-making and outcomes of feeding tubes. DESIGN: Mortality follow-back survey. Sample weights were used to account for oversampling and survey design. A multivariate model examined the association between feeding tube use and overall quality of care rating regarding the last week of life. SETTING: Nursing homes, hospitals, and assisted living facilities. PARTICIPANTS: Respondents whose relative had died from dementia in five states with varying feeding tube use. MEASUREMENTS: Respondents were asked about discussions, decision-making, and outcomes related to their loved ones' feeding problems. RESULTS: Of 486 family members surveyed, representing 9,652 relatives dying from dementia, 10.8% reported that the decedent had a feeding tube, 17.6% made a decision not to use a feeding tube, and 71.6% reported that there was no decision about feeding tubes. Of respondents for decedents with a feeding tube, 13.7% stated that there was no discussion about feeding tube insertion, and 41.6% reported a discussion that was shorter than 15 minutes. The risks associated with feeding tube insertion were not discussed in one-third of the cases, 51.8% felt that the healthcare provider was strongly in favor of feeding tube insertion, and 12.6% felt pressured by the physician to insert a feeding tube. The decedent was often physically (25.9%) or pharmacologically restrained (29.2%). Respondents whose loved ones died with a feeding tube were less likely to report excellent end-of-life care (adjusted odds ratio=0.42, 95% confidence interval=0.18-0.97) than those who were not. CONCLUSION: Based on the perceptions of bereaved family members, important opportunities exist to improve decision-making in feeding tube insertion. PMID- 21539525 TI - Associations between drug burden index and falls in older people in residential aged care. AB - OBJECTIVES: To evaluate the association between the Drug Burden Index (DBI), a measure of a person's total exposure to anticholinergic and sedative medications that includes principles of dose-response and maximal effect and is associated with impaired physical function in community-dwelling older people, and falls in residents of residential aged care facilities (RACFs). DESIGN: Data were drawn from participants in a randomized controlled trial that investigated falls and fractures. SETTING: RACFs in Sydney, Australia. PARTICIPANTS: Study participants (N=602; 70.9% female) were recruited from 51 RACFs. Mean age was 85.7 +/- 6.4, and mean DBI was 0.60 +/- 0.66. MEASUREMENTS: Medication history was obtained on each participant. Drugs were classified as anticholinergic or sedative and a DBI was calculated. Falls were measured over a 12-month period. Comorbidity, cognitive impairment (Mini-Mental State Examination) and depression (Geriatric Depression Scale) were determined. RESULTS: There were 998 falls in 330 individuals during a follow-up period of 574.2 person-years, equating to an average rate of 1.74 falls per person-year. The univariate negative binomial regression model for falls showed incidence rate ratios of 1.69 (95% confidence interval (CI)=1.22-2.34) for low DBI (<1) and 2.11 (95% CI=1.47-3.04) for high DBI (>=1) when compared with those who had a DBI of 0. After adjusting for age, sex, history of falling, cognitive impairment, depression, use of a walking aid, comorbidities, polypharmacy, and incontinence, incident rate ratios of 1.61 (95% CI=1.17-2.23) for low DBI and 1.90 (95% CI=1.30-2.78) for high DBI were obtained. CONCLUSION: DBI is significantly and independently associated with falls in older people living in RACFs. Interventional studies designed for this population are needed to determine whether reducing DBI, through dose reduction or cessation of anticholinergic and sedative drugs, can prevent falls. PMID- 21539526 TI - Physical, mental, and cognitive function in a convenience sample of centenarians in Australia. AB - OBJECTIVES: To examine the physical, mental, and cognitive function of centenarians. DESIGN: Descriptive study using a structured questionnaire and convenience sampling. SETTING: Residential care facilities and private dwellings in Australia. PARTICIPANTS: A convenience sample of 188 centenarians. MEASUREMENTS: The Hospital Anxiety and Depression Scale (HADS) screened for anxiety and depression. The Katz Index of Independence in Activities of Daily Living (Katz ADL) was used to assess functional status. The Quality of Life Scale was used to assess quality of life. The Mini-Mental State Examination (MMSE) was used to screen for dementia. Structured responses were obtained for living arrangement, marital status, social relationships, and supports. RESULTS: Centenarians had regular contact with friends (59%), neighbors (62%), and families (72%); 54% were religious and 43.5% had received social supports. Average MMSE and Katz ADL scores were 21.5 and 3.7, respectively; 45% had scores on the MMSE indicative of dementia, 10% indicated anxiety and 14% depression on the HADS. Participants with poor ratings of health experienced higher rates of anxiety and depression than their healthier counterparts. CONCLUSION: In this convenience sample of Australian centenarians, anxiety and depression was relatively nonexistent, and most reported a high quality of life. This was despite objective deterioration in functional status, paralleling the aging process, and high dependence on others for everyday tasks. Potentially, this is suggestive of a unique ability within the sample to adapt to aging and its limitations. PMID- 21539527 TI - Patterns of antimicrobial use for respiratory tract infections in older residents of long-term care facilities. AB - OBJECTIVES: To describe patterns of antimicrobial use for respiratory tract infections (RTIs) in older residents of long-term care facilities (LTCFs). DESIGN: Data from a prospective, randomized, controlled study of the effect of vitamin E supplementation on RTIs conducted from April 1998 through August 2001 were analyzed. SETTING: Thirty-three LTCFs in the greater Boston area. PARTICIPANTS: Six hundred seventeen subjects aged 65 and older residing in LTCFs. MEASUREMENTS: RTIs, categorized as acute bronchitis, pneumonia, common cold, influenza-like illness, pharyngitis, and sinusitis, were studied for appropriateness of antimicrobial use, type of antibiotics used, and factors associated with their use. For cases in which drug treatment was administered, antibiotic use was rated as appropriate (when an effective drug was used), inappropriate (when a more-effective drug was indicated), or unjustified (when use of any antimicrobial was not indicated). RESULTS: Of 752 documented episodes of RTI, overall treatment was appropriate in 79% of episodes, inappropriate in 2%, and unjustified in 19%. For acute bronchitis, treatment was appropriate in 35% and unjustified in 65% of cases. For pneumonia, treatment was appropriate in 87% of episodes. Of the most commonly used antimicrobials, macrolide use was unjustified in 43% of cases. No statistically significant differences in the patterns of antibiotic use were observed when stratified according to age, sex, race, or comorbid conditions, including diabetes mellitus, dementia, and chronic kidney disease. CONCLUSION: Antimicrobials were unjustifiably used for one-fifth of RTIs and more than two-thirds of cases of acute bronchitis, suggesting a need for programs to improve antibiotic prescribing at LTCFs. PMID- 21539528 TI - The use of a sound-enabled device to measure pressure during insertion of an epidural catheter in women in labour. AB - The insertion of an epidural catheter for labour analgesia may be challenging. This observational study compared pressures during insertion of an epidural catheter in pregnant (n = 35) and non-pregnant (n = 10) women, using an acoustic device for locating the epidural space that also records and stores pressure data during the procedure. In both groups, we compared the maximum pressure just before loss of resistance, the pressure in the epidural space and the pressure in the inserted epidural catheter. Maximum pressure just before loss of resistance in the pregnant women was significantly lower compared with the non-pregnant women. Pressures in the epidural space and with the disposable tubing connected to the inserted epidural catheter were greater in pregnant women than in non pregnant women. The results support the hypothesis that physiological changes in the third trimester of pregnancy are the reason why epidural catheters are more difficult to insert in women in labour. PMID- 21539529 TI - Non-invasive prediction of fluid responsiveness in infants using pleth variability index. AB - This prospective study assessed whether respiratory variations in velocity time integral, peak blood flow velocity and non-invasive pleth variability index are useful measurements in infants undergoing congenital heart surgery and determined threshold values that may help guide fluid administration. In 27 infants receiving mechanical ventilation, of mean (SD) weight 10.4 (6.3) kg, 13 increased their stroke volume index >= 15% following a fluid challenge and 14 did not. The best area under the receiver operating characteristic curve was for the echocardiographic-derived variables respiratory variation in blood peak flow velocity (area under the ROC curve = 0.92; p = 0.0002) and respiratory variation of the velocity time integral (area under the ROC curve = 0.84; p = 0.002). The pleth variability index also predicted fluid responsiveness (area under the ROC curve = 0.79; p = 0.01), in contrast to heart rate (area under the ROC curve = 0.53; p = 0.75) and central venous pressure (area under the ROC curve = 0.57; p = 0.52). PMID- 21539530 TI - Intra-operative rewarming with Hot Dog((r)) resistive heating and forced-air heating: a trial of lower-body warming. AB - Resistive heating is an alternative to forced-air warming which is currently the most commonly used intra-operative warming system. We therefore tested the hypothesis that rewarming rates are similar with Hot Dog((r)) (Augustine Biomedical) resistive and Bair Hugger((r)) (Arizant) forced-air heating systems. We evaluated 28 patients having major maxillary tumour surgery. During the establishment of invasive monitoring, patients became hypothermic, dropping their core temperature to about 35 degrees C. They were then randomly assigned to rewarming with lower-body resistive (n = 14) or forced-air (n = 14) heating, with each system set to 'high'. Our primary outcome was the rewarming rate during active heating over a core temperature range from 35 to 37 degrees C. Morphometric characteristics were comparable in both groups. Temperature increased at twice the rate in patients assigned to forced-air warming, with an estimated mean (SE) slope of 0.49 (0.03) degrees C.h(-1) vs 0.24 (0.02) degrees C.h(-1) (p < 0.001). Resistive heating warmed at half the rate of forced air. PMID- 21539531 TI - Influenza A-induced rhabdomyolysis and acute kidney injury complicated by posterior reversible encephalopathy syndrome. AB - We report a case of Influenza A-induced rhabdomyolysis causing acute kidney injury in a young adult female who required invasive ventilation and renal replacement therapy. This case was further complicated by posterior reversible encephalopathy syndrome. Although this represents an extremely rare neurological complication of Influenza A infection, an appreciation of the condition and its management is important, given the high numbers of critically ill patients recently affected by H1N1 Influenza A in intensive care units in the UK. PMID- 21539532 TI - Proton pump inhibitor and clopidogrel interaction: have we forgotten aspirin? PMID- 21539533 TI - Excess bone marrow B-cells in patients with multiple myeloma achieving complete remission following autologous stem cell transplantation is a biomarker for improved survival. PMID- 21539534 TI - Disabled-2 modulates homotypic and heterotypic platelet interactions by binding to sulfatides. AB - Disabled-2 (Dab2) inhibits platelet aggregation by competing with fibrinogen for binding to the alpha(IIb) beta(3) integrin receptor, an interaction that is modulated by Dab2 binding to sulfatides at the outer leaflet of the platelet plasma membrane. The disaggregatory function of Dab2 has been mapped to its N terminus phosphotyrosine-binding (N-PTB) domain. Our data show that the surface levels of P-selectin, a platelet transmembrane protein known to bind sulfatides and promote cell-cell interactions, are reduced by Dab2 N-PTB, an event that is reversed in the presence of a mutant form of the protein that is deficient in sulfatide but not in integrin binding. Importantly, Dab2 N-PTB, but not its sulfatide binding-deficient form, was able to prevent sulfatide-induced platelet aggregation when tested under haemodynamic conditions in microfluidic devices at flow rates with shear stress levels corresponding to those found in vein microcirculation. Moreover, the regulatory role of Dab2 N-PTB extends to platelet leucocyte adhesion and aggregation events, suggesting a multi-target role for Dab2 in haemostasis. PMID- 21539535 TI - Moving on from voluntary non-remunerated donors: who is the best blood donor? AB - Blood transfusion safety in sub-Saharan Africa (SSA) is marred by the high prevalence of infectious agents, chronic blood shortage and lack of resources. However, considerable pressure is applied by richer countries and international transfusion bodies to establish voluntary, non-remunerated blood donors (VNRD) as the only source of blood, excluding the traditional family/replacement donors on the grounds of a higher level of safety. Such a policy increases the cost of a unit of blood by two to fivefold and exacerbates the pre-existing blood shortage. This review provides compelling evidence that first-time VNRD are no safer than family/replacement donors and that only repeat donation provides improved blood safety. In order to limit blood shortage and maintain affordability of the blood supply in SSA, both types of donors should be accepted and both should be encouraged to donate regularly. PMID- 21539536 TI - Kruppel-like Factor 4 activates HBG gene expression in primary erythroid cells. AB - The SP1/Kruppel-like Factor (SP1/KLF) family of transcription factors plays a role in diverse cellular processes, including proliferation, differentiation and control of gene transcription. The discovery of KLF1 (EKLF), a key regulator of HBB (beta-globin) gene expression, expanded our understanding of the role of KLFs in erythropoiesis. In this study, we investigated a mechanism of HBG (gamma globin) regulation by KLF4. siRNA-mediated gene silencing and enforced expression of KLF4 in K562 cells substantiated the ability of KLF4 to positively regulate endogenous HBG gene transcription. The physiological significance of this finding was confirmed in primary erythroid cells, where KLF4 knockdown at day 11 significantly attenuated HBG mRNA levels and enforced expression at day 28 stimulated the silenced HBG genes. In vitro binding characterization using the gamma-CACCC and beta-CACCC probes demonstrated KLF4 preferentially binds the endogenous gamma-CACCC, while CREB binding protein (CREBBP) binding was not selective. Co-immunoprecipitation studies confirmed protein-protein interaction between KLF4 and CREBBP. Furthermore, sequential chromatin immunoprecipitation assays showed co-localization of both factors in the gamma-CACCC region. Subsequent luciferase reporter studies demonstrated that KLF4 trans-activated HBG promoter activity and that CREBBP enforced expression resulted in gene repression. Our data supports a model of antagonistic interaction of KLF4/CREBBP trans-factors in HBG regulation. PMID- 21539537 TI - Review of the cardiac long-term effects of therapy for Hodgkin lymphoma. AB - Patients diagnosed with Hodgkin lymphoma have a high cure rate. However, long term survivors of the disease are at significantly increased risk for a number of late effects, with cardiovascular disease being the most common non-malignant cause of death in these patients. This review summarizes the available data regarding the types of cardiac complications, timing of their onset in relationship to initial treatment, associated risk factors, and available studies on the role of screening for subclinical cardiac disease. Given the known correlation between the extent of Hodgkin lymphoma therapy and subsequent cardiac risks, current trials investigating treatment reduction, including using lower radiation dose, smaller radiation field size and abbreviated chemotherapy will hopefully help in limiting cardiac toxicity. Screening for and aggressive management of traditional cardiac risk factors are also important strategies in reducing risks of cardiac disease in long-term Hodgkin lymphoma survivors. PMID- 21539538 TI - Fibrosis is associated with adiponectin resistance in chronic hepatitis C virus infection. AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequently associated with insulin resistance which has been suggested to promote fibrotic progression. Adiponectin, an adipocyte-derived insulin-sensitizing hormone, might play a protective role against hepatic fibrosis. MATERIALS AND METHODS: This observational case-control study investigated the adiponectin status in insulin resistant, nondiabetic, chronic HCV-infected patients (n=54; 13 women, 41 men) compared with age-, sex- and BMI-matched healthy controls. Liver biopsies from patients with chronic HCV hepatitis were analysed for the adiponectin and adiponectin receptors (ADIPOR) 1 and 2 mRNA and protein expressions. RESULTS: Serum adiponectin levels were higher in patients with chronic HCV hepatitis than in healthy controls (12.1+/-4.7 vs. 9.5+/-4.4 mg L(-1) in men, P = 0.01; 18.2+/ 4.4 vs. 13.6+/-5.3mgL(-1) in women, P=0.02). BMI, HDL cholesterol and triglycerides levels correlated with adiponectin levels both in patients and in controls, while no correlation with glucose, insulin and HOMA-IR values could be detected. Nonetheless, insulin resistance was predictive of steatosis and fibrosis in chronic HCV-infected patients. Interestingly, patients with none or mild fibrosis showed serum adiponectin levels similar to those in healthy controls, while hyperadiponectinemia was associated with moderate to severe stages of fibrosis. Hyperadiponectinemia was unlikely sustained by liver production as hepatocytes did not express the protein. ADIPOR1 mRNA, but not ADIPOR2 levels, was reduced in chronic HCV hepatitis. The reduced ADIPOR1 expression was confirmed by immunohistochemistry. CONCLUSIONS: In patients with chronic HCV hepatitis, fibrosis was associated with hyperadiponectinemia. Chronic HCV-infected hepatocytes showed reduced ADIPOR1 expression, suggesting a pattern of adiponectin resistance. PMID- 21539541 TI - Correct nomenclature and recommendations for preserving and cataloguing voucher material and genetic sequences. PMID- 21539540 TI - A bidirectional interface growth model for cranial interosseous suture morphogenesis. AB - Interosseous sutures exhibit highly variable patterns of interdigitation and corrugation. Recent research has identified fundamental molecular mechanisms of suture formation, and computer models have been used to simulate suture morphogenesis. However, the role of bone strain in the development of complex sutures is largely unknown, and measuring suture morphologies beyond the evaluation of fractal dimensions remains a challenge. Here we propose a morphogenetic model of suture formation, which is based on the paradigm of Laplacian interface growth. Computer simulations of suture morphogenesis under various boundary conditions generate a wide variety of synthetic sutural forms. Their morphologies are quantified with a combination of Fourier analysis and principal components analysis, and compared with natural morphological variation in an ontogenetic sample of human interparietal suture lines. Morphometric analyses indicate that natural sutural shapes exhibit a complex distribution in morphospace. The distribution of synthetic sutures closely matches the natural distribution. In both natural and synthetic systems, sutural complexity increases during morphogenesis. Exploration of the parameter space of the simulation system indicates that variation in strain and/or morphogen sensitivity and viscosity of sutural tissue may be key factors in generating the large variability of natural suture complexity. PMID- 21539543 TI - Lipid class dynamics and storage depots in juvenile weakfish Cynoscion regalis and their application to condition assessment. AB - Lipid class dynamics, the pattern of change in the primary form and location of lipid stores and their relationship with standard length (L(S) ), were investigated in collections of young-of-the-year weakfish Cynoscion regalis for the purpose of determining the utility of this analysis as an indication of condition. The separation of total lipids into individual classes and the analysis of potential storage depots revealed the general patterns of lipid class dynamics and energy storage in C. regalis during their period of juvenile estuarine residency. Phospholipid and cholesterol exhibited moderate but variable (8.1-40.0 and 1.3-21.5 mg g(-1) , respectively) concentrations across the entire juvenile period and were the predominant lipid classes in juveniles <100 mm L(S) , while wax ester concentrations were low (c. 1 mg g(-1) ) and exhibited the least amount of variability among lipid classes. Triacylglycerols (TAG) and free fatty acids (FFA) exhibited similar dynamics, with relatively low concentrations (<15 mg g(-1) ) in individuals <=100 mm L(S) . In larger juveniles both TAG and FFA concentrations generally increased rapidly, though there was considerable variability in both measures (0.0-199.7 and 0.0-49.7 mg g(-1) , respectively). Increasing levels of lipids, primarily in the form of TAG, with size indicated an accumulation of energy reserves with growth, thus providing an indication of individual condition for larger juveniles. Separate analysis of liver, viscera and the remaining carcass indicated that liver and viscera did not represent a significant depot of TAG reserves. Analysis of samples derived from whole juvenile C. regalis thus provided an accurate estimate of energy reserves. PMID- 21539544 TI - Alternative life histories in Xiphophorus multilineatus: evidence for different ages at sexual maturity and growth responses in the wild. AB - In order to examine potential trade-offs in alternative life histories of the high-backed pygmy swordtail Xiphophorus multilineatus, otoliths were used from wild-caught males to determine if sneaker males had the advantage of maturing earlier in natural environments. The sneakers matured significantly earlier than courters, but there was no difference among the three courter variants. In addition, analyses suggested that the effect of the pituitary locus on size at sexual maturity and growth rates was a consequence of age at sexual maturity. Finally, one of the courter variants had a significantly different relationship between age and size at sexual maturity than the other variants, suggesting that in this variant, age at sexual maturity may be more closely related to size and therefore may be less plastic in its growth responses. PMID- 21539545 TI - Ontogeny of swimming speed, schooling behaviour and jellyfish avoidance by Japanese anchovy Engraulis japonicus. AB - The ontogeny of swimming speed, schooling behaviour and jellyfish avoidance was studied in hatchery-reared Japanese anchovy Engraulis japonicus to compare its life-history strategy with two other common pelagic fishes, jack mackerel Trachurus japonicus and chub mackerel Scomber japonicus. Cruise swimming speed of E. japonicus increased allometrically from 1.4 to 3.9 standard length (L(S) ) per s (L(S) s(-1) ) from early larval to metamorphosing stage. Burst swimming speed also increased from 6.1 to 28 L(S) s(-1) in these stages. Cruise speed was inferior to that of S. japonicus, as was burst speed to that of T. japonicus. Engraulis japonicus larvae were highly vulnerable to predation by moon jellyfish Aurelia aurita and were readily eaten until they reached 23 mm L(S) , but not at 26 mm L(S) . Schooling behaviour (indicated by parallel swimming) started at c. 17 mm L(S) . Average distance to the nearest neighbour was shorter than values reported in other pelagic fishes. The relatively low predator avoidance capability of E. japonicus may be compensated for by their transparent and thus less conspicuous body, in addition to their early maturation and high fecundity. PMID- 21539546 TI - Morphological, morphometric, meristic and osteological evidence for two species of hake (Actinopterygii: Gadiformes: Merluccius) in Argentinean waters. AB - Morphologically, both classic and landmark-based morphometry and meristic analyses of 241 specimens of Merluccius, along with the re-examination of six paratype specimens of Merluccius hubbsi, the holotype and three paratypes of Merluccius patagonicus and the syntype of Merluccius australis revealed the presence of only two species of Merluccius in Argentinean waters. Internal structures (hyomandibula, urohyal and sagitta otolith) of M. hubbsi were compared to those reported for M. patagonicus and were shown to have identical morphology. Type specimens of M. patagonicus showed a complete overlap in morphometric and meristic characters with M. hubbsi, whereas M. australis had a greater number of second dorsal and anal-fin rays, and more lateral-line scales. In addition, M. australis had a smaller eye and longer snout than M. hubbsi and M. patagonicus. The results indicate that there is no evidence for a third hake species in Argentinean waters. Merluccius patagonicus is a synonym of M. hubbsi. PMID- 21539547 TI - Ultrastructure and osmoregulatory function of the kidney in larvae of the Persian sturgeon Acipenser persicus. AB - The localization of Na(+) , K(+) -ATPase (NKA) and the ultrastructural features of kidney were examined in larvae of the Persian sturgeon Acipenser persicus (L 31-41 mm total length and 182.3-417.3 mg). Investigations were conducted through light and electron microscopy and through immunofluorescence for NKA detection. The kidney nephrons consisted of a large glomerulus and tubules (neck, proximal, distal and collecting), which connected to the ureters. Posteriorly, ureters extended and joined together into a thin-walled ureter terminal sac. Ultrastructurally, the glomerular cells (podocytes) possessed distinctive pedicels that extended to the basal membrane. The proximal tubule (PT) showed two different cells. The cells lining the anterior part of PT possessed apical tall microvilli (c. 2.7 um), a sub-apical tubular system, a basal nucleus and dense granules. Posteriorly in the cells, the sub-apical tubular system and granules were absent and round mitochondria associated with basolateral infoldings were found; the apical microvilli were reduced. Distal and collecting tubular cells showed the typical features of osmoregulatory cells, i.e. well-developed basolateral infoldings associated with numerous mitochondria. No immunofluorescence of NKA was detected in the glomeruli. A weak immunostaining was observed at the basolateral side of the cells lining the neck and PT. A strong immunostaining of NKA was observed in the entire cells of the distal tubules, collecting tubules and in some isolated cells of the ureters. In all immunostained cells, the basolateral region showed a much higher fluorescence and nuclei were immunonegative. In conclusion, the epithelial cells of kidney tubules had morphological and enzymatic features of ionocytes, particularly in the distal and collecting tubules. Thus, the kidney of A. persicus larvae possesses active ion exchange capabilities and, beside its implication in excretion, participates in osmoregulation. PMID- 21539548 TI - Quantification of the maternal-embryonal nutritional relationship of elasmobranchs: case study of wobbegong sharks (genus Orectolobus). AB - The present study used wobbegong sharks (genus Orectolobus) to assess the threshold value proposed by previous research to categorize strict lecithotrophic from incipient histotrophic species. Totals of 236 and 135 ornate wobbegong Orectolobus ornatus and spotted wobbegong Orectolobus maculatus, respectively, were collected from the New South Wales commercial fishery between June 2003 and May 2006. Eight pregnant gulf wobbegong Orectolobus halei were also recorded outside the sampling period for the first time. The three species were reproductively synchronous with a gestation of c. 10-11 months. Embryos started to be macroscopically visible during January and external yolk sacs were fully absorbed by June to July when embryos were c. 200 mm total length (L(T) ). Internal yolk sacs were first observed during April to May when embryos were c. 160 mm L(T) , reached a peak during June and persisted in embryos immediately prior to parturition. The total wet mass from uterine egg to full-term embryos increased by 44-89% and 45-62%, whereas the total organic mass decreased by 32 33% and 26%, for O. ornatus and O. maculatus, respectively, suggesting that these species are strict lecithotrophic yolk-sac viviparous sharks with no maternal nutrient input. A review of the literature identified various issues and suggested that the previously proposed organic mass loss threshold value separating strict lecithotrophic species from incipient histotrophic species might not be appropriate. Instead, it is recommended that a combination of methods (e.g. estimation of organic mass gain or loss between ovarian egg and developed embryo, histology and electron microscopy of the uterus, radio-tracer assay and uterine fluid analysis throughout gestation) is used to discern between strict lecithotrophic and incipient histotrophic species. PMID- 21539549 TI - Early marine migration of European silver eel Anguilla anguilla in northern Norway. AB - To study the migratory behaviour in wild northern European silver eel Anguilla anguilla during sea entry and early marine migration, 32 individuals were tagged with acoustic transmitters and registered at four automatic listening station arrays from the mouth of the north Norwegian River Alta and throughout the Alta Fjord. The A. anguilla entered the fjord during all parts of the tidal cycle and did not seem to utilize the outgoing tidal currents. They migrated mainly during the night, in both the river mouth and the fjord. On average, they spent 2.7 days travelling from the river mouth to the outermost array, 31 km from the river mouth, corresponding to an average migratory speed of 0.5 km h(-1) . The A. anguilla generally migrated in the central part of the fjord and in the uppermost 10-25% of the water column, but with frequent dives to greater depths. Already 4 km after sea entry, A. anguilla were observed diving deeper than 130 m within 20 30 min periods. Hence, this study demonstrated that A. anguilla may perform an active diving behaviour during the early marine migration. The study took place in a pristine area with a minimum of anthropogenic interventions and by individuals from a population still uninfected by the introduced parasite Anguillicoloides crassus. The results may therefore be used as a baseline for future studies of the A. anguilla early marine migration. PMID- 21539550 TI - Assessing the overlap between the diet of a coastal shark and the surrounding prey communities in a sub-tropical embayment. AB - An elasmobranch survey of sub-tropical Hervey Bay, Australia, captured the slit eye shark Loxodon macrorhinus at only one of three sites sampled. The dietary composition of this small shark species was compared to the prey communities within Hervey Bay to test whether prey availability was driving this observation. Dietary analysis of prey groups revealed that teleosts dominated the diet, per cent index of relative importance, % I(RI) (79.5%) and per cent geometric index of importance, % G(II) (52.7%), with shrimp-like invertebrates and cephalopods identified as the most important invertebrate prey groups. Baited remote underwater video (BRUV) used to sample prey communities at each site, demonstrated a highly diverse and significantly different community composition among the sites. There was no significant overlap between the diet of L. macrorhinus and any of the prey communities detected by BRUVs according to one way analysis of similarities and the simplified Morisita index. Habitat electivity analysis revealed affinity of L. macrorhinus for the site with the highest water clarity (Secchi disc depth), opposing that of three other shark species. Overall, the results suggest that the distribution of L. macrorhinus is not driven by prey availability but other factors such as water clarity, predator avoidance or a reduction in interspecies competition. PMID- 21539551 TI - Post-release feeding and growth of hatchery-reared Japanese flounder Paralichthys olivaceus: relevance to stocking effectiveness. AB - The feeding and growth of hatchery-reared (HR) Japanese flounder Paralichthys olivaceus of c. 100 mm total length (L(T) ) released off the coast of Fukushima, Japan, were investigated. From 2 to 15 days after release, the HR P. olivaceus frequently exhibited high empty-stomach frequency (>40%), low stomach-content mass (<1% of body mass), reduced somatic condition from release (c.-10%) and negligible growth. Thereafter, empty-stomach frequency decreased, the stomach content mass of HR fish increased to 2-8% of body mass, the somatic condition recovered and growth rate increased to 0.5-1.5 mm day(-1) . Prey items were initially mysids, shifting thereafter to fishes such as the Japanese anchovy Engraulis japonica, as observed similarly in wild counterparts. The proportion of mysids decreased with time after release irrespective of size at release, indicating the importance of mysids for adaptation to natural food. Recapture rates at age 1 year, derived from fish market surveys, varied greatly among release years (4-11%). The variation in the recapture rates was largely accounted for by the post-release growth rates (r(2) = 0.5), suggesting a relationship between the post-release growth of HR fish and their survival and subsequent stocking effectiveness. PMID- 21539552 TI - Behavioural responses of hatchery-reared and wild cod Gadus morhua to mechano acoustic predator signals. AB - The behavioural responses of wild (predator-experienced) and hatchery-reared (predator-naive) cod Gadus morhua to standardized mechano-acoustic (MA) stimuli were compared in the laboratory. Wild fish responded mainly with freezing and fast-start escapes away from the stimulus, whereas hatchery-reared fish often ignored or approached the stimulus. Wild fish also had stronger responses, turning faster during escapes and reducing activity immediately after the stimulus. Both fish types were less active on a 'risky' bare substratum after the stimulus. The antipredator responses of wild fish were consistent to repeated stimuli, whereas hatchery-reared fish that had generally only encountered harmless stimuli showed more variable responses with lower repeatability. This suggests that experience plays a role in shaping the behavioural response of fishes to MA stimuli. PMID- 21539553 TI - Morphological differences in parr of Atlantic salmon Salmo salar from three regions in Norway. AB - Morphological characters were compared in parr (total length 33-166 mm) of Atlantic salmon Salmo salar sampled from eight wild populations in three regions, three in northern, two in the middle and three in southern Norway, covering a distance of 1700 km (from 70 degrees N to 58 degrees N). On the basis of morphological characters 94.6% of the individuals were correctly classified into the three regions. Discrimination between populations within these three regions also had a high degree of correct classification (89.0-95.8%). Principle component analysis identified largest differences to be in head characters, notably eye diameter and jawbone, with the smallest diameter and head size among the northernmost populations. Fish from the southern rivers had a deeper body form whereas fish from the middle region had larger heads and pectoral fins. This illustrates that S. salar already in the early parr stage has morphological traits, which can be used in discrimination between regions and populations and that these differences are discernible in spite of the volume of escaped farmed fish spawning in Norwegian rivers during the past 30 years. PMID- 21539554 TI - Morphological development of larval cobia Rachycentron canadum and the influence of dietary taurine supplementation. AB - The morphological development of larval cobia Rachycentron canadum from 3 days post hatch (dph) until weaning (27 dph) was examined using S.E.M. Two groups of fish were studied: a control group (CF), reared under standard feeding protocol, and a group in which prey items were enriched with supplemental taurine (4 g l( 1) day(-1) ; TF). TF fish grew faster (P < 0.001), attained greater size (mean +/ s.e. 55.1 +/- 1.5 v. 33.9 +/- 1.0 mm total length) and had better survival (mean +/-s.e. 29.3 +/- 0.4 v. 7.1 +/- 1.2 %) than CF fish. Canonical variance analysis confirmed findings with respect to differences in growth between the treatment groups with separation being explained by two cranial measurements. S.E.M. revealed that 3 dph larvae of R. canadum (in both groups) possess preopercular spines, superficial neuromasts on the head and body, taste buds in the mouth, an olfactory epithelium which takes the form of simple concave depressions, and primordial gill arches. Gill filaments start to form as early as 6 dph and lamellae buds are visible at 8 dph in both groups. In CF fish, the cephalic lateral line system continues its development at 12-14 dph with invagination of both supra- and infraorbital canals. At the same time, a thorn-like or acanthoid crest forms above the eye. At 14 dph, invaginations of the mandibular and preopercular canals are visible and around 22 dph enclosure of all cranial canals nears completion. In CF larvae, however, completely enclosed cranial canals were not observed within the course of the trial, i.e. 27 dph. In TF larvae, grooves of the cephalic lateral line system form 4 days earlier than observed in CF larvae of R. canadum (i.e. at 8 dph), with enclosure commencing at 16 dph, and completed by 27 dph. Along the flanks of 6 dph larvae of either treatment, four to five equally spaced neuromasts delineate the future position of the trunk lateral line. As myomeres are added to the growing larvae, new neuromasts appear such that at 16 dph a neuromast is associated with each myomere. By 27 dph, the trunk lateral line starts to invaginate in CF larvae, while it initiates closure in TF larvae. These findings elucidate important features of the larval development of R. canadum and show that dietary taurine supplementation benefits larval development, growth and survival in this species. Moreover, they suggest a conditional requirement for taurine in larval R. canadum. PMID- 21539555 TI - The importance of incorporating age and sex when backcalculating length in bullhead Cottus gobio. AB - The present study backcalculated body length for a data set of a bullhead Cottus gobio population located at different sampling sites in a river network. Model comparison between various growth models, which included successively new parameters, showed the effect and importance of taking sex, age and the location in the river network into account. The data sets obtained by backcalculation were fitted by the von Bertalanffy growth function, which revealed the effect of the backcalculation formula on the estimation of the von Bertalanffy growth parameters. Fitting results and parameter estimates showed again the importance of incorporating age and sex when backcalculating body length in the C. gobio population studied. PMID- 21539556 TI - Proteomic analysis of inviable salmonid hybrids between female masu salmon Oncorhynchus masou masou and male rainbow trout Oncorhynchus mykiss during early embryogenesis. AB - Early embryos of inviable hybrids between female masu salmon Oncorhynchus masou masou and male rainbow trout Oncorhynchus mykiss at 9, 12, 15 and 20 days after fertilization were examined for protein expression profiles. A total of 44 proteins, mostly down-regulated products of house-keeping genes and those involved in nucleic acid metabolism or chromatin replication, were identified in hybrid embryos by mass spectrometry analysis and protein database searching. The identified down-regulated proteins may be responsible for the inviability in the hybrids. PMID- 21539557 TI - The influence of freshwater inflows on spawning success and early growth of an estuarine resident fish species, Acanthopagrus butcheri. AB - The influence of freshwater inflows and salinity on spawning success of black bream Acanthopagrus butcheri (Sparidae) was investigated over 2 years in a small estuary on the east coast of Tasmania, Australia. The individual spawning seasons experienced quite different freshwater inflows; 2004-2005 was characterized by low flows throughout the season whereas during 2005-2006 there were three relatively large discharge events in the first part of the season. Macroscopic gonad staging of adults was used to define the spawning season and daily increment analysis of otoliths from recently settled recruits was used to backcalculate spawning dates. Gonad staging indicated that adults were in spawning condition over a 3 to 4 month period during spring and summer. The timing and duration of successful spawning, however, differed markedly between years and was linked to the timing of freshwater inflows and salinity conditions, with successful spawning occurring during periods of low freshwater discharge and when salinities in the upper estuary were above c. 15. Growth rates of the recently settled recruits did not differ between years, nor did the timing of spawning within the season influence growth rates. While the latter finding was unexpected, especially given within season temperature variability, these results imply that by the onset of winter earlier spawned fish would be larger than later spawned individuals, potentially conferring advantages for survival and competition for food. Climate change predictions for eastern Tasmania indicate a decrease in river flows in spring and an increase during summer, potentially increasing environmental variability between and within years, with implications for spawning success and subsequent recruitment. PMID- 21539558 TI - Trophic ecology of Atlantic bluefin tuna Thunnus thynnus larvae. AB - Feeding intensity, diet composition, selectivity, energy ingestion and dietary niche breadth of larval Atlantic bluefin tuna Thunnus thynnus were studied on the eastern (Mediterranean) spawning grounds of the species. Larval T. thynnus were collected in the Balearic Archipelago (north-west Mediterranean Sea) during 2004 and 2005 using surveys specific for larval scombrids. Larvae between 2.6 and 8.7 mm standard length (L(S) ) are diurnal feeders, and 94% of the guts collected during daylight hours were full. The mean +/-s.d. number of prey per gut was 7.1 +/- 5.7, with mean +/-s.d. ranging from 3.0 +/- 1.6 in the smallest T. thynnus larvae to 11.1 +/- 5.8 in 5.0-6.0 mm L(S) larvae. Up to 21 prey were found in a single larval gut (5.0-6.0 mm L(S) ) at the end of the day. Larvae progressively selected larger prey and exhibited increased carbon content concurrent with preflexion development of feeding and locomotory structures. Larvae of 5.0-6.0 mm L(S) exhibited positive selection of cladocerans over other prey (Chesson's index), whereas copepod nauplii dominated the diets of earlier stages. The dietary niche breadth measured increased initially but decreased at c. 5.5 mm L(S) . Appendicularians were found in the diet of larger larval sizes, but no piscivory was observed. Results are discussed in light of the sparse existing data for larval T. thynnus and other larval tuna species. PMID- 21539559 TI - Feeding ecology of King George whiting Sillaginodes punctatus (Perciformes) recruits in seagrass and unvegetated habitats. Does diet reflect habitat utilization? AB - This study investigated the feeding ecology of King George whiting Sillaginodes punctatus recruits to determine how diet composition varies between habitat types (seagrass and unvegetated habitats), and between sites separated by distance. Broad-scale sampling of seagrass and unvegetated habitats at nine sites in Port Phillip Bay (Australia) indicated the diet composition varied more by distance into the bay than by habitat. Near the entrance to the bay the diet was dominated by harpacticoids and gammarid amphipods, in the middle reaches of the bay the diet was completely dominated by harpacticoids, while at sites furthest into the bay, mysids and crab zoea were also important. Abundances of prey in guts was significantly higher between 1000 and 2200 hours compared with other times, indicating diurnal feeding. Laboratory determined gut evacuation rate (based on an exponential model) was estimated to be -0.54. Daily rations were highly variable among sites and habitat types. Sillaginodes punctatus recruits consumed much higher quantities of prey on unvegetated habitat than seagrass habitat at some middle reach sites; with prey consumption of harpacticoid copepods on unvegetated habitat approaching 3000 individuals per day at one site. The results of this study provide insight into why habitat associations of S. punctatus recruits within mosaics of seagrass and unvegetated habitat show high spatial variation. PMID- 21539560 TI - First record of Lagocephalus laevigatus (Tetraodontiformes, Tetraodontidae) from Galician waters (north-west Spain), a northernmost occurrence in the north-east Atlantic Ocean. AB - The first record of the smooth puffer Lagocephalus laevigatus from Galician waters (north-west Spain) is reported. Three possible mechanisms of introduction of the specimen are considered: natural displacement, the aquarist trade and transport in ballast water. PMID- 21539561 TI - Low cytochrome b variation in bream Abramis brama. AB - Variability in cytochrome b (cytb) in European populations of bream Abramis brama was assessed. The cytb gene was found to be strongly conserved in A. brama relative to other cyprinid taxa. This limits the usefulness of this marker in examining geographical genetic structure in this species and raises interesting questions as to the recent evolutionary history of the species. PMID- 21539562 TI - The ontogenetic development of egg-spots in the haplochromine cichlid fish Astatotilapia burtoni. AB - A series of Astatotilapia burtoni photographs were used to investigate the ontogenetic development of male egg-spots, a putative evolutionary key innovation of haplochromine cichlids. Four stages of egg-spot development were defined and all males had developed true egg-spots (stage 4) before reaching a standard length of 25 mm. Raising condition only slightly influenced the timing of the first appearance of true egg-spots. PMID- 21539565 TI - AnyStitch: a tool for combining electron backscatter diffraction data sets. AB - Recent advances in electron backscatter diffraction equipment and software have permitted increased data acquisition rates on the order of hundreds of points per second with additional increases in the foreseeable future likely. This increase in speed allows users to collect data from statistically significant areas of samples by combining beam-control scans and automated stage movements. To facilitate data analysis, however, the individual tiles must be combined, or stitched, into a single data set. In this paper, we describe a matlab((r)) (The Mathworks, Inc., Natick, MA, USA) program to facilitate stitching of electron backscatter diffraction data. The method offers users a wide range of controls for tile placement including independent overlaps for horizontal and vertical tiles and also includes a parameter to account for systematic stage positioning errors or improperly calibrated scan rotation. The code can stitch data collected on either square or hexagonal grids and contains a function to reduce the resolution of square grid data if the resulting file is too large (or has too many grains) to be opened by the analysis software. The software was primarily written to work with TSL((r)) OIMTM data sets and includes a function to quickly read compressed *.osc files into a variable in the matlab((r)) workspace as opposed to using slower, text-reading functions. The output file is in *.ang format and can be opened directly by TSL((r)) OIMTM Analysis software. A set of functions to facilitate stitching of text-based *.ctf files produced by Oxford Instruments HKL systems are also included. Finally, the code can also be used to combine *.tif images to produce a montage. The source code, a graphical user interface and a compiled version of the software was made available in the online version of this paper. PMID- 21539566 TI - The future of CT imaging (... as I see it!). PMID- 21539567 TI - Structural characteristics of the soft palate and meatus nasopharyngeus in brachycephalic and non-brachycephalic dogs analysed by CT. AB - OBJECTIVES: The goal of this study was to compare the dimensions of the soft palate and cross-sectional area of the meatus nasopharyngeus in non brachycephalic dogs and brachycephalic dogs with different degrees of severity of brachycephalic airway syndrome using computed tomography. METHODS: A total of 26 brachycephalic dogs that had at least one of four major symptoms of snoring, inspiratory effort, stress or exercise intolerance, and syncope were included in this prospective study. The dogs were grouped by the frequency of different clinical signs into absent/minimal brachycephalic airway syndrome and severe brachycephalic airway syndrome groups. Five non-brachycephalic dogs were studied as control animals. All dogs underwent pharyngeal area computed tomography. Seven measurements were made on the transverse and midsagittal reconstructions. All parameters were compared between controls, absent/minimal and severe brachycephalic airway syndrome groups. RESULTS: The dogs with severe brachycephalic airway syndrome had significantly thicker soft palates compared to absent/minimal brachycephalic airway syndrome (P<0.05) and control (P<0.05) dogs. There were no significant differences among groups with regard to the length of the soft palate or the cross-sectional area of the airway at the level of the meatus nasopharyngeus. CLINICAL RELEVANCE: These results support the thickening of the soft palate as a component of severe brachycephalic airway syndrome. Further studies are required to confirm the association between this anatomical characteristic and functional impairment. PMID- 21539568 TI - Lifestyle risk factors for progesterone-related diabetes mellitus in elkhounds - a case-control study. AB - OBJECTIVES: This study aims to investigate lifestyle risk factors for the development of progesterone-related diabetes mellitus in female elkhounds. METHODS: Owners of 48 diabetic elkhounds and 58 healthy elkhounds were interviewed by phone concerning lifetime diet and exercise routines. A logistic model was developed to assess the impact of diet and exercise on diabetes diagnosis. The agreement between lifetime owner-perceived body condition score (BCS) and veterinary-perceived BCS at inclusion was estimated in healthy control dogs using the Kappa statistic. RESULTS: The model showed that diabetic dogs had increased odds for having been overweight (before diagnosis) compared with controls (OR=2.8, 95% confidence interval 1.1-7.5, P=0.034). Although feeding other food than commercial dog feed was associated with diabetes case status, the effect was not significant after BCS was entered into the model. The overall agreement between lifetime owner- and veterinary-perceived BCS at inclusion in the study was 75% and had a Kappa statistic of 0.16 (P=0.12). CLINICAL SIGNIFICANCE: This study indicates that a high owner-perceived lifetime BCS is associated with progesterone-related diabetes in elkhounds. PMID- 21539569 TI - Echocardiographic values in clinically healthy adult dogue de Bordeaux dogs. AB - OBJECTIVES: To assess the influence of body surface area, age and gender on echocardiographic parameters and to establish echocardiographic reference values for dogue de Bordeaux dogs. METHODS: Thirty-nine healthy dogue de Bordeaux dogs of both sexes, older than one year, were recruited and 31 of these were included in the study. The classic linear regression model proved to be the best way to analyse the data. The reference limits of the echocardiographic measurements were calculated using the regression equations. The difference between the mean values of body surface area in both gender groups was evaluated by using one-way ANOVA. RESULTS: A significant correlation was seen between several echocardiographic parameters and body surface area or body surface area and age, and high coefficients of determination (R2) were found. No effect of gender was detected on echocardiographic variables, except for the thickness of the left ventricular posterior wall at end diastole. CLINICAL SIGNIFICANCE: The echocardiographic parameters related to body surface area, in the absence of correlation with other independent variables (gender and age) should be interpreted with caution because their variation could be significant for the presence of heart disease. The proposed statistical model allows estimation of echocardiographic parameters in dogue de Bordeaux dogs with different body surface areas and ages. PMID- 21539570 TI - The association between the signalment, common causes of canine otitis externa and pathogens. AB - OBJECTIVE: To determine whether associations exist between pathogens, allergies, conformational abnormalities, endocrinopathies and signalment in canine otitis externa (OE). METHODS: Medical records of 149 dogs which met predetermined inclusion criteria were evaluated retrospectively. Correlations between pathogens and the presence of allergy, endocrinopathy, conformational abnormalities and signalment were evaluated statistically. RESULTS: The shar-pei, German shepherd and cocker spaniel breeds were over-represented compared with the hospital's breed distribution (P<0.001). German shepherd dogs and cocker spaniels were statistically more prone to infection with rod-shaped organisms and Labrador retrievers less than other breeds (P=0.034). Almost all dogs that were older than five years when diagnosed with OE had cocci (P=0.01) and also had higher levels of rods (P=0.028). The incidence of rods was higher in endocrinopathies (P=0.004), while that of Malassezia spp. tended to be higher in allergies (P=0.098). There were no statistically significant differences among the groups for all the other parameters examined. CLINICAL SIGNIFICANCE: OE infection is usually not influenced by primary causes or predisposing factors. Endocrinopathies may be followed by a more severe otitis, however. OE may be more severe when it affects older dogs. PMID- 21539571 TI - Serum cardiac troponin I in dogs with primary immune-mediated haemolytic anaemia. AB - OBJECTIVES: The assessment of serum cardiac troponin I concentrations in dogs with a range of nonprimary cardiac illnesses has revealed that cardiac myocyte damage is commonplace in many canine diseases. Whilst it is well established that dogs with fatal immune-mediated haemolytic anaemia frequently have cardiac pathology based on post-mortem examinations, there is limited information on the incidence of cardiac myocyte damage in this population of dogs. METHODS: Serum cardiac troponin I concentrations were measured in 11 healthy dogs, 27 dogs with primary haemolytic anaemia and 49 hospitalised dogs without primary cardiac or haematological disorders. RESULTS: Dogs with primary haemolytic anaemia have higher serum concentrations of cardiac troponin I than hospitalised ill dogs (P<0.005) and healthy dogs (P<0.01). Using a cut-off of less than 0.1 ng/mL, 20 of 27 dogs with primary haemolytic anaemia had increased serum cardiac troponin I concentrations, which was a significantly higher proportion compared to the hospitalised ill dogs (P<0.001, 16 out of 49 dogs) and healthy dogs (P<0.05, 3 out of 11 dogs). CLINICAL SIGNIFICANCE: Dogs with primary haemolytic anaemia have a higher incidence of subclinical myocyte damage than healthy dogs or dogs with non-haematological or primary cardiac illnesses. The prognostic significance of increased serum cardiac troponin I concentrations in dogs with primary haemolytic anaemia merits further investigation. PMID- 21539572 TI - Ectopic cervical thymic carcinoma in a dog. AB - A 10-year-old male German shepherd dog was referred for evaluation of a cranial cervical mass causing progressively worsening respiratory distress. A fine-needle aspirate of the mass was obtained and the cytology results were compatible with a carcinoma. The dog underwent chemotherapy without clinical improvement and was ultimately euthanased because of clinical deterioration. At post-mortem examination, an irregular multi-lobated mass in the cranial cervical region was observed causing ventro-lateral tracheal deviation. Histopathology and immunohistochemistry revealed a mixed population of CD3 lymphocytes and macrophages in an exuberant fibrous stroma, associated with dispersed cytokeratin positive epithelial cells with marked eosinophilic cytoplasm. Some of the epithelial cells were arranged in concentric clusters that were interpreted as Hassall's corpuscles. Histopathological examination of the thyroid gland revealed several neoplastic emboli composed of epithelial cells similar to those observed in the cervical mass. To the authors' knowledge, this is the first report of an ectopic cervical thymic carcinoma in a dog. PMID- 21539573 TI - Reversible pulmonary hypertension in a cat. AB - A 13-year-old, neutered female domestic shorthair cat was presented for sudden respiratory distress following palliative radiotherapy and the combined administration of a single dose of carboplatin for the treatment of recurrent fibrosarcoma. Clinical and radiographic findings were suggestive of pleural effusion. Echocardiography revealed marked right-sided cardiac enlargement associated with tricuspid regurgitation and Doppler evidence of pulmonary hypertension. After 25 days of treatment for congestive heart failure and suspected pulmonary thromboembolism, clinical signs and echocardiographic and Doppler evidence of right-sided cardiac enlargement and pulmonary hypertension had completely resolved. To the best of the authors' knowledge, this is the first report of reversible pulmonary hypertension, likely secondary to pulmonary thromboembolism, in a cat. PMID- 21539574 TI - Putting plant resistance traits on the map: a test of the idea that plants are better defended at lower latitudes. AB - * It has long been believed that plant species from the tropics have higher levels of traits associated with resistance to herbivores than do species from higher latitudes. A meta-analysis recently showed that the published literature does not support this theory. However, the idea has never been tested using data gathered with consistent methods from a wide range of latitudes. * We quantified the relationship between latitude and a broad range of chemical and physical traits across 301 species from 75 sites world-wide. * Six putative resistance traits, including tannins, the concentration of lipids (an indicator of oils, waxes and resins), and leaf toughness were greater in high-latitude species. Six traits, including cyanide production and the presence of spines, were unrelated to latitude. Only ash content (an indicator of inorganic substances such as calcium oxalates and phytoliths) and the properties of species with delayed greening were higher in the tropics. * Our results do not support the hypothesis that tropical plants have higher levels of resistance traits than do plants from higher latitudes. If anything, plants have higher resistance toward the poles. The greater resistance traits of high-latitude species might be explained by the greater cost of losing a given amount of leaf tissue in low-productivity environments. PMID- 21539575 TI - Presence/absence, differential expression and sequence polymorphisms between PiAVR2 and PiAVR2-like in Phytophthora infestans determine virulence on R2 plants. AB - * A detailed molecular understanding of how oomycete plant pathogens evade disease resistance is essential to inform the deployment of durable resistance (R) genes. * Map-based cloning, transient expression in planta, pathogen transformation and DNA sequence variation across diverse isolates were used to identify and characterize PiAVR2 from potato late blight pathogen Phytophthora infestans. * PiAVR2 is an RXLR-EER effector that is up-regulated during infection, accumulates at the site of haustoria formation, and is recognized inside host cells by potato protein R2. Expression of PiAVR2 in a virulent P. infestans isolate conveys a gain-of-avirulence phenotype, indicating that this is a dominant gene triggering R2-dependent disease resistance. PiAVR2 presence/absence polymorphisms and differential transcription explain virulence on R2 plants. Isolates infecting R2 plants express PiAVR2-like, which evades recognition by R2. PiAVR2 and PiAVR2-like differ in 13 amino acids, eight of which are in the C-terminal effector domain; one or more of these determines recognition by R2. Nevertheless, few polymorphisms were observed within each gene in pathogen isolates, suggesting limited selection pressure for change within PiAVR2 and PiAVR2-like. * Our results direct a search for R genes recognizing PiAVR2-like, which, deployed with R2, may exert strong selection pressure against the P. infestans population. PMID- 21539576 TI - Attentional capture by size singletons is determined by top-down search goals. AB - The question whether attentional capture by salient visual stimuli is driven by bottom-up salience or is contingent on top-down task set is still under dispute. We show that the ability of size singletons to capture attention is determined by current search goals. Participants searched for small or large target singletons among medium-size distractors. Attentional capture by small or large size singleton cues that preceded target search displays was reflected by spatial cueing effects and N2pc components. These effects were observed only when these cues matched the current target-defining feature, but not for physically identical but mismatching cues. Results demonstrate that attentional capture by size singletons is not driven by bottom-up salience, but is controlled by feature specific task settings. PMID- 21539577 TI - The effect of cancellous autograft and novel plate design on radiographic healing and postoperative complications in tibial tuberosity advancement for cranial cruciate-deficient canine stifles. AB - OBJECTIVE: To assess the effect of autogenous cancellous bone graft (autograft) and novel plate use on radiographic healing and complications in tibial tuberosity advancement (TTA) for treatment of cranial cruciate ligament (CrCL) deficient stifles in dogs. STUDY DESIGN: Prospective clinical study. ANIMALS: Consecutive dogs (n=125) with unilateral CrCL-deficient stifles. METHODS: Four treatment groups: CPG, conventional plate with autograft; CPNG, conventional plate without autograft; NPG, novel plate with autograft; NPNG, novel plate without autograft were studied. Radiographs from 60 dogs were scored for healing at 6 and 10 weeks postoperatively; all 125 dogs were assessed for radiographic complications. Variables evaluated for relationship with healing scores and radiographic complications were age, weight, sex, cage and plate size, implant type, and graft use. RESULTS: Dogs with autograft had overall higher healing scores at 6 and 10 weeks. Radiographic complications occurred in 13 dogs (12 minor, 1 major), and were not influenced by graft or novel plate use. CONCLUSION: Autograft increases healing scores, but was not found to have a significant impact on the rate of complications in TTA. The novel plate was not found to have healing scores or radiographic complication rates significantly different from the conventional plate design. PMID- 21539578 TI - In vitro biomechanical comparison of dynamic compression plates with a rough contact surface and a polished contact surface for fixation of osteotomized equine third metacarpal bones. AB - OBJECTIVES: To compare the number of cycles to failure of 4.5 mm broad dynamic compression plates (DCP), 4.5 mm broad limited-contact dynamic compression plates (4.5-LC-DCP), and 5.5 mm broad limited-contact dynamic compression plates (5.5-LC DCP) having a rough (denoted by a prefix R-) versus a standard smooth contact surface for the fixation of osteotomized equine 3rd metacarpal (MC3) bones. STUDY DESIGN: Experimental. ANIMAL POPULATION: Fifteen pairs of adult equine cadaveric MC3 bones. METHODS: Fifteen pairs of equine MC3 were divided into 3 test groups (5 pairs each) for comparison of (1) R-DCP fixation with DCP fixation, (2) R-4.5 LC-DCP fixation with 4.5-LC-DCP fixation, and (3) R-5.5-LC-DCP fixation with 5.5 LC-DCP fixation to repair osteotomized equine MC3 bones under palmarodorsal 4 point bending cyclic fatigue testing. For each group an 8-hole plate with rough contact surface was applied to the dorsal surface of one randomly selected bone from each pair and a corresponding 8-hole plate with smooth contact surface was applied dorsally to the contralateral bone from each pair. All plates and screws were applied using standard ASIF techniques. All MC3 bones had mid-diaphyseal osteotomies. Mean number of cycles to failure for each method were compared using a paired t-test within each group. Significance was set at P < .05. RESULTS: Mean cycles to failure +/- standard deviation was significantly greater for the R-DCP fixation (230,025 +/- 23,129) compared with the DCP fixation (103,451 +/- 14,556), for the R-4.5-LC-DCP fixation (99,237 +/- 14,390) compared with the 4.5 LC-DCP fixation (46,464 +/- 6325) and for the R-5.5-LC-DCP fixation (65,113 +/- 7796) compared with the 5.5-LC-DCP fixation (34,224 +/- 3835). CONCLUSION: For the fixation of osteotomized MC3 bones, the constructs with plates having rough contact surface were superior to the corresponding constructs with plates having standard smooth contact surfaces in resisting cyclic fatigue under palmarodorsal 4-point bending. PMID- 21539579 TI - Analysis of suture anchor eyelet position on suture failure load. AB - OBJECTIVE: To compare mechanical performance of 2 orientations of the 5 mm Corkscrew(r) suture anchor with #5 Fiberwire(r) . STUDY DESIGN: In vitro biomechanical study. SAMPLE POPULATION: Suture anchor-suture constructs (n=40). METHODS: Acute and cyclic tensile loads were applied to suture threaded through eyelets of 40 anchors perpendicular to the long axis of the anchor. Eyelets were positioned so that the suture pull was in line with (anchor rotation angle of 0 degrees [ARA 0]) or 90 degrees (ARA 90) to the eyelet plane. Load at failure, stiffness, and cycles to failure were determined. RESULTS: All constructs failed by suture breakage at the eyelet. Mean load at failure was significantly higher in the ARA 90 group (634 +/- 93 N) compared with the ARA 0 group (495 +/- 52 N; P=.0015). No significant difference was found between groups for mean number of cycles to failure (270 +/- 177 versus 178 +/- 109; P=.2166) and stiffness (50 +/- 4 versus 48 +/- 5 N/mm; P=.3141). CONCLUSIONS: The Corkscrew(r) 5 mm suture anchor with Fiberwire(r) suture fails via suture breakage at the eyelet under higher acute loads if the suture is loaded at an angle of 90 degrees compared with 0 degrees with respect to the plane of the eyelet. PMID- 21539580 TI - Surgical treatment of disk-associated wobbler syndrome by a distractable vertebral titanium cage in seven dogs. AB - OBJECTIVE: To evaluate a distractable titanium cage for the treatment of disk associated wobbler syndrome (DAWS). STUDY DESIGN: Prospective study. ANIMALS: Dogs (n = 7) with DAWS. METHODS: After total discectomy of C5-C6 and C6-C7, the median part of the vertebral body of C6 was removed with preservation of the lateral walls and dorsal cortex. The removed cancellous bone was collected. The implant was placed in the bony defect of C6. After placement, the titanium cage was distracted and affixed by 4 screws. Finally, the implant was filled and covered with cancellous bone. Dogs had follow-up examinations at 1, 3, 6, 12, and 24 months. Six months after surgery, cervical radiographs and computed tomography (CT) were performed. RESULTS: Although no intraoperative complications occurred, correct placement of the cage was technically challenging. Revision surgery was necessary in 2 dogs because of implant loosening and aggravation of vertebral tilting. All dogs improved after discharge from the hospital. In 1 dog, recurrence of clinical signs caused by articular facet proliferation at an adjacent intervertebral disk space occurred. Radiographs at 6 months demonstrated cage subsidence in 4 dogs. In all dogs, CT was suggestive for fusion of the bone graft with the vertebral body. CONCLUSIONS: Although results are promising, technical adaptations will be necessary to make this specific surgical technique, designed for humans, suitable for routine use in dogs. PMID- 21539581 TI - Pulmonary gas exchange and plasma lactate in horses with gastrointestinal disease undergoing emergency exploratory laparotomy: a comparison with an elective surgery horse population. AB - OBJECTIVE: To characterize pulmonary gas exchange and arterial lactate in horses with gastrointestinal disease undergoing anesthesia, compared with elective surgical horses, and to correlate these variables with postoperative complications and mortality. STUDY DESIGN: Prospective clinical study. ANIMALS: Horses undergoing emergency laparotomy for acute intestinal disease (n = 50) and healthy horses undergoing elective surgery in dorsal recumbency (n = 20). METHODS: Arterial blood gas analysis was performed at predetermined intervals on horses undergoing a standardized anesthetic protocol. Alveolar-arterial oxygen gradient was calculated. Predictive factors for postoperative complications and death in colic horses were determined. RESULTS: Arterial oxygen tension (P(a) O(2)) varied widely among horses in both groups. P(a) O(2) significantly increased in the colic group after exteriorization of the ascending colon. P(a) O(2) and alveolar-arterial oxygen gradient were not significantly different between groups, and neither were correlated with horse outcome. Arterial lactate in recovery >= 5 mmol/L was associated with a 2.25 times greater relative risk of complications and lactate >= 7 mmol/L was associated with a 10.5 times higher relative risk of death. CONCLUSION: Colic horses in this population were not more likely to be hypoxemic than elective horses, nor was gas exchange impaired to a greater degree in colic horses relative to controls. Arterial lactate sampled immediately after anesthetic recovery was predictive for postoperative complications and death. PMID- 21539582 TI - Distal gut microbiota of adolescent children is different from that of adults. AB - Human intestinal microbiota plays a number of important roles in human health and is also implicated in several gastrointestinal disorders. Although the diversity of human gut microbiota in adults and in young children has been examined, few reports of microbiota composition are available for adolescents. In this work, we used Microbiota Array for high-throughput analysis of distal gut microbiota in adolescent children 11-18 years of age. Samples obtained from healthy adults were used for comparison. Adolescent and adult groups could be separated in the principal components analysis space based on the relative species abundance of their distal gut microbiota. All samples were dominated by class Clostridia. A core microbiome of 46 species that were detected in all examined samples was established; members of genera Ruminococcus, Faecalibacterium, and Roseburia were well represented among core species. Comparison of intestinal microbiota composition between adolescents and adults revealed a statistically significantly higher abundance of genera Bifidobacterium and Clostridium among adolescent samples. The number of detected species was similar between sample groups, indicating that it was the relative abundances of the genera and not the presence or absence of a specific genus that differentiated adolescent and adult samples. In summary, contrary to the current belief, this study suggests that the gut microbiome of adolescent children is different from that of adults. PMID- 21539583 TI - The Pseudomonas quinolone signal (PQS), and its precursor HHQ, modulate interspecies and interkingdom behaviour. AB - The Pseudomonas quinolone signal (PQS), and its precursor 2-heptyl-4-quinolone (HHQ), play a key role in coordinating virulence in the important cystic fibrosis pathogen Pseudomonas aeruginosa. The discovery of HHQ analogues in Burkholderia and other microorganisms led us to investigate the possibility that these compounds can influence interspecies behaviour. We found that surface-associated phenotypes were repressed in Gram-positive and Gram-negative bacteria as well as in pathogenic yeast in response to PQS and HHQ. Motility was repressed in a broad range of bacteria, while biofilm formation in Bacillus subtilis and Candida albicans was repressed in the presence of HHQ, though initial adhesion was unaffected. Furthermore, HHQ exhibited potent bacteriostatic activity against several Gram-negative bacteria, including pathogenic Vibrio vulnificus. Structure function analysis using synthetic analogues provided an insight into the molecular properties that underpin the ability of these compounds to influence microbial behaviour, revealing the alkyl chain to be fundamental. Defining the influence of these molecules on microbial-eukaryotic-host interactions will facilitate future therapeutic strategies which seek to combat microorganisms that are recalcitrant to conventional antimicrobial agents. PMID- 21539584 TI - Polyketide synthase pathways identified from a metagenomic library are derived from soil Acidobacteria. AB - Polyketides are structurally diverse secondary metabolites, many of which have antibiotic or anticancer activity. Type I modular polyketide synthase (PKS) genes are typically large and encode repeating enzymatic domains that elongate and modify the nascent polyketide chain. A fosmid metagenomic library constructed from an agricultural soil was arrayed and the macroarray was screened for the presence of conserved ketosynthase [beta-ketoacyl synthase (KS)] domains, enzymatic domains present in PKSs. Thirty-four clones containing KS domains were identified by Southern hybridization. Many of the KS domains contained within metagenomic clones shared significant similarity to PKS or nonribosomal peptide synthesis genes from members of the Cyanobacteria or the Proteobacteria phyla. However, analysis of complete clone insert sequences indicated that the blast analysis for KS domains did not reflect the true phylogenetic origin of many of these metagenomic clones that had a %G+C content and significant sequence similarity to genes from members of the phylum Acidobacteria. This conclusion of an Acidobacteria origin for several clones was further supported by evidence that cultured soil Acidobacteria from different subdivisions have genetic loci closely related to PKS domains contained within metagenomic clones, suggesting that Acidobacteria may be a source of novel polyketides. This study also demonstrates the utility of combining data from culture-dependent and -independent investigations in expanding our collective knowledge of microbial genomic diversity. PMID- 21539585 TI - Saprotrophic basidiomycete mycelia and their interspecific interactions affect the spatial distribution of extracellular enzymes in soil. AB - Saprotrophic cord-forming basidiomycetes are important decomposers of lignocellulosic substrates in soil. The production of extracellular hydrolytic enzymes was studied during the growth of two saprotrophic basidiomycetes, Hypholoma fasciculare and Phanerochaete velutina, across the surface of nonsterile soil microcosms, along with the effects of these basidiomycetes on fungi and bacteria within the soil. Higher activities of alpha-glucosidase, beta glucosidase, cellobiohydrolase, beta-xylosidase, phosphomonoesterase and phosphodiesterase, but not of arylsulphatase, were recorded beneath the mycelia. Despite the fact that H. fasciculare, with exploitative hyphal growth, produced much denser hyphal cover on the soil surface than P. velutina, with explorative growth, both fungi produced similar amounts of extracellular enzymes. In the areas where the mycelia of H. fasciculare and P. velutina interacted, the activities of N-acetylglucosaminidase, alpha-glucosidase and phosphomonoesterase, the enzymes potentially involved in hyphal cell wall damage, and the utilization of compounds released from damaged hyphae of interacting fungi, were particularly increased. No significant differences in fungal biomass were observed between basidiomycete-colonized and noncolonized soil, but bacterial biomass was reduced in soil with H. fasciculare. The increases in the activities of beta-xylosidase, beta-glucosidase, phosphomonoesterase and cellobiohydrolase with increasing fungal:bacterial biomass ratio indicate the positive effects of fungal enzymes on nutrient release and bacterial abundance, which is reflected in the positive correlation of bacterial and fungal biomass content. PMID- 21539586 TI - Review article: Drug-induced liver injury--its pathophysiology and evolving diagnostic tools. AB - BACKGROUND: Drug-induced liver injury (DILI) is a significant cause of morbidity and mortality accounting for at least 13% of acute liver failure cases in the US. It is the leading cause of acute liver failure among patients referred for liver transplantation and the most common reason that drugs in development do not obtain FDA approval. The incidence of DILI has been reported to be one in 10,000 to one in 100,000 patients; however, the actual incidence is probably higher due in part to the difficulty of diagnosis. AIM: To present a review of the current literature on DILI with a focus on its pathophysiology and evolving diagnostic modalities. METHODS: A PubMed literature search was conducted using the terms 'drug induced liver injury', 'pathophysiology', 'causality', 'diagnosis', 'toxicogenomics' and 'pharmacogenetics'. RESULTS: Drug-induced liver injury is an area of ongoing research. From the time it was first recognised, our understanding of the pathophysiology, its classification, diagnosis and reporting by established national networks continues to challenge and evolve. Metabonomics, pharmacogenetics, proteomics and transcriptomics are more recent areas of study that have been applied to further the understanding of DILI. CONCLUSIONS: Despite recent advances in our understanding of drug-induced liver injury, many aspects of its pathophysiology and clinical impact remain unclear. In addition, genomic based studies are evolving concepts, which undoubtedly continue to contribute to our understanding of the underlying mechanisms of drug-induced liver injury. PMID- 21539587 TI - Reflux parameters as modified by EsophyX or laparoscopic fundoplication in refractory GERD. AB - BACKGROUND: EsophyX is a novel transoral incisionless fundoplication device developed to mimic surgical fundoplication. EsophyX fundoplication improves acid reflux parameters in proton pump inhibitor (PPI)-responsive GERD patients but its efficacy in refractory GERD has been scarcely studied. AIM: To assess reflux parameters before and after EsophyX or laparoscopic fundoplication and their relationship with symptoms in refractory GERD. METHODS: In an open-label study, we enrolled prospectively patients with heartburn/regurgitation persisting despite high-dose PPI therapy. Impedance-pH monitoring was performed on PPI therapy before intervention and off PPI therapy 3 months after intervention. RESULTS: Ten patients chose to undergo EsophyX (EndoGastric Solutions, Redmond, WA, USA) fundoplication while ten chose laparoscopic fundoplication, and the baseline characteristics were comparable. Distal and proximal refluxes were significantly reduced post-operatively in the surgical but not in the endoscopic group and the median values were significantly lower in the former than in the latter. The oesophageal acid exposure time was normal in 50% of cases after EsophyX and in 100% of cases after surgery (P=0.033); the number of distal refluxes was normal in 20% and 90% of cases (P=0.005) and the number of proximal refluxes was normal in 40% and 100% of cases (P=0.011), respectively. A positive persisting symptom-reflux association was found post-operatively in 6/10 patients in the EsophyX group and in 0/10 patients in the surgical group (P=0.011). CONCLUSIONS: In patients with refractory GERD, EsophyX fundoplication is significantly less effective than laparoscopic fundoplication in improving reflux parameters and accordingly, in inducing symptom remission. PMID- 21539588 TI - Review article: Causative factors and the clinical management of patients with Crohn's disease who lose response to anti-TNF-alpha therapy. AB - BACKGROUND: The addition of antitumour necrosis factor-alpha (TNF-alpha) agents to the therapeutic armamentarium against Crohn's disease has been a revolution in its management. However, approximately 25 to 40% of patients who initially benefit from anti-TNF-alpha treatment develop intolerable adverse events or lose their response during maintenance therapy. AIM: To summarise the current knowledge on the mechanisms underlying loss of response in these patients and the therapeutic strategies available to counteract this clinical challenge. METHOD: A literature search using PubMed, MedLine and Embase databases has been performed. RESULTS: Anti-infliximab antibodies formation and autoantibodies (ANA, anti-DNA and other autoantibodies) have been associated with loss of response. Individual differences in drug metabolism may contribute to loss of response. Smoking may be a risk factor for loss of response. Dose escalation, reduction of infusion intervals and switch to other anti-TNF-alpha agents are effective as rescue strategies. CONCLUSIONS: Loss of response appears to result from different causes not fully established by now. Optimization of therapies, or switch to other anti TNF-alpha, are currently the best studied strategies in case of loss of response, and can be successful in 40-60% of patients who lose response. PMID- 21539589 TI - Colonic mast cells in controls and slow transit constipation patients. AB - BACKGROUND: There is recent evidence that mast cells may play important roles in the gut, especially concerning visceral hypersensitivity and motor activity. However, most data are only available for clinical conditions characterised by diarrhoea, where MC have chiefly investigated in the mucosal layer of the colon and there is almost no information concerning constipation. AIM: To investigate mast cells distribution in all colonic layers in controls and severely constipated patients. METHODS: Full-thickness specimens from colons of patients undergoing surgery for slow transit constipation (n=29), compared with controls, were obtained and the number of mast cells (evaluated by specific monoclonal antibodies) counted as a whole and in single colonic segments (caecum, ascending, transverse, descending and sigmoid). RESULTS: Compared with controls, constipated patients revealed significantly higher number of mast cells, both as overall number and in single colonic segments. The distribution of mast cells resulted fairly homogeneous in the various segment of the large bowel, in both controls and patients, and no significant difference in the percentage of degranulated cells was found between groups. CONCLUSIONS: Colonic mast cells display a homogeneous distribution within the viscus. This cell population is shown to increase in severely constipated patients, which might represent a mechanism trying to compensate for the impaired propulsive activity of these patients. PMID- 21539590 TI - Social amplification of risk in the Internet environment. AB - This article analyzes the dynamic process of risk amplification in the Internet environment with special emphasis on public concern for environmental risks from a high-speed railway tunnel construction project in South Korea. Environmental organizations and activists serving as social stations collected information about the project and its ecological impact, and communicated this with the general public, social groups, and institutions. The Internet provides social stations and the public with an efficient means for interactive communication and an open space for active information sharing and public participation. For example, while the website of an organization such as an environmental activist group can initially trigger local interest, the Internet allows this information to be disseminated to a much wider audience in a manner unavailable to the traditional media. Interaction among social stations demonstrates an amplifying process of public attention to the risk. Analyses of the volume of readers' comments to online newspaper articles and public opinions posted on message board of public and nonprofit organizations show the ripple effects of the amplification process as measured along temporal, geographical, and sectoral dimensions. Public attention is also influenced by the symbolic connotations of risk information. Interpretations of risk in religious, political, or legal terms intensify public concern for the environmental risk. PMID- 21539591 TI - The effect of instrument alignment on peripheral refraction measurements by automated optometer. AB - PURPOSE: Interest in peripheral refraction measurement has grown in recent years in response to the insight it may provide into myopia development. In light of the likely increase in the clinical use of open-field autorefractors for peripheral refraction measurements, the question of instrument alignment and its impact on the accuracy of refraction measurements is raised. The aim of this study was to investigate the accuracy and precision when an open-field device was moved away from alignment with the corneal reflex towards the pupil margins, and to determine the optimum alignment position for peripheral refraction measurements. METHODS: Autorefractions were performed on the right eyes of 10 healthy participants using the Shin-Nippon NVision-K 5001 autorefractor. At least five measurements were taken with the subject fixating a distance target in the primary position of gaze, and then four peripheral fixation targets located along the horizontal meridian (10 degrees and 20 degrees eccentricities in the nasal and temporal retina). Measurements were taken at seven alignment positions across the pupil for each fixation angle. Refraction was recorded as the spherical and cylindrical power. RESULTS: The central objective refraction achieved under cycloplegia based on the autorefraction result for the whole sample, ranged between -5.62 D and +1.85 D for the value of sphere, with a maximum astigmatism of -1.00 D. Acceptable alignment position range varied with fixation angle but was -1.0 to +1.0 mm in width across the pupil. Peripheral refraction measurements centred on the entrance pupil were as reliable as those centred on the corneal reflex. CONCLUSIONS: Our data suggest that for peripheral refraction measurements, there is a range of acceptable positions and operators can be confident of the validity of results obtained if aligned half way between the pupil centre and corneal reflex. The alignment becomes more critical at greater eccentricities. PMID- 21539592 TI - The M4 muscarinic antagonist MT-3 inhibits myopia in chick: evidence for site of action. AB - PURPOSE: It is well established that the broad-band muscarinic antagonist, atropine is effective at inhibiting the progression of myopia and does so by preventing the elongation of the vitreous chamber of the eye. However, uncertainty remains as to whether this effect occurs through a receptoral mechanism and, if so, which muscarinic receptor subtype mediates this effect. Previous work, in avian and mammalian models of myopia, implicates the M1 and M4 receptors as potential targets. The current study used physiologically relevant concentrations of highly selective muscarinic antagonists (MT-3 and MT-7) to further characterise the role of the M4 receptor in the control of myopia in the chick model of refractive development. METHODS: Nine groups of week-old chicks underwent 5 days of monocular deprivation, with a translucent occluder, to induce myopia. These animals had either no injection, scleral puncture with a needle, or daily intravitreal injections of MT-3 (M4-selective), MT-7 (M1-selective) or vehicle. Three concentrations of each antagonist were delivered (250 nm, 2.5 MUm and 10 MUm). After the treatment period, keratometry, retinoscopy and A-Scan ultrasound were used to assess ocular biometry. RESULTS: MT-3 treatment produced a significant dose-dependent reduction in relative myopia (treated-control eye) compared to vehicle treatment (vehicle -10.1 +/- 1.1 D vs 10 MUm MT-3 -4.0 +/- 1.5 D, p < 0.01). The majority of this effect was due to reduced relative vitreous chamber elongation in drug treated eyes (vehicle +0.26 +/- 0.04 mm, 10 MUm MT-3 +0.08 +/- 0.07 mm, p < 0.05). In contrast, MT-7 had no significant effect on the development of myopia (MT-7 10 MUm: myopia, -12.1 +/- 0.8 D and vitreous chamber depth, +0.23 +/- 0.07 mm). Calculations indicate that the experimentally achieved concentrations of MT-3 at intraocular receptors necessary to inhibit 50% of myopia development (between 5 and 50 nm) were consistent with published in vitro affinity constants for the M4 receptor and below those for the M1 receptor. Histology demonstrated that MT-3 at the doses used had no gross effects on the retina, indicating a non-toxic mode of action. CONCLUSIONS: In the chick, which lacks a homologue of the mammalian M1 receptor, the above findings represent compelling evidence that muscarinic antagonists prevent myopia progression through an M4-receptor mediated mechanism, most likely located in the retina. PMID- 21539593 TI - Diversity and quantitative analysis of Archaea in aggressive periodontitis and periodontally healthy subjects. AB - AIM: To investigate the diversity, levels and proportions of Archaea in the subgingival biofilm of generalized aggressive periodontitis (GAgP; n=30) and periodontally healthy (PH; n=30) subjects. MATERIALS AND METHODS: Diversity was determined by sequencing archaeal 16S rRNA gene libraries from 20 samples (10/group). The levels and proportions of Archaea were analysed by quantitative PCR (qPCR) in four and two samples/subject in GAgP and PH groups, respectively. RESULTS: Archaea were detected in 27/28 subjects and 68% of the sites of the GAgP group, and in 26/30 subjects and 58.3% sites of the PH group. Methanobrevibacter oralis was found in all 20 samples studied, Methanobacterium curvum/congolense in three GAgP and six PH samples, and Methanosarcina mazeii in four samples from each group. The levels and proportions of Archaea were higher in GAgP than in PH, whereas no differences were observed between the two probing depth category sites from the GAgP group. CONCLUSION: Archaea were frequently found in subjects with periodontal health and GAgP, especially M. oralis. However, the higher levels and proportions (Archaea/total prokaryotes) of this domain observed in GAgP in comparison with PH subjects indicate a possible role of some of these microorganisms as an environmental modifier in GAgP. PMID- 21539594 TI - Brain abscess associated with Aggregatibacter actinomycetemcomitans: case report and review of literature. AB - INTRODUCTION: Aggregatibacter actinomycetemcomitans is considered a major pathogen in localized and generalized aggressive periodontitis. A. actinomycetemcomitans has been found in various extra oral infections and most frequently in endocarditis. We report a patient with multiple brain abscesses due to infection with A. actinomycetemcomitans and review the English language literature related to this subject. CASE REPORT: A 42-year-old patient with no underlying medical conditions presented with multiple brain lesions initially thought to be metastatic lesions of a tumour of unknown origin. Findings during drainage and subsequent histopathological conclusions made infection more likely. Culture of drained material remained negative; however, 16S rDNA polymerase chain reaction and sequence analysis on direct material revealed A. actinomycetemcomitans as the causative agent of the infection. The most likely source of infection was the poor dentition of the patient. After repeated drainage of the lesions and antibiotic treatment the patient gradually improved, although cognitive impairment remained. CONCLUSIONS: Our report illustrates that a poor dental condition, notably destructive periodontal disease, can be a risk for life-threatening extra oral disease, and thus contributes to the total inflammatory burden of the body. PMID- 21539595 TI - A morphometric comparative study of the medial geniculate body of the rabbit and the fox. AB - SUMMARY: Unbiased stereological methods were used to morphometrically examine and compare the medial geniculate body (MGB) of two species from different mammalian orders. The MGB had a similar nuclear pattern, and it was parcelled into three major cytoarchitectural areas: the dorsal nucleus (MGd), the ventral nucleus (MGv) and the medial nucleus (MGm). The MGd was predominant in the fox, where it contributed nearly 50% to the total MGB volume, while in the rabbit, the MGv was insignificantly larger than the MGd. In both species, the percentage contribution of the MGm was the lowest. The MGd in the fox was also characterized by twice as many neurons per mm(3) as in the rabbit, whereas a reverse proportion was observed in the MGm, although the numerical density in the MGv was very similar in both species. The total number of MGB neurons in the fox was over twice higher than that in the rabbit. The variability in the percentage contribution of the MGd, MGv and MGm cells to the total neuronal population of the MGB was different in both mammals. In the rabbit, there was a larger contribution from the MGv and MGm, while in the fox, the MGd was predominant. These data demonstrate that the main areas of the MGB complex differ in terms of the morphometric characteristics in both species. Our results also show that the negative correlation between the volume and numerical density in the sensory centres of the brain might not be as distinct as in the non-sensory brain structures. PMID- 21539596 TI - Cytoskeletal abnormalities in relation with meiotic competence and ageing in porcine and bovine oocytes during in vitro maturation. AB - We investigated the frequencies of cytoskeletal anomalies in metaphase-II (M-II) and incompetent [arrested at an immature metaphase (IM) stage] porcine and bovine oocytes during in vitro maturation (IVM) in relation with ageing by immunostaining and confocal microscopy. In porcine oocytes, meiotic arrest at the IM stage was associated with abnormalities of cortical actin but not with abnormal spindles. Prolongation of IVM culture to 52 h did not affect microfilament and spindle abnormalities, but reduced the microfilament-rich area overlaying the spindle. Meiotic arrest of bovine oocytes at the IM stage was associated with degenerations of microfilaments, and the frequencies of abnormal spindles were also higher than those of M-II oocytes. Ageing of bovine oocytes (IVM for 30 h) did not affect cortical microfilaments but increased the frequency of spindle alterations in both M-II and IM bovine oocytes. These results suggest that, in both species, altered ability of oocytes to polymerize F-actin might be a possible reason for the failure of polar body extrusion during IVM. Also, there seem to be differences between the two species in the sensitivity of oocytes to suffer ageing-related spindle damages. PMID- 21539597 TI - Origin, course and distribution of the hypoglossal nerve in the New Zealand rabbit (Oryctolagus cuniculus L). AB - With 8 figures SUMMARY: This study aimed at revealing the origin, course and distribution of the hypoglossal nerve in 20 adult male New Zealand rabbits. In all the animals dissected, the hypoglossal nerve arose from the ventrolateral side of the medulla oblongata with two main roots and gave off a descending branch to the ansa cervicalis before reaching the division of the common carotid artery. This branch was not seen on the right side of only one case. At the lateral aspect of the hyoglossus muscle, the nerve then divided into the lateral and medial main branches, sent branches to the styloglossus, hyoglossus, genioglossus and geniohyoideus muscles and terminated in the intrinsic tongue muscles. A communicating branch was observed between the hypoglossal and accessory nerves in the right side of one animal and between the hypoglossal nerve and the ganglion nodosum in the right retropharyngeal area of another animal. An additional branch was observed innervating the stylohyoideus muscle in one animal only. A lateral lingual-hypoglossal communication was also seen between the lateral branch of the hypoglossal nerve and terminal branches of the lingual nerve. PMID- 21539598 TI - CT sialography in the dog - a cadaver study. AB - To document computed tomographic topography of salivary glands and their ducts in dogs, a retrograde filling with methylcellulose and iodinated contrast medium was performed in three cadavers. Demarcation of the parotid, mandibular and zygomatic glands was achieved. Surrounding structures were imaged without beam hardening artefacts. Landmarks for the parotid, mandibular and zygomatic glands were the external acoustic canal, the mandibular angle and the pterygopalatine fossa, respectively. Sialograms of the parotid, mandibular and zygomatic ducts were achieved, whereas neither the sublingual glands nor their ducts could be contrasted. The images provide a three-dimensional visualization of the salivary glands and their ducts. PMID- 21539599 TI - Determination of aspartase activity in dairy Propionibacterium strains. AB - Propionic acid bacteria (PAB) are important as starter cultures for the dairy industry in the manufacture of Swiss-type cheeses, in which they are involved in the formation of eyes and are responsible for the typical flavour and aroma. These characteristics are mainly due to the classical propionic acid fermentation, but also the conversion of aspartate to fumarate and ammonia by the enzyme aspartase and the subsequent reduction of fumarate to succinate, which occur in dairy Propionibacterium freudenreichii ssp. shermanii and ssp. freudenreichii starter strains. Additionally, the metabolism of free amino acids may be partly responsible for secondary fermentation and the subsequent split defects in cheese matrix. Here a method for aspartase activity was established and a number of dairy propionibacteria belonging to P. freudenreichii ssp. shermanii and freudenreichii were screened for this enzyme activity. A wide range of aspartase activity could be found in PAB isolates originating from cheese. The majority, i.e. 70% of the 100 isolates tested, showed very low levels of aspartate activity. PMID- 21539600 TI - Coronary flow reserve, strain and strain rate imaging during pharmacological stress before and after percutaneous coronary intervention: comparison and correlation. AB - INTRODUCTION: Coronary flow reserve (CFR) could apply reliable information about the coronary circulation, and strain (S) and strain rate imaging (SRI) are able to quantify the left ventricular myocardial performance. The aim of this study was to assess myocardial performance in relation to the function of the coronary circulation before and after successful percutaneous coronary intervention (PCI) of the left anterior descending artery. MATERIAL AND METHOD: Fourteen patients (10 men, 4 women, mean age 53.2 +/- 11.4 years) with severe left anterior descending stenosis who had a successful selective PCI were recruited into this study. CFR and myocardial deformity indices (S and SR) were recorded before and after percutaneous intervention, both at rest and during stress echo test. RESULTS: CFR, S, and SR increased after intervention significantly. There was significant correlation between CFR ratio and poststress systolic strain (SS) ratio and early diastolic strain rate (ESR) ratio (P < 0.05 and r > 0.6). Also CFR improvement had significant relationship with changes of poststress Systolic SR and poststress Systolic S (P < 0.05 and r > 0.6). Based on regression analysis the amount of change in CFR was independently associated with change in SS during stress and systolic SR. CONCLUSION: PCI improves CFR (a marker of coronary perfusion), strain, and strain rate (markers of regional cardiac wall deformation). The independent association between CFR improvement and poststress systolic strain and strain rate means that SRI parameters can independently predict CFR changes after PCI. PMID- 21539602 TI - Differences in the duration of total ejection between right and left ventricles in chronic pulmonary hypertension. AB - BACKGROUND: Chronic pulmonary hypertension (cPH) is known to delay pulmonic valve closure resulting in a closely split second heart sound. We decided to measure total duration of right (RV) and left ventricular (LV) outflow tract (RVOT and LVOT) spectral signals using pulsed Doppler to determine if this approach was useful in identifying this narrowing in auscultation that should then result in a shorter temporal difference between the ejection of both ventricles. METHODS: Standard measures of RV and LV performance as well as Doppler data was collected from 85 patients divided into two groups according to their estimated pulmonary artery systolic pressure obtained at the time of their echocardiographic examination. Difference in ejection between the ventricles was defined as the difference in ejection time between RVOT and LVOT, measured in milliseconds. RESULTS: Chronic PH patients had a shorter total duration between RVOT and LVOT ejection time (-15 +/- 16 ms vs. 22 +/- 14 ms; P < 0.0001) than individuals without PH. This difference in total duration between RVOT and LVOT ejection not only showed a significant negative correlation with both PASP (r = -0.65; P < 0.0001) but also with pulmonary vascular resistance (PVR; r = -0.60; P < 0.0001). CONCLUSIONS: Shorter duration between RVOT and LVOT ejection is likely to explain the closely split second heart sound in cPH patients. When accurate echocardiographic assessment of RV function in cPH patients remains problematic due to the unusual geometry of this cardiac chamber; Doppler measures can simplify patient identification and follow up. PMID- 21539601 TI - Speckle tracking imaging in acute inflammatory pericardial diseases. AB - BACKGROUND: Left ventricular (LV) function in acute perimyocarditis is variable. We evaluated LV function in patients with acute perimyocarditis with speckle tracking. METHODS: Thirty-eight patients with acute perimyocarditis and 20 normal subjects underwent echocardiographic examination. Three-layers strain and twist angle were assessed with a speckle tracking. Follow-up echo was available in 21 patients. RESULTS: Strain was higher in normal subjects than in patients with perimyocarditis. Twist angle was reduced in perimyocarditis--10.9 degrees +/- 5.4 versus 17.6 degrees +/- 5.8, P < 0.001. Longitudinal strain and twist angle were higher in normal subjects than in patients with perimyocarditis and apparently normal LV function. Follow-up echo in 21 patients revealed improvement in longitudinal strain. CONCLUSIONS: Patients with acute perimyocarditis have lower twist angle, longitudinal and circumferential strain. Patients with perimyocarditis and normal function have lower longitudinal strain and twist angle. Short-term follow-up demonstrated improvement in clinical parameters and longitudinal strain despite of residual regional LV dysfunction. PMID- 21539603 TI - A quantitative analysis of left ventricular filling pressures in patients with a reduced ejection fraction, with or without concomitant left bundle branch block. AB - AIM: This study aimed to prove that a mathematical model can be used to quantify the relationship between the left ventricular filling pressure (LVFP) determined as the E/e' ratio and the pulmonary capillary wedge pressure (PCWP) assessed by right heart catheterization (RHC) in patients with reduced ejection fractions (EF), with or without a left bundle branch block (LBBB). We hypothesize that such an approach will be clinically beneficial, especially for patients in the so called "gray area," for whom E/e' is not a reliable index for assessment of the LVFP. METHOD: We enrolled 64 patients in sinus rhythm and with a reduced EF, 31 of whom exhibited a LBBB on an ECG. The e' was obtained from the septal (e'(sept)) and lateral sites (e'(lat)) of the mitral annulus. The averaged e' (e'(aver)) was also calculated (e'(sept) + e'(lat)/2). RESULTS: Although we found a good correlation (r = 0.641; e'(lat)/0.641; e'(sept)/0.607; e'(aver)) between E/e' and the mean PCWP in patients without LBBB, regardless of the e' used, the equation only yielded significance (P = 0.03) when the e'(aver) was used (PCWP = 6.7 + E/e'(aver)). In patients with LBBB, we found a moderate correlation between the LVFP and the mean PCWP (r = 0.451; e'(lat)/r = 0.413; e'(sept)/r = 0.454; e'(aver)), although all of the used e' positions lacked significance (P = 0.065 e'(lat)/0.075 e'(sept)/0.082 e'(aver)). CONCLUSION: Our results suggest that in patients with reduced EF and without LBBB, it is possible to quantify the LVFP using an equation. These results are of great clinical benefit, especially for "gray area" patients. PMID- 21539604 TI - Placental IGF-I, IGFBP-1, zinc, and iron, and maternal and infant anthropometry at birth. AB - AIM: To correlate placental protein levels of insulin-like growth factor (IGF)-I and insulin-like growth factor binding protein (IGFBP)-1, with previously determined levels of IGF-I and IGF-II mRNA expression, and the micronutrients zinc and iron, and maternal and newborn anthropometry. METHODS: Placental samples were collected from rural field sites in Pakistan. Samples were divided into small and large for gestational age groups (SGA and LGA, respectively). IGFBP-1 levels were assessed using Western immunoblotting. IGF-I protein levels were assessed using ELISA techniques. IGF mRNA expression, zinc, and iron, were quantified as previously described and were used for comparative purposes only. RESULTS: Thirty-three subjects were included (SGA, n = 12; LGA n = 21). Higher levels of IGFBP-1 were seen in the SGA group (p < 0.01). IGFBP-1 correlated positively with maternal and infant triceps skin-fold thickness in the LGA and SGA groups, respectively (p < 0.05). Significantly lower IGF-I protein levels were seen in the SGA group. IGF-I levels correlated significantly with maternal and newborn anthropometry. IGFBP-1 correlated significantly with IGF-II mRNA expression (p < 0.05). CONCLUSION: Placental protein levels of IGF-I and IGFBP-1 appear to be associated with maternal anthropometry. Maternal anthropometry may thus influence IGFBP-1 and IGF-I levels and may possibly be used for screening of pregnancies, with the potential for timely identification of these high-risk pregnancies. PMID- 21539605 TI - Treatment of oral squamous cell carcinoma with accelerated radiation therapy and concomitant carboplatin in cats. AB - BACKGROUND: Feline oral squamous cell carcinoma (SCC) carries a very poor prognosis with traditional treatments. HYPOTHESIS/OBJECTIVES: To examine the effectiveness of adding carboplatin to a previously published accelerated radiation protocol in the treatments of oral SCC in cats. ANIMALS: Thirty-one cases of oral SCC in cats. Tumor sites included lingual (n = 9), mandible (n = 10), maxilla (n = 7), tonsil (n = 4), and cheek (n = 1). METHODS: Prospective trial using a planned radiation protocol consisting of 14 fractions of 3.5 Gy given within a 9-day period with the addition of carboplatin given at 90-100 mg/m(2) on day 1 and day 4.5. Treatments were twice daily with a 6-hour delay between treatments. All cats presenting with oral SCC without evidence of distant metastasis were eligible. RESULTS: Median survival for all cats was 163 days (range 53-770 days) with a mean of 319 +/- 53 days with significant predictors of survival being site (P = .004) and whether there was a complete response at 30 days (P = .001). Cats with tumors of tonsil origin or cheek responded best to therapy and were long-term survivors with a mean survival of 724 days and the median had not been reached because of continued survival of 4 cats. CONCLUSIONS AND CLINICAL IMPORTANCE: This protocol offers an aggressive yet tolerable treatment of oral SCC in cats that might offer improved survival as compared with previously reported treatments. The long-term survival of cats with tonsillar SCC has not been reported previously. PMID- 21539606 TI - Bartonella spp. DNA in cardiac tissues from dogs in Colorado and Wyoming. AB - BACKGROUND: Several Bartonella species (spp.) have been identified in dogs diagnosed with infectious endocarditis (IE) or myocarditis. OBJECTIVE: To interrogate cardiac tissues of dogs with suspected IE for the presence of Bartonella spp. DNA of dogs in the Rocky Mountain states. ANIMALS: Nine dogs with a clinical diagnosis of endocarditis from January 1990 to June 2008 were included. METHODS: In this retrospective study, medical records at the Veterinary Teaching Hospital were searched. Animals were excluded if there was no diagnosis of IE in the original necropsy report. Paraffin embedded tissue blocks and medical records were available from 9 dogs. Total DNA was extracted from the cardiac tissues and assessed for Bartonella spp. DNA by 3 polymerase chain reaction (PCR) methods. For positive samples, the Bartonella spp. were determined by genetic sequencing or fluorogenic real-time PCR. RESULTS: Bartonella henselae DNA was amplified from the tissues of 7 dogs; Bartonella vinsonii subsp berkhoffii DNA was amplified concurrently from 3 dogs. Six dogs were from Colorado and 1 was from Wyoming. Flea or tick infestations were reported in 2 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Bartonella spp. should be on the differential list for dogs in the Rocky Mountain states. The results emphasize the need for routine use of external parasite control products even in regions perceived to have low risk for flea and tick infestations. PMID- 21539609 TI - Management of radial artery perforation complicating coronary intervention: a stepwise approach. AB - The radial approach is an elegant alternative to femoral access for diagnostic and interventional coronary procedures; this access site is infrequently associated with vascular complications, although less than the femoral approach. We present our experience in management of iatrogenic radial artery perforation in 3 cases; one case managed conservatively through prolonged guiding catheter positioning proximal to the perforated segment and external compression by sphygmomanometer cuff. The second case required prolonged balloon inflation after failure of conservative management mentioned above. In the third case, the above mentioned conservative measures and prolonged balloon inflation failed to seal the perforation; complete reconstruction of the perforation was achieved by a polytetrafluoroethylene (PTFE) coronary covered stent. To our knowledge, this is the first case to be managed utilizing this approach. PMID- 21539610 TI - Drug-eluting stents during ST-segment elevation acute myocardial infarction: a critical analysis. AB - Primary percutaneous coronary intervention is the preferred reperfusion therapy for ST-segment elevation acute myocardial infarction patients within 12 hours of symptom-onset. Routine stent implantation during the procedure significantly reduces the rate of target vessel revascularization, although restenosis still represents a current limitation of the technique. Drug-eluting stents were developed to treat and prevent coronary restenosis. Randomized trials, meta analysis, and registries proved their efficacy and safety in different clinical situations, including acute myocardial infarction. However, the increased risk of late stent thrombosis associated with drug-eluting stents during primary percutaneous coronary interventions encourages a careful analysis to identify which patients most benefit from them, as well as those where a prolonged dual antiplatelet therapy does not represent a limiting factor. PMID- 21539611 TI - Intravascular ultrasound guided percutaneous coronary intervention: a practical approach. AB - Percutaneous coronary intervention (PCI) with stent implantation has become the predominant revascularization therapy for coronary artery disease. However, stent thrombosis and instent restenosis remain 2 major complications. Limitations of stand-alone angiographic guidance play a significant role in the pathogenesis of these complications. Intravascular ultrasound (IVUS) guidance intuitively offers the best chance of optimizing the acute procedural outcomes, which translates to lower incidences of thrombosis and restenosis. This article aims to provide a practical approach on preintervention and postintervention lesion assessment by IVUS. Emphases of this article are on correct interpretation and application of the various vascular parameters obtained during IVUS imaging. Although consensus on some areas is lacking, the most commonly agreed IVUS concepts and criteria are presented. Limitations of the IVUS-guided PCI on routine clinical practice are also addressed. A summary of the randomized study comparing IVUS- versus angiographic-guided PCI, together with a critical appraisal of the data, are also presented. The roles of IVUS in PCI are likely to undergo revolutionary change in the era of plaque characterization and drug-eluting stents. PMID- 21539612 TI - Percutaneous closure of patent foramen ovale in patients with anatomical and clinical high-risk characteristics: long-term efficacy and safety. AB - BACKGROUND: Transcatheter closure of patent foramen ovale (PFO) is a widespread procedure, but no randomized study on its outcome in high-risk patients is available. Our aims were to determine the efficacy and safety of this procedure in a cohort of high-risk patients through the observation of clinical adverse events and residual shunt, to evaluate the impact of transesophageal echocardiography (TEE) guidance during the procedure, and investigate the relationship between the anatomical and clinical characteristics and the outcome. METHODS AND RESULTS: Ninety-five patients underwent PFO closure for cryptogenic cerebral ischemia; each of them presented one or more of the following risk factors: recurrent cerebral ischemia (9.5%), atrial septum aneurysm (ASA, 74.5%), prominent Eustachian valve (EV, 23.2%), severe basal shunt (9.5%), thrombophilic factors (20%), deep vein thrombosis (4.2%). The procedure was performed successfully in all patients. On median follow-up of 18 months, the neurologic recurrent events rate was 1.1% and the major adverse cardiac event (MACE) rate was 1.1%. At 6-month TEE follow-up, the residual shunt rate was 12.6% (3.1% moderate to severe). A significant correlation was found between residual shunt and prominent EV alone (P = 0.036) or in association with ASA (P = 0.021). All adverse events occurred in the first 8 months, and the event-free survival rate was 86.2%. CONCLUSIONS: Our study suggests that transcatheter PFO closure is a safe procedure even in a selected population of high-risk patients, presenting satisfactory efficacy and safety. The presence of a prominent EV alone or with ASA correlates positively with the occurrence of residual shunt. PMID- 21539613 TI - The incidence and risk factors of immediate type food allergy during the first year of life in Korean infants: a birth cohort study. AB - OBJECTIVES: We conducted this study to determine the incidence of food allergy (FA) in Korean infants and identify the risk factors of FAs during the first year of life in a birth cohort study. METHODS: Pregnant women >=34 weeks of gestation were enrolled in this study. Participants were asked to complete questionnaires describing basic demographic information including family history of allergic diseases. Since birth, all the babies were regularly followed up for FA symptoms through telephone interviews at 4, 8, and 12 months of age. FA was defined as a repetitive convincing history of immediate allergic reactions following the ingestion of offending food. RESULTS & CONCLUSIONS: A total of 1177 infants and their parents completed this study. The prevalence of FA was 5.3% in infants. The three leading food allergens were hen's eggs (33/62), cow's milk (20/62) and peanut/nuts (8/62). Children with a history of maternal AD showed a significantly higher prevalence of FA (P = 0.012) [aRR = 3.17]. In addition, children who were born during autumn had a higher prevalence than those born during spring (p = 0.005) [aRR = 3.48]. In conclusion, we identified several characteristics that may influence the development of FA in the next generation, including maternal AD and autumn birth. PMID- 21539614 TI - Partially hydrolyzed cow's milk formula has a therapeutic effect on the infants with mild to moderate atopic dermatitis: a randomized, double-blind study. AB - OBJECTIVE: The allergy-preventing effect of partially hydrolyzed cow's milk formula (phCMF) in infants at high risk of atopic dermatitis (AD) has been demonstrated in many studies. However, the therapeutic potential of phCMF in treating the infants with AD has not been reported. We sought to assess such therapeutic efficacy of phCMF in infants with mild to moderate AD. METHODS: From 2006 to 2008, 113 infants <6 months of age with AD were randomized to receive either partially hydrolyzed cow's milk formula (phCMF) or conventional cow's milk formula (CMF) in a double-blind clinical trial. Assessments were made at enrollment and at weeks 4, 8, and 12. The severity of AD was assessed using two scoring systems: Standard guideline for management (diagnosis, severity scoring, and therapy) of AD by the Japanese Dermatological Association Scoring System (JDASS) and the SCORing Atopic Dermatitis (SCORAD). Growth status of the infants was evaluated. Allergy profile was assessed by measuring total blood eosinophils (EOS), total/specific IgE, Th1/Th2 cytokine profiles, and the percentage of regulatory T cells. RESULTS: After follow-up for 12 wk, 27 infants (23.89%) dropped off study. Analysis was performed on 86 infants by the end of 12-wk observation. The AD severity scores were significantly reduced in the phCMF group (n = 56) compared with CMF group (n = 30) after 12 wk (p < 0.05). The severity scores of phCMF group were significantly reduced at weeks 4, 8, and 12 compared to enrollment (p < 0.05). In contrast, no significant improvement was observed for CMF group at any of those time points (p > 0.05). The number of AD flare-ups was significantly decreased in the phCMF group (p = 0.002). Th1/Th2 ratio in phCMF was significantly increased compared with CMF group (p = 0.041). The growth rates did not differ significantly between these feeding groups at any assessed time point (p > 0.05) and were in the normal range. CONCLUSION: This study suggests a novel therapeutic effect of phCMF in treating infants with mild to moderate AD during the first 6 months of their life without affecting their nutritional status. PMID- 21539615 TI - Exploring CCL18, eczema severity and atopy. AB - BACKGROUND: Childhood atopic dermatitis (AD) is a distressing disease associated with pruritus, sleep disturbance, and impaired quality of life. The pathophysiology of AD is complex, and the chemokine CCL18/pulmonary and activation-regulated chemokine (PARC) may be involved. OBJECTIVE: To evaluate whether CCL18 was associated with disease severity, quality of life, nocturnal scratching, serum eosinophil, and IgE levels. PATIENTS AND METHODS: Patients with AD aged 20 yr or younger were recruited. Disease severity was assessed with the SCORing Atopic Dermatitis (SCORAD) index, quality of life with the Children's Dermatology Life Quality Index (CDLQI), and nocturnal scratching with a wrist motion monitor. Concentrations of plasma CCL18/PARC, serum total IgE, and eosinophil counts were measured in these patients. RESULTS: One hundred and eight patients with AD (mean [s.d.] age of 10.5 [4.4] yr) were recruited. The mean (s.d.) plasma concentration of CCL18/PARC was 162.2 (129.0) pg/ml, respectively. CCL18/PARC was significantly correlated with objective SCORAD (r = 0.44, p < 0.001), extent (r = 0.45, p < 0.001), intensity (r = 0.43, p < 0.001), the symptoms of pruritus (r = 0.20, p = 0.04), and sleep loss (r = 0.19, p = 0.049) but not with CDLQI or nocturnal scratching activities. CCL18/PARC levels were also correlated with eosinophil counts (r = 0.37, p < 0.001) and IgE(log) (r = 0.27, p = 0.005). Positive correlation with SCORAD was present even in patients without bronchial hyper-reactivity. CONCLUSIONS: Serum levels of CCL18 correlate with the clinical severity score, serum eosinophil, and IgE levels. CCL18 is associated with AD and atopy. PMID- 21539616 TI - Maternal dietary patterns during pregnancy and risk of wheeze and eczema in Japanese infants aged 16-24 months: the Osaka Maternal and Child Health Study. AB - BACKGROUND: Maternal diet during pregnancy might influence the development of childhood allergic disorders. AIMS: This prospective study examined the relationship between maternal dietary patterns during pregnancy and the risk of wheeze and eczema in the offspring aged 16-24 months. MATERIALS & METHODS: Subjects were 763 mother-child pairs. Data on maternal intake during pregnancy were assessed with a diet history questionnaire. Dietary patterns were derived from factor analysis of 33 predefined food groups. Symptoms of wheeze and eczema were based on criteria of the International Study of Asthma and Allergies in Childhood. Adjustment was made for maternal age, gestation, residential municipality, family income, maternal and paternal education, maternal and paternal history of allergic disorders, changes in maternal diet in pregnancy, season at baseline, maternal smoking during pregnancy, baby's older siblings, sex, birth weight, age at the third survey, household smoking, and breastfeeding duration. RESULTS: Three dietary patterns were identified: 'healthy', characterized by high intake of green and yellow vegetables, seaweed, mushrooms, white vegetables, pulses, potatoes, fish, sea products, fruit, and shellfish; 'Western', characterized by high intake of vegetable oil, salt-containing seasonings, beef and pork, processed meat, eggs, chicken, and white vegetables; and 'Japanese', characterized by high intake of rice, miso soup, sea products, and fish. There was a tendency for an inverse exposure-response relationship between the maternal Western pattern during pregnancy and the risk of childhood wheeze by crude analysis. After adjustment for the confounding factors under study, the inverse relationship was strengthened: the adjusted OR between extreme quartiles was 0.59 (95% CI: 0.35-0.98, p for trend = 0.02). No such inverse association was observed for childhood eczema. Neither the maternal healthy pattern nor the Japanese pattern during pregnancy was related to childhood wheeze or eczema. CONCLUSION: The maternal Western pattern during pregnancy may be preventive against wheeze in the offspring. PMID- 21539617 TI - Prediction of atopic dermatitis in 2-yr-old children by cord blood IgE, genetic polymorphisms in cytokine genes, and maternal mentality during pregnancy. AB - Atopic dermatitis (AD) is the most common skin disease in childhood and the first step of atopic march. This study aimed to investigate whether AD in children could be better predicted by biologic markers (cord blood IgE [cbIgE], LT alphaNcoI alleles, and FcepsilonRI-beta E237G genotypes) and maternal mentality during pregnancy, taking into account gender, socio-demographic factors, and parental atopy. From 2001 to 2005, 1264 mother-infant pairs were recruited to participate in a birth cohort study. Prenatal questionnaire was used to collect family history, maternal gestational conditions and mentality, and environmental exposures. Cord blood was collected and assayed for genotypes and IgE levels. Phone interviews at 6 months and 2 yrs of age were conducted to inquire children's health status, including AD occurrence. In addition to the known risk factors such as gender, maternal education, and parental atopy, biomarkers and maternal mentality during pregnancy were screened by logistic regression as candidate predictors of AD. Area-under-curve (AUC) statistic from receiver operating characteristic (ROC) curve analysis was used to compare two predicting models with and without biomarkers and maternal mentality. A total of 730 pairs completed the prenatal questionnaire and phone interview and were included in final analysis. The prevalence of ever having physician-diagnosed AD by 2-yr-olds was 5.9%. Elevated cbIgE levels (>=0.5 kU/l), LT-alphaNcoI alleles, FcepsilonRI beta E237G genotype, and maternal psychologic stress during pregnancy were significantly associated with AD. Comparison with AUCs of the classic model (including gender, maternal education, and parental atopy), the model adding cbIgE levels, genotypes in cytokine genes, and maternal stress (model 2) showed higher ability to discriminate between children with and without AD (AUC statistics: 0.63 [95% CI = 0.60-0.67] vs. 0.73 [95% CI = 0.70-0.76], respectively; model comparison, p = 0.027). We conclude that elevated cbIgE, LT alpha and FcepsilonRI-beta genotypes, and maternal stress during pregnancy were associated with ever having physician-diagnosed AD in 2-yr-old children and increased the predictive ability for AD after taking into account gender, maternal education, and parental atopic history. PMID- 21539618 TI - Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases. AB - Multiphoton tomography (MPT) is an in vivo imaging technique with very high spatial resolution and efforts are made to combine MPT with other non-invasive imaging methods. The goals of the present study were the description of the features of different dermatological entities as seen in MPT and confocal laser scanning microscopy (CLSM) comparison of these two novel techniques and the 'classical' diagnostic measures visual inspection, dermoscopy and histology with respect to the strengths and weaknesses of the different methods and the potential benefit from their combined implementation. After study approval by the local Ethics Committee, 47 patients (31 male, 16 female, age range: 24-88 years) were recruited from the Department of Dermatology of the University Hospital Jena. In this work, we present an illustrative selection of eleven cases from a clinical study combining in vivo MPT with in vivo CLSM. The patients presented with a broad range of dermatological disorders including seborrheic keratoses, angioma, actinic keratoses, melanocytic nevi, malignant melanoma, psoriasis, pemphigus vulgaris and scarring. Both methods, CLSM and MPT, were found to be suitable for in vivo imaging of superficial skin layers and may therefore be useful in dermatological practice for the diagnosis of skin diseases. However, both methods differ in their technical and physical principles. Thus, despite of many similarities concerning the morphological presentation of cells and tissues, important differences are recognized. Synergies of the combination of CLSM and MPT may be obtained by combined implementation in order to benefit from the fast overview given by CLSM and the detailed imaging of skin structures by MPT. PMID- 21539619 TI - Regulation of caspase 14 expression in keratinocytes by inflammatory cytokines--a possible link between reduced skin barrier function and inflammation? AB - Caspase 14 is a unique member of the cysteinyl aspartate-specific proteinase family. Its expression is confined primarily to cornified epithelium such as the skin. Caspase 14 has been associated with the processing of filaggrin monomers and the development of natural moisturising factors of the skin, and thus, it could be speculated that caspase 14 dysregulation is implicated in the development of an impaired skin barrier function. We have investigated the regulation of caspase 14 transcription in cultured primary keratinocytes following stimulation with a number of factors present in inflamed skin, including T(H)1- and T(H)2-associated cytokines in addition to LPS and peptidoglycan. In particular, we found that T(H)2-associated cytokines reduced the caspase 14 mRNA level significantly. Furthermore, we found that the expression of caspase 14 was reduced in skin biopsies from patients with atopic dermatitis (AD), psoriasis and contact dermatitis, further supporting a role for this kinase in inflammatory skin conditions. Hence, the regulation of caspase 14 levels provides a possible link between impaired skin barrier function and inflammatory reactions in skin diseases such as AD and may offer an explanation to the skin barrier dysfunction in inflamed skin lesions. PMID- 21539620 TI - Electrical impedance spectroscopy and the diagnostic accuracy for malignant melanoma. AB - BACKGROUND: The accuracy of diagnosis of skin cancer and especially of early malignant melanoma is most important to reduce its morbidity and mortality. Previous pilot studies using electrical impedance measurements indicate statistically significant accuracies for the detection of skin cancer. OBJECTIVES: The aim of this study is to investigate the accuracy of electrical impedance spectra to distinguish between malignant melanoma and benign skin lesions using an automated classification algorithm. PATIENTS/METHODS: Electrical impedance spectra were measured in a multi-centre study at 12 clinics around Europe. Data from 285 histologically analysed lesions were used to train an algorithm to sort out lesions for automatic detection of melanoma. Another data cohort of 210 blinded lesions (148 various benign lesions and 62 malignant melanomas where 38 being from Breslow thickness <=1 mm) from 183 patients was thereafter used to estimate the accuracy of the technique. RESULTS: Observed sensitivity to malignant melanoma is 95% (59/62) and observed specificity 49% (72/148). CONCLUSIONS: The results suggest that electrical impedance spectra can distinguish between malignant melanoma and benign skin lesions. Although it is indicated that the accuracy of the device is clinically promising, the overall performance, and the sensitivity to thin malignant melanomas, must be improved and thoroughly validated before the instrument can be used as a routine stand alone diagnostic decision support tool. The technique is under revision to further improve the reproducibility, specificity and sensitivity. PMID- 21539621 TI - Human keratinocytes release high levels of inducible heat shock protein 70 that enhances peptide uptake. AB - BACKGROUND: The stress-inducible chaperone heat shock protein (HSP) 70 is considered a 'danger signal' if released into the extracellular environment. It has been proposed to play a role in the pathogenesis of skin diseases such as psoriasis and lupus erythematosus (LE). OBJECTIVES: The aim of this study was to decipher the role of human primary keratinocytes with regard to release and reactivity to HSP70. METHODS: We determined HSP70 and IFNgamma in cell supernatants by ELISA. Uptake of labelled HSP70 or labelled peptide by human primary keratinocytes or macrophages was analysed by flow cytometry and fluorescent microscopy. RESULTS: We found that living keratinocytes are an important source of HSP70 in the skin compartment. They release considerably more HSP70 than fibroblasts, macrophages or lymphocytes. Interestingly, keratinocytes also bind and internalise HSP70/HSP70-peptide complexes. TNFalpha, IL-27 as well as HMGB-1 enhanced the uptake of HSP70. No difference with regard to HSP70 release or uptake was observable between keratinocytes from healthy donors or patients with cutaneous LE. Keratinocytes pulsed with HSP70-peptide complexes significantly increased IFNgamma production by autologous T cells. CONCLUSIONS: Production and uptake of inducible HSP70 by keratinocytes may critically influence the chronic course of inflammatory skin diseases. PMID- 21539623 TI - Development of a new guinea-pig model of shigellosis. AB - Shigellosis is a major form of bacillary dysentery caused by Shigella spp. To date, there is no suitable animal model to evaluate the protective efficacy of vaccine candidates against this pathogen. Here, we describe a successful experimental shigellosis in the guinea-pig model, which has shown the characteristic features of human shigellosis. This model yielded reproducible results without any preparatory treatment besides cecal ligation. In this study, guinea-pigs were discretely infected with virulent Shigella dysenteriae type 1 and Shigella flexneri type 2a into the cecocolic junction after ligation of the distal cecum. All the experimental animals lost ~10% of their body weight and developed typical dysentery within 24-h postinfection. In the histological analysis, distal colon showed edema, hemorrhage, exudation and inflammatory infiltrations in the lamina propria. Orally immunized animals with heat-killed S. dysenteriae type 1 and S. flexneri type 2a strains showed high levels of serum immunoglobulin G (IgG) and mucosal IgA antibodies and conferred significant homologous protective immunity against subsequent challenges with the live strains. The direct administration of shigellae into the cecocolic junction induces acute inflammation, making this animal model useful for assessing shigellosis and evaluating the protective immunity of Shigella vaccine candidates. PMID- 21539622 TI - CD109 release from the cell surface in human keratinocytes regulates TGF-beta receptor expression, TGF-beta signalling and STAT3 activation: relevance to psoriasis. AB - Transforming growth factor (TGF)-beta is an important cytokine that negatively regulates keratinocyte proliferation. Deregulation of TGF-beta signalling has been reported in psoriasis, where despite increased expression of TGF-beta, psoriatic keratinocytes continue to hyperproliferate. Recently, we have identified CD109, a glycosyl phosphatidylinositol (GPI)-anchored protein, as a novel co-receptor and negative regulator of TGF-beta signalling. In the current work, we demonstrate that release of CD109 from the cell surface or the addition of CD109 protein results in downregulation of TGF-beta signalling and TGF-beta receptor expression in human keratinocytes. Moreover, these effects are associated with an increase in phospho-STAT3 levels, enhanced total STAT3 and Bcl 2 expression and an increase in cell growth and survival, suggesting that released/soluble CD109 is able to induce molecular changes that are known to occur in psoriasis. Analysis of CD109 expression in psoriasis patients reveals that CD109 protein expression is markedly decreased in psoriatic epidermis as compared to adjacent uninvolved skin. In contrast, CD109 mRNA expression is unchanged in psoriatic plaques in comparison with normal skin. This raises a possibility that CD109 protein release is enhanced in psoriatic keratinocytes. Furthermore, psoriatic epidermis displays decreased expression of TGF-beta receptors, consistent with the results obtained in vitro in keratinocytes with CD109 release or addition of CD109 recombinant protein. Together our findings suggest that aberrant CD109 release from the cell surface in human keratinocytes may induce molecular changes that are usually observed in psoriasis and may explain TGF-beta receptor downregulation and decrease in TGF-beta signalling in psoriasis. PMID- 21539624 TI - Identification of a haemolysin-like peptide with antibacterial activity using the draft genome sequence of Staphylococcus epidermidis strain A487. AB - Our interest in Staphylococcus epidermidis strain A487 was prompted by the unusual nature of its inhibitory activity in screening tests against methicillin resistant Staphylococcus aureus isolates. The inhibitory activity was detected in deferred antagonism tests only if the agar plate was preheated for at least 35 min at >= 55 degrees C before inoculation of the indicator bacteria, this phenomenon indicating possible involvement of a heat-labile immunity agent or protease. The inhibitor was purified to homogeneity by ammonium sulphate precipitation, followed by cation-exchange and reversed-phase chromatography. Tandem MS revealed a novel peptide of molecular weight 2588.4 Da. The draft genome sequence of strain A487 was determined using 454 GS FLX technology, allowing the identification of the structural gene (hlp) encoding the mature peptide MQFITDLIKKAVDFFKGLFGNK. The deduced amino acid sequence of peptide 487 exhibited 70.8% similarity to that of a putative haemolysin from Staphylococcus cohnii. Analysis of the genome of strain A487 showed several additional inhibitor encoding genes, including hld, the determinant for staphylococcal delta-lysin. This work indicates that potentially useful inhibitors could be overlooked in agar-based inhibitor screening programmes lacking a heat pretreatment step and also highlights the utility of draft genome sequence examination in antibacterial agent discovery. PMID- 21539625 TI - The CodY pleiotropic repressor controls virulence in gram-positive pathogens. AB - CodY is involved in the adaptive response to starvation in at least 30 different low G+C gram-positive bacteria. After dimerization and activation by cofactor binding, CodY binds to a consensus palindromic DNA sequence, leading to the repression of approximately 5% of the genome. CodY represses the transcription of target genes when bound to DNA by competition with the RNA polymerase for promoter binding, or by interference with transcriptional elongation as a roadblock. CodY displays enhanced affinity for its DNA target when bound to GTP and/or branched chain amino acids (BCAA). When nutrients become limiting in the postexponential growth phase, a decrease of intracellular levels of GTP and BCAA causes a deactivation of CodY and decreases its affinity for DNA, leading to the induction of its regulon. CodY-regulated genes trigger adaptation of the bacteria to starvation by highly diverse mechanisms, such as secretion of proteases coupled to expression of amino acid transporters, and promotion of survival strategies like sporulation or biofilm formation. Additionally, in pathogenic bacteria, several virulence factors are regulated by CodY. As a function of their access to nutrients, pathogenic gram-positive bacteria express virulence factors in a codY-dependant manner. This is true for the anthrax toxins of Bacillus anthracis and the haemolysins of Staphylococcus aureus. The purpose of this review is to illustrate CodY-regulated mechanisms on virulence in major gram positive pathogens. PMID- 21539626 TI - Decisions about transferring nursing home residents to hospital: highlighting the roles of advance care planning and support from local hospital and community health services. AB - AIMS AND OBJECTIVES: To explore current practice and opportunities to improve practice in decision-making about transfer of nursing home residents to hospital. BACKGROUND: Nursing home staff are often faced with the decision of whether to send a resident to hospital for medical treatment. While many residents will benefit from going to hospital, there are also several risks associated with this. This study sought to add to the existing body of research on this issue by seeking the views of nursing home managers, who are the persons most frequently involved in making these decisions. DESIGN: Qualitative design using purposive, quota sampling. METHOD: Qualitative interviews with 41 nursing home managers from south-western Sydney, Australia. RESULTS: Factors affecting the decision to transfer a resident to hospital include acuteness of their condition; level and style of medical care available; role of family members; numbers, qualifications and skills mix of staff; and concern about criticism for not transferring to hospital. Two factors that have not featured as strongly in previous research are the roles of advance care planning and support from local hospital and community health services. CONCLUSION: While transferring a nursing home resident to hospital is often necessary, there are many situations where they could be cared for in the nursing home; therefore, avoid complications associated with being in hospital. Apart from a range of factors already identified in the literature, this study has highlighted the important role that advance care planning and support from local health services can play in reducing unnecessary transfers to hospital. RELEVANCE TO CLINICAL PRACTICE: There are several strategies that nursing homes and local health authorities can adopt to promote advance care planning and build better support systems between the two sectors, thereby reducing the numbers of residents who need to be transferred to hospital for their health care. PMID- 21539627 TI - Spanish nurses' attitudes towards research and perceived barriers and facilitators of research utilisation: a comparative survey of nurses with and without experience as principal investigators. AB - AIMS AND OBJECTIVE: To examine attitudes towards research and perceived barriers and facilitators of research utilisation in clinical practice in a broad cross section of Spanish nurses. BACKGROUND: Nurses' attitudes towards research are critical in determining whether study findings are used to improve practice. DESIGN: Cross-sectional comparative survey in Hospitals, Primary Care Centres and University-affiliated schools of nursing. METHODS: Surveys were completed by 917 nurses: 69 who received funding from the Spanish national agency (1998-2004) and a nationally representative sample of 848 nurses who did not have the same research experience (the Comparison group). Two instruments (BARRIERS and Attitudes towards nursing research) were translated and culturally adapted for use in Spain. A descriptive analysis of demographic and practice characteristics was performed. Total scale scores, as well as subscale scores, were computed and compared across the two groups using one-way analysis of variance (anova) and multivariate analysis of variance (manova) with post hoc tests. Pearson product moment correlation coefficients were computed between the total tool scores and subscales measuring barriers and attitudes in both groups. RESULTS: The investigators differed from other nurses on several demographic and work characteristics (more males, older age and more likely to work a fixed day shift schedule). On the whole, investigators showed more favourable attitudes but perceived several elements as posing greater barriers to research utilisation than the Comparison groups. Across all respondents, issues related to the quality of research were rated as the greatest barriers to research utilisation, followed by organisational barriers, barriers involving the communication of findings and finally, those related to nurses' values, awareness and skills. CONCLUSIONS: Very similar profiles of perceptions and attitudes regarding research were found in these samples of Spanish nurses relative to those from other countries in earlier reports. Nurses who had experience conducting research demonstrated more favourable research-related attitudes and perceived barriers differently than those without such experience. RELEVANCE TO CLINICAL PRACTICE: Understanding different organisational and experience perspectives is important to identify challenges and opportunities to ensure research utilisation in clinical practice. PMID- 21539628 TI - The impact of antipsychotic side effects on attitudes towards medication in people with schizophrenia and related disorders. AB - AIMS AND OBJECTIVES: This research aimed to: (i) investigate the prevalence and perceived severity of antipsychotic side effects in people with schizophrenia and related disorders living in communities in Singapore; (ii) examine the relationship between antipsychotic variables (type, dose, route, prescription duration) and side effects; and (iii) examine the relationship between side effects and attitudes towards medication. BACKGROUND: Antipsychotics are the mainstay treatment in schizophrenia and other psychotic disorders. However, antipsychotics are associated with a wide range of side effects, which potentially have adverse effects on patients' functioning. A lack of studies comparing the frequency of side effects and their associated levels of distress across multiple antipsychotics and different medication variables has been noted. Additionally, it is essential to assess patients' attitudes towards antipsychotics in relation to their experience of side effects. DESIGN: A cross sectional, non-experimental research design was used. METHOD: A convenience sample of 96 adults with schizophrenia and related disorders on antipsychotic treatment and attending the hospital's outpatient clinic was recruited. Variables collected included antipsychotic type, dose, route, prescription duration and side effects, attitudes towards medication and demographic and clinical variables. They were analysed with descriptive statistics and correlational analyses. RESULTS: Many participants experienced psychic (80.2%), extrapyramidal (69.8%) and miscellaneous side effects (61.5%). Side effects positively correlated with dose (p = 0.016) and negatively correlated with prescription duration (p = 0.014). Negative attitudes towards medication were positively correlated with side effects in general (p = 0.023), along with hormonal (p = 0.013) and psychic side effects (p = 0.008). CONCLUSION: Findings revealed that majority of the participants experienced and were distressed over psychic, extrapyramidal and weight gain, which may be related to high doses and treatment duration. Additionally, patients experiencing psychic and hormonal side effects are at risk of developing negative attitudes towards medication. RELEVANCE TO CLINICAL PRACTICE: Findings guide the development of appropriate nursing interventions that aim to alleviate side effects, reduce negative attitudes towards medication and prevent compliance problems. PMID- 21539629 TI - Comparing the efficacy of aquatic exercises and land-based exercises for patients with knee osteoarthritis. AB - AIMS: The study aims to compare changes over time among three study groups on the primary outcome, pain, as well as on the secondary outcomes, other symptoms, activities of daily living function, sport and recreation function, knee-related quality of life, knee range of motions and the six-minute walk test and to investigate whether aquatic exercises would be superior compared with land exercise on pain reduction. BACKGROUND: Osteoarthritis is a prevalent musculoskeletal disorder. Appropriate exercise may prevent osteoarthritis associated disabilities and increase life quality. To date, research that compares the effects of different types of exercise for knee osteoarthritis has been limited. DESIGN: The study is a randomised trial. METHODS: Eighty-four participants with knee osteoarthritis were recruited from local community centres. Participants were randomly assigned to the control, aquatic or land based exercise group. Exercise in both groups ran for 60 minutes, three times a week for 12 weeks. Data were collected at baseline, week 6 and week 12 during 2006-2007. The instruments included the Knee Injury and Osteoarthritis Outcome Score, a standard plastic goniometer and the six-minute walk test. Generalised estimation equations were used to compare changes over time among groups for key outcomes. RESULTS: Results showed statistically significant group-by-time interactions in pain, symptoms, sport/recreation and knee-related quality of life dimensions of Knee Injury and Osteoarthritis Outcome Score, knee range of motions and the six-minute walk test. However, the aquatic group did not show any significant difference from the land group at both weeks 12 and 6. CONCLUSIONS: Both aquatic and land-based exercise programmes are effective in reducing pain, improving knee range of motions, six-minute walk test and knee-related quality of life in people with knee osteoarthritis. The aquatic exercise is not superior to land-based exercise in pain reduction. RELEVANCE TO CLINICAL PRACTICE: Similar outcomes could be possible with the two programmes. Health care professionals may consider suggesting well-designed aquatic or land-based exercise classes for patients with osteoarthritis, based on their preferences and convenience. PMID- 21539630 TI - Addiction research centres and the nurturing of creativity. Monitoring the European drug situation: the ongoing challenge for the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). AB - The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is the designated hub for drug-related information in the European Union. The organization's role is to provide the European Union (EU) and its Member States with a factual overview of European drug problems and a common information framework to support the drugs debate. In order to achieve its mission, the EMCDDA coordinates and relies on a network of 30 national monitoring centres, the Reitox National Focal Points. The Centre publishes on a wide range of drug related topics, across epidemiology, interventions, laws and policies. Every November, the EMCDDA publishes its Annual Report, providing a yearly update on the European drug situation, translated into 23 EU languages. In line with its founding regulation, the EMCDDA has a role acting as an interface between the worlds of science and policy. While not a research centre in the formal sense, the results the Centre generates serve as catalysts for new research questions and help to identify priorities. Current challenges facing the agency include continuing to increase scientific standards while maintaining a strong institutional role, as well as supporting European efforts to identify, share and codify best practice in the drugs field. PMID- 21539631 TI - Alcohol harm - the urgent need for a global response. PMID- 21539632 TI - Conversation with Raul Caetano. AB - In this occasional series we record the views and personal experience of people who have especially contributed to the evolution of ideas in the Journal's field of interest. Raul Caetano qualified in medicine in Brazil. While retaining close academic and cultural links with his native country, he has developed a career as an alcohol epidemiologist with research positions first in Berkeley,California and then at the University of Texas. He has contributed very widely to epidemiological research on drinking but with a sustained ability to develop the important ethnic dimensions of such studies. PMID- 21539633 TI - Conversation with Ian Stolerman. PMID- 21539634 TI - Promoting smoking cessation through smoking reduction during Ramadan. PMID- 21539635 TI - Randomized comparison between pulmonary vein antral isolation versus complex fractionated electrogram ablation for paroxysmal atrial fibrillation. AB - INTRODUCTION: Circumferential pulmonary vein antral isolation (PVAI) and atrial complex fractionated electrograms (CFEs) are both ablative techniques for the treatment of paroxysmal atrial fibrillation (PAF). However, data on the comparative value of these 2 ablation strategies are very limited. METHODS AND RESULTS: We randomized 118 patients with drug-refractory PAF to receive PVAI ablation (n = 60) or CFE ablation (n = 58). For CFE group, spontaneous/induced AF was mapped using validated, automated software to guide ablation until all CFE areas were eliminated. For PVAI group, all 4 pulmonary vein antra were electrically isolated as confirmed by circular mapping catheter. Patients with spontaneous/inducible AF after the initial ablation procedure were crossed over to the other arms. After initial ablation procedure, AF persisted/inducible in 24/59 patients (41%), and 34/58 patients (59%) assigned to PVAI and CFE ablation, respectively (P = 0.05). Then 58 patients underwent PVAI + CFE ablation. After 22.6 +/- 6.4 months, PVAI ablation group was more likely than CFE ablation group to achieve control of any AF/atrial tachycardia (AT) off drugs (43/60, 72% vs 33/58, 57%, P = 0.075) and lower recurrence rate of AT (11.9% vs 34.5%, P = 0.004). Patients who received CFE ablation alone (38%) had significantly lower overall success rate to achieve control of AF/AT off drugs compared with patients who received PVAI ablation (77%, P = 0.002) alone or PVAI + CFE ablation (69%, P = 0.008) due to higher recurrence rate of AT (50% vs 6% vs 13%, P < 0.01). CONCLUSIONS: CFE ablation in PAF patients was associated with higher occurrence rate of postprocedure AT compared with PVAI ablation, whereby making it less likely to be a sole ablation strategy for PAF patients. PMID- 21539636 TI - The electroanatomic mechanisms of atrial tachycardia in patients with tetralogy of Fallot and double outlet right ventricle. AB - BACKGROUND: Atrial tachycardias (AT) are common after palliation or repair of congenital heart disease. The electroanatomic mechanism of AT in postoperative tetralogy of Fallot (TOF) and double outlet right ventricle (DORV) patients has not been fully explored. METHODS AND RESULTS: Retrospective analysis of TOF or DORV patients was performed in the electrophysiology (EP) lab from January 1997 to March 2010. Sustained ATs were mapped using the Carto system (Biosense Webster, Diamond Bar, CA, USA). Fifty-eight patients were identified with 82 EP studies performed and 127 ATs identified. The first EP study for AT was performed at a median age of 35 years (2-58 years). Ninety-five IART circuits were identified, 5 in a figure-of-8 pattern. There were 13 focal ATs, 4 ectopic ATs, and 15 presentations of atrial fibrillation (AF). The cavotricuspid isthmus (CTI) was the critical area for ablation in the majority of TOF and DORV patients (53%). The CTI, along with the lateral RA wall, made up 85% of IART circuits. Excluding AF, the acute success rate for ablation was 90%. Of the 58 patients, 20 had additional ablation attempts, 19 within 3 years of their first ablation. CONCLUSION: The CTI and lateral RA wall are critical corridors of conduction in 85% of IART circuits in TOF and DORV patients. The acute success rate for AT ablations is high, but a substantial number of patients have required additional ablation procedures. Recurrences may be reduced if both the CTI and lateral RA wall are targeted and blocked, even if the mapped circuit points only to 1 region. PMID- 21539637 TI - A completely subcutaneous implantable cardioverter defibrillator in a patient with situs inversus totalis. PMID- 21539638 TI - Inappropriate shocks in patients with Fidelis(r) lead fractures: impact of remote monitoring and the lead integrity algorithm. AB - INTRODUCTION: The role of remote monitoring combined with lead integrity algorithm (LIA) in patients with Fidelis (Medtronic Inc., Minneapolis, MN, USA) lead fractures is not well defined. METHODS: We retrospectively identified patients with Fidelis lead fractures at our institution, documenting all pertinent data (remote monitoring use, clinical presentation, lead fracture diagnosis criteria). Patients were classified into subgroups based on the type of home monitoring and whether LIA was uploaded before lead fracture. Subgroups were compared based on delivery of inappropriate shocks (IS). RESULTS: A total of 131 patients (mean age 62 +/- 16 years, 70% male, 69% primary prevention implants) were followed until lead fracture (average 32 +/- 12 months). IS were delivered in 21% of patients (n = 11/52) with LIA versus 52% (n = 41/79) without LIA, P < 0.001. LIA significantly decreased the number of IS (2.1 +/- 1.0 IS vs 7.9 +/- 12 IS, P < 0.001) and significantly increased the number of patients diagnosed through audible alert (P < 0.001). Wireless monitoring significantly decreased the time interval to reprogram defibrillators OFF (mean 1.5 +/- 1 days vs 15.6 +/ 18 days with nonwireless CareLink [Medtronic Inc.] and 12.4 +/- 20 days without CareLink, P < 0.001); 14% of patients with LIA and wireless monitoring combined received IS. Without LIA, 63% of patients with wireless monitoring received IS. CONCLUSION: This study confirms that LIA significantly decreases IS therapy in patients with Fidelis lead fractures. Wireless technology enhances LIA benefits by significantly shortening time to reprogram defibrillators. However, despite the "best scenario" of combining LIA and wireless monitoring, 14% of patients with lead fractures still get IS. Further refinements of detection algorithms are required to eliminate this significant clinical problem. PMID- 21539639 TI - Atrioventricular node ablation and pacemaker implantation for recurrent syncope in a patient with postural tachycardia syndrome (POTS). AB - Ablate and pace for POTS. A 42-year-old woman with postural tachycardia syndrome (POTS) was admitted to our hospital with severe palpitations, light-headedness, and syncope. Several drugs had been administered previously, but all had been discontinued due to intolerable adverse effects or limited efficacy. One of the drugs, the I(f) current inhibitor ivabradine, effectively slowed the patient's heart rate and relieved the symptoms, but was discontinued due to allergy. After unsuccessful sinus node ablation, atrioventricular node ablation and dual chamber pacemaker implantation was performed, which dramatically improved her symptoms and eliminated syncope. Atrioventricular node ablation could modify the cardiac autonomic balance and thereby suppressed the excessive orthostatic sympathetic activity. PMID- 21539640 TI - Termination of persistent atrial fibrillation during left atrial mapping. AB - Termination of Persistent AF During Mapping. Complex fractionated atrial electrograms (CFAEs) may represent critical areas for the maintenance of atrial fibrillation (AF). While AF organization and termination have been reported with CFAE ablation, no reports of arrhythmia termination during left atrial mapping exist. We report a case of reproducible AF termination with catheter pressure at a site of CFAE remote from the site of AF. PMID- 21539641 TI - Unusual response of an accessory atrioventricular connection to adenosine. PMID- 21539642 TI - Ventricular tachycardia ablation remains treatment of last resort in structural heart disease: argument for earlier intervention. AB - INTRODUCTION: Despite advances in ablation of ventricular tachycardia (VT), recognized toxicity of amiodarone, and potential harm of implantable cardioverter defibrillator (ICD) shocks, there appears to be reluctance to pursue catheter ablation. METHODS AND RESULTS: We tested the hypothesis that patients with structural heart disease and VT are referred late for ablation and may have worse outcomes as a result. Consecutive patients with VT and structural heart disease referred to a single center, between January 2008 and April 2009 were studied. Patients with prior VT ablations were excluded. Late referrals were defined as those with 2 or more episodes of VT, separated by at least 1 month. Ninety-eight consecutive patients were analyzed. Ninety-six percent of patients had an ICD implanted prior to ablation, 58% were in VT storm and 67% taking >=400 mg daily of amiodarone or amiodarone intolerant (10%). Thirty-six patients fit the definition of early referral and 62 late. Overall acute procedural success was achieved in 89%. Amiodarone dose decreased from a mean and median of 559 and 400 mg daily preablation to 98 and 0 postablation (P < 0.01). Mean and median VT episodes decreased from 17 and 6 in the month preceding ablation to 1 and 0 in the 6 months following ablation (P < 0.01). In Kaplan-Meier analysis, the early referral group had superior 1-year VT free survival (P = 0.01). CONCLUSIONS: VT ablation is frequently reserved for patients receiving recurrent ICD shocks despite high dose amiodarone. Stronger consideration should be given to earlier referral for VT ablation in patients with structural heart disease. PMID- 21539643 TI - Heart rate turbulence can predict cardiac mortality following myocardial infarction in patients with diabetes mellitus. AB - BACKGROUND: Previous studies have described the clinical utility of heart rate turbulence (HRT) as an autonomic predictor in risk-stratifying patients after myocardial infarction (MI). Some reports showed that diabetes mellitus (DM) affects the prognostic value of autonomic markers. We assessed the utility of HRT as a risk marker in post-MI patients with DM and without DM. METHODS: We prospectively enrolled 231 consecutive DM patients and 300 non-DM patients after acute MI. HRT was measured using an algorithm based on 24-hour Holter electrocardiograms (ECGs), assessing 2 parameters: turbulence onset (TO) and turbulence slope (TS). HRT was considered positive when both TO >=0% and TS <=2.5 ms/R-R interval were met. The endpoint was defined as cardiac mortality. RESULTS: Of patients with DM, 9 patients (4%) were not utilized for HRT assessment because of frequent ventricular contractions or presence of atrial fibrillation. Forty two of 222 patients (19%) were HRT positive. During follow-up of 876 +/- 424 days, 26 patients (22%) reached the endpoint. Several factors including left ventricular ejection fraction (LVEF), renal dysfunction, documentation of nonsustained ventricular tachycardia (VT), and a HRT-positive outcome had significant association with the endpoint. Multivariate analysis determined that renal dysfunction and a positive HRT outcome had significant value with a hazard ratio (HR) of 4.7 (95%CI, 1.9-11.5; P = 0.0008) and 3.5 (95%CI, 1.4-8.8; P = 0.007), respectively. In non-DM patients, only a positive HRT outcome had significant value. CONCLUSIONS: This study reveals that HRT detected by 24-hour Holter ECG can predict cardiac mortality in post-MI patients whether DM is present or not. PMID- 21539645 TI - Abstracts of the 31st Annual Meeting of the American Society for Reproductive Immunology. May 19-22, 2011. Salt Lake City, Utah, USA. PMID- 21539646 TI - Comparison of retention and strain energies of stud attachments for implant overdentures. AB - PURPOSE: The retentive forces and the strain energies absorbed during dislodging of implant overdenture stud attachments are useful parameters to consider in the selection of attachments. The purpose of this study was to compare the retentive forces and strain energies of the Nobel Biocare standard ball, Nobel Biocare newer generation ball (Yorba Linda, CA), Zest Anchor, Zest Anchor Advanced Generation (Escondido, CA), Sterngold-Implamed ERA white, and Sterngold-Implamed orange attachments (Attleboro, MA) on an implant-retained in vitro overdenture model. MATERIALS AND METHODS: The attachments were tested using two permanently placed Branemark system implants on a test model attached to an Instron machine. Each attachment had one part embedded in a denture-like housing, and the other part screwed into the implants. Dislodging tensile forces were applied to the housings in two directions simulating function: vertical and oblique. Eight tests were done in two directions with six specimens of each attachment. Retentive forces generated and strain energies absorbed during displacement were determined. A 1-way ANOVA followed by the Tukey studentized range test was used to determine groups that were significantly different at the p < 0.05 level. RESULTS: The Zest Anchor Advanced Generation attachment had significantly the highest retentive vertical and oblique forces [37.2 (5.5) N and 25.9 (3.2) N, respectively]. The Zest Anchor had the lowest vertical force [10.8 (4.2) N], and Nobel Biocare Standard had the lowest oblique retentive force [10.6 (3.0) N]. The Nobel Biocare Standard Ball attachment had the highest strain energies [29.7 * 10(-3) (11.9 * 10(-3)) J, 30.3 * 10(-3) (14.3 * 10(-3)) J, respectively, in the vertical and oblique directions]. The Sterngold-Implamed ERA White and Zest Anchor had the lowest strain energies [5.3 * 10(-3) (3.2 * 10(-3)) J and 4.5 * 10(-3) (1.1 * 10(-3)) J, respectively, in the vertical and oblique directions]. CONCLUSION: The retentive forces and strain energies of implant overdenture stud attachments are different and should be considered during prosthesis selection. PMID- 21539647 TI - Time course of the angiogenic response during normotrophic and hypertrophic scar formation in humans. AB - Previous research suggests that in hypertrophic scars (HSs), an excess of microvessels is present compared with normotrophic scars (NSs). The aim of our study was to quantify vascular densities in HSs and normotrophic scars and to provide an insight into the kinetics of changes in the expression of angiogenic factors in time during wound healing and HS formation. Human presternal wound healing after cardiothoracic surgery through a sternotomy incision was investigated in a standardized manner. Skin biopsies were collected at consecutive time points, i.e., during surgery and 2, 4, 6, 12, and 52 weeks postoperatively. The expression levels of angiopoietin-1, angiopoietin-2, Tie-2, vascular endothelial growth factor, and urokinase-type plasminogen activator were measured by real-time reverse transcription-polymerase chain reaction. Quantification of angiogenesis and cellular localization of the proteins of interest were based on immunohistochemical analysis. Microvessel densities were higher in the HSs compared with the normotrophic scars 12 weeks (p=0.017) and 52 weeks (p=0.030) postoperatively. Angiopoietin-1 expression was lower in the hypertrophic group (p<0.001), which, together with a nonsignificant increase of angiopoietin-2 expression, represented a considerable decrease in the angiopoietin-1/angiopoietin-2 ratio in the hypertrophic group 4 weeks (p=0.053), 12 weeks (p<0.001), and 52 weeks (p<0.001) postoperatively. The expression of urokinase-type plasminogen activator was up-regulated during HS formation (p=0.008). Vascular endothelial growth factor expression was not significantly different when comparing both groups. In summary, the differential expression of angiopoietin-1, angiopoietin-2, and urokinase-type plasminogen activator in time is associated with an increased vascular density in HSs compared with normotrophic scars. PMID- 21539648 TI - Development of the DESIGN-R with an observational study: an absolute evaluation tool for monitoring pressure ulcer wound healing. AB - DESIGN is a seven-item (depth, exudates, size, inflammation/infection, granulation, necrosis, and pocket) monitoring scale for pressure ulcers developed in 2002 by the scientific education committee of the Japanese Society of Pressure Ulcers. DESIGN is a very useful tool for chronological monitoring of each pressure ulcer, but a key limitation of this tool is its inability to compare the wound-healing process among different pressure ulcers in different patients due to a lack of statistical item weighting. Our aim was to weight DESIGN items by statistical analysis and develop a new validated tool to overcome this limitation. Subjects comprised 3,601 patients with pressure ulcers. Patients were followed every week during the study period. To establish the weighting of each item and grade, we estimated the probabilities of wound healing at 12-month follow-up using multivariable Cox's regression analysis. Weighting (-beta value) for each item in order of the highest rank was: pocket, 2.289; size, 1.573; inflammation/infection, 0.778; granulation tissue, 0.682; exudate, 0.543; and necrotic tissue, 0.529. Based on these findings, a new, validated "DESIGN-Rating tool" for monitoring the progression of pressure ulcer healing was developed, implying the development of an absolute evaluation tool and clinical indicator to assess the quality of medical care. PMID- 21539649 TI - A novel noncontact method to assess the biomechanical properties of wound tissue. AB - A novel noncontact optical coherence tomography based air-jet indentation system was developed for characterizing the biomechanical properties of soft tissue in a noncontact way. This study aimed to measure the stiffness of diabetic foot ulcer tissues by using this air-jet indentation system, and examining the test/retest reliability. Eight subjects with diabetes (seven males, one female), with a total of 10 foot ulcers between them, participated in the study. A total of 20 measuring sites located at the central wound bed (n=10) or peri-ulcer areas (n=10), respectively, were evaluated with the air-jet indentation system. Four cycles of loading and unloading, each with a duration of approximately 36 seconds at an indentation rate of 0.08 mm/s, were carried out for each indentation trial. The test/retest reliability was examined at all measuring points. The average stiffness coefficient of the peri-ulcer area (mean +/- SD: 0.47 +/- 0.15 N/mm) was significantly larger than that of the central wound bed area (mean +/- SD: 0.35 +/- 0.23 N/mm; p=0.042). A high value for test/retest reliability was shown (intraclass correlation coefficient: 0.986; Pearson's correlation: r=0.972, p<0.001). Our preliminary findings showed that the peri-ulcer area had greater stiffness than the central wound bed. This greater magnitude of hardness and inelasticity at the peri-ulcer region may scatter part of the contractile forces for wound contraction during the healing process. We found the novel air-jet system to be a reliable tool for characterizing the stiffness of soft tissues around the wound in a noncontact way. PMID- 21539650 TI - Evaluation of effects of nutrition intervention on healing of pressure ulcers and nutritional states (randomized controlled trial). AB - The objective of this study was to evaluate the effects of nutrition intervention on nutritional states and healing of pressure ulcers by standardizing or unified factors including nursing, care and treatment in a multicenter open randomized trial. Tube-fed patients with Stage III-IV pressure ulcers were selected. The control group (30 patients) received the same nutrition management as before participating in this trial, whereas the intervention group (30 patients) was given calories in the range of Basal Energy Expenditure (BEE) * 1.1 * 1.3 to 1.5. The intervention period was 12 weeks. The efficacy and safety were evaluated based on the nutritional states and the sizes of ulcers (length * width), and on the incidence of adverse events related to the study, respectively. The calories administered to the control and intervention groups were 29.1 +/- 4.9 and 37.9 +/ 6.5 kcal/kg/day, respectively. Significant interactions between the presence or absence of the intervention and the intervention period were noted for nutritional states (p<0.001 for body weight, p<0.05 for prealbumin). Similarly, the size of ulcers differed significantly between subjects in the intervention group and in the control group (p<0.001). The results suggest that nutrition intervention could directly enhance the healing process in pressure ulcer patients. PMID- 21539651 TI - Statistical approach for avoiding pseudoreplication and increasing power in wound healing studies. AB - Many animal wound-healing models measure the progression of healing over time, resulting in counts of fully healed wounds from different treatments at several time points. Data from these models are usually analyzed using contingency table methods. However, pooling data from multiple animals without appropriate correction for animal-to-animal variability results in pseudoreplication. Kaiser and colleagues, overcame pseudoreplication by adjusting the estimate of healing variation to account for the interanimal covariance. This solution nevertheless is limited by the ability to accurately estimate the adjustment factor due to the small number of animals used. An improved method is described that both overcomes pseudoreplication and increases power. It involves estimating the time for half of the wounds within each animal to be completely healed (TCH(50)), rather than a pooled estimate for all animals (HT(50)). Subsequent ANOVA testing of the individual TCH(50) values, using a model with fixed treatments and random animals, generates unbiased estimates of treatment means and differences between means, and accurate p-values for these differences and for the overall model. This method has sufficient power to detect treatment differences with fewer animals. Furthermore, it is fully applicable to analyses of results from human trials having similar data organization. PMID- 21539652 TI - Prevention of imported pediatric malaria--travel medicine misses the bull's eye. PMID- 21539653 TI - A local, regional, and national assessment of pediatric malaria in the United States. AB - BACKGROUND: Imported malaria remains a public health concern in the United States, but the health impact on children and the financial costs to society have not been well defined. METHODS: Inpatient and outpatient malaria cases diagnosed at Children's National Medical Center (CNMC) in Washington, DC over an 8-year period are retrospectively reviewed. Cases are mapped against Census Bureau population data. These observations are compared with the national burden of pediatric malaria, including both disease severity and cost, by reviewing inpatient malaria cases in the Pediatric Health Information System (PHIS), January 2003 to June 2008. RESULTS: At CNMC, malaria most commonly affects children who traveled to West Africa to visit friends and relatives. Poor adherence to prophylaxis and self-treatment with antimalarial medications were commonly identified. Mapping demonstrates case clustering in communities with large sub-Saharan African populations. The cumulative incidence (CI) of malaria at CNMC of 9.0 per 10,000 admissions is 7.6 times the national average. The CI of malaria at PHIS hospitals is 1.2 per 10,000 admissions with an average cost of $17,519. CONCLUSIONS: Malaria is a preventable disease for which the risk to life and costs of treatment are significant. Patterns of risk can be used by health planners to target prevention strategies at the community level. In regions with a high density of immigrants, particularly from sub-Saharan Africa, physicians must be aware of the risk, understand recommended prophylaxis and treatment regimens, and advocate for their appropriate use in the community. PMID- 21539654 TI - Malaria prophylaxis in African and Asiatic children traveling to their parents' home country: a Florentine Study. AB - BACKGROUND: The majority of malaria cases in Europe occur in immigrated adults and children settled in nonendemic countries but who had traveled to their home country to visit friends and relatives. METHODS: We carried out a study on a sample of 71 parents immigrated from high-risk countries to investigate awareness of malaria risk and use of pharmacological and nonpharmacological (repellents, insecticides, nets, and insecticide-treated nets) prophylaxis. A questionnaire was administered to a convenience sample of immigrant parents who presented their children for acute care to the Emergency Department, Anna Meyer Children's University Hospital, Florence, Italy between August and November 2009. RESULTS: Fifty-nine out of 71 (83.1%) parents were aware of malaria risk in their native country. Forty-one (57.7%) children had traveled to their parents' home country. Nonpharmacological prophylaxis was used in 30 (73.1%) children. Eight (19.5%) children had received pharmacological prophylaxis, the mostly used drug being mefloquine in six out of eight (75%) patients. Seven out of eight (87.5%) children completed prophylaxis appropriately. Adverse drug reaction was reported in one (12.5%) patient. While abroad, eight (19.5%) parents and one (2.4%) child reported to have developed malaria. A significantly higher proportion of children traveling to Africa compared to children traveling to Asia (5/11 = 46% vs 3/30 = 10%, p = 0.036) had received pharmacological prophylaxis. CONCLUSIONS: Our data highlight the need for educational actions in Italy about malaria prophylaxis among immigrants. Larger epidemiological investigations are needed at this regard. PMID- 21539655 TI - Malaria in paradise: characterization of imported cases in Gran Canaria Island (1993-2006). AB - BACKGROUND: Spain obtained the official certificate of malaria eradication in 1964. However, imported malaria cases have been increasing during the last few decades in this country. This study aims to describe the clinical and epidemiological features of patients diagnosed with malaria on Gran Canaria Island. METHODS: A retrospective study was conducted based on case review of all patients diagnosed with malaria microbiologically confirmed from 1993 to 2006, at the three referral teaching hospitals on Gran Canaria Island. RESULTS: One hundred eighty-four episodes in 181 patients were diagnosed, 170 of them were analyzed. Most of them (82%) were travelers. Nearly 15% (14.7%) declared having had some chemoprophylaxis, but only half of them completed the treatment. Twenty cases (10.9%) were diagnosed who had just arrived as immigrants, mainly children. Malaria was acquired in Africa by 94.7% of the cases and Plasmodium falciparum was responsible for the majority of the cases (84.1%). Clinical and epidemiological differences were observed among different groups of patients formed by their origin and travel purposes. At least one indicator of severe malaria was established in 22.9% of the cases. However, global mortality was 3.8%. CONCLUSIONS: Malaria in Gran Canaria Island is imported from endemic areas, mainly from African countries, observed mostly among young adult males, but clinical and epidemiological features may change among different groups of patients. The number of immigrants diagnosed with malaria is increasing in this area nowadays. PMID- 21539656 TI - Knowledge, attitudes, and practices on malaria prevention among Chinese international travelers. AB - BACKGROUND: To address the lack of understanding in malaria prevention among Chinese international travelers, we have conducted knowledge, attitudes, and practices (KAP) study in five different Chinese geographic areas. This survey represents one part of the background information needed to analyze imported malaria. METHODS: Standardized questionnaires were distributed to Chinese international travelers in departure lounges at international airports in Guangzhou, Beijing, Shanghai, Qingdao, and Nanjing. The data were entered into the Epidata 3.1 (Jens M. Lauritsen, Odense, Denmark) and analyzed by the SPSS 12.0 statistical package (SPSS Inc., Chicago, IL, USA). RESULTS: Overall 2,495 completed questionnaires were collected from departing Chinese passengers; 1,573 were contributed by travelers who were going to malaria risk countries. More than half of all travelers spent less than 7 days to organize their trip abroad. Pre travel medical advice was sought by 998 travelers (40.0%), 65.1% of them did so for 1-7 days before departure. Only 4.0% travelers received their knowledge from travel health providers. Among 389 travelers who were going to high malaria risk countries, only 18.0% realized that there is a high malaria risk in sub-Saharan Africa. Most travelers going to risk areas knew about personal protection measures against mosquito bites, but only 21.4% and 12.1% carried mosquito repellents or insecticides, respectively. Only 18.7% of the 1,573 potentially exposed travelers carried malaria tablets, all of them for self-treatment, none for prophylaxis. CONCLUSION: KAP about malaria among exposed Chinese travelers is far from satisfactory. To reduce the rate of imported malaria, specific educational tools should be developed for those at high risk to make them understand and become compliant with chemoprophylaxis. PMID- 21539657 TI - Reported cases of measles in international air travelers to the United States, August 2005-March 2008. AB - BACKGROUND: In countries with high rates of measles immunization, imported cases of measles represent an important continuing source of measles infection. METHODS: Airlines and state health departments report cases of suspected measles in international travelers to the Centers for Disease Control and Prevention Quarantine Stations. We reviewed these reports, maintained in an electronic database, to determine the demographic and epidemiologic characteristics of international air travelers infected with measles. RESULTS: We reviewed 35 confirmed cases of measles in air travelers and analyzed their demographic and epidemiologic characteristics. The median age of case travelers was 17 (range: 4 months-50 years). These travelers arrived from all regions of the world, including 10 countries with immunization rates of measles-containing vaccine below 90% and five others experiencing local outbreaks. Of 17 travelers for whom immunization status was known, 2 had been adequately immunized with at least two doses of a measles-virus containing vaccine, 9 were inadequately immunized, and an additional 6 infants had not been immunized because of age. CONCLUSIONS: Measles importations continue in the United States. Travelers should be aware of the importance of assuring up-to-date immunizations, especially when visiting countries experiencing a local measles outbreak. In addition, parents traveling with infants, and their physicians, should be aware of recommendations regarding the early administration of a dose of measles-containing vaccine for infants at least 6 months old traveling internationally. PMID- 21539658 TI - Molecular surveillance of circulating dengue genotypes through European travelers. AB - BACKGROUND: Dengue viruses (DENV) are the most widespread arthropod-borne viruses, which have shown an unexpected geographic expansion, as well as an increase in number and severity of outbreaks in the last decades. Although the emergence of dengue is considered to be due to a number of complex factors, epidemiological studies have shown that some strains of dengue might be associated with increased severity and higher transmission rates than others. In this context, surveillance and identification of the appearance or introduction of more virulent strains, along with fluctuation of DENV among endemic areas are now considered essential public health activities. METHODS: Samples from travelers returning from the tropics with acute dengue infections were analyzed to obtain up-dated information on circulating dengue strains. A short nucleotide fragment located in the carboxyl terminus of the dengue E gene was used for the characterization of DENV strains and the identification of their sero- and genotype. RESULTS: One hundred eighty-six new dengue strains have been classified into 12 distinct genotype groups within the four dengue serotypes. The identification of the emergence of different sero- and genotypes, the appearance of new clades correlating with outbreaks, and the identification of a dengue-4 genotype not previously reported have been achieved. Interestingly, African strains characterized in this study have provided valuable data on dengue circulation on the continent. CONCLUSIONS: This work demonstrates the convenience of routine application of molecular epidemiology analyses in dengue diagnosis laboratories. The use of molecular epidemiology tools on the analysis of imported dengue infections strengthens data acquisition on dengue strain movements correlating with epidemiological changes. The importance of surveillance of imported diseases contributing data for the epidemiological knowledge of infectious diseases in endemic areas has been once more demonstrated. PMID- 21539659 TI - Neurocysticercosis in travelers: a nation-wide study in Israel. AB - BACKGROUND: Cysticercosis, a human infestation by Taenia solium is endemic in many resource-limited countries. In developed countries it is mostly encountered among immigrant populations. Only few cases are reported in travelers. This report summarizes a nation-wide study of neurocysticercosis (NCC) diagnosed among Israeli travelers to endemic countries, with an estimation of disease incidence among the traveler population. METHODS: We performed a retrospective, nation-wide survey of travel-related NCC in Israel between the years 1994 and 2009. RESULTS: Nine cases of NCC were diagnosed in Israeli travelers during the study years. Most patients had traveled to South and/or Southeast Asia. The most common symptom at diagnosis was a seizure. The average interval between return from the suspected travel and symptom onset was 3.2 +/- 1.8 years. Two patients suffered from multiple lesions, whereas the rest had a single lesion. Antihelminthic treatment was given to most patients with resolution of symptoms. Median duration of antiepileptic treatment was 16 +/- 41 months after albendazole was given. Antiepileptic treatment was discontinued without any complications. The estimated attack rate of clinical disease was 1 : 275,000 per travel episode to an endemic region. CONCLUSIONS: NCC in travelers is a rare phenomenon commonly presenting as seizure disorder manifesting months to years post-travel. Antihelminthic therapy followed by 12 to 24 months of antiepileptic therapy resulted in complete resolution of symptoms in our patients. PMID- 21539660 TI - Predictors for the uptake of recommended vaccinations in Mecca travelers who visited the Public Health Service Amsterdam for mandatory meningitis vaccination. AB - BACKGROUND: Hajj, the pilgrimage to Mecca, is one of the obligatory religious duties of Islam. The travel clinic of the Public Health Service (PHS) Amsterdam administers vaccinations, including the required meningitis ACYW135 vaccine, and provides travelers with individual recommendations for all their travels. METHODS: We extracted all data from the PHS database pertaining to Muslims who visited the clinic before travel to Mecca. From 2001 to 2009, the characteristics are described and trends are analyzed retrospectively. Acceptance of dTP vaccine was used as a proxy for acceptance of recommended vaccinations. For the years 2007 to 2009, predictive factors for the acceptance of advised vaccinations are analyzed. RESULTS: From 2001 to 2009, significantly more women and people older than 50 years of age traveled to Mecca. Since 2007, only 527 of 2,156 (24%) of those who were advised to take vaccines accepted the recommendation. Independent factors for acceptance were being female, of younger age, and being less healthy. Specifically, Mecca travelers with heart disorders and with liver or gastrointestinal disorders accepted recommended vaccinations more often than those without. CONCLUSIONS: Only a quarter of Mecca travelers who visit the travel clinic for their mandatory meningitis vaccination also take other, recommended, vaccinations. To improve the acceptance rate, Islamic organizations that inform Mecca travelers in preparation for their travel should be supplied with up-to-date advice, not only about the requirements but also about recommended vaccinations and health precautions. PMID- 21539661 TI - Attitudes and behaviors of international air travelers toward pandemic influenza. AB - BACKGROUND: Air travelers play a significant role in the spread of novel strains of influenza viruses; however, little is understood about the knowledge, attitudes, and practices of international air travelers toward pandemic influenza in relation to public health interventions and personal protective behaviors at overseas destinations. METHODS: Prior to the 2009 H1N1 influenza pandemic, we surveyed a convenience sample of 404 departing international travelers at Detroit Metropolitan Wayne County Airport. Presented with a hypothetical pandemic influenza scenario occurring overseas, the participants predicted their anticipated protective behaviors while abroad and recorded their attitudes toward potential screening measures at US ports of entry (POE). The survey also qualitatively explored factors that would influence compliance with health entry screening at POE. RESULTS: Those who perceived pandemic influenza to be serious were more likely to state that they would be comfortable with screening (p = 0.006), and if they had influenza-like illness (ILI) overseas, would be more willing to see a physician and delay return travel (p = 0.006 and 0.002, respectively). Other demographic variables, including age and race, were associated with protective behaviors in response to ILI. Travelers also identified diverse information requirements which would influence their behavior in response to entry screening, including characteristics of the pandemic, severity of illness, and screening operations. CONCLUSIONS: Demographic characteristics and perceived severity of illness are important factors that may influence the protective behaviors of travelers overseas. Our results indicate that educational material and advice directed to international travelers could be differentially tailored to traveler subpopulations. PMID- 21539663 TI - Cutaneous abscess after Conus textile sting. AB - We present a 31-year-old man who, after a Conus textile sting acquired in New Caledonia, developed a cutaneous abscess on a buttock. The abscess was accompanied by pain, paraesthesia, general malaise, and fever. Complete remission was achieved by sodium hypochlorite packs and oral amoxicillin/clavulanic acid, metronidazole, and tramadol. PMID- 21539664 TI - Self-limited travelers' diarrhea by Isospora belli in a patient with dengue infection. AB - Isospora belli diarrhea is usually associated with immunosuppression. This parasite has rarely been reported as a cause of travelers' diarrhea in immunocompetent patients. We present a clinical case of travelers' diarrhea due to I belli in a patient with transient lymphopenia secondary to dengue infection. PMID- 21539665 TI - Are UK commercial expeditions complying with wilderness medical society guidelines on ascent rates to altitude? AB - The incidence of acute mountain sickness can be reduced by ascending slowly to altitude. We compared a recommended ascent rate with those offered by commercial companies to three of the most popular high-altitude destinations in the world. While the majority complied with the recommended ascent rate, ascents on Kilimanjaro did not. PMID- 21539667 TI - Self-reporting compared to prospective surveillance to evaluate the incidence of diarrhea among French Army personnel deployed to N'djamena, Chad. AB - Self-reporting seems more appropriate than medical-based surveillance to estimate true incidence of diarrhea during deployment of military troops. Most soldiers self-reported multiple episodes, 42% leading to medical care, mainly the first episode, resulting in a threefold higher incidence. Mathematical models integrating self-reported data should better predict outbreaks during military deployments and define a more complete assessment of disease burden. PMID- 21539668 TI - Crohn's disease or tuberculosis? AB - A Nepali-born migrant was diagnosed with intestinal tuberculosis (TB) after being initially considered for Crohn's disease. Differentiating the two diseases is challenging but important owing to variation in treatment, the potential for dissemination of TB under immunosuppression for Crohn's disease, and emergent Australian migration from TB endemic countries. PMID- 21539670 TI - Urticaria and periorbital edema as prodromal presenting signs of acute hepatitis B infection. AB - A 34-year-old patient presented with giant, transient urticarial skin lesions and periorbital edema after a 3-month stay in DR Congo. Retrospective analysis of stored samples revealed that these signs were prodromal manifestations of acute hepatitis B infection. The hepatitis B infection was spontaneously cleared; the skin lesion did not recur. PMID- 21539671 TI - Vaccination acceptability in Hajj pilgrims. PMID- 21539673 TI - Tumor length assessed by miniprobe endosonography can predict the survival of the advanced esophageal squamous cell carcinoma with stricture receiving concurrent chemoradiation. AB - There were tumor strictures commonly encountered in the esophageal squamous cell carcinoma (ESCC) to limit the conventional echoendoscope for exact tumor staging and size measurements. This study evaluated the role of miniprobe endosonography (EUS) to predict the survival of ESCC patients after concurrent chemoradiation therapy (CCRT). This study prospectively enrolled ESCC patients to receive high frequency miniprobe EUS for the assessments of the tumor size and tumor-node metastasis (TNM) stage. For the patients defined with advanced stages to receive CCRT as initial therapy, the tumor size parameters assessed by EUS were analyzed for their correlation with the treatment response and the patients' survivals. Fifty-four patients, >96% with advanced TNM stage III or IV, were enrolled with a medium follow-up of 320.5 days. Almost all of the 54 cases had partial or complete stricture of the esophageal lumens due to the tumor obstructions at enrollment. The overall median survival was 18.6 months, and the 1- and the 2 year survival rates were 64.9 and 45.2%, respectively. Patients with initial tumor length <6 cm assessed by the pre-CCRT EUS had a better survival than those with length >=6 cm (median survival: >56.5 months vs. 11.5 months, P= 0.006). The patients with initial tumor length <6 cm had a higher rate of downstage than those with tumor length >=6 cm after the first course of CCRT (80.0% vs. 16.7%, P= 0.035). Multivariate Cox regression confirmed the initial tumor length (hazard ratio [HR]= 1.21, P= 0.034) as well as the presence of distal metastasis are both independent predictors of the survival in ESCC patients receiving CCRT. For the ESCC patients, commonly with tumor stricture, the miniprobe EUS to assess tumor length before CCRT can predict the treatment response and the survivals. PMID- 21539674 TI - Thoracoscopic enucleation of esophageal schwannoma exhibiting (18) F fluorodeoxyglucose uptake on positron emission tomography. PMID- 21539675 TI - Endoscopic diagnosis and resection of esophageal granular cell tumors. AB - Granular cell tumors (GCT) are uncommon neoplasms. There is controversy regarding the endoscopic diagnosis and treatment of esophageal GCT. We studied the endoscopic diagnosis and management of esophageal GCT among 23 patients identified in a single-institution pathology database. Medical records, pathology, and endoscopic images were reviewed. All patients underwent endoscopy and endoscopic ultrasonography (EUS), and endoscopic resection was performed in 10 patients. Seven of 23 patients had more than one esophageal GCT. Only six lesions exhibited a classic yellow discoloration. Among patients with a single GCT, three, four, and nine lesions were located in the proximal, middle, and distal esophagus, respectively. EUS showed hypoechoic, smooth-edged lesions usually confined to deep mucosa and submucosa. Standard forceps biopsy was diagnostic in 19 of 23 patients (83%). Ten GCT <= 10 mm in diameter underwent successful endoscopic mucosal resection without complication. The endoscopic appearance, location, and number of esophageal GCT are highly variable. Histological proof is still necessary for the differential diagnosis of this rare neoplasm. Endoscopic forceps biopsy is usually diagnostic. Endoscopic resection appears safe and effective in selected cases with lesions <= 10 mm. PMID- 21539676 TI - Meta-analysis: non-steroidal anti-inflammatory drug use and the risk of esophageal squamous cell carcinoma. AB - The relationship between non-steroidal anti-inflammatory drug (NSAID) use and esophageal squamous cell carcinoma (ESCC) has remained unclear. To evaluate the relationship between NSAID use and risk of ESCC, we searched the MEDLINE, Biosis, Web of Science and ISI proceedings databases up to September 2010, together with a manual search of reference lists of relevant articles. Studies evaluating the association between exposure to NSAIDs and risk of ESCC were included. The analyses used random-effect or fixed-effect model based on homogeneity analysis. Seven studies (six case-control studies and one nested case-control study) were included in this meta-analysis. NSAID use was associated with a reduced risk of ESCC (odds ratio = 0.58, 95% confidence interval = 0.47 to 0.72). Specific analysis for aspirin and non-aspirin NSAIDs yielded similar results. There was a protective association between NSAIDs and ESCC. This finding warrants more prospective studies evaluating the relationship between NSAIDs and ESCC. PMID- 21539677 TI - Effects of DNA methyltransferase 1 inhibition on esophageal squamous cell carcinoma. AB - To explore the role of DNA methyltransferase 1 (DNMT1) in esophageal squamous cell carcinoma (ESCC) and the potential of DNMT1-targeted small interfering RNA as ESCC therapy, we examined expression changes of DNMT1 in ESCC and investigated the effect of DNMT1 knockdown by RNA interference in a human ESCC cell line, KYSE30. DNMT1 messenger RNA was over-expressed in seven out of 12 ESCC samples, and the percentage of cells expressing DNMT1 was significantly higher in ESCC tissues compared with paired non-cancerous tissues. DNMT1 protein levels correlated with lymph node metastasis, but exhibited no correlation with sex, age, tumor site, or tumor differentiation. Knockdown of DNMT1 in KYSE30 cells using RNA interference resulted in a reduction of promoter methylation and re expression of methyl-guanine methyl-transferase and retinoic acid receptors beta, inhibition of cell proliferation/viability and induction of cell apoptosis. These results indicate that DNMT1 over-expression is involved in ESCC and correlated with lymph node metastasis. Knockdown of DNMT1 led to promoter demethylation and re-expression of several tumor suppressor genes thereby inhibiting cell proliferation/viability and inducing cell apoptosis. PMID- 21539679 TI - Outcome, risk, and error and the child with obstructive sleep apnea. AB - Adenotonsillectomy is the mainstay of treatment for pediatric obstructive sleep apnea syndrome (OSAS). However, there is evidence that the child with severe OSAS is at increased risk of respiratory compromise. The most difficult risk factor to assess is the severity of OSAS, and these difficulties are reviewed. PMID- 21539680 TI - Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial. AB - BACKGROUND AND OBJECTIVE: Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial. METHODS: Subgroup analysis from a randomized, double-blinded, placebo controlled trial of tiotropium 18 ug daily in COPD. Primary end-point was rate of decline in FEV(1) . Secondary end-points included spirometry at individual time points, health-related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality. RESULTS: Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m(2) ; post-bronchodilator FEV(1) : 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV(1) although annual decline was less in Asian patients. Morning pre bronchodilator FEV(1) and forced vital capacity improved in Asian patients (P < 0.05). Tiotropium reduced number of exacerbations (rate ratio (95% confidence interval (CI)): 0.73 (0.57-0.94)). Hazard ratios (95%CI) for exacerbations and hospitalized exacerbations (tiotropium/control) were 0.81 (0.62-1.05) and 0.85 (0.61-1.19), respectively. St George's Respiratory Questionnaire total score improved by 1.5-6.1 units (P < 0.05 for months 18, 24, 30 and 36) with tiotropium. Fatal events occurred in 34 tiotropium (18.5%) and 42 control (23.6%) patients. CONCLUSIONS: In COPD patients from Asia, tiotropium improves lung function, improves health-related quality of life and reduces exacerbations over 4 years of treatment. PMID- 21539681 TI - Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker. AB - The emphasis in anticancer drug discovery has always been on finding a drug with great antitumor potential but few side-effects. This can be achieved if the drug is specific for a molecular site found only in tumor cells. Here, we find the enhancer of zeste homolog 2 (EZH2) to be highly overexpressed in lung and other cancers, and show that EZH2 is integral to proliferation in cancer cells. Quantitative real-time PCR analysis revealed higher expression of EZH2 in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P < 0.0001), and we confirmed that a wide range of cancers also overexpress EZH2, using cDNA microarray analysis. Immunohistochemical analysis showed positive staining for EZH2 in 14 of 29 cases of bladder cancer, 135 of 292 cases of non small-cell lung cancer (NSCLC), and 214 of 245 cases of colorectal cancer, whereas no significant staining was observed in various normal tissues. We found elevated expression of EZH2 to be associated with poor prognosis for patients with NSCLC (P = 0.0239). In lung and bladder cancer cells overexpressing EZH2, suppression of EZH2 using specific siRNAs inhibited incorporation of BrdU and resulted in significant suppression of cell growth, even though no significant effect was observed in the normal cell strain CCD-18Co, which has undetectable EZH2. Because EZH2 expression was scarcely detectable in all normal tissues we examined, EZH2 shows promise as a tumor-specific therapeutic target. Furthermore, as elevated levels of EZH2 are associated with poor prognosis of patients with NSCLC, its overexpression in resected specimens could prove a useful molecular marker, indicating the necessity for a more extensive follow-up in some lung cancer patients after surgical treatment. PMID- 21539682 TI - Evaluation of effectiveness and satisfaction outcomes of a mental health screening and referral clinical pathway for community nursing care. AB - The study aimed to explore the effectiveness of a mental health screening and referral clinical pathway for generalist community nursing care of war veterans and war widow(er)s in Australia on outcomes of client self-reported mental health, quality of life, and client and carer satisfaction. The pathway was developed by literature review and consultation, then trialled and evaluated. Validated screening tools were embedded within the pathway to support generalist nurses' mental health decision making. Pre- and post-measures were applied. Clients on whom the pathway was trialled were invited to complete an evaluation survey questionnaire, as were their informal carers. Most clients and carers who responded to these questionnaires were highly satisfied or satisfied with care provided through application of the pathway. This study adds understanding about one way that community nurses might identify people with mental health difficulties. The trialled pathway, which was modified and refined following the study, is now available on the Internet as an evidence-based resource for community nurses in Australia to guide practice and maximize holistic care for war veterans and war widow(er)s where that care is funded by Department of Veterans' Affairs. PMID- 21539683 TI - Effect of visual art on patient anxiety and agitation in a mental health facility and implications for the business case. AB - There is a growing body of evidence on the impact of the environment on health and well-being. This study focuses on the impact of visual artworks on the well being of psychiatric patients in a multi-purpose lounge of an acute care psychiatric unit. Well-being was measured by the rate of pro re nata (PRN) medication issued by nurses in response to visible signs of patient anxiety and agitation. Nurses were interviewed to get qualitative feedback on the patient response. Findings revealed that the ratio of PRN/patient census was significantly lower on the days when a realistic nature photograph was displayed, compared to the control condition (no art) and abstract art. Nurses reported that some patients displayed agitated behaviour in response to the abstract image. This study makes a case for the impact of visual art on mental well-being. The research findings were also translated into the time and money invested on PRN incidents, and annual cost savings of almost $US30,000 a year was projected. This research makes a case that simple environmental interventions like visual art can save the hospital costs of medication, and staff and pharmacy time, by providing a visual distraction that can alleviate anxiety and agitation in patients. PMID- 21539684 TI - Prevalence and correlates of seclusion with or without restraint in a Canadian psychiatric hospital: a 2-year retrospective audit. AB - Seclusion with or without restraint is a measure used to manage patients with challenging behaviours. Although controversial, the intervention remains poorly documented, especially in Canadian psychiatric hospitals. The purpose of this study is to assess the prevalence of the measure and identify any correlated demographic characteristics and psychiatric disorders. Episodes of seclusion with or without restraint were extracted from a computerized, hospital-based system introduced specifically to track such interventions. Of 2721 patients hospitalized during that time, 23.2% (n = 632) were secluded with or without restraint, and 17.5% (n = 476) were secluded with restraint. Younger age, schizophrenia or other psychosis, bipolar and personality disorder, and longer stay in hospital are predictors of an episode of seclusion with or without restraint. Younger age, bipolar and personality disorders and a longer stay in hospital are predictors of an episode of seclusion with restraint. For patients who spent longer in seclusion and under restraint, there is a positive association with longer stay in hospital. In this inpatient psychiatric facility, seclusion with or without restraint thus appears to be common. More research is warranted to better identify the principal factors associated with seclusion and restraint and help reduce resort to these measures. PMID- 21539685 TI - So what exactly is nursing knowledge? AB - This paper aims to present a discussion about intrinsic nursing knowledge. The paper stems from the author's study of knowledge claims enshrined in nursing journal articles, books and conference speeches. It is argued that claims by academic nurses have largely depended on principles drawn from continental and not Analytic (British-American) philosophy. Thus, claims are credible only insofar as they defer propositional logic. This is problematic inasmuch as nursing is a practice-based activity usually carried out in medical settings. Transpersonal nursing models are particularly criticizable in respect of their unworldly character as are also concepts based on shallow usages of physics or mathematics. I argue that sensible measurements of the 'real world' are possible- without endorsing positivism--and that nursing requires little recourse to logically unsustainable claims. The paper concludes with an analysis of a recent review of nursing knowledge, which analysis indicates the circularity that attends many discussions on the topic. PMID- 21539686 TI - Work-related behaviour and experience pattern in nurses: impact on physical and mental health. AB - Nursing is associated with high levels of emotional strain and heavy workloads. Changing working conditions raise the importance of investigating job satisfaction, stress and burnout and its consequences for nurses. The aim of the study was to investigate whether work-related behaviour and experience patterns are associated with mental and physical health status in nurses. A sample of 356 nurses in four German hospitals were interviewed using questionnaires regarding work-related behaviour and experience patterns, work stress, depression, anxiety and physical symptoms ('Work-related Behaviour and Experience Pattern'--AVEM and ERI). The main result of this study is that unhealthy work-related behaviour and experience patterns (i.e. the excessive ambitious type and the resigned type) are associated with reduced mental and physical health. Preventive, as well as intervention, strategies are needed that focus both on the individual as well as on working conditions. PMID- 21539687 TI - Medication-taking behaviours in young adults with schizophrenia: a pilot study. AB - The purpose of this prospective and observational study was to explore medication taking behaviours in community-based young adults with schizophrenia using an electronic monitoring system and patient self-report questionnaires. The Medication Event Monitoring System (MEMS(r)), the Index for Medication Adherence (IMA) and the Brief Evaluation of Medication Influences and Beliefs (BEMIB) measured medication-taking behaviours. Data were collected at baseline, 4 and 8 weeks. Descriptive statistics were used in analysis. A total of 11 subjects were recruited; one dropped out. Five were male, and five were female. Average age was 32.64 (SD = 5.70) years. Four (40%) were White people; six (60%) were non-White people. The average number of medications treating schizophrenia was 1.9 (SD = 0.57). MEMS(r) identified 71.77% (SD = 30.47) dose adherence and 55.92% (SD = 31.27) day adherence. Most subjects took medications irregularly (early, late or missing). The BEMIB demonstrated that 50%, 20% and 30% of subjects considered themselves to be adherent to their medications at baseline, 4 weeks and 8 weeks, while the IMA reported 90%, 90% and 80% at baseline, 4 weeks and 8 weeks, respectively. Regarding the observed discrepancies between patients' reports and their actual medication-taking behaviours, clinical implications were discussed. Effective interventions improving medication adherence in schizophrenia are needed for practice and for future studies. PMID- 21539688 TI - Women in medium secure care: tracking treatment progress for changes in risk profiles and treatment engagement. AB - The treatment and risk management programmes in a women's medium secure service are described. Changes in risk profiles and its relationship to treatment engagement are examined in a cohort of women during their stay in a medium secure service. Findings show that clinically significant reductions in risk behaviours were paralleled by increases in treatment engagement. The clinical healthcare implications of these findings are discussed along with the need for further research. PMID- 21539689 TI - Stories from the streets: people's experiences of homelessness. AB - This study explores how people speak about their experiences of homelessness, and how these experiences have affected their identity claims and their mental health. The mental health of the homeless population is a growing concern for the UK government and non-governmental agencies. There is however, little research looking at the mental health needs of homeless people and their experiences. For this study, a qualitative, narrative approach was used. Eight people were interviewed who described themselves as homeless. The subsequent data were analysed through a narrative analysis process paying particular attention to how people construct their identities. Although each participant is homeless, they speak about their experiences very differently. People's identities have been affected by their experiences, and because of the trauma and indignity of homelessness, their identities have had to be reshaped. While it might be considered normal for people's identities to relate to families and occupation, homeless people construct identities around illness, drugs and exclusion. Experiences of homelessness negatively affect people's sense of identity to destructive proportions. Nevertheless, participants demonstrate a way of coping by forming strong opinions about policy and service provision. PMID- 21539690 TI - An evaluation of a screening and brief intervention pilot project for hazardous and harmful drinkers within the accident and emergency department of Manchester Royal Infirmary. AB - Hazardous and harmful drinkers make up a significant percentage of A and E attendees, and brief interventions have been shown to reduce harm among this particular group. This paper evaluates a pilot project which introduced a screening and brief intervention programme within the A and E department. This project aimed to screen and offer brief interventions to attendees and to refer on to local alcohol services if required. PMID- 21539691 TI - Alleviating psychological distress of suicide survivors: evaluation of a volunteer care programme. AB - The crisis level in the worldwide suicide rate has revealed a severe suicide problem in Taiwan that is now well above the world average of 16 per 100,000 individuals. Many countries have relied on suicide care volunteers training programmes to conduct suicide prevention programmes. However, there is a dearth of research evaluating the effect of volunteers on psychological distress and the impact of volunteer experience level. An evaluation of the impact of experienced and novice volunteers in alleviating psychological distress of suicide survivors was conducted. A supervised programme trained 15 volunteers at Years 1 and 2. Year 1 volunteers completed 400 h of service with continuing education. Programme evaluation occurred after Year 2 volunteers had completed training. Eighty-two suicide survivors were recruited. With 60 suicide survivors completing 3 month of volunteer care, a significant group difference with time interaction in suicide survivors who exhibited moderate to severe distress between the veteran care and novice care groups was found. Compared with novice volunteers, veteran volunteers with at least 1 year of experience are more effective with suicide survivors reporting higher psychological distress. PMID- 21539692 TI - Falls in older adult psychiatric patients: equipping nurses with knowledge to make a difference. AB - Falls are the most common cause of accidental death among older adults and are associated with increased morbidity and mortality. A particularly serious sequela of falls is osteoporotic fractures. Older adults with mental illness are at increased risk of both falls and subsequent fractures, because of a range of complex risk factors. Many falls are preventable and an awareness of the risk factors for falls among nurses will empower them to promptly refer a patient at risk to the multidisciplinary team. A multidisciplinary approach is required to be successful in any efforts to reduce an individual's risk of falls and nurses have a central role in achieving this. This article reviews the relevant literature on the causes and consequences of falls in older adults with mental illness in order to enable nurses to reduce falls and subsequent fractures. PMID- 21539693 TI - Training 'adoption smart' professionals. PMID- 21539694 TI - Central nervous system bleeding in patients with rare bleeding disorders. AB - Central nervous system (CNS) bleeding is one of the most severe and debilitating manifestations occurring in patients with rare bleeding disorders (RBDs). The aim of this study was to retrospectively collect data on patients affected with RBDs who had CNS bleeding, to establish incidence of recurrence, death rate, neurological sequences, most frequent location, type of bleeding and efficacy of treatments. Results pertained to 36 CNS bleeding episodes in 24 patients with severe deficiency except one with moderate factor VII (FVII) deficiency. Six patients (25%) experienced a recurrence and two had more than one recurrence. Seven patients (29%) had an early onset of CNS bleeding before the first 2 years of life, others (71%) later in life. In 76% of cases, CNS bleeding was spontaneous. CNS bleeding was intracerebral in 19 cases (53%), extracerebral in 10 (28%) and both intracerebral and extracerebral in two cases (6%). Neurosurgery was performed in 11 cases, in association with replacement therapy in seven cases. Seizures were noted in four patients. Residual psychomotor abnormalities were seen in two patients. No death was recorded. To prevent recurrence, 17/24 patients (71%) were put on secondary prophylaxis. In conclusion, recurrence of CNS bleeding was confirmed to be relatively frequent in patients with severe FV, FX, FVII and FXIII deficiencies. Most patients were managed with replacement therapy alone, surgery being reserved for those with worsening neurological conditions. Our results indicate that some RBDs require early prophylactic treatment to prevent CNS bleeding. Optimal dosage and frequency of treatment need further evaluation. PMID- 21539695 TI - Survey of current prophylaxis practices and bleeding characteristics of children with severe haemophilia A in US haemophilia treatment centres. AB - Every other day (qod) factor VIII prophylaxis prevents joint bleeds in children with severe haemophilia A. Although three times weekly or qod prophylaxis is recommended by the National Hemophilia Foundation (NHF), how widely these practices have been adopted is not known. We sought to define current prophylaxis practices at US haemophilia treatment centres (HTCs). An email survey was distributed to US HTCs, utilizing web-based membership rosters of the Centers for Disease Control (CDC) and the Hemostasis Thrombosis Research Society (HTRS). Of 62 HTCs responding, prophylaxis is initiated on a three times weekly schedule in 29 (46.8%), twice weekly in 13 HTCs (21.0%) and once weekly in 20 HTCs (32.2%). Central venous catheters are used to infuse factor prophylactically at 55 HTCs (88.7%), including in 100% of children initiating prophylaxis at 19 HTCs (30.6%) and in 50% of those at 41 HTCs (66.1%), but avoided altogether at seven HTCs (11.3%). Prophylaxis is initiated after one or more bleeds in 56 HTCs (90.3%), but after the first bleed in only 28 HTCs (25.2%). Among 226 newborns with severe haemophilia A in 62 HTCs, 1.82 births/HTC/year, the median age at first bleed, excluding circumcision, is 7 months. Of the 113 (53.5%) newborns who underwent circumcision, 62 (54.9%) bled. Despite a recommended standard of three times weekly prophylaxis, over half of surveyed HTCs do not follow these guidelines, and nearly one-third begin prophylaxis on a once weekly schedule to delay or avoid the need for central venous access. PMID- 21539696 TI - Habitual physical activity in Dutch children and adolescents with haemophilia. AB - For patients with haemophilia, a physically active lifestyle is important to maintain musculoskeletal health and to prevent chronic diseases, such as cardiovascular disease. Therefore, we studied physical activity levels, in Dutch children and adolescents with haemophilia as well as its association with aerobic fitness and joint health. Forty-seven boys with haemophilia (aged 8-18) participated. Physical activity was measured using the Modifiable Activity Questionnaire (MAQ) and was compared with the general population. Aerobic fitness was determined using peak oxygen uptake (VO(2peak)). Joint health was measured using the Haemophilia Joint Health Score (HJHS). Associations between physical activity, joint health and aerobic fitness were evaluated by correlation analysis. Subjects were 12.5 (SD 2.9) years old, had a Body Mass Index (BMI) of 19.5 (SD 3.1; z-score 0.5) and a median HJHS score of 0 (range 0-6). Cycling, physical education and swimming were most frequently reported (86%, 69% and 50% respectively). Children with severe haemophilia participated significantly less in competitive soccer and more in swimming than children with non-severe haemophilia. Physical activity levels were similar across haemophilia severities and comparable to the general population. VO(2peak) kg-1 was slightly lower than healthy boys (42.9 +/- 8.6 vs. 46.9 +/- 1.9 mL kg-1 min-1; P = 0.03). Joint health, aerobic fitness and physical activity showed no correlation. Dutch children with haemophilia engaged in a wide range of activities of different intensities and showed comparable levels of physical activity to the general population. Aerobic fitness was well preserved and showed no associations with physical activity levels or joint health. PMID- 21539697 TI - The impact of 'best-practice' patient care in fibromyalgia on practice economics. AB - OBJECTIVE: The office time required for primary care physicians (PCPs) to diagnose, treat and manage fibromyalgia (FM) patients can be extensive. The study objective was to determine if PCPs can positively impact practice economics by requiring fewer patient visits and less office time, while still achieving an acceptable quality of life, as reported by the physician. STUDY DESIGN: Survey of PCPs who diagnose, manage and treat FM patients. METHODS: Surveys were administered to US private practice PCPs, obtaining information on the number of office visits, and time spent with FM patients. PCPs were allotted into two groups: FM-efficient (FME; n = 40) and FM usual care (FMUC; n = 54), based on their reported ability to achieve an acceptable quality of life for >=50% of their FM patients in less than four office visits post FM diagnosis. An economic model estimated the monetary value of each PCP cohorts' time spent with a newly diagnosed FM patient over a 2-year timeframe. RESULTS: Significant office time cost differences across 2 years exist between FME PCPs and FMUC PCPs ($840 vs. $1117, P < 0.05). FME PCPs had a significantly lower cost of scheduled time to confirm diagnosis ($243 vs. $339, P < 0.05) and time to find right treatment ($264 vs. $365, P < 0.05) than FMUC PCPs. Both groups incurred costs related to excess visit time, but it was less for FME PCPs ($119, 29 minutes) than FMUC PCPs ($182, 44 minutes, P < 0.01), driven by quicker diagnosis confirmation (P < 0.01) and treatment initiation (P < 0.01). CONCLUSIONS: Research suggests that efficient FM care delivery during diagnosis and treatment can be associated with improved practice economics. PMID- 21539699 TI - Hyperventilation as a simple cure for severe exercise-associated muscle cramping. PMID- 21539698 TI - Prescription analgesic use among young adults: adherence to physician instructions and diversion. AB - OBJECTIVES: To understand the extent to which medication adherence was related to diversion of prescription analgesics. DESIGN: Cross-sectional analyses of data from the College Life Study, a prospective study of young adults. SETTING: Participants were originally sampled as incoming first-time first-year college students from one large public university in the Mid-Atlantic United States. PARTICIPANTS: One hundred ninety-two young adults aged 21-26 who were prescribed an analgesic to treat acute pain in the past year. OUTCOME MEASURE: Diversion of prescription analgesics. The study tested two competing hypotheses: 1) individuals who skip doses (under-users) are at greatest risk for diversion because they have leftover medication; and 2) individuals who over-use their prescriptions (over-users) are at greatest risk for diversion, perhaps because of a general propensity to engage in deviant behavior. RESULTS: Fifty-eight percent followed physician's instructions regarding their prescription analgesic medication; 27% under-used their prescribed medication and 16% over-used their prescribed medication. Twenty-seven percent of the total sample diverted their medication, with over-users being the most likely to divert (63%). Holding constant demographic characteristics and perceived harmfulness of nonmedical use, over-users were almost five times as likely as adherent users to divert analgesic medications (P < 0.05). CONCLUSIONS: Further research is needed to better understand the relationship between adherence and diversion. If these findings are replicated, physicians who are involved in pain management for acute conditions among young adults should take steps to monitor adherence and reduce diversion of prescription analgesics. PMID- 21539700 TI - The relationships among pain, nonpain symptoms, and quality of life measures in older adults with cancer receiving hospice care. AB - OBJECTIVE: Gathering firsthand or reported information about patients in the final stages of terminal cancer is difficult due to patient frailty, cognitive impairment, excessive fatigue, and severity of illness, as well as gatekeeping by hospice providers and caregivers, and highly variable documentation practices. We sought to further understand and elucidate end-of-life experiences in older cancer patients through the application of validated tools employed in the hospice setting. This article summarizes data collected about pain, non-pain symptoms, and other aspects of quality of life (QOL) as reported by older hospice patients or by their caregivers during the 2 weeks of hospice care. DESIGN: Data was collected from an ongoing Institutional Human Subjects Review Board-approved research project with 94 older adults with cancer or their caregivers receiving service in a home setting from 14 Midwestern hospices. Participants completed one or two telephone interviews. Instruments used to gather information include the Brief Pain Inventory and the Brief Hospice Inventory. RESULTS: Data analysis showed mean "worst pain" ratings significantly decreased from Interview 1 to Interview 2, and pain reports were significantly correlated with fatigue, anxiety, appetite, comfort, symptom control, and overall QOL. CONCLUSIONS: Our findings reinforce previously held views that older patients with cancer experience pain and non-pain symptoms. And both pain and non-pain symptoms can impact and confound the treatment of other symptoms and interfere with the patient's overall QOL. The results of this study support the assertion that hospice care can have a positive impact on pain severity and related suffering, as well as patient QOL as death approaches. PMID- 21539701 TI - Psychological flexibility may reduce insomnia in persons with chronic pain: a preliminary retrospective study. AB - OBJECTIVE: Sleep disturbance is a common complaint in people with chronic pain, and is associated with a range of adverse outcomes including reports of greater pain and disability. Research into insomnia with chronic pain sufferers has not yet examined the role of psychological flexibility, a process from acceptance and commitment therapy. We examined this role. DESIGN: Participants in this study were 159 adult patients attending an assessment at a specialist pain center. They were mostly women, 63%, and the mean age was 43.8 years. RESULTS: In preliminary analyses 79% of participants met the criteria for significant insomnia based on their self-reported symptoms. As predicted, significant positive correlations were found between components of psychological flexibility, particularly acceptance of pain and values-based action, and all measures of sleep quality. In regression analyses, the components of psychological flexibility considered together accounted for between 11% and 19% of variance across a range of measures of sleep quality. CONCLUSION: These results suggest the need to further develop treatment services for people with chronic pain and insomnia. PMID- 21539702 TI - Predictors of a favorable response to transforaminal injection of steroids in patients with lumbar radicular pain due to disc herniation. AB - BACKGROUND: Transforaminal injection of steroids (TFIS) is effective for some patients with lumbar radicular pain caused by disc herniation. Factors associated with better outcomes are unknown. OBJECTIVE: To identify clinical and radiological features predictive of a favorable response to TFIS. METHODS: Seventy-one patients with lumbar radicular pain caused by disc herniation were treated with TFIS as part of a previously reported, randomized, clinical trial. The clinical features analyzed were the presence of neurologic symptom, neurologic signs, and the duration of sciatica. Radiological features evaluated using magnetic resonance imaging (MRI) were the segmental level of the pathology, the location and morphological features of the disc herniation, the cross sectional area of the disc herniation and its ratio to the cross-sectional area of the spinal canal, and the grade of nerve root compression. RESULTS: None of the clinical features was associated with successful outcome from treatment. The only radiological feature associated with successful outcome was the grade of nerve root compression. Of patients with low-grade root compression, 75% responded favorably to TFIS. Only 26% of patients with high-grade nerve root compression responded. DISCUSSION: These results indicate that TFIS is more often successful in patients without significant compression of the nerve root and, therefore, in whom an inflammatory basis for radicular pain is most likely. In such patients, a success rate of 75% renders TFIS an attractive alternative to surgery. In patients with significant compression of the nerve root, the likelihood of benefiting from TFIS is low. The success rate may be no more than that of a placebo effect, and surgery may be a more appropriate consideration. PMID- 21539703 TI - Police officer, deal-maker, or health care provider? Moving to a patient-centered framework for chronic opioid management. AB - How we frame our thoughts about chronic opioid therapy greatly influences our ability to practice patient-centered care. Even providers who strive to be nonjudgmental may approach clinical decision-making about opioids by considering if the pain is real or they can trust the patient. Not only does this framework potentially lead to poor or unshared decision-making, it likely adds to provider and patient discomfort by placing the provider in the position of a police officer or a judge. Similarly, providers often find themselves making deals with patients using a positional bargaining approach. Even if a compromise is reached, this framework can potentially inadvertently weaken the therapeutic relationship by encouraging the idea that the patient and provider have opposing goals. Reframing the issue can allow the provider to be in a more therapeutic role. As recommended in the American Pain Society/American Academy of Pain Medicine guidelines, providers should decide whether the benefits of opioid therapy are likely to outweigh the harms for a specific patient (or sometimes, for society) at a specific time. This article discusses how providers can use a benefit-to harm framework to make and communicate decisions about the initiation, continuation, and discontinuation of opioids for managing chronic nonmalignant pain. Such an approach focuses decisions and discussions on judging the treatment, not the patient. It allows the provider and the patient to ally together and make shared decisions regarding a common goal. Moving to a risk benefit framework may allow providers to provide more patient-centered care, while also increasing provider and patient comfort with adequately monitoring for harm. PMID- 21539704 TI - Intravenous injection of leconotide, an omega conotoxin: synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain. AB - OBJECTIVE: Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain. DESIGN: Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312-5.0 mg/kg intraperitoneal) and leconotide (0.002-200 ug/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations. RESULTS: Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED(50) = 2.40 +/- 1.24 mg/kg), which were increased by coadministration of leconotide 20 ug/kg (morphine ED(50) = 0.16 +/- 1.30 mg/kg); 0.2 ug/kg (morphine ED(50) = 0.39 +/- 1.27 mg/kg); and 0.02 ug/kg (morphine ED(50) = 1.24 +/- 1.30 mg/kg). CONCLUSIONS: Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug. CLINICAL IMPLICATION: Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life. PMID- 21539705 TI - Epidural contrast flow patterns of transforaminal epidural steroid injections stratified by commonly used final needle-tip position. AB - OBJECTIVE: To evaluate the relationship between commonly used final needle-tip positions and subsequent contrast flow and patient-reported pain relief in transforaminal epidural steroid injections (TFESIs). DESIGN: Retrospective cross sectional study. METHODS: Medical records of subjects (N = 83) having undergone a TFESI between January 2008 and January 2009 were reviewed to compare TFESIs using the superior-anterior (SA) vs. the superior-posterior (SP) quadrant. OUTCOME MEASURES: Outcome measures included ventral and dorsal epidural contrast flow as well as near-to-complete pain relief as measured by numerical rating scale pain score pre- and post-procedure. RESULTS: SA TFESIs were associated with greater ventral epidural contrast flow as compared with SP TFESIs (100% vs 61.4%, P < 0.001). SA TFESIs with ventral epidural contrast flow were also associated with flow to a greater number of vertebral levels than SP TFESIs with ventral epidural contrast flow (41% vs 14.8%, P < 0.001). SP TFESIs were associated with greater dorsal epidural contrast flow than SA TFESIs (95.5% vs 43.6%, P < 0.05). SA TFESIs were also associated with a larger proportion of patients who achieved near-to-complete pain relief (P < 0.05) and greater reduction than SP TFESIs in post-procedure pain score relative to pre-procedure (3.3 vs 1.5, P < 0.01). DISCUSSION: The evolution of TFESIs must balance both safety and efficacy. The efficacy of SA TFESIs is demonstrated to be superior to that of SP TFESIs with regards to ventral epidural flow and patient-reported pain relief. Further efforts should focus on demonstrating efficacy while optimizing safety. PMID- 21539706 TI - Identical domains of Yarrowia lipolytica Vps23 are required for both ESCRT and Rim pathways, but the latter needs an interaction between the Vps23 UEV domain and Rim8/PalF. AB - A conserved pathway, called Rim or Pal, transduces the ambient pH signal in ascomycetous yeasts and fungi, respectively. This pathway requires most of the components of the endosomal sorting complex required for transport (ESCRT) pathway. In the yeast Yarrowia lipolytica, a functional analysis of the ESCRT-I subunit Vps23 was carried out by in-frame deletions of each of the conserved domains to test whether Vps23 functions in the Rim and ESCRT pathways could be separated. These two pathways were shown to necessitate both the coiled-coil domain and the C-terminal steadiness box. However, the central proline-rich region seems to be required for neither of them. Both pathways involve the N terminal ubiquitin E2 variant (UEV) domain. Thus, identical domains of YlVps23 are required for both Rim and ESCRT pathways, but the UEV domain was shown to bind the arrestin-like protein Rim8/PalF in the Rim pathway, whereas it binds Vps27 in the ESCRT pathway. Vps23 is therefore required to link pH signalling and endocytosis. PMID- 21539707 TI - Determination of the membrane topology of Arv1 and the requirement of the ER luminal region for Arv1 function in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, ARV1 encodes a 321 amino acid transmembrane protein localized to the endoplasmic reticulum (ER) and Golgi. It has been shown previously that arv1 cells harbor defects in sphingolipid and glycosylphosphatidylinositol biosyntheses, and may harbor sterol trafficking defects. Using C-terminal fusion to Suc2-His4, we determined the orientation of full-length Arv1 in the ER membrane. Once membrane topology was determined, we used this information and truncation analysis to establish the minimum protein length required for Arv1 function and phenotypic suppression. By understanding the topology of Arv1 we can now further analyze its putative lipid and glycosylphosphatidylinositol intermediate transport activities. PMID- 21539708 TI - Animal-type melanoma - tumor cell invasion of dermal lymphatics and molecular identification of lymph node metastasis. AB - Animal-type melanoma (ATM) represents a rare subtype within the wide spectrum of melanocytic tumors. Clinically, ATM lesions appear as sharply demarcated, brown, black and dark blue pigmented nodules, which show grey-white surface elements on dermatoscopy. The tumor is restricted to the dermis and arranged in irregular fascicles, which are composed of spindle-shaped and epithelioid melanocytes. Moderate tumor cell pleomorphism, mitoses and apoptotic cells all suggest a malignant process. Abundant, finely dispersed melanin pigment within tumor cells as well as numerous melanophages are strongly suggestive of ATM. Even though locoregional lymph node metastases are frequently found at diagnosis, the course of ATM is generally benign. Specific molecular changes may be detected in melanocytes from lesions and lymph nodes on fluorescence in situ hybridization (FISH). Such findings strongly indicate the malignant potential of ATM. The peculiar biology of ATM, as a moderately malignant tumor, is reflected in a new histopathological classification within the spectrum of dermal borderline melanocytic tumors (BMT). PMID- 21539709 TI - Research in practice: Different dendritic cell types in skin with various functions - important implications for intradermal vaccines. AB - It was long believed that epidermal Langerhans cells (LC) are responsible for the initiation of cellular immunity. Only recently it has been shown that in skin alone 5 different subtypes of dendritic cells (DC) can be identified. Among these, LC, but also two Langerin-expressing dermal DC populations and two more Langerin-negative DC subtypes exist. Novel findings in the model disease leishmaniasis, as well as evidence from research in contact hypersensitivity, have revealed that activation of LC in skin leads to induction of regulatory, immunosuppressive T cells, whereas the other skin DC subtypes stimulate effector T cells. Thus, when producing vaccines designed for intradermal use, it would seem advisable to attempt to activate dermal DC subtypes while avoiding activation of epidermal LC. PMID- 21539710 TI - Editorial: Dementia and delirium - the need to fix the system. PMID- 21539711 TI - Guest editorial: Time for a change. PMID- 21539712 TI - Guest editorial: the challenge of detecting delirium in older adults. PMID- 21539713 TI - Delirium in older adults attending adult day care and family caregiver distress. AB - BACKGROUND; Delirium is a critical, costly, frequently reversible problem in older adults. Findings of previous studies indicate that delirium occurs in up to 65% of hospitalised older adults and up to 80% of terminally ill patients. Few studies address the frequency of delirium in community dwelling older adults and the extent to which delirium symptoms create distress for their family caregivers. AIMS: To determine the frequency of delirium in older people attending two adult day centers (ADC) in the United States and identify the extent to which delirium symptoms were associated with family caregivers' mental health symptoms, and ways of coping with the older adults' care. METHOD: A descriptive, cross-sectional design was used. Thirty older adults and their family caregivers were randomly selected from the rosters of the ADC. RESULTS: Only 6.7% of the older adults had a positive screen for delirium. The majority of family caregivers (96.6%) stated that they had no knowledge of delirium prior to participating in this study. IMPLICATIONS FOR PRACTICE: Both older adults and their family caregivers need education about delirium symptoms and risks. PMID- 21539714 TI - Experiences of relocation in dementia care from the perspective of six care workers. AB - BACKGROUND: Relocation of persons with dementia might be considered when quality of care cannot be sustained due to increasing needs. Relocation has been studied from the aspects of mortality and morbidity. AIM. To explore the thoughts and experiences of care workers when relocating a person with dementia within municipal sheltered housing. METHOD: This qualitative study was conducted in Sweden and based on interviews with six care workers involved in the relocation of two persons with dementia. Latent content analysis was applied. RESULTS: The findings of one narrative are summarised in the theme 'Walking the tightrope: trying to balance conflicting needs'. In the other narrative the theme 'Balancing closeness and distance' emerged. Eight sub-themes were identified illustrating the relocation time-line. CONCLUSION: Relocation from the care workers' perspective is a complex process with conflicting values and practical issues that hinder the provision of good care and security. IMPLICATIONS FOR PRACTICE: Supporting next of kin in the relocation decision-making process presupposes time for reflection in dialogue with staff. The risk of moral distress should be observed and support for care workers could be provided in the form of supervision, ethical consultations and local guidelines. PMID- 21539715 TI - How older people nurses assess cognitive function through daily observation. AB - AIM: To obtain knowledge and insight into how older people nurses observe the cognitive function of their patients. BACKGROUND: In cases of cognitive decline not due to delirium, the daily observation of cognitive function by nurses has not been standardised in hospital wards specialised in the care of older people. DESIGN: A qualitative study with purposive sampling and semi-structured interviews. Methods. Data were obtained by interviewing 10 Dutch nursing experts in the field of cognitive function in older patients. The interviews were recorded, transcribed and analysed by two independent researchers. RESULTS: All the respondents stated that daily observation of cognitive function yields valuable information. The concept of cognitive function was operationalised differently by institute and by nurse. Observation and reporting methods varied, as did the goals set by the nurses. Nurses reported using many days of observation to reach final judgements. CONCLUSIONS: Observations of cognitive functioning should include several cognitive domains, be restricted to a few days of observation and aim to both contribute to medical diagnoses and guide nursing interventions. RELEVANCE TO CLINICAL PRACTICE: Until a valid instrument becomes available, nursing staff must standardise daily observations themselves. This paper describes input to achieve this. PMID- 21539716 TI - Perceptions and implications of violence from care home residents with dementia: a review and commentary. AB - AIMS AND OBJECTIVES: This paper presents a critical review of the literature related to the violence staff in care homes experience from people with dementia. It attempts to identify the psychological consequences abuse has on care workers and the implications this has for practice. BACKGROUND: Abuse in the form of violence or aggression against healthcare professionals is not new. However, when this is from residents with dementia in care homes it is considered to be part of the job. Consequently it is largely underreported and ignored which masks its true extent. CONCLUSION: The magnitude of violence in care homes crosses cultural boundaries. Fear of being blamed, job insecurity and resignation that abuse should be accepted as part of the job is unique to this care setting. The cumulative effect of psychological abuse leads to emotional exhaustion and depersonalisation which results in care workers emotionally and physically withdrawing from residents. Being subjected to abuse, feeling undervalued, unsupported and lacking essential skills may compromise a workforces' ability to provide person-centred care. A rising ageing population and prevalence of dementia will place demands on commissioners and providers to deliver high quality care. Consistent recording and reporting procedures, dementia specific training and infrastructures to support staff is therefore crucial. PMID- 21539717 TI - Insights gained through Marte Meo counselling: experiences of nurses in dementia specific care units. AB - AIM: This study sought to uncover what nurses perceived to have learned, during their participation in video supported counselling, based on Marte Meo principles, in four dementia specific care units. METHODS: This was a descriptive qualitative study. Data were collected through 12 individual and four focus group interviews. In addition, supplementary data from two video recordings and one written log were included. Findings emerged through content analysis and re examination of the text based on the initial analysis. RESULTS: The nurses experienced that they acquired new knowledge about the residents through Marte Meo Counselling (MMC), resulting in improved capability to interpret the residents' expressions, and increased awareness of the residents' competence. New knowledge about themselves as nurses also emerged; they recognised how their actions entailed consequences for the interaction, in turn making them conscious of the usefulness of taking time, pacing their interactions, maintaining eye contact and describing the situation in words when the interaction took place. This appeared to increase the resident's perception of being able to cope. CONCLUSIONS: This study indicates that MMC helped the nurses to gain knowledge about how to improve interactions with residents suffering from dementia. Further research is warranted into the effectiveness of MMC. PMID- 21539718 TI - Predictive value and validation of the NEECHAM Confusion Scale using DSM-IV criteria for delirium as gold standard. AB - BACKGROUND: Delirium is common among older people in hospital and various instruments have been developed for detecting delirium. One of these, the NEECHAM Confusion Scale, is easy for nurses to administrate but needs to be tested further. AIMS AND OBJECTIVES: The aim of the present study was to assess the validity and predictive value of the NEECHAM Confusion Scale. METHODS: The study was conducted among 149 patients aged >= 65, who had undergone surgery for a hip fracture. The patients were observed daily using DSM-IV criteria for delirium. The NEECHAM Confusion Scale was performed upon admission and prior to discharge. RESULTS: The incidence of DSM-IV related delirium was 24%. Patients who scored below 25 points on the NEECHAM scale had a 12 times higher risk of developing DSM IV related delirium. During admission, the sensitivity of NEECHAM was zero because all patients with DSM-IV delirium were excluded, the specificity was 75%. On discharge, it was 100% and 91% respectively. CONCLUSIONS: This study adds to the body of knowledge that NEECHAM discriminates for delirium. It is a valid and reliable screening instrument for predicting delirium. The instrument can be used for clinical practice to identify patients who are at risk of contracting delirium and when considering prevention measures. PMID- 21539719 TI - Korean nurses' attitudes towards older people with dementia in acute care settings. AB - AIM: To identify and describe Korean nurses' attitudes towards older people with dementia in acute care settings and to examine the effect of selected socio demographics and nursing work characteristics on attitudes. BACKGROUND: In Korea, older people receive health care services in acute care settings because long term care settings are not the norm. Culturally, it is considered shameful to place parents or relatives in a long-term care facility. DESIGN: A descriptive survey design. METHOD: Attitudes towards older people with dementia were measured in Korean registered nurses (n = 100) working in acute care settings of two hospitals in southern Korea in 2009. The Attitudes toward the Elderly with Dementia (AED) and the Approaches to Dementia Questionnaire (ADQ) were administered to participants. RESULTS: Moderately positive attitudes towards older people with dementia in the acute care setting were found. Two-thirds of the nurse participants (n = 65, 65.7%) working in medical wards demonstrated significantly more positive attitudes than those working in surgical wards (n = 34, 34.3%). Demographics including years of experience in the current unit and in the service, and nurses' position did not correlate significantly with their attitudes. CONCLUSION: The environment, work routine and technology may influence the likelihood of negative attitude towards people with dementia. IMPLICATIONS FOR PRACTICE. There may be conflict between nurses' cultural values and care practices in acute care settings. Therefore, there is a need for ongoing education of nurses in dementia care that may reduce the potential of such conflicts. PMID- 21539720 TI - Management of person with dementia with aggressive and violent behaviour: a systematic literature review. AB - AIM: Studies indicate that physical and pharmacological restraints are still often in the frontline of aggression management in a large number of nursing homes. In the present literature review the aim was to describe, from a nursing perspective, aggressive and violent behaviour in people with dementia living in nursing home units and to find alternative approaches to the management of dementia related aggression as a substitute to physical and chemical restraints. METHODS: A systematic literature review in three phases, including a content analysis of 21 articles published between 1999 and August 2009 has been conducted. RESULTS: The results could be summarised in two themes: 'origins that may trigger violence' and 'activities that decrease the amount of violent behaviour'. Together, the themes showed that violence was a phenomenon that could be described as being connected to a premorbid personality and often related to the residents' personal care. It was found that if the origin of violent actions was the residents' pain, it was possible to minimise it through nursing activities. This review also indicated that an organisation in special care units for residents who exhibit aggressive and violent behaviour led to the lesser use of mechanical restraints, but also an increased use of non-mechanical techniques. CONCLUSION: The optimal management of aggressive and violent actions from residents with dementia living in nursing homes was a person-centred approach to the resident. Qualitative studies focusing on violence were sparsely found, and this underlines the importance of further research in this area to elucidate how violence and aggressiveness is experienced and understood by both staff and patients. RELEVANCE TO CLINICAL PRACTICE: To communicate with people with dementia provides a challenge for nurses and other health caregivers. To satisfy the needs of good nursing care, an important aspect is therefore to get knowledge and understanding about aggressive and violent behaviour and its management. PMID- 21539721 TI - Epac1 promotes melanoma metastasis via modification of heparan sulfate. AB - Our previous report suggested the potential role of the exchange protein directly activated by cyclic AMP (Epac) in melanoma metastasis via heparan sulfate (HS) mediated cell migration. In order to obtain conclusive evidence that Epac1 plays a critical role in modification of HS and melanoma metastasis, we extensively investigated expression and function of Epac1 in human melanoma samples and cell lines. We have found that, in human melanoma tissue microarray, protein expression of Epac1 was higher in metastatic melanoma than in primary melanoma. In addition, expression of Epac1 positively correlated with that of N-sulfated HS, and N-deacetylase/N-sulfotransferase-1 (NDST-1), an enzyme that increases N sulfation of HS. Further, an Epac agonist increased, but ablation of Epac1 decreased, expressions of NDST-1, N-sulfated HS, and cell migration in various melanoma cell lines. Finally, C8161 cells with stable knockdown of Epac1 showed a decrease in cell migration, and metastasis in mice. These data suggest that Epac1 plays a critical role in melanoma metastasis presumably because of modification of HS. PMID- 21539722 TI - Acute myeloid leukemia: leukemia stem cells write a prognostic signature. AB - In a recent interesting article, analysis of gene expression between phenotypically defined acute myeloid leukemia (AML) leukemia stem cells (LSCs) and more mature leukemia progenitor cells is used to generate a differentially expressed gene signature for LSCs. Through clever bioinformatic weighting analysis, the authors describe a method to convert this signature into a single score for any given sample and then test the prognostic utility of this 'LSC score' in publicly available gene expression profiles from bulk AML samples. They demonstrate that a high LSC score is associated with poor prognosis in AML patients and further demonstrate that the score is independent of known prognostic factors, including age, karyotype and mutation of the FLT3 or NPM1 genes. These findings are important and directly relate transcriptional dysregulation in AML LSCs with the outcome in patient samples, thus reinforcing the belief that these cellular populations are crucial for the initial propagation and subsequent relapse and resistance of leukemia. PMID- 21539723 TI - A zinc finger protein Zfp521 directs neural differentiation and beyond. AB - Neural induction is largely considered a default process, whereas little is known about intrinsic factors that drive neural differentiation. Kamiya and colleagues now demonstrate that a transcription factor, Zfp521, is capable of directing embryonic stem (ES) cells into neural progenitors. They discovered that Zfp521 transcripts were enriched in early neural lineage of ES cell differentiation. Forced expression of Zfp521 turned ES cells into neural progenitors in culture conditions that would normally inhibit neural differentiation. Zfp521 was expressed in mouse embryos during gastrulation. The protein was shown to associate with a co-activator p300 and directly induce expression of early neural genes. Knockdown of the Zfp521 by shRNA halted cells at the epiblast stage and suppressed neural differentiation. Zfp521 is a nuclear protein with 30 Kruppel like zinc fingers mediating multiple protein-protein interactions, and regulates transcription in diverse tissues and organs. The protein promotes proliferation, delays differentiation and reduces apoptosis. The findings by Kamiya and colleagues that Zfp521 directs and sustains early neural differentiation now opens up a series of studies to investigate roles of Zfp521 in stem cells and brain development of mice and men. PMID- 21539725 TI - Investigational drugs for the treatment of AD: what can we learn from negative trials? AB - Given the level of interest and activity in the race to find a treatment for Alzheimer's disease, it is expected that a reasonably safe and effective drug will be identified within the next decade. It may be worthwhile to pause periodically during the course of this race to take stock of what we have learned. Over the past few years, a number of trials have been conducted with promising new compounds (including some with novel mechanisms of action) that failed to meet primary endpoints and so were discontinued from clinical development. This article reviews a set of molecules with a range of mechanisms that have been trialed but with negative results. This article also examines the reasons for the negative findings and summarizes some of what we have learned from these experiences. PMID- 21539724 TI - Biochemical markers of ongoing joint damage in rheumatoid arthritis--current and future applications, limitations and opportunities. AB - Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with potentially debilitating joint inflammation, as well as altered skeletal bone metabolism and co-morbid conditions. Early diagnosis and aggressive treatment to control disease activity offers the highest likelihood of preserving function and preventing disability. Joint inflammation is characterized by synovitis, osteitis, and/or peri-articular osteopenia, often accompanied by development of subchondral bone erosions, as well as progressive joint space narrowing. Biochemical markers of joint cartilage and bone degradation may enable timely detection and assessment of ongoing joint damage, and their use in facilitating treatment strategies is under investigation. Early detection of joint damage may be assisted by the characterization of biochemical markers that identify patients whose joint damage is progressing rapidly and who are thus most in need of aggressive treatment, and that, alone or in combination, identify those individuals who are likely to respond best to a potential treatment, both in terms of limiting joint damage and relieving symptoms. The aims of this review are to describe currently available biochemical markers of joint metabolism in relation to the pathobiology of joint damage and systemic bone loss in RA; to assess the limitations of, and need for additional, novel biochemical markers in RA and other rheumatic diseases, and the strategies used for assay development; and to examine the feasibility of advancement of personalized health care using biochemical markers to select therapeutic agents to which a patient is most likely to respond. PMID- 21539727 TI - Generalized anxiety disorder and online intelligence: a phenomenological account of why worrying is unhelpful. AB - Worrying is the central feature of generalized anxiety disorder (GAD). Many people worry from time to time, but in GAD the worrying is prolonged and difficult to control. Worrying is a specific way of coping with perceived threats and feared situations. Meanwhile, it is not considered to be a helpful coping strategy, and the phenomenological account developed in this paper aims to show why. It builds on several phenomenological notions and in particular on Michael Wheeler's application of these notions to artificial intelligence and the cognitive sciences. Wheeler emphasizes the value of 'online intelligence' as contrasted to 'offline intelligence'. I discuss and apply these concepts with respect to worrying as it occurs in GAD, suggesting that GAD patients overrate the value of detached contemplation (offline intelligence), while underrating their embodied-embedded adaptive skills (online intelligence). I argue that this phenomenological account does not only help explaining why worrying is used as a coping strategy, but also why cognitive behavioral therapy is successful in treating GAD. PMID- 21539726 TI - Neural tissue engineering using embryonic and induced pluripotent stem cells. AB - With the recent start of the first clinical trial evaluating a human embryonic stem cell-derived therapy for the treatment of acute spinal cord injury, it is important to review the current literature examining the use of embryonic stem cells for neural tissue engineering applications with a focus on diseases and disorders that affect the central nervous system. Embryonic stem cells exhibit pluripotency and thus can differentiate into any cell type found in the body, including those found in the nervous system. A range of studies have investigated how to direct the differentiation of embryonic cells into specific neural phenotypes using a variety of cues to achieve the goal of replacing diseased or damaged neural tissue. Additionally, the recent development of induced pluripotent stem cells provides an intriguing alternative to the use of human embryonic stem cell lines for these applications. This review will discuss relevant studies that have used embryonic stem cells to replicate the tissue found in the central nervous system as well as evaluate the potential of induced pluripotent stem cells for the aforementioned applications. PMID- 21539728 TI - Impact of chromium histidinate on high fat diet induced obesity in rats. AB - BACKGROUND: Chromium (Cr) is an essential trace element that has garnered interest for use as a weight loss aid, but its molecular mechanism in obesity is not clear. In this study, an attempt has been made to investigate the effects of chromium histidinate (CrHis) on glucose transporter-2 (GLUT-2), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B (NF-kappaB p65) and the oxidative stress marker 4-hydroxynonenal adducts (HNE) expressions in liver of rats fed high fat diet (HFD). METHODS: Male Wistar rats (n = 40, 8 wk-old) were divided into four groups. Group I was fed a standard diet (12% of calories as fat); Group II was fed a standard diet and supplemented with 110 MUg CrHis/kg BW/d; Group III was fed a HFD (40% of calories as fat); Group IV was fed HFD and supplemented with 110 MUg CrHis/kg BW/d. RESULTS: Rats fed HFD possessed greater serum insulin (40 vs.33 pmol/L) and glucose (158 vs. 143 mg/dL) concentration and less liver Cr (44 vs.82 MUg/g) concentration than rats fed the control diet. However, rats supplemented with CrHis had greater liver Cr and serum insulin and lower glucose concentration in rats fed HFD (P < 0.05). The hepatic nuclear factor-kappa B (NF-kappaB p65) and HNE were increased in high fat group compared to control group, but reduced by the CrHis administration (P < 0.05). The levels of hepatic Nrf2 and HO-1 were increased by supplementation of CrHis (P < 0.05). CONCLUSION: These findings demonstrate that supplementation of CrHis is protective against obesity, at least in part, through Nrf2-mediated induction of HO-1 in rats fed high fat diet. PMID- 21539729 TI - The relation between cartilage biomarkers (C2C, C1,2C, CS846, and CPII) and the long-term outcome of rheumatoid arthritis patients within the CAMERA trial. AB - INTRODUCTION: The aim of this study was to investigate whether serum biomarker levels of C2C, C1,2C, CS846, and CPII can predict the long-term course of disease activity and radiographic progression early in the disease course of rheumatoid arthritis (RA). METHODS: In patients in the CAMERA trial, levels of biomarkers were evaluated at baseline and after 1 year of treatment. Relations of (changes in) biomarker values with the mean yearly radiographic progression rate and mean disease activity over a 5-year period were evaluated by using regression analysis. The added predictive value of biomarkers over established predictors for long-term outcome was analyzed by multiple linear regression analysis. RESULTS: Of 133 patients, serum samples were available at baseline and after 1 year of treatment. In the regression analysis C1,2C at baseline, the change in C2C, C1,2C, and the sum of the standardized changes in C2C + C1,2C scores were statistically significantly associated with the mean yearly radiographic progression rate; the change in CPII was associated with the mean disease activity over 5 years of treatment. In the multiple linear regression analysis, only the change in C1,2C was of added predictive value (P = 0.004) for radiographic progression. Explained variances of models for radiographic progression and disease activity were low (0.28 and 0.34, respectively), and the biomarkers only marginally improved the explained variance. CONCLUSIONS: The change in C1,2C in the first year after onset of RA has a small added predictive value for disease severity over a 5-year period, but the predictive value of this biomarker combined with current predictive factors is too small to be of use for individual patients. PMID- 21539730 TI - Always one step ahead: How pathogenic bacteria use the type III secretion system to manipulate the intestinal mucosal immune system. AB - The intestinal immune system and the epithelium are the first line of defense in the gut. Constantly exposed to microorganisms from the environment, the gut has complex defense mechanisms to prevent infections, as well as regulatory pathways to tolerate commensal bacteria and food antigens. Intestinal pathogens have developed strategies to regulate intestinal immunity and inflammation in order to establish or prolong infection. The organisms that employ a type III secretion system use a molecular syringe to deliver effector proteins into the cytoplasm of host cells. These effectors target the host cell cytoskeleton, cell organelles and signaling pathways. This review addresses the multiple mechanisms by which the type III secretion system targets the intestinal immune response, with a special focus on pathogenic E. coli. PMID- 21539731 TI - Quality of life of residents with dementia in long-term care settings in the Netherlands and Belgium: design of a longitudinal comparative study in traditional nursing homes and small-scale living facilities. AB - BACKGROUND: The increase in the number of people with dementia will lead to greater demand for residential care. Currently, large nursing homes are trying to transform their traditional care for residents with dementia to a more home-like approach, by developing small-scale living facilities. It is often assumed that small-scale living will improve the quality of life of residents with dementia. However, little scientific evidence is currently available to test this. The following research question is addressed in this study: Which (combination of) changes in elements affects (different dimensions of) the quality of life of elderly residents with dementia in long-term care settings over the course of one year? METHODS/DESIGN: A longitudinal comparative study in traditional and small scale long-term care settings, which follows a quasi-experimental design, will be carried out in Belgium and the Netherlands. To answer the research question, a model has been developed which incorporates relevant elements influencing quality of life in long-term care settings. Validated instruments will be used to evaluate the role of these elements, divided into environmental characteristics (country, type of ward, group size and nursing staff); basic personal characteristics (age, sex, cognitive decline, weight and activities of daily living); behavioural characteristics (behavioural problems and depression); behavioural interventions (use of restraints and use of psychotropic medication); and social interaction (social engagement and visiting frequency of relatives). The main outcome measure for residents in the model is quality of life. Data are collected at baseline, after six and twelve months, from residents living in either small-scale or traditional care settings. DISCUSSION: The results of this study will provide an insight into the determinants of quality of life for people with dementia living in traditional and small-scale long-term care settings in Belgium and the Netherlands. Possible relevant strengths and weaknesses of the study are discussed in this article. TRIAL REGISTRATION: ISRCTN: ISRCTN23772945. PMID- 21539732 TI - Should global burden of disease estimates include depression as a risk factor for coronary heart disease? AB - The 2010 Global Burden of Disease Study estimates the premature mortality and disability of all major diseases and injuries. In addition it aims to quantify the risk that diseases and other factors play in the aetiology of disease and injuries. Mental disorders and coronary heart disease are both significant public health issues due to their high prevalence and considerable contribution to global disease burden. For the first time the Global Burden of Disease Study will aim to assess mental disorders as risk factors for coronary heart disease. We show here that current evidence satisfies established criteria for considering depression as an independent risk factor in development of coronary heart disease. A dose response relationship appears to exist and plausible biological pathways have been proposed. However, a number of challenges exist when conducting a rigorous assessment of the literature including heterogeneity issues, definition and measurement of depression and coronary heart disease, publication bias and residual confounding. Therefore, despite some limitations in the available data, it is now appropriate to consider major depression as a risk factor for coronary heart disease in the new Global Burden of Disease Study. PMID- 21539734 TI - Antiviral activity of alpha-helical stapled peptides designed from the HIV-1 capsid dimerization domain. AB - BACKGROUND: The C-terminal domain (CTD) of HIV-1 capsid (CA), like full-length CA, forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. Mutations of the residues at the CTD dimer interface impair virus assembly and render the virus non-infectious. Therefore, the CTD represents a potential target for designing anti-HIV-1 drugs. RESULTS: Due to the pivotal role of the dimer interface, we reasoned that peptides from the alpha helical region of the dimer interface might be effective as decoys to prevent CTD dimer formation. However, these small peptides do not have any structure in solution and they do not penetrate cells. Therefore, we used the hydrocarbon stapling technique to stabilize the alpha-helical structure and confirmed by confocal microscopy that this modification also made these peptides cell penetrating. We also confirmed by using isothermal titration calorimetry (ITC), sedimentation equilibrium and NMR that these peptides indeed disrupt dimer formation. In in vitro assembly assays, the peptides inhibited mature-like virus particle formation and specifically inhibited HIV-1 production in cell-based assays. These peptides also showed potent antiviral activity against a large panel of laboratory-adapted and primary isolates, including viral strains resistant to inhibitors of reverse transcriptase and protease. CONCLUSIONS: These preliminary data serve as the foundation for designing small, stable, alpha helical peptides and small-molecule inhibitors targeted against the CTD dimer interface. The observation that relatively weak CA binders, such as NYAD-201 and NYAD-202, showed specificity and are able to disrupt the CTD dimer is encouraging for further exploration of a much broader class of antiviral compounds targeting CA. We cannot exclude the possibility that the CA-based peptides described here could elicit additional effects on virus replication not directly linked to their ability to bind CA-CTD. PMID- 21539736 TI - Current models broadly neglect specific needs of biodiversity conservation in protected areas under climate change. AB - BACKGROUND: Protected areas are the most common and important instrument for the conservation of biological diversity and are called for under the United Nations' Convention on Biological Diversity. Growing human population densities, intensified land-use, invasive species and increasing habitat fragmentation threaten ecosystems worldwide and protected areas are often the only refuge for endangered species. Climate change is posing an additional threat that may also impact ecosystems currently under protection. Therefore, it is of crucial importance to include the potential impact of climate change when designing future nature conservation strategies and implementing protected area management. This approach would go beyond reactive crisis management and, by necessity, would include anticipatory risk assessments. One avenue for doing so is being provided by simulation models that take advantage of the increase in computing capacity and performance that has occurred over the last two decades.Here we review the literature to determine the state-of-the-art in modeling terrestrial protected areas under climate change, with the aim of evaluating and detecting trends and gaps in the current approaches being employed, as well as to provide a useful overview and guidelines for future research. RESULTS: Most studies apply statistical, bioclimatic envelope models and focus primarily on plant species as compared to other taxa. Very few studies utilize a mechanistic, process-based approach and none examine biotic interactions like predation and competition. Important factors like land-use, habitat fragmentation, invasion and dispersal are rarely incorporated, restricting the informative value of the resulting predictions considerably. CONCLUSION: The general impression that emerges is that biodiversity conservation in protected areas could benefit from the application of modern modeling approaches to a greater extent than is currently reflected in the scientific literature. It is particularly true that existing models have been underutilized in testing different management options under climate change. Based on these findings we suggest a strategic framework for more effectively incorporating the impact of climate change in models exploring the effectiveness of protected areas. PMID- 21539737 TI - Plasmablastic lymphoma in the ano-rectal junction presenting in an immunocompetent man: a case report. AB - INTRODUCTION: Plasmablastic lymphoma is an aggressive non-Hodgkin lymphoma classically occurring in individuals infected with HIV. Plasmablastic lymphoma has a predilection for the oral cavity and jaw. However, recent case reports have shown lymphoma in the stomach, lung, nasal cavity, cervical lymph nodes and jejunum in HIV-negative individuals. We report what is, to the best of our knowledge, the first case of plasmablastic lymphoma occurring in the ano-rectal junction of an HIV-negative man. CASE PRESENTATION: A previously healthy 59-year old Caucasian man presented with painless rectal bleeding. Colonoscopy revealed a lesion in the ano-rectal junction, with pathological examination demonstrating atypical lymphoid cells consisting primarily of plasmablasts with rounded nuclei, coarse chromatin, small nucleoli and multiple mitotic figures. Immunohistochemical analysis showed the atypical cells were negative for CD45, CD20, CD79a and immunoglobulin light chains, but were strongly positive for CD138 and EBV-encoded RNA. The results were consistent with a diagnosis of plasmablastic lymphoma. Aggressive systemic chemotherapy and involved field radiation therapy resulted in complete clinical and pathological remission. CONCLUSION: Increasing awareness of plasmablastic lymphoma in HIV-negative individuals and in this location is warranted. PMID- 21539735 TI - Fever screening during the influenza (H1N1-2009) pandemic at Narita International Airport, Japan. AB - BACKGROUND: Entry screening tends to start with a search for febrile international passengers, and infrared thermoscanners have been employed for fever screening in Japan. We aimed to retrospectively assess the feasibility of detecting influenza cases based on fever screening as a sole measure. METHODS: Two datasets were collected at Narita International Airport during the 2009 pandemic. The first contained confirmed influenza cases (n = 16) whose diagnosis took place at the airport during the early stages of the pandemic, and the second contained a selected and suspected fraction of passengers (self-reported or detected by an infrared thermoscanner; n = 1,049) screened from September 2009 to January 2010. The sensitivity of fever (38.0 degrees C) for detecting H1N1-2009 was estimated, and the diagnostic performances of the infrared thermoscanners in detecting hyperthermia at cut-off levels of 37.5 degrees C, 38.0 degrees C and 38.5 degrees C were also estimated. RESULTS: The sensitivity of fever for detecting H1N1-2009 cases upon arrival was estimated to be 22.2% (95% confidence interval: 0, 55.6) among nine confirmed H1N1-2009 cases, and 55.6% of the H1N1 2009 cases were under antipyretic medications upon arrival. The sensitivity and specificity of the infrared thermoscanners in detecting hyperthermia ranged from 50.8-70.4% and 63.6-81.7%, respectively. The positive predictive value appeared to be as low as 37.3-68.0%. CONCLUSIONS: The sensitivity of entry screening is a product of the sensitivity of fever for detecting influenza cases and the sensitivity of the infrared thermoscanners in detecting fever. Given the additional presence of confounding factors and unrestricted medications among passengers, reliance on fever alone is unlikely to be feasible as an entry screening measure. PMID- 21539738 TI - The potential for bi-lateral agreements in medical tourism: A qualitative study of stakeholder perspectives from the UK and India. AB - BACKGROUND: Globalisation has prompted countries to evaluate their position on trade in health services. However, this is often done from a multi-lateral, rather than a regional or bi-lateral perspective. In a previous review, we concluded that most of the issues raised could be better addressed from a bi lateral relationship. We report here the results of a qualitative exercise to assess stakeholders' perceptions on the prospects for such a bi-lateral system, and its ability to address concerns associated with medical tourism. METHODS: 30 semi-structured interviews were carried out with stakeholders, 20 in India and 10 in the UK, to assess their views on the potential offered by a bi-lateral relationship on medical tourism between both countries. Issues discussed include data availability, origin of medical tourists, quality and continuity of care, regulation and litigation, barriers to medical tourism, policy changes needed, and prospects for such a bi-lateral relationship. RESULTS: The majority of stakeholders were concerned about the quality of health services patients would receive abroad, regulation and litigation procedures, lack of continuity of care, and the effect of such trade on the healthcare available to the local population in India. However, when considering trade from a bi-lateral point of view, there was disagreement on how these issues would apply. There was further disagreement on the importance of the Diaspora and the validity of the UK's 'rule' that patients should not fly more than three hours to obtain care. Although the opinion on the prospects for an India-UK bi-lateral relationship was varied, there was no consensus on what policy changes would be needed for such a relationship to take place. CONCLUSIONS: Whilst the literature review previously carried out suggested that a bi-lateral relationship would be best-placed to address the concerns regarding medical tourism, there was scepticism from the analysis provided in this paper based on the over-riding feeling that the political 'cost' involved was likely to be the major impediment. This makes the need for better evidence even more acute, as much of the current policy process could well be based on entrenched ideological positions, rather than secure evidence of impact. PMID- 21539739 TI - Conventional and diffusion-weighted magnetic resonance imaging findings of benign fibromatous paratesticular tumor: a case report. AB - INTRODUCTION: The vast majority of paratesticular masses are benign. Magnetic resonance imaging of the scrotum may provide valuable information in the pre operative work-up of scrotal masses, by allowing the precise localization of the lesion and helping in characterizing its nature. Diffusion-weighted magnetic resonance imaging is an evolving technique that can be used to improve tissue characterization, when interpreted with the findings of conventional magnetic resonance sequences. We present the case of an adenomatoid tumor of the tunica albuginea, with abundant fibrosis evaluated by magnetic resonance imaging of the scrotum, including both conventional and diffusion-weighted sequences. To the best of our knowledge, there are very few reports in the English literature regarding the magnetic resonance imaging features of this rare benign paratesticular tumor and no report on the diffusion-weighted magnetic resonance findings. We discuss the value of magnetic resonance imaging in the pre-operative diagnosis of benign fibromatous paratesticular tumors and differential diagnosis. CASE PRESENTATION: A 45-year-old Caucasian man was referred to us with a palpable left scrotal mass. Magnetic resonance imaging of his scrotum revealed the presence of a multilobular left paratesticular mass, mainly detected with very low signal intensity on T2-weighted images and restricted diffusion on apparent diffusion coefficient maps. These findings were suggestive of a fibrous component, and were confirmed on histology following lesion excision. CONCLUSION: Magnetic resonance imaging of the scrotum, by using both conventional and diffusion-weighted sequences, could have a potential role in the evaluation of scrotal masses. PMID- 21539740 TI - Umbilical hernia rupture with evisceration of omentum from massive ascites: a case report. AB - INTRODUCTION: The incidence of hernias is increased in patients with alcoholic liver disease with ascites. To the best of our knowledge, this is the first report of an acute rise in intra-abdominal pressure from straining for stool as the cause of a ruptured umbilical hernia. CASE PRESENTATION: An 81-year-old Caucasian man with a history of alcoholic liver disease presented to our emergency department with an erythematous umbilical hernia and clear, yellow discharge from the umbilicus. On straining for stool, after initial clinical assessment, our patient noted a gush of fluid and evisceration of omentum from the umbilical hernia. An urgent laparotomy was performed with excision of the umbilicus and devitalized omentum. CONCLUSION: We report the case of a patient with a history of alcoholic liver disease with ascites. Ascites causes a chronic increase in intra-abdominal pressure. A sudden increase in intra-abdominal pressure, such as coughing, vomiting, gastroscopy or, as in this case, straining for stool can cause rupture of an umbilical hernia. The presence of discoloration, ulceration or a rapid increase in size of the umbilical hernia signals impending rupture and should prompt the physician to reduce the intra abdominal pressure. PMID- 21539741 TI - Diversification across an altitudinal gradient in the Tiny Greenbul (Phyllastrephus debilis) from the Eastern Arc Mountains of Africa. AB - BACKGROUND: The Eastern Arc Mountains of Africa have become one of the focal systems with which to explore the patterns and mechanisms of diversification among montane species and populations. One unresolved question is the extent to which populations inhabiting montane forest interact with those of adjacent lowland forest abutting the coast of eastern Africa. The Tiny Greenbul (Phyllastephus debilis) represents the only described bird species within the Eastern Arc/coastal forest mosaic, which is polytypic across an altitudinal gradient: the subspecies albigula (green head) is distributed in the montane Usambara and Nguru Mountains whereas the subspecies rabai (grey head) is found in Tanzanian lowland and foothill forest. Using a combination of morphological and genetic data, we aim to establish if the pattern of morphological differentiation in the Tiny Greenbul (Phyllastrephus debilis) is the result of disruptive selection along an altitudinal gradient or a consequence of secondary contact following population expansion of two differentiated lineages. RESULTS: We found significant biometric differences between the lowland (rabai) and montane (albigula) populations in Tanzania. The differences in shape are coupled with discrete differences in the coloration of the underparts. Using multi-locus data gathered from 124 individuals, we show that lowland and montane birds form two distinct genetic lineages. The divergence between the two forms occurred between 2.4 and 3.1 Myrs ago.Our coalescent analyses suggest that limited gene flow, mostly from the subspecies rabai to albigula, is taking place at three mid altitude localities, where lowland and montane rainforest directly abut. The extent of this introgression appears to be limited and is likely a consequence of the recent expansion of rabai further inland. CONCLUSION: The clear altitudinal segregation in morphology found within the Tiny Greenbul is the result of secondary contact of two highly differentiated lineages rather than disruptive selection in plumage pattern across an altitudinal gradient. Based on our results, we recommend albigula be elevated to species rank. PMID- 21539742 TI - Prospero and Pax2 combinatorially control neural cell fate decisions by modulating Ras- and Notch-dependent signaling. AB - BACKGROUND: The concept of an equivalence group, a cluster of cells with equal potential to adopt the same specific fate, has served as a useful paradigm to understand neural cell type specification. In the Drosophila eye, a set of five cells, called the 'R7 equivalence group', generates a single photoreceptor neuron and four lens-secreting epithelial cells. This choice between neuronal versus non neuronal cell fates rests on differential requirements for, and cross-talk between, Notch/Delta- and Ras/mitogen-activated protein kinase (MAPK)-dependent signaling pathways. However, many questions remain unanswered related to how downstream events of these two signaling pathways mediate distinct cell fate decisions. RESULTS: Here, we demonstrate that two direct downstream targets of Ras and Notch signaling, the transcription factors Prospero and dPax2, are essential regulators of neuronal versus non-neuronal cell fate decisions in the R7 equivalence group. Prospero controls high activated MAPK levels required for neuronal fate, whereas dPax2 represses Delta expression to prevent neuronal fate. Importantly, activity from both factors is required for proper cell fate decisions to occur. CONCLUSIONS: These data demonstrate that Ras and Notch signaling are integrated during cell fate decisions within the R7 equivalence group through the combinatorial and opposing activities of Pros and dPax2. Our study provides one of the first examples of how the differential expression and synergistic roles of two independent transcription factors determine cell fate within an equivalence group. Since the integration of Ras and Notch signaling is associated with many developmental and cancer models, these findings should provide new insights into how cell specificity is achieved by ubiquitously used signaling pathways in diverse biological contexts. PMID- 21539743 TI - Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm. AB - BACKGROUND: Proadrenomedullin (ProADM) confers additional prognostic information to established clinical risk scores in lower respiratory tract infections (LRTI). We aimed to derive a practical algorithm combining the CURB65 score with ProADM levels in patients with community-acquired pneumonia (CAP) and non-CAP-LRTI. METHODS: We used data of 1359 patients with LRTI enrolled in a multicenter study. We chose two ProADM cut-off values by assessing the association between ProADM levels and the risk of adverse events and mortality. A composite score (CURB65-A) was created combining CURB65 classes with ProADM cut-offs to further risk stratify patients. RESULTS: CURB65 and ProADM predicted both adverse events and mortality similarly well in CAP and non-CAP-LRTI. The combined CURB65-A risk score provided better prediction of death and adverse events than the CURB65 score in the entire cohort and in CAP and non-CAP-LRTI patients. Within each CURB65 class, higher ProADM-levels were associated with an increased risk of adverse events and mortality. Overall, risk of adverse events (3.9%) and mortality (0.65%) was low for patients with CURB65 score 0-1 and ProADM <=0.75 nmol/l (CURB65-A risk class I); intermediate (8.6% and 2.6%, respectively) for patients with CURB65 score of 2 and ProADM <=1.5 nmol/l or CURB classes 0-1 and ProADM levels between 0.75-1.5 nmol/L (CURB65-A risk class II), and high (21.6% and 9.8%, respectively) for all other patients (CURB65-A risk class III). If outpatient treatment was recommended for CURB65-A risk class I and short hospitalization for CURB65-A risk class II, 17.9% and 40.8% of 1217 hospitalized patients could have received ambulatory treatment or a short hospitalization, respectively. CONCLUSIONS: The new CURB65-A risk score combining CURB65 risk classes with ProADM cut-off values accurately predicts adverse events and mortality in patients with CAP and non-CAP-LRTI. Additional prospective cohort or intervention studies need to validate this score and demonstrate its safety and efficacy for the management of patients with LRTI. TRIAL REGISTRATION: Procalcitonin-guided antibiotic therapy and hospitalisation in patients with lower respiratory tract infections: the prohosp study; isrctn.org Identifier: ISRCTN: ISRCTN95122877. PMID- 21539744 TI - Impact of a maternal health voucher scheme on institutional delivery among low income women in Pakistan. AB - BACKGROUND: Only 39% of deliveries in Pakistan are attended by skilled birth attendants, while Pakistan's target for skilled birth attendance by 2015 is > 90%. METHODS: A 12-month maternal health voucher intervention was implemented in Dera Ghazi Khan City, located in Southern Punjab, Pakistan in 2009. A pre test/post-test non-experimental study was conducted to assess the impact of the intervention. Household interviews were conducted with randomly selected women who delivered in 2008 (the year prior to the voucher intervention), and with randomly selected women who delivered in 2009. A strong outreach model was used and voucher booklets valued at $50, containing redeemable coupons for three antenatal care (ANC) visits, a postnatal care (PNC) visit and institutional delivery, were sold for $1.25 to low-income women targeted by project workers. Regression analysis was conducted to determine the impact of the voucher scheme on ANC, PNC, and institutional delivery. Marginal effects estimated from logistic regression analyses were used to assess the magnitude of the impact of the intervention. RESULTS: The women targeted by voucher outreach workers were poorer, less educated, and at higher parity. After adjusting for these differences, women who delivered in 2009 and were sold voucher booklets were significantly more likely than women who delivered in 2008 to make at least three ANC visits, deliver in a health facility, and make a postnatal visit. Purchase of a voucher booklet was associated with a 22 percentage point increase in ANC use, a 22 percentage point increase in institutional delivery, and a 35 percentage point increase in PNC use. CONCLUSIONS: A voucher intervention implemented for 12 months was associated with a substantial increase in institutional delivery. A substantial scale-up of maternal health vouchers that focus on institutional delivery is likely to bring Pakistan closer to achieving its 2015 target for institutional delivery. PMID- 21539745 TI - MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer. AB - BACKGROUND: Hormone therapy is the standard of care for newly diagnosed or recurrent prostate cancers. It uses anti-androgen agents, castration, or both to eliminate cancer promoting effect of testicular androgen. The p53 tumor suppressor controls a major pathway that can block cell proliferation or induce apoptosis in response to diverse forms of oncogenic stress. Activation of the p53 pathway in cancer cells expressing wild-type p53 has been proposed as a novel therapeutic strategy and recently developed MDM2 antagonists, the nutlins, have validated this in preclinical models of cancer. The crosstalk between p53 and androgen receptor (AR) signaling suggest that p53 activation could augment antitumor outcome of androgen ablation in prostate cancer. Here, we test this hypothesis in vitro and in vivo using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP. RESULTS: Using charcoal-stripped serum as a cellular model of androgen deprivation, we show an increased apoptotic effect of p53 activation by nutlin-3a in the androgen-dependent LNCaP cells and to a lesser extent in androgen-independent but responsive 22Rv1 cell line. This effect is due, at least in part, to an enhanced downregulation of AR expression by activated p53. In vivo, androgen deprivation followed by two weeks of nutlin administration in LNCaP-bearing nude mice led to a greater tumor regression and dramatically increased survival. CONCLUSIONS: Since majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy. PMID- 21539746 TI - Who is to blame? Perspectives of caregivers on barriers to accessing healthcare for the under-fives in Butere District, Western Kenya. AB - BACKGROUND: Kenya, like many developing nations, continues to experience high childhood mortality in spite of the many efforts put in place by governments and international bodies to curb it. This study sought to investigate the barriers to accessing healthcare services for children aged less than five years in Butere District, a rural district experiencing high rates of mortality and morbidity despite having relatively better conditions for child survival. METHODS: Exit interviews were conducted among caregivers seeking healthcare for their children in mid 2007 in all the 6 public health facilities. Additionally, views from caregivers in the community, health workers and district health managers were sought through focus group discussions (FGDs) and key informant interviews (KIs). RESULTS: Three hundred and ninety-seven respondents were surveyed in exit interviews while 45 respondents participated in FGDs and KIs. Some practices by caregivers including early onset of child bearing, early supplementation, and utilization of traditional healers were thought to increase the risk of mortality and morbidity, although reported rates of mosquito net utilization and immunization coverage were high. The healthcare system posed barriers to access of healthcare for the under fives, through long waiting time, lack of drugs and poor services, incompetence and perceived poor attitudes of the health workers. FGDs also revealed wide-spread concerns and misconceptions about health care among the caregivers. CONCLUSION: Caregivers' actions were thought to influence children's progression to illness or health while the healthcare delivery system posed recurrent barriers to the accessing of healthcare for the under-fives. Actions on both fronts are necessary to reduce childhood mortality. PMID- 21539747 TI - Cardiovascular magnetic resonance in cardiac sarcoidosis with MR conditional pacemaker in situ. AB - Cardiovascular implantable electronic devices represent important limitations to magnetic resonance imaging (MRI). Recently, MRI-conditional dual chamber pacemakers and leads have become available. We describe a case of a patient with neuro-sarcoidosis presenting with diplopia and hydrocephalus requiring an MRI conditional programmable ventriculo-peritoneal shunt, who developed complete heart block. In view of the ongoing need for neuro-imaging, MRI-conditional dual chamber pacemaker and leads were implanted. Cardiac and brain MRI were requested to guide immunosupression. Overall the scans demonstrated stable neurological disease, but confirmed cardiac sarcoid, with oedema on T2 weighted images suggesting active disease and extensive sub-endocardial late gadolinium enhancement, including the basal septum. This case illustrates why sarcoid patients who develop bradyarrhythmias should ideally have an MRI-conditional pacing system. PMID- 21539748 TI - Regulation of gene expression in human tendinopathy. AB - BACKGROUND: Chronic tendon injuries, also known as tendinopathies, are common among professional and recreational athletes. These injuries result in a significant amount of morbidity and health care expenditure, yet little is known about the molecular mechanisms leading to tendinopathy. METHODS: We have used histological evaluation and molecular profiling to determine gene expression changes in 23 human patients undergoing surgical procedures for the treatment of chronic tendinopathy. RESULTS: Diseased tendons exhibit altered extracellular matrix, fiber disorientation, increased cellular content and vasculature, and the absence of inflammatory cells. Global gene expression profiling identified 983 transcripts with significantly different expression patterns in the diseased tendons. Global pathway analysis further suggested altered expression of extracellular matrix proteins and the lack of an appreciable inflammatory response. CONCLUSIONS: Identification of the pathways and genes that are differentially regulated in tendinopathy samples will contribute to our understanding of the disease and the development of novel therapeutics. PMID- 21539749 TI - Through the looking glass: understanding non-inferiority. AB - Non-inferiority trials test whether a new product is not unacceptably worse than a product already in use. This paper introduces concepts related to non inferiority, and discusses the regulatory views of both the European Medicines Agency and the United States Food and Drug Administration. PMID- 21539750 TI - CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion. AB - BACKGROUND: Chemotherapy heavily relies on apoptosis to kill breast cancer (BrCa) cells. Many breast tumors respond to chemotherapy, but cells that survive this initial response gain resistance to subsequent treatments. This leads to aggressive cell variants with an enhanced ability to migrate, invade and survive at secondary sites. Metastasis and chemoresistance are responsible for most cancer-related deaths; hence, therapies designed to minimize both are greatly needed. We have recently shown that CCR9-CCL25 interactions promote BrCa cell migration and invasion, while others have shown that this axis play important role in T cell survival. In this study we have shown potential role of CCR9-CCL25 axis in breast cancer cell survival and therapeutic efficacy of cisplatin. METHODS: Bromodeoxyuridine (BrdU) incorporation, Vybrant apoptosis and TUNEL assays were performed to ascertain the role of CCR9-CCL25 axis in cisplatin induced apoptosis of BrCa cells. Fast Activated Cell-based ELISA (FACE) assay was used to quantify In situ activation of PI3Kp85, AktSer473, GSK-3betaSer9 and FKHRThr24 in breast cancer cells with or without cisplatin treatment in presence or absence of CCL25. RESULTS: CCR9-CCL25 axis provides survival advantage to BrCa cells and inhibits cisplatin-induced apoptosis in a PI3K-dependent and focal adhesion kinase (FAK)-independent fashion. Furthermore, CCR9-CCL25 axis activates cell-survival signals through Akt and subsequent glycogen synthase kinase-3 beta (GSK-3beta) and forkhead in human rhabdomyosarcoma (FKHR) inactivation. These results show that CCR9-CCL25 axis play important role in BrCa cell survival and low chemotherapeutic efficacy of cisplatin primarily through PI3K/Akt dependent fashion. PMID- 21539751 TI - Medical tourism and policy implications for health systems: a conceptual framework from a comparative study of Thailand, Singapore and Malaysia. AB - Medical tourism is a growing phenomenon with policy implications for health systems, particularly of destination countries. Private actors and governments in Southeast Asia are promoting the medical tourist industry, but the potential impact on health systems, particularly in terms of equity in access and availability for local consumers, is unclear. This article presents a conceptual framework that outlines the policy implications of medical tourism's growth for health systems, drawing on the cases of Thailand, Singapore and Malaysia, three regional hubs for medical tourism, via an extensive review of academic and grey literature. Variables for further analysis of the potential impact of medical tourism on health systems are also identified. The framework can provide a basis for empirical, in country studies weighing the benefits and disadvantages of medical tourism for health systems. The policy implications described are of particular relevance for policymakers and industry practitioners in other Southeast Asian countries with similar health systems where governments have expressed interest in facilitating the growth of the medical tourist industry. This article calls for a universal definition of medical tourism and medical tourists to be enunciated, as well as concerted data collection efforts, to be undertaken prior to any meaningful empirical analysis of medical tourism's impact on health systems. PMID- 21539753 TI - Periodic fever syndromes in Eastern and Central European countries: results of a pediatric multinational survey. AB - OBJECTIVE: To analyze the prevalence of diagnosed and suspected autoinflammatory diseases in Eastern and Central European (ECE) countries, with a particular interest on the diagnostic facilities in these countries. METHODS: Two different strategies were used to collect data on patients with periodic fever syndromes from ECE countries- the Eurofever survey and collection of data with the structured questionnaire. RESULTS: Data from 35 centers in 14 ECE countries were collected. All together there were 11 patients reported with genetically confirmed familial Mediterranean fever (FMF), 14 with mevalonate-kinase deficiency (MKD), 11 with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and 4 with chronic infantile neurological cutaneous and articular syndrome (CINCA). Significantly higher numbers were reported for suspected cases which were not genetically tested. All together there were 49 suspected FMF patients reported, 24 MKD, 16 TRAPS, 7 CINCA and 2 suspected Muckle Wells syndrome (MWS) patients. CONCLUSIONS: The number of genetically confirmed patients with periodic fever syndromes in ECE countries is very low. In order to identify more patients in the future, it is important to organize educational programs for increasing the knowledge on these diseases and to establish a network for genetic testing of periodic fever syndromes in ECE countries. PMID- 21539752 TI - Evolution of an endofungal lifestyle: Deductions from the Burkholderia rhizoxinica genome. AB - BACKGROUND: Burkholderia rhizoxinica is an intracellular symbiont of the phytopathogenic zygomycete Rhizopus microsporus, the causative agent of rice seedling blight. The endosymbiont produces the antimitotic macrolide rhizoxin for its host. It is vertically transmitted within vegetative spores and is essential for spore formation of the fungus. To shed light on the evolution and genetic potential of this model organism, we analysed the whole genome of B. rhizoxinica HKI 0454 - a type strain of endofungal Burkholderia species. RESULTS: The genome consists of a structurally conserved chromosome and two plasmids. Compared to free-living Burkholderia species, the genome is smaller in size and harbors less transcriptional regulator genes. Instead, we observed accumulation of transposons over the genome. Prediction of primary metabolic pathways and transporters suggests that endosymbionts consume host metabolites like citrate, but might deliver some amino acids and cofactors to the host. The rhizoxin biosynthesis gene cluster shows evolutionary traces of horizontal gene transfer. Furthermore, we analysed gene clusters coding for nonribosomal peptide synthetases (NRPS). Notably, B. rhizoxinica lacks common genes which are dedicated to quorum sensing systems, but is equipped with a large number of virulence-related factors and putative type III effectors. CONCLUSIONS: B. rhizoxinica is the first endofungal bacterium, whose genome has been sequenced. Here, we present models of evolution, metabolism and tools for host-symbiont interaction of the endofungal bacterium deduced from whole genome analyses. Genome size and structure suggest that B. rhizoxinica is in an early phase of adaptation to the intracellular lifestyle (genome in transition). By analysis of tranporters and metabolic pathways we predict how metabolites might be exchanged between the symbiont and its host. Gene clusters for biosynthesis of secondary metabolites represent novel targets for genomic mining of cryptic natural products. In silico analyses of virulence associated genes, secreted proteins and effectors might inspire future studies on molecular mechanisms underlying bacterial-fungal interaction. PMID- 21539754 TI - The novel roles of four and a half LIM proteins 1 and 2 in the cardiovascular system. AB - Four and a half LIM domains protein 1 (FHL1) and FHL2, as the name suggests, contain four and a half LIM domain binding proteins. Proteins in this family capable of interacting with many types of proteins, including structural proteins, kinases, and several classes of transcription factors, have been identified. These interactions have been found to have important roles in a variety of fundamental processes including transcriptional regulation, cardiovascular development, hypertrophy, atherosclerosis, and angiogenesis. This article reviews recent advances in the characterization of FHL1 and FHL2, their biological roles, LIM domain binding proteins, and functions in the cardiovascular system. PMID- 21539755 TI - Mitochondrial dysfunction, metabolic deficits, and increased oxidative stress in Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder, characterized by an array of different psychiatric manifestations, cognitive decline and choreiform movements. The underlying molecular genetic defect is an expanded trinucleotide (CAG)n repeat encoding a polyglutamine stretch in the N-terminus of the huntingtin protein. The mechanisms by which mutant huntingtin causes neuronal dysfunction and degeneration are not fully understood. Nevertheless, impaired ubiquitin-proteasome activity, defective autophagy-lysosomal function, transcriptional dysregulation, oxidative stress, apoptosis, mitochondrial and metabolic dysfunction, and abnormal protein-protein interaction have been shown to play important roles in the pathogenesis of HD. Neurons are energy-demanding and more susceptible to energetic failure and oxidative damage than other types of cell. Given that mitochondria play a central role in both processes of metabolism and oxidative stress, and increasing direct evidence shows mitochondrial abnormalities in both HD mouse models and patients, this article will review the studies of mitochondrial dysfunction, metabolic deficits, and increased oxidative stress in HD, and discuss the potential therapeutics targeting these abnormalities. PMID- 21539756 TI - Academic achievements of doctors who studied at a domestic institute for clinical medicine. AB - BACKGROUND: The purpose of this study was to investigate the outcomes of doctors who studied at a graduate degree program at a domestic institute for clinical medicine. METHODS: The academic results of 45 doctors who studied at the Graduate Institute of Clinical Medical Sciences-Kaohsiung Branch (GICMS-KB) of Chang Gung University (CGU) were analyzed and compared with those of 83 doctors who had studied abroad or at domestic institutions other than CGU (non-CGU), as well as with 263 who did not pursue further graduate studies (no GS) during the study period from 2003 to 2007. The 128 doctors who had pursued graduate study were sent a survey consisting of 6 questions about factors which hamper research activity. RESULTS: The average number of Science Citation Index (SCI) articles published by the doctors of GICMS-KB as the first author over five years was 3.16 +/- 0.52, which was significantly higher than 1.51 +/- 0.22 in the no GS group (p = 0.005) and 2.31 +/- 0.39 in the non-CGU group. The average number of research grants was 3.62 +/- 0.64 in GICMS-KB group, which was higher than 1.57 +/- 0.28 in the non-CGU and 1.56 +/- 0.20 in the no GS groups (p < 0.001 in both). The percentage of the doctors with faculty positions was 58% in GICMS-KB group, higher than 43% in the non-CGU and 38% in the no GS groups, with a p value of 0.055 comparing GICMS-KB with the no GS group. The survey indicated that all doctors who pursued post-graduate training had similar problems, such as lack of time and lack of research manpower with no difference between the GICMS-KB and non-CGU groups. CONCLUSION: The academic performance of doctors who did postgraduate study at our graduate institute for clinical medicine was generally better than those who did not pursue further graduate studies or those with postgraduate studies outside CGU. Factors such as adaptation of the GICMS-KB doctors to our system and policies which include enforced grant writing and publication for graduation during the training course may account for the difference. PMID- 21539757 TI - The natural vibration characteristics of human ossicles. AB - BACKGROUND: Recently, a model of the ossicular chain for finite element analysis has been developed. However, the natural vibration characteristics of human ossicles have never been studied. Herein, we investigated the dynamic characteristics of the coupling of in-vivo ossicles using finite element analysis. METHODS: The geometry of the ossicular chain was obtained by high resolution computed tomography of the temporal bone, and a 3D model of the ossicular chain was reconstructed by the medical imaging software, Amira(r). The file was then imported into the finite element analysis software, ANSYS(r). The natural vibration characteristics of human ossicles were measured by finite element analysis. RESULTS: The characteristic dimensions of the model were measured and compared with previously published data. The malleus resonated to sound stimuli at 3 kHz and 4 kHz; the incus and stapes did not resonate to sound stimuli at any frequency. A coupling of the incus and malleus easily resonated to sound stimuli at 5 kHz. A coupling of the incus and stapes easily resonated to sound stimuli at 3 kHz. The coupling of the ossicular chain easily resonated to sound stimuli at 5 kHz, 6 kHz and 8 kHz. CONCLUSION: The dynamic characteristics of the ossicular chain were analyzed by finite element analysis method. The characteristics of a free vibration model of the ossicles could be determined, which would be helpful in evaluation and consultation for ossicular prosthesis development. PMID- 21539758 TI - Magnetic resonance imaging of the in-vivo human tympanic membrane. AB - BACKGROUND: To obtain magnetic resonance images of the in-vivo human tympanic membrane to avoid radiation exposure. METHODS: Images of the in-vivo human tympanic membrane were obtained by magnetic resonance imaging (MRI). The differences in resolution of the images obtained by multi slice single echo (MSSE) and 3-dimentional (3D) SNAP sequences were then compared. RESULTS: The resolution of the 2D MR images acquired by MSSE sequences was higher than that obtained by 3D SNAP. The voxel size of the MR images was smaller than that with 3D SNAP because of the narrower slice thickness. Therefore, the spatial resolution of the 3D SNAP sequenced images was better than that of MSSE images. The scanning time for MSSE and 3D SNAP were 12 minutes and 40 seconds and 1 minute and 42 seconds respectively. The signal-to-noise ratio (SNR) of MR images with 3D SNAP was 0.32 decibels higher than that with MSSE. CONCLUSION: In this study, MR images of the in-vivo human tympanic membrane could be obtained with a 9-cm surface coil with MSSE and 3D SNAP sequences. The spatial resolution of MR images acquired with 3D SNAP was better than that with MSSE. The scanning time with 3D SNAP was shorter than that with MSSE based on similar SNRs. The structure and geometry of the tympanic membrane can be observed clearly, which would be helpful for diagnosis in clinics and can avoid radiation exposure. PMID- 21539759 TI - Efficacy of intramuscular nalbuphine versus diphenhydramine for the prevention of epidural morphine-induced pruritus after cesarean delivery. AB - BACKGROUND: Pruritus is the most common side effect of epidural morphine analgesia. Diphenhydramine is a widely used agent for the treatment of urticarial pruritus. Nalbuphine is a mixed opioid agonist-antagonist and has been reported to be effective in treating opioid-induced pruritus. We compared the effectiveness of intramuscular diphenhydramine and nalbuphine for the prevention of epidural morphine-induced pruritus after cesarean section. METHODS: One hundred and fifty, American Society of Anesthesiologists physical status I or II, women undergoing cesarean section with epidural anesthesia were randomly assigned to three groups. Group S, group D, and group N received intramuscular normal saline (1 ml; n = 50), diphenhydramine (30 mg/1 ml; n = 50), and nalbuphine (10 mg/1 ml; n = 50), respectively, after delivery of the baby. The occurrence and the severity of pruritus were assessed at 1, 4, 12, and 24 hours after surgery. RESULTS: The overall incidence of pruritus during the 24 hr follow-up period was 72%, 68%, and 44% for group S, group D, and group N, respectively. Pruritus occurred less frequently in group N than group D (p = 0.027). At 4 and 12 hrs postoperatively, the pruritus severity was significantly different (p = 0.003 and p = 0.002) and was significantly less in group N than group D in the intergroup comparison (p = 0.013 and p = 0.012). CONCLUSION: Nalbuphine proved better than diphenhydramine for prevention of epidural morphine-induced pruritus in patients who underwent cesarean section. Prophylactic intramuscular nalbuphine (10 mg) is effective in decreasing the incidence and severity of pruritus and does not affect analgesia. PMID- 21539760 TI - Early endoscopic primary realignment decreases stricture formation and reduces medical costs in traumatic complete posterior urethral disruption in a 2-year follow-up. AB - BACKGROUND: There are presently several options for the management of posterior urethral disruption. However, these options remain controversial for several reasons. Thus, this medical issue has been continuously investigated. METHODS: From 1991 to 2001, 22 patients with complete posterior urethral disruption out of 720 urethral injury cases were retrospectively reviewed using strict criteria. The 22 cases were grouped into two different management groups, the endoscopic early realignment (ER) group and the delayed urethrotomy (DU) group. The frequency of optic internal urethrotomy for urethral strictures and individual medical costs were evaluated over a two-year period. RESULTS: The ER group had a mean frequency of 1.3 +/- 0.82 urethrotomies in the first year and 1.8 +/- 1.23 over two years while the DU group had a significantly higher urethrotomy frequency, 2.5 +/- 1.35 in the first year and 4.1 +/- 1.91 over two years. The costs for the DU group were 50% higher than the ER group at the end of second year. CONCLUSION: An early endoscopic realignment operation saved up to NT 36,000 (New Taiwan Dollars) in costs with an average of 2.3 fewer further urethrotomy procedures in each case during the 2-year follow-up period. Therefore, early urethral realignment for traumatic complete posterior urethral disruption should be encouraged to prevent intractable urethral stricture and lower medical costs. PMID- 21539761 TI - Quality of life in patients with psoriasis in northern Taiwan. AB - BACKGROUND: Psoriasis has a significant negative impact on quality of life. The aim of this study was to identify factors associated with the quality of life of patients with psoriasis in Taiwan. METHODS: A retrospective study analyzing data from psoriasis patients who visited the outpatient clinics in the Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Taipei, Taoyuan and Keelung from July 2009 to January 2010 was performed. RESULTS: A total of 480 patients who had completed the assessment of disease severity and the dermatology life quality index (DLQI) questionnaire were analyzed. Of these patients, 67.5% were men. The mean score on the DLQI was 9.16 +/- 6.3 and 67% of all patients reported a moderate to extremely large impact on their quality of life (DLQI > 6). A higher psoriasis area and severity index (PASI), younger age and initial lesions on the nails significantly negatively impacted patients' quality of life. Smoking, alcohol intake and gender were also weakly correlated. CONCLUSION: The clinical severity, age and site of initial lesions are associated with negative impacts on the quality of life of patients with psoriasis. These findings provide significant new insights into factors that affect the life quality of patients with psoriasis in Taiwan. PMID- 21539762 TI - Prevalence and association of suicide ideation among Taiwanese elderly--a population-based cross-sectional study. AB - BACKGROUND: Elders commit suicide almost twice as frequently as people in the general population. This study aimed to investigate the prevalence and associated factors of suicide ideation among a representative sample of elderly people in Taiwan. METHODS: We used data from the Health Promotion Knowledge, Attitudes, and Performance Survey in Taiwan and focused on 3,853 subjects with over 65 years old. Univariate and multivariate logistic regression were used to compare subjects with and without suicide ideation in terms of their subject characteristics, smoking, disability, depressive symptoms, physical disorders, and pain symptoms. RESULTS: The point prevalence of elderly suicidal ideation was 6.1%. Female gender, age over 85 years, low level of of education, single status, unemployment. no income, disability, current smoking, self-perceived bad to very bad health, depressive symptoms, various physical disorders (heart disease, diabetes, asthma, osteoporosis), and pain symptoms (joint pain, lower back pain, neck pain, sciatica, headache) were strongly associated with suicide ideation. Multivariate analyses showed that the female gender, former smoker, no income, depressive symptoms, and heart disease were the predictors of elderly suicide ideation. CONCLUSION: Elderly subjects who are women, or former smokers, and have depressive symptoms, heart disease or no income should be cautioned about the risk of suicide. PMID- 21539763 TI - Intravenous ondansetron as antiemetic prophylaxis for postoperative nausea and vomiting after shoulder arthroscopy. AB - BACKGROUND: Nausea and vomiting are common chief postoperative complaints. The clinical literature indicates that postoperative nausea and vomiting (PONV) is common after orthopedic surgery. This study examines the clinical therapeutic efficacy of Ondansetron injected intravenously before the end of shoulder arthroscopy as antiemetic prophylaxis to help reduce the incidence of PONV. METHODS: Participants were identified through retrospective chart review and patients undergoing shoulder arthroscopy performed by the same orthopedic surgeon at the same hospital from 2005 to 2009 were analyzed. Subjects were classified into two groups based on whether Ondansetron was given. Differences in the incidence of PONV among the two groups were compared. Basic patient information, anesthesia records, and surgical records were obtained, as well as records on PONV, postoperative pain intensity, and postoperative analgesic injections within 24 hours after surgery. RESULTS: The study involved 90 patients. The Group A contained 34 patients who did not receive Ondansetron, and the Group B contained 56 patients who were given Ondansetron. Analytical results for the postoperative 24 hour period showed a significant difference in the incidence of vomiting between the two groups, with a lower incidence (p < 0.05) for the. Group B. However there was no significant difference in the incidence of nausea between the two groups in the same postoperative 24 hour period, although there was a trend of a lower incidence in the Group B (p = 0.17). The overall incidence of PONV during the 24-hour period was lower in the Group B (14%) than the Group A (32%), and the Group B demonstrated lower pain intensity and lower analgesic injection needs. CONCLUSION: Routine intravenous injection of Ondansetron 30 minutes before completion of shoulder arthroscopy can reduce the incidence of vomiting and overall PONV in patients. Additionally, the patients using Ondansetron demonstrated lower pain intensity and lower analgesic injection needs than the control group. PMID- 21539764 TI - Peripheral primitive neuroectodermal tumor of the chest wall in childhood: clinico-pathological significance, management and literature review. AB - Peripheral primitive neuroectodermal tumor of the chest wall is a rare malignant tumor usually occurring in children. The tumor shares a similar histology, immunohistology and cytogenetics to Ewing's sarcoma. The location of the tumor in the chest wall poses a major challenge with respect to the diagnostic workup and treatment which involves multidisciplinary management. Neoadjuvant chemotherapy is given initially and is followed by complete surgical resectioning of the mass followed by repeat chemotherapy with or without radiotherapy. We report a case of peripheral primitive neuroectodermal tumor of the chest wall in a 5-year-old boy and review the literature regarding its diagnosis and management. PMID- 21539765 TI - Usefulness of the WuScope to facilitate double-lumen endotracheal tube placement in a patient with ankylosing spondylitis. AB - Functional separation of the lungs may be accomplished by several methods. Patients with a stiff neck and limited mouth opening restrict options to a one lung ventilation. We report the use of the WuScope video system, a new tool for facilitating double-lumen endotracheal tube placement for one-lung ventilation, in a patient who suffered from ankylosing spondylitis with a stiff, flexed neck and limited mouth opening for his recurrent spontaneous pneumothorax. PMID- 21539766 TI - Salvage radiotherapy after high-intensity focused ultrasound treatment for localized prostate cancer: feasibility, tolerance and efficacy. AB - BACKGROUND: The objective of this study is to evaluate the feasibility, tolerance and efficacy of salvage external beam radiotherapy (EBRT) in persistent or recurrent prostate cancer after failed high intensity focused ultrasound (HIFU) therapy. METHODS: We reviewed data on tolerance and oncologic outcomes for all patients with biopsy-proven locally recurrent or persistent prostate cancer who underwent salvage EBRT in our department between April 2004 and June 2008. Minimum follow-up for inclusion was 2 years. Failure with EBRT was defined as biochemical relapse (Phoenix definition) or introduction of androgen deprivation therapy (ADT). Gastrointestinal and urinary toxicity and urinary stress incontinence were scored at 12 and 24 months (Radiation Therapy Oncology Group and Ingelman Sundberg rating, respectively). RESULTS: The mean age of the patients was 68.8 years (range: 60-79). Mean prostate-specific antigen (PSA) before EBRT was 5.57 ng/mL (range: 2.5-14.8). Median follow-up was 36.5 +/- 10.9 months (range: 24-54). No patient received adjunctive ADT. The EBRT course was well-tolerated and completed by all patients. The mean PSA nadir was 0.62 ng/mL (range: 0.03-2.4) and occurred after a median of 22 months (range: 12-36). One patient experienced biochemical failure and was prescribed ADT 30 months after EBRT. The disease-free survival rate was 83.3% at 36.5 months. There was no major EBRT-related toxicity at 12 or 24 months. CONCLUSIONS: Our early clinical results confirm the feasibility and good tolerance of salvage radiotherapy after HIFU failure. Oncological outcomes were promising. A prospective study with longer follow-up is needed to identify factors predictive of success for salvage EBRT therapy after HIFU failure. PMID- 21539767 TI - Undergraduate exposure to urology: impact of the distributed model of medical education in British Columbia. AB - BACKGROUND: With the increased development of distributed sites for medical education across Canada, it is imperative we ensure that the quality of education is comparable between the different campuses. Our objective was to assess medical student experience and comfort with common urologic clinical encounters and to determine whether any differences exist between the distributed education sites at the University of British Columbia (UBC). METHODS: Questionnaires assessing urologic education were delivered simultaneously to all final-year UBC medical students attending campuses in Vancouver, Victoria and Prince George. Results were analyzed using descriptive statistics. RESULTS: Overall, 55.8% of students felt their exposure to urology was adequate in the medical curriculum; learners in the Northern Program (Prince George) ranked their clinical and didactic experiences significantly higher. Areas requiring improvement include teaching of the male genitourinary exam, digital rectal exam and sexual history, in which learners rated teaching "good/outstanding" in only 18.2%, 47.7% and 43.2% of cases, respectively. Overall, students were most comfortable with the following clinical encounters: urinary tract infection, nephrolithiasis, benign prostatic hyperplasia, hematuria, incontinence and prostate cancer. Few differences in student experience or comfort were noted related to campus site, gender or urology clerkship exposure. CONCLUSION: A significant minority of learners perceived that they had inadequate exposure to urology in the undergraduate curriculum. Experience in urology was comparable across the distributed sites and was congruent with teaching objectives. Students were comfortable with the clinical scenarios deemed most important in the literature. Learners in the Northern Program were significantly more satisfied with their urologic teaching, which potentially highlights the advantages of learning in a smaller academic setting. PMID- 21539768 TI - "Just what the doctor ordered": Factors associated with oncology patients' decision to bank sperm. AB - INTRODUCTION: The purpose of this cross-sectional study was to explore factors associated with oncology patients' decision to bank sperm prior to cancer treatment. MATERIALS AND METHODS: Patients who were referred to the oncology sperm banking program between January 2009 and March 2010 were invited to complete an 18-item questionnaire during one of their sperm banking visits. RESULTS: Of the 157 cancer patients referred to the Mount Sinai Oncology Sperm and Tissue Bank for sperm banking during the 15-month period, 79 questionnaires were returned (50% response rate). Of the respondents, 89% were informed about sperm banking by their physician. Future family planning was cited as the main reason to bank. Cost was not a barrier for the vast majority of respondents. Forty percent of respondents banked sperm within 4 days prior to initiating cancer treatment. Most respondents relied on their physician for verbal information on sperm banking. Eighty-one percent were unaware of any patient organizations that have educational materials on oncology fertility preservation. CONCLUSION: Sperm banking prior to cancer treatment is the only proven method of preserving fertility for cancer patients. The two main determinants associated with deciding whether to bank sperm were: the physician's recommendation and the patient's desire for future fatherhood. Physicians play a key role in influencing patients' decisions. The recommendation to bank sperm is a persuasive message if patients are clearly informed about their potential risk of infertility post cancer treatment, and that sperm banking is an effective way of preserving fertility. Providing patients with education materials might enhance compliance in sperm banking. PMID- 21539769 TI - A smoking cessation program as a resource for bladder cancer patients. AB - BACKGROUND: Continued tobacco use following a bladder cancer (CaB) diagnosis puts patients at risk for other tobacco-associated diseases and has also been associated with heightened risks of treatment-related complications, tumour recurrence, morbidity and mortality. Our aim was to determine if patients with CaB who continue to smoke warrant a smoking cessation program as a resource for improving their prognosis and long-term health. METHODS: A cross-sectional quantitative questionnaire-based study was performed between January and April 2009. We surveyed patients with a pathologically confirmed diagnosis of CaB during their cystoscopy appointments at a single cancer centre. RESULTS: One hundred patients completed the survey with 72% of them admitting to smoking in their lifetime. A third of respondents smoked at the time of their diagnosis; 76% of patients who had been active smokers at the time of their diagnosis (n = 33) reported smoking at some point thereafter and 58% continued to smoke. Among continued smokers, they were classified in the following categories: 26% were in "precontemplation," 5% in "contemplation," 16% in "preparation," and 53% in "action;" 37% of patients who continued to smoke were interested in a hospital based smoking cessation program. Overall, 70% reported smoking as a risk factor for a poor CaB prognosis. The two most common barriers to quitting were "trouble managing stress and mood" and "fear of gaining weight." CONCLUSION: Based on the data from our centre, patients with CaB who continue to smoke after their diagnosis warrant a smoking cessation program as a resource for improving prognosis and long-term health. Further research should focus on establishing an efficacious and cost-effective program that provides these patients with the resources they need to quit smoking. PMID- 21539770 TI - Study comparing the applicability of dorsal lumbotomy in older children. AB - OBJECTIVE: : Dismembered pyeloplasty through dorsal lumbotomy to correct ureteropelvic junction obstruction is mainly successfully performed in children under 5 years old for technical reasons. We compared children who underwent dorsal lumbotomy by age group (<5 vs. >=5 years old) to determine if the surgical success and long-term results were comparable. MATERIALS AND METHODS: : We retrospectively reviewed the charts of 134 children undergoing a pyeloplasty. Group 1 consisted of children <5 years old (n = 90) and Group 2 consisted of children >=5 years old. Patients' characteristics, as well as hospital stay, narcotic use, radiologic follow-up and success rate, were compared. Success was defined by absence of symptoms and >=50% reduction in renal pelvis anteroposterior diameter and/or scintigraphic normalization of the drainage T1/2 when obtained. Univariate analysis was performed to compare the groups. RESULTS: : Mean age (years) and weight (kg) at surgery for Groups 1 and 2 were 1/8 kg and 11/35 kg, respectively. Mean operative time was 98 minutes versus 120 minutes, respectively; mean hospital stay was 2.5 days for both groups and analgesia requirement was 50% higher in Group 2. A Pippi-Salle stent was used in 90% (n = 120) of cases. Mean follow-up was 26 months and the success rate was 89% and 90% for Groups 1 and 2, respectively. CONCLUSION: : Our study showed comparable success rates. We can infer that, as a technique, dismembered pyeloplasty is effective and safe in the younger and older children. PMID- 21539771 TI - Isolated renal hydatid disease in a non-endemic country: a single centre experience. AB - OBJECTIVE: Isolated renal hydatid disease (HD) is rare in non-endemic countries. Clinical and radiological suspicion warrants appropriate serological tests, preoperative treatment and intra-operative precautions. We present a tertiary care centre experience of isolated renal HD in a non-endemic country. METHODS: We reviewed the medical records of patients with HD treated in the past 20 years. We identified patients with the definitive diagnosis of isolated renal HD and described their management. RESULTS: Of the 119 cases with HD, 6 were found to have isolated renal involvement (5%). Their median age was 46.5 (28-70) years. Five patients presented with flank pain and 1 had an incidentally discovered renal mass. Radiologic investigations raised the suspicion of possible HD in 4 cases, while 2 cases were diagnosed as renal tumours. Computerized tomography showed complex renal cyst in 4, solid renal mass with heterogonous enhancement in 2 and calcification in 5. Eosinophilia and indirect hemagglutination test (IHA) were positive in 3 of the 4 suspected cases. Three cases were treated as renal tumours, while 3 were managed as HD. Four cases had total nephrectomy and 2 had partial nephrectomy. Histopathology revealed that all cases had renal HD. Patients were followed for a median of 7.3 (0.4-11.3) years with no evidence of recurrence. CONCLUSIONS: Isolated renal HD is a challenging preoperative diagnosis in non-endemic countries. The definitive diagnosis is only possible by histopathology. Retrospectively, HD mimicked renal tumours in half the cases and should be considered in the differential diagnosis of renal space occupying lesions. PMID- 21539772 TI - How robust are protein folding simulations with respect to force field parameterization? AB - Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headpiece using four different force fields. In each simulation, we observed a large number of transitions between the unfolded and folded states, and in all four cases, both the rate of folding and the structure of the native state were in good agreement with experiments. We found, however, that the folding mechanism and the properties of the unfolded state depend substantially on the choice of force field. We thus conclude that although it is important to match a single, experimentally determined structure and folding rate, this does not ensure that a given simulation will provide a unique and correct description of the full free energy surface and the mechanism of folding. PMID- 21539773 TI - Direct observations of shifts in the beta-sheet register of a protein-peptide complex using explicit solvent simulations. AB - Using explicit solvent molecular dynamics simulations, we were able to obtain direct observations of shifts in the hydrogen-bonding register of an intermolecular beta-sheet protein-peptide complex. The beta-sheet is formed between the FHA domain of cancer marker protein Ki67 (Ki67FHA) and a peptide fragment of the hNIFK signaling protein. Potential encounter complexes of the Ki67FHA receptor and hNIFK peptide are misregistered states of the beta-sheet. Rearrangements of one of these misregistered states to the native state were captured in three independent simulations. All three rearrangements occurred by a common mechanism: an aromatic residue of the peptide (F263) anchors into a transient hydrophobic pocket of the receptor to facilitate the formation of native hydrogen bonds. To our knowledge, these simulations provide the first atomically detailed visualizations of a mechanism by which nature might correct for errors in the alignment of intermolecular beta-sheets. PMID- 21539774 TI - Impact of heparan sulfate chains and sulfur-mediated bonds on the mechanical properties of bovine lens capsule. AB - We assessed the importance of glycosaminoglycans and sulfur-mediated bonds for the mechanical properties of lens capsules by comparing the stress-strain responses from control and treated pairs of bovine source. No significant change in mechanical properties was observed upon reduction of disulfide bonds. However, removal of glycosaminoglycan chains resulted in a significantly stiffer lens capsule, whereas high concentrations of reducing agent, which is expected to reduce the recently reported sulfilimine bond of collagen IV, resulted in a significantly less stiff lens capsule. A comparison of the diffraction patterns of the control and strongly reduced lens capsules indicated structural rearrangements on a nanometer scale. PMID- 21539775 TI - Wall shear stress-based model for adhesive dynamics of red blood cells in malaria. AB - Red blood cells (RBCs) infected by the Plasmodium falciparum (Pf-RBCs) parasite lose their membrane deformability and they also exhibit enhanced cytoadherence to vascular endothelium and other healthy and infected RBCs. The combined effect may lead to severe disruptions of normal blood circulation due to capillary occlusions. Here we extend the adhesion model to investigate the adhesive dynamics of Pf-RBCs as a function of wall shear stress (WSS) and other parameters using a three-dimensional, multiscale RBC model. Several types of adhesive behavior are identified, including firm adhesion, flipping dynamics, and slow slipping along the wall. In particular, the flipping dynamics of Pf-RBCs observed in experiments appears to be due to the increased stiffness of infected cells and the presence of the solid parasite inside the RBC, which may cause an irregular adhesion behavior. Specifically, a transition from crawling dynamics to flipping behavior occurs at a Young's modulus approximately three times larger than that of healthy RBCs. The simulated dynamics of Pf-RBCs is in excellent quantitative agreement with available microfluidic experiments if the force exerted on the receptors and ligands by an existing bond is modeled as a nonlinear function of WSS. PMID- 21539776 TI - Excitation energy transfer and trapping in higher plant Photosystem II complexes with different antenna sizes. AB - We performed picosecond fluorescence measurements on well-defined Photosystem II (PSII) supercomplexes from Arabidopsis with largely varying antenna sizes. The average excited-state lifetime ranged from 109 ps for PSII core to 158 ps for the largest C(2)S(2)M(2) complex in 0.01% alpha-DM. Excitation energy transfer and trapping were investigated by coarse-grained modeling of the fluorescence kinetics. The results reveal a large drop in free energy upon charge separation (>700 cm(-1)) and a slow relaxation of the radical pair to an irreversible state (~150 ps). Somewhat unexpectedly, we had to reduce the energy-transfer and charge separation rates in complexes with decreasing size to obtain optimal fits. This strongly suggests that the antenna system is important for plant PSII integrity and functionality, which is supported by biochemical results. Furthermore, we used the coarse-grained model to investigate several aspects of PSII functioning. The excitation trapping time appears to be independent of the presence/absence of most of the individual contacts between light-harvesting complexes in PSII supercomplexes, demonstrating the robustness of the light-harvesting process. We conclude that the efficiency of the nonphotochemical quenching process is hardly dependent on the exact location of a quencher within the supercomplexes. PMID- 21539777 TI - Interpretation of fluctuation spectra in lipid bilayer simulations. AB - Atomic resolution and coarse-grained simulations of dimyristoylphosphatidylcholine lipid bilayers were analyzed for fluctuations perpendicular to the bilayer using a completely Fourier-based method. We find that the fluctuation spectrum of motions perpendicular to the bilayer can be decomposed into just two parts: 1), a pure undulation spectrum proportional to q( 4) that dominates in the small-q regime; and 2), a molecular density structure factor contribution that dominates in the large-q regime. There is no need for a term proportional to q(-2) that has been postulated for protrusion fluctuations and that appeared to have been necessary to fit the spectrum for intermediate q. We suggest that earlier reports of such a term were due to the artifact of binning and smoothing in real space before obtaining the Fourier spectrum. The observability of an intermediate protrusion regime from the fluctuation spectrum is discussed based on measured and calculated material constants. PMID- 21539778 TI - Determination of electron density profiles and area from simulations of undulating membranes. AB - The traditional method for extracting electron density and other transmembrane profiles from molecular dynamics simulations of lipid bilayers fails for large bilayer systems, because it assumes a flat reference surface that does not take into account long wavelength undulations. We have developed what we believe to be a novel set of methods to characterize these undulations and extract the underlying profiles in the large systems. Our approach first obtains an undulation reference surface for each frame in the simulation and subsequently isolates the long-wavelength undulations by filtering out the intrinsic short wavelength modes. We then describe two methods to obtain the appropriate profiles from the undulating reference surface. Most combinations of methods give similar results for the electron density profiles of our simulations of 1024 DMPC lipids. From simulations of smaller systems, we also characterize the finite size effect related to the boundary conditions of the simulation box. In addition, we have developed a set of methods that use the undulation reference surface to determine the true area per lipid which, due to undulations, is larger than the projected area commonly reported from simulations. PMID- 21539779 TI - Tryptophan-lipid interactions in membrane protein folding probed by ultraviolet resonance Raman and fluorescence spectroscopy. AB - Aromatic amino acids of membrane proteins are enriched at the lipid-water interface. The role of tryptophan on the folding and stability of an integral membrane protein is investigated with ultraviolet resonance Raman and fluorescence spectroscopy. We investigate a model system, the beta-barrel outer membrane protein A (OmpA), and focus on interfacial tryptophan residues oriented toward the lipid bilayer (trp-7, trp-170, or trp-15) or the interior of the beta barrel pore (trp-102). OmpA mutants with a single tryptophan residue at a nonnative position 170 (Trp-170) or a native position 7 (Trp-7) exhibit the greatest stability, with Gibbs free energies of unfolding in the absence of denaturant of 9.4 and 6.7 kcal/mol, respectively. These mutants are more stable than the tryptophan-free OmpA mutant, which exhibits a free energy of unfolding of 2.6 kcal/mol. Ultraviolet resonance Raman spectra of Trp-170 and Trp-7 reveal evolution of a hydrogen bond in a nonpolar environment during the folding reaction, evidenced by systematic shifts in hydrophobicity and hydrogen bond markers. These observations suggest that the hydrogen bond acceptor is the lipid acyl carbonyl group, and this interaction contributes significantly to membrane protein stabilization. Other spectral changes are observed for a tryptophan residue at position 15, and these modifications are attributed to development of a tryptophan-lipid cation-pi interaction that is more stabilizing than an intraprotein hydrogen bond by ~2 kcal/mol. As expected, there is no evidence for lipid-protein interactions for the tryptophan residue oriented toward the interior of the beta-barrel pore. These results highlight the significance of lipid-protein interactions, and indicate that the bilayer provides more than a hydrophobic environment for membrane protein folding. Instead, a paradigm of lipid-assisted membrane protein folding and stabilization must be adopted. PMID- 21539780 TI - Physical determinants of beta-barrel membrane protein folding in lipid vesicles. AB - The spontaneous folding of two Neisseria outer membrane proteins, opacity associated (Opa)(60) and Opa(50) into lipid vesicles was investigated by systematically varying bulk and membrane properties. Centrifugal fractionation coupled with sodium dodecyl sulfate polyacrylamide gel electrophoresis mobility assays enabled the discrimination of aggregate, unfolded membrane-associated, and folded membrane-inserted protein states as well as the influence of pH, ionic strength, membrane surface potential, lipid saturation, and urea on each. Protein aggregation was reduced with increasing lipid chain length, basic pH, low salt, the incorporation of negatively charged guest lipids, or by the addition of urea to the folding reaction. Insertion from the membrane-associated form was improved in shorter chain lipids, with more basic pH and low ionic strength; it is hindered by unsaturated or ether-linked lipids. The isolation of the physical determinants of insertion suggests that the membrane surface and dipole potentials are driving forces for outer membrane protein insertion and folding into lipid bilayers. PMID- 21539781 TI - Docking, not fusion, as the rate-limiting step in a SNARE-driven vesicle fusion assay. AB - In vitro vesicle fusion assays that monitor lipid mixing between t-SNARE and v SNARE vesicles in bulk solution exhibit remarkably slow fusion on the nonphysiological timescale of tens of minutes to several hours. Here, single vesicle, fluorescence resonance energy transfer-based assays cleanly separate docking and fusion steps for individual vesicle pairs containing full-length SNAREs. Docking is extremely inefficient and is the rate-limiting step. Of importance, the docking and fusion kinetics are comparable in the two assays (one with v-SNARE vesicles tethered to a surface and the other with v-SNARE vesicles free in solution). Addition of the V(C) peptide synaptobrevin-2 (syb(57-92)) increases the docking efficiency by a factor of ~30, but docking remains rate limiting. In the presence of V(C) peptide, the fusion step occurs on a timescale of ~10 s. In previous experiments involving bulk fusion assays in which the addition of synaptotagmin/Ca(2+), Munc-18, or complexin accelerated the observed lipid-mixing rate, the enhancement may have arisen from the docking step rather than the fusion step. PMID- 21539782 TI - Membrane adhesion via homophilic saccharide-saccharide interactions investigated by neutron scattering. AB - Solid-supported membrane multilayers doped with membrane-anchored oligosaccharides bearing the LewisX motif (Le(X) lipid) were utilized as a model system of membrane adhesion mediated via homophilic carbohydrate-carbohydrate interactions. Specular and off-specular neutron scattering in bulk aqueous electrolytes allowed us to study multilayer structure and membrane mechanics at full hydration at various Ca(2+) concentrations, indicating that membrane anchored Le(X) cross-links the adjacent membranes. To estimate forces and energies required for cross-linking, we theoretically modeled the interactions between phospholipid membranes and compared this model with our experimental results on membranes doped with Le(X) lipids. We demonstrated that the bending rigidity, extracted from the off-specular scattering signals, is not significantly influenced by the molar fraction of Le(X) lipids, while the vertical compression modulus (and thus the intermembrane confinement) increases with the molar fraction of Le(X) lipids. PMID- 21539783 TI - Stable and unstable lipid domains in ceramide-containing membranes. AB - We applied x-ray diffraction, calorimetry, and infrared spectroscopy to lipid mixtures of palmitoyl-oleoyl phosphatidylcholine, sphingomyelin, and ceramide. This combination of experimental techniques allowed us to probe the stability and structural properties of coexisting lipid domains without resorting to any molecular probes. In particular, we found unstable microscopic domains (compositional/phase fluctuations) in the absence of ceramide, and macroscopically separated fluid and gel phases upon addition of ceramide. We also observed phase fluctuations in the presence of ceramide within the broad phase transition regions. We compare our results with fluorescence spectroscopy data and complement the previously reported phase diagram. We also obtained electron paramagnetic resonance data to assess the possible limitations of techniques employing a single label. Our study demonstrates the necessity of applying a combination of experimental techniques to probe local/global structural and fast/slow motional properties in complex lipid mixtures. PMID- 21539784 TI - Effects of specific versus nonspecific ionic interactions on the structure and lateral organization of lipopolysaccharides. AB - We report x-ray reflectivity and grazing incidence x-ray diffraction measurements of lipopolysaccharide (LPS) monolayers at the water-air interface. Our investigations reveal that the structure and lateral ordering of the LPS molecules is very different from phospholipid systems and can be modulated by the ionic strength of the aqueous subphase in an ion-dependent manner. Our findings also indicate differential effects of monovalent and divalent ions on the two dimensional ordering of lipid domains. Na(+) ions interact unspecifically with LPS molecules based on their ability to efficiently screen the negative charges of the LPS molecules, whereas Ca(2+) ions interact specifically by cross-linking adjacent molecules in the monolayer. At low lateral pressures, Na(+) ions present in the subphase lead to a LPS monolayer structure ordered over large areas with high compressibility, nearly hexagonal packing of the hydrocarbon chains, and high density in the LPS headgroup region. At higher film pressures, the LPS monolayer becomes more rigid and results in a less perfect, oblique packing of the LPS hydrocarbon chains as well as a smaller lateral size of highly ordered domains on the monolayer. Furthermore, associated with the increased surface pressure, a conformational change of the sugar headgroups occurs, leading to a thickening of the entire LPS monolayer structure. The effect of Ca(2+) ions in the subphase is to increase the rigidity of the LPS monolayer, leading to an oblique packing of the hydrocarbon chains already at low film pressures, an upright orientation of the sugar moieties, and much smaller sizes of ordered domains in the plane of the monolayer. In the presence of both Na(+)- and Ca(2+) ions in the subphase, the screening effect of Na(+) is predominant at low film pressures, whereas, at higher film pressures, the structure and lateral organization of LPS molecules is governed by the influence of Ca(2+) ions. The unspecific charge-screening effect of the Na(+) ions on the conformation of the sugar moiety becomes less dominant at biologically relevant lateral pressures. PMID- 21539785 TI - Sensory rhodopsin-I as a bidirectional switch: opposite conformational changes from the same photoisomerization. AB - The phototaxis receptor sensory rhodopsin I (SRI) exists in two protein conformations, each of which is converted to the other by light absorption by the protein's retinylidene chromophore. One conformer inhibits a histidine-kinase attached to its bound transducer HtrI and its formation induces attractant motility responses, whereas the other conformer activates the kinase and its formation induces repellent responses. We performed Fourier transform infrared spectroscopy with temperature, pH, and mutation-induced shifts in the conformer equilibrium, and found that both conformers when present in the unphotolyzed dark state contain an all-trans retinal configuration that is photoisomerized to 13 cis, i.e., the same photoisomerization causes the opposite conformational change in the photointerconvertible pair of conformers depending on which conformer is present in the dark. Therefore, switching between the protein global conformations that define the two conformers is independent of the direction of isomerization. Insights into this phenomenon are gained from analysis of the evolution of the receptor from light-driven proton pumps, which use similar conformers for transport. The versatility of the conformational changes of microbial rhodopsins, including conformer interexchangeability in the photocycle as shown here, is likely a significant factor in the evolution of the diverse functionality of this protein family. PMID- 21539786 TI - Cardiolipin affects the supramolecular organization of ATP synthase in mitochondria. AB - F(1)F(0) ATP synthase forms dimers that tend to assemble into large supramolecular structures. We show that the presence of cardiolipin is critical for the degree of oligomerization and the degree of order in these ATP synthase assemblies. This conclusion was drawn from the statistical analysis of cryoelectron tomograms of cristae vesicles isolated from Drosophila flight-muscle mitochondria, which are very rich in ATP synthase. Our study included a wild-type control, a cardiolipin synthase mutant with nearly complete loss of cardiolipin, and a tafazzin mutant with reduced cardiolipin levels. In the wild-type, the high curvature edge of crista vesicles was densely populated with ATP synthase molecules that were typically organized in one or two rows of dimers. In both mutants, the density of ATP synthase was reduced at the high-curvature zone despite unchanged expression levels. Compared to the wild-type, dimer rows were less extended in the mutants and there was more scatter in the orientation of dimers. These data suggest that cardiolipin promotes the ribbonlike assembly of ATP synthase dimers and thus affects lateral organization and morphology of the crista membrane. PMID- 21539787 TI - Coordinated reversal of flagellar motors on a single Escherichia coli cell. AB - An Escherichia coli cell transduces extracellular stimuli sensed by chemoreceptors to the state of an intracellular signal molecule, which regulates the switching of the rotational direction of the flagellar motors from counterclockwise (CCW) to clockwise (CW) and from CW back to CCW. Here, we performed high-speed imaging of flagellar motor rotation and show that the switching of two different motors on a cell is controlled coordinatedly by an intracellular signal protein, phosphorylated CheY (CheY-P). The switching is highly coordinated with a subsecond delay between motors in clear correlation with the distance of each motor from the chemoreceptor patch localized at a cell pole, which would be explained by the diffusive motion of CheY-P molecules in the cell. The coordinated switching becomes disordered by the expression of a constitutively active CheY mutant that mimics the CW-rotation stimulating function. The coordinated switching requires CheZ, which is the phosphatase for CheY-P. Our results suggest that a transient increase and decrease in the concentration of CheY-P caused by a spontaneous burst of its production by the chemoreceptor patch followed by its dephosphorylation by CheZ, which is probably a wavelike propagation in a subsecond timescale, triggers and regulates the coordinated switching of flagellar motors. PMID- 21539788 TI - Interaction strengths between the ribosome and tRNA at various steps of translocation. AB - Transfer RNA (tRNA) translocates inside the ribosome during translation. We studied the interaction strengths between the ribosome and tRNA at various stages of translocation. We utilized an optical trap to measure the mechanical force to rupture tRNA from the ribosome. We measured the rupture forces of aminoacyl tRNA or peptidyl tRNA mimic from the ribosome in a prepeptidyl transfer state, the pretranslocational state, and the posttranslocational state. In addition, we measured the interaction strength between the ribosome and aminoacyl-tRNA in presence of viomycin. Based on the interaction strengths between the ribosome and tRNA under these conditions, 1), we concluded that tRNA interaction with the 30S subunit is far more important than the interaction with the 50S subunit in the mechanism of translocation; and 2), we propose a mechanism of translocation where the ribosomal ratchet motion, with the aid of EF-G, drives tRNA translocation. PMID- 21539789 TI - Protein-DNA interactions determine the shapes of DNA toroids condensed in virus capsids. AB - DNA toroids that form inside the bacteriophage capsid present different shapes according to whether they are formed by the addition of spermine or polyethylene glycol to the bathing solution. Spermine-DNA toroids present a convex, faceted section with no or minor distortions of the DNA interstrand spacing with respect to those observed in the bulk, whereas polyethylene glycol-induced toroids are flattened to the capsid inner surface and show a crescent-like, nonconvex shape. By modeling the energetics of the DNA toroid using a free-energy functional composed of energy contributions related to the elasticity of the wound DNA, exposed surface DNA energy, and adhesion between the DNA and the capsid, we established that the crescent shape of the toroidal DNA section comes from attractive interactions between DNA and the capsid. Such attractive interactions seem to be specific to the PEG condensation process and are not observed in the case of spermine-induced DNA condensation. PMID- 21539790 TI - Electronic structure of neighboring extein residue modulates intein C-terminal cleavage activity. AB - Protein splicing is an autocatalytic reaction where an intervening element (intein) is excised and the remaining two flanking sequences (exteins) are joined. The reaction requires specific conserved residues, and activity may be affected by both the intein and the extein sequence. Predicting how sequence will affect activity is a challenging task. Based on first-principles density functional theory and multiscale quantum mechanics/molecular mechanics, we report C-terminal cleavage reaction rates for five mutations at the first residue of the C-extein (+1), and describe molecular properties that may be used as predictors for future mutations. Independently, we report on experimental characterization of the same set of mutations at the +1 residue resulting in a wide range of C terminal cleavage activities. With some exceptions, there is general agreement between computational rates and experimental cleavage, giving molecular insight into previous claims that the +1 extein residue affects intein catalysis. These data suggest utilization of attenuating +1 mutants for intein-mediated protein manipulations because they facilitate precursor accumulation in vivo for standard purification schemes. A more detailed analysis of the "+1 effect" will also help to predict sequence-defined effects on insertion points of the intein into proteins of interest. PMID- 21539791 TI - Direct visualization of exciton reequilibration in the LH1 and LH2 complexes of Rhodobacter sphaeroides by multipulse spectroscopy. AB - The dynamics of the excited states of the light-harvesting complexes LH1 and LH2 of Rhodobacter sphaeroides are governed, mainly, by the excitonic nature of these ring-systems. In a pump-dump-probe experiment, the first pulse promotes LH1 or LH2 to its excited state and the second pulse dumps a portion of the excited state. By selective dumping, we can disentangle the dynamics normally hidden in the excited-state manifold. We find that by using this multiple-excitation technique we can visualize a 400-fs reequilibration reflecting relaxation between the two lowest exciton states that cannot be directly explored by conventional pump-probe. An oscillatory feature is observed within the exciton reequilibration, which is attributed to a coherent motion of a vibrational wavepacket with a period of ~150 fs. Our disordered exciton model allows a quantitative interpretation of the observed reequilibration processes occurring in these antennas. PMID- 21539792 TI - Systematic examination of polymorphism in amyloid fibrils by molecular-dynamics simulation. AB - Amyloid fibrils often exhibit polymorphism. Polymorphs are formed when proteins or peptides with identical sequences self-assemble into fibrils containing substantially different arrangements of the beta-strands. We used atomistic molecular-dynamics simulation to examine the thermodynamic stability of a amyloid fibrils in different polymorphic forms by performing a systematic investigation of sequence and symmetry space for a series of peptides with a range of physicochemical properties. We show that the stability of fibrils depends on both sequence and the symmetry because these factors determine the availability of favorable interactions between the peptide strands within a sheet and in intersheet packing. By performing a detailed analysis of these interactions as a function of symmetry, we obtained a series of simple design rules that can be used to determine which polymorphs of a given sequence are most likely to form thermodynamically stable fibrils. These rules can potentially be employed to design peptide sequences that aggregate into a preferred polymorphic form for nanotechnological purposes. PMID- 21539793 TI - Compaction properties of an intrinsically disordered protein: Sic1 and its kinase inhibitor domain. AB - IDPs in their unbound state can transiently acquire secondary and tertiary structure. Describing such intrinsic structure is important to understand the transition between free and bound state, leading to supramolecular complexes with physiological interactors. IDP structure is highly dynamic and, therefore, difficult to study by conventional techniques. This work focuses on conformational analysis of the KID fragment of the Sic1 protein, an IDP with a key regulatory role in the cell-cycle of Saccharomyces cerevisiae. FT-IR spectroscopy, ESI-MS, and IM measurements are used to capture dynamic and short lived conformational states, probing both secondary and tertiary protein structure. The results indicate that the isolated Sic1 KID retains dynamic helical structure and populates collapsed states of different compactness. A metastable, highly compact species is detected. Comparison between the fragment and the full-length protein suggests that chain length is crucial to the stabilization of compact states of this IDP. The two proteins are compared by a length-independent compaction index. PMID- 21539794 TI - Role of hydration in collagen recognition by bacterial adhesins. AB - Protein-protein recognition regulates the vast majority of physiological or pathological processes. We investigated the role of hydration in collagen recognition by bacterial adhesin CNA by means of first principle molecular dynamics samplings. Our characterization of the hydration properties of the isolated partners highlights dewetting-prone areas on the surface of CNA that closely match the key regions involved in hydrophobic intermolecular interactions upon complex formation, suggesting that the hydration state of the ligand-free CNA predisposes the protein to the collagen recognition. Moreover, hydration maps of the CNA-collagen complex reveal the presence of a number of structured water molecules that mediate intermolecular interactions at the interface between the two proteins. These hydration sites feature long residence times, significant binding free energies, and a geometrical distribution that closely resembles the hydration pattern of the isolated collagen triple helix. These findings are striking evidence that CNA recognizes the collagen triple helix as a hydrated molecule. For this structural motif, the exposure of several unsatisfied backbone carbonyl groups results in a strong interplay with the solvent, which is shown to also play a role in collagen recognition. PMID- 21539795 TI - Torsion stiffness of a protein pair determined by magnetic particles. AB - We demonstrate the ability to measure torsion stiffness of a protein complex by applying a controlled torque on a magnetic particle. As a model system we use protein G bound to an IgG antibody. The protein pair is held between a magnetic particle and a polystyrene substrate. The angular orientation of the magnetic particle shows an oscillating behavior upon application of a rotating magnetic field. The amplitude of the oscillation increases with a decreasing surface coverage of antibodies on the substrate and with an increasing magnitude of the applied field. For decreasing antibody coverage, the torsion spring constant converges to a minimum value of 1.5 * 10(3) pN.nm/rad that corresponds to a torsion modulus of 4.5 * 10(4) pN.nm(2). This torsion stiffness is an upper limit for the molecular bond between the particle and the surface that is tentatively assigned to a single protein G-IgG protein pair. This assignment is supported by interpreting the measured stiffness with a simple mechanical model that predicts a two orders of magnitude larger stiffness for the protein G-IgG complex than values found for micrometer length dsDNA. This we understand from the structural properties of the molecules, i.e., DNA is a long and flexible chain-like molecule, whereas the antibody-antigen couple is orders of magnitude smaller and more globular in shape due to the folding of the molecules. PMID- 21539796 TI - Modulation of contact order effects in the two-state folding of stefins A and B. AB - It is well established that contact order and folding rates are correlated for small proteins. The folding rates of stefins A and B differ by nearly two orders of magnitude despite sharing an identical native fold and hence contact order. We break down the determinants of this behavior and demonstrate that the modulation of contact order effects can be accounted for by the combined contributions of a framework-like mechanism, characterized by intrinsic helix stabilities, together with nonnative helical backbone conformation and nonnative hydrophobic interactions within the folding transition state. These contributions result in the formation of nonnative interactions in the transition state as evidenced by the opposing effects on folding rate and stability of these proteins. PMID- 21539797 TI - The signal transfer from the receptor NpSRII to the transducer NpHtrII is not hampered by the D75N mutation. AB - Sensory rhodopsin II (NpSRII) is a phototaxis receptor of Natronomonas pharaonis that performs its function in complex with its cognate transducer (NpHtrII). Upon light activation NpSRII triggers by means of NpHtrII a signal transduction chain homologous to the two component system in eubacterial chemotaxis. The D75N mutant of NpSRII, which lacks the blue-shifted M intermediate and therefore exhibits a significantly faster photocycle compared to the wild-type, mediates normal phototaxis responses demonstrating that deprotonation of the Schiff base is not a prerequisite for transducer activation. Using site-directed spin labeling and time resolved electron paramagnetic-resonance spectroscopy, we show that the mechanism revealed for activation of the wild-type complex, namely an outward tilt motion of the cytoplasmic part of the receptor helix F and a concomitant rotation of the transmembrane transducer helix TM2, is also valid for the D75N variant. Apparently, the D75N mutation shifts the ground state conformation of NpSRII-D75N and its cognate transducer into the direction of the signaling state. PMID- 21539798 TI - Disaccharide binding to galectin-1: free energy calculations and molecular recognition mechanism. AB - Galectin-1, a member of the conserved family of carbohydrate-binding proteins with affinity for beta-galactosides, is a key modulator of diverse cell functions such as immune response and regulation. The binding affinity and specificity of galectin-1 for eight different beta-galactosyl terminal disaccharides was studied using molecular-dynamics simulations in which the ligand was pulled away from the binding site using a mechanical force. We present what we believe to be a novel procedure, based on combinations of multistep trajectories, that was used to estimate the binding free energy (DeltaG) of each disaccharide. The computed binding free energy differences show excellent correlation with experimental values determined previously. The small differences in affinity among the disaccharides are the result of an exquisite balance between the strengths of the galectin-sugar H-bonds and the H-bonds the protein and the disaccharides make with the solvent. Analysis of the free energies along the reaction coordinate shows that disaccharide unbinding/binding presents no energetic barrier and, therefore, is diffusion-limited. In addition, the calculations revealed that as the ligand is undocked from the binding site, breaking of protein-disaccharide H bonds takes place in stages with intermediate states in which the interactions are bridged by water molecules. PMID- 21539799 TI - Characterization of the solution structure of human serum albumin loaded with a metal porphyrin and fatty acids. AB - The structure of human serum albumin loaded with a metal porphyrin and fatty acids in solution is characterized by orientation-selective double electron electron resonance (DEER) spectroscopy. Human serum albumin, spin-labeled fatty acids, and Cu(II) protoporphyrin IX-a hemin analog-form a fully self-assembled system that allows obtaining distances and mutual orientations between the paramagnetic guest molecules. We report a simplified analysis for the orientation selective DEER data which can be applied when the orientation selection of one spin in the spin pair dominates the orientation selection of the other spin. The dipolar spectra reveal a dominant distance of 3.85 nm and a dominant orientation of the spin-spin vectors between Cu(II) protoporphyrin IX and 16-doxyl stearic acid, the electron paramagnetic resonance reporter group of the latter being located near the entry points to the fatty acid binding sites. This observation is in contrast to crystallographic data that suggest an asymmetric distribution of the entry points in the protein and hence the occurrence of various distances. In conjunction with the findings of a recent DEER study, the obtained data are indicative of a symmetric distribution of the binding site entries on the protein's surface. The overall anisotropic shape of the protein is reflected by one spin-spin vector orientation dominating the DEER data. PMID- 21539800 TI - Amyloid oligomer formation probed by water proton magnetic resonance spectroscopy. AB - Formation of amyloid oligomers, the most toxic species of amyloids in degenerative diseases, is critically coupled to the interplay with surrounding water. The hydrophobic force driving the oligomerization causes water removal from interfaces, changing the surface-hydration properties. Here, we show that such effects alter the magnetic relaxation response of local water in ways that may enable oligomer detection. By using water proton magnetic resonance spectroscopy, we measured significantly longer transverse magnetic relaxation (T(2)) times in mixtures of serum and amyloidogenic Abeta(1-42) peptides versus similar concentration solutions of serum and nonamyloidogenic scrambled Abeta(42 1) peptides. Immunochemistry with oligomer-specific antibodies, electron microscopy and computer simulations demonstrated that the hyperintense magnetic signal correlates with Abeta(1-42) oligomerization. Finding early biophysical markers of the oligomerization process is crucial for guiding the development of new noninvasive imaging techniques, enabling timely diagnosis of amyloid-related diseases and pharmacological intervention. PMID- 21539801 TI - On the distribution of protein refractive index increments. AB - The protein refractive index increment, dn/dc, is an important parameter underlying the concentration determination and the biophysical characterization of proteins and protein complexes in many techniques. In this study, we examine the widely used assumption that most proteins have dn/dc values in a very narrow range, and reappraise the prediction of dn/dc of unmodified proteins based on their amino acid composition. Applying this approach in large scale to the entire set of known and predicted human proteins, we obtain, for the first time, to our knowledge, an estimate of the full distribution of protein dn/dc values. The distribution is close to Gaussian with a mean of 0.190 ml/g (for unmodified proteins at 589 nm) and a standard deviation of 0.003 ml/g. However, small proteins <10 kDa exhibit a larger spread, and almost 3000 proteins have values deviating by more than two standard deviations from the mean. Due to the widespread availability of protein sequences and the potential for outliers, the compositional prediction should be convenient and provide greater accuracy than an average consensus value for all proteins. We discuss how this approach should be particularly valuable for certain protein classes where a high dn/dc is coincidental to structural features, or may be functionally relevant such as in proteins of the eye. PMID- 21539802 TI - Comment on the article by J. Elgeti, U. B. Kaupp, and G. Gompper: hydrodynamics of sperm cells near surfaces. AB - A recent study by Elgeti et al. used multiparticle collision dynamics to simulate a long-standing problem: the approach of sperm to surfaces, and subsequent accumulation. The authors highlight differences in their predictions with those of the earlier Stokes flow simulations of Smith et al. attributing the differences to methodological flaws in the earlier article. In this Comment, we discuss the criticisms leveled in detail, and review some recently published work that shows how species-specific details of cell morphology provides a more likely explanation for the differing predictions of the two studies. We also highlight experimental work that supports the study of Smith et al. PMID- 21539804 TI - Identification of a polymeric beta-cyclodextrin-binding peptide from a phage displayed peptide library. AB - In this work, a phage-displayed peptide library was applied to identification of beta-cyclodextrin (CD)-binding peptide tag, capable of being combined to target peptides or proteins in a homogeneous way by established methods such as peptide synthesis and the recombinant DNA technique. Four enriched sequences were obtained after five rounds of biopanning against polymeric beta-CD beads. One of the sequences showed high binding affinity to beta-CD beads with a dissociation constant of approximately 7*10(-6)M. The beta-CD-binding sequence was used for immobilization of a hepatitis C virus (HCV) antigenic peptide on beta-CD beads. The functionalized beta-CD beads were successfully used for immunoassay of anti HCV antibody with a detection limit of 1 ng. These results demonstrate that the identified peptide sequence has the potential of being used as an affinity tag to beta-CD-containing surfaces. PMID- 21539805 TI - Comparative evaluation and selection of a method for lipid and fatty acid extraction from macroalgae. AB - A comparative evaluation of Bligh and Dyer, Folch, and Cequier-Sanchez methods for quantitative determination of total lipids (TLs) and fatty acids (FAs) was accomplished in selective green (Ulva fasciata), red (Gracilaria corticata), and brown algae (Sargassum tenerrimum) using a full factorial categorical design. Applications of sonication and buffer individually on lipid extraction solvent systems were also evaluated. The FA recoveries obtained from the aforementioned methods were compared with those of direct transesterification (DT) methods to identify the best extraction methods. The experimental design showed that macroalgal matrix, extraction method, and buffer were key determinants for TL and FA recoveries (P<=0.05), exhibiting significant interactions. But sonication gave erratic results with no interaction with any of the factors investigated. The buffered solvent system of Folch rendered the highest TL yield in U. fasciata and G. corticata while the buffered system of Bligh and Dyer gave the highest yield in S. tenerrimum. DT methods were more convenient and accurate for FA quantification and rendered 1.5-2 times higher yields when compared with the best conventional method, minimizing the use of chlorinated solvents, their cost of analysis, and disposal. The buffered solvent system was found to be the most appropriate for lipid research in macroalgae. PMID- 21539807 TI - Sll1466, a glycosyl transferase homolog involved in global cellular regulation and high-light tolerance of Synechocystis PCC6803. AB - In Synechocystis sp. PCC 6803, the loop domain (aa 1-70) of the phycobilisome core-membrane linker, L(CM), was found to interact with the glycosyl transferase homolog, Sll1466. Growth of a Sll1466 knock-out mutant was slightly faster in low light, but strongly inhibited in high light; the phenotype is discussed in relation to the regulation of light energy transfer to photosystem II. At the molecular level, the mutant shows the following changes compared to the wild type: (1) a smaller size and higher mobility of phycobilisomes on the thylakoid membrane, and (2) a changed lipid composition of the thylakoid membrane, especially decreased amounts of digalactosyl diacylglycerol. These results indicate a profound regulatory role for Sll1466 in regulating photosynthetic energy transfer. PMID- 21539806 TI - Working memory deficits in neuronal nitric oxide synthase knockout mice: potential impairments in prefrontal cortex mediated cognitive function. AB - Neuronal nitric oxide synthase (nNOS) forms nitric oxide (NO), which functions as a signaling molecule via S-nitrosylation of various proteins and regulation of soluble guanylate cyclase (cGC)/cyclic guanosine monophosphate (cGMP) pathway in the central nervous system. nNOS signaling regulates diverse cellular processes during brain development and molecular mechanisms required for higher brain function. Human genetics have identified nNOS and several downstream effectors of nNOS as risk genes for schizophrenia. Besides the disease itself, nNOS has also been associated with prefrontal cortical functioning, including cognition, of which disturbances are a core feature of schizophrenia. Although mice with genetic deletion of nNOS display various behavioral deficits, no studies have investigated prefrontal cortex-associated behaviors. Here, we report that nNOS knockout (KO) mice exhibit hyperactivity and impairments in contextual fear conditioning, results consistent with previous reports. nNOS KO mice also display mild impairments in object recognition memory. Most importantly, we report for the first time working memory deficits, potential impairments in prefrontal cortex mediated cognitive function in nNOS KO mice. Furthermore, we demonstrate Disrupted-in-Schizophrenia 1 (DISC1), another genetic risk factor for schizophrenia that plays roles for cortical development and prefrontal cortex functioning, including working memory, is a novel protein binding partner of nNOS in the developing cerebral cortex. Of note, genetic deletion of nNOS appears to increase the binding of DISC1 to NDEL1, regulating neurite outgrowth as previously reported. These results suggest that nNOS KO mice are useful tools in studying the role of nNOS signaling in cortical development and prefrontal cortical functioning. PMID- 21539808 TI - In the absence of cellular poly (A) binding protein, the glycolytic enzyme GAPDH translocated to the cell nucleus and activated the GAPDH mediated apoptotic pathway by enhancing acetylation and serine 46 phosphorylation of p53. AB - The cytoplasmic poly (A) binding protein (PABP) interacts with 3' poly (A) tract of eukaryotic mRNA and is important for both translation and stability of mRNA. Previously, we have shown that depletion of PABP by siRNA prevents protein synthesis and consequently leads to cell death through apoptosis. In the present investigation, we studied the mechanism of cell apoptosis. We show that in the absence of PABP, the glycolytic enzyme GAPDH translocated to the cell nucleus and activated the GAPDH mediated apoptotic pathway by enhancing acetylation and serine 46 phosphorylation of p53. As a result, p53 translocated to the mitochondria to initiate Bax mediated apoptosis. PMID- 21539809 TI - Glutathione is a physiologic reservoir of neuronal glutamate. AB - Glutamate, the principal excitatory neurotransmitter of the brain, participates in a multitude of physiologic and pathologic processes, including learning and memory. Glutathione, a tripeptide composed of the amino acids glutamate, cysteine, and glycine, serves important cofactor roles in antioxidant defense and drug detoxification, but glutathione deficits occur in multiple neuropsychiatric disorders. Glutathione synthesis and metabolism are governed by a cycle of enzymes, the gamma-glutamyl cycle, which can achieve intracellular glutathione concentrations of 1-10mM. Because of the considerable quantity of brain glutathione and its rapid turnover, we hypothesized that glutathione may serve as a reservoir of neural glutamate. We quantified glutamate in HT22 hippocampal neurons, PC12 cells and primary cortical neurons after treatment with molecular inhibitors targeting three different enzymes of the glutathione metabolic cycle. Inhibiting 5-oxoprolinase and gamma-glutamyl transferase, enzymes that liberate glutamate from glutathione, leads to decreases in glutamate. In contrast, inhibition of gamma-glutamyl cysteine ligase, which uses glutamate to synthesize glutathione, results in substantial glutamate accumulation. Increased glutamate levels following inhibition of glutathione synthesis temporally precede later effects upon oxidative stress. PMID- 21539810 TI - Crystal structure of the middle domain of human poly(A)-binding protein interacting protein 1. AB - In eukaryotes, the poly(A)-binding protein (PABP) is one of the important factors for initiation of messenger RNA translation. PABP activity is regulated by the PABP-interacting proteins (Paips), which include Paip1, Paip2A, and Paip2B. Human Paip1 has three different isoforms. Here, we report the crystal structure of the middle domain of Paip1 isoform 2 (Paip1M) as determined by single-wavelength anomalous dispersion phasing. The structure reveals a crescent-shaped domain consisting of 10 alpha-helices and two antiparallel beta-strands forming a beta hairpin. The 10 alpha-helices are arranged as five HEAT repeats which form a double layer of alpha helices with a convex and a concave surface. Despite low sequence identity, the overall fold of Paip1M is similar to the middle domain of human eIF4GII and yeast eIF4GI. Moreover, the amino-acid sequence motif and the local structure of eIF4G involved in binding of eIF4A, are conserved in Paip1. The structure reported here is the first of a member of the Paip family, thereby filling a gap in our understanding of initiation of eukaryotic mRNA translation in three dimensions. PMID- 21539811 TI - Nek6 suppresses the premature senescence of human cancer cells induced by camptothecin and doxorubicin treatment. AB - Cellular senescence plays an important role in tumor suppression. The mitotic kinase Nek6 has recently been shown to be overexpressed in various cancers and has been implicated in tumorigenesis. Previously, we reported that the down regulation of Nek6 expression was required for p53-induced senescence. In this study, we examined the effect of Nek6 overexpression on the premature senescence of cancer cells induced by the anticancer drugs camptothecin (CPT) and doxorubicin (DOX). We found that CPT- and DOX-induced morphology changes and increases in senescence-associated beta-galactosidase staining were significantly inhibited in EJ human bladder cancer cells and H1299 human lung cancer cells overexpressing HA-Nek6. DOX-induced G2/M cell cycle arrest and the reduction in cyclin B and cdc2 levels after DOX treatment were significantly reduced by Nek6 overexpression. In addition, an increase in the intracellular levels of ROS in response to DOX was also inhibited in cells overexpressing Nek6. These results suggest that the increased expression of Nek6 renders cancer cells resistant to premature senescence, and targeting Nek6 could be an efficient strategy for cancer treatment. PMID- 21539812 TI - Geminin is required for left-right patterning through regulating Kupffer's vesicle formation and ciliogenesis in zebrafish. AB - Geminin plays an important role in coordinating the cell cycle with anterior posterior patterning during embryonic development. However, whether it is involved in the regulation of left-right (LR) patterning remains unknown. Here, we reported that geminin is required for setting up heart and visceral laterality during zebrafish development. Defective heart and visceral laterality was observed in geminin morphants. Further study demonstrated that the left-sided nodal/spaw in the lateral plate mesoderm (LPM) as well as the sideness of its downstream targets lefty2 and lefty1 was perturbed in geminin morphants. Upstream of the left-sided Nodal signal along the regulatory cascade of LR asymmetry, knock down of geminin resulted in defective Kupffer's vesicle (KV) formation and ciliogenesis rather than middle line defects. Predominant distribution of an antisense morpholino against geminin in dorsal forerunner cells (DFCs) led to defective KV morphogenesis and perturbed LR asymmetry, similar to those of geminin morphants, indicating a cell-autonomous role of geminin in regulating KV formation and ciliogenesis. Our results demonstrate that geminin is required for proper KV formation and ciliogenesis, thus playing an important part in setting up LR asymmetry. PMID- 21539813 TI - The VEGFR2 receptor tyrosine kinase undergoes constitutive endosome-to-plasma membrane recycling. AB - The VEGFR2 receptor tyrosine kinase regulates vascular physiology and animal development. The mechanism underlying VEGFR2 membrane trafficking is not well understood. Herein, we show that VEGFR2 undergoes membrane recycling in both vascular and non-vascular cells. In primary human endothelial cells, VEGFR2 normally distributes between the plasma membrane and early endosomes undergoing endocytosis and recycling. This pathway is independent of VEGFR tyrosine kinase activity and occurs constitutively, similar to other integral membrane proteins such as the transferrin receptor and beta1 integrin. Expression of a VEGFR2-EGFP hybrid protein in non-vascular cells revealed plasma membrane and endosome distribution. The VEGF-A ligand stimulated phosphorylation of residue Y1175 on VEGFR2-EGFP which is a key hallmark of receptor activation. Live cell imaging and quantitative analysis showed that activated VEGFR2-EGFP displayed reduced mobility linked to endocytosis and recycling between the plasma membrane and endosomes. Total internal reflection microscopy and kinetics indicates that VEGFR2 undergoes recycling between the plasma membrane and peripheral endosomes proximal to the membrane bilayer. We thus provide evidence that the VEGFR2 receptor tyrosine kinase undertakes a constitutive recycling pathway between the peripheral endosomes and cell surface and this exists in both vascular and non vascular cells. PMID- 21539814 TI - The Ca2+/Mg2+ sites of troponin C modulate crossbridge-mediated thin filament activation in cardiac myofibrils. AB - The Ca(2+)/Mg(2+) sites (III and IV) located in the C-terminal domain of cardiac troponin C (cTnC) have been generally considered to play a purely structural role in keeping the cTnC bound to the thin filament. However, several lines of evidence, including the discovery of cardiomyopathy-associated mutations in the C domain, have raised the possibility that these sites may have a more complex role in contractile regulation. To explore this possibility, the ATPase activity of rat cardiac myofibrils was assayed under conditions in which no Ca(2+) was bound to the N-terminal regulatory Ca(2+)-binding site (site II). Myosin-S1 was treated with N-ethylmaleimide to create strong-binding myosin heads (NEM-S1), which could activate the cardiac thin filament in the absence of Ca(2+). NEM-S1 activation was assayed at pCa 8.0 to 6.5 and in the presence of either 1mM or 30 MUM free Mg(2+). ATPase activity was maximal when sites III and IV were occupied by Mg(2+) and it steadily declined as Ca(2+) displaced Mg(2+). The data suggest that in the absence of Ca(2+) at site II strong-binding myosin crossbridges cause the opening of more active sites on the thin filament if the C-domain is occupied by Mg(2+) rather than Ca(2+). This finding could be relevant to the contraction-relaxation kinetics of cardiac muscle. As Ca(2+) dissociates from site II of cTnC during the early relaxing phase of the cardiac cycle, residual Ca(2+) bound at sites III and IV might facilitate the switching off of the thin filament and the detachment of crossbridges from actin. PMID- 21539815 TI - New microbial mannan catabolic pathway that involves a novel mannosylglucose phosphorylase. AB - The consecutive genes BF0771-BF0774 in the genome of Bacteroides fragilis NCTC 9343 were found to constitute an operon. The functional analysis of BF0772 showed that the gene encoded a novel enzyme, mannosylglucose phosphorylase that catalyzes the reaction, 4-O-beta-d-mannopyranosyl-d-glucose+Pi->mannose-1 phosphate+glucose. Here we propose a new mannan catabolic pathway in the anaerobe, which involves 1,4-beta-mannanase (BF0771), a mannobiose and/or sugar transporter (BF0773), mannobiose 2-epimerase (BF0774), and mannosylglucose phosphorylase (BF0772), finally progressing to glycolysis. This pathway is distributed in microbes such as Bacteroides, Parabacteroides, Flavobacterium, and Cellvibrio. PMID- 21539816 TI - Role of Twist in vasculogenic mimicry formation in hypoxic hepatocellular carcinoma cells in vitro. AB - Vasculogenic mimicry (VM) refers to the unique ability of highly aggressive human tumor cells to form matrix-rich networks de novo when cultured on a three dimensional matrix, thus mimicking embryonic vasculogenesis. Some studies have shown that tumor hypoxia can promote tumor cells to form vessel-like tubes in vitro and express genes associated with VM. Although, the mechanisms involved in hypoxia-induced VM remain elusive, we hypothesized that the epithelial mesenchymal transition (EMT) regulator Twist may play a major role in hypoxia induced VM. We investigated this hypothesis in vitro by pretreating hepatocellular carcinoma cells under hypoxic conditions. Following the hypoxia treatment, the cells formed typical pipe-like VM networks. Moreover, the expression of VM markers was increased. Hypoxia-induced VM was accompanied by the increased expression of Twist. Twist siRNA reversed the effects of hypoxia on VM. These results suggest that the overexpression of Twist correlates to hypoxia induced VM in hepatocellular carcinoma cells. PMID- 21539817 TI - Single-domain antibodies that compete with the natural ligand fibroblast growth factor block the internalization of the fibroblast growth factor receptor 1. AB - Single-domain antibodies in VHH format specific for fibroblast growth factor receptor 1 (FGFR1) were isolated from a phage-display llama naive library. In particular, phage elution in the presence of the natural receptor ligand fibroblast growth factor (FGF) allowed for the identification of recombinant antibodies that compete with FGF for the same region on the receptor surface. These antibodies posses a relatively low affinity for FGFR1 and were never identified when unspecific elution conditions favoring highly affine binders were applied to panning procedures. Two populations of competitive antibodies were identified that labeled specifically the receptor-expressing cells in immunofluorescence and recognize distinct epitopes. Antibodies from both populations effectively prevented FGF-dependent internalization and nuclear accumulation of the receptor in cultured cells. This achievement indicates that these antibodies have a capacity to modulate the receptor physiology and, therefore, constitute powerful reagents for basic research and a potential lead for therapeutic applications. PMID- 21539818 TI - Bilayer structures in dioctadecyldimethylammonium bromide/oleic acid dispersions. AB - This paper reports on the properties of bilayers composed of dioctadecyldimethylammonium bromide (DODAB) and oleic acid (OA) at various molar ratios. The mole fraction of OA, X(OA), was varied in the range of 0-1 and the total lipid content was constant and equal to 10 mM. The DODAB/OA dispersions were extruded at a temperature higher than that of the gel-liquid transition of DODAB. The morphology of bilayer structures formed in the dispersions was inspected using a cryogenic transmission electron microscopy (cryo-TEM) and a differential interference contrast microscopy (DIC). The observations revealed that the incorporation of OA into DODAB bilayer results in a decrease of the membrane curvature. Anisotropy measurements using 1,6-diphenylhexatriene (DPH) as a rotator probe demonstrated that the DODAB/OA membrane microviscosity decreased considerably for X(OA)>0.4. The thermal behavior of DODAB/OA membranes has been studied by differential scanning calorimetry (DSC). In the case of the systems in which X(OA)<0.8, the DODAB/OA membranes are in the gel phase at room temperature. Additionally, Langmuir monolayer experiments of the DODAB/OA mixtures showed that due to the electrostatic interactions between the oppositely charged head groups of DODAB and OA they get close to each other, which results in a decrease of the mean area per molecule. The results were next discussed based on the packing parameter concept. The reduction of the mean area per head group (a) in the DODAB/OA systems leads to subsequent increase in the so-called packing parameter (S), which governs the morphology of surfactant aggregates. PMID- 21539819 TI - Increased levels of total oxidant status and decreased activity of arylesterase in migraineurs. AB - OBJECTIVES: There is strong evidence associating migraine with a variety of comorbid disorders, including cardiovascular disease and stroke, in which oxidative stress seems to be an important underlying mechanism. The aim of the study was to investigate in migraineurs the body oxidant/antioxidant balance and paraoxonase enzyme activities as a measure of HDL functionality. DESIGN AND METHODS: Oxidative stress index, total oxidant status and antioxidant status were examined in addition to the paraoxonase and arylesterase enzyme activities in sixty-two migraineurs and fifty healthy control subjects. RESULTS: Serum arylesterase activities were significantly lower in migraineurs (p=0.0065), whereas total oxidant status was higher in patients compared to the controls (p=0.0035). CONCLUSIONS: This preliminary study showed that oxidative/antioxidative balance shifted towards the oxidative status in migraine. Moreover, the results also suggested that decreased arylesterase activities might be associated with HDL-related disfunction. PMID- 21539820 TI - Evaluation of the URIT-2900 automated hematology analyzer for screening of thalassemia and hemoglobinopathies in Southeast Asian populations. AB - BACKGROUND: The effectiveness of the URIT-2900 Hematology Analyzer for screening of hemoglobinopathies commonly found in Southeast Asian populations was examined. METHODS: Appropriate cut-off values of MCV and MCH for screening of alpha(0) and beta thalassemias were derived from the receiver operator characteristic curve conducted initially on 279 subjects with various thalassemia genotypes. Validation was performed additionally in a cohort of another unrelated 313 subjects. RESULTS: The best cut off values of MCV and MCH were found to be 78fL and 27pg, respectively. Using these cut off values in combination with the dichlorophenolindophenol test in screening of alpha(0) thalassemia, beta thalassemia and Hb E in a cohort study revealed 100% sensitivity, 79.6% specificity, 80.0% positive predictive value and 100% negative predictive value. CONCLUSION: The combined blood cell counting using the URIT-2900 Automated Hematology Analyzer and dichlorophenolindophenol test is suitable for population screening of thalassemia and hemoglobinopathies in Southeast Asia. PMID- 21539821 TI - Rapid and reliable detection of IDH1 R132 mutations in acute myeloid leukemia using high-resolution melting curve analysis. AB - OBJECTIVE: The mutations of isocitrate dehydrogenase 1 (IDH1) gene have been identified in a proportion of hematologic malignancies including acute myeloid leukemia (AML). The aim of the present study was to explore the reliability of the high-resolution melting analysis (HRMA) for the identification of IDH1 R132 mutations in AML. DESIGNS AND METHODS: We evaluated the sensitivity of HRMA in the detection of IDH1 R132 mutation and screened IDH1 mutations in 110 AML patients using HRMA. The results of HRMA were validated by direct DNA sequencing. RESULTS: The reproducible sensitivity of HRMA was 5% for the detection of IDH1 R132 mutation, higher than 10% of direct DNA sequencing. Heterozygous IDH1 mutations were identified in 4 (3.6%) AML cases, which were R132H in 3 cases and R132S in 1 case confirmed by DNA sequencing. CONCLUSION: The HRMA is a rapid, accurate, reliable, high-throughput method to screen IDH1 gene mutations. PMID- 21539822 TI - Increased levels of bone remodeling biomarkers (osteoprotegerin and osteopontin) in hypertensive individuals. AB - OBJECTIVES: Osteoprotegerin (OPG) and osteopontin (OPN) are bone metabolism biomarkers which are involved in the regulation of vascular calcification processes and prediction of future adverse cardiac events. DESIGN AND METHODS: OPG, OPN levels and classic risk factors were determined in 130 asymptomatic and hypertensive subjects. Receiver operator characteristic (ROC) analysis was performed and the area under the curve (AUC) was calculated. RESULTS: The hypertensive subjects had elevated OPG, OPN, fibrinogen, CRP and fasting glucose levels in comparison to the normotensive ones. There were significant correlations between age, CRP and OPG. Multiple regression analysis showed that as well as inflammation (CRP), age and hypertension were predictors of increased OPG levels. OPN increase was correlated with CRP and glucose levels. The AUCs were similar for OPG and OPG biomarkers. CONCLUSIONS: Plasma OPG and OPN levels were significantly associated with inflammation and arterial hypertension. They might be useful as additional biomarkers for monitoring endothelial dysfunction and prognosis of cardiovascular diseases. PMID- 21539823 TI - Characterization of a serum protein pattern from NSCLC patients treated with Gefitinib. AB - OBJECTIVES: The purpose of this study was to evaluate the efficacy of a protein based pattern in serum previously determined by MALDI-TOF-MS (Matrix Assisted Laser Desorption Ionization-Time of Flight) and considered potentially useful for prediction of clinical outcome of EGFR (epidermal growth factor receptor) TKIs (tyrosine kinase inhibitors) treated patients. DESIGN AND METHODS: We generated SELDI-TOF (Surface Enhanced Laser Desorption Ionization-Time of Flight) spectra in sera of 11 advanced NSCLC treated with Gefitinib. We detected the clusters with m/z 5843, 11445, 11529, 11685, 11759 and 11903 which were previously reported to be potential predictors of response to Gefitinib treatment. RESULTS: Four cluster peaks with m/z 5843, 11445, 11529, 11685 corresponded to SAA (serum amyloid A) protein on the basis on their calculated molecular weight, peptide fingerprinting and antibodies recognition. CONCLUSIONS: We confirm that several proteins already reported were isoforms of SAA but further studies are in development in order to evaluate the predictive value of such algorithm. PMID- 21539824 TI - Pinpointing the expression of piRNAs and function of the PIWI protein subfamily during spermatogenesis in the mouse. AB - PIWI proteins and piRNAs have been linked to transposon silencing in the primordial mouse testis, but their function in the adult testis remains elusive. Here we report the cytological characterization of piRNAs in the adult mouse testis and the phenotypic analysis of Miwi(-/-); Mili(-/-) mice. We show that piRNAs are specifically present in germ cells, especially abundant in spermatocytes and early round spermatids, regardless of the type of the genomic sequences to which they correspond. piRNAs and PIWI proteins are present in both the cytoplasm and nucleus. In the cytoplasm, they are enriched in the chromatoid body; whereas in the nucleus they are enriched in the dense body, a male-specific organelle associated with synapsis and the formation of the XY body during meiosis. Moreover, by generating Miwi(-/-); Mili(-/-) mice, which lack all PIWI proteins in the adult, we show that PIWI proteins and presumably piRNAs in the adult are required only for spermatogenesis. Spermatocytes without PIWI proteins are arrested at the pachytene stage, when the sex chromosomes undergo transcriptional silencing to form the XY body. These results pinpoint a function of the PIWI protein subfamily to meiosis during spermatogenesis. PMID- 21539825 TI - The transcription factors AP-2beta and AP-2alpha are required for survival of sympathetic progenitors and differentiated sympathetic neurons. AB - Differentiation of sympathetic neurons is controlled by a group of transcription factors, including Phox2b, Ascl1, Hand2 and Gata3, induced by bone morphogenetic proteins (BMPs) in progenitors located in ganglion primordia at the dorsal aorta. Here, we address the function of the transcription factors AP-2beta and AP 2alpha, expressed in migrating neural crest cells (NCC) and maintained in sympathetic progenitors and differentiated neurons. The elimination of both AP 2alpha and AP-2beta results in the virtually complete absence of sympathetic and sensory ganglia due to apoptotic cell death of migrating NCC. In the AP-2beta knockout only sympathetic ganglia (SG) are targeted, leading to a reduction in ganglion size by about 40%, which is also caused by apoptotic death of neural crest progenitors. The conditional double knockout of AP-2alpha and AP-2beta in sympathetic progenitors and differentiated noradrenergic neurons results in a further decrease in neuron number, leading eventually to small sympathetic ganglion rudiments postnatally. The elimination of AP-2beta also leads to the complete absence of noradrenergic neurons of the Locus coeruleus (LC). Whereas AP 2alpha/beta transcription factors are in vivo not required for the onset or maintenance of noradrenergic differentiation, their essential survival functions are demonstrated for sympathetic progenitors and noradrenergic neurons. PMID- 21539826 TI - Disrupted dorsal neural tube BMP signaling in the cilia mutant Arl13b hnn stems from abnormal Shh signaling. AB - In the embryonic neural tube, multiple signaling pathways work in concert to create functional neuronal circuits in the adult spinal cord. In the ventral neural tube, Sonic hedgehog (Shh) acts as a graded morphogen to specify neurons necessary for movement. In the dorsal neural tube, bone morphogenetic protein (BMP) and Wnt signals cooperate to specify neurons involved in sensation. Several signaling pathways, including Shh, rely on primary cilia in vertebrates. In this study, we used a mouse mutant with abnormal cilia, Arl13b(hnn), to study the relationship between cilia, cell signaling, and neural tube patterning. Arl13b(hnn) mutants have abnormal ventral neural tube patterning due to disrupted Shh signaling; in addition, dorsal patterning defects occur, but the cause of these is unknown. Here we show that the Arl13b(hnn) dorsal patterning defects result from abnormal BMP signaling. In addition, we find that Wnt ligands are abnormally expressed in Arl13b(hnn) mutants; surprisingly, however, downstream Wnt signaling is normal. We demonstrate that Arl13b is required non-autonomously for BMP signaling and Wnt ligand expression, indicating that the abnormal Shh signaling environment in Arl13b(hnn) embryos indirectly causes dorsal defects. PMID- 21539827 TI - Ephrin-B reverse signaling controls septation events at the embryonic midline through separate tyrosine phosphorylation-independent signaling avenues. AB - We report that the disruption of bidirectional signaling between ephrin-B2 and EphB receptors impairs morphogenetic cell-cell septation and closure events during development of the embryonic midline. A novel role for reverse signaling is identified in tracheoesophageal foregut septation, as animals lacking the cytoplasmic domain of ephrin-B2 present with laryngotracheoesophageal cleft (LTEC), while both EphB2/EphB3 forward signaling and ephrin-B2 reverse signaling are shown to be required for midline fusion of the palate. In a third midline event, EphB2/EphB3 are shown to mediate ventral abdominal wall closure by acting principally as ligands to stimulate ephrin-B reverse signaling. Analysis of new ephrin-B2(6YFDeltaV) and ephrin-B2(DeltaV) mutants that specifically ablate ephrin-B2 tyrosine phosphorylation- and/or PDZ domain-mediated signaling indicates there are at least two distinct phosphorylation-independent components of reverse signaling. These involve both PDZ domain interactions and a non canonical SH2/PDZ-independent form of reverse signaling that may utilize associations with claudin family tetraspan molecules, as EphB2 and activated ephrin-B2 molecules are specifically co-localized with claudins in epithelia at the point of septation. Finally, the developmental phenotypes described here mirror common human midline birth defects found with the VACTERL association, suggesting a molecular link to bidirectional signaling through B-subclass Ephs and ephrins. PMID- 21539828 TI - Functional analyses of vertebrate TCF proteins in C. elegans embryos. AB - In the canonical Wnt pathway, signaling results in the stabilization and increased levels of beta-catenin in responding cells. beta-catenin then enters the nucleus, functioning as a coactivator for the Wnt effector, TCF/LEF protein. In the absence of Wnt signaling, TCF is complexed with corepressors, together repressing Wnt target genes. In C. elegans, Wnt signaling specifies the E blastomere to become the endoderm precursor. Activation of endoderm genes in E requires not only an increase in beta-catenin level, but a concomitant decrease in the nuclear level of POP-1, the sole C. elegans TCF. A decrease in nuclear POP 1 levels requires Wnt-induced phosphorylation of POP-1 and 14-3-3 protein mediated nuclear export. Nuclear POP-1 levels remain high in the sister cell of E, MS, where POP-1 represses the expression of endoderm genes. Here we express three vertebrate TCF proteins (human TCF4, mouse LEF1 and Xenopus TCF3) in C. elegans embryos and compare their localization, repression and activation functions to POP-1. All three TCFs are localized to the nucleus in C. elegans embryos, but none undergoes Wnt-induced nuclear export. Although unable to undergo Wnt-induced nuclear export, human TCF4, but not mouse LEF1 or Xenopus TCF3, can repress endoderm genes in MS, in a manner very similar to POP-1. This repressive activity requires that human TCF4 recognizes specific promoter sequences upstream of endoderm genes and interacts with C. elegans corepressors. Domain swapping identified two regions of POP-1 that are sufficient to confer nuclear asymmetry to human TCF4 when swapped with its corresponding domains. Despite undergoing Wnt-induced nuclear export, the human TCF4/POP-1 chimeric protein continues to function as a repressor for endoderm genes in E, a result we attribute to the inability of hTCF4 to bind to C. elegans beta-catenin. Our results reveal a higher degree of species specificity among TCF proteins for coactivator interactions than for corepressor interactions, and uncover a basic difference between how POP-1 and human TCF4 steady state nuclear levels are regulated. PMID- 21539829 TI - The Dkk1 dose is critical for eye development. AB - During mammalian ocular development, several signaling pathways control the spatiotemporal highly defined realization of the three-dimensional eye architecture. Given the complexity of these inductive signals, the developing eye is a sensitive organ for several diseases. In this study, we investigated a Dkk1+/- haploinsufficiency during eye development, resulting in coloboma and anterior eye defects, two common developmental eye disorders. Dkk1 impacts eye development from a defined developmental time point on, and is critical for lens separation from the surface ectoderm via beta-catenin mediated Pdgfralpha and E cadherin expression. Dkk1 does not impact the dorso ventral retina patterning in general but is critical for Shh dependent Pax2 extension into the midline region. The described results also indicate that the retinal Dkk1 dose is critical for important steps during eye development, such as optic fissure closure and cornea formation. Further analysis of the relationship between Dkk1 and Shh signaling revealed that Dkk1 and Shh coordinatively control anterior head formation and eye induction. During eye development itself, retinal Dkk1 activation is depending on cilia mediated Gli3 regulation. Therefore, our data essentially improve the knowledge of coloboma and anterior eye defects, which are common human eye developmental defects. PMID- 21539831 TI - Hmx4 regulates Sonic hedgehog signaling through control of retinoic acid synthesis during forebrain patterning. AB - Mutations in H6-homeobox (HMX) genes are linked to neural mispatterning and neural tube closure defects in humans. We demonstrate that zebrafish Hmx4 regulates the signaling of two morphogens critical for neural development, retinoic acid (RA) and Sonic hedgehog (Shh). Hmx4-depleted embryos have a strongly narrowed eye field and reduced forebrain Shh target gene expression. hmx4 morphants fail to properly transcribe the Shh signal transducer gli3, and have reduced ventral forebrain specification. Hmx4-depleted embryos also have neural tube patterning defects that phenocopy RA-deficiency. We show that Hmx4 is required for the initiation and maintenance of aldh1a2, the principal RA synthesizing gene. Loss of RA is the primary defect in Hmx4-depleted embryos, as RA treatment rescues a number of the neural patterning defects. Surprisingly, RA treatment also rescues forebrain morphology, gli3 transcription, and Shh signaling. We propose that Hmx4 is a critical regulator of retinoic acid synthesis in a developing embryo, and that this regulation is essential for controlling Shh signaling and forebrain development. PMID- 21539830 TI - Protein deiminases: new players in the developmentally regulated loss of neural regenerative ability. AB - Spinal cord regenerative ability is lost with development, but the mechanisms underlying this loss are still poorly understood. In chick embryos, effective regeneration does not occur after E13, when spinal cord injury induces extensive apoptotic response and tissue damage. As initial experiments showed that treatment with a calcium chelator after spinal cord injury reduced apoptosis and cavitation, we hypothesized that developmentally regulated mediators of calcium dependent processes in secondary injury response may contribute to loss of regenerative ability. To this purpose we screened for such changes in chick spinal cords at stages of development permissive (E11) and non-permissive (E15) for regeneration. Among the developmentally regulated calcium-dependent proteins identified was PAD3, a member of the peptidylarginine deiminase (PAD) enzyme family that converts protein arginine residues to citrulline, a process known as deimination or citrullination. This post-translational modification has not been previously associated with response to injury. Following injury, PAD3 up regulation was greater in spinal cords injured at E15 than at E11. Consistent with these differences in gene expression, deimination was more extensive at the non-regenerating stage, E15, both in the gray and white matter. As deimination paralleled the extent of apoptosis, we investigated the effect of blocking PAD activity on cell death and deiminated-histone 3, one of the PAD targets we identified by mass-spectrometry analysis of spinal cord deiminated proteins. Treatment with the PAD inhibitor, Cl-amidine, reduced the abundance of deiminated histone 3, consistent with inhibition of PAD activity, and significantly reduced apoptosis and tissue loss following injury at E15. Altogether, our findings identify PADs and deimination as developmentally regulated modulators of secondary injury response, and suggest that PADs might be valuable therapeutic targets for spinal cord injury. PMID- 21539832 TI - Lineage mapping the pre-implantation mouse embryo by two-photon microscopy, new insights into the segregation of cell fates. AB - The first lineage segregation in the pre-implantation mouse embryo gives rise to cells of the inner cell mass and the trophectoderm. Segregation into these two lineages during the 8-cell to 32-cell stages is accompanied by a significant amount of cell displacement, and as such it has been difficult to accurately track cellular behavior using conventional imaging techniques. Consequently, how cellular behaviors correlate with cell fate choices is still not fully understood. To achieve the high spatial and temporal resolution necessary for tracking individual cell lineages, we utilized two-photon light-scanning microscopy (TPLSM) to visualize and follow every cell in the embryo using fluorescent markers. We found that cells undergoing asymmetric cell fate divisions originate from a unique population of cells that have been previously classified as either outer or inner cells. This imaging technique coupled with a tracking algorithm we developed allows us to show that these cells, which we refer to as intermediate cells, share features of inner cells but exhibit different dynamic behaviors and a tendency to expose their cell surface in the mouse embryo between the fourth and fifth cleavages. We provide an accurate description of the correlation between cell division order and cell fate, and demonstrate that cell cleavage angle is a more accurate indicator of cellular polarity than cell fate. Our studies demonstrate the utility of two-photon imaging in answering questions in the pre-implantation field that have previously been difficult or impossible to address. Our studies provide a framework for the future use of specific markers to track cell fate molecularly and with high accuracy. PMID- 21539833 TI - Blastema induction in aneurogenic state and Prrx-1 regulation by MMPs and FGFs in Ambystoma mexicanum limb regeneration. AB - Urodele amphibians can regenerate amputated limbs. It has been considered that differentiated dermal tissues generate multipotent and undifferentiated cells called blastema cells during limb regeneration. In early phases of limb regeneration, blastema cells are induced by nerves and the apical epithelial cap (AEC). We had previously investigated the role of neurotrophic factors in blastema or blastema-like formation consisting of Prrx-1 positive cells. A new system suitable for investigating early phases of limb regeneration, called the accessory limb model (ALM), was recently developed. In this study, we performed a comparative transcriptome analysis between a blastema and wound using ALM. Matrix metalloproteinase (MMP) and fibroblast growth factor (FGF) signaling components were observed to be predominantly expressed in ALM blastema cells. Furthermore, we found that MMP activity induced a blastema marker gene, Prrx-1, in vitro, and FGF signaling pathways worked in coordination to maintain Prrx-1 expression and ALM blastema formation. Furthermore, we demonstrated that these two activities were sufficient to induce an ALM blastema in the absence of a nerve in vivo. PMID- 21539835 TI - A residue W756 in the P-loop segment of the sodium channel is critical for primaquine binding. AB - Our study on the wild-type and mutants of the voltage-dependent sodium channel in the rat skeletal muscle Na(v) 1.4 was to examine the possible binding site of primaquine PQ by using an experimental approach. We used a standard voltage-clamp in oocytes. Previously, we had demonstrated that PQ blocks the voltage-dependent sodium current in rat myocytes and that this blocking is concentration-dependent and voltage-independent. The direct-site mutagenesis in the P-loop segment W402C, W756C, W1239C, W1531A at the outer tryptophan-rich lip, and D400C, E758C, K1237C, A1529C of the DEKA locus helped us to identify residues playing a key role in aminoquinoline binding. In full agreement with our computed results, where a 1000 fold reduction of inhibition was measured, the tryptophan 756 is crucial for the reversible modulating effects of PQ. The W756C decreased the blocking effect of PQ in voltage-clamp assays. This new binding site may be important to the development of new drugs that modulate sodium inward currents. PMID- 21539834 TI - Developmental downregulation of Xenopus cyclin E is phosphorylation and nuclear import dependent and is mediated by ubiquitination. AB - Cyclins are regulatory subunits that bind to and activate catalytic Cdks. Cyclin E associates with Cdk2 to mediate the G1/S transition of the cell cycle. Cyclin E is overexpressed in breast, lung, skin, gastrointestinal, cervical, and ovarian cancers. Its overexpression correlates with poor patient prognosis and is involved in the etiology of breast cancer. We have been studying how cyclin E is normally downregulated during development in order to determine if disruption of similar mechanisms could either contribute to its overexpression in cancer, or be exploited to decrease its expression. In Xenopus laevis embryos, cyclin E protein level is high and constant until its abrupt destabilization by an undefined mechanism after the 12th cell cycle, which corresponds to the midblastula transition (MBT) and remodeling of the embryonic to the adult cell cycle. Since degradation of mammalian cyclin E is regulated by the ubiquitin proteasome system and is phosphorylation dependent, we examined the role of phosphorylation in Xenopus cyclin E turnover. We show that similarly to human cyclin E, phosphorylation of serine 398 and threonine 394 plays a role in cyclin E turnover at the MBT. Immunofluorescence analysis shows that cyclin E relocalizes from the cytoplasm to the nucleus preceding its degradation. When nuclear import is inhibited, cyclin E stability is markedly increased after the MBT. To investigate whether degradation of Xenopus cyclin E is mediated by the proteasomal pathway, we used proteasome inhibitors and observed a progressive accumulation of cyclin E in the cytoplasm after the MBT. Ubiquitination of cyclin E precedes its proteasomal degradation at the MBT. These results show that cyclin E destruction at the MBT requires both phosphorylation and nuclear import, as well as proteasomal activity. PMID- 21539836 TI - The semi-synthetic kaurane ent-16alpha-methoxykauran-19-oic acid induces vascular relaxation and hypotension in rats. AB - The present work investigates the mechanisms involved in the vasorelaxant effect of ent-16alpha-methoxykauran-19-oic acid (KA-OCH3), a semi-synthetic derivative obtained from the kaurane-type diterpene ent-kaur-16-en-19-oic acid (kaurenoic acid). Vascular reactivity experiments were performed in aortic rings isolated from male Wistar rats using standard muscle bath procedures. The cytosolic calcium concentration ([Ca2+]c) was measured by confocal microscopy using the fluorescent probe Fluo-3 AM. Blood pressure measurements were performed in conscious rats. KA-OCH3 (10, 50 and 100 MUmol/l) inhibited phenylephrine-induced contraction in either endothelium-intact or endothelium-denuded rat aortic rings. KA-OCH3 also reduced CaCl2-induced contraction in a Ca2+-free solution containing KCl (30 mmol/l) or phenylephrine (0.1 MUmol/l). KA-OCH3 (0.1-300 MUmol/l) concentration-dependently relaxed endothelium-intact and endothelium-denuded aortas pre-contracted with either phenylephrine or KCl, to a greater extent than kaurenoic acid. Moreover, a Ca2+ mobilisation study showed that KA-OCH3 (100 MUmol/l) inhibited the increase in Ca2+ concentration in smooth muscle and endothelial cells induced by phenylephrine or KCl. Pre-incubation of intact or denuded aortic rings with NG-nitro-L-arginine methyl ester (L-NAME, 100 MUmol/l), 7-nitroindazole (100 MUmol/l), wortmannin (0.5 MUmol/l) and 1H [1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 MUmol/l) produced a rightward displacement of the KA-OCH3 concentration-response curve. Intravenous administration of KA-OCH3 (1-10 mg/kg) reduced mean arterial blood pressure in normotensive rats. Collectively, our results show that KA-OCH3 induces vascular relaxation and hypotension. The mechanisms underlying the cardiovascular actions of KA-OCH3 involve blockade of Ca2+ influx and activation of the NO-cGMP pathway. PMID- 21539837 TI - Pemirolast reduces cisplatin-induced kaolin intake in rats. AB - Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK(1) receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT(3) receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK(1) receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release. PMID- 21539838 TI - Identification of short-acting kappa-opioid receptor antagonists with anxiolytic like activity. AB - The kappa-opioid receptor plays a central role in mediating the response to stressful life events. Inhibiting kappa-opioid receptor signaling is proposed as a mechanism for treating stress-related conditions such as depression and anxiety. Preclinical testing consistently confirms that disruption of kappa opioid signaling is efficacious in animal models of mood disorders. However, concerns about the feasibility of developing antagonists into drugs stem from an unusual pharmacodynamic property of prototypic kappa-opioid receptor-selective antagonists; they inhibit receptor signaling for weeks to months after a single dose. Several fundamental questions include - is it possible to identify short acting antagonists; is long-lasting inhibition necessary for efficacy; and is it safe to develop long-acting antagonists in the clinic. Here, we test representative compounds (AZ-ECPC, AZ-MTAB, and LY-DMPF) from three new chemical series of kappa-opioid receptor ligands for long-lasting inhibition. Each compound dose-dependently reversed kappa-opioid agonist-induced diuresis. However, unlike the prototypic antagonist, nBNI, which fully inhibited evoked diuresis for at least four weeks, the new compounds showed no inhibition after one week. The two compounds with greater potency and selectivity were tested in prenatally-stressed rats on the elevated plus maze, an exploration-based model of anxiety. Spontaneous exploration of open arms in the elevated plus maze was suppressed by prenatal stress and restored with both compounds. These findings indicate that persistent inhibition is not an inherent property of kappa-opioid selective antagonists and that post-stress dosing with transient inhibitors can be effective in a mood disorder model. This further supports kappa-opioid receptor as a promising target for developing novel psychiatric medications. PMID- 21539839 TI - Olive polyphenol hydroxytyrosol prevents bone loss. AB - Polyphenols reportedly exert physiological effects against diseases such as cancer, arteriosclerosis, hyperlipidemia and osteoporosis. The present study was designed to evaluate the effects of oleuropein, hydroxytyrosol and tyrosol, the major polyphenols in olives, on bone formation using cultured osteoblasts and osteoclasts, and on bone loss in ovariectomized mice. No polyphenols markedly affected the proliferation of osteoblastic MC3T3-E1 cells at concentrations up to 10MUM. Oleuropein and hydroxytyrosol at 10 to 100MUM had no effect on the production of type I collagen and the activity of alkaline phosphatase in MC3T3 E1 cells, but stimulated the deposition of calcium in a dose-dependent manner. In contrast, oleuropein at 10 to 100MUM and hydroxytyrosol at 50 to 100MUM inhibited the formation of multinucleated osteoclasts in a dose-dependent manner. Furthermore, both compounds suppressed the bone loss of trabecular bone in femurs of ovariectomized mice (6-week-old BALB/c female mice), while hydroxytyrosol attenuated H(2)O(2) levels in MC3T3-E1 cells. Our findings indicate that the olive polyphenols oleuropein and hydroxytyrosol may have critical effects on the formation and maintenance of bone, and can be used as effective remedies in the treatment of osteoporosis symptoms. PMID- 21539840 TI - C-fibers, but not the transient potential receptor vanilloid 1 (TRPV1), play a role in experimental allergic airway inflammation. AB - The activation of C-fibers in the airways induces coughing, mucus production and bronchoconstriction, which are also symptoms of airway diseases. In this study, we evaluated the role of the C-fibers and the TRPV1 (transient receptor potential vanilloid 1) receptor in an experimental mouse model of allergic airway inflammation. To study the role of C-fibers, we either degenerated the C-fibers persistently (capsaicin administration in neonate mice) or transiently (capsaicin administration in adult mice). No alteration was observed in eosinophil recruitment to the bronchoalveolar lavage fluid in animals treated with capsaicin in the neonatal period. However, in adult animals, capsaicin treatment after the first ovalbumin challenge (in the establishment of the inflammatory process) decreased the eosinophil numbers. This effect was more pronounced in adult animals treated with capsaicin before beginning the ovalbumin immunization (in the development of the inflammatory process). In addition, interleukin (IL)-5 and chemokine ligand 11 (CCL11) levels in the bronchoalveolar lavage fluid, as well as P-selectin expression and p65 nuclear factor kappaB (NF-kappaB) activation in the lung were also decreased. No alterations were observed in the IL-10 and IL-13 levels. Next we determined the effect of TRPV1 receptor blockade on allergic airway inflammation. SB366791 administrated in mice by intraperitoneal (500MUg/kg) or intranasal (0.1, 1 or 10nmol/site) route failed to decrease eosinophil recruitment to the bronchoalveolar lavage fluid or alter any other metrics cited above. Thus, the present results confirm and extend previous data supporting the involvement of C-fibers, but not the TRPV1 receptor, in allergic airway inflammation. PMID- 21539841 TI - Ubiquitin family modifications and template switching. AB - Homologous recombination plays an important role in the maintenance of genome integrity. Arrested forks and DNA lesions trigger strand annealing events, called template switching, which can provide for accurate damage bypass, but can also lead to chromosome rearrangements. Advances have been made in understanding the underlying mechanisms for these events and in elucidating the factors involved. Ubiquitin- and SUMO-mediated modification pathways have emerged as key players in regulating damage-induced template switching. Here I review the biological significance of template switching at the nexus of DNA replication and recombination, and the role of ubiquitin-like modifications in mediating and controlling this process. PMID- 21539843 TI - Short-term consequences of reproductive mode variation on the genetic architecture of energy metabolism and life-history traits in the pea aphid. AB - Cyclically parthenogenetic animals such as aphids are able alternating sexual and asexual reproduction during its life cycle, and represent good models for studying short-term evolutionary consequences of sex. In aphids, different morphs, whether sexual or asexual, winged or wingless, are produced in response to specific environmental cues. The production of these morphs could imply a differential energy investment between the two reproductive phases (i.e., sexual and asexual), which can also be interpreted in terms of changes in genetic variation and/or trade-offs between the associated traits. In this study we compared the G-matrices of energy metabolism, life-history traits and morph production in 10 clonal lineages (genotypes) of the pea aphid, Acyrthosiphon pisum, during both sexual and asexual phases. The heritabilities (broad-sense) were significant for almost all traits in both phases; however the only significant genetic correlation we found was a positive correlation between resting metabolic rate and production of winged parthenogenetic females during the asexual phase. These results suggest the pea aphid shows some lineage specialization in terms of energy costs, but a higher specialization in the production of the different morphs (e.g., winged parthenogenetic females). Moreover, the production of winged females during the asexual phase appears to be more costly than wingless females. Finally, the structures of genetic variance covariance matrices differed between both phases. These differences were mainly due to the correlation between resting metabolic rate and winged parthenogenetic females in the asexual phase. This structural difference would be indicating that energy allocation rules changes between phases, emphasizing the dispersion role of asexual morphs. PMID- 21539842 TI - Mediators of oligodendrocyte differentiation during remyelination. AB - Myelin, a dielectric sheath that wraps large axons in the central and peripheral nervous systems, is essential for proper conductance of axon potentials. In multiple sclerosis (MS), autoimmune-mediated damage to myelin within the central nervous system (CNS) leads to progressive disability primarily due to limited endogenous repair of demyelination with associated axonal pathology. While treatments are available to limit demyelination, no treatments are available to promote myelin repair. Studies examining the molecular mechanisms that promote remyelination are therefore essential for identifying therapeutic targets to promote myelin repair and thereby limit disability in MS. Here, we present our current understanding of the critical extracellular and intracellular pathways that regulate the remyelinating capabilities of oligodendrocyte precursor cells (OPCs) within the adult CNS. PMID- 21539844 TI - Is Raf1 a nexus for cardiac hypertrophic signaling in human disease? PMID- 21539846 TI - Decreased angiogenin concentration in vitreous and serum in proliferative diabetic retinopathy. AB - Diabetic retinopathy is the most common cause of vision loss in young adults in developed countries. The disease therapy with anti-vascular endothelial growth factor (VEGF) agents gives some positive results, but is associated with retinal ischemia and vasoconstriction. Therefore, determination of factors involved in the physiological and pathological angiogenesis in the diabetic eye is of great importance for understanding of the pathogenesis of diabetic retinopathy and its effective treatment. Previously, we found that diabetic patients were characterized by increased serum concentration of VEGF, but decreased levels of other proangiogenic factor-angiogenin. The involvement of VEGF in pathogenesis of diabetic retinopathy is well established, but there is lack of data regarding angiogenin in retinopathy. Therefore, in the present study we measured angiogenin concentration in vitreous and serum samples of the patients with type 1 diabetes to determine its role in diabetic retinopathy. In addition, in each time, we compared the level of angiogenin with level of VEGF as a known factor involved in the pathogenesis of the disease. Angiogenin was found to be significantly more abundant in serum than in vitreous in both diabetic groups. In addition, patients with retinopathy had twofold lower vitreous angiogenin levels than diabetic individuals without complications. On the contrary, vitreous concentration of VEGF was dramatically increased only in participants with retinopathy. Patients without diabetic complications had significantly lower VEGF levels in vitreous than in serum and were characterized by high local and systemic concentration of angiogenin. These data suggest a local imbalance between two proangiogenic factors-VEGF and angiogenin in retinopathy. Low vitreous concentration of angiogenin in diabetic patients suggests that this factor is not responsible for pathological neovascularization in diabetic eye. Further studies will elucidate if angiogenin can be used to improve the insufficient angiogenesis in diabetes and prevent retinal ischemia after retinopathy treatment with anti-VEGF agents. PMID- 21539845 TI - Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension. AB - Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models of heart failure. The efficacious compounds target class I, class IIb and, to a lesser extent, class IIa HDACs. It is hypothesized that a selective inhibitor of a specific HDAC class (or an isoform within that class) will provide a favorable therapeutic window for the treatment of heart failure, although the optimal selectivity profile for such a compound remains unknown. Genetic studies have suggested that class I HDACs promote pathological cardiac remodeling, while class IIa HDACs are protective. In contrast, nothing is known about the function or regulation of class IIb HDACs in the heart. We developed assays to quantify catalytic activity of distinct HDAC classes in left and right ventricular cardiac tissue from animal models of hypertensive heart disease. Class I and IIa HDAC activity was elevated in some but not all diseased tissues. In contrast, catalytic activity of the class IIb HDAC, HDAC6, was consistently increased in stressed myocardium, but not in a model of physiologic hypertrophy. HDAC6 catalytic activity was also induced by diverse extracellular stimuli in cultured cardiac myocytes and fibroblasts. These findings suggest an unforeseen role for HDAC6 in the heart, and highlight the need for pre-clinical evaluation of HDAC6-selective inhibitors to determine whether this HDAC isoform is pathological or protective in the setting of cardiovascular disease. PMID- 21539847 TI - Blockade of gC1qR/p33, a receptor for C1q, inhibits adherence of Staphylococcus aureus to the microvascular endothelium. AB - Endovascular infections with Staphylococcus aureus (S. aureus) are associated with high mortality. gC1qR/p33 (gC1qR), a receptor for the complement component C1q expressed on endothelial cells, interacts with protein A of S. aureus and gC1qR blockade reduces S. aureus colonization during infective endocarditis. The aim of this study was to analyze in vivo whether this observation is due to a decreased interaction of S. aureus with the microvascular endothelium. A dorsal skinfold chamber was prepared in Syrian golden hamsters, which were treated with the monoclonal antibody (MAb) 74.5.2 directed against gC1qR or vehicle. The interaction of fluorescein isothiocyanate (FITC)-labeled staphylococci and leukocytes with the endothelium was analyzed under physiological conditions as well as after TNF-alpha-induced inflammation using intravital fluorescence microscopy. Administration of MAb 74.5.2 significantly reduced adherence of S. aureus to the endothelium in untreated and TNF-alpha-exposed tissue. In addition, we could demonstrate in vitro that S. aureus adherence to human endothelial cells was inhibited by MAb 74.5.2. Blockade of gC1qR did not affect leukocyte endothelial cell interaction. In conclusion, our findings indicate that immunological inhibition of gC1qR may be therapeutically used to decrease the interaction of S. aureus with the microvascular endothelium. PMID- 21539848 TI - Carisbamate has powerful disease-modifying effects in the lithium-pilocarpine model of temporal lobe epilepsy. AB - Lithium-pilocarpine, a relevant model of temporal lobe epilepsy was used to test the neuroprotective and antiepileptogenic effects of carisbamate. Status epilepticus (SE) was induced in adult rats by lithium and pilocarpine. Carisbamate (30, 60, 90, and 120 mg/kg) was injected at 1 and 9 h after SE onset and continued twice daily for 6 additional days. The reference groups received diazepam instead of carisbamate. Neuroprotection was assessed during the first 24 h of SE with Fluoro-Jade B and after 14 days with thionine staining. SE severity and epileptic outcome were assessed by video, and surface and depth electroencephalographic recordings. At the two highest doses, carisbamate treatment reduced SE severity; produced strong neuroprotection of hippocampus, ventral cortices, thalamus, and amygdala; prevented mossy fiber sprouting in the dentate gyrus of the hippocampus; and delayed or suppressed the occurrence of spontaneous motor seizures. Rats with no spontaneous motor seizures displayed spike-and-wave discharges that share all the characteristics of absence seizures. In conclusion, carisbamate is able to induce strong neuroprotection and affect the nature of epileptogenic events occurring during and after lithium-pilocarpine status epilepticus, reflecting marked insult- and disease-modifying effects. PMID- 21539849 TI - From pantomime to actual use: how affordances can facilitate actual tool-use. AB - The main goal of the study was to investigate whether the presence of affordances, such as physical properties of given objects and resulting movement constraints, induce a performance increase in actual tool-use compared to demonstrating it with only the tool or pantomiming it without the tool and recipient object. In the present study the perception of affordances was manipulated by omission or supply of contextual information. The three execution modes - pantomiming, demonstration and actual use, - were investigated concerning the actions hammering and scooping in 25 patients with left unilateral brain damage and 10 healthy controls. The content of the movement, the grip formation, the direction and the location of the movement were evaluated with video analysis. The results show that the pantomime condition is most prone to errors. The information given by the tool and the recipient object in the actual use task seems to facilitate especially scooping - the more complex tool-use action. A factor analysis and the high correlation between performance-scores show that the three execution modes of both actions have a major common factor. One possible joint commonality of the execution modes could be the nature of an action related working memory component, which is responsible for the recall and the integration of semantic information into a movement-plan. Additional analyses with a smaller group revealed a second factor, that might depict the online processing of spatial relationships of the hand, the tool and the recipient objects. The results indicate that performance improvement can be achieved by providing perceptual cues and reducing the degrees of freedom for the required action. It is concluded that manipulating affordances in a tool use context should be taken into consideration for future investigation of therapeutic approaches. PMID- 21539850 TI - Grip-dependent cortico-spinal excitability during grasping imagination and execution. AB - Studies converge in indicating a substantial similarity of the rules and mechanisms underlying execution, observation and imagery of actions, along with a large overlapping of their neural substrates. Recent transcranial magnetic stimulation (TMS) studies have demonstrated a muscle-specific facilitation of the observer's motor system for force requirement and type of grip during grasping observation. However, whether similar fine-tuned muscle-specificity occurs even during imagination, when subjects are free to select the most convenient grip configuration, is still unknown. Here we applied TMS over the primary motor cortex and measured the corticospinal excitability (MEP) in three muscles (FDI, ADM and FDS) while subjects imagined grasping spheres of different dimensions and materials. This range of object weights and sizes (diameters) allowed subjects to freely imagine the most suitable grip configuration among several possibilities. Activation measured during grasping imagination has been also compared to that obtained during real execution (EMG recorded from the same muscles). We found that during imagination of grasping small objects, the FDI muscle was more active than the ADM and the FDS, whereas the opposite pattern was found for big objects. Imagination of medium size objects, instead, required an equal involvement of the three muscles. The same pattern was observed when subjects were asked to perform the action. This suggests that during imagination, the cortico-spinal system is modulated in a muscle-specific/grip-specific way, as if the action would be really performed. However, when force was required (i.e., for the aluminum objects), the motor activation obtained during action execution was more fine tuned to object dimensions than the facilitation recorded during imagination, suggesting a separate control of force production. PMID- 21539851 TI - Programs for action in superior parietal cortex: a triple-pulse TMS investigation. AB - Converging evidence from neurological patients and functional brain imaging studies strongly supports the notion that the posterior parietal cortex (PPC), especially in the left hemisphere, plays a critical role in both the programming (i.e., setting the initial movement parameters of the reach) and the online control of goal-directed reaching movements. Importantly, however, there is no clear consensus on how different subregions within the PPC contribute to the programming and online control of reaching. In the current study, we investigated the role of the inferior (IPL) and superior (SPL) parietal lobules in reach programming using MRI-guided event-related transcranial magnetic stimulation (TMS). Specifically, we applied triple-pulse (tp) TMS to either the left IPL or the left SPL at different time points during reaching movements either at target onset (programming) or at movement onset (online control) while participants (n=16) made pointing movements to targets in the periphery without visual feedback of the moving hand. Stimulating the SPL but not the IPL resulted in a significant increase in endpoint errors when tp-TMS was applied during the programming phase compared to the online control phase. In short, these data demonstrate that the SPL plays a critical role in real-time movement programming. PMID- 21539852 TI - Opioidergic consequences of dietary-induced binge eating. AB - Endogenous opioids are involved in the hedonic aspects of eating. Opioid impairments and alterations have been implicated in the pathophysiology of bulimia nervosa and binge eating disorder. Specific contributions by Bartley G. Hoebel have furthered the understanding how cyclical caloric restriction and intermittent optional access to sugar solutions result in opioid-like forebrain neural alterations and dependency in rodents. The present study sought to investigate caudal brainstem and nodose ganglion mu-opioid receptor mRNA alterations in a rodent model of dietary-induced binge eating of sweetened fat (vegetable shortening blended with 10% sucrose). Five groups (n=7 or 8) of adult female Sprague Dawley rats were exposed to various dietary conditions for 6 weeks. As measured by in situ hybridization, there was reduced (approximately 25% from naive) mu-opioid receptor mRNA in the nucleus of the solitary tract (NTS) in the binge access group, which had intermittent calorie restriction and optional limited access to the sweetened fat. A similar reduction in expression was demonstrated in the continuous access group, which has unlimited optional sweetened fat and an obese phenotype. In the nodose ganglion, mu-opioid receptor mRNA was increased (approximately 30% from groups with sweetened fat access) in rats with intermittent caloric restriction alone. Our findings and the body of work from the Hoebel laboratory suggest that dietary-induced binge eating can consequentially alter opioidergic forebrain and hindbrain feeding-related neural pathways. Future work is needed to determine whether similar alterations are involved in the maintenance and progression of binge eating and other related eating pathologies. PMID- 21539853 TI - Completion and timing of the three-dose human papillomavirus vaccine series among adolescents attending school-based health centers in Oregon. AB - OBJECTIVE: Many adolescents do not complete the 3-dose human papillomavirus vaccine series in the recommended time frame, or at all. Given the challenges of administering a multi-dose vaccine to adolescents, especially those in vulnerable populations, we evaluated completion of the human papillomavirus vaccine series in 19 of Oregon's school-based health centers. METHODS: Among persons aged 0-17 who initiated the human papillomavirus vaccine series at a study school-based health center in 2007, we identified all subsequent human papillomavirus doses administered at the school-based health centers, or found in Oregon's immunization information system, in 2007-2008. We describe the proportion completing the vaccine series and mean intervals between doses, stratified by age, race, and insurance status. RESULTS: Four hundred fifty persons initiated the human papillomavirus series in 2007. By December 2008, 51% of these had received all 3 doses. Series completion increased significantly with age, differed significantly between race groups (highest among white persons (56%); lowest among black persons (38%)), and did not differ significantly by insurance status. Mean intervals between doses did not differ significantly by race or insurance status. CONCLUSIONS: Even in challenging conditions, school-based health centers provide excellent preventive care to vulnerable youth. These results support the importance of maintaining and expanding school-based health center access in vulnerable adolescent populations. PMID- 21539854 TI - Commentary: Soda taxes, obesity, and the shifty behavior of consumers. AB - Rising obesity is a threat to public health, and taxing sugar-sweetened beverages (SSBs) in order to reduce consumption and thus caloric intake could be a viable policy response. But raising the price of SSB calories will raise the quantity demanded of relatively cheaper calories, and net effect on obesity is unclear. I review the evidence on shifting calorie demand and discuss the viability of soda taxes to achieve improvements in public health. PMID- 21539855 TI - The relationship between pregnancy intention and preconception health behaviors. AB - OBJECTIVE: To describe smoking, heavy drinking, and folic acid supplementation in preconception women and determine if the likelihood of healthy preconception behaviors differs by whether and when women intend future pregnancy. METHODS: Analysis was based on 35,351 nonpregnant women who participated in the 2004 Behavioral Risk Factor Surveillance System who were of reproductive age (18-44 years), sexually active, and capable of future pregnancy. The association between future pregnancy intention and preconception behaviors was determined adjusting for diabetes, weight category, age group, race/ethnicity, marital status, education, income, and children living in household. RESULTS: Eighty percent of women were non-smokers, 94.3% were non-heavy drinkers, and 42.6% were daily folic acid users. In adjusted analysis, only the odds of folic acid supplementation remained higher in women intending pregnancy in the next 12 months (adjusted odds ratio, 1.57; 95% confidence interval, 1.21-2.04) compared with women not intending future pregnancy. Women intending pregnancy later or ambivalent about future pregnancy were no more likely to be engaging in healthy preconception behaviors than women not intending future pregnancy. CONCLUSION: Women intending pregnancy within 12 months were more likely to use folic acid, but pregnancy intention was not associated with preconception smoking or heavy drinking. PMID- 21539856 TI - Screening of a functional polysaccharide from Zizyphus Jujuba cv. Jinsixiaozao and its property. AB - Chinese jujube has been used as a kind of Chinese medicinal herb for a long time. In this paper, the polysaccharides from Zizyphus Jujuba cv. Jinsixiaozao (ZSP), one of the major Chinese jujube varieties, were extracted and purified sequentially so that its water-soluble immunobiological fractions were screened. The crude ZSP was found to dramatically increase thymus and spleen indices in mice, enhance the proliferation of splenocytes and peritoneal macrophages, and have potential anti-complementary activity. Immunobiological tests indicated that two fractions of ZSP, coded ZSP3c and ZSP4b, were the main active components. ZSP3c was rich in pectin with a degree of esterification (DE) of 49%, which may be related to its stronger immunological activity. PMID- 21539857 TI - NH exchange in point mutants of human ubiquitin. AB - Several point mutants of human ubiquitin (Ub(T9V), Ub(F45W), Ub(F45G), and Ub(A46S)) were prepared by recombinant techniques. The NH exchange rate constants were measured by the NMR diffusion and the MEXICO methods and compared with those in the wild type to examine the influence of structural changes and to improve the understanding of this important reaction in studies of protein folding and denaturation. The observed changes follow qualitatively the polarity and steric alterations caused by the introduced amino acids. Attempts to reproduce quantitatively the observed changes by modeling studies and molecular dynamics simulations were not satisfactory. PMID- 21539858 TI - Dextran-g-PEI nanoparticles as a carrier for co-delivery of adriamycin and plasmid into osteosarcoma cells. AB - Combination of chemotherapy and gene therapy of cancer has synergistic effects on overcoming drug resistance. Macromolecular materials such as dextran and PEI have been a potential module for chemotherapeutics and gene delivery. Herein, we hypothesize the combinational strategy of chemotherapy and gene therapy in a single dextran-PEI nanoplatform. The physicochemical properties, cytotoxicity, transfection efficiency were investigated in vitro. Ultra-violet spectrum and (1)H NMR revealed adriamycin and PEI were grafted to dextran chain. Agarose gel electrophoresis demonstrated that the migration of plasmid was completely retarded when the N/P ratio of complex was 4. The sizes of DEX-ADM-PEI/DNA nanoparticles decreased and the zeta potentials enhanced with the increasing N/P ratio. Transmission electron microscope indicated a round morphology of the nanoparticles. DEX-ADM-PEI conjugation has higher cytotoxicity, compared to free adriamycin, in MG-63 and Saos-2 osteosarcoma cells but DEX-PEI maintained over 65% cell viability at the concentration of 8 mg/mL. The transfection efficiency of DEX-ADM-PEI/pEGFP-N1 at N/P ratio of 4:1 both in MG-63 and Saos-2 cell were slightly low than that of PEI 25k. But our nanoplatform efficiently delivered both plasmid pEGFP-N1 and adriamycin into osteosarcoma cells. This study demonstrated that DEX-ADM-PEI efficiently and selectively delivered both plasmid pEGFP-N1 and adriamycin to osteosarcoma cells with low cytotoxicity. PMID- 21539859 TI - Development and comparison of a Primer-Probe Energy Transfer based assay and a 5' conjugated Minor Groove Binder assay for sensitive real-time PCR detection of infectious laryngotracheitis virus. AB - In this study the design and development of two real-time PCR assays for the rapid, sensitive and specific detection of infectious laryngotracheitis virus (ILTV) DNA is described. A Primer-Probe Energy Transfer (PriProET) assay and 5' conjugated Minor Groove Binder (MGB) method are compared and contrasted. Both have been designed to target the thymidine kinase gene of the ILTV genome. Both PriProET and MGB assays are capable of detecting 20 copies of a DNA standard per reaction and are linear from 2*10(8) to 2*10(2)copies/MUl. Neither PriProET, nor MGB reacted with heterologous herpesviruses, indicating a high specificity of the two methods as novel tools for virus detection and identification. This study demonstrates the suitability of PriProET and 5' conjugated MGB probes as real time PCR chemistries for the diagnosis of respiratory diseases caused by ILTV. PMID- 21539860 TI - Development of sensitive methods for detection of porcine endogenous retrovirus-C (PERV-C) in the genome of pigs. AB - Porcine endogenous retroviruses (PERV) represent a risk for xenotransplantation using pig cells, tissues or organs. PERV-A and PERV-B are present in the genome of all pigs and both infect human cells in vitro. PERV-C infects only pig cells and it is integrated in the genome of most, but not all pigs. Recombinants between PERV-A and PERV-C were described that infect human cells and replicate at high titres. To avoid such recombinations, PERV-C positive animals should not be used for breeding animals suited for xenotransplantation. In order to detect PERV C positive pigs, different methods were developed such as specific PCRs using different primers, a highly sensitive nested PCR and a real-time PCR allowing measurement of proviral copy numbers. The real-time PCR was found to be useful to discriminate between contamination and actual provirus copies. The PCRs were optimized and their sensitivity was determined. Screening can be started with PCR1, if the result is negative, PCR2 to PCR5 or the nested PCR should be used, if the result is positive, the real-time PCR should be used to exclude contaminations. All methods were used to evaluate the prevalence of PERV-C and to identify PERV-C free animals. Due to the risk of contamination with cells from other animals testing should be performed with blood cells, not with ear biopsies. PMID- 21539861 TI - Resistance testing of clinical varicella-zoster virus strains. AB - Acyclovir resistance of varicella-zoster virus (VZV) has been reported in rare cases of immunocompromised patients. In this study, the natural polymorphism of the thymidine kinase (TK) and DNA polymerase (pol) genes was examined in 51 clinical VZV isolates sensitive to acyclovir (ACV). In addition, 16 VZV strains with clinical resistance to ACV were analyzed. None of the ACV-sensitive strains of the clades 1, 3 and 5 showed gene polymorphism of the TK. By contrast, the DNA pol gene exhibited polymorphism-related substitutions as a function of the VZV clade. The novel substitutions M286I, E824Q, R984H and H1089Y were detected in strains of clades 3 and 5. In the TK gene of 7 VZV strains with clinical ACV resistance, the novel substitutions L73I, A163stop, W225R, T256M, N334stop and the deletion of nucleotides 19-223 were found to be associated most likely with resistance. In one strain showing the substitution W225R, ACV resistance could be confirmed by the viral phenotype. In the DNA pol gene, the novel amino acid substitutions T237K and A955T could be detected, but their significance remains unclear. In conclusion, the characterization of resistance using genetic analysis of the TK and DNA pol genes has to be considered the method of choice for the determination of VZV resistance to antiviral drugs. In a considerable number of patients with clinical ACV-resistant VZV infections, resistance cannot be verified by virological methods. PMID- 21539862 TI - Retrospective revaluation and its neural circuit in rats. AB - Contingency learning is essential for establishing predictive or causal judgements. Retrospective revaluation captures essential aspects of the updating of this knowledge, according to new experience. In the present study, retrospective revaluation and its neural substrate was investigated in a rat conditioned magazine approach. One element of a previously food-reinforced Tone Light compound stimulus was either further reinforced (inflation) or extinguished (extinction). These treatments affected the predictive value of the alternate stimulus (target), but only when the target was a weakly salient stimulus such as a Light, and the inflation/extinction procedure concerned the more salient element, that is the Tone. As the predictive value of the Light was decreased in comparison with a relevant control group, this revaluation was interpreted as backward blocking, and not unovershadowing. This observation challenges retrospective revaluation models focused on acquisition and prediction error detection, and is better accounted for by retrieval-based associative theories such as the comparator model (Miller and Matzel) [5]. Immunohistochemical detection of the Fos protein after the test phase revealed activation of the orbitofrontal and infralimbic cortices as well as nucleus accumbens core and shell, in rats that exhibited retrospective revaluation. Our results suggest that rats integrate successive experiences at the retrieval stage of retrospective revaluation, and that prefronto-accumbal interactions are involved in this function. PMID- 21539863 TI - Signalling pathway of goldfish melanin-concentrating hormone receptors 1 and 2. AB - Melanin-concentrating hormone (MCH) is the natural ligand for the MCH-1 receptor (MCHR1) and MCH-2 receptor (MCHR2). The MCH-MCHR1 system plays a central role in energy metabolism in rodents. Recently, we identified MCHR1 and MCHR2 orthologues in goldfish, designated gfMCHR1 and gfMCHR2. In a mammalian cell-based assay, calcium mobilization was evoked by gfMCHR2 via both Galphai/o and Galphaq, while the gfMCHR1-mediated response was exclusively dependent on Galphaq. This coupling capacity to G proteins is in contrast to human MCHR1 and MCHR2. Here, we extended our previous characterization of the two gfMCHRs by examining their different signalling pathway. We found that MCH caused activation of extracellular signal regulated kinases 1 and 2 (ERK1/2) via both gfMCHR1 and gfMCHR2 in dose-dependent manners. Unlike the case for gfMCHR2, gfMCHR1 signalling was not sensitive to pertussis toxin, suggesting Galphaq coupling of gfMCHR1 in the ERK1/2 pathway as well as a calcium mobilization system. Cyclic AMP assays revealed that gfMCHR2 was efficiently coupled to Galphai/o, while gfMCHR1 was weakly coupled to Galphas. Finally, we investigated the transduction features stimulated by two mammalian MCH analogues. As expected, Compound 15, which is a full agonist of human MCHR1, was a potent gfMCHR1 agonist in multiple signalling pathways. On the other hand, Compound 30, which is a human MCHR1-selective antagonist with negligible agonist potency, unexpectedly acted as a selective agonist of gfMCHR1. These results are the first to demonstrate that gfMCHR1 and gfMCHR2 have quite different signalling properties from human MCHRs. PMID- 21539864 TI - Histidine-rich protein Hpn from Helicobacter pylori forms amyloid-like fibrils in vitro and inhibits the proliferation of gastric epithelial AGS cells. AB - Helicobacter pylori causes various gastric diseases, such as gastritis, peptic ulcerations, gastric cancer and mucosa-associated lymphoid tissue lymphoma. Hpn is a histidine-rich protein abundant in this bacterium and forms oligomers in physiologically relevant conditions. In this present study, Hpn oligomers were found to develop amyloid-like fibrils as confirmed by negative stain transition electron microscopy, thioflavin T and Congo red binding assays. The amyloid-like fibrils of Hpn inhibit the proliferation of gastric epithelial AGS cells through cell cycle arrest in the G2/M phase, which may be closely related to the disruption of mitochondrial bioenergetics as reflected by the significant depletion of intracellular ATP levels and the mitochondrial membrane potential. The collective data presented here shed some light on the pathologic mechanisms of H. pylori infections. PMID- 21539865 TI - The PKB/FOXO switch in aging and cancer. AB - Aging is characterized by the general decline in tissue and body function and the increased susceptibility to age-related pathologies, such as cancer. To maintain optimal tissue and body function, organisms have developed complex mechanisms for tissue homeostasis. Importantly, it is becoming apparent that these same mechanisms when deregulated also result in the development of age-related disease. The build in fail safe mechanisms of homeostasis, which prevent skewing toward disease, themselves contribute to aspects of aging. Thus, longevity is limited by an intrinsic trade-off between optimal tissue function and disease. Consequently, aging and age-related diseases, such as cancer and diabetes are driven by the same genetic determinants. Illustrative in this respect is the insulin/IGF-1 signaling pathway acting through PI3K/PKB and FOXO. Loss of PKB signaling contributes to diabetes, whereas gain of function of PKB drives cancer. Enhanced FOXO activity, at least in model organism contributes to extended lifespan and acts as a tumor suppressive mechanism. Here, we focus on the linkage between PKB and FOXO as a central switch in contributing to tissue homeostasis and age-related diseases in particular cancer. This article is part of a Special Issue entitled: P13K-AKT-FoxO axis in cancer and aging. PMID- 21539866 TI - C/EBPalpha and C/EBPbeta binding proteins modulate hepatocyte apoptosis through iNOS signaling pathway. AB - Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) involve many pathophysiologic conditions. The expression of iNOS is regulated at multiple stages. Presently, the regulatory details of iNOS signaling are still unclear. This study aimed to investigate the regulatory role of C/EBPalpha and C/EBPbeta in iNOS signaling pathway. By employing the techniques such as EMSA, ChIP assay, site-directed mutagenesis, and siRNA silencing, the relationship between iNOS and C/EBPalpha/C/EBPbeta in rat hepatocytes was clarified. iNOS promoter was the direct transcriptional targets of the C/EBPalpha, C/EBPbeta, and NF-kappaB binding proteins. There was the interactive influence between NF-kappaB and C/EBPalpha/C/EBPbeta. The expression of iNOS was modulated by C/EBPalpha/C/EBPbeta transcription factors. Moreover, the iNOS expression mediated glycochenodeoxycholate (GCDC)-induced apoptosis in hepatocytes. C/EBPalpha/C/EBPbeta binding proteins could affect the GCDC-induced apoptosis through iNOS cascade. These findings indicate that C/EBPalpha and C/EBPbeta regulate the iNOS expression, which may further modify cell responses such as apoptosis and cell survival. PMID- 21539867 TI - Insights into the genome of the xanthan-producing phytopathogen Xanthomonas arboricola pv. pruni 109 by comparative genomic hybridization. AB - The phytopathogenic bacterium Xanthomonas arboricola pv. pruni is the causal agent of Prunus Bacterial Spot disease that infects cultivated Prunus species and their hybrids. Furthermore, X. arboricola pv. pruni (Xap) plays a role in biotechnology since it produces xanthan gum, an important biopolymer used mainly in the food, oil, and cosmetics industry. To gain first insights into the genome composition of this pathovar, genomic DNA of X. arboricola pv. pruni strains was compared to the genomes of reference strains X. campestris pv. campestris B100 (Xcc B100) and X. campestris pv. vesicatoria 85-10 (Xcv 85-10) applying microarray-based comparative genomic hybridizations (CGH). The results implied that X. arboricola pv. pruni 109 lacks 6.67% and 5.21% of the genes present in the reference strains Xcc B100 and Xcv 85-10, respectively. Most of the missing genes were found to be organized in clusters and do not belong to the core genome of the two reference strains. Often they encode mobile genetic elements. Furthermore, the absence of gene clusters coding for the lipopolysaccharide (LPS) O-antigens of Xcc B100 and Xcv 85-10 indicates that the structure of the O antigen of X. arboricola pv. pruni 109 differs from that of Xcc B100 and Xcv 85 10. PMID- 21539868 TI - Equine rhinitis A virus-like particle expressing DNA vaccine induces a virus neutralising immune response in mice. AB - Equine rhinitis A virus (ERAV) is a respiratory pathogen of horses. Candidate vaccines to date have been hindered by low expression levels and the induction of non-neutralising antibodies. The immunodominant epitope of ERAV is conformational and is located within the quaternary structure of the capsid. This site should be retained in ERAV virus-like particles (VLPs) to stimulate the induction of neutralising antibodies. The immunogenicity of a plasmid-based DNA vaccine designed to express ERAV VLPs was assessed. The plasmid construct, pcD.P12A.3C, contained the capsid precursor (P1-2A) and the viral protease 3C, under the transcriptional control of a cytomegalovirus (CMV) promoter. Mature viral capsid proteins and VLPs were detected in vitro in transfected COS7 cells. Immunisation of BALB/c mice with pcD.P12A.3C induced virus neutralising antibodies and enhanced the virus neutralising antibody response to purified, UV-inactivated ERAV. This study further supports the use of DNA vaccines to elicit neutralising antibodies to complex antigenic proteins. PMID- 21539869 TI - Identification of the role of RIG-I, MDA-5 and TLR3 in sensing RNA viruses in porcine epithelial cells using lentivirus-driven RNA interference. AB - Pathogen recognition receptors are essential for antiviral host immune responses. These specialized receptors detect conserved viral compounds and induce type I interferons (IFN) and pro-inflammatory cytokines. Here we evaluated the contribution of RIG-I, MDA-5 and TLR3 to the recognition of classical swine fever (CSFV), foot-and-mouth disease virus (FMDV), vesicular stomatitis virus (VSV) and influenza A virus (IAV) to IFN-beta responses in the porcine epithelial cell line PK-15. To this end, we identified porcine gene specific small interfering RNA sequences and employed a lentivirus (LV)-based system to deliver the corresponding short hairpin RNA. With this, gene knockdown cell lines were created and tested with regard to the knockdown levels over time and following IFN-beta stimulation. During several passages of the transduced cells, the expression of both the reporter gene eGFP and the reduced RNA levels of the targeted gene were stable, although the latter was relatively variable. IFN-beta induced IFN-responsive genes such as RIG-I, but the levels of the silenced cell line remained reduced compared to the control cells. Based on virus-induced IFN beta mRNA responses, our results indicate that in PK-15 cells FMDV-detection is solely mediated by MDA-5, whereas VSV and IAV are mainly detected by RIG-I with a minor contribution of MDA-5, and CSFV is sensed by MDA-5, RIG-I and TLR3. PMID- 21539870 TI - Attenuated live vaccine usage affects accurate measures of virus diversity and mutation rates in avian coronavirus infectious bronchitis virus. AB - The full-length genomes of 11 infectious bronchitis virus (IBV) field isolates from three different types of the virus; Massachusetts (Mass), Connecticut (Conn) and California (CAL) isolated over a 41, 25 and 8 year period respectively, were sequenced and analyzed to determine the mutation rates and level of polymorphisms across the genome. Positive selection was not detected and mutation rates ranged from 10(-4) to 10(-6)substitutions/site/year for Mass and Conn IBV types where attenuated live vaccines are routinely used to control the disease. In contrast, for CAL type viruses, for which no vaccine exists, positive selection was detected and mutation rates were 10 fold higher ranging from 10(-2) to 10( 3)substitutions/site/year. Lower levels of genetic diversity among the Mass and Conn viruses as well as sequence similarities with vaccine virus genomes suggest that the origin of the Mass and all but one of the Conn viruses was likely vaccine virus that had been circulating in the field for an unknown but apparently short period of time. The genetic data also identified a recombinant IBV isolate with 7 breakpoints distributed across the entire genome suggesting that viruses within the same serotype can have a high degree of genetic variability outside of the spike gene. These data are important because inaccurate measures of genetic diversity and mutation rates could lead to underestimates of the ability of IBV to change and potentially emerge to cause disease. PMID- 21539871 TI - C-terminal truncation of the transmembrane protein of an attenuated lentiviral vaccine alters its in vitro but not in vivo replication and weakens its potential pathogenicity. AB - Preliminary studies revealed that the gene of the gp45 transmembrane protein (TM) of the attenuated equine infectious anemia virus (EIAV) vaccine strain EIAV(FDDV13) had a high frequency of a premature stop codon at position 261W, which generated a 154-residue truncation at the C-terminus. EIAV(FDDV-TM36), a recombinant virus with the TM truncated at the intracytoplasmic (CT) domain due to the presence of a stop codon, was constructed based on EIAV(FDDV)3-8, which is a proviral derivative of the vaccine. EIAV(FDDV-TM36) had a significantly reduced replication capability compared to EIAV(FDDV)3-8 in equine or donkey monocyte derived macrophages and a decreased ability to induce apoptosis. However, both viruses raised a similar plasma viral load in inoculated horses and did not induce clinical symptoms of EIA. To further compare the in vivo behavior between EIAV(FDDV-TM36) and EIAV(FDDV)3-8, inoculated horses were transiently immunosuppressed with dexamethasone. While three of the four horses inoculated with EIAV(FDDV)3-8 demonstrated significant increases in viral loads after the drug treatment, none of the four horses inoculated with EIAV(FDDV-TM36) showed a statistically increased plasma viral load. Significantly increased neutralizing antibody levels were also observed in the group of horses inoculated with EIAV(FDDV)3-8, but not EIAV(FDDV-TM36), after immunosuppression. Our results indicate that although the CT truncation of TM decreased viral replication in cultivated equine and donkey macrophages, the primary target cell of EIAV, and did not influence the plasma viral load of inoculated hosts, it weakened the potential pathogenicity of the vaccine. The host immunity is presumably responsible for the equal in vivo replication levels of viruses with either the CT-truncated or prototype TM. PMID- 21539872 TI - Novel tocotrienol-entrapping vesicles can eradicate solid tumors after intravenous administration. AB - The therapeutic potential of tocotrienol, a vitamin E extract with anti-cancer properties, is hampered by its failure to specifically reach tumors after intravenous administration. In this work, we demonstrated that novel transferrin bearing, tocopheryl-based multilamellar vesicles entrapping tocotrienol significantly improved tocotrienol uptake by cancer cells overexpressing transferrin receptors. This led to a dramatically improved therapeutic efficacy in vitro, ranging from 17-fold to 72-fold improvement depending on the cell lines, compared to the free drug. In vivo, the intravenous administration of this novel tocotrienol formulation led to complete tumor eradication for 40% of B16 F10 murine melanoma tumors and 20% of A431 human epidermoid carcinoma tumors. Animal survival was improved by more than 20 days compared to controls, for the two tumor models tested. These therapeutic effects, together with the lack of toxicity, potentially make transferrin-bearing vesicles entrapping tocotrienol a highly promising therapeutic system as part as an anti-cancer therapeutic strategy. PMID- 21539873 TI - Effects of cathelicidin and its fragments on three key enzymes of HIV-1. AB - Cathelicidins exhibit anti-HIV activity but it is not known if they reduce the activity of enzymes crucial to the life cycle of the retrovirus. It is shown in this investigation that human cathelicidin LL37 and its fragments LL13-37 and LL17-32 inhibited HIV-1 reverse transcriptase dose-dependently with an IC50 value of 15MUM, 7MUM, and 70MUM, respectively. The three peptides inhibited HIV-1 protease with a weak potency, achieving 20-30% inhibition at 100MUM. The mechanism of inhibition was protein-protein interaction as revealed by surface plasmon resonance. The peptides were devoid of the ability to inhibit translocation of HIV-1 integrase, which has been labeled with green fluorescent protein, into the nucleus. The peptides did not exert toxicity on human peripheral blood mononuclear cells. PMID- 21539874 TI - Suppression of ANP secretion by somatostatin through somatostatin receptor type 2. AB - Somatostatin is a cyclic-14 amino acid peptide which mainly distributed in digestive system and brain. Somatostatin receptor (SSTR) is a G-protein coupled receptor and all five SSTR subtypes are expressed in cardiomyocytes. The aim of this study was to investigate the effect of somatostatin on atrial natriuretic peptide (ANP) secretion and its signaling pathway. Somatostatin (0.01 and 0.1nM) decreased ANP secretion in isolated beating rat atrium in a dose-dependent manner. But atrial contractility and translocation of extracellular fluid were not changed. Somatostatin-induced decrease in ANP secretion was significantly attenuated by the pretreatment with CYN 154806 (SSTR type 2 antagonist; 0.1MUM), but not by BIM 23056 (SSTR type 5 antagonist; 0.1MUM) and urantide (urotensin II receptor antagonist; 0.1MUM). When pretreated with an agonist for SSTR type 2 (Seglitide, 0.1nM) and SSTR type 5 (L 817818, 0.1nM), only Seglitide reduced ANP secretion similar to that of somatostatin. The suppressive effect of somatostatin on ANP secretion was attenuated by the pretreatment with an inhibitor for adenylyl cyclase (MDL-12330A, 5MUM) or protein kinase A (KT 5720, 0.1MUM). In diabetic rat atria, the suppressive effect of somatostatin on ANP secretion and concentration was attenuated. Real time-PCR and western blot shows the decreased level of SSTR type 2 mRNA and protein in diabetic rat atria. These data suggest that somatostatin decreased ANP secretion through SSTR type 2 and an attenuation of suppressive effect of somatostatin on ANP secretion in diabetic rat atria is due to a down-regulation of SSTR type 2. PMID- 21539875 TI - A novel antimicrobial peptide from skin secretions of the earthworm, Pheretima guillelmi (Michaelsen). AB - A novel lumbricin-like antimicrobial peptide named lumbricin-PG was isolated from skin secretions of the earthworm, Pheretima guillelmi (Michaelsen), using a procedure of one step Sephadex G-50 gel filtration and one step C(8) reverse phase high-performance liquid chromatography (RP-HPLC). Its amino acid sequence was determined as FSRYARMRDSRPWSDRKNNYSGPQFTYPPEKAPPEKLIKWNN EGSPIFEMPAEGGHIEP by Edman degradation combined with cDNA cloning and mass spectrometry analysis. The cDNA encoding lumbricin-PG was cloned by cDNA library screening. The predicted protein from the cDNA sequence was composed of 73 amino acid residues including a mature lumbricin-PG and predicted signal peptide. It showed similarity with lumbricin antimicrobial peptide from the earthworm, Lumbricus rubellus by BLAST search. Purified lumbricin-PG exerted potential antimicrobial activities against bacteria and fungi; it showed weak hemolysis activity against human and rabbit red cells. PMID- 21539876 TI - Identification of PSA peptide mimotopes using phage display peptide library. AB - Prostate cancer (PCa) is one of the most common types of cancer in men in the United States and is the second leading cause of cancer related death in men. Clinically, secreted prostate specific antigen (PSA) has gained recognition because of its proteolytic activity being directly linked to PCa cell proliferation leading to disease initiation and progression. Using phage display technology, we identified four distinct cyclical peptides. These peptides apart from differences in their amino acid sequence, elicited minimal cross reactive antibody responses against each other. One of the four peptides analyzed produced an antibody response that recognizes the PSA protein. We demonstrate that the synthetic PSA peptide mimics identified in our study are immunologically active and produce neutralizing activity and this has relevance and utility for prostate cancer disease progression. PMID- 21539877 TI - Post-thymic regulation of CD5 levels in human memory T cells is inversely associated with the strength of responsiveness to interleukin-15. AB - Immunologic memory is a critical feature of the adaptive immune system to fight recurrent infections. However, the mechanisms that shape the composition and function of the human memory T-cell pool remain incompletely understood. We here demonstrate that post-thymic human T-cell differentiation was associated with the downregulation, but not loss, of the inhibitory molecule CD5. The sensitivity of human CD8(+) and CD4(+) memory T cells to interleukin (IL)-15 was inversely associated with the level of CD5 expression. CD5 expression was downregulated by IL-15-mediated signaling in vitro and CD5(lo) memory T cells accumulated in the bone marrow. Persistent antigenic stimulation, as in the case of cytomegalovirus infection and rheumatoid arthritis (RA), was also associated with an increased number of CD5(lo) memory T cells. In conclusion, CD5 may be a useful marker to identify memory T-cell subsets with distinct responsiveness to the homeostatic cytokine IL-15. PMID- 21539878 TI - Differential expression of antimicrobial peptides in active and latent tuberculosis and its relationship with diabetes mellitus. AB - Tuberculosis (TB) is one of the most important infectious diseases, causing 1.8 million deaths annually worldwide. This problem has increased because of the association with human immmunodeficiency virus and diabetes mellitus type 2, mainly in developing countries. In the past few years it has been highlighted the significance of antimicrobial peptides in the immunopathogenesis of TB ex vivo and in experimental models studies. In this study we analyzed the expression of CAMP, DEFA1, DEFB4, and DEFB103A in patients with latent TB and progressive TB with and without comorbidity with diabetes mellitus type 2. Antimicrobial peptide gene expression increased during progressive TB, which could be used as a biomarker for reactivation. By contrast, patients with diabetes mellitus type 2 have lower antimicrobial peptides gene expression, suggesting that the lack of its proper production in these patients contribute to enhance the risk for TB reactivation. PMID- 21539879 TI - A model to evaluate mass vaccination against pneumococcus as a countermeasure against pandemic influenza. AB - A mathematical model has been developed for the purpose of evaluating vaccination against pneumococcus as a countermeasure against pandemic influenza. As the characteristics of a future pandemic cannot be known in advance, three distinct pandemic scenarios were considered, corresponding to a 1918-like pandemic, a 1957/1968-like pandemic and a 2009-like pandemic. Model estimates for each of these pandemic scenarios are presented for two options of vaccination programme; universal vaccination of the entire UK population and vaccination only of those people considered to be at heightened risk of developing influenza complications. We find that the benefits of each option (in terms of estimated number of deaths and hospital admissions avoided and the courses of antibiotics saved) are high in a 1918-like pandemic and very small in a 2009-like pandemic. Given that the decision regarding deployment of the counter measure would occur prior to knowledge of the flu-strain characteristics being available, we also present the weighted average of the outcomes from the three pandemic scenarios. Based on the historical occurrence of pandemics over the last 100 years, the weighted average of outcomes is an estimated 1400 deaths prevented by the universal vaccination option and 400 deaths saved by the targeted vaccination option (at a cost of approximately 400 million and 50 million courses of vaccine respectively). Finally, the longer term implications of using PPV as a countermeasure against pandemic influenza have been considered by estimating the expected number of courses of vaccine bought and the expected number of deaths and hospital admissions prevented over time under each policy. PMID- 21539880 TI - A large observational study to concurrently assess persistence of measles specific B-cell and T-cell immunity in individuals following two doses of MMR vaccine. AB - The measurement of measles-specific neutralizing antibodies, directed against the surface measles virus hemagglutinin and fusion proteins, is considered the gold standard in measles serology. We assessed functional measles-specific neutralizing antibody levels in a racially diverse cohort of 763 young healthy adolescents after receipt of two doses of measles-mumps-rubella vaccine, by the use of an automated plaque reduction microneutralization (PRMN) assay, and evaluated their relevance to protective antibody levels, as well as their associations with demographic and clinical variables. We also concurrently assessed measles-specific IFNgamma Elispot responses and their relation to the observed antibody concentrations. The geometric mean titer for our cohort was 832mIU/mL (95% CIs: 776; 891). Sixty-eight subjects (8.9%) had antibody concentrations of less than the protective threshold of 210mIU/mL (corresponding to PRMN titer of 120; suggesting protection against symptomatic disease), and 177 subjects (23.2%) demonstrated persisting antibody concentrations above 1841mIU/mL (corresponding to PRMN titer of 1052; suggesting total protection against viral infection), 7.4 years after vaccination, in the absence of wild-type virus boosting. The mean measles-specific IFNgamma Elispot response for our cohort was 46 (95% CIs: 43; 49) IFNgamma-positive spots per 200,000 cells with no relation of cellular immunity measures to the observed antibody concentrations. No significant associations between antibody titers and demographic and clinical variables, including gender and race, were observed in our study. In conclusion, in a large observational study of measles immunity, we used an automated high throughput measles virus-specific neutralization assay to measure humoral immunity, and concurrently determined measles-specific cellular immunity to aid the assessment of potential susceptibility to measles in vaccinated populations. PMID- 21539881 TI - Detection of platelet-binding anti-measles and anti-rubella virus IgG antibodies in infants with vaccine-induced thrombocytopenic purpura. AB - A 15-month-old infant presented with thrombocytopenic purpura after sequential administration of measles-rubella combined vaccine, varicella vaccine and mumps vaccine every 4 weeks. Her thrombocytopenia persisted for more than 12 months. Both anti-measles and anti-rubella virus IgG antibodies were detected in the patient's-isolated platelets on day 154 of illness, which were not detected when there was a reduction of the serum IgG antibody titers on days 298 and 373 of illness, respectively.We also detected the isolated platelet-binding anti-measles and anti-rubella virus IgG antibodies in two other pediatric patients. This is the first report demonstrating direct evidence of vaccine-induced thrombocytopenic purpura. PMID- 21539882 TI - Serotype-specific avidity is achieved following a single dose of the 7-valent pneumococcal conjugate vaccine, and is enhanced by 23-valent pneumococcal polysaccharide booster at 12 months. AB - AIM: To evaluate whether the avidity of serotype-specific IgG to pneumococcal serotypes is enhanced by an increased number of doses of the 7-valent pneumococcal conjugate vaccine (PCV) in infancy or by a 12 month 23-valent pneumococcal polysaccharide vaccine (23vPPS) booster, and/or subsequent re exposure to a small dose of pneumococcal polysaccharide antigens (mPPS) at 17 months. METHODS: Fijian infants aged 6 weeks were recruited, stratified by ethnicity and randomized to 8 groups to receive 0, 1, 2, or 3 doses of PCV, with or without 23vPPS at 12 months. All children received mPPS at 17 months of age. Avidity of serotype-specific IgG for PCV serotypes in the first 12 months and for all 23vPPS serotypes thereafter was assessed by EIA after sodium thiocyanate elution. RESULTS: At one month post primary series, the 2 and 3 PCV dose groups demonstrated similar avidity, with the single dose group tending to have lower avidity. However, by age 9 months, the single dose group had similar avidity to the 2 and 3 PCV groups for most serotypes. The 23vPPS booster enhanced affinity maturation for most serotypes and this was most marked in those groups that received a single PCV dose. There was little further increase following the mPPS. CONCLUSIONS: By 9 months of age, similar avidity can be induced following one, 2 or 3 doses of PCV. A 23vPPS booster at 12 months enhanced affinity maturation with an increase in antibody avidity for most serotypes. Subsequent re-challenge with mPPS at 17 months did not further enhance the avidity of serotype-specific response in the 12 month 23vPPS groups. PMID- 21539883 TI - What are the best reference values for a normal serum alanine transaminase activity (ALT)? Impact on the presumed prevalence of drug induced liver injury (DILI). AB - BACKGROUND: In clinical research, the definition of the upper limit of normal (ULN) is rarely detailed. For alanine transaminase (ALT), there are several definitions of ULN-ALT but no recognized global reference. Furthermore the inter laboratory variability of results expressed using ULN-ALT is higher than using the actual value of ULN expressed in IU/L. Regulatory agencies still use ULN-ALT for the definition of drug adverse events such as drug induced liver disease (DILI). METHODS: We applied two extreme definitions of ULN-ALT (26 and 66 IU/L) in two populations with different liver disease risk: 7463 consecutive volunteers representative a low risk population, and 6865 consecutive patients hospitalized in a tertiary referral center. The same assay technique was used for both populations on fresh plasma in the same laboratory. RESULTS: In the low risk population the liver disease estimates ranged from 0% to 1.99% according to ULN ALT definition and gender; prevalence of liver disease as defined by Temple's criteria (3*ULN) decreased significantly with increased ULN-ALT threshold and prevalence of liver disease was lower in females compared to males (all P<0.001). In the high risk population the estimates of liver disease prevalence ranged from 0.78% to 15.85%; disease prevalence using both Temple's corollary and Hy's law criteria (3*ULN-ALT and bilirubin >34 MUmol/L) decreased significantly with increased ULN-ALT threshold and females compared to males. In the low risk population the two major factors associated with ULN variability were gender and BMI. CONCLUSION: Artificial statistical modifications of the procedures chosen for the ULN-ALT definition change dramatically the prevalence of DILI estimates. A consensus in liver disease definitions seems mandatory for DILI studies in order to prevent misleading conclusions. PMID- 21539884 TI - The regulatory use of the Local Lymph Node Assay for the notification of new chemicals in Europe. AB - The regulatory use of the Local Lymph Node Assay (LLNA) for new chemicals registration was monitored by screening the New Chemicals Database (NCD), which was managed by the former European Chemicals Bureau (ECB) at the European Commission Joint Research Centre (JRC). The NCD centralised information for chemicals notified after 1981, where toxicological information has been generated predominantly according to approved test methods. The database was searched to extract notifications for which the information for skin sensitisation labelling was based on results derived with the LLNA. The details of these records were extracted and pooled, and evaluated with regard to the extent of use of the LLNA over time, as well as for analysing the information retrieved on critical aspects of the procedure e.g. strain and amount of animals used, lymph node processing, solvent and doses selected, stimulation indices, and for assessing their level of compliance to the OECD Test Guideline 429. In addition the accuracy of the reduced LLNA when applied to new chemicals was investigated. PMID- 21539885 TI - High molecular weight persimmon tannin ameliorates cognition deficits and attenuates oxidative damage in senescent mice induced by D-galactose. AB - Mice were subcutaneously injected with d-galactose (D-gal, 150 mg/kg per day) for 6 weeks and were administered high molecular weight persimmon condensed tannin (HMWPT) simultaneously. After 6 weeks of treatment, the animal behavior was observed in the open field test and water maze test, and the morphology of hippocampus and skin were checked. Meanwhile, the activities of antioxidant enzymes, the levels of non-enzymatic antioxidants, as well as malondialdehyde (MDA) were evaluated. The results indicated that HMWPT markedly inhibited the d gal induced learning and memory impairment in both open field test and Morris water maze. Biochemical examination revealed that HMWPT significantly increased the decreased activities of superoxide dismutase (SOD), catalase (CAT), elevated the lowered total anti-oxidation capability (T-AOC), glutathione (GSH) and hydroxyproline (Hyp) contents (p<0.01 or p<0.05), and decreased the raised monoamine oxidase (MAO), total cholinesterase (TChE) activities and MDA level (p<0.01) in serum, liver or brain of aging mice induced by d-gal in a dose dependent fashion. Furthermore, HMWPT significantly and (p<0.01) attenuated the d gal induced number decrease, neuronal degeneration and karyopycnosis in cells in the hippocampus and decrease of thickness of skin epidermis and dermis. PMID- 21539886 TI - Selective toxicity of glycyrrhetinic acid against tumorigenic r/m HM-SFME-1 cells is potentially attributed to downregulation of glutathione. AB - Natural products from plants are expected to play significant roles in creating new, safe and improved chemopreventive and therapeutic antitumor agents. Selectivity is also an important issue in cancer prevention and therapy. The present study was designed to extend our previous study on the c-Ha-ras and c-myc induced tumor cell-selective antiproliferative effects of a licorice component, glycyrrhetinic acid (GA). An in silico ligand-receptor docking simulation revealed that GA acts as an 11beta-hydroxysteroid dehydrogenase type 2 inhibitor. GA disrupted the redox balance in tumor cells through upregulation of reactive oxygen species and downregulation of glutathione (GSH). The GA-induced GSH reduction and cytotoxicity were enhanced by an inhibitor of GSH, l-buthionine [S,R]-sulfoximine. N-acetyl-l-cysteine, an antioxidant and precursor of GSH, restored the GA-induced GSH reduction and cytotoxicity in tumor cells. Taken together, these data highlighting the downregulation of GSH by GA and the efficacy of GSH in ameliorating GA-mediated cytotoxicity support the notion that GSH is involved in the selective toxicity of GA toward tumor cells. PMID- 21539887 TI - Hypothalamic but not pituitary or ovarian defects underlie the reproductive abnormalities in Axl/Tyro3 null mice. AB - AXL and TYRO3, members of the TYRO3, AXL and MER (TAM) family of tyrosine kinase receptors, modulate GnRH neuronal cell migration, survival and gene expression. Axl/Tyro3 null mice exhibit a selective loss of GnRH neurons, delayed sexual maturation and irregular estrous cycles. Here we determined whether the defects were due to direct ovarian defects, altered pituitary sensitivity to GnRH and/or an impaired LH surge mechanism. Ovarian histology and markers of folliculogenesis and atresia as well as corpora luteal development and ovarian response to superovulation were not impaired. Axl/Tryo3 null mice exhibited a robust LH response to exogenous GnRH, suggesting no altered pituitary sensitivity. Ovariectomized Axl/Tyro3 null mice, however, demonstrated an impaired ability to mount a steroid-induced LH surge. Loss of GnRH neurons in Axl/Tyro3 null mice impairs the sex hormone-induced gonadotropin surge resulting in estrous cycle abnormalities confirming that TAM family members contribute to normal female reproductive function. PMID- 21539888 TI - Isolation of mouse pancreatic alpha, beta, duct and acinar populations with cell surface markers. AB - Tools permitting the isolation of live pancreatic cell subsets for culture and/or molecular analysis are limited. To address this, we developed a collection of monoclonal antibodies with selective surface labeling of endocrine and exocrine pancreatic cell types. Cell type labeling specificity and cell surface reactivity were validated on mouse pancreatic sections and by gene expression analysis of cells isolated using FACS. Five antibodies which marked populations of particular interest were used to isolate and study viable populations of purified pancreatic ducts, acinar cells, and subsets of acinar cells from whole pancreatic tissue or of alpha or beta cells from isolated mouse islets. Gene expression analysis showed the presence of known endocrine markers in alpha and beta cell populations and revealed that TTR and DPPIV are primarily expressed in alpha cells whereas DGKB and GPM6A have a beta cell specific expression profile. PMID- 21539889 TI - Stimulatory effect of pituitary adenylate-cyclase activating polypeptide (PACAP) and its PACAP type I receptor (PAC1R) on prolactin synthesis in rat pituitary somatolactotroph GH3 cells. AB - In this present study, we investigated the role of pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor, PACAP type I receptor (PAC1R) on prolactin synthesis in pituitary somatolactotroph GH3 cells. PACAP increased prolactin promoter activity up to 1.3 +/- 0.1-fold. This increase, while significant, was less than the increase resulting from thyrotropin-releasing hormone (TRH) stimulation. By transfection of a PAC1R expression vector to the cells, the response to PACAP on prolactin promoter activity was dramatically potentiated to a degree proportional to the amount of PAC1R transfected. In the PAC1R expressing GH3 cells, TRH and PACAP alone increased prolactin promoter up to 3.3 +/- 0.3-fold and 4.9 +/- 0.2-fold, respectively, and combined treatment with TRH and PACAP further increased prolactin promoters up to 6.8 +/- 0.6-fold. PACAP binds both Gs- and Gq-coupled receptors and stimulates adenylate cyclase/cAMP and protein kinase C/extracellular signal-regulated kinase (ERK) signaling pathways. PACAP increased ERK phosphorylation in PAC1R expressing cells to the same degree as TRH. Combined treatment with TRH and PACAP had a synergistic effect on ERK activation. GH3 cells produce both prolactin and growth hormone. Stimulation of GH3 cells with TRH significantly increased the mRNA level of prolactin and attenuated growth hormone mRNA expression. PACAP increased both prolactin and growth hormone mRNA levels, particularly in PAC1R expressing cells. In addition, increasing amount of PAC1R in GH3 cells potentiated the action of TRH on prolactin promoter activity, as well as on ERK phosphorylation. PAC1R was induced by PACAP itself, but not by TRH. Our current study demonstrates that PACAP and its PAC1R, functions as a stimulator of prolactin alone or with TRH in prolactin producing cells. PMID- 21539890 TI - A putative role for endogenous FGF-2 in FGF-1 mediated differentiation of human preadipocytes. AB - The defining characteristic of obesity is increased adipose tissue (AT) mass following chronic positive energy supply. AT mass is determined by adipocyte number and size, which reflect proliferation and differentiation of preadipocytes and hypertrophy of pre-existing adipocytes. The molecular pathways governing AT expansion are incompletely defined. We previously reported that FGF-1 primes proliferating primary human preadipocytes (phPA), thereby increasing adipogenesis. Here we examined whether FGF-1's adipogenic actions were due to modulation of other FGFs. Treatment of phPA with FGF-1 reduced FGF-2 mRNA/protein by 80%. To examine a putative functional role we performed siRNA knockdown studies. Following FGF-2 knockdown preadipocyte proliferation was decreased and expression of adipogenic genes (PPARgamma, G3PDH and adiponectin) was increased at day 1 of differentiation. These results suggest that changes in endogenous FGF 2 levels contribute to FGF-1's early adipogenic effects and highlight the complexity of the paracrine interplay between FGFs within human AT. PMID- 21539891 TI - Post-exercise changes in myostatin and actRIIB expression in obese insulin resistant rats. AB - We evaluated the expression of MSTN and ActRIIB mRNA in muscle and adipose tissue in diet-induced obesity and insulin resistance in rats subjected to exercise. There was no difference in the expression of MSTN between exercised and sedentary high-fat fed rats in muscle after swimming training. The expression of ActRIIB mRNA in muscle was not significantly different among the groups. In BAT, MSTN mRNA expression was higher in exercised high-fat fed group (EHF) compared with sedentary high-fat fed group (SHF). ActRIIB mRNA expression in BAT was higher in EHF compared with SHF. In mesenteric fat, MSTN mRNA was lower in EHF compared with SHF and ActRIIB mRNA was lower in EHF compared with SHF. In conclusion, the results demonstrate that the expression of MSTN and ActRIIB mRNA changes in both adipose tissue and skeletal muscle in diet-induced obese and exercised rats and suggest the participation of MSTN in energy homeostasis. PMID- 21539892 TI - p75NTR suppression in rat bone marrow stromal stem cells significantly reduced their rate of apoptosis during neural differentiation. AB - Most of the transplanted cells within central nervous system (CNS) undergo extensive cell death. Preventing the death of stem cell-derived neuron-like cells within adult CNS would enhance the efficiency of transplantation in clinics. We have employed an interfering RNA (RNAi) approach to elevate the survival rate of neurally differentiated bone marrow stromal stem cells (BMSCs), by means of suppressing p75NTR expression. Our data revealed that stably overexpressing a specific shRNA against p75NTR transcript could effectively reduce the expression of endogenous p75NTR in neurally differentiated BMSCs. As p75NTR can induce neuronal death in target cells, its suppression is followed by a significant reduction of apoptosis in neural-like cells derived from BMSCs. Thus, our data provides a method to increase the survival of stem cells being employed in transplantation within CNS and hence increase the success rate of cell-based therapies in damaged area of brain and spinal cord. PMID- 21539893 TI - In vivo imaging reveals rapid morphological reactions of astrocytes towards focal lesions in an ALS mouse model. AB - Pathophysiology of the motoneuron disease amyotrophic lateral sclerosis (ALS) is non-cell-autonomous. In mouse models of familiar ALS, neurotoxicity is derived not only from mutant motor neurons but also from mutant neighbouring glial cells. In vivo imaging by two-photon laser-scanning microscopy was used to study rapid morphological reactions of astroglial cells towards laser-induced axonal transection in ALS-linked transgenic SOD1(G93A) mice. In the affected lateral spinal cord, mutated astroglial cells extended branches towards injured axons within a time frame of minutes to hours post lesion while in control animals astrocytes lack any rapid morphological alteration within the studied time frame. This suggests that astrocytes partially contribute to the rapid response of non neuronal cells to acute axonal lesions in ALS mice. PMID- 21539894 TI - The effect of heliox treatment in a rat model of focal transient cerebral ischemia. AB - Manipulation of inhaled gases during ischemia/reperfusion is a potential novel therapy for acute stroke. We previously found that treatment with a mixture of 70%/30% helium/oxygen (heliox) or 100% oxygen protects the brain against acute focal ischemia-reperfusion injury. This study evaluates the potential neuro protective effects of delayed heliox treatment and its dose response effects in a rat transient focal cerebral ischemia model. Adult male rats were subjected to 2 h middle cerebral artery occlusion and then assigned to 1 of 4 inhaled gas exposure groups: I: 70%/30% nitrogen/oxygen (control); II: 70%/30% helium/oxygen administered immediately after occlusion; III: 70%/30% helium/oxygen administered after a 30-60 min delay; or, IV: 40%/30%/30% nitrogen/helium/oxygen administered immediately after occlusion. Outcome measurements included infarct size and neurological deficit score. Mean infarct sizes from groups I to IV were 228, 35, 109, and 124 mm3 respectively (p=0.012). Only group II had significantly smaller infarct size compared to the control group (p=0.008). In addition, only Group II had a significantly lower neurological deficit score at 24h post ischemia when compared to the control group (p<0.001). Since heliox reduced infarct size and improved neurological deficit scores if initiated immediately after onset of ischemia, it may be a useful adjuvant to other stroke therapies. PMID- 21539895 TI - Differential regulation of AMPA receptor GluA1 phosphorylation at serine 831 and 845 associated with activation of NMDA receptor subpopulations. AB - AMPA receptors and NMDA receptors are the main subtypes of ionotropic glutamate receptors in the vertebrate central nervous system. Accumulating evidence demonstrates that two serine sites, S831 and S845, on the AMPA receptor GluA1 subunit, are phosphorylation-regulated and profoundly involved in NMDA receptor dependent synaptic plasticity. On the other hand, recent studies have revealed distinct functional consequences of activating synaptic or extrasynaptic NMDA receptors, or of activating GluN2A- or GluN2B-containing NMDA receptors. Therefore, it is essential to determine how phosphorylation of the GluA1 at S831 and S845 is regulated by NMDA receptor subpopulations. In this study, we demonstrated transiently increased phosphorylation of GluA1 at S831 and persistently decreased phosphorylation of GluA1 at S845 by bath application of NMDA to hippocampal slices from rats. Interestingly, we also found a differential regulation of phosphorylation of GluA1 at S831 and S845 by activation of NMDA receptor subpopulations: the synaptic and/or the GluN2A-containing NMDA receptors were more likely to mediate up-regulation of GluA1 phosphorylation at S831 and down-regulation of GluA1 phosphorylation at S845, while the extrasynaptic NMDA receptors down-regulated GluA1 phosphorylation at S831. Taken together, our results suggest the NMDA receptor subpopulations differentially regulate GluA1 phosphorylation, which may contribute to NMDA receptor-dependent synaptic plasticity. PMID- 21539896 TI - Therapeutic effect of co-transplantation of neuregulin-1-transfected Schwann cells and bone marrow stromal cells on spinal cord hemisection syndrome. AB - The aim of this present study is to evaluate the therapeutic effect of co transplantation of neuregulin-1-transfected Schwann cells (SCs) and bone marrow stromal cells (BMSCs) on a rat model of spinal cord hemi-section injuries (Brown Sequard syndrome), which is relevant to human clinical spinal cord injury. Both in vivo and in vitro data we received demonstrated that co-transplantation BMSCs with NRG1-transfected SCs reduced the size of cystic cavities, promoted axonal regeneration and hind limb functional recovery in comparison with SCs or BMSCs transplantation alone or together, and this treatment could provide important insights into potential therapies of spinal cord hemi-section injuries. PMID- 21539897 TI - Cytotoxicity and inhibition of platelet aggregation caused by an l-amino acid oxidase from Bothrops leucurus venom. AB - BACKGROUND: Multifunctional l-amino acid oxidases (LAAOs) occur widely in snake venoms. METHODS: The l-AAO from Bothrops leucurus (Bl-LAAO) venom was purified using a combination of molecular exclusion and ion-exchange chromatographies. We report some biochemical features of Bl-LAAO associated with its effect on platelet function and its cytotoxicity. RESULTS: Bl-LAAO is a 60kDa monomeric glycoprotein. Its N-terminal sequence shows high homology to other members of the snake-venom LAAO family. Bl-LAAO catalyzes oxidative deamination of l-amino acids with the generation of H2O2. The best substrates were: l-Met, l-Norleu, l-Leu, l Phe and l-Trp. The effects of snake venom LAAOs in hemostasis, especially their action on platelet function remain largely unknown. Bl-LAAO dose-dependently inhibited platelet aggregation of both human PRP and washed platelets. Moreover, the purified enzyme exhibited a killing effect in vitro against Leishmania sp., promastigotes, with a very low EC(50) of 0.07MUM. Furthermore, the cytotoxicity of Bl-LAAO was observed in the stomach cancer MKN-45, adeno carcinoma HUTU, colorectal RKO and human fibroblast LL-24 cell lines. The enzyme released enough H2O2 in culture medium to induce apoptosis in cells in a dose- and time-dependent manner. The biological effects were inhibited by catalase. CONCLUSION: Bl-LAAO, a major component of B. leucurus venom, is a cytotoxin acting primarily via the generation of high amounts of H2O2 which kill the cells. GENERAL SIGNIFICANCE: These results allow us to consider the use of LAAOs as anticancer agents, as tools in biochemical studies to investigate cellular processes, and to obtain a better understanding of the envenomation mechanism. PMID- 21539898 TI - Long-term potentiation of synaptic response and intrinsic excitability in neurons of the rat medial vestibular nuclei. AB - Using intracellular recordings, we investigated the effects of high frequency stimulation (HFS) of the primary vestibular afferents on the evoked excitatory postsynaptic potential (EPSP) and intrinsic excitability (IE) of type-A and type B neurons of the medial vestibular nucleus (MVN), in male rat brainstem slices. HFS induces long-term potentiation (LTP) of both EPSP and IE, which may occur in combination or separately. Synaptic LTP is characterized by an increase in the amplitude, slope and decay time constant of EPSP and IE-LTP through enhancements of spontaneous and evoked neuron firing and of input resistance (Rin). Moreover, IE-LTP is associated with a decrease in action potential afterhyperpolarization (AHP) amplitude and an increase in interspike slope steepness (ISS). The more frequent effects of HFS are EPSP-LTP in type-B neurons and IE-LTP in type-A neurons. In addition, the development of EPSP-LTP is fast in type-B neurons but slow in type-A, whereas IE-LTP develops slowly in both types. We have demonstrated that activation of N-methyl-d aspartate receptors (NMDARs) is only required for EPSP-LTP induction, whereas metabotropic glutamate receptors type-1 (mGluR1) are necessary for IE-LTP induction as well as the full development and maintenance of EPSP-LTP. Taken together, these findings demonstrate that brief and intense activation of vestibular afferent input to the MVN neurons may provoke synaptic LTP and/or IE-LTP that, induced in combination or separately, may assure the different selectivity of the MVN neuron response enhancement to the afferent signals. PMID- 21539899 TI - Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A. AB - Botulinum toxin A (BTX-A) is approved for treatment of different cholinergic hyperactivity disorders, and, recently, migraine headache. Although suggested to act only locally, novel observations demonstrated bilateral reduction of pain after unilateral toxin injection, and proposed retrograde axonal transport, presumably in sensory neurons. However, up to now, axonal transport of BTX-A from periphery to CNS was identified only in motoneurons, but with unknown significance. We assessed the effects of low doses of BTX-A injected into the rat whisker pad (3.5 U/kg) or into the sensory trigeminal ganglion (1 U/kg) on formalin-induced facial pain. Axonal transport was prevented by colchicine injection into the trigeminal ganglion (5 mM, 2 MUl). To find the possible site of action of axonally transported BTX-A, we employed immunohistochemical labeling of BTX-A-truncated synaptosomal-associated protein 25 (SNAP-25) in medullary dorsal horn of trigeminal nucleus caudalis after toxin injection into the whisker pad. Both peripheral and intraganglionic BTX-A reduce phase II of formalin induced pain. Antinociceptive effect of BTX-A was prevented completely by colchicine. BTX-A-truncated SNAP-25 in medullary dorsal horn (spinal trigeminal nucleus) was evident 3 days following the peripheral treatment, even with low dose applied (3.5 U/kg). Presented data provide the first evidence that axonal transport of BTX-A, obligatory for its antinociceptive effects, occurs via sensory neurons and is directed to sensory nociceptive nuclei in the CNS. PMID- 21539900 TI - Hypothalamic cocaine- and amphetamine-regulated transcript and corticotrophin releasing factor neurons are stimulated by extracellular volume and osmotic changes. AB - Several studies suggest that hypothalamic cocaine- and amphetamine-regulated transcript (CART) may interact with the hypothalamic-pituitary-adrenal (HPA) axis in the control of neuroendocrine function and may also participate in cardiovascular regulation. Therefore, this study aimed to evaluate, in experimental models of isotonic (I-EVE) and hypertonic (H-EVE) extracellular volume expansion and water deprivation (WD), the activation of CART- and corticotrophin releasing factor (CRF)-immunoreactive neurons, as well as the relative expression of CART and CRF mRNAs in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. Both H-EVE (0.30M NaCl, 2mL/100g of body weight, in 1 minute) and 24 hours of WD significantly increased plasma sodium concentrations, producing, respectively, either an increase or a decrease in extracellular volume. I-EVE (0.15M NaCl, 2mL/100g of body weight, in 1 minute) evoked a significant increase in the circulating volume accompanied by unaltered plasma concentrations of sodium. CART-expressing neurons of both magnocellular and parvocellular hypothalamic divisions were activated to produce Fos in response to H-EVE but not in response to I-EVE. Furthermore, increased expression of CART mRNA was found in the PVN of H-EVE but not I-EVE rats. These data show for the first time that EVE not only activates hypothalamic CRF neurons but also increases CRF mRNA expression in the PVN. In contrast, WD increases the number of CART-immunoreactive neurons activated to produce Fos in the PVN and SON but does not change the number of neurons double labeled for Fos and CRF or expression of CRF mRNA in the PVN. These findings provided new insights into the participation of CART in diverse processes within the PVN and SON, including its possible involvement in activation of the HPA axis and cardiovascular regulation in response to changes in extracellular volume and osmolality. PMID- 21539901 TI - Gap junction blockade eliminates supralinear summation of fast (> 200 Hz) oscillatory components during sensory integration in the rat barrel cortex. AB - The vibrissa-barrel system of rodents has become one of the dominant models for studying sensory information processing. Fast oscillations (>200 Hz) have been shown to play an important role in cortical integration of inputs from several whiskers. The mechanism subserving such integration remains, however, unknown. To address this issue, we examined the influence of the gap junction blocker (carbenoxolone, CBX) topically applied on the cortical surface on the high frequency component evoked by multiple-whisker stimulation. The magnitude of the fast oscillatory response to simultaneous stimulation of three whiskers was shown to be higher compared to its linear prediction (defined as the sum of corresponding single whisker responses). Application of CBX eliminated this supra linear enhancement of fast oscillations. These results indicate that gap junctions are involved in the synchronization of cortical high frequency oscillations and integration of multiple whisker responses. PMID- 21539902 TI - Tandem termination signal in plant mRNAs. AB - It was proposed that if some mRNA characteristics resulted in a low efficiency of termination signal, an additional closely located stop codon (tandem stop codons) could be used to prevent the harmful readthrough. However, the role of tandem terminators in higher eukaryotes was not verified and remains hypothetical. In this work the sequence features of Arabidopsis thaliana and Oryza sativa mRNAs were analyzed. It was found that plant mRNAs with UGA terminator were characterized by a higher frequency of nonsense codons in the first triplet position of 3'-UTR that could result from a weak natural selection for "reserve" stop signal. Interestingly, the presence of tandem stop codons positively correlated with a specific amino acid composition in the C-terminal position of the encoded proteins. In particular, C-terminal glycine positively correlated with significantly higher frequencies of reserve terminators at the beginning positions of 3'-UTR in UGA-containing mRNAs. This finding coincides with some earlier observations concerning the role of glycine and its codons in inefficient termination of translation and recoding (e.g., 2A oligopeptide). PMID- 21539903 TI - Genomics and personalized medicine. AB - The role of genomics in personalized medicine continues to undergo profound changes, in step with dramatic technological advances. Ability to sequence the entire human genome with relative ease raises expectations that we can use an individual's complete genomic blueprint to understand disease risk and predicting therapy outcomes, thereby, optimizing drug therapy. Yet, doubts persist as to what extent genetic/genomic factors influence disease and treatment outcomes or whether robust predictive biomarker tests can be developed. Encompassing more than just DNA sequences, the definition of genomics now often is taken to include transcriptomics, proteomics, metabolomics, and epigenomics, with integration of genomic and environmental factors, in an area referred to systems biology. While we can learn much about a cell's innermost workings, summation of these diverse areas is far from enabling the prediction of therapeutic outcomes. Typically, only a handful of specific biomarkers, genetic or otherwise, are 'actionable', i.e., they can be used to guide therapy. I will focus on pharmacogenetic biomarkers, highlighting current successes but also the main challenges that remain in optimizing individualized therapy. PMID- 21539904 TI - N-terminal specificity of PEGylation of human bone morphogenetic protein-2 at acidic pH. AB - Site-specific PEGylation offers the possibility to modify a therapeutic protein without interfering with its biological activity. Previously, a preferential N terminal PEGylation has been reported for several proteins when the reaction was performed at acidic pH. In the present study it was explored if acidic pH favors N-terminal PEGylation of bone morphogenetic protein-2 (BMP-2). PEGylation by poly(ethylene glycol) aldehyde (PEG-AL) or poly(ethylene glycol) carboxymethyl succinimidyl ester (PEG-NHS) was performed at moderate acidic pH of 4. Comparing with PEG-NHS, PEG-AL converted more BMP-2 mainly to mono- or di-PEGylated derivatives at much less molar excess and shorter duration. Analysis of Tryptic fragments of the PEGylated derivatives indicated a partial N-terminal PEGylation specificity. PEG-AL exhibited higher specificity than PEG-NHS. UV spectrometry proved that PEGylation improved the solubility of BMP-2 in PBS. Surface plasmon resonance showed that PEGylation decreased the binding of BMP-2 proteins to a type II receptor. Remarkably, mono-PEGylated BMP-2 with PEG-AL showed higher cellular bioactivity than unmodified protein. Higher N-terminal PEGylation specificity correlates with higher receptor binding affinity and cellular activity. In summary, PEGylation of BMP-2 by PEG-AL and PEG-NHS at acidic pH exhibits a partial N-terminal specificity which however might be sufficient for an efficient site-specific PEGylation process. PMID- 21539905 TI - Evaluation of sugammadex self-association. AB - Sugammadex, a thiolated gammaCD derivative used as an antagonist of steroidal blockers, was studied with regard to its tendency to self-associate in aqueous solution. Three independent methods - permeation through semi-permeable cellophane membranes, dynamic light scattering, and sedimentation equilibrium analytical ultracentrifugation - were used for this purpose. The results were in agreement with each other and showed no evidence of self-association in a wide sugammadex concentration range from 0.25 to 100mg/ml. PMID- 21539906 TI - Digestion of extracellular DNA is required for giant colony formation of Staphylococcus aureus. AB - Staphylococcus aureus spreads on soft agar surfaces and forms giant colonies. Here, we examined the inhibitory role of extracellular DNA on the colony spreading activity. The double-deletion mutation of nuc1 and nuc2, which encode secretory nucleases, increased extracellular DNA and showed a decreased ability to form giant colonies. The addition of DNase I or micrococcal nuclease to the soft agar restored the ability of the nuc1-nuc2 double mutant to form giant colonies. In addition, the promoter activities of nuc1 and nuc2 in the wild-type strain were elevated in the peripheral region of the giant colony. These findings suggest that the digestion of extracellular DNA by secretory nucleases is required for the colony spreading activity of S. aureus. PMID- 21539907 TI - Diverse effects of Porphyromonas gingivalis on human osteoclast formation. AB - Porphyromonas gingivalis is associated with periodontitis, a chronic inflammatory disease of the tooth-supporting tissues. A major clinical symptom is alveolar bone loss due to excessive resorption by osteoclasts. P. gingivalis may influence osteoclast formation in diverse ways; by interacting directly with osteoclast precursors that likely originate from peripheral blood, or indirectly by activating gingival fibroblasts, cells that can support osteoclast formation. In the present study we investigated these possibilities. Conditioned medium from viable or dead P. gingivalis, or from gingival fibroblasts challenged with viable or dead P. gingivalis were added to human mononuclear osteoclast precursors. After 21 days of culture the number of multinucleated (>=3 nuclei) tartrate resistant acid phosphatase (TRACP)-positive cells was determined as a measure for osteoclast formation. Conditioned medium from viable P. gingivalis, and from fibroblasts with viable P. gingivalis stimulated osteoclast formation (1.6-fold increase p < 0.05). Conditioned medium from dead bacteria had no effect on osteoclast formation, whereas conditioned medium from fibroblasts with dead bacteria stimulated formation (1.4-fold increase, p < 0.05). Inhibition of P. gingivalis LPS activity by Polymyxin B reduced the stimulatory effect of conditioned medium. Interestingly, when RANKL and M-CSF were added to cultures, conditioned media inhibited osteoclast formation (0.6-0.7-fold decrease, p < 0.05). Our results indicate that P. gingivalis influences osteoclast formation in vitro in different ways. Directly, by bacterial factors, likely LPS, or indirectly, by cytokines produced by gingival fibroblasts in response to P. gingivalis. Depending on the presence of RANKL and M-CSF, the effect of P. gingivalis is either stimulatory or inhibitory. PMID- 21539908 TI - Inhibition of cell proliferation, invasion and migration by ursolic acid in human lung cancer cell lines. AB - Ursolic acid (UA) is a pentacyclic triterpene naturally occurring in many plant foods. Apoptotic, anti-invasive and anti-migratory effects of UA at 2, 4, 8, or 16 MUmol/L in human non-small cell lung cancer A549, H3255 and Calu-6 cell lines were examined. The impact of this compound upon associated biomarkers such as vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase (MMP) was also evaluated. UA treatments concentration-dependently decreased cell viability, and lowered Na(+)-K(+)-ATPase activity (P<0.05). This compound at 4-16 MUmol/L concentration-dependently increased DNA fragmentation, and reduced VEGF and transforming growth factor beta1 levels in test cancer cells (P<0.05). UA concentration-dependently suppressed ICAM-1 expression (P<0.05). This compound significantly declined fibronectin expression (P<0.05), but concentration-dependent effect was shown in H3255 cells only (P<0.05). UA treatments significantly suppressed the expression of MMP-9 and MMP-2 (P<0.05), and inhibited protein kinase C activity in test cell lines (P<0.05). UA treatments also concentration-dependently reduced cell invasion (P<0.05); however, this compound at 4-16 MUmol/L significantly decreased cell migration (P<0.05), and concentration-dependent effect was shown in A549 and Calu-6 cells (P<0.05). These findings suggested that this triterpene was a potent anti-lung cancer agent, and it might be able to retard invasion and metastasis of lung cancer cells. PMID- 21539909 TI - Sleep and circadian rhythm regulate circulating complement factors and immunoregulatory properties of C5a. AB - The sleep-wake cycle is characterized by complex interactions among the central nervous, the endocrine and the immune systems. Continuous 24-h wakefulness prevents sleep-associated hormone regulation resulting in impaired pro inflammatory cytokine production. Importantly, cytokines and hormones also modulate the complement system, which in turn regulates several adaptive immune responses. However, it is unknown whether sleep affects the activation and the immunoregulatory properties of the complement system. Here, we determined whether the 24-h sleep-wake cycle has an impact on: (i) the levels of circulating complement factors; and (ii) TLR4-mediated IL-12 production from human IFN-gamma primed monocytes in the presence or absence of C5a receptor signaling. For this purpose, we analyzed the blood and blood-derived monocytes of 13 healthy donors during a regular sleep-wake cycle in comparison to 24 h of continuous wakefulness. We found decreased plasma levels of C3 and C4 during nighttime hours that were not affected by sleep. In contrast, sleep was associated with increased complement activation as reflected by elevated C3a plasma levels during nighttime sleep. Sleep deprivation prevented such activation. At the cellular level, C5a negatively regulated TLR4-mediated IL-12p40 and p70 production from human monocytes. Importantly, this regulatory effect of C5a on IL-12p70 production was effective only during daytime hours. Thus, similar to hormones, some complement factors and immunoregulatory properties of C5a are influenced by sleep and the circadian rhythm. Our findings that continuous wakefulness has a negative impact on complement activation may provide a rationale for the immunosupportive functions of sleep. PMID- 21539910 TI - Abnormal peripubertal development of the rat mammary gland following exposure in utero and during lactation to a mixture of genistein and the food contaminant vinclozolin. AB - The impact of early exposure to endocrine disruptor mixtures on mammary gland development is poorly known. Here, we identify the effects of a conception to weaning exposure of rats to the phytoestrogen genistein (G) and/or the antiandrogen vinclozolin (V) at 1mg/kg-d, alone or in association. Using several approaches, we found that G- and GV-exposed rats displayed significantly greater epithelial branching and proliferation, wider terminal end buds than controls at PND35, as well as ductal hyperplasia and periductal fibrosis. Focal branching defects were present in V-exposed rats. An increased ER and AR expression was observed in G- and GV- as compared to V-exposed rats at PND35. Surprisingly, a significant number of GV- and to a lesser extent, V-exposed animals displayed abnormal hyperplasic alveolar structures at PND50. Thus, gestational and lactational exposure to low doses of genistein plus vinclozolin may seriously affect peripubertal development of the rat mammary gland. PMID- 21539911 TI - Peroxiredoxin 2 in the nucleus and cytoplasm distinctly regulates androgen receptor activity in prostate cancer cells. AB - Currently, few therapies are effective against castration-resistant prostate cancer. Increased activation of the androgen/androgen receptor (AR) signaling pathway is thought to promote castration-resistant prostate cancer. Herein, we report that peroxiredoxin (Prx) gene expression in castration-resistant prostate cancer and hydrogen peroxide-resistant cells was upregulated. Prx2 was overexpressed in castration-resistant prostate cancer at the mRNA and protein levels and was localized to the nucleus and cytoplasm. Overexpression of Prx2 increased AR transactivation, whereas Prx2 overexpression in the nucleus suppressed AR transactivation. These effects of Prx2 on AR activity were abolished by the introduction of function-disrupting mutations into Cys51 and Cys172. Silencing Prx2 reduced the expression of androgen-regulated genes and suppressed the growth of AR-expressing prostate cancer cells by inducing cell cycle arrest at the G1 phase. Furthermore, Prx2 knockdown also suppressed cell growth in castration-resistant prostate cancer cells. These findings indicate that Prx2 is involved in the proliferation of AR-expressing prostate cancer cells by modulating AR activity. Designing therapeutics targeting Prx2 may offer a novel strategy for developing treatments for prostate cancer, including castration-resistant prostate cancer, which is dependent on AR signaling. PMID- 21539912 TI - MOB control: reviewing a conserved family of kinase regulators. AB - The family of Mps One binder (MOB) co-activator proteins is highly conserved from yeast to man. At least two different MOB proteins have been identified in every eukaryote analysed to date. Initially, yeast genetics revealed essential roles for Mob1p and Mob2p in the regulation of mitotic exit and cell morphogenesis. Studies in flies then showed that dMOB1/MATS is a core component of Hippo signalling. Loss of dMOB1 resulted in increased cell proliferation and decreased cell death, suggesting that MOB1 acts as tumour suppressor protein. Recent work focused primarily on mammalian cells has shown how hMOB1 can regulate NDR/LATS kinases, a function that can to be counteracted by hMOB2. Here we summarise and discuss our current knowledge of this emerging protein family, with emphasis on subcellular localisation, protein-protein interactions and biological functions in apoptosis, mitosis, morphogenesis, cell proliferation and centrosome duplication. PMID- 21539913 TI - Scarless skin wound healing in FOXN1 deficient (nude) mice is associated with distinctive matrix metalloproteinase expression. AB - Similar to mammalian fetuses FOXN1 deficient (nude) mice are able to restore the structure and integrity of injured skin in a scarless healing process by mechanisms independent of the genetic background. Matrix metalloproteinases (MMPs) are required for regular skin wound healing and the distinctive pattern of their expression has been implicated to promote scarless healing. In this study, we analyzed the temporal and spatial expression patterns of these molecules during the incisional skin wounds in adult nude mice. Macroscopic and histological analyses of skin wounds revealed an accelerated wound healing process, minimal granulation tissue formation and markedly diminished scarring in nude mice. Quantitative RT-PCR (Mmp-2, -3, -8, -9, -10, -12, -13, -14 and Timp-1, -2, -3), Western blots (MMP-13) and gelatin zymography (MMP-9) revealed that MMP 9 and MMP-13 showed a unique, bimodal pattern of up-regulation during the early and late phases of wound healing in nude mice. Immunohistochemically MMP-9 and MMP-13 were generally detected in epidermis during the early phase and in dermis during the late (remodeling) phase. Consistent with these in vivo observations, dermal fibroblasts cultured from nude mice expressed higher levels of types I and III collagen, MMP-9 and MMP-13 mRNA levels and higher MMP enzyme activity than wild type controls. Collectively, these finding suggest that the bimodal pattern of MMP-9 and MMP-13 expression during skin repair process in nude mice could be a major component of their ability for scarless healing. PMID- 21539914 TI - Divergent upstream osteogenic events contribute to the differential modulation of MG63 cell osteoblast differentiation by MMP-1 (collagenase-1) and MMP-13 (collagenase-3). AB - Previously we showed that MMP-1 (collagenase-1) and MMP-13 (collagenase-3) differentially regulate the expression of osteoblastic markers in a heterogenous population of primary human periodontal ligament cells. The mechanisms for these differential responses are not known, but may result from divergence in regulation of early osteogenic transcription factors. The purpose of this study was to elucidate where in the hierarchy of osteoblast-specific transcription factors and markers the differences in MMP-1- and -13-mediated regulation of osteoblastic differentiation arise. We found that the overexpression of MMP-1 resulted in significant decreases in BMP-2, Dlx5, AP, OP and BSP and increases in TGF-beta1 and MSX2. In contrast, MMP-13 overexpression resulted in significant decreases in Runx2, OP and BSP, and increases in TGF-beta1, MSX2 and OC. The knockdown of MMP-1 caused significant increases in all osteoblastic markers. MMP 13 knockdown produced significant increases only in TGF-beta1, MSX2 and Osx, but decreases in Runx2 and OC. Suppression of both MMPs together resulted in significant increases of all osteoblastic markers except Runx2. MMP-1 had a more robust and generalized effect in regulating osteoblast transcription factors and markers than MMP-13. Finally, of the markers and transcription factors assayed, Runx2 is the most early stage transcription factor induced by suppression of MMP 1, while Osx and MSX2 are the most early stage transcription factors regulated by MMP-13. These data show that MMP-1's and -13's differential regulation of osteoblastic markers in MG63 cells likely results from their modulation of divergent signaling pathways involved in osteoblastic differentiation. PMID- 21539915 TI - Matrilin-4 is processed by ADAMTS-5 in late Golgi vesicles present in growth plate chondrocytes of defined differentiation state. AB - The two aggrecanases ADAMTS-4 and ADAMTS-5 have been shown to not only play roles in the breakdown of cartilage extracellular matrix in osteoarthritis, but also mediate processing of matrilins in the secretory pathway. The matrilins are adaptor proteins with a function in connecting fibrillar and network-like components in the cartilage extracellular matrix. Cleavage resulting in processed matrilins with fewer ligand-binding subunits could make these less efficient in providing matrix cohesion. In this study, the processing and degradation of matrilin-4 during cartilage remodeling in the growth plate of the developing mouse long bones were studied in greater detail. We show that ADAMTS-5 and a matrilin-4 neoepitope, revealed upon ADAMTS cleavage, colocalize in prehypertrophic/hypertrophic chondrocytes while they are not detected in proliferating chondrocytes of the growth plate. ADAMTS-5 and the cleaved matrilin 4 are preferentially detected in vesicles derived from the Golgi apparatus. The matrilin-4 neoepitope was not observed in the growth plate of ADAMTS-5 deficient mice. We propose that in the growth plate ADAMTS-5, and not ADAMTS-4, has a physiological function in the intracellular processing of matrilins and potentially of other extracellular matrix proteins. PMID- 21539916 TI - In vitro inhibition of human and rat platelets by NO donors, nitrosoglutathione, sodium nitroprusside and SIN-1, through activation of cGMP-independent pathways. AB - Three different NO donors, S-nitrosoglutathione (GSNO), sodium nitroprusside (SNP) and 3-morpholino-sydnonimine hydrochloride (SIN-1) were used in order to investigate mechanisms of platelet inhibition through cGMP-dependent and independent pathways both in human and rat. To this purpose, we also evaluated to what extent cGMP-independent pathways were related with the entity of NO release from each drug. SNP, GSNO and SIN-1 (100 MUM) effects on platelet aggregation, in the presence or absence of a soluble guanylate cyclase inhibitor (ODQ), on fibrinogen receptor (alpha(IIb)beta(3)) binding to specific antibody (PAC-1), and on the entity of NO release from NO donors in human and rat platelet rich plasma (PRP) were measured. Inhibition of platelet aggregation (induced by ADP) resulted to be greater in human than in rat. GSNO was the most powerful inhibitor (IC(50) values, MUM): (a) in human, GSNO=0.52+/-0.09, SNP=2.83 +/- 0.53, SIN-1=2.98 +/- 1.06; (b) in rat, GSNO = 28.4 +/- 6.9, SNP = 265 +/- 73, SIN-1=108 +/- 85. GSNO action in both species was mediated by cGMP-independent mechanisms and characterized by the highest NO release in PRP. SIN-1 and SNP displayed mixed mechanisms of inhibition of platelet aggregation (cGMP-dependent and independent), except for SIN-1 in rat (cGMP-dependent), and respectively lower or nearly absent NO delivery. Conversely, all NO-donors prevalently inhibited PAC-1 binding to alpha(IIb)beta(3) through cGMP-dependent pathways. A modest relationship between NO release from NO donors and cGMP-independent responses was found. Interestingly, the species difference in NO release from GSNO and inhibition by cGMP-independent mechanism was respectively attributed to S nitrosylation of non-essential and essential protein SH groups. PMID- 21539917 TI - Membrane trafficking events underlying axon repair, growth, and regeneration. AB - Two central challenges for the field of neurobiology are to understand how axons grow and make proper synaptic connections under normal conditions and how they repair their membranes and mount regenerative responses after injury. At the most reductionist level, the first step toward addressing these challenges is to delineate the cellular and molecular processes by which an axon extends from its cell body. Underlying axon extension are questions of appropriate timing and mechanisms that establish or maintain the axon's polarity, initiate growth cone formation, and promote axon outgrowth and synapse formation. After injury, the problem is even more complicated because the neuron must also repair its damaged membrane, redistribute or manufacture what it needs in order to survive, and grow and form new synapses within a more mature, complex environment. While other reviews have focused extensively on the signaling events and cytoskeletal rearrangements that support axon outgrowth and regeneration, we focus this review instead on the underlying membrane trafficking events underlying these processes. Though the mechanisms are still under active investigation, the key roles played by membrane trafficking events during axon repair, growth, and regeneration have been elucidated through elegant comparative studies in both invertebrate and vertebrate organisms. Taken together, a model emerges indicating that the critical requirements for ensuring proper membrane sealing and axon extension include iterative bouts of SNARE mediated exocytosis, endocytosis, and functional links between vesicles and the actin cytoskeleton, similar to the mechanisms utilized during synaptic transmission. This article is part of a Special Issue entitled 'Neuronal Function'. PMID- 21539918 TI - A simplified polyethylenimine-mediated transfection process for large-scale and high-throughput applications. AB - Transient gene expression in mammalian cells is a valuable alternative to stable cell lines for the rapid production of large amounts of recombinant proteins. While the establishment of stable cell lines takes 2-6 months, milligram amounts of protein can be obtained within a week following transfection. The polycation polyethylenimine (PEI) is one of the most utilized reagents for small- to large scale transfections as it is simple to use and, when combined with optimized expression vectors and cell lines, provides high transfection efficiency and titers. As with most transfection reagents, PEI-mediated transfection involves the formation of nanoparticles (polyplexes) which are obtained by its mixing with plasmid DNA. A short incubation period that allows polyplexes to reach their optimal size is performed prior to their addition to the culture. As the quality of polyplexes directly impacts transfection efficiency and productivity, their formation complicates scalability and automation of the process, especially when performed in large-scale bioreactors or small-scale high-throughput formats. To avoid variations in transfection efficiency and productivity that arise from polyplexes formation step, we have optimized the conditions for their creation directly in the culture by the consecutive addition of DNA and PEI. This simplified approach is directly transferable from suspension cultures grown in 6 well plates to shaker flasks and 5-L WAVE bioreactors. As it minimizes the number of steps and does not require an incubation period for polyplex formation, it is also suitable for automation using static cultures in 96-well plates. This "direct" transfection method thus provides a robust platform for both high throughput expression and large-scale production of recombinant proteins. PMID- 21539919 TI - The variable detergent sensitivity of proteases that are utilized for recombinant protein affinity tag removal. AB - Recombinant proteins typically include one or more affinity tags to facilitate purification and/or detection. Expression constructs with affinity tags often include an engineered protease site for tag removal. Like other enzymes, the activities of proteases can be affected by buffer conditions. The buffers used for integral membrane proteins contain detergents, which are required to maintain protein solubility. We examined the detergent sensitivity of six commonly-used proteases (enterokinase, factor Xa, human rhinovirus 3C protease, SUMOstar, tobacco etch virus protease, and thrombin) by use of a panel of 94 individual detergents. Thrombin activity was insensitive to the entire panel of detergents, thus suggesting it as the optimal choice for use with membrane proteins. Enterokinase and factor Xa were only affected by a small number of detergents, making them good choices as well. PMID- 21539920 TI - Efficient secretory expression of functional barley limit dextrinase inhibitor by high cell-density fermentation of Pichia pastoris. AB - The limit dextrinase inhibitor (LDI) from barley seeds acts specifically on limit dextrinase (LD), an endogenous starch debranching enzyme. LDI is a 14 kDa hydrophobic protein containing four disulfide bonds and one unpaired thiol group previously found to be either glutathionylated or cysteinylated. It is a member of the so-called CM-protein family that includes alpha-amylase and serine protease inhibitors, which have been extremely challenging to produce recombinantly in functional form and in good yields. Here, LDI is produced in very high yields by secretory expression by Pichia pastoris applying high cell density fermentation in a 5L fed-batch bioreactor. Thus about 200mg of LDI, which showed twofold higher inhibitory activity towards LD than LDI from barley seeds, was purified from 1L of culture supernatant by His-tag affinity chromatography and gel filtration. Electrospray ionization mass spectrometry verified the identity of the produced glutathionylated LDI-His(6). At a 1:1M ratio the recombinant LDI completely inhibited hydrolysis of pullulan catalyzed by 5-10 nM LD. LDI retained stability in the pH 2-12 range and at pH 6.5 displayed a half life of 53 and 33 min at 90 and 93 degrees C, respectively. The efficient heterologous production of LDI suggests secretory expression by P. pastoris to be a promising strategy to obtain other recombinant CM-proteins. PMID- 21539921 TI - Structural and biophysical characterization of Mycobacterium tuberculosis dodecin Rv1498A. AB - Dodecins (assembly of twelve monomers) are the smallest known flavoprotein with only 65-73 amino acids and are involved in binding and storage of flavins in archaea. Here we report the crystal structure of Rv1498A, a Mycobacterium tuberculosis dodecin. This bacterial dodecin structure is similar to that of other reported dodecins. Each monomer has a 3 stranded beta-sheet and an alpha helix perpendicular to it. This protein has polyextreme (halophilic and thermophilic) properties. Interestingly, positively and negatively charged residues aggregate separately and do not seem to contribute to thermophilic and halophilic stability. We have examined the interactions that stabilize the Rv1498A dodecamer by preparing selected point mutants that break salt bridges and hydrophobic contacts, thereby leading to collapse of the assembly. PMID- 21539922 TI - Involvement of peroxinectin in the defence of red swamp crayfish Procambarus clarkii against pathogenic Aeromonas hydrophila. AB - Cell adhesion factors are important immune components for invertebrate to immobilize, phagocytose or encapsulate invasive microorganisms and foreign particles. In this study, a new cell adhesion factor, peroxinectin (refered as Pcpxin) was isolated from hemocytes of red swamp crayfish (Procambarus clarkii). The full-length cDNA of Pcpxin was 3014 bp encoding a protein of 819 amino acid residues with a predicted molecular weight of 89.0 kDa and a calculational isoelectric point of 6.93. The putative amino acid sequence contained a peroxidase domain and a signal peptide of 21 amino acid residues, and exhibited high identity to peroxinectin from Pacifastacus leniusculus (85%), Fenneropenaeus chinensis (62%) and Scylla serrata (58%), as well as peroxidase from Camponotus floridanus (40%), Pediculus humanus corporis (39%), and Culex quinquefasciatus (38%). Quantitative real time PCR revealed that mRNA expression of Pcpxin in hemocytes could be inhibited by challenge with heat-killed Aeromonas hydrophila, suggesting that Pcpxin was involved in immune responses to A. hydrophila. RNA interference (RNAi) experiment demonstrated that silencing Pcpxin significantly reduced the survival rate of red swamp crayfishes after challenge with A. hydrophila, which indicated that Pcpxin was important for P. clarkii to survive A. hydrophila infection. Moreover, silencing Pcpxin inhibited the up-regulation of crustin1 and lysozyme expression in response to challenge with heat-killed A. hydrophila. This result suggested that Pcpxin might participate in antibacterial peptide gene expression and thereby might be involved in signal transduction pathway regulating the expression of antibacterial peptide gene. PMID- 21539923 TI - Neural correlates of binding features within- or cross-dimensions in visual conjunction search: an fMRI study. AB - The fMRI technique was used to investigate the functional neuroanatomy of binding features within- or cross-dimension during visual conjunction search. Participants were asked to perform feature search (FS; e.g., search for a vertical bar among tilted bars), within-dimension search (WS; e.g., search for an upright T among non-target oriented Ts and Ls), cross-dimension search (CS; e.g., search for an orange vertical bar among blue vertical bars and orange tilted bars), and complex search combining within- and cross-dimension features (WCS; e.g., search for an orange upright T among orange leftward Ts and blue Ls). Reaction times (RTs) taken to decide whether a target was present or absent were faster in the FS than in the WS, CS, and WCS conditions, but did not differ between the latter three conditions. Neuroimaging results revealed a set of fronto-parietal regions, including frontal eye field and intraparietal sulcus, to be consistently activated in conjunction search (WS, CS, and WCS) relative to feature search, suggesting that these regions play a more prominent role in matching visual input against the target template in conjunction search. Furthermore, left occipito-temporal cortex was more activated in within-dimension conjunction search, and bilateral intraparietal sulci were more activated in cross-dimension conjunction search. This suggests that features from the same dimension are 'bound' at a higher stage of the ventral pathway by conjoining the inputs from lower-level neurons, whereas neurons along the intraparietal sulcus appear to be necessary for discerning the presence of cross-dimensional conjunctions. PMID- 21539924 TI - Phylogenetic relationships between Sophophora and Lordiphosa, with proposition of a hypothesis on the vicariant divergences of tropical lineages between the Old and New Worlds in the family Drosophilidae. AB - Despite many studies on the phylogeny of the subgenus Sophophora, its monophyly has not been established, especially in relation to its putative relative, the genus Lordiphosa. We analyzed their phylogenetic relationships using DNA sequence data of two mitochondrial genes (ND2 and COII) and two nuclear genes (Adh and 28SrRNA). In constructing phylogenetic trees, we accounted for the problem of among-taxa nucleotide compositional heterogeneity, and took a sequence partitioning approach to allow multiple substitution models for nucleotide sequences that have evolved under different evolutionary processes, particularly developing a novel, sequence-partitioning procedure for Neighbor Joining (NJ) tree construction. Trees constructed by different methods showed an almost identical and strongly supported topology in which Sophophora was paraphyletic: Lordiphosa was placed as the sister to the Neotropical Sophophora consisting of the saltans and willistoni groups, and Sophophora was divided into the clade of Lordiphosa+Neotropical Sophophora and the clade of the obscura+melanogaster groups. Based on the estimated time, 45.9 Mya, of divergence between the Old World Lordiphosa and the Neotropical Sophophora and evidence from paleontology, paleo-geography and -climatology, we propose a hypothesis that this vicariant divergence should have occurred when the North Atlantic Land Bridge between Europe and North America broke in the middle Eocene Epoch. PMID- 21539925 TI - Evolution of the courtship display of Melittobia (Hymenoptera: Eulophidae). AB - Melittobia, a polyphagous pupal parasitoid of many solitary bees and wasps, has a complex courtship display, the evolutionary history of which is poorly understood. The current phylogeny of this genus suggests the complexity of the courtship has increased over time. We test this hypothesis using Bayesian and Maximum likelihood techniques to construct a molecular phylogeny of Melittobia the first for this genus using modern techniques--using two intergenic regions (Internal Transcribed Spacer regions 1 and 2) and Cytochrome Oxidase 1 (CO1), and reconstruct the ancestral state of each major node in the phylogeny for five behaviors coincidental to major shifts in display complexity. We show that species-groups identified solely on behavioral characters are reliable, although the relationships among groups are different than those previously hypothesized. We also show that behaviors traditionally used in the courtship studies do not support a hypothesis of increasing display complexity over time. PMID- 21539926 TI - Natural Products Genomics: A novel approach for the discovery of anti-cancer therapeutics. AB - Plants continue to retain some advantages over combinatorial chemistry as sources of novel compounds, for example, they can generate metabolites with a complexity beyond synthetic chemistry. However, this comes with its own problems in production and synthetic modification of these compounds. Natural Products Genomics (NPG) aims to access the plants own genomic capacity to increase yields, and modify complex bioactive metabolites, to alleviate these limitations. NPG uses a combination of gain of function mutagenesis and selection to a) mimic the evolution of novel compounds in plants, and b) to increase yields of known bioactive metabolites. This process is performed rapidly at the cell culture level in large populations of mutants. Two examples demonstrating proof of concept in Nicotiana tabacum (tobacco) and proof of application in the medicinal plant species Catharanthus roseus, are included to illustrate the feasibility of this approach. This biotechnology platform may alter the way in which plant drug discovery is perceived by the pharmaceutical industry, and provides an alternative to combinatorial chemistry for the discovery, modification and production of highly complex bioactive molecules. PMID- 21539927 TI - Caudate nucleus-dependent response strategies in a virtual navigation task are associated with lower basal cortisol and impaired episodic memory. AB - The present research examined the relationship between endogenous glucocorticoids, navigational strategies in a virtual navigation task, and performance on standard neuropsychological assessments of memory. Healthy young adult participants (N=66, mean age: 21.7) were tested on the 4 on 8 virtual maze (4/8 VM) and standard neuropsychological tests such as the Rey-Osterrieth Complex Figure (RO) and the Rey Auditory Verbal Learning Task (RAVLT), which measure episodic memory. The 4/8 VM differentiates between navigational strategies, where participants either use a hippocampal-dependent spatial strategy by building relationships between landmarks, or a caudate nucleus-dependent stimulus-response strategy by automatizing a pattern of open and closed arms to learn the location of objects within the maze. Degree of stress was assessed by administering the Perceived Stress Scale (PSS) questionnaire. Cortisol samples were taken on two consecutive days upon waking, 30 min after waking, at 11 am, 4 pm, and 9 pm. There was a significant difference in basal levels of cortisol between spatial and response learners. Interestingly, response learners had significantly lower cortisol levels throughout the day. The two groups did not differ in terms of perceived stress as measured with the PSS questionnaire. Moreover, there was no significant correlation between PSS scores and salivary cortisol levels, indicating that the higher cortisol levels in the spatial group were not associated with greater perceived stress. In addition, participants who spontaneously used a spatial strategy performed significantly better on the RAVLT and RO. These data indicate that the cortisol levels in the spatial group may be optimal in terms of episodic memory performance whereas the cortisol levels in the response group may be associated with poorer memory. These results are suggestive of an inverted U-shaped curve describing the effects of basal levels of circulating cortisol on memory in young adults. PMID- 21539928 TI - Melatonin effects on gut motility are independent of the relaxation mediated by the nitrergic system in the goldfish. AB - Melatonin is a key neuroendocrine transducer in the circadian organization of vertebrates. However, its role in gastrointestinal physiology has not been explored in depth. In goldfish, a role for melatonin as a modulator of intestinal motility has been reported, whereby it attenuates the cholinergic contraction. The aim of the present work was to investigate this relaxation induced by melatonin in the gut smooth muscle of the goldfish, studying the possible involvement of nitric oxide. An in vitro model of isolated goldfish intestine was used to test the effects on intestinal motility. The addition of melatonin (10 pM 100 MUM) to the organ bath relaxed acetylcholine- and serotonin-stimulated gut strips, but no effect was observed on KCl-contracted preparations. The addition of L-NAME (nitric oxide synthase inhibitor) increased the amplitude of the spontaneous slow waves, while sodium nitroprusside (SNP, nitric oxide donor) abolished them. All these results support a role for the nitrergic system in goldfish gut motility. However, neither L-NAME, nor SNP nor the nitric oxide precursor, l-arginine, modified the melatonin relaxing effect. These results highlight the existence of a basal nitrergic tone in the gut of goldfish, where melatonin would exert a calcium-dependent, nitric oxide-independent relaxing effect on serotonergic and cholinergic contraction. PMID- 21539929 TI - Electroneutral cation-Cl- cotransporters NKCC2beta and NCCbeta expressed in the intestinal tract of Japanese eel Anguilla japonica. AB - In the present study, we aimed to elucidate the mechanisms of intestinal Na(+) and Cl(-) absorption in Japanese eel, focusing on electroneutral cation-Cl(-) cotransporters, NKCC2beta and NCCbeta, expressed in the intestinal tract. First, we cloned cDNAs encoding NKCC2beta and NCCbeta from the intestinal tract of Japanese eel. In both freshwater- and seawater-acclimated eels, quantitative PCR analysis showed that NKCC2beta was predominantly expressed in the anterior and posterior intestines, and that NCCbeta expression was specifically high in the rectum. According to immunohistochemistry with anti-eel NKCC2beta (reacting with NKCC2beta but not with NCCbeta) and T4 antibody (reacting with both NKCC2beta and NCCbeta), NKCC2beta was localized in the apical surface of the epithelial cells in the anterior and posterior intestines, whereas NCCbeta was likely to be distributed to that in the rectum. Furthermore, a specific NCC inhibitor, hydrochlorothiazide, inhibited of Na(+) and Cl(-) absorption, as well as water absorption, in the rectal sac preparations from seawater eel, indicating the involvement of NCCbeta in ion absorption in the rectum. Our findings indicate that NKCC2beta expressed in the anterior and posterior intestines and NCCbeta in the rectum are importantly involved in ion absorption to reduce osmolality of ingested seawater prior to water absorption in seawater-acclimated eel. PMID- 21539930 TI - [Imported histoplasmosis in Navarra: presentation of four cases]. AB - OBJECTIVE: Histoplasmosis is a fungal infection caused by the dimorphic fungi Histoplasma capsulatum. Its incidence in Spain has increased in recent years, mainly due to the increased presence of immigrants from Latin America and increased travel to the continent for tourism and cooperation. Our aim was to review the clinical characteristics of cases of histoplasmosis diagnosed in our hospital during the last six years. CASE REPORTS: We diagnosed 4 cases from 4 patients from South America, 3 of whom were HIV positive and 1 diagnosed with dermatomyositis was treated with immunosuppressive drugs. The laboratory diagnosis was carried out by histological and microbiological study, by culture and specific PCR directly on the sample. DISCUSSION: As it is an imported infection there needs to be a high level of suspicion and a detailed history taken to get a diagnosis. This infection requires a differential diagnosis between febrile syndrome in immunosuppressed patients, both HIV positive and immunosuppressive therapy, which originate from endemic areas, or who have a history of staying in them. PMID- 21539931 TI - Cellular radioprotecting potential of glyzyrrhizic acid, silver nanoparticle and their complex. AB - Silver nanoparticles (SN) of particle size of less than 50nm were redispersed in aqueous solution of Pluronic F127 and complexed with the phytoceutical, glyzyrrhizic acid (GLY). Radioprotecting ability of the obtained nanoparticle glyzyrrhizic acid complex (SN-GLY) was evaluated in an in vivo model using Swiss albino mice. Oral administration of SN-GLY, SN and GLY one hour prior to radiation exposure reduced the radiation induced damage in peripheral blood leucocytes, bone marrow cells and spleen cells of mice as revealed by comet assay. Exposure of mice to whole body gamma irradiation resulted in formation of micronuclei in blood reticulocytes and chromosomal aberrations in bone marrow cells while SN-GLY, SN or GLY administration resulted in reduction in micronucleus formation and chromosomal aberrations indicating radioprotection. In SN-GLY treated mice the cellular DNA was found protected to a greater extent compared to GLY or SN treated mice. The studies, under in vivo radiation exposure conditions, showed effective radiation protection. PMID- 21539933 TI - The effects of Dechlorane Plus on toxicity and mRNA expression in chicken embryos: a comparison of in vitro and in ovo approaches. AB - Dechlorane Plus (DP) is an additive chlorinated flame retardant comprising two major isomers, syn- and anti-DP, that is used in a variety of commercial/industrial products. It has been detected in biotic and abiotic matrices including the eggs of herring gulls collected from the Laurentian Great Lakes. However, data on potential toxicological and molecular responses to exposure are lacking, especially for avian species. A combined in vitro/in ovo approach was used to determine concentration-dependent effects of DP in chicken embryonic hepatocytes (CEH) and chicken embryos following injection of DP into the air cell of eggs prior to incubation. Overt toxicity (i.e. cytotoxicity and pipping success) and mRNA expression levels of transcripts previously determined to be responsive to a brominated flame retardant were assessed in CEH and hepatic tissue. DP was not cytotoxic up to a maximum concentration of 3 MUM in CEH, and no effects on pipping success were observed up to the highest nominal dose group of 500 ng/g egg. A significant shift in isomeric content of syn- and anti-DP was detected between stock solutions of the commercial mixture and hepatic tissue; the proportion of the syn-DP isomer increased from 0.34 to 0.65 with a concomitant decrease of anti-DP from 0.66 to 0.35. None of the mRNA transcripts changed as a result of in vitro or in ovo exposure to DP indicating that, although there was concordance between the two approaches, DP may evoke its toxicity through other modes of action. At current environmental exposure levels, no adverse effects of DP on embryonic viability or pathways associated with the genes assessed are predicted. PMID- 21539934 TI - To the editor--Programming tips and practical programming. PMID- 21539932 TI - Interaction of enterocyte FABPs with phospholipid membranes: clues for specific physiological roles. AB - Intestinal and liver fatty acid binding proteins (IFABP and LFABP, respectively) are cytosolic soluble proteins with the capacity to bind and transport hydrophobic ligands between different sub-cellular compartments. Their functions are still not clear but they are supposed to be involved in lipid trafficking and metabolism, cell growth, and regulation of several other processes, like cell differentiation. Here we investigated the interaction of these proteins with different models of phospholipid membrane vesicles in order to achieve further insight into their specificity within the enterocyte. A combination of biophysical and biochemical techniques allowed us to determine affinities of these proteins to membranes, the way phospholipid composition and vesicle size and curvature modulate such interaction, as well as the effect of protein binding on the integrity of the membrane structure. We demonstrate here that, besides their apparently opposite ligand transfer mechanisms, both LFABP and IFABP are able to interact with phospholipid membranes, but the factors that modulate such interactions are different for each protein, further implying different roles for IFABP and LFABP in the intracellular context. These results contribute to the proposed central role of intestinal FABPs in the lipid traffic within enterocytes as well as in the regulation of more complex cellular processes. PMID- 21539935 TI - Counting down before blasting off. PMID- 21539936 TI - Evidence of recombination in the Banana bunchy top virus genome. AB - Viruses serve as good model for evolutionary studies, owing to their short generation times and small genomes. Banana bunchy top virus (BBTV) is a significant subject being multicomponent circular single stranded DNA virus. BBTV belongs to family Nanoviridae and contains DNA-R, -U3, -S, -M, -C, and -N as integral genomic components. Evolutionary studies have shown genetic re assortment of components among its isolates and revealed a concerted type evolution in non-coding regions of its genome. The DNA U3 having been shown as the most diverse component in our previous studies, was subjected to sequencing from some Pakistani isolates for the first time. Sequence analysis revealed intergenomic recombination in DNA-U3 among the isolates of two sub-groups and a very rare intragenomic recombination in Pakistani BBTV population. This indicates that like other evolutionary processes including intergenomic recombination, intragenomic recombination among the genomic components of the same isolate may also have a significant contribution in the evolution of BBTV genome. Intragenomic recombination therefore appears to be a unique way to generate genetic diversity in the multicomponent ssDNA viruses. PMID- 21539937 TI - Hepatitis B virus infection from an evolutionary point of view: how viral, host, and environmental factors shape genotypes and subgenotypes. AB - Hepatitis B virus (HBV) has an overwhelming distribution in the world and causes important human health problems. It has infected one-third of the global population and more than 350 million people are chronic carriers. Several aspects of HBV infection confer adaptive advantages that lead to a highly efficient dissemination of the virus through different routes of transmission. HBV genotypes and subgenotypes have been associated with differences in clinical and virological characteristics, indicating that they may play a role in the virus host relationship. In particular, a clear association between genotype A and chronic outcomes in both children and adults depending on the subgenotype involved, and between genotype C and a higher risk of complications from HBV infection, has been demonstrated. Interestingly, subgenotype A2 and genotype C are respectively likely to predominate in high-risk groups for sexual transmission and in areas where perinatal transmission is the major mode of HBV dissemination. An evolutionary approach to HBV infection, based on the principles of natural selection, may offer explanations for how modes of transmission may favor some genotypes and subgenotypes over others and, ultimately, influence HBV virulence. PMID- 21539939 TI - Cardiovascular safety of anti-TNF-alpha therapies: facts and unsettled issues. AB - Tumor necrosis factor alpha (TNFa) plays a central role in the pathogenesis of both rheumatoid arthritis (RA) and heart failure (HF). Over the last years RA could benefit from TNFa inhibitors that mitigated disease activity, decreased structural damage, and prevented cardiovascular events. Contraindications to clinical use of TNFa inhibitors may include infections, autoimmune disorders, demyelinating disease, cancer, and heart failure. Overall, these pathological conditions do not appear to increase significantly during treatment with TNFa antagonists compared to placebo. Clinical trials probed these drugs in non RA HF patients produced disappointing results and formed the basis to contraindicate TNFa inhibitors in patients with moderate-severe HF. Although National Registries provide apparently encouraging data about HF safety of anti-TNFa therapies, they cannot adequately assess the actual risk, as these drugs are administered to patients with no cardiac dysfunction. These findings introduced a "rheumatological dilemma" in the clinical management of RA with anti-TNFa. Probably, in RA patients anti-TNFa agents would intercept TNFa and prevent its toxic effects on heart function, while in patients with advanced heart damage (NYHA class III-IV HF), anti-TNFa agents would interfere with the beneficial preconditioning effects of TNFa. PMID- 21539938 TI - Mutagenesis and computer modeling studies of a GPCR conserved residue W5.43(194) in ligand recognition and signal transduction for CB2 receptor. AB - W5.43(194), a conserved tryptophan residue among G-protein coupled receptors (GPCRs) and cannabinoid receptors (CB), was examined in the present report for its significance in CB2 receptor ligand binding and adenylyl cyclase (AC) activity. Computer modeling postulates that this site in CB2 may be involved in the affinity of WIN55212-2 and SR144528 through aromatic contacts. In the present study, we reported that a CB2 receptor mutant, W5.43(194)Y, which had a tyrosine (Y) substitution for tryptophan (W), retained the binding affinity for CB agonist CP55940, but reduced binding affinity for CB2 agonist WIN55212-2 and inverse agonist SR144528 by 8-fold and 5-fold, respectively; the CB2 W5.43(194)F and W5.43(194)A mutations significantly affect the binding activities of CP55940, WIN55212-2 and SR144528. Furthermore, we found that agonist-mediated inhibition of the forskolin-induced cAMP production was dramatically diminished in the CB2 mutant W5.43(194)Y, whereas W5.43(194)F and W5.43(194)A mutants resulted in complete elimination of downstream signaling, suggesting that W5.43(194) was essential for the full activation of CB2. These results indicate that both aromatic interaction and hydrogen bonding are involved in ligand binding for the residue W5.43(194), and the mutations of this tryptophan site may affect the conformation of the ligand binding pocket and therefore control the active conformation of the wild type CB2 receptor. W5.43(194)Y/F/A mutations also displayed noticeable enhancement of the constitutive activation probably attributed to the receptor conformational changes resulted from the mutations. PMID- 21539940 TI - The metabolic syndrome: the crossroads between rheumatoid arthritis and cardiovascular risk. AB - Rheumatoid arthritis (RA) patients have an incidence of cardiovascular (CV) diseases at least two times higher than the general population. Atherosclerosis, the main determinant of CV morbidity and mortality, and carotid intima-media thickness, an early preclinical marker of atherosclerosis, also occur early on in RA. Traditional CV risk factors seem to have the same prevalence in RA and non-RA patients, and thus do not fully explain the increased CV burden, suggesting that RA inflammation and therapies play a role in increasing CV risk in these patients. The metabolic syndrome and fat tissue are likely to be the major players in this complex network. The metabolic syndrome (MetS) represents a cluster of cardiovascular risk factors that have in common insulin resistance and increased visceral adiposity. This entity has received great attention in the last few years due to its contribution to the burden of cardiovascular morbidity and mortality. Moreover, recently the adipose tissue has emerged as a dynamic organ that releases several inflammatory and immune mediators (adipokines). The association of MetS and atherosclerosis is thought to be partly mediated by altered secretion of adipokines by the adipose tissue and, on the other hand, there are evidence that adipokines may play some role in inflammatory arthritides. Obesity is now regarded as a systemic, low-grade inflammatory state, and inflammation as a link between obesity, metabolic syndrome, and cardiovascular diseases. To obtain a full control of the CV risk, data suggest that it is therefore mandatory a "tight control" of both RA and MetS inflammations. PMID- 21539941 TI - Dual role of TGF-beta1 on Fas-induced apoptosis in lung epithelial cells. AB - Recent evidence suggests that TGF-beta1 has a dual role in regulating cell response to Fas/Fas ligand (FasL)-induced apoptosis. TGF-beta1 may play a positive or negative role on cell sensitivity to apoptosis via Fas/FasL system, depending on cell types and their specific environment. TGF-beta1 and the Fas/FasL system are also involved in pathological processes of acute lung injury (ALI) and interstitial lung diseases including early lung injury and subsequent tissue repair. However, it is not well understood how TGF-beta1 regulates Fas/FasL mediated apoptotic signaling in lung epithelium. In this study, we found that TGF-beta1 could affect the sensitivity of lung epithelial A549 cells to Fas/FasL mediated apoptosis in a time-dependent manner. Apoptosis of A549 cells could be enhanced significantly by co-treatment with TGF-beta1 and FasL, or pretreatment with TGF-beta1 followed by FasL exposure, as evidenced by markedly increased caspase-8 and JNK activities. However, prolonged exposure to TGF-beta1 could result in an obvious inhibition of the Fas/FasL-induced apoptosis, accompanied by down-regulation of Fas and up-regulation of c-Flip. Our results also showed that the effect of TGF-beta1 on cell sensitivity to Fas-mediated apoptosis was independent of Akt pathway activation. These findings suggest that timely interplay of TGF-beta1 and the Fas/FasL system could determine the final outcomes of cell survival/death signaling, for example, switching cell death signaling to survival signaling during early injury and later repair process of lung epithelium. PMID- 21539942 TI - Pulmonary fibroblasts from COPD patients show an impaired response of elastin synthesis to TGF-beta1. AB - Insufficiency of tissue repair by pulmonary fibroblasts may contribute to the decrease in elastic fibres in chronic obstructive pulmonary disease (COPD). In this study, the repair function of COPD fibroblasts was assessed by examining the response to transforming growth factor (TGF)-beta1. Primary pulmonary fibroblasts were cultured from lung tissue of COPD patients and smoking control subjects. Cellular proliferation was measured with Alamar Blue reduction method. Levels of tropoelastin mRNA and soluble elastin was measured using real-time RT-PCR and Fastin elastin assay respectively. The percentage of increase in proliferation and elastin production after TGF-beta1 (1 ng/ml) treatment was calculated for fibroblasts from each subject. COPD fibroblasts showed slower proliferation than control fibroblasts, and a reduced response to TGF-beta1 stimulation. The promotive effect of TGF-beta1 on elastin synthesis in control fibroblasts was significantly diminished in fibroblasts from COPD patients. Our findings indicate that COPD lung fibroblasts have a significantly decreased response to TGF-beta1 in terms of proliferation and elastin production. PMID- 21539943 TI - Conformational, receptor interaction and alanine scan studies of glucose dependent insulinotropic polypeptide. AB - Glucose-dependent insulinotropic polypeptide (GIP) is an insulinotropic incretin hormone that stimulates insulin secretion during a meal. GIP has glucose lowering abilities and hence is considered as a potential target molecule for type 2 diabetes therapy. In this article, we present the solution structure of GIP in membrane-mimicking environments by proton NMR spectroscopy and molecular modelling. GIP adopts an alpha-helical conformation between residues Phe(6) Gly(31) and Ala(13)-Gln(29) for micellar and bicellar media, respectively. Previously we examined the effect of N-terminal Ala substitution in GIP, but here eight GIP analogues were synthesised by replacing individual residues within the central 8-18 region with alanine. These studies showed relatively minor changes in biological activity as assessed by insulin releasing potency. However, at higher concentration, GIP(Ala(16)), and GIP(Ala(18)) showed insulin secreting activity higher than the native GIP (P<0.01 to P<0.001) in cultured pancreatic BRIN-BD11 cells. Receptor interaction studies of the native GIP with the extracellular domain of its receptor were performed by using two different docking algorithms. At the optimised docking conformation, the complex was stabilised by the presence of hydrophobic interactions and intermolecular hydrogen bonding. Further, we have identified some potentially important additional C-terminal interactions of GIP with its N-terminal extracellular receptor domain. PMID- 21539945 TI - An analysis of the natural course of compensatory sweating following thoracoscopic sympathectomy. AB - BACKGROUND: To evaluate the long-term results of thoracoscopic sympathectomy in the treatment of hyperhydrosis. METHODS: Theatre log books were used to identify all patients who underwent thoracoscopic sympathectomy between 2000 and 2006. Details of pre-operative symptoms, surgical procedure and post-operative complications were collected from the patient notes. Each patient was sent a questionnaire regarding success of the procedure, compensatory sweating and overall satisfaction. RESULTS: 46 hyperhydrosis patients (34 females) age range 14-57 years. 20 patients suffered with hyperhydrosis in a combination of areas, 14 in the axillae alone, 9 palms alone and with 2 facial symptoms. There were 2 early post-operative complications, 1 haemothorax which required a chest drain and a chest infection. 3 patients required redo procedures. Of follow-up of 42 months (range 6-84), 32 (69.5%) patients reported complete dryness or a significant improvement in symptoms and 15 a substantial improvement in quality of life. However 43 patients (93%) suffered with compensatory sweating, of these 27 had to change clothes more than once daily. Compensatory sweating was graded as severe in 18 and incapacitating in 2. Of note only 5 patients noticed an improvement in the compensatory sweating over time. Only 26 (56%) would recommend thoracoscopic sympathectomy to others with hyperhydrosis. CONCLUSION: Thoracoscopic sympathectomy is effective in the treatment of hyperhydrosis. However compensatory sweating seems unavoidable and infrequently improves with time. Patients need to be carefully counselled before committing to surgery. PMID- 21539944 TI - Direct deposited porous scaffolds of calcium phosphate cement with alginate for drug delivery and bone tissue engineering. AB - This study reports the preparation of novel porous scaffolds of calcium phosphate cement (CPC) combined with alginate, and their potential usefulness as a three dimensional (3-D) matrix for drug delivery and tissue engineering of bone. An alpha-tricalcium phosphate-based powder was mixed with sodium alginate solution and then directly injected into a fibrous structure in a Ca-containing bath. A rapid hardening reaction of the alginate with Ca(2+) helps to shape the composite into a fibrous form with diameters of hundreds of micrometers, and subsequent pressing in a mold allows the formation of 3-D porous scaffolds with different porosity levels. After transformation of the CPC into a calcium-deficient hydroxyapatite phase in simulated biological fluid the scaffold was shown to retain its mechanical stability. During the process biological proteins, such as bovine serum albumin and lysozyme, used as model proteins, were observed to be effectively loaded onto and released from the scaffolds for up to more than a month, proving the efficacy of the scaffolds as a drug delivering matrix. Mesenchymal stem cells (MSCs) were isolated from rat bone marrow and then cultured on the CPC-alginate porous scaffolds to investigate the ability to support proliferation of cells and their subsequent differentiation along the osteogenic lineage. It was shown that MSCs increasingly actively populated and also permeated into the porous network with time of culture. In particular, cells cultured within a scaffold with a relatively high porosity level showed favorable proliferation and osteogenic differentiation. An in vivo pilot study of the CPC alginate porous scaffolds after implantation into the rat calvarium for 6 weeks revealed the formation of new bone tissue within the scaffold, closing the defect almost completely. Based on these results, the newly developed CPC-alginate porous scaffolds could be potentially useful as a 3-D matrix for drug delivery and tissue engineering of bone. PMID- 21539946 TI - DcHsp17.7, a small heat shock protein in carrot, is tissue-specifically expressed under salt stress and confers tolerance to salinity. AB - The expression and function of DcHsp17.7, a small heat shock protein in carrot (Daucus carota L.), were examined under salt stress, which is an exacerbating environmental condition due to water shortage and irrigation. DcHsp17.7 was constitutively expressed in leaf and stem tissues under normal growth conditions. Upon exposure to 300 mM NaCl, the protein level of DcHsp17.7 increased dramatically in leaf tissue, but did not significantly change in stem tissue. Native-PAGE analysis showed tissue-specific oligomer formation. Under normal growth conditions, DcHsp17.7 was found in an approximately 240 kDa complex in both tissues. However, NaCl treatment induced an additional approximately 160 kDa complex containing DcHsp17.7. This occurred only in leaf tissue, suggesting tissue-specific oligomeric complex formation. To examine the functional mechanism of DcHsp17.7 under stress conditions, the DcHsp17.7 coding gene was introduced into Escherichia coli. Heterologous expression of DcHsp17.7 was induced by isopropyl beta-d-1-thiogalactopyranoside treatment. Upon exposure to salinity, protein levels of DcHsp17.7 decreased, and the protein was not detected after 16 hours. Native-PAGE analysis showed that DcHsp17.7 was present in an approximately 250 kDa complex both before and after salt treatment. Salinity reduced bacterial cell viability; however, the transgenic E. coli expressing DcHsp17.7 exhibited a higher survival rate than control E. coli under salt stress. When the level of soluble proteins was measured under salt stress, transgenic E. coli expressing DcHsp17.7 reproducibly showed slightly higher levels than control cells. This suggests that DcHsp17.7 performs molecular chaperone activity in salt-stressed transgenic E. coli. Our results suggest that DcHsp17.7 is likely to be involved in tolerance not only to thermal stresses but also to other abiotic stresses, such as salinity. PMID- 21539947 TI - Clustering of MS spectra for improved protein identification rate and screening for protein variants and modifications by MALDI-MS/MS. AB - It is an established fact that allelic variation and post-translational modifications create different variants of proteins, which are observed as isoelectric and size subspecies in two-dimensional gel based proteomics. Here we explore the stromal proteome of spinach and Arabidopsis chloroplast and show that clustering of mass spectra is a useful tool for investigating such variants and detecting modified peptides with amino acid substitutions or post-translational modifications. This study employs data mining by hierarchical clustering of MALDI MS spectra, using the web version of the SPECLUST program (http://bioinfo.thep.lu.se/speclust.html). The tool can also be used to remove peaks of contaminating proteins and to improve protein identification, especially for species without a fully sequenced genome. Mutually exclusive peptide peaks within a cluster provide a good starting point for MS/MS investigation of modified peptides, here exemplified by the identification of an A to E substitution that accounts for the isoelectric heterogeneity in protein isoforms. PMID- 21539948 TI - Molecular characterization and interactome analysis of Trypanosoma cruzi tryparedoxin 1. AB - Trypanosoma cruzi tryparedoxin 1 (TcTXN1) is an oxidoreductase belonging to the thioredoxin superfamily, which mediates electron transfer between trypanothione and peroxiredoxins. In trypanosomes TXNs, and not thioredoxins, constitute the oxido-reductases of peroxiredoxins. Since, to date, there is no information concerning TcTXN1 substrates in T. cruzi, the aim of this work was to characterize TcTXN1 in two aspects: expression throughout T. cruzi life cycle and subcellular localization; and the study of TcTXN1 interacting-proteins. We demonstrate that TcTXN1 is a cytosolic and constitutively expressed protein in T. cruzi. In order to start to unravel the redox interactome of T. cruzi we designed an active site mutant protein lacking the resolving cysteine, and validated the complex formation in vitro between the mutated TcTXN1 and a known partner, the cytosolic peroxiredoxin. Through the expression of this mutant protein in parasites with an additional 6xHis-tag, heterodisulfide complexes were isolated by affinity chromatography and identified by 2-DE/MS. This allowed us to identify fifteen TcTXN1 proteins which are involved in two main processes: oxidative metabolism and protein synthesis and degradation. Our approach led us to the discovery of several putatively TcTXN1-interacting proteins thereby contributing to our understanding of the redox interactome of T. cruzi. PMID- 21539949 TI - Accuracy and safety of high pitch computed tomography imaging in young children with complex congenital heart disease. AB - Multidetector computed tomographic angiography defines anatomy in complex congenital heart disease, but radiation exposure and general anesthesia requirements limit its application. The aim of this study was to compare radiation exposure, anesthesia use, and diagnostic accuracy between standard pitch, single-source computed tomography and high-pitch, dual-source computed tomography for image quality and risk in a clinical pediatric population. Consecutive computed tomographic scans were evaluated in patients aged <2 years with complex congenital heart disease. Two groups were compared on the basis of standard- versus high-pitch scans. High-pitch scans were further divided into variable pitch (2.25 to 3.0) and highest pitch (3.4) groups. Image quality, radiation exposure, anesthesia use, and diagnostic confidence and accuracy were determined. Sixty-one scans were reviewed (29 at standard pitch, 32 at high pitch). Body surface area, scan length, and indications were similar. The median dose-length product for standard-pitch scans was 66 mGy . cm (range 29 to 372) compared to 7 mGy . cm (range 3 to 50) in all high-pitch scans. The median dose length product was 28 mGy . cm (range 8 to 50) for variable high-pitch scans and 5 mGy . cm (range 3 to 12) for the highest fixed-pitch scans. Diagnostic confidence was similar, although high-pitch scans had higher image noise and lower contrast-to-noise ratios. All high-pitch scans were performed under sedation with free breathing, and all standard-pitch scans required general anesthesia. Diagnostic accuracy was 100% in the 2 groups, with 17 standard-pitch and 16 high-pitch patients undergoing procedural validation. In conclusion, high pitch, dual-source computed tomography provides excellent diagnostic accuracy and markedly reduces radiation dose, although image quality is mildly reduced. PMID- 21539950 TI - Cognitive impairment in chronic heart failure and the need for screening. PMID- 21539952 TI - SIU Scholar: Dr. Peter Olufemi Areo. PMID- 21539951 TI - The editor's roundtable: JUPITER follow-up. PMID- 21539953 TI - SIU Scholar: Dr. Tamer Mohammed Abou Youssif. PMID- 21539954 TI - Great meaningless questions in urology: which is better, open, laparoscopic, or robotic radical prostatectomy? PMID- 21539955 TI - Editorial comment. PMID- 21539957 TI - Editorial comment. PMID- 21539959 TI - Editorial comment. PMID- 21539961 TI - Editorial comment. PMID- 21539963 TI - Erectile dysfunction is associated with severe retinopathy in diabetic men. AB - OBJECTIVE: Erectile dysfunction (ED) and retinopathy are prevalent in diabetic men. However, the association between ED and diabetic retinopathy (DR) with relation to DR severity levels has never been studied. MATERIALS AND METHODS: For this cross-sectional study, data were obtained prospectively at the retina clinic of a tertiary medical center. The study group included men with proliferative diabetic retinopathy (PDR) or with severe nonproliferative diabetic retinopathy (NPDR). The control group included diabetic men without retinopathy or with mild NPDR. All men had type 2 diabetes mellitus. All men filled in the Sexual Health Inventory for Males questionnaire (SHIM) to detect significant ED. Significant ED was defined as SHIM questionnaire score <17. RESULTS: The cohort included 102 diabetic men: 64 (62.7%) men in the study group and 38 (37.3%) men in the control group. Mean age for the entire cohort was 64.0 +/- 8.2 years, and mean diabetes duration was 14.5 +/- 8.9 years. Mean SHIM score for the entire cohort was 11.4 +/- 6.5, and 75 (73.5%) men had significant ED. Men in the study group had higher prevalence of significant ED compared with men in the control group (87.5% vs 50.0%; P <.0001), as well as lower mean SHIM questionnaire scores (9.5 +/- 5.4 vs 14.7 +/- 6.9; P <.0001). Binary logistic regression analysis and linear regression analysis showed that significant ED and SHIM scores, respectively, were associated with DR severity (P = .001 for both), independent of age, diabetes duration, ischemic heart disease, cerebrovascular disease, hypertension, hyperlipidemia, and smoking. CONCLUSIONS: Significant ED is associated with DR severity independent of age, diabetes duration, macrovascular comorbidities, and cardiovascular risk factors. PMID- 21539964 TI - Editorial comment. PMID- 21539966 TI - Editorial comment. PMID- 21539967 TI - Editorial comment. PMID- 21539970 TI - Editorial comment. PMID- 21539969 TI - Once-daily dasatinib: expansion of phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer. AB - OBJECTIVES: To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC. METHODS: Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase). RESULTS: The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by >=40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3-4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (>=20%) were fatigue, nausea, diarrhea, headache, and anorexia. CONCLUSIONS: Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC. PMID- 21539972 TI - Editorial comment. PMID- 21539975 TI - Editorial comment. PMID- 21539976 TI - Characterizing behavior of corpus cavernosum in chloride-free condition. AB - OBJECTIVE: To elucidate the role of chloride currents in erectile function through characterizing the behavior of corpus cavernosum (CC) in chloride-free (Cf) medium, which has not been evaluated before. METHODS: Isolated rabbit CC strips were suspended in thermo-regulated organ baths containing oxygenated Tyrode for isometric tension recording. Cf Tyrode was prepared by substituting sodium chloride, calcium chloride, and potassium chloride (KCl) with equivalent molar concentrations of sodium acetate, calcium acetate, and potassium acetate salts. Resting cavernosal tone and contractions by noradrenaline, histamine, and KCl were assessed in Cf Tyrode with or without chloride channel blockers, niflumic acid (NFA), and anthracene-9-carboxylic acid (A9C). RESULTS: Withdrawal of extracellular chloride caused myogenic contractions in the unstimulated CC strips (n = 18). In addition, peak contractions by noradrenaline (n = 14) and histamine (n = 13) were augmented in Cf buffer by 47.2 +/- 5.9% and 85.4 +/- 13.2%, respectively (P <.05), whereas KCl contractions were not significantly altered (17.6 +/- 4.6%; n = 7). Interestingly, Cf buffer exerted opposing effects, potentiation and reduction, respectively, on the plateau phase of contractions mediated by noradrenaline and histamine. The stimulatory effect of Cf buffer on the intrinsic myogenic tone was diminished by NFA (30 MUM), and A9C (300 MUM-1 mM). NFA (30-100 MUM), however, specifically reduced the plateau phase without significantly modifying the peak contraction of noradrenaline in Cf buffer. CONCLUSIONS: These results reiterate the importance of chloride currents as a mechanism underlying the maintenance of penile cavernosal tone. Thus, chloride channel could be an effective alternative target to regulate penile erection. PMID- 21539977 TI - Circulating microRNAs (miRNA) in serum of patients with prostate cancer. AB - OBJECTIVES: To analyze circulating microRNAs (miRNA) in serum as non-invasive biomarker in patients with localized prostate cancer (PCA), benign prostate hyperplasia (BPH) and healthy individuals (HI). METHODS: Total RNA was isolated from serum samples and the circulating levels of different RNA species (miRNA, miR-16; small nuclear RNA, RNU1A-1; messenger RNA, HPRT1), as well as of 4 oncogenic miRNAs (miR-26a, miR-32, miR-195, miR-let7i), were determined using a quantitative real-time polymerase chain reaction. We also evaluated miRNA levels in a second cohort of 10 PCA patients in cancer/nonmalignant tissue, and pre- and post-prostatectomy serum samples. RESULTS: The levels of miR-16 and RNU1A-1 were reliably measured, whereas HPRT1 levels were often below the detection limit of our assay. Circulating oncogenic miRNA levels were different, and especially the miR-26a level allowed sensitive (89%) discrimination of PCA and BPH patients at a moderate specificity (56%; area under the curve [AUC]: 0.703); the analysis of oncogenic miRNAs in combination increased the diagnostic accuracy (sensitivity: 78.4%; specificity: 66.7%; AUC: 0.758). Despite the low number of patients limiting the statistical power of the study, we observed correlations with clinical-pathologic parameters: miR-16, miR-195, and miR-26a were significantly correlated with surgical margin positivity; miR-195 and miR-let7i were significantly correlated with the Gleason score. Tissue miRNA levels were correlated with preprostatectomy miRNA levels in serum, and serum miRNA decreased after prostatectomy, thereby indicating tumor-associated release of miRNA. CONCLUSIONS: Tumor-associated miRNAs in serum allow noninvasive discrimination of PCA and BPH. PMID- 21539978 TI - Re: Chen et al.: New use of foley catheter for exposing urethral stump during vesicourethral anastomosis in laparoscopic radical prostatectomy (Urology 2010;76:1109-1110). PMID- 21539979 TI - Re: Shinbo et al.: Resistive index as risk factor for acute urinary retention in patients with benign prostatic hyperplasia (Urology 2010;76:1440-1445). PMID- 21539980 TI - On the use of "stem cells" for optic nerve hypoplasia. PMID- 21539981 TI - Intraoperative phacoemulsification complication rates of second- and third-year ophthalmology residents a 5-year comparison. AB - OBJECTIVE: To determine whether year of residency is associated with intraoperative phacoemulsification complication rates. DESIGN: Retrospective cohort study. PARTICIPANTS: One attending physician supervised 691 resident performed phacoemulsification procedures on 492 patients. Second- and third-year residents performed 228 and 463 cases, respectively. METHODS: All resident performed phacoemulsification procedures performed between October 2003 and June 2008 and supervised by one attending surgeon (SR) were considered for this study. Data were collected on the residency year of the physician performing the surgery, preoperative risk indicators, and intraoperative complications, including anterior and posterior capsular tears with or without vitreous loss, zonular dialysis or dehiscence, burns, nuclear fragment loss, and Descemet's membrane tear. Cases were classified as difficult if they had 1 or more preoperative risk indicators including: pseudoexfoliation; proliferative diabetic retinopathy; prior vitrectomy; a 4+ dense, white, or brunescent cataract; current Flomax (Boehringer-Ingelheim, Ingelheim, Germany) use, pre-existing zonular dialysis; and intraoperative use of Trypan blue, iris hooks, or pupil dilator. Intraoperative complications are presented as rate per 100 surgeries (95% confidence intervals [CIs]). MAIN OUTCOME MEASURES: Intraoperative complication rates and case difficulty. RESULTS: Fifty-three patients experienced at least 1 complication, with 25 cases experiencing multiple complications. Intraoperative complication rates were similar among second- and third-year resident groups (7.9% vs. 7.6%; P = 0.88). Similarly, vitreous loss rates among second- and third year residents were comparable (4.8% vs. 3.0%; P = 0.27). Risk indicators were more common among third-year cases (24.6% vs. 15.8%; P = 0.008). Having 1 or more risk indicators increased the odds of an intraoperative complication (odds ratio [OR], 3.09; 95% CI, 1.73-5.49). After controlling for risk indicators, second year resident surgeries still had a similar risk of intraoperative complications as third-year resident surgeries (OR, 1.15; 95% CI, 0.6-2.19). CONCLUSIONS: The year of residency did not significantly influence intraoperative complication rates, even after controlling for differences in case difficulty. PMID- 21539982 TI - Assessment of visual function in glaucoma: a report by the American Academy of Ophthalmology. AB - OBJECTIVE: To review the published literature to summarize and evaluate the effectiveness of visual function tests in diagnosing glaucoma and in monitoring progression. METHODS: Literature searches of the PubMed and Cochrane Library databases were conducted last on May 7, 2010, and were restricted to citations published on or after January 1, 1994. The search yielded 1063 unique citations. The first author reviewed the titles and abstracts of these articles and selected 185 of possible clinical relevance for further review. The panel members reviewed the full text of these articles and determined that 85 met inclusion criteria. They conducted data abstraction of the 85 studies, and the panel methodologist assigned a level of evidence to each of the selected articles. One study was rated as level I evidence. The remaining articles were classified broadly as providing level II evidence. Studies deemed to provide level III evidence were not included in the assessment. RESULTS: Standard white-on-white automated perimetry remains the most commonly performed test for assessing the visual field, with the Swedish interactive threshold algorithm (SITA) largely replacing full-threshold testing strategies. Frequency-doubling technology and its refinement into Matrix perimetry, as well as short-wavelength automated perimetry, now available with SITA, have been evaluated extensively. Machine learning classifiers seem to be ready for incorporation into software to help distinguish glaucomatous from nonglaucomatous fields. Other technologies, such as multifocal visual-evoked potential and electroretinography, which were designed as objective measures of visual function, provide testing free of patient input, but issues prevent their adoption for glaucoma management. CONCLUSIONS: Advances in technology and analytic tools over the past decade have provided us with more rapid and varied ways of assessing visual function in glaucoma, but they have yet to produce definitive guidance on the diagnosis of glaucoma or its progression over time. Further research on an objective measure of visual function is needed. PMID- 21539983 TI - Viscoelastic-assisted DSAEK. PMID- 21539984 TI - Growth factors in aqueous humor. PMID- 21539985 TI - Ranibizumab for retinal neovascularization. PMID- 21539986 TI - Charles Bonnet Syndrome and glaucoma. PMID- 21539987 TI - Outer retinal layers. PMID- 21539988 TI - Acute primary angle closure structural damage. PMID- 21539989 TI - Glaucoma screening in the real world. PMID- 21539992 TI - Diurnal intraocular pressure assessment. PMID- 21539994 TI - Central corneal thickness measurement. PMID- 21539995 TI - CF101 for dry eye. PMID- 21539998 TI - Subconjunctival anesthesia for laser treatment. PMID- 21540000 TI - Retinal vascular fractals. PMID- 21540002 TI - World Health Day 2011--antimicrobial resistance: no action today, no cure tomorrow. PMID- 21540003 TI - Pharmacotherapy of spasticity in children with cerebral palsy. AB - Spasticity is a common disability in children with cerebral palsy. Pharmacological and non-pharmacological treatments, including physical therapy, occupational therapy, orthotics, rhizotomy, and orthopedic surgery, all play important roles in the management of spasticity. The purpose of this article is to provide an overview of available medications for treatment of spasticity in children with cerebral palsy. Common medications include benzodiazepines, dantrolene sodium, baclofen, tizanidine, botulinum toxins, phenol, alcohol and intrathecal baclofen. In general, oral medications and intrathecal baclofen are used for treating generalized spasticity, whilst chemodenervation agents (botulinum toxins, phenol, and alcohol) are used to treat localized spasticity. There is more sufficient evidence for the recommendation of botulinum toxin A as an effective anti-spasticity treatment in children with cerebral palsy. However, more data concerning safety and long-term effects of botulinum toxin A is needed. Further study is needed to determine which kinds of medications can cause substantial improvement in daily activity, participation level, self-competence, or quality of life in children with cerebral palsy. PMID- 21540004 TI - Prospective survey for the etiology and outcome of peptic ulcer bleeding: a community based study in southern Taiwan. AB - BACKGROUND/PURPOSE: Helicobacter pylori infection and drugs are the two major risk factors for peptic ulcer bleeding. The role of these two factors may change with changes in the prevalence of H pylori and use of NSAIDs. This study aimed to determine the cause, endoscopic features, and outcome of peptic ulcer bleeding in a community hospital in southern Taiwan. METHODS: Patients who received esophagogastroduodenoscopy on arrival at the emergency department and were found to have actively bleeding ulcers or ulcers with stigmata of recent hemorrhage were included. H pylori infection was documented by the rapid urease test, histology, and/or C-13 urease breath test. Medication history, comorbidities, requirement for endoscopic therapy, blood transfusion, hospitalization days, and rebleeding rates were analyzed. RESULTS: A total of 204 patients were enrolled with a mean age of 64.8 +/- 15.2 years, with 58.3% of the subjects being female. There were 62 patients (30.4%) with H pylori infection only, 40 patients (19.6%) with drug use only, 67 patients (32.8%) with H pylori infection and drug use, and 37 patients (17.2%) without H pylori or drug use. A total of 107 patients (52.5%) were found to have had drug exposure. Drug exposure had an odds ratio (OR) of 2.34 [95% Confidence Interval (CI) = 1.30-4.20] for gastric ulcer bleeding and H pylori had an OR of 2.64 (95% CI = 1.17-5.97) for combined gastric and duodenal ulcer bleeding. The mean hospitalization period was 5.7 +/- 4.0 days and the overall re-bleeding rate was 4.0%. The H pylori negative and drug negative subjects needed more endoscopic therapy (p < 0.05). CONCLUSION: Drug use, especially NSAIDs, aspirin, and clopidogrel has become an important cause of peptic ulcer bleeding in southern Taiwan. PMID- 21540005 TI - Brugada-type electrocardiogram in the Taiwanese population--is it a risk factor for sudden death? AB - BACKGROUND/PURPOSE: People receive electrocardiogram (ECG) examination for various reasons in a hospital setting. An important clinical practice issue may be that cardiologists need to be consulted for Brugada-type ECGs identified through routine screening. We investigated the prevalence and prognosis of patients with Brugada-type ECG in a hospital-based population in an attempt to improve the management of these patients. METHODS: In 20,562 patients seeking medical care for non-cardiovascular reasons, 74,955 ECGs were performed from December 1999 to February 2001. The diagnostic criteria for Brugada-like ECG from the European Society of Cardiology were used. International Statistical Classification of Diseases codes and city residents' records were documented to indicate the reasons for visiting clinics or hospitalization and mortality outcome. Medical records were reviewed and telephone interviews were conducted. RESULTS: Twenty-six (0.13%) of the 20,562 patients were confirmed to have Brugada type ECGs. None of these patients had ever experienced syncope, near syncope or sudden cardiac death. After 57.1 +/- 15.8 months of follow-up, there were four deaths out of the 26 patients with Brugada-type ECG (15.4%, 95% CI: 1.53-2.9%) compared with 2899 of those without (14.1%, 95% CI: 13.6-14.5%; p=0.89, log-rank test). Neither sudden cardiac death (p=0.61) nor hospitalized death (p=0.55) was different between patients with and without Brugada-type ECG. CONCLUSION: Patients with Brugada-type ECGs are not rare in a hospital-based population. The presence of Brugada-type ECGs in patients without syncope or sudden cardiac death was not associated with hospitalized mortality. PMID- 21540006 TI - Factors associated with in vitro interferon-gamma production in tuberculosis. AB - BACKGROUND/PURPOSE: Macrophage activation assisted by interferon-gamma (IFN gamma) is a primary mechanism by which Mycobacterium tuberculosis is killed, but IFN-gamma (production is inhibited in tuberculosis (TB) patients. The production of IFN-gamma is influenced by many factors, such as interleukin (IL)-10, IL-12, IL-18, and clinical diseases; but the relative importance of each factor is unclear. METHODS: We evaluated the effects of these factors in 46 healthy individuals, 81 patients with TB, and 88 patients with non-TB pneumonia. The responses of IFN-gamma, IL-10, IL-12 and IL-18 were determined from phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMCs). RESULTS: General linear model analysis showed that disease status and IL-12 response were the independent factors associated with the IFN-gamma response. The production of IFN-gamma was not affected by IL-10 and IL-18. There was a significant relationship between the IFN-gamma response and the IL-12 response among patients with non-TB pneumonia, patients with TB, and healthy participants (Pearson's correlation coefficients of 0.466, 0.483, and 0.464, respectively). CONCLUSION: Production of IFN-gamma in PBMCs was associated with active pulmonary TB and IL-12 response. PMID- 21540007 TI - Prevalence and correlates of geriatric frailty in a northern Taiwan community. AB - BACKGROUND/PURPOSE: Frailty is the core of geriatric syndromes in the elderly. However, there is no solid prevalence data in Taiwan even with the rapid growth of the elderly population. The aim of this study was to explore the prevalence of frailty defined by different instruments and to identify the factors associated with frailty in a northern Taiwan community. METHODS: The 65-79-year old community-dwelling residents randomly selected from Toufen were first screened with a telephone version of the Chinese Canadian Study of Health and Aging Clinical Frailty Scale (CCSHA-CFS; level 1-7). Those who scored 3-6 with this instrument were evaluated at a local hospital with the Fried Frailty Index (FFI) and the Edmonton Frail Scale (EFS). Other baseline characteristics including health and functional performance were also evaluated. RESULTS: Among the 2900 population representative samples, 845 (29.1%) completed the CCSHA-CFS telephone interview with the prevalence of frailty approximately 11.0% [95% confidence interval (CI) 8.9-13.1]. Among the 275 who completed assessments with FFI and EFS, prevalence of frailty was 11.3% (95% CI = 7.6-15.0) by FFI and 14.9% (95% CI = 10.7-19.1) by EFS. About 57.5% of respondents had memory impairment, 29.8% experienced pain, 25.1% experienced falls, 16.7% had depression, 14.5% had urinary incontinence, and 5.8% had polypharmacy. Being older, having more complaints with falls, pain, dysphagia, polypharmacy, depression, comorbidity, longer time for the Timed Up and Go test, less education, lower Mini-Mental State Examination score, and lower Barthel Index were associated with frailer status. In multinomial logistic regression analysis, increasing age, less education status, lower Barthel Index score and depression were positively associated with physical frailty. CONCLUSION: In this study, the prevalence of frailty was from 11.0% to 14.9% by different criteria and methodology. Various correlates were independently associated with frailty status. It is suggested that intervention for frailty requires an interdisciplinary approach. PMID- 21540008 TI - Prognostic predictors of outcome in an operative series in traumatic brain injury patients. AB - BACKGROUND: Although several prognostic factors for traumatic brain injury (TBI) have been evaluated, a useful predictive scoring model for outcome has yet to be developed for TBI patients. The aim of this study was to determine independent predictors and develop a multivariate logistic regression equation to determine prognosis in TBI patients. METHODS: A total of 13 different variables were evaluated. All 84 patients in this study were retrospectively evaluated between October 2003 and January 2008 and all underwent craniectomy or craniotomy for hematoma removal and were fitted with intracranial pressure (ICP) microsensor monitors. By using univariate, multiple logistic regression and prognostic regression scoring equations it was possible to draw Receiver-Operating Characteristic curves (ROC) to predict Glasgow Outcome Scale (GOS) 6 months after TBI. RESULTS: We found that patients over 40 years of age (p < 0.001), unresponsive pre-op pupil reaction (p =0.001), pre-op midline shift (p =0.008), higher injury severity score (ISS; p=0.007), and craniectomy (p < 0.05) were associated with poor outcome in patients with TBI. Using ROC curve to predict the probability of unfavorable outcome, the sensitivity was 97.5% and the specificity was 90.7%. CONCLUSION: In our preliminary findings, five variables to predict poor outcomes 6 months after TBI were useful. These sensitive variables can be used as a referential guideline in our daily practice to decide whether or not to perform advanced management or avoid decompressive craniectomy. PMID- 21540009 TI - Ectopic dentigerous cyst manifests as facial cellulitis. PMID- 21540010 TI - Standardized mortality ratio of inpatient suicide in a general hospital. AB - Inpatient suicide rates are seldom reported using age-standardized methods. This study aimed to estimate the standardized suicide rate in a general hospital. A total of 27 suicidal patients were identified by the adverse event reports during hospitalization from 1995 to 2004. Standardized suicide mortality ratios (SMR) were examined using the Poisson regression model. The SMR of inpatient suicide was 8.25 (95% CI = 5.67-12.06). Hospital suicide rates were considerably higher than the corresponding general population rates for all age groups and were particularly high in age categories of 25-29, 30-34, 40-44, and 55-59 years after controlling for sex and calendar year. Hospitalized patients had an eight times higher risk of suicide mortality than that of the general population. While the elderly are at increased risk for suicide in the general population, young- and middle-aged patients are the age group at risk for suicide mortality during hospitalization. PMID- 21540011 TI - Successful treatment of bronchoesophageal fistula with esophageal and bronchial stenting. AB - Bronchoesophageal fistula is reported in 5-10% of patients with esophageal cancer. In most of these cases, the insertion of a single stent, either a tracheobronchial or an esophageal stent, is sufficient to seal off the fistula. In this case we describe a 67-year-old man with esophageal cancer and complications of bronchoesophageal fistula, which resulted in repeated pneumonia and acute respiratory failure. Initially, two expandable metallic membranous esophageal stents were placed to cover the fistula. However, the esophageal stent failed to stop the air leak and dislodged into the stomach. Thereafter, a bronchial stent was placed at the right intermediate bronchus and successfully stopped the air leak. The patient was then weaned from the ventilator 1 week after the insertion of a bronchial stent. In conclusion, stenting in both the esophagus and airways should be considered when both are severely invaded by malignancy, when the airway is compressed, or when the fistula is insufficiently sealed by an esophageal stent. PMID- 21540012 TI - Sustainable landfilling or sustainable society without landfilling? PMID- 21540013 TI - Interfraction prostate rotation determined from in-room computerized tomography images. AB - Fiducial markers (FMs) are commonly used as a correction technique for interfraction translations of the prostate. The aim of this investigation was to determine the magnitude of prostate rotations using 2 methods: FM coordinates and the anatomical border of the prostate and rectum. Daily computed tomography (CT) scans (n = 346) of 10 prostate cancer patients with 3 implanted FMs were acquired using the CT on rails. FM coordinates were used to determine rotation in the sagittal, transverse, and coronal planes, and CT contours of the prostate and rectum were used to determine rotation along the sagittal plane. An adaptive technique based on a subset of images (n = 6; planning and first 5 treatment CTs) to reduce systematic rotation errors in the sagittal plane was tested. The standard deviation (SD) of systematic rotation from FM coordinates was 7.6 degrees , 7.7 degrees , and 5.0 degrees in the sagittal, transverse and coronal planes. The corresponding SD of random error was 10.2 degrees , 15.8 degrees , and 6.5 degrees . Errors in the sagittal plane, determined from prostate and rectal contours, were 10.1 degrees (systematic) and 7.7 degrees (random). These results did not correlate with rotation computed from FM coordinates (r = -0.017; p = 0.753, n = 337). The systematic error could be reduced by 43% to 5.6 degrees when the mean prostate position was estimated from 6 CT scans. Prostate rotation is a significant source of error that appears to be more accurately determined using the anatomical border of the prostate and rectum rather than FMs, thus highlighting the utility of CT image guidance. PMID- 21540014 TI - Skin cancer. PMID- 21540015 TI - No end in sight: the skin cancer epidemic continues. AB - The incidence of nonmelanoma skin cancer (NMSC) continues to increase. Multiple reports from the United States and Europe suggest we are in the midst of an epidemic. European studies show substantial NMSC incidence increases during the last 2 decades. In the United States, a recent analysis of Medicare Claims data showed that procedures performed for NMSC nearly doubled from 1994 to 2006. From these data, the total number of new NMSC in 2006 was estimated to be 3,507,693. Procedure data for 2006-2008 from the 5% Medicare Claims sample dataset corroborate the reported trajectory of incidence increase. Destructions, excisions, and Mohs procedures for NMSC have increased by 2.6% per year during the last 2 years. On the basis of this current rate of increase, the annual incidence of NMSC in the United States in 2008 would be nearly 3.69 million. Recognizing the NMSC epidemic is critical as the incidence-and cost-will continue to increase. PMID- 21540017 TI - Do lasers or topicals really work for nonmelanoma skin cancers? AB - Novel strategies are urgently needed to address the millions of nonmelanoma skin cancers treated in the United States annually. The need is greatest for those patients who are poor surgical candidates or those prone to numerous nonmelanoma skin cancers and therefore at risk for marked disfigurement. Traditional treatment strategies include electrosurgery with curettage, radiation therapy, cryotherapy, excision, and Mohs micrographic surgery. Alternatives to traditional treatment, including topical medications and light or laser therapies, are becoming popular; however, there are various degrees of efficacy among these alternative tactics. These alternatives include topical retinoids, peels, 5 fluorouracil, imiquimod, photodynamic therapy, and lasers. The purpose of this paper is to review the available data regarding these alternative strategies and permit the reader to have a sense of which therapies are reasonable options for care. PMID- 21540018 TI - Update on the management of high-risk squamous cell carcinoma. AB - Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy occurring in white patients in the United States and incidence rates are increasing. While the majority of the 87,000-760,000 cases that occur yearly in the U.S. are curable, 4% develop lymph node metastases and 1.5% die from the disease. Given the frequency of occurrence of CSCC, it is estimated to cause as many deaths yearly as melanoma, with the majority occurring in patients with high risk tumors or in those at high risk for metastasis due to a variety of host factors, most commonly systemic immunosuppression. There are currently no standardized prognostic or treatment models to assist clinicians in most effectively identifying and managing these patients. Identification of patients at risk for poor outcomes as well as standardization regarding classification, staging, and treatment of high-risk tumors is critical for optimizing patient care. In this article, available literature on the classification and management of high risk CSCC is briefly summarized, emphasizing new information. PMID- 21540016 TI - New agents for prevention of ultraviolet-induced nonmelanoma skin cancer. AB - With the incidence of nonmelanoma skin cancer on the rise, current prevention methods, such as the use of sunscreens, have yet to prove adequate to reverse this trend. There has been considerable interest in identifying compounds that will inhibit or reverse the biochemical changes required for skin cancers to develop, either by pharmacologic intervention or by dietary manipulation. By targeting different pathways identified as important in the pathogenesis of nonmelanoma skin cancers, a combination approach with multiple agents or the addition of chemopreventative agents to topical sunscreens may offer the potential for novel and synergistic therapies in treating nonmelanoma skin cancer. PMID- 21540019 TI - Current approaches to skin cancer management in organ transplant recipients. AB - Approximately 225,000 people are living with organ transplants in the United States. Organ transplant recipients have a greater risk of developing skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, with an approximately 250 times greater incidence of squamous cell carcinoma in certain transplant recipients, compared with the general population. Because skin cancers are the most common posttransplant malignancy, the resultant morbidity and mortality in these high-risk patients is quite significant. PMID- 21540021 TI - The role of targeted molecular inhibitors in the management of advanced nonmelanoma skin cancer. AB - Surgical treatment remains the standard of care for nonmelanoma skin cancer and is successful for the vast majority of patients with these tumors. The treatment of patients with metastatic or unresectable nonmelanoma skin cancer, however, has until recently been based solely on traditional methods of chemotherapy and radiation. However, these methods have high rates of treatment failure, morbidity, and mortality, and alternative treatment modalities for patients with aggressive or advanced disease are needed. As in other areas of cancer therapeutics, recent research elucidating the molecular basis of cancer development, and the subsequent arrival of targeted molecular inhibitors for cancer therapy, have been met with much excitement. In this review, we seek to illuminate recent developments and future possibilities in the use of targeted molecular inhibitors for treatment of advanced squamous cell carcinoma, basal cell carcinoma, and dermatofibrosarcoma protuberans. PMID- 21540020 TI - Merkel cell carcinoma: update and review. AB - Merkel cell carcinoma (MCC) is a rare, aggressive, and often fatal cutaneous malignancy that is not usually suspected at the time of biopsy. Because of its increasing incidence and the discovery of a possible viral association, interest in MCC has escalated. Recent effort has broadened our breadth of knowledge regarding MCC and developed instruments to improve data collection and future study. This article provides an update on current thinking about the Merkel cell and MCC. PMID- 21540022 TI - Evolution of motor innervation to vertebrate fins and limbs. AB - The evolution and diversification of vertebrate behaviors associated with locomotion depend highly on the functional transformation of paired appendages. Although the evolution of fins into limbs has long been a focus of interest to scientists, the evolution of neural control during this transition has not received much attention. Recent studies have provided significant progress in the understanding of the genetic and developmental bases of the evolution of fin/limb motor circuitry in vertebrates. Here we compare the organization of the motor neurons in the spinal cord of various vertebrates. We also discuss recent advances in our understanding of these events and how they can provide a mechanistic explanation for the evolution of fin/limb motor circuitry in vertebrates. PMID- 21540023 TI - The mechanism of lens placode formation: a case of matrix-mediated morphogenesis. AB - Although placodes are ubiquitous precursors of tissue invagination, the mechanism of placode formation has not been established and the requirement of placode formation for subsequent invagination has not been tested. Earlier measurements in chicken embryos supported the view that lens placode formation occurs because the extracellular matrix (ECM) between the optic vesicle and the surface ectoderm prevents the prospective lens cells from spreading. Continued cell proliferation within this restricted area was proposed to cause cell crowding, leading to cell elongation (placode formation). This view suggested that continued cell proliferation and adhesion to the ECM between the optic vesicle and the surface ectoderm was sufficient to explain lens placode formation. To test the predictions of this "restricted expansion hypothesis," we first confirmed that the cellular events that accompany lens placode formation in chicken embryos also occur in mouse embryos. We then showed that the failure of lens placode formation when the transcription factor, Pax6 was conditionally deleted in the surface ectoderm was associated with greatly diminished accumulation of ECM between the optic vesicle and ectoderm and reduced levels of transcripts encoding components of the ECM. In accord with the "restricted expansion hypothesis," the Pax6 deleted ectoderm expanded, rather than being constrained to a constant area. As a further test, we disrupted the ECM by deleting Fn1, which is required for matrix assembly and cell-matrix adhesion. As in Pax6(CKO) embryos, the Fn1(CKO) lens ectoderm expanded, rather than being constrained to a fixed area and the lens placode did not form. Ectoderm cells in Fn1(CKO) embryos expressed markers of lens induction and reorganized their cytoskeleton as in wild type ectoderm, but did not invaginate, suggesting that placode formation establishes the minimal mechanical requirements for invagination. PMID- 21540024 TI - Eszopiclone stimulates the hypothalamo-pituitary-adrenal axis in the rat. AB - Eszopiclone (Lunesta(r)) is used for the treatment of insomnia. It is the S (+) enantiomer of racemic zopiclone, a cyclopyrrolone with no structural similarity to the hypnotic drugs zolpidem and zaleplon or to the benzodiazepines and barbiturates. Although eszopiclone interacts with the gamma-aminobutyric acid A type (GABA(A)) receptor complex, it has a different binding profile than other sedative/hypnotic agents and modulates the receptor complex in a unique manner. Thus, eszopiclone might produce different pharmacological effects compared to other sedative/hypnotic agents. Beside their behavioral properties, sedative/hypnotic drugs affect the hypothalamo-pituitary-adrenal (HPA) axis. In general, low doses of benzodiazepine-type drugs decrease, whereas high doses increase the activity of the HPA axis. Furthermore, benzodiazepines reduce stress induced increases in HPA axis activity. The goal of the present study was to characterize the effects of eszopiclone on the HPA axis in the rat. Male rats were injected with saline or eszopiclone and trunk blood was collected for the measurement of plasma levels of adrenocorticotropin (ACTH) and corticosterone by radioimmunoassay. The acute administration of eszopiclone produced dose-dependent increases in plasma levels of ACTH and corticosterone, and tolerance developed to these effects after repeated drug administration. Pretreatment with eszopiclone did not affect stress-induced stimulation of the HPA axis. These results show that eszopiclone and the benzodiazepine-type drugs differentially affect the HPA axis. PMID- 21540025 TI - C5b-9-activated, K(v)1.3 channels mediate oligodendrocyte cell cycle activation and dedifferentiation. AB - Voltage-gated potassium (K(v)) channels play an important role in the regulation of growth factor-induced cell proliferation. We have previously shown that cell cycle activation is induced in oligodendrocytes (OLGs) by complement C5b-9, but the role of K(v) channels in these cells had not been investigated. Differentiated OLGs were found to express K(v)1.4 channels, but little K(v)1.3. Exposure of OLGs to C5b-9 modulated K(v)1.3 functional channels and increased protein expression, whereas C5b6 had no effect. Pretreatment with the recombinant scorpion toxin rOsK-1, a highly selective K(v)1.3 inhibitor, blocked the expression of K(v)1.3 induced by C5b-9. rOsK-1 inhibited Akt phosphorylation and activation by C5b-9 but had no effect on ERK1 activation. These data strongly suggest a role for K(v)1.3 in controlling the Akt activation induced by C5b-9. Since Akt plays a major role in C5b-9-induced cell cycle activation, we also investigated the effect of inhibiting K(v)1.3 channels on DNA synthesis. rOsK-1 significantly inhibited the DNA synthesis induced by C5b-9 in OLG, indicating that K(v)1.3 plays an important role in the C5b-9-induced cell cycle. In addition, C5b-9-mediated myelin basic protein and proteolipid protein mRNA decay was completely abrogated by inhibition of K(v)1.3 expression. In the brains of multiple sclerosis patients, C5b-9 co-localized with NG2(+) OLG progenitor cells that expressed K(v)1.3 channels. Taken together, these data suggest that K(v)1.3 channels play an important role in controlling C5b-9-induced cell cycle activation and OLG dedifferentiation, both in vitro and in vivo. PMID- 21540026 TI - cDNA microarray analysis and immunohistochemistry reveal a distinct molecular phenotype in serous endometrial cancer compared to endometrioid endometrial cancer. AB - PURPOSE: The main objective of this study was to refine more precisely the gene expression patterns used to distinguish serous from endometrioid endometrial carcinoma. METHODS: A low-density cDNA microarray containing 492 genes was designed and constructed. The gene expression profiles of 32 endometrioid and 5 serous endometrial cancer tissue samples were compared. The expression of 5 differentially expressed genes: NDC80, BUB1, FUT8, ANXA4 and BBC3 in endometrioid and serous adenocarcinoma samples was further evaluated by quantitative real-time PCR and immunohistochemistry. RESULTS: Unsupervised cluster analysis revealed that the 5 serous adenocarcinomas clustered together. These were separated from the endometrioid adenocarcinomas which were further sorted into 3 additional clusters. A comparative analysis indicated that there was a significant difference in FIGO stage with no significant difference in depth of myometrial invasion among the 4 clusters. The FIGO ternary grading system could not distinctly separate the 3 clusters of endometrioid adenocarcinomas, but a binary grading system was able to do so. Using a supervised analysis, we have identified 46 genes exhibiting >2-fold differences that can be used to statistically differentiate serous adenocarcinomas from endometrioid adenocarcinomas. The directions of gene and protein expression change of five differentially expressed genes estimated by real-time PCR and immunohistochemistry are consistent with those estimated from microarray. CONCLUSIONS: Serous adenocarcinoma exhibits distinct gene expression profiles, compared with those of endometrioid adenocarcinoma. These differences make it feasible to validate microarray data by immunohistochemistry, and they will ultimately allow us to identify tumors according to their immunohistochemical phenotype. The accuracy of classifying endometrial tumors using a system based on their gene expression patterns is much higher than the accuracy of the FIGO grading system. Thus, this gene expression pattern-based system may prove to be crucial in developing novel treatment strategies for endometrial cancers at the molecular level in future. PMID- 21540027 TI - Suppressor of cytokine signaling-3 and intimal hyperplasia in porcine coronary arteries following coronary intervention. AB - AIMS: The growth and differentiation of cells is regulated by cytokines by binding to cell-surface receptors and activating intracellular signal transduction cascade. Suppressor of cytokine signaling (SOCS)-3 is a negative regulator of cytokines. In this study we examined the expression of SOCS-3 in porcine coronary artery smooth muscle cells (PCASMCs) in vitro and in proliferating smooth muscle cells of neointimal lesions after coronary artery intervention in a swine model. METHODS AND RESULTS: PCASMCs were cultured and stimulated with TNF-alpha and/or IGF-1 individually or in combination. Protein expression of SOCS-3 was examined using Western blot. For in vivo studies, six female Yucatan miniswine were fed with special high cholesterol diet for 8 months. At 4 months of high cholesterol diet, animals underwent coronary balloon angioplasty. At the end of 8 months animals were euthanized, coronary arteries were isolated and morphological and histological studies were performed. Western blot data revealed significantly high SOCS-3 expression in PCASMCs in the presence of either TNF-alpha or IGF-1 (5-6 fold) alone. However, in the presence of both TNF-alpha and IGF-1 the SOCS-3 expression was significantly decreased (4 5 fold). Results from morphological studies including, H&E and Masson's trichrome stain showed typical lesions with significant neointimal proliferation. Histological evaluation showed expression of smooth muscle alpha-actin and significantly increased proliferating cell nuclear antigen (PCNA) in neointimal lesion. Interestingly, there was significantly decreased expression of SOCS-3 in smooth muscle cells of neointima as compared to control. CONCLUSIONS: These data suggest that SOCS-3 expression is decreased in proliferating smooth muscle cells of neointimal lesions. This leads to uncontrolled growth of vascular smooth muscle cells in injured arteries leading to restenosis. Therefore, local delivery of SOCS-3 gene at the site of injury after coronary artery intervention could regulate the proliferation of vascular smooth muscle cells and help in preventing the neointimal hyperplasia and restenosis. PMID- 21540028 TI - Specific inhibition of Candida albicans growth in vitro by antibodies from experimental Candida keratitis mice. AB - To investigate the role of humoral immunity in the response to experimental keratitis, Balb/c mice were primed by one of three protocols: i) intranasal inhalation of live Candida spores; ii) subcutaneous injection of heat-inactivated spores; or iii) induction and healing of primary CaK. Experimental murine CaK was then induced in the three groups of primed mice and one group of unprimed mice by intrastromal injection of live Candida albicans spores. Totally 30 mice were included in each group. Sera collected after CaK induction were subjected to serial dilution and their effects on fungal growth and survival were tested as an assay for fungicidal activity in vitro. Corneas removed at various stages of disease were examined histologically, and fungal loads were determined using quantitative real-time PCR. Compared to corneas from mice with primary CaK, all corneas from CaK mice that had been previously primed exhibited milder histological disruptions that were faster to resolve, contained higher immunoglobulin and IFNgamma titers, and had lower pathogen load (P < 0.05). Infiltration of pro-Inflammatory cells, which comprised mainly leukocytes other than lymphocytes, also initiated earlier in the primed mice compared to the controls (at day 3 versus day 7 respectively), and this should be due to differential production of cytokines. Sera from primed CaK mice exhibited stronger fungicidal activity and this was relatively specific for the original pathogen. Based on these findings, we proposed that the humoral response elicited by CaK plays important role in host protection against secondary C. albicans infections, and this might be achieved by pathogen-specific inhibition of fungal survival and/or growth. PMID- 21540029 TI - Modulation of the canonical Wnt pathway by Benzalkonium Chloride in corneal epithelium. AB - Benzalkonium Chloride (BAC) is commonly used in eyedrops. Although the cytotoxicity of BAC has been reported, the mechanism underlying its toxic effect has not been elucidated. The present study investigated the role of the Wnt signaling pathway in the cytotoxicity of BAC in corneal epithelial cells and in the rat cornea. We demonstrated that phosphorylation of beta-catenin, a downstream effector of the canonical Wnt pathway, was down-regulated by a short exposure to BAC in both cultured human corneal epithelial cells (HCE) and a cultured mouse corneal epithelial progenitor cell line (TKE2), suggesting an activation of the Wnt pathway. The activation of Wnt pathway is correlated with the decrease of cell viability induced by BAC. On the other hand, a specific Wnt pathway inhibitor, secreted frizzled-related protein-1 (sFRP1), reversed BAC induced down-regulating effects on the level of phosphorylation of beta-catenin and ameliorated cell viability in cells treated with BAC. In the rat cornea, the levels of total beta-catenin were significantly up-regulated 8 h after the topical administration of BAC. Taken together, these results provided novel evidence suggesting that the cytotoxicity of BAC may be mediated through modulation of the Wnt pathway. PMID- 21540030 TI - A swimmer in the bile duct. Diagnosis: Fasciola hepatica. PMID- 21540033 TI - Queen-specific volatile in a higher termite Nasutitermes takasagoensis (Isoptera: Termitidae). AB - In social insect colonies, queen-produced pheromones have important functions in social regulation. These substances influence the behavior and physiology of colony members. A queen-produced volatile that inhibits differentiation of new neotenic reproductives was recently identified in the lower termite Reticulitermes speratus. However, there are no known queen-specific volatiles of this type in any other termite species. Here, we report volatile compounds emitted by live queens of the higher termite Nasutitermes takasagoensis. We used headspace gas chromatography mass spectroscopy (HS GC-MS) to analyze volatiles emitted by live primary queens, workers, soldiers, alates, and eggs collected in a Japanese subtropical forest. Among 14 detected compounds, 7 were soldier specific, 1 was alate-specific, 1 was egg-specific, and 1 was queen-specific. The queen-specific volatile was phenylethanol, which is different than the compound identified in R. speratus. The identification of this queen-specific volatile is the first step in determining its functions in higher termite social regulation. Comparisons of queen pheromone substances regulating caste differentiation among various termite taxa will contribute to a better understanding of the evolution of social systems in termites. PMID- 21540032 TI - Phylogenetic and phylogeographic relationships in Ixodes holocyclus and Ixodes cornuatus (Acari: Ixodidae) inferred from COX1 and ITS2 sequences. AB - We inferred the phylogenetic and phylogeographic relationships in ticks, which were identified morphologically as Ixodes holocyclus and Ixodes cornuatus, from mitochondrial cytochrome oxidase subunit 1 (COX1) and nuclear internal transcribed spacer 2 (ITS2) sequences. We obtained COX1 (640bp) and ITS2 (527 568bp) sequences from 429 ticks from 49 localities in Tasmania, Victoria, New South Wales and Queensland, Australia. Our analyses show that there are two species of Ixodes in eastern Australia that cause paralysis in dogs and other mammals: I. holocyclus and I. cornuatus. Further, we conclude that the morphological criteria used to differentiate female I. holocyclus and I. cornuatus are equivocal but I. holocyclus can be distinguished from I. cornuatus using COX1 and/or ITS2 sequences. Intraspecific genetic variation in I. holocyclus and I. cornuatus was less than 0.86% and 0.19% for COX1 and ITS2, respectively. Ixodes holocyclus could be genetically distinguished between different geographic ranges. There were no significant genetic differences between I.cornuatus from Tasmania and mainland Australia, but there are some COX1 haplotypes of I. cornuatus from the mainland that were not detected in Tasmanian and vice versa. PMID- 21540034 TI - Microscopic and molecular characterization of ovarian follicle atresia in Rhodnius prolixus Stahl under immune challenge. AB - In this work we characterized the degenerative process of ovarian follicles of the bug Rhodnius prolixus challenged with the non-entomopathogenic fungus Aspergillus niger. An injection of A. niger conidia directly into the hemocoel of adult R. prolixus females at the onset of vitellogenesis caused no effect on host lifespan but elicited a net reduction in egg batch size. Direct inspection of ovaries from the mycosed insects revealed that fungal challenge led to atresia of the vitellogenic follicles. Light microscopy and DAPI staining showed follicle shrinkage, ooplasm alteration and disorganization of the monolayer of follicle cells in the atretic follicles. Transmission electron microscopy of thin sections of follicle epithelium also showed nuclei with condensed chromatin, electron dense mitochondria and large autophagic vacuoles. Occurrence of apoptosis of follicle cells in these follicles was visualized by TUNEL labeling. Resorption of the yolk involved an increase in protease activities (aspartyl and cysteinyl proteases) which were associated with precocious acidification of yolk granules and degradation of yolk protein content. The role of follicle atresia in nonspecific host-pathogen associations and the origin of protease activity that led to yolk resorption are discussed. PMID- 21540035 TI - The effect of dietary nickel on the immune responses of Spodoptera litura Fabricius larvae. AB - By exposing Spodoptera litura Fabricius larvae to nickel (Ni) in artificial diets for successive three generations, we investigated the impacts of the dietary Ni on growth and immune response of the fifth and sixth instar larvae at 24 h intervals. The time of newly moulted fifth instar larvae was labelled as 0 h. After exposure to 5 mg/kg Ni for two generations, Ni exposure significantly improved larval phenoloxidase activity and encapsulation grade in fifth instar larvae when compared to controls, except for encapsulation grade at 72-120 h in the second generation. However, higher concentrations of Ni (>=10 mg/kg) only significantly reduced encapsulation grade at 72-120 h. In the third generation, insects given higher dietary levels of Ni (>=10 mg/kg) showed lower immune responses and retarded relative growth rate (RGR) compared to controls, but those exposed to lower Ni levels (<=5 mg/kg) had a significantly improved encapsulation grade at 24-72 h. Larvae at lower Ni level (<=5 mg/kg) treatments had significantly higher RGR in comparison with that in controls. There was no significant difference in food relative consumption rate (RCR) and RGR among any treatment of the fifth instar larvae in three successive generations. These results indicated that the type and extent of effects on growth and immune responses of S. litura varied with the Ni concentrations and exposure periods. PMID- 21540036 TI - Selectivity and permeation of alkali metal ions in K+-channels. AB - Ion conduction in K(+)-channels is usually described in terms of concerted movements of K(+) progressing in a single file through a narrow pore. Permeation is driven by an incoming ion knocking on those ions already inside the protein. A fine-tuned balance between high-affinity binding and electrostatic repulsive forces between permeant ions is needed to achieve efficient conduction. While K(+)-channels are known to be highly selective for K(+) over Na(+), some K(+) channels conduct Na(+) in the absence of K(+). Other ions are known to permeate K(+)-channels with a more moderate preference and unusual conduction features. We describe an extensive computational study on ion conduction in K(+)-channels rendering free energy profiles for the translocation of three different alkali ions and some of their mixtures. The free energy maps for Rb(+) translocation show at atomic level why experimental Rb(+) conductance is slightly lower than that of K(+). In contrast to K(+) or Rb(+), external Na(+) block K(+) currents, and the sites where Na(+) transport is hindered are characterized. Translocation of K(+)/Na(+) mixtures is energetically unfavorable owing to the absence of equally spaced ion-binding sites for Na(+), excluding Na(+) from a channel already loaded with K(+). PMID- 21540037 TI - Which conditions promote negative density dependent selection on prey aggregations? AB - Negative density dependent selection on individuals in prey aggregations (negative DDS, the preferential selection by predators of spatially isolated prey) is assumed to contribute in many cases to the evolution and maintenance of aggregation. Both positive and negative DDS on prey groups have been documented in nature but there is no existing framework to predict when each of these forms of natural selection is most likely. By exploiting the tendency of artificial neural networks to exhibit consumer-like emergent behaviours, I isolate at least two environmental factors impinging on the consumer organism that may determine which form of density dependent natural selection is shown: the distribution of prey group size attacked by the predator and the spatial conformation (dispersed or compacted) of the prey group. Numerous forms of DDS on artificial prey (positive, negative, and non-DDS) are displayed through different combinations of these factors. I discuss in detail how the predictions of the model may be tested by empiricists in order to assess the usefulness of the framework presented. I stress the importance of understanding DDS on prey groups given the recent emergence of these systems as test beds for ideas on biological self organisation. PMID- 21540038 TI - Diffusion coefficient of modern humans outcompeting Neanderthals. AB - A nonlinear mathematical model is used to describe Neanderthals extinction about 35,000 years before present. Using archaeological data, radiocarbon re-calibrate speed among others, we show that the diffusion coefficient describing Modern Humans spread corresponds to 1596 km(2)/yr. The model is well established since all archaeological parameters, including Neanderthal-Modern interaction coefficient, become estimated. PMID- 21540039 TI - Estimating phylogenetic trees from pairwise likelihoods and posterior probabilities of substitution counts. AB - The field of phylogenetic tree estimation has been dominated by three broad classes of methods: distance-based approaches, parsimony and likelihood-based methods (including maximum likelihood (ML) and Bayesian approaches). Here we introduce two new approaches to tree inference: pairwise likelihood estimation and a distance-based method that estimates the number of substitutions along the paths through the tree. Our results include the derivation of the formulae for the probability that two leaves will be identical at a site given a number of substitutions along the path connecting them. We also derive the posterior probability of the number of substitutions along a path between two sequences. The calculations for the posterior probabilities are exact for group-based, symmetric models of character evolution, but are only approximate for more general models. PMID- 21540040 TI - Launching "the evolution of cooperation". AB - This article describes three aspects of the author's early work on the evolution of the cooperation. First, it explains how the idea for a computer tournament for the iterated Prisoner's Dilemma was inspired by the artificial intelligence research on computer checkers and computer chess. Second, it shows how the vulnerability of simple reciprocity of misunderstanding or misimplementation can be eliminated with the addition of some degree of generosity or contrition. Third, it recounts the unusual collaboration between the author, a political scientist, and William D. Hamilton, an evolutionary biologist. PMID- 21540041 TI - Mathematical modeling of fungal infection in immune compromised individuals: implications for drug treatment. AB - We present a mathematical model that describes treatment of a fungal infection in an immune compromised patient in which both susceptible and resistant strains are present. The resulting nonlinear differential equations model the biological outcome, in terms of strain growth and cell number, when an individual, who has both a susceptible and a resistant population of fungus, is treated with a fungicidal or fungistatic drug. The model demonstrates that when the drug is only successful at treating the susceptible strain, low levels of the drug cause both strains to be in stable co-existence and high levels eradicate the susceptible strain while allowing the resistant strain to persist or to multiply unchecked. A modified model is then described in which the drug is changed to one in which both strains are susceptible, and subsequently, at the appropriate level of treatment, complete eradication of both fungal strains ensues. We discuss the model and implications for treatment options within the context of an immune compromised patient. PMID- 21540042 TI - MicroRNA in lung cancer diagnostics and treatment. AB - MicroRNAs (miRs) are short RNA chains that regulate gene expression by inhibition of mRNA translation. Their expression is often deranged in cancer. Increasing evidence indicates that these molecules play an important role in oncogenesis and cancer progression. This review focuses on the clinical application of miRs in lung cancer, with the emphasis on detection of early lung cancer, prognostication and chemotherapy sensitivity prediction. Methodological aspects of studies on prognostic markers in early NSCLC are outlined in detail. Finally, modulation of miR expression in lung cancer as a therapeutic possibility is discussed. PMID- 21540043 TI - Mutagenic adaptive response to high-LET radiation in human lymphoblastoid cells exposed to low doses of heavy-ion radiation. AB - Adaptive response (AR) and bystander effect are two important phenomena involved in biological responses to low doses of ionizing radiation (IR). Furthermore, there is a strong interest in better understanding the biological effects of high LET radiation. We previously demonstrated the ability of low doses of X-rays to induce an AR to challenging heavy-ion radiation [8]. In this study, we assessed in vitro the ability of priming low doses (0.01Gy) of heavy-ion radiation to induce a similar AR to a subsequent challenging dose (1-4Gy) of high-LET IR (carbon-ion: 20 and 40keV/MUm, neon-ion: 150keV/MUm) in TK6, AHH-1 and NH32 cells. Our results showed that low doses of high-LET radiation can induce an AR characterized by lower mutation frequencies at hypoxanthine-guanine phosphoribosyl transferase locus and faster DNA repair kinetics, in cells expressing p53. PMID- 21540044 TI - Driving performance during word generation--testing the function of human brain lateralization using fTCD in an ecologically relevant context. AB - It has been hypothesized that cerebral lateralization of function enhances cognitive performance. Evidence was found in birds and fish. However, recent research in humans did not support this hypothesis. We aimed to replicate and extend these findings for single- and dual-task performance in an ecologically relevant task. We combined a word generation task which is assumed to be primarily processed in the left hemisphere with a driving task which is assumed to be primarily processed in the right hemisphere. For each task the individual strength and direction of hemispheric lateralization was assessed by using functional transcranial Doppler sonography (fTCD). For each subject (36 right handed, 35 nonright-handed) performance was measured in the two single-tasks and in the dual-task condition. On average, subjects showed a left hemisphere bias for the word generation task, a right hemisphere bias for the driving task and dual-task interference. Within subjects, lateralization of language and driving were statistically independent. In accordance with earlier studies, the results show no indication of a positive effect of strength of lateralization on performance in single-tasks or dual-task efficiency. We also found no advantage of a typical compared to an atypical or a contralateral compared to an ipsilateral lateralization pattern. In right-handers, but not in nonright handers, we even found a negative relationship between strength of lateralization and dual-task efficiency for atypically lateralized subjects. This further supports the suggestion that lateralization does not enhance cognitive performance in humans. PMID- 21540045 TI - A domain-specific system for representing knowledge of both man-made objects and human actions. Evidence from a case with an association of deficits. AB - We report the single-case study of a brain-damaged individual, JJG, presenting with a conceptual deficit and whose knowledge of living things, man-made objects, and actions was assessed. The aim was to seek for empirical evidence pertaining to the issue of how conceptual knowledge of objects, both living things and man made objects, is related to conceptual knowledge of actions at the functional level. We first found that JJG's conceptual knowledge of both man-made objects and actions was similarly impaired while his conceptual knowledge of living things was spared as well as his knowledge of unique entities. We then examined whether this pattern of association of a conceptual deficit for both man-made objects and actions could be accounted for, first, by the "sensory/functional" and, second, the "manipulability" account for category-specific conceptual impairments advocated within the Feature-Based-Organization theory of conceptual knowledge organization, by assessing, first, patient's knowledge of sensory compared to functional features, second, his knowledge of manipulation compared to functional features and, third, his knowledge of manipulable compared to non manipulable objects and actions. The later assessment also allowed us to evaluate an account for the deficits in terms of failures of simulating the hand movements implied by manipulable objects and manual actions. The findings showed that, contrary to the predictions made by the "sensory/functional", the "manipulability", and the "failure-of-simulating" accounts for category-specific conceptual impairments, the patient's association of deficits for both man-made objects and actions was not associated with a disproportionate impairment of functional compared to sensory knowledge or of manipulation compared to functional knowledge; manipulable items were not more impaired than non manipulable items either. In the general discussion, we propose to account for the patient's association of deficits by the hypothesis that concepts whose core property is that of being a mean of achieving a goal - like the concepts of man made objects and of actions - are learned, represented and processed by a common domain-specific conceptual system, which would have evolved to allow human beings to quickly and efficiently design and understand means to achieve goals and purposes. PMID- 21540046 TI - Effects of ovariectomy and 17-beta estradiol replacement on rat brown adipose tissue mitochondrial function. AB - Taking into account the sexual dimorphism previously reported regarding mitochondrial function and biogenesis in brown adipose tissue, the aim of the present study was to go further into these differences by investigating the effect of ovariectomy and 17-beta estradiol (E2) replacement on brown adipose tissue mitochondrial function. In this study, fourteen-week-old control female and ovariectomized female Wistar rats were used. Rats were ovariectomized at 5 weeks of age and were treated every 2 days with placebo (OVX group) or E2 (10 MUg/kg) (OVX+E2 group) for 4 weeks before sacrifice. We studied the levels of oxidative capacity, antioxidant defence and oxidative damage markers in brown adipose tissue. Moreover, the levels of key elements of mitochondrial biogenesis as well as UCP1 protein levels, as an index of mitochondrial thermogenic capacity, were also determined. In response to ovariectomy, mitochondrial proliferation increased, resulting in less functional mitochondria, since oxidative capacity and antioxidant defences decreased. Although E2 supplementation was able to restore the serum levels of E2 shown by control rats, the treatment reverted the effects of the ovariectomy only in part, and oxidative and antioxidant capacities in OVX+E2 rats did not reach the levels shown by control females. Taking these results into account, we suggest that ovarian hormones are responsible, at least in part, for the sexual dimorphism in BAT mitochondrial function. However, other signals produced by ovary, rather than E2, would play an important role in the control of mitochondrial function in BAT. PMID- 21540047 TI - Preference for binocular concordant visual input in early postnatal development remains despite prior monocular deprivation. AB - Short daily periods of binocular vision, if concordant and continuous, have been shown to outweigh or protect against much longer daily periods of monocular deprivation to allow the development of normal visual acuity in both eyes of kittens. The greater weight placed on binocular visual input could arise because of an inherent bias for binocular input within the visual pathway at all times during development (Binocular model), or else from a more passive process that follows from its match to a highly binocular template at the time mixed daily visual input began (Template model). To distinguish between the predictions of these two models, kittens were monocularly deprived from normal eye-opening until either 4, 5, or 6 weeks of age at which time they received mixed daily visual input for 4 weeks. According to the Template model, the preferred input for these animals would be monocular exposure (ME) because of its match to the monocular template produced by a period of preceding monocular deprivation. However, instead of short daily period of ME offsetting much longer periods of binocular exposure (BE) to perpetuate the dire effects of the prior deprivation, short daily periods of BE promoted significant recovery of vision in the deprived eye. The fit to the Binocular model implies the existence of a robust substrate for binocular vision that is highly resistant to disruption and which could form the substrate for binocular approaches to treatment of amblyopia. PMID- 21540048 TI - Glutamate receptors - prenatal insults, long-term consequences. AB - Glutamate receptors play an important role in brain development. Any factor interfering with glutamate receptors might have potentially harmful effects by modulation and impacting on functional brain development. Increased glutamate levels and subsequent activation of glutamate receptors can cause excitotoxic cell death. In this review we describe the developmental regulation and role of glutamate receptors in brain development. Furthermore, we discuss environmental factors that potentially modify glutamate receptors in the fetal brain during pregnancy. We also highlight the importance of glutamate receptors in the pathophysiology of brain injury in preterm born infants and discuss anti excitotoxic treatments currently investigated in preclinical animal models of developmental brain injury. PMID- 21540049 TI - Could clinical decision rules relying on cardiovascular risk models increase psychosocial inequalities in health? Results from the PRIME cohort study. AB - OBJECTIVE: Guidelines on cardiovascular prevention relying on common cardiovascular risk scoring could result in delayed drug therapy for patients with low psychosocial status because of underestimation of true cardiovascular risk. We aimed to assess the potential delay in drug therapy for subjects with adverse psychosocial factors. METHOD: The study population consisted of 6185 French men from the PRIME (Prospective Epidemiological Study of Myocardial Infarction) cohort study (1991-2003). The number of extra years to reach a risk threshold for subjects without adverse psychosocial factor compared to subject with adverse psychosocial factor was estimated using a coronary risk model including biomedical factors and a psychosocial variable (education, occupation, living conditions or a depression score). RESULTS: Coronary risk was significantly higher only for subjects with a high depression score (odds ratio=1.34; 95% confidence interval 1.04, 1.72) or low educational attainment (odds ratio=1.39; 95% confidence interval=1.07, 1.81). For a given risk threshold, subjects with high depression scores were 4.5 years (95% confidence interval=0.0, 15.4 years) younger than subjects with low depression scores. The age difference was 4.1 years (95% confidence interval=-0.5, 15.8 years) between subjects with low and high educational attainment. CONCLUSION: Clinical decision rules relying on classic cardiovascular risk scoring could result in delayed drug therapy for patients with depression or low educational attainment. PMID- 21540050 TI - Growing tumor vessels: more than one way to skin a cat - implications for angiogenesis targeted cancer therapies. AB - The establishment of a functional, integrated vascular system is instrumental for tissue growth and homeostasis. Without blood vessels no adequate nutrition and oxygen would be provided to cells, nor could the undesired waste products be efficiently removed. Blood vessels constitute therefore one of the largest and most complex body network whose assembly depends on the precise balance of growth factors acting in a complementary and coordinated manner with cells of several identities. However, the vessels that are crucial for life can also foster death, given their involvement in cancer progression towards malignancy and metastasis. Targeting tumor vasculature has thus arisen as an appealing anti-cancer therapeutic approach. Since the milestone achievements that vascular endothelial growth factor (VEGF) blockade suppressed angiogenesis and tumor growth in mice and prolonged the survival of cancer patients when administered in combination with chemotherapy, the clinical development of anti-VEGF(R) drugs has accelerated remarkably. FDA has approved the use of bevacizumab - a humanized monoclonal antibody against VEGF - in colorectal, lung and metastatic breast cancers in combination with standard chemotherapy. Additional broad-spectrum VEGF receptor tyrosine kinase inhibitors, such as sunitinib and sorafenib, are used in monotherapy for metastatic renal carcinoma, while sunitinib is also approved for imatinib resistant gastrointestinal stromal tumors and sorafenib for advanced stage hepatocellular carcinoma. Nevertheless, the survival benefit offered by VEGF(R) blockers, either as single agents or in combination with chemotherapy, is calculated merely in the order of months. Posterior studies in preclinical models have reported that despite reducing primary tumor growth, the inhibition of VEGF increased tumor invasiveness and metastasis. The clinical implications of these findings urge the need to reconcile these conflicting results. Anti-angiogenic therapy represents a significant step forth in cancer therapy and in our understanding of cancer biology, but it is also clear that we need to learn how to use it. What is the biological consequence of VEGF-blockade? Does VEGF inhibition starve the tumor to death - as initially postulated - or does it rather foster malignancy? Can anti-VEGF(R) therapy favor tumor vessel formation by VEGF-independent means? Tumors are very diverse and plastic entities, able to adapt to the harshest conditions; this is also reflected by the tumor vasculature. Lessons from the bench to the bedside and vice versa have taught us that the diversity of signals underlying tumor vessel growth will likely be responsive (or resistant) to distinct therapeutic approaches. In this review, we propose a reflection of the different strategies tumors use to grow blood vessels and how these can have impact on the (un)success of current anti-angiogenic therapies. PMID- 21540051 TI - The defensin gene family expansion in the tick Ixodes scapularis. AB - Ixodid ticks transmit a variety of pathogens by blood feeding. Here, we report computational identification of two multigene families of defensin-like peptides (DLPs) in the Ixodes scapularis genome, one corresponding to scapularisin and the other named scasin. Members in the scapularisin family share high sequence similarity to some antibacterial ancient invertebrate-type defensins (AITDs) isolated from primitive insects, arachnids, bivalvia, and fungi whereas scasins represent a novel family of DLPs identified by their overall acidic molecular surface and low sequence similarity to any known defensins. Codon-substitution models support neutral evolution in scapularisins but strong positive selection signal was found throughout the molecules of scasins. The synthetic gamma-core region of scapularisin-20 exhibits a wide-spectrum of antimicrobial activity at micromolar concentrations. The finding of extensive gene expansion of DLPs in a vector arachnida may be valuable in the understanding of its role in pathogen transmission. PMID- 21540052 TI - Transporters associated with antigen processing (TAP) in sea bass (Dicentrarchus labrax, L.): molecular cloning and characterization of TAP1 and TAP2. AB - The transporters associated with antigen processing (TAP), play an important role in the MHC class I antigen presentation pathway. In this work, sea bass (Dicentrarchus labrax) TAP1 and TAP2 genes and transcripts were isolated and characterized. Only the TAP2 gene is structurally similar to its human orthologue. As other TAP molecules, sea bass TAP1 and TAP2 are formed by one N terminal accessory domain, one core membrane-spanning domain and one canonical C terminal nucleotide-binding domain. Homology modelling of the sea bass TAP dimer predicts that its quaternary structure is in accordance with that of other ABC transporters. Phylogenetic analysis segregates sea bass TAP1 and TAP2 into each subfamily cluster of transporters, placing them in the fish class and suggesting that the basic structure of these transport-associated proteins is evolutionarily conserved. Furthermore, the present data provides information that will enable more studies on the class I antigen presentation pathway in this important fish species. PMID- 21540054 TI - Toward accurate volumetry of brain aneurysms: combination of an algorithm for automatic thresholding with a 3D eraser tool. AB - The present study describes a new approach for aneurysm volume quantification on three-dimensional angiograms, which focuses on solving three common technical problems: the variability associated with the use of manual thresholds, the irregular morphology of some aneurysms, and the imprecision of the limits between the parent artery and the aneurysm sac. The method consists of combining an algorithm for automatic threshold determination with a spherical eraser tool that allows the user to separate the image of the aneurysm from the parent artery. The accuracy of volumetry after automatic thresholding was verified with an in vitro experiment in which 57 measurements were performed using four artificial aneurysms of known volume. The reliability of the method was compared to that obtained with the technique of ellipsoid approximation in a clinical setting of 15 real angiograms and 150 measurements performed by five different users. The mean error in the measurement of the artificial aneurysms was 7.23%. The reliability of the new approach was significantly higher than that of the ellipsoid approximation. Limits of agreement between two measurements were determined with Bland-Altman plots and ranged from -14 to 13% for complex and from -10.8 to 11.03% for simple-shaped sacs. The reproducibility was lower (>20% of variation) for small aneurysms (<70 mm3) and for those presenting a very wide neck (dome-to-neck ratio<1). The method is potentially useful in the clinical practice, since it provides relatively precise, reproducible, volume quantification. A safety coiling volume can be established in order to perform sufficient but not excessive filling of the aneurysm pouch. PMID- 21540053 TI - Intensity-invariant coding in the auditory system. AB - The auditory system faithfully represents sufficient details from sound sources such that downstream cognitive processes are capable of acting upon this information effectively even in the face of signal uncertainty, degradation or interference. This robust sound source representation leads to an invariance in perception vital for animals to interact effectively with their environment. Due to unique nonlinearities in the cochlea, sound representations early in the auditory system exhibit a large amount of variability as a function of stimulus intensity. In other words, changes in stimulus intensity, such as for sound sources at differing distances, create a unique challenge for the auditory system to encode sounds invariantly across the intensity dimension. This challenge and some strategies available to sensory systems to eliminate intensity as an encoding variable are discussed, with a special emphasis upon sound encoding. PMID- 21540056 TI - Strategies to quantify unspliced and multiply spliced mRNA expression in HIV-2 infection. AB - HIV-2 infection is associated with a slower rate of disease progression with limited impact on the survival of the majority of infected adults, and much lower plasma viral load than HIV-1. In spite of the major differences in viremia, the quantitative assessment of HIV-2 proviral load documented levels similar to those observed in HIV-1 infected individuals, suggesting an equivalent number of circulating infected cells in both infections. It remains unclear whether this apparent paradox results from a contribution of latent/quiescent viruses or from transcriptional and/or post-transcriptional control of HIV-2 replication. In order to investigate these possibilities, a one-step and two-step reverse transcription quantitative real-time PCR based methods (RT-qPCR) for gag and tat mRNA HIV-2 transcripts were developed. These methods were validated and compared to assess the expression of HIV-2 gag and tat transcripts in parallel with proviral DNA and viral production. The results suggest that the two-step approach may allow a better detection of low level gag and tat mRNA HIV-2 transcripts. PMID- 21540057 TI - Detection and differentiation of bovine herpesvirus 1 and 5 using a multiplex real-time polymerase chain reaction. AB - A multiplex real-time PCR was developed for the detection and differentiation of two closely related bovine herpesviruses 1 (BoHV-1) and 5 (BoHV-5). The multiplex real-time PCR combines a duplex real-time PCR that targets the DNA polymerase gene of BoHV-1 and BoHV-5 and a real-time PCR targeting mitochondrial DNA, as a house-keeping gene, described previously by Cawthraw et al. (2009). The assay correctly identified 22 BoHV-1 and six BoHV-5 isolates from the Biosecurity Sciences Laboratory virus collection. BoHV-1 and BoHV-5 were also correctly identified when incorporated in spiked semen and brain tissue samples. The detection limits of the duplex assay were 10 copies of BoHV-1 and 45 copies of BoHV-5. The multiplex real-time PCR had reaction efficiencies of 1.04 for BoHV-1 and 1.08 for BoHV-5. Standard curves relating Ct value to template copy number had correlation coefficients of 0.989 for BoHV-1 and 0.978 for BoHV-5. The assay specificity was demonstrated by testing bacterial and viral DNA from pathogens commonly isolated from bovine respiratory and reproductive tracts. The validated multiplex real-time PCR was used to detect and differentiate BoHV-1 and BoHV-5 in bovine clinical samples with known histories. PMID- 21540055 TI - Direct injection into the dorsal root ganglion: technical, behavioral, and histological observations. AB - Direct injection of agents into the dorsal root ganglia (DRGs) offers the opportunity to manipulate sensory neuron function at a segmental level to explore pathophysiology of painful conditions. However, there is no described method that has been validated in detail for such injections in adult rats. We have found that 2 MUl of dye injected through a pulled glass pipette directly into the distal DRG, exposed by a minimal foraminotomy, produces complete filling of the DRG with limited extension into the spinal roots. Injection into the spinal nerve required 3 MUl to achieve comparable DRG filling, produced preferential spread into the ventral root, and was accompanied by substantial leakage of injected solution from the injection site. Injections into the sciatic nerve of volumes up to 10 MUl did not reach the DRG. Transient hypersensitivity to mechanical stimulation at threshold (von Frey) and noxious levels (pin) developed after 2 MUl saline injection directly into the DRG that was in part attributable to the surgical exposure procedure alone. Only minimal astrocyte activation in the spinal dorsal horn was evident after DRG saline injections. Injection of adeno associated virus (AAV) vector conveying green fluorescent protein (GFP) transgene resulted in expression as soon as 1 day after injection into the DRG, including fibers in the spinal dorsal horn and columns. AAV injection into the DRG produced additional thermal hypersensitivity and withdrawal from the stroke of a brush and compromised motor performance. These findings demonstrate a method for selective injection of agents into single DRGs for anatomically restricted actions. PMID- 21540058 TI - Recombinant glycoprotein E produced in mammalian cells in large-scale as an antigen for varicella-zoster-virus serology. AB - A recombinant glycoprotein E (gE) from varicella-zoster virus (VZV) was generated and produced in Chinese Hamster Ovary (CHO) cells, in the development of a specific antigen for analysis of IgG antibodies to VZV. Several stable gE secreting clones were established and one clone was adapted to growth in serum free suspension culture. When the cells were cultured in a perfusion bioreactor, gE was secreted into the medium, from where it could be easily purified. The recombinant gE was then evaluated as a serological antigen in ELISA. When compared to a conventional whole virus antigen, the VZV gE showed similar results in ELISA-based seroprevalence studies of 854 samples derived from blood donors, students, ischemic stroke patients and their controls, including samples with border-line results in previous analyses. Eight samples (0.9%) were discordant, all being IgG-negative by the VZV gE ELISA and positive by the whole virus ELISA. The sensitivity and specificity of the VZV gE ELISA were 99.9% and 100%, respectively, compared to 100% and 88.9% for the VZV whole virus ELISA. The elderly subjects showed similar reactivities to both antigens, while VZV gE gave lower signals in the younger cohorts, suggesting that antibodies to gE may increase with age. It was concluded that the recombinant VZV gE from CHO cells was suitable as a serological antigen for the detection of IgG antibodies specific for VZV. PMID- 21540059 TI - Significant effects of 4-aminopyridine and tetraethylammonium in the treatment of 6-hydroxydopamine-induced Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder characterizing by degeneration of dopaminergic neurons in the nigrostriatal pathway. The discovery of levodopa revolutionized the treatment of PD however, after several years of treatment most patients develop involuntary movements which significantly impair the quality of life. 4-Aminopyridine (4-AP) and tetraethylammonium (TEA) are wide-spectrum potassium channel blockers which based on the animal model studies and clinical trials have beneficial effects in treatment of several neurological disorders such as ataxia, Alzheimer disease and multiple sclerosis. Current study investigates effect of these blockers in the treatment of 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. After surgical injection of 6-OHDA into medial forebrain bundle, behavioral tests were performed in the 2nd and 3rd weeks post-surgery. Only animals which showed more than 100 apomorphine-induced rotations/1h in the 3rd week were selected for evaluation of the blocker effects. Statistical analysis of results from rotational test shows that application of high dose of 4-AP (1mg/kg) and moderate dose of TEA (2mg/kg) attenuate behavioral symptoms of the Parkinsonism while high dose of TEA (5mg/kg) and application both 4-AP and TEA exacerbates these symptoms. Results from elevated body swing test confirmed the effects of TEA but not 4-AP on the rotational test. However, experiments performed on the partial Parkinsonian rats show that application of high dose of TEA attenuates apomorphine-induced rotational asymmetry significantly. Our findings indicating TEA and 4-AP could have significant effects in attenuation of PD symptoms but these effects are sensitive to dose and degree of severity of PD. PMID- 21540060 TI - Schedule-induced polydipsia in the spontaneously hypertensive rat and its relation to impulsive behaviour. AB - Eight Spontaneously Hypertensive Rat (SHR), 8 Wistar-Kyoto (WKY) and 8 Wistar rats, all male, maintained at 80-85% of their free-feeding weight by controlled access to food, were exposed to a series of fixed time (FT) schedules whereby food pellets were regularly delivered regardless of the animals' behaviour. The FT values used were 9, 15, 30, 60, 120 and 180 s, with the order of presentation of the schedules among the animals being counterbalanced (except under the FT 120 s and 180-s schedules, which were successively presented as the last two of the series). Due to freely available access to water, the animals developed schedule induced drinking under all FT schedules, marked by the characteristic bitonic function that relates the number of licks and amount of water drunk to the length of the inter-food interval. Wistar and WKY rats displayed maximum drinking under an FT 15-s schedule, with WKY rats registering lower quantities across all FT values. Among SHR rats, maximum schedule-induced polydipsia was observed under the FT 30-s schedule, with a rightward shift in the bitonic function compared to controls. For long FT values, the temporal distribution of licks within inter food intervals was shifted slightly towards the right in the SHR rats. In a subsequent study, only the SHR and Wistar rats were used, and the animals were exposed to a delay-discounting procedure. The rats were faced with successive choices, in which they could choose between an immediate reward of one food pellet and another of four food pellets at a delay of 3, 6, 12 or 24s. In the case of the longer delays, SHR rats chose the immediate reward of lower magnitude more often than did their Wistar counterparts, and also committed a greater number of omissions during the forced-choice trials of the procedure. The results indicate that differences in schedule-induced polydipsia are related to indexes of cognitive rather than motor impulsivity, a finding in line with the theoretical idea that adjunctive behaviour is linked to operant reinforcement processes. PMID- 21540061 TI - Neonatal exposure to propofol affects BDNF but not CaMKII, GAP-43, synaptophysin and tau in the neonatal brain and causes an altered behavioural response to diazepam in the adult mouse brain. AB - Animal studies have shown that neonatal anaesthesia is associated with acute signs of neurodegeneration and later behavioural changes in adult animals. The anaesthetic effect of propofol is thought to be mediated by gamma-amino butyric acid (GABA)(A) receptors. The present study investigated the effects on proteins important for normal neonatal brain development (i.e. BDNF, CaMKII, GAP-43, synaptophysin and tau), and adult spontaneous motor and anxiety-like behaviours in response to diazepam, after neonatal exposure to propofol. Ten-day-old mice were exposed to 0, 10 or 60 mg/kg bodyweight propofol. Neonatal propofol exposure changed the levels of BDNF in the brain, 24h after exposure, but did not alter any of the other proteins. Neonatal propofol exposure significantly changed the adult response to the GABA-mimetic drug diazepam, manifest as no change in spontaneous motor activity and/or reduced sedative effect and an extinguished effect on the reduction of anxiety-like behaviours in an elevated plus maze. Although no adult spontaneous behavioural changes were detected after neonatal propofol exposure, the exposure caused an adult dose-dependent decrease in the response to the GABA-mimetic drug diazepam. These changes may be due to neonatal alterations in BDNF levels. PMID- 21540063 TI - Assembly and characterization of lipid-lipid binding protein particles. AB - Lipid-protein complexes, lipoplexes, are currently of great interest because of their immunogenic, gene free, and low cost properties. For their applications as potential vaccines, it is critical to display a target protein on the surface of lipoplex particles to allow external interactions to take place. However, how to effectively assemble lipoplexes with target proteins externally accessible is a constant challenge. In this study, human liver fatty acid binding protein 1 (hl FABP1) was used as a model protein in lipoplex assembly with a non-lipid binding protein, bovine serum albumin (BSA), serving as a comparison. The protein-lipid particles were assembled by four different processes and characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), flow cytometry (FCM), and a modified ELISA. Results indicate that by incubating the target protein with pre-formed liposomes at a temperature higher than all transition temperatures (T(m)) of the lipids used through an extended period of time, 1.48*10(-6)nmol per lipoplex of incorporated proteins can be detected by ELISA and are externally accessible. Additional experiments showed that most of those externally accessible proteins are likely embedded in the lipid bilayer structure and are not subject to dissociation from the lipoplex particles at elevated salt concentrations. PMID- 21540062 TI - Auditory cortical tuning to band-pass noise in primate A1 and CM: a comparison to pure tones. AB - We examined multiunit responses to tones and to 1/3 and 2/3 octave band-pass noise (BPN) in the marmoset primary auditory cortex (A1) and the caudomedial belt (CM). In both areas, BPN was more effective than tones, evoking multiunit responses at lower intensity and across a wider frequency range. Typically, the best responses to BPN remained at the characteristic frequency. Additionally, in both areas responses to BPN tended to be of greater magnitude and shorter latency than responses to tones. These effects are consistent with the integration of more excitatory inputs driven by BPN than by tones. While it is generally thought that single units in A1 prefer narrow band sounds such as tones, we found that best responses for multi units in both A1 and CM were obtained with noises of narrow spectral bandwidths. PMID- 21540064 TI - Redundancy in putrescine catabolism in solvent tolerant Pseudomonas putida S12. AB - Pseudomonas putida S12 is a promising platform organism for the biological production of substituted aromatic compounds due to its extreme tolerance towards toxic chemicals. Solvent or aromatic stress tolerance may be due to membrane modifications and efflux pumps; however in general, polyamines have also been implicated in stressed cells. Previous transcriptomics results of P. putida strains producing an aromatic compound, or being exposed to the solvent toluene, indicated differentially expressed genes involved in polyamine transport and metabolism. Therefore, the metabolism of the polyamine, putrescine was investigated in P. putida S12, as no putrescine degradation pathways have been described for this strain. Via transcriptome analysis various, often redundant, putrescine-induced genes were identified as being potentially involved in putrescine catabolism via oxidative deamination and transamination. A series of knockout mutants were constructed in which up to six of these genes were sequentially deleted, and although putrescine degradation was affected in some of these mutants, complete elimination of putrescine degradation in P. putida S12 was not achieved. Evidence was found for the presence of an alternative pathway for putrescine degradation involving gamma-glutamylation. The occurrence of multiple putrescine degradation routes in the solvent-tolerant P. putida S12 is indicative of the importance of controlling polyamine homeostasis, as well as of the high metabolic flexibility exhibited by this microorganism. PMID- 21540065 TI - High levan accumulation in transgenic tobacco plants expressing the Gluconacetobacter diazotrophicus levansucrase gene. AB - Bacterial levansucrase (EC 2.4.1.10) converts sucrose into non-linear levan consisting of long beta(2,6)-linked fructosyl chains with beta(2,1) branches. Bacterial levan has wide food and non-food applications, but its production in industrial reactors is costly and low yielding. Here, we report the constitutive expression of Gluconacetobacter diazotrophicus levansucrase (LsdA) fused to the vacuolar targeting pre-pro-peptide of onion sucrose:sucrose 1 fructosyltransferase (1-SST) in tobacco, a crop that does not naturally produce fructans. In the transgenic plants, levan with degree of polymerization above 10(4) fructosyl units was detected in leaves, stem, root, and flowers, but not in seeds. High levan accumulation in leaves led to gradual phenotypic alterations that increased with plant age through the flowering stage. In the transgenic lines, the fructan content in mature leaves varied from 10 to 70% of total dry weight. No oligofructans were stored in the plant organs, although the in vitro reaction of transgenic LsdA with sucrose yielded beta(2,1)-linked FOS and levan. Transgenic lines with levan representing up to 30mgg(-1) of fresh leaf weight produced viable seeds and the polymer accumulation remained stable in the tested T1 and T2 progenies. The lsdA-expressing tobacco represents an alternative source of highly polymerized levan. PMID- 21540066 TI - Identification of a potent MAR element from the mouse genome and assessment of its activity in stable and transient transfections. AB - Matrix attachment regions are DNA sequences found throughout eukaryotic genomes that are believed to define boundaries interfacing heterochromatin and euchromatin domains, thereby acting as epigenetic regulators. When included in expression vectors, MARs can improve and sustain transgene expression, and a search for more potent novel elements is therefore actively pursued to further improve recombinant protein production. Here we describe the isolation of new MARs from the mouse genome using a modified in silico analysis. One of these MARs was found to be a powerful activator of transgene expression in stable transfections. Interestingly, this MAR also increased GFP and/or immunoglobulin expression from some but not all expression vectors in transient transfections. This effect was attributed to the presence or absence of elements on the vector backbone, providing an explanation for earlier discrepancies as to the ability of this class of elements to affect transgene expression under such conditions. PMID- 21540067 TI - Perceptual and lexical knowledge of vegetables in preadolescent children. AB - The present study investigated the visual and lexical knowledge of vegetables in children. The purpose of this was to identify both liked and disliked familiar vegetables which will be used in a further study. We explored children's lexical knowledge with a free listing test and their visual knowledge with a picture's sorting test. 145 children between the ages of 8 and 11 years from various living environments of the Rhone-Alpes Region, France, completed both tests. Overall, 54 vegetables were cited, 16 of which were cited by more than 9% of the sample. Carrots, tomatoes and lettuce were the most named vegetables and the best visually recognized by children. Lexical knowledge increased gradually with age. Children from rural areas named significantly more vegetables than those from urban areas. However, visual recognition of vegetables did not change as a function of age or living environment. This suggests that visual categorization allows easier accessing to semantic knowledge than verbal questioning. Finally, the data showed a relation between visual familiarity and liking: the majority of raw vegetables recognized visually were also classified as "liked vegetables". In addition, children declared that they did not want to try most of the unknown vegetables. PMID- 21540068 TI - Lower concentrations of methyl-beta-cyclodextrin combined with interleukin-2 can preferentially induce activation and proliferation of natural killer cells in human peripheral blood. AB - Previous studies have demonstrated that high concentrations of methyl-beta cyclodextrin (MbetaCD, 10-15 mM) can interfere with the formation of lipid rafts and inhibit activation of lymphocytes. In this report, we determined that lower concentrations of MbetaCD (1-4 mM) could accelerate the proliferation of lymphocytes in human peripheral blood mononuclear cells (PBMCs). In the expanded cells, CD3(-)CD56(+) natural killer (NK) cells were the dominant subpopulation, and a significant dose-effect relationship existed between the proportion of NK cells and the concentration of MbetaCD. In the groups treated with 3-4 mM MbetaCD, the proportions of NK cells reached a level of more than 60%. When PBMCs were treated with MbetaCD, CD69 was more preferentially expressed on CD3( )CD56(+) cells than on CD3(+) cells at 48 and 72 hours. The expression of CD25 had no distinct difference at 48 hours, but when recombinant human interleukin-2 (IL-2) was added for a further 24 hours, it was also preferentially expressed on NK cells. MbetaCD and IL-2 synergistically could also induce interferon-gamma (IFN-gamma) production in CD56(+) human PBMCs. Mechanistic studies revealed that IFN-gamma production in response to MbetaCD plus IL-2 was IL-12 independent but depended on endogenous IL-18 and IL-1beta, and CD56(+)CD14(+) dendritic cell-like cells and B cells might mediate the ability of MbetaCD to activate NK cells. The MbetaCD-activated NK cells also had high cytotoxicity against the natural killer cell-sensitive K562 cells or lymphokine-activated killer cell-sensitive DAUDI cells in vitro. These studies indicated that lower concentrations of MbetaCD combined with IL-2 can preferentially induce activation and proliferation of NK cells in PBMCs. PMID- 21540069 TI - Evaluation of the antioxidant and antiproliferative potential of bioflavors. AB - alpha-Terpineol is a relatively cheap and abundant aroma compound. It is widely used in food, cosmetics, and household products. Many of its monoterpene counterparts have been applied in antiproliferative assays, leading to promising results in the prevention or even treatment of cancers. However, despite its theoretic potential, no paper reports the evaluation of antiproliferative capacity of this alcohol. Thus, antioxidant potential of three monoterpenoids (carvone, perillyl alcohol, and alpha-terpineol) was measured using two methods: DPPH and ORAC. Also, the antiproliferative effect of these monoterpenoids against nine cancerous cell lines were performed and compared to limonene and doxorubicin. Results showed that all samples tested had very low antioxidant activity in the DPPH assay, but alpha-terpineol (2.72MUmolTrolox equiv./MUmol) could be compared to commercial antioxidants in the ORAC assay. The antiproliferative results obtained encourage future in vivo studies for alpha terpineol, since this monoterpenoid presented cytostatic effect against six cell lines, especially for breast adenocarcinoma and chronic myeloid leukemia, in a range of 181-588MUM. PMID- 21540070 TI - Toxicity of a novel anti-tumor agent 20(S)-ginsenoside Rg3: a 26-week intramuscular repeated administration study in Beagle dogs. AB - The potential subchronic toxicity of a dammarane-type triterpenoid saponin with antitumor effect, 20(S)-Ginsenoside Rg3, was studied repeated intramuscular administration in Beagle dogs over a 26-week period. 20(S)-Ginsenoside Rg3 was administrated intramuscularly at 0, 0.70, 2.86 or 7.20 mg/kg/day doses for 26 weeks in both male and female dogs (n = 4 for male and female dogs for each dose). During the test period as well as during the 8-week recovery period, clinical signs, mortality, body weights, food consumption, respiratory frequency, electrocardiogram, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. In dogs treated with doses of 2.86 or 7.20 mg/kg, hematological investigations revealed a dose dependent increase in the total white blood cell (WBC) count and in the percentage of neutrophils, but a decrease in the percentage of lymphocytes. These effects were completely reversed during the recovery period, and no other adverse effects were observed. The no-observed-adverse-effect levels for both male and female dogs were considered to be 7.20 mg/kg/day. PMID- 21540071 TI - In utero and lactational beta-carotene supplementation attenuates D-galactose induced hearing loss in newborn rats. AB - D-Galactose could give rise to free radical damage by disturbing the some maternal antioxidants. The oxidative stress induced by D-galactose is a potent inducer of apoptosis, which is accompanied by the activation of protein-splitting enzymes called caspases. Apoptosis is a crucial physiological determinant of embryonic and neonatal development, and play an essential role in the development of the inner ear structures. Recently the increasing of D-galactose exposure is due to high consumption of dairy foods or reduced galactose metabolism. An overwhelming presence of D-galactose is known to become highly ototoxicity to humans. The purpose of this study was to investigate whether supplementation of pregnant and lactational mothers with beta-carotene could attenuate cochlear function damage and hair cells apoptosis induced by d-galactose in newborn rats. Pregnant rats were supplemented with D-galactose, or D-galactose and beta carotene from gestational day (GD) 7 until postnatal day (PND) 21. On PND 22, offspring were examined in the distortion product otoacoustic emission (DPOAE) task, cochleae were then harvested for assessment of apoptosis by immunohistochemical stain for cysteine-aspartic acid proteases 3 (caspase-3) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. Maternal and offspring blood samples were then collected by direct cardiac puncture in heparin tubes, blood levels of D-galactose and beta-carotene were measured, plasma was separated for malondialdehyde (MDA) analysis, erythrocytes were left for superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH). D-Galactose could significantly disturb the balance between maternal antioxidants and free radicals, and induce hearing loss in the offspring and cochlear hair cell apoptosis. In contrast, beta-carotene supplementation, coincidentally with D-galactose exposure, ameliorated these changes. Our data offer a conceptual framework for designing clinical trials using a safe micronutrient, beta-carotene, as a simple preventive strategy for D-galactose induced ototoxicity. PMID- 21540073 TI - Circum-menopausal changes in women's preferences for sexually dimorphic shape cues in peer-aged faces. AB - Recent studies suggest that post-menopausal women demonstrate stronger preferences for feminine characteristics in male and female faces than do pre menopausal women, potentially reflecting stronger preferences for healthy men and greater derogation of attractive women among more fertile women. A limitation of this work was that it assessed circum-menopausal women's face preferences using images of young adults only. Here, we found that post-menopausal women demonstrated stronger preferences for feminine characteristics in male and female peer-aged faces that did pre-menopausal women. These data present novel evidence for circum-menopausal variation in face perception and confirm that the circum menopausal variation in face preferences observed previously was not an artefact of the young faces employed as stimuli. PMID- 21540072 TI - Plasma oxytocin is related to lower cardiovascular and sympathetic reactivity to stress. AB - In addition to known reproductive and social affiliation functions, oxytocin (OT) has been identified as a cardiovascular hormone. OT synthesis and receptors are found in cardiac and vascular tissue. Animal studies suggest that OT activates an 'anti-stress' response that reduces cardiovascular and neuroendocrine stress reactivity. We tested 28 early postpartum mothers, obtaining multiple blood samples for OT, the sympathetic marker, norepinephrine (NE), and the lactation hormone, prolactin, while monitoring their cardiovascular responses to two stressors: public speaking and forehead cold pressor. Although plasma OT did not increase reliably from pre-stress levels during stressors, greater overall OT level was related to greater vasodilation and cardiac stroke volume responses to both tasks, to reduction in heart rate to the cold pressor, as well as to lower plasma NE and higher prolactin levels. In contrast, higher NE was linked to increases in heart rate and decreases in stroke volume. These data support a cardioprotective role for OT, which may influence the magnitude and hemodynamic determinants of cardiovascular stress responses. PMID- 21540074 TI - Forced expression of the histone demethylase Fbxl10 maintains self-renewing hematopoietic stem cells. AB - OBJECTIVE: The methylation status of histones changes dramatically depending on cellular context and defines cell type-specific gene expression profiles. Histone demethylases have recently been implicated in this process. However, it is unknown how histone demethylases function in the maintenance of self-renewing hematopoietic stem cells (HSCs). MATERIALS AND METHODS: We profiled the expression of histone demethylase genes in mouse hematopoietic cells and listed genes preferentially expressed in HSCs. We analyzed the impact of a selected gene by transducing CD34(-)c-Kit(+)Sca-1(+)lineage marker(-) (CD34(-)KSL) HSCs using retroviral system followed by in vitro methylcellulose colony assays and in vivo competitive repopulation assays. RESULTS: We found that F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b or Kdm2b), is highly expressed in CD34(-)KSL HSCs. Fbxl10 encodes a demethylase specific to the histone H3 mono/di methylated at lysine 36 (H3K36me1/me2) and forms complexes with polycomb-group proteins, essential regulators of HSCs. Forced expression of Fbxl10 in HSCs expanded numbers of colony-forming cells with multilineage differentiation potential in culture and prevented exhaustion of the long-term repopulating potential of HSCs following serial transplantation. Fbxl10 tightly repressed the expression of cyclin-dependent kinase inhibitor genes, including Ink4a, Ink4b, and Ink4c, through direct binding to their promoters and gene bodies and demethylation at H3K36. Increased levels of mono-ubiquitylation of H2A at target loci also suggested the collaboration of Fbxl10 with polycomb-group proteins. CONCLUSIONS: Our findings implicate Fbxl10 in the maintenance of self-renewal capacity of HSCs, thus highlight a role of histone demethylation for the first time in the epigenetic regulation of HSCs. PMID- 21540075 TI - Mathematical analysis of a cholera model with public health interventions. AB - Cholera, an acute gastro-intestinal infection and a waterborne disease continues to emerge in developing countries and remains an important global health challenge. We formulate a mathematical model that captures some essential dynamics of cholera transmission to study the impact of public health educational campaigns, vaccination and treatment as control strategies in curtailing the disease. The education-induced, vaccination-induced and treatment-induced reproductive numbers R(E), R(V), R(T) respectively and the combined reproductive number R(C) are compared with the basic reproduction number R(0) to assess the possible community benefits of these control measures. A Lyapunov functional approach is also used to analyse the stability of the equilibrium points. We perform sensitivity analysis on the key parameters that drive the disease dynamics in order to determine their relative importance to disease transmission and prevalence. Graphical representations are provided to qualitatively support the analytical results. PMID- 21540076 TI - Calcium dependence of purinergic subtype P2Y1 receptor modulation of C6 glioma cell migration. AB - We have examined activation of purinergic P2Y1 receptor-dependent Ca2+-signaling pathways in mediating C6 glioma cell migration. The administration of 2 methylthioadenosine 5'-diphosphate (2MeSADP), a selective agonist for P2Y1R, induced marked increases in patterns of glioma migration in both scratch wound and Boyden chamber assays. Antagonism of P2Y1R with either the broad spectrum purinergic blocker, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS) or the specific P2Y1R antagonist, 2'-deoxy-N6-methyladenosine-3',5'-bisphosphate (MRS2179), significantly inhibited C6 cell migration. Calcium-sensitive spectrofluorometry showed 2MeSADP stimulation of glioma cells caused a biphasic change in intracellular Ca2+ ([Ca2+]i). The rapid transient phase was unchanged in Ca2+-free solution reflecting a [Ca2+]i component due to intracellular stores release subsequent to activation of a metabotropic P2Y subtype receptor. The secondary prolonged phase of [Ca2+]i was abolished in Ca2+-free solution or in glioma cells treated with the store-operated channel (SOC) blocker, SKF96365. Treatment of glioma with either MRS2179 or PPADS significantly attenuated both the rapid and prolonged phases of [Ca2+]i. These results suggest critical roles for activation of P2Y1R in mediating glioma cell mobility and migration with changes in [Ca2+]i contributing as a mechanistic link between activated receptor and functional response. Our findings suggest that pharmacological modulation of metabotropic P2Y1R-dependent signaling pathways may serve as a novel therapeutic procedure to slow glioma progression. PMID- 21540077 TI - Myt/NZF family transcription factors regulate neuronal differentiation of P19 cells. AB - During mammalian central nervous system development, neural stem cells differentiate and then mature into various types of neurons. Myelin transcription factor (Myt)/neural zinc finger (NZF) family proteins were first identified as myelin proteolipid protein promoter binding factors and were shown to be involved in oligodendrocyte development. In this study, we found that Myt/NZF family molecules were expressed during neuronal differentiation in vivo and in vitro. Transient over-expression of Myt/NZF family genes could convert undifferentiated P19 cells into neurons without induction by retinoic acid (RA), and the ability of these genes to induce neuronal differentiation was comparable to that of Neurog1 and Neurod1. Additionally, we found that St18 (or NZF-3) was induced by several bHLH transcription factors. When NZF-3 and Neurog1 were co-expressed in P19 cells, the rate of neuronal differentiation was significantly increased. These data suggest not only that NZF-3 works downstream of Neurog1 but also that it plays a crucial role together with Neurog1 in neuronal differentiation. PMID- 21540078 TI - Effects of visual stimulus complexity on event-related brain potentials and viewing duration in a free-viewing task. AB - The anterior N2 is a component of the event-related brain potential (ERP) elicited by visual novel stimuli. Previous studies have reported that the stimuli that were viewed for longer periods of time elicited a larger anterior N2 than the stimuli viewed for shorter periods of time. To scrutinize this relationship between the ERP and viewing duration in response to visual materials, 18 university students were asked to look at various random polygons one-by-one for as long as they wished. ERPs time-locked to stimulus onset were averaged separately for three levels of complexity (12-, 24-, and 48-sided polygons). We found that the more complex the stimulus, the larger the anterior negativity (N2, 200-300 ms) and the posterior positivity (late positive potential [LPP], 400-800 ms), and the longer the viewing duration. However, when ERPs were calculated separately for the stimuli viewed for longer or shorter than the median viewing time of each participant at each complexity level, no amplitude differences were found in either component. These results suggest that the previously reported correlation between the anterior N2 and visual duration is spurious and produced by a third variable, namely, the perceptual demand of the eliciting stimulus such as complexity. PMID- 21540079 TI - Gait initiation is affected during emotional conflict. AB - The present study examined whether emotion eliciting images affected motor output when a whole body movement was concerned: gait initiation. From a standing posture, 15 young adults were instructed to initiate gait (several steps) towards pleasant or unpleasant images corresponding to a congruent (CO) or an incongruent (IC) task. The movement was performed as soon as possible after the onset of images, using a paradigm of go/nogo. Because an emotional conflict had to be overcome in IC trials, we hypothesized that the longest reaction times and lowest amplitude of early postural adjustments were found during IC trials, as compared to CO trials. We also anticipated that conflict resolution would be improved if the previous trial was IC rather than CO, as previously reported in a typical press button task. Results demonstrated longer reaction times in IC than CO trials revealing that emotional conflict resolution interfered with cognitive resources involved in motor planning. Although the peak of forward velocity reached by the centre of body mass at the end of the first step and length of this step were similar between CO and IC trials, the amplitude of early postural modifications was reduced in IC trials. All together, these findings provided supporting evidence that a defensive response, possibly a freezing-like behaviour, was implemented during IC trials, but in a transient manner. Furthermore, conflict resolution was improved when the previous trial was IC rather than CO in terms of amplitude of early postural response, but not reaction time. PMID- 21540080 TI - Gonadal hormone regulation of the emotion circuitry in humans. AB - Gonadal hormones are known to influence the regulation of emotional responses and affective states. Whereas fluctuations in progesterone and estradiol are associated with increased vulnerability for mood disorders, testosterone is mainly associated with social dominance, aggressive, and antisocial behavior. Here, we review recent functional neuroimaging studies that have started to elucidate how these hormones modulate the neural circuitry that is important for emotion regulation, which includes the amygdala and the medial prefrontal (mPFC) and orbitofrontal cortex (OFC). The amygdala is thought to generate emotional responses, and the prefrontal brain regions to regulate those responses. Overall, studies that have investigated women during different phases of the menstrual cycle suggest that progesterone and estradiol may have opposing actions on the amygdala and prefrontal cortex. In addition, the influence of exogenous progesterone appears to be dose-dependent. Endogenous testosterone concentrations are generally positively correlated to amygdala and OFC responses, and exogenous testosterone increases amygdala reactivity. Whereas the administration of progesterone increases amygdala reactivity and its connectivity with the mPFC, testosterone administration increases amygdala reactivity but decreases its connectivity with the OFC. We propose that this opposing influence on amygdala prefrontal coupling may contribute to the divergent effects of progesterone and testosterone on emotion regulation and behavioral inhibition, respectively, which may promote the differential vulnerability to various psychiatric disorders between women and men. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. PMID- 21540081 TI - Progranulin enhances neural progenitor cell proliferation through glycogen synthase kinase 3beta phosphorylation. AB - Progranulin (PGRN) is an estrogen-inducible growth factor thought to affect multiple processes in the CNS, including brain sexual differentiation, adult neurogenesis in the hippocampus, and development of neurodegenerative diseases. However, the precise physiological functions of PGRN in individual nerve cells are not fully understood. The aim of the present study was to enhance the understanding of PGRN function in the CNS by investigating the effects of PGRN on neural progenitor cells (NPCs). We found that significant amounts of endogenous PGRN were secreted from isolated NPCs in cultures. To assess the bioactivities of endogenous and exogenous PGRN, we studied NPCs derived from wild-type mice (WT NPCs) and PGRN-deficient mice (KO-NPCs). We found that proliferation of KO-NPCs was significantly enhanced by PGRN treatment; however, PGRN treatment apparently did not affect proliferation of WT-NPCs perhaps because of the high levels of endogenous PGRN expression. NPC death and asymmetric cellular division of KO-NPCs and WT-NPCs, which results in production of neural stem cells, astrocytes, or oligodendrocytes, were not affected by PGRN treatment. We also investigated the signaling mechanism(s) that mediate PGRN-induced NPC proliferation and found that phosphorylation of serine 9 (S9) of glycogen synthase kinase 3-beta (GSK3beta), which was dependent on phosphatidylinositol 3-kinase (PI3K) activity, was induced by PGRN treatment. In addition, a GSK3beta-specific inhibitor enhanced NPC proliferation. Taken together, our observations indicate that PGRN enhanced NPC proliferation, at least in part, via inducing GSK3beta phosphorylation. PMID- 21540082 TI - Suppression of cAMP-dependent gene expression by cholecystokinin in the hippocampus. AB - Our previous study suggests that "the neuropeptidergic system" might promote a diversity of the mechanisms that regulate signal transmission in the hippocampus. Cholecystokinin (CCK) is the mostly expressed neuropeptide gene in the hippocampus. Here, we investigated whether CCK regulates immediate-early genes (Egr1/zif268 and Fos), critical indicators of cortical neuronal activity. We showed that CCK increased Egr1/zif268 promoter activity in a neuronal cell line, which is transfected with CCK(B) receptor. Unexpectedly, in living hippocampal slices, CCK significantly suppressed cAMP-induced expression of Egr1/zif268 and Fos through CCK(B) receptor activation. This suppression was involved in activating GABA(B) and cannabinoid 1 receptors. In addition to transient CCK modulation of action potentials on hippocampal principal neurons, we suggest that release of endogenous CCK might indirectly produce the suppression of cAMP dependent gene expression in the hippocampus. PMID- 21540083 TI - Characterization of human FHL2 transcript variants and gene expression regulation in hepatocellular carcinoma. AB - The four-and-a-half LIM protein 2 (FHL2) was originally identified to be expressed abundantly in the heart, as well as in a wide range of tissues demonstrated in various studies. The human FHL2 gene expresses different transcripts which are known to differ only in the 5'UTR region. However, little is known about the functional role of the different variants and the mechanism of gene regulation. In the present study, we characterized the different alternative spliced transcripts of FHL2 by in silico analysis and RT-PCR analysis. A novel transcript variant was identified. The FHL2 gene produces transcripts by different 5' exons, which may be responsible for tissue-specific regulation. To study the mechanism of FHL2 gene regulation, the potential promoter region was investigated. We have identified a functional promoter region upstream of the transcription start site. Deletion mutation analysis of 5' flanking region showed that the fragment from -138 to +292 bp have positive regulatory effect. We identified the binding sites of Pax-5/ZF5 in this region and found that Pax-5 and ZF5 expression in HCC samples had a significant positive correlation with FHL2 expression, suggesting a possible role for these transcription factors in the regulation of FHL2 expression. PMID- 21540084 TI - Role of the Nrf2-ARE pathway in acrylamide neurotoxicity. AB - Acrylamide (ACR) intoxication is associated with selective nerve terminal damage in the central and peripheral nervous systems. As a soft electrophile, ACR could form adducts with nucleophilic sulfhydryl groups on cysteine residues of kelch like erythroid cell-derived protein with CNS homology-associated protein 1 (Keap1) leading to dissociation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 activation of the antioxidant responsive element (ARE) and subsequent upregulated gene expression of phase II detoxification enzymes and anitoxidant proteins might provide protection in neuronal regions with transcriptional capabilities (e.g., cell body). In contrast, non-transcriptional cell regions (axons, nerve terminals) might be vulnerable to electrophile-induced damage. To test this possibility, immunoblot analysis was used to measure protein products of Nrf2-activated ARE genes in nerve terminals and in cytosolic/nuclear factions of neuronal cell bodies isolated from rats intoxicated at two different ACR dose-rates; i.e., 50mg/kg/d*10 days, 21mg/kg/d*38 days. To detect possible differences in cell specific induction, the cytoprotective response to ACR intoxication was determined in hepatic cells. Results show that control brain and hepatic cell fractions exhibited distinct subcellular distributions of Nrf2, Keap1 and several ARE protein products. ACR intoxication, however, did not alter the levels of these proteins in synaptosomal, brain cytoplasm or liver cell fractions. These data indicate that ACR was an insufficient electrophilic signal for ARE induction in all subcellular fractions tested. Because a cytoprotective response was not induced in any fraction, nerve terminal vulnerability to ACR cannot be ascribed to the absence of transcription-based defense mechanisms in this neuronal region. PMID- 21540085 TI - Docetaxel-loaded-lipid-based-nanosuspensions (DTX-LNS): preparation, pharmacokinetics, tissue distribution and antitumor activity. AB - The purpose of the study was to design lipid-based-nanosuspensions (LNS) for Docetaxel (DTX) without Tween 80 for clinical intravenous administration (i.v.). DTX-LNS were prepared by high pressure homogenization method, and then lyophilization was carried out to improve the stability. The physical-chemical properties in terms of particle size, size distribution, zeta potential and morphology were evaluated, respectively. The in vitro cytotoxic activity was assessed by MTT against SKOV-3 and malignant melanoma B16 cells. The in vivo pharmacokinetics, tissue distribution as well as antitumor efficacy were investigated in B16 melanoma-bearing Kunming mice. The particle size and zeta potential of DTX-LNS were (200.0 +/- 3.42)nm and (-11.15 +/- 0.99)mV, respectively. Compared with Duopafei, it was shown that DTX-LNS exhibited higher antitumor efficacy by reducing tumor volume (P<0.05) and increasing survival rate in B16 melanoma-bearing mice and strongly reduced the anticancer drug toxicity. The results of biodistribution studies clearly indicated the superiority of DTX LNS to Duopafei in increasing the accumulation of DTX within tumor and the organs rich in macrophages (liver, lungs and spleen), while, the drug concentration in heart and kidney decreased. Together these results suggested that DTX-LNS could effectively inhibit tumor growth, reduce toxicity during the therapeutic procedure and hold the potential to be an appropriate choice for the clinical administration of DTX. PMID- 21540086 TI - Probing the mechanism of insulin aggregation during agitation. AB - Agitation of insulin during its storage and transport has been reported to denature the protein, resulting in its inactivation. The physical changes accompanying the denaturation process which result in aggregation of insulin are poorly understood. In this work, we study the aggregates formed following agitation of insulin under defined conditions by different physical and chemical techniques. We show that both non-disulphide-mediated covalent bonds as well as non-covalent interactions are involved in the formation of aggregates. The two step kinetics of aggregation could be clearly seen, with discrete 'early' and 'late' stages of fibrillation. Understanding the nature of agitation-induced aggregates will help in devising a strategy to protect this therapeutic protein against instability during its storage and transport. PMID- 21540087 TI - Inhalation performance of pollen-shape carrier in dry powder formulation: effect of size and surface morphology. AB - In a previous study, pollen-shape drug carriers are compared with traditional carriers at different drug mixing ratios and flow rates. It is found that pollen shape drug carriers can deliver large amount of drug particles and reduce drug losses especially at low flow rates and high drug mixing ratios. In this study, the effect of size and surface morphology of pollen-shape carriers on drug delivery performance is assessed. Pollen-shape carrier particles having various sizes and surface asperities are synthesized. Budesonide (Bd) is used as the model drug. The drug delivery performances of the pollen-shape carrier particles are investigated using an Andersen Cascade Impactor (ACI) equipped with a Rotahaler at gas flow rates of 30 and 60 L/min. Three drug mixing ratios are considered. While an increase in the carrier particle size has a mild improvement on the ED, it significantly improves the FPF. A sparse surface asperity has negligible effect on the ED at low flow rates but it improves the FPF compared to a dense surface asperity under all experimental conditions. PMID- 21540088 TI - Preparation and evaluation of glyceryl monooleate-coated hollow-bioadhesive microspheres for gastroretentive drug delivery. AB - The purpose of this study was to produce hollow and bioadhesive microspheres to lengthen drug retention time in the stomach. In these microspheres, ethylcellulose was used as the matrix, Eudragit EPO was employed to modulate the release rate, and glyceryl monooleate (GMO) was the bioadhesive polymer in situ. The morphological characteristics of the microspheres were defined using scanning electron microscopy. The in vitro release test showed that the release rate of drug from the microspheres was pH-dependent, and was not influenced by the GMO coating film. The prepared microspheres demonstrated strong mucoadhesive properties with good buoyancy both in vitro and in vivo. Pharmacokinetic analysis indicated that the elimination half-life time of the hollow-bioadhesive microspheres was prolonged, and that the elimination rate was decreased. In conclusion, the hollow-bioadhesive synergic drug delivery system may be advantageous in the treatment of stomach diseases. PMID- 21540089 TI - Improvement of some physicochemical properties of arundic acid, (R)-(-)-2 propyloctanonic acid, by complexation with hydrophilic cyclodextrins. AB - Arundic acid, (R)-(-)-2-propyloctanonic acid, is a novel neurological agent for intractable neurodegenerative diseases. However, arundic acid, an oily drug, has low aqueous solubility and severe bitter/irritating tastes. Consequently, these physicochemical properties of arundic acid need to be improved to develop its pharmaceutical preparations. In the present study, we evaluated whether parent cyclodextrins (CyDs) and 2-hydroxypropylated CyDs (HP-CyDs) can interact with arundic acid, and have powderization, solubilization and taste-masking properties. Of various CyDs, HP-beta-CyD had the most potent solubilizing effect for arundic acid. UV and (1)H NMR spectroscopic studies demonstrated that arundic acid formed inclusion complexes with CyDs at a molar ratio of 1:1 in solution. The complexation with CyDs changed an oily form of arundic acid to a solid form. The gustatory sensation studies indicate that of various CyDs, HP-beta-CyD and gamma-CyD showed the most significant taste-masking effects in solution and powders, respectively. HP-beta-CyD significantly reduced the response of the electric potential caused by the adsorption of arundic acid to the taste sensor. These results suggest that hydrophilic CyDs have potential as multifunctional excipients for preparing solutions and powders containing arundic acid. PMID- 21540090 TI - Potent dried drug nanosuspensions for oral bioavailability enhancement of poorly soluble drugs with pH-dependent solubility. AB - The objective of this study was to enhance the oral bioavailability of itraconazole (ITZ) with dried drug nanosuspensions. The feasibility of using poloxamer 407 or HPMC (50 cp) as stabilizers for preparing ITZ nanosuspensions by facile acid-base neutralization was investigated. Dried ITZ nanosuspensions were prepared by spray drying. The effect of matrix former on the dissolution rate of dried ITZ nanosuspensions was investigated. Results from dissolution test revealed that spray-dried ITZ nanosuspensions (ITZ:HPMC:mannitol 1:0.5:2, w/w) preserved the high dissolution rate from nanosuspensions. After oral administration in rats, the AUC(0-36) from dried ITZ nanosuspensions was 1.5-fold and 1.8-fold higher than the AUC(0-36) from sporanox pellets (commercial product) in the fed and fasted states, respectively (p<0.05). More importantly, the AUC(0 36) from dried ITZ nanosuspensions showed no difference between fed/fasted states, because this formulation could enhance the adsorption of ITZ in target site (small intestine) regardless of food intake. In addition, dried ITZ nanosuspensions showed a lower inter-individual variability in terms of bioavailability. Positive results demonstrate that dried drug nanosuspensions formulation prepared by acid-base neutralization combined with spray drying may be a promising method for enhancing the oral bioavailability of poorly soluble drugs with pH-dependent solubility. PMID- 21540091 TI - Degradation kinetics of metronidazole and olsalazine by bacteria in ascending colon and in feces of healthy adults. AB - PURPOSE: To compare the degradation kinetics of metronidazole and olsalazine by the bacteria of ascending colon and the bacteria of feces of healthy adults. METHODS: Contents of the ascending colon of seven healthy adults were collected under conditions simulating the bioavailability/bioequivalence studies in the fasted and in the fed states on a crossover basis. Material from the contents of the ascending colon was prepared by ultracentrifuging and diluting the precipitate with a volume of normal saline equivalent to that of the supernatant. Fecal material was prepared from feces of three healthy adults collected at two occasions that were separated by at least 6 months. Ex vivo drug degradation kinetics were evaluated under anaerobic conditions. RESULTS: Mean half-lives of metronidazole degradation in material from the contents of the ascending colon collected in the fasted state and in fecal material were 16.1 and 2.4 min, respectively (p<0.001). The corresponding numbers for olsalazine were 57.8 and 9.2 min, respectively (p<0.001). Both compounds were stable in material from the contents of ascending colon collected in the fed state. CONCLUSIONS: Compared with data in fecal material, degradation of metronidazole and olsalazine in material from the contents of the ascending colon is significantly slower and it becomes non-significant during the arrival of fresh food remnants in the region. PMID- 21540092 TI - Organic nanotubes for drug loading and cellular delivery. AB - Organic nanotubes made of synthetic amphiphilic molecules are novel materials that form by self-assembly. In this study, organic nanotubes with a carboxyl group (ONTs) at the surface were used as a carrier for the anticancer drug doxorubicin, which has a weak amine group. The IC(50) values of ONT for cells were higher than that of conventional liposomes, suggesting that ONTs are safe. The results showed that the drug loading of ONTs was susceptible to the effect of ionic strength and H(+) concentration in the medium, and drug release from ONTs was promoted at lower pH, which is favorable for the release of drugs in the endosome after cellular uptake. ONTs loaded with the drug were internalized, and the drug was released quickly in the cells, as demonstrated on transmission electron microscopy images of ONTs and the detection of a 0.05% dose of ONT chelating gadolinium in the cells. Moreover, ONT could be modified chemically with folate by simply mixing with a folate-conjugate lipid. Therefore, these novel, biodegradable organic nanotubes have the potential to be used as drug carriers for controlled and targeting drug delivery. PMID- 21540093 TI - Spanlastics--a novel nanovesicular carrier system for ocular delivery. AB - The work describes usefulness of a novel, surfactants based elastic vesicular drug carrier system (spanlastics), for targeting topically applied drug(s) to the posterior segment of the eye. The system constituted span 60 and a edge activator (tween 80). Ketoconazole, a lipophilic drug with a large molecular weight of 531.44 Da and a limiting solubility of 0.04 mg/ml is expected to show a poor transport across the cornea; hence no ocular formulations are available. Developed spanlastics were of nanosize and elastic in nature. They showed 2 times better corneal permeation (p <= 0.001) in comparison to correspondingly prepared niosomal formulation. The system was tested for stability for 2 months under refrigerated conditions. It was found to be safe in terms of genotoxicity (Ames test), cytotoxicity (MTT assay; Normal human gingival fibroblast), acute dermal/eye irritation/corrosion and chronic eye irritation/corrosion tests (OECD guidelines). Safety was an important issue considering that the system is novel (Indian Patent Application 2390/DEL/2008; 1447/DEL/2010) and is totally surfactant based (spans plus edge activators). Fluorescent vesicles labeled with 6-carboxyfluorescein when applied topically to the rabbit eye were observed intact in vitreous and the internal eye tissues 2h post application. Results confirm that spanlastics can be used to deliver drugs to the posterior segment of the eye. PMID- 21540094 TI - Viral protein complexed liposomes for intranasal delivery of hepatitis B surface antigen. AB - The present work investigates prospective of recombinantly expressed influenza surface protein haemagglutinin (HA) complexed liposomes for intranasal delivery of HBsAg. Liposomes encapsulating HBsAg were prepared and complexed with HA. The prepared formulations were extensively characterized for vesicle size, polydispersity index, entrapment efficiency, HA complexation efficiency, in vitro release, etc. Stability of protein molecules was accessed by SDS-PAGE. The antigenicity of protein HBsAg was determined by EIA and the functional stability of HA was evaluated by haemagglutination assay. Subsequently, in vivo study was carried out to study their feasibility as nasal vaccine carriers. A significant and perdurable immune response was obtained following in vivo administration of the developed formulations that was comparable with alum adsorbed HBsAg administered intramuscularly. The HA complexed liposomal formulations elicited sIgA in mucosal secretions and also demonstrated cellular immune response both of which are not induced in the case of alum adsorbed HBsAg vaccine. Further, the HA complexed liposomes produced higher immune response as compared to plain liposomes that might be due to higher uptake of former as evidenced in microscopy study of nasal tissues. The higher cellular response generated by HA complexed liposomes may be possibly due to characteristic pH dependent fusion property of HA protein. PMID- 21540095 TI - Physicochemical characterization of drug-loaded rigid and elastic vesicles. AB - Ketorolac loaded rigid and elastic vesicles were prepared by sonication and the physicochemical properties of the drug loaded-vesicle formulations were examined. Rigid and elastic vesicles were prepared from the double chain surfactant sucrose ester laurate (L-595) and the single chain surfactant octaoxyethylene-laurate ester (PEG-8-L). Sulfosuccinate (TR-70) was used as a negative charge inducer. Evaluation of the prepared vesicle was performed by dynamic light scattering, extrusion and by (1)H NMR (T(2) relaxation studies). The vesicles mean size varied between 90 and 150 nm. The elasticity of the vesicles was enhanced with increasing PEG-8-L/L-595 ratio, while an increase in loading of ketorolac resulted in a reduction in vesicle elasticity. (1)H NMR measurements showed that the molecular mobility of ketorolac was restricted, which indicates that ketorolac molecules were entrapped within the vesicle bilayers. The T(2) values of the aromatic protons of ketorolac increased gradually at higher PEG-8-L levels, indicating that ketorolac mobility increased in the vesicle bilayer. The chemical stability of ketorolac was dramatically improved in the vesicle formulation compared to a buffer solution. The strong interactions of ketorolac with the bilayers of the vesicles might be the explanation for this increased stability of ketorolac. PMID- 21540096 TI - Enhanced bioavailability and retinal accumulation of lutein from self-emulsifying phospholipid suspension (SEPS). AB - Ability of any formulation to keep the drug in solubilized form in vivo is essential for bioavailability (BA) enhancement rather than the solubility of drug in the formulation vehicle/matrix itself. Besides, utilization of an excess amount of surfactants/co-surfactants to solubilize the drug in the lipid formulation poses potential pharmaceutical as well as health problems. To address this problem, self-emulsifying phospholipid suspension (SEPS) consisting of high amount of phospholipid (an endogenous lipid with efficient in vivo emulsification capability) and relatively low amount of surfactant/co-surfactant has been proposed to enhance the bioavailability (BA) of lutein. In this study, the ability of SEPS formulation to enhance the BA of lutein was assessed from three SEPS formulations with various amounts of phospholipid (SEPS-0, SEPS-I, and SEPS II with 0mg, 250 mg, and 500 mg of Phosal 53 MCT, respectively) in beagle dogs following a single oral administration of lutein equivalent to 100mg, and were compared with commercial formulation (CF). In addition, the retinal accumulation of lutein in Sprague Dawley (SD) rats' eyes from SEPS-II formulation (lutein dose of 100mg/kg/day) was investigated following single daily oral administration for a period of 14 days. CF and placebo (vegetable oil without lutein) were also administered for the same period of time and were compared with the SEPS-II formulation. In the relative BA study in beagle dogs, no significant differences were observed between the pharmacokinetic (PK) parameters of formulation SEPS-O and CF. However, the C(max) in comparison to CF was 3.70 folds and 11.76 folds higher for SEPS-I and SEPS-II, respectively. Relative BA compared to CF was 178.88% and 473.13% for SEPS-I and SEPS-II, respectively. The retinal lutein accumulation was 0.91 +/- 0.31 ng/g, 3.45 +/- 1.63 ng/g, and 14.72 +/- 2.02 ng/g for placebo, CF, and SEPS-II, respectively. This enhancement was about 16.1 folds and 4.27 folds compared to placebo and CF, respectively. The relative BA study in dogs and retinal accumulation study in rats demonstrated the excellent ability of SEPS to enhance the BA of lutein. For this reason, SEPS containing lutein could be a promising lipid based delivery system for the prevention of ocular diseases. PMID- 21540097 TI - Chitosan/sulfobutylether-beta-cyclodextrin nanoparticles as a potential approach for ocular drug delivery. AB - Development of efficient ocular delivery nanosystems remains a major challenge to achieve sustained therapeutic effect. The purpose of this work was to develop chitosan nanoparticles using sulfobutylether-beta-cyclodextrin (SBE-beta-CD) as polyanionic crosslinker and to investigate the potential of using those nanostructures as ocular drug delivery systems. Econazole nitrate (ECO) was chosen as model drug molecule. The influence of different process variables (chitosan molecular weight and the concentration of the two ionic agents) on particle size, polydispersity index, zeta potential, drug content, in vitro release and mucoadhesive properties was investigated. The results showed that the prepared nanoparticles were predominant spherical in shape having average particle diameter from 90 to 673 nm with positive zeta potential values from 22 to 33 mV and drug content values ranging from 13 to 45%. Drug release from optimized nanoparticles was controlled with approximately 50% of the original amount released over a 8h period. The release profile of nanoparticles followed a zero-order release kinetics. The optimized nanoparticles were tested for their use as ocular drug delivery systems on albino rabbits. The in vivo studies revealed that the prepared mucoadhesive nanoparticles had better ability in sustaining the antifungal effect of ECO than the ECO solution. Therefore, chitosan/SBE-beta-CD nanoparticles developed showed a promising carrier for controlled delivery of drug to the eye. PMID- 21540098 TI - An improved cochlear implant electrode array for use in experimental studies. AB - Experimental studies play an important role in establishing the safety and efficacy of cochlear implants and they continue to provide insight into a new generation of electrode arrays and stimulation strategies. One drawback has been the limited depth of insertion of an electrode array in experimental animals. We compared the insertion depth and trauma associated with the insertion of Cochlear Ltd's Hybrid-L (HL) array with a standard 8 ring array in cat cochleae. Both arrays were inserted into cadaver cochleae and an X-ray recorded their anatomical location. The implanted cochlea was serially sectioned and photographed at 300 MUm intervals for evidence of electrode insertion trauma. Subsequently two cats were chronically implanted with HL arrays and electrically-evoked potentials recorded over a three month period. Mean insertion depth for the HL arrays was 334.8 degrees (SD = 21 degrees ; n = 4) versus 175.5 degrees (SD = 6 degrees ; n = 2) for the standard array. This relates to ~10.5 mm and 6 mm respectively. A similar insertion depth was measured in a chronically implanted animal with an HL array. Histology from each cadaver cochleae showed that the electrode array was always located in the scala tympani; there was no evidence of electrode insertion trauma to the basilar membrane, the osseous spiral lamina or the spiral ligament. Finally, evoked potential data from the chronically implanted animals exhibited significantly lower thresholds compared with animals implanted with a standard 8 ring array, with electrical thresholds remaining stable over a three-month observation period. Cochlear Ltd's HL electrode array can be safely inserted ~50% of the length of the cat scala tympani, placing the tip of the array close to the 4 kHz place. This insertion depth is considerably greater than is routinely achieved using a standard 8-ring electrode array (~12 kHz place). The HL array evokes low thresholds that remain stable over three months of implantation. This electrode array has potential application in a broad area of cochlear implant related research. PMID- 21540099 TI - Olive (Olea europaea L.) leaf extract attenuates early diabetic neuropathic pain through prevention of high glucose-induced apoptosis: in vitro and in vivo studies. AB - AIM OF STUDY: Since the leaves of olive have been recommended in the literature as a remedy for the treatment of diabetes and they also contain antioxidant agents, we decided to investigate the possible effects of olive leaf extract (OLE) on in vitro and in vivo models of diabetic pain neuropathy. MATERIALS AND METHODS: The high glucose-induced cell damage in naive and NGF-treated Pheochromocytoma (PC12) cells and streptozotocin-induced diabetic rats were used. Tail-flick test was used to access nociceptive threshold. Cell viability was determined by MTT assay. Biochemical markers of neural apoptosis were evaluated using immunoblotting. RESULTS: We found that elevation of glucose (4 times of normal) sequentially increases functional cell damage and caspase-3 activation in NGF-treated PC12 cells. Incubation of cells with OLE (200, 400 and 600 MUg/ml) decreased cell damage. Furthermore, the diabetic rats developed neuropathic pain which was evident from decreased tail-flick latency (thermal hyperalgesia). Activated caspase 3 and Bax/Bcl2 ratio were significantly increased in spinal cord of diabetic animals. OLE treatment (300 and 500 mg/kg per day) ameliorated hyperalgesia, inhibited caspase 3 activation and decreased Bax/Bcl2 ratio. Furthermore, OLE exhibited potent DPPH free radical scavenging capacity. CONCLUSION: The results suggest that olive leaf extract inhibits high glucose induced neural damage and suppresses diabetes-induced thermal hyperalgesia. The mechanisms of these effects may be due, at least in part, to reduce neuronal apoptosis and suggest therapeutic potential of olive leaf extract in attenuation of diabetic neuropathic pain. PMID- 21540100 TI - Ethnopharmacological survey of plants used for the treatment of female infertility in Baham, Cameroon. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Infertility affects many women in Cameroon, with a rate of about 25%. This study aimed at collecting and documenting information on herbal remedies traditionally used for the treatment of women infertility in Baham subdivision (Western Region of Cameroon). MATERIALS AND METHODS: Fieldwork was undertaken as an ethnopharmacological survey involving thirty-two traditional medicine practitioners interviewed in 8 villages of the Baham sub-division. Personal information on interviewees as well as issues related to medicinal use of plants were recorded using structured questionnaires. A literature investigation on the therapeutic or pharmacological properties of recorded medicinal plants was further undertaken. RESULTS: From this inventory, a total of 46 plant species belonging to 43 genera and 26 families have been registered. These plants are used in 32 recipes and prepared as maceration (43%) or decoction (40%) of only one plant (25%) or of the mixture of two (22%), three (28%), four (22%) or even seven (3%) medicinal plants. Globally, they are given orally during 30 days, at an average dosage of two glasses per day. The literature confirms the use of the majority of these plants for the treatment of the woman infertility and illnesses that are associated to it. CONCLUSION: This research shows that traditional healers of the Baham subdivision use various recipes of medicinal plants for the treatment of female infertility. The valorization of this potential could be important for the conservation of these plants and the improvement of women reproductive health. PMID- 21540101 TI - Antroquinonol from ethanolic extract of mycelium of Antrodia cinnamomea protects hepatic cells from ethanol-induced oxidative stress through Nrf-2 activation. AB - AIM OF THE STUDY: In recent years, the medicinal mushroom Antrodia cinnamomea, known as "niu-chang chih" has received much attention with regard to its possible health benefits; especially its hepatoprotective effects against various drugs, toxins, and alcohol induced liver diseases. However, the molecular mechanism underlying this protective effect of Antrodia cinnamomea and its active compound antroquinonol was poorly understood. In the present study we evaluated to understand the hepatoprotective efficacy of antroquinonol and ethanolic extracts of mycelia of Antrodia cinnamomea (EMAC) in vitro and in vivo. MATERIALS AND METHODS: The protective mechanism of antroquinonol and EMAC against ethanol induced oxidative stress was investigated in cultured human hepatoma HepG2 cells and ICR mice model, respectively. HepG2 cells were pretreated with antroquinonol (1-20MUM) and oxidative stress was induced by ethanol (100mM). Meanwhile, male ICR mice were pretreated with EMAC for 10 days and hepatotoxicity was generated by the addition of ethanol (5g/kg). Hepatic enzymes, cytokines and chemokines were determined using commercially available assay kits. Western blotting and real-time PCR were subjected to analyze HO-1 and Nr-2 expression. EMSA was performed to monitor Nrf-2 ARE binding activity. Possible changes in hepatic lesion were observed using histopathological analysis. RESULTS: Antroquinonol pretreatment significantly inhibited ethanol-induced AST, ALT, ROS, NO, MDA production and GSH depletion in HepG2 cells. Western blot and RT-PCR analysis showed that antroquinonol enhanced Nrf-2 activation and its downstream antioxidant gene HO-1 via MAPK pathway. This mechanism was then confirmed in vivo in an acute ethanol intoxicated mouse model: serum ALT and AST production, hepatocellular lipid peroxidation and GSH depletion was prevented by EMAC in a dose-dependent manner. EMAC significantly enhanced HO-1 and Nrf-2 activation via MAPKs consistent with in vitro studies. Ethanol-induced hepatic swelling and hydropic degeneration of hepatocytes was significantly inhibited by EMAC in a dose-dependent manner. CONCLUSIONS: These results provide a scientific basis for the hepatoprotective effects of Antrodia cinnamomea. Data also imply that antroquinonol, a potent bioactive compound may be responsible for the hepatoprotective activity of Antrodia cinnamomea. Moreover, the present study highly supported our traditional knowledge that Antrodia cinnamomea as a potential candidate for the treatment of alcoholic liver diseases. PMID- 21540102 TI - Hepatoprotective effects of lychee (Litchi chinensis Sonn.): a combination of antioxidant and anti-apoptotic activities. AB - AIM OF THE STUDY: Gimjeng and Chakapat lychee (Litchi chinensis Sonn.) were evaluated for hepatoprotective activity on CCl(4)-induced hepatotoxicity in rats. MATERIALS AND METHODS: Fruit pulp extracts of the lychees were examined for vitamin C, phenolic contents, anti-lipid peroxidation activity and hepatoprotective effect. Male Wistar albino rats were intraperitoneally injected (ip) with CCl(4) (2 ml/kg), then were orally administered (po) with silymarin (100mg/kg), and Gimjeng or Chakapat extracts (100 and 500 mg/kg). After ten days, the rats were sacrificed and their livers were examined histopathologically and immunohistochemically. Their serum glutamate-pyruvate transaminase, glutamate oxalate transaminase, and alkaline phosphatase activities were analyzed. Apoptotic activity of the livers was assessed quantitatively. RESULTS: The Gimjeng and Chakapat extracts showed the contents of vitamin C (1.2+/-0.6 and 4.3+/-0.1mg/100g) and phenolics like trans-cinnamic acid and pelargonidin-3-O glucoside (9.80+/-0.21 and 19.56+/-0.4 mg GAE/g extract, respectively), and trolox equivalent antioxidant capacity (TEAC) values (11.64 and 9.09 g/mg trolox), respectively. The Gimjeng as compared to the Chakapat demonstrated a better antioxidant activity as revealed by anti-lipid peroxidation activity with the TEAC values. Administration of CCl(4) in rats elevated the serum GPT, GOT, and ALP level whereas silymarin, Gimjeng and Chakapat extracts prevented these increases significantly. Significant decrease of apoptotic cells together with restoration of morphological changes confirmed the hepatoprotective effect in the CCl(4)-induced rats pretreated with the extracts. CONCLUSION: Antioxidant properties of the Gimjeng and Chakapat lychees as evidenced by the vitamin C and phenolic compounds, anti-lipid peroxidation and anti-apoptosis could explain the hepatoprotective effects in CCl(4)-induced hepatotoxicity. PMID- 21540103 TI - Experimental methods and modeling techniques for description of cell population heterogeneity. AB - With the continuous development, in the last decades, of analytical techniques providing complex information at single cell level, the study of cell heterogeneity has been the focus of several research projects within analytical biotechnology. Nonetheless, the complex interplay between environmental changes and cellular responses is yet not fully understood, and the integration of this new knowledge into the strategies for design, operation and control of bioprocesses is far from being an established reality. Indeed, the impact of cell heterogeneity on productivity of large scale cultivations is acknowledged but seldom accounted for. In order to include population heterogeneity mechanisms in the development of novel bioprocess control strategies, a reliable mathematical description of such phenomena has to be developed. With this review, we search to summarize the potential of currently available methods for monitoring cell population heterogeneity as well as model frameworks suitable for describing dynamic heterogeneous cell populations. We will furthermore underline the highly important coordination between experimental and modeling efforts necessary to attain a reliable quantitative description of cell heterogeneity, which is a necessity if such models are to contribute to the development of improved control of bioprocesses. PMID- 21540104 TI - Genome diversity in the smallest marine photosynthetic eukaryotes. AB - Unicellular algae of the class Mamiellophyceae are widespread in our oceans and their apparent uniformity conceals an impressive array of biologically distinct species. Each of the five complete genomes analysed so far reveals densely packed coding sequences, with strong evolutionary divergence from its nearest phylogenetically defined neighbours. These species lie at the base of the green lineage, but various metabolic processes reflect their marine life-styles and distinguish them from land plants, including a high proportion of selenoprotein enzymes and C4 photosynthesis. They all possess two unusual chromosomes, with lower GC content and atypical gene content, whose function so far remains enigmatic. PMID- 21540105 TI - Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-kappaB signaling in the intestine. AB - Hyperactivation of NF-kappaB is a key factor in the pathophysiology of inflammatory bowel disease (IBD). We previously showed that the bile salt nuclear Farnesoid X Receptor (FXR) counter-regulates intestinal inflammation, possibly via repression of NF-kappaB. Here, we examine whether mutual antagonism between NF-kappaB and FXR exists. FXR and its target genes IBABP and FGF15/19 expression were determined in HT29 colon carcinoma cells and ex vivo in intestinal specimens of wild type (WT) and Fxr-ko mice, treated with/without FXR ligands (GW4064/INT 747) and inflammatory stimuli (TNFalpha/IL-1beta). In addition, FXR activation was studied in vivo in WT and Fxr-ko mice with DSS-colitis. The involvement of NF kappaB in decreasing FXR activity was investigated by reporter assays and Glutathione S-transferase pulldown assays. FXR target gene expression was highly reduced by inflammatory stimuli in all model systems, while FXR mRNA expression was unaffected. In line with these results, reporter assays showed reduced FXR transcriptional activity upon TNFalpha/IL-1beta stimulation. We show that this reduction in FXR activity is probably mediated by NF-kappaB, since overexpression of NF-kappaB subunits p50 and/or p65 also lead to inhibition of FXR activity. Finally, we report that p65 and p50 physically interact with FXR in vitro. CONCLUSIONS: Together, these results indicate that intestinal inflammation strongly reduces FXR activation, probably via NF-kappaB-dependent tethering of FXR. Therefore, FXR not only inhibits inflammation, but also is targeted by the inflammatory response itself. This could result in a vicious cycle where reduced FXR activity results in less repression of inflammation, contributing to development of chronic intestinal inflammation. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. PMID- 21540106 TI - Vancomycin pharmacokinetics during continuous ambulatory peritoneal dialysis in patients with peritonitis. AB - The aim of this study was to define a two-compartments pharmacokinetic model and to estimate the pharmacokinetic parameters of IP administered vancomycin in patients with continuous ambulatory peritoneal dialysis (CAPD) associated peritonitis. Ten patients with peritoneal dialysis treatment and peritonitis were prospectively enrolled in the study. The empiric treatment is: vancomycin 2 g every 5-7 days and ceftazidime 1500 mg per exchange, once daily. Pharmacokinetic modeling and parameter calculations were carried out using the nonlinear regression. The mean peritoneal concentration 10 min after the first peritoneal exchange of vancomycin free dialysis liquid was 9.5+/-7.3 MUg/ml, showing that antibiotic quickly crosses from "systemic" to "peritoneal" compartment. Then, we can appreciate a progressive reduction in the mean peritoneal concentration till last sample time at 168 h. The mean plasma concentration 4 h after the first peritoneal exchange of vancomycin-free dialysis liquid was 39.6+/-7.6 MUg/ml, inside classic interval therapeutic range for the peak concentration of vancomycin. Then, we can appreciate a progressive reduction in the mean plasma concentration till last sample time at 168 h. Simultaneous joint analysis of the experimental plasma and peritoneal data of vancomycin in patients under CAPD with peritonitis, using the two-compartments model, sets up a physiologic model that adapts suitably to the intraperitoneal pharmacotherapy. PMID- 21540107 TI - Prediction of time-dependent CYP3A4 drug-drug interactions by physiologically based pharmacokinetic modelling: impact of inactivation parameters and enzyme turnover. AB - Predicting the magnitude of time-dependent metabolic drug-drug (mDDIs) interactions involving cytochrome P-450 3A4 (CYP3A4) from in vitro data requires accurate knowledge of the inactivation parameters of the inhibitor (K(I), k(inact)) and of the turnover of the enzyme (k(deg)) in both the gut and the liver. We have predicted the magnitude of mDDIs observed in 29 in vivo studies involving six CYP3A4 probe substrates and five mechanism based inhibitors of CYP3A4 of variable potency (azithromycin, clarithromycin, diltiazem, erythromycin and verapamil). Inactivation parameters determined anew in a single laboratory under standardised conditions together with data from substrate and inhibitor files within the Simcyp Simulator (Version 9.3) were used to determine a value of the hepatic k(deg) (0.0193 or 0.0077h(-1)) most appropriate for the prediction of mDDIs involving time-dependent inhibition of CYP3A4. The higher value resulted in decreased bias (geometric mean fold error - 1.05 versus 1.30) and increased precision (root mean squared error - 1.29 versus 2.30) of predictions of mean ratios of AUC in the absence and presence of inhibitor. Depending on the k(deg) value used (0.0193 versus 0.0077h(-1)), predicted mean ratios of AUC were within 2-fold of the observed values for all (100%) and 27 (93%) of the 29 studies, respectively and within 1.5-fold for 24 (83%) and 17 (59%) of the 29 studies, respectively. Comprehensive PBPK models were applied for accurate assessment of the potential for mDDIs involving time-dependent inhibition of CYP3A4 using a hepatic k(deg) value of 0.0193h(-1) in conjunction with inactivation parameters determined by the conventional experimental approach. PMID- 21540108 TI - Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers. AB - A clinical study was conducted to assess the ability of a microdose (100 MUg) to predict the human pharmacokinetics (PK) following a therapeutic dose of clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen) and phenobarbital, both within the study and by reference to the existing literature on these compounds and to explore the source of any nonlinearity if seen. For each drug, 6 healthy male volunteers were dosed with 100 MUg (14)C-labelled compound. For clarithromycin, sumatriptan, and propafenone this labelled dose was administered alone, i.e. as a microdose, orally and intravenously (iv) and as an iv tracer dose concomitantly with an oral non-labelled therapeutic dose, in a 3 way cross over design. The oral therapeutic doses were 250, 50, and 150 mg, respectively. Paracetamol was given as the labelled microdose orally and iv using a 2-way cross over design, whereas phenobarbital was given only as the microdose orally. Plasma concentrations of total (14)C and parent drug were measured using accelerator mass spectrometry (AMS) or HPLC followed by AMS. Plasma concentrations following non-(14)C-labelled oral therapeutic doses were measured using either HPLC-electrochemical detection (clarithromycin) or HPLC-UV (sumatriptan, propafenone). For all five drugs an oral microdose predicted reasonably well the PK, including the shape of the plasma profile, following an oral therapeutic dose. For clarithromycin, sumatriptan, and propafenone, one parameter, oral bioavailability, was marginally outside of the normally acceptable 2-fold prediction interval around the mean therapeutic dose value. For clarithromycin, sumatriptan and propafenone, data obtained from an oral and iv microdose were compared within the same cohort of subjects used in the study, as well as those reported in the literature. For paracetamol (oral and iv) and phenobarbital (oral), microdose data were compared with those reported in the literature only. Where 100 MUg iv (14)C-doses were given alone and with an oral non-labelled therapeutic dose, excellent accord between the PK parameters was observed indicating that the disposition kinetics of the drugs tested were unaffected by the presence of therapeutic concentrations. This observation implies that any deviation from linearity following the oral therapeutic doses occurs during the absorption process. PMID- 21540109 TI - P-glycoprotein limits the absorption of the anti-HIV drug zidovudine through rat intestinal segments. AB - Zidovudine (AZT) was the first drug approved for the treatment of Acquired Immunodeficiency Syndrome (AIDS) in humans, and although its clinical efficacy has been demonstrated, suboptimal pharmacokinetic aspects still remain a concern. To assess the basis of its highly variable oral bioavailability, this work deals with the study of AZT intestinal absorption by applying the gut sac technique. Permeation through the rat jejunum and ileum segments was analyzed at different drug concentrations and gut regions, with higher apparent permeability coefficients (P(app)) being found for the proximal regions of the small intestine compared to distal ones. Bi-directional permeation assays demonstrated that AZT is subjected to efflux mechanisms in distal regions of small intestine, which are blocked by verapamil (VER), thus demonstrating a P-glycoprotein (P-gp) mediated mechanism. The efficiency of AZT efflux increased in the distal ileum as consequence of exposure to AZT, with the amount of drug permeating from the mucosal to the serosal side diminishing after 35 min. Molecular modeling techniques were applied to analyze the binding mode of AZT to P-gp, which was compared to that of VER and AZT-Ac, a novel prodrug of AZT. The energy required for their solvation was found to constitute a critical feature in their binding to this efflux protein. The present work updates the impact of P-gp in AZT oral bioavailability, highlighting the need for further study of the dynamic nature of its expression at intestinal level. PMID- 21540110 TI - ToF-SIMS analysis of ocular tissues reveals biochemical differentiation and drug distribution. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to obtain mass spectra from three ocular tissues, the lens, the vitreous and the retina. All three tissues were extracted from control ovine eyes and ovine eyes treated with model drug. To identify variations in surface biochemistry of each ocular tissue, principal component analysis (PCA) was applied to ToF-SIMS data. Interesting physiological differences in Na(+) and K(+) distribution were shown across the three tissue types, with other elements including Ca(2+) and Fe(2+) distribution also detected. In addition to the identification of small molecules and smaller molecular fragments, larger molecules such as phosphocholine were also detected. The ToF-SIMS data were also used to identify the presence of a model drug compound (amitriptyline--chosen as a generic drug structure) within all three ocular tissues, with model drug detected predominantly across the vitreous tissue samples. This study demonstrates that PCA can be successfully applied to ToF-SIMS data from different ocular tissues and highlights the potential of coupling multivariate statistics with surface analytical techniques to gain a greater understanding of the biochemical composition of tissues and the distribution of pharmaceutically active small molecules within these tissues. PMID- 21540111 TI - Cis-acting mutation and duplication: History of molecular evolution in a P450 haplotype responsible for insecticide resistance in Culex quinquefasciatus. AB - A cytochrome P450 gene, Cyp9m10, is more than 200-fold overexpressed in a pyrethroid resistant strain of Culex quinquefasciatus, JPal-per. The haplotype of this strain contains two copies of Cyp9m10 resulted from recent tandem duplication. In this study, we discovered and isolated a Cyp9m10 haplotype closely related to this duplicated Cyp9m10 haplotype from JHB, a strain used for the recent genome project for this mosquito species. The isolated haplotype (JHB NIID-B haplotype) shared the same insertion of a transposable element upstream of the coding region with JPal-per strain but not duplicated. The JHB-NIID-B haplotype was considered to have diverged from the JPal-per lineage just before the duplication event. Cyp9m10 was moderately overexpressed in larvae with the JHB-NIID-B haplotype. The overexpressions in JHB-NIID-B and JPal-per haplotypes were developmentally regulated in similar pattern indicating both haplotypes share a common cis-acting mutation responsible for the overexpressions. The isolated moderately overexpressed haplotype conferred resistance, however, its efficacy was relatively small. We hypothesized that the first cis-acting mutation modified the consequence of the subsequent duplication in JPal-per lineage to confer stronger phenotypic effect than that if it occurred before the first cis acting mutation. PMID- 21540112 TI - 2050: Ending the odyssey of the great white plague. Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni. AB - The United Nation's Millennium Development Goal of tuberculosis (TB) elimination by 2050 may be a realizable goal by concerting efforts of the numerous stakeholders involved in the development of novel antituberculous therapeutics. Improving pre-clinical models by the research community is one aspect of the drug development pipeline that will continue to require refinement. Better in vitro and animal models are needed to expand the chemical scaffolds of anti-TB agents. These constructs must be designed and utilized in a manner that is also pertinent to the pediatric population by addressing varying age-based drug metabolism rates. Novel technologies that utilize nanomedicine and genomic research may as well have a significant impact on future therapeutics; however, their development must acknowledge the key populations whose underlying disease pathology continues to drive the pandemic - both adults and children with latent TB, HIV/AIDS and diabetes. Challenging the long-standing orthodoxy of applying equivalent TB treatments for standard first line regimens among the adult and pediatric populations must also continue to be a major focus in future drug development strategies. Studies that include pediatric populations will require a greater variety of medication formulations, biomarkers that do not rely on sputum production and diagnostic technologies that are efficacious in paucibacillary disease. Significant programmatic barriers currently exist in key aspects of the described drug development pipeline, but strategic approaches can overcome these roadblocks - including the complex regulatory requirements involving the inclusion of children in drug trials. All such endeavors will require not only more focused research initiatives, but greater institutional support from the pharmaceutical industry, non-governmental organizations and national health sectors. PMID- 21540113 TI - Purification and functional motifs of the recombinant ATPase of orf virus. AB - Our previous study showed that the recombinant ATPase encoded by the A32L gene of orf virus displayed ATP hydrolysis activity as predicted from its amino acids sequence. This viral ATPase contains four known functional motifs (motifs I-IV) and a novel AYDG motif; they are essential for ATP hydrolysis reaction by binding ATP and magnesium ions. The motifs I and II correspond with the Walker A and B motifs of the typical ATPase, respectively. To examine the biochemical roles of these five conserved motifs, recombinant ATPases of five deletion mutants derived from the Taiping strain were expressed and purified. Their ATPase functions were assayed and compared with those of two wild type strains, Taiping and Nantou isolated in Taiwan. Our results showed that deletions at motifs I-III or IV exhibited lower activity than that of the wild type. Interestingly, deletion of AYDG motif decreased the ATPase activity more significantly than those of motifs I-IV deletions. Divalent ions such as magnesium and calcium were essential for ATPase activity. Moreover, our recombinant proteins of orf virus also demonstrated GTPase activity, though weaker than the original ATPase activity. PMID- 21540114 TI - Orange-spotted grouper (Epinephelus coioides) TLR2, MyD88 and IL-1beta involved in anti-Cryptocaryon irritans response. AB - Cryptocaryon irritans is one of the most important ectoparasites of marine fish, and can have a devastating effect on aquacultured fish populations. The role of TLR signaling pathways in anti-parasitic immune responses is poorly understood in fish. In this paper, we first cloned Epinephelus coioides MyD88 full-length cDNA (EcMyD88) and its respective gene. The open reading frame (ORF) of cDNA is 873bp encoding 291 amino acid residues. Similar to other species, the EcMyD88 gene contains of five conserved exons and four diverse introns. The constitutive expression of EcMyD88 was detected in the gill, trunk kidney, head kidney, spleen, and heart in high concentrations, while the skin, brain, liver, and muscles contained much lower titers, indicating that EcMyD88 may play a crucial role in host innate immunologic surveillance. To identify the potential role of TLR pathways in fish anti-C. irritans immune responses, we chose three important molecules involved in anti-parasite responses, TLR2, MyD88 and IL-1beta to indicate TLR pathway's signal-in, signal transduction, and signal-out functions, respectively. The expression profile of these three genes was detected in grouper infected by C. irritans. Results showed these molecules each experience significant changes within the skin, gill (two infected mucosal sites), head kidney and spleen (two systematic immune organs) after C. irritans infection. These findings indicate the TLR signaling pathway may play an important role in host defense against C. irritans. PMID- 21540115 TI - The blind executive. PMID- 21540116 TI - Medial prefrontal cortex activity correlates with time-on-task: what does this tell us about theories of cognitive control? AB - A paper by Grinband et al. (this issue) argues that dorsal medial prefrontal cortex (mPFC) activity reflects time-on-task rather than conflict or error likelihood. In this commentary, Brown suggests that the findings are consistent with a new model in which mPFC learns to predict the nature and timing of action outcomes. The new model predicts that time-on-task effects coexist with distinct error likelihood effects, a result which is consistent with other recent findings from fMRI and monkey neurophysiology. PMID- 21540117 TI - Evolution of the hymenopteran megaradiation. AB - The Hymenoptera--ants, bees and wasps--represent one of the most successful but least understood insect radiations. We present the first comprehensive molecular study spanning the entire order Hymenoptera. It is based on approximately 7 kb of DNA sequence from 4 gene regions (18S, 28S, COI and EF-1alpha) for 116 species representing all superfamilies and 23 outgroup taxa from eight orders of Holometabola. Results are drawn from both parsimony and statistical (Bayesian and likelihood) analyses, and from both by-eye and secondary-structure alignments. Our analyses provide the first firm molecular evidence for monophyly of the Vespina (Orussoidea+Apocrita). Within Vespina, our results indicate a sister group relationship between Ichneumonoidea and Proctotrupomorpha, while the stinging wasps (Aculeata) are monophyletic and nested inside Evaniomorpha. In Proctotrupomorpha, our results provide evidence for a novel core clade of proctotrupoids, and support for the recently proposed Diaprioidea. An unexpected result is the support for monophyly of a clade of wood-boring sawflies (Xiphydrioidea+Siricoidea). As in previous molecular studies, Orussidae remain difficult to place and are either sister group to a monophyletic Apocrita, or the sister group of Stephanidae within Apocrita. Both results support a single origin of parasitism, but the latter would propose a controversial reversal in the evolution of the wasp-waist. Generally our results support earlier hypotheses, primarily based on morphology, for a basal grade of phytophagous families giving rise to a single clade of parasitic Hymenoptera, the Vespina, from which predatory, pollen-feeding, gall-forming and eusocial forms evolved. PMID- 21540118 TI - Morphological, molecular and biogeographic evidence support two new species in the Uroptychus naso complex (Crustacea: Decapoda: Chirostylidae). AB - The tropical to subtropical squat lobster Uroptychus nasoVan Dam, 1933 (Chirostylidae) is a widely distributed species originally described from Indonesia, subsequently reported from the Philippines, Taiwan, Japan and it has recently been discovered on the continental slope of north-western Australia. Populations of U. naso occur along the Indo-Pacific Ocean continental margin crossing the recently proposed marine analog of Wallace's line, responsible for past population fragmentation and ancient speciation. Sequence data from mitochondrial (COI, 16S) and nuclear (H3) DNA regions were used to assess genealogical relationships among geographically disjoint populations of the species throughout its known distribution range. Several mitochondrial lineages, corresponding to geographically isolated populations and three cryptic species were encountered, namely, U. naso sensu stricto and two new species, Uroptychus cyrano and Uroptychus pinocchio spp. nov. U. pinocchio is encountered only in Japan, Taiwan and the Philippines; U. cyrano is confined to north-western Australia; and U. naso consists of three genetically distinct populations distributed on both sides of the marine Wallace's line. Fossil-calibrated divergence time approximations indicated a most recent common ancestor (MRCA) for U. naso and U. cyrano from early Eocene whilst northern and southern populations of the former have been separated probably since the Miocene. These patterns may represent a standard distribution trend for several other deep-sea invertebrate species with similar geographical ranges. PMID- 21540119 TI - Multi-gene analysis provides a well-supported phylogeny of Rosales. AB - Despite many attempts to resolve evolutionary relationships among the major clades of Rosales, some nodes have been extremely problematic and have remained unresolved. In this study, we use two nuclear and 10 plastid loci to infer phylogenetic relationships among all nine families of Rosales. Rosales were strongly supported as monophyletic; within Rosales all family relationships are well-supported with Rosaceae sister to all other members of the order. Remaining Rosales can be divided into two subclades: (1) Ulmaceae are sister to Cannabaceae plus (Urticaceae+Moraceae); (2) Rhamnaceae are sister to Elaeagnaceae plus (Barbeyaceae+Dirachmaceae). One noteworthy result is that we recover the first strong support for a sister relationship between the enigmatic Dirachmaceae and Barbeyaceae. These two small families have distinct morphologies and potential synapomorphies remain unclear. Future studies should try to identify nonDNA synapomorphies uniting Barbeyaceae with Dirachmaceae. PMID- 21540120 TI - The role of histone acetylation in age-associated memory impairment and Alzheimer's disease. AB - Learning and memory are cognitive processes that are tightly regulated. A proper genome-environment interaction is a pre-requisite for cognitive function. Epigenetic processes are central regulators of genome-environment interactions. In line with this, it has been shown that the epigenetic machinery is essential for cognitive function. With a specific focus on histone acetylation, we will discuss recent research in the field of epigenetic mechanisms of learning and memory. We will also specifically address the role of histone acetylation in age associated memory impairment and Alzheimer's disease and ask the question why targeting the epigenome could be a suitable strategy for neuroprotection and neuroregeneration. PMID- 21540121 TI - Allogeneic transplant physician and center capacity in the United States. AB - Shortage of manpower and center capacity is expected to be a major challenge to the anticipated future growth in the utilization of allogeneic hematopoietic cell transplantation (HCT) in the United States. Using data from the National Marrow Donor Program's Transplant Center Network Renewal Survey, we describe transplant center and transplant physician capacity in the United States from 2005 to 2009. Over this 5-year period, the number of allogeneic transplants increased by 30%, bed capacity increased by 17%, and physician full-time equivalents increased by 26%. The number of related donor HCT increased by 15% and unrelated donor HCT increased by 45%. In addition to large centers, small- and medium-sized centers also made a major contribution to overall national transplant volumes for both related and unrelated donor HCT. Increase in utilization of unrelated donor HCT occurred in centers irrespective of their size. The majority of transplant centers were performing more transplantations using existing physician and bed capacity. Our study provides important descriptions of allogeneic transplant activity and capacity of U.S. centers, and our data will assist policy makers plan for the projected growth in the use of transplantation. PMID- 21540122 TI - Reevaluation of the efficacy and safety of the neutrophil elastase inhibitor, Sivelestat, for the treatment of acute lung injury associated with systemic inflammatory response syndrome; a phase IV study. AB - INTRODUCTION: Sivelestat, a neutrophil elastase inhibitor, has been approved in Japan for the treatment of patients with acute lung injury (ALI) associated with systemic inflammatory response syndrome (SIRS). The Pharmaceuticals and Medical Devices Agency (PMDA) has ordered to conduct a postmarket clinical study in order to reevaluate the efficacy and safety of Sivelestat in actual clinical settings in Japan. METHODS: According to the PMDA's order, we evaluated the efficacy and safety of Sivelestat in Japanese patients with ALI associated with SIRS using ventilator-free days (VFD) as the primary endpoint. The surrogate endpoints are ventilator-weaning rate, ICU discharge rate, and 180-day survival rate. Study design was an open-label, non-randomized, multi-center clinical trial. Sivelestat was intravenously administered at 0.2 mg/kg/h continuously for a maximum of 14 days. Sivelestat group and control group were compared by adjusting the outcome values using an inverse probability of treatment weighted method based on the propensity scores. RESULTS: Four hundred and four Sivelestat group patients and 177 control group patients were enrolled. The adjusted mean number of VFD was 15.7 and 12.1 in the Sivelestat group and control group, respectively (P = 0.0022). Both the adjusted ventilator-weaning rate and ICU discharge rate were significantly higher in the Sivelestat group than in the control group (P = 0.0028 and P = 0.019, respectively). The adjusted 180-day survival rate was significantly higher in the Sivelestat group than in the control group (71.8 percent vs. 56.3 percent). CONCLUSIONS: Sivelestat contributed to early weaning from the mechanical ventilation, while showing no negative effect on the long term outcomes of ALI associated with SIRS. The results of this study suggest the clinical usefulness of Sivelestat in this patient population. PMID- 21540123 TI - Targeting metabolic pathways for cancer therapy. PMID- 21540124 TI - Evidence for hormesis in mutagenicity dose-response relationships. AB - This study assessed the occurrence of hormetic dose responses from three previously published data sets [1-3] with 825 chemicals in three Ames assay tester strains (i.e., TA97, TA98, TA100) with and without the S9 fraction, using a five dose protocol and semi-log dose spacing. Ninety-five (95) (11.5%) chemicals satisfied the multiple a priori entry criteria, with a total of 107 assays. Of the assays satisfying the entry criteria, 61 involved TA100, a strain that detects base-pair substitution mutations. 29.5% (18/61) satisfied the statistical evaluative criteria for hormesis, exceeding that predicted by chance by 4.0-fold (p<0.001). The remaining 46 assays involved TA97 and TA98, strains that detect frameshift mutations. Of these 46 assays, the overall responses for the lowest two doses closely approximated the control response (e.g., 101.77% of the control for TA98; 99.20% for TA97). Only 2.2% (1/46) of the assays satisfied the evaluative criteria for hormesis. In conclusion, these data support a hormetic model for TA100, whereas the responses for TA97 and TA98 are consistent with a threshold dose-response model. PMID- 21540125 TI - Epigenetics, spermatogenesis and male infertility. AB - Epigenetic modifications characterized by DNA methylation, histone modifications, and chromatin remodeling are important regulators in a number of biological processes, including spermatogenesis. Several genes in the testes are regulated through epigenetic mechanisms, indicating a direct influence of epigenetic mechanisms on the process of spermatogenesis. In the present article, we have provided a comprehensive review of the epigenetic processes in the testes, correlation of epigenetic aberrations with male infertility, impact of environmental factors on the epigenome and male fertility, and significance of epigenetic changes/aberrations in assisted reproduction. The literature review suggested a significant impact of epigenetic aberrations (epimutations) on spermatogenesis, and this could lead to male infertility. Epimutations (often hypermethylation) in several genes, namely MTHFR, PAX8, NTF3, SFN, HRAS, JHM2DA, IGF2, H19, RASGRF1, GTL2, PLAG1, D1RAS3, MEST, KCNQ1, LIT1, and SNRPN, have been reported in association with poor semen parameters or male infertility. Environmental toxins/drugs may affect fertility via epigenetic modifications. For example, 5-aza-2'-deoxycytidine, an anticancer agent, causes a decrease in global DNA methylation that leads to altered sperm morphology, decreased sperm motility, decreased fertilization capacity, and decreased embryo survival. Similarly, Endocrine disruptors, such as methoxychlor (an estrogenic pesticide) and vinclozolin (an anti-androgenic fungicide) have been found by experiments on animals to affect epigenetic modifications that may cause spermatogenic defects in subsequent generations. Assisted reproduction procedures that have been considered rather safe, are now being implicated in inducing epigenetic changes that could affect fertility in subsequent generations. Techniques such as intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI) may increase the incidence of imprinting disorders and adversely affect embryonic development by using immature spermatozoa that may not have established proper imprints or global methylation. Epigenetic changes, in contrast to genetic aberrations, may be less deleterious because they are potentially reversible. Further research could identify certain drugs capable of reversing epigenetic changes. PMID- 21540126 TI - Evaluation of performance of some enrichment designs dealing with high placebo response in psychiatric clinical trials. AB - Dealing with high placebo response remains a big challenge to conventional clinical trials for psychiatric disorders. A widely-used design strategy is to implement a placebo lead-in phase prior to randomization. The sequentially parallel design (SPD) proposed by Fava et al., which contains two consecutive double-blind treatment stages, has recently been promoted to reduce both the high placebo response and the required sample size in clinical trials for psychiatric disorders. Our work aims to study these two design strategies and evaluate the relevant statistical approaches for continuous measures under SPD in the presence of missing data. Based on the FDA archived database, we found that a longer placebo lead-in period seemed to help in identifying more placebo responders and thus increase the chance to detect a drug-placebo difference on continuous efficacy endpoint. Using a simple weighted ordinary least square test statistic Z(OLS), we analytically showed that, under the SPD with re-randomization of placebo non-responders at the second stage (SPD-ReR), Z(OLS) can be used as a viable alternative to the weighted test statistic based on seemingly unrelated regression estimate Z(SUR) proposed by Tamura and Huang to assess treatment efficacy. Results from simulation study comparing three imputation methods (last observation-carried-forward approach, multiple imputation, and mixed-effects model for repeated measures (MMRM)) demonstrate that, when data are missing-at random under SPD-ReR and the dropout rate is moderate, the weighted test statistic based on MMRM estimates appears to be the most robust test statistic for SPD-ReR in terms of type I error control, power performance, and estimation accuracy. PMID- 21540127 TI - Replication stalling by catalytically impaired Twinkle induces mitochondrial DNA rearrangements in cultured cells. AB - Pathological mitochondrial DNA (mtDNA) rearrangements have been proposed to result from repair of double-strand breaks caused by blockage of mitochondrial DNA (mtDNA) replication. As mtDNA deletions are seen only in post-mitotic tissues, it has been suggested that they are selected out in actively dividing cells. By electron microscopy we observed rearranged mtDNA molecules in cultured human cells expressing a catalytically impaired helicase. As these molecules were undetectable by PCR, we propose that deleted mtDNA molecules in cultured cells are fragile and sensitive to heating. Further consequences of mtDNA replication stalling are discussed. PMID- 21540128 TI - Mutation in the mitochondrial tRNA(Val) causes mitochondrial encephalopathy, lactic acidosis and stroke-like episodes. AB - An m.1630A>G mutation in the mitochondrial tRNA(Val) (MTTV) was identified in a patient with hearing impairment, short stature and new onset of stroke. This mutation has previously been identified in a patient with the mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). The mother of the proband also had high levels of the m.1630A>G allele present in blood and other tissues, without symptoms. To confirm the pathogenicity of this mutation, we created cybrid cell lines with various mutation loads. The m.1630A>G mutation impairs oxygen consumption, affects the stability of the MTTV and reduces the levels of subunits of the electron transport chain. PMID- 21540130 TI - A 17q12 chromosomal duplication associated with renal disease and esophageal atresia. AB - Chromosomal imbalance of the 17q12 region (which includes the HNF1B transcription factor) has recently emerged as a frequent condition. 17q12 deletion was found in patients with various renal abnormalities, diabetes mellitus (MODY type 5), genital tract or liver test abnormalities, while 17q12 duplication was identified in a subset of patients with autism, mental retardation, epilepsy and/or schizophrenia but no renal disorder. We report here two first-degree relatives carrying a 17q12 duplication and harboring various renal abnormalities (bilateral hypoplastic kidneys with vesico-ureteric reflux or multicystic dysplatic kidney with contralateral hyperechogenic kidney). Esophageal atresia (EA) type C was identified at birth in one patient while none had neurological disorder. Because EA has already been identified in patients with 17q12 duplication or HNF1B point mutation, we screened HNF1B (QMPSF and direct sequencing) in nine additional patients with EA and renal abnormalities but failed to identify any pathogenic variant. This is the second report of HNF1B mutation associated with EA. Moreover, we showed herein, that renal malformations may be part of the 17q12 duplication syndrome. PMID- 21540129 TI - Structural studies of vacuolar plasmepsins. AB - Plasmepsins (PMs) are pepsin-like aspartic proteases present in different species of parasite Plasmodium. Four Plasmodium spp. (P. vivax, P. ovale, P. malariae, and the most lethal P. falciparum) are mainly responsible for causing human malaria that affects millions worldwide. Due to the complexity and rate of parasite mutation coupled with regional variations, and the emergence of P. falciparum strains which are resistant to antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is constant pressure to find new and lasting chemotherapeutic drug therapies. Since many proteases represent therapeutic targets and PMs have been shown to play an important role in the survival of parasite, these enzymes have recently been identified as promising targets for the development of novel antimalarial drugs. The genome of P. falciparum encodes 10 PMs (PMI, PMII, PMIV-X and histo-aspartic protease (HAP)), 4 of which (PMI, PMII, PMIV and HAP) reside within the food vacuole, are directly involved in degradation of human hemoglobin, and share 50-79% amino acid sequence identity. This review focuses on structural studies of only these four enzymes, including their orthologs in other Plasmodium spp.. Almost all original crystallographic studies were performed with PMII, but more recent work on PMIV, PMI, and HAP resulted in a more complete picture of the structure-function relationship of vacuolar PMs. Many structures of inhibitor complexes of vacuolar plasmepsins, as well as their zymogens, have been reported in the last 15 years. Information gained by such studies will be helpful for the development of better inhibitors that could become a new class of potent antimalarial drugs. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. PMID- 21540131 TI - Parent-of-origin differences of mutant HTT CAG repeat instability in Huntington's disease. AB - BACKGROUND: Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). The CAG domain of mutant HTT is unstable upon intergenerational transmission, however, little is known about the underlying mechanisms. METHODS: From the HD archives of the Leiden University Medical Centre DNA samples from all parent offspring pairs involving 36 CAG repeats or more were selected. To minimize procedural variability, CAG repeat lengths in both mutant and normal HTT were reassessed using the same standardized protocol, which resulted in the identification of 337 parent-offspring transmissions. The effects of both parental (mutant and normal CAG repeat size, age and gender) and offspring (gender and season of conception) characteristics on CAG repeat instability were assessed. RESULTS: Paternal transmissions were often associated with CAG repeat expansion, whereas maternal transmissions mainly resulted in CAG repeat contraction (mean change: +1.76 vs. -0.07, p<0.001). Only in paternal transmissions larger mutant CAG repeat size was associated with a greater degree of CAG repeat expansion (beta=0.73; p<0.001). Conversely, only in maternal transmissions larger CAG repeat size of the normal allele was associated with a greater degree of CAG repeat contraction (beta=-0.07; p=0.029). Parental age, offspring gender and season of conception were not related to CAG repeat instability. CONCLUSION: Our findings suggest a slight maternal contraction bias as opposed to a paternal expansion bias of the mutant HTT CAG repeat during intergenerational transmission, which only in the maternal line is associated with normal HTT CAG repeat size. PMID- 21540132 TI - Letter regarding the article: "21 Mb deletion in chromosome band 13q22.2-q32.1 associated with mild/moderate psychomotor retardation, growth hormone insufficiency, short neck, micrognathia, hypotonia, dysplastic ears and other dysmorphic features" by Grigori et al. PMID- 21540133 TI - Targeted mass spectrometry approaches for protein biomarker verification. AB - The search for protein biomarkers has been a highly pursued topic in the proteomics community in the last decade. This relentless search is due to the constant need for validated biomarkers that could facilitate disease risk stratification, disease diagnosis, prognosis, monitoring as well as drug development, which ultimately would improve our quality of life. The recent development of proteomic technologies including the advancement of mass spectrometers with high sensitivity and speed has greatly advanced the discovery of potential biomarkers. One of the bottlenecks lies in the development of well established verification assays to screen the biomarker candidates identified in the discovery stage. Recently, absolute quantitation using multiple-reaction monitoring mass spectrometry (MRM-MS) in combination with isotope-labeled internal standards has been extensively investigated as a tool for high throughput protein biomarker verification. In this review, we describe and discuss recent developments and applications of MRM-MS methods for biomarker verification. PMID- 21540134 TI - Numerical simulation of cooling rates in vitrification systems used for oocyte cryopreservation. AB - Oocyte cryopreservation is of key importance in the preservation and propagation of germplasm. Interest in oocyte cryopreservation has increased in recent years due to the application of assisted reproductive technologies in farm animals such as in vitro fertilization, nuclear transfer and the need for the establishment of ova/gene banks worldwide. However, the cryopreservation of the female gamete has been met with limited success mainly due to its small surface-area:volume ratio. In the past decade, several vitrification devices such as open pulled straws (OPS), fine and ultra fine pipette tips, nylon loops and polyethylene films have been introduced in order to manipulate minimal volumes and achieve high cooling rates. However, experimental comparison of cooling rates presents difficulties mainly because of the reduced size of these systems. To circumvent this limitation, a numerical simulation of cooling rates of various vitrification systems immersed in liquid nitrogen was conducted solving the non-stationary heat transfer partial differential equation using finite element method. Results indicate the nylon loop (Cryoloop(r)) is the most efficient heat transfer system analyzed, with a predicted cooling rate of 180,000 degrees C/min for an external heat transfer coefficient h= 1000 W/m(2)K when cooling from 20 to -130 degrees C; in contrast, the open pulled straw method (OPS) showed the lowest performance with a cooling rate of 5521 degrees C/min considering the same value of external heat transfer coefficient. Predicted cooling rates of Miniflex(r) and Cryotop(r) (polyethylene film system) were 6164 and 37,500 degrees C/min, respectively, for the same heat transfer coefficient. PMID- 21540135 TI - Slovakia health system review. AB - The Health Systems in Transition (HiT) profiles are country-based reports that provide a detailed description of a health system and of policy initiatives in progress or under development. HiTs examine different approaches to the organization, financing and delivery of health services, and the role of the main actors in health systems; describe the institutional framework, process, content and implementation of health and health care policies; and highlight challenges and areas that require more in-depth analysis. The Slovak health system is a system in progress. Major health reform in the period 2002 to 2006 introduced a new approach based on managed competition. Although large improvements have been made since the 1990s (for example in life expectancy and infant mortality), health outcomes are generally still substantially worse than the average for the EU15 but close to the other Visegrad Four countries. Per capita health spending (in purchasing power parity [PPP]) was around half the EU15 average. A large share of these resources was absorbed by pharmaceutical spending (28% in 2008, compared to 16% in OECD countries). Some important utilization indicators signal plenty of resources in the system but may also indicate excess bed capacity and overutilization. The number of physicians and nurses per capita has been actively reduced since 2001 but remains above the average of the EU12 (i.e. the 12 countries that joined the EU in 2004 and 2007). An ageing workforce and professional migration may reinforce a shortage of health care workers. People have free choice of general practitioner (GP) and specialist. Their services are provided without cost-sharing from patients, with the notable exception of dental procedures. Inpatient care and specialized ambulatory care are provided in general hospitals and specialized hospitals. Pharmaceutical expenditure per capita accounts for one-third of public expenditure on health care. Long-term care is provided by health care facilities and social care facilities. Slovakia has a progressive system of financing health care. However, the health reforms of 2002 to 2006 led to an increase in the number of households that contributed more from their income and the distributive impacts were not equitable. This was mainly caused by the introduction of a reference pricing scheme for pharmaceuticals. Some key challenges remain: improving the health status of the population and the quality of care while securing the future financial sustainability of the system. PMID- 21540136 TI - Solitary mastocytoma with histologic features of eosinophilic cellulites. PMID- 21540137 TI - [Clinical symptoms and symptomatic management of brain metastases]. AB - Cancer patients frequently develop brain metastases. Symptomatic treatments are important to stabilize these patients before an oncological procedure (usually radiotherapy, sometimes surgery or chemotherapy) can be started. These symptomatic treatments mainly rely on steroids to reduce the peritumoral edema; anti-epileptic drugs for patients who previously had seizures, and low-molecular weight heparin for patients at risk of thrombo-embolic events. PMID- 21540138 TI - [Brain metastases from breast cancer: usefulness and limits of prognostic scores]. AB - Approximately 10 to 30% of patients with metastatic breast cancer will develop brain metastases (BM) during the disease course. Whole-brain radiation therapy (WBRT) is considered the standard treatment for most patients, particularly those with extensive intracranial disease, providing symptom relief and increasing median and overall survival. Despite WBRT, the prognosis for the general population of patients with BM remains poor, with a median survival time of approximately five months. Several studies have examined the relative contributions of patient characteristics to survival and have attempted to identify subgroups of patients with substantially different outcomes in order to tailor therapy and to influence the design, stratification and interpretation of future clinical trials. This review examines prognostic scores and their validation in patients with BM from breast carcinoma. We also discuss the prognostic value of specific parameters for breast carcinoma, such as tumor HR status, HER2 over-expression or specific treatment parameters, and the value and limits of these prognostic scores in clinical practice. PMID- 21540139 TI - [Brain metastases in breast cancer. Epidemiology and natural history. The Institut Curie experience]. AB - Breast cancer is the second cause for brain metastases. Their incidence is rising, partly due to the therapeutic improvements which alter the natural history of breast cancer. Predictive factors for brain metastases have been identified: HER2 oncogene overexpression, lack of expression of hormone receptors, young age and triple negative status. Brain metastases prognosis remains poor with a median survival shorter than 1 year, except for solitary lesions treated by surgery or radiosurgery. We have analysed two series of data from Institut Curie (Paris and Saint-Cloud). In women younger than 65 years, with HER2 negative breast carcinoma, median survival was 7.1 months. In women older than 65 years, median survival was 4 months. PMID- 21540140 TI - [Multiple brain metastases after breast cancer and their radiotherapy management: what is the optimal treatment?]. AB - Whole brain radiotherapy remains standard in the management of breast cancer patients with brain metastases. It allows for symptomatic improvement and good local control in most patients. However, its results remain suboptimal in terms of both efficacy and toxicity. In highly selected patients, stereotactic radiotherapy demonstrated very good local control with low toxicity. With purpose of improving the efficacy/toxicity ratio, strategies of biomodulation of tumor radiosensitivity were recently developed. First results are promising and warrant further assessment. At the same time, new technologies and new irradiation modalities demonstrated their ability in providing high dosimetric homogeneity, delivering integrated radiation boosts, and avoiding critical structures that are involved in long-term neurological toxicity. Further assessment is required and recruitment of breast cancer patients into clinical trials is encouraged. PMID- 21540141 TI - [Brain metastasis of breast cancer; imaging evaluation]. AB - CNS involvement in breast cancer modifies the prognosis and the treatment of the disease. Imaging plays a leading role for the diagnosis, the pretherapeutic assessment and the follow-up. MRI is the most sensitive modality for the detection of infraclinic lesions, reported in about 15% of metastatic breast cancers. In addition to conventional MR study, diffusion MR, perfusion MR and spectroscopy have a diagnostic value with specificity of more than 95%; 3D study is required if neurosurgical resection or stereotactic radiosurgery is contemplated. The use of new drugs in clinical trials needs a precise and accurate follow up to assess their usefulness; appreciation of the response is based on the precise measure of the number of targets and of their size; The WHO and recently the RECIST have established the guidelines for measurement of the tumoral targets and to assess the response to treatments. Brain modifications related to surgery or stereotactic radiosurgery are well studied by MRI. PMID- 21540142 TI - Traumatic panniculitis with hypertrichosis. PMID- 21540143 TI - Wound closure by secondary intention is successful in the treatment of squamous cell carcinomas in recessive dystrophic epidermolysis bullosa. PMID- 21540144 TI - Submaximal exercise intensities do not provoke variations in plasma magnesium concentration in well-trained euhydrated endurance athletes with no magnesium deficiency. AB - The purpose of this study was to assess the effect of exercise intensity during an incremental exercise test on plasma Mg concentration in well-trained euhydrated athletes. Twenty-seven well-trained endurance athletes carried out a cycloergometer test: after a warm-up of 10 min at 2.0 W.kg(-1), the workload increased by 0.5 W.kg(-1) every 10 min until exhaustion. Oxygen uptake (VO(2)), blood lactate concentration ([La(-)](b)), catecholamines, and plasma Mg were measured at rest, at the end of each stage and at 3, 5 and 7 minutes post exercise. Urine specific gravity (U(SG)) was analyzed before and after the test, and subjects drank water ad libitum. Fat oxidation rate (FAT(oxr)), carbohydrate oxidation rate (CHO(oxr)), energy expenditure from fat (EE(FAT)), energy expenditure from carbohydrate (EE(CHO)), and total EE (EE(TOTAL)) were estimated using stoichiometric equations. Plasma Mg concentration at each relative exercise intensity (W.kg(-1)) were compared by means of repeated-measures ANOVA. Pearson's correlations were performed to assess the relationship between variables. The significance level was set at p<0.05. No significant differences were found in U(SG) between before and after the test (1.014+/-0.004 vs 1.014+/-0.004 g.cm( 3)). Nor were significant differences found in plasma Mg as a function of the different exercise intensities. Further, no significant correlations were detected between Mg and metabolic variables. In conclusion, acute exercise at a range of submaximal intensities in euhydrated well-trained endurance athletes does not affect plasma Mg concentration, suggesting that the plasma volume plays an important role in Mg homeostasis during exercise. PMID- 21540145 TI - [Brain metastasis from breast cancer: who?, when? and special considerations about the role of technology in neurosurgery]. AB - Questions about both the place and the role of surgery on brain metastasis from breast cancer are arising more and more frequently in practice due to the increase of brain metastasis in patients suffering from a form of cancer recognized as one of the most recurrent cancers in adults but also one of the most sensitive to general treatments of the systemic disease. With improvements in anaesthesia, in surgical instruments, and in global care, neurosurgery has taken advantage of new techniques such as pre- and even per-operative imagery and also neuronavigation. These techniques enable radical and effective surgical intervention with a high level of safety for the patient, making neurosurgery perfectly competitive with other therapeutic modalities, particularly on functional grounds. As for symptomatic treatments or other anti-metastasis treatments, most situations allow a reflection on the global therapeutic strategy which can be adapted to individual cases depending on the patient's general prognosis. In developing this global therapeutic strategy, surgical treatment is still as relevant as ever. PMID- 21540146 TI - Contact dermatitis from topical antibiotics. PMID- 21540147 TI - [Leptomeningeal meningitis related to breast cancer overexpressing HER2: is there a place for a more specific treatment?]. AB - Leptomeningeal metastases are very commonly associated with breast cancer. The prognosis is very poor in the short term with an overall median survival less than 6 months. Based on pragmatic and historical considerations intrathecal chemotherapy (IT) are considered to be the adequate treatment. However overall results are disappointing. Despite specific and symptomatic treatment, improvement in survival and quality of life remains very modest, highlighting the importance for ongoing research for developing new molecules or on improving the use a better use of those available today. The incidence of leptomeningeal metastases is particularly marked in cases of overexpression of HER2. The main hypothesis is there may be a better control of extra-cerebral localisations with trastuzumab therefore intra-cerebral recurrences may be encountered preferentially as they are not reached by this high molecular weight monoclonal antibody (148 kD). Analyses performed in the cerebrospinal fluid following intravenous trastuzumab showed extremely low levels of the antibody and support the hypothesis that leptomeningeal metastasis of HER2-overexpressing breast carcinoma remain potentially sensitive to HER2-type receptor inhibition by a target agent under the condition of by-passing the meningeal blood brain barrier. Intra-ventricular or IT administered with trastuzumab would reach high loco regional therapeutic concentrations in the cerebro-meningeal without risk for normal non-expressing HER2 leptomeningeal tissue. This strategy has been successfully tested on several animal models. A limited number of administrations in humans have been described in the literature, with weekly doses up to 100 mg. No specific toxicity has been described and some data suggest a potential benefit in survival despite the real difficulties for adequate interpretations. Furthermore, a multicentric phase I-II clinical trial, of which the Curie institute is the sponsor and investigating the intra-thecal administration and the efficacy of the trastuzumab will begin very soon. More studies are needed to measure the exact impact of small molecule inhibitors of tyrosine kinase on the leptomeningeal localizations. PMID- 21540148 TI - [Prevention strategies for brain metastases from HER2-positive breast cancer]. AB - The incidence of brain metastases is particularly high in HER2-overexpressing (HER2+) breast cancer. Several hypotheses have been raised trying to explain this peculiar phenomenon, including a better control of extra-cerebral metastases with HER2-targeting agents, but also the own effect of HER2+ tumor cells that may have a marked brain tropism. In this context, the development of prevention strategies is highly relevant. After a brief description of the natural history of HER2+ breast cancer, three different prevention strategies are discussed in this article, including a secondary prevention strategy by systematic screening of brain metastases, and two primary prevention strategies with prophylactic cerebral irradiation and the optimisation of the adjuvant treatment. None of these strategies has been validated to date. A prolonged follow-up is crucial in order to detail the natural history of HER2+ breast cancers and to evaluate the impact of new treatments on the incidence of brain metastases. PMID- 21540149 TI - Chemical burn caused by excrement after ingestion of kerosene. PMID- 21540150 TI - [The immuno-endocrine system. A new endocrine theory: the problem of the packed transport]. AB - Since the eighties of the last century hormone content was justified in immune cells (lymphocytes, granulocytes, monocytes, macrophages and mast cells), which produce, store and secrete these hormones. Although the amount of these materials in immune cells is relatively small, the mass of the producers (immune cells) is so large, that the phenomenon must be considered from endocrinological point of view, underlying the important differences between the "classical" and immuno endocrine systems. Cells of the classic (built-in) endocrine system are mono producers, while immune cells can synthesize many types of hormones (polyproducers). In addition, these cells can transport the whole hormone producing machinery to the site of need, producing a local effect. This can be observed, for example, in the case of endorphin producing immune cells during inflammation and during early pregnancy around the chorionic villi. Hormone producing immune cells also have receptors for many hormones, so that they are poly-receivers. Via hormone producing and receiving capacity there is a bidirectional connection between the neuro-endocrine and immuno-endocrine systems. In addition, there is a network inside the immuno-endocrine system. The packed transport theory attempts to explain the mechanism and importance of the immuno-endocrine system. PMID- 21540151 TI - [Novel laparoscopic techniques in gynecologic surgery]. AB - The practice of gynecologic surgery has been revolutionized by laparoscopic techniques in the past decades. Nowadays minimal invasive procedures are feasible and safe standard options in the management of most benign and malignant gynecologic diseases. Natural orifices transluminal endoscopic surgery (NOTES) and laparoendoscopic single-site surgery (LESS) have been developed in an attempt to further reduce the morbidity and scarring with minimal invasive procedures. These techniques share a common conception that a reduction in the number of transcutaneous points of access may benefit patients in terms of port-related complications, risk of hernia formation, recovery time, pain and cosmetics by potentially performing scarless surgery. The development of LESS has been facilitated by the concept of scarless surgical procedures. Increasing experience revealed by recent publications have allowed for the expansion of NOTES and LESS techniques in the gynecologic surgery. Almost all laparoscopic procedures can be performed by acquiring these concepts. Although these surgical methods are feasible and safe, certain technical problems (e.g. loss of triangulation, problems of visualization, ergonomic considerations) has yet to be solved and several questions must be answered before LESS and NOTES could gain widespread acceptance as single procedures. Despite successful technical developments these methods remain investigational approaches and refinement of indications as well as further development of instrumentation are expected to define its area of future application. PMID- 21540152 TI - [Myocardial Infarction Registry conducted forty years ago in Hungary]. AB - AIMS: Authors summarize the most important findings of the Myocardial Infarction Community Registry conducted in Hungary 40 years ago. The report is important because data are not available on the internet through literature search and since 40 years such study has not been performed. The incidence of acute myocardial infarction in subjects older than 20 years of age in the population of South Pest with 400 000 inhabitants in 1971 was 50.9/10 000 in men and 23.7/10 000 in women. The mortality rate of myocardial infarction during the first year was 56.2% in men and 60.7% in women. Two-third of the first-year death occurred in the first 24 hours and 85% of it in the prehospital period. Only 6% of the patients with acute myocardial infarction were admitted and treated in Coronary Care Units. Based on the data of the Myocardial Infarction Community Registry, measures were introduced which decreased the 28-days mortality rate at the population level. CONCLUSIONS: Authors emphasize that in the last decades the diagnosis and treatment of myocardial infarction has substantially changed which makes it necessary to re-evaluate by epidemiologic methods the natural history, incidence and mortality of acute myocardial infarction in Hungary. PMID- 21540153 TI - [Novel indicator for the assessment of hospital bed occupancy]. AB - In the past decades the bed occupancy of hospitals in Hungary has been calculated from the average of in-patient days and the number of beds during a given period of time. This is the only measure being currently looked at when evaluating the performance of hospitals and changing their bed capacity. The author outlines how limited is the use of this indicator and what other statistical indicators may characterize the occupancy of hospital beds. Since adjustment of capacity to patient needs becomes increasingly important, it is essential to find indicator(s) that can be easily applied in practice and can assist medical personal and funders who do not work with statistics. Author recommends the use of daily bed occupancy as a base for all these statistical indicators. PMID- 21540154 TI - [Novel mutation in a patient with Carney complex]. AB - Carney complex is a rare disease inherited in an autosomal dominant manner. It is mostly caused by inactivating mutations of the subunit of protein kinase A. Carney complex is associated with atrial myxoma, nevi or myxomas of the skin, breast tumors and endocrine overactivity. Primary pigmented nodular adrenocortical disease is the specific endocrine manifestation. The authors present the history of a 53-year-old female patient who had undergone surgery for atrial myxomas, thyroid tumor and breast cancer. She was also operated for an adrenal adenoma causing Cushing's syndrome. Genetic study revealed a mutation in the regulatory subunit of protein kinase A (ivs2-1G>A splice mutation in intron 2). Her heterozygous twins were also genetically screened and one of them carried the same mutation. The authors emphasize that despite the absence of specific treatment for patients with Carney complex, confirmation of the diagnosis by genetic studies is important for the close follow-up of the patient and early identification of novel manifestations. PMID- 21540155 TI - ["Only the future is certain, the past is ever changing." The legend of Lajos Markusovszky]. PMID- 21540156 TI - [Hungarian Physicians' Federation and its journal]. PMID- 21540158 TI - CMAJ 2011 election survey: health human resources. PMID- 21540159 TI - Zombies, myths and pharmacare. PMID- 21540160 TI - Data-mining case tests boundaries of medical privacy. PMID- 21540161 TI - CMAJ 2011 election survey: pharmacare. PMID- 21540162 TI - Acute obstructive pancreatitis caused by a migrated balloon gastrostomy tube. PMID- 21540163 TI - Primary hyperparathyroidism. PMID- 21540164 TI - CMAJ 2011 election survey: research. PMID- 21540166 TI - Changes in relative fitness and frailty across the adult lifespan: evidence from the Canadian National Population Health Survey. AB - BACKGROUND: The prevalence of frailty increases with age in older adults, but frailty is largely unreported for younger adults, where its associated risk is less clear. Furthermore, less is known about how frailty changes over time among younger adults. We estimated the prevalence and outcomes of frailty, in relation to accumulation of deficits, across the adult lifespan. METHODS: We analyzed data for community-dwelling respondents (age 15-102 years at baseline) to the longitudinal component of the National Population Health Survey, with seven two year cycles, beginning 1994-1995. The outcomes were death, use of health services and change in health status, measured in terms of a Frailty Index constructed from 42 self-reported health variables. RESULTS: The sample consisted of 14,713 respondents (54.2% women). Vital status was known for more than 99% of the respondents. The prevalence of frailty increased with age, from 2.0% (95% confidence interval [CI] 1.7%-2.4%) among those younger than 30 years to 22.4% (95% CI 19.0%-25.8%) for those older than age 65, including 43.7% (95% CI 37.1% 50.8%) for those 85 and older. At all ages, the 160-month mortality rate was lower among relatively fit people than among those who were frail (e.g., 2% v. 16% at age 40; 42% v. 83% at age 75 or older). These relatively fit people tended to remain relatively fit over time. Relative to all other groups, a greater proportion of the most frail people used health services at baseline (28.3%, 95% CI 21.5%-35.5%) and at each follow-up cycle (26.7%, 95% CI 15.4%-28.0%). INTERPRETATION: Deficits accumulated with age across the adult spectrum. At all ages, a higher Frailty Index was associated with higher mortality and greater use of health care services. At younger ages, recovery to the relatively fittest state was common, but the chance of complete recovery declined with age. PMID- 21540167 TI - Dispatch from the medical front: a world away. PMID- 21540168 TI - Legislative approaches to tackling the obesity epidemic. PMID- 21540170 TI - Frailty: joining the giants. PMID- 21540171 TI - Can Canada get on with national pharmacare already? PMID- 21540172 TI - CMAJ 2011 election survey: home/palliative care. PMID- 21540173 TI - Unbiased histological examinations in toxicological experiments (or, the informed leading the blinded examination). PMID- 21540174 TI - Histologic and cytologic detection of endocrine and reproductive tract effects of exemestane in female rats treated for up to twenty-eight days. AB - The objective of this study was to determine the shortest period of time necessary to detect histologic evidence of estrous cycle disruption in Sprague Dawley rats treated for up to 28 days with the aromatase inhibitor exemestane at 1,000 mg/kg. Rats were evaluated on day 5, 8, 15, or 29. Vaginal mucification, uterine and cervical epithelial atrophy, uterine luminal epithelial vacuolation, decreased uterine granulocytes, and hypertrophy/hyperplasia of mammary ducts and alveoli were noted by day 5 and persisted throughout the study. From day 8 to day 29, absence of recent basophilic corpora lutea, increased atresia of antral follicles, interstitial cell hyperplasia, and increased luteinized follicles were present in the ovaries of treated rats. Vaginal smears detected persistent diestrus, confirming estrous cycle disruption between days 5 and 8. Ovary and uterine weights were largely unaffected. Serum hormone levels were not useful due to the study design employed. Other effects of exemestane included decreased adrenal weights and decreased cell size in both the adrenal zona fasciculata and the pituitary pars distalis. While early histologic changes were evident on day 5, only after 8 days of treatment were findings considered sufficient to clearly identify exemestane-induced estrous cycle disruption using microscopy alone. PMID- 21540175 TI - Employment and work schedule are related to telomere length in women. AB - OBJECTIVES: To examine the association of employment and work schedule with shorter DNA telomeres, a marker of cellular ageing and disease risk factor, and consider whether differences were related to health, behaviours and sociodemographic factors, or varied by stress levels or menopausal status. METHODS: This cross-sectional analysis of 608 women aged 35-74 in the Sister Study examined determinants of relative telomere length (rTL) measured by quantitative PCR in leucocyte DNA. Age-adjusted regression models estimated base pair (bp) rTL differences for current and lifetime schedule characteristics (ie, part-time, full-time or overtime hours; multiple jobs; irregular hours; shiftwork; work at night). Covariates included race, smoking, perceived stress, sleep, physical activity, health and menopausal status, education, marital status, live births, children under 18, measured body mass index and urinary stress hormones. RESULTS: Compared with non-employed women with moderate or substantial past work histories (n=190), those currently working full-time (n=247; median 40 h/week) had a shorter rTL, an age-adjusted difference of -329 bp (95% CI -110 to -548). Longer-duration full-time work was also associated with shorter rTL (age-adjusted difference of -472 bp, 95% CI -786 to -158 for 20+ vs 1 5 years). Findings were not explained by health and demographic covariates. However, rTL differences for working at least full-time were greater in women with higher stress and epinephrine levels. CONCLUSIONS: Current and long-term full-time work were associated with shorter rTL, with differences of similar magnitude to smoking and history of heart disease or diabetes. Longitudinal data with specific stress measures are needed to further evaluate the impact of work schedule on rTL. PMID- 21540176 TI - Transient receptor potential mucolipin 1 (TRPML1) and two-pore channels are functionally independent organellar ion channels. AB - NAADP is a potent second messenger that mobilizes Ca(2+) from acidic organelles such as endosomes and lysosomes. The molecular basis for Ca(2+) release by NAADP, however, is uncertain. TRP mucolipins (TRPMLs) and two-pore channels (TPCs) are Ca(2+)-permeable ion channels present within the endolysosomal system. Both have been proposed as targets for NAADP. In the present study, we probed possible physical and functional association of these ion channels. Exogenously expressed TRPML1 showed near complete colocalization with TPC2 and partial colocalization with TPC1. TRPML3 overlap with TPC2 was more modest. TRPML1 and to some extent TRPML3 co-immunoprecipitated with TPC2 but less so with TPC1. Current recording, however, showed that TPC1 and TPC2 did not affect the activity of wild-type TRPML1 or constitutively active TRPML1(V432P). N-terminally truncated TPC2 (TPC2delN), which is targeted to the plasma membrane, also failed to affect TRPML1 and TRPML1(V432P) channel function or TRPML1(V432P)-mediated Ca(2+) influx. Whereas overexpression of TPCs enhanced NAADP-mediated Ca(2+) signals, overexpression of TRPML1 did not, and the dominant negative TRPML1(D471K) was without affect on endogenous NAADP-mediated Ca(2+) signals. Furthermore, the single channel properties of NAADP-activated TPC2delN were not affected by TRPML1. Finally, NAADP-evoked Ca(2+) oscillations in pancreatic acinar cells were identical in wild-type and TRPML1(-/-) cells. We conclude that although TRPML1 and TPCs are present in the same complex, they function as two independent organellar ion channels and that TPCs, not TRPMLs, are the targets for NAADP. PMID- 21540177 TI - Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha). AB - Sterol regulatory element binding proteins (SREBPs) regulate the expression of a number of enzymes, which catalyze the synthesis of fatty acids, cholesterol, triglycerides, and phospholipids. SREBP1c is the most relevant isoform in the adult liver, and its expression is controlled by the nutritional state. Transcriptional regulation studies into the SREBP1c gene, performed in the last few years, have improved our knowledge of the variability of signals that converge on its promoter region. Insulin, cholesterol derivatives, T3 and other endogenous molecules have been demonstrated to regulate the SREBP1c expression, particularly in rodents. The present study aimed to perform a detailed analysis of the human SREBP1c gene promoter structure in liver cells by focusing on responses to diverse metabolic signals. Serial deletion and mutation assays reveal that both SREBP (SRE) and LXR (LXRE) response elements are involved in SREBP1c transcription regulation mediated by insulin and cholesterol derivatives. We discovered that peroxisome proliferation-activated receptor alpha (PPARalpha) agonists enhance the activity of the SREBP1c promoter; a DR1 element, at -453 in the human promoter was involved in this activation. Moreover, PPARalpha agonists act in cooperation with LXR or insulin to induce lipogenesis. Collectively, our results identify PPARalpha as a novel regulatory factor in SREBP1c regulation which plays a relevant role in the interplay between lipids and insulin metabolic regulation. PMID- 21540178 TI - RTEF-1, an upstream gene of hypoxia-inducible factor-1alpha, accelerates recovery from ischemia. AB - The amount of available hypoxia-inducible factor (HIF)-1alpha has been considered to be largely a consequence of post-translational modification by multiple ubiquitin-proteasome pathways. However, the role of transcriptional regulation of HIF-1alpha is less certain, and the mechanisms of transcriptional regulation of HIF-1alpha require further investigation. Here we report that related transcriptional enhancer factor-1 (RTEF-1), a member of the TEF transcriptional factor family, transcriptionally regulates the HIF-1alpha gene under normoxic and hypoxic conditions. The expression of HIF-1alpha mRNA was decreased in endothelial cells in which RTEF-1 was knocked down with siRNA. Sequential deletional analysis of the HIF-1alpha promoter revealed that the MCAT-like element in the HIF-1alpha promoter was essential for HIF-1alpha transcription. Binding of RTEF-1 to the MCAT-like element was confirmed by ChIP. Treatment of endothelial cells with a HIF-1 inhibitor resulted in retardation of RTEF-1 induced proliferation and tube formation. Moreover, increased HIF-1alpha expression was observed in transgenic mice expressing RTEF-1 under the VE cadherin promoter (VE-Cad/RTEF-1). VE-Cad/RTEF-1 mice subjected to hindlimb ischemia demonstrated increased levels of HIF-1alpha, accelerated recovery of blood flow, and increased capillary density compared with littermate controls. These results identify RTEF-1 as a regulator of HIF-1alpha transcription, which results in up-regulation of HIF-1alpha and acceleration of recovery from ischemia. PMID- 21540179 TI - Differential regulation of the postsynaptic clustering of gamma-aminobutyric acid type A (GABAA) receptors by collybistin isoforms. AB - Collybistin promotes submembrane clustering of gephyrin and is essential for the postsynaptic localization of gephyrin and gamma-aminobutyric acid type A (GABA(A)) receptors at GABAergic synapses in hippocampus and amygdala. Four collybistin isoforms are expressed in brain neurons; CB2 and CB3 differ in the C terminus and occur with and without the Src homology 3 (SH3) domain. We have found that in transfected hippocampal neurons, all collybistin isoforms (CB2(SH3+), CB2(SH3-), CB3(SH3+), and CB3(SH3-)) target to and concentrate at GABAergic postsynapses. Moreover, in non-transfected neurons, collybistin concentrates at GABAergic synapses. Hippocampal neurons co-transfected with CB2(SH3-) and gephyrin developed very large postsynaptic gephyrin and GABA(A) receptor clusters (superclusters). This effect was accompanied by a significant increase in the amplitude of miniature inhibitory postsynaptic currents. Co transfection with CB2(SH3+) and gephyrin induced the formation of many (supernumerary) non-synaptic clusters. Transfection with gephyrin alone did not affect cluster number or size, but gephyrin potentiated the clustering effect of CB2(SH3-) or CB2(SH3+). Co-transfection with CB2(SH3-) or CB2(SH3+) and gephyrin did not affect the density of presynaptic GABAergic terminals contacting the transfected cells, indicating that collybistin is not synaptogenic. Nevertheless, the synaptic superclusters induced by CB2(SH3-) and gephyrin were accompanied by enlarged presynaptic GABAergic terminals. The enhanced clustering of gephyrin and GABA(A) receptors induced by collybistin isoforms was not accompanied by enhanced clustering of neuroligin 2. Moreover, during the development of GABAergic synapses, the clustering of gephyrin and GABA(A) receptors preceded the clustering of neuroligin 2. We propose a model in which the SH3- isoforms play a major role in the postsynaptic accumulation of GABA(A) receptors and in GABAergic synaptic strength. PMID- 21540180 TI - Syntaxin-1A interacts with distinct domains within nucleotide-binding folds of sulfonylurea receptor 1 to inhibit beta-cell ATP-sensitive potassium channels. AB - The ATP-sensitive potassium (K(ATP)) channel regulates pancreatic beta-cell function by linking metabolic status to electrical activity. Syntaxin-1A (Syn 1A), a SNARE protein mediating exocytotic fusion, binds and inhibits the K(ATP) channel via the nucleotide-binding folds (NBFs) of its sulfonylurea receptor-1 (SUR1) regulatory subunit. In this study, we elucidated the precise regions within the NBFs required for Syn-1A-mediated K(ATP) inhibition, using in vitro binding assays, whole cell patch clamp and FRET assay. Specifically, NBF1 and NBF2 were each divided into three subregions, Walker A (W(A)), signature sequence linker, and Walker B (W(B)), to make GST fusion proteins. In vitro binding assays revealed that Syn-1A associates with W(A) and W(B) regions of both NBFs. Patch clamp recordings on INS-1 and primary rat beta-cells showed that Syn-1A-mediated channel inhibition was reversed by co-addition of NBF1-W(B) (not NBF1-W(A)), NBF2 W(A), and NBF2-W(B). The findings were corroborated by FRET studies showing that these truncates disrupted Syn-1A interactions with full-length SUR1. To further identify the binding sites, series single-site mutations were made in the Walker motifs of the NBFs. Only NBF1-W(A) (K719M) or NBF2-W(A) (K1385M) mutant no longer bound to Syn-1A; K1385M failed to disrupt Syn-1A-mediated inhibition of K(ATP) channels. These data suggest that NBF1-W(A) (Lys-719) and NBF2-W(A) (Lys-1385) are critical for Syn-1A-K(ATP) channel interaction. Taken together, Syn-1A intimately and functionally associates with the SUR1-NBF1/2 dimer via direct interactions with W(A) motifs and sites adjacent to W(B) motifs of NBF1 and NBF2 but transduces its inhibitory actions on K(ATP) channel activity via some but not all of these NBF domains. PMID- 21540181 TI - Inhibition of alanine aminotransferase in silico and in vivo promotes mitochondrial metabolism to impair malignant growth. AB - Cancer cells commonly exhibit increased nonoxidative D-glucose metabolism whereas induction of mitochondrial metabolism may impair malignant growth. We have first used an in silico method called elementary mode analysis to identify inhibition of ALAT (L-alanine aminotransferase) as a putative target to promote mitochondrial metabolism. We then experimentally show that two competitive inhibitors of ALAT, L-cycloserine and beta-chloro-L-alanine, inhibit L-alanine production and impair D-glucose uptake of LLC1 Lewis lung carcinoma cells. The latter inhibition is linked to an initial energy deficit, as quantified by decreased ATP content, which is then followed by an activation of AMP-activated protein kinase and subsequently increased respiration rates and mitochondrial production of reactive oxygen species, culminating in ATP replenishment in ALAT inhibited LLC1 cells. Moreover, we observe altered phosphorylation of p38 MAPK (mitogen-activated protein kinase 14), ERK (extracellular signal-regulated kinase 1/2), and Rb1 (retinoblastoma 1) proteins, as well as decreased expression of Cdc25a (cell decision cycle 25 homolog A) and Cdk4 (cyclin-dependent kinase 4). Importantly, these sequelae of ALAT inhibition culminate in similarly reduced anchorage-dependent and anchorage-independent growth rates of LLC1 cells, together suggesting that inhibition of ALAT efficiently impairs cancer growth by counteracting the Warburg effect due to compensatory activation of mitochondrial metabolism. PMID- 21540182 TI - Down-regulation of hepatic urea synthesis by oxypurines: xanthine and uric acid inhibit N-acetylglutamate synthase. AB - We previously reported that isobutylmethylxanthine (IBMX), a derivative of oxypurine, inhibits citrulline synthesis by an as yet unknown mechanism. Here, we demonstrate that IBMX and other oxypurines containing a 2,6-dione group interfere with the binding of glutamate to the active site of N-acetylglutamate synthetase (NAGS), thereby decreasing synthesis of N-acetylglutamate, the obligatory activator of carbamoyl phosphate synthase-1 (CPS1). The result is reduction of citrulline and urea synthesis. Experiments were performed with (15)N-labeled substrates, purified hepatic CPS1, and recombinant mouse NAGS as well as isolated mitochondria. We also used isolated hepatocytes to examine the action of various oxypurines on ureagenesis and to assess the ameliorating affect of N carbamylglutamate and/or l-arginine on NAGS inhibition. Among various oxypurines tested, only IBMX, xanthine, or uric acid significantly increased the apparent K(m) for glutamate and decreased velocity of NAGS, with little effect on CPS1. The inhibition of NAGS is time- and dose-dependent and leads to decreased formation of the CPS1-N-acetylglutamate complex and consequent inhibition of citrulline and urea synthesis. However, such inhibition was reversed by supplementation with N-carbamylglutamate. The data demonstrate that xanthine and uric acid, both physiologically occurring oxypurines, inhibit the hepatic synthesis of N-acetylglutamate. An important and novel concept emerging from this study is that xanthine and/or uric acid may have a role in the regulation of ureagenesis and, thus, nitrogen homeostasis in normal and disease states. PMID- 21540183 TI - Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity. AB - SIRT1 is involved in the pathogenesis of obesity, diabetes, and aging. However, it is not clear how SIRT1 activity is regulated by intracellular kinases in cells. In this study, we investigated SIRT1 phosphorylation and protein degradation in response to JNK1 activation in obese mice. Mouse SIRT1 is phosphorylated by JNK1 at Ser-46 (Ser-47 in human SIRT1), which is one of the four potential residues targeted by JNK1. The phosphorylation induces a brief activation of SIRT1 function and degradation of SIRT1 thereafter by the proteasome. Ubiquitination occurs in SIRT1 protein after the phosphorylation. Mutation of Ser-46 to alanine prevents the phosphorylation, ubiquitination, and degradation. In vivo, SIRT1 undergoes an extensive degradation in hepatocytes in obesity as a consequence of persistent activation of JNK1. The degradation leads to inhibition of SIRT1 function, which contributes to development of hepatic steatosis. The degradation disappears in obesity when JNK1 is inactivated in mice. JNK2 exhibits an opposite activity in the regulation of SIRT1 degradation. The JNK1-SIRT1 pathway provides a new molecular mechanism for the pathogenesis of hepatic steatosis in obesity. PMID- 21540185 TI - The acylation state of surface lipoproteins of mollicute Acholeplasma laidlawii. AB - Acylation of the N-terminal Cys residue is an essential, ubiquitous, and uniquely bacterial posttranslational modification that allows anchoring of proteins to the lipid membrane. In gram-negative bacteria, acylation proceeds through three sequential steps requiring lipoprotein diacylglyceryltransferase, lipoprotein signal peptidase, and finally lipoprotein N-acyltransferase. The apparent lack of genes coding for recognizable homologs of lipoprotein N-acyltransferase in gram positive bacteria and Mollicutes suggests that the final step of the protein acylation process may be absent in these organisms. In this work, we monitored the acylation state of eight major lipoproteins of the mollicute Acholeplasma laidlawii using a combination of standard two-dimensional gel electrophoresis protein separation, blotting to nitrocellulose membranes, and MALDI-MS identification of modified N-terminal tryptic peptides. We show that for each A. laidlawii lipoprotein studied a third fatty acid in an amide linkage on the N terminal Cys residue is present, whereas diacylated species were not detected. The result thus proves that A. laidlawii encodes a lipoprotein N-acyltransferase activity. We hypothesize that N-acyltransferases encoded by genes non-homologous to N-acyltransferases of gram-negative bacteria are also present in other mollicutes and gram-positive bacteria. PMID- 21540184 TI - Urokinase-type plasminogen activator (uPA) induces pulmonary microvascular endothelial permeability through low density lipoprotein receptor-related protein (LRP)-dependent activation of endothelial nitric-oxide synthase. AB - Urokinase plasminogen activator (uPA) and PA inhibitor type 1 (PAI-1) are elevated in acute lung injury, which is characterized by a loss of endothelial barrier function and the development of pulmonary edema. Two-chain uPA and uPA PAI-1 complexes (1-20 nM) increased the permeability of monolayers of human pulmonary microvascular endothelial cells (PMVECs) in vitro and lung permeability in vivo. The effects of uPA-PAI-1 were abrogated by the nitric-oxide synthase (NOS) inhibitor L-NAME (N(D)-nitro-L-arginine methyl ester). Two-chain uPA (1-20 nM) and uPA-PAI-1 induced phosphorylation of endothelial NOS-Ser(1177) in PMVECs, which was followed by generation of NO and the nitrosylation and dissociation of beta-catenin from VE-cadherin. uPA-induced phosphorylation of eNOS was decreased by anti-low density lipoprotein receptor-related protein-1 (LRP) antibody and an LRP antagonist, receptor-associated protein (RAP), and when binding to the uPA receptor was blocked by the isolated growth factor-like domain of uPA. uPA induced phosphorylation of eNOS was also inhibited by the protein kinase A (PKA) inhibitor, myristoylated PKI, but was not dependent on PI3K-Akt signaling. LRP blockade and inhibition of PKA prevented uPA- and uPA-PAI-1-induced permeability of PMVEC monolayers in vitro and uPA-induced lung permeability in vivo. These studies identify a novel pathway involved in regulating PMVEC permeability and suggest the utility of uPA-based approaches that attenuate untoward permeability following acute lung injury while preserving its salutary effects on fibrinolysis and airway remodeling. PMID- 21540187 TI - Inhibitor of cyclin-dependent kinase (CDK) interacting with cyclin A1 (INCA1) regulates proliferation and is repressed by oncogenic signaling. AB - The cell cycle is driven by the kinase activity of cyclin.cyclin-dependent kinase (CDK) complexes, which is negatively regulated by CDK inhibitor proteins. Recently, we identified INCA1 as an interaction partner and a substrate of cyclin A1 in complex with CDK2. On a functional level, we identified a novel cyclin binding site in the INCA1 protein. INCA1 inhibited CDK2 activity and cell proliferation. The inhibitory effects depended on the cyclin-interacting domain. Mitogenic and oncogenic signals suppressed INCA1 expression, whereas it was induced by cell cycle arrest. We established a deletional mouse model that showed increased CDK2 activity in spleen with altered spleen architecture in Inca1(-/-) mice. Inca1(-/-) embryonic fibroblasts showed an increase in the fraction of S phase cells. Furthermore, blasts from acute lymphoid leukemia and acute myeloid leukemia patients expressed significantly reduced INCA1 levels highlighting its relevance for growth control in vivo. Taken together, this study identifies a novel CDK inhibitor with reduced expression in acute myeloid and lymphoid leukemia. The molecular events that control the cell cycle occur in a sequential process to ensure a tight regulation, which is important for the survival of a cell and includes the detection and repair of genetic damage and the prevention of uncontrolled cell division. PMID- 21540188 TI - Role of p38 protein kinase in the ligand-independent ubiquitination and down regulation of the IFNAR1 chain of type I interferon receptor. AB - Phosphorylation-dependent ubiquitination and degradation of the IFNAR1 chain of type I interferon (IFN) receptor is a robust and specific mechanism that limits the magnitude and duration of IFNalpha/beta signaling. Besides the ligand inducible IFNAR1 degradation, the existence of an "inside-out" signaling that accelerates IFNAR1 turnover in the cells undergoing the endoplasmic reticulum (ER) stress and activated unfolded protein responses has been recently described. The latter pathway does not require either presence of ligands (IFNalpha/beta) or catalytic activity of Janus kinases (JAK). Instead, this pathway relies on activation of the PKR-like ER kinase (PERK) and ensuing specific priming phosphorylation of IFNAR1. Here, we describe studies that identify the stress activated p38 protein kinase as an important regulator of IFNAR1 that acts downstream of PERK. Results of the experiments using pharmacologic p38 kinase inhibitors, RNA interference approach, and cells from p38alpha knock-out mice suggest that p38 kinase activity is required for priming phosphorylation of IFNAR1 in cells undergoing unfolded protein response. We further demonstrate an important role of p38 kinase in the ligand-independent stimulation of IFNAR1 ubiquitination and degradation and ensuing attenuation of IFNalpha/beta signaling and anti-viral defenses. We discuss the distinct importance of p38 kinase in regulating the overall responses to type I IFN in cells that have been already exposed to IFNalpha/beta versus those cells that are yet to encounter these cytokines. PMID- 21540189 TI - Down-modulation of the G-protein-coupled estrogen receptor, GPER, from the cell surface occurs via a trans-Golgi-proteasome pathway. AB - GPER is a G(s)-coupled seven-transmembrane receptor that has been linked to specific estrogen binding and signaling activities that are manifested by plasma membrane-associated enzymes. However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface, an observation that has caused controversy regarding its role as a plasma membrane estrogen receptor. Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin coated pits. Nonvisual arrestins-2/-3 do not co-localize with GPER, and expression of arrestin-2 dominant-negative mutants lacking clathrin- or beta adaptin interaction sites fails to block GPER internalization suggesting that arrestins are not involved in GPER endocytosis. Like beta1AR, which recycles to the plasma membrane, GPER co-traffics with transferrin+, Rab11+ recycling endosomes. However, endocytosed GPER does not recycle to the cell surface, but instead returns to the trans-Golgi network (TGN) and does not re-enter the ER. GPER is ubiquitinated at the cell surface, exhibits a short half-life (t1/2;) <1 h), and is protected from degradation by the proteasome inhibitor, MG132. Disruption of the TGN by brefeldin A induces the accumulation of endocytosed GPER in Rab11+ perinuclear endosomes and prevents GPER degradation. Our results provide an explanation as to why GPER is not readily detected on the cell surface in some cell types and further suggest that TGN serves as the checkpoint for degradation of endocytosed GPER. PMID- 21540190 TI - Sex and gender issues in competitive sports: investigation of a historical case leads to a new viewpoint. AB - Based on DNA analysis of a historical case, the authors describe how a female athlete can be unknowingly confronted with the consequences of a disorder of sex development resulting in hyperandrogenism emerging early in her sports career. In such a situation, it is harmful and confusing to question sex and gender. Exposure to either a low or high level of endogenous testosterone from puberty is a decisive factor with respect to sexual dimorphism of physical performance. Yet, measurement of testosterone is not the means by which questions of an athlete's eligibility to compete with either women or men are resolved. The authors discuss that it might be justifiable to use the circulating testosterone level as an endocrinological parameter, to try to arrive at an objective criterion in evaluating what separates women and men in sports competitions, which could prevent the initiation of complicated, lengthy and damaging sex and gender verification procedures. PMID- 21540191 TI - Does the way concussion is portrayed affect public awareness of appropriate concussion management: the case of rugby league. AB - It is important to identify factors that might adversely affect appropriate medical consultation and management of concussion. One factor that might present a barrier to timely intervention is media portrayal of concussion in sporting events, such as professional rugby league. Accordingly, the current study employed a surveillance method of publicly available broadcast information to establish the incidence rate of probable concussion in the National Rugby League's Telstra Premiership 2010 season and examined how these injury events were shown to be managed with respect to return-to-play procedures. The incident rate for probable concussion was higher than previously reported: 11.10?1000 player hours (95% CI 5.78 to 16.40) and was likely underestimated. Importantly, most injured players were shown to continue playing or return to play despite being visibly concussed and described as such by the commentary team. Although 'return-to-play decisions' for professional players are guided by medical assessment, the authors discuss whether the way concussion is portrayed might affect public awareness of appropriate concussion management. PMID- 21540192 TI - Substance P accelerates hypercellularity and angiogenesis in tendon tissue and enhances paratendinitis in response to Achilles tendon overuse in a tendinopathy model. AB - BACKGROUND: Tenocytes produce substance P (SP), and its receptor (neurokinin-1 receptor (NK-1R)) is expressed throughout the tendon tissue, especially in patients with tendinopathy and tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering the known effects of SP, one might ask whether SP contributes to these changes. OBJECTIVES: To test whether development of tendinosis-like changes (hypercellularity and angiogenesis) is accelerated during a 1-week course of exercise with local administration of SP in an established Achilles tendinopathy model. METHODS: Rabbits were subjected to a protocol of Achilles tendon overuse for 1 week, in conjunction with SP injections in the paratenon. Exercised control animals received NaCl injections or no injections, and unexercised, uninjected controls were also used. Tenocyte number and vascular density, as well as paratendinous inflammation, were evaluated. Immunohistochemistry and in situ hybridisation to detect NK-1R were conducted. Results There was a significant increase in tenocyte number in the SP-injected and NaCl-injected groups compared with both unexercised and exercised, uninjected controls. Tendon blood vessels increased in number in the SP-injected group compared with unexercised controls, a finding not seen in NaCl-injected controls or in uninjected, exercised animals. Paratendinous inflammation was more pronounced in the SP-injected group than in the NaCl controls. NK-1R was detected in blood vessel walls, nerves, inflammatory cells and tenocytes. CONCLUSIONS: SP accelerated the development of tendinosis-like changes in the rabbit Achilles tendon, which supports theories of a potential role of SP in tendinosis development; a fact of clinical interest since SP effects can be effectively blocked. The angiogenic response to SP injections seems related to paratendinitis. PMID- 21540193 TI - Changes in anteroposterior patellar tendon diameter support a continuum of pathological changes. AB - OBJECTIVES: A continuum of pathological ultrasound patellar tendon changes from normal tendons, followed by diffuse and then focal change in echogenicity has been proposed. The anteroposterior (AP) diameter of each pathological state and whether change in pathological state is accompanied by change in AP diameter are not known. The aims of this study were to (1) investigate the AP diameter of previously described patellar tendon ultrasound groups (normal, diffuse and focal change in echogenicity) and (2) investigate the change in AP diameter among active volleyball players during a season and whether this corresponds with change in ultrasound group. METHODS: The grey-scale ultrasound pathological groups (normal, diffuse, focal) and AP diameter were measured among 102 volleyball players at the beginning of a season and 58 volleyball players at 6 one-monthly intervals during a 5-month indoor season. RESULTS: There was a significant ordinal relationship (analysis of variance, Student-Neuman-Keuls post hoc test, p < 0.05) between AP diameter and normal tendons, diffuse and focally abnormal tendons among men (3.4 +/- 0.4, 4.9 +/- 0.4, 6.5 +/- 1.8 mm) and women (3.2 +/- 0.4, 4.2 +/- 0.4, 4.6 +/- 0.7 mm). Tendons that stayed in the same group tended to have a smaller mean change than tendons that changed group. CONCLUSIONS: These findings support the proposed continuum of tendon pathology. Mild patellar tendon thickening (>4.2 mm among men, >4 mm among women) may indicate pathology among active athletes. PMID- 21540194 TI - Using a community-based participatory research approach to develop a faith-based obesity intervention for African American children. AB - Childhood obesity is a major epidemic, with African American (AA) children aged 6 to 11 years experiencing increased burden. The AA faith community has numerous assets that point to the need for the intersection of faith and health to address obesity-related racial disparities. The purpose of the Our Bodies, God's Temples (OBGT) study was to examine diet, physical activity, and body image behaviors among AA children aged 6 to 11 years; receptivity to a faith-based obesity intervention among AA children, parents, and church leaders; and strengths and barriers of implementing a faith-based obesity curriculum in the Sunday school setting. A community-based participatory research approach was used to develop an obesity intervention to be integrated into the church Sunday school setting for AA children. A Community Advisory Network worked with researchers to develop a 12 week culturally appropriate faith-based obesity intervention. Future work will test the effectiveness of the newly created curriculum on obesity-related outcomes in AA children. PMID- 21540195 TI - Successful recruitment and retention of Latino study participants. AB - A high prevalence of risk behaviors among the rapidly growing Latino youth population in the United States adds urgency to the need to identify effective recruitment and retention strategies for research studies and prevention programs. The objectives of this study are to (a) describe the culturally responsive recruitment and retention strategies used in the Familias Fuertes Georgia program and (b) discuss the evaluation of the relative importance of these strategies. Familias Fuertes (i.e., Strong Families) is a community-based, primary prevention program for families in Latin America with children between the ages of 10 and 14 years. The main program goal is to reduce high-risk behaviors among adolescents by strengthening family relationships and promoting self-regulation and positive conflict resolution strategies. A pilot feasibility study was conducted to determine the appropriateness of the Familias Fuertes program for Latino families living in the United States. To promote participation, 15 culturally responsive recruitment and retention strategies were developed using a three-step process. These strategies contributed to the successful recruitment and retention of Familias Fuertes-Georgia study participants. Participating parents, the community liaison, and the community leader evaluated the relative importance of the 15 culturally responsive recruitment and retention strategies. Three of the strategies emerged as more important than others: face-to-face recruitment by the community liaison; bilingual, bicultural, and experienced facilitators; and free on-site child care. Further research is needed to develop strategies promoting the participation of male caregivers/fathers. PMID- 21540196 TI - Perceptions of part-time faculty by chairpersons of undergraduate health education programs. AB - In recent years, it has become commonplace for universities to hire part-time and non-tenure track faculty to save money. This study examined how commonly part time faculty are used in health education and how they are used to meet program needs. The American Association of Health Education's 2009 "Directory of Institutions Offering Undergraduate and Graduate Degree Programs in Health Education" was used to send a three-wave mailing to programs that were not schools of public health (n = 215). Of the 125 departments (58%) that responded, those that used part-time faculty averaged 7.5 part-time faculty in the previous academic year, teaching on average a total of 10 classes per year. A plurality of departments (38%) were currently using more part-time faculty than 10 years ago and 33% perceived that the number of part-time faculty has resulted in decreases in the number of full-time positions. Although 77% of department chairs claimed they would prefer to replace all of their part-time faculty with one full-time tenure track faculty member. As colleges downsize, many health education programs are using more part-time faculty. Those faculty members who take part-time positions will likely be less involved in academic activities than their full time peers. Thus, further research is needed on the effects of these changes on the quality of health education training and department productivity. PMID- 21540197 TI - A drive through Web 2.0: an exploration of driving safety promotion on FacebookTM. AB - This study explored FacebookTM to capture the prevalence of driving safety promotion user groups, obtain user demographic information, to understand if FacebookTM user groups influence reported driving behaviors, and to gather a sense of perceived effectiveness of FacebookTM for driving safety promotion targeted to young adults. In total, 96 driving safety FacebookTM groups (DSFGs) were identified with a total of 33,368 members, 168 administrators, 156 officers, 1,598 wall posts representing 12 countries. A total of 85 individuals participated in the survey. Demographic findings of this study suggest that driving safety promotion can be targeted to young and older adults. Respondents' ages ranged from 18 to 66 years. A total of 62% of respondents aged <= 24 years and 57.8% of respondents aged >= 25 years reported changing their driving-related behaviors as a result of reading information on the DSFGs to which they belonged. A higher proportion of respondents >= 25 years were significantly more likely to report FacebookTM and YouTubeTM as an effective technology for driving safety promotion. This preliminary study indicates that DSFGs may be effective tools for driving safety promotion among young adults. More research is needed to understand the cognition of FacebookTM users as it relates to adopting safe driving behavior. The findings from this study present descriptive data to guide public health practitioners for future health promotion activities on FacebookTM. PMID- 21540198 TI - Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. AB - OBJECTIVE: This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1beta monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment. METHODS: In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4*4-weekly doses of canakinumab (50+50+25+25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks. RESULTS: A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses >=50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28-0.38, p<=0.0083), and the percentage of patients experiencing >=1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing >=1 flare for canakinumab doses >=50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28-0.36, p<=0.05). The incidence of adverse events was similar across treatment groups. CONCLUSIONS: Single canakinumab doses >=50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg. PMID- 21540200 TI - 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis. AB - This paper presents the second update of the Assessment in SpondyloArthritis international Society (ASAS) consensus statement on the use of anti-tumour necrosis factor (anti-TNF) agents in patients with axial spondyloarthritis (SpA). A major change from the previous recommendations is that patients fulfilling the ASAS axial SpA criteria, which also include patients fulfilling the modified New York criteria for ankylosing spondylitis, can be treated with anti-TNF agents. This makes an earlier start in the disease process possible. A second major change is the mandatory pretreatment before anti-TNF agents can be started. All patients should have tried a minimum of two non-steroidal anti-inflammatory drugs for a minimum of 4 weeks in total. This is significantly shorter than the previous requirement of 3 months. As previously, patients with axial symptoms require no further pretreatment. Patients with symptomatic peripheral symptoms should normally have had an adequate therapeutic trial of a disease-modifying antirheumatic drug, preferably sulfasalazine. Sulfasalazine is no longer mandatory in this group of patients. Finally, efficacy should be evaluated after at least 12 weeks. The remaining recommendations stayed largely unchanged. PMID- 21540199 TI - 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. AB - This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made - if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good. PMID- 21540201 TI - Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative. AB - OBJECTIVE: A patient-derived composite measure of the impact of rheumatoid arthritis (RA), the rheumatoid arthritis impact of disease (RAID) score, takes into account pain, functional capacity, fatigue, physical and emotional wellbeing, quality of sleep and coping. The objectives were to finalise the RAID and examine its psychometric properties. METHODS: An international multicentre cross-sectional and longitudinal study of consecutive RA patients from 12 European countries was conducted to examine the psychometric properties of the different combinations of instruments that might be included within the RAID combinations scale (numeric rating scales (NRS) or various questionnaires). Construct validity was assessed cross-sectionally by Spearman correlation, reliability by intraclass correlation coefficient (ICC) in 50 stable patients, and sensitivity to change by standardised response means (SRM) in 88 patients whose treatment was intensified. RESULTS: 570 patients (79% women, mean +/- SD age 56 +/- 13 years, disease duration 12.5 +/- 10.3 years, disease activity score (DAS28) 4.1 +/- 1.6) participated in the validation study. NRS questions performed as well as longer combinations of questionnaires: the final RAID score is composed of seven NRS questions. The final RAID correlated strongly with patient global (R=0.76) and significantly also with other outcomes (DAS28 R=0.69, short form 36 physical -0.59 and mental -0.55, p<0.0001 for all). Reliability was high (ICC 0.90; 95% CI 0.84 to 0.94) and sensitivity to change was good (SRM 0.98 (0.96 to 1.00) compared with DAS28 SRM 1.06 (1.01 to 1.11)). CONCLUSION: The RAID score is a patient-derived composite score assessing the seven most important domains of impact of RA. This score is now validated; sensitivity to change should be further examined in larger studies. PMID- 21540202 TI - Self-management of fatigue in rheumatoid arthritis: a randomised controlled trial of group cognitive-behavioural therapy. AB - OBJECTIVES: To investigate the effect of group cognitive behavioural therapy (CBT) for fatigue self-management, compared with groups receiving fatigue information alone, on fatigue impact among people with rheumatoid arthritis (RA). METHODS: Two-arm, parallel randomised controlled trial in adults with RA, fatigue >= 6/10 (Visual Analogue Scale (VAS) 0-10, high bad) and no recent change in RA medication. Group CBT for fatigue self-management comprised six (weekly) 2 h sessions, and consolidation session (week 14). Control participants received fatigue self-management information in a 1 h didactic group session. Primary outcome at 18 weeks was the impact of fatigue measured using two methods (Multi dimensional Assessment of Fatigue (MAF) 0-50; VAS 0-10), analysed using intention to-treat analysis of covariance with multivariable regression models. RESULTS: Of 168 participants randomised, 41 withdrew before entry and 127 participated. There were no major baseline differences between the 65 CBT and 62 control participants. At 18 weeks CBT participants reported better scores than control participants for fatigue impact: MAF 28.99 versus 23.99 (adjusted difference 5.48, 95% CI -9.50 to -1.46, p=0.008); VAS 5.99 versus 4.26 (adjusted difference 1.95, 95% CI -2.99 to -0.90, p<0.001). Standardised effect sizes for fatigue impact were MAF 0.59 (95% CI 0.15 to 1.03) and VAS 0.77 (95% CI 0.33 to 1.21), both in favour of CBT. Secondary outcomes of perceived fatigue severity, coping, disability, depression, helplessness, self-efficacy and sleep were also better in CBT participants. CONCLUSIONS: Group CBT for fatigue self-management in RA improves fatigue impact, coping and perceived severity, and well-being. TRIAL REGISTRATION: ISRCTN 32195100. PMID- 21540203 TI - Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 vaccine in a large cohort of autoimmune rheumatic diseases. AB - BACKGROUND: Despite the WHO recommendation that the 2010-2011 trivalent seasonal flu vaccine must contain A/California/7/2009/H1N1-like virus there is no consistent data regarding its immunogenicity and safety in a large autoimmune rheumatic disease (ARD) population. METHODS: 1668 ARD patients (systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic sclerosis, psoriatic arthritis (PsA), Behcet's disease (BD), mixed connective tissue disease, primary antiphospholipid syndrome (PAPS), dermatomyositis (DM), primary Sjogren's syndrome, Takayasu's arteritis, polymyositis and Granulomatosis with polyangiitis (Wegener's) (GPA)) and 234 healthy controls were vaccinated with a non-adjuvanted influenza A/California/7/2009(H1N1) virus-like strain flu. Subjects were evaluated before vaccination and 21 days post-vaccination. The percentage of seroprotection, seroconversion and the factor increase in geometric mean titre (GMT) were calculated. RESULTS: /st> After immunisation, seroprotection rates (68.5% vs 82.9% p<0.0001), seroconversion rates (63.4% vs 76.9%, p<0.001) and the factor increase in GMT (8.9 vs 13.2 p<0.0001) were significantly lower in ARD than controls. Analysis of specific diseases revealed that seroprotection significantly reduced in SLE (p<0.0001), RA (p<0.0001), PsA (p=0.0006), AS (p=0.04), BD (p=0.04) and DM (p=0.04) patients than controls. The seroconversion rates in SLE (p<0.0001), RA (p<0.0001) and PsA (p=0.0006) patients and the increase in GMTs in SLE (p<0.0001), RA (p<0.0001) and PsA (p<0.0001) patients were also reduced compared with controls. Moderate and severe side effects were not reported. CONCLUSIONS: The novel recognition of a diverse vaccine immunogenicity profile in distinct ARDs supports the notion that a booster dose may be recommended for diseases with suboptimal immune responses. This large study also settles the issue of vaccine safety. (ClinicalTrials.gov #NCT01151644). PMID- 21540204 TI - Concepts of functioning and health important to people with systemic sclerosis: a qualitative study in four European countries. AB - OBJECTIVE: To describe the experiences of people with systemic sclerosis (SSc) in different European countries of functioning and health and to link these experiences to the WHO International Classification of Functioning, Disability and Health (ICF) to develop a common understanding from a bio-psycho-social perspective. METHOD: A qualitative multicentre study with focus-group interviews was performed in four European countries: Austria, Romania, Sweden and Switzerland. The qualitative data analysis followed a modified form of 'meaning condensation' and the concepts that emerged in the analysis were linked to the ICF. RESULTS: 63 people with SSc participated in 13 focus groups. In total, 86 concepts were identified. 32 (37%) of these were linked to the ICF component body functions and structures, 21 (24%) to activities and participation, 26 (30%) to environmental factors, 6 (7%) to personal factors and 1 (1%) to the health condition itself. 19 concepts (22%) were identified in all four countries and included impaired hand function, household activities, paid work, drugs, climate and coldness, support from others and experiences with healthcare institutions, non-pharmacological treatment, social security and benefits. CONCLUSION: Concepts identified in all four countries could be used for guiding clinical assessment, as well as interdisciplinary team care and rheumatological rehabilitation for patients with SSc. For a full understanding of the aspects of the disease that were most relevant to people with SSc, people with SSc from multiple countries needed to be involved. PMID- 21540205 TI - Ventilator-associated tracheitis in children: does antibiotic duration matter? AB - BACKGROUND: The optimal duration of antibiotic therapy for ventilator-associated tracheitis (VAT) has not been defined, which may result in unnecessarily prolonged courses of antibiotics. The primary objective of this study was to determine whether prolonged-course (>=7 days in duration) therapy for VAT was more protective against progression to hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP), compared with short-course antibiotics (<7 days in duration). The secondary objective was to determine whether prolonged course therapy was more likely to result in the acquisition of multidrug resistant organisms (MDROs) compared with short-course therapy. METHODS: We conducted a retrospective cohort study of children <=18 years of age hospitalized in the intensive care unit and intubated for >=48 h from January 2007 through December 2009 who received antibiotic therapy for VAT. RESULTS: Of the 1616 patients intubated for at least 48 h, 150 received antibiotics for clinician suspected VAT, although only 118 of these patients met VAT criteria. Prolonged course antibiotics were not protective against subsequent development of HAP or VAP (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.40-2.91). Factors associated with subsequent MDRO colonization or infection included prolonged course antibiotic therapy (HR, 5.15; 95% CI, 1.54-7.19), receipt of combination antibiotic therapy (HR, 3.24; 95% CI, 1.54-6.82), and days of hospital exposure prior to completing antibiotic therapy (HR, 1.08; 95% CI, 1.04-1.12). CONCLUSIONS: A prolonged course of antibiotics for VAT does not appear to protect against progression to HAP or VAP compared with short-course therapy. Furthermore, prolonged antibiotic courses were associated with a significantly increased risk of subsequent MDRO acquisition. PMID- 21540206 TI - The cost-effectiveness of screening for chronic hepatitis B infection in the United States. AB - BACKGROUND: Hepatitis B virus (HBV) continues to cause significant morbidity and mortality in the United States. Current guidelines suggest screening populations with a prevalence of >=2%. Our objective was to determine whether this screening threshold is cost-effective and whether screening lower-prevalence populations might also be cost-effective. METHODS: We developed a Markov state transition model to examine screening of asymptomatic outpatients in the United States. The base case was a 35-year-old man living in a region with an HBV infection prevalence of 2%. Interventions (versus no screening) included screening for Hepatitis B surface antigen followed by treatment of appropriate patients with (1) pegylated interferon-alpha2a for 48 weeks, (2) a low-cost nucleoside or nucleotide agent with a high rate of developing viral resistance for 48 weeks, (3) prolonged treatment with low-cost, high-resistance nucleoside or nucleotide, or (4) prolonged treatment with a high-cost nucleoside or nucleotide with a low rate of developing viral resistance. Effectiveness was measured in quality adjusted life years (QALYs) and costs in 2008 US dollars. RESULTS: Screening followed by treatment with a low-cost, high-resistance nucleoside or nucleotide was cost-effective ($29,230 per QALY). Sensitivity analyses revealed that screening costs <$50,000 per QALY in extremely low-risk populations unless the prevalence of chronic HBV infection is <.3%. CONCLUSIONS: The 2% threshold for prevalence of chronic HBV infection in current Centers for Disease Control and Prevention/US Public Health Service screening guidelines is cost-effective. Furthermore, screening of adults in the United States in lower-prevalence populations (eg, as low as .3%) also is likely to be cost-effective, suggesting that current health policy should be reconsidered. PMID- 21540207 TI - Economic analysis of hepatitis B screening and treatment. PMID- 21540208 TI - Neurosurgical gram-negative bacillary ventriculitis and meningitis: a retrospective study evaluating the efficacy of intraventricular gentamicin therapy in 31 consecutive cases. AB - BACKGROUND: Gram-negative bacillary (GNB) ventriculitis and meningitis are rare but serious complications after neurosurgery. Prospective studies on antibiotic treatment for these infections are lacking, and retrospective reports are sparse. At our hospital in Uppsala, Sweden, meropenem has been recommended as empirical therapy since 1996, with the addition of intraventricular gentamicin in cases that do not respond satisfactorily to treatment. In this study, we retrospectively compare the efficacy of combination treatment with intraventricular gentamicin to that of systemic antibiotics alone. In addition, we report our experience of meropenem for the treatment of GNB ventriculomeningitis. METHODS: Adult consecutive patients with gram-negative bacteria isolated from cerebrospinal fluid during a 10-year period and with postneurosurgical GNB ventriculitis or meningitis were included retrospectively. Data were abstracted from the medical records. RESULTS: Thirty-one patients with neurosurgical GNB ventriculitis or meningitis and follow-up for 3 months were identified. The main intravenous therapies were meropenem (n = 24), cefotaxime (n = 3), ceftazidime (n = 2), imipenem (n = 1), and trimethoprim-sulfamethoxazole (n = 1). Thirteen patients were given combination treatment with appropriate intraventricular gentamicin. These patients had a higher cure rate and a lower relapse rate than did those treated with intravenous antibiotics alone (P = .03). Relapse occurred in 0 of 13 patients treated intraventricularly and in 6 of 18 patients treated with systemic antibiotics alone. The mortality rate was 19%; 3 patients in each group died, but in no case was death considered to be attributable to meningitis. CONCLUSIONS: Our results support combination treatment with intraventricular gentamicin for postneurosurgical GNB ventriculomeningitis. Meropenem seems to be an effective and safe alternative for the systemic antibiotic treatment of these neurointensive care infections. PMID- 21540209 TI - Solution structure of all parallel G-quadruplex formed by the oncogene RET promoter sequence. AB - RET protein functions as a receptor-type tyrosine kinase and has been found to be aberrantly expressed in a wide range of human diseases. A highly GC-rich region upstream of the promoter plays an important role in the transcriptional regulation of RET. Here, we report the NMR solution structure of the major intramolecular G-quadruplex formed on the G-rich strand of this region in K(+) solution. The overall G-quadruplex is composed of three stacked G-tetrad and four syn guanines, which shows distinct features for all parallel-stranded folding topology. The core structure contains one G-tetrad with all syn guanines and two other with all anti-guanines. There are three double-chain reversal loops: the first and the third loops are made of 3 nt G-C-G segments, while the second one contains only 1 nt C10. These loops interact with the core G-tetrads in a specific way that defines and stabilizes the overall G-quadruplex structure and their conformations are in accord with the experimental mutations. The distinct RET promoter G-quadruplex structure suggests that it can be specifically involved in gene regulation and can be an attractive target for pathway-specific drug design. PMID- 21540210 TI - The role of Doppler echocardiography in pulmonary artery hypertension: the importance of proving the obvious. PMID- 21540211 TI - Oxygen for obesity hypoventilation syndrome: a double-edged sword? PMID- 21540213 TI - Coronary stent implantation in patients committed to long-term oral anticoagulation therapy: successfully navigating the treatment options. AB - Current guidelines and recommendations on the antithrombotic management of patients committed to long-term oral anticoagulation (OAC) therapy undergoing coronary stent implantation are recognized to be flawed by numerous limitations. Nevertheless, triple therapy (TT) (warfarin, aspirin, and clopidogrel) is regarded as the most effective regimen for preventing major adverse cardiac events, stent thrombosis, and stroke, albeit at the price of an increased risk of bleeding. Recent insights into the efficacy and safety of TT derived from larger, prospective studies have expanded current knowledge by showing that TT is likely associated with minor, rather than major bleeding, and that accurate stratification of thromboembolic and hemorrhagic risk may enable optimization of the antithrombotic strategy at discharge. Therefore, TT should be prescribed to patients at moderate to high thromboembolic risk, owing to a favorable net clinical benefit. Discontinuation of OAC and substitution with dual antiplatelet therapy is the optimal strategy for patients at low thromboembolic risk. PMID- 21540212 TI - Pediatric sleep apnea: the brain-heart connection. PMID- 21540214 TI - Assessing evidence of interaction between smoking and warfarin: a systematic review and meta-analysis. AB - BACKGROUND: Chronic smoking, theoretically, can interfere with warfarin metabolism through enzyme-inducing effects of polycyclic aromatic hydrocarbons. However, clinical evidence of interactions between warfarin and smoking are inconclusive. This study aimed to systematically review all relevant clinical evidence of this interaction. METHODS: We performed a systematic search using computerized databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL, Allied and Complementary Medicine, PsycINFO, International Pharmaceutical Abstracts, and ClinicalTrials.gov from 1966 to December 2008. Keywords included "warfarin" with "smoking," "tobacco," "cigarette," and "polycyclic aromatic hydrocarbons." Original articles reporting interaction between warfarin and smoking were included. All articles were reviewed independently by two investigators for study design, population, outcomes, and quality of evidence. RESULTS: Of the 1,240 studies retrieved, one experimental pharmacokinetic study and 12 cross-sectional studies were included. The pooled analyses of multivariate studies suggested that smoking was associated with a 12.13% (95% CI, 6.999-17.265; P < .001) increase in warfarin dosage requirement and an additional 2.26 mg (95% CI, 2.529-7.042; P = .355) per week compared with nonsmoking. Additional sensitivity analysis of four multivariate studies with adjustment for pharmacogenomic factors suggested that smoking was associated with a 13.21% (95% CI, 8.59%-17.83%; P < .001) increase in warfarin dosage requirement compared with nonsmokers. Results of an experimental pharmacokinetic study lend theoretical support to the findings. CONCLUSIONS: Evidence suggests that smoking may potentially cause significant interaction with warfarin by increasing warfarin clearance, which leads to reduced warfarin effects. Close monitoring of warfarin therapy should be instituted when there is a change in smoking status of patients requiring warfarin therapy. PMID- 21540215 TI - Interaction between adaptive and innate immune pathways in the pathogenesis of atopic asthma: operation of a lung/bone marrow axis. AB - Atopic asthma is the most common form of asthma, particularly during childhood, and in many cases it persists into adult life. Although atopy is clearly a risk factor for development of this disease, only a small subset of subjects sensitized to aeroallergens express persistent symptoms, suggesting that additional pathogenic mechanisms are involved. Recent studies have implicated respiratory viral infections as key cofactors in asthma development in atopic patients. In relation to initial expression of the asthma phenotype in early childhood, it has been shown that although both atopic sensitization and early severe lower respiratory tract infections can operate as independent asthma risk factors, the persistence of asthma is most frequent among children who experience both insults, suggesting that the relevant inflammatory pathways interact to maximally drive disease pathogenesis. Importantly, it has been established that both these factors must be operative contemporaneously for these interactions to occur (ie, the interactions are likely to be direct). Recent studies on viral induced asthma exacerbations in atopic children have provided a plausible mechanism for these interactions. Notably, it has been demonstrated that signals triggered during the innate immune response to the virus can lead to the release of large numbers of migrating high-affinity IgE receptor-bearing bone marrow derived precursors of mucosal dendritic cells into the blood. The subsequent trafficking of these cells to the infected airway mucosa where dendritic cell turnover is very high provides a potential mechanism for recruitment of underlying aeroallergen-specific T-helper 2 immunity into the already inflamed milieu in the infected airway mucosa. PMID- 21540216 TI - Pneumonia due to Pseudomonas aeruginosa: part II: antimicrobial resistance, pharmacodynamic concepts, and antibiotic therapy. AB - Pseudomonas aeruginosa carries a notably higher mortality rate than other pneumonia pathogens. Because of its multiple mechanisms of antibiotic resistance, therapy has always been challenging. This problem has been magnified in recent years with the emergence of multidrug-resistant (MDR) pathogens often unharmed by almost all classes of antimicrobials. The objective of this article is to assess optimal antimicrobial therapy based on in vitro activity, animal studies, and pharmacokinetic/pharmacodynamic (PK/PD) observations so that evidence-based recommendations can be developed to maximize favorable clinical outcomes. Mechanisms of antimicrobial resistance of P aeruginosa are reviewed. A selective literature review of laboratory studies, PK/PD concepts, and controlled clinical trials of antibiotic therapy directed at P aeruginosa pneumonia was performed. P aeruginosa possesses multiple mechanisms for inducing antibiotic resistance to antimicrobial agents. Continuous infusion of antipseudomonal beta-lactam antibiotics enhances bacterial killing. Although the advantages of combination therapy remain contentious, in vitro and animal model studies plus selected meta analyses of clinical trials support its use, especially in the era of MDR. Colistin use and the role of antibiotic aerosolization are reviewed. An evidence based algorithmic approach based on severity of illness, Clinical Pulmonary Infection Score, and combination antibiotic therapy is presented; clinical outcomes may be improved, and the emergence of MDR pathogens should be minimized with this approach. PMID- 21540217 TI - Cardiac silhouette findings and mediastinal lines and stripes: radiograph and CT scan correlation. AB - Despite the increased use of CT imaging, chest radiography remains a very important diagnostic modality in the evaluation of lung parenchymal and mediastinal diseases, providing a vast amount of useful information. This information is generally derived from the relationships among the normal anatomic structures of the mediastinum, pleura, and lungs, which represent the basis of the "cardiac silhouette" and "mediastinal lines-and-stripes" concepts that potentially play an important role in the establishment of a diagnosis or a spectrum of diagnoses before proceeding to CT imaging. The capability of recognizing an abnormal chest radiograph on the basis of the displacement, deformation, or obscuration of one of these structures when compared with those in normal findings is often mandatory prior to requesting a potentially useful CT scan examination. Therefore, radiologists, trainees, and physicians must be familiar with the anatomic basis of those findings to be able to recognize the normal and abnormal appearance of structures when developing an appropriate differential diagnosis. In this review, we briefly describe the cardiac silhouette concepts and the mediastinal lines-and-stripes configurations as they relate to the radiographic and CT scan appearance of structures for a spectrum of pathologic diseases and list the possible underlying causes of the displacement, deformation, or obscuration of the structures. PMID- 21540218 TI - Infant pulmonary function testing: overview of technology and practical considerations--new current procedural terminology codes effective 2010. AB - Infant pulmonary function testing has evolved from a research technique into a diagnostic tool. As such, new current procedural terminology (CPT) codes have been created and are available for use as of January 1, 2010. The technology now available has a range of applications. Through a series of vignettes, this article illustrates the methodology of the tests, some of their applications, and how to code and bill for the procedures. PMID- 21540219 TI - Antibiotic dosing in multiple organ dysfunction syndrome. AB - Although early and appropriate antibiotic therapy remains the cornerstone of success for the treatment of septic shock, few data exist to guide antibiotic dose optimization in critically ill patients, particularly those with multiple organ dysfunction syndrome (MODS). It is well known that MODS significantly alters the patient's physiology, but the effects of these variations on pharmacokinetics have not been reviewed concisely. Therefore, the aims of this article are to summarize the disease-driven variations in pharmacokinetics and pharmacodynamics and to provide antibiotic dosing recommendations for critically ill patients with MODS. The main findings of this review are that the two parameters that vary with greatest significance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the first day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary, "front loaded" doses of antibiotic during the first 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, maintenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction. PMID- 21540220 TI - Sleep medicine training across the spectrum. AB - There is now a new pathway and examination for sleep medicine, sponsored by the American Board of Internal Medicine, and a number of accredited sleep medicine fellowship programs through the Accreditation Council for Graduate Medical Education. This review takes an historical approach to discuss the process of education for sleep physiology and disorders not only in the postgraduate period but also at all levels of instruction. In reality, there is a continuum of knowledge that needs to be reinforced up and down the educational system, of which Sleep Medicine subspecialty training is just one part. Although progress has been made at all educational levels up to this point, the future of training and education will depend on a sustained effort at several levels from undergraduate to postgraduate continuing medical education and will be facilitated by professional societies and other specialties who will collectively promote the value of and outcomes for clinical sleep medicine. PMID- 21540221 TI - A 74-year-old man with an incidental right-sided pleural effusion. PMID- 21540222 TI - A 71-year-old woman with an unusual cause for pleural effusions. PMID- 21540223 TI - Azithromycin in posttransplant bronchiolitis obliterans syndrome. PMID- 21540224 TI - Assessing the performance of the HAS-BLED score: is the C statistic sufficient? PMID- 21540225 TI - The HAS-BLED score and renal failure. PMID- 21540226 TI - More rigor needed in systematic reviews on "waterpipe" (hookah, narghile, shisha) smoking. PMID- 21540227 TI - FEV(1)/FVC fixed ratio again! PMID- 21540228 TI - Abandoning FEV(1)/FVC < 0.70 to detect airway obstruction: an essential debate but with the right emphasis? PMID- 21540229 TI - Community-acquired pneumonia: diagnostic vs prognostic significance of the platelet count. PMID- 21540230 TI - Simulator training for recognition of murmurs: give a kid a hammer? PMID- 21540231 TI - The relationship between emphysema on CT scan and lung cancer. PMID- 21540232 TI - Comparative analysis reveals selective recognition of glycans by the dendritic cell receptors DC-SIGN and Langerin. AB - DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) and Langerin are homologous C-type lectins expressed as cell-surface receptors on different populations of dendritic cells (DCs). DC-SIGN interacts with glycan structures on HIV-1, facilitating virus survival, transmission and infection, whereas Langerin, which is characteristic of Langerhans cells (LCs), promotes HIV-1 uptake and degradation. Here we describe a comprehensive comparison of the glycan specificities of both proteins by probing a synthetic carbohydrate microarray comprising 275 sugar compounds using the bacterially produced and fluorescence labeled, monomeric carbohydrate-recognition domains (CRDs) of DC-SIGN and Langerin. In this side-by-side study DC-SIGN was found to preferentially bind internal mannose residues of high-mannose-type saccharides and the fucose containing blood-type antigens H, A, B, Le(a), Le(b) Le(x), Le(y), sialyl-Le(a) as well as sulfatated derivatives of Le(a) and Le(x). In contrast, Langerin appeared to recognize a different spectrum of compounds, especially those containing terminal mannose, terminal N-acetylglucosamine and 6-sulfogalactose residues, but also the blood-type antigens H, A and B. Of the Lewis antigens, only Le(b), Le(y), sialyl-Le(a) and the sialyl-Le(x) derivative with 6' sulfatation at the galactose (sialyl-6SGal Le(x)) were weakly bound by Langerin. Notably, Ca(2+)-independent glycan-binding activity of Langerin could not be detected either by probing the glycan array or by isothermal titration calorimetry of the CRD with mannose and mannobiose. The precise knowledge of carbohydrate specificity of DC-SIGN and Langerin receptors resulting from our study may aid the future design of microbicides that specifically affect the DC SIGN/HIV-1 interaction while not compromising the protective function of Langerin. PMID- 21540233 TI - Evidence that serum levels of the soluble receptor for advanced glycation end products are inversely associated with pancreatic cancer risk: a prospective study. AB - Cigarette smoking, obesity, type 2 diabetes, and, to a lesser extent, meat cooked at high temperatures are associated with pancreatic cancer. Cigarette smoke and foods cooked at higher temperatures are major environmental sources of advanced glycation end products (AGE). AGEs accumulate during hyperglycemia and elicit oxidative stress and inflammation through interaction with the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) acts as an anti-inflammatory factor to neutralize AGEs and block the effects mediated by RAGE. In this study, we investigated the associations of prediagnostic measures of N(epsilon)-(carboxymethyl)-lysine (CML) AGE and sRAGE with pancreatic cancer in a case-cohort study within a cohort of 29,133 Finnish male smokers. Serum samples and exposure information were collected at baseline (1985-1988). We measured CML-AGE, sRAGE, glucose, and insulin concentrations in fasting serum from 255 incident pancreatic cancer cases that arose through April 2005 and from 485 randomly sampled subcohort participants. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI, adjusted for age, years of smoking, and body mass index. CML-AGE and sRAGE were mutually adjusted. CML-AGE levels were not associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.68 (0.38-1.22), P(trend) = 0.27]. In contrast, sRAGE levels were inversely associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.46 (0.23-0.73), P(trend) = 0.002]. Further adjustment for glucose or insulin levels did not change the observed associations. Our findings suggest that sRAGE is inversely associated with pancreatic cancer risk among Finnish male smokers. PMID- 21540234 TI - mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. AB - mTOR is a central mediator of cancer cell growth, but it also directs immune cell differentiation and function. On this basis, we had explored the hypothesis that mTOR inhibition can enhance cancer immunotherapy. Here, we report that a combination of alphaCD40 agonistic antibody and the ATP-competitive mTOR kinase inhibitory drug AZD8055 elicited synergistic antitumor responses in a model of metastatic renal cell carcinoma. In contrast to the well-established mTOR inhibitor rapamycin, AZD8055 increased the infiltration, activation, and proliferation of CD8(+) T cells and natural killer cells in liver metastatic foci when combined with the CD40 agonist. AZD8055/alphaCD40-treated mice also display an increased incidence of matured macrophages and dendritic cells compared with that achieved in mice by alphaCD40 or AZD8055 treatment alone. We found that the combination treatment also increased macrophage production of TNFalpha, which played an indispensable role in activation of the observed antitumor immune response. Levels of Th1 cytokines, including interleukin 12, IFN-gamma, TNFalpha, and the Th1-associated chemokines RANTES, MIG, and IP-10 were each elevated significantly in the livers of mice treated with the combinatorial therapy versus individual treatments. Notably, the AZD8055/alphaCD40-induced antitumor response was abolished in IFN-gamma(-/-) and CD40(-/-) mice, establishing the reliance of the combination therapy on host IFN-gamma and CD40 expression. Our findings offer a preclinical proof of concept that, unlike rapamycin, the ATP-competitive mTOR kinase inhibitor AZD8055 can contribute with alphaCD40 treatment to trigger a restructuring of the tumor immune microenvironment to trigger regressions of an established metastatic cancer. PMID- 21540235 TI - Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells. AB - Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy. PMID- 21540236 TI - Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. AB - Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment. PMID- 21540238 TI - Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance. AB - PURPOSE: High inhibitor of differentiation-1 (Id1) levels have been found in some tumor types. We aimed to study Id1 levels and their prognostic impact in a large series of stages I to IV non-small cell lung cancer (NSCLC) patients. Experiments in cell lines and cells derived from malignant pleural effusions (MPE) were also carried out. EXPERIMENTAL DESIGN: A total of 346 NSCLC samples (three different cohorts), including 65 matched nonmalignant tissues, were evaluated for Id1 expression by using immunohistochemistry. Additional data from a fourth cohort including 111 patients were obtained for Id1 mRNA expression analysis by using publicly available microarrays. In vitro proliferation assays were conducted to characterize the impact of Id1 on growth and treatment sensitivity. RESULTS: Significantly higher Id1 protein levels were found in tumors compared with normal tissues (P < 0.001) and in squamous carcinomas compared with adenocarcinomas (P < 0.001). In radically treated stages I to III patients and stage IV patients treated with chemotherapy, higher Id1 levels were associated with a shorter disease-free survival and overall survival in adenocarcinoma patients in a log rank test. A Cox model confirmed the independent prognostic value of Id1 levels for both stages I to III and stage IV patients. In silico analysis confirmed a correlation between higher Id1 mRNA levels and poor prognosis for adenocarcinoma subjects. In vitro Id1 silencing in radio/chemotherapy-resistant adenocarcinoma cells from MPEs restored sensitivity to both therapies. CONCLUSIONS: In our series, Id1 levels showed an independent prognostic value in patients with adenocarcinoma, regardless of the stage. Id1 silencing may sensitize adenocarcinoma cells to radiotherapy and chemotherapy. PMID- 21540239 TI - Programmed death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells. AB - PURPOSE: Programmed death ligand 1 (PD-L1) is expressed on antigen-presenting cells and inhibits activation of T cells through its receptor PD-1. PD-L1 is aberrantly expressed on some epithelial malignancies and Hodgkin lymphomas and may prevent effective host antitumor immunity. The role of PD-L1 in non-Hodgkin lymphomas (NHL) is not well characterized. EXPERIMENTAL DESIGN: PD-L1 expression was analyzed in cell lines and lymphoma specimens by using flow cytometry and immunohistochemistry. Functional activity of PD-L1 was studied by incubating irradiated lymphoma cells with allogeneic T cells with or without anti-PD-L1 blocking antibody; T-cell proliferation and IFN-gamma secretion served as measures of T-cell activation. Similar experiments were conducted using cultures of primary lymphoma specimens containing host T cells. RESULTS: PD-L1 was expressed uniformly by anaplastic large cell lymphoma (ALCL) cell lines, but rarely in B-cell NHL, confined to a subset of diffuse large B-cell lymphomas (DLBCL) with activated B-cell features (3 of 28 cell lines and 24% of primary DLBCL). Anti-PD-L1 blocking antibody boosted proliferation and IFN-gamma secretion by allogeneic T cells responding to ALCL and DLBCL cells. In autologous cultures of primary ALCL and DLBCL, PD-L1 blockade enhanced secretion of inflammatory cytokines IFN-gamma, granulocyte macrophage colony-stimulating factor, interleukin (IL)-1, IL-6, IL-8, IL-13, TNF-alpha, and macrophage inflammatory protein-1alpha. In establishing cell lines from an aggressive PD L1(+) mature B-cell lymphoma, we also noted that PD-L1 expression could be lost under certain in vitro culture conditions. CONCLUSIONS: PD-L1 may thwart effective antitumor immune responses and represents an attractive target for lymphoma immunotherapy. PMID- 21540237 TI - Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. AB - PURPOSE: MET signaling has been suggested a potential role in malignant peripheral nerve sheath tumors (MPNST). Here, MET function and blockade were preclinically assessed. EXPERIMENTAL DESIGN: Expression levels of MET, its ligand hepatocyte growth factor (HGF), and phosphorylated MET (pMET) were examined in a clinically annotated MPNST tissue microarray (TMA) incorporating univariable and multivariable statistical analyses. Human MPNST cells were studied in vitro and in vivo; Western blot (WB) and ELISA were used to evaluate MET and HGF expression, activation, and downstream signaling. Cell culture assays tested the impact of HGF-induced MET activation and anti-MET-specific siRNA inhibition on cell proliferation, migration, and invasion; in vivo gel-foam assays were used to evaluate angiogenesis. Cells stably transduced with anti-MET short hairpin RNA (shRNA) constructs were tested for growth and metastasis in severe combined immunodeficient (SCID) mice. The effect of the tyrosine kinase inhibitor XL184 (Exelixis) targeting MET/VEGFR2 (vascular endothelial growth factor receptor 2) on local and metastatic MPNST growth was examined in vivo. RESULTS: All three markers were expressed in MPNST human samples; pMET expression was an independent prognosticator of poor patient outcome. Human MPNST cell lines expressed MET, HGF, and pMET. MET activation increased MPNST cell motility, invasion, angiogenesis, and induced matrix metalloproteinase-2 (MMP2) and VEGF expression; MET knockdown had inverse effects in vitro and markedly decreased local and metastatic growth in vivo. XL184 abrogated human MPNST xenograft growth and metastasis in SCID mice. CONCLUSIONS: Informative prognosticators and novel therapies are crucially needed to improve MPNST management and outcomes. We show an important role for MET in MPNST, supporting continued investigation of novel anti-MET therapies in this clinical context. PMID- 21540240 TI - Disrupted-in-Schizophrenia-1 (Disc1) is necessary for migration of the pyramidal neurons during mouse hippocampal development. AB - The hippocampus has a highly ordered structure and is composed of distinct layers. Neuronal migration is an essential part of the process of the layer formation because neurons are primarily generated near the ventricle and must migrate to arrive at their final locations during brain development. Impairment of brain development is thought to underlie the etiology of psychiatric disorders. Consistent with this idea, many genetic risk factors for psychiatric disorders play critical roles during brain development. As one example, Disrupted in-Schizophrenia-1 (DISC1) is a genetic risk factor for major psychiatric disorders and plays various roles during neurodevelopment. To examine the role of Disc1 in the hippocampal development, we suppressed expression of Disc1 in the CA1 region of the developing mouse hippocampus by using the RNA interference (RNAi) technology and an in utero electroporation system. Disc1 suppression was found to impair migration of the CA1 pyramidal neurons. This effect was especially apparent while the majority of the transfected neurons were passing through the stratum pyramidale of the developing hippocampus. The migration of neurons was restored by expression of an RNAi-resistant wild-type mouse Disc1, indicating that the migration defect was caused by specific suppression of Disc1. In the mature hippocampus, the migration defect resulted in malposition and disarray of the pyramidal neurons. These findings indicate that Disc1 is required for migration and layer formation by the CA1 pyramidal neurons during hippocampal development. PMID- 21540241 TI - Wild-type Drosophila melanogaster as an alternative model system for investigating the pathogenicity of Candida albicans. AB - Candida spp. are opportunistic pathogens in humans, and their systemic infections display upwards of 30% mortality in immunocompromised patients. Current mammalian model systems have certain disadvantages in that obtaining results is time consuming owing to the relatively long life spans and these results have low statistical resolution because sample sizes are usually small. We have therefore evaluated the potential of Drosophila melanogaster as an additional model system with which to dissect the host-pathogen interactions that occur during Candida albicans systemic infection. To do this, we monitored the survival of wild-type flies infected with various C. albicans clinical isolates that were previously ranked for murine virulence. From our lifetime data we computed two metrics of virulence for each isolate. These correlated significantly with murine survival, and were also used to group the isolates, and this grouping made relevant predictions regarding their murine virulence. Notably, differences in virulence were not predictably resolvable using immune-deficient spz(-/-) flies, suggesting that Toll signalling might actually be required to predictably differentiate virulence. Our analysis reveals wild-type D. melanogaster as a sensitive and relevant model system; one that offers immense genetic tractability (having an extensive RNA interference library that enables tissue-specific gene silencing), and that is easy to manipulate and culture. Undoubtedly, it will prove to be a valuable addition to the model systems currently used to study C. albicans infection. PMID- 21540242 TI - A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in the death of motor neurons in the brain and spinal cord. The disorder generally strikes in mid-life, relentlessly leading to paralysis and death, typically 3-5 years after diagnosis. No effective treatments are available. Up to 10% of ALS is familial, usually autosomal dominant. Several causative genes are known and, of these, mutant superoxide dismutase 1 (SOD1) is by far the most frequently found, accounting for up to 20% of familial ALS. A range of human mutant SOD1 transgenic mouse strains has been produced, and these largely successfully model the human disease. Of these, the most widely used is the SOD1 mouse, which expresses a human SOD1 transgene with a causative G93A mutation. This mouse model is excellent for many purposes but carries up to 25 copies of the transgene and produces a great excess of SOD1 protein, which might affect our interpretation of disease processes. A variant of this strain carries a deletion of the transgene array such that the copy number is dropped to eight to ten mutant SOD1 genes. This 'deleted' 'low-copy' mouse undergoes a slower course of disease, over many months. Here we have carried out a comprehensive analysis of phenotype, including nerve and muscle physiology and histology, to add to our knowledge of this 'deleted' strain and give baseline data for future studies. We find differences in phenotype that arise from genetic background and sex, and we quantify the loss of nerve and muscle function over time. The slowly progressive pathology observed in this mouse strain could provide us with a more appropriate model for studying early-stage pathological processes in ALS and aid the development of therapies for early-stage treatments. PMID- 21540243 TI - Pathogen and host factors are needed to provoke a systemic host response to gastrointestinal infection of Drosophila larvae by Candida albicans. AB - Candida albicans systemic dissemination in immunocompromised patients is thought to develop from initial gastrointestinal (GI) colonisation. It is unclear what components of the innate immune system are necessary for preventing C. albicans dissemination from the GI tract, but studies in mice have indicated that both neutropenia and GI mucosal damage are crucial for allowing widespread invasive C. albicans disease. Mouse models, however, provide limited applicability to genome wide screens for pathogen or host factors - factors that might influence systemic dissemination following GI colonisation. For this reason we developed a Drosophila model to study intestinal infection by Candida. We found that commensal flora aided host survival following GI infection. Candida provoked extensive JNK-mediated death of gut cells and induced antimicrobial peptide expression in the fat body. From the side of the host, nitric oxide and blood cells influenced systemic antimicrobial responses. The secretion of SAP4 and SAP6 (secreted aspartyl proteases) from Candida was also essential for activating systemic Toll-dependent immunity. PMID- 21540244 TI - FINHYST, a prospective study of 5279 hysterectomies: complications and their risk factors. AB - BACKGROUND: Hysterectomy guidelines highlight an increase in urinary tract injuries with laparoscopic hysterectomy (LH). This national survey analyses complications of LH, abdominal hysterectomy (AH) and vaginal hysterectomy (VH). METHODS: A prospective cohort undergoing hysterectomy for benign indications during 2006 was drawn from 53 hospitals in Finland; all communal hospitals participated. Detailed questionnaires covered surgical data and intra- and post operative major and minor complications, for which risk factors were analysed by a multivariate logistic regression model adjusted for surgical data and patient characteristics. RESULTS: Major complications rates in AH (n= 1255, 24%), LH (1679, 32%) and VH (2345, 44%) were 4.0, 4.3 and 2.6%, and total complications rates were 19.2, 15.4 and 11.7%, respectively. Logistic regression showed no statistically significant differences between approaches for any organ injuries or other major complications. Most bladder and bowel injuries (88 and 83%), but not ureter injuries (10%), were recognized intra-operatively. The ureter injury rate was low after LH (0.3%), as it was after other types of hysterectomy. Compared with LH, AH increased the odds of wound infection, and was an independent risk factor for urinary infections and febrile events. Compared with AH, LH and VH both presented a higher risk for pelvic infection; surgically treated equally often regardless of the type of hysterectomy. No differences in complications emerged between LH and VH. Obesity was a risk factor for many infections. Surgical adhesiolysis [odds ratio (OR) 2.41, 95% confidence interval (CI) 1.38-4.21] was the strongest single risk factor for major complications as a whole. Bladder injury was associated with a history of caesarean section (OR 4.01, 95% CI 2.06-7.83) and with a large uterus >=500 g (OR 2.88, 95% CI 1.05 7.90), while bowel injury was associated with adhesiolysis (OR 29.07, 95% CI 7.17 117.88). CONCLUSIONS: FINHYST is a large prospective hysterectomy study illustrating actual complications. Whenever possible, hysterectomy should be minimally invasive. PMID- 21540245 TI - Simultaneous laparoscopic uterine artery ligation and laparoscopic myomectomy for symptomatic uterine myomas with and without in situ morcellation. AB - BACKGROUND: To determine the optimal surgical approach for laparoscopic uterine artery ligation (LUAL) combined with myomectomy in the management of women with symptomatic uterine fibroids. METHODS: This is a prospective study. One hundred and six women with symptomatic uterine myomas underwent LUAL + laparoscopic morcellation after enucleation (enucleation group) (n = 51) or LUAL + laparoscopic in situ morcellation (ISM group) (n = 55). The outcome was measured by comparing surgical techniques, symptom control, recurrence and pregnancy during a 3-year follow-up in both groups. RESULTS: General characteristics of the patients were similar in both groups, except the myomas were larger in the ISM group. The operative time (mean +/- SD) was significantly shorter in the ISM group than the enucleation group (107 +/- 30 min versus 128 +/- 49 min, P = 0.009). There were no differences in the therapeutic outcomes of the two groups at the 3-year follow-up, with low recurrence rates and good symptom control rates. Of the sexually active patients without contraception, the pregnancy and live birth rates were 87.5 and 100% in the ISM group and 66.7 and 83.3% in the enucleation group (all NS). CONCLUSIONS: The LUAL + myomectomy, either by enucleation or ISM, is acceptable in the management of symptomatic uterine fibroids. However, the LUAL + ISM technique might be more feasible, as it requires less operative time. PMID- 21540246 TI - Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. AB - BACKGROUND: Elevated serum progesterone levels at the end of the follicular phase in controlled ovarian stimulation (COS) leads to a poorer ongoing pregnancy rate in IVF cycles due to reduced endometrial receptivity. The objective of this study was to use microarray technology to compare endometrial gene expression profiles at the window of implantation according to the levels of circulating progesterone. METHODS: For this prospective cohort study, microarray data were obtained from endometrial biopsies from 12 young healthy oocyte donors undergoing COS with pituitary suppression by either gonadotrophin-releasing hormone (GnRH) agonists or antagonists, and recombinant FSH. On the day of recombinant chorionic gonadotrophin (rCG) administration, six women had serum progesterone levels (P) >1.5 ng/ml (study group) and six had serum P levels <1.5 ng/ml (control group). Endometrial samples were collected using a Pipelle catheter 7 days after the rCG injection. RESULTS: Using the parametric test, we identified 140 genes significantly dysregulated (64 up- and 76 down-regulated) in the study group endometria compared with the control endometria, regardless of the GnRH analogue employed. These genes are related to cell adhesion, developmental processes, the immune system and others, which are all required for normal endometrial function development. Of the 25 gene targets previously proposed as markers for endometrial receptivity, 13 appeared over-regulated in the study group. CONCLUSIONS: Our results reveal that elevated progesterone levels on the day of rCG administration can induce significant alterations in the gene expression profile of the endometrium. PMID- 21540247 TI - Mevalonate depletion mediates the suppressive impact of geranylgeraniol on murine B16 melanoma cells. AB - The diterpene geranylgeraniol (all trans-3,7,11,15-tetramethyl-2,6,10,14 hexadecatetraen-1-ol) suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach and blood tumors with undefined mechanisms. We evaluated the growth-suppressive activity of geranylgeraniol in murine B16 melanoma cells. Geranylgeraniol induced dose-dependent suppression of B16 cell growth (IC(50) = 55 +/- 13 umol/L) following a 48-h incubation in 96-well plates. Cell cycle arrest at the G1 phase, manifested by a geranylgeraniol-induced increase in the G1/S ratio and decreased expression of cyclin D1 and cyclin-dependent kinase 4, apoptosis detected by Guava NexinTM assay and fluorescence microscopy following acridine orange and ethidium bromide dual staining, and cell differentiation shown by increased alkaline phosphatase activity, contributed to the growth suppression. Murine 3T3-L1 fibroblasts were 10-fold more resistant than B16 cells to geranylgeraniol-mediated growth suppression. Geranylgeraniol at near IC(50) concentration (60 umol/L) suppressed the mRNA level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by 50%. The impact of geranylgeraniol on B16 cell growth, cell cycle arrest and apoptosis were attenuated by supplemental mevalonate, the product of HMG-CoA reductase that is essential for cell growth. Geranylgeraniol and d-delta-tocotrienol, a down-regulator of HMG-CoA reductase, additively suppressed the growth of B16 cells. These results support our hypothesis that mevalonate depletion mediates the tumor-specific growth suppressive impact of geranylgeraniol. Geranylgeraniol may have potential in cancer chemoprevention and/or therapy. PMID- 21540248 TI - Arsenic trioxide inhibits invasion/migration in SGC-7901 cells by activating the reactive oxygen species-dependent cyclooxygenase-2/matrix metalloproteinase-2 pathway. AB - Arsenic trioxide (As(2)O(3)) has been shown to inhibit invasion/migration in cancer cells. However, the underlying mechanism is poorly understood. To identify the role of As(2)O(3) in regulating invasion/migration activity in human gastric cancer SGC-7901 cells, the effects of As(2)O(3) on cell invasion/migration activity, the expression of cyclooxygenase-2 (Cox-2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2), leukotriene B4 (LTB4), and matrix metalloproteinase-2 (MMP 2) and intracellular reactive oxygen species (ROS) were examined. Furthermore, N acetyl-l-cysteine (NAC, a radical scavenger) and celecoxib (a Cox-2 inhibitor) were used to explore the molecular mechanism. The results demonstrated that As(2)O(3) (1 and 2 MUmol/L) inhibited invasion/migration activity in SGC-7901 cells at 24 h and suppressed the expression of Cox-2, PGE2 and MMP-2 (P < 0.05), whereas the same treatment had no significant effect on TXB2 and LTB4 expression. In contrast, intracellular ROS were increased (P < 0.05). Moreover, NAC eliminated the excessive ROS and restored the expression of Cox-2 and MMP-2 and invasion/migration activity in As(2)O(3)-treated cells (P < 0.05). These results suggest that ROS may be a critical factor in regulating the invasion/migration process. Moreover, celecoxib significantly decreased Cox-2, MMP-2 and PGE2 expression and inhibited invasion/migration activity in As(2)O(3)-treated cells (P < 0.05), indicating that As(2)O(3) inhibits invasion/migration by regulating the expression of Cox-2/PGE2/MMP-2. In conclusion, these results suggest that increased ROS play a critical role in inhibiting invasion/migration by suppressing the Cox-2/MMP-2 pathway in As(2)O(3)-treated SGC-7901 cells and regulating intracellular ROS levels may be a promising strategy in gastric cancer therapy. PMID- 21540249 TI - Medusa structure of the gene regulatory network: dominance of transcription factors in cancer subtype classification. AB - Gene expression profiles consisting of ten thousands of transcripts are used for clustering of tissue, such as tumors, into subtypes, often without considering the underlying reason that the distinct patterns of expression arise because of constraints in the realization of gene expression profiles imposed by the gene regulatory network. The topology of this network has been suggested to consist of a regulatory core of genes represented most prominently by transcription factors (TFs) and microRNAs, that influence the expression of other genes, and of a periphery of 'enslaved' effector genes that are regulated but not regulating. This 'medusa' architecture implies that the core genes are much stronger determinants of the realized gene expression profiles. To test this hypothesis, we examined the clustering of gene expression profiles into known tumor types to quantitatively demonstrate that TFs, and even more pronounced, microRNAs, are much stronger discriminators of tumor type specific gene expression patterns than a same number of randomly selected or metabolic genes. These findings lend support to the hypothesis of a medusa architecture and of the canalizing nature of regulation by microRNAs. They also reveal the degree of freedom for the expression of peripheral genes that are less stringently associated with a tissue type specific global gene expression profile. PMID- 21540250 TI - Psychological biases and their impact on operating room efficiency. PMID- 21540251 TI - Recognizing medicalization and demedicalization: discourses, practices, and identities. AB - Scholars of the medicalization of social problems have paid inadequate attention to medicalization's multiple dimensions - discourses, practices and identities - and to the multiple levels of analysis at which it occurs - macro, meso and micro. As a result, scholars of a given social problem typically examine only a few aspects of its medicalization, fail to recognize changes in medicalization, and miss occasions where medicalization and demedicalization occur simultaneously. Moreover, by conceptualizing medicalization as a category or state rather than a continuous value, and failing to specify the threshold at which a phenomenon becomes 'medicalized' or 'demedicalized', scholars have discouraged attention to demedicalization. The article provides a new typology of medicalization and illustrates its utility through an analysis of two episodes in American abortion history. Previous analysts of these episodes miss many aspects of medicalization and disagree about whether these episodes involve medicalization or demedicalization. The typology helps resolve these differences. PMID- 21540252 TI - Negotiating hearing disability and hearing disabled identities. AB - Using disability theory as a framework and social science theories of identity to strengthen the arguments, this article explores empirically how working-age adults confront the medical diagnosis of hearing impairment. For most participants hearing impairment threatens the stability of social interaction and the construction of hearing disabled identities is seen as shaped in the interaction with the hearing impaired person's surroundings. In order to overcome the potential stigmatization the 'passing' as normal becomes predominant. For many the diagnosis provokes radical redefinitions of the self. The discursively produced categorization and subjectivity of senescence mean that rehabilitation technologies such as hearing aids identify a particular life-style (disabled) which determines their social significance. Thus wearing a hearing aid works against the contemporary attempt to create socially ideal bodily presentations of the self, as the hearing aid is a symbolic extension of the body's lack of function. PMID- 21540253 TI - Network gatekeeping: complementary medicine information on the websites of medical institutions. AB - Integrative medicine - complementary and alternative medicine (CAM) practised in mainstream healthcare organizations - combines medical treatments based on incommensurable paradigms. As the Internet has been portrayed as a crucial pathway to CAM and sites administered by reputable organizations are considered to be relatively reliable sources of medical information, the research sought to explore and compare the ways in which CAM is presented on the Internet websites of diverse medical institutions. The contents of the websites of the Ministry of Health, the Israeli Medical Association and Israeli healthcare organizations were analysed, using an interdisciplinary theory of network gatekeeping. The websites were analysed not only according to the degree to which they are considered to be informative, but also with regard to the perceptions of integration that they convey. Comparison of the websites of community healthcare organizations and hospitals indicates that while the former display CAM treatments as an attractive commodity, the latter convey a message stressing the need to subject CAM to bio medical scrutiny. Little or no information was provided concerning a number of important issues, such as research findings about efficacy and safety, risks and ethical considerations. PMID- 21540254 TI - Editorial. PMID- 21540255 TI - Extrathyroidal thyroid hormone synthesis? AB - A paper published in this issue of the Journal of Endocrinology has revisited the hypothesis that thyroid hormones may be generated by tissues outside the thyroid gland in higher organisms including mammals. This commentary appraises the strengths and weaknesses of the study, the alternative explanations for the findings and possible future measures to investigate further. The concept of extrathyroidal thyroxine and triiodothyronine synthesis has previously been proposed; by assuming that Nagao et al. and earlier authors are correct, the plausibility and possible mechanisms underlying the hypothesis are discussed. PMID- 21540256 TI - Motor neurone disease. PMID- 21540257 TI - Patient information on prescribed drugs. PMID- 21540258 TI - Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective endocarditis: before and after study. AB - OBJECTIVE: To quantify the change in prescribing of antibiotic prophylaxis before invasive dental procedures for patients at risk of infective endocarditis, and any concurrent change in the incidence of infective endocarditis, following introduction of a clinical guideline from the National Institute for Health and Clinical Excellence (NICE) in March 2008 recommending the cessation of antibiotic prophylaxis in the United Kingdom. DESIGN: Before and after study. SETTING: England. Population All patients admitted to hospital in England with a primary or secondary discharge diagnosis of acute or subacute infective endocarditis. MAIN OUTCOME MEASURES: Monthly number of prescriptions for antibiotic prophylaxis consisting of a single 3 g oral dose of amoxicillin or a single 600 mg oral dose of clindamycin, and monthly number of cases of infective endocarditis, infective endocarditis related deaths in hospital, or cases of infective endocarditis with a possible oral origin for streptococci. RESULTS: After the introduction of the NICE guideline there was a highly significant 78.6% reduction (P < 0.001) in prescribing of antibiotic prophylaxis, from a mean 10,277 (SD 1068) prescriptions per month to 2292 (SD 176). Evidence that the general upward trend in cases of infective endocarditis before the guideline was significantly altered after the guideline was lacking (P = 0.61). Using a non-inferiority test, an increase in the number of cases of 9.3% or more could be excluded after the introduction of the guideline. Similarly an increase in infective endocarditis related deaths in hospital of 12.3% or more could also be excluded. CONCLUSION: Despite a 78.6% reduction in prescribing of antibiotic prophylaxis after the introduction of the NICE guideline, this study excluded any large increase in the incidence of cases of or deaths from infective endocarditis in the two years after the guideline. Although this lends support to the guideline, ongoing data monitoring is needed to confirm this, and further clinical trials should determine if antibiotic prophylaxis still has a role in protecting some patients at particularly high risk. PMID- 21540259 TI - Medicalization. A new deal on disease definition. PMID- 21540260 TI - Bad medicine: sports medicine. Leon Creaney responds to Des Spence. PMID- 21540261 TI - Bad medicine: sports medicine. Ultrasound and healing. PMID- 21540262 TI - Bad medicine: sports medicine. Surgery is effective for rotator cuff and cruciate injuries. PMID- 21540263 TI - Fall prevention with vitamin D. Clarifications needed, please. PMID- 21540264 TI - Supporting patients. Doctor does know best. PMID- 21540265 TI - Supporting patients. The future is already here. PMID- 21540266 TI - Statins and pneumonia. Beware statins with macrolides. PMID- 21540267 TI - Perinatal palliative care. Don't forget bereaved siblings. PMID- 21540268 TI - ABCD of hypertension treatment. Case described is rare. PMID- 21540269 TI - ABCD of hypertension treatment. Tell patients risk of acute kidney injury. PMID- 21540270 TI - ABCD of hypertension treatment. Ask about lithium, too. PMID- 21540276 TI - Spanish surgeons perform country's first renal transplant chain involving altruistic donor. PMID- 21540277 TI - Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. AB - Cadmium is a toxic heavy metal and distributed widely in the environment. In addition to damaging the liver, kidneys, and bone, cadmium causes anemia through hemolysis, iron deficiency, and insufficient erythropoietin (EPO) production (renal anemia) along with changes in iron metabolism. Here, we investigated the role of iron in the interdependent progress of three types of anemia in cadmium injected rats fed iron-sufficient or iron-deficient diets for 1 or 3 months. Cadmium injections for 1 month induced renal anemia without renal injury. Injections for 3 months induced hemolysis, iron deficiency, and renal anemia, accompanied by hepatic and renal damage. Iron concentrations in the liver, kidney, and spleen were increased, derived from internally released iron from hemolyzed red blood cells, increased duodenal iron absorption, insufficient erythropoiesis, and hepatic ferritin overproduced by cadmium-induced interleukin 6. Therefore, the iron deficiency anemia was actually apparent. Cadmium suppressed renal EPO production through a direct effect, accumulated iron, and destruction of EPO-producing cells. Increased duodenal iron absorption could be attributed to hypertrophy of the duodenal mucosa derived from anemia. Thus, insufficient EPO production and iron accumulation are the central factors driving anemia in cadmium toxicity. PMID- 21540278 TI - Enhancing the algorithm for developmental-behavioral surveillance and screening in children 0 to 5 years. AB - OBJECTIVE: To determine if the 2006 American Academy of Pediatrics developmental surveillance and screening algorithm is adequate or if revisions are needed. METHODS: A comprehensive literature search was conducted to investigate a clinician's ability to perform developmental-behavioral surveillance in children 0 to 5 years. RESULTS: Even when a broad-band developmental screen is typical, pediatricians should refer when they confidently suspect a delay but be far more suspicious about children who seem asymptomatic. Periodic screening enhances surveillance by improving early detection and early intervention (EI) eligibility rates. Nevertheless, children with concerning screens are not consistently referred and interlinked to EI. Once referred, approximately half are deemed EI ineligible, even though they typically perform well below average and have numerous, predictive academic and psychosocial risk factors. Meanwhile, clinicians struggle with tracking at-risk children. CONCLUSION: Revisions are needed to optimize early detection, prevention, and monitoring. Greater emphasis is needed on developmental-behavioral promotion and referral care coordination. PMID- 21540279 TI - No more tears? Maternal involvement during the newborn screening examination. AB - BACKGROUND: Babies often show signs of discomfort and distress by crying during the neonatal screening examination (NSE). The authors hypothesized that supporting the baby with maternal participation may reduce infant crying during NSE. The objective of this study was to document incidental infant crying during NSE, before and after training residents, on maternal involvement and infant comfort techniques to help. METHODS: A total of 20 NSEs of normal newborn babies by pediatric residents were observed (video-recorded) following informed consent of the doctor and the baby's mother. The examining doctors were then taught how to use maternal participation and developmental care (MPDC) comfort techniques to support the baby during NSE. Mothers were shown how to focus on their baby's needs by supporting the baby's head (preventing atonic neck reflexes) and, if necessary, providing nonnutritive sucking to the baby and an encouraging, repetitive low-tone voices to sooth the baby. A further 14 NSEs on different babies were video-recorded using these techniques. The video recordings were analyzed by independent observers for total length of crying and duration of crying during specific components of the NSE. Mothers in both groups were given a questionnaire to assess their opinions of the NSE. RESULTS: The median length of crying was significantly longer in the pre-MPDC group (93.5 seconds; range 0-198 seconds) compared with the post-MPDC infants (0 seconds; range 0-123 seconds; P = .001). Only 1 of 20 infants in the pre-MPDC did not cry during NSE compared with 8 of 14 babies in the post-MPDC group. CONCLUSION: Newborn infants cry less and mothers were more satisfied with NSEs when shown simple support and comfort techniques for their babies. PMID- 21540280 TI - Pediatric volleyball-related injuries treated in US emergency departments, 1990 2009. AB - This study describes the epidemiology of pediatric volleyball-related injuries treated in US hospital emergency departments. Data for children younger than 18 years obtained from the National Electronic Injury Surveillance System of the US Consumer Product Safety Commission from 1990 through 2009 were analyzed. An estimated 692 024 volleyball-related injuries to children younger than 18 years occurred during the study period. The annual number of injuries declined significantly by 23% during the study period; however, the annual injury rate remained unchanged, and the number of volleyball-related concussions/closed head injuries increased significantly. Upper (48%) and lower (39%) extremity injuries occurred most frequently, as did strains/sprains (54%). Contact with the net/pole was associated with concussions/closed head injury our findings indicate opportunities for making volleyball an even safer sport for children. Protective padding, complying with US volleyball standards, should cover all volleyball poles and protruding hardware to prevent impact-related injuries. PMID- 21540281 TI - A pilot study: microbiological conditions of the oral cavity in minipigs for peri implantitis models. AB - As peri-implantitis is an emerging problem, the development of validated animal models is mandatory. The aim of this pilot study was to provide a first step in describing the normal oral flora of minipigs. In five minipigs, samples of the oral flora were collected with sterile cotton swabs from the buccal gingiva of the lower jaw. Two swabs per animal were collected, followed by bacterial isolation under both aerobe and anaerobe conditions. Microbiological analyses included biochemical tests, matrix-assisted laser desorption/ionization time-of flight mass spectrometry and 16S rDNA gene sequence analysis. A total of 61 taxa were detected, 14-21 different bacterial taxa from each minipig. Among the Gram positive cocci, mainly staphylococcal and streptococcal species were identified. Different Actinomyces species were the most abundant taxa in the group of Gram positive rods. Among the anaerobic bacteria, the Gram-negative genera Fusobacterium, Bacteroides and Prevotella were the most often observed taxa. This is the first study which begins to describe the normal oral flora in minipigs in cultures to allow for the detection of a broad spectrum. Several bacterial species identified are different from human ones. No specific species for peri implantitis could be detected in that healthy sample. PMID- 21540283 TI - Endoplasmic reticulum oxidoreductin-1-like beta (ERO1lbeta) regulates susceptibility to endoplasmic reticulum stress and is induced by insulin flux in beta-cells. AB - Hyperglycemia increases insulin flux through the endoplasmic reticulum (ER) of pancreatic beta-cells, and the unfolded protein response pathway is required to enhance insulin processing. Pancreatic and duodenal homeobox 1 (PDX1), a key pancreatic transcription factor, regulates insulin along with targets involved in insulin processing and secretion. Here we find that PDX1 is a direct transcriptional regulator of ER oxidoreductin-1-like beta (Ero1lbeta), which maintains the oxidative environment of the ER to facilitate disulfide bond formation. PDX1 deficiency reduced Ero1lbeta transcript levels in mouse islets and mouse insulinoma (MIN6) cells; moreover, PDX1 occupied the Ero1lbeta promoter in beta-cells. ERO1lbeta levels were induced by high glucose concentrations and by the reducing agent dithiothreitol, indicating potential roles in adaptation to increased oxidative protein folding load in the beta-cell ER. In MIN6 cells, small interfering RNA-mediated silencing of Ero1lbeta decreased insulin content and increased susceptibility to ER stress-induced apoptosis. These findings demonstrate roles for the PDX1 target ERO1lbeta in maintaining insulin content and regulating cell survival during ER stress. PMID- 21540282 TI - Visualization of estrogen receptor transcriptional activation in zebrafish. AB - Estrogens regulate a diverse range of physiological processes and affect multiple tissues. Estrogen receptors (ERs) regulate transcription by binding to DNA at conserved estrogen response elements, and such elements have been used to report ER activity in cultured cells and in transgenic mice. We generated stable, transgenic zebrafish containing five consecutive elements upstream of a c-fos minimal promoter and green fluorescent protein (GFP) to visualize and quantify transcriptional activation in live larvae. Transgenic larvae show robust, dose dependent estrogen-dependent fluorescent labeling in the liver, consistent with er gene expression, whereas ER antagonists inhibit GFP expression. The nonestrogenic steroids dexamethasone and progesterone fail to activate GFP, confirming ER selectivity. Natural and synthetic estrogens activated the transgene with varying potency, and two chemicals, genistein and bisphenol A, preferentially induce GFP expression in the heart. In adult fish, fluorescence was observed in estrogenic tissues such as the liver, ovary, pituitary gland, and brain. Individual estrogen-responsive neurons and their projections were visualized in the adult brain, and GFP-positive neurons increased in number after 17beta-estradiol exposure. The transgenic estrogen-responsive zebrafish allow ER signaling to be monitored visually and serve as in vivo sentinels for detection of estrogenic compounds. PMID- 21540284 TI - Individual polychlorinated biphenyl (PCB) congeners produce tissue- and gene specific effects on thyroid hormone signaling during development. AB - Polychlorinated biphenyls (PCB) are industrial chemicals linked to developmental deficits that may be caused in part by disrupting thyroid hormone (TH) action by either reducing serum TH or interacting directly with the TH receptor (TR). Individual PCB congeners can activate the TR in vitro when the metabolic enzyme cytochrome P4501A1 (CYP1A1) is induced, suggesting that specific PCB metabolites act as TR agonists. To test this hypothesis in vivo, we compared two combinations of PCB congeners that either activate the TR (PCB 105 and 118) or not (PCB 138 and 153) in the presence or absence of a PCB congener (PCB 126) that induces CYP1A1 in vitro. Aroclor 1254 was used as a positive control, and a group treated with propylthiouracil was included to characterize the effects of low serum TH. We monitored the effects on TH signaling in several peripheral tissues by measuring the mRNA expression of well-known TH-response genes in these tissues. Aroclor 1254 and its component PCB 105/118/126 reduced total T(4) to the same extent as that of propylthiouracil but increased the expression of some TH target genes in liver. This effect was strongly correlated with CYP1A1 expression supporting the hypothesis that metabolism is necessary. Effects were gene and tissue specific, indicating that tissue-specific metabolism is an important component of PCB disruption of TH action and that PCB metabolites interact in complex ways with the TR. These are essential mechanisms to consider when evaluating the health risks of contaminant exposures, for both PCB and other polycyclic compounds known to interact with nuclear hormone receptors. PMID- 21540285 TI - Minireview: IGF, Insulin, and Cancer. AB - In recent years, the influence of the IGF system and insulin on cancer growth has been widely studied. Observational human studies have reported increased cancer mortality in those with obesity and type 2 diabetes, which may be attributable to hyperinsulinemia, elevated IGF-I, or potentially both factors. Conversely, those with low insulin, IGF-I and IGF-II levels appear to be relatively protected from cancer development. Initial attention focused on the role of IGF-I in tumor development. The results of these investigations allowed for the development of therapies targeting the IGF-I receptor signaling pathway. However, after in vitro and in vivo studies demonstrating that insulin may also play a significant and independent role in tumorigenesis, insulin is now receiving more attention in this regard. Some studies suggest that targeting insulin receptor signaling may be an important alternative or adjunct to targeting IGF-I receptor signaling. In this minireview, we discuss some of the recent in vitro, animal, and clinical studies that have elaborated our understanding of the influence of IGF and insulin on tumorigenesis. These studies have shed more light on the interaction between insulin and IGF signaling in cancer cells. They have made possible the development of novel targeted therapies and highlighted some of the potential future directions for research and therapeutics. PMID- 21540286 TI - Highly visible expression of an oxytocin-monomeric red fluorescent protein 1 fusion gene in the hypothalamus and posterior pituitary of transgenic rats. AB - We have generated rats bearing an oxytocin (OXT)-monomeric red fluorescent protein 1 (mRFP1) fusion transgene. The mRFP1 fluorescence was highly visible in ventral part of the supraoptic nucleus (SON) and the posterior pituitary in a whole mount. mRFP1 fluorescence in hypothalamic sections was also observed in the SON, the paraventricular nucleus (PVN), and the internal layer of the median eminence. Salt loading for 5 d caused a marked increase in mRFP1 fluorescence in the SON, the PVN, the median eminence, and the posterior pituitary. In situ hybridization histochemistry revealed that the expression of the mRNA encoding the OXT-mRFP1 fusion gene was observed in the SON and the PVN of euhydrated rats and increased dramatically after chronic salt loading. The expression of the endogenous OXT and the arginine vasopressin (AVP) genes were significantly increased in the SON and the PVN after chronic salt loading in both nontransgenic and transgenic rats. These responses were not different between male and female rats. Compared with nontransgenic rats, euhydrated and salt-loaded male and female transgenic rats showed no significant differences in plasma osmolality, sodium concentration, OXT, and AVP levels. Finally, we succeeded in generating a double-transgenic rat that expresses both the OXT-mRFP1 fusion gene and the AVP enhanced green fluorescent protein fusion gene. Our new transgenic rats are valuable new tools to study the physiology of the hypothalamo-neurohypophysial system. PMID- 21540288 TI - Prenatal glucocorticoid overexposure causes permanent increases in renal erythropoietin expression and red blood cell mass in the rat offspring. AB - Glucocorticoids promote maturation of fetal systems, including erythropoiesis, in preparation for extrauterine life. However, recent studies have shown that prenatal glucocorticoid excess can cause long-term deleterious cardiometabolic and other consequences to the offspring. Here, we examined the effect of prenatal treatment with the synthetic glucocorticoid dexamethasone (DEX) during the last week of gestation on red blood cell (RBC) mass in the rat offspring. DEX-treated offspring at 9 months of age had significantly higher RBC count (9.4 +/- 0.1 vs. 8.8 +/- 0.2 * 10(12) liter; P = 0.02), hematocrit (50.0 +/- 0.5 vs. 46.7 +/- 0.7%; P=0.004), hemoglobin (17.3 +/- 0.2 vs. 16.2 +/- 0.2 g/dl; P = 0.02) and number of reticulocytes (258.2 +/- 8.8 vs. 235.7 +/- 5.6 * 10(9) liter; P = 0.04), compared with offspring of vehicle-treated control pregnancies. White blood cells and platelets were unaltered. Renal mRNA expression and plasma concentrations of erythropoietin, the main regulator of erythropoiesis, were increased by nearly 100% in both newborn and adult DEX-treated rats (P < 0.01). This increase was accompanied by marked elevation in renal expression of hepatocyte nuclear factor 4alpha mRNA, whereas other erythropoietin-regulating transcription factors, such as hypoxia-inducible factor 1, hypoxia-inducible factor 2, and GATA2 were unchanged. These data indicate that RBC mass can be programmed by prenatal glucocorticoid excess, and if extrapolatable to humans, provide a novel mechanism for fetal origins of polycythemia and its associated complications. PMID- 21540287 TI - Estrogen protection in Friedreich's ataxia skin fibroblasts. AB - Estrogens have been shown to have protective effects on a wide range of cell types and animal models for many neurodegenerative diseases. The present study demonstrates the cytoprotective effects of 17beta-estradiol (E2) and estrogen like compounds in an in vitro model of Friedreich's ataxia (FRDA) using human donor FRDA skin fibroblasts. FRDA fibroblasts are extremely sensitive to free radical damage and oxidative stress, produced here using l-buthionine (S,R) sulfoximine to inhibit de novo glutathione synthesis. We have shown that the protective effect of E2 in the face of l-buthionine (S,R)-sulfoximine -induced oxidative stress is independent of estrogen receptor-alpha, estrogen receptor beta or G protein-coupled receptor 30 as shown by the inability of either ICI 182,780 or G15 to inhibit the E2-mediated protection. These cytoprotective effects appear to be dependent on antioxidant properties and the phenolic structure of estradiol as demonstrated by the observation that all phenolic compounds tested were protective, whereas all nonphenolic compounds were inactive, and the observation that the phenolic compounds reduced the levels of reactive oxygen species, whereas the nonphenolic compounds did not. These data show for the first time that phenolic E2-like compounds are potent protectors against oxidative stress-induced cell death in FRDA fibroblasts and are possible candidate drugs for the treatment and prevention of FRDA symptoms. PMID- 21540289 TI - Adipose triglyceride lipase and hormone-sensitive lipase are involved in fat loss in JunB-deficient mice. AB - Proteins of the activator protein-1 family are known to have roles in many physiological processes such as proliferation, apoptosis, and inflammation. However, their role in fat metabolism has yet to be defined in more detail. Here we study the impact of JunB deficiency on the metabolic state of mice. JunB knockout (JunB-KO) mice show markedly decreased weight gain, reduced fat mass, and a low survival rate compared with control mice. If fed a high-fat diet, the weight gain of JunB-KO mice is comparable to control mice and the survival rate improves dramatically. Along with normal expression of adipogenic marker genes in white adipose tissue (WAT) of JunB-KO mice, this suggests that adipogenesis per se is not affected by JunB deficiency. This is supported by in vitro data, because neither JunB-silenced 3T3-L1 cells nor mouse embryonic fibroblasts from JunB-KO mice show a change in adipogenic potential. Interestingly, the key enzymes of lipolysis, adipose triglyceride lipase and hormone-sensitive lipase, were significantly increased in WAT of fasted JunB-KO mice. Concomitantly, the ratio of plasma free fatty acids per gram fat mass was increased, suggesting an elevated lipolytic rate under fasting conditions. Furthermore, up-regulation of TNFalpha and reduced expression of perilipin indicate that this pathway is also involved in increased lipolytic rate in these mice. Additionally, JunB-KO mice are more insulin sensitive than controls and show up-regulation of lipogenic genes in skeletal muscle, indicating a shuttling of energy substrates from WAT to skeletal muscle. In summary, this study provides valuable insights into the impact of JunB deficiency on the metabolic state of mice. PMID- 21540290 TI - GH receptor plays a major role in liver regeneration through the control of EGFR and ERK1/2 activation. AB - GH is a pleiotropic hormone that plays a major role in proliferation, differentiation, and metabolism via its specific receptor. It has been previously suggested that GH signaling pathways are required for normal liver regeneration but the molecular mechanisms involved have yet to be determined. The aim of this study was to identify the mechanisms by which GH controls liver regeneration. We performed two thirds partial hepatectomies in GH receptor (GHR)-deficient mice and wild-type littermates and showed a blunted progression in the G(1)/S transition phase of the mutant hepatocytes. This impaired liver regeneration was not corrected by reestablishing IGF-1 expression. Although the initial response to partial hepatectomy at the priming phase appeared to be similar between mutant and wild-type mice, cell cycle progression was significantly blunted in mutant mice. The main defect in GHR-deficient mice was the deficiency of the epidermal growth factor receptor activation during the process of liver regeneration. Finally, among the pathways activated downstream of GHR during G(1) phase progression, namely Erk1/2, Akt, and signal transducer and activator of transcription 3, we only found a reduced Erk1/2 phosphorylation in mutant mice. In conclusion, our results demonstrate that GH signaling plays a major role in liver regeneration and strongly suggest that it acts through the activation of both epidermal growth factor receptor and Erk1/2 pathways. PMID- 21540291 TI - Toll-like receptor-initiated testicular innate immune responses in mouse Leydig cells. AB - The testis is an immunoprivileged site, where the local cell-initiated testicular innate immune responses play a crucial role in defense against microbial infections. Mechanisms modulating the testicular cell-built defense system remain to be clarified. In this article, we demonstrate that Leydig cells, a major cell population in the testicular interstitium, initiate innate immunity through the activation of Toll-like receptors (TLRs). Several TLRs are expressed in mouse Leydig cells; among these, TLR3 and TLR4 are expressed at relatively high levels compared with other TLR members. Both TLR3 and TLR4 can be activated by their agonists (polyinosinic:polycytidylic acid and lipopolysaccharide) in Leydig cells and subsequently induce the production of inflammatory factors, such as IL-1beta, IL-6, TNF-alpha, and type 1 interferons (IFN) (IFN-alpha and IFN-beta). Notably, the activation of TLR3 and TLR4 suppresses steroidogenesis by Leydig cells. Further, we provide evidence that Axl and Mer receptor tyrosine kinases are expressed in Leydig cells and regulate TLR-mediated innate immune responses negatively. Data presented here describe a novel function of Leydig cells in eliciting testicular innate immune responses that should contribute to the protection of the testis from microbial infections. PMID- 21540293 TI - Down-regulation of ATP-binding cassette C2 protein expression in HepG2 cells after rifampicin treatment is mediated by microRNA-379. AB - microRNAs (miRNAs), which contribute to the post-transcriptional processing through 3'-untranslated region-interference, have been shown to be involved in the regulation of ATP-binding cassette (ABC) membrane transporters. The aim of this study was to investigate whether ABCC2, an important efflux transporter for various endogenous and exogenous compounds at several compartment barriers, is subject to miRNA-mediated post-transcriptional gene regulation. We screened the expression of 377 human miRNAs in HepG2 cells after 48 h of treatment with 5 MUM rifampicin [a pregnane X receptor (PXR) ligand] or vehicle using reverse transcription-polymerase chain reaction-based low-density arrays. Specific miRNA, ABCC2 mRNA, and protein expression were monitored in HepG2 cells undergoing rifampicin treatment for 72 h. Loss- and gain-of-function experiments and reporter gene assays were performed for further confirmation. Highly deregulated miRNAs compared with in silico data revealed miRNA (miR) 379 as candidate miRNA targeting ABCC2 mRNA. Under rifampicin treatment, ABCC2 mRNA increased significantly, with a maximal fold change of 1.56 +/- 0.43 after 24 h. In addition, miR-379 increased (maximally 4.10 +/- 1.33-fold after 48 h), whereas ABCC2 protein decreased with a maximal fold change of 0.47 +/- 0.08 after 72 h. In contrast, transfection of miR-379 inhibitor led to an elevation of ABCC2 protein expression after rifampicin incubation for 48 h. We identify a miRNA negatively regulating ABCC2 on the post-transcriptional level and provide evidence that this miRNA impedes overexpression of ABCC2 protein after a PXR mediated external transcriptional stimulus in HepG2 cells. PMID- 21540292 TI - Regulation of neuropeptide processing enzymes by catecholamines in endocrine cells. AB - Treatment of cultured bovine adrenal chromaffin cells with the catecholamine transport blocker reserpine was shown previously to increase enkephalin levels severalfold. To explore the biochemical mechanism of this effect, we examined the effect of reserpine treatment on the activities of three different peptide precursor processing enzymes: carboxypeptidase E (CPE) and the prohormone convertases (PCs) PC1/3 and PC2. Reserpine treatment increased both CPE and PC activity in extracts of cultured chromaffin cells; total protein levels were unaltered for any enzyme. Further analysis showed that the increase in CPE activity was due to an elevated V(max), with no change in the K(m) for substrate hydrolysis or the levels of CPE mRNA. Reserpine activation of endogenous processing enzymes was also observed in extracts prepared from PC12 cells stably expressing PC1/3 or PC2. In vitro experiments using purified enzymes showed that catecholamines inhibited CPE, PC1/3, and PC2, with dopamine quinone the most potent inhibitor (IC(50) values of ~50-500 MUM); dopamine, norepinephrine, and epinephrine exhibited inhibition in the micromolar range. The inhibition of purified CPE with catecholamines was time-dependent and, for dopamine quinone, dilution-independent, suggesting covalent modification of the protein by the catecholamine. Because the catecholamine concentrations found to be inhibitory to PC1/3, PC2, and CPE are well within the physiological range found in chromaffin granules, we conclude that catecholaminergic transmitter systems have the potential to exert considerable dynamic influence over peptidergic transmitter synthesis by altering the activity of peptide processing enzymes. PMID- 21540294 TI - Heteropoda toxin 2 interaction with Kv4.3 and Kv4.1 reveals differences in gating modification. AB - Kv4 (Shal) potassium channels are responsible for the transient outward K(+) currents in mammalian hearts and central nervous systems. Heteropoda toxin 2 (HpTx2) is an inhibitor cysteine knot peptide toxin specific for Kv4 channels that inhibits gating of Kv4.3 in the voltage-dependent manner typical for this type of toxin. HpTx2 interacts with four independent binding sites containing two conserved hydrophobic amino acids in the S3b transmembrane segments of Kv4.3 and the closely related Kv4.1. Despite these similarities, HpTx2 interaction with Kv4.1 is considerably less voltage-dependent, has smaller shifts in the voltage dependences of conductance and steady-state inactivation, and a 3-fold higher K(d) value. Swapping four nonconserved amino acids in S3b between the two channels exchanges the phenotypic response to HpTx2. To understand these differences in gating modification, we constructed Markov models of Kv4.3 and Kv4.1 activation gating in the presence of HpTx2. Both models feature a series of voltage-dependent steps leading to a final voltage-independent transition to the open state and closely replicate the experimental data. Interaction with HpTx2 increases the energy barrier for channel opening by slowing activation and accelerating deactivation. The greater degree of voltage-dependence in Kv4.3 occurs because it is the voltage-dependent transitions that are most affected by HpTx2; in contrast, it is the voltage-independent step in Kv4.1 that is most affected by the presence of toxin. These data demonstrate the basis for subtype specificity of HpTx2 and point the way to a general model of gating modifier toxin interaction with voltage-gated ion channels. PMID- 21540295 TI - Ezrin is required for efficient Rap1-induced cell spreading. AB - The Rap family of small GTPases regulate the adhesion of cells to extracellular matrices. Several Rap-binding proteins have been shown to function as effectors that mediate Rap-induced adhesion. However, little is known regarding the relationships between these effectors, or about other proteins that are downstream of or act in parallel to the effectors. To establish whether an array of effectors was required for Rap-induced cell adhesion and spreading, and to find new components involved in Rap-signal transduction, we performed a small scale siRNA screen in A549 lung epithelial cells. Of the Rap effectors tested, only Radil blocked Rap-induced spreading. Additionally, we identified a novel role for Ezrin downstream of Rap1. Ezrin was necessary for Rap-induced cell spreading, but not Rap-induced cell adhesion or basal adhesion processes. Furthermore, Ezrin depletion inhibited Rap-induced cell spreading in several cell lines, including primary human umbilical vein endothelial cells. Interestingly, Radixin and Moesin, two proteins with high homology to Ezrin, are not required for Rap-induced cell spreading and cannot compensate for loss of Ezrin to rescue Rap-induced cell spreading. Here, we present a novel function for Ezrin in Rap1 induced cell spreading and evidence of a non-redundant role of an ERM family member. PMID- 21540296 TI - Condensin phosphorylated by the Aurora-B-like kinase Ark1 is continuously required until telophase in a mode distinct from Top2. AB - Condensin is a conserved protein complex that functions in chromosome condensation and segregation. It has not been previously unequivocally determined whether condensin is required throughout mitosis. Here, we examined whether Schizosaccharomyces pombe condensin continuously acts on chromosomes during mitosis and compared its role with that of DNA topoisomerase II (Top2). Using double mutants containing a temperature-sensitive allele of the condensin SMC2 subunit cut14 (cut14-208) or of top2, together with the cold-sensitive nda3-KM311 mutation (in beta-tubulin), temperature-shift experiments were performed. These experiments allowed inactivation of condensin or Top2 at various stages throughout mitosis, even after late anaphase. The results established that mitotic chromosomes require condensin and Top2 throughout mitosis, even in telophase. We then showed that the Cnd2 subunit of condensin (also known as Barren) is the target subunit of Aurora-B-like kinase Ark1 and that Ark1-mediated phosphorylation of Cnd2 occurred throughout mitosis. The phosphorylation sites in Cnd2 were determined by mass spectrometry, and alanine and glutamate residue replacement mutant constructs for these sites were constructed. Alanine substitution mutants of Cnd2, which mimic the unphosphorylated protein, exhibited broad mitotic defects, including at telophase, and overexpression of these constructs caused a severe dominant-negative effect. By contrast, glutamate substitution mutants, which mimic the phosphorylated protein, alleviated the segregation defect in Ark1-inhibited cells. In telophase, the condensin subunits in cut14-208 mutant accumulated in lumps that contained telomeric DNA and proteins that failed to segregate. Condensin might thus serve to keep the segregated chromosomes apart during telophase. PMID- 21540297 TI - VEGF-mediated PI3K class IA and PKC signaling in cardiomyogenesis and vasculogenesis of mouse embryonic stem cells. AB - VEGF-, phosphoinositide 3-kinase (PI3K)- and protein kinase C (PKC)-regulated signaling in cardiac and vascular differentiation was investigated in mouse ES cells and in ES cell-derived Flk-1+ cardiovascular progenitor cells. Inhibition of PI3K by wortmannin and LY294002, disruption of PI3K catalytic subunits p110alpha and p110delta using short hairpin RNA (shRNA), or inhibition of p110alpha with compound 15e and of p110delta with IC-87114 impaired cardiac and vascular differentiation. By contrast, TGX-221, an inhibitor of p110beta, and shRNA knockdown of p110beta were without significant effects. Antagonists of the PKC family, i.e. bisindolylmaleimide-1 (BIM-1), GO 6976 (targeting PKCalpha/betaII) and rottlerin (targeting PKCdelta) abolished vasculogenesis, but not cardiomyogenesis. Inhibition of Akt blunted cardiac as well as vascular differentiation. VEGF induced phosphorylation of PKCalpha/betaII and PKCdelta but not PKCzeta. This was abolished by PI3K inhibitors and the VEGFR-2 antagonist SU5614. Furthermore, phosphorylation of Akt and phosphoinositide-dependent kinase 1 (PDK1) was blunted upon inhibition of PI3K, but not upon inhibition of PKC by BIM-1, suggesting that activation of Akt and PDK1 by VEGF required PI3K but not PKC. In summary, we demonstrate that PI3K catalytic subunits p110alpha and p110delta are central to cardiovasculogenesis of ES cells. Akt downstream of PI3K is involved in both cardiomyogenesis and vasculogenesis, whereas PKC is involved only in vasculogenesis. PMID- 21540298 TI - The champions' mitochondria: is it genetically determined? A review on mitochondrial DNA and elite athletic performance. AB - Aerobic ATP generation by the mitochondrial respiratory oxidative phosphorylation system (OXPHOS) is a vital metabolic process for endurance exercise. Notably, mitochondrial DNA (mtDNA) codifies 13 of the 83 polypeptides implied in the respiratory chain. As such, there is a strong rationale for identifying an association between mtDNA variants and "aerobic" (endurance) exercise phenotypes. The aim of this review is to summarize current knowledge on the association between mtDNA, nuclear genes involved in mitochondriogenesis, and elite endurance athletic status. Several studies in nonathletic people have demonstrated an association between certain mtDNA lineages and aerobic performance, characterized by maximal oxygen uptake (VO2max). Whether mtDNA haplogroups are also associated with the status of being an elite endurance athlete is more controversial, with differences between studies arising from the different ethnic backgrounds of the athletic cohorts (Caucasian of mixed geographic origin, Asiatic, or East African). PMID- 21540299 TI - Metabolic cycles in a circannual hibernator. AB - Hibernation as manifested in ground squirrels is arguably the most plastic and extreme of physiological phenotypes in mammals. Homeostasis is challenged by prolonged fasting accompanied by heterothermy, yet must be facilitated for survival. We performed LC and GC-MS metabolomic profiling of plasma samples taken reproducibly during seven natural stages of the hibernator's year, three in summer and four in winter (each n >= 5), employing a nontargeted approach to define the metabolite shifts associated with the phenotype. We quantified 231 named metabolites; 106 of these altered significantly, demarcating a cycle within a cycle where torpor-arousal cycles recur during the winter portion of the seasonal cycle. A number of robust hibernation biomarkers that alter with season and winter stage are identified, including specific free fatty acids, antioxidants, and previously unpublished modified amino acids that are likely to be associated with the fasting state. The major pattern in metabolite levels is one of either depletion or accrual during torpor, followed by reversal to an apparent homeostatic level by interbout arousal. This finding provides new data that strongly support the predictions of a long-standing hypothesis that periodic arousals are necessary to restore metabolic homeostasis. PMID- 21540300 TI - Transcriptional profiling reveals a role for RORalpha in regulating gene expression in obesity-associated inflammation and hepatic steatosis. AB - Retinoid-related orphan receptor (ROR)alpha4 is the major RORalpha isoform expressed in adipose tissues and liver. In this study we demonstrate that RORalpha-deficient staggerer mice (RORalpha(sg/sg)) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of RORalpha(sg/sg) mice. In contrast, overexpression of RORalpha in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in RORalpha(sg/sg) liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by RORalpha. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of RORalpha(sg/sg) mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in RORalpha(sg/sg) WAT. Moreover, RORalpha(sg/sg) mice fed with an HFD were protected from the development of insulin resistance. RORalpha(sg/sg) mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that RORalpha plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, RORalpha may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. PMID- 21540301 TI - Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components. AB - In Fischer 344 (F344) rats, renin-angiotensin system (RAS) blockade for 1 yr with the angiotensin II type 1 (AT(1)) receptor blocker L-158,809 prevents age-related impairments in metabolic function, similar to transgenic rats with low glial angiotensinogen (Aogen). Brain RAS regulation may contribute to the benefits of long-term systemic AT(1) antagonism. We assessed the mRNA of RAS components in the dorsomedial medulla of F344 rats at 3 (young; n = 8) or 15 mo of age (old; n = 7) and in rats treated from 3 to 15 mo of age with 20 mg/l of the AT(1) receptor antagonist L-158,809 (Old+L; n = 6). Aogen and renin mRNA were lower in the young compared with old group. Angiotensin-converting enzyme (ACE) mRNA was lower in the old and Old+L compared with the young group. ACE2 and neprilysin expression were significantly higher in Old+L compared with young or old rats. AT(1b), AT(2), and Mas receptor mRNA were higher with treatment. Leptin receptor mRNA was lower in the old rats and this was prevented by L-158,809 treatment. Dual-specificity phosphatase 1 (DUSP1) mRNA was highest in the Old+L group. Aggregate correlate summation revealed a positive relationship for Mas receptor mRNA with food intake. The findings provide evidence for regulation of dorsomedial medullary renin and Aogen mRNA during aging. Long-term AT(1) receptor blockade increases the mRNA of the enzymes ACE2 and neprilysin and the MAS receptor, which could potentially shift the balance from ANG II to ANG-(1-7) and prevent age-related declines in the leptin receptor and its signaling pathway. PMID- 21540302 TI - Selective chemoprecipitation and subsequent release of tagged species for the analysis of nitropeptides by liquid chromatography-tandem mass spectrometry. AB - Tyrosine nitration is a low-abundance post-translational protein modification that requires appropriate enrichment techniques to enable proteomic analyses. We report a simple yet highly specific method to enrich nitropeptides by chemoprecipitation involving only two straightforward chemical modifications of the nitropeptides before capturing the obtained derivatives with a strategically designed solid-phase active ester reagent. Specifically, capping of the aliphatic amines in the peptides is done first by reductive methylation to preserve the charge state of peptides for electrospray ionization mass spectrometric analysis, followed by reduction of nitrotyrosines to the corresponding aminotyrosines. These peptides are then immobilized on the solid-phase active ester reagent, whereas other peptides carrying no free amino groups are separated from the immobilized species by thoroughly washing the beads from which the tagged peptide derivatives can easily be released by acid-catalyzed hydrolysis at room temperature. The benefits of selective enrichment from a matrix of unmodified peptides for liquid chromatography-tandem mass spectrometry are demonstrated on three synthetic nitropeptides that are nitrated fragments of biologically relevant proteins. Identification of several in vitro nitrated human plasma proteins, also implicated under various pathological processes, by database searches from the enriched and tagged tryptic nitropeptides is presented as a practical application. We also show that converting the nitro-group to the small 4-formylbenzoylamido tag does not significantly alter fragmentation properties upon collision-induced dissociation compared with those of the native nitropeptides, and at the same time this derivatization actually improves electron capture dissociation due to conversion of the electron-predator nitro group to this novel tag. PMID- 21540303 TI - TACE/TGF-alpha/EGFR regulates CXCL8 in bronchial epithelial cells exposed to particulate matter components. AB - Airborne particulate matter (PM) may induce or exacerbate neutrophilic airway disease by triggering the release of inflammatory mediators, such as CXC chemokine ligand (CXCL)8, from the airway epithelium. It is still unclear which PM components are driving CXCL8 responses, as most candidates occur at low concentrations in the dusts. We therefore hypothesised that different PM constituents may contribute through common mechanisms to induce CXCL8. Human bronchial epithelial cells (BEAS-2B) were exposed to different PM components (Zn2+/Fe2+ salts, 1-nitropyrene, lipopolysaccharide and diesel exhaust/mineral particles). Gene expression patterns were detected by real-time PCR array. CXCL8 responses were measured by real-time PCR and ELISA. CXCL8 regulation was assessed with a broad inhibitor panel and neutralising antibodies. Epidermal growth factor receptor (EGFR) phosphorylation was examined by immunoprecipitation and Western blotting. Component-induced gene expression was mainly linked to nuclear factor kappaB, Ca2+/protein kinase C, phospholipase C, low-density lipoprotein and mitogenic signalling. Many inhibitors attenuated CXCL8 release induced by all PM components, but to varying extents. However, EGFR inhibition strongly reduced CXCL8 release induced by all test compounds and selected compounds increased EGFR phosphorylation. Interference with transforming growth factor (TGF)-alpha or tumour necrosis factor-alpha-converting enzyme (TACE), which mediates TGF-alpha ectodomain shedding, also attenuated CXCL8 release. Different PM constituents induced CXCL8 partly through similar signalling pathways but the relative importance of the different pathways varied. However, TACE/TGF-alpha/EGFR signalling appears to be a convergent pathway regulating innate immune responses of airway epithelial cells upon exposure to multiple airborne pollutants. PMID- 21540304 TI - Bronchoalveolar lavage for the evaluation of interstitial lung disease: is it clinically useful? AB - Although the application of thoracic high-resolution computed tomography (HRCT) to clinical pulmonology has revolutionised the diagnostic approach to patients with suspected interstitial lung disease (ILD), additional testing is often needed to make a confident ILD diagnosis. Bronchoalveolar lavage (BAL) can play a significant role in making an accurate and confident diagnosis of specific forms of ILD. When BAL is used in conjunction with comprehensive clinical information and HRCT, BAL nucleated immune cell patterns can frequently provide useful information for diagnostic evaluation and lessen the need to proceed to more invasive procedures, such as surgical lung biopsy. Additionally, BAL can identify confounding conditions, such as infection or malignancy. However, BAL technique, and protocols for processing and analysing BAL fluid are critically important for providing useful information. This perspective reviews the current status of using BAL as a diagnostic tool for the diagnosis of ILD. PMID- 21540305 TI - Recognition of pleural mesothelioma by mucin-1(950-958)/human leukocyte antigen A*0201-specific CD8+ T-cells. AB - Recent clinical investigations have demonstrated that T-cell-based immunotherapy of malignant pleural mesothelioma (MPM) could represent an alternative to the other therapeutic strategies. However, its development suffers from the lack of identified tumour antigenic targets. Mucin (MUC)1, which is expressed and recognised by cytotoxic T-cells in numerous cancer types, has not been investigated as a potential immune target in MPM. Thus, the objective of this study was to analyse MUC1 expression by MPM cells and to determine whether this antigen can be the target of cytotoxic CD8+ T-cells (cytotoxic T-lymphocytes (CTLs)). We first evaluated the expression and glycosylation of MUC1 by MPM cell lines using different MUC1-specific monoclonal antibodies. We then obtained a CTL clone specific for a MUC1 peptide (residues 950-958) presented by human leukocyte antigen (HLA)-A*0201 and studied its interferon-gamma and cytotoxic response to MPM cell lines. We found that all MPM cell lines expressed MUC1 protein at the cell surface with different glycosylation profiles. We also observed that HLA A*0201+ MPM cell lines are recognised and lysed by a HLA-A*0201/MUC1(950-958) specific CTL clone independently of the MUC1 glycosylation profile. Thus, MUC1 expression and antigen presentation by MPM cells may represent an attractive target for immunotherapeutic treatment of MPM despite its hyperglycosylated profile. PMID- 21540306 TI - Deterioration of exercise capacity after neonatal extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) provides life support in acute reversible cardiorespiratory failure. Assessment of long-term morbidity is essential to confirm survival advantage. This study aimed to assess exercise capacity in the first 12 yrs of life after neonatal ECMO, and to evaluate the effect of primary diagnosis, lung function or perinatal characteristics on exercise capacity. 120 children who, as neonates, underwent ECMO performed 191 reliable exercise tests according to the Bruce treadmill protocol at ages 5, 8 and/or 12 yrs between 2001 and 2010. Primary diagnoses were meconium aspiration syndrome (n=66), congenital diaphragmatic hernia (n=18) and other diagnoses (n=36). At ages 5, 8 and 12 yrs, ANOVA resulted in mean +/- se standard deviation score endurance time on the treadmill of -0.5 +/- 0.1, -1.1 +/- 0.1, and -1.5 +/- 0.2, respectively, all significantly less than zero (p<0.001). Exercise capacity declined significantly over time irrespective of the primary diagnosis. Neonates treated with ECMO are at risk of decreased exercise capacity at school age. We therefore propose prolonged follow-up. Proactive advice on sports participation or referral to a physical therapist is recommended, especially when either the parents or the children themselves report impaired exercise capacity. PMID- 21540307 TI - A 5-aza-2'-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive tumour with a limited response to conventional therapy. The aim of this study was to evaluate the anticancer effect of a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5 azaCdR), and two histone deacetylase inhibitors, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA). Human mesothelioma cells were treated with each epigenetic drug, either alone or in combinations. The cytotoxic effects on treated cells and the expression of specific tumour antigens were evaluated. The recognition of treated cells by a specific CD8+ T-cell clone was also measured. Additionally, the effect of combined treatments was tested in a murine model of mesothelioma. We showed that VPA and SAHA synergised with 5-azaCdR to kill MPM cells and induce tumour antigen expression in the remaining living tumour cells. As a consequence, tumour cells expressing these antigens were recognised and lysed by specific CD8+ cytotoxic T-cells. In vivo, treatment with 5-azaCdR/VPA inhibited tumour growth, and promoted lymphocyte infiltration and an immune response against tumour cells. Appropriate epigenetic drug combinations, in addition to inducing mesothelioma cell death, also affect the immunogenic status of these cells. This property could be exploited in clinical investigations to develop MPM treatments combining chemotherapeutic and immunotherapeutic approaches. PMID- 21540308 TI - T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis. AB - Upregulation of genes for interferon (IFN)-gamma and CXC chemokine receptor (CXCR)3 expression, two crucial molecules in sarcoid inflammation and granuloma formation, is directly controlled by the T-helper (Th)1 transcription factor T bet (T-box, expressed in T-cells). However, there is no information on T-bet expression in sarcoidosis or its relationship with "sarcoidosis-associated" genes. Therefore, we investigated expression of T-bet mRNA and, in parallel, a spectrum of genes known to be involved in sarcoidosis pathogenesis. Transcripts were determined in bronchoalveolar lavage (BAL) cells from 62 sarcoidosis patients and 25 controls by quantitative RT-PCR; T-bet protein was localised by immunohistochemistry. Patient's BAL cells expressed higher mRNA T-bet levels than those of controls (mean +/- sd fold change 3.64 +/- 1.72; p = 0.00006). T-bet mRNA expression did not vary between clinical phenotypes as assessed by chest radiography stage, presence/absence of Lofgren's syndrome, extrapulmonary/pulmonary involvement or progressing/remitting disease (p > 0.05). T-bet mRNA expression correlated with expression of IFN-gamma, CC chemokine ligand 5, CXC chemokine ligand (CXC)10, interleukin (IL)-2 receptor/IL-15 receptor beta, CXCR3 and CXCR6 (p < 0.01). T-bet protein was localised to alveolar macrophages and lymphocytes, tissue multinucleated giant cells, macrophages and lymphocytes. In pulmonary sarcoidosis, T-bet upregulation is associated with changes in expression of IFN-gamma, CXCR3 and chemokines/receptors involved in the pathogenesis of sarcoidosis, which suggests a role for T-bet in this Th1 disease, including modulation of some sarcoidosis associated genes. PMID- 21540309 TI - E-cadherin gene polymorphisms in asthma patients using inhaled corticosteroids. AB - E-cadherins form intercellular junctions that maintain epithelial integrity. Epithelial integrity is impaired in asthma and can be restored by inhaled corticosteroids (ICSs). Our aim was to investigate the association of CDH1 gene polymorphisms (single-nucleotide polymorphisms (SNPs)) with airway remodelling, inflammation and forced expiratory volume in 1 s (FEV1) decline in asthma patients and assess whether ICSs modulate these effects. Bronchial biopsies of 138 asthmatics were available (population 1). Associations of 17 haplotype tagging SNPs with epithelial E-cadherin expression, biopsy parameters and FEV1/vital capacity (VC) ratio were tested. FEV1 and VC data were collected in 281 asthmatics with 30-yr follow-up (population 2). Linear mixed-effect models were used to assess associations of SNPs with FEV1 decline. Seven out of the 17 SNPs were associated with airway remodelling, three with CD8+ T-cell counts, two with eosinophil counts and seven with FEV1 decline. All associations occurred only in patients using ICS. In general, alleles associated with less remodelling correlated with less FEV1 decline and higher FEV1/VC. Decreased epithelial E cadherin expression was associated with five SNPs in non-ICS users. In conclusion, our data show that CDH1 polymorphisms are associated with epithelial E-cadherin expression and suggest that epithelial adhesion is an important contributor to airway remodelling and lung function in asthma. These effects are modified by the use of inhaled corticosteroids. PMID- 21540310 TI - A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1. AB - Sarcoidosis is a complex systemic inflammatory disease of unknown aetiology that is influenced by a variety of genetic and environmental factors. To identify further susceptibility loci for sarcoidosis, a genome-wide association study (GWAS) was conducted in 381 patients and 392 control individuals based on Affymetrix 100k GeneChip data. The top 25 single-nucleotide polymorphisms (SNPs) were selected for validation in an independent study panel (1,582 patients versus 1,783 controls). Variant rs10484410 on chromosome 6p12.1 was significantly associated, with a Bonferroni-corrected p-value of 2.90 * 10-2 in the validation sample and a nominal p-value of 2.64 * 10-4 in the GWAS. Extensive fine mapping of the novel locus narrowed down the signal to a region comprising the genes BAG2, C6orf65, KIAA1586, ZNF451 and RAB23. Verification of the sarcoidosis associated nonsynonymous SNP rs1040461 in a further independent case-control sample and quantitative mRNA expression studies point to the RAB23 gene as the most likely risk factor. RAB23 is proposed to be involved in antibacterial defence processes and regulation of the sonic hedgehog signalling pathway. The identified association of the 6p12.1 locus with sarcoidosis implicates this locus as a further susceptibility factor and RAB23 as a potential signalling component that may open up new perspectives in the pathophysiology of sarcoidosis. PMID- 21540311 TI - Association between domestic mould and mould components, and asthma and allergy in children: a systematic review. AB - Critical reviews over the past 10 yrs have found increased respiratory and allergic health outcomes for children living in damp and mouldy environments. However, recent studies have suggested that early childhood exposure to specific mould components may actually protect children from developing allergy. We conducted a systematic review of observational studies published in English from January 1980 to July 2010. This review was conducted according to systematic guidelines for Meta-analyses of Observational Studies in Epidemiology (MOOSE). The literature was searched using a computerised bibliographic database, PubMed. In order to increase the quality of the reviewed studies, meta-analyses of the effects of visible mould exposure on allergic health outcomes were performed and we evaluated the findings according to the Bradford Hill criteria for evidence of causation. The literature search identified 1,398 peer-reviewed scientific publications, and 61 studies that fulfilled the inclusion criteria were included in this review. We observed increased risks of allergic respiratory health outcomes in children exposed to visible mould and mould spores. These findings were confirmed by the results of the meta-analysis and in line with the evaluation criteria according to Bradford Hill. Visible mould was positively associated with asthma (OR 1.49 (95% CI 1.28-1.72)), wheeze (OR 1.68 (95% CI 1.48 1.90)) and allergic rhinitis (OR 1.39 (95% CI 1.28-1.51)). However, there was a tendency of lower risk for allergic health outcomes in children exposed to mould derived components such as (1,3)-beta-d-glucan and extracellular polysaccharides. These findings suggest that home environments with visible mould and mould spore exposure increase the risk of allergic respiratory health outcomes in children. However, further investigations are needed to examine the effects of exposure to mould-derived components as the current literature is inconclusive. In order to disentangle the different effects of overall microbial exposure on children's health, research should focus on specific microbial markers in the home, in combination with new assessment techniques including molecular methods. PMID- 21540312 TI - An Atropa belladonna L. poisoning with acute subdural hematoma. AB - Atropa belladonna L. is a plant long known to cause poisoning. But no cases of acute subdural hematoma resulting from such poisoning have been reported so far. Care must also be taken in terms of acute pancreatitis and rhabdomyolysis in cases of such poisoning. The plant may sometimes be mistaken for the Caucasian blueberry, V. arctostaphylos L. At least one anti-cholinesterase toxidrome finding was determined in all the nine cases of belladonna poisoning in this series. No elevated creatine kinase was reported in one case with acute subdural hematoma and hyperamylasemia. PMID- 21540313 TI - Sentinel node biopsy for head and neck melanoma: a systematic review. AB - OBJECTIVE: This systematic review was conducted to examine the test performance of sentinel node biopsy in head and neck melanoma, including the identification rate and false-negative rate. DATA SOURCES: PubMed, EMBASE, ASCO, and SSO database searches were conducted to identify studies fulfilling the following inclusion criteria: sentinel node biopsy was performed, lesions were located on the head and neck, and recurrence data for both metastatic and nonmetastatic patients were reported. REVIEW METHODS: Dual-blind data extraction was conducted. Primary outcomes included identification rate and test performance based on completion neck dissection or nodal recurrence. RESULTS: A total of 3442 patients from 32 studies published between 1990 and 2009 were reviewed. Seventy-eight percent of studies were retrospective and 22% were prospective. Trials varied from 9 to 755 patients (median 55). Mean Breslow depth was 2.53 mm. Median sentinel node biopsy identification rate was 95.2%. More than 1 basin was reported in 33.1% of patients. A median of 2.56 sentinel nodes per patient were excised. Sentinel node biopsy was positive in 15% of patients. Subsequent completion neck dissection was performed in almost all of these patients and revealed additional positive nodes in 13.67%. Median follow-up was 31 months. Across all studies, predictive value positive for nodal recurrence was 13.1% and posttest probability negative was 5%. Median false-negative rate for nodal recurrence was 20.4%. CONCLUSION: Sentinel node biopsy of head and neck melanoma is associated with an increased false-negative rate compared with studies of non head and neck lesions. Positive sentinel node status is highly predictive of recurrence. PMID- 21540314 TI - Graft uptake rates with isoamyl-2-cyanoacrylate in myringoplasty procedures: a 10 year retrospective study. AB - OBJECTIVE: To assess graft uptake rates with the use of cyanoacrylate adhesives in myringoplasty procedures. STUDY DESIGN: Case series with chart review. Setting. Tertiary care center. SUBJECTS AND METHODS: Five hundred forty-two patients selected with safe central perforations were divided into 4 groups based on perforation size and each divided into 2 subgroups depending on the presence or absence of preexisting pathology on the remnant tympanic membrane. Myringoplasty without ossicular reconstruction was done postaurally or by transcanal approach, with inlay graft placed and adhesive applied. Ear pack was removed on the seventh postoperative day. Graft uptake rates, graft uptake time (neotympanum intact and mobile), and postoperative sequelae were noted. RESULTS: Graft uptake was about 99% at 3 months postsurgery. Residual perforation was seen in 2 patients in group 2 and 1 in group 4 and thinned-out tympanum in 1 patient in group 4. Mean uptake time was 21 days. Neotympanum mobility was sluggish in 9 cases postoperatively in group 4 and in 2 cases in group 3. Patients with successful (neotympanum intact and mobile) graft uptake showed significant improvement. Postoperative inflammatory signs in the external auditory canal were seen in 3 cases. CONCLUSION: Cyanoacrylate use in myringoplasty obtains graft uptake rates of 99% compared with most studies, which report 80% to 90%. This also allows removal of the pack by the seventh day, allowing close follow-up of the graft and less patient discomfort. Importantly, it has not interfered with the formation of the neotympanum or compromised hearing improvement. PMID- 21540315 TI - Median nerve injury associated with radial forearm free flap harvest. PMID- 21540316 TI - Cholesteatoma with congenital eustachian tube obstruction. PMID- 21540317 TI - Ectopic adrenocorticotrophic hormone syndrome associated with poor prognosis in metastatic parotid acinic cell carcinoma. PMID- 21540318 TI - Potassium, calcium, and magnesium intakes and risk of stroke in women. AB - The authors examined the association between dietary potassium, calcium, and magnesium intakes and the incidence of stroke among 34,670 women 49-83 years of age in the Swedish Mammography Cohort who completed a food frequency questionnaire in 1997. The authors used Cox proportional hazards regression models to estimate relative risks and 95% confidence intervals. During a mean follow-up of 10.4 years (1998-2008), 1,680 stroke events were ascertained, including 1,310 cerebral infarctions, 154 intracerebral hemorrhages, 79 subarachnoid hemorrhages, and 137 unspecified strokes. There was no overall association between potassium, calcium, or magnesium intake and the risk of any stroke or cerebral infarction. However, among women with a history of hypertension, potassium intake was inversely associated with risk of all types of stroke (for highest vs. lowest quintile, adjusted relative risk = 0.64, 95% confidence interval (CI): 0.45, 0.92) and cerebral infarction (corresponding adjusted relative risk = 0.56, 95% CI: 0.38, 0.84), and magnesium intake was inversely associated with risk of cerebral infarction (corresponding adjusted relative risk = 0.63, 95% CI: 0.42, 0.93). Calcium intake was positively associated with risk of intracerebral hemorrhage (for highest vs. lowest tertile, adjusted relative risk = 2.04, 95% CI: 1.24, 3.35). These findings suggest that potassium and magnesium intakes are inversely associated with the risk of cerebral infarction among hypertensive women. PMID- 21540319 TI - Utility of the National Death Index in ascertaining mortality in acquired immunodeficiency syndrome surveillance. AB - To assess the utility of the National Death Index (NDI) in improving the ascertainment of deaths among people diagnosed with acquired immunodeficiency syndrome (AIDS), the authors determined the number and characteristics of additional deaths identified through NDI linkage not ascertained by using standard electronic linkage with Florida Vital Records and the Social Security Administration's Death Master File. Records of people diagnosed with acquired immunodeficiency syndrome between 1993 and 2007 in Florida were linked to the NDI. The demographic characteristics and reported human immunodeficiency virus (HIV) transmission modes of people whose deaths were identified by using the NDI were compared with those whose deaths were ascertained by standard linkage methods. Of the 15,094 submitted records, 719 had confirmed matches, comprising 2.1% of known deaths (n = 34,504) within the cohort. Hispanics, males, people 40 years of age or older, and injection drug users were overrepresented among deaths ascertained only by the NDI. In-state deaths comprised 59.0% of newly identified deaths, and human immunodeficiency virus was less likely to be a cause of death among newly identified compared with previously identified deaths. The newly identified deaths were not previously ascertained principally because of slight differences in personal identifying information and could have been identified through improved linkages with Florida Vital Records. PMID- 21540320 TI - Sexually transmitted disease core theory: roles of person, place, and time. AB - The authors' purpose was to expand sexually transmitted disease core theory by examining the roles of person, place, and time in differentiating geographic core areas from outbreak areas. The authors mapped yearly census-tract-level syphilis rates for San Francisco, California, based on new primary and secondary syphilis cases reported to the San Francisco City sexually transmitted disease surveillance program between January 1, 1985, and December 31, 2007. SaTScan software (Information Management Services, Inc., Silver Spring, Maryland) was used to identify geographic clusters of significantly elevated syphilis rates over space and time. The authors graphed epidemic curves for 1) core areas, 2) outbreak areas, 3) neither core nor outbreak areas, and 4) noncore areas, where noncore areas included outbreaks, and stratified these curves according to demographic characteristics. Five clusters of significantly elevated primary and secondary syphilis rates were identified. A 5-year threshold was useful for differentiating core clusters from outbreak clusters. Epidemic curves for core areas, outbreak areas, neither core nor outbreak areas, and noncore areas were perfectly synchronized in phase trends and wavelength over time, even when broken down by demographic characteristics. Between epidemics, the occurrence of syphilis affected all demographic groups equally. During an epidemic, a temporary disparity in syphilis occurrence arose and a homogeneous core group of cases could be defined. PMID- 21540321 TI - Re.: "Reconsidering the role of social disadvantage in physical and mental health: stressful life events, health behaviors, race, and depression". PMID- 21540322 TI - Potential for bias in case-crossover studies with shared exposures analyzed using SAS. AB - The case-crossover method is an efficient study design for evaluating associations between transient exposures and the onset of acute events. In one common implementation of this design, odds ratios are estimated using conditional logistic or stratified Cox proportional hazards models, with data stratified on each individual event. In environmental epidemiology, where aggregate time-series data are often used, combining strata with identical exposure histories may be computationally convenient. However, when the SAS software package (SAS Institute Inc., Cary, North Carolina) is used for analysis, users can obtain biased results if care is not taken to properly account for multiple cases observed at the same time. The authors show that fitting a stratified Cox model with the "Breslow" option for handling tied failure times (i.e., ties = Breslow) provides unbiased health-effects estimates in case-crossover studies with shared exposures. The authors' simulations showed that using conditional logistic regression-or equivalently a stratified Cox model with the "ties = discrete" option-in this setting leads to health-effect estimates which can be biased away from the null hypothesis of no association by 22%-39%, even for small simulated relative risks. All methods tested by the authors yielded unbiased results under a simulated scenario with a relative risk of 1.0. This potential bias does not arise in R (R Foundation for Statistical Computing, Vienna, Austria) or Stata (Stata Corporation, College Station, Texas). PMID- 21540323 TI - The gap of visual impairment between economic groups in Shahroud, Iran: a Blinder Oaxaca decomposition. AB - The authors assessed the role of economic inequality in visual impairment and decomposed the gap between high and low income groups. Study data were extracted from the first phase of the Shahroud Eye Cohort Study, performed in 2009, with 5,190 participants aged between 40 and 64 years. The participants were divided into low, medium, and high economic groups according to their assets by using a principal component analysis. The gap between low and high economic groups was decomposed to its determinants by using the Blinder-Oaxaca method. The prevalence of visual impairment, a presenting vision worse than 20/40 in the better eye, was 3.57% and 11.07% in the high and low economic groups, respectively. Age and education were the major factors in the decomposition model, contributing to 41.38% of the gap. Insurance status, gender, and education of the head of the household had no effect on this gap. Economic inequality in visual impairment was noteworthy. Although part of the gap between low and high economic groups was explained by differences in age and education, the greater part (58.62%) could be due to differences in health-care access and utilization. PMID- 21540324 TI - Association of symptomatic benign prostatic hyperplasia and prostate cancer: results from the prostate cancer prevention trial. AB - This study examined the association between symptomatic benign prostatic hyperplasia (BPH) and prostate cancer risk in 5,068 placebo-arm participants enrolled in the Prostate Cancer Prevention Trial (1993-2003). These data include 1,225 men whose cancer was detected during the 7-year trial--556 detected for cause (following abnormal prostate-specific antigen or digital rectal examination) and 669 detected not for cause (without indication), as well as 3,843 men who had biopsy-proven absence of prostate cancer at the trial end. Symptomatic BPH was assessed hierarchically as self-report of surgical or medical treatment, moderately severe symptoms (International Prostate Symptom Score >14), or physician diagnosis, and analyses were completed by BPH status at baseline (prevalent) or BPH prior to cancer diagnosis or study end (prevalent plus incident). Controlled for age, race, and body mass index, neither prevalent (risk ratio = 1.03, 95% confidence interval: 0.92, 1.14) nor prevalent plus incident (risk ratio = 0.96, 95% confidence interval: 0.87, 1.06) symptomatic BPH was associated with prostate cancer risk. This lack of association was consistent across subgroups defined by type of BPH-defining event (treatment, symptoms, or physician diagnosis), prompt for prostate cancer diagnosis, and prostate cancer grade. This study provides the strongest evidence to date that BPH does not increase the risk of prostate cancer. PMID- 21540325 TI - Re.: "The health status of nonparticipants in a population-based health study: the Hordaland Health Study". PMID- 21540326 TI - The effect of small class sizes on mortality through age 29 years: evidence from a multicenter randomized controlled trial. AB - Limiting the number of students per classroom in the early years has been shown to improve educational outcomes. Improved education is, in turn, hypothesized to improve health. The authors examined whether smaller class sizes affect mortality through age 29 years and whether cognitive factors play a role. They used data from the Project Student Teacher Achievement Ratio, a 4-year multicenter randomized controlled trial of reduced class sizes in Tennessee involving 11,601 students between 1985 and 1989. Children randomized to small classes (13-17 students) experienced improved measures of cognition and academic performance relative to those assigned to regular classes (22-25 students). As expected, these cognitive measures were significantly inversely associated with mortality rates (P < 0.05). However, through age 29 years, students randomized to small class size nevertheless experienced higher mortality rates than those randomized to regular size classes (hazard ratio (HR) = 1.58, 95% confidence interval (CI): 1.07, 2.32). The groups at risk included males (HR = 1.73, 95% CI: 1.05, 2.85), whites/Asians (HR = 1.68, 95% CI: 1.04, 2.72), and higher income students (HR = 2.20, 95% CI: 1.06, 4.57). The authors speculate that small classes might produce behavior changes that increase mortality through young adulthood that are stronger than the protective effects of enhanced cognition. PMID- 21540327 TI - Agreement on cause of death between proxies, death certificates, and clinician adjudicators in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. AB - Death certificates may lack accuracy and misclassify the cause of death. The validity of proxy-reported cause of death is not well established. The authors examined death records on 336 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a national cohort study of 30,239 community-dwelling US adults (2003-2010). Trained experts used study data, medical records, death certificates, and proxy reports to adjudicate causes of death. The authors computed agreement on cause of death from the death certificate, proxy, and adjudication, as well as sensitivity and specificity for certain diseases. Adjudicated cause of death had a higher rate of agreement with proxy reports (73%; Cohen's kappa (kappa) statistic = 0.69) than with death certificates (61%; kappa = 0.54). The agreement between proxy reports and adjudicators was better than agreement with death certificates for all disease specific causes of death. Using the adjudicator assessments as the "gold standard," for disease-specific causes of death, proxy reports had similar or higher specificity and higher sensitivity (sensitivity = 50%-89%) than death certificates (sensitivity = 31%-81%). Proxy reports may be more concordant with adjudicated causes of death than with the causes of death listed on death certificates. In many settings, proxy reports may represent a better strategy for determining cause of death than reliance on death certificates. PMID- 21540329 TI - Neuroanatomical dissociation for taxonomic and thematic knowledge in the human brain. AB - It is thought that semantic memory represents taxonomic information differently from thematic information. This study investigated the neural basis for the taxonomic-thematic distinction in a unique way. We gathered picture-naming errors from 86 individuals with poststroke language impairment (aphasia). Error rates were determined separately for taxonomic errors ("pear" in response to apple) and thematic errors ("worm" in response to apple), and their shared variance was regressed out of each measure. With the segmented lesions normalized to a common template, we carried out voxel-based lesion-symptom mapping on each error type separately. We found that taxonomic errors localized to the left anterior temporal lobe and thematic errors localized to the left temporoparietal junction. This is an indication that the contribution of these regions to semantic memory cleaves along taxonomic-thematic lines. Our findings show that a distinction long recognized in the psychological sciences is grounded in the structure and function of the human brain. PMID- 21540330 TI - Cysteine-rich intestinal protein 2 (CRIP2) acts as a repressor of NF-kappaB mediated proangiogenic cytokine transcription to suppress tumorigenesis and angiogenesis. AB - Chromosome 14 was transferred into tumorigenic nasopharyngeal carcinoma and esophageal carcinoma cell lines by a microcell-mediated chromosome transfer approach. Functional complementation of defects present in the cancer cells suppressed tumor formation. A candidate tumor-suppressor gene, cysteine-rich intestinal protein 2 (CRIP2), located in the hot spot for chromosomal loss at 14q32.3, was identified as an important candidate gene capable of functionally suppressing tumor formation. Previous studies have shown that CRIP2 is associated with development. To date, no report has provided functional evidence supporting a role for CRIP2 in tumor development. The present study provides unequivocal evidence that CRIP2 can functionally suppress tumorigenesis. CRIP2 is significantly down-regulated in nasopharyngeal carcinoma cell lines and tumors. CRIP2 reexpression functionally suppresses in vivo tumorigenesis and angiogenesis; these effects are induced by its transcription-repressor capability. It interacts with the NF-kappaB/p65 to inhibit its DNA-binding ability to the promoter regions of the major proangiogenesis cytokines critical for tumor progression, including IL6, IL8, and VEGF. In conclusion, we provide compelling evidence that CRIP2 acts as a transcription repressor of the NF-kappaB mediated proangiogenic cytokine expression and thus functionally inhibits tumor formation and angiogenesis. PMID- 21540331 TI - Two distinct conformations of helix 6 observed in antagonist-bound structures of a beta1-adrenergic receptor. AB - The beta(1)-adrenergic receptor (beta(1)AR) is a G-protein-coupled receptor whose inactive state structure was determined using a thermostabilized mutant (beta(1)AR-M23). However, it was not thought to be in a fully inactivated state because there was no salt bridge between Arg139 and Glu285 linking the cytoplasmic ends of transmembrane helices 3 and 6 (the R(3.50) - D/E(6.30) "ionic lock"). Here we compare eight new structures of beta(1)AR-M23, determined from crystallographically independent molecules in four different crystals with three different antagonists bound. These structures are all in the inactive R state and show clear electron density for cytoplasmic loop 3 linking transmembrane helices 5 and 6 that had not been seen previously. Despite significantly different crystal packing interactions, there are only two distinct conformations of the cytoplasmic end of helix 6, bent and straight. In the bent conformation, the Arg139-Glu285 salt bridge is present, as in the crystal structure of dark-state rhodopsin. The straight conformation, observed in previously solved structures of beta-receptors, results in the ends of helices 3 and 6 being too far apart for the ionic lock to form. In the bent conformation, the R(3.50)-E(6.30) distance is significantly longer than in rhodopsin, suggesting that the interaction is also weaker, which could explain the high basal activity in beta(1)AR compared to rhodopsin. Many mutations that increase the constitutive activity of G-protein coupled receptors are found in the bent region at the cytoplasmic end of helix 6, supporting the idea that this region plays an important role in receptor activation. PMID- 21540332 TI - Chemical reporters for fluorescent detection and identification of O-GlcNAc modified proteins reveal glycosylation of the ubiquitin ligase NEDD4-1. AB - The dynamic modification of nuclear and cytoplasmic proteins by the monosaccharide N-acetyl-glucosamine (GlcNAc) continues to emerge as an important regulator of many biological processes. Herein we describe the development of an alkynyl-modified GlcNAc analog (GlcNAlk) as a new chemical reporter of O-GlcNAc modification in living cells. This strategy is based on metabolic incorporation of reactive functionality into the GlcNAc biosynthetic pathway. When combined with the Cu(I)-catalyzed [3 + 2] azide-alkyne cycloaddition, this chemical reporter allowed for the robust in-gel fluorescent visualization of O-GlcNAc and affinity enrichment and identification of O-GlcNAc-modified proteins. Using in gel fluorescence detection, we characterized the metabolic fates of GlcNAlk and the previously reported azido analog, GlcNAz. We confirmed previous results that GlcNAz can be metabolically interconverted to GalNAz, whereas GlcNAlk does not, thereby yielding a more specific metabolic reporter of O-GlcNAc modification. We also used GlcNAlk, in combination with a biotin affinity tag, to identify 374 proteins, 279 of which were not previously reported, and we subsequently confirmed the enrichment of three previously uncharacterized proteins. Finally we confirmed the O-GlcNAc modification of the ubiquitin ligase NEDD4-1, the first reported glycosylation of this protein. PMID- 21540333 TI - What about European alvarezsauroids? PMID- 21540334 TI - In vitro cytotoxic evaluation of processed natural coral in human osteoblasts. AB - This study aimed to evaluate the in vitro cytotoxic effects of locally produced processed natural coral (PNC) using human osteoblasts (HOS). Cytotoxicity was not observed when HOS cells were cultured with PNC, as assessed by (3-(4,5 dimethylthiazol-2-yl)-2-5-diphenyl tetrazolium bromide; MTT) and Neutral Red (NR) assays at concentration up 200 mg/mL for up to 72 hours. Flow cytometry (FCM) analysis showed that PNC (200 mg/mL) did not decrease viability of HOS cells after 48 and 72 hours of treatment. In a cell attachment study, the HOS cells attached to the edge of the PNC disc, and later grew into the pores of the PNC disc. All results from these studies indicate that locally produced PNC material is noncytotoxic and favors the growth of HOS cells. PMID- 21540335 TI - Chemical and mechanistic toxicology evaluation of exon skipping phosphorodiamidate morpholino oligomers in mdx mice. AB - AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) designed to induce skipping of dystrophin exon 51 and restore its expression in patients with Duchenne muscular dystrophy (DMD). Preclinically, restoration of dystrophin in the dystrophic mdx mouse model requires skipping of exon 23, achieved with the mouse-specific PMO, AVI-4225. Herein, we report the potential toxicological consequences of exon skipping and dystrophin restoration in mdx mice using AVI 4225. We also evaluated the toxicological effects of AVI-4658 in both mdx and wild-type mice. In both studies, animals were dosed once weekly for 12 weeks up to the maximum feasible dose of 960 mg/kg per injection. Both AVI-4658 and AVI 4225 were well-tolerated at all doses. Findings in AVI-4225-treated animals were generally limited to mild renal tubular basophilia/vacuolation, without any significant changes in renal function and with evidence of reversing. No toxicity associated with the mechanism of action of AVI-4225 in a dystrophic animal was observed. PMID- 21540336 TI - Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of duchenne muscular dystrophy. AB - AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) drug designed to restore dystrophin expression in a subset of patients with Duchenne muscular dystrophy (DMD). Previous reports demonstrated this clinical proof-of-principle in patients with DMD following intramuscular injection of AVI-4658. This preclinical study evaluated the toxicity and toxicokinetic profile of AVI-4658 when administered either intravenously (IV) or subcutaneously (SC) to cynomolgus monkeys once weekly over 12 weeks, at doses up to the maximum feasible dose of 320 mg/kg per injection. No drug-related effects were noted on survival, clinical observations, body weight, food consumption, opthalmoscopic or electrocardiographic evaluations, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic evaluations. Drug-related microscopic renal effects were dose-dependent, apparently reversible, and included basophilic granules (minimal), basophilic tubules (minimal to moderate), and tubular vacuolation (minimal to mild). These data establish the tolerability of AVI-4658 at doses up to and including the maximum feasible dose of 320 mg/kg by IV bolus or SC injection. PMID- 21540337 TI - New application of the comet assay: chromosome--comet assay. AB - The comet assay is a well-established, simple, versatile, visual, rapid, and sensitive tool used extensively to assess DNA damage and DNA repair quantitatively and qualitatively in single cells. The comet assay is most frequently used to analyze white blood cells or lymphocytes in human biomonitoring studies, although other cell types have been examined, including buccal, nasal, epithelial, and placental cells and even spermatozoa. This study was conducted to design a protocol that can be used to generate comets in subnuclear units, such as chromosomes. The new technique is based on the chromosome isolation protocols currently used for whole chromosome mounting in electron microscopy, coupled to the alkaline variant of the comet assay, to detect DNA damage. The results show that migrant DNA fragments can be visualized in whole nuclei and isolated chromosomes and that they exhibit patterns of DNA migration that depend on the level of DNA damage produced. This protocol has great potential for the highly reproducible study of DNA damage and repair in specific chromosomal domains. PMID- 21540338 TI - Protective effect of caspase inhibition on compression-induced muscle damage. AB - There are currently no effective therapies for treating pressure-induced deep tissue injury. This study tested the efficacy of pharmacological inhibition of caspase in preventing muscle damage following sustained moderate compression. Adult Sprague-Dawley rats were subjected to prolonged moderate compression. Static pressure of 100 mm Hg compression was applied to an area of 1.5 cm2 in the tibialis region of the right limb of the rats for 6 h each day for two consecutive days. The left uncompressed limb served as intra-animal control. Rats were randomized to receive either vehicle (DMSO) as control treatment (n =8) or 6 mg kg-1 of caspase inhibitor (z-VAD-fmk; n =8) prior to the 6 h compression on the two consecutive days.Muscle tissues directly underneath the compression region of the compressed limb and the same region of control limb were harvested after the compression procedure.Histological examination and biochemical/molecular measurement of apoptosis and autophagy were performed. Caspase inhibition was effective in alleviating the compression-induced pathohistology of muscle. The increases in caspase-3 protease activity, TUNEL index, apoptotic DNA fragmentation and pro-apoptotic factors (Bax, p53 and EndoG) and the decreases in anti-apoptotic factors (XIAP and HSP70) observed in compressed muscle of DMSO-treated animals were not found in animals treated with caspase inhibitor. The mRNA content of autophagic factors (Beclin-1, Atg5 and Atg12) and the protein content of LC3, FoxO3 and phospho-FoxO3 that were down regulated in compressed muscle of DMSO-treated animals were all maintained at their basal level in the caspase inhibitor treated animals. Our data provide evidence that caspase inhibition attenuates compression-induced muscle apoptosis and maintains the basal autophagy level. These findings demonstrate that pharmacological inhibition of caspase/apoptosis is effective in alleviating muscle damage as induced by prolonged compression. PMID- 21540339 TI - Transient receptor potential vanilloid 4 (TRPV4)-dependent calcium influx and ATP release in mouse oesophageal keratinocytes. AB - Gastro-oesophageal reflux disease (GERD) is a multi-factorial disease that may involve oesophageal hypersensitivity to mechanical or heat stimulus as well as acids. Intraganglionic laminar endings (IGLEs) are the most prominent terminal structures of oesophageal vagal mechanosensitive afferents and may modulate mechanotransduction via purinergic receptors. Transient receptor potential channel vanilloid 4 (TRPV4) can detect various stimuli such as warm temperature, stretch and some chemicals, including 4alpha-phorbol 12,13-didecanoate (4alpha PDD) and GSK1016790A. TRPV4 is expressed in many tissues, including renal epithelium, skin keratinocytes and urinary bladder epithelium, but its expression and function in the oesophagus is poorly understood. Here, we show anatomical and functional TRPV4 expression in mouse oesophagus and its involvement in ATP release. TRPV4 mRNA and protein were detected in oesophageal keratinocytes. Several known TRPV4 activators (chemicals, heat and stretch stimulus) increased cytosolic Ca2+ concentrations in cultured WT keratinocytes but not in TRPV4 knockout (KO) cells. Moreover, the TRPV4 agonist GSK1016790A and heat stimulus evoked TRPV4-like current responses in isolated WT keratinocytes, but not in TRPV4KO cells. GSK1016790A and heat stimulus also significantly increased ATP release from WT oesophageal keratinocytes compared to TRPV4KO cells. The vesicle trafficking inhibitor brefeldin A (BFA) inhibited the ATP release. This ATP release could be mediated by the newly identified vesicle ATP transporter, VNUT, which is expressed by oesophageal keratinocytes at the mRNA and protein levels. In conclusion, in response to heat, chemical and possibly mechanical stimuli, TRPV4 contributes to ATP release in the oesophagus. Thus, TRPV4 could be involved in oesophageal mechano- and heat hypersensitivity. PMID- 21540340 TI - Chronic intrauterine hypoxia interferes with aortic development in the late gestation ovine fetus. AB - This study explored arterial remodelling in fetuses growth restricted by hypoxia. Chronically catheterized fetal sheep were made moderately or severely hypoxic by placental embolization for 15 days starting at gestational age 116-118 (term ~147 days). Cross-sections of the aorta were analysed for collagen and elastin content using histological procedures, while immunofluorescence was applied to measure markers of vascular smooth muscle cell (VSMC) type. In frozen aortae quantitative PCR was used to measure mRNA levels of extracellular matrix (ECM) precursor proteins as well as molecular regulators of developmental and pathological remodelling. Relative to Control (n =6), aortic wall thickness was increased by 23% in the Moderate group (n =5) and 33% (P <0.01) in the Severe group (n =5). Relative to Control, the Severe group exhibited a 5-fold increase in total collagen content (P <0.01) that paralleled increases in mRNA levels of procollagen I (P <0.05) and III and transforming growth factor beta (TGF-beta1) (P <0.05). The percentage area stained for alpha-actin was inversely related to fetal arterial oxygen saturation (P <0.05) and total alpha-actin content was 45% higher in the Moderate group and 65% (P <0.05) higher in the Severe group, compared to Control. A 12% and 39% (P <0.05) reduction in relative elastic fibre content was observed in Moderate and Severe fetuses, respectively. mRNA levels of the elastolytic enzyme, matrix metalloproteinase-2 (MMP-2) were inversely correlated with fetal arterial oxygen saturation (P <0.05) (Fig. 7) and mRNA levels of its activator, membrane-type MMP (MTI-MMP), were elevated in the Severe group (P <0.05). Marked neointima formation was apparent in Severe fetuses (P <0.05) concomitant with an increase in E-selectin mRNA expression (P <0.05). Thus, aberrant aortic formation in utero mediated by molecular regulators of arterial growth occurs in response to chronic hypoxaemia. PMID- 21540341 TI - Direct demonstration of inhibitory interactions between long interval intracortical inhibition and short interval intracortical inhibition. AB - A subthreshold conditioning stimulation (CS) suppresses the motor-evoked potential (MEP) generated by a test stimulation (TS) at interstimulus intervals (ISIs) of 1-5ms in a paired-pulse transcranial magnetic stimulation (TMS) protocol, a phenomenon termed short interval intracortical inhibition (SICI). Intracortical facilitation (ICF) occurs at ISIs of 7-30ms. Long interval intracortical inhibition (LICI) is elicited with suprathreshold CS preceding the TS at ISIs of 50-200 ms. Previous studies showed that SICI is decreased in the presence of LICI but whether this is due to changes in descending indirect waves (I-waves) induced by LICI or true inhibitory interactions between LICI and SICI has not been resolved. To address this issue, we recorded I-waves in two patients with implanted cervical epidural electrodes and investigated how SICI and ICF changed I-waves in the presence of LICI. SICI alone reduced late I-waves but in the presence of LICI, neither the I-waves nor the MEP were further inhibited by SICI. ICF alone increased MEP amplitude but the I-waves were not facilitated. There was no change of ICF in the presence of LICI compared with ICF alone. We conclude that decreased SICI in the presence of LICI is not due to changes in I wave content induced by LICI and is caused by their interactions at the cortical level. PMID- 21540342 TI - Genes and elite athletes: a roadmap for future research. AB - There is compelling evidence that genetic factors influence several phenotype traits related to physical performance and training response as well as to elite athletic status. Previous case-control studies showed that ~20 genetic variants seem to be associated with elite endurance athletic status. The present review aims to introduce novel methodological approaches in the field of sports genetics research, which can be applied in the near future to analyse the genotype profile associated with elite athletic status. These include genotype-phenotype association studies using gene expression analysis, analysis of post transcriptional factors, particularly microRNAs, genome-wide scan linkage or genome-wide association studies, and novel algorithm approaches, such as 'genotype scores'. Several gaps in the current body of knowledge have been identified including, among others: small sample size of most athletic cohorts, lack of corroboration with replication cohorts of different ethnic backgrounds (particularly, made up of non-Caucasian athletes), the need of research accounting for the potential role of epigenetics in elite athletic performance, and also the need for future models that take into account the association between athletic status and complex gene-gene and gene-environment interactions. Some recommendations are provided to minimize research limitations in the field of sport genetics. PMID- 21540343 TI - Force decline during fatigue is due to both a decrease in the force per individual cross-bridge and the number of cross-bridges. AB - Fatigue occurring during exercise can be defined as the inability to maintain the initial force or power output. As fatigue becomes pronounced, force and maximum velocity of shortening are greatly reduced and force relaxation is prolonged. In principle, force loss during fatigue can result from a decrease in the number of cross-bridges generating force or a decrease of the individual cross-bridge force or to both mechanisms. The present experiments were made to investigate this point in single fibres or small fibre bundles isolated from flexor digitorum brevis (FDB) of C57BL/6 mice at 22-24?C. During a series of 105 tetanic contractions, we measured force and fibre stiffness by applying small sinusoidal length oscillations at 2.5 or 4 kHz frequency to the activated preparation and measuring the resulting force changes. Stiffness data were corrected for the influence of compliance in series with the cross-bridge ensemble. The results show that the force decline during the first 20 tetani is due to the reduction of force developed by the individual cross-bridges and thereafter as fatigue becomes more severe, the number of cross-bridges decreases. In spite of the force reduction in the early phase of fatigue, there was an increased rate of tetanic force development and relaxation. In the latter stages of fatigue, the rate of force development and relaxation became slower. Thus, the start of fatigue is characterised by decreased cross-bridge force development and as fatigue becomes more marked, the number of cross-bridges decreases. These findings are discussed in the context of the current hypotheses about fatigue mechanisms. PMID- 21540344 TI - Periodic stimulation induces long-range modulation of cortical responses and visual perception. AB - Periodic sensory stimuli are prevalent in natural environment and may signal events of particular importance. However, whether periodic and aperiodic stimuli are differentially processed by neural circuits remains unclear. Here we show that periodic stimuli exert influences over longer distances than aperiodic stimuli at both neuronal and perceptual levels. Whole-cell recording from rat visual cortex showed that periodic visual stimulation (1-11 Hz) outside the neuronal receptive field evoked robust membrane potential oscillation at the stimulation frequency, while the same stimulus applied aperiodically had little effect. Human psychophysical experiments showed that periodic luminance changes in the distant surround also exert a stronger modulation of perceived brightness of a centre test stimulus than that exerted by aperiodic changes. Furthermore, both perceptual and neuronal modulation increased with the number of stimulation cycles for periodic surround stimuli. Thus, periodic stimuli can modulate both cortical responses and visual perception over larger spatial scales, generating more global impact on cortical information processing. PMID- 21540345 TI - Hysteresis in the sympathetic baroreflex: role of baseline nerve activity. AB - Sympathetic baroreflex sensitivity (BRS) is greater during decreasing compared to increasing diastolic blood pressure (DBP) in young men and women. In older men and women there is no difference in sympathetic BRS to increasing and decreasing DBP. We investigated whether the sensitivity of the central nervous system to increasing and decreasing DBP is dependent upon baseline muscle sympathetic nerve activity (MSNA). We hypothesised that the difference in sympathetic BRS between falling and rising segments of DBP would be positively related to baseline MSNA in 30 young men, 21 young women, 14 older men and 14 postmenopausal women. MSNA was measured using peroneal microneurography and BRS was measured using the spontaneous baroreflex threshold technique. On average, sympathetic BRS was greater during decreasing compared to increasing DBP in young men (P <0.05) and women (P <0.05). In older men and women, mean sympathetic BRS was similar in response to increasing and decreasing DBP. The difference (delta) between the falling and rising BRS correlated with baseline MSNA in young (r =0.58, P <0.05) and older men (r =0.66, P <0.05) and postmenopausal women (r =0.74, P <0.05). Thus, all men, and older women, with higher BRS to falling DBP had lower baseline MSNA. This relationship was not observed in young women (r =0.14, P >0.05). In summary, baseline MSNA plays a role in determining sympathetic BRS to falling and rising DBP in young and older men and postmenopausal women, but not in young women. This relationship is consistent with a decreased potential for sympathoexcitation in people with higher resting MSNA. Furthermore, the lack of relationship in young women suggests important contributions of sex hormones to differential responses of MSNA to falling and rising pressures. PMID- 21540346 TI - Determinants of human cerebral pressure-flow velocity relationships: new insights from vascular modelling and Ca2+ channel blockade. AB - The fundamental determinants of human dynamic cerebral autoregulation are poorly understood, particularly the role of vascular compliance and the myogenic response. We sought to 1) determine whether capacitive blood flow associated with vascular compliance and driven by the rate of change in mean arterial blood pressure (dMAP/dt) is an important determinant of middle cerebral artery velocity (MCAv) dynamics and 2) characterise the impact of myogenic blockade on these cerebral pressure-flow velocity relations in humans. We measured MCAv and mean arterial pressure (MAP) during oscillatory lower body negative pressure (n =8) at 0.10 and 0.05 Hz before and after cerebral Ca2+ channel blockade (nimodipine). Pressure-flow velocity relationships were characterised using transfer function analysis and a regression-based Windkessel analysis that incorporates MAP and dMAP/dt as predictors of MCAv dynamics. Results show that incorporation of dMAP/dt accounted for more MCAv variance (R2 0.80-0.99) than if only MAP was considered (R2 0.05-0.90). The capacitive gain relating dMAP/dt and MCAv was strongly correlated to transfer function gain (0.05 Hz, r =0.93, P<0.01; 0.10 Hz, r =0.91, P<0.01), but not to phase or coherence. Ca2+ channel blockade increased the conductive gain relation between MAP and MCAv (P<0.05), and reduced phase at 0.05 Hz (P<0.01). Capacitive and transfer function gain were unaltered. The findings suggest capacitive blood flow is an important determinant of cerebral haemodynamics that bears strong relations to some metrics of dynamic cerebral autoregulation derived from transfer function analysis, and that Ca2+ channel blockade enhances pressure-driven resistive blood flow but does not alter capacitive blood flow. the causes and effects of cerebrovascular diseases such as stroke and dementia. PMID- 21540347 TI - To the interstitial space--and beyond! PMID- 21540348 TI - A conserved tryptophan at the membrane-water interface acts as a gatekeeper for Kir6.2/SUR1 channels and causes neonatal diabetes when mutated. AB - We identified a novel heterozygous mutation, W68R, in the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, in a patient with transient neonatal diabetes. This tryptophan is absolutely conserved in mammalian Kir channels. The functional effects of mutations at residue 68 of Kir6.2 were studied by heterologous expression in Xenopus oocytes, and by homology modelling. We found the Kir6.2-W68R mutation causes a small reduction in ATP inhibition in the heterozygous state and an increase in the whole-cell KATP current. This can explain the clinical phenotype of the patient. The effect of the mutation was not charge or size dependent, the order of potency for ATP inhibition being W= 50% efficacious vaccine was highly cost-effective [< 1* per capita gross domestic product (GDP) ($4,289)] up to a total vaccination cost of $60 and cost-effective [< 3* per capita GDP ($12,868)] up to a total vaccination cost of $200. When the total vaccine series was $1.50, many scenarios were cost saving. PMID- 21540388 TI - Modeling the effect of chronic schistosomiasis on childhood development and the potential for catch-up growth with different drug treatment strategies promoted for control of endemic schistosomiasis. AB - In areas endemic for schistosomiasis having limited healthcare, targeted drug treatment of school-age children is recommended for control of Schistosoma associated morbidity. However, optimal timing, number, and frequency of treatments are not established. Because longitudinal studies of long-term impact of treatment are few, for current policy considerations we performed quantitative simulation (based on calibrated modeling of Schistosoma-associated disease formation) to project the impact of different school-age treatment regimens. Using published efficacy data from targeted programs, combined with age-specific risk for growth retardation and reinfection, we examined the likely impact of different strategies for morbidity prevention. Results suggest the need for early, repeated treatment through primary school years to optimally prevent the disabling sequelae of stunting and undernutrition. Dynamics of infection/reinfection during childhood and adolescence, combined with early treatment effects against reversible infection-associated morbidities, create a need for aggressive retreatment of preadolescents to achieve optimal suppression of morbidity where drug-based control is used. PMID- 21540389 TI - Quality of life in patients with neurocysticercosis in Mexico. AB - The objective of this study was to compare quality of life measures in patients with neurocysticercosis (NCC) to those of a matched control group. The NCC outpatients and their controls were recruited from two neurology referral hospitals in Mexico City, Mexico during 2007-2008. The quality of life of 224 NCC patients was compared with 224 age-sex-hospital-day matched controls using the short form 12 v2 (SF-12 v2) quality of life survey. Medical chart reviews were also conducted for the NCC outpatients to evaluate presenting clinical manifestations. Compared with the controls, NCC patients had a significantly lower score for each of the eight domains of health evaluated and significantly lower Physical and Mental Component Summary scores. Chart reviews indicated that hydrocephalus (48%), severe headaches (47%), and epilepsy (31%) were the most common clinical manifestations in these NCC outpatients. PMID- 21540390 TI - Schistosomiasis among young children in Usoma, Kenya. AB - Although schistosomiasis burden is greatest among school-age children (SAC) (6-15 years of age), infection among preschool-age children (PSAC) (1-5 years), may be underestimated in endemic areas. We conducted a cross-sectional study evaluating Schistosoma mansoni infection among children 1-15 years of age in a highly endemic community in Kenya. Diagnostic tests included stool exam (Kato/Katz technique), serum testing for schistosome-specific antibodies, and urine testing for circulating cathodic antigen (CCA). Overall, 268 SAC and 216 PSAC were enrolled; prevalence increased with age, with 14% of 1 year olds and more than 90% of children > 10 years of age infected. Stool exam was more sensitive among SAC than PSAC, but performance was similar after adjusting for infection intensity (based on CCA). Schistosomiasis poses a threat to PSAC in endemic areas, and stool exam may underestimate the prevalence of infection. Control programs in such areas should consider PSAC in addition to SAC. PMID- 21540392 TI - Formative ethnographic research to improve evaluation of a novel water system in Ghana. AB - The accessibility of potable water is fundamental to public health. A private for profit company is installing kiosk-based drinking-water systems in rural and peri urban villages in Ghana, and we evaluated their performance. Preceding an observational study to measure the effect of these kiosks on the incidence of water-related disease in recipient communities, we conducted ethnographic research to assess local water-related practices and the ways these practices would affect adoption of the new technology. We conducted fieldwork in two communities in Ghana and interviewed stakeholders throughout the water sector. Our findings illustrate the complexity of water-related behaviors and indicate several factors that may sustain disease transmission despite the presence of the new technology. This formative ethnographic research also improved the precision of our subsequent evaluation of the intervention by providing a site-specific, culturally-appropriate knowledge base. This study demonstrates the value of incorporating qualitative research techniques into evaluations of water-related projects. PMID- 21540391 TI - Epidemiology of hookworm infection in Kintampo North Municipality, Ghana: patterns of malaria coinfection, anemia, and albendazole treatment failure. AB - A cross-sectional pilot study of hookworm infection was carried out among 292 subjects from 62 households in Kintampo North, Ghana. The overall prevalence of hookworm infection was 45%, peaking in those 11-20 years old (58.5%). In children, risk factors for hookworm infection included coinfection with malaria and increased serum immunoglobulin G reactivity to hookworm secretory antigens. Risk factors for infection in adults included poor nutritional status, not using a latrine, not wearing shoes, and occupation (farming). Although albendazole therapy was associated with an overall egg reduction rate of 82%, 37 subjects (39%) remained infected. Among those who failed therapy, treatment was not associated with a significant reduction in egg excretion, and nearly one-third had higher counts on repeat examination. These data confirm a high prevalence of low-intensity hookworm infection in central Ghana and its association with poor nutritional status. The high rate of albendazole failure raises concern about emerging resistance. PMID- 21540393 TI - Risk factors for delayed access to specialized care in French Guiana. AB - The variables influencing the interval between diagnosis and effective access to specialized care were studied in a cohort of 2,661 human immunodeficiency virus (HIV)-positive patients in French Guiana between 1992 and 2008. Patients with a subsequent follow-up interruption were significantly more likely to have a delayed first consultation after the HIV diagnosis. Ordinal logistic regression showed that younger persons, women, and French citizens were independently associated with greater delays between the HIV diagnosis and the first specialized consultation. However, persons with acquired immunodeficiency syndrome (AIDS) were less likely to have a delay between the HIV diagnosis and the first specialized consultation. Focusing on the link between the private sector and specialized health care may shorten delays and improve care and follow up. PMID- 21540394 TI - Influence of pregnancy on Trypanosoma cruzi parasitemia in chronically infected women in a rural Bolivian community. AB - To determine the role of pregnancy on Trypanosoma cruzi parasitemia, a matched cohort study was carried out in a rural Bolivian community comparing parasite rates in gravidae, puerperae, and non-pregnant infected women. A selection of 67 chronically infected women, who delivered between March 2004 and May 2005, were initially evaluated during the third trimester of pregnancy and again after delivery. They were matched for age, parity, and location with 104 seropositive non-pregnant women, who likewise had submitted blood for microscopic examination for T. cruzi parasites in June 2005. Seroreactive pregnant women had a higher rate of T. cruzi parasitemia (14.9%) than matched non-pregnant infected women (2.9%; P = 0.004). After delivery, parasitemia significantly decreased during puerperium (1.5%) compared with the period of pregnancy (14.9%; P = 0.03). This study showed an increase of parasite loads in maternal peripheral blood, during the third trimester, and a significant decline after delivery. PMID- 21540395 TI - Therapeutic efficacy and effects of artemether-lumefantrine and artesunate amodiaquine coformulated or copackaged on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in Southwest Nigeria. AB - The therapeutic efficacy and effects of artemether-lumefantrine (AL) and artesunate-amodiaquine co-formulated (AAcf) or co-packaged (AAcp) on malaria associated anemia (MAA) were evaluated in 285 children < 12 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive one of the three drug combinations. Fever and parasite clearance times were similar in all treatment groups. Mean drug-attributable fall in hematocrit (DAFH), defined as difference between hematocrit values pre- and 3 d post-initiation of treatment, was low (< 4.5%) and rates of recovery from MAA were similar with all treatments. Mean areas under curve (AUCs) of the plot of deficit in hematocrit levels from 30% versus time in anemic children were similar in all groups. All regimens were well tolerated. AL, AAcf and AAcp cleared fever and parasitemia rapidly and had similar rates of resolution of MAA after treatment in malarious Nigerian children. PMID- 21540396 TI - Evaluation of a comprehensive refresher training program in malaria microscopy covering four districts of Uganda. AB - Microscopy remains the gold standard for malaria diagnosis. However, quality microscopy services are severely lacking in most African countries. To improve capacity for malaria microscopy in Uganda, a 3-day refresher training program was conducted in four districts. Training impact was measured through a written examination and evaluation of the quality of blood-slide preparation and accuracy of field microscopy. A total of 184 of 192 (96%) identified laboratory personnel participated in the training. Average test scores improved from 41% to 75% (P < 0.001). A total of 1,079 and 1,190 routinely made thick blood smears were collected before and after the training, respectively. Sensitivity improved from 84% to 95% (P < 0.001), and specificity improved from 87% to 97% (P < 0.001). The proportion of well-prepared blood smears improved from 6% to 75% (P < 0.001). Supplemental training can have a significant impact on the knowledge of staff, accuracy of microscopy, and quality of blood-slide preparation. PMID- 21540397 TI - Plasmodium falciparum infection during suppressive prophylaxis with mefloquine does not induce an antibody response to merozoite surface protein-1(42). AB - A sensitive biomarker of malaria infection would obviate the need for placebo control arms in clinical trials of malaria prophylactic drugs. Antibodies to the 42-kDa fragment of merozoite surface protein-1 (MSP1(42)) have been identified as a potential marker of malaria exposure in individuals receiving prophylaxis with mefloquine. We conducted an open-label trial to determine the sensitivity of seroconversion to MSP1(42), defined as a fourfold rise in enzyme-linked immunosorbant assay (ELISA) titer, among 23 malaria naive volunteers receiving mefloquine prophylaxis and 6 controls after Plasmodium falciparum sporozoite challenge. All members of the control cohort but none of the mefloquine cohort developed patent parasitemia. Four of six controls but zero of the mefloquine cohort seroconverted to MSP1(42). We conclude that malaria infection during suppressive prophylaxis does not induce antibody response to the blood-stage antigen MSP1(42) in a malaria-naive study population. PMID- 21540398 TI - Continuing intense malaria transmission in northern Uganda. AB - Recent reports of reductions in malaria transmission in several African countries have resulted in optimism that malaria can be eliminated in parts of Africa where it is currently endemic. It is not known whether these trends are global or whether they are also present in areas where political instability has hindered effective malaria control. We determined malaria parasite carriage and age dependent antibody responses to Plasmodium falciparum antigens in cross-sectional surveys in Apac, northern Uganda that was affected by political unrest. Under five parasite prevalence was 55.8% (115/206) by microscopy and 71.9% (41/57) by polymerase chain reaction. Plasmodium ovale alone, or as a co-infection, was detected in 8.6% (12/139) and Plasmodium malariae in 4.3% (6/139) of the infections. Age seroprevalence curves gave no indication of recent changes in malaria transmission intensity. Malaria control remains a tremendous challenge in areas that have not benefited from large-scale interventions, illustrated here by the district of Apac. PMID- 21540399 TI - Toxoplasmic encephalitis in an AIDS cohort at Puerto Rico before and after highly active antiretroviral therapy (HAART). AB - Highly active antiretroviral therapy (HAART) significantly reduced the toxoplasmic encephalitis (TE) incidence in acquired immunodeficiency syndrome (AIDS) patients. The TE incidence and mortality were evaluated in an AIDS cohort followed in Puerto Rico before, during, and after HAART implementation in the Island. Of the 2,431 AIDS studied patients 10.9% had TE diagnosis, with an incidence density that decreased from 5.9/100 person-years to 1.1/100 person years after HAART. Cox proportional hazard analysis showed substantial mortality reduction among TE cases who received HAART. No mortality reduction was seen in those cases who received TE prophylaxis. Although this study shows a TE incidence and mortality reduction in the AIDS cohort after HAART, the incidence was higher than those reported in the United States AIDS patients. Poor TE prophylaxis compliance might explain the lack of impact of this intervention. Strengthening the diagnostic and opportune TE diagnosis and prompt initiation of HAART in susceptible patients is important to control this opportunistic infection. PMID- 21540400 TI - Painting a moving picture: large-scale proteomics efforts and their potential for changing patient care. PMID- 21540402 TI - Comment: worsening heart failure in the setting of dronedarone initiation. PMID- 21540403 TI - Pancreatic enzyme products: digesting the changes. AB - OBJECTIVE: To review the pharmacology, dosage regimens, efficacy, and safety of currently marketed pancreatic enzyme products (PEPs). DATA SOURCES: Studies were identified by PubMed (1966-January 2011), clinicaltrials.gov, fda.gov, and International Pharmaceutical Abstracts. Search terms included pancreatic enzyme, lipase, Creon, Zenpep, Pancreaze, and exocrine pancreatic insufficiency (EPI). STUDY SELECTION AND DATA EXTRACTION: All human studies evaluating the efficacy of currently approved or potential PEPs were reviewed. DATA SYNTHESIS: PEPs are composed of porcine lipase, amylase, and protease and are used in patients with EPI secondary to cystic fibrosis, chronic pancreatitis, and pancreatectomy. In 1938, PEPs were exempted from the Food, Drug, and Cosmetic Act of 1938 and never underwent a formal Food and Drug Administration (FDA) review process. In response to reports of treatment failures during product interchange, the FDA conducted a review of available PEP products. This review found a large variability of response between the unapproved PEP products, which resulted in the FDA requiring approval of all PEP products by April 2010. The 3 delayed-release, enteric-coated PEPs currently approved by the FDA (Creon, Zenpep, and Pancreaze) have demonstrated efficacy and safety in EPI secondary to cystic fibrosis. Creon has also demonstrated safety and efficacy in EPI secondary to chronic pancreatitis and pancreatectomy. Cost difference between the 3 products is minimal. Treatment related adverse events in clinical studies for all PEPs were less than or similar to those with placebo. CONCLUSIONS: At this time, Creon is an appropriate first line agent, as it has been approved for chronic pancreatitis, pancreatectomy, and cystic fibrosis. PMID- 21540404 TI - Current treatment strategies for clozapine-induced sialorrhea. AB - OBJECTIVE: To provide an understanding of the underlying pathophysiology and current treatment options for clozapine-induced sialorrhea. DATA SOURCES: Literature was retrieved through MEDLINE (1977-February 2011) using the key search terms clozapine, sialorrhea, hypersalivation, drooling, and treatment. In addition, reference citations from identified publications were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data source were evaluated and included in the review. DATA SYNTHESIS: Sialorrhea is a common and disabling adverse effect of clozapine use. Current treatment options include topical and oral antimuscarinic medications and alpha adrenergic agents. New areas of investigation include glycopyrrolate, botulinum toxin, and substitute benzamide derivatives. Thirteen clinical trials (2 retrospective, 5 open-label, 6 double-blind) and 13 case reports were reviewed. Overall, there are weak data on use of antimuscarinic agents, consisting mostly of small open-label or retrospective studies. Glycopyrrolate, however, demonstrated significant reduction of hypersalivation in a randomized controlled trial. Medications with activity at alpha-adrenergic receptors have shown positive results in case reports, retrospective evaluations, and an open-label trial, but have not been investigated in a double-blind, controlled fashion. Botulinum toxin also significantly improved sialorrhea in both a case report and double-blind study, although the trial included hypersalivation from other etiologies in addition to clozapine. Substitute benzamide derivatives have demonstrated significant improvements in randomized controlled trials; however, they are not available in the US. Overall, few treatment strategies have been evaluated in controlled settings, warranting further randomized controlled trials to identify more effective treatment options. CONCLUSIONS: Current pharmacologic treatment options for clozapine-induced sialorrhea are limited in number and efficacy. Although few randomized controlled trials have been conducted, this review identifies potential treatment alternatives for this common and sometimes severe adverse effect. PMID- 21540405 TI - Extended-infusion eptifibatide to prevent stent thrombosis in a patient undergoing orthopedic surgery. AB - OBJECTIVE: To report the use of extended-infusion eptifibatide in a patient who had undergone placement of a drug-eluting stent and required repeat intervention of a hip fracture following mechanical failure. CASE SUMMARY: An 82-year-old female with an extensive history of coronary disease who had undergone placement of a drug-eluting stent was admitted following continued problems with her surgically repaired right hip. Radiographic imaging of the area revealed mechanical failure of the surgically repaired hip, requiring intervention. Clopidogrel and aspirin therapy was discontinued and intravenous eptifibatide 1 MUg/kg/min was initiated prior to surgery; the drugs were then discontinued 4 hours before the procedure. During this admission, the patient received a total of 155 hours of eptifibatide to prevent acute coronary stent thrombosis while awaiting surgical intervention. Postoperatively, the patient experienced anemia and severe thrombocytopenia and required 11 units of packed red blood cells, but displayed no signs of stent thrombosis. DISCUSSION: Use of eptifibatide in this patient minimized the potential risk for stent thrombosis by reducing the interruption in antiplatelet therapy from 5 days, as is recommended for use with clopidogrel, to 4 hours. While this patient required several transfusions and experienced severe thrombocytopenia postoperatively, she recovered and had no cardiac-related problems. It is unclear whether the use of eptifibatide contributed to these complications, given the chronology of events. CONCLUSIONS: Extended-infusion eptifibatide appears to be an option for prevention of stent thrombosis in patients who require an interruption in antiplatelet therapy and are scheduled to undergo major orthopedic procedures. Careful consideration should be given regarding the risks and benefits of extended infusions of eptifibatide, as the potential for significant hemorrhage is a concern. Further research is warranted in this area. PMID- 21540406 TI - Dabigatran etexilate: a novel oral thrombin inhibitor for thromboembolic disease. AB - OBJECTIVE: To evaluate the efficacy and safety of dabigatran etexilate, approved by the Food and Drug Administration (FDA) in October 2010 for the prevention of cardioembolic stroke in patients with atrial fibrillation; potential off-label use is treatment and prevention of venous thromboembolic disorders. DATA SOURCES: Literature was accessed through MEDLINE (1977-April 2011) and International Pharmaceutical Abstracts (1977-April 2011) using the terms dabigatran, dabigatran etexilate, BIBR 1048, direct thrombin inhibitor, anticoagulant, and thromboembolism. In addition, US government Web sites, including clinicaltrials.gov and fda.gov, were reviewed for pertinent information. Lastly, reference citations from publications identified in the initial search were reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. For the evaluation of clinical efficacy and safety, only Phase 2 and 3 studies are included in this review. DATA SYNTHESIS: In 6 published Phase 3 trials to date, dabigatran has exhibited a similar efficacy and safety profile to that of comparator drugs, including dose adjusted warfarin and enoxaparin, at various dosages. In the largest of these trials, RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), dabigatran was at least as effective as dose-adjusted warfarin in reducing stroke or systemic embolism. Overall bleeding risks were similar; however, dabigatran may be associated with a lower incidence of intracranial bleeding and hemorrhagic stroke but a higher incidence of gastrointestinal bleeding. Although dabigatran is not approved for venous thromboembolism (VTE) prevention or treatment, results of the RE-MODEL and RE-NOVATE trials suggest similar efficacy to once-daily dosing of enoxaparin 40 mg but inferior efficacy to the FDA-approved twice-daily dosing of enoxaparin 30 mg in the RE-MOBILIZE trial. CONCLUSIONS: Dabigatran is an effective and safe alternative to oral vitamin K antagonists for stroke prevention in patients with nonvalvular atrial fibrillation, with fewer drug interactions and monitoring requirements. Additionally, dabigatran may be a viable alternative to enoxaparin in VTE prevention and warfarin in VTE treatment, although current trial data are limited. PMID- 21540407 TI - Use of inhaled epoprostenol in patients with H1N1 influenza-associated acute respiratory distress syndrome: a case series. AB - OBJECTIVE: To report a series of patients with confirmed novel influenza A (H1N1) and refractory hypoxemia secondary to acute respiratory distress syndrome (ARDS) treated with inhaled epoprostenol. CASE SUMMARY: Four patients admitted to our institution with confirmed H1N1 and refractory hypoxemia were treated with inhaled epoprostenol as potential salvage therapy. All patients were treated initially with antimicrobial agents, followed by oral oseltamivir at the time of suspicion or confirmation of H1N1. None of the patients received intravenous peramivir or extracorporeal membrane oxygenation. Clinically significant improvement in oxygenation was seen in only 1 of the patients receiving inhaled epoprostenol. Mortality was significant, with only 1 patient discharged from the hospital. DISCUSSION: Use of inhaled epoprostenol for the treatment of hypoxemia secondary to ARDS has been reported, with conflicting results. Deliveries via the inhalational route compared to the intravenous route theoretically preferentially vasodilate well-ventilated areas of the pulmonary vasculature, improving arterial oxygenation and pulmonary gas exchange. Increase in the ratio of arterial oxygen tension to fraction of inhaled oxygen is greatest upon initiation of inhaled epoprostenol, but this benefit has not been conclusively demonstrated to persist throughout therapy. Serious H1N1 presents a unique challenge for clinicians, often requiring the use of salvage therapies to treat critically ill patients. CONCLUSIONS: Given the variable response to treatment, it remains unclear whether inhaled epoprostenol is beneficial in H1N1-associated ARDS. Identification of patients for whom this therapy is most appropriate remains a clinical challenge. PMID- 21540408 TI - Divergence time estimation using fossils as terminal taxa and the origins of Lissamphibia. AB - Were molecular data available for extinct taxa, questions regarding the origins of many groups could be settled in short order. As this is not the case, various strategies have been proposed to combine paleontological and neontological data sets. The use of fossil dates as node age calibrations for divergence time estimation from molecular phylogenies is commonplace. In addition, simulations suggest that the addition of morphological data from extinct taxa may improve phylogenetic estimation when combined with molecular data for extant species, and some studies have merged morphological and molecular data to estimate combined evidence phylogenies containing both extinct and extant taxa. However, few, if any, studies have attempted to estimate divergence times using phylogenies containing both fossil and living taxa sampled for both molecular and morphological data. Here, I infer both the phylogeny and the time of origin for Lissamphibia and a number of stem tetrapods using Bayesian methods based on a data set containing morphological data for extinct taxa, molecular data for extant taxa, and molecular and morphological data for a subset of extant taxa. The results suggest that Lissamphibia is monophyletic, nested within Lepospondyli, and originated in the late Carboniferous at the earliest. This research illustrates potential pitfalls for the use of fossils as post hoc age constraints on internal nodes and highlights the importance of explicit phylogenetic analysis of extinct taxa. These results suggest that the application of fossils as minima or maxima on molecular phylogenies should be supplemented or supplanted by combined evidence analyses whenever possible. PMID- 21540410 TI - Navigating the challenges of in-flight emergencies. PMID- 21540409 TI - Survey of branch support methods demonstrates accuracy, power, and robustness of fast likelihood-based approximation schemes. AB - Phylogenetic inference and evaluating support for inferred relationships is at the core of many studies testing evolutionary hypotheses. Despite the popularity of nonparametric bootstrap frequencies and Bayesian posterior probabilities, the interpretation of these measures of tree branch support remains a source of discussion. Furthermore, both methods are computationally expensive and become prohibitive for large data sets. Recent fast approximate likelihood-based measures of branch supports (approximate likelihood ratio test [aLRT] and Shimodaira-Hasegawa [SH]-aLRT) provide a compelling alternative to these slower conventional methods, offering not only speed advantages but also excellent levels of accuracy and power. Here we propose an additional method: a Bayesian like transformation of aLRT (aBayes). Considering both probabilistic and frequentist frameworks, we compare the performance of the three fast likelihood based methods with the standard bootstrap (SBS), the Bayesian approach, and the recently introduced rapid bootstrap. Our simulations and real data analyses show that with moderate model violations, all tests are sufficiently accurate, but aLRT and aBayes offer the highest statistical power and are very fast. With severe model violations aLRT, aBayes and Bayesian posteriors can produce elevated false-positive rates. With data sets for which such violation can be detected, we recommend using SH-aLRT, the nonparametric version of aLRT based on a procedure similar to the Shimodaira-Hasegawa tree selection. In general, the SBS seems to be excessively conservative and is much slower than our approximate likelihood based methods. PMID- 21540411 TI - The cover. The young woman of Albano (L'Albanaise). PMID- 21540412 TI - A piece of my mind. It's never too late. PMID- 21540413 TI - FDA considers data on potential risks of anesthesia use in infants, children. PMID- 21540414 TI - Updated guidelines target reductions in catheter-related bloodstream infections. PMID- 21540415 TI - Treatment for lupus, first in 50 years, offers modest benefits, hope to patients. PMID- 21540416 TI - Quality improvement interventions in intensive care units. PMID- 21540417 TI - Thrombocytopenia and sarcoidosis. PMID- 21540418 TI - Hospitalist efforts and improving discharge planning. PMID- 21540419 TI - Centers for Disease Control and Prevention 2006 human immunodeficiency virus testing recommendations and state testing laws. PMID- 21540420 TI - Coronary revascularization trends in the United States, 2001-2008. AB - CONTEXT: Coronary revascularization is among the most common hospital-based major interventional procedures performed in the United States. It is uncertain how new revascularization technologies, new clinical evidence from trials, and updated clinical guidelines have influenced the volume and distribution of coronary revascularizations over the past decade. OBJECTIVE: To examine national time trends in the rates and types of coronary revascularizations. DESIGN, SETTING, AND PATIENTS: A serial cross-sectional study with time trends of patients undergoing coronary artery bypass graft (CABG) surgery or percutaneous coronary interventions (PCIs) between 2001 and 2008 at US hospitals in the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, which reports inpatient coronary revascularizations. These data were supplemented by Medicare outpatient hospital claims. MAIN OUTCOME MEASURES: Annual procedure rates of coronary revascularizations, CABG surgery, and PCI. RESULTS: A 15% decrease (P < .001) in the annual rate of coronary revascularizations was observed from 2001-2002 to 2007-2008. The annual CABG surgery rate decreased steadily from 1742 (95% confidence interval [CI], 1663-1825) CABG surgeries per million adults per year in 2001-2002 to 1081 (95% CI, 1032-1133) CABG surgeries per million adults per year in 2007-2008 (P < .001), but PCI rates did not significantly change (3827 [95% CI, 3578-4092] PCI per million adults per year in 2001-2002 vs 3667 [95% CI, 3429-3922] PCI per million adults per year in 2007-2008, P = .74). Between 2001 and 2008, the number of hospitals in the Nationwide Inpatient Sample providing CABG surgery increased by 12% (212 in 2001 vs 241 in 2008, P = .03), and the number of PCI hospitals increased by 26% (246 in 2001 vs 331 in 2008, P < .001). The median CABG surgery caseload per hospital decreased by 28% (median [interquartile range], 253 [161-458] in 2001 vs 183 [98-292] in 2008; P < .001) and the number of CABG surgery hospitals providing fewer than 100 CABG surgeries per year increased from 23 (11%) in 2001 to 62 (26%) in 2008 (P < .001). CONCLUSIONS: In US hospitals between 2001 and 2008, a substantial decrease in CABG surgery utilization rates was observed, but PCI utilization rates remained unchanged. PMID- 21540421 TI - Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. AB - CONTEXT: Extrapolations from observational studies and short-term intervention trials suggest that population-wide moderation of salt intake might reduce cardiovascular events. OBJECTIVE: To assess whether 24-hour urinary sodium excretion predicts blood pressure (BP) and health outcomes. DESIGN, SETTING, AND PARTICIPANTS: Prospective population study, involving 3681 participants without cardiovascular disease (CVD) who are members of families that were randomly enrolled in the Flemish Study on Genes, Environment, and Health Outcomes (1985 2004) or in the European Project on Genes in Hypertension (1999-2001). Of 3681 participants without CVD, 2096 were normotensive at baseline and 1499 had BP and sodium excretion measured at baseline and last follow-up (2005-2008). MAIN OUTCOME MEASURES: Incidence of mortality and morbidity and association between changes in BP and sodium excretion. Multivariable-adjusted hazard ratios (HRs) express the risk in tertiles of sodium excretion relative to average risk in the whole study population. RESULTS: Among 3681 participants followed up for a median 7.9 years, CVD deaths decreased across increasing tertiles of 24-hour sodium excretion, from 50 deaths in the low (mean, 107 mmol), 24 in the medium (mean, 168 mmol), and 10 in the high excretion group (mean, 260 mmol; P < .001), resulting in respective death rates of 4.1% (95% confidence interval [CI], 3.5% 4.7%), 1.9% (95% CI, 1.5%-2.3%), and 0.8% (95% CI, 0.5%-1.1%). In multivariable adjusted analyses, this inverse association retained significance (P = .02): the HR in the low tertile was 1.56 (95% CI, 1.02-2.36; P = .04). Baseline sodium excretion predicted neither total mortality (P = .10) nor fatal combined with nonfatal CVD events (P = .55). Among 2096 participants followed up for 6.5 years, the risk of hypertension did not increase across increasing tertiles (P = .93). Incident hypertension was 187 (27.0%; HR, 1.00; 95% CI, 0.87-1.16) in the low, 190 (26.6%; HR, 1.02; 95% CI, 0.89-1.16) in the medium, and 175 (25.4%; HR, 0.98; 95% CI, 0.86-1.12) in the high sodium excretion group. In 1499 participants followed up for 6.1 years, systolic blood pressure increased by 0.37 mm Hg per year (P < .001), whereas sodium excretion did not change (-0.45 mmol per year, P = .15). However, in multivariable-adjusted analyses, a 100-mmol increase in sodium excretion was associated with 1.71 mm Hg increase in systolic blood pressure (P.<001) but no change in diastolic BP. CONCLUSIONS: In this population based cohort, systolic blood pressure, but not diastolic pressure, changes over time aligned with change in sodium excretion, but this association did not translate into a higher risk of hypertension or CVD complications. Lower sodium excretion was associated with higher CVD mortality. PMID- 21540422 TI - Availability of comparative efficacy data at the time of drug approval in the United States. AB - CONTEXT: Comparative effectiveness is taking on an increasingly important role in US health care, yet little is known about the availability of comparative efficacy data for drugs at the time of their approval in the United States. OBJECTIVE: To quantify the availability of comparative efficacy data for new molecular entities (NMEs) approved in the United States. DATA SOURCES: Approval packages publicly available through the online database of drug products approved by the US Food and Drug Administration (FDA). STUDY SELECTION: Identification of efficacy studies that supported approval of each NME approved by FDA between 2000 and 2010. DATA EXTRACTION: We determined whether eligible studies were head-to head active controlled trials and whether the results of such studies were available in the approval packages. We recorded the approved indication, whether the NME was an orphan product, whether the NME had undergone priority review, and whether the control group was a specific active comparator or standard care. RESULTS: Of 197 NMEs identified that met eligibility criteria, 100 (51% [95% confidence interval {CI}, 44%-58%]) met criteria for having comparative efficacy data available at the time of market authorization. After excluding NMEs designated as orphan products (n = 37) and those approved for indications for which no alternative treatments existed (n = 17), this proportion increased to 70% (95% CI, 62%-77%). The proportions of NMEs with available comparative efficacy data varied widely by therapeutic area, from 33% (95% CI, 9%-67%) for hormones and contraceptives to 89% (95% CI, 56%-99%) for diabetes medications. CONCLUSION: Publicly available FDA approval packages contain comparative efficacy data for about half of NMEs recently approved in the United States and for more than two-thirds of NMEs for which alternative treatment options exist. We did not investigate the extent to which available comparative efficacy information is useful for clinical guidance. PMID- 21540423 TI - Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. AB - CONTEXT: Regular exercise improves glucose control in diabetes, but the association of different exercise training interventions on glucose control is unclear. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized controlled clinical trials (RCTs) assessing associations of structured exercise training regimens (aerobic, resistance, or both) and physical activity advice with or without dietary cointervention on change in hemoglobin A(1c) (HbA(1c)) in type 2 diabetes patients. DATA SOURCES: MEDLINE, Cochrane-CENTRAL, EMBASE, ClinicalTrials.gov, LILACS, and SPORTDiscus databases were searched from January 1980 through February 2011. STUDY SELECTION: RCTs of at least 12 weeks' duration that evaluated the ability of structured exercise training or physical activity advice to lower HbA(1c) levels as compared with a control group in patients with type 2 diabetes. DATA EXTRACTION: Two independent reviewers extracted data and assessed quality of the included studies. DATA SYNTHESIS: Of 4191 articles retrieved, 47 RCTs (8538 patients) were included. Pooled mean differences in HbA(1c) levels between intervention and control groups were calculated using a random-effects model. Overall, structured exercise training (23 studies) was associated with a decline in HbA(1c) level (-0.67%; 95% confidence interval [CI], -0.84% to -0.49%; I(2), 91.3%) compared with control participants. In addition, structured aerobic exercise (-0.73%; 95% CI, -1.06% to -0.40%; I(2), 92.8%), structured resistance training (-0.57%; 95% CI, -1.14% to 0.01%; I(2), 92.5%), and both combined (-0.51%; 95% CI, -0.79% to -0.23%; I(2), 67.5%) were each associated with declines in HbA(1C) levels compared with control participants. Structured exercise durations of more than 150 minutes per week were associated with HbA(1c) reductions of 0.89%, while structured exercise durations of 150 minutes or less per week were associated with HbA(1C) reductions of 0.36%. Overall, interventions of physical activity advice (24 studies) were associated with lower HbA(1c) levels (-0.43%; 95% CI, -0.59% to -0.28%; I(2), 62.9%) compared with control participants. Combined physical activity advice and dietary advice was associated with decreased HbA(1c) (-0.58%; 95% CI, -0.74% to 0.43%; I(2), 57.5%) as compared with control participants. Physical activity advice alone was not associated with HbA(1c) changes. CONCLUSIONS: Structured exercise training that consists of aerobic exercise, resistance training, or both combined is associated with HbA(1c) reduction in patients with type 2 diabetes. Structured exercise training of more than 150 minutes per week is associated with greater HbA(1c) declines than that of 150 minutes or less per week. Physical activity advice is associated with lower HbA(1c), but only when combined with dietary advice. PMID- 21540424 TI - Patient-physician communication: it's about time. PMID- 21540425 TI - Would accommodating some conscientious objections by physicians promote quality in medical care? PMID- 21540426 TI - What next for QALYs? PMID- 21540427 TI - Consideration of insurance reimbursement for physical activity and exercise programs for patients with diabetes. PMID- 21540428 TI - John Harvey Kellogg and the pursuit of wellness. PMID- 21540429 TI - JAMA patient page. Rheumatoid arthritis. PMID- 21540430 TI - A pregnancy and postpartum lifestyle intervention in women with gestational diabetes mellitus reduces diabetes risk factors: a feasibility randomized control trial. AB - OBJECTIVE: To pilot, among women with gestational diabetes mellitus (GDM), the feasibility of a prenatal/postpartum intervention to modify diet and physical activity similar to the Diabetes Prevention Program. The intervention was delivered by telephone, and support for breastfeeding was addressed. RESEARCH DESIGN AND METHODS: The goal was to help women return to their prepregnancy weight, if it was normal, or achieve a 5% reduction from prepregnancy weight if overweight. Eligible participants were identified shortly after a GDM diagnosis; 83.8% consented to be randomly assigned to intervention or usual medical care (96 and 101 women, respectively). The retention was 85.2% at 12 months postpartum. RESULTS: The proportion of women who reached the postpartum weight goal was higher, although not statistically significant, in the intervention condition than among usual care (37.5 vs. 21.4%, absolute difference 16.1%, P=0.07). The intervention was more effective among women who did not exceed the recommended gestational weight gain (difference in the proportion of women meeting the weight goals: 22.5%, P=0.04). The intervention condition decreased dietary fat intake more than the usual care (condition difference in the mean change in percent of calories from fat: -3.6%, P=0.002) and increased breastfeeding, although not significantly (condition difference in proportion: 15.0%, P=0.09). No differences in postpartum physical activity were observed between conditions. CONCLUSIONS: This study suggests that a lifestyle intervention that starts during pregnancy and continues postpartum is feasible and may prevent pregnancy weight retention and help overweight women lose weight. Strategies to help postpartum women overcome barriers to increasing physical activity are needed. PMID- 21540431 TI - Performance of the chronic kidney disease epidemiology collaboration equation to estimate glomerular filtration rate in diabetic patients. AB - OBJECTIVE: The best method to estimate glomerular filtration rate (GFR) in diabetic patients is still largely debated. We compared the performance of creatinine-based formulas in a European diabetic population. RESEARCH DESIGN AND METHODS: We compared the performance of Cockcroft and Gault, simplified Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equations in 246 diabetic patients by calculating the mean bias and the interquartile range (IQR) of the bias, 10% (P10) and 30% (P30) accuracies, and Bland-Altman plots. GFR was measured by inulin clearance. RESULTS: For the whole population, the IQR was slightly lower for CKD-EPI, but the mean bias was lower and P10 and P30 were higher for MDRD. Similar results were observed in specific subgroups, including patients with mild renal insufficiency, obese patients, or type 2 diabetic patients. CONCLUSIONS: In our population, the CKD-EPI formula does not exhibit better performance than the simplified MDRD formula for estimating GFR. PMID- 21540432 TI - Time-dependent impact of diabetes on mortality in patients after major lower extremity amputation: survival in a population-based 5-year cohort in Germany. AB - OBJECTIVE: To estimate the impact of diabetes on mortality in patients after first major lower extremity amputation (LEA). RESEARCH DESIGN AND METHODS: Using claims data of a nationwide statutory health insurance, we assessed all deaths in a cohort of all 444 patients with a first major LEA since 2005 (71.8% male; mean age 69.1 years; 58.3% diabetic; 43% with amputation above the knee) up to 2009. Using Cox regression, we estimated the time-dependent hazard ratios to compare patients with and without diabetes. RESULTS: The cumulative 5-year mortality was 68% in diabetic and 59% in nondiabetic individuals. In the first course, mortality was lower in diabetic compared with nondiabetic patients. Later, the diabetes risk increased yielding crossed survival curves after 2 to 3 years (time dependency of diabetes; P = 0.003). Age- and sex-adjusted hazard ratios for diabetes were as follows: 0-30 days: 0.50 [95% CI 0.31-0.84]; 31-60 days: 0.60 [0.25-1.41]; 61 days to 6 months: 0.75 [0.38-1.48]; >6-12 months: 1.27 [0.63 2.53]; >12-24 months: 1.65 [0.88-3.08]; >24-36 months: 2.02 [0.80-5.09]; and >36 60 months: 1.91 [0.70-5.21]. The pattern was similar in both sexes. In the full model, significant risk factors for mortality were age (1.05; 1.03-1.06), amputation above the knee (1.50; 1.16-1.94), and quartile category 3 or 4 of the number of prescribed medications (1.64; 1.12-2.40 and 1.76; 1.20-2.59). Further adjustment for comorbidity did not alter the results. CONCLUSIONS: In this population-based study, we found a time-dependent mortality risk of diabetes following first major LEA, which may be in part a result of a healthier lifestyle in diabetic patients or the access to specific treatment structures in diabetic individuals. PMID- 21540433 TI - Phloem-specific expression of Yang cycle genes and identification of novel Yang cycle enzymes in Plantago and Arabidopsis. AB - The 5-methylthioadenosine (MTA) or Yang cycle is a set of reactions that recycle MTA to Met. In plants, MTA is a byproduct of polyamine, ethylene, and nicotianamine biosynthesis. Vascular transcriptome analyses revealed phloem specific expression of the Yang cycle gene 5-METHYLTHIORIBOSE KINASE1 (MTK1) in Plantago major and Arabidopsis thaliana. As Arabidopsis has only a single MTK gene, we hypothesized that the expression of other Yang cycle genes might also be vascular specific. Reporter gene studies and quantitative analyses of mRNA levels for all Yang cycle genes confirmed this hypothesis for Arabidopsis and Plantago. This includes the Yang cycle genes 5-METHYLTHIORIBOSE-1-PHOSPHATE ISOMERASE1 and DEHYDRATASE-ENOLASE-PHOSPHATASE-COMPLEX1. We show that these two enzymes are sufficient for the conversion of methylthioribose-1-phosphate to 1,2-dihydroxy-3 keto-5-methylthiopentene. In bacteria, fungi, and animals, the same conversion is catalyzed in three to four separate enzymatic steps. Furthermore, comparative analyses of vascular and nonvascular metabolites identified Met, S-adenosyl Met, and MTA preferentially or almost exclusively in the vascular tissue. Our data represent a comprehensive characterization of the Yang cycle in higher plants and demonstrate that the Yang cycle works primarily in the vasculature. Finally, expression analyses of polyamine biosynthetic genes suggest that the Yang cycle in leaves recycles MTA derived primarily from polyamine biosynthesis. PMID- 21540434 TI - BARREN STALK FASTIGIATE1 is an AT-hook protein required for the formation of maize ears. AB - Ears are the seed-bearing inflorescences of maize (Zea mays) plants and represent a crucial component of maize yield. The first step in the formation of ears is the initiation of axillary meristems in the axils of developing leaves. In the classic maize mutant barren stalk fastigiate1 (baf1), first discovered in the 1950s, ears either do not form or, if they do, are partially fused to the main stalk. We positionally cloned Baf1 and found that it encodes a transcriptional regulator containing an AT-hook DNA binding motif. Single coorthologs of Baf1 are found in syntenic regions of brachypodium (Brachypodium distachyon), rice (Oryza sativa), and sorghum (Sorghum bicolor), suggesting that the gene is likely present in all cereal species. Protein-protein interaction assays suggest that BAF1 is capable of forming homodimers and heterodimers with other members of the AT-hook family. Another transcriptional regulator required for ear initiation is the basic helix-loop-helix protein BARREN STALK1 (BA1). Genetic and expression analyses suggest that Baf1 is required to reach a threshold level of Ba1 expression for the initiation of maize ears. We propose that Baf1 functions in the demarcation of a boundary region essential for the specification of a stem cell niche. PMID- 21540435 TI - Identification of an Arabidopsis plasma membrane-located ATP transporter important for anther development. AB - ATP acts as an extracellular signal molecule in plants. However, the nature of the mechanisms that export this compound into the apoplast are under debate. We identified the protein PM-ANT1 as a candidate transporter able to mediate ATP export. PM-ANT1 joins the mitochondrial carrier family, lacks an N-terminal amino acid extension required for organelle localization, and locates to the plasma membrane. Recombinant PM-ANT1 transports ATP, and the gene is substantially expressed in mature pollen grains. Artificial microRNA (amiRNA) mutants show reduced silique length and less seeds per silique but increased seed weight associated with unchanged pollen viability. Anthers from amiRNA mutants exhibited a normal early development, but stomium breakage is inhibited, leading to impaired anther dehiscence. This results in reduced self-pollination and thus decreased fertilization efficiency. amiRNA pollen grains showed increased intracellular ATP levels but decreased extracellular ATP levels. The latter effects are in line with transport properties of recombinant PM-ANT1, supporting in planta that functional PM-ANT1 resides in the plasma membrane and concur with the PM-ANT1 expression pattern. We assume that PM-ANT1 contributes to ATP export during pollen maturation. ATP export may serve as an extracellular signal required for anther dehiscence and is a novel factor critical for pollination and autogamy. PMID- 21540436 TI - Two-phase resolution of polyploidy in the Arabidopsis metabolic network gives rise to relative and absolute dosage constraints. AB - The abundance of detected ancient polyploids in extant genomes raises questions regarding evolution after whole-genome duplication (WGD). For instance, what rules govern the preservation or loss of the duplicated genes created by WGD? We explore this question by contrasting two possible preservation forces: selection on relative and absolute gene dosages. Constraints on the relative dosages of central network genes represent an important force for maintaining duplicates (the dosage balance hypothesis). However, preservation may also result from selection on the absolute abundance of certain gene products. The metabolic network of the model plant Arabidopsis thaliana is a powerful system for comparing these hypotheses. We analyzed the surviving WGD-produced duplicate genes in this network, finding evidence that the surviving duplicates from the most recent WGD (WGD-alpha) are clustered in the network, as predicted by the dosage balance hypothesis. A flux balance analysis suggests an association between the survival of duplicates from a more ancient WGD (WGD-beta) and reactions with high metabolic flux. We argue for an interplay of relative and absolute dosage constraints, such that the relative constraints imposed by the recent WGD are still being resolved by evolution, while they have been essentially fully resolved for the ancient event. PMID- 21540437 TI - Extending SILAC to proteomics of plant cell lines. AB - Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) is a widespread method for metabolic labeling of cells and tissues in quantitative proteomics; however, incomplete incorporation of the label has so far restricted its wider use in plants. Here, we argue that differential labeling by two different versions of the labeled amino acids renders SILAC fully applicable to dark-grown plant cell lines. By comparing Arabidopsis thaliana cell cultures labeled with two versions of heavy Lys (Lys-4 and Lys-8), we show that this simple modification of the SILAC protocol enables similar quantitation accuracy, precision, and reproducibility as conventional SILAC in animal cells. PMID- 21540439 TI - Estimation of total incremental health care costs in patients with atrial fibrillation in the United States. AB - BACKGROUND: Detailed information on the cost burden of atrial fibrillation (AF) is limited. To provide an up-to-date estimate of the national cost of AF, we conducted a retrospective, observational cohort study using administrative claims from the MarketScan Commercial and Medicare Supplemental research data bases, 2004 to 2006. METHODS AND RESULTS: Patients aged >=20 years with >=1 inpatient or >=2 outpatient AF diagnoses in 2005 (first diagnosis=index) and >=12 months' enrollment before and after index were selected. AF patients were propensity score-matched (1:1) with non-AF control subjects. Medical costs (2008 US$), including AF costs, other cardiovascular, and noncardiovascular costs, were examined over 1 year after index. National incremental costs of AF were based on age-/sex-specific AF prevalence projections for 2010. In total, 89 066 AF patients were matched to non-AF control subjects. Over 1 year, 37.5% of AF versus 17.5% of control subjects were hospitalized and 2.1% versus 0.1% died during hospitalization. For AF versus control subjects, mean annual inpatient costs per patient were $7841 versus $2622 (incremental cost, $5218), outpatient medical costs were $9225 versus $5629 ($3596), and outpatient pharmacy costs were $3605 versus $3714 (-$109) (all P<0.001). The total incremental cost of AF was $8705 per patient. The national incremental cost of AF was $26.0 billion (AF, $6.0 billion; other cardiovascular, $9.9 billion; noncardiovascular, $10.1 billion). Cardiovascular costs were based on claims with a primary disease diagnosis and may be underestimates. CONCLUSIONS: On the basis of current US age- and sex specific prevalence data, the national incremental AF cost is estimated to range from $6.0 to $26.0 billion. PMID- 21540440 TI - Atrioventricular conduction disturbance characterization in transcatheter aortic valve implantation with the CoreValve prosthesis. AB - BACKGROUND: Atrioventricular (AV) block is one of the most frequent complications of CoreValve transcatheter aortic valve implantation (TAVI). The aim of this study was to analyze the effects of CoreValve implantation on AV conduction. METHODS AND RESULTS: Electrophysiological study was performed immediately before and after CoreValve implantation in 18 consecutive, permanent pacemaker-free patients. An electrode was placed on the His bundle during valve implantation, and data were continuously recorded during the procedure. With surface ECG, a median (first, third quartile) QRS width of 96 (84, 116) to 150 (121, 164) ms (P=0.001) and PR interval of 180 (159, 216) to 210 (190, 240) ms (P=0.008) were significantly prolonged, and QRS axis was left deviated 30 degrees (-32 degrees , 46 degrees ) to -20 degrees (-60 degrees , 2 degrees ) (P=0.005). With intracardiac electrograms, the AH (97 [70, 123] to 115 [96, 135] ms, P=0.021) and HV (52 [42, 55] to 60 [50, 70] ms, P=0.002) intervals were increased. At the end of the procedure, we observed significant ECG- or electrophysiological study persistent conduction disturbances in 14 (78%) patients. Five patients experienced transient changes (2 AV blocks and 3 left bundle branch blocks). CONCLUSIONS: CoreValve implantation worsens AV conduction in most patients, either transiently or permanently. This worsening is the result of direct damage either on the His bundle or on the AV node. PMID- 21540441 TI - Long-term outcome of percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: a Scandinavian multicenter study. AB - BACKGROUND: Single-center reports on percutaneous transluminal septal myocardial ablation (PTSMA) in patients with hypertrophic obstructive cardiomyopathy have shown considerable differences in outcome. METHODS AND RESULTS: We report the long-term outcome of 313 PTSMA procedures performed in 279 patients with hypertrophic obstructive cardiomyopathy aged 59+/-14 years from 1999 to 2010 in 4 Scandinavian centers. Sixty-nine percent of patients had >=1 comorbidity at baseline. The median (interquartile range) of left ventricular outflow tract gradient at rest was reduced from 58 mm Hg (34 to 89 mm Hg) at baseline to 12 mm Hg (8 to 24 mm Hg) at 1-year (P<0.001) and during Valsalva maneuver from 93 mm Hg (70 to 140 mm Hg) to 21 mm Hg (11 to 42 mm Hg) (P<0.001). The proportion of patients with syncope was reduced from 18% to 2% (P<0.001), and the proportion in New York Heart Association class III/IV was reduced from 94% to 21% (P<0.001). All treatment effects remained stable during the follow-up. New York Heart Association class III/IV at the most recent follow-up (2.9+/-2.6 years) was associated with diabetes mellitus (P=0.03), chronic obstructive pulmonary disease (P=0.02), and valve disease unrelated to hypertrophic cardiomyopathy (P<0.01). In hospital mortality was 0.3%. The 1-, 5- and 10-year survival rates were 97%, 87%, and 67%, respectively (P=0.06 versus an age- and sex-matched background population) in all patients and 99%, 94%, and 88%, respectively (P=0.12) in patients aged <60 years (48+/-9 years, n=141). Age (hazard ratio, 1.07; 95% CI, 1.03 to 1.1) was the only predictor of survival. CONCLUSIONS: In this multicenter study, the in-hospital mortality after PTSMA was low despite considerable comorbidities. The hemodynamic and symptomatic effects were sustained long term. The long-term symptomatic outcome was associated with baseline comorbidities. The 10-year survival rate was comparable to that in an age- and sex-matched background population, and age was the only predictor of survival. PMID- 21540442 TI - Local paclitaxel delivery for treatment of peripheral arterial disease. PMID- 21540443 TI - Tumor characteristics associated with mammographic detection of breast cancer in the Ontario breast screening program. AB - BACKGROUND: Few studies have compared the prognostic value of tumor characteristics by type of breast cancer diagnosed in the interval between mammographic screenings with screen-detected breast cancers. METHODS: We conducted a case-case study within the cohort of women (n = 431 480) in the Ontario Breast Screening Program who were aged 50 years and older and were screened between January 1, 1994, and December 31, 2002. Interval cancers, defined as breast cancers diagnosed within 24 months after a negative screening mammogram, were designated as true interval cancers (n = 288) or missed interval cancers (n = 87) if they were not identified at the time of screening but were identified in retrospect. Screen-detected breast cancers (n = 450) were selected to match interval cancers. Tumors were evaluated for stage, grade, mitotic index, histology, and expression of hormone receptors and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression. RESULTS: Both true and missed interval cancers were of higher stage and grade than matched screen-detected breast cancers. However, true interval cancers had a higher mitotic index (OR = 3.13, 95% CI = 1.81 to 5.42), a higher percentage of nonductal histology (OR = 1.94, 95% CI = 1.05 to 3.59), and were more likely to be both estrogen receptor-negative (OR = 2.09, 95% CI = 1.32 to 3.30) and progesterone receptor-negative (OR = 2.49, 95% CI = 1.68 to 3.70) compared with matched screen-detected tumors. CONCLUSIONS: In this study, interval cancers were of higher stage and grade compared with screen-detected cancers. True interval cancers were more likely to have additional adverse prognostic features of estrogen and progesterone receptor negativity and nonductal morphology. The findings suggest a need for more sensitive screening modalities to detect true interval breast cancers and different approaches for early detection of fast growing tumors. PMID- 21540444 TI - Hyperketonemia increases monocyte adhesion to endothelial cells and is mediated by LFA-1 expression in monocytes and ICAM-1 expression in endothelial cells. AB - Frequent episodes of hyperketonemia are associated with a higher incidence of vascular disease. The objective of this study was to examine the hypothesis that hyperketonemia increases monocyte-endothelial cell (EC) adhesion and the development of vascular disease in diabetes. Human U937 and THP-1 monocyte cell lines and human umbilical vein endothelial cells (HUVECs) were cultured with acetoacetate (AA) (0-10 mM) or beta-hydroxybutyrate (BHB) (0-10 mM) for 24 h prior to evaluating adhesion and adhesion molecule expression. The results demonstrate a significant (P < 0.01) increase in both U937 and THP-1 adhesion to HUVEC monolayers treated with 4 mM AA compared with control. Equal concentrations of BHB resulted in similar increases in monocyte-EC adhesion. Similarly, treatments of AA or BHB to isolated monocytes from human blood also show increases in adhesion to endothelial cells. intercellular adhesion molecule-1 (ICAM-1) was significantly increased on the surface of HUVECs and an increase in total protein expression with AA treatment compared with control. The expression level of lymphocyte function-associated antigen-1 (LFA-1) was increased in monocytes treated with AA, and LFA-1 affinity was altered from low to high affinity following treatment with both AA and BHB. Monocyte adhesion could be blocked when cells were preincubated with an antibody to ICAM-1 or LFA-1. Results also show a significant increase in IL-8 and MCP-1 secretion in monocytes and HUVECs treated with 0-10 mM AA. These results suggest that hyperketonemia can induce monocyte adhesion to endothelial cells and that it is mediated via increased ICAM-1 expression in endothelial cells and increased expression and affinity of LFA-1 in monocytes. PMID- 21540445 TI - The role of the gut sweet taste receptor in regulating GLP-1, PYY, and CCK release in humans. AB - The recent identification of sweet taste receptors in the gastrointestinal tract has important implications in the control of food intake and glucose homeostasis. Lactisole can inhibit the sweet taste receptor T1R2/T1R3. The objective was to use lactisole as a probe to investigate the physiological role of T1R2/T1R3 by assessing the effect of T1R2/T1R3 blockade on GLP-1, PYY, and CCK release in response to 1) intragastric administration of nutrients or 2) intraduodenal perfusion of nutrients. The study was performed as a randomized, double-blind, placebo-controlled crossover study that included 35 healthy subjects. In part I, subjects received intragastrically 75 g of glucose in 300 ml of water or 500 ml of a mixed liquid meal with or without lactisole. In part II, subjects received an intraduodenal perfusion of glucose (29.3 g glucose/100 ml; rate: 2.5 ml/min for 180 min) or a mixed liquid meal (same rate) with or without lactisole. The results were that 1) lactisole induced a significant reduction in GLP-1 and PYY but not CCK secretion in both the intragastric and the intraduodenal glucose stimulated parts (P <= 0.05), 2) comparison of the inhibitory effect of lactisole showed a significantly greater suppression of the hormone response in the intragastric part (P = 0.023), and 3) lactisole had no effect on liquid meal stimulated parameters. We conclude that T1R2/T1R3 is involved in glucose dependent secretion of satiation peptides. However, the results of the liquid meal-stimulated parts show that the receptor alone is not responsible for peptide secretion. PMID- 21540446 TI - Arginine synthesis from enteral glutamine in healthy adults in the fed state. AB - Recent studies have documented transfer of labeled nitrogen from [2 (15)N]glutamine to citrulline and arginine in fasting human adults. Conversely, in neonates and piglets we have shown no synthesis of arginine from [2 (15)N]glutamate, and others have shown in mice that glutamine is a nitrogen, but not a carbon donor, for arginine synthesis. Therefore, we performed a multitracer study to determine whether glutamine is a nitrogen and/or carbon donor for arginine in healthy adult men. Two glutamine tracers, 2-(15)N and 1-(13)C, were given enterally to five healthy men fed a standardized milkshake diet. There was no difference in plasma enrichments between the two glutamine tracers. 1-(13)C isotopomers of citrulline and arginine were synthesized from [1-(13)C]glutamine. Three isotopomers each of citrulline and arginine were synthesized from the [2 (15)N]glutamine tracer: 2-(15)N, 5-(15)N, and 2,5-(15)N(2). Significantly greater enrichment was found of both [5-(15)N]arginine (0.75%) and citrulline (3.98%) compared with [2-(15)N]arginine (0.44%) and [2-(15)N]citrulline (2.62%), indicating the amino NH(2) from glutamine is mostly transferred to arginine and citrulline by transamination. Similarly, the enrichment of the 1-(13)C isotopomers was significantly less than the 2-(15)N isotopomers, suggesting rapid formation of alpha-ketoglutarate and recycling of the nitrogen label. Our results show that the carbon for 50% of newly synthesized arginine comes from dietary glutamine but that glutamine acts primarily as a nitrogen donor for arginine synthesis. Hence, studies using [2-(15)N]glutamine will overestimate arginine synthesis rates. PMID- 21540448 TI - Adipokines identified as new downstream targets for adiponectin: lessons from adiponectin-overexpressing or -deficient mice. AB - Adipokines play a central role in the pathogenesis of the metabolic syndrome. Among them, adiponectin (ApN), a master regulator of immune and fuel homeostasis, is decreased. Identifying downstream adipokines targeted by ApN may help in deciphering this syndrome. We have generated transgenic mice, allowing persistent and moderate overexpression of ApN (ApN-Overex) specifically in white adipose tissue (AT). We took advantage of this model to unravel the adipokine secretion profile triggered by ApN. AT was fractionated into adipocytes and stromal vascular cells (SVC), which were cultured for 8 h. Profiling of secretory products by antibody arrays and subsequent ELISAs showed that the secretion of three proinflammatory factors (IL-17B, IL-21, TNFalpha) and three hematopoietic growth factors [GF; thrombopoietin and granulocyte (macrophage) colony stimulating-factors] was reduced in adipocytes of ApN-Overex mice compared with wild-type mice. In the SVC of these mice, besides the hematopoietic GFs, the secretion of another GF (vascular endothelial GF receptor 1), two chemokines (RANTES and ICAM-1), and two proinflammatory factors (IL-6 and IL-12p70) was reduced as well. Only one cytokine, IL-1 receptor 4, was oversecreted by SVC of ApN-Overex mice, which may exhibit anti-inflammatory properties. Most of these changes in secretion were due to corresponding changes in mRNAs. A reverse profile of adipokine expression was observed in ApN-KO mice. In conclusion, ApN regulates in vivo the secretion of downstream adipokines, thereby inducing a shift of the immune balance in both adipocytes and SVC toward a less inflammatory phenotype. These downstream adipokines may be new therapeutic targets for the management of the metabolic syndrome. PMID- 21540447 TI - Differential effects of glucocorticoids on energy homeostasis in Syrian hamsters. AB - Syrian hamsters, like many humans, increase food intake and body adiposity in response to stress. We hypothesized that glucocorticoids (cortisol and corticosterone) mediate these stress-induced effects on energy homeostasis. Because Syrian hamsters are dual secretors of cortisol and corticosterone, differential effects of each glucocorticoid on energy homeostasis were investigated. First, adrenal intact hamsters were injected with varying physiological concentrations of cortisol, corticosterone, or vehicle to emulate our previously published defeat regimens (i.e., 1 injection/day for 5 days). Neither food intake nor body weight was altered following glucocorticoid injections. Therefore, we investigated the effect of sustained glucocorticoid exposure on energy homeostasis. This was accomplished by implanting hamsters with supraphysiological steady-state pellets of cortisol, corticosterone, or cholesterol as a control. Cortisol, but not corticosterone, significantly decreased food intake, body mass, and lean and fat tissue compared with controls. Despite decreases in body mass and adiposity, cortisol significantly increased circulating free fatty acids, triglyceride, cholesterol, and hepatic triglyceride concentrations. Although corticosterone did not induce alterations in any of the aforementioned metabolic end points, Syrian hamsters were responsive to the effects of corticosterone since glucocorticoids both induced thymic involution and decreased adrenal mass. These findings indicate that cortisol is the more potent glucocorticoid in energy homeostasis in Syrian hamsters. However, the data suggest that cortisol alone does not mediate stress-induced increases in food intake or body mass in this species. PMID- 21540449 TI - Acute injection of ASP in the third ventricle inhibits food intake and locomotor activity in rats. AB - Acylation-stimulating protein (ASP; also known as C3adesArg) stimulates triglyceride synthesis and glucose transport via interaction with its receptor C5L2, which is expressed peripherally (adipose tissue, muscle) and centrally. Previous studies have shown that ASP-deficient mice (C3KO) and C5L2-deficient mice (C5L2KO) are hyperphagic (59 to 229% increase, P < 0.0001), which is counterbalanced by increased energy expenditure measured as oxygen consumption (Vo(2)) and a lower RQ. The aim of the present study was to evaluate ASP's effect on food intake, energy expenditure, and neuropeptide expression. Male rats were surgically implanted with intracerebroventricular (icv) cannulas directed toward the third ventricle. After a 5-h fast, rats were injected, and food intake was assessed at 0.5, 1, 2, 4, 16, 24, and 48 h, with a 5- to 7-day washout period between each injection. Acute icv injections of ASP (0.3-1,065 pmol) had a time dependent effect on decreasing food intake by 20 to 57% (P < 0.05). Decreases were detected by 30 min (maximum 57%, P < 0.01) and at the highest dose effects extended to 48 h (19%, P < 0.05, 24- to 48-h period). Daily body weight gain was decreased by 131% over the first 24 h and 29% over the second 24 h (P < 0.05). A conditioned taste aversion test indicated that there was no malaise. Furthermore, acute ASP injection affected energy substrate usage, demonstrated by decreased Vo(2) and RQ (P < 0.05; implicating greater fatty acid usage), with a 49% decrease in total activity over 24 h (P < 0.05). ASP administration also increased anorexic neuropeptide POMC expression (44%) in the arcuate nucleus, with no change in NPY. Altogether ASP may have central in addition to peripheral effects. PMID- 21540452 TI - Deletion of the bis gene results in a marked increase in the production of corticosterone that is associated with thymic atrophy in mice. AB - Bis (Bag3) is known to be involved in cell survival, migration, the regulating of chaperones, and protein quality control. We reported recently on the production of bis gene-deleted mice, which show early lethality within 3 wk after birth with a phenotype showing severe malnutrition and shrinkage of the thymus. In this report, we provide evidence to show that an intrinsic problem of adrenal gland is the the primary cause for the severe atrophy of the thymus in bis(-/-) mice. The bis(-/-) mice show significantly higher levels of corticosterone, but CRH and ACTH levels were considerably lower than those of wild littermates. The transcription of steroidogenic enzymes was increased in the adrenal glands of bis(-/-) mice, accompanied by an increase in the thickness of the zona reticularis. An analysis of thymus tissue from bis(-/-) mice revealed that the severe atrophy of the thymus is due to the specific loss of immature double positive (CD4(+)CD8(+)) cortical thymocytes by apoptosis, as evidenced by immunohistochemical examination and flow cytometric analysis, which were restored by injection of an inhibitor of glucocorticoid synthesis. In vitro cultures of thymocytes with increasing doses of dexamethasone exhibited a similar degree of apoptosis between wild and bis(-/-) thymocytes. The corticosterone levels from fasted wild littermates were one-half those of bis(-/-) mice, although serum glucose levels were similar. Thus, the deletion of the bis gene resulted in the intrinsic defect in the adrenal gland, leading to a marked increase in glucocorticoid levels, probably upon starvation stress, which accounts for the massive apoptosis of the thymus. PMID- 21540451 TI - Urocortin 1 reduces food intake and ghrelin secretion via CRF(2) receptors. AB - Although it is known that urocortin 1 (UCN) acts on both corticotropin-releasing factor receptors (CRF(1) and CRF(2)), the mechanisms underlying UCN-induced anorexia remain unclear. In contrast, ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, stimulates food intake. In the present study, we examined the effects of CRF(1) and CRF(2) receptor antagonists (CRF(1)a and CRF(2)a) on ghrelin secretion and synthesis, c-fos mRNA expression in the caudal brain stem, and food intake following intracerebroventricular administration of UCN. Eight-week-old, male Sprague-Dawley rats were used after 24-h food deprivation. Acylated and des-acylated ghrelin levels were measured by enzyme-linked immunosorbent assay. The mRNA expressions of preproghrelin and c fos were measured by real-time RT-PCR. The present study provided the following important insights into the mechanisms underlying the anorectic effects of UCN: 1) UCN increased acylated and des-acylated ghrelin levels in the gastric body and decreased their levels in the plasma; 2) UCN decreased preproghrelin mRNA levels in the gastric body; 3) UCN-induced reduction of plasma ghrelin and food intake were restored by CRF(2)a but not CRF(1)a; 4) UCN-induced increase of c-fos mRNA levels in the caudal brain stem containing the nucleus of the solitary tract (NTS) was inhibited by CRF(2)a; and 5) UCN-induced reduction of food intake was restored by exogenous ghrelin and rikkunshito, an endogenous ghrelin secretion regulator. Thus, UCN increases neuronal activation in the caudal brain stem containing NTS via CRF(2) receptors, which may be related to UCN-induced inhibition of both ghrelin secretion and food intake. PMID- 21540450 TI - Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. AB - Glucocorticoids and mineralocorticoids are steroid hormones classically thought to be secreted exclusively by the adrenal glands. However, recent evidence has shown that corticosteroids can also be locally synthesized in various other tissues, including primary lymphoid organs, intestine, skin, brain, and possibly heart. Evidence for local synthesis includes detection of steroidogenic enzymes and high local corticosteroid levels, even after adrenalectomy. Local synthesis creates high corticosteroid concentrations in extra-adrenal organs, sometimes much higher than circulating concentrations. Interestingly, local corticosteroid synthesis can be regulated via locally expressed mediators of the hypothalamic pituitary-adrenal (HPA) axis or renin-angiotensin system (RAS). In some tissues (e.g., skin), these local control pathways might form miniature analogs of the pathways that regulate adrenal corticosteroid production. Locally synthesized glucocorticoids regulate activation of immune cells, while locally synthesized mineralocorticoids regulate blood volume and pressure. The physiological importance of extra-adrenal glucocorticoids and mineralocorticoids has been shown, because inhibition of local synthesis has major effects even in adrenal intact subjects. In sum, while adrenal secretion of glucocorticoids and mineralocorticoids into the blood coordinates multiple organ systems, local synthesis of corticosteroids results in high spatial specificity of steroid action. Taken together, studies of these five major organ systems challenge the conventional understanding of corticosteroid biosynthesis and function. PMID- 21540453 TI - New roles for lysosomal trafficking in morphogen gradient sensing. AB - The way in which cells recognize their position in a gradient of morphogen controls differentiation during embryogenesis. New findings indicate that the rate at which internalized morphogen receptors are trafficked to lysosomes is key to the accurate and precise sensing of morphogen gradients and the appropriate initiation of differentiation programs during development. PMID- 21540454 TI - Male fertility depends on Ca2+ absorption by TRPV6 in epididymal epithelia. AB - TRPV6 [transient receptor potential vanilloid 6] is a calcium ion (Ca2+) selective channel originally identified in the duodenal epithelium and in placenta; replacement of a negatively charged aspartate in the pore-forming region with an uncharged alanine (D541A) renders heterologously expressed TRPV6 channels nonfunctional. We found that male, but not female, mice homozygous for this mutation (Trpv6(D541A/D541A)) showed severely impaired fertility. The motility and fertilization capacity of sperm were markedly reduced, despite intact spermatogenesis. Trpv6 was expressed in epididymal epithelium where the protein was detected in the apical membrane, whereas it was not expressed in spermatozoa or the germinal epithelium. The Ca2+ concentration of the fluid in the cauda epididymis of Trpv6(D541A/D541A) males was 10 times higher than that of wild-type mice, which was accompanied by a seven- to eightfold decrease in Ca2+ absorption through the epididymal epithelium and was associated with reduced sperm viability. Thus, appropriate Ca2+ absorption and a consequent TRPV6 mediated decrease in the extracellular Ca2+ concentration toward the distal segments of the epididymal duct are essential for the acquisition of basic functions and the survival of spermatozoa. PMID- 21540455 TI - Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A. AB - Monophosphoryl lipid A (MLA), a nontoxic derivative of the endotoxin lipopolysaccharide (LPS), has been approved in the United States for use as a vaccine adjuvant. LPS and MLA are ligands of Toll-like receptor 4 (TLR4), and it has been unclear why LPS triggers toxic inflammation, whereas MLA generates safe and effective immunostimulation. Signaling downstream of TLR4 is mediated by the adaptor proteins TRIF [Toll-interleukin-1 (IL-1) receptor (TIR) domain-containing adaptor-inducing interferon-beta], which is required for adaptive immune outcomes, and MyD88 (myeloid differentiation marker 88), which is responsible for many proinflammatory effects. Two models have provided nonexclusive explanations for the differential effects of LPS and MLA. According to the first model, MLA fails to induce maturation of the proinflammatory cytokine IL-1beta because it fails to activate caspase-1, which is required for the conversion of pro-IL-1beta into its bioactive form. The second model suggests that MLA triggers unequal engagement of both of the signaling adaptor pathways of TLR4, such that signaling mediated by TRIF is largely intact, whereas signaling mediated by MyD88 is incomplete. We show that the TRIF-biased signaling that is characteristic of low toxicity MLA explains its failure to activate caspase-1. Defective induction of NLRP3, which depends on MyD88, led to decreased assembly of components of the IL 1beta-activating inflammasome required for the activation of preformed, inactive procaspase-1. In addition, we elucidated the contributions of MyD88 and TRIF to priming of the NLRP3 inflammasome and demonstrated that TRIF-biased TLR4 activation by MLA was responsible for the defective production of mature IL 1beta. PMID- 21540457 TI - GM-CSF-based fusion cytokines as ligands for immune modulation. AB - Chromosomal translocations that combine distinct functional domains of unrelated proteins are an experiment in nature. They demonstrate how endogenous regulatory checkpoints can be overridden by altered cell biochemistry, informing a means to engineering an aberrant signal that the cell is incapable of counterregulating. Thus, our laboratory and others have synthesized fusions of GM-CSF with peptides, ILs, and chemokines, which we have termed fusokines, with the aim of inducing an enhanced immune response against cancer, aiming to overcome the maladapted biological processes causing disease. In doing so, we found that these fusokines did not behave as merely the sum of their natural unfused counterparts, but as entirely novel ligands co-opting their cognate receptor to communicate a unique message to responsive cellular targets. In this review, we discuss how fusion proteins combining different bioactive ligands can alter immune responses and briefly discuss the regulatory pathways that they circumvent. PMID- 21540458 TI - Calcineurin-dependent negative regulation of CD94/NKG2A expression on naive CD8+ T cells. AB - Immune responses lead to expression of immunoregulatory molecules on T cells, including natural killer (NK) receptors, such as CD94/NKG2A on CD8(+) T cells; these receptors restrain CD8(+) responses, thereby preventing T-cell exhaustion in chronic infections and limiting immunopathology. Here, we examined the requirements for inducing CD94/NKG2A on T cells responding to antigen. In vitro, moderate induction of CD94/NKG2A expression occurred after exposure of naive CD8(+) (but not CD4(+)) cells to CD3 ligation or specific peptide. Surprisingly, expression was inhibited by CD28/B7 costimulation. Such inhibition applied only to CD94/NKG2A and not other NK receptors (NKG2D) and was mediated by IL-2. Inhibition by IL-2 occurred via a NFAT cell-independent component of the calcineurin pathway, and CD94/NKG2A induction was markedly enhanced in the presence of calcineurin blockers, such as FK506 or using calcineurin-deficient T cells, both in vitro and in vivo. In addition to CD28-dependent inhibition by IL 2, CD94/NKG2A expression was impaired by several other cytokines (IL-4, IL-23, and transforming growth factor-beta) but enhanced by others (IL-6, IL-10, and IL 21). The complex interplay between these various stimuli may account for the variable expression of CD94/NKG2A during responses to different pathogens in vivo. PMID- 21540459 TI - How I treat the acquired von Willebrand syndrome. AB - The acquired von Willebrand syndrome (AVWS) is a bleeding disorder that is frequently unrecognized or is misdiagnosed as von Willebrand disease. AVWS is characterized by structural or functional defects of von Willebrand factor (VWF) that are secondary to autoimmune, lymphoproliferative or myeloproliferative, malignant, cardiovascular, or other disorders. VWF abnormalities in these disorders can result from (1) antibody-mediated clearance or functional interference, (2) adsorption to surfaces of transformed cells or platelets, or (3) increased shear stress and subsequent proteolysis. Diagnosis can be challenging as no single test is usually sufficient to prove or exclude AVWS. Furthermore, there are no evidence-based guidelines for management. Treatments of the underlying medical condition, including chemo/radiotherapy, surgery, or immunosuppressants can result in remission of AVWS, but is not always feasible and successful. Because of the heterogeneous mechanisms of AVWS, more than one therapeutic approach is often required to treat acute bleeds and for prophylaxis during invasive procedures; the treatment options include, but are not limited to, desmopressin, VWF-containing concentrates, intravenous immunoglobulin, plasmapheresis or recombinant factor VIIa. Here, we review the management of AVWS with an overview on the currently available evidence and additional considerations for typical treatment situations. PMID- 21540460 TI - Prophylactic transfer of BCR-ABL-, PR1-, and WT1-reactive donor T cells after T cell-depleted allogeneic hematopoietic cell transplantation in patients with chronic myeloid leukemia. AB - Donor lymphocyte infusions have been effective in patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation, but their use is associated with the risk of graft-versus-host disease. We investigated the effects of prophylactic infusion of in vitro-generated donor T cells reactive against peptides derived from CML-associated antigens. Fourteen CML patients received conditioning therapy followed by CD34(+)-selected peripheral blood stem cells from matched siblings (n = 7) or unrelated (n = 7) donors. Donor-derived mature dendritic cells generated in vitro from CD14(+) monocytes were loaded with human leukocyte Ag-restricted peptides derived from PR1, WT1, and/or B-cell receptor-ABL and used to repetitively stimulate donor CD8(+) T cells in the presence of IL-2 and IL-7. Stimulated T cells were infused 28, 56, and 112 days after transplantation. Thirteen patients are alive and 7 remain in molecular remission (median follow-up, 45 months). Interestingly, all 4 patients receiving CD8(+) T cells displaying marked cytotoxic activity in vitro and detectable peptide-reactive CD8(+) T cells during follow-up have not experienced graft versus-host disease or relapse. Our study reveals that prophylactic infusion of allogeneic CD8(+) T cells reactive against peptides derived from CML-associated antigens is a safe and promising therapeutic strategy. This trial was registered at www.clinicaltrials.gov as #NCT00460629. PMID- 21540461 TI - A genome-wide association study identifies novel loci associated with susceptibility to chronic myeloid leukemia. AB - In the current study, we identified 2 genetic markers for susceptibility to chronic myeloid leukemia (CML) using a genome-wide analysis. A total of 2744 subjects (671 cases and 2073 controls) were included, with 202 Korean CML patients and 497 control subjects enrolled as a discovery set. Significant findings in the discovery set were validated in a second Korean set of 237 patients and 1000 control subjects and in an additional Canadian cohort of European descent, including 232 patients and 576 control subjects. Analysis revealed significant associations of 2 candidate loci, 6q25.1 and 17p11.1, with CML susceptibility, with the lowest combined P values of 2.4 * 10-6 and 1.3 * 10 12, respectively. Candidate genes in those regions include RMND1, AKAP12, ZBTB2, and WSB1. The locus 6q25.1 was validated in both Korean and European cohorts, whereas 17p11.1 was validated only in the Korean cohort. These findings suggest that genetic variants of 6q25.1 and 17p11.1 may predispose one to the development of CML. PMID- 21540462 TI - Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. AB - The impact of early human cytomegalovirus (HCMV) replication on leukemic recurrence was evaluated in 266 consecutive adult (median age, 47 years; range, 18-73 years) acute myeloid leukemia patients, who underwent allogeneic stem cell transplantation (alloSCT) from 10 of 10 high-resolution human leukocyte Ag identical unrelated (n = 148) or sibling (n = 118) donors. A total of 63% of patients (n = 167) were at risk for HCMV reactivation by patient and donor pretransplantation HCMV serostatus. In 77 patients, first HCMV replication as detected by pp65-antigenemia assay developed at a median of 46 days (range, 25 108 days) after alloSCT. Taking all relevant competing risk factors into account, the cumulative incidence of hematologic relapse at 10 years after alloSCT was 42% (95% confidence interval [CI], 35%-51%) in patients without opposed to 9% (95% CI, 4%-19%) in patients with early pp65-antigenemia (P < .0001). A substantial and independent reduction of the relapse risk associated with early HCMV replication was confirmed by multivariate analysis using time-dependent covariate functions for grades II to IV acute and chronic graft-versus-host disease, and pp65-antigenemia (hazard ratio = 0.2; 95% CI, 0.1-0.4, P < .0001). This is the first report that demonstrates an independent and substantial reduction of the leukemic relapse risk after early replicative HCMV infection in a homogeneous population of adult acute myeloid leukemia patients. PMID- 21540463 TI - Molecular interventions (2001-2011): an experiment completed. PMID- 21540464 TI - Florence Nightingale: the biostatistician. PMID- 21540465 TI - Lady Mildmay's modern medical cures. PMID- 21540466 TI - Matters of the heart: the case of TNFalpha-targeting drugs. PMID- 21540467 TI - Microvesicles: intercellular vectors of biological messages. PMID- 21540469 TI - Asthma therapeutics: recent strides, new hurdles. PMID- 21540468 TI - Mind the dbGAP: the application of data mining to identify biological mechanisms. PMID- 21540470 TI - The secrets of a successful clinical trial: compliance, compliance, and compliance. PMID- 21540471 TI - New therapeutic approaches to combat arterial thrombosis: better drugs for old targets, novel targets, and future prospects. AB - Cardiovascular disease and stroke are predominant causes of death in developed countries. Rupture of atherosclerotic plaque in an artery wall and the ensuing thrombotic events are the triggers for acute ischemic injury in these diseases. Platelet activation and aggregation play key roles in this process of atherothrombosis. Anti-platelet drugs thus provide the primary therapeutic strategy to combat these diseases. Dual therapy with aspirin and clopidogrel is the current standard of care for most patients, but it has significant limitations. This provides an impetus for developing new anti-platelet drugs. One new drug has received FDA approval recently; prasugrel targets the platelet P2Y(12) receptor, just like clopidogrel. Several other new drugs are showing great promise in clinical trials and appear to be nearing approval. Some of these drugs have traditional targets on the platelets; others, such as vorapaxar, terutroban, and sarpogrelate, generate more excitement as they are directed against novel targets. PMID- 21540472 TI - Finding homes for orphan cytochrome P450s: CYP4V2 and CYP4F22 in disease states. AB - The cytochrome P450 (CYP) 4 family of enzymes contains several recently identified membersthat are referred to as "orphan P450s" because their endogenous substrates are unknown.Human CYP4V2 and CYP4F22 are two such orphan P450s that are strongly linked to ocular andskin disease, respectively. Genetic analyses have identified a wide spectrum of mutations in the CYP4V2gene from patients suffering from Bietti's crystalline corneoretinal dystrophy, and mutations in theCYP4F22 gene have been linked to lamellar ichthyosis. The strong gene-disease associations provideunique opportunities for elucidating the substrate specificity of these orphan P450s and unraveling thebiochemical pathways that may be impacted in patients with CYP4V2 and CYP4F22 functional deficits. PMID- 21540473 TI - CHK1 inhibitors in combination chemotherapy: thinking beyond the cell cycle. AB - Cellular sensing of DNA damage, along with concomitant cell cycle arrest, is mediated by a great many proteins and enzymes. One focus of pharmaceutical development has been the inhibition of DNA damage signaling, and checkpoint kinases (Chks) in particular, as a means to sensitize proliferating tumor cells to chemotherapies that damage DNA. 7-Hydroxystaurosporine, or UCN-01, is a clinically relevant and well-studied kinase activity inhibitor that exerts chemosensitizing effects by inhibition of Chk1, and a multitude of Chk1 inhibitors have entered development. Clinical development of UCN-01 has overcome many initial obstacles, but the drug has nevertheless failed to show a high level of clinical activity when combined with chemotherapeutic agents. One very likely reason for the lack of clinical efficacy of Chk1 inhibitors may be that the inhibition of Chk1 causes the compensatory activation of ATM and ERK1/2 pathways. Indeed, inhibition of many enzyme activities, not necessarily components of cell cycle regulation, may block Chk1 inhibitor-induced ERK1/2 activation and enhance the toxicity of Chk1 inhibitors. This review examines the rationally hypothesized actions of Chk1 inhibitors as cell cycle modulatory drugs as well as the impact of Chk1 inhibition upon other cell survival signaling pathways. An understanding of Chk1 inhibition in multiple signaling contexts will be essential to the therapeutic development of Chk1 inhibitors. PMID- 21540476 TI - Anterior segment optical coherence tomography analysis of clinically unilateral pseudoexfoliation syndrome: evidence of bilateral involvement and morphologic factors related to asymmetry. AB - PURPOSE: To compare the morphology of the anterior chamber angle (ACA) and iris in eyes with pseudoexfoliation (PEX) syndrome to that of their clinically unaffected fellow eyes and normal control eyes. METHODS: Forty-two patients with unilateral PEX syndrome and 42 normal subjects were studied. Eyes were separated into those with PEX, their clinically unaffected fellow eyes, and normal eyes. The dark-light changes of the ACA and iris were documented by anterior segment optical coherence tomography (AS-OCT) video recordings. The nasal ACA parameters including the angle opening distance at 500 MUm (AOD500), the trabecular-iris space at 500 MUm (TISA500), and the trabecular-iris angle at 500 MUm (TIA500); anterior chamber depth (ACD); iris-lens contact distance (ILCD), and iris configuration were analyzed with the built-in software and a customized program. RESULTS: The ACA parameters were not significantly different among all three groups in the dark. The PEX eyes had significantly smaller ACA parameters than their fellow eyes and normal control eyes in the light. PEX eyes also had significantly shallower ACD, longer ILCD, and greater iris convexity (both in dark and light), and thinner iris (in dark) than their fellow eyes. The fellow eyes had significantly lower ACD both in the dark and light, and smaller angle opening distance at 500 MUm and ILCD in the light than normal controls. There were no significant differences in the iris area among the three groups. CONCLUSIONS: Differences in the anterior segmental morphology are present between PEX and fellow eyes. These disparities may be related to the asymmetry in patients with the unilateral PEX syndrome. PMID- 21540474 TI - Spindle poisons and cell fate: a tale of two pathways. AB - Spindle poisons, such as paclitaxel and vinblastine, exert their potent anti neoplastic effects through activation of the spindle assembly checkpoint (SAC), thereby arresting cells in mitosis. Unfortunately, only certain cancers are susceptible to these drugs, and many patients fail to respond to treatment. We review the pathways that are triggered by spindle poisons and highlight recent studies that describe the great variability of tumor cells in responding to these drugs. We also describe the recent identification of an apoptotic pathway that is activated by mitotic arrest in response to spindle poisons. Emerging from these studies is not only a greater understanding of how these classic antimitotic agents bring about cell death, but also a wealth of potential new targets of anticancer therapeutics. PMID- 21540477 TI - Herpes simplex virus type 1-induced transcriptional networks of corneal endothelial cells indicate antigen presentation function. AB - PURPOSE: To determine the transcriptional response of cultured human corneal endothelial (HCEn) cells after herpes simplex virus type (HSV-1) infection and to characterize the primary functional elements and antiviral responses. METHODS: Immortalized HCEn cells were infected with HSV-1, and the global transcriptional profile was determined. The transcriptional networks of HCEn cells were constructed, and the inflammatory network nodes were evaluated for induction of candidate inflammatory mediators by protein array analyses. HSV-1-specific allogeneic T cells isolated from HSV-1-infected donors were co-cultured with HSV 1-pulsed HCEn cells, and T cell activation was assessed for antigen-specific proliferation. RESULTS: HSV-1 infection induced a global transcriptional activation with 331 genes significantly up- or downregulated compared with mock infected HCEn cells (P < 0.01; 4< or 0.25> threshold). Network analysis showed that the HSV-1-induced transcriptome was specifically associated with antigen presentation, interferon-related responses, and cellular development, and was characterized by NF-kappaB and extracellular signal-regulated kinase signaling pathways. The primary associated function in the transcriptome was antigen presentation. Protein array analysis identified significant elevation of genes related to antigen presentation: IL-6, IP-10, HVEML, and interferon-gamma. In addition, inflammatory cytokines including IL-8, MCP-1, TIMP-1, RANTES, I-309, MIF, MCP-2, IL-10, and SDF-1, in descending order, were significantly elevated. Mixed lymphocyte reaction assays showed that HSV-1-pulsed HCEn cells stimulated antigen-specific proliferation of allogeneic T lymphocytes. CONCLUSIONS: HCEn cells respond to HSV-1 infection by initiating antigen presentation-related inflammatory responses, and they may serve as antigen-presenting cells. PMID- 21540478 TI - Development of emulsification-resistant silicone oils: can we go beyond 2000 mPas silicone oil? AB - PURPOSE: To develop new blends of emulsification-resistant silicone oil based on high molecular weight (HMW) silicone oil for use as an endotamponade in vitreoretinal surgery. METHODS: Viscosity and elasticity of various silicone oil blends (Siluron 1000, Siluron 2000, Siluron 5000, 7% HMW + Siluron 1000, 10% HMW + Siluron 1000, and 15% HMW + Siluron 1000; Fluoron GmbH, Ulm, Germany) were measured using a piezoelectric axial vibrator. Emulsification was induced using a sonication device. Pluronic 10%, plasma, and serum were used as emulsifiers. The emulsion area was photographed and measured using ImageJ software (developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; available at http://rsb.info.nih.gov/ij/index.html). RESULTS: Viscosity increased proportionally to HMW concentrations. Fluid elasticity was optimum using 10% HMW. Emulsification was at a minimum when using 10% or 15% HMW blends. CONCLUSIONS: A new silicone oil-based tamponade was developed with a viscosity similar to Siluron 5000 (at 37 degrees C) but with significantly less emulsification tendency than Siluron 5000 or Siluron 2000. HMW concentration increases the fluid elasticity, thereby reducing the emulsification tendency. PMID- 21540479 TI - Effects of anisometropic amblyopia on visuomotor behavior, III: Temporal eye-hand coordination during reaching. AB - PURPOSE: To examine the effects of anisometropic amblyopia on the temporal pattern of eye-hand coordination during visually-guided reaching. METHODS: Eighteen patients with anisometropic amblyopia and 18 control subjects were recruited. Participants executed reach-to-touch movements toward visual targets under three viewing conditions: binocular, monocular amblyopic eye, and monocular fellow eye viewing. Temporal coordination between eye and hand movements was examined during reach planning (interval between the initiation of saccade and reaching) and reach execution (interval between the initiation of saccade and reach peak velocity). The frequency and dynamics of secondary saccades were also examined. RESULTS: Patients with severe amblyopia spent a longer time planning the reaching response after fixating the target in comparison with control subjects and patients with mild amblyopia (P = 0.029). In comparison with control subjects, all patients extended the acceleration phase of the reach after target fixation (P = 0.018). Secondary (reach-related) saccades were initiated during the acceleration phase of the reach and patients executed these saccades with greater frequency than control subjects (P < 0.0001). The amplitude and peak velocity of reach-related saccades were higher when patients viewed with the amblyopic eye in comparison with the other viewing conditions (P < 0.001). CONCLUSIONS: This is the first study to show that patients with anisometropic amblyopia modified the temporal dynamics of eye-hand coordination during visually guided reaching. They extended the planning and execution intervals after target fixation and increased the frequency of secondary, reach-related saccades. These may represent visuomotor strategies to compensate for the spatiotemporal visual deficits to achieve good reaching accuracy and precision. PMID- 21540480 TI - Perceptions of diabetes symptoms and self-management strategies: a cross-cultural comparison. AB - PURPOSE: The purpose of this research was to compare and contrast perceived symptoms of type 2 diabetes mellitus and self management strategies between Russian-speaking Slavic immigrant American women and non-Hispanic, nonimmigrant White American women. METHODS: The qualitative-descriptive study design was conducted with a convenience sample of Slavic immigrant women 50 years of age and older with type 2 diabetes (n = 10), and non-Hispanic, nonimmigrant White American women 50 years of age and older with type 2 diabetes (n = 10). RESULTS: Slavic immigrants reported more global holistic symptoms of diabetes, whereas nonimmigrants reported more specific physiological somatic symptoms. The nonimmigrant women used more complex diabetes self-management techniques compared with the Slavic group. A lack of education and awareness of hypoglycemia may contribute to less medication adherence in Slavic immigrants and may prevent them from being motivated to participate in diabetes self-management. DISCUSSION AND CONCLUSIONS: Health care providers caring for Slavic immigrant women with diabetes need to be aware that these women may fail to recognize the symptoms of hypoglycemia and seldom acknowledge depression, although depressive symptoms are often present. Culturally congruent health care will increase adherence and improve health outcomes for Slavic immigrant women. PMID- 21540481 TI - Indications for growth hormone therapy in children. AB - Growth hormone (GH) therapy has now been available for over 5 decades, with all GH now biosynthetically produced, and administered by daily injection. Paediatric GH is currently licensed in six different conditions: growth hormone deficiency (GHD), Turner syndrome (TS), small for gestational age (SGA), Prader-Willi syndrome (PWS), chronic renal insufficiency (CRI), and short stature due to SHOX deficiency; all of these have been ratified by the most recent (2010) NICE review. Whilst the primary purpose of paediatric GH therapy in most indications is to improve short and long-term growth, in others (eg. PWS) it has a role in improvement of body composition. Recent UK national audits indicate approximately 4700 children receiving GH therapy, with approximately 760 new starts a year, with most prescription still via historical growth centres. There are currently 7 different manufacturers of GH, and while most UK units currently offer free patient choice for GH device, with preliminary evidence indicating that this may improve adherence with therapy, the 30% price difference may limit choice in the future. PMID- 21540482 TI - Outcomes following admission to intensive care for asthma. AB - OBJECTIVE: Acute severe asthma in children is a common cause of admission to intensive care units (ICU), but there are few reports on long-term outcomes. This study describes outcomes for children with asthma admitted to an ICU. METHODS: All children with asthma aged 2-18 years admitted to the ICU at the Royal Children's Hospital Melbourne between 1990 and 2004 were eligible for the study. Data were collected by reviewing medical records and through telephone interviews. RESULTS: Complete data were obtained for 410 (61%) of 684 eligible patients. The mean duration of follow-up was 10.3+/-4.6 years. After the index admission, 67% were readmitted to hospital for asthma and 17% to the ICU. Eighty eight per cent continued to have asthma: 46% had episodic asthma and 42% persistent asthma. Twelve patients (1.8%) subsequently died from asthma. Five per cent of those who required ventilation at their index admission died within 10 years. Risk factors for ICU readmission were admission for asthma in the preceding year (AOR 4.7; 95% CI 2.4 to 9.3) and ventilation at admission (AOR 2.4; 95% CI 1.0 to 5.3). Risk factors for subsequent mortality were multiple ICU admissions (AOR 5.0; 95% CI 1.3 to 19), persistent asthma (AOR 5.8; 95% CI 1.2 to 28.5) and ventilation at admission (AOR 4.5; 95% CI 1.3 to 15.7). CONCLUSION: Admission to the ICU for asthma is a predictor of hospital readmission. Those with persistent asthma or requiring ventilation are at significant risk of mortality in subsequent years and require close follow-up. PMID- 21540483 TI - Urinary trichlorophenol levels and increased risk of attention deficit hyperactivity disorder among US school-aged children. AB - BACKGROUND: Trichlorophenols (TCPs) are organochlorine compounds which are ubiquitous in the environment and well known for their carcinogenic effects. However, little is known about their neurotoxicity in humans. OBJECTIVES: Our goal was to examine the association between body burden of TCPs (ie, 2,4,5-TCP and 2,4,6-TCP) and attention deficit hyperactivity disorder (ADHD). METHODS: We calculated ORs and 95% CIs from logistic regression analyses using data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to evaluate the association between urinary TCPs and parent-reported ADHD among 2546 children aged 6-15 years. RESULTS: Children with low levels (<3.58 MUg/g) and high levels (>=3.58 MUg/g) of urinary 2,4,6-TCP had a higher risk of parent-reported ADHD compared to children with levels below the limit of detection (OR 1.54, 95% CI 0.97 to 2.43 and OR 1.77, 95% CI 1.18 to 2.66, respectively; p for trend=0.006) after adjusting for covariates. No association was found between urinary 2,4,5 TCP and parent-reported ADHD. CONCLUSION: Exposure to TCP may increase the risk of behavioural impairment in children. The potential neurotoxicity of these chemicals should be considered in public health efforts to reduce environmental exposures/contamination, especially in countries where organochlorine pesticides are still commonly used. PMID- 21540484 TI - Conserved catalytic residues of the ALDH1L1 aldehyde dehydrogenase domain control binding and discharging of the coenzyme. AB - The C-terminal domain (C(t)-FDH) of 10-formyltetrahydrofolate dehydrogenase (FDH, ALDH1L1) is an NADP(+)-dependent oxidoreductase and a structural and functional homolog of aldehyde dehydrogenases. Here we report the crystal structures of several C(t)-FDH mutants in which two essential catalytic residues adjacent to the nicotinamide ring of bound NADP(+), Cys-707 and Glu-673, were replaced separately or simultaneously. The replacement of the glutamate with an alanine causes irreversible binding of the coenzyme without any noticeable conformational changes in the vicinity of the nicotinamide ring. Additional replacement of cysteine 707 with an alanine (E673A/C707A double mutant) did not affect this irreversible binding indicating that the lack of the glutamate is solely responsible for the enhanced interaction between the enzyme and the coenzyme. The substitution of the cysteine with an alanine did not affect binding of NADP(+) but resulted in the enzyme lacking the ability to differentiate between the oxidized and reduced coenzyme: unlike the wild-type C(t)-FDH/NADPH complex, in the C707A mutant the position of NADPH is identical to the position of NADP(+) with the nicotinamide ring well ordered within the catalytic center. Thus, whereas the glutamate restricts the affinity for the coenzyme, the cysteine is the sensor of the coenzyme redox state. These conclusions were confirmed by coenzyme binding experiments. Our study further suggests that the binding of the coenzyme is additionally controlled by a long-range communication between the catalytic center and the coenzyme-binding domain and points toward an alpha-helix involved in the adenine moiety binding as a participant of this communication. PMID- 21540485 TI - Computationally efficient bioelectric field modeling and effects of frequency dependent tissue capacitance. AB - Standard bioelectric field models assume that the tissue is purely resistive and frequency independent, and that capacitance, induction, and propagation effects can be neglected. However, real tissue properties are frequency dependent, and tissue capacitance can be important for problems involving short stimulation pulses. A straightforward interpolation scheme is introduced here that can account for frequency-dependent effects, while reducing runtime over a direct computation by several orders of magnitude. The exact Helmholtz solution is compared to several approximate field solutions and is used to study neural stimulation. Results show that frequency-independent tissue capacitance always acts to attenuate the stimulation pulse, thereby increasing firing thresholds, while the dispersion effects introduced by frequency-dependent capacitance may decrease firing thresholds. PMID- 21540486 TI - Recordings of cultured neurons and synaptic activity using patch-clamp chips. AB - Planar patch-clamp chip technology has been developed to enhance the assessment of novel compounds for therapeutic efficacy and safety. However, this technology has been limited to recording ion channels expressed in isolated suspended cells, making the study of ion channel function in synaptic transmission impractical. Recently, we developed single- and dual-recording site planar patch-clamp chips and demonstrated their capacity to record ion channel activity from neurons established in culture. Such capacity provides the opportunity to record from synaptically connected neurons cultured on-chip. In this study we reconstructed, on-chip, a simple synaptic circuit between cultured pre-synaptic visceral dorsal 4 neurons and post-synaptic left pedal dorsal 1 neurons isolated from the mollusk Lymnaea stagnalis. Here we report the first planar patch-clamp chip recordings of synaptic phenomena from these paired neurons and pharmacologically demonstrate the cholinergic nature of this synapse. We also report simultaneous dual-site recordings from paired neurons, and demonstrate dedicated cytoplasmic perfusion of individual neurons via on-chip subterranean microfluidics. This is the first application of planar patch-clamp technology to examine synaptic communication. PMID- 21540487 TI - Repetitive transcranial magnetic stimulator with controllable pulse parameters. AB - The characteristics of transcranial magnetic stimulation (TMS) pulses influence the physiological effect of TMS. However, available TMS devices allow very limited adjustment of the pulse parameters. We describe a novel TMS device that uses a circuit topology incorporating two energy storage capacitors and two insulated-gate bipolar transistor (IGBT) modules to generate near-rectangular electric field pulses with adjustable number, polarity, duration, and amplitude of the pulse phases. This controllable pulse parameter TMS (cTMS) device can induce electric field pulses with phase widths of 10-310 us and positive/negative phase amplitude ratio of 1-56. Compared to conventional monophasic and biphasic TMS, cTMS reduces energy dissipation up to 82% and 57% and decreases coil heating up to 33% and 41%, respectively. We demonstrate repetitive TMS trains of 3000 pulses at frequencies up to 50 Hz with electric field pulse amplitude and width variability less than the measurement resolution (1.7% and 1%, respectively). Offering flexible pulse parameter adjustment and reduced power consumption and coil heating, cTMS enhances existing TMS paradigms, enables novel research applications and could lead to clinical applications with potentially enhanced potency. PMID- 21540488 TI - Comparison of pinhole collimator materials based on sensitivity equivalence. AB - Pinhole SPECT often provides an excellent resolution sensitivity trade-off for radionuclide imaging compared to SPECT with parallel holes, particularly when imaging small experimental animals like rodents. High absorption pinhole materials are often chosen because of their low edge penetration and therefore good system resolution. Capturing more photons in the edges however results in decreased system sensitivity if the pinhole diameter remains the same, which may partly undo the beneficial effect on the resolution. In the search for an optimal trade-off we have compared pinhole projection data and reconstructed images of different materials with pinhole aperture diameters adjusted to obtain equal sensitivity. Monte Carlo calculations modeling the transmission, penetration and scattering of gamma radiation in single pinholes of uranium, gold, tungsten and lead were performed for a range of pinhole opening angles, diameters and gamma ray energies. In addition, reconstructed images of a hot rod phantom were determined for a multipinhole SPECT system and for a system that can image the 511 keV annihilation photons of positron emitting tracers with clustered pinholes. Our results indicate that, under the condition of equal sensitivity, tungsten and for SPECT also lead pinholes perform just as well as gold and uranium ones, indicating that a significant cost reduction can be achieved in pinhole collimator manufacturing while the use of rare or impractical materials can be avoided. PMID- 21540489 TI - Modelling of the oxygen enhancement ratio for ion beam radiation therapy. AB - The poor treatment prognosis for tumours with oxygen-deficient areas is usually attributed to the increased radioresistance of hypoxic cells. It can be expressed by the oxygen enhancement ratio (OER), which decreases with increasing linear energy transfer (LET) suggesting a potential clinical advantage of high-LET radiotherapy with heavy ion beams compared to low-LET photon or proton irradiation. The aim of this work is to review the experimental cell survival data from the literature and, based on them, to develop a simple OER model to estimate the clinical impact of OER variations. For this purpose, the standard linear-quadratic model and the Alper-Howard-Flanders model are used. According to our calculations for a carbon ion spread-out Bragg peak at clinically relevant intermediate oxygen levels (0.5-20 mmHg), the advantage of carbon ions might be relatively moderate, with OER values about 1%-15% smaller than for protons. Furthermore, the variations of OER with LET are much smaller in vivo than in vitro due to different oxygen partial pressures used in cell experiments or measured inside tumours. The proposed OER model is a simple tool to quantify the oxygen effect in a practical way and provides the possibility to do hypoxia-based biological optimization in treatment planning. PMID- 21540490 TI - Robust principal component analysis-based four-dimensional computed tomography. AB - The purpose of this paper for four-dimensional (4D) computed tomography (CT) is threefold. (1) A new spatiotemporal model is presented from the matrix perspective with the row dimension in space and the column dimension in time, namely the robust PCA (principal component analysis)-based 4D CT model. That is, instead of viewing the 4D object as a temporal collection of three-dimensional (3D) images and looking for local coherence in time or space independently, we perceive it as a mixture of low-rank matrix and sparse matrix to explore the maximum temporal coherence of the spatial structure among phases. Here the low rank matrix corresponds to the 'background' or reference state, which is stationary over time or similar in structure; the sparse matrix stands for the 'motion' or time-varying component, e.g., heart motion in cardiac imaging, which is often either approximately sparse itself or can be sparsified in the proper basis. Besides 4D CT, this robust PCA-based 4D CT model should be applicable in other imaging problems for motion reduction or/and change detection with the least amount of data, such as multi-energy CT, cardiac MRI, and hyperspectral imaging. (2) A dynamic strategy for data acquisition, i.e. a temporally spiral scheme, is proposed that can potentially maintain similar reconstruction accuracy with far fewer projections of the data. The key point of this dynamic scheme is to reduce the total number of measurements, and hence the radiation dose, by acquiring complementary data in different phases while reducing redundant measurements of the common background structure. (3) An accurate, efficient, yet simple-to-implement algorithm based on the split Bregman method is developed for solving the model problem with sparse representation in tight frames. PMID- 21540491 TI - Development and evaluation of gallium nitride-based thin films for x-ray dosimetry. AB - X-ray radiation plays an important role in medical procedures ranging from diagnostics to therapeutics. Due to the harm such ionizing radiation can cause, it has become common practice to closely monitor the dosages received by patients. To this end, precise online dosimeters have been developed with the dual objectives of monitoring radiation in the region of interest and improving therapeutic methods. In this work, we evaluate GaN thin film high electron mobility heterostructures with sub-mm(2) detection areas as x-ray radiation detectors. Devices were tested using 40-300 kV Bremsstrahlung x-ray sources. We find that the photoconductive device response exhibits a large gain, is almost independent of the angle of irradiation, and is constant to within 2% of the signal throughout this medical diagnostic x-ray range, indicating that these sensors do not require recalibration for geometry or energy. Furthermore, the devices show a high sensitivity to x-ray intensity and can measure in the air kerma rate (free-in-air) range of 1 uGy s(-1) to 10 mGy s(-1) with a signal stability of +/-1% and a linear total dose response over time. Medical conditions were simulated by measurements of device responses to irradiation through human torso phantoms. Direct x-ray imaging is demonstrated using the index finger and wrist sections of a human phantom. The results presented here indicate that GaN based thin film devices exhibit a wide range of properties, which make them promising candidates for dosimetry applications. In addition, with potential detection volumes smaller than 10(-6) cm(3), they are well suited for high resolution x-ray imaging. Moreover, with additional engineering steps, these devices can be adapted to potentially provide both in vivo biosensing and x-ray dosimetry. PMID- 21540492 TI - Second harmonic inversion for ultrasound contrast harmonic imaging. AB - Ultrasound contrast agents (UCAs) are small micro-bubbles that behave nonlinearly when exposed to an ultrasound wave. This nonlinear behavior can be observed through the generated higher harmonics in a back-scattered echo. In past years several techniques have been proposed to detect or image harmonics produced by UCAs. In these proposed works, the harmonics generated in the medium during the propagation of the ultrasound wave played an important role, since these harmonics compete with the harmonics generated by the micro-bubbles. We present a method for the reduction of the second harmonic generated during nonlinear propagation-dubbed second harmonic inversion (SHI). A general expression for the suppression signals is also derived. The SHI technique uses two pulses, p' and p", of the same frequency f(0) and the same amplitude P(0) to cancel out the second harmonic generated by nonlinearities of the medium. Simulations show that the second harmonic is reduced by 40 dB on a large axial range. Experimental SHI B-mode images, from a tissue-mimicking phantom and UCAs, show an improvement in the agent-to-tissue ratio (ATR) of 20 dB compared to standard second harmonic imaging and 13 dB of improvement in harmonic power Doppler. PMID- 21540493 TI - Uncertainty in hyperthermia treatment planning: the need for robust system design. AB - Hyperthermia treatment planning (HTP) is an important tool to improve the quality of hyperthermia treatment. It is a practical way of designing new hyperthermia systems and can be used to optimize the phase and amplitude settings to achieve optimal heating. One of the main challenges to be dealt with however is the uncertainty in the modeling parameters. The role of dielectric and combined dielectric and perfusion uncertainty on optimization was investigated by means of HTP for six different systems: the 70 MHz AMC-4 (AMC: Academic Medical Center) and AMC-8 system, a 130 MHz version of the AMC-8 system, a three-ring AMC-12 system operating at 130 MHz, the BSD SigmaEye applicator and a dipole applicator with three rings each containing six dipole pairs operated at 150 MHz. For five patients with cervix uteri carcinoma, a patient model was created based on a hyperthermia planning CT. Variation of tissue parameters resulted in 16 dielectric models for every patient. In addition, four thermal models were created to study the combined effect of perfusion and dielectric uncertainty. The impact of dielectric uncertainty on optimization is found to be clearly dependent on the number of channels and increased from 0.5 degrees C for four channels to 1.5 degrees C for the 18-channel system. As a result, the potential gain relative to the AMC-4 system for the 70 MHz AMC-8 system was found to be largely compromised, while for the remaining systems a robust improvement in T(90) was observed. The dipole applicator showed the best target heating for two out of five patients, while for three others heating efficacy was comparable to the 130 MHz AMC-12 system or the 130 MHz AMC-8 system (one patient). Considering the increase in complexity when the number of channels is increased from 12 to 18, the AMC-12 system is considered as a good compromise between heating efficacy and robustness while still being a manageable heating system in clinical practice. PMID- 21540494 TI - Optimization of the magnetic potential for alpha-Fe. AB - A second generation of empirical potentials is produced for alpha-Fe within the framework of the magnetic potential formalism (Dudarev and Derlet 2005 J. Phys.: Condens. Matter 17 7097). A materials database that, in addition to ab initio derived point defect formation energies, now includes third-order elastic constant and ab initio-derived string potential data controlling, respectively, the thermal expansion properties and the core structure of the 1/2(111) screw dislocation. Three parameterizations are presented in detail, all of which exhibit positive thermal expansion and produce a non-degenerate configuration for the relaxed 1/2(111) screw dislocation easy core structure. These potentials, along with two other published potentials, are investigated in terms of defect formation volume, early stage dislocation loop clustering energetics, (110) dumbbell interstitial diffusion, and the zero-stress 1/2(111) screw dislocation Peierls barrier and its corresponding kink formation energies. PMID- 21540495 TI - Model of hopping excitons in GaInNAs: simulations of sharp lines in micro photoluminescence spectra and their dependence on the excitation power and temperature. AB - The model of hopping excitons in semiconductors proposed by Baranovskii et al (1998 Phys. Rev. B 58 13081) has been modified and applied to explain sharp lines observed in micro-photoluminescence (MU-PL) spectra of GaInNAs alloys and their changes with excitation power and temperature. Instead of two types of recombination centres (radiative and nonradiative centres) introduced by Baranovskii et alwe have proposed one kind of localization centre with radiative and nonradiative rates. Such a modification is justifiable due to our recent experimental observations for GaInNAs alloys and allows us to explain the fast thermal quenching of localized emission from this alloy. Our simulations clearly show that the individual sharp PL lines observed at low temperatures appear for this material due to exciton hopping between localization centres. Taking into account saturation effects and the exciton dissociation phenomenon, it has been shown that the observed changes in power- and temperature dependent MU-PL spectra can be excellently reproduced by the modified model. PMID- 21540496 TI - Effect of 50 MeV Li3+ irradiation on structural and electrical properties of Mn doped ZnO. AB - The present work aims to study the effect of ion irradiation on structural and electrical properties and their correlation with the defects in the Zn(1 - x)Mn(x)O-type system. Zn(1 - x)Mn(x)O (x = 0.02, 0.04) samples have been synthesized by the solid-state reaction method and have been irradiated with 50 MeV Li(3+) ions. The concomitant changes have been probed by x-ray diffraction (XRD), temperature-dependent electrical resistivity and positron annihilation lifetime (PAL) spectroscopy. The XRD result shows a single-phase wurtzite structure for Zn(0.98)Mn(0.02)O, whereas for the Zn(0.96)Mn(0.04)O sample an impurity phase has been found, apart from the usual peaks of ZnO. Ion irradiation removes this impurity peak. The grain size of the samples is found to be uniform. For Zn(0.98)Mn(0.02)O, the observed sharp decrease in room temperature resistivity (rho(RT)) with irradiation is consistent with the lowering of the full width at half maximum of the XRD peaks. However, for Zn(0.96)Mn(0.04)O, rho(RT) decreases for the initial fluence but increases for a further increase in fluence. All the irradiated Zn(0.98)Mn(0.02)O samples show a metal-semiconductor transition in temperature-dependent resistivity measurements at low temperature. But all the irradiated Zn(0.96)Mn(0.04)O samples show a semiconducting nature in the whole range of temperatures. Results of room temperature resistivity, XRD and PAL measurements are consistent with each other. PMID- 21540497 TI - Reducing thermal conductivity of binary alloys below the alloy limit via chemical ordering. AB - Substitutional solid solutions that exist in both ordered and disordered states will exhibit markedly different physical properties depending on their exact crystallographic configuration. Many random substitutional solid solutions (alloys) will display a tendency to order given the appropriate kinetic and thermodynamic conditions. Such order-disorder transitions will result in major crystallographic reconfigurations, where the atomic basis, symmetry, and periodicity of the alloy change dramatically. Consequently, the dominant scattering mechanism in ordered alloys will be different than that in disordered alloys. In this study, we present a hypothesis that ordered alloys can exhibit lower thermal conductivities than their disordered counterparts at elevated temperatures. To validate this hypothesis, we investigate the phononic transport properties of disordered and ordered AB Lennard-Jones alloys via non-equilibrium molecular dynamics and harmonic lattice dynamics calculations. It is shown that the thermal conductivity of an ordered alloy is the same as the thermal conductivity of the disordered alloy at ~0.6T(melt) and lower than that of the disordered alloy above 0.8T(melt). PMID- 21540498 TI - DFT calculations of crystal-field parameters for the lanthanide ions in the LaCl3 crystal. AB - We present herein a calculation of crystal-field (CF) parameters for the lanthanide ions in the LaCl(3) crystal, using the density functional theory-based orbital-free embedding formalism in conjunction with the effective Hamiltonian method. The calculated values for the second- and fourth-rank CF parameters agree fairly well with the experimental data. It is found that the effect of ligand polarization plays a crucial role in determining the sign and magnitude of the second-rank CF parameters, while the effect of Pauli repulsion between 4f electrons and the ligands is important for the fourth-rank CF parameters. The usefulness of the present approach is illustrated by a study of the relative preference of Eu(3 + ) occupation on the two distinct Pb(2 + ) sites in the KPb(2)Cl(5) crystal. The computational approach and results discussed in this work are useful for a better understanding and simulation of the CF effect in the lanthanide-containing systems. PMID- 21540499 TI - Small gold clusters on graphene, their mobility and clustering: a DFT study. AB - Motivated by the experimentally observed high mobility of gold atoms on graphene and their tendency to form nanometer-sized clusters, we present a density functional theory study of the ground state structures of small gold clusters on graphene, their mobility and clustering. Our detailed analysis of the electronic structures identifies the opportunity to form strong gold-gold bonds and the graphene-mediated interaction of the pre-adsorbed fragments as the driving forces behind gold's tendency to aggregate on graphene. While clusters containing up to three gold atoms have one unambiguous ground state structure, both gas phase isomers of a cluster with four gold atoms can be found on graphene. In the gas phase the diamond-shaped Au(4)(D) cluster is the ground state structure, whereas the Y-shaped Au(4)(Y) becomes the actual ground state when adsorbed on graphene. As we show, both clusters can be produced on graphene by two distinct clustering processes. We also studied in detail the stepwise formation of a gold dimer out of two pre-adsorbed adatoms, as well as the formation of Au(3). All reactions are exothermic and no further activation barriers, apart from the diffusion barriers, were found. The diffusion barriers of all studied clusters range from 4 to 36 meV only, and are substantially exceeded by the adsorption energies of - 0.1 to - 0.59 eV. This explains the high mobility of Au(1-4) on graphene along the C-C bonds. PMID- 21540500 TI - High pressure studies on RuIn3 single crystal. AB - Temperature- and pressure-dependent electrical resistivity studies have been carried out on RuIn(3) single crystal in the 4-300 K range at various pressures between 0 and 5 GPa. While intrinsic semiconducting behaviour is inferred at higher temperatures above 275 K, the low temperature resistivity is primarily dictated by impurity effects. An insulator to metal transition is observed in the low temperature regime around ~ 1.2 GPa pressure. Band structure calculations show a monotonic decrease of energy gap from a value of 0.222 eV at 0 GPa to 0.167 eV at 8 GPa with increasing pressure, consistent with the experimental findings. PMID- 21540501 TI - First-principles study of diffusion of interstitial and vacancy in alpha U-Zr. AB - Metallic uranium-zirconium alloys are of interest for a variety of fast reactor designs, and there is substantial experience with the behavior of metallic fuels. Yet, there remain a number of questions regarding the mechanisms controlling fission-gas-driven swelling in these alloys. Here we present results of ab initio calculations of the diffusion behavior of interstitial and vacancy point defects in alpha U-Zr alloys. The formation energy and migration barrier of vacancy and interstitial defects, and the influence of Zr on these values, is obtained and compared with experimental results. Our results confirm that self-diffusion in pure alpha U is via a simple vacancy mechanism, and shows anisotropic character. The calculated values of activation energy are consistent with the experimental results in the literature. For interstitial diffusion, the kick-out mechanism was found to have the smallest energy barrier. The calculations of point defects, and later Xe, in U-Zr alloys will provide a foundation for computational modeling of fission gas bubble nucleation and growth. PMID- 21540502 TI - Magnetic field dependence of the magnetic susceptibility and the specific heat of the doped plasticized polyaniline (PANI-DB3EPSA)0.5. AB - Specific heat, magnetization and electron spin resonance (ESR) data obtained from a self-standing film of the doped plasticized polyaniline (PANI-DB3EPSA)(0.5) are shown. No long range magnetic order has been observed at zero magnetic field, above 2 K. For a magnetic field of 3.3 kOe applied perpendicular to the plane of the film, a clear signature of an induced ordered state can be seen in the specific heat data and ESR also reveals this antiferromagnetic order. An electronic contribution is detected from ESR, magnetization and specific heat; however, for T <= 5 K, the specific heat data show the existence of a gap. Magnetization data also show a low temperature dominant Curie behaviour which cannot be seen from ESR, probably due to a very large linewidth, suggesting short range correlations among spin 1/2 polarons. PMID- 21540503 TI - Analyzing the success of T-matrix diagrammatic theories in representing a modified Hubbard model. AB - We present a systematic study of various forms of renormalization that can be applied in the calculation of the self-energy of the Hubbard model within the T matrix approximation. We compare the exact solutions of the attractive and repulsive Hubbard models, for linear chains of lengths up to eight sites, with all possible taxonomies of the T-matrix approximation. For the attractive Hubbard model, the success of a minimally self-consistent theory found earlier in the atomic limit (Verga et al 2005 Phys. Rev. B 71 155111) is not maintained for finite clusters unless one is in the very strong correlation limit. For the repulsive model, in the weak correlation limit at low electronic densities-that is, where one would expect a self-consistent T-matrix theory to be adequate-we find the fully renormalized theory to be most successful. In our studies we employ a modified Hubbard interaction that eliminates all Hartree diagrams, an idea which was proposed earlier (Zlatic et al 2000 Phys. Rev. B 63 035104). PMID- 21540504 TI - The role of correlations in the high-pressure phase of FeSe. AB - This study addresses the structural and electronic properties of the NiAs- and MnP-type phases dominating in FeSe at high pressures. The analysis is performed using first-principle band structure calculations within the framework of the B3LYP hybrid exchange-correlation functional. Based on the volume-pressure relation deduced from the available experimental data, we optimize the form and internal coordinates of the unit cell, which agree reasonably well with experiment. In particular, the present calculations resolve the structural NiAs MnP phase transition which occurs at about 10 GPa. Both structures are found to be semiconducting at low pressures and metallizing at about 80-90 GPa. Using the complementary LDA + U approach the semiconducting state can be explained as the result of the strong local correlations within the Fe d-shell. PMID- 21540505 TI - Electric field gradient in FeTiO3 by nuclear magnetic resonance and ab initio calculations. AB - Temperature dependence of nuclear magnetic resonance (NMR) spectra of (47)Ti and (49)Ti in polycrystalline ilmenite FeTiO(3) was measured in the range from 5 to 300 K under an external magnetic field of 9.401 T. NMR spectra collected between 300 and 77 K exhibit a resolved quadrupole splitting. The electric field gradient (EFG) tensor was evaluated for Ti nuclei and the ratio of (47)Ti and (49)Ti nuclear quadrupole moments was refined during the fitting procedure. Below 77 K, the fine structure of quadrupole splitting disappears due to the enormous increase of anisotropy. As a counterpart, ab initio calculations were performed using full potential augmented plane waves + local orbitals. The calculated EFG tensors for Ti and Fe were compared to the experimental ones evaluated from NMR and the Mossbauer spectroscopy experiments. PMID- 21540506 TI - X-ray absorption study of the local order around Mn in Mn:ZnO thin films: the role of vacancies and structural distortions. AB - This work reports an x-ray absorption near-edge structure spectroscopy (XANES) study at both Mn and Zn K edges in Zn(0.95)Mn(0.05)O thin films prepared with different sputtering gases (pure Ar, Ar/N(2) and Ar/O(2)). We have studied the local order around Mn in the films, with special emphasis on the role played by both oxygen and zinc vacancies and by the structural distortion associated with the substitution of Zn by Mn in the ZnO host. Our results indicate that the dependence of the magnetic properties of these Mn:ZnO thin films on the different sputtering gases used in the preparation is related to the structural distortion around Mn sites. PMID- 21540507 TI - Measuring the mobility of single crystalline wires and its dependence on temperature and carrier density. AB - Kinetic transport parameters are fundamental for the development of electronic nanodevices. We present new results for the temperature dependence of mobility and carrier density in single crystalline In(2)O(3) samples and the method of extraction of these parameters which can be extended to similar systems. The data were obtained using a conventional Hall geometry and were quantitatively described by the semiconductor transport theory characterizing the electron transport as being controlled by the variable range hopping mechanism. A comprehensive analysis is provided showing the contribution of ionized impurities (low temperatures) and acoustic phonon (high temperatures) scattering mechanisms to the electron mobility. The approach presented here avoids common errors in kinetic parameter extraction from field effect data, serving as a versatile platform for direct investigation of any nanoscale electronic materials. PMID- 21540508 TI - Spin-polarized electron transport through graphene nanoribbon with zigzag edges. AB - We investigate the electron transport through a graphene nanoribbon (GNR) junction with zigzag edges. It is shown that the edge state and the magnetization properties of a GNR greatly influence its electron transport properties. By applying sufficient back-gate voltages to the lead parts of a zigzag GNR, the magnetization of the edges is quenched in the leadings parts, but is preserved in the center part of the junction. Without applying external transverse electric field, we show that, by preparing the junction in a ferromagnetic state, a strongly spin-polarized electron current can be obtained even though the incident electron current has no spin polarization. PMID- 21540509 TI - Magnetic control of ferroelectric interfaces. AB - We report the strong magnetic field dependence of ferroelectric PbZr(0.52)Ti(0.48)O(3) (PZT) films on half-metallic oxide La(0.67)Sr(0.33)MnO(3) (LSMO) electrodes. As the field H is increased, the hysteresis loop first broadens (becomes lossy) and then disappears at approximately H = 0.34 T and ambient temperatures. The data are compared with the theories of Pirc et al (2009 Phys. Rev. B 79 214114), Parish and Littlewood (2008 Phys. Rev. Lett. 101 166602) and Catalan (2006 Appl. Phys. Lett. 88 102902). The results are interpreted as due not to magnetocapacitance but to the sharp negative magnetoresistance in LSMO at low magnetic fields (Hwang et al 1996 Phys. Rev. Lett. 77 2041), which causes a dramatic increase in leakage current through the PZT. PMID- 21540510 TI - An ab initio calculation study of silicon and carbon binary clusters C7Si(n) (n = 1-7). AB - Binary C(7)Si(n) (n = 1-7) clusters are studied using density functional calculations at the level of B3LYP/6-311G(d). Lowest-energy structures have been determined theoretically and their properties such as binding energies, second differences in energy and highest-occupied and lowest-unoccupied molecular orbital gaps have been analyzed. It is found that the lowest-energy structures of the C(7)Si(n) (n = 1-7) clusters change from linear to planar when n >= 3, and in the planar structures C atoms prefer to form five- and six-membered rings surrounded by extra Si atoms in the form of the C(2)Si units. PMID- 21540511 TI - Photosensitization of carbon nanotubes using dye aggregates. AB - Ordered assemblies of dye molecules, dye aggregates, possess significantly larger molar optical absorptivity than dye monomers. Yet, aggregates have not been utilized for photosensitizing nanoscale electronic devices. We find that single walled carbon nanotubes, which are cleaned down to the atomic scale, template the growth of squaraine dye aggregates and these aggregates effectively photosensitize nanotubes. Templating of aggregates by nanotubes and functionalization of nanotubes with ordered molecular films are reported for the first time. The sensitivity achieved by aggregate-functionalized nanotube network devices is approximately an order of magnitude better than those of similar nanotube devices functionalized with dye monomers and photoactive polymers. PMID- 21540512 TI - Determination of the magnetic contribution to the heat capacity of cobalt oxide nanoparticles and the thermodynamic properties of the hydration layers. AB - We present low temperature (11 K) inelastic neutron scattering (INS) data on four hydrated nanoparticle systems: 10 nm CoO.0.10H(2)O (1), 16 nm Co(3)O(4).0.40H(2)O (2), 25 nm Co(3)O(4).0.30H(2)O (3) and 40 nm Co(3)O(4).0.026H(2)O (4). The vibrational densities of states were obtained for all samples and from these the isochoric heat capacity and vibrational energy for the hydration layers confined to the surfaces of these nanoparticle systems have been elucidated. The results show that water on the surface of CoO nanoparticles is more tightly bound than water confined to the surface of Co(3)O(4), and this is reflected in the reduced heat capacity and vibrational entropy for water on CoO relative to water on Co(3)O(4) nanoparticles. This supports the trend, seen previously, for water to be more tightly bound in materials with higher surface energies. The INS spectra for the antiferromagnetic Co(3)O(4) particles (2-4) also show sharp and intense magnetic excitation peaks at 5 meV, and from this the magnetic contribution to the heat capacity of Co(3)O(4) nanoparticles has been calculated; this represents the first example of use of INS data for determining the magnetic contribution to the heat capacity of any magnetic nanoparticle system. PMID- 21540513 TI - Melting of graphene: from two to one dimension. AB - The high temperature behaviour of graphene is studied by atomistic simulations based on an accurate interatomic potential for carbon. We find that clustering of Stone-Wales defects and formation of octagons are the first steps in the process of melting which proceeds via the formation of carbon chains. The molten state forms a three-dimensional network of entangled chains rather than a simple liquid. The melting temperature estimated from the two-dimensional Lindemann criterion and from extrapolation of our simulation for different heating rates is about 4900 K. PMID- 21540514 TI - The effects of disorder and interactions on the Anderson transition in doped graphene. AB - We undertake an exact numerical study of the effects of disorder on the Anderson localization of electronic states in graphene. Analyzing the scaling behaviors of inverse participation ratio and geometrically averaged density of states, we find that the Anderson metal-insulator transition can be introduced by the presence of quenched random disorder. In contrast with the conventional picture of localization, four mobility edges can be observed for the honeycomb lattice with specific disorder strength and impurity concentration. Considering the screening effects of interactions on disorder potentials, the experimental findings of the scale enlargements of puddles can be explained by reviewing the effects of both interactions and disorder. PMID- 21540515 TI - Thermodynamics of face-centered-cubic silicon nucleation at the nanoscale from laser ablation. AB - The thermodynamic nucleation and the phase transition of the face-centered-cubic structure of Si (fcc-Si) on the nanoscale are performed by taking the effect of nanosize-induced additional pressure on the fcc-Si formation under the conditions generated by laser ablation in liquid into account. The thermodynamic analyses showed that the formation of fcc-Si nanocrystals with sizes of 2-6 nm would take place prior to that of large fcc-Si nanocrystals, and the phase transition probability from diamond-like structure Si (d-Si) to fcc-Si is rather high, up to 10(-3)-10(-2), under the conditions created by laser ablation of an Si target in water. These theoretical results suggest that laser ablation in liquid would be an effective industrial route to prepare ultrasmall fcc-Si nanocrystals. PMID- 21540516 TI - Boron and nitrogen impurities in SiC nanoribbons: an ab initio investigation. AB - Using ab initio calculations based on density-functional theory we have performed a theoretical investigation of substitutional boron and nitrogen impurities in silicon carbide (SiC) nanoribbons. We have considered hydrogen terminated SiC ribbons with zigzag and armchair edges. In both systems we verify that the boron and nitrogen atoms energetically prefer to be localized at the edges of the nanoribbons. However, while boron preferentially substitutes a silicon atom, nitrogen prefers to occupy a carbon site. In addition, our electronic-structure calculations indicate that (i) substitutional boron and nitrogen impurities do not affect the semiconducting character of the armchair SiC nanoribbons, and (ii) the half-metallic behavior of the zigzag nanoribbons is maintained in the presence of substitutional boron impurities. In contrast, nitrogen atoms occupying edge carbon sites transform half-metallic zigzag nanoribbons into metallic systems. PMID- 21540517 TI - Microscopic theory of ultrafast spin linear reversal. AB - A recent experiment (Vahaplar et al 2009 Phys. Rev. Lett. 103 117201) showed that a single femtosecond laser can reverse the spin direction without spin precession, or spin linear reversal (SLR), but its microscopic theory has been missing. Here we show that SLR does not occur naturally. Two generic spin models, the Heisenberg and Hubbard models, are employed to describe magnetic insulators and metals, respectively. We find analytically that the spin change is always accompanied by a simultaneous excitation of at least two spin components. The only model that has prospects for SLR is the Stoner single-electron band model. However, under the influence of the laser field, the orbital angular momenta are excited and are coupled to each other. If a circularly polarized light is used, then all three components of the orbital angular momenta are excited, and so are their spins. The generic spin commutation relation further reveals that if SLR exists, it must involve a complicated multiple state excitation. PMID- 21540518 TI - Mossbauer studies of the superconducting cobalt/nickel-doped BaFe2As2. Whither go the injected electron(s)? AB - Mossbauer studies of cobalt- and nickel-doped BaFe(2)As(2) show that the s electron density at the (57)Fe nuclei, as measured by the isomer shift, is the same as that for the parent BaFe(2)As(2). Apparently, the electron population of the d shell, which shields the s-electron density at the nuclei, remains unchanged. We invoke the involvement of p-orbital hybridization with the d orbital in Fe-As bonding. Furthermore, the shrinkage of the lattice on substitution enhances the As-As sp hybridization, providing a path for the migration of additional electrons. The proposed mechanism is consistent with Hall coefficient and thermoelectric effect measurements. PMID- 21540519 TI - First-principles prediction of shape memory behavior and ferrimagnetism in Mn2NiSn. AB - Using first-principles density functional theory, we show that, in Mn(2)NiSn, an energy lowering phase transition from the cubic to tetragonal phase occurs which indicates a martensitic phase transition. This structural phase transition is nearly volume-conserving, implying that this alloy can exhibit shape memory behavior. The magnetic ground state is a ferrimagnetic one with antiparallel Mn spin moments. The calculated moments with different electronic structure methods in the cubic phase compare well with each other but differ from the experimental values by more than 1 MU(B). The reason behind this discrepancy is explored by considering antisite disorder in our calculations, which indicates that the site ordering in this alloy can be quite complex. PMID- 21540520 TI - Evolution of a metastable phase with a magnetic phase coexistence phenomenon and its unusual sensitivity to magnetic field cycling in the alloys Tb(5 - x)Lu(x)Si3 (x <= 0.7). AB - Recently, we reported an anomalous enhancement of the positive magnetoresistance beyond a critical magnetic field in Tb(5)Si(3) in the magnetically ordered state, attributable to 'inverse metamagnetism'. This results in unusual magnetic hysteresis loops for the pressurized specimens, which are relevant to the topic of 'electronic phase separation'. In this paper, we report the influence of small substitutions of Lu for Tb, to show the evolution of these magnetic anomalies. We find that, at low temperatures, the high-field high-resistivity phase could be partially stabilized on returning the magnetic field to zero in many of these Lu substituted alloys, as measured through the electrical resistivity (rho). Also, the relative fractions of this phase and the virgin phase appear to be controlled by a small tuning of the composition and temperature. Interestingly, at 1.8 K a sudden 'switch-over' of the value of rho for this mixed phase to that for the virgin phase for some compositions is observed at low fields after a few field cycles, indicating metastability of this mixed phase. PMID- 21540521 TI - Conductance anisotropy and linear magnetoresistance in La(2 - x)Sr(x)CuO4 thin films. AB - We have performed a detailed study of conductance anisotropy and magnetoresistance (MR) of La(2 - x)Sr(x)CuO(4) (LSCO) thin films (0.10 < x < 0.25). These two observables are promising for the detection of stripes. Subtle features of the conductance anisotropy are revealed by measuring the transverse resistance R(xy) in zero magnetic field. It is demonstrated that the sign of R(xy) depends on the orientation of the LSCO Hall bar with respect to the terrace structure of the substrate. Unit-cell-high substrate step edges must therefore be a dominant nucleation source for antiphase boundaries during film growth. We show that the measurement of R(xy) is sensitive enough to detect the cubic-tetragonal phase transition of the SrTiO(3)(100) (STO) substrate at 105 K. The MR of LSCO thin films shows for 0.10 < x < 0.25 a non-monotonic temperature dependence, resulting from the onset of a linear term in the MR above 90 K. We show that the linear MR scales with the Hall resistivity as [Formula: see text], with the constant of proportionality independent of temperature. Such scaling suggests that the linear MR originates from current distortions induced by structural or electronic inhomogeneities. The possible role of stripes for both the MR and the conductance anisotropy is discussed throughout the paper. PMID- 21540523 TI - Dy2(SO3)2(SO4)(H2O)2: the first lanthanide mixed sulfate-sulfite inorganic compound. AB - The first lanthanide mixed sulfate-sulfite inorganic coordination polymer, poly[diaqua-MU(4)-sulfato-di-MU(4)-sulfito-didysprosium(III)], [Dy(2)(SO(3))(2)(SO(4))(H(2)O)(2)](n), has been obtained, in which both sulfate and sulfite groups originate from the disproportionation of S(2)O(3)(2-) under hydrothermal and weakly acidic conditions. The crystal structure of the title compound exhibits a three-dimensional framework. The Dy(III) ion is surrounded by eight O atoms from one water molecule and two sulfate and five sulfite groups. These DyO(8) polyhedra have two shared edges and form an infinite zigzag Dy-O chain. In the bc plane, neighbouring chains are integrated through SO(3) trigonal pyramids, forming a two-dimensional sheet. Along the a-axial direction, the sulfate group, with the central S atom lying on a twofold axis, links adjacent two-dimensional sheets via two S-O-Dy connections, thus generating the three dimensional framework. PMID- 21540522 TI - Effects of phosphate-buffered saline concentration and incubation time on the mechanical and structural properties of electrochemically aligned collagen threads. AB - A key step during the synthesis of collagen constructs is the incubation of monomeric collagen in phosphate buffer saline (PBS) to promote fibrillogenesis in the collagen network. Optimal PBS-treatment conditions for monomeric collagen solutions to induce gelation are well established in the literature. Recently, a report in the literature (Cheng et al 2008 Biomaterials 29 3278-88) showed a novel method to fabricate highly oriented electrochemically aligned collagen (ELAC) threads which have orders of magnitude greater packing density than collagen gels. The optimal PBS-treatment conditions for induction of D-banding pattern in such a dense and anisotropic collagen network are unknown. This study aimed to optimize PBS treatment of ELAC threads by investigating the effect of phosphate ion concentration (0.5*, 1*, 5* and 10*) and incubation time (3, 12 and 96 h) on the mechanical strength and ultrastructural organization by monotonic mechanical testing, small angle x-ray scattering and transmission electron microscopy (TEM). ELAC threads incubated in water (no PBS) served as the control. ELAC threads incubated in 1* PBS showed significantly higher extensibility compared to those in 0.5* or 10* PBS along with the presence of D-banded patterns with a periodicity of 63.83 nm. Incubation of ELAC threads in 1* PBS for 96 h resulted in significantly higher ultimate stress compared to 3 or 12 h. However, these threads lacked the D-banding pattern. TEM observations showed no significant differences in the microfibril diameter distribution of ELAC threads treated with or without PBS. This indicates that microfibrils lacked D-banding following electrochemical alignment and the subsequent PBS-treatment-induced D banding by reorganization within microfibrils. It was concluded that incubation of aligned collagen in 1* PBS for 12 h results in mechanically competent, D banded ELAC threads which can be used for the regeneration of load bearing tissues such as tendons and ligaments. PMID- 21540524 TI - Synthetic ferric sulfate trihydrate, Fe2(SO4)3.3H2O, a new ferric sulfate salt. AB - Ferric sulfate trihydrate has been synthesized at 403 K under hydrothermal conditions. The structure consists of quadruple chains of [Fe(2)(SO(4))(3)(H(2)O)(3)](0)(infinity) parallel to [010]. Each quadruple chain is composed of equal proportions of FeO(4)(H(2)O)(2) octahedra and FeO(5)(H(2)O) octahedra sharing corners with SO(4) tetrahedra. The chains are joined to each other by hydrogen bonds. This compound is a new hydration state of Fe(2)(SO(4))(3).nH(2)O; minerals with n = 0, 5, 7.25-7.75, 9 and 11 are found in nature. PMID- 21540525 TI - A sodium salt of the dimer of boronoterephthalic acid anhydride. AB - The title compound, sodium bis(6-carboxy-1-hydroxy-3-oxo-1,3-dihydro-2,1 benzoxaborol-1-yl)oxidanium, Na(+).C(16)H(15)B(2)O(13)(-), was prepared in two steps from 2-bromo-p-xylene. Its crystal structure was determined at 140 K and has triclinic ( P1) symmetry. The compound presents a unique structural motif, including two units of the cyclic anhydride of boronoterephthalic acid, joined by a protonated, and thereby trivalent, oxonium center. Association in the crystal is realized by complementary hydrogen bonding of the carboxyl groups, as well as by coordination of the sodium cations to the oxygen centers on the five-membered rings. PMID- 21540526 TI - Bis(4-methylbenzylammonium) tetrachloridozincate: a new noncentrosymmetric structure characterized by 13C CP-MAS NMR spectroscopy. AB - A new noncentrosymmetric organic-inorganic hybrid material, (C(8)H(12)N)(2)[ZnCl(4)], has been synthesized as single crystals at room temperature and characterized by X-ray diffraction and solid-state NMR spectroscopy. Its novel structure consists of two 4-methylbenzylammonium cations and one [ZnCl(4)](2-) anion connected by N-H...Cl and C-H...Cl hydrogen bonds, two of which are three-centre interactions. The Zn(II) metal centre has a slightly distorted tetrahedral coordination geometry. Results from (13)C CP-MAS NMR spectroscopy are in good agreement with the X-ray structure. Density functional theory calculations allow the assignment of the carbon peaks to the independent crystallographic sites. PMID- 21540527 TI - MU-Acetato-MU-aqua-MU-hydroxido-bis[(1,10-phenanthroline)copper(II)] dinitrate monohydrate. AB - The triply bridged title dinuclear copper(II) compound, [Cu(2)(C(2)H(3)O(2))(OH)(C(12)H(8)N(2))(2)(H(2)O)](NO(3))(2).H(2)O, (I), consists of a [Cu(2)(MU(2)-CH(3)COO)(MU(2)-OH)(phen)(2)(MU(2)-OH(2))](2+) cation (phen is 1,10-phenanthroline), two uncoordinated nitrate anions and one water molecule. The title cation contains a distorted square-pyramidal arrangement around each metal centre with a CuN(2)O(3) chromophore. In the dinuclear unit, both Cu(II) ions are linked through a hydroxide bridge and a triatomic bridging carboxylate group, and at the axial positions through a water molecule. The phenanthroline groups in neighbouring dinuclear units interdigitate along the [010] direction, generating several pi-pi contacts which give rise to planar arrays parallel to (001). These are in turn connected by hydrogen bonds involving the aqua and hydroxide groups as donors with the nitrate anions as acceptors. Comparisons are made with isostructural compounds having similar cationic units but different counter-ions; the role of hydrogen bonding in the overall three-dimensional structure and its ultimate effect on the cell dimensions are discussed. PMID- 21540528 TI - Diammonium hexakis(thiocyanato-kappaN)rhenate(IV) dimethyl sulfone tetrasolvate. AB - The title compound, (NH(4))(2)[Re(NCS)(6)].4C(2)H(6)O(2)S, was obtained by solvothermal synthesis as part of a project on rhenium thiocyanate catalysts and starting materials for further aggregation to molecular magnets. The compound is the ammonium salt of octahedral hexakis(thiocyanato-kappaN)rhenate(IV) anions, which lie on centres of inversion. The dimethyl sulfone solvent molecules are involved in R(4)(2)(8) and D N-H...O hydrogen-bonded motifs. N-H...S and S...S short contacts are also present. Hydrogen-bonded ammonium-dimethyl sulfone layers alternate with layers formed by the complex anion (with S...S short contacts) parallel to (100). PMID- 21540529 TI - A novel two-dimensional (4,4) network based on dinuclear cadmium secondary building units: poly[(MU5-benzene-1,4-diacetato)[MU2-1,4-bis(1,2,4-triazol-1 yl)butane]cadmium(II)]. AB - In the title mixed-ligand metal-organic polymeric compound, [Cd(C(10)H(8)O(4))(C(8)H(12)N(6))](n) or [Cd(PBEA)(BTB)](n) [H(2)PBEA is benzene 1,4-diacetic acid and BTB is 1,4-bis(1,2,4-triazol-1-yl)butane], the asymmetric unit contains one Cd(II) ion, one BTB molecule and one PBEA(2-) anion. The Cd(II) ion is in a slightly distorted pentagonal-bipyramidal geometry, coordinated by five carboxylate O atoms from three distinct PBEA(2-) anions and by two BTB N atoms. There are two coordination patterns for the carboxylate groups of the PBEA(2-) ligand, one being a MU(1)-eta(1):eta(1) chelating mode and the other a MU(2)-eta(2):eta(1) bridging mode, while the BTB molecule shows a trans-trans trans conformation. The crystal structure is constructed from the secondary building unit (SBU) [Cd(2)(CO(2))(4)N(2)O(2)], in which the two metal centres are held together by two PBEA(2-) linkers. The SBU is connected by BTB and PBEA(2-) bridges to form a two-dimensional grid-like (4,4) layer with meshes of dimensions 14.69 * 11.28 A. PMID- 21540530 TI - Bis[(dihydrogen pyrophosphato-kappa(2)O,O')(2,2':6',2''-terpyridine kappa(3)N,N',N'')copper(II)] 4.5-hydrate. AB - The title copper complex, [Cu(H(2)P(2)O(7))(C(15)H(11)N(3))](2).4.5H(2)O, consists of two very similar independent Cu(Tpy)H(2)P(2)O(7) monomeric units (Tpy is 2,2':6',2''-terpyridine) plus four and a half water molecules of hydration, some of which are disordered. Tpy units bind through the usual triple bite via their N atoms, and the H(2)P(2)O(7)(2-) anions coordinate through two O atoms from two different phosphate units. Each independent CuN(3)O(2) chromophore can be described as a slightly deformed square pyramid, with one of them having a sixth, semicoordinated, O atom from a centrosymmetrically related CuN(3)O(2) unit in a weakly bound second apical position suggesting an octahedral environment for the cation and weak dimerization of the molecule. The two independent complex molecules are connected via two strong O-H...O interactions between the phosphate groups to form hydrogen-bonded dinuclear units, further linked into [111] columns, resulting in a very complex three-dimensional supramolecular structure through a variety of classical and nonclassical hydrogen bonds, as well as pi-pi interactions. PMID- 21540531 TI - Poly[tetra-MU2-L-lactato-indium(III)sodium(I)]. AB - The asymmetric unit of the title compound, [InNa(C(3)H(5)O(3))(4)](n), consists of one In(III) ion, one Na(I) ion and four crystallographically independent L lactate monoanions. The coordination of the In(III) ion is composed of five carboxylate O and two hydroxy O atoms in a distorted pentagonal-bipyramidal coordination geometry. The Na(I) ion is six-coordinated by four carboxylate O atoms and two hydroxy O atoms from four L-lactate ligands in a distorted octahedral geometry. Each In(III) ion is coordinated by four surrounding L lactate ligands to form an [In(L-lactate)(4)](-) unit, which is further linked by Na(I) ions through Na-O bonds to give a two-dimensional layered structure. Hydrogen bonds between the hydroxy groups and carboxylate O atoms are observed between neighbouring layers. PMID- 21540532 TI - Two polymorphs of tetraethylammonium [hydrogen tris(3,5 dimethylpyrazolyl)borato]di-MU2-sulfido-disulfido(eta(2) tetrasulfido)ditungsten(V) with Z' = 1 and 2. AB - Two polymorphs of the title compound, (C(8)H(20)N)[W(2)S(4)(S(4))(C(15)H(22)BN(6))], have been obtained unexpectedly by attempted recrystallization of a mixed-metal-sulfur cluster complex from different solvents. The dinuclear complex anion contains W(V) in two different coordination environments, one of them distorted octahedral with a tris(pyrazolyl)borate anion, a terminal sulfide and two bridging sulfide ligands, the other distorted square-pyramidal with a terminal sulfide, two bridging sulfide and a chelating tetrasulfide ligand. The three independent anions in the two polymorphs have essentially the same geometry. The central W(2)S(2) ring is a slightly folded rhombus with acute angles at the S atoms, and the WS(4) chelate ring is an envelope with one noncoordinating S atom as the flap. The second polymorph, with Z' = 2 and pseudo-inversion symmetry relating the anions of the asymmetric unit, also displays pseudo-translation features in its layer structure, and all examined crystals were found to be twinned, possibly as a consequence of this structural feature. PMID- 21540533 TI - trans-Dichloridobis(4,8-dimethyl-2-phenyl-2-phosphabicyclo[3.3.1]nonane kappaP)platinum(II). AB - The crystal structure of the title compound, trans-[PtCl(2)(C(16)H(23)P)(2)], has been determined at 100 K. The Pt atom is located on a twofold axis and adopts a distorted square-planar coordination geometry. The structure is only the second example of a coordination complex containing a derivative of the 4,8-dimethyl-2 phosphabicyclo[3.3.1]nonane (Lim) phosphine ligand family. The ligand contains four chiral C atoms, with the stereochemistry at three of these fixed during synthesis, therefore resulting in two possible ligand stereoisomers. The compound crystallizes in the chiral space group P4(3)2(1)2 but is racemic, comprising an equimolar mixture of both stereoisomers disordered on a single ligand site. The effective cone angles for both isomers are the same at 146 degrees . PMID- 21540534 TI - A new double-cube nitride complex containing titanium and potassium. AB - The reaction of the imide-nitride complex [{Ti(eta(5)-C(5)Me(5))(MU-NH)}(3)(MU(3) N)] with potassium iodide in pyridine at room temperature affords the adduct di MU-iodido-1:1'kappa(4)I-bis{tri-MU(3)-imido 1:2:3kappa(3)N;1:2:4kappa(3)N;1:3:4kappa(3)N-MU(3)-nitrido-2:3:4kappa(3)N tris[2,3,4(eta(5))-pentamethylcyclopentadienyl](pyridine-1kappaN)-tetrahedro potassiumtrititanium(IV)}, [K(2)Ti(6)(C(10)H(15))(6)I(2)N(2)(NH)(6)(C(5)H(5)N)(2)] or [(C(5)H(5)N)(MU I)K{(MU(3)-NH)(3)Ti(3)(eta(5)-C(5)Me(5))(3)(MU(3)-N)}](2). The crystal structure contains two [KTi(3)N(4)] cube-type units held together by two bridging I atoms. There is a centre of inversion located in the middle of this unprecedented discrete K(2)I(2) unit. The geometry around K is best described as distorted trigonal prismatic, with three imide groups, two bridging I atoms and one pyridine ligand. PMID- 21540535 TI - The hydrogen-bonded dimers of N,N',N''-tricyclohexylphosphoric triamide in new tin(IV) and copper(II) complexes. AB - In the new tin(IV) and copper(II) complexes, cis-dichlorido-trans-dimethyl-cis bis(N,N',N''-tricyclohexylphosphoric triamide-kappaO)tin(IV), [Sn(CH(3))(2)Cl(2)(C(18)H(36)N(3)OP)(2)], (I), and trans-diaquabis(N,N',N'' tricyclohexylphosphoric triamide-kappaO)copper(II) dinitrate-N,N',N'' tricyclohexylphosphoric triamide (1/2), [Cu(C(18)H(36)N(3)OP)(2)(H(2)O)(2)](NO(3))(2).2C(18)H(36)N(3)OP, (II), the N,N',N''-tricyclohexylphosphoric triamide (PTA) ligands exist as hydrogen-bonded dimers via P=O...H-N interactions around the metal center. The asymmetric unit in (I) consists of one complete complex molecule located on a general position. The Sn(IV) coordination geometry is octahedral with two cis hydrogen-bonded PTA ligands, two cis chloride ligands and two trans methyl groups. The asymmetric unit in (II) contains one half of a [Cu(PTA)(2)(H(2)O)(2)](2+) dication on a special position (site symmetry 1 for the Cu atom), one nitrate anion and one free PTA molecule, both on general positions. The complex adopts a square-planar trans-[CuO(2)O(2)] coordination geometry, with the Cu(II) ion coordinated by two PTA ligands and two water molecules. Each of the noncoordinated PTA molecules is hydrogen bonded to a neighboring coordinated PTA molecule and an adjacent water molecule; the phosphoryl O atom acts as a double-H-atom acceptor. The P atoms in the PTA ligands of both complexes and in the noncoordinated hydrogen-bonded molecules in (II) adopt a slightly distorted tetrahedral environment. PMID- 21540536 TI - trans-Carbonylchloridobis(ferrocenyldiphenylphosphane-kappaP)rhodium(I) dichloromethane monosolvate and trans carbonylchloridobis(ferrocenyldiphenylphosphane-kappaP)iridium(I) dichloromethane monosolvate. AB - The isomorphous crystal structures of the title compounds, [Fe(2)M(C(5)H(5))(2)(C(17)H(14)P)Cl(CO)].CH(2)Cl(2) or trans [MCl(CO)(PPh(2)Fc)(2)].CH(2)Cl(2) (M = Rh or Ir, and Fc is ferrocenyl), are reported. The data collection for M = Rh was performed at 293 (2) K, while the M = Ir data were collected at 160 (2) K. The compounds crystallize with two independent half-molecules in the asymmetric unit, both occupying inversion centres, and are accompanied by a single dichloromethane molecule on a general position. Due to the symmetry, there is 0.50/0.50 disorder present in the chloride and carbonyl positions. One molecule in each structure also has a second type of disorder in the chloride and carbonyl positions, which was refined over another two positions of equal distribution. The steric impact of the bulky PPh(2)Fc ligands was evaluated using the Tolman cone-angle model, resulting in an average value of 172 degrees for the four molecules in both structures. PMID- 21540537 TI - Two isomorphous transition metal complexes containing a protonated diaminopurine ligand: diaquabis(2,6-diamino-7H-purin-1-ium-kappaN9)bis(homophthalato kappaO)nickel(II) tetrahydrate and the cobalt(II) analogue. AB - The two isomorphous title compounds, [M(C(5)H(7)N(6))(2)(C(9)H(6)O(4))(2)(H(2)O)(2)].4H(2)O or M(2+)(Hdap(+))(2)(hpt(2 ))(2)(H(2)O)(2).4H(2)O {where dap is 2,6-diaminopurine, H(2)hpt is homophthalic acid [2-(2-carboxyphenyl)acetic acid] and M is Ni(II) or Co(II)}, consist of neutral M(2+)(Hdap(+))(2)(hpt(2-))(2)(H(2)O)(2) monomers, where the M(II) cation lies on an inversion centre and its MN(2)O(4) octahedral environment is defined by one N atom (from Hdap(+)), two O atoms (from one hpt(2-) dianion and one water molecule) and their inversion images. The structures are unusual in that the Hdap(+) cation occurs in an uncommon protonated state (as 2,6-diamino-7H-purin-1 ium) and both ligands bind in an unprecedented monodentate fashion. The existence of a large number of donors and acceptors for hydrogen bonding, together with pi pi interactions, leads to a rather complex three-dimensional structure. PMID- 21540538 TI - Multiple intramolecular hydrogen bonds in 2,4-di-tert-butyl-6-[N-(2,6 diisopropylphenyl)-P,P-diphenylphosphorimidoyl]phenol. AB - The title compound, C(38)H(48)NOP, isolated from the reaction of (2 diphenylphosphanyl-4,6-di-tert-butyl)phenol with 2,6-diisopropylphenyl azide at 273 K, can act as an N,O-bidentate ligand. Crystal structure analysis shows a deviation from ideal tetrahedral symmetry around the P atom. The molecule exists as a monomer in the solid state, whose conformation is stabilized via multiple intramolecular hydrogen bonds. Geometric parameters from both experimental and theoretical calculations are compared. PMID- 21540539 TI - The effect of Cl...pi interactions on the conformations of 4-chloro-5-(2 phenoxyethoxy)phthalonitrile and 4-chloro-5-[2 (pentafluorophenoxy)ethoxy]phthalonitrile. AB - 4-Chloro-5-(2-phenoxyethoxy)phthalonitrile, C(16)H(11)ClN(2)O(2), (I), and 4 chloro-5-[2-(pentafluorophenoxy)ethoxy]phthalonitrile, C(16)H(6)ClF(5)N(2)O(2), (II), show different types of electrostatic interaction. In (I), the phenoxy and phthalonitrile (benzene-1,2-dicarbonitrile) moieties are well separated in an open conformation and intermolecular C-H...pi interactions are observed in the crystal packing. On the other hand, in (II), the pentafluorophenoxy moiety interacts closely with the Cl atom to form a folded conformation containing an intramolecular halogen-pi interaction. PMID- 21540540 TI - (2R*,4S*)-2-(pyridin-3-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol: a three dimensional framework built from O-H...N, C-H...O and C-H...pi(arene) hydrogen bonds. AB - The title compound, C(15)H(16)N(2)O, crystallizes in the space group P2(1)2(1)2(1) with Z' = 1. The seven-membered ring adopts a chair-type conformation with the hydroxy and pyridyl substituents in equatorial sites. Molecules are linked into a three-dimensional framework structure by a combination of O-H...N, C-H...O and C-H...pi(arene) hydrogen bonds, but N-H...O and N-H...pi(arene) interactions are absent from the structure. Comparisons are made with some related compounds. PMID- 21540541 TI - Acidic and anionic forms of 1,3-cyclic dihydroxyacetone phosphate (cDHAP) dimethyl acetal. AB - The six-membered cyclic phosphate diester, 5,5-dimethoxy-2-hydroxy-1,3,2 dioxaphosphorinan-2-one, C(5)H(11)O(6)P or (MeO)(2)cDHAP, which is the dimethyl acetal of cyclic dihydroxyacetone phosphate (cDHAP), has been obtained in the form of two new cyclohexylammonium (cha) salts, cyclohexylammonium 5,5-dimethoxy 2-oxo-1,3,2-dioxaphosphorinan-2-olate monohydrate, (cha)[(MeO)(2)cDHAP].H(2)O or C(6)H(14)N(+).C(5)H(10)O(6)P(-).H(2)O, and cyclohexylammonium 5,5-dimethoxy-2-oxo 1,3,2-dioxaphosphorinan-2-olate, (cha)[(MeO)(2)cDHAP] or C(6)H(14)N(+).C(5)H(10)O(6)P(-), as well as in the form of the anhydrous free acid, (MeO)(2)cDHAP. It is shown that protonation of the cyclic phosphate group influences the chair conformation of the P/O/C/C/C/O 1,3,2-dioxaphosphorinane ring, and that differences in the ring conformation correlate with different deformations observed in the ionized and protonated phosphate groups. The ring is more evenly puckered in the anions, in contrast with the flattening observed in the structure of the free acid. PMID- 21540542 TI - 2-(Benzoylsulfanyl)acetic acid and 2,5-dioxopyrrolidin-1-yl 2 (benzoylsulfanyl)acetate by powder X-ray diffraction studies. AB - The structures of the title compounds, C(9)H(8)O(3)S, (I), and C(13)H(11)NO(5)S, (II), were determined by X-ray powder diffraction. Both were solved using the direct-space parallel tempering algorithm and refined using the Rietveld method. In (I), the C-S-C bond angle is slightly smaller than normal, indicating more p character in the bonding orbitals of the S atom. The carboxylic acid group joins across an inversion centre to form a dimer. The crystal packing includes a weak C H...O hydrogen bond between an aromatic C-H group and a carboxylic acid O atom to form a two-dimensional network parallel to (10 1). The C-S-C bond angle in (II) is larger than its counterpart in (I), indicating that the S atom of (II) has less p character in its bonding orbitals than that of (I), according to Bent's rule. The crystal structure of (II) includes weak C-H...O hydrogen bonds between the H atoms of the methylene groups and carbonyl O atoms, forming a three dimensional network. PMID- 21540543 TI - Conformational polymorphism of (E,E)-N,N'-bis(4-nitrobenzylidene)benzene-1,4 diamine. AB - Two polymorphs of (E,E)-N,N'-bis(4-nitrobenzylidene)benzene-1,4-diamine, C(20)H(14)N(4)O(4), (I), have been identified. In each case, the molecule lies across a crystallographic inversion centre. The supramolecular structure of the first polymorph, (I-1), features stacking based on pi-pi interactions assisted by weak hydrogen bonds involving the nitro groups. The second polymorph, (I-2), displays a perpendicular arrangement of molecules linked via the nitro groups, combined with weak C-H...O hydrogen bonds. Both crystal structures are compared with that of the carbon analogue (E,E)-1,4-bis[2-(4-nitrophenyl)ethenyl]benzene, (II). PMID- 21540544 TI - A novel Janus-type AT nucleoside with benzoyl protecting groups forming a pleated sheet structure. AB - The title compound, 5-amino-8-(2,3,5-tri-O-benzoyl-beta-D ribofuranosyl)pyrimido[4,5-d]pyrimidine-2,4(3H,8H)-dione methanol monosolvate, C(32)H(25)N(5)O(9).CH(4)O, which crystallized slowly from methanol, exhibits an anti conformation with a glycosyl-bond torsion angle of chi=-141.28 (17) degrees . The furanose moiety adopts an N-type sugar puckering ((3)T(4)). The corresponding pseudorotation phase angle and maximum amplitude are P=24.5 (2) degrees and tau(m)=38.3 (2) degrees , respectively. In the solid state, one methanol molecule acts as a bridge joining adjacent nucleoside molecules head-to head, leading to a pleated-ribbon supramolecular structure, with the base moieties located in the centre of the ribbon and the sugar residues protruding to the outside of the layers, as in a DNA helix. The pleated-ribbon supramolecular structure is tethered together into a two-dimensional infinite pleated-sheet structure through aromatic stacking between the nucleobase planes and the benzene rings of the benzoyl protecting groups on the 5'-OH group of furanose. PMID- 21540545 TI - Pseudopolymorphs of 2,6-diaminopyrimidin-4-one and 2-amino-6-methylpyrimidin-4 one: one or two tautomers present in the same crystal. AB - The derivatives of pyrimidin-4-one can adopt either a 1H- or a 3H-tautomeric form, which affects the hydrogen-bonding interactions in cocrystals with compounds containing complementary functional groups. In order to study their tautomeric preferences, we crystallized 2,6-diaminopyrimidin-4-one and 2-amino-6 methylpyrimidin-4-one. During various crystallization attempts, four structures of 2,6-diaminopyrimidin-4-one were obtained, namely solvent-free 2,6 diaminopyrimidin-4-one, C(4)H(6)N(4)O, (I), 2,6-diaminopyrimidin-4-one dimethylformamide-water (3/4/1), C(4)H(6)N(4)O.1.33C(3)H(7)NO.0.33H(2)O, (Ia), 2,6-diaminopyrimidin-4-one dimethylacetamide monosolvate, C(4)H(6)N(4)O.C(4)H(9)NO, (Ib), and 2,6-diaminopyrimidin-4-one-N-methylpyrrolidin 2-one (3/2), C(4)H(6)N(4)O.1.5C(5)H(9)NO, (Ic). The 2,6-diaminopyrimidin-4-one molecules exist only as 3H-tautomers. They form ribbons characterized by R(2)(2)(8) hydrogen-bonding interactions, which are further connected to form three-dimensional networks. An intermolecular N-H...N interaction between amine groups is observed only in (I). This might be the reason for the pyramidalization of the amine group. Crystallization experiments on 2-amino-6-methylpyrimidin-4 one yielded two isostructural pseudopolymorphs, namely 2-amino-6-methylpyrimidin 4(3H)-one-2-amino-6-methylpyrimidin-4(1H)-one-dimethylacetamide (1/1/1), C(5)H(7)N(3)O.C(5)H(7)N(3)O.C(4)H(9)NO, (IIa), and 2-amino-6-methylpyrimidin 4(3H)-one-2-amino-6-methylpyrimidin-4(1H)-one-N-methylpyrrolidin-2-one (1/1/1), C(5)H(7)N(3)O.C(5)H(7)N(3)O.C(5)H(9)NO, (IIb). In both structures, a 1:1 mixture of 1H- and 3H-tautomers is present, which are linked by three hydrogen bonds similar to a Watson-Crick C-G base pair. PMID- 21540546 TI - (R)-4-(4-Aminophenyl)-2,2,4-trimethylchroman and (S)-4-(4-aminophenyl)-2,2,4 trimethylthiachroman. AB - The title compounds, C(18)H(21)NO and C(18)H(21)NS, in their enantiomerically pure forms are isostructural with the enantiomerically pure 4-(4-hydroxyphenyl) 2,2,4-trimethylchroman and 4-(2,4-dihydroxyphenyl)-2,2,4-trimethylchroman analogues and form extended linear chains via N-H...O or N-H...S hydrogen bonding along the [100] direction. The absolute configuration for both compounds was determined by anomalous dispersion methods with reference to both the Flack parameter and, for the light-atom compound, Bayesian statistics on Bijvoet differences. PMID- 21540547 TI - Supramolecular patterns in benzyladeninium p-toluenesulfonate. AB - In the title compound (systematic name: 6-benzylamino-7H-purin-3-ium p toluenesulfonate), C(12)H(12)N(5)(+).C(7)H(7)O(3)S(-), the adenine moiety exists as the N(3)-protonated N(7)-H tautomer. The dihedral angle between the adenine ring system and the phenyl ring is 82.76 (11) degrees . Two of the sulfonate O atoms form C-H...O and N-H...O hydrogen bonds with the H atoms on the N and C atoms in the 3- and 8-positions, respectively, of the adenine moiety, leading to a zigzag chain. Two antiparallel zigzag chains are linked by the remaining sulfonate O atom through Hoogsteen-site H atoms (i.e. those on the N atoms in the 6- and 7-positions) of the adenine moiety, leading to a double chain. An annulus formed by a pair of inversion-related anions and cations has been identified. An intramolecular toluenesulfonate-phenyl C-H...pi interaction is also present. PMID- 21540548 TI - Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. AB - In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas. PMID- 21540549 TI - Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets. AB - The success of a non-live vaccine requires improved formulation and adjuvant selection to generate robust T cell immunity following immunization. Here, using protein linked to a TLR7/8 agonist (conjugate vaccine), we investigated the functional properties of vaccine formulation, the cytokines, and the DC subsets required to induce protective multifunctional T cell immunity in vivo. The conjugate vaccine required aggregation of the protein to elicit potent Th1 CD4+ and CD8+ T cell responses. Remarkably, the conjugate vaccine, through aggregation of the protein and activation of TLR7 in vivo, led to an influx of migratory DCs to the LN and increased antigen uptake by several resident and migratory DC subsets, with the latter effect strongly influenced by vaccine-induced type I IFN. Ex vivo migratory CD8-DEC205+CD103-CD326- langerin-negative dermal DCs were as potent in cross-presenting antigen to naive CD8+ T cells as CD11c+CD8+ DCs. Moreover, these cells also influenced Th1 CD4+ T cell priming. In summary, we propose a model in which broad-based T cell-mediated responses upon vaccination can be maximized by codelivery of aggregated protein and TLR7/8 agonist, which together promote optimal antigen acquisition and presentation by multiple DC subsets in the context of critical proinflammatory cytokines. PMID- 21540550 TI - CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. AB - Targeted T cell immunotherapies using engineered T lymphocytes expressing tumor directed chimeric antigen receptors (CARs) are designed to benefit patients with cancer. Although incorporation of costimulatory endodomains within these CARs increases the proliferation of CAR-redirected T lymphocytes, it has proven difficult to draw definitive conclusions about the specific effects of costimulatory endodomains on the expansion, persistence, and antitumor effectiveness of CAR-redirected T cells in human subjects, owing to the lack of side-by-side comparisons with T cells bearing only a single signaling domain. We therefore designed a study that allowed us to directly measure the consequences of adding a costimulatory endodomain to CAR-redirected T cells. Patients with B cell lymphomas were simultaneously infused with 2 autologous T cell products expressing CARs with the same specificity for the CD19 antigen, present on most B cell malignancies. One CAR encoded both the costimulatory CD28 and the zeta endodomains, while the other encoded only the zeta-endodomain. CAR+ T cells containing the CD28 endodomain showed strikingly enhanced expansion and persistence compared with CAR+ T cells lacking this endodomain. These results demonstrate the superiority of CARs with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell immunotherapies. PMID- 21540551 TI - COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. AB - Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of end-stage renal failure. Identification of single-gene causes of SRNS has generated some insights into its pathogenesis; however, additional genes and disease mechanisms remain obscure, and SRNS continues to be treatment refractory. Here we have identified 6 different mutations in coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping. Each mutation was linked to early-onset SRNS with sensorineural deafness. The deleterious effects of these human COQ6 mutations were validated by their lack of complementation in coq6-deficient yeast. Furthermore, knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q10 treatment. In rats, COQ6 was located within cell processes and the Golgi apparatus of renal glomerular podocytes and in stria vascularis cells of the inner ear, consistent with an oto-renal disease phenotype. These data suggest that coenzyme Q10-related forms of SRNS and hearing loss can be molecularly identified and potentially treated. PMID- 21540552 TI - The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells. AB - Neovessel formation is a complex process governed by the orchestrated action of multiple factors that regulate EC specification and dynamics within a growing vascular tree. These factors have been widely exploited to develop therapies for angiogenesis-related diseases such as diabetic retinopathy and tumor growth and metastasis. WNT signaling has been implicated in the regulation and development of the vascular system, but the detailed mechanism of this process remains unclear. Here, we report that Dickkopf1 (DKK1) and Dickkopf2 (DKK2), originally known as WNT antagonists, play opposite functional roles in regulating angiogenesis. DKK2 induced during EC morphogenesis promoted angiogenesis in cultured human endothelial cells and in in vivo assays using mice. Its structural homolog, DKK1, suppressed angiogenesis and was repressed upon induction of morphogenesis. Importantly, local injection of DKK2 protein significantly improved tissue repair, with enhanced neovascularization in animal models of both hind limb ischemia and myocardial infarction. We further showed that DKK2 stimulated filopodial dynamics and angiogenic sprouting of ECs via a signaling cascade involving LRP6-mediated APC/Asef2/Cdc42 activation. Thus, our findings demonstrate the distinct functions of DKK1 and DKK2 in controlling angiogenesis and suggest that DKK2 may be a viable therapeutic target in the treatment of ischemic vascular diseases. PMID- 21540553 TI - IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells. AB - Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3' triiodothyronine (T3) that occurs in chronically ill patients; the degree of reduction in T3 is associated with overall prognosis and survival. Iodthyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T4 to active T3, whereas the type III enzyme (D3) inactivates T4 and T3. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS, but the role of cytokines in altered thyroid hormone metabolism is poorly understood. Here, we measured the effect of IL-6 on both endogenous cofactor mediated and dithiothreitol-stimulated (DTT-stimulated) cell sonicate deiodinase activities in human cell lines. Active T3 generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (and mRNAs). N-acetyl-cysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6-induced inhibitory effect on D1- and D2 mediated T3 production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3-mediated inactivation of T3. Taken together, these results identify a single pathway by which IL-6-induced oxidative stress can reduce D1- and D2 mediated T4-to-T3 conversion as well as increasing D3-mediated T3 (and T4) inactivation, thus mimicking events during illness. PMID- 21540554 TI - Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis. AB - Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor (Gcgr) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr-/- mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr-/- mice by generating Gcgr-/-Glp1r-/- mice. Although insulin sensitivity was similar in all genotypes, fasting glucose was increased in Gcgr-/-Glp1r-/- mice. Elimination of the Glp1r normalized gastric emptying and impaired intraperitoneal glucose tolerance in Gcgr-/- mice. Unexpectedly, deletion of Glp1r in Gcgr-/- mice did not alter the improved oral glucose tolerance and increased insulin secretion characteristic of that genotype. Although Gcgr-/ Glp1r-/- islets exhibited increased sensitivity to the incretin glucose-dependent insulinotropic polypeptide (GIP), mice lacking both Glp1r and the GIP receptor (Gipr) maintained preservation of the enteroinsular axis following reduction of Gcgr signaling. Moreover, Gcgr-/-Glp1r-/- islets expressed increased levels of the cholecystokinin A receptor (Cckar) and G protein-coupled receptor 119 (Gpr119) mRNA transcripts, and Gcgr-/-Glp1r-/- mice exhibited increased sensitivity to exogenous CCK and the GPR119 agonist AR231453. Our data reveal extensive functional plasticity in the enteroinsular axis via induction of compensatory mechanisms that control nutrient-dependent regulation of insulin secretion. PMID- 21540556 TI - A case of acne fulminans in a patient with ulcerative colitis successfully treated with prednisolone and diaminodiphenylsulfone: a literature review of acne fulminans, rosacea fulminans and neutrophilic dermatoses occurring in the setting of inflammatory bowel disease. AB - A 19-year-old Japanese man had been treated for ulcerative colitis for 2 years. He was admitted to our hospital with nodulocystic inflammatory papules and pustules on his face and chest, high-grade fever, arthralgia and general malaise. A biopsy specimen from a pustule showed prominent infiltration of neutrophils in the epidermis and dermis, particularly around hair follicles. We made a diagnosis of acne fulminans. The systemic administration of prednisolone at 30 mg daily for 1 week immediately improved his skin lesions and other symptoms; however, during tapering of prednisolone at 20 mg daily, skin lesions flared up. The addition of oral diaminodiphenylsulfone improved the skin lesions. Although there have been a few reports of acne fulminans associated with Crohn's disease, this is the first case report of acne fulminans in a patient with ulcerative colitis. It is noteworthy that the addition of diaminodiphenylsulfone was effective for treating the relapse of acne fulminans in this case. PMID- 21540555 TI - Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma. AB - A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8+ T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4+ T cells and then subjected to surgical excision of large established B16 melanomas. Mice with vitiligo generated 10-fold larger populations of CD8+ memory T cells specific for shared melanoma/melanocyte antigens. CD8+ T cells in mice with vitiligo acquired phenotypic and functional characteristics of effector memory, suggesting that they were supported by ongoing antigen stimulation. Such responses were not generated in melanocyte-deficient mice, indicating a requirement for melanocyte destruction in maintaining CD8+ T cell immunity to melanoma. Vitiligo-associated memory CD8+ T cells provided durable tumor protection, were capable of mounting a rapid recall response to melanoma, and did not demonstrate phenotypic or functional signs of exhaustion even after many months of exposure to antigen. This work establishes melanocyte destruction as a key determinant of lasting melanoma-reactive immune responses, thus illustrating that immune-mediated destruction of normal tissues can perpetuate adaptive immune responses to cancer. PMID- 21540557 TI - Folding, assembly, and aggregation of recombinant murine amelogenins with T21I and P41T point mutations. AB - Two point mutations (T21I and P40T) within amelogenin have been identified from human DNA sequences in 2 instances of amelogenesis imperfecta. We studied the folding and self-assembly of recombinant amelogenin (rM180) compared to the T21I and P40T mutants analogs. At pH 5.8 and 25 degrees C, rM180 and the P41T mutant existed as monomers, whereas the T21I mutant formed small oligomers. At pH 8 and 25 degrees C, all of the amelogenin samples formed nanospheres with hydrodynamic radii (R(H)) of around 15-16 nm. Upon heating to 37 degrees C, particles of P41T increased in size (R(H) = 18 nm). During thermal denaturation at pH 5.8, both of the mutant proteins refolded more slowly than the wild-type (WT) rM180. Variable temperature tryptophan fluorescence and dynamic light scattering studies showed that the WT transformed to a partially folded conformation upon heating and remained stable. Thermal denaturation and refolding studies indicated that the mutants were less stable and exhibit a greater ability to prematurely aggregate compared to the WT. Our data suggest that in the case of P41T, alterations in the self-assembly of amelogenin are a consequence of destabilization of the secondary structure, while in the case of T21I they are a consequence of change in the overall hydrophobicity at the N-terminal region. We propose that alterations in the assembly (i.e. premature aggregation) of mutant amelogenins may have a profound effect on intra- and extracellular processes such as amelogenin secretion, proteolysis, and its interactions with nonamelogenins as well as with the forming mineral. PMID- 21540558 TI - Middle-aged couples' exchanges of support with aging parents: patterns and association with marital satisfaction. AB - We examined the context of intergenerational support exchanges with aging parents and its association with middle-aged couples' marital satisfaction. A sample of 197 middle-aged couples reported support they gave to and received from their parents (n = 440). Results indicated that couples provided more total support to and received more from their parents as a function of number of living parents, but the amount of support each parent received ('parent-adjusted support') was lower when there were more living parents. The amount of support given to and received from parents had no association with the couple's marital satisfaction, but discrepancies in support given to and received from parents did have a significant association with marital satisfaction. Husbands who gave more support to their living parent(s) than their wives reported lower marital satisfaction. A similar effect on marital satisfaction was found for wives who gave more support to their living parents than their husbands. These findings contrast with caregiving studies where amount of support affected marital satisfaction and suggest that inequalities in involvement with parents may be a critical dimension in marriages of midlife adults. PMID- 21540559 TI - A novel SRD5A2 mutation with loss of function identified in Chinese patients with hypospadias. AB - OBJECTIVE: To investigate the functional change of SRD5A2 gene mutations identified in patients with 5alpha-reductase type 2 deficiency. PATIENTS AND METHODS: Three unrelated subjects born with ambiguous genitalia were included. All patients were initially reared as girls, but they gradually exhibited variable degrees of virilization at puberty without breast development, followed by a change of gender role. Sequencing analysis of the SRD5A2 gene was performed and enzymatic activities of 5alpha-reductase type 2 were assessed. RESULTS: Three compound heterozygous mutations in the SRD5A2 gene were identified: patient 1 with p.G203S/ c.655delT, patient 2 with p.Q6X/p.G203S, and patient 3 with p.G203S/c.755_756insT. Heterozygosity for the p.V89L polymorphism was also found in patients 2 and 3. The c.655delT mutation led to a complete loss of the enzymatic activity, whereas mutants p.G203S and c.755_756insT resulted in a reduction of the enzymatic activities by 60 and 90%, respectively. CONCLUSION: Two frameshift heterozygous mutations, c.655delT and c.755_756insT, led to a dramatic reduction in 5alpha-reductase activity, and the latter had not been reported previously. In addition, the heterozygous mutation (p.G203) identified in the 3 patients presumably suggests a founder effect in the Chinese population and may explain the similarity in phenotype among the patients. PMID- 21540560 TI - Effect of fiber diameter on the spreading, proliferation and differentiation of chondrocytes on electrospun chitosan matrices. AB - Tissue-engineered neocartilage with appropriate biomechanical properties holds promise not only for graft applications but also as a model system for controlled studies of chondrogenesis. Our objective in the present research study is to better understand the impact of fiber diameter on the cellular activity of chondrocytes cultured on nanofibrous matrices. By using the electrospinning process, fibrous scaffolds with fiber diameters ranging from 300 nm to 1 MUm were prepared and the physicomechanical properties of the scaffolds were characterized. Bovine articular chondrocytes were then seeded and maintained on the scaffolds for 7 and 14 days in culture. An upregulation in the gene expression of collagen II was noted with decreasing fiber diameters. For cells that were cultured on scaffolds with a mean fiber diameter of 300 nm, a 2-fold higher ratio of collagen II/collagen I was noted when compared to cells cultured on sponge-like scaffolds prepared by freeze drying and lyophilization. Integrin (alpha(5), alphav, beta(1)) gene expression was also observed to be influenced by matrix morphology. Our combined results suggest that matrix geometry can regulate and promote the retention of the chondrocyte genotype. PMID- 21540561 TI - Ethnic, racial and cultural identity and perceived benefits and barriers related to genetic testing for breast cancer among at-risk women of African descent in New York City. AB - BACKGROUND: Due to disparities in the use of genetic services, there has been growing interest in examining beliefs and attitudes related to genetic testing for breast and/or ovarian cancer risk among women of African descent. However, to date, few studies have addressed critical cultural variations among this minority group and their influence on such beliefs and attitudes. METHODS: We assessed ethnic, racial and cultural identity and examined their relationships with perceived benefits and barriers related to genetic testing for cancer risk in a sample of 160 women of African descent (49% self-identified African American, 39% Black-West Indian/Caribbean, 12% Black-Other) who met genetic risk criteria and were participating in a larger longitudinal study including the opportunity for free genetic counseling and testing in New York City. All participants completed the following previously validated measures: (a) the multi-group ethnic identity measure (including ethnic search and affirmation subscales) and other-group orientation for ethnic identity, (b) centrality to assess racial identity, and (c) Africentrism to measure cultural identity. Perceived benefits and barriers related to genetic testing included: (1) pros/advantages (including family related pros), (2) cons/disadvantages (including family-related cons, stigma and confidentiality concerns), and (3) concerns about abuses of genetic testing. RESULTS: In multivariate analyses, several ethnic identity elements showed significant, largely positive relationships to perceived benefits about genetic testing for breast and/or ovarian cancer risk, the exception being ethnic search, which was positively associated with cons/disadvantages, in general, and family related cons/disadvantages. Racial identity (centrality) showed a significant association with confidentiality concerns. Cultural identity (Africentrism) was not related to perceived benefits and/or barriers. CONCLUSIONS: Ethnic and racial identity may influence perceived benefits and barriers related to genetic testing for breast and/or ovarian cancer risk among at-risk women of African descent. Genetic counseling services may want to take into account these factors in the creation of culturally-appropriate services which best meet the needs of this heterogenous population. PMID- 21540563 TI - Relationship between N-terminal pro-B-type natriuretic peptide plasma levels and renal function evaluated with different formulae in older adult subjects admitted because of dyspnea. AB - BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma levels are associated with congestive heart failure severity, and are an important diagnostic tool for assessing patients with acute dyspnea. Reduced renal function increases NT-proBNP concentrations, and therefore it might be a confounding factor in chronic kidney disease (CKD) patients. OBJECTIVE: The aim of the present study was to relate NT-proBNP plasma levels to different stages of renal function assessed with different methods in older adult subjects admitted because of dyspnea. METHODS: NT-proBNP plasma levels (Roche Diagnostic, Mannheim, Germany) were measured in 134 older adult patients (age: 80 +/- 6 years) admitted to hospital because of dyspnea. Anthropometrics, anamnesis, and biochemical data were collected. Glomerular filtration rate (GFR) was evaluated with different equations, the 4 variables MDRD equations (GFR(MDRD186), GFR(MDRD175)), Mayo Clinic Quadratic formula (GFR(MAYO)), and the new CKD-EPI formula (GFR(CKD-EPI)). Patients were classified into the five K/DOQI stages of CKD and median NT-proBNP values were calculated evaluating their relationship with GFR. RESULTS: Median NT proBNP values were better stratified into the five K/DOQI stages by GFR(MAYO) (stage 1 (n = 10) 1,640 pg/ml vs. stage 2 (n = 61) 2,371 pg/ml vs. stage 3 (n = 42) 3,815 pg/ml vs. stage 4 (n = 18) 6,320 pg/ml vs. stage 5 (n = 3) 7,256 pg/ml, p = 0.017). However, similar results were obtained with the other formulae. NT proBNP was negatively correlated with GFR as evaluated with all the different formulae (r -0.25 to -0.29; all p < 0.01). Multiple regression analysis confirmed the independent association between LnNT-proBNP and GFR. CONCLUSION: NT-proBNP plasma levels progressively increase with worsening of renal function, and appear to be related to the five K/DOQI stages of CKD. For this purpose, GFR assessed with the GFR(MAYO) formula appears to better stratify NT-proBNP in older adult subjects. Renal function should be considered when interpreting NT-proBNP levels in older adult patients admitted for dyspnoea. PMID- 21540562 TI - HER2 evaluation and its impact on breast cancer treatment decisions. AB - BACKGROUND: Eighteen to twenty percent of breast cancer tumors show abnormal amplification of the Human Epidermal growth factor Receptor 2 (HER2) gene and increased expression of the associated protein. HER2 amplification is associated with rapid tumor proliferation and shorter disease-free and overall survival. Because women with HER2 amplification are more likely to benefit from treatment with the drug trastuzumab, testing for HER2 is recommended to guide therapy. However, little is known about use of HER2 testing in real-world settings. This study examined uptake, use, appropriateness of HER2 testing, and the relationship between HER2 test results and treatment decisions. METHODS: We assessed electronic data from 3,634 patients with invasive breast cancer diagnosed from 1998 to 2007 in a large integrated health system. We collected data on patient and tumor characteristics, HER2 testing status, test results, and trastuzumab treatment. RESULTS: From 1998 to 2000, the percent of patients who underwent HER2 evaluation increased from 12 to 94%; <3% of women with ductal carcinoma in situ, for whom HER2 testing is not recommended, were tested. Trastuzumab use increased 5-fold after 2004, when guidelines expanded to include recommending adjuvant treatment for early-stage breast cancer in addition to metastatic treatment. Ninety-five percent of women receiving trastuzumab had a positive HER2 result. After 2004, 55% of women with invasive breast cancer and overexpression of HER2 received trastuzumab treatment; this ranged from 44% of women with localized breast cancer to 80% of women with distant metastatic disease. CONCLUSIONS: These findings illustrate appropriate and effective implementation of a HER2 testing strategy in a managed care setting. PMID- 21540564 TI - Chronic obstructive pulmonary disease patient well-being and its relationship with clinical and patient-reported outcomes: a real-life observational study. AB - BACKGROUND: Quality of life is an umbrella concept that refers to all aspects of a person's life, including health status and well-being. While health status measure focuses on the impact of the disease on physical functioning, well-being represents the self-representation of the emotional states related to the disease itself. OBJECTIVES: The objective of this study was to evaluate the psychological well-being and its determining factors in a real-life chronic obstructive pulmonary disease (COPD) population and to evaluate if patients with a different well-being differ in illness perception, health status and alexithymia. METHODS: Psychological well-being (Psychological General Well-Being Index), health status (SF-36), illness perception (Illness Perception Questionnaire), alexithymia (Toronto Alexithymia Scale), as well as clinical parameters were assessed in COPD out-patients. RESULTS: One hundred and sixty-four patients, with a mean forced expiratory volume in 1 s of 58.5%, were recruited. Forty percent of them had a moderately/severely impaired well-being, not correlated with forced expiratory volume in 1 s and the Charlson index value but significantly with the Medical Research Council score (p = 0.0001) that appeared to be the dominant factor. Patients with impaired well-being showed a different illness perception in terms of correct identification of symptoms, disease consequences, emotional representation and confidence in treatment compared with those having a positive well-being. The latter presented a lower alexithymia prevalence and a better health status. CONCLUSIONS: In order to minimize the disease-negative effects on patients' lives, assessment of well-being and its determining factors, as well as planning specific behavioural, educational and therapeutic interventions seem to be relevant and useful. PMID- 21540565 TI - Economies of intraoperative drawing: blood, an autologous skin marker. PMID- 21540566 TI - Idiopathic calcinosis cutis in a child: chemical composition of the calcified deposits. AB - Idiopathic calcinosis cutis (CC) is a rare disease in a child. The chemical composition of the calcified deposits in idiopathic CC was first qualitatively and quantitatively examined using vibrational microspectroscopy via spectral diagnosis. The combined application of the Fourier transform infrared (FT-IR) and Raman microscopic techniques was used to detect and identify the nature of the components of the calcified deposits in idiopathic CC and to compare the results with histopathological findings. Two major components of type B carbonated apatite and beta-carotene interspersing subcutaneous tissue were clearly evidenced to make up the calcified deposits in idiopathic CC in our pediatric patient. Moreover, the calcified deposits of idiopathic CC contained a relatively larger amount of type B carbonated apatite and a smaller amount of type A carbonated apatite than the calcified deposits analyzed in dystrophic CC. This is the first report on the chemical composition of calcified deposits in idiopathic CC established by spectral analysis. The combination of FT-IR and Raman microscopic techniques was very useful for simultaneous assessment of the intact components of the calcified deposits in idiopathic CC. PMID- 21540567 TI - Chromosomal variants in klinefelter syndrome. AB - Klinefelter syndrome (KS) describes the phenotype of the most common sex chromosome abnormality in humans and occurs in one of every 600 newborn males. The typical symptoms are a tall stature, narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, absent spermatogenesis, normal to moderately reduced Leydig cell function, increased secretion of follicle stimulating hormone, androgen deficiency, and normal to slightly decreased verbal intelligence. Apart from that, amongst others, osteoporosis, varicose veins, thromboembolic disease, or diabetes mellitus are observed. Some of the typical features can be very weakly pronounced so that the affected men often receive the diagnosis only at the adulthood by their infertility. With a frequency of 4%, KS is described to be the most common genetic reason for male infertility. The most widespread karyotype in affected patients is 47,XXY. Apart from that, various other karyotypes have been described, including 46,XX in males, 47,XXY in females, 47,XX,der(Y), 47,X,der(X),Y, or other numeric sex chromosome abnormalities (48,XXXY, 48,XXYY, and 49,XXXXY). The focus of this review was to abstract the different phenotypes, which come about by the various karyotypes and to compare them to those with a 'normal' KS karyotype. For that the patients have been divided into 6 different groups: Klinefelter patients with an additional isochromosome Xq, with additional rearrangements on 1 of the 2 X chromosomes or accordingly on the Y chromosome, as well as XX males and true hermaphrodites, 47,XXY females and Klinefelter patients with other numeric sex chromosome abnormalities. In the latter, an almost linear increase in height and developmental delay was observed. Men with an additional isochromosome Xq show infertility and other minor features of 'normal' KS but not an increased height. Aside from the infertility, in male patients with other der(X) as well as der(Y) rearrangements and in XXY women no specific phenotype is recognizable amongst others due to the small number of cases. The phenotype of XX males depends on the presence of SRY (sex-determining region Y) and the level of X inactivation at which SRY-negative patients are generally rarely observed. PMID- 21540568 TI - Fibroblast growth factor-9 in marsupial testicular development. AB - FGF9 is a member of the fibroblast growth factor (FGF) family and is critical for early testicular development and germ cell survival in the mouse. Fgf9 reinforces the testis determinant Sox9 and antagonizes Wnt4, an ovarian factor. To determine whether FGF9 has a conserved role in the mammalian gonad, we examined its expression in the gonads of a marsupial, the tammar wallaby Macropus eugenii, and compared it to WNT4 expression. Marsupial FGF9 is highly conserved with orthologues from eutherian mammals, including humans. FGF9 protein was detected in both the testis and ovary before sexual differentiation, but it subsequently became sexually dimorphic during the period of testicular differentiation. The protein was specifically enriched in the seminiferous cords of the developing testis in the Sertoli and germ cells. FGF9 mRNA expression was upregulated in the tammar testis at the time of seminiferous cord formation and downregulated in the developing ovary in an opposite profile to that of marsupial WNT4. These observations suggest that FGF9 promotes male fate in the early gonad of marsupials through an antagonistic relationship with WNT4 as it does in eutherian mammals. PMID- 21540569 TI - Cutaneous T-cell/histiocyte-rich B-cell lymphoma: a case report and review of the literature. AB - BACKGROUND: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) primarily presenting on the skin is an extremely rare entity with only sporadic cases reported in the literature. METHODS: We here report an extraordinary case of primary cutaneous THRLBCL with self-healing and 24 months of follow-up. RESULTS: The lesion was a dermohypodermal/subcutaneous circumscribed ulcerated nodosity. Histological examination with immunohistochemical, molecular analysis and comparative genomic hybridization were performed. A complete staging was negative for secondary involvement. CONCLUSION: Our case is remarkable because it is the second well-documented primary cutaneous THRLBCL in which we observed a complete self-regression of skin lesions without recurrences or dissemination of the disease. According to the literature, we highlight that the tumoral microenvironment, in our case, could play a relevant role in stopping lymphoma growth. Furthermore, this case supports the observation that THRLBCL primarily presenting on the skin shows an overall good prognosis. PMID- 21540570 TI - Canine scabies in humans: a case report and review of the literature. AB - BACKGROUND: Sarcoptes scabiei causes mange in many domestic and wild mammals, and it has been reported to be transmitted from animals to humans. Canine scabies is known to infest humans, as well. CASE REPORT: We report a 27-year-old woman who presented with severe pruritic papules on the trunk and arms. The patient reported that she had just bought a puppy which was also itchy. Direct microscopy from the dog showed scabies mites. The patient was treated by 5% permethrin which accomplished full recovery. DISCUSSION: Canine scabies in humans is a challenging disease to diagnose since mites are hard to find on skin scrapings of dogs and the burrows that are the hallmark of scabies are absent. Dermatological examination of the lesions in our patient did not show any burrows or a specific dermoscopic image of scabies. Instead, we observed curvilinear crusts on most of the papules. CONCLUSION: To our knowledge, dermoscopic appearance of canine scabies in humans has not been described before. We think this special pattern of excoriations is the result of superficially dug tunnels that had been torn leaving vacant curved linear remnants behind, and this may provide a good support for the diagnosis of canine scabies contributing to the spectrum of entodermoscopy. PMID- 21540571 TI - Evolving pattern with age of cutaneous signs in neurofibromatosis type 1: a cross sectional study of 728 patients. AB - BACKGROUND: Neurofibromatosis type 1 is fully penetrant by the age of 8 years, and 3 criteria of diagnosis are dermatological: cafe-au-lait spots (CLS), intertriginous freckling and neurofibromas (NF). OBJECTIVES: The aim of our study was to determine the evolving pattern of cutaneous manifestations during adulthood. METHODS: Phenotypic data of patients seen in our center between March 2003 and December 2009 were studied. Patients were classified in 10-year groups. Following clinical characteristics, the number of CLS and the number of cutaneous and subcutaneous NF were compared according to age. RESULTS: 728 subjects, 404 females and 324 males (mean age of 32.4 years, range 6-80 years) were studied. Four hundred eighty-nine patients were over 20 years old (67%). The number of CLS (small or large) was significantly decreased with age while the number of cutaneous and subcutaneous NF was strongly increased (p < 0.001). CONCLUSIONS: The decrease in CLS with age has not been previously reported while an increase in the number of NF is well described during puberty and pregnancy and with age. PMID- 21540572 TI - Tumescent liposuction: partitioning of lidocaine at a lower dose (252 mg/l). AB - BACKGROUND: The popularity of large-volume liposuction and the toxicity of lidocaine have led to a reduction of lidocaine dosage in tumescent liposuction. We have gradually reduced the concentration of lidocaine from 500 to 252 mg/l over the past decade. OBJECTIVE: To evaluate the partitioning and the recovery of lidocaine at a lower concentration in tumescent liposuction. METHODS: 10 consecutive patients' aspirate samples were analysed for the lidocaine concentration in the fat and the fluid component, the percentage of injected lidocaine removed by aspiration and its partition coefficient in fat versus fluid. RESULTS: 7.5% of the injected lidocaine was removed; its partition coefficient was 0.21. CONCLUSION: 7.5% of the total lidocaine was aspirated in tumescent liposuction. The fat uptake of lidocaine was lower than in previous reports, which was of particular interest for future studies on lidocaine toxicity for the safety of the patients undergoing tumescent liposuction. PMID- 21540573 TI - Erythema scarlatiniforme desquamativum recidivans (Fereol-Besnier)--report of three cases localized to the thumb. PMID- 21540574 TI - Methylation status of cMHM and expression of sex-specific genes in adult sex reversed female chickens. AB - The objective of the current study was to analyze the methylation status of the chicken male hypermethylation (cMHM) region and mRNA expression levels of sex dependent genes in adult female-to-male sex-reversed chickens. Sex reversal from genetic females into phenotypic males was induced by injection of 1.0 mg fadrozole, an aromatase inhibitor, into fertilized eggs at 3.0 days of incubation. Birds aged 30 weeks were classified into 4 groups according to the histological structure of their gonads and the natural logarithm of the ratio of testosterone to estradiol in serum, namely standard females, slightly sex reversed females with left ovotestes, highly sex-reversed females with left testes, and standard males. The results showed that methylation of the cMHM amplicon was lowest in the ovaries of standard females and highest in testes of standard males. Methylation levels were significantly higher in the left testes of highly sex-reversed females than in the left ovotestes of slightly sex reversed females (p < 0.05). Expression analysis of 9 sex-specific genes in the gonad indicated that DMRT1 and HINTZ had a similar expression pattern, with significantly higher levels in standard males as compared to standard females, slightly and highly sex-reversed females (p < 0.05). Expression of FOXL2, AMH, P450arom, SF1, and ERalpha was obviously higher in standard females than in standard males, slightly and highly sex-reversed females (p < 0.05). Expression of SOX9 in standard females was similar to that in slightly sex-reversed females and lower than in highly sex-reversed females and standard males (p < 0.05). PMID- 21540575 TI - Holocentric chromosomes of Luzula elegans are characterized by a longitudinal centromere groove, chromosome bending, and a terminal nucleolus organizer region. AB - The structure of holocentric chromosomes was analyzed in mitotic cells of Luzula elegans. Light and scanning electron microscopy observations provided evidence for the existence of a longitudinal groove along each sister chromatid. The centromere-specific histone H3 variant, CENH3, colocalized with this groove and with microtubule attachment sites. The terminal chromosomal regions were CENH3 negative. During metaphase to anaphase transition, L. elegans chromosomes typically curved to a sickle-like shape, a process that is likely to be influenced by the pulling forces of microtubules along the holocentric axis towards the corresponding microtubule organizing regions. A single pair of 45S rDNA sites, situated distal to Arabidopsis-telomere repeats, was observed at the terminal region of one chromosome pair. We suggest that the 45S rDNA position in distal centromere-free regions could be required to ensure chromosome stability. PMID- 21540576 TI - Properties of a hybrid zone between highly distinct chromosomal races of the house mouse (Mus musculus domesticus) in Northern Italy, and comparisons with other hybrid zones. AB - Here we provide the first detailed description of the hybrid zone between the Cremona chromosomal race of house mouse (ICRE; 2n = 22) and the standard all telocentric race (40ST; 2n = 40), with full karyotypes of 106 individuals from 17 localities along a transect between the 2 races to the west of Lake Garda in Northern Italy. The ICRE race is characterised by 9 pairs of metacentric chromosomes in a homozygous state and we use the metacentric frequency data along the transect to fit tanh metacentric clines. The clines are narrow (5-8 km, standardised width) suggesting low hybrid fitness. However, the lack of occurrence of ICRE * 40ST F(1) hybrids and presence of other hybrid types suggests that the F(1) hybrids initially produced in this hybrid zone were at least partially fertile, despite having 9 meiotic trivalent configurations. We apply the same cline-fitting methodology to 3 previously studied hybrid zones between metacentric races and the 40ST race. Taken together with published clinal data on 4 further metacentric-40ST hybrid zones, we are able to make objective generalisations on the characteristics of such zones in the house mouse. Zones involving 22-chromosome races are narrower, on average, than other metacentric 40ST hybrid zones and do not show a tendency towards the generation of new races as found with zones where the metacentric race has a higher 2n. It appears that metacentric-40ST zones are unlikely to be sites of speciation (even when a 22 chromosome race is involved), although a mosaic structure to the hybrid zone may enhance this possibility. We make a comparison between metacentric-40ST zones and contacts between 2 metacentric races, for a comprehensive perspective of chromosomal hybrid zones in the house mouse. PMID- 21540577 TI - Getting personal with prostate cancer: adding new pieces to an incomplete jigsaw puzzle. AB - Prostate cancer is a multifaceted molecular anomaly that is insurmountable to date because of the orchestrated network of negative regulators that drive carcinogenesis. A substantial fraction of information has been added that gives yet an unclear snapshot of therapeutic interventions in prostate cancer. Increasing sophisticated interpretations point towards some important aspects of prostate cancer aggressiveness like microRNAs, prostate cancer stem cells and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) refractoriness. In this review, we will evaluate the push and pull between oncomirs and tumor suppressors in tipping the scales of cancer. Furthermore, multicomponent rational drug designs with a claim to overcome stumbling blocks will be discussed. Translation of the outcomes achieved in the understanding of carcinogenesis at the patient's bedside is possibly the principal challenge in cancer research. PMID- 21540578 TI - Mechanisms of growth plate maturation and epiphyseal fusion. AB - Longitudinal growth occurs within the long bones at the growth plate. During childhood, the growth plate matures, its total width decreases and eventually it disappears at the end of puberty with complete replacement by bone along with cessation of longitudinal growth. The exact mechanism of epiphyseal fusion is still not completely understood and experimental studies are complicated by the fact that there is a species difference between humans and rabbits that do fuse their growth plates and rodents that do not. This mini review summarizes hypotheses and theories postulated in the literature regarding growth plate maturation and epiphyseal fusion. Growth factors, local regulators and hormones involved in growth plate maturation are described as well as four postulated hypotheses and theories regarding the final steps in epiphyseal fusion: apoptosis, autophagy, transdifferentiation and hypoxia. A better insight into the mechanisms of epiphyseal fusion may ultimately help to develop new strategies for the treatment of cartilage and growth disorders. PMID- 21540579 TI - Pretreatment serum level of 15-kDa granulysin might have a prognostic value in patients with diffuse large B cell lymphoma. AB - AIM: Granulysin (cytolytic molecules of cytotoxic T lymphocytes and natural killer cells) is synthesized as cytosolic 9-kDa and secretary 15-kDa isoforms. We evaluated the prognostic significance of the pretreatment serum level of 15-kDa granulysin in patients with diffuse large B cell lymphoma (DLBCL). PATIENTS AND METHODS: A retrospective analysis was conducted on 88 DLBCL patients treated homogeneously with standard chemotherapy. The granulysin level was quantified in pretreatment samples. RESULTS: The granulysin level in DLBCL patients was significantly lower than that in healthy controls (522 +/- 496 vs. 1,945 +/- 1,696 pg/ml; p < 0.0001), and the level in patients who experienced recurrence within 3 years was significantly lower than that of patients without recurrence (305 +/- 337 vs. 720 +/- 607 pg/ml; p = 0.001). Patients with granulysin levels higher than the median level showed significantly longer progression-free and overall survival according to univariate analysis (p = 0.031 and p = 0.014, respectively). In multivariate analysis, the granulysin level was an independently significant prognostic factor of overall survival (p = 0.018; hazard ratio, 0.521; 95% confidence interval, 0.188-0.841). CONCLUSIONS: Pretreatment serum level of 15-kDa granulysin may be a valuable prognostic marker in DLBCL patients treated with standard chemotherapy. PMID- 21540580 TI - The antioxidant EPC-K1 attenuates renal ischemia-reperfusion injury in a rat model. AB - BACKGROUND: Acute kidney injury (AKI) occurs frequently in the intensive care unit. A primary cause is renal ischemia/reperfusion (I/R) injury, during which excess reactive oxygen species (ROS) are produced. ROS subsequently damage renal cells, leading to the development of AKI. Here, we investigated whether renal I/R injury could be attenuated by the antioxidant EPC-K1. METHODS: We divided male Wistar rats into the following three groups: (1) a renal I/R group, (2) an EPC-K1 + renal I/R group and (3) a control group. Rats were sacrificed 24 h after treatment (I/R or sham). To measure oxidative stress in renal tissue, histological examinations were performed and serum levels of blood urea nitrogen (BUN) and creatinine were measured. The antioxidant action of EPC-K1 was also evaluated in RAW264.7 cells stimulated with antimycin A. RESULTS: Serum BUN and creatinine levels were elevated in the I/R group; however, this increase was significantly attenuated by EPC-K1 in the EPC-K1 + I/R group. Renal tissue injury was also significantly lower in the EPC-K1 + I/R group compared with the I/R group. In vitro experiments showed that EPC-K1 significantly attenuated the generation of ROS induced by antimycin A. CONCLUSION: In our study, EPC-K1 was able to attenuate AKI due to renal I/R by reducing oxidative stress. These results suggest that EPC-K1 may be effective against various types of I/R injury. PMID- 21540581 TI - Intake of medication and vitamin status in the elderly. AB - BACKGROUND/AIMS: An inadequate vitamin status is associated with higher morbidity and frailty in the elderly and might be due to medication. This study aimed to evaluate the status of several vitamins in relation to regular intake of medication in this population. METHODS: A total of 102 non-institutionalized subjects aged 70-90 years were recruited. Plasma levels of vitamins A, D, E, K and C were determined by HPLC. The functional parameters of vitamins B(1), B(2) and B(6), i.e. the activities of the erythrocyte enzymes transketolase, glutathione reductase and glutamic oxaloacetic transaminase were analyzed photometrically; plasma folate and vitamin B(12) were determined by RIA. RESULTS: The status of vitamins A, E and C was generally satisfactory. Eighty-eight percent and 42% of participants were deficient in vitamins D and K, respectively, as were 29% in B(6); up to 10% were deficient in vitamins B(1), B(2), B(12) and folate. A considerable percentage of participants was, however, at risk for vitamin deficiencies (vitamins B(1), B(6), B(12) and folate: 20-30%; vitamin B(2): 60%). Regular intake of maximally 2 drugs per day was not adversely related to the status of several vitamins; intake of >= 3 drugs per day was significantly negatively associated with the status of vitamins D, K, B(6) and folate. CONCLUSION: Daily intake of >= 3 drugs was found to be adversely associated with the status of some vitamins in the elderly. Hence, the medication schedule and nutritional status of these subjects should be monitored closely to ensure that the daily micronutrient requirement is fulfilled. PMID- 21540582 TI - The trends of metabolic syndrome in normal-weight Tehranian adults. AB - BACKGROUND: In recent decades, more attention has been directed to the clustering of cardiometabolic risk factors in normal-weight adults. This study investigates trends of the prevalence of metabolic syndrome (MetS) in a normal-weight Tehranian adult population during 6.6 years of follow-up. METHODS: In this population-based cohort study of 5,269 participants aged >= 20 years during the 3 phases (1999-2001, 2002-2005 and 2005-2008) of the Tehran Lipid and Glucose Study, we selected 390 males and 358 females with a normal body mass index (18.5 24.9) during all 3 periods of follow-up. MetS was defined according to the International Diabetes Federation criteria, and waist circumference (WC) cut points were >= 89 cm for males and >= 91 cm for females. RESULTS: The overall prevalence of MetS increased from 2.3 and 4.0% in phases I and II to 9.6% in phase III. This trend was significant in males (p < 0.001) but not in females (p = 0.6). No significant changes in components of MetS were seen, except in WC among males. In the 3 study phases, prevalence of abdominal obesity was 3.1, 18.5 and 36.2% in males, respectively. CONCLUSIONS: There was a dramatic 4-fold increase in the prevalence of MetS in the Tehranian normal-weight adult population, highlighting the importance of MetS components, especially of WC, in normal-weight adult males. PMID- 21540583 TI - A combination of (omega-3) polyunsaturated fatty acids, polyphenols and L carnitine reduces the plasma lipid levels and increases the expression of genes involved in fatty acid oxidation in human peripheral blood mononuclear cells and HepG2 cells. AB - BACKGROUND: Hyperlipidemia and obesity are associated with metabolic syndrome and increased risk in developing diabetes and cardiovascular disease. Nutritional supplements, e.g. L-carnitine and polyunsaturated fatty acids (PUFAs), exert lipid-lowering effects. Hence, the hypothesis that dietetic intervention reduces plasma lipid levels and metabolic enzymes in overweight hyperlipidemic subjects was tested. SUBJECTS AND METHODS: In a prospective placebo-controlled double blind study in 22 moderately hyperlipidemic obese humans consuming low-fat yoghurt enriched with a combination of low-dose PUFAs, polyphenols and L carnitine (PPC) twice a day for 12 weeks were compared to 20 matching participants ingesting low-fat yoghurt. The effects on plasma lipids and expression of enzymes involved in regulation of fatty acid oxidation in peripheral blood mononuclear cells (PBMCs) and HepG2 cells were evaluated. RESULTS: PPC consumption led to significantly reduced plasma free fatty acid ( 29%) and triglyceride (-24%) concentrations (each p < 0.05). PPC application increased significantly peroxisome proliferator-activated receptor alpha (PPARalpha) mRNA abundances and those of PPARalpha target genes (carnitine palmitoyltransferases-1, CPT1A and CPT1B, carnitine acetyltransferase and organic cation transporter 2; each p < 0.05) in PBMCs. In controls, plasma lipid levels and PBMC gene expression did not change. These findings were substantiated by the results of cell culture experiments in HepG2 cells. CONCLUSION: Supplementation of PPC had marked lipid-lowering effects and PBMC gene expression profiles seemed to reflect nutrition-related metabolic changes. PMID- 21540584 TI - The impact of cochlear implantation on tinnitus, stress and quality of life in postlingually deafened patients. AB - Tinnitus is a common complaint in the candidates for cochlear implantation (CI). Tinnitus-related distress has often been measured in these patients using categorical ratings, which lack information about tinnitus severity, stress and health-related quality of life or their correlation. Here, using 4 validated questionnaires, we evaluated psychometric parameters and the quality of life of 32 postlingually deafened patients before and after CI. The data regarding pre-CI were collected retrospectively. Of all patients included in this study, 28 (87.5%) suffered from tinnitus before implantation. Following a mean of 24 months after surgery, these patients reported a significant decrease (39.2%) of tinnitus impairment, as measured by the Tinnitus Questionnaire. In none of the 28 patients has tinnitus worsened. Moreover, the 4 tinnitus-free patients remained so after the CI surgery. In addition, the implant supply resulted in 36.7% reduction in perceived stress and in 15.4% reduction in evasive coping. In addition, the focus on positive coping has improved by 12.3%, whereas the health-related quality of life improved by 53.4% in all patients. Tinnitus impairment and stress were reduced more strongly in patients who had initially higher scores. Interestingly, a significant correlation between the psychometric scores was found mainly after CI. Our results indicate that patients with higher tinnitus-related distress have a lower quality of life, lesser coping abilities and perceive more stress, but before implantation it is masked by deafness. We conclude that tinnitus-related screening of patients before and after CI is an important step in the identification of individuals who would benefit from specific fitting and/or tinnitus therapy after implantation. PMID- 21540585 TI - Ocular vestibular evoked myogenic potentials: frequency tuning to air-conducted acoustic stimuli in healthy subjects and Meniere's disease. AB - Ocular vestibular evoked myogenic potentials (oVEMP) in response to 250-, 500- and 1000-Hz air-conducted short tone bursts were studied in 22 healthy subjects and 37 Meniere's disease patients. The goal of this study was to investigate normal tuning characteristics of the oVEMP and the possible oVEMP changes with respect to frequency dependence in Meniere's disease. In unilateral Meniere's disease patients, a distinction was made between affected ears and unaffected ears. It was found that in normal subjects, the oVEMP tunes to a stimulus frequency of 500 Hz, with the highest amplitude and lowest threshold at this particular frequency. Generally, Meniere's disease patients showed lower amplitudes and higher thresholds than normal subjects at all 3 stimulus frequencies in both the affected and the unaffected ear. Additionally, for ears affected by Meniere's disease, the best stimulus frequency was 1000 Hz. With the use of this altered tuning for these ears, we tried to find a criterion for distinguishing normal from Meniere's disease ears. PMID- 21540586 TI - A new device to quantify ocular counterroll using retinal afterimages. AB - BACKGROUND: The integrity of vertical semicircular canal and otolith function remains difficult to assess in the clinical setting, partly due to difficulties in recording ocular counterroll. Here, we quantify static ocular counterroll from head tilt using a new head-mounted device. METHODS: The device consists of an LED positioned 42 cm in front of one eye and a striated lens which produces a streak of light on the retina. The LED is illuminated at full intensity (80 cd) to generate a retinal afterimage. Subsequently, in darkness, the subject's head is tilted in the roll plane. Finally, the LED is illuminated dimly (0.2 cd) and the subject rotates the striated lens to superimpose the dim light streak onto the afterimage. An angular scale indicates the angle through which the lens is rotated, giving a measure of the ocular counterroll. To validate the device, we recorded binocular counterroll simultaneously with 3D computerised video oculography of the other eye in 16 normal subjects; 2 patients with acquired bilateral loss of vestibular function were also tested. RESULTS: In the normal subjects, there was no significant difference between the two techniques (p=0.24) when recording ocular counterroll and the correlation between the two techniques was R2=0.78. The 2 avestibular patients essentially showed no ocular counterroll with both techniques. CONCLUSIONS: We have devised a non-invasive, quick and reliable test of ocular counterroll. The lack of response in the 2 avestibular patients indicates that this device is clinically applicable to assess otolith function. PMID- 21540587 TI - Factors influencing dialysis modality for end-stage renal disease in developing countries: a survey of Filipino nephrologists. AB - BACKGROUND: In the Philippines, 86% of incident dialysis patients are started on hemodialysis (HD) and 14% are treated with peritoneal dialysis (PD), representing a decline over a 2-year period. One important factor which affects patients' choice of dialysis modality is the input of their physicians. Our objective was to identify the factors affecting attitudes and recommendations of Filipino nephrologists regarding HD and PD. METHODS: Attendees of the annual national nephrology meeting completed an anonymous self-administered questionnaire. RESULTS: Respondents were heavily involved in clinical dialysis work, and 86.7% had most/all of their patients on HD. Recommendations about dialysis modality were based most strongly on overall cost to patient (4.4 on a scale of 1 [not important] to 5 [most important], residual renal function (RRF) preservation (4.4), patient preference (4.3) availability of dialysis support staff (4.3), and comparative quality of life data (4.3). Least important was physician reimbursement (2.8). Patient-related factors favoring HD were: poor personal hygiene, impaired vision and manual dexterity; while favoring PD were: age <10 years, living far from HD unit, and the availability of trainable family members. When asked which modality they would recommend to an equally eligible patient, 49.2% responded they would not recommend either modality and would allow the patient to choose, while 40.7% would recommend HD and 10.2% would recommend PD. CONCLUSION: Respondents consider overall cost and RRF preservation as the most important factors in dialysis modality selection, yet only 10.2% would recommend PD as first choice. It is likely that factors other than those addressed in the survey are stronger determinants of the patient's final choice of modality. PMID- 21540588 TI - Treatment of Akata EBV-positive cells with doxorubicin causes more EBV reactivation than treatment with etoposide. AB - BACKGROUND/AIMS: EBV has been associated with Burkitt lymphoma (BL). It establishes a latent infection but its reactivation has been observed in patients receiving long-term chemotherapy. The effect of doxorubicin on virus reactivation has been described previously, but the effect of etoposide or cytarabine on EBV reactivation has not been reported in the literature. The aim of this work was to carry out such a study. METHODS: Akata EBV-positive cell lines were treated with etoposide, doxorubicin or cytarabine. Viable cells were analyzed by trypan blue, programmed cell death by TUNEL assay, mRNA levels by RT-PCR and cellular or viral proteins by Western blot. Viruses were visualized by electron microscopy. RESULTS: All of the studied drugs caused cell death by apoptosis. Comparing the effect of etoposide and doxorubicin (at their IC(50)) in the EBV-positive cells, etoposide caused less EBV reactivation than doxorubicin. Cytarabine apparently did not reactivate EBV. CONCLUSION: When treating Akata EBV-positive cells with the respective IC(50) of the following drugs, etoposide induced less EBV reactivation than doxorubicin, and cytarabine apparently did not induce EBV reactivation. PMID- 21540589 TI - Brugada type 1 electrocardiographic pattern induced by severe hyponatremia. AB - Brugada syndrome is characterized electrocardiographically by ST segment elevation in the right precordial leads, followed by a negative T wave unrelated to ischemia, electrolyte disturbance or drug effects and prone to rapid polymorphic ventricular tachycardia capable of degenerating into ventricular fibrillation. The ECG pattern may be dynamic and is often concealed. Sodium channel blockers, drugs, electrolyte imbalances, fever and several other clinical circumstances are recognized inducers of a Brugada type 1 ECG in susceptible patients. We describe a case of a Brugada type 1 ECG pattern induced by severe hyponatremia. PMID- 21540590 TI - A rare case of aortic valve myxoma: an unusual cause of embolic stroke. AB - Aortic valve myxoma is an extremely rare cardiac tumour. We describe a 60-year old woman found to have an aortic valve myxoma and a patent foramen ovale (PFO) presenting as a stroke. In view of the recurrent cerebral ischaemic events, the aortic valve myxoma was surgically removed and the PFO was closed. To the best of our knowledge, this is the first reported case of aortic valve myxoma with a PFO. We also highlight the importance of identifying a possible cardiac source of embolism in a stroke patient and considering this rare tumour as a cause in patients with a cryptogenic stroke. PMID- 21540592 TI - Advanced liver resection. PMID- 21540593 TI - Hepatic resection with in situ hypothermic perfusion is superior to other resection techniques. AB - Through the years, liver resection and bleeding control techniques have progressively evolved. However, for liver tumors located unfavorably, the standard techniques are not suitable due to either failure to control the bleeding or to liver ischemia induced by prolonged interruption of perfusion. In this regard, total vascular exclusion (TVE) with in situ hypothermic perfusion is advantageous as it protects the parenchyma, achieves better vascular control and enables difficult vascular reconstructions or reimplantations. The advantages of this procedure described as early as 1960s by Fortner were also confirmed by our team in a subsequent report. We showed that TVE with in situ hypothermic perfusion is superior to TVE alone if used for more than 60 min in complex resections with or without vascular reconstruction. Other techniques (ex situ liver resection developed by Pichlmayr and ante situm liver resection by Hannoun) have been described; however, they have not been widely accepted due to a high rate of complications. In this article, we report our operative technique as well as discuss some important operative points. PMID- 21540594 TI - Hypothermic ante situm resection in tumors of the hepatocaval confluence. AB - Primary liver malignancies together with metastatic liver tumors are among the most common tumors in human. The best available treatment option for these diseases is surgical resection. One major parameter which had been considered as contraindication for liver resection owing to technical difficulties in achieving tumor-free margins was the involvement of the hepatocaval confluence. To overcome this problem, several techniques including hypothermic in situ, ante situm and ex situ liver resection have been introduced. The common basis for these liver resections is the total vascular exclusion of the liver, and perfusion of the organ by preservation solution under hypothermic conditions. The major indications for the ante situm liver resection are tumors in the liver that are either unresectable or inadequately resectable by conventional surgery because they involve the venous confluence and/or the retrohepatic vena cava, or are in close proximity to them. This technique is a realistic option to achieve surgical cure or substantial gain of life time with quality of life in otherwise unresectable tumors of the liver. Due to fewer anastomoses, the ante situm approach is easier and safer than the ex situ approach, with an acceptable morbidity and mortality rate. Patient selection is of utmost importance to achieve a good outcome. To minimize the postoperative morbidities and mortality, this procedure requires a multidisciplinary approach and should be performed in experienced centers with a high case volume of hepatobiliary surgeries. PMID- 21540595 TI - From mesohepatectomy to mini-mesohepatectomy: evolving the concept of resectability of hepatic tumors at the hepatocaval confluence. AB - In the case of tumors in contact with or invading the middle hepatic vein (MHV) at the hepatocaval confluence, extended right hepatectomy or mesohepatectomy is usually recommended. Major or extended hepatectomy is associated with significant rates of morbidity and mortality, and a more conservative approach would be desirable. Thus, we developed a new conservative operation, the so-called mini mesohepatectomy that, in some specific circumstances, allowed the en-bloc resection of segment 8, segment 4-sup and the MHV at the hepatocaval confluence and at the same time preservation of the remaining parenchyma of the right anterior section and left median section drained by the MHV. The present work describes the rationale, indications, as well as the surgical technique of this new operation which we believe should be part of the armamentarium of the modern hepatic surgeon, and will probably limit the need for a formal mesohepatectomy. PMID- 21540596 TI - Complete radiological response of colorectal liver metastases after chemotherapy: what can we expect? AB - Missing metastases, also called vanishing or disappearing liver metastases, concern about 5% of patients with colorectal liver metastasis undergoing chemotherapy, and this phenomenon is likely to become more frequent in the near future, with the widespread use of highly efficient chemotherapy. As their definition is highly dependent on the quality of initial imaging, a DLM on preoperative computed tomography scan should be systematically confirmed by a second imaging modality, ideally magnetic resonance imaging. It is important to note that a complete clinical response does not mean a complete pathologic response. Currently, there are no absolute criteria of a complete pathologic response. However, treatment with neoadjuvant and adjuvant hepatic arterial infusion in patients <60 years old with an initially low carcinoembryonic antigen level that normalizes under chemotherapy and who have no detectable lesion on both computed tomography and magnetic resonance imaging is probably more likely to yield a complete pathologic response. Whatever their treatment, patients with DLM run a high risk of recurrence that could be decreased with the use of HAI. Despite a high recurrence rate, the overall 5-year survival rate of patients with DLM ranges from 40 to 80%. Having a DLM should no longer be a contraindication to hepatic surgery since long-term survival is expected in these highly chemosensitive patients. The use of adjuvant HAI in addition to efficient systemic chemotherapy could reduce the risk of hepatic relapse. PMID- 21540597 TI - Two-stage hepatectomy procedure to treat initially unresectable multiple bilobar colorectal liver metastases: technical aspects. AB - A two-stage hepatectomy procedure is a therapeutic strategy for patients presenting with initially unresectable multiple and bilobar colorectal liver metastases in order to achieve a curative R0 resection. The main goal of this approach is to minimize the risk of postoperative liver failure resulting from a too small remnant liver after completing a curative resection. This procedure combines two sequential liver resections that involve perioperative chemotherapy and portal vein embolization. This article describes our standardized strategy of two-stage hepatectomy combined with portal vein embolization used over the last 15 years and discusses the alternative procedures as well as their respective advantages and drawbacks. PMID- 21540598 TI - Liver resection combined with local ablation: where are the limits? AB - BACKGROUND/AIMS: Partial hepatectomy for liver tumors is potentially curative but unfortunately available only for a limited number of patients. Local tumor destruction by ablation has expanded criteria for treatment and potential cure for patients with liver tumors. This paper gives an overview of the possibilities and limitations of ablation of liver tumors. METHODS: A search of relevant peer reviewed literature was conducted. RESULTS: Investigations in the second half of the 18th century paved the way for application of electromagnetic fields in living organisms. Currently, indications for thermoablation are (1) unresectable liver tumors, (2) bridging therapy for a more definitive treatment, (3) debulking of symptomatic hormonally active liver tumors, and (4) patients unfit for major abdominal procedures. Although randomized trials on the use of radiofrequency ablation (RFA) are scarce, the results thus far suggest that the combination of partial liver resection and local ablation offers cure rates in the same order of magnitude as partial liver resection - the 'gold standard' - alone. Additionally, RFA seems to be associated with a lower morbidity and mortality rate as compared to partial liver resection. One of the disadvantages is the reported high incidence of ablation site recurrences of sometimes up to 30%. This is especially related to a larger size of ablated tumors and tumors close to large vessels. Also, RFA is a rather time-consuming procedure. On theoretical grounds, ablation with microwaves is more effective and faster and seems to be associated with a lower incidence of ablation site recurrences. CONCLUSIONS: Ablation has acquired a place in the arsenal of treatment modalities for patients with liver tumors and expanded the indications for treatment with a curative intent. Further evolution of the technique and the proof that it has at least the same oncological result with a lower morbidity as partial hepatectomy are required in the near future. PMID- 21540599 TI - Laparoscopic liver resection for hepatocellular carcinoma in cirrhosis: long-term outcomes. AB - BACKGROUND: Few data regarding survival or pattern of recurrence after laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) on cirrhosis have been reported so far. METHODS: A retrospective analysis of a prospectively maintained database of 109 laparoscopic interventional procedures performed for HCC in cirrhotic liver between 2000 and 2008 was conducted. RESULTS: Sixty-five patients underwent an LLR. Morbidity rates were 20% (13/65), whereas there was only 1 death (1.5%). Reoperation was required in 2 patients. The overall mean postoperative hospital stay was 8.2 (2.6; 3-15) days. The actuarial overall 1-, 3-, and 5-year survival rates were 95, 70, and 55%, respectively, with a median overall survival of 75 months. Excluding the one hospital death, the actuarial 1-, 3-, and 5-year disease-free survival rates were 81, 62, and 32%, respectively, with a median overall disease-free survival of 42 months (95% confidence interval, CI: 18-65). On multivariate analysis, tumor grade (OR: 3.5, 95% CI: 1.1-10.7, p = 0.026) and microvascular invasion (OR: 4.9, 95% CI: 1.2-18.8, p = 0.020) resulted as independent predictors of overall survival. On multivariate analysis, gender (OR: 3.4, 95% CI: 1.1-10.2, p = 0.023), satellite tumor (OR: 4.3, 95% CI: 1.5-12.3, p = 0.006), microvascular invasion (OR: 3.3, 95% CI: 1.0-10.1, p = 0.036) and surgical margin (OR: 3.7, 95% CI: 1.0-10.1, p = 0.036) were identified as independent prognostic predictors of better disease-free survival. After a median follow-up of 29 (range 3-81) months, 31 (48%) out of 64 patients had recurrence. The cumulative recurrence rates at 1, 3, and 5 years were 19, 39, and 68%, respectively. CONCLUSION: This prospective observational study has confirmed the feasibility and safety of LLR in selected patients with HCC in cirrhotic liver, and proved that it can warrant long-term outcome similar to those reported with the traditional open approach. PMID- 21540600 TI - Extent of liver resection for hilar cholangiocarcinoma (Klatskin tumor): how much is enough? AB - BACKGROUND: Hilar resection in combination with extended liver resections has resulted in a higher rate of R0 resections and increased survival in patients with hilar cholangiocarcinoma (HCCA). This aggressive surgical approach is, however, associated with high rates of operative morbidity and mortality, largely due to postresectional liver failure. We previously reported a series after resection of HCCA in which R0 resection rate was 59% with a mortality rate of 10%. In this study, we assessed mortality of extended liver resections after optimizing liver functional reserve and application of parenchyma-sparing techniques. METHODS: From 2008 until June 2010, 41 consecutive patients underwent resection on the suspicion of HCCA. Preoperative workup included staging laparoscopy, preoperative biliary drainage, assessment of volume/function of future remnant liver and radiation therapy to prevent seeding metastases. Modified right and left extended hemihepatectomies were performed preserving parts of segments 4 and 8, respectively, while pursuing complete excision of the tumor. Outcomes of resection were evaluated. RESULTS: The majority of resections (78%) were performed for Bismuth type III-IV tumors. Preoperative biliary drainage was undertaken in 37 (90%) patients. Hilar resection in combination with liver resection was performed in 35 (85%) patients. Of these resections, 61% were modified extended resections including central liver resections. The R0 resection rate was 92%. Postoperative morbidity and mortality rates were 54 and 7%, respectively. CONCLUSION: Strategies to optimize liver function and to reduce removal of functional liver parenchyma were associated with a decrease in mortality (7%) while undertaking extended resection for HCCA with an R0 resection rate of 92%. PMID- 21540601 TI - Two types of extended liver resection for advanced gallbladder cancer: how to do it. AB - BACKGROUND: Extended liver resection is necessary for advanced gallbladder cancer with hepatic involvement to achieve R0 resection. However, its type or extent and its surgical technique have yet to be established. METHODS: To exclude systemic disease, frozen section biopsy following systematic para-aortic lymphadenectomy is recommended before starting extended surgery with curative intent because para aortic nodes are involved more frequently than expected. Right hepatectomy with biliary reconstruction should be indicated for the hepatic hilum type of advanced gallbladder cancer in which a relatively small tumor in the gallbladder neck infiltrates the hepatic hilum and causes obstructive jaundice. Ventral hepatectomy without biliary reconstruction can be applied for the hepatic bed type in which a large mass in the gallbladder fundus and body penetrates into the hepatic parenchyma through the gallbladder bed. RESULTS: The two types of extended liver resection were successfully performed in representative cases. Detailed procedures were described. Long-term survival without disease recurrence has been achieved in both cases. CONCLUSION: The type of extended liver resection should be chosen according to the mode of tumor spread in advanced gallbladder cancer without distant metastasis. PMID- 21540602 TI - Association of operating time and gastrectomy with initiation of postoperative oral food intake. AB - BACKGROUND: Fast-track programs optimizing perioperative care have been initiated along with the advancement of laparoscopic colorectal surgery. To clarify that these programs were evidence based for gastrectomy cases, we assessed the effect of operating time and gastrectomy type [open partial (OPG), open total (OTG), laparoscopic partial (LPG) and laparoscopic total (LTG)] on postoperative commencement of oral food intake. METHODS: Among 14,465 cases of gastrectomy across 837 hospitals, we examined the demographics, comorbidity, complications, postoperative epidural analgesia, rehabilitation and teaching status. The impact of gastrectomy type and operating time on postoperative fasting period was assessed using mixed regression models to distill off the hospital practice belief. RESULTS: We identified 2,775 laparoscopic gastrectomies and 10,064 partial gastrectomies, 2,485 of which were conducted via laparoscopy. Operating time was shortest in OPG and longest in LTG. The fasting period was shortest in LPG and longest in OTG. Longer operating time prolonged the fasting period, except for LTG. Postoperative epidural analgesia and earlier rehabilitation, but not laparoscopic gastrectomy, were associated with a shortened fasting period. CONCLUSION: When developing a fast-track program for gastrectomy, clinicians should recognize the impact of longer operating time and perioperative care rather than that of gastrectomy type on oral intake. PMID- 21540603 TI - Laparoscopy-assisted percutaneous gastrostomy tube placement along with laparoscopic gastropexy. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) has gained wide acceptance for patients suffering malnutrition. However, the PEG technique is not always feasible in cases in which endoscopic passage is not possible due to an obstruction in the esophagus. METHODS: Under general anesthesia, a 2.0 nylon suture with a straight needle was inserted into the peritoneal cavity approximately 1 cm cranial to the planned gastrostomy. After this straight needle was held with the laparoscopic needle holder, the layers of the anterior gastric wall were sutured, and then the needle was put through the abdominal wall. The same procedures were performed at 2 cm on the caudal side of the first suture. A trocar with a peel-away sheath was used to penetrate the gastric wall. The peel away sheath was removed and a balloon catheter was placed between the two gastropexy sutures. RESULTS: This surgical procedure was performed in 6 cases. The mean operation time was 46.7 +/- 10.0 min, the postoperative courses were uneventful, and feeding was started on postoperative day 1 in all cases. CONCLUSIONS: This laparoscopic gastrostomy procedure should be especially useful in patients in whom endoscopic passage is not possible due to a neck or esophageal stenosis. PMID- 21540604 TI - Nasogastric decompression for radical gastrectomy for gastric cancer: a prospective randomized controlled study. AB - BACKGROUND: The purpose of this study was to evaluate the necessity of a nasogastric decompression in radical gastrectomy for gastric cancer patients by a prospective randomized controlled trial. METHODS: From 2007 to 2009, 161 gastric cancer patients who underwent radical gastrectomy were randomly selected and entered into three groups: tube group (TG), intra-operative tube group (ITG), and no-tube group (NTG). The variables studied among the groups were demographic characteristics, surgical characteristics, postoperative recovery and complications. RESULTS: With respect to demographic and surgical characteristics, there were no significant differences among the 3 groups. The time of the first passage of flatus, tolerance of water intake, liquid diet and semiliquid diet were similar among TG, ITG and NTG. Postoperative hospital stay was increased in patients from TG compared to NTG (11.3 vs. 10.2 days, p = 0.031). The incidence of nausea was significantly higher in TG than in ITG or NTG (64 vs. 36.8 and 29.6%). The overall postoperative complication rate was not significantly different among these groups (20, 15.8 and 20.4% in TG, ITG and NTG, respectively, p = 0.612). CONCLUSIONS: Radical gastrectomy can be performed safely without nasogastric decompression for gastric cancer patients. The routine prophylactic nasogastric decompression is unnecessary. PMID- 21540605 TI - Management of liver adenomatosis by radiofrequency ablation. AB - Traditionally, surgical resection has been the treatment of choice in many patients with hepatocellular adenoma because of the risk of rupture, hemorrhage and malignant transformation. However, some patients are not amenable for surgery due to the extensive involvement of the liver, as in patients with liver adenomatosis. We report 2 cases with liver adenomatosis in which we combined surgery with open and percutaneous radiofrequency ablation for lesions located in both lobes of the liver. Minimal invasive treatment including radiofrequency ablation may offer new perspectives in the treatment of patients with liver adenomatosis. PMID- 21540606 TI - Drain versus no-drain after gastrectomy for patients with advanced gastric cancer: systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: A wide range of outcomes are seen in the literature on the use of drains after gastrectomy. However, there is little consensus on whether or not drains are beneficial in patients with gastric cancer. The purpose of this meta-analysis was to evaluate drain versus no-drain after gastrectomy by using evidence from available randomized controlled trials (RCTs). METHODS: We searched PubMed, the Cochrane Library, Embase, VIP, and CNKI for the terms 'gastric cancer', 'gastrectomy' and 'drains' used in combination with the medical subject headings. RCTs were considered. Meta-analysis was performed by RevMan 5.0 software. RESULTS: Four RCTs involving 438 patients were included. There were no differences between the drain and no-drain groups in the incidence of wound infection, postoperative pulmonary infection, intra-abdominal abscess, mortality, number of postoperative days until passing of flatus and initiation of soft diet. Both the incidence of postoperative complications and the length of hospital stay for patients in the no-drain group after gastrectomy were lower than in the drain group (p = 0.03, 95% CI 0.32, 0.95) and (p = 0.009, 95% CI -1.21, -0.18), respectively. CONCLUSION: Avoiding the use of abdominal drains may reduce drain related complications and shorten hospital stay after gastrectomy. PMID- 21540607 TI - Risk factors and management of postoperative bile leakage after hepatectomy without bilioenteric anastomosis. AB - BACKGROUND/AIMS: Bile leakage frequently causes major complications after hepatic resection. We investigated perioperative risk factors and management of postoperative bile leakage after hepatic resection without extrahepatic biliary resection and reconstruction. METHODS: We included 247 consecutive patients who underwent elective hepatic resection without bilioenteric anastomosis at our institution between 2002 and 2009. Perioperative risk factors, including patient and surgical variables, were evaluated using univariate and logistic regression analyses. RESULTS: Postoperative bile leakage occurred in 26 patients (10.5%). The surgical drain was retained in 6 patients (23%); 9 (35%) underwent drain salvage and 11 (42%) underwent percutaneous puncture under computed tomography or ultrasound guidance. Eight patients underwent endoscopic nasobiliary drainage (ENBD) for postoperative bile leakage, and bile leakage healed at a median interval of 19.5 days after ENBD. By univariate analysis, postoperative bile leakage was associated with central bisectionectomy, surgical time and intraoperative blood loss. Logistic regression analysis identified central bisectionectomy as an independent risk factor for postoperative bile leakage (p = 0.0003, odds ratio 16.724). CONCLUSION: Meticulous procedures are necessary during parenchymal hepatic resection, especially during central bisectionectomy. Drain management should be precise in the case of postoperative bile leakage. We believe ENBD may rapidly cure postoperative major bile leakage. PMID- 21540608 TI - Elective laparoscopic cholecystectomy: the effect of age on conversions, complications and long-term results. AB - BACKGROUND/AIMS: The purpose of the present study was to analyze the appropriateness and long-term results of elective laparoscopic cholecystectomy in the treatment of gallstone disease in the elderly. METHODS: We studied all elderly (>=75 years) patients (n = 80) who underwent laparoscopic cholecystectomy at our institution during the years 1992-2001. Two control groups (65-74 years and <65 years) included the same amount of patients. For determining the long term results, we asked the patients to specify their overall satisfaction with the results of the procedure (very satisfied, satisfied, no effect, worse). RESULTS: There were no statistically significant differences in mean operative time (61, 65, 72 min) or conversions to open surgery (6, 11, 16%) between the age groups (<65, 65-74, >=75 years). The mean hospitalization time (2.1, 3.3, 4.4 days) and complications (0, 11, 13%) increased with the age of the patients. Neither severe complications nor mortality were encountered. The vast majority of the patients were very satisfied or satisfied with the long-term results of the procedure in all age groups (97% <65 years, 83% 65-74 years, 80% >=75 years). CONCLUSION: Elective laparoscopic cholecystectomy is also a safe and feasible operation with good long-term results in the elderly. PMID- 21540609 TI - Surgery versus conservative antibiotic treatment in acute appendicitis: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND/AIMS: Although standard treatment typically consists of an early appendectomy, there has recently been an increase in the use of antibiotic therapy as primary treatment for acute appendicitis (AA). The aim of this analysis is to systematically evaluate the evidence available in relevant literature in order to compare the relative effectiveness of antibiotic therapy as a viable alternative to appendectomies in the treatment of AA. METHODS: Literature was searched for randomized clinical trials (RCTs) comparing the efficacy of surgery versus antibiotic therapy. Differences in pooled odds ratios (OR) for outcomes within 95% confidence intervals (CI) were calculated. RESULTS: Four RCTs were identified including 741 patients. Efficacy was significantly higher for surgery (OR = 6.01, 95% CI = 4.27-8.46). No differences were found in the numbers of perforated appendices (OR = 0.73, 95% CI = 0.29-1.84) and patients treated with antibiotics (OR = 0.04, 95% CI = 0.00-3.27). Complication rates were significantly higher for surgery (OR = 1.92, 95% CI = 1.30-2.85). CONCLUSION: Although a nonsurgical approach in AA can reduce the complications rate, the lower efficacy prevents antibiotic treatment from being a viable alternative to surgery. Since only a small number of RCTs of poor methodological quality are available, well-designed RCTs are needed for further investigation. PMID- 21540610 TI - Tumor thrombectomy via a surgically reopened umbilical vein combined with right hemihepatectomy in a patient with hepatocellular carcinoma. AB - This report presents a case of a patient with a huge hepatocellular carcinoma in the right lobe of the liver with an extensive portal venous tumor thrombus extending into the main portal trunk and left portal branch. The patient underwent extended right hemihepatectomy with tumor thrombectomy with direct extraction from an opening of the ventral wall of the right portal vein and using a balloon catheter to push the tumor thrombus via the surgically reopened umbilical vein. This technique seems useful in cases of tumor thrombus that extend deep into the umbilical portion of the left portal vein. In addition, this technique may have minimized the intraoperative migration of the tumor thrombus into the future remnant liver by occluding portal flow with the balloon catheter during the thrombectomy. PMID- 21540611 TI - Analysis of the surgical outcome and prognostic factors for hilar cholangiocarcinoma: a Chinese experience. AB - PURPOSES: Hilar cholangiocarcinoma (HC) is the most common location for bile duct cancer. It represents a significant technical challenge for surgical operation due to the close proximity to major vascular structures and to the liver and arborization of the right and left biliary tree. The objective of this study was to assess the therapeutic strategies and prognostic factors that could influence the clinical outcome of HC. METHODS: From January 1990 to December 2009, a total of 215 HC patients undergoing resection were included in this study. Survival and follow-up were calculated from the date of initial histologic diagnosis to the dates of first recurrence or death and last contact, respectively. Uni- and multivariate analyses were performed to examine factors affecting clinical outcome and recurrence. RESULTS: 215 patients underwent resection: 141 (65.6%) had an R0 resection (negative histologic margins), 46 (21.4%) had an R1 resection (positive histologic margins), 28 (13.0%) had an R2 resection. The 1-, 3- and 5 year cumulative survival rates (%) of the patients were 60.3, 37.2 and 29.7%. The median survival time after R0 resection was 47.1 months, 17.2 months after R1 resection, and 12.1 months after R2 resection. The results from univariate analyses suggest that poor histopathological grade (p = 0.004), lymph node metastasis (p = 0.000), vascular invasion (p = 0.005), neuroinvasion (p = 0.044), R1 resection (p = 0.000) and T2 or T3 stage (p = 0.009) were significant predictors for poor survival rates. By multivariate analysis, only the lymph node metastasis (RR = 2.450, 95% CI 1.677-3.579) and R1 resection (RR = 0.283, 95% CI 0.183-0.437) were significantly associated with poor survival rates. CONCLUSIONS: Negative histologic margins were associated with improved outcome after all HC resections. Complete resection remains the only therapy that offers the possibility of long-term survival, and hepatic resection is a critical component of the surgical approach. PMID- 21540612 TI - Pancreatoduodenectomy with subtotal stomach-preserving and uncut Roux reconstruction. AB - BACKGROUND/PURPOSE: Pylorus-preserving pancreatoduodenectomy (PD) has become the therapy of choice for resectable tumors located in the head of the pancreas and periampullary region. In addition, a distal gastrectomy may still be required for tumors located in the dorsal part of the pancreatic head or when there is evidence of proximal duodenal invasion. This may lead to postoperative complications, including gastric dumping, marginal ulceration, and bile reflux gastritis. This study reports on the postoperative course following subtotal stomach-preserving PD with the uncut Roux reconstruction diverting biliary and pancreatic secretions from the gastric remnant. METHODS: A technique combining subtotal stomach-preserving PD with the uncut Roux reconstruction was applied in 10 patients. The postoperative clinical follow-up data are reviewed, and clinical criteria of biliary gastric reflux and gastritis were evaluated. RESULTS: The postoperative course was uneventful in 4 patients and complicated in 6 patients. Delayed gastric emptying occurred in 3 patients. No deaths occurred in the postoperative period. One patient suffered from occasional nausea with abdominal discomfort for which endoscopy and cholescintigraphy were performed. Endoscopy confirmed complete occlusion of the afferent jejunal limb and showed marginal ulceration within the gastrojejunal anastomosis. Cholescintigraphy showed signs of enterogastric reflux. The check-up endoscopy following typical antisecretory therapy revealed complete ulcer healing. Four patients died of tumor recurrence 6, 7, 8, and 12 months following surgery. CONCLUSION: This pilot study suggests that the uncut Roux reconstruction may represent a good alternative to gastrointestinal reconstruction following PD. Further studies including the determination of intragastric bile acid concentration and radionuclide isotope scanning in a larger number of patients are warranted. PMID- 21540613 TI - Proliferative and anti-apoptotic activity of esophageal mucosa in gastroesophageal reflux disease is not affected by fundoplication: a 4-year follow-up study. AB - BACKGROUND: The role of fundoplication in the prevention of esophageal adenocarcinoma is controversial. Development of cancer is associated with proliferation and anti-apoptosis, for which little data exist regarding their response to fundoplication. METHODS: Ki-67 and Bcl-2 expression was assessed in the esophagogastric junction (EGJ) and the distal and proximal esophagus of 20 patients with gastroesophageal reflux disease (GERD) treated by fundoplication and in 7 controls. Endoscopy was performed preoperatively and 6 (20 patients) and 48 months (16 patients) postoperatively. RESULTS: There were positive correlations between Ki-67 and Bcl-2 levels in the EGJ (p > 0.001) and in the distal (p = 0.001) and proximal esophagus (p = 0.013). Compared to the preoperative level, Ki-67 expression was elevated in the distal (p = 0.012) and proximal (p = 0.007) esophagus at 48 months. In addition, compared to control values, Ki-67 expression was lower at the 6-month follow-up in the EGJ (p = 0.037) and the proximal esophagus (p = 0.003), and higher at the 48-month follow up in the distal esophagus (p = 0.002). Compared to control values, Bcl-2 was lower at 6 months in the EGJ (p = 0.038). CONCLUSIONS: Proliferative activity after fundoplication increased in the long term in the distal esophagus despite a normal fundic wrap and healing of GERD. PMID- 21540614 TI - Surgical treatment of 26 patients with necrotizing pneumonia. AB - BACKGROUND: This study aimed to review the outcome of patients treated with surgical resection for necrotizing lung infection with various co-morbidities and complications. METHODS: The records of 26 patients treated with pulmonary resection for necrotizing pneumonia between July 2004 and January 2010 were retrospectively reviewed. Surgical procedures included large wedge resection (n = 1), lobectomy (n = 19) and bilobectomy (n = 6). RESULTS: The study cohort consisted of 21 men and 5 women aged 35-85 years (mean 64.7 +/- 15.0 years). Twenty-three (88.5%) patients had underlying risk factors. At surgical consultation, 17 patients presented with progressive respiratory distress; 6 required ventilatory support; 12 had empyema, and in 5 patients the conditions were complicated by bronchopleural fistula. Four patients had septic shock requiring vasopressor support. Three patients developed hemoptysis. Two patients had bilateral diffuse pneumonia. Klebsiella pneumoniaeand Streptococcusviridans were the most common pathogens. The right lower (n = 13) and right middle lobes (n = 10) were the most frequently affected. Four deaths (15.4%) occurred: 3 due to perioperative progressing pulmonary infection/inflammation and 1 due to hepatorenal failure. Postoperative empyema occurred in 3 patients. One patient became ventilator dependent. CONCLUSION: Pulmonaryresection for necrotizing pneumonia is a feasible treatment option in patients with progressive pulmonary sepsis. PMID- 21540615 TI - Feasibility of delayed hyperthermic intraperitoneal chemotherapy in case of unforeseen complications. AB - BACKGROUND: Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) can improve the prognosis of selected patients with peritoneal surface malignancy (PSM). Usually, treatment is performed as an extensive one-step approach. We investigated the feasibility of delayed HIPEC, if the one-step procedure was interrupted precociously. METHODS: 42 patients with PSM who underwent CRS and delayed HIPEC from 2006-2008 were studied. HIPEC was performed 5 days after treatment with mitomycin, cisplatin and hyperthermia. Perioperative complications and toxicity were analyzed. RESULTS: Delayed HIPEC was successfully completed in 40 of the 42 patients. In 2 cases, HIPEC was omitted because of complications during chemotherapy (anastomotic leakage and retroperitoneal edema). Minor and major surgical complications occurred in 18 and 9 of the 40 patients treated with HIPEC (45 vs. 22.5%), respectively. Toxicity grade II-IV (WHO criteria) was observed in 4 of them (10%). Median stay in the intensive care unit was 9 days (range 2-31) while the mean hospitalization time was 24 days (range 14-59). In this series, there was no mortality. CONCLUSION: Postponement of HIPEC after CRS (two-step approach) is feasible. Analysis of morbidity and mortality showed no significant difference to the one-step approach reported in the literature and no disadvantages for the patient. The two-step approach is an alternative option for patients who had to discontinue the one step approach due to unpredictable intraoperative complications. PMID- 21540616 TI - Quality of life and myelomeningocele: an ethical and evidence-based analysis of the Groningen Protocol. AB - In 2005, a group of pediatricians at the University Medical Center in Groningen, The Netherlands, published the Groningen Protocol (GP) for Euthanasia in Newborns. This protocol is a set of guidelines devised in 2001 to clarify and facilitate the assessment of clinically stable neonates deemed to be in unbearable suffering for whom the prognosis is felt to be hopeless. At the time of publication, the GP had been in use for 7 years, and 22 patients, all with diagnosed myelomeningocele (MMC), had met the selection criteria for euthanasia by lethal injection. MMC is the most common neurological congenital anomaly, affecting approximately 300,000 newborns yearly worldwide. Neurosurgeons have a unique perspective on this disease and therefore an important voice, given the significant role they have in caring for these patients at all stages of their lives. This paper reviews the principal ethical arguments presented to date in the literature regarding the GP. It also provides an evidence-based critique of the GP in light of quality-of-life studies addressing adults with MMC, and ascertains whether or not the GP meets the criteria for an evidence-based guideline. PMID- 21540617 TI - Commentary on 'quality of life and myelomeningocele: an ethical and evidence based analysis of the Groningen Protocol' by Sean Barry, Pediatr Neurosurg 2010;46:409-414. PMID- 21540618 TI - Ruptured brain arteriovenous malformations in children: correlation of clinical outcome with admission parameters. AB - AIMS: To gain a better understanding of how clinical outcome in children with ruptured brain arteriovenous malformations (bAVMs) correlates with clinical and imaging parameters on admission. METHODS: The authors retrospectively reviewed patients with bAVMs, aged 18 or below, managed at their hospital between January 1992 and December 2008. Clinical outcome was assessed using the modified Rankin Scale (mRS). Patients with ruptured bAVMs were analyzed; their clinical parameters and computerized tomography findings on admission were recorded. Clinical outcome was then evaluated against admission scores using the Glasgow Coma Scale (GCS), the World Federation of Neurosurgical Societies Grading System of Subarachnoid Hemorrhage (WFNS-SAH), the Spetzler-Martin grade, the intracerebral hemorrhage score and 2 other independent parameters, namely pupillary response and significant focal neurological injuries. Spearman's correlation coefficient, linear regression analysis and multivariate logistic regression analysis were used for data analysis. RESULTS: 40 pediatric patients with bAVMs were found and 32 of them presented with hemorrhage (80%). In the 32 children with ruptured bAVMS, follow-up ranged between 7 and 204 months (median 100.5 months). The complete excision/obliteration rate as confirmed by digital subtraction angiography was 73.3%. The mRS scores at the last follow-up were: grades 0-II in 87.5%; grades IV-V in 6.25%, and grade VI in 6.25%. The Spetzler Martin grade, the intracerebral hemorrhage score, the WFNS-SAH grade, the GCS scores, and a combined scoring scale consisting of the GCS, pupillary response and significant focal neurological injuries correlated significantly with clinical outcome 6 months after hemorrhage. However, on the scatter diagrams, it appeared that only the combined scoring scale might be valid for clinical practice. Multivariate logistic regression analysis showed that the combined scoring scale was a statistically significant independent predictor of clinical outcome 6 months after hemorrhage. CONCLUSION: In this series of pediatric patients with ruptured bAVMs, although various grading scales correlated significantly with clinical outcome 6 months after hemorrhage, only the combined scoring scale might have the potential to be applied to predict clinical outcome in these children. PMID- 21540619 TI - Vein of Galen aneurysms: presentation and endovascular management. AB - BACKGROUND: We present our experience with managing 13 cases of vein of Galen aneurysm with a special focus on endovascular strategies. This clinical review deals with the multivariable clinical presentation of vein of Galen aneurysms and the role of transarterial endovascular treatment. METHODS: Thirteen patients diagnosed with vein of Galen aneurysms have been reviewed. Clinical presentation, diagnostic modalities and treatment strategies are also documented for each. MRI and three-dimensional CT angiogram (3D CTA) were performed for all patients. Transarterial embolization with Histoacryl was performed in 8 patients proved to have true vein of Galen aneurysmal malformation (VGAM). RESULTS: Clinical presentation was variable including hydrocephalus, headaches, heart failure, coma, epilepsy, and even left orbital swelling. MRI demonstrated large vein of Galen aneurysms in all the cases. 3D CTA demonstrated true VGAM in 10 patients. Two cases proved to have vein of Galen varices. Endovascular treatment was conducted successfully in 8 patients and resulted in arrest of head growth, resolution of headaches and improvement of cardiac condition. CONCLUSION: The transarterial approach proved to be a successful way of management of true VGAM that yielded better outcomes. PMID- 21540620 TI - Endoscopic third ventriculostomy in obstructive infantile hydrocephalus: remarks about the so-called 'unsuccessful cases'. AB - BACKGROUND: The failure rate following endoscopic third ventriculostomy (ETV) in infants younger than 2 years of age has been reported to be higher compared with that of older children, and it is unclear whether ETV might be superior to shunt placement in this age group. METHODS: Between 2003 and 2009, 23 patients younger than 6 months and without a previous history of shunting underwent ETV in our institution. A review of the literature was performed on the basis of publications presenting detailed data on age and etiology in every single patient. RESULTS: In our own patients, total success rate was 39.1%. In the successful cases, median age was 140 days, whereas in the unsuccessful cases it was 47 days. The difference between the two groups was statistically significant (p = 0.01). The median ages of both successful and unsuccessful groups corresponded to data gained from an analysis of the literature (p = 0.04). At a median follow-up of 47 months, 2 out of 14 patients shunted after a failed ETV were revised for ventriculoperitoneal shunt malfunction. CONCLUSION: The impact of age on ETV failure in infants is clear and becomes crucial during the first 2 months of life, even when excluding etiological factors. Nevertheless, age cannot be considered the only parameter of the decision-making process, especially in these very young patients. Probably, the definition of 'unsuccessful ETV' should be reevaluated in light of decreased risk of shunt malfunction observed after a failed ETV. PMID- 21540621 TI - Cerebral anomalies and Chiari type 1 malformation. AB - OBJECTIVE: To analyze the association of diverse cerebral anomalies in a series of pediatric patients with cerebellar tonsillar ectopia. METHODS: We reviewed the medical records of 60 children diagnosed with Chiari type 1 malformation (CM1), of these, 20 patients (11 boys and 9 girls; mean age 7.2 years, range 2-16 years) had an associated cerebral anomaly. Symptoms of tonsillar ectopia evolved over a mean of 12 months (range 3 months to 4 years). Syringomyelia was present in 5 cases. All patients underwent a posterior fossa decompression. RESULTS: Disclosed anomalies included: congenital hydrocephalus (n = 11), cervicomedullary kinking (n = 5), focal cerebral heterotopia with epilepsy (n = 4), partial agenesis of the corpus callosum (n = 4), hypoplastic brain stem (n = 2), holoprosencephaly (n = 1), and subcortical dysplasia in the context of neurofibromatosis type 1 (n = 1). Other malformations included: subcortical hamartoma associated with neurofibromatosis type 1, craniofacial dysmorphism secondary to Noonan syndrome, congenital occipital plagiocephaly, os odontoideum, craniofacial cleft, juvenile rheumathoid arthritis with platybasia, and osteogenesis imperfecta with bathrocephaly and scoliosis. CONCLUSION: Craniocerebral anomalies in children treated for CM1 may be found consistently. The association of hydrocephalus, which was the most common anomaly in this cohort, with cerebellar tonsillar ectopia may contribute to a poor outcome in regard to tonsillar herniation symptoms. PMID- 21540622 TI - An intracranial aneurysm and dural arteriovenous fistula in a newborn. AB - The authors present the case of a newborn with an intracerebral aneurysm and a dural arteriovenous fistula. The patient initially presented with intraventricular hemorrhage and hydrocephalus, with evidence of remote subarachnoid hemorrhage, left hemispheric stroke, and sagittal sinus thrombosis. He was treated with a ventriculoperitoneal shunt and subsequent staged endovascular obliteration of both the aneurysm and fistula. Interestingly, the aneurysm did not appear on an artery feeding the abnormal fistula. Intracerebral aneurysms in the neonatal population are rare, and dural arteriovenous fistulae even more so; we present a case of a 2-month-old infant with both, as well as a review of the literature concerning these rare vascular abnormalities. PMID- 21540623 TI - Anaplastic astroblastoma presenting as massive, sudden-onset, intraparenchymal hemorrhage. AB - Astroblastoma is a rare primary glial tumor of children and young adults, typically located in the cerebral hemispheres and presenting as a well circumscribed, nodular, often cystic enhancing mass. The existence of astroblastoma as a distinct clinicopathologic entity has long been debated but is recognized in the 2007 WHO classification of CNS tumors. The grading of these tumors remains unsettled. Currently, no grade has been established and there are no clearly defined diagnostic criteria for low- or high-grade tumors. Astroblastomas in general are thought to have a favorable outcome with low rates of recurrence following gross total resection. We report a case of astroblastoma with 'high-grade/anaplastic' histology in a 12-year-old, previously healthy girl. The patient experienced severe, sudden-onset headache, and quickly became comatose. Head CT showed a massive intraparenchymal hemorrhage in the right frontal lobe with surrounding edema. She underwent emergent posterior frontal craniotomy for decompression and hematoma evacuation. Pathologic examination revealed a sharply demarcated hemorrhagic heterogeneous glial tumor with focal papillary architecture, densely hyalinized blood vessels, and intensely GFAP positive perivascular cells. The tumor showed unequivocal high-grade features including an elevated proliferative index. The diagnosis of anaplastic astroblastoma was rendered. The patient expired on postoperative day 30. This case illustrates the potential poor outcome of high-grade astroblastoma and highlights the morphologic heterogeneity of this rare neoplasm. PMID- 21540624 TI - Clear cell meningioma of the fourth ventricle in a child: a case report and literature review. AB - Clear cell meningiomas are rare meningioma variants and are recognized as World Health Organization grade II tumours. They may be difficult to manage given their propensity to recur early especially if present in surgically challenging locations. We describe a rare case of a fourth ventricular clear cell meningioma without dural attachment in a 14-year-old boy with an unusual presentation of failure to thrive. The case is presented in detail and a review of the recent literature is discussed. PMID- 21540625 TI - Widespread methodological problems limit validity of meta-analytic results. PMID- 21540627 TI - Cognitive-behavioral group therapy versus sertraline for obsessive-compulsive disorder: five-year follow-up. PMID- 21540628 TI - IC3D classification of corneal dystrophies. AB - The International Committee for Classification of Corneal Dystrophies (IC3D) has provided an update of our knowledge on corneal dystrophies. This chapter gives the summary of clinical findings, onset, course, genetics, nosology, light and electron microscopy as well as immunohistochemistry for 25 different entities included as corneal dystrophies in this survey. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. PMID- 21540629 TI - The clinical landmarks of corneal dystrophies. AB - The International Committee for Classification of Corneal Dystrophies, briefly IC3D, was founded to develop a new, internationally accepted classification of corneal dystrophies (CDs) based on modern clinical, histological and genetical knowledge. Being members of the IC3D, the authors of this chapter present a clinical landmark survey of the different CDs. The ophthalmologist is the first to examine and to diagnose a new patient with a probable CD using a slit lamp. The presented landmarks are supposed to be a bridge for the ophthalmologists to precisely define the corneal opacities of a presumed CD. This bridge makes it easier for them to study the IC3D publication and to get more information including adequate differential diagnosis. PMID- 21540630 TI - Histological landmarks in corneal dystrophy: pathology of corneal dystrophies. AB - Corneal dystrophies are bilateral, progressive, genetically determined noninflammatory diseases restricted to the cornea. These are characterized by deposition of nonnative protein or other material, both intracellular and extracellular, within the corneal layers. Dystrophies are classified based on the anatomical location of the lesions as: anterior corneal dystrophies (affecting the epithelium and extending into the superficial stroma), stromal dystrophies (which involve the stroma only) and posterior corneal dystrophies (which include the Descemet's membrane and endothelium). Recent additions in the field of genetics and molecular basis of the dystrophies have led to the evolution of a new classification which incorporates genotypic-phenotypic features. While histopathologic study is the gold standard for the diagnosis, various other techniques help provide additional information in this area. Corneal dystrophies can be considered unique as the association of gene-protein-disease has been approached both in the forward direction as well as the reverse order. In this chapter, we attempt to highlight the histological features of corneal dystrophies from the cumulative evidence obtained from the study of corneal buttons, enucleated specimens, corneal biopsies, electron microscopic studies, histochemistry and immunohistochemistry. PMID- 21540631 TI - The genetics of the corneal dystrophies. AB - Several comprehensive reviews have been written recently that summarize what is currently known about the molecular genetic basis of the corneal dystrophies. The one that is the current definitive reference on the subject is the IC3D classification of the corneal dystrophies, written by an international group of experts on the corneal dystrophies. In this work, each gene in which a pathogenic mutation has been identified in a patient with a corneal dystrophy is listed and an appendix is provided with a complete list of the genes and the mutations listed at the nucleotide and amino acid levels (with references). As the IC3D classification of the corneal dystrophies is readily available to the reader both in print and online, this chapter will not focus on reviewing the genes and mutations that have been associated with the corneal dystrophies. Instead, it will provide an overview of the genetics of the corneal dystrophies, discussing first the clinical and genetic spectrum of the corneal dystrophies and then the limitations of a genetically based classification system for the corneal dystrophies. The last section of this chapter will discuss how the discovery of mutations that cause the corneal dystrophies is not the end of the process of scientific discovery, but only the beginning, as vision scientists attempt to determine how the identified mutations lead to the formation of corneal deposits or loss of endothelial function, and develop strategies to modulate gene expression. PMID- 21540632 TI - Differential diagnosis of Schnyder corneal dystrophy. AB - Schnyder corneal dystrophy (SCD) is a rare corneal dystrophy characterized by abnormally increased deposition of cholesterol and phospholipids in the cornea leading to progressive vision loss. SCD is inherited as an autosomal dominant trait with high penetrance and has been mapped to the UBIAD1 gene on chromosome 1p36.3. Although 2/3 of SCD patients also have systemic hypercholesterolemia, the incidence of hypercholesterolemia is also increased in unaffected members of SCD pedigrees. Consequently, SCD is thought to result from a local metabolic defect in the cornea. The corneal findings in SCD are very predictable depending on the age of the individual, with initial central corneal haze and/or crystals, subsequent appearance of arcus lipoides in the third decade and formation of midperipheral haze in the late fourth decade. Because only 50% of affected patients have corneal crystals, the International Committee for Classification of Corneal Dystrophies recently changed the original name of this dystrophy from Schnyder crystalline corneal dystrophy to Schnyder corneal dystrophy. Diagnosis of affected individuals without crystalline deposits is often delayed and these individuals are frequently misdiagnosed. The differential diagnosis of the SCD patient includes other diseases with crystalline deposits such as cystinosis, tyrosinemia, Bietti crystalline dystrophy, hyperuricemia/gout, multiple myeloma, monoclonal gammopathy, infectious crystalline keratopathy, and Dieffenbachia keratitis. Depositions from drugs such as gold in chrysiasis, chlorpromazine, chloroquine, and clofazamine can also result in corneal deposits and are different from SCD. Diseases of systemic lipid metabolism that cause corneal opacification, such as lecithin-cholesterol acyltransferase deficiency, fish eye disease and Tangier disease, should also be considered although these are autosomal recessive disorders. PMID- 21540633 TI - Clinical and basic aspects of gelatinous drop-like corneal dystrophy. AB - Gelatinous drop-like corneal dystrophy (GDLD) was first reported in 1914 as a peculiar corneal dystrophy with an autosomal recessive inheritance mode. GDLD is rare in many countries, but relatively prevalent in Japan. The typical finding of GDLD is grayish, mulberry-like, protruding subepithelial depositions with a prominent hyperfluorescence of the cornea. Histologically, GDLD corneas are characterized by subepithelial amyloid depositions that were identified as lactoferrin by amino acid sequencing analysis. In 1998, the TACSTD2 gene was identified as a causative gene for this disease through a linkage analysis and a candidate gene approach. To date, 14 reports have demonstrated 21 mutations comprised of 9 missense, 6 nonsense, and 6 frameshift mutations from 9 ethnic back grounds. Currently, it is hypothesized that the loss of TACSTD2 gene function causes decreased epithelial barrier function, thereby facilitating tear fluid permeation into corneal tissue, the permeated lactoferrin then transforming into amyloid depositions via an unknown mechanism. For the visual rehabilitation of patients with GDLD, ophthalmologists currently employ various types of keratoplasties; however, almost all patients will experience a recurrence of the disease within a few years after such interventions. Wearing of a soft contact lens is sometimes considered as an alternative treatment for GDLD. PMID- 21540634 TI - Stage-related therapy of corneal dystrophies. AB - Corneal dystrophies typically result in a gradual bilateral loss of vision in a primary 'white eye' - often in conjunction with epithelial defects in later stages. Treatment of corneal dystrophies needs to be stage-related. To ensure a stage-related therapeutic approach, an adequate classification based on clinical, histopathological and genetic knowledge is indispensable. In principle, topical medications, contact lenses and various microsurgical approaches are applicable. In case of predominantly superficial dystrophies of the epithelium, basal membrane and/or Bowman's layer (map-dot-fingerprint, Meesmann, Lisch, Reis Bucklers, Thiel-Behnke), recurrent epithelial defects may complicate the clinical picture. If conservative therapy with gels/ointments, application of therapeutic contact lenses and/or conventional corneal abrasion are not successful, phototherapeutic keratectomy (PTK) using a 193-nm excimer laser is the method of choice today. PTK can be repeated several times, thus post poning corneal transplantation (lamellar or even penetrating) for a long time. Three major goals may be achieved by PTK depending on the diagnosis: (1) to remove superficial opacities; (2) to regularize the surface and treat irregular astigmatism, and (3) to improve the adherence of the epithelium. In dystrophies with depositions predominantly in the stroma (e.g. granular, lattice, macular, recurrence on the graft), PTK may be a reasonable alternative to anterior lamellar or penetrating keratoplasty (PKP) depending on the exact localization of the lesions. Besides exact determination of the depth of depositions using a slit lamp, a preoperative topography analysis is indispensable. The therapy of endothelial dystrophies depends on diagnosis and age: Fuchs endothelial corneal dystrophy will need corneal transplantation (e.g. when visual acuity drops below 0.4). In contrast, transplantation will only be very rarely necessary in posterior polymorphous corneal dystrophy, but the intraocular pressure has to be checked frequently. Especially in elderly patients with reduced compliance, posterior lamellar keratoplasty - preferably in the form of Descemet stripping automated endothelial keratoplasty - may be performed instead of PKP. In case of congenital hereditary endothelial dystrophy, the best time point of PKP has to be determined with regard to amblyopia (surgery too late) and inadequate follow-up (surgery too early) together with parents and pediatric ophthalmologists on an individual basis. In conclusion, for stage-related therapy of corneal dystrophies, besides contact lenses, PTK and PKP, various techniques of lamellar keratoplasties represent an indispensable enrichment of our corneal microsurgical spectrum today. PMID- 21540635 TI - Polymorphisms in genes involved in innate immunity and susceptibility to benzene induced hematotoxicity. AB - Benzene, a recognized hematotoxicant and carcinogen, can damage the human immune system. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and benzene hematotoxicity in a cross sectional study of workers exposed to benzene (250 workers and 140 controls). A total of 1,236 tag SNPs in 149 gene regions of six pathways were included in the analysis. Six gene regions were significant for their association with white blood cell (WBC) counts (MBP, VCAM1, ALOX5, MPO, RAC2, and CRP) based on gene region (P<0.05) and SNP analyses (FDR<0.05). VCAM1 rs3176867, ALOX5 rs7099684, and MPO rs2071409 were the three most significant SNPs. They showed similar effects on WBC subtypes, especially granulocytes, lymphocytes, and monocytes. A 3 SNP block in ALOXE3 (rs7215658, rs9892383, and rs3027208) showed a global association (omnibus P = 0.0008) with WBCs even though the three SNPs were not significant individually. Our study suggests that polymorphisms in innate immunity genes may play a role in benzene-induced hematotoxicity; however, independent replication is necessary. PMID- 21540637 TI - Reproductive tract and spermatid abnormalities of hybrid males from reciprocal crosses between Drosophila mojavensis and D. arizonae. AB - Hybrid males from reciprocal crosses of specific strains of the closely related species Drosophila mojavensis and Drosophila arizonae are sterile. The sterile hybrid males exhibit testis and seminal vesicle phenotypes that differ from their parental strains and from each other both in lengths of the organs and the development of the spermatids as seen in light and electron microscopy. Incompatibilities affecting spermiogenesis differ in reciprocal crosses, suggesting that hybrid male sterility may originate from a range of different underlying mechanisms. PMID- 21540636 TI - A comprehensive study of the contribution of Salmonella enterica serovar Typhimurium SPI2 effectors to bacterial colonization, survival, and replication in typhoid fever, macrophage, and epithelial cell infection models. AB - Salmonella enterica serovars are Gram-negative bacterial pathogens responsible for human diseases including gastroenteritis and typhoid fever. After ingestion, Salmonella cross the intestinal epithelial barrier, where they are phagocytosed by macrophages and dendritic cells, which then enables their spread to systemic sites during cases of typhoid fever. Salmonella use two type 3 secretion systems encoded by Salmonella pathogenicity islands (SPI) 1 and 2 to inject virulence proteins into host cells to modify cellular functions. SPI1 is involved in host cell invasion and inflammation, whereas SPI2 is required for intracellular survival and replication within phagocytes, and systemic spread. In this study the contribution of nearly all known SPI2 effectors was examined in an in vivo model of murine typhoid fever and cell culture models of macrophage and epithelial cell infection. Unmarked, in-frame deletions of SPI2 effectors were engineered in S. enterica serovar Typhimurium and the ability of the 16 different mutants to colonize and replicate was examined. In the typhoid model, we found that DeltaspvB and DeltaspiC mutants were attenuated for colonization of intestinal and systemic sites, while the DeltasseF mutant was attenuated in systemic organs. In epithelial cells, all mutants replicated to the same extent as the wild-type. In macrophages, DeltaspiC, DeltasteC, DeltaspvB, DeltassseK1/K2/K3, DeltasifA, and DeltasifB strains replicated poorly in comparison to wild-type Salmonella. This study provides a thorough screen of the majority of the known SPI2 effectors evaluated under the same conditions in various models of infection, providing a foundation for comparative examination of the roles and interactions of these effectors. PMID- 21540638 TI - Planar cell polarity and tissue design: Shaping the Drosophila wing membrane. AB - Planar cell polarity (PCP) describes the orientation of a cell within the plane of an epithelial cell layer. During tissue development, epithelial cells normally align their PCP so that they face in the same direction. This alignment allows cells to move in a common direction, or to generate structures with a common orientation. A classic system for studying the coordination of epithelial PCP is the developing Drosophila wing. The alignment of epithelial PCP during pupal wing development allows the production of an array of cell hairs that point towards the wing tip. Multiple studies have established that the Frizzled (Fz) PCP signaling pathway coordinates wing PCP. Recently, we have found that the same pathway also controls the formation of ridges on the Drosophila wing membrane. However, in contrast to hair polarity, ridge orientation differs between the anterior and posterior wing. How can the Fz PCP pathway generate a different relationship between hair and ridge orientation in different parts of the wing? In this Extra View article, we discuss membrane ridge development drawing upon our recent PLoS Genetics paper and other, published and unpublished, data. We also speculate upon how our findings impact the ongoing debate concerning the interaction of the Fz PCP and Fat/Dachsous pathways in the control of PCP. PMID- 21540639 TI - Oviposition site preferences and performance in natural resources in the human commensals Drosophila melanogaster and D. simulans. AB - The choice of egg laying site and progeny's performance in a rearing site are important components of habitat selection. Despite the huge amount of genetic, morphological, behavioral and physiological data regarding Drosophila melanogaster Meigen and D. simulans Sturtevant, oviposition site preferences remain poorly known. We investigated resource preference (acceptance and choice) and performance (measured as larval viability, developmental time and wing size) in Vitis vinifera Linneo (grape) and Cydonia oblonga Miller (quince), two fruit plants that D. melanogaster and D. simulans use as breeding substrates in Western Argentina. Females of both species preferred V. vinifera over C. oblonga when offered to lay eggs on grape and/or quince, with D. melanogaster showing a more biased preference for V. vinifera than its sibling. Concerning performance, flies reared in C. oblonga developed faster than in V. vinifera, regardless of the species and D. simulans had a shorter developmental time than D. melanogaster. We also observed inter and intraspecific (between flies reared in different resources) differences in wing size and shape. Our study provides novel data concerning ecological aspects scarcely addressed in these species, and suggest that the use of different resource may be a relevant factor in their recent evolutionary history. PMID- 21540641 TI - Multiple pathways counteract cell death induced by RB1 loss: implications for cancer. AB - Inactivation of the tumor suppressor RB1 leads to cell proliferation, cell death and abortive differentiation in certain tissues and physiological contexts. Anti apoptotic signals are thought to be the most important mechanism by which RB1 mutant cells escape cell death. Indeed, in the course of neoplastic transformation RB1 is often inactivated in conjunction with a mutation in the pro apoptotic tumor suppressor p53. We have previously devised a biological framework to identify factors that maintain survival of differentiating Rb-deficient muscle fibers. We showed that differentiating Rb-deficient myoblasts fuse to form short myotubes that degenerate in a process associated with enhanced autophagy, and that degeneration was rescued by antagonists of apoptosis or autophagy, induction of mitochondrial-biogenesis or hypoxia-induced glycolytic shift, leading to long, twitching myotubes. Here, we also show that lithium slows the collapse of Rb deficient myotubes and surprisingly, this is independent of autophagy, cyclin D3 and beta-catenin. Thus, several distinct processes can suppress cell death induced by RB1 loss. We discuss these pathways and how they may cooperate with RB1 inactivation in the course of cancer initiation. PMID- 21540640 TI - Aberrant TGFbeta/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, RunX1T1 in ovarian cancer. AB - Aberrant TGFbeta signaling pathway may alter the expression of down-stream targets and promotes ovarian carcinogenesis. However, the mechanism of this impairment is not fully understood. Our previous study has identified RunX1T1 as a putative SMAD4 target in an immortalized ovarian surface epithelial cell line, IOSE. In this study, we report that transcription of RunX1T1 was confirmed to be positively regulated by SMAD4 in IOSE cells and epigenetically silenced in a panel of ovarian cancer cell lines by promoter hypermethylation and histone methylation at H3 lysine 9. SMAD4 depletion increased repressive histone modifications of RunX1T1 promoter without affecting promoter methylation in IOSE cells. Epigenetic treatment can restore RunX1T1 expression by reversing its epigenetic status in MCP3 ovarian cancer cells. When transiently treated with a demethylating agent, the expression of RunX1T1 was partially restored in MCP3 cells, but gradual re-silencing through promoter re-methylation was observed after the treatment. Interestingly, SMAD4 knockdown accelerated this re-silencing process, suggesting that normal TGF-beta signaling is essential for the maintenance of RunX1T1 expression. In vivo analysis confirmed that hypermethylation of RunX1T1 was detected in 35.7% (34/95) of ovarian tumors with high clinical stages (P=0.035) and in 83% (5/6) of primary ovarian cancer initiating cells. Additionally, concurrent methylation of RunX1T1 and another SMAD4 target, FBXO32 which was previously found to be hypermethylated in ovarian cancer was observed in this same sample cohort (P< 0.05). Restoration of RunX1T1 inhibited cancer cell growth. Taken together, dysregulated TGFbeta/SMAD4 signaling may lead to epigenetic silencing of a putative tumor suppressor, RunX1T1, during ovarian carcinogenesis. PMID- 21540642 TI - Vision in venture: angels of innovation. Interviewed by Catarina Wylie. PMID- 21540643 TI - Multiple functions of PINK1 at different intracellular locations: beyond neurodegenerative diseases. PMID- 21540644 TI - Mechanism of K+/Na+ selectivity in potassium channels from the perspective of the non-selective bacterial channel NaK. AB - Studies of the non-selective NaK channel as a model system provided detailed structural and functional insights into different factors that modulate selective ion conductance. The combination of structural and functional studies of WT- and mutant forms of NaK channel show that apparent conservation of the multiple binding sites in the canonical selectivity filter of K-channel is essential component of the observed robust Na (+) discrimination. PMID- 21540645 TI - Conformational stability and aggregation of therapeutic monoclonal antibodies studied with ANS and Thioflavin T binding. AB - Characterization of aggregation profiles of monoclonal antibodies (mAb) is gaining importance because an increasing number of mAb-based therapeutics are entering clinical studies and gaining marketing approval. To develop a successful formulation, it is imperative to identify the critical biochemical properties of each potential mAb drug candidate. We investigated the conformational change and aggregation of a human IgG1 using external dye-binding experiments with fluorescence spectroscopy and compared the aggregation profiles obtained to the results of size-exclusion chromatography. We show that using an appropriate dye at selected mAb concentration, unfolding or aggregation can be studied. In addition, dye-binding experiments may be used as conventional assays to study therapeutic mAb stability. PMID- 21540646 TI - A single mutation turns a non-binding germline-like predecessor of broadly neutralizing antibody into a binding antibody to HIV-1 envelope glycoproteins. AB - Broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV)-1 are rare in natural infection and elicitation of HIV-1 bnAbs has not been achieved by any vaccine candidates. We and others have reported that HIV-1 bnAbs are highly diversified from their germline-like predecessors, and the germline like predecessors of bnAbs lack measurable binding to HIV-1 envelope (Env) glycoproteins, suggesting that Env structures containing the epitopes of bnAbs may not initiate somatic maturation pathway, which may partially explain the rarity of HIV-1 bnAbs. To determine the minimum mutations required for converting non-binding germline-like predecessors to Env-binding antibodies, we started with the bnAb b12 as a prototype and generated six "chimeric" scFv b12 variants by sequentially replacing the heavy chain V-segment (HV), D(J)-segment [HD(J)] in the heavy chain variable region (VH), and the whole light chain variable region (VL) in b12 germline-like predecessor with the mature counterparts. We tested the recombinant scFv variants for binding and neutralizing activities. Results showed that a single point mutation in germline D-segment was enough to convert nonbinding germline-like b12 to an Env-binding antibody. Replacement with either mature HV or mature VL also made the germline-like b12 bind to Env, but none of single segment replacements conferred neutralization ability to the germline antibody. Mature VL in combination with mature HD(J), or mature HV, or both conferred increasing neutralization activity to the germline antibody. However, hybrid scFv, mature VH / germline VL did not neutralize the virus, suggesting the importance of mature VL in neutralizing the virus. These results may have implications for vaccine development. PMID- 21540647 TI - Highly specific off-target binding identified and eliminated during the humanization of an antibody against FGF receptor 4. AB - Off-target binding can significantly affect the pharmacokinetics (PK), tissue distribution, efficacy and toxicity of a therapeutic antibody. Herein we describe the development of a humanized anti- fibroblast growth factor receptor 4 (FGFR4) antibody as a potential therapeutic for hepatocellular carcinoma (HCC). A chimeric anti FGFR4 monoclonal antibody (chLD1) was previously shown to block ligand binding and to inhibit FGFR4 mediated signaling as well as tumor growth in vivo. A humanized version of chLD1, hLD1.vB, had similar binding affinity and in vitro blocking activity, but it exhibited rapid clearance, poor target tissue biodistribution and limited efficacy when compared to chLD1 in a HUH7 human HCC xenograft mouse model. These problems were traced to instability of the molecule in rodent serum. Size exclusion high performance liquid chromatography, immunoprecipitation and mass spectral sequencing identified a specific interaction between hLD1.vB and mouse complement component 3 (C3). A PK study in C3 knock-out mice further confirmed this specific interaction. Subsequently, an affinity-matured variant derived from hLD1.vB (hLD1.v22), specifically selected for its lack of binding to mouse C3 was demonstrated to have a PK profile and in vivo efficacy similar to that of chLD1 in mice. Although reports of non-specific off-target binding have been observed for other antibodies, this represents the first report identifying a specific off-target interaction that affected disposition and biological activity. Screens developed to identify general non specific interactions are likely to miss the rare and highly specific cross reactivity identified in this study, thus highlighting the importance of animal models as a proxy for avoiding unexpected clinical outcomes. PMID- 21540648 TI - Bioengineered skin allografts: a new method to prevent humoral response. AB - We previously reported that a bioengineered interface consisting of a nano barrier membrane (NB-LVF4) used as an artificial interface between skin allografts and wound surfaces significantly prolonged graft survival without immunosuppression. We now evaluated whether NB-LVF4 could serve as a targeted drug delivery system to further improve outcomes. Fibroblast growth factor-1 (FGF 1) was selected for its known function as a wound hormone. Full-thickness 8-mm skin grafts were cross-transplanted between out-bred mice. Controls were transplanted without treatment. In test groups, the NB-LVF4, with or without FGF 1, was applied to both basolateral skin and wound surfaces with polymerization resulting in a tridimensional transparent membrane. The mice were evaluated for T cell activation and development of donor-specific antibody. Rejection occurred in controls by 7 days. NB-LVF4 treatment, with or without FGF-1, was found to significantly prolong allograft survival (27 and 28 days, respectively [p < 0.05]). Untreated controls stimulated 10-fold shift in the number of circulating CD4+ cells while test groups exhibited substantially reduced shifts in CD4+ cells. The group treated with FGF-1 did not develop donor-specific antibody. Treatment with the NB-LVF4 membrane delays the onset of allograft rejection in the absence of systemic immunosuppression. FGF-1 appears to prevent the development of a humoral response by preventing B cell activation. PMID- 21540649 TI - Sex differences in survival of cutaneous melanoma are age dependent: an analysis of 7338 patients. AB - This study identified sex differences in clinical presentation and survival for primary cutaneous melanoma without clinical evidence of metastasis at diagnosis from 1976 to 2008 in southern Germany. Melanoma-specific survival curves and estimated survival probabilities were generated using the Kaplan-Meier method. Multivariate survival analyses were carried out using the Cox modeling. Male patients had significantly thicker and more frequently ulcerated tumors and a lower 10-year disease-specific survival (DSS) and recurrence-free survival probability compared with females among patients of 43 years old or younger (DSS: 86.1 vs. 93.2%, P<0.001) and 44-60 years old (DSS: 83.5 vs. 90.1%, P<0.001). The survival advantage of female patients in terms of 10-year DSS and 10-year recurrence-free survival was not observed after an age of 60 years (P=0.21 and 0.51, respectively). Sex was of prognostic importance for DSS and survival after recurrence [hazards ratio (HR): 1.3; 95% confidence interval (CI): 1.1-1.6; P=0.002 and HR: 1.2; 95% CI: 1.0-1.5; P=0.018, respectively]. Stratified by age groups, sex remained of prognostic importance for DSS only in patients of 43 years or younger, and 44-60 years old (HR: 1.5; 95% CI: 1.0-2.1; P=0.03 and HR: 1.4; 95% CI: 1.1-2.0; P=0.02, respectively). Sex is an independent prognostic factor in surviving melanoma. The sex difference in survival with a better outcome for women is confined to melanoma patients of 60 years and younger. In addition, in younger age groups, male patients present with prognostically unfavorable features of primary melanoma. A female survival advantage is also known for other solid tumors such as colon and lung cancer; however, age dependency has not been studied. PMID- 21540650 TI - A rare case of metaphyseodiaphyseal chondroblastoma of proximal femur presenting with constitutional symptoms in a six-year-old child. AB - Primary metaphyseodiaphyseal chondroblastoma is rare. To our knowledge, very few such cases have been reported in the English literature. Insidious onset of pain is the most common complaint in patients with chondroblastoma. A clinical presentation of constitutional symptoms along with a metaphyseodiaphyseal lesion on radiographs in a young child usually points toward a diagnosis of Ewing's sarcoma or infection. Here, we document a case of metaphyseodiaphyseal chondroblastoma of femur in a 6-year-old child presenting with chief local complaints of an intermediate onset pain and swelling along with systemic complaints of fever and malaise. The patient was operated by excision of the tumor and reconstruction using autogenous-free fibular graft. PMID- 21540651 TI - The Boldt debacle. PMID- 21540652 TI - Measuring pain and analgesic response. PMID- 21540654 TI - Insignificant effect of desflurane-fentanyl-thiopental on hepatocellular integrity -- a comparison with total intravenous anaesthesia using propofol remifentanil: Retraction. PMID- 21540653 TI - European Society of Anaesthesiology Clinical Trials Network. PMID- 21540655 TI - Influence of controlled hypotension using esmolol and sodium nitroprusside on natriuretic peptides in patients undergoing endonasal sinus surgery: Retraction. PMID- 21540656 TI - Hepatocellular integrity in patients requiring parenteral nutrition: comparison of structured MCT/LCT vs. a standard MCT/LCT emulsion and a LCT emulsion: Retraction. PMID- 21540657 TI - Individual titration of propofol plasma target improves anaesthetic stability in patients undergoing major abdominal surgery: a comparison with manually controlled infusion: Retraction. PMID- 21540658 TI - Balanced hydroxyethylstarch preparations: are they all the same? In-vitro thrombelastometry and whole blood aggregometry: Retraction. PMID- 21540659 TI - Placebo-controlled comparison of dolasetron and metoclopramide in preventing postoperative nausea and vomiting in patients undergoing hysterectomy: Retraction. PMID- 21540660 TI - Effects of sodium nitroprusside-induced controlled hypotension on pancreatic function assessed by pancreatitis-associated protein in patients undergoing radical prostatectomy: Retraction. PMID- 21540661 TI - Do we necessarily need local anaesthetics for venous cannulation? A comparison of different cannula sizes: Retraction. PMID- 21540662 TI - Why emergency medicine needs senior decision makers. PMID- 21540663 TI - Repeated episodes of airway obstruction caused by a pyolaryngocele. PMID- 21540664 TI - Mediastinal pancreatic pseudocyst and pleural effusion. PMID- 21540665 TI - Introduction. Trabectedin treatment in GYN cancers. AB - Ovarian cancer is the second most common gynecological cancer, representing 5% of all cancers in women. It has the highest case-fatality rate of all gynecological malignancies. In the European Union, there are approximately 48,000 new cases of ovarian cancer and 31,000 deaths per year. Similarly, in the United States, there are approximately 25,500 new cases per year, with 16,000 deaths associated. PMID- 21540666 TI - Efficacy of trabectedin in platinum-sensitive-relapsed ovarian cancer: new data from the randomized OVA-301 study. AB - The results of the OVA-301 study show that trabectedin in combination with pegylated liposomal doxorubicin (PLD) results in improved progression-free survival and response rate in patients with advanced ovarian cancer. The trial has also demonstrated a trend toward improvement in overall survival. A subgroup analysis indicates that in the subset of patients with platinum-free interval (PFI) of 6 to 12 months, the combined treatment resulted in a 6-month improvement in overall survival. Furthermore, in the patients who have received third-line treatment with a platinum agent, it was found that the survival was better in those who had received trabectedin and PLD. These results suggest that prolonging the PFI by a nonplatinum-effective regimen improves the outcome with subsequent, third-line platinum treatment. This strategy may also have positive effects in treatment tolerability, as it allows extra time to recover from platinum-induced toxicities. This hypothesis is currently been tested in the INOVATYON (INternational OVArian Cancer Patients Trial With YONdelis) phase III study. PMID- 21540667 TI - An increasing role for trabectedin in gynecological cancers: efficacy in uterine sarcomas. AB - Trabectedin is indicated for patients with advanced soft tissue sarcoma after failure of treatment with anthracyclines and ifosfamide or for patients who are unsuited to receive these agents. The agent has shown activity in patients with advanced uterine leiomyosarcoma, with an acceptable safety profile. Thus, the results of phase II studies have shown that treatment with trabectedin results in 30% progression-free survival at 6 months. More than 50% of these pretreated patients were alive at 1 year. The response rate, progression-free survival, and overall survival compared favorably with other single agents (eg, doxorubicin, ifosfamide, and gemcitabine), with clinical benefit in 50% of patients in second line treatment. These results are being confirmed in a current prospective phase II study in first-line uterine leiomyosarcoma combining trabectedin with doxorubicin. PMID- 21540668 TI - Safety profile of trabectedin in combination with liposomal pegylated doxorrubicin in relapsed ovarian carcinoma: considerations for optimal management. AB - The toxicity profile of trabectedin in the OVA-301 trial, that combined trabectedin with pegylated liposomal doxorubicin for the treatment of patients with ovarian cancer, has shown to be predictable and manageable. No unexpected toxicities were found, with neutropenia and transient increase in transaminases as the most common adverse events reported. The elevation in transaminases appeared early and generally decreased in incidence and intensity over subsequent cycles, with no major clinical consequences. A similar safety profile was seen in the analysis of the older patients in the trial. There were no detrimental effects in quality of life with the combination. Moreover, the Global Health Status score was better for the combination arm in those patients with a PFI of 6 to 12 months that were in response after 5 cycles. Trabectedin with pegylated liposomal doxorubicin is not associated with cumulative end-organ toxicities (renal, cardiac, or neurological toxicities). The toxicity profile is different from other second-line strategies without the presence of inconvenient side effects, such as alopecia, hypersensitivity reactions, hand-foot syndrome, or mucositis. PMID- 21540669 TI - Benefits of enhancing the platinum-free interval in the treatment of relapsed ovarian cancer: more than just a hypothesis? AB - There is some evidence from in vitro studies as well as case series that patients with documented platinum resistance will respond to platinum after a nonplatinum drug. In addition, retrospective case studies have demonstrated the difficulty in determining if delaying second platinum is detrimental or beneficial. For that reason, a prospective Italian randomized trial conducted by the Multicenter Italian Trials in Ovarian Cancer (MITO) Group (MITO-8), comparing nonplatinum with platinum-based therapy is being performed to assess the effects of delaying platinum on survival. PMID- 21540670 TI - Late postoperative atrial fibrillation: minor surgery complication or major cardiovascular issue? PMID- 21540671 TI - Cardiac resynchronization therapy in heart failure diabetic population: a challenging issue. PMID- 21540672 TI - Changes in mood states after coronary bypass surgery: can we do better? PMID- 21540673 TI - Impact of diabetes on long-term mortality after presentation with acute myocardial infarction. PMID- 21540674 TI - Spontaneous coronary artery dissection and elevated levels of lipoprotein(a) in a young man: a causal association? PMID- 21540675 TI - Myocardial infarction and spontaneous dissection of coronary artery due to oral contraceptive. PMID- 21540676 TI - Asymptomatic homozygous gene carrier in a family with Ile68Leu ATTR amyloidosis: a new endemic region in northern Tuscany? PMID- 21540677 TI - Pharmacological treatment of chronic systolic heart failure: are we scraping the bottom of the barrel? PMID- 21540679 TI - Practicing to the full extent of our ability: the role of nurses in healthcare reform. PMID- 21540680 TI - Health courts: an alternative to traditional tort law. AB - The current adversarial tort-based system of adjudicating malpractice claims is flawed. Alternate methods of compensation for birth injuries related to oxygen deprivation or mechanical injury are being utilized in Virginia and Florida. Although utilization of both of these schemes is limited, and they are not without problems in application, both have been successful in reducing the number of malpractice claims in the tort system and in reducing malpractice premiums. While the Florida and Virginia programs are primarily focused on compensation, other models outside the US focus include compensation as well as enhanced dispute resolution and potential for clinical practice change through peer review. Experts in the fields of law and public policy in the United States have evaluated a variety of approaches and have proposed models for administrative health courts that would provide both compensation and dispute resolution for medical and nursing malpractice claims. These alternative models are based on transparency and disclosure, with just compensation for injuries, and opportunities for improvements in patient safety. PMID- 21540681 TI - Perinatal patient safety and quality. AB - The leadership team and clinicians in hospitals and healthcare system must focus on perinatal safety and quality to minimize risk of preventable harm to mothers and infants. A review of current issues in perinatal patient safety and quality is presented. PMID- 21540682 TI - Politics, power, and birth. AB - Politics is the process and method of decision making for individuals and groups. Politics may define the power relationships between women and their healthcare providers. Politics may shape the experience for the woman. Nurses and birthing women can learn to negotiate the politics and power relationships surrounding the birth experience. PMID- 21540683 TI - Redirecting treatment during neonatal transport. AB - Neonatal transport teams comprise multidisciplinary health care providers who are skilled in patient care, communication and customer service, and equipment mechanics. They are extensively trained in resuscitation and stabilization, preparing for accelerating care, and their focus is preservation of life. In any situation focused on caring for critically ill patients, ethical issues and questions may arise. For instance, is it compassionate and/or cost-effective to separate mothers and infants when continuing/accelerating care is futile, and when and how should care be redirected from acute and lifesaving care to comfort care and bereavement support for the family? The knowledge and skills required to address such situations and communicate and participate in a redirection of care may not be adequately emphasized in the preparation of the professionals responsible for stabilizing and transporting critically ill newborns. This article raises issues relating to transport and redirecting care such as eligibility for transport, parental request and consent, separation of mothers and infants, palliative and bereavement care, ethical considerations, competitive transport environment, and customer service. A shared mental model is essential. The focus of this article is not to provide answers to all of these issues, but to highlight the complexity of the topic of redirecting treatment during neonatal transport. Redirecting treatment needs to be discussed, and health care professionals should be prepared during their transport team training. Each family and situation must be approached individually, with the acceptance that there will always be more questions than answers. PMID- 21540684 TI - Finding the leader within: thoughts on leadership in nursing. AB - Leadership is an important topic in nursing. We recognize the importance of leaders who represent us well to those outside of the profession, yet many nurses do not view themselves as "leaders." This is unfortunate, because real leadership is less about a title or institutionally granted power, and more about how we "show up" in the many situations that make up our days. The image of the nursing profession is formed in the many day-to-day interactions between nurses and patients, families, the public, physicians, and administrators. Nurses who can find their inner leader and use it in their practice, at whatever level of the organization they contribute, will find that they are able to positively impact patient care and outcomes. This paper describes a framework for finding your inner leader that is based upon 5 "skill-cepts" (skills derived from leadership concepts), which we have found essential to leading. PMID- 21540685 TI - Impact on neonatal nursing globally: exemplars of how US neonatal/perinatal nurses can get involved. AB - Neonatal and perinatal nurses are responding to the global call by the United Nations Millennium Development Goals to decrease maternal, neonatal, and child mortality. But how does one get involved? This article describes the global needs with exemplars from Japan and Russia illustrating how nurses work globally. PMID- 21540686 TI - Patient safety in the NICU: a comprehensive review. AB - Patient safety is a worldwide priority aimed at preventing medical errors before they cause death, harm, or injury. Medical errors impact 1 in 10 patients worldwide (WHO), and their implications may include death, permanent, or temporary harm, financial loss, and psychosocial harm to the patient and in some cases to the caregiver. The unique aspects and the complexity of the neonatal intensive (NICU) environment, in addition to the vulnerability of the neonatal population increase the risk for medical errors. The following article offers an overview of safety issues specific to neonatal intensive care and provides strategies and examples on how to ensure safe practice. In particular, the authors focus on strategies to improve the team process. Practice recommendations and research implications are presented. PMID- 21540687 TI - Balancing the scale: directions for future research for perinatal advanced practice nurses. AB - Advanced practice nurses, including midwives, are well positioned to conduct, participate, or both in both basic and translational research to improve the outcomes and processes of perinatal care. This article contains suggestions for future research by perinatal advanced practice nurses, conceptualized around a scale to promote balance in outcomes. More research is needed in a number of areas, examples include collaborative practice, normal birth, and translation of the evidence concerning skin-to-skin practice. Health disparities; maternal, neonatal, and infant morbidity and mortality; formula feeding; and other vulnerabilities need more research to decrease these problematic outcomes. Advanced practice nurses are encouraged to be actively involved in perinatal research, to help confront and reduce health disparities, and to apply evidence in practice, broadly promoting wellness for women and their families. PMID- 21540688 TI - Global and cultural perinatal nursing research: improving clinical practice. AB - High-quality perinatal nursing care should be based on the best evidence including research findings, clinical expertise, and the preferences of women and their families. Principles of perinatal research initiatives are defined, with suggested research priorities designed to close current gaps in the micro and macro environments of perinatal nursing throughout the world. Nearly a decade ago, the following question was asked, "Where is the 'E' (evidence) in maternal child health?" Improving the quality and safety of perinatal nursing care for culturally diverse women globally is the primary goal of nurse researchers leading the future of perinatal healthcare. PMID- 21540689 TI - Genetics and genomics: impact on perinatal nursing. AB - In 1953, Watson and Crick first described the structure of the DNA molecule, an event that led to a new understanding of the nature of heredity. Just 50 years later, a conference was held in Bethesda, Maryland to announce the completion of the sequencing of the human genome. The era of genomic healthcare has begun, and it has profound implications for nursing education, nursing practice, and nursing research. This article will highlight some important areas in perinatal and neonatal nursing that have been affected by genetics and genomics, as well as some emerging areas of research that will be relevant to perinatal and neonatal nursing. PMID- 21540690 TI - Routine obstetrical interventions: research agenda for the next decade. AB - There are many interventions performed as a part of the active management of labor and birth that have remained unchanged over the years. Separating ritual from beneficial nursing care can guide the development of a research agenda. The agenda for the next 10 years can address some of the gaps remaining in the evidence-based foundation for routine interventions used during labor and birth. The gaps identify areas where unanswered questions prevent optimal care from occurring. These unanswered questions include optimal time for epidural administration; management of maternal movement during labor when routine interventions make this difficult; changing the practice of immediate, closed glottis coached pushing at 10 cm; continuous electronic fetal monitoring; routine administration of intravenous fluids; and finally, the use of oxytocin as augmentation or induction of labor. PMID- 21540691 TI - Overcoming challenges for nurse-led research in the neonatal intensive care unit. AB - Nurse researchers have made considerable contributions to the science of nursing. Conducting studies in the clinical environment is the best way to determine what interventions are most effective. Because most research is conducted by nurses from academic settings, they often are not viewed as credible by nurses in clinical practice, nor are they accepted readily into the neonatal intensive care unit (NICU) to conduct research. This article addresses the barriers to implementing and conducting studies in the NICU setting, and provides suggestions for creating collaborative and mutually satisfying relationships between nurse researchers and healthcare staff in the NICU. Partnerships built on mutual respect are necessary to have successful research outcomes, and to continue to build knowledge for the best neonatal care. PMID- 21540692 TI - Microbiome aspects of perinatal and neonatal health. AB - Our human cells are outnumbered 10 to 1 by bacterial cells. For this reason, the role of microorganisms, specifically bacteria, in health and disease has brought forth intense research via the Human Microbiome Project. The Human Microbiome Project is a National Institutes of Health sponsored effort to build upon the Human Genome Project in understanding human genetic and physiologic diversity. Perinatal and neonatal health represents areas of high importance for knowledge generated by the Human Microbiome Project as the microbiome is largely influenced during pregnancy, birth, and the neonatal period by nutrition, lifestyle, environmental factors of care, and the administration of medications, specifically antibiotics. As nurses have a depth of expertise in these areas, they will make a significant contribution toward better understanding the role of the microbiome in disease, and how to manipulate the microbiome to advantage patients toward health. This article describes the human microbiome and why it is important to overall health and disease. Three major unsolved problems in perinatal and neonatal health including (1) preterm birth; (2) the neonatal consequences of vaginal versus cesarean birth; and (3) neonatal gastrointestinal disease, specifically, necrotizing enterocolitis, are discussed in the context of current and future research on the human microbiome. PMID- 21540694 TI - Family-centered developmental care practices and research: what will the next century bring? AB - Family-centered developmental care is an essential element of neonatal intensive care. It is of particular importance when the infant is vulnerable and at greater risk for poor outcomes complicated by a family unit that is easily challenged by the unique needs of the infant. Yet, all infants and their families deserve this philosophy of caregiving. Family-centered developmental care must continue to be tested through research to determine which interventions work, what does not work, and which interventions need further refinement. This article provides a brief history of where we have been in neonatal caregiving, provides definitions for family-centered developmental caregiving and offers some "predictions" about where these practices need to be in the next century. Research questions and strategies are also addressed. As we continue to forge ahead integrating this philosophy into the caregiving arena, it is important to remember that there are many unanswered questions. PMID- 21540695 TI - Simulation-based training: the future of competency? AB - Traditionally, continuing education has focused on cognitive skills and technical skills, namely, what the provider needs to know and what the provider needs to be able to do. Successful completion of such education programs has conferred some degree of competence on the learner. For the most part, continuing education has been performed in silos with each healthcare provider discipline developing a program designed to meet the needs of their group. The Institute of Medicine and the Joint Commission have issued reports addressing patient safety, morbidity, and mortality of the newborn infant and maternal mortality, respectively. These reports call for the education of healthcare providers to include multidisciplinary team training and/or drills. Simulation-based training (SBT) is a methodology of education that is uniquely able to address cognitive and technical skills as well as behavioral skills and is ideal for multidisciplinary team training. As a result, SBT is beginning to be adopted in healthcare education. However, the following questions remain: Is a dedicated simulation space necessary, how should SBT be incorporated into the existing education program, and will it confer competency? PMID- 21540696 TI - Interdisciplinary and interprofessional education: what are the key issues and considerations for the future? AB - The identification of key issues and considerations for interdisciplinary and interprofessional education are explored. Both benefits and barriers to interprofessional education are discussed. The concept of simulation is reviewed relative to interprofessional education primarily as a catalyst for implementation of collaboration. The promise of interprofessional education and outcome studies direct where the future is headed. PMID- 21540697 TI - Electronic fetal heart rate monitoring: where are we now? AB - Electronic fetal heart rate monitoring (EFM) continues to be the primary method utilized for fetal assessment in the United States. Standardization of nomenclature associated with this perinatal technology has evolved over the past 40 years such that the current nomenclature recommended by the National Institute of Child Health and Human Development (NICHD) has been adopted by professional perinatal organizations as the agreed-upon method for professional communication and documentation. Current research continues to focus on the optimal management of intrapartum fetal heart rate tracings. The clinical controversies and challenges related to electronic fetal heart rate monitoring continue to evolve. PMID- 21540699 TI - Beyond the classroom: using technology to meet the educational needs of multigenerational perinatal nurses. AB - For the first time in history, there are 4 distinct generations of nurses working side by side at the clinical bedside: Veterans, Baby Boomers, Generation X, and Generation Y. All the generations have their unique personalities, beliefs, values, and learning styles. Approach to learning range from the traditional instructional method preferred by the Veteran's nurses to the more advanced technology (eg, Web-based, webinars, simulations, podcasts, and blogs) approach favored by Generation Y. Nurse educators and clinical nurse specialists must consider each generation's style of learning to best engage, stimulate, and promote transference and assimilations of new knowledge. This article briefly describes the generational learning style differences and explores alternative educational modalities to the traditional classroom instruction. PMID- 21540700 TI - Educating neonatal nurse practitioners in the 21st century. AB - The purpose of this education project is to prepare neonatal nurse practitioners using a nonlinear (random exposure to information delivered in context rather than abstracting information as is done in a traditional lecture), asynchronous approach. The Internet-based 3-dimensional virtual "living world" classroom will have a living textbook and a virtual neonatal intensive care unit (NICU). Deploying the program within a virtual living world will enhance program accessibility and overcome the challenges of nurses returning to school. Greater accessibility can help to alleviate the shortage of neonatal providers, which are needed to meet the needs of the growing population.A Neonatal Curriculum Consortium comprising expert neonatal nurse practitioners and faculty are developing multimedia learning modules for core content defined by national organizations and certifying bodies. Our Internet-based, multisite, nonlinear, asynchronous universal neonatal curriculum has at its core a 3-dimensional virtual "living text book" for didactic instruction and a "living world" NICU for "deliberate practice." The NICU will feature an interactive virtual infant patient. Our "Virtual NICU" will assist students to transition from the classroom, to the simulation laboratory, and ultimately to the clinical area. Providing clinical learning experiences in the virtual NICU will enhance the students' opportunities to learn to care for the culturally diverse populations they will serve as neonatal nurse practitioners. PMID- 21540701 TI - Educational challenges in neonatal nursing practice and advanced practice. AB - Education for advanced practice has been debated since the development of the position on the doctor of nursing practice for advanced clinical practice. This article explores the issues that have emerged with an emphasis on the advanced practice roles in neonatal nursing. Licensure, certification, and scope of practice are addressed. PMID- 21540704 TI - Multiple ligament-injured (dislocated) knee. PMID- 21540705 TI - Normal anatomy and biomechanics of the knee. AB - Functionally, the knee comprises 2 articulations-the patellofemoral and tibiofemoral. Stability of the joint is governed by a combination of static ligaments, dynamic muscular forces, meniscocapsular aponeurosis, bony topography, and joint load. The surgeon is ill equipped to undertake surgical treatment of a dislocated knee without a sound footing in the anatomic complexities of this joint. We review the normal anatomy of the knee, emphasizing connective tissue structures and common injury patterns. PMID- 21540706 TI - Initial assessment of the acute and chronic multiple-ligament injured (dislocated) knee. AB - Multiple-ligament injured knees resulting from knee dislocations are uncommon but serious injuries. These injuries can present to the emergency room acutely or in clinic on a delayed basis, but regardless of the setting they require a complete and detailed assessment to evaluate the extent of the injury. Complicating the diagnosis of a knee dislocation is the fact that acute knee dislocations often spontaneously reduce or are reduced by paramedics in the field before evaluation by a physician. In most cases, pain in the knee, a large knee effusion, and swelling of the effected limb are the only signs and symptoms of a knee dislocation. Quick and accurate assessment of these injuries is required to determine the presence of any limb threatening arterial injuries. In this chapter, we present the complete assessment of acute and chronic multiple ligament knee injuries. PMID- 21540707 TI - Surgical treatment of acute and chronic anterior and posterior cruciate ligament and medial-side injuries of the knee. AB - KD-IIIM knee injuries are challenging injuries that can do well when anatomic reconstruction techniques are used. This article describes the authors preferred reconstructions, timing of surgery, and rehabilitation techniques. The reconstructions are generally initiated 3 or 4 weeks after the injury when the local soft tissue injury allows and associated fractures have already been stabilized. The posterior cruciate ligament, posteromedial corner, and meniscus injuries are addressed in the initial operation. The corresponding author prefers to come back 6 weeks later and reconstruct the anterior cruciate ligament and assure that acceptable progress has been made regarding knee motion. PMID- 21540708 TI - Surgical treatment of acute and chronic anterior and posterior cruciate ligament and lateral side injuries of the knee. AB - Combined anterior cruciate ligament, posterior cruciate ligament, and lateral sided injuries of the knee most often occurs secondary to a forced varus moment or after knee dislocation. Management controversies include the optimal timing of surgery, operative techniques, and postoperative rehabilitation. Recent systematic literature reviews have demonstrated higher rates of failure with repair of the lateral and posterolateral corner structures, as opposed to reconstruction. However, the ideal ligament reconstruction techniques remain unclear. This chapter will review the combined anterior cruciate ligament/posterior cruciate ligament/lateral-sided injury pattern, including the physical examination findings, imaging, timing of surgery, graft selection, operative techniques, and postoperative rehabilitation protocols. PMID- 21540710 TI - Management of arterial and venous injuries in the dislocated knee. AB - Although uncommonly encountered, knee dislocation is frequently associated with major vascular injury. Serious injuries resulting in ischemia demand prompt recognition and efficient management to prevent devastating long-term sequelae. In this review, we detail mechanisms of knee dislocation and associated popliteal vascular injuries. Diagnostic modalities used to evaluate the extent of vascular injury are individually discussed. Appropriate initial management of vascular injuries is crucial and an algorithm for diagnosis and management will be reviewed. We elaborate on the salient points of vascular reconstruction in the context of the dislocated knee: surgical approach, conduct of the procedure, and adjunctive maneuvers are described. PMID- 21540709 TI - Combined PCL-ACL lateral and medial side injuries: treatment and results. AB - The multiple ligament-injured knee is a complex problem in orthopedic surgery. These injuries may or may not present as acute knee dislocations, and careful assessment of the extremity vascular and neurologic status is essential because of the possibility of arterial and/or venous compromise, and nerve injury. These complex injuries require a systematic approach to evaluation and treatment. Physical examination and imaging studies enable the surgeon to make a correct diagnosis and formulate a treatment plan. Knee stability is improved postoperatively when evaluated with knee ligament rating scales, arthrometer testing, and stress radiographic analysis. Surgical timing depends on the injured ligaments, vascular status of the extremity, reduction stability, and the overall health of the patient. The use of allograft tissue is preferred because of the strength of these large grafts, and the absence of donor site morbidity. PMID- 21540711 TI - Drop foot after knee dislocation: evaluation and treatment. AB - Although knee dislocations are relatively rare, serious complications make treatment difficult. Common peroneal nerve (CPN) palsy is a debilitating complication and its incidence has been reported as high as 50%. Even after successful ligament construction, unresolved CPN palsy is a major factor contributing to poor outcomes after knee dislocations. CPN palsy is more common with open dislocations, rotatory dislocations, and especially occurs in patients with posterolateral corner injuries. CPN palsy can be readily diagnosed clinically, although a high index of suspicion is needed. The risk versus benefits of surgical exploration in the acute setting is still under debate. Conservative management can be appropriate in the early phase of treatment, however, for persistent nerve damage, surgery is the treatment of choice because it results in better functional outcomes. Neurolysis, primary nerve repair, nerve grafting, and posterior tibialis tendon transfer have all been used by surgeons as viable surgical treatment options. As late surgical treatment of CPN typically results in poor prognosis, awareness of this injury, thorough physical examination and documentation of the nerve injury, and close follow-up are of paramount importance. PMID- 21540712 TI - Management of chronic tibial subluxation in the multiple-ligament injured knee. AB - Chronic tibial subluxation is a rare and complicated problem that requires careful evaluation and planning to achieve the desired outcome and patient satisfaction. Reconstruction of catastrophic knee injury requires obtaining a balance in 2 opposing goals: stability and range of motion. Complete understanding of the impact of each of the involved ligamentous structures on knee stability and motion is particularly important, given the absence of ligamentous restraints and landmarks in the multiligamentous knee injury. Three critical operative steps are necessary to produce a desired outcome: (1) complete release and excision of scar tissue, (2) recreation of the central knee axis through anterior cruciate ligament and posterior cruciate ligament allograft reconstruction, and (3) maintenance of postoperative stability and functional motion with an external hinge fixator or functional knee brace. Careful postoperative clinical and radiographic follow-up completes the process toward an excellent result in this difficult clinical scenario. PMID- 21540713 TI - Complications associated with treatment of multiple ligament injured (dislocated) knee. AB - Multiple ligament injured knee is a heterogenous group of injuries, which remains a challenging entity for physicians to manage. Complications that are associated with this severe injury can occur from the injury itself or can arise from emergency or definitive treatment. The development of these complications can alter management options and compromise patient outcomes. PMID- 21540714 TI - Rehabilitation after multiple-ligament reconstruction of the knee. AB - Diagnosis and management of multiple-ligament knee injuries has evolved over the years, and now treatment often includes surgical intervention. Rehabilitation after multiple-knee ligament reconstruction requires a precarious balance between restoring range of motion and function to the knee without compromising the static stability and integrity of the grafted tissues. It is imperative that the patient is aware of the time commitment, restrictions, and the fact that the entire rehabilitation process will likely take a full year before returning to unrestricted activity. The purpose of this study is to define the current approach to postsurgical management after posterior cruciate ligament-based multiple knee-ligament reconstruction. PMID- 21540715 TI - Outcomes of operative and nonoperative treatment of multiligament knee injuries: an evidence-based review. AB - Knee dislocation is an uncommon orthopedic diagnosis with a high rate of neurovascular complications. The goal of definitive management is to provide a pain free and functional knee through restoration of ligamentous stability and range of motion. Operative management has been suggested to be superior to nonoperative management for knee dislocations largely in part owing to a meta analysis on the topic published a decade ago. The purpose of this study was to summarize the results of operative and nonoperative treatment of knee dislocations over the past 10 year period. There were a total of 855 patients from 31 studies managed operatively and 61 patients from 4 studies managed nonoperatively. The overall methodological quality of the studies was poor as measured by the Newstead-Ottawa scale. Data regarding functional outcome, instability, contracture, and return to activity were all in favor of operative management. Significant differences were found for return to employment (P<0.001) and return to sport (P=0.001). The results of this study provide further evidence for the superiority of operative management, compared with nonoperative management, for knee dislocations across several clinical and functional domains. There is a need for higher level studies to assist the treating surgeon in the management of these challenging injuries. PMID- 21540716 TI - Clinical value of combined single photon emission computerized tomography and conventional computer tomography (SPECT/CT) in sports medicine. AB - Integrated hybrid single photon emission computerized tomography (SPECT)/computer tomography (CT) is a promising new diagnostic imaging modality for orthopedic patients. A high diagnostic yield is available from combining the detection of abnormal bone metabolism with SPECT, to the precise anatomical detail available in high resolution CT. With this review, we endeavor to illustrate the clinical value and future perspectives of SPECT/CT in sports medicine. PMID- 21540717 TI - Everolimus and minimization of cyclosporine in renal transplantation: 24-month follow-up of the EVEREST study. PMID- 21540718 TI - Successful ABO incompatible kidney transplant after an isolated intestinal transplant. PMID- 21540719 TI - Successful pediatric cardiac transplant from a donor heart with an unexpected myocardial tumor found post-CPB by intraoperative transesophageal echocardiogram. PMID- 21540720 TI - Flow-independent exhaled nitric oxide parameters in pediatric lung and cardiac transplant recipients. PMID- 21540721 TI - A review of blunt force injury homicides of children aged 0 to 5 years in Bexar County, Texas, from 1988 to 2009. AB - It is essential that clinical physicians, medical personnel, medical examiners, and law enforcement agencies understand the types of injuries seen and demographics of children affected by intentional blunt force as this understanding can be crucial to the death and/or criminal investigations. An understanding of the injuries can also assist in drawing conclusions regarding how those injuries could have been sustained. This study discusses the types and patterns of injuries seen in blunt force homicides in children younger than 6 years. The study found that male infants are more often intentionally injured than are female infants and that fatal head injuries most frequently occur in the first year of life, whereas most fatal thoracoabdominal injuries occur in the first 3 years of life. In children with head injuries, subdural hemorrhage was the most common finding, followed by subarachnoid hemorrhage. In 2.5% of deaths due to head injury, concurrent neck injury was seen, a percentage far lower than previous literature would suggest if shaking was the primary mechanism of injury. Twelve legal confessions were also reviewed, none of which disclosed a pure mechanism of shaking the infant. PMID- 21540722 TI - Double suicide. AB - Most suicides are solitary and private; but few result from a pact between 2 people to die together. Two young men made a pact to commit suicide by hanging from a tree. It was the first case among 1320 single suicides in more than 2 decades in eastern Croatia. Double suicide between people of the same gander is an unusual event. It is predominantly made by male-female partners and by less violent methods. One of the 2 members experienced depression. He may have been the initiator and the other partner may have been the dependent. The initiator usually plans the act and stimulates the other party. Whether the decision was evenly shared by both partners and initiative came from one of the two or it was result of 2 independent decisions remains open for analysis. Double suicide is also very interesting from the perspective of medical examiners. They need to make comprehensive postmortem examination to finally conclude the proper cause and the manner of death. PMID- 21540723 TI - Collateral damage--penetrating head injury and orbital injury: a case report. AB - We report a case of an accidental death or potential suicide by revolver with subsequent injury of another person. A 44-year-old man shot himself in the head while manipulating his .38 caliber special revolver in the kitchen in the presence of his wife, standing approximately 1.5 m next to him. After passing through the husband's head, the lead round-nose bullet entered the region underneath his wife's left eye. When the bullet left the man's head, it retained the energy to penetrate the soft tissue at this distance, including the skin and thin bone plates like the orbital wall. Owing to the low energy of the projectile, the entry wound was of atypical in shape and without loss of tissue. Only a small line--resembling a cut--was externally visible. The man died in the hospital from his injuries; his wife suffered visual loss of her left eye. PMID- 21540724 TI - In response to "suicide and ethnicity in Malaysia". PMID- 21540725 TI - Dithranol: an unusual agent to produce artificial (false) bruise: a case report. AB - Injuries are simulated by people for various reasons and may be labeled as "false/fictitious/forged." These may be self-inflicted or self-suffered. One such "injury" is an artificial/false bruise that may be produced by applying the juices of various irritant vegetable poisons. However, the present case is of an inmate of jail who used dithranol for producing 20 such artificial bruises on the back of his body. The purpose of such an act was to bring a charge of torture/beating against the jail officials.A good, thorough history taking and detailed and meticulous examination of the affected area, supplemented by relevant investigations and photography by a trained forensic expert, are a must to differentiate the "true" from the "false." PMID- 21540726 TI - Delayed breast implant reconstruction: is radiation therapy associated with capsular contracture or reoperations? AB - We evaluated the association between radiation therapy and severe capsular contracture or reoperation after 717 delayed breast implant reconstruction procedures (288 1- and 429 2-stage procedures) identified in the prospective database of the Danish Registry for Plastic Surgery of the Breast during the period between 1999 and 2006. A history of radiation therapy was associated with increased risk of severe capsular contracture for 1- and 2-stage procedures, with adjusted hazard ratios (HR) of 3.3 (95% confidence interval [CI]: 0.9-12.4) and 7.2 (95% CI: 2.4-21.4), respectively. Similarly, a history of radiation therapy was associated with a non-significantly increased risk of reoperation after both 1-stage (HR = 1.4; 95% CI: 0.7-2.5) and 2-stage (HR = 1.6; 95% CI: 0.9-3.1) procedures. Reconstruction failure was highest (13.2%) in the 2-stage procedures with a history of radiation therapy. Breast reconstruction approaches other than implants should be seriously considered among women who have received radiation therapy. PMID- 21540727 TI - The medial sural artery as recipient vessel and the impact on the medial gastrocnemius. AB - Microsurgical free tissue transfer is a valuable technique for the reconstruction of soft-tissue defects around the knee, and the medial sural artery (MSA) is an ideal recipient vessel for anastomosis. Previously, the vessel has been described as the dominant supply to the medial gastrocnemius, but no research has addressed the subsequent effect to the muscle after interruption of MSA. The volume of the postoperative medial gastrocnemius of 4 patients treated with free flap reconstruction using MSA as recipient, was assessed clinically and using magnetic resonance imaging, with muscle function assessed using a patient questionnaire, and measurement of ankle torque with concurrent electromyography. Magnetic resonance imaging volume assessment revealed the postoperative medial head of gastrocnemius proportional to its synergist of separate blood supply, the lateral gastrocnemius and functional assessment suggest little difference between limbs such that the MSA should be used with confidence as recipient vessel for free flap reconstruction of soft-tissue defects around the knee. PMID- 21540728 TI - Hair transplantation in patients with inadequate head donor supply using nonhead hair: report of 3 cases. AB - Follicular unit extraction is becoming an increasingly popular technique for hair transplantation, as it obviates the linear scarring associated with strip harvesting, and can provide highly presentable results. Using this technique, a few reports have described the small scale use of nonhead hair for head hair transplantation in men with inadequate head hair donor supply. In this report, 3 patients who were severely bald had hair transplanted from the chest, abdomen, legs, shoulders, or beard, as well as the head to achieve full coverage and excellent hairlines. Of the 3 cases, 2 had undergone previously unsuccessful hair transplant surgeries. Approximately 80% to 85% of the transplanted grafts survived. Although hair length and quality, surgery time, and the requirement for improved surgical skills remain challenges when using this technique, the sufficiently good outcomes from these selected candidates suggest that this technique may offer the possibility of restoring even severely bald states to normality in patients who would otherwise not be candidates for traditional hair transplantation surgery. PMID- 21540729 TI - Palmoplantar keratoderma: treatment with CO2 laser case report and review of the literature. AB - Palmoplantar keratoderma is a heterogeneous group of disorders affecting keratinization on the palms and soles of the feet. The benign lesions cause pain and limit function. Treatment of palmoplantar keratoderma remains problematic and restricted to symptomatic therapy; no cure exists. Medical treatments and surgical excision are currently the mainstay of therapy; however, these treatments have limited success, significant morbidity, and recurrence is common. We present a case report of successful treatment with CO2 laser therapy and a review of the literature. PMID- 21540730 TI - The effect of angiotensin (1-7) on survival of random pattern skin flaps with nicotine-induced ischemia in rats. AB - OBJECTIVE: The purpose of this study was to reveal the effect of angiotensin (1 7) on survival of random pattern, nicotinized, ischemic flap model in rats. MATERIALS AND METHODS: We used female Sprague Dawley rats weighing between 250 and 300 g. The study was performed on 3 groups each of them was consisted of 30 rats (control [C], angiotensin (1-7) [A] and vehicle [V]).While group C was subjected to 1 mL saline subcutaneous injection once daily for 28 days, groups A and V were nicotinized by 2 mg/kg nicotine subcutaneous injection, twice a day. At the end of this period, McFarlane random flap was constructed in all rats. No drug was applied to the flap bed in the group C, whereas for group A angiotensin (1-7) (A [1-7]) was delivered and a vehicle without an active ingredient was applied to the group V.Following surgery, immediately, Na-fluorescein diffusion tests were performed on 10 subjects of every group and necrotic areas were determined by millimetric paper method. After this, for determining angiogenesis, 10 subjects were killed from each group on the second day and fourth day. Finally, on the seventh day, necrotic areas were measured in 10 subjects of each group. They were then killed after photographs were taken. Specimens were collected from distal and critical zones of flaps, in all the groups, for immunohistochemical and histopathologic analyses. RESULTS: Macroscopic measurements revealed equal ischemic areas for groups A and V in 30 minutes which were both larger than those of the group C (P < 0.005). Measurements performed on the seventh day showed a significant decrease of ischemia, which advanced to necrosis in the group A (P < 0.005). Groups V and C showed a direct progress to necrosis without changes in ischemia levels. Microscopic analysis exhibited a statistically significant increase in the number of microvascular structures and diameters of mature vascular structures in the group A compared with those of groups C and V (P < 0.005). CONCLUSION: A (1-7) increased vasodilatation in nicotinized flaps, triggered angiogenesis in the first 2 days, and contributed remarkably to the flap survival. PMID- 21540731 TI - Contact pressures in radiocarpal and triquetrohamate joints after vascularized capitate transposition. AB - The vascularized capitate transposition has been designed to treat advanced Kienbock disease, in which the necrotic lunate is excised and the vascularized capitate bone graft is proximally shifted into the lunate fossa to reconstruct the radiocarpal joint. Since it notably alters the normal anatomy of the wrist, the anatomical alterations are thought to be responsible for the increased tendency to develop symptomatic arthritis. Clinically, however, more than 1-year follow-up does not show any arthrosis in the reconstructed radiocarpal joint after this procedure. We tied to investigate the reason of no postsurgical arthrosis by documenting the contact pressures in the radiocarpal and triquetrohamate joints in a cadaveric wrist model. The contact pressures were measured by the super low pressure Fuji prescale film in 6 different wrist positions. No statistically significant difference existed in the average contact pressures of the scaphoid fossa, lunate fossa, triangular fibrocartilage, and triquetrohamate articulation in each wrist position between pre- and postsurgically. These results suggest that this procedure does not necessarily result in increased rate of postsurgical arthritis. PMID- 21540732 TI - Effect of preoperative magnetic resonance imaging diagnosis of osteomyelitis on the surgical management and outcomes of pressure ulcers. AB - Despite advances in imaging technology, it is unclear whether preoperative MRI diagnosis of osteomyelitis influences surgical management and improves surgical outcome. The purpose of this retrospective study was to determine whether preoperative diagnosis of osteomyelitis by pelvic MRI influenced the surgical management of pressure sores and flap outcomes. The characteristics, pre- and intraoperative management, and surgical outcomes of the most recent flap surgery in 2 groups were compared: 26 patients diagnosed with osteomyelitis by preoperative MRI and 21 patients diagnosed by culture growth from an intraoperative bone specimen postoperatively. Patients with osteomyelitis diagnosed by MRI had 10 ulcer recurrences at the same site (39%) versus 6 (29%) among patients with osteomyelitis diagnosed by bone culture (odds ratio = 2.4, P = 0.22). We found that patients with a diagnostic preoperative MRI did not differ significantly in rates of antibiotic administration, ostectomy, dehiscence, revision, or infection. PMID- 21540733 TI - Selective epithelial ischemia of transferred free jejunum after late loss of its vascular pedicle. AB - Free flaps are considered to revascularize from the surrounding tissue and survive without their original pedicle flow after a certain period postoperatively. We report 2 patients who developed mucosal ischemia of the transferred jejunum by ligation of its vascular pedicle 10 and 25 months after microvascular free jejunal transfer. Both patients had a history of heavy smoking, and had undergone definitive radiotherapy and previous surgery to the recipient bed. Both were treated conservatively; however, a stenotic change of the transferred jejunum remained in 1 patient. If poorly revascularized flaps, such as jejunal flaps, were transferred to the irradiated and scarred recipient bed, revascularization might never reach completion. If pedicle division is required in such cases, reanastomosis of the pedicle would be ideal regardless of the time after the transfer. PMID- 21540734 TI - Pedicled fasciocutaneous anterolateral thigh flap for the reconstruction of a large postoncologic abdominal wall resection defect: a case report. AB - The anterolateral thigh (ALT) flap has been used to cover defects between the proximal third of the leg and lower abdomen, and with modification, may cover epigastric defects. We used the ALT flap to cover a full-thickness defect of over half the anterior abdominal wall. We conclude that abdominal wall defects of large sizes can be successfully reconstructed using an appropriately designed ALT flap; a simple, single-stage effective reconstruction. PMID- 21540735 TI - Prevention of web creep using a new frame after synpolydactyly surgery. AB - The main goal in syndactyly surgery is to create a normal web space; however, it is difficult to achieve the best clinical results in older and complex cases with bony fusions and joint deformities requiring osteotomies. In these complex cases, proper postoperative wound care is difficult to achieve due to the web contractures and deformities. In our report, we introduce a new technique using a frame that we called the "Hittite Sun," which helps in proper wound management to reduce wound healing problems that lead to web creep. Between 2002 and 2006, this frame was used in operations for 46 webs, and the results were compared with those of 30 operated webs in which conventional wound management technique was used. It was found that significantly lower complication rate and lesser web creep formation was seen in these patients, which were managed using the frame, compared with the cases with conventional wound care. The frame was found to be effective for prevention of severe web creep especially in complex synpolydactyly surgery. PMID- 21540736 TI - Inclusion of tissue beyond a midline scar in the deep inferior epigastric perforator flap. AB - BACKGROUND: A lower abdominal midline scar is known to restrict the amount of tissue that can be included in a deep inferior epigastric perforator (DIEP) flap. However, reconstructive demands have occasionally led us to include substantial territory beyond the scar. The purpose of this study is to review our experience with such flaps and to determine whether a meaningful amount of tissue can be reliably harvested across a midline scar. METHODS: Within a series of 125 DIEP flaps harvested across the entire lower abdomen (zones I-IV), 11 contained a midline scar. These 11 cases were compared with the remaining 114 in terms of (1) the amount of tissue beyond the scar that could be retained with the flap based on intraoperative assessment of vascularity and (2) postoperative complications. RESULTS: A significantly smaller percentage of the flap volume could be retained in scarred abdomens (70% of the harvested ellipse [ie, 20% beyond the midline]) versus unscarred abdomens (83%; P = 0.01). Complications were more frequent in the flaps with scars (55% vs. 25%; P = 0.04), although most of these complications were easily manageable and acceptable outcomes were achieved in all 11 cases. CONCLUSION: The rate of complications is significantly higher when tissue across a midline scar is included in a DIEP flap. However, in our experience, these complications are relatively mild, and in most cases, a substantial amount of tissue beyond the midline can be used, thereby increasing the volume available for reconstruction without resorting to dual-supply procedures. PMID- 21540737 TI - Vascularized lymph node transfer based on the hilar perforators improves the outcome in upper limb lymphedema. AB - BACKGROUND: Maintenance of the blood supply to the lymph nodes is necessary for survival and function. We report the outcome of vascularized lymph node transfer with hilar perforators compared with the conventional technique. PATIENTS: A total of 21 patients affected by early stage II upper limb lymphedema were included in this study. Of them, 11 patients received a free groin flap containing lymph nodes, and 10 patients received vascularized inguinal lymph nodes with hilar perforators. Mean follow-up was 46 and 40 months, respectively. Complications, secondary procedures, circumference of the limb, and subjective symptomatology were registered. The differences were evaluated statistically. RESULTS: The limb circumferences decreased significantly in the new group. The number of secondary procedures was significantly higher in the standard group. There were 2 cases of partial flap loss and donor site lymphorrhea in the standard group. In both the groups, visual analog scale scores improved after the operation. CONCLUSIONS: Transfer of vascularized inguinal lymph nodes based on the hilar perforators improves the outcomes in the treatment of early lymphedema of the upper extremity. PMID- 21540739 TI - Fear-avoidance beliefs, catastrophizing, and distress: a longitudinal subgroup analysis on patients with musculoskeletal pain. AB - PURPOSE: The aim of the present study was to describe fear-avoidance beliefs, catastrophizing, and emotional distress among musculoskeletal pain patients in primary healthcare and to explore the relationship of psychological risk profiles for pain, function, and sick leave from baseline through 1-year and 3-year follow ups. METHODS: Ratings from 110 musculoskeletal pain patients were collected and cluster analysis was used to identify subgroups with similar patterns on fear avoidance beliefs, catastrophizing, and emotional distress. The clusters were examined cross-sectionally and prospectively on sick leave, function, and pain. RESULTS: Five distinct profiles were found: "low scores cluster," "high score cluster," "fear-avoidance beliefs and catastrophizing cluster," "distress only cluster," and "medium catastrophizing cluster." The "low scores cluster" and "distress only cluster" had the most favorable scores on outcome variables. The analysis of common developmental pathways showed considerable stability over time. Reorganization of clusters in a psychological "high risk cluster" and a "low risk cluster" showed significant differences at 1-year and 3-year follow-ups in functional ability as well as in decreased sick leave. There were no significant differences between the groups on average pain ratings at the 2 measure points. CONCLUSIONS: Distinct profiles of catastrophizing, fear-avoidance beliefs, and emotional distress were extracted and meaningfully related to future sick leave and dysfunction outcomes. The structures of the profiles were essentially stable and became more accentuated across a 3-year period. The results underscore the need to address psychological aspects as fear-avoidance beliefs, catastrophizing, and emotional distress in the management of patients with musculoskeletal pain and may open the path for a better tailored treatment approach for this patient group. PMID- 21540738 TI - A peripheral adrenoceptor-mediated sympathetic mechanism can transform stress induced analgesia into hyperalgesia. AB - BACKGROUND: Stress has paradoxical effects on pain, causing stress-induced analgesia but also exacerbating pain via poorly understood mechanisms. Adrenergic neurotransmission is integral in pathways that regulate the response to both pain and stress. Hyperalgesia is often associated with enhanced adrenergic sensitivity of primary afferents, but sympathetic nervous system outflow has not been demonstrated to exacerbate pain perception after stress. METHODS: Rats or C57/BL6 wild-type mice treated with alpha-2 receptor antagonists or alpha-2A receptor knockout mice were exposed to ultrasonic noise stress or footshock stress and subsequently tested for hotplate paw withdrawal latencies. The sensory sensitivity of alpha-2A knockout mice to electrical and chemical stimuli was tested neurophysiologically and behaviorally. The effects of sympatholytic treatments were investigated. RESULTS: Noise and footshock stressors induced thermal hyperalgesia in rats pretreated systemically with alpha-2 antagonists. Wild-type mice pretreated with alpha-2 antagonists and alpha-2A knockout mice also exhibited thermal hyperalgesia induced by noise stress. Local spinal or intraplantar injection of an alpha-2 antagonist counteracted stress-induced analgesia without causing hyperalgesia. The alpha-2A knockout mice had decreased thresholds for peripheral sensitization with sulprostone and for windup of the dorsal horn neuronal response to repetitive electrical stimuli. Stress-induced hyperalgesia was abolished and the sensitization was attenuated by sympathectomy or systemic administration of an alpha-1-adrenergic antagonist. CONCLUSIONS: Sympathetic postganglionic nerves can enhance pain sensation via a peripheral alpha-1-adrenoceptor mechanism when sympathetic outflow is disinhibited. The net effect of stress on pain sensation reflects a balance between descending spinal inhibition and sympathetic outflow that can shift toward pain facilitation when central and peripheral alpha-2-adrenoceptor inhibitory mechanisms are attenuated. PMID- 21540740 TI - A comparative study of 2 manual-based self-help interventions, acceptance and commitment therapy and applied relaxation, for persons with chronic pain. AB - OBJECTIVE: The aim of this study was to compare 2 self-help-based interventions; a coping-oriented approach, applied relaxation (AR) and an acceptance-oriented approach, acceptance and commitment therapy (ACT), for persons with chronic pain. METHOD: This study is a randomized control trial (N=90) with a mixed between within participants design with repeated measures. Interventions in both conditions comprised an initial face-to-face session, a 7-week manual-based self help intervention including weekly therapist telephone support and a concluding face-to-face session. Outcome measures included satisfaction with life, depression, anxiety, acceptance of chronic pain, level of function, and pain intensity. Effects were measured at preintervention and postintervention and at 6 and 12 months after the end of intervention. RESULTS: The results show that the ACT condition increased their level of acceptance significantly compared with the AR condition. There was also a marginally significant interaction effect regarding satisfaction with life in which the ACT condition had improved in comparison to the AR condition. Further, the ACT condition reported a higher level of function and decreased pain intensity compared with the AR condition. Both conditions improved significantly regarding depression and anxiety. CONCLUSIONS: A manual-based self-help intervention with weekly therapist support in an ACT format adds value to the treatment repertoire for persons suffering with chronic pain. PMID- 21540741 TI - A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction. AB - OBJECTIVES: To evaluate the postoperative analgesic efficacy of GW842166, a noncannabinoid CB2 agonist, in patients undergoing third molar tooth extraction. METHODS: This randomized, double-blind, placebo-controlled study compared the analgesic efficacy of single doses of GW842166 (100 or 800 mg) or ibuprofen with placebo in patients undergoing extraction of at least 1 fully or partially impacted third molar tooth. Eligible participants were dosed preoperatively within 1 hour of surgery. Participants allocated to active comparator received a second dose of ibuprofen (400 mg), 4 hours after the first 800 mg dose. Participants in the GW842166 and placebo groups received placebo at 4 hours. Procedures for the assessment of efficacy included a visual analog scale and verbal rating scale for scoring pain up to 10 hours postsurgery, duration of analgesia, patient global evaluation, proportion of patients requiring rescue medication, and elapsed time to rescue analgesia. Analysis of covariance was used to compare efficacy variables. Patient global evaluation was analyzed using Wilcoxon rank-sum tests and time to data was analyzed using the log-rank test. RESULTS: Ibuprofen was significantly more effective than placebo across all endpoints. Trends for an improvement in pain scores for GW842166 800 mg failed to be of either clinical or statistical significance. GW842166 100 mg showed little separation from placebo. There was no evidence for any beneficial adjunctive effect after coadministration of rescue analgesia with GW842166. All treatments were well tolerated. DISCUSSION: In comparison to ibuprofen, single doses of GW842166 (100 and 800 mg) failed to demonstrate clinically meaningful analgesia in the setting of acute dental pain. PMID- 21540742 TI - Factors associated with initiation of prolonged analgesic use among patients in the HIV Outpatient Study (HOPS). AB - BACKGROUND: Analgesic use is common but remains poorly described among human immunodeficiency virus (HIV)-infected persons in the highly active antiretroviral therapy era. METHODS: We studied HIV Outpatient Study participants during 1996 to 2008. We used Cox proportional hazards regression to assess variables associated with initiation of prolonged analgesia (>=90 consecutive days of analgesics); logistic regression to explore variables associated with initiation of prolonged opioid analgesia among those taking any prolonged analgesia; and linear regression to determine temporal trends in prolonged analgesia. RESULTS: Among 4180 patients, 931 (22%) initiated prolonged analgesia. Factors independently associated (P<0.05) with prolonged analgesia included: age above 40 years (hazard ratio=1.20), female sex (1.43), injection drug use as an HIV risk factor (1.33), public healthcare payer (1.88), nadir CD4+ less than 200 cells/mm (1.29), tobacco use (1.43), prior opportunistic infection(s) (1.25), antidepressant use (1.76), and anxiolytic use (1.51). Independent correlates of prolonged opioid analgesia were white race (odds ratio=1.64), baseline CD4+ less than 350 cells/mm (1.88), and anxiolytic use (1.87). Prolonged analgesia ranged from 11% to 15% each year. CONCLUSIONS: In the highly active antiretroviral therapy era, up to 15% of HIV Outpatient Study patients used prolonged analgesic therapy each year. Variables associated with the initiation of prolonged analgesia included HIV and non-HIV related factors. PMID- 21540743 TI - Long-term impact of human papillomavirus vaccination on infection rates, cervical abnormalities, and cancer incidence. AB - BACKGROUND: Vaccination against human papillomavirus (HPV) types 16/18 is being implemented in many countries. There may be indirect benefit of HPV vaccination to nonvaccinated women, who may experience a reduced risk of infection with vaccine-preventable types (herd immunity). We attempt to disentangle the direct and indirect effects of HPV vaccination, while accounting for 14 oncogenic HPV types in a dynamic modeling framework. METHODS: On the basis of vaccine uptake among preadolescent girls in the Netherlands, we calculated how heterosexual transmission of HPV-16/18 is expected to change as a result of vaccination, and used these predictions in an individual-based simulation model of cervical carcinogenesis that considers 14 high-risk HPV types. Models were parameterized to match prevaccine data on type-specific HPV infection and cervical disease. RESULTS: At 50% vaccine coverage, the estimated lifetime infection risk in nonvaccinated women dropped from 0.46 (95% credible interval = 0.35-0.54) to 0.37 (0.26-0.46) for HPV-16, and from 0.40 (0.32-0.46) to 0.31 (0.22-0.36) [corrected] for HPV-18. For the whole population, we calculated an eventual 47% reduction in cervical cancer incidence, with 1 in 4 cases prevented among nonvaccinated women. The number of indirectly averted cancer cases was highest with vaccine coverage between 50% and 70%, approximating 70 cases per 100,000 women born from 2010 onward. CONCLUSIONS: HPV-16/18 vaccination of preadolescent girls will markedly lower infection rates among nonvaccinated women. Reduced transmission of vaccine preventable HPV becomes a prominent aspect of cervical cancer control, especially in populations with moderate vaccine coverage. PMID- 21540744 TI - Differences between marginal structural models and conventional models in their exposure effect estimates: a systematic review. AB - BACKGROUND: Marginal structural models were developed to address time-varying confounding in nonrandomized exposure effect studies. It is unclear how estimates from marginal structural models and conventional models might differ in real settings. METHODS: We systematically reviewed the literature on marginal structural models since 2000. RESULTS: Data to compare marginal structural models and conventional models were obtained from 65 papers reporting 164 exposure outcome associations. In 58 (40%), estimates differed by at least 20%, and in 18 (11%), the 2 techniques resulted in estimates with opposite interpretations. In 88 papers, marginal structural models were used to analyze real data; only 53 (60%) papers reported the use of stabilized inverse-probability weights and only 28 (32%) reported that they verified that the mean of the stabilized inverse probability weights was close to 1.0. CONCLUSIONS: We found important differences in results from marginal structural models and from conventional models in real studies. Furthermore, reporting of marginal structural models can be improved. PMID- 21540745 TI - Emergence delirium: can pain be totally ruled out as a cause after giving block? PMID- 21540746 TI - Hepatitis B virus-related hepatocellular carcinoma: primary, secondary, and tertiary prevention. AB - With respect to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), primary, secondary, and tertiary prevention measures have been or should be adopted. In primary prevention, behavioral patterns represent an important risk factor for HBV infection and should be controlled, discouraging those favoring infection. Interferon treatment shows a modest effect in reducing HCC risk in treated patients, but the data obtained cannot be converted in clinical practice. Nucleoside analogs significantly reduce, but do not abolish, HCC risk in patients with cirrhosis, and should therefore be used in patients with cirrhosis and also to diminish the risk of the other potential complications. With respect to secondary prevention, surveillance with semiannual ultrasound examination is indicated in patients with HBV-related cirrhosis as well as in other subgroups of patients, depending on racial and geographical pattern. Finally, the role of interferon in tertiary prevention of HCC relapse after radical treatment is still under debate; some evidence in favor of the treatment is present, but side effects due to toxicity are frequent and severe enough to limit patients' compliance substantially. As there is definitely no agreement on the efficacy and cost-effectiveness of antiviral treatment in HCC prevention, there is still a need for well-constructed, large size, and randomized prospective trials to confirm what is still required based on expert opinion rather than on sound scientific evidence. PMID- 21540747 TI - Meta-analysis of prospective studies of red meat consumption and colorectal cancer. AB - The relationship between red meat consumption and colorectal cancer (CRC) has been the subject of scientific debate. To estimate the summary association between red meat intake and CRC and to examine sources of heterogeneity, a meta analysis of prospective studies was conducted. Thirty-four prospective studies of red meat and CRC were identified, of which 25 represented independent nonoverlapping study populations. Summary relative risk estimates (SRREs) for high versus low intake and dose-response relationships were calculated. In the high versus low intake meta-analysis, the SRRE was 1.12 (95% CI: 1.04-1.21) with significant heterogeneity (P=0.014). Summary associations were modified by tumor site and sex. The SRREs for colon cancer and rectal cancer were 1.11 (95% CI: 1.03-1.19) and 1.19 (95% CI: 0.97-1.46), respectively. The SRREs among men and women were 1.21 (95% CI: 1.04-1.42) and 1.01 (95% CI: 0.87-1.17), respectively. The available epidemiologic data are not sufficient to support an independent and unequivocal positive association between red meat intake and CRC. This conclusion is based on summary associations that are weak in magnitude, heterogeneity across studies, inconsistent patterns of associations across the subgroup analyses, and the likely influence of confounding by other dietary and lifestyle factors. PMID- 21540748 TI - Current and projected prevalence of arterial hypertension in sub-Saharan Africa by sex, age and habitat: an estimate from population studies. AB - INTRODUCTION: In sub-Saharan Africa (SSA), data on hypertension prevalence in terms of urban or rural and sex difference are lacking, heterogeneous or contradictory. In addition, there are no accurate estimates of hypertension burden. OBJECTIVE: To estimate the age-specific and sex-specific prevalence of arterial hypertension in SSA in urban and rural adult populations. METHODS: We searched for population studies, conducted from 1998 through 2008 in SSA. We extracted data from selected studies on available prevalences and used a logistic regression model to estimate all age/sex/habitat (urban/rural)/country-specific prevalences for SSA up to 2008 and 2025. On the basis of the United Nations Population Fund data for 2008 and predictions for 2025, we estimated the number of hypertensives in both years. RESULTS: Seventeen studies pertaining to 11 countries were analysed. The overall prevalence rate of hypertension in SSA for 2008 was estimated at 16.2% [95% confidence interval (CI) 14.1-20.3], ranging from 10.6% in Ethiopia to 26.9% in Ghana. The estimated prevalence was 13.7% in rural areas, 20.7% in urban areas, 16.8% in males, and 15.7% in women. The total number of hypertensives in SSA was estimated at 75 million (95% CI 65-93 million) in 2008 and at 125.5 million (95% CI 111.0-162.9 million) by 2025. CONCLUSION: The estimated number of hypertensives in 2008 is nearly four times higher than the last (2005) estimate of the World Health Organization Regional Office for Africa. Prevalences were significantly higher in urban than in rural populations. Population data are lacking in many countries underlining the need for national surveys. PMID- 21540749 TI - Descriptive analysis of workflow variables associated with barcode-based approach to medication administration. AB - Bedside barcode technology is used during medication administration to ensure patient safety. This study evaluated the workflow variables related to a bedside barcode technology-based medication administration process. A time-and-motion technique was used to assess the observational episodes related to medication administration conducted by registered nurses. In an observational episode, nurses spent adequate time in "documenting medications" and "giving medications." Nurses were primarily engaged in tasks at the patient's bedside. PMID- 21540750 TI - Utility of 3-year torso computed tomography and head imaging in asymptomatic patients with high-risk melanoma. AB - There is no general consensus regarding the optimal follow-up strategy for patients with melanoma. We sought to determine the utility and cost effectiveness of radiological restaging of patients with stage IIB-IIIC melanoma at the 3-year follow-up time point. A retrospective review of 210 patients diagnosed with stage IIB-IIIC melanoma seen in the Cutaneous Oncology Program at Beth Israel Deaconess Medical Center between January, 2001 and July, 2006 was conducted. Fifty-two patients were asymptomatic and continuously disease free and underwent restaging head computed tomography (CT) or MRI and torso CT scans 3 years after completion of local-regional therapy or initiation of adjuvant treatment. True positive, false positive and normal scans were identified and the cost per diagnosis calculated. Fifty-five percent of patients developed melanoma recurrences: 88% before 3 years (median time to recurrence 12 months, 95% confidence interval: 10 16 months). The majority of patients (69%) recurred with disease symptoms. Twenty five head CT scans, 27 head MRIs, and 52 torso CTs were performed. One false positive head CT and five abnormal torso CT scans (three false positive, two true positive) were identified. The total cost per diagnosis was $312,990. Extensive 3 year restaging imaging seems to be of limited value for symptomatic and continuously disease-free patients with stage IIB-IIIC melanoma. Furthermore, given the low risk of recurrence beyond 3 years, it is likely that subsequent routine imaging would have similarly low utility. PMID- 21540751 TI - Receiver operating characteristic analysis: calculation for the marker 'melanoma inhibitory activity' in metastatic uveal melanoma patients. AB - The serological marker melanoma inhibitory activity (MIA) has been shown to be significantly higher in the serum of patients suffering from metastatic uveal melanoma than in progression-free patients. The objective of this study was to calculate a meaningful receiver operating characteristic (ROC) curve for MIA based on a large patient collective and to find an appropriate threshold value. MIA tumor marker levels of 503 outpatients suffering from uveal melanoma were evaluated using enzyme-linked immunosorbent assay. Fifty-four patients had confirmed metastases and 449 patients showed no overt metastatic disease at the time the blood sample was taken. ROC analysis was performed and the area under the curve (AUC) was calculated. Metastatic patients showed significantly higher MIA levels (median 11.69 ng/ml) than patients in the group without overt metastatic disease (median 6.97 ng/ml) (the Mann-Whitney test, P<0.001). The AUC was 0.84 (95% confidence interval: 0.76-0.91). The ROC resulting from our study can be applied for test comparison by means of AUC. The AUC value of 0.84 for MIA demonstrates the accurate performance of the test. On the basis of this ROC curve, we propose a MIA threshold value for uveal melanoma patients of 8.3 ng/ml (with a corresponding sensitivity of 82% and specificity of 77%, positive predictive value of 0.30 and negative predictive value of 0.97). In patients with higher MIA serum levels, further diagnostics should be initiated. PMID- 21540752 TI - Review: mucosal melanoma of the head and neck. AB - Head and neck mucosal melanoma (MM) is a rare and aggressive neoplasm, with high rates of local, regional, and distant failure. Owing to the small size of most reported series and their retrospective nature, and the lack of uniform comprehensive staging system, the effect of various treatment strategies on disease control and survival has been difficult to assess. The optimal management of head and neck MM is not well defined. Surgical treatment has being advocated as the primary treatment modality, with growing consideration for postoperative radiotherapy, as wide surgical resection in the head and neck region is often difficult. Radiotherapy is recently reported as a beneficial management modality, regardless of the fact that MM has been considered to be radioresistant. As significant morbidity is expected in high doses of radiotherapy to the head and neck region, new radiographic modalities with better precision are required. Furthermore, high-energy radiotherapy was suggested as a better therapy to mucosal MM due to the suggested biology of the tumor. The high rates of locoregional recurrence and distant metastasis also suggest that a systemic treatment is needed. Currently, there is no role for adjuvant systemic therapy for patients who have been successfully resected, but recent developments in the understanding of the biology of melanoma and, in particular, specific growth pathways holds promise for the future. We strongly recommend further evaluation of the role of chemotherapy and immunotherapy to decrease the rates of distant metastasis and improve survival. PMID- 21540753 TI - Combined resistance and endurance exercise training improves arterial stiffness, blood pressure, and muscle strength in postmenopausal women. AB - OBJECTIVE: Menopause is associated with increased arterial stiffness and reduced muscle strength. Combined resistance (RE) and endurance (EE) exercise training can decrease brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, in young men. We tested the hypothesis that combined circuit RE and EE training would improve baPWV, blood pressure (BP), and muscle strength in postmenopausal women. METHODS: Twenty-four postmenopausal women (age 47-68 y) were randomly assigned to a "no exercise" control (n = 12) or to combined exercise training (EX; n = 12) group. The EX group performed concurrent circuit RE training followed by EE training at 60% of the predicted maximal heart rate (HR) 3 days per week. Brachial systolic BP, diastolic BP, mean arterial pressure, baPWV, HR, and dynamic and isometric muscle strength were measured before and after the 12-week study. RESULTS: Mean +/- SE baPWV (-0.8 +/- 0.2 meters/s), systolic BP (-6.0 +/- 1.9 mm Hg), diastolic BP (-4.8 +/- 1.7 mm Hg), HR (-4.0 +/- 1.0 beats/min), and mean arterial pressure (-5.1 +/- 1.6 mm Hg) decreased (P < 0.05), whereas dynamic leg strength (5.1 +/- 1.0 vs 0.6 +/- 1.0 kg for the EX and control groups, respectively) and isometric handgrip strength (2.8 +/- 0.7 vs 0.6 +/- 1.2 kg) increased (P < 0.05) in the EX group but not in the control group. CONCLUSIONS: Our findings indicate that a 12-week moderate-intensity combined circuit RE and EE training improves arterial stiffness, hemodynamics, and muscle strength in previously sedentary postmenopausal women. This study provides evidence that combined training may have important health implications for the prevention of hypertension and frailty in postmenopausal women. PMID- 21540754 TI - Distribution of cyclooxygenases 1 and 2 in the uterus and breast of cynomolgus monkeys-effects of hormone treatment. AB - OBJECTIVE: The aim of this study was to compare the distribution and immunoreactivity of cyclooxygenase (COX) 1 and COX-2 in normal uterus and breast after long-term hormone therapy in postmenopausal monkeys. METHODS: Female adult cynomolgus macaques were bilaterally ovariectomized 3 months before the initiation of hormone treatment. The animals were either treated (experiment 1) with conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE + MPA, or tamoxifen or designated as controls (C). In experiment 2, the animals were either treated with CEE, CEE + MPA, or tibolone or designated as C. Breast tissue and uteri were collected, fixed, and paraffin embedded. Immunohistochemistry assays for COX-1 and COX-2 were performed. RESULTS: COX-1 immunostaining was decreased by tamoxifen and CEE treatment in the endometrial stroma and by CEE + MPA in the myometrium. COX-1 immunostaining of the breast epithelia was down-regulated by CEE + MPA, whereas other cell types in the breast seem to be less affected by hormone treatment.COX-2 immunoreactivity in the endometrial stroma was increased by CEE + MPA. In the glandular epithelium, CEE + MPA and tibolone treatment increased COX-2 immunostaining compared with CEE treatment only and no treatment at all (C). No effect from hormone treatment on COX-2 immunostaining was found in the myometrium. COX-2 immunostaining in the glandular epithelium of the breast was, in experiment 2, increased after CEE treatment compared with no treatment (C). No other effects by hormone therapy on COX-2 expression were found in the breast. CONCLUSIONS: Our results show that COX 1 and COX-2 are differently distributed and regulated by hormones in the normal uterus and breast of ovariectomized macaques. COX-1 is prevailing in the uterus, whereas COX-2 is dominant in the mammary gland. PMID- 21540755 TI - Escitalopram treatment of menopausal hot flashes. AB - OBJECTIVE: The aim of this study was to determine the effects of 10 and 20 mg/day of escitalopram on objectively recorded hot flashes and on the rectal temperature threshold for sweating. METHODS: Two studies were performed: 16 women received 10 mg/day and 26 women received 20 mg/day escitalopram for 8 weeks. They were randomly assigned in equal numbers to receive active drug or placebo in a double blind fashion. Hot flash frequency was measured with an ambulatory recorder during the first 3 weeks and during the 8th week of the study. Rectal temperature threshold for sweating was measured during the 1st and 8th weeks of the study using published methods. RESULTS: In the first study, there were no significant effects whatsoever for any measure. In the second study, the escitalopram group showed an average decline in hot flash frequency of 14.4%, whereas the placebo group showed an average increase of 6.7% (P < 0.05). However, there were no significant effects across time for either group. There were no significant effects whatsoever for rectal temperature sweating thresholds. CONCLUSIONS: Escitalopram at 10 or 20 mg/day is not effective in the treatment of menopausal hot flashes. PMID- 21540756 TI - Functional evaluation using multistep registration with standard magnetic resonance and ADAM brain images. AB - OBJECTIVE: Image analysis of 123I ADAM single photon emission computed tomography is used to evaluate the functional activities in apparatus or in the brain regions. We have earlier proposed a two-step registration method for registering intrasubject long-time 2-[(2-((dimethyl-amino) methyl)phenyl)thio]-5 iodophenylamine (ADAM) images. However, this method requires acquisition of individual MRI, 10-min ADAM, and 6-h ADAM images. METHODS: In this study, we propose using standard (std) brains to replace the individual MRI and 10-min ADAM images. We first use the MRI std instead of the individual MRI. We then use the 10-min ADAM std to replace the individual 10-min ADAM image. RESULTS: The results produced using the MRI std method are close to the original two-step registration method (specific/nonspecific binding ratio, 4.211 vs. 4.326, P=0.055); and the 10 min ADAM std method is close to the MRI std method (specific/nonspecific binding ratio, 4.095 vs. 4.211, P=0.070). CONCLUSION: The proposed 10-min ADAM std method yields acceptable quantitative measurements and significantly reduces patient loading by eliminating the additional individual MRI and 10-min ADAM imaging. More important, the interobserver problem can be solved because the area of interest (AOI) is drawn on the MRI std once; the AOI drawn on the MRI std can be mapped onto the registered 10-min ADAM std, and the individual 6 h ADAM image can then be automatically evaluated with the AOI on the 10-min ADAM std after the proposed registration. Thus, the examination of 123I ADAM thus becomes less expensive, more convenient, and useful for clinical applications. PMID- 21540757 TI - The importance of scatter correction for the assessment of lung shunting prior to yttrium-90 radioembolization therapy. AB - BACKGROUND: Treatment of inoperable hepatocellular carcinoma or secondary metastases by radioembolization using yttrium-90 (90Y) microspheres is a promising method for the treatment of unresectable liver metastases. A pretreatment scintigraphy planar scan using 99mTc-labelled macroaggregated albumin (99mTc-MAA) injected directly into the hepatic artery is carried out to assess the degree of portal shunting of blood between the liver and the lungs. The quantitative results of this scan are used to modulate the activity of therapeutic 90Y microspheres injected into the patient to limit the radiation dose received by the lungs. The presence of scattered events in the MAA lung shunt scan leads to an overestimation of the true shunting ratio, which in turn leads to the administered therapeutic activity being lowered unnecessarily to comply with the protocols of radiation protection. Overall, this may impact the efficacy of treatment. MATERIALS AND METHODS: This study analyses the impact of a window-based analytical scatter-correction method on lung shunt analysis using an anthropomorphic torso phantom, and retrospectively analysed three patient case studies. RESULTS: Our results of scatter in the phantom show a marked decrease in the lung shunt percentage. Clinical analysis of patient data shows that the lung shunt percentage can be overestimated by up to 50% in clinical cases, and depending on the lung shunt percentage, the efficacy of treatment by therapeutic dose reduction may be compromised. CONCLUSION: Our results indicate that scatter correction should be used on 90Y pretreatment 99mTc-MAA scans in order to more accurately assess the lung shunting percentage before therapy. PMID- 21540758 TI - Assessment of intrapartum antibiotic prophylaxis for the prevention of early onset group B Streptococcal disease. AB - BACKGROUND: Most early-onset group B streptococcal (GBS) disease in recent years has occurred in newborns of prenatally GBS-negative mothers who missed intrapartum antibiotic prophylaxis (IAP). We aimed to assess the accuracy of prenatal culture in predicting GBS carriage during labor, the IAP use, and occurrence of early-onset GBS disease. METHODS: We obtained vaginal-rectal swabs at labor for GBS culture from 5497 women of >= 32 weeks' gestation and surface cultures at birth from newborns between February 5, 2008 and February 4, 2009 at 3 hospitals in Houston, TX and Oakland, CA. Prenatal cultures were performed by a healthcare provider during routine care, and culture results were obtained from medical records. The accuracy of prenatal culture in predicting intrapartum GBS carriage was assessed by positive and negative predictive values. Mother-to newborn transmission of GBS was assessed. Newborns were monitored for early-onset GBS disease. RESULTS: GBS carriage was 24.5% by prenatal and 18.8% by labor cultures. Comparing prenatal with labor GBS cultures of 4696 women, the positive predictive value was 50.5% and negative predictive value was 91.7%. IAP, administered to 93.3% of prenatally GBS-positive women, was 83.7% effective in preventing newborn's GBS colonization. Mother-to-newborn transmission of GBS occurred in 2.6% of elective cesarean deliveries. Two newborns developed early onset GBS disease (0.36/1000 births); the prenatal GBS culture of one was negative, the other's was unknown. CONCLUSIONS: IAP was effective in interrupting mother-to-newborn transmission of GBS. However, approximately 10% of prenatally GBS-negative women were positive during labor and missed IAP, whereas approximately 50% of prenatally GBS-positive women were negative during labor and received IAP. These findings emphasize the need for rapid diagnostics during labor. PMID- 21540759 TI - Parainfluenza virus infections in children with hematologic malignancies. AB - BACKGROUND: Parainfluenza virus (PIV) infections are an important cause of morbidity in children with upper or lower respiratory tract infection (URTI and LRTI, respectively). However, the epidemiology of PIV infections in children with cancer has not been well studied. METHODS: This retrospective study sought to determine the epidemiology of PIV infections and risk factors for progression to an LRTI in 1381 children diagnosed with leukemia or lymphoma, between 2000 and 2009. RESULTS: PIV infections were diagnosed in 83 (10%) of 820 children tested for respiratory infections. PIV type 3 accounted for 49 (61%) of the PIV infections. Of the 83 infections, 75 (90%) were community acquired. Children less than 2 years of age were more likely to have PIV infection (P = 0.002; odds ratio, 2.69; 95% confidence interval, 1.5-4.8). PIV infections were more common in children with acute lymphoblastic leukemia as compared with other malignancies (P < 0.0001; odds ratio, 4.13; 95% confidence interval, 2.37-7.21). The majority of patients, 66 (80%), had URTI. Children with LRTI were a median age of 27 months as compared with 56 months for children with URTI (P = 0.005). Fever with severe neutropenia was more common in patients with LRTI than with URTI (P = 0.02). LRTI was significantly associated with absolute neutrophil count <500 cells/MUL (P = 0.002) and absolute lymphocyte count <100 cells/MUL (P = 0.008) at onset of PIV infection. There was no mortality attributed to PIV infections, although 3 children required mechanical ventilation for respiratory failure due to PIV infection. CONCLUSIONS: PIV was the second most common respiratory viral infection in this population after influenza (A and B). Young children were more likely to have PIV infection and LRTI. Severe neutropenia and lymphopenia were associated with LRTI. PMID- 21540760 TI - Immunogenicity of 10-valent pneumococcal nontypeable Haemophilus Influenzae Protein D Conjugate Vaccine when administered as catch-up vaccination to children 7 months to 5 years of age. AB - BACKGROUND: We evaluated catch-up vaccination schedules with 10-valent pneumococcal nontypeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD CV). METHODS: In this open, controlled study, children stratified into 4 age groups (N = 150 each) were vaccinated with PHiD-CV: (a) <6 months reference group: 3 primary doses with booster at 12 to 15 months, (b) 7 to 11 months: 2 doses and booster at 12 to 15 months, (c) 12 to 23 months: 2 doses, and (d) 2 to 5 years: 1 dose. Serotype-specific pneumococcal responses were measured by 22F inhibition enzyme-linked immunosorbent assay (ELISA) and opsonophagocytic activity (OPA) assay. RESULTS: In the 7 to 11 months group postbooster antibody geometric mean concentrations (except for 2 serotypes) and OPA geometric mean titers (GMTs) were in the same ranges or higher relative to postbooster values in the <6 months reference group. Following 2 doses in the 12 to 23 months group, the percentages reaching threshold levels for ELISA (except for serotypes 6B and 23F) and OPA (except for serotype 1) were comparable or higher than <6 months reference postbooster values. Antibody geometric mean concentrations and OPA GMTs, while comparable or higher than reference postprimary values, were for some serotypes lower than reference postbooster values. Following 1 dose in the 2 to 5 years group ELISA responses were lower than the reference group for several serotypes. CONCLUSIONS: A catch-up PHiD-CV schedule of 2 doses and booster for children 7 to 11 months of age was acceptable. For children 12 to 23 months of age, 2 doses seem to provide adequate priming although a booster dose might confer further benefit. Responses following 1 dose in children 2 to 5 years of age suggest that 2 doses may be preferable. PMID- 21540761 TI - Association between DRD2/ANKK1 Taq1A genotypes, depression and smoking cessation with nicotine replacement therapy. AB - OBJECTIVES: Tobacco dependence and depression are believed to have a common familial component, most probably genetic, and mood disorders have been reliably associated with failure to stop smoking. Variant genotypes of the Taq1A (DRD2/ANKK1, 32806T, rs1800497) polymorphism have been associated with failure to stop smoking in some studies, but not others. We investigated the association between Taq1A genotypes and smoking cessation, while also considering mental health. MATERIALS AND METHODS: This was a prospective study in 419 smokers who attended a smoking cessation clinic and used standard doses of nicotine replacement therapy. DNA samples and baseline measures including demographics, severity of tobacco dependence, mental health history and history of drug misuse were taken. Smoking cessation at the end of treatment was biochemically verified using expired-air carbon monoxide. RESULTS: We found no simple relation between Taq1A genotype and smoking cessation, although the association between cessation and lifetime depression was significantly modified by genotype. The relationship was such that for those having only common alleles there was no association between depression and stopping smoking, whereas for those with at least one variant allele (A1A2/A1A1) depression was associated with a two-fold reduction in the likelihood of stopping. CONCLUSION: Those having a Taq1A variant allele and a history of depression are likely to experience particular difficulty when trying to stop smoking and may require treatment other than standard doses of nicotine replacement. This finding might explain previous conflicting results for Taq1A and smoking cessation in studies where depression history was not measured, and may help to explain the underlying link between depression and smoking. PMID- 21540762 TI - Common polymorphisms in FMO1 are associated with nicotine dependence. AB - BACKGROUND: Cigarette smoking and other forms of tobacco use are the leading cause of preventable mortality in the world. A better understanding of the etiology of nicotine addiction may help to increase the success rate of cessation and to decrease the massive morbidity and mortality associated with smoking. METHODS: To identify genetic polymorphisms that contribute to nicotine dependence, our group undertook a genetic association study including three enzyme families that potentially influence nicotine metabolism: cytochrome P450 enzymes, flavin monooxygenases (FMOs), and UDP-glucuronosyl transferases. RESULTS: Several polymorphisms in FMO1 showed association in a discovery sample, and were tested in an independent replication sample. One polymorphism, rs10912765, showed an association that remained significant after Bonferroni correction (nominal P=0.0067, corrected P=0.0134). Several additional polymorphisms in linkage disequilibrium with this single nucleotide polymorphism also showed association. Subsequent in-vitro experiments characterized FMO1 as a more efficient catalyst of nicotine N-oxidation than FMO3. In adult humans, FMO1 is primarily expressed in the kidney and is likely to be a major contributor to the renal metabolism and clearance of therapeutic drugs. FMO1 is also expressed in the brain and could contribute to the nicotine concentration in this tissue. CONCLUSION: These findings suggest that polymorphisms in FMO1 are significant risk factors in the development of nicotine dependence and that the mechanism may involve variation in nicotine pharmacology. PMID- 21540763 TI - Polymorphisms of MDM4 and risk of squamous cell carcinoma of the head and neck. AB - PURPOSE: Mouse double minute 4 (MDM4), a homolog of MDM2, is one of the key negative regulators of p53, and its amplification or overexpression contributes to carcinogenesis by inhibiting the p53 tumor suppressor activity. We investigated the association between MDM4 polymorphisms and the risk of squamous cell carcinoma of the head and neck (SCCHN). METHODS: We genotyped three MDM4 tagging polymorphisms, two in the 3' untranslated region (rs11801299G>A and rs10900598G>T) and one in intron 1 (rs1380576C>G), in a case-control study of 1075 non-Hispanic white SCCHN patients and 1079 cancer-free controls, and evaluated their associations with SCCHN risk. RESULTS: Although none of these three polymorphisms individually had a statistically significant effect on the risk of SCCHN, nor did their combined number of putative risk genotypes (i.e. rs11801299GG, rs1380576CG+GG, and rs10900598GG) [odds ratio (OR)=1.16; 95% confidence interval (95% CI) =0.93-1.45], we found that individuals with 1-3 risk genotypes had statistically significant increased risk of oropharyngeal cancer (OR=1.32; 95% CI=1.00-1.73), particularly for those with T1-2 stage (OR=1.40; 95% CI=1.02-1.94), those with regional lymph node metastases (N1-3) (OR=1.44; 95% CI=1.07-1.95), and those with late stages (III and IV) (OR=1.34; 95% CI=1.01 1.77). CONCLUSION: These results suggest that the joint effect of MDM4 variants may contribute to the risk of oropharyngeal cancer in non-Hispanic whites. Additional studies are warranted to unravel whether the particular stage distribution of oropharyngeal cancer with the strongest association (T1-2, N1-3, and III-IV) is a possible link with human papillomavirus-related oropharyngeal cancers. PMID- 21540764 TI - Scanning laser ophthalmoscope imaging stabilized microperimetry in dry age related macular degeneration. AB - PURPOSE: To determine the effect of drusen and geographic atrophy (GA) in dry age related macular degeneration on retinal sensitivity using an eye tracking scanning laser ophthalmoscope microperimetry. METHODS: A total of 44 eyes from 22 patients with dry age-related macular degeneration and drusen and 11 patients with GA were imaged with scanning laser ophthalmoscope microperimetry (OPKO Health, Miami, FL). A custom microperimetry pattern was used to evaluate retinal sensitivity to a Goldmann III size target (108 MUm on the retina). The perimetry used a 4-2 stepladder algorithm to determine maximal sensitivity. Microperimetry and optical coherence tomography were performed using a standardized protocol. Twenty-eight eyes with drusen and 16 eyes with GA were analyzed. RESULTS: Retinal sensitivity overlying drusen was significantly reduced compared with the adjacent uninvolved retina. There was a significant correlation between retinal sensitivity and drusen volume, as well as the grading of the photoreceptor inner segment/outer segment junction score. In patients with GA, an absolute scotoma was confirmed. Retinal sensitivity at the margin of GA was significantly decreased compared with the adjacent uninvolved retina. CONCLUSION: Scanning laser ophthalmoscope microperimetry is able to detect changes in retinal sensitivity in AMD patients overlying drusen and at the margin of GA. It is a useful device to grade focal retinal sensitivity in patients with dry age-related macular degeneration. PMID- 21540765 TI - Surgical treatment of lamellar macular hole associated with epimacular membrane. AB - BACKGROUND: Although the surgical treatment of full-thickness macular hole is well established, the utility of pars plana vitrectomy in the treatment of lamellar macular hole (LMH) remains less clear. The purpose of the study is to report functional results of surgical treatment of LMH associated with epiretinal membrane. METHODS: Retrospective chart review of patients undergoing pars plana vitrectomy and peeling of epiretinal membrane and internal limiting membrane, with or without air or gas tamponade, for symptomatic LMH associated with epimacular membrane. RESULTS: Forty-five eyes of 44 patients were operated for LMH associated with epimacular membrane between May 2000 and July 2009. Pars plana vitrectomy and membrane peeling were combined with air or gas tamponade in 43 of 45 cases. Mean logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.4 preoperatively to 0.13 postoperatively (P < 0.0001). Improvement in visual acuity ranged from 0 Early Treatment Diabetic Retinopathy Study (ETDRS) lines to 8.9 ETDRS lines (mean, 2.65 ETDRS lines). Visual acuity improved by >= 1 ETDRS line(s) in 40 of 45 eyes (89%) and by >= 2 ETDRS lines in 26 of 45 eyes (58%) after the surgical procedure. No patient lost vision. CONCLUSION: This small retrospective study suggests that surgical treatment of LMH associated with epimacular membrane may improve visual acuity in symptomatic patients. PMID- 21540766 TI - Development and validation of a quality of life scale specific for lumbar spinal stenosis. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: To develop a reliable and valid instrument to measure quality of life (QOL) specifically targeting patients with lumbar spinal stenosis (LSS). SUMMARY OF BACKGROUND DATA: Studies on LSS have investigated the effectiveness of various types of treatments using health related QOL. However, patients with LSS have various symptoms, and these symptoms change with posture, typical activities of daily living, etc. Thus, an LSS specific scale to measure QOL is needed. METHODS: We postulated 7 subdomains for LSS-specific QOL and accordingly, item pool was developed, focus group interviews of patients with LSS and qualitative analysis were conducted, resulting in preliminary version of QOL scale. Then, 189 patients with a diagnosis of LSS completed this preliminary version. Exploratory factor analysis was conducted to examine the factorial validity. Cronbach alpha coefficient and the test-retest method were used to assess the reliability. The criterion-based validity was determined using walking capacity, recommended treatment level judged by orthopedists, and LSS symptom scale scores. RESULTS: Qualitative study confirmed the 7 domains but showed needs of addition and deletion of some items, resulting in 31 items. With factor analysis, after exclusion of 3 items, the remaining 28 items demonstrated strong unidimensionality. Cronbach alpha was 0.96. The coefficient of test-retest reliability was 0.86. Walking capacity, recommended treatment level, and LSS symptom scale scores were significantly correlated with the QOL scale scores. CONCLUSION: A 28-item QOL scale specifically targeting patients with LSS was developed, and its reliability and validity were confirmed. PMID- 21540767 TI - Presence of anterior compression of the spinal cord after laminoplasty inhibits upper extremity motor recovery in patients with cervical spondylotic myelopathy. AB - STUDY DESIGN: A retrospective single-center study. OBJECTIVE: To investigate how functional recovery is influenced by anterior compression of the spinal cord (ACS) and instability at the level of ACS after laminoplasty in patients with cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: There have been many reports that patients whose spinal cord cannot be decompressed sufficiently after laminoplasty are likely to show unsatisfactory neurologic outcomes. Notably, postoperative ACS is well known to cause problems. Clinically, however, it remains unknown how functional recovery is inhibited by postoperative ACS. METHODS: Sixty-four consecutive patients who underwent expansive laminoplasty for the treatment of myelopathy at our hospital between 1998 and 2005 were reviewed. All 64 patients were available for follow-up. The average follow-up period was 97 months (60-156 months). Patients were divided into 2 groups: the ACS(+) group comprised 16 patients who had ACS 3 years postoperatively, and the ACS(-) group comprised 48 patients with no ACS. Clinical outcome was compared in terms of the Japanese Orthopaedic Association score (mean total score, mean score of each item, and recovery rates). RESULTS: Demographics were similar between the 2 groups. Mean Japanese Orthopaedic Association score at final follow-up was 12.1 points (recovery rate 34.0%) in the ACS(+) group and 13.8 points (recovery rate 56.6%) in the ACS(-) group, and there was a significant difference in recovery rate between the groups (P < 0.05). Notably, a significant difference was found between the 2 groups in improvement of upper extremity motor function (P < 0.05). In addition, we found that not only the presence of ACS but also postoperative hypermobility of the intervertebral segment with ACS influenced clinical outcome negatively. CONCLUSION: These results demonstrate that ACS after laminoplasty could be a risk factor for clinical outcome and might prevent improvement in upper extremity motor function in patients with myelopathy. PMID- 21540768 TI - Impact of direct vertebral body derotation on rib prominence: are preoperative factors predictive of changes in rib prominence? AB - STUDY DESIGN: Multicenter retrospective review of prospectively collected data. OBJECTIVE: To determine the extent of rib deformity correction that can be expected with direct vertebral body derotation (DVBD) and investigate factors that may correlate with improved rib deformity correction. SUMMARY OF BACKGROUND DATA: DVBD is a powerful tool in the surgical correction of axial rotation in adolescent idiopathic scoliosis. The application of DVBD has decreased the use of thoracoplasty for cosmetic rib deformity correction, but the outcomes of DVBD without adjuvant thoracoplasty have not been well defined. METHODS: A multicenter database was retrospectively queried to identify patients with adolescent idiopathic scoliosis who underwent posterior spinal fusion with at least 2 years of follow-up and Lenke type 1 to 3 curves. All patients had undergone DVBD maneuvers during their surgery, and patients having undergone concurrent thoracoplasty were excluded from the study. The absolute change and percentage change from preoperative inclinometer readings were correlated with preoperative clinical and radiographic data. RESULTS: A total of 148 patients fulfilled the inclusion criteria. The mean age was 14.7 +/- 2.1 years with a mean primary thoracic curve of 55.3 degrees +/- 9.3 degrees . The mean preoperative inclinometer reading was 14.8 degrees +/- 4.5 degrees , which reduced to 7.5 degrees +/- 4.0 degrees postoperatively. Patients had a mean improvement of 54% +/- 29% in rib prominence using DVBD. We attempted to correlate 23 of the most commonly used preoperative clinical, radiographic, and operative measures with postoperative inclinometer improvement. Interestingly, none correlated with rib deformity correction, including preoperative rib deformity (P = 0.16), thoracic curve flexibility (P = 0.71), presence of osteotomies (P = 0.60), and thoracic curve magnitude (P = 0.78). CONCLUSION: Utilizing DVBD, the surgeon can expect approximately 50% reduction in the rib deformity as assessed by inclinometer. This is irrespective of preoperative inclinometer measures, thoracic curve flexibility, and vertebral body rotation on standing and bending radiographs. PMID- 21540769 TI - Comparative immunolocalization of the elastin fiber-associated proteins fibrillin 1, LTBP-2, and MAGP-1 with components of the collagenous and proteoglycan matrix of the fetal human intervertebral disc. AB - STUDY DESIGN: A comparative immunolocalization study of elastin-associated proteins and established intervertebral disc (IVD) extracellular matrix (ECM) components. OBJECTIVE: To localize for the first time, elastic fiber-associated proteins with structural fibrillar components in the annulus fibrosus (AF) of the fetal IVD. SUMMARY OF BACKGROUND DATA: Elastin has been identified histochemically in adult bovine, human, and immature rat IVDs, and in fetal human IVDs using electron microscopy; however, no immunolocalization studies have been undertaken for associated components in human fetal IVDs. METHODS: En-bloc fixation of thoracolumbar spinal segments in formalin and Histochoice followed by standard histochemical processing, paraffin embedding, microtome sectioning, and identification of IVD ECM components using a range of specific mono- and polyclonal antibodies and bright-field and laser scanning confocal microscopy. RESULTS: The elastic fiber-associated proteins fibrillin-1, LTBP-2, and MAGP-1 were prominently immunolocalized in the outer lamellar layers of the AF of the human fetal IVD. Dual localization of selected components by confocal microscopy demonstrated that versican and LTBP-2 were colocalized with fibrillin-1 microfibrils in the AF lamellae with a similar distribution to the elastin fibers. LTBP-2 was also associated with pericellular perlecan in the outer AF. These interconnections between elastin-associated proteins resulted in an elastic network, which connected the AF cells with the adjacent cartilaginous vertebral bodies. CONCLUSION: Specific immunolocalization of fibrillin-1, MAGP-1, and versican with elastin in the outer AF of the fetal human IVD has been demonstrated. We deduce from the established distributions of the elastin associated proteins and their known interactivities with matrix components that these stabilize and aid in the integration of the elastic fibers in the annular lamellae and may be responsible for the generation of tensional forces in the outer AF, which direct the assembly of this tissue. PMID- 21540770 TI - Effects of epidural steroid injections on blood glucose levels in patients with diabetes mellitus. AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: To evaluate the effects of epidural steroid injections (ESIs) on blood glucose levels in patients with diabetes mellitus. SUMMARY OF BACKGROUND DATA: ESIs are commonly used in the treatment of multiple spinal disorders. Corticosteroid injections have been evaluated in the total joints and hand literature showing systemic effects to diabetics. METHODS: Diabetic patients who were scheduled for an ESI were given an opportunity to enroll in our IRB-approved study. We collected the patient's most recent hemoglobin A(1c) (hA(1c)) and then asked them to track their blood glucose numbers at least twice per day for 2 weeks prior to and after their ESIs. RESULTS: We noted a statistically significant increase in blood glucose levels in diabetic patients (n = 30) after ESI. The mean blood glucose level prior to ESI was 160.18 +/- 47.46, and, after ESI, it was 286.13 +/- 111.11. This represents an average 125.96 +/- 100.97 increase in blood glucose levels after injection. Using a nonlinear mixed effect model, the estimated half-life of this increase was 1.06 days (95% CI 0.80, 1.58), meaning that the patients were back within their normal standard deviation mean glucose levels within 2 days of injection. There was no association between observed glucose level change and preinjection hA(1c) levels or age (Spearman = 0.0326 and -0.1091 separately), indicating that there is no correlation between preinjection hA(1c) levels and systemic response to ESI. CONCLUSION: ESIs were noted to cause a significant increase in the blood glucose levels in diabetics. There was no correlation between preinjection diabetic control, represented by hA(1c) levels, and postinjection response. Diabetics who are candidates for ESI should be counseled that a blood glucose increase may be apparent post intervention, but effects should not last longer than approximately 2 days. PMID- 21540771 TI - A rare presentation of cervical osteochondroma arising in a spinous process. AB - STUDY DESIGN: The case of a 21-year-old woman with a palpable neck mass is reported. OBJECTIVE: To describe the rare presentation of an osteochondroma arising in the right bifid tip of the C5 spinous process presenting as a palpable neck mass. Emphasis will be placed on the pathophysiology, symptomatology, complications, imaging, and surgical management. SUMMARY OF BACKGROUND DATA: Osteochondromas rarely occur in the cervical spine and lesions arising from the neural arch may present as a palpable neck mass. METHODS: The patient's medical and imaging history and medical literature were reviewed. RESULTS: A 21-year-old woman presented with a hard palpable mass in her lower cervical spine. Review of radiography, CT, MRI, and skeletal scintigraphy demonstrated an expansile bone lesion arising in the right bifid tip of the C5 spinous process with dense chondroosseous matrix in the distal tip of the lesion. Wide C5 laminectomy with en bloc resection of the tumor alleviated her symptoms. Biopsy revealed osteochondroma without malignant degeneration. CONCLUSIONS: Patients with cervical spine osteochondromas may present with a multitude of symptoms and complications depending on the size and location of the lesion. These may include pathologic fracture, spinal stenosis, nerve root compression, cranial nerve deficits, myelomalacia, and malignant degeneration to chondrosarcoma. Advanced imaging modalities are required for characterization, diagnosis, surgical planning, and management of these rare spinal lesions. PMID- 21540772 TI - Rejuvenation of nucleus pulposus cells using extracellular matrix deposited by synovium-derived stem cells. AB - STUDY DESIGN: After plating for 6 passages on either plastic flasks or extracellular matrix (ECM) deposited by synovium-derived stem cells (SDSCs), expanded nucleus pulposus (NP) cells were evaluated for redifferentiation capacity. OBJECTIVE: The aim was to assess the feasibility of using ECM deposited by a tissue-specific stem cell to provide a 3-dimensional microenvironment for NP cell rejuvenation. SUMMARY OF BACKGROUND DATA: Autologous disc cell-based therapy is a promising approach for intervertebral disc regeneration. Unfortunately, the current in vitro expansion of NP cells in monolayer results in dedifferentiation of these cells. METHODS: Primary NP cells were plated on either plastic flasks or ECM for 6 consecutive passages. At each passage, cell numbers were counted for proliferation rate, cell phenotype was evaluated using flow cytometry, and cell differentiation status was assessed using real-time polymerase chain reaction (PCR). The pellets from expanded NP cells at passages 1, 4, and 6 were incubated in a serum-free defined medium for 14 days. Redifferentiation capacity of the expanded NP cells was evaluated using histology, biochemistry, and real-time PCR. RESULTS: NP cells expanded on ECM grew much faster with a smaller size and fibroblast-like shape compared with those on plastic flasks. ECM-treated NP cells acquired an enhanced CD90 expression and higher mRNA levels of types I, II, and X collagen and aggrecan, as well as a robust redifferentiation capacity, evidenced by dramatically increased type II collagen, aggrecan, and Sox9 and decreased type I collagen for up to 6 passages. CONCLUSION: SDSC-derived ECM can provide a tissue-specific microenvironment for the rejuvenation of NP cells with a higher proliferation rate and redifferentiation capacity. These characteristics may play a role in improving an autologous disc cell-based minimally invasive therapeutic approach toward physiological reconstruction of a biologically functional disc in the clinical setting. PMID- 21540773 TI - Subsequent, unplanned spine surgery and life survival of patients operated for neuropathic spine deformity. AB - STUDY DESIGN: Retrospective study of a prospectively assembled cohort. OBJECTIVE: To characterize the survival from subsequent spine surgery and the life survival of patients treated surgically for severe spinal deformity due to neuropathic diseases. SUMMARY OF BACKGROUND DATA: Survivorship analysis is widely used to study the natural history of disease processes and of treatments provided, but has very seldom been used to study patients' course after surgery for spinal deformity associated with neuropathic diseases. METHODS: Patients with neuropathic spinal deformity treated with primary posterior instrumentation and arthrodesis from 1989 through 2002 were identified and studied by review of charts and radiographs, and by mail survey. Subsequent spine surgery and death events, and the time interval from surgery were identified. Fifteen variables possibly influencing survivorship were studied. RESULTS: There were no perioperative deaths, spinal cord injuries, or acute wound infections in the 117 eligible patients. Reoperation and life survival statuses were available for 110 patients (94%) at an average follow-up of 11.89 years (+/-5.3; range: 2-20.9 yr). Twelve patients (11%) had subsequent spine surgery. Survival from subsequent spine surgery was 91% at 5 years, 90% at 10 and 15 years, and 72% at 20 years. Proximal fixation problems occurred in 4 patients. Twenty-two patients (20%) had died from 4 to 20 years postoperative. Life survival was 98% at 5 years, 89% at 10 years, 81% at 15 years, and 56% at 20 years. The only variable associated with life survival was the occurrence of one or more perioperative complications, P = 0.0032. The younger half of the series at operation (<13.75 yr) was significantly more likely to have one or more perioperative complications, P = 0.0068. Spinal deformity type and magnitude were similar for the younger and older halves of the patients. Life survival of the patients with cerebral-palsy and not-cerebral palsy upper motor neuron disease was not different. One-hundred-two of 105 were at least satisfied or would have the surgery again for the same condition. CONCLUSION: Survival from subsequent spine operation was similar to adolescent idiopathic scoliosis series studied in the same manner. Life survival decline began at 4 years postoperative and was significantly associated with the occurrence of one or more perioperative complications. Even after successful spine deformity surgery, this population's health status is often precarious. PMID- 21540774 TI - Five-year follow-up evaluation of surgical treatment for cervical myelopathy caused by ossification of the posterior longitudinal ligament: a prospective comparative study of anterior decompression and fusion with floating method versus laminoplasty. AB - STUDY DESIGN: Prospective, comparative clinical study. OBJECTIVE: To compare the clinical outcome of anterior decompression and fusion with floating method and laminoplasty in the treatment of cervical myelopathy caused by ossification of the posterior longitudinal ligament (OPLL). SUMMARY OF BACKGROUND DATA: There have been no reports that have accurately and prospectively compared surgical outcomes after anterior decompression and posterior decompression. METHODS: For cervical myelopathy caused by OPLL, we performed anterior decompression and fusion with floating method (ADF) in 1997, 1999, 2001, 2003, and 2004 and French door laminoplasty (LAMP) in 1996, 1998, 2000, and 2002 at one institution. Twenty patients in the ADF group and 22 patients in the LAMP group were evaluated for 5 years' follow-up. The following criteria were evaluated: operation time, blood loss, complications, and Japanese Orthopedic Association score. For radiographic evaluation, canal narrowing ratio of OPLL, lordotic angle at C2-C7, and postoperative progression of the ossified lesion were measured. RESULTS: The operation time in the ADF group was longer than that in the LAMP group. The average blood loss showed no statistical difference between the 2 groups. Complications occurred in 5 cases in the ADF group, but none occurred in the LAMP group. The mean Japanese Orthopedic Association score system for cervical myelopathy and the recovery rate in the ADF group were superior to those in the LAMP group, especially for cases with greater than 50% of the spinal canal compromised by OPLL or kyphotic alignment of the cervical spine, preoperatively. Postoperative progression of OPLL was observed in 5% of the ADF group and 50% of the LAMP group. CONCLUSION: ADF is considered especially suitable for cases with massive OPLL and preoperative kyphotic alignment of the cervical spine, although it leads to a higher incidence of surgery-related complications compared with LAMP. PMID- 21540775 TI - Clinically relevant anatomy of recurrent laryngeal nerve. AB - STUDY DESIGN: An anatomic study of anterior cervical dissection of 11 embalmed cadavers. OBJECTIVE: To determine the anatomic relationship of the recurrent laryngeal nerve (RLN) to the cervical spine and demonstrate vulnerability of the nerve during anterior surgical approach. SUMMARY OF BACKGROUND DATA: The most common complications of anterior neck surgery are dysphagia and RLN palsy. The morbidity of these complications has led to the investigation of the impact of sidedness in anterior cervical spine surgery. METHODS: Eleven adult cadavers (5 male/6 female) were dissected bilaterally to expose the path of the recurrent laryngeal nerve. RESULTS: The right RLN branched from the vagus nerve at the level of T1-T2 or inferior in all specimens. After looping around the subclavian artery, the right RLN became invested in the tracheoesophageal fascia greater than 0.5 cm inferior to C7-T1 in all specimens. The RLN traveled superiorly, slightly anterior to the tracheoesophageal groove, before coursing between the trachea and the thyroid. In 82% (9 of 11) of right-sided dissections, the RLN entered the larynx at or inferior to C6-C7. After looping around the aortic arch, the left RLN was invested in the tracheoesophageal fascia inferior to the T2 level in 100% (10 of 10) of cadavers. The nerve traveled slightly anterior to the tracheoesophageal groove and within the tracheoesophageal fascia before coursing between the trachea and thyroid. In all the left-sided dissections, the RLN entered the larynx at or inferior to C6-C7. CONCLUSION: This study found that superior to C7-T1, both RLNs had similar anatomic courses and received similar protection via surrounding soft-tissue structures. From an anatomic perspective, the authors did not appreciate a side-to-side difference superior to this level that could place either nerve under greater risk for injury. PMID- 21540777 TI - Comparative analysis of clinical outcome and complications in primary versus revision adult scoliosis surgery. AB - STUDY DESIGN: A retrospective case comparison study. OBJECTIVE: We compared clinical outcome and complications in adult patients who underwent primary (P) versus revision (R) scoliosis surgery. SUMMARY OF BACKGROUND DATA: There is a paucity of data comparing P versus R adult scoliosis patients with respect to their complication rates and clinical outcome. METHODS: Assessment of 250 consecutive adult patients who underwent P versus R surgery for idiopathic or de novo scoliosis between 2002 and 2007, with a minimum 2-year follow-up, was performed. RESULTS: There were 126 patients in the P group and 124 in the R group. Mean age at surgery (P = 51.2 vs. R = 51.6 years, P = 0.79), length of follow-up (P = 3.6 vs. R = 3.6 years, P = 0.94), comorbidities (P = 0.43), and smoking status (P = 0.98) were similar between the 2 groups. Body mass index (P = 25.5 vs. R = 27.4 kg/m, P = 0.01), number of final instrumented levels (P = 10.5 vs. R 12.1 levels, P = 0.00), fusion to the sacrum (P = 61.0% vs. R = 87.1%, P = 0.00), osteotomy (P = 14.3% vs. R = 54.9%, P = 0.00), length of surgery (P = 6.5 vs. R = 8.2 hours, P = 0.00), and estimated blood loss (P = 1072.1 vs. R = 1401.3 mL, P = 0.05) were different. Primary patients had significantly lower overall complications than revision patients (P = 45.2% vs. R = 58.2%, P = 0.042). Primary patients reported significantly higher preoperative and final clinical outcome measures in function, pain, and subscore SRS domains and ODI compared with revision patients (all P < 0.05). Patients older than 60 years of age, however, reported similar SRS and ODI scores between the 2 groups. The extent of surgical benefit patients received, that is, final minus preoperative score, was similar in all categories between the 2 groups. CONCLUSION: Adult patients undergoing primary scoliosis surgery had significantly lower overall complications compared with revision patients. Primary patients reported higher preoperative and final clinical outcome measures than revision patients, although this difference disappeared in older patients. The benefit of surgery was similar between the 2 groups. PMID- 21540778 TI - Could junctional problems at the end of a long construct be addressed by providing a graduated reduction in stiffness? A biomechanical investigation. AB - STUDY DESIGN: The effect of long, rigid fixation on adjacent level hypermobility was investigated in a human cadaver model with and without a transitional posterior dynamic stabilization (PDS) device placed at the last caudal level. OBJECTIVE: To evaluate if PDS devices are useful in the setting of spinal deformities to restore increased adjacent level motions, which occur in long constructs. The hypothesis is that load-sharing benefits of these devices will be most suitable in long constructs and may reduce thoracolumbar junctional effects. The PDS device evaluated has a compressive spacer and flexion-dampening bumper. SUMMARY OF BACKGROUND DATA: Mechanical factors such as excessive mobility, increased disc height due to instrumentation, and abnormal loading are thought to accentuate distal level problems, which occur in extended instrumentation. Specifically adjacent level degeneration and distal junctional kyphosis are known to occur in these cases. METHODS: Seven cadaver spines were tested from T7 to L3. Long instrumentation was applied in 2 rigid groups, R1: Rigid (T8-L2) and R2: Rigid (T8-L1), and PDS to the last caudal level of each, RP1: Rigid (T8-L1) + PDS (L1-L2), and RP2: Rigid (T8-T12) + PDS (T12-L1). Range of motion was evaluated at surgical and distal adjacent levels after displacement controlled loading in a spine tester. RESULTS: Distal adjacent level motion was increased after 5- and 6 level rigid fixation in flexion-extension, lateral bending, and axial rotation. Most of the increases were seen in axial rotation and lateral bending. Replacing the last caudal instrumented level with the PDS test device was able to alleviate hypermobile conditions of the adjacent noninstrumented level, closer to intact (24%, 12% reduction in RP2, RP1, respectively). CONCLUSION: Reduction of hypermobility caused by extended arthrodesis may represent a new and ideally suited function for PDS devices. Mechanically, the devices were seen to kinematically restore abnormal distal motion, especially with placement of the PDS at the thoracolumbar junction. PMID- 21540779 TI - Validation of a miniature thermochron for monitoring thoracolumbosacral orthosis wear time. AB - STUDY DESIGN: Prospective validation study. OBJECTIVE: To establish the accuracy of miniature thermochrons for estimating thoracolumbosacral orthosis (TLSO) wear time in patients with adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: There has been an emphasis in recent years on measuring wear time as opposed to using subjective methods such as relying on the patient or parent estimation. By measuring the amount of time that was spent in the orthosis, uncertainty is reduced and the validity of the research is improved. Several types of devices have been employed for direct monitoring of orthosis wear time including strap tension monitors, pressure sensors, and temperature-time sensors (thermochrons). Direct monitoring studies have shown that relying on patient or parent report is inaccurate; the patient/parent report is clearly biased towards overestimation of wear time. METHODS: Three miniature thermochrons (DS1922L iButton, Maxim Integrated Products, Inc., Sunnyvale, CA) were mounted underneath padding in the TLSOs of 7 participants diagnosed with adolescent idiopathic scoliosis. The participants wore their TLSO for 1 month. During this time, participants kept meticulous records of wear time in diaries. An algorithm was developed to automatically detect donning/doffing of the orthosis, and the results of the data reduction algorithm were compared with the diary (gold standard). RESULTS: Total wear time accuracy was 98.5% (0.37 hours/day), while the precise timing of donning/doffing was 92% accurate. CONCLUSION: An inexpensive, commercially available miniature thermochron and a simple robust algorithm can estimate TLSO wear time to a high degree of accuracy. This method is suitable for large-scale prospective studies examining the efficacy of bracing in adolescent idiopathic scoliosis, which remains a topic of controversy. PMID- 21540780 TI - Quantification of intradiscal pressures below thoracolumbar spinal fusion constructs: is there evidence to support "saving a level"? AB - STUDY DESIGN: In vitro cadaveric study. OBJECTIVE: The purpose of this study was to quantify the relative biomechanical protection resulting from "saving a level" in long spinal fusions. SUMMARY OF BACKGROUND DATA: "Saving levels" in spinal deformity surgery is desirable. Constructs with lowest instrumented vertebra (LIV) in the lumbar spine may increase loads on unfused lumbar intervertebral discs, leading to accelerated disc degeneration. No study to date has quantified the relative pressure changes that occur in the unfused caudal discs with progressively longer fusions. METHODS: We used a validated in vitro cadaveric long fusion model to assess intradiscal pressures (IDPs) below simulated fusions. Eight fresh frozen T8-S1 specimens were instrumented from T8 to L5. A follower type loading system and 7.5-N.m moments were applied in flexion and extension. IDP profiles were assessed with a pressure transducer. After acquiring IDP measurements at a given construct length, the rod was cut 1 level higher until LIV = T12. IDP data from each unfused disc were averaged and normalized to the mean value of the disc when immediately subjacent to the LIV. RESULTS: In both flexion and extension, the mean normalized IDP of the unfused discs below the LIV increased with increasing fusion length. For each 1-level increase in construct length, pressure increased by 3.2% +/- 4.8% in flexion and 4.3% +/- 4.5% in extension for each unfused disc. Although the differences in pressure for a given unfused disc with differing LIV were not significant, there were significant differences between unfused discs at a given LIV. With shorter fusion lengths, pressure in the disc immediately subjacent to the fusion was consistently greater than for the caudal-most discs. CONCLUSION: Unfused caudal lumbar discs experienced increased IDPs with increasing length of instrumentation, most notably at the subjacent discs closest to the LIV. PMID- 21540781 TI - Brain-derived neurotrophic factor inhibition at the punctured intervertebral disc downregulates the production of calcitonin gene-related peptide in dorsal root ganglia in rats. AB - STUDY DESIGN: Retrograde neurotracing and immunohistochemical investigation of brain-derived neurotrophic factor (BDNF)-related sensory innervation of punctured lumbar intervertebral discs (IVDs) in rat dorsal root ganglia (DRG). OBJECTIVE: To investigate the association between BDNF and sensory innervation of multiple punctured lumbar IVD in rats. SUMMARY OF BACKGROUND DATA: BDNF--a neurotrophin in DRG neurons--is anterogradely transported to the spinal cord and transmits pain signals. Its presence in the peripheral sites of degenerative IVDs has been recently reported, although its association with discogenic pain remains unclear. METHODS: Forty female Sprague-Dawley rats were equally divided into four groups: naive, sham, and two agent-treated groups (vehicle [saline-treated] group and anti-BDNF [anti-BDNF antibody] group). L5-L6 IVDs of the agent-treated rats were exposed and injured by repeated punctures. The retrograde neurotracer Fluoro-Gold (FG) and treatment agents were intradiscally applied. In the sham group, FG alone was applied onto uninjured IVD. One week later, L1-L3 DRGs were harvested and immunolabeled for the inflammatory pain-related calcitonin gene-related peptide (CGRP), that is, the pain marker. The proportions of FG-labeled CGRP immunoreactive (-ir) DRG neurons were assessed. Each L5-L6 IVD was resected for measuring the BDNF concentration using enzyme-linked immunosorbent assay. RESULTS: FG-labeled DRG neurons were almost equally prevalent at each DRG level. The proportions of FG-labeled CGRP-ir DRG neurons in the two agent-treated groups were significantly elevated (average 37.9% +/- 7.2% and 25.4% +/- 9.1%; vehicle and anti-BDNF groups, respectively; P < 0.05) in comparison with the naive and sham groups (19.6% +/- 1.3% and 19.2% +/- 3.6%, respectively) and were significantly decreased in the anti-BDNF group in comparison with the vehicle group (P < 0.05). BDNF concentrations were elevated maximally in the vehicle group (18.5 +/- 5.2 pg/g) but suppressed in the anti-BDNF group (14.0 +/- 3.0 pg/g). CONCLUSION: Direct intradiscal application of the anti-BDNF antibody significantly suppressed both CGRP production and the local concentration of BDNF. Our results indicate a possible association between the local production of BDNF and the pathophysiology of discogenic pain. PMID- 21540782 TI - Judgmental sampling. PMID- 21540783 TI - Retrieval-related deaths-risks to the team. PMID- 21540784 TI - Belly fat. What your waistline may say about your health. PMID- 21540785 TI - Age-related macular degeneration may be on decline in U.S. PMID- 21540786 TI - Antibiotic treatment may ease symptoms of irritable bowel syndrome. PMID- 21540787 TI - Diabetes plus depression can be deadly combination in women. PMID- 21540788 TI - Heartburn. Find relief without overdoing the medications. PMID- 21540789 TI - Mayo Clinic office visit. Prophylactic oophorectomy. An interview with Walter Rocca, M.D. PMID- 21540790 TI - A bicycle built for you. Getting a handle on your options. PMID- 21540791 TI - Is it true that cinnamon can lower my blood sugar levels if I have diabetes? PMID- 21540792 TI - How can I find out if I'm eligible for a clinical trial? PMID- 21540793 TI - Molecular morphology of pituitary cells, from conventional immunohistochemistry to fluorescein imaging. AB - In situ hybridization (ISH) at the electron microscopic (EM) level is essential for elucidating the intracellular distribution and role of mRNA in protein synthesis. EM-ISH is considered to be an important tool for clarifying the intracellular localization of mRNA and the exact site of pituitary hormone synthesis on the rough endoplasmic reticulum. A combined ISH and immunohistochemistry (IHC) under EM (EM-ISH&IHC) approach has sufficient ultrastructural resolution, and provides two-dimensional images of the subcellular localization of pituitary hormone and its mRNA in a pituitary cell. The advantages of semiconductor nanocrystals (quantum dots, Qdots) and confocal laser scanning microscopy (CLSM) enable us to obtain three-dimensional images of the subcellular localization of pituitary hormone and its mRNA. Both EM-ISH&IHC and ISH & IHC using Qdots and CLSM are useful for understanding the relationships between protein and mRNA simultaneously in two or three dimensions. CLSM observation of rab3B and SNARE proteins such as SNAP-25 and syntaxin has revealed that both rab3B and SNARE system proteins play important roles and work together as the exocytotic machinery in anterior pituitary cells. Another important issue is the intracellular transport and secretion of pituitary hormone. We have developed an experimental pituitary cell line, GH3 cell, which has growth hormone (GH) linked to enhanced yellow fluorescein protein (EYFP). This stable GH3 cell secretes GH linked to EYFP upon stimulation by Ca2+ influx or Ca2+ release from storage. This GH3 cell line is useful for the real-time visualization of the intracellular transport and secretion of GH. These three methods from conventional immunohistochemistry and fluorescein imaging allow us to consecutively visualize the process of transcription, translation, transport and secretion of anterior pituitary hormone. PMID- 21540794 TI - Diversity-oriented synthesis of a library of substituted tetrahydropyrones using oxidative carbon-hydrogen bond activation and click chemistry. AB - Eighteen (2RS,6RS)-2-(4-methoxyphenyl)-6-(substituted ethyl)dihydro-2H-pyran 4(3H)ones were synthesized via a DDQ-mediated oxidative carbon-hydrogen bond activation reaction. Fourteen of these tetrahydropyrans were substituted with triazoles readily assembled via azide-alkyne click-chemistry reactions. Examples of a linked benzotriazole and pyrazole motif were also prepared. To complement the structural diversity, the alcohol substrates were obtained from stereoselective reductions of the tetrahydropyrone. This library provides rapid access to structurally diverse non-natural compounds to be screened against a variety of biological targets. PMID- 21540795 TI - Cytotoxicity and oral acute toxicity studies of Lantana camara leaf extract. AB - BACKGROUND: The objective of this study was to investigate the toxicity of Lantana camara methanol extract. METHODS: In order to evaluate the toxicity of Lantana camara, the acute toxicity of the methanolic extract on adult mice and cytotoxicity test on Vero cell line were investigated. A fixed large dose of 2 g/kg body weight of L. camara leaf extract was administrated by a single oral gavage according to the OECD procedure. RESULTS: In 2 weeks, L. camara leaf extract showed no obvious acute toxicity. While female mice lost body weight after being treated with single dose of leaf extract in acute toxicity test, male ones lost organ mass, particularly for heart and kidney. The biochemical liver function tests showed significantly elevated TBIL and ALT in the L. camara leaf extract treated female mice group compared with the control group. Cytotoxicity effect of leaf extract of L. camara was estimated through a MTT assay. Cytotoxicity tests on Vero cell line disclosed that leaf extract at concentrations up to 500 ug/mL inhibited the growth of cells 2.5 times less than did Triton 100 * 1%. More interestingly, the cytotoxicity initiated to decline at elevated concentrations of this extract. CONCLUSIONS: The results of both tests confirm that L. camara shows a pro toxic effect. PMID- 21540796 TI - High affinity, developability and functional size: the holy grail of combinatorial antibody library generation. AB - Since the initial description of phage display technology for the generation of human antibodies, a variety of selection methods has been developed. The most critical parameter for all in vitro-based approaches is the quality of the antibody library. Concurrent evolution of the libraries has allowed display and selection technologies to reveal their full potential. They come in different flavors, from naive to fully synthetic and differ in terms of size, quality, method of preparation, framework and CDR composition. Early on, the focus has mainly been on affinities and thus on library size and diversity. Subsequently, the increased awareness of developability and cost of goods as important success factors has spurred efforts to generate libraries with improved biophysical properties and favorable production characteristics. More recently a major focus on reduction of unwanted side effects through reduced immunogenicity and improved overall biophysical behavior has led to a re-evaluation of library design. PMID- 21540797 TI - Inhibition of inflammatory mediators by neobavaisoflavone in activated RAW264.7 macrophages. AB - Flavonoids and coumarins are the major bioactive constituents identified in Psoralea corylifolia. The active fraction isolated from fruits, seeds and roots possesses antibacterial, antioxidative and immunomodulatory properties. Neobavaisoflavone is one of the flavonoids found in Psoralea corylifolia. In the present study we investigated in vitro the anti-inflammatory activity of neobavaisoflavone. Macrophages play an important role in inflammation through the release of inflammatory mediators involved in the immune response. Inappropriate and prolonged macrophage activation is largely responsible for the pathology of acute and chronic inflammatory conditions. Neobavaisoflavone significantly inhibited the production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and cytokines: IL-1beta, IL-6, IL-12p40, IL-12p70, TNF-alpha in LPS+IFN-gamma- or PMA- stimulated RAW264.7 macrophages. PMID- 21540798 TI - Simultaneous and rapid determination of main lignans in different parts of Schisandra sphenanthera by micellar electrokinetic capillary chromatography. AB - Lignans are imporant active ingredients of Schisandra sphenanthera. A micellar electrokinetic chromatography method was developed for the simultaneous determination of eight lignans--schizandrin, schisandrol B, schisantherin A, schisanhenol, anwulignan, deoxyschizandrin, schizandrin B and schizandrin C--in different parts of S. sphenanthera. The key factors for separation and determination were studied and the best analysis conditions were obtained using a background electrolyte of 10 mM phosphate-37.5 mM SDS-35% v/v acetonitrile (pH 8.0) at the separation voltage of 28 kV and detection at 214 nm, whereby the plant samples could be analyzed within 9.0 min. Analysis yielded good reproducibility (RSD between 1.19-2.28%) and good recovery (between 92.2-103.8%). The detection limits (LOD) and limit of quantification (LOQ) were within 0.4-1.2 mg/L and 1.5-4.0 mg/L. This method is promising to improve the quality control of different parts of S. sphenanthera. PMID- 21540799 TI - Implications of a comprehensive clinical approach in the treatment of critically ill patients requiring mechanical ventilation. PMID- 21540800 TI - Surgery and immunity. PMID- 21540801 TI - Do use ScvO2 and O2ERe as therapeutical goals. PMID- 21540802 TI - Bispectral Index for sleep screening: it is time to move on. PMID- 21540803 TI - Glutamine induces heat shock protein 70 expression via O-GlcNAc modification and subsequent increased expression and transcriptional activity of heat shock factor 1. AB - BACKGROUND: Glutamine (Gln) has been shown to induce heat shock protein (HSP) expression and to attenuate lipopolysaccharide (LPS)-mediated cardiovascular dysfunction, but the underlying mechanisms are not fully clear. We tested the hypothesis that protection by Gln-induced HSP70 expression is due to enhanced O linked beta-N-acetylglucosamine (O-GlcNAc) modification levels and subsequent increases in the levels of endonuclear heat shock protein factor-1 (HSF-1) expression and HSF-1 transcriptional activity in LPS-treated cardiomyocytes. METHODS: Primary cultures of neonatal rat cardiomyocytes were divided into control, LPS (4 MUg/mL), Gln+LPS (Gln 5 mM+LPS 4 MUg/mL), Gln+LPS+Alloxan (an O linked-N-acetyl glucosamine transferase inhibitor, 1 mM) and Gln+LPS+PUGNAc (an O GlcNAcase inhibitor; 100 MUM) groups. After incubation for six hours, the levels of cardiomyocyte viability, lactate dehydrogenase (LDH) activity, O-GlcNAc modification, endonuclear HSF-1 expression, HSF-1 transcription activity and cellular HSP70 expression were measured in all groups. RESULTS: There were no significant differences in cell viability among the five groups. LDH activity levels were much higher in the LPS group than in the control group, but they markedly decreased in the Gln+LPS group (P<0.05). Gln's protection in the Gln+LPS group was associated with a significant increase in the levels of O-GlcNAc modification, endonuclear HSF-1 expression, HSF-1 transcription activity and cellular HSP70 expression compared to the LPS group (P<0.05). The protective action by Gln in LPS-treated cardiomyocytes could either be mimicked by 1 MUM PUGNAc or banished by 1 mM alloxan. CONCLUSION: Gln induces HSP70 expression and attenuates LPS-induced cardiomyocyte damage. The molecular mechanism of Gln induced HSP70 expression appears to be mediated via enhancement of O-GlcNAc modification and subsequently to increase levels of endonuclear HSF-1 expression and HSF-1 transcription activity. PMID- 21540804 TI - Sevoflurane reduces spinal reciprocal Ia-inhibition in humans. AB - BACKGROUND: Potentiation of inhibitory transmissions in the spinal cord is considered to be an important mechanism for the mediation of the immobilizing effects of anesthetics. However, the depressant effects on motoneurons could be counterbalanced by presynaptic effects that inhibit the depressant pathways. Here we investigated the effect of sevoflurane on a disynaptic inhibitory pathway onto motoneurons in a human reflex model. METHODS: The study was performed with 9 volunteers receiving sevoflurane anesthesia (end tidal: 0.8% sevoflurane). Reciprocal inhibition was estimated from the depression of the H-reflex following a conditioning stimulation of the muscle spindle afferents from the tibialis anterior muscle. Measurements were performed before, during and after drug administration. RESULTS: The inhibition (mean +/- SE) amounted to 15.4% +/- 6.8%, 1.9% +/- 4.2% and 15.7% +/- 8.8% for measurements before, during and after sevoflurane administration, respectively. Differences between the anesthetic state and the two controls were statistically significant (mixed-effect ANOVA, p<0.01). CONCLUSION: Sevoflurane reduces reciprocal Ia-inhibition on motoneurons in humans. These findings seem to contradict the accepted view that sevoflurane enhances inhibitory synaptic transmission. This contradiction might be explained by the inhibitory actions of sevoflurane within the disynaptic pathway prior to the final glycinergic transmission onto the motoneuron. Our results suggest that even in presumably simple pathways, postsynaptic effects of anesthetics could be superimposed by their presynaptic effects. PMID- 21540805 TI - Methylprednisolone reduces the rates of postextubation stridor and reintubation associated with attenuated cytokine responses in critically ill patients. AB - BACKGROUND: Treatment with corticosteroids can reduce the incidence of postextubation stridor (PES) and reintubation in critically ill adult patients, but the mechanisms remain unknown. METHODS: A randomized, controlled clinical trial was conducted in an adult medical and surgical Intensive Care Unit (ICU) of a teaching hospital. Seventy-one patients who had a cuff leak percentage <24% of tidal volume received either a bolus injection of methylprednisolone at 40 mg (treated group, n=38) or normal saline (placebo group, n=33) 4 h prior to a planned extubation. The cuff leak percentage was re-assessed 1 h and 4 h post injection. Eighty patients who had a cuff leak percentage >= 24% served as a control group. Plasma concentrations of multiple cytokines and C-reactive protein (CRP) were measured at baseline, 4 h and 24 h after the intervention. RESULTS: The incidences of PES (15.8% vs. 39.4%, P<0.05) and reintubation rate (7.9% vs. 30.3%, P<0.05) were lower in the treated group compared to the placebo group. The plasma concentrations of IL-4 and IL-10 increased while the levels of IL-6 and IL 8 decreased at 24 h in the treated group compared to the placebo group. No difference in CRP levels was observed between the treated and placebo groups. CONCLUSION: A single injection of methylprednisolone at the dose used 4 h prior to planned extubation effectively reduced the incidence of PES and the reintubation rate. These beneficial effects were associated with the up regulation of IL-4 and IL-10 and the down-regulation of IL-6 and IL-8 in the critically ill adult patients. PMID- 21540806 TI - Systematic approach for severe respiratory failure due to novel A (H1N1) influenza. AB - AIM: In April 2009, a novel influenza A (H1N1) virus appeared in Mexico. It rapidly acquired the characteristics of a pandemic disease. Our objective is to present a case series of mechanically ventilated patients with severe influenza, treated with a systematic approach. METHODS: Prospective, observational, single center study in a University Hospital. A (H1N1) virus was confirmed by rRT-PCR. In this report, we only considered patients that required mechanical ventilation (MV). All patients received antibiotics, steroids and oseltamivir from the time of admission. The main strategies incorporated in the systematic approach were a lung-protective strategy, PEEP adjusted for each patient, protocol-guided sedoanalgesia, restrictive fluid management, weaning protocol, and prolonged prone ventilation and extracorporeal membrane oxygenation (ECMO) as rescue therapies. RESULTS: We studied 19 patients: age 41 +/- 13 years old, APACHE II 16 +/- 7 and SOFA 8 +/- 4. All patients presented PaO2/FiO2 <= 200 before connection to MV. Their worst values within the first 24 hours for oxygenation index, PaO2/FiO2, and PaCO2 on MV were 21.8 +/- 13, 98 +/- 39, and 48 +/- 16 mmHg, respectively. Sixteen patients achieved ARDS; three exhibited acute lung injury criteria. Ten required a prone position, and two required ECMO (one patient required both therapies). Time on MV was 16 +/- 13 days. Length of stay in the ICU and in hospital was 18 +/- 12 and 28 +/- 17 days, respectively. Mortality was 21%. CONCLUSION: Severe hypoxemia and a high rate of rescue therapies were observed among our patients. Nevertheless, mortality was lower than previously reported in comparable populations, which may be related to the management by a critical care team and the use of a systematic approach for ventilatory and non ventilatory therapeutic strategies. PMID- 21540807 TI - HLA-DR and B7-2 (CD86) monocyte expressions after major cancer surgery: profile in sepsis. AB - AIM: HLA-DR monocyte expression may be affected by major surgery. A potential mechanism for monocyte activation is the engagement of costimulatory receptors (B7-2 or CD-86). The aim of the present study was to determine the possible role of monocyte HLA-DR and B7-2 molecules in the occurrence of postoperative sepsis after major cancer surgery. METHODS: This was an observational study in 25 consecutive patients undergoing major elective surgery. Flow cytometry measures were used to determine the expression of HLA-DR and its costimulatory receptors before (day 0) and after surgery (day 1 and day 2). RESULTS: After surgery, the rate of monocytes expressing HLA-DR decreased significantly in all the patients. As compared with day 0, the rate of monocytes expressing B7-2 decreased in all the patients (P<0.03). In the septic group, it remained significantly decreased postoperatively. In the non-septic group, it reached baseline levels at day 2. CONCLUSION: Results suggest a key role for costimulatory molecules in modulating inflammatory response in the context of subsequent postoperative sepsis after major cancer surgery. These molecules may be involved, in association with HLA DR, in postoperative monocyte dysfunction. PMID- 21540808 TI - Current trends in simulation training in anesthesia: a review. AB - Anesthesiology as a specialty has made numerous prescient commitments to better patient care. Physicians entering residency are reaching the zenith of their educational odyssey and primarily acquire knowledge and skill through active involvement. Simulation training and associated assessment offers a chance for active involvement to the learner. The goal of the training is to accelerate skill acquisition, improve skill retention and reduce the extinction of skills. Simulation training programs have been shown to increase the skill of anesthesiologists. This increase in skill is expected to translate to evidence of improved patient care. Direct evidence that simulation directly improves patient care continues to be difficult to establish. In the future, the intuitive benefit of simulation as a means to improve the safety and quality of patient care is likely to become established by clinical research. PMID- 21540809 TI - Ventilatory management of one-lung ventilation. AB - Hypoxemia is considered to be the most important challenge during one-lung ventilation (OLV). Recent studies, however, have shown that one-lung ventilation can involve some lung damage and can therefore be per se a cause of hypoxemia. OLV can be associated to an injury: but the techniques used to improve oxygenation may also damage the lung. A new ventilator approach should be used and applied with regards to what is so far known in terms of "lung protection" also during OLV. PMID- 21540810 TI - Protective and ultra-protective ventilation: using pumpless interventional lung assist (iLA). AB - Acute lung failure is associated with high mortality and usually requires mechanical ventilation to ensure adequate gas exchange. However, mechanical ventilation itself can be associated with major complications and can aggravate pre-existing lung disease, thus contributing to morbidity and mortality. Extracorporeal gas exchange is increasingly used when conventional mechanical ventilation has failed. In contrast to veno-venous extracorporeal membrane oxygenation (ECMO), pumpless extracorporeal interventional lung assist (iLA) is applied via an arterio-venous bypass into which a gas exchange membrane is integrated. iLA allows for efficient carbon dioxide removal, which allows for a significant reduction in ventilator settings. iLA may be a useful tool in protective or even 'ultraprotective' ventilation, enabling the application of very low tidal volumes in patients with acute respiratory failure of different etiologies. This article reviews the current status and the potential role of interventional (pumpless) lung-assist iLA within the context of lung-protective ventilation strategies. PMID- 21540811 TI - Goal-directed therapy in anesthesia: any clinical impact or just a fashion? AB - Goal-directed therapy (GDT) describes the protocolized use of cardiac output and related parameters as end-points for fluid and/or inotropic therapy administration. Identifying the patient who will benefit from it has implications throughout perioperative management. The fundamental principle behind GDT is optimizing tissue perfusion by manipulating heart rate, stroke volume, hemoglobin and arterial oxygen saturation to improve oxygen delivery by using fluids, inotropes, red blood cells and supplementary oxygen. Although cardiac output and SvO2 were previously measured using the pulmonary artery catheter, a number of less invasive methods are now available. For intraoperative GDT, the esophageal Doppler-derived Flow Time correct (FTc) is the parameter used most frequently, although other parameters such as stroke volume obtained from Vigileo, PICCO and/or LiDCO, mixed and/or central venous oxygen saturation (SvO2/ScvO2), oxygen delivery and global end diastolic volume (PiCCO system) may be applied in daily clinical practice. The correct target to be followed during the intraoperative period must be clearly established. Most parameters depend primarily on O2 consumption and are not reliable or useful during anesthesia. To date, the quantity and the type of fluids to administer during major elective surgery remain an object of continuing debate. In conclusion, in terms of evidence-based medicine, GDT during anesthesia has a clinical impact when performed using an FTc based fluids algorithm protocol. In contrast, GDT can be considered unreliable if confusing targets such as SvO2 or ScvO2 higher than 70% during anesthesia are followed. PMID- 21540812 TI - Hyperammonemia and neonatal cardiac failure. AB - Severe hyperammonemia (hyperNH3) in neonatal cardiac failure after cardiac surgery is rare. We report a case of a 2470-g female infant born at the week 37 of gestation with complex congenital heart disease (truncus arteriosus type III, interrupted aortic arch and tricuspid valve insufficiency) and hemodynamically non-significant intrahepatic arterio-venous malformation. She developed hyperNH3 (highest NH3 blood level: 467 umol/L) without severe liver failure (INR of 1.9). The origin of the hyperNH3 was multifactorial including limited capacity of liver detoxification function due to congenital porto-caval shunt, liver ischemia, excessive protein intake and increased protein catabolic rate. HyperNH3 treatment partially succeeded in decreasing ammonia level and included discontinuation of protein intake, administration of phenylacetate and sodium benzoate. This case highlights the fact that NH3 detoxification by the liver has limitations for a neonate with multifactorial causes that decrease liver perfusion. PMID- 21540813 TI - Comparison of the tracheal intubation using Macintosh laryngoscope and GlideScope(r) videolaryngoscope by advanced cardiac life support providers in a manikin study. PMID- 21540815 TI - Editors-in-Chief statement regarding published clinical trials conducted without IRB approval by Joachim Boldt. PMID- 21540817 TI - Efficient polyethylene glycol (PEG) mediated transformation of the moss Physcomitrella patens. AB - A simple and efficient method to transform Physcomitrella pantens protoplasts is described. This method is adapted from protocols for Physocmitrella protonemal protoplast and Arabidopsis mesophyll protoplast transformation. Due to its capacity to undergo efficient mitotic homologous recombination, Physcomitrella patens has emerged as an important model system in recent years. This capacity allows high frequencies of gene targeting, which is not seen in other model plants such as Arabidopsis. To take full advantage of this system, we need an effective and easy method to deliver DNA into moss cells. The most common ways to transform this moss are particle bombardment and PEG-mediated DNA uptake. Although particle bombardment can produce a high transformation efficiency, gene guns are not readily available to many laboratories and the protocol is difficult to standardize. On the other hand, PEG mediated transformation does not require specialized equipments, and can be performed in any laboratory with a sterile hood. Here, we show a simple and highly efficient method for transformation of moss protoplasts. This method can generate more than 120 transient transformants per microgram of DNA, which is an improvement from the most efficient protocol previously reported. Because of its simplicity, efficiency, and reproducibility, this method can be applied to projects requiring large number of transformants as well as for routine transformation. PMID- 21540816 TI - Use of a hanging weight system for coronary artery occlusion in mice. AB - Murine studies of acute injury are an area of intense investigation, as knockout mice for different genes are becoming increasingly available. Cardioprotection by ischemic preconditioning (IP) remains an area of intense investigation. To further elucidate its molecular basis, the use of knockout mouse studies is particularly important. Despite the fact that previous studies have already successfully performed cardiac ischemia and reperfusion in mice, this model is technically very challenging. Particularly, visual identification of the coronary artery, placement of the suture around the vessel and coronary occlusion by tying off the vessel with a supported knot is technically difficult. In addition, re opening the knot for intermittent reperfusion of the coronary artery during IP without causing surgical trauma adds additional challenge. Moreover, if the knot is not tied down strong enough, inadvertent reperfusion due to imperfect occlusion of the coronary may affect the results. In fact, this can easily occur due to the movement of the beating heart. Based on potential problems associated with using a knotted coronary occlusion system, we adopted a previously published model of chronic cardiomyopathy based on a hanging weight system for intermittent coronary artery occlusion during IP. In fact, coronary artery occlusion can thus be achieved without having to occlude the coronary by a knot. Moreover, reperfusion of the vessel can be easily achieved by supporting the hanging weights which are in a remote localization from cardiac tissues. We tested this system systematically, including variation of ischemia and reperfusion times, preconditioning regiments, body temperature and genetic backgrounds. In addition to infarct staining, we tested cardiac troponin I (cTnI) as a marker of myocardial infarction in this model. In fact, plasma levels of cTnI correlated with infarct sizes (R2=0.8). Finally, we could show in several studies that this technique yields highly reproducible infarct sizes during murine IP and myocardial infarction. Therefore, this technique may be helpful for researchers who pursue molecular mechanisms involved in cardioprotection by IP using a genetic approach in mice with targeted gene deletion. Further studies on cardiac IP using transgenic mice may consider this technique. PMID- 21540818 TI - A calcium bioluminescence assay for functional analysis of mosquito (Aedes aegypti) and tick (Rhipicephalus microplus) G protein-coupled receptors. AB - Arthropod hormone receptors are potential targets for novel pesticides as they regulate many essential physiological and behavioral processes. The majority of them belong to the superfamily of G protein-coupled receptors (GPCRs). We have focused on characterizing arthropod kinin receptors from the tick and mosquito. Arthropod kinins are multifunctional neuropeptides with myotropic, diuretic, and neurotransmitter function. Here, a method for systematic analyses of structure activity relationships of insect kinins on two heterologous kinin receptor expressing systems is described. We provide important information relevant to the development of biostable kinin analogs with the potential to disrupt the diuretic, myotropic, and/or digestive processes in ticks and mosquitoes. The kinin receptors from the southern cattle tick, Boophilus microplus (Canestrini), and the mosquito Aedes aegypti (Linnaeus), were stably expressed in the mammalian cell line CHO-K1. Functional analyses of these receptors were completed using a calcium bioluminescence plate assay that measures intracellular bioluminescence to determine cytoplasmic calcium levels upon peptide application to these recombinant cells. This method takes advantage of the aequorin protein, a photoprotein isolated from luminescent jellyfish. We transiently transfected the aequorin plasmid (mtAEQ/pcDNA1) in cell lines that stably expressed the kinin receptors. These cells were then treated with the cofactor coelenterazine, which complexes with intracellular aequorin. This bond breaks in the presence of calcium, emitting luminescence levels indicative of the calcium concentration. As the kinin receptor signals through the release of intracellular calcium, the intensity of the signal is related to the potency of the peptide. This protocol is a synthesis of several previously described protocols with modifications; it presents step-by-step instructions for the stable expression of GPCRs in a mammalian cell line through functional plate assays (Staubly et al., 2002 and Stables et al., 1997). Using this methodology, we were able to establish stable cell lines expressing the mosquito and the tick kinin receptors, compare the potency of three mosquito kinins, identify critical amino acid positions for the ligand-receptor interaction, and perform semi-throughput screening of a peptide library. Because insect kinins are susceptible to fast enzymatic degradation by endogenous peptidases, they are severely limited in use as tools for pest control or endocrinological studies. Therefore, we also tested kinin analogs containing amino isobutyric acid (Aib) to enhance their potency and biostability. This peptidase-resistant analog represents an important lead in the development of biostable insect kinin analogs and may aid in the development of neuropeptide based arthropod control strategies. PMID- 21540819 TI - Particle agglutination method for poliovirus identification. AB - In the Global Polio Eradication Initiative, laboratory diagnosis plays a critical role by isolating and identifying PV from the stool samples of acute flaccid paralysis (AFP) cases. In the World Health Organization (WHO) Global Polio Laboratory Network, PV isolation and identification are currently being performed by using cell culture system and real-time RT-PCR, respectively. In the post eradication era of PV, simple and rapid identification procedures would be helpful for rapid confirmation of polio cases at the national laboratories. In the present study, we will show the procedure of novel PA assay developed for PV identification. This PA assay utilizes interaction of PV receptor (PVR) molecule and virion that is specific and uniform affinity to all the serotypes of PV. The procedure is simple (one step procedure in reaction plates) and rapid (results can be obtained within 2 h of reaction), and the result is visually observed (observation of agglutination of gelatin particles). PMID- 21540820 TI - Physiological, morphological and neurochemical characterization of neurons modulated by movement. AB - The role of individual neurons and their function in neuronal circuits is fundamental to understanding the neuronal mechanisms of sensory and motor functions. Most investigations of sensorimotor mechanisms rely on either examination of neurons while an animal is static or record extracellular neuronal activity during a movement. While these studies have provided the fundamental background for sensorimotor function, they either do not evaluate functional information which occurs during a movement or are limited in their ability to fully characterize the anatomy, physiology and neurochemical phenotype of the neuron. A technique is shown here which allows extensive characterization of individual neurons during an in vivo movement. This technique can be used not only to study primary afferent neurons but also to characterize motoneurons and sensorimotor interneurons. Initially the response of a single neuron is recorded using electrophysiological methods during various movements of the mandible followed by determination of the receptive field for the neuron. A neuronal tracer is then intracellularly injected into the neuron and the brain is processed so that the neuron can be visualized with light, electron or confocal microscopy (Fig. 1). The detailed morphology of the characterized neuron is then reconstructed so that neuronal morphology can be correlated with the physiological response of the neuron (Figs. 2,3). In this communication important key details and tips for successful implementation of this technique are provided. Valuable additional information can be determined for the neuron under study by combining this method with other techniques. Retrograde neuronal labeling can be used to determine neurons with which the labeled neuron synapses; thus allowing detailed determination of neuronal circuitry. Immunocytochemistry can be combined with this method to examine neurotransmitters within the labeled neuron and to determine the chemical phenotypes of neurons with which the labeled neuron synapses. The labeled neuron can also be processed for electron microscopy to determine the ultrastructural features and microcircuitry of the labeled neuron. Overall this technique is a powerful method to thoroughly characterize neurons during in vivo movement thus allowing substantial insight into the role of the neuron in sensorimotor function. PMID- 21540821 TI - Migratory behavior of cells generated in ganglionic eminence cultures. AB - Migration of cells is a common process that leads to the development and maturation of the vertebrate central nervous system (Hatten, '99). The cerebral cortex consists of two basic neuronal types: excitatory and inhibitory. These cells arise in distinct areas and migrate into the cortex along different routes (Pearlman et al., '98). Inhibitory interneurons migrate tangentially from subcortical sources, mostly from different regions of the ganglionic eminences (Gelman et al., '09; Xu et al., '04). Their movement requires precise spatiotemporal control imposed by environmental cues, to allow for the establishment of proper cytoarchitecture and connectivity in the cerebral cortex (Caviness & Rakic, '78; Hatten, '90; Rakic, '90). To study the migratory behavior of cells generated in proliferative zones of the ganglionic eminences (GE) in newborn ferrets in vitro we used a 3 dimensional culture arrangement in a BD Matrigel Matrix. The culture setup consisted of two GE explants and a source of tested proteins extracted from the cerebral cortex and adsorbed on fluorescent latex Retrobeads IX positioned between the explants (Hasling et al., '03; Riddle et al., '97). After 2-3 days of culture, the cells start to appear at the edge of the explant showing a propensity to leave the tissue in a radial direction. Live imaging allowed observation of migratory patterns without the necessity of labeling or marking the cells. When exposed to fractions of the protein extract obtained from isochronic ferret cortex, the GE cells displayed different behaviors as judged by quantitative kinetic analysis of individual moving cells. PMID- 21540822 TI - Isolation and culture of cells from the nephrogenic zone of the embryonic mouse kidney. AB - Embryonic development of the kidney has been extensively studied both as a model for epithelial-mesenchymal interaction in organogenesis and to gain understanding of the origins of congenital kidney disease. More recently, the possibility of steering naive embryonic stem cells toward nephrogenic fates has been explored in the emerging field of regenerative medicine. Genetic studies in the mouse have identified several pathways required for kidney development, and a global catalog of gene transcription in the organ has recently been generated http://www.gudmap.org/, providing numerous candidate regulators of essential developmental functions. Organogenesis of the rodent kidney can be studied in organ culture, and many reports have used this approach to analyze outcomes of either applying candidate proteins or knocking down the expression of candidate genes using siRNA or morpholinos. However, the applicability of organ culture to the study of signaling that regulates stem/progenitor cell differentiation versus renewal in the developing kidney is limited as cultured organs contain a compact extracellular matrix limiting diffusion of macromolecules and virus particles. To study the cell signaling events that influence the stem/progenitor cell niche in the kidney we have developed a primary cell system that establishes the nephrogenic zone or progenitor cell niche of the developing kidney ex vivo in isolation from the epithelial inducer of differentiation. Using limited enzymatic digestion, nephrogenic zone cells can be selectively liberated from developing kidneys at E17.5. Following filtration, these cells can be cultured as an irregular monolayer using optimized conditions. Marker gene analysis demonstrates that these cultures contain a distribution of cell types characteristic of the nephrogenic zone in vivo, and that they maintain appropriate marker gene expression during the culture period. These cells are highly accessible to small molecule and recombinant protein treatment, and importantly also to viral transduction, which greatly facilitates the study of candidate stem/progenitor cell regulator effects. Basic cell biological parameters such as proliferation and cell death as well as changes in expression of molecular markers characteristic of nephron stem/progenitor cells in vivo can be successfully used as experimental outcomes. Ongoing work in our laboratory using this novel primary cell technique aims to uncover basic mechanisms governing the regulation of self renewal versus differentiation in nephron stem/progenitor cells. PMID- 21540823 TI - Modified mouse embryonic stem cell based assay for quantifying cardiogenic induction efficiency. AB - Differentiation of pluripotent stem cells is tightly controlled by temporal and spatial regulation of multiple key signaling pathways. One of the hurdles to its understanding has been the varied methods in correlating changes of key signaling events to differentiation efficiency. We describe here the use of a mouse embryonic stem (ES) cell based assay to identify critical time windows for Wnt/beta-catenin and BMP signal activation during cardiogenic induction. By scoring for contracting embryonic bodies (EBs) in a 96-well plate format, we can quickly quantify cardiogenic efficiency and identify crucial time windows for Wnt/beta-catenin and BMP signal activation in a time course following specific modulator treatments. The principal outlined here is not limited to cardiac induction alone, and can be applied towards the study of many other cell lineages. In addition, the 96-well format has the potential to be further developed as a high throughput, automated assay to allow for the testing of more sophisticated experimental hypotheses. PMID- 21540824 TI - Associated chromosome trap for identifying long-range DNA interactions. AB - Genetic information encoded by DNA is organized in a complex and highly regulated chromatin structure. Each chromosome occupies a specific territory, that may change according to stage of development or cell cycle. Gene expression can occur in specialized transcriptional factories where chromatin segments may loop out from various chromosome territories, leading to co-localization of DNA segments which may exist on different chromosomes or far apart on the same chromosome. The Associated Chromosome Trap (ACT) assay provides an effective methodology to identify these long-range DNA associations in an unbiased fashion by extending and modifying the chromosome conformation capture technique. The ACT assay makes it possible for us to investigate mechanisms of transcriptional regulation in trans, and can help explain the relationship of nuclear architecture to gene expression in normal physiology and during disease states. PMID- 21540825 TI - Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death. AB - Studies of cellular apoptosis have been significantly impacted since the introduction of flow cytometry-based methods. Propidium iodide (PI) is widely used in conjunction with Annexin V to determine if cells are viable, apoptotic, or necrotic through differences in plasma membrane integrity and permeability. The Annexin V/PI protocol is a commonly used approach for studying apoptotic cells. PI is used more often than other nuclear stains because it is economical, stable and a good indicator of cell viability, based on its capacity to exclude dye in living cells. The ability of PI to enter a cell is dependent upon the permeability of the membrane; PI does not stain live or early apoptotic cells due to the presence of an intact plasma membrane. In late apoptotic and necrotic cells, the integrity of the plasma and nuclear membranes decreases, allowing PI to pass through the membranes, intercalate into nucleic acids, and display red fluorescence. Unfortunately, we find that conventional Annexin V/ PI protocols lead to a significant number of false positive events (up to 40%), which are associated with PI staining of RNA within the cytoplasmic compartment. Primary cells and cell lines in a broad range of animal models are affected, with large cells (nuclear: cytoplasmic ratios <0.5) showing the highest occurrence. Herein, we demonstrate a modified Annexin V/ PI method that provides a significant improvement for assessment of cell death compared to conventional methods. This protocol takes advantage of changes in cellular permeability during cell fixing to promote entry of RNase A into cells following staining. Both the timing and concentration of RNase A have been optimized for removal of cytoplasmic RNA. The result is a significant improvement over conventional Annexin V/ PI protocols (< 5% events with cytoplasmic PI staining). PMID- 21540826 TI - Transcriptome analysis of single cells. AB - Many gene expression analysis techniques rely on material isolated from heterogeneous populations of cells from tissue homogenates or cells in culture. In the case of the brain, regions such as the hippocampus contain a complex arrangement of different cell types, each with distinct mRNA profiles. The ability to harvest single cells allows for a more in depth investigation into the molecular differences between and within cell populations. We describe a simple and rapid method for harvesting cells for further processing. Pipettes often used in electrophysiology are utilized to isolate (using aspiration) a cell of interest and conveniently deposit it into an Eppendorf tube for further processing with any number of molecular biology techniques. Our protocol can be modified for the harvest of dendrites from cell culture or even individual cells from acute slices. We also describe the aRNA amplification method as a major downstream application of single cell isolations. This method was developed previously by our lab as an alternative to other gene expression analysis techniques such as reverse-transcription or real-time polymerase chain reaction (PCR). This technique provides for linear amplification of the polyadenylated RNA beginning with only femtograms of material and resulting in microgram amounts of antisense RNA. The linearly amplified material provides a more accurate estimation than PCR exponential amplification of the relative abundance of components of the transcriptome of the isolated cell. The basic procedure consists of two rounds of amplification. Briefly, a T7 RNA polymerase promoter site is incorporated into double stranded cDNA created from the mRNA transcripts. An overnight in vitro transcription (IVT) reaction is then performed in which T7 RNA polymerase produces many antisense transcripts from the double stranded cDNA. The second round repeats this process but with some technical differences since the starting material is antisense RNA. It is standard to repeat the second round, resulting in three rounds of amplification. Often, the third round in vitro transcription reaction is performed using biotinylated nucleoside triphosphates so that the antisense RNA produced can be hybridized and detected on a microarray. PMID- 21540827 TI - An optic nerve crush injury murine model to study retinal ganglion cell survival. AB - Injury to the optic nerve can lead to axonal degeneration, followed by a gradual death of retinal ganglion cells (RGCs), which results in irreversible vision loss. Examples of such diseases in human include traumatic optic neuropathy and optic nerve degeneration in glaucoma. It is characterized by typical changes in the optic nerve head, progressive optic nerve degeneration, and loss of retinal ganglion cells, if uncontrolled, leading to vision loss and blindness. The optic nerve crush (ONC) injury mouse model is an important experimental disease model for traumatic optic neuropathy, glaucoma, etc. In this model, the crush injury to the optic nerve leads to gradual retinal ganglion cells apoptosis. This disease model can be used to study the general processes and mechanisms of neuronal death and survival, which is essential for the development of therapeutic measures. In addition, pharmacological and molecular approaches can be used in this model to identify and test potential therapeutic reagents to treat different types of optic neuropathy. Here, we provide a step by step demonstration of (I) Baseline retrograde labeling of retinal ganglion cells (RGCs) at day 1, (II) Optic nerve crush injury at day 4, (III) Harvest the retinae and analyze RGC survival at day 11, and (IV) Representative result. PMID- 21540828 TI - Detection of post-translational modifications on native intact nucleosomes by ELISA. AB - The genome of eukaryotes exists as chromatin which contains both DNA and proteins. The fundamental unit of chromatin is the nucleosome, which contains 146 base pairs of DNA associated with two each of histones H2A, H2B, H3, and H4. The N-terminal tails of histones are rich in lysine and arginine and are modified post-transcriptionally by acetylation, methylation, and other post-translational modifications (PTMs). The PTM configuration of nucleosomes can affect the transcriptional activity of associated DNA, thus providing a mode of gene regulation that is epigenetic in nature. We developed a method called nucleosome ELISA (NU-ELISA) to quantitatively determine global PTM signatures of nucleosomes extracted from cells. NU-ELISA is more sensitive and quantitative than western blotting, and is useful to interrogate the epiproteomic state of specific cell types. This video journal article shows detailed procedures to perform NU-ELISA analysis. PMID- 21540829 TI - Lipid vesicle-mediated affinity chromatography using magnetic activated cell sorting (LIMACS): a novel method to analyze protein-lipid interaction. AB - The analysis of lipid protein interaction is difficult because lipids are embedded in cell membranes and therefore, inaccessible to most purification procedures. As an alternative, lipids can be coated on flat surfaces as used for lipid ELISA and Plasmon resonance spectroscopy. However, surface coating lipids do not form microdomain structures, which may be important for the lipid binding properties. Further, these methods do not allow for the purification of larger amounts of proteins binding to their target lipids. To overcome these limitations of testing lipid protein interaction and to purify lipid binding proteins we developed a novel method termed lipid vesicle-mediated affinity chromatography using magnetic-activated cell sorting (LIMACS). In this method, lipid vesicles are prepared with the target lipid and phosphatidylserine as the anchor lipid for Annexin V MACS. Phosphatidylserine is a ubiquitous cell membrane phospholipid that shows high affinity to the protein Annexin V. Using magnetic beads conjugated to Annexin V the phosphatidylserine-containing lipid vesicles will bind to the magnetic beads. When the lipid vesicles are incubated with a cell lysate the protein binding to the target lipid will also be bound to the beads and can be co-purified using MACS. This method can also be used to test if recombinant proteins reconstitute a protein complex binding to the target lipid. We have used this method to show the interaction of atypical PKC (aPKC) with the sphingolipid ceramide and to co-purify prostate apoptosis response 4 (PAR-4), a protein binding to ceramide-associated aPKC. We have also used this method for the reconstitution of a ceramide-associated complex of recombinant aPKC with the cell polarity-related proteins Par6 and Cdc42. Since lipid vesicles can be prepared with a variety of sphingo- or phospholipids, LIMACS offers a versatile test for lipid-protein interaction in a lipid environment that resembles closely that of the cell membrane. Additional lipid protein complexes can be identified using proteomics analysis of lipid binding protein co-purified with the lipid vesicles. PMID- 21540830 TI - Socioeconomic status and weight gain in early infancy. AB - CONTEXT: The association between low socioeconomic status (SES) and childhood obesity foreshadows lifelong inequalities in health. Insight into the causal mechanisms linking childhood adversity to long-term health could be provided by discovering when the negative SES gradient in weight emerges and what early life experiences are associated with it. OBJECTIVE: SES differences in infant weight gain in the first 3 months of life were examined, and contributions of parental body mass index, maternal smoking and feeding method to this association were assessed. DESIGN: Observational study using longitudinal weight data from 2402 families taking part in the Gemini Study; a twin birth cohort recruited from all twin births between March and December 2007 in England and Wales. OUTCOME MEASURES: Infant weights at birth and 3 months converted to standard deviation scores (SDS), change in weight SDS and rapid growth. SES was indexed by occupation and maternal education. RESULTS: There were no SES differences in birth weight, but lower SES was associated with higher 3-month weight, greater change in weight and a higher prevalence of rapid growth (all P < 0.01), with graded associations across levels of SES. Including parental overweight or smoking in pregnancy in the regression model did not affect the association between SES and weight gain, but including feeding method attenuated the SES effect on weight gain by at least 62% and rendered it nonsignificant. CONCLUSION: The foundations for lifelong socioeconomic inequalities in obesity risk may be laid in early infancy, with infant-feeding practices having a part in the diverging weight trajectories. PMID- 21540831 TI - Dietary fat intake and polymorphisms at the PPARG locus modulate BMI and type 2 diabetes risk in the D.E.S.I.R. prospective study. AB - CONTEXT: Fat-rich diets are involved in many disorders such as obesity and type 2 diabetes (T2D). The Pro12Ala variant of peroxisome proliferator-activated receptor-gamma (PPARgamma) is known to modulate body mass index (BMI) and T2D risk. OBJECTIVE: Our aim was to study the interaction effect between PPARgamma gene (PPARG) polymorphisms Pro12Ala and 1431C>T and fat intake on incident T2D and BMI in a 9-year prospective cohort drawn from the French general population, the D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study (n=4676). METHODS: Nutritional intake was assessed by a food frequency self-questionnaire completed by each participant. Statistical analyses included logistic regression, analysis of covariance and haplotype analysis, with adjustment for confounding variables. RESULTS: A high fat consumption (the third sex-specific tertile of fat intake, as a percentage of energy intake) was associated with an increased T2D risk among ProPro and CC homozygotes (P(interaction)=0.05, odds ratio (OR) (95% confidence interval (95% CI))=1.73 (1.19-2.52) P=0.004 and OR=1.85 (1.27-2.71) P=0.001, respectively) but not in Ala and T carriers. There was a significant interaction effect between Pro12Ala and 1431C>T on BMI (P(interaction)=0.004); Ala was associated with lower BMI in CC homozygotes and with higher BMI in T carriers while the opposite was found for ProPro. There was also an interaction effect between Pro12Ala and dietary fat intake on BMI (P(interaction)=0.02); AlaAla individuals had a higher BMI than Pro carriers among high fat consumers (27.1 +/- 1.0 versus 24.9 +/- 0.1 for AlaAla and Pro+, respectively). There was no interaction effect between the 1431C>T single-nucleotide polymorphism and fat intake on BMI. CONCLUSION: Our results indicate strong genetic and nutritional interaction effects on BMI and T2D risk at the PPARG locus in a general population. PMID- 21540832 TI - Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control. AB - OBJECTIVE: Adverse effects of obesity on glucose homeostasis are linked to low grade adipose tissue inflammation and accumulation of lipids in non-adipose tissues. The goal of this study was to evaluate the role of adipose tissue plasticity in a less severe deterioration of glucose homeostasis in females compared with males during the course of high-fat (HF) feeding in mice. DESIGN: Mice of the C57BL/6N strain were fed either a chow or obesogenic HF diet for up to 35 weeks after weaning. Metabolic markers and hormones in plasma, glucose homeostasis, adipocyte size and inflammatory status of gonadal (gWAT) and subcutaneous (scWAT) adipose depots and liver steatosis were evaluated at 15 and 35 weeks of HF feeding. RESULTS: HF-fed males were heavier than females until week ~20, after which the body weights stabilized at a similar level (55-58 g) in both sexes. Greater weight gain and fat accumulation in females were associated with larger adipocytes in gWAT and scWAT at week 35. Although adipose tissue macrophage infiltration was in general less frequent in scWAT, it was reduced in both fat depots of female as compared with male mice; however, the expression of inflammatory markers in gWAT was similar in both sexes at week 35. In females, later onset of the impairment of glucose homeostasis and better insulin sensitivity were associated with higher plasma levels of adiponectin (weeks 0, 15 and 35) and reduced hepatosteatosis (weeks 15 and 35). CONCLUSIONS: Compared with males, female mice demonstrate increased capacity for adipocyte enlargement in response to a long-term HF feeding, which is associated with reduced adipose tissue macrophage infiltration and lower fat deposition in the liver, and with better insulin sensitivity. Our data suggest that adipose tissue expandability linked to adiponectin secretion might have a role in the sex differences observed in obesity-associated metabolic disorders. PMID- 21540833 TI - Novel genes and cellular pathways related to infection with adenovirus-36 as an obesity agent in human mesenchymal stem cells. AB - OBJECTIVE: The objective of this study was to investigate the molecular mechanisms underlying adenovirus-36 (Ad-36)-induced obesity by the identification of novel genes and cellular pathways. DESIGN: Viral growth, intracellular lipid accumulation and gene expression profiles were determined in human mesenchymal stem cells (hMSCs) infected with Ad-36 or Ad-2. A microarray assay and gene set enrichment analysis (GSEA) were performed to assess alterations in global gene expression profiles. RESULTS: Ad-36, but not Ad-2, induced lipid accumulation and upregulated adipogenesis-related genes. There was no difference in viral growth between Ad-36 infection and Ad-2 infection in hMSCs. GSEA revealed that Ad-36 infection was more frequently associated with activation of novel pathways, including the PPAR-gamma signaling pathway, and inflammation compared with Ad-2 infection, raising the possibility that these pathways may be key regulators of Ad-36-induced adipogenesis. CONCLUSION: This study may help foster a better understanding of the roles of several cellular factors in Ad-36-induced obesity. PMID- 21540834 TI - AT1R-CB1R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II. AB - The mechanism of G protein-coupled receptor (GPCR) signal integration is controversial. While GPCR assembly into hetero-oligomers facilitates signal integration of different receptor types, cross-talk between Galphai- and Galphaq coupled receptors is often thought to be oligomerization independent. In this study, we examined the mechanism of signal integration between the Galphai coupled type I cannabinoid receptor (CB(1)R) and the Galphaq-coupled AT1R. We find that these two receptors functionally interact, resulting in the potentiation of AT1R signalling and coupling of AT1R to multiple G proteins. Importantly, using several methods, that is, co-immunoprecipitation and resonance energy transfer assays, as well as receptor- and heteromer-selective antibodies, we show that AT1R and CB(1)R form receptor heteromers. We examined the physiological relevance of this interaction in hepatic stellate cells from ethanol-administered rats in which CB(1)R is upregulated. We found a significant upregulation of AT1R-CB(1)R heteromers and enhancement of angiotensin II-mediated signalling, as compared with cells from control animals. Moreover, blocking CB(1)R activity prevented angiotensin II-mediated mitogenic signalling and profibrogenic gene expression. These results provide a molecular basis for the pivotal role of heteromer-dependent signal integration in pathology. PMID- 21540835 TI - Eed/Sox2 regulatory loop controls ES cell self-renewal through histone methylation and acetylation. AB - Transcription factors and epigenetic modulators are involved in the maintenance of self-renewal in embryonic stem (ES) cells. Here, we demonstrate the existence of a regulatory loop in ES cells between Sox2, an indispensable transcription factor for self-renewal, and embryonic ectoderm development (Eed), an epigenetic modulator regulating histone methylation. We found that Sox2 and Eed positively regulate each other's expression. Interestingly, Sox2 overexpression suppressed the induction of differentiation-associated genes in Eed-deficient ES cells without restoring histone methylation. This Sox2-mediated suppression was prevented by knockdown of the histone acetyltransferase (HAT), Tip60 or Elp3, and Sox2 stimulated expression of these HATs. Furthermore, forced expression of either HAT resulted in repression of differentiation-associated genes in Eed deficient cells. These results suggest that Sox2 overcame the phenotype of Eed deficient ES cells by promoting histone acetylation. We also found that knockout of Eed and knockdown of these HATs synergistically enhanced the upregulation of differentiation-associated genes in ES cells. Taken together, our results suggest that the Eed/Sox2 regulatory loop contributes to the maintenance of self-renewal in ES cells by controlling histone methylation and acetylation. PMID- 21540836 TI - Recognition and suppression of transfected plasmids by protein ZNF511-PRAP1, a potential molecular barrier to transgene expression. AB - Nonviral vectors present considerable advantages over viral counterparts in gene transfer. However, the poor expression efficiency of the transfected genes poses a challenge for their use in gene therapy, primarily due to the inability of these vectors to overcome various barriers, including the biological barriers. Here, we report that ZNF511-PRAP1 may be involved in the recognition and inactivation of transfected plasmids. ZNF511-PRAP1 is induced by transfection of plasmid DNA and suppresses the transcription of transfected plasmids. It binds directly to the p21 promoter in transfected plasmids but not the endogenous counterpart. Similarly, ZNF511-PRAP1 suppresses the expression of the green fluorescent protein reporter gene on transiently transfected plasmids but not an integrated red fluorescence reporter gene with the same cytomegalovirus (CMV) promoter. Therefore, ZNF511-PRAP1 is able to differentiate between exogenous/nonintegrated and endogenous/integrated DNA. The suppression by ZNF511 PRAP1 is independent of DNA methylation and can be abolished by trichostatin A (TSA) treatment and knockdown of HDAC2 and/or ZNF511-PRAP1. Furthermore, ZNF511 PRAP1 interacts directly with HDAC2. Our results revealed that transfected plasmids are recognized by ZNF511-PRAP1 and suppressed by a repressor complex comprising ZNF511-PRAP1 and HDAC2 and suggest that ZNF511-PRAP1 could play a role as a potential molecular barrier in nonviral transgene expression. PMID- 21540838 TI - Travelling-wave resonant four-wave mixing breaks the limits of cavity-enhanced all-optical wavelength conversion. AB - Wave mixing inside optical resonators, while experiencing a large enhancement of the nonlinear interaction efficiency, suffers from strong bandwidth constraints, preventing its practical exploitation for processing broad-band signals. Here we show that such limits are overcome by the new concept of travelling-wave resonant four-wave mixing (FWM). This approach combines the efficiency enhancement provided by resonant propagation with a wide-band conversion process. Compared with conventional FWM in bare waveguides, it exhibits higher robustness against chromatic dispersion and propagation loss, while preserving transparency to modulation formats. Travelling-wave resonant FWM has been demonstrated in silicon coupled ring resonators and was exploited to realize a 630-MUm-long wavelength converter operating over a wavelength range wider than 60 nm and with 28-dB gain with respect to a bare waveguide of the same physical length. Full compatibility of the travelling-wave resonant FWM with optical signal processing applications has been demonstrated through signal retiming and reshaping at 10 Gb s(-1). PMID- 21540837 TI - Stem cell gene therapy for fanconi anemia: report from the 1st international Fanconi anemia gene therapy working group meeting. AB - Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA. PMID- 21540839 TI - Two-dimensional enzyme diffusion in laterally confined DNA monolayers. AB - Addressing the effects of confinement and crowding on biomolecular function may provide insight into molecular mechanisms within living organisms, and may promote the development of novel biotechnology tools. Here, using molecular manipulation methods, we investigate restriction enzyme reactions with double stranded (ds)DNA oligomers confined in relatively large (and flat) brushy matrices of monolayer patches of controlled, variable density. We show that enzymes from the contacting solution cannot access the dsDNAs from the top-matrix interface, and instead enter at the matrix sides to diffuse two-dimensionally in the gap between top- and bottom-matrix interfaces. This is achieved by limiting lateral access with a barrier made of high-density molecules that arrest enzyme diffusion. We put forward, as a possible explanation, a simple and general model that relates these data to the steric hindrance in the matrix, and we briefly discuss the implications and applications of this strikingly new phenomenon. PMID- 21540840 TI - Cooperative material transport during the early stage of sintering. AB - The complex transport processes contributing to sintering are not yet fully understood, partially because in-situ observations of sintering in three dimensions (3D) are very difficult. Here we report a novel experiment in which monocrystalline copper spheres are first marked with microscopic boreholes drilled using a focused ion beam, after which high-resolution synchrotron X-ray tomography is carried out to measure translational, rolling and intrinsic rotation movements of some hundred spheres during sintering. Unlike in 1D and 2D systems, we show that, in 3D, intrinsic rotations are more pronounced than angular rolling rearrangements of the particle centres and become the dominant mechanism of particle movement. We conclude that in addition to the well-known neck growth and centre approach mechanisms, grain boundary sliding caused by the different crystallographic orientations of the individual spheres occurs. PMID- 21540841 TI - Melt migration in basalt columns driven by crystallization-induced pressure gradients. AB - The structure of columnar-jointed lava flows and intrusions has fascinated people for centuries and numerous hypotheses on the mechanisms of formation of columnar jointing have been proposed. In cross-section, weakly developed semicircular internal structures are a near ubiquitous feature of basalt columns. Here we propose a melt-migration model, driven by crystallization and a coeval specific volume decrease inside cooling and solidifying columns, which can explain the observed macroscopic features in columnar-jointed basalts. We study basalts from Hreppholar (Iceland), combining macroscopic observations, detailed petrography, thermodynamic and rheological modelling of crystallization sequences, and Anisotropy of Magnetic Susceptibility (AMS) of late crystallizing phases (that is, titanomagnetite). These are all consistent with our proposed model, which also suggests that melt-migration features are more likely to develop in certain evolved basaltic lava flows (with early saturation of titanomagnetite), and that the redistribution of melt within individual columns can modify cooling processes. PMID- 21540842 TI - Women in science. PMID- 21540843 TI - Focus on stem cells. PMID- 21540844 TI - The transcriptional and signalling networks of pluripotency. AB - Pluripotency and self-renewal are the hallmarks of embryonic stem cells. This state is maintained by a network of transcription factors and is influenced by specific signalling pathways. Current evidence indicates that multiple pluripotent states can exist in vitro. Here we review the recent advances in studying the transcriptional regulatory networks that define pluripotency, and elaborate on how manipulation of signalling pathways can modulate pluripotent states to varying degrees. PMID- 21540845 TI - Harnessing the potential of induced pluripotent stem cells for regenerative medicine. AB - The discovery of methods to convert somatic cells into induced pluripotent stem cells (iPSCs) through expression of a small combination of transcription factors has raised the possibility of producing custom-tailored cells for the study and treatment of numerous diseases. Indeed, iPSCs have already been derived from patients suffering from a large variety of disorders. Here we review recent progress that has been made in establishing iPSC-based disease models, discuss associated technical and biological challenges, and highlight possible solutions to overcome these barriers. We believe that a better understanding of the molecular basis of pluripotency, cellular reprogramming and lineage-specific differentiation of iPSCs is necessary for progress in regenerative medicine. PMID- 21540846 TI - Emerging models and paradigms for stem cell ageing. AB - Ageing is accompanied by a progressive decline in stem cell function, resulting in less effective tissue homeostasis and repair. Here we discuss emerging invertebrate models that provide insights into molecular pathways of age-related stem cell dysfunction in mammals, and we present various paradigms of how stem cell functionality changes with age, including impaired self-renewal and aberrant differentiation potential. PMID- 21540847 TI - Ferreting out stem cells from their niches. AB - Over the past decade, it has become increasingly clear that many tissues have regenerative capabilities. The challenge has been to find the stem cells or progenitors that are responsible for tissue renewal and repair. The revolution in technological advances that permit sophisticated spatial, temporal and kinetic analyses of stem cells has allowed stem cell hunters to ferret out where stem cells live, and to monitor when they come and go from these hiding places. PMID- 21540848 TI - Squishy matter and active chemistry: understanding membrane organization. PMID- 21540850 TI - Mitochondria unite to survive. AB - Starvation of animals or cells triggers autophagic degradation of cell contents to retrieve nutrients, but, paradoxically, mitochondria enlarge. This is now shown to result from inhibition of mitochondrial fission through PKA-mediated phosphorylation of the GTPase DRP1. Elongation of mitochondria optimizes ATP production and spares them from autophagy-mediated destruction. PMID- 21540851 TI - iPS cells forgive but do not forget. AB - Induced pluripotent stem (iPS) cells offer the possibility to generate patient specific cell types for use in regenerative medicine. However, a long-lasting question remains: are iPS and embryonic stem cells equivalent? iPS cells retain a transcriptional memory of their origin, which is now shown to endure with passages and to correlate with defects in the re-establishment of DNA methylation. Both selective pressure and genomic environment may account for these defects. PMID- 21540852 TI - Transforming ER exit: protein secretion meets oncogenesis. AB - COPII-coated vesicles drive protein export from the endoplasmic reticulum (ER), although the regulation of this event, both spatially and kinetically, remains unclear. TFG is now defined as a factor that modulates recruitment of the coat and links ER sequestration of kinases to oncogenesis. PMID- 21540856 TI - Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. AB - CD4(+)CD25(high)CD127(low/-) forkhead box p3 (Foxp3)(+) regulatory T cells (T(reg) cells) possess functional plasticity. Here we describe a higher frequency of T helper type 1 (T(H)1)-like, interferon-gamma (IFN-gamma)-secreting Foxp3(+) T cells in untreated subjects with relapsing remitting multiple sclerosis (RRMS) as compared to healthy control individuals. In subjects treated with IFN-beta, the frequency of IFN-gamma(+)Foxp3(+) T cells is similar to that in healthy control subjects. In vitro, human T(reg) cells from healthy subjects acquire a T(H)1-like phenotype when cultured in the presence of interleukin-12 (IL-12). T(H)1-like T(reg) cells show reduced suppressive activity in vitro, which can partially be reversed by IFN-gamma-specific antibodies or by removal of IL-12. PMID- 21540857 TI - Statistical issues in the use of dynamic allocation methods for balancing baseline covariates. AB - BACKGROUND: The procedure for allocating patients to a treatment arm in comparative clinical trials is frequently chosen with only minor deliberation. This decision may, however, ultimately impact the trial inference, credibility, and even validity of the trial analysis. Cancer researchers are increasingly using dynamic allocation (DA) procedures, which balance treatment arms across baseline prognostic factors for clinical trials in place of historical methods such as simple randomisation or allocation via the random permuted blocks. METHODS: This article gives an overview of DA methods, the statistical controversy that surrounds these procedures, and the potential impact on a clinical trial results. RESULTS: Simple examples are provided to illustrate the use of DA methods and the inferential mistakes, notably on the P-value, if incorrect analyses are performed. INTERPRETATION: The decision about which method to use for allocating patients should be given as much consideration as other aspects of a clinical trial. Appropriately choosing between methods can affect the statistical tests required and what inferences are possible, while affecting the trial credibility. Knowledge of the different methods is key to appropriate decision-making. PMID- 21540858 TI - Occupational exposure to dusts and risk of renal cell carcinoma. AB - BACKGROUND: Occupational exposures to dusts have generally been examined in relation to cancers of the respiratory system and have rarely been examined in relation to other cancers, such as renal cell carcinoma (RCC). Although previous epidemiological studies, though few, have shown certain dusts, such as asbestos, to increase renal cancer risk, the potential for other occupational dust exposures to cause kidney damage and/or cancer may exist. We investigated whether asbestos, as well as 20 other occupational dust exposures, were associated with RCC risk in a large European, multi-center, hospital-based renal case-control study. METHODS: General occupational histories and job-specific questionnaires were reviewed by occupational hygienists for subject-specific information. Odds ratios (ORs) and 95% confidence intervals (95% CIs) between RCC risk and exposures were calculated using unconditional logistic regression. RESULTS: Among participants ever exposed to dusts, significant associations were observed for glass fibres (OR: 2.1; 95% CI: 1.1-3.9), mineral wool fibres (OR: 2.5; 95% CI: 1.2-5.1), and brick dust (OR: 1.5; 95% CI: 1.0-2.4). Significant trends were also observed with exposure duration and cumulative exposure. No association between RCC risk and asbestos exposure was observed. CONCLUSION: Results suggest that increased RCC risk may be associated with occupational exposure to specific types of dusts. Additional studies are needed to replicate and extend findings. PMID- 21540859 TI - Low immunogenicity of seasonal trivalent influenza vaccine among patients receiving docetaxel for a solid tumour: results of a prospective pilot study. AB - BACKGROUND: Patients receiving cytotoxic therapy for solid tumours are at risk of severe influenza. However, few data are available regarding the immunogenical efficacy of influenza vaccine in these patients. METHODS: In this prospective study, 25 patients with breast (n=13) or prostate (n=12) cancer received a trivalent inactivated influenza vaccine along with docetaxel (Taxotere) administration. The influenza virus type A and B antibody titres were measured using haemagglutinin inhibition (Garten et al, 2009) before and 21 days after the vaccination. Seroconversion rate was defined as the percentage of patients with an increase in the serum titres >= 4 after vaccination. RESULTS: Median age was 65 years (range: 33-87 years); 52% were females. Seroconversion rates were low: 28% (95% CI: 23.1-33.3) for H1N1, 8% (95% CI: 7.7-8.3) for H3N2 and 16% (95% CI: 7.7-25) for the B strain. The geometric mean titres ratios were 2.16 (H1N1), 1.3 (H3N2) and 1.58 (B). No serious adverse event (AE) related to the vaccine was reported. All the reported AE were from mild-to-moderate intensity. CONCLUSION: In the patients receiving docetaxel for solid tumours, influenza vaccine triggers an immune response in only one third. Strategies using more immunogenic influenza vaccines must be evaluated in such patients. PMID- 21540860 TI - Prescription patterns of analgesics in the last 3 months of life: a retrospective analysis of 10202 lung cancer patients. AB - BACKGROUND: To describe the prescription patterns of analgesics during the last 3 months of life in lung cancer and to determine the associated factors. METHODS: Data on lung cancer patients (N=10,202) who died during 2000-2008 were extracted from the General Practice Research Database (GPRD). This database records prescriptions of patients received from UK general practices (GP), but not those from non-GP routes. Prescription prevalences were estimated. The associated factors were investigated using log-binomial regression. RESULTS: The overall prescription prevalences were 50.4% (95% confidence interval (CI): 49.4-51.4%) for level 1 (e.g., paracetamol), 34.1% (95% CI: 33.2-35.0%) for level 2 (weak opioids), and 55.5 % (95% CI: 54.5-56.4%) for level 3 analgesics (strong opioids). Prescription prevalence of analgesics of all levels showed an increasing trend over the period 2000-2008 (annual increases range: 1.1-1.5%) but a decreasing trend with age (average decrease per group range: -5.8 to -1.8%). Patients in the older age groups were less likely to be prescribed level 3 analgesics than those in the younger age groups (PR('90+' vs '<50')=0.55 (95% CI: 0.45-0.67); PR('80-89' vs '<50')=0.73 (95% CI: 0.66-0.79); PR('70-79' vs '<50')=0.84 (95% CI: 0.77-0.90)). CONCLUSION: Analgesics have been increasingly prescribed in lung cancer. However, analgesics, especially at level 3, were relatively under-prescribed to people older than 70 years, warranting further investigation. PMID- 21540861 TI - Vatalanib for metastatic gastrointestinal stromal tumour (GIST) resistant to imatinib: final results of a phase II study. AB - BACKGROUND: Vatalanib (PTK787/ZK 222584) inhibits a few tyrosine kinases including KIT, platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs). We report efficacy and safety results of vatalanib in advanced gastrointestinal stromal tumour (GIST) resistant to imatinib or both imatinib and sunitinib. PATIENTS AND METHODS: Forty-five patients whose metastatic GIST had progressed on imatinib were enrolled. Nineteen (42.2%) patients had received also prior sunitinib. Vatalanib 1250 mg was administered orally daily. RESULTS: Eighteen patients (40.0%; 95% confidence interval (CI), 25.7-54.3%) had clinical benefit including 2 (4.4%) confirmed partial remissions (PR; duration, 9.6 and 39.4 months) and 16 (35.6%) stabilised diseases (SDs; median duration, 12.5 months; range, 6.0-35.6+ months). Twelve (46.2%) out of the 26 patients who had received prior imatinib only achieved either PR or SD compared with 6 (31.6%, all SDs) out of the 19 patients who had received prior imatinib and sunitinib (P=0.324). The median time to progression was 5.8 months (95% CI, 2.9-9.5 months) in the subset without prior sunitinib and 3.2 (95% CI, 2.1-6.0) months among those with prior imatinib and sunitinib (P=0.992). Vatalanib was generally well tolerated. CONCLUSION: Vatalanib is active despite its narrow kinome interaction spectrum in patients diagnosed with imatinib-resistant GIST or with imatinib and sunitinib-resistant GIST. PMID- 21540862 TI - Explaining the difference in prognosis between screen-detected and symptomatic breast cancers. AB - BACKGROUND: We analysed 10-year survival data in 19,411 women aged 50-64 years diagnosed with invasive breast cancer in the West Midlands region of the United Kingdom. The aim was to estimate the survival advantage seen in cases that were screen detected compared with those diagnosed symptomatically and attribute this to shifts in prognostic variables or survival differences specific to prognostic categories. METHODS: We studied tumour size, histological grade and the Nottingham Prognostic Index in very narrow categories and investigated the distribution of these prognostic factors within screen-detected and symptomatic tumours. We also adjusted for lead time bias. RESULTS: The unadjusted 10-year breast cancer survival in screen-detected cases was 85.5% and in symptomatic cases 62.8%; after adjustment for lead time bias, survival in the screen-detected cases was 79.3%. Within narrow categories of prognostic variables, survival differences were small, indicating that the majority of the survival advantage of screen detection is due to differences in the distributions of size and node status. CONCLUSION: Our results suggested that a combination of lead time with size and node status in 10 categories explained almost all (97%) of the survival advantage. Only a small proportion remained to be explained by biological differences, manifested as length bias or overdiagnosis. PMID- 21540863 TI - Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases. AB - BACKGROUND: Anti-angiogenic therapy with bevacizumab (an anti-vascular endothelial growth factor (VEGF) antibody) predominantly targets immature blood vessels. Bevacizumab has shown a survival benefit in non-small cell lung carcinoma (NSCLC) and has recently been demonstrated to be safe in patients with brain metastases. However, it is not known whether bevacizumab is effective against brain metastases or whether metastases are representative of their primary in terms of VEGF expression, hypoxia, proliferation and vascular phenotype. The aim of this study was to evaluate these factors in a series of matched primary NSCLCs and brain metastases. METHODS AND RESULTS: Immunohistochemistry showed strong correlation of carbonic anhydrase 9 expression (a marker of hypoxia) in primary and secondary cancers (P=0.0002). However, the proliferation index, VEGF expression, microvessel density and the proportion of mature vessels were discordant between primary and secondary cancers. The mean proportion of mature vessels was 63.2% higher in the brain metastases than the primary tumours (P=0.004). Moreover, the vascular pattern of the primary tumour was not representative of the metastasis. CONCLUSIONS: Brain metastases have a significantly higher proportion of mature vasculature, suggesting that they may be refractory to anti-VEGF therapy. These findings may have implications for clinical trials and biomarker studies evaluating anti-angiogenic agents in brain metastases. PMID- 21540864 TI - Immunohistochemical and molecular analyses of HER2 status in breast cancers are highly concordant and complementary approaches. AB - BACKGROUND: Immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) are currently the most commonly used methods to assess HER2 status. PCR based assays allow quantitative determination of HER2 amplification (Q-PCR) or overexpression (Q-RT-PCR), but are not routinely used. We evaluated the relevance of Q-RT-PCR for HER2 status determination. METHODS: We compared IHC and Q-RT-PCR in 466 breast tumours. In discordant or equivocal cases, five additional methods (IHC with two other antibodies, FISH, silver in situ hybridisation (SISH) and Q PCR) were combined to determine HER2 status. Two cases with HER2 intra-tumour heterogeneity were further explored by allelic profiles analysis and HUMARA clonality determination after microdissection. RESULTS: We observed 97.3% concordance between Q-RT-PCR and non-equivocal IHC. Twelve out of 466 cases (3%) revealed discordances between the two methods. The power of Q-RT-PCR to predict HER2 status (defined by seven methods) was similar to that of IHC. Although rare, some discordances between techniques might be due to HER2 intra-tumour heterogeneity and we report two examples, one tumour containing two distinct clones, another tumour consisting of HER2 amplified and non-amplified subclones. CONCLUSION: Q-RT-PCR and IHC are highly concordant methods for HER2 status assessment, and Q-RT-PCR allows a highly reliable quantitative assessment and could be a useful adjunct to IHC. PMID- 21540865 TI - Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part. AB - BACKGROUND: Novel therapies are needed to improve the poor prognosis of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN). METHODS: ADVANTAGE is a phase I/II, multicentre study evaluating the integrin inhibitor cilengitide combined with cetuximab and platinum-based chemotherapy in patients with recurrent and/or metastatic SCCHN. The phase I part tested cilengitide (500, 1000 and 2000 mg) twice weekly with standard doses of cetuximab, cisplatin and 5-fluorouracil. RESULTS: Ten patients (9 male, 1 female; median 56 years old) were included in the phase I part. No dose-limiting toxicities (DLTs: grade 3/4 toxicities in the first 3 weeks as defined per protocol) or deaths occurred. The most common adverse events (AEs) were constipation, rash, nausea, anorexia and fatigue. Cilengitide-related grade 3/4 AEs, all of which occurred after the DLT observation period, were anaemia, angioedema, asthenia, mucosal inflammation, nausea and vomiting (one event per category). Best overall tumour response was partial response (PR) for 4 out of 10 patients and stable disease (SD) for 6 out of 10 patients across all cohorts. Disease control rate (complete response, PR and SD) was 100%. CONCLUSION: Cilengitide combined with cetuximab and platinum-based chemotherapy was well tolerated. No DLTs or unexpected AEs were observed. Cilengitide 2000 mg was considered safe and was selected for the subsequent randomised phase II part assessing progression-free survival. PMID- 21540866 TI - A new Speedy/RINGO protein may help regulate male meiosis. PMID- 21540867 TI - An update on penile reconstruction. AB - Penile reconstruction still represents a formidable challenge for the urologist. In this review, the most recent advances in penile reconstruction after trauma, excision of benign and malignant disease and in patients with micropenis, aphallia or female to male gender dysphoria are reported. PMID- 21540869 TI - LM23 is a novel member of the Speedy/Ringo family at the crossroads of life and death of spermatogenic cell. AB - LM23 is a gene specifically expressed in the testis of Rattus norvegicus, as previously reported by our laboratory. The aim of the study is to further investigate the biological function of LM23. Several bioinformatic tools were utilized, including PROSITE and BLAST. To determine the subcellullar localization of LM23, a polyclonal antibody specific for LM23 was generated via the immunization of rabbits. The LM23 gene was cloned from rat testis tissue, and LM23 protein was expressed in Escherichia coli. The biological function of LM23 was analyzed with microarray analysis and immunohistochemistry, using a rat model of LM23 gene knockdown. The results suggested that LM23 belongs to the Speedy/Ringo family. LM23 regulated the G1/S and G2/M transitions of the cell cycle during spermatogenesis. Downregulation of the LM23 gene during spermatogenesis could lead to the activation of both the Fas-FasL pathway and the mitochondrial pathway. These novel findings indicate that LM23 has a diverse array of functions that are important in both the life and death of the spermatogenic cell. PMID- 21540868 TI - Ion channels, phosphorylation and mammalian sperm capacitation. AB - Sexually reproducing animals require an orchestrated communication between spermatozoa and the egg to generate a new individual. Capacitation, a maturational complex phenomenon that occurs in the female reproductive tract, renders spermatozoa capable of binding and fusing with the oocyte, and it is a requirement for mammalian fertilization. Capacitation encompasses plasma membrane reorganization, ion permeability regulation, cholesterol loss and changes in the phosphorylation state of many proteins. Novel tools to study sperm ion channels, image intracellular ionic changes and proteins with better spatial and temporal resolution, are unraveling how modifications in sperm ion transport and phosphorylation states lead to capacitation. Recent evidence indicates that two parallel pathways regulate phosphorylation events leading to capacitation, one of them requiring activation of protein kinase A and the second one involving inactivation of ser/thr phosphatases. This review examines the involvement of ion transporters and phosphorylation signaling processes needed for spermatozoa to achieve capacitation. Understanding the molecular mechanisms leading to fertilization is central for societies to deal with rising male infertility rates, to develop safe male gamete-based contraceptives and to preserve biodiversity through better assisted fertilization strategies. PMID- 21540870 TI - In vivo magnetization transfer MRI shows dysmyelination in an ischemic mouse model of periventricular leukomalacia. AB - Periventricular leukomalacia, PVL, is the leading cause of cerebral palsy in prematurely born infants, and therefore more effective interventions are required. The objective of this study was to develop an ischemic injury model of PVL in mice and to determine the feasibility of in vivo magnetization transfer (MT) magnetic resonance imaging (MRI) as a potential monitoring tool for the evaluation of disease severity and experimental therapeutics. Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal day 5 (P5); at P60, in vivo T2-weighted (T2w) and MT-MRI were performed and correlated with postmortem histopathology. In vivo T2w MRI showed thinning of the right corpus callosum, but no significant changes in hippocampal and hemispheric volumes. Magnetization transfer MRI revealed significant white matter abnormalities in the bilateral corpus callosum and internal capsule. These quantitative MT-MRI changes correlated highly with postmortem findings of reduced myelin basic protein in bilateral white matter tracts. Ventriculomegaly and persistent astrogliosis were observed on the ligated side, along with evidence of axonopathy and fewer oligodendrocytes in the corpus callosum. We present an ischemia-induced mouse model of PVL, which has pathologic abnormalities resembling autopsy reports in infants with PVL. We further validate in vivo MRI techniques as quantitative monitoring tools that highly correlate with postmortem histopathology. PMID- 21540871 TI - Spatiotemporal characteristics of postischemic hyperperfusion with respect to changes in T1, T2, diffusion, angiography, and blood-brain barrier permeability. AB - The spatiotemporal dynamics of postischemic hyperperfusion (HP) remains incompletely understood. Diffusion, perfusion, T2, T1, angiographic, dynamic susceptibility-contrast magnetic resonance imaging (MRI) and magnetic resonance angiography were acquired longitudinally at multiple time points up to 7 days after stroke in rats subjected to 30-, 60-, and 90-minutes middle cerebral artery occlusion (MCAO). The spatiotemporal dynamics of postischemic HP was analyzed and compared with T1, T2 and blood-brain barrier (BBB) changes. No early HP within 3 hours after recanalization was observed. Late (?12 hours) HP was present in all animals of the 30-minute MCAO group (N=20), half of the animals in the 60-minute MCAO group (N=8), and absent in the 90-minute MCAO group (N=9). Dynamic susceptibility-contrast MRI and magnetic resonance angiography corroborated HP. Hyperperfusion preceded T2 increase in some animals, but HP and T2 changes temporally coincided in others. T2 peaked first at 24 hours whereas HP peaked at 48 hours after occlusion, and HP resolved by day 7 in most animals at which point the arteries became tortuous. Pixel-by-pixel tracking analysis showed that tissue did not infarct (migrated from core or mismatch at 30 minutes to normal at 48 hours) showed normal cerebral blood flow (CBF), whereas infarct tissue (migrated from core or mismatch at 30 minutes to infarct at 48 hours) showed exaggerated CBF, indicating that HP was associated with poor outcome. PMID- 21540872 TI - Cerebral autoregulation in Alzheimer's disease. AB - Cerebral autoregulation aims to stabilize blood flow to the brain during variations in perfusion pressure, thus protecting the brain against the risks of low or high systemic blood pressure. This vital mechanism is severely impaired in the transgenic mouse model of Alzheimer's disease (AD) that abundantly produces amyloid-beta peptide beta(1-42). These observations have been extrapolated to human AD, wherein impairment of autoregulation could have important implications for the clinical management and prevention of AD. Research on cerebral autoregulation in human AD, however, has only recently become available. Contrary to the animal models, preliminary studies suggest that cerebral autoregulation is preserved in patients with AD. Further research is urgently needed to elucidate this discrepancy in the current literature, given the accumulating evidence that implicates cerebrovascular pathology in AD. PMID- 21540873 TI - Effect of dietary fiber intake on breast cancer risk according to estrogen and progesterone receptor status. AB - BACKGROUND/OBJECTIVES: There is few data on the association between dietary fiber intake and estrogen receptor (ER)/progesterone receptor (PR)-defined breast cancer risk. The present study aimed to investigate the associations between total dietary fiber and dietary fiber fractions intake and breast cancer risk by ER and PR status in a hospital-based case-control study among Chinese women. SUBJECTS/METHODS: Four hundred and thirty-eight cases with primary breast cancer were consecutively recruited from June 2007 to August 2008 and frequency matched to 438 controls by age (5-year interval) and residence (rural/urban). A validated food frequency questionnaire was used to assess the dietary intake through a face to-face interview. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence interval (CI) after adjusting for various potential confounders. RESULTS: A statistically significant inverse association was found between total dietary fiber and fiber fractions intake and breast cancer risk. The adjusted ORs (95% CIs) for the highest versus the lowest quartile of intake were 0.31 (0.20-0.47) for total dietary fiber, 0.73 (0.48 1.11) for soy fiber, 0.48 (0.22-0.97) for vegetable fiber and 0.54 (0.31-0.92) for fruit fiber. No association was observed for cereal fiber intake and risk. An inverse association between dietary fiber intake and breast cancer risk was observed in ER+, ER-, PR+, ER+PR+ and ER-PR+ tumors. CONCLUSIONS: Our results suggest that consumption of total dietary fiber and fiber from vegetable and fruit was inversely associated with breast cancer risk. These inverse associations were more prominent in some subtypes of ER and PR breast cancers. PMID- 21540874 TI - Bioavailability of vitamin D2 from UV-B-irradiated button mushrooms in healthy adults deficient in serum 25-hydroxyvitamin D: a randomized controlled trial. AB - BACKGROUND/OBJECTIVES: Mushrooms contain very little or any vitamin D(2) but are abundant in ergosterol, which can be converted into vitamin D(2) by ultraviolet (UV) irradiation. Our objective was to investigate the bioavailability of vitamin D(2) from vitamin D(2)-enhanced mushrooms by UV-B in humans, and comparing it with a vitamin D(2) supplement. SUBJECTS/METHODS: Fresh mushrooms were irradiated with an UV-B dose of 1.5 J/cm(2), increasing vitamin D(2) content from <1 to 491 MUg/100 g and made to an experimental soup. In this 5-week, single-blinded, randomized, placebo-controlled trial, 26 young subjects with serum 25 hydroxyvitamin D (25OHD) <= 50 nmol/l were randomly assigned into three groups ((a) mushroom, (b) supplement and (c) placebo). They received during winter (a) 28,000 IU (700 MUg) vitamin D(2) via the experimental soup, or (b) 28,000 IU vitamin D(2) via a supplement or (c) placebo, respectively. RESULTS: After 2 weeks, serum 25OHD was significantly higher in the mushroom than in the placebo group (P=0.001). The serum 25OHD concentrations in the mushroom and supplement groups rose significantly and similarly over the study period by 3.9 nmol/l (95% confidence interval (95% CI): 2.9, 4.8) and by 4.7 nmol/l per week (95% CI: 3.8, 5.7), respectively. CONCLUSIONS: We are the first to demonstrate in humans that the bioavailability of vitamin D(2) from vitamin D(2)-enhanced button mushrooms via UV-B irradiation was effective in improving vitamin D status and not different to a vitamin D(2) supplement. This trial was registered at http://germanctr.de as DRKS00000195. PMID- 21540875 TI - A case-control study of nutritional factors associated with chronic suppurative otitis media in Yemeni children. AB - BACKGROUND/OBJECTIVES: Undernutrition and chronic suppurative otitis media (CSOM) in children are common in low resource settings, but there are few studies of their interactions. The aim is to evaluate nutritional factors associated with CSOM in Yemeni children. SUBJECTS/METHODS: A case-control study of 75 children with CSOM and 74 healthy controls. Assessment included dietary history, anthropometry, haemoglobin (Hb) and serum analytes zinc (Zn), copper (Cu), selenium (Se), iron, calcium, phosphate (PO(4)) and total 25-hydroxy vitamin D (25(OH)D). RESULTS: Cases had lower mean Z-scores for weight-for-age, weight-for height, body mass index and mid-upper arm circumference (MUAC) (all P<0.05), and lower mean concentrations of serum Zn (P=0.032), Se (P<0.001) and calcium adjusted for albumin (P=0.026). Age-adjusted Hb and iron biomarkers did not differ between cases and controls. There was high prevalence of low serum Zn concentration (>= 90%) and vitamin D deficiency in both cases (80%) and controls (96%). Duration of ear discharge was negatively correlated with total 25(OH)D (P=0.028), calcium adjusted for albumin (P<0.001), PO(4) (P=0.002), transferrin receptor/log ferritin ratio (P<0.001) and Cu (P<0.001), and positively correlated with child age and MUAC (both P<0.001). CONCLUSIONS: Children with CSOM were more undernourished than controls with lower mean serum Zn, Se and calcium concentrations. Vitamin D-deficient and iron-replete children had longer duration of infection, although this association was lost with age adjustment. Trials evaluating specific micronutrients are required in order to investigate specific nutrient-infection interactions in CSOM. PMID- 21540876 TI - A randomised trial to investigate the effects of acute consumption of a blackcurrant juice drink on markers of vascular reactivity and bioavailability of anthocyanins in human subjects. AB - BACKGROUND/OBJECTIVES: To study the bioavailability of anthocyanins and the effects of a 20% blackcurrant juice drink on vascular reactivity, plasma antioxidant status and other cardiovascular disease risk markers. SUBJECTS/METHODS: The study was a randomised, cross-over, double-blind, placebo controlled acute meal study. Twenty healthy volunteers (11 females and 9 males) were recruited, and all subjects completed the study. Fasted volunteers consumed a 20% blackcurrant juice drink (250 ml) or a control drink following a low flavonoid diet for the previous 72 h. Vascular reactivity was assessed at baseline and 120 min after juice consumption by laser Doppler imaging (LDI). Plasma and urine samples were collected periodically over an 8-h period for analysis, with a final urine sample collected at 24 h. The cross-over was performed after a 4-week washout. RESULTS: There were no significant effects of the 20% blackcurrant juice drink on acute measures of vascular reactivity, biomarkers of endothelial function or lipid risk factors. Consumption of the test juice caused increases in plasma vitamin C (P=0.006), and urinary anthocyanins (P<0.001). Delphinidin-3-rutinoside and cyanidin-3-rutinoside were the main anthocyanins excreted in urine with delphinidin-3-glucoside also detected. The yield of anthocyanins in urine was 0.021+/-0.003% of the dietary intake of delphinidin glycosides and 0.009+/-0.002% of the dietary intake of cyanidin glycosides. CONCLUSIONS: The juice consumption did not have a significant effect on vascular reactivity. Anthocyanins were present at low concentrations in the urine, and microbial metabolites of flavonoids were detected in plasma after juice consumption. PMID- 21540877 TI - Nutrient profiling and food label claims: evaluation of dairy products in three major European countries. AB - BACKGROUND/OBJECTIVES: This study reviews commercially available dairy products with nutrition or health-related on-pack communication against selected nutrient profiling models. It aims to provide guidance on the model characteristics required to appropriately categorise products into those that are suitable for carrying claims, versus those whose overall nutritional composition does not support such product communication. SUBJECTS/METHODS: More than 300 dairy products carrying claims were identified in Germany, France and the UK and evaluated against six existing nutrient profiling models. All models were assessed regarding their underlying principles, generated results and inter-model agreement levels. RESULTS: In most cases, products failed the criteria of a given model because of too high levels of total fat, saturated fatty acids, sugars and/ or sodium. The Swedish Keyhole and the Smart Choices Program were the most restrictive models and showed the highest level of agreement. In general, the application of nutrient profiles helped to select products with significantly lower average levels of nutrients that are linked to chronic diseases when consumed in excess. However, calcium levels were also highly impacted in some cases. CONCLUSIONS: A nutrient profiling model that targets saturated fatty acids, sugars and sodium can meaningfully and comprehensively identify dairy products with a favourable nutritional composition. However, thresholds have to be set carefully to not reduce the average calcium contribution of the category. The use of separate criteria for cheeses and other dairy products seems necessary to take into account intrinsic compositional differences. PMID- 21540878 TI - Transcription by RNA polymerase III: more complex than we thought. AB - RNA polymerase (Pol) III is highly specialized for the production of short non coding RNAs. Once considered to be under relatively simple controls, recent studies using chromatin immunoprecipitation followed by sequencing (ChIP-seq) have revealed unexpected levels of complexity for Pol III regulation, including substantial cell-type selectivity and intriguing overlap with Pol II transcription. Here I describe these novel insights and consider their implications and the questions that remain. PMID- 21540879 TI - The case for locus-specific databases. AB - Locus-specific databases are the most useful repositories of the sequence information underlying medical genetic conditions and, for this reason, they need our continued support. PMID- 21540880 TI - Evolutionary genomics: fission yeast compared and contrasted. PMID- 21540881 TI - Unlocking SOAR releases STIM. AB - A crucial component of the receptor-evoked Ca(2+) signal is Ca(2+) influx mediated by the store-operated Ca(2+) channels (SOCs). The molecular makeup of one SOC is the endoplasmic reticulum (ER) Ca(2+) sensor STIM1 and the pore forming Orai1. Ca(2+) release from the ER leads to co-clustering of STIM1 and Orai1 to activate Orai1. The short STIM1 SOAR/CAD domain (STIM1 Orai1-activating region/CRAC-activating domain), which has two coiledcoil (C-C) domains, interacts with the Orai1 C terminus C-C domain to activate the channel. How the function of SOAR is regulated is not known. Korzeniowski et al (2010) and Muik et al (2011; this issue) now identified an autoinhibitory domain in STIM1 that occludes SOAR. Release of SOAR involves a conformational transition that is aided by the Orai1 C C domain. PMID- 21540882 TI - Interkinetic nuclear migration: cell cycle on the move. AB - Interkinetic nuclear migration (INM) is a common feature of developing neuroepithelia, consisting of the periodic movement of the cell nucleus in phase with cell-cycle progression. In this issue of The EMBO Journal, Kosodo et al provide a first molecular mechanism to couple nuclear migration and cell cycle: the microtubule-associated protein Tpx2 redistributes from the nucleus to the apical process during the S-G2 transition, modulating microtubule organization to promote apical nuclear migration. PMID- 21540884 TI - Clinical utility gene card for: fragile X mental retardation syndrome, fragile X associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. PMID- 21540885 TI - A unified approach to the estimation and interpretation of resistance costs in plants. AB - Plants exhibit a number of adaptive defence traits that endow resistance to past and current abiotic and biotic stresses. It is generally accepted that these adaptations will incur a cost when plants are not challenged by the stress to which they have become adapted--the so-called 'cost of adaptation'. The need to minimise or account for allelic variation at other fitness-related loci (genetic background control) is frequently overlooked when assessing resistance costs associated with plant defence traits. We provide a synthesis of the various experimental protocols that accomplish this essential requirement. We also differentiate those methods that enable the identification of the trait-specific or mechanistic basis of costs (direct methods) from those that provide an estimate of the impact of costs by examining the evolutionary trajectories of resistance allele frequencies at the population level (indirect methods). The advantages and disadvantages for each proposed experimental design are discussed. We conclude that plant resistance systems provide an ideal model to address fundamental questions about the cost of adaptation to stress. We also propose some ways to expand the scope of future studies for further fundamental and applied insight into the significance of adaptation costs. PMID- 21540886 TI - Spatial and seasonal distribution of aerosol chemical components in New York City: (1) Incineration, coal combustion, and biomass burning. AB - We describe spatial and temporal patterns of fine particulate matter (PM(2.5)) and of 12 of its constituent chemical elements commonly observed in measurements at residential locations in New York City (NYC). These elements, that is, Ni, V, As, Se, S, Cl, Na, K, Pb, Cu, Zn, and Mn, had significant spatial and temporal variability at 10 PM(2.5) sampling locations during our winter and summer sampling campaigns. By grouping the elements into traditional source apportionment categories, we show that specific chemical components of PM(2.5) considered to have a common source category, such as As and Se for coal combustion, do not always follow the same temporal or spatial pattern. PM(2.5) mass had only limited spatial variability and a slight summertime concentration enhancement. Measurements at residential locations were, on average, consistent with EPA sampling network measurements, although we found that during times of low regional concentration, EPA measurements underestimated the PM(2.5) concentration at residential locations. These results have implications for improved understanding of exposures to specific sources of PM(2.5), and raise some concerns about source profiles used in source-receptor modeling tracer input selection. PMID- 21540887 TI - The influence of human and environmental exposure factors on personal NO(2) exposures. AB - The US Environmental Protection Agency's (US EPA) Detroit Exposure and Aerosol Research Study (DEARS) deployed a total of over 2000 nitrogen dioxide, NO(2,) passive monitors during 3 years of field data collections. These 24-h based personal, residential outdoor and community-based measurements allowed for the investigation of NO(2) spatial, temporal, human and environmental factors. The relationships between personal exposures to NO(2) and the factors that influence the relationship with community-based measurements were of interest. Survey data from 136 participants were integrated with exposure findings to allow for mixed model effect analyses. Ultimately, 50 individual factors were selected for examination. NO(2) analyses revealed that season, exposure to environmental tobacco smoke and residential gas appliances were strong influencing factors. Only modest associations between community-based measures of nitrogen dioxide and personal exposures impacted by various exposure factors for heating (r=0.44) or non-heating seasons (r=0.34) were observed, indicating that use of ambient-based monitoring as a surrogate of personal exposure might result in sizeable exposure misclassification. PMID- 21540889 TI - RAF-isotype switching: from B to C through PDE. PMID- 21540893 TI - Physician liability: electronic medical records. PMID- 21540894 TI - Abdomino-phrenic dyssynergia in patients with abdominal bloating and distension. AB - OBJECTIVES: The abdomen normally accommodates intra-abdominal volume increments. Patients complaining of abdominal distension exhibit abnormal accommodation of colonic gas loads (defective contraction and excessive protrusion of the anterior wall). However, abdominal imaging demonstrated diaphragmatic descent during spontaneous episodes of bloating in patients with functional gut disorders. We aimed to establish the role of the diaphragm in abdominal distension. METHODS: In 20 patients complaining of abdominal bloating and 15 healthy subjects, we increased the volume of the abdominal cavity with a colonic gas load, while measuring abdominal girth and electromyographic activity of the anterior abdominal muscles and of the diaphragm. RESULTS: In healthy subjects, the colonic gas load increased girth, relaxed the diaphragm, and increased anterior wall tone. With the same gas load, patients developed significantly more abdominal distension; this was associated with paradoxical contraction of the diaphragm and relaxation of the internal oblique muscle. CONCLUSIONS: In this experimental provocation model, abnormal accommodation of the diaphragm is involved in abdominal distension. PMID- 21540891 TI - Constructing and decoding unconventional ubiquitin chains. AB - One of the most notable discoveries in the ubiquitin system during the past decade is the extensive use of diverse chain linkages to control signaling networks. Although the utility of Lys48- and Lys63-linked chains in protein turnover and molecular assembly, respectively, are well known, we are only beginning to understand how unconventional chain linkages are formed on target proteins and how such linkages are decoded by specific binding proteins. In this review, we summarize recent efforts to elucidate the machinery and mechanisms controlling assembly of Lys11-linked and linear (or Met1-linked) ubiquitin chains, and describe current models for how these chain types function in immune signaling and cell-cycle control. PMID- 21540899 TI - Is refractory celiac disease more severe in old Europe? AB - Refractory celiac disease (RCD) is subdivided into two subtypes (RCDI and II), based on a normal or abnormal phenotype of intraepithelial lymphocytes, respectively. RCDII is the most severe form and seems to be more frequently observed in Europe than in the United States. We discussed below the diagnostic criteria of RCDI and RCDII, and the possible factors underlying the more severe expression of celiac disease in Europe. PMID- 21540900 TI - Pancreatic cancer surveillance: learning as we go. AB - The concept of pancreatic cancer prevention through surveillance of high-risk patients has come of age. It is cost-effective to provide surveillance of patients who have a lifetime risk of pancreatic cancer that is >=16%. Studies are currently ongoing that contribute to our understanding of the imaging methodologies that are best suited for surveillance and the best algorithm for the clinical management of patients who are at risk of this highly lethal disease. Long-term outcomes analyses will help shed light on the best management of these patients, as well as a better understanding of the natural history of familial pancreatic cancer. PMID- 21540902 TI - Is the risk of inflammatory bowel disease-related colorectal carcinoma limited? PMID- 21540903 TI - Isotretinoin use and the risk of inflammatory bowel disease. PMID- 21540906 TI - Efficacy of traditional chinese medicine in functional constipation. PMID- 21540907 TI - Ketamine-induced cholangiopathy: a case report. PMID- 21540908 TI - Acute generalized exanthematous pustulosis induced by azathioprine in a patient with ulcerative colitis. PMID- 21540909 TI - The Effects of IL-28B and ITPA polymorphisms on treatment of hepatitis C virus genotype 6. PMID- 21540910 TI - The utility of rectal retroflexion. PMID- 21540911 TI - Interval signet-ring cell adenocarcinoma of the colon: missed or de novo? PMID- 21540916 TI - Double-T metamaterial for parallel and normal transverse electric incident waves. AB - Electric and magnetic hybridized plasmonic modes are obtained by stacking two T shaped resonators. We show that head-to-toe configuration leads to inverse the hybridization. The frequency shift between the resonances is finely controlled by adjusting the gap between the two resonators. A negative refractive index close to -1 is numerically and experimentally demonstrated at 4.3 GHz for TE waves. This left-handed behavior is similar for parallel and normal TE incident wave vectors. The proposed double-T unit cell is well adapted for developing terahertz and IR metamaterials. PMID- 21540917 TI - Crystalline Cr2+:ZnSe/chalcogenide glass composites as active mid-IR materials. AB - We propose new transition metal (TM)-doped ZnSe/As2S3:As2Se3 composite materials for mid-IR fiber lasers. The composites are the suspension of crystalline micro- and nanosized TM2+:ZnSe or TM2+:ZnS powders in chalcogenide glasses with the refraction index matching. Mid-IR room-temperature lasing of Cr2+:ZnSe/As2S3:As2Se3 microcomposite material is demonstrated at the 2.4 MUm wavelength. PMID- 21540918 TI - Second-harmonic optical spectroscopy on split-ring-resonator arrays. AB - Previous second-harmonic-generation experiments on metallic split-ring-resonator arrays have been performed at fixed fundamental laser center frequency. Here, we perform nonlinear optical spectroscopy on a first set of samples, revealing pronounced resonances. Furthermore, to clarify the role of higher-order split ring resonances, we perform additional experiments on a second set of samples in which the fundamental split-ring-resonator resonance frequencies are lithographically tuned, whereas the higher-order resonances are fixed. We find that the higher-order resonances merely reabsorb the second-harmonic generation, revealing the fundamental split-ring resonance as the nonlinear source. PMID- 21540919 TI - Fiber fuse effect in hollow optical fibers. AB - We examined nonlinear fiber fuse effect (FFE) in hollow optical fibers (HOFs) that consist of a central air hole surrounded by a high-index ring core and silica cladding. In contrast to conventional solid-core fibers, the HOF with a hole diameter of 4 MUm showed high threshold power of 4 W, and resulted in unique tadpole-like voids in periodic arrays after the FFE. As the hole diameter increased to 6 MUm, plasma propagation was suppressed within the distance of 1 mm inside of the HOF. Detailed comparisons were made in terms of threshold power, void formation, and penetration length. PMID- 21540920 TI - Acousto-optic-assisted diffuse optical tomography. AB - We introduce and experimentally demonstrate acousto-optic-assisted diffuse optical tomography (DOT) using a holography-based acousto-optic setup. The method is based on probing a scattering medium with a localized acoustical modulation of the phase of the scattered light. The optical properties of the scattering medium are recovered with ultrasound-limited resolution by applying DOT reconstruction methods on a set of the measured intensities of light, modulated at different locations throughout the medium. PMID- 21540921 TI - Fano resonances in dipole-quadrupole plasmon coupling nanorod dimers. AB - We theoretically investigate the plasmon coupling in metallic nanorod dimers. A pronounced dip is found in the extinction spectrum due to plasmonic Fano resonance, which is induced by destructive interference between the bright dipole plasmon of a short nanorod and the dark quadrupole plasmon of a long nanorod. This Fano interference can also be explained as the coupling between the bright and dark modes both supported by the whole dimer. The Fano resonance can be tuned by adjusting the spatial or spectral separation between two nanorods in the dimer. PMID- 21540922 TI - Universal soliton pattern formations in passively mode-locked fiber lasers. AB - We investigate multiple-soliton pattern formations in a figure-of-eight passively mode-locked fiber laser. Operation in the anomalous dispersion regime with a double-clad fiber amplifier allows generation of up to several hundreds of solitons per round trip. We report the observation of remarkable soliton distributions: soliton gas, soliton liquid, soliton polycrystal, and soliton crystal, thus indicating the universality of such complexes. PMID- 21540923 TI - High-sensitivity temperature sensor based on an alcohol-filled photonic crystal fiber loop mirror. AB - A compact temperature sensor based on a fiber loop mirror (FLM) combined with an alcohol-filled high-birefringence photonic crystal fiber (PCF) is proposed and experimentally demonstrated. The output of the FLM is an interference spectrum with many resonant dips, of which the wavelengths are quite sensitive to the change of the refractive index of the filled alcohol for the interference of the FLM. Simulation analysis predicts a high temperature sensitivity, and experimental results show it reaches up to 6.6 nm/ degrees C for the 6.1-cm-long PCF used in the FLM. PMID- 21540924 TI - Photon lifetime in a cavity containing a slow-light medium. AB - We investigate experimentally the lifetime of the photons in a cavity containing a medium exhibiting strong positive dispersion. This intracavity positive dispersion is provided by a metastable helium gas at room temperature in the electromagnetically induced transparency regime, in which light propagates at a group velocity of the order of 104 m.s-1. The results definitely prove that the lifetime of the cavity photons is governed by the group velocity of light in the cavity and not its phase velocity. PMID- 21540925 TI - Room temperature single-frequency output from a diode-pumped Tm,Ho:YAP laser. AB - Single-frequency operation in the range of 2102.45-2102.54 nm and 2130.72-2130.82 nm is demonstrated from a Tm,Ho:YAP laser at room temperature. To our knowledge, this is the first time a room temperature single-frequency Tm,Ho:YAP laser of up to 72.6 mW at 2102.5 nm with Fabry-Perot etalons has been obtained. Regulating the elevation angle of the two etalons, 42.0 mW at 2130.8 nm was obtained. The single-longitudinal-mode laser can be used as a seed laser for coherent wind measurements and differential absorption lidar systems. PMID- 21540926 TI - Highly efficient Yb-doped silica fibers prepared by powder sinter technology. AB - We report on the characteristics of an active fiber with core material made by sintering of Yb-doped silica powders as an alternative to a conventional modified chemical vapor deposition (MCVD) technique. This material provides the possibility to design very large and homogenously rare-earth doped active fiber cores. We have determined a fiber background attenuation of 20 dB/km and measured a slope efficiency of 80%. These values are comparable to established fibers made by MCVD technology. PMID- 21540927 TI - Demultiplexing of OTDM-DPSK signals based on a single semiconductor optical amplifier and optical filtering. AB - We propose and demonstrate the use of a single semiconductor optical amplifier (SOA) and optical filtering to time demultiplex tributaries from an optical time division multiplexing-differential phase shift keying (OTDM-DPSK) signal. The scheme takes advantage of the fact that phase variations added to the target channel by cross-phase modulation from the control signal are effectively subtracted in the differential demodulation scheme employed for DPSK signals. Demultiplexing from 80 to 40 Gbit/s is demonstrated with moderate power penalty using an SOA with recovery time twice as long as the bit period at 80 Gbit/s. Large dynamic ranges for the input power and SOA current are experimentally demonstrated. The scheme is expected to be scalable toward higher bit rates. PMID- 21540928 TI - Symmetry breaking of optical vortices: birth and annihilation of singularities in the evanescent field. AB - The interaction of optical vortices (or phase singularities, or screw dislocations) with ordinary matter is treated with a simple approach. Using the total internal reflection phenomenon and the superposition of four plane waves incident on a material with a refractive index lower than the original propagating medium, we are able to show the birth and annihilation of optical vortices in an evanescent field with curved topological features. Until now, this phenomenon has been explored only in free space propagation. By a suitable tuning process involving the incident angles and the amplitudes of the incident plane waves, it is possible to create unusual topological features of optical vortices in the vicinity of the material. We believe that this work can open new aspects of curved optical vortex manipulation in near-field optics. PMID- 21540929 TI - Lasing action at around 1.9 MUm from an ultrafast laser inscribed Tm-doped glass waveguide. AB - We report optical guiding and laser action at around 1.9 MUm in a Tm3+-doped fluorogermanate glass waveguide fabricated using ultrafast laser inscription. A monolithic laser cavity was constructed by directly butt coupling dielectric mirrors to each facet of the 6.0 mm long Tm3+-doped waveguide. When the waveguide was pumped by a Ti:sapphire laser tuned to 791 nm, laser oscillation was achieved at around 1.91 MUm. This waveguide laser exhibited a maximum slope efficiency of 6% and a maximum output power of 32 mW when pumped with 620 mW of incident laser power. PMID- 21540930 TI - Experimental investigation of harmonic and subharmonic synchronization of 40 GHz mode-locked quantum-dash laser diodes. AB - Synchronization of a 40 GHz quantum-dash mode-locked (ML) Fabry-Perot laser diode with optically injected pulse streams is experimentally studied. Injected signals consist of nonmodulated and modulated trains of 1.6 ps pulses at various repetition rates, ranging from 10 to 160 GHz and 10 to 160 Gbps, respectively. Subharmonic, fundamental, and harmonic synchronization of the ML laser allows retrieval of stable 40 GHz clock pulses featuring a width of 1.8 ps. Frequency components at 10 and 20 GHz do not create any amplitude modulation on the recovered 40 GHz clock pulses when injecting signals at 10 and 20 GHz/Gbps. In addition, external synchronization of the laser with pulse streams at 80 and 160 GHz/Gbps is sustained despite the absence of significant components at or below 40 GHz. PMID- 21540931 TI - Direct generation of 81 nJ pulses and external compression to a subpicosecond regime with a 4.9 MHz chirped-pulse multipass-cavity Cr4+:forsterite oscillator. AB - We report direct generation of 81 nJ chirped pulses from a room-temperature, Kerr lens mode-locked Cr4+:forsterite oscillator operating at 1258 nm. To increase the pulse energy, the pulse repetition rate of the short x-type resonator was lowered from 143 to 4.9 MHz by the addition of a q-preserving multipass cavity, which provided an additional effective optical path length of 59.4 m. The duration of the chirped pulses was around 5.5 ps with a spectral width of 21 nm. The pulses were externally compressed to 607 fs by using a diffraction grating pair. To our knowledge, this is the highest reported pulse energy directly generated from a room-temperature mode-locked Cr4+:forsterite laser. PMID- 21540932 TI - In-band pumped highly efficient Ho:YAG ceramic laser with 21 W output power at 2097 nm. AB - We report on the high-power and high-efficiency operation of a polycrystalline Ho:YAG ceramic laser in-band pumped by a Tm fiber laser at ~1907 nm. Lasing characteristics of a 1.5 at.% and a 2.0 at.% Ho3+-doped YAG ceramic were investigated and compared. Using an output coupler of 6% transmission, over 21.4 W of cw output power at 2097 nm has been generated with the 1.5 at.% doped Ho:YAG ceramic under 35 W of incident pump power, corresponding to an average slope efficiency with respect to the incident pump power of 63.6% and an optical-to optical conversion efficiency of 61.1%. PMID- 21540933 TI - Impact of dispersion on amplitude and frequency noise in a Yb-fiber laser comb. AB - We describe a Yb-fiber-based laser comb, with a focus on the relationship between the net-cavity dispersion and frequency noise on the comb. While tuning the net cavity dispersion from anomalous to normal, we measure the relative intensity noise, offset frequency (f(CEO)) linewidth, and the resulting frequency noise spectrum on the f(CEO). We find that the laser operating at zero net-cavity dispersion has many advantages, including an approximately 100* reduction in free running f(CEO) linewidth and frequency noise power spectral density when compared to the normal-dispersion regime. At the zero-dispersion point, we demonstrate a phase-locked f(CEO) beat with low residual noise. PMID- 21540934 TI - Simple expressions for the maximum omnidirectional bandgap of bilayer photonic crystals. AB - We propose three dimensionless approximate expressions to predict the thickness filling factor, gap center, and gap width of the maximum omnidirectional gap (MODG) for various refractive indices in one-dimensional photonic crystals. These expressions are simple and do not include trigonometric or inverse trigonometric functions. It is easy to obtain the MODG from given refractive indices but also to estimate the refractive indices from the MODG based on the results. PMID- 21540935 TI - Multiple coupling of surface plasmons in quasiperiodic gratings. AB - Whereas periodic gratings enable us to couple light into a surface plasmon polariton only at a specific angle and wavelength, we show here that quasiperiodic gratings enable the coupling of light at multiple wavelengths and angles. The quasiperiodic grating can be designed in a systematic manner using the dual-grid method, thereby enabling us to control the coupling strength and grating dimensions. We verified the method experimentally by efficiently coupling light into a surface plasmon from several different illumination angles using a single quasiperiodic grating. PMID- 21540936 TI - Fifty percent internal slope efficiency femtosecond direct-written Tm3+:ZBLAN waveguide laser. AB - We report a 790 nm pumped, Tm3+ doped ZBLAN glass buried waveguide laser that produces 47 mW at 1880 nm, with a 50% internal slope efficiency and an M2 of 1.7. The waveguide cladding is defined by two overlapping rings created by femtosecond direct-writing of the glass, which results in the formation of a tubular depressed-index-cladding structure, and the laser resonator is defined by external dielectric mirrors. This is, to the best of our knowledge, the most efficient laser created in a glass host via femtosecond waveguide writing. PMID- 21540937 TI - Harmonic mode locking in a sliding-frequency fiber laser. AB - We demonstrate a sliding-frequency mode-locked (SFM) erbium fiber laser generating 20 ps pulses with center wavelengths rapidly sweeping across a spectral range of 50 nm. Excess optical nonlinearity in the laser cavity leads to multipulsing, with a tendency to tight pulse bunching (<3 ns) at the fundamental cavity frequency of 25 MHz. The addition of a parallel optical delay line, with a path difference equal to a rational fraction of the cavity length, distributes the pulses uniformly across the entire cavity and achieves a harmonic SFM up to 1 GHz. The result establishes cavity nonlinearity as a critical design parameter for picosecond wavelength-swept lasers. PMID- 21540938 TI - Two degrees-of-freedom Lloyd-mirror interferometer for superior pattern coverage area. AB - In this study, we have developed a tunable Lloyd-mirror interferometer with two degrees of freedom, in contrast to a traditional system with one degree of freedom. This new Lloyd-mirror interferometer allows an angular rotation of the mirror independently from that of a sample stage, resulting in an increased pattern coverage area with tunable pattern periodicity. Both theoretical and experimental results verify that the tunable characteristic of the modified configuration enhances the nanopatterning capabilities of the Lloyd-mirror interference lithography system especially in achieving greater pattern coverage area for larger pattern periodicities. PMID- 21540940 TI - Numerical characterization of Yb-signal-aided cladding-pumped Er:Yb-codoped fiber amplifiers. AB - In this Letter, high-power cladding-pumped Er:Yb-codoped fiber amplifiers (EYDFAs) coseeded with a Yb-band signal are numerically characterized according to the wavelength and power of the aiding signal, the length of the gain fiber, and the wavelength of the pump. The results show that properly designing these parameters not only helps to suppress the parasitic lasing and improve the pump conversion efficiency but also helps to improve the output power stability of high-power EYDFAs. PMID- 21540939 TI - Numerical simulation of partially coherent broadband optical imaging using the finite-difference time-domain method. AB - Rigorous numerical modeling of optical systems has attracted interest in diverse research areas ranging from biophotonics to photolithography. We report the full vector electromagnetic numerical simulation of a broadband optical imaging system with partially coherent and unpolarized illumination. The scattering of light from the sample is calculated using the finite-difference time-domain (FDTD) numerical method. Geometrical optics principles are applied to the scattered light to obtain the intensity distribution at the image plane. Multilayered object spaces are also supported by our algorithm. For the first time, numerical FDTD calculations are directly compared to and shown to agree well with broadband experimental microscopy results. PMID- 21540941 TI - High-power diode-pumped cryogenically cooled Yb:CaF2 laser with extremely low quantum defect. AB - High-power diode-pumped laser operation at 992-993 nm under a pumping wavelength of 981 of 986 nm is demonstrated with Yb:CaF2 operating at cryogenic temperature (77 K), leading to extremely low quantum defects of 1.2% and 0.7%, respectively. An average output power of 33 W has been produced with an optical efficiency of 35%. This represents, to the best of our knowledge, the best laser performance ever obtained at such low quantum defects on intense laser lines. PMID- 21540942 TI - Flattop focusing with full Poincare beams under low numerical aperture illumination. AB - In this Letter, we propose and experimentally demonstrate the generation of second-order full Poincare beams and its applications in two-dimensional flattop beam shaping with spatially variant polarization under low NA focusing condition. High-quality flattop profiles with steep edge roll-off can be obtained with this technique. The experiment results also demonstrate that flattop profile can be maintained for different input beam sizes by conveniently rotating a half-wave plate. PMID- 21540943 TI - Terahertz generation based on parametric conversion: from saturation of conversion efficiency to back conversion. AB - By stacking alternatively rotated gallium phosphide (GaP) plates, the maximum photon conversion efficiency of 40% for the terahertz (THz) generation based on difference-frequency generation has been achieved. The corresponding peak power generated inside the four GaP plates approaches 4 kW. As the number of plates is increased from four to five, the THz output power is significantly decreased, due to back parametric conversion. PMID- 21540944 TI - GaN-based LEDs surrounded with a two-dimensional nanohole photonic crystal structure for effective laterally guided mode coupling. AB - Traditional implementation of photonic crystals (PhCs) on LED light emission surfaces results in weak coupling of light with the PhCs. Here we introduce a GaN based LED surrounded with a nanohole PhC structure along the mesa edges. The laterally guided modes in the epi-structure can be effectively coupled with the two-dimensional periodic structure. The proposed structure results in the improvement of LED light extraction and provides flexibility of radiation directionality control. PMID- 21540945 TI - Efficient generation of Xe K-shell x rays by high-contrast interaction with submicrometer clusters. AB - The interaction between a 25 TW laser and Xe clusters at a peak intensity of 1 * 1019 W/cm2 has been investigated. Xe K-shell x rays, whose energies are approximately 30 keV, were clearly observed with a hard x-ray CCD at 3.4 MPa. Moreover, we studied the yield of the Xe K-shell x rays by changing the pulse duration of the laser at a constant laser energy and found that the pulse duration of 40 fs is better than that of 300 fs for generating Xe K-shell x rays. PMID- 21540946 TI - Propagation properties of an optical vortex carried by an Airy beam: experimental implementation. AB - In this Letter, we experimentally studied the propagation dynamics of Airy beams (AiBs) carrying phase singularity or an optical vortex (OV). A 3/2 phase mask encoded with phase singularity was used to generate AiBs and OVs enjoying precise position alignment and compact optical configuration simultaneously. Experimental results showed that the OV deflection velocity was faster than that of the main lobe of the AiB, agreeing with the analytical prediction. Numerical simulation results are also in agreement with the experimental results. Furthermore, OVs with larger topological charges were also studied experimentally with the same approach. PMID- 21540947 TI - Fast extended focused imaging in digital holography using a graphics processing unit. AB - We present a simple and effective method for reconstructing extended focused images in digital holography using a graphics processing unit (GPU). The Fresnel transform method is simplified by an algorithm named fast Fourier transform pruning with frequency shift. Then the pixel size consistency problem is solved by coordinate transformation and combining the subpixel resampling and the fast Fourier transform pruning with frequency shift. With the assistance of the GPU, we implemented an improved parallel version of this method, which obtained about a 300-500-fold speedup compared with central processing unit codes. PMID- 21540948 TI - Rapid programmable/code-length-variable, time-domain bit-by-bit code shifting for high-speed secure optical communication. AB - We propose and experimentally demonstrate a time-domain bit-by-bit code-shifting scheme that can rapidly program ultralong, code-length variable optical code by using only a dispersive element and a high-speed phase modulator for improving information security. The proposed scheme operates in the bit overlap regime and could eliminate the vulnerability of extracting the code by analyzing the fine structure of the time-domain spectral phase encoded signal. It is also intrinsically immune to eavesdropping via conventional power detection and differential-phase-shift-keying (DPSK) demodulation attacks. With this scheme, 10 Gbits/s of return-to-zero-DPSK data secured by bit-by-bit code shifting using up to 1024 chip optical code patterns have been transmitted over 49 km error free. The proposed scheme exhibits the potential for high-data-rate secure optical communication and to realize even one time pad. PMID- 21540949 TI - Plasmonic metamaterial wave retarders in reflection by orthogonally oriented detuned electrical dipoles. AB - We demonstrate that a pair of perpendicular electrical dipolar scatterers resonating at different frequencies can be used as a metamaterial unit cell to construct a nanometer-thin retarder in reflection, designing nanocross and nanobrick plasmonic configurations to function as reflecting quarter-wave plates at ~1520 and 770 nm, respectively. The design is corroborated experimentally with a monolayer of gold nanobricks, transforming linearly polarized incident radiation into circularly polarized radiation at ~780 nm. PMID- 21540950 TI - Proposal for photonic quantization with differential encoding using a phase modulator and delay-line interferometers. AB - A photonic quantization approach to implementing analog-to-digital conversion (ADC) in the optical domain with differential encoding employing a phase modulator and delay-line interferometers (DLIs) is proposed and demonstrated. In the proposed ADC system, the phase-modulated signal is sent to an array of DLIs that have identical time delay difference, but different phase shifts, which are employed to achieve quantization with differential encoding. A proof-of-concept experiment is performed. The quantization of a 10 GHz sinusoidal signal with a bit length of 4 is experimentally demonstrated. PMID- 21540951 TI - Exact solution for the gigantic amplification of ultrashort pulses in counterpumped Raman amplifiers. AB - We exactly solve the initial-boundary value problem of interaction of three waves in the limit when one of these waves is strongly damped. The solution is applied to the characterization of transient effects in Raman amplifiers, with a special emphasis on the possibility of generating Stokes pulses with peak powers that are orders of magnitude higher than the input power of the pump beam. PMID- 21540952 TI - Compact direct space-to-time pulse shaping with a phase-only spatial light modulator. AB - A very compact and innovative pulse shaper is proposed and demonstrated. The standard architecture for pulse shaping that is composed of diffraction gratings associated with an amplitude-phase spatial light modulator (SLM) is replaced by a single phase-only SLM. It acts as a pulse stretcher and as an amplitude and phase modulator at the same time. Preliminary experiments demonstrate the accurate control of amplitude and phase of shaped pulses. PMID- 21540953 TI - Synthesis of structured partially spatially coherent beams. AB - We report on the generation and rapid characterization of structured beams of arbitrary spatial coherence. An experimental setup is introduced capable of generating partially coherent fields by incoherently superposing fully coherent fields. The characterization is performed using the spectral information in the interferogram produced when using a two-dimensional nonredundant array of pinholes. An example of a partially coherent "doughnut" beam is given and proved to be partially coherent. PMID- 21540954 TI - Negative refraction and the spectral filtering of terahertz radiation by a photonic crystal prism. AB - We demonstrate how micromachined photonic crystals can be used to negatively refract terahertz frequency light. The photonic crystals, which are constructed from conventional dielectric materials, manipulate the incident beam via interaction with their photonic bands. Consequently, we show that different components of a broadband beam incident on the structure may be positively or negatively refracted, depending upon its frequency and that the structure can be used as an effective spectral filter of THz radiation. PMID- 21540955 TI - Operation of a Raman laser in bulk silicon. AB - A Raman laser based on a bulk silicon single crystal with 1.127 MUm emission wavelength is demonstrated. The Si crystal with 30 mm length was placed into an external cavity and pumped by a Q-switched Nd:YAG master oscillator power amplifier system. Strong defocusing of the pump and Raman laser beam by free carriers was compensated by an intracavity lens. Raman laser operation with a pulse duration of 2.5 ns was identified by a Raman laser threshold significantly lower than the single-pass stimulated Raman-scattering threshold. Linear absorption losses of the 1.06415 MUm pump radiation are strongly reduced by cooling the Si crystal to a temperature of 10 K. PMID- 21540956 TI - Pilot-based cross-phase modulation compensation for coherent optical orthogonal frequency division multiplexing long-haul optical communications systems. AB - A pilot-based nonlinearity compensator (PB-NLC) is shown in this Letter to be an effective method for compensating cross-phase modulation (XPM) in coherent optical orthogonal frequency division multiplexing (CO-OFDM) systems. An unmodulated pilot tone is transmitted at the center of each OFDM channel to detect phase errors caused by the Kerr effect, which converts intensity fluctuations from all channels to phase errors. The pilots are then used to cancel the XPM phase errors for each OFDM channel at the receiver after each channel's self-phase modulation (SPM) has been compensated, using its intensity waveform to determine its SPM. Numerical simulations of a 58 Gb/s single polarization 2375 km system with inline dispersion compensation show that the signal quality, Q, at the optimal launch power is increased by 2.4 dB if SPM compensation is used before the PB-NLC. This contrasts with only a 0.9 dB improvement if the PB-NLC is used without an SPM compensator for the same link. This shows the PB-NLC can effectively mitigate XPM but not SPM. PMID- 21540957 TI - Proof of concept of directed OR/NOR and AND/NAND logic circuit consisting of two parallel microring resonators. AB - We propose and demonstrate a directed OR/NOR and AND/NAND logic circuit consisting of two parallel microring resonators (MRRs). We use two electrical signals representing the two operands of the logical operation to modulate the two MRRs through the thermo-optic effect, respectively. The final operation results are represented by the output optical signals. Both OR/NOR and AND/NAND operations at 10 kbps are demonstrated. PMID- 21540958 TI - Asymmetric chiral metamaterial circular polarizer based on four U-shaped split ring resonators. AB - An asymmetric chiral metamaterial structure is constructed by using four double layered U-shaped split ring resonators, which are each rotated by 90 degrees with respect to their neighbors. The peculiarity of the suggested design is that the sizes of the electrically and magnetically excited rings are different, which allows for equalizing the orthogonal components of the electric field at the output interface with a 90 degrees phase difference when the periodic structure is illuminated by an x-polarized wave. As a result, left-hand circular polarization and right-hand circular polarization are obtained in transmission at 5.1 GHz and 6.4 GHz, respectively. The experiment results are in good agreement with the numerical results. PMID- 21540959 TI - Extinction coefficient imaging of turbid media using dual structured laser illumination planar imaging. AB - We demonstrate a technique, named dual structured laser illumination planar imaging (SLIPI), capable of acquiring depth-resolved images of the extinction coefficient. This is achieved by first suppressing the multiply scattered light intensity and then measuring the intensity reduction caused by signal attenuation between two laser sheets separated by Deltaz mm. Unlike other methods also able to measure this quantity, the presented approach is based solely on side scattering detection. The main advantages of dual SLIPI is that it accounts for multiple scattering, provides two-dimensional information, and can be applied on inhomogeneous media. PMID- 21540960 TI - Noise bandwidth dependence of soliton phase in simulations of stochastic nonlinear Schrodinger equations. AB - We demonstrate that soliton perturbation theory, though widely used, predicts an incorrect phase distribution for solitons of stochastically driven nonlinear Schrodinger equations in physically relevant parameter regimes. We propose a simple variational model that accounts for the effect of radiation on phase evolution and correctly predicts its distribution. PMID- 21540961 TI - Tunable, polarization independent, narrow-band filtering with one-dimensional crossed resonant gratings. AB - We propose an optical component for widely tunable, narrow-band filtering. It takes advantage of the tunability properties, with respect to the angle of incidence, of guided-mode resonance filters. The intrinsic polarization sensitivity of the resonances is suppressed by exciting the modes through two identical, differently oriented one-dimensional gratings flanking a thick substrate. An example is provided that theoretically shows a polarization independent peak at 1.6 MUm with a Q factor of 13,000 and a reflectivity greater than 99% at resonance, which is tunable over 100 nm. Finally, we discuss the fabrication limitations and conclude that the proposed configuration is realistic. PMID- 21540962 TI - Single-shot ultrabroadband two-dimensional electronic spectroscopy of the light harvesting complex LH2. AB - Here we present two-dimensional (2D) electronic spectra of the light-harvesting complex LH2 from purple bacteria using coherent pulses with bandwidth of over 100 nm FWHM. This broadband excitation and detection has allowed the simultaneous capture of both the B800 and B850 bands using a single light source. We demonstrate that one laser pulse is sufficient to capture the entire 2D electronic spectrum with a high signal-to-noise ratio. At a waiting time of 800 fs, we observe population transfer from the B800 to B850 band as manifested by a prominent cross peak. These results will enable observation of the dynamics of biological systems across both ultrafast (<1 ps) and slower (>1 ms) timescales simultaneously. PMID- 21540963 TI - Structural analysis of photonic crystal fibers by side scattering of laser light. AB - A side-scattering technique for investigating the inner microstructure of photonic crystal fibers (PCFs) is reported. Multiple scattering is reduced by filling the hollow PCF channels with index-matching fluid. The scattered signal is measured for fixed angles of incidence and detection while the fiber is rotated. A pattern of peaks, unique to each PCF, whether solid or hollow core, correlates closely with the symmetry planes of the PCF structure. As an example of the technique, the twist profile of a structural rocking filter is directly measured. PMID- 21540964 TI - Broadband, rapidly tunable Ti:sapphire-pumped BiB3O6 femtosecond optical parametric oscillator. AB - We report a femtosecond optical parametric oscillator (OPO) based on the nonlinear material BiB3O6 (BIBO) pumped directly by a Kerr lens mode-locked Ti:sapphire laser. Using a 1.5 mm long BIBO crystal cut at theta=11.4 degrees for collinear type I (e->o+o) phase matching in the xz optical plane, femtosecond signal pulses across 1.4-1.6 MUm, and idler pulses across 1.6-1.87 MUm spectral range are generated, limited by the reflectivity bandwidth of the OPO mirrors. The high nonlinear gain and large spectral acceptance for type I interaction in the xz plane of BIBO permit rapid and continuous tuning across the entire range by simple fine adjustment of OPO cavity delay or through small changes in the pump wavelength, without varying any other parameters. Additionally, owing to the near-zero group velocity mismatch and dispersion, the OPO supports broad spectrum as wide as 33 nm, which results in self-compressed signal pulses. For 150 fs pump pulses, signal pulses with durations down to 106 fs with a time-bandwidth product of 0.48 are obtained without the need for intracavity dispersion compensation. PMID- 21540965 TI - Lossless single-photon shaping via heralding. AB - Using spontaneous optical parametric downconversion, we experimentally demonstrate heralded generation of shaped single photons, whose modes are tailored indirectly by applying amplitude modulation on the pump field that drives the downconversion process. Our experiment opens a door to creating high quality, mode-shaped single photons at a substantially higher efficiency than is possible with the existing method of direct single-photon shaping. PMID- 21540966 TI - Effect of coherence and polarization on resolution of optical imaging system. AB - The effect of coherence properties of illumination on image resolution, well known in a scalar case, is studied for the case of vector electromagnetic illumination. Using an example of vector Gaussian Schell-model illumination, we analyze the dependence of optical system resolution on the transverse correlation lengths of the orthogonal field components and on the ratio of the powers of these components, each taken separately. PMID- 21540967 TI - Characterization of high-intensity sub-4-fs laser pulses using spatially encoded spectral shearing interferometry. AB - We report on the full amplitude and phase characterization of high-intensity few cycle laser pulses generated in a single-stage hollow core fiber system with subsequent compression by ultrabroadband chirped mirrors. We use a spatially encoded arrangement (SEA) spectral phase interferometry for direct electric field reconstruction (SPIDER) with spectral filters for ancilla generation to characterize the sub-4 fs pulses with spatial resolution. PMID- 21540968 TI - Near-field investigation of induced transparency in similarly oriented double split-ring resonators. AB - We present near-field measurements of an induced transparency behavior using a double split-ring resonator geometry. Mapping the out-of-plane electric field component directly reveals that the induced transparency is linked to an asymmetric mode profile with the subunits oscillating in antiphase. The measurements are compared to complementary numerical simulations, and excellent agreement is found. PMID- 21540969 TI - Spectral amplitude and phase measurement of ultrafast pulses using all-optical differential tomography. AB - We demonstrate a simple, all-optical, fiber-based method for characterizing the spectral amplitude and phase of ultrafast pulses using a differential tomographic measurement realized via four-wave mixing. The technique is applied to subpicosecond pulses in the C-band of the telecommunication spectrum. Characterization of amplified pulses and propagation through dispersive media is demonstrated and compared with autocorrelation measurements and calculated predictions. We show how our approach can be extended to larger bandwidths in similar systems, extending tomographic reconstruction of coherent fields to nearly an octave of bandwidth while maintaining a robust, waveguide-based geometry. PMID- 21540970 TI - Guided-mode resonance in curved grating structures. AB - The guided-mode resonance phenomenon in curved grating structures was studied. By using finite-difference time-domain simulation in the cylindrical coordinate system, we investigated the dependence of the peak reflectivity and bandwidth of the resonance upon the curvature radius. We clarified that the reflectivity and bandwidth were similar to those of flat grating structures for a finite range of curvature. We also discussed the key factor that determines the performance of reflection. PMID- 21540971 TI - Analysis and improvement of Laguerre-Gaussian beam position estimation using quadrant detectors. AB - Laguerre-Gaussian beams have become increasingly important in areas like optical manipulation and quantum communications. A good understanding of the accuracy and sensitivity of their displacement measurements are required for these applications. In this Letter, we present a method to analyze and compare the performance of these measurements, and an estimation technique is proposed to improve their measurement accuracies. The effectiveness of our methods is verified by simulation studies. PMID- 21540972 TI - Semiconductor-doped liquid-core optical fiber. AB - A semiconductor liquid-core optical fiber has been made by simply filling the hollow core of a capillary waveguide with nanoparticles suspended in toluene media. Under a low continuous optical power excitation at 532 nm, the emission of PbSe particles was clearly demonstrated in the infrared region and then partially maintained in the core of the fiber by the total internal reflection mechanism. Finally, due to the guided propagation, which results in multiple absorption effects, a linear shift of the emission peak toward longer wavelengths was observed (~0.32 nm/cm). As a proof of concept, this original demonstration of visible-to-infrared conversion could lead to the development of active fibered devices at wavelengths not covered by the conventional rare-earth ion doping. PMID- 21540973 TI - Precision angle sensor using an optical lever inside a Sagnac interferometer. AB - We built an ultra-low-noise angle sensor by combining a folded optical lever and a Sagnac interferometer. The instrument has a measured noise floor of 1.3 prad/?Hz at 2.4 kHz. We achieve this record angle sensitivity using a proof-of concept apparatus with a conservative N=11 bounces in the optical lever. This technique could be extended to reach subpicoradian/?Hz sensitivities with an optimized design. PMID- 21540974 TI - Two Lagrange-like optical invariants and some applications. AB - Geometric optics can be completely derived from Fermat's principle, as classical mechanics can be obtained by the application of the Hamilton principle. In Lagrangian optics, for optical systems with rotational symmetry, is known the invariant L3, the Lagrange optical invariant. For systems built only with spherical lenses, we demonstrate there are two other optical invariants, L1 and L2, analogous to L3. A proof based on Snell's law, the Weierstrass-Erdman jump condition, and the expression of the ray between two optical surfaces in the Hamiltonian formalism is reported. The presence of a conserved vector, L, allows us to write the equation of an emerging ray without any approximation. PMID- 21540975 TI - Matrix Fabry-Perot resonance mechanism in high-contrast gratings. AB - We present a simple analytic formalism to explain the unique resonance phenomenon in subwavelength high-contrast gratings (HCG). We show that the resonances are due to strong coupling between two surface-normal waveguide array modes resulting from abrupt and large index contrast. Simple expression for HCG quality factor is derived that agrees with spectral-fitting approaches reported in literature. PMID- 21540976 TI - Adaptive phase compensation for ultracompact laser scanning endomicroscopy. AB - We present an approach to laser scanning endomicroscopy that requires no moving parts and can be implemented with no distal scanners or optics, permitting extremely compact endoscopic probes to be developed. Our approach utilizes a spatial light modulator to correct for phase variations across a fiber imaging bundle and to encode for arbitrary wavefronts at the distal end of the fiber bundle. Thus, it is possible to realize both focusing and beam scanning at the output of the fiber bundle with no distal components. We present proof of principle results to illustrate three-dimensional scanning of the focal spot and exemplar images of a United States Air Force resolution test chart. PMID- 21540977 TI - A hybrid solitary-conical self-guided light beam in self-focusing media. AB - In addition to subluminal solitons and superluminal conical beams, self-focusing media also support a luminal nonspreading beam with hybrid solitary-conical properties. Its existence reveals that spatial solitons may also have a conical structure, and vice versa. PMID- 21540978 TI - Enhanced optical absorption in nanopatterned silicon thin films with a nano-cone hole structure for photovoltaic applications. AB - In this paper, the optical properties of the silicon nano-cone-hole (NCH) structure array are studied. The ultimate efficiency of the optimized NCH array is enhanced by 23.11% compared to an optimized nanohole array of the same thickness. The absorptance enhancement of the NCH arrays is attributed to its lowered reflectance, more supported resonant modes, and enhanced mode interaction. The angular dependence of ultimate efficiency is also investigated. PMID- 21540979 TI - Hybrid cable television and orthogonal-frequency-division-multiplexing transport system basing on single wavelength polarization and amplitude remodulation schemes. AB - A hybrid community antenna television (CATV) and orthogonal-frequency-division multiplexing (OFDM) transport system is proposed and experimentally demonstrated to transmit multiple CATV channels and bi-directional radio frequency signals on a single optical carrier. By polarization remodulating an optical CATV signal with downstream OFDM signals and then amplitude remodulating upstream OFDM signals with the hybrid CATV/OFDM signals, this architecture can efficiently utilize only one optical carrier to support optical analog/digital CATV transmission and bi-directional wireless broadband services for each client. Good experimental results prove that this architecture provides a proper wavelength utilization scheme for future multiwavelength optical transport systems. PMID- 21540980 TI - Phase retrieval in quantitative x-ray microtomography with a single sample-to detector distance. AB - Phase retrieval extracts quantitative phase information from x-ray propagation based phase-contrast images. Notwithstanding inherent approximations, phase retrieval using a single sample-to-detector distance (SDD) is very attractive, because it imposes no setup complications or additional radiation dose compared to absorption-based imaging. Considering the phase-attenuation duality (epsilon=delta/beta, where epsilon is constant), a simple absorption correction factor is proposed for the modified Bronnikov algorithm in x-ray propagation based phase-contrast computed tomography (PPCT). Moreover, a practical method for calculating the optimal epsilon value is proposed, which requires no prior knowledge of the sample. Tests performed on simulation and experimental data successfully distinguished different materials in a quasihomogeneous and weakly absorbing sample from a single SDD-PPCT data point. PMID- 21540981 TI - Photon-number-resolving detection at 1.04 MUm via coincidence frequency upconversion. AB - We demonstrate photon-number-resolving detection based on coincidence frequency upconversion. Pumped by synchronized pulses, the photon signal of the coherent state at 1.04 MUm was upconverted into visible replicas with preserved photon number distribution. The upconverted photons were then registered by a silicon multipixel photon counter. The photon-number-resolving performance was improved by reducing the background counts with a synchronous pump as the coincidence gate and reducing the intrinsic parametric fluorescence influence with long-wavelength pumping. A total detection efficiency of 3.7% was achieved with a quite low noise probability per pulse of 0.0002. PMID- 21540982 TI - Influence of turbulence strength on temporal correlation of scintillation. AB - Through extensive laboratory experimentation we demonstrate that the temporal frequency content of turbulence-induced scintillation strongly depends on the temperature gradient exerted at the propagation path of a collimated laser beam. We find a power law relating the turbulence strength induced by convection with the vertical temperature gradient and we show that the cutoff frequency of scintillation shows an approximately linear growth with turbulence strength, measured by angle-of-arrival fluctuations. The impact of these findings are discussed in the context of free-space optical communications. PMID- 21540983 TI - Ultracompact 160 Gbaud all-optical demultiplexing exploiting slow light in an engineered silicon photonic crystal waveguide. AB - We demonstrate all-optical demultiplexing of a high-bandwidth, time-division multiplexed 160 Gbit/s signal to 10 Gbit/s channels, exploiting slow light enhanced four-wave mixing in a dispersion engineered, 96 MUm long planar photonic crystal waveguide. We report error-free (bit error rate<10-9) operation of all 16 demultiplexed channels, with a power penalty of 2.2-2.4 dB, highlighting the potential of these structures as a platform for ultracompact all-optical nonlinear processes. PMID- 21540984 TI - Highly sensitive miniature photonic crystal fiber refractive index sensor based on mode field excitation. AB - A highly sensitive miniature photonic crystal fiber refractive index sensor based on field mode excitation is presented. The sensor is fabricated by melting one end of a photonic crystal fiber into a rounded tip and splicing and collapsing the other end with a single-mode fiber. The rounded tip is able to induce cladding mode excitation, which resulted in an additional phase delay. Linear response of 262.28 nm/refractive index unit in the refractive index range of 1.337 to 1.395 is obtained for the physical length of a 953 MUm sensor. The sensor is also shown to be insensitive to environmental temperature. PMID- 21540985 TI - Photodegradation of melanin by an interferometric technique. AB - Photodegradation of melanin thin films is investigated for a UVA wavelength of 355 nm and a UVC wavelength of 244 nm. The technique involves interferometric exposure of melanin with two coherent beams from a low-power UV laser. The periodic photodegradation-grating pattern is monitored by diffraction of a second low-power He-Ne laser. Dependence of the photodegradation rate on UV intensity as well as the effect of ambient humidity is investigated and explained with a simple model. The technique has promise for investigating photo-induced effects in other biomolecular substrates as well. PMID- 21540986 TI - Source transformation device formed by one-dimensional photonic crystal. AB - Photonic bandgap structures can also be utilized for the realization of transformational optical devices like metamaterials. In this Letter, the possibility of cylindrical to plane wave source transformation in an open cavity formed by one dimensional photonic crystal is demonstrated. It is observed that the gap solitary wave behavior at the near-bandgap regime is fair enough to produce highly directional plane waves out of the point source placed inside the open cavity. The limitations of such a source transformation device are governed by the strength of the bandgap that decides the amplitude of the emitted plane waves. PMID- 21540987 TI - What is the purpose of launching World Journal of Biological Chemistry? AB - The first issue of World Journal of Biological Chemistry (WJBC), whose preparatory work was initiated on July 01, 2009, will be published on January 26, 2010. The WJBC Editorial Board has now been established and consists of 341 distinguished experts from 37 countries. Our purpose of launching WJBC is to publish peer-reviewed, high-quality articles via an open-access online publishing model, thereby acting as a platform for communication between peers and the wider public, and maximizing the benefits to editorial board members, authors and readers. PMID- 21540988 TI - Role of autophagy in liver physiology and pathophysiology. AB - Autophagy is a highly conserved intracellular degradation pathway by which bulk cytoplasm and superfluous or damaged organelles are enveloped by double membrane structures termed autophagosomes. The autophagosomes then fuse with lysosomes for degradation of their contents, and the resulting amino acids can then recycle back to the cytosol. Autophagy is normally activated in response to nutrient deprivation and other stressors and occurs in all eukaryotes. In addition to maintaining energy and nutrient balance in the liver, it is now clear that autophagy plays a role in liver protein aggregates related diseases, hepatocyte cell death, steatohepatitis, hepatitis virus infection and hepatocellular carcinoma. In this review, I discuss the recent findings of autophagy with a focus on its role in liver pathophysiology. PMID- 21540989 TI - Role of post-translational modifications of HTLV-1 Tax in NF-kappaB activation. AB - Human T-cell leukemia virus type 1 (HTLV-1), the first human retrovirus discovered, is the etiological agent of adult-T-cell leukemia/lymphoma. The HTLV 1 encoded Tax protein is a potent oncoprotein that deregulates gene expression by constitutively activating nuclear factor-kappaB (NF-kappaB). Tax activation of NF kappaB is critical for the immortalization and survival of HTLV-1-infected T cells. In this review, we summarize the present knowledge on mechanisms underlying Tax-mediated NF-kappaB activation, with an emphasis on post translational modifications of Tax. PMID- 21540990 TI - Deacetylase inhibitors - focus on non-histone targets and effects. AB - Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases, including cancer. The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes, by interfering with the acetylation status of nuclear histone proteins, hence the name histone deacetylase inhibitors was coined. Yet, this view could not explain the high specificity for tumor cells and recent evidence now suggests that non histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation, survival and cell death induction. PMID- 21540991 TI - State of the art and the dark side of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a disorder that involves the degeneration of motor neurons, muscle atrophy, and paralysis. In a few familiar forms of ALS, mutations in the superoxide dismutase-1 (SOD1) gene have been held responsible for the degeneration of motor neurons. Nevertheless, after the discovery of the SOD1 mutations no consensus has emerged as to which cells, tissues and pathways are primarily implicated in the pathogenic events that lead to ALS. Ubiquitous overexpression of mutant SOD1 in transgenic animals recapitulates the pathological features of ALS. However, the toxicity of mutant SOD1 is not necessarily limited to the central nervous system. Views about ALS pathogenesis are now enriched by the recent discovery of mutations in a pair of DNA/RNA binding proteins called TDP-43 and FUS/TLS as causes of familial and sporadic forms of ALS. Although the steps that lead to the pathological state are well defined, several fundamental issues are still controversial: are the motor neurons the first direct targets of ALS; and what is the contribution of non neuronal cells, if any, to the pathogenesis of ALS? The state of the art of ALS pathogenesis and the open questions are discussed in this review. PMID- 21540992 TI - Role of matricellular proteins in cardiac tissue remodeling after myocardial infarction. AB - After onset of myocardial infarction (MI), the left ventricle (LV) undergoes a continuum of molecular, cellular, and extracellular responses that result in LV wall thinning, dilatation, and dysfunction. These dynamic changes in LV shape, size, and function are termed cardiac remodeling. If the cardiac healing after MI does not proceed properly, it could lead to cardiac rupture or maladaptive cardiac remodeling, such as further LV dilatation and dysfunction, and ultimately death. Although the precise molecular mechanisms in this cardiac healing process have not been fully elucidated, this process is strictly coordinated by the interaction of cells with their surrounding extracellular matrix (ECM) proteins. The components of ECM include basic structural proteins such as collagen, elastin and specialized proteins such as fibronectin, proteoglycans and matricellular proteins. Matricellular proteins are a class of non-structural and secreted proteins that probably exert regulatory functions through direct binding to cell surface receptors, other matrix proteins, and soluble extracellular factors such as growth factors and cytokines. This small group of proteins, which includes osteopontin, thrombospondin-1/2, tenascin, periostin, and secreted protein, acidic and rich in cysteine, shows a low level of expression in normal adult tissue, but is markedly upregulated during wound healing and tissue remodeling, including MI. In this review, we focus on the regulatory functions of matricellular proteins during cardiac tissue healing and remodeling after MI. PMID- 21540993 TI - Is tau a suitable therapeutical target in tauopathies? AB - Tau is an intracellular protein, found mainly in neurons, but it can also be found in the extracellular space in pathological situations. Here we discuss whether intracellular tau, in aggregated form or modified by phosphorylation, could be toxic inside a neuron. On the other hand, it has been proposed that extracellular tau could be toxic. In this review, we address the question if the elimination of tau would be a possible therapeutic method to avoid tauopathy disorder and we suggest ways to eliminate intracellular and extracellular tau as treatment. PMID- 21540994 TI - Swine-origin influenza-virus-induced acute lung injury: Novel or classical pathogenesis? AB - Influenza viruses are common respiratory pathogens in humans and can cause serious infection that leads to the development of pneumonia. Due to their host range diversity, genetic and antigenic diversity, and potential to reassort genetically in vivo, influenza A viruses are continual sources of novel influenza strains that lead to the emergence of periodic epidemics and outbreaks in humans. Thus, newly emerging viral diseases are always major threats to public health. In March 2009, a novel influenza virus suddenly emerged and caused a worldwide pandemic. The novel pandemic influenza virus was genetically and antigenically distinct from previous seasonal human influenza A/H1N1 viruses; it was identified to have originated from pigs, and further genetic analysis revealed it as a subtype of A/H1N1, thus later called a swine-origin influenza virus A/H1N1. Since the novel virus emerged, epidemiological surveys and research on experimental animal models have been conducted, and characteristics of the novel influenza virus have been determined but the exact mechanisms of pulmonary pathogenesis remain to be elucidated. In this editorial, we summarize and discuss the recent pandemic caused by the novel swine-origin influenza virus A/H1N1 with a focus on the mechanism of pathogenesis to obtain an insight into potential therapeutic strategies. PMID- 21540995 TI - Contribution of plasma membrane Ca ATPase to cerebellar synapse function. AB - The cerebellum expresses one of the highest levels of the plasma membrane Ca(2+) ATPase, isoform 2 in the mammalian brain. This highly efficient plasma membrane calcium transporter protein is enriched within the main output neurons of the cerebellar cortex; i.e. the Purkinje neurons (PNs). Here we review recent evidence, including electrophysiological and calcium imaging approaches using the plasma membrane calcium ATPase 2 (PMCA2) knockout mouse, to show that PMCA2 is critical for the physiological control of calcium at cerebellar synapses and cerebellar dependent behaviour. These studies have also revealed that deletion of PMCA2 throughout cerebellar development in the PMCA2 knockout mouse leads to permanent signalling and morphological alterations in the PN dendrites. Whilst these findings highlight the importance of PMCA2 during cerebellar synapse function and development, they also reveal some limitations in the use of the PMCA2 knockout mouse and the need for additional experimental approaches including cell-specific and reversible manipulation of PMCAs. PMID- 21540996 TI - Role of plasma membrane calcium ATPase 2 in spinal cord pathology. AB - A number of studies have indicated that plasma membrane calcium ATPases (PMCAs) are expressed in the brain and spinal cord and could play important roles not only in the maintenance of cellular calcium homeostasis but also in the survival and function of central nervous system cells under pathological conditions. The different regional and cellular distributions of the various PMCA isoforms and splice variants in the nervous system and the diverse phenotypes of PMCA knockout mice support the notion that each isoform might play a distinct role. Especially in the spinal cord, the survival of neurons and, in particular, motor neurons could be dependent on PMCA2. This is indicated by the knockdown of PMCA2 in pure spinal cord neuronal cultures that leads to cell death via a decrease in collapsing response mediator protein 1 levels. Moreover, the progressive decline in the number of motor neurons in PMCA2-null mice and heterozygous mice further supports this notion. Therefore, the reported reduction in PMCA2 mRNA and protein levels in the inflamed spinal cord of mice affected by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, and after spinal cord contusion injury, suggests that changes in PMCA2 expression could be a cause of neuronal pathology and death during inflammation and injury. Glutamate excitotoxicity mediated via kainate receptors has been implicated in the neuropathology of both EAE and spinal cord injury, and has been identified as a trigger that reduces PMCA2 levels in pure spinal cord neuronal cultures through degradation of the pump by calpain without affecting PMCA2 transcript levels. It remains to be determined which other stimuli modulate PMCA2 mRNA expression in the aforementioned pathological conditions of the spinal cord. PMID- 21540997 TI - Soluble and insoluble signals sculpt osteogenesis in angiogenesis. AB - The basic tissue engineering paradigm is tissue induction and morphogenesis by combinatorial molecular protocols whereby soluble molecular signals are combined with insoluble signals or substrata. The insoluble signal acts as a three dimensional scaffold for the initiation of de novo tissue induction and morphogenesis. The osteogenic soluble molecular signals of the transforming growth factor-beta (TGF-beta) supergene family, the bone morphogenetic/osteogenic proteins (BMPs/OPs) and, uniquely in the non-human primate Papio ursinus (P. ursinus), the three mammalian TGF-beta isoforms induce bone formation as a recapitulation of embryonic development. In this paper, I discuss the pleiotropic activity of the BMPs/OPs in the non-human primate P. ursinus, the induction of bone by transitional uroepithelium, and the apparent redundancy of molecular signals initiating bone formation by induction including the three mammalian TGF beta isoforms. Amongst all mammals tested so far, the three mammalian TGF-beta isoforms induce endochondral bone formation in the non-human primate P. ursinus only. Bone tissue engineering starts by erecting scaffolds of biomimetic biomaterial matrices that mimic the supramolecular assembly of the extracellular matrix of bone. The molecular scaffolding lies at the hearth of all tissue engineering strategies including the induction of bone formation. The novel concept of tissue engineering is the generation of newly formed bone by the implantation of "smart" intelligent biomimetic matrices that per se initiate the ripple-like cascade of bone differentiation by induction without exogenously applied BMPs/OPs of the TGF-beta supergene family. A comprehensive digital iconographic material presents the modified tissue engineering paradigm whereby the induction of bone formation is initiated by intelligent smart biomimetic matrices that per se initiate the induction of bone formation without the exogenous application of the soluble osteogenic molecular signals. The driving force of the intrinsic induction of bone formation by bioactive biomimetic matrices is the shape of the implanted substratum. The language of shape is the language of geometry; the language of geometry is the language of a sequence of repetitive concavities, which biomimetizes the remodelling cycle of the primate osteonic bone. PMID- 21540999 TI - Discovery of the strong antioxidant selenoneine in tuna and selenium redox metabolism. AB - A novel selenium-containing compound, selenoneine, has been isolated as the major form of organic selenium in the blood and tissues of tuna. Selenoneine harbors a selenium atom in the imidazole ring, 2-selenyl-N(alpha), N(alpha), N(alpha) trimethyl-L-histidine, and is a selenium analog of ergothioneine. This selenium compound has strong antioxidant capacity and binds to heme proteins, such as hemoglobin and myoglobin, to protect them from iron auto-oxidation, and it reacts with radicals and methylmercury (MeHg). The organic cations/carnitine transporter OCTN1 transports selenoneine and MeHg, regulates Se-enhanced antioxidant activity, and decreases MeHg toxicity. Thus, the dietary intake of selenoneine, by consuming fish, might decrease the formation of reactive oxygen radicals that could oxidize nucleotides in DNA, and thereby inhibit carcinogenesis, chronic diseases, and aging. PMID- 21540998 TI - Functional interactions between steroid hormones and neurotrophin BDNF. AB - Brain-derived neurotrophic factor (BDNF), a critical neurotrophin, regulates many neuronal aspects including cell differentiation, cell survival, neurotransmission, and synaptic plasticity in the central nervous system (CNS). Though BDNF has two types of receptors, high affinity tropomyosin-related kinase (Trk)B and low affinity p75 receptors, BDNF positively exerts its biological effects on neurons via activation of TrkB and of resultant intracellular signaling cascades including mitogen-activated protein kinase/extracellular signal-regulated protein kinase, phospholipase Cgamma, and phosphoinositide 3 kinase pathways. Notably, it is possible that alteration in the expression and/or function of BDNF in the CNS is involved in the pathophysiology of various brain diseases such as stroke, Parkinson's disease, Alzheimer's disease, and mental disorders. On the other hand, glucocorticoids, stress-induced steroid hormones, also putatively contribute to the pathophysiology of depression. Interestingly, in addition to the reduction in BDNF levels due to increased glucocorticoid exposure, current reports demonstrate possible interactions between glucocorticoids and BDNF-mediated neuronal functions. Other steroid hormones, such as estrogen, are involved in not only sexual differentiation in the brain, but also numerous neuronal events including cell survival and synaptic plasticity. Furthermore, it is well known that estrogen plays a role in the pathophysiology of Parkinson's disease, Alzheimer's disease, and mental illness, while serving to regulate BDNF expression and/or function. Here, we present a broad overview of the current knowledge concerning the association between BDNF expression/function and steroid hormones (glucocorticoids and estrogen). PMID- 21541000 TI - Drosophila as a model for antiviral immunity. AB - The fruit fly Drosophila melanogaster has been successfully used to study numerous biological processes including immune response. Flies are naturally infected with more than twenty RNA viruses making it a valid model organism to study host-pathogen interactions during viral infections. The Drosophila antiviral immunity includes RNA interference, activation of the JAK/STAT and other signaling cascades and other mechanisms such as autophagy and interactions with other microorganisms. Here we review Drosophila as an immunological research model as well as recent advances in the field of Drosophila antiviral immunity. PMID- 21541002 TI - Physio-pathological roles of transglutaminase-catalyzed reactions. AB - Transglutaminases (TGs) are a large family of related and ubiquitous enzymes that catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In the absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. The TG enzymes are also capable of catalyzing other reactions important for cell viability. The distribution and the physiological roles of TG enzymes have been widely studied in numerous cell types and tissues and their roles in several diseases have begun to be identified. "Tissue" TG (TG2), a member of the TG family of enzymes, has definitely been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology: i.e. celiac disease (CD). TG activity has also been hypothesized to be directly involved in the pathogenetic mechanisms responsible for several other human diseases, including neurodegenerative diseases, which are often associated with CD. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, supranuclear palsy, Huntington's disease and other recently identified polyglutamine diseases, are characterized, in part, by aberrant cerebral TG activity and by increased cross-linked proteins in affected brains. In this review, we discuss the physio-pathological role of TG catalyzed reactions, with particular interest in the molecular mechanisms that could involve these enzymes in the physio-pathological processes responsible for human neurodegenerative diseases. PMID- 21541003 TI - Protective effects of anti-ricin A-chain antibodies delivered intracellularly against ricin-induced cytotoxicity. AB - AIM: To evaluate the ability of anti-ricin A-chain antibodies, delivered intracellularly, to protect against ricin-induced cytotoxicity in RAW264.7 cells. METHODS: Anti-deglycosylated ricin A-chain antibody and RAC18 anti-ricin A-chain monoclonal antibody were delivered intracellularly by encapsulating in liposomes or via conjugation with the cell-penetrating MTS-transport peptide. RAW264.7 cells were incubated with these antibodies either before or after ricin exposure. The changes in cytotoxicity were estimated by MTT assay. Co-localization of internalized antibody and ricin was evaluated by fluorescence microscopy. RESULTS: Internalized antibodies significantly increased cell viability either before or after ricin exposure compared to the unconjugated antibodies. Fluorescence microscopy confirmed the co-localization of internalized antibodies and ricin inside the cells. CONCLUSION: Intracellular delivery of antibodies to neutralize the ricin toxin after cellular uptake supports the potential use of cell-permeable antibodies for post-exposure treatment of ricin intoxication. PMID- 21541001 TI - Uniform categorization of biocommunication in bacteria, fungi and plants. AB - This article describes a coherent biocommunication categorization for the kingdoms of bacteria, fungi and plants. The investigation further shows that, besides biotic sign use in trans-, inter- and intraorganismic communication processes, a common trait is interpretation of abiotic influences as indicators to generate an appropriate adaptive behaviour. Far from being mechanistic interactions, communication processes within organisms and between organisms are sign-mediated interactions. Sign-mediated interactions are the precondition for every cooperation and coordination between at least two biological agents such as cells, tissues, organs and organisms. Signs of biocommunicative processes are chemical molecules in most cases. The signs that are used in a great variety of signaling processes follow syntactic (combinatorial), pragmatic (context dependent) and semantic (content-specific) rules. These three levels of semiotic rules are helpful tools to investigate communication processes throughout all organismic kingdoms. It is not the aim to present the latest empirical data concerning communication in these three kingdoms but to present a unifying perspective that is able to interconnect transdisciplinary research on bacteria, fungi and plants. PMID- 21541004 TI - Simon Labbe's work on iron and copper homeostasis. AB - Iron and copper have a wealth of functions in biological systems, which makes them essential micronutrients for all living organisms. Defects in iron and copper homeostasis are directly responsible for diseases, and have been linked to impaired development, metabolic syndromes and fungal virulence. Consequently, it is crucial to gain a comprehensive understanding of the molecular bases of iron- and copper-dependent proteins in living systems. Simon Labbe maintains parallel programs on iron and copper homeostasis using the fission yeast Schizosaccharomyces pombe (Schiz. pombe) as a model system. The study of fission yeast transition-metal metabolism has been successful, not only in discerning the genes and pathways functioning in Schiz. pombe, but also the genes and pathways that are active in mammalian systems and for other fungi. PMID- 21541005 TI - Attenuation of ultrasound in severely plastically deformed nickel. AB - Ultrasound attenuation was measured in nickel specimens of about 30 mm diameter prepared using the high pressure torsion technique. The cold working process produced an equivalent shear strain increasing from zero at the center up to 1000% at the edge of the specimen. The fragmentation of the grains due to multiple dislocations led to an ultrafine microstructure with large angle grain boundaries. The mean value of the grain size distribution gradually decreased from ~50 MUm at the center to 0.2 MUm at the edge. Laser pulses of 5 ns were employed for the excitation of broadband ultrasound pulses covering the spectral range of 0.1-150 MHz. The ultrasound pulses were measured from the opposite side of the specimen by means of an optical interferometer and a piezoelectric foil transducer in two experimental setups. The features of the detected signal forms are discussed. The absolute value of the attenuation decreases from the center to the edge of the specimen showing nearly linear frequency dependence. The variation of the phase velocity was measured in a 6 mm-thick high pressure torsion nickel sample, revealing a velocity increase from the center to the edge. PMID- 21541006 TI - Fuzzy logic: A "simple" solution for complexities in neurosciences? AB - BACKGROUND: Fuzzy logic is a multi-valued logic which is similar to human thinking and interpretation. It has the potential of combining human heuristics into computer-assisted decision making, which is applicable to individual patients as it takes into account all the factors and complexities of individuals. Fuzzy logic has been applied in all disciplines of medicine in some form and recently its applicability in neurosciences has also gained momentum. METHODS: This review focuses on the use of this concept in various branches of neurosciences including basic neuroscience, neurology, neurosurgery, psychiatry and psychology. RESULTS: The applicability of fuzzy logic is not limited to research related to neuroanatomy, imaging nerve fibers and understanding neurophysiology, but it is also a sensitive and specific tool for interpretation of EEGs, EMGs and MRIs and an effective controller device in intensive care units. It has been used for risk stratification of stroke, diagnosis of different psychiatric illnesses and even planning neurosurgical procedures. CONCLUSIONS: In the future, fuzzy logic has the potential of becoming the basis of all clinical decision making and our understanding of neurosciences. PMID- 21541007 TI - Clinical features of central isolated unilateral foot drop: A case report and review of the literature. AB - BACKGROUND: Intracranial cause of isolated unilateral foot drop is very rare. There may be a delay in the diagnosis of the cause of central foot drop or patients with such lesions might be misdiagnosed and subjected to unnecessary interventions. One of the reasons for the diagnostic uncertainty might be the absence of upper motor neuron (UMN) signs in the initial examination of such patients. CASE DESCRIPTION: We present a very rare case of a 78-year-old woman who had presented with a five-year progressive right-sided unilateral isolated foot drop from a left-sided parasagittal tumor. Previously, she had undergone biopsy of an abnormality on the right C7/T1 facet, which was found to be benign. On examination of the patient, she had UMN signs in the ipsilateral foot. On magnetic resonance imaging scan of her head, a 3-cm left parasagittal lesion, consistent with it being a meningioma, was noted. The patient had significant medical history and declined to undergo surgical removal of the lesion. CONCLUSION: We review the literature on central foot drop from various intracranial pathologies and discern its clinical features. Patients with central foot drop often have UMN signs; however, these may be absent causing diagnostic uncertainty, and physicians should be vigilant of these variations in the presentation. PMID- 21541008 TI - The application of intraoperative near-infrared indocyanine green videoangiography and analysis of fluorescence intensity in cerebrovascular surgery. AB - OBJECTIVE: To evaluate the usefulness and limitations of the intraoperative near infrared (NIR) indocyanine green videoangiography (ICG-VA) and analysis of fluorescence intensity in cerebrovascular surgery. METHODS: Forty-eight patients received ICG-VA during various surgical procedures from May 2010 to August 2010. Included among them were 45 cases of cerebral aneurysms and 3 cases of cerebral arteriovenous malformations (AVMs). The infrared fluorescence module integrated into the surgical microscope was used to visualize fluorescent areas in the surgical field. An integrated analytical visualization tool constantly analyzed the fluorescence video sequence and generated it in the form of an intensity diagram for objective interpretation. RESULTS: Overall, the procedure of ICG VA was done 158 times in 48 patients. There was no adverse effect of ICG dye. In cerebral aneurysm cases, the images obtained were of high resolution. In 4 cases, incomplete clipping was detected by ICG-VA and allowed suitable adjustment to completely obliterate the aneurysm. In 3 aneurysm cases, the intensity diagram of ICG VA provided valuable information. ICG-VA identified the feeding arteries, the draining veins, and nidus in all 3 AVM cases, which was confirmed by an immediate analysis of fluorescence intensity. CONCLUSIONS: ICG-VA provides high resolution images allowing real-time assessment of the blood flow in surgical field. The intensity analysis function, in addition, is a useful adjunct to improve the accuracy of the clipping and decrease the complication rates in cerebral aneurysm cases. In cerebral AVM cases, with the help of color map and intensity diagram function, the superficial feeders, drainers, and nidus can be identified easily. PMID- 21541009 TI - Local de novo assembly of RAD paired-end contigs using short sequencing reads. AB - Despite the power of massively parallel sequencing platforms, a drawback is the short length of the sequence reads produced. We demonstrate that short reads can be locally assembled into longer contigs using paired-end sequencing of restriction-site associated DNA (RAD-PE) fragments. We use this RAD-PE contig approach to identify single nucleotide polymorphisms (SNPs) and determine haplotype structure in threespine stickleback and to sequence E. coli and stickleback genomic DNA with overlapping contigs of several hundred nucleotides. We also demonstrate that adding a circularization step allows the local assembly of contigs up to 5 kilobases (kb) in length. The ease of assembly and accuracy of the individual contigs produced from each RAD site sequence suggests RAD-PE sequencing is a useful way to convert genome-wide short reads into individually assembled sequences hundreds or thousands of nucleotides long. PMID- 21541010 TI - Elevated [11C]-D-deprenyl uptake in chronic Whiplash Associated Disorder suggests persistent musculoskeletal inflammation. AB - There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer (11)C-D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that (11)C-D-deprenyl is a promising tracer for these purposes. PMID- 21541011 TI - A sustained dietary change increases epigenetic variation in isogenic mice. AB - Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection. PMID- 21541013 TI - Gains, losses and changes of function after gene duplication: study of the metallothionein family. AB - Metallothioneins (MT) are small proteins involved in heavy metal detoxification and protection against oxidative stress and cancer. The mammalian MT family originated through a series of duplication events which generated four major genes (MT1 to MT4). MT1 and MT2 encode for ubiquitous proteins, while MT3 and MT4 evolved to accomplish specific roles in brain and epithelium, respectively. Herein, phylogenetic, transcriptional and polymorphic analyses are carried out to expose gains, losses and diversification of functions that characterize the evolutionary history of the MT family. The phylogenetic analyses show that all four major genes originated through a single duplication event prior to the radiation of mammals. Further expansion of the MT1 gene has occurred in the primate lineage reaching in humans a total of 13 paralogs, five of which are pseudogenes. In humans, the reading frame of all five MT1 pseudogenes is reconstructed by sequence homology with a functional duplicate revealing that loss of invariant cysteines is the most frequent event accounting for pseudogeneisation. Expression analyses based on EST counts and RT-PCR experiments show that, as for MT1 and MT2, human MT3 is also ubiquitously expressed while MT4 transcripts are present in brain, testes, esophagus and mainly in thymus. Polymorphic variation reveals two deleterious mutations (Cys30Tyr and Arg31Trp) in MT4 with frequencies reaching about 30% in African and Asian populations suggesting the gene is inactive in some individuals and physiological compensation for its loss must arise from a functional equivalent. Altogether our findings provide novel data on the evolution and diversification of MT gene duplicates, a valuable resource for understanding the vast set of biological processes in which these proteins are involved. PMID- 21541014 TI - Evolution of competitive ability: an adaptation speed vs. accuracy tradeoff rooted in gene network size. AB - Ecologists have increasingly come to understand that evolutionary change on short time-scales can alter ecological dynamics (and vice-versa), and this idea is being incorporated into community ecology research programs. Previous research has suggested that the size and topology of the gene network underlying a quantitative trait should constrain or facilitate adaptation and thereby alter population dynamics. Here, I consider a scenario in which two species with different genetic architectures compete and evolve in fluctuating environments. An important trade-off emerges between adaptive accuracy and adaptive speed, driven by the size of the gene network underlying the ecologically-critical trait and the rate of environmental change. Smaller, scale-free networks confer a competitive advantage in rapidly-changing environments, but larger networks permit increased adaptive accuracy when environmental change is sufficiently slow to allow a species time to adapt. As the differences in network characteristics increase, the time-to-resolution of competition decreases. These results augment and refine previous conclusions about the ecological implications of the genetic architecture of quantitative traits, emphasizing a role of adaptive accuracy. Along with previous work, in particular that considering the role of gene network connectivity, these results provide a set of expectations for what we may observe as the field of ecological genomics develops. PMID- 21541012 TI - Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium. AB - While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations. PMID- 21541015 TI - The timing of the cognitive cycle. AB - We propose that human cognition consists of cascading cycles of recurring brain events. Each cognitive cycle senses the current situation, interprets it with reference to ongoing goals, and then selects an internal or external action in response. While most aspects of the cognitive cycle are unconscious, each cycle also yields a momentary "ignition" of conscious broadcasting. Neuroscientists have independently proposed ideas similar to the cognitive cycle, the fundamental hypothesis of the LIDA model of cognition. High-level cognition, such as deliberation, planning, etc., is typically enabled by multiple cognitive cycles. In this paper we describe a timing model LIDA's cognitive cycle. Based on empirical and simulation data we propose that an initial phase of perception (stimulus recognition) occurs 80-100 ms from stimulus onset under optimal conditions. It is followed by a conscious episode (broadcast) 200-280 ms after stimulus onset, and an action selection phase 60-110 ms from the start of the conscious phase. One cognitive cycle would therefore take 260-390 ms. The LIDA timing model is consistent with brain evidence indicating a fundamental role for a theta-gamma wave, spreading forward from sensory cortices to rostral corticothalamic regions. This posteriofrontal theta-gamma wave may be experienced as a conscious perceptual event starting at 200-280 ms post stimulus. The action selection component of the cycle is proposed to involve frontal, striatal and cerebellar regions. Thus the cycle is inherently recurrent, as the anatomy of the thalamocortical system suggests. The LIDA model fits a large body of cognitive and neuroscientific evidence. Finally, we describe two LIDA-based software agents: the LIDA Reaction Time agent that simulates human performance in a simple reaction time task, and the LIDA Allport agent which models phenomenal simultaneity within timeframes comparable to human subjects. While there are many models of reaction time performance, these results fall naturally out of a biologically and computationally plausible cognitive architecture. PMID- 21541016 TI - Drug use and receipt of highly active antiretroviral therapy among HIV-infected persons in two U.S. clinic cohorts. AB - OBJECTIVE: Drug use and receipt of highly active antiretroviral therapy (HAART) were assessed in HIV-infected persons from the Comprehensive Care Center (CCC; Nashville, TN) and Johns Hopkins University HIV Clinic (JHU; Baltimore, MD) between 1999 and 2005. METHODS: Participants with and without injection drug use (IDU) history in the CCC and JHU cohorts were evaluated. Additional analysis of persons with history of IDU, non-injection drug use (NIDU), and no drug use from CCC were performed. Activity of IDU and NIDU also was assessed for the CCC cohort. HAART use and time on HAART were analyzed according to drug use category and site of care. RESULTS: 1745 persons were included from CCC: 268 (15%) with IDU history and 796 (46%) with NIDU history. 1977 persons were included from JHU: 731 (35%) with IDU history. Overall, the cohorts differed in IDU risk factor rates, age, race, sex, and time in follow-up. In multivariate analyses, IDU was associated with decreased HAART receipt overall (OR = 0.61, 95% CI: [0.45-0.84] and OR = 0.58, 95% CI: [0.46-0.73], respectively for CCC and JHU) and less time on HAART at JHU (0.70, [0.55-0.88]), but not statistically associated with time on HAART at CCC (0.78, [0.56-1.09]). NIDU was independently associated with decreased HAART receipt (0.62, [0.47-0.81]) and less time on HAART (0.66, [0.52 0.85]) at CCC. These associations were not altered significantly whether patients at CCC were categorized according to historical drug use or drug use during the study period. CONCLUSIONS: Persons with IDU history from both clinic populations were less likely to receive HAART and tended to have less cumulative time on HAART. Effects of NIDU were similar to IDU at CCC. NIDU without IDU is an important contributor to HAART utilization. PMID- 21541017 TI - Pre-admission statin use and in-hospital severity of 2009 pandemic influenza A(H1N1) disease. AB - BACKGROUND: Statins are drugs that are used to lower plasma cholesterol levels. Recently, contradictory claims have been made about possible additional effects of statins on progression of a variety of inflammatory disorders, including infections. We therefore examined the clinical course of patients admitted to hospital with 2009 pandemic influenza A(H1N1), who were or weren't taking statins at time of admission. METHODS: A retrospective case-control study was performed using the United Kingdom Influenza Clinical Information Network (FLU-CIN) database, containing detailed information on 1,520 patients admitted to participating hospitals with confirmed 2009 pandemic influenza A(H1N1) infection between April 2009 and January 2010. We confined our analysis to those aged over 34 years. Univariate analysis was used to calculate unadjusted odds ratios (OR) and 95 percent confidence intervals (95%CI) for factors affecting progression to severe outcome (high dependency or intensive care unit level support) or death (cases); two multivariable logistic regression models were then established for age and sex, and for age, sex, obesity and "indication for statin" (e.g., heart disease or hypercholesterolaemia). RESULTS: We found no statistically significant association between pre-admission statin use and severity of outcome after adjustment for age and sex [adjusted OR: 0.81 (95% CI: 0.46-1.38); n = 571]. After adjustment for age, sex, obesity and indication for statin, the association between pre-admission statin use and severe outcome was not statistically significant; point estimates are compatible with a small but clinically significant protective effect of statin use [adjusted OR: 0.72 (95% CI: 0.38 1.33)]. CONCLUSIONS: In this group of patients hospitalized with pandemic influenza, a significant beneficial effect of pre-admission statin use on the in hospital course of illness was not identified. Although the database from which these observations are derived represents the largest available suitable UK hospital cohort, a larger study would be needed to confirm whether there is any benefit in this setting. PMID- 21541018 TI - Blood magnesium, and the interaction with calcium, on the risk of high-grade prostate cancer. AB - BACKGROUND: Ionized calcium (Ca) and magnesium (Mg) compete as essential messengers to regulate cell proliferation and inflammation. We hypothesized that inadequate Mg levels, perhaps relative to Ca levels (e.g. a high Ca/Mg ratio) are associated with greater prostate cancer risk. STUDY DESIGN: In this biomarker sub study of the Nashville Men's Health Study (NMHS), we included 494 NMHS participants, consisting of 98 high-grade (Gleason>=7) and 100 low-grade cancer cases, 133 prostate intraepithelial neoplasia (PIN) cases, and 163 controls without cancer or PIN at biopsy. Linear and logistic regression were used to determine associations between blood Ca, Mg, and the Ca/Mg ratio across controls and case groups while adjusting for potential confounding factors. RESULTS: Serum Mg levels were significantly lower, while the Ca/Mg ratio was significantly higher, among high-grade cases vs. controls (p = 0.04, p = 0.01, respectively). Elevated Mg was significantly associated with a lower risk of high-grade prostate cancer (OR = 0.26 (0.09, 0.85)). An elevated Ca/Mg ratio was also associated with an increased risk of high-grade prostate cancer (OR = 2.81 (1.24, 6.36) adjusted for serum Ca and Mg). In contrast, blood Ca levels were not significantly associated with prostate cancer or PIN.Mg, Ca, or Ca/Mg levels were not associated with low-grade cancer, PIN, PSA levels, prostate volume, or BPH treatment. CONCLUSION: Low blood Mg levels and a high Ca/Mg ratio were significantly associated with high-grade prostate cancer. These findings suggest Mg affects prostate cancer risk perhaps through interacting with Ca. PMID- 21541019 TI - Ants in a labyrinth: a statistical mechanics approach to the division of labour. AB - Division of labour (DoL) is a fundamental organisational principle in human societies, within virtual and robotic swarms and at all levels of biological organisation. DoL reaches a pinnacle in the insect societies where the most widely used model is based on variation in response thresholds among individuals, and the assumption that individuals and stimuli are well-mixed. Here, we present a spatially explicit model of DoL. Our model is inspired by Pierre de Gennes' 'Ant in a Labyrinth' which laid the foundations of an entire new field in statistical mechanics. We demonstrate the emergence, even in a simplified one dimensional model, of a spatial patterning of individuals and a right-skewed activity distribution, both of which are characteristics of division of labour in animal societies. We then show using a two-dimensional model that the work done by an individual within an activity bout is a sigmoidal function of its response threshold. Furthermore, there is an inverse relationship between the overall stimulus level and the skewness of the activity distribution. Therefore, the difference in the amount of work done by two individuals with different thresholds increases as the overall stimulus level decreases. Indeed, spatial fluctuations of task stimuli are minimised at these low stimulus levels. Hence, the more unequally labour is divided amongst individuals, the greater the ability of the colony to maintain homeostasis. Finally, we show that the non-random spatial distribution of individuals within biological and social systems could be caused by indirect (stigmergic) interactions, rather than direct agent-to-agent interactions. Our model links the principle of DoL with principles in the statistical mechanics and provides testable hypotheses for future experiments. PMID- 21541020 TI - Smaller gene networks permit longer persistence in fast-changing environments. AB - The environments in which organisms live and reproduce are rarely static, and as the environment changes, populations must evolve so that phenotypes match the challenges presented. The quantitative traits that map to environmental variables are underlain by hundreds or thousands of interacting genes whose allele frequencies and epistatic relationships must change appropriately for adaptation to occur. Extending an earlier model in which individuals possess an ecologically critical trait encoded by gene networks of 16 to 256 genes and random or scale free topology, I test the hypothesis that smaller, scale-free networks permit longer persistence times in a constantly-changing environment. Genetic architecture interacting with the rate of environmental change accounts for 78% of the variance in trait heritability and 66% of the variance in population persistence times. When the rate of environmental change is high, the relationship between network size and heritability is apparent, with smaller and scale-free networks conferring a distinct advantage for persistence time. However, when the rate of environmental change is very slow, the relationship between network size and heritability disappears and populations persist the duration of the simulations, without regard to genetic architecture. These results provide a link between genes and population dynamics that may be tested as the -omics and bioinformatics fields mature, and as we are able to determine the genetic basis of ecologically-relevant quantitative traits. PMID- 21541021 TI - Risk factors for non-adherence and loss to follow-up in a three-year clinical trial in Botswana. AB - BACKGROUND: Participant non-adherence and loss to follow-up can compromise the validity of clinical trial results. An assessment of these issues was made in a 3 year tuberculosis prevention trial among HIV-infected adults in Botswana. METHODS AND FINDINGS: Between 11/2004-07/2006, 1995 participants were enrolled at eight public health clinics. They returned monthly to receive bottles of medication and were expected to take daily tablets of isoniazid or placebo for three years. Non adherence was defined as refusing tablet ingestion but agreeing to quarterly physical examinations. Loss to follow-up was defined as not having returned for appointments in >=60 days. Between 10/2008-04/2009, survey interviews were conducted with 83 participants identified as lost to follow-up and 127 identified as non-adherent. As a comparison, 252 randomly selected adherent participants were also surveyed. Multivariate logistic regression analysis was used to identify associations with selected risk factors. Men had higher odds of being non-adherent (adjusted odds ratio (AOR), 2.24; 95% confidence interval [95%CI] 1.24-4.04) and lost to follow-up (AOR 3.08; 95%CI 1.50-6.33). Non-adherent participants had higher odds of reporting difficulties taking the regimen or not knowing if they had difficulties (AOR 3.40; 95%CI 1.75-6.60) and lower odds associated with each year of age (AOR 0.95; 95%CI 0.91-0.98), but other variables such as employment, distance from clinic, alcohol use, and understanding study requirements were not significantly different than controls. Among participants who were non-adherent or lost to follow-up, 40/210 (19.0%) reported that they stopped the medication because of work commitments and 33/210 (15.7%) said they thought they had completed the study. CONCLUSIONS: Men had higher odds of non adherence and loss to follow-up than women. Potential interventions that might improve adherence in trial participants may include:targeting health education for men, reducing barriers, clarifying study expectations, educating employers about HIV/AIDS to help reduce stigma in the workplace, and encouraging employers to support employee health. TRIAL REGISTRATION: ClinicalTrials.gov NCT00164281. PMID- 21541022 TI - Environmental stress-dependent effects of deletions encompassing Hsp70Ba on canalization and quantitative trait asymmetry in Drosophila melanogaster. AB - Hsp70 genes may influence the expression of wing abnormalities in Drosophila melanogaster but their effects on variability in quantitative characters and developmental instability are unclear. In this study, we focused on one of the six Hsp70 genes, Hsp70Ba, and investigated its effects on within- and among individual variability in orbital bristle number, sternopleural bristle number, wing size and wing shape under different environmental conditions. To do this, we studied a newly constructed deletion, Df(3R)ED5579, which encompasses Hsp70Ba and nine non-Hsp genes, in the heterozygous condition and another, Hsp70Ba(304), which deletes only Hsp70Ba, in the homozygous condition. We found no significant effect of both deletions on within-individual variation quantified by fluctuating asymmetry (FA) of morphological traits. On the other hand, the Hsp70Ba(304)/Hsp70Ba(304) genotype significantly increased among-individual variation quantified by coefficient of variation (CV) of bristle number and wing size in female, while the Df(3R)ED5579 heterozygote showed no significant effect. The expression level of Hsp70Ba in the deletion heterozygote was 6 to 20 times higher than in control homozygotes, suggesting that the overexpression of Hsp70Ba did not influence developmental stability or canalization significantly. These findings suggest that the absence of expression of Hsp70Ba increases CV of some morphological traits and that HSP70Ba may buffer against environmental perturbations on some quantitative traits. PMID- 21541023 TI - Calcium uptake and proton transport by acidocalcisomes of Toxoplasma gondii. AB - Acidocalcisomes are acidic calcium stores found in diverse organisms, being conserved from bacteria to humans. They possess an acidic matrix that contains several cations bound to phosphates, which are mainly present in the form of short and long polyphosphate chains. Their matrix is acidified through the action of proton pumps such as a vacuolar proton ATPase and a vacuolar proton pyrophosphatase. Calcium uptake occurs through a Ca(2+)/H(+) countertransporting ATPase located in the membrane of the organelle. Acidocalcisomes have been identified in a variety of microorganisms, including Apicomplexan parasites such as Plasmodium and Eimeria species, and in Toxoplasma gondii. We report the purification and characterization of an acidocalcisome fraction from T. gondii tachyzoites after subcellular fractionation and further discontinuous iodixanol gradient purification. Proton and calcium transport activities in the fraction were characterized by fluorescence microscopy and spectrophotometric methods using acridine orange and arsenazo III, respectively. This work will facilitate the understanding of the function of acidocalcisomes in Apicomplexan parasites, as we can now isolate highly purified fractions that could be used for proteomic analysis to find proteins that may clarify the biogenesis of these organelles. PMID- 21541024 TI - First-line matched related donor hematopoietic stem cell transplantation compared to immunosuppressive therapy in acquired severe aplastic anemia. AB - INTRODUCTION: Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials. METHODS: A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival. RESULTS: 26 non randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies. CONCLUSIONS: Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies. PMID- 21541025 TI - Consensus pathways implicated in prognosis of colorectal cancer identified through systematic enrichment analysis of gene expression profiling studies. AB - BACKGROUND: A large number of gene expression profiling (GEP) studies on prognosis of colorectal cancer (CRC) has been performed, but no reliable gene signature for prediction of CRC prognosis has been found. Bioinformatic enrichment tools are a powerful approach to identify biological processes in high throughput data analysis. PRINCIPAL FINDINGS: We have for the first time collected the results from the 23 so far published independent GEP studies on CRC prognosis. In these 23 studies, 1475 unique, mapped genes were identified, from which 124 (8.4%) were reported in at least two studies, with 54 of them showing consisting direction in expression change between the single studies. Using these data, we attempted to overcome the lack of reproducibility observed in the genes reported in individual GEP studies by carrying out a pathway-based enrichment analysis. We used up to ten tools for overrepresentation analysis of Gene Ontology (GO) categories or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in each of the three gene lists (1475, 124 and 54 genes). This strategy, based on testing multiple tools, allowed us to identify the oxidative phosphorylation chain and the extracellular matrix receptor interaction categories, as well as a general category related to cell proliferation and apoptosis, as the only significantly and consistently overrepresented pathways in the three gene lists, which were reported by several enrichment tools. CONCLUSIONS: Our pathway-based enrichment analysis of 23 independent gene expression profiling studies on prognosis of CRC identified significantly and consistently overrepresented prognostic categories for CRC. These overrepresented categories have been functionally clearly related with cancer progression, and deserve further investigation. PMID- 21541026 TI - Regulator or driving force? The role of turgor pressure in oscillatory plant cell growth. AB - Turgor generates the stress that leads to the expansion of plant cell walls during cellular growth. This has been formalized by the Lockhart equation, which can be derived from the physical laws of the deformation of viscoelastic materials. However, the experimental evidence for such a direct correlation between growth rate and turgor is inconclusive. This has led to challenges of the Lockhart model. We model the oscillatory growth of pollen tubes to investigate this relationship. We couple the Lockhart equation to the dynamical equations for the change in material properties. We find that the correct implementation of the Lockhart equation within a feedback loop leading to low amplitude oscillatory growth predicts that in this system changes in the global turgor do not influence the average growth rate in a linear manner, consistent with experimental observations. An analytic analysis of our model demonstrates in which regime the average growth rate becomes uncorrelated from the turgor pressure. PMID- 21541027 TI - Monitoring procalcitonin in febrile neutropenia: what is its utility for initial diagnosis of infection and reassessment in persistent fever? AB - BACKGROUND: Management of febrile neutropenic episodes (FE) is challenged by lacking microbiological and clinical documentation of infection. We aimed at evaluating the utility of monitoring blood procalcitonin (PCT) in FE for initial diagnosis of infection and reassessment in persistent fever. METHODS: PCT kinetics was prospectively monitored in 194 consecutive FE (1771 blood samples): 65 microbiologically documented infections (MDI, 33.5%; 49 due to non-coagulase negative staphylococci, non-CNS), 68 clinically documented infections (CDI, 35%; 39 deep-seated), and 61 fever of unexplained origin (FUO, 31.5%). RESULTS: At fever onset median PCT was 190 pg/mL (range 30-26'800), without significant difference among MDI, CDI and FUO. PCT peak occurred on day 2 after onset of fever: non-CNS-MDI/deep-seated-CDI (656, 80-86350) vs. FUO (205, 33-771; p<0.001). PCT >500 pg/mL distinguished non-CNS-MDI/deep-seated-CDI from FUO with 56% sensitivity and 90% specificity. PCT was >500 pg/ml in only 10% of FUO (688, 570-771). A PCT peak >500 pg/mL (1196, 524-11950) occurred beyond 3 days of persistent fever in 17/21 (81%) invasive fungal diseases (IFD). This late PCT peak identified IFD with 81% sensitivity and 57% specificity and preceded diagnosis according to EORTC-MSG criteria in 41% of cases. In IFD responding to therapy, median days to PCT <500 pg/mL and defervescence were 5 (1-23) vs. 10 (3 22; p = 0.026), respectively. CONCLUSION: While procalcitonin is not useful for diagnosis of infection at onset of neutropenic fever, it may help to distinguish a minority of potentially severe infections among FUOs on day 2 after onset of fever. In persistent fever monitoring procalcitonin contributes to early diagnosis and follow-up of invasive mycoses. PMID- 21541028 TI - A mighty small heart: the cardiac proteome of adult Drosophila melanogaster. AB - Drosophila melanogaster is emerging as a powerful model system for the study of cardiac disease. Establishing peptide and protein maps of the Drosophila heart is central to implementation of protein network studies that will allow us to assess the hallmarks of Drosophila heart pathogenesis and gauge the degree of conservation with human disease mechanisms on a systems level. Using a gel-LC MS/MS approach, we identified 1228 protein clusters from 145 dissected adult fly hearts. Contractile, cytostructural and mitochondrial proteins were most abundant consistent with electron micrographs of the Drosophila cardiac tube. Functional/Ontological enrichment analysis further showed that proteins involved in glycolysis, Ca(2+)-binding, redox, and G-protein signaling, among other processes, are also over-represented. Comparison with a mouse heart proteome revealed conservation at the level of molecular function, biological processes and cellular components. The subsisting peptidome encompassed 5169 distinct heart associated peptides, of which 1293 (25%) had not been identified in a recent Drosophila peptide compendium. PeptideClassifier analysis was further used to map peptides to specific gene-models. 1872 peptides provide valuable information about protein isoform groups whereas a further 3112 uniquely identify specific protein isoforms and may be used as a heart-associated peptide resource for quantitative proteomic approaches based on multiple-reaction monitoring. In summary, identification of excitation-contraction protein landmarks, orthologues of proteins associated with cardiovascular defects, and conservation of protein ontologies, provides testimony to the heart-like character of the Drosophila cardiac tube and to the utility of proteomics as a complement to the power of genetics in this growing model of human heart disease. PMID- 21541029 TI - Transcriptome profiling of bovine milk oligosaccharide metabolism genes using RNA sequencing. AB - This study examines the genes coding for enzymes involved in bovine milk oligosaccharide metabolism by comparing the oligosaccharide profiles with the expressions of glycosylation-related genes. Fresh milk samples (n = 32) were collected from four Holstein and Jersey cows at days 1, 15, 90 and 250 of lactation and free milk oligosaccharide profiles were analyzed. RNA was extracted from milk somatic cells at days 15 and 250 of lactation (n = 12) and gene expression analysis was conducted by RNA-Sequencing. A list was created of 121 glycosylation-related genes involved in oligosaccharide metabolism pathways in bovine by analyzing the oligosaccharide profiles and performing an extensive literature search. No significant differences were observed in either oligosaccharide profiles or expressions of glycosylation-related genes between Holstein and Jersey cows. The highest concentrations of free oligosaccharides were observed in the colostrum samples and a sharp decrease was observed in the concentration of free oligosaccharides on day 15, followed by progressive decrease on days 90 and 250. Ninety-two glycosylation-related genes were expressed in milk somatic cells. Most of these genes exhibited higher expression in day 250 samples indicating increases in net glycosylation-related metabolism in spite of decreases in free milk oligosaccharides in late lactation milk. Even though fucosylated free oligosaccharides were not identified, gene expression indicated the likely presence of fucosylated oligosaccharides in bovine milk. Fucosidase genes were expressed in milk and a possible explanation for not detecting fucosylated free oligosaccharides is the degradation of large fucosylated free oligosaccharides by the fucosidases. Detailed characterization of enzymes encoded by the 92 glycosylation-related genes identified in this study will provide the basic knowledge for metabolic network analysis of oligosaccharides in mammalian milk. These candidate genes will guide the design of a targeted breeding strategy to optimize the content of beneficial oligosaccharides in bovine milk. PMID- 21541030 TI - Inhibition of fried meat-induced colorectal DNA damage and altered systemic genotoxicity in humans by crucifera, chlorophyllin, and yogurt. AB - Dietary exposures implicated as reducing or causing risk for colorectal cancer may reduce or cause DNA damage in colon tissue; however, no one has assessed this hypothesis directly in humans. Thus, we enrolled 16 healthy volunteers in a 4 week controlled feeding study where 8 subjects were randomly assigned to dietary regimens containing meat cooked at either low (100 degrees C) or high temperature (250 degrees C), each for 2 weeks in a crossover design. The other 8 subjects were randomly assigned to dietary regimens containing the high-temperature meat diet alone or in combination with 3 putative mutagen inhibitors: cruciferous vegetables, yogurt, and chlorophyllin tablets, also in a crossover design. Subjects were nonsmokers, at least 18 years old, and not currently taking prescription drugs or antibiotics. We used the Salmonella assay to analyze the meat, urine, and feces for mutagenicity, and the comet assay to analyze rectal biopsies and peripheral blood lymphocytes for DNA damage. Low-temperature meat had undetectable levels of heterocyclic amines (HCAs) and was not mutagenic, whereas high-temperature meat had high HCA levels and was highly mutagenic. The high-temperature meat diet increased the mutagenicity of hydrolyzed urine and feces compared to the low-temperature meat diet. The mutagenicity of hydrolyzed urine was increased nearly twofold by the inhibitor diet, indicating that the inhibitors enhanced conjugation. Inhibitors decreased significantly the mutagenicity of un-hydrolyzed and hydrolyzed feces. The diets did not alter the levels of DNA damage in non-target white blood cells, but the inhibitor diet decreased nearly twofold the DNA damage in target colorectal cells. To our knowledge, this is the first demonstration that dietary factors can reduce DNA damage in the target tissue of fried-meat associated carcinogenesis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00340743. PMID- 21541031 TI - Comparison of Bayesian clustering and edge detection methods for inferring boundaries in landscape genetics. AB - Recently, techniques available for identifying clusters of individuals or boundaries between clusters using genetic data from natural populations have expanded rapidly. Consequently, there is a need to evaluate these different techniques. We used spatially-explicit simulation models to compare three spatial Bayesian clustering programs and two edge detection methods. Spatially-structured populations were simulated where a continuous population was subdivided by barriers. We evaluated the ability of each method to correctly identify boundary locations while varying: (i) time after divergence, (ii) strength of isolation by distance, (iii) level of genetic diversity, and (iv) amount of gene flow across barriers. To further evaluate the methods' effectiveness to detect genetic clusters in natural populations, we used previously published data on North American pumas and a European shrub. Our results show that with simulated and empirical data, the Bayesian spatial clustering algorithms outperformed direct edge detection methods. All methods incorrectly detected boundaries in the presence of strong patterns of isolation by distance. Based on this finding, we support the application of Bayesian spatial clustering algorithms for boundary detection in empirical datasets, with necessary tests for the influence of isolation by distance. PMID- 21541032 TI - Fabrication of porous scaffolds with a controllable microstructure and mechanical properties by porogen fusion technique. AB - Macroporous scaffolds with controllable pore structure and mechanical properties were fabricated by a porogen fusion technique. Biodegradable material poly (d, l lactide) (PDLLA) was used as the scaffold matrix. The effects of porogen size, PDLLA concentration and hydroxyapatite (HA) content on the scaffold morphology, porosity and mechanical properties were investigated. High porosity (90% and above) and highly interconnected structures were easily obtained and the pore size could be adjusted by varying the porogen size. With the increasing porogen size and PDLLA concentration, the porosity of scaffolds decreases, while its mechanical properties increase. The introduction of HA greatly increases the impact on pore structure, mechanical properties and water absorption ability of scaffolds, while it has comparatively little influence on its porosity under low HA contents. These results show that by adjusting processing parameters, scaffolds could afford a controllable pore size, exhibit suitable pore structure and high porosity, as well as good mechanical properties, and may serve as an excellent substrate for bone tissue engineering. PMID- 21541033 TI - Antioxidant status and immune activity of glycyrrhizin in allergic rhinitis mice. AB - Oxidative stress is considered as a major risk factor that contributes to increased lipid peroxidation and declined antioxidants in some degenerative diseases. Glycyrrhizin is widely used to cure allergic diseases due to its medicinal properties. In the present study, we evaluated the role of glycyrrhizin on lipid peroxidation and antioxidant status in the blood and nasal mucosa of allergic rhinitis (AR) mice. Mice were divided into six groups: normal control mice, model control (MC) mice, three glycyrrhizin-treated mice groups and lycopene-treated mice. Sensitization-associated increase in lipid peroxidation was observed in the blood and nasal mucosa of MC mice. Activities of antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), total antioxidant capacity (TAOC) and levels of glutathione (GSH) were found to be significantly decreased in the blood and nasal mucosa in MC mice when compared to normal control mice. However, normalized lipid peroxidation and antioxidant defenses were reported in the glycyrrhizin-treated and lycopene treated mice. Moreover, glycyrrhizin treatment still enhanced IFN-gamma and reduced IL-4 levels in glycyrrhizin-treated mice. These findings demonstrated that glycyrrhizin treatment enhanced the antioxidant status and decreased the incidence of free radical-induced lipid peroxidation and improved immunity activities in the blood and nasal mucosa of AR mice. PMID- 21541034 TI - Effects of chitin and its derivative chitosan on postharvest decay of fruits: a review. AB - Considerable economic losses to harvested fruits are caused by postharvest fungal decay during transportation and storage, which can be significantly controlled by synthetic fungicides. However, considering public concern over pesticide residues in food and the environment, there is a need for safer alternatives for the control of postharvest decay to substitute synthetic fungicides. As the second most abundant biopolymer renewable source in nature, chitin and its derivative chitosan are widely used in controlling postharvest decay of fruits. This review aims to introduce the effect of chitin and chitosan on postharvest decay in fruits and the possible modes of action involved. We found most of the actions discussed in these researches rest on physiological mechanisms. All of the mechanisms are summarized to lay the groundwork for further studies which should focus on the molecular mechanisms of chitin and chitosan in controlling postharvest decay of fruits. PMID- 21541035 TI - Formation and morphology of Zn(2)Ti(3)O(8) powders using hydrothermal process without dispersant agent or mineralizer. AB - Synthesis of Zn(2)Ti(3)O(8) powders for attenuating UVA using TiCl(4), Zn(NO(3))(2).6H(2)O and NH(4)OH as precursor materials by hydrothermal process has been investigated. The X-ray diffractometry (XRD) results show the phases of ZnO, anatase TiO(2) and Zn(2)Ti(3)O(8) coexisted when the zinc titanate powders were calcined at 600 degrees C for 1 h. When calcined at 900 degrees C for 1 h, the XRD results reveal the existence of ZnO, Zn(2)TiO(4), rutile TiO(2) and ZnTiO(3). Scanning electron microscope (SEM) observations show extensive large agglomeration in the samples. Transmission electron microscope (TEM) and electron diffraction (ED) examination results indicate that ZnTiO(3) crystallites formed with a size of about 5 nm on the matrix of plate-like ZnO when calcined at 700 degrees C for 1 h. The calcination samples have acceptable absorbance at a wavelength of 400 nm, indicating that the zinc titanate precursor powders calcined at 700 degrees C for 1 h can be used as an UVA-attenuating agent. PMID- 21541036 TI - Structural determination of three different series of compounds as Hsp90 inhibitors using 3D-QSAR modeling, molecular docking and molecular dynamics methods. AB - Hsp90 is involved in correcting, folding, maturation and activation of a diverse array of client proteins; it has also been implicated in the treatment of cancer in recent years. In this work, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), molecular docking and molecular dynamics were performed on three different series of Hsp90 inhibitors to build 3D-QSAR models, which were based on the ligand-based or receptor-based methods. The optimum 3D-QSAR models exhibited reasonable statistical characteristics with averaging internal q(2) > 0.60 and external r(2) (pred) > 0.66 for Benzamide tetrahydro-4H-carbazol-4-one analogs (BT), AT13387 derivatives (AT) and Dihydroxylphenyl amides (DA). The results revealed that steric effects contributed the most to the BT model, whereas H-bonding was more important to AT, and electrostatic, hydrophobic, H-bond donor almost contributed equally to the DA model. The docking analysis showed that Asp93, Tyr139 and Thr184 in Hsp90 are important for the three series of inhibitors. Molecular dynamics simulation (MD) further indicated that the conformation derived from docking is basically consistent with the average structure extracted from MD simulation. These results not only lead to a better understanding of interactions between these inhibitors and Hsp90 receptor but also provide useful information for the design of new inhibitors with a specific activity. PMID- 21541037 TI - Identification of receptor tyrosine kinase, discoidin domain receptor 1 (DDR1), as a potential biomarker for serous ovarian cancer. AB - Ovarian cancer, one of the most common gynecological malignancies, has an aggressive phenotype. It is necessary to develop novel and more effective treatment strategies against advanced disease. Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways involved in tumorigenesis, and represent potential targets for anticancer therapies. In this study, we performed cDNA subtraction following polymerase chain reaction (PCR) using degenerate oligonucleotide primers to identify specifically overexpressed PTKs in ovarian cancer. Three PTKs, janus kinase 1, insulin-like growth factor 1 receptor, and discoidin domain receptor 1 (DDR1), were identified and only DDR1 was overexpressed in all ovarian cancer tissues examined for the validation by quantitative real-time PCR. The DDR1 protein was expressed in 63% (42/67) of serous ovarian cancer tissue, whereas it was undetectable in normal ovarian surface epithelium. DDR1 was expressed significantly more frequently in high grade (79%) and advanced stage (77%) tumors compared to low-grade (50%) and early stage (43%) tumors. The expression of the DDR1 protein significantly correlated with poor disease-free survival. Although its functional role and clinical utility remain to be examined in future studies, our results suggest that the expression of DDR1 may serve as both a potential biomarker and a molecular target for advanced ovarian cancer. PMID- 21541038 TI - Epigenetic regulation of cancer-associated genes in ovarian cancer. AB - The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the DNA hypomethylation of some genes. Recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. This discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. The emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. Given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. This review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer associated genes in ovarian cancer. In addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. A better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes. PMID- 21541040 TI - Chemically induced breast tumors in rats are detectable in early stages by contrast enhanced magnetic resonance imaging but not by changes in the acute phase reactants in serum. AB - The present study was undertaken to develop a rat model for monitoring the early development of breast cancer. Twelve female rats were divided into two groups of six rats that were either treated with N-methyl-N-nitrosourea to induce breast cancer or with bacterial lipopolysaccharide to induce inflammation. Serum samples taken from the rats prior to the treatment were used as controls. By the 14th week, presence of the tumor was detectable by contrast enhanced magnetic resonance imaging and confirmed by histopathology. When the serum proteins of the rats were examined by 2-dimensional electrophoresis (2-DE), no difference could be detected in the profiles of all proteins before and 18 weeks after administration of N-methyl-N-nitrosourea. However, higher expression of alpha-1B glycoprotein was detectable by 2-DE in serum samples of rats at the 18th week post-treatment with lipopolysaccharide. PMID- 21541039 TI - Role of versican, hyaluronan and CD44 in ovarian cancer metastasis. AB - There is increasing evidence to suggest that extracellular matrix (ECM) components play an active role in tumor progression and are an important determinant for the growth and progression of solid tumors. Tumor cells interfere with the normal programming of ECM biosynthesis and can extensively modify the structure and composition of the matrix. In ovarian cancer alterations in the extracellular environment are critical for tumor initiation and progression and intra-peritoneal dissemination. ECM molecules including versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis. This review focuses on versican, HA, and CD44 and their potential as therapeutic targets for ovarian cancer. PMID- 21541041 TI - Photodynamic treatment induces an apoptotic pathway involving calcium, nitric oxide, p53, p21-activated kinase 2, and c-Jun N-terminal kinase and inactivates survival signal in human umbilical vein endothelial cells. AB - Photodynamic treatment (PDT) elicits a diverse range of cellular responses, including apoptosis. Previously, we showed that PDT stimulates caspase-3 activity, and subsequent cleavage and activation of p21-activated kinase 2 (PAK2) in human epidermal carcinoma A431 cells. In the current study, pretreatment with nitric oxide (NO) scavengers inhibited PDT-induced mitochondrial membrane potential (MMP) changes, activation of caspase-9, caspase-3, p21-activated protein kinase 2 (PAK2) and c-Jun N-terminal kinase (JNK), and gene expression of p53 and p21 involved in apoptotic signaling. Moreover, PAK2 activity was required for PDT-induced JNK activation and apoptosis. Inhibition of p53 mRNA expression using small interfering RNA (siRNA) additionally blocked activation of PAK2 and apoptosis induced by PDT. Importantly, our data also show that PDT triggers cell death via inactivation of ERK-mediated anti-apoptotic pathway. PDT triggers cell death via inactivation of the HSP90/multi-chaperone complex and subsequent degradation of Ras, further inhibiting anti-apoptotic processes, such as the Ras >ERK signal transduction pathway. Furthermore, we did not observe two-stage JNK activation for regulation of PAK2 activity in the PDT-induced apoptotic pathway in HUVECs, which was reported earlier in A431 cells. Based on the collective results, we have proposed a model for the PDT-triggered inactivation of the survival signal and apoptotic signaling cascade with Rose Bengal (RB), which sequentially involves singlet oxygen, Ca(2+), NO, p53, caspase-9, caspase-3, PAK2, and JNK. PMID- 21541042 TI - FurinDB: A database of 20-residue furin cleavage site motifs, substrates and their associated drugs. AB - FurinDB (freely available online at http://www.nuolan.net/substrates.html) is a database of furin substrates. This database includes experimentally verified furin cleavage sites, substrates, species, experimental methods, original publications of experiments and associated drugs targeting furin substrates. The current database release contains 126 furin cleavage sites from three species: mammals, bacteria and viruses. A main feature of this database is that all furin cleavage sites are recorded as a 20-residue motif, including one core region (eight amino acids, P6-P2') and two flanking solvent accessible regions (eight amino acids, P7-P14, and four amino acids, P3'-P6'), that represent our current understanding of the molecular biology of furin cleavage. This database is important for understanding the molecular evolution and relationships between sequence motifs, 3D structures, cellular functions and physical properties required by furin for cleavage, and for elucidating the molecular mechanisms and the progression of furin cleavage associated human diseases, including pathogenic infections, neurological disorders, tumorigenesis, tumor invasion, angiogenesis, and metastasis. FurinDB database will be a solid addition to the publicly available infrastructure for scientists in the field of molecular biology. PMID- 21541043 TI - In vitro binding capacity of bile acids by defatted corn protein hydrolysate. AB - Defatted corn protein was digested using five different proteases, Alcalase, Trypsin, Neutrase, Protamex and Flavourzyme, in order to produce bile acid binding peptides. Bile acid binding capacity was analyzed in vitro using peptides from different proteases of defatted corn hydrolysate. Some crystalline bile acids like sodium glycocholate, sodium cholate and sodium deoxycholate were individually tested using HPLC to see which enzymes can release more peptides with high bile acid binding capacity. Peptides from Flavourzyme defatted corn hydrolysate exhibited significantly (p < 0.05) stronger bile acid binding capacity than all others hydrolysates tested and all crystalline bile acids tested were highly bound by cholestyramine, a positive control well known as a cholesterol-reducing agent. The bile acid binding capacity of Flavourzyme hydrolysate was almost preserved after gastrointestinal proteases digestion. The molecular weight of Flavourzyme hydrolysate was determined and most of the peptides were found between 500-180 Da. The results showed that Flavourzyme hydrolysate may be used as a potential cholesterol-reducing agent. PMID- 21541044 TI - Lycium barbarum polysaccharides reduce exercise-induced oxidative stress. AB - The purpose of the present study was to investigate the effects of Lycium barbarum polysaccharides (LBP) on exercise-induced oxidative stress in rats. Rats were divided into four groups, i.e., one control group and three LBP treated groups. The animals received an oral administration of physiological saline or LBP (100, 200 and 400 mg/kg body weight) for 28 days. On the day of the exercise test, rats were required to run to exhaustion on the treadmill. Body weight, endurance time, malondialdehyde (MDA), super oxide dismutase (SOD) and glutathione peroxidase (GPX) level of rats were measured. The results showed that the body weight of rats in LBP treated groups were not significantly different from that in the normal control group before and after the experiment (P > 0.05). After exhaustive exercise, the mean endurance time of treadmill running to exhaustion of rats in LBP treated groups were significantly prolonged compared with that in the normal control group. MDA levels of rats in LBP treated groups were significantly decreased compared with that in the normal control group (P < 0.05). SOD and GPX levels of rats in LBP treated groups were significantly increased compared with that in the normal control group (P < 0.05). Together, these results indicate that LBP was effective in preventing oxidative stress after exhaustive exercise. PMID- 21541045 TI - Design of new competitive dengue NS2B/NS3 protease inhibitors-a computational approach. AB - Dengue is a serious disease which has become a global health burden in the last decade. Currently, there are no approved vaccines or antiviral therapies to combat the disease. The increasing spread and severity of the dengue virus infection emphasizes the importance of drug discovery strategies that could efficiently and cost-effectively identify antiviral drug leads for development into potent drugs. To this effect, several computational approaches were applied in this work. Initially molecular docking studies of reference ligands to the DEN2 NS2B/NS3 serine protease were carried out. These reference ligands consist of reported competitive inhibitors extracted from Boesenbergia rotunda (i.e., 4 hydroxypanduratin A and panduratin A) and three other synthesized panduratin A derivative compounds (i.e., 246DA, 2446DA and 20H46DA). The design of new lead inhibitors was carried out in two stages. In the first stage, the enzyme complexed to the reference ligands was minimized and their complexation energies (i.e., sum of interaction energy and binding energy) were computed. New compounds as potential dengue inhibitors were then designed by putting various substituents successively on the benzyl ring A of the reference molecule. These substituted benzyl compounds were then computed for their enzyme-ligand complexation energies. New enzyme-ligand complexes, exhibiting the lowest complexation energies and closest to the computed energy for the reference compounds, were then chosen for the next stage manipulation and design, which involved substituting positions 4 and 5 of the benzyl ring A (positions 3 and 4 for 2446DA) with various substituents. PMID- 21541046 TI - Effect of CO(2) enrichment on synthesis of some primary and secondary metabolites in ginger (Zingiber officinale Roscoe). AB - The effect of two different CO(2) concentrations (400 and 800 MUmol mol(-1)) on the photosynthesis rate, primary and secondary metabolite syntheses and the antioxidant activities of the leaves, stems and rhizomes of two Zingiber officinale varieties (Halia Bentong and Halia Bara) were assessed in an effort to compare and validate the medicinal potential of the subterranean part of the young ginger. High photosynthesis rate (10.05 MUmol CO(2) m(-2)s(-1) in Halia Bara) and plant biomass (83.4 g in Halia Bentong) were observed at 800 MUmol mol( 1) CO(2). Stomatal conductance decreased and water use efficiency increased with elevated CO(2) concentration. Total flavonoids (TF), total phenolics (TP), total soluble carbohydrates (TSC), starch and plant biomass increased significantly (P <= 0.05) in all parts of the ginger varieties under elevated CO(2) (800 MUmol mol(-1)). The order of the TF and TP increment in the parts of the plant was rhizomes > stems > leaves. More specifically, Halia Bara had a greater increase of TF (2.05 mg/g dry weight) and TP (14.31 mg/g dry weight) compared to Halia Bentong (TF: 1.42 mg/g dry weight; TP: 9.11 mg/g dry weight) in average over the whole plant. Furthermore, plants with the highest rate of photosynthesis had the highest TSC and phenolics content. Significant differences between treatments and species were observed for TF and TP production. Correlation coefficient showed that TSC and TP content are positively correlated in both varieties. The antioxidant activity, as determined by the ferric reducing/antioxidant potential (FRAP) activity, increased in young ginger grown under elevated CO(2). The FRAP values for the leaves, rhizomes and stems extracts of both varieties grown under two different CO(2) concentrations (400 and 800 MUmol mol(-1)) were significantly lower than those of vitamin C (3107.28 MUmol Fe (II)/g) and alpha-tocopherol (953 MUmol Fe (II)/g), but higher than that of BHT (74.31 MUmol Fe (II)/g). These results indicate that the plant biomass, primary and secondary metabolite synthesis, and following that, antioxidant activities of Malaysian young ginger varieties can be enhanced through controlled environment (CE) and CO(2) enrichment. PMID- 21541047 TI - Effects of intermediates between vitamins K(2) and K(3) on mammalian DNA polymerase inhibition and anti-inflammatory activity. AB - Previously, we reported that vitamin K(3) (VK(3)), but not VK(1) or VK(2) (=MK 4), inhibits the activity of human DNA polymerase gamma (pol gamma). In this study, we chemically synthesized three intermediate compounds between VK(2) and VK(3), namely MK-3, MK-2 and MK-1, and investigated the inhibitory effects of all five compounds on the activity of mammalian pols. Among these compounds, MK-2 was the strongest inhibitor of mammalian pols alpha, kappa and lambda, which belong to the B, Y and X families of pols, respectively; whereas VK(3) was the strongest inhibitor of human pol gamma, an A-family pol. MK-2 potently inhibited the activity of all animal species of pol tested, and its inhibitory effect on pol lambda activity was the strongest with an IC(50) value of 24.6 MUM. However, MK-2 did not affect the activity of plant or prokaryotic pols, or that of other DNA metabolic enzymes such as primase of pol alpha, RNA polymerase, polynucleotide kinase or deoxyribonuclease I. Because we previously found a positive relationship between pol lambda inhibition and anti-inflammatory action, we examined whether these compounds could inhibit inflammatory responses. Among the five compounds tested, MK-2 caused the greatest reduction in 12-O tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear. In addition, in a cell culture system using mouse macrophages, MK-2 displayed the strongest suppression of the production of tumor necrosis factor (TNF)-alpha induced by lipopolysaccharide (LPS). Moreover, MK-2 was found to inhibit the action of nuclear factor (NF)-kappaB. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of MK-2 in mice led to suppression of TNF-alpha production in serum. In conclusion, this study has identified VK(2) and VK(3) intermediates, such as MK-2, that are promising anti-inflammatory candidates. PMID- 21541048 TI - Expression and clinical role of protein of regenerating liver (PRL) phosphatases in ovarian carcinoma. AB - The present study analyzed the expression and clinical role of the protein of regenerating liver (PRL) phosphatase family in ovarian carcinoma. PRL1-3 mRNA expression was studied in 184 tumors (100 effusions, 57 primary carcinomas, 27 solid metastases) using RT-PCR. PRL-3 protein expression was analyzed in 157 tumors by Western blotting. PRL-1 mRNA levels were significantly higher in effusions compared to solid tumors (p < 0.001), and both PRL-1 and PRL-2 were overexpressed in pleural compared to peritoneal effusions (p = 0.001). PRL-3 protein expression was significantly higher in primary diagnosis pre-chemotherapy compared to post-chemotherapy disease recurrence effusions (p = 0.003). PRL-1 mRNA expression in effusions correlated with longer overall survival (p = 0.032), and higher levels of both PRL-1 and PRL-2 mRNA correlated with longer overall survival for patients with pre-chemotherapy effusions (p = 0.022 and p = 0.02, respectively). Analysis of the effect of laminin on PRL-3 expression in ovarian carcinoma cells in vitro showed dose-dependent PRL-3 expression in response to exogenous laminin, mediated by Phospholipase D. In contrast to previous studies associating PRL-3 with poor outcome, our data show that PRL-3 expression has no clinical role in ovarian carcinoma, whereas PRL-1 and PRL-2 expression is associated with longer survival, suggesting that PRL phosphatases may be markers of improved outcome in this cancer. PMID- 21541049 TI - Antioxidant activities of fractions of polymeric procyanidins from stem bark of Acacia confusa. AB - The polymeric procyanidins extracted from Acacia confusa stem bark were fractionated with a step gradient of water, methanol and acetone on a Sephadex LH 20 column. The antioxidant activity of the collected fractions was investigated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and ferric reducing/antioxidant power (FRAP) assays. All fractions possessed potent antioxidant activity with the highest activity observed for fraction F9. The matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and reversed-phase high performance liquid chromatography (RP HPLC) analyses suggested that the collected fractions consisted primarily of oligomeric and polymeric procyanidins, with different polymer ranges and most abundant polymer size. For each fraction, catechin and epicatechin were present as both terminal and extension units, and epicatechin was the major component in the extended chain. The mean degree of polymerization (mDP) of each fraction differed, ranging from 1.68 (fraction F2) to 17.31 (fraction F11). There was a relationship between antioxidant activity (IC50/DPPH and FRAP) and mDP (R(2) (DPPH) = 0.861, P = 0.006 and R(2) (FRAP) = 0.608, P = 0.038), respectively. However, the highest antioxidant activity of fraction (F9) was not coincident with the maximum mDP of fraction (F11). PMID- 21541050 TI - Correlation of the rates of solvolysis of neopentyl chloroformate-a recommended protecting agent. AB - The specific rates of solvolysis of neopentyl chloroformate (1) have been determined in 21 pure and binary solvents at 45.0 degrees C. In most solvents the values are essentially identical to those for ethyl and n-propyl chloroformates. However, in aqueous-1,1,1,3,3,3-hexafluoro-2-propanol mixtures (HFIP) rich in fluoroalcohol, 1 solvolyses appreciably faster than the other two substrates. Linear free energy relationship (LFER) comparison of the specific rates of solvolysis of 1 with those for phenyl chloroformate and those for n propyl chloroformate are helpful in the mechanistic considerations, as is also the treatment in terms of the Extended Grunwald-Winstein equation. It is proposed that the faster reaction for 1 in HFIP rich solvents is due to the influence of a 1,2-methyl shift, leading to a tertiary alkyl cation, outweighing the only weak nucleophilic solvation of the cation possible in these low nucleophilicity solvents. PMID- 21541051 TI - Development of a chitosan-based biofoam: application to the processing of a porous ceramic material. AB - Developing biofoams constitutes a challenging issue for several applications. The present study focuses on the development of a chitosan-based biofoam. Solutions of chitosan in acetic acid were dried under vacuum to generate foams with high order structures. Chitosan concentration influenced significantly the morphology of developed porosity and the organization of pores in the material. Physico chemical characterizations were performed to investigate the effects of chitosan concentration on density and thermal conductivity of foams. Even if chitosan based biofoams exhibit interesting insulating properties (typically around 0.06 W.m(-1).K(-1)), it has been shown that their durabilities are limited when submitted to a wet media. So, a way of application consists to elaborate a ceramic material with open porosity from a slurry prepared with an organic solvent infiltrating the porous network of the foam. PMID- 21541052 TI - N-acetyl glucosamine obtained from chitin by chitin degrading factors in Chitinbacter tainanesis. AB - A novel chitin-degrading aerobe, Chitinibacter tainanensis, was isolated from a soil sample from southern Taiwan, and was proved to produce N-acetyl glucosamine (NAG). Chitin degrading factors (CDFs) were proposed to be the critical factors to degrade chitin in this work. When C. tainanensis was incubated with chitin, CDFs were induced and chitin was converted to NAG. CDFs were found to be located on the surface of C. tainanensis. N-Acetylglucosaminidase (NAGase) and endochitinase activities were found in the debris, and the activity of NAGase was much higher than that of endochitinase. The optimum pH of the enzymatic activity was about 7.0, while that of NAG production by the debris was 5.3. These results suggested that some factors in the debris, in addition to NAGase and endochitinase, were crucial for chitin degradation. PMID- 21541053 TI - Studies of new fused benzazepine as selective dopamine D3 receptor antagonists using 3D-QSAR, molecular docking and molecular dynamics. AB - In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q(2) = 0.603, R(2) (ncv) = 0.829, R(2) (pre) = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q(2) = 0.506, R(2) (ncv) =0.838, R(2) (pre) = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R(3) substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R(1) substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists. PMID- 21541054 TI - Role of rho kinase in microvascular damage following cerebral ischemia reperfusion in rats. AB - Rho kinase (ROCK) is a well-known downstream effector of Rho and plays an important role in various physiopathological processes. In this study, we aim to investigate the correlation between ROCK and microvascular damage in rat brain subjected to middle cerebral artery occlusion (MCAO) and reperfusion, and to elucidate the mechanisms underlying the microvascular damage. ROCK and matrix metalloproteinase 9 (MMP9) mRNA levels were determined by real time quantitative PCR, Laminin was detected by immunofluorescence and Blood Brain Barrier (BBB) permeability was examined by Evans Blue (EB) in rat MCAO models. We observed similar patterns of changes in ROCK expression, brain EB content, and Laminin expression at different time points after brain ischemia. Statistical analysis further confirmed a significant linear correlation of ROCK expression with the onset of microvascular damage in brain. Furthermore, the ROCK inhibitor fasudil decreased brain EB content but increased Laminin expression. These results provide strong evidence that ROCK mediates microvascular damage. In addition, we found that fasudil could significantly inhibit MMP9 expression induced by ischemia. Thus, our findings suggest that ROCK promotes microvascular damage by upregulating MMP9 and reveal ROCK as a promising therapeutic target for stroke. PMID- 21541055 TI - Characterization and emulsification properties of rhamnolipid and sophorolipid biosurfactants and their applications. AB - Due to their non-toxic nature, biodegradability and production from renewable resources, research has shown an increasing interest in the use of biosurfactants in a wide variety of applications. This paper reviews the characterization of rhamnolipid and sophorolipid biosurfactants based on their hydrophilicity/hydrophobicity and their ability to form microemulsions with a range of oils without additives. The use of the biosurfactants in applications such as detergency and vegetable oil extraction for biodiesel application is also discussed. Rhamnolipid was found to be a hydrophilic surfactant while sophorolipid was found to be very hydrophobic. Therefore, rhamnolipid and sophorolipid biosurfactants in mixtures showed robust performance in these applications. PMID- 21541056 TI - Molecular arrangement in self-assembled azobenzene-containing thiol monolayers at the individual domain level studied through polarized near-field Raman spectroscopy. AB - 6-[4-(phenylazo)phenoxy]hexane-1-thiol self-assembled monolayers deposited on a gold surface form domain-like structures possessing a high degree of order with virtually all the molecules being identically oriented with respect to the surface plane. We show that, by using polarized near-field Raman spectroscopy, it is possible to derive the Raman scattering tensor of the ordered layer and consequently, the in-plane molecular orientation at the individual domain level. More generally, this study extends the application domain of the near-field Raman scattering selection rules from crystals to ordered organic structures. PMID- 21541057 TI - A classification study of respiratory Syncytial Virus (RSV) inhibitors by variable selection with random forest. AB - Experimental pEC(50)s for 216 selective respiratory syncytial virus (RSV) inhibitors are used to develop classification models as a potential screening tool for a large library of target compounds. Variable selection algorithm coupled with random forests (VS-RF) is used to extract the physicochemical features most relevant to the RSV inhibition. Based on the selected small set of descriptors, four other widely used approaches, i.e., support vector machine (SVM), Gaussian process (GP), linear discriminant analysis (LDA) and k nearest neighbors (kNN) routines are also employed and compared with the VS-RF method in terms of several of rigorous evaluation criteria. The obtained results indicate that the VS-RF model is a powerful tool for classification of RSV inhibitors, producing the highest overall accuracy of 94.34% for the external prediction set, which significantly outperforms the other four methods with the average accuracy of 80.66%. The proposed model with excellent prediction capacity from internal to external quality should be important for screening and optimization of potential RSV inhibitors prior to chemical synthesis in drug development. PMID- 21541058 TI - Application of molecular topology for the prediction of reaction yields and anti inflammatory activity of heterocyclic amidine derivatives. AB - Topological-mathematical models based on multiple linear regression analyses have been built to predict the reaction yields and the anti-inflammatory activity of a set of heterocylic amidine derivatives, synthesized under environmental friendly conditions, using microwave irradiation. Two models with three variables each were selected. The models were validated by cross-validation and randomization tests. The final outcome demonstrates a good agreement between the predicted and experimental results, confirming the robustness of the method. These models also enabled the screening of virtual libraries for new amidine derivatives predicted to show higher values of reaction yields and anti-inflammatory activity. PMID- 21541059 TI - Effect of annealing temperature on the optical spectra of CdS thin films deposited at low solution concentrations by Chemical Bath Deposition (CBD) Technique. AB - Two different concentrations of CdCl(2) and (NH(2))(2)CS were used to prepare CdS thin films, to be deposited on glass substrate by chemical bath deposition (CBD) technique. CdCl(2) (0.000312 M and 0.000625 M) was employed as a source of Cd(2+) while (NH(2))(2)CS (0.00125 M and 0.000625 M) for S(2-) at a constant bath temperature of 70 degrees C. Adhesion of the deposited films was found to be very good for all the solution concentrations of both reagents. The films were air-annealed at a temperature between 200 degrees C to 360 degrees C for one hour. The minimum thickness was observed to be 33.6 nm for film annealed at 320 degrees C. XRD analyses reveal that the films were cubic along with peaks of hexagonal phase for all film samples. The crystallite size of the films decreased from 41.4 nm to 7.4 nm with the increase of annealing temperature for the CdCl(2) (0.000312 M). Optical energy band gap (E(g)), Urbach energy (E(u)) and absorption coefficient (alpha) have been calculated from the transmission spectral data. These parameters have been discussed as a function of annealing temperature and solution concentration. The best transmission (about 97%) was obtained for the air-annealed films at higher temperature at CdCl(2) (0.000312 M). PMID- 21541060 TI - The effects of G-CSF on proliferation of mouse myocardial microvascular endothelial cells. AB - This paper explores the effect of granulocyte colony-stimulating factor (G-CSF) on mouse myocardial microvascular endothelial cell (CMECs) proliferation. CMECs were harvested from C57/BL6 mice. CMECs were cultured in medium containing G-CSF (0 ng/mL, 20 ng/mL, 40 ng/mL, 60 ng/mL) for five days. Proliferative activity of CMECs was examined by CCK-8 method. Hypoxia inducible factor-1 (HIF-1) and p53 expression levels was determined from the mRNA obtained by reverse transcription polymerase chain reaction (RT-PCR). Results showed that the purity quotient of the CMECs, which were cultured by the method of modified myocardial tissue explant culture, was higher than 95%. Compared with control untreated cells, the proliferative activity of CMECs and the expression level of HIF-1 mRNA in these cells were enhanced by G-CSF treatment, whereas the expression level of p53 mRNA was markedly reduced. It may be concluded that G-CSF could promote the proliferative activity of CMECs, which might be mediated by upregulation of HIF-1 and downregulation of p53. PMID- 21541061 TI - Accounting for large amplitude protein deformation during in silico macromolecular docking. AB - Rapid progress of theoretical methods and computer calculation resources has turned in silico methods into a conceivable tool to predict the 3D structure of macromolecular assemblages, starting from the structure of their separate elements. Still, some classes of complexes represent a real challenge for macromolecular docking methods. In these complexes, protein parts like loops or domains undergo large amplitude deformations upon association, thus remodeling the surface accessible to the partner protein or DNA. We discuss the problems linked with managing such rearrangements in docking methods and we review strategies that are presently being explored, as well as their limitations and success. PMID- 21541063 TI - In vitro and in vivo anti-hyperglycemic effects of Omija (Schizandra chinensis) fruit. AB - The entrocytes of the small intestine can only absorb monosaccharides such as glucose and fructose from our diet. The intestinal absorption of dietary carbohydrates such as maltose and sucrose is carried out by a group of alpha glucosidases. Inhibition of these enzymes can significantly decrease the postprandial increase of blood glucose level after a mixed carbohydrate diet. Therefore, the inhibitory activity of Omija (Schizandra chinensis) extract against rat intestinal alpha-glucosidase and porcine pancreatic alpha-amylase were investigated in vitro and in vivo. The in vitro inhibitory activities of water extract of Omija pulp/skin (OPE) on alpha-glucosidase and alpha-amylase were potent when compared to Omija seeds extract (OSE). The postprandial blood glucose lowering effect of Omija extracts was compared to a known type 2 diabetes drug (Acarbose), a strong alpha-glucosidase inhibitor in the Sprague-Dawley (SD) rat model. In rats fed on sucrose, OPE significantly reduced the blood glucose increase after sucrose loading. Furthermore, the oxygen radical absorbance capacity (ORAC) of OSE and OPE was evaluated. OPE had higher peroxyl radical absorbing activity than OSE. These results suggest that Omija, which has high ORAC value with alpha-glucosidase inhibitory activity and blood glucose lowering effect, could be physiologically useful for treatment of diabetes, although clinical trials are needed. PMID- 21541062 TI - Claudin 4 Is differentially expressed between ovarian cancer subtypes and plays a role in spheroid formation. AB - Claudin 4 is a cellular adhesion molecule that is frequently overexpressed in ovarian cancer and other epithelial cancers. In this study, we sought to determine whether the expression of claudin 4 is associated with outcome in ovarian cancer patients and may be involved in tumor progression. We examined claudin 4 expression in ovarian cancer tissues and cell lines, as well as by immunohistochemical staining of tissue microarrays (TMAs; n = 500), spheroids present in patients' ascites, and spheroids formed in vitro. Claudin 4 was expressed in nearly 70% of the ovarian cancer tissues examined and was differentially expressed across ovarian cancer subtypes, with the lowest expression in clear cell subtype. No association was found between claudin 4 expression and disease-specific survival in any subtype. Claudin 4 expression was also observed in multicellular spheroids obtained from patients' ascites. Using an in vitro spheroid formation assay, we found that NIH:OVCAR5 cells treated with shRNA against claudin 4 required a longer time to form compact spheroids compared to control NIH:OVCAR5 cells that expressed high levels of claudin 4. The inability of the NIH:OVCAR5 cells treated with claudin 4 shRNA to form compact spheroids was verified by FITC-dextran exclusion. These results demonstrate a role for claudin 4 and tight junctions in spheroid formation and integrity. PMID- 21541064 TI - Biodegradable tri-block copolymer poly(lactic acid)-poly(ethylene glycol)-poly(l lysine)(PLA-PEG-PLL) as a non-viral vector to enhance gene transfection. AB - Low cytotoxicity and high gene transfection efficiency are critical issues in designing current non-viral gene delivery vectors. The purpose of the present work was to synthesize the novel biodegradable poly (lactic acid)-poly(ethylene glycol)-poly(l-lysine) (PLA-PEG-PLL) copolymer, and explore its applicability and feasibility as a non-viral vector for gene transport. PLA-PEG-PLL was obtained by the ring-opening polymerization of Lys(Z)-NCA onto amine-terminated NH(2)-PEG PLA, then acidolysis to remove benzyloxycarbonyl. The tri-block copolymer PLA-PEG PLL combined the characters of cationic polymer PLL, PLA and PEG: the self assembled nanoparticles (NPs) possessed a PEG loop structure to increase the stability, hydrophobic PLA segments as the core, and the primary E-amine groups of lysine in PLL to electrostatically interact with negatively charged phosphate groups of DNA to deposit with the PLA core. The physicochemical properties (morphology, particle size and surface charge) and the biological properties (protection from nuclease degradation, plasma stability, in vitro cytotoxicity, and in vitro transfection ability in HeLa and HepG2 cells) of the gene-loaded PLA PEG-PLL nanoparticles (PLA-PEG-PLL NPs) were evaluated, respectively. Agarose gel electrophoresis assay confirmed that the PLA-PEG-PLL NPs could condense DNA thoroughly and protect DNA from nuclease degradation. Initial experiments showed that PLA-PEG-PLL NPs/DNA complexes exhibited almost no toxicity and higher gene expression (up to 21.64% in HepG2 cells and 31.63% in HeLa cells) than PEI/DNA complexes (14.01% and 24.22%). These results revealed that the biodegradable tri block copolymer PLA-PEG-PLL might be a very attractive candidate as a non-viral vector and might alleviate the drawbacks of the conventional cationic vectors/DNA complexes for gene delivery in vivo. PMID- 21541065 TI - Comparison of free energy surfaces calculations from ab initio molecular dynamic simulations at the example of two transition metal catalyzed reactions. AB - We carried out ab initio molecular dynamic simulations in order to determine the free energy surfaces of two selected reactions including solvents, namely a rearrangement of a ruthenium oxoester in water and a carbon dioxide addition to a palladium complex in carbon dioxide. For the latter reaction we also investigated the gas phase reaction in order to take solvent effects into account. We used two techniques to reconstruct the free energy surfaces: thermodynamic integration and metadynamics. Furthermore, we gave a reasonable error estimation of the computed free energy surface. We calculated a reaction barrier of DeltaF = 59.5 +/- 8.5 kJ mol(-1) for the rearrangement of a ruthenium oxoester in water from thermodynamic integration. For the carbon dioxide addition to the palladium complex in carbon dioxide we found a DeltaF = 44.9 +/- 3.3 kJ mol(-1) from metadynamics simulations with one collective variable. The investigation of the same reactions in the gas phase resulted in DeltaF = 24.9 +/- 6.7 kJ mol(-1) from thermodynamic integration, in DeltaF = 26.7 +/- 2.3 kJ mol(-1) from metadynamics simulations with one collective variable, and in DeltaF = 27.1 +/- 5.9 kJ mol(-1) from metadynamics simulations with two collective variables. PMID- 21541066 TI - Anchoring intrinsically disordered proteins to multiple targets: lessons from N terminus of the p53 protein. AB - Anchor residues, which are deeply buried upon binding, play an important role in protein-protein interactions by providing recognition specificity and facilitating the binding kinetics. Up to now, studies on anchor residues have been focused mainly on ordered proteins. In this study, we investigated anchor residues in intrinsically disordered proteins (IDPs) which are flexible in the free state. We identified the anchor residues of the N-terminus of the p53 protein (Glu17-Asn29, abbreviated as p53N) which are involved in binding with two different targets (MDM2 and Taz2), and analyzed their side chain conformations in the unbound states. The anchor residues in the unbound p53N were found to frequently sample conformations similar to those observed in the bound complexes (i.e., Phe19, Trp23, and Leu26 in the p53N-MDM2 complex, and Leu22 in the p53N Taz2 complex). We argue that the bound-like conformations of the anchor residues in the unbound state are important for controlling the specific interactions between IDPs and their targets. Further, we propose a mechanism to account for the binding promiscuity of IDPs in terms of anchor residues and molecular recognition features (MoRFs). PMID- 21541067 TI - Pregnant and nonpregnant women in cape town, South Africa: drug use, sexual behavior, and the need for comprehensive services. AB - The multiple risks associated with methamphetamine use are of serious concern for women. These risks and consequences are magnified during pregnancy. This secondary analysis of a parent study compared 26 pregnant to 356 nonpregnant women in Cape Town, South Africa, on selected demographic, psychosocial, and HIV risk domains to identify their treatment service needs. Proportionally, more pregnant than nonpregnant women are using methamphetamine, P = .01, although a very high rate of women used methamphetamine. Women reported similar monthly rates of sexual intercourse, but pregnant women were significantly less likely to report condom use, P < .0001, maintaining their risky behavior. Both groups reported elevated Center for Epidemiological Studies Depression Scale CES-D means, suggesting a need for depression treatment. Results demonstrate a pervasive need for women's comprehensive treatment, regardless of pregnancy status. Moreover, findings support the urgent need for women-focused and pregnancy-specific treatment services for methamphetamine use. Finally, a job skills training/employment component focus is suggested. PMID- 21541068 TI - HIV-Associated Tuberculosis in the Newborn and Young Infant. AB - Each year, approximately 250 000 women die during pregnancy, delivery, or postpartum. Maternal mortality rates due to tuberculosis (TB) and HIV in Sub Saharan Africa now supersede obstetric-related causes of mortality. The majority of cases occur in population-dense regions of Africa and Asia where TB is endemic. The vertical transmission rate of tuberculosis is 15%, the overall vertical transmission rate of HIV in resource-limited settings with mono- or dual ARV therapy varies from 1.9% to 10.7%. If the millennium development goals are to be achieved, both HIV and TB must be prevented. The essential aspect of TB prevention and detection in the newborn is the maternal history and a positive HIV status in the mother. Perinatal outcomes are guarded even with treatment of both diseases. Exclusive breast feeding is recommended. The community and social impact are crippling. The social issues aggravate the prognosis of these two diseases. PMID- 21541069 TI - Initial feasibility of a woman-focused intervention for pregnant african-american women. AB - African-American women who use crack are vulnerable to HIV because of the complex social circumstances in which they live. Drug-abuse treatment for these women during pregnancy may provide time for changing risk behaviors. This paper examines the initial 6-month feasibility of a women-focused HIV intervention, the Women's CoOp, adapted for pregnant women, relative to treatment-as-usual among 59 pregnant African-American women enrolled in drug-abuse treatment. At treatment entry, the women were largely homeless, unemployed, practicing unsafe sex, and involved in violence. Results indicated marked reductions in homelessness, use of cocaine and illegal drugs, involvement in physical violence, and an increase in knowledge of HIV from baseline to 6-month followup for both conditions. Findings suggest that the Women's CoOp intervention could be successfully adapted to treat this hard-to-reach population. Future studies should examine the efficacy of the pregnancy-adapted Women's CoOp for women not enrolled in drug-abuse treatment. PMID- 21541070 TI - Toxicokinetics of kava. AB - Kava is traditionally consumed by South Pacific islanders as a drink and became popular in Western society as a supplement for anxiety and insomnia. Kava extracts are generally well tolerated, but reports of hepatotoxicity necessitated an international reappraisal of its safety. Hepatotoxicity can occur as an acute, severe form or a chronic, mild form. Inflammation appears to be involved in both forms and may result from activation of liver macrophages (Kupffer cells), either directly or via kava metabolites. Pharmacogenomics may influence the severity of this inflammatory response. PMID- 21541071 TI - ModEnzA: Accurate Identification of Metabolic Enzymes Using Function Specific Profile HMMs with Optimised Discrimination Threshold and Modified Emission Probabilities. AB - Various enzyme identification protocols involving homology transfer by sequence sequence or profile-sequence comparisons have been devised which utilise Swiss Prot sequences associated with EC numbers as the training set. A profile HMM constructed for a particular EC number might select sequences which perform a different enzymatic function due to the presence of certain fold-specific residues which are conserved in enzymes sharing a common fold. We describe a protocol, ModEnzA (HMM-ModE Enzyme Annotation), which generates profile HMMs highly specific at a functional level as defined by the EC numbers by incorporating information from negative training sequences. We enrich the training dataset by mining sequences from the NCBI Non-Redundant database for increased sensitivity. We compare our method with other enzyme identification methods, both for assigning EC numbers to a genome as well as identifying protein sequences associated with an enzymatic activity. We report a sensitivity of 88% and specificity of 95% in identifying EC numbers and annotating enzymatic sequences from the E. coli genome which is higher than any other method. With the next-generation sequencing methods producing a huge amount of sequence data, the development and use of fully automated yet accurate protocols such as ModEnzA is warranted for rapid annotation of newly sequenced genomes and metagenomic sequences. PMID- 21541072 TI - Obstetric opinions regarding the method of delivery in women that have had surgery for retinal detachment. AB - OBJECTIVES: We sought to determine international obstetric opinions regarding the influence of a history of rhegmatogenous retinal detachment on the management of labour and to review the evidence base. DESIGN: A questionnaire containing closed questions, with pre-coded response opinions, was designed to obtain a cross section of the obstetric opinions. SETTING: Questionnaires were distributed at the 20th European Congress of Obstetrics and Gynaecology in Lisbon, Portugal. PARTICIPANTS: One hundred questionnaires were distributed among obstetricians attending the congress and 74 agreed to participate. MAIN OUTCOME MEASURES: Participants were asked to state their preferred method of delivery in such patients and the reasons for their recommendation. Furthermore, we questioned whether there was any difference in opinions depending on generation. RESULTS: The majority of respondents (76%) would recommend assisted delivery (either Caesarean section or instrumental delivery), whereas the remaining 24% would advise normal delivery. Generation is not a factor influencing this decision. The majority (58%) based their decision to alter the management of labour on their personal opinion of standard of care. CONCLUSION: The literature shows that there is little evidence to support the belief that previous retinal surgery increases the risk of re-detachment of the retina during spontaneous vaginal delivery. This short survey shows that the majority of an international sample of obstetricians questioned does not share this viewpoint. Therefore, unnecessary interventions may be occurring in otherwise fit women with a history of retinal detachment. PMID- 21541073 TI - Spontaneous empyema necessitatis caused by Aspergillus fumigatus in an immunocompetent patient. PMID- 21541074 TI - First report of isolation of Mycobacterium elephantis from bronchial lavage of a patient in Asia. PMID- 21541075 TI - Trigemino-cardiac reflex during chronic subdural haematoma removal: report of chemical initiation of dural sensitization. PMID- 21541076 TI - Pneumothorax after nasogastric tube insertion. PMID- 21541077 TI - Simple treatment of stridor caused by achalasia of the cardia. PMID- 21541078 TI - Acute compartment syndrome with an atypical presentation: a useful clinical lesson. PMID- 21541079 TI - Pulmonary and extrapulmonary infection caused by Mycobacterium conceptionense: the first report from Iran. PMID- 21541081 TI - A case of Noonan's syndrome with anomalous lymphorenal communication. PMID- 21541080 TI - Nutritional supplementation and dietary restriction in the resolution of enthesitis-related arthritis. PMID- 21541082 TI - Unusual cause of neurological symptoms in a young man. PMID- 21541083 TI - The correlation of anxiety and depression levels with response to neoadjuvant chemotherapy in patients with breast cancer. AB - BACKGROUND: The aim was to evaluate and correlate anxiety and depression levels with response to neoadjuvant chemotherapy in patients with breast cancer. The study also assessed the effects of family support on distress levels. DESIGN: It was a prospective study in a cohort of 84 patients with locally advanced breast cancer. These assessments were done using the Hospital Anxiety and Depression Scale (HADS). SETTING: A prospective study in a developing world setting. PARTICIPANTS: Eighty-four patients with locally advanced breast cancer receiving neoadjuvant chemotherapy were included after taking an informed consent and ethical committee clearance. MAIN OUTCOME MEASURES: A significant correlation was observed between response to neoadjuvant chemotherapy and depression levels in breast cancer patients. Joint family and literacy levels also had an impact on the levels of depression observed. RESULTS: A total of 84 patients receiving neoadjuvant chemotherapy for breast cancer were evaluated using HADS. The effect of family support, literacy levels and employment on the psychological status of these patients were also assessed. CONCLUSIONS: The response to neoadjuvant chemotherapy had a direct correlation with the levels of depression, the distress levels being lower in responders. This was found to be the most important variable determining the psychological status of the patients. It was also observed that Indian patients in comparison to their Western counterparts react differently to cancer-related stress. PMID- 21541084 TI - An unusual presentation of sclerosing mesenteritis mimicking inflammatory bowel disease in a teenager. PMID- 21541085 TI - Tuberculosis of the elbow joint. PMID- 21541086 TI - Old cavity, new cancer - is it time to re-think? PMID- 21541087 TI - An unusual ankle injury. PMID- 21541088 TI - The role of cranial CT in the investigation of meningitis. AB - OBJECTIVE: To assess the usage of cranial computed tomography (CT) in patients admitted with meningitis. DESIGN: Retrospective study. SETTING: Heart of England NHS foundation trust, a teaching hospital in the West Midlands. PARTICIPANTS: Two groups of adult patients admitted with meningitis between April 2001 and September 2004 and from September 2006 until September 2009. MAIN OUTCOME MEASURES: The numbers of patients having cranial CT and lumbar puncture and whether any complications had arisen following lumbar puncture. The appropriateness of the CT request according to local criteria. RESULTS: A total of 111 patients were admitted in the initial time period and 47 patients in the second time period. In the first group, 67 patients underwent CT (61%), compared with 36 patients (80%) in the second group. There were eight abnormal scans (12%) in the initial group including three patients with radiological features of cerebral oedema. Of these patients, one underwent lumbar puncture and had no neurological sequelae. In the second group, there were five abnormal scans (14%) with one presenting a contraindication for lumbar puncture due to mild ventricular dilatation. A lumbar puncture was performed in this patient without complication. All patients with abnormal scans had clinical features to suggest raised intracranial pressure. CT scan requests were considered inappropriate in 26% of patients in the initial study period and 56% of patients in the second study period. CONCLUSION: More patients with meningitis are undergoing CT and the number of inappropriate requests are increasing. There are few abnormal CT scans presenting a contraindication for lumbar puncture and the majority of these patients usually have clinical signs to suggest raised intracranial pressure. PMID- 21541089 TI - Does the academic performance of psychiatrists influence success in the NHS Clinical Excellence Award Scheme? AB - OBJECTIVES: Given the uncertainty about factors that influence receipt of Clinical Excellence Awards (CEA) and recent availability of advanced research metrics, we examined the factors that predict CEA success using a convenience sample of English psychiatrists. DESIGN: Observational study examining region, subspecialty, H-index, M-index, number of publications, years since registration and years in specialty. SETTING: ACCEA Nominal Roll, cross-referenced with data from the GMC's list of registered medical practitioners and Thompson's Web of Science database. PARTICIPANTS: A total of 494 psychiatrists including 245 with national levels awards and a random sample with local level awards. MAIN OUTCOME MEASURES: Receipt of local or national CEA awards in 2008 and 2009. RESULTS: Of those with national awards, 126 had university contracts and 119 NHS contracts. Across all staff, years since qualification in medicine and H-index were the dominant influences. For local awards we found that years worked in the specialty was the main predictor of a CEA award with a smaller contribution from H-index. For national awards to university staff (academics) years on the medical register and publication rate were significant predictors. For national awards to NHS staff (non-academics) H-index and total cites were predictive, but these were themselves related to age. CONCLUSIONS: Progression in CEAs among psychiatrists is strongly influenced by age (years spent in specialty and years on the medical register) with an additional contribution from research productivity. Currently, research impact is crudely assessed in the CEA process. We suggest that CEA committees formally assess the impact of NHS-related research using standardized research metrics which are openly available. We also suggest that supporting organizations and local trusts adhere to the rules mandated by the ACCEA. PMID- 21541090 TI - Junior doctor titles following implementation of Modernising Medical Careers in the UK. AB - OBJECTIVE: Recent changes in postgraduate medical training in the UK collectively organized under the auspices of Modernising Medical Careers (MMC) have created new labels for junior doctors in training. It would appear that many nurses and other health workers do not understand the new terminology. We aimed to investigate the knowledge of nursing staff about new junior doctor titles in a district general hospital. As far as we are aware, this is the first survey to determine the views and knowledge of the new terms among staff working in the NHS. DESIGN: Questionnaire study. SETTING: District general hospital, West Midlands, UK. PARTICIPANTS: Fifty-five randomly selected staff nurses working in the surgical directorate. MAIN OUTCOME MEASURE: Questions were asked about their views and knowledge of the current nomenclature. To objectively assess knowledge of the new titles respondents were asked to match equivalent positions with those based on the old system. RESULTS: Only 22% (n = 12) of respondents felt that they fully understand current terms in usage. Seventy-six percent (n = 42) felt that it was 'very important' that titles accurately convey role and seniority of the doctor. The most common titles correctly matched were FY1 and House Officer (n = 45, 81%) and FY2 and First Year Senior House Officer (n = 35, 64%). Only 9% (n = 5) of staff nurses correctly matched ST3 to Junior Registrar and 13% (n = 7) correctly matched ST7 to Senior Registrar. Ward-based staff nurses demonstrated greater familiarity with titles when compared to nurses who work mainly in the outpatient clinic and theatre setting (p = 0.017). We did not identify a statistically significant association with demographic characteristics (age, gender, experience) and knowledge of the new terms (p > 0.05). Approximately 98% (n = 54) of the staff surveyed felt that terms are confusing to nurses and need to be simplified. CONCLUSIONS: Our survey revealed that nursing staff lacked knowledge of the current terminology to describe doctors in training. This may have implications for staff expectations regarding specific role of junior doctor in terms of clinical decision-making, working relationships and communication between team members, and ultimately patient care. PMID- 21541091 TI - Horner's syndrome as a presenting sign of metastatic testicular malignancy. PMID- 21541092 TI - Methanogenic Archaea and oral infections - ways to unravel the black box. AB - Archaea, organisms that make up the third domain of cellular life are members of the human oral microflora. They are strikingly less diverse than oral bacteria and appear to be relatively rare with respect to their numerical abundance. Since they have been exclusively found in association with oral infections such as periodontitis and apical periodontitis and given their unique physiology and energy metabolism, it is highly plausible that they are more than just secondary colonizers of infected areas, but instead are actively involved in the overall poly-microbial infection process. Conversely, it is a highly challenging task to clearly demonstrate their possible active participation - mostly due to the difficulty to grow them in routine microbiology laboratories. This current review points out the importance for understanding the medical impact of methanogens and aims at devising strategies for elucidating the true function of archaea in the oral ecosystem. PMID- 21541093 TI - Genomic comparison of invasive and rare non-invasive strains reveals Porphyromonas gingivalis genetic polymorphisms. AB - BACKGROUND: Porphyromonas gingivalis strains are shown to invade human cells in vitro with different invasion efficiencies, varying by up to three orders of magnitude. OBJECTIVE: We tested the hypothesis that invasion-associated interstrain genomic polymorphisms are present in P. gingivalis and that putative invasion-associated genes can contribute to P. gingivalis invasion. DESIGN: Using an invasive (W83) and the only available non-invasive P. gingivalis strain (AJW4) and whole genome microarrays followed by two separate software tools, we carried out comparative genomic hybridization (CGH) analysis. RESULTS: We identified 68 annotated and 51 hypothetical open reading frames (ORFs) that are polymorphic between these strains. Among these are surface proteins, lipoproteins, capsular polysaccharide biosynthesis enzymes, regulatory and immunoreactive proteins, integrases, and transposases often with abnormal GC content and clustered on the chromosome. Amplification of selected ORFs was used to validate the approach and the selection. Eleven clinical strains were investigated for the presence of selected ORFs. The putative invasion-associated ORFs were present in 10 of the isolates. The invasion ability of three isogenic mutants, carrying deletions in PG0185, PG0186, and PG0982 was tested. The PG0185 (ragA) and PG0186 (ragB) mutants had 5.1*10(3)-fold and 3.6*10(3)-fold decreased in vitro invasion ability, respectively. CONCLUSION: The annotation of divergent ORFs suggests deficiency in multiple genes as a basis for P. gingivalis non-invasive phenotype. PMID- 21541094 TI - A mechanism for extremely weak SpaP-expression in Streptococcus mutans strain Z1. AB - BACKGROUND: Streptococcus mutans surface-protein antigen (SpaP, PAc, or antigen I/II) has been well known to play an important role in initial attachment to tooth surfaces. However, strains with weak SpaP-expression were recently reported to be found in natural populations of S. mutans. The S. mutans gbpC-negative strain Z1, which we previously isolated from saliva and plaque samples, apparently expresses relatively low levels of SpaP protein compared to S. mutans strains MT8148 or UA159. OBJECTIVE: To elucidate the mechanism for weak SpaP expression in this strain, the spaP gene region in strain Z1 was amplified by polymerase chain reaction (PCR) and analyzed. METHODS: Allelic exchange mutants between strains Z1 and UA159 involving the spaP gene region were constructed. The SpaP protein expressed in the mutants was detected with Coomasie Brilliant Blue (CBB)-staining and Western blot analysis following SDS-PAGE. RESULTS: The 4689 bp spaP gene coding sequence for Z1 appeared to be intact. In contrast, a 20 bp nucleotide sequence appeared to be deleted from the region immediately upstream from the Z1 spaP gene when compared to the same region in UA159. The 216 bp and 237 bp intergenic fragments upstream from the spaP gene, respectively, from Z1 and UA159 were isolated, modified, and transformed into the other strain by allelic replacement. The resultant UA159-promoter region-mutant exhibited extremely weak SpaP-expression similar to that of strain Z1 and the Z1 complemented mutant expressed Spa protein levels like that of strain UA159. CONCLUSION: These results suggest that weak SpaP-expression in strain Z1 resulted from a 20 bp-deletion in the spaP gene promoter region. PMID- 21541095 TI - Systemic helter-skelter: are current child psychiatric services missing the boat? PMID- 21541097 TI - Stuck on screens: patterns of computer and gaming station use in youth seen in a psychiatric clinic. PMID- 21541096 TI - Stuck on screens: patterns of computer and gaming station use in youth seen in a psychiatric clinic. AB - OBJECTIVE: Computer and gaming-station use has become entrenched in the culture of our youth. Parents of children with psychiatric disorders report concerns about overuse, but research in this area is limited. The goal of this study is to evaluate computer/gaming-station use in adolescents in a psychiatric clinic population and to examine the relationship between use and functional impairment. METHOD: 102 adolescents, ages 11-17, from out-patient psychiatric clinics participated. Amount of computer/gaming-station use, type of use (gaming or non gaming), and presence of addictive features were ascertained along with emotional/functional impairment. Multivariate linear regression was used to examine correlations between patterns of use and impairment. RESULTS: Mean screen time was 6.7+/-4.2 hrs/day. Presence of addictive features was positively correlated with emotional/functional impairment. Time spent on computer/gaming station use was not correlated overall with impairment after controlling for addictive features, but non-gaming time was positively correlated with risky behavior in boys. CONCLUSIONS: Youth with psychiatric disorders are spending much of their leisure time on the computer/gaming-station and a substantial subset show addictive features of use which is associated with impairment. Further research to develop measures and to evaluate risk is needed to identify the impact of this problem. PMID- 21541098 TI - The Normal Inhibition of Associations is Impaired by Clonidine in Tourette Syndrome. AB - OBJECTIVE: We examined the inhibition of stimulus-stimulus associations (formally 'conditioned inhibition') in Tourette syndrome (TS). METHOD: The present study used video game style conditioned inhibition procedures suitable for children and adolescents. We tested 15 participants with a clinical diagnosis of TS in the absence of co-morbid attention deficit hyperactivity disorder and compared them with 19 typically developing age and sex matched controls (both groups aged 10-20 years). All children were tested for inhibition by summation test using two test stimuli in each of two conditioned inhibition tasks. RESULTS: TS participants showed overall normal inhibition of stimulus-stimulus associations, and there was no correlation between inhibitory learning scores and symptom severity ratings. However, there was a clear reduction in conditioned inhibition in 7 TS participants medicated with clonidine. There was no significant effect of medication on excitatory learning of the stimulus-stimulus associations. CONCLUSIONS: We suggest that clonidine's effect on inhibitory as opposed to excitatory learning could be related to reduced noradrenergic activity. In terms of clinical implications for TS, impaired conditioned inhibition could reduce the ability of susceptible individuals to learn to control tics in the presence of associative triggers. PMID- 21541099 TI - Effect of Research Questionnaires on Satisfaction with Treatment Care in Suicidal Adolescents and their Parents. AB - OBJECTIVE: Few psychosocial treatment methods have been empirically validated as effective for the prevention of suicide in suicidal adolescents, in part due to concerns that research could compromise quality of care. The study assessed the impact of research batteries on satisfaction with psychiatric care in suicidal adolescents and their parents. METHOD: Suicidal adolescents presenting to the emergency department of a major urban pediatric hospital were divided into two groups, one receiving treatment as usual and the other exposed to psychometric testing of the type typically used in research protocols both before and after their treatment. Following treatment, the patients of both groups and their parents were given questionnaires to assess satisfaction with the services they had received. Differences between the two groups were analyzed. RESULTS: No significant intergroup differences were found (p>0.05) in either patients or their parents regarding treatment received from the emergency-room team, regardless of whether they had been subjected to the psychometric testing. CONCLUSIONS: There is no evidence in the study to support concerns that extensive psychometric testing of the type frequently encountered in research studies undermines patient satisfaction with the care they receive. PMID- 21541100 TI - A preliminary investigation of wait times for child and adolescent mental health services in Canada. AB - OBJECTIVES: THE OBJECTIVES OF THIS STUDY WERE TO: 1) describe wait times at agencies providing child and adolescent mental health services (CAMHS) in Canada; and 2) determine whether agency and waiting list characteristics are associated with wait times for different clinical priority levels. METHOD: A web-based survey was distributed to 379 agencies providing CAMHS in Canada. The survey contained questions about agency characteristics, waiting list characteristics and agency wait times. Pearson's correlations were used to determine the bivariate relationship between agency and waiting list characteristics and wait times. RESULTS: The response rate was 30.6% (n=116). Only 8.6% of agencies reported no waiting lists for their programs or services. Estimated mean wait times for initial assessment decreased with increasing levels of clinical priority. However, the ranges of wait times at each clinical priority level were substantial. In addition, only 31.4% of agencies reported being "mostly" or "always" able to meet the Canadian Psychiatric Association's wait time benchmark for scheduled care for psychiatric services. Wait times were positively correlated with size of the waiting list for those considered at lower clinical priority. CONCLUSIONS: The findings confirm concerns about the prevalence of wait times for CAMHS in Canada, and also note marked variability. Though shorter wait times for higher priority children and youth is appropriate, current practice does not meet proposed standards of care as they relate to wait times. Future research should determine the impact of service reform efforts on reducing wait times for children with differing clinical priority levels. PMID- 21541101 TI - Change in mental health status of young children participating in a respite service. AB - OBJECTIVE: The objective of this study was to determine the extent of changes in mental health status of children in a respite service as little has been reported on this aspect of respite care. METHOD: All families enrolled in a new centre based respite program in a moderately large urban center in Canada were invited to participate. The child's primary caregiver completed the Strengths and Difficulties Questionnaire (SDQ) at baseline, mid-point and endpoint, as did respite staff. A comparison group of primary caregivers seeking respite care also completed the same ratings at baseline and at one-follow-up point. RESULTS: The children's primary caregivers perceived high levels of mental health difficulties in their children at baseline; significantly more than respite providers. No significant changes were found between SDQ baseline and endpoint values for either primary caregivers or respite workers. The amount of change between baseline and midpoint was no different for the intervention and comparison group. CONCLUSIONS: No evidence of a positive impact on child mental health status by the new respite program as measured by the SDQ was detected. Specific evidence based child mental health interventions may need to be paired with respite care to improve child mental health outcomes. PMID- 21541102 TI - An adaptation of prolonged exposure therapy for pediatric single incident trauma: a case series. AB - OBJECTIVE: To assess the efficacy of a modification for Prolonged Exposure (PE) therapy for single incident trauma in youth and examine the effective component(s) of treatment. METHOD: Fifteen youth (2 boys, 13 girls; mean age= 10.8 years) were treated with a developmentally modified version of PE called Trauma Mastery Therapy (TMT). The youth were evaluated pre-treatment, every 2 treatment sessions, and at 1 month follow-up. PRIMARY OUTCOME MEASURE: the Child PTSD Symptom Scale (CPSS), a self administered PTSD questionnaire. RESULTS: Post treatment, 13 participants did not meet criteria for PTSD. Patients showed significant improvement at post-treatment. Analysis of variance models with pair wise contrasts showed significantly higher scores at initiation of treatment as compared to the end of the exposure phase and, to a lesser extent, as compared to the psychoeducational phase, but no further significant improvement following the relapse prevention or follow-up phases. CONCLUSIONS: TMT appears to be a promising treatment for single incident trauma in youth. Flexibility within the structure of TMT may facilitate treatment success. The study suggests exposure, and to some extent, psychoeducation, to be important components of treatment. Additional research is required to further validate these initial findings. PMID- 21541103 TI - Barriers and facilitators to implementation of a metabolic monitoring protocol in hospital and community settings for second-generation antipsychotic-treated youth. AB - OBJECTIVE: 1) Assess perceived barriers associated with metabolic monitoring in second-generation antipsychotic (SGA)-treated youth; and 2) Propose a metabolic monitoring protocol (MMP) and implementation strategies. METHOD: Online surveys were created for community mental health teams (CMHTs) and BC Children's Hospital (BCCH) with questions designed to evaluate knowledge of physical health care, confidence, communication with primary care, and practical issues. RESULTS: 26/50 (52%) of CMHT and 44/111 (40%) of BCCH surveys were completed. While both groups agreed that monitoring is their responsibility, 26% of CMHTs and 35% of BCCH professionals agreed that providing information about SGA side-effects would influence medication adherence. CMHTs reported lower overall confidence and more practical issues as monitoring barriers. While higher overall confidence was reported at BCCH, there was still a substantial proportion (23%) of hospital professionals who reported not knowing what parameters to monitor and how frequently. Communication with primary care, including inadequate systems for sharing results and identifying responsibility for acting on abnormal results, appear to be common barriers shared by both settings. CONCLUSIONS: Barriers to metabolic monitoring were more frequently reported by CMHTs who had limited access to nursing staff. We propose hands-on training, educational resources, pre printed orders, and regular quality assurance evaluation as facilitators to promote MMP uptake. PMID- 21541104 TI - Reversible oral dyskinesia associated with quetiapine in an adolescent: a case report. PMID- 21541105 TI - Interview with Dr. Richard Tremblay, PhD: (interviewed by Normand Carrey MD, October 28, 2010). PMID- 21541106 TI - Functional analysis and treatment of human-directed undesirable behavior exhibited by a captive chimpanzee. AB - A functional analysis identified the reinforcer maintaining feces throwing and spitting exhibited by a captive adult chimpanzee (Pan troglodytes). The implementation of a function-based treatment combining extinction with differential reinforcement of an alternate behavior decreased levels of inappropriate behavior. These findings further demonstrate the utility of function-based approaches to assess and treat behavior problems exhibited by captive animals. PMID- 21541107 TI - Effects of pedestrian prompts on motorist yielding at crosswalks. AB - Pedestrian safety is a serious concern at busy intersections and pedestrian campuses across the nation. Although crosswalks and signs inform pedestrians where to cross, there is no standard protocol for pedestrians to signal drivers that they wish to use the crosswalks, except to stand in or at the crosswalk. We examined the effects of two pedestrian prompts, a raised hand and extended arm, on motorist yielding at uncontrolled crosswalks. The two prompts were effective at increasing yielding. PMID- 21541108 TI - Generalization of posture training to computer workstations in an applied setting. AB - Improving employees' posture may decrease the risk of musculoskeletal disorders. The current paper is a systematic replication and extension of Sigurdsson and Austin (2008), who found that an intervention consisting of information, real time feedback, and self-monitoring improved participant posture at mock workstations. In the current study, participants worked in an applied setting, and posture data were collected at participants' own workstations and a mock workstation. Intervention in the mock setting was associated with consistent improvement in safe posture at the mock workstation, but generalization to the actual workstation was limited. PMID- 21541109 TI - Increasing compliance with medical examination requests directed to children with autism: effects of a high-probability request procedure. AB - The purpose of this study was to evaluate the effectiveness of a high-probability (high-p) request sequence as a means of increasing compliance with medical examination tasks. Participants were children who had been diagnosed with autism and who exhibited noncompliance during general medical examinations. The inclusion of the high-p request sequence effectively increased compliance with medical examination tasks. In addition, the procedure was efficient, could be implemented by parents and medical professionals, and did not involve aversive procedures. PMID- 21541110 TI - Evaluation of fixed momentary dro schedules under signaled and unsignaled arrangements. AB - Fixed momentary schedules of differential reinforcement of other behavior (FM DRO) generally have been ineffective as treatment for problem behavior. Because most early research on FM DRO included presentation of a signal at the end of the DRO interval, it is unclear whether the limited effects of FM DRO were due to (a) the momentary response requirement of the schedule per se or (b) discrimination of the contingency made more salient by the signal. To separate these two potential influences, we compared the effects of signaled versus unsignaled FM DRO with 4 individuals with developmental disabilities whose problem behavior was maintained by social-positive reinforcement. During signaled FM DRO, the experimenter presented a visual stimulus 3 s prior to the end of the DRO interval and delivered reinforcement contingent on the absence of problem behavior at the second the interval elapsed. Unsignaled DRO was identical except that interval termination was not signaled. Results indicated that signaled FM DRO was effective in decreasing 2 subjects' problem behavior, whereas an unsignaled schedule was required for the remaining 2 subjects. These results suggest that the response requirement per se of FM DRO may not be problematic if it is not easily discriminated. PMID- 21541111 TI - Parent-implemented mand training: acquisition of framed manding in a young boy with partial hemispherectomy. AB - This study examined the effects of parent-implemented mand training on the acquisition of framed manding in a 4-year-old boy who had undergone partial hemispherectomy. Framed manding became the predominant mand form when and only when the intervention was implemented with each preferred toy, but minimal generalization to untrained toys nevertheless occurred. A pure mand test suggested that manding was controlled by the relevant motivating operation. PMID- 21541112 TI - Assessment and treatment of foot-shoe fetish displayed by a man with autism. AB - Results of a functional analysis indicated that a man diagnosed with autism engaged in bizarre sexual behavior in the presence of women wearing sandals. Several treatments proved to be ineffective or impractical. By contrast, a response-interruption/time-out procedure quickly eliminated the problem behavior in multiple settings. PMID- 21541113 TI - Temporal discounting predicts student responsiveness to exchange delays in a classroom token system. AB - Typical assessments of temporal discounting involve presenting choices between hypothetical monetary outcomes. Participants choose between smaller immediate rewards and larger delayed rewards to determine how the passage of time affects the subjective value of reinforcement. Few studies, however, have compared such discounting to actual manipulations of reward delay. The present study examined the predictive validity of a temporal discounting procedure developed for use with children. Forty-six sixth-grade students completed a brief discounting assessment and were then exposed to a classwide intervention that involved both immediate and delayed reinforcement in a multiple baseline design across classrooms. The parameters derived from two hyperbolic models of discounting correlated significantly with actual on-task behavior under conditions of immediate and delayed exchange. Implications of temporal discounting assessments for behavioral assessment and treatment are discussed. PMID- 21541114 TI - Response interruption and redirection for vocal stereotypy in children with autism: a systematic replication. AB - This study systematically replicated and extended previous research on response interruption and redirection (RIRD) by assessing instructed responses of a different topography than the target behavior, percentage of session spent in treatment, generalization of behavior reduction, and social validity of the intervention. Results showed that RIRD produced substantial decreases in vocal stereotypy. Limitations of this study were that behavior reduction did not generalize to novel settings or with novel instructors and that appropriate vocalizations did not improve. PMID- 21541116 TI - Transitional and steady-state choice behavior under an adjusting-delay schedule. AB - Twelve rats made repeated choices on an adjusting-delay schedule between a smaller reinforcer (A) that was delivered immediately after a response and a larger reinforcer (B) that was delivered after a delay which increased or decreased by 20% depending on the subject's choices in successive blocks of trials. In two phases of the experiment (100 sessions and 40 sessions), reinforcer sizes were selected which enabled theoretical parameters expressing the rate of delay discounting and sensitivity to reinforcer size to be estimated from the ratio of the indifference delays obtained in the two phases. Indifference delays, calculated from adjusting delays in the last 10 sessions of each phase, were shorter when the sizes of A and B were 14 and 25 ul of a 0.6 M sucrose solution than when they were 25 and 100 ul of the same solution. The ratio of the indifference delays was significantly smaller than that predicted on the basis of an assumed linear relation between reinforcer size and instantaneous reinforcer value, consistent with a previous proposal that this relation may be hyperbolic in form. Estimates of the rate of delay discounting based on the ratio of the two indifference delays (mean, 0.08 s(-1)) were similar to values obtained previously using different intertemporal choice protocols. Estimates of the size sensitivity parameter (mean 113 ul) were similar to estimates recently derived from performance on progressive-ratio schedules. In both phases of the experiment, adjusting delays in successive blocks of trials were analyzed using the Fourier transform. The power spectrum obtained from individual rats had a dominant frequency that corresponded to a period of oscillation of the adjusting delay between 30 and 100 trial blocks (mean, 78). Power in the dominant frequency band was highest in the early sessions of the first phase and declined with extended training. It is suggested that this experimental protocol may have utility in neurobehavioral studies of intertemporal choice. PMID- 21541117 TI - Effects of daily morphine administration and deprivation on choice and demand for remifentanil and cocaine in rhesus monkeys. AB - Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or cocaine. Four rhesus monkeys chose between remifentanil and cocaine during daily sessions. Demand curves for both drugs were subsequently obtained. The effects of daily injections of 3.2 mg/kg morphine on both choice and demand for these drugs was assayed 3 and 20.5 hr after each morphine injection, and then during a postmorphine period. Three hours following morphine injections, choice of remifentanil over cocaine decreased and demand for remifentanil--but not cocaine--became more elastic. During morphine withdrawal (20.5 hr postinjection), choice of remifentanil increased and remifentanil demand became more inelastic in 3 of 4 monkeys. Cocaine demand also became more inelastic during this period. Four to five weeks following the morphine regimen, demand for both drugs was more inelastic relative to the initial determination. The results suggest that both the relative and absolute reinforcing effectiveness of remifentanil decreased following morphine administration and increased during morphine withdrawal. The absolute reinforcing effectiveness of cocaine also increased during morphine withdrawal. In addition, extended exposure to drug self administration and/or exposure to the morphine regimen produced long-term increases in demand for both drugs. PMID- 21541118 TI - A model of resurgence based on behavioral momentum theory. AB - Resurgence is the reappearance of an extinguished behavior when an alternative behavior reinforced during extinction is subsequently placed on extinction. Resurgence is of particular interest because it may be a source of relapse to problem behavior following treatments involving alternative reinforcement. In this article we develop a quantitative model of resurgence based on the augmented model of extinction provided by behavioral momentum theory. The model suggests that alternative reinforcement during extinction of a target response acts as both an additional source of disruption during extinction and as a source of reinforcement in the context that increases the future strength of the target response. The model does a good job accounting for existing data in the resurgence literature and makes novel and testable predictions. Thus, the model appears to provide a framework for understanding resurgence and serves to integrate the phenomenon into the existing theoretical account of persistence provided by behavioral momentum theory. In addition, we discuss some potential implications of the model for further development of behavioral momentum theory. PMID- 21541119 TI - Effects of acute and chronic flunitrazepam on delay discounting in pigeons. AB - Delay to delivery of a reinforcer can decrease responding for that reinforcer and increase responding for smaller reinforcers that are available concurrently and delivered without delay; acute administration of drugs can alter responding for large, delayed reinforcers, although the impact of chronic treatment on delay discounting is not well understood. In this experiment, the effects of repeated administration of the benzodiazepine flunitrazepam were studied in 6 pigeons responding on one key to receive food that was delivered immediately and on a second key to receive a larger amount of food that was delivered following delays which increased across a single session. Pigeons responded predominantly for the large reinforcer when there were no delays and when delays were short; however, as delays increased, responding for the large reinforcer decreased. Acutely, flunitrazepam (0.32, 1.0 and 3.2 mg/kg) dose-dependently increased responding for the large reinforcer, shifting the discounting curve rightward and upward. Repeated administration of flunitrazepam (0.32, 1.0 and 3.2 mg/kg, each for six sessions, separated by one session during which vehicle was administered) did not markedly alter its effects on responding for the large reinforcer, indicating that the development of tolerance to this effect of flunitrazepam is modest under these conditions. PMID- 21541120 TI - Requiem for my lovely. PMID- 21541121 TI - Extended pausing by humans on multiple fixed-ratio schedules with varied reinforcer magnitude and response requirements. AB - We conducted three experiments to reproduce and extend Perone and Courtney's (1992) study of pausing at the beginning of fixed-ratio schedules. In a multiple schedule with unequal amounts of food across two components, they found that pigeons paused longest in the component associated with the smaller amount of food (the lean component), but only when it was preceded by the rich component. In our studies, adults with mild intellectual disabilities responded on a touch sensitive computer monitor to produce money. In Experiment 1, the multiple schedule components differed in both response requirement and reinforcer magnitude (i.e., the rich component required fewer responses and produced more money than the lean component). Effects shown with pigeons were reproduced in all 7 participants. In Experiment 2, we removed the stimuli that signaled the two schedule components, and participants' extended pausing was eliminated. In Experiment 3, to assess sensitivity to reinforcer magnitude versus fixed-ratio size, we presented conditions with equal ratio sizes but disparate magnitudes and conditions with equal magnitudes but disparate ratio sizes. Sensitivity to these manipulations was idiosyncratic. The present experiments obtained schedule control in verbally competent human participants and, despite procedural differences, we reproduced findings with animal participants. We showed that pausing is jointly determined by past conditions of reinforcement and stimuli correlated with upcoming conditions. PMID- 21541123 TI - Reinforcing saccadic amplitude variability. AB - Saccadic endpoint variability is often viewed as the outcome of neural noise occurring during sensorimotor processing. However, part of this variability might result from operant learning. We tested this hypothesis by reinforcing dispersions of saccadic amplitude distributions, while maintaining constant their medians. In a first experiment we reinforced the least frequent saccadic amplitudes to increase variability, and then reinforced the central part of the amplitude distributions to reduce variability. The target was placed at a constant distance from the fovea after the saccade to maintain the postsaccadic visual signal constant and an auditory reinforcement was delivered depending on saccadic amplitude. The second experiment tested the effects of the contingency. We reinforced high levels of variability in 4 participants, whereas 4 other participants were assigned to a yoked control group. On average, saccadic amplitude standard deviations were doubled while the medians remained mostly unchanged in the experimental participants in both experiments, and variability returned to baseline level when low variability was reinforced. In the control group no consistent changes in amplitude distributions were observed. These results, showing that variability can be reinforced, challenge the idea of a stochastic neural noise. We instead propose that selection processes constrain saccadic amplitude distributions. PMID- 21541124 TI - The role of common motor responses in stimulus categorization by preschool children. AB - The purpose of this study was to assess the role of common motor responses as the "speaker" behavior on stimulus class formation, and the emergence of functional classes. Experiment 1 examined whether training one motor response to a set of three stimuli and a second motor response to another set of three stimuli would result in correct category-sort responses for 5 typically developing preschool children. Three of the children passed the categorization tests. Experiment 2 examined whether the classes formed in Experiment 1 were functional classes, and whether participants who did not pass categorization tests in Experiment 1 would do so following common vocal tact training. The 2 participants who failed categorization tests in Experiment 1 passed these tests in Experiment 2, although none of the participants passed the tests for functional classes. The results of the current study did not unequivocally support the naming hypothesis. Future research should therefore evaluate other possible sources of control that aid in stimulus categorization. PMID- 21541125 TI - Effects of a history of differential reinforcement on preference for choice. AB - The effects of a history of differential reinforcement for selecting a free choice versus a restricted-choice stimulus arrangement on the subsequent responding of 7 undergraduates in a computer-based game of chance were examined using a concurrent-chains arrangement and a multiple-baseline-across-participants design. In the free-choice arrangement, participants selected three numbers, in any order, from an array of eight numbers presented on the computer screen. In the restricted-choice arrangement, participants selected the order of three numbers preselected from the array of eight by a computer program. In initial sessions, all participants demonstrated no consistent preference or preference for restricted choice. Differential reinforcement of free-choice selections resulted in increased preference for free choice immediately and in subsequent sessions in the absence of programmed differential outcomes. For 5 participants, changes in preference for choice were both robust and lasting, suggesting that a history of differential reinforcement for choice may affect preference for choice. PMID- 21541126 TI - Modeling the effect of reward amount on probability discounting. AB - The present study with college students examined the effect of amount on the discounting of probabilistic monetary rewards. A hyperboloid function accurately described the discounting of hypothetical rewards ranging in amount from $20 to $10,000,000. The degree of discounting increased continuously with amount of probabilistic reward. This effect of amount was not due to changes in the rate parameter of the discounting function, but rather was due to increases in the exponent. These results stand in contrast to those observed with the discounting of delayed monetary rewards, in which the degree of discounting decreases with reward amount due to amount-dependent decreases in the rate parameter. Taken together, this pattern of results suggests that delay and probability discounting reflect different underlying mechanisms. That is, the fact that the exponent in the delay discounting function is independent of amount is consistent with a psychophysical scaling interpretation, whereas the finding that the exponent of the probability-discounting function is amount-dependent is inconsistent with such an interpretation. Instead, the present results are consistent with the idea that the probability-discounting function is itself the product of a value function and a weighting function. This idea was first suggested by Kahneman and Tversky (1979), although their prospect theory does not predict amount effects like those observed. The effect of amount on probability discounting was parsimoniously incorporated into our hyperboloid discounting function by assuming that the exponent was proportional to the amount raised to a power. The amount dependent exponent of the probability-discounting function may be viewed as reflecting the effect of amount on the weighting of the probability with which the reward will be received. PMID- 21541127 TI - On the development and mechanics of delayed matching-to-sample performance. AB - Despite its frequent use to assess effects of environmental and pharmacological variables on short-term memory, little is known about the development of delayed matching-to-sample (DMTS) performance. This study was designed to examine the dimensions and dynamics of DMTS performance development over a long period of exposure to provide a more secure foundation for assessing stability in future research. Six pigeons were exposed to a DMTS task with variable delays for 300 sessions (i.e., 18,000 total trials; 3,600 trials per retention interval). Percent-correct and log-d measures used to quantify the development of conditional stimulus control under the procedure generally and at each of five retention intervals (0, 2, 4, 8 and 16-s) individually revealed that high levels of accuracy developed relatively quickly under the shorter retention intervals, but increases in accuracy under the longer retention intervals sometimes were not observed until 100-150 sessions had passed, with some still increasing at Session 300. Analyses of errors suggested that retention intervals induced biases by shifting control from the sample stimulus to control by position, something that was predicted by observed response biases during initial training. These results suggest that although it may require a great deal of exposure to DMTS prior to obtaining asymptotic steady state, quantification of model parameters may help predict trends when extended exposure is not feasible. PMID- 21541128 TI - Functional analysis and treatment of coprophagia. AB - In the current investigation, functional analysis results suggested that coprophagia, the ingestion of fecal matter, was maintained by automatic reinforcement. Providing noncontingent access to alternative stimuli decreased coprophagia, and the intervention was generalized to two settings. PMID- 21541129 TI - Response competition and stimulus preference in the treatment of automatically reinforced behavior: a comparison. AB - Clinicians are particularly challenged by the development of interventions for behavior maintained by automatic reinforcement because reinforcers that maintain the responses often cannot be directly observed or manipulated. Researchers have conducted either preference assessments or competing items assessments when developing effective treatments for behavior maintained by automatic reinforcement. However, interventions based on these assessments have not been directly compared. The current study evaluated procedures to make such a comparison. High-competition items resulted in greater reductions in vocal stereotypy than did high-preference items for a preschool boy with autism. PMID- 21541130 TI - Further evaluation of response interruption and redirection as treatment for stereotypy. AB - The effects of 2 forms of response interruption and redirection (RIRD)-motor RIRD and vocal RIRD-were examined with 4 boys with autism to evaluate further the effects of this intervention and its potential underlying mechanisms. In Experiment 1, the effects of motor RIRD and vocal RIRD on vocal stereotypy and appropriate vocalizations were compared for 2 participants. In Experiment 2, the effects of both RIRD procedures on both vocal and motor stereotypy and appropriate vocalizations were compared with 2 additional participants. Results suggested that RIRD was effective regardless of the procedural variation or topography of stereotypy and that vocal RIRD functioned as a punisher. This mechanism was further explored with 1 participant by manipulating the schedule of RIRD in Experiment 3. Results were consistent with the punishment interpretation. PMID- 21541131 TI - Fixed-time schedule effects in combination with response-dependent schedules. AB - We evaluated the effects of fixed-interval (FI), fixed-time (FT), and conjoint (combined) FI FT reinforcement schedules on the responding of 3 adults who had been diagnosed with schizophrenia. Responding on vocational tasks decreased for 2 of 3 participants under FT alone relative to FI alone. Responding under FI FT resulted in response persistence for 2 of 3 participants. Results have implications for the maintenance of desirable behavior, as well as for situations in which FT treatment has been implemented for problem behavior and problem behavior is nevertheless reinforced by caregivers. PMID- 21541132 TI - The effects of training on caregiver implementation of incidental teaching. AB - A brief training package consisting of modeling, rehearsal, and feedback was evaluated to train caregivers to use incidental teaching to teach 3 children with autism to request an item or activity. The training package improved correct implementation of the incidental teaching procedure by caregivers. In addition, probes indicated that caregivers could apply these skills to teach the child an additional skill. PMID- 21541133 TI - A feedback intervention to increase digital and paper checklist performance in technically advanced aircraft simulation. AB - This study examined whether pilots operating a flight simulator completed digital or paper flight checklists more accurately after receiving postflight graphic and verbal feedback. The dependent variable was the number of checklist items completed correctly per flight. Following treatment, checklist completion with paper and digital checklists increased from 38% and 39%, respectively, to nearly 100% and remained close to 100% after feedback and praise for improvement were withdrawn. Performance was maintained at or near 100% during follow-up probes. PMID- 21541134 TI - Embedded prompting may function as embedded punishment: detection of unexpected behavioral processes within a typical preschool teaching strategy. AB - This study describes an unexpected behavioral process that influenced behavior during the teaching of concepts to a 4-year-old girl. The efficacy of and preference for three strategies that varied in teacher directedness were assessed in a multielement design and concurrent-chains arrangement, respectively. The strategy that involved the most teacher direction was most efficacious and preferred. In addition, embedded teacher prompts, common in child-led teaching procedures, functioned as a punisher for the child's toy play. Implications for designing effective and preferred teaching conditions are discussed. PMID- 21541135 TI - Evaluation of developmental surveillance by physicians at the two-month preventive care visit. AB - We evaluated the effects of feedback and instruction on resident physician performance during developmental surveillance of infants at 2-month preventive care visits. Baseline data were obtained by videotaping 3 residents while they performed the physical and developmental exam components. Training consisted of individualized feedback and a brief instructional module, after which the residents were again videotaped while they performed preventive care visits. All 3 residents showed improved performance following training. PMID- 21541136 TI - Reinforcement of vocalizations through contingent vocal imitation. AB - Maternal vocal imitation of infant vocalizations is highly prevalent during face to-face interactions of infants and their caregivers. Although maternal vocal imitation has been associated with later verbal development, its potentially reinforcing effect on infant vocalizations has not been explored experimentally. This study examined the reinforcing effect of maternal vocal imitation of infant vocalizations using a reversal probe BAB design. Eleven 3- to 8-month-old infants at high risk for developmental delays experienced contingent maternal vocal imitation during reinforcement conditions. Differential reinforcement of other behavior served as the control condition. The behavior of 10 infants showed evidence of a reinforcement effect. Results indicated that vocal imitations can serve to reinforce early infant vocalizations. PMID- 21541137 TI - Evaluating the separate and combined effects of positive and negative reinforcement on task compliance. AB - Positive and negative reinforcement are effective for treating escape-maintained destructive behavior. The current study evaluated the separate and combined effects of these contingencies to increase task compliance. Results showed that a combination of positive and negative reinforcement was most effective for increasing compliance. PMID- 21541138 TI - Toward a technology of derived stimulus relations: an analysis of articles published in the journal of applied behavior analysis, 1992-2009. AB - Every article on stimulus equivalence or derived stimulus relations published in the Journal of Applied Behavior Analysis was evaluated in terms of characteristics that are relevant to the development of applied technologies: the type of participants, settings, procedure (automated vs. tabletop), stimuli, and stimulus sensory modality; types of relations targeted and emergent skills demonstrated by participants; and presence versus absence of evaluation of generalization and maintenance. In most respects, published reports suggested the possibility of applied technologies but left the difficult work of technology development to future investigations, suggestions for which are provided. PMID- 21541139 TI - An evaluation of three methods of saying "no" to avoid an escalating response class hierarchy. AB - We evaluated the effects of three different methods of denying access to requested high-preference activities on escalating problem behavior. Functional analysis and response class hierarchy (RCH) assessment results indicated that 4 topographies of problem behaviors displayed by a 13-year-old boy with high functioning autism constituted an RCH maintained by positive (tangible) reinforcement. Identification of the RCH comprised the baseline phase, during which computer access was denied by saying "no" and providing an explanation for the restriction. Two alternative methods of saying "no" were then evaluated. These methods included (a) denying computer access while providing an opportunity to engage in an alternative preferred activity and (b) denying immediate computer access by arranging a contingency between completion of a low-preference task and subsequent computer access. Results indicated that a hierarchy of problem behavior may be identified in the context of denying access to a preferred activity and that it may be possible to prevent occurrences of escalating problem behavior by either presenting alternative options or arranging contingencies when saying "no" to a child's requests. PMID- 21541140 TI - Classroom application of a trial-based functional analysis. AB - We evaluated a trial-based approach to conducting functional analyses in classroom settings. Ten students referred for problem behavior were exposed to a series of assessment trials, which were interspersed among classroom activities throughout the day. Results of these trial-based functional analyses were compared to those of more traditional functional analyses. Outcomes of both assessments showed correspondence in 6 of the 10 cases and partial correspondence in a 7th case. Results of the standard functional analysis suggested reasons for obtained differences in 2 cases of noncorrespondence, which were verified when portions of the trial-based functional analyses were modified and repeated. These results indicate that a trial-based functional analysis may be a viable assessment method when resources needed to conduct a standard functional analysis are unavailable. Implications for classroom-based assessment methodologies and future directions for research are discussed. PMID- 21541141 TI - Response latency as an index of response strength during functional analyses of problem behavior. AB - Dependent variables in research on problem behavior typically are based on measures of response repetition, but these measures may be problematic when behavior poses high risk or when its occurrence terminates a session. We examined response latency as the index of behavior during assessment. In Experiment 1, we compared response rate and latency to the first response under acquisition and maintenance conditions. In Experiment 2, we compared data from existing functional analyses when graphed as rate versus latency. In Experiment 3, we compared results from pairs of independent functional analyses. Sessions in the first analysis were terminated following the first occurrence of behavior, whereas sessions in the second analysis lasted for 10 min. Results of all three studies showed an inverse relation between rate and latency, indicating that latency might be a useful measure of responding when repeated occurrences of behavior are undesirable or impractical to arrange. PMID- 21541142 TI - Using accelerator pedal force to increase seat belt use of service vehicle drivers. AB - This study evaluated a device that applied a sustained increase in accelerator pedal back force whenever drivers exceeded a preset speed criterion without buckling their seat belts. This force was removed once the belt was fastened. Participants were 6 commercial drivers who operated carpet-cleaning vans. During baseline, no contingency was in place for unbuckled trips. The pedal resistance was introduced via a multiple baseline design across groups. On the first day of treatment, the device was explained and demonstrated for all drivers of the vehicle. The treatment was associated with an immediate sustained increase in seat belt compliance to 100%. Occasionally, drivers initially did not buckle during a trip and encountered the force. In all instances, they buckled within less than 25 s. These results suggest that the increased force was sufficient to set up an establishing operation to reinforce seat belt buckling negatively. Drivers indicated that they were impressed with the device and would not drive very long unbelted with the pedal force in place. PMID- 21541143 TI - Effects of motivating operations on problem and academic behavior in classrooms. AB - The current study examined the effects of motivating operations on problem behavior and academic engagement for 2 students with autism. Classroom sessions were preceded by periods in which the participants had access or no access to the items functionally related to their problem behavior. Results suggested that presession access may result in lower levels of problem behavior and higher levels of academic engagement during classroom instruction. PMID- 21541145 TI - An investigation of differential reinforcement of alternative behavior without extinction. AB - We manipulated relative reinforcement for problem behavior and appropriate behavior using differential reinforcement of alternative behavior (DRA) without an extinction component. Seven children with developmental disabilities participated. We manipulated duration (Experiment 1), quality (Experiment 2), delay (Experiment 3), or a combination of each (Experiment 4), such that reinforcement favored appropriate behavior rather than problem behavior even though problem behavior still produced reinforcement. Results of Experiments 1 to 3 showed that behavior was often sensitive to manipulations of duration, quality, and delay in isolation, but the largest and most consistent behavior change was observed when several dimensions of reinforcement were combined to favor appropriate behavior (Experiment 4). Results suggest strategies for reducing problem behavior and increasing appropriate behavior without extinction. PMID- 21541146 TI - The effects of exergaming on physical activity among inactive children in a physical education classroom. AB - Childhood obesity, which is due in part to lack of physical activity, is a serious concern that requires the attention of the behavioral community. Although excessive video game play has been noted in the literature as a contributor to childhood obesity, newer video gaming technology, called exergaming, has been designed to capitalize on the reinforcing effects of video games to increase physical activity in children. This study evaluated the effects of exergaming on physical activity among 4 inactive children in a physical education (PE) classroom. Results showed that exergaming produced substantially more minutes of physical activity and more minutes of opportunity to engage in physical activity than did the standard PE program. In addition, exergaming was socially acceptable to both the students and the PE teacher. Exergaming appears to hold promise as a method for increasing physical activity among inactive children and might be a possible intervention for childhood obesity. PMID- 21541147 TI - Further evaluation of antecedent interventions on compliance: the effects of rationales to increase compliance among preschoolers. AB - Functional analyses were conducted to identify reinforcers for noncompliance exhibited by 6 young children. Next, the effects of rationales (statements that describe why a child should comply with a caregiver-delivered instruction) were evaluated. In Experiment 1, 3 participants received the rationales immediately after the therapist's instruction. In Experiment 2, 3 additional participants received more practical rationales immediately before the therapist's instruction. The results indicate that rationales were ineffective for all 6 children. A guided compliance procedure increased compliance for 1 child; contingent access to preferred items with or without response cost increased compliance for the other participants. Although levels of problem behavior varied within and across participants, they were often higher in the rationale and guided compliance conditions. PMID- 21541148 TI - Using the stimulus equivalence paradigm to teach course material in an undergraduate rehabilitation course. AB - In 2 experiments, we examined whether the stimulus equivalence instructional paradigm could be used to teach relations among names, definitions, causes, and common treatments for disabilities using a selection-based intraverbal training format. Participants were pre- and posttested on vocal intraverbal relations and were trained using multiple-choice worksheets in which selection-based intraverbal relations were taught and feedback was delivered until mastery. Most participants in Experiment 1 showed the emergence of vocal intraverbal relations, but responding did not generalize to final written intraverbal tests. Participants in Experiment 2 showed the emergence of not only vocal intraverbal relations but also written intraverbal relations on final tests. Results suggest that the stimulus equivalence paradigm can be effectively implemented using a selection-based intraverbal training format, the protocol may be an effective means of emphasizing important concepts in a college course, and emergent skills may generalize to novel response topographies. PMID- 21541149 TI - Matrix training of preliteracy skills with preschoolers with autism. AB - Matrix training is a generative approach to instruction in which words are arranged in a matrix so that some multiword phrases are taught and others emerge without direct teaching. We taught 4 preschoolers with autism to follow instructions to perform action-picture combinations (e.g., circle the pepper, underline the deer). Each matrix contained 6 actions on 1 axis and 6 pictures on the other axis. We used most-to-least prompting to train the instructions along the diagonal of each matrix and probed the untrained combinations. For 2 participants, untrained responding emerged after the minimum amount of training. The other 2 participants required further training before untrained combinations emerged. At the end of the study, 3 of the 4 participants performed the trained actions with previously known pictures, letters, and numbers. This study demonstrated that matrix training is an efficient approach to teaching language and literacy skills to children with autism. PMID- 21541150 TI - Development and modification of a response class via positive and negative reinforcement: a translational approach. AB - When responses function to produce the same reinforcer, a response class exists. Researchers have examined response classes in applied settings; however, the challenges associated with conducting applied research on response class development have recently necessitated the development of an analogue response class model. To date, little research has examined response classes that are strengthened by negative reinforcement. The current investigation was designed to develop a laboratory model of a response class through positive reinforcement (i.e., points exchangeable for money) and through negative reinforcement (i.e., the avoidance of scheduled point losses) with 11 college students as participants and clicks as the operant. Results of both the positive and negative reinforcement evaluations showed that participants usually selected the least effortful response that produced points or the avoidance of point losses, respectively. The applied implications of the findings are discussed, along with the relevance of the present model to the study of punishment and resurgence. PMID- 21541151 TI - Spoon distance fading with and without escape extinction as treatment for food refusal. AB - Little is known about the characteristics of meals that serve as motivating operations (MOs) for escape behavior. In the current investigation, we showed that the distance at which a therapist held a spoon from a child's lips served as an MO for escape behavior. Based on these results, we implemented spoon distance fading, compared fading with and without escape extinction (EE), and compared fading plus EE to EE alone. Initially, inappropriate mealtime behavior decreased during fading, but this effect was not maintained as fading progressed. Inappropriate mealtime behavior was lower initially when we combined fading and EE relative to EE alone, but acceptance increased more rapidly with EE than with fading plus EE. These results suggest that a number of mealtime characteristics might function as MOs for escape behavior and that analyses of MOs may be useful for developing treatments for food refusal. PMID- 21541152 TI - Component analyses using single-subject experimental designs: a review. AB - A component analysis is a systematic assessment of 2 or more independent variables or components that comprise a treatment package. Component analyses are important for the analysis of behavior; however, previous research provides only cursory descriptions of the topic. Therefore, in this review the definition of component analysis is discussed, and a notation system for evaluating the experimental designs of component analyses is described. Thirty articles that included a component analysis were identified via a literature search. The majority of the studies successfully identified a necessary component; however, most of these studies did not evaluate the sufficiency of the necessary component. The notation system may be helpful in developing experimental designs that best suit the purpose of studies aimed at conducting component analyses of treatment packages. PMID- 21541153 TI - Increasing the vocal responses of children with autism and developmental disabilities using manual sign mand training and prompt delay. AB - The purpose of this study was to determine the effect of manual sign mand training combined with prompt delay and vocal prompting on the production of vocal responses in nonvocal children with developmental disabilities. A multiple baseline design across participants verified the effectiveness of this intervention. All participants showed increases in vocal responses following the implementation of the independent variables. PMID- 21541154 TI - Effects of number and location of bins on plastic recycling at a university. AB - The proportion of plastic bottles that consumers placed in appropriate recycling receptacles rather than trash bins was examined across 3 buildings on a university campus. We extended previous research on interventions to increase recycling by controlling the number of recycling receptacles across conditions and by examining receptacle location without the use of posted signs. Manipulating the appearance or number of recycling bins in common areas did not increase recycling. Consumers recycled substantially more plastic bottles when the recycling bins were located in classrooms. PMID- 21541155 TI - A comparison of the effects of providing activity and material choice to children with autism spectrum disorders. AB - The present study compares the effects of providing choice between activities or between materials for completion of activities on the on-task behavior of 4 boys with autism spectrum disorders. Results showed that the participants displayed higher levels of on-task behavior during the choice conditions than in the no choice condition. However, the type of choice opportunity did not seem to have a differential effect. PMID- 21541156 TI - Functional analysis and treatment of aggression maintained by preferred conversational topics. AB - After an initial functional analysis of a participant's aggression showed unclear outcomes, we conducted preference and reinforcer assessments to identify preferred forms of attention that may maintain problem behavior. Next, we conducted an extended functional analysis that included a modified attention condition. Results showed that the participant's aggression was maintained by access to preferred conversational topics. A function-based intervention decreased aggression and increased an appropriate communicative response. PMID- 21541157 TI - The effects of response effort on safe performance by therapists at an autism treatment facility. AB - The effects of response effort on safe behaviors (i.e., glove wearing, hand sanitizing, and electrical outlet replacement) exhibited by therapists at an autism treatment center were examined. Participants were exposed to 2 or 3 levels of effort (i.e., high, medium, low) for each dependent variable. Results showed increased safe performance during the low-effort conditions relative to other conditions across all dependent variables for all participants. PMID- 21541158 TI - An analysis of stimuli that influence compliance during the high-probability instruction sequence. AB - When we evaluated variables that influence the effectiveness of the high probability (high-p) instruction sequence, the sequence was associated with a precipitous decrease in compliance with high-p instructions for 1 participant, thereby precluding continued use of the sequence. We investigated the reasons for this decrease. Stimuli associated with the low-p instruction were systematically added and removed in the context of the high-p instructions, and results suggest that the stimuli associated with the low-p instruction influenced compliance with the high-p instructions. PMID- 21541159 TI - Comparison of bite-presentation methods in the treatment of food refusal. AB - The current study examined the rate of expulsions and mouth cleans across 3 presentation methods (upright spoon, flipped spoon, Nuk brush) for a 3-year-old girl with a feeding disorder. The participant expelled all bites presented on an upright spoon. Results showed reduced rates of expulsions and increased mouth cleans during the flipped spoon and Nuk brush presentation methods. PMID- 21541160 TI - Functional analysis and treatment of the delusional statements of a man with multiple disabilities: a four-year follow-up. AB - Although delusional statements in people with intellectual disabilities and traumatic brain injury can be treated using behavioral interventions, none have demonstrated long-term treatment effects. In the current study, a functional analysis demonstrated that delusional statements were maintained by attention. Differential reinforcement of alternative behavior and extinction of delusional statements resulted in near elimination of delusional statements and an increase in nondelusional statements. Follow-up at 6 months, 1, 2, and 4 years indicated that treatment gains were maintained with continued staff training. PMID- 21541161 TI - An evaluation of advance notice to increase compliance among preschoolers. AB - Advance notice of an upcoming instruction was evaluated to increase compliance among 3 children (4 to 5 years old) who exhibited noncompliance. Results show that the procedure was ineffective for all 3 participants. Advance notice plus physical guidance or physical guidance alone was necessary to increase compliance. PMID- 21541162 TI - The effects of behavioral skills training on mand training by staff and unprompted vocal mands by children. AB - We evaluated the effects of a training package, including instructions, modeling, rehearsal, and feedback, for training staff members to conduct mand training with children. Experimenters collected data on staff performance on each step of a task analysis of mand training and on unprompted child vocal mands. Training resulted in increases in staff performance in mand training and in unprompted mands by children. We observed replication of these effects across settings for all staff and for 3 of the children. PMID- 21541164 TI - Using stimulus equivalence technology to teach statistical inference in a group setting. AB - Computerized lessons employing stimulus equivalence technology, used previously under laboratory conditions to teach inferential statistics concepts to college students, were employed in a group setting for the first time. Students showed the same directly taught and emergent learning gains as in laboratory studies. A brief paper-and-pencil examination, suitable for classroom use, captured effects demonstrated previously through laboratory tests. The results support the extension of the lessons to more naturalistic settings. PMID- 21541165 TI - An experimental analysis of negative reinforcement contingencies for adult delivered reprimands. AB - Seven adults participated in simulated teaching sessions with an experimenter who role played as a student with developmental disabilities. The experimenter engaged in problem behavior and either (a) terminated problem behavior contingent on participant reprimands (negative reinforcement) or (b) did not terminate problem behavior contingent on reprimands (extinction). Results suggested that reprimands were sensitive to negative reinforcement in the form of the immediate cessation of problem behavior. These preliminary findings support role play as a potentially viable laboratory model for analyzing behaviors of typical adults. PMID- 21541166 TI - Recent research on emergent verbal behavior: clinical applications and future directions. AB - This paper describes recent studies that have evaluated the functional independence of verbal operants. Procedures that facilitate the emergence of untrained verbal operants and important areas of future research to increase efficiency of language programs for children diagnosed with developmental disabilities are discussed. PMID- 21541168 TI - The canine sand maze: an appetitive spatial memory paradigm sensitive to age related change in dogs. AB - Aged dogs exhibit a spectrum of cognitive abilities including a syndrome similar to Alzheimer's disease. A major impediment to research so far has been the lack of a quick and accurate test of visuospatial memory appropriate for community based animals. We therefore report on the development and validation of the Canine Sand Maze. A 4.5-m-diameter circular pool was filled with a sand and powdered food reward mix to a depth of 10 cm. Dogs were given 4 habituation and 16 learning trials which alternated a food reward being half (control trials) or fully-buried (acquisition trials) in a fixed location. After a 90-min break, a probe trial was conducted. Cognitively normal, aged (> 8 years, n = 11) and young (1-4 years, n = 11), breed-matched dogs were compared. After correction for differences in control trials, average probe times were 2.97 and 10.81 s for young and aged dogs, respectively. In the probe trial, both groups spent significantly more time in the target quadrant but there was a trend for young dogs to cross a 1 m(2) annulus zone around the buried reward more frequently (2.6 times) than aged dogs (1.5 times). Test-retest reliability in a subset of young dogs (n = 5) was high. On the basis of these findings, the Canine Sand Maze is presented as a quick, sensitive and nonaversive tool for assessing spatial learning and reference memory in dogs. PMID- 21541167 TI - Errorless learning of a conditional temporal discrimination. AB - In the present study we extended errorless learning to a conditional temporal discrimination. Pigeons' responses to a left-red key after a 2-s sample and to a right-green key after a 10-s sample were reinforced. There were two groups: One learned the discrimination through trial and error and the other through an errorless learning procedure. Then, both groups were presented with three types of tests. First, they were exposed to intermediate durations between 2 s and 10 s, and given a choice between both keys (stimulus generalization test). Second, a delay from 1 s to 16 s was included between the offset of the sample and the onset of the choice keys (delay test). Finally, pigeons learned a new discrimination in which the stimuli were switched (reversal test). Results showed that pigeons from the Errorless group made significantly fewer errors than those in the Trial-and-Error group. Both groups performed similarly during the stimulus generalization test and the reversal test, but results of the delay test suggested that, on long stimulus trials, responding in the errorless training group was less disrupted by delays. PMID- 21541169 TI - Recombinative reading derived from pseudoword instruction in a miniature linguistic system. AB - A miniature linguistic system was used to study acquisition of recombinative symbolic behavior. Three studies evaluated the teaching conditions of conditional discriminations with printed and spoken pseudowords that could potentially generate recombinative reading. Fifty-four college students across all studies learned to match 12 printed pseudowords to 12 spoken pseudowords. Some also matched pictures to the same spoken words. Each two-syllable pseudoword was formed by symbols from an arbitrarily created alphabet composed of four vowels and four consonants. Letters had univocal correspondence with phonemes. Recombinative receptive reading, comprehensive reading, and textual responding to pseudowords were periodically assessed. Experiment 1 (n = 20) showed that recombinative reading increased as the number of trained words composed of the same symbols increased. Experiment 2 (n = 14) showed that overtraining the same two words did not produce recombinative reading for most participants. Experiment 3 (n = 20), in which training with pictures was omitted, showed that elemental control by within-syllable units can develop even when the trained pseudowords are meaningless (not related to pictures). The present results support the utility of the miniature linguistic system methodology for identifying and controlling environmental determinants of rudimentary reading skills. PMID- 21541170 TI - Effects of time between trials on rats' and pigeons' choices with probabilistic delayed reinforcers. AB - Parallel experiments with rats and pigeons examined reasons for previous findings that in choices with probabilistic delayed reinforcers, rats' choices were affected by the time between trials whereas pigeons' choices were not. In both experiments, the animals chose between a standard alternative and an adjusting alternative. A choice of the standard alternative led to a short delay (1 s or 3 s), and then food might or might not be delivered. If food was not delivered, there was an "interlink interval," and then the animal was forced to continue to select the standard alternative until food was delivered. A choice of the adjusting alternative always led to food after a delay that was systematically increased and decreased over trials to estimate an indifference point--a delay at which the two alternatives were chosen about equally often. Under these conditions, the indifference points for both rats and pigeons increased as the interlink interval increased from 0 s to 20 s, indicating decreased preference for the probabilistic reinforcer with longer time between trials. The indifference points from both rats and pigeons were well described by the hyperbolic-decay model. In the last phase of each experiment, the animals were not forced to continue selecting the standard alternative if food was not delivered. Under these conditions, rats' choices were affected by the time between trials whereas pigeons' choices were not, replicating results of previous studies. The differences between the behavior of rats and pigeons appears to be the result of procedural details, not a fundamental difference in how these two species make choices with probabilistic delayed reinforcers. PMID- 21541171 TI - Reflexivity in pigeons. AB - A recent theory of pigeons' equivalence-class formation (Urcuioli, 2008) predicts that reflexivity, an untrained ability to match a stimulus to itself, should be observed after training on two "mirror-image" symbolic successive matching tasks plus identity successive matching using some of the symbolic matching stimuli. One group of pigeons was trained in this fashion; a second group was trained similarly but with successive oddity (rather than identity). Subsequently, comparison-response rates on novel matching versus mismatching sequences with the remaining symbolic matching stimuli were measured on nonreinforced probe trials. Higher rates were observed on matching than on mismatching probes in the former group. The opposite effect--higher rates on mismatching than matching probes--was mostly absent in the latter group, despite being predicted by the theory. Nevertheless, the ostensible reflexivity effect observed in former group may be the first time this phenomenon has been demonstrated in any animal. PMID- 21541172 TI - Associative symmetry by pigeons after few-exemplar training. AB - The present experiment investigated whether pigeons can show associative symmetry on a two-alternative matching-to-sample procedure. The procedure consisted of a within-subject sequence of training and testing with reinforcement, and it provided (a) exemplars of symmetrical responding, and (b) all prerequisite discriminations among test samples and comparisons. After pigeons had learned two arbitrary-matching tasks (A-B and C-D), they were given a reinforced symmetry test for half of the baseline relations (B1-A1 and D1-C1). To control for the effects of reinforcement during testing, two novel, nonsymmetrical responses were concurrently reinforced using the other baseline stimuli (D2-A2 and B2-C2). Pigeons matched at chance on both types of relations, thus indicating no evidence for symmetry. These symmetrical and nonsymmetrical relations were then directly trained in order to provide exemplars of symmetry and all prerequisite discriminations for a second test. The symmetrical test relations were now B2-A2 and D2-C2 and the nonsymmetrical relations were D1-A1 and B1-C1. On this test, 1 pigeon showed clear evidence of symmetry, 2 pigeons showed weak evidence, and 1 pigeon showed no evidence. The previous training of all prerequisite discriminations among stimuli, and the within-subject control for testing with reinforcement seem to have set favorable conditions for the emergence of symmetry in nonhumans. However, the variability across subjects shows that methodological variables still remain to be controlled. PMID- 21541173 TI - Observing behavior and atypically restricted stimulus control. AB - Restricted stimulus control refers to discrimination learning with atypical limitations in the range of controlling stimuli or stimulus features. In the study reported here, 4 normally capable individuals and 10 individuals with intellectual disabilities (ID) performed two-sample delayed matching to sample. Sample-stimulus observing was recorded with an eye-tracking apparatus. High accuracy scores indicated stimulus control by both sample stimuli for the 4 nondisabled participants and 4 participants with ID, and eye tracking data showed reliable observing of all stimuli. Intermediate accuracy scores indicated restricted stimulus control for the remaining 6 participants. Their eye-tracking data showed that errors were related to failures to observe sample stimuli and relatively brief observing durations. Five of these participants were then given interventions designed to improve observing behavior. For 4 participants, the interventions resulted initially in elimination of observing failures, increased observing durations, and increased accuracy. For 2 of these participants, contingencies sufficient to maintain adequate observing were not always sufficient to maintain high accuracy; subsequent procedure modifications restored it, however. For the 5th participant, initial improvements in observing were not accompanied by improved accuracy, an apparent instance of observing without attending; accuracy improved only after an additional intervention that imposed contingencies on observing behavior. Thus, interventions that control observing behavior seem necessary but may not always be sufficient for the remediation of restricted stimulus control. PMID- 21541174 TI - Choice in quail neonates: the origins of generalized matching. AB - Although newborns have surprised scientists with their learning skills, proficiency on concurrent schedules of reinforcement requires (in effect) the ability to integrate and compare behavior-consequence relations over time. Can very young animals obey the quantitative relation that applies to such repeated choices, the generalized matching law? The provenance of the skill is not well understood, and this study provides the first investigation of matching in neonates. Northern bobwhite (Colinus virginianus) hatchlings pecked left and right targets on a touchscreen for heat delivery on a concurrent variable interval reinforcement schedule. Within 5 days after hatching, the chicks showed sensitivity levels significantly greater than zero, but short of typical adult levels. However, stable sequential patterns emerged almost immediately, including a consistent choose-rich tendency after unreinforced responses, one that entails some degree of temporal integration. These exploratory data suggest that the basic ability to match develops quickly in this precocial species, but that more extensive experience may be required to achieve the higher sensitivities typically seen in adults. PMID- 21541175 TI - Signaled and unsignaled terminal links in concurrent chains I: effects of reinforcer probability and immediacy. AB - Eight pigeons responded in a three-component concurrent-chains procedure, with either independent or dependent initial links. Relative probability and immediacy of reinforcement in the terminal links were both varied, and outcomes on individual trials (reinforcement or nonreinforcement) were either signaled or unsignaled. Terminal-link fixed-time schedules were varied across components within conditions to yield immediacy ratios of 1?2, 1?1 and 2?1. The probabilities of reinforcement were varied across conditions to yield reinforcer ratios of 1?5, 1?2, 2?1 and 5?1. Results showed that a model based on the generalized matching law provided a good description of response allocation, accounting for 92% of the variance overall. As expected, sensitivity to probability was greater in the unsignaled conditions. However, sensitivity to immediacy was also greater in the unsignaled conditions, suggesting that the effect of signaling terminal-link outcomes may not be limited to probability but apply to reinforcer variables in general. The effects of signaling can be explained in terms of conditioned reinforcement added to each alternative's outcomes in the matching law. There was some evidence for an interaction between reinforcer probability and immediacy, particularly for the dependent-schedules group, such that sensitivity to immediacy was greater at moderate rather than extreme reinforcer ratios. However, further analysis suggested that this could have been due to a ceiling effect on response allocation imposed by dependent scheduling. Overall, the present results show that the generalized matching law can provide a useful account of choice between outcomes that vary in both probability and immediacy of reinforcement. PMID- 21541176 TI - Derived transformation of children's pregambling game playing. AB - Contemporary behavior-analytic perspectives on gambling emphasize the impact of verbal relations, or derived relational responding and the transformation of stimulus functions, on the initiation and maintenance of gambling. Approached in this way, it is possible to undertake experimental analysis of the role of verbal/mediational variables in gambling behavior. The present study therefore sought to demonstrate the ways new stimuli could come to have functions relevant to gambling without those functions being trained directly. Following a successful derived-equivalence-relations test, a simulated board game established high- and low-roll functions for two concurrently presented dice labelled with members of the derived relations. During the test for derived transformation, children were reexposed to the board game with dice labelled with indirectly related stimuli. All participants except 1 who passed the equivalence relations test selected the die that was indirectly related to the trained high-roll die more often than the die that was indirectly related to low-roll die, despite the absence of differential outcomes. All participants except 3 also gave the derived high-roll die higher liking ratings than the derived low-roll die. The implications of the findings for behavior-analytic research on gambling and the development of verbally-based interventions for disordered gambling are discussed. PMID- 21541177 TI - Rate, probability and matching: comments on "The identities hidden in the matching laws, and their uses" by David Thorne. AB - David Thorne's (2010) article, "The identities hidden in the matching laws, and their uses" performs a valuable service in pointing out alternative expressions of matching. However, some identities tend to obscure rather than illuminate empirical relationships. Three such problematic instances are discussed: interresponse time as a function of interval and ratio schedule parameters; probability equality as implying rate matching; the apparent simplicity of probabilistic functions, as opposed to response rate functions, of reinforcement rate. PMID- 21541178 TI - The role of molecular imaging in the diagnosis and management of neuropsychiatric disorders. AB - Neuropsychiatric disorders are becoming a major socioeconomic burden to modern society. In recent years, a dramatic expansion of tools has facilitated the study of the molecular basis of neuropsychiatric disorders. Molecular imaging has enabled the noninvasive characterization and quantification of biological processes at the cellular, tissue, and organism levels in intact living subjects. This technology has revolutionized the practice of medicine and has become critical to quality health care. New advances in research on molecular imaging hold promise for personalized medicine in neuropsychiatric disorders, with adjusted therapeutic doses, predictable responses, reduced adverse drug reactions, early diagnosis, and personal health planning. In this paper, we discuss the development of radiotracers for imaging dopaminergic, serotonergic, and noradrenergic systems and beta-amyloid plaques. We will underline the role of molecular imaging technologies in various neuropsychiatric disorders, describe their unique strengths and limitations, and suggest future directions in the diagnosis and management of neuropsychiatric disorders. PMID- 21541179 TI - Primary pulmonary mucinous cystadenocarcinoma: a case report. AB - Primary pulmonary mucinous cystadenocarcinoma (PMCAC) is an extremely rare cystic neoplasm. A case of a 56-year-old male with a cystic lesion of the right lower lobe is described. Preoperative fine needle aspiration cytology and bronchoscopy were inconclusive. The patient underwent a formal right lower lobectomy and mediastinal lymph node dissection. Diagnosis was established intraoperatively. The biological behavior of primary PMCAC is unknown. Therefore, careful long-term follow-up is considered necessary because of lack of experience globally. PMID- 21541180 TI - MicroRNA gene dosage alterations and drug response in lung cancer. AB - Chemotherapy resistance is a key contributor to the dismal prognoses for lung cancer patients. While the majority of studies have focused on sequence mutations and expression changes in protein-coding genes, recent reports have suggested that microRNA (miRNA) expression changes also play an influential role in chemotherapy response. However, the role of genetic alterations at miRNA loci in the context of chemotherapy response has yet to be investigated. In this study, we demonstrate the application of an integrative, multidimensional approach in order to identify miRNAs that are associated with chemotherapeutic resistance and sensitivity utilizing publicly available drug response, miRNA loci copy number, miRNA expression, and mRNA expression data from independent resources. By instigating a logical stepwise strategy, we have identified specific miRNAs that are associated with resistance to several chemotherapeutic agents and provide a proof of principle demonstration of how these various databases may be exploited to derive relevant pharmacogenomic results. PMID- 21541181 TI - Discovering the unknown: improving detection of novel species and genera from short reads. AB - High-throughput sequencing technologies enable metagenome profiling, simultaneous sequencing of multiple microbial species present within an environmental sample. Since metagenomic data includes sequence fragments ("reads") from organisms that are absent from any database, new algorithms must be developed for the identification and annotation of novel sequence fragments. Homology-based techniques have been modified to detect novel species and genera, but, composition-based methods, have not been adapted. We develop a detection technique that can discriminate between "known" and "unknown" taxa, which can be used with composition-based methods, as well as a hybrid method. Unlike previous studies, we rigorously evaluate all algorithms for their ability to detect novel taxa. First, we show that the integration of a detector with a composition-based method performs significantly better than homology-based methods for the detection of novel species and genera, with best performance at finer taxonomic resolutions. Most importantly, we evaluate all the algorithms by introducing an "unknown" class and show that the modified version of PhymmBL has similar or better overall classification performance than the other modified algorithms, especially for the species-level and ultrashort reads. Finally, we evaluate the performance of several algorithms on a real acid mine drainage dataset. PMID- 21541182 TI - Left transperitoneal adrenalectomy with a laparoendoscopic single-site surgery combined technique: initial case reports. AB - Laparoendoscopic single-site surgery (LESS) is a step toward the development of minimally invasive surgery. It is initially difficult for surgeons with limited experience to perform the surgery. We describe two cases of left adrenalectomy with a LESS combined with the addition of an accessory port. After a 2.5-cm skin incision was made at the level of the paraumbilicus to insert the primary 12-mm trocar for the laparoscope, a 5-mm nonbladed trocar was placed through the skin incision side-by-side with the primary trocar. A second 3-mm nonbladed trocar was then placed along the anterior axillary line; a multichannel trocar was not used as a single port. Both adrenalectomies were completed successfully. In patients with a minor adrenal tumor, a combined technique using LESS and an additional port is easier than LESS alone and may, therefore, be a bridge between the conventional laparoscopic approach and LESS. PMID- 21541184 TI - Acral lentiginous melanoma: a case control study and guidelines update. AB - Background. Malignant melanoma incidence is increasing dramatically. We report herein a case of the rarest acral lentiginous type. Case Report. A 58-year-old man presented with a melanoma resembling lesion over the sole of his right foot, measuring 15-20 mm in diameter. An excisional biopsy with a narrow (2 mm) margin of surrounding skin was obtained. Histological findings were consistent with a diagnosis of acral lentiginous melanoma. Sentinel lymph node biopsy was also performed and micrometastases were not identified in frozen-section examination. According to the AJCC system, the tumor stage was IB (T2aN0M0). A wide local excision of the biopsy scar with a margin of 2 cm was performed. A split thickness thick skin graft was used to reconstruct the excisional defect. During an 18-month followup, no local or distant recurrence has been observed. This paper aims to extract an updated rational approach to the management of this disease out of an enormous body of knowledge. PMID- 21541183 TI - Urinary elimination of coproporphyrins is dependent on ABCC2 polymorphisms and represents a potential biomarker of MRP2 activity in humans. AB - MRP2 encoded by ABCC2 gene is involved in the secretion of numerous drugs and endogenous substrates. Patients with Dubin-Johnson syndrome due to mutation in ABCC2 gene have elevated urinary coproporphyrin ratio (UCP I/(I + III)). Here we investigated whether this ratio could serve as a biomarker of MRP2 function. Phenotype-genotype relationships were studied in 74 healthy subjects by measuring individual UCP I/(I + III) ratio obtained on 24-hour urine and by analyzing five common SNPs in ABCC2 gene. The UCP I/(I + III) ratio varied from 14.7% to 46.0% in our population. Subjects with 3972TT genotype had a higher ratio (P = .04) than those carrying the C allele. This higher UCP I/(I + III) ratio was correlated with a higher level of isomer I excretion. This study provides a proof of concept that UCP I/(I + III) ratio can be used as a biomarker of MRP2 function in clinical studies as it provides quantitative information about the in vivo activity of MRP2 in a given patient. PMID- 21541185 TI - Tocotrienol-rich fraction prevents cell cycle arrest and elongates telomere length in senescent human diploid fibroblasts. AB - This study determined the molecular mechanisms of tocotrienol-rich fraction (TRF) in preventing cellular senescence of human diploid fibroblasts (HDFs). Primary culture of HDFs at various passages were incubated with 0.5 mg/mL TRF for 24 h. Telomere shortening with decreased telomerase activity was observed in senescent HDFs while the levels of damaged DNA and number of cells in G(0)/G(1) phase were increased and S phase cells were decreased. Incubation with TRF reversed the morphology of senescent HDFs to resemble that of young cells with decreased activity of SA-beta-gal, damaged DNA, and cells in G(0)/G(1) phase while cells in the S phase were increased. Elongated telomere length and restoration of telomerase activity were observed in TRF-treated senescent HDFs. These findings confirmed the ability of tocotrienol-rich fraction in preventing HDFs cellular ageing by restoring telomere length and telomerase activity, reducing damaged DNA, and reversing cell cycle arrest associated with senescence. PMID- 21541186 TI - Two immigrants with tuberculosis of the ear, nose, and throat region with skull base and cranial nerve involvement. AB - We report two immigrants with tuberculosis of the skull base and a review of the literature. A Somalian man presented with bilateral otitis media, hearing loss, and facial and abducens palsy. Imaging showed involvement of both mastoid and petrous bones, extending via the skull base to the nasopharynx, suggesting tuberculosis which was confirmed by characteristic histology and positive auramine staining, while Ziehl-Neelsen staining and PCR were negative. A Sudanese man presented with torticollis and deviation of the uvula due to paresis of N. IX and XI. Imaging showed a retropharyngeal abscess and lysis of the clivus. Histology, acid-fast staining, and PCR were negative. Both patients had a positive Quantiferon TB Gold in-tube result and improved rapidly after empiric treatment for tuberculosis. Cultures eventually yielded M. tuberculosis. These unusual cases exemplify the many faces of tuberculosis and the importance to include tuberculosis in the differential diagnosis of unexplained problems. PMID- 21541187 TI - A novel animal model of hippocampal cognitive deficits, slow neurodegeneration, and neuroregeneration. AB - Long-term adrenalectomy (ADX) results in an extensive and specific loss of dentate gyrus granule cells in the hippocampus of adult rats. This loss of granule cells extends over a period of weeks to months and ultimately results in cognitive deficits revealed in a number of tasks that depend on intact hippocampal function. The gradual nature of ADX-induced cell death and the ensuing deficits in cognition resemble in some important respects a variety of pathological conditions in humans. Here, we characterize behavioural and cellular processes, including adult neurogenesis, in the rat ADX model. We also provide experimental evidence for a neurogenic treatment strategy by which the lost hippocampal cells may be replaced, with the goal of functional recovery in mind. PMID- 21541188 TI - Purulent Meningitis as an Unusual Presentation of Staphylococcus aureus Endocarditis: A Case Report and Literature Review. AB - On presentation of Staphylococcus aureus endocarditis, unusual manifestations may represent the main clinical features of the disease. Isolated bacterial meningitis as the first manifestation of endocarditis is considered to be an unusual neurological complication. Here, we describe a case S. aureus endocarditis presenting as isolated meningitis and mimicking meningococcal septicaemia. Because of the high mortality rate of the disease, the prompt recognition of this infectious syndrome is of crucial importance for the correct management of patients. PMID- 21541189 TI - Autologous peripheral blood mononuclear cell recognition of autologous proliferating tumor cells in the context of a patient-specific vaccine trial. AB - Metastatic melanoma patients who were treated with patient-specific vaccines consisting of dendritic cells loaded with autologous tumor cells had a 5-year survival of over 50%. Enzyme-linked immunospot (ELISPOT) has been used to detect antigen reactive T cells as a means of determining immune response. We wished to determine whether IFN-gamma secretion in an ELISPOT assay was prognostic or predictive for survival following treatment. Peripheral blood mononuclear cells (PBMCs) collected at weeks 0 and 4 were evaluated by ELISPOT assay for response to autologous tumor cells. Overall, there was slight increase in the number of tumor reactive lymphocytes from week 0 to week 4. Using >5 spots/100 K PBMC as the cutoff, a log-rank analysis revealed only a slight statistical significance in overall survival for patients who lacked tumor reactive PBMCs at week 4. The sensitivity of ELISPOT in the context of patient-specific cellular vaccines is unclear. PMID- 21541190 TI - Virus-negative active lymphocytic myocarditis progressing to a fibrotic stage. AB - We report a fairly special case of lymphocytic myocarditis progressing to a fibrotic stage, described using multimodality imaging and confirmed on histopathology. This paper presents an uncommon diagnosis with a probable guarded prognosis. PMID- 21541191 TI - Natural killer cells in human cancer: from biological functions to clinical applications. AB - Natural killer (NK) cells are central components of the innate immunity. In murine models, it has been shown that NK cells can control both local tumor growth and metastasis due to their ability to exert direct cellular cytotoxicity without prior sensitization and to secrete immunostimulatory cytokines like IFN gamma. The latter participates in cancer elimination by inhibiting cellular proliferation and angiogenesis, promoting apoptosis, and stimulating the adaptive immune system, and it is instrumental for enhancing Ag processing and presentation. Nevertheless, NK cells display impaired functionality and capability to infiltrate tumors in cancer patients. Also, NK cells are feasible targets of stimulation to participate in immunotherapeutic approaches like antibody-based strategies and adoptive cell transfer. Thus, multiple attempts currently aim to manipulate NK for utilization in the immunotherapy of cancer. PMID- 21541192 TI - Immunological and clinical effects of vaccines targeting p53-overexpressing malignancies. AB - Approximately 50% of human malignancies carry p53 mutations, which makes it a potential antigenic target for cancer immunotherapy. Adoptive transfer with p53 specific cytotoxic T-lymphocytes (CTL) and CD4(+) T-helper cells eradicates p53 overexpressing tumors in mice. Furthermore, p53 antibodies and p53-specific CTLs can be detected in cancer patients, indicating that p53 is immunogenic. Based on these results, clinical trials were initiated. In this paper, we review immunological and clinical responses observed in cancer patients vaccinated with p53 targeting vaccines. In most trials, p53-specific vaccine-induced immunological responses were observed. Unfortunately, no clinical responses with significant reduction of tumor-burden have occurred. We will elaborate on possible explanations for this lack of clinical effectiveness. In the second part of this paper, we summarize several immunopotentiating combination strategies suitable for clinical use. In our opinion, future p53-vaccine studies should focus on addition of these immunopotentiating regimens to achieve clinically effective therapeutic vaccination strategies for cancer patients. PMID- 21541193 TI - Quantifying tumor vascular heterogeneity with dynamic contrast-enhanced magnetic resonance imaging: a review. AB - Tumor microvasculature possesses a high degree of heterogeneity in its structure and function. These features have been demonstrated to be important for disease diagnosis, response assessment, and treatment planning. The exploratory efforts of quantifying tumor vascular heterogeneity with DCE-MRI have led to promising results in a number of studies. However, the methodological implementation in those studies has been highly variable, leading to multiple challenges in data quality and comparability. This paper reviews several heterogeneity quantification methods, with an emphasis on their applications on DCE-MRI pharmacokinetic parametric maps. Important methodological and technological issues in experimental design, data acquisition, and analysis are also discussed, with the current opportunities and efforts for standardization highlighted. PMID- 21541194 TI - Extranodal NK/T-cell lymphoma: toward the identification of clinical molecular targets. AB - Extranodal natural killer (NK)/T-cell lymphoma of nasal type (NKTCL) is a malignant disorder of cytotoxic lymphocytes of NK or more rarely T cells associated with clonal Epstein-Barr virus infection. Extranodal NKTCL is rare in Western countries, but in Asia and Central and South America it can account for up to 10% of non-Hodgkin's lymphomas. It is an aggressive neoplasm with very poor prognosis. Although the pathogenesis of extranodal NKTCL remains poorly understood, some insights have been gained in the recent years, especially from genome-wide studies. Based on our own experience and knowledge of the literature, we here review some of the genomic and functional pathway alterations observed in NKTCL that could provide a rationale for the development of innovative therapeutic strategies. PMID- 21541195 TI - Functions of MDMX in the modulation of the p53-response. AB - The MDM family proteins MDM2 and MDMX are two critical regulators of the p53 tumor suppressor protein. Expression of both proteins is necessary for allowing the embryonal development by keeping the activity of p53 in check. Upon stresses that need to activate p53 to perform its function as guardian of the genome, p53 has to be liberated from these two inhibitors. In this review, we will discuss the various mechanisms by which MDMX protein levels are downregulated upon various types of stress, including posttranslational modifications of the MDMX protein and the regulation of mdmx mRNA expression, including alternative splicing. In addition, the putative function(s) of the described MDMX splice variants, particularly in tumor development, will be discussed. Lastly, in contrast to common belief, we have recently shown the existence of a p53-MDMX feedback loop, which is important for dampening the p53-response at later phases after genotoxic stress. PMID- 21541196 TI - Methotrexate toxicity in growing long bones of young rats: a model for studying cancer chemotherapy-induced bone growth defects in children. AB - The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy-induced skeletal defects remain largely unclear. Methotrexate (MTX), the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical observations but also have increased our understanding of the mechanisms underlying chemotherapy-induced skeletal damage. These models revealed that high-dose MTX can cause growth plate dysfunction, damage osteoprogenitor cells, suppress bone formation, and increase bone resorption and marrow adipogenesis, resulting in overall bone loss. While recent rat studies have shown that antidote folinic acid can reduce MTX damage in the growth plate and bone, future studies should investigate potential adjuvant treatments to reduce chemotherapy-induced skeletal toxicities. PMID- 21541198 TI - Target therapies in lung cancer. AB - Targeting intracellular signaling molecules is an attractive approach for treatment of malignancies. In particular lung cancer has reached a plateau regarding overall survival, and target therapies could offer the possibility to improve patients' outcome beyond cytotoxic activity. The goal for target therapies is to identify agents that target tumor-specific molecules, thus sparing normal tissues; those molecules are called biomarkers, and their identification is recommended because it has a predictive value, for example, provides information on outcome with regard to a specific treatment. The increased specificity should lead to decreased toxicity and better activity. Herein we provide an update of the main target therapies in development or already available for the treatment of nonsmall cell lung cancer. PMID- 21541199 TI - Single-stage posterior midline approach for dumbbell tumors of the thoracic spine, with intraoperative CT guidance. AB - BACKGROUND: Several different procedures have been advocated for thoracic spine dumbbell tumor resection, combining thoracic and neurosurgical approaches, in single and multiple stages, using various incisions and positions. These have led to controversies in the ideal management. The authors report their analysis of a series of 11 patients successfully treated through a one-step midline approach for complete resection and instrumentation when indicated under intraoperative CT (ICT) guidance. METHODS: The patients' clinical presentations, imaging results, operative findings and follow-up were reviewed in 11 patients (age ranged from 11 to 62 years), over the period from August 2007 to May 2010. A single-stage, posterior midline incision approach with laminectomy, facetectomy, costotransversectomy, for complete resection of intraspinal and paraspinal components of tumor was used. Spinal instrumentation under ICT guidance was also carried out in relevant (six) cases with tumors involving junctional spinal regions such the cervico-thoracic or thoraco-lumbar region. RESULTS: The initial clinical presenting symptom was pain in eight patients and paresthesia in one, while two patients were detected incidentally on routine chest X-rays. Total excision was achieved in 10 patients (9 schwanommas, 1 neurofibroma) with the exception of one patient who had a recurrent malignant peripheral nerve sheath tumor adherent to the vertebral artery. No significant postoperative complications occurred and an early mobilization/discharge was achieved in all patients with an average hospital stay of 5 days. CONCLUSIONS: A one-step approach through a posterior midline incision is feasible, safe and efficient for complete excision of thoracic dumbbell tumors. This approach facilitates laminectomy, facetectomy, costotransversectomy and instrumentation under ICT guidance, while limiting muscle damage, blood loss, operative time, postoperative pain, thus enabling early mobilization with a reduced hospital stay. PMID- 21541197 TI - Immunologic monitoring of cellular responses by dendritic/tumor cell fusion vaccines. AB - Although dendritic cell (DC)- based cancer vaccines induce effective antitumor activities in murine models, only limited therapeutic results have been obtained in clinical trials. As cancer vaccines induce antitumor activities by eliciting or modifying immune responses in patients with cancer, the Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria, designed to detect early effects of cytotoxic chemotherapy in solid tumors, may not provide a complete assessment of cancer vaccines. The problem may, in part, be resolved by carrying out immunologic cellular monitoring, which is one prerequisite for rational development of cancer vaccines. In this review, we will discuss immunologic monitoring of cellular responses for the evaluation of cancer vaccines including fusions of DC and whole tumor cell. PMID- 21541200 TI - An evidence-based mobile decision support system for subaxial cervical spine injury treatment. AB - Bringing evidence to practice is a key issue in modern medicine. The key barrier to information searching is time. Clinical decision support systems (CDSS) can improve guideline adherence. Mounting evidence exists that mobile CDSS on handheld computers support physicians in delivering appropriate care to their patients. Subaxial cervical spine injuries account for almost half of spine injuries, and a majority of spinal cord injuries. A valid and reliable classification exists, including evidence-based treatment algorithms. A mobile CDSS on this topic was not yet available. We developed and tested an iPhone application based on the Subaxial Injury Classification (SLIC) and 5 evidence based treatment algorithms for the surgical approach to subaxial cervical spine injuries. The application can be downloaded for free. Users are cordially invited to provide feedback in order to direct further development and evaluation of CDSS for traumatic lesions of the spinal column. PMID- 21541201 TI - Neuronavigation-assisted single transseptal catheter implantation and shunt in patients with posthemorrhagic hydrocephalus and accentuated lateral ventricles dilatation. AB - BACKGROUND: To assess the treatment of posthemorrhagic hydrocephalus with accentuated lateral ventricles dilatation by employing a single biventricular neuronavigation-assisted transseptal-implanted catheter with programmable valve and distal peritoneal derivation. METHODS: A neuronavigation-assisted single transseptal biventricular catheter implantation with distal peritoneal shunt system was performed in 11 patients with posthemorrhagic hydrocephalus and accentuated lateral ventricles dilatations between 2001 and 2010. Patients with concomitant third ventricle dilatation were excluded. Several sequential frustrated attempts of temporary drainage occlusion on both sides confirmed the isolation of the lateral ventricles. Neuronavigation was employed to accurately establish the catheter surgical corridor (trajectory) across the lateral ventricles and throughout the septum pellucidum. The neurological and radiological outcomes were assessed at least 6 months after the procedure. RESULTS: Catheter implantation was successfully performed in all patients. Only one catheter was found to be monoventricular on delayed computer tomography controls. Procedure-related complications (bleeding of infections) were not observed. No additional neurological deficits were found after shunt surgery. Six months after procedure, none required additional ventricular catheter implantations or shunt revisions. Radiological and clinical controls confirmed the shunt function and the improved neurological status of all patients. CONCLUSION: Single neuronavigation-assisted transseptal-implanted biventricular catheter is a valid option for the treatment of posthemorrhagic hydrocephalus with accentuated lateral ventricles dilatation. This technique reduces the number of catheters and minimizes the complexity and timing of the surgical procedure as well as potential infection's risks associated with the use of multiple shunting systems. PMID- 21541202 TI - Ruptured de novo posterior communicating artery aneurysm associated with arteriosclerotic stenosis of the internal carotid artery at the supraclinoid portion. AB - BACKGROUND: Several de novo intracranial aneurysms have been described related to changes in hemodynamics after therapeutic occlusion of internal carotid artery (ICA); however, de novo aneurysms related to a supraclinoid arteriosclerotic stenosis of the ICA have not been described yet. Authors consider that it is important to bear in mind the possibility of developing an aneurysm in these special conditions. CASE DESCRIPTION: The evolution of a 62-year-old patient with subarachnoid hemorrhage, intraparenchymal frontal hematoma with some atypical circumstances that were presented together as well as the treatment he received are shown in this report. We can see this patient suffered a right thalamic hemorrhage at the age of 51 years; this condition was associated to a severe atherosclerotic stenosis of right supraclinoid ICAy. A long term had elapsed since the diagnosis of the stenosis and the discovery of a ruptured ipsilateral de novo supraclinoid internal carotid artery-posterior communicating artery (ICA PcomA) aneurysm. CONCLUSIONS: IT SEEMS LIKE BOTH CONDITIONS: the atherosclerotic supraclinoid ICA which tells of an Samano et at: Ruptured De Novo PcomA Aneurysm Associated with Arteriosclerotic Stenosis of Supraclinoid ICA. Altered vessel environment coupled to a long exposure time, hemodynamic changes, unbalance in the wall sheer stress could all of them lead to the development of the de novo aneurysm. PMID- 21541203 TI - Monitoring of brain tissue oxygenation in surgery of middle cerebral artery incidental aneurysms. AB - INTRODUCTION: The management of incidental unruptured aneurysms remains a matter of controversy; middle-sized or large anterior circulation incidental aneurysms, in young or middle age patients, should be considered for treatment. Surgical clipping is an accepted treatment for middle cerebral artery unruptured aneurysms. Ischemic events can occur even in cases of incidental aneurysm surgery. Since regional cerebral blood flow can be compromised due to temporary arterial clipping or to incorrect placement of defi nitive clip, we performed intra-operative monitoring of brain tissue oxygen concentration (PtiO(2)), to detect changes in brain oxygenation due to reduced blood fl ow, eventually leading to ischemia, during surgery of middle cerebral artery incidental aneurysms. METHODS: PtiO(2) monitoring was performed during surgery of eight patients harboring incidental MCA aneurysms, using a polarographic microcatheter (Licox, GMS - Kiel, Germany), placed in the temporal lobe on the side of the lesion, from dural opening to dural closure. RESULTS: Basal values varied between 2.3 and 27.3 mmHg; these values are lower than those previously described in the literature as "normal" for uninjured brain or in cases of subarachnoid hemorrhage. In all patients, a significant decrease in PtiO2 was found in every period of temporary clipping of MCA. Post-operative infarction in the territory of middle cerebral artery occurred in one patient and, in that case, there was a persistent minimum value of 0.6 mmHg, without recovery after the placement of the definitive clip. In another patient, an incorrect placement of the definitive clip could be predicted by a decrease in PtiO(2) value. CONCLUSIONS: PtiO(2) monitoring during aneurysm surgery shows brain tissue perfusion in real time and there is a correlation between any episode of reduced blood flow to the affected vascular territory during surgery and a decrease of PtiO2 values. Unexpected low basal values were obtained in "uninjured" brain, with no influence from subarachnoid hemorrhage. The values of risk for brain infarction during temporary arterial occlusion still need further studies, but an incomplete recovery or a persistent fall in PtiO(2) values after definitive clipping should be considered as an indication for verification of the position of the clip. PMID- 21541204 TI - The International Tethered Cord Partnership: Beginnings, process, and status. AB - BACKGROUND: Spina bifida presents a significant cause of childhood morbidity in lower- and middle-income nations. Unfortunately, there is a paucity of literature examining outcomes among children with spina bifida in these countries. The goal of the International Tethered Cord Parternship is twofold: (1) to establish an international surveillance database to examine the correlation between time of repair and clinical outcomes in children with spina bifida and tethered cord; and (2) to foster collaboration among international institutions around pediatric neurosurgical concerns. METHODS: Twelve institutions in 7 countries committed to participating in the International Tethered Cord Partnership. A neurosurgeon at each institution will evaluate all children presenting with spina bifida and/or tethered cord using the survey instrument after appropriate consent is obtained. The instrument was developed collaboratively and based on previous measures of motor and sensory function, ambulation, and continence. All institutions who have begun collecting data received appropriate Institutional Review Board approval. All data will be entered into a Health Insurance Portability and Accountability Act (HIPAA) compliant database. In addition, a participant restricted internet forum was created to foster communication and includes non-project-specific communications, such as case and journal article discussion. RESULTS: From October 2010 to December 2010, 82 patients were entered from the various study sites. CONCLUSION: To our knowledge this is the first international pediatric neurosurgical database focused on clinical outcomes and predictors of disease progression. The collaborative nature of the project will not only increase knowledge of spina bifida and tethered cord, but also foster discussion and further collaboration between neurosurgeons internationally. PMID- 21541205 TI - Vertebral artery injury after cervical spine trauma: A prospective study using computed tomographic angiography. AB - BACKGROUND: Although the vertebral artery injuries (VAI) associated with cervical spine trauma are usually clinically occult, they may cause fatal ischemic damage to the brain stem and cerebellum. METHODS: We performed a prospective study using computed tomographic angiography (CTA) to determine the frequency of VAI associated with cervical spine injuries and investigate the clinical and radiological characteristics. Between January 2005 and August 2007, 99 consecutive patients with cervical spine fractures and/or dislocations were prospectively evaluated for patency of the VA, using the CTA, at the time of injury. RESULTS: Complete disruption of blood flow through the VA was demonstrated in seven patients with unilateral occlusion (7.1%). There were four men and three women with a mean age of 43 (range, 33-55 years). Unilateral occlusion of the right vertebral artery occurred in four patients and of the left in three. Regarding the cervical injury type, two cases were cervical burst fractures (C6 and C7), two had C4-5 fracture/dislocations, two had a unilateral transverse foraminal fracture, and one had dens type III fracture. All patients presented with good patency of the contralateral VA. None of the patients developed secondary neurological deterioration due to vertebrobasilar ischemia during the follow-up period with a mean duration of 23 months. CONCLUSIONS: VAI should be suspected in patients with cervical trauma that have cervical spine fractures and/or dislocations or transverse foramen fractures. CTA was useful as a rapid diagnostic method for ruling out VAI after cervical spine trauma. PMID- 21541206 TI - Neurocytoma of the cerebellum. AB - BACKGROUND: Neurocytomas are benign central nervous system tumor composed of small cells with characteristics of neuronal differentiation; they are usually located in the supratentorial periventricular region, in close relation to the septum pellucidum and the foramen of Monro. CASE DESCRIPTION: Herein we report a rare case of a neurocytoma located in the cerebellar hemisphere. To date there are only four such reported cases. CONCLUSION: Neurocytomas should be considered in the differential diagnosis of mass lesions in the cerebellum. PMID- 21541207 TI - Molecular genetic markers in female reproductive cancers. PMID- 21541208 TI - X-Linked Lymphoproliferative Syndrome and Common Variable Immunodeficiency May Not Be Differentiated by SH2D1A and XIAP/BIRC4 Genes Sequence Analysis. AB - The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency characterized by recurrent episodes of hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphomas. Recently, X-linked inhibitor of apoptosis (XIAP/BIRC4) gene defects, in families with XLP but without SH2D1A gene defects, has been defined. The distinction from primary immunodeficiencies with a defined genetic cause is mandatory. A six-year-old male patient was admitted with the complaints of persistent general lymphadenopathy, for two years had fever, bilateral cervical multiple microlymphadenopathy, hepatic/splenic enlargement with laboratory findings as decreased serum immunoglobulins, negative EBV VCA IgM (viral capsid antigen) and anti-EBV EA (antibody to early D antigen), positive EBV VCA IgG (viral capsid antigen) and EBV EBNA (antibody to nuclear antigen). SH2D1A gene analysis was negative. XIAP/BIRC4 sequencing revealed two novel single nucleotide variants (exon 7, 1978G > A, and 1996T > A) in the 3'UTR of the gene in both patient and mother which were not disease causing. XIAP protein expression was found to be normal. The clinical and laboratory resemblance, no gene mutations, and normal XIAP protein expression led us to think that there may be another responsible gene for XLP. The patient will to be followed up as CVID until he presents new diagnostic signs or until the identification of a new gene. PMID- 21541209 TI - Insulin versus Lipid Emulsion in a Rabbit Model of Severe Propranolol Toxicity: A Pilot Study. AB - Background and objective. Beta-blocker overdose may result in intractable cardiovascular collapse despite conventional antidotal treatments. High dose insulin/glucose (ING), and more recently intravenous lipid emulsion (ILE), have been proposed as potentially beneficial therapies in beta blocker intoxication. We compare efficacy of the novel antidotes ING, with ILE, in a rabbit model of combined enteric/intravenous propranolol toxicity. Methods. Sedated, mechanically ventilated and invasively monitored New Zealand White rabbits underwent mini laparotomy and enterostomy formation with 40 mg/kg propranolol instilled into the proximal small bowel. At 30 minutes propranolol infusion was commenced at 4 mg/kg/hr and continued to a target mean arterial pressure (MAP) of 50% baseline MAP. Animals were resuscitated with insulin at 3 U/kg plus 0.5 g/kg glucose (ING group), or 10 mL/kg 20% Intralipid (ILE group). Results. Rate pressure product (RPP; RPP = heart rate * mean arterial pressure) was greatest in the ING group at 60 minutes (P < .05). A trend toward greater heart rate was observed in the ING group (P = .06). No difference was observed in survival between groups (4/5 ING versus 2/5 ILE; P = .524). Conclusions. High dose insulin resulted in greater rate pressure product compared with lipid emulsion in this rabbit model of severe enteric/intravenous propranolol toxicity. PMID- 21541210 TI - Case series of post-thrombolysis patients undergoing hemicraniectomy for malignant anterior circulation ischaemic stroke. AB - While ischaemic stroke remains a leading cause of death and disability, there have been recent advancements in treatment modalities including thrombolysis and decompressive hemicraniectomy. A retrospective review of patients treated in our NHS teaching hospital, in Plymouth (UK), over a 2 year period identified 17 thrombolysed patients, of whom two had undergone subsequent decompressive hemicraniectomy. These were non-dominant hemisphere strokes in young patients, aged 51 and 57. Initial NIHSS scores were 16 and 17, and they received thrombolysis at 2 hrs 42 min and 5 hrs 10 min post onset of symptoms respectively. CT imaging demonstrated cerebral swelling with significant midline shift in both cases, and decompressive hemicraniectomy was undertaken at 29 hrs 8 min and 27 hrs 30 min post-thrombolysis. We found no significant intra-operative complications attributable to prior use of thrombolytics. Both patients have had acceptable psychological and physical outcomes, with Barthel Index scores of 40 and 25, and MMSE scores of 29/30 and 27/30. We conclude that the use of thrombolytic therapy does not contra-indicate subsequent decompressive hemicraniectomy in well selected patients with non-dominant hemisphere strokes. More research in this field is required to elucidate factors which would facilitate recognition of stroke patients who will benefit most from aggressive medical and neurosurgical intervention. PMID- 21541212 TI - Development of 68Ga-glycopeptide as an imaging probe for tumor angiogenesis. AB - Objective. This study was aimed to study tissue distribution and tumor imaging potential of (68)Ga-glycopeptide (GP) in tumor-bearing rodents by PET. Methods. GP was synthesized by conjugating glutamate peptide and chitosan. GP was labeled with (68)Ga chloride for in vitro and in vivo studies. Computer outlined region of interest (counts per pixel) of the tumor and muscle (at the symmetric site) was used to determine tumor-to-muscle count density ratios. To ascertain the feasibility of (68)Ga-GP in tumor imaging in large animals, PET/CT imaging of (68)Ga-GP and (18)F-FDG were conducted in New Zealand white rabbits bearing VX2 tumors. Standard uptake value of tumors were determined by PET up to 45 min. To determine blood clearance and half-life of (68)Ga-GP, blood samples were collected from 10 seconds to 20 min. Results. Radiochemical purity of (68)Ga-GP determined by instant thin-layer chromatography was >95%. Tumor uptake values (SUV) for (68)Ga-GP and (18)F-FDG in New Zealand white rabbits bearing VX2 tumors were 3.25 versus 7.04. PET images in tumor-bearing rats and rabbits confirmed that (68)Ga-GP could assess tumor uptake. From blood clearance curve, the half life of (68)Ga-GP was 1.84 hr. Conclusion Our data indicate that it is feasible to use (68)Ga-GP to assess tumor angiogenesis. PMID- 21541211 TI - Nicotinic acetylcholine receptor signaling in tumor growth and metastasis. AB - Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneficial effects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These effects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Specific signal transduction cascades that emanate from different nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor effects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent efforts to target the nicotinic acetylcholine receptors to combat cancer. PMID- 21541213 TI - An update on the controversies in anemia management in chronic kidney disease: lessons learned and lost. AB - Background. Erythropoietin deficiency and anemia occur in Chronic Kidney Disease (CKD) and may be treated with Erythropoietin Stimulating Agents (ESAs). The optimal hemoglobin, in non-End Stage Renal Disease CKD, is controversial. Methods. We review three recent randomized trials in anemia in CKD: CHOIR, CREATE, and TREAT. Results. CHOIR (N = 1432) was terminated early with more frequent death and cardiovascular outcomes in the higher Hb group (HR 1.34: 95% C.I. 1.03-1.74, P = .03). CREATE (N = 603) showed no difference in primary cardiovascular endpoints. Stroke was more common in the higher Hb group (HR 1.92; 95% C.I. 1.38-2.68; P < .001) in TREAT (N = 4038). Conclusions. There is no benefit to an Hb outside the 10-12 g/dL range in this population. To avoid transfusions and improve Quality of Life, ESAs should be used cautiously, especially in patients with Diabetes, CKD, risk factors for stroke, and ESA resistance. PMID- 21541214 TI - Growing teratoma syndrome and peritoneal gliomatosis. AB - The growing teratoma syndrome (GTS) is defined as a detection of an enlarged mass during or after chemotherapy treatment for germ cell tumor. We report a case of an 18-year-old girl treated for growing teratoma syndrome after chemotherapy for malignant germ cell tumor of the ovary associated with peritoneal gliomatosis. Chemotherapy induced normalisation of alpha-fetoprotein rate whereas there was an enlargement of the mass. Subsequent complete resection was performed, and the patient remained in good control for 60 months. This clinical picture suggested the diagnosis of "GTS". This syndrome can lead to confusion with progression or relapse of a germ cell tumour because of increase in tumour volume during chemotherapy, so it is important to recognize it. PMID- 21541215 TI - Kaposi's Sarcoma-Associated Herpesvirus-Related Solid Lymphoma Involving the Heart and Brain. AB - Since its discovery in 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with lymphoproliferative disorders, particularly in patients infected with human immunodeficiency virus (HIV). The disorders most strongly linked to KSHV are multicentric Castleman's Disease (MCD), primary effusion lymphoma, and diffuse large B-cell lymphomas. We report an unusual case of KSHV associated lymphoma in an HIV-infected patient manifesting with myocardial and central nervous system involvement. We discuss this case in the context of increasing array of KSHV-associated lymphomas. In the HIV-infected patient with a mass lesion, a history of cutaneous Kaposi's sarcoma and prolonged immunosuppression should alert clinicians as to the possibility of KSHV associated lymphoproliferative disorders, in order to establish a timely diagnosis. PMID- 21541216 TI - Optimization of Inulinase Production from Garlic by Streptomyces sp. in Solid State Fermentation Using Statistical Designs. AB - Plackett-Burman design was employed for screening 18 nutrient components for the production of inulinase using Garlic as substrate by Streptomyces sp. in solid state fermentation (SSF). From the experiments, 4 nutrients, namely, NH(4)NO(3), MnSO(4).7H(2)O, Soya bean cake, and K(2)HPO(4) were found to be most significant nutrient components. Hence, these 4 components are selected. The selected components were optimized using response surface methodology (RSM). The optimum conditions are NH(4)NO(3)-6.63 mg/gds, MnSO(4).7H(2)O-26.16 mg/gds, Soya bean cake-60.6 mg/gds, and K(2)HPO(4)-5.24 mg/gds. Under these conditions, the production of inulinase was found to be 76 U/gds. PMID- 21541218 TI - A new case of spontaneous regression of inflammatory hepatic pseudotumor. AB - Introduction. Inflammatory pseudo-tumors (IPT) of the liver are rare and difficult to diagnose, because mimicking malignant tumors. Aim. We report a case of IPT of the liver wich diagnosis was made on clinical, radiological and evolutif features. Observation. A 15-year-old man had a 4-month history of abdominal pain in the right upper quadrant with fever and cought. Two successives ultrasonographies revealed a hypoechoic lesion occuping the segment VIII with 8 cm of diametre. Physical examination was normal. Laboratory investigation showed normal blood counts, liver function test and tumoral markers. Another ultrasonography was interpretated as normal. Tomodensitometry had showon a 3-cm lesion wich enhanced later after contrast injection. A second tomodensitometry done one mounth later described a 2-cm sub capsular heaptic lesion. Discussion. On routine activiy, pre operative diagnosis of IPT of the liver is difficut, and rarely made with certitude because mimicking a malignant tumor. In our cae report here, the analysis of previous history, of clinical, biological and radiological presentation, had permittes us to pose the diagnosis of PTI of the liver and this despite the absence of histological confirmation by percutaneous biopsy. PMID- 21541217 TI - Synthesis and evaluation of amino acid-based radiotracer 99mTc-N4-AMT for breast cancer imaging. AB - PURPOSE: This study was to develop an efficient synthesis of (99m)Tc-O-[3 (1,4,8,11-tetraazabicyclohexadecane)-propyl]-alpha-methyl tyrosine ((99m)Tc-N4 AMT) and evaluate its potential in cancer imaging. METHODS: N4-AMT was synthesized by reacting N4-oxalate and 3-bromopropyl AMT (N-BOC, ethyl ester). In vitro cellular uptake kinetics of (99m)Tc-N4-AMT was assessed in rat mammary tumor cells. Tissue distribution of the radiotracer was determined in normal rats at 0.5-4 h, while planar imaging was performed in mammary tumor-bearing rats at 30-120 min. RESULTS: The total synthesis yield of N4-AMT was 14%. Cellular uptake of (99m)Tc-N4-AMT was significantly higher than that of (99m)Tc-N4. Planar imaging revealed that (99m)Tc-N4-AMT rendered greater tumor/muscle ratios than (99m)Tc-N4. CONCLUSIONS: N4-AMT could be synthesized with a considerably high yield. Our in vitro and in vivo data suggest that (99m)Tc-N4-AMT, a novel amino acid-based radiotracer, efficiently enters breast cancer cells, effectively distinguishes mammary tumors from normal tissues, and thus holds the promise for breast cancer imaging. PMID- 21541220 TI - Fatal Myocarditis in Course of Plasmodium falciparum Infection: Case Report and Review of Cardiac Complications in Malaria. AB - We describe a fatal case of imported malaria where the sole finding revealed at the postmortem evaluation was an acute lymphocytic myocarditis with myocardiolysis. This case recalls the potential importance of myocardial injury in the prognosis of malaria and prompts a reevaluation of current perspectives on the pathogenesis of severe falciparum infection. In the light of this, we have reviewed the cases of cardiac complications in malaria published to date. PMID- 21541219 TI - Rapid decrease of CD16 (FcgammaRIII) expression on heat-shocked neutrophils and their recognition by macrophages. AB - Accumulation of neutrophils in the site of inflammation is a typical mechanism of innate immunity. The accumulated neutrophils are exposed to stressogenic factors usually associated with inflammation. Here, we studied response of human peripheral blood neutrophils subjected to short, febrile-range heat stress. We show that 90 min heat stress slowed down the spontaneous apoptosis of neutrophils. In the absence of typical markers of apoptosis the heat-shocked neutrophils induced antiinflammatory effect in human monocyte-derived macrophages (hMDMs), yet without being engulfed. Importantly, the expression of FcgammaRIII (CD16) was sharply reduced. Surprisingly, concentration of the soluble CD16 did not change in heat-shocked neutrophil supernates indicating that the reduction of the cell surface CD16 was achieved mainly by inhibition of fresh CD16 delivery. Inhibitors of 90 kDa heat shock protein (HSP90), a molecular chaperone found in membrane platforms together with CD16 and CD11b, significantly increased the observed effects caused by heat shock. The presented data suggest a novel systemic aspect of increased temperature which relies on immediate modification by heat of a neutrophil molecular pattern. This effect precedes cell death and may be beneficial in the initial phase of inflammation providing a nonphlogistic signal to macrophages before it comes from apoptotic cells. PMID- 21541221 TI - The etiological role of blood-brain barrier dysfunction in seizure disorders. AB - A wind of change characterizes epilepsy research efforts. The traditional approach, based on a neurocentric view of seizure generation, promoted understanding of the neuronal mechanisms of seizures; this resulted in the development of potent anti-epileptic drugs (AEDs). The fact that a significant number of individuals with epilepsy still fail to respond to available AEDs restates the need for an alternative approach. Blood-brain barrier (BBB) dysfunction is an important etiological player in seizure disorders, and combination therapies utilizing an AED in conjunction with a "cerebrovascular" drug could be used to control seizures more effectively than AED therapy alone. The fact that the BBB plays an etiologic role in other neurological diseases will be discussed in the context of a more "holistic" approach to the patient with epilepsy, where comorbidity variables are also encompassed by drug therapy. PMID- 21541222 TI - Identification of missense mutation (I12T) in the BSND gene and bioinformatics analysis. AB - Nonsyndromic hearing loss is a paradigm of genetic heterogeneity with 85 loci and 39 nuclear disease genes reported so far. Mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and deafness and nonsyndromic nearing loss. We studied a Pakistani consanguineous family. Clinical examinations of affected individuals did not reveal the presence of any associated signs, which are hallmarks of the Bartter syndrome type IV. Linkage analysis identified an area of 18.36 Mb shared by all affected individuals between markers D1S2706 and D1S1596. A maximum two-point LOD score of 2.55 with markers D1S2700 and multipoint LOD score of 3.42 with marker D1S1661 were obtained. BSND mutation, that is, p.I12T, cosegregated in all extant members of our pedigree. BSND mutations can cause nonsyndromic hearing loss, and it is a second report for this mutation. The respected protein, that is, BSND, was first modeled, and then, the identified mutation was further analyzed by using different bioinformatics tools; finally, this protein and its mutant was docked with CLCNKB and REN, interactions of BSND, respectively. PMID- 21541223 TI - Rare presentation of rhino-orbital-cerebral zygomycosis: bilateral facial nerve palsy. AB - Rhino-orbital-cerebral zygomycosis afflicts primarily diabetics and immunocompromised individual, but can also occur in normal hosts rarely. We here presented an interesting case of facial nerve palsy and multiple cold abscesses of neck due to rhino-orbital-cerebral zygomycosis in an otherwise healthy man. Although some reports of facial nerve paralysis in conjunction with rhino-orbital cerebral zygomycosis exist, no case of bilateral complete facial paralysis has been reported in the literature to date. PMID- 21541225 TI - Evaluation of WHO Criteria for Viral Failure in Patients on Antiretroviral Treatment in Resource-Limited Settings. AB - Our objective was to evaluate outcomes in patients with sustained viral suppression compared to those with episodes of viremia. Methods. In a prospective cohort of patients started on ART in Uganda and followed for 48 months, patients were categorized according to viral load (VL): (1) sustained-suppression: (VL <=1,000 copies/mL) (2) VL 1,001-10,000, or (3) VL >10,000. Results. Fifty-Three (11.2%) and 84 (17.8%) patients had a first episode of intermediate and high viremia, respectively. Patients with sustained suppression had better CD4+ T cell count increases over time compared to viremic patients (P < .001). The majority of patients with viremia achieved viral suppression when the measurement was repeated. Only 39.6% of patients with intermediate and 19.1% with high viremia eventually needed to be switched to second line (P = .008). Conclusions. The use of at least one repeat measurement rather than a single VL measurement could avert from 60% to 80% of unnecessary switches. PMID- 21541226 TI - Detrusor Arreflexia as an End Stage of Neurogenic Bladder in HAM/TSP? AB - The HTLV-1 virus is a known agent involved in the development of HAM/TSP. Past studies have typically observed patients with autonomic dysfunction consisting of detrusor overactivity and detrusor-sphincter dyssynergia, with the occasional observation of underactive detrusor or detrusor arreflexia. However, studies have not yet evaluated the progression of neurogenic bladder over time. In this paper, we describe a HAM/TSP patient with the initial development of overactive detrusor, and subsequent development of detrusor arreflexia. Given a paucity of studies characterizing the effects of HTLV-1 on the autonomic nervous system, particularly aspects controlling continence, this patient's clinical course may represent one type of end point for patients with HAM/TSP and neurogenic bladder. Further cohort or case-series studies, with particular emphasis on the progression of neurogenic bladder, are needed to evaluate the significance of this described case in relation to typical disease progression patterns. PMID- 21541224 TI - The multifaceted poliovirus 2A protease: regulation of gene expression by picornavirus proteases. AB - After entry into animal cells, most viruses hijack essential components involved in gene expression. This is the case of poliovirus, which abrogates cellular translation soon after virus internalization. Abrogation is achieved by cleavage of both eIF4GI and eIF4GII by the viral protease 2A. Apart from the interference of poliovirus with cellular protein synthesis, other gene expression steps such as RNA and protein trafficking between nucleus and cytoplasm are also altered. Poliovirus 2A(pro) is capable of hydrolyzing components of the nuclear pore, thus preventing an efficient antiviral response by the host cell. Here, we compare in detail poliovirus 2A(pro) with other viral proteins (from picornaviruses and unrelated families) as regard to their activity on key host factors that control gene expression. It is possible that future analyses to determine the cellular proteins targeted by 2A(pro) will uncover other cellular functions ablated by poliovirus infection. Further understanding of the cellular proteins hydrolyzed by 2A(pro) will add further insight into the molecular mechanism by which poliovirus and other viruses interact with the host cell. PMID- 21541227 TI - The effects of erythropoietin dose titration during high-fat diet-induced obesity. AB - Erythropoietin (Epo) is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg) on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg) significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment. PMID- 21541228 TI - Erythema and burning pain in the vulva: a possible phenotype of erythromelalgia. AB - We report a case of burning vulvar pain accompanied by erythema responding to an oral combination of a benzodiazepine and a beta blocker. The positive response to two medication classes used in the treatment of erythromelalgia supports the possibility of a localized manifestation of this disorder in the genital region. PMID- 21541229 TI - Animal models of middle ear cholesteatoma. AB - Middle ear acquired cholesteatoma is a pathological condition associated with otitis media, which may be associated with temporal bone resorption, otorrhea and hearing loss, and occasionally various other complications. Cholesteatoma is characterized by the enhanced proliferation of epithelial cells with aberrant morphologic characteristics. Unfortunately, our understanding of the mechanism underlying its pathogenesis is limited. To investigate its pathogenesis, different animal models have been used. This paper provides a brief overview of the current status of research in the field of pathogenesis of middle ear acquired cholesteatoma, four types of animal models previously reported on, up-to date cholesteatoma research using these animal models, our current studies of the local hybrid ear model, and the future prospect of new animal models of middle ear cholesteatoma. PMID- 21541230 TI - Metastatic ureteral involvement of non-small cell lung cancer. AB - Metastases from a variety of malignant tumors can involve the ureters, but ureteral involvement by lung cancer is extremely rare and usually described at autopsy. We report a rare case of a 76-year-old man who presented with a three month history of right flank dullness and was noted to have a nonhomogeneous retroperitoneal mass with hydronephrosis of the right kidney on computed tomography of the abdomen. Computed tomography of the thorax showed a nodule in the lower lobe, measuring 3 * 2 cm, in the right lung. After excluding the presence of other primary tumors and metastases, we reached a final diagnosis of solitary retroperitoneal metastasis of adenocarcinoma of the lung. Although rare, in patients of non-small cell lung cancer, presence of hydronephrosis should alert the physician to the possibility of metastasis. PMID- 21541232 TI - May ingestion of leachate from decomposed corpses cause appendicitis? A case report. AB - The general consensus is that appendicitis is basically provoked by fecaliths or lymphoid hyperplasic obstruction. Several studies based on histological diagnosis have not confirmed this hypothesis. On the contrary, obstruction has been proved in only a minority of cases. Diverse infections by parasites, bacteria, fungus, and noninfective agents have been associated with appendicitis in the medical literature. We describe a firefighter, who ingested a small quantity of leachate from decomposing corpses while working and developed enteritis a few hours later, which lasted several days and evolved to appendicitis. This case raises the possibility that the high quantity of bacteria concentration present in the leachate could have provoked enteritis and the subsequent appendicitis due to a direct effect of the bacteria on the appendix. PMID- 21541231 TI - Roles of the WHHL rabbit in translational research on hypercholesterolemia and cardiovascular diseases. AB - Conquering cardiovascular diseases is one of the most important problems in human health. To overcome cardiovascular diseases, animal models have played important roles. Although the prevalence of genetically modified animals, particularly mice and rats, has contributed greatly to biomedical research, not all human diseases can be investigated in this way. In the study of cardiovascular diseases, mice and rats are inappropriate because of marked differences in lipoprotein metabolism, pathophysiological findings of atherosclerosis, and cardiac function. On the other hand, since lipoprotein metabolism and atherosclerotic lesions in rabbits closely resemble those in humans, several useful animal models for these diseases have been developed in rabbits. One of the most famous of these is the Watanabe heritable hyperlipidemic (WHHL) rabbit, which develops hypercholesterolemia and atherosclerosis spontaneously due to genetic and functional deficiencies of the low-density lipoprotein (LDL) receptor. The WHHL rabbit has been improved to develop myocardial infarction, and the new strain was designated the myocardial infarction-prone WHHL (WHHLMI) rabbit. This review summarizes the importance of selecting animal species for translational research in biomedical science, the development of WHHL and WHHLMI rabbits, their application to the development of hypocholesterolemic and/or antiatherosclerotic drugs, and future prospects regarding WHHL and WHHLMI rabbits. PMID- 21541233 TI - Technetium-99m-labeled autologous serum albumin: a personal-exclusive source of serum component. AB - Technetium-99m human serum albumin ((99m)Tc-HSA) is an important radiopharmaceutical required in nuclear medicine studies. However, the risk of transfusion-transmitted infection remains a major safety concern. Autopreparation of serum component acquired from patient provides a "personal-exclusive" source for radiolabeling. This paper is to evaluate the practicality of on-site elusion and subsequent radiolabeling efficacy for serum albumin. Results showed that the autologous elute contained more albumin fraction than serum without extraction procedure. Good radiochemical purity and stability were demonstrated after radiolabeling. Biodistribution study showed that labeled albumin accumulated immediately in the lung, liver, and kidney. It was cleared steadily and excreted in the urine. The biologic half-life was defined, and all samples passed the pyrogenicity and sterility tests. In conclusion, autoalbumin could be extracted and radiolabeled properly in a nuclear medicine setting. Moreover, the risk of transfusion-transmitted infection associated with nonautologous, multisource (99m)Tc-HSA agents can be reduced. PMID- 21541234 TI - Anesthesic management for escobar syndrome: case report. AB - Escobar syndrome is a rare autosomal recessive disorder which is characterized by growth retardation, axillary, antecubital, popliteal digital, and intercrural joint flexion contracture, pterygium in the eyes, cleft palate, decreased lung capacity, genital abnormalities, and spinal deformity. In this case, we presented the anesthesic management of a 2-year-old child undergoing frontal sling operation for ptosis and amblyopia etiology exploration. PMID- 21541235 TI - Cloning and expression of highly pathogenic avian influenza virus full-length nonstructural gene in Pichia pastoris. AB - Avian influenza (AI) is a highly contagious and rapidly evolving pathogen of major concern to the poultry industry and human health. Rapid and accurate detection of avian influenza virus is a necessary tool for control of outbreaks and surveillance. The AI virus A/Chicken/Malaysia/5858/2004 (H5N1) was used as a template to produce DNA clones of the full-length NS1 genes via reverse transcriptase synthesis of cDNA by PCR amplification of the NS1 region. Products were cloned into pCR2.0 TOPO TA plasmid and subsequently subcloned into pPICZalphaA vector to construct a recombinant plasmid. Recombinant plasmid designated as pPICZalphaA-NS1 gene was confirmed by PCR colony screening, restriction enzyme digestion, and nucleotide sequence analysis. The recombinant plasmid was transformed into Pichia pastoris GS115 strain by electroporation, and expressed protein was identified by SDS-PAGE and western blotting. A recombinant protein of approximately ~28 kDa was produced. The expressed protein was able to bind a rabbit polyclonal antibody of nonstructural protein (NS1) avian influenza virus H5N1. The result of the western blotting and solid-phase ELISA assay using H5N1 antibody indicated that the recombinant protein produced retained its antigenicity. This further indicates that Pichia pastoris could be an efficient expression system for a avian influenza virus nonstructural (NS1). PMID- 21541236 TI - Unusual clinical and pathological features in pemphigus vulgaris: a potential diagnostic pitfall. AB - We describe the case of a 67-year-old woman affected by pemphigus vulgaris with a dry whitish scaly lesion in the upper lip. Clinically, this lesion resembled an actinic keratosis. Although histological examination revealed a focal acantholysis, the finding of a moderate-to-severe dysplastic epithelium was consistent with the diagnosis of acantholytic actinic keratosis with moderate/severe dysplasia. Nevertheless, the complete resolution of the lip lesion after systemic therapy for pemphigus vulgaris led us to reconsider the possibility that we were dealing with a pemphigus vulgaris with unusual clinical and histological features. The previously reported cytological dysplasia was better regarded reactive rather than neoplastic, likely as the result to the inflammatory injury. PMID- 21541237 TI - New trends in tinnitus management. AB - Tinnitus is a perception of sound in absence of sound stimulation. Tinnitus in many cases cannot be eliminated by conventional medical treatment with drugs or surgery. Some people who begin to notice tinnitus, whether spontaneous or induced by noise, trauma or other insult, will experience spontaneous resolution, but many patients will have persistent tinnitus. For some of them, tinnitus sensation will be joined by tinnitus suffering, with many adverse effects like anxiety, depression and sleep disorders. For these tinnitus sufferers the psychological and acoustic approach proposed by the Tinnitus Retraining Therapy and Acoustic Desensitization Protocol may be helpful. Periodically new treatments are suggested like low-frequency repetitive transcranial magnetic stimulation and sequential phase shift sound cancellation treatment based on the frequency and loudness matching of the tinnitus. The aim of this work is to review modern considerations for the treatment of tinnitus. PMID- 21541238 TI - Genetically modified mouse models used for studying the role of the AT2 receptor in cardiac hypertrophy and heart failure. AB - The actions of Angiotensin II have been implicated in many cardiovascular conditions. It is widely accepted that the cardiovascular effects of Angiotensin II are mediated by different subtypes of receptors: AT(1) and AT(2). These membrane-bound receptors share a part of their nucleic acid but seem to have different distribution and pathophysiological actions. AT(1) mediates most of the Angiotensin II actions since it is ubiquitously expressed in the cardiovascular system of the normal adult. Moreover AT(2) is highly expressed in the developing fetus but its expression in the cardiovascular system is low and declines after birth. However the expression of AT(2) appears to be modulated by pathological states such as hypertension, myocardial infarction or any pathology associated to tissue remodeling or inflammation. The specific role of this receptor is still unclear and different studies involving in vivo and in vitro experiments have shown conflicting data. It is essential to clarify the role of the AT(2) receptor in the different pathological states as it is a potential site for an effective therapeutic regimen that targets the Angiotensin II system. We will review the different genetically modified mouse models used to study the AT(2) receptor and its association with cardiac hypertrophy and heart failure. PMID- 21541239 TI - Proteomics. PMID- 21541240 TI - Brown adipose tissue can be activated or inhibited within an hour before 18F-FDG injection: a preliminary study with microPET. AB - Brown adipose tissue (BAT) is emerging as a potential target for treating human obesity. It has been indicated that BAT is rich in innervations of sympathetic nerve control. Using (18)F-FDG microPET imaging, this study aims at evaluating how factors related to sympathetic activation/inhibition changed BAT metabolism of mice. BAT (18)F-FDG uptake were semiquantitatively evaluated in different groups of mice under temperature (cold or warm stimulus) or pharmacological interventions (norepinephrine, epinephrine, isoprenaline, or propranolol) and were compared with the corresponding controls. It was found that BAT activation can be stimulated by cold exposure (P = 1.96 * 10(-4)), norepinephrine (P = .002), or both (P = 2.19 * 10(-6)) within an hour before (18)F-FDG injection and can also be alleviated by warming up (P = .001) or propranolol lavage (P = .027). This preliminary study indicated that BAT function could be evaluated by (18)F FDG PET imaging through short-term interventions, which paved the way for further investigation of the relationship between human obesity and BAT dysfunction. PMID- 21541241 TI - Intermittent chemotherapy and erlotinib for nonsmokers or light smokers with advanced adenocarcinoma of the lung: a phase II clinical trial. AB - BACKGROUND: Intermittent application of chemotherapy and tyrosine kinase inhibitors may avoid antagonism between the two classes of drugs. This hypothesis was tested in a Phase II clinical trial. PATIENTS AND METHODS: Eligible patients were nonsmokers or light smokers, chemo-naive, with metastatic adenocarcinoma of the lung. TREATMENT: 4 to 6 cycles of gemcitabine 1250 mg/m(2) on days 1 and 4, cisplatin 75 mg/m(2) on day 2, and erlotnib 150 mg daily on days 5-15, followed by erlotinib as maintenance. RESULTS: 24 patients entered the trial. Four pts had grade 3 toxicity. Complete remission (CR) and partial remission (PR) were seen in 5 pts and 9 pts, respectively (response rate 58%). Median time to progression (TTP) was 13.4 months and median overall survival (OS) was 23 months. When compared to patients with negative or unknown status of EGFR mutations, 8 patients with EGFR gene activating mutations had significantly superior experience: 4 CR and 4 PR, with median TTP 21.5 months and OS 24.2 months (P < .05). CONCLUSIONS: Intermittent schedule with gemcitabine, cisplatin and erlotinib has mild toxicity. For patients who are positive for EGFR gene activating mutations, this treatment offers excellent response rate, time to progression and survival. PMID- 21541242 TI - Diagnostic value of I-131 NP-59 SPECT/CT scintigraphy in patients with subclinical or atypical features of primary aldosteronism. AB - Accumulating evidence has shown the adverse effect of long-term hyperaldosteronism on cardiovascular morbidity that is independent of blood pressure. However, the diagnosis of primary aldosteronism (PA) remains a challenge for patients who present with subtle or atypical features or have chronic kidney disease (CKD). SPECT/CT has proven valuable in the diagnosis of a number of conditions. The aim of this study was to determine the usefulness of I 131 NP-59 SPECT/CT in patients with atypical presentations of PA and in those with CKD. The records of 15 patients with PA were retrospectively analyzed. NP-59 SPECT/CT was able to identify adrenal lesion(s) in CKD patients with suspected PA. Patients using NP-59 SPECT/CT imaging, compared with those not performing this procedure, significantly featured nearly normal serum potassium levels, normal aldosterone-renin ratio, and smaller adrenal size on CT and pathological examination and tended to feature stage 1 hypertension and non-suppressed plasma renin activity. These findings show that noninvasive NP-59 SPECT/CT is a useful tool for diagnosis in patients with subclinical or atypical features of PA and those with CKD. PMID- 21541243 TI - Chromosome mapping of repetitive sequences in Rachycentron canadum (Perciformes: Rachycentridae): implications for karyotypic evolution and perspectives for biotechnological uses. AB - The cobia, Rachycentron canadum, a species of marine fish, has been increasingly used in aquaculture worldwide. It is the only member of the family Rachycentridae (Perciformes) showing wide geographic distribution and phylogenetic patterns still not fully understood. In this study, the species was cytogenetically analyzed by different methodologies, including Ag-NOR and chromomycin A(3) (CMA(3))/DAPI staining, C-banding, early replication banding (RGB), and in situ fluorescent hybridization with probes for 18S and 5S ribosomal genes and for telomeric sequences (TTAGGG)(n). The results obtained allow a detailed chromosomal characterization of the Atlantic population. The chromosome diversification found in the karyotype of the cobia is apparently related to pericentric inversions, the main mechanism associated to the karyotypic evolution of Perciformes. The differential heterochromatin replication patterns found were in part associated to functional genes. Despite maintaining conservative chromosomal characteristics in relation to the basal pattern established for Perciformes, some chromosome pairs in the analyzed population exhibit markers that may be important for cytotaxonomic, population, and biodiversity studies as well as for monitoring the species in question. PMID- 21541244 TI - A novel algorithm for the assessment of blood-brain barrier permeability suggests that brain topical application of endothelin-1 does not cause early opening of the barrier in rats. AB - There are a number of different experimental methods for ex vivo assessment of blood-brain barrier (BBB) opening based on Evans blue dye extravasation. However, these methods require many different steps to prepare the brain and need special equipment for quantification. We here report a novel, simple, and fast semiquantitative algorithm to assess BBB integrity ex vivo. The method is particularly suitable for cranial window experiments, since it keeps the spatial information about where the BBB opened. We validated the algorithm using sham controls and the established model of brain topical application of the bile salt dehydrocholate for early BBB disruption. We then studied spreading depolarizations in the presence and the absence of the vasoconstrictor endothelin 1 and found no evidence of early BBB opening (three-hour time window). The algorithm can be used, for example, to assess BBB permeability ex vivo in combination with dynamic in vivo studies of BBB opening. PMID- 21541245 TI - What is Next for the Genetics of Multiple Sclerosis? AB - We review here our current understanding of the genetic aetiology of the common complex neurological disease multiple sclerosis (MS). The strongest genetic risk factor for MS is the major histocompatibility complex which was identified in the 1970s. In 2011, after a number of genome-wide association studies have been completed and have identified approximately 20 new genes for MS, we ask the question-what is next for the genetics of MS? PMID- 21541246 TI - Life-Threatening Laryngeal Edema and Hyponatremia during Hysteroscopy. AB - We report on a 43-year-old patient undergoing a hysteroscopic myomectomy. After 80 minutes of operation, the patient developed laryngeal edema, requiring emergency tracheostomy. Hyponatremia (serum sodium 78 mmoL/L) indicated an irrigation fluid absorption. The patient developed shock, acute respiratory distress syndrome, acute renal failure, and diffuse intravascular coagulopathy. Resuscitation including continuous venovenous hemodiafiltration was required. Finally, the patient made a full clinical recovery. Hysteroscopy usually has low risks. However, absorption of the irrigation fluid can result in life-threatening fluid overload and electrolyte disturbances. Accurate fluid balancing and limiting the operation time may prevent these complications. PMID- 21541248 TI - Frequency of HIV Infection among Sailors in South of Iran by Rapid HIV Test. AB - Information on the prevalence and risk factors for HIV infection among sailors is scarce. The aim of this seroprevalence study was to evaluate the frequency of HIV infection among sailors in south of Iran using rapid HIV test. The study included 400 consecutive participants in Lengeh, Shahid Rajaie, and Shahid Bahonar ports in south of Iran in May 2010. We observed only one case (0.25%) of HIV infection in this sample of sailors. While prevalence appears low at present, we recommend periodic HIV serosurveillance with detailed behavioral measures for this population in the future. PMID- 21541247 TI - Perspectives on the role of fospropofol in the monitored anesthesia care setting. AB - Monitored anesthesia care (MAC) is a safe, effective, and appropriate form of anesthesia for many minor surgical procedures. The proliferation of outpatient procedures has heightened interest in MAC sedation agents. Among the most commonly used MAC sedation agents today are benzodiazepines, including midazolam, and propofol. Recently approved in the United States is fospropofol, a prodrug of propofol which hydrolyzes in the body by alkaline phosphatase to liberate propofol. Propofol liberated from fospropofol has unique pharmacological properties, but recently retracted pharmacokinetic (PK) and pharmacodynamic (PD) evaluations make it difficult to formulate clear conclusions with respect to fospropofol's PK/PD properties. In safety and efficacy clinical studies, fospropofol demonstrated dose-dependent sedation with good rates of success at doses of 6.5 mg/kg along with good levels of patient and physician acceptance. Fospropofol has been associated with less pain at injection site than propofol. The most commonly reported side effects with fospropofol are paresthesia and pruritus. Fospropofol is a promising new sedation agent that appears to be well suited for MAC sedation, but further studies are needed to better understand its PK/PD properties as well its appropriate clinical role in outpatient procedures. PMID- 21541249 TI - Biochemical Characterization and 16S rRNA Sequencing of Few Lipase-Producing Thermophilic Bacteria from Taptapani Hot Water Spring, Orissa, India. AB - Three lipase-producing thermophilic bacteria (AK-P1, AK-P2, and AK-P3) were isolated from the Taptapani hot water spring in Orissa, India. The crude extra cellular lipases from cell-free culture supernatant were reacted in an olive oil mixture, and their lipolytic activities were compared. Identification of the bacteria was carried out using biochemical tests, 16SrRNA sequencing and sequences submitted to NCBI GenBank. Strain AK-P3, exhibited the highest lipolytic activity of 5.5 U/mL was identified as Porphyrobacter sp. The lipolytic activities of strains AK-P1 and AK-P 2 were 4.5 U/mL and 3.5 U/mL, respectively. Strains AK-P1 and AK-P2 were identified as Acinetobacter sp. and Brevibacillus spp. The GenBank accession numbers of the 16S rRNA gene sequences determined in this study for the strains AK-P1, AK-P2, and AK-P3 are HM359120, HM359119, and HM359118, respectively. PMID- 21541250 TI - Interactions of human myeloid cells with natural killer cell subsets in vitro and in vivo. AB - In both human and mouse it has been recently realized that natural killer (NK) cells do not emerge from the bone marrow with full functional competence but rather acquire functions in interaction with antigen-presenting cells (APCs), primarily dendritic cells (DCs). Here we review the mechanisms and the consequences of this NK-cell preactivation, as well as discuss new experimental models that now allow investigating these interactions for human NK cells and their response to human pathogens in vivo. These investigations will allow harnessing NK cells during vaccination for improved innate and adaptive immunity. PMID- 21541251 TI - Corticotrophin-releasing factor, related peptides, and receptors in the normal and inflamed gastrointestinal tract. AB - Corticotrophin-releasing factor (CRF) is mainly known for its role in the stress response in the hypothalamic-pituitary-adrenal axis. However, increasing evidence has revealed that CRF receptor signaling has additional peripheral effects. For instance, activation of CRF receptors in the gastrointestinal tract influences intestinal permeability and motility. These receptors, CRF1 and CRF2, do not only bind CRF, but are also activated by urocortins. Most interestingly, CRF-related signaling also assumes an important role in inflammatory bowel diseases in that it influences inflammatory processes, such as cytokine secretion and immune cell activation. These effects are characterized by an often contrasting function of CRF1 and CRF2. We will review the current data on the expression of CRF and related peptides in the different regions of the gastrointestinal tract, both in normal and inflamed conditions. We next discuss the possible functional roles of CRF signaling in inflammation. The available data clearly indicate that CRF signaling significantly influences inflammatory processes although there are important species and inflammation model differences. Although further research is necessary to elucidate this apparently delicately balanced system, it can be concluded that CRF-related peptides and receptors are (certainly) important candidates in the modulation of gastrointestinal inflammation. PMID- 21541252 TI - Phonological processing in human auditory cortical fields. AB - We used population-based cortical-surface analysis of functional magnetic imaging data to characterize the processing of consonant-vowel-consonant syllables (CVCs) and spectrally matched amplitude-modulated noise bursts (AMNBs) in human auditory cortex as subjects attended to auditory or visual stimuli in an intermodal selective attention paradigm. Average auditory cortical field (ACF) locations were defined using tonotopic mapping in a previous study. Activations in auditory cortex were defined by two stimulus-preference gradients: (1) Medial belt ACFs preferred AMNBs and lateral belt and parabelt fields preferred CVCs. This preference extended into core ACFs with medial regions of primary auditory cortex (A1) and the rostral field preferring AMNBs and lateral regions preferring CVCs. (2) Anterior ACFs showed smaller activations but more clearly defined stimulus preferences than did posterior ACFs. Stimulus preference gradients were unaffected by auditory attention suggesting that ACF preferences reflect the automatic processing of different spectrotemporal sound features. PMID- 21541253 TI - Subtle Morphological Changes in the Mandible of Tabby Mice Revealed by Micro-CT Imaging and Elliptical Fourier Quantification. AB - X-linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disorder due to a mutation of the EDA gene and is mainly characterized by an impaired formation of hair, teeth and sweat glands, and craniofacial dysmorphologies. Although tooth abnormalities in Tabby (Ta) mutant mice - the murine model of XLHED - have been extensively studied, characterization of the craniofacial complex, and more specifically the mandibular morphology has received less attention. From 3D micro CT reconstructions of the left mandible, the mandibular outline observed in lateral view, was quantified using 2D elliptical Fourier analysis. Comparisons between Ta specimens and their wild-type controls were carried out showing significant shape differences between mouse strains enabling a clear distinction between hemizygous Ta specimens and the other mouse groups (WT and heterozygous Eda(Ta/+) specimens). Morphological differences associated with HED correspond not only to global mandibular features (restrained development of that bone along dorsoventral axis), but also to subtle aspects such as the marked backward projection of the coronoid process or the narrowing of the mandibular condylar neck. These modifications provide for the first time, evidence of a predominant effect of the Ta mutation on the mandibular morphology. These findings parallel the well described abnormalities of jugal tooth row and skeletal defects in Ta mice, and underline the role played by EDA-A in the reciprocal epithelial mesenchymal interactions that are of critical importance in normal dental and craniofacial development. PMID- 21541254 TI - Morbidity, including fatal morbidity, throughout life in men entering adult life as obese. AB - BACKGROUND: The association between obesity in adults and excess morbidity and mortality is well established, but the health impact throughout adult life of being obese in early adulthood needs elucidation. We investigated somatic morbidity, including fatal morbidity, throughout adulthood in men starting adult life as obese. METHODS: Among 362,200 Danish young men, examined for military service between 1943 and 1977, all obese (defined as BMI>=31.0 kg/m(2)), and, as controls, a random 1% sample of the others was identified. In the age range of 18 25 years, there were 1,862 obese, which encompass the men above the 99.5 percentile, and 3,476 controls. Information on morbidity was obtained via national registers. Cox regression models were used to estimate the relative morbidity assessed as first incidence of disease, occurrence of disease in the year preceding death and prevalent disease at time of death. RESULTS: From age 18 through 80 years the obese had an increased risk of becoming diseased by or die from a broad range of diseases. Generally, the incidence of first event, occurrence in the year prior to death, and prevalence at time of death showed the same pattern. As an example, the relative hazard of type 2 diabetes was constant throughout life at 4.9 (95% confidence intervals [CI]: 4.1-5.9), 5.2 (95% CI: 3.6 7.5), and 6.8 (95% CI: 4.6-10.1), respectively. CONCLUSIONS: Our findings strongly support the continued need to avoid beginning adult life as obese, as obese young men experience an increased morbidity, including fatal morbidity, from many diseases throughout life. PMID- 21541255 TI - The Effect of Training on Motoneuron Survival in Amyotrophic Lateral Sclerosis: Which Motoneuron Type is Saved? PMID- 21541256 TI - Selective stimulation of the spinal cord surface using a stretchable microelectrode array. AB - By electrically stimulating the spinal cord, it is possible to activate functional populations of neurons that modulate motor and sensory function. One method for accessing these neurons is via their associated axons, which project as functionally segregated longitudinal columns of white-matter funiculi (i.e., spinal tracts). To stimulate spinal tracts without penetrating the cord, we have recently developed technology that enables close-proximity, multi-electrode contact with the spinal cord surface. Our stretchable microelectrode arrays (sMEAs) are fabricated using an elastomer polydimethylsiloxane substrate and can be wrapped circumferentially around the spinal cord to optimize electrode contact. Here, sMEAs were used to stimulate the surfaces of rat spinal cords maintained in vitro, and their ability to selectively activate axonal surface tracts was compared to rigid bipolar tungsten microelectrodes pressed firmly onto the cord surface. Along dorsal column tracts, the axonal response to sMEA stimulation was compared to that evoked by rigid microelectrodes through measurement of their evoked axonal compound action potentials (CAPs). Paired t tests failed to reveal significant differences between the sMEA's and the rigid microelectrode's stimulus resolution, or in their ranges of evoked CAP conduction velocities. Additionally, dual-site stimulation using sMEA electrodes recruited spatially distinct populations of spinal axons. Site-specific stimulation of the ventrolateral funiculus - a tract capable of evoking locomotor-like activity - recruited ventral root efferent activity that spanned several spinal segments. These findings indicate that the sMEA stimulates the spinal cord surface with selectivity similar to that of rigid microelectrodes, while possessing potential advantages concerning circumferential contact and mechanical compatibility with the cord surface. PMID- 21541257 TI - Toward an integrated approach to perception and action: conference report and future directions. AB - This article was motivated by the conference entitled "Perception & Action - An Interdisciplinary Approach to Cognitive Systems Theory," which took place September 14-16, 2010 at the Santa Fe Institute, NM, USA. The goal of the conference was to bring together an interdisciplinary group of neuroscientists, roboticists, and theorists to discuss the extent and implications of action perception integration in the brain. The motivation for the conference was the realization that it is a widespread approach in biological, theoretical, and computational neuroscience to investigate sensory and motor function of the brain in isolation from one another, while at the same time, it is generally appreciated that sensory and motor processing cannot be fully separated. Our article summarizes the key findings of the conference, provides a hypothetical model that integrates the major themes and concepts presented at the conference, and concludes with a perspective on future challenges in the field. PMID- 21541258 TI - The behavioral relevance of landmark texture for honeybee homing. AB - Honeybees visually pinpoint the location of a food source using landmarks. Studies on the role of visual memories have suggested that bees approach the goal by finding a close match between their current view and a memorized view of the goal location. The most relevant landmark features for this matching process seem to be their retinal positions, the size as defined by their edges, and their color. Recently, we showed that honeybees can use landmarks that are statically camouflaged, suggesting that motion cues are relevant as well. Currently it is unclear how bees weight these different landmark features when accomplishing navigational tasks, and whether this depends on their saliency. Since natural objects are often distinguished by their texture, we investigate the behavioral relevance and the interplay of the spatial configuration and the texture of landmarks. We show that landmark texture is a feature that bees memorize, and being given the opportunity to identify landmarks by their texture improves the bees' navigational performance. Landmark texture is weighted more strongly than landmark configuration when it provides the bees with positional information and when the texture is salient. In the vicinity of the landmark honeybees changed their flight behavior according to its texture. PMID- 21541259 TI - Depletion of new neurons by image guided irradiation. AB - Ionizing radiation continues to be a relevant tool in both imaging and the treatment of cancer. Experimental uses of focal irradiation have recently been expanded to studies of new neurons in the adult brain. Such studies have shown cognitive deficits following radiation treatment and raised caution as to possible unintentional effects that may occur in humans. Conflicting outcomes of the effects of irradiation on adult neurogenesis suggest that the effects are either transient or permanent. In this study, we used an irradiation apparatus employed in the treatment of human tumors to assess radiation effects on rat neurogenesis. For subjects we used adult male rats (Sprague-Dawley) under anesthesia. The irradiation beam was directed at the hippocampus, a center for learning and memory, and the site of neurogenic activity in adult brain. The irradiation was applied at a dose-rate 0.6 Gy/min for total single-fraction, doses ranging from 0.5 to 10.0 Gy. The animals were returned to home cages and recovered with no sign of any side effects. The neurogenesis was measured either 1 week or 6 weeks after the irradiation. At 1 week, the number of neuronal progenitors was reduced in a dose-dependent manner with the 50% reduction at 0.78 Gy. The dose-response curve was well fitted by a double exponential suggesting two processes. Examination of the tissue with quantitative immunohistochemistry revealed a dominant low-dose effect on neuronal progenitors resulting in 80% suppression of neurogenesis. This effect was partially reversible, possibly due to compensatory proliferation of the remaining precursors. At higher doses (>5 Gy) there was additional, nearly complete block of neurogenesis without compensatory proliferation. We conclude that notwithstanding the usefulness of irradiation for experimental purposes, the exposure of human subjects to doses often used in radiotherapy treatment could be damaging and cause cognitive impairments. PMID- 21541260 TI - Comparative gene expression analysis among vocal learners (bengalese finch and budgerigar) and non-learners (quail and ring dove) reveals variable cadherin expressions in the vocal system. AB - Birds use various vocalizations to communicate with one another, and some are acquired through learning. So far, three families of birds (songbirds, parrots, and hummingbirds) have been identified as having vocal learning ability. Previously, we found that cadherins, a large family of cell-adhesion molecules, show vocal control-area-related expression in a songbird, the Bengalese finch. To investigate the molecular basis of evolution in avian species, we conducted comparative analysis of cadherin expressions in the vocal and other neural systems among vocal learners (Bengalese finch and budgerigar) and a non-learner (quail and ring dove). The gene expression analysis revealed that cadherin expressions were more variable in vocal and auditory areas compared to vocally unrelated areas such as the visual areas among these species. Thus, it appears that such diverse cadherin expressions might have been related to generating species diversity in vocal behavior during the evolution of avian vocal learning. PMID- 21541261 TI - Low level primary blast injury in rodent brain. AB - The incidence of blast attacks and resulting traumatic brain injuries has been on the rise in recent years. Primary blast is one of the mechanisms in which the blast wave can cause injury to the brain. The aim of this study was to investigate the effects of a single sub-lethal blast over pressure (BOP) exposure of either 48.9 kPa (7.1 psi) or 77.3 kPa (11.3 psi) to rodents in an open-field setting. Brain tissue from these rats was harvested for microarray and histopathological analyses. Gross histopathology of the brains showed that cortical neurons were "darkened" and shrunken with narrowed vasculature in the cerebral cortex day 1 after blast with signs of recovery at day 4 and day 7 after blast. TUNEL-positive cells were predominant in the white matter of the brain at day 1 after blast and double-labeling of brain tissue showed that these DNA damaged cells were both oligodendrocytes and astrocytes but were mainly not apoptotic due to the low caspase-3 immunopositivity. There was also an increase in amyloid precursor protein immunoreactive cells in the white matter which suggests acute axonal damage. In contrast, Iba-1 staining for macrophages or microglia was not different from control post-blast. Blast exposure altered the expression of over 5786 genes in the brain which occurred mostly at day 1 and day 4 post-blast. These genes were narrowed down to 10 overlapping genes after time course evaluation and functional analyses. These genes pointed toward signs of repair at day 4 and day 7 post-blast. Our findings suggest that the BOP levels in the study resulted in mild cellular injury to the brain as evidenced by acute neuronal, cerebrovascular, and white matter perturbations that showed signs of resolution. It is unclear whether these perturbations exist at a milder level or normalize completely and will need more investigation. Specific changes in gene expression may be further evaluated to understand the mechanism of blast-induced neurotrauma. PMID- 21541262 TI - Self-informant Agreement for Personality and Evaluative Person Descriptors: Comparing Methods for Creating Informant Measures. AB - Little attention typically is paid to the way self-report measures are translated for use in self-informant agreement studies. We studied two possible methods for creating informant measures: (a) the traditional method in which self-report items were translated from the first- to the third-person and (b) an alternative meta-perceptual method in which informants were directed to rate their perception of the targets' self-perception. We hypothesized that the latter method would yield stronger self-informant agreement for evaluative personality dimensions measured by indirect item markers. We studied these methods in a sample of 303 undergraduate friendship dyads. Results revealed mean-level differences between methods, similar self-informant agreement across methods, stronger agreement for Big Five dimensions than for evaluative dimensions, and incremental validity for meta-perceptual informant rating methods. Limited power reduced the interpretability of several sparse acquaintanceship effects. We conclude that traditional informant methods are appropriate for most personality traits, but meta-perceptual methods may be more appropriate when personality questionnaire items reflect indirect indicators of the trait being measured, which is particularly likely for evaluative traits. PMID- 21541263 TI - Predicting the risk for corneal graft rejection by aqueous humor analysis. AB - PURPOSE: Cytokine patterns determined in the aqueous humor before penetrating keratoplasty (PK) may enable us to predict immune reactions (IR). We therefore analyzed 6 cytokines in the aqueous humor of patients before PK. By prospective clinical follow-up, we tested whether patients who developed an IR would present different preoperative cytokine patterns compared to patients without IR. METHODS: We analyzed 18 samples of aqueous humor from 18 patients undergoing PK. The following cytokines were analyzed by cytometric bead array: interleukin 2 (IL 2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 10 (IL-10), tumor necrosis-factor alpha (TNF-alpha), and interferon gamma (INF-gamma). Seven patients presented with signs of IR during follow up. We performed Cox proportional hazards analysis to determine significant predictors for IR. We iteratively eliminated all co-variates with p values over 0.1 from the survival model (backward selection). RESULTS: Our final Cox model included the hazardous factors IL-4 (p=0.043) and INF-gamma (p=0.059), protective factors IL-2 (p=0.081), IL-5 (p=0.028), and age at time of surgery (p=0.029). We performed a linear discriminant analysis based on these coefficients. The resulting function was: (-9.979*IL5) + (9.262*IL4) + (-3.928*IL2) + (1.709*IFN-gamma) + ( 0.183*age). A median of -4.97 separated patients with and without IR with no classification error. CONCLUSIONS: We demonstrate that cytokine levels in the aqueous humor can be predictive for IR. Our method allowed an almost 100% separation between patients with and without IR. This finding has the potential to improve the aftercare of PK fundamentally. However, our results need to be confirmed in a larger prospective cohort. PMID- 21541264 TI - Potential linkage of different phenotypic forms of childhood strabismus to a recessive susceptibility locus (16p13.12-p12.3). AB - PURPOSE: To perform linkage analysis on an inbred family with members who exhibit different phenotypic forms of childhood strabismus. METHODS: Prospective clinical examination and linkage analysis. RESULTS: three of the ten siblings and their cousin each had a different phenotypic form of childhood strabismus: infantile esotropia with convergence excess, esotropia associated with anisometropic amblyopia, unilateral esotropic Duane syndrome, and monocular elevation deficiency. Linkage analysis for the four strabismic individuals, an unaffected sibling, and the unaffected parents identified a single disease locus on chromosome 16p13.12-p12.3 (Ensembl cytogenetic band) with a 2.5 maximum logarithm of odds score. The region is 6 MB in size and comprises 80 genes. DISCUSSION: Linkage analysis in this unique family suggests that childhood strabismus can be recessive and that different phenotypic forms of childhood strabismus can share the same underlying genotype. PMID- 21541266 TI - A complement receptor C5a antagonist regulates epithelial to mesenchymal transition and crystallin expression after lens cataract surgery in mice. AB - PURPOSE: To evaluate the effects of complement employing a mouse model for secondary cataract. METHODS: The role of complement receptor C5a (CD88) was evaluated after cataract surgery in mice. An antagonist specific to C5a receptor was administered intraperitoneally to mice. Epithelial to mesenchymal transition (EMT) was evaluated by alpha-smooth muscle actin (alpha-SMA) staining and proliferation by bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU) incorporation. Gene expression patterns was examined by microarray analysis and quantitative polymerase chain reaction (QPCR). RESULTS: We found that administration of a C5aR antagonist in C57BL/6J mice decreases EMT, as evidenced by alpha-SMA expression, and cell proliferation. Gene expression by microarray analysis reveals discreet steps of gene regulation in the two major stages that of EMT and lens fiber differentiation in vivo. A hallmark of the microarray analysis is that the antagonist seems to be a novel stage-specific regulator of crystallin genes. At week two, which is marked by lens fiber differentiation genes encoding 12 crystallins and 3 lens-specific structural proteins were severely down-regulated. CONCLUSIONS: These results suggest a possible therapeutic role of an antagonist to C5aR in preventing secondary cataracts after surgery. Also these results suggest that crystallin gene expression can be regulated by pro-inflammatory events in the eye. PMID- 21541265 TI - Quantal amplitude at the cone ribbon synapse can be adjusted by changes in cytosolic glutamate. AB - PURPOSE: Vision is encoded at photoreceptor synapses by the number of released vesicles and size of the post-synaptic response. We hypothesized that elevating cytosolic glutamate could enhance quantal size by increasing glutamate in vesicles. METHODS: We introduced glutamate (10-40 mM) into cone terminals through a patch pipette and recorded excitatory post-synaptic currents (EPSCs) from horizontal or OFF bipolar cells in the Ambystoma tigrinum retinal slice preparation. RESULTS: Elevating cytosolic glutamate in cone terminals enhanced EPSCs as well as quantal miniature EPSCs (mEPSCs). Enhancement was prevented by inhibiting vesicular glutamate transport with 1S,3R-1-aminocyclopentane-1,3 dicarboxylate in the patch pipette. A low affinity glutamate receptor antagonist, gammaD-glutamylglycine (1 mM), less effectively inhibited EPSCs evoked from cones loaded with glutamate than control cones indicating that release from cones with supplemental glutamate produced higher glutamate levels in the synaptic cleft. Raising presynaptic glutamate did not alter exocytotic capacitance responses and exocytosis was observed after inhibiting glutamate loading with the vesicular ATPase inhibitor, concanamycin A, suggesting that release capability is not restricted by low vesicular glutamate levels. Variance-mean analysis of currents evoked by flash photolysis of caged glutamate indicated that horizontal cell AMPA receptors have a single channel conductance of 10.1 pS suggesting that ~8.7 GluRs contribute to each mEPSC. CONCLUSIONS: Quantal amplitude at the cone ribbon synapse is capable of adjustment by changes in cytosolic glutamate levels. The small number of channels contributing to each mEPSC suggests that stochastic variability in channel opening could be an important source of quantal variability. PMID- 21541267 TI - Complement factor B polymorphism 32W protects against age-related macular degeneration. AB - PURPOSE: The 32Q (rs641153; A) and 32W (rs12614; T) variants of complement factor B (CFB) cause less efficient complement activation in vitro than the common 32R variant. This is thought to be the reason that the 32Q variant is associated with decreased risk of age-related macular degeneration (AMD). We investigated whether the 32W variant was also associated with decreased risk of AMD. METHODS: We genotyped 367 cases with neovascular AMD and 251 disease-free controls. Association with the disease phenotype was assessed by logistic regression for polymorphisms of CFB alone and in combination with smoking status and genetic risk markers of complement factor H (CFH) and HtrA serine peptidase 1 (HTRA1). We performed meta-analysis of all previously published reports of 32W allele frequency in AMD cases and controls. RESULTS: The CFB variant 32W was associated with protection against neovascular AMD, compared to the common 32R variant (odds ratio 0.64, p<0.05, in logistic regression with CFB variants; odds ratio 0.53, p<0.05, in logistic regression with CFB variants, CFH haplotypes, HTRA1 rs10490924 genotype, and smoking status). Meta-analysis (n=1,795) including this study and two others of neovascular AMD showed a combined odds ratio of 0.75 (p<0.05) for 32W, compared to 32R. Meta-analysis (n=2,600) of all reported studies of all types of AMD showed a combined odds ratio of 0.79 (p<0.01). CONCLUSIONS: Our study shows that the 32W variant of CFB is associated with protection against AMD, in keeping with evidence of its functional effect on the complement system. The protective effect is less strong than that associated with 32Q. PMID- 21541268 TI - Patterns of mRNA and protein expression during minus-lens compensation and recovery in tree shrew sclera. AB - PURPOSE: To increase our understanding of the mechanisms that remodel the sclera during the development of lens-induced myopia, when the sclera responds to putative "go" signals of retinal origin, and during recovery from lens-induced myopia, when the sclera responds to retinally-derived "stop" signals. METHODS: Seven groups of tree shrews were used to examine mRNA levels during minus lens compensation and recovery. Starting 24 days after eye opening (days of visual experience [VE]) lens compensation animals wore a monocular -5D lens for 1, 4, or 11 days. Recovery animals wore the -5D lens for 11 days, which was then removed for 1 or 4 days. Normal animals were examined at 24 and 38 days of VE. All groups contained 8 animals. Scleral mRNA levels were examined in the treated and contralateral control eyes with quantitative real-time polymerase chain reaction (qPCR) for 27 genes divided into four categories: 1) signaling molecules, 2) matricellular proteins, 3) metalloproteinases (MPs) and tissue inhibitors of metalloproteinases (TIMPs), and 4) cell adhesion and other proteins. Four groups (n=5 per group) were used to examine protein levels. One group wore a -5D lens for 4 days. A second group recovered for 4 days after 11 days of -5D lens treatment. Two groups were used to examine age-matched normal protein levels at 28 and 39 days of VE. The levels of six scleral proteins that showed differential mRNA expression were examined with quantitative western blots. RESULTS: Nineteen of the genes showed differential (treated eye versus control eye) expression of mRNA levels in at least one group of animals. Which genes showed differential expression differed after 1 and 4 days of compensation and after 1 or 4 days of recovery. The mRNA level for one gene, a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), was upregulated in the treated eyes after 1 day of compensation. After 4 days, transforming growth factor beta receptor 3 (TGFBR3), transforming growth factor-beta-induced protein ig-h3 (TGFBI), and matrix metalloproteinase 14 (MMP14) mRNA levels were upregulated. Downregulated were mRNA levels for transforming growth factor beta-1 (TGFB1), transforming growth factor beta-2 (TGFB2), thrombospondin 1 (THBS1), tenascin (TNC), osteonectin (SPARC), osteopontin (SPP1), tissue inhibitor of metalloproteinases 3 (TIMP3), and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5). After 11 days of lens wear, there was no differential expression. During recovery, after 1 day, treated-eye mRNA downregulation was found for TGFB2, TGFBR1, TGFBR2, TGFBR3, SPARC, ADAMTS1, ADAMTS5, syndecan 4 (SDC4), and collagen type VI, alpha 1 (COL6A1). After 4 days, TGFB1, TGFB2, TGFB3, THBS2, and TIMP3 mRNA levels were upregulated in the recovering eye. Significant downregulation, relative to normal eyes, was found in both the control and treated eyes for most genes after 1 day of compensation; a similar decrease was found, compared to lens-compensated eyes, after one day of recovery. Protein levels for THBS1 showed positive correlation with the differential mRNA levels and TGFBR3 showed a negative correlation. No differential protein expression was found for TGFB2, TGFBI, MMP14, and TIMP3. CONCLUSIONS: The different patterns of differential mRNA expression during minus lens compensation (hyperopia) and recovery (myopia) show that scleral fibroblasts distinguish between "go" and "stop" conditions. There is evidence of binocular global downregulation of genes at the start of both lens wear and recovery. As additional information accumulates about changes in gene expression that occur during compensation and recovery the "signature" of differential changes may help us to understand in more detail how the sclera responds in "go" and "stop" conditions. PMID- 21541269 TI - An immunohistochemical analysis of the neuroprotective effects of memantine, hyperbaric oxygen therapy, and brimonidine after acute ischemia reperfusion injury. AB - PURPOSE: This study applies treatment methods to rat retinas subjected to acute ischemia reperfusion injury and compares the efficacy of memantine, hyperbaric oxygen (HBO) therapy, and brimonidine by histopathological examination. METHODS: Thirty adult Wistar albino rats were divided into five groups after retinal ischemia was induced by elevating the intraocular pressure to 120 mmHg. The groups were as follows: group 1: control; group 2: acute retinal ischemia (ARI) model but without treatment group; group 3: memantine (MEM) treatment group; group 4: HBO therapy group; and group 5: brimonidine treatment (BRI) group. In the control group, right eyes were cannulated with a 30-gauge needle and removed without causing any intraocular pressure change. The ARI group was an acute retinal ischemia model, but without treatment. In the MEM group, animals were given a unique dose of intravenous 25 mg/kg memantine by the tail vein route after inducing ARI. In the HBO group, at 2 h following ARI, HBO treatment was applied for nine days. In the BRI group, a 0.15% brimonidine tartrate eye drop treatment was applied twice a day (BID) for seven days before ARI. Twenty-one days after establishing ischemia reperfusion, the right eyes were enucleated after the cardiac gluteraldehyde perfusion method, and then submitted to histological evaluation. RESULTS: On average, the total retinal ganglion cell number was 239.93 +/- 8.60 in the control group, 125.14 +/- 7.18 in the ARI group, 215.89 +/- 8.36 in the MEM group, 208.69 +/- 2.05 in the HBO group, and 172.27 +/- 8.16 in the BRI group. Mean apoptotic indexes in the groups were 1.1 +/- 0.35%, 57.71 +/- 0.58%, 23.57 +/- 1.73%, 15.63 +/- 0.58%, and 29.37 +/- 2.55%, respectively. CONCLUSIONS: The present study shows that memantine, HBO, and brimonidine therapies were effective in reducing the damage induced by acute ischemia reperfusion in the rat retina. Our study suggests that these treatments had beneficial effects due to neuroprotection, and therefore may be applied in clinical practice. PMID- 21541270 TI - Two novel mutations of TACSTD2 found in three Japanese gelatinous drop-like corneal dystrophy families with their aberrant subcellular localization. AB - PURPOSE: To report two novel mutation of the tumor-associated calcium signal transducer 2 (TACSTD2) gene in 3 Japanese patients with gelatinous drop-like corneal dystrophy (GDLD). METHODS: Genomic DNAs were extracted from the peripheral blood of 3 Japanese families. The coding region of TACSTD2 was amplified by polymerase chain reaction (PCR) and subjected to direct sequencing analysis. Plasmid vectors harboring normal and mutated TACSTD2 were transfected to the immortalized human corneal epithelial cells to identify the subcellular localization of the normal and mutated TACSTD2 gene products. RESULTS: Sequencing analysis of TACSTD2 revealed two novel homozygous mutations (c.840_841insTCATCATCGCCGGCCTCATC and c.675C>A which may result in frameshift (p.Ile281SerfsX23) and nonsense (p.Tyr225X) mutations, respectively) in the 3 GDLD patients. Protein expression analysis showed that the mutated gene product was distributed diffusely in the cytoplasm, whereas the normal gene product accumulated at the cell-to-cell borders. CONCLUSIONS: This study reports two novel mutations in 3 GDLD families and expands the spectrum of mutations in TACSTD2 that may cause pathological corneal amyloidosis. PMID- 21541271 TI - The association of age-related maculopathy susceptibility 2 polymorphisms with phenotype in typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. AB - PURPOSE: To determine the association of age-related maculopathy susceptibility 2 (ARMS2) gene polymorphisms with the phenotype of typical neovascular age-related macular degeneration (tAMD) and polypoidal choroidal vasculopathy (PCV) and the effects of photodynamic therapy (PDT). METHODS: The single nucleotide polymorphisms at rs10490924 (A69S) in ARMS2 of 68 tAMD and 119 PCV patients who underwent PDT were genotyped using the TaqMan assay. The baseline best corrected visual acuity (BCVA) and lesion size were compared among the three genotypes at rs10490924. A multivariate regression analysis was performed to evaluate the influence of the baseline BCVA, greatest linear dimension (GLD), and lesion phenotype (tAMD or PCV) on the association of rs10490924 with the BCVA 12 months after the first PDT. RESULTS: The mean lesion size was significantly different among the GG, GT, and TT genotypes at rs10490924 in the PCV group, although no significant differences were detected in the tAMD group. PCV patients with a G allele had significantly better vision at 3 months after the initial PDT. tAMD patients with a TT genotype had significantly poorer vision at 12 months after the first PDT. In the multivariate regression analysis, the additive model of the G allele at rs10490924 was associated with a significantly better BCVA 12 months after the first PDT in tAMD and PCV patients. CONCLUSIONS: ARMS2 variants are likely associated with the phenotype and the effects of PDT in tAMD and PCV. PMID- 21541272 TI - Hematologic biomarkers in childhood cataracts. AB - PURPOSE: To date, more than thirty nine genetic loci have been associated with congenital cataracts. Despite this progress, current diagnostic techniques are insufficient for unraveling the underlying genetic defect in sporadic patients and small families. In the present manuscript we demonstrate the contribution of routine laboratory tests in the search for genetic defects of childhood cataracts. METHODS: Two families with congenital cataracts and hematologic findings that included hyperferritinemia and the "ii" blood type underwent detailed ophthalmologic and clinical examinations. Mutation analysis of the ferritin light chain (FTL) and glucosaminyl (N-acetyl) transferase 2, I-branching enzyme (GCNT2) genes was performed in the two families, respectively. RESULTS: In the family with the "ii" blood group we found a novel GCNT2 mutation c.G935A (p.G312D) in the cataract patients, while in the family with hyperferritinemia cataract syndrome we identified a G->C heterozygous mutation at position +32 of FTL. CONCLUSIONS: Hematologic biomarkers may simplify the search for the underlying molecular defect in families with congenital cataract. PMID- 21541273 TI - The retinal pigment epithelium undergoes massive apoptosis during early differentiation and pigmentation of the optic cup. AB - PURPOSE: The aim of our work was to study apoptosis during the development of the retinal pigment epithelium (RPE) in mice between embryonic day (E) 10.5 and E12.5 and to examine a possible link between apoptosis and pigmentation. METHODS: We collected mouse embryos at E10.5, E11.5, and E12.5 and labeled apoptotic cells in 5-um paraffin sections, using the terminal deoxynucleotidyl transferase dUTP nick end labeling technique. We counted the total number of cells and the number of apoptotic cells in the early developing RPE and calculated the percentage of apoptosis at each stage. RESULTS: In the C57BL/6J mouse, 17% of the RPE cells were apoptotic at E10.5 compared to 0.9% at E12.5. At E11.5, three-quarters of the RPE cells began to pigment, and apoptotic cells were located mostly in the nonpigmented part. In contrast, in the BALB/c mouse (tyrosinase-deficient) and pJ mouse (carrying mutations in the p gene) hypopigmented strains, the RPE contained significantly fewer apoptotic cells (7.5% and 10.1%, respectively) at E10.5 than controls. Subsequently at E11.5 and E12.5, the two hypopigmented strains displayed different apoptotic patterns; the BALB/c RPE had a similar percentage of apoptotic cells to controls (1.5% and 1.1%, respectively, for BALB/c versus 3.0% and 0.9%, respectively, for C57BL/6J), whereas the pJ RPE contained significantly more apoptosis (7.5% and 3.5%, respectively). Overall we observed differences in the evolution of the relative total number of RPE cells between the three strains. CONCLUSIONS: Apoptosis is a main event during the first stages of normal RPE development, indicating an essential role during RPE differentiation. Moreover, the early apoptotic pattern and possibly the whole early development of the RPE is different between hypopigmented and pigmented strains, as well as between BALB/c and pJ mice. This suggests the existence of regulatory and developmental differences with a more complex origin than just differing pigmentation levels. PMID- 21541274 TI - Screening of TYR, OCA2, GPR143, and MC1R in patients with congenital nystagmus, macular hypoplasia, and fundus hypopigmentation indicating albinism. AB - BACKGROUND: A broad spectrum of pigmentation of the skin and hair is found among patients diagnosed with ocular albinism (OA) and oculocutaneous albinism (OCA). Even though complexion is variable, three ocular features, i.e., hypopigmentation of the fundus, hypoplasia of the macula, and nystagmus, are classical pathological findings in these patients. We screened 172 index patients with a clinical diagnosis of OA or OCA based on the classical findings, to evaluate the frequency of sequence variants in tyrosinase (TYR), P-gene, P-protein (OCA2), and the G-protein-coupled receptor 143 gene, OA1 (GPR143). In addition, we investigated the association of sequence variants in the melanocortin receptor 1 gene (MC1R) and OCA2. METHODS: Pigmentation of the hair, skin, iris, and fundus were included in the evaluation of OCA and OA. Male OA patients showing X-linked inheritance were screened for GPR143. Females showing OA without family history were regarded as representing autosomal recessive OA (OA3). Direct sequencing was applied to PCR products showing aberrant single-strand conformation polymorphism banding patterns. RESULTS: Fifty-seven male index patients were screened for OA. We identified 16 potentially pathogenic sequence variations in GPR143 (10 novel) in 22 males. In TYR, we identified 23 (7 novel), and in OCA2 28 (11 novel) possibly pathogenic variants. Variants on both alleles were identified in TYR or OCA2 in 29/79 OCA patients and 14/71 OA patients. Sequence changes in TYR were identified almost exclusively in OCA patients, while sequence changes in OCA2 occurred in OCA and OA patients. MC1R sequencing was performed in 47 patients carrying mutations in OCA2 and revealed MC1R mutations in 42 of them. CONCLUSIONS: TYR gene mutations have a more severe effect on pigmentation than mutations in OCA2 and the GPR143 gene. Nevertheless, mutations in these genes affect the development of visual function either directly or by interaction with other genes like MC1R, which can be deduced from a frequent association of MC1R variants with p.R305W or p.R419Q in OCA2. PMID- 21541275 TI - Apolipoprotein E gene and age-related macular degeneration in a Chinese population. AB - PURPOSE: To examine the association between apolipoprotein E (APOE) polymorphisms and age-related macular degeneration (AMD) in a Chinese population. METHODS: The study consisted of 712 subjects, including 201 controls, 363 cases with early AMD, and 148 cases with exudative AMD. Genomic DNA was extracted from venous blood leukocytes. Common allelic variants of APOE (epsilon2, epsilon3, and epsilon4) were analyzed by PCR and direct sequencing. RESULTS: APOE epsilon3epsilon3 was the most frequent genotype, with a frequency of 72.6% in controls, 72.5% in early AMD, and 70.3% in exudative AMD. Frequency of the epsilon2 allele was 6.7% in controls, 7.4% in early AMD, and 8.8% in exudative AMD. Frequency of the epsilon4 allele was 8.7% in controls, 7.7% in early AMD, and 7.8% in exudative AMD. No statistically significant difference in APOE genotype and allele frequency distribution was observed among controls, cases with early AMD, and cases with exudative AMD. For epsilon2 allele carriers, the odds ratio was 1.12 (95% confidence interval [CI], 0.65-1.93) for early AMD and 1.06 (95% CI, 0.53-2.10) for exudative AMD. For epsilon4 allele carriers, the odds ratio was 1.04 (95% CI, 0.61-1.75) for early AMD and 0.83 (95% CI, 0.42 1.62) for exudative AMD. CONCLUSIONS: Our data provide no evidence to support an association of APOE polymorphisms with early or exudative AMD, suggesting that APOE is less likely to be a major AMD susceptibility gene in the Chinese population. PMID- 21541276 TI - Eosinophil cationic protein as a marker for assessing the efficacy of tacrolimus ophthalmic solution in the treatment of atopic keratoconjunctivitis. AB - PURPOSE: To examine the clinical efficacy and anti-inflammatory effects of tacrolimus eye drops; we studied the changes in clinical ocular findings and measured tear eosinophil cationic protein (ECP) levels of atopic keratoconjunctivitis (AKC) patients before and after the treatment. METHODS: Nine eyes of 9 patients (8 males, 1 female; mean age: 16.9 +/- 11.4 years; range: 6-44 years) diagnosed with moderate or severe AKC disease were enrolled in this prospective study and treated with tacrolimus. All patients received 0.1% tacrolimus eye drops 2 times a day for 1 month. Tear samples were taken before and after treatment and ECP concentrations were obtained. Corneal fluorescein staining and conjunctival injection, edema, and papillary formation were graded on the recruitment day and one month later. Analysis of pre- and post-treatment findings was done using the Wilcoxon signed test. The ECP concentrations were correlated with the clinical signs using Spearman correlation tests. RESULTS: Post-treatment tear ECP levels were significantly reduced compared to the pre treatment level. Clinical corneal scores also improved significantly after one month treatment with tacrolimus eye-drops. The mean conjunctival injection and conjunctival edema scores were significantly (p<0.05) decreased after the drug therapy. Strong positive linear correlations between ECP values and clinical signs were observed. Patients did not present side effects during the treatment with tacrolimus. CONCLUSIONS: In this pilot study, tacrolimus eye drops were found to reduce signs of AKC. ECP proved to correlate well with clinical signs of AKC. PMID- 21541277 TI - The association of a single nucleotide polymorphism in the promoter region of the LAMA1 gene with susceptibility to Chinese high myopia. AB - PURPOSE: High myopia is a severe hereditary ocular disease leading to blindness. LAMA1 (alpha subunit of laminin) is a promising candidate gene for high myopia present in the MYP2 (myopia 2) region. The purpose of this study was to determine if high myopia is associated with single nucleotide polymorphism (SNP) variants in LAMA1 in Chinese subjects. METHODS: Ninety-seven Chinese subjects with high myopia and ethnically and sexually matched 103 normal controls were enrolled. Genomic DNA was prepared from peripheral blood. The 5 SNPs of LAMA1 were analyzed using PCR and SNaPshot. Allele frequencies were tested for Hardy-Weinberg disequilibrium. The genotype and allele frequencies were evaluated using the chi(2) tests or the Fisher exact tests. RESULTS: One of the 5 SNPs showed a significant difference between patients and control subjects (rs2089760: p(genotype)=0.005, p(allel)=0.003). There were no statistically significant differences between patients and control subjects for the other four SNPs: rs566655, rs11664063, rs607230, and rs3810046. CONCLUSIONS: Our results indicate that the polymorphism of rs2089760, located in the promoter region of LAMA1, may be associated with high myopia in the Chinese population and should be investigated further. PMID- 21541278 TI - Accelerated retinal ganglion cell death in mice deficient in the Sigma-1 receptor. AB - PURPOSE: The sigma-1 receptor (sigmaR1), a ligand-operated chaperone, has been inferred to be neuroprotective in previous studies using sigmaR1 ligands. The sigmaR1 specificity of the protective function, however, has yet to be firmly established, due to the existence of non-sigmaR1 targets of the ligands. Here, we used the sigmaR1-knockout mouse (Sigmar1(-/-)) to demonstrate unambiguously the role of the sigmaR1 in protecting the retinal ganglion cells against degeneration after acute damage to the optic nerve. METHODS: Retinal sigmaR binding sites were labeled with radioiodinated sigmaR ligands and analyzed by autoradiography. Localization of the sigmaR1 was performed by indirect immunofluorescence on frozen retinal sections. Retinal ganglion cell death was induced by acute optic nerve crush in wild-type and Sigmar1(-/-) mice. Surviving cells in the ganglion cell layer were counted on Nissl-stained retinal whole mounts 7 days after the crush surgery. RESULTS: Photoaffinity labeling indicated the presence of the sigmaR1 in the retina, in concentrations equivalent to those in liver tissue. Immunolabeling detected this receptor in cells of both the ganglion cell layer and the photoreceptor cell layer in wild-type retinas. Quantification of cells remaining after optic nerve crush showed that 86.8+/-7.9% cells remained in the wild-type ganglion cell layer, but only 68.3+/-3.4% survived in the Sigmar1(-/-), demonstrating a significant difference between the wild-type and the Sigmar1(-/-) in crush-induced ganglion cell loss. CONCLUSIONS: Our data indicated faster retinal ganglion cell death in Sigmar1(-/-) than in wild-type mice under the stresses caused by optic nerve crush, providing direct evidence for a role of the sigmaR1 in alleviating retinal degeneration. This conclusion is consistent with the previous pharmacological studies using sigmaR1 agonists. Thus, our study supports the idea that the sigmaR1 is a promising therapeutic target for neurodegenerative retinal diseases, such as glaucoma. PMID- 21541279 TI - Amyloid beta resistance in nerve cell lines is mediated by the Warburg effect. AB - Amyloid beta (Abeta) peptide accumulation in the brains of patients with Alzheimer's disease (AD) is closely associated with increased nerve cell death. However, many cells survive and it is important to understand the mechanisms involved in this survival response. Recent studies have shown that an anti apoptotic mechanism in cancer cells is mediated by aerobic glycolysis, also known as the Warburg effect. One of the major regulators of aerobic glycolysis is pyruvate dehydrogenase kinase (PDK), an enzyme which represses mitochondrial respiration and forces the cell to rely heavily on glycolysis, even in the presence of oxygen. Recent neuroimaging studies have shown that the spatial distribution of aerobic glycolysis in the brains of AD patients strongly correlates with Abeta deposition. Interestingly, clonal nerve cell lines selected for resistance to Abeta exhibit increased glycolysis as a result of activation of the transcription factor hypoxia inducible factor 1. Here we show that Abeta resistant nerve cell lines upregulate Warburg effect enzymes in a manner reminiscent of cancer cells. In particular, Abeta resistant nerve cell lines showed elevated PDK1 expression in addition to an increase in lactate dehydrogenase A (LDHA) activity and lactate production when compared to control cells. In addition, mitochondrial derived reactive oxygen species (ROS) were markedly diminished in resistant but not sensitive cells. Chemically or genetically inhibiting LDHA or PDK1 re-sensitized resistant cells to Abeta toxicity. These findings suggest that the Warburg effect may contribute to apoptotic-resistance mechanisms in the surviving neurons of the AD brain. Loss of the adaptive advantage afforded by aerobic glycolysis may exacerbate the pathophysiological processes associated with AD. PMID- 21541280 TI - Neural mechanisms of human perceptual learning: electrophysiological evidence for a two-stage process. AB - BACKGROUND: Humans and other animals change the way they perceive the world due to experience. This process has been labeled as perceptual learning, and implies that adult nervous systems can adaptively modify the way in which they process sensory stimulation. However, the mechanisms by which the brain modifies this capacity have not been sufficiently analyzed. METHODOLOGY/PRINCIPAL FINDINGS: We studied the neural mechanisms of human perceptual learning by combining electroencephalographic (EEG) recordings of brain activity and the assessment of psychophysical performance during training in a visual search task. All participants improved their perceptual performance as reflected by an increase in sensitivity (d') and a decrease in reaction time. The EEG signal was acquired throughout the entire experiment revealing amplitude increments, specific and unspecific to the trained stimulus, in event-related potential (ERP) components N2pc and P3 respectively. P3 unspecific modification can be related to context or task-based learning, while N2pc may be reflecting a more specific attentional related boosting of target detection. Moreover, bell and U-shaped profiles of oscillatory brain activity in gamma (30-60 Hz) and alpha (8-14 Hz) frequency bands may suggest the existence of two phases for learning acquisition, which can be understood as distinctive optimization mechanisms in stimulus processing. CONCLUSIONS/SIGNIFICANCE: We conclude that there are reorganizations in several neural processes that contribute differently to perceptual learning in a visual search task. We propose an integrative model of neural activity reorganization, whereby perceptual learning takes place as a two-stage phenomenon including perceptual, attentional and contextual processes. PMID- 21541281 TI - Acquisition and assimilation of nitrogen as peptide-bound and D-enantiomers of amino acids by wheat. AB - Nitrogen is a key regulator of primary productivity in many terrestrial ecosystems. Historically, only inorganic N (NH(4)(+) and NO(3)(-)) and L-amino acids have been considered to be important to the N nutrition of terrestrial plants. However, amino acids are also present in soil as small peptides and in D enantiomeric form. We compared the uptake and assimilation of N as free amino acid and short homopeptide in both L- and D-enantiomeric forms. Sterile roots of wheat (Triticum aestivum L.) plants were exposed to solutions containing either (14)C-labelled L-alanine, D-alanine, L-trialanine or D-trialanine at a concentration likely to be found in soil solution (10 uM). Over 5 h, plants took up L-alanine, D-alanine and L-trialanine at rates of 0.9+/-0.3, 0.3+/-0.06 and 0.3+/-0.04 umol g(-1) root DW h(-1), respectively. The rate of N uptake as L trialanine was the same as that as L-alanine. Plants lost ca.60% of amino acid C taken up in respiration, regardless of the enantiomeric form, but more (ca.80%) of the L-trialanine C than amino acid C was respired. When supplied in solutions of mixed N form, N uptake as D-alanine was ca.5-fold faster than as NO(3)(-), but slower than as L-alanine, L-trialanine and NH(4)(+). Plants showed a limited capacity to take up D-trialanine (0.04+/-0.03 umol g(-1) root DW h(-1)), but did not appear to be able to metabolise it. We conclude that wheat is able to utilise L-peptide and D-amino acid N at rates comparable to those of N forms of acknowledged importance, namely L-amino acids and inorganic N. This is true even when solutes are supplied at realistic soil concentrations and when other forms of N are available. We suggest that it may be necessary to reconsider which forms of soil N are important in the terrestrial N cycle. PMID- 21541282 TI - A new method for isolation of interstitial fluid from human solid tumors applied to proteomic analysis of ovarian carcinoma tissue. AB - Major efforts have been invested in the identification of cancer biomarkers in plasma, but the extraordinary dynamic range in protein composition, and the dilution of disease specific proteins make discovery in plasma challenging. Focus is shifting towards using proximal fluids for biomarker discovery, but methods to verify the isolated sample's origin are missing. We therefore aimed to develop a technique to search for potential candidate proteins in the proximal proteome, i.e. in the tumor interstitial fluid, since the biomarkers are likely to be excreted or derive from the tumor microenvironment. Since tumor interstitial fluid is not readily accessible, we applied a centrifugation method developed in experimental animals and asked whether interstitial fluid from human tissue could be isolated, using ovarian carcinoma as a model. Exposure of extirpated tissue to 106 g enabled tumor fluid isolation. The fluid was verified as interstitial by an isolated fluid:plasma ratio not significantly different from 1.0 for both creatinine and Na(+), two substances predominantly present in interstitial fluid. The isolated fluid had a colloid osmotic pressure 79% of that in plasma, suggesting that there was some sieving of proteins at the capillary wall. Using a proteomic approach we detected 769 proteins in the isolated interstitial fluid, sixfold higher than in patient plasma. We conclude that the isolated fluid represents undiluted interstitial fluid and thus a subproteome with high concentration of locally secreted proteins that may be detected in plasma for diagnostic, therapeutic and prognostic monitoring by targeted methods. PMID- 21541284 TI - Endophytic bacteria in toxic South African plants: identification, phylogeny and possible involvement in gousiekte. AB - BACKGROUND: South African plant species of the genera Fadogia, Pavetta and Vangueria (all belonging to Rubiaceae) are known to cause gousiekte (literally 'quick disease'), a fatal cardiotoxicosis of ruminants characterised by acute heart failure four to eight weeks after ingestion. Noteworthy is that all these plants harbour endophytes in their leaves: nodulating bacteria in specialized nodules in Pavetta and non-nodulating bacteria in the intercellular spaces between mesophyll cells in Fadogia and Vangueria. PRINCIPAL FINDINGS: Isolation and analyses of these endophytes reveal the presence of Burkholderia bacteria in all the plant species implicated in gousiekte. Although the nodulating and non nodulating bacteria belong to the same genus, they are phylogenetically not closely related and even fall in different bacterial clades. Pavetta harborii and Pavetta schumanniana have their own specific endophyte--Candidatus Burkholderia harborii and Candidatus Burkholderia schumanniana--while the non-nodulating bacteria found in the other gousiekte-inducing plants show high similarity to Burkholderia caledonica. In this group, the bacteria are host specific at population level. Investigation of gousiekte-inducing plants from other African countries resulted in the discovery of the same endophytes. Several other plants of the genera Afrocanthium, Canthium, Keetia, Psydrax, Pygmaeothamnus and Pyrostria were tested and were found to lack bacterial endophytes. CONCLUSIONS: The discovery and identification of Burkholderia bacteria in gousiekte-inducing plants open new perspectives and opportunities for research not only into the cause of this economically important disease, but also into the evolution and functional significance of bacterial endosymbiosis in Rubiaceae. Other South African Rubiaceae that grow in the same area as the gousiekte-inducing plants were found to lack bacterial endophytes which suggests a link between bacteria and gousiekte. The same bacteria are consistently found in gousiekte-inducing plants from different regions indicating that these plants will also be toxic to ruminants in other African countries. PMID- 21541283 TI - Sim1 is a novel regulator in the differentiation of mouse dorsal raphe serotonergic neurons. AB - BACKGROUND: Mesencephalic dopaminergic neurons (mDA) and serotonergic (5-HT) neurons are clinically important ventral neuronal populations. Degeneration of mDA is associated with Parkinson's disease; defects in the serotonergic system are related to depression, obsessive-compulsive disorder, and schizophrenia. Although these neuronal subpopulations reveal positional and developmental relationships, the developmental cascades that govern specification and differentiation of mDA or 5-HT neurons reveal missing determinants and are not yet understood. METHODOLOGY: We investigated the impact of the transcription factor Sim1 in the differentiation of mDA and rostral 5-HT neurons in vivo using Sim1-/- mouse embryos and newborn pups, and in vitro by gain- and loss-of function approaches. PRINCIPAL FINDINGS: We show a selective significant reduction in the number of dorsal raphe nucleus (DRN) 5-HT neurons in Sim1-/- newborn mice. In contrast, 5-HT neurons of other raphe nuclei as well as dopaminergic neurons were not affected. Analysis of the underlying molecular mechanism revealed that tryptophan hydroxylase 2 (Tph2) and the transcription factor Pet1 are regulated by Sim1. Moreover, the transcription factor Lhx8 and the modulator of 5-HT(1A)-mediated neurotransmitter release, Rgs4, exhibit significant higher expression in ventral hindbrain, compared to midbrain and are target genes of Sim1. CONCLUSIONS: The results demonstrate for the first time a selective transcription factor dependence of the 5-HT cell groups, and introduce Sim1 as a regulator of DRN specification acting upstream of Pet1 and Tph2. Moreover, Sim1 may act to modulate serotonin release via regulating RGS4. Our study underscores that subpopulations of a common neurotransmitter phenotype use distinct combinations of transcription factors to control the expression of shared properties. PMID- 21541285 TI - Expression of a dominant negative CELF protein in vivo leads to altered muscle organization, fiber size, and subtype. AB - BACKGROUND: CUG-BP and ETR-3-like factor (CELF) proteins regulate tissue- and developmental stage-specific alternative splicing in striated muscle. We previously demonstrated that heart muscle-specific expression of a nuclear dominant negative CELF protein in transgenic mice (MHC-CELFDelta) effectively disrupts endogenous CELF activity in the heart in vivo, resulting in impaired cardiac function. In this study, transgenic mice that express the dominant negative protein under a skeletal muscle-specific promoter (Myo-CELFDelta) were generated to investigate the role of CELF-mediated alternative splicing programs in normal skeletal muscle. METHODOLOGY/PRINCIPAL FINDINGS: Myo-CELFDelta mice exhibit modest changes in CELF-mediated alternative splicing in skeletal muscle, accompanied by a reduction of endomysial and perimysial spaces, an increase in fiber size variability, and an increase in slow twitch muscle fibers. Weight gain and mean body weight, total number of muscle fibers, and overall muscle strength were not affected. CONCLUSIONS/SIGNIFICANCE: Although these findings demonstrate that CELF activity contributes to the normal alternative splicing of a subset of muscle transcripts in vivo, the mildness of the effects in Myo-CELFDelta muscles compared to those in MHC-CELFDelta hearts suggests CELF activity may be less determinative for alternative splicing in skeletal muscle than in heart muscle. Nonetheless, even these small changes in CELF-mediated splicing regulation were sufficient to alter muscle organization and muscle fiber properties affected in myotonic dystrophy. This lends further evidence to the hypothesis that dysregulation of CELF-mediated alternative splicing programs may be responsible for the disruption of these properties during muscle pathogenesis. PMID- 21541286 TI - Differential roles for STIM1 and STIM2 in store-operated calcium entry in rat neurons. AB - The interaction between Ca(2+) sensors STIM1 and STIM2 and Ca(2+) channel-forming protein ORAI1 is a crucial element of store-operated calcium entry (SOCE) in non excitable cells. However, the molecular mechanism of SOCE in neurons remains unclear. We addressed this issue by establishing the presence and function of STIM proteins. Real-time polymerase chain reaction from cortical neurons showed that these cells contain significant amounts of Stim1 and Stim2 mRNA. Thapsigargin (TG) treatment increased the amount of both endogenous STIM proteins in neuronal membrane fractions. The number of YFP-STIM1/ORAI1 and YFP-STIM2/ORAI1 complexes was also enhanced by such treatment. The differences observed in the number of STIM1 and STIM2 complexes under SOCE conditions and the differential sensitivity to SOCE inhibitors suggest their distinct roles. Endoplasmic reticulum (ER) store depletion by TG enhanced intracellular Ca(2+) levels in loaded with Fura-2 neurons transfected with YFP-STIM1 and ORAI1, but not with YFP STIM2 and ORAI1, which correlated well with the number of complexes formed. Moreover, the SOCE inhibitors ML-9 and 2-APB reduced Ca(2+) influx in neurons expressing YFP-STIM1/ORAI1 but produced no effect in cells transfected with YFP STIM2/ORAI1. Moreover, in neurons transfected with YFP-STIM2/ORAI1, the increase in constitutive calcium entry was greater than with YFP-STIM1/ORAI1. Our data indicate that both STIM proteins are involved in calcium homeostasis in neurons. STIM1 mainly activates SOCE, whereas STIM2 regulates resting Ca(2+) levels in the ER and Ca(2+) leakage with the additional involvement of STIM1. PMID- 21541287 TI - Wnt4 enhances murine hematopoietic progenitor cell expansion through a planar cell polarity-like pathway. AB - BACKGROUND: While the role of canonical (beta-catenin-mediated) Wnt signaling in hematolymphopoiesis has been studied extensively, little is known of the potential importance of non-canonical Wnt signals in hematopoietic cells. Wnt4 is one of the Wnt proteins that can elicit non-canonical pathways. We have previously shown that retroviral overexpression of Wnt4 by hematopoietic cells increased thymic cellularity as well as the frequency of early thymic progenitors and bone marrow hematopoietic progenitor cells (HPCs). However, the molecular pathways responsible for its effect in HPCs are not known. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that Wnt4 stimulation resulted in the activation of the small GTPase Rac1 as well as Jnk kinases in an HPC cell line. Jnk activity was necessary, while beta-catenin was dispensable, for the Wnt4-mediated expansion of primary fetal liver HPCs in culture. Furthermore, Jnk2-deficient and Wnt4 hemizygous mice presented lower numbers of HPCs in their bone marrow, and Jnk2 deficient HPCs showed increased rates of apoptosis. Wnt4 also improved HPC activity in a competitive reconstitution model in a cell-autonomous, Jnk2 dependent manner. Lastly, we identified Fz6 as a receptor for Wnt4 in immature HPCs and showed that the absence of Wnt4 led to a decreased expression of four polarity complex genes. CONCLUSIONS/SIGNIFICANCE: Our results establish a functional role for non-canonical Wnt signaling in hematopoiesis through a pathway involving Wnt4, Fz6, Rac1 and Jnk kinases. PMID- 21541288 TI - Agonist-directed desensitization of the beta2-adrenergic receptor. AB - The beta(2)-adrenergic receptor (beta(2)AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the beta(2)AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective beta(2)AR desensitization at the whole cell level. PMID- 21541289 TI - Spreading depression sends microglia on Levy flights. AB - Spreading depression (SD) is thought to cause migraine aura, and perhaps migraine, and includes a transient loss of synaptic activity preceded and followed by increased neuronal excitability. Activated microglia influence neuronal activity and play an important role in homeostatic synaptic scaling via release of cytokines. Furthermore, enhanced neuronal function activates microglia to not only secrete cytokines but also to increase the motility of their branches, with somata remaining stationary. While SD also increases the release of cytokines from microglia, the effects on microglial movement from its synaptic activity fluctuations are unknown. Accordingly, we used time-lapse imaging of rat hippocampal slice cultures to probe for microglial movement associated with SD. We observed that in uninjured brain whole microglial cells moved. The movements were well described by the type of Levy flight known to be associated with an optimal search pattern. Hours after SD, when synaptic activity rose, microglial cell movement was significantly increased. To test how synaptic activity influenced microglial movement, we enhanced neuronal activity with chemical long term potentiation or LPS and abolished it with TTX. We found that microglial movement was significantly decreased by enhanced neuronal activity and significantly increased by activity blockade. Finally, application of glutamate and ATP to mimic restoration of synaptic activity in the presence of TTX stopped microglial movement that was otherwise seen with TTX. Thus, synaptic activity retains microglial cells in place and an absence of synaptic activity sends them off to influence wider expanses of brain. Perhaps increased microglial movements after SD are a long-lasting, and thus maladaptive, response in which these cells increase neuronal activity via contact or paracrine signaling, which results in increased susceptibility of larger brain areas to SD. If true, then targeting mechanisms that retard activity-dependent microglial Levy flights may be a novel means to reduce susceptibility to migraine. PMID- 21541290 TI - Dance type and flight parameters are associated with different mushroom body neural activities in worker honeybee brains. AB - BACKGROUND: Honeybee foragers can transmit the information concerning the location of food sources to their nestmates using dance communication. We previously used a novel immediate early gene, termed kakusei, to demonstrate that the neural activity of a specific mushroom body (MB) neuron subtype is preferentially enhanced in the forager brain. The sensory information related to this MB neuron activity, however, remained unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used kakusei to analyze the relationship between MB neuron activity and types of foraging behavior. The number of kakusei-positive MB neurons was higher in the round dancers that had flown a short distance than in the waggle dancers that had flown a long distance. Furthermore, the amount of kakusei transcript in the MBs inversely related to the waggle-phase duration of the waggle dance, which correlates with the flight distance. Using a narrow tunnel whose inside was vertically or axially lined, we manipulated the pattern of visual input, which is received by the foragers during flight, and analysed kakusei expression. The amount of kakusei transcript in the MBs was related to the foraging frequency but not to the tunnel pattern. In contrast, the number of kakusei-positive MB neurons was affected by the tunnel patterns, but not related to foraging frequency. CONCLUSIONS/SIGNIFICANCE: These results suggest that the MB neuron activity depends on the foraging frequency, whereas the number of active MB neurons is related to the pattern of visual input received during foraging flight. Our results suggest that the foraging frequency and visual experience during foraging are associated with different MB neural activities. PMID- 21541291 TI - PTB domain-directed substrate targeting in a tyrosine kinase from the unicellular choanoflagellate Monosiga brevicollis. AB - Choanoflagellates are considered to be the closest living unicellular relatives of metazoans. The genome of the choanoflagellate Monosiga brevicollis contains a surprisingly high number and diversity of tyrosine kinases, tyrosine phosphatases, and phosphotyrosine-binding domains. Many of the tyrosine kinases possess combinations of domains that have not been observed in any multicellular organism. The role of these protein interaction domains in M. brevicollis kinase signaling is not clear. Here, we have carried out a biochemical characterization of Monosiga HMTK1, a protein containing a putative PTB domain linked to a tyrosine kinase catalytic domain. We cloned, expressed, and purified HMTK1, and we demonstrated that it possesses tyrosine kinase activity. We used immobilized peptide arrays to define a preferred ligand for the third PTB domain of HMTK1. Peptide sequences containing this ligand sequence are phosphorylated efficiently by recombinant HMTK1, suggesting that the PTB domain of HMTK1 has a role in substrate recognition analogous to the SH2 and SH3 domains of mammalian Src family kinases. We suggest that the substrate recruitment function of the noncatalytic domains of tyrosine kinases arose before their roles in autoinhibition. PMID- 21541292 TI - Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept. AB - There is a paradox offered up by the cancer stem cell hypothesis. How are the mixed populations that are characteristic of heterogeneous solid tumors maintained at constant proportion, given their high, and different, mitotic indices? In this study, we evaluate a well-characterized mouse model of human basaloid tumors (induced by the oncogene Wnt1), which comprise mixed populations of mammary epithelial cells resembling their normal basal and luminal counterparts. We show that these cell types are substantially inter-dependent, since the MMTV LTR drives expression of Wnt1 ligand in luminal cells, whereas the functional Wnt1-responsive receptor (Lrp5) is expressed by basal cells, and both molecules are necessary for tumor growth. There is a robust tumor initiating activity (tumor stem cell) in the basal cell population, which is associated with the ability to differentiate into luminal and basal cells, to regenerate the oncogenic paracrine signaling cell pair. However, we found an additional tumor stem cell activity in the luminal cell population. Knowing that tumors depend upon Wnt1-Lrp5, we hypothesized that this stem cell must express Lrp5, and found that indeed, all the stem cell activity could be retrieved from the Lrp5-positive cell population. Interestingly, this reflects post-transcriptional acquisition of Lrp5 protein expression in luminal cells. Furthermore, this plasticity of molecular expression is reflected in plasticity of cell fate determination. Thus, in vitro, Wnt1-expressing luminal cells retro-differentiate to basal cell types, and in vivo, tumors initiated with pure luminal cells reconstitute a robust basal cell subpopulation that is indistinguishable from the populations initiated by pure basal cells. We propose this is an important proof of concept, demonstrating that bipotential tumor stem cells are essential in tumors where oncogenic ligand receptor pairs are separated into different cell types, and suggesting that Wnt induced molecular and fate plasticity can close paracrine loops that are usually separated into distinct cell types. PMID- 21541293 TI - T cell chemo-vaccination effects after repeated mucosal SHIV exposures and oral pre-exposure prophylaxis. AB - Pre-exposure prophylaxis (PrEP) with anti-viral drugs is currently in clinical trials for the prevention of HIV infection. Induction of adaptive immune responses to virus exposures during anti-viral drug administration, i.e., a "chemo-vaccination" effect, could contribute to PrEP efficacy. To study possible chemo-vaccination, we monitored humoral and cellular immune responses in nine rhesus macaques undergoing up to 14 weekly, low-dose SHIV(SF162P3) rectal exposures. Six macaques concurrently received PrEP with intermittent, oral Truvada; three were no-PrEP controls. PrEP protected 4 macaques from infection. Two of the four showed evidence of chemo-vaccination, because they developed anti SHIV CD4(+) and CD8(+) T cells; SHIV-specific antibodies were not detected. Control macaques showed no anti-SHIV immune responses before infection. Chemo vaccination-induced T cell responses were robust (up to 3,940 SFU/10(6) PBMCs), predominantly central memory cells, short-lived (<=22 weeks), and appeared intermittently and with changing specificities. The two chemo-vaccinated macaques were virus-challenged again after 28 weeks of rest, after T cell responses had waned. One macaque was not protected from infection. The other macaque concurrently received additional PrEP. It remained uninfected and T cell responses were boosted during the additional virus exposures. In summary, we document and characterize PrEP-induced T cell chemo-vaccination. Although not protective after subsiding in one macaque, chemo-vaccination-induced T cells warrant more comprehensive analysis during peak responses for their ability to prevent or to control infections after additional exposures. Our findings highlight the importance of monitoring these responses in clinical PrEP trials and suggest that a combination of vaccines and PrEP potentially might enhance efficacy. PMID- 21541294 TI - Monitoring and prevalence rates of metabolic syndrome in military veterans with serious mental illness. AB - BACKGROUND: Cardiovascular disease is the leading cause of mortality among patients with serious mental illness (SMI) and the prevalence of metabolic syndrome--a constellation of cardiovascular risk factors--is significantly higher in these patients than in the general population. Metabolic monitoring among patients using second generation antipsychotics (SGAs)--a risk factor for metabolic syndrome--has been shown to be inadequate despite the release of several guidelines. However, patients with SMI have several factors independent of medication use that predispose them to a higher prevalence of metabolic syndrome. Our study therefore examines monitoring and prevalence of metabolic syndrome in patients with SMI, including those not using SGAs. METHODS AND FINDINGS: We retrospectively identified all patients treated at a Veterans Affairs Medical Center with diagnoses of schizophrenia, schizoaffective disorder or bipolar disorder during 2005-2006 and obtained demographic and clinical data. Incomplete monitoring of metabolic syndrome was defined as being unable to determine the status of at least one of the syndrome components. Of the 1,401 patients included (bipolar disorder: 822; schizophrenia: 222; and schizoaffective disorder: 357), 21.4% were incompletely monitored. Only 54.8% of patients who were not prescribed SGAs and did not have previous diagnoses of hypertension or hypercholesterolemia were monitored for all metabolic syndrome components compared to 92.4% of patients who had all three of these characteristics. Among patients monitored for metabolic syndrome completely, age-adjusted prevalence of the syndrome was 48.4%, with no significant difference between the three psychiatric groups. CONCLUSIONS: Only one half of patients with SMI not using SGAs or previously diagnosed with hypertension and hypercholesterolemia were completely monitored for metabolic syndrome components compared to greater than 90% of those with these characteristics. With the high prevalence of metabolic syndrome seen in this population, there appears to be a need to intensify efforts to reduce this monitoring gap. PMID- 21541295 TI - Simultaneous siRNA targeting of Src and downstream signaling molecules inhibit tumor formation and metastasis of a human model breast cancer cell line. AB - BACKGROUND: Src and signaling molecules downstream of Src, including signal transducer and activator of transcription 3 (Stat3) and cMyc, have been implicated in the development, maintenance and/or progression of several types of human cancers, including breast cancer. Here we report the ability of siRNA mediated Src knock-down alone, and simultaneous knock-down of Src and Stat3 and/or cMyc to inhibit the neoplastic phenotype of a highly metastatic human model breast cancer cell line, MDA-MB-435S, a widely used model for breast cancer research. METHODOLOGY/RESULTS: Src and its downstream signaling partners were specifically targeted and knocked-down using siRNA. Changes in the growth properties of the cultured cancer cells/tumors were documented using assays that included anchorage-dependent and -independent (in soft agar) cell growth, apoptosis, and both primary and metastatic tumor growth in the mouse tumor model. siRNA-mediated Src knock-down alone, and simultaneous knock-down of Src and Stat3 and/or cMyc inhibited the neoplastic phenotype of a highly metastatic human model breast cancer cell line, MDA-MB-435S. This knock-down resulted in reduced growth in monolayer and soft agar cultures, and a reduced ability to form primary tumors in NOD/SCID mice. In addition, direct intra-tumoral injection of siRNAs targeting these signaling molecules resulted in a substantial inhibition of tumor metastases as well as of primary tumor growth. Simultaneous knock-down of Src and Stat3, and/or Myc exhibited the greatest effects resulting in substantial inhibition of primary tumor growth and metastasis. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate the effectiveness of simultaneous targeting of Src and the downstream signaling partners Stat3 and/or cMyc to inhibit the growth and oncogenic properties of a human cancer cell line. This knowledge may be very useful in the development of future therapeutic approaches involving targeting of specific genes products involved in tumor growth and metastasis. PMID- 21541296 TI - Live bird markets of Bangladesh: H9N2 viruses and the near absence of highly pathogenic H5N1 influenza. AB - Avian influenza surveillance in Bangladesh has been passive, relying on poultry farmers to report suspected outbreaks of highly pathogenic H5N1 influenza. Here, the results of an active surveillance effort focusing on the live-bird markets are presented. Prevalence of influenza infection in the birds of the live bird markets is 23.0%, which is similar to that in poultry markets in other countries. Nearly all of the isolates (94%) were of the non-pathogenic H9N2 subtype, but viruses of the H1N2, H1N3, H3N6, H4N2, H5N1, and H10N7 subtypes were also observed. The highly pathogenic H5N1-subtype virus was observed at extremely low prevalence in the surveillance samples (0.08%), and we suggest that the current risk of infection for humans in the retail poultry markets in Bangladesh is negligible. However, the high prevalence of the H9 subtype and its potential for interaction with the highly pathogenic H5N1-subtype, i.e., reassortment and attenuation of host morbidity, highlight the importance of active surveillance of the poultry markets. PMID- 21541297 TI - Linkage mapping and comparative genomics using next-generation RAD sequencing of a non-model organism. AB - Restriction-site associated DNA (RAD) sequencing is a powerful new method for targeted sequencing across the genomes of many individuals. This approach has broad potential for genetic analysis of non-model organisms including genotype phenotype association mapping, phylogeography, population genetics and scaffolding genome assemblies through linkage mapping. We constructed a RAD library using genomic DNA from a Plutella xylostella (diamondback moth) backcross that segregated for resistance to the insecticide spinosad. Sequencing of 24 individuals was performed on a single Illumina GAIIx lane (51 base paired-end reads). Taking advantage of the lack of crossing over in homologous chromosomes in female Lepidoptera, 3,177 maternally inherited RAD alleles were assigned to the 31 chromosomes, enabling identification of the spinosad resistance and W/Z sex chromosomes. Paired-end reads for each RAD allele were assembled into contigs and compared to the genome of Bombyx mori (n = 28) using BLAST, revealing 28 homologous matches plus 3 expected fusion/breakage events which account for the difference in chromosome number. A genome-wide linkage map (1292 cM) was inferred with 2,878 segregating RAD alleles inherited from the backcross father, producing chromosome and location specific sequenced RAD markers. Here we have used RAD sequencing to construct a genetic linkage map de novo for an organism that has no previous genome data. Comparative analysis of P. xyloxtella linkage groups with B. mori chromosomes shows for the first time, genetic synteny appears common beyond the Macrolepidoptera. RAD sequencing is a powerful system capable of rapidly generating chromosome specific data for non-model organisms. PMID- 21541298 TI - Anaerobic carbon monoxide dehydrogenase diversity in the homoacetogenic hindgut microbial communities of lower termites and the wood roach. AB - Anaerobic carbon monoxide dehydrogenase (CODH) is a key enzyme in the Wood Ljungdahl (acetyl-CoA) pathway for acetogenesis performed by homoacetogenic bacteria. Acetate generated by gut bacteria via the acetyl-CoA pathway provides considerable nutrition to wood-feeding dictyopteran insects making CODH important to the obligate mutualism occurring between termites and their hindgut microbiota. To investigate CODH diversity in insect gut communities, we developed the first degenerate primers designed to amplify cooS genes, which encode the catalytic (beta) subunit of anaerobic CODH enzyme complexes. These primers target over 68 million combinations of potential forward and reverse cooS primer-binding sequences. We used the primers to identify cooS genes in bacterial isolates from the hindgut of a phylogenetically lower termite and to sample cooS diversity present in a variety of insect hindgut microbial communities including those of three phylogenetically-lower termites, Zootermopsis nevadensis, Reticulitermes hesperus, and Incisitermes minor, a wood-feeding cockroach, Cryptocercus punctulatus, and an omnivorous cockroach, Periplaneta americana. In total, we sequenced and analyzed 151 different cooS genes. These genes encode proteins that group within one of three highly divergent CODH phylogenetic clades. Each insect gut community contained CODH variants from all three of these clades. The patterns of CODH diversity in these communities likely reflect differences in enzyme or physiological function, and suggest that a diversity of microbial species participate in homoacetogenesis in these communities. PMID- 21541299 TI - Zebrafish Her8a is activated by Su(H)-dependent Notch signaling and is essential for the inhibition of neurogenesis. AB - Understanding how diversity of neural cells is generated is one of the main tasks of developmental biology. The Hairy/E(spl) family members are potential targets of Notch signaling, which has been shown to be fundamental to neural cell maintenance, cell fate decisions, and compartment boundary formation. However, their response to Notch signaling and their roles in neurogenesis are still not fully understood. In the present study, we isolated a zebrafish homologue of hairy/E(spl), her8a, and showed this gene is specifically expressed in the developing nervous system. her8a is positively regulated by Su(H)-dependent Notch signaling as revealed by a Notch-defective mutant and injection of variants of the Notch intracellular regulator, Su(H). Morpholino knockdown of Her8a resulted in upregulation of proneural and post-mitotic neuronal markers, indicating that Her8a is essential for the inhibition of neurogenesis. In addition, markers for glial precursors and mature glial cells were down-regulated in Her8a morphants, suggesting Her8a is required for gliogenesis. The role of Her8a and its response to Notch signaling is thus similar to mammalian HES1, however this is the converse of what is seen for the more closely related mammalian family member, HES6. This study not only provides further understanding of how the fundamental signaling pathway, Notch signaling, and its downstream genes mediate neural development and differentiation, but also reveals evolutionary diversity in the role of H/E(spl) genes. PMID- 21541300 TI - Cannabinoid receptor 2 signaling does not modulate atherogenesis in mice. AB - BACKGROUND: Strong evidence supports a protective role of the cannabinoid receptor 2 (CB(2)) in inflammation and atherosclerosis. However, direct proof of its involvement in lesion formation is lacking. Therefore, the present study aimed to characterize the role of the CB(2) receptor in Murine atherogenesis. METHODS AND FINDINGS: Low density lipoprotein receptor-deficient (LDLR(-/-)) mice subjected to intraperitoneal injections of the selective CB(2) receptor agonist JWH-133 or vehicle three times per week consumed high cholesterol diet (HCD) for 16 weeks. Surprisingly, intimal lesion size did not differ between both groups in sections of the aortic roots and arches, suggesting that CB(2) activation does not modulate atherogenesis in vivo. Plaque content of lipids, macrophages, smooth muscle cells, T cells, and collagen were also similar between both groups. Moreover, CB(2) (-/-)/LDLR(-/-) mice developed lesions of similar size containing more macrophages and lipids but similar amounts of smooth muscle cells and collagen fibers compared with CB(2) (+/+)/LDLR(-/-) controls. While JWH-133 treatment reduced intraperitoneal macrophage accumulation in thioglycollate elicited peritonitis, neither genetic deficiency nor pharmacologic activation of the CB(2) receptor altered inflammatory cytokine expression in vivo or inflammatory cell adhesion in the flow chamber in vitro. CONCLUSION: Our study demonstrates that both activation and deletion of the CB(2) receptor do not relevantly modulate atherogenesis in mice. Our data do not challenge the multiple reports involving CB(2) in other inflammatory processes. However, in the context of atherosclerosis, CB(2) does not appear to be a suitable therapeutic target for reduction of the atherosclerotic plaque. PMID- 21541301 TI - The EHEC type III effector NleL is an E3 ubiquitin ligase that modulates pedestal formation. AB - Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes hemorrhagic colitis and may result in potentially fatal hemolytic uremia syndrome in humans. EHEC colonize the intestinal mucosa and promote the formation of actin-rich pedestals via translocated type III effectors. Two EHEC type III secreted effectors, Tir and EspFu/TccP, are key players for pedestal formation. We discovered that an EHEC effector protein called Non-LEE-encoded Ligase (NleL) is an E3 ubiquitin ligase. In vitro, we showed that the NleL C753 residue is critical for its E3 ligase activity. Functionally, we demonstrated that NleL E3 ubiquitin ligase activity is involved in modulating Tir-mediated pedestal formation. Surprisingly, EHEC mutant strain deficient in the E3 ligase activity induced more pedestals than the wild-type strain. The canonical EPEC strain E2348/69 normally lacks the nleL gene, and the ectopic expression of the wild-type EHEC nleL, but not the catalytically-deficient nleL(C753A) mutant, in this strain resulted in fewer actin-rich pedestals. Furthermore, we showed that the C. rodentium NleL homolog is a E3 ubiquitin ligase and is required for efficient infection of murine colonic epithelial cells in vivo. In summary, our study demonstrated that EHEC utilizes NleL E3 ubiquitin ligase activity to modulate Tir-mediated pedestal formation. PMID- 21541302 TI - Importance of glycosylation on function of a potassium channel in neuroblastoma cells. AB - The Kv3.1 glycoprotein, a voltage-gated potassium channel, is expressed throughout the central nervous system. The role of N-glycans attached to the Kv3.1 glycoprotein on conducting and non-conducting functions of the Kv3.1 channel are quite limiting. Glycosylated (wild type), partially glycosylated (N220Q and N229Q), and unglycosylated (N220Q/N229Q) Kv3.1 proteins were expressed and characterized in a cultured neuronal-derived cell model, B35 neuroblastoma cells. Western blots, whole cell current recordings, and wound healing assays were employed to provide evidence that the conducting and non-conducting properties of the Kv3.1 channel were modified by N-glycans of the Kv3.1 glycoprotein. Electrophoretic migration of the various Kv3.1 proteins treated with PNGase F and neuraminidase verified that the glycosylation sites were occupied and that the N-glycans could be sialylated, respectively. The unglycosylated channel favored a different whole cell current pattern than the glycoform. Further the outward ionic currents of the unglycosylated channel had slower activation and deactivation rates than those of the glycosylated Kv3.1 channel. These kinetic parameters of the partially glycosylated Kv3.1 channels were also slowed. B35 cells expressing glycosylated Kv3.1 protein migrated faster than those expressing partially glycosylated and much faster than those expressing the unglycosylated Kv3.1 protein. These results have demonstrated that N-glycans of the Kv3.1 glycoprotein enhance outward ionic current kinetics, and neuronal migration. It is speculated that physiological changes which lead to a reduction in N-glycan attachment to proteins will alter the functions of the Kv3.1 channel. PMID- 21541303 TI - Multi-representation of symbolic and nonsymbolic numerical magnitude in Chinese number processing. AB - Numerical information can be conveyed by either symbolic or nonsymbolic representation. Some symbolic numerals can also be identified as nonsymbolic quantities defined by the number of lines (e.g., I, II, III in Roman and -, =, = in Japanese Kanji and Chinese). Here we report that such multi-representation of magnitude can facilitate the processing of these numerals under certain circumstances. In a magnitude comparison task judging 1 to 9 (except 5) Chinese and Arabic numerals presented at the foveal (at the center) or parafoveal (3 degrees left or right of the center) location, multi-representational small value Chinese numerals showed a processing advantage over single-representational Arabic numerals and large-value Chinese numerals only in the parafoveal condition, demonstrated by lower error rates and faster reaction times. Further event-related potential (ERP) analysis showed that such a processing advantage was not reflected by traditional ERP components identified in previous studies of number processing, such as N1 or P2p. Instead, the difference was found much later in a N400 component between 300-550 msec over parietal regions, suggesting that those behavioral differences may not be due to early processing of visual identification, but later processing of subitizing or accessing mental number line when lacking attentional resources. These results suggest that there could be three stages of number processing represented separately by the N1, P2p and N400 ERP components. In addition, numerical information can be represented simultaneously by both symbolic and nonsymbolic systems, which will facilitate number processing in certain situations. PMID- 21541304 TI - Somatotopic organization of the primate Basal Ganglia. AB - Somatotopic organization is a fundamental and key concept to understand how the cortico-basal ganglia loop works. It is also indispensable knowledge to perform stereotaxic surgery for movement disorders. Here I would like to describe the somatotopic organization of the basal ganglia, which consist of the striatum, subthalamic nucleus, globus pallidus, and substantia nigra. Projections from motor cortical regions representing different body parts terminate in different regions of these nuclei. Basal ganglia neurons respond not only to the stimulation of the corresponding regions of the motor cortices, but also to active and passive movements of the corresponding body parts. On the basis of these anatomical and physiological findings, somatotopic organization can be identified in the motor territories of these nuclei in the basal ganglia. In addition, projections from functionally interrelated cortical areas partially converge through the cortico-basal ganglia loop, but nevertheless the somatotopy is still preserved. Disorganized somatotopy may explain, at least in part, the pathophysiology of movement disorders, such as Parkinson's disease and dystonia. PMID- 21541305 TI - Emergence of physiological oscillation frequencies in a computer model of neocortex. AB - Coordination of neocortical oscillations has been hypothesized to underlie the "binding" essential to cognitive function. However, the mechanisms that generate neocortical oscillations in physiological frequency bands remain unknown. We hypothesized that interlaminar relations in neocortex would provide multiple intermediate loops that would play particular roles in generating oscillations, adding different dynamics to the network. We simulated networks from sensory neocortex using nine columns of event-driven rule-based neurons wired according to anatomical data and driven with random white-noise synaptic inputs. We tuned the network to achieve realistic cell firing rates and to avoid population spikes. A physiological frequency spectrum appeared as an emergent property, displaying dominant frequencies that were not present in the inputs or in the intrinsic or activated frequencies of any of the cell groups. We monitored spectral changes while using minimal dynamical perturbation as a methodology through gradual introduction of hubs into individual layers. We found that hubs in layer 2/3 excitatory cells had the greatest influence on overall network activity, suggesting that this subpopulation was a primary generator of theta/beta strength in the network. Similarly, layer 2/3 interneurons appeared largely responsible for gamma activation through preferential attenuation of the rest of the spectrum. The network showed evidence of frequency homeostasis: increased activation of supragranular layers increased firing rates in the network without altering the spectral profile, and alteration in synaptic delays did not significantly shift spectral peaks. Direct comparison of the power spectra with experimentally recorded local field potentials from prefrontal cortex of awake rat showed substantial similarities, including comparable patterns of cross-frequency coupling. PMID- 21541306 TI - Narcolepsy and orexins: an example of progress in sleep research. AB - Narcolepsy is a chronic neurodegenerative disease caused by a deficiency of orexin-producing neurons in the lateral hypothalamus. It is clinically characterized by excessive daytime sleepiness and by intrusions into wakefulness of physiological aspects of rapid eye movement sleep such as cataplexy, sleep paralysis, and hypnagogic hallucinations. The major pathophysiology of narcolepsy has been recently described on the bases of the discovery of the neuropeptides named orexins (hypocretins) in 1998; considerable evidence, summarized below, demonstrates that narcolepsy is the result of alterations in the genes involved in the pathology of the orexin ligand or its receptor. Deficient orexin transmission is sufficient to produce narcolepsy, as we describe here, animal models with dysregulated orexin signaling exhibit a narcolepsy-like phenotype. Remarkably, these narcoleptic models have different alterations of the orexinergic circuit, this diversity provide us with the means for making comparison, and have a better understanding of orexin-cell physiology. It is of particular interest that the most remarkable findings regarding this sleep disorder were fortuitous and due to keen observations. Sleep is a highly intricate and regulated state, and narcolepsy is a disorder that still remains as one of the unsolved mysteries in science. Nevertheless, advances and development of technology in neuroscience will provide us with the necessary tools to unravel the narcolepsy puzzle in the near future. Through an evaluation of the scientific literature we traced an updated picture of narcolepsy and orexins in order to provide insight into the means by which neurobiological knowledge is constructed. PMID- 21541307 TI - Towards intelligent environments: an augmented reality-brain-machine interface operated with a see-through head-mount display. AB - The brain-machine interface (BMI) or brain-computer interface is a new interface technology that uses neurophysiological signals from the brain to control external machines or computers. This technology is expected to support daily activities, especially for persons with disabilities. To expand the range of activities enabled by this type of interface, here, we added augmented reality (AR) to a P300-based BMI. In this new system, we used a see-through head-mount display (HMD) to create control panels with flicker visual stimuli to support the user in areas close to controllable devices. When the attached camera detects an AR marker, the position and orientation of the marker are calculated, and the control panel for the pre-assigned appliance is created by the AR system and superimposed on the HMD. The participants were required to control system compatible devices, and they successfully operated them without significant training. Online performance with the HMD was not different from that using an LCD monitor. Posterior and lateral (right or left) channel selections contributed to operation of the AR-BMI with both the HMD and LCD monitor. Our results indicate that AR-BMI systems operated with a see-through HMD may be useful in building advanced intelligent environments. PMID- 21541309 TI - Temperature tolerance and stress proteins as mechanisms of invasive species success. AB - Invasive species are predicted to be more successful than natives as temperatures increase with climate change. However, few studies have examined the physiological mechanisms that theoretically underlie this differential success. Because correlative evidence suggests that invasiveness is related to the width of a species' latitudinal range, it has been assumed--but largely untested--that range width predicts breadth of habitat temperatures and physiological thermotolerances. In this study, we use empirical data from a marine community as a case study to address the hypotheses that (1) geographic temperature range attributes are related to temperature tolerance, leading to greater eurythermality in invasive species, and (2) stress protein expression is a subcellular mechanism that could contribute to differences in thermotolerance. We examined three native and six invasive species common in the subtidal epibenthic communities of California, USA. We assessed thermotolerance by exposing individuals to temperatures between 14 degrees C and 31 degrees C and determining the temperature lethal to 50% of individuals (LT(50)) after a 24 hour exposure. We found a strong positive relationship between the LT(50) and both maximum habitat temperatures and the breadth of temperatures experience across the species' ranges. In addition, of the species in our study, invasives tended to inhabit broader habitat temperature ranges and higher maximum temperatures. Stress protein expression may contribute to these differences: the more thermotolerant, invasive species Diplosoma listerianum expressed higher levels of a 70-kDa heat-shock protein than the less thermotolerant, native Distaplia occidentalis for which levels declined sharply above the LT(50). Our data highlight differences between native and invasive species with respect to organismal and cellular temperature tolerances. Future studies should address, across a broader phylogenetic and ecosystem scope, whether this physiological mechanism has facilitated the current success of invasive species and could lead to greater success of invasives than native species as global warming continues. PMID- 21541308 TI - Decision salience signals in posterior cingulate cortex. AB - Despite its phylogenetic antiquity and clinical importance, the posterior cingulate cortex (CGp) remains an enigmatic nexus of attention, memory, motivation, and decision making. Here we show that CGp neurons track decision salience - the degree to which an option differs from a standard - but not the subjective value of a decision. To do this, we recorded the spiking activity of CGp neurons in monkeys choosing between options varying in reward-related risk, delay to reward, and social outcomes, each of which varied in level of decision salience. Firing rates were higher when monkeys chose the risky option, consistent with their risk-seeking preferences, but were also higher when monkeys chose the delayed and social options, contradicting their preferences. Thus, across decision contexts, neuronal activity was uncorrelated with how much monkeys valued a given option, as inferred from choice. Instead, neuronal activity signaled the deviation of the chosen option from the standard, independently of how it differed. The observed decision salience signals suggest a role for CGp in the flexible allocation of neural resources to motivationally significant information, akin to the role of attention in selective processing of sensory inputs. PMID- 21541310 TI - Homologous recombination is stimulated by a decrease in dUTPase in Arabidopsis. AB - Deoxyuridine triphosphatase (dUTPase) enzyme is an essential enzyme that protects DNA against uracil incorporation. No organism can tolerate the absence of this activity. In this article, we show that dUTPase function is conserved between E. coli (Escherichia coli), yeast (Saccharomyces cerevisiae) and Arabidopsis (Arabidopsis thaliana) and that it is essential in Arabidopsis as in both micro organisms. Using a RNA interference strategy, plant lines were generated with a diminished dUTPase activity as compared to the wild-type. These plants are sensitive to 5-fluoro-uracil. As an indication of DNA damage, inactivation of dUTPase results in the induction of AtRAD51 and AtPARP2, which are involved in DNA repair. Nevertheless, RNAi/DUT1 constructs are compatible with a rad51 mutation. Using a TUNEL assay, DNA damage was observed in the RNAi/DUT1 plants. Finally, plants carrying a homologous recombination (HR) exclusive substrate transformed with the RNAi/DUT1 construct exhibit a seven times increase in homologous recombination events. Increased HR was only detected in the plants that were the most sensitive to 5-fluoro-uracils, thus establishing a link between uracil incorporation in the genomic DNA and HR. Our results show for the first time that genetic instability provoked by the presence of uracils in the DNA is poorly tolerated and that this base misincorporation globally stimulates HR in plants. PMID- 21541311 TI - Potential associations between severity of infection and the presence of virulence-associated genes in clinical strains of Staphylococcus aureus. AB - BACKGROUND: The clinical spectrum of Staphylococcus aureus infection ranges from asymptomatic nasal carriage to osteomyelitis, infective endocarditis (IE) and death. In this study, we evaluate potential association between the presence of specific genes in a collection of prospectively characterized S. aureus clinical isolates and clinical outcome. METHODOLOGY/PRINCIPAL FINDINGS: Two hundred thirty nine S. aureus isolates (121 methicillin-resistant S. aureus [MRSA] and 118 methicillin-susceptible S. aureus [MSSA]) were screened by array comparative genomic hybridization (aCGH) to identify genes implicated in complicated infections. After adjustment for multiple tests, 226 genes were significantly associated with severity of infection. Of these 226 genes, 185 were not in the SCCmec element. Within the 185 non-SCCmec genes, 171 were less common and 14 more common in the complicated infection group. Among the 41 genes in the SCCmec element, 37 were more common and 4 were less common in the complicated group. A total of 51 of the 2014 sequences evaluated, 14 non-SCCmec and 37 SCCmec, were identified as genes of interest. CONCLUSIONS/SIGNIFICANCE: Of the 171 genes less common in complicated infections, 152 are of unknown function and may contribute to attenuation of virulence. The 14 non-SCCmec genes more common in complicated infections include bacteriophage-encoded genes such as regulatory factors and autolysins with potential roles in tissue adhesion or biofilm formation. PMID- 21541312 TI - Virulence evolution of the human pathogen Neisseria meningitidis by recombination in the core and accessory genome. AB - BACKGROUND: Neisseria meningitidis is a naturally transformable, facultative pathogen colonizing the human nasopharynx. Here, we analyze on a genome-wide level the impact of recombination on gene-complement diversity and virulence evolution in N. meningitidis. We combined comparative genome hybridization using microarrays (mCGH) and multilocus sequence typing (MLST) of 29 meningococcal isolates with computational comparison of a subset of seven meningococcal genome sequences. PRINCIPAL FINDINGS: We found that lateral gene transfer of minimal mobile elements as well as prophages are major forces shaping meningococcal population structure. Extensive gene content comparison revealed novel associations of virulence with genetic elements besides the recently discovered meningococcal disease associated (MDA) island. In particular, we identified an association of virulence with a recently described canonical genomic island termed IHT-E and a differential distribution of genes encoding RTX toxin- and two partner secretion systems among hyperinvasive and non-hyperinvasive lineages. By computationally screening also the core genome for signs of recombination, we provided evidence that about 40% of the meningococcal core genes are affected by recombination primarily within metabolic genes as well as genes involved in DNA replication and repair. By comparison with the results of previous mCGH studies, our data indicated that genetic structuring as revealed by mCGH is stable over time and highly similar for isolates from different geographic origins. CONCLUSIONS: Recombination comprising lateral transfer of entire genes as well as homologous intragenic recombination has a profound impact on meningococcal population structure and genome composition. Our data support the hypothesis that meningococcal virulence is polygenic in nature and that differences in metabolism might contribute to virulence. PMID- 21541313 TI - Waist circumference as compared with body-mass index in predicting mortality from specific causes. AB - BACKGROUND: Whether waist circumference provides clinically meaningful information not delivered by body-mass index regarding prediction of cause specific death is uncertain. METHODS: We prospectively examined waist circumference (WC) and body-mass index (BMI) in relation to cause-specific death in 225,712 U.S. women and men. Cox regression was used to estimate relative risks and 95% confidence intervals (CI). Statistical analyses were conducted using SAS version 9.1. RESULTS: During follow-up from 1996 through 2005, we documented 20,977 deaths. Increased WC consistently predicted risk of death due to any cause as well as major causes of death, including deaths from cancer, cardiovascular disease, and non-cancer/non-cardiovascular diseases, independent of BMI, age, sex, race/ethnicity, smoking status, and alcohol intake. When WC and BMI were mutually adjusted in a model, WC was related to 1.37 fold increased risk of death from any cancer and 1.82 fold increase risk of death from cardiovascular disease, comparing the highest versus lowest WC categories. Importantly, WC, but not BMI showed statistically significant positive associations with deaths from lung cancer and chronic respiratory disease. Participants in the highest versus lowest WC category had a relative risk of death from lung cancer of 1.77 (95% CI, 1.41 to 2.23) and of death from chronic respiratory disease of 2.77 (95% CI, 1.95 to 3.95). In contrast, subjects in the highest versus lowest BMI category had a relative risk of death from lung cancer of 0.94 (95% CI, 0.75 to 1.17) and of death from chronic respiratory disease of 1.18 (95% CI, 0.89 to 1.56). CONCLUSIONS: Increased abdominal fat measured by WC was related to a higher risk of deaths from major specific causes, including deaths from lung cancer and chronic respiratory disease, independent of BMI. PMID- 21541314 TI - Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3beta independent of JNK activation. AB - BACKGROUND: The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic beta-cell death. This study examines the synergistic effects of glucose and FFA on beta-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined. PRINCIPAL FINDINGS: Increasing glucose (5-25 mM) with palmitate (400 uM) had synergistic effects on apoptosis. Jun NH2 terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3beta (Gsk3beta) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3beta. CONCLUSIONS/SIGNIFICANCE: Glucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3beta activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet beta-cell Gsk3beta as a potential therapeutic target. PMID- 21541315 TI - Structural basis for dual-inhibition mechanism of a non-classical Kazal-type serine protease inhibitor from horseshoe crab in complex with subtilisin. AB - Serine proteases play a crucial role in host-pathogen interactions. In the innate immune system of invertebrates, multi-domain protease inhibitors are important for the regulation of host-pathogen interactions and antimicrobial activities. Serine protease inhibitors, 9.3-kDa CrSPI isoforms 1 and 2, have been identified from the hepatopancreas of the horseshoe crab, Carcinoscorpius rotundicauda. The CrSPIs were biochemically active, especially CrSPI-1, which potently inhibited subtilisin (Ki = 1.43 nM). CrSPI has been grouped with the non-classical Kazal type inhibitors due to its unusual cysteine distribution. Here we report the crystal structure of CrSPI-1 in complex with subtilisin at 2.6 A resolution and the results of biophysical interaction studies. The CrSPI-1 molecule has two domains arranged in an extended conformation. These two domains act as heads that independently interact with two separate subtilisin molecules, resulting in the inhibition of subtilisin activity at a ratio of 1:2 (inhibitor to protease). Each subtilisin molecule interacts with the reactive site loop from each domain of CrSPI-1 through a standard canonical binding mode and forms a single ternary complex. In addition, we propose the substrate preferences of each domain of CrSPI-1. Domain 2 is specific towards the bacterial protease subtilisin, while domain 1 is likely to interact with the host protease, Furin. Elucidation of the structure of the CrSPI-1: subtilisin (1?2) ternary complex increases our understanding of host-pathogen interactions in the innate immune system at the molecular level and provides new strategies for immunomodulation. PMID- 21541316 TI - Crystal structure of the HIV-2 neutralizing Fab fragment 7C8 with high specificity to the V3 region of gp125. AB - 7C8 is a mouse monoclonal antibody specific for the third hypervariable region (V3) of the human immunodeficiency virus type 2 (HIV-2)-associated protein gp125. The three-dimensional crystal structure of the Fab fragment of 7C8, determined to 2.7 A resolution, reveals a deep and narrow antigen-binding cleft with architecture appropriate for an elongated epitope. The highly hydrophobic cleft is bordered on one side by the negatively charged second complementarity determining region (CDR2) and the unusually long positively charged CDR3 of the heavy chain and, on the other side, by the CDR1 of the light chain. Analysis of 7C8 in complex with molecular models of monomeric and trimeric gp125 highlights the importance of a conserved stretch of residues FHSQ that is localized centrally on the V3 region of gp125. Furthermore, modeling also indicates that the Fab fragment neutralizes the virus by sterically impairing subsequent engagement of the gp125 trimer with the co-receptor on the target cell. PMID- 21541317 TI - Incongruence in doping related attitudes, beliefs and opinions in the context of discordant behavioural data: in which measure do we trust? AB - BACKGROUND: Social psychology research on doping and outcome based evaluation of primary anti-doping prevention and intervention programmes have been dominated by self-reports. Having confidence in the validity and reliability of such data is vital. METHODOLOGY/PRINCIPAL FINDINGS: The sample of 82 athletes from 30 sports (52.4% female, mean age: 21.48+/-2.86 years) was split into quasi-experimental groups based on i) self-admitted previous experience with prohibited performance enhancing drugs (PED) and ii) the presence of at least one prohibited PED in hair covering up to 6 months prior to data collection. Participants responded to questionnaires assessing a range of social cognitive determinants of doping via self-reports; and completed a modified version of the Brief Implicit Association Test (BIAT) assessing implicit attitudes to doping relative to the acceptable nutritional supplements (NS). Social projection regarding NS was used as control. PEDs were detected in hair samples from 10 athletes (12% prevalence), none of whom admitted doping use. This group of 'deniers' was characterised by a dissociation between explicit (verbal declarations) and implicit (BIAT) responding, while convergence was observed in the 'clean' athlete group. This dissociation, if replicated, may act as a cognitive marker of the denier group, with promising applications of the combined explicit-implicit cognitive protocol as a proxy in lieu of biochemical detection methods in social science research. Overall, discrepancies in the relationship between declared doping-related opinion and implicit doping attitudes were observed between the groups, with control measures remaining unaffected. Questionnaire responses showed a pattern consistent with self-reported doping use. CONCLUSIONS/SIGNIFICANCE: Following our preliminary work, this study provides further evidence that both self-reports on behaviour and social cognitive measures could be affected by some form of response bias. This can question the validity of self-reports, with reliability remaining unaffected. Triangulation of various assessment methods is recommended. PMID- 21541318 TI - Epileptiform activity in alcohol dependent patients and possibilities of its indirect measurement. AB - BACKGROUND: Alcohol dependence during withdrawal and also in abstinent period in many cases is related to reduced inhibitory functions and kindling that may appear in the form of psychosensory symptoms similar to temporal lobe epilepsy frequently in conditions of normal EEG and without seizures. Because temporal lobe epileptic activity tend to spread between hemispheres, it is possible to suppose that measures reflecting interhemispheric information transfer such as electrodermal activity (EDA) might be related to the psychosensory symptoms. METHODS AND FINDINGS: We have performed measurement of bilateral EDA, psychosensory symptoms (LSCL-33) and alcohol craving (ACQ) in 34 alcohol dependent patients and 32 healthy controls. The results in alcohol dependent patients show that during rest conditions the psychosensory symptoms (LSCL-33) are related to EDA transinformation (PTI) between left and right EDA records (Spearman r = 0.44, p<0.01). CONCLUSIONS: The result may present potentially useful clinical finding suggesting a possibility to indirectly assess epileptiform changes in alcohol dependent patients. PMID- 21541319 TI - Diet and cell size both affect queen-worker differentiation through DNA methylation in honey bees (Apis mellifera, Apidae). AB - BACKGROUND: Young larvae of the honey bee (Apis mellifera) are totipotent; they can become either queens (reproductives) or workers (largely sterile helpers). DNA methylation has been shown to play an important role in this differentiation. In this study, we examine the contributions of diet and cell size to caste differentiation. METHODOLOGY/PRINCIPAL FINDINGS: We measured the activity and gene expression of one key enzyme involved in methylation, Dnmt3; the rates of methylation in the gene dynactin p62; as well as morphological characteristics of adult bees developed either from larvae fed with worker jelly or royal jelly; and larvae raised in either queen or worker cells. We show that both diet type and cell size contributed to the queen-worker differentiation, and that the two factors affected different methylation sites inside the same gene dynactin p62. CONCLUSIONS/SIGNIFICANCE: We confirm previous findings that Dnmt3 plays a critical role in honey bee caste differentiation. Further, we show for the first time that cell size also plays a role in influencing larval development when diet is kept the same. PMID- 21541320 TI - Active suppression of early immune response in tobacco by the human pathogen Salmonella Typhimurium. AB - The persistence of enteric pathogens on plants has been studied extensively, mainly due to the potential hazard of human pathogens such as Salmonella enterica being able to invade and survive in/on plants. Factors involved in the interactions between enteric bacteria and plants have been identified and consequently it was hypothesized that plants may be vectors or alternative hosts for enteric pathogens. To survive, endophytic bacteria have to escape the plant immune systems, which function at different levels through the plant-bacteria interactions. To understand how S. enterica survives endophyticaly we conducted a detailed analysis on its ability to elicit or evade the plant immune response. The models of this study were Nicotiana tabacum plants and cells suspension exposed to S. enterica serovar Typhimurium. The plant immune response was analyzed by looking at tissue damage and by testing oxidative burst and pH changes. It was found that S. Typhimurium did not promote disease symptoms in the contaminated plants. Live S. Typhimurium did not trigger the production of an oxidative burst and pH changes by the plant cells, while heat killed or chloramphenicol treated S. Typhimurium and purified LPS of Salmonella were significant elicitors, indicating that S. Typhimurium actively suppress the plant response. By looking at the plant response to mutants defective in virulence factors we showed that the suppression depends on secreted factors. Deletion of invA reduced the ability of S. Typhimurium to suppress oxidative burst and pH changes, indicating that a functional SPI1 TTSS is required for the suppression. This study demonstrates that plant colonization by S. Typhimurium is indeed an active process. S. Typhimurium utilizes adaptive strategies of altering innate plant perception systems to improve its fitness in the plant habitat. All together these results suggest a complex mechanism for perception of S. Typhimurium by plants. PMID- 21541321 TI - Collective irrationality and positive feedback. AB - Recent experiments on ants and slime moulds have assessed the degree to which they make rational decisions when presented with a number of alternative food sources or shelter. Ants and slime moulds are just two examples of a wide range of species and biological processes that use positive feedback mechanisms to reach decisions. Here we use a generic, experimentally validated model of positive feedback between group members to show that the probability of taking the best of options depends crucially on the strength of feedback. We show how the probability of choosing the best option can be maximized by applying an optimal feedback strength. Importantly, this optimal value depends on the number of options, so that when we change the number of options the preference of the group changes, producing apparent "irrationalities". We thus reinterpret the idea that collectives show "rational" or "irrational" preferences as being a necessary consequence of the use of positive feedback. We argue that positive feedback is a heuristic which often produces fast and accurate group decision-making, but is always susceptible to apparent irrationality when studied under particular experimental conditions. PMID- 21541322 TI - ANS: aberrant neurodevelopment of the social cognition network in adolescents with autism spectrum disorders. AB - BACKGROUND: Autism spectrum disorders (ASD) are characterized by aberrant neurodevelopment. Although the ASD brain undergoes precocious growth followed by decelerated maturation during early postnatal period of childhood, the neuroimaging approach has not been empirically applied to investigate how the ASD brain develops during adolescence. METHODOLOGY/PRINCIPAL FINDINGS: We enrolled 25 male adolescents with high functioning ASD and 25 typically developing controls for voxel-based morphometric analysis of structural magnetic resonance image. Results indicate that there is an imbalance of regional gray matter volumes and concentrations along with no global brain enlargement in adolescents with high functioning ASD relative to controls. Notably, the right inferior parietal lobule, a role in social cognition, have a significant interaction of age by groups as indicated by absence of an age-related gain of regional gray matter volume and concentration for neurodevelopmental maturation during adolescence. CONCLUSIONS/SIGNIFICANCE: The findings indicate the neural correlates of social cognition exhibits aberrant neurodevelopment during adolescence in ASD, which may cast some light on the brain growth dysregulation hypothesis. The period of abnormal brain growth during adolescence may be characteristic of ASD. Age effects must be taken into account while measures of structural neuroimaging have been clinically put forward as potential phenotypes for ASD. PMID- 21541323 TI - High-throughput protein expression using a combination of ligation-independent cloning (LIC) and infrared fluorescent protein (IFP) detection. AB - Protein expression in heterologous hosts for functional studies is a cumbersome effort. Here, we report a superior platform for parallel protein expression in vivo and in vitro. The platform combines highly efficient ligation-independent cloning (LIC) with instantaneous detection of expressed proteins through N- or C terminal fusions to infrared fluorescent protein (IFP). For each open reading frame, only two PCR fragments are generated (with three PCR primers) and inserted by LIC into ten expression vectors suitable for protein expression in microbial hosts, including Escherichia coli, Kluyveromyces lactis, Pichia pastoris, the protozoon Leishmania tarentolae, and an in vitro transcription/translation system. Accumulation of IFP-fusion proteins is detected by infrared imaging of living cells or crude protein extracts directly after SDS-PAGE without additional processing. We successfully employed the LIC-IFP platform for in vivo and in vitro expression of ten plant and fungal proteins, including transcription factors and enzymes. Using the IFP reporter, we additionally established facile methods for the visualisation of protein-protein interactions and the detection of DNA-transcription factor interactions in microtiter and gel-free format. We conclude that IFP represents an excellent reporter for high-throughput protein expression and analysis, which can be easily extended to numerous other expression hosts using the setup reported here. PMID- 21541324 TI - Highly tissue specific expression of Sphinx supports its male courtship related role in Drosophila melanogaster. AB - Sphinx is a lineage-specific non-coding RNA gene involved in regulating courtship behavior in Drosophila melanogaster. The 5' flanking region of the gene is conserved across Drosophila species, with the proximal 300 bp being conserved out to D. virilis and a further 600 bp region being conserved amongst the melanogaster subgroup (D. melanogaster, D. simulans, D. sechellia, D. yakuba, and D. erecta). Using a green fluorescence protein transformation system, we demonstrated that a 253 bp region of the highly conserved segment was sufficient to drive sphinx expression in male accessory gland. GFP signals were also observed in brain, wing hairs and leg bristles. An additional ~800 bp upstream region was able to enhance expression specifically in proboscis, suggesting the existence of enhancer elements. Using anti-GFP staining, we identified putative sphinx expression signal in the brain antennal lobe and inner antennocerebral tract, suggesting that sphinx might be involved in olfactory neuron mediated regulation of male courtship behavior. Whole genome expression profiling of the sphinx knockout mutation identified significant up-regulated gene categories related to accessory gland protein function and odor perception, suggesting sphinx might be a negative regulator of its target genes. PMID- 21541325 TI - A requirement of TolC and MDR efflux pumps for acid adaptation and GadAB induction in Escherichia coli. AB - BACKGROUND: The TolC outer membrane channel is a key component of several multidrug resistance (MDR) efflux pumps driven by H(+) transport in Escherichia coli. While tolC expression is under the regulation of the EvgA-Gad acid resistance regulon, the role of TolC in growth at low pH and extreme-acid survival is unknown. METHODS AND PRINCIPAL FINDINGS: TolC was required for extreme-acid survival (pH 2) of strain W3110 grown aerobically to stationary phase. A tolC deletion decreased extreme-acid survival (acid resistance) of aerated pH 7.0-grown cells by 10(5)-fold and of pH 5.5-grown cells by 10-fold. The requirement was specific for acid resistance since a tolC defect had no effect on aerobic survival in extreme base (pH 10). TolC was required for expression of glutamate decarboxylase (GadA, GadB), a key component of glutamate dependent acid resistance (Gad). TolC was also required for maximal exponential growth of E. coli K-12 W3110, in LBK medium buffered at pH 4.5-6.0, but not at pH 6.5-8.5. The TolC growth requirement in moderate acid was independent of Gad. TolC-associated pump components EmrB and MdtB contributed to survival in extreme acid (pH 2), but were not required for growth at pH 5. A mutant lacking the known TolC-associated efflux pumps (acrB, acrD, emrB, emrY, macB, mdtC, mdtF, acrEF) showed no growth defect at acidic pH and a relatively small decrease in extreme acid survival when pre-grown at pH 5.5. CONCLUSIONS: TolC and proton-driven MDR efflux pump components EmrB and MdtB contribute to E. coli survival in extreme acid and TolC is required for maximal growth rates below pH 6.5. The TolC enhancement of extreme-acid survival includes Gad induction, but TolC-dependent growth rates below pH 6.5 do not involve Gad. That MDR resistance can enhance growth and survival in acid is an important consideration for enteric organisms passing through the acidic stomach. PMID- 21541326 TI - A recombinant influenza A virus expressing domain III of West Nile virus induces protective immune responses against influenza and West Nile virus. AB - West Nile virus (WNV) continues to circulate in the USA and forms a threat to the rest of the Western hemisphere. Since methods for the treatment of WNV infections are not available, there is a need for the development of safe and effective vaccines. Here, we describe the construction of a recombinant influenza virus expressing domain III of the WNV glycoprotein E (Flu-NA-DIII) and its evaluation as a WNV vaccine candidate in a mouse model. FLU-NA-DIII-vaccinated mice were protected from severe body weight loss and mortality caused by WNV infection, whereas control mice succumbed to the infection. In addition, it was shown that one subcutaneous immunization with 10(5) TCID(50) Flu-NA-DIII provided 100% protection against challenge. Adoptive transfer experiments demonstrated that protection was mediated by antibodies and CD4+T cells. Furthermore, mice vaccinated with FLU-NA-DIII developed protective influenza virus-specific antibody titers. It was concluded that this vector system might be an attractive platform for the development of bivalent WNV-influenza vaccines. PMID- 21541327 TI - Alpha-tomatine induces apoptosis and inhibits nuclear factor-kappa B activation on human prostatic adenocarcinoma PC-3 cells. AB - BACKGROUND: Alpha-tomatine (alpha-tomatine) is the major saponin in tomato (Lycopersicon esculentum). This study investigates the chemopreventive potential of alpha-tomatine on androgen-independent human prostatic adenocarcinoma PC-3 cells. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of highly aggressive human prostate cancer PC-3 cells with alpha-tomatine resulted in a concentration dependent inhibition of cell growth with a half-maximal efficient concentration (EC(50)) value of 1.67+/-0.3 uM. It is also less cytotoxic to normal human liver WRL-68 cells and normal human prostate RWPE-1 cells. Assessment of real-time growth kinetics by cell impedance-based Real-Time Cell Analyzer (RTCA) showed that alpha-tomatine exhibited its cytotoxic effects against PC-3 cells as early as an hour after treatment. The inhibitory effect of alpha-tomatine on PC-3 cancer cell growth was mainly due to induction of apoptosis as evidenced by positive Annexin V staining and decreased in mitochondrial membrane potential but increased in nuclear condensation, polarization of F-actin, cell membrane permeability and cytochrome c expressions. Results also showed that alpha tomatine induced activation of caspase-3, -8 and -9, suggesting that both intrinsic and extrinsic apoptosis pathways are involved. Furthermore, nuclear factor-kappa B (NF-kappaB) nuclear translocation was inhibited, which in turn resulted in significant decreased in NF-kappaB/p50 and NF-kappaB/p65 in the nuclear fraction of the treated cells compared to the control untreated cells. These results provide further insights into the molecular mechanism of the anti proliferative actions of alpha-tomatine. CONCLUSION/SIGNIFICANCE: alpha-tomatine induces apoptosis and inhibits NF-kappaB activation on prostate cancer cells. These results suggest that alpha-tomatine may be beneficial for protection against prostate cancer development and progression. PMID- 21541329 TI - Continuous activation of the CD122/STAT-5 signaling pathway during selection of antigen-specific regulatory T cells in the murine thymus. AB - Signaling events affecting thymic selection of un-manipulated polyclonal natural CD25(+)foxp3(+) regulatory T cells (nTreg) have not been established ex vivo. Here, we report a higher frequency of phosphorylated STAT-5 (pSTAT-5) in nTreg cells in the adult murine thymus and to a lesser extent in the periphery, compared to other CD4(+)CD8(-) subsets. In the neonatal thymus, the numbers of pSTAT-5(+) cells in CD25(+)foxp3(-) and nTreg cells increased in parallel, suggesting that pSTAT-5(+)CD25(+)foxp3(-) cells might represent the precursors of foxp3(+) regulatory T cells. This "specific" pSTAT-5 expression detected in nTreg cells ex vivo was likely due to a very recent signal given by IL-2/IL-15 cytokines in vivo since (i) it disappeared rapidly if cells were left unstimulated in vitro and (ii) was also observed if total thymocytes were stimulated in vitro with saturating amounts of IL-2 and/or IL-15 but not IL-7. Interestingly, STAT-5 activation upon IL-2 stimulation correlated better with foxp3 and CD122 than with CD25 expression. Finally, we show that expression of an endogenous superantigen strongly affected the early Treg cell repertoire but not the proportion of pSTAT-5(+) cells within this repertoire. Our results reveal that continuous activation of the CD122/STAT-5 signaling pathway characterize regulatory lineage differentiation in the murine thymus. PMID- 21541328 TI - Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats. AB - BACKGROUND: Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation. METHODS/PRINCIPAL FINDINGS: Proof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl) N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6 dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic "sugar" cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic "sugar" cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress. CONCLUSIONS/SIGNIFICANCE: Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed. PMID- 21541330 TI - Identification and localization of proteins associated with biomineralization in the iron deposition vesicles of honeybees (Apis mellifera). AB - Honeybees (Apis mellifera) form superparamagnetic magnetite to act as a magnetoreceptor for magnetoreception. Biomineralization of superparamagnetic magnetite occurs in the iron deposition vesicles of trophocytes. Even though magnetite has been demonstrated, the mechanism of magnetite biomineralization is unknown. In this study, proteins in the iron granules and iron deposition vesicles of trophocytes were purified and identified by mass spectrometry. Antibodies against such proteins were produced. The major proteins include actin, myosin, ferritin 2, and ATP synthase. Immunolabeling and co-immunoprecipitation studies suggest that iron is stored in ferritin 2 for the purpose of forming 7.5 nm diameter iron particles and that actin-myosin-ferritin 2 may serve as a transporter system. This system, along with calcium and ATP, conveys the iron particles (ferritin) to the center of iron deposition vesicles for iron granules formation. These proteins and reactants are included in iron deposition vesicles during the formation of iron deposition vesicles from the fusion of smooth endoplasmic reticulum. A hypothetical model for magnetite biomineralization in iron deposition vesicles is proposed for honeybees. PMID- 21541331 TI - Upregulation of MiR-155 in nasopharyngeal carcinoma is partly driven by LMP1 and LMP2A and downregulates a negative prognostic marker JMJD1A. AB - The role of microRNA-155 (miR-155) has been associated with oncogenesis of several human tumors. However the expression pattern of miR-155 has not been investigated in nasopharyngeal carcinoma (NPC). The present study was to assess miR-155 expression pattern and its possible function in NPC, to identify its targets and evaluate their clinical applications in NPC. MiR-155 was found to be upregulated in two Epstein-Barr virus (EBV) negative NPC derived cell lines CNE1 and TW03, as well as in NPC clinical samples by quantitative Real-time PCR and in situ hybridization detection. EBV encoded LMP1 and LMP2A could further enhance the expression of miR-155 in NPC CNE1 and TW03 cells. JMJD1A and BACH1 were identified as putative targets of miR-155 in a bioinformatics screen. Overexpression of miR-155 downregulated a luciferase transcript fused to the 3'UTR of JMJD1A and BACH1. MiR-155 mimic could downregulate the expression of JMJD1A and BACH1, while miR-155 inhibitor could upregulate JMJD1A expression in NPC cell lines. Moreover, downregulation of JMJD1A was significantly correlated with N stage in TNM classification (p = 0.023), a lower five-year survival rate (p = 0.021), and a lower five-year disease-free survival rate (p = 0.049) of NPC patients. Taken together, up-regulation of miR-155 in NPC is partly driven by LMP1 and LMP2A, and results in downregulation of JMJD1A, which is associated with N stage and poor prognosis of NPC patients. The potential of miR-155 and JMJD1A as therapeutic targets in NPC should be further investigated. PMID- 21541332 TI - Genome evolution of a tertiary dinoflagellate plastid. AB - The dinoflagellates have repeatedly replaced their ancestral peridinin-plastid by plastids derived from a variety of algal lineages ranging from green algae to diatoms. Here, we have characterized the genome of a dinoflagellate plastid of tertiary origin in order to understand the evolutionary processes that have shaped the organelle since it was acquired as a symbiont cell. To address this, the genome of the haptophyte-derived plastid in Karlodinium veneficum was analyzed by Sanger sequencing of library clones and 454 pyrosequencing of plastid enriched DNA fractions. The sequences were assembled into a single contig of 143 kb, encoding 70 proteins, 3 rRNAs and a nearly full set of tRNAs. Comparative genomics revealed massive rearrangements and gene losses compared to the haptophyte plastid; only a small fraction of the gene clusters usually found in haptophytes as well as other types of plastids are present in K. veneficum. Despite the reduced number of genes, the K. veneficum plastid genome has retained a large size due to expanded intergenic regions. Some of the plastid genes are highly diverged and may be pseudogenes or subject to RNA editing. Gene losses and rearrangements are also features of the genomes of the peridinin-containing plastids, apicomplexa and Chromera, suggesting that the evolutionary processes that once shaped these plastids have occurred at multiple independent occasions over the history of the Alveolata. PMID- 21541333 TI - ALMS1-deficient fibroblasts over-express extra-cellular matrix components, display cell cycle delay and are resistant to apoptosis. AB - Alstrom Syndrome (ALMS) is a rare genetic disorder (483 living cases), characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM) and fibrosis, cellular architecture/motility and apoptosis). ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra- and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions. PMID- 21541334 TI - Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro. AB - The success of Imatinib (IM) therapy in chronic myeloid leukemia (CML) is compromised by the development of IM resistance and by a limited IM effect on hematopoietic stem cells. Danusertib (formerly PHA-739358) is a potent pan-aurora and ABL kinase inhibitor with activity against known BCR-ABL mutations, including T315I. Here, the individual contribution of both signaling pathways to the therapeutic effect of Danusertib as well as mechanisms underlying the development of resistance and, as a consequence, strategies to overcome resistance to Danusertib were investigated. Starting at low concentrations, a dose-dependent inhibition of BCR-ABL activity was observed, whereas inhibition of aurora kinase activity required higher concentrations, pointing to a therapeutic window between the two effects. Interestingly, the emergence of resistant clones during Danusertib exposure in vitro occurred considerably less frequently than with comparable concentrations of IM. In addition, Danusertib-resistant clones had no mutations in BCR-ABL or aurora kinase domains and remained IM-sensitive. Overexpression of Abcg2 efflux transporter was identified and functionally validated as the predominant mechanism of acquired Danusertib resistance in vitro. Finally, the combined treatment with IM and Danusertib significantly reduced the emergence of drug resistance in vitro, raising hope that this drug combination may also achieve more durable disease control in vivo. PMID- 21541335 TI - hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure. AB - After severe myocardial infarction (MI), heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-induced chronic heart failure, this therapy could be further improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression profiles by use of microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for 4 weeks. Thereafter, we administered L6-WT (n = 15) or L6 HGF (n = 16) myoblast sheet therapy. Control rats (n = 13) underwent LAD ligation and rethoracotomy without therapy, and five rats underwent a sham operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy, and analyzed cardiac angiogenesis and left ventricular architecture from histological sections at 4 weeks. Paracrine mediators from L6 HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF expression. PMID- 21541336 TI - Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. AB - The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD:NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I-IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor. PMID- 21541337 TI - Genes influencing circadian differences in blood pressure in hypertensive mice. AB - Essential hypertension is a common multifactorial heritable condition in which increased sympathetic outflow from the central nervous system is involved in the elevation in blood pressure (BP), as well as the exaggerated morning surge in BP that is a risk factor for myocardial infarction and stroke in hypertensive patients. The Schlager BPH/2J mouse is a genetic model of hypertension in which increased sympathetic outflow from the hypothalamus has an important etiological role in the elevation of BP. Schlager hypertensive mice exhibit a large variation in BP between the active and inactive periods of the day, and also show a morning surge in BP. To investigate the genes responsible for the circadian variation in BP in hypertension, hypothalamic tissue was collected from BPH/2J and normotensive BPN/3J mice at the 'peak' (n = 12) and 'trough' (n = 6) of diurnal BP. Using Affymetrix GeneChip(r) Mouse Gene 1.0 ST Arrays, validation by quantitative real-time PCR and a statistical method that adjusted for clock genes, we identified 212 hypothalamic genes whose expression differed between 'peak' and 'trough' BP in the hypertensive strain. These included genes with known roles in BP regulation, such as vasopressin, oxytocin and thyrotropin releasing hormone, as well as genes not recognized previously as regulators of BP, including chemokine (C-C motif) ligand 19, hypocretin and zinc finger and BTB domain containing 16. Gene ontology analysis showed an enrichment of terms for inflammatory response, mitochondrial proton-transporting ATP synthase complex, structural constituent of ribosome, amongst others. In conclusion, we have identified genes whose expression differs between the peak and trough of 24-hour circadian BP in BPH/2J mice, pointing to mechanisms responsible for diurnal variation in BP. The findings may assist in the elucidation of the mechanism for the morning surge in BP in essential hypertension. PMID- 21541338 TI - Proteomic analyses of nucleoid-associated proteins in Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus. AB - BACKGROUND: The bacterial nucleoid contains several hundred kinds of nucleoid associated proteins (NAPs), which play critical roles in genome functions such as transcription and replication. Several NAPs, such as Hu and H-NS in Escherichia coli, have so far been identified. METHODOLOGY/PRINCIPAL FINDINGS: Log- and stationary-phase cells of E. coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus were lysed in spermidine solutions. Nucleoids were collected by sucrose gradient centrifugation, and their protein constituents analyzed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Over 200 proteins were identified in each species. Envelope and soluble protein fractions were also identified. By using these data sets, we obtained lists of contaminant-subtracted proteins enriched in the nucleoid fractions (csNAP lists). The lists do not cover all of the NAPs, but included Hu regardless of the growth phases and species. In addition, the csNAP lists of each species suggested that the bacterial nucleoid is equipped with the species-specific set of global regulators, oxidation-reduction enzymes, and fatty acid synthases. This implies bacteria individually developed nucleoid associated proteins toward obtaining similar characteristics. CONCLUSIONS/SIGNIFICANCE: Ours is the first study to reveal hundreds of NAPs in the bacterial nucleoid, and the obtained data set enabled us to overview some important features of the nucleoid. Several implications obtained from the present proteomic study may make it a landmark for the future functional and evolutionary study of the bacterial nucleoid. PMID- 21541339 TI - alpha-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson's disease patients. AB - BACKGROUND: Auto-antibodies with specificity to self-antigens have been implicated in a wide variety of neurological diseases, including Parkinson's (PD) and Alzheimer's diseases, being sensitive indicators of neurodegeneration and focus for disease prevention. Of particular interest are the studies focused on the auto-immune responses to amyloidogenic proteins associated with diseases and their applications in therapeutic treatments such as vaccination with amyloid antigens and antibodies in PD, Alzheimer's disease and potentially other neurodegeneration ailments. METHODOLOGY/PRINCIPAL FINDINGS: Generated auto antibodies towards the major amyloidogenic protein involved in PD Lewy bodies- alpha-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance. We found significantly higher antibody levels towards monomeric alpha-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression (P<0.0001). This indicates potential protective role of autoimmunity in maintaining the body homeostasis and clearing protein species whose disbalance may lead to amyloid assembly. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards alpha-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression (P<0.0001). Pooled IgGs from PD patients and controls interacted also with the amyloid fibrils of Abeta (1-40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to the generic amyloid conformational epitope, displaying higher specificity towards human amyloid species associated with neurodegeneration. CONCLUSIONS/SIGNIFICANCE: Our findings may suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein--alpha-synuclein can be of value in the development of treatment and diagnostic strategies, especially during the early disease stages. PMID- 21541340 TI - A suspected parasite spill-back of two novel Myxidium spp. (Myxosporea) causing disease in Australian endemic frogs found in the invasive Cane toad. AB - Infectious diseases are contributing to the decline of endangered amphibians. We identified myxosporean parasites, Myxidium spp. (Myxosporea: Myxozoa), in the brain and liver of declining native frogs, the Green and Golden Bell frog (Litoria aurea) and the Southern Bell frog (Litoria raniformis). We unequivocally identified two Myxidium spp. (both generalist) affecting Australian native frogs and the invasive Cane toad (Bufo marinus, syn. Rhinella marina) and demonstrated their association with disease. Our study tested the identity of Myxidium spp. within native frogs and the invasive Cane toad (brought to Australia in 1935, via Hawaii) to resolve the question whether the Cane toad introduced them to Australia. We showed that the Australian brain and liver Myxidium spp. differed 9%, 7%, 34% and 37% at the small subunit rDNA, large subunit rDNA, internal transcribed spacers 1 and 2, but were distinct from Myxidium cf. immersum from Cane toads in Brazil. Plotting minimum within-group distance against maximum intra-group distance confirmed their independent evolutionary trajectory. Transmission electron microscopy revealed that the brain stages localize inside axons. Myxospores were morphologically indistinguishable, therefore genetic characterisation was necessary to recognise these cryptic species. It is unlikely that the Cane toad brought the myxosporean parasites to Australia, because the parasites were not found in 261 Hawaiian Cane toads. Instead, these data support the enemy-release hypothesis predicting that not all parasites are translocated with their hosts and suggest that the Cane toad may have played an important spill-back role in their emergence and facilitated their dissemination. This work emphasizes the importance of accurate species identification of pathogens relevant to wildlife management and disease control. In our case it is paving the road for the spill-back role of the Cane toad and the parasite emergence. PMID- 21541341 TI - Virtual mutagenesis of the yeast cyclins genetic network reveals complex dynamics of transcriptional control networks. AB - Study of genetic networks has moved from qualitative description of interactions between regulators and regulated genes to the analysis of the interaction dynamics. This paper focuses on the analysis of dynamics of one particular network--the yeast cyclins network. Using a dedicated mathematical model of gene expression and a procedure for computation of the parameters of the model from experimental data, a complete numerical model of the dynamics of the cyclins genetic network was attained. The model allowed for performing virtual experiments on the network and observing their influence on the expression dynamics of the genes downstream in the regulatory cascade. Results show that when the network structure is more complicated, and the regulatory interactions are indirect, results of gene deletion are highly unpredictable. As a consequence of quantitative behavior of the genes and their connections within the network, causal relationship between a regulator and target gene may not be discovered by gene deletion. Without including the dynamics of the system into the network, its functional properties cannot be studied and interpreted correctly. PMID- 21541342 TI - Blockade of persistent sodium currents contributes to the riluzole-induced inhibition of spontaneous activity and oscillations in injured DRG neurons. AB - In addition to a fast activating and immediately inactivating inward sodium current, many types of excitable cells possess a noninactivating or slowly inactivating component: the persistent sodium current (I(NaP)). The I(NaP) is found in normal primary sensory neurons where it is mediated by tetrodotoxin sensitive sodium channels. The dorsal root ganglion (DRG) is the gateway for ectopic impulses that originate in pathological pain signals from the periphery. However, the role of I(NaP) in DRG neurons remains unclear, particularly in neuropathic pain states. Using in vivo recordings from single medium- and large diameter fibers isolated from the compressed DRG in Sprague-Dawley rats, we show that local application of riluzole, which blocks the I(NaP), also inhibits the spontaneous activity of A-type DRG neurons in a dose-dependent manner. Significantly, riluzole also abolished subthreshold membrane potential oscillations (SMPOs), although DRG neurons still responded to intracellular current injection with a single full-sized spike. In addition, the I(NaP) was enhanced in medium- and large-sized neurons of the compressed DRG, while bath applied riluzole significantly inhibited the I(NaP) without affecting the transient sodium current (I(NaT)). Taken together, these results demonstrate for the first time that the I(NaP) blocker riluzole selectively inhibits I(NaP) and thereby blocks SMPOs and the ectopic spontaneous activity of injured A-type DRG neurons. This suggests that the I(NaP) of DRG neurons is a potential target for treating neuropathic pain at the peripheral level. PMID- 21541343 TI - The energy computation paradox and ab initio protein folding. AB - The routine prediction of three-dimensional protein structure from sequence remains a challenge in computational biochemistry. It has been intuited that calculated energies from physics-based scoring functions are able to distinguish native from nonnative folds based on previous performance with small proteins and that conformational sampling is the fundamental bottleneck to successful folding. We demonstrate that as protein size increases, errors in the computed energies become a significant problem. We show, by using error probability density functions, that physics-based scores contain significant systematic and random errors relative to accurate reference energies. These errors propagate throughout an entire protein and distort its energy landscape to such an extent that modern scoring functions should have little chance of success in finding the free energy minima of large proteins. Nonetheless, by understanding errors in physics-based score functions, they can be reduced in a post-hoc manner, improving accuracy in energy computation and fold discrimination. PMID- 21541344 TI - The association between physical health and delusional-like experiences: a general population study. AB - OBJECTIVE: Delusional-like experiences (DLE) are prevalent in the community. Recent community based studies have found that DLE are more common in those with depression and anxiety disorders, and in those with subclinical symptoms of depression and anxiety. Chronic physical disorders are associated with comorbid depression and anxiety; however, there is a lack of evidence about the association of DLE with common physical conditions. The aim of this study was to explore associations between the common physical disorders and DLE using a large population sample. METHODS: Subjects were drawn from the Australian National Survey of Mental Health and Wellbeing 2007, a national household survey of 8841 residents aged between 16 and 85 years. The presence of DLE, selected common physical disorders and symptoms were assessed using a modified World Mental Health Composite International Diagnostic Interview (CIDI) schedule. We examined the relationship between DLE, and physical health-related variables using logistic regression, with adjustments for potential confounding factors. RESULTS: Of the 8771, 776 (8.4%) subjects positively endorsed one or more DLE. Of the six physical disorders examined, only diabetes and arthritis were significantly associated with the endorsement of DLE. Of the seven broad physical symptoms explored, only hearing problems were consistently associated with DLE. CONCLUSION: Delusional-like experiences are common in the Australian community, and are associated with selected chronic physical disorders and with impaired hearing. The direction of causality between these variables warrants closer research scrutiny. PMID- 21541346 TI - A bayesian model of sensory adaptation. AB - Recent studies reported two opposite types of adaptation in temporal perception. Here, we propose a bayesian model of sensory adaptation that exhibits both types of adaptation. We regard adaptation as the adaptive updating of estimations of time-evolving variables, which determine the mean value of the likelihood function and that of the prior distribution in a bayesian model of temporal perception. On the basis of certain assumptions, we can analytically determine the mean behavior in our model and identify the parameters that determine the type of adaptation that actually occurs. The results of our model suggest that we can control the type of adaptation by controlling the statistical properties of the stimuli presented. PMID- 21541345 TI - Evolution from XIST-independent to XIST-controlled X-chromosome inactivation: epigenetic modifications in distantly related mammals. AB - X chromosome inactivation (XCI) is the transcriptional silencing of one X in female mammals, balancing expression of X genes between females (XX) and males (XY). In placental mammals non-coding XIST RNA triggers silencing of one X (Xi) and recruits a characteristic suite of epigenetic modifications, including the histone mark H3K27me3. In marsupials, where XIST is missing, H3K27me3 association seems to have different degrees of stability, depending on cell-types and species. However, the complete suite of histone marks associated with the Xi and their stability throughout cell cycle remain a mystery, as does the evolution of an ancient mammal XCI system. Our extensive immunofluorescence analysis (using antibodies against specific histone modifications) in nuclei of mammals distantly related to human and mouse, revealed a general absence from the mammalian Xi territory of transcription machinery and histone modifications associated with active chromatin. Specific repressive modifications associated with XCI in human and mouse were also observed in elephant (a distantly related placental mammal), as was accumulation of XIST RNA. However, in two marsupial species the Xi either lacked these modifications (H4K20me1), or they were restricted to specific windows of the cell cycle (H3K27me3, H3K9me2). Surprisingly, the marsupial Xi was stably enriched for modifications associated with constitutive heterochromatin in all eukaryotes (H4K20me3, H3K9me3). We propose that marsupial XCI is comparable to a system that evolved in the common therian (marsupial and placental) ancestor. Silent chromatin of the early inactive X was exapted from neighbouring constitutive heterochromatin and, in early placental evolution, was augmented by the rise of XIST and the stable recruitment of specific histone modifications now classically associated with XCI. PMID- 21541347 TI - Cardioprotective effect of nicorandil, a mitochondrial ATP-sensitive potassium channel opener, prolongs survival in HSPB5 R120G transgenic mice. AB - BACKGROUND: Transgenic (TG) mice with overexpression of an arg120gly (R120G) missense mutation in HSPB5 display desmin-related cardiomyopathy, which is characterized by formation of aggresomes. It is also known that progressive mitochondrial abnormalities and apoptotic cell death occur in the hearts of R120G TG mice. The role of mitochondrial dysfunction and apoptosis in disease progression, however, remains uncertain. METHODS AND RESULTS: Mitochondrial abnormalities and apoptotic cell death induced by overexpression of HSPB5 R120G were analyzed in neonatal rat cardiomyocytes. Overexpression of mutant HSPB5 led to development of aggresomes with a concomitant reduction in cell viability in the myocytes. Overexpression of mutant HSPB5 induced a reduction in the cytochrome c level in the mitochondrial fraction and a corresponding increase in the cytoplasmic fraction in the myocytes. Down-regulation of BCL2 and up regulation of BAX were detected in the myocytes expressing the mutant HSPB5. Concomitant with mitochondrial abnormality, the activation of caspase-3 and increased apoptotic cell death was observed. Cell viability was dose-dependently recovered in myocytes overexpressing HSPB5 R120G by treatment with nicorandil a mitochondrial ATP-sensitive potassium channel opener. Nicorandil treatment also inhibited the increase in BAX, the decrease in BCL2, activation of caspase-3 and apoptotic cell death by mutant HSPB5. To confirm the results of the in-vitro study, we analyzed the effect of nicorandil in HSPB5 R120G TG mice. Nicorandil treatment appeared to reduce mitochondrial impairment and apoptotic cell death and prolonged survival in HSPB5 R120G TG mice. CONCLUSIONS: Nicorandil may prolong survival in HSPB5 R120G TG mice by protecting against mitochondrial impairments. PMID- 21541348 TI - Th17 cells and activated dendritic cells are increased in vitiligo lesions. AB - BACKGROUND: Vitiligo is a common skin disorder, characterized by progressive skin de-pigmentation due to the loss of cutaneous melanocytes. The exact cause of melanocyte loss remains unclear, but a large number of observations have pointed to the important role of cellular immunity in vitiligo pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we characterized T cell and inflammation-related dermal dendritic cell (DC) subsets in pigmented non lesional, leading edge and depigmented lesional vitiligo skin. By immunohistochemistry staining, we observed enhanced populations of CD11c+ myeloid dermal DCs and CD207+ Langerhans cells in leading edge vitiligo biopsies. DC LAMP+ and CD1c+ sub-populations of dermal DCs expanded significantly in leading edge and lesional vitiligo skin. We also detected elevated tissue mRNA levels of IL-17A in leading edge skin biopsies of vitiligo patients, as well as IL-17A positive T cells by immunohistochemistry and immunofluorescence. Langerhans cells with activated inflammasomes were also noted in lesional vitiligo skin, along with increased IL-1beta mRNA, which suggest the potential of Langerhans cells to drive Th17 activation in vitiligo. CONCLUSIONS/SIGNIFICANCE: These studies provided direct tissue evidence that implicates active Th17 cells in vitiligo skin lesions. We characterized new cellular immune elements, in the active margins of vitiligo lesions (e.g. populations of epidermal and dermal dendritic cells subsets), which could potentially drive the inflammatory responses. PMID- 21541349 TI - Social and structural factors associated with HIV infection among female sex workers who inject drugs in the Mexico-US border region. AB - BACKGROUND: FSWs who inject drugs (FSW-IDUs) can acquire HIV through high risk sexual and injection behaviors. We studied correlates of HIV infection among FSW IDUs in northern Mexico, where sex work is quasi-legal and syringes can be legally obtained without a prescription. METHODS: FSW-IDUs>18 years old who reported injecting drugs and recent unprotected sex with clients in Tijuana and Ciudad Juarez underwent surveys and HIV/STI testing. Logistic regression identified correlates of HIV infection. RESULTS: Of 620 FSW-IDUs, prevalence of HIV, gonorrhea, Chlamydia, trichomonas, syphilis titers >=1:8, or any of these infections was 5.3%, 4%, 13%, 35%, 10% and 72%, respectively. Compared to other FSW-IDUs, HIV-positive women were more likely to: have syphilis titers >=1:8 (36% vs. 9%, p<0.001), often/always inject drugs with clients (55% vs. 32%, p = 0.01), and experience confiscation of syringes by police (49% vs. 28%, p = 0.02). Factors independently associated with HIV infection were syphilis titers >=1:8, often/always injecting with clients and police confiscation of syringes. Women who obtained syringes from NEPs (needle exchange programs) within the last month had lower odds of HIV infection associated with active syphilis, but among non NEP attenders, the odds of HIV infection associated with active syphilis was significantly elevated. CONCLUSIONS: Factors operating in both the micro-social environment (i.e., injecting drugs with clients) and policy environment (i.e., having syringes confiscated by police, attending NEPs) predominated as factors associated with risk of HIV infection, rather than individual-level risk behaviors. Interventions should target unjustified policing practices, clients' risk behaviors and HIV/STI prevention through NEPs. PMID- 21541350 TI - jMOTU and Taxonerator: turning DNA Barcode sequences into annotated operational taxonomic units. AB - BACKGROUND: DNA barcoding and other DNA sequence-based techniques for investigating and estimating biodiversity require explicit methods for associating individual sequences with taxa, as it is at the taxon level that biodiversity is assessed. For many projects, the bioinformatic analyses required pose problems for laboratories whose prime expertise is not in bioinformatics. User-friendly tools are required for both clustering sequences into molecular operational taxonomic units (MOTU) and for associating these MOTU with known organismal taxonomies. RESULTS: Here we present jMOTU, a Java program for the analysis of DNA barcode datasets that uses an explicit, determinate algorithm to define MOTU. We demonstrate its usefulness for both individual specimen-based Sanger sequencing surveys and bulk-environment metagenetic surveys using long read next-generation sequencing data. jMOTU is driven through a graphical user interface, and can analyse tens of thousands of sequences in a short time on a desktop computer. A companion program, Taxonerator, that adds traditional taxonomic annotation to MOTU, is also presented. Clustering and taxonomic annotation data are stored in a relational database, and are thus amenable to subsequent data mining and web presentation. CONCLUSIONS: jMOTU efficiently and robustly identifies the molecular taxa present in survey datasets, and Taxonerator decorates the MOTU with putative identifications. jMOTU and Taxonerator are freely available from http://www.nematodes.org/. PMID- 21541351 TI - Soccer attenuates the asymmetry of rectus abdominis muscle observed in non athletes. AB - PURPOSE: To determine the volume and degree of asymmetry of the rectus abdominis muscle (RA) in professional soccer players. METHODS: The volume of the RA was determined using magnetic resonance imaging (MRI) in 15 professional male soccer players and 6 non-active male control subjects. RESULTS: Soccer players had 26% greater RA volume than controls (P<0.05), due to hypertrophy of both the dominant (28% greater volume, P<0.05) and non-dominant (25% greater volume, P<0.01) sides, after adjusting for age, length of the RA muscle and body mass index (BMI) as covariates. Total volume of the dominant side was similar to the contralateral in soccer players (P = 0.42) and in controls (P = 0.75) (Dominant/non-dominant = 0.99, in both groups). Segmental analysis showed a progressive increase in the degree of side-to-side asymmetry from the first lumbar disc to the pubic symphysis in soccer players (r = 0.80, P<0.05) and in controls (r = 0.75, P<0.05). The slope of the relationship was lower in soccer players, although this trend was not statistically significant (P = 0.14). CONCLUSIONS: Professional soccer is associated with marked hypertrophy of the rectus abdominis muscle, which achieves a volume that is 26% greater than in non-active controls. Soccer induces the hypertrophy of the non-dominant side in proximal regions and the dominant side in regions closer to pubic symphysis, which attenuates the pattern of asymmetry of rectus abdominis observed in non-active population. It remains to be determined whether the hypertrophy of rectus abdominis in soccer players modifies the risk of injury. PMID- 21541352 TI - Full-length L1CAM and not its Delta2Delta27 splice variant promotes metastasis through induction of gelatinase expression. AB - Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression. PMID- 21541353 TI - CD4-independent human immunodeficiency virus infection involves participation of endocytosis and cathepsin B. AB - During a comparison of the infectivity of mNDK, a CD4-independent human immunodeficiency virus type 1 (HIV-1) strain, to various cell lines, we found that HeLa cells were much less susceptible than 293T and TE671 cells. Hybridoma cells between HeLa and 293T cells were as susceptible as 293T cells, suggesting that cellular factors enhance the mNDK infection in 293T cells. By screening a cDNA expression library in HeLa cells, cystatin C was isolated as an enhancer of the mNDK infection. Because cathepsin B protease, a natural ligand of cystatin C, was upregulated in HeLa cells, we speculated that the high levels of cathepsin B activities were inhibitory to the CD4-independent infection and that cystatin C enhanced the infection by impairing the excessive cathepsin B activity. Consistent with this idea, pretreatment of HeLa cells with 125 uM of CA-074Me, a cathepsin B inhibitor, resulted in an 8-fold enhancement of the mNDK infectivity. Because cathepsin B is activated by low pH in acidic endosomes, we further examined the potential roles of endosomes in the CD4-independent infection. Suppression of endosome acidification or endocytosis by inhibitors or by an Eps15 dominant negative mutant reduced the infectivity of mNDK in which CD4-dependent infections were not significantly impaired. Taken together, these results suggest that endocytosis, endosomal acidification, and cathepsin B activity are involved in the CD4-independent entry of HIV-1. PMID- 21541354 TI - Regulation of cancer aggressive features in melanoma cells by microRNAs. AB - MicroRNAs (miRNAs) are small non-coding RNAs with regulatory roles, which are involved in a broad spectrum of physiological and pathological processes, including cancer. A common strategy for identification of miRNAs involved in cell transformation is to compare malignant cells to normal cells. Here we focus on identification of miRNAs that regulate the aggressive phenotype of melanoma cells. To avoid differences due to genetic background, a comparative high throughput miRNA profiling was performed on two isogenic human melanoma cell lines that display major differences in their net proliferation, invasion and tube formation activities. This screening revealed two major cohorts of differentially expressed miRNAs. We speculated that miRNAs up-regulated in the more-aggressive cell line contribute oncogenic features, while the down-regulated miRNAs are tumor suppressive. This assumption was further tested experimentally on five candidate tumor suppressive miRNAs (miR-31, -34a, -184, -185 and -204) and on one candidate oncogenic miRNA (miR-17-5p), all of which have never been reported before in cutaneous melanoma. Remarkably, all candidate Suppressive miRNAs inhibited net proliferation, invasion or tube formation, while miR-17-5p enhanced cell proliferation. miR-34a and miR-185 were further shown to inhibit the growth of melanoma xenografts when implanted in SCID-NOD mice. Finally, all six candidate miRNAs were detected in 15 different metastatic melanoma specimens, attesting for the physiological relevance of our findings. Collectively, these findings may prove instrumental for understanding mechanisms of disease and for development of novel therapeutic and staging technologies for melanoma. PMID- 21541355 TI - Attentional modulation of temporal contrast sensitivity in human vision. AB - Recent psychophysical studies have shown that attention can alter contrast sensitivities for temporally broadband stimuli such as flashed gratings. The present study examined the effect of attention on the contrast sensitivity for temporally narrowband stimuli with various temporal frequencies. Observers were asked to detect a drifting grating of 0-40 Hz presented gradually in the peripheral visual field with or without a concurrent letter identification task in the fovea. We found that removal of attention by the concurrent task reduced the contrast sensitivity for gratings with low temporal frequencies much more profoundly than for gratings with high temporal frequencies and for flashed gratings. The analysis revealed that the temporal contrast sensitivity function had a more band-pass shape with poor attention. Additional experiments showed that this was also true when the target was presented in various levels of luminance noise. These results suggest that regardless of the presence of external noise, attention extensively modulates visual sensitivity for sustained retinal inputs. PMID- 21541356 TI - Franchising rabies vaccine delivery: the case of Indian immunologicals. PMID- 21541357 TI - Strategies for introducing Wolbachia to reduce transmission of mosquito-borne diseases. AB - Certain strains of the endosymbiont Wolbachia have the potential to lower the vectorial capacity of mosquito populations and assist in controlling a number of mosquito-borne diseases. An important consideration when introducing Wolbachia carrying mosquitoes into natural populations is the minimisation of any transient increase in disease risk or biting nuisance. This may be achieved by predominantly releasing male mosquitoes. To explore this, we use a sex-structured model of Wolbachia-mosquito interactions. We first show that Wolbachia spread can be initiated with very few infected females provided the infection frequency in males exceeds a threshold. We then consider realistic introduction scenarios involving the release of batches of infected mosquitoes, incorporating seasonal fluctuations in population size. For a range of assumptions about mosquito population dynamics we find that male-biased releases allow the infection to spread after the introduction of low numbers of females, many fewer than with equal sex-ratio releases. We extend the model to estimate the transmission rate of a mosquito-borne pathogen over the course of Wolbachia establishment. For a range of release strategies we demonstrate that male-biased release of Wolbachia infected mosquitoes can cause substantial transmission reductions without transiently increasing disease risk. The results show the importance of including mosquito population dynamics in studying Wolbachia spread and that male-biased releases can be an effective and safe way of rapidly establishing the symbiont in mosquito populations. PMID- 21541358 TI - HTLV-1 tax specific CD8+ T cells express low levels of Tim-3 in HTLV-1 infection: implications for progression to neurological complications. AB - The T cell immunoglobulin mucin 3 (Tim-3) receptor is highly expressed on HIV-1 specific T cells, rendering them partially "exhausted" and unable to contribute to the effective immune mediated control of viral replication. To elucidate novel mechanisms contributing to the HTLV-1 neurological complex and its classic neurological presentation called HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis), we investigated the expression of the Tim-3 receptor on CD8(+) T cells from a cohort of HTLV-1 seropositive asymptomatic and symptomatic patients. Patients diagnosed with HAM/TSP down-regulated Tim-3 expression on both CD8(+) and CD4(+) T cells compared to asymptomatic patients and HTLV-1 seronegative controls. HTLV-1 Tax-specific, HLA-A*02 restricted CD8(+) T cells among HAM/TSP individuals expressed markedly lower levels of Tim-3. We observed Tax expressing cells in both Tim-3(+) and Tim-3(-) fractions. Taken together, these data indicate that there is a systematic downregulation of Tim-3 levels on T cells in HTLV-1 infection, sustaining a profoundly highly active population of potentially pathogenic T cells that may allow for the development of HTLV-1 complications. PMID- 21541359 TI - Congenital cytomegalovirus mortality in the United States, 1990-2006. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection is the most common intrauterine infection in the United States disproportionately affecting minority races and those of lower socio-economic class. Despite its importance there is little information on the burden of congenital CMV-related mortality in the US. To measure congenital CMV-associated mortality in the US and assess possible racial/ethnic disparities, we reviewed national death certificate data for a 17 year period. METHODS: Congenital CMV-associated deaths from 1990 through 2006 were identified from multiple-cause-coded death records and were combined with US census data to calculate mortality rates. RESULTS: A total of 777 congenital CMV associated deaths occurred over the 17-year study period resulting in 56,355 years of age-adjusted years of potential life lost. 71.7% (557) of congenital CMV associated deaths occurred in infants (age less than 1 year). Age-adjusted mortality rates stratified by race/ethnicity revealed mortality disparities. Age adjusted rate ratios were calculated for each racial/ethnic group using whites as the reference. Native Americans and African Americans were 2.34 (95% CI, 2.11 2.59) and 1.89 (95% CI, 1.70-2.11) times respectively, more likely to die from congenital CMV than whites. Asians and Hispanics were 0.54 (95% CI, 0.44-0.66) and 0.96 (95% CI, 0.83-1.10) times respectively, less likely to die from congenital CMV than whites. CONCLUSIONS/SIGNIFICANCE: Congenital CMV infection causes appreciable mortality in the US exacting a particular burden among African Americans and Native Americans. Enhanced surveillance and increased screening are necessary to better understand the epidemiology of congenital CMV infection in addition to acceleration of vaccine development efforts. PMID- 21541360 TI - Gene Atlasing of digestive and reproductive tissues in Schistosoma mansoni. AB - BACKGROUND: While considerable genomic and transcriptomic data are available for Schistosoma mansoni, many of its genes lack significant annotation. A transcriptomic study of individual tissues and organs of schistosomes could play an important role in functional annotation of the unknown genes, particularly by providing rapid localisation data and thus giving insight into the potential roles of these molecules in parasite development, reproduction and homeostasis, and in the complex host-parasite interaction. METHODOLOGY/PRINCIPAL FINDINGS: Quantification of gene expression in tissues of S. mansoni was achieved by a combination of laser microdissection microscopy (LMM) and oligonucleotide microarray analysis. We compared the gene expression profile of the adult female gastrodermis and male and female reproductive tissues with whole worm controls. The results revealed a total of 393 genes (contigs) that were up-regulated two fold or more in the gastrodermis, 4,450 in the ovary, 384 in the vitelline tissues of female parasites, and 2,171 in the testes. We have also supplemented these data with the identification of highly expressed genes in different regions of manually dissected male and female S. mansoni. Though relatively crude, this dissection strategy provides low resolution localisation data for critical regions of the adult parasites that are not amenable to LMM isolation. CONCLUSIONS: This is the first detailed transcriptomic study of the reproductive tissues and gastrodermis of S. mansoni. The results obtained will help direct future research on the functional aspects of these tissues, expediting the characterisation of currently unannotated gene products of S. mansoni and the discovery of new drug and vaccine targets. PMID- 21541361 TI - Neglected tropical diseases in the Catholic world. PMID- 21541362 TI - Individual predisposition, household clustering and risk factors for human infection with Ascaris lumbricoides: new epidemiological insights. AB - BACKGROUND: Much of our current understanding of the epidemiology of Ascaris lumbricoides infections in humans has been acquired by analyzing worm count data. These data are collected by treating infected individuals with anthelmintics so that worms are expelled intact from the gastrointestinal tract. Analysis of such data established that individuals are predisposed to infection with few or many worms and members of the same household tend to harbor similar numbers of worms. These effects, known respectively as individual predisposition and household clustering, are considered characteristic of the epidemiology of ascariasis. The mechanisms behind these phenomena, however, remain unclear. In particular, the impact of heterogeneous individual exposures to infectious stages has not been thoroughly explored. METHODOLOGY/PRINCIPAL FINDINGS: Bayesian methods were used to fit a three-level hierarchical statistical model to A. lumbricoides worm counts derived from a three-round chemo-expulsion study carried out in Dhaka, Bangladesh. The effects of individual predisposition, household clustering and household covariates of the numbers of worms per host (worm burden) were considered simultaneously. Individual predisposition was found to be of limited epidemiological significance once household clustering had been accounted for. The degree of intra-household variability among worm burdens was found to be reduced by approximately 58% when household covariates were included in the model. Covariates relating to decreased affluence and quality of housing construction were associated with a statistically significant increase in worm burden. CONCLUSIONS/SIGNIFICANCE: Heterogeneities in the exposure of individuals to infectious eggs have an important role in the epidemiology of A. lumbricoides infection. The household covariates identified as being associated with worm burden provide valuable insights into the source of these heterogeneities although above all emphasize and reiterate that infection with A. lumbricoides is inextricably associated with acute poverty. PMID- 21541363 TI - Improving effective surgical delivery in humanitarian disasters: lessons from Haiti. AB - Kathryn Chu and colleagues describe the experiences of Medecins sans Frontieres after the 2010 Haiti earthquake, and discuss how to improve delivery of surgery in humanitarian disasters. PMID- 21541364 TI - Force-velocity measurements of a few growing actin filaments. AB - The polymerization of actin in filaments generates forces that play a pivotal role in many cellular processes. We introduce a novel technique to determine the force-velocity relation when a few independent anchored filaments grow between magnetic colloidal particles. When a magnetic field is applied, the colloidal particles assemble into chains under controlled loading or spacing. As the filaments elongate, the beads separate, allowing the force-velocity curve to be precisely measured. In the widely accepted Brownian ratchet model, the transduced force is associated with the slowing down of the on-rate polymerization. Unexpectedly, in our experiments, filaments are shown to grow at the same rate as when they are free in solution. However, as they elongate, filaments are more confined in the interspace between beads. Higher repulsive forces result from this higher confinement, which is associated with a lower entropy. In this mechanism, the production of force is not controlled by the polymerization rate, but is a consequence of the restriction of filaments' orientational fluctuations at their attachment point. PMID- 21541365 TI - Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis. AB - The neurosteroid dehydroepiandrosterone (DHEA), produced by neurons and glia, affects multiple processes in the brain, including neuronal survival and neurogenesis during development and in aging. We provide evidence that DHEA interacts with pro-survival TrkA and pro-death p75(NTR) membrane receptors of neurotrophin nerve growth factor (NGF), acting as a neurotrophic factor: (1) the anti-apoptotic effects of DHEA were reversed by siRNA against TrkA or by a specific TrkA inhibitor; (2) [(3)H]-DHEA binding assays showed that it bound to membranes isolated from HEK293 cells transfected with the cDNAs of TrkA and p75(NTR) receptors (K(D): 7.4 +/- 1.75 nM and 5.6 +/- 0.55 nM, respectively); (3) immobilized DHEA pulled down recombinant and naturally expressed TrkA and p75(NTR) receptors; (4) DHEA induced TrkA phosphorylation and NGF receptor mediated signaling; Shc, Akt, and ERK1/2 kinases down-stream to TrkA receptors and TRAF6, RIP2, and RhoGDI interactors of p75(NTR) receptors; and (5) DHEA rescued from apoptosis TrkA receptor positive sensory neurons of dorsal root ganglia in NGF null embryos and compensated NGF in rescuing from apoptosis NGF receptor positive sympathetic neurons of embryonic superior cervical ganglia. Phylogenetic findings on the evolution of neurotrophins, their receptors, and CYP17, the enzyme responsible for DHEA biosynthesis, combined with our data support the hypothesis that DHEA served as a phylogenetically ancient neurotrophic factor. PMID- 21541366 TI - A yeast model for understanding ALS: fast, cheap, and easy to control. PMID- 21541367 TI - Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. AB - TDP-43 and FUS are RNA-binding proteins that form cytoplasmic inclusions in some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, mutations in TDP-43 and FUS are linked to ALS and FTLD. However, it is unknown whether TDP-43 and FUS aggregate and cause toxicity by similar mechanisms. Here, we exploit a yeast model and purified FUS to elucidate mechanisms of FUS aggregation and toxicity. Like TDP-43, FUS must aggregate in the cytoplasm and bind RNA to confer toxicity in yeast. These cytoplasmic FUS aggregates partition to stress granule compartments just as they do in ALS patients. Importantly, in isolation, FUS spontaneously forms pore-like oligomers and filamentous structures reminiscent of FUS inclusions in ALS patients. FUS aggregation and toxicity requires a prion-like domain, but unlike TDP-43, additional determinants within a RGG domain are critical for FUS aggregation and toxicity. In further distinction to TDP-43, ALS-linked FUS mutations do not promote aggregation. Finally, genome-wide screens uncovered stress granule assembly and RNA metabolism genes that modify FUS toxicity but not TDP-43 toxicity. Our findings suggest that TDP-43 and FUS, though similar RNA binding proteins, aggregate and confer disease phenotypes via distinct mechanisms. These differences will likely have important therapeutic implications. PMID- 21541369 TI - A stereoselective total synthesis of 7,8-O-isopropylidene iriomoteolide-3a. AB - A stereoselective total synthesis of 7,8-O-isopropylidene iriomoteolide-3a has been achieved by using Yamaguchi esterification, Julia-Kocienski olefination, organocatalytic alpha-oxidation, and ring-closing metathesis reaction as key bond forming steps. PMID- 21541368 TI - A yeast model of FUS/TLS-dependent cytotoxicity. AB - FUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression. PMID- 21541370 TI - Phosphotungstic acid functionalized silica nanocomposites with tunable bicontinuous mesoporous structure and superior proton conductivity and stability for fuel cells. AB - A novel proton exchange membrane using phosphotungstic acid (HPW) as proton carrier and cubic bicontinuous Ia3d mesoporous silica (meso-silica) as framework material is successfully developed as proton exchange membranes for fuel cells. Meso-silica is functionalized by 80wt% HPW using a vacuum impregnation method. The HPW-functionalized meso-silica (HPW-meso-silica) nanocomposites are characterized by transmission electron microscopy (TEM), small angle X-ray scattering (SAXS), N(2) adsorption/desorption isotherms, thermogravimetric analysis (TGA), water uptake and four-probe conductivity. The results show that the mesoporous structure of silica hosts can be altered by the hydrothermal temperature. Conductivity measurements indicate that meso-silica host with pore diameter of 5.0 nm has the highest proton conductivity of 0.11 S cm(-1) at 80 degrees C and 100% relative humidity (RH) with an activation energy of ~14 kJ mol(-1) and better stability as compared to that with large mesopores. The proton conductivity and performance of HPW-meso-silica nanocomposites also increase with the RH, but it is far less sensitive to RH changes as compared to conventional perfluorosulfonic acid (PFSA) polymers such as Nafion. The maximum power density of the cell with HPW-meso-silcia nanocomposite membranes is 221 mW cm(-2) at 80 degrees C and 100% RH and decreases to 171 mW cm(-2) when RH is reduced to 20%, a 20% decrease in power output. In the case of a cell with Nafion 115 membranes, the decrease in power density is 95% under identical test conditions. The results demonstrate that the HPW-meso-silica nanocomposite has an exceptionally high water retention capability and is a promising proton exchange membrane material for fuel cells operating at reduced humidity and elevated temperatures. PMID- 21541371 TI - In silico screening of metal-organic frameworks in separation applications. AB - Porous materials such as metal-organic frameworks (MOFs) and zeolitic imidazolate frameworks (ZIFs) offer considerable potential for separating a variety of mixtures such as those relevant for CO(2) capture (CO(2)/H(2), CO(2)/CH(4), CO(2)/N(2)), CH(4)/H(2), alkanes/alkenes, and hydrocarbon isomers. There are basically two different separation technologies that can be employed: (1) a pressure swing adsorption (PSA) unit with a fixed bed of adsorbent particles, and (2) a membrane device, wherein the mixture is allowed to permeate through a micro porous crystalline layer. In view of the vast number of MOFs, and ZIFs that have been synthesized there is a need for a systematic screening of potential candidates for any given separation task. Also of importance is to investigate how MOFs and ZIFs stack up against the more traditional zeolites such as NaX and NaY with regard to their separation characteristics. This perspective highlights the potency of molecular simulations in determining the choice of the best MOF or ZIF for a given separation task. A variety of metrics that quantify the separation performance, such as adsorption selectivity, working capacity, diffusion selectivity, and membrane permeability, are determined from a combination of Configurational-Bias Monte Carlo (CBMC) and Molecular Dynamics (MD) simulations. The practical utility of the suggested screening methodology is demonstrated by comparison with available experimental data. PMID- 21541372 TI - Evaluation of affinity of molecules for carbon nanotubes. AB - Recent developments of non-covalent functionalization of carbon nanotubes (CNTs) require a systematic understanding of the interaction between molecule and CNTs (CNT-molecular interaction); however, it has been difficult to evaluate the "net" interaction between the CNTs and molecules. We now use silica gel particles coated with the pristine single-walled carbon nanotubes (SWNTs) in a monolayer fashion as the stationary phase of a HPLC column. The newly developed column (SWNT-column) worked as a powerful tool for ranking the interactions between the SWNTs and molecules with a high precision. We describe the binding affinity analysis of polyaromatic hydrocarbons onto the surfaces of SWNTs. The obtained ranking is determined in the order of benzene < naphthalene < biphenyl < fluorene < phenanthrene < anthracene ~ pyrene < triphenylene < p-terphenyl < tetraphene < tetracene. PMID- 21541373 TI - Chemoenzymatic synthesis of (2R,3R,4R)-dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf2. AB - Dehydroxymethylepoxyquinomicin (DHMEQ, 1a) is a specific and potent inhibitor of NF-kappaB, and it is now being developed as an anti-inflammatory and anticancer agent. While previously only the (2S,3S,4S)-form had been available from the racemate by using lipase-catalyzed enantioselective resolution, in the present study a new route for production of the (2R,3R,4R)-form was established by use of a chemoenzymatic approach. (1R*,2R*,3R*)-2,3-Epoxy-5-N-[(2-hydroxybenzoyl)amino] 4,4-dimethoxycyclohex-5-en-1-ol (2a) was hexanoylated on both secondary and phenolic hydroxy groups, and subjected to Burkholderia cepacia lipase-catalyzed hydrolysis. The reaction proceeded in a highly enantioselective manner (E >500) to give (1S,2S,3S)-2a in an enantiomerically pure state. Several chemical steps of transformation from the enzyme reaction product gave (2R,3R,4R)-DHMEQ (1a) without any loss of stereochemical purity. Moreover, we newly found that (2R,3R,4R)-DHMEQ activated Nrf2, which is a transcription factor that induces the expression of multiple antioxidant enzymes. It activated Nrf2 in a promoter reporter assay. It also increased the expression of target antioxidant proteins and cancelled ROS-induced cell death in a neuronal cell line. Thus, (2R,3R,4R) DHMEQ was efficiently prepared by a newly designed route using lipase, and it may be useful as a new anti-inflammatory agent. PMID- 21541374 TI - Quantification of GPCR internalization by single-molecule microscopy in living cells. AB - Receptor internalization upon ligand stimulation is a key component of a cell's response and allows a cell to correctly sense its environment. Novel fluorescent methods have enabled the direct visualization of the agonist-stimulated G-protein coupled receptors (GPCR) trafficking in living cells. However, it is difficult to observe internalization of GPCRs in vivo due to intrinsic autofluorescence and cytosolic signals of fluorescently labeled GPCRs. This study uses the superior positional accuracy of single-molecule fluorescence microscopy to visualize in real time the internalization of Dictyostelium discoideum cAMP receptors, cAR1, genetically encoded with eYFP. This technique made it possible to follow the number of receptors in time revealing that the fraction of cytosolic receptors increases after persistent agonist stimulation and that the majority of the receptors were degraded after internalization. The observed internalization process was phosphorylation dependent, as shown with the use of a phosphorylation deficient cAR1 mutant, cm1234-eYFP, or stimulation with an antagonist, Rp-cAMPS that does not induce receptor phosphorylation. Furthermore, experiments done in mound-stage cells suggest that intrinsic, phosphorylation-induced internalization of cAR1 is necessary for Dictyostelium wild type cells to progress properly through multicellular development. To our knowledge, this observation illustrates for the first time phosphorylation-dependent internalization of single cAR1 molecules in living cells and its involvement in multicellular development. This very sensitive imaging of receptor internalization can be a useful and universal approach for pharmacological characterization of GPCRs in other cell types. PMID- 21541375 TI - Augmented stress-responsive characteristics of cell lines in narrow confinements. AB - Adaptabilities of mammalian cells in physiological confinements of the vasculature and tissue-matrices remain unaddressed. As the adaptation to coupled chemo-mechanical stimuli becomes a pivotal factor for cell survival, we investigate here the prospect of confinement induced alterations in the stress adaptive behavior of mammalian cell lines. To comprehend the physical dynamics of cells during stress adaptation, we employ a microfluidic platform coupled with a microfabrication compatible traction force microscopy system and lipid raft imaging method to examine the confinement effect. With the variations of the microchannel height and the flow shear stress, we detect a sigmoidal shaped declination in the cellular response time. This occurs when the channel height is decreased below a threshold value of 70 MUm and concurrently, stress is elevated beyond 10 dynes cm(-2). Origin of this transition is probed to be connected to the augmentation of secreted growth factor concentration and amplification of fluid shear stress in the microfluidic environment. Two phenomena together, then, lead to elevated activation level of Epidermal Growth Factor Receptors. Thus, our findings reveal a hitherto unknown enhanced stress adaptive response of cells, which may be further exploited in the understanding of tumor progression in vivo and designing microfluidics based drug screening platforms. PMID- 21541376 TI - On-chip background noise reduction for cell-based assays in droplets. AB - Droplet-based microfluidics provides an excellent platform for high-throughput biological assays. Each droplet serves as a reaction vessel with a volume as small as a few picolitres. This is an important technology for a high variety of applications. However this technology is restricted to homogeneous assays as it is very difficult to wash reagents from the reaction vessel. To help overcome this limitation, we introduce a method to effectively dilute the content of a droplet while retaining the high throughput. We use electrocoalescence to merge the parent drop with a much larger drop containing only solvent, thereby increasing the volume of the drop by as much as a factor of 14. Three T-junctions then break the larger drop into eight smaller droplets. This dilution and break up process can be repeated, thus leading to many drops comparable in size to the original one but with much lower concentration of reagents. The system is fully integrated in a PDMS device. To demonstrate its power, we perform a labelling reaction at the surface of the cells by coencapsulating yeast cells expressing S6 peptide tags with the enzyme SFP synthase and the fluorescent substrate CoA 488. After reaction, the droplets are diluted twice using the system and the intensity of their fluorescence is measured. This noise reduction method enables us to more easily distinguish the fluorescence at the surface of a single cell from the fluorescent background inside the droplet. PMID- 21541377 TI - FRET-based probing to gain direct information on siRNA sustainability in live cells: Asymmetric degradation of siRNA strands. AB - Investigation of the intracellular fate of small interference RNA (siRNA) following their delivery into cells is of great interest to elucidate dynamics of siRNA in cytoplasm. However, its cellular delivery and sustainability should be understood at the molecular level and improved for the successful in vivo application of siRNA. Here we present a fluorescence resonance energy transfer (FRET) based method using oligonucleotide probes to study intracellular dissociation (or melting) and sustainability of siRNAs in live cells. The FRET probes were specifically designed to observe intracellular dissociation (or melting) and degradation of short synthetic RNAs in real-time, thus providing the desired kinetic information in cells. Intracellular FRET analysis shows that siRNA duplex is gradually diffused into cytosol, dissociated, and degraded for a duration of 3.5 h, which is confirmed by confocal microscopy colocalization measurements. In addition, our FRET assays reveal the asymmetric degradation as well as the time-dependent dissociation of each siRNA strand. The application of this FRET technique can allow for direct information on siRNA integrity inside living cells, providing a detection tool for dynamics of biological molecules. PMID- 21541378 TI - Biosafety assessment of Gd@C82(OH)22 nanoparticles on Caenorhabditis elegans. AB - Gd@C(82)(OH)(22), a water-soluble endohedral metallofullerene derivative, has been proven to possess significant antineoplastic activity in mice. Toxicity studies of the nanoparticle have shown some evidence of low or non toxicity in mice and cell models. Here we employed Caenorhabditis elegans (C. elegans) as a model organism to further evaluate the short- and long-term toxicity of Gd@C(82)(OH)(22) and possible behavior changes under normal and stress culture conditions. With treatment of Gd@C(82)(OH)(22) at 0.01, 0.1, 1.0 and 10 MUg ml( 1) within one generation (short-term), C. elegans showed no significant decrease in longevity or thermotolerance compared to the controls. Furthermore, when Gd@C(82)(OH)(22) treatment was extended up to six generations (long-term), non toxic effects to the nematodes were found. In addition, data from body length measurement, feeding rate and egg-laying assays with short-term treatment demonstrated that the nanoparticles have no significant impact on the individual growth, feeding behavior and reproductive ability, respectively. In summary, this work has shown that Gd@C(82)(OH)(22) is tolerated well by worms and it has no apparent toxic effects on longevity, stress resistance, growth and behaviors that were observed in both adult and young worms. Our work lays the foundations for further developments of this anti-neoplastic agent for clinical applications. PMID- 21541380 TI - Throwing light on dark states of alpha-oligothiophenes of chain lengths 2 to 6: radical anion photoelectron spectroscopy and excited-state theory. AB - In this work, we apply photodetachment photoelectron spectroscopy (PD-PES) on radical anions to access the lowest excited electronic states of neutral alpha oligothiophenes nT (n = 2-6, where n denotes the number of thiophene rings) in the gas phase. Besides electron affinities, the spectra provide the energies of the T(1) and T(2) states which are otherwise difficult to investigate in neutral molecules due to spin selection rules. The assignment of the spectra is assisted by quantum chemical calculations using a combined density functional theory and multi-reference configuration interaction approach. For all alpha-oligothiophenes investigated in this work, the T(2) state is situated below S(1). In the gas phase, the S(1) state energies lie higher than in non-polar solution (0.2 to 0.4 eV). The geometry optimizations show that the S(0) state and especially the excited states gain planarity with increasing chain length. A non-planar structure or out-of-plane vibrational activity is needed to allow an efficient intersystem crossing (ISC) dynamics from S(1) to T(2), followed by internal conversion to T(1). Our theoretical calculations predict that in 6T a doubly excited state becomes nearly isoenergetic to S(1). This state is not observed by PD-PES, which is explained by the analysis of the calculated contributing electron configurations. PMID- 21541379 TI - The use of symmetry in enantioselective synthesis: four pairs of chrysene enantiomers prepared from 19-nortestosterone. AB - Expansion of the D-ring of 19-norsteroids with incorporation of the steroid C-18 methyl group into a newly formed six-membered ring provides easy access to the chrysene ring system. By taking advantage of the symmetry of the chrysene ring system and avoiding meso chrysene intermediates, four optically pure 2,8 difunctionalized (C-2 hydroxyl group and C-8 oxo group) hexadecahydrochrysene diastereomers, and their corresponding optically pure enantiomers were prepared from 19-nortestosterone. The eight chrysene stereoisomers are of interest as starting materials for preparing chrysene analogues of physiologically important neurosteroids. PMID- 21541381 TI - Conditional reversible work method for molecular coarse graining applications. AB - Systematically coarse grained models for complex fluids usually lack chemical and thermodynamic transferability. Efforts to improve transferability require the development of effective potentials with unequivocal physical significance. In this paper, we introduce conditional reversible work (CRW) potentials that describe nonbonded interactions in coarse grained models at the pair level. The method used to obtain these potentials is straightforward to implement, can be readily extended to compute hydration contributions in implicit-solvent potentials, and is easy to automize. As a first illustration of the method, we present CRW potentials for 3-site models of hexane and toluene. The temperature transferability of the liquid phase density obtained with these potentials has been investigated, and a comparison has been made with effective potentials obtained by the iterative Boltzmann inversion method. PMID- 21541382 TI - One-electron oxidation of ferrocenes by short-lived N-oxyl radicals. The role of structural effects on the intrinsic electron transfer reactivities. AB - A kinetic study of the one electron oxidation of substituted ferrocenes (FcX: X = H, COPh, COMe, CO(2)Et, CONH(2), CH(2)OH, Et, and Me(2)) by a series of N-oxyl radicals (succinimide-N-oxyl radical (SINO), maleimide-N-oxyl radical (MINO), 3 quinazolin-4-one-N-oxyl radical (QONO) and 3-benzotriazin-4-one-N-oxyl radical (BONO)), has been carried out in CH(3)CN. N-oxyl radicals were produced by hydrogen abstraction from the corresponding N-hydroxy derivatives by the cumyloxyl radical. With all systems, the rate constants exhibited a satisfactory fit to the Marcus equation allowing us to determine self-exchange reorganization energy values (lambda(NO/NO(-))) which have been compared with those previously determined for the PINO/PINO(-) and BTNO/BTNO(-) couples. Even small modification of the structure of the N-oxyl radicals lead to significant variation of the lambda(NO/NO(-)) values. The lambda(NO/NO(-)) values increase in the order BONO < BTNO < QONO < PINO < SINO < MINO which do not parallel the order of the oxidation potentials. The higher lambda(NO/NO(-)) values found for the MINO and SINO radicals might be in accordance with a lower degree of spin delocalization in the radicals MINO and SINO and charge delocalization in the anions MINO(-) and SINO( ) due to the absence of an aromatic ring in their structure. PMID- 21541383 TI - Octaalkyl tetracene-1,2,3,4,7,8,9,10-octacarboxylates: synthesis by twofold [2+2+2] cocyclization and crystallochromy. AB - Tetracene octaesters, which were prepared by twofold [2+2+2] cocyclization, were isolated as red, orange, and orange-yellow solids for the methyl, ethyl, and propyl ester derivatives, respectively. X-Ray crystallographic analysis reveals that the difference in solid-state color arises owing to differences in molecular packing. PMID- 21541384 TI - Editorial on nanobiology. PMID- 21541385 TI - Metal-containing peptide nucleic acid conjugates. AB - Peptide Nucleic Acids (PNAs) are non-natural DNA/RNA analogues with favourable physico-chemical properties and promising applications. Discovered nearly 20 years ago, PNAs have recently re-gained quite a lot of attention. In this Perspective article, we discuss the latest advances on the preparation and utilisation of PNA monomers and oligomers containing metal complexes. These metal conjugates have found applications in various research fields such as in the sequence-specific detection of nucleic acids, in the hydrolysis of nucleic acids and peptides, as radioactive probes or as modulators of PNA.DNA hybrid stability, and last but not least as probes for molecular and cell biology. PMID- 21541386 TI - Alternative chiral thiols for preparation of chiral CdS quantum dots covered immediately by achiral thiols. AB - Developing of alternative chiral thiol stabilizers from the assembly of achiral thiol (e.g. thioglycolic acid) and chiral ligand (e.g. arginine) via both hydrogen bonding and electrostatic interactions was proposed and successfully applied to an efficient preparation of chiral CdS quantum dots (QDs). Chiral CdS QDs capped mainly with achiral thioglycolic acid were also obtained that may allow the chiral QDs to be modified for extended applications. PMID- 21541387 TI - Rapid screening for synthetic antidiabetic drug adulteration in herbal dietary supplements using direct analysis in real time mass spectrometry. AB - Adulteration of herbal supplements with synthetic drugs is illegal. A rapid and reliable method which utilizes direct analysis in real time mass spectrometry (DART-MS) was developed for the identification of seven synthetic antidiabetic drugs used as adulterants in herbal dietary supplements. The supplement sample was simply extracted with methanol/water by manually shaking several times and directly analyzed using DART-MS. The presence of synthetic drug adulterants was confirmed through the accurate m/z values and MS/MS data obtained via quadruple time of flight mass spectrometry (QTOF MS). Parameters for the DART source were systematically optimized, and the limits of detection (LODs) in herbal supplement matrices were measured. This method was successfully applied to examine five commercial herbal dietary supplements, and two of them proved to be adulterated with metformin without labeling. PMID- 21541388 TI - Photophysical properties of Kuratowski-type coordination compounds [M(II)Zn4Cl4(Me2bta)6] (M(II) = Zn or Ru) featuring long-lived excited electronic states. AB - The syntheses of Kuratowski-type pentanuclear clusters featuring {MZn(4)Cl(4)} cores (M(II) = Ru or Zn) that incorporate triazolate ligands are described. The coordination compounds are characterized by single-crystal X-ray diffraction, X ray powder diffraction (XRD), FTIR- and UV-vis spectroscopy. [Ru(II)Zn(4)Cl(4)(Me(2)bta)(6)].2DMF (Me(2)bta(-) = 5,6-dimethyl-1,2,3 benzotriazolate) (1) crystallizes in the cubic system, while [Zn(5)Cl(4)(ta)(6)] (ta(-) = 1,2,3-triazolate) (3) crystallizes in the tetragonal system. Both compounds feature structurally similar cluster topologies in which the central octahedrally coordinated metal ion is coordinated to six triazolate ligands. Each triazolate ligand is coordinated with two zinc ions (MU(3)-bridging mode), leading altogether to a pentanuclear cluster of T(d) point group symmetry. Photophysical investigations reveal that compound [Zn(5)Cl(4)(Me(2)bta)(6)].2DMF (2) shows a short-lived excited electronic state, which can be populated with high quantum yield. The isostructural compound [Ru(II)Zn(4)Cl(4)(Me(2)bta)(6)].2DMF (1), on the other hand, shows a long-lived photoexcited state, owing to an internal singlet to triplet conversion of the electronic states, as revealed by time-resolved fluorescence spectroscopy. Insights gained from these studies open up novel design strategies towards photocatalytically active metal-organic frameworks incorporating photoactive Kuratowski-type secondary building units such as MFU-4 (Metal-Organic Framework Ulm University-4). PMID- 21541389 TI - Direct detection of RNAs in living cells using peptide-inserted Renilla luciferase. AB - In this study, non-engineered RNAs were detected in living cells using bioluminescence. Two types of probe were utilized: a peptide inserted RLuc (PI RLuc) probe and a split-RNA probe. Incorporation of the PI-RLuc and split-RNA probes enabled the direct detection of RNA introduced into living cells. PMID- 21541390 TI - A novel precursor system and its application to produce tin doped indium oxide. AB - A new type of precursor has been developed by molecular design and synthesised to produce tin doped indium oxide (ITO). The precursor consists of a newly developed bimetallic indium tin alkoxide, Me(2)In(O(t)Bu)(3)Sn (Me = CH(3), O(t)Bu = OC(CH(3))(3)), which is in equilibrium with an excess of Me(2)In(O(t)Bu). This quasi single-source precursor is applied in a sol-gel process to produce powders and coatings of ITO using a one-step heat treatment process under an inert atmosphere. The main advantage of this system is the simple heat treatment that leads to the disproportionation of the bivalent Sn(II) precursor into Sn(IV) and metallic tin, resulting in an overall reduced state of the metal in the final tin doped indium oxide (ITO) material, hence avoiding the usually necessary reduction step. Solid state (119)Sn-NMR measurements of powder samples confirm the appearance of Sn(II) in an amorphous gel state and of metallic tin after annealing under nitrogen. The corresponding preparation of ITO coatings by spin coating on glass leads to transparent conductive layers with a high transmittance of visible light and a low electrical resistivity without the necessity of a reduction step. PMID- 21541391 TI - Laboratory-based separation techniques for insoluble compound mixtures: methods for the purification of metal-organic framework materials. AB - In this article, techniques for separating mixtures of insoluble compounds are discussed with respect to the small quantities found in laboratory preparations, as opposed to industrial quantities. The techniques include separations based on density, surface area and differences in particle size. Also discussed are simple apparatus, readily available in the laboratory or from commercial suppliers, for achieving these techniques. PMID- 21541392 TI - Bridging, terminal, free, anti and gauche BPA ligands in a 1D hybrid organic inorganic Mn(II)-cyanate system. AB - A hybrid organic-inorganic chain compound of the family Mn(II)-bpa-(NCO) is presented. It contains, unusually, five different dispositions for the bpa [1,2 bis(4-pyridyl)ethane] ligand. Water molecules and free bpa ligands occupy the voids of the structure. The compound shows significant antiferromagnetic-type interactions as a consequence of different exchange pathways. PMID- 21541409 TI - Mechanistic considerations of guanidine-catalyzed reactions. AB - This feature article discusses the various mechanistic aspects of guanidine catalyzed reactions. Guanidines are well known as strong organic bases; however, in the first section, three most common commercially available guanidines, TMG, TBD and MTBD, will be used to illustrate the use of guanidines as nucleophilic catalysts. In the second section, different modes of hydrogen bonding interactions of the conjugate acid of guanidine, the guanidinium, are discussed. Particularly interesting are the possibilities of mono-functional or bifunctional activation of a nucleophile and an electrophile by guanidinium. PMID- 21541410 TI - Synthesis, structure, magnetic properties and DFT calculations of two hydroxo bridged complexes based on Mn(III)(Schiff-Bases). AB - Two hydroxo-bridged complexes, {[Mn(III)(3 CH(3)O)salen](2)[Cr(III)(salen)(OH)(2)]}ClO(4).6H(2)O (1) and {[Mn(III)(5 CH(3))salen](2)(OH)}ClO(4).3H(2)O (2) [salen = N,N' ethylenebis(salicylideneiminato) dianion], have been synthesized by the hydrolysis of the corresponding Mn(III)(Schiff-Bases) derivatives and [Cr(salen)(H(2)O)(2)]Cl precursors. X-Ray structure characterization reveals the discrete linear arched trinuclear structure of 1 and the 1D chain arrangement of 2. Magnetic experimental data and density functional theory (DFT) calculations both indicate the dominant antiferromagnetic interaction mediated by the hydroxo bridges in both 1 and 2. Frequency-dependent AC susceptibilities reveal slow relaxation of 1 in low temperature. It is worth noting that the structure and magnetic properties of 1 is comparable to a reported cyano-bridged SMM, K[(5 Brsalen)(2)(H(2)O)(2)Mn(2)Cr(CN)(6)].2H(2)O. PMID- 21541393 TI - Metallic radionuclides in the development of diagnostic and therapeutic radiopharmaceuticals. AB - Metallic radionuclides are the mainstay of both diagnostic and therapeutic radiopharmaceuticals. Therapeutic nuclear medicine is less advanced but has tremendous potential if the radionuclide is accurately targeted. Great interest exists in the field of inorganic chemistry for developing target specific radiopharmaceuticals based on radiometals for non-invasive disease detection and cancer radiotherapy. This perspective will focus on the nuclear properties of a few important radiometals and their recent applications to developing radiopharmaceuticals for imaging and therapy. Other topics for discussion will include imaging techniques, radiotherapy, analytical techniques, and radiation safety. The ultimate goal of this perspective is to introduce inorganic chemists to the field of nuclear medicine and radiopharmaceutical development, where many applications of fundamental inorganic chemistry can be found. PMID- 21541411 TI - 2D-SEIRA spectroscopy to highlight conformational changes of the cytochrome c oxidase induced by direct electron transfer. AB - Potentiometric titrations of the cytochrome c oxidase (CcO) immobilized in a biomimetic membrane system were followed by two-dimensional surface-enhanced IR absorption spectroscopy (2D SEIRAS) in the ATR-mode. Direct electron transfer was employed to vary the redox state of the enzyme. The CcO was shown to undergo a conformational transition from a non-activated to an activated state after it was allowed to turnover in the presence of oxygen. Differences between the non activated and activated state were revealed by 2D SEIRA spectra recorded as a function of potential. The activated state was characterized by a higher number of correlated transitions as well as a higher number of amino acids associated with electron transfer. PMID- 21541412 TI - Kinetics of immunoassays with particles as labels: effect of antibody coupling using dendrimers as linkers. AB - In this article, we report on poly(amidoamine) dendrimers (PAMAM) as coupling agents for recombinant single-chain (ScFv) antibodies to nanoparticle (NP) labels, for use in immunoassay. We present a simple theory for the kinetics of particle capture onto a surface by means of an antibody-antigen reaction, in which the important parameter is the fraction of the particle surface that is active for reaction. We describe how increasing the generation number of the linking dendrimers significantly increased the fraction of the NP surface that is active for antigen binding and consequently also increased the assay kinetic rates. Use of dendrimers for conjugation of the NP to the antibody resulted in a significantly higher surface coverage of active antibody, in comparison with mono valent linker chemistry. As a direct consequence, the increase in effective avidity significantly out-weighed any effect of a decreased diffusion coefficient due to the NP, when compared to that of a molecular dye-labelled antibody. The signal to noise ratio of the G4.5 dendrimer-sensitised nanoparticles out performed the dye-labelled antibody by approximately four-fold. Particle aggregation experiments with the multi-valent antigen CRP demonstrated reaction limited aggregation whose rate increased significantly with increasing generation number of the dendrimer linker. PMID- 21541413 TI - Detecting DNA methylation through changes in transverse proton relaxation. AB - We present a facile, simple method to detect DNA methylation by measuring the transverse proton relaxation behaviour. Positively charged nanoparticles are arranged along the negatively charged backbone of DNA strands through electrostatic interactions. The arrangement of NPs along DNA strands aids to amplify and compare the transverse proton relaxation signal for un-cut versus cut DNA strands cleaved by sequence specific restriction enzymes. Results from this study suggest that the presence of methylation on DNA can be detected using superparamagnetic NPs using NMR. PMID- 21541414 TI - Raman spectroscopic monitoring of the osteogenic differentiation of human mesenchymal stem cells. AB - The differentiation of stem cells into multi-lineages is essential to aid the development of tissue engineered materials that replicate the functionality of their tissue of origin. For this study, Raman spectroscopy was used to monitor the formation of a bone-like apatite mineral during the differentiation of human mesenchymal stem cells (hMSCs) towards an osteogenic lineage. Raman spectroscopy observed dramatic changes in the region dominated by the stretching of phosphate groups (950-970 cm(-1)) during the period of 7-28 days. Changes were also seen at 1030 cm(-1) and 1070 cm(-1), which are associated with the P-O symmetric stretch of PO(4)(3-) and the C-O vibration in the plane stretch of CO(3)(2-). Multivariate factor analysis revealed the presence of various mineral species throughout the 28 day culture period. Bone mineral formation was observed first at day 14 and was identified as a crystalline, non-substituted apatite. During the later stages of culture, different mineral species were observed, namely an amorphous apatite and a carbonate, substituted apatite, all of which are known to be Raman markers for a bone-like material. Band area ratios revealed that both the carbonate-to-phosphate and mineral-to-matrix ratios increased with age. When taken together, these findings suggest that the osteogenic differentiation of hMSCs at early stages resembles endochondral ossification. Due to the various mineral species observed, namely a disordered amorphous apatite, a B-type carbonate-substituted apatite and a crystalline non-substituted hydroxyapatite, it is suggested that the bone-like mineral observed here can be compared to native bone. This work demonstrates the successful application of Raman spectroscopy combined with biological and multivariate analyses for monitoring the various mineral species, degree of mineralisation and the crystallinity of hMSCs as they differentiate into osteoblasts. PMID- 21541415 TI - On the mechanism of the aza-Morita-Baylis-Hillman reaction: ESI-MS interception of a unique new intermediate. AB - Solutions of aza-Morita-Baylis-Hillman (aza-MBH) reactions were directly monitored by ESI(+)-MS(/MS) spectrometry to obtain information on their mechanism. A unique bis-sulfonamide intermediate was intercepted and characterized and, based on this novel species, a mechanism that rationalizes the uniqueness of aza-MBH reactions is proposed. PMID- 21541416 TI - Synthesis of Pt@Fe2O3 nanorods as MRI probes for in vivo application. AB - Magnetic Fe(2)O(3) nanorods with low cell toxicity were successfully synthesized via a wet-chemical method. In vivo studies with a rabbit model show that the nanorods exhibit excellent T(2) signal enhancement. This work demonstrates that magnetic nanorods may provide a new type of MR enhancement agent for use in biomedical applications. PMID- 21541417 TI - Supramolecular photocatalysis: insights into cucurbit[8]uril catalyzed photodimerization of 6-methylcoumarin. AB - Guest induced shape change of the cucurbit[8]uril cavity is likely rate limiting in the supramolecular photocatalytic cycle for CB8 mediated photodimerization of 6-methylcoumarin. PMID- 21541419 TI - Efficient charge generation and collection in organic solar cells based on low band gap dyad molecules. AB - Low band gap dyad molecules were prepared that have absorption spectra matched well with the solar spectrum, and the construction of efficient charge transport pathways was observed. Under AM 1.5 illumination, the devices have achieved the highest J(SC) (4.79 mA cm(2)) and FF (0.46) in dyad-based organic solar cells to date. PMID- 21541418 TI - Direct reductive amination of aromatic aldehydes catalyzed by gold(I) complex under transfer hydrogenation conditions. AB - The direct reductive amination of aromatic aldehydes has been achieved with excellent isolated yields (89-96%) using readily accessible Ph(3)PAuCl/AgOTf catalyst along with ethyl Hantzsch ester as hydrogen source under mild reaction conditions. PMID- 21541420 TI - DNA diagnostics with a bacterial reporter probe. AB - A DNA diagnostic system has been developed by using a bacterial reporter probe. DNA hybridization-driven magnetic isolation of E. coli, followed by exponential bacterial growth and fluorescent protein expression, allows the translation of a target binding event into a vastly amplified signal and a highly sensitive/selective detection platform. PMID- 21541422 TI - Ship-in-a-bottle entrapment of molecules in porous nanocapsules. AB - Size-selective pores in the shells of hollow polymer nanocapsules enable combined assembly and entrapment of molecules. Small building blocks enter the capsule through the pores. The assembled molecules, which are larger than the pores, remain entrapped in the nanocapsules. Porous nanometre-thin walls permit unhindered functionalization of entrapped molecules. PMID- 21541421 TI - In situ ion exchange synthesis of the novel Ag/AgBr/BiOBr hybrid with highly efficient decontamination of pollutants. AB - A novel Ag/AgBr/BiOBr hybrid was prepared by a rational in situ ion exchange reaction between BiOBr hierarchical microspheres and AgNO(3) in ethylene glycol followed by light reduction, which displayed superior visible light driven photocatalytic activities in sterilization of pathogenic organism and degradation of organic dye compared to N-doped P25. PMID- 21541423 TI - Pd(II)-catalyzed decarboxylative cross-coupling of oxamic acids with potassium phenyltrifluoroborates under mild conditions. AB - A novel Pd-catalyzed decarboxylative cross-coupling of oxamic acids with potassium phenyltrifluoroborates has been realized under mild reaction conditions. This method provides an efficient access to N-mono- or N,N disubstituted benzamides and benzoates. PMID- 21541424 TI - Regenerable electrochemical immunological sensing at DNA nanostructure-decorated gold surfaces. AB - A regenerable electrochemical immunosensor with novel 3D DNA nanostructure decorated gold surfaces was developed by taking advantage of DNA-directed antibody conjugation and high resistance to non-specific protein adsorption. PMID- 21541425 TI - Engineering of a redox protein for DNA-directed assembly. AB - Engineered enzyme conjugate of the small laccase enzyme from Streptomyces coelicolor and zinc finger DNA binding domain from Zif268 is demonstrated to bind double stranded DNA in a site specific manner while retaining enzymatic activity. PMID- 21541426 TI - Efficient catalytic cycloalkane oxidation employing a "helmet" phthalocyaninato iron(III) complex. AB - We have examined the catalytic activity of an iron(III) complex bearing the 14,28 [1,3-diiminoisoindolinato]phthalocyaninato (diiPc) ligand in oxidation reactions with three substrates (cyclohexane, cyclooctane, and indan). This modified metallophthalocyaninato complex serves as an efficient and selective catalyst for the oxidation of cyclohexane and cyclooctane, and to a far lesser extent indan. In the oxidations of cyclohexane and cyclooctane, in which hydrogen peroxide is employed as the oxidant under inert atmosphere, we have observed turnover numbers of 100.9 and 122.2 for cyclohexanol and cyclooctanol, respectively. The catalyst shows strong selectivity for alcohol (vs. ketone) formation, with alcohol to ketone (A/K) ratios of 6.7 and 21.0 for the cyclohexane and cyclooctane oxidations, respectively. Overall yields (alcohol + ketone) were 73% for cyclohexane and 92% for cyclooctane, based upon the total hydrogen peroxide added. In the catalytic oxidation of indan under similar conditions, the TON for 1-indanol was 10.1, with a yield of 12% based upon hydrogen peroxide. No 1 indanone was observed in the product mixture. PMID- 21541427 TI - Peripherally cyclometalated iridium complexes of dipyridylporphyrin. AB - Two types of novel iridium pincer complexes bearing a porphyrin backbone were synthesized and characterized from dipyridylporphyrin. One of the complexes has a Lewis acidic site on the iridium center in the mer-coordination mode. The other complex takes the fac-coordination, which is rarely observed in benzene-based pincer complexes. PMID- 21541428 TI - Chirogenic [3 + 2]-photocycloaddition reactions of 2-substituted naphthoquinones with cyclic alkenes. AB - The formal [3 + 2]-photocycloaddition of 2-hydroxy- (2a) and 2-amino-1,4 naphthoquinone (2b) to olefins was studied in various solvents aiming at a possible enantioselective reaction course. The reaction conditions were optimised for irradiation at low temperature in a nonpolar solvent employing external fluorescent lamps as irradiation sources. Best yields for the reaction of 2 hydroxy-1,4-naphthoquinone (2a) with 1-methyl-2-butene were obtained when using a large excess of the olefin (200 equiv.) in toluene as the solvent at an irradiation wavelength of lambda = 419 nm. Under these conditions a variety of cyclic alkenes (cyclopentene, cyclohexene, dihydropyran, 1-methylcyclohex-1-ene) underwent the photocycloaddition in yields of 22-84%. Reactions with 2-hydroxy 1,4-naphthoquinone (2a) could be performed enantioselectively at -60 degrees C in toluene as the solvent employing a chiral hydrogen bonding template. The enantiomeric excess (<=11%) remained low, however. Possible reasons for this lack of selectivity are discussed. PMID- 21541429 TI - Hydroxy-group effect on the regioselectivity in a photochemical oxetane formation reaction (the Paterno-Buchi Reaction) of geraniol derivatives. AB - The Paterno-Buchi (PB) reaction of geraniol derivatives 1, which contain allylic alcohol functionality and unfunctionalized double bonds, with benzophenone was investigated to see the effect of the hydroxyl group on the regioselectivity of the oxetane formation, i.e., 2/3. At low concentration of geraniol (1a), oxetanes 2a and 3a were formed in a ratio of 2a/3a = ca. 50/50. The oxetane 2a is derived from the PB reaction at the allylic alcohol moiety, whereas the PB reaction at the unfunctionalized double bond produces the oxetane 3a. The PB reaction of the hydroxy-protected methyl ether 1b and acetate 1c gave selectively oxetanes 3b,c derived from the reaction at the more nucleophilic double bond, 2/3~ 15/85. The hydroxyl-group effect was found to be small, but apparently increased the formation of 2a in the PB reaction with geraniol (1a). PMID- 21541430 TI - A mixed valence manganese triangle in a trigonal lattice: structure and magnetism. AB - The synthesis, structural and magnetic characterisation of trinuclear manganese cluster, [Mn(3)O(O(2)C-anth)(6)(HOCH(3))(3)] 1 (where O(2)C-anth = 9 anthracenecarboxylate), with crystallographic three-fold (C(3)) symmetry, are described. The cluster was prepared by a carboxylate exchange reaction between HO(2)C-anth and [Mn(12)O(12)(O(2)CMe)(16)(H(2)O)(4)] with concomitant fragmentation of the dodecanuclear Mn core of the starting material to form a trinuclear Mn(3)(MU(3)-O) cluster capped by six carboxylate ligands. Bond valence sum calculations and SQUID magnetometric measurements establish the oxidation states of the metal ions as Mn(II).2 Mn(III) which are antiferromagnetically coupled. PMID- 21541431 TI - The switch-on luminescence sensing of histidine-rich proteins in solution: a further application of a Cu2+ ligand. AB - A new probe/Cu(2+) complex for the detection of his-tagged protein has been developed, based on an improved probe, Dansyl-Gly-Py (1), by closely mimicing the structure of a peptide, ATCUN. In aqueous solution, 1/Cu(2+) has good selectivity to histidine and cysteine, and further can detect histidine-rich protein by releasing the quenched fluorescence of 1. PMID- 21541432 TI - Biosynthesis via carbocations: theoretical studies on terpene formation. AB - This review describes applications of quantum chemical calculations in the field of terpene biosynthesis, with a focus on insights into the mechanisms of terpene forming carbocation rearrangements arising from theoretical studies. PMID- 21541433 TI - The challenges of integrating molecular imaging into the optimization of cancer therapy. AB - We review novel, in vivo and tissue-based imaging technologies that monitor and optimize cancer therapeutics. Recent advances in cancer treatment centre around the development of targeted therapies and personalisation of treatment regimes to individual tumour characteristics. However, clinical outcomes have not improved as expected. Further development of the use of molecular imaging to predict or assess treatment response must address spatial heterogeneity of cancer within the body. A combination of different imaging modalities should be used to relate the effect of the drug to dosing regimen or effective drug concentration at the local site of action. Molecular imaging provides a functional and dynamic read-out of cancer therapeutics, from nanometre to whole body scale. At the whole body scale, an increase in the sensitivity and specificity of the imaging probe is required to localise (micro)metastatic foci and/or residual disease that are currently below the limit of detection. The use of image-guided endoscopic biopsy can produce tumour cells or tissues for nanoscopic analysis in a relatively patient compliant manner, thereby linking clinical imaging to a more precise assessment of molecular mechanisms. This multimodality imaging approach (in combination with genetics/genomic information) could be used to bridge the gap between our knowledge of mechanisms underlying the processes of metastasis, tumour dormancy and routine clinical practice. Treatment regimes could therefore be individually tailored both at diagnosis and throughout treatment, through monitoring of drug pharmacodynamics providing an early read-out of response or resistance. PMID- 21541434 TI - From simple to complex: investigating the effects of lipid composition and phase on the membrane interactions of biomolecules using in situ atomic force microscopy. AB - Biomembrane lipid composition and lateral heterogeneity vary significantly both spatially and temporally and have been shown to be associated with cell functions. Lipid raft-based membrane heterogeneity might be involved with cell physiological and pathological processes. Therefore, there is a great need to investigate the roles of lipid composition and lateral heterogeneity in membrane related physiological and pathological processes. Supported lipid bilayers (SLBs) of increasing complexity are excellent membrane model systems to investigate the effects of lipid composition and phase on the membrane interactions of biomolecules. In situ AFM is a powerful tool to examine the dynamic interactions between SLBs and biomolecules on a nanoscale. Therefore, the in situ AFM measurements between SLBs of increasing complexity and biomolecules are excellent ways to investigate the effects of lipid composition and phase on the membrane related processes. In this review, the following basic knowledge is first discussed: biomembrane lipid composition, lipid raft, lipid phase separation, SLBs, and AFM. Then the biological applications of in situ AFM to visualize the interactions between SLBs of increasing complexity and biomolecules are discussed. PMID- 21541435 TI - Calix[4]arene nitroxide tetraradical and octaradical. AB - 1,3-Alternate calix[4]arene with para-phenylene spacers connecting nitroxide monoradicals and high-spin (S = 1) diradicals provides tetraradical and octaradical scaffolds that possess conformations with slow electron spin relaxation rates (1/T(1)). Such scaffolds may facilitate tuning of relaxation rates that are more favorable for MRI or DNP applications. PMID- 21541436 TI - Synthesis and characterization of sterically encumbered beta-ketoiminate complexes of iron(II) and zinc(II). AB - The synthesis, structure, and spectroscopic signatures of a series of four coordinate iron(II) complexes of beta-ketoiminates and their zinc(II) analogues are presented. An unusual five-coordinate iron(II) triflate with three oxygen bound protonated beta-ketoimines is also synthesized and structurally characterized. Single-crystal X-ray crystallographic analysis reveals that the deprotonated bis(chelate)metal complexes are four-coordinate with various degrees of distortion depending on the degree of steric bulk and the electronics of the metal center. Each of the high-spin iron(II) centers exhibits multiple electronic transitions including ligand pi to pi*, metal-to-ligand charge transfer, and spin forbidden d-d bands. The (1)H NMR spectra of the paramagnetic high-spin iron(II) centers are assigned on the basis of chemical shifts, longitudinal relaxation times (T(1)), relative integrations, and substitution of the ligands. The electrochemical studies support variations in the ligand strength. Parallel mode EPR measurements for the isopropyl substituted ligand complex of iron(II) show low-field resonances (g > 9.5) indicative of complex aggregation or crystallite formation. No suitable solvent system or glassing mixture was found to remedy this phenomenon. However, the bulkier diisopropylphenyl substituted ligand exhibits an integer spin signal consistent with an isolated iron(ii) center [S = 2; D = -7.1 +/- 0.8 cm(-1); E/D = 0.1]. A tentative molecular orbital diagram is assembled. PMID- 21541437 TI - Accessing the long-lived emissive 3IL triplet excited states of coumarin fluorophores by direct cyclometallation and its application for oxygen sensing and upconversion. AB - We studied four cyclometallated Pt(II) complexes, in which the thiazo-coumarin ligands (Pt-2, Pt-3 and Pt-4) or the phenylthiazo ligand (Pt-1) were directly cycloplatinated. Pt-2 shows intense absorption in visible region but other complexes show blue-shifted absorption. Room temperature phosphorescence was observed for all the complexes, and the emission wavelength is dependent on the size of the pi-conjugation, not the intramolecular charge transfer (ICT) feature of the C^N ligands. Pt-2 shows longer phosphorescence lifetime (tau = 20.3 MUs) than other complexes (below 2.0 MUs). Furthermore, Pt-2 shows phosphorescence quantum yield Phi = 0.37, whereas Pt-3 and Pt-4 show much smaller Phi values (0.03 and 0.01, respectively). DFT/TDDFT calculations indicate (3)IL triplet excited states for the complexes. The complexes were used as for luminescence O(2) sensing and triplet-triplet-annihilation (TTA) based upconversion. Stern Volmer quenching constant K(SV) = 0.026 Torr(-1) was observed for Pt-2, ca. 89 fold of that of Pt-3. TTA upconversion is achieved with Pt-2 (lambda(em) = 400 nm with lambda(ex) = 473 nm, anti-Stokes shift is 0.47 eV, excitation power density is at 70 mW cm(-2)). The upconversion quantum yield with Pt-2 as triplet sensitizer is up to 15.4%. The TTET efficiency (K(SV) = 1.33 * 10(5) M(-1), k(q) = 6.57 * 10(9) M(-1) s(-1). DPA as quencher) of Pt-2 is 34-fold of the model complex [Ru(dmb)(3)][PF(6)](2). Our results show that the (3)IL state can be readily accessed by direct cyclometallation of organic fluorophores and this approach will be useful for preparation and applications of transition metal complexes that show intense absorption in visible region and the long-lived emissive (3)IL excited states. PMID- 21541438 TI - Sensitive on-chip detection of a protein biomarker in human serum and plasma over an extended dynamic range using silicon photonic microring resonators and sub micron beads. AB - We demonstrate a three-step assay on a silicon photonic microring resonator-based detection platform that enables the quantitation of the cardiac biomarker C reactive protein (CRP) over a dynamic range spanning six orders of magnitude. Using antibody-modified microrings, we sequentially monitor primary CRP binding, secondary recognition of bound CRP by a biotinylated antibody, and tertiary signal amplification using streptavidin-functionalized beads. This detection methodology is applied to CRP quantitation in human serum and plasma samples. PMID- 21541439 TI - Emergent behavior in particle-laden microfluidic systems informs strategies for improving cell and particle separations. AB - Colloidal particles placed in an energy landscape interact with each other, giving rise to complex dynamic behavior that affects the ability to process and manipulate suspensions of these particles. Propagating across scales ranging from the local behavior of 10's of particles to non-local behavior encompassing >10(6) particles, these particle interactions are pervasive and challenging to describe quantitatively, especially in the confined environments typical of microfluidic devices. To better understand the effects of particle interactions in this context, we have performed experiments and simulations involving a simple microfluidic device in which hydrodynamic and electrostatic forces are leveraged to concentrate and separate particle mixtures. These investigations reveal the mechanisms underlying the dynamic patterns formed by micron-scale particles as they impinge on a dielectrophoretic force barrier: their tendency to aggregate and recirculate under constant operating conditions, and to reorganize when the operating conditions are changed. The emergent behaviors of these ensembles of interacting particles exhibit features of dynamical frustration and cooperativity that suggest non-intuitive strategies for concentrating and sorting suspensions. Finally, we present a simple analytic model based on hydrodynamic coupling that captures important features of strongly interacting particle suspensions. PMID- 21541440 TI - Templated assembly of organic-inorganic materials using the core shell structure of the P22 bacteriophage. AB - Biomimetic chemistry offers new approaches to supramolecular materials synthesis and assembly. We have demonstrated that an assembled viral protein cage, comprising an organic core-shell structure, can be used as a template for the size constrained synthesis of Fe(2)O(3). Particle nucleation is directed by the inner scaffold protein layer, while the size constraints are determined by the outer capsid layer. PMID- 21541441 TI - Widespread deregulation of phosphorylation-based signaling pathways in multiple myeloma cells: opportunities for therapeutic intervention. AB - Multiple myeloma (MM) is a neoplasm of plasma cell origin that is largely confined to the bone marrow (BM). Chromosomal translocations and other genetic events are known to contribute to deregulation of signaling pathways that lead to transformation of plasma cells and progression to malignancy. However, the tumor stroma may also provide trophic support and enhance resistance to therapy. Phosphorylation of proteins on tyrosine, serine and threonine residues plays a pivotal role in cell growth and survival. Therefore, knowing the status of phosphorylation-based signaling pathways in cells may provide key insights into how cell growth and survival is promoted in tumor cells. To provide a more comprehensive molecular analysis of signaling disruptions in MM, we conducted a kinome profile comparison of normal plasma cells and MM plasma cells as well as their surrounding cells from normal BM and diseased BM. Integrated pathway analysis of the profiles obtained reveals deregulation of multiple signaling pathways in MM cells but also in surrounding bone marrow blood cells compared to their normal counterparts. The deregulated kinase activities identified herein, which include the mTOR (mammalian target of rapamycin)/p70S6K and ERK1/2 (extracellular signal-regulated kinases 1 and 2) pathways, are potential novel molecular targets in this lethal disease. PMID- 21541442 TI - Intraclonal cell expansion and selection driven by B cell receptor in chronic lymphocytic leukemia. AB - The mutational status of the immunoglobulin heavy-chain variable region (IGHV) genes utilized by chronic lymphocytic leukemia (CLL) clones defines two disease subgroups. Patients with unmutated IGHV have a more aggressive disease and a worse outcome than patients with cells having somatic IGHV gene mutations. Moreover, up to 30% of the unmutated CLL clones exhibit very similar or identical B cell receptors (BcR), often encoded by the same IG genes. These "stereotyped" BcRs have been classified into defined subsets. The presence of an IGHV gene somatic mutation and the utilization of a skewed gene repertoire compared with normal B cells together with the expression of stereotyped receptors by unmutated CLL clones may indicate stimulation/selection by antigenic epitopes. This antigenic stimulation may occur prior to or during neoplastic transformation, but it is unknown whether this stimulation/selection continues after leukemogenesis has ceased. In this study, we focused on seven CLL cases with stereotyped BcR Subset #8 found among a cohort of 700 patients; in six, the cells expressed IgG and utilized IGHV4-39 and IGKV1-39/IGKV1D-39 genes, as reported for Subset #8 BcR. One case exhibited special features, including expression of IgM or IgG by different subclones consequent to an isotype switch, allelic inclusion at the IGH locus in the IgM-expressing cells and a particular pattern of cytogenetic lesions. Collectively, the data indicate a process of antigenic stimulation/selection of the fully transformed CLL cells leading to the expansion of the Subset #8 IgG-bearing subclone. PMID- 21541446 TI - Heonir Rocha award 2010. PMID- 21541447 TI - Impact of hepatitis C in mortality in patients on hemodialysis. AB - OBJECTIVE: Cardiovascular diseases are the most important causes of mortality in patients with end-stage renal disease. However, viral infections (hepatitis B and C) have acquired great importance for patients undergoing hemodialysis, because they affect patients' survival and increase morbidity and mortality. This study aimed at assessing the influence of hepatitis C on the mortality of patients undergoing hemodialysis. METHODS: This is a non-concurrent cohort study during a period of ten years. RESULTS: Each cohort comprised 74 patients. Hepatitis C did not increase the risk of death, and the survival of infected patients was better than that of patients without hepatitis C. The one-year and five-year survivals of non-infected patients were 93.9% and 52.3%, respectively, while those of noninfected patients were 95.5% and 73.1%, respectively (Cox-Mantel log-rank, p = 0.02). CONCLUSION: No increase in mortality risk was observed. Hepatitis C did not correlate with an increase in mortality in patients with end-stage renal disease undergoing hemodialysis. PMID- 21541448 TI - The nephrologist as a consultant for acute poisoning: epidemiology of severe poisonings in the State of Rio Grande do Sul and techniques to enhance renal elimination. AB - Accidental and intentional poisonings or drug overdoses constitute a significant cause of aggregate morbidity and mortality, and health care expenditures. The nephrologist is frequently called to the emergency room and ICU as a consultant to help with the indication of measures to enhance renal depuration of toxic agents. This study reviews the use of dialysis in acute poisonings due to medications or pesticides, whose specialized toxicological support was provided via telephone by the poison control center of the state of Rio Grande do Sul (CIT RS from Portuguese). The correlation between need for dialysis and death was assessed in a retrospective cohort (1998-2000). Of the 36,055 cases registered, 337 were identified as severe, and 245 met the inclusion criteria required. Mean age was 30 +/- 18 years, and 53% of the patients were women. The most commonly involved medications were anticonvulsants and antidepressants, and the pesticides were organophosphates, bipyridyl compounds, and glyphosate. Techniques to enhance elimination included urinary alkalinization (n = 37) and dialysis. In severe poisonings, dialysis was performed in 4.5% of the cases (n = 11), 3.67 procedures/year (1/22.7 reports of severe cases). In the group undergoing dialysis, 91% involved a suicide attempt (mainly phenobarbital and paraquat). Two cases required hemoperfusion (chloramphenicol and paraquat). Death among non dialyzed severely ill patients occurred in 25.6%, versus 36.3% of dialyzed patients (RR = 0.89; 95% CI = 0.54-1.35). The findings can be explained by the statistic power associated with the number of procedures performed. The nephrologist should be aware of situations requiring the use of dialysis, even if not necessarily aimed at renal replacement, but at enhancing depuration of a toxic agent. PMID- 21541443 TI - Strain differences in alveolar neutrophil infiltration and macrophage phenotypes in an acute lung inflammation model. AB - Pulmonary infection is a major cause of mortality and morbidity, and the magnitude of the lung inflammatory response correlates with patient survival. Previously, we have shown that neutrophil migration into joints is regulated by arthritis severity quantitative trait loci (QTLs). However, it is unclear whether these QTLs contribute to the regulation of lung inflammation in pneumonias. Therefore, to more clearly define the factors regulating acute inflammatory responses in the lung, we examined two inbred rat strains, DA and F344, that differ in these QTLs and their susceptibility to joint inflammation. Staphylococcal cell wall components lipoteichoic acid (LTA) and peptidoglycan (PGN), administered intratracheally, significantly increased the numbers of neutrophils retrieved in the bronchoalveolar lavage fluid (BALF). F344 had approximately 10-fold more neutrophils in the BALF compared with DA (P < 0.001) and higher BALF concentrations of total protein, tumor necrosis factor-alpha and macrophage inflammatory protein 2. LTA/PGN administration in DA*F344 congenic strains (Cia3d, Cia4, Cia5a, and Cia6) resulted in inflammation similar to that in DA, demonstrating that the genes responsible for the differences in pulmonary inflammation are not contained within the chromosomal intervals carried by these congenic strains. Alveolar macrophages (AMs) isolated from naive F344 stimulated in vitro with LTA/PGN produced significantly higher levels of keratinocyte derived chemokine and macrophage inflammatory protein 2 than alveolar macrophages from DA rats. The differences were related to differential mitogen-activated protein kinase phosphorylation. We conclude that the factors contributing to inflammation can be site and challenge dependent. A better understanding of site specific inflammation may lead to more effective treatment of acute lung inflammation and injury. PMID- 21541449 TI - Importance of the monthly biochemical evaluation to identify patients on hemodialysis with malnutrition. AB - INTRODUCTION: Malnutrition is a frequent complication in patients on hemodialysis and early diagnosis is important to reduce the morbidity and mortality of treatment. OBJECTIVE: To investigate the usefulness of biochemical tests performed monthly in order to identify hemodialysis patients with malnutrition. METHODS: The nutritional status of 252 patients was evaluated by objective and subjective global assessment, and the patients classified as malnourished and not malnourished. Then, during 4 consecutive months, serum creatinine, phosphorus, urea pre-and post-dialysis and Kt/V were recorded for calculation of averages. After analysis of these variables by the ROC curve we calculated the sensitivity and specificity of these parameters to identify patients with malnutrition. RESULTS: In ROC curve, the area under the curve for urea was 0.683, 0.71 for phosphorus, 0.724 for Kt/V and 0.765 for creatinine. For values of urea <= 90 mg/dL, phosphorus <= 4.2 mg/dL, Kt/V >= 1.6 and creatinine <= 6.5 mg/dL, the specificity ranged between 80% and 88% and sensitivity between 26% and 51%. The negative predictive value ranged between 90% and 92% and positive predictive value between 23% and 32%. The association of two or more of these indices did not change significantly these values. CONCLUSIONS: Our results suggest that serum urea <= 90 mg/dL, creatinine <= 6.5 mg/dL, phosphorus <= 4.2 mg/dL, and Kt/V >= 1.6 can be used for screening patients with malnutrition. However, using these cutoffs the parameters tend to overestimate the number of patients with malnutrition. PMID- 21541450 TI - Repercussion of physiotherapy intradialytic protocol for respiratory muscle function, grip strength and quality of life of patients with chronic renal diseases. AB - INTRODUCTION: Chronic kidney disease consists in the slow, progressive and irreversible loss in renal function and it is considered a social and economic problem worldwide, since it is linked to numerous diseases, as well as to higher public health spending. It is known that dialysis patients undergo a long period of restricted physical activity reflects in dysfunctions in various organical systems and in the quality of their lives. OBJECTIVE: To verify the results of physical therapy intervention in patients on hemodialysis, for respiratory muscle function, grip strength and quality of life. METHODOLOGY: Experimental, nonrandomized, quantitative and qualitative of a sample of 13 patients, 43.69 +/- 9.28 years, on hemodialysis in the hospital Santa Casa de Diamantina/MG, selected by convenience. All patients were evaluated for maximal respiratory pressures (PI(max) e PE(max) ) and peak expiratory flow (PFE), before and after physiotherapy, which consisted of 3 sessions per week for a period of 2 months weeks: exercises for upper limbs, with technique PNF and breathing diaphragmatic; strengthening exercises for lower limbs and use of exerciser ball. Statistical analysis was performed using the student-t test and significance value at p < 0.05. RESULTS: Respective means for the variables before and after intervention were: PImax (97.69 +/- 28.3 cmH2O e 98.46 +/- 23.39 cmH2O) p = 0.93; PEmax (83.07 +/- 31.19 cmH(2)O e 88.46 +/- 14.0 cmH(2)O) p = 0.46 e PF (375.38 +/- 75.23 L/min e 416.15 +/- 57.37 L/min) p = 0.02. The dynamometer average pre intervention was: 57.23 +/- 17.39 kgf and post intervention: 56.61 +/- 16.09 kgf. In the SF-36, which evaluates the quality of life, improvement was observed in the eight domains, except the item 'vitality'. Of all the variables measured only the PFE was statistically significant. CONCLUSION: The proposed physical therapy protocol did not promote significant improvements in those variables, the statistical point, explaining in part the small sample size, time of protocol and proposed interventions. PMID- 21541451 TI - Effects of aerobic training during hemodialysis on heart rate variability and left ventricular function in end-stage renal disease patients. AB - INTRODUCTION: Decreased heart rate variability (HRV) in patients with end stage renal disease (ESRD) undergoing hemodialysis is predictive of cardiac death, especially due to sudden death. OBJECTIVE: To evaluate the effects of aerobic training during hemodialysis on HRV and left ventricular function in ESRD patients. METHODS: Twenty two patients were randomized into two groups: exercise (n = 11; 49.6 +/- 10.6 years; 4 men) and control (n = 11; 43.5 +/- 12.8; 4 men). Patients assigned to the exercise group were submitted to aerobic training, performed during the first two hours of hemodialysis, three times weekly, for 12 weeks. HRV and left ventricular function were assessed by 24 hours Holter monitoring and echocardiography, respectively. RESULTS: After 12 weeks of protocol, no significant differences were observed in time and frequency domains measures of HRV in both groups. The ejection fraction improved non-significantly in exercise group (67.5 +/- 12.6% vs. 70.4 +/- 12%) and decreased non significantly in control group (73.6 +/- 8.4% vs. 71.4 +/- 7.6%). CONCLUSION: A 12-week aerobic training program performed during hemodialysis did not modify HRV and did not significantly improve the left ventricular function. PMID- 21541452 TI - Brazilian dialysis census, 2009. AB - INTRODUCTION: National dialysis data are fundamental for treatment planning. OBJECTIVE: To report data of the annual survey of the Brazilian Society of Nephrology about chronic renal failure patients on dialysis in January 2009. METHODS: A survey based on data of dialysis units from the whole country. The data collection was performed by using a questionnaire filled out by the dialysis units in Brazil. RESULTS: 427 (69.8%) of the dialysis units in the country answered the questionnaire. National data were estimated for the overall dialysis population. In January 2009, the total estimated number of patients on dialysis was 77,589. The estimated prevalence and incidence rates of chronic renal failure on maintenance dialysis were 405 and 144 patients per million population, respectively. The estimated number of new patients starting dialysis program in 2009 was 27,612. The annual gross mortality rate was 17.1%. For prevalent patients, 39.9% were aged 60 years or older, 89.6% were on hemodialysis and 10.4% on peritoneal dialysis, 30,419 (39.2%) were on a waiting list of renal transplant, 27% were diabetics, 37.9% had serum phosphorus > 5.5 mg/dL and 42.8% hemoglobin < 11 g/dL. A venous catheter was the vascular access for 12.4% of the hemodialysis patients. CONCLUSIONS: The prevalence of chronic renal failure on maintenance dialysis is increasing in Brazil, although in 2009 the estimate is lower than in 2008. The data call attention to indicators of the quality of maintenance dialysis that need to be improved and highlight the importance of the census to guide chronic dialysis therapy. PMID- 21541453 TI - Renal diseases in the elderly underwent to percutaneous biopsy of native kidneys. AB - INTRODUCTION: The elderly population is growing and aging in better clinical conditions than in the past. However, the distribution and course of kidney diseases in elderly patients are not well known partially due to reluctance to indicate renal biopsies in those patients. OBJECTIVE: To evaluate the distribution, clinical features, and outcomes of nephropathies diagnosed by biopsy in the elderly. PATIENTS AND METHODS: Seventy-one patients (47 males, 24 females) aged 60 years or older (67.3 +/- 6.5 years), undergoing biopsy from January 1990 to December 2006, were evaluated. They were grouped according to their clinical syndromes. RESULTS: Nephrotic syndrome was observed in 35 patients (49.3%), mainly associated with membranous nephropathy (17 patients), followed by amyloidosis and focal segmental glomerulosclerosis (seven patients each). Acute kidney injury (AKI) was diagnosed in 19 patients, and the main histopathological diagnoses were acute tubular necrosis (six patients) and cast nephropathy (three patients). Of those 19 patients, only two had a favorable course, while the others died early or progressed toward advanced chronic kidney disease. Twelve patients undergoing biopsy because of asymptomatic hematuria or proteinuria had different diagnoses, but most of them already had significant chronic nephropathy. In five patients with nephritic syndrome, the biopsies also showed several diagnoses. CONCLUSIONS: Nephrotic syndrome was the major indication for renal biopsy, and membranous nephropathy was the most frequent diagnosis. Among patients with AKI and asymptomatic hematuria or proteinuria, different diagnoses were found with high levels of advanced chronic nephropathy. PMID- 21541455 TI - Leptospirosis-associated acute kidney injury. AB - Leptospirosis is the most important zoonosis in the world. Patients are typically young men. Several factors are involved in acute kidney injury (AKI) in leptospirosis, including direct nephrotoxic action of the leptospira, hyperbilirubinemia, rhabdomyolysis and hypovolemia. The major histological findings are acute interstitial nephritis and acute tubular necrosis. Leptospirosis-induced AKI is usually nonoliguric and hypokalemic. Tubular function abnormalities precede a decline in the glomerular filtration rate, which could explain the high frequency of hypokalemia. Antibiotic treatment is efficient in the early and late and/or severe phases. For critically ill leptospirosis patients, the following measures are recommended: early and daily hemodialysis; low volume infusion (due to the risk of pulmonary hemorrhage); and lung-protective strategies. Mortality in leptospirosis-associated AKI is around 22%. PMID- 21541454 TI - Translation, cultural adaptation and aplication of a pain questionnaire for patients with polycystic kidney disease. AB - INTRODUCTION: Pain is a common symptom in patients with autosomal dominant polycystic kidney disease (ADPKD), affecting around 60% of cases. OBJECTIVE: Translate a pain questionnaire developed and validated for ADPKD in USA into Portuguese and to perform its cultural adaptation and apply it. METHOD: The cultural adaptation performed by a panel of experts resulted in small changes consisting of words substitution by synonyms or deletion of terms not commonly used in our culture in 12 out of the 46 questions posed, to solve patients difficulties in understanding the questionnaire. RESULTS: There has been equivalence between the adapted form of the instrument with the back-translation. The final form of the questionnaire applied in 97 patients with ADPKD (64F/33M, 35 +/- 12 years) showed that 65 (67%) had isolated or associated pain in multiple locations , more often at lumbar region (77%), followed by abdominal (66%), headache (15%) and chest (4%). The questionnaire revealed that after family history, pain was the second factor contributing to the diagnosis of ADPKD in this population (55% and 22% of cases, respectively). DISCUSSION: Clinical and laboratory data from medical records showed that patients referring pain had renal volume and size of the largest cyst significantly higher than those without pain. CONCLUSION: We conclude that the use of a specific pain questionnaire for ADPKD population provided a better characterization of this symptom, as well as its relationship with the associated complications that commonly occur in this setting. PMID- 21541456 TI - Horseshoe kidney with cysts and a single ureter: a case report. AB - Horseshoe kidney is the most common of all renal fusion anomalies, occurring in approximately 0.25% of the general population. Horseshoe kidney with only a single ureter is a rare anomaly. A 60-year-old man was admitted to hospital for routine health screening. His family history was negative for kidney diseases, and there was no abnormality in his physical examination. A computed tomography (CT) scan revealed an atypical horseshoe kidney with cysts and three-dimensional spiral CT reconstruction showed the presence of a single ureter. The patient has since been followed up for two years without any signs of clinical disease. We report a rare case of a patient with a horseshoe kidney with cysts and a single ureter that was diagnosed incidentally. PMID- 21541457 TI - World Kidney Day 2011 albuminuria and creatinine: simple, inexpensive and essential tests in the course of chronic kidney disease. PMID- 21541458 TI - World Kidney Day 2011: protect your kidneys, save your heart. PMID- 21541459 TI - Comparison of cognitive function between patients on chronic hemodialysis who carry out assisted physical activity and inactive ones. AB - Physical inactivity is a determinant of clinical disorders and psychological problems in patients with chronic kidney disease patients. In two satellite clinics, a program of physical activity (PA) was offered to 86 patients undergoing hemodialysis. Of those, 49 patients entered the PA program spontaneously and 37 remained inactive. After six months, a satisfaction self reported questionnaire and the Modified Mini-Mental State (3MS) Examination for assessment of cognitive function were applied. Cognition was compared between inactive patients and those participating in the PA program for at least three months. Regardless of age and duration of dialysis, patients showed a cognitive deficit greater than expected. In the general group, better cognitive function was observed in active patients as compared to the inactive ones (p < 0.05). When separated by age groups, active patients over the age of 60 years had better results than the inactive ones (p < 0.05). We concluded that patients with better cognitive responses are more physically active and/or physical activity contributes to better cognitive function. PMID- 21541460 TI - Profile and scientific production of CNPq researchers in Nephrology and Urology. AB - OBJECTIVE: This study aimed at evaluating the profile and scientific production of researchers in Nephrology and Urology, receiving grants in the area of Clinical Medicine from the Brazilian National Research Council. METHODS: The standardized online curriculum vitae (Curriculum Lattes) of 39 researchers in Medicine receiving grants in the 2006-2008 triennium were included in the analysis. The variables analyzed were: gender, affiliation, time from completion of the PhD program, scientific production, and supervision of undergraduate students, and master's and PhD programs. RESULTS: Males (74.4%) and category 2 grants (56.4%) predominated. The following three Brazilian states are responsible for 90% of the researchers: Sao Paulo (28; 71.8%); Rio Grande do Sul (4; 10.3%); and Minas Gerais (3; 7.7%). Four institutions are responsible for 70% of the researchers: UNIFESP (14; 36%); USP (8; 20.5%); UFMG (3, 7.7%); and UNICAMP (3; 7.7%). Considering the academic career, the assessed researchers published 3,195 articles in medical journals, with a median of 75 articles per researcher (QI = 52-100). The researchers received a total of 25,923 citations at the database Web of Science(r), with a median of 452 citations per researcher (QI = 161-927). The average number of citations per article was 13.8 citations (SD = 11.6). CONCLUSIONS: The Southeastern region of Brazil concentrates researchers in Nephrology and Urology. Our study has shown an increase in the scientific production of most researchers in the last five years. By knowing the profile of researchers in Nephrology and Urology, more effective strategies to encourage the scientific production and the demand for resources to finance research projects can be defined. PMID- 21541461 TI - Factors associated with the quality of life of incident patients on PD in Brazil (BRAZPD). AB - INTRODUCTION: The number of patients on peritoneal dialysis (PD) in Brazil is significant, with a higher prevalence of diabetic and elderly individuals on PD than on hemodialysis. These data point to a selection bias in that population. OBJECTIVE: To assess the quality of life (QOL) of patients starting PD in Brazil. METHODS: The study assessed 6,198 patients participating in a multicenter prospective cohort study, using data from BRAZPD. The QOL was assessed by use of the Karnofsky index (QOL assessment by health professionals) and the SF-36 (patient's self-assessment) in 1,624 incident patients. RESULTS: Of the patients analyzed, 40% were diabetic and 47% were elderly (over the age of 60 years). Patients had low QOL scores in all the SF-36 domains, the "physical role" domain being the most affected and the "social functioning" domain having the best score. On the other hand, according to the Karnofsky index, most patients had high QOL scores. Elderly and diabetic patients had lower QOL as compared with non elderly and non-diabetic by using both the SF-36 and Karnofsky index. CONCLUSION: The overall evaluation by use of the SF-36 showed a reduction in the QOL. The Karnofsky index showed a better QOL as compared with the SF-36 assessment, but similar results were found in the subgroups evaluated: the ederly and the diabetic patients had the worst QOL in both assessments. PMID- 21541462 TI - Low response to intradermal hepatitis B vaccination in incident hemodialysis patients. AB - INTRODUCTION: Hepatitis B (HB) may progress to cirrhosis and liver carcinoma. Its prevalence is estimated at 3.2 % in hemodialysis (HD) patients. HB vaccine when applied intramuscularly (IM) in end-stage renal disease patients often does not induce appropriate antibody titers. However, there has been suggestion for intradermal (ID) to be a more effective inoculation method. OBJECTIVE: To compare the immune response to IM or ID vaccine administration on HD patients. PATIENTS AND METHODS: Thirty one incident HD patients were randomly assigned alternately to IM or ID vaccine inoculation. Vaccine doses were applied at three monthly intervals, with patients being followed-up for six months. Sixteen patients were assigned to IM (40 mg/dose) and 15 to ID (4 mg/dose) vaccine administration. HB virus surface antibody titer, hematimetric parameters, serum urea level and Kt/V were monthly evaluated. C-reactive protein, parathormone, ferritin, aminotransferases and albumin serum levels were evaluated before and at the sixth month of the initial inoculation. RESULTS: Urea levels were significantly higher in the ID group (P(1) = 0.031); ferritin levels were higher in the IM (P(2) = 0.037) and C-reactive protein levels tended to be higher in the ID group. An interim evaluation by the Safety Monitoring Committee recommended discontinuing the study as IM vaccination had converted 62.5% of the exposed subjects, while ID inoculation converted only 13.3%. CONCLUSION: As performed, ID applied vaccine was inferior to the IM inoculation. Such result may depend on the inoculated doses or some other factor, such as inflammation. PMID- 21541463 TI - Nephrolithiasis in pediatric patients: metabolic and anatomical investigation. AB - Metabolic disorders are frequently observed in pediatric patients with renal lithiasis. OBJECTIVES: Study the metabolic and anatomical alterations and perform the chemical analysis of stones found in children with nephrolithiasis in our region. METHODS: A retrospective study on 158 children with evidence of recent renal stone formation was performed. One hundred and nine children concluded the metabolic study. Laboratory investigation consisted in two samples of 24-hour urine for calcium, uric acid, citrate, oxalate, sodium and creatinine; qualitative cystinuria, urinary pH following 12-hour fasting and water restriction, urine culture and chemical analysis when the stones were available. Renal imaging techniques included, at least, renal ultrasound and excretory urogram. RESULTS: A cause for nephrolithiasis was identified in 96.3% of children. The main metabolic alteration was hypercalciuria (73.4%). Chemical analysis of stones showed calcium oxalate in 90.9% of the cases. Anatomical alterations were found in 18.0% of the investigated cases and the most frequently found alteration was pyelo-ureteral duplication (28.6%). CONCLUSIONS: Hypercalciuria was the most frequently found disorder and pyelo-ureteral duplication was the most common anatomical alteration; moreover, calcium oxalate was the most frequent chemical constituent. The present study showed the characteristics of pediatric patients with nephrolithiasis in our region. PMID- 21541464 TI - Assessment of methods to identify protein-energy wasting in patients on hemodialysis. AB - INTRODUCTION: The method capable of best identifying protein-energy wasting (PEW) in hemodialysis (HD) patients is controversial. Thus, we assessed the nutritional status of HD patients by use of different methods and verified which one identified the highest number of patients with PEW. METHODS: The study assessed the nutritional status of 15 HD patients (age: 52.7 +/- 10.1 years; males: 33.3%) by use of anthropometric measurements, subjective global assessment (SGA), serum albumin, and dietary intake (24-hour food recall). Body fat was assessed by use of anthropometry. The International Society of Renal Nutrition and Metabolism (ISRNM) criteria were used to diagnose PEW. RESULTS: The body mass index (24.2 +/ 4.4 kg/m2) and the percentage of standard value for mid-arm muscle circumference were within the normal limits (102.6 +/- 13%). Nevertheless, the percentage of standard value for triceps skinfold was below the normal limits (females, 75.3 +/ 40.4%; and males, 73.5 +/- 20.6%), although a high body fat percentage was observed (females, 34.5 +/- 7.3%; males, 23.6 +/- 4.2%). When assessing the nutritional status by use of SGA, most patients (80%, n = 12) were malnourished, and SGA was the method that identified the highest number of patients with PEW. By using the ISRNM criteria, PEW was diagnosed in only two patients. CONCLUSION: All patients were diagnosed with PEW by use of one of the methods studied. The SGA was the method that, in isolation, could detect the greatest number of patients with PEW. PMID- 21541465 TI - Effects of inspiratory muscle training in hemodialysis patients. AB - INTRODUCTION: Chronic kidney disease associated with hemodialysis can have a variety of musculoskeletal complications, in addition to repercussions in pulmonary function. OBJECTIVE: To evaluate the effects of inspiratory muscle training on inspiratory muscle strength, pulmonary function, and functional capacity in patients with chronic kidney failure undergoing hemodialysis. METHOD: Non-controlled clinical trial, comprising 15 individuals diagnosed with chronic kidney failure and undergoing hemodialysis. Maximum inspiratory (PImax) and expiratory (PEmax) pressures were assessed by use of pressure vacuum meter reading. Pulmonary function was assessed by use of spirometry. Functional capacity was assessed by use of walked distance and oxygen consumption obtained in the six-minute walk test (6MWT). For eight weeks, the inspiratory muscle training (IMT) protocol was applied during hemodialysis sessions, with load set to 40% of PImax and weekly frequency of three alternate days. RESULTS: A significant increase in the walked distance was observed after training (455.5 +/ 98 versus 557.8 +/- 121.0; p = 0.003). No statistically significant difference was observed in the other variables when comparing their pre- and posttraining values. CONCLUSION: The study showed no statistically significant difference in respiratory muscle strength, pulmonary function, and oxygen consumption. An increase in the walked distance was observed in the 6MWT. PMID- 21541466 TI - Effects of customary dinner on dietetical profile of patients undergoing hemodialysis. AB - INTRODUCTION: To assess the effects of the habit of having evening dinner on the dietary macro- and micronutrient profile of chronic kidney failure patients on hemodialysis. METHODS: Cross-sectional study carried out at a dialysis clinic at the city of Belo Horizonte, state of Minas Gerais. The study comprised 90 patients undergoing hemodialysis. Personal, clinical, and dietary (three-day food record) data were collected. The habit of having dinner was considered as having a complete evening meal, and the lack of that habit was considered as not having it or replacing it by a fast meal. The amounts of nutrient intake were estimated in the specific software Dietwin(r). RESULTS: The carbohydrate, thiamine, riboflavin, ascorbic acid, calcium, and selenium intake values showed no difference between the group having a complete evening meal and that not having it (p > 0.05). Both groups did not differ in the following: body mass index, and energy, protein, lipid, niacin, pantothenic acid, pyridoxine, folic acid, cobalamin, potassium, phosphorus, zinc, and magnesium intake values (p < 0.05). Regarding nutrient adequacy, the complete evening meal group performed better than the other group, except for carbohydrates, lipids, pantothenic acid, ascorbic acid, potassium, calcium, and zinc (p < 0.05). None of the patients showed the adequate pyridoxine, folic acid, and selenium intake values. Few patients in both groups showed adequate energy, pantothenic acid, and zinc intake values. CONCLUSION: The habit of having a complete evening meal influenced positively the micro and macronutrient intakes in chronic kidney failure patients on hemodialysis. PMID- 21541467 TI - Cardiac morphology and function in patients with and without residual diuresis on hemodialysis. AB - In patients with chronic renal failure on hemodialysis, left ventricular hypertrophy is related to the increase in total peripheral vascular resistance and volume overload. The presence of residual diuresis enables greater control of the volemia of these. We evaluated the morpho-functional changes of the left ventricle in patients with chronic kidney disease on hemodyalisis treatment with and without residual diuresis. A total of 31 non diabetic patients were studied and they were divided into two groups: with residual diuresis (RD+) (n = 17) and without residual diuresis (RD-) (n = 14). In both groups, RD+ vs. RD-, using data from a Doppler echocardiogram differences were found, respectively, in the cardiac index (3.9 +/- 0.2 vs. 3.0 +/- 0.2 L/min/m2; p = 0.0056), systolic index (54 +/- 2.9 vs. 45 +/- 3.3 mL/b/m2; p = 0.04), end diastolic volume (141 +/- 6.7 vs. 112 +/- 7.6 mL; p = 0.008), end diastolic diameter (52 +/- 0.7 vs. 48 +/- 1.1 mm; p = 0.0072) and total peripheral resistance index (1121 +/- 56 vs. 1529 +/- 111 dyne.sec.cm-5; p = 0.001). RD+ had lower relative wall thickness than RD- (0.38 +/- 0.01 vs. 0.45 +/- 0.01; p = 0.0008). The ejection fraction and the left ventricular mass index were similar in both groups. The urinary 24-hour volume correlated with the relative wall thickness (r = -0.42; p = 0.0186) and with peripheral resistance index (r = -0.48; p = 0.0059). In conclusion, there were distinct ventricular geometric patterns and different functional performances between RD+ and RD- groups. The presence of residual diuresis can be responsible by these modifications in systolic function. PMID- 21541468 TI - Comparison of trisodium citrate and heparin as catheter-locking solution in hemodialysis patients. AB - INTRODUCTION: The high incidence of patients beginning dialysis treatment with venous catheters, as well as the growing number of patients with permanent catheter access, has increased catheter- related blood infections and their consequences. Thus the search for substances with anticoagulant properties that also prevent catheter contamination is necessary. OBJECTIVE: This study aimed at comparing heparin and trisodium citrate used as long-term catheter locking solutions regarding the occurrence of pyrogenic reaction, bacteremia, infection- related hospitalizations, thrombosis, and death. METHODS: Retrospective study on the infection data from the Infection and Adverse Event Prevention Control Program registry, which included all hemodialysis patients using long-term catheters from April, 2006 to March, 2008. During the first 365 days, catheters were locked with heparin (Heparin group) and, during the following 365 days, with 46.7% trisodium citrate (Citrate group). Sixty-five patients were included in the study using 92 catheters. The groups were compared regarding the occurrence of pyrogenic reaction, bacteremia, hospitalization, catheter thrombosis, and death. RESULTS: The catheter-related bacteremia episodes were significantly lower and hospitalization time was significantly shorter in the Citrate group when compared with those in the Heparin group. A tendency towards a lower occurrence of access site infection-related hospitalization was observed in the Citrate group (p = 0.055), and no difference was observed in catheter thrombosis leading to dysfunction between groups. Bacteremia-free and hospitalization-free times were longer in the Citrate group. The occurrence of bacteremia was associated with the presence of diabetes and heparin use. In multivariate analysis, being in the Heparin group was the only factor associated with bacteremia. CONCLUSION: The use of 46.7% citrate solution effectively reduced bacteremia episodes and hospitalization in chronic kidney disease patients on hemodialysis with long-term catheters. PMID- 21541469 TI - Chronic kidney disease: importance of early diagnosis, immediate referral and structured interdisciplinary approach to improve outcomes in patients not yet on dialysis. AB - At present, chronic kidney disease (CKD) is broadly defined on the basis of changes in the glomerular filtration rate and/or the presence of parenchymal damage present for at least 3 months. Although the diagnosis of CKD is now quite straightforward, the proportion of patients with end-stage renal disease seen by a nephrologist for the first time immediately before the initiation of dialysis is still unacceptable. Early diagnosis and immediate nephrology referral are key steps in management because enable predialysis education, allow implementation of preventive measures that delay or even halt progression of CKD to end stage renal disease, as well as decrease initial morbidity and mortality. In this review, we discuss the complexity of CKD and the multiplicity of interventions currently recommended in its secondary prevention, different models of healthcare delivery, and examine the rational and outcomes of patients followed in interdisciplinary care clinics. PMID- 21541470 TI - Cellular congenital mesoblastic nephroma: case report. AB - INTRODUCTION: Congenital Mesoblastic Nephroma (CMN) is a rare pediatric renal tumor. It comprises two histological subtypes, namely classic and cellular, with the second accounting for two thirds of all cases and being more often associated with poor prognosis. It remains a diagnostic challenge for pathologists due to its similarity with other more frequent pediatric kidney neoplasms. CASE REPORT: We describe the case of a 2-year- old girl who presented with a left renal mass. After nephrectomy, the specimen analysis showed, on gross examination, an extensive, granular and whitish tumor lesion occupying almost the entire kidney, invading the renal sinus, capsule and perirenal fat, with areas of hemorrhage and necrosis. Histologically, it was characterized by ovoid spindle cells, mitoses and no cell atypia, which led to a diagnosis of cellular mesoblastic nephroma. Adjuvant chemotherapy was carried out, but tumor recurrence occurred in the first year, presenting as an unresectable tumor that did not respond to adjuvant chemotherapy and the patient died at 4 years of age. DISCUSSION: The cellular variant tends to be more aggressive, with a survival rate of 85% versus 100% for the classic variant. Recurrence generally occurs in the first year, particularly with the cellular variant. PMID- 21541471 TI - Assessment and management of cardiovascular disease in patients with chronic kidney disease. PMID- 21541472 TI - Buttonhole: an old technique rediscovered. PMID- 21541473 TI - Oncogenesis in HIV-infection. AB - The presence of human Kaposi's sarcoma associated herpesvirus-like sequences (KSHV) was examined in different epidemiological variants of Kaposi's sarcoma (KS) and in KS-derived cell cultures by polymerase chain reaction (PCR). KSHV DNA was present in all tumor biopsies of AIDS-associated KS (59 biopsies), endemic KS (26 biopsies; 21 African endemic KS, 5 Greek endemic KS), sporadic/classical KS (28 biopsies) and post-transplant/iatrogenic KS (6 of 7 biopsies). On the contrary, these sequences were only detected rarely in non-involved skin of KS patients (3 positive specimens of 12), in the peripheral blood mononuclear cells of HIV-infected patients (3 positive specimens of 54) and in lymphoma-biopsies (3 positive specimens of 47). Cell cultures derived from KS skin lesions were positive for KSHV DNA only in the first two passages. However, two longer-term positive cultures from a biopsy of a patient affected with sporadic KS and a biopsy of a patient affected with epidemic KS was identified. A strong association of KSHV with KS tissue was observed in all the different epidemiological variants of KS. Long-term positive KS-derived cell cultures will be an important tool to study the herpesvirus-like agent and to investigate its functional role in the initiation and progression of KS. PMID- 21541474 TI - Expression of ets family of genes in systemic lupus erythematosus and Sjogren's syndrome. AB - We have examined the expression of three members of the ets family of genes, ETS1, ETS2 and ERGB/Fli-1, in lymphocytes from patients with systemic lupus erythematosus and in two murine autoimmune model systems. The ERGB/Fli-1 gene is expressed at a higher level in lymphocytes from autoimmune disease patients than healthy individuals. In addition, we found that the ERGB/Fli-1 gene expression is higher in splenic T-cells from lupus prone mice and in infiltrating lymphocytes in the salivary glands of HTLV-I tax transgenic mice. Taken together, these results suggest that the elevated expression of the ERGB/Fli-1 gene in lymphocytes may be a prelude to the development of autoimmune diseases. PMID- 21541475 TI - Catalytic lectin (leczyme) from bullfrog (Rana catesbeiana) eggs. AB - Catalytic lectins (leczymes) of frog eggs are sialic acid-binding lectins that have intrinsic RNase activity. They inhibit tumor cell proliferation in vitro and in vivo, although their cytotoxic mechanism remains unclear. RNase A has no tumoricidal activity. It is hypothesized that leczymes bind to cell surface sialoglycoconjugate receptors, enter the cell, and subsequently degrade RNA. In order to investigate the cytotoxic mechanism of cSBL, a leczyme from Rana catesbeiana eggs, we established cSBL-resistant clone RC-150 from mouse leukemia P388 cells. cSBL-treated P388 cells showed extensive RNA degradation over the course of 1 h, whereas cSBL-treated RC-150 cells showed no RNA degradation even over the course of 24 h. Treatment of P388 cells with cSBL led to decreased concentration of intracellular Ca2+, decreased protein kinase A activity, and increased protein kinase G activity. Incubation with cSBL decreased glutathione levels and enhanced glutathione-S-transferase (GST) activity in P388 cells, but had no effect on RC-150 cells. We conclude that cSBL-specific degradation of RNA occurs in cSBL-sensitive tumor cells, that cSBL leads to alteration of signal transduction and an intracellular protein kinase cascade reaction, and that internalized cSBL is detoxified by GST or thioltransferase. Our findings support a bifunctional model in which a leczyme is both an adhesive protein (binding to sialoglycoconjugates) and an enzyme (displaying RNnase activity). PMID- 21541476 TI - Low dose calcium leucovorin with continuous 5-fluorouracil infusion. AB - Two hundred and sixty patients with malignant disease were treated, first with an intramuscular injection of 15 mg of calcium (ca.) leucovorin followed in 16 hours by a continuous infusion of 1000 mg/M(2) of 5-fluorouracil and 15 mg of ca, leucovorin; both given over 24 hours for 5 days. Courses were repeated, toxicity permitting, every 21 days. Severe stomatitis and marrow suppression occurred in every patient but were tolerable and rapidly reversible. Severe diarrhea occurred in only 12 patients. No patient died as a result of therapy. In patients with metastatic carcinoma of the large bowel who had not been treated in the past with a fluorinated pyrimidine, 39% of patients had a partial or complete remission, with a mean duration of response of 16.5 months. In those with carcinoma of the breast who had not received prior non-hormonal therapy, 39% had a partial or complete remission. It is our impression that the response rate and the duration of response in both these neoplasms are substantially better than that seen with fluorouracil alone. PMID- 21541477 TI - Human and rodent expression pattern of a fusion gene isolated from an MCF7 cDNA library. AB - A cDNA library established from the human mammary carcinoma cell line MCF7 was used to screen for transcripts related to or representing the gene coding for the estrogen receptor-related protein ERD5. Among the two populations of cDNAs isolated, one group (3 clones) represented heat shock protein transcripts (HSP27), the other (2 clones) appeared identical in their insert size and restriction enzyme banding pattern. Detailed analysis of one of them revealed its nature as a fusion sequence composed of two genes. At the 5'-end it consists of the last 157 bp of the HSP28 gene. At its 3'-part, it is identical to the 3' portion of thr nuclear factor IV gene. The genuine expression of this fusion gene was demonstrated by Northern blots and RT-PCR. It appears to be ubiquitously expressed in a variety of normal tissues and malignant cells in man, mouse and rat. PMID- 21541478 TI - Ectopic expression of vascular endothelial growth factor (VEGF) by C6 glioma cells does not increase tumour growth in vivo despite an increase in angiogenesis. AB - The growth of solid tumours is dependent on a number of processes and one of the most important is angiogenesis. Several growth factors have been demonstrated to have angiogenic activity, yet only one factor, vascular endothelial growth factor (VEGF) appears to act specifically as a mitogen on endothelial cells. To date, two receptors for VEGF have been characterised, VEGF-R1 and VEGF-R2 which are expressed on endothelial cells. However, the precise role(s) of each of these receptors in the process of tumour neovascularisation is not entirely clear. It has been demonstrated that the inhibition of VEGF expression in rat C6 glioma cells results in the suppression of tumour growth in vivo. Therefore, it was of interest to determine whether an increase in VEGF expression in C6 cells would promote an accelerated tumourigenicity in vivo. In order to address the role(s) of VEGF in tumour angiogenesis and growth, we have generated rat C6 glioma cells that express VEGF(165) in constitutively high levels and investigated their growth properties in vitro and in vivo as well as the vasculature they generate in vivo. The cell lines expressing VEGF are morphologically different to the parental C6 cells and grow at a slower rate ia vitro. In vivo, the VEGF expressing rumours also grew slowly, were highly vascularised and contained varying degrees of necrosis and eosinophilic infiltrate. Therefore, VEGF appears to be essential for neovascularisation of tumours but this process does not result in a more rapid tumour growth rate of C6 cells and is not sufficient in preventing the onset of tumour necrosis nor an eosinophilic immune response. PMID- 21541479 TI - Expression of Gal beta 1-4GlcNAc sequences by human gastrointestinal neoplasms and their precursors as detected by Erythrina cristagalli and Erythrina corallodendron lectins. AB - Lectins from Erythrina cristagalli (EGA) and Erythrina corallodendron (ECorA) are well-known to detect type 2 chain oligosaccharides (Gal beta 1-4GlcNAc). These carbohydrate moieties are the biosynthetic precursors of various ABH and Lewis blood group antigens and are therefore also related to tumor-associated carbohydrate antigens. For this reason, we investigated the expression of ECA and ECorA binding sites in a series of gastric, colorectal and pancreatic carcinomas as well as corresponding normal tissues. Additionally, a series of hyperplastic and adenomatous colorectal polyps was analyzed. According to our results, both lectins exhibited a strong reactivity with the great majority of gastrointestinal carcinomas. Regarding gastric carcinomas, a stronger reactivity with intestinal type compared to the diffuse-type species could be observed. Some poorly differentiated tumors were not or only very faintly stained. In the case of colorectal carcinomas, liver metastases which were investigated comparatively, exhibited the same binding pattern as the primary tumors. Colorectal adenomas were stained in about half of the cases without significant relation to the grade of cellular atypia. Positivity observed in normal epithelia (i.e, gastric superficial epithelia, fundus neck cells and deep pyloric mucous glands, pancreatic acini and ductal structures) is in keeping with histogenetic relations between these normal histological structures and corresponding neoplasms. In areas exhibiting intestinal metaplasia, various portions showed cytoplasmic staining of columnar cells and/or of goblet cell vacuoles. On the other hand, columnar and goblet cells in normal colorectal tissue were only weakly stained in a number of specimens. Therefore, it can be concluded that Gal beta 1-4GlcNAc is overexpressed in neoplastic colorectal tissues. Summarized, ECA and ECorA are suitable tools to analyze the expression of Gal beta 1-4GlcNAc, the common precursor substance of various tumor-associated type 2 chain antigens in neoplastic tissues. PMID- 21541480 TI - Expression of Fas and anti-Fas-mediated apoptosis in human renal cell carcinoma. AB - We investigated Fas expression and Fas-mediated apoptosis on 25 surgically resected renal cell carcinoma (RCC) tissues and 8 RCC cell lines. Immunohistochemistry demonstrated that cancer cells in the 25 tissues expressed Fas (100%). Fas expression was confirmed in all cell lines at protein and mRNA levels, but the 7 cell lines were resistant or low sensitive to anti-Fas induced apoptosis. In addition, cancer cells in all of the RCC tissues and all cell lines expressed an anti-apoptotic proto-oncogene, bcl-2 product. In conclusion, i) Fas/Fas-ligand system may be often impaired in RCCs despite their frequent expression; and ii) their frequent Bcl-2 expression may further contribute to the resistance to various apoptotic stimuli. PMID- 21541481 TI - Nimodipine as a modulator of resistance to doxorubicin in human colon adenocarcinoma cells. AB - The potential of the dihydropyridine nimodipine (NIMO), a drug currently used for cerebrovascular disorders, in modulating the cytotoxicity of doxorubicin (DX) was investigated, in comparison to verapamil (VER), in human colon adenocarcinoma cell lines sensitive (LoVo) or resistant (LoVo/DX) to anthracycline. NIMO selectively enhanced DX activity in the resistant cell line. In particular, the DX concentration able to inhibit cell growth by 50% was reduced by 2.6 to 5.7 fold as a function of the time of exposure to the modulator. The increase in DX accumulation in LoVo/DX nuclei after exposure to NIMO was about 4-fold that observed in the nuclei of resistant cells exposed to DX alone. Similar results were obtained in LoVo/DX cells following treatment with equimolar concentrations of VER. Again, both NIMO and VER failed to interfere with the immunoreactivity of LoVo/DX cells to the MRK16 monoclonal antibody. NIMO did not inhibit H-3 azidopine binding to LoVo/DX cells, but, unlike VER, it caused a selective hyperpolarization of the cell membrane in resistant cells. PMID- 21541482 TI - Heterogeneity of cytokeratin expression as revealed using monoclonal antibodies in salivary adenocarcinomas. AB - Numerous neoplastic lesions of the salivary glands often share a number of similar histopathological features and different areas of the same tumor specimen, not infrequently, may show a diverse histomorphology. The present study evaluates expression of single keratin proteins recognized by monoclonal anti-K7, K8, K18, K19 and keratins recognized by monoclonal KL1 and K8.12 in tubular-duct like or cribriform structures, solid nests, clear cells, microcystic, basaloid cells and squamous metaplastic histomorphology present in tissue specimens of adenoid cystic carcinoma (n=11), acinic cell carcinoma (n=5), polymorphous low grade adenocarcinoma (n=1) and adenocarcinoma, not otherwise specified (NOS, n=5) of salivary glands. Expression of vimentin in the epithelial tumor cells was further evaluated using an anti-vimentin monoclonal antibody. A great heterogeneity of keratin expression was observed in the luminal and abluminal cells forming the tubular-duct-like and cribriform structures. The abluminal cells in more than half of the instances of adenoid cystic carcinoma had immunoreactive vimentin. In addition, heterogeneity was more pronounced in tumor cells forming the solid nests, comedo-necrosis, microcysts, clear cells or squamous metaplasia. A heterogeneity of keratin profile in different histomorphologies of different tumor types and even in different areas of the same tumor specimen, in the present study, and the available evidence so far limits the use of cytokeratin immunostaining in the differential diagnosis of neoplastic salivary lesions and characterization of a particular histomorphology which, in many instances, are ubiquitous in different tumor subtypes. PMID- 21541483 TI - The role of human leukocyte antigen and tumor necrosis factor D as a prognostic, preventive and therapeutic factor in gastric cancer. AB - In order to clarify the immunogenetical background, host factors in oncology, human leukocyte antigen (HLA) and tumor necrosis factor (TNF) beta alleles as prognostic, preventive and therapeutic indicators were investigated in 712 patients with a histologic diagnosis of adenocarcinoma of the stomach treated with gastrectomy. HLA and TNF beta alleles were tested serologically and by DNA PCR typing. The absence of HLA Cw1 antigen may represent resistant and prognostic factors. HLA-B51, B61 and TNF beta 10.5 kb homozygote alleles are therapeutic, survival and prognostic factors. Considering the relation with lymph node metastasis, HLA-DR4 antigen and HLA-DRB 1*0405 allele were found to be risk factors for lymph node metastasis in poorly differentiated adenocarcinoma. TNF beta 10.5 kb homozygote allele also represented a risk factor for lymph node metastasis. TNF beta 5.5 kb homozygote allele was considered a resistant factor for lymph node metastasis in poorly differentiated adenocarcinoma. HLA and TNF beta alleles can play an important role as prognostic, preventive and therapeutic indicators in gastric cancer. Therefore, TNMH (TNM with host factor) should be proposed as a new approach. PMID- 21541484 TI - Usefulness of 22-oxa-1,25-dihydroxyvitamin D-3 (OCT) as a single agent or combined therapy with aromatase inhibitor (CGS 16949A) on 7,12 dimethylbenz[a]anthracene-induced rat mammary tumors. AB - The antitumor effects of 22-oxa-1,25-dihydroxy-vitamin D-3 (OCT), a vitamin D-3 analogue, were evaluated on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumors. The combined effects of OCT (0.3 mu g/kg) with tamoxifen (0.5 mg/kg) medroxyprogesterone acetate (MPA) 2.5 mg/kg), or a new aromatase inhibitor, CGS 16949A (0.8 mg/kg) were also evaluated. OCT significantly suppressed the growth of tumors without hypercalcemia in a dose dependent manner at the fourth week from the start of treatment. Tumor size in the OCT+CGS 16949A group was significantly decreased compared with that in the OCT or CGS 16949A alone. However, there was no significant difference in tumor size between OCT alone and combined therapy with tamoxifen or MPA. We conclude that a single administration of OCT, which does not cause hypercalcemia, is effective for breast cancer and that a combination of OCT and aromatase inhibitor, CGS 16949A augments the antitumor effect on tumors compared to each single agent. PMID- 21541485 TI - Transforming growth factor beta 1 (TGF-beta 1) expression in proliferating thyroid disease. AB - In order to clarify some of the molecular mechanisms involved in the pathogenesis of thyroid proliferating diseases we have investigated the role of TGF-beta in thyroid carcinoma, adenoma and multinodular goiter. TGF-beta 1 expression studies were carried out in surgically removed thyroid tissue isolated from 15 patients affected by multinodular goiter, 4 patients affected by papillary carcinoma and 4 patients affected by follicular adenoma. TGF-beta 1 gene expression, evaluated by Northern analysis, dramatically increased in malignant proliferating thyroid disease and decreased drasticly in multinodular goiter patients with respect to normal thyroid. Immunocytochemical analysis demonstrated that TGF-beta 1 is produced by an autocrine mechanism in the carcinoma and in the benign thyroid disease (multinodular goiter), whereas TGF-beta seems to be produced in adenoma tissues in both an autocrine and a paracrine fashion. This feature further supports the hypothesis that TGF-beta may contribute to regulation of thyrocyte growth and differentiation. PMID- 21541486 TI - Murine model of cancer gene therapy. AB - In order to examine how the adenovirus-mediated gene therapy induce anti adenoviral immunity, we set up experiments for a murine cancer model. We first administered adenovirus carrying LacZ (AxCALacZ) gene to DBA/2 mice intraperitoneally, then two weeks after administration of the virus, P815 tumor cells infected with adenovirus carrying LacZ gene were inoculated intraperitoneally to the AxCALacZ immune mice. The mice rejected the P815 tumor infected with AxCALacZ and survived for long periods. The peritoneal T cells in adenovirus immune mice had a strong killing effect of adenovirus-infected P815 cells. Further, parental P815 tumor cells were inoculated into the mice, which rejected the P815 tumor infected with AxCALacZ. All mice rejected P815 tumor cells and survived for long periods. These mice developed P815 specific tumor immunity, which was confirmed by a cytotoxicity assay. PMID- 21541487 TI - Genetic status of p53 and induction of apoptosis by radiation or isoflavones in human gastric carcinoma cell lines. AB - We have shown previously that various human cancer cell lines undergo morphological changes and internucleosomal DNA fragmentation characteristic of apoptosis after exposure to ionizing radiation or isoflavones. Here, we assessed the role of p53 gene in cell cycle and apoptosis following treatment of 11 gastric carcinoma cell lines with gamma-rays, genistein, biochanin A, or daidzein. Cell survival was measured by trypan blue staining, and apoptosis was assessed by fluorochrome staining. The rate of cell survival and apoptosis of the cells by gamma-irradiation or isoflavones did not correlate with p53 gene abnormalities. Flow cytometric measurement of DNA content demonstrated that while gamma-irradiation and genistein induced G(2) arrest, biochanin A and daidzein blocked the cell cycle of all carcinoma cells at G(1) phase. At multiple time points following irradiation, G(2) arrest was observed at 12-16 h in the wild type and mutant p53 cell lines. Induction of p53 and p21 proteins was not observed in wild-type p53 lines after exposure to gamma-irradiation or isoflavones by Western blotting. Moreover, transfection of the wild-type p53 gene into MKN-1 cells failed to induce G(1) arrest by gamma-irradiation and genistein. Based on these results, we hypothesize that gastric cancer cells may possess a signal pathway which is different from the usual mechanisms of the p53-mediated DNA damage response in normal or hematopoietic tumor cells. PMID- 21541488 TI - Mechanisms of preferential metastasis of breast cancer to bone - (Review). AB - Breast cancer frequently and preferentially spreads to bone. Once breast cancer colonizes bone, it is essentially incurable. The cellular and molecular mechanisms by which breast cancer selectively metastasizes to bone remain largely unknown. Elucidation of these mechanisms should lead to the development of effective and specific therapeutic strategies for bone metastasis of breast cancer. PMID- 21541489 TI - HER-2/neu, c-Myc and cyclin-A in human breast cancer. AB - To better understand the role of HER-2/neu, c-myc and cyclin-A which seem to be activated in different steps of tumor cell growth, we analyzed a series of breast cancers from patients subjected to radical mastectomy with regard to HER-2/neu amplification (N=171) and expression of HER-2/neu (N=114), c-myc (N=31) and cyclin-A (N=71). Molecular evaluation demonstrated that HER-2/neu was amplified in 20% of cases and overexpressed in 27%, and its alterations were associated with a higher proliferative activity (H-3-Tdr-labeling index), although not statistically significant in patients without lymph node metastases, c-myc was overexpressed in 16% of cases and was weakly correlated to proliferation activity. Cyclin-A was overexpressed in 15% of cases and was significantly correlated to the percentage of the H-3-Tdr labeled cell fraction (p=0.002). Cyclin-A alterations were also significantly associated with well-differentiated tumors, suggesting that this gene could be involved in the control of the normal cell cycle rather than to cell proliferation during tumor growth. PMID- 21541490 TI - In vitro modulation of MCF-7 breast cancer cell growth by myoepithelial cells. AB - Growth and differentiation of MCF-7 breast adenocarcinoma cells were studied in mixed cultures of MCF-7 cells and PA 16/23 myoepithelial cells and in isolated cultures of MCF-7 cells grown in the absence and presence of conditioned medium of PA 16/23 cells. In the cocultures, the MCF-7 cells grew in smaller aggregates and showed a more differentiated phenotype than in the isolated cultures. The conditioned medium of PA 16/23 cells enhanced growth and reduced differentiation of the MCF-7 cells. Hence, a direct relationship between MCF-7 cells and PA 16/23 cells seems to play a leading role in influencing the behaviour of the former cells, thus overriding the opposite effects of soluble factors secreted by the PA 16/23 cells. PMID- 21541491 TI - Intrasplenic vaccination against experimental melanoma. AB - The immunodominant component of a formalinized extracellular antigen (fECA) vaccine prepared from B16 F10 melanoma cells is the melanoma-associated antigen B700. We now demonstrate that a single prophylactic intrasplenic inoculation of B700 antigen (1-10 mu g) stimulates the production of antibodies which have antiproliferative effects on B16 F10 melanoma cells in vitro. In addition, potential cytotoxic effects of splenocytes from B700 antigen inoculated mice were evaluated for two cellular immune effector functions, natural killer (NK) cell activity and lymphokine activated killer (LAK) cell activity; both activities were increased following B700 antigen inoculation. Intrasplenic injection of B700 antigen elicited an increase in the expression of the CD25 surface antigen (IL-2 R alpha) by T lymphocytes and up-regulated the expression of IL-2 R alpha mRNA. Thus both humoral and cellular cytotoxic immune responses might play roles in the decreased growth of primary tumors in B700 antigen inoculated mice and in the higher survival rate in this group of animals. PMID- 21541492 TI - Relative effects of immunohistochemical expressions of c-erbB-2, p53, and bcl-2 oncoproteins on the survival of advanced breast cancer patients after endocrine therapy. AB - c-erbB-2, p53, and bcl-2 oncoproteins were detected immunohistochemically in 92 recurrent or advanced breast cancer tumors just before an endocrine therapy, adreno-oophorectomy. Estrogen receptors (ER) and partly progesterone receptors were concomitantly assayed in the same tumor tissues. Twenty-eight percent (26/92) of c-erbB-2, 16% (15/92) of p53, and 11% (10/92) of bcl-2 expressions were shown to be positive. There were no significant correlations of these oncoproteins with clinical background characteristics of the patients, except the inverse relation between p53 expression and ER status (p=0.0033). Of these covariates, ER status was shown to be the only predictor of response to endocrine therapy. In the absence of ER measurement, p53 expression was a significant predictor of the response. Kaplan-Meier curves showed that ER had a significant and p53 expression had a marginal effect on the overall survival length of the patients, c-erB-2 or bcl-2 were indifferent to survival or response. It is concluded that p53 immunohistochemical expression might be a supplementary predictor next to ER status of the overall survival as well as response of advanced breast cancer patients treated with endocrine therapy, and that p53 alteration might modify the ER dependent hormone-responsiveness of breast cancer. PMID- 21541493 TI - Image cytometry characterization of ploidy level, proliferative activity and chromatin pattern in 50 nasal polyps. AB - A computer-assisted microscope analysis of Feulgen-stained nuclei was carried out on a series of 50 nasal polyps in order to try to identify specific biological subgroups. The present series of 50 nasal polyps includes single polyps both associated (n=9) and unassociated (n=9) with allergy and diffuse polyposis both associated (n=7) and unassociated (n=9) with allergy, cystic fibrosis (n=9) and ASA (aspirin-sinusitis-asthma) related polyposis (n=7). The computer-assisted microscope analysis provides 36 quantitative variables which include 1 variable describing proliferative activity, 9 describing the nuclear desoxyribonucleic acid distribution (DNA ploidy level) and 26 describing nucleus morphology, i.e. its size and chromatin pattern. The results show that the methodology proposed here enabled four major groups of nasal polyps to be identified, i.e. diffuse polyposis associated with allergy, cystic fibrosis-related polyposis, single polyps both associated and unassociated either with allergy and a fourth group including diffuse polyposis not associated with allergy and ASA-related polyposis. These four groups of nasal polyps differed markedly in their morphonuclear characteristics, but not in the proliferative activity- and DNA ploidy-related variables. PMID- 21541494 TI - Different types of DNA cleavage involved in osteosarcoma cell death. AB - To induce cell death in osteosarcoma, a murine osteosarcoma clone, DOS C14 was exposed to: i) topoisomerase II-reactive epipodophyllotoxin, etoposide (ETO); ii) glucocorticoid analogue, dexamethasone (DEX); and iii) ultraviolet light (UV) irradiation. In MTT assay, fifty micromolar ETO, 100 mu M DEX and UV irradiation for 90 min reduced the cell number to 20% of that of the control. The cytotoxic effects of ETO and DEX were dose-dependent, while those of UV irradiation were time-dependent. Endonuclease cleavage of DNA into internucleosomal fragments was not recognized on DOS C14 osteosarcoma treated with 50 mu M ETO, 100 mu M DEX or UV irradiation. Aurintricarboxylic acid (ATA) also failed to inhibit the reduction in the number of viable cells. However, DNA from DOS C14 osteosarcoma cells exposed to 1 h UV irradiation showed smearing DNA fragments after treatment with S1 endonuclease, while such single strand modification was not detected in DNA extracted from cells exposed to ETO or DEX. On the other hand, pulse field gel electrophoresis revealed that cleavage of DNA into high molecular weight fragments estimated as 50-150 kilobase pairs (kbp) with a peak of 100 kbp was found in DOS C14 osteosarcoma cells exposed to 50 mu M ETO and 100 mu M DEX. The cytotoxicity of ETO and DEX was reduced by okadaic acid, while UV-induced cytotoxicity was not reduced by okadaic acid. Furthermore, okadaic acid inhibited the formation of high molecular weight DNA fragments in a dose-dependent manner. These results suggest that two types of DNA degradation exist in osteosarcoma death; one is random breakage of DNA, and the other is large DNA fragmentation, which may be produced by an activation of putative ATA-insensitive and okadaic acid-sensitive endonuclease. PMID- 21541495 TI - Gel fiberglass as a new matrix of affinity chromatography columns for isolation of colon cancer-associated antigens. AB - Gel fiberglass (GFG), a new affinity biosensor, was used to isolate human p53 antigen with rabbit anti-rat p53 IgG. The biosensor was prepared as a membrane from glass fibers covered with oxysilanes. A thin layer of protein, trapped in gel glass during its preparation, is deposited on the surface of a lattice of glass fibers. In such conditions, a maximum number of protein molecules may contact external agents percolated through a membrane. The membranes demonstrate high stability and can be stored in dry conditions or several months at room temperature. Columns for affinity chromatography were prepared from the GFG membranes and were used to isolate various proteins, including the tumor associated antigens (TAA). The capacity of such columns was calculated as the amount mg of protein isolated from 1 ml of TAA-containing serum. In colon cancer patients, up to 5-6 mg TAA were extracted from 1 mi of sera. Two main components of cytoplasmic TAA isolated in our experiments were p64 and p53 proteins. Their concentration was determined by HPLC. The p53 protein has been isolated from the serum of cancer patients in the highest concentration yet reported, up to 3-4 mg/ml. In our previous studies, isolation of p53 protein was based on its affinity reaction with anti-p53 IgG generated against antigens of the same species. Herein, we report for the first time the capability to isolate human p53 antigen using GFG columns with entrapped anti-rat p53 IgG. Blood levels of p53 antigen isolated were very similar in both experiments. This has both theoretical and practical significance, demonstrating that the GFG membranes have great potential for isolating macromolecules utilizing various ligands. The finding facilitates an easy and highly effective method to isolate antigens from different organs, both animal and human, which can be used for important goals including diagnosis, therapy and generation of specific antibodies. PMID- 21541496 TI - A comparison of hyperthermia inhibition of sublethal radiation damage recovery in four human cell lines with different radiosensitivity. AB - Four human cell lines, one normal fibroblast and three tumour lines of differing radiosensitivities were evaluated for recovery from radiation damage, and for inhibition of this recovery by hyperthermia. The normal fibroblast, the glioma and the resistant ovarian carcinoma had about the same radiation resistance and sublethal damage recovery (SLDR) capacity. The sensitive ovarian carcinoma cell line had a much lower SLDR capacity. The potentially lethal damage repair (PLDR) capacity was greatest in the fibroblast and least in the resistant ovarian carcinoma. Hyperthermia for 30 min at 43 degrees C resulted in inhibition of SLDR and PLDR in all cell lines. Heating immediately after irradiation was most effective. In general, SLDR inhibition was greatest in the cell lines with the highest SLDR capacity while there was no such correlation with PLDR. Hyperthermia was most effective in the four cell lines tested when given immediately after the first dose of radiation of the split dose regimen. Thus, for clinical fractionated treatment, it may be most efficacious to give hyperthermia immediately after irradiation. PMID- 21541497 TI - bcl-2 plays a critical role in growth and in spontaneous or induced apoptosis in myeloma cell lines. AB - The role of bcl-2 in spontaneous and drug-induced apoptosis in multiple myeloma (MM) is not yet established, particularly since the frequency of t(14:18) in MM is relatively low. In recent studies, we have investigated the steady-state levels of bcl-2 mRNA transcripts and bcl-2 protein in 8 MM cell lines and found inverse correlation between the levels of bcl-2 and sensitivity to dexamethasone (DEX)-induced apoptosis. Moreover, we have shown that bcl-2 was further down regulated in DEX sensitive cell lines, but not in DEX resistance cell lines, in the course of DEX-induced apoptosis (Int J Oncol 8: 719-726, 1996). Herein, we report the results of transfection studies of 2 DEX sensitive MM cell lines, expressing relatively low levels of bcl-2, with a bcl-2 inducible gene construct expressed under the control of lac repressor operon. Thus, switching-on of bcl-2 by IPTG resulted in increased bcl-2 protein in the cells, enhancement of cell growth, and a decrease in spontaneous apoptosis, concomitant with increased resistance to DEX. Switching-off of bcl-2 protein expression by removal of IPTG resulted in restoration of sensitivity to DEX-induced apoptosis. We, therefore, conclude that bcl-2 plays a central role in cell growth and in spontaneous and induced apoptosis in MM cell lines. PMID- 21541498 TI - PKCs. AB - Molecular cloning and biochemical characterization of individual members of the protein kinase C (PKC) family demonstrated that single PKC isoenzymes display distinct structure, activation conditions, substrate specificity and tissue distribution. In the last few years a number of studies based on isoenzyme overexpression indicated that the PKC family coordinates a complex network of pivotal signal transduction pathways and pathway crosstalks, which regulate cell growth and differentiation, neoplastic transformation and malignant progression. This study reviews recent progress in PKC investigation, and focuses on achievements which have been shown to be relevant to cancer research. PMID- 21541499 TI - Production of IL-5, a classical T(H)2 cytokine, following bacillus Calmette guerin immunotherapy of bladder cancer. AB - Among the many immunological events associated with successful intravesical bacillus Calmette Guerin (BCG) immunotherapy of bladder cancer is the induction of a wide range of cytokines including the T helper 2 (T(H)2) designated cytokines Interleukin-6 (IL-6) and IL-10, but not IL-4, in the urine of the patients. The aim of this work was to determine if this treatment resulted in the production of IL-5, a classical T(H)2 cytokine. Following treatment using ELISA this cytokine was detected in the urine of all patients examined confirming that intravesical BCG therapy does not induce in bladder cancer patients solely a T(H)1 response but rather T(H)1/2 or T(H)0 like response. PMID- 21541500 TI - Drug resistance. AB - An overview of the current mechanisms identified as associated with the expression of multidrug resistance is provided. The clinical relevance of multidrug resistance associated with the overexpression of the three major drug resistance-associated proteins namely, P-glycoprotein, MRP and/or LRP, is discussed. Alternate forms of multidrug resistance involving the reduced or altered expression of either or both of the topoisomerases is next considered, followed by a short section relating to resistance to the platinum complexes and the contribution of altered DNA repair. For those involved in new drug discovery programmes for cancer chemotherapy, the identification and study of these new major intracellular targets makes this an exciting era. PMID- 21541501 TI - Increase of the epidermal growth factor receptor expression by interferon-beta. AB - The epidermal growth factor receptor (EGF-R) is expressed on both normal and malignant epithelial tissue. Recent efforts in cancer therapy use the EGF-R as a target for an antibody therapy. A further increase of the EGF-R expression possibly by interferon (IFN) could improve the efficacy of such an antibody therapy. The effects of IFN on the EGF-R and on the cell proliferation were first evaluated on a human squamous cell carcinoma cell line HLac 79. Several types of IFN were screened for their influence on the receptor expression by flow cytometric studies. IFN-beta caused a doubling of the measured EGF-R expression at a concentration of 100 IU/ml for 48 h. Scatchard analysis with I-125-EGF after IFN treatment showed a doubling of the EGF-R expression and a third of the receptor affinity compared to untreated cells. These alterations were associated with a decrease of the cell proliferation as measured by a bromodeoxyuridine (BrdU) assay. Results were confirmed with xenografts on NMRI nu/nu mice. IFN-beta (intra tumoral) treated xenografts showed a significantly higher amount of EGF-R (393+/-59 fmol/mg protein) and significantly reduced tumour growth compared to untreated xenografts (262+/-51 fmol/mg protein). This study shows that IFN-beta results in an increase of the EGF-R expression in a carcinoma cell line and in xeno-grafts. Cell proliferation is decreased, resulting in reduced growth of the xenograft. PMID- 21541502 TI - Identification and partial characterization of novel genes by differential display of mRNAs in squamous papillomas induced in skin of SENCAR mice. AB - Using the technique of differential display of mRNAs, we isolated 42 differentially expressed cDNAs from squamous papillomas induced in the skin of SENCAR mice by a standard 7,12-dimethylbenz(a)anthracene initiation and 12-O tetradecanoylphorbol-13-acetate promotion protocol. Thirty-one of the cDNAs were cloned and sequenced and the sequences compared with the catalogued sequences in the GenBank/EMBL DNA databases. Two of the cDNA clones-pJTM-4 and pJTM-12-showed insignificant homology with the known murine DNA and protein sequences and thus are novel gene transcripts. Putative protein product of the cDNA clone pJTM-15 showed homology to a stretch of amino acids (with a difference of two amino acids out of 16 compared) within the coding region of the previously reported murine platelet derived growth factor inducible KC protein cDNA (KC/Gro, a member of small cytokine family). By Northern blot analysis, transcripts of pJTM-4 and pJTM 12 cDNAs were found to be expressed in mRNA samples prepared from similarly induced skin tumors in other mice but were not expressed in the epidermis of either untreated mice or in uninvolved epidermis of the tumor bearing mice. Expression of pJTM-4 and pJTM-12 was also detected in mouse sarcoma and lymphosarcoma cell lines but not in a melanoma cell line. These results suggest possible involvement of these novel genes in non-melanoma skin cancer. Full length sequences of these novel transcripts and characterization of their protein products may provide useful information regarding the molecular events which occur during multistage skin carcinogenesis. PMID- 21541503 TI - Anti-tumor and cell cycle responses in KB cells treated with a chimeric anti-EGFR monoclonal antibody in combination with cisplatin. AB - Overexpression of the epidermal growth factor receptor (EGFR) has been found to correlate with a poor prognosis for many cancers. The EGFR appears to play an important role in regulating cell growth during tumorigenesis and blockade of the EGFR/ligand interaction may be a means of inducing cell cytotoxicity, terminal differentiation, or apoptosis. In this report, we show that the growth of well established xenografts of the human epidermoid carcinoma cell line KB could be significantly inhibited by the combination of cisplatin plus C225, a chimeric anti-EGFR monoclonal antibody, whereas the individual treatments had no effect on tumor growth. Substantive changes in the protein expression levels of the EGFR as well as several important cell cycle regulatory proteins were found in cells treated with the combination. In addition, cisplatin plus C225 inhibited the overall phosphorylation patterns including EGFR activation. These in vitro data suggest a mechanism of action for the in vivo therapeutic effects of C225 plus cisplatin. PMID- 21541504 TI - Metastatic phenotype of mouse-human melanoma cell hybrids is associated with the presence of chromosome 17 from highly metastatic human melanoma cells. AB - We have previously shown that in interspecific mouse-human melanoma cell hybrids obtained by fusion of nonmetastatic mouse with metastatic human melanoma cells, the metastatic phenotype predominates. The purpose of this study was to identify human chromosome(s) which could be responsible for conferring metastatic potential upon nonmetastatic mouse melanoma cells and therefore harbor the genes important for the metastatic properties of human melanoma cells. Seven mouse human melanoma hybrids were examined; five were derived from the fusion of nonmetastatic (C19) and metastatic (C3) mouse K-1735 melanoma clones with highly metastatic clone (C15) of human melanoma A375 and the two others had as a human partner a nonmetastatic clone (Cls) of the A375 melanoma. The hybrids were examined during segregation of human chromosomes in vitro and in vivo for metastatic properties in nude mice and for the retaining human chromosomes. In the hybrid H7, which demonstrated the highest metastatic potential, the presence of human chromosomes was studied by GTG-banding and by fluorescence in situ hybridization (FISH) analysis. In the other hybrids, only FISH detection of human chromosomes was applied. All hybrids derived from nonmetastatic mouse and metastatic human melanoma cells demonstrated metastatic properties from early passages, when they contained the majority of the human chromosomes. Their metastatic phenotype remained stable during further segregation of most of the human chromosomes except for 17. Chromosome 17 was retained most consistently in all examined hybrids. However, the metastatic phenotype of the hybrids was associated only with the presence of chromosome 17 from the metastatic human donor cells. This chromosome was also found in almost 100% of cells recovered from lung metastases derived from the hybrid cells. In one lung metastasis developed from the H7 hybrid, chromosome 17 was detected as the sole human chromosome and these cells preserved the acquired high metastatic properties. Based on these results we conclude that human chromosome 17 from metastatic melanoma cells (A375 C15), when functional in the mouse genetic background, can be sufficient to render the recipient nonmetastatic mouse cells to a fully malignant phenotype. Additional data suggest that this ability might be related to the expression of the mutated human p53 gene. PMID- 21541505 TI - Spontaneously transformed rat pancreatic epithelial oval cells give rise to ductal type adenocarcinomas. AB - Oval epithelial cells that proliferate in the pancreas of the rats maintained on a copper-deficient diet are considered as stem cells with a potential to differentiate into hepatocytes. We isolated these oval cells from a copper deficient rat and maintained these as a cell line in our laboratory. During 13th passage, oval cells showed increased growth and cellular pleomorphism and were analyzed for spontaneous transformation by anchorage-independent growth in soft agar and tumorigenicity in nude mice. Oval cells formed large colonies in soft agar and developed tumors in nude mice after subcutaneous transplantation. The tumors, by light and electron microscopy, showed features of well differentiated ductal-type adenocarcinomas. The phenotypic properties of these tumors included expression of neutral mucins, keratin filaments, carcinoembryonic antigen and glutathione S-transferase-pi and absence of gamma-glutamyltranspeptidase. The results of this study demonstrate that spontaneously transformed oval cells can form typical ductal-type adenocarcinomas. These observations are of particular interest, since bonafide ductal adenocarcinomas have not been described in the rat pancreas before. PMID- 21541506 TI - Differential effects of a murine monoclonal antibody reactive with the disialylgalactosyl residue on the growth of melanoma cells and T cell activation. AB - A murine monoclonal antibody, S2-566, was generated by immunization with a melanoma line, SK-MEL-28. Although AbS2-566 showed a similar reaction pattern with that of anti-GD3 mAbR24 in cell surface serology, it recognized a disialyl galactosyl structure not only in GD3 but in GT1a and GQ1b. The suppression of the growth of cultured melanoma cells by AbS2-566 was not obvious, in contrast with AbR24. However, the mitogenic effects of AbS2-566 on peripheral lymphocytes were observed showing similar kinetics to those of mAbR24, suggesting different signaling effects based on the different epitope structures. PMID- 21541507 TI - Expression of prothymosin-alpha and c-myc mRNA in human gastric cancer. AB - Prothymosin-alpha (PT-alpha) is a nuclear protein involved in cell proliferation. c-myc is implicated in the carcinogenesis of many human cancers. PT-alpha gene transcription is reported to be regulated by the c-myc gene in vitro. However, little has been reported on the PT-alpha and c-myc mRNA expressions in gastric cancer. We semi-quantitatively determined the PT-alpha and c-myc mRNA expressions in 60 pairs of gastric cancer tissue (T) and corresponding normal tissue (N) using the reverse transcriptase-polymerase chain reaction method. The average of T/N ratio was 1.20 for PT-alpha and 1.30 for c-myc. Cases demonstrating a T/N ratio of more than 1.0 were seen in 33 (55%) and 30 (50%) cases for PT-alpha and c-myc, respectively. No significant correlation was observed between either of these two mRNA expressions and any of the examined clinicopathologic factors for gastric cancer. However, a significant correlation was seen between the expressions of both genes (p<0.0001). The findings support the hypothesis that, regarding human gastric cancer, the transcription of PT-alpha is considered to be under the control of c-myc gene, however, the value of these gene expressions do not reflect biological behavior. PMID- 21541508 TI - Prospective study of fatty acid synthetase (FAS) expression in breast cancer and progression of disease. AB - Fatty acid synthetase (FAS) mRNA was determined in breast carcinomas of 91 patients. The patients were followed for an average of 47 months. Disease-free survival and overall survival were compared with the expression of FAS-mRNA in the tumour. Sixty-five patients remained disease-free during the follow-up period; twenty-six had recurrent disease, and of those 18 died of the disease. Seventy-five percent of the tumours had low FAS-mRNA levels and there were fewer deaths in this group of patients (15%) than in that with high FAS-mRNA levels (35%). The proportion of recurrences was also smaller in the group with low FAS mRNA. The probability of survival for five years was over 80% for the low FAS mRNA group, and about 50% for the high FAS-mRNA group. PMID- 21541509 TI - Value of immunohistochemical detection of noncollagenous proteins of bone for the diagnosis of bone tumours. AB - The expression of osteonectin, osteopontin, bone sialoprotein, and osteocalcin was evaluated by immunohistochemistry in 57 cases of osteoid-forming and non osteoid-forming bone tumours using specific polyclonal antibodies and the avidin biotin peroxidase complex method. A positive immunostaining was found in all of the osteoid-forming rumours (osteoblastoma and osteosarcoma), both in the cells and in the extracellular matrix. Among non-osteoid-forming tumours, immunoreactivity to noncollagenous proteins was present in the cells but not in the matrix of chondrosarcoma, malignant fibrous histiocytoma, and fibrosarcoma, as well as in the mononuclear component of giant-cell rumours. Contrary to small cell osteosarcoma, Ewing's sarcoma was always negative for all of the noncollagenous proteins considered. These results suggest that the immunohistochemical evaluation of noncollagenous proteins of bone may be a useful tool for the differential diagnosis of bone neoplasms, particularly among the heterogeneous group of small round cell tumours. PMID- 21541510 TI - Multipotent human breast stem cell line MCF1OAT. AB - Human breast epithelial MCF10AT cells injected with Matrigel into the subcutis of nude/beige mice form simple ducts which, with time, resemble human proliferative breast disease and sporadically progress to carcinoma. Basement membrane was visualized with a silver stain and myoepithelial cells detected by their reactivity with antibody against smooth muscle actin. The ducts formed in situ are bilayered, composed of both myoepithelial and luminal epithelial layers circumscribed by a distinct basement membrane. The human origins of both luminal and myoepithelial layers were confirmed with fluorescent in situ hybridization with a probe for human chromosome 9. Electron microscopic studies reveal actin bundles and the formation of hemidesmosomes bordering the basement membrane, consistent with myoepithelium, as well as the formation of desmosomes between luminal and myoepithelial cells. PMID- 21541511 TI - No significant changes in the expression of the fas,fasl,bcl-2 and bax genes in apoptosis of an erythroleukemic cell line by p53. AB - A murine erythroleukemic cell line (1-2-3) which expresses only the temperature sensitive mutant p53 gene (Ala-to-Val substitution at codon 135) was established. When these cells were cultured at 32 degrees C, the growth rate was reduced significantly and DNA fragmentation, a typical character of apoptosis, was observed. In this process, p53 migrated from cytoplasm to nucleus and protein complexes binding to the p53-responsive element were detected in nuclear extracts of the cells cultured at 32 degrees C by gel-shift assay and transactivation from the p53-responsive element was detected. The expression of the p21 (waf1/cip1/sdi1), cyclin G and gadd45 genes was increased (about 3- to 4-fold that at 37 degrees C), when the cells were cultured at 32 degrees C. However, no significant change was detected in expression of the mdm2, bax and fas genes. No change in the amount of Fas antigen was observed by flow cytometric analysis. Transcripts of the bcl-2 and fas1 gene were not detected in the cells either at 37 degrees C or 32 degrees C. These results suggest that other gene(s) than bax, fas, fas1 and bcl-2 may be important for induction of apoptosis of this erythroleukemic cell line by p53. PMID- 21541512 TI - Inhibition of membrane ruffling and ezrin translocation by gamma linolenic acid. AB - Membrane ruffling of a tumour cell is correlated with its motile and metastatic behaviour. This study examined the effect of gamma linolenic acid (GLA), an anti cancer agent, on HGF/SF induced membrane ruffling in the human cancer cell line, HT115. HGF induced a rapid appearance of membrane ruffling which was related to increased motility and the tyrosine phosphorylation and translocation of ezrin, a membrane-cytoskeleton linker protein. The presence of GLA significantly inhibited both the membrane ruffling and cell motility of the tumour cells, at sub-toxic concentrations. Western blotting revealed that the tyrosine phosphorylation of ezrin was inhibited by GLA. The translocation ezrin from cytosol and generalised areas of cell membrane to ruffled areas of the membrane induced by HGF/SF was also inhibited as shown by both indirect immunofluorescence and transmission electron microscopy. It is concluded that GLA inhibits HGF/SF induced membrane ruffling via its effect on ezrin, and this provides a further molecular explanation for the anti-tumour action of GLA. PMID- 21541513 TI - Enhanced expression of hepatitis B surface antigen by sodium butyrate in PLC/PRF/5 human hepatoma cells. AB - The effect of butyric acid, a natural fermentation product of colonic bacterial flora, on hepatitis B surface antigen (HBsAg) expression was investigated in HBsAg-positive PLC/PRF/5 human hepatoma cells. By Northern blot analysis, the levels of HBsAg mRNA increased dose-dependently using sodium butyrate (0-2 mmol/l). In transient chloramphenicol acetyltransferase plasmid transfection experiments, the HBsAg-preS2 promoter activity as well as the HBV enhancer 1 activity was stimulated by sodium butyrate, whereas the HBsAg-preS1 promoter activity was not. These results indicate that butyric acid functions as a physiological regulator of HBsAg expression through the portal blood flow and possibly contributes to increased expression ratio of preS2/S to preS1 polypeptides recognized in persistant HBV infection. PMID- 21541514 TI - DCC gene alterations in histological types and clinical stages of epithelial ovarian cancer. AB - We examined loss of heterozygosity (LOH) and mRNA expression of the DCC gene in 77 tissues and 6 cell lines of human ovarian cancer. LOH was seen in serous and endometrioid adenocarcinomas but was not in clear cell and mucinous adenocarcinomas. LOH was exhibited in all clinical stages including stage I. In the DCC mRNA expression, 6 of 9 (66.7%) cancer tissues and all of 6 (100%) cancer cell lines showed loss or marked reduction. These results suggest that alterations of the DCC gene may play important roles in the pathway of carcinogenesis of human ovarian cancer, especially serous and endometrioid adenocarcinomas. PMID- 21541515 TI - Correlated susceptibility between interferon-beta and UV in human cell lines, F IFr and RSa. AB - The human cell line F-IFr is a variant with an increased resistance to cell proliferation inhibition (CPI) by human interferon (HuLFN)-beta, established from RSa cells with high sensitivity to CPI. The parent RSa cells were recently found to be unusually hypermutable after irradiation with far-ultraviolet light (UV), as assessed by two different methods; estimation of the cloning efficiency of ouabain-resistant (Oua(R)) mutants and detection of K-ras codon 12 mutation in genomic DNA identified by polymerase chain reaction following differential dot blot hybridization. In the present study, F-IFr cells were found to be hypomutable; less than one Oua(R) mutant per 10(4) survival cells after UV (0-12 J/m(2)), in contrast to 0.51-85 Oua(R) mutants per 10(4) survivors in RSa cells, and no detectable K-ras codon 12 mutation at any UV dose tested. However, F-IFr cells, when cultured with medium containing the protease inhibitor antipain immediately and transiently after UV irradiation displayed hypermutability to almost the same extent as RSa cells by both phenotypic and genetic mutation analyses. The refractoriness of F-IFr cells to HuIFN-beta CPI was also suppressed by culture with medium containing antipain during HuIFN-beta exposure. Moreover, F-IFr cells irradiated with UV or treated with HuIFN-beta showed elevation of antipain-sensitive protease activity, but not the irradiated or treated RSa cells. UV- and HuIFN-beta-susceptibility were not modulated by antipain in RSa cells. These antipodal characteristics between the two cell lines suggested that antipain-sensitive proteases and/or cellular functions may be involved in increased resistance of F-IFr cells to both Wand HuIFN-beta refractoriness. PMID- 21541516 TI - Influence of induction of HSP70 on the cytotoxicity of oxazaphosphorine compounds and cisplatin. AB - Induction of HSP70 and thermotolerance may also decrease the cytotoxicity of cytostatic agents or their combination with hyperthermia in clinically used thermochemotherapy. HSP70 and thermotolerance were induced by hyperthermia (42 degrees C, 1 h) in two human tumor cell lines in vitro and in vivo. The influence of thermotolerance on the cytotoxicity of CDDP and the oxazaphosphorine compounds Mafo and Ifo and their combination with hyperthermia (42 degrees C or 43 degrees C, 1 h) were studied. The results show that neither thermotolerance nor HSP70 affects the tumor cell sensitivity to CDDP or oxazaphosphorine compounds. However, the additive effect of hyperthermia and CDDP was found to be attenuated in thermotolerant cells. The cytotoxicity of oxazaphosphorine compounds combined with hyperthermia was not altered after preheating, suggesting a different mechanism may be responsible for the drug-hyperthermia interaction of CDDP and oxazaphosphorine compounds. There were no differences between in vitro and in vivo results suggesting mechanisms at the cellular level being responsible for the influence of thermotolerance on drug- and drug-hyperthermia action. PMID- 21541517 TI - Hematopoietic rescue in mice via alpha 1-adrenoceptors on bone marrow B cell precursors. AB - We demonstrated that adrenergic agents may affect hematopoiesis via high and low affinity al-adrenergic receptors (alpha 1-ARs) present on bone marrow cells. Here we show that the high affinity, alpha 1-AR is present on Mac1(-) B220(+)sIgM(-) (pre-B) cells. The low affinity alpha 1-AR seems to be present on Mac1(+) B220(-) cells. Noradrenaline administration in mice rescued hematopoiesis from the toxic effect of carboplatin or X-rays sublethal irradiation. The protection was reflected by higher leukocyte and platelets counts as well as by increased bone marrow granulocyte/macrophage colony-forming units (GM-CFU). At its most effective dose (3 mg/kg, s.c.), noradrenaline protected 77% of the mice injected i.v. with 200 mg/kg of carboplatin (LD 100:170 mg/kg). The contemporary administration of the alpha 1-AR antagonist prazosin brought the percent of surviving mice down to 30% indicating that alpha 1-ARs mediated most of the noradrenaline-induced hematopoietic rescue. In vitro, noradrenaline (1 mu M) rescued GM-CFU in unseparated bone marrow cells containing the adherent population expressing the high affinity alpha 1-AR. Consistently, the hematopoietic rescue was counteracted by low concentrations (0.1 nM-10 nM) of the alpha 1-antagonist prazosin. Our findings describe a novel mechanism of hematopoietic regulation and might find application in preventing the myeloablative effect of anticancer treatments. PMID- 21541518 TI - Inhibition of B16 melanoma metastasis by the immunomodulator AS101. AB - The immunomodulator ammonium trichloro (dioxyethylene-O-O')tellurate (AS101) has previously been found to induce secretion of various cytokines in mouse and human, which include interleukin-l, interleukin-2, colony-stimulating factor, interferon-gamma, tumor necrosis factor, etc. It also protects mice from lethal and sublethal effects of chemotherapy and irradiation. The present studies were designed to evaluate its effect on pulmonary metastasis following intravenous (i.v.) injection of mouse B16 melanoma cells on day 0 of the experiment. AS101, given 10 mu g/mouse intraperitoneally in 7 daily injections starting the day before B16 cell infusion (day -1) led to a significant inhibition by 60%. When B16 cells were pretreated with AS101 for 24 h before injection, the lung metastases were further reduced by subsequent AS101 treatment of the tumor-loaded mice. In mice that had been depleted of natural killer (NK) cells using anti asialo-GM1 antisera, AS101 was deprived of its stimulatory effect on the NK activity. The inhibition by AS101 on the B16 lung metastasis was also profoundly reduced by the antisera. Moreover, in vitro treatment of B16 cells with AS101 resulted in suppression of the cell growth in a semisolid culture. This was accompanied by an inhibition of the DNA synthesis and a dephosphorylation/activation of the retinoblastoma susceptibility protein (RE), a tumor suppressor gene product, in the B16 cells. Taken together, these data suggest that AS101 possesses an anti-metastatic activity, which probably involves two mechanisms: the stimulation of the host NK cell activity and the inhibition of the tumor cell proliferation. PMID- 21541519 TI - Genetics of colorectal cancer (Review). AB - There is an increasing awareness of the genetic basis of colon cancer and the application of gene therapy. The most commonly altered oncogenes are c-Ki-ras and c-myc, with less frequent involvement of c-src and c-erb. The loss of heterozygosity (LOH) on chromosome 5q has been frequently associated with adenomas, occurring on 17q, 18q, 1p35, 8p22 and 22q11-13 loci. This results in a loss of tumor suppressor gene for these chromosomes. The LOH on 5q was noted on the adenomatous polyposis coli (APC) and the gene on chrome-some 5 was mutated in over 55% cases of colorectal cancer, termed mutated in colon cancer (MCC). MCC is regarded as a tumor suppressor gene which is responsible for the initiation of colon cancer. The deleted in colon cancer gene (DCC) on 18q21 is a common cause of adenomas and the LOH on 17q in p53 gene are frequently seen in bowel cancer. Comparison of frequency with which tumor suppressor and oncogenes are altered in the adenomas and carcinomas suggests that there is a preferred order for their occurrence in the adenoma-carcinoma sequence. Our studies indicate that supplement with tumor suppressor oncoprotein may open a new avenue for gene therapy of colorectal cancer but steps in the identification of the gene(s) await further exploration. PMID- 21541520 TI - Prognostic value of Ki 67/MIB1 automated and quantitative immunolabelling in primary operable breast carcinomas. AB - The prognostic significance of Ki 67/MIB1 immunohistochemical assays (ICAs) was investigated in optimal technical conditions in 139 breast carcinomas. Automated ICAs (immunoperoxidase/Ventana device) was performed on frozen sections. Immunoprecipitates were quantified by computerized analysis (SAMBA) of digitized microscopic images. Mean positive surfaces (%) and quantitative immunocytochemical (QIC) index were correlated to the patients survival (8-year survival). The results showed that Ki 67/MIB1 large surfaces (cutpoint, 20%) and high QIC index (cutpoint, 12) correlated with poor overall survival (Kaplan Meier, log rank test, p=0.011 and p=0.037, BMDP software). In node positive, but not in node negative patients, large Ki 67/MIB1 surface (cutpoint, 20%) and high QIC index (cut-off 12) correlated with the overall patient survival (p=0.0037 and p=0.049). Also large Ki 67/MIB1 positive surface (cut-off, 20%) correlated with disease-free survival in all patients and node positive patients (p=0.022 and p=0.0057) but not in node negative patients. It is concluded that in optimal technical conditions (automated and quantitative immunohistochemical assays on frozen sections) Ki 67 antigen immunohistochemical expression in breast carcinomas tissue has a prognostic significance in node positive patients but not in node negative patients. PMID- 21541521 TI - Human papillomaviruses (HPV) are associated with multiple myeloma. AB - Human papillomaviruses (HPV) are small DNA tumor viruses, and are associated with epithelial neoplasias. Although HPV are believed to be exclusively permissive in terminally differentiated squamous cells, we have previously identified HPV sequences in lymphoid tissues of five patients. Because this result suggested that the range of the host virus cells could include cells of lymphoid origin, we used PCR and in situ hybridization to analyze nonepithelial tissues of patients with multiple myeloma from two institutions. A statistically significant association was established between HPV and multiple myeloma (p<0.001). This study supports the hypothesis that HPV can infect lymphoid cells. PMID- 21541522 TI - Postoperative 5-fluorouracil plus levamisole combined with radiation therapy for high risk rectal cancer patients. AB - Adjuvant chemotherapy in rectal cancer patients is aimed at decreasing the relapse rate of the disease, increasing the disease-free and the overall survival of the patients. The combinations of radiation therapy and several drugs have been tested, but the efficacy of 5-fluorouracil plus levamisole in rectal cancer is not determined yet. Sixty-two consecutive Dukes' B2 or C rectal cancer patients were enrolled into a prospective phase II study. Within 4 to 6 weeks following en-block resection of the tumor and lymphatics, adjuvant chemotherapy had to be started. Combination of 5-FU 375 mg/m(2)/day was given intravenously over 15-20 min for 5 consecutive days, every 4 weeks for 1 year. Levamisole 50 mg t.i.d. was administered orally during the first 3 days of each course of chemotherapy. Radiation therapy included 50 Gy, given by a linear accelerator 8 MV, to a pelvic BOX field. Dose per fraction was 1.8-2.0 Gy daily, administered for 5 consecutive days a week. Follow-up time of the whole group ranges from 7 to 53 months (median 18). Failure rate was 32.3%. The most common site for first relapse was the liver followed by recurrence in the pelvis or the surgical bed. Age, sex, tumor grade and number of involved lymph nodes were not associated with rate nor with site of relapse. Fifty-five percent of the relapses were observed in patients during the year of the adjuvant treatment. Toxicity included diarrhea (33.9%), nausea and vomiting (19.4%), weakness and mucositis. The disease-free survival rate for a median follow-up of 18 months in our study is 75%. The 3.5 year disease-free survival is 67% for the whole group. Our phase II study results point to the feasibility and acceptable toxicity of post-operative combination of 5-FU plus low-dose levamisole and radiation therapy in rectal cancer patients. PMID- 21541523 TI - Correlation of glutathione S-transferases with overall survival in patients with gastric carcinoma. AB - Glutathione S-transferases (GST) are enzymes involved in the detoxification of xenobiotics and are divided into four subclasses, Alpha, Mu, Pi, and Theta. Most human gastrointestinal tumors contain increased amounts of GST Pi and GST enzyme activity. The relationship between GST parameters and tumor and patient characteristics, including overall survival, were studied retrospectively in normal and malignant gastric tissue from 49 patients with primary gastric carcinoma. Twelve patients (24%) were alive at the end of the study with a mean follow-up time of 4.1+/-0.4 years. Levels of GST Alpha, Mu, Pi and GST enzyme activity were not related to tumor stage, localization and diameter of the tumor, number of eosinophils in the tumor, presence of intestinal metaplasia in normal gastric mucosa, or gender and age of the patient. Optimal dichotomization and uni and multivariate analyses were done with the Cox proportional hazard model. None of the clinicopathological parameters were associated with survival, except the number of eosinophils in the tumor. In contrast, high levels of GST Pi in both normal mucosa (Hazard ratio 3.0, p=0.02) and in gastric carcinoma (HR 2.2, p=0.05) and the presence of GST Mu in normal (HR 0.4, p=0.05) and malignant (HR 0.3, p=0.009) gastric tissue were found to have a significant prognostic value, independent from the clinicopathological parameters, when added separately to a Cox model. In conclusion, the levels of GST Mu and Pi in both normal or carcinomatous gastric tissue have an independent prognostic impact on overall survival. PMID- 21541524 TI - Resistance to TGF beta in SV40 large T-immortalized rat intestinal epithelial cells is associated with down-regulation of TGF beta type I receptor. AB - A new continuous cell line designated ESKI-1 was established by transfection of rat fetal intestinal epithelial cells with ecotropic retroviruses containing SV40 large T oncogene. The ESKI-1 cell line exhibits morphologic features of an epithelial cell line and expresses the OCI-5 and cytokeratin 8 transcripts associated with epithelial cells in the small intestine. Signal transduction and proliferation responses to TGF beta has been characterized in ESKI-1 cells, in comparison with the spontaneously-immortalized IEC cell lines originating from neonatal rat duodenum and ileum. ESKI-1 express both TGF alpha and TGF beta. However, despite a marked increase in TGF beta-stimulated p78 kinase activity observed in ESKI-1 and IEC cells, TGF beta did not modulate growth, or extracellular matrix expression in ESKI-1 cells. Resistance to growth modulation was associated with downregulation of TGF beta. Type I receptor expression in the SV40 large T-immortalized cells. Thus, proliferative resistance to TGF beta inhibition can result from depletion of the TGF beta type I receptor and disruption of the TGF beta signaling pathway downstream the p78 serine/threonine kinase. These molecular defects constitute two early events during the SV40LT mediated immortalization and neoplastic progression of the intestinal epithelia. PMID- 21541525 TI - bcl-2 plays a major role in resistance to dexamethasone induced apoptosis in multiple myeloma cell lines. AB - The role of bcl-2 in protection against apoptosis is well established in a great variety of cells and has become a hallmark of drug-resistance in many tumor cell lines, notably in lymphomas and leukemias. However, the role of bcl-2 in spontaneous and drug induced apoptosis in multiple myeloma (MM), is not yet established, particularly since the frequency of t(14:18) in MM is relatively low. We have recently studied the steady-state levels of mRNA transcripts for bcl 2, bar and P53 in 8 MM cell lines and found inverse correlation between the levels of bcl-2 mRNA transcripts and sensitivity to dexamethasone (DEX) induced apoptosis. Moreover, we have also shown that mRNA transcripts for bcl-2 were further down-regulated in 2 DEX sensitive cell lines in the course of DEX induced apoptosis, whereas mRNA transcripts for bcl-2 were unchanged in 2 DEX-resistant MM cell lines (Int J Oncol 8: 719-726, 1996). In this study, we determined the steady-state levels of bcl-2, P53 and bar proteins in 4 myeloma cell lines, and the levels were correlated with sensitivity to DEX induced apoptosis. Two cell lines (HS-Sultan and ARH-77) expressed relatively high levels of bcl-2 protein and were highly resistant to DEX induced apoptosis. Two cell lines (8226 and ARP 1) expressed relatively low levels of bcl-2 protein, and were 2-3 logs more sensitive to DEX. In contrast, the levels of bar protein were similar in all cell lines tested. The steady-state levels of P53 protein varied among the various cell lines but did not correlate with resistance to DEX. Induction of apoptosis in the DEX sensitive cells resulted in an early down-regulation of bcl-2 and P53 protein, whereas the levels of bar protein were only slightly decreased. In contrast to the DEX sensitive cell lines, the levels of bcl-2, bar and P53 proteins in the DEX resistant cell lines were unchanged during 72 h of treatment with DEX. Thus, the changes in the protein levels are in good agreement with the changes reported earlier for mRNA transcript of these oncogenes. PMID- 21541526 TI - Effects of new bombesin antagonists given singly or in combination with a somatostatin analog on nitrosamine-induced pancreatic cancers in hamsters. AB - In three experiments, hamsters with N-nitroso-bis(2-oxopropyl)amine-induced pancreatic cancers were treated for two months with bombesin/GRP antagonists RC 3095 [D-Tpi(6),Leu(13)psi(CH2NH)Leu(14)-bombesin(6-14)], RC-3910-II [D Tpi(6),Leu(13)psi(CH2N)Tac(14)-bombesin(6-14)], RC-3940-II [Hca(6),Leu(13)psi(CH2N)Tac(14)-bombesin(6-14)], RC-3950-II [D Phe(6),Leu(13)psi(CH2N)Tac(14)-bombesin(6-14)], somatostatin analog RC-160 (D-Phe Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2), or the combination of RC-3095 with RC160. All peptides inhibited pancreatic cancers to various degrees, reducing the number of tumorous animals, lowering the weight of tumorous pancreata by 40-55% and decreasing AgNOR numbers which are indicators of cell proliferation rate. Combination therapy with RC-3095 and RC-160 did not inhibit tumors better than single peptides. Among new bombesin/GRP antagonists, RC-3940-II had the strongest inhibitory effect. RC-3950-II and RC-3095 caused similar inhibition, but RC-3910 II was less effective. Tumor inhibitory activity of the bombesin/GRP antagonists was correlated with their binding affinities to bombesin receptors on tumor cells. RC-3940-II caused 50% inhibition of specific binding of [I-125 Tyr(4)]bombesin to tumor cell membranes at 0.96 nM concentration, while the IC50 for RC-3950-II was 5.27 nM and 12.94 nM for RC-3095. Our findings suggest that in addition to RC-3095, other bombesin/GRP antagonists such as RC-3950-II and especially RC-3940-II could be further developed for therapy of human pancreatic cancer. PMID- 21541527 TI - WAF1 expression is independent of p53 gene alterations and protein expression in human lung cancer cells. AB - Accumulation of wild-type p53 protein arrests cells primarily at G(1)-S. This arrest is characterized by accumulation of the cyclin-dependent kinase inhibitor p21 (WAF1/CIP1) protein. Since the WAF1 gene is itself a target of p53, we investigated p53 gene expression to understand the mechanism 3 of p21 regulation in cellular transformation in human non-small cell lung cancer lines and tumor tissues. Northern and Western blot analyses in cell lines carrying wild-type or mutated p53 showed that WAFI mRNA and protein expression varied among different cell lines. WAFI expression was not directly correlated with the p53 status of the cells. WAFI was also expressed at high levels in the absence of p53 expression in a p53-deleted cell line (H358). Abrogation of p53 protein in H226b (wild-type p53) and H322 (mutated p53) cell lines by antisense RNA reduced WAFI expression in both lines, indicating that mutations in the p53 gene may not necessarily abrogate p53-mediated regulation of WAFI expression. Fourteen primary lung tumors were analyzed for p53 status by SSCP analysis and DNA sequencing. Eight of 14 lung tumor tissues examined contained p53 mutations. Six of 14 contained wildtype p53. Enhanced p21 expression was detected in two lung tumors containing p53 mutations by immunohistochemistry. Together, these data indicate that WAFI expression is independent of p53 gene alterations and protein expression in non-small cell lung tumor cells. PMID- 21541528 TI - Characterisation of a myofibroblast-like cell line from an angiosarcoma. AB - We have isolated a cell line (ASMM) by serial passage of cells from explant cultures of an angiosarcoma resected from the calf of a 62 year old female. ASMM has been in continuous culture for over eighteen months (>150 population doublings) and has a Fibroblast-like morphology with a doubling time of approximately 72 h. ASMM has a normal diploid karyology and is unable to generate tumors in nude mice or produce colonies in soft agar. Examination of the cytoskeletal proteins shows both desmin and vimentin and a low level of alpha smooth muscle actin, which can be upregulated by treatment with TGF beta. Low levels of basal VCAM-1 are significantly upregulated with TNF alpha and reduced by the presence of TCF beta. Basal ICAM-1 is also upregulated with TNF alpha and we show an additional upregulation through TGF beta. ASMM expresses high levels of the hyaluronate receptor CD44, including the variant exons 6, 8 and 10. In addition, ASMM synthesises high levels of hyaluronate (HA), as did the original tumor. Unlike human umbilical vein endothelial cells (HUVECs) these cells were unable to generate capillary-like tubes when seeded onto basement membrane gels, and generated cords of cells containing many synthetic organelles and intermediate filaments. We were unable to detect the expression of factor VIII related antigen, von Willebrand factor (vWF), CD31 or CD34, and were not able to induce expression of E-selectin after TNF alpha stimulation. In conclusion, this cell line represents a partially transformed population of cells which show characteristics consistent with myofibroblast-like cells. The production of high levels of HA and expression of CD44 may help to explain the high degree of agressiveness of the tumor from which ASMM was derived, as these molecules have been shown to play a role in cell motility and adhesion. PMID- 21541529 TI - Immunohistologic c-myc protein in benign breast disease and cancer. AB - We have studied the histopathology and differential distribution of the c-myc protein (Myc) in human breast tissues including 17 cases of infiltrating mammary carcinoma, 4 cases of fibroadenoma, 5 cases with fibrocystic changes, and 1 case of reduction mammoplasty (as a control). Using a sensitive immunohistochemical method on frozen tissue sections, both a rabbit polyclonal anti-c-myc antibody and a mouse monoclonal anti-c-myc antibody, H51C116, produced high levels of Myc staining in the nuclei of epithelial cells of infiltrating mammary carcinomas (30 90% of cells stained). In contrast, the nuclei of epithelial cells of fibroadenomas, and breast tissues with fibrocystic changes stained infrequently. We studied benign tissue surrounding the tumors in four cases; three were essentially negative, and one showed nuclear epithelial cell staining throughout the lobules. Sixteen of the tumors were examined in parallel, using formalin fixed, paraffin-embedded samples. Immunohistological procedures for Myc produced uniform, intense epithelial cell cytoplasmic staining (8 cases); light epithelial cell cytoplasmic staining (5 cases) or were unstained (3 cases). We argue that the differences between frozen and paraffin sections are incompatible with the notion of simple displacement of nuclear Myc to the cytoplasm during fixation. Elevated levels of nuclear Myc in tumor cells and subsets of benign tissue are consistent with a role for Myc in mammary cell proliferation and tumorigenesis. PMID- 21541530 TI - Effect of cytochrome P450 inducers on expression of oncogenes and a tumor suppressor gene in human colon cancer cells. AB - To examine the possibility that chemical inducers of cytochrome P450 may have effects on the expression of oncogenes and a tumor suppressor gene, human colon LS174T cells were treated with different cytochrome P450 inducers such as benzanthracene (Ba), pyrazole (Pyr) and phenobarbital-hydrocortisone (Pb-Hc). Three forms of cytochrome P450 (CYP1A1, CYP1A2 and CYP2E1) were detected in the colon cell line and all of them were induced following chemical treatments. Altered expression of c-fos, c-myc, c-jun, was observed following the treatments. c-src, K-ras and p53 were not significantly affected by any of the treatments at the time-point selected. Interestingly, c-fos expression was the most dramatically altered by different treatments, showing repression with all of the treatments. These data show that some oncogenes are responsive to inducers of cytochrome P450, the enzyme system by which many carcinogens are activated. PMID- 21541531 TI - Autocrine motility factor and its receptor expressions in human oral squamous cell carcinoma (SCC) cells. AB - Autocrine motility factor (AMF) a tumor-secreted 55 kDa cytokine induces tumor cell motility by a signal transduction pathway mediated by interaction with its receptor (AMFR) a cell surface glycoprotein of 78 kDa (gp78). Here, AMF secreted by the metastatic LMF4 human oral squamous-cell carcinoma (SCC) cells, induced dose- and time-dependent morphological changes and chemotaxis of the producing cells. Expression of AMFR mRNA was associated with the metastatic ability of SCC cell variants. The data presented show for the first time that SCC cells produce AMF and express AMFR and the expression is related to their invasiveness and metastatic potentials. PMID- 21541532 TI - Altered expression of p53 and Rb tumor suppressor genes in lung cancer. AB - The aim of this study was to evaluate the frequency of altered expression of pRb and p53, two well known tumor suppressor genes, in lung cancer and to relate it to the prognosis of the patients affected by this type of neoplasm. We evaluated 68 specimens from patients with surgically resected lung cancer. Of the 68 neoplasms investigated, 29 (42.6%) displayed a positive nuclear staining for p53. Ten (15.7%) of the investigated tumors showed absence of pRb nuclear immunoreactivity. p53 overexpression correlated statistically with short-term survival. On the other hand no statistically significant difference (p=ns) in survival was detected between pRb producers and nonproducer patients. In addition, we divided our specimens into two groups according to the p53 and pRb status. The first group consisted of all the p53(+) pRb specimens. The second group contained all the remaining specimens. Comparison between these two groups did not reveal any significant difference in overall survival time. These findings confirm that only p53 overexpression can be considered an independent prognostic factor in lung cancer. PMID- 21541533 TI - Vapreotide labeled with Tc-99m for imaging tumors. AB - Vapreotide (RC-160), an octapeptide analog of somatostatin, has a high affinity for somatostatin receptor subtypes SSTR2 and SSTR5. Vapreotide binds differently to the tumors of the breast, ovary, exocrine pancreas, prostate and colon, than octreotide another octapeptide analog of somatostatin. Vapreotide was labeled with Tc-99m, a radionuclide highly suitable for scintigraphic imaging. The labeling procedure was simple, produced >70% yields and could be applicable to label other peptides containing a cystine bridge. HPLC analysis showed that the tracer was stable when Tc-99m-RC-160 was challenged with 100 fold molar excess DTPA (diethylenetriaminepentaacetic acid), HSA (human serum albumin) or cysteine and incubated at 37 degrees C for 4 h. HPLC analysis of urine samples obtained from mice that received Tc-99m-RC-160 showed that the preparation was stable in vivo. Rat brain cortex membrane receptor displacement assays showed that the Kd values for Tc-99m-RC-160 (71x10(-9) M) and Tc-99m-octreotide (86x10(-9) M) (Sandostatin(R)) were in nM range, and were similar to that for I-125-RC-160 (46x10(-9) M). High binding affinity of Tc-99m-RC-160 for human breast tumor cells SKBR-3 was also observed. These results suggest that Tc-99m-RC-160 is worthy of evaluation as an agent for scintigraphic imaging of tumors rich in somatostatin receptor subtypes SSTR2 and SSTR5. PMID- 21541534 TI - Telomerase activity in human intestine. AB - In human somatic cells without the activity of telomerase, the ends of chromosomes consisting of the telomeric repeats TTAGGG progressively erode with each cell division. In germline and immortal cells telomerase activity maintains telomere length and thus compensates for the 'end-replication problem'. Progressive telomere shortening and reactivation of telomerase activity have been considered to be one of the key mechanisms in cellular senescence and immortalization. It has been shown that while most somatic cells do not have detectable telomerase activity, almost all cancers do have telomerase activity. Thus, detection of telomerase activity may have utility in the early diagnosis of cancer and may be a new target for therapeutic intervention. However, there is recent evidence that some cells of renewal tissues, such as hematopoietic cells and basal cells of the epidermis, have detectable telomerase activity. In the present study, we report detectable telomerase activity in normal human intestinal mucosa. This activity is localized to the lower third of each crypt and may be derived from intestinal stem cells. Since intestinal telomeric repeats are shorter in adults when compared to children, the telomerase activity in the intestine is insufficient to maintain telomere length but may be sufficient to provide extended proliferative capacity for such renewal tissues. PMID- 21541535 TI - Antigen heterogeneity in advanced colorectal and breast cancer. AB - The association of several monoclonal antibody defined tumour-associated antigens with colorectal and breast carcinoma tissues was investigated by immunocytochemistry. The antigens included CEA and the related antigen, NCA (NCA 1), modified blood group substances (Le(y) hapten), a tumour glycolipid antigen and the MUC1 mucin. The molecular expression of these antigens in tumour cell membranes was analysed by identification of antigens in detergent extracts by SDS PAGE analysis and Western blotting. The capacity of viable tumour tissue to release these antigens as soluble components into short term tissue culture supernatants was further examined. The findings provide a basis for the defining those membrane-associated antigens which would be appropriate targets for monoclonal antibody based targeted therapies in colorectal and breast cancer. PMID- 21541536 TI - Organ-specific expression of the colon cancer antigen A33, a cell surface target for antibody-based therapy. AB - Monoclonal antibody mAbA33 recognizes a unique cell surface protein of colorectal cancer, the A33 antigen. Phase I/II studies have shown highly selective targeting of radio-labeled mAbA33 in patients with metastatic colorectal cancer, opening up the possibility of A33-directed therapy. To better understand the basis of selective mAbA33 targeting in patients, the present study was designed to define the A33 distribution in normal organs and examine A33 expression in a broad range of tumor types. Immunohistochemical analysis of normal tissues identified the large and small intestinal mucosa as the principal sites of A33 expression. Tests with over 450 tumor samples showed that only tumors of the gastrointestinal tract are consistently A33-positive. For example, A33 is found in 95% of primary and metastatic colorectal cancers (86 of 90 cases tested), with uniform expression throughout the tumors in most cases. A33 was detected in a subset of gastric cancers (14/24 cases), with uniform expression in 10 cases (including 5 signer ring adenocarcinomas). Among esophageal cancers, squamous cell tumors typed A33 negative (9 cases), whereas one case each of mucinous and intestinal type was A33 positive. A subset of pancreatic carcinomas (6/12 cases) showed A33 expression, although with marked heterogeneity. Other epithelial cancers, sarcomas, neuroectodermal tumors, and lymphoid neoplasms were generally A33-negative. A33 is the first example of a constitutively expressed, organ-specific epithelial membrane antigen permitting highly specific tumor targeting in patients with colorectal cancer. PMID- 21541537 TI - Dysregulation of transforming growth factor-beta 1 expression in N nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. AB - Alterations in the expression of transforming growth factor-beta 1 (TGF-beta 1) have been implicated for malignancies of both human and experimental animal models. To further investigate the role of TGF-beta 1 in chemically-induced esophageal tumorigenesis, the expression of TGF-beta 1 was analyzed by reverse transcription-polymerase chain reaction (T-PCR) and immunohistochemical studies in N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. We observed no significant difference in TGF-beta 1 mRNA levels between 25-week papillomas and normal rat esophageal epithelium. However, TGF-beta 1 mRNA levels were increased 2.9-fold (p<0.05) in 45-week papillomas induced by NMBA, when compared to normal rat esophageal epithelium. Immunohistochemical studies revealed a decreased intracellular TGF-beta 1 immunoreactivity in the papillomas when compared to the normal rat esophageal epithelium, indicating the existence of a discordance between TGF-beta 1 mRNA and protein expression. Furthermore, by immunohistochemical staining of proliferating cell nuclear antigen (PCNA), a predominantely mutually exclusive staining pattern was observed for TGF-beta 1 and PCNA. These findings suggest that overexpression of TGF-beta 1 mRNA occurs late in NMBA-induced rat esophageal tumorigenesis, and the discordant mRNA and protein expression may result in tumor evasion from TGF-beta 1 controlled negative growth regulation, thus promoting tumor progression in this model. PMID- 21541538 TI - Chromosomal assignment of three human melanocyte-specific genes. AB - To identify genes expressed in normal human melanocytes but not in malignant melanomas, we previously applied subtractive cDNA hybridization combined with PCR amplification, which led to the isolation of several human melanocyte-enriched partial cDNAs. Three of these cDNA clones were used to isolate their corresponding genomic clones. The chromosomal location of each of the three genes encoded by the individual genomic clones was determined by fluorescent in situ hybridization. The first gene mapped to human chromosome 3p14, the second gene to chromosome 19q13.1, and the third to 2p16-14. In addition, RNase A protection and in situ hybridization analyses documented expression of the gene, located on 3p14, in normal human melanocytes but not in malignant melanomas. PMID- 21541539 TI - Insulin-like growth factor II activates mitogenic signaling in pancreatic cancer cells via IRS-1. AB - Insulin-like growth factor-II (IGF-II) action and expression were examined in 3 human pancreatic cancer cell lines. IGF-II expression was also studied in 17 normal and 12 malignant pancreatic tissues. IGF-II enhanced the growth of all 3 cell lines. In COLO-357 and PANC-1 cells, one-half maximal stimulation occurred at 0.3 and 0.4 nM IGF-II, respectively. In ASPC-1 cells, one-half maximal stimulation occurred at 0.9 nM IGF-II. A monoclonal antibody (alpha IR3) that blocks ligand binding to the insulin-like growth factor I (IGF-I) receptor (IGF IR) inhibited IGF-II-mediated growth stimulation, and IGF-II enhanced insulin receptor substrate 1 (IRS-1) phosphorylation. IGF-II mRNA transcripts were present in COLO-357 cells, in 4 of 17 normal human pancreatic tissues, and in 8 of the 12 cancer samples. By immunohistochemistry, IGF-II was present in the islets of both normal and malignant pancreatic tissues, and occasionally in the cancer cells within the tumor mass. These findings indicate that IGF-II acts via IGF-IR to enhance mitogenic signaling in pancreatic cancer cells and suggest that islet-derived IGF-II may contribute to pancreatic cancer cell growth in vivo. PMID- 21541540 TI - Cell-cycle regulator cyclin D1 mRNA and protein overexpression occurs in primary malignant gliomas. AB - Gliomas are malignant brain tumors thought to arise through multi-step tumorigenesis, involving both the activation of oncogenes and the loss of tumor suppressor genes. The cyclin D1 gene encodes a proto-oncogenic cell cycle regulator implicated in the pathogenesis of several types of cancer, including gliomas. Northern blot analysis revealed expression of cyclin D1 mRNA in 7 (47%) of 15 primary glioma specimens. Immunohistochemistry using an antibody specific for cyclin D1 showed strong positivity amongst neoplastic glial cells in the same glioma samples. No cyclin D1 mRNA or protein was detected in 5 normal brain specimens. Cyclin B, which has not been linked to tumorigenesis and serves as a marker for cellular proliferation, was expressed in all tumor, but not control, samples. These data provide the first evidence for the overexpression of cyclin D1 mRNA and protein in primary human gliomas, and are consistent with a proposed oncogenic role of cyclin D1 in these tumors. It is suggested that excessive levels of cyclin D1 with or without several other D-type cyclin proteins may lead to deregulation of G(1) control in subsets of human gliomas. These results are further discussed in the context of putative functional redundancy of D-type cyclins and the role of the D-type cyclin/p16-ink4/pRB pathway in tumorigenesis. PMID- 21541541 TI - Antiproliferative effects of interleukin-1 alpha and nitric oxide release in a human ovarian carcinoma cell line. AB - Interleukin-1 (IL-1) exerts direct antiproliferative effects on a number of human tumor cell lines, but the mechanisms involved are still poorly understood. Nitric oxide (NO) has been shown to mediate some of the actions of IL-1. Therefore, we investigated the role played by NO in the cytostatic effects of IL-1 alpha on NIH:OVCAR-3 cells, a cell line which has been shown to possess IL-1 receptors and to respond to the cytokine with growth arrest; the involvement of NO release in the synergistic interaction between IL-1 alpha and adriamycin (ADR) observed in this cell line was also studied. 72 h exposure to concentrations of IL-1 alpha similar to its IC50 value, were found to enhance NO release. This was significantly reduced by co-incubation with 1 mM L-NAME, which however did not significantly affect the IC50 values, either for IL-1 alpha or for the combination IL-1 alpha:ADR (1:20,000). We conclude that induction of NO synthesis in IL-1 alpha-treated cells is probably a side effect originating from transcription factor activation by the cytokine, and that neither the antiproliferative effects of IL-1 alpha nor its potentiation of ADR cytotoxicity depend on NO release. PMID- 21541542 TI - Leptomeningeal metastases due to melanoma. AB - A Phase II study of combined modality therapy of leptomeningeal metastases (LM) in melanoma was carried out. Central nervous system (CNS) metastases occur commonly in patients with clinically advanced melanoma. 16 patients (median age 47; range 32-62 years) with LM due to metastatic melanoma were treated. Neurologic presentation included: headache (9 patients); cranial neuropathies (6); cauda equina syndrome (4); gait ataxia (3); hemiparesis (2); radiculopathy (2); myelopathy (1); and seizure (1). All patients underwent CNS staging followed by radiotherapy (14 patients) and intraventricular chemotherapy (methotrexate 16 patients; ara-C 13 patients; thio-TEPA 7 patients). CNS imaging demonstrated: interrupted CSF flow (9 patients); parenchymal brain metastases (7); spinal cord subarachnoid nodules (5); hydrocephalus (3); and epidural spinal cord compression (2). CSF cytologic responses were seen in 4 patients to first-, 6 to second-, and 3 to third-line chemotherapy. Treatment-related toxicity included 13 patients with meningitis (12 chemical; 1 bacterial) and 12 patients (18 episodes) with myelosupression (4 episodes secondary to intraventricular chemotherapy). Median survival was 4 months (range: 2-8). Twelve patients (75%) died of progressive LM or combined LM and systemic disease progression. LM in patients with metastatic melanoma may be palliated with combined modality therapy, however, median survival is quite short suggesting a re-evaluation of such an approach in similarly affected patients. PMID- 21541543 TI - Production of group II phospholipase A(2) in advanced gastric cancer. AB - We examined the immunohistochemical expression of membrane-associated phospholipase A(2) (M-PLA(2)), belonging to group II PLA(2), in 44 advanced gastric cancers, using the ABC method and monoclonal antibody anti-human M PLA(2). M-PLA(2) mRNA was also examined in the same rumours by Northern blot analysis. In addition, the content of M-PLA(2) protein and prostaglandin E(2) (PGE(2)) in the malignant lesion and in the non-malignant gastric mucosa was examined. The expression was detected in cancer cells in 31 out of 44 advanced gastric cancer tissues (70.4%) by the ABC method. M-PLA(2) mRNA was detected in 36 out of 44 gastric cancer tissues (81.8%), and the density was observed to be higher in tumour tissues than in the adjacent nonmalignant gastric mucosa. The M PLA(2) protein was detected both in malignant tissues and in non-malignant gastric mucosa, and the content of M-PLA(2) protein was significantly higher in malignant tissues than in the non-malignant gastric mucosa. There was a significant positive correlation between the expression of M-PLA(2) mRNA and the amount of M-PLA(2) protein. PGE, was also detected in the malignant tissues and in the non-malignant mucosa. The content of PGE, was significantly higher in the former. These results indicate that M-PLA(2) is produced both in malignant and nonmalignant cells of the stomach, the former producing higher amounts of this enzyme than the latter. M-PLA(2) may be involved in cancer progression through its function or through the function of products of this enzyme's action such as PGE(2) in gastric cancer. PMID- 21541544 TI - Enhancement of anti-proliferative activities of 5-FU, HCFU, SN-38, THP and ACNU by a serine protease inhibitor, FOY-305. AB - The effects of a synthetic serine protease inhibitor, FOY-305, on the proliferation of normal and transformed mouse fibroblasts were investigated in vitro by MTT colorimetric assay. FOY-305 inhibited the growth of normal NIH3T3 cells and their src- and erbB2-transformed cells with a half maximum inhibitory concentration (IC50) of 1-1.2 mg/ml whereas it suppressed the growth of ras transformed cells more effectively (IC50 was 0.5-0.6 mg/ml). Flow cytometric analysis using synchronized NIH3T3 cells has shown that the growth-inhibitory activity of FOY-305 was due to the suppression of G(1)/S transition. The synergistic effects between FOY-305 and traditional anticancer drugs were also investigated by the MTT assay and the results showed that FOY-305 significantly enhanced the antiproliferative activities of 5-fluorouracil (5-FU), 1 hexylcarbamoyl-5-fluorouracil (HCFU), 7-ethyl-1-hydroxy-7-ethyl-10-[4-(1 piperidino)-1-piperidino] camptothecin (SN-38), pirarubicin (THP) and 1-(4-amino 2-methyl-5-pyrimidinyl)-methyl-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). PMID- 21541545 TI - In vivo bystander effect in the intracranial model with rat glioma cells reflects the clonal difference of HSV-TK positive cells. AB - We have investigated clonal variations on the in vivo bystander effect of herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV) system, using an intracranial tumor model with 9L rat gliosarcoma cells. For this purpose, we established three 9L clones transduced with HSV-TK gene (9L-TK), each of which had similar TK activity but showed different tumor growth rate in vivo. The use of GCV in vitro confirmed previous reports that the bystander effect was manifest in a confluent culture condition, but not in a low cell density condition. In contrast, the therapeutic benefit of the in vivo bystander effect varied among each 9L-TK clone, and had a positive correlation with the in vivo growth rate of the clone. Thus, the bystander effect seems to reflect the growth rate of TK positive cells, and these data raise a crucial point for applying the bystander effect to clinical trials. PMID- 21541546 TI - In vitro antitumor activity of MIC2 protein-doxorubicin conjugates. AB - The pseudoautosomal encoded MIC2 glycoprotein is a tumor-associated antigen of Ewing's sarcoma (ES) and closely related tumors of unknown function. To investigate the use of this protein as selective drug carrier recombinant MIC2 was coupled to doxorubicin by a two step glutaraldehyde method (molar ratio DOX/MIC2 of 32 and 16). The conjugates showed dose-dependent cytostatic activity against the ES cell line SK-ES1, the peripheral neuroectodermal line KAL and the prostate cancer cell line PC-3 concurrent with reduced toxicity against normal lymphoblasts. In comparison to free doxorubicin the MIC2-doxorubicin conjugates exhibited highest activity against the PC-3 cell line. Confocal microscopy showed intracellular accumulation of MIC2 conjugates. PMID- 21541547 TI - Allelotype of non-small cell lung cancer. AB - Loss of heterozygosity (LOH) studies have been used extensively to identify regions on chromosomes that may contain putative tumour suppressor genes. We have undertaken extensive allelotyping of 45 specimens of non-small cell lung cancer (NSCLC) using 92 polymorphic microsatellite markers on 39 chromosome arms. The most frequent allelic imbalances were found on chromosome arms 3p, 9p and 17p. Significant allelic imbalance was found on other chromosome arms including, 5q (21%), 8p (19%), 13q (24%) and 17q (18%). The LOH data on 3p was subdivided into the four chromosomal regions considered to contain putative tumour suppressor genes 3p25-p24 (10%), 3p21 (10%), 3p14 (25%) and 3p13-p12 (22%). The frequency of loss in the different regions on 9p were: 9pter-p23 (31%), 9p23-p22 (45%) and 9p21-cent (30%). LOH on 17p was separated into three regions: 17pter-p13 (9%), 17p13 (33%) and 17p13-cent (22%). No correlation was found between LOH on any of the chromosomal arms and any of the clinicopathological parameters such as pathology, level of differentiation, TNM staging or alcohol intake. Only one significant association was found between LOH and tumour types. A significant difference was found between LOH on 17q in adenocarcinomas and squamous cell carcinomas (p=0.037). The fractional allele loss (FAL) values for this group of 45 NSCLC gave a median value of 0.9 (range 0-0.45). No correlation was found between FAL and nodes at pathology (p>0.05) and between FAL and tumour grade (p>0.05). No correlation was found between p53 or ras mutations in these NSCLC specimens and their FAL values. Accumulated genetic damage, as provided by this allelotype analysis, provides a useful molecular parameter by which to assess NSCLC and may, in time, assist in the determination of the clinical behaviour and clinical outcome of these tumours. PMID- 21541548 TI - Prognostic value of proliferating cell nuclear antigen (PCNA) expression in unresectable hepatocellular carcinoma. AB - Recent studies indicate that evaluation of cell proliferation in mallignant tumors may have prognostic value, but limited data are available on its expression in hepatocellular carcinoma. We therefore evaluated the prognostic tool of PCNA antigen expression on paraffin-embedded sections of 54 patients with hepatocellular carcinoma and concomitant cirrhosis. According to the number of positive cells, the PCNA expression ranged between 0.8 and 47%, and was divided into two groups (Group A, PCNA less than or equal to 5.5%; Group B, PCNA >5.5%). The two groups of patients were numerically well balanced. Median survival was 16 months for group A and 12 months for group B. According to the Cox multivariate analysis, PCNA expression (P=0.002),TNM stage (P=0.009) and ECOG performance status (P<0.001) significantly correlated with survival. In conclusion, PCNA antigen expression was found to be a significant prognostic faeature in unresectable hepatocellular carcinoma and may be a useful tool for future trials. PMID- 21541549 TI - Expression of the human Bcl-2 increases resistance of Ewing's sarcoma cells to apoptosis and inhibits poly(ADP-ribose) polymerase cleavage induced by radiation. AB - We reported previously that Ewing's sarcoma (ES) cells respond to ionizing radiation exposure by arrest in G(2)/M phase and induction of apoptosis which occurs in conjunction with poly(ADP-ribose) polymerase (PARP) proteolytic cleavage. ES cells (A4573 cell line) do not express immunodetectable levels of Bcl-2. To determine if expression of Bcl-2 could modulate radiation-induced ES cell death, we have stably transfected A4573 cells with a full-length human bcl-2 cDNA. Expression of Bcl-2 protein rendered ES cells relatively resistant to radiation-induced apoptosis. Moreover, the anti-apoptotic activity of Bcl-2 was directly related to levels of its expression in different ES clones. Cell cycle characteristics were similar for both parental and Bcl-2 expressing ES cells following radiation treatment, although bcl-2 transfectants exhibited a more protracted G(2)/M phase arrest and lower rate of apoptosis after release from the block. Constitutive expression of Bcl-2 resulted in about two-fold inhibition of PARR cleavage in ES cells dying after ionizing radiation exposure. These data support a role for Bcl-2 protein as a negative regulatory element of PARP proteolysis at the early stages of radiation-induced apoptosis in ES cells. PMID- 21541550 TI - p53 and cyclin D1 protein expression in glottic laryngeal squamous cell carcinomas involving the anterior commissure (pT1bN0M0). AB - The prognosis of patients carrying glottic squamous cell carcinomas (GSCCs) involving the anterior commissure is often unpredictable. In order to assess the possible prognostic role of new and reliable parameters, p53 and cyclin D1 protein expression was immunohistochemically analysed in pathological samples from 27 patients with GSCG (pTlbNOMO) and a median follow-up of 90 months. p53 protein expression was observed in the majority of patients (15/27), but it did not correlate with their clinical outcome; p53 protein immunoreactivity was frequently observed in normal (9/14), mildy dysplastic (10/14) and highly dysplastic (3/7) mucosa samples, suggesting that its overexpression may be involved in the earliest phases of the multistep tumourigenesis of laryngeal squamous cell carcinomas (LSCCs); neither the non-neoplastic nor the neoplastic samples expressed any cyclin D1. As cyclin D1 protein expression has been associated with a high frequency of nodal metastases, its absence in our series could ba related to the rarity of nodal involvement in early glottic LSCCs. PMID- 21541551 TI - Polymorphisms in the promoter region of the WAF1/CIP1 gene. AB - The WAF1/CIP1 gene encodes p21(waf1), a CDK inhibitor which is implicated in cell growth arrest and differentiation, and is activated by wild-type p53. We examined the presence of mutations in a part of the 5' flanking region which is known to contain p53 binding sites, in 50 cases of lung cancer and 11 individuals with no history of cancer. Polymorphisms were identified in the region close to: but not within, the p53 binding sites. The first polymorphism occurred at nucleotide 2203 prior to the transcription start site, four base pairs upstream of a p53 binding site and created an MscI restriction site. The second polymorphism was more complex and included four sites (nucleotides -1463, -1526, -1533 and -1594). Two patterns (alleles) were identified for this region. These polymorphisms were observed at similar percentages in DNAs from lung cancer patients and individuals who had no history of cancer. A computer transcription factor motif analysis showed that these polymorphic sites are homologous (>85%) to consensus sequences of transcription factors such as ETS-1, Elk-l, GATA-1 and AP4 but their role in the regulation of p21(waf1) expression is still unclear. This is the first report of polymorphisms in this region of the WAF1/CIP1 promoter. PMID- 21541552 TI - bcl-2 proto-oncogene, apoptosis and oncogenesis. AB - Cell death has gained considerable interest during the last few years since, along with mitosis, it contributes to the determination of normal or neoplastic state of tissues. Cell death can occur in two ways: necrosis Or 'accidental' death and apoptosis or 'programmed' death. The focus on apoptosis is very recent. Like cell division it involves an interesting set of genetic regulations. The apoptosis-preventing bcl-2 gene, therefore emerges as a key-gene at the crossroad of cell death and cell proliferation: the two facets of the oncogenesis-governing equation. PMID- 21541553 TI - Antibody-directed enzyme prodrug therapy (ADEPT). AB - A conjugate of the bacterial enzyme carboxypeptidase G2 and the F(ab)(2) fragment of the anti-CEA monoclonal antibody A5B7 was directed in vitro at the human colon tumour cell line LS174T and the human non-small cell lung line COR-L23. Indirect immunofluorescence microscopy was used to show that the conjugate bound to LS174T cells but not to COR-L23. The cytotoxicity generated by addition of a phenol mustard prodrug to each cell line after pre-incubation with conjugate was found to be significantly greater for LS174T cells (IC50=0.24 mu M) than COR-L23 cells (IC50=108 mu M). However, for a 1:1 mixture of these cells an IC50, of 3.4 mu M was obtained. These data show that phenol mustard released by a localised conjugate can exert a bystander effect on neighbouring cells to which the conjugate does not bind. PMID- 21541554 TI - Neo-adjuvant organ-preserving chemotherapy in the management of locally advanced oral cavity and oropharynx cancer. AB - We designed an open, non-randomized clinical study to assess as the first endpoint the feasibility of sparing surgery and of preserving organ/function by using neo-adjuvant chemotherapy (NAG) in oral cavity and oropharynx cancer patients, and, as the second endpoint, the clinical response to this treatment approach and its duration. Moreover, an attempt was made to scale the extent of surgery by means of an Arbitrary Scale assigning different percentages to the different extents of surgical resection. Twenty-five patients with primary oral cavity and oropharynx cancer (stage III-TV) were enrolled in the study and were assigned to either the classical Al-Sarrafs regimen (1) (n=15) or to a regimen (2) consisting of cisplatin 80 mg/m(2) i.v. on day 1, 5-FU 600 mg/m(2) on days 2 5 and vinorelbine 20 mg/m(2) on days 2 and 8 (n=10). The 25 patients were all evaluable for response to NAC and 20 of them were evaluable for organ preservation. The overall response (OR) rate was 86.6% (13/15 patients) for regimen 1 (cisplatin + 5-FU) and 80% (8/10 patients) for regimen 2 (cisplatin + 5 FU + vinorelbine). The median follow-up duration was 20.6 months. 5/20 (25%) patients completely avoided surgery, 5/20 (25%) patients had a reduced extent of surgical resection, while: 10/20 (50%) patients received the previously planned surgical resection. Altogether, 10/20 (50%) patients treated with NAC either avoided or achieved a reduction in the previously planned surgical resection. Moreover, organ function was evaluated to support the assessment of treatment outcome in our patients. For this purpose we selected the Performance Status Scale for Head and Neck Cancer Patients: as expected, no significant impairment was detected in the area of comprehensibility of speech, but we were rather surprised that no significant impairment was found in the two areas of eating in public and normalcy of diet. NAG-associated toxicity was moderate and similar in the two chemotherapy regimens. The most relevant contributions offered by our study are represented by i) a Scale aimed at measuring as precisely as possible the reduction of surgical resection made possible by NAC compared to surgery planned before NAC and ii) an attempt to support the results with an assessment of treatment outcome. PMID- 21541555 TI - Mutations of p53, E-cadherin, alpha- and beta-catenin genes and tyrosine phosphorylation of beta-catenin in human gastric carcinomas. AB - We investigated whether dysfunction of p53 and E-cadherin participate in invasiveness and metastasis of human gastric carcinoma. We examined twenty-five human gastric carcinomas for p53, E-cadherin, alpha- and beta-catenin gene alteration by the reverse transcription-polymerase chain reaction-single strand conformation polymorphism (RT-PCR-SSCP) method and sequencing analysis. Three samples (13%) showed p53 gene mutation (two missense mutations and 6 bp deletion). 25% (3/12) of the carcinomas with lymph node metastasis had p53 gene mutations. One sample (4%) showed E-cadherin silent mutation. We were not able to detect alpha- or beta-catenin gene alteration. Therefore we investigated tyrosine phosphorylation of E-cadherin, a and beta-catenin. Tyrosine-phosphorylated beta catenin was detected in 13% (2/15) of poorly differentiated carcinomas. These results suggest that the p53 gene mutations have some correlation with lymph node metastasis, and tyrosine phosphorylation of beta-catenin rather than cadherin/catenin gene mutation is at least partly responsible for the loosening of cell-cell contact and invasiveness of poorly differentiated carcinomas. PMID- 21541556 TI - Supersensitive detection of prostate-specific antigen in lyophilisation concentrated serum. AB - We evaluated the use of serum-concentration for early detection of PSA after radical prostatectomy (RP) to improve sensitivity of automated assays 4-fold. 600 sera after RP were lyophilisation-concentrated 2-, 3- and 4-fold and analysed in parallel both native and concentrated with 3 assays. Results were identical in the 3 assays in >90%, of the native and concentrated sera. However by concentration 8.32% (n=50) additional positive samples were identified. Positivity in concentrated serum precedes positivity in native serum by about 300 days. Concentration-induced supersensitive detection increases sensitivity of standard PSA assays. It is simple, reliable and easy to perform. PMID- 21541557 TI - Higher concentrations of specific polychlorinated biphenyl congeners in adipose tissue from non-Hodgkin's lymphoma patients compared with controls without a malignant disease. AB - In earlier studies non-Hodgkin's lymphoma (NHL) has been associated with exposure to phenoxyacetic acids or chlorophenols, but also impurities such as polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) are of concern since these compounds as well as polychlorinated biphenyls (PCBs) are immunotoxic and promoters in carcinogenesis. The aim of this study was to determine the concentrations of specific PCDDs, PCDFs and PCBs, 1,1-dichloro-2, 2 bis(p-chlorophenyl) ethylene (p,p'-DDE), and hexachlorobenzene (HCB) in cases with NHL and surgical controls: The study included 28 NHL cases of the B-cell type and 17 controls. Seven PCDDs and 10 PCDFs substituted with chlorine in the 2,3,7,8-position and three co-planar PCB congeners were determined in 20 cases and 17 controls without showing differences. Almost all of the analysed PCB congeners were higher, PCB No. 156, No. 157, sum of No. 182 and 187, No. 171, sum of No. 172 and No. 192, sum of No. 170 and No. 190, No. 189, No. 202, No. 201, No. 194, and No. 208 significantly so (p<0.05), in 27 NHL cases compared with the 17 controls. The mean sum of PCBs was for the cases 1614 ng/g lipid, range 637 4705, versus 1213 for the controls, range 366-2282 (p=0.06). An odds ratio of 2.7, 95% confidence interval 0.8-9.4, was obtained for cases with the sum of PCBs higher than the median concentration of 1300 ng/g lipid. The sum of PCBs was similar for different stages of NHL. No significant differences were found between the 28 cases and 17 controls regarding p,p'-DDE and HCB. PMID- 21541558 TI - Prevalence of human papillomavirus type 16-related DNA in cutaneous Bowen's disease and squamous cell cancer. AB - Human papillomavirus (HPV) type 16 and related types are frequently found in genital located Bowen's disease but they are only rarely identified in non genital cutaneous Bowen's disease and squamous cell cancer (SCC). We used the polymerase chain reaction to detect HPV 16 and related DNA sequences in 205 formalin-fixed non-genital cutaneous Bowen's disease and SCC specimens from 159 non-immunosuppressed patients. HPV 16 and related DNA sequences could be detected in 12 of 198 cutaneous specimens from extra-genital sites other than the fingers and in 2 of 7 specimens from digital lesions. Our study suggests a minor but still not negligible role of HPV 16 and related HPV-types in the etiology of non genital non-melanoma skin cancer of the general population. PMID- 21541559 TI - Phase II pilot trial of preoperative high-dose chemotherapy in patients with malignant tumors of the upper gastrointestinal tract. AB - The purpose of this trial was to test feasibility and tolerability of a multimodality treatment approach for patients with tumors in the upper gastrointestinal tract (EC, esophageal cancer; JC, cancer of the gastro esophageal junction; GC, gastric cancer) including preoperative chemotherapy with the EAP-protocol as induction and a consecutive high-dose-chemotherapy for responding patients. Sixteen patients with locally advanced tumors of the esophagus, the gastro-esophageal junction or the stomach were treated with two cycles of EAP-chemotherapy (etoposide, 3x120 mg/m(2); adriamycin, 2x20 mg/m(2); cisplatin, 2x40 mg/m(2)). Responding (cPR, cCR) patients were included into a high-dose MCVB-chemotherapy protocol (mitomycin, 10 mg/m(2); cisplatin, 4x40 mg/m(2); vepeside, 5x200 mg/m(2); BCNU 300 mg/m(2)) and subsequent rescue with peripheral blood stem cells (PBSC). After a second restaging, surgery was performed in patients with no change or further response. Postoperative chemotherapy was given with either two cycles of EAP or FAMTX (methotrexate, 1,500 mg/m(2) + folinic acid rescue; 5-flourouracil, 1,500 mg/m(2); adriamycin, 30 mg/m(2)) according to pathological staging results. A total of 16 patients (EC, 7; JC, 6; GC 3) were treated within the protocol. Six patients achieved a major response upon EAP and 5/6 were included in the high-dose MCVB-protocol with stem cell rescue. All 5 could be yielded R(0) by definitive surgery and 2/5 had a pCR upon surgery. MCVB toxicity was predominantly hematologic (grade 4 in all 5 patients) with non-hematological toxicity not exceeding grade 2 (predominantly mucositis). Median survival time is 12 months for the non-responding patients and has not been reached for the MCVB patients. In conclusion, multimodality therapy including high-dose chemotherapy and stem cell rescue is feasible with tolerable toxicity in patients with locally advanced tumors of the upper gastrointestinal tract and should be further studied in phase II and III trials. PMID- 21541560 TI - High establishment efficiency of lymph node stromal cells which spontaneously produce multiple cytokines derived from adult T-cell leukemia/lymphoma patients. AB - Stromal cells isolated from lymph nodes of adult T-cell leukemia/lymphoma (ATL) patients were cultured. Such lymph node stromal cells (LNSC) could be maintained for more than one year, whereas LNSC from other lymphoproliferative disorders ceased to proliferate within months. The rate of human T lymphotropic virus type I (HTLV-I) integration in these LNSC was examined by nested polymerase chain reaction (PCR) and estimated to be about 1 genome per 100 cells. These LNSC showed the same combination of cytokine production irrespective of the patient origin, granulocyte-macrophage (GM)-CSF, G-CSF, interleukin (IL)-1 beta, IL-6, interferon (IFN)-gamma and IL-8, being positive but not M-CSF, IL-1 alpha, IFN alpha, tumor necrosis factor (TNF)-alpha, IL-2, LD78 and the IL-1 receptor antagonist (IL-1ra). The results show that LNSC from ATL patients have pronounced proliferation activity and constitutively secrete various cytokines. They therefore provide useful models for studying the microenvironment of lymph nodes in vitro, and especially the growth mechanism of ATL cells. PMID- 21541561 TI - Synergistic and antagonistic interactions between docetaxel and interferon-beta on growth of human breast cancer cells in vitro. AB - Docetaxel and interferon-beta (IFN-beta) were tested alone and in combination for their antiproliferative activity against the estradiol receptor (ER) positive MCF 7 and the ER negative MDA-MB231 breast cancer cell lines. Cell growth inhibition was determined after a 3 day incubation by the sulforhodamine B assay. The antiproliferative effects of the drug combinations were analysed using Berenbaum's hyperplane theorem to determine additive, synergistic and antagonistic effects. Docetaxel was found to be equally effective in inhibiting cell growth of both cell lines. On the other hand MCF-7 cells were more sensitive to the antiproliferative activity of IFN-beta than MDA-MB231 cells. At low docetaxel:IFN-beta molar concentration ratios a synergistic interaction was observed for MCF-7 cells, whereas an additive interaction was found for MDA TMB231 cells. Higher molar ratios resulted in additive interactions on MCF-7 and antagonistic interactions on MDA-MB231 cells. MCF-7 cells seem to be more sensitive to treatment by the combination of docetaxel and IFN-beta than the MDA MB231 cells. Therefore an ER positive breast carcinoma may possibly profit by the combination of docetaxel and IFN-beta, but further studies are necessary to clarify the therapeutic usefulness and optimal scheduling of the drug combination. PMID- 21541562 TI - Alterations in gene expression between EMT-6 mammary carcinoma monolayers and spheroids identified by differential display. AB - Differential display was used to define differences in gene expression between murine EMT-6 mammary carcinoma cells grown in monolayer or as spheroids in cell culture. Eighty different combinations of primer sets made of four anchored oligodeo(dT) primers (T(12)MG, T(12)MA, T(12)MT or T(12)MC) and twenty arbitrary ten base primers (AP1-20) were used for RT-PCR of total purified RNA from EMT-6 monolayers or spheroids. After re-screening, fourteen DNA fragments were identified as being selectively expressed in EMT-6 cells grown as spheroids. The fragments were cloned into the pCR II vector. Two of the fourteen cDNA fragments corresponded to mRNA selectively expressed in EMT-6 cells grown as spheroids. These clones were sequenced and found by database searching to correspond to murine heme oxygenase and murine beta(2)-microglobulin. There was a 5.3-fold higher expression of beta(2)-microglobulin and a 5.3-fold greater expression of heme oxygenase in EMT-6 cells grown as spheroids than in the same cells grown as monolayers. These studies reflect the phenotypic flexibility of cells depending upon the growth environment. PMID- 21541563 TI - Changes in liver glycogen and lipid metabolism during transient graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivity. AB - We investigated the influence of transient graft-versus-leukemia (GvL) and graft versus-host reactivity (GvH) following allogeneic immune cell transfer on the glycogen and lipid metabolism in the liver of affected mice to better understand the underlying mechanism of these phenomena. As model we used a well established adoptive cellular immunotherapy (ADI) system. This involves transfer of in situ activated anti-tumor immune spleen lymphocytes (ISPL) from the tumor-resistant mouse strain B10.D2 (H-2(d), M1s(b)) into 5 Gy sublethally irradiated syngeneic ESb-MP lymphoma-bearing DBA/2 (H-2(d), M1s(a)) mice. Experiments were performed by transfer of ISPL from B10.D2 into DBA/2 tumor-bearing mice (GvL effect on liver metabolism) and into DBA/2 non-tumor-bearing mice (GvH effect on liver metabolism). Our results show that glycogen in hepatocytes decreased dramatically 5 days after ISPL transfer, which coincided with a high increase of large fat granules. 8 days after ISPL transfer, livers started to re-express glycogen and to decrease their lipid content. Normalization of both parameters was seen after day 30. These changes were qualitatively similar in both GvL and GvH. Measurement of activity of the liver marker enzymes, GOT and GPT, in the sera of animals subjected to GvL or GvH, showed peak values also at day 5, coinciding with the loss of glycogen. Quantitative differences were seen, however, in that much higher levels were reached in GvL than in GvH. Immune system recovery from irradiation damage and liver regeneration after immune cell mediated liver damage are likely explanations for the reversibility of the metabolic changes and for the lack of GVH disease and mortality in this new and effective cellular cancer immunotherapy model. PMID- 21541564 TI - Significant effects of preoperative intraluminal brachytherapy on the survival rate after resection of rectal carcinoma. AB - We investigated whether or not preoperative intraluminal brachytherapy (IBT) contributes to a prolongation of the survival after resection of rectal carcinoma. Eighty-five patients with middle and lower rectal carcinoma with penetration into or through the rectal wall were treated with preoperative IBT (30 Gy) and radical resection. The patients were divided into the major effect group (n=59, proportion of remaining viable cells less than 25% of the background stroma) and the minor effect group (n=26, proportion of viable cells over 25%). The major effect group had more down-staged tumors, and a lower rate of positive nodes. Local recurrence rate, distant recurrence rate, and survival rate of the major effect group were 9% (31% in the minor effect group), 15% (55% in minor group) and 74% (36% in minor group), respectively (all parameters: p<0.05). Multivariate analysis indicated that nodal involvement, tumor depth, and proportion of viable cells were the prognostic factors. Preoperative IBT affected not only the tumor morphology but also the prognosis. Our criterion of the proportion of residual viable cells was significantly correlated to the patients' survival. The analyses revealed the positive effects of IBT on the prognosis of rectal cancer. PMID- 21541565 TI - Expression of apoptosis-related antigen Le(Y) in superficial colorectal adenoma and adenocarcinoma. AB - To investigate the characteristics of superficial type colorectal epithelial neoplasia (SN) (adenoma, SAd; adenocarcinoma, SCa; superficial-elevation type, E; superficial-depression type, D), the expression of Lewis y (Le(Y)), a marker of apoptosis, and the labeling index of proliferative cell nuclear antigen staining (PCNA-LI) in the intramucosal regions of 56 SN lesions were investigated. Expression of Le(Y) was observed in cytoplasm or cell membrane from the surface to deep within some tubules in SN lesions. Le(Y) was detected at higher rates in SCa lesions than in SAd lesions, in SCa lesions greater than 11 mm in diameter than in those less than 10 mm in diameter, in SCa-E lesions than in SCa-D lesions, in SCa lesions deeper than middle third of the submucosal layer, and was not related to size or macroscopical appearance of SAd lesions. PCNA-LI rate was higher in SCa lesions than in SAd lesions, in SCa lesions with carcinoma invasion to the submucosal layer than in SCa lesions with carcinoma invasion limited to the propria mucosa, and that of SAd lesions was inversely correlated with tumor size although that of SCa lesions was positively correlated with tumor size. There was a relationship between the high degree of expression of Le(Y) and PCNA LI. In SCa lesions apoptosis and cell proliferation reflected that the enlargement and/or deeper invasion of carcinomatous tissue and in SAd lesions apoptosis had no relationship to tumor size although the cell proliferation inversely correlated with tumor size. This suggested that SCa-D lesions and the SCa-E with much higher proportions of apoptotic cells progressed to the ulcerative advanced cancer, and the size of many SAd lesions had a limit. PMID- 21541566 TI - Radioimmunolymphoscintigraphy in the preoperative staging of primary breast cancer. AB - Thirty-one primary breast cancer patients were evaluated by radioimmunolymphoscintigraphy (RILS) and ex vivo scintigraphy (EVS) following subcutaneous injection of human monoclonal antibody In-111-LiLo-16.88. Lymph nodes (370) were assessed by EVS, pathology and immunohistochemistry. The positive predictive value (EVS) for antigen positive nodes, metastatic and hyperplastic, was 90% in stages O-IIB, and the sensitivity and specificity for all stages were 60% and 80% respectively. Four EVS positive nodes with follicular hyperplasia contained micrometastases. RILS and EVS correlate well by the Spearman Rank test (R=0.87). These results suggest RILS may be clinically useful and selectively limit the extent of the surgical procedure. PMID- 21541567 TI - Novel cellular markers in breast cancer. AB - Epidemiological studies have revealed that Parsi women have a higher incidence of breast cancer than non-Parsis and that they are more susceptible to breast cancer. We have studied the cellular distribution of two prosomal proteins p23K in parallel to the p30.33K and proliferation marker Ki-67 as potential markers to identify high risk population for breast cancers. Flow cytometry data demonstrated that the Parsi benign and non-Parsi malignants have a higher number of cells labelled with these two prosomal protein antibodies than the non-Parsi benign and European 'normals'. Using immunohistochemical methods, p23 K was found to be significantly higher in Parsi and non-Parsi malignants as well as in non Parsi benigns. In our FCM analysis, intergroup comparison showed, interestingly, a significantly higher expression of both p23K and p30.33K in Parsi benigns as compared to non-Parsis, raising the possibility that benign tumors of Parsis represent already premalignant lesions. The present study, in addition, proposes the prosomal antigens as likely cell proliferation markers comparable to Ki-67. PMID- 21541568 TI - Impact of tumor cell kinetics on the outcome of induction chemotherapy in oral carcinoma patients. AB - Pretherapeutic S-phase fractions of 68 carcinomas of the tongue and the floor of mouth were analysed by DNA flow cytometry immediately before intra-arterial induction chemotherapy with cisplatin and epirubicin or 5-fluorouracil. Patients with diploid tumors had an excellent 5-year survival rate of 89% in contrast to only 31% in the aneuploid group. Cell proliferation had no impact on the outcome of diploid cases. Node-positive patients with aneuploid tumors had a poor 18% 5 year survival rate, independent of S-phase fractions. Survival was significantly worse in nodenegative patients with high proliferating aneuploid tumors (45%) compared to the low-proliferative N-0 group (83%). PMID- 21541569 TI - Survival benefit for patients with colorectal cancer detected by population-based screening program using an immunochemical fecal occult blood test. AB - The effectiveness of screening for colorectal cancer by an immunochemical fecal occult blood test was investigated by comparing the survival time of 194 screen detected colorectal cancer subjects (screen-detected group) with that of 352 routinely diagnosed subjects (control group). The rate of Dukes' A cancers was significantly higher in screen-detected group than in the control group (43.8% vs 16.8%, p<0.0001), whereas that of Dukes' D cancer was the opposite (5.7% vs 21.3%, p<0.0001). The survival rate for screen-detected group was higher than that for the control group (Kaplan-Meier method, p<0.0001). By a proportional hazard model with adjustment for prognostic factors except stage, the risk ratio of death from colorectal cancer was 0.40 (p=0.0007) for screen-detected group versus the control group. Therefore, the screening was suggested to be effective in survival benefit, although there might be potential biases inherent in observational studies. PMID- 21541570 TI - Diagnostic evaluation of cancer antigens RAK .1. Cervical and ovarian cancer. AB - Cancer antigens RAK-p120, p42, and p25, which exhibit biological, immunological and molecular similarity to the proteins expressed by Human Immunodeficiency Virus 1 (HIV-1), were found in 47 of 47 tested cases of serous adenocarcinoma of the ovary, and 45 of 45 tested cases of squamous carcinoma of the cervix. Normal ovary and cervix did not express antigens RAK. High molecular weight protein (RAK p160) was detected in the blood of over 61% of ovarian and 72% of cervical cancer patients, and in 14.3% of healthy women with family history of breast and/or gynecological cancer. Antigens RAK might represent new diagnostic markers. PMID- 21541571 TI - Novel allele of the hMLH1 gene bearing a TTC deletion in the 3' untranslated region. AB - SSCP analysis of the hMLH1 gene in two kindreds affected by hereditary nonpolyposis colorectal cancer (HNPCC) revealed the presence of unique conformers in all patients affected by colorectal cancer. Sequence analysis of the corresponding region of the gene revealed a 3 base pairs deletion within a TTC tandem repeat (G TTC TCC T-->G TTC T) beginning 29 base pairs downstream of the termination codon of the gene in the 3' untranslated region. This deletion causes the loss of an MboII restriction site. Analysis extended to 113 healthy unrelated individuals and 27 unrelated HNPCC patients demonstrated the occurrence of this novel variant of the hMLH1 gene at similar frequencies in unrelated HNPCC patients (3.7%) and in control individuals (2.2%). The allele bearing the TTC deletion appears to be expressed at levels comparable to those of the wild-type allele. PMID- 21541572 TI - Clinicopathologic comparison of hepatitis B virus-related and hepatitis C virus related hepatocellular carcinoma. AB - 137 cases of hepatocellular carcinoma associated with cirrhosis that had undergone resection between 1991-95 have been analyzed. One hundred and three had hepatitis C (positive for anti HCV alone) and 34 hepatitis B (positive for HBsAg alone). The hepatitis C cases were older and were associated with more severe cirrhosis. The tumors from hepatitis B cases were on average larger and histologically less-differentiated, and were more likely to occur in the background of macronodular cirrhosis than hepatitis C cases. PMID- 21541573 TI - Vascular endothelial growth factor and basic fibroblast growth factor in primary lung carcinomas and the incidence of metastases. AB - Paraffin-embedded tumor sections from 166 patients with squamous cell lung carcinomas (n=114) and lung adenocarcinomas (n=52) were analyzed for the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) by immunohistochemistry. The results were compared with the incidence of metastatic spread. Sixty-five tumors were characterized as VEGF negative and 101 tumors as VEGF-positive. Fifty-eight tumors were bFGF-negative and 108 tumors classified as bFGF-positive. Tumors with expression of VEGF or bFGF showed an increase in the formation of metastases. Combining the VEGF and bFGF expressions improved the prognostic value. Corresponding results were obtained when the analysis was restricted to squamous cell lung carcinomas or adenocarcinomas of the lung. These data provide evidence that VEGF and bFGF may be relevant factors associated with the metastatic potential of primary lung carcinomas. PMID- 21541574 TI - Induction of p53 DNA-binding activity by tumor necrosis factor-alpha. AB - Tumor necrosis factor-alpha (TNF-alpha) has been reported to activate the murine p53 promoter, which was mediated by activation and binding of the NF-kappa B transcription factor to the intact p53 consensus binding site. We show in this report that TNF-alpha at concentrations of 0.1 nM induced the DNA-binding activity of wild-type p53 fivefold in the H460a human lung carcinoma cell line. The increases in p53 DNA-binding activity by TNF-alpha in H460a cells resulted from a post-translational activation mechanism, since levels of the p53 protein remained unchanged in TNF-alpha-treated cells. Furthermore, Northern and nuclear run-off analyses ruled out an increase in transcriptional activity of the promoter of the human p53 gene in TNF-alpha-treated cells. These results are in contrast to those reported for the murine p53 gene, whose promoter is induced by TNF-alpha through activation of the NF-kappa B transcription factor. To determine the molecular basis for the lack of activation of the human p53 gene promoter by TNF-alpha, the binding of NF-kappa B to the kappa B-like sites in the murine and human p53 promoters was compared in nuclei of TNF-alpha-treated NSCLC cells by electrophoretic mobility shift assay. The human kappa B-like site differs from the murine by the substitution of two base pairs. With the exception of the H460a cell line, all NSCLC cell lines treated with 0.1 nM concentrations of TNF-alpha exhibited increased NF-kappa B DNA-binding activity. The kappa B-like site located in the murine p53 promoter bound strongly to NF-kappa B complexes in p53 negative H1299 cells. However, the kappa B-related site in the human p53 promoter showed a much lower affinity for NF-kappa B complexes. In addition, p50 homodimers specifically interacted with the human kappa B site, whereas p65/p50 heterodimers bound selectively to the mouse kappa B site. We conclude that TNF alpha can activate human wild-type p53 in NSCLC cells by a post-translational mechanism. Moreover, the inability of TNF-alpha to activate the human p53 gene promoter, in contrast to that reported for the murine p53 gene, may be the result of differences in the interactions of the murine and human kappa B sites with NF kappa B complexes. PMID- 21541575 TI - Modulation of fibronectin synthesis by cancer cell-fibroblast interaction. AB - Conditioned medium (CM) of human rectal adenocarcinoma cell line RCM-1 stimulated both cellular (c-) and plasma (p-) fibronectin (FN) production by human fibroblasts and modulated the alternative splicing of its primary transcript at the EDA region to express more EDA-containing (+) mRNA. This EDA(+) mRNA stimulating effect of CM was inhibited by treatment with an anti-human transforming growth factor (TGF)-beta antibody. TGF-beta production by RCM-1 cells was demonstrated by immunoblotting and RT-PCR. Thus, FN synthesis and splicing-in at the EDA region in fibroblasts were stimulated by cancer cells predominantly via TGF-beta. Since RCM-1 cells adhered to cFN, which contains EDA, more efficiently than pFN and adhesion to extracellular matrix proteins such as FN is the first step to migration, the cancer stroma modulated by cancer cell fibroblast interaction may facilitate cancer invasion. PMID- 21541576 TI - Loss of heterozygosity at chromosome 1p in human breast cancer. AB - 232 human primary invasive breast tumors were analyzed with 13 polymorphic microsatellite markers specific to chromosome 1p. Loss of heterozygosity (LOH) was observed in 126 cases or 54% of the tumors. One marker, D1S496, at the 1p35 region showed the highest LOH, 28%. High frequencies of LOH were also detected by the markers, D1S488, D1S167 and D1S435, at the 1p31 region, 25%, 24% and 26% LOH, respectively. This suggests the presence of tumor suppressor genes at these two regions. Tumors with and without LOH at 1p were tested for association with clinico-pathological features of the tumors such as estrogen- and progesterone receptor content (ER and PgR), age at diagnosis, tumor size, node status, histological type, S-phase fraction, ploidy, survival and LOH at chromosomes 3p, 6q, 9p, 11p, 11q, 13q, 16q, 17p and 17q. A significant association was found between LOH at chromosome 1p and high S-phase fraction and lower survival rate. Association was also found between LOH at 1p and chromosome regions 3p, 6q, 9p and 17q. A multivariate model including prognostic variables, showed that LOH at 1p is an independent prognostic variable and patients who have breast tumors with LOH at 1p have approximately a two-fold increase in relative risk of death. We conclude that screening for 1p deletions gives additional prognostic information that might be useful in breast cancer treatment. PMID- 21541577 TI - Co-cultured endothelial and Kupffer cells regulate hepatocyte replication. AB - We studied the effect of co-culture with endothelial and/or Kupffer cells on hepatocyte replication in primary culture by means of [H-3]-thymidine incorporation. Hepatocytes, sinusoidal endothelial and Kupffer cells were extracted from rat liver by a two-step perfusion and subsequent two-step elutriation method. The replication was promoted in proportion with the densities of endothelial cells, but inversely suppressed by co-culture with Kupffer cells. The replicative effect of endothelial cells was not observed with the high number of hepatocytes cultured, however. The hepatocyte replication was also regulated in accordance with the ratios of endothelial/Kupffer cells. These results indicate that endothelial cells have a positive effect and Kupffer cells have a negative effect on hepatocyte replication, and that this replication may be associated with hepatocarcinogenesis and/or tumor-growth of hepatocellular carcinoma. PMID- 21541578 TI - Serum carcinoembryonic antigen (CEA) correlates with the survival time during 5 FU hepatic arterial infusion chemotherapy for unresectable colorectal hepatic metastases. AB - We investigated whether carcinoembryonic antigen (CEA) could be used to predict the response and survival of patients treated with 5-FU. Between 1984 and 1994, 58 patients with unresectable hepatic metastases from colorectal carcinoma were enrolled in this study. Forty-three patients underwent resection of the primary colorectal malignancy, and a catheter was inserted into the hepatic artery during the operation (HAI group). Fifteen patients received no adjuvant therapy (non-HAI group). Patients with CEA values reduced by greater than or equal to 30% at 2 months after the start of 5-FU infusion had a significantly longer survival period than patients with a decrease of <30%. Terminal cases in CEA reduced by greater than or equal to 30% group revealed that CEA re-elevation was observed at 7 months, and the patients died 8 months later at 15 months. Our findings suggest that serum CEA monitoring is useful for predicting the survival time following 5 FU hepatic arterial infusion. PMID- 21541579 TI - Low levels of alpha-L-fucosidase activity in colorectal cancer are due to decreased amounts of the enzymatic protein and are related with Dukes' stage. AB - Colorectal cancer remains a major medical problem and survival of the patients is directly correlated to the possibility of metastases occurrence. We searched for biochemical differences between colorectal adenocarcinomas and their precursor normal cells with the aim of complementing histological methods for the classification and prognosis of human colorectal tumours. Increased fucosylation is one of the most common phenomena associated with malignant transformation, invasion and metastases. It might be expected that the enzyme alpha-L-fucosidase (alpha-L-fucosidase fucohydrolase E.C.3.2.1.51), involved in the breakdown of fucose-containing glycoproteins and glycolipids, would play an important role in the maintenance of the fucose content of aberrant fucosylated glycoconjugates. Statistical evaluation of 110 patients with colorectal adenocarcinoma has shown that there is a significant decrease of alpha-L-fucosidase activity in the malignant tissue compared with the healthy colonic mucosa of the same patient. Characterisation studies have shown that there are remarkable similarities in the physicochemical and kinetic properties of the enzyme in both tissues. Using an immunodetection assay we conclude that the observed decrease of alpha-L fucosidase activity is due to a significant decrease of alpha-L-fucosidase protein in colorectal tumours. Our results further demonstrate that the alpha-L fucosidase content (either as enzymatic activity or as enzymatic protein) is lower in primary tumours at advanced stages (Dukes' B and C) than in primaries at early stages (Dukes' A). PMID- 21541580 TI - Clinical significance of E-cadherin and vimentin co-expression in breast cancer. AB - We examined the clinical significance of E-cadherin and vimentin expression in 83 patients with breast dancer. E-cadherin expression was correlated with axillary metastases, histologic grade, recurrence and disease-free survival, but not with overall survival. On the other hand, vimentin expression was correlated with axillary metastases and histologic grade, but not with recurrence, disease-free or overall survival. However, the co-expression of E-cadherin and vimentin was associated with axillary metastases, histologic grade and recurrence, and appeared as the most important prognostic factor in disease-free and overall survival. We therefore concluded that E-cadherin and vimentin expression in combination might provide prognostic information for breast cancer patients. PMID- 21541581 TI - Second malignancies. AB - The secondary development of malignant tumors after the treatment of Hodgkin's disease has been termed the price of success, but is relevant also to other types of cancer and gives an opportunity to study mechanisms of carcinogenesis and tumor induction. The authors review here their experience with second malignant neoplasms (SMN) as well as the result of an extensive search of the recent literature. The primary malignancies discussed in this article include Hodgkin's disease, pediatric cancer, breast cancer, lung cancer and other types of tumors. The international literature was searched (Medline 1989-1995) for reports of SMN with special emphasis on risk factors and the molecular mechanisms of tumor induction. In Hodgkin's disease, a 3 to 5-fold elevated risk for SMN was recognized, with a 15-year cumulative incidence in the range of 11-18%. All types of malignancies have a statistically increased risk (leukemias, non-Hodgkin's lymphomas, solid tumors). The risk for leukemia is related to the intensity of treatment with alkylating agents. Some solid tumors like lung cancer or breast cancer are related to radiation therapy. Present-day treatments may carry a lower risk of inducing secondary malignancies than treatments in the past. For non Hodgkin's lymphoma as primary malignancy, fewer data exist on SMN. In pediatric cancer, no general risk estimate can be given and the genetic influence is greater as a cause of SMN. The improved prognosis for acute lymphoblastic leukemia has led to a changing pattern of pediatric SMN. In head and neck- and in lung cancer, the same etiologic factors which cause the primary tumor may also cause SMN. SMN occur as part of familial cancer syndromes. Two types of treatment related leukemias (mostly AMLs) exist and can be recognized by cytogenetic and molecular analysis. A complete follow-up is necessary to fully appreciate the risk of second malignancy. The goal to prevent SMN must be reached without decreasing the cure rates of the primary tumor. New treatment approaches need to be carefully monitored for SMN. Improved tests of mutagenesis and molecular screening may help to recognize patients prone to develop SMN and permit to estimate certain types of risk. Screening and prevention strategies are useful in high-risk situations. PMID- 21541582 TI - Primary extranodal lymphomas of Waldeyer's ring, stage IE and IIE. AB - We reviewed 45 cases of Waldeyer's ring lymphomas (25 stage IE, 20 IIE): 73% had high-grade histology according to Kiel's classification. Fourteen patients received radiotherapy alone and 31 chemotherapy, combined with radiotherapy in 28. Complete remission rate was 95% and relapse rate 32%. At 8 years overall disease-related survival (DRS) and event-free survival (EFS) were 69% and 57% respectively. Combined treatment provided both significantly better DRS (82% vs 42%) and EFS (76% vs 25%) than radiotherapy alone. Most of the patients with high grade histology (26/33) received the combined treatment and this subgroup achieved a long-term EFS of 78%. Both DRS and EFS were also significantly longer in patients under 60. At multivariate analysis favorable prognostic factors were lower age for DRS and combined treatment for EFS. PMID- 21541583 TI - Measurement of O-6-methylguanine-DNA methyltransferase activity using oligonucleotides and restriction enzyme in human brain tumors. AB - We determined the levels of MGMT activity in 46 human brain tumors, using oligonucleotides containing O-6-methylguanine at a PvuII recognition site, and correlated MGMT activity with chemotherapeutic effectiveness in 14 patients with high-grade gliomas who received ACNU chemotherapy. The results characterize MGMT activities among different types and within individual types of human brain tumors. A certain fraction of gliomas exhibited a low value of MGMT activity. Tumors showing a low MGMT activity responded well to ACNU and resulted in prolongation in the time to tumor progression. Thus, the low MGMT activity of gliomas may provide a theoretical basis for application of CENU chemotherapy. PMID- 21541584 TI - p53 expression and tumor proliferative activity in testicular germ-cell tumors. AB - We evaluated p53 expression and tumor proliferative activity (TPA) using monoclonal antibodies to Ki-67 and proliferating cell nuclear antigen (PCNA) in 26 patients with seminomatous and nonseminomatous testicular germ-cell tumors (GCTs). Correlation between p53 expression and TPA, as well as the clinical correlation with the expression of these proteins were also assessed. There were eight cases of pure seminoma and 18 cases of nonseminomatous GCTs, collectively consisting of 45 tumors or tumor components. The nonseminomatous GCTs were mixed or pure and included choriocarcinoma (CC), embryonal carcinoma (EC), immature teratoma (IMT), mature teratoma (MT), seminoma, and yolk sac tumor (YST). The ages of the patients with seminomatous GCTs ranged from 24 to 47 years (mean, 34 years) and those for patients with nonseminomatous GCTs ranged from 17 to 43 years (mean, 29 years). Sixteen (44%) of the 36 nonseminomatous GCTs or tumor components were positive for p53 protein. Ten (91%) of eleven ECs, three (38%) of eight YSTs, two (20%) of ten MTs, and the single case of CC were positive for p53 protein. All nine seminomas and three of six IMTs were only focally positive for p53 protein. The p53 expression in ECs and YSTs was significantly higher than that in IMTs, MTs, and seminomas (P=0.0001). TPA was present in the majority of the seminomatous and nonseminomatous GCTs, and was significantly higher in ECs and YSTs than in seminomas, MTs, and IMTs (Ki-67, P=0.0001; PCNA, P=0.0006). In the majority of the cases PCNA expression was higher than Ki-67 expression (P=0.0001). The mean TPA percentage was significantly higher in the p53-positive tumors or tumor components (EC and YST) when compared with the mean TPA percentage in those neoplasms that were focally positive or negative for p53 protein (Ki-67, P=0.003; PCNA, P=0.046). p53 expression was also associated with histologically aggressive tumors (ECs and YSTs) that also exhibit high TPA. No relationship appears to exist between the three tumor markers and the clinical stage or the patients' follow-up and outcome in this small series. Further studies are necessary to elucidate the roles of p53 and proliferation markers in testicular tumorigenesis and as prognostic markers. PMID- 21541585 TI - Structural status of the int loci in women showing high incidence of breast cancer. AB - Mammary carcinomas in certain mice strains are induced following infection by the MMTV. Insertion of MMTV provirus into the int-1 and int-2 loci results in transcriptional activation of these two proto-oncogenes and is thought to be a key step in breast tumorigenesis in mice. A viral etiology for human breast cancers, though proposed several years ago, is far from proven. However, morphological structures resembling Bittner's particles have been observed earlier in about 39% samples of breast tumor and milk sediments of Parsi women. We therefore investigated in the Parsis, the structural integrity of two potential sites of integration (int-1 and int-2) of the hypothetical human mammary tumor virus and have used for this purpose a large number of patient DNA. The results obtained however failed to distinguish any major structural change existing at the int-1 or the int-2 sites that may point to a proviral integration event having occured in human breast cancers. We have, however, observed differences in the physical structure of the int-1 map, compared to the one reported and sequenced, and have therefore felt it necessary to present a new one indicating our findings, notably, the polymorphic PvuII sites. In addition, we report a single case of Parsi woman, with infiltrating grade 3 ductal carcinoma, whose DNA contains an alteration in the int-2 structure. PMID- 21541586 TI - Ability of tannins extracted from the leaves of various trees and shrubs to inhibit the biomarkers of tumor promotion in mouse skin in vivo. AB - Eight heterogeneous tannin samples (HTSs) extracted from various tree/shrub leaves of African and Himalayan origin were tested topically for their ability to inhibit the biomarkers of tumor promotion in mouse skin in vivo. HTS2 (from Dichostachys cinerea) and HTS6 (from Cassia sieberiana) consistently inhibit tumor promoter-stimulated ornithine decarboxylase activity, DNA synthesis, hydroperoxide production, and edema formation almost as much as loblolly pine bark condensed tannin (LPB-CT), which is known to inhibit skin tumor promotion. The other HTSs tested have lesser or only partial inhibitory effects. The ability of HTSs to inhibit the biomarkers of tumor promotion may be related to their reducing power but there is no apparent correlation between their inhibitory effects and their proanthocyanidin contents expressed as absorbance units, protein precipitation activities, and relative degrees of polymerization. HTS6 is effective against a wide spectrum of tumor-promoting agents unrelated to 12-O tetradecanoyl-phorbol-13-acetate. The antioxidant effects of HTS6 and LPB-CT are similar but do not resemble that of tannic acid. HTS6 and LPB-CT both fail to alter the covalent binding of a tumor-initiating dose of 7,12-dimethylbenz[a] anthracene to DNA but inhibit the stimulation of DNA synthesis caused by a carcinogenic dose of this compound. Some foliage tannins, therefore, have potent antioxidant and anti-inflammatory activities and may inhibit hyperplasia and tumor promotion but their efficacy may vary considerably depending on their origin, chemical composition, and biological properties. PMID- 21541587 TI - Mechanism of antiproliferative activity of luteolin against stilbene-estrogen stimulation of proliferation of hamster renal epithelial cells. AB - In the present study, we have investigated the influence of a naturally occurring plant flavone luteolin on cell proliferation, nuclear tyrosine kinase activity, and expression of insulin-like growth factor-I (IGF-I) receptor in Syrian hamster renal epithelial cells. Diethylstilbestrol (DES)-induced cell proliferation was inhibited in a dose-dependent manner by cotreatment with luteolin. We also tested the influence of luteolin on nuclear protein tyrosine kinase activity and the expression of IGF-I receptor. The nuclear tyrosine kinase activity was inhibited in a dose-dependent manner by both genistein and luteolin. Luteolin was five times more effective in inhibiting nuclear tyrosine kinase activity than genistein. Data of kinetic constants suggest that luteolin is a noncompetitive inhibitor of nuclear protein tyrosine kinases. Co-treatment of luteolin significantly inhibited DES-induce IGF-I receptor expression. These findings indicate that blocking effects of DES-induced cell proliferation by luteolin may be through the inhibition of nuclear tyrosine kinase activity and of IGF-I receptor expression. PMID- 21541588 TI - Effects of epidermal growth factor and mitogenic blockers on rat colonic tumour growth in vivo. AB - A protocol for tumour cell inoculation (Per192NR and Per237 rat colon cancer cells) and implantation of mini-osmotic pumps in inbred rats was established. Surgical procedures and tumour growth did not affect red and white blood cell counts. Per237 did not grow in these rats while Per192NR formed poorly differentiated carcinomas which were not affected by EGF intraperitoneal (IP) or intravenous (IV), oleic acid (IP) or verapamil (IP or oral) administration. Haematological parameters and rat growth rates were not affected by EGF (IP and IV), verapamil (IP) and oleic acid (IP) treatment. This protocol provides a method for studying the effect of various cancer drugs in vivo. PMID- 21541589 TI - Cell density-dependent regulation of mdr-1 gene expression in murine colon cancer cells. AB - We studied the regulation of mdr-1 and P-glycoprotein in sparse and confluent cultures of murine CT-26 colon carcinoma cells. The expression level of mdr-1 mRNA transcripts (analyzed by Northern blot and in situ hybridization) and P glycoprotein (analyzed by flow cytometry) inversely correlated with cell density. The modulation of mdr gene expression in sparse and confluent cells was not related to cell division, nutrient depletion, inhibition of protein synthesis, gap junction status, extracellular ATP, or the presence of various extracellular matrixes, but may be related to cell-density and cell-contact mediated changes in phosphatase activity. The confluence-mediated downmodulation of mdr-1 increased the chemosensitivity of the cells to several anticancer drugs commonly associated with an in vitro MDR phenotype by increasing the intracellular accumulation of the drugs. These data may explain some of the discrepancies in results obtained when analyzing mdr gene expression in tumors growing in vivo or in vitro, and why mdi expression in tumors is localized to the periphery of the lesions. PMID- 21541590 TI - Multidrug resistance in cancer (review). AB - The development of resistance to anticancer agents during treatment is a major obstacle in the chemotherapy of cancer. Cells expressing high levels of the P glycoprotein exhibit a multidrug resistance phenotype. The P-glycoprotein is a membrane phosphoprotein which serves as a drug efflux pump to reduce intracellular drug accumulation, and hence the cytotoxicity of anticancer drugs. Several studies have shown that protein kinase activators and inhibitors may modulate the biological activity of P-glycoprotein through covalent modification by phosphorylation. Most of these drugs may have additional mechanisms of action and may alter drug accumulation within multidrug resistant cells with or without their effects on phosphorylation of P-glycoprotein. In addition, transcriptional regulation of MDR 1 gene has been found to be regulated by protein kinase A type I and protein kinase C. Therefore, these kinases may be important candidates in studies of the reversal of multidrug resistance and hence in enhancing the efficacy of anticancer drugs. PMID- 21541591 TI - Glucosaminylmuramyldipeptide-induced changes in phenotype of melanoma cells result in their increased lysis by peripheral blood cells. AB - Flow cytometry was used to show that biologically active N-acetylglucosamine containing muramylpeptides (GMPs) induced in vitro dose-dependent increase in the expression of tumor-associated antigens (TAAs) characteristic for colon and mammary gland carcinomas, melanoma and lung adenocarcinoma. Forty to two hundred percent enhancement in TAA-expressing cells was observed after 18-48 h incubation with GMPs. In contrast, MHC class I antigen expression was not altered. Using MTT and chromium-release assays, melanoma cells treated in vitro with GMDP were shown to be more susceptible to killing by peripheral blood cells of healthy donors than non-treated cells. Fractionation of blood cells revealed that platelets were responsible for this effect. PMID- 21541592 TI - Prognostic relevance of detection of ligands for vertebrate galectins and a Lewis(Y)-specific monoclonal antibody. AB - Tissue sections taken from 157 potentially curatively operated lung carcinoma patients (70 epidermoid carcinomas, 68 adenocarcinomas, 15 large cell anaplastic, and 4 small cell anaplastic carcinomas) were examined by a standardized histochemical protocol in a prospective study evaluating the extent of various types of probes to serve as prognostic indicators in lung cancer. Detailed clinical records and survival data (minimum 56 weeks, maximum 96 weeks) were correlated to the results of the histochemical reactions. The study centres on monitoring the expression of galactoside-containing epitopes in tumor cells by human, animal and plant lectins: and with a monoclonal antibody. In addition, affinity-purified subfractions of natural antibodies from human serum with preferential affinity to alpha- and beta-galactosides, respectively, were employed. Significant contributions to the estimation of the survival of patients are given by clinical parameters (pT, pN stage), number of resected and positive lymph nodes and presence of tumor metastases into specific lymph nodes (No. 5 and No. 6 right and left). With respect to the relevance of subsets of beta galactosides, the galectin from chicken liver (CL-16) and the Le(y)-specific monoclonal antibody unveiled a negative correlation at a statistically significant level. The predictive value of binding of the animal lectin CL-16 was especially pronounced for patients with advanced tumor stages, pointing to a potential role of such lectin-reactive beta-galactosides in late tumor stages or progression. PMID- 21541593 TI - Prognostic significance of multiple genetic lesions on chromosomes 19, 10, and 17 in oligodendrogliomas. AB - Patients diagnosed with oligodendrogliomas/oligoastrocytomas and with somatic loss of genes on chromosome 19q13.2-q13.3 survived for >5-6 years, a survival period typical of the tumors of oligodendroglial origin. One patient with oligoastrocytoma, harboring allelic loss on chromosome 10p in the tumor DNA, had a recurrence five years later with progression to anaplastic astrocytoma. However, another patient with oligoastrocytoma, whose tumor suffered multiple genetic lesions on chromosomes 19q13.2-13.3, 10q22-24, and 17p13.1 (a point mutation in the p53 gene), had two subsequent recurrences as anaplastic astrocytomas and a survival period of 29 months. Our data suggest that in tumors of oligodendroglial origin the inactivation of a tumor suppressor gene on chromosome 10, especially in conjunction with other genetic aberrations, is indicative of aggressive clinical course. PMID- 21541594 TI - Significance of alpha-1-antitrypsin mRNA expression in esophageal carcinoma. AB - Alpha-1-antitrypsin (alpha 1AT) is present not only in the normal gastrointestine, but in malignant gastrointestinal tissue as well. We studied the expression of alpha 1AT mRNA in 30 cases of esophageal carcinoma using a Northern blot analysis. In addition, we also examined the expression of matrix metalloproteinase 7 (MMP7) mRNA in the latest 15 cases by reverse transcriptase polymerase chain reaction (RT-PCR) method to clarify the relationship between the alpha 1AT and MMP7. In 25 of the 30, the expression of alpha 1AT mRNA in esophageal carcinomatous tissue (T) was lower than that in the corresponding normal tissue (N) of the esophagus. The T/N ratio of alpha 1AT mRNA expression showed a significant inverse correlation with the depth of tumor invasion, lymph node metastasis and stage of disease (p=0.042, p=0.0001 and p=0.002, respectively). The T/N ratio of alpha 1AT bad a converse correlation with that of MMP7 (p=0.034). The current study thus suggested that i) the lower expression of T/N expression may be a marker for the biological aggressiveness of esophageal carcinoma, and ii) the reduction of alpha 1AT may be partially correlated with the overexpression of MMP7 in tumor tissue. PMID- 21541595 TI - Analysis of mutant K-ras in multiple sites of normal appearing mucosa of colorectal cancer patients. AB - While 50% of colorectal tumors were found to harbor K-ms codon 12 mutation, only 18% of the respective patients contain this mutation in the normal appearing tissue when enriched PCR, a sensitive method that enables detection of one mutant allele in 10(4) normal alleles, is used. To determine whether the lower percentage could be attributed to the low incidence of this mutation or to the method of sampling, we have analyzed multiple normal appearing samples obtained from the same patient. Of 90 non-neoplastic mucosal samples collected from 20 patients with colorectal cancer, K-ras codon 12 mutation was identified in 6 samples taken from 5 patients. These results indicate that only one or two of the multiple samples contain mutant ras alleles. The presence of mutant ras alleles in the normal appearing tissues did not always correlate with that in the tumor site with respect to its presence and/or the type of base pair alterations, indicating independent or late events. While pointing to the importance of proper sampling method, the ability to detect ms mutation in normal mucosal tissues suggests it may serve as a useful biomarker of internal/external exposure which precede colorectal cancer development. PMID- 21541596 TI - Coexpression of EGF receptor and TGF alpha mRNA and protein occurs in primary meningiomas. AB - Meningiomas are benign brain tumors thought to arise by multi-step tumorigenesis, involving both the activation of proto-oncogenes and the loss of tumor suppressor genes. The EGFR gene encodes a protooncogenic tyrosine kinase growth factor receptor implicated in the pathogenesis of several types of cancer, including gliomas. TGF alpha, the ligand for EGFR, is thought to act through autocrine stimulation of EGFR present on the same and adjacent cells. Northern blot analysis revealed expression of EGFR mRNA in 9 of 11 (82%), and TGF alpha mRNA in 2 of 11 (18%), primary meningioma specimens. III situ hybridization verified EGFR and TGF alpha gene expression by meningioma cells. Immunocytochemistry using specific antibodies for EGFR and TGF alpha showed strong positivity amongst meningeal cells in the same meningioma samples. No EGFR or TGF alpha protein was detected in a sample of normal meninges. These data indicate that the autocrine coexpression of EGFR and TGF alpha mRNA and protein may occur in only a small proportion of primary meningiomas. PMID- 21541597 TI - Quantification of microvessel density in human tumours. AB - The current use of tumour microvascular density measurements in clinical practice is limited by the methods employed to identify and quantify the microvessels. The aim of this study was to assess tumour vascularity with three of the most commonly used endothelial markers and with different pre-treatment methods to determine which combination results in the best visualisation of endothelial cells. Serial sections of colorectal carcinoma were treated with microwave oven irradiation, pressure cooking or proteolytic digestion prior to immunostaining with von Willebrand factor (vWf), CD31 or CD34. The sensitivity of staining was enhanced by microwave pre-treatment for CD31 and CD34, and trypsinization for vWf. There was a statistically significant difference between microvascular counts obtained using antibodies for CD34 and vWf (p=0.004), and CD34 and CD31 (p=0.007), but not for CD31 and vWf (p=0.775). We conclude that the use of CD34 antibody on microwaved tissues is the most sensitive method to visualize and quantify vascular density in tumours. PMID- 21541598 TI - Antiapoptotic activity of bovine papilloma virus. AB - Transformed fibroblasts have been recently shown to be sensitive for induction of apoptosis by TGF-beta-treated neighbouring untransformed cells. Cells transformed by a variety of different transformation principles were regularly sensitive for intercellular induction of apoptosis, but fibroblasts transformed by bovine papillomavirus (BPV) represented a striking exception. In contrast to chemically transformed C127 cells, BPV-transformed C127 cells showed resistance against intercellular induction of apoptosis. In addition, BPV-transformed cells were resistant against induction of apoptosis by ROS in glutathione depleted cells. The antiapoptotic function of papillomaviruses may be of central importance for papillomavirus-induced tumor formation as it can protect transformed cells from intercellular control of oncogenesis. PMID- 21541599 TI - Modulation of cisplatin sensitivity and resistance by buthionine sulfoximine and cyclosporin A in human esophageal cancer cells. AB - We established a 2.4-fold cisplatin (CDDP)-resistant human esophageal cancer cell line (TE2R) from the parent TE2 line. CDDP accumulation was reduced in TE2R. The Na+, K+-ATPase inhibitor ouabain inhibited CDDP accumulation in TE2 but not TE2R, suggesting that TE2R may have alterations in the Na+, K+-ATPase and defective CDDP uptake mechanism. Buthionine sulfoximine (BSO) enhanced CDDP sensitivity of both cell lines and cyclosporin A (CsA) modified CDDP resistance in TE2R. These effects were associated with increased CDDP accumulation. Thus, BSO and CsA may be useful for modulation of CDDP sensitivity or resistance in esophageal cancer. PMID- 21541600 TI - Cancer gene therapy and immunotherapy (review). AB - Gene therapy is a newly hatched field of biomedical research aimed at introducing therapeutically important genes into somatic cells of patients for the treatment of human disease. Whereas for inborn errors of metabolism transfer of a single gene can correct the disorder, cancer is a complex disease involving mutations in a number of protooncogenes and tumor suppressor genes as well as an imbalance and disarray in phosphorylation events and regulatory circuits of the cell cycle; transfer of the wild-type p53 or p21 tumor suppressor genes is a successful gene therapy approach leading to apoptotic death of cancer cells or in restrain of their chaotic growth. A different promising approach is transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene (suicide gene) and systemic treatment with the prodrug ganciclovir which is converted by HSV-tk into a toxic drug killing dividing cells. Expression of suicide genes, p53, and other therapeutic genes preferentially in cancer cells can be achieved by regulatory elements from tumor-specific genes such as carcinoembryonic antigen, BRCA1, and PSA. PMID- 21541601 TI - pO(2) measurement in murine tumors by Eppendorf 'Histograph'. AB - The purpose of this study was to assess the usefulness of the Eppendorf 'Kistograph' as a device for measuring pO(2) in tumor and normal tissues of the laboratory mouse. To determine the appropriate calibration and electrode condition, nitrogen bubbling time was changed, and the current during calibration was recorded. Reproducibility of pO(2) measurements was tested in the series of human xenografts and murine isoplants at different time points or in the same tumor in successive determinations. pO(2) values obtained with the Eppendorf 'Histograph' were compared to those obtained with a manually controlled needle type electrode manufactured by the Diamond-General Company. The pO(2) values after 9 min of nitrogen bubbling were closer to the expected values than those after 3 min bubbling. The current during nitrogen bubbling in calibration declined following the pO(2) measurement by an amount corresponding to 0.8 mm Hg. Good reproducibility of pO(2) measurement was shown in i) pO(2) values in the same cell line at different time points and ii) pO(2) values in two or three consecutive measurements in related regions within the same tumor. The Eppendorf 'Histograph' and the Diamond-General device showed no significant differences in pO(2) distribution in either subcutaneous tissue or MCaIV tumors. In conclusion, results of the Eppendorf 'Histograph' were consistent and reproducible and were similar to those obtained by the Diamond-General set-up. PMID- 21541602 TI - The characterization of biological features in dedifferentiated liposarcomas by means of principal components and discriminant analyses of 25 computer-generated variables from Feulgen-stained nuclei and histological slides. AB - Several groups of lipomatous tumors are not yet clearly characterized on the biological level. In order to attempt to classify the dedifferentiated liposarcomas with respect to other types of malignant liposarcomas, 80 adipose tumors were submitted to the combination of two computer-assisted methodologies. These two methodologies consisted of i) the determination of 25 variables, and ii) the analysis of the diagnostic information contributed by these 25 variables by means of two complementary techniques, i.e. principal components and discriminant analyses. The 25 variables were computed by means of image cytometry on Feulgen-stained nuclei and histological slides, quantitatively describing distinct biological characteristics relating to morphonuclear (chromatin pattern) features (14 variables), nuclear DNA content distribution (9 variables), and tissue architecture pattern (2 variables). The 80 adipose tumors included 21 typical lipomas, 7 atypical lipomas (defined as extremity adipose tumors with a histopathological pattern of well-differentiated liposarcomas), 16 retroperitoneal and 5 non-retroperitoneal abdominal well-differentiated liposarcomas, 9 dedifferentiated liposarcomas, 8 myxoid (intermediate-grade tumor) and 14 pleomorphic (high-grade tumor) liposarcomas. The data strongly suggest that the dedifferentiated liposarcomas exhibit biological characteristics which are distinct from those of low- and high-grade liposarcomas, but similar to those of intermediate ones. The results also show that typical and atypical lipomas are two distinct biological entities. In contrast, the atypical lipomas and the well-differentiated retroperitoneal and non-retroperitoneal liposarcomas exhibited a high number of similar biological characteristics. Computer-assisted methods contribute valuable information to characterize lipomatous tumor biology. PMID- 21541603 TI - Sequential administration of interleukin-3 and granulocyte-macrophage colony stimulating factor following intensified, accelerated CEE (cyclophosphamide, epirubicin, etoposide) chemotherapy in patients with solid tumors. AB - The biological mechanisms by which the association of interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is expected to effectively reduce the hematological toxicity associated with chemotherapy (CT) are not completely elucidated. We exploited the cell kinetic changes of the bone marrow CD34(+) cell subset after CT followed by the IL-3+GM-CSF together with the clinical effects of this association. Eighteen patients with advanced cancers and normal hematopoiesis were treated with an intensified CT course (mg/m(2): CTX 1100, epirubicin 100, VP-16 200; iv day 1). Six cycles were planned at 14-day intervals with the support of IL-3 (5 mu g/kg/day; from day 2 to 6) sequenced with GM-CSF (same dose; from day 7 to 11). DNA content and bromodeoxyuridine incorporation were evaluated using flow cytometry on immunomagnetically-sorted bone marrow CD34(+) cells, at baseline and at different times (days 5, 6, 7, 8, 11 and 14) after CT followed by IL-3+GM-CSF. Treatment with IL-3 induced a marked increase in the % of myeloid precursors with respect to the baseline and in the % of CD34(+) cells in S-phase. However, while the first parameter remained elevated until day 14, the enhanced proliferative activity of the CD34(+) cell subset decreased after IL-3 was stopped and remained significantly low during GM-CSF administration. These data suggest a negative rebound effect on CD34(+) cell proliferation after IL-3 discontinuation which is maintained during GMCSF, that led to kinetic refractoriness of the hyperplastic marrow. In the 99 courses completed a rapid neutrophil and platelet recovery was obtained without cumulative multilineage toxicity. The modifications of CD34(+) cell cycling after CT followed by IL-3+GM-CSF could provide additional myeloprotection during multicyclic, dose-intensive programs. PMID- 21541604 TI - Breast cancer estrogen and progesterone receptors. AB - Data from 2933 consecutive cases of primary breast carcinoma, observed in our Institute from 1984 to 1994, having documented estrogen (ER) and progesterone (PR) receptor levels, were obtained from the Institute's Hospital Tumor Registry and analysed after being categorised as follows: age, less than or equal to 60 vs. >60; menopausal status, pre-menopausal vs. post-menopausal; histology, ductal vs. lobular vs. others; tumor size, T-1 vs. T-2, T-3, T-4; nodal status, N-0, vs. N+; histologic grade, 1-2 vs. 3; focality, unifocal vs. multifocal; ER status, <10 fmol/mg protein vs. greater than or equal to 15. At multivariate analysis, using a logistic model including age, histology, tumor size, nodal status, histologic grade, uni-multifocality and PGF/ER status, significant associations were, for ER status: PGR status (OR = 34.01, 95% CI:20.08-57.80), histology (OR = 3.24, 95% CI:1.85-5.67), histologic grade (OR = 2.18, 95% CI:1.38-3.42), menopausal status (OR = 2.17, 95% CI:1.26-3.74), age (OR = 34.01, 95% CI:20.08 57.80), menopausal status (OR = 5.27, 95% CI:1.43-3.33), age (OR = 1.71, 95% CI:1.13-2.59). The finding that estrogen receptor positivity was more prevalent among tumors with lobular histology seems to suggest the possibility of fundamental differences in tumor biology ductal and lobular cancers. PMID- 21541605 TI - Expression and synthesis of insulin-like growth factor (IGF)-I, -II and their receptors in human glioma cell lines. AB - Insulin-like growth factor (IGF)-I and -II are involved in the regulation of brain development and are thought to play a pivotal role in the proliferation of gliomas. Expression of IGF-I, IGF-II, the type I and type II IGF receptor were studied in a panel of thirty glioma cell lines by Northern blotting and PCR analysis. IGF-II mRNA expression with transcripts of 4.8 and 6.0 kb was shown only in one glioma cell line (NCE-G96) and no transcripts for IGF-I, IGF-I-R and IGF-II-R could be detected by Northern analysis in total RNA. However, PCR analysis revealed signals in 19/28 cell lines for IGF-I, 27/30 for ICE-II, 19/28 for IGF-I-R and 22/28 glioma cell lines for IGF-II-R. Additional IGF-I, IGF-II, IGF-I-R and IGF-II-R PCR products were detected which might represent alternative splicing products or variants. In addition, the secretion of IGF-I and IGF-II peptides was measured by radioimmunoassay. IGF receptor status and binding characteristics were established by Scatchard analysis. Proliferation assays showed different effects of IGFs and IGF analogues on the proliferation of these cell lines. Des-(1-3)IGF-I showed an unexpected inhibitory activity on glioma cell proliferation. This may have either been due to a direct effect of the ligand for the induction of a more differentiated state refractory to its action. PMID- 21541606 TI - Specific targeting of tumor cells by the creatine analog cyclocreatine. AB - Creatine kinase (CK) an enzyme involved in cellular ATP homeostasis has been implicated in tumorigenesis. Cyclocreatine (CCr) a CK substrate analog was shown to be cytotoxic to a broad spectrum of solid tumors. We have measured and compared the CK activity and CCr sensitivity of 49 transformed and non transformed cell lines. Among tumor cell lines, there was a strong correlation between the two (p = 0.0026, regression analysis); cell lines expressing high levels of CK (>0.10 Units/mg protein) were generally sensitive to the drug and cell lines with low CK were resistant. Tumor cell lines highest in CK and most sensitive to CCr were derived from prostate, small cell lung and neuronal tissue. The hematopoetic tumor lines tested were generally low in CK and all were resistant to CCr. Fourteen non-transformed cell lines were examined and all were resistant to the compound, including six with high levels of CK. Thus, CCr preferentially targeted tumor cells. Further, CCr inhibited tumor cell proliferation more efficiently than macromolecular synthesis indicating that, rather than exerting a general effect on energy metabolism, CCr may act on a specific pathway involved in controlling tumor cell proliferation. PMID- 21541607 TI - Cancer in the elderly. AB - The objective of this study was to assess the patterns of cancer incidence of elderly populations on a geographic and ethnic basis. Internationally published incidence data was used to characterize the status of cancer in the elderly in selected world locations. Cancer sites reviewed are those common in the elderly. Incidence data was measured as published by the International Agency for Research Against Cancer and in appropriate statistical tests. The results indicate that the Western societies have a consistently higher proportion of cancer patients who are 65 and older, even when controlling for the age distribution factor. Also, the male/female ratio in the elderly is high due mainly to a relatively earlier occurrence of gynecological cancer. Three patterns characterizing a differentially retarding pattern of cancer incidence with age were found: i) a continuous increase, with some slowing pace of growth in the US and other Western countries. ii) a peak in the 75-79 age category followed by a decline. This is noted in less prosperous European populations, like the former Eastern Bloc countries. iii) a plateau, seen in developing countries like India or Gambia. Non etiologic factors contributing to international cancer distribution variations among the elderly may include quality and frequency of diagnostic work-up. This is largely a reflection of a nation's healthcare system, as well as its social norms vis-a-vis the elderly. The positive global ageing trend promises increased cancer incidence and prevalence, and the need for greater resource allocation for the care of elderly cancer patients. PMID- 21541608 TI - Cytokeratins and proliferation in breast cancer patients. AB - Tissue polypeptide antigen (TPA) was studied in 242 sera and 165 tumor cell cytosols (both evaluations in 67 cases) of breast cancer patients, for which proliferative activity, determined by the TLI technique, was also available. The TPA serum and tumor cell cytosol median values (utilized for measure analysis as cut-off) were 70 U/1 and 377 U/mg cytosol protein, respectively. High serum TPA levels were associated with unfavourable clinicopathological characteristics whereas a higher tumor cell cytosol TPA level was associated with better cytohistological tumor differentiation. Furthermore, no overall correlation was found between serum and tumor cell cytosol TPA levels or between their levels and TLI. When analyzing cases in which serum and tumor cell cytosol TPA values were higher than 100 U/l and 500 U/mg cytosol protein, respectively (n = 28), serum TPA was positively associated with TLI (slope = 12.3 r = 0.55, p < 0.01), while cytosolic TPA resulted negatively associated with TLI (slope = -87.4 r = 0.41, p < 0.01). Finally, a strong inverse relationship between cytosolic and serum TPA (p < 0.0005) became evident. We suggest that TPA could represent a serum marker for tumor cell proliferation in specific patient subgroups with original high serum and/or cytosol TPA expression. PMID- 21541609 TI - Progress in anti-invasion and anti-metastasis research and treatment. AB - Invasion and subsequent establishment of distant metastasis is the most life threatening consequence for patients with cancer. Last decade has seen a major expansion in our knowledge and the understanding of the molecular and cellular mechanisms in tumour invasion and metastasis. Such understanding may also lead to the exploration of anti invasion/metastasis strategies. Some agents have already shown early promise in combating these processes. This article summarises progress in the anti-invasion and metastasis research and treatment. PMID- 21541610 TI - Involvement of P-glycoprotein in an in vitro blood-brain barrier model. AB - The P-glycoprotein (P-gp) multidrug transporter is present at the luminal face of the brain capillary endothelial cells that contribute to the blood-brain barrier. To study its role in transendothelial anticancer drug transport, we made use of a co-culture system formed of bovine brain capillary endothelial cells and astrocytes which allows the in vitro maintenance of specialized properties of the brain endothelial cells, including expression of P-gp as assessed by Northern and Western blot analyses. Vinblastine, an anticancer drug substrate for P-gp and known not to enter the brain, was found to be poorly transferred across the endothelial cell monolayer. This low vinblastine transport was however strongly increased in the presence of verapamil, a well known P-gp blocker. Moreover, verapamil was shown to increase the accumulation of the anticancer drug in the brain endothelial cells through inhibition of drug efflux. These results suggest that P-gp activity evidenced in the co-culture model is involved in the low transendothelial transport of vinblastine, thus supporting the conclusion that P gp expressed at the blood-brain barrier level may prevent xenobiotics, including anticancer drugs, from entering the central nervous system. PMID- 21541611 TI - Neo-adjuvant (primary) organ-preserving chemotherapy in the management of locally advanced laryngeal carcinoma. AB - We designed an open, non-randomized, phase II clinical study to assess as the first endpoint the feasibility of sparing surgery and of preserving organ/function by using neoadjuvant chemotherapy (NAC) laryngeal cancer patients, and, as the second endpoint, the clinical response to this treatment approach and its duration. 32 patients with primary laryngeal cancer (stage III-IV) were enrolled in the study and were assigned to either the classical Al-Sarrafs regimen (20 patients) or to a regimen consisting of cisplatin 80 mg/m(2) i.v. on day 1, 5-FU 600 mg/m(2) on days 2-5 and vinorelbine 20 mg/m(2) on days 2 and 8 (12 patients). The patients were divided into 2 groups: A) those requiring total laryngectomy (TL) and B) those not requiring TL, i.e. patients eligible for conservative for conservative surgery. The 32 patients were all evaluable for response to NAC and 31 were evaluable for The complete remission rate was 50% (16/32) and the partial remission rate was 46.9% (15/32) with an overall response rate of 96.9%. The median follow-up duration was 20.2 months. Overall, 23 patients required TL (group A) and 8 patients a conservative laryngectomy (group B). 7/23 (30.5%) patients of group A did not undergo surgery (score 4) and 6/23 (26%) achieved a partial larynx preservation (3/23 score 3, 1/23 score 2, 2/23 score 1), while 10/23 (43.5%) received the previously planned TL (score 0). 5/8 (62.5%) patients of group B did not undergo surgery, whereas 3/8 (37.5%) received the previously planned surgery (score 0). Therefore, 12/31 patients (38.7%) completely avoided surgery and 6/31 (19.4%) achieved a reduction in the extent of planned surgical resection, that is 18/31 patients (58.1%) achieved a reduction in the extent of previously planned surgery attributable to NAG. Moreover, 3/31 patients underwent the previously planned conservative surgery consisting of H SGL/HG. Altogether 21/31 (67.7%) patients preserved function. The most relevant contributions offered by our study are represented by i) a scale aimed at measuring as precisely as possible the reduction of surgical resection made possible by NAC compared to surgery planned before NAC and ii) by an attempt to support the results with an assessment of patients treatment outcome. Although the scale provided by us is an arbitrary one, it must be emphasized that our goal was to address the issue of quality of life in cancer patients by a more precise quantification of organ/function preservation. PMID- 21541612 TI - Biomarkers in airway tumors. AB - Despite advances and improvements in diagnosis and treatment of upper aerodigestive tumors including head and neck and lung cancers, the overall survival rate of these patients remains poor. Prevention, early diagnosis, and novel therapy are under active investigation to improve the outcome of the diseases. In particular, chemopreventive strategy is a novel approach to reduce the invasive tumors by reversing the premalignant lesions with certain differentiating agents (i.e., retinoids). To conduct effective chemopreventive trials, there has been a great surge of interest in defining the biomarkers associated with the specific stages of the carcinogenesis and with intermediate end points during the therapy. Carcinogenesis in the upper aerodigestive tract has been explained by two theories, field cancerization and multistep process. The driving forces behind these processes are noted by accumulated genetic abnormalities in the entire epithelium of the airway. These genetic abnormalities include chromosome abnormalities, specific gene alterations (i.e., ras gene family, tumor suppressor genes, growth factors and their receptors), and proliferation and differentiation markers. These biomarkers are herein described in this review article. PMID- 21541613 TI - Regional differences of physiological functions and cancer susceptibility in the human large intestine. AB - Regional differences in function, metabolism and morphology between proximal colon, distal colon and rectum may be important in the pathogenesis and biologic behaviour of tumours originating from these segments. Thus, the effect of primary prevention of colorectal cancer may also differ from one large bowel segment to another. Therefore, this review underscores that one should be careful extrapolating results obtained in a short segment of the large bowel to the entire colorectum. Obviously, future studies concerning the pathogenesis and possibilities for prevention of large bowel cancer should certainly examine results by subsite as a routine procedure. PMID- 21541614 TI - Cytomorphometric parameters in exfoliated cells as biomarkers in head and neck cancer chemoprevention. AB - Quantitative DNA analysis has often been proposed as a potential tool capable of detecting preneoplastic tissue and as such to function as an intermediate endpoint in cancer chemoprevention trials. The first aim of this study was to test whether cytomorphometric parameters could be used to detect field cancerization characteristics in cytological preparations of oral mucosa. Cytomorphometric parameters in exfoliated cells of apparently normal oral mucosa of head and neck cancer patients were compared with those of healthy controls. The second aim was to assess the value of these parameters subsequently as intermediate endpoint biomarkers in the mucosa of 70 patients receiving N acetylcysteine and/or retinyl-palmitate as chemopreventive drugs. No differences were detected between 'high risk' and healthy mucosa, nor were differences observed before and after treatment. PMID- 21541615 TI - Expression of PDGF, VEGF and their receptors in non-small cell lung tumor cell lines. AB - Cell lines derived from non-small cell carcinomas of the lung (NSCLC) often express a variety of polypeptide growth factors able to activate receptors that encode tyrosine kinases. These receptors initiate numerous biological responses, including cell proliferation, and constitutive activation can result in cellular transformation. Consequently, it is possible that the aberrant growth properties of NSCLC cell lines is due at least in part to the action of mutated or perpetually activated receptor tyrosine kinases (RTK)s. As a first step in the process of testing this hypothesis we set out to examine the different RTKs expressed in NSCLC cell lines. A small group of NSCLC cell lines was screened for the expression of RTKs using a reverse transcriptase PCR approach with nested degenerate primers. We found four different RTKs expressed: the fibroblast growth factor receptor (FGFR) type III, the FGFR type IV, the platelet-derived growth factor beta receptor (beta PDGFR) and Flk-1/KDR, one of the receptors that binds vascular endothelial growth factor (VEGF). Since Flk-1/KDR and the beta PDGFR are not usually expressed in epithelial cells, we verified that they are expressed in NSCLC by Northern and Western blot analysis. To assess the incidence of expression of these RTKs in NSCLC cell lines a larger panel of cell lines was examined by Western blot analysis. The beta PDGFR was expressed in 30% (3/10) of the cell lines examined, while Flk-1/KDR was expressed in 10% (1/10). We also examined the expression of ligands for these RTKs. PDGF-A, PDGF-B and VEGF were expressed in 89%, 0% and 78%, respectively. While the high incidence of ligand expression made it likely that receptor and growth factor would be coexpressed, we found that in most instances this was not the case. Furthermore, in the cell lines in which the RTK and its ligand were coexpressed, we were unable to detect a functional autocrine loop. These studies indicate that while NSCLC cell lines aberrantly express various RTKs and growth factors, this does not always result in the establishment of an autocrine loop. These findings suggest that growth factors such as PDGF and VEGF act in a paracrine manner to contribute to the growth, survival and angiogenic program of a lung tumor. PMID- 21541616 TI - Allele loss of tumour suppressor genes on chromosome 17 in human testicular germ cell tumours. AB - The molecular genetics of testicular germ cell tumours (TGCT) are still largely unknown. We investigated 20 TGCT tumours for allelic losses (LOH) of tumour supressor genes BRCA1, TP53 and of THRA1 on chromosome 17. We observed an overall loss of 50% for the whole chromosome. Detailed deletion mapping revealed no losses for the BRCA1 gene, 42% LOH for THRA1 and 11% allelic loss for the region telomeric to BRCA1. We observed 11% LOH for TP53. Our results suggest that allelic losses of BRCA1 and TP53 genes do not play a pivotal role in TGCT but that dysfunction of THRA1 or tumour suppressor gene(s) in this region may have an impact in the development of this cancer. PMID- 21541617 TI - Inhibition of growth of human small cell and non-small cell lung carcinomas by antagonists of growth hormone-releasing hormone (GH-RH). AB - Insulin-like growth factors-I and-II (IGF-I and IGF-II) may be involved in the proliferation of human lung carcinomas. The purpose of this study was to investigate the effects of two potent antagonists of growth hormone-releasing hormone (GH-RH), MZ-4-71 and MZ-5-156 on the growth of the H69 human small cell lung cancer (SCLC) and H157 non-SCLC (NSCLC) lines transplanted into nude mice or cultured in vitro. Nude mice bearing H69 and H157 tumors were treated for 3-5 weeks with MZ-4-71 or MZ-5-156 injected s.c. twice a day at a dose of 20 mu g/animal. Growth of H69 and H157 tumors in nude mice was significantly inhibited by MZ-4-71 and MZ-5-156 as shown by a reduction in tumor volume and weight. In animals bearing H157 NSCLC, treatment with MZ-4-71 decreased IGF-I and IGF-II levels in tumor tissue. Levels of IGF-I, but not of IGF-II in serum and liver tissue of H157 tumor-bearing nude mice treated with MZ-4-71 were decreased. High affinity binding sites for ICF-I were demonstrated on membranes of H69 and H157 tumors. In cell cultures, the proliferation rate of H69 SCLC cells was suppressed by 10(-7)-10(-5) M MZ-4-71, but H157 NSCLC line was only inhibited by 10(-5) M antagonist. Our findings demonstrate that the GHRH antagonists MZ-4-71 and MZ-5 156 can inhibit the growth of SCLC and NSCLC. This new approach to the management of lung cancer merits further investigation. PMID- 21541618 TI - Fresh peripheral blood mononuclear cell preparations are a better starting material than bone marrow after cryopreservation for immunomagnetic harvesting of CD34(+) hematopoietic cells. AB - Immunomagnetic separation using anti-CD34 monoclonal antibodies and paramagnetic microspheres has been used to enrich hematopoietic stem cells from human bone marrow, whole cord blood, or mobilized peripheral blood mononuclear cell collections. This method has been reported to achieve high separation purity of CD34+ cells in small scale experiments with fresh material. The aim of the present study was to compare the efficacy of the CD34+ cell selection technique, when thawed bone marrow or fresh peripheral blood mononuclear cells were enriched. Starting with thawed bone marrow containing 2.9% CD34+ cells the final product purity was 67.7% with a 6% CD34+ cell yield (enrichment factor 25.7), and a 85-fold CFU-GM enrichment. Using fresh mobilized peripheral blood mononuclear cells the released cells contained 77.6% CD34+ cells with a 47% yield (enrichment 86.5-fold), and a 46-fold CFU-GM enrichment. These results indicate that CD34+ cells can be selected from cryopreserved bone marrow using immunomagnetic procedures. However, fresh leukapheresis products seem to be a much better material for a positive immunomagnetic stem cell selection technique in terms of purity, yield and enrichment. PMID- 21541619 TI - Novel growth inhibitory effect of 8-Cl-cAMP is dependent on serum factors that modulate protein kinase A expression but not the hydrolysis of 8-Cl-cAMP. AB - 8-Chloro-cyclic AMP (8-Cl-cAMP) exhibits growth inhibition in vitro and in vivo in a broad spectrum of cancer cell lines. We examined whether the hydrolyzed metabolite is involved in the effect of 8-Cl-cAMP. 8-Cl-cAMP (5 mu M, 3 days) exerted varying degrees (0-51%) of growth inhibition on the same cell line cultured in the medium containing different heat-inactivated serum. HPLC analysis neither detected 8-Cl-adenosine in the medium nor demonstrated any correlation between the decrease in 8-Cl-cAMP concentration in the medium and the degree of growth inhibition. The low K-m phosphodiesterase activity in the sera did not correlate with the varying degrees of growth inhibition. The cAMP-dependent protein kinase RI(alpha) subunit expression in the same cell line varied widely with the different serum supplements. 8-Cl-CAMP-, but not 8-Cl-adenosine-induced, growth inhibition correlated with the basal levels of RI(alpha) and specific downregulation of RI(alpha). 8-Cl-cAMP, but not 8-Cl-phenyl-thio-cAMP or N-6 benzyl-cAMP, inhibited cell growth in serum-free medium. These results show that 8-Cl-cAMP induces growth inhibition through down-regulation of protein kinase A type I in the absence of its hydrolysis. PMID- 21541620 TI - Host cell reactivation of cisplatin-treated adenovirus is reduced in nucleotide excision repair deficient mammalian cells and several human tumour cells. AB - Cisplatin is widely used for chemotherapy of a variety of human cancers. Cisplatin exerts its toxic effect by covalently binding to DNA, resulting in monofunctional adducts, intrastrand crosslinks, and interstrand crosslinks. Several recent reports suggest that the cellular capacity for DNA repair, especially nucleotide excision repair (NER), is an important determinant in the sensitivity of cells to cisplatin. We have used a sensitive host cell reactivation (HCR) technique to examine the repair capacity for cisplatin-damaged DNA in several different mammalian cell types. HCR of cisplatin-damaged adenovirus (Ad) was reduced in all UV-sensitive NER deficient Chinese hamster ovary (CHO) cells examined (complementation groups 1 to 6) compared to NER proficient CHO cells. HCR of cisplatin-damaged Ad was also reduced in fibroblasts from patients with xeroderma pigmentosum (XP) complementation groups A, B, C, D, F, and G compared to that in normal human fibroblasts. Differences in the HCR of cisplatin-treated Ad were also detected among human cancer cell lines, suggesting some tumour cells may be deficient in the NER of cisplatin-DNA adducts. PMID- 21541621 TI - Luteinizing hormone-releasing hormone agonist triptorelin antagonizes signal transduction and mitogenic activity of epidermal growth factor in human ovarian and endometrial cancer cell lines. AB - This study was designed to elucidate the signal transduction mechanisms, mediating the antiproliferative effects of analogs of luteinizing hormone releasing hormone (LHRH) on cell lines derived from human cancers of the ovary (EFO-21, EFO-27) and the endometrium (HEC-1A, Ishikawa). The LHRH agonist triptorelin had no measurable effects on the activity of phospholipase C, protein kinase C, or adenylate cyclase in all 4 cell lines, though these enzymes could be activated through pharmacological stimuli. The proliferation of EFO-21, EFO-27 and HEC-1A cells in serum/phenol red-free medium was significantly stimulated by epidermal growth factor (EGF). This mitogenic effect of EGF was dose dependently antagonized by triptorelin, without affecting the concentrations of EGF receptors. Net tyrosine phosphorylation induced by 1 nM EGF was nearly completely suppressed by simultaneous addition of 10 mu M triptorelin or preincubation for 48 h with 100 nM triptorelin. This inhibitory effect of the LHRH agonist on EGF induced net tyrosine phosphorylation was partly antagonized by exposure to 100 mu M sodium vandate, an inhibitor of phosphotyrosine phosphatase. In EFO-21, EFO-27, and HEC-1A cells exposure to 100 nM EGF for 5 min induced an approximately 5-fold increase in activity of mitogen activated protein kinase (MAP kinase)/extracellular signal regulated kinase (ERK) which was virtually nullified, when the cells were exposed for 15 min to 10 mu M triptorelin. These data suggest that LHRH signal transduction mechanisms based on the activation of phospholipase C, protein kinase C, and adenylate cyclase, which operate in the pituitary gonadotroph, are not necessarily involved in the mediation of the antiproliferative effects of triptorelin in these ovarian and endometrial cancer cell lines. Instead our findings support the hypothesis that triptorelin interferes with mitogenic signal transduction, probably through antagonizing tyrosine kinase activity of the EGF receptor. PMID- 21541622 TI - Increased concentrations of chlordane in adipose tissue from non-Hodgkin's lymphoma patients compared with controls without a malignant disease. AB - Chlordane is a pesticide which is lipophilic, bioaccumulates, and may cause immunological impairment in exposed subjects. The aim of this study was to determine the concentrations of chlordane and its metabolites in cases with NHL and surgical controls without a malignant disease. Adipose tissue was obtained from the abdominal wall and analysis was performed using gas chromatograph coupled to mass spectrometer. The study included 27 NHL cases of the B-cell type and 17 controls. Significantly increased concentrations were found in NHL patients versus (vs) controls of trans-nonachlor, mean 98.9 vs 47.0, range 24.9 389 vs 16.3-88.2 ng/g lipid (p = 0.002), cis-nonachlor, mean 17.1 vs 7.4, range 4.1-68.3 vs 1.7-13.6 (p = 0.010), oxy-chlordane, mean 39.7 vs 24.5, range 8.5-144 vs 8.9-49.0, (p = 0.028) nonachlor III, mean 18.4 vs 8.7, range 6.3-67.6 vs 3.0 19.3 (p = 0.002) and sum of chlordanes, 180 vs 92.8, range 48.3-678 vs 37.0-164 ng/g lipid (p = 0.002). For cases with a concentration higher than the median for all subjects significantly increased odds ratios (OR) and 95% confidence intervals (CI) were calculated for trans-nonachlor (OR = 4.1, CI = 1.1-15), nonachlor LII (OR = 6.5, CI = 1.7-25), and sum of chlordanes (OR = 4.1, CI = 1.1 15); median concentrations were 61.2, 11.3, and 119 ng/g lipid, respectively. PMID- 21541623 TI - Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. AB - Flavopiridol is a new synthetic flavone, structurally related to a natural alkaloid, originally purified from Dysoxylum binectariferum, a plant indigenous to India and used in Indian folk medicine. Flavopiridol was detected by a tandem screening system consisting in inhibition of the EGF-receptor Tyrosine phosphokinase and cytotoxicity. As a cytostatic mechanism, however, Flavopiridol strongly inhibits the cyclin-dependent kinases (cdk1, cdk2, cdk4, cdk7), with the potential to cause inhibition of cell cycle progression in G(1) and G(2) by multiple mechanisms relatable to cdk inhibition. In certain cell types, Flavopiridol induces apoptosis. The antitumor activity of that compound on human xenograft tumors is similar to standard cytostatic drugs and superior to them at least in prostate carcinoma. The dose limiting toxicity is diarrhea. Compared with other flavonoids or other kinase inhibitors Flavopiridol can be regarded as unique as no other compound is yet known that as specifically and potently inhibits nearly all the main cyclin dependent kinases and by that mechanisms can arrest cell cycle progression in G(1) as well as in G(2) and no other specific kinase inhibitor is known, which after i.v. or oral application reduces the growth of subcutaneous or subrenal xenografts of human tumors of different types. Initial results of a phase I study at the National Cancer Institute (NCI), USA, (Investigational New Drug Application no. 46211) provided some clinical and laboratory evidence for antineoplastic effect at nontoxic doses (no grade IV toxicities encountered). Thus, Flavopiridol is clearly in need of further clinical evaluation of its tumor therapeutic potential. In this review the chemical profile, tumorpharmacology (in vitro activity, inhibition of cdk's and preclinical in vivo activity), preclinical toxicology and pharmacokinetic of Flavopiridol are reviewed to provide a comprehensive source to aid further developmental efforts. PMID- 21541624 TI - Telomerase activity in bladder cancer, bladder washings and in urine. AB - With only a few exceptions, the ribonucleoprotein telomerase has been found in malignant, but not in benign tissues. Telomerase is thus a potentially new diagnostic marker. Carcinoma of the urinary bladder is the most frequent malignant tumor of the urinary tract and, after prostatic carcinoma, the second most common malignancy of the genitourinary system. In order to evaluate the diagnostic capabilities of telomerase in bladder carcinomas, four cell lines derived from human urothelial carcinomas of the bladder, 75 tissue samples from bladder carcinomas, eight tissue samples of normal bladder urothelium, 40 bladder washings and 30 urine samples were examined for telomerase activity. The four cell lines derived from urothelial carcinoma of the bladder (F975, 582, SCaBER, UM-UC-3) all exhibited high telomerase activity and were thus used as positive controls. Telomerase activity was found in nearly all (96%) tissue samples obtained from histologically confirmed urothelial carcinoma of the bladder. None of the normal tissue samples examined showed telomerase activity. Telomerase activity was similarly found in 73% of bladder washings in patients with histologically confirmed bladder carcinoma. There were no false positive results. The determination of telomerase activity in bladder washing samples thus represents a new diagnostic method for detection of tumor cells in rinsing media. Because of the early inactivation or degradation of telomerase there was no detection of the enzyme in native urine in the present study. PMID- 21541625 TI - Inhibition of invasion in vitro and stimulation of aggregation by 13-cis retinoic acid correlates with the clustering of N-CAM in c-Ha-ras transformed glial cells. AB - Invasion distinguishes malignant from benign primary brain tumors. The molecular mechanisms which permit malignant brain tumor cells to escape from the primary tumor mass and by which they can migrate through normal brain tissue are largely unknown. 13-cis retinoic acid (cRA) can induce morphological, biochemical and functional differentiation characteristics in various malignant tumors. Upon treatment of diffusely invasive hamster glial cells (CxT24neo3) with 30 mu M cRA, we found a significant reduction in cell proliferation in monolayer and spheroid cultures. cRA also inhibits invasion of CxT24neo3 through a reconstituted basement membrane (Matrigel(R)) in a dose dependent manner. Homotypic cell-cell adhesion, on the contrary, is stimulated in the absence of extracellular Ca++ by either treatment or pretreatment of CxT24neo3 with cRA. These phenotypic changes correlate with the induction of the clustering of the neural cell adhesion molecule: N-CAM at sites of cell-cell contact. This phenomenon is observed following immunohistochemical staining for N-CAM of CxT24neo3 cells that were treated with cRA in monolayer cultures. The relationship between reduction of proliferation and invasion in vitro and the increased homotypic cell-cell adhesion with clustering of N-CAM implicates N-CAM as a molecular effector molecule for reduction of malignancy by cRA. PMID- 21541626 TI - Gene expression of neuropeptide Y and neuropeptide-Y1 receptor in relation to proto-oncogene tyrosine kinase A, nerve-growth-factor low-affinity-receptor and the transcription factor N-myc in human neuroblastomas. AB - The expression of neuropeptide Y (NPY) and NPY-Y1 receptor (NPY-Y1R) in relation to that of tyrosine kinase A (trkA), nerve-growth-factor low-affinity-receptor (LNGFR) and the transcription factor N-myc was studied in 26 neuroblastomas and one ganglioneuroma by quantitative Northern-blot analysis. A correlation of NPY Y1R with LNGFR (r = 0.85, p < 0.01) and trkA (r = 0.38, p < 0.05), respectively, could be shown, while no correlation between NPY and its receptor NPY-Y1R was observed. Comparison of a high and a low level NPY expressing group revealed that the high NPY expressing group also had high LNGFR and high trkA levels while the low NPY expressing group had low LNGFR and low trkA levels which were significantly different (NPY: p = 0.035, trkA: p = 0.008, LNGFR p = 0.004). Dividing the tumors in a high and a low N-myc expressing group showed that the low N-myc expressing group contained both high and low trkA expressing tumors while the high N-myc expressing group exclusively were low level trkA expressing tumors. The frequency distribution in both groups concerning trkA expression showed a significant difference (p < 0.01). In conclusion the coexpression of NPY Y1R and LNGFR or trkA may indicate a similar gene regulation during ontogenesis of the peripheral nervous system. PMID- 21541627 TI - Bovine papillomavirus type 4. AB - Papillomavirus induce benign tumours (papillomas) in a variety of animals. The papillomas generally regress but occassionally persist and may eventually progress to squamous cell carcinoma. One of the most extensively studies papillomaviruses is bovine papillomavirus type 4 (BPV4). BPV-4 induces papillomas of the upper alimentary canal which are at high risk of progressing to cancer in cattle eating bracken fern. In this review, several aspects of the biology of the virus are described and compared with other papillomavirus systems, including regulation of transcription of the viral oncogenes, function of the viral oncoproteins, cooperation between virus and chemical cofactors, and prophylactic and therapeutic vaccination programmes. PMID- 21541628 TI - Human telomeric binding proteins recognizing single and double stranded DNA. AB - Telomeres of human chromosomes consist of a repeated TTAGGG sequence, and at the terminal of this repeat sequence, the 3' strand is longer than the 5' strand. In this study, we characterized single and double stranded telomere binding proteins (ssTBPs and dsTBPs) by gel mobility shift assay and South-Western blotting assay. At least two protein components with molecular weights of 29 and 33 kDa were bound to a single stranded telomeric sequence, and also two proteins with molecular weights of about 44 kDa and 70 kDa were bound to a double stranded telomeric sequence. A competition assay demonstrated that the binding properties of ssTBPs and dsTBPs were specific to the telomeric sequence. We further cloned a ssTBP cDNA (ssTBP-1) by screening a lambda-gt11 expression library and identified ssTBP-1 as a human heterogeneous nuclear ribonucleoprotein (hnRNP) Al on the basis of cDNA sequence. We also found that the expression of the hnRNP Al gene significantly decreased during in vitro passage of human microvascular endothelial cells. PMID- 21541629 TI - Expression of E-cadherin in 230 infiltrating ductal breast carcinoma. AB - The immunohistochemical expression of E-cadherin (E-CD) was correlated to differentiation grade, tumor size, axillary lymph node metastasis, hormone receptor status and disease outcome in 230 infiltrating ductal breast carcinomas. E-CD expression was reduced in 116 tumors (50.4%). Reduced E-CD expression was more frequently found in high histological grade and progesterone receptor negative tumors. In contrast, preserved E-CD expression was more frequently observed in tumors with axillary lymph node metastasis, particularly in the group of patients with 1 to 3 positive lymph nodes. A weak association between reduced E-CD expression and shortened overall survival was found in univariate survival analysis, that was lost when the patients were adjusted for other pathological factors in multivariate analysis. These data indicate that E-CD may be considered a differentiation marker in ductal carcinomas of non special type. However, the relationship between E-CD expression and lymph node metastasis and disease outcome remains to be established. PMID- 21541630 TI - Expression of cyclin D1 proto-oncogene mRNA in primary meningiomas may contribute to tumorigenesis. AB - Meningiomas are benign brain tumors thought to arise by multi-step tumorigenesis, involving both the activation of oncogenes and the loss of tumor suppressor genes. The cell cycle regulator proto-oncogene cyclin D1 has been implicated in the pathogenesis of several types of cancer. Northern blot analysis revealed expression of cyclin D1 mRNA in 8 (53%), and cyclin B mRNA in 12 of 14 (86%), primary meningiomas. Immunocytochemistry using an antibody specific for cyclin D1 showed strong positivity amongst meningeal cells in the same meningioma samples. No cyclin D1 mRNA was detected in a sample of normal pachymeninges. Cyclin B, which has not yet been linked to tumorigenesis and serves as a marker for cellular proliferation, was expressed in a higher proportion of meningioma samples. These data provide the first evidence for the overexpression of cyclin D1 and B mRNA and protein in primary human meningiomas, and are consistent with a proposed oncogenic role of cyclin D1 in tumorigenesis. Excessive levels of the cyclin D1 proto-oncogene may lead to deregulation of G1 control in a proportion of arachnoid cap cells leading to tumorigenesis. PMID- 21541631 TI - Growth of human pancreatic cancer cells, induced by human pancreatic phospholipase A(2), is mediated via its specific receptor but not via its catalytic property. AB - Human pancreatic phospholipase A(2) type I (hPLA(2)-I) has been found to stimulate the growth of human pancreatic cancer cell line, MIAPaCa-2, which has a receptor for PLA(2). In the present study, half-maximal inhibitory concentrations (IC(50)s) for the mature- and pro-form of hPLA(2)-I and certain eukaryotic and prokaryotic PLA(2)s were determined using ligand binding studies. The IC50 for the mature form was 3.5x10(-9) M compared to those for the pro-form and non-human PLA(2)s (over 5.0x10(-7) M), suggesting receptor specificity for mature hPLA(2) I. Receptor binding was independent of Ca2+, which is required for PLA(2)'s digestive activity. Lysophospholipids, generated by PLA(2), showed no proliferative effect on the MIAPaCa-2 cells. Furthermore, MIAPaCa-2 cells treated with hPLA(2)-I did not release fatty acids. This implies that proliferation of these cells is mediated by binding of hPLA(2)-I to the specific receptor, not by its enzymatic activity. The hPLA(2)-I induced cell proliferation was blocked by preincubation of the enzyme with anti-hPLA(2)-I monoclonal antibody. PMID- 21541632 TI - Telomerase activity and telomere length in different areas of renal cell carcinoma. AB - Telomerase activity and telomere length were analyzed in a total of 59 surgically removed primary renal cell carcinoma (RCC). The study includes tissue from the centre of the tumor, several different peripheral tumor areas, metastases and secondary tumors. None of the normal renal cortex tissues used as control exhibited telomerase activity. In contrast, telomerase activity was detected in 55 out df 59 (=93%) tested primary RCC. There was no case with intratumoral heterogeneity concerning the telomerase activity status. All metastases and secondary tumors were telomerase-positive. In the four telomerase deficient tumors all measured telomeric repeat fragments were shortened in comparison to the normal tissue. As these patients exhibit no metastases or secondary tumors a less malignant variant of RCC is supposed. There was no correlation between telomerase activity and specific histopathological subtypes of RCC or specific chromosomal aberrations. As telomerase activity is not associated with advanced stages of tumors it may be an important early event in the development of RCC. Thus, telomerase activity may be a prevalent marker for early and late stages of all subtypes of RCC. PMID- 21541633 TI - 8-chloro-cAMP enhances the growth inhibitory effect of cytotoxic drugs in human colon cancer cells. AB - 8-Cl-cAMP is a novel agent able to inhibit the growth of a wide variety of cancer cell types in vitro and in vivo by interfering with the protein kinase A type I (PKAI), a protein directly involved in mitogenic signalling and neoplastic transformation. In a recent phase I study conducted in cancer patients we have demonstrated that 8-Cl-cAMP, at doses devoid of toxicity, may achieve plasma concentrations in a range previously shown effective for cancer cell growth inhibition. In the present study we have investigated the effect of 8-Cl-cAMP in association with cytotoxic drugs acting by different mechanisms of action on the growth of LS174T and GEO human colon cancer cells. We here demonstrate that 8-Cl cAMP administered after the cytotoxic drugs does not interfere with their growth inhibitory effect but rather is additive with most of them. Moreover, a synergistic effect was observed when 8-Cl-cAMP was administered after cisplatin or paclitaxel. The sequence of treatment seems to be important since pretreatment with 8-Cl-cAMP interferes with the effect of the cytoxic drugs. These results demonstrate that 8-Cl-cAMP is not only able to induce cell growth inhibition when used alone but also exhibit the capacity to enhance the efficacy of different cytotoxic drugs. PMID- 21541634 TI - Gene therapy to human diseases. AB - The identification of defective genes associated with a number of human disorders (tyrosine hydroxylase for Parkinson's disease, aspartylglucosaminidase in lysosomal storage disease, CFTR in cystic fibrosis, and LDL receptor in familial hypercholesterolemia) has promoted the development of strategies aimed at transferring to the somatic cells of the patient or of animal models vectors carrying the corrected gene. The obstacles to overcome include targeting the specific cell type or organ (liver for Factors VIII and IX in hemophilia), enhancing entry to cells into non-lysosomal compartments, nuclear import, percentage of cells transduced with the therapeutic gene, sustained expression of the transgene in human tissues, and immunogenicity of the transduced cells expressing the recombinant or viral proteins. Improvements in each single of these steps are likely to enhance enormously the potential of gene transfer for the treatment of human diseases. A number of human diseases including HIV infections and hypertension are approached by somatic gene transfer. VEGF regulating vascular permeability, growth of endothelial cells and angiogenesis, and TGF-B implicated in wound healing and in stimulation in synthesis of extracellular matrix, are potential targets for restenosis, atherosclerosis, and cancer. PMID- 21541635 TI - Coexpression of cyclin D1 and retinoblastoma gene product (pRb) in human squamous cell lung carcinomas is associated with increased tumor take rate in nude mice. AB - Samples from 72 squamous cell lung carcinomas were analyzed immunohistochemically for the expression of cyclin D1 and pRb. Expression of cyclin D1 was found in 61% and expression of pRb in 39% of the cases. The take rate of human squamous cell lung carcinomas in nude mice was significantly different according to the expression of cyclin D1 and expression of pRb in primary human tumors [cyclin D1 negative (32%) vs. cyclin D1-positive (59%); P=0.026; pRb-negative (34%) vs. pRb positive (71%); P=0.002]. The take rate was improved by coexpression of both proteins [both proteins negative/both proteins positive: 12% vs. 80% (P=0.00005)]. An association of the take rate and clinical parameters (age, extent of tumors, lymph node involvement, stage) could not be observed. Coexpression of cyclin D1 and pRb is also a prognostic factor for the patients' survival. PMID- 21541636 TI - Regulation of p185 expression in B104-1 cells transfected with antisense neu retrovirus vectors. AB - In this study, we examined the effect of antisense neu recombinant murine retroviral vectors on the p185 expression in B104-1 cells. Two fragments containing the 5' end and the transmembrane region of neu* were inserted in an inverted orientation relative to the 5' long terminal repeat (LTR) of the pDOL retroviral vector and used in transfecting B104-1 cells. The results obtained from RNAse protection assays were not consistent with the proposed mechanism of the antisense action by other investigators. Elevated expression of p185 was observed in several antisense vector-transfected clones, presumably caused by the promoter-insertion type of activation. PMID- 21541637 TI - In vitro and in vivo correlation of the effect of granulocytemacrophage colony stimulating factor gene transfer on the tumorigenicity and immunogenicity of B16 melanoma. AB - Transduction of murine B16 melanoma cells with a GM-CSF gene, the B16-MG tumor line, showed reduced tumorigenicity. In vitro studies demonstrated no remarkable difference between the parent and transduced tumor lines in their ability to induce secondary response to generate the anti-tumor killer cells (immunogenicity), or in their susceptibility to the killing by anti-tumor killer cells (immunosensitivity). Both CD4(+) and CD8(+) cells were required for the generation of the effecters. Nevertheless the effecters were determined to be Thy1.2(+), CD8(-), and NK1.1(-). At least two antigenic specificities could be defined in the cytolytic reactions. One was a broadly cross-reactive antigen shared by a variety of tumor cells, and the other apparently a tumor-specific antigen which was only present in B16 tumors. Cold target inhibition experiment confirmed these specificities. In the in vivo tumor transplantation study, the B16-MG cell line was not only more immunogenic but also was more immunosensitive than the parent line. More than 50% of the mice which were immunized with B16-MG remained tumor free after challenge with the parent tumor B16, indicating that GM CSF gene transfer makes an effective tumor vaccine. The in vivo protective effect was specific for B16 tumor, thus only the tumor-specific antigen could function as transplantation antigen. Both CD4(+) and CD8(+) cells were required for providing the in vivo protection. Both the B16 and B16-MG tumor bearing hosts could generate anti-tumor killer cells, hence the development of progressive growth of B16 tumor was not due to the lack of anti-tumor immune response. It appears that the overall effect of in vivo tumor immunity is determined by a complex network of interactions among different compartments of host immune cells and different compartments of host immune cells and different immune-regulatory molecules derived from the host and from the tumor. PMID- 21541638 TI - UV irradiation leads to transient changes in phosphorylation and stability of tumor suppressor protein p53. AB - Tumor suppressor protein p53 is thought to play a crucial role in maintaining the integrity of the genome. DNA damage caused by genotoxic drugs, UV or gamma irradiation leads to accumulation of p53 and activation of its DNA binding and transcriptional activities and subsequently to cell cycle arrest or apoptosis. We investigated whether the apparent activation of p53 might be due to post translational modification. The rat fibroblast cell lines REF52, 208F, and rat1 were irradiated with W-A and the synthesis, stability and phosphorylation state of p53 were investigated by pulse chase experiments, SDS-PAGE and two-dimensional phosphopeptide mapping. The three cell lines exhibited different sensitivities and biological responses to UV irradiation, REF52 cells responded with a growth arrest whereas 208F and rat1 cells underwent apoptosis. The fate of p53 was similar in all cases. Both the stability of p53 and its phosphorylation increased instantaneously but transiently. However, the amount of p53 that accumulated after UV treatment was much higher in 208F and rat1 than in REF52 cells. Interestingly, p53 that was synthesized early after irradiation was stable for more than 14 h whereas molecules synthesized 8 or more hours post irradiation were increasingly susceptible to degradation. Moreover, between 14 and 20 h after treatment, the rate of synthesis of p53 decreased to a level lower than in untreated cells suggesting negative feed back control. The expression of different p53-responsive genes, waf1/cip1, Gadd45, and bax was investigated by protein analyses. Surprisingly, p21(waf1) was expressed only in REF52 cells but not in the others. Furthermore, UV irradiation led only to a moderate increase of p21(waf1) expression. Expression of Gadd45 and box was detectable in both cell types but its expression did not change significantly upon UV treatment. Our results suggest i) that both cell types share a common pathway which upon UV irradiation results in enhanced stability and phosphorylation of p53 and ii) that the decision whether a cell undergoes a growth arrest or apoptosis may be determined independent of p53 by the cellular environment i.e. the expression patterns of genes that mediate the response. PMID- 21541639 TI - The 3' untranslated region of the human poly(ADP-ribose) polymerase gene is a nuclear matrix anchoring site. AB - The nuclear matrix displays the most dramatic changes among all cellular structures during carcinogenesis. Matrix attachment regions (MARs) organize chromatin into domains, harbor origins of replication and display a notable transcriptional enhancer activity. To understand the nature of MARs and their involvement in gene expression, replication, and carcinogenesis, we have cloned the MAR DNA fragments, of a size of 0.1-5.0 kb, isolated from human cells in culture. Over 150 clones have been sequenced. One MAR clone was identified as a stretch of 393 bp from the 3' untranslated region (3' UTR) of the human poly(ADP ribose) polymerase (PARR) gene (100% homology). The 393 bp MAR fragment contains several repeats of TTGTTTTGT and related sequences (the TG boxes) and motifs with similarity to the binding site of the general yeast transcription factor GFI and to the ARS origins of replication in yeast. In addition, the 3' UTR of the PARP gene harbors MAR-type sequences found in other genes, kinked and curved DNA, two imperfect inverted repeats, and short alternating GA- and CT-rich motifs. The presence of TG-, GA-, and CT-rich motifs and of potential cruciforms is proposed to identify a novel type of MAR sequence. This report suggests that MAR sequences may reside in the 3' untranslated region of other genes and has important implications for a potential role of the nuclear matrix in transcription termination. PMID- 21541640 TI - Hepatic arterial bolus chemotherapy for colorectal metastases using an implantable port. AB - Twenty-one patients with isolated colorectal liver metastases underwent hepatic artery infusion (HAI) port implantation for regional chemotherapy with bolus injections of 5-FU, LV and fast drip of cisplatin. Ten of the 21 patients had previously failed systemic chemotherapy before HAI. Toxicity was moderate and no need for modulation of the chemotherapeutic dose was required. The objective response rate of the whole group was 52.4%. The patients, who had not previously received systemic chemotherapy, had a significantly higher response rate of 81.8% compared to patients treated previously by systemic chemotherapy, who had a response rate of 20% (p=0.0089). In addition, there was a difference in cumulative survival between these two groups. The HAI combined chemotherapy with 5-FU, LV and cisplatin given by bolus injection through an implantable port is effective therapy with similar response rate but considerable reduced toxicity compared to continuous HAI with FUdR. We assume that this therapy might prolong survival significantly especially in patients not treated before by systemic chemotherapy. PMID- 21541641 TI - Mutation in the K-ras gene at codon 12 does not correlate with disease progression in colorectal carcinoma patients treated with 5-FU/folinic acid biomodulated chemotherapy. AB - To date the response rates to biomodulated 5-fluorouracil in patients with metastatic or unresectable colorectal carcinoma have been varied. Potentially responsive patients are difficult to identify and treatment schedules are both expensive and toxic. Thus, any method that could be used to predict patient response would be both clinically and economically valuable. Increased p53 protein levels have previously been shown to correlate with disease progression in a series of colorectal carcinoma patients treated with 5-FU/folinic acid biomodulated chemotherapy. In addition to mutation of the p53 tumour suppressor gene, mutation of the K-ras gene at codon 12 has also been shown to be a frequent occurrence in the step-wise progression from normal colonic mucosa to adenocarcinoma. Oncogenic activity in the ras family has recently been shown to correlate with decreased levels of apoptosis and thus increased resistance to both radiation and certain chemotherapeutic agents. The aim of the present study was therefore to investigate if a correlation existed between mutation of the K ras gene at codon 12 and disease progression in the series of colorectal carcinoma patients previously evaluated for levels of p53 protein expression. Response to 5-FU/folinic acid was assessed radiologically by CAT scan (WHO criteria) and clinically by Karnofsky performance scale (KPS) 3 months after the initial treatment. The presence of a K-ras gene mutation was assessed with radiolabelled oligonucleotide probes on amplified patient DNA, dot blotted on to a nylon membrane. Fifty-two patients were assessed and 25% were found to possess mutations at codon 12 of their K-ras gene. In contrast to increased levels of p53 protein, K-ras mutation at codon 12 did not correlate with disease progression when assessed either radiologically or clinically. PMID- 21541642 TI - Association of K-ras codon 12 transversions with short survival in non-small cell lung cancer. AB - K-ras activating point mutations appear to have a role in human lung cancer, however, the prognostic significance of these abnormalities remains unclear. The aim of our work was to clarify the role of K-ras mutations as prognostic indicators in patients affected by non-small cell lung cancer (NSCLC). We studied 94 resected primary NSCLCs for K-ras mutations by the PCR-RFLP technique, followed by sequencing. K-ras activating mutations were present in 34% of tumors, a higher incidence being detected in adenocarcinomas. Comparing the impact of K ras mutation types, we found that K-ras transversions were associated with a shorter survival in NSCLC. PMID- 21541643 TI - Spatial competences in Prader-Willi syndrome: a radial arm maze study. AB - The present study was aimed at investigating the spatial abilities in Prader Willi syndrome (PWS) by using the Radial Arm Maze (RAM) task. We trained PWS individuals with the deletion subtype in two different RAM paradigms that tapped different aspects of spatial memory. To evaluate the extent of spatial deficit in PWS individuals, it seemed interesting to compare their performances with those of individuals with Williams syndrome (WS) in which deficits in spatial abilities have been well described. The two syndromic groups were compared to typically developing (TD) individuals mental-age and gender matched. The findings evidenced the impairment of PWS individuals in solving the RAM task with variable severity depending on the paradigm requests. Since the RAM is a task that allows the acquisition of spatial competences through the movement, we advance that the spatial deficits observed in PWS individuals may be related to the malfunctioning of spatial and motor integrative processing. PMID- 21541644 TI - From molecules to behavior: lessons from the study of rare genetic disorders. AB - Rare diseases are defined as conditions with a prevalence of less than 1/2,000. To date between 6,000 and 7,000 rare diseases have been identified and many of those have manifestations that include intellectual disability, developmental disorders or other behavioural phenotypes. In this special issue we bring together a range of papers where rare diseases were used as models to delineate specific aspects of learning and memory, or behaviour. In this introductory paper we summarize some of the lessons we can learn from rare diseases. Firstly, we learn that, collectively, rare diseases are not at all rare. As many as 1 in 20 individuals may be affected by a rare disease at some point in their life. Secondly, we learn that rare diseases may share common pathophysiological mechanisms. A discovery in one can therefore have direct relevance to many others. A third lesson is that the study of rare diseases can lead to an understanding of common disorders, as exemplified by the relationship between Trisomy 21 (Down syndrome) and Alzheimer's disease. A fourth lesson from rare diseases is that the 'one gene-one functional consequence' assumption is not correct. Finally, rare diseases have shed new light on the strengths and weaknesses of animal models in the study of behavioural phenotypes. PMID- 21541645 TI - Peripheral gangrene in a breast fed neonate--is hypernatremic dehydration the cause? AB - Hypernatremic dehydration in breast fed neonates is a rare but increasingly recognized problem. If not identified early, it may lead to potentially life threatening complications. The authors describe a neonate who developed thrombosis and lower limb ischemia secondary to hypernatremic dehydration. Peripheral gangrene, as a result of hypernatremic dehydration is extremely uncommon and has rarely been reported before. PMID- 21541646 TI - Management of septic shock. AB - Septic shock is an important cause of mortality in children with sepsis. The incidence of septic shock is 2-4% of admissions in western pediatric intensive care units and 40%-67% for Indian PICUs. Early goal-directed resuscitation that includes aggressive fluid resuscitation of up to 60 mL/kg as boluses of 20 mL/kg by IV push, to achieve desired heart rates and blood pressure, has emerged as mainstay of treatment in the initial stage. Crystalloids are the preferred fluids, while colloids may be used in some situations. Fluid refractory shock warrants use of vasoactive drugs. Dopamine is the first choice. Dobutamine and low dose epinephrine are the preferred inotropic drugs while nor-epinephrine is a vasopressor. Children with cold shock and normal blood pressure may benefit from nitrosodilators like nitroprusside and nitroglycerine. Inodilators such as milrinone are also useful in this situation. Targeting clinical therapeutic end points assists the management. Good supportive care is also essential for improving the outcomes. PMID- 21541647 TI - Acute chest pain. AB - Chest pain is a worrisome symptom that often causes parents to bring their child to emergency department(ED) for evaluation. In the majority of cases, the etiology of the chest pain is benign, but in one-fourth of the cases symptoms are distressing enough to cause children to miss school. The clinician's primary goal in ED evaluation of chest pain is to identify serious causes and rule out organic pathology. The diagnostic evaluation includes a thorough history and physical examination. Younger children are more likely to have a cardiorespiratory source for their chest pain, whereas an adolescent is more likely to have a psychogenic cause. Children having an organic cause of chest pain are more likely to have acute pain, sleep disturbance due to pain and associated fever or abnormal examination findings, whereas those with non-organic chest pain are more likely to have pain for a longer duration. Chest radiograph is required in some, especially in patients with history of trauma . In children, myocardial ischemia is rare, thus routine ECG is not required on every patient. However, both pericarditis and myocarditis can present with chest pain and fever. Musculoskeletal chest pain, such as caused by costochondritis and trauma, is generally reproducible on palpation and is exaggerated by physical activity or breathing. Pneumonia with or without pleural effusion, usually presents with fever and tachypnea; chest pain may be presenting symptom sometimes. In asthmatic children bronchospasm and persistent coughing can lead to excess use of chest wall muscles and chest pain. Patients' who report acute pain and subsequent respiratory distress should raise suspicion of a spontaneous pneumothorax or pneumomediastinum. ED management includes analgesics, specific treatment directed at underlying etiology and appropriate referral. PMID- 21541648 TI - Acute community acquired pneumonia in emergency room. AB - Community acquired pneumonia is the leading killer of children under the age of 5 years. In ER, a diagnosis of pneumonia may be made and the severity graded on basis of WHO's classification for pneumonia in children up to 5 years of age. It relies on age-specific respiratory rate, presence of lower chest indrawing and signs of severe illness. A diagnosis of pneumonia is made if a febrile child has history of cough and difficult or rapid breathing and a respiratory rate above age specific threshold; however, signs of airway obstruction should be ruled out. Severe pneumonia is diagnosed if with the above features lower chest wall retraction is present; nonetheless, all infants below 2 months and children with moderate to severe malnutrition with pneumonia are categorized as having severe pneumonia. A chest radiograph is indicated only if the diagnosis is in doubt; complications are suspected and there is severe/very severe or recurrent pneumonia. Non-severe pneumonia is treated at home with oral amoxicillin for 3-5 days. If there is no improvement in 48 h it is changed to amoxicillin clavulanate. Azithromycin is added for atypical pneumonia. Indications for hospitalization include age <2 months, treatment failure on oral antibiotics, severe/very severe or recurrent pneumonia, shock, hypoxemia, severe malnutrition, immunocompromised state. Severe pneumonia is treated with injectable ampicillin; Cloxacillin is added if clinical/radiographic features suggest Staphylococcal infection. On review after 48 h, if improved, the child may be sent home on oral amoxicillin for 5 more days; if not, it is treated as very severe pneumonia. Very severe pneumonia is treated with injectable Ampicillin plus gentamicin. If improved after 48 h, oral amoxicillin and gentamicin are continued for 10 days. If not, respiratory support is enhanced, antibiotics are changed to intravenous ceftriaxone and amikacin and further work up is planned. Children with chronic diseases and recurrent pneumonia require specific antibiotics depending on the underlying cause. PMID- 21541649 TI - Risk assessment strategy for prediction of pathological hyperbilirubinemia in neonates. AB - OBJECTIVE: To evaluate combined ability of clinical risk factors and transcutaneous bilirubin (TcB) in predicting pathological hyperbilirubinemia (PHB) needing treatment during first week of life in healthy term and late preterm neonates. METHODS: This prospective cohort study included healthy neonates with gestation >=35 wk and birth weight >=2000 g. TcB was measured with a multi-wavelength transcutaneous bilirubinometer (Bilichek(r)) at 30 +/- 12 h of postnatal age. Follow-up was conducted as per American Academy of Pediatrics guidelines. For diagnosis of PHB, TcB was measured at each follow-up visit. Serum bilirubin was measured if TcB was >15 mg/dL or within 2 mg/dL of phototherapy cut off. RESULTS: Among 462 neonates [birth weight (g; mean +/- SD): 2711 +/- 431, gestation (wk; median, IQR): 38 (37-39), male: 52%] enrolled in the study, 392 (84.9%) completed followup and PHB was observed in 65 (16.6%) neonates. Discriminant ability of risk model, including both clinical risk factors and TcB, was better than the risk models with clinical risk factors or TcB alone (c statistic: 0.86 vs. 0.74 vs. 0.77). On logistic regression analysis risk factors found significant were TcB (OR: 1.65, 95% CI: 1.4-1.9), gestation at birth (OR: 0.6, 95% CI: 0.50-0.77) and primiparity (OR: 2.1, 95% CI: 1.1-3.9). A risk prediction score was developed with these three risk factors as ordinal/dichotomous variables. Negative and positive predictive values for score <8 and >12 were 97% and 46%, respectively. CONCLUSIONS: Risk score consisting of TcB, gestation at birth and parity status was able to accurately predict pathological hyperbilirubinemia in derivation cohort of healthy term and late preterm north Indian neonates. PMID- 21541650 TI - Tuberous sclerosis: diagnosis and prenatal diagnosis by MLPA. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, caused due to mutations in the TSC1 and TSC2 genes. Mutations in TSC2 gene are more common than in TSC1 gene and mostly they are in the form of large genomic deletions or duplications. The authors report on a novel deletion in TSC2 gene, prenatal diagnosis and genetic counseling in a family with a 3- year- old affected male child. This is the first report on MLPA based mutation analysis of TSC1 and TSC2 genes from India. PMID- 21541651 TI - Does Clostridium botulinum neurotoxin A exhibit molecular mimicry with thyroid autoantigens and cause thyroid complications in predisposed persons? PMID- 21541652 TI - Prognostic factors and follow-up of patients with differentiated thyroid carcinoma with false negative or nondiagnostic FNAC before surgery. Comparison with a control group. AB - Since the clinical implementation of fine needle aspiration cytology (FNAC) to diagnose thyroid carcinoma, few patients remain misdiagnosed and little is known about their clinical outcomes. An observational retrospective study was carried out to analyse prognostic factors and follow-up of patients with differentiated thyroid carcinoma (DTC) not disclosed by FNAC before surgery, compared to a control group. From October 2003 to July 2010, 308 patients underwent surgery as treatment for nodular goitre and 53 had DTC. Cases were 12 subjects with DTC and benign (n = 7) or nondiagnostic (n = 5) FNAC. Controls were 39 subjects with DTC and suspicious (n = 19) or malignant (n = 20) FNAC. Prognostic factors, recurrence and survival rates were compared. Cases had longer time from FNAC to surgery than the control group (86.8 +/- 74.1 vs. 16.4 +/- 23.8 weeks; P < 0.001), higher prevalence of follicular carcinoma (33.3 vs. 2.6%; P = 0.009), and of two-time total thyroidectomy (75 vs. 30.8%; P = 0.016). Average follow-up was 42.7 +/- 25.3 months (2-86 months). There were no deaths. Disease-free survival for cases was 66.9 +/- 5.8 months, and for controls 78.7 +/- 3.9 months (P: ns). In patients with DTC, the result of the FNAC performed before surgery was not an independent predictor of recurrences or mortality in the first 7 years of follow up. Thus, false negative or nondiagnostic FNAC in a patient with DTC does not seem to be a primary prognostic factor, but it may reveal other adverse prognostic factors such as longer time to therapy and higher prevalence of follicular carcinoma that may influence long-term outcomes. PMID- 21541653 TI - The effect of selective oestrogen receptor antagonists in an in vitro model of growth plate chondrogenesis. AB - While oestrogen is recognized to play a key role in regulating growth, particularly in relation to epiphyseal fusion, the mechanisms that mediate its effects are still unclear. We utilized an in vitro model of chondrogenesis, the RCJ3.1C5.18 cell line, to explore the effect of oestrogen on this process. We demonstrated the presence of oestrogen receptors (ER) alpha and beta in these cells, with increased abundance of both receptor sub-types evident as the cells differentiated. ERalpha localized to the nucleus, suggesting it was signalling by genomic pathways, while ERbeta was seen predominantly in the cytoplasm, suggesting it may be utilizing non-genomic signalling. While exogenous oestrogen had no effect on proliferation or differentiation, we found some evidence for the endogenous production of oestrogen (intracrinology), as suggested by the expression of aromatase in these cells. Selective ERalpha blockade with methyl piperidinopyrazole (MPP) led to a significant reduction in both proliferation and differentiation, while ERbeta blockade with R,R tetrahydrochrysene (THC) led to an increase in these parameters. This is in keeping with results from mouse knockout models suggesting that unopposed ERbeta signalling leads to an inhibition of skeletal growth. Our results are further evidence for the importance of differential ER signalling in regulating chondrogenesis. Future studies examining in vivo effects of these agents are required to extrapolate these findings to a mammalian model. PMID- 21541654 TI - Pro-apoptotic versus anti-apoptotic properties of dietary resveratrol on tumoral and normal cardiac cells. AB - Resveratrol is a natural dietary polyphenol found in grape skin, red wine, and various other food products. Resveratrol has proved to be an effective chemopreventive agent for different malignant tumors. It has also been shown to prevent vascular alterations such as atherosclerosis and inflammatory-associated events. In view of these observations, we investigated the anti-proliferative and pro-apoptotic activities of resveratrol on a tumoral cardiac cell line (HL-1 NB) derived from mouse tumoral atrial cardiac myocytes. These effects were compared with those found on normal neonatal mouse cardiomyocytes. HL-1 NB cells and neonatal cardiomyocytes were treated with resveratrol (5, 30, and/or 100 MUM) for different times of culture (24, 48, and/or 72 h). Resveratrol effects were determined by various microscopical and flow cytometric methods. After resveratrol treatment, a strong inhibition of tumoral cardiac HL1-NB cell growth associated with a loss of cell adhesion was observed. This cell proliferation arrest was associated with an apoptotic process revealed by an increased percentage of cells with fragmented and/or condensed nuclei (characteristic of apoptotic cells) identified after staining with Hoechst 33342 and by the presence of cells in subG1. At the opposite, on normal cardiomyocytes, no cytotoxic effects of resveratrol were observed, and a protective effect of resveratrol against norepinephrine-induced apoptosis was found on normal cardiomyocytes. Altogether, the present data demonstrate that resveratrol (1) induces apoptosis of tumoral cardiac HL1-NB cells, (2) does not induce cell death on normal cardiomyocytes, and (3) prevents norepinephrine-induced apoptosis on normal cardiomyocytes. PMID- 21541655 TI - Partial occlusion of a Blalock-Taussig shunt in a 3-month-old with systemic fungal infection. PMID- 21541656 TI - Normal autonomic nervous system responses in uncomplicated familial Mediterranean fever: a comparative case-control study. AB - There is a paucity of knowledge regarding the autonomic nervous system function in patients with familial Mediterranean fever (FMF). Therefore, our aim was to evaluate autonomic responses in patients with FMF using complementary tests. The study groups included 33 patients with uncomplicated FMF and 39 control subjects. Autonomic function was evaluated by measuring responses to metronomic breathing, the Valsalva maneuver, and the Ewing maneuver. Autonomic parameters were computed from electrocardiograms with designated computer software. There were no statistically significant differences in any of the measured parameters of autonomic function between the patient and control group. The measured autonomic parameters of both groups were similar to those previously reported in healthy individuals. In conclusion, patients with FMF who did not develop amyloidosis due to continuous colchicine treatment appeared to have normal autonomic function, as reflected by the normal response to physiological autonomic stimuli. PMID- 21541657 TI - Sequential morphological characteristics of murine fetal liver hematopoietic microenvironment in Swiss Webster mice. AB - Embryonic hematopoiesis occurs via dynamic development with cells migrating into various organs. Fetal liver is the main hematopoietic organ responsible for hematopoietic cell expansion during embryologic development. We describe the morphological sequential characteristics of murine fetal liver niches that favor the settlement and migration of hematopoietic cells from 12 days post-coitum (dpc) to 0 day post-partum. Liver sections were stained with hematoxylin and eosin, Lennert's Giemsa, Sirius Red pH 10.2, Gomori's Reticulin, and Periodic Acid Schiff/Alcian Blue pH 1.0 and pH 2.5 and were analyzed by bright-field microscopy. Indirect imunohistochemistry for fibronectin, matrix metalloproteinase-1 (MMP-1), and MMP-9 and histochemistry for naphthol AS-D chloroacetate esterase (NCAE) were analyzed by confocal microscopy. The results showed that fibronectin was related to the promotion of hepatocyte and trabecular differentiation; reticular fibers did not appear to participate in fetal hematopoiesis but contributed to the physical support of the liver after 18 dpc. During the immature phase, hepatocytes acted as the fundamental stroma for the erythroid lineage. The appearance of myeloid cells in the liver was related to perivascular and subcapsular collagen, and NCAE preceded MMP-1 expression in neutrophils, an occurrence that appeared to contribute to their liver evasion. Thus, the murine fetal liver during ontogenesis shows two different phases: one immature and mainly endodermic (<14 dpc) and the other more developed (endodermic mesenchymal; >15 dpc) with the maturation of hepatocytes, a better definition of trabecular pattern, and an increase in the connective tissue in the capsule, portal spaces, and liver parenchyma. The decrease of hepatic hematopoiesis (migration) coincides with hepatic maturation. PMID- 21541659 TI - Integration of gene chip and topological network techniques to screen a candidate biomarker gene (CBG) for predication of the source water carcinogenesis risks on mouse Mus musculus. AB - Screening of a candidate biomarker gene (CBG) to predicate the carcinogenesis risks in the Yangtze River source of drinking water in Nanjing area (YZR-SDW-NJ) on mouse (Mus musculus) was conducted in this research. The effects of YZR-SDW-NJ on the genomic transcriptional expression levels were measured by the GeneChip((r)) Mouse Genome and data treated by the GO database analysis. The 298 genes discovered as the differently expressed genes (DEGs) were down-regulated and their values were <=-1.5-fold. Of the 298 DEGs, 25 were cancer-related genes selected as the seed genes to build a topological network map with Genes2Networks software, only 7 of them occurred at the constructed map. Smad2 gene was at the constructed map center and could be identified as a candidate biomarker gene (CBG) primarily which involves the genesis and development of colorectal, leukemia, lung and prostate cancers directly. Analysis of the gene signal pathway further approved that smad2 gene had the relationships closely to other 16 cancer related genes and could be used as a CBG to indicate the carcinogenic risks in YZR-SDW-NJ. The data suggest that integration of gene chip and network techniques may be a way effectively to screen a CBG. And the parameter values for further judgment of the CBG through signal pathway relationship analysis also will be discussed. PMID- 21541658 TI - Mechanisms and consequences of TGF-beta overexpression by podocytes in progressive podocyte disease. AB - In patients with progressive podocyte disease, such as focal segmental glomerulosclerosis (FSGS) and membranous nephropathy, upregulation of transforming growth factor-beta (TGF-beta) is observed in podocytes. Mechanical pressure or biomechanical strain in podocytopathies may cause overexpression of TGF-beta and angiotensin II (Ang II). Oxidative stress induced by Ang II may activate the latent TGF-beta, which then activates Smads and Ras/extracellular signal-regulated kinase (ERK) signaling pathways in podocytes. Enhanced TGF-beta activity in podocytes may lead to thickening of the glomerular basement membrane (GBM) by overproduction of GBM proteins and impaired GBM degradation in podocyte disease. It may also lead to podocyte apoptosis and detachment from the GBM, and epithelial-mesenchymal transition (EMT) of podocytes, initiating the development of glomerulosclerosis. Furthermore, activated TGF-beta/Smad signaling by podocytes may induce connective tissue growth factor and vascular endothelial growth factor overexpression, which could act as a paracrine effector mechanism on mesangial cells to stimulate mesangial matrix synthesis. In proliferative podocytopathies, such as cellular or collapsing FSGS, TGF-beta-induced ERK activation may play a role in podocyte proliferation, possibly via TGF-beta induced EMT of podocytes. Collectively, these data bring new mechanistic insights into our understanding of the TGF-beta overexpression by podocytes in progressive podocyte disease. PMID- 21541660 TI - Historical record and source apportionment of polycyclic aromatic hydrocarbons in the Lianhuan Lake sediments. AB - Polycyclic aromatic hydrocarbons (PAHs) in a sediment core from the north Lianhuan Lake were collected to investigate its historical changes in the last one hundred years and its possible influence on ecological system in the lake. GC MS was used to determine the concentrations of PAHs, and sediment chronological age was examined by (137)Cs dating approach. The concentrations of 16 different kinds of PAHs in the sediment samples ranged from 297 to 1,327 ng g(-1), and the low molecular weight (LMW) were predominant. The intensification of industrial and anthropogenic activities in the Daqing oil field may play the key role in the increase of PAHs concentrations in the late 1950s. To the early 1980s, the PAHs concentrations significantly decreased due to the grain size coarsening in the sediment samples, which was confirmed by the precipitation information. The 5-6 rings PAHs concentrations increased in the early 1980s may be attributed to the consumption of petroleum, coal and wood. The results showed that both the PAHs historical record and current concentrations may cause some influence on the Lianhuan Lake ecological system. The toxicology research on this ecological system should be done in the further investigations for determining the PAHs damage on human and ecological system health. PMID- 21541661 TI - Lack of association between XPD Lys751Gln and Asp312Asn polymorphisms and colorectal cancer risk: a meta-analysis of case-control studies. AB - PURPOSE: The published data on the association between xeroderma pigmentosum group D (XPD) Lys751Gln and Asp312Asn polymorphisms and colorectal cancer remained controversial. The present meta-analysis of literatures was performed to derive a more precise estimation of the relationship. MATERIALS AND METHODS: A comprehensive literature search was conducted to identify all case-control studies of Lys751Gln and Asp312Asn polymorphisms on the susceptibility of different tumor site of colorectal cancer (colon, rectum, and colon/rectum cancer). A total of 22 eligible studies were selected for this meta-analysis, including 3,042 cases and 4,627 controls for Lys751Gln and 1,581 cases and 2,846 controls for Asp312Asn. RESULTS: Overall, no significantly elevated colorectal cancer risk was found in all genetic models when all studies were pooled into the meta-analysis (for Lys751Gln polymorphism: Lys/Gln vs. Lys/Lys, OR = 1.01, 95% CI = 0.90-1.14; Gln/Gln vs. Lys/Lys, OR = 1.04, 95% CI = 0.85-1.26; dominant model, OR = 1.03, 95% CI = 0.93-1.15; recessive model, OR = 1.04, 95% CI = 0.87-1.25; and for Asp312Asn polymorphism: Asp/Asn vs. Asp/Asp, OR = 1.11, 95% CI = 0.91 1.35; Asn/Asn vs. Asp/Asp, OR = 1.13, 95% CI = 0.87-1.47; dominant model, OR = 1.09, 95% CI = 0.94-1.26; recessive model, OR = 1.11, 95% CI = 0.88-1.41). And for the additive model, individuals carrying the 751Gln or 312Asn allele were not significantly associated with increased risk to colorectal cancer (OR = 1.02, 95% CI = 0.94-1.11, OR = 1.07, 95% CI = 0.95-1.20). CONCLUSION: This meta-analysis suggests that XPD Lys751Gln and Asp312Asn polymorphisms may not be associated with colorectal cancer development. PMID- 21541662 TI - The clinical analysis of 34 cases of intestinal tuberculosis in China's big city hospitals. AB - AIMS: Intestinal tuberculosis is not uncommon in developing countries. The diagnosis of this disease is quite difficult. The purpose of our research was to recall the clinical, colonoscopic, and histopathological features of this disease. METHODS: The clinical, colonoscopic, and histopathological findings were retrospectively analyzed in 34 patients with intestinal colonic tuberculosis in recent 5 years. RESULTS: The mean age of the patients was 34.7 +/- 10.5 years. There were 18 males and 16 females in this group. Abdominal pain, fever, diarrhea, weight loss, and fatigue were the commonest symptoms. Extraintestinal tuberculosis was present in 14 patients. Colonoscopy revealed ulcers in 18 patients, nodules in 11, a deformed cecum and ileocecal valve in 17, strictures in five, polypoid lesions in four, and fibrous bands forming mucosal bridges in three. The cecum and ascending colon were the commonest sites involved. Segmental tuberculosis was seen in five of the 34 patients in whom full-length colonoscopy could be performed. Two or more sites were involved in 18 patients. Histopathology revealed well-formed granulomas in 23 patients. Fourteen of the above patients had caseation and 11 had confluence of the granulomas. Ill-formed granulomas were seen in seven patients and chronic inflammatory changes in 13. Both caseation granulomas and stain for acid-fast bacilli in the biopsies positive were from four patients. We divided the patients into groups I (definitive intestinal tuberculosis, 27 cases) and II (suspected intestinal tuberculosis, seven cases). Despite the various histopathological findings, all of the patients responded to antitubercular treatment and continued to remain asymptomatic during the follow-up period. CONCLUSIONS: Colonoscopy with biopsy is essential for diagnosing colonic tuberculosis. Even in the absence of the classic histopathological features, a therapeutic trial may be indicated in a given clinical and colonoscopic setting. Follow-up is important. PMID- 21541663 TI - Intestinal ischemia. AB - Ischemic changes of the abdominal organs are crucial since they develop slowly and are therefore often diagnosed at a late stage. Due to this general aspect, mortality from this disease could not be significantly reduced over the last decade. One of the main causes of these high mortality rates is the insufficient integration of the overall clinical picture into the diagnostic work-up. Acute mesenteric ischemia should be differentiated from chronic visceral ischemia. Acute intestinal ischemia is a vascular emergency with a mortality rate of 60 80%. The incidence of chronic visceral vascular disorders accounts for approximately 1-2% of all abdominal conditions and has to be differentiated from the acute form, since intestinal ischemia has a progressive nature and usually is related to general atherosclerotic disease. Therefore, this condition is associated with an increase of arteriosclerotic-related multimorbidity in an increasingly elderly population. Due to excellent collateralization, extensive chronic occlusion processes affecting the visceral arteries can be asymptomatically treated on a long-term basis. PMID- 21541664 TI - Accuracy of functional surfaces on comparatively modeled protein structures. AB - Identification and characterization of protein functional surfaces are important for predicting protein function, understanding enzyme mechanism, and docking small compounds to proteins. As the rapid speed of accumulation of protein sequence information far exceeds that of structures, constructing accurate models of protein functional surfaces and identify their key elements become increasingly important. A promising approach is to build comparative models from sequences using known structural templates such as those obtained from structural genome projects. Here we assess how well this approach works in modeling binding surfaces. By systematically building three-dimensional comparative models of proteins using MODELLER: , we determine how well functional surfaces can be accurately reproduced. We use an alpha shape based pocket algorithm to compute all pockets on the modeled structures, and conduct a large-scale computation of similarity measurements (pocket RMSD and fraction of functional atoms captured) for 26,590 modeled enzyme protein structures. Overall, we find that when the sequence fragment of the binding surfaces has more than 45% identity to that of the template protein, the modeled surfaces have on average an RMSD of 0.5 A, and contain 48% or more of the binding surface atoms, with nearly all of the important atoms in the signatures of binding pockets captured. PMID- 21541665 TI - Embryogenic potential and expression of embryogenesis-related genes in conifers are affected by treatment with a histone deacetylase inhibitor. AB - Somatic embryogenesis is used for vegetative propagation of conifers. Embryogenic cultures can be established from zygotic embryos; however, the embryogenic potential decreases during germination. In Arabidopsis, LEAFY COTYLEDON (LEC) genes are expressed during the embryonic stage, and must be repressed to allow germination. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) causes de-repression of LEC genes. ABSCISIC ACID3 (ABI3) and its Zea mays ortholog VIVIPAROUS1 (VP1) act together with the LEC genes to promote embryo maturation. In this study, we have asked the question whether TSA treatment in a conifer affects the embryogenic potential and the expression of embryogenesis related genes. We isolated two conifer LEC1-type HAP3 genes, HAP3A and HAP3B, from Picea abies and Pinus sylvestris. A comparative phylogenetic analysis of plant HAP3 genes suggests that HAP3A and HAP3B are paralogous genes originating from a duplication event in the conifer lineage. The expression of HAP3A is high, in both somatic and zygotic embryos, during early embryo development, but decreases during late embryogeny. In contrast, the expression of VP1 is initially low but increases during late embryogeny. After exposure to TSA, germinating somatic embryos of P. abies maintain the competence to differentiate embryogenic tissue, and simultaneously the germination progression is partially inhibited. Furthermore, when embryogenic cultures of P. abies are exposed to TSA during embryo maturation, the maturation process is arrested and the expression levels of PaHAP3A and PaVP1 are maintained, suggesting a possible link between chromatin structure and expression of embryogenesis-related genes in conifers. PMID- 21541668 TI - Pedicle subtraction osteotomy for correction of congenital scoliokyphosis. PMID- 21541669 TI - Transpedicular hemivertebra resection and instrumented fusion for congenital scoliosis. PMID- 21541667 TI - The effects of dynamic loading on the intervertebral disc. AB - Loading is important to maintain the balance of matrix turnover in the intervertebral disc (IVD). Daily cyclic diurnal assists in the transport of large soluble factors across the IVD and its surrounding circulation and applies direct and indirect stimulus to disc cells. Acute mechanical injury and accumulated overloading, however, could induce disc degeneration. Recently, there is more information available on how cyclic loading, especially axial compression and hydrostatic pressure, affects IVD cell biology. This review summarises recent studies on the response of the IVD and stem cells to applied cyclic compression and hydrostatic pressure. These studies investigate the possible role of loading in the initiation and progression of disc degeneration as well as quantifying a physiological loading condition for the study of disc degeneration biological therapy. Subsequently, a possible physiological/beneficial loading range is proposed. This physiological/beneficial loading could provide insight into how to design loading regimes in specific system for the testing of various biological therapies such as cell therapy, chemical therapy or tissue engineering constructs to achieve a better final outcome. In addition, the parameter space of 'physiological' loading may also be an important factor for the differentiation of stem cells towards most ideally 'discogenic' cells for tissue engineering purpose. PMID- 21541670 TI - Anterior lumbar discectomy and disc replacement. PMID- 21541672 TI - Genetic evidence for involvement of the alternative sigma factor SigI in controlling expression of the cell wall hydrolase gene lytE and contribution of LytE to heat survival of Bacillus subtilis. AB - The Bacillus subtilis cell wall hydrolase LytE is involved in cell wall turnover and cell separation during vegetative growth. lytE transcription is known to be driven by a YycF-activated SigA-dependent promoter. The cell wall regulator SigI is an alternative sigma factor that has been shown to be heat stress-inducible and to be essential for survival of B. subtilis at high temperature. However, none of the previously identified target genes of SigI contribute to heat resistance. We now demonstrate that lytE expression is heat-inducible and that heat induction of lytE expression is strongly dependent on SigI. We have also found that the lytE mutant shows the same growth defect at high temperature as the sigI mutant. Introducing an extra copy of lytE into the sigI mutant could rescue its growth defect. Our data strongly suggest that SigI-dependent lytE expression under heat stress is important for heat survival of B. subtilis. PMID- 21541671 TI - A prospective survey of Aspergillus spp. in respiratory tract samples: prevalence, clinical impact and antifungal susceptibility. AB - A three-month laboratory-based prospective survey was conducted at four major university hospitals covering one-third of the Danish population in order to determine the prevalence, significance, and susceptibility pattern of aspergilli in airway samples. Samples received in January-March 2007 for routine microbiologic investigation were examined for Aspergillus following routine procedures and with extended incubation (5 days). Identification was done by morphologic criteria and susceptibility testing using EUCAST method for azoles and amphotericin B E-test. Invasive aspergillosis (IA) was evaluated using modified EORTC/MSG criteria. A total of 11,368 airway samples were received. Growth of Aspergillus spp. was found in 129 and 151 patients using routine and extended incubation, respectively. Three patients had proven IA (2%), 11 probable (7%), four had allergic bronchopulmonary aspergillosis (ABPA) (3%), but the majority was colonised (88%). Underlying conditions were cystic fibrosis in 82 patients (55%), chronic obstructive pulmonary disease in 19 (13%) and haematological disorder in 11 (7%). Twenty-six patients (18%) were at intensive care unit and 69 (47%) received steroid treatment. Azole MICs were elevated for five isolates as follows (itraconazole, posaconazole, voriconazole MICs [mg/L]): two A. fumigatus isolates (>4; >4; 2 and >4; 0.125; 1), one A. lentulus isolate (2; 2; 0.5) and two A. terreus isolates (2; 2; 2 and 2; 0.125; 1). For four isolates the amphotericin B MIC was >1 MUg/ml (3/112 A. fumigatus, 1/2 A. terreus). In conclusion, Aspergillus appears to be an important pathogen in Denmark. Elevated itraconazole MICs were detected in 4% of the isolates including a multi-azole resistant isolate. PMID- 21541673 TI - Does simultaneous UV-B exposure enhance the lethal and sub-lethal effects of aquatic hypoxia on developing anuran embryos and larvae? AB - Recent catastrophic global amphibian declines have been partially linked to increases in UV-B radiation as a consequence of stratospheric ozone depletion. Previous studies have shown that in the presence of other environmental stressors including aquatic pH and temperature and the presence of contaminants or pathogens, the lethal effects of UV-B on amphibian larvae are enhanced due to interactions between the stressors. Little is known about the interactions between UV-B and aquatic hypoxia, a common and significant natural stressor of amphibian larvae. We examined the potential effects of UV-B and aquatic hypoxia in combination on embryonic survival, developmental rate, body mass and locomotor performance of embryos and larvae of the striped marsh frog, Limnodynastes peronii. We found that while both UV-B and hypoxia independently had substantial negative effects on the developing embryos of L. peronii, they did not interact in a multiplicative or antagonistic manner. The effects of the stressors in combination were as might be predicted based on the knowledge of their independent actions alone (i.e. an additive effect). In all cases developing embryos exposed to both UV-B and hypoxia were more severely affected than those exposed to either UV-B or hypoxia alone. The results of this study show the importance of examining both the direct actions of individual stressors and how these may be influenced by the presence of other environmental factors. PMID- 21541674 TI - Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) in preoperative serum as independent prognostic markers in patients with colorectal cancer. AB - Colorectal cancer is one of the leading causes of cancer related death in developed countries. One of the reasons is the absence of tumor specific diagnostic and prognostic markers. The aim of this study was to examine the correlation of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) expressions in serum and clinicopathological features of the colorectal adenocarcinoma. Another aim was to examine expression of MMP-9 in the tissue of the colorectal carcinoma in MMP-9 serum positive patients. In addition, we tried to establish the correlation between preoperative levels of serum markers (CEA and CA 19-9) and presence of MMP-2 or MMP-9. The study was performed on 32 patients with colorectal adenocarcinoma who underwent surgery and 11 patients in a control group who were operated for benign diseases. The samples were analyzed by SDS PAGE to determine the molecular mass and SDS-PAGE zymography to determine levels of MMP-2 and MMP-9. Expression of MMP-9 was determined immunohistochemically in the tissue of the colorectal carcinoma of MMP-9 serum positive patients. MMP-2 and MMP-9 levels were increased in the serum of the patients with colorectal cancer compared to the control group. There was significant correlation in MMPs levels among the patients with tumor stage I and II and the patients with tumor stage III and IV. Obtained results did not demonstrate correlation between levels of CEA, CA 19-9 and presence of MMP-2 or MMP-9. MMP-9 expression was positive in 85% of MMP-9 serum positive patients with colorectal carcinoma. The overexpression of MMP-2 and MMP-9 strongly suggests its association with colorectal adenocarcinoma. Detection of MMP-2 and MMP-9 in serum might be useful for identification of patients with higher risk for colorectal cancer recurrence. PMID- 21541675 TI - Effect of trichostatin A and 5-Aza-2'-deoxycytidine on transgene reactivation and epigenetic modification in transgenic pig fibroblast cells. AB - Transgenic technology has greatly facilitated our understanding of gene function, producing pharmaceutical proteins, and generating models for the study of human diseases. However, epigenetic silencing is still the most major limitation. In this study, we employed DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5 Aza-dC) and histone deacetylase inhibitor Trichostatin A (TSA) to study the reactivation of silenced green fluorescent protein (GFP) transgene driven by the cytomegalovirus (CMV) promoter in three fibroblast cell lines from transgenic pigs (tPFs). Analysis showed that porcine fetal fibroblasts (PFF) treated with 0.5 MUM 5-Aza-dC for 48 h or 0.25 MUM TSA for 24 h had no significantly relevant deaths and no considerably morphological changes. We observed that transgene underwent progressive silencing in a long time course of culture in vitro, and this was correlated with DNA hypermethylation and hypoacetylation of specific histone H3 lysines in the CMV promoter region. Moreover, silenced transgene could be reactivated with 5-Aza-dC or/and TSA treatment by reversing the CMV promoter status of histone hypoacetylation and DNA hypermethylation, and the combination treatment with both agents resulted in a synergistic activation of the transgene, suggesting a cross talk between histone acetylation and DNA methylation. Furthermore, the combination treatment once per 10 days could maintain transgene expression in a high level for more than 60 days by sustaining DNA hypomethylation and histone hyperacetylation. In conclusion, our results suggest that methyltransferase inhibitor 5-Aza-dC and histone deacetylase inhibitor TSA can reactivate silenced transgene and maintain transgene expression by induction of DNA hypomethylation and histone hyperacetylation in the promoter region. PMID- 21541676 TI - Novelty of Axin 2 and lack of Axin 1 gene mutation in colorectal cancer: a study in Kashmiri population. AB - Colorectal cancer is (CRC) one of the leading causes of mortality and morbidity. Various genetic factors have been reported to be involved in the development of colorectal cancers including Axin gene. Axin, a major scaffold protein, plays an important role in various bio signaling pathways. We aim to study mutational pattern of Axin gene in colorectal cancer patients of Kashmiri population. The paired tumor and adjacent normal tissue specimens of 50 consecutive patients with CRC were used in our study. The DNA preparations were evaluated for the occurrence of Axin 1 and Axin 2 gene mutations by direct DNA sequencing. We analyzed exon 1a, 1b, 1c, 2, 4, 6, and 10 of Axin 1 and exon 7 of Axin 2. In this study, we found a novel mutation of G>T (GCT>TCT) transversion in exon 7 of Axin 2 gene at codon G695T (p.alanine > serine) at a frequency of 6% (3/50). In the same exon of Axin 2 gene a single nucleotide polymorphism (SNP) was detected in codon L688L (CCT>CTT) at a frequency of 36% (18/50). In exon 1c of Axin 1 a SNP was detected at codon D726D (GAT>GAC) at a frequency of 62.5% (31/50). Both the SNPs were synonymous hence do not lead to change of amino acid. Although Axin 1 and Axin 2 gene mutations have been found to be involved in the development of colorectal cancers, it seems to be a relatively rare event in Kashmiri population. However, an interesting finding of this study is the novelty of Axin 2 gene mutations which may be a predisposing factor in ethnic Kashmiri population to CRC. PMID- 21541677 TI - Acyl-CoA binding proteins interact with the acyl-CoA binding domain of mitochondrial carnitine palmitoyl transferase I. AB - Although the rate limiting step in mitochondrial fatty acid oxidation, catalyzed by carnitine palmitoyl transferase I (CPTI), utilizes long-chain fatty acyl-CoAs (LCFA-CoA) as a substrate, how LCFA-CoA is transferred to CPTI remains elusive. Based on secondary structural predictions and conserved tryptophan residues, the cytoplasmic C-terminal domain was hypothesized to be the LCFA-CoA binding site and important for interaction with cytoplasmic LCFA-CoA binding/transport proteins to provide a potential route for LCFA-CoA transfer. To begin to address this question, the cytoplasmic C-terminal region of liver CPTI (L-CPTI) was recombinantly expressed and purified. Data herein showed for the first time that the L-CPTI C-terminal 89 residues were sufficient for high affinity binding of LCFA-CoA (K (d) = 2-10 nM) and direct interaction with several cytoplasmic LCFA CoA binding proteins (K (d) < 10 nM), leading to enhanced CPTI activity. Furthermore, alanine substitutions for tryptophan in L-CPTI (W391A and W452A) altered secondary structure, decreased binding affinity for LCFA-CoA, and almost completely abolished L-CPTI activity, suggesting that these amino acids may be important for ligand stabilization necessary for L-CPTI activity. Moreover, while decreased activity of the W452A mutant could be explained by decreased binding of lipid binding proteins, W391 itself seems to be important for activity. These data suggest that both interactions with lipid binding proteins and the peptide itself are important for optimal enzyme activity. PMID- 21541679 TI - A straightforward route to enantiopure 2-substituted-3,4-dehydro-beta-proline via ring closing metathesis. AB - The synthesis of unusual cyclic amino acids, that may be envisaged as proline analogs, is an area of great interest for their potential applications as scaffolds for the design of bioactive peptidomimetics or units for the creation of novel foldamers. We have carried out the preparation of cyclic dehydro-beta amino acids starting from allylic carbonates via a two-step allylic amination/ring closing metathesis (RCM) protocol. The introduction of the allylamino moiety has been carried out either without a catalyst, through an S(N)2' reaction, or in the presence of iridium complexes. The backbone of the allylamino intermediates contains two unsaturations, thus suggesting that RCM could be a valuable tool for the preparation of dihydropyrrole scaffolds. A similar reaction has been already reported in the literature for racemic aromatic substituted substrates, but no examples of enantiopure derivatives bearing aliphatic chains have been reported. The reaction was optimized by testing different Grubbs' catalysts and carbamate nitrogen protecting groups. Moreover, in view of a future application of these dehydro-beta-amino acids as central core of peptidomimetics, the malonate chain was also used to protect nitrogen prior to RCM. PMID- 21541678 TI - The effect of antioxidants on the response of the rabbit urinary bladder to in vitro ischemia/reperfusion. AB - To evaluate the protective effects of two naturally occurring antioxidants, alpha Lipoic acid and coenzyme Q10 on the response to in vitro ischemia of the rabbit urinary bladder. We measured free fatty acid (FFA) content, phospholipid (PL) content, malondialdehyde (MDA) levels, and phospholipase A(2) activity (PLA) of subcellular compartments. Twenty New Zealand White male rabbits were separated into four groups of five rabbits each. The in vitro whole bladders from Groups 1 and 2 received a 3 h incubation under normal oxygenated physiological conditions. The bladders were stimulated by field stimulation at 1 and 3 h. The bladders from groups 3 and 4 underwent 1 h incubation time under normal oxygenated physiological conditions. After 1 h, the bladders were stimulated with field stimulation. After a maximal pressure response was recorded, the stimulation was turned off and the bath medium changed to one equilibrated with 95% nitrogen, 5% oxygen without glucose (ischemic medium) and incubated for 1 h with field stimulations occurring at 5 min intervals during this time. At the end of this hour of ischemia with repetitive stimulation, the bath was changed to an oxygenated medium with glucose for a 1-h reperfusion period after which the stimulation was repeated. The rabbits from groups 2 and 4 received alpha-Lipoic acid (10 mg/kg/day) + Coenzyme Q10 (3 mg/kg/day) by gavage for 4 weeks before the experiment. At the end of the experimental period, each bladder was opened longitudinally, and the muscle and mucosa separated by blunt dissection, frozen under liquid nitrogen, and stored at -80 degrees C for biochemical analyses. Each tissue was fractionated by differential centrifugation into nuclear, mitochondrial, synaptosomal, and cytosol (supernatant) components. PL, FFA, MDA, and PLA were analyzed using standard biochemical techniques. Post-ischemic contractility only returned to 30% of control of the untreated group. However, post-ischemic contractility of the treated group returned to approximately 70% of control. PL loss in the muscle mitochondria and synaptosomes was prevented by antioxidant treatment, while the mucosal layer showed a significant drop in PL with antioxidants treatment. Administration of CoQ + LA significantly decreased MDA levels in both control and ischemic tissues in both the muscle and mucosal bladder layers, especially substantial in the microsomal and mitochondrial components. Treatment had variable effects on PLA(2) activity. Treatment of bladder dysfunction with antioxidants daily can be beneficial in man to prevent or delay the onset of progressive loss of bladder function especially that due to ischemic damage to mitochondrial and microsomal lipids. CoQ10 + LA can provide similar protection of the bladder muscle and mucosa against lipid oxidative stress as they have been shown to protect against protein oxidative damage. PMID- 21541680 TI - A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids. AB - The synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids has been refined to improve both the efficiency and the simplicity. These improvements provide a shorter and easier access to the racemic cis-cyclobutane beta-amino acid core. Derivatization of this material with a chiral non-racemic oxazolidin-2-one allows easy diastereoisomeric separation and presents the advantage of allowing the non-destructive cleavage of the chiral auxiliary either by hydrolysis or by ammonolysis, thus providing an efficacious access to N protected derivatives of all four stereoisomers of Boc-2 aminocyclobutanecarboxylic acid. PMID- 21541681 TI - Synthesis and structural study of highly constrained hybrid cyclobutane-proline gamma,gamma-peptides. AB - Two diastereomeric series of hybrid gamma,gamma-peptides derived from conveniently protected derivatives of (1R,2S)- and (1S,2R)-3-amino-2,2 dimethylcyclobutane-1-carboxylic acid and cis-4-amino-L: -proline joined in alternation have efficiently been prepared through convergent synthesis. High resolution NMR experiments show that these compounds present defined conformations in solution affording very compact structures as the result of intra and inter residue hydrogen-bonded ring formation. (R,S)-cyclobutane containing peptides adopt more twisted conformations than (S,R) diastereomers. In addition, all these gamma-peptides have high tendency to aggregation providing vesicles of nanometric size, which were stable when allowed to stand for several days, as verified by transmission electron microscopy. PMID- 21541683 TI - Can stereotactic sample biopsies accurately diagnose mixed germ cell tumors? PMID- 21541686 TI - Cinacalcet HCl suppresses Cyclin D1 oncogene-derived parathyroid cell proliferation in a murine model for primary hyperparathyroidism. AB - Cinacalcet HCl (cinacalcet) is a calcimimetic compound, which suppresses parathyroid (PTH) hormone secretion from parathyroid glands in both primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism (SHPT). We previously reported the suppressive effect of cinacalcet on PTH secretion in vivo in a PHPT model mouse, in which parathyroid-targeted overexpression of the cyclin D1 oncogene caused chronic biochemical hyperparathyroidism and parathyroid cell hyperplasia. Although cinacalcet suppressed parathyroid cell proliferation in SHPT in 5/6-nephrectomized uremic rats, its effect on PHPT has not yet been determined. In this study, the effect of cinacalcet on parathyroid cell proliferation was analyzed in PHPT mice. Cinacalcet (1 mg/g) was mixed into the rodent diet and orally administrated to 80-week-old PHPT mice for 10 days before death. 5-Bromo-2'-deoxyuridine (BrdU, 6 mg/day) was infused by an osmotic pump for 5 days before death, followed by immunostaining of the thyroid-parathyroid complex using an anti-BrdU antibody to estimate parathyroid cell proliferation. Compared to untreated PHPT mice, cinacalcet significantly suppressed both serum calcium and PTH. The proportion of BrdU-positive cells to the total cell number in the parathyroid glands increased considerably in untreated PHPT mice (9.5 +/- 3.1%) compared to wild-type mice (0.7 +/- 0.1%) and was significantly suppressed by cinacalcet (1.2 +/- 0.2%). Cinacalcet did not affect apoptosis in the parathyroid cells of PHPT mice. These data suggest that cinacalcet suppressed both serum PTH levels and parathyroid cell proliferation in vivo in PHPT. PMID- 21541685 TI - Bigger is bigger. Better is better. PMID- 21541687 TI - CT angiography for evaluation of cerebral vasospasm following acute subarachnoid haemorrhage. AB - INTRODUCTION: Cerebral vasospasm (CV) is one of the most dreaded complications in patients who survive acute subarachnoid haemorrhage (SAH), and conventional cerebral angiography (DSA) is the gold standard for its diagnosis. We evaluated CT angiography (CTA) as a non-invasive alternative for diagnosis of CV and assessed if CTA could have a role in choosing appropriate treatment. METHODS: Consecutive patients with SAH and suspected vasospasm were included when DSA was performed within 24 h from CTA. Two neuro-radiologists retrospectively analysed CTA and DSA studies independently. Assessment included presence of central and peripheral vasospasm and grading of severity of central CV. A treatment recommendation based on CTA was compared to actual treatment received. RESULTS: Final analysis included 34 patients. CTA was more accurate for diagnosis of central then for peripheral CV with high sensitivity (reader 1, 91%; reader 2, 92%), specificity (reader 1, 73%; reader 2, 90%), accuracy, positive predictive value and negative predictive value for central vasospasm. For grading the severity of CV CTA's sensitivity, specificity and accuracy were high for most central arteries. The reader's recommendation of angioplasty according to CTA was significantly predictive of actual receipt of angioplasty but overestimated actual receipt of triple H treatment. CONCLUSION: CTA is adequate for detecting central vasospasm in symptomatic SAH patients. A negative result should not prevent further investigation especially when evaluating arterial segments adjacent to metal artefacts from coils or clips. CTA is helpful in treatment decision making specifically regarding the need for balloon angioplasty. PMID- 21541688 TI - Discriminant analysis to classify glioma grading using dynamic contrast-enhanced MRI and immunohistochemical markers. AB - INTRODUCTION: The purpose of the present study was to look for the possible predictors which might discriminate between high- and low-grade gliomas by pooling dynamic contrast-enhanced (DCE)-perfusion derived indices and immunohistochemical markers. METHODS: DCE-MRI was performed in 76 patients with different grades of gliomas. Perfusion indices, i.e., relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), permeability (k (trans) and k (ep)), and leakage (v (e)) were quantified. MMP-9-, PRL-3-, HIF-1alpha-, and VEGF expressing cells were quantified from the excised tumor tissues. Discriminant function analysis using these markers was used to identify discriminatory variables using a stepwise procedure. To look for correlations between immunohistochemical parameters and DCE metrics, Pearson's correlation coefficient was also used. RESULTS: A discriminant function for differentiating between high- and low-grade tumors was constructed using DCE-MRI-derived rCBV, k (ep), and v (e). The form of the functions estimated are "D (1) = 0.642 * rCBV + 0.591 * k (ep) - 1.501 * v (e) - 1.550" and "D (2) = 1.608 * rCBV + 3.033 * k (ep) + 5.508 * v (e) - 8.784" for low- and high-grade tumors, respectively. This function classified overall 92.1% of the cases correctly (89.1% high-grade tumors and 100% low-grade tumors). In addition, VEGF expression correlated with rCBV and rCBF, whereas MMP-9 expression correlated with k (ep). A significant positive correlation of HIF-1alpha with rCBV and VEGF expression was also found. CONCLUSION: DCE-MRI may be used to differentiate between high-grade and low-grade brain tumors non-invasively, which may be helpful in appropriate treatment planning and management of these patients. The correlation of its indices with immunohistochemical markers suggests that this imaging technique is useful in tissue characterization of gliomas. PMID- 21541690 TI - Advanced nurse-patient communication system. AB - Effective communication is the most important part of any healthcare organization. For many years, hospital nurse call solutions had been stand-alone systems with occasional integration to pocket paging for outputting patient call alerts to mobile staff. In the late 1990's, technology enabled in-building wireless phones to supplement or replace paging systems as a means of not only sending alerts, but also enabling voice communication between mobile staff and patients. Today's nurse call market requires integration of additional information from location and ADT (admit, discharge, transfer) systems into what have traditionally been nurse call applications. This system information is required not only at the nursing station, pagers, and phones, but also at PC's placed on each patient care floor in hallways, nurse stations, and offices, and at areas away from the patients, including administrator and clinical engineering offices. It is crucial that nurses have the latest patient information in their hand wherever they go in the hospital. In this paper, MatchMaker.NET has been developed to integrate all these technologies into the hospital's LAN to improve nurse-patient communication. PMID- 21541689 TI - Lutein inhibits the function of the transient receptor potential A1 ion channel in different in vitro and in vivo models. AB - Transient receptor potential (TRP) ion channels, such as TRP vanilloid 1 and ankyrin repeat domain 1 (TRPV1 and TRPA1), are expressed on primary sensory neurons. Lutein, a natural tetraterpene carotenoid, can be incorporated into membranes and might modulate TRP channels. Therefore, the effects of the water soluble randomly methylated-beta-cyclodextrin (RAMEB) complex of lutein were investigated on TRPV1 and TRPA1 activation. RAMEB-lutein (100 MUM) significantly diminished Ca(2+) influx to cultured rat trigeminal neurons induced by TRPA1 activation with mustard oil, but not by TRPV1 stimulation with capsaicin, as determined with microfluorimetry. Calcitonin gene-related peptide release from afferents of isolated tracheae evoked by mustard oil, but not by capsaicin, was inhibited by RAMEB-lutein. Mustard oil-induced neurogenic mouse ear swelling was also significantly decreased by 100 MUg/ml s.c. RAMEB-lutein pretreatment, while capsaicin-evoked edema was not altered. Myeloperoxidase activity indicating non neurogenic granulocyte accumulation in the ear was not influenced by RAMEB-lutein in either case. It is concluded that lutein inhibits TRPA1, but not TRPV1 stimulation-induced responses on cell bodies and peripheral terminals of sensory neurons in vitro and in vivo. Based on these distinct actions and the carotenoid structure, the ability of lutein to modulate lipid rafts in the membrane around TRP channels can be suggested. PMID- 21541691 TI - Extracting insights from electronic health records: case studies, a visual analytics process model, and design recommendations. AB - Current electronic health record (EHR) systems facilitate the storage, retrieval, persistence, and sharing of patient data. However, the way physicians interact with EHRs has not changed much. More specifically, support for temporal analysis of a large number of EHRs has been lacking. A number of information visualization techniques have been proposed to alleviate this problem. Unfortunately, due to their limited application to a single case study, the results are often difficult to generalize across medical scenarios. We present the usage data of Lifelines2 (Wang et al. 2008), our information visualization system, and user comments, both collected over eight different medical case studies. We generalize our experience into a visual analytics process model for multiple EHRs. Based on our analysis, we make seven design recommendations to information visualization tools to explore EHR systems. PMID- 21541692 TI - Replication in prevention science. AB - Replication research is essential for the advancement of any scientific field. In this paper, we argue that prevention science will be better positioned to help improve public health if (a) more replications are conducted; (b) those replications are systematic, thoughtful, and conducted with full knowledge of the trials that have preceded them; and (c) state-of-the art techniques are used to summarize the body of evidence on the effects of the interventions. Under real world demands it is often not feasible to wait for multiple replications to accumulate before making decisions about intervention adoption. To help individuals and agencies make better decisions about intervention utility, we outline strategies that can be used to help understand the likely direction, size, and range of intervention effects as suggested by the current knowledge base. We also suggest structural changes that could increase the amount and quality of replication research, such as the provision of incentives and a more vigorous pursuit of prospective research registers. Finally, we discuss methods for integrating replications into the roll-out of a program and suggest that strong partnerships with local decision makers are a key component of success in replication research. Our hope is that this paper can highlight the importance of replication and stimulate more discussion of the important elements of the replication process. We are confident that, armed with more and better replications and state-of-the-art review methods, prevention science will be in a better position to positively impact public health. PMID- 21541693 TI - Clostridium difficile infection in non-HIV-immunocompromised patients and in HIV infected patients. AB - Clostridium difficile infection is a common cause of morbidity in patients with HIV infection and in patients with non-HIV immune deficiency. The frequency of C. difficile--associated diarrhea (CDAD) seen in these two patient populations has been attributed to immune deficiency, as well as to increased exposure to hospital environments and antibiotic therapy, both of which are major risk factors for CDAD. This article reviews recent data useful in the evaluation, treatment, and prevention of C. difficile infection in these patient groups. Recent publications relating to C. difficile infection in specific immunocompromised conditions are also discussed. PMID- 21541694 TI - Combinatorics of RNA-RNA interaction. AB - RNA-RNA binding is an important phenomenon observed for many classes of non coding RNAs and plays a crucial role in a number of regulatory processes. Recently several MFE folding algorithms for predicting the joint structure of two interacting RNA molecules have been proposed. Here joint structure means that in a diagram representation the intramolecular bonds of each partner are pseudoknot free, that the intermolecular binding pairs are noncrossing, and that there is no so-called "zigzag" configuration. This paper presents the combinatorics of RNA interaction structures including their generating function, singularity analysis as well as explicit recurrence relations. In particular, our results imply simple asymptotic formulas for the number of joint structures. PMID- 21541695 TI - Distinguishing authentic mitochondrial and plastid DNAs from similar DNA sequences in the nucleus using the polymerase chain reaction. AB - DNA sequences similar to those in the organellar genomes are also found in the nucleus. These non-coding sequences may be co-amplified by PCR with the authentic organellar DNA sequences, leading to erroneous conclusions. To avoid this problem, we describe an experimental procedure to prevent amplification of this "promiscuous" DNA when total tissue DNA is used with PCR. First, primers are designed for organelle-specific sequences using a bioinformatics method. These primers are then tested using methylation-sensitive PCR. The method is demonstrated for both end-point and real-time PCR with Zea mays, where most of the DNA sequences in the organellar genomes are also present in the nucleus. We use this procedure to quantify those nuclear DNA sequences that are near-perfect replicas of organellar DNA. This method should be useful for applications including phylogenetic analysis, organellar DNA quantification and clinical testing. PMID- 21541696 TI - Factors associated with differential response to online cognitive behavioural therapy. AB - PURPOSE: Patients differ in their response to treatments. There is obvious clinical utility in establishing patient characteristics that are associated with differential treatment responses (i.e., are effect modifiers or moderators of treatment response). Factors that moderate response to cognitive behavioural therapy (CBT) remain unclear. This study investigates whether factors prognostic of general depression outcome generally are also moderators of response to online CBT in a sample of depressed patients recruited through U.K. general practices. METHODS: Secondary analysis of a randomised controlled trial, internet-based psychotherapy for depression. A total of 297 patients referred from 55 U.K. general practices and suffering from depression were randomly allocated to receive either online CBT or waiting list control. Treatment effect was measured by comparing depression score at 4 months between randomization groups. Treatment effect modification was assessed using regression analyses focusing on interactions between treatment effect and putative moderator variables. RESULTS: Pretreatment severity and marital status moderated treatment response. More severe patients, and patients who were separated, widowed, or divorced, benefited most from the intervention. Weak evidence suggested that treatment effectiveness diminished with increasing recent adverse life events. No evidence was found to suggest that educational attainment, age, and history of depression-moderated treatment response. CONCLUSIONS: Secondary analyses of trials comparing two or more treatments allow factors that may moderate treatment response to be distinguished from more general prognostic indicators, although caution is needed in interpreting such exploratory analyses. PMID- 21541697 TI - Unemployment among patients with newly diagnosed first-episode psychosis: prevalence and clinical correlates in a U.S. sample. AB - PURPOSE: Although it is well established that people with schizophrenia have markedly high rates of unemployment, less is known about the prevalence and clinical correlates of unemployment in patients newly diagnosed with first episode psychosis. This analysis documented the prevalence of unemployment and examined previously reported clinical correlates of unemployment in patients with first-episode psychosis hospitalized in an urban, public-sector setting in the southeastern US. METHODS: Participants (n = 181) were assessed as part of an overarching study of first-episode psychosis using a variety of standardized research instruments. The rate of unemployment was compared to that documented in the general population according to US census data. Bivariate tests of associations between employment status and a number of variables of interest were followed by a multiple logistic regression model based on a previous study from Dublin, Ireland. RESULTS: Some 65.0% of first-episode patients were unemployed in the month prior to hospital admission, which is substantially higher than the rate of unemployment during the same period in the two counties in which recruitment took place. In bivariate tests, unemployment was associated with younger age, fewer years of educational attainment, lower global functioning scores, and more severe negative symptoms. In the logistic regression model, only age and global functioning were independently significant correlates. CONCLUSIONS: The remarkably high rate of unemployment in this young, first episode sample, and the evidence of associations between unemployment, greater symptomatology, and poorer functioning, argue for further research and development on supported employment programs for such patients. PMID- 21541699 TI - gammadelta T-cells: cross-talk between innate and adaptive immunity. PMID- 21541698 TI - Searching for "signal 2": costimulation requirements of gammadelta T cells. AB - T cell activation requires the integration of signals that arise from various types of receptors. Although TCR triggering is a necessary condition, it is often not sufficient to induce full T-cell activation, as reflected in cell proliferation and cytokine secretion. This has been firmly demonstrated for conventional alphabeta T cells, for which a large panel of costimulatory receptors has been identified. By contrast, the area remains more obscure for unconventional, innate-like gammadelta T cells, as the literature has been scarce and at times contradictory. Here we review the current state of the art on the costimulatory requirements of gammadelta T cell activation. We highlight the roles of members of the immunoglobulin (like CD28 or JAML) or tumour necrosis factor receptor (like CD27) superfamilies of coreceptors, but also of more atypical costimulatory molecules, such as NKG2D or CD46. Finally, we identify various areas where our knowledge is still markedly insufficient, hoping to provoke future research on gammadelta T cell costimulation. PMID- 21541700 TI - Anterior cruciate ligament reconstruction creating the femoral tunnel through the anteromedial portal. Surgical technique. AB - The anterior cruciate ligament reconstruction is a common procedure that improves stability and function of the knee. The surgical technique continues to evolve and many issues are still under debate. These mainly include: (1) graft selection (patellar tendon, hamstring, quadriceps tendon, or allografts), (2) surgical technique (double versus single bundle), and (3) femoral tunnel drilling. Currently, the most controversial one is the femoral tunnel drilling (transtibial vs. anteromedial portal drilling). Common opinion is that drilling the femoral tunnel through the anteromedial (AM) allows a more anatomic placement of the graft and a better rotational stability; therefore, this technique is gaining in popularity compared with the transtibial drilling despite a greater difficulty and the risk of medial condyle damage, tunnel back wall blowout, and inadequate socket length. The aim of this article is to describe the surgical technique of the anterior cruciate ligament reconstruction (single and double bundle), drilling the femoral tunnel through the AM portal. PMID- 21541701 TI - An exploratory study of the role of trust in medication management within mental health services. AB - OBJECTIVE: To develop understandings of the nature and influence of trust in the safe management of medication within mental health services. SETTING: Mental health services in the UK. METHOD: Qualitative methods were applied through focus groups across three different categories of service user--older adult, adults living in the community and forensic services. An inductive thematic analysis was carried out, using the method of constant comparison derived from grounded theory. MAIN OUTCOME MEASURE: Participants' views on the key factors influencing trust and the role of trust in safe medication management. RESULTS: The salient factors impacting trust were: the therapeutic relationship; uncertainty and vulnerability; and social control. Users of mental health services may be particularly vulnerable to adverse events and these can damage trust. CONCLUSION: Safe management of medication is facilitated by trust. However, this trust may be difficult to develop and maintain, exposing service users to adverse events and worsening adherence. Practice and policy should be oriented towards developing trust. PMID- 21541702 TI - Evidence for a link between TNFRSF11A and risk of breast cancer. AB - Intracellular signaling mediated by the receptor activator of nuclear factor kappaB [Rank, encoded by the tumor necrosis factor receptor superfamily, member 11a (Tnfrsf11a) gene] is fundamental for mammary gland development in mice, regulating the expansion of stem and progenitor cell compartments. Conversely, Rank overexpression in mice promotes abnormal proliferation and impairs differentiation, leading to an increased incidence of tumorigenesis. Here, we show that a common genetic variant near the 5'-end of TNFRSF11A, rs7226991, is associated with breast cancer risk in the general population and among carriers of mutations in the breast cancer 2, early onset (BRCA2) gene. Akin to the results of the Cancer and Genetics Markers of Susceptibility initiative, combined analysis of rs7226991 in two Spanish case-control studies (1,365 controls and 1,323 cases in total) revealed a significant association with risk: odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.78-0.98, P (trend) = 0.025. Subsequent examination of BRCA1 (n = 1,017) and BRCA2 (n = 885) mutation carriers revealed a consistent association in the latter group: weighted hazard ratio ((w)HR) = 0.70; 95% CI 0.55-0.88; and P (trend) = 0.003; compared to BRCA1 mutation carriers, (w)HR = 0.91; 95% CI 0.76-1.10; and P (trend) = 0.33. The results of this study need to be replicated in other populations and with larger numbers of BRCA1/2 mutation carriers. PMID- 21541703 TI - Failure of ovarian ablation with goserelin in a pre-menopausal breast cancer patient resulting in pregnancy: a case report and review of the literature. AB - To report an unanticipated pregnancy during ovarian ablation treatment with goserelin (10.8 mg SC every 12 weeks) in a 26-year old female with breast cancer. Review of the current literature and reports in MEDLINE, PubMED, and EMBASE using searches with keywords "goserelin, pregnancy, breast cancer, breast neoplasms, fertility, ovarian ablation, gonadotropin releasing hormone agonists/analogs, leuprolide, pregnancy complications, teratogens" (July-September 2010). Only 3 other reports of failures with goserelin administration at ablative doses in breast cancer patients were discovered. For physicians and breast cancer patients using a GnRH analog, it is important to be aware of the possibility of inadequate ovarian function suppression and the potential for pregnancy. PMID- 21541704 TI - Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth. AB - Although estrogen receptor alpha (ERalpha) and insulin-like growth factor (IGF) signaling are important for normal mammary development and breast cancer, cross talk between these pathways, particularly at the level of transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3 or 24 h. IGF-I regulated mRNA of five to tenfold more genes than E2, and many genes were co-regulated by both ligands. Importantly, expression of these co-regulated genes correlated with poor prognosis of human breast cancer. Closer examination revealed enrichment of repressed transcripts. Interestingly, a number of potential tumor suppressors, for example, B-cell linker (BLNK), were down-regulated by IGF-I and E2. Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ERalpha. However, repression by IGF-I or E2 required common kinases, such as PI3K and MEK, suggesting downstream convergence of the two pathways. In conclusion, E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. There is enrichment of repressed transcripts, and, for some genes, the down-regulation is independent at the receptor level. This may be important clinically, as tumors with active ERalpha and IGF-IR signaling may require co-targeting of both pathways. PMID- 21541705 TI - Hydrogen sulfide down-regulates the expression and release of osteoprotegerin (OPG) by vascular endothelial cells. PMID- 21541706 TI - Efficacy of immunohistological methods in detecting functionally viable mechanoreceptors in the remnant stumps of injured anterior cruciate ligaments and its clinical importance. AB - PURPOSE: Various histological and immunological methods have been used to detect the mechanoreceptors and nerve fibers on the intact ACLs as well as on the remnant stumps. However, some of these methods lack standardization, and the variable thickness of slices used often leads to misinterpretation. The study was based on the hypothesis that immunohistological methods are easier and more reliable means to demonstrate mechanoreceptors in the remnant ACL stumps as compared with the conventional methods. We also attempted to validate the methodology of immunohistology as a means of characterizing functional mechanoreceptors in the residual stump of an injured ACL. METHODS: The remnants of the ruptured ACL in 95 patients were harvested during arthroscopic ACL reconstruction and evaluated immunohistologically using hematoxylin and eosin (H&E), and monoclonal antibodies to S-100 and NFP. Multiple sections from each specimen were serially examined by two histologists. RESULTS: The positivity of monoclonal antibody against NFP showed a statistically significant relationship with the presence of morphologically normal mechanoreceptors, whereas the positivity of monoclonal antibody against S-100 showed a statistically significant relationship with the presence of free nerve ending in the residual stump of an injured ACL. CONCLUSIONS: Immunological methods are more reliable and easier to use as compared with the conventional methods of histological staining for identifying remnant stumps likely to be of some proprioceptive benefit after an ACL injury. Such an identification might help us preserve certain remnant stumps during ACL reconstruction which might in turn improve the postoperative functional outcomes. PMID- 21541707 TI - Previous fracture surgery is a major risk factor of infection after total knee arthroplasty. AB - PURPOSE: Total knee arthroplasty (TKA) has been proven to be the most effective treatment for patients with severe joint disease. Although infection is not a frequent complication, it is certainly one of the most dreaded. The purpose of this study was to identify factors associated with infection after TKA. METHODS: Between 1995 and 2006, 2,022 primary TKAs in 1,146 patients were evaluated. Flexible Nichidai Knee (FNK) was used as a prothesis in all subjects. Twenty-four patient-specific data items were collected via chart review for each patient. Revision arthroplasty procedures and infected knees were excluded. The medical records were reviewed to extract the following information: age, gender, body mass index (BMI), preoperative C-reactive protein (CRP), preoperative erythrocyte sedimentation rate (ESR), preoperative total protein (TP), duration of surgery, operative blood loss, total blood loss, duration of surgical drain, duration of antibiotic prophylaxis, primary diagnoses, smoking, diabetes mellitus, steroid or disease modifying anti-rheumatic drugs (DMARDs) therapy, previous operation around the knee joint, previous arthroscopic surgery, previous non-arthroscopic surgery, previous high tibial osteotomy (HTO) or open reduction internal fixation (ORIF), remnants of previous internal fixation material, bone graft, patella replacement, and bone cement. RESULTS: The median age of the patients at the time of primary TKA was 72 (range, 26-91) years. The median follow-up period after primary TKA was 42 (range, 6-145) months. During the study period, 17 infected knee arthroplasties in 17 patients were identified. Previous history of ORIF, male gender, remnants of previous internal fixation material, and BMI showed significant correlation with postoperative infection. CONCLUSION: This study identified previous history of fracture and remnants of internal fixation as major risk factors of infection after TKA. For clinical relevance, surgeons should be aware of potential infection when performing TKA in patients with these risk factors and patients should be informed of the potential risks. PMID- 21541708 TI - Image-matching technique can detect rotational and AP instabilities in chronic ACL-deficient knees. AB - PURPOSE: The purpose of this study was to quantify rotational and antero posterior instabilities using biplanar image-matching technique. METHODS: Biplanar radiographs of both chronic ACL-deficient knees and contralateral uninjured knees were taken in the pivot shift test and in the "giving way position" and lateral radiographs in stress arthrometer at 30 degrees and 90 degrees . Three-dimensional knee models were constructed using computed tomography. Using biplanar image-matching technique, the external rotational angle and the translation of the center of the both condyles of the femur were analyzed. RESULTS: The external rotation angle of geometric center axis in the pivot shift test was 16.9 degrees +/- 5.6 degrees and 10.9 degrees +/- 7.3 degrees (P = 0.004), and in the "giving way position" was 16.1 degrees +/- 5.7 degrees and 10.7 degrees +/- 6.6 degrees (P = 0.004) in ACL-deficient knees and intact knees, respectively. In the pivot shift test, the medial and the lateral femoral condylar centers of ACL-deficient knees were translated 1.2 +/- 5.1 mm anteriorly and 3.9 +/- 3.4 mm posteriorly, respectively, and in the "giving way position," 2.0 +/- 3.7 mm anteriorly and 2.9 +/- 2.6 mm posteriorly, respectively. In stress arthrometer at 30 degrees , the medial and the lateral femoral condylar center translated 7.1 +/- 6.0 and 6.6 +/- 4.8 mm posteriorly (n.s.), respectively, and at 90 degrees translated 2.7 +/- 3.4 and 2.6 +/- 3.5 mm posteriorly (n.s.), respectively. CONCLUSION: Rotational instability was evaluable in the pivot shift test and in the "giving way position." Translation of both condylar centers was similar in stress arthrometry. The image-matching technique is able to quantify dynamic rotational and antero-posterior instabilities with static parameters in ACL-deficient knees. PMID- 21541709 TI - Discoid lateral meniscus in children: magnetic resonance imaging after arthroscopic resection. AB - PURPOSE: The discoid meniscus is a common meniscal anomaly. Symptomatic discoid menisci treated by arthroscopic surgery were examined preoperatively and postoperatively by magnetic resonance imaging (MRI). Aim of this study was to quantify the amount of meniscal resection when treating discoid meniscus in children by partial meniscectomy. The hypothesis was that partial meniscectomy left sufficient amounts of meniscal tissue. METHODS: A quantitative evaluation of meniscal size comparing preoperative and postoperative data after partial meniscectomy was performed by MRI (n = 6). The anteroposterior meniscal diameter and anterior and posterior thickness were measured. The relative postoperative thickness to preoperative thickness was defined. All patients were graded according to Lysholm score and Ikeuchi knee scale. RESULTS: The quantitative MRI evaluation showed a pronounced reduction of the anteroposterior meniscal diameter (42%) and anterior thickness (41%) after partial meniscectomy, whereas the posterior thickness showed a mean increase of 50%. According to Ikeuchi, all clinical postoperative findings were excellent and displayed an increase in Lysholm score. CONCLUSIONS: MRI findings showed that the amount of remaining tissue after partial meniscectomy was smaller than aspired. Especially in the anterior joint, the final size of remaining meniscal tissue was overestimated intraoperatively. It may be concluded that in arthroscopic partial meniscectomy, the final meniscal size, especially in the anterior part of the joint, is difficult to assess. As it is known that the extent of meniscal resection plays a crucial role in the clinical course of discoid menisci, these data claim retentiveness in resecting meniscal tissue. PMID- 21541710 TI - Fractionation of high-dose electron beam irradiation of BPTB grafts provides significantly improved viscoelastic and structural properties compared to standard gamma irradiation. AB - PURPOSE: Irradiation >30 kGy is required to achieve sterility against bacterial and viral pathogens in ACL allograft sterilization. However, doses >20 kGy substantially reduce the structural properties of soft-tissue grafts. Fractionation of irradiation doses is a standard procedure in oncology to reduce tissue damage but has not been applied in tissue graft sterilization. METHODS: Forty-four human 10-mm wide bone-patellar-tendon-bone grafts were randomized into four groups of sterilization with (1) 34 kGy of ebeam (2) 34 kGy gamma (3) 34 kGy fractionated ebeam, and (4) non sterilized controls. Graft's biomechanical properties were evaluated at time zero. Biomechanical properties were analyzed during cyclic and load-to-failure testing. RESULTS: Fractionation of ebeam irradiation resulted in significantly higher failure loads (1,327 +/- 305) than with one-time ebeam irradiation (1,024 +/- 204; P = 0.008). Compared to gamma irradiation, significantly lower strain (2.9 +/- 1.5 vs. 4.6 +/- 2.0; P = 0.008) and smaller cyclic elongation response (0.3 +/- 0.2 vs. 0.6 +/- 0.4; P = 0.05), as well as higher failure loads (1,327 +/- 305 vs. 827 +/- 209; P = 0.001), were found. Compared to non-irradiated BPTB grafts, no significant differences were found for any of the biomechanical parameters. Non-irradiated controls had significantly lower cyclic elongation response and higher failure loads than ebeam and gamma irradiation. CONCLUSIONS: In this study, it was found that fractionation of high-dose electron beam irradiation facilitated a significant improvement of viscoelastic and structural properties of BPTB grafts compared to ebeam and gamma irradiation alone, while maintaining levels of non-irradiated controls. Therefore, this technique might pose an important alternative to common methods for sterilization of soft-tissue allografts. PMID- 21541711 TI - Good outcome after stripping the plantaris tendon in patients with chronic mid portion Achilles tendinopathy. AB - PURPOSE: Achilles tendinopathy is a problem that is generally difficult to treat. The pain is frequently most prominent on the medial side of the mid-portion of the tendon, where the plantaris tendon is running parallel to the Achilles tendon. The purpose of this study was to assess whether excision of the plantaris tendon would relieve symptoms. METHODS: Three patients with pain and stiffness at the mid-portion of the Achilles tendon were treated by excision of the plantaris tendon. Preoperatively, these patients experienced recognizable tenderness on palpation of the medial side of the mid-portion of the Achilles tendon with localized nodular thickening at 4-7 cm proximal to the insertion. MRI indicated Achilles tendinopathy with the involvement of the plantaris tendon. RESULTS: The plantaris tendon was bluntly retrieved and excised with a tendon stripper through a 4-cm incision in the proximal calf. We report a good-to-excellent outcome of this novel procedure in three patients with chronic mid-portion Achilles tendinopathy CONCLUSION: The medial pain might be based on the involvement of the plantaris tendon in the process. LEVEL OF EVIDENCE: IV. PMID- 21541712 TI - Mechanical functions of the three bundles consisting of the human anterior cruciate ligament. AB - PURPOSE: The reconstruction technique to individually reconstruct multi-bundles of the anterior cruciate ligament (ACL) has been improved in the last decade. For further improvement of the technique, the present study was conducted to determine the force sharing among the three bundles (the medial and lateral bundles (AMM and AML) of the anteromedial (AM) bundle and the posterlateral (PL) bundle) of the human ACL in response to hyperextension, passive flexion-extension and anterior force to the knee. METHODS: Using a 6-DOF robotic system, the human cadaveric knee specimens were subjected to hyperextension, passive flexion extension and anterior-posterior tests, while recording the 6-DOF motion and force/moment of the knees. The intact knee motions recorded during the tests were reproduced after sequential bundle transection to determine the bundle forces. RESULTS: The bundle forces were around 10 N at 5 N-m of hyperextension and remained less than 5 N during passive flexion-extension. In response to 100 N of anterior force, the AMM and PL bundle forces were slightly higher than the AML bundle force at full extension. The AMM bundle force remained at a high level up to 90 degrees of flexion, with significant differences versus the AML bundle force at 15 degrees , 30 degrees and 60 degrees of flexion and the PL bundle force at 90 degrees of flexion. CONCLUSION: The AMM bundle is the primary stabilizer to tibial anterior drawer through wide range of motion, while the AML bundle is the secondary stabilizer in deep flexion angles. The PL bundle is the crucial stabilizer to hyperextension as well as tibial anterior drawer at full extension. PMID- 21541713 TI - Conservative treatment of lumbar spondylolysis in young soccer players. AB - PURPOSE: The purpose of this study was to report the functional outcomes of young active soccer players with lumbar spondylolysis undergoing conservative treatment. METHODS: Between 2002 and 2004, all soccer players diagnosed with spondylolysis with a minimum 2-year follow-up were retrospectively reviewed. All patients were treated nonoperatively with cessation of sports activity and rehabilitation for 3 months. The rehabilitation protocol was identical for all patients and emphasized strengthening of abdominal muscles, stretching of the hamstrings, "core" stability exercises, and trunk rotational movements in a pain free basis. Those patients with pain at rest and with daily life activities were also treated with a thoracolumbar orthosis. Symptomatic patients or those with positive SPECT were not allowed to return to sports and continued the rehabilitation protocol for 3 more months. RESULTS: The mean time of cessation of sports activity was 3.9 months (SD 0.8) and 5.2 months (SD 2.1) for a complete return to sports. At the 2-year follow-up, 28 patients (82%) obtained excellent results, 4 (12%) good results, 1 patient (3%) a fair result, and 1 patient (3%) a poor result. CONCLUSIONS: Conservative treatment of spondylolysis in young soccer players with cessation of sports and rehabilitation, with or without thoracolumbar orthosis, was associated with excellent functional results in terms of return to sports and level of achievable physical activity. PMID- 21541714 TI - Development of L-tryptophan production strains by defined genetic modification in Escherichia coli. AB - Construction and improvement of industrial strains play a central role in the commercial development of microbial fermentation processes. L-tryptophan producers have usually been developed by classical random mutagenesis due to its complicated metabolic network and regulatory mechanism. However, in the present study, an L-tryptophan overproducing Escherichia coli strain was developed by defined genetic modification methodology. Feedback inhibitions of 3-deoxy-D arabinoheptulosonate 7-phosphate synthase (AroF) and anthranilate synthase (TrpED) were eliminated by site-directed mutagenesis. Expression of deregulated AroF and TrpED was achieved by using a temperature-inducible expression plasmid pSV. Transcriptional regulation of trp repressor was removed by deleting trpR. Pathway for L-Trp degradation was removed by deleting tnaA. L-phenylalanine and L tyrosine biosynthesis pathways that compete with L-tryptophan biosynthesis were blocked by deleting their critical genes (pheA and tyrA). The final engineered E. coli can produce 13.3 g/l of L-tryptophan. Fermentation characteristics of the engineered strains were also analyzed. PMID- 21541716 TI - Appendiceal diverticulitis in a femoral hernia causing necrotizing fasciitis of the right inguinal region: report of a unique case. AB - De Garengeot's hernia--a rare finding occurring mostly in women--is defined by the presence of the vermiform appendix within the sac of a femoral hernia. The incidence of appendicitis is rarer still, with less than a 100 cases reported to date. We present a unique case of an 84-year-old male patient with perforated appendiceal diverticulitis within a De Garengeot's hernia causing abscess and necrotizing infection of the overlying soft tissues. PMID- 21541715 TI - Impulse control disorders in Parkinson's disease: seeking a roadmap toward a better understanding. AB - The development of an impulse control disorder (ICD) is now recognized as a potential nonmotor adverse effect of dopamine replacement therapy in Parkinson's disease (PD). Here, recent epidemiological, neurophysiological and genetic advances are summarized to outline potential mechanisms involved. It is safe to say that dopaminergic drugs, particularly dopamine agonists, are able to induce ICDs only in a minority of patients, while the majority are somehow protected from this adverse effect. While it seems clear that men with early-onset PD are more vulnerable, other predisposing factors, such as various current or pre-PD personality traits, are a matter of debate. In terms of neurophysiological advances, one may find striking analogies to the addiction literature suggesting a causal chain beginning with certain predisposing conditions of striatal dopamine synapses, an "unnatural" increase of dopamine stimulation and a characteristic pattern of resulting functional changes in remote networks of appetitive drive and impulse control. Future prospects include potential add-on medications and the possible identification of genetic predispositions at a genome-wide scale. Functional imaging of pharmacogenetic interactions (imaging pharmacogenomics) may be an important tool on that road. PMID- 21541718 TI - Off-label use of recombinant activated coagulation factor VII for bleeding may raise the risk of arterial thrombosis. PMID- 21541717 TI - Risky sexual behavior: a race-specific social consequence of obesity. AB - Scant attention has been given to the consequence of actual weight status for adolescents' sexual wellbeing. In this article, we investigate the race-specific connection between obesity and risky sexual behavior among adolescent girls. Propensity scores and radius matching are used to analyze a sample of 340 adolescents aged 16-17 who participated in the National Longitudinal Survey of Youth Young Adult Survey in 2000 or 2002. Nearly even numbers of these participants identified as white and black (183 and 157, respectively). We find that compared to their non-obese white peers, obese white adolescent girls exhibit higher rates of multiple sex partners and sex with older partners, and are also less likely to use condoms. None of these factors are significantly related to high BMI within the black sample. These findings indicate that the negative social consequences of obesity extend beyond future economic and marriage outcomes to adolescent white women's sexual outcomes. They also highlight the importance of context: the implications of being obese during adolescence depend on cultural meanings of obesity. PMID- 21541719 TI - 1st International congress on mycorrhizal symbiosis: ecosystems and environment of Mediterranean area (MYCOMED). PMID- 21541720 TI - Molecular insights into the pathogenicity of variants associated with the aromatic amino acid decarboxylase deficiency. AB - Dopa decarboxylase (DDC or AADC) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the decarboxylation of L-aromatic amino acids into the corresponding aromatic amines. AADC deficiency is an inborn error of neurotransmitters biosynthesis with an autosomal recessive inheritance. About 30 pathogenic mutations have been identified, but the enzymatic phenotypes causing AADC deficiency are unknown, and the therapeutic management is challenging. Here, we report biochemical and bioinformatic analyses of the human wild-type DDC and the pathogenic variants G102S, F309L, S147R and A275T whose mutations concern amino acid residues at or near the active site. We found that the mutations cause, even if to different extents, a decreased PLP binding affinity (in the range 1.4-170-fold), an altered state of the bound coenzyme and of its microenvironment, and a reduced catalytic efficiency (in the range 17-930-fold). Moreover, as compared to wild-type, the external aldimines formed by the variants with L-aromatic amino acids exhibit different spectroscopic features, do not protect against limited proteolysis, and lead to the formation, in addition to aromatic amines, of cyclic-substrate adducts. This suggests that these external Schiff bases are not properly oriented and anchored, i.e., in a conformation not completely productive for decarboxylation. The external aldimines that the variants form with D-Dopa also appear not to be correctly located at their active site, as suggested by the rate constants of PLP-L-Dopa adduct production higher than that of the wild-type. The possible therapeutic implications of the data are discussed in the light of the molecular defects of the pathogenic variants. PMID- 21541721 TI - Clinical manifestations and treatment of mucopolysaccharidosis type I patients in Latin America as compared with the rest of the world. AB - BACKGROUND: Mucopolysaccharidosis I (MPS I) comprises a spectrum of clinical manifestations and is divided into three phenotypes reflecting clinical severity: Hurler, Hurler-Scheie, and Scheie syndromes. There may be important variations in clinical manifestations of this genetic disease in patients residing in different regions of the world. METHODS: Using data from the MPS I Registry (as of September 2009), we evaluated patients from Latin America (n = 118) compared with patients from the rest of the world [ROW (n = 727)]. RESULTS: Phenotype distribution differed among patients in Latin America compared to ROW (Hurler 31 vs. 62%, Hurler-Scheie 36 vs. 21%, Scheie 10 vs. 11%, and unknown 22 vs. 6%). The frequency of certain symptoms, such as cardiac valve abnormalities, sleep impairment, and joint contractures, also differed between Latin America and ROW for some phenotypes. Median age at MPS I diagnosis was earlier in the ROW than Latin America for all phenotypes, and age at first treatment for Hurler and Hurler-Scheie patients was also earlier in the ROW. Hurler patients in Latin America showed a gap of 3.1 years between median ages of diagnosis and first treatment compared to only 0.5 years in the ROW. Treatment allocation in Latin America compared to ROW was as follows: enzyme replacement therapy (ERT) only, 80 vs. 45%; hematopoietic stem cell transplantation (HSCT) only, 0.9 vs. 27%; both ERT and HSCT, 0 vs. 16%; and neither treatment, 19 vs. 13%. CONCLUSION: These data highlight important differences in MPS I patients between Latin America and ROW in terms of phenotypic distribution, clinical manifestations, and treatment practices. PMID- 21541722 TI - Interrupting the mechanisms of brain injury in a model of maple syrup urine disease encephalopathy. AB - Maple syrup urine disease (MSUD) was first recognized as an inherited lethal encephalopathy beginning in the first week of life and associated with an unusual odor in the urine of affected children. It was later confirmed as a deficiency of branched-chain keto acid dehydrogenase (BCKDH), which is the second step in branched-chain amino acid (BCAA) breakdown. MSUD is characterized by BCAA and branched-chain keto acid (BCKA) accumulation. BCAAs are essential amino acids and powerful metabolic signals with severe consequences of both deprivation and accumulation. Treatment requires life-long dietary restriction and monitoring of BCAAs. However, despite excellent compliance, children commonly suffer metabolic decompensation during intercurrent illness resulting in life-threatening cerebral edema and dysmyelination. The mechanisms underlying brain injury have been poorly understood. Recent studies using newly developed mouse models of both classic and intermediate MSUD have yielded insight into the consequences of rapid BCAA accumulation. Additionally, these models have been used to test preliminary treatments aimed at competing with blood-brain barrier transport of BCAA using norleucine. Assessment of biochemical changes with and without treatment suggests different roles for BCAA and BCKA in the mechanism of brain injury. PMID- 21541723 TI - Proton nuclear magnetic resonance spectroscopic detection of oligomannosidic n glycans in alpha-mannosidosis: a method of monitoring treatment. AB - In Alpha-mannosidosis (MIM 248500) the patients accumulate mainly unbranched oligosaccharide chains in the lysosomes in all body tissues, including the brain. With ensuing therapeutic modalities in man (BMT and ERT) non-invasive methods of monitoring the effect of treatment are needed. Paramount is the possible effect of the treatment on the brain, since this organ is regarded as difficult to reach because of the blood-brain barrier. We therefore performed proton nuclear magnetic resonance spectroscopy (MRS) of the brain in two untreated patients, and a 16-year-old patient treated with BMT at the age of 10 to assess whether this non-invasive method could be applied in the monitoring of the accumulation of abnormal chemicals in the brain of patients. We found an abnormal peak that was not present in the treated patient. A similar pattern was also found in MRS of urine from patients, reflecting the concentration of oligosaccharides in serum and tissues. We therefore conclude that MRS can be a useful method to monitor the effect of treatment for Alpha-Mannosidosis. PMID- 21541725 TI - Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2-CDG): expression analysis of PMM2-CDG mutations. AB - Deficiency of phosphomannomutase (PMM2, MIM#601785) is the most common congenital disorder of glycosylation. Herein we report the genetic analysis of 22 Spanish PMM2 deficient patients and the functional analysis of 14 nucleotide changes in a prokaryotic expression system in order to elucidate their molecular pathogenesis. PMM2 activity assay revealed the presence of six protein changes with no enzymatic activities (p.R123Q, p.R141H, p.F157S, p.P184T, p.F207S and p.D209G) and seven mild protein changes with residual activities ranging from 16 to 54% (p.L32R, p.V44A p.D65Y, p.P113L p.T118S, p.T237M and p.C241S) and also one variant change with normal activity (p.E197A). The results obtained from Western blot analysis, degradation time courses of 11 protein changes and structural analysis of the PMM2 protein, suggest that the loss-of-function of most mutant proteins is based on their increased susceptibility to degradation or aggregation compared to the wild type protein, considering PMM2 deficiency as a conformational disease. We have identified exclusively catalytic protein change (p.D209G), catalytic protein changes affecting protein stability (p.R123Q and p.R141H), two protein changes disrupting the dimer interface (p.P113L and p.T118S) and several misfolding changes (p.L32R, p.V44A, p.D65Y, p.F157S, p.P184T, p.F207S, p.T237M and p.C241S). Our current work opens a promising therapeutic option using pharmacological chaperones to revert the effect of the characterized misfolding mutations identified in a wide range of PMM2 deficient patients. PMID- 21541724 TI - Mitochondrial DNA transcription regulation and nucleoid organization. AB - Mitochondrial biogenesis is a complex process depending on both nuclear and mitochondrial DNA (mtDNA) transcription regulation to tightly coordinate mitochondrial levels and the cell's energy demand. The energy requirements for a cell to support its metabolic function can change in response to varying physiological conditions, such as, proliferation and differentiation. Therefore, mitochondrial transcription regulation is constantly being modulated in order to establish efficient mitochondrial oxidative metabolism and proper cellular function. The aim of this article is to review the function of major protein factors that are directly involved in the process of mtDNA transcription regulation, as well as, the importance of mitochondrial nucleoid structure and its influence on mtDNA segregation and transcription regulation. Here, we discuss the current knowledge on the molecular mode of action of transcription factors comprising the mitochondrial transcriptional machinery, as well as the action of nuclear receptors on regulatory regions of the mtDNA. PMID- 21541726 TI - Nijmegen paediatric CDG rating scale: a novel tool to assess disease progression. AB - Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous inborn errors of metabolism. At present, treatment is available for only one CDG, but potential treatments for the other CDG are on the horizon. It will be vitally important in clinical trials of such agents to have a clear understanding of both the natural history of CDG and the corresponding burden of disability suffered by patients. To date, no multicentre studies have attempted to document the natural history of CDG. This is in part due to the lack of a reliable assessment tool to score CDG's diverse clinical spectrum. Based on our earlier experience evaluating disease progression in disorders of oxidative phosphorylation, we developed a practical and semi-quantitative rating scale for children with CDG. The Nijmegen Paediatric CDG Rating Scale (NPCRS) has been validated in 12 children, offering a tool to objectively monitor disease progression. We undertook a successful trial of the NPCRS with a collaboration of nine experienced physicians, using video records of physical and neurological examination of patients. The use of NPCRS can facilitate both longitudinal and natural history studies that will be essential for future interventions. PMID- 21541728 TI - [Erratum to: X-ray in trauma and orthopedic surgery.] PMID- 21541727 TI - Pre-attentive processing in children with early and continuously-treated PKU. Effects of concurrent Phe level and lifetime dietary control. AB - Sixty-four children, aged 7 to 14 years, with early-treated PKU, were compared with control children on visual evoked potential (VEP) amplitudes and latencies and auditory mismatch negativity (MMN) amplitudes. It was further investigated whether indices of dietary control would be associated with these evoked potentials parameters. There were no significant differences between controls and children with PKU in VEP- and MMN-indices. However, higher lifetime Phe levels were, in varying degree and stronger than concurrent Phe level, related to increased N75 amplitudes, suggesting abnormalities in attention, and longer P110 latencies, indicating a reduction in speed of neural processing, possibly due to deficits in myelination or reduced dopamine levels in brain and retina. Similarly, higher lifetime Phe levels and Index of Dietary Control (IDC) were associated with decreased MMN amplitudes, suggesting a reduced ability to respond to stimulus change and poorer triggering of the frontally mediated attention switch. In summary, the present study in children with PKU investigated bottom-up information processing, i.e., triggered by external events, a fundamental prerequisite for the individual's responsiveness to the outside world. Results provide evidence that quality of dietary control may affect the optimal development of these pre-attentive processes, and suggest the existence of windows of vulnerability to Phe exposure. PMID- 21541729 TI - [Modified Lambrinudi arthrodesis with additional posterior tibial tendon transfer in adult drop foot]. AB - OBJECTIVE: Treatment of adult instable drop foot by modified Lambrinudi arthrodesis (removal of a wedge between the talus and calcaneus), followed by a posterior tibial tendon transfer to the medial cuneiform in order to provide active dorsiflexion. INDICATIONS: Severe drop foot (of various etiologies) in combination with hindfoot instability. Sufficient function of the posterior tibial muscle. CONTRAINDICATIONS: Neurologic dysfunction of the posterior tibial muscle, infection of foot/hindfoot, Charcot arthropathy, and insufficient patient compliance. RELATIVE CONTRAINDICATIONS: Previous surgery of posterior tibial tendon, critical soft tissues/skin conditions, insufficient neurovascular conditions. SURGICAL TECHNIQUE: Lateral skin incision. Debridement of sinus tarsi and removal of the bifurcate ligament to expose the subtalar, calcaneocuboidal, and talonavicular joints. Resection of a bone wedge from the calcaneus and talus (25-30 degrees ) to correct the drop foot deformity. Cartilage removal from the calcaneocuboid joint. Debridement of both the talar head and the navicular to allow adequate fitting. After reduction (neutral dorsiflexion and 10 degrees foot abduction), preliminary fixation with Kirschner wires. Final fixation with canulated screws (talonavicular, calcaneocuboidal, and subtalar joints). Medial skin incision at the navicular tuberositas to deattach the posterior tibial tendon with a bony fragment. The tendon stump is harvested 10 cm proximal to the tibiotalar joint. Small skin incision at the anterolateral aspect of the distal lower leg. The posterior tibial tendon is transferred through the interosseous membrane and reattached to the medial cuneiform with a screw. POSTOPERATIVE MANAGEMENT: Immobilization with a removable short leg cast for 2-4 days. Ambulation with full weightbearing in a cast for 8 weeks. Radiographic assessment 8 weeks postoperatively. After bony healing, mobilization in normal shoes is allowed. Intensive physiotherapy to train the dorsiflexion. RESULTS: The average correction of drop foot deformity was 18.7 degrees . Active dorsiflexion increased significantly from 30 degrees preoperatively to 10 degrees postoperatively. PMID- 21541730 TI - Identification of change-points in the relationship between food groups in the Mediterranean diet and overall mortality: an 'a posteriori' approach. AB - BACKGROUND: Adherence to Mediterranean diet has been shown to be associated with a better health and greater survival. The aim of the present study was to identify change-points in the relationship between food groups composing Mediterranean diet and overall mortality. METHODS: The population of the Greek EPIC prospective cohort study (23,349 adult men and women in the Greek EPIC sample who had not previously been diagnosed as having cancer, coronary heart disease or diabetes mellitus at enrolment) was analysed. Segmented logistic regression analysis was conducted to examine the association between each of the food groups contributing to the Mediterranean diet score and overall mortality. RESULTS: This analysis allowed the determination of the following change-points: among men: 1 change-point for vegetables, legumes, cereals, fish and seafood and dairy products and 2 change-points for fruit and nuts, meat and meat products and ethanol; among women: 1 change-point for legumes and fish and seafood and 2 change-points for the remaining food groups. These cut-off points were used to construct an 'a posteriori' score that may be better in capturing the health promoting potential of the traditional Mediterranean diet. CONCLUSION: Identification of change-points in the relationship between components of the Mediterranean diet and mortality can be used to increase the discriminatory ability of a widely used Mediterranean diet score in relation to mortality. PMID- 21541731 TI - Is vitamin D status known among children living in Northern Italy? AB - PURPOSE: To assess vitamin D status in children aged 2-220 months in northeastern Italy (latitude 46 degrees ). Serum 25-hydroxyvitamin D (25OHD) concentration was assessed in 93 children afferent to the Pediatric Department of the Hospital of Udine. METHODS: Vitamin D status was defined as follows: sufficient with serum 25OHD between 50 and 250 nmol/l (level 4); insufficient between 37.5 and 50 nmol/l (level 3); deficient less than 37.5 nmol/l (level 2); severely deficient if less than 12.5 nmol/l (level 1). We investigated the potential risk factors of vitamin D deficit. RESULTS: We found that six children (6.4%) had level 1, 36 (38.7%) had level 2, 9 (9.7%) had level 3, and only 45.2% had sufficient level of 25OHD. Immigrate children had a higher risk for vitamin D deficiency if compared with Italians: 75% of non-Italian children had an insufficient 25OHD level compared with 47.0% of Italian children (p = 0.0036). There was a marked seasonal effect on 25OHD level: when plasma sample was withdrawn between November and May, only 29.4% of children showed sufficient vitamin D level, while 70.5% was insufficient (p < 0.0001). Among the obese children, 9.0% had sufficient level of 25OHD with 90% being deficient (p = 0.01). We did not find any significant difference in vitamin D status among children in different age groups. CONCLUSION: Vitamin D deficiency is common in children living in northeastern Italy. The risk factors were winter season for blood withdrawal, non-Caucasian race, and obesity. These high-risk groups should be targeted for screening and educated about the need of sunlight exposure. PMID- 21541732 TI - Eight weeks of conjugated linoleic acid supplementation has no effect on antioxidant status in healthy overweight/obese Korean individuals. AB - PURPOSE: The aim of this study was to evaluate the effect of CLA supplementation on antioxidant metabolism in healthy overweight/obese Korean individuals. METHODS: We performed a randomized, double-blind, placebo-controlled trial, where 29 healthy overweight/obese (BMI >= 23 kg/m(2)) participants (2 men and 27 women) were randomly selected to receive placebo (n = 15, 2.4 g olive oil/day) or 2.4 g/day CLA mixture (n = 14, 36.9% of cis-9, trans-11 and 37.9% of trans-10, cis 12) for 8 weeks. RESULTS: There were no significant differences in plasma total radical-trapping antioxidant potential (TRAP), lipid peroxidation (conjugated dienes), lipid-soluble antioxidant vitamin concentration, erythrocyte antioxidant enzyme (superoxide dismutase, catalase, glutathione peroxidase) activities, and leukocyte DNA damage between the CLA and placebo groups. CONCLUSIONS: The data suggest that short-term supplementation (8 weeks) with CLA (2.4 g/day) might have no significant effects on lipid peroxidation and antioxidant metabolism. PMID- 21541733 TI - ESR1 amplification is rare in breast cancer and is associated with high grade and high proliferation: a multiplex ligation-dependent probe amplification study. AB - BACKGROUND: Expression of estrogen receptor alpha (ERalpha) is predictive for endocrine therapy response and an important prognostic factor in breast cancer. Overexpression of ERalpha can be caused by estrogen receptor 1 (ESR1) gene amplification and was originally reported to be a frequent event associated with a significantly longer survival for ER-positive women treated with adjuvant tamoxifen monotherapy, which was however questioned by subsequent studies. METHODS: This study aimed to reanalyze the frequency of ESR1 amplification by multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridisation (FISH), and to assess clinicopathologic correlations. MLPA was performed in a group of 135 breast cancer patients, and gains/amplifications were subjected to FISH. RESULTS: True ESR1 amplification by MLPA was rare (2%) and only 6% more patients showed a modest gain of ESR1. All MLPA-detected ESR1 amplifications and nearly all ESR1 gains were also FISH amplified and gained, but not all FISH amplifications/gains were MLPA amplified/gained, leading to an overall concordance of only 60% between both techniques. All 3 MLPA and FISH ESR1 amplified cases had high ERalpha expression, but there was no obvious correlation between ESR1 gain and ER status by IHC. ESR1 gains/amplifications were not associated with HER2 gain/amplification, but seemed to be associated with older age. Surprisingly, ESR1 gain/amplification was not associated with low grade as reported previously, but correlated with high grade and high proliferation. Furthermore, ESR1 gain/amplification by MLPA was not associated with nodal status or tumor size (pT status). CONCLUSIONS: ESR1 amplification as detected by MLPA is rare in breast cancer, and seems to be associated with high ERalpha expression, high age, high grade and high proliferation. This study confirms previous studies that showed differences in the ESR1 amplification frequencies detected by different techniques. PMID- 21541734 TI - Genetic profile of adenoid cystic carcinomas (ACC) with high-grade transformation versus solid type. AB - BACKGROUND: ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features, and to compare results to solid ACC. METHODS: Genome wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, four with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), and five solid ACC. In addition, Ki67 index and p53 immunopositivity was assessed. RESULTS: ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component. CONCLUSION: ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC. PMID- 21541735 TI - Midlife muscle strength and human longevity up to age 100 years: a 44-year prospective study among a decedent cohort. AB - We studied prospectively the midlife handgrip strength, living habits, and parents' longevity as predictors of length of life up to becoming a centenarian. The participants were 2,239 men from the Honolulu Heart Program/Honolulu-Asia Aging Study who were born before the end of June 1909 and who took part in baseline physical assessment in 1965-1968, when they were 56-68 years old. Deaths were followed until the end of June 2009 for 44 years with complete ascertainment. Longevity was categorized as centenarian (>=100 years, n = 47), nonagenarian (90-99 years, n = 545), octogenarian (80-89 years, n = 847), and <=79 years (n = 801, reference). The average survival after baseline was 20.8 years (SD = 9.62). Compared with people who died at the age of <=79 years, centenarians belonged 2.5 times (odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.23-5.10) more often to the highest third of grip strength in midlife, were never smokers (OR = 5.75 95% CI = 3.06-10.80), had participated in physical activity outside work (OR = 1.13 per daily hour, 95% CI = 1.02-1.25), and had a long-lived mother (>=80 vs. <=60 years, OR = 2.3, 95% CI = 1.06-5.01). Associations for nonagenarians and octogenarians were parallel, but weaker. Multivariate modeling showed that mother's longevity and offspring's grip strength operated through the same or overlapping pathway to longevity. High midlife grip strength and long-lived mother may indicate resilience to aging, which, combined with healthy lifestyle, increases the probability of extreme longevity. PMID- 21541736 TI - Opportunities and limitations of drug-coated balloons in interventional therapies. AB - Drug-coated balloons (DCB) represent a novel clinical treatment modality for coronary and peripheral artery disease. Advantages over standard angioplasty and stent technologies including homogeneous drug delivery to the vessel wall, immediate drug release without the use of a polymer, the option of using balloon catheters alone or in combination with a bare metal stent, no foreign object that remains in the body, the potential of reducing antiplatelet therapy, and lower restenosis rates in some indications. As with drug-eluting stents (DES), one cannot assume a class effect for DCB. So far, data from randomized clinical trials identify the treatment of coronary in-stent restenosis (ISR) and of de novo and restenotic lesions in peripheral artery disease as viable options. Furthermore, treatment of de novo lesions in small coronary vessels, bifurcation lesions, long lesions, pediatric interventions, and cerebrovascular applications are potential beneficial indications. In the coronary application, a strategy of DCB angioplasty with provisional spot-stenting in the case of severe dissections may become a better alternative in long and complex lesions, bifurcations, or in patients with contraindications for DES. PMID- 21541737 TI - [Treatment strategies for chronic total occlusion: current status and outlook]. AB - The present article discusses the current status of treatment strategies for chronic total occlusion (CTO) and the prospects offered by new therapies. The indication for revascularisation recognized in the current European guidelines includes the presence of typical symptoms and evidence of ischemia of over 10% of the total myocardium, while in patients with multiple vascular diseases the aim is complete revascularisation. Although the vast majority of patients with CTO fulfil these criteria, they are currently not receiving interventional treatment as frequently as expected. The reasons often given for this include the low success rates and high recurrence rates. However, both problems have been improved by drug-eluting stents (DES) on the one hand and by wire techniques and strategies on the other, such that results almost comparable with non-occluded coronary lesions can be achieved. While more advanced approaches like retrograde recanalization should be restricted to specialized centres, marked improvements can be achieved even without these special techniques by means of consistent further training and the application of modern techniques. Despite the aggressiveness of these approaches to pass through an occluded artery, the complication rate is not higher than with non-occluded lesions when the specific complications of recanalization are avoided in a careful approach. Further technical improvements are expected with the use of modern imaging techniques such as intravascular ultrasound and high-resolution CT imaging of coronary arteries. PMID- 21541738 TI - New strategies in the treatment of coronary bifurcations. AB - Despite major improvements in stent technology (i.e., drug-eluting stents, DES), treatment of coronary bifurcations is an ever occurring problem of the interventional cardiology. While stenting the main branch with provisional side branch stenting seems to be the prevailing approach, in the era of DES various two-stent techniques emerged (crush) or were re-introduced (V or simultaneous kissing stents, crush, T, culottes, etc.) to allow stenting in the side branch when needed. New techniques in imaging like optical coherence tomography help in better understanding bifurcation anatomy and, thus, have the potential to help us better treat this challenging subset of lesions. In addition, new dedicated bifurcation stents have been proposed in an attempt to overcome limitations associated with current approaches, and they showed promising results in early studies; however, the safety and the efficacy of these devices remain to be seen in the ongoing and upcoming trials. This review focuses on the current approaches and the development of new techniques employed for the treatment of bifurcation disease. PMID- 21541739 TI - A Curtin-Hammett mechanism for the copolymerization of ethylene and methyl acrylate monomer using a PymNox nickel catalyst as revealed by DFT computational studies. AB - In this work, the copolymerization of ethylene and methyl acrylate (MA) as catalyzed by a new Ni-based PymNox organometallic compound was studied computationally. We recently tested the behavior of this type of catalyst in ethylene homopolymerization. Experimental results show that the unsubstituted catalyst Ni2 (aldimino PymNox catalyst) is unable to incorporate the MA monomer, whereas methyl-substituted Ni1 (acetaldimino PymNox catalyst) is able to achieve copolymerization. The reactivities of both catalysts were examined using density functional theory (DFT) models. Based on energy profiles calculated at the BP86 level, a Curtin-Hammett mechanism was proposed to explain the different reactivities of the catalysts in ethylene/MA copolymerization. Our results indicate that the methyl substituent Ni1 introduces additional steric hindrance that results in a catalyst conformation that is better suited to polar monomer incorporation. This model provides insights into the design of new catalysts to produce polar functionalized copolymers based on ethylene. PMID- 21541740 TI - In silico investigations of possible routes of assembly of ORF 3a from SARS-CoV. AB - ORF 3a of human severe acute respiratory syndrome corona virus (SARS-CoV) has been identified as a 274 amino acid membrane protein. When expressed in Xenopus oocytes the protein forms channels. Based on bioinformatics approaches the topology has been identified to include three transmembrane domains (TMDs). Since structural models from experiments are still lacking, computational methods can be challenged to generate such models. In this study, a 'sequential approach' for the assembly is proposed in which the individual TMDs are assembled one by one. This protocol is compared with a concerted protocol in which all TMDs are assembled simultaneously. The role of the loops between the TMDs during assembly of the monomers into a bundle is investigated. Molecular dynamics simulations for 20 ns are performed as a short equilibration to assess the bundle stability in a lipid environment. The results suggest that bundles are likely with the second TMD facing the putative pore. All the putative bundles show water molecules trapped within the lumen of the pore with only occasional events of complete crossing. PMID- 21541741 TI - Molecular dynamics simulations of nafion and sulfonated poly ether sulfone membranes II. Dynamic properties of water and hydronium. AB - We measured the self-diffusion coefficients of water in a Nafion membrane and two sulfonated polyethersulfone (SPES) membranes with varying ion-exchange capacities (IEC) in terms of relative humidity using the pulse field gradient NMR (PFG-NMR) technique. The self-diffusion coefficients were plotted against the number of water molecules per sulfonic acid group, lambda, and compare these values with the results of molecular dynamics (MD) simulations. Classical MD simulations for all membranes were carried out using a consistent force field at lambda = 3, 6, 9, 12, and 15. The dynamic properties of water (H(2)O) and hydronium (H(3)O(+)) on a molecular level were estimated as self-diffusion coefficients and residence times around a sulfonate group ([Formula: see text]). The diffusion coefficients of H(2)O and H(3)O(+) followed the order, Nafion > SPES with IEC = 1.4 > SPES with IEC = 1.0 > SPES with IEC = 0.75, which agreed with the experimental data. The residence time distribution of H(2)O around [Formula: see text] in Nafion was in the range of 1-6 ps, whereas H(2)O in the SPES exhibited a residence time of greater than 20 ps. PMID- 21541742 TI - Sigma-holes, pi-holes and electrostatically-driven interactions. AB - A positive pi-hole is a region of positive electrostatic potential that is perpendicular to a portion of a molecular framework. It is the counterpart of a sigma-hole, which is along the extension of a covalent bond to an atom. Both sigma-holes and pi-holes become more positive (a) in going from the lighter to the heavier atoms in a given Group of the periodic table, and (b) as the remainder of the molecule is more electron-withdrawing. Positive sigma- and pi holes can interact in a highly directional manner with negative sites, e.g., the lone pairs of Lewis bases. In this work, the complexes of 13 pi-hole-containing molecules with the nitrogen lone pairs of HCN and NH(3) have been characterized computationally using the MP2, M06-2X and B3PW91 procedures. While the electrostatic interaction is a major driving force in pi-hole bonding, a gradation is found from weakly noncovalent to considerably stronger with possible indications of some degree of coordinate covalency. PMID- 21541743 TI - Insight into the reaction mechanism of cis,cis-muconate lactonizing enzymes: a DFT QM/MM study. AB - MLEs derived from mycobacterium smegmatis and seudomonas fluorescens share ~76% identity and have a very similar arrangement of catalytic residues in their active site configuration. However, while they catalyze the conversion of cis,cis muconate to the same achiral product, muconolactone, studies in deuterated solvent surprisingly show that the cyclo-isomerization proceeds with the formation of a chiral product. In this paper we discuss the application of DFT QM/MM calculations on both MLEs, to our knowledge the first reported in the literature on this protein. We investigate the proposal that the base involved in the catalytic reaction is the lysine residue found at the end of the 2(nd) strand given: (a) that the lysine residue at the end of the 6(th) strand is in an apparently equally effective position to catalyze reaction and (b) that the structural related epimerase in-fact achieve their stereo-specific outcomes by relying on either the base from the 2(nd) or 6(th) strand. PMID- 21541744 TI - Investigation of the acylation mechanism of class C beta-lactamase: pKa calculation, molecular dynamics simulation and quantum mechanical calculation. AB - beta-Lactamases are bacterial enzymes that act as a bacterial defense system against beta-lactam antibiotics. beta-Lactamase cleaves the beta-lactam ring of the antibiotic by a two step mechanism involving acylation and deacylation steps. Although class C beta-lactamases have been investigated extensively, the details of their mechanism of action are not well understood at the molecular level. In this study, we investigated the mechanism of the acylation step of class C beta lactamase using pKa calculations, molecular dynamics (MD) simulations and quantum mechanical (QM) calculations. Serine64 (Ser64) is an active site residue that attacks the beta-lactam ring. In this study, we considered three possible scenarios for activation of the nucleophile Ser64, where the activation base is (1) Tyrosine150 (Tyr150), (2) Lysine67 (Lys67), or (3) substrate. From the pKa calculation, we found that Tyr150 and Lys67 are likely to remain in their protonated states in the pre-covalent complex between the enzyme and substrate, although their role as activator would require them to be in the deprotonated state. It was found that the carboxylate group of the substrate remained close to Ser64 for most of the simulation. The energy barrier for hydrogen abstraction from Ser64 by the substrate was calculated quantum mechanically using a large truncated model of the enzyme active site and found to be close to the experimental energy barrier, which suggests that the substrate can initiate the acylation mechanism in class C beta-lactamase. PMID- 21541745 TI - Instability of C60 fullerene interacting with lipid bilayer. AB - Due to the large number of possible applications of nanoparticles in cosmetic and medical products, the possible hazards of nanoparticles in the human body are a major concern. A worst-case scenario is that nanoparticles might cause health issues such as skin damage or even induce cancer. As a first step to study the toxicity of nanoparticles, we investigate the energy behaviour of a C(60) fullerene interacting with a lipid bilayer. Using the 6-12 Lennard-Jones potential function and the continuous approximation, the equilibrium spacing between the two layers of a bilayer is predicted to be 3.36 A. On assuming that there is a circular hole in the lipid bilayer, a relation for the molecular interaction energy is determined, involving the circular radius b of the hole and the perpendicular distance Z of the spherical fullerene from the hole. A graph of the minimum energy location Z ( min ) verses the hole radius b shows that a C(60) fullerene first penetrates through a lipid bilayer when b > 6.81 A, and shows a simple circular relation [Formula: see text] for Z ( min ) positive and b <= 6.81 A. For b > 6.81, the fullerene relocates from the surface of the bilayer to the interior, and as the hole radius increases further it moves to the centre of the bilayer and remains there for increasing hole radii. Accordingly, our modelling indicates that at least for the system with no external forces, the C(60) fullerene will not penetrate through the lipid bilayer but rather remains encased between the two layers at the mid-plane location. PMID- 21541746 TI - Comparative modeling of 25-hydroxycholesterol-7alpha-hydroxylase (CYP7B1): ligand binding and analysis of hereditary spastic paraplegia type 5 CYP7B1 mutations. AB - CYP7B1 mutations have been linked directly with the neurodegenerative disease hereditary spastic paraplegia (HSP), with mutations in the CYP7B1 gene identified as being directly responsible for autosomal recessive HSP type 5A (SPG5). To evaluate the potential impact of CYP7B1 mutations identified in SPG5 on binding and protein function, a comparative model of cytochrome P450 7B1 (CYP7B1) was constructed using human CYP7A1 as a template during model construction. The secondary structure was predicted using the PSIPRED and GOR4 prediction methods, the lowest energy CYP7B1 model was generated using MOE, and then this model was assessed in terms of stereochemical quality and the side chain environment using RAMPAGE, Verify3D and ProSA. Evaluation of the active site residues of the CYP7B1 model and validation of the active site architecture were performed via molecular docking experiments: the docking of the substrates 25-hydroxycholesterol and 27 hydroxycholesterol and the inhibitor 3alpha-Adiol identified structurally and functionally important residues. Mutational analysis of CYP7B1 amino acid mutations related to hereditary spastic paraplegia type 5 considered phosphorylation, ligand/substrate binding and the structural roles of mutated amino acid residues, with R112, T297 and S363 mutations expected to have a direct impact on ligand binding, while mutations involving R417 would indirectly affect ligand binding as a result of impairment in catalytic function. PMID- 21541747 TI - Study of the interaction between 8-azaguanine and bovine serum albumin using optical spectroscopy and molecular modeling methods. AB - The interaction between 8-azaguanine (8-Azan) and bovine serum albumin (BSA) in Tris-HCl buffer solutions at pH 7.4 was investigated by means of fluorescence and ultraviolet-visible (UV-Vis) spectroscopy. At 298 K and 310 K, at a wavelength of excitation (lambda (ex)) of 282 nm, the fluorescence intensity decreased significantly with increasing concentrations of 8-Azan. Fluorescence static quenching was observed for BSA, which was attributed to the formation of a complex between 8-Azan and BSA during the binding reaction. This was illuminated further by the UV-Vis absorption spectra and the decomposition of the fluorescence spectra. The thermodynamic parameters ?G, ?H, ?S were calculated. The results showed that the forces acting between 8-Azan and BSA were typical hydrophobic forces, and that the interaction process was spontaneous. The interaction distance r between 8-Azan and BSA, evaluated according to fluorescence resonance energy transfer theory, suggested that there is a high possibility of energy transfer from BSA to 8-Azan. Theoretical investigations based on homology modeling and molecular docking suggested that binding between 8 Azan and BSA is dominated by hydrophilic forces and hydrogen bonding. The theoretical investigations provided a good structural basis to explain the phenomenon of fluorescence quenching between 8-Azan and BSA. PMID- 21541748 TI - Geometric distortions on a three-coordinated T1 Cu site model as a potential strategy to modulate redox potential. A theoretical study. AB - A model of the three-coordinated T1 Cu site from Trametes versicolor was considered to evaluate the effect on redox potential of geometrical distortions in the copper coordination sphere. Systematic modifications of geometrical parameters (distances and angles) of the coordination sphere of the T1 Cu site were carried out within a density functional theory (DFT) framework, to evaluate their effects on electron affinity directly related to redox potential. The most promising result in terms of redox potential increment was distortion of the dihedral angle C(methylthiolate)-S-Cu-N(ImA) (omega), which can be rationalized as a decrease in the overlap of imidazole orbitals in the redox-active molecular orbital (beta-LUMO). This overlap is minimized when omega achieves the value of 10 degrees , therefore, this conformation might have the highest redox potential. From the molecular orbital viewpoint, a parallelism was found between the effect caused by the presence of a fourth ligand and the distorted three-coordination, which could be extrapolated to spectroscopic properties. It was also found that solvation effects on the redox potentials during geometrical distortions produce a very similar tendency, independently of the polarity of the solvent. PMID- 21541749 TI - Combining molecular dynamics and docking simulations of the cytidine deaminase from Mycobacterium tuberculosis H37Rv. AB - Cytidine Deaminase (CD) is an evolutionarily conserved enzyme that participates in the pyrimidine salvage pathway recycling cytidine and deoxycytidine into uridine and deoxyuridine, respectively. Here, our goal is to apply computational techniques in the pursuit of potential inhibitors of Mycobacterium tuberculosis CD (MtCDA) enzyme activity. Molecular docking simulation was applied to find the possible hit compounds. Molecular dynamics simulations were also carried out to investigate the physically relevant motions involved in the protein-ligand recognition process, aiming at providing estimates for free energy of binding. The proposed approach was capable of identifying a potential inhibitor, which was experimentally confirmed by IC(50) evaluation. Our findings open up the possibility to extend this protocol to different databases in order to find new potential inhibitors for promising targets based on a rational drug design process. PMID- 21541750 TI - The intraperitoneal inoculation of Lactobacillus casei in mice induces total protection against Trichinella spiralis infection at low challenge doses. AB - The following effects of Lactobacillus casei in NIH mice were evaluated: the establishment of Trichinella spiralis adult worms in the intestine (AWI), larvae per gram of muscle tissue (LPG), levels of IgG and IgA, and levels of IL-4 and IFN-gamma. One hundred and eight mice were allocated at random into 18 groups of six mice each. Each mouse in treated or non-treated groups was inoculated intraperitoneally once a week during 6 weeks with L. casei or phosphate-buffered solution. Later each mouse was challenged either with 200, 50, or 25 T. spiralis infective larvae. When the infection dose was 200 T. spiralis infective larvae, the reductions in AWI were 78.6% at 4 days after infection (dai) and 76.7% at 10 dai; while the reduction of LPG was 80.9% with respect to control groups. When the infection dose was 50 or 25 T. spiralis infective larvae, the reductions of AWI were 100% both at 4 and 10 dai; while the reduction of LPG at 30 dai was also 100% with respect to control groups. The levels of IgG and IgA anti-T. spiralis and IL-4 were significantly higher (P < 0.01) at 4 and 10 dai in mice from groups treated with L. casei than in animals in control groups; while at 10 dai, the levels of IFN-gamma were higher in control mice (P < 0.01) than in L. casei treated animals. The results suggest that frequent treatment of mice with L. casei induces a total protection against infection with low doses of T. spiralis. PMID- 21541751 TI - Genital myiasis by Wohlfahrtia magnifica (Diptera, Sarcophagidae) in Sicily (Italy). AB - Wohlfahrtia magnifica (Schiner, 1862; Diptera: Sarcophagidae), known also as flesh fly or screwworm, is a fly distributed especially in south Europe, Middle East, North Africa and China. Maggots of W. magnifica are responsible for traumatic myiasis in warm-blooded vertebrate animals and humans. In Italy data on wohlfahrtiosis in animals and humans are scant. This paper reports three cases of genital myiasis by W. magnifica in Sicily that occurred in a goat, a ram and a dog, respectively. Maggots were found in the vulva of a goat, in a wound localised in the scrotum of a ram and in the prepuce of a dog. Although the disease was not recorded before in the region, data collected from a questionnaire specifically designed for the study suggest that the disease is endemic in the area for more than 20 years. Larger epidemiological studies in the region are needed to get more data on disease prevalence and pattern of infestation as well as more information and education is needed for both farmers and veterinarians on wohlfahrtiosis and its strategies of control and treatment. PMID- 21541752 TI - Contact and fumigant toxicity of hexane flower bud extract of Syzygium aromaticum and its compounds against Pediculus humanus capitis (Phthiraptera: Pediculidae). AB - The head lice, Pediculus humanus capitis De Geer is an obligate ectoparasite of humans that causes pediculosis capitis, a nuisance for millions of people worldwide, with high prevalence in children. P. humanus capitis has been treated by methods that include the physical remotion of lice, various domestic treatments, and conventional insecticides. None of these methods render complete protection, and there is clear evidence for the evolution of resistance and cross resistance to conventional insecticides. Non-toxic alternative options are hence needed for head lice treatment and/or prevention, and natural products from plants are good candidates for safer control agents that may provide good anti lice activity. The plant extracts are good and safe alternatives due to their low toxicity to mammals and easy biodegradability. The present study carried out the pediculocidal activity using the hexane flower bud extract of Syzygium aromaticum (Myrtaceae) against P. humanus capitis examined by direct contact and fumigant toxicity (closed- and open-container methods) bioassay. The chemical composition of S. aromaticum flower bud hexane extract was analyzed by gas chromatography mass spectrometry. The major chemical constituent (58.79%) of flower bud hexane extract S. aromaticum was identified as chavibetol (5-allyl-2-methoxyphenol) by comparison of mass spectral data and retention times. The hexane extract of S. aromaticum was subjected to gas chromatography analysis, and totally 47 compounds were detected, of which chavibetol was predominantly present. The other major constituents present in the hexane extract were eugenol acetate (phenol,2-methoxy 4-(2-propenyl)-,acetate (15.09%), caryophyllene-(I1) (2,6,10,10-tetramethyl bicyclo [7.2.0] undeca-1,6-diene (13.75%), caryophyllene oxide (3.04%), 2,6,6,9 tetramethyl-1,4,8-cycloundecatriene (1.67%), and copaene (1.33%). The filter paper contact bioassay study showed pronounced pediculicidal activity in the flower bud hexane extract of S. aromaticum. The toxic effect was determined for every five in an 80-min treatment. The result showed percent mortality of 40, 82, and 100 at 5, 10, and 20 min, and the median lethal time (LT(50)) value was 5.83 (0.5 mg/cm(2)); 28, 82, and 100 at 5, 10, and 30 min. (LT(50) = 6.54; 0.25 mg/cm(2)); and 13, 22, 42, 80, and 100 at 5, 10, 20, 40, and 80 min (LT(50) = 18.68; 0.125 mg/cm(2)), respectively. The vapor phase toxicity was tested at 0.25 mg/cm(2). There was a significant difference in pediculicidal activity of S. aromaticum extract against P. humanus capitis between closed- and open-container methods. Adult mortalities were determined for every five in 60 min (closed method) and for every ten in 180 min (open method). The closed method showed the percent mortality was 45, 88, and 100 at 5, 10, and 15 min (LT(50) = 5.39), respectively. In the open-container method, the percent mortality was observed 5, 20, 47, 84, and 100 at 10, 20, 60, 120, and 180 min (LT(50) = 47.91), respectively. The mortality was more effective in the closed containers than in open ones, indicating that the effect of hexane extract was largely a result of action in the vapor phase exhibited fumigant toxicity. Studies of anti-lice activity of extract provide the basis for preliminary conclusions of structure activity relationships; although no clear patterns can yet be drawn. We here attempt to provide a concise compilation of the available information on anti lice activity of plant extracts and plant-derived compounds. PMID- 21541753 TI - Seroprevalence of Toxoplasma gondii infection among immigrant and native pregnant women in Eastern Spain. AB - In European countries, toxoplasma antenatal screening is recommended to prevent toxoplasmosis. The seroprevalence of these infections in immigrants can be different than in native population. From February 2006 to June 2010, a cross sectional study was carried out in all pregnant women attended at a reference unit in Elche, Spain. An enzyme immunoassay was used for detection of IgG antibodies against Toxoplasma gondii. For each immigrant woman, one Spanish pregnant woman of the same age cared for in the same day was recruited (Spanish control group). A total of 1,627 migrant pregnant women participated in this study. The adherence to screening among migrants was 91.9% (95% CI, 90.5-93.1%), similar than that found in Spaniards (92.2%; 95% CI, 90.8-93-4%). Among migrant women, 619 were positive for IgG anti-T. gondii antibodies (41.4%; 95% CI, 38.9 43.9%), compared with 12.0% (95% CI, 10.5-13.8%) among Spaniards (odds ratio (OR), 5.2 (95% CI, 4.3-6.3). Seroprevalence in pregnant women from Latin America, northern Africa, Eastern Europe, Africa Sub-Saharan and Western Europe was higher than in the Spanish control group (OR, 5.4, 5.8, 6.5, 5.4, and 2.4, respectively; p < 0.001). No Asian pregnant woman was immune. Seroprevalence increased with increasing age in migrant pregnant women: 15-25 years, 38.2%; 26-35 years, 40.7%; and 36-45 years, 52.8%. The seroprevalence of T. gondii infection in migrant pregnant women living in Spain was higher than in the native population. However, no cases were found in Asian immigrants, highlighting the importance of primary prevention of this infection in pregnant women coming from that geographic region. PMID- 21541754 TI - Multiplex PCR identification of Taenia spp. in rodents and carnivores. AB - The genus Taenia includes several species of veterinary and public health importance, but diagnosis of the etiological agent in definitive and intermediate hosts often relies on labor intensive and few specific morphometric criteria, especially in immature worms and underdeveloped metacestodes. In the present study, a multiplex PCR, based on five primers targeting the 18S rDNA and ITS2 sequences, produced a species-specific banding patterns for a range of Taenia spp. Species typing by the multiplex PCR was compared to morphological identification and sequencing of cox1 and/or 12S rDNA genes. As compared to sequencing, the multiplex PCR identified 31 of 32 Taenia metacestodes from rodents, whereas only 14 cysts were specifically identified by morphology. Likewise, the multiplex PCR identified 108 of 130 adult worms, while only 57 were identified to species by morphology. The tested multiplex PCR system may potentially be used for studies of Taenia spp. transmitted between rodents and carnivores. PMID- 21541755 TI - Antiplasmodial activity of artecyclopentyl mether a new artemisinin derivative and its effect on pathogenesis in Plasmodium yoelii nigeriensis infected mice. AB - In an effort to evaluate novel derivatives from artemisinin, possessing potential antimalarial activity, a new derivative artecyclopentyl mether (CPM-1) was derivatized and evaluated for its dose-dependent efficacy in Plasmodium yoelii nigeriensis infected mice. The survivability of mice at 7.5 mg/kg was >28 days with negligible parasitaemia and recovered anemia (66.16-72.62%). Artecyclopentyl mether was also found to modulate the pro- and anti-inflammatory cytokines (IFN gamma, 39.64-56.92%; TNF, 49.10-74.31%; IL-4, 11.53-43.22%; IL-10, 37.60-53.52%) favourably besides optimizing the oxidative stress to the infected subjects as evident by the nitric oxide (88.76-95.43%), lipid peroxidation (59.30-76.05%) and glycaemic data (62.70-76.66%). The results indicate the potentiality of the new derivative as an antimalarial against asexual stages of the parasite. PMID- 21541756 TI - Fasciola hepatica: time-dependent disruption of spermatogenesis following in vivo treatment with triclabendazole. AB - Sheep infected with the Cullompton isolate of Fasciola hepatica were treated with triclabendazole at a concentration of 10 mg/kg at 12 weeks post-infection. Adult flukes were recovered from the liver and, where present, from the gall bladder at 48, 72 and 96 h post-treatment (pt). Gross changes to the spermatogenic cells of the testis were examined by histology and ultrastructural alterations were visualised via transmission electron microscopy. Disruption was progressive in nature, with the testis tubules becoming shrunken, vacuolated and gradually more denuded of cellular content over the 96-h time period. From 48 h pt, the number of primary and secondary spermatogonia decreased and multinucleate spermatogonial cells were frequent. Later, developmental stages were uncommon, giving rise to much empty space within the tubules. By 72 h pt, the tubules contained many apoptotic and degraded cells and had an extremely disorganised appearance. At 96 h pt, the tubules were almost completely empty, with the exception of the remains of degraded spermatogenic cells. These results indicate that triclabendazole severely disrupts spermatogenesis in the liver fluke from 48 h pt in vivo. PMID- 21541757 TI - System consolidation of memory during sleep. AB - Over the past two decades, research has accumulated compelling evidence that sleep supports the formation of long-term memory. The standard two-stage memory model that has been originally elaborated for declarative memory assumes that new memories are transiently encoded into a temporary store (represented by the hippocampus in the declarative memory system) before they are gradually transferred into a long-term store (mainly represented by the neocortex), or are forgotten. Based on this model, we propose that sleep, as an offline mode of brain processing, serves the 'active system consolidation' of memory, i.e. the process in which newly encoded memory representations become redistributed to other neuron networks serving as long-term store. System consolidation takes place during slow-wave sleep (SWS) rather than rapid eye movement (REM) sleep. The concept of active system consolidation during sleep implicates that (a) memories are reactivated during sleep to be consolidated, (b) the consolidation process during sleep is selective inasmuch as it does not enhance every memory, and (c) memories, when transferred to the long-term store undergo qualitative changes. Experimental evidence for these three central implications is provided: It has been shown that reactivation of memories during SWS plays a causal role for consolidation, that sleep and specifically SWS consolidates preferentially memories with relevance for future plans, and that sleep produces qualitative changes in memory representations such that the extraction of explicit and conscious knowledge from implicitly learned materials is facilitated. PMID- 21541758 TI - Atrial-selective sodium channel block by dronedarone: sufficient to terminate atrial fibrillation? PMID- 21541759 TI - Proteomic analysis of NME1/NDPK A null mouse liver: evidence for a post translational regulation of annexin IV and EF-1Balpha. AB - NME/NDPK family proteins are involved in the control of intracellular nucleotide homeostasis as well as in both physiological and pathological cellular processes, such as proliferation, differentiation, development, apoptosis, and metastasis dissemination, through mechanisms still largely unknown. One family member, NME1/NDPK-A, is a metastasis suppressor, yet the primary physiological functions of this protein are still missing. The purpose of this study was to identify new NME1/NDPK-A-dependent biological functions and pathways regulated by this gene in the liver. We analyzed the proteomes of wild-type and transgenic NME1-null mouse livers by combining two-dimensional gel electrophoresis and mass spectrometry (matrix-assisted laser desorption/ionization time of flight and liquid chromatography-tandem mass spectrometry). We found that the levels of three proteins, namely, phenylalanine hydroxylase, annexin IV, and elongation factor 1 Balpha (EF-1Balpha), were strongly reduced in the cytosolic fraction of NME1(-/-) mouse livers when compared to the wild type. This was confirmed by immunoblotting analysis. No concomitant reduction in the corresponding messenger RNAs or of total protein level was observed, however, suggesting that NME1 controls annexin IV and EF-1Balpha amounts by post-translational mechanisms. NME1 deletion induced a change in the subcellular location of annexin IV in hepatocytes resulting in enrichment of this protein at the plasma membrane. We also observed a redistribution of EF-1Balpha in NME1(-/-) hepatocytes to an intracytoplasmic compartment that colocalized with a marker of the reticulum endoplasmic. Finally, we found reduced expression of annexin IV coincident with decreased NME1 expression in a panel of different carcinoma cell lines. Taken together, our data suggest for the first time that NME1 might regulate the subcellular trafficking of annexin IV and EF-1Balpha. The potential role of these proteins in metastatic dissemination is discussed. PMID- 21541761 TI - Intravascular mucinosis: a rare cause of cerebral infarction. PMID- 21541760 TI - Idebenone inhibition of glutamate release from rat cerebral cortex nerve endings by suppression of voltage-dependent calcium influx and protein kinase A. AB - The present study was aimed at investigating the effect and the possible mechanism of idebenone on endogenous glutamate release in nerve terminals of rat cerebral cortex (synaptosomes). Idebenone inhibited the release of glutamate that was evoked by exposing synaptosomes to the K(+) channel blocker 4-aminopyridine (4-AP), and this phenomenon was concentration dependent. Inhibition of glutamate release by idebenone was prevented by chelating extracellular Ca(2+), or by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to DL-threo beta-benzyl-oxyaspartate, a glutamate transporter inhibitor. Idebenone decreased the depolarization-induced increase in the cytosolic free Ca(2+) concentration ([Ca(2+)](C)),whereas it did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization. The inhibitory effect of idebenone on evoked glutamate release was prevented by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels, but not by blocking intracellular Ca(2+) release or Na(+)/Ca(2+) exchange. Furthermore, the idebenone effect on 4-AP-evoked Ca(2+) influx and glutamate release was completely abolished by the protein kinase A (PKA) inhibitors, H89 and KT5720. On the basis of these results, it was concluded that idebenone inhibits glutamate release from rat cortical synaptosomes and this effect is linked to a decrease in [Ca(2+)](C) contributed by Ca(2+) entry through presynaptic voltage-dependent Ca(2+) channels and to the suppression of PKA signaling cascade. PMID- 21541762 TI - Expression analysis of dopaminergic neurons in Parkinson's disease and aging links transcriptional dysregulation of energy metabolism to cell death. AB - Dopaminergic (DA) neuron degeneration is a feature of brain aging but is markedly increased in patients with Parkinson's disease (PD). Recent data indicate elevated metabolic stress as a possible explanation for DA neuron vulnerability. Using laser capture microdissection, we isolated DA neurons from the substantia nigra pars compacta of PD patients, age-matched and young controls to determine transcriptional changes by expression profiling and pathway analysis. We verified our findings by comparison to a published dataset. Parallel processing of isolated neurons and bulk tissue allowed the discrimination of neuronal and glial transcription signals. Our data show that genes known to be involved in neural plasticity, axon and synaptic function, as well as cell fate are differentially regulated in aging DA neurons. The transcription patterns in aging suggest a largely maintained expression of genes in energy-related pathways in surviving neurons, possibly supported by the mediation of PPAR/RAR and CREB signaling. In contrast, a profound down-regulation of genes coding for mitochondrial and ubiquitin--proteasome system proteins was seen in PD when compared to the age matched controls. This is in accordance with the established mitochondrial dysfunction in PD and provides evidence for mitochondrial impairment at the transcriptional level. In addition, the PD neurons had disrupted pathways that comprise a network involved in the control of energy metabolism and cell survival in response to growth factors, oxidative stress, and nutrient deprivation (PI3K/Akt, mTOR, eIF4/p70S6K and Hif-1alpha). PI3K/Akt and mTOR signaling are central hubs of this network which is of relevance to longevity and--together with induction of mitochondrial biogenesis--may constitute potential targets for therapeutic intervention. PMID- 21541764 TI - Aortic, cerebral and lower limb arterial and venous response to orthostatic stress after a 60-day bedrest. AB - The objective of this study is to assess by echography and Doppler the Cerebral (Vmca), Aortic (Vao) and Femoral (Vfem) arterial flow velocity and calf vein (Tibial, Gastrocnemius) section (Tib, Gast) during orthostatic intolerance (OI) test after a 60-day, head down tilt bed rest (HDBR). Twenty-four women (25-40 years) underwent a 60-day HDBR at -6 degrees : eight as control (Con), eight with exercise against lower body negative pressure (Ex-Lb) and eight with nutrition supplement (Nut). Before and after (R0) HDBR, all subjects underwent a 10-min, 80 degrees tilt followed by progressive LBNP until presyncope. After the post-HDBR Tilt + LBNP test, two groups were identified: finishers (F, n = 11) who completed the Tilt and non-finishers (NF, n = 13). A higher percentage decrease in Vao flow, higher percentage distension of Tib vein and a lack of increase in Vmca/Vfem ratio during the post-HDBR Tilt + LBNP compared to pre-HDBR were correlated to OI, but not all of these abnormal responses were present in each of the NF subjects. Abnormal responses were more frequent in Con and Nut than in Ex Lb subjects. (1) HDBR did not affect the cardiac, arterial and venous responses to the orthostatic test to the same extent in each subject. (2) Exercise within LBNP partially preserved the cardiovascular response to Tilt, while Nutrition supplementation had no efficacy. (3) Cerebral/femoral flow ratio and aortic flow were the parameters most closely related to OI. (4) Reduction in aortic flow was not the major hemodynamic change preceding syncope. PMID- 21541765 TI - Anticipatory scaling of grip forces when lifting objects of everyday life. AB - The ability to predict and anticipate the mechanical demands of the environment promotes smooth and skillful motor actions. Thus, the finger forces produced to grasp and lift an object are scaled to the physical properties such as weight. While grip force scaling is well established for neutral objects, only few studies analyzed objects known from daily routine and none studied grip forces. In the present study, eleven healthy subjects each lifted twelve objects of everyday life that encompassed a wide range of weights. The finger pads were covered with force sensors that enabled the measurement of grip force. A scale registered load forces. In a control experiment, the objects were wrapped into paper to prevent recognition by the subjects. Data from the first lift of each object confirmed that object weight was anticipated by adequately scaled forces. The maximum grip force rate during the force increase phase emerged as the most reliable measure to verify that weight was actually predicted and to characterize the precision of this prediction, while other force measures were scaled to object weight also when object identity was not known. Variability and linearity of the grip force-weight relationship improved for time points reached after liftoff, suggesting that sensory information refined the force adjustment. The same mechanism seemed to be involved with unrecognizable objects, though a lower precision was reached. Repeated lifting of the same object within a second and third presentation block did not improve the precision of the grip force scaling. Either practice was too variable or the motor system does not prioritize the optimization of the internal representation when objects are highly familiar. PMID- 21541763 TI - Biobehavioral markers of adverse effect in fetal alcohol spectrum disorders. AB - Identification of children with fetal alcohol spectrum disorders (FASD) is difficult because information regarding prenatal exposure is often lacking, a large proportion of affected children do not exhibit facial anomalies, and no distinctive behavioral phenotype has been identified. Castellanos and Tannock have advocated going beyond descriptive symptom-based approaches to diagnosis to identify biomarkers derived from cognitive neuroscience. Classical eyeblink conditioning and magnitude comparison are particularly promising biobehavioral markers of FASD-eyeblink conditioning because a deficit in this elemental form of learning characterizes a very large proportion of alcohol-exposed children; magnitude comparison because it is a domain of higher order cognitive function that is among the most sensitive to fetal alcohol exposure. Because the neural circuitry mediating both these biobehavioral markers is well understood, they have considerable potential for advancing understanding of the pathophysiology of FASD, which can contribute to development of treatments targeted to the specific deficits that characterize this disorder. PMID- 21541766 TI - Farmers' perceptions of safe use of pesticides: determinants and training needs. AB - PURPOSE: With focus on the impact of age, farmers' perceptions of importance and competence on pesticide safety measures as well as factors that influence these perceptions were explored in Fars Province of Iran. Farmers' training needs on the pesticide safety measures were also identified and compared using the Borich Needs Assessment Model. METHODS: The study included 155 farmers who were up to 35 years old (young farmers), above 35 up to 50 years old (middle-aged farmers), and above 50 years old (old farmers). Farmers evaluated twenty-two pesticide safety measures divided into three stages of pesticide handling, i.e., before, during, and after use. RESULTS: There was no significant relationship either between age and total importance of the safety measures or between age and total competence on the safety measures due to the impacts of other mediating variables. The most important predictors for the perceived importance and competence of farmers on the safety measures were the experience of pesticide-related adverse health effects in the past and the formal education of farmers, respectively. CONCLUSIONS: The relationship between farmers' age and these two variables should not be considered either positively or negatively for predicting farmers' attitudes on safety issues of pesticide use without taking into account other mediating variables that can also affect farmers' behavior. Differences in the perceived importance and competence of farmers on the safety measures revealed considerably different needs of farmers for future training as a result of differences in age along with other background characteristics. PMID- 21541768 TI - The role of Notch signaling in adult neurogenesis. AB - Neurogenesis occurs throughout adulthood in the mammalian brain. Newly born neurons are incorporated into the functional networks of both the olfactory bulb and the hippocampal dentate gyrus, and there is growing evidence that adult neurogenesis is important for various brain functions. Continuous neurogenesis is achieved by the coordinated proliferation and differentiation of adult neural stem cells. In this review, we discuss the recent findings concerning the roles of Notch signaling in adult neural stem cells. PMID- 21541769 TI - Combined esophagectomy and pancreaticoduodenectomy: expanded indication for supercharged jejunal interposition. AB - INTRODUCTION: Combined pancreaticoduodenectomy and esophagectomy poses a challenge for reconstruction. CASE REPORT: We report a case of a combined pancreaticoduodenectomy and esophagectomy for synchronous pancreatic and esophageal cancer, with reconstruction using a supercharged jejunal interposition. DISCUSSION: The supercharged jejunal anastomosis is a versatile option for foregut reconstruction. PMID- 21541770 TI - Alkaline phosphatase: does it have a role in predicting hepatocellular carcinoma recurrence? AB - BACKGROUNDS: Surgical resection remains the first line of treatment for earlier stages of hepatocellular carcinoma (HCC), and it offers the best prognosis for long-term survival. Nevertheless, the recurrence rates after resection are still high in reports. Therefore, it is still essential to explore any potential prognostic factors to attain relatively longer-term survival of HCC patients. MATERIALS AND METHODS: In the period from 1983 to 2005, 1,685 patients who underwent hepatectomy at Chang Gung Memorial hospital were enrolled in the study, and their clinicopathological data were retrospectively reviewed for survival analysis. RESULTS: The 1-, 3-, 5-, and 10-year disease-free survival (DFS) rates in this series were 60.3%, 39.7%, 31.3%, and 24.0%, respectively, whereas the 1-, 3-, 5-, and 10-year overall survival (OS) rates were 80.1%, 59.1%, 46.6%, and 27.7%, respectively. Gross vascular invasion, tumor status, lymph node involvement, satellite lesion, positive surgical margin, alkaline phosphatase (ALP), albumin, presence of cirrhosis, and Child grade B or C were independent prognostic factors for prediction of DFS; while alpha-fetoprotein, ALP, surgical factors, including complications, blood transfusion, positive resection margin, and tumor characters including tumor status, vascular invasion, and lack of tumor encapsulation were found to be independent predicting factors for OS, as determined by Cox regression analysis. Interestingly, we found that preoperative level of ALP was one of the most important independent predictors of recurrence, even more important that alpha-fetoprotein (AFP) as we noticed that elevation of ALP above (82 U/L) predicted poor prognosis in patients where AFP levels was less than 66 ng/ml. It is worth to mention that ALP was statistically related to other liver function tests, but not tumor characters by hierarchical clustering; which means that we were able to correlate ALP with prognosis statistically, but not with pathological criteria of the tumor; to elucidate these finding, further basic science research is required. CONCLUSION: ALP among liver function tests, in addition to other tumor characters were independent factors for DFS and OS; our results suggest that preoperative ALP levels could be utilized to monitor and predict recurrence in high risk HCC patients. PMID- 21541771 TI - Fronto-temporal lobar degeneration: neuropathology in 60 cases. AB - Sixty cases of frontotemporal lobar degeneration (FTLD) were collected over 22 years. Brain weight was negatively correlated with disease duration. The neuronal and/or glial inclusions were labeled by anti-TDP, anti-FUS or anti-TAU antibodies, respectively, in 40, 3 and 12 cases. In the FTLD-TDP group, mutation of the progranulin gene was found in four cases (FTD-GRN), with nuclear, cat eye inclusions and severe neuronal loss in CA1 and subiculum. The motor neurons were involved in 27 cases (fronto-temporal dementia with amyotrophic lateral sclerosis = FTD-ALS). Familial FTD-ALS cases lived longer than sporadic ones. In nine cases, there was no ALS, no GRN mutation (FTD-NAP). The cases in the FTD-ALS and FTD-NAP subgroups were of Sampathu type 2 (TDP-positive inclusions located mostly in cell bodies and short neurites) with the exception of five cases which belonged to type 1 (long TDP-positive neurites in the superficial layers of the cortex). All of the FTLD-FUS of this series cases were affected by neuronal intermediate filament inclusion disease (NIFID). They were young. The survival was short. In the FTLD-tau group, mutations P301P (previously not recognized as pathogenic), P301L and S305N were identified. Pick disease (n = 5) appeared as a homogeneous sporadic disorder. The current nomenclature allows the neuropathological classification of nearly all the cases of FTD. The prevalence of the different types of FTD is tightly linked to the recruitment. This series was enriched in motor neuron disease (explaining the overall predominance of type 2 TDP inclusions). PMID- 21541772 TI - Prognostic prediction in patients with hip fracture: risk factors predicting difficulties with discharge to own home. AB - BACKGROUND: Little is known about risk factors that may prevent hip fracture patients from being discharged to home. The present study was developed to investigate possible prognostic factors. MATERIALS AND METHODS: We studied 345 patients with hip fracture treated at our hospital since 1997, who were living at home before the injury. There were 84 males and 261 females. Mean age at injury was 81.6 years. Fracture type was femoral neck fracture in 152 patients and trochanteric fracture in 193. Patients were divided into those who were discharged to home (home discharge group) and those who were discharged to rehabilitation facilities or died in hospital (non-home discharge group). Gender, age at admission, fracture type, and other factors were investigated. Multivariate analysis was conducted on these variables for the home discharge and non-home discharge groups. RESULTS: There were 202 patients (58.6%) in the home discharge group and 143 patients (41.4%) in the non-home discharge group. The factors significantly associated with not achieving the goal of discharge to home were age 85 years or above [odds ratio (OR) = 1.79, P = 0.0204], chronic systemic diseases (OR = 1.77, p = 0.0225), dementia (OR = 3.17, P < 0.0001), and walking disability before injury (OR = 5.70, P = 0.0328). CONCLUSIONS: In elderly patients with hip fracture, the risk factors that predict difficulties with discharge to home include age at admission, concomitant chronic systemic diseases and dementia, and walking disability before injury. PMID- 21541773 TI - Low-level laser irradiation treatment reduces CCL2 expression in rat rheumatoid synovia via a chemokine signaling pathway. AB - Rheumatoid arthritis (RA) is an inflammatory joint disorder whose progression leads to the destruction of cartilage and bone. Although low-level laser irradiation (LLLI) is currently being evaluated for the treatment of RA, the molecular mechanisms underlying its effectiveness remain unclear. To investigate possible LLLI-mediated antiinflammatory effects, we utilized a collagen-induced arthritis (CIA) rat model and analyzed gene expression profiles in the synovial membranes of the knee joint. Total RNA was isolated from the synovial membrane tissue of the joints of untreated CIA rats or CIA rats treated with LLLI (830 nm Ga-Al-As diode), and gene expression profiles were analyzed by DNA microarray (41,000 rat genes), coupled with Ingenuity pathways analysis (IPA). DNA microarray analysis showed that CCL2 gene expression was increased in CIA tissue, and that LLLI treatment significantly decreased CIA-induced CCL2 mRNA levels. IPA revealed that chemokine signal pathways were involved in the activation of CCL2 production. These microarray data were further validated using real-time PCR and reverse transcription PCR. Immunohistochemistry confirmed that CCL2 production was decreased in CIA rats treated with LLLI. These findings suggest that decreased CCL2 expression may be one of the mechanisms involved in LLLI-mediated RA inflammation reduction. PMID- 21541774 TI - Image quality and dose performance of 80 kV low dose scan protocol in high-pitch spiral coronary CT angiography: feasibility study. AB - To investigate the image quality and dose performance of 80 kV high-pitch spiral (HPS) coronary CT angiography (CCTA). 106 patients consecutively enrolled into prospectively ECG-triggering HPS CCTA (pitch = 3.4) exam using kV/ref. mAs = 80/400, 100/370, and 120/370 when patient BMI was <=22.5 (n = 40), between 22.5 and 27.5 (n = 53) and >27.5 kg/m2 (n = 13). Image quality was assessed per segment by two observers independently using a 4-point scale (1-excellent, 4-non diagnosable). Image noise and signal-to-noise ratio (SNR), contrast-to-noise ratio were measured. Diagnostic image quality was obtained in 503 of 507, 687 of 693, 164 of 167 coronary segments in 80, 100, 120 kV groups without significant difference (P = 0.482). The proportions of segments with score 1-4 were not significantly different among three kV groups (all P > 0.05). Image noise were significantly higher in 80 kV group than 100 and 120 groups (P < 0.001), while SNR was not (P = 0.097). The effective dose of 80 kV group (0.36 +/- 0.03 mSv) was significantly lower than that of 100 kV group (0.86 +/- 0.08 mSv) and 120 kV group (1.77 +/- 0.18 mSv). The mean +/- SD of HR in all patients was 54.8 +/- 5.1 bpm. 80 kV HPS CCTA is feasible for patient with BMI <= 22.5 kg/m2 which can save 58% dose than 100 kV group, while maintain diagnosable image quality. PMID- 21541775 TI - Comparative imaging of cardiac structures and function for the optimization of transcatheter approaches for valvular and structural heart disease. AB - The detailed assessment of cardiac anatomy using multiple imaging modalities is essential to understand the high degree of variations that exist in human hearts (i.e., with and without pathologies). Additionally, such information should provide one with important insights regarding which imaging modality will best provide the required visualization of device placement via a given transcatheter approach. We describe here an unique set of such studies performed on either preserved heart specimens or within reanimated large mammalian hearts, including human (using Visible Heart((r)) methodologies). Such anatomical and device-tissue interface knowledge is critical for both design engineers and clinicians that seek to develop and/or employ less invasive cardiac repair approaches for patients with acquired or congenital structural heart defects. PMID- 21541776 TI - A middle mediastinal tumor. PMID- 21541777 TI - Near-shore distribution of heavy metals in the Albanian part of Lake Ohrid. AB - The heavy metal contamination in Lake Ohrid, a lake shared between Albania and Macedonia, was studied. Lake Ohrid is believed to be one of the oldest lakes in the world, with a large variety of endemic species. Different anthropogenic pressures, especially heavy metal influxes from mining activities, might have influenced the fragile equilibrium of the lake ecosystem. Heavy metal concentrations in water, sediment, emergent vegetation, and fish were investigated at selected sites of the lake and a study of the heavy metals in five tributaries was conducted. The lake surface water was found to have low levels of heavy metals, but sediments contained very high levels mostly near river mouths and mineral dump areas with concentrations reaching 1,501 mg/kg for Ni, 576 mg/kg for Cr, 116.8 mg/kg for Co and 64.8 g/kg for Fe. Sequential extraction of metals demonstrates that heavy metals in the sediment are mainly present in the residual fraction varying from 75% to 95% in different sites. High heavy metal levels (400 mg/kg Ni, 89 mg/kg Cr, and 39 mg/kg Co) were found in plants (stem of Phragmites australis), but heavy metals could not be detected in fish tissue (gill, muscle, and liver of Salmo letnica and Salmothymus ohridanus). PMID- 21541778 TI - Analysis of volatile organic compounds released during food decaying processes. AB - A number of volatile organic compounds (VOCs) including acetone, methyl ethyl ketone, toluene, ethylbenzene, m,p-xylene, styrene, and o- xylene released during food decaying processes were measured from three types of decaying food samples (Kimchi (KC), fresh fish (FF), and salted fish (SF)). To begin with, all the food samples were contained in a 100-mL throwaway syringe. These samples were then analyzed sequentially for up to a 14-day period. The patterns of VOC release contrasted sharply between two types of fish (FF and SF) and KC samples. A comparison of data in terms of total VOC showed that the mean values for the two fish types were in the similar magnitude with 280 +/- 579 (FF) and 504 +/- 1,089 ppmC (SF), while that for KC was much lower with 16.4 +/- 7.6 ppmC. There were strong variations in VOC emission patterns during the food decaying processes between fishes and KC that are characterized most sensitively by such component as styrene. The overall results of this study indicate that concentration levels of the VOCs differed significantly between the food types and with the extent of decaying levels through time. PMID- 21541779 TI - Spatial and seasonal variability of pore water phosphorus concentration in shallow Lake Swarzedzkie, Poland. AB - Pore waters play an important role in phosphorus dynamics in aquatic ecosystems. Phosphorus concentrations in pore waters are much higher than above the bottom. This is confirmed by the results of this study concerning the hypereutrophic lake. Pore water was analyzed at 11 sampling stations in the upper layer of bottom sediments. This water was separated by centrifugation and phosphorus level was measured spectrophotometrically with ascorbic acid as a reducer. Total phosphorus concentration in pore waters ranged from 0.5 to 8.1 mgP l(-1) (mean 3.2 mgP l(-1)). Mean phosphorus concentration in pore water samples of this lake was the highest in summer and the lowest in winter. High concentrations were observed in samples from the pelagial and low from the macrophyte zone. PMID- 21541780 TI - Anything new in EU pharmacovigilance? PMID- 21541781 TI - Macitentan: entry-into-humans study with a new endothelin receptor antagonist. AB - PURPOSE: To study the pharmacokinetics, pharmacodynamics, and tolerability of rising single doses of macitentan, an endothelin receptor antagonist, in healthy male subjects. METHODS: This double-blind, placebo-controlled study was performed in seven groups of eight healthy male subjects. Doses of 0.2, 1, 5, 25, 100, 300 and 600 mg or placebo (two subjects per group) were administered. Plasma macitentan and endothelin-1 and serum total bile salt concentrations were measured and analysed non-compartmentally. Plasma and urine were analysed qualitatively for the presence of metabolites and one of these, ACT-132577, was also measured quantitatively in plasma. Standard tolerability measurements were performed throughout the study. RESULTS: Macitentan was slowly absorbed and, at a dose of 300 mg, the t(1/2) (95% confidence interval, CI) was 17.5 h (14.1, 21.8). The dose-proportionality coefficient beta for C(max) (95% CI) was 0.83 (0.79, 0.87) indicating less than dose-proportional pharmacokinetics of macitentan. In plasma, a pharmacologically active oxidative depropyl metabolite, ACT-132577, was found whereas in urine two minor metabolites were detected. The t(1/2) of ACT 132577 (95% CI) was 65.6 h (53.1, 80.9). Macitentan dose-dependently increased endothelin-1 concentrations up to 2.2-fold (95% CI 1.4, 2.4) at a dose of 600 mg, but had no consistent effect on total bile salts. Macitentan was well tolerated up to and including a dose of 300 mg, the maximum tolerated dose. Headache, nausea and vomiting were dose-limiting adverse events. CONCLUSION: The pharmacokinetic and tolerability profile of macitentan is consistent with a once a-day dosing regimen and warrants further investigation in clinical studies. PMID- 21541782 TI - Soybean cyst nematode resistance in soybean is independent of the Rhg4 locus LRR RLK gene. AB - To test the function of candidate genes in soybean for resistance to the soybean cyst nematode (SCN), a large collection of EMS-mutants from the SCN-resistant soybean cultivar "Forrest" was developed for Targeting Induced Local Lesions IN Genomes (TILLING). Additionally, due to the complexity of the soybean genome, an integrated set of genomic and genetic analysis tools was employed to complement the TILLING approach. The efficiency of this integrated set of tools was tested using a candidate soybean gene for resistance to SCN, encoding a leucine-rich repeat receptor-like kinase (LRR-RLK) that was identified by map-based cloning at the Rhg4 locus. The Rhg4 locus is one of the major quantitative trait loci controlling soybean resistance against SCN race 3 (HG type 0) in cv. Forrest, but the gene(s) sequence for resistance remains to be determined. Using TILLING, a Forrest mutant containing a nonsense mutation in the LRR domain of the candidate resistance protein was identified and confirmed; however, the SCN-resistant phenotype of the mutant was not altered. Haplotyping and EcoTILLING of recombinant inbred lines along with complementation analysis corroborated the TILLING result and ruled out the possibility of functional redundancy by a second copy of the LRR-RLK gene identified in the soybean genome. This study validates the use of TILLING, in combination with an integrated set of genomic tools, as an efficient means of testing candidate genes for SCN resistance in soybean. PMID- 21541783 TI - Diabetes, treatments for diabetes and their effect on cancer incidence and mortality: attempts to disentangle the web of associations. AB - The association between type 2 diabetes and some types of cancer is well established and the complexity of this association is receiving increasing recognition. Many factors influence the risk of both diabetes and cancer including age, sex, ethnicity, socioeconomic status, obesity/insulin resistance, diet (including alcohol intake), physical activity levels and smoking history. The presence of diabetes may influence the uptake of cancer screening. Using an experimental approach to investigate the effect of better control of diabetes is helpful in assessing whether hyperglycaemia has a causal relationship with cancer. Diabetes treatments may influence the risk of cancer independently of their effect on glycaemia and complicate investigation of the association between diabetes and cancer. This article discusses the complexity involved in attempting to clarify the factors that contribute to the associations between diabetes, hyperglycaemia, diabetes treatment and cancer. PMID- 21541784 TI - The influence of organizational jurisdiction, organizational attributes, and training measures on perceptions of public health preparedness in Alberta. AB - OBJECTIVES: Recent international events including the H1N1 influenza pandemic and the rising incidence of West Nile Virus throughout North America have brought critical attention to the Canadian public health system and how prepared the system is to respond to various types of contemporary public health threats. The current work assessed the association of organizational jurisdiction, organizational attributes, and training opportunities with three different measures of public health preparedness in the province of Alberta, Canada. METHODS: Organizational representatives involved in the delivery of public health systems completed an online questionnaire that asked about organizational attributes and training opportunities available to employees, their perception of organizational preparedness, and their connections to other organizations in Alberta. RESULTS: Findings revealed that (1) perceived human and material resources preparedness was associated with training opportunities, (2) perceived informational needs was associated with organizational size, and (3) whether an organization exercised their written preparedness plan in 2006 was associated with organizational jurisdiction. CONCLUSIONS: These findings help fill a gap in the literature with respect to identifying how organizational characteristics are associated with different aspects of preparedness. PMID- 21541785 TI - A case of glycine-receptor antibody-associated encephalomyelitis with rigidity and myoclonus (PERM): clinical course, treatment and CSF findings. PMID- 21541787 TI - Involvement of ligninolytic enzymes and Fenton-like reaction in humic acid degradation by Trametes sp. AB - Trametes sp. M23, isolated from biosolids compost was found to decompose humic acids (HA). A low N (LN) medium (C/N, 53) provided suitable conditions for HA degradation, whereas in a high N (HN) medium (C/N, 10), HA was not degraded. In the absence of Mn(2+), HA degradation was similar to that in Mn(2+)-containing medium. In contrast, MnP activity was significantly affected by Mn(2+). Laccase activity exhibited a negative correlation to HA degradation, while LiP activity was not detected. Thus, ligninolytic enzymes activity could provide only a partial explanation for the HA-degradation mechanism. The decolorization of two dyes, Orange II and Brilliant Blue R250, was also determined. Similar to HA degradation, under LN conditions, decolorization occurred independently of the presence of Mn(2+). We investigated the possible involvement of a Fenton-like reaction in HA degradation. The addition of DMSO, an OH-radical scavenger, to LN media resulted in a significant decrease in HA bleaching. The rate of extracellular Fe(3+) reduction was much higher in the LN vs. HN medium. In addition, the rate of reduction was even higher in the presence of HA in the medium. In vitro HA bleaching in non-inoculated media was observed with H(2)O(2) amendment to a final concentration of 200 mM (obtained by 50 mM amendments for 4 days) and Fe(2+) (36 mM). After 4 days of incubation, HA decolorization was similar to the biological treatment. These results support our hypothesis that a Fenton-like reaction is involved in HA degradation by Trametes sp. M23. PMID- 21541786 TI - Natural variation at position 45 in the D1 domain of lineage III killer cell immunoglobulin-like receptors (KIR) has major effects on the avidity and specificity for MHC class I. AB - Alternative lysine and methionine residues at position 44 in the D1 domain determine the specificities of human lineage III killer cell immunoglobulin-like receptors (KIR) for the C1 and C2 epitopes of HLA-C. KIR having glutamate 44 are also present in orangutans (Popy2DLB) and chimpanzees (Pt-2DL9) but notably absent from humans. Popy2DLB exhibits broad specificity for both the C1 and C2 epitopes, whereas Pt-2DL9 has narrow specificity for C2. Mutation of phenylalanine 45 in Popy2DLB to the cysteine residue present in Pt-2DL9 was sufficient to narrow the Popy2DLB specificity to be like that of Pt-2DL9. In contrast, replacement of cysteine 45 in Pt-2DL9 by phenylalanine had no effect on its C2 specificity, but reduced the avidity. In a similar manner, replacement of phenylalanine 45 with cysteine in Popy2DLA, which has lysine 44 and recognizes C1, maintained this specificity while reducing avidity. Position 45 is exceptionally variable, exhibiting twelve residues that distinguish KIR of different lineages and species. Our study demonstrates the potential for variation at position 45 to modulate KIR avidity and specificity for HLA-C. The various effects of position 45 mutation are consistent with a model in which a Popy2DLB-like receptor, having glutamate 44 and broad specificity for C1 and C2, facilitated the evolution of the C2 epitope from the C1 epitope and C2-specific KIR from C1-specific KIR. With the acquisition of C2 and C2-specific receptors, the selection against this broadly specific receptor led to its loss from the human line and narrowing of its specificity on the chimpanzee line. PMID- 21541788 TI - Transcriptome analysis shows differential gene expression in the saprotrophic to parasitic transition of Pochonia chlamydosporia. AB - Expression profiles were identified in the fungus Pochonia chlamydosporia, a biological control agent of plant parasitic nematodes, through a cDNA-amplified fragment length polymorphism approach. Two isolates with different host ranges, IMI 380407 and IMI 331547, were assayed in conditions of saprotrophic-to parasitic transition, through in vitro assays. Gene expression profiles from three different nutritional conditions and four sampling times were generated, with eggs of host nematodes Globodera pallida and Meloidogyne incognita. Expression of transcripts changed in RNA fingerprints obtained under different nutritional stresses (starvation in presence/absence of eggs, or rich growth media). Transcript derived fragments (TDFs) obtained from the expression profiles corresponded to 6,800 products. A subset was sequenced and their expression profile confirmed through RT PCR. A total of 57 TDFs were selected for further analysis, based on similarities to translated or annotated sequences. Genes expressed during egg parasitism for both IMI 380407 and IMI 331547 were involved in metabolic functions, cellular signal regulation, cellular transport, regulation of gene expression, DNA repair, and other unknown functions. Multivariate analysis of TDF expression showed three groups for IMI 380407 and one for IMI 331547, each characterized by expression of genes related to eggs parasitism. Common amplification profiles among TDF clusters from both isolates also reflected a pool of constitutive genes, not affected by the nutritional conditions and nematode associations, related to general metabolic functions. The differential expression of parasitism related genes suggest a network of induced/repressed products, playing a role in fungal signaling and infection, with partial overlaps in host infection and parasitism traits. PMID- 21541790 TI - Upregulation of p21-activated Kinase 6 in rat brain cortex after traumatic brain injury. AB - p21-activated Kinase 6 (PAK6) is a serine/threonine kinase belonging to the p21 activated kinase (PAK) family. PAK kinases are well-known regulators of a wide variety of cellular functions, including regulation of cytoskeleton rearrangement, cell survival, apoptosis and the mitogen-activated protein kinase signaling pathway. To elucidate the expressions and possible functions of PAK6 in central nervous system (CNS) lesion and repair, we performed a traumatic brain injury (TBI) model in adult rats. Western blot analysis revealed that PAK6 level significantly increased at day 3 after damage, and then declined during the following days. Besides, double immunofluorescence staining showed PAK6 was primarily expressed in the neurons and a few of glial cells in the normal group. While after injury, the expression of PAK6 was increased significantly in the astrocytes and neurons, and the astrocytes had largely proliferated. We also examined the expression of proliferating cell nuclear antigen (PCNA) whose change was correlated with the expression of PAK6. Importantly, double immunofluorescence staining revealed that cell proliferation evaluated by PCNA appeared in many PAK6-expressing cells at day 3 after injury. In addition, injury induced expression of PAK6 was co-labeled by active caspase-3 during neuronal apoptosis after injury. Collectively, we hypothesized PAK6 may play important roles in CNS pathophysiology after TBI and further research is needed to have a good understanding of its function and mechanism. PMID- 21541791 TI - Theoretical issues in the study of asexuality. AB - Academic interest in asexual people is new and researchers are beginning to discuss how to proceed methodologically and conceptually with the study of asexuality. This article explores several of the theoretical issues related to the study of asexuality. Researchers have tended to treat asexuality either as a distinct sexual orientation or as a lack of sexual orientation. Difficulties arise when asexual participants are inconsistent in their self-identification as asexual. Distinguishing between sexual and romantic attraction resolves this confusion, while simultaneously calling into question conceptualizations of the asexual population as a single homogenous group. Arguments are considered in favor of exploring diversity within the asexual population, particularly with respect to gender and romantic orientation, proposing that the categorical constructs employed in (a)sexuality research be replaced with continuous ones. Furthermore, given the recently noted bias toward including only self-identified asexuals, as opposed to non-self-identified asexuals or "potential-asexuals," in research about asexuality, the nature and meaning of asexual self-identification are discussed. Particular attention is paid to the theoretical importance of acknowledging asexual self-identification or lack thereof in future research into asexuality. This article discusses what these current theoretical issues mean for the study of asexuality and sexuality more generally, including a brief consideration of ethical implications for research with asexual participants. Finally, directions for future research are suggested. PMID- 21541789 TI - Clinical activity of mammalian target of rapamycin inhibitors in solid tumors. AB - The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is vital for cell metabolism, growth, and proliferation. mTOR is frequently upregulated in many tumor types and hence has become an important target in cancer treatment. Sirolimus and its derivatives (rapalogs) interact with the intracellular receptor FK506 binding protein 12 (FKBP12), forming a complex with high affinity for mTOR and thus disrupting its activity. Rapalogs are being evaluated extensively in cancer patients with different formulations and schedules. Significant clinical activity has led to their approval for the treatment of kidney cancer, mantle cell lymphoma, and subependymal giant cell astrocytoma; however, despite increasing knowledge about cancer cell biology, their activity in other malignancies is unclear. Further research is needed to identify optimal dosage, administration and targeted combination as well as the subset of patients likely to respond to mTOR/PI3K inhibition. This review focuses on a discussion of the pathway, its implications in cancer biology and results of clinical trials of rapalogs alone or in combination, organizing them by common malignancy type. PMID- 21541793 TI - Anti-CD52 antibody-mediated immune ablation with autologous immune recovery for the treatment of refractory juvenile polymyositis. AB - Autologous hematopoietic stem cell transplantation (HSCT) has been used for the treatment of both adult and pediatric autoimmune diseases. However, HSCT has significant side effects (neutropenia, thrombocytopenia, infertility, cardiotoxicity) and costs (HSC collection/harvesting, blood product support). In an attempt to avoid the toxicities and costs associated with HSCT, we investigated whether immune ablation similar to that achieved following myeloablative HSCT could be achieved by the intensive administration of an anti CD52 antibody (Campath-1H antibody). The first patient treated with the treatment regime, who had refractory juvenile polymyositis, achieved immune ablation (the elimination of pre-therapy antigen-specific T lymphocyte immunity) and has had stable clinical improvement for more than 6 years. PMID- 21541792 TI - Effects of CD70 and CD11a in immune thrombocytopenia patients. AB - INTRODUCTION: CD70 and CD11a are co-stimulatory molecules that are important for the immune functions of T, B lymphocytes. Over-expressions of CD70 or CD11a cause T cell to be autoreactive. OBJECTIVES: The purpose of this study was to explore the effect of CD70 and CD11a in immune thrombocytopenia (ITP). METHODS: CD70 and CD11a mRNAs and protein expressions in CD4(+) T cells from ITP patients were measured respectively by real-time quantitative-PCR (RT-PCR) and flow cytometry. The apoptosis of T cells, B cells, and platelets in the PBMCs were analyzed by flow cytometry, and secretion of IL-4, IFN-gamma, as well as IgG in the reaction supernatant were detected by ELISA. In order to investigate the effects of CD70 and CD11a over-expression on pathogenesis of ITP, anti-CD70, and anti-CD11a mAbs were used to block the signaling pathways. RESULTS: CD70 and CD11a mRNAs and protein expressions in CD4(+) T cells from ITP patients were significantly higher than healthy controls. In vitro co-culturing of PBMCs with anti-CD70 or anti CD11a, the apoptosis of T, B lymphocytes were significantly increased but apoptosis of platelets were reduced. Anti-CD11a and anti-CD70 both significantly suppressed the secretion of IFN-gamma, while anti-CD11a significantly promoted the secretion of IL-4. There was no significant difference in the healthy group. CONCLUSIONS: CD70 and CD11a facilitate the survival of T, B lymphocytes and indirectly enhance the destruction of platelets in ITP. Blockade of CD70 or CD11a are promising therapeutic approaches for ITP. PMID- 21541794 TI - Lead contamination and its potential sources in vegetables and soils of Fujian, China. AB - Lead (Pb) contents and partition in soils collected from eleven vegetable-growing lands in Fujian Province, China, were investigated using a modification of the BCR (Community Bureau of Reference) sequential extraction procedure coupled with the Pb isotope ratio technique. Pb contents in Chinese white cabbage (B. Chinensis L.) grown on the lands for this study were also measured. Results showed that Pb concentrations in fifty samples of topsoil ranged from 456 to 21.5 mg kg(-1), with each mean concentration of six sampling lands exceeding the national standard (50 mg kg(-1)); while Pb concentrations in edible portions of thirty-two vegetable samples ranged from 0.009 to 2.20 mg kg(-1), with four sampling sites exceeding the national sanitary standard (0.2 mg kg(-1)). A significant correlation (r = 0.971, P < 0.01) of Pb contents in the acid extractable fractions by BCR approach and the vegetables was observed, which indicates that the acid-extractable Pb is useful for evaluating the metal bioavailability for plants and potential risk for human health in soils. The determination of lead isotope ratios in different chemical forms of soils by BCR sequential extraction procedures provides useful information on the Pb isotopic composition associated with different soil fractions (especially in the acid extractable fractions), and the result is helpful for the further study on controlling and reducing Pb contamination in vegetable-growing soils. PMID- 21541795 TI - Adherence to physician recommendation to colorectal cancer screening colonoscopy among Hispanics. AB - BACKGROUND: Colorectal cancer (CRC) is the second most commonly diagnosed cancer among Hispanics in the United States (US), yet the use of CRC screening is low in this population. Physician recommendation has consistently shown to improve CRC screening. OBJECTIVE: To identify the characteristics of Hispanic patients who adhere or do not adhere to their physician's recommendation to have a screening colonoscopy. DESIGN: A cross-sectional study featuring face-to-face interviews by culturally matched interviewers was conducted in primary healthcare clinics and community centers in New York City. PARTICIPANTS: Four hundred Hispanic men and women aged 50 or older, at average risk for CRC, were interviewed. Two hundred and eighty (70%) reported receipt of a physician's recommendation for screening colonoscopy and are included in this study. MAIN MEASURES: Dependent variable: self report of having had screening colonoscopy. INDEPENDENT VARIABLES: sociodemographics, healthcare and health promotion factors. KEY RESULTS: Of the 280 participants, 25% did not adhere to their physician's recommendation. Factors found to be associated with non-adherence were younger age, being born in the US, preference for completing interviews in English, higher acculturation, and greater reported fear of colonoscopy testing. The source of colonoscopy recommendation (whether it came from their usual healthcare provider or not, and whether it occurred in a community or academic healthcare facility) for CRC screening was not associated with adherence. CONCLUSIONS: This study indicates that potentially identifiable subgroups of Hispanics may be less likely to follow their physician recommendation to have a screening colonoscopy and thus may decrease their likelihood of an early diagnosis and prompt treatment. Raising physicians' awareness to such patients' characteristics could help them anticipate patients who may be less adherent and who may need additional encouragement to undergo screening colonoscopy. PMID- 21541796 TI - Now what should I do? Primary care physicians' responses to older adults expressing thoughts of suicide. AB - BACKGROUND: Many older adults who die by suicide have had recent contact with a primary care physician. As the risk-assessment and referral process for suicide is not readily comparable to procedures for other high-risk behaviors, it is important to identify areas in need of quality improvement (QI). OBJECTIVE: Identify patterns in physician-patient communication regarding suicide to inform QI interventions. DESIGN: Qualitative thematic analysis of video-taped clinical encounters in which suicide was discussed. PARTICIPANTS: Adult primary care patients (n = 385) 65 years and older and their primary care physicians. RESULTS: Mental health was discussed in 22% of encounters (n = 85), with suicide content found in less than 2% (n = 6). Three patterns of conversation were characterized: (1) Arguing that "Life's Not That Bad." In this scenario, the physician strives to convince the patient that suicide is unwarranted, which results in mutual fatigue and discouragement. (2) "Engaging in Chitchat." Here the physician addresses psychosocial matters in a seemingly aimless manner with no clear therapeutic goal. This results in a superficial and misleading connection that buries meaningful risk assessment amidst small talk. (3) "Identify, assess, and...?" This pattern is characterized by acknowledging distress, communicating concern, eliciting information, and making treatment suggestions, but lacks clearly articulated treatment planning or structured follow-up. CONCLUSIONS: The physicians in this sample recognized and implicitly acknowledged suicide risk in their older patients, but all seemed unable to go beyond mere assessment. The absence of clearly articulated treatment plans may reflect a lack of a coherent framework for managing suicide risk, insufficient clinical skills, and availability of mental health specialty support required to address suicide risk effectively. To respond to suicide's numerous challenges to the primary care delivery system, QI strategies will require changes to physician education and may require enhancing practice support. PMID- 21541797 TI - Characterization of a novel positive transcription regulatory element that differentially regulates the alpha-2-macroglobulin gene in replicative senescence. AB - Alpha-2-macroglobulin (alpha2M), a protease inhibitor, is implicated in Alzheimer's disease, atherosclerosis, and other age-related diseases. The elevated level of alpha2M mRNA has been described in replicative senescence and it could be used as a biomarker of the aging cells. However, the mechanism responsible for the up-regulation of its expression is still unclear. This report identified a novel transcriptional regulatory element, the alpha2M transcription enhancement element (ATEE), within the alpha2M promoter. This element differentially activates alpha2M expression in senescent versus young fibroblasts. Electrophoretic mobility shift assays revealed abundant complexes in senescent cell nuclear extracts compared with young cell nuclear extracts. The DNase I footprint revealed the protein-binding core sequence through which the protein binds the ATEE. Mutation within ATEE selectively abolished alpha2M promoter activity in senescent (but not young) cells. These results indicated the ATEE, as a positive transcription regulatory element, contributes to the up regulation of alpha2M during replicative senescence. PMID- 21541798 TI - Cardiorespiratory fitness in young adults with a history of renal transplantation in childhood. AB - Limited knowledge exists on cardiorespiratory fitness (CR fitness) in adults having a renal transplant (Rtx) during childhood. Our aim was to assess CR fitness (V0(2peak)) with a maximal treadmill test in former Rtx children reaching adulthood (ped-tx, n = 31), compared to patients Rtx as adults (adult-tx, n = 17) and healthy controls (HC, n = 36). Median age was 26.9 (19-41), 28.6 (23.5-34) and 33.5 (20-42) years, respectively. Median time since first Rtx was 18.1 (7-29) and 3.7 (1.2-12.6) years. Body composition was measured by dual-energy X-ray absorptiometry (DXA). V0(2peak) was median 37.9 (12.5-56.3), 40.8 (26.5-57.5), and 44.4 (29.5-65.6) ml kg (-1)min (-1) in the ped-tx, adult-tx, and HC, respectively. Ped-tx had significantly lower V0(2peak) compared to HC (p = 0.01). Adult-tx had higher exercise capacity (test duration) compared to ped-tx (median 10.5 (7.5-16) and 9 (6-14) min, respectively (p = 0.016). In multiple linear regression analysis, test duration, fat-free mass (FFM, kg) and Hgb (g/dl) were significant predictors of V0(2peak) explaining 86% of its variance. There was no significant difference between ped-tx and adult-tx in V0(2peak.) CR fitness depicts long-term health outcome in Rtx patients both in regard to physical functioning and is a plausible indirect marker of CV health. PMID- 21541799 TI - Compression anastomosis revisited: prospective audit of short- and medium-term outcomes in 62 rectal anastomoses. AB - BACKGROUND: The ColonRingTM represents a further advancement in compression anastomosis by using superelastic materials. In contrast to other compression devices, its field of application is identical to circular staplers. Yet, limited data are available and there are no reports on the use of this compression device for anastomoses in the lower rectum and in diverted cases. METHODS: Between November 2008 and March 2010 a nonrandomized prospective study of patients undergoing colorectal resection was done. RESULTS: Sixty-two patients (30 female) with a median age of 67 years (range = 23-87) underwent surgery for benign (35) and malignant (27) indications;the surgery was performed laparoscopically in 53 (85.5%) cases. There were no leaks or other major complications related to the compression anastomosis. One patient died from sepsis caused by a leak of a colonic J-pouch. Three of 12 (25%) patients after (ultra-)low anterior resection experienced pain caused by the presence of the ring. Of 53 undiverted patients, rings were passed spontaneously in 52 (98.1%). No spontaneous passage occurred in patients with a stoma. Their rings were removed transanally prior to stoma closure. After a median of 6 months, endoscopic follow-up was performed in 60 patients (96.8%). Two anastomotic stenoses were detected (3.3%). CONCLUSION: Construction of rectal anastomosis using this novel compression device is feasible and safe and appears to cause only few anastomotic strictures in the medium term. Discomfort or pain from the presence of the ring at anastomosis following (ultra-)low anterior resection can be observed in a relevant number of patients. PMID- 21541801 TI - Surgical outcome for mycotic aortic and iliac anuerysm. AB - BACKGROUND: The present study was designed to review surgical outcomes for mycotic aneurysm of the aortic or iliac arteries at a single center. METHODS: The study was based on retrospective chart review of patients undergoing operation for mycotic aneurysm. RESULTS: From January 1998 to December 2007, 56 patients received surgical treatment for mycotic aneurysm of the aortic or iliac arteries. Aneurysm sites included the aortic arch (n=5), proximal thoracic aorta (n=4), distal thoracic aorta (n=5), paravisceral aorta (n=5), juxtarenal aorta (n=4), infrarenal aorta (n=30), and iliac arteries (n=3). Salmonella was the leading pathogen (n=34). Nineteen patients with suprarenal lesions underwent in situ prosthetic graft replacement (n=17), extra-anatomic bypass (n=1), or endovascular aneurysm repair (EVAR) (n=1), and 37 patients with infrarenal lesions underwent the same procedures (n=16, 20, and 1, respectively). Overall in-hospital mortality was 23%. After discharge, four patients (7%) developed reinfection that led to fatal sepsis. Graft infection developed after three in situ prosthetic grafts (9%) and one extra-anatomic bypass (5%). Patients with suprarenal aortic lesions had poorer in-hospital (34%) and late (16%) mortality rates than those with infrarenal lesions (p=0.025). Those with suprarenal lesions also had a lower cumulative survival rate (p=0.016). CONCLUSIONS: The location of mycotic aneurysm was the determinant of mortality. Mycotic aneurysm of the suprarenal aorta has poor prognosis and requires alternative surgical treatment. PMID- 21541802 TI - Therapeutic strategies for epiphrenic diverticula: systematic review. AB - Most patients with epiphrenic diverticula are asymptomatic. When dysphagia or regurgitation is limited and respiratory complaints are absent, these patients usually can live with the diverticulum left in place. Fewer than one-third of the diverticula produce symptoms severe enough to seek medical attention or to warrant surgery. The purpose of this systematic review was to analyze the therapeutic strategies for epiphrenic diverticula-from a nonsurgical alternative such as endoscopic dilatation for symptomatic patients unfit for surgery, to the traditional approach of surgical resection (left thoracotomy), and finally to the minimally invasive techniques (thoracoscopy, laparoscopy) used more recently. Whatever treatment and approach are used for the patient with epiphrenic diverticula, a tailored protocol always involves detailed study of the esophageal morphology and function. PMID- 21541803 TI - Current and historical hybridization with differential introgression among three species of cyprinid fishes (genus Cyprinella). AB - Hybridization is common among freshwater fishes, particular among the Cyprinidae. We used two mitochondrial genes and one nuclear gene to characterize hybridization among two species pairs of Cyprinella in southwestern North America. Genalogical patterns revealed that C. lutrensis and C. venusta are currently hybridizing in several localities producing apparent F(1), F(2) and backcross generations, yet there was no evidence for introgression outside of local hybrid zones. Alternatively, mitochondrial haplotypes from C. lutrensis appear to have introgressed into a C. lepida population in the Nueces River completely replacing the native C. lepida haplotype. There was no evidence of introgression of nuclear DNA and there does not appear to be ongoing hybridization. The population of C. lepida from the nearby Frio River exhibits no evidence of hybridization with C. lutrensis. Thus, contact between C. lutrensis and C. venusta results in the formation of localized hybrid swarms, while contact between C. lutrensis and C. lepida has resulted in complete mitochondrial introgression in the Nueces River or no apparent hybridization in the Frio River. The three different outcomes of contact between these species illustrate the variable nature of interspecific reproductive interactions and provide an excellent system in which to better understand the factors influencing hybridization among freshwater fishes. PMID- 21541804 TI - Body composition monitor measurement technique for the detection of volume status in peritoneal dialysis patients: the effect of abdominal fullness. AB - BACKGROUND: Bioimpedance spectroscopy (BIS) is used to assess volume status in peritoneal dialysis (PD) patients. However, it is proposed that it may be troubling in patients with abnormal fluid distribution and body geometry. It is not clear whether having an empty abdomen or not interferes with the BIS results and its relation with echocardiographic findings in PD patients. METHODS: Twenty five prevalent PD patients were enrolled. Echocardiography and body composition analysis using BIS technique (50 frequencies, the Body Composition Monitor, BCM) were performed. Overhydration (OH), extracellular water (ECW) in liters and OH/ECW ratio were used as volume status indices. Differences in volume and echocardiographic findings, in patients with empty and with full abdomen, and their correlations with echocardiographic parameters were investigated. RESULTS: Mean age and PD duration were 61 +/- 2.5 years and 42 +/- 33 months, respectively. Sixty-four percent were male and 24% were diabetic. Mean left ventricular mass index (LVMi) was 131 +/- 43 g/m (,) (2) mean left atrium diameter (LA) was 4.1 +/- 0.1 cm, mean left ventricular ejection fraction (EF) was 64 +/- 10%. Mean OH in patients with full abdomen were 1.67 +/- 1.51 L and 1.68 +/- 1.48 L, depending on the inclusion or exclusion of the dialysate volume, respectively. In patients with an empty abdomen, mean OHs were 2.12 +/- 1.76 L and 1.91 +/- 1.56 L, depending on the inclusion or exclusion of the dialysate volume. BIS measurements with an empty, but not with a full abdomen, was related to the echocardiographic parameters. CONCLUSION: BIS is a reliable method to evaluate volume status in PD patients. BIS performed after peritoneal equilibration test with an empty abdomen, better reflects overhydration and is related to echocardiographic parameters. PMID- 21541805 TI - Individual decisions to migrate during civil conflict. AB - The existing literature on forced migration limits our understanding of how violence affects migration to competing destinations. This article adds to the literature on forced migration by studying how armed violence during a period of civil conflict in south-central Nepal influenced the likelihood of local, internal, and international migration. We find that violence has a nonlinear effect on migration, such that low to moderate levels of violence reduce the odds of movement, but when violence reaches high levels, the odds of movement increase. We also find that the effect of violence on mobility increases as the distance of the move increases. When we consider the influence of violence on microlevel decision-making, we find that the effects of individual and household level determinants were mostly consistent with hypotheses derived from contemporary theories of voluntary migration and that no predictor of migration influenced the decision to migrate differently in the presence of violence. PMID- 21541806 TI - Diagnosing preoperative hyperglycemia in non-diabetic patients: a challenge and an opportunity. PMID- 21541808 TI - Is it a he or a she? Behavioral and computational approaches to sex categorization. AB - Can people categorize the sex of neonate faces? Our experiment tested the sex categorization of neonate faces by adult participants. We used a set of 120 Caucasian faces (adults and 4-day-old neonates) that were presented just once to a large sample of participants. A computational model of low-level visual processing, based on Gabor filters, was used to explore the relation between spatial-frequency information and sex categorization. The results showed that participants were able to categorize the sex of the faces, but were less accurate with neonate (d' = 0.36, beta = -.97) than with adult (d' = 3.02, beta = -.93) faces. Moreover, faces were more frequently categorized as boys' than girls' faces. The computational model suggests that specific spatial-frequency channels carry most of the useful information for the categorization task. Overall, the findings reveal that subtle differences in neonate facial structure were enough to allow the sex categorization of neonate faces, although accuracy was low in both adults and the computational model of low-level visual processing. PMID- 21541809 TI - Personally-significant information affects performance only within the focus of attention: a direct manipulation of attention. AB - It has been suggested that personally significant (PS) information interferes with performance only when presented within the focus of attention. However, this claim was never tested by a systematic manipulation of attention, but only by using correlative measures of its locus. We addressed this issue in two experiments, utilizing a cued visual search paradigm that allowed us to directly manipulate attention and to measure behavioral and physiological responses. One of the stimuli in the search display had a higher luminance value (i.e., was cued), and, orthogonally, one of the stimuli could be a PS or neutral name. When the cue did not predict target location, PS distractors mildly interfered with task performance, regardless of the cue's location. However, when the cue predicted target location, responses were facilitated for cued targets, indicating that attention was shifted to the cue. Importantly, PS distractors interfered with task performance and elicited enhanced orienting responses only when they were cued. This implies that PS information affects performance only when presented within but not outside the focus of attention. PMID- 21541810 TI - Halt and recovery of illusory motion perception from peripherally viewed static images. AB - We quantitatively investigated the halt and recovery of illusory motion perception in static images. With steady fixation, participants viewed images causing four different motion illusions. The results showed that the time courses of the Fraser-Wilcox illusion and the modified Fraser-Wilcox illusion (i.e., "Rotating Snakes") were very similar, while the Ouchi and Enigma illusions showed quite a different trend. When participants viewed images causing the Fraser Wilcox illusion and the modified Fraser-Wilcox illusion, they typically experienced disappearance of the illusory motion within several seconds. After a variable interstimulus interval (ISI), the images were presented again in the same retinal position. The magnitude of the illusory motion from the second image presentation increased as the ISI became longer. This suggests that the same adaptation process either directly causes or attenuates both the Fraser-Wilcox illusion and the modified Fraser-Wilcox illusion. PMID- 21541807 TI - Hematopoietic cytokines for cardiac repair: mobilization of bone marrow cells and beyond. AB - Hematopoietic cytokines, traditionally known to influence cellular proliferation, differentiation, maturation, and lineage commitment in the bone marrow, include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor, stem cell factor, Flt-3 ligand, and erythropoietin among others. Emerging evidence suggests that these cytokines also exert multifarious biological effects on diverse nonhematopoietic organs and tissues. Although the precise mechanisms remain unclear, numerous studies in animal models of myocardial infarction (MI) and heart failure indicate that hematopoietic cytokines confer potent cardiovascular benefits, possibly through mobilization and subsequent homing of bone marrow-derived cells into the infarcted heart with consequent induction of myocardial repair involving multifarious mechanisms. In addition, these cytokines are also known to exert direct cytoprotective effects. However, results from small-scale clinical trials of G-CSF therapy as a single agent after acute MI have been discordant and largely disappointing. It is likely that cardiac repair following cytokine therapy depends on a number of known and unknown variables, and further experimental and clinical studies are certainly warranted to accurately determine the true therapeutic potential of such therapy. In this review, we discuss the biological features of several key hematopoietic cytokines and present the basic and clinical evidence pertaining to cardiac repair with hematopoietic cytokine therapy. PMID- 21541811 TI - Electrical stimulation of the mesencephalic ventral tegmental area evokes skeletal muscle vasodilatation in the cat and rat. AB - To test the hypothesis that the mesencephalic ventral tegmental area (VTA) plays a role in autonomic control of the cardiovascular system, we examined the cardiovascular effects of electrical stimulation of the mesencephalic ventral areas in anesthetized, paralyzed cats and rats. Electrical stimulation of the VTA for 30 s (100-MUA current intensity; 40-50-Hz pulse frequency; 0.5-1-ms pulse duration) increased femoral blood flow by 130-162% in anesthetized cats and rats, whereas the identical stimulation of the substantial nigra (SN) failed to increase femoral blood flow. Electrical stimulation of the VTA also increased the arterial blood pressure and heart rate in anesthetized rats, but did not alter them in anesthetized cats. Accordingly, femoral vascular conductance was increased by 102-134% in both cats and rats. Atropine methyl nitrate (0.1 mg/kg) injected intravenously in the cats markedly attenuated the increases in femoral blood flow and vascular conductance. VTA stimulation was able to produce substantial increases in femoral blood flow and vascular conductance following a decerebration procedure performed at the premammillary and precollicular level in the cats, although their responses tended to attenuate to 55-69% of the control before the decerebration. Thus, it is likely that electrical stimulation of the VTA, but not the SN, is capable of evoking skeletal muscle vasodilatation, particularly via a sympathetically mediated cholinergic mechanism in the cat, and that the ascending projection from the VTA to the forebrain may not be responsible for the muscle vasodilatation. PMID- 21541812 TI - Transcatheter arterial embolization of intramuscular active hemorrhage with N butyl cyanoacrylate. AB - PURPOSE: This study was designed to evaluate the clinical efficacy and safety of transcatheter arterial embolization (TAE) with n-butyl cyanoacrylate (NBCA) for intramuscular active hemorrhage of varied etiologies and anatomic sites. METHODS: Eighteen patients who demonstrated hematoma with pseudoaneurysm and/or active extravasation of contrast media underwent TAE with NBCA. Etiologies of hematoma included trauma, postoperative complication, and coagulopathy (due to underlying disease or anticoagulation therapy). Sites of embolization included chest wall, abdomen wall, retroperitoneum, and extremity. TAE was performed by using 1:3 to 1:5 mixtures of NBCA and iodized oil, either solely (n = 15) or in combination with microcoil (n = 3). The technical and clinical success rate, procedure related complications, and clinical outcomes were evaluated. RESULTS: The technical and clinical success rates were 100% and 83% (15/18), respectively. Two patients expired while admitted due to other comorbidities. One patient expired due to recurrent bleeding at another site. There were no serious complications relating to the embolization procedure. CONCLUSIONS: TAE with NBCA is effective and safe treatment modality for intramuscular active hemorrhage. PMID- 21541813 TI - Developing and implementing an advanced communication training program in oncology at a comprehensive cancer center. AB - Cancer patients report significant levels of unmet needs in the realm of communication. Communication skills training programs have been shown to improve clinical communication. However, advanced communication skills training programs in oncology have lacked institutional integration, and thus have not attended to institutional norms and cultures that may counteract explicit communication skills training. We developed and implemented an advanced communication skills training program made up of nine teaching modules for faculty, fellows, and residents. Training included didactic and experiential small group work. Self efficacy and behavior change were assessed for individual participants. Since 2006, 515 clinicians have participated in this training program. Participants have shown significant gains in self-efficacy regarding communicating with patients in various contexts. Our initial work in this area demonstrates the implementation of such a program at a major cancer center to be feasible, to be acceptable, and to have a significant impact on participants' self-efficacy. PMID- 21541814 TI - A confidant support and problem solving model of divorced fathers' parenting. AB - This study tested a hypothesized social interaction learning (SIL) model of confidant support and paternal parenting. The latent growth curve analysis employed 230 recently divorced fathers, of which 177 enrolled support confidants, to test confidant support as a predictor of problem solving outcomes and problem solving outcomes as predictors of change in fathers' parenting. Fathers' parenting was hypothesized to predict growth in child behavior. Observational measures of support behaviors and problem solving outcomes were obtained from structured discussions of personal and parenting issues faced by the fathers. Findings replicated and extended prior cross-sectional studies with divorced mothers and their confidants. Confidant support predicted better problem solving outcomes, problem solving predicted more effective parenting, and parenting in turn predicted growth in children's reduced total problem behavior T scores over 18 months. Supporting a homophily perspective, fathers' antisociality was associated with confidant antisociality but only fathers' antisociality influenced the support process model. Intervention implications are discussed regarding SIL parent training and social support. PMID- 21541815 TI - The effects of biliopancreatic diversion on type 2 diabetes mellitus in patients with mild obesity (BMI 30-35 kg/m2) and simple overweight (BMI 25-30 kg/m2): a prospective controlled study. AB - BACKGROUND: Beneficial effects of BPD on T2DM in BMI >35 kg/m(2) patients are far better than those in patients with BMI 25-35. This study was aimed at investigating if a similar difference exists between patients with mild obesity (OB, BMI 30-35) or simple overweight (OW, BMI 25-30). METHODS: Fifteen OB (six M) and 15 OW (13 M), diabetic for >= 3 years, with HbA1c >= 7.5% despite medical therapy, underwent BPD. OB/OW: age 55.1 +/- 8.0/57.8 +/- 6.7 years, BMI 33.1 +/- 1.5/28.0 +/- 1.3 kg/m(2), diabetes duration 11.6 +/- 8.0/11.1 +/- 6.1 years, insulin therapy 4/8 p. FSG and HbA1c were determined preoperatively and up to 2 years. Insulin resistance and beta-cell function were explored by means of HOMA IR and IVGTT (AIR). Thirty-eight diabetic patients on medical therapy served as controls. RESULTS: Mean BMI stabilized around 27 since the 4th month in OB, and 24 since 1st month in OW. FSG in OB/OW preop, 1, 12, 24 months: 234 +/- 76/206 +/ 62 mg/dL, 154 +/- 49/176 +/- 75, 131 +/- 32/167 +/- 48, 134 +/- 41/154 +/- 41 (cross-sectional n.s. at all times); HbA1c: 9.5 +/- 1.6/9.1 +/- 1.3, 7.3 +/- 1.1/7.3 +/- 1.2, 5.9 +/- 0.6/7.1 +/- 1.1 (p < 0.01), 5.9 +/- 0.9/6.9 +/- 1.1 (p < 0.01). HOMA-IR, preoperatively 10.7 +/- 5.8/7.5 +/- 5.4, went below 3.0 at 1 month and remained such until 2 years in both groups. AIR, preoperatively 1.11 +/ 3.17/1.27 +/- 2.68 MUIU/mL, in OB significantly increased at 4 months to 7.63 +/ 5.79, maintained up to 2 years with 6.95 +/- 3.19, whereas in OW, statistical significance was reached only at 2 years with 5.02 +/- 4.87. CONCLUSIONS: Significantly different BPD effect, thus biological severity of T2DM, also exists between mildly obese and simply overweight patients. The rise of AIR allows hoping that an increase of beta-cell mass may occur in the long run. PMID- 21541816 TI - MALDI tissue imaging: from biomarker discovery to clinical applications. AB - Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) is a powerful tool for the generation of multidimensional spatial expression maps of biomolecules directly from a tissue section. From a clinical proteomics perspective, this method correlates molecular detail to histopathological changes found in patient-derived tissues, enhancing the ability to identify candidates for disease biomarkers. The unbiased analysis and spatial mapping of a variety of molecules directly from clinical tissue sections can be achieved through this method. Conversely, targeted IMS, by the incorporation of laser-reactive molecular tags onto antibodies, aptamers, and other affinity molecules, enables analysis of specific molecules or a class of molecules. In addition to exploring tissue during biomarker discovery, the integration of MALDI IMS methods into existing clinical pathology laboratory practices could prove beneficial to diagnostics. Querying tissue for the expression of specific biomarkers in a biopsy is a critical component in clinical decision-making and such markers are a major goal of translational research. An important challenge in cancer diagnostics will be to assay multiple parameters in a single slide when tissue quantities are limited. The development of multiplexed assays that maximize the yield of information from a small biopsy will help meet a critical challenge to current biomarker research. This review focuses on the use of MALDI IMS in biomarker discovery and its potential as a clinical diagnostic tool with specific reference to our application of this technology to prostate cancer. PMID- 21541817 TI - Myocardial perfusion PET: a split function? PMID- 21541818 TI - Safety of regadenoson as a pharmacologic stress agent for myocardial perfusion imaging in chronic kidney disease patients not on hemodialysis. AB - BACKGROUND: Pharmacokinetic studies suggest delayed clearance of Regadenoson (REG), a new selective A2A receptor agonist in chronic kidney disease (CKD). The safety of REG in large series of CKD patients in daily clinical practice remains unstudied. METHODS: Retrospective study of patients with eGFR < 60 mL/min (n = 411, Grp 1, CKD) were compared to patients with eGFR >= 60 mL/min (n = 638, Grp 2, Control) undergoing REG-SPECT from Jan to Nov 2009. Patient demographics, REG SPECT data, side effects, and arrhythmia occurrences were evaluated. RESULTS: No major adverse events were noted immediately after REG-SPECT or at 1 week of follow-up. There were no differences in any arrhythmias in between the two groups (Grp 1, 47.2% vs Grp 2, 42.9%, P = ns). Ninety-nine percent of arrhythmias in CKD patients were PACs or PVCs. Transient junctional rhythm was observed in one CKD patient. There were no occurrences of second degree or higher degree AV block. Grp 1 had a blunted heart rate response (16.6 +/- 16.1 vs 24.9 +/- 20.3 bpm, P <= .001) and greater systolic blood pressure drop response (-7.4 +/- 21.1 vs -1.4 +/ 20.9 mm Hg, P <= .001) compared to Grp 2. Transient headache was more in Grp 2 (15.8% vs 22.6%, P <= .007). Aminophylline use to ward-off the side effects was comparable (9.5% vs 9.9%, P = ns). CONCLUSION: REG-SPECT can be safely performed in CKD non-dialysis patients with excellent tolerability, minimal side effects, and favorable hemodynamic responses compared to control group. PMID- 21541819 TI - First record of Batrachochytrium dendrobatidis infecting four frog families from Peninsular Malaysia. AB - The fungal pathogen Batrachochytrium dendrobatidis (Bd) infects amphibians on every continent where they occur and is linked to the decline of over 200 amphibian species worldwide. At present, only three published Bd surveys exist for mainland Asia, and Bd has been detected in South Korea alone. In this article, we report the first survey for Bd in Peninsular Malaysia. We swabbed 127 individuals from the six amphibian families that occur on Peninsular Malaysia, including two orders, 27 genera, and 47 species. We detected Bd on 10 out of 127 individuals from four of five states and five of 11 localities, placing the 95% confidence interval for overall prevalence at 4-14%. We detected no variation in Bd prevalence among regions, elevations, or taxonomic groups. The infection intensity ranged from 1 to 157,000 genome equivalents. The presence of Bd infections in native species without clinical signs of disease suggests that Bd may be endemic to the region. Alternately, Bd may have been introduced from non native amphibians because of the substantial amphibian food trade in Peninsular Malaysia. Under both scenarios, management efforts should be implemented to limit the spread of non-native Bd and protect the tremendous amphibian diversity in Peninsular Malaysia. PMID- 21541820 TI - Multilevel confirmatory factor analysis of the Systems of Care Implementation Survey (SOCIS). AB - A major impediment to obtaining national information on systems of care implementation has been the lack of a psychometrically sound large-scale survey instrument. The present study provided information on the factorial and concurrent validity of the Systems of Care Implementation Survey scales. Multilevel confirmatory factor analysis and multilevel regression analysis were used to test these indicators of internal and external validity. Two hundred twenty-five counties were randomly selected and stratified by population size and poverty level. Nine hundred ten informants responded to the survey questionnaire, M = 4.04 informants per county (SD = 3.17). Results indicated that all models had at least adequate fit to the data, with nine of the 14 factor models having excellent fit. Overall, 11 of the 14 factors had some indication that receiving federal funding to create systems of care was associated with higher scores on the factors. Implications for future research were discussed. PMID- 21541821 TI - The Cognitive Reflection Test as a predictor of performance on heuristics-and biases tasks. AB - The Cognitive Reflection Test (CRT; Frederick, 2005) is designed to measure the tendency to override a prepotent response alternative that is incorrect and to engage in further reflection that leads to the correct response. In this study, we showed that the CRT is a more potent predictor of performance on a wide sample of tasks from the heuristics-and-biases literature than measures of cognitive ability, thinking dispositions, and executive functioning. Although the CRT has a substantial correlation with cognitive ability, a series of regression analyses indicated that the CRT was a unique predictor of performance on heuristics-and biases tasks. It accounted for substantial additional variance after the other measures of individual differences had been statistically controlled. We conjecture that this is because neither intelligence tests nor measures of executive functioning assess the tendency toward miserly processing in the way that the CRT does. We argue that the CRT is a particularly potent measure of the tendency toward miserly processing because it is a performance measure rather than a self-report measure. PMID- 21541822 TI - Ethnography and the making of modern health professionals. PMID- 21541823 TI - Adrenalectomy: is volume a surrogate for quality? PMID- 21541824 TI - The impact of tumor morcellation during surgery on the outcomes of patients with apparently early low-grade endometrial stromal sarcoma of the uterus. AB - BACKGROUND: The purpose of this study was to evaluate the impact of tumor morcellation on the outcomes of patients with apparently early low-grade endometrial stromal sarcoma (LGESS). METHODS: Outcomes were retrospectively compared between patients with apparently early LGESS who did not (group A, n=27) or did (group B, n=23) undergo tumor morcellation. RESULTS: There were no between group differences in age, menopausal status, parity, body mass index, and preoperative presumptive diagnosis, nor were there between-group differences in tumor stage, tumor size, myometrial invasion, lymphovascular space invasion, frequency of ovarian preservation, adjuvant therapy, or follow-up time. More patients in group A underwent lymph node dissection (51.9 vs. 21.7%; P=0.029). Only 1 patient in each group had distant recurrence. There were 2 patients (7.4%) in group A and 7 (31.4%) in group B who had abdominopelvic recurrence. The risk of abdominopelvic recurrence was significantly higher in group B than in group A (odds ratio [OR], 5.47; 95% confidence interval [95% CI], 1.04-29.70; P=0.035). The 5-year disease-free survival (DFS) rates were 84% for group A and 55% for group B (P=0.028) and the 5-year abdominopelvic DFS rates were 89 and 58% (P=0.023), respectively. Multivariate analysis showed that tumor morcellation were significantly associated with poorer DFS (OR, 4.03; 95% CI, 1.06-15.30; P=0.040) and abdominopelvic DFS (OR, 5.06; 95% CI, 1.02-25.04; P=0.047). CONCLUSIONS: Inadvertent tumor morcellation during surgery has an adverse impact on the outcomes of patients with early LGESS. PMID- 21541825 TI - Inguinopelvic lymphadenectomy following positive inguinal sentinel lymph node biopsy in melanoma: true frequency of synchronous pelvic metastases. AB - BACKGROUND: True frequency of synchronous pelvic metastases with positive inguinal sentinel lymph node (SLN) biopsy is unknown. Role of pelvic dissection in the SLN era is unclear. METHODS: From 1994 to 2004, 1 surgeon routinely performed nonselective, complete inguinopelvic lymphadenectomy after positive inguinal SLN biopsy. All cases were identified from a prospectively maintained database. Clinicopathologic features associated with pelvic disease were assessed. RESULTS: A total of 40 patients with positive inguinal SLN underwent, without additional selection, 42 complete inguinopelvic lymphadenectomies. Median age was 46.5 years (range 25-79 years); 79% had lower extremity primaries. Median Breslow depth was 2.3 mm (range 1.0-10.0 mm), Clark's IV/V 98%, ulceration 26%. Frequency of synchronous pelvic disease upon completion lymphadenectomy was 5 of 42 (11.9%). Patients with and without pelvic disease were similar in age, sex, Breslow depth, Clark's level, ulceration, and mitoses. All 5 cases with pelvic metastases had extremity primaries (4 distal, 1 proximal). Of the 5, 3 (60%) had >=3 total involved inguinal nodes, compared with only 1 (2.7%) of the 37 cases without pelvic disease (P=.003). Ratio of positive to total number inguinal nodes retrieved was >0.20 in 80% of cases with pelvic disease and 8.6% of cases without (P=.002). Upon lymphoscintigraphy review, secondary pelvic drainage was present in 80% of cases with pelvic disease compared with 56% of cases without pelvic disease, though the trend was statistically insignificant (P=.63). CONCLUSIONS: In this cohort of unselected, SLN-positive patients with complete inguinopelvic lymphadenectomy, frequency of synchronous pelvic disease was 11.9%. Patients with >=3 total involved inguinal nodes or inguinal node ratio >0.20 appear more likely to harbor pelvic disease. PMID- 21541826 TI - The clinical significance of peripherally inserted central venous catheter related deep vein thrombosis. AB - BACKGROUND: Peripherally inserted central venous catheters (PICCs) are being increasingly utilized in hospitalized patients as alternatives to centrally inserted central venous catheters (CICVCs). However, concern exists over the risk of PICC-related large vein thrombosis (PRLVT). The incidence rate and significance of symptomatic PRLVT in critically ill patients admitted to the neurological intensive care unit (ICU) is not known. METHODS: Retrospective descriptive study of consecutive PICCs placed in critically ill patients admitted to a tertiary care neurological ICU between March 2008 and February 2010. Symptomatic PRVLT was defined as an event that prompted Duplex ultrasound of the ipsilateral extremity in which an acute, proximal large vein thrombosis was confirmed in association with the PICC or confirmed within 5 days of PICC removal. Incidence rate of PRLVT and catheter-related complications were calculated per "line" (catheter). Descriptive statistics were performed with two sample, and t-tests for age and categorical variables were assessed by Chi-square test or Fishers exact test as appropriate RESULTS: Four hundred and seventy-nine lines were placed during the study period with 39 developing a symptomatic PRLVT (incidence rate = 8.1%). Male gender was associated with development of a thrombosis (P = 0.02), but size (P = 0.21) and location of catheter were not (P = 0.30). Median line dwell time was 12 days (IQR 16) with a dwell time of 8 days (IQR 9) until thrombosis diagnosis. Pulmonary embolus attributed to PRLVT occurred in 1.3% of line placements and 15% of symptomatic PRLVT. The majority of patients had their line removed. In addition, some patients also had anticoagulation initiated or a superior vena cava filter placed. CONCLUSIONS: Symptomatic PRLVT is not uncommon in critically ill patients admitted to the neurological ICU. Future research should focus on indentifying modifiable risk factors for PRLVT and on comparing major cumulative complication rates between PICCs and CICVCs. PMID- 21541827 TI - Are couple-oriented interventions effective across chronic illnesses? A commentary on Martire et al. PMID- 21541828 TI - 3D simulation of internal tablet strength during tableting. AB - This study presents a new approach to model powder compression during tableting. The purpose of this study is to introduce a new discrete element simulation model for particle-particle bond formation during tablet compression. This model served as the basis for calculating tablet strength distribution during a compression cycle. Simulated results were compared with real tablets compressed from microcrystalline cellulose/theophylline pellets with various compression forces. Simulated and experimental compression forces increased similarly. Tablet breaking forces increased with the calculated strengths obtained from the simulations. The calculated bond strength distribution inside the tablets showed features similar to those of the density and pressure distributions in the literature. However, the bond strength distributions at the center of the tablets varied considerably between individual tablets. PMID- 21541829 TI - Effect of freezing and type of mucosa on ex vivo drug permeability parameters. AB - The porcine esophageal mucosa has been proposed as a substitute for the buccal mucosa barrier on ex vivo permeability studies mainly due to its large surface area as well as its easier preparation. Therefore, this study compared the ex vivo permeability parameters of two drugs (carmabazepine (CBZ) and triamcinolone acetonide (TAC)) with different permeabilities and physicochemical properties through buccal and esophageal mucosae using a Franz diffusion cell system and HPLC as detection method. The freezing effects on drug permeability parameters were also evaluated by comparing them when fresh and frozen tissues were used. The barrier properties were not affected by the freezing process since the obtained parameters for both drugs were similar in frozen and fresh tissues (buccal and esophageal mucosae). However, an increase of CBZ retention was shown in frozen tissues. Fresh and frozen esophageal mucosae provided higher permeation of TAC than on buccal mucosae while the obtained permeability parameters for CBZ were similar on both mucosae. According to our results, porcine esophageal mucosa could be used as a substitute for buccal mucosa on ex vivo studies involving CBZ but not TAC. Frozen tissues could be used as substitute for fresh tissues in both cases. However, any substitution should be done with care and only if previous tests were performed, because the results could differ depending on the tested drug. PMID- 21541831 TI - Effects of treatment of myofascial trigger points on the pain of fibromyalgia. AB - Myofascial pain syndromes (MPSs) from trigger points (TrPs) and fibromyalgia syndrome (FMS) are common musculoskeletal pain conditions that frequently coexist in the same patients. In recent decades, it has become evident that these entities greatly influence each other's clinical expression. FMS is mainly rooted in the central nervous system, while TrPs have a peripheral origin. However, the nociceptive impulses from TrPs may have significant impact on symptoms of FMS, probably by enhancing the level of central sensitization typical of this condition. Several attempts have been made to assess the effects of treatment of co-occurring TrPs in FMS. We report the outcomes of these studies showing that local extinction of TrPs in patients with fibromyalgia produces significant relief of FMS pain. Though further studies are needed, these findings suggest that assessment and treatment of concurrent TrPs in FMS should be systematically performed before any specific fibromyalgia therapy is undertaken. PMID- 21541832 TI - [Panorama of dermatologic practice]. PMID- 21541833 TI - [Operative dermatology--a status report]. PMID- 21541834 TI - [Autoinflammatory syndromes/fever syndromes]. AB - Hereditary periodic (fever) syndromes, also called autoinflammatory syndromes, are characterized by relapsing fever and additional manifestations such as skin rashes, mucosal manifestations, or joint symptoms. Some of these disorders present with organ involvement and serological signs of inflammation without fever. There is a strong serological inflammatory response with an elevation of serum amyloid A (SAA), resulting in an increased risk of secondary amyloidosis. There are monogenic disorders (familial mediterranean fever (FMF), hyper-IgD syndrome (HIDS), cryopyrin-associated periodic syndromes (CAPS), "pyogenic arthritis, acne, pyoderma gangrenosum" (PAPA), and "pediatric granulomatous arthritis (PGA) where mutations in genes have been described, which in part by influencing the function of the inflammasome, in part by other means, lead to the induction of the production of IL-1beta. In "early-onset of enterocolitis (IBD)", a functional IL-10 receptor is lacking. Therapeutically, above all, the IL-1 receptor antagonist anakinra is used. In case of TRAPS and PGA, TNF-antagonists (etanercept) may also be used; in FMF colchicine is first choice. As additional possible autoinflammatory syndromes, PFAPA syndrome (periodic fever with aphthous stomatitis, pharyngitis and adenitis), Schnitzler syndrome, Still's disease of adult and pediatric onset, Behcet disease, gout, chronic recurrent multifocal osteomyelitis (CRMO) and Crohn's disease also are mentioned. PMID- 21541835 TI - Feasibility of TEE-guided stroke risk assessment in atrial fibrillation background, aims, design and baseline data of the TIARA pilot study. AB - BACKGROUND: Antithrombotic management in atrial fibrillation (AF) is currently based on clinical characteristics, despite evidence of potential fine-tuning with transoesophageal echocardiography (TEE). This open, randomised, multicentre study addresses the hypothesis that a comprehensive strategy of TEE-based aspirin treatment in AF patients is feasible and safe. METHODS: Between 2005 and 2009, ten large hospitals in the Netherlands enrolled AF patients with a moderate risk of stroke. Patients without thrombogenic TEE characteristics were randomised to aspirin or vitamin K antagonists (VKA). The primary objective is to show that TEE based aspirin treatment is safe compared with VKA therapy. The secondary objective tests feasibility of TEE as a tool to detect echocardiographic features of high stroke risk. This report compares randomised to non-randomised patients and describes the feasibility of a TEE-based approach. RESULTS: In total, 310 patients were included. Sixty-nine patients were not randomised because of non visualisation (n = 6) or TEE risk factors (n = 63). Compared with non-randomised patients, randomised patients (n = 241) were younger (65 +/- 11 vs. 69 +/- 9 years, p = 0.004), had less coronary artery disease (9 vs. 20%, p = 0.018), previous TIA (1.7 vs. 7.2%, p = 0.029), AF during TEE (25 vs. 54%, p < 0.001), mitral incompetence (55 vs. 70%, p = 0.038), VKA use (69 vs. 82%, p = 0.032), had a lower mean CHADS(2) score (1.2 +/- 0.6 vs. 1.6 +/- 1.0, p = 0.004), and left ventricular ejection fraction (59 +/- 8 vs. 56 +/- 8%, p = 0.016). CONCLUSIONS: This study shows that a TEE-based approach for fine-tuning stroke risk in AF patients with a moderate risk for stroke is feasible. Follow-up data will address the safety of this TEE-based approach. PMID- 21541836 TI - Diagnostic and prognostic value of absence of coronary artery calcification in patients with stable chest symptoms. AB - The aim of this study was to determine the prognostic value of a coronary artery calcium score (CACS) of 0 in patients with stable chest symptoms and to compare it as a first-line test with bicycle exercise testing (X-ECG). Altogether, 315 consecutive patients over 44 years of age, with stable chest symptoms and no previous diagnosis of coronary artery disease (CAD) visited the outpatient clinic of our community hospital and underwent both CACS and X-ECG. The mean age was 60.54 years (SD 9.7; range 45-88 years). Of these patients, 141 had no detectable coronary calcium (44.8%) We excluded patients who did not sign informed consent (n = 4). Three patients were lost to follow-up. The follow-up group therefore consisted of 134 patients. The mean follow-up period was 44.6 months (25th-75th percentile: 35.5-54.3 months), during which no major adverse cardiac events (MACE) occurred. The negative predictive value (NPV) was 100%. X-ECG was negative in only 89 patients, equivocal in 39 patients and false-positive in 6 patients requiring additional stress myocardial imaging in 45 patients. NPV as a first line test was therefore 66.4%. IN CONCLUSION: patients over 44 years with stable chest symptoms and no detectable coronary calcium have an excellent prognosis. CACS performs better compared with X-ECG as an initial test in patients with stable chest symptoms. PMID- 21541837 TI - Contrast-enhancement cardiac magnetic resonance imaging beyond the scope of viability. AB - The clinical applications of cardiovascular magnetic resonance imaging with contrast enhancement are expanding. Besides the direct visualisation of viable and non-viable myocardium, this technique is increasingly used in a variety of cardiac disorders to determine the exact aetiology, guide proper treatment, and predict outcome and prognosis. In this review, we discuss the value of cardiovascular magnetic resonance imaging with contrast enhancement in a range of cardiac disorders, in which this technique may provide insights beyond the scope of myocardial viability. PMID- 21541838 TI - Kinetics of optical control of enzyme activity with photoswitchable inhibitors. AB - This paper presents theoretical and simulation studies on controlling enzymatic reactions with photoswitchable inhibitors. It is found that the maximum attainable switching ratio (ratio of the steady state rates of product formation in the "on" and the "off" state) of a photoswitchable inhibitor is dependent on its photoswitching factor (ratio of the equilibrium constants of the photostationary states under the "off" and the "on" illuminations). Attachment of multiple photoswitchable groups to an inhibitor molecule increases the theoretically attainable switching ratio. The affinity of the enzyme for the substrate and the inhibitor is the rate-limiting factor of the switching between active and inactive states. Use of inhibitors with high enzyme affinity and photoswitchable groups with high photoswitching factor would provide high switching ratio. These results may help to design better systems for optical control of biochemical processes. PMID- 21541839 TI - The molecular clock in terms of quantum information processing of coherent states, entanglement and replication of evolutionarily selected decohered isomers. AB - Evolutionary pressures have selected quantum uncertainty limits -DeltaxDeltap ( x ) >= 1/2h-to operate on metastable amino DNA protons. This introduces a probability of molecular clock arrangement, keto-amino -> enol-imine, where product protons are entangled and participate in coupled quantum oscillation at frequencies of ~ 10(13) s(-1). The ket "seen by" the transcriptase, reading a coherent enol-imine G'-state, is |phi >= alpha| + + > +beta|+- > +gamma|-+ > +delta|-->. The transcriptase implements its measurement and generates an output qubit of observable genetic specificity information in an interval Deltat ? 10( 13) s. These quantum measurements can specify the relative distribution of coherent G'-C' states at time of measurement. The ensuing quantum entanglement between coherent protons and transcriptase units is utilized as a resource to generate proper decoherence and introduce selected time-dependent substitutions, ts, and deletions, td. Topal-Fresco ts are G'202 -> T, G'002 -> C, *G020(0) -> A and *C202(2) -> T, whereas td are exhibited at coherent *A-*T sites. Variation in clock 'tic-rate' is a consequence of clock introduction of initiation codons - UUG, CUG, AUG, GUG - and stop codons, UAA, UAG, UGA. Using approximate quantum methods for times t < ~ 100 y, the probability, P(t), of keto-amino -> enolimine arrangement is P ( rho )(t) = 1/2(gamma ( rho )/h)(2) t (2) where gamma ( rho ) is the energy shift. This introduces a quantum Darwinian evolution model which provides insight into biological consequences of coherent states populating human genes, including inherited (CAG)( n ) repeat tracts. PMID- 21541840 TI - In silico prediction and characterization of 3D structure and binding properties of catalase from the commercially important crab, Scylla serrata. AB - The enzyme catalase breaks down H(2)O(2), a potentially harmful oxidant, to H(2)O and O(2). Besides oxidase activity, the enzyme also exhibits peroxidase activity. Therefore, it plays an important role in maintaining health and regulating pathophysiology of the organisms. However, 3D structure of this important enzyme in invertebrates particularly in crabs is not yet available. Therefore, an attempt has been made to predict the structure of the crab catalase and to envisage its catalytic interaction with H(2)O(2). A three dimensional model of crab catalase was constructed using the NADPH binding site on Beef Liver catalase from Bos taurus (PDBID: 7CAT) as template by comparative modeling approach. Backbone conformation of the modeled structure by PROCHECK revealed that more than 98% of the residues fell in the allowed regions, ERRAT results confirmed good quality of modeled structure and VERIFY3D profile was satisfying. Molecular docking has been used to know the binding modes of hydrogen peroxide with the crab catalase protein. The receptor structures used for docking were derived from molecular dynamics (MD) simulations of homology modeled structure. The docking results showed that the three important determinant residues Arg68, Val70 and Arg108 in catalase were binding with H(2)O(2) as they had strong hydrogen bonding contacts with the substrate. Our analysis provides insight into the structural properties of crab catalase and defines its active sites for binding with substrate. These data are important for further studies of catalase of invertebrates in general and that of crabs in particular. PMID- 21541841 TI - QSAR study for cytotoxicity of diterpenoid tanshinones. AB - A quantitative structure-activity relationship (QSAR) of a series of tanshinone compounds with cytotoxicity against murine leukemia cell lines P-388 has been studied using density functional theory (DFT) method combined with statistical analysis. Four main independent factors contributing to the cytotoxicity including the maximum molecular electrostatic potential at the SAS surface (SAS (max)), the average nucleophilic superdelocalizability (ANS), the dihedral between ring A and B (u) and the net atomic charge of C (12) (Q(C (12))) were selected by stepwise multiple regression method, then the QSAR equation was established via multiple linear regression (MLR) analysis. These descriptors accounted for 74.2% of the variation in the in vitro biological activity among the tanshinone analogues. The QSAR equation was used to estimate the cytotoxicity for new compounds of this series by calculating the four descriptors. Based on this model, six new compounds with higher cytotoxicity were theoretically designed. PMID- 21541842 TI - Fitting evolutionary process of influenza A virus nucleoproteins using analytical solution of system of differential equations. AB - Very recently we explored the possibility of using differential equations to describe the evolution of proteins. In this study we used the amino-acid pair predictability to quantify 1709 nucleoproteins of influenza A viruses isolated from 1918 to 2008 to represent their evolutionary process, thereafter we used the analytical solution of system of differential equations to fit the evolution of the nucleoprotein family. The results showed that the analytical solution could fit the nucleoprotein evolution and the obtained parameters were useful for timing of future mutations. Our approach provided a way to quantitatively analyze protein dynamics and evolution. PMID- 21541843 TI - Which value should be used as the lethal concentration 50 (LC(50)) with bacteria? AB - Computations of lethal concentration 50 (LC(50)) of a data-set of a toxicity study on an herbicide against a cyanobacterium were performed by general linear regression, Spearman-Karber and probit transformation methods, for evaluation of the methods used. It is shown that the linear regression method yields some faulty LC(50) value, while both of Spearman-Karber and probit methods yield similar and statistically respectable LC(50) values. In the Spearman-Karber method, a prerequisite of some uniform dose-interval of test-chemical and tiring calculations were involved. But, the probit method is less tiring and additionally computed LC(25) and LC(75) values help assess the solicited accuracy of the LC(50) value and other test-statistics, including minimum inhibitory concentration (MIC), highest-permissive concentration (HPC), and a few more with respect to lethal concentration 100 (LC(100)) without prerequisite of any uniform dose-interval of test-chemical. Further, the redundancy of computations of standard error (SE) and 95% confidence limits (CL) of the LC(50) value is suggested, as CL values are so wide to spoil LC(50) accuracy that is solicited in toxicology. PMID- 21541844 TI - A compact review on the comparison of conventional and non-conventional interactions on the structural stability of therapeutic proteins. AB - Therapeutic proteins carry out the most difficult tasks in living cells. They do so by interacting specifically with other molecules. This requires that they fold to a unique and more stable conformation. A prerequisite for comprehending the folding processes in their immense complexity entails a thorough understanding of many weak interactions. The purpose of this review is to systematically study the role of weak interactions such as cation-pi, C-H......pi, N-H......pi and O H......pi, in the set of 49 therapeutic proteins. The importance of many of these interactions (for example, cationic residues interacting with pi system) is revealed by the higher degree of conservation observed for them in protein structures. These interactions are mainly formed by long-range contacts and significant percentage of cation-pi, C-H......pi, N-H......pi and O-H......pi interacting residues had one or more stabilization centers. Further, a comparison of conventional and nonconventional interactions in the present data set unambiguously highlights the significance of these weak interactions in the structural stability of therapeutic proteins. We propose that the incorporation of the entirety of these interactions leads to a more complete description of the problem, and that this could provide new perspectives and new possible answers. PMID- 21541846 TI - Pesticidal copper (I) oxide: environmental fate and aquatic toxicity. AB - Besides being a naturally occurring element and an essential micronutrient, copper is used as a pesticide, but at generally higher concentrations. Copper, unlike organic pesticides, does not degrade, but rather enters a complex biogeochemical cycle. In the water column, copper can exist bound to both organic and inorganic species and as free or hydrated copper ions. Water column chemistry affects copper speciation and bioavailability. In all water types (saltwater, brackish water, and freshwater), organic ligands in the water column can sequester the majority of dissolved copper, and therefore, organic ligands play the largest role in copper bioavailability. In freshwater, however, the geochemistry of a particular location, including water column characteristics such as water hardness and pH, is a significant factor that can increase copper bioavailability and toxicity. In most cases, organic ligand concentrations greatly exceed copper ion concentrations in the water column and therefore provide a large buffering capacity. Hence, copper bioavailability can be grossly overestimated if it is based on total dissolved copper (TDCu) concentrations alone. Other factors that influence copper concentrations include location in the water column, season, temperature, depth, and level of dissolved oxygen. For example, concentrations of bioavailable copper may be significantly higher in the bottom waters and sediment pore waters, where organic ligands degrade much faster and dissolved copper is constantly resuspended and recycled into the aquatic system. Aquatic species differ greatly in their sensitivity to copper. Some animals, like mollusks, can tolerate high concentrations of the metal, while others are adversely affected by very low concentrations of copper. Emerging evidence shows that very low, sublethal copper levels can adversely affect the sense of smell and behavior of fish. The developmental stage of the fish at the time of copper exposure is critical to the reversibility of sensory function effects. The fish olfactory system may be the most sensitive structure to copper pollution. The major factors that influence copper-induced toxicity are dissolved organic carbon and water salinity. Dissolved organic carbon reduces copper toxicity by sequestering bioavailable copper and forming organic complexes with it. Salinity, on the other hand, influences copper bioavailability at the biological action site and also affects metal biodistribution and bioaccumulation in the organism. Therefore, the salinity gradient can increase or decrease copper toxicity in different aquatic species. In some killifish, copper may affect different organs at different times, depending on the water salinity. The most studied and best explained copper toxicity mechanisms involve inhibition of key enzymes and disruption of osmoregulation in the gill. Other toxicity mechanisms may involve reactive oxygen species generation and changes of gene transcription in the fish olfactory signaling pathway. More studies are needed to evaluate the potential magnitude of copper remobilization from the sediment that may result from climate change and its effects on surface waters. Moreover, the environmental exposure, fate, and ecotoxicity of emerging metal nanoparticles, including nanocopper, will require additional studies as new forms of copper appear from application of nanotechnology to copper compounds. PMID- 21541845 TI - Neurodevelopmental abnormalities in ADHD. AB - Structural and functional imaging studies in subjects with attention deficit hyperactivity disorder (ADHD) are reviewed with the goal of gleaning information about neurodevelopmental abnormalities characterizing the disorder. Structural imaging studies, particularly those with longitudinal designs, suggest that brain maturation is delayed by a few years in ADHD. However, a maturational delay model alone is incomplete: alternate courses are suggested by differences associated with phenotypic factors, such as symptom remission/persistence and exposure to stimulant treatment. Findings from functional imaging studies point to multiple loci of abnormalities that are not limited to frontal-striatal circuitry, which is important for executive and motivational function, but also include parietal, temporal and motor cortices, and the cerebellum. However, a definitive conclusion about maturational delays or alternate trajectories cannot be drawn from this work as activation patterns are influenced by task-specific factors that may induce variable performance levels and strategies across development. In addition, no studies have implemented cross-sectional or longitudinal designs, without which the developmental origin of differences in activation cannot be inferred. Thus, current task-evoked functional imaging provides information about dynamic or state-dependent differences rather than fixed or trait-related differences. In the future, task-free functional imaging holds promise for revealing neurodevelopmental information that is minimally influenced by performance/strategic differences. Further, studies using longitudinal designs that identify sources of phenotypic heterogeneity in brain maturation and characterize the relationship between brain function and underlying structural properties are needed to provide a comprehensive view of neurodevelopmental abnormalities in ADHD. PMID- 21541847 TI - Human exposure, biomarkers, and fate of organotins in the environment. AB - Organotin compounds result from the addition of organic moieties to inorganic tin.Thus, one or more tin-carbon bonds exist in each organotin molecule. The organo-tin compounds are ubiquitous in the environment. Organotin compounds have many uses, including those as fungicides and stabilizers in plastics, among others in industry. The widespread use of organotins as antifouling agents in boat paints has resulted in pollution of freshwater and marine ecosystems. The presence of organotin compounds in freshwater and marine ecosystems is now understood to be a threat, because of the amounts found in water and the toxicity of some organotin compounds to aquatic organisms, and perhaps to humans as well. Organotin com-pounds are regarded by many to be global pollutants of a stature similar to biphenyl,mercury, and the polychlorinated dibenzodioxins. This stature results from the high toxicity, persistence, bioaccumulation, and endocrine disruptive features of even very low levels of selected organotin compounds.Efforts by selected governmental agencies and others have been undertaken to find a global solution to organotin pollution. France was the first country to ban the use of the organotins in 1980. This occurred before the international maritime organization (IMO) called for a global treaty to ban the application of tributyltin (TBT)-based paints. In this chapter, we review the organotin compounds with emphasis on the human exposure, fate, and distribution of them in the environment. The widespread use of the organotins and their high stability have led to contamination of some aquatic ecosystems. As a result, residues of the organotins may reach humans via food consumption. Notwithstanding the risk of human exposure, only limited data are available on the levels at which the organotins exist in foodstuffs consumed by humans. Moreover, the response of marine species to the organotins, such as TBT, has not been thoroughly investigated. Therefore, more data on the organotins and the consequences of exposure to them are needed. In particular, we believe the following areas need attention: expanded toxicity testing in aquatic species, human exposure, human body burdens, and the research to identify biomarkers for testing the toxicity of the organotins to marine invertebrates. PMID- 21541848 TI - Shellfish and residual chemical contaminants: hazards, monitoring, and health risk assessment along French coasts. AB - In this review, we address the identification of residual chemical hazards in shellfish collected from the marine environment or in marketed shellfish. Data, assembled on the concentration of contaminants detected, were compared with the appropriate regulatory and food safety standards. Moreover, data on human exposure and body burden levels were evaluated in the context of potential health risks.Shellfish farming is a common industry along European coasts. The primary types of shellfish consumed in France are oysters, mussels, king scallops, winkles,whelks, cockles, clams, and other scallops. Shellfish filter large volumes of water to extract their food and are excellent bioaccumulators. Metals and other pollutants that exist in the marine environment partition into particular organs, according to their individual chemical characteristics. In shellfish, accumulation often occurs in the digestive gland, which plays a role in assimilation, excretion, and detoxification of contaminants. The concentrations of chemical contaminants in bivalve mollusks are known to fluctuate with the seasons.European regulations limit the amount and type of contaminants that can appear in foodstuffs. Current European standards regulate the levels of micro-biological agents, phycotoxins, and some chemical contaminants in food. Since 2006, these regulations have been compiled into the "Hygiene Package." Bivalve mollusks must comply with maximum levels of certain contaminants as follows:lead (1.5 mg kg-1), cadmium (1 mg kg-1), mercury (0.5 mg kg-1), dioxins (4 pg g-1 and dioxins + DL-PCBs 8 pg g-1), and benzo[a]pyrene (10 MUp.g kg-1).In this review, we identify the levels of major contaminants that exist in shellfish(collected from the marine environment and/or in marketed shellfish). The follow-ing contaminants are among those that are profiled: Cd, Pb, Hg, As, Ni, Cr, V,Mn, Cu, Zn, Co, Se, Mg, Mo, radionuclides, benzo[a]pyrene, PCBs, dioxins and furans, PAHs, TBT, HCB, dieldrin, DDT, lindane, triazines, PBDE, and chlorinated paraffins.In France, the results of contaminant monitoring have indicated that Cd, but not lead (< 0.26 mg kg-1) or mercury (< 0.003 mg kg 1), has had some non-compliances. Detections for PCBs and dioxins in shellfish were far below the regulatory thresholds in oysters (< 0.6 pg g-l), mussels (< 0.6 pg g-1), and king scallops (< 0.4 pg g-1). The benzo[a]pyrene concentration in marketed mussels and farmed shellfish does not exceed the regulatory threshold. Some monitoring data are available on shellfish flesh contamination for unregulated organic contaminants.Of about 100 existing organo stannic compounds, residues of the mono-, di-, and tributyltin (MBT, DBT, and TBT) and mono-, di-, and triphenyltin (MPT, DPT,and TPT) compounds are the most frequently detected in fishery products. Octyltins are not found in fishery products. Some bivalve mollusks show arsenic levels up to 15.8 mg kg-1. It seems that the levels of arsenic in the environment derive less from bioaccumulation, than from whether the arsenic is in an organic or an inorganic form. In regard to the other metals, levels of zinc and magnesium are higher in oysters than in mussels.To protect shellfish from chemical contamination, programs have been established to monitor water masses along coastal areas. The French monitoring network(ROCCH) focuses on environmental matrices that accumulate contaminants. These include both biota and sediment. Example contaminants were studied in a French coastal lagoon (Arcachon Bay) and in an estuary (Bay of Seine), and these were used to illustrate the usefulness of the monitoring programs. Twenty-one pesticidal and biocidal active substances were detected in the waters of Arcachon Bay during the summers from 1999 to 2003, at concentrations ranging from a few nanograms per liter to several hundred nanograms per liter. Most of the detected substances were herbicides, including some that are now banned. Organotin compounds have been detected in similarly semi-enclosed waters elsewhere (bays, estuaries, and harbors).However, the mean concentrations of cadmium, mercury, lead, and benzo[a]pyrene,in transplanted mussels, were below the regulatory limits.In 2007, the mean daily consumption of shellfish in the general French population was estimated to be 4.5 g in adults; however, a wide variation occurs by region and season (INCA 2 study). Tabulated as a proportion of the diet, shellfish consumption represents only 0.16% of overall solid food intake. However, the INCA 2 survey was not well suited to estimating shellfish consumption because of the small number of shellfish consumers sampled. In contrast, the mean consumption rate of bivalve mollusks among adult high consumers of fish and seafood products, i.e., adults who eat fish or seafood at least twice a week, was estimated to be 153 g week-1 (8 kg yr-1). The highest mean consumption is for king scallops (39 g week-1), followed by oysters (34 g week-1) and mussels (22 g week-1). Thus, for high seafood consumers, the contribution of shellfish to inorganic contaminant levels is 1-10% TWI or PTWI for Cd, MeHg, and Sn (up to 19% for Sn), and the arsenic body burden is higher for 22% of individuals studied.The human health risks associated with consuming chemical contaminants in shellfish are difficult to assess for several reasons: effects may only surface after long-term exposure (chronic risk), exposures may be discontinuous, and contamination may derive from multiple sources (food, air, occupational exposure, etc.).Therefore, it is not possible to attribute a high body burden specifically to shellfish consumption even if seafood is a major dietary contributor of any contaminant, e.g.,arsenic and mercury.The data assembled in this review provide the arguments for maintaining the chemical contaminant monitoring programs for shellfish. Moreover, the results presented herein suggest that monitoring programs should be extended to other chemicals that are suspected of presenting a risk to consumers, as illustrated by the high concentration reported for arsenic (in urine) of high consumers of seafood products from the CALIPSO study. In addition, the research conducted in shellfish-farming areas of Arcachon Bay highlights the need to monitor TBT and PAH contamination levels to ensure that these chemical pollutants do not migrate from the harbor to oyster farms.Finally, we have concluded that shellfish contamination from seawater offers a rather low risk to the general French population, because shellfish do not constitute a major contributor to dietary exposure of chemical contaminants. Notwithstanding,consumer vigilance is necessary among regular shellfish consumers, and especially for those residing in fishing communities, for pregnant and breast-feeding women,and for very young children. PMID- 21541849 TI - Lead uptake, toxicity, and detoxification in plants. AB - Lead has gained considerable attention as a persistent toxic pollutant of concern,partly because it has been prominent in the debate concerning the growing anthropogenic pressure on the environment. The purpose of this review is to describe how plants take lead up and to link such uptake to the ecotoxicity of lead in plants.Moreover, we address the mechanisms by which plants or plant systems detoxify lead.Lead has many interesting physico-chemical properties that make it a very useful heavy metal. Indeed, lead has been used by people since the dawn of civilization.Industrialization, urbanization, mining, and many other anthropogenic activities have resulted in the redistribution of lead from the earth's crust to the soil and to the environment.Lead forms various complexes with soil components, and only a small fraction of the lead present as these complexes in the soil solution are phyto available. Despite its lack of essential function in plants, lead is absorbed by them mainly through the roots from soil solution and thereby may enter the food chain. The absorption of lead by roots occurs via the apoplastic pathway or via Ca2+-permeable channels.The behavior of lead in soil, and uptake by plants, is controlled by its speciation and by the soil pH, soil particle size, cation-exchange capacity, root surface area,root exudation, and degree of mycorrhizal transpiration. After uptake, lead primarily accumulates in root cells, because of the blockage by Casparian strips within the endodermis. Lead is also trapped by the negative charges that exist on roots' cell walls.Excessive lead accumulation in plant tissue impairs various morphological, physiological, and biochemical functions in plants, either directly or indirectly, and induces a range of deleterious effects. It causes phytotoxicity by changing cell membrane permeability, by reacting with active groups of different enzymes involved in plant metabolism and by reacting with the phosphate groups of ADP or ATP,and by replacing essential ions. Lead toxicity causes inhibition of ATP production, lipid peroxidation, and DNA damage by over production of ROS. In addition, lead strongly inhibits seed germination, root elongation, seedling development, plant growth, transpiration, chlorophyll production, and water and protein content. The negative effects that lead has on plant vegetative growth mainly result from the following factors: distortion of chloroplast ultrastructure, obstructed electron transport,inhibition of Calvin cycle enzymes, impaired uptake of essential elements, such as Mg and Fe, and induced deficiency of CO2 resulting from stomatal closure.Under lead stress, plants possess several defense strategies to cope with lead toxicity. Such strategies include reduced uptake into the cell; sequestration of lead into vacuoles by the formation of complexes; binding of lead by phytochelatins,glutathione, and amino acids; and synthesis of osmolytes. In addition, activation of various antioxidants to combat increased production of lead-induced ROS constitutes a secondary defense system. PMID- 21541850 TI - Before the curtain falls: endocrine-active pesticides--a German contamination legacy. AB - The European Parliament recently approved a new EU regulation aimed at eliminating the use of pesticides that have unwanted endocrine-disrupting properties. The test criteria for these chemicals are slated to be finalized by 2013. For this reason, in this review, we have evaluated the meta data of lists and databanks that address pesticides with potentially endocrine-disrupting properties, and have checked which of the 250 active ingredients currently in use in Germany are affected. Azoles, dithio-carbamates/carbamates, and pyrethroids were most frequently rated as endocrine-active ingredients. In Germany, assessments have shown that total environmental pesticide emission is equivalent to approximately 0.1% of total pesticide use.Courtyard drainage and field runoff are regarded to constitute the most important sources of pesticide emission into the aquatic environment. In addition, in several investigations of drinking- and groundwater contamination, various pesticide-active ingredients and their metabolites were confirmed to be contaminants. Water suppliers recorded the following pesticides or their metabolites as being most frequently detected in drinking water: atrazine, desethylatrazine, diuron, simazine, isoproturon,and its dichlobenil metabolite 2,6-dichlorobenzamide. Surface water contamination results mainly from substances that are no longer approved by EU pesticide regulation. The most frequently detected pesticides in streaming waters that are still authorized were bentazone, diuron, glyphosate, isoproturon, MCPA, mecoprop,metamitron, pendimethalin, and tebuconazole. Pesticide residues in comestible goods of herbal origin are periodically detected in all EU member countries. The European Commission recently published results showing that 54% of all monitoring samples were devoid of positive findings. Of samples showing detectable residues, 42% were below, and 4.4% exceeded the EUMRLs. Monitoring data over a 10-year period revealed that the percentage of foodstuff without detectable pesticide residues has continuously decreased from 64 to 51.5%. In Germany, herbal samples mainly contained residues of maneb, iprodion,procymidone and deltamethrin. Notwithstanding these detections, chronic health risk evaluations indicated that there were no violations of ADI values. However,for carbaryl, methomyl, and procymidone, ARfDs were exceeded substantially for intake of grapefruit and bell peppers. As a result, the EU withdrew the methomyl authorization in 2008 and revised procymidone guideline values. PMID- 21541851 TI - Conserved domains, conserved residues, and surface cavities of C-reactive protein (CRP). AB - C-reactive protein (CRP) is a highly conserved plasma protein belonging to pentraxins, a superfamily which has significant proinflammatory role. Therefore, CRP can be a good target for drug discovery to prevent disease pathogenesis, especially cardioprotection in acute myocardial infarction and neuroprotection in stroke. Hence, the knowledge of the structure of CRP is very important. In this paper, we have demonstrated three-dimensional structure, conserved domains, and surface structure of human CRP with the help of bioinformatics analysis. We have also depicted that evolutionary relationship of CRP exists among the different species. Simultaneously, WebLogo has been generated to know the more conserved part of this medically important protein. PMID- 21541852 TI - Tomato fruit weight 11.3 maps close to fasciated on the bottom of chromosome 11. AB - Fruit weight is an important character in many crops. In tomato (Solanum lycopersicum), fruit weight is controlled by many loci, some of which have a major effect on the trait. Fruit weight 11.3 (fw11.3) and fasciated (fas) have been mapped to the same region on chromosome 11. We sought to determine whether these loci represent alleles of the same or separate genes. We show that fas and fw11.3 are not allelic and instead represent separate genes. The fw11.3 locus was fine-mapped to a 149-kb region comprised of 22 predicted genes. Unlike most fruit weight loci, gene action at fw11.3 indicates that the mutant allele is partially dominant over the wild allele. We also investigate the nature of the genome rearrangement at the fas locus and demonstrate that the mutation is due to a 294 kb inversion disrupting the YABBY gene known to underlie the fas locus. PMID- 21541854 TI - Putting risk into perspective: the US medical eligibility criteria for contraceptive use. AB - Unintended pregnancy remains a considerable problem in the United States, with health risks for both mother and infant. These risks may be increased among women with medical conditions, for whom pregnancy can lead to severe adverse outcomes. Highly effective and safe contraceptive methods are available to prevent unintended pregnancy. However, women with medical conditions and their providers also may be concerned about potential risks associated with contraceptive method use. Evidence-based guidance documents can be helpful tools for clinicians to efficiently use evidence and put risks into perspective. The US Medical Eligibility Criteria for Contraceptive Use, 2010, provides evidence-based recommendations for the safety of contraceptive use among women with medical conditions and other characteristics. While some contraceptive methods pose risks for some women, these must be considered in context and weighed against such considerations as the absolute risk of adverse events and the risks associated with pregnancy. Most women, even women with medical conditions, can safely use highly effective methods of contraception and promoting their use will further efforts to reduce unintended pregnancy. PMID- 21541853 TI - miRNAs stem cell reprogramming for neuronal induction and differentiation. AB - Mimicking the natural brain environment during neurogenesis represents the main challenge for efficient in vitro neuronal differentiation of stem cells. The discovery of miRNAs opens new possibilities in terms of modulation of stem cells lineage commitment and differentiation. Many studies demonstrated that in vitro transient overexpression or inhibition of brain-specific miRNAs in stem cells significantly directed differentiation along neuronal cell lineages. Modulating miRNA expression offers new pathways for post-transcriptional gene regulation and stem cell commitment. Neurotrophins and neuropoietins signaling pathways are the main field of investigation for neuronal commitment, differentiation, and maturation. This review will highlight examples of crosstalk between stem-cell specific and brain-specific signaling pathways and key miRNA candidates for neuronal commitment. Recent progress on understanding miRNAs genetic networks offers promising prospects for their increasing application in the development of new cellular therapies in humans. PMID- 21541855 TI - Correlated wavefunction methods in bioinorganic chemistry. AB - In this commentary the challenges faced in the application of wavefunction-based ab initio methods to (open-shell) transition metal complexes of (bio)inorganic interest are briefly touched on. Both single-reference and multireference methods are covered. It is stressed that the generation and nature of the reference wavefunction is a subject of major importance. How erroneous results can be easily obtained even with coupled-cluster theory is illustrated through the example of the septet-quintet separation in iron(IV)-oxo complexes. Second, the interplay between relativistic and correlation effects is important. This is demonstrated with coupled-cluster calculations on models for dinuclear copper active sites, where relativity has a major influence on the relative stabilities of the bis(MU-oxo) and side-on peroxo species. PMID- 21541856 TI - Vitamin D levels in Swiss multiple sclerosis patients. AB - BACKGROUND: Vitamin D levels have not been previously published for Swiss multiple sclerosis (MS) patients. An association between vitamin D status and disease activity in MS has been suggested. AIM: To define 25-hydroxy-vitamin D (25(OH)D) levels in Swiss multiple sclerosis patients. METHOD: Cross sectional case control study. RESULTS: 25(OH)D levels of 80 patients (76.3% female, mean age 37.9 +/- 10.6 years, mean Expanded Disability Status Scale (EDSS) 2.6 +/- 1.2) were collected. Mean levels of 25(OH)D were 57.0 +/- 29.7 nmol/l (range 18 175 nmol/l) in all patients. A total of 21.3% of patients had levels <=37 nmol/l and 75% had levels <=70 nmol/l. 25(OH)D levels in patients with previous high disease activity were 52.8 +/- 23.1 nmol/l versus 58.9 +/- 32.3 nmol/l in the low disease activity group (p = 0.4). CONCLUSION: The prevalence of 25(OH)D deficiency was high in Swiss MS patients. PMID- 21541857 TI - Aggression, impulsivity, and suicide behavior: a review of the literature. AB - This article reviews the literature on the association between impulsivity aggression and suicide. The key words impulsivity, aggression, and suicide were entered into the pubmed, psychlit, and proqest databases. Significant articles were scrutinized for relevant information. Impulsivity and aggression are highly correlated with suicidal behavior across psychiatric samples, nosological borders, and non-psychiatric populations. Impulsivity and aggression are related but the nature of this relationship remains unclear. The literature is confusing and contradictory. This is probably due to the difficulty in defining and separating out these concepts and the fact that there is much overlap between them. Future research should aim at clarifying and refining these concepts as well as their link to all the different forms of suicidal behavior. PMID- 21541858 TI - Associations between risk behaviors and suicidal ideation and suicide attempts: do racial/ethnic variations in associations account for increased risk of suicidal behaviors among Hispanic/Latina 9th- to 12th-grade female students? AB - The objective of this study was to identify factors that may account for the disproportionately high prevalence of suicidal behaviors among Hispanic/Latina youth by examining whether associations of health risk behaviors with suicidal ideation and suicide attempts vary by race/ethnicity among female students. Data from the school-based 2007 national Youth Risk Behavior Survey were analyzed. Analyses were conducted among female students in grades 9 through 12 and included 21 risk behaviors related to unintentional injuries and violence; tobacco use; alcohol and other drug use; sexual behaviors that contribute to unintended pregnancy and sexually transmitted infections, including human immunodeficiency virus; physical activity; obesity and weight control; and perceived health status. With the exception of physical activity behaviors and obesity, all risk behaviors examined were associated with suicidal ideation and suicide attempts. Associations of risk behaviors with suicidal ideation varied by race/ethnicity for 5 of 21 behaviors, and for 0 of 21 behaviors for suicide attempts. Stratified analyses provided little insight into factors that may account for the higher prevalence of suicidal behaviors among Hispanic/Latina female students. These results suggest that the increased risk of suicidal behaviors among Hispanic/Latina female students cannot be accounted for by differential associations with these selected risk behaviors. Other factors, such as family characteristics, acculturation, and the socio-cultural environment, should be examined in future research. PMID- 21541860 TI - Screening for suicidality in the emergency department: when must researchers act to protect subjects' interests? AB - The emergency department (ED) is a key site in preventing suicide. Yet there has been very little research on ED screening and interventions targeting the suicidal patient. Conducting research on interventions for preventing suicidal behavior in the ED population may evoke the dilemma of how to fulfill ethical obligations to protect research subjects when doing so can impair the validity of the study. In this paper we present a case study of a research protocol on the utility of routine screening with a brief intervention for suicidal ideation that raised issues regarding researchers' obligation to disclose information about subjects' suicidality to ED staff. After exploring the imperfect relationship between suicidal ideation and completed suicide (i.e., many people with ideation never attempt or commit suicide), we present an analysis of the causal relationship between these phenomena. This leads us to suggest that it should not be mandatory for researchers to disclose to ED staff when a subject reveals suicide ideation in a screening questionnaire-although other preventive measures may be called for. In general, the extent of the duty placed on researchers to intervene on behalf of their subjects should be proportional to the likelihood and magnitude of risk presented to subjects by the underlying condition, and should be balanced against the importance of the research question. PMID- 21541859 TI - Suicidal intent among young suicides in rural China. AB - To understand psychometric characteristics of Beck Suicide Intent Scale (SIS) and different characteristics of suicides between high and low intent in Chinese culture. Data of 386 suicides and 416 living controls aged 15-34 years were used to analyze psychometric characteristics of SIS with 6 items. SIS with 6 items had high reliability and validity. Different characteristics were found between suicides with high intent and low intent. Hopelessness, depression, impulsivity, and approach coping skill were common factors of suicide with high and low intent. Education years, marriage, social support, and mental disorders were specific factors of suicide with low intent. High intent suicides had different characteristics from low intent suicides. SIS with 6 items is suitable for use in young rural China. PMID- 21541861 TI - Polydrug use and attempted suicide among Hispanic adolescents in Puerto Rico. AB - This study was aimed at examining the relationship between suicidal attempts, polydrug use, and depression in adolescents. A sample of 691 adolescents and their parents were interviewed. Subjects who met the criteria for depression and those who used alcohol were significantly more likely to be suicidal attempters (OR = 6.8, p < 0.001; OR = 7.5, p < 0.001). Polydrug users were significantly more likely to attempt suicide (OR = 8.8, p = 0.032). Adolescents with mothers who met the criteria for depression were more likely to report suicide attempts (OR = 2.4, p = 0.069). Health professionals need to screen for polydrug use and depression to prevent future suicidal behaviors. PMID- 21541863 TI - Sex and emotion in the acquired capability for suicide. AB - This article examined the impact of distress tolerance on sex differences in the acquired capability for suicide. Two hundred undergraduate participants filled out a series of questionnaires related to emotions and suicide risk. Males exhibited higher mean levels of the acquired capability than did women and distress tolerance interacted with sex to predict the acquired capability (beta = -.70, p < .02), such that males with high distress tolerance were at the greatest risk. These results indicate that the degree to which an individual can tolerate negative emotions impacts the strength of the relationship between sex and the acquired capability for suicide. PMID- 21541862 TI - Predictors of treatment utilization in major depression. AB - Suicide attempters with major depression are at risk for repeat attempts and often do not utilize treatment. Identifying predictors of treatment non utilization could inform interventions to motivate treatment use and reduce suicide risk in major depression. Two hundred and seventy three participants with a major depressive episode as part of a major depressive disorder or bipolar disorder, were assessed for socio-demographic and clinical characteristics at baseline and again 1 year later to identify predictors of treatment utilization. Treatment utilization rate was high 1 year after initial evaluation (72.5%). Severity of baseline depression, baseline treatment status, and education were associated with treatment utilization at 1 year. Interventions focused on increasing knowledge about depression and treatment efficacy may improve treatment adherence when treating depression. PMID- 21541865 TI - Laypeople blog about fruit and vegetables for self-expression and dietary influence. AB - Private health information websites run by laypeople are more often visited than websites of official agencies. Understanding the role of weblogs in dietetic communication-i.e., sharing personal perceptions on healthy eating-is still lacking. This study aims to describe the nature of noncommercial Swedish blogs with fruits and vegetables (F&V)-related content and to identify different blogger types. A qualitative content analysis with abduction was performed on 50 weblogs. Most bloggers presented themselves as women. Only one-third reported their age (range 17 to over 50 years). The bloggers had either an active or passive influential purpose, and they approached F&V through either lived or mediated experiences. From these two dimensions, four F&V blogger ideal types were identified: the Persuader, the Authority, the Exhibitionist, and the Mediator. Particularly women wrote about their lived experiences close to the personal level, whereas men were more equally distributed across the different ideal types. Self-expression (typical for the Exhibitionist) and purpose to influence others' diets (typical for the Persuader and the Authority) were frequently expressed in these weblogs. The current findings on blogging purposes, approaches, and F&V blogger types may help to improve online dietetic communication, which sets new challenges for media strategies of health and nutritional professionals. PMID- 21541866 TI - Heavy viewing: emergent frames in contemporary news coverage of obesity. AB - In the last 10 years, rising rates of obesity in the United States have drawn significant and increasing public attention from various quarters, which has led to commensurately increased news coverage of the issue. A handful of scholars to date have examined how obesity has been "framed" in the news, given that news framing of issues has proven effects on cultural and political attitudes, practices, and policies as regards the subject of coverage. Consistent with these studies, this qualitative framing analysis assesses how obesity is framed in more recent mainstream news coverage. Framing patterns identified in this analysis represent a notable departure from those identified in earlier studies, specifically as relevant to troubling the individual/environmental attribution binary that historically has characterized public discourse around obesity, in particular, and health more broadly. These findings signal important shifts for contemporary cultural attitudes toward obesity and, accordingly, public health policies designed to redress the issue. Further, the findings suggest a reconsideration and elaboration of established tenets of framing theory. PMID- 21541868 TI - Client perceptions of cultural competence of community-based nurses. AB - Cultural competence is best understood by assessing provider and client perspectives. In this descriptive quantitative study, clients assessed dimensions of nurses' cultural competence including communication, decision-making, and interpersonal style. Nurses in 7 county health departments in North Carolina assessed their own cultural competence. Sixty-nine clients completed the Interpersonal Processes of Care and 71 nurses completed the Cultural Competence Assessment. Clients perceived their nursing care to contain key components of cultural competence. Nurses rated themselves as moderate to high cultural competence. Consistencies were noted between the clients' and nurse perceptions of cultural competence. These findings contribute to the enhancement of cultural competence among community nurses. PMID- 21541867 TI - Unhealthy and unsafe practices associated with symptoms of depression among injured patients. PMID- 21541869 TI - Promotores and the Chronic Care Model: an organizational assessment. AB - Although promising research is developing related to promotores and the Chronic Care Model (CCM), studies of the effectiveness of the integration of these two system innovations in addressing health disparities are limited. This article reports on an organizational assessment and analysis of promotores working in a system of federally-sponsored community health clinics along the United States Mexico border where the CCM has been operationalized. The work of promotores was found to be largely invisible within the CCM. This highlights the need for further investigation if the potential of these combined system innovations to address health disparities among Hispanics is to be realized. PMID- 21541870 TI - Correlations between spirituality and health-promoting behaviors among sheltered homeless women. AB - This study examined the relationship between spirituality and health-promoting behaviors in a convenience sample of 90 sheltered homeless women using the Health Promotion Lifestyle Profile II, the Spiritual Well-Being Scale, and a demographic questionnaire. A moderate positive correlation was found between spiritual well being and overall health promoting lifestyle (r = .426). Moderate to strong positive correlations were found between the Spiritual Well-Being Scale and the Health Promotion Lifestyle Profile II dimension subscales (physical activity, nutrition, spiritual growth, interpersonal relations, and stress management). The results support the importance of spirituality in relation to health-promoting behaviors among sheltered homeless women. PMID- 21541871 TI - Reflections of a homeless population's lived experience with substance abuse. AB - The aim of this study was to describe a homeless population's lived experience with substance abuse. A retrospective descriptive design was used to collect data from a sample of 75 homeless adults participating in a community-based homeless recovery residential program. Each participant was interviewed concerning gender, age, marital status, race, religion, education, employment, substance abuse, family history, psychiatric history, and legal history. Characteristics that emerged from the data were grouped into categories using content analysis. Seventy-three of the 75 homeless participants reported a history of substance abuse and provided in-depth descriptions of issues concerning their substance abuse. PMID- 21541872 TI - "Step-by-step we are stronger": women's empowerment through photovoice. AB - Photovoice, as one method of participatory action research, has been used to better understand local realities and promote health in many countries and with diverse populations. It has been especially effective as a process for women to explore health and contextual issues often related to oppression and marginalization. This article discusses the impact of a photovoice process on a small group of lone mothers carrying out a community health assessment in eastern Canada. According to the women, their level of empowerment increased considerably in the 2 years of the study and their stories of the project's impact provide the evidence. PMID- 21541874 TI - The effect of mystery shopper reports on age verification for tobacco purchases. AB - Mystery shops involving attempted tobacco purchases by young buyers have been implemented in order to monitor retail stores' performance in refusing underage sales. Anecdotal evidence suggests that mystery shop visits with immediate feedback to store personnel can improve age verification. This study investigated the effect of monthly and twice-monthly mystery shop reports on age verification. Mystery shoppers visited 45 Walgreens stores 20 times. The stores were randomly assigned to 1 of 3 conditions. Control group stores received no feedback, whereas 2 treatment groups received feedback communications on every visit (twice monthly) or on every second visit (monthly) after baseline. Logit regression models tested whether each treatment group improved verification rates relative to the control group. Postbaseline verification rates were higher in both treatment groups than in the control group, but only the stores receiving monthly communications had a significantly greater improvement compared with the control group stores. Verification rates increased significantly during the study period for all 3 groups, with delayed improvement among control group stores. Communication between managers regarding the mystery shop program may account for the delayed age-verification improvements observed in the control group stores. Encouraging interstore communication might extend the benefits of mystery shop programs beyond those stores that receive this intervention. PMID- 21541875 TI - The art and science of patient storytelling-harnessing narrative communication for behavioral interventions: the ACCE project. AB - Narrative communication is an emerging form of persuasive communication used in health education to solicit actual patient stories. Eliciting a narrative is an open-ended process and may or may not map to desired intervention objectives or underlying behavioral constructs. In addition, incorporating actual, unscripted narratives into multimedia interventions is challenging. The authors evaluated a protocol of editing narratives for a multimedia intervention to promote smoking cessation in the African American community that maintains fidelity to the original message and was related to behavioral constructs from social cognitive theory. The authors used four steps: (a) narrative collection (videotaping), (b) narrative review (rating of content), (c) narrative editing (documentary style), and (d) pilot testing (usability and assessment of transportation). The authors videotaped 50 personal smoking cessation narratives. After coding for presence of theoretical constructs, perceived risks of smoking (present in 53% of narratives) was the most common related behavioral construct. Four narratives were chosen for inclusion in the DVD. Pilot testing showed viewers reported high level of transportation into the narrative. The authors found that some behavioral constructs were rare and difficult to solicit in this population but that the final product was engaging to the viewers. Lessons learned may be useful for other video-based behavioral interventions that incorporate personal narratives. PMID- 21541876 TI - Obesity stigma in online news: a visual content analysis. AB - This study conducted a content analysis to examine the types of images that accompany online news stories about obesity and to determine how obese people are portrayed in news photographs. Images were selected from news articles about obesity obtained from 5 major news Web sites, during a 2-week period in September of 2009. Images accompanying news stories about obesity (N = 549) were systematically coded. Of 441 individuals identified in news photographs, 65% were overweight/obese and 27% were nonoverweight. Overall, 72% of images that depicted an overweight or obese person were portrayed in a negative, stigmatizing manner. Overweight/obese individuals were significantly more likely to have their heads cut out of the photos, to be portrayed showing only their abdomens or lower bodies, and to be shown eating or drinking than were nonoverweight individuals. Overweight/obese individuals were significantly less likely to be shown fully clothed, wearing professional clothing, or exercising than were nonoverweight individuals. Obese individuals are frequently stigmatized in online news photographs; this phenomenon has important implications for public perceptions of obese persons and may reinforce pervasive prejudice and discrimination. PMID- 21541877 TI - Nitrates in drinking water and the risk of death from brain cancer: does hardness in drinking water matter? AB - The objectives of this study were to (1) examine the relationship between nitrate levels in public water supplies and risk of death from brain cancer and (2) determine whether calcium (Ca) and magnesium (Mg) levels in drinking water might modify the influence of nitrates on development of brain cancer. A matched cancer case-control study was used to investigate the relationship between the risk of death from brain cancer and exposure to nitrates in drinking water in Taiwan. All brain cancer deaths of Taiwan residents from 2003 through 2008 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to cancer cases by gender, year of birth, and year of death. Information on the levels of nitrate nitrogen (NO3-N), Ca, and Mg in drinking water was obtained from Taiwan Water Supply Corporation (TWSC). The municipality of residence for cancer cases and controls was presumed to be the source of the subject's NO3-N, Ca, and Mg exposure via drinking water. Relative to individuals whose NO3-N exposure level was <0.38 ppm, the adjusted OR (95% CI) for brain cancer occurrence was 1.04 (0.85-1.27) for individuals who resided in municipalities served by drinking water with a NO3-N exposure >= 0.38 ppm. No marked effect modification was observed due to Ca and Mg intake via drinking water on brain cancer occurrence. PMID- 21541878 TI - Effects of flaxseed lignan and oil on bone health of breast-tumor-bearing mice treated with or without tamoxifen. AB - Previous studies showed that flaxseed lignan (secoisolariciresinol diglucoside, SDG) and oil (FO) inhibit established breast tumor growth in athymic mice with or without tamoxifen (TAM) treatment. TAM was found to increase bone mineral content (BMC) and density (BMD) in breast cancer patients. It is not known whether SDG or FO alone or combined with TAM affects bone health. Hence, the effects of SDG and FO, alone or in combination, on BMC, BMD, and biomechanical bone strength in ovariectomized athymic mice with established human breast tumors (MCF-7) treated with or without TAM were studied. In a factorial design, mice were divided into four non-TAM and four TAM groups. Each group consisted of mice fed a basal diet (BD), SDG (1 g/kg), FO (38.5 g/kg) or SDG + FO (combination) diets. The TAM group had TAM implants that provide a 5-mg TAM dose released over 60 d. TAM exerted an overall significant effect in increasing BMC, BMD, and biomechanical strength in femurs and lumbar vertebra. Without TAM treatment, SDG produced significant lower femur BMD (6%) while FO produced lower vertebrae BMC (8%) and BMD (6%). With TAM treatment, SDG and FO did not exert an effect on BMC and BMD at the femur or vertebra. SDG and FO produced no marked effect on biomechanical bone strength with or without TAM treatment. In conclusion, FS components did not significantly attenuate the positive effects on bone induced by TAM in this model system, indicating no apparent adverse effects on bone health. PMID- 21541879 TI - Nitrates in drinking water and the risk of death from childhood brain tumors in Taiwan. AB - The objective of this study was to (1) examine the relationship between nitrate (NO3-N) levels in public water supplies and risk of death from childhood brain tumors (CBT) and (2) determine whether calcium (Ca) and magnesium (Mg) levels in drinking water might modify the effects of NO3-N on development of CBT. A matched cancer case-control study was used to investigate the relationship between the risk of death attributed to CBT and exposure to NO3-N in drinking water in Taiwan. All CBT deaths of Taiwan residents from 1999 through 2008 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to the cases by gender, year of birth, and year of death. Information on the levels of nitrate nitrogen NO3-N, Ca, and Mg in drinking water were collected from Taiwan Water Supply Corporation. The municipality of residence for CBT cases and controls was presumed to be the source of the subject's NO3-N, Ca, and Mg exposure via drinking water. Relative to individuals whose NO3-N exposure level was <= 0.31 ppm, and the adjusted odds ration (OR) (95% confidence interval [CI]) for CBT occurrence was 1.4 (1.07-1.84) for individuals who resided in municipalities served by drinking water with a NO3-N exposure > 0.31 ppm. No significant effect modification was observed by Ca and Mg intake via drinking water. Data suggest that exposure to NO3-N in drinking water is associated with a higher risk of CBT development in Taiwan. PMID- 21541880 TI - Hepatotoxicity and nephrotoxicity produced by 4-hydroxy-2-nonenal (4-HNE) following 4-week oral administration to Sprague-Dawley rats. AB - 4-Hydroxy-2-nonenal (4-HNE) is a major end product of lipid peroxidation of membrane n-6 polyunsaturated fatty acids, which are found in food products. In order to examine the toxicity attributed to 4-HNE, a subacute toxicity study was conducted in Sprague-Dawley (SD) rats. For this study, 4 groups of 10 male and 10 female rats were administered by gavage either 0 (control), 0.5, 2.5, or 12.5 mg 4-HNE/kg body weight/d for 28 d, and then sacrificed for blood and tissue sampling. No significant changes in body weight or clinical signs were observed, but biochemical analysis showed significant alterations in hepatotoxicity biomarkers, such as levels of serum albumin and total bilirubin, and aspartate aminotransferase (AST) activity, and in nephrotoxicity biomarkers, such as levels of blood urea nitrogen (BUN) and creatinine and activity of alkaline phosphatase (ALP), and urinary creatinine and protein levels at 0.5 mg/kg/d. In addition, significant increases in kidney and brain weights and a significant decrease in small intestine weight were noted at 12.5 mg/kg/d. Histologic examinations of kidneys showed hyaline droplets or accumulation of hyaline bodies in renal tubules and degeneration of tubular epithelium cells. These results demonstrate that oral daily exposure to 4-HNE for 28 d produced hepatotoxicity and nephrotoxicity. The no-observed-adverse-effect level (NOAEL) for 4-HNE was calculated to be <0.5 mg 4-HNE/kg/d. PMID- 21541881 TI - Toxicological evaluation of lung responses after intratracheal exposure to non dispersed titanium dioxide nanorods. AB - Fine- and coarse-sized titanium dioxide (TiO2) particles are considered to be relatively inert when inhaled. The goal of this study was to assess potential lung toxicity associated with well-characterized, non-dispersed rutile TiO2 nanorods (10 * 40 nm). In vitro bioreactivity of TiO2 nanorods was determined by electron spin resonance (ESR) to measure free radical production. To assess pulmonary effects in vivo, Sprague-Dawley rats were intratracheally instilled with saline, silica, or TiO2 nanorods (10 MUg, 100 MUg, or 1 mg/rat). On d 1, 3, and 6 posttreatment, left lungs were preserved for microscopy and histopathology, and lung lavage was performed on right lungs. Additional rats were treated with saline or TiO2 nanorods (100 MUg or 1 mg/rat) on d 0, intratracheally inoculated with 5 * 10(5) Listeria monocytogenes on d 3, and bacterial clearance was assessed. ESR showed a significant concentration-dependent generation of hydroxyl radicals by TiO2 nanorods in the presence and absence of macrophages; however, the hydroxyl radical signals from TiO2 samples were low compared to silica. Rats exposed to 1 mg of TiO2 nanorods had significantly elevated levels of lung injury, inflammation, and lavage fluid monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-2 on d 1 and 3 that subsided by d 6, unlike the silica response that persisted. Immune cytokine secretion in the lung and bacterial clearance were not affected by preexposure to TiO2 nanorods. To summarize, non-dispersed TiO2 nanorods were found to induce radical formation and cellular oxidant production, and to generate transient and reversible pneumotoxic effects, and to not markedly alter pulmonary immune function. PMID- 21541882 TI - Triphlorethol-a improves the non-homologous end joining and base-excision repair capacity impaired by formaldehyde. AB - Formaldehyde (HCHO) generates reactive oxygen species (ROS) that induce DNA base modifications and DNA strand breaks and contributes to mutagenesis and other pathological processes. DNA non-homologous end-joining (NHEJ), a major mechanism for repairing DNA double-stranded breaks (DSB) in mammalian cells, involves the formation of a Ku protein heterodimer and recruitment of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to the site of DNA damage. HCHO treatment induced DSB and decreased the protein expressions of Ku 70 and phosphorylated DNA PKcs. Triphlorethol-A reduced DNA strand breaks and restored the expression of NHEJ-related proteins. In response to oxidative DNA base damage, 8-oxoguanine DNA glycosylase 1 (OGG1) plays a vital role in repair of 8-hydroxy-2'-deoxyguanosine (8-OhdG) via the base-excision repair (BER) process. In this study, HCHO significantly increased 8-OhdG levels, whereas triphlorethol-A lowered 8-OhdG levels. Suppression of 8-OhdG formation by triphlorethol-A was related to enhanced OGG1 protein expression. Triphlorethol-A also enhanced the expression of phosphorylated Akt (the active form of Akt), a regulator of OGG1, which was found to be decreased by HCHO treatment. The phosphoinositol 3-kinase (PI3K)-specific inhibitor LY294002 abolished the cytoprotective effects induced by triphlorethol A, suggesting that OGG1 restoration by triphlorethol-A is involved in the PI3K/Akt pathway. These results suggest that triphlorethol-A may protect cells against HCHO-induced DNA damage via enhancement of NHEJ and BER capacity. PMID- 21541883 TI - Canine hypothyroidism: a review of aetiology and diagnosis. AB - Hypothyroidism is recognised as an important endocrine disorder of dogs, and a frequent differential for numerous presenting complaints. Its diagnosis has never been straight forward as results suggestive of hypothyroidism can occur for a variety of reasons in dogs with normal thyroid function (euthyroid). As a consequence, the accurate investigation of hypothyroidism has been hindered by the potential inclusion of a number of cases not truly hypothyroid. In recent years, the development of newer diagnostic tests, e.g. free thyroxine, canine thyroid stimulating hormone, thyroglobulin autoantibodies, has significantly improved our ability to reliably differentiate hypothyroidism from other clinically similar disorders. This has led to a marked increase in our knowledge of the phenotypic, genotypic and aetiological aspects of this disorder in dogs. PMID- 21541884 TI - Congenital hypothyroidism of dogs and cats: a review. AB - Congenital hypothyroidism is a rare and underdiagnosed congenital endocrine disorder in dogs and cats and the true incidence is unknown. The disorder may cause a range of clinical signs depending on the primary defect, which affect production of thyroid hormones; some cases present when adult. Hallmark clinical signs of congenital hypothyroidism are mental impairment and skeletal developmental abnormalities, resulting in disproportionate dwarfism; goitre may or may not be present. Documented causes of congenital hypothyroidism in dogs include deficiency of, or unresponsiveness to, thyrotropin-releasing hormone (TRH) or thyroid-stimulating hormone (TSH), thyroid dysgenesis, dyshormonogenesis and iodine deficiency. In cats, TSH unresponsiveness, thyroid dysgenesis, dyshormonogenesis and iodine deficiency have been confirmed. Adequate replacement therapy results in a successful outcome in the majority of cases, especially when started early in life, as permanent developmental abnormalities can be prevented. This review describes reported cases in dogs and cats, diagnostic investigation, and recommendations for treatment. PMID- 21541885 TI - The use of allied health therapies on competition horses in the North Island of New Zealand. AB - AIM: To obtain data on the use of allied health therapy within competitive equestrian sport in the North Island of New Zealand. METHODS: Data were collected during January 2010 by survey at show jumping and dressage championships in the North Island, and from racing yards in the Central Districts of New Zealand. The survey consisted of 30 open, closed and multiple-choice questions, and was conducted face-to-face, by the same interviewer. Information on the demographics of riders or trainers and horses in each discipline (show jumping, dressage, and Thoroughbred racing), the use of allied health therapy (physiotherapy, chiropractic and equine sports massage) on horses, and knowledge of training and qualifications of the allied health therapists was obtained. Univariable and multivariable logistic regression were used to examine relationships between demographic variables and the use of allied health therapists. RESULTS: In total, 110 riders or trainers participated in the survey. The relative contribution of responses across disciplines was 39/110 (36%), 41/110 (37%) and 30/110 (27%) for show jumping, dressage, and Thoroughbred racing respectively. Allied health therapists were used by 68/110 (62%) respondents to treat their horses. The most common types of allied health therapy used were chiropractic (25/68; 37%) and physiotherapy (16/68; 24%). The main reasons for using allied health therapies were for back pain (22/68; 32%) and lameness (17/68; 25%). Only 5/68 (7%) respondents chose a type of allied health therapy based on veterinary advice, and 49/68 (72%) stated that their veterinarian and allied health therapist did not work together when treating their horses. The final multivariable model for use of allied health therapists included the explanatory variables discipline of the rider or trainer and the number of horses in training per season. CONCLUSIONS AND CLINICAL RELEVANCE: The use of allied health therapies for the treatment of competition and racehorses was widespread. Many riders or trainers perceived allied health therapy to be beneficial, however many therapists and veterinarians do not work together and therefore the integrative treatment approach to rehabilitation is lost. PMID- 21541886 TI - Effects of intramammary infections on somatic cell score and milk yield in Sarda sheep. AB - AIM: To evaluate the effects of intramammary infections (IMI) on somatic cell score (SCS) and milk yield in dairy ewes. METHODS: Monthly milk samples were collected from a flock of 202 Sarda sheep, over a period of 7 months, for bacteriological culture and measurement of somatic cell counts (SCC). During the same period, milk yield was measured daily using electronic milk meters connected to each half-udder cluster of the milking machine. SCC was transformed to SCS using a base-2 log transformation. One SCS is equivalent to a SCC of 25,000 cells/ml, and each increase of 1 in SCS is associated with doubling of the SCC. IMI was defined by the presence of five or more colonies of similar morphology isolated from a milk sample (>=500 cfu/ml). The effect of IMI on SCS and milk yield was assessed using a generalised estimating equation (GEE). RESULTS: There were 1,186 udder halves with IMI from 2,828 milk samples, a prevalence of 41.9%. The distribution of bacterial species within the 1,186 culture-positive samples was comprised of 476 (40.1%) Staphylococcus epidermidis, 172 (14.5%) Staph. chromogenes, 38 (3.2%) Staph. caprae, 134 (11.3%) Staph. simulans, 114 (9.6%) Streptococcus uberis, 123 (10.4%) Strep. dysgalactiae, and 129 (10.9%) Strep. equi subsp. zooepidemicus. SCS was greater in udder halves with IMI (mean 7.71; SD 0.82) than in udder halves without IMI (mean 5.53; SD 1.02) (p<0.01). IMI due to streptococcal species were associated with greater SCS (mean 8.24; SD 0.62) than those due to staphylococcal species (mean 7.48; SD 0.79) (p<0.01). Milk yield from udder halves with IMI was lower (mean 439 (SD 162) ml/half udder/day) than from udder halves without IMI (mean 602 (SD 170) ml/half udder/day) (p<0.01). IMI due to staphylococcal species was associated with a lower milk yield (mean 399 (SD 167) ml/half udder/day) than IMI due to streptococcal species (mean 427 (SD 156) ml/half udder/day) (p<0.01). CONCLUSIONS: These findings provide sheep milk producers with information on the losses associated with subclinical mastitis, which can be used to evaluate the economics of prevention and treatment protocols concerning udder health in ovine dairy flocks. PMID- 21541887 TI - Age, breed, sex distribution and nutrition of a population of working farm dogs in New Zealand: results of a cross-sectional study of members of the New Zealand Sheep Dog Trial Association. AB - AIM: To establish baseline information about age, breed, sex distribution and feeding practices for a population of working farm dogs owned by members of the New Zealand Sheep Dog Trial Association (NZSDTA) throughout New Zealand. METHODS: Questionnaires were sent to members of the NZSDTA in August 2007, requesting information on the size and terrain of the farms where they worked, as well as the breed, weight, age and sex of each working dog they owned, feeding regime employed, diet fed, work levels, and general health of their dogs. RESULTS: The survey was completed by 542/676 (81%) of the eligible sample population, and provided information on 2,861 dogs, excluding those <1 year old. All of the dog owners surveyed worked on sheep and beef-cattle farms. The median farm size was 440 [Inter-quartile range (IQR) 132-1,200] ha and varied with region. The majority of farms were situated on either hill country (184/542; 34%) or a mixture of hilly and flat terrain (260/542; 48%), and had a median of six (IQR 5 8) working dogs per farm. The median age of dogs was 3.0 (IQR 2.0-6.0) years. Heading dogs were the most common type of working dog (1,510/2,861; 52.8%), followed by Huntaways (1,161/2,861; 40.6%). The gender distribution of all dogs was biased towards males (57%), but this decreased with age. There was a positive association between the number of dogs on a farm and perceived level of tiredness of dogs (p<0.001), but there were no differences in levels of tiredness between farms of different terrain. Most owners (526/542; 97%) fed their dogs once a day. The most common diet fed was a combination of dry food and homekill, which was fed by 328/542 (61%) owners during peak and 313/542 (58%) during off-peak periods of work. CONCLUSIONS AND CLINICAL RELEVANCE: This study has established baseline information on the age, breed, gender and nutrition of a large population of working farm dogs in New Zealand. Current feeding practices employed by owners include offering a substantial amount of homekill to their animals. Homekill may be deficient or marginal in vitamins and minerals, therefore opportunities could exist to improve the diets and therefore the longevity and performance of these dogs. PMID- 21541888 TI - Serosurvey of leptospirosis and investigation of a possible novel serovar Arborea in farmed deer in New Zealand. AB - AIM: To investigate the prevalence of Leptospira spp. and possible novel serovar Arborea infection in farmed deer in New Zealand. METHODS: In September 2006, five serum samples from a serum bank from each of 70 farms sampled for a previous national prevalence survey were forwarded to the World Health Organisation/Food and Agriculture Organisation/World Organisation for Animal Health (WHO/FAO/OIE) reference laboratory for leptospirosis in Brisbane, Australia, to test for reactivity to a reference panel of 23 serovars, most believed to be exotic to New Zealand, using the microscopic agglutination test (MAT). Eleven farms were seropositive for Arborea, a serovar novel to New Zealand. In July 2007, 126 additional banked serum samples from nine of those 11 farms (n=8-20/farm) were sent to the reference laboratory for similar serology. Two farms in the Southland region were considered positive for serovar Arborea. Tissue from deer kidneys (n=43) from these two farms collected at a deer slaughter premises (DSP) was cultured in November 2007 and November 2008. Sera from those deer were also sent to the laboratory in Brisbane. RESULTS: From the initial 350 sera, 96 (27.4%) and 19 (5.4%) samples were positive for Leptospira borgpetersenii serovar Hardjo bovis and Leptospira interrogans serovar Pomona respectively. There were cross reactions between serovar Hardjo-bovis with serovars Medanensis and Szwajizak. Serological evidence of serovars Tarassovi, Grippotyphosa, Celledoni, Australis, Zanoni, Robinsoni, Canicola, Kremastos, Bulgarica, Cynopteri, Ballum, Bataviae, Djasiman, Javanica, Panama, Shermani and Topaz was negative or sporadic, generally with titres of 1:50 and therefore likely non-specific. Fourteen (4.0%) samples from 11 farms were positive for serovar Arborea, justifying further investigation. The prevalence of serovar Arborea was 15% and 30% on two farms, from the 126 samples. None of 43 kidney and serum samples collected subsequently from those two farms were positive by culture or serology for serovar Arborea. CONCLUSIONS: While there were samples serologically positive for serovar Arborea in deer, attempts to isolate the organism were unsuccessful. The sample size for the follow-up investigation was insufficient to validate the presence or absence of infection, so further study should be undertaken to verify the status of this serovar of Leptospira spp. in New Zealand, in both deer and other livestock species. PMID- 21541889 TI - Cutaneous malignant melanoma in an 11-month-old Russian blue cat. AB - CASE HISTORY: A grey mass developed on the tail base of an 11-month-old Russian blue cat. The mass grew slowly for 2 months and then became ulcerated. CLINICAL FINDINGS: The mass was excised, and histology revealed it to be a malignant melanoma. Skin adjacent to the melanoma and underlying tissue contained large aggregates of melanin and numerous melanophages. Seven months later, an additional malignant melanoma was excised from the skin on the left thorax. Three months after the second melanoma was excised, the left axillary lymph nodes were enlarged; four were excised, and found to contain metastases. The cat became lethargic and anorexic, and was subject to euthanasia at 26 months of age. Post mortem examination revealed numerous small well-circumscribed melanomas scattered within the S/C tissue overlying the left thorax and within the left axilla. These were interpreted to be in-transit metastases. Metastatic foci were also visible within the spleen, liver, lungs, lymph nodes and a rib; numerous small melanomas were also present throughout the mesentery. DIAGNOSIS: Cutaneous malignant melanoma with numerous distant and in-transit metastases. CLINICAL RELEVANCE: Although cutaneous malignant melanomas appear to be rare in young cats, they can display a similar clinical behaviour to malignant melanomas in humans, and a guarded prognosis should be suggested for neoplasms of this type. In humans, in transit metastases are a well-recognised consequence of removing lymph nodes that drain areas containing neoplastic disease. This manifestation of metastatic disease has not previously been reported in the veterinary literature. PMID- 21541890 TI - Photosensitisation, crystal-associated cholangiohepatopathy, and acute renal tubular necrosis in calves following ingestion of Phytolacca octandra (inkweed). AB - CASE HISTORY: In March 2006, an outbreak of photosensitivity affecting 6-8-month old Friesian heifer calves on a farm in the Rangitikei district of New Zealand was investigated. The calves were grazing wheat stubble paddocks that also had a variety of weeds, especially Phytolacca octandra (inkweed). They also had access to pond water that contained potentially toxic concentrations of the cyanobacteria (blue-green algae) Microcystis and Planktothrix spp. CLINICAL FINDINGS: Initially, affected animals showed acute irritation, agitation, reluctance to walk, recumbency in some animals, hyperaemia of unpigmented skin and jaundice. Serum chemistry revealed elevated liver enzyme activities and azotaemia. Later in the outbreak, exudative dermatitis with formation of crusts on unpigmented skin, dehydration and inappetence were notable signs, as well as occasional diarrhoea. PATHOLOGICAL AND TOXICOLOGICAL FINDINGS: Post-mortem examinations following euthanasia of four severely affected calves and a fifth animal that died naturally revealed livers that were grossly orange brown and mildly enlarged, and kidneys that were enlarged and pale brown. Microscopic lesions in the liver were mild; however, small birefringent crystals in the bile ducts were noted in the first two cases. In contrast, renal lesions were moderate to severe, and included prominent segmental tubular necrosis, granular and cellular casts, and mild interstitial non-suppurative inflammation. In the kidneys of animals examined later in the outbreak, there was early interstitial fibrosis as well as tubular regeneration, with numerous hyaline casts in the renal medulla. Inkweed plants had been heavily browsed, and recognisable portions of the plant were found in the gastrointestinal tracts of affected calves. Chemical analysis of inkweed material revealed triterpene saponins. No known hepatotoxic or nephrotoxic plants were identified in the paddocks. The hepatic lesions were not consistent with published descriptions of cyanobacterial toxicity. Sporidesmin toxicity was ruled out. DIAGNOSIS: Hepatogenous photosensitivity, crystal-associated cholangiohepatopathy, toxic acute renal tubular necrosis, associated with the ingestion of P. octandra, and possibly complicated by cyanobacteria in the water. CLINICAL RELEVANCE: Crystal-associated cholangiohepatopathy with photosensitivity in cattle is rare, and has only been reported in steroidal saponin-containing Brachiaria decumbens poisoning, in Brazil. The consistent pattern of toxic acute renal tubular necrosis was similar to that caused by the ingestion of Quercus, Amaranthus or Lantana spp. A combination of toxicities was conceivable but circumstantial evidence strongly implicated P. octandra. Further toxicological investigation of this plant is warranted before it can be listed as a known nephrotoxin of cattle. PMID- 21541899 TI - Inverse association between dietary vitamin D and risk of cutaneous melanoma in a northern Italy population. AB - The possibility of an inverse association between vitamin D and risk of cancer and, in particular, of cutaneous malignant melanoma has been suggested, but results of epidemiologic studies are still conflicting. We examined the relation between dietary vitamin D intake and melanoma risk through a population-based case-control study (380 cases, 719 controls) in a northern region of Italy, a country with an average vitamin D intake lower than that in northern Europe or the United States. We assessed average daily intake of vitamin D from foodstuffs using the European Prospective Investigation into Cancer and Nutrition (EPIC) semiquantitative food frequency questionnaire. In this population, levels of vitamin D intake were considerably lower than those observed in recent U.S. studies. We found an inverse relation between dietary vitamin D and melanoma risk in the sample as a whole, in both crude and adjusted analyses. In sex- and age specific analyses, this association appeared to be stronger among males and among older subjects. These findings suggest that, at the relatively low levels of intake observed in this sample, an inverse relation between dietary vitamin D and risk of cutaneous malignant melanoma may exist. PMID- 21541900 TI - Weight change and its correlates among breast cancer survivors. AB - We assessed weight change from diagnosis to approximately 18 mo after cancer diagnosis and evaluated its correlates in a large, population-based, cohort study of women diagnosed with stage 0-IV breast cancer. A total of 4,561 cases with weight information 1 yr prior to diagnosis, at diagnosis, and at the 18-mo postdiagnosis interview were included in the study. Multinomial logistic regression models were conducted to examine the association of weight change from diagnosis to 18 mo after diagnosis with sociodemographic, clinical, and lifestyle factors. The mean weight change from diagnosis to 18 mo after diagnosis was a gain of 1.7 kg (median: 2.0). Overall, 61% of women gained weight, 27% gained 2-5 kg, and 24% gained >=5 kg, while approximately 14% lost >2 kg during the 18-mo postdiagnosis period. Greater weight gain was significantly related to younger age, premenopausal status, mixed receptor status, more advanced disease stage, prediagnosis weight loss, higher dietary intake, and cigarette smoking. Women with obesity and serious comorbidity were more likely to lose weight. Moderate exercise was not significantly related to weight change. Weight gain is common among breast cancer survivors. Sociodemographic, clinical, and lifestyle factors are related to weight change. Appropriate intervention strategies should be developed. PMID- 21541901 TI - Modulating effects of rooibos and honeybush herbal teas on the development of esophageal papillomas in rats. AB - Widespread consumption of herbal teas has stimulated interest in their role as cancer preventive agents. The present investigation monitored the modulation of methylbenzylnitrosamine (MBN)-induced esophageal squamous cell carcinogenesis by rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia) herbal and Camellia sinensis teas in male F344 rats. The tumor multiplicity was significantly (P < 0.05) inhibited by unfermented honeybush (45.5%), green (50%), and black (36%) teas, while the other teas exhibited weaker effects (<30% inhibition). The mean total papilloma size was reduced by unfermented rooibos (87%), unfermented honeybush (94%), and fermented honeybush (74%) due to the absence of large papillomas (>10 mm(3)). Reduction of the mean total papilloma number correlated with the total polyphenol (TPP) (r = 0.79; P < 0.02) and flavanol/proanthocyanidin (FLAVA) (r = 0.89; P < 0.008) intake (mg/100 g body weight) of the teas and the FLAVA (r = 0.89; P < 0.04) and flavonol/flavones/xanthones (r = 0.99; P < 0.002) intake when considering only the herbal teas. A daily TPP intake threshold of 7 mg/100 g body weight existed below where no inhibition of papilloma development was observed. Fermentation of herbal teas reduced the inhibitory effects on papilloma development associated with a reduction in the polyphenolic constituents. The inhibitory effect of herbal teas on papilloma development is associated with different flavonoid subgroups and/or combination thereof. PMID- 21541903 TI - [Obstetric management of fetal growth retardation]. AB - Intrauterine growth restriction (IGUR) can have different etiologies, but placental insufficiency is the clinically most relevant. Fetuses with IUGR have a significantly higher morbidity and mortality than normally grown fetuses of the same gestational age. It is important to distinguish a growth restricted fetus from a normal, small fetus and from a fetus being small because of a disease, e.g., an aneuploidy. This differentiation requires the knowledge of the gestational age and the use of multiple imaging modalities. Serial assessments of fetal growth by ultrasound are necessary to recognize declining growth. Doppler sonography can detect changes in the uteroplacentar and the fetal perfusion. Blood vessels of clinical relevance are the uterine arteries, the umbilical artery, the middle cerebral artery and the ductus venosus. When no fetal anomalies can be detected, fetal growth is parallel to the percentiles and Doppler sonography measurements are normal, IUGR is unlikely. In most IUGR fetuses, a typical sequence of circulatory changes and ultrasound findings can be observed. As there is no evidence-based treatment option for IUGR until now, obstetric management consists in defining the optimal time of delivery. This means weighing the risks of prematurity against the risks of a potentially hostile intrauterine environment. PMID- 21541902 TI - The role of vitamins in cancer: a review. AB - Vitamins are essential nutrients for human metabolism, playing an important role as coenzymes or enzymes in many vital processes for the normal functioning of the body. In recent years, it has become apparent that vitamins are crucial in health and human disease, due to several studies that studied this relationship. Currently, it is known that vitamins can have an important role in the prevention and treatment of cancer, but until now no conclusive results were obtained. In this review, we will present the work and more relevant conclusions obtained in recent years of investigation about the relationship between vitamins and cancer, namely vitamin A, vitamin B complex, vitamin C, vitamin D, vitamin E, and vitamin K. PMID- 21541904 TI - 3-Dimensional sonographic volumetry of fetal brain, liver and myocardial mass- interdisciplinary clinical validation of the method and application in fetuses with and without structural heart disease. AB - BACKGROUND: Prenatal 3-dimensional (3D) ultrasound allows volumetry of the fetal brain, liver and measurement of myocardial mass (MM). We studied the reliability of this method in an interdisciplinary approach, defined the relation of the values throughout gestation, and evaluated the results in fetuses with congenital heart disease (CHD). METHODS: In 104 fetuses (39 with CHD) between 14 and 38 weeks of gestation 3D ultrasound was prospectively performed. Data sets of brain, abdomen and heart were stored for off-line analysis of volumes and MM. Descriptive statistics, coefficients of correlation and of variation (CV) were performed. RESULTS: Volumetric data set acquirement was feasible in all pregnancies, lasted approximately 10 min, but off-line analysis was feasible in only 66% lasting about 45 min. MM increased in a linear fashion during gestation. CV were 11.0 and 10.8 for the left, 14.39 and 12.66, respectively, for the right MM. Median ratio between right and left MM was 0.88 in normal fetuses, and 8.25 in fetuses with hypoplastic left heart syndrome. Intra- and interobserver variabilities revealed CVs of 2.46 and 11.80, respectively, for brain volumetry, and CVs of 3.16 and 29.2, respectively, for liver volumetry. Both brain and liver volumes were positively associated with gestational age, and did not show different growth patterns in fetuses with CHD. CONCLUSIONS: Prenatal volumetry is time-consuming, but reliable especially for left MM and brain volume. Linear growth of brain and liver volume is present in utero irrespective of CHD. Application of our reference graphs of MM growth allows early differentiation in CHD. PMID- 21541905 TI - [Impact and limitations of ultrasound examination immediately before delivery--a prospective evaluation with 1127 pregnant women]. AB - OBJECTIVE: Birth weight is an important confounder to foetal morbidity and mortality. There is controversy about the necessity of ultrasound examinations immediately before delivery. As only few studies on unselected populations have been published, some recommendations exist in the context with shoulder dystocia, water delivery and breech delivery. PATIENTS AND METHODS: Within 1 year we examined 1,127 consecutive pregnant women with 1,151 foetuses on the basis of a routine ultrasound examination. RESULTS: A total of 92% of all women were examined by ultrasound. Nearly 80% of these examinations took place within 72 h prior to delivery. The accuracy of foetal weight estimate (+/-10% variance) was 72% and did not gain due to the grade of the examiner's experience. There was no difference between routine and complicated conditions such as oligohydramnios, obesity, contractions. Also week of gestation had no influence. Macrosomic foetuses were underestimated in more than 50%. In 85% of pregnancies there was at least one risk factor and rate of Cesarean sections was due to this fact. Overall there were 8.5% macrosomic foetuses and 15.1% were SGA. 16.5% of the women were obese with BMI >30. CONCLUSION: Foetal weight estimation by means of ultrasound is easy and fast and does not need a high level of experience. There is no negative influence on accuracy of weight estimate by examination conditions and week of gestation. Ultrasound examinations also give information about foetal position, placental localisation and amount of amniotic fluid. Together with maternal risk factors, the prospective planning and leading of birth requires ultrasound biometry prior to delivery. PMID- 21541906 TI - [Predictors for low birth weight--an epidemiological case-control study with women in childbed in the federal state Saarland, Germany]. AB - BACKGROUND AND AIMS: Low birth weight is associated with elevated health-care costs and adverse conditions for the newborn's start to life. A variety of health problems and an impaired potential for the infant's development are known long term effects. Only few studies have examined the role of psychosocial and socioeconomic determinants for the incidence of low birth weight, especially in Germany. The aim of our study was to test the impact of maternal socioeconomic and psychosocial characteristics as well as health behaviour on the infant's birth weight. METHODS: In an exploratory case-control study we tested whether the before mentioned potential determinants of low birth weight were observed more often among cases (birth weight <2,500 g) than among controls. Standardised interviews were conducted with maternal cases and controls. RESULTS: The results show that mothers in the control group more often were married or cohabiting (100% vs. 77%; p<0.05) and that they had a higher occupational status (83% non manual vs. 54%; p<0.05). Level of education was not significantly related to birth weight. Mothers in the case group more often reported exhaustion (p<0.05) and marital problems [M=1.8 (1.1) vs. M=1.3 (0.5); p<0.05). They were characterised by a higher burden of work-strain in terms of weather conditions, heat or infiltration [M=1.7 (1.0) vs. M=1.1 (0.4); p<0.05). The available living space was slightly smaller in the case group [M=96.5 m(2) (31.5 m(2)) vs. M=118.5 m(2) (46.8 m(2)); p<0.1). DISCUSSION AND CONCLUSIONS: Our results confirm international studies showing differences regarding the social context of women who give birth to a child with normal or low birth weight. Apart from vertical status characteristics, marital conditions and resulting psychosocial stressors seem to have an impact. PMID- 21541907 TI - [Maternal Ehlers-Danlos syndrome type II occuring with foetal duodenal atresia and annular pancreas: first description]. AB - A double-bubble sign was detected by ultrasonography in a GII, PII, who suffers from Ehlers-Danlos syndrome type II. The delivery was done by Caesarean section based on the suspicion of premature placental separation. Postnatally, the child was found to have duodenal atresia caused by an annular pancreas. These features have not been described in EDS so far. Molecular genetic analysis showed a novel COL5A1 splice mutation in the mother, which is responsible for the EDS phenotype. The mutation is absent in the male newborn. Therefore, we assume that maternal EDS and the malformation of the child are not related. PMID- 21541908 TI - [Neonatal infection with Salmonella apapa after contact with a reptile in the home]. AB - Salmonella apapa is transmitted by reptiles, e.g., bearded dragons. To date only few cases of S. apapa-related human infections have been reported. Because the bacteria are transmitted through the feces of animals or direct contact with low infection doses, infection in early infancy is possible. We report an 18-day-old newborn with sepsis caused by Salmonella apapa. Salmonella apapa was isolated from the feces of a bearded dragon living along with the family. PMID- 21541909 TI - [Erich saling foundation: testimony for an important but still new epoch of gynaecology]. PMID- 21541910 TI - [Acceptance of killing of animals: survey among veterinarians and other professions]. AB - Professional veterinarians are one of the most affected professions when it comes to killing animals. However, in some situations the opinion about the acceptance of killing of animals differs between people, which can cause a dilemma for the executing person. In a pilot study based on questionnaires, veterinarians from different working fields and students of different branches stated their acceptance of killing of animals in diverse concrete situations. The result clearly demonstrates a higher acceptance of killing of animals among veterinarians with longtime experience in contrast to other groups and the almost same acceptance among agricultural students. The acceptance increased with age, however, we could not find a gender specific difference except of within a narrow age interval. The variability of acceptance within the same profession group differs between the situations. Veterinarians should be aware of their different thinking about killing of animals in some situations compared to other people and should know the reason of such differences. This is important not least to protect themselves and their opinion and to contribute to their societal responsibility by their veterinarian activity. PMID- 21541911 TI - [Severe gastrointestinal bleeding secondary to lornoxicam in the dog]. AB - Six dogs with lornoxicam induced severe gastrointestinal bleeding are described. The ingested dose ranged between 0.5 - 5.1 mg/kg BW (median 0.63 mg/kg BW). The severity of the bloodloss anemia was moderate to severe with PCV values ranging between 12 - 27 % (median 16 %) and serum albumin concentrations between 12 - 22 g/l (median 16 g/l). One dog had evidence of chronic thrombocytopathia over 13 days and clinicopathologic findings of gastrointestinal bleeding over 55 days. None of the dogs developed kidney injuries. The clinical condition required transfusion of blood products in 5 of 6 cases. One dog with a perforated duodenal ulcer and septic peritonitis survived until discharge but had to be euthanized later on due to recrudescent clinical signs (hematemesis, melena). The median length of hospitalisation was 12 days (5 - 14). No correlation was seen between the ingested dose and severity of clinical signs. Lornoxicam ingestion leads to severe and longlasting gastrointestinal bleeding in the dog and requires immediate intensive therapy. PMID- 21541912 TI - [Life-threatening injuries of the subcutaneous ventral abdominal veins in dairy cows]. AB - Injuries of the superficial veins on the ventral abdomen of dairy cows can result in life-threatening haemorrhage. Treatment of these injuries can be difficult because of the characteristics of the veins. Five cows aged 6.5 to 12 years were referred to the Animal Hospitale Zurich, because of intermittent haemorrhage from a ventral abdominal vein. Four of the cows were near term and one had calved two weeks before referral. Intermittent bleeding was seen from the highly convoluted and dilated subcutaneous tributaries to the cranial superficial epigastric vein (milk vein). The haematocrit of 2 cows was markedly lower than normal. Emergency slaughter of one of the cows was carried out because of advanced age. The other 4 cows were sedated and after application of local anaesthetic, the wounds were debrided and sutured. Two of the cows required a blood transfusion before being operated. There were no postoperative complications. This type of injury seems to occur predominantly in pluriparous dairy cows close to term, in which the tributaries to the milk vein have undergone varicose changes. Treatment should consist of surgical resection of the injured tissue and suturing of the venous wall, subcutaneous tissues and skin. PMID- 21541913 TI - [Survival duration for different forms of canine megaesophagus]. PMID- 21541915 TI - [The injury-minimizing responsibility]. PMID- 21541916 TI - [Ecology in veterinary practice]. PMID- 21541917 TI - [Personal costs, a barrel without a bottom]. PMID- 21541919 TI - The nutrition transition in amazonia: rapid economic change and its impact on growth and development in Ribeirinhos. AB - The goal of this longitudinal study was to assess the impact of economic change and increased market integration on subsistence strategies, living conditions, growth, and nutritional status of Ribeirinhos living in the rural Amazon, Brazil. Data on weight, height, skinfolds, and circumferences, as well as data on economic strategies and living conditions were collected from 469 individuals in 2002 and 429 in 2009. Of these, 204 individuals were measured on both occasions. Independent and paired t-tests were used to identify changes in nutritional status over time in the larger sample and smaller, longitudinal subsample, respectively. Multiple linear regressions were used to examine the relationship between changes in economic/living conditions and nutritional status in the longitudinal subsample. Results indicate modest improvements in linear growth (HAZ) and among male children the observed increase was related to enrollment in the Brazilian conditional cash transfer program, Bolsa Familia (P = 0.03). In terms of short-term measures of nutritional status, we found a significant increase in ZTSF and a reduction in ZUMA in most age/sex groups. Among subadults, there was a negative relationship between ZUMA and access to electricity (P = 0.01) and positive relationship between ZUMA and the sale of the acai fruit (P = 0.04). Significant changes in weight and BMI (P < 0.01) were found among adult females and both were negatively related to household cash income (P = 0.02 and P = 0.03, respectively). Despite significant changes in economic strategies and lifestyle, changes in nutritional status were modest which may be explained by increased food insecurity documented during this early stage of transition. PMID- 21541920 TI - Brief communication: co-detection of Bartonella quintana and Yersinia pestis in an 11th-15th burial site in Bondy, France. AB - Historical and anthropological data suggest that skeletons excavated from an 11th to 15th century mass grave in Bondy, France, may be those of victims of the Great Plague. Using high-throughput real-time PCR investigation of the dental pulp collected from 14 teeth from five such skeletons, we detected Bartonella quintana DNA in three individuals and Yersinia pestis DNA in two individuals. DNA from five other deadly pathogens was not found. Suicide PCR genotyping confirmed Y. pestis DNA belonging to the Orientalis biotype. One individual had co-infection. These data suggest a plague epidemic in a population already infected by the body louse-transmitted B. quintana or a body louse-driven transmission of the plague that drove a medieval epidemic in inland Europe. PMID- 21541922 TI - Brief communication: oxygen isotopes as a biomarker for sickle-cell disease? Results from transgenic mice expressing human hemoglobin S genes. AB - The origins of sickle-cell disease (SCD) are well understood, as are its evolutionary pressures on humans and pathological presentation. However, because it has not been possible to identify SCD in archaeological contexts, its biocultural effects on past populations are unknown. Previous research investigating oxygen isotope fractionation during respiration among anemics suggests that oxygen isotopes in bone apatite may provide a biological marker for SCD in skeletal remains. This pilot study reports delta(18) O ratios in bone apatite of transgenic laboratory mice expressing human SCD globins and compares them to healthy control mice. The delta(18) O ratios of sick mice are significantly lower than those of healthy mice (-5.60/00 vs. -4.50/00; P = 0.002), and the sickest mice exhibit the lowest ratios of all (mean delta(18) O = -5.80/00). These preliminary results suggest that this method may be usefully applied to skeletal materials of past human populations whose diets and water sources do not differ substantially. PMID- 21541921 TI - Indirect evidence for the genetic determination of short stature in African Pygmies. AB - Central African Pygmy populations are known to be the shortest human populations worldwide. Many evolutionary hypotheses have been proposed to explain this short stature: adaptation to food limitations, climate, forest density, or high mortality rates. However, such hypotheses are difficult to test given the lack of long-term surveys and demographic data. Whether the short stature observed nowadays in African Pygmy populations as compared to their Non-Pygmy neighbors is determined by genetic factors remains widely unknown. Here, we study a uniquely large new anthropometrical dataset comprising more than 1,000 individuals from 10 Central African Pygmy and neighboring Non-Pygmy populations, categorized as such based on cultural criteria rather than height. We show that climate, or forest density may not play a major role in the difference in adult stature between existing Pygmies and Non-Pygmies, without ruling out the hypothesis that such factors played an important evolutionary role in the past. Furthermore, we analyzed the relationship between stature and neutral genetic variation in a subset of 213 individuals and found that the Pygmy individuals' stature was significantly positively correlated with levels of genetic similarity with the Non-Pygmy gene-pool for both men and women. Overall, we show that a Pygmy individual exhibiting a high level of genetic admixture with the neighboring Non Pygmies is likely to be taller. These results show for the first time that the major morphological difference in stature found between Central African Pygmy and Non-Pygmy populations is likely determined by genetic factors. PMID- 21541923 TI - Ontogeny of limb proportions in late through final Jomon period foragers. AB - This study reports on developmental patterning in the intralimb indices of Late/Final Jomon period (4000-2300 BP) people. Jomon foragers represent the descendants of migrants from Northeast Asia, who arrived in the Japanese Islands around 20,000 BP. Among adults, Jomon brachial indices are elevated and similar to warm adapted, low latitude people, while crural indices are intermediate and similar to people from moderate latitudes. Two hypotheses regarding the development of intralimb indices among Jomon period foragers are tested: (1) intralimb indices of Jomon people maintain predicted ecogeographic relationships over ontogeny; (2) greater evolvability will be observed in the brachial index, while greater developmental constraint will be observed in the crural index. Changes in intralimb proportions in a Jomon skeletal growth series are compared to those in two contrasting samples: Inuit from Point Hope (cold adapted) and Nubians from Kulubnarti (warm adapted). A quadratic equation best describes the ontogeny of brachial and crural indices, with high indices in infancy followed by a decline in childhood and an increase in adolescence. Despite these shifts, ecogeographically predicted differences and similarities in the indices are maintained between samples throughout ontogeny. In addition, radial relative to humeral length is significantly less correlated than tibial relative to femoral length. These results suggest genetic conservation of intralimb indices over the course of development. However, radial and humeral lengths are less correlated than tibial and femoral lengths among Jomon subadults and adults, potentially suggesting greater evolvability of the brachial index and more developmental constraint on the crural index. PMID- 21541924 TI - Brief communication: dental development timing in captive Pan paniscus with comparisons to Pan troglodytes. AB - Dental eruption provides markers of growth and is one component of a chimpanzee's physical development. Dental markers help characterize transitions between life stages, e.g., infant to juvenile. Most of what we know about the timing of development in chimpanzees derives from Pan troglodytes. Much less is known about the sister species, Pan paniscus, with few in captivity and a restricted wild range in central Africa. Here we report on the dental eruption timing for female captive P. paniscus (n = 5) from the Milwaukee and San Diego Zoos whose ages are known and range from birth to age 8.54 years. Some observations were recorded in zoo records on the gingiva during life; others were made at death on the gingiva and on the skeleton. At birth, P. paniscus infants have no teeth emerged. By 0.83 years, all but the deciduous second molars (dm(2) ) (when both upper and lower dentitions are referenced collectively, no super or subscript notation is used) and canines (dc) are emerged. For permanent teeth, results show a sequence polymorphism for an early P4 eruption, not previously described for P. paniscus. Comparisons between P. paniscus and P. troglodytes document absolute timing differences of emergence in upper second incisors (I(2) ), and upper and lower canines (C) and third molars (M3). The genus Pan encompasses variability in growth not previously recognized. These preliminary data suggest that physical growth in captive P. paniscus may be accelerated, a general pattern found in captive P. troglodytes. PMID- 21541925 TI - Fusion of coccyx to sacrum in humans: prevalence, correlates, and effect on pelvic size, with obstetrical and evolutionary implications. AB - Humans do not have a tail, but we have four rudimentary coccygeal vertebrae. This study considers several issues pertaining to fusion of the coccyx to the sacrum, including prevalence, sexual differences, effect on pelvic size, and obstetrical and evolutionary implications. Previous research on sacral-coccygeal fusion has reported: (1) lower prevalence in females than males, (2) prevalence increases with age, (3) range in prevalence among 13 samples from 0 to 72%, and (4) obstetrical complications. This study uses a sample of 2,354 American skeletons of known sex, age 20 years and older to ascertain prevalence of sacral-coccygeal fusion and to evaluate some of its correlates. Results show that the sexes do not differ in prevalence of sacral-coccygeal fusion for five of seven decades of life, but that prevalence does increase with advancing age-from 24 to 47% from the third to eighth decades of life in females. Pelvimetric analysis of 132 females shows that those with sacral-coccygeal fusion have a shorter posterior sagittal diameter of the outlet compared to those without fusion; more than half of those with sacral-coccygeal fusion have an obstetrically contracted posterior sagittal diameter. Shortening of the posterior sagittal diameter is important, because its conjoint occurrence with a narrow subpubic arch may result in an obstetrically inadequate outlet. This study concludes that sacral-coccygeal fusion is a principal contributor to the evolution of sexual dimorphism in sacral angulation, which is a determinant of the length of the posterior sagittal diameter of the outlet. PMID- 21541926 TI - Study of femoral torsion during prenatal growth: interpretations associated with the effects of intrauterine pressure. AB - The developing fetus is protected from external environmental influences by maternal tissues. However, these structures have a limited elasticity, such that the fetus must grow in a confined space, constraining its size at the end of pregnancy. Can these constraints modify the morphology of the fetal skeleton? The intensity of these constraints increases between 5 months and birth, making it the most appropriate period to address this question. A sample of 89 fetal femora was analyzed, and results provide evidence that during this period, the torsion of the femoral shaft (quantified by means of a new three-dimensional method) increases gradually. Two explanations were considered: this increase could signal effects of constraints induced by the intrauterine cavity, developmental patterning, or some combination of these two. Different arguments tend to support the biomechanical explanation, rather than a programming pattern formation. Indeed, the identification of the femur as a first degree lever, created by the hyperflexion of the fetal lower limbs on the pelvis, could explain the increase in femoral shaft torsion during prenatal life. A comparison with femora of infants is in accordance with this mechanical interpretation, which is possible through bone modeling/remodeling. Although genetic and epigenetic mechanisms may regulate timing of fetal development, our data suggest that at birth, the fetal skeleton also has an intrauterine mechanical history through adaptive bone plasticity. PMID- 21541927 TI - Technical note: some observations on the conversion of dental enamel delta18O(p) values to delta18O(w) to determine human mobility. AB - It has become a widespread practice to convert delta(18)O(p) values measured in human and animal dental enamel to a corresponding value of delta(18)O(w) and compare these data with mapped delta(18)O(w) groundwater or meteoric water values to locate the region where the owner of the tooth lived during the formation of the enamel. Because this is a regression procedure, the errors associated with the predicted delta(18)O(w) values will depend critically on the correlation between the comparative data used to perform the regression. By comparing four widely used regression equations we demonstrate that the smallest 95% error is likely to be greater than +/-1% in delta(18)O(w) , and could be as large as +/ 3.5%. These values are significantly higher than those quoted in some of the recent literature, and measurements with errors at the higher end of this range would render many of the published geographical attributions statistically unsupportable. We suggest that the simplest solution to this situation is to make geographical attributions based on the direct comparison of measured values of delta(18)O(p) rather than on predicted values of delta(18)O(w). PMID- 21541928 TI - Pattern and pace of dental eruption in Tarsius. AB - This article uses data on the dental eruption pattern and life history of Tarsius to test the utility of Schultz's rule. Schultz's rule claims a relationship between the relative pattern of eruption and the absolute pace of dental development and life history and may be useful in reconstructing life histories in extinct primates. Here, we document an unusual eruption pattern in Tarsius combining early eruption (relative to molars) of anterior replacement teeth (P2 and incisors) and relatively late eruption of the posterior replacement teeth (C, P3, and P4). This eruption pattern does not accurately predict the "slow" pace of life documented for Tarsius [Roberts: Int J Primatol 15 (1994) 1-28], nor aspects of life history directly associated with dental development as would be expected using Schultz's rule. In Tarsius, the anterior teeth and M1 erupt at an early age and therefore are not only fast in a relative sense but also fast in an absolute sense. This seems to be related to a developmental anomaly in the deciduous precursor teeth, which are essentially skipped. This decoupling among dental eruption pattern, dental eruption pace, and life history pace in Tarsius undermines the assumptions that life histories can accurately be described as "fast" or "slow" and that dental eruption pattern alone can be used to infer overall life history pace. The relatively and absolutely early eruption of the anterior dentition may be due to the utility of these front teeth in early food acquisition rather than with the pace of life history. PMID- 21541929 TI - Brief communication: DNA from early Holocene American dog. AB - We present the oldest genetically identified dog in the Americas, directly dated to 9,260 +/- 170 Cal. B.P. The DNA was extracted from an occipital condyle imbedded in a human paleofecal sample from Hinds Cave in southwest Texas. A 368 base pair fragment of the mitochondrial genome control region was sequenced. These data were analyzed with comparable data, which included other ancient dogs and extant dogs, wolves and coyotes from around the world. Compiled with published data, our results characterize ancient American dogs within clades rooted by Eurasian wolves. In the Americas, these data provide no evidence of local interbreeding with wolves. This is a departure from the genetic pattern in other areas of the world where interbreeding with local wolf populations is apparent. Our discovery of domestic dog bone in a human paleofecal sample provides the earliest direct evidence for human consumption of dogs in the New World. These data support the hypothesis that dogs were a food source for early Paleoamericans. PMID- 21541930 TI - A new brain endocast of Homo erectus from Hulu Cave, Nanjing, China. AB - A new brain endocast of Homo erectus from Hulu Cave, Tangshan, Nanjing is described and compared with a broad sample of endocasts of H. erectus, Neanderthals, and recent modern humans. The Nanjing 1 endocast is reconstructed based on two portions of endocranial casts taken from the original fossil fragments. The fossil was discovered in 1993, near Nanjing, South China and is dated to ~ 0.58-0.62 Ma. The cranial capacity is ~ 876 cc, as determined by endocast water displacement. There are some common features of Nanjing 1 and other H. erectus endocasts that differentiate them from the Neanderthals and modern humans in our sample. These include small cranial capacity, low height dimensions, simple middle meningeal vessel patterns, a high degree of cerebral over-cerebellar lobe overhang, elongated and quite separated cerebellar lobes, and a narrow, low, short and flat frontal region. Some features are found to vary among H. erectus, Neanderthals and modern humans, such as the lateral Sylvian fissure position and the venous sinus and petalial patterns. The Nanjing 1 endocast has unique, large, superior frontal convolutions, and strongly protruding Broca's caps. In contrast to other Chinese H. erectus from Hexian and Zhoukoudian, Nanjing 1 lacks strong posterior projection of the occipital lobes. Bivariate and principal component analyses indicate that the small volume and shape of Nanjing 1 is most similar to KNM-WT 15000, KNM-ER 3883, Sangiran 2 and Hexian, illustrating the combination of narrow, low, and short frontal lobes with wide posterior lobes. PMID- 21541931 TI - The postcranial dimensions of the La Chapelle-aux-saints 1 Neandertal. AB - The La Chapelle-aux-Saints 1 Neandertal has figured prominently in considerations of Neandertal body size and proportions. In this context, a reassessment of its major long bones and a reassembly of its principal pelvic elements (sacrum and right ilium) was undertaken. There are secure measurements for its humeral and radial lengths and its femoral head diameter, but the femoral and tibial lengths were almost certainly greater than previous values. The resultant humeral, femoral and tibial lengths are similar to those of other male Neandertals, its femoral head diameter is among the largest known for Middle and Late Pleistocene humans, but its radial length is relatively short. The pelvic assembly provides modest bi-iliac and inlet transverse diameters compared with the few sufficiently complete and undistorted Middle and Late Pleistocene archaic human pelves, but its dimensions are similar to those of large male early modern humans. PMID- 21541932 TI - Feeding behavior and nutrient intake in spiny forest-dwelling ring-tailed lemurs (Lemur catta) during early gestation and early to mid-lactation periods: compensating in a harsh environment. AB - Strong resource seasonality in Madagascar has led to the evolution of female feeding priority and weaning synchrony in most lemur species. For these taxa, pregnancy/early lactation periods coincide with low food availability, and weaning of infants is timed with increased resources at the onset of the rainy season. Reproductive females experience high metabolic requirements, which they must accommodate, particularly when food resources are scarce. Female ring-tailed lemurs (Lemur catta) residing in spiny forest habitat must deal with resource scarcity, high temperatures (~36-40 degrees C) and little shade in early to mid lactation periods. Considered "income breeders," these females must use resources obtained from the environment instead of relying on fat stores; thus, we expected they would differ from same-sized males in time spent on feeding and in the intake of food and nutrients. We investigated these variables in two groups (N = 11 and 12) of Lemur catta residing in spiny forest habitat during early gestation and early to mid-lactation periods. Focal animal data and food plant samples were collected, and plants were analyzed for protein, kcal, and fiber. We found no sex differences for any feeding or nutrient intake variable for the top five food species consumed. Females in early gestation spent more time feeding compared with early/mid-lactation. Physiological compensation for spiny forest-dwelling females may be tied to greater time spent resting compared with gallery forest conspecifics, consuming foods high in protein, calories, and water, reduced home range defense in a sparsely populated habitat, and for Lemur catta females in general, production of relatively dilute milk compared with many strepsirrhines. PMID- 21541933 TI - Secular changes in craniofacial morphology of the Portuguese using geometric morphometrics. AB - This study examines patterns of secular change in cranial morphology in the New Lisbon collection, a documented skeletal collection from Lisbon, Portugal with birth years from 1806 to 1954. This period represents a time when Lisbon was undergoing increased urbanization and population growth, as well as changes in mortality and fertility patterns. Previous studies from the U.S., Europe, and Japan have reported significant secular changes in cranial morphology over the past 200 years. In the current study, secular changes were analyzed using three dimensional geometric morphometrics methods. The results from this study demonstrate a significant change in cranial morphology over the roughly 150-year period. Allometry was rejected as a causal factor of this change because there was no association found between temporal change and size. The pattern of temporal change is similar to that observed in other populations in the U.S., Europe, and Japan, including decreased facial breadth and a more inferiorly placed cranial base. This study, along with previous research, suggests a similar pattern of change occurs in genetically and geographically diverse populations experiencing modern environmental conditions. We argue that because the secular changes are focused in the cranial base, a region of the skull that experiences a relatively early growth curve, changes related to declines in childhood morbidity and mortality are likely important factors related to the observed changes. PMID- 21541934 TI - The maternal legacy of Basques in northern navarre: New insights into the mitochondrial DNA diversity of the Franco-Cantabrian area. AB - Autochthonous Basques are thought to be a trace from the human population contraction that occurred during the Last Glacial Maximum, based mainly on the salient frequencies and coalescence ages registered for haplogroups V, H1, and H3 of mitochondrial DNA in current Basque populations. However, variability of the maternal lineages still remains relatively unexplored in an important fraction of the Iberian Basque community. In this study, mitochondrial DNA diversity in Navarre (North Spain) was addressed for the first time. To that end, HVS-I and HVS-II sequences from 110 individuals were examined to identify the most relevant lineages, including analysis of coding region SNPs for the refinement of haplogroup assignment. We found a prominent frequency of subhaplogroup J1c (11.8%) in Navarre, coinciding with previous studies on Basques. Subhaplogroup H2a5, a putative autochthonous Basque lineage, was also observed in Navarre, pointing to a common origin of current Basque geographical groups. In contrast to other Basque subpopulations, comparative analyses at Iberian and European scales revealed a relevant frequency of subhaplogroup H3 (10.9%) and a frequency peak for U5b (15.5%) in Navarre. Furthermore, we observed low frequencies for maternal lineages HV0 and H1 in Navarre relative to other northern Iberian populations. All these findings might be indicative of intense genetic drift episodes generated by population fragmentation in the area of the Franco-Cantabrian refuge until recent times, which could have promoted genetic microdifferentiation between the different Basque subpopulations. PMID- 21541935 TI - "How pendulum-like are siamangs? Energy exchange during brachiation". AB - Hylobatidae (gibbons and siamangs) are known for their brachiation skills. The comparison of brachiation with a pendulum is made several times in the literature, and the costs and benefits of being pendulum-like are well described. However, the amount of energy exchange during brachiation of gibbons has rarely been determined. In this study, the amount of energy recovery (ER) during brachiation is assessed for three siamangs in a seminatural environment. The animals were recorded by four cameras while voluntarily brachiating on three different setups. The effects of locomotion speed, brachiation type, and setup on ER as well as on the external mechanical work during brachiation are determined. It is hypothesized that the amount of ER decreases with an increasing setup complexity while the external mechanical work increases. Additionally, we expect that support arm kinematics will be adjusted according to spatial complexity in order to maintain high recovery percentages. Our results show that ER is mainly determined by brachiation speed. Regardless of type of brachiation or setup, brachiation is done with a lower ER when brachiating faster. Within our limited range of setup variation, the expected effect of increasing complexity is not found. Although there is significant variation in support arm joint angles, no clear relation with speed, brachiation type, or setup is observed. PMID- 21541936 TI - Hepatectomy for recurrent colorectal liver metastases after radiofrequency ablation. AB - BACKGROUND: The results of surgery for recurrent colorectal liver metastases (CLM) after radiofrequency ablation (RFA) have not been evaluated. METHODS: From 1993 to 2009, data on patients who underwent resection or RFA for recurrent CLM were collected prospectively. Inclusion criteria for this study were RFA as initial treatment for CLM and resection of recurrent CLM after RFA. Postoperative results and oncological outcomes were analysed. RESULTS: Twenty-eight patients (median number of tumours 1 (1-3), median size 2.8 (2.0-4.0) cm) met the inclusion criteria. Of these, 22 had recurrence at the site of RFA only, two developed new lesions, whereas four had both recurrent and de novo metastases. At the time of resection, patients had a median of 1 (1-13) CLM with a median maximum tumour diameter of 5.0 (1.8-11.0) cm, significantly larger than at the time of RFA (P = 0.021). Ninety-day postoperative morbidity and mortality rates were 46 per cent (13 of 28) and 7 per cent (2 of 28) respectively. After a median follow-up of 35 (0-70) months, 3-year overall and disease-free survival rates calculated by Kaplan-Meier analysis were 60 and 29 per cent respectively. Plasma carcinoembryonic antigen level over 5 ng/ml at the time of resection and a rectal primary tumour were associated with worse survival (P = 0.041 and P = 0.021 respectively). CONCLUSION: Resection for recurrence after RFA is associated with significant morbidity and modest long-term benefit. PMID- 21541937 TI - PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach. AB - The objective of this study is to assess the effectiveness of physiologically based pharmacokinetic (PBPK) models for simulating human plasma concentration time profiles for the unique drug dataset of blinded data that has been assembled as part of a Pharmaceutical Research and Manufacturers of America initiative. Combinations of absorption, distribution, and clearance models were tested with a PBPK approach that has been developed from published equations. An assessment of the quality of the model predictions was made on the basis of the shape of the plasma time courses and related parameters. Up to 69% of the simulations of plasma time courses made in human demonstrated a medium to high degree of accuracy for intravenous pharmacokinetics, whereas this number decreased to 23% after oral administration based on the selected criteria. The simulations resulted in a general underestimation of drug exposure (Cmax and AUC0- t ). The explanations for this underestimation are diverse. Therefore, in general it may be due to underprediction of absorption parameters and/or overprediction of distribution or oral first-pass. The implications of compound properties are demonstrated. The PBPK approach based on in vitro-input data was as accurate as the approach based on in vivo data. Overall, the scientific benefit of this modeling study was to obtain more extensive characterization of predictions of human PK from PBPK methods. PMID- 21541938 TI - PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: comparative assessement of prediction methods of human clearance. AB - The objective of this study was to evaluate the performance of various allometric and in vitro-in vivo extrapolation (IVIVE) methodologies with and without plasma protein binding corrections for the prediction of human intravenous (i.v.) clearance (CL). The objective was also to evaluate the IVIVE prediction methods with animal data. Methodologies were selected from the literature. Pharmaceutical Research and Manufacturers of America member companies contributed blinded datasets from preclinical and clinical studies for 108 compounds, among which 19 drugs had i.v. clinical pharmacokinetics data and were used in the analysis. In vivo and in vitro preclinical data were used to predict CL by 29 different methods. For many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. In addition, 66 methods of predicting oral (p.o.) area under the curve (AUCp.o. ) were evaluated for 107 compounds using rational combinations of i.v. CL and bioavailability (F), and direct scaling of observed p.o. CL from preclinical species. Various statistical and outlier techniques were employed to assess the predictability of each method. Across methods, the maximum success rate in predicting human CL for the 19 drugs was 100%, 94%, and 78% of the compounds with predictions falling within 10-fold, threefold, and twofold error, respectively, of the observed CL. In general, in vivo methods performed slightly better than IVIVE methods (at least in terms of measures of correlation and global concordance), with the fu intercept method and two-species-based allometry (rat-dog) being the best performing methods. IVIVE methods using microsomes (incorporating both plasma and microsomal binding) and hepatocytes (not incorporating binding) resulted in 75% and 78%, respectively, of the predictions falling within twofold error. IVIVE methods using other combinations of binding assumptions were much less accurate. The results for prediction of AUCp.o. were consistent with i.v. CL. However, the greatest challenge to successful prediction of human p.o. CL is the estimate of F in human. Overall, the results of this initiative confirmed predictive performance of common methodologies used to predict human CL. PMID- 21541939 TI - Solubilities and transfer free energies of hydrophobic amino acids in polyol solutions: importance of the hydrophobicity of polyols. AB - The purpose of this work was to investigate the difference in the hydrophobicities of various polyols and the nature of interactions between hydrophobic amino acid side chains and polyols. The interactions were explored by conducting solubility studies of three amino acid derivatives, N-acetyl tryptophanamide (NATA), N-acetyl leucinamide (NALA), and N-acetyl glycinamide (NAGA), in the solutions of sorbitol, sucrose, trehalose, glycerol, ethylene glycol, ribose, and deoxyribose. Hydrophobicity index of polyols was calculated using molecular modeling. An increase in the solubility of the hydrophobic side chains of tryptophan and leucine was observed with an increase in the hydrophobicity index of polyols. Transfer free energies of NATA from water to polyols solutions were negative, whereas those for NALA were positive for all polyols except glycol. This study shows that the hydrophobic nature of polyols plays an important role in polyol-side chain interactions. Solubility behavior observed for NATA and NALA in different polyols indicates that polyols can interact differently with the same side chain depending on the nature of the polyol and the side chain. PMID- 21541940 TI - Feasibility of atomic force microscopy for determining crystal growth rates of nifedipine at the surface of amorphous solids with and without polymers. AB - Amorphous nifedipine (NFD), which has a smooth surface immediately after preparation, was shown to have structures resembling clusters of curling and branching fibers approximately 1 MUm wide by atomic force microscopy (AFM) after storage at 25 degrees C. The size of the cluster-like structures increased with storage over time, implying crystal growth. The average elongation rate of the fibers determined by AFM at ambient room temperature was 1.1 * 10(-9) m/s, and this agreed well with the crystal growth rate of 1.6 * 10(-9) m/s determined by polarized light microscopy. The crystal growth rate of NFD in solid dispersions with 5% polyethylene glycol (PEG) was found to be 5.0 * 10(-8) m/s by AFM. Although this value was approximately the same as that obtained by polarized light microscopy, three-dimensional information obtained by AFM for the crystallization of NFD in a solid dispersion with PEG revealed that the changes in topography were not a consequence of surface crystal growth, but rather attributable to the growth of crystals formed in the amorphous bulk. For solid dispersions with alpha,beta-poly(N-5-hydroxypentyl)-l-aspartamide, acceleration of NFD crystallization by tapping with an AFM probe was observed. The present study has demonstrated the feasibility and application of AFM for interpretation of surface crystallization data. PMID- 21541941 TI - Translocation and re-translocation of selenium taken up from nutrient solution during vegetative growth in spring wheat. AB - BACKGROUND: Selenium (Se) is an essential micronutrient for humans, but the Se level in food plants in northern Europe is generally inadequate to meet human nutritional requirements. Commonly, food plant Se fortification is achieved by selenate fertilisation, but the effect of nitrogen (N) and sulphur (S) supply on the translocation and re-translocation of Se is unknown. Therefore the effect of N and S supply on 75selenate/75Se translocation and re-translocation during vegetative growth in spring wheat (Triticum aestivum) was studied. RESULTS: The 75Se activity in wheat varied from 148 to 549, from 277 to 1815 and from 171 to 1343 Bq 75Se in plants exposed at Zadoks growth stages Z1.4, Z1.5 and Z1.6 respectively. Approximately 85% of the plant 75Se was translocated into young leaves. High N supply enhanced the re-translocation of 75Se from the stem to maturing leaves, while S inhibited this process. The relative proportion of 75Se in L4, L5 and L6 increased with increasing N supply at low sulfate concentrations. CONCLUSION: Selenium in the stem is more re-transportable than Se in the leaves, and the re-translocation is dependent on sulfate supply. When the sulfate supply is sufficient for plant development, less 75Se is re-translocated from older to growing leaves. PMID- 21541942 TI - Comparison of gas chromotography, spectrophotometry and near infrared spectroscopy to quantify prussic acid potential in forages. AB - BACKGROUND: Sorghum [Sorghum bicolor (L.) Moench] has been shown to contain the cyanogenic glycoside dhurrin, which is responsible for the disorder known as prussic acid poisoning in livestock. The current standard method for estimating hydrogen cyanide (HCN) uses spectrophotometry to measure the aglycone, p hydroxybenzaldehyde (p-HB), after hydrolysis. Errors may occur due to the inability of this method to solely estimate the absorbance of p-HB at a given wavelength. The objective of this study was to compare the use of gas chromatography (GC) and near infrared spectroscopy (NIRS) methods, along with a spectrophotometry method to estimate the potential for prussic acid (HCNp) of sorghum and sudangrasses over three stages maturities. RESULTS: It was shown that the GC produced higher HCNp estimates than the spectrophotometer for the grain sorghums, but lower concentrations for the sudangrass. Based on what is known about the analytical process of each method, the GC data is likely closer to the true HCNp concentrations of the forages. Both the GC and spectrophotometry methods yielded robust equations with the NIRS method; however, using GC as the calibration method resulted in more accurate and repeatable estimates. CONCLUSION: The HCNp values obtained from using the GC quantification method are believed to be closer to the actual values of the forage, and that use of this method will provide a more accurate and easily automated means of quantifying prussic acid. PMID- 21541943 TI - Korean red ginseng prevents gentamicin-induced hearing loss in rats. AB - OBJECTIVES: To evaluate the preventive effects of Korean red ginseng (KRG) on gentamicin (GM)-induced ototoxicity and to identify the effective components of KRG. STUDY DESIGN: In vivo and in vitro studies. METHODS: Thirty-five Sprague Dawley rats were divided into four groups. The GM group (n = 15) received intraperitoneal injections (IPI) of GM (160 mg/kg) for 5 days. The KRG + GM group (n = 12) was treated with intragastric feeding of KRG (500 mg/kg) for 12 days with 5 days of IPIs of GM. KRG (n = 4) and control (n = 4) groups were treated with KRG and saline, respectively. Auditory brainstem response (16 or 32 kHz) and Rotarod treadmill tests were done before and after treatments. Cochleas were evaluated by a scanning electron microscope (SEM) and phalloidin staining. Ginsenosides Rb1, Rb2, Rg1, and Re were evaluated as the water-soluble terazolium salt assay, annexin V/propidium iodide assay, and Western blots in HEI-OC1 cells. RESULTS: Posttreatment hearing thresholds in GM, KRG + GM, KRG, and control groups were: 27.7 +/- 7.2 dB, 23.1 +/- 4.1 dB, 16.9 +/- 2.6 dB, and 21.3 +/- 3.5 dB, respectively, for 16 kHz, 30.5 +/- 6.6 dB, 25.2 +/- 4.3 dB, 22.5 +/- 2.7 dB, and 22.5 +/- 3.8 dB, respectively for 32 kHz. The KRG + GM group had significantly better hearing than the GM group (P < .05). On SEM and phalloidin staining, the GM group showed severe loss of stereocilia in the basal outer hair cells and a few losses in the middle turns, whereas the KRG + GM group showed relatively intact hair cells. Balance impairment in treadmill tests was not definite in any group. Rb1 and Rb2 showed more effective protection than other components. CONCLUSIONS: KRG protects against GM-induced hearing loss and hair cell death in rats. Laryngoscope, 2011. PMID- 21541944 TI - Timing for repair of mandible fractures. AB - OBJECTIVES/HYPOTHESIS: Timing for repair of mandible fractures is a significant factor with regard to the rate of complication. STUDY DESIGN: Retrospective chart review of the previous 5 years (January 2005-January 2010). METHODS: All patients undergoing mandible fracture fixation performed in the study period and having complete records were analyzed (n = 83). Patients were stratified by time to fixation following initial injury. Subjects were then separated by the presence or absence of any of the following complications: infection, malunion, and nonunion. Logistical regression was then performed. RESULTS: Out of 83 patients there were 4 patients with six complications including malunion (n = 4) and infection (n = 2). There were no cases of nonunion. Delay in surgical intervention did not influence the complication rate. CONCLUSIONS: Complications from repair of mandible fractures are rare; it is difficult to detect significant variables that may impact outcomes. We found no relationship between complications and timing to repair. PMID- 21541945 TI - The relationship between depressive symptoms and initial quality of life and function in head and neck cancer. AB - OBJECTIVES: To determine the incidence of depression in head and neck cancer (HNCA) patients and the effect of depression on baseline head- and neck-specific measures of quality of life and function. STUDY DESIGN: Prospective cohort analysis. METHODS: A total of 255 patients were prospectively evaluated using the Beck Depression Inventory Fast-Screen (BDI-FS) survey, University of Washington Quality of Life (UW QOL), Voice Handicap Index (VHI), and MD Anderson Dysphagia Inventory (MDADI) questionnaires. Patients with a preexisting diagnosis of depression were excluded. RESULTS: Complete data were available for 77 patients with HNCA and 53 controls. Depressive symptoms were identified in 9% of controls and 19% of HNCA patients, and were significantly associated with a HNCA diagnosis (OR = 4.1, P = .044). Among patients with HNCA, depression was significantly more common in black patients (OR = 15.8, P = .017). A significant negative correlation was found between BDI-FS score and UW global QOL score (r = -0.4, P = .0019). Depression was significantly associated with poorer UW global QOL (beta = -22.46, P = .0004), recreation (beta = -13.77, P = .037), speech (beta = -24.05, P = .004), and MDADI functional (beta = -17.31, P = .009), physical (beta = 14.99, P = .032), and emotional (beta = -11.60, P = .049) domain scores but not with other UW QOL or VHI domains, after controlling for all other variables. CONCLUSIONS: Patients with HNCA have a high incidence of depressive symptoms at diagnosis, which is significantly higher in black patients, and is associated with poorer QOL and MDADI scores. Pretreatment depression may serve as a marker for patients with increased risk of swallowing impairment and reduced QOL who would benefit from targeted intervention. PMID- 21541946 TI - Method for removing hypopharyngeal salivary bypass tubes. AB - OBJECTIVE: To describe a novel method for the removal of the salivary bypass tube (SBT) that precludes the need for extraction under general anesthesia. STUDY DESIGN: Retrospective case series. METHODS/TECHNIQUE: Patients who had undergone laryngectomy/laryngopharyngectomy with subsequent development of pharyngocutaneous fistula and intraoperative placement of a salivary bypass tube were included in this series. The tubes were removed at the bedside or in clinic utilizing a Fogarty-type method over a Foley catheter. RESULTS: Three patients underwent removal of hypopharyngeal salivary bypass tubes 1 to 2 weeks after placement. Inflation of the Foley catheter within the lumen of the salivary bypass tube facilitated successful removal without the need for additional procedures. All three patients required only topical anesthetic and tolerated the procedure with minimal discomfort. CONCLUSIONS: Compared to current methods, this technique is cost-effective and time-efficient while not compromising patient safety or comfort. PMID- 21541947 TI - Primary versus delayed tracheoesophageal puncture for laryngopharyngectomy with free flap reconstruction. AB - OBJECTIVES: To determine whether postoperative complication rates and speech outcomes differ between patients undergoing primary versus secondary tracheoesophageal puncture following total laryngectomy with free flap reconstruction. STUDY DESIGN: Retrospective clinical study in a tertiary academic center. METHODS: Between November 2004 and June 2010, 137 patients underwent total laryngectomy or laryngopharyngectomy with pharyngeal free flap reconstruction for malignant disease. Data was collected on patient and operative demographics, early postoperative complications, speech outcomes, and predictive factors for tracheoesophageal puncture failure. RESULTS: Thirty patients (22%) had a primary tracheoesophageal puncture performed at the time of laryngectomy, 27 patients (20%) received secondary punctures (>3 months postlaryngectomy), and 80 patients (58%) never received a puncture. Patient and operative demographics were similar between groups (P < .05), apart from proportionately more hypopharyngeal tumors in the "no puncture" group (P < .002). Similar numbers of patients in primary and secondary puncture groups achieved intelligible speech (67% vs. 71%, P = .82) and both groups reported good patient-perceived voice related quality of life. Salvage surgery and nonpatch radial forearm free flap reconstruction both trended toward increased early postoperative complication rates (P = .09). CONCLUSIONS: There is no difference in the early postoperative complication rate for primary versus secondary tracheoesophageal puncture following total laryngectomy with concurrent free flap reconstruction. Radial forearm patch free flap reconstruction achieves good speech outcomes. PMID- 21541948 TI - Evaluation of the hybrid-L24 electrode using microcomputed tomography. AB - OBJECTIVES/HYPOTHESIS: To compare electrode array position, and depth of insertion of the Cochlear Hybrid-L24 electrode array following traditional cochleostomy and round window (RW) insertion. STUDY DESIGN: Prospective cadaveric temporal bone study. METHODS: Ten cadaveric temporal bones were implanted with the Hybrid-L24 electrode array; half were introduced through a RW approach, whereas the other half were inserted through a traditional scala tympani cochleostomy. A micro-CT scanner was then used to evaluate electrode position, intracochlear trauma, and depth of insertion. RESULTS: All electrodes were inserted into the scala tympani without significant resistance. No electrodes demonstrated tip fold-over or through-fracturing of the osseous spiral lamina, basilar membrane, or spiral ligament. The average angular depth of insertion for all 10 electrodes was 252.4 degrees . Compared to cochleostomy insertions, electrodes inserted through the RW more commonly acquired a proximal perimodiolar orientation, followed a more predictable course, and less commonly contacted critical soft tissue structures. CONCLUSIONS: The results of this study demonstrate that the Hybrid-L24 electrode can be successfully inserted using a RW or traditional cochleostomy technique with minimal intracochlear trauma. Our data also suggests that with this model, RW insertions may provide particular advantages with respect to hearing preservation over the traditional cochleostomy approach. PMID- 21541949 TI - In reference to are routine dissolvable nasal dressings necessary following endoscopic sinus surgery? PMID- 21541950 TI - Prevalence and clinical significance of hepatitis D virus co-infection in patients with chronic hepatitis B in Korea. AB - Hepatitis D virus (HDV) infection can cause severe acute and chronic liver disease in patients infected with hepatitis B virus (HBV). Despite the significant decline in the global HDV infection, it remains a major health concern in some countries. This study aimed to investigate the prevalence and clinical features of HDV co-infection in patients with chronic HBV infection in Korea, where HBV infection is endemic. Nine hundred forty patients [median age, 48 (18-94) years; men, 64.5%] infected chronically with HBV were enrolled consecutively. All patients who were positive for hepatitis B surface antigen (HBsAg) for at least 6 months and were tested for anti-HDV. A portion of the HDV delta antigen was amplified, sequenced, and subjected to molecular and phylogenetic analysis using sera from the patients who were anti-HDV positive. Clinical features and virologic markers were evaluated. Inactive HBsAg carriers, chronic hepatitis B, cirrhosis and hepatocellular carcinoma accounted for 29.5%, 44.7%, 17.9%, and 8.0%, respectively. Only three patients were positive for anti HDV, corresponding to a 0.32% positive rate. All patients who were positive for anti-HDV were inactive HBsAg carriers. HDV RNA could be amplified by PCR from the sera of two patients. Phylogenetic analysis showed that both carried HDV genotype 1. In conclusion, the prevalence of HDV infection is very low (0.32%) in Korea. All HDVs were genotype 1 and detected in inactive HBsAg carriers. Therefore, HDV co-infection may not have a significant clinical impact in Korean patients with chronic HBV infection. PMID- 21541951 TI - pi-pi interaction of quinacridone derivatives. AB - The pi-pi stacking interactions play an important role in molecular assemblies of quinacridone derivatives (QAs). In our previous work (Sun et al., J Phys Chem A 2008, 112, 11382), we have shown that quinacridone derivatives can be self associated as dimers in solution by means of NMR study. Herein, we perform theoretical studies on the molecular interaction in the dimers of QAs to illustrate pi-pi interactions in terms of their strength, geometrical preference, substituent effect, and physical nature. Density functional theory (DFT-D) was adopted to calculate potential energy surfaces. The detailed analysis on the intermolecular interaction in diversity of dimeric configurations reveals that the displaced conformations with specific geometries in both parallel and antiparallel stacking manners can be stabilized, which are in agreement with NMR experimental findings. PMID- 21541952 TI - Methylation of zebularine investigated using density functional theory calculations. AB - Deoxyribonucleic acid (DNA) methylation is an epigenetic phenomenon, which adds methyl groups into DNA. This study reveals methylation of a nucleoside antibiotic drug 1-(beta-D-ribofuranosyl)-2-pyrimidinone (zebularine or zeb) with respect to its methylated analog, 1-(beta-D-ribofuranosyl)-5-methyl-2-pyrimidinone (d5) using density functional theory calculations in valence electronic space. Very similar infrared spectra suggest that zeb and d5 do not differ by types of the chemical bonds, but distinctly different Raman spectra of the nucleoside pair reveal that the impact caused by methylation of zeb can be significant. Further valence orbital-based information details on valence electronic structural changes caused by methylation of zebularine. Frontier orbitals in momentum space and position space of the molecules respond differently to methylation. Based on the additional methyl electron density concentration in d5, orbitals affected by the methyl moiety are classified into primary and secondary contributors. Primary methyl contributions include MO8 (57a), MO18 (47a), and MO37 (28a) of d5, which concentrates on methyl and the base moieties, suggest certain connection to their Frontier orbitals. The primary and secondary methyl affected orbitals provide useful information on chemical bonding mechanism of the methylation in zebularine. PMID- 21541953 TI - Variational transition-state theory study of the rate constant of the DMS.OH scavenging reaction by O2. AB - The chemical tropospheric dimethyl sulfide (DMS, CH3SCH3) degradation involves several steps highly dependent on the environmental conditions. So, intensive efforts have been devoted during the last years to enhance the understanding of the DMS oxidation mechanism under different conditions. The reaction of DMS with OH is considered to be the most relevant process that initiates the whole oxidation process. The experimental observations have been explained by a two channel mechanism consisting of a H-abstraction process leading to CH3S(O)CH3 and HO2 and an addition reaction leading to the DMS.OH adduct. In the presence of O2, the DMS.OH adduct is competitively scavenged increasing the contribution of the addition channel to the overall DMS oxidation. Recent experimental measurements have determined from a global fit that the rate constant of this scavenging process is independent of pressure and temperature but this rate constant cannot be directly measured. In this article, a variational transition-state theory calculation of the low- and high-pressure rate constants for the reaction between DMS.OH and O2 has been carried out as a function of temperature. Our proposal is that the slight temperature dependence of the scavenging rate constant can only be explained if the H-abstraction bottleneck is preceded by a dynamical bottleneck corresponding to the association process between the DMS.OH adduct and the O2 molecule. The agreement between the low-pressure and high-pressure rate constants confirms the experimental observations. PMID- 21541954 TI - Dipole preserving and polarization consistent charges. AB - A method for estimating dipole preserving and polarization consistent (DPPC) charges is described, which reproduces exactly the molecular dipole moment as well as the local, atomic hybridization dipoles determined from the corresponding wave function and can yield accurate molecular polarization. The method is based on a model described by Thole and van Duijnen and a new feature is introduced to treat molecular polarization. Thus, the DPPC method offers a convenient procedure to describe molecular polarization in applications using semiempirical models and ab initio molecular orbital theory with relatively small basis functions such as 6-31+G(d,p) or without inclusion of electron correlation; these methods tend to underestimate molecular polarizability. The trends of the DPPC partial atomic charges are found to be in good accord with those of the CM2 model, a class IV charge analysis method that has been used in a variety of applications. The DPPC method is illustrated to mimic the correct molecular polarizability in a water dimer test case and in water-halide ion complexes using the explicit polarization (X-Pol) potential with the Austin model 1 Hamiltonian. PMID- 21541955 TI - Fast docking using the CHARMM force field with EADock DSS. AB - The prediction of binding modes (BMs) occurring between a small molecule and a target protein of biological interest has become of great importance for drug development. The overwhelming diversity of needs leaves room for docking approaches addressing specific problems. Nowadays, the universe of docking software ranges from fast and user friendly programs to algorithmically flexible and accurate approaches. EADock2 is an example of the latter. Its multiobjective scoring function was designed around the CHARMM22 force field and the FACTS solvation model. However, the major drawback of such a software design lies in its computational cost. EADock dihedral space sampling (DSS) is built on the most efficient features of EADock2, namely its hybrid sampling engine and multiobjective scoring function. Its performance is equivalent to that of EADock2 for drug-like ligands, while the CPU time required has been reduced by several orders of magnitude. This huge improvement was achieved through a combination of several innovative features including an automatic bias of the sampling toward putative binding sites, and a very efficient tree-based DSS algorithm. When the top-scoring prediction is considered, 57% of BMs of a test set of 251 complexes were reproduced within 2 A RMSD to the crystal structure. Up to 70% were reproduced when considering the five top scoring predictions. The success rate is lower in cross-docking assays but remains comparable with that of the latest version of AutoDock that accounts for the protein flexibility. PMID- 21541956 TI - Role of nonlocal exchange in molecular crystals: the case of two proton-ordered phases of ice. AB - We present a periodic density functional theory investigation of two proton ordered phases of ice. Their equilibrium lattice parameters,relative stabilities, formation energies, and densities of states have been evaluated. Nine exchange correlation functionals, representative of the generalized gradient approximation (GGA), global hybrids,range-separated hybrids, meta-GGA, and hybrid meta-GGA families have been taken into account, considering two oxygen basis sets. Although the hydrogen-bond network of ice is well reproduced at the B3LYP,M06-L, or LC- wPBE levels, formation energies are only correctly evaluated with the two former functionals. Band gaps on the other hand are only quantitatively reproduced at the B3LYP level. These results indicate that this last functional, a de facto reference for molecular calculations, gives in average the most accurate results for the considered ice properties. PMID- 21541957 TI - Toward robust computational electrochemical predicting the environmental fate of organic pollutants. AB - A number of density functionals was utilized for the calculation of electron attachment free energy for nitrocompounds, quinones and azacyclic compounds. Different solvation models have been tested on the calculation of difference in free energies of solvation of oxidized and reduced forms of nitrocompounds in aqueous solution, quinones in acetonitrile, and azacyclic compounds in dimethylformamide. Gas-phase free energies evaluated at the mPWB1K/tzvp level and solvation energies obtained using SMD model to compute solvation energies of neutral oxidized forms and PCM(Pauling) to compute solvation energies of anion radical reduced forms provide reasonable accuracy of the prediction of electron attachment free energy, difference in free solvation energies of oxidized and reduced forms, and as consequence yield reduction potentials in good agreement with experimental data (mean absolute deviation is 0.15 V). It was also found that SMD/M05-2X/tzvp method provides reduction potentials with deviation of 0.12 V from the experimental values but in cases of nitrocompounds and quinones this accuracy is achieved due to the cancelation of errors. To predict reduction ability of naturally occurred iron containing species with respect to organic pollutants we exploited experimental data within the framework of Pourbaix (Eh - pH) diagrams. We conclude that surface-bound Fe(II) as well as certain forms of aqueous Fe(II)aq are capable of reducing a variety of nitroaromatic compounds, quinones and novel high energy materials under basic conditions (pH > 8). At the same time, zero-valent iron is expected to be active under neutral and acidic conditions. PMID- 21541958 TI - Comparing and combining implicit ligand sampling with multiple steered molecular dynamics to study ligand migration processes in heme proteins. AB - The ubiquitous heme proteins perform a wide variety of tasks that rely on the subtle regulation of their affinity for small ligands like O2, CO, and NO. Ligand affinity is characterized by kinetic association and dissociation rate constants, that partially depend on ligand migration between the solvent and active site, mediated by the presence of internal cavities or tunnels. Different computational methods have been developed to study these processes which can be roughly divided in two strategies: those costly methods in which the ligand is treated explicitly during the simulations, and the free energy landscape of the process is computed; and those faster methods that use prior computed Molecular Dynamics simulation without the ligand, and incorporate it afterwards, called implicit ligand sampling (ILS) methods. To compare both approaches performance and to provide a combined protocol to study ligand migration in heme proteins, we performed ILS and multiple steered molecular dynamics (MSMD) free energy calculations of the ligand migration process in three representative and well theoretically and experimentally studied cases that cover a wide range of complex situations presenting a challenging benchmark for the aim of the present work. Our results show that ILS provides a good description of the tunnel topology and a reasonable approximation to the free energy landscape, while MSMD provides more accurate and detailed free energy profile description of each tunnel. Based on these results, a combined strategy is presented for the study of internal ligand migration in heme proteins. PMID- 21541959 TI - Efficiency of tabu-search-based conformational search algorithms. AB - Efficient conformational search or sampling approaches play an integral role in molecular modeling, leading to a strong demand for even faster and more reliable conformer search algorithms. This article compares the efficiency of a molecular dynamics method, a simulated annealing method, and the basin hopping (BH) approach (which are widely used in this field) with a previously suggested tabu search-based approach called gradient only tabu search (GOTS). The study emphasizes the success of the GOTS procedure and, more importantly, shows that an approach which combines BH and GOTS outperforms the single methods in efficiency and speed. We also show that ring structures built by a hydrogen bond are useful as starting points for conformational search investigations of peptides and organic ligands with biological activities, especially in structures that contain multiple rings. PMID- 21541960 TI - Acceleration of a QM/MM-QMC simulation using GPU. AB - We accelerated an ab initio molecular QMC calculation by using GPGPU. Only the bottle-neck part of the calculation is replaced by CUDA subroutine and performed on GPU. The performance on a (single core CPU + GPU) is compared with that on a (single core CPU with double precision), getting 23.6 (11.0) times faster calculations in single (double) precision treatments on GPU. The energy deviation caused by the single precision treatment was found to be within the accuracy required in the calculation, ~10(-5) hartree. The accelerated computational nodes mounting GPU are combined to form a hybrid MPI cluster on which we confirmed the performance linearly scales to the number of nodes. PMID- 21541961 TI - PyADF--a scripting framework for multiscale quantum chemistry. AB - Applications of quantum chemistry have evolved from single or a few calculations to more complicated workflows, in which a series of interrelated computational tasks is performed. In particular multiscale simulations, which combine different levels of accuracy, typically require a large number of individual calculations that depend on each other. Consequently, there is a need to automate such workflows. For this purpose we have developed PYADF, a scripting framework for quantum chemistry. PYADF handles all steps necessary in a typical workflow in quantum chemistry and is easily extensible due to its object-oriented implementation in the Python programming language. We give an overview of the capabilities of PYADF and illustrate its usefulness in quantum-chemical multiscale simulations with a number of examples taken from recent applications. PMID- 21541962 TI - Implementation and evaluation of a docking-rescoring method using molecular footprint comparisons. AB - A docking-rescoring method, based on per-residue van der Waals (VDW), electrostatic (ES), or hydrogen bond (HB) energies has been developed to aid discovery of ligands that have interaction signatures with a target (footprints) similar to that of a reference. Biologically useful references could include known drugs, inhibitors, substrates, transition states, or side-chains that mediate protein-protein interactions. Termed footprint similarity (FPS) score, the method, as implemented in the program DOCK, was validated and characterized using: (1) pose identification, (2) crossdocking, (3) enrichment, and (4) virtual screening. Improvements in pose identification (6-12%) were obtained using footprint-based (FPS(VDW+ES)) vs. standard DOCK (DCE(VDW+ES)) scoring as evaluated on three large datasets (680-775 systems) from the SB2010 database. Enhanced pose identification was also observed using FPS (45.4% or 70.9%) compared with DCE (17.8%) methods to rank challenging crossdocking ensembles from carbonic anhydrase. Enrichment tests, for three representative systems, revealed FPSVDW+ES scoring yields significant early fold enrichment in the top 10% of ranked databases. For EGFR, top FPS poses are nicely accommodated in the molecular envelope defined by the reference in comparison with DCE, which yields distinct molecular weight bias toward larger molecules. Results from a representative virtual screen of ca. 1 million compounds additionally illustrate how ligands with footprints similar to a known inhibitor can readily be identified from within large commercially available databases. By providing an alternative way to rank ligand poses in a simple yet directed manner we anticipate that FPS scoring will be a useful tool for docking and structure-based design. PMID- 21541963 TI - Acceleration of the GAMESS-UK electronic structure package on graphical processing units. AB - The approach used to calculate the two-electron integral by many electronic structure packages including generalized atomic and molecular electronic structure system-UK has been designed for CPU-based compute units. We redesigned the two-electron compute algorithm for acceleration on a graphical processing unit (GPU). We report the acceleration strategy and illustrate it on the (ss|ss) type integrals. This strategy is general for Fortran-based codes and uses the Accelerator compiler from Portland Group International and GPU-based accelerators from Nvidia. The evaluation of (ss|ss) type integrals within calculations using Hartree Fock ab initio methods and density functional theory are accelerated by single and quad GPU hardware systems by factors of 43 and 153, respectively. The overall speedup for a single self consistent field cycle is at least a factor of eight times faster on a single GPU compared with that of a single CPU. PMID- 21541964 TI - SwissParam: a fast force field generation tool for small organic molecules. AB - The drug discovery process has been deeply transformed recently by the use of computational ligand-based or structure-based methods, helping the lead compounds identification and optimization, and finally the delivery of new drug candidates more quickly and at lower cost. Structure-based computational methods for drug discovery mainly involve ligand-protein docking and rapid binding free energy estimation, both of which require force field parameterization for many drug candidates. Here, we present a fast force field generation tool, called SwissParam, able to generate, for arbitrary small organic molecule, topologies, and parameters based on the Merck molecular force field, but in a functional form that is compatible with the CHARMM force field. Output files can be used with CHARMM or GROMACS. The topologies and parameters generated by SwissParam are used by the docking software EADock2 and EADock DSS to describe the small molecules to be docked, whereas the protein is described by the CHARMM force field, and allow them to reach success rates ranging from 56 to 78%. We have also developed a rapid binding free energy estimation approach, using SwissParam for ligands and CHARMM22/27 for proteins, which requires only a short minimization to reproduce the experimental binding free energy of 214 ligand-protein complexes involving 62 different proteins, with a standard error of 2.0 kcal mol(-1), and a correlation coefficient of 0.74. Together, these results demonstrate the relevance of using SwissParam topologies and parameters to describe small organic molecules in computer-aided drug design applications, together with a CHARMM22/27 description of the target protein. SwissParam is available free of charge for academic users at www.swissparam.ch. PMID- 21541965 TI - Conformational state-specific free energy differences by one-step perturbation: protein secondary structure preferences of the GROMOS 43A1 and 53A6 force fields. AB - The one-step free energy perturbation approach can be applied to obtain conformational state-specific free energy differences (FEDs) associated with changes in force field parameters, and thus offers the possibility to consider conformational equilibria during force field parameterization. In this work, using the alanine decapeptide in explicit water solution as a model, the alpha helical and beta-hairpin state-specific FEDs associated with force field changes between two widely used parameter sets of the GROMOS force field, namely, 43A1 and 53A6, were determined using one-step perturbation. The results mostly deviated by only 1 kJ mol(-1) in absolute or a few percent in relative values from thermodynamic integration results, suggesting that the convergence ranges of one-step perturbation were large enough to cover the substantial changes in nonbonded parameters between the two parameter sets. It was also found that one step perturbation may give larger errors when the changes from the reference state include a large decrease in van der Waals radius, as indicated by the result for the beta-hairpin state-specific free energy change going from 53A6 to 43A1. According to the free energy results, the alpha-helical state of the alanine decapeptide is destabilized by 15 kJ mol(-1), i.e., 1.5 kJ mol(-1) per residue, relative to the beta-hairpin state when going from 43A1 to 53A6, in agreement with previous direct simulations in which native alpha-helices were often found to be unstable in simulations using 53A6, despite that the 53A6 parameters better reproduce a range of thermodynamic properties of small molecular systems. By applying one-step perturbation to analyze the effects of perturbing individual parameters, the differential stabilization of the two secondary structure states can be traced to the changes in van der Waals parameters, especially a van der Waals parameter involved in third-neighbor interactions. This study provides an example of the efficiency of one-step perturbation in force field development, reducing the computational cost by orders of magnitude. PMID- 21541966 TI - Computational study of energetic nitrogen-rich derivatives of 1,1'- and 5,5' bridged ditetrazoles. AB - Density functional theory method was used to study the heats of formation (HOFs), electronic structure, energetic properties, and thermal stability for a series of bridged ditetrazole derivatives with different linkages and substituent groups. The results show that the -N3 group and azo bridge (-N=N-) play a very important role in increasing the HOF values of the ditetrazole derivatives. The effects of the substituents on the HOMO-LUMO gap are combined with those of the bridge groups. The calculated detonation velocities and detonation pressures indicate that the -NO2, -NF2, -N=N-, or -N(O)=N- group is an effective structural unit for enhancing the detonation performance for the derivatives. An analysis of the bond dissociation energies for several relatively weak bonds suggests that the N-N bond in the ring or outside the ring is the weakest one and the N-N cleavage is possible to happen in thermal decomposition. Overall, the -CH2-CH2- or -NH-NH- group is an effective bridge for enhancing the thermal stability of the bridged ditetrazoles. Because of their desirable detonation performance and thermal stability, five compounds may be considered as the potential candidates of high energy density materials (HEDMs). These results provide basic information for the molecular design of novel HEDMs. PMID- 21541967 TI - QSAR model reproducibility and applicability: a case study of rate constants of hydroxyl radical reaction models applied to polybrominated diphenyl ethers and (benzo-)triazoles. AB - The crucial importance of the three central OECD principles for quantitative structure-activity relationship (QSAR) model validation is highlighted in a case study of tropospheric degradation of volatile organic compounds (VOCs) by OH, applied to two CADASTER chemical classes (PBDEs and (benzo-)triazoles). The application of any QSAR model to chemicals without experimental data largely depends on model reproducibility by the user. The reproducibility of an unambiguous algorithm (OECD Principle 2) is guaranteed by redeveloping MLR models based on both updated version of DRAGON software for molecular descriptors calculation and some freely available online descriptors. The Genetic Algorithm has confirmed its ability to always select the most informative descriptors independently on the input pool of variables. The ability of the GA-selected descriptors to model chemicals not used in model development is verified by three different splittings (random by response, K-ANN and K-means clustering), thus ensuring the external predictivity of the new models, independently of the training/prediction set composition (OECD Principle 5). The relevance of checking the structural applicability domain becomes very evident on comparing the predictions for CADASTER chemicals, using the new models proposed herein, with those obtained by EPI Suite. PMID- 21541968 TI - Correlation between circulatory, local prostatic, and intra-prostatic androgen levels. AB - BACKGROUND: Testosterone is converted to the more potent androgen dihydrotestosterone (DHT) in the prostate. DHT and androgen metabolites are inactivated by uridine diphospho (UDP)-glucuronosyl transferase (UGT) enzymes. Here we have studied the influence of the prostate gland on the systemic levels of DHT. Moreover, genetic variation in androgen metabolizing UGT enzymes and the intra-prostatic levels of glucuronidated DHT metabolites were investigated. METHODS: We collected peripheral serum, serum from the local prostatic veins and prostatic tissue from 25 patients undergoing radical prostatectomy. The serum and intra-tissular level of different androgen metabolites were determined by immunological assays and gas chromatography-mass spectrometry (GCMS), respectively. RESULTS: We found a significant positive correlation between the local prostatic serum DHT levels and (a) prostate weight and (b) circulatory serum levels. There were no correlation between in intra-prostatic hormonal levels and local DHT serum levels. The DHT metabolite 3alpha-diol-17-glucuronide and 3alpha-diol-3-glucuronide were significantly associated with UGT2B17 deletion and UGT2B15 Asp85Tyr polymorphisms, respectively. CONCLUSION: These results indicate that local prostatic DHT production has an influence on systemic serum DHT levels. Moreover, our results support the evidence that the prostate is the main DHT producer and that UGTs are important in the intra-prostatic regulation of androgens. PMID- 21541969 TI - Elevated GnRH receptor expression plus GnRH agonist treatment inhibits the growth of a subset of papillomavirus 18-immortalized human prostate cells. AB - BACKGROUND AND AIMS: Human metastatic prostate cancer cell growth can be inhibited by GnRH analogs but effects on virus-immortalized prostate cells have not been investigated. METHODS: Virus-immortalized prostate cells were stably transfected with rat GnRH receptor cDNA and levels of GnRH binding were correlated with GnRH effects on signaling, cell cycle, growth, exosome production, and apoptosis. RESULTS: High levels of cell surface GnRH receptor occurred in transfected papillomavirus-immortalized WPE-1-NB26 epithelial cells but not in non-tumourigenic RWPE-1, myoepithelial WPMY-1 cells, or SV40 immortalized PNT1A. Endogenous cell surface GnRH receptor was undetectable in non transfected cells or cancer cell lines LNCaP, PC3, and DU145. GnRH receptor levels correlated with induction of inositol phosphates, elevation of intracellular Ca(2+) , cytoskeletal actin reorganization, modulation of ERK activation and cell growth-inhibition with GnRH agonists. Hoechst 33342 DNA staining-cell sorting indicated accumulation of cells in G2 following agonist treatment. Release of exosomes from transfected WPE-1-NB26 was unaffected by agonists, unlike induction observed in HEK293([SCL60]) cells. Increased PARP cleavage and apoptotic body production were undetectable during growth-inhibition in WPE-1-NB26 cells, contrasting with HEK293([SCL60]) . EGF receptor activation inhibited GnRH-induced ERK activation in WPE-1-NB26 but growth-inhibition was not rescued by EGF or PKC inhibitor Ro320432. Growth of cells expressing low levels of GnRH receptor was not affected by agonists. CONCLUSIONS: Engineered high-level GnRH receptor activation inhibits growth of a subset of papillomavirus immortalized prostate cells. Elucidating mechanisms leading to clone-specific differences in cell surface GnRH receptor levels is a valuable next step in developing strategies to exploit prostate cell anti-proliferation using GnRH agonists. PMID- 21541970 TI - Leptin signaling and apoptotic effects in human prostate cancer cell lines. AB - BACKGROUND: Prostate cancer (PCa) progression is often associated with transactivation of the androgen receptor (AR) by endogenous hormones/growth factors. One such factor affecting growth, proliferation, and apoptostis (pro /anti-) in various cancers is the adipokine leptin. This research studied leptin induced signaling and apoptosis in androgen sensitive (LNCaP, PC3/AR) and insensitive (PC3, DU145) PCa cell lines. METHODS: Signaling was studied by immunoblotting in cells overexpressing leptin receptors (LRb), Janus kinase 2 (JAK2), and kinase negative-HER2-YFP cDNAs. Apoptosis was measured by immunoblotting of apoptotic proteins and by Hoechst staining of condensed DNA. RESULTS: Leptin rapidly induced activation of JAK2, STAT3, and MAPK (ERK1/2) signaling cascades; it may also induce HER2 transactivation via leptin-induced phospho-JAK2. Leptin was then shown to exert clear pro-apoptotic effects, increasing levels of caspase 3, cleavage of its substrate, poly (ADP-ribose) polymerase (PARP) to cleaved PARP(89) , levels of CK 18, a cytoskeletal protein formed during apoptosis, and DNA condensation. Kinase inhibitors indicated that leptin-induced apoptosis is probably mediated by balanced activation of JAK2/STAT3, p38 MAPK, and PKC pathways in PCa cells. A human leptin mutein LRb antagonist, L39A/D40A/F41A, fully inhibited leptin-induced phosphorylation of JAK2, ERK1/2, and Akt/PKB, and partially abrogated effects on apoptotic proteins. In LNCaP and PC3/AR cells, leptin increased AR protein levels in correlation with raised apoptotic markers. Thus, AR may mediate, at least partly, the leptin induced apoptotic response. CONCLUSIONS: Leptin can clearly induce apoptosis in human PCa cell lines. These findings could lead to development of new leptin agonists with enhanced pro-apoptotic effects and targeted for use in human PCa. PMID- 21541971 TI - PKCdelta activation mediates angiogenesis via NADPH oxidase activity in PC-3 prostate cancer cells. AB - BACKGROUND: PKCdelta is generally known as a pro-apoptotic and anti-proliferative enzyme in human prostate cancer cells. METHODS: Here, we investigated the role of PKCdelta on the growth of PC-3 human prostate cancer cells in vivo and in vitro. RESULTS: We found that sustained treatment with a specific PKCdelta activator (psidelta receptor for active C kinase, psideltaRACK) increased growth of PC-3 xenografts. There was increased levels of HIF-1alpha, vascular endothelial growth factor and CD31-positive cells in PC-3 xenografts, representative of increased tumor angiogenesis. Mechanistically, PKCdelta activation increased the levels of reactive oxygen species (ROS) by binding to and phosphorylating NADPH oxidase, which induced its activity. Also, PKCdelta-induced activation of NADPH oxidase increased the level of HIF-1alpha. CONCLUSIONS: Our results using tumors from the PC-3 xenograft model suggest that PKCdelta activation increases angiogenic activity in androgen-independent PC-3 prostate cancer cells by increasing NADPH oxidase activity and HIF-1alpha levels and thus may partly be responsible for increased angiogenesis in advanced prostate cancer. PMID- 21541972 TI - Functional annotation of risk loci identified through genome-wide association studies for prostate cancer. AB - BACKGROUND: The majority of established prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) identified from genome-wide association studies do not fall into protein coding regions. Therefore, the mechanisms by which these SNPs affect PCa risk remain unclear. Here, we used a series of bioinformatic tools and databases to provide possible molecular insights into the actions of risk SNPs. METHODOLOGY/PRINCIPAL FINDINGS: We performed a comprehensive assessment of the potential functional impact of 33 SNPs that were identified and confirmed as associated with PCa risk in previous studies. For these 33 SNPs and additional SNPs in linkage disequilibrium (LD) (r(2) >= 0.5), we first mapped them to genomic functional annotation databases, including the encyclopedia of DNA elements (ENCODE), 11 genomic regulatory elements databases defined by the University of California Santa Cruz (UCSC) table browser, and androgen receptor (AR)-binding sites defined by a ChIP-chip technique. Enrichment analysis was then carried out to assess whether the risk SNP blocks were enriched in the various annotation sets. Risk SNP blocks were significantly enriched over that expected by chance in two annotation sets, including AR-binding sites (P = 0.003), and FoxA1-binding sites (P = 0.05). About one-third of the 33 risk SNP blocks are located within AR-binding regions. CONCLUSIONS/SIGNIFICANCE: The significant enrichment of risk SNPs in AR-binding sites may suggest a potential molecular mechanism for these SNPs in PCa initiation, and provide guidance for future functional studies. PMID- 21541973 TI - Regulation of androgen receptor expression through angiotensin II type 1 receptor in prostate cancer cells. AB - BACKGROUND: Although the local renin-angiotensin system (RAS) of the prostate gland is related to cell proliferation and angiogenesis, the detailed mechanism remains unclear. We examined the effects of the angiotensin II type 1 receptor (AT1R) on androgen receptor (AR) expression in prostate cancer cells. METHODS: AR modulation by AT1R was examined by Western blot analysis, luciferase assay, and Immunocytochemical staining. The influence of AR expression by angiotensin II (Ang-II) and AT1R inhibition using siRNA was determined. Furthermore, using angiotensinogen or AT1R knockout (KO) mice, we performed quantitative real-time PCR to investigate the expression of AR. RESULTS: Ang-II induced cell proliferation with enhancement of AR, prostate specific antigen (PSA), NF-kappaB, and c-myc, and the activity of AR and PSA promoter. Cell proliferation of LNCaP transfected with AT1R siRNA was decreased by 75% at 7 days by inhibition of AR, PSA, NF-kappaB, and c-myc. Immunocytochemical staining confirmed the suppression of AR translocation into the nucleus in AT1R siRNA cells. AT1R KO mice showed a decrease in AR expression in the prostate gland. We also found that the expression level of AT1R could modulate the transcriptional level of AR by affecting NF-kappaB and c-myc expression. CONCLUSIONS: Knocking down of the AT1R protein resulted in significant inhibition of cell growth, associated with a marked decrease of AR protein. These results indicate that inhibition of AT1R has the potential to influence AR expression in prostate cells, and is anticipated to contribute to the development of novel therapeutic agents for prostate cancer. PMID- 21541974 TI - Anti-angiogenic effects and mechanism of prazosin. AB - BACKGROUND: Alpha1-adrenoceptors antagonists (doxazosin, terazosin, prazosin) are commonly prescribed for benign prostate hyperplasia and hypertension. Doxazosin and terazosin exhibit anti-angiogenic effects and apoptotic activities against multiple cell types and are potential preventive agents for prostate cancer. Prazosin induces apoptosis in three prostate cancer cell lines. We hypothesized that prazosin, a more potent alpha1-adrenoceptor antagonist with a distinct mechanism, exhibits anti-angiogenic activity. METHODS: We examined the effect of prazosin on growth and tube formation of human umbilical vascular endothelial cells (HUVECs). We used flow cytometry to assess the effect of prazosin on cell cycle progression and Western blotting to assess its effect on the expression of various apoptotic proteins. RESULTS: Prazosin inhibited the growth of HUVEC with an IC(50) of 6.53 uM and suppressed tube formation in a dose-dependent manner. Unlike prostate cancer cells, prazosin did not arrest cell cycle progression at the G2/M checkpoint. We used rhodamine 123 staining to show that prazosin (20 uM) treatment induced a loss of mitochondrial membrane potential by 12 hr. Prazosin treatment of HUVECs resulted in reduced MCL-1 expression, increased Bad, and Bcl xL expression, cytochrome c release, and induction of apoptosis via the intrinsic apoptosis pathway. Prazosin induced apoptosis in prostate cancer cells and normal HUVEC cells via different mechanisms. CONCLUSIONS: These data suggest that prazosin exhibits anti-angiogenic activity and differentially modulates apoptotic pathways depending on the cell type. PMID- 21541975 TI - Disparities at presentation, diagnosis, treatment, and survival in African American men, affected by prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) remains the most common malignancy and the second leading cause of cancer death among men in the United States. PCa exhibits the most striking racial disparity, as African American men are at 1.4 times higher risk of being diagnosed, and 2-3 times higher risk of dying of PCa, compared to Caucasian men. The etiology of the disparity has not been clearly elucidated. The objective of this article is to critically review the literature and summarize the most prominent PCa racial disparities accompanied by proposed explanations. METHODS: The present literature on disparities at presentation, diagnosis, treatment, and survival of African American men affected by PCa was systematically reviewed. Original research as well as relevant review articles were included. RESULTS: African American men persistently present with more advanced disease than Caucasian men, are administered different treatment regimens than Caucasian men, and have shorter progression-free survival following treatment. In addition, African American men report more treatment-related side effects that translates to the diminished quality of life (QOL). CONCLUSIONS: PCa racial disparity exists at stages of presentation, diagnosis, treatment regimens, and subsequent survival, and the QOL. The disparities are complex involving biological, socio-economic, and socio-cultural determinants. These mounting results highlight an urgent need for future clinical, scientific, and socio cultural research involving transdisciplinary teams to elucidate the causes for PCa racial disparities. PMID- 21541976 TI - Retargeting of T cells to prostate stem cell antigen expressing tumor cells: comparison of different antibody formats. AB - BACKGROUND: Prostate cancer (PCa) is the most common malignant disease in men. Novel treatment options are needed for patients after development of metastatic, hormone-refractory disease or for those who have failed a local treatment. The prostate stem cell antigen (PSCA) is expressed in >80% of primary PCa samples and bone metastases. Its expression is increased both in androgen-dependent and independent prostate tumors, particularly in carcinomas of high stages and Gleason scores. Therefore, PSCA is an attractive target for immunotherapy of PCa by retargeting of T cells to tumor cells. METHODS: A series of different bispecific antibody formats for retargeting of T cells to tumor cells were described but, only very limited data obtained by side by side comparison of the different antibody formats are available. We established two novel bispecific antibodies in different formats. The functionality of both constructs was analyzed by FACS and chromium release assays. In parallel, the release of pro inflammatory cytokines was determined by ELISA. RESULTS AND CONCLUSIONS: Irrespective of the underlying antibody format, both novel bispecific antibodies cause an efficient killing of PSCA-positive tumor cells by pre- and non-pre activated T cells. Killing and release of pro-inflammatory cytokines requires an antigen specific cross-linkage of the T cells with the target cells. PMID- 21541977 TI - Vitamin D deficiency promotes prostate cancer growth in bone. AB - BACKGROUND: Vitamin D is considered as an important determinant of bone turnover as well as cancer growth. Using a murine model of bone metastasis, we investigated the effect of vitamin D deficiency on prostate cancer cell growth in bone. METHODS: Three-week-old male nude mice were fed either normal chow (control) or a diet deficient in vitamin D. The latter diet resulted in severe hypovitaminosis D within 6 weeks. At this point of time, 5 * 10(4) cells of the prostate cancer cell line, PC-3, were injected either into the bone marrow (tibia) or subcutaneously into soft tissues. Osteoprotegerin (OPG) was co administered in subgroups of mice to suppress bone remodeling. Osteolytic lesions were monitored by serial X-ray, while soft tissue tumor growth was measured by caliper. All tissues were analyzed by micro-CT and histology at endpoint. RESULTS: Bone turnover was significantly accelerated in vitamin D deficient compared to vitamin D sufficient mice from week 6 onwards. Intra-tibially implanted PC-3 cells resulted in mixed osteolytic and osteosclerotic lesion. At endpoint, osteolytic and osteosclerotic lesion areas, total tumor area, and tumor mitotic activity were all significantly increased in vitamin D deficient mice compared to controls. Regardless of diet, OPG reduced bone turnover, total tumor, and osteosclerotic area as well as tumor mitotic activity, while promoting cell apoptosis. In contrast, vitamin D deficiency did not alter tumor growth in soft tissues. CONCLUSION: Vitamin D deficiency stimulates prostate cancer growth in bone through modulating the bone microenvironment. PMID- 21541978 TI - High dosage of aripiprazole-induced dysphagia. AB - BACKGROUND: Dysphagia as a main manifestation of extrapyramidal symptoms is an uncommon adverse effect of second-generation antipsychotics. METHOD: We present a 54-year-old drug-naive patient with schizophrenia, who developed dysphagia with aripiprazole 30 mg daily treatment. RESULTS: This is the first case report on aripiprazole-induced dysphagia. We discuss the risk factors that led to dysphagia in this case. CONCLUSION: Aripiprazole-induced dysphagia is rare, and it is important to be aware that it does occur with high-dosage treatment. PMID- 21541979 TI - Fear of food as a treatment target: exposure and response prevention for anorexia nervosa in an open series. AB - OBJECTIVE: Anorexia nervosa (AN) is a severe mental illness with high rates of relapse and rehospitalization. New treatment approaches are needed. We aimed to evaluate the potential utility of addressing eating-related fear in the treatment of AN using psychotherapy techniques known to be effective in the treatment of anxiety disorders and obsessive compulsive disorder, namely exposure therapy and response prevention. METHOD: We developed a brief treatment intervention for AN (AN-EXRP) and evaluated its effects in an open series of nine individuals with AN towards the end of acute weight restoration. We focused on eating behavior as the primary outcome, as it is related both to anxiety and to longer term course. RESULTS: Change in anxiety with AN-EXRP was associated with greater caloric intake. DISCUSSION: These findings support the anxiety-centered model of AN and suggest the potential utility of further developing this treatment approach. PMID- 21541981 TI - Topographic mapping of retinal neurons in the European anchovy by nuclear staining and immunohistochemistry. AB - The anchovy retina is unique among vertebrates in being designed for polarization contrast vision and has a marked cone area in the ventrotemporal quadrant for acute vision in the frontal field of view. Whereas cone topography and fine structure have been well examined in the European anchovy, the morphological organization of its inner retina is poorly understood so far. Using fluorescence staining of cell nuclei in combination with antibody stainings, the 3D pattern of cell nuclei was recorded coevally in all three retinal cell layers by confocal laser scanning microscopy, and the topographies of several neuron types were mapped separately across the retina. Cell classification and quantification succeeded for rods, cones, three types of horizontal cells (H1-3), rod and cone bipolars, amacrines, ganglion cells, and displaced amacrines as well as Muller cells; moreover, the morphology of H1 horizontal cells (calretinin-positive), rod bipolars (protein kinase C-positive), and a subtype of cone bipolars (parvalbumin positive) is shown. Most cell types follow the cone topography, with a cell density maximum in the ventrotemporal quadrant (e.g., 730 cones, 2,800 cone bipolars, 230 GCL cells per 10(4) MUm(2) ), showing their affiliation to the photopic system, except rods and rod bipolars (showing a cell density minimum in the cone area). The correlation of density maps of different cell types provides insight into convergence and divergence patterns in cone and rod pathways. PMID- 21541980 TI - Amphetamine induced dopamine release increases anxiety in individuals recovered from anorexia nervosa. AB - OBJECTIVE: Genetic, pharmacologic, and physiological data suggest that individuals with anorexia nervosa (AN) have altered striatal dopamine (DA) function. METHOD: We used an amphetamine challenge and positron emission tomography [(11) C]raclopride paradigm to explore DA striatal transmission in 10 recovered (REC) AN compared with 9 control women (CW). RESULTS: REC AN and CW were similar for baseline, postamphetamine [(11) C]raclopride binding potential (BP(ND) ) and change (Delta) in BP(ND) for all regions. In CW, ventral striatum Delta BP(ND) was associated with euphoria (r = -0.76; p = 0.03), which was not found for REC AN. Instead, REC AN showed a significant relationship between anxiety and Delta BP(ND) in the precommissural dorsal caudate (r = -0.62, p = 0.05). DISCUSSION: REC AN have a positive association between endogenous DA release and anxiety in the dorsal caudate. This finding could explain why food related DA release produces anxiety in AN, whereas feeding is pleasurable in healthy participants. PMID- 21541982 TI - Reversible inhibition of hydrogen peroxide elimination by calcium in brain mitochondria. AB - In the present work, the Ca(2+) dependence of mitochondrial H(2) O(2) elimination was investigated. Mitochondria isolated from guinea pig brain were energized by glutamate and malate and incubated with micromolar concentrations of Ca(2+) in the presence of ADP, preventing permeability transition pore formation. After the completion of Ca(2+) uptake, mitochondria were challenged with H(2) O(2) (5 MUM), then at various time points residual H(2) O(2) was determined using the Amplex red method and compared with that in mitochondria incubated with H(2) O(2) without Ca(2+) addition. Dose-dependent inhibition of H(2) O(2) elimination by Ca(2+) was detected, which was prevented by the Ca(2+) -uptake inhibitor Ru 360. Stimulation of Ca(2+) release from Ca(2+) -loaded mitochondria by a combined addition of Ru 360 and Na(+) decreased the Ca(2+) -evoked inhibition of H(2) O(2) removal. After Ca(2+) uptake (50 MUM), mitochondrial aconitase activity was found to be decreased, which was partially attributable to the impaired elimination of endogenously produced reactive oxygen species. We found that the effects of Ca(2+) and H(2) O(2) on the activity of aconitase were additive. These results confirm that Ca(2+) inhibits elimination of H(2) O(2) in mitochondria and demonstrate that this effect is concentration dependent and reversible. The phenomenon described here can play a role in the modulation of ROS handling under conditions involving excessive cellular Ca(2+) load. PMID- 21541983 TI - The "B space" of mitochondrial phosphorylation. AB - It was recently shown that, in progressively depolarizing mitochondria, the F(0) F(1) ATP synthase and the adenine nucleotide translocase (ANT) may change directionality independently from each other (Chinopoulos et al. [2010] FASEB J. 24:2405). When the membrane potentials at which these two molecular entities reverse directionality, termed reversal potential (Erev), are plotted as a function of matrix ATP/ADP ratio, an area of the plot is bracketed by the Erev_ATPase and the Erev_ANT, which we call "B space". Both reversal potentials are dynamic, in that they depend on the fluctuating values of the participating reactants; however, Erev_ATPase is almost always more negative than Erev_ANT. Here we review the conditions that define the boundaries of the "B space". Emphasis is placed on the role of matrix substrate-level phosphorylation, because during metabolic compromise this mechanism could maintain mitochondrial membrane potential and prevent the influx of cytosolic ATP destined for hydrolysis by the reversed F(0) -F(1) ATP synthase. PMID- 21541984 TI - Functional morphology of the luminescence system of Siphamia versicolor (Perciformes: Apogonidae), a bacterially luminous coral reef fish. AB - Previous studies of the luminescence system of Siphamia versicolor (Perciformes: Apogonidae) identified a ventral light organ, reflector, lens, duct, and a ventral diffuser extending from the throat to the caudal peduncle. The control and function of luminescence in this and other species of Siphamia, however, have not been defined. Morphological examination of fresh and preserved specimens identified additional components of the luminescence system involved in control and ventral emission of luminescence, including a retractable shutter over the ventral face of the light organ, contiguity of the ventral diffuser from the caudal peduncle to near the chin, and transparency of the bones and other tissues of the lower jaw. The shutter halves retract laterally, allowing the ventral release of light, and relax medially, blocking ventral light emission; topical application of norepinephrine to the exposed light organ resulted in retraction of the shutter halves, which suggests that operation of the shutter is under neuromuscular control. The extension of the diffuser to near the chin and transparency of the lower jaw allow a uniform emission of luminescence over the entire ventrum of the fish. The live aquarium-held fish were found to readily and consistently display ventral luminescence. At twilight, the fish left the protective association with their longspine sea urchin, Diadema setosum, and began to emit ventral luminescence and to feed on zooplankton. Ventral luminescence illuminated a zone below and around the fish, which typically swam close to the substrate. Shortly after complete darkness, the fish stopped feeding and emitting luminescence. These observations suggest that S. versicolor uses ventral luminescence to attract and feed on zooplankton from the reef benthos at twilight. Ventral luminescence may allow S. versicolor to exploit for feeding the gap at twilight in the presence of potential predators as the reef transitions from diurnally active to nocturnally active organisms. PMID- 21541985 TI - Evidence for operation of nicotinic and muscarinic acetylcholine receptor dependent survival pathways in human coronary artery endothelial cells. AB - Nicotinic acetylcholine receptors (nAChRs) have recently emerged as critical players in modulation of endothelial function. In particular, studies on endothelial cells from different vascular beds have shown anti-apoptotic actions of nicotinic stimulation, but whether there is actually activation of survival signaling downstream nAChR function has not been explored. In the present work we used human coronary artery endothelial cells (HCAECs) and a pharmacological approach to examine the impact of cholinergic stimulation on survival signaling pathways. Our findings show that cholinergic receptors promote activation of three typical survival routes: the phosphatidyl-inositol-3-kinase (PI3K)/AKT axis, activated downstream muscarinic and nAChRs; the JAK2/STAT3 axis, activated downstream nAChR; and ERK1/2 MAP kinases, activated by both muscarinic acetylcholine receptor (mAChR) and nAChR. Based on their sensitivity to alpha bungarotoxin, nicotinic regulation of JAK2/STAT3 and ERK1/2 occurs downstream alpha7-nAChRs. The present findings suggest that in HCAECs the two cholinergic receptors may act concertedly to induce an efficient survival response of coronary cells when exposed to pro-apoptotic stimuli. PMID- 21541986 TI - Focal palatine erosion in captive and free-living cheetahs (Acinonyx jubatus) and other felid species. AB - We examined 1,092 skulls of captive and free-living individuals, representing 33 felid species, to determine the prevalence of focal palatine erosion (FPE). FPE was detected in 3.2% of cats evaluated, including cheetah (Acinonyx jubatus) and 14 other felid species. The prevalence of FPE between cheetah (9.4%; n = 64) and non-cheetah species (2.8%; n = 1,028) (chi(2) test; P = 0.004) and between captive (5.7%; n = 246) and free-living (2.4%; n = 824) individuals (chi(2) test; P = 0.010) were significantly different, with prevalence between captive (19%; n = 21) and free-living (2.9%; n = 34) cheetahs approaching significance (Fisher's exact test; P = 0.064). FPE was diagnosed with equal prevalence in skulls from individuals in which the lower molars did not meet the palatine bone (60.6%) and individuals in which it did (39.4%; n = 33) (chi(2) test; P = 0.139). In cheetahs with FPE, one was a captive animal in Germany, one a free-living cheetah from Mali, one captive cheetah from Kenya, and three captive cheetahs of unknown origin. Additionally, we evaluated the medical records of 49 captive cheetahs in Namibia. Of these cheetahs, 48 (98.0%) had clinical signs consistent with FPE, although only 16 of these 48 (39.6%) had perforation of the palatine bone. Based on physical examinations, FPE was diagnosed in two caracals (Caracal caracal) and one fishing cat (Prionailurus viverrinus) from a North American Zoo. Results from this study confirm FPE in cheetahs outside of Namibia, in a minimum of 15 felid species, and a higher FPE prevalence in captive individuals than free-living ones. Clinical implications of these findings and recommendations for future studies are provided. PMID- 21541987 TI - Affiliative and aggressive behavior in a group of female Somali wild ass (Equus africanus somalicus). AB - We observed a group of three young female Somali wild asses to develop an ethogram of social behavior in the first phase of a longer term study of social, sexual, and maternal/infant behavior. The most unexpected finding was the frequency and extent of aggressive interactions, which included Charge, Drive, Neck Wrestle, Head Butt, and Body Slam, behaviors previously reported only for males of other equid species. The overall frequency of aggressive behavior was higher than that of affiliative behavior (84+/-16.5 vs. 32+/-5.5, P=0.03), yet no injuries occurred. The dyadic directionality of aggressive behavior suggested a dominance hierarchy, a feature not previously reported for either wild ass or domestic donkeys. The aggression observed may be an accurate representation of the behavior of this species, or their relatively young ages, or their recent transfer from their natal group through quarantine and into a new enclosure may have heightened agonistic tendencies. Further studies will determine whether with time their aggressive behavior becomes more intense or dissipates with maturity. PMID- 21541988 TI - Functional characterization and immunolocalization of odorant binding protein 1 in the lucerne plant bug, Adelphocoris lineolatus (GOEZE). AB - In the insect phylum, the relationships between individuals and their environment are often modulated by chemical communication. Odorant binding proteins (OBPs) are widely and robustly expressed in insect olfactory organs and play a key role in chemosensing and transporting hydrophobic odorants across the sensillum lymph to the olfactory receptor neuron. In this study, a novel OBP gene (AlinOBP1) in the lucerne plant bug, Adelphocoris lineolatus was identified, cloned and expressed. Real-time PCR results indicated that the expression level of AlinOBP1 gene differed in each developmental stage (from first instar to adult) and was predominantly expressed in the antennae of adults. The expression level of AlinOBP1 was 1.91 times higher in male antennae than in female antennae. The binding properties of AlinOBP1 with 114 odorants were measured using a fluorescence probe, N-phenyl-1-naphthylamine (1-NPN), with fluorescence competitive binding. The results revealed that AlinOBP1 exhibits high binding abilities with two major putative pheromone components, ethyl butyrate and trans 2-hexenyl butyrate. In addition, it was observed that six volatiles released from cotton, octanal, nonanal, decanal, 2-ethyl-1-hexanol, beta-caryophyllene and beta ionone also bind to AlinOBP1. Immunocytochemistry analysis showed that AlinOBP1 was expressed in the sensillum lymph of sensilla trichodica and sensilla basiconca. Our results demonstrate that AlinOBP1 may function as a carrier in the chemoperception of the lucerne plant bug. PMID- 21541989 TI - Molecular characterization and oxidative stress response of an intracellular Cu/Zn superoxide dismutase (CuZnSOD) of the whitefly, Bemisia tabaci. AB - Superoxide dismutases (SODs) are important for the survival of insects under environmental and biological stresses; however, little attention has been devoted to the functional characterization of SODs in whitefly. In this study, an intracellular copper/zinc superoxide dismutase of whitefly (Bemisia tabaci) (Bt CuZnSOD) was cloned. Sequence analysis indicated that the full length cDNA of Bt CuZnSOD is of 907 bp with a 471 bp open reading frame encoding 157 amino acids. The deduced amino acid sequence shares common consensus patterns with the CuZnSODs of various vertebrate and invertebrate animals. Phylogenetic analysis revealed that Bt-CuZnSOD is grouped together with intracellular CuZnSODs. Bt CuZnSOD was then over-expressed in E. coli and purified using GST purification system. The enzymatic activity of purified Bt-CuZnSOD was assayed under various temperatures. When whiteflies were exposed to low (4 degrees C) and high (40 degrees C) temperatures, the in vivo activity of Bt-CuZnSOD was significantly increased. Furthermore, we measured the activities of several antioxidant enzymes, including SOD, catalase and peroxidase, in the whitefly after transferring the whitefly from cotton to tobacco (an unfavorable host plant). We found that the activity of SOD increased rapidly on tobacco plant. Taken together, these results suggest that the Bt-CuZnSOD plays a major role in protecting the whitefly against various stress conditions. PMID- 21541990 TI - Juvenile hormone changes associated with diapause induction, maintenance, and termination in the beet webworm, Loxostege sticticalis (Lepidoptera: Pyralidae). AB - At 22 degrees C and under a long-day photoperiod of L:D 16:8, all the last fifth instar Loxostege sticticalis larvae undergo prepupal stage and pupate without diapause. Under a short-day photoperiod of L:D 12:12, in contrast, they all enter diapause with approximately 36 days diapause maintenance and then terminate diapause spontaneously, although only 44% of the larvae terminated diapause successfully. Changes in hemolymph juvenile hormone (JH I) titers of diapause destined larvae across diapause induction, maintenance and termination were examined using HPLC, and were compared with those of non-diapause-destined larvae from the fifth instar through pupation. JH I titer of the earliest fifth instar diapause-destined larvae remained at a high level with a peak of 220.4 ng/ml, though it decreased continuously to a minimum of 69.0 ng/ml on day 5 in the fifth instar when the larvae stopped feeding to enter diapause. During the diapause maintenance, JH I titer of the mature larvae increased significantly and maintained a high level until day 31 in prepupae. JH I titer declined and fluctuated at low level from 5 days before pupation. In contrast, JH I titer of both the fifth instar non-diapause-destined larvae and prepupae remained and fluctuated at low level consistently, as well as decreased before pupation. These results indicate that diapause induction and maintenance in this species might be a consequence of high JH, whereas diapause termination can be attributed to low JH titer, which was in agreement with the hormonal regulation observed in many other larval-diapausing insects. PMID- 21541991 TI - Lawrence G. Raisz November 13, 1925-August 25, 2010. PMID- 21541992 TI - FoxO1: a molecule for all seasons. AB - The FoxO family of forkhead transcription factors is at the crossroads of many signal transduction pathways that are evolutionarily conserved. Such pathways have been co-opted in differentiated tissues for a variety of vital and specialized functions, such as differentiation, proliferation, and survival in cells as diverse as adipocytes, hepatocytes, beta-cells, myoblasts, thymocytes, and cancer cells. FoxO metabolic functions are relevant to glucose metabolism, tumor suppression, hematopoiesis, angiogenesis, and antioxidant defense. Among the FoxO isoforms, FoxO1 is a main target of insulin signaling and regulates metabolic homeostasis and organismal survival at many different levels. FoxO1 entered into the field of skeletal biology by a property that is unique among its functions in other organs. With the osteoblast as its target cell, FoxO1 not only acts on it to regulate bone homeostasis but also through it as a transcriptional modulator of the endocrine function of the skeleton in regulating glucose metabolism. Through its direct skeletal actions, FoxO1 promotes osteoblast proliferation by maintaining protein synthesis and redox balance. Through its endocrine actions on target tissues of insulin, FoxO1 acts by way of osteocalcin to suppress glucose production by pancreatic beta cells and hepatocytes and to decrease insulin production and sensitivity. These two parallel but opposing actions, one in favor of the skeleton and the other in disadvantage of glucose regulating tissues, may signify an adaptive mechanism that integrates responses between different organs and is beneficial for whole-body physiology during stress and aging. PMID- 21541993 TI - Identification of genetic modifiers of monogenic (bone) diseases: new tools available, but with limitations. PMID- 21541995 TI - Is bone loss the reversal of bone accrual? Evidence from a cross-sectional study in daughter-mother-grandmother trios. AB - Bone adapts to mechanical loads applied on it. During aging, loads decrease to a greater extent at those skeletal sites where loads increase most in earlier life. Thus, the loss of bone may occur preferentially at sites where most bone has been deposited previously; ie, bone loss could be the directional reversal of accrual. To test this hypothesis, we compared the bone mass distribution at weight-bearing (tibia) and non-weight-bearing (radius) bones among 18-year-old girls, their premenopausal mothers, and their postmenopausal maternal grandmothers. Bone and muscle properties were measured by pQCT, and polar distribution of bone mass was obtained in 55 girl-mother-maternal grandmother trios. Site-matched differences in bone mass were compared among three generations. The differences between girls and mothers and between mothers and grandmothers were used to represent the patterns of bone mass accrual from early adulthood to middle age and bone loss from middle to old age, respectively. Compared to the mothers, 18-year old girls had less bone mass in the anterior and medial-posterior regions of the tibial shaft, while the grandmothers had less bone in the anterior and posterior regions. In contrast, the bone mass differences in the radial shaft between girls and mothers and mothers and grandmothers were relatively uniform. We conclude that both bone accrual and loss are direction-specific in weight-bearing bones but relatively uniform in non-weight-bearing bones. Bone loss in old age is largely, but not completely, a reversal of the preferential deposition of bone in the most highly loaded regions during early life. PMID- 21541994 TI - Camurati-Engelmann disease: unique variant featuring a novel mutation in TGFbeta1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand. AB - We report a 32-year-old man and his 59-year-old mother with a unique and extensive variant of Camurati-Engelmann disease (CED) featuring histopathological changes of osteomalacia and alterations within TGFbeta1 and TNFSF11 encoding TGFbeta1 and RANKL, respectively. He suffered leg pain and weakness since childhood and reportedly grew until his late 20s, reaching 7 feet in height. He had deafness, perforated nasal septum, torus palatinus, disproportionately long limbs with knock-knees, low muscle mass, and pseudoclubbing. Radiographs revealed generalized skeletal abnormalities, including wide bones and cortical and trabecular bone thickening in keeping with CED, except that long bone ends were also affected. Lumbar spine and hip BMD Z-scores were + 7.7 and + 4.4, respectively. Biochemical markers of bone turnover were elevated. Hypocalciuria accompanied low serum 25-hydroxyvitamin D (25[OH]D) levels. Pituitary hypogonadism and low serum insulin-like growth factor (IGF)-1 were present. Karyotype was normal. Despite vitamin D repletion, iliac crest histology revealed severe osteomalacia. Exon 1 of TNFRSF11A (RANK), exons 2, 3, and 4 of LRP5, and all coding exons and adjacent mRNA splice junctions of TNFRSF11B (OPG), SQSTM1 (sequestosome 1), and TNSALP (tissue nonspecific alkaline phosphatase) were intact. His asymptomatic and less dysmorphic 5'11" mother, also with low serum 25(OH)D, had milder clinical, radiological, biochemical, and histopathological findings. Both individuals were heterozygous for a novel 12-bp duplication (c.27_38dup, p.L10_L13dup) in exon 1 of TGFbeta1, predicting four additional leucine residues in the latency-associated-peptide segment of TGFbeta1, consistent with CED. The son was also homozygous for a single base transversion in TNFSF11, predicting a nonconservative amino acid change (c.107C > G, p.Pro36Arg) in the intracellular domain of RANKL that was heterozygous in his nonconsanguineous parents. This TNFSF11 variant was not found in the SNP Database, nor in published TNFSF11 association studies, but it occurred in four of the 134 TNFSF11 alleles (3.0%) we tested randomly among individuals without CED. Perhaps the unique phenotype of this CED family is conditioned by altered RANKL activity. PMID- 21541996 TI - Associations between dietary flavonoid intakes and bone health in a Scottish population. AB - Flavonoids are bioactive polyphenols found particularly in fruit and vegetables, but little is known about their role in bone health in humans. The aim of this observational study was to investigate whether dietary flavonoid intake was associated with bone mineral density (BMD) and bone resorption in a large group of perimenopausal Scottish women. Over 3000 women completed a food frequency questionnaire as part of an osteoporosis screening study. The diets were analyzed for flavonoid intake using a food composition database. BMD was measured at the femoral neck (FN) and lumbar spine (LS) by dual-energy X-ray absorptiometry (DXA). Free pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by high performance liquid chromatography (HPLC) in second early morning fasted urine samples. The mean flavonoid intake of the diet was 307 +/-199 mg/d. The catechin family contributed the most to flavonoid intakes (55%), and the flavones the least (<1%). Associations were found between energy-adjusted total flavonoid intakes and BMD at the FN and LS (FN r = 0.054, LS r = 0.036, p <= .05). Annual percent change in BMD was associated with intakes of procyanidins and catechins (p <= .05), and flavanones were negatively associated with bone-resorption markers (PYD r = -0.049, DPD r = -0.057, p <= .001). These associations were still seen after adjusting for confounders. It is concluded that dietary flavonoid intakes are associated with BMD, supporting the evidence from animal and cellular studies. PMID- 21541997 TI - Vitamin K status in spaceflight and ground-based models of spaceflight. AB - Bone loss is a well-documented change during and after long-duration spaceflight. Many types of countermeasures to bone loss have been proposed, including vitamin K supplementation. The objective of this series of studies was to measure change in vitamin K status in response to microgravity under a variety of spaceflight and spaceflight analog (model) conditions, including long-duration spaceflight studies (n = 15), three bed rest studies (n = 15, 49, and 24), and a 14-day saturation dive (n = 6). In crew members who flew 2-6 months on the International Space Station, in-flight and postflight plasma phylloquinone concentrations were unchanged from the preflight mean. Consistent with this finding, urinary gamma carboxyglutamic acid (GLA), a measure of vitamin K-dependent protein turnover, did not change in response to flight. Serum undercarboxylated osteocalcin (%ucOC), a measure of vitamin K function, was generally unchanged in response to flight. Spaceflight findings were corroborated by findings of no changes in phylloquinone, urinary GLA, or %ucOC during or after bed rest in three separate bed rest studies (21-90 days in duration) or after a 14-day saturation dive. The data presented here do not support either a need for vitamin K supplementation during spaceflight or the suggestion of using vitamin K as a bone loss countermeasure in spaceflight. PMID- 21541998 TI - Serum uric acid is associated with bone health in older men: a cross-sectional population-based study. AB - Serum uric acid (UA) is a strong endogenous antioxidant. Since oxidative stress has been linked to osteoporosis, we examined the association between serum UA levels and bone mineral density (BMD), prevalent vertebral and nonvertebral fractures, and laboratory measures such as calcitropic hormones and bone turnover marker levels. This cross-sectional analysis consisted of 1705 community-dwelling men aged 70 years or over who participated in the baseline part of the Concord Health and Ageing in Men Project (CHAMP), a population-based study of older men in Sydney, Australia. BMD at all sites was significantly higher among men with serum UA levels above the group median than among men with UA levels below the median. In multiple regression analyses adjusted for potential confounders, serum UA remained associated with BMD at all sites (beta = 0.12 to 0.14, p < .001), serum calcium (beta = 0.11, p = .001), parathyroid hormone (beta = 0.09, p = .002), 25-hydroxyvitamin D (beta = 0.09, p = .005), and was negatively associated with urinary excretion amino-terminal cross-linked telopeptide of type 1 collagen (beta = -0.09, p = .006). Overall, serum UA accounted for 1.0% to 1.44% of the variances in BMD (R(2) = 0.10 to 0.22). In multiple logistic regression analyses, above-median serum UA levels were associated with a lower prevalence of osteoporosis at the femoral neck [odds ratio (OR) = 0.42, 95% confidence interval (CI) 0.22-0.81, p = .010) and lumbar spine (OR = 0.44, 95% CI 0.23-0.86, p = .016) and a lower prevalence of vertebral (OR = 0.62, 95% CI 0.43-0.91, p = .015) and nonvertebral (OR = 0.51, 95% CI 0.29-0.89, p = .018) fractures. In conclusion, higher serum UA levels are associated with higher BMD at all skeletal sites and with a lower prevalence of vertebral and nonvertebral fractures in older men. PMID- 21541999 TI - Finite element analysis performed on radius and tibia HR-pQCT images and fragility fractures at all sites in men. AB - Few studies have investigated bone microarchitecture and biomechanical properties in men. This study assessed in vivo both aspects in a population of 185 men (aged 71 +/- 10 years) with prevalent fragility fractures, compared to 185 controls matched for age, height, and weight, from the Structure of the Aging Men's Bones (STRAMBO) cohort. In this case-control study, areal BMD (aBMD) was measured by DXA, bone microarchitecture was assessed by high resolution (HR)-pQCT, and finite element (uFE) analysis was based on HR-pQCT images of distal radius and tibia. A principal component (PC) analysis (PCA) was used to study the association of synthetic PCs with fracture by computing their odds ratio (OR [95%CI]) per SD change. Specific associations with vertebral fracture (n = 100), and nonvertebral fracture (n = 85) were also computed. At both sites, areal and volumetric BMD, cortical thickness and trabecular number, separation, and distribution were significantly worse in cases than in controls, with differences ranging from -6% to 15%. uFE-derived stiffness and failure load were 8% to 9% lower in fractures (p < .01). No difference in load distribution was found between the two groups. After adjustment for aBMD, only differences of uFE-derived stresses, stiffness, and failure load at the tibia remained significant (p < .05). PCA resulted in defining 4 independent PCs, explaining 83% of the total variability of bone characteristics. Nonvertebral fractures were associated with PC1, reflecting bone quantity and strength at the radius (tibia) with OR = 1.64 [1.27-2.12] (2.21 [1.60-3.04]), and with PC2, defined by trabecular microarchitecture, with OR = 1.27 [1.00-1.61]. Severe vertebral fractures were associated with PC1, with OR = 1.56 [1.16-2.09] (2.21 [1.59-3.07]), and with PC2, with OR = 1.55 [1.17-2.06] (1.45 [1.06-1.98]). In conclusion, microarchitecture and biomechanical properties derived from uFE were associated with all types of fractures in men, showing that radius and tibia mechanical properties were relatively representative of distant bone site properties. PMID- 21542000 TI - Mechanical contributions of the cortical and trabecular compartments contribute to differences in age-related changes in vertebral body strength in men and women assessed by QCT-based finite element analysis. AB - The biomechanical mechanisms underlying sex-specific differences in age-related vertebral fracture rates are ill defined. To gain insight into this issue, we used finite element analysis of clinical computed tomography (CT) scans of the vertebral bodies of L3 and T10 of young and old men and women to assess age- and sex-related differences in the strength of the whole vertebra, the trabecular compartment, and the peripheral compartment (the outer 2 mm of vertebral bone, including the thin cortical shell). We sought to determine whether structural and geometric changes with age differ in men and women, making women more susceptible to vertebral fractures. As expected, we found that vertebral strength decreased with age 2-fold more in women than in men. The strength of the trabecular compartment declined significantly with age for both sexes, whereas the strength of the peripheral compartment decreased with age in women but was largely maintained in men. The proportion of mechanical strength attributable to the peripheral compartment increased with age in both sexes and at both vertebral levels. Taken together, these results indicate that men and women lose vertebral bone differently with age, particularly in the peripheral (cortical) compartment. This differential bone loss explains, in part, a greater decline in bone strength in women and may contribute to the higher incidence of vertebral fractures among women than men. PMID- 21542002 TI - Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort. AB - Bisphosphonates are the primary therapy for postmenopausal and glucocorticoid induced osteoporosis. Case series suggest a potential link between prolonged use of bisphosphonates and low-energy fracture of subtrochanteric or diaphyseal femur as a consequence of oversuppression of bone resorption. Using health care utilization data, we conducted a propensity score-matched cohort study to examine the incidence rates (IRs) and risk of subtrochanteric or diaphyseal femur fractures among oral bisphosphonate users compared with raloxifene or calcitonin users. A Cox proportional hazards model evaluated the risk of these fractures associated with duration of osteoporosis treatment. A total of 104 subtrochanteric or diaphyseal femur fractures were observed among 33,815 patients. The estimated IR of subtrochanteric or diaphyseal femur fractures per 1000 person-years was 1.46 [95% confidence interval (CI) 1.11-1.88] among the bisphosphonate users and 1.43 (95% CI 1.06-1.89) among raloxifene/calcitonin users. No significant association between bisphosphonate use and subtrochanteric or diaphyseal femur fractures was found [hazard ratio (HR) = 1.03, 95% CI 0.70 1.52] compared with raloxifene/calcitonin. Even with this large study size, we had little precision in estimating the risk of subtrochanteric or diaphyseal femur fractures in patients treated with bisphosphonates for longer than 5 years (HR = 2.02, 95% CI 0.41-10.00). The occurrence of subtrochanteric or diaphyseal femur fracture was rare. There was no evidence of an increased risk of subtrochanteric or diaphyseal femur fractures in bisphosphonate users compared with raloxifene/calcitonin users. However, this study cannot exclude the possibility that long-term bisphosphonate use may increase the risk of these fractures. PMID- 21542003 TI - Differential effects of teriparatide on regional bone formation using (18)F fluoride positron emission tomography. AB - Teriparatide increases skeletal mass, bone turnover markers, and bone strength, but local effects on bone tissue may vary between skeletal sites. We used positron emission tomography (PET) to study (18)F-fluoride plasma clearance (K(i)) at the spine and standardized uptake values (SUVs) at the spine, pelvis, total hip, and femoral shaft in 18 postmenopausal women with osteoporosis. Subjects underwent a 1-hour dynamic scan of the lumbar spine and a 10-minute static scan of the pelvis and femurs at baseline and after 6 months of treatment with 20 ug/day teriparatide. Blood samples were taken to derive the arterial input function and lumbar spine K(i) values evaluated using a three-compartment model. SUVs were calculated for the spine, pelvis, total hip, and femoral shaft. After 6 months treatment with teriparatide, spine K(i) values increased by 24% (p = .0003), while other model parameters were unchanged except for the fraction of tracer going to bone mineral (k(3)/[k(2) + k(3)]), which increased by 23% (p = .0006). In contrast to K(i) , spine SUVs increased by only 3% (p = .84). The discrepancy between changes in K(i) and SUVs was explained by a 20% decrease in (18)F(-) plasma concentration. SUVs increased by 37% at the femoral shaft (p = .0019), 20% at the total hip (p = .032), and 11% at the pelvis (p = .070). Changes in bone turnover markers and BMD were consistent with previous trials. We conclude that the changes in bone formation rate during teriparatide treatment as measured by (18)F(-) PET differ at different skeletal sites, with larger increases in cortical bone than at trabecular sites. PMID- 21542004 TI - Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones. AB - Therapeutic enhancement of fracture healing would help to prevent the occurrence of orthopedic complications such as nonunion and revision surgery. Sclerostin is a negative regulator of bone formation, and treatment with a sclerostin monoclonal antibody (Scl-Ab) results in increased bone formation and bone mass in animal models. Our objective was to investigate the effects of systemic administration of Scl-Ab in two models of fracture healing. In both a closed femoral fracture model in rats and a fibular osteotomy model in cynomolgus monkeys, Scl-Ab significantly increased bone mass and bone strength at the site of fracture. After 10 weeks of healing in nonhuman primates, the fractures in the Scl-Ab group had less callus cartilage and smaller fracture gaps containing more bone and less fibrovascular tissue. These improvements at the fracture site corresponded with improvements in bone formation, bone mass, and bone strength at nonfractured cortical and trabecular sites in both studies. Thus the potent anabolic activity of Scl-Ab throughout the skeleton also was associated with an anabolic effect at the site of fracture. These results support the potential for systemic Scl-Ab administration to enhance fracture healing in patients. PMID- 21542001 TI - Once-yearly zoledronic acid and days of disability, bed rest, and back pain: randomized, controlled HORIZON Pivotal Fracture Trial. AB - The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90-0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87-1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR = 0.58, 95% CI 0.47-0.72) and 7 or more limited-activity days owing to a fracture (RR = 0.67, 95% CI 0.58-0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that patients reported back pain, limited activity owing to back pain, and limited activity and bed rest owing to a fracture. PMID- 21542005 TI - Epidermal growth factor receptor plays an anabolic role in bone metabolism in vivo. AB - While the epidermal growth factor receptor (EGFR)-mediated signaling pathway has been shown to have vital roles in many developmental and pathologic processes, its functions in the development and homeostasis of the skeletal system has been poorly defined. To address its in vivo role, we constructed transgenic and pharmacologic mouse models and used peripheral quantitative computed tomography (pQCT), micro-computed tomography (uCT) and histomorphometry to analyze their trabecular and cortical bone phenotypes. We initially deleted the EGFR in preosteoblasts/osteoblasts using a Cre/loxP system (Col-Cre Egfr(f/f)), but no bone phenotype was observed because of incomplete deletion of the Egfr genomic locus. To further reduce the remaining osteoblastic EGFR activity, we introduced an EGFR dominant-negative allele, Wa5, and generated Col-Cre Egfr(Wa5/f) mice. At 3 and 7 months of age, both male and female mice exhibited a remarkable decrease in tibial trabecular bone mass with abnormalities in trabecular number and thickness. Histologic analyses revealed decreases in osteoblast number and mineralization activity and an increase in osteoclast number. Significant increases in trabecular pattern factor and structural model index indicate that trabecular microarchitecture was altered. The femurs of these mice were shorter and smaller with reduced cortical area and periosteal perimeter. Moreover, colony forming unit-fibroblast (CFU-F) assay indicates that these mice had fewer bone marrow mesenchymal stem cells and committed progenitors. Similarly, administration of an EGFR inhibitor into wild-type mice caused a significant reduction in trabecular bone volume. In contrast, Egfr(Dsk5/+) mice with a constitutively active EGFR allele displayed increases in trabecular and cortical bone content. Taken together, these data demonstrate that the EGFR signaling pathway is an important bone regulator and that it primarily plays an anabolic role in bone metabolism. PMID- 21542006 TI - Unique roles of phosphorus in endochondral bone formation and osteocyte maturation. AB - The mechanisms by which inorganic phosphate (P(i)) homeostasis controls bone biology are poorly understood. Here we used Dmp1 null mice, a hypophosphatemic rickets/osteomalacia model, combined with a metatarsal organ culture and an application of neutralizing fibroblast growth factor 23 (FGF-23) antibodies to gain insight into the roles of P(i) in bone biology. We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells and (2) that osteoblast extracellular matrix mineralization, growth plate maturation, secondary ossification center formation, and osteoblast differentiation are phosphate-dependent. Finally, a working hypothesis is proposed to explain how phosphate and DMP1 control osteocyte maturation. PMID- 21542007 TI - The calcium-sensing receptor mediates bone turnover induced by dietary calcium and parathyroid hormone in neonates. AB - We have investigated, in neonates, whether the calcium-sensing receptor (CaR) mediates the effects of dietary calcium on bone turnover and/or modulates parathyroid hormone (PTH)-induced bone turnover. Wild-type (WT) pups and pups with targeted deletion of the Pth (Pth(-/-)) gene or of both Pth and CaR (Pth(-/ )CaR(-/-)) genes were nursed by dams on a normal or high-calcium diet. Pups nursed by dams on a normal diet received daily injections of vehicle or of PTH(1 34) (80 ug/kg) for 2 weeks starting from 1 week of age. In pups receiving vehicle and fed by dams on a normal diet, trabecular bone volume, osteoblast number, type 1 collagen-positive area, and mineral apposition rate, as well as the expression of bone-formation-related genes, all were reduced significantly in Pth(-/-) pups compared with WT pups and were decreased even more dramatically in Pth(-/-)CaR(-/ ) pups. These parameters were increased in WT and Pth(-/-) pups but not in Pth(-/ )CaR(-/-) pups fed by dams on a high-calcium diet compared with pups fed by dams on a normal diet. These parameters also were increased in WT, Pth(-/-), and Pth( /-)CaR(-/-) pups following exogenous PTH treatment; however, the percentage increase was less in Pth(-/-)CaR(-/-) pups than in WT and Pth(-/-) pups. In vehicle-treated pups fed by dams on either the normal or high-calcium diet and in PTH-treated pups fed by dams on a normal diet, the number and surfaces of osteoclasts and the ratio of RANKL/OPG were reduced significantly in Pth(-/-) pups and less significantly in Pth(-/-)CaR(-/-) pups compared with WT pups. These parameters were further reduced significantly in WT and Pth(-/-) pups from dams fed a high-calcium diet but did not decrease significantly in similarly treated Pth(-/-)CaR(-/-) pups, and they increased significantly in PTH-treated pups compared with vehicle-treated, genotype-matched pups fed by dams on the normal diet. These results indicate that in neonates, the CaR mediates alterations in bone turnover in response to changes in dietary calcium and modulates PTH stimulated bone turnover. PMID- 21542008 TI - Involvement of calcitonin and its receptor in the control of calcium-regulating genes and calcium homeostasis in zebrafish (Danio rerio). AB - Calcitonin (CT) is one of the hormones involved in vertebrate calcium regulation. It has been proposed to act as a hypocalcemic factor, but the regulatory pathways remain to be clarified. We investigated the CT/calcitonin gene-related peptide (CGRP) family in zebrafish and its potential involvement in calcium homeostasis. We identified the presence of four receptors: CTR, CRLR1, CRLR2, and CRLR3. From the phylogenetic analysis, together with the effect observed after CT and CGRP overexpression, we concluded that CTR appears to be a CT receptor and CRLR1 a CGRP receptor. The distribution of these two receptors shows a major presence in the central nervous system and in tissues involved in ionoregulation. Zebrafish embryos kept in high-Ca(2+)-concentration medium showed upregulation of CT and CTR expression and downregulation of the epithelial calcium channel (ECaC). Embryos injected with CT morpholino (CALC MO) incubated in high-Ca(2+) medium, showed downregulation of CTR together with upregulation on ECaC mRNA expression. In contrast, overexpression of CT cRNA induced the downregulation of ECaC mRNA synthesis, concomitant with the downregulation in the calcium content after 30 hours postfertilization. At 4 days postfertilization, CT cRNA injection induced upregulation of hypercalcemic factors, with subsequent increase in the calcium content. These results suggest that CT acts as a hypocalcemic factor in calcium regulation, probably through inhibition of ECaC synthesis. PMID- 21542009 TI - APPswe/Abeta regulation of osteoclast activation and RAGE expression in an age dependent manner. AB - Alzheimer's disease (AD), one of the most dreaded neurodegenerative disorders, is characterized by cortical and cerebrovascular amyloid beta peptide (Abeta) deposits, neurofibrillary tangles, chronic inflammation, and neuronal loss. Increased bone fracture rates and reduced bone density are commonly observed in patients with AD, suggesting one or more common denominators between both disorders. However, very few studies are available that have addressed this issue. Here, we present evidence for a function of amyloid precursor protein (APP) and Abeta in regulating osteoclast (OC) differentiation in vitro and in vivo. Tg2576 mice, which express the Swedish mutation of APP (APPswe) under the control of a prion promoter, exhibit biphasic effects on OC activation, with an increase of OCs in younger mice (< 4 months old), but a decrease in older Tg2576 mice (> 4 months old). The increase of OCs in young Tg2576 mice appears to be mediated by Abeta oligomers and receptor for advanced glycation end products (RAGE) expression in bone marrow macrophages (BMMs). However, the decrease of OC formation and activity in older Tg2576 mice may be due to the increase of soluble rage (sRAGE) in aged Tg2576 mice, an inhibitor of RANKL-induced osteoclastogenesis. These results suggest an unexpected function of APPswe/Abeta, reveal a mechanism underlying altered bone remodeling in AD patients, and implicate APP/Abeta and RAGE as common denominators for both AD and osteoporosis. PMID- 21542010 TI - The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts. AB - Osteoporosis, which results from excessive bone resorption by osteoclasts, is the major cause of morbidity for elder people. Identification of clinically relevant regulators is needed to develop novel therapeutic strategies. Rho GTPases have essential functions in osteoclasts by regulating actin dynamics. This is of particular importance because actin cytoskeleton is essential to generate the sealing zone, an osteoclast-specific structure ultimately mediating bone resorption. Here we report that the atypical Rac1 exchange factor Dock5 is necessary for osteoclast function both in vitro and in vivo. We discovered that establishment of the sealing zone and consequently osteoclast resorbing activity in vitro require Dock5. Mechanistically, our results suggest that osteoclasts lacking Dock5 have impaired adhesion that can be explained by perturbed Rac1 and p130Cas activities. Consistent with these functional assays, we identified a novel small-molecule inhibitor of Dock5 capable of hindering osteoclast resorbing activity. To investigate the in vivo relevance of these findings, we studied Dock5(-/-) mice and found that they have increased trabecular bone mass with normal osteoclast numbers, confirming that Dock5 is essential for bone resorption but not for osteoclast differentiation. Taken together, our findings characterize Dock5 as a regulator of osteoclast function and as a potential novel target to develop antiosteoporotic treatments. PMID- 21542012 TI - Activation of c-Jun NH(2)-terminal kinase 1 increases cellular responsiveness to BMP-2 and decreases binding of inhibitory Smad6 to the type 1 BMP receptor. AB - Bone morphogenetic protein 2 (BMP-2) plays a critical role in the differentiation of precursor cells and has been approved for clinical application to induce new bone formation. To date, unexpectedly high doses of recombinant BMP-2 have been required to induce bone healing in humans. Thus, enhancing cellular responsiveness to BMP-2 potentially has critically important clinical implications. BMP responsiveness may be modulated in part by cross-talk with other signaling pathways, including mitogen-activated protein kinases (MAPKs). c Jun NH(2)-terminal kinase (JNK) is a MAPK that has been reported to be required for late-stage differentiation of preosteoblasts and BMP-2-induced differentiation of preosteoblasts and pleuripotent cells. In this study we determined that MC3T3-E1-clone 24 cells (MC-24) can be induced by BMP-2 to differentiate into mineralizing osteoblast cultures. Using this inducible system, we employed both JNK loss-of-function and gain-of-function reagents to make three key observations: (1) JNK is required for phosphorylation of Smad1 by BMP-2 and subsequent activation of Smad1 signaling and osteoblast differentiation, (2) JNK1, but not JNK2, is required for BMP-2-induced formation of mineralized nodules, and (3) JNK1 activation decreases binding of inhibitory Smad6 to the type I BMP receptor (BMPR-I) and reciprocally increases binding of Smad1, both observations that would increase responsiveness to BMP-2. Understanding this and other pathways that lead to increased cellular responsiveness to BMPs could greatly aid more cost-effective and safe clinical delivery of these important molecules. PMID- 21542011 TI - Impact of maturational status on the ability of osteoblasts to enhance the hematopoietic function of stem and progenitor cells. AB - Osteoblasts (OBs) exert a prominent regulatory effect on hematopoietic stem cells (HSCs). We evaluated the difference in hematopoietic expansion and function in response to co-culture with OBs at various stages of development. Murine calvarial OBs were seeded directly (fresh) or cultured for 1, 2, or 3 weeks prior to seeding with 1000 Lin-Sca1 + cKit+ (LSK) cells for 1 week. Significant increases in the following hematopoietic parameters were detected when comparing co-cultures of fresh OBs to co-cultures containing OBs cultured for 1, 2, or 3 weeks: total hematopoietic cell number (up to a 3.4-fold increase), total colony forming unit (CFU) number in LSK progeny (up to an 18.1-fold increase), and percentage of Lin-Sca1+ cells (up to a 31.8-fold increase). Importantly, these studies were corroborated by in vivo reconstitution studies in which LSK cells maintained in fresh OB co-cultures supported a significantly higher level of chimerism than cells maintained in co-cultures containing 3-week OBs. Characterization of OBs cultured for 1, 2, or 3 weeks with real-time PCR and functional mineralization assays showed that OB maturation increased with culture duration but was not affected by the presence of LSK cells in culture. Linear regression analyses of multiple parameters measured in these studies show that fresh, most likely more immature OBs better promote hematopoietic expansion and function than cultured, presumably more mature OBs and suggest that the hematopoiesis-enhancing activity is mediated by cells present in fresh OB cultures de novo. PMID- 21542013 TI - Functional relevance of the BMD-associated polymorphism rs312009: novel involvement of RUNX2 in LRP5 transcriptional regulation. AB - LRP5 is an osteoporosis susceptibility gene. Association analyses reveal that individual single-nucleotide polymorphisms (SNPs) determine variation in bone mineral density (BMD) among individuals as well as fracture risk. In a previous study, we identified a lumbar spine BMD-associated SNP, rs312009, located in the LRP5 5' region. A RUNX2 binding site was identified in this region by gel-shift experiments. Here we test the functionality of this SNP and examine whether RUNX2 is indeed a regulator of LRP5 expression. Gene reporter assays were used to test rs312009 functionality. Bioinformatic predictive tools and gel-shift and gene reporter assays were used to identify and characterize additional RUNX2 binding elements in the 3.3-kb region upstream of LRP5. Allelic differences in the transcriptional activity of rs312009 were observed in two osteoblastic cell lines, the T allele being a better transcriber than the C allele. RUNX2 cotransfection in HeLa cells revealed that the LRP5 5' region responded to RUNX2 in a dose-dependent manner and that the previously identified RUNX2 binding site participated in this response. Also, RUNX2 inhibition by RNAi led to nearly 60% reduction of endogenous LRP5 mRNA in U-2 OS cells. Four other RUNX2 binding sites were identified in the 5' region of LRP5. Luciferase experiments revealed the involvement of each of them in the RUNX2 response. The allelic differences observed point to the involvement of rs312009 as a functional SNP in the observed association. To our knowledge, this is the first time that the direct action of RUNX2 on LRP5 has been described. This adds evidence to previously described links between two important bone-regulating systems: the RUNX2 transcription factor cascade and the Wnt signaling pathway. PMID- 21542015 TI - Uric acid as a potential disease modifier in patients with multiple system atrophy. AB - BACKGROUND: Recent studies have suggested that mitochondrial dysfunction and oxidative stress play a key role in the pathogenesis of multiple system atrophy. METHODS: We evaluated the influence of serum uric acid levels on disease progression in 52 patients with multiple system atrophy using changes in the annualized Unified Multiple System Atrophy Rating Scale scores. RESULTS: The mean annualized Unified Multiple System Atrophy Rating Scale changes were significantly lower in patients with the highest uric acid quartile compared with those with the lowest quartile (8.4 +/- 5.1 vs 20.2 +/- 16.0, P = .038). Serum uric acid levels had a significant negative correlation with the annualized Unified Multiple System Atrophy Rating Scale changes (r = -0.40, P = .004). Multiple linear regression analysis showed that only serum uric acid concentration was significantly correlated with the annualized Unified Multiple System Atrophy Rating Scale changes (beta = -2.687, P = .011). CONCLUSIONS: These data suggest that serum uric acid may act as a potential disease modifier in multiple system atrophy. PMID- 21542014 TI - Effects of 25-hydroxyvitamin D(3) on proliferation and osteoblast differentiation of human marrow stromal cells require CYP27B1/1alpha-hydroxylase. AB - 1,25-Dihydroxyvitamin D(3)[1,25(OH)(2)D(3)] has many noncalcemic actions that rest on inhibition of proliferation and promotion of differentiation in malignant and normal cell types. 1,25(OH)(2)D(3) stimulates osteoblast differentiation of human marrow stromal cells (hMSCs), but little is known about the effects of 25 hydroxyvitamin D(3)[25(OH)D(3)] on these cells. Recent evidence shows that hMSCs participate in vitamin D metabolism and can activate 25(OH)D(3) by CYP27B1/1alpha hydroxylase. These studies test the hypothesis that antiproliferative and prodifferentiation effects of 25(OH)D(3) in hMSCs depend on CYP27B1. We studied hMSCs that constitutively express high (hMSCs(hi-1alpha) ) or low (hMSCs(lo 1alpha)) levels of CYP27B1 with equivalent expression of CYP24A1 and vitamin D receptor. In hMSCs(hi-1alpha), 25(OH)D(3) reduced proliferation, downregulated proliferating cell nuclear antigen (PCNA), upregulated p21(Waf1/Cip1), and decreased cyclin D1. Unlike 1,25(OH)(2)D(3), the antiapoptotic effects of 25(OH)D(3) on Bax and Bcl-2 were blocked by the P450 inhibitor ketoconazole. The antiproliferative effects of 25(OH)D(3) in hMSCs(hi-1alpha) and of 1,25(OH)(2)D(3) in both samples of hMSCs were explained by cell cycle arrest, not by increased apoptosis. Stimulation of osteoblast differentiation in hMSCs(hi 1alpha) by 25(OH)D(3) was prevented by ketoconazole and upon transfection with CYP27B1 siRNA. These data indicate that CYP27B1 is required for 25(OH)D(3)'s action in hMSCs. Three lines of evidence indicate that CYP27B1 is required for the antiproliferative and prodifferentiation effects of 25(OH)D(3) on hMSCs: Those effects were not seen (1) in hMSCs with low constitutive expression of CYP27B1, (2) in hMSCs treated with ketoconazole, and (3) in hMSCs in which CYP27B1 expression was silenced. Osteoblast differentiation and skeletal homeostasis may be regulated by autocrine/paracrine actions of 25(OH)D(3) in hMSCs. PMID- 21542016 TI - Pardoprunox in early Parkinson's disease: results from 2 large, randomized double blind trials. AB - This report presents the results of 2 randomized trials-Rembrandt and Vermeer-on the efficacy and safety of pardoprunox in patients with early Parkinson's disease. Patients with Parkinson's disease with a Unified Parkinson's Disease Rating Scale-Motor score >= 10 and modified Hoehn and Yahr stage <= 3 were randomized to pardoprunox (fixed doses of 6 mg/day [n = 115] or 12 mg/day [n = 118] or a flexible-dose range of 12-42 mg/day [n = 116]) or placebo (n = 119) in Rembrandt and pardoprunox 12-42 mg/day (n = 108), pramipexole 1.5-4.5 mg/day (n = 116), or placebo (n = 110) in Vermeer. Pardoprunox showed a significant benefit over placebo in the primary efficacy variable, least-square mean change from baseline in Unified Parkinson's Disease Rating Scale-Motor score: Rembrandt-fixed doses of 6 and 12 mg/day, -6.0 and -4.7 points, respectively; flexible-dose 12-42 mg/day, -5.5 points; placebo, -2.9 points; Vermeer-flexible-dose 12-42 mg/day, 4.9 points; placebo, -2.5 points; pramipexole, -5.7 points. No minimum effective dose was established. Secondary efficacy parameters supported the results of the primary efficacy variable. Pardoprunox tolerability was dose related: flexible dose 12-42 mg/day showed the highest dropout rate due to treatment-emergent adverse events (Rembrandt, 56.0%; Vermeer, 46.3%) and overall incidence of treatment-emergent adverse events (Rembrandt, 97.4%; Vermeer, 92.6%), primarily due to nausea, somnolence, and dizziness. Because pardoprunox showed similar efficacy across all dose groups, these observations suggest that the 12-42 mg/day dose range was higher than therapeutically required. Furthermore, the early onset of treatment-emergent adverse events and dropouts observed for pardoprunox suggest that titration was too rapid. Pardoprunox significantly improved motor symptoms in patients with early Parkinson's disease, but further investigation into the dose and titration schedule is required to improve tolerability. PMID- 21542017 TI - Mortalin inhibition in experimental Parkinson's disease. AB - Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6-hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT-077, a rhodamine-123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham-operated, and 6 hydroxydopamine-denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6-hydroxydopamine-treated rats in comparison with sham-operated animals. MKT-077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT-077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease. PMID- 21542018 TI - Tongue control for swallowing in Parkinson's disease: effects of age, rate, and stimulus consistency. AB - BACKGROUND: Patients with Parkinson's disease often suffer from swallowing problems, especially at more advanced stages of the disease. Efficient swallows require well-coordinated tongue movements during bolus flow, but little is known about such movements in Parkinson's disease. METHODS: The current study presents data on tongue movements for patients with mild to moderate Parkinson's disease (n=10), age-matched adults (n=13), and younger healthy adults (n=15). RESULTS: Participants with Parkinson's disease showed smaller and more variable movements in the horizontal movement plane, indicating that tongue movements are affected in early stages of Parkinson's disease. CONCLUSIONS: The small and more variable movements in the horizontal plane of Patients with Parkinson's disease may pose challenges for swallowing liquids efficiently and safely. PMID- 21542019 TI - Parkinson's disease, cortical dysfunction, and alpha-synuclein. AB - The ability to understand how Parkinson's disease neurodegeneration leads to cortical dysfunction will be critical for developing therapeutic advances in Parkinson's disease dementia. The overall purpose of this project was to study the small-amplitude cortical myoclonus in Parkinson's disease as an in vivo model of focal cortical dysfunction secondary to Parkinson's disease neurodegeneration. The objectives were to test the hypothesis that cortical myoclonus in Parkinson's disease is linked to abnormal levels of alpha-synuclein in the primary motor cortex and to define its relationship to various biochemical, clinical, and pathological measures. The primary motor cortex was evaluated for 11 Parkinson's disease subjects with and 8 without electrophysiologically confirmed cortical myoclonus (the Parkinson's disease + myoclonus group and the Parkinson's disease group, respectively) who had premortem movement and cognitive testing. Similarly assessed 9 controls were used for comparison. Measurements for alpha-synuclein, Abeta-42 peptide, and other biochemical measures were made in the primary motor cortex. A 36% increase in alpha-synuclein was found in the motor cortex of Parkinson's disease + myoclonus cases when compared with Parkinson's disease without myoclonus. This occurred without significant differences in insoluble alpha-synuclein, phosphorylated to total alpha-synuclein ratio, or Abeta-42 peptide levels. Higher total motor cortex alpha-synuclein levels significantly correlated with the presence of cortical myoclonus but did not correlate with multiple clinical or pathological findings. These results suggest an association between elevated alpha-synuclein and the dysfunctional physiology arising from the motor cortex in Parkinson's disease + myoclonus cases. Alzheimer's disease pathology was not associated with cortical myoclonus in Parkinson's disease. Cortical myoclonus arising from the motor cortex is a model to study cortical dysfunction in Parkinson's disease. PMID- 21542020 TI - Development of Holmes' tremor following hemi-cerebellar infarction. PMID- 21542021 TI - Subthalamic nucleus neuronal firing rate increases with Parkinson's disease progression. AB - Parkinson's disease is a neurodegenerative disorder characterized by progressive loss of dopaminergic cells in the central nervous system, in particular the substantia nigra, resulting in an unrelenting loss of motor and nonmotor function. Animal models of Parkinson's disease reveal hyperactive neurons in the subthalamic nucleus that have increased firing rates and bursting activity compared with controls. Although subthalamic nucleus activity has been characterized in patients with advanced-stage Parkinson's disease, it has not been described in patients with early-stage Parkinson's disease. Here we present the results of subthalamic nucleus neuronal recordings from patients with early stage Parkinson's disease (Hoehn and Yahr stage II) enrolled in an ongoing clinical trial compared with recordings from age- and sex-matched patients with advanced Parkinson's disease. Subthalamic nucleus neurons had a significantly lower firing rate in early versus advanced Parkinson's disease (28.7 vs 36.3 Hz; P<.01). The overall activity of the subthalamic nucleus was also significantly lower in early versus late Parkinson's disease, as measured by background neuronal noise (12.4 vs 14.0 mV; P<.05). No significant difference was identified between groups in the bursting or variability of neuronal firing in the subthalamic nucleus, as measured by a burst index or the interspike interval coefficient of variability. The results suggest that neuronal firing in the subthalamic nucleus increases with Parkinson's disease progression. PMID- 21542022 TI - Brain perfusion and markers of neurodegeneration in rapid eye movement sleep behavior disorder. AB - Potential early markers of neurodegeneration such as subtle motor signs, reduced color discrimination, olfactory impairment, and brain perfusion abnormalities have been reported in idiopathic rapid eye movement sleep behavior disorder, a risk factor for Parkinson's disease and Lewy body dementia. The aim of this study was to reproduce observations of regional cerebral blood flow abnormalities in a larger independent sample of patients and to explore correlations between regional cerebral blood flow and markers of neurodegeneration. Twenty patients with idiopathic rapid eye movement sleep behavior disorder and 20 healthy controls were studied by single-photon emission computerized tomography. Motor examination, color discrimination, and olfactory identification were examined. Patients with rapid eye movement sleep behavior disorder showed decreased regional cerebral blood flow in the frontal cortex and in medial parietal areas and increased regional cerebral blood flow in subcortical regions including the bilateral pons, putamen, and hippocampus. In rapid eye movement sleep behavior disorder, brain perfusion in the frontal cortex and occipital areas was associated with poorer performance in the color discrimination test. Moreover, a relationship between loss of olfactory discrimination and regional cerebral blood flow reduction in the bilateral anterior parahippocampal gyrus, a region known to be involved in olfactory functions, was found. This study provides further evidence of regional cerebral blood flow abnormalities in rapid eye movement sleep behavior disorder that are similar to those seen in Parkinson's disease and Lewy body dementia. Moreover, regional cerebral blood flow anomalies were associated with markers of neurodegeneration. PMID- 21542023 TI - Does cardiovascular autonomic dysfunction contribute to fatigue in Parkinson's disease? AB - Patients with Parkinson's disease often complain of fatigue, and although cardiac sympathetic denervation is thought to be associated with fatigue, this link remains unclear. Previously, we detected cardiac sympathetic denervation in patients with Parkinson's disease using dobutamine, a selective beta-1 stimulant. To clarify the involvement of autonomic dysfunction in fatigue in Parkinson's disease, we conducted autonomic function tests on 33 patients with Parkinson's disease (mean age, 66.1 +/- 5.6 years; 20 men, 13 women) and evaluated their relationships to fatigue. We divided patients into 2 groups, fatigued (n = 12) and nonfatigued (n = 21), based on an average score >= 3.3 on the Parkinson fatigue scale. Autonomic function tests included the coefficient of variation of R-R intervals, head-up tilt test, norepinephrine and dobutamine infusion tests, and cardiac (123) I-metaiodobenzylguanidine scintigraphy. The coefficient of variation of R-R intervals and the systolic blood pressure changes accompanying the head-up tilt test did not show significant differences between the 2 groups; however, the pressor responses in the norepinephrine and dobutamine infusion tests were significantly greater in the fatigued group than in the nonfatigued group. The (123) I-metaiodobenzylguanidine heart-to-mediastinal uptake ratio was lower in the fatigued group than in the nonfatigued group. Partial correlation analyses, using disease duration and Hoehn and Yahr stage as control variables, also demonstrated significant correlations between the Parkinson fatigue scale score and the results of the autonomic function tests and cardiac (123) I metaiodobenzylguanidine uptake. Our results suggest that autonomic dysfunction, including cardiac sympathetic denervation, is associated with fatigue in patients with Parkinson's disease. PMID- 21542024 TI - Progressive supranuclear palsy-like phenotype caused by progranulin p.Thr272fs mutation. PMID- 21542025 TI - SCOPA-cognition cutoff value for detection of Parkinson's disease dementia. AB - The SCOPA-Cognition is a reliable and valid test to evaluate cognitive functioning in Parkinson's disease and is widely used in clinical and research settings. Recently, the Movement Disorder Society introduced criteria for Parkinson's disease dementia. The objective of the present study was to use these criteria to determine SCOPA-Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. A total of 282 patients with Parkinson's disease were assessed with the SCOPA-Cognition and the Movement Disorder Society's Parkinson's disease dementia criteria. From the 275 patients with a complete assessment of the dementia criteria, 12% (n = 32) fulfilled the criteria. Data from 268 patients with complete assessments of both the dementia criteria and the SCOPA-Cognition were used to determine cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. The area under the curve was 0.91 (95% confidence interval, 0.85-0.97), showing a strong association between the dementia criteria and the SCOPA-Cognition. The cutoff for maximum accuracy was 22/23, based on the highest sum of sensitivity (0.80) and specificity (0.87), with positive and negative predictive values of 0.43 and 0.97, respectively. The optimal screening cutoff was 24/25, and the optimal diagnostic cutoff was 17/18. Using the recently published Parkinson's disease dementia criteria as a reference, the current study presents SCOPA-Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. The availability of SCOPA-Cognition cutoffs for Parkinson's disease dementia may contribute to the scale's usefulness and promote its further use in both clinical and research settings. PMID- 21542026 TI - The effects of a modest dose of alcohol on executive functioning and prospective memory. AB - RATIONALE: Acute alcohol intoxication selectively impairs executive functioning and prospective memory (PM). Much previous researches in this area have used laboratory-based tasks that may not mimic functions that individuals with dysexecutive syndrome have problems with in their everyday life. The present study aimed to assess the effects of a modest dose of alcohol on executive functioning and PM using a virtual reality task and investigate the role of executive planning in PM performance. METHODS: Forty healthy participants were administered 0.4 g/kg alcohol or matched placebo in a double-blind design. Executive function and PM were assessed using the Jansari-Agnew-Akesson-Murphy (JAAM) task, requiring participants to play the role of an office worker. RESULTS: Alcohol intoxication selectively impaired executive function and PM. The participants in the alcohol condition performed worse on the planning, prioritisation, creativity and adaptability executive subscales and also on the time-based and event-based PM tasks. However, alcohol did not impair the selection executive function task or the action-based PM task. CONCLUSIONS: The results provide further support for the effects of alcohol on executive functioning and PM. In addition, the results suggest that such deficits may be present at relatively modest doses of alcohol and in the absence of a subjective feeling of intoxication. PMID- 21542027 TI - Alcohol effects on simulated driving in frequent and infrequent binge drinkers. AB - OBJECTIVE: Compared with non-bingers, binge drinkers are more likely to drive while intoxicated. The extent to which binge frequency impacts confidence in driving and subsequent driving impairment is unknown. This study compared the effects of an experimenter-delivered alcohol binge on subjective impairment and simulated driving ability in female high-frequency and low-frequency bingers. METHODS: Female drinkers were assigned to high-frequency (n = 30) or low frequency (n = 30) binge groups based on their Alcohol Use Questionnaire responses. At 30-min intervals within a 2-h period, participants received either a placebo drink (n = 15 per group) or a 0.2 g/kg dose of alcohol (n = 15 per group; cumulative dose 0.8 g/kg). Self-reported impairment, driving confidence, and simulated driving were then measured. RESULTS: Self-reported confidence in driving was significantly lower after alcohol than after placebo in low-frequency but not highfrequency bingers. Self-reported impairment and collisions during simulated driving were significantly greater after alcohol than after placebo in both low-frequency and high-frequency bingers. CONCLUSIONS: The impairing effects of a single alcohol binge on driving ability in women are not influenced by binge frequency. However, high binge frequency may be associated with a less cautious approach to post-binge driving. PMID- 21542028 TI - Can carcinogenic potency be predicted from in vivo genotoxicity data?: a meta analysis of historical data. AB - Genotoxicity is generally a parameter used for hazard identification, however, the applicability of using in vivo genotoxicity tests for hazard characterization has never been thoroughly investigated in a quantitative manner. Genotoxicity assays could be useful for the determination of cancer potency parameters given that genotoxicty tests measure mutations and/or chromosomal aberrations which are strongly associated with carcinogenesis. A detailed literature survey was performed in search for dose-response data in various in vivo genotoxicity and carcinogenicity studies. The benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST. Dose-response data were available from 18 compounds in the micronucleus assay (MN), the in vivo transgenic rodent mutation assay (TG) and the comet assay, and their BMD(10) values were compared to the BMD(10) from carcinogenicity studies in mice. Of the 18 compounds, 15 had acceptable dose-response data from the MN and the TG, but only 4 from the comet assay. A major limitation in our analysis was the lack of proper dose-response studies using the recommended protocols. Nevertheless, our findings are promising because even with these suboptimal studies, a positive correlation was observed when the lowest BMD(10) from the genotoxicity tests (MN and TG) was compared to the tissue-matched carcinogenicity BMD(10) . It is evident that more compounds need to be analyzed with proper dose-response schemes to further validate our initial findings. Experimental designs of genotoxicity assays need to shift from focusing only on hazard identification where positive and negative results are reported, to a more quantitative, dose-response assessment. PMID- 21542029 TI - Analysis of mutations in the Pig-a gene of spleen T-cells from N-ethyl-N nitrosourea-treated fisher 344 rats. AB - A rapid in vivo somatic cell gene mutation assay is being developed that measures mutation in the endogenous X-linked phosphatidylinositol glycan, class A gene (Pig-a). The assay detects Pig-a mutants by flow cytometric identification of cells deficient in glycosylphosphatidyl inositol (GPI) anchor synthesis. GPI deficient, presumed Pig-a mutant cells also can be detected in a cloning assay that uses proaerolysin (ProAER) selection. Previously, we demonstrated that ProAER-resistant (ProAER(r) ) rat spleen T-cells have mutations in the Pig-a gene. In the present study, we report on a more complete analysis of ProAER(r) rat spleen T-cell mutants and describe a mutation spectrum for mutants isolated from rats 4 weeks after treatment with three consecutive doses of 35.6 mg/kg N ethyl-N-nitrosourea (ENU). We identified a total of 55 independent mutations, with the largest percentage (69%) involving basepair substitution at A:T. The overall spectrum of Pig-a gene mutations was consistent with the types of DNA adducts formed by ENU and was very similar to what has been described for in vivo ENU-induced mutation spectra in other rodent reporter genes (e.g., in the endogenous Hprt gene and transgenic shuttle vectors). These data are consistent with the rat Pig-a assay detecting test-agent-induced mutational responses. PMID- 21542030 TI - Coarctate versus pericyclic reactivity in naphthalene-fused azo-ene-ynes: synthesis of benzocinnolines and benzoisoindazoles. AB - The cyclization reactions of naphthalene-fused azo-ene-yne compounds are explored both computationally and experimentally. Calculations reveal that naphtho-fusion to an azo-ene-yne scaffold does not significantly alter the transition state energies compared to the benzene-based systems; however, fusing the naphthalene in an angular fashion leads to lower energy intermediates due to the creation of arenes possessing greater aromaticity. Experimentally, the cyclization of the angular systems yields not only the expected monomeric benzocinnolines and benzoisoindazoles, but also several dimeric structures, including one that readily isomerizes in the presence of light and/or trace acid. PMID- 21542031 TI - Anchor points for the unified Bronsted acidity scale: the rCCC model for the calculation of standard Gibbs energies of proton solvation in eleven representative liquid media. AB - The COSMO cluster-continuum (CCC) solvation model is introduced for the calculation of standard Gibbs solvation energies of protons. The solvation sphere of the proton is divided into an inner proton-solvent cluster with covalent interactions and an outer solvation sphere that interacts electrostatically with the cluster. Thus, the solvation of the proton is divided into two steps that are calculated separately: 1) The interaction of the proton with one or more solvent molecules is calculated in the gas phase with high-level quantum-chemical methods (modified G3 method). 2) The Gibbs solvation energy of the proton-solvent cluster is calculated by using the conductor-like screening model (COSMO). For every solvent, the solvation of the proton in at least two (and up to 11) proton solvent clusters was calculated. The resulting Gibbs solvation energies of the proton were weighted by using Boltzmann statistics. The model was evaluated for the calculation of Gibbs solvation energies by using experimental data of water, MeCN, and DMSO as a reference. Allowing structural relaxation of the proton solvent clusters and the use of structurally relaxed Gibbs solvation energies improved the accordance with experimental data especially for larger clusters. This variation is denoted as the relaxed COSMO cluster-continuum (rCCC) model, for which we estimate a 1sigma error bar of 10 kJ mol(-1) . Gibbs solvation energies of protons in the following representative solvents were calculated: Water, acetonitrile, sulfur dioxide, dimethyl sulfoxide, benzene, diethyl ether, methylene chloride, 1,2-dichloroethane, sulfuric acid, fluorosulfonic acid, and hydrogen fluoride. The obtained values are absolute chemical standard potentials of the proton (pH=0 in this solvent). They are used to anchor the individual solvent specific acidity (pH) scales to our recently introduced absolute acidity scale. PMID- 21542032 TI - Reduced molybenum-oxide-based core-shell hybrids: "blue" electrons are delocalized on the shell. AB - The present study refers to a variety of reduced metal-oxide core-shell hybrids, which are unique with regard to their electronic structure, their geometry, and their formation. They contain spherical {Mo72Fe30} Keplerate-type shells encapsulating Keggin-type polyoxomolybdates based on very weak interactions. Studies on the encapsulation of molybdosilicate as well as on the earlier reported molybdophosphate, coupled with the use of several physical methods for the characterization led to unprecedented results (see title). Upon standing in air at room temperature, acidified aqueous solutions obtained by dissolving sodium molybdate, iron(II) chloride, acetic acid, and molybdosilicic acid led to the precipitation of monoclinic greenish crystals (1). A rhombohedral variant (2) has also been observed. Upon drying at room temperature, compound 3 with a layer structure was obtained from 1 in a solid-state reaction based on cross-linking of the shells. The compounds 1, 2, and 3 have been characterized by a combination of methods including single-crystal X-ray crystallography, magnetic studies, as well as IR, Mossbauer, (resonance) Raman, and electronic absorption spectroscopy. In connection with detailed studies of the guest-free two-electron-reduced {Mo72Fe30}-type Keplerate (4) and of the previously reported molybdophosphate based hybrids (including 31P NMR spectroscopy results), it is unambiguously proved that 1, 2, and 3 contain non-reduced Keggin ion cores and reduced {Mo72Fe30}-type shells. The results are discussed in terms of redox considerations (the shell as well as the core can be reduced) including those related to the reduction of "molybdates" by FeII being of interdisciplinary including catalytic interest (the MoVI/MoV and FeIII/FeII couples have very close redox potentials!), while also referring to the special formation of the hybrids based on chemical Darwinism. PMID- 21542033 TI - Pathway-dependent self-assembly of perylene diimide/peptide conjugates in aqueous medium. AB - Most molecular self-assembly strategies involve equilibrium systems, leading to a single thermodynamic product as a result of weak, reversible non-covalent interactions. Yet, strong non-covalent interactions may result in non-equilibrium self-assembly, in which structural diversity is achieved by forming several kinetic products based on a single covalent building block. We demonstrate that well-defined amphiphilic molecular systems based on perylene diimide/peptide conjugates exhibit kinetically controlled self-assembly in aqueous medium, enabling pathway-dependent assembly sequences, in which different organic nanostructures are evolved in a stepwise manner. The self-assembly process was characterized using UV/Vis circular dichroism (CD) spectroscopy, and cryogenic transmission electron microscopy (cryo-TEM). Our findings show that pathway controlled self-assembly may significantly broaden the methodology of non covalent synthesis. PMID- 21542034 TI - Mechanistic insights into photochromic behavior of a ruthenium(II)-pterin complex. AB - The pterin-coordinated ruthenium complex, [Ru(II) (dmdmp)(tpa)](+) (1) (Hdmdmp=N,N-dimethyl-6,7-dimethylpterin, tpa=tris(2-pyridylmethyl)amine), undergoes photochromic isomerization efficiently. The isomeric complex (2) was fully characterized to reveal an apparent 180 degrees pseudorotation of the pterin ligand. Photoirradiation to the solution of 1 in acetone with incident light at 460 nm resulted in dissociation of one pyridylmethyl arm of the tpa ligand from the Ru(II) center to give an intermediate complex, [Ru(dmdmp)(tpa)(acetone)](2+) (I), accompanied by structural change and the coordination of a solvent molecule to occupy the vacant site. The quantum yield (phi) of this photoreaction was determined to be 0.87 %. The subsequent thermal process from intermediate I affords an isomeric complex 2, as a result of the rotation of the dmdmp(2-) ligand and the recoordination of the pyridyl group through structural change. The thermal process obeyed first-order kinetics, and the rate constant at 298 K was determined to be 5.83*10(-5) s(-1). The activation parameters were determined to be DeltaH(?) =81.8 kJ mol(-1) and DeltaS(?) =-49.8 J mol(-1) K(-1). The negative DeltaS(?) value indicates that this reaction involves a seven-coordinate complex in the transition state (i.e., an interchange associative mechanism). The most unique point of this reaction is that the recoordination of the photodissociated pyridylmethyl group occurs only from the direction to give isomer 2, without going back to starting complex 1, and thus the reaction proceeds with 100 % conversion efficiency. Upon heating a solution of 2 in acetonitrile, isomer 2 turned back into starting complex 1. The backward reaction is highly dependent on the solvent: isomer 2 is quite stable and hard to return to 1 in acetone; however, 2 was converted to 1 smoothly by heating in acetonitrile. The activation parameters for the first-order process in acetonitrile were determined to be DeltaH(?) =59.2 kJ mol(-1) and DeltaS(?) = 147.4 kJ mol(-1) K(-1). The largely negative DeltaS(?) value suggests the involvement of a seven-coordinate species with the strongly coordinated acetonitrile molecule in the transition state. Thus, the strength of the coordination of the solvent molecule to the Ru(II) center is a determinant factor in the photoisomerization of the Ru(II)-pterin complex. PMID- 21542035 TI - Probing the role of the linker in ferrocene-ATP conjugates: monitoring protein kinase catalyzed phosphorylations electrochemically. AB - The synthesis and electrochemical properties of ferrocene conjugates are presented for the purpose of investigating adenosine 5'-[gamma-ferrocenoylalkyl] triphosphate (1 a-4 a, ferrocene (Fc)-ATP) as co-substrates for phosphorylation reactions. Compounds 1 a-4 a were synthesized, purified by HPLC, and characterized by NMR spectroscopy and mass spectrometry. In solution, all Fc-ATP bioconjugates exhibit a reversible one-electron redox process with a half-wave potential (E(1/2)) in the 390-430 mV range, peak separations (DeltaE(p)) in the 40-70 mV range, and the peak current ratio (i(pa)/i(pc)) near unity. The peptide modified surface Glu-Gly-Ile-Tyr-Asp-Val-Pro was used to study the sarcoma related protein (Src) kinase activity by employing the Fc-ATP bioconjugates as co substrates. Subsequent kinase-catalyzed transfer of the gamma-Fc-phosphate group to the tyrosine residues of the surface-bound peptides was characterized by a formal potential (E degrees ) ~390 mV (vs. Ag/AgCl). The Fc-coverage, estimated by time-of-flight secondary-ion mass spectrometry (TOF-SIMS) and cyclic voltammetry (CV), suggested validity of Fc-ATP conjugates as kinase co substrates. Depending on the length of the alkyl spacer of the Fc-ATP conjugate, different current densities were obtained, pointing to a direct correlation between the two. Molecular modeling revealed that the structural constraint imposed by the short alkyl spacer (1 a) causes a steric congestion and negatively affects the outcome of phosphorylation reaction. An optimal analytical response was obtained with the Fc-ATP conjugates with linker lengths longer than six CH(2) groups. PMID- 21542036 TI - 4,4'-dithiobisdipicolinic acid: a small and convenient lanthanide binding tag for protein NMR spectroscopy. AB - Pseudocontact shifts (PCS) from paramagnetic lanthanide ions present powerful long-range structure restraints for studies of proteins by nuclear magnetic resonance spectroscopy. To elicit PCSs, the lanthanide must be attached site specifically to the target protein. In addition, it needs to be attached rigidly to avoid averaging of the PCSs due to mobility with respect to the protein and it must not interfere with the function of the protein. Here, we present a dipicolinic acid reagent that spontaneously forms a disulfide bond with thiol groups of accessible cysteine residues. A minimal number of rotatable bonds between the cysteine side chain and the tag helps to minimise mobility. Combined with the small size of the tag and quantitative tagging yields, these features make it a highly attractive tool for generating structure restraints by paramagnetic lanthanides. PMID- 21542037 TI - Silica nanocapsules of fluorescent conjugated polymers and superparamagnetic nanocrystals for dual-mode cellular imaging. AB - We describe here a facile and benign synthetic strategy to integrate the fluorescent behavior of conjugated polymers and superparamagnetic properties of iron oxide nanocrystals into silica nanocapsules, forming a new type of bifunctional magnetic fluorescent silica nanocapsule (BMFSN). The resultant BMFSNs are uniform, colloidally stable in aqueous medium, and exhibit the desired dual functionality of fluorescence and superparamagnetism in a single entity. Four conjugated polymers with different emissions were used to demonstrate the versatility of employing this class of fluorescent materials for the preparation of BMFSNs. The applicability of BMFSNs in cellular imaging was studied by incubating them with human liver cancer cells, the result of which demonstrated that the cells could be visualized by dual-mode fluorescence and magnetic resonance imaging. Furthermore, the superparamagnetic behavior of the BMFSNs was exploited for in vitro magnetic-guided delivery of the nanocapsules into the cancer cells, thereby highlighting their potential for targeting biomedical applications. PMID- 21542038 TI - Quantifying the electronic effects of carbohydrate hydroxy groups by using aminosugar models. AB - Methyl amino-deoxy-glycosides with alpha- and beta-gluco, alpha-galacto, or alpha manno stereochemistry with the amino functionality in each of the four possible non-anomeric positions have been synthesized and their pK(a) values determined by titration. These model compounds were chosen because they are the amino derivatives of the most common glycosyl acceptors. From this study it was possible to evaluate the electron density at each of the given positions in the carbohydrate and compare them. Some general trends were observed: The basicity of the amino groups decreases in the order 6-NH(2)>3-NH(2)>2-NH(2)>4-NH(2) (referring to the position). The basicity of a of an amino-deoxy-sugar generally increases when one or more substituents on the sugar ring are axial. The basicity decreases when the amine is antiperiplanar to an oxygen atom. These findings are in agreement with the observations obtained from glycosylation chemistry and the regioselective protection of sugars. PMID- 21542039 TI - Multistep oligometal complexation of the macrocyclic tris(N2O2) hexaoxime ligand. AB - A macrocyclic oxime ligand H(6)L, which has an O(6) cavity surrounded by three N(2)O(2) chelate sites, was synthesized and the multistep oligometal complexation behavior was investigated. Upon complexation with zinc(II), the H(6)L ligand afforded two kinds of hexanuclear complexes, L(2)Zn(6) then LZn(6). Each of the complexation steps proceeded highly efficiently. In the latter complex, a Zn(3)(MU(3)-OH) unit was incorporated into the trimetalated ligand, LZn(3). The integrated N(2)O(2) chelate coordination sites provide a unique environment for a homometallic complex. The different nature of the peripheral N(2)O(2) sites and the central O(6) site is particularly suitable for the selective formation of heterometallic complexes. Complexation with the zinc(II) ion in the presence of alkaline earth (Ca and Ba) or rare earth (La, Eu, Lu) metal ions afforded the heterotetranuclear complexes LZn(3)M (M=Ca, Ba, La, Eu, Lu), in which zinc(II) and ion M occupied the N(2)O(2) and O(6) sites, respectively. Titration experiments showed that the heterometallic complexes LZn(3) Ca and LZn(3) Ba were converted into the homometallic complex LZn(6) whereas LZn(3)La was not. As a result, the binding affinity in the central O(6) site of the LZn(3) unit is apparently in the order of Ca(2+), Ba(2+) 0.05). Likewise, the expression level of PmMAPK1 in early cortical rod and mature (IV) ovaries was significantly greater than that in previtellogenic (I) and vitellogenic (II) ovaries of eyestalk-ablated broodstock (P < 0.05). The PmMAPK1 transcript was localized in ooplasm of previtellogenic oocytes. In intact broodstock, the expression of the PmMAPK1 protein was clearly increased from previtellogenic ovaries in subsequent stages of ovarian development (P < 0.05). In contrast, the level of ovarian PmMAPK1 protein was comparable during oogenesis in eyestalk-ablated broodstock (P > 0.05). The PmMAPK1 protein was localized in ooplasm of previtellogenic and vitellogenic oocytes. It was also detected around the nuclear membrane of early cortical rod oocytes in both intact and eyestalk-ablated broodstock. Results indicated that PmMAPK1 gene products seem to play functional roles in the development and maturation of oocytes/ovaries in P. monodon. PMID- 21542049 TI - Altered testicular gene expression patterns in mice lacking the polyubiquitin gene Ubb. AB - Ubiquitin (Ub) is an essential protein found in all eukaryotic cells and plays important roles in a variety of cellular functions including germ cell development. We have previously reported that targeted disruption of the polyubiquitin gene Ubb results in male and female infertility in Ubb(-/-) mice, with germ cells arrested at meiotic prophase I. Although reduced Ub levels in germ cells are believed to be responsible for the fertility defect in Ubb(-/-) mice, it is still unclear how reduced Ub levels result in sterility. Here we describe the results of a microarray analysis of the murine testicular transcriptome, which demonstrates dramatically altered gene expression patterns in Ubb(-/-) mice, possibly related to reduced levels of histone 2A (H2A) ubiquitylation. We find that large numbers of genes related to fertility, metabolism, transcription, and the ubiquitin-proteasome system (UPS) are misregulated in Ubb(-/-) mice. Such wide-ranging alterations in gene expression suggest that loss of the Ubb gene does not mimic a single-gene defect phenotype, but instead may affect gene expression more globally. These dramatic changes in gene expression could, at least in part, contribute to the complex fertility and metabolic phenotypes seen in these mice. PMID- 21542050 TI - Nucleoli from growing oocytes inhibit the maturation of enucleolated, full-grown oocytes in the pig. AB - In mammals, the nucleolus of full-grown oocyte is essential for embryonic development but not for oocyte maturation. In our study, the role of the growing oocyte nucleolus in oocyte maturation was examined by nucleolus removal and/or transfer into previously enucleolated, growing (around 100 um in diameter) or full-grown (120 um) pig oocytes. In the first experiment, the nucleoli were aspirated from growing oocytes whose nucleoli had been compacted by actinomycin D treatment, and the enucleolated oocytes were matured in vitro. Most of non treated or actinomycin D-treated oocytes did not undergo germinal vesicle breakdown (GVBD; 13% and 12%, respectively). However, the GVBD rate of enucleolated, growing oocytes significantly increased to 46%. The low GVBD rate of enucleolated, growing oocytes was restored again by the re-injection of nucleoli from growing oocytes (23%), but not when nucleoli from full-grown oocytes were re-injected into enucleolated, growing oocytes (49%). When enucleolated, full-grown oocytes were injected with nucleoli from growing or full grown oocytes, the nucleolus in the germinal vesicle was reassembled (73% and 60%, respectively). After maturation, the enucleolated, full-grown oocytes injected with nucleoli from full-grown oocytes matured to metaphase II (56%), whereas injection with growing-oocyte nucleoli reduced this maturation to 21%. These results suggest that the growing-oocyte nucleolus is involved in the oocyte's meiotic arrest, and that the full-grown oocyte nucleolus has lost the ability. PMID- 21542052 TI - Acetyl-L-carnitine-mediated neuroprotection during hypoxia is attributed to ERK1/2-Nrf2-regulated mitochondrial biosynthesis. AB - Neuronal damage in hypoxia and several neurodegenerative disorders is invariably associated with oxidative damage and mitochondrial dysfunction. Administration of acetyl-L-carnitine (ALCAR) on the other hand attenuates neuronal damage, prevents apoptosis, and improves energy status in hypoxic stress through less understood mechanisms. Becasue mitochondrial biogenesis could be a possible mechanism for ALCAR-induced improvement in bioenergetics in neurons, the present study aimed at exploring signaling pathways of ALCAR-induced neuroprotection in hypoxia and possible occurrence of mitochondrial biogenesis. To create global hypoxia, adult Sprague-Dawley rats were exposed to a simulated altitude of 7,620 m at standard temperature and humidity conditions. We here demonstrate that administration of ALCAR to hypoxic rats for a period of 2 weeks effectively protected hippocampal neurons from mitochondrial dysfunction, excitotoxicity, and neurodegeneration. ALCAR administration resulted in peroxisome proliferator-activated receptor gamma coactivator-1alpha and nuclear respiratory factor-1-induced mitochondrial biogenesis, the expression of which was regulated by an extracellular-related kinase-nuclear factor erythroid 2-related factor 2 (ERK-Nrf2)-mediated mechanism. Most notably, calcium buffering into nonfunctional mitochondria ameliorated excitotoxicity and improved bioenergetic status of the hippocampal neurons. Together, the data reveal the immense therapeutic potential of ALCAR for the treatment of ischemia, stroke, and other neurodegenerative disorders associated with hypoxic stress and excitotoxicity. PMID- 21542051 TI - Choline supplementation mitigates trace, but not delay, eyeblink conditioning deficits in rats exposed to alcohol during development. AB - Children exposed to alcohol prenatally suffer from a range of physical, neuropathological, and behavioral alterations, referred to as fetal alcohol spectrum disorders (FASD). Both the cerebellum and hippocampus are affected by alcohol exposure during development, which may contribute to behavioral and cognitive deficits observed in children with FASD. Despite the known neuropathology associated with prenatal alcohol exposure, many pregnant women continue to drink (heavy drinkers, in particular), creating a need to identify effective treatments for their children who are adversely affected by alcohol. We previously reported that choline supplementation can mitigate alcohol's effects on cognitive development, specifically on tasks which depend on the functional integrity of the hippocampus. The present study examined whether choline supplementation could differentially mitigate alcohol's effects on trace eyeblink classical conditioning (ECC, a hippocampal-dependent task) and delay ECC (a cerebellar-dependent task). Long-Evans rats were exposed to 5.25 g/kg/day alcohol via gastric intubation from postnatal days (PD) 4-9, a period of brain development equivalent to late gestation in humans. A sham-intubated control group was included. From PD 10-30, subjects received subcutaneous injections of 100 mg/kg choline chloride or vehicle. Beginning on PD 32-34, subjects were trained on either delay or trace eyeblink conditioning. Performance of subjects exposed to alcohol was significantly impaired on both tasks, as indicated by significant reductions in percentage and amplitude of conditioned eyeblink responses, an effect that was attenuated by choline supplementation on the trace, but not delay conditioning task. Indeed, alcohol-exposed subjects treated with choline performed at control levels on the trace eyeblink conditioning task. There were no significant main or interactive effects of sex. These data indicate that choline supplementation can significantly reduce the severity of trace eyeblink conditioning deficits associated with early alcohol exposure, even when administered after the alcohol insult is complete. These findings have important implications for the treatment of fetal alcohol spectrum disorders. PMID- 21542054 TI - Context-dependent modulation of hippocampal and cortical recruitment during remote spatial memory retrieval. AB - According to systems consolidation, as hippocampal-dependent memories mature over time, they become additionally (or exclusively) dependent on extra-hippocampal structures. We assessed the recruitment of hippocampal and cortical structures on remote memory retrieval in a performance-degradation resistant (PDR; no performance degradation with time) versus performance-degradation prone (PDP; performance degraded with time) context. Using a water-maze task in two contexts with a hidden platform and three control conditions (home cage, visible platform with or without access to distal cues), we compared neuronal activation (c-Fos imaging) patterns in the dorsal hippocampus and the medial prefrontal cortex (mPFC) after the retrieval of recent (5 days) versus remote (25 days) spatial memory. In the PDR context, the hippocampus exhibited greater c-Fos protein expression on remote than recent memory retrieval, be it in the visible or hidden platform group. In the PDP context, hippocampal activation increased at the remote time point and only in the hidden platform group. In the anterior cingulate cortex, c-Fos expression was greater for remote than for recent memory retrieval and only in the PDR context. The necessity of the mPFC for remote memory retrieval in the PDR context was confirmed using region-specific lidocaine inactivation, which had no impact on recent memory. Conversely, inactivation of the dorsal hippocampus impaired both recent and remote memory in the PDR context, and only recent memory in the PDP context, in which remote memory performance was degraded. While confirming that neuronal circuits supporting spatial memory consolidation are reorganized in a time-dependent manner, our findings further indicate that mPFC and hippocampus recruitment (i) depends on the content and perhaps the strength of the memory and (ii) may be influenced by the environmental conditions (e.g., cue saliency, complexity) in which memories are initially formed and subsequently recalled. PMID- 21542053 TI - Post-training cocaine exposure facilitates spatial memory consolidation in C57BL/6 mice. AB - In this study, we examined the ability of post-training injections of cocaine to facilitate spatial memory performance using the Morris water maze (MWM). We also investigated the role that hippocampal protein kinase A (PKA) and extracellular signal-regulated kinase 1/2 (ERK) signaling may play in cocaine-mediated spatial memory consolidation processes. Male and female C57BL/6 mice were first trained in a MWM task (eight consecutive trials) then injected with cocaine (0, 1.25, 2.5, 5, or 20 mg/kg), and memory for the platform location was retested after a 24 h delay. Cocaine had a dose-dependent effect on spatial memory performance because only the mice receiving 2.5 mg/kg cocaine displayed a significant reduction in latency to locate the platform. No sex differences in MWM performance were observed; however, females showed higher hippocampal levels of PKA when compared with males. A second experiment demonstrated that 2.5 mg/kg cocaine enhanced MWM performance only when administered within 2, but not 4 h after spatial training. We also found that cocaine (2.5 mg/kg) increased ERK2 phosphorylation within the hippocampus and one of its downstream targets (ribosomal S6 kinase), a mechanism that may be responsible, at least in part, for the enhanced cocaine-mediated spatial memory performance. Overall, these data demonstrate that a low dose of cocaine (2.5 mg/kg) administered within 2 h after training facilitates MWM spatial memory performance in C57BL/6 mice. PMID- 21542055 TI - Inactivation of ventral midline thalamus produces selective spatial delayed conditional discrimination impairment in the rat. AB - The reuniens (Re) and rhomboid (Rh) nuclei are organized to influence activity in distributed limbic networks involving hippocampus and medial prefrontal cortex (mPFC). To elucidate the role of these nuclei in spatial memory we inactivated Re and Rh in rats with the GABA(A) agonist muscimol and compared effects on two spatial delayed conditional discriminations: delayed nonmatching to position (DNMTP) and varying choice radial maze delayed nonmatching (VC-DNM). DNMTP is trained in operant chambers and requires rats to choose between the same two levers on all trials. VC-DNM is trained in automated radial mazes and requires rats to choose between two arms, randomly selected from eight alternatives on each trial. DNMTP is affected by hippocampal and mPFC lesions while VC-DNM is affected by hippocampal, but not mPFC lesions (Porter et al. (2000) Behav Brain Res 109:69-81). We found evidence of a localized (low dose) effect of ReRh inactivation on DNMTP but not VC-DNM. This was confirmed by comparison with muscimol injections in an anatomical control site. These results are consistent with evidence that Re and Rh affect measures of spatial working memory that depend on interactions between hippocampus and mPFC, but not measures that depend on hippocampus alone. PMID- 21542056 TI - Hippocampal context processing is critical for interference free recall of odor memories in rats. AB - Interference is a critical problem for memory systems and a primary cause of retrieval failure. One strategy for minimizing interference is to associate the items to be remembered with the context in which they were learned. For example, human subjects who learn two lists of words in separate contexts experience less interference and better recall than subjects who learn both lists in the same context. The hippocampus has long been known to be involved in processing contextual information and recent studies have shown that hippocampal neurons exhibit context-unique firing patterns that could serve as a neural representation of the context. These observations suggest that hippocampal context processing may play a critical role in overcoming interference. To test this hypothesis, we adapted the context based list learning procedure for use with rats. Control rats and rats given temporary lesions of the hippocampus were trained on two lists of eight odor pairs, either in the same context or in different contexts. To induce interference, some of the odors appeared on both lists with their predictive value reversed. As with human subjects, rats that learned the two lists in different contexts performed significantly better than rats that learned the lists in the same context. However, hippocampal lesions completely abolished this contextual learning advantage. We also trained rats on a low interference version of the task by using lists that did not contain any common items. Interestingly, rats with hippocampal lesions were entirely unimpaired when the learning situation did not involve high levels of interference. These findings are consistent with the idea that the hippocampus encodes contexts and further suggest that hippocampal context coding is beneficial because it provides a means of overcoming interference. PMID- 21542057 TI - Activation of immobility-related hippocampal theta by cholinergic septohippocampal neurons during vestibular stimulation. AB - The vestibular system has been suggested to participate in spatial navigation, a function ascribed to the hippocampus. Vestibular stimulation during spatial navigation activates a hippocampal theta rhythm (4-10 Hz), which may enhance spatial processing and motor response. We hypothesize that a cholinergic, atropine-sensitive theta is generated during passive whole-body rotation in freely behaving rats. Hippocampal EEGs were recorded by implanted electrodes in CA1 while rats were rotated on a vertical axis, for a minute or longer, at different angular velocities. Rotation induced a continuous hippocampal theta rhythm while the rat was immobile, in both light and dark conditions. Theta peak frequency showed a significant increase during high (50-70 rpm) as compared with a lower (20-49 rpm) rotational velocity. Rotation-induced theta was abolished by muscarinic receptor antagonist atropine sulfate (50 mg/kg i.p.) but not by atropine methyl nitrate (50 mg/kg i.p.), which did not pass the blood-brain barrier. Theta was attenuated in rats in which cholinergic neurons in the medial septum (MS) were lesioned with 192 IgG-saporin (0.14 MUg in 0.4 MUl), as confirmed by depletion of MS cells immunoreactive to choline acetyltransferase and an absence of acetylcholinesterase staining in the hippocampus. Bilateral lesion of the vestibular receptors by sodium arsanilate (30 mg in 0.1 ml, intratympanically) also attenuated the rotation-induced theta rhythm. In intact rats, field excitatory postsynaptic potentials (fEPSPs) in CA1 evoked by commissural stimulation were smaller during walking or rotation as compared with during immobility. Modulation of fEPSP was absent following atropine sulfate in intact rats and in 192 IgG-saporin lesion rats. In summary, this is the first report of a continuous atropine-sensitive hippocampal theta in the rat induced by vestibular stimulation during rotation, and accompanied by cholinergic modulation of hippocampal synaptic transmission. Vestibular-activated septohippocampal cholinergic activity could be an important component in sensorimotor processing and spatial memory. PMID- 21542058 TI - Duplication of the EFNB1 gene in familial hypertelorism: imbalance in ephrin-B1 expression and abnormal phenotypes in humans and mice. AB - Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ~1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities. PMID- 21542059 TI - Characterization of copy number-stable regions in the human genome. AB - In the past few years the number of copy number variants (CNVs) identified in the human genome has increased significantly, but our understanding of the functional impact of CNVs is still limited. Clinically significant variations cannot easily be distinguished from benign, complicating interpretation of patient data. Multiple studies have focused on analysis of regions that vary in copy number in specific disorders. Here we use the opposite strategy and focus our analysis on regions that never seem to vary in the general population, hypothesizing that these are copy number stable because variations within them are deleterious. Our results show that copy number stable regions are characterized by correlation with a number of genomic features, allowing us to define a list of genomic regions that are dosage sensitive in humans. We find that these dosage-sensitive regions show significant overlap with de novo CNVs identified in patients with intellectual disability or autism. There is also a significant association between copy number stable regions and rare inherited variants in autism patients, but not in controls. Based on this predictive power, we propose that copy number stable regions can be used to complement maps of known CNVs to facilitate interpretation of patient data. PMID- 21542060 TI - Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys Dietz syndromes. AB - The Marfan (MFS) and Loeys-Dietz (LDS) syndromes are caused by mutations in the fibrillin-1 (FBN1) and Transforming Growth Factor Beta Receptor 1 and 2 (TGFBR1 and TGFBR2) genes, respectively. With the current conventional mutation screening technologies, analysis of this set of genes is time consuming and expensive. We have tailored a cost-effective and reliable mutation discovery strategy using multiplex PCR followed by Next Generation Sequencing (NGS). In a first stage, genomic DNA from five MFS or LDS patient samples with previously identified mutations and/or polymorphisms in FBN1 and TGFBR1 and 2 were analyzed and revealed all expected variants. In a second stage, we validated the technique on 87 samples from MFS patients fulfilling the Ghent criteria. This resulted in the identification of 75 FBN1 mutations, of which 67 were unique. Subsequent Multiplex Ligation-dependent Probe Amplification (MLPA) analysis of the remaining negative samples identified four large deletions/insertions. Finally, Sanger sequencing identified a missense mutation in FBN1 exon 1 that was not included in the NGS workflow. In total, there was an overall mutation identification rate of 92%, which is in agreement with data published previously. We conclude that multiplex PCR of all coding exons of FBN1 and TGFBR1/2 followed by NGS analysis and MLPA is a robust strategy for time- and cost-effective identification of mutations. PMID- 21542062 TI - Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism. AB - Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS. PMID- 21542063 TI - A leaky splicing mutation affecting SMN1 exon 7 inclusion explains an unexpected mild case of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder resulting, in most cases, from homozygous deletions of the SMN1 gene or, in rare cases, from SMN1 intragenic mutations. Here we describe the identification and characterization of c.835-3C>T, a novel SMA-causing mutation detected in the intron 6 of the single SMN1 allele of a type IV SMA patient. We demonstrate both ex vivo and in vivo that c.835-3C>T is a deleterious splicing mutation that induces a modest but unequivocal exclusion of exon 7 from the SMN1 transcripts, its "leakiness" explaining the exceptionally mild phenotype of this patient. This mutation creates a putative high-affinity binding site for the splicing repressor protein hnRNP A1 overlapping the splice acceptor site of exon 7 (UAG|GGU). Our findings support the current therapeutic strategies aiming at correcting exon 7 splicing in SMA patients, and bring clues about the level of exon 7 inclusion required to achieve a therapeutic effect. PMID- 21542061 TI - ACTN3 genotype, athletic status, and life course physical capability: meta analysis of the published literature and findings from nine studies. AB - The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For life course physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research program, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (P = 0.09, n = 7,672 in males; P = 0.90, n = 7,839 in females), standing balance, timed get up and go, or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population. PMID- 21542064 TI - Pseudoexon exclusion by antisense therapy in 6-pyruvoyl-tetrahydropterin synthase deficiency. AB - Antisense oligonucleotide therapy to modulate splicing mutations in inherited diseases is emerging as a treatment option also for metabolic defects. In this article, we report the effect of cellular antisense therapy to suppress pseudoexon activation in primary dermal fibroblasts from patients with mutations in the PTS gene encoding 6-pyruvoyltetrahydropterin synthase (PTPS), which leads to tetrahydrobiopterin and monoamine neurotransmitter deficiency. Pathogenic inclusion of SINE or LINE-derived cryptic exons in different PTPS patients due to the intronic mutations c.84-322A>T, c.163 + 695_163 + 751del57, or c.164-712A>T was demonstrated by transcript analysis in fibroblasts and minigene ex vivo assays. Antisense morpholino oligonucleotides (AMOs) directed to the pseudoexons 3' or 5' splice sites were designed with the aim of preventing the pathological pseudoexon inclusion. At the time of AMO transfection, we investigated patients' cells for correct PTS-mRNA splicing and functional recovery of the PTPS protein. Transcriptional profiling after 24 hr posttransfection revealed a dose- and sequence-specific recovery of normal splicing. Furthermore, PTPS enzyme activity in all three patients' fibroblasts and the pterin profile were close to normal values after antisense treatment. Our results demonstrate proof-of-concept for pseudoexon exclusion therapy using AMO in inherited metabolic disease. PMID- 21542065 TI - Liver dysfunction and immunosuppressive therapy. PMID- 21542066 TI - New genetic data support an association between celiac disease and inflammatory bowel disease. PMID- 21542067 TI - Endoprosthetic management of refractory ileocolonic anastomotic strictures after resection for Crohn's disease: report of nine-year follow-up and review of the literature. AB - BACKGROUND: The role of endoluminal stenting in benign obstruction, especially for Crohn's disease (CD), is controversial, with limited data and widely disparate outcomes. The purpose of this study was to determine the long-term efficacy and safety of this technology in the treatment of fibrostenotic CD and to review the existing literature on this topic. METHODS: We undertook a retrospective review of all patients undergoing endoluminal stenting for CD strictures at our institution from 2001 to 2010. Outcome measures included technical success, clinical improvement, duration of stent and luminal patency, and need for re-intervention. RESULTS: Five patients underwent this procedure with a 100% rate of technical and an 80% rate of clinical success. Mean follow-up was 28 months (range 3 weeks to 109 months) and mean long-term luminal patency was 34.8 months (range 4.5-109 months). There was one complication involving reobstruction which required surgical intervention and no mortalities. CONCLUSIONS: Endoluminal stenting of CD strictures is a safe and effective alternative to surgery which can provide lasting benefit in select patients. Further studies are necessary to clarify the full impact of this technology on long-term management of this complex disease. PMID- 21542068 TI - Missing environmental factor in inflammatory bowel disease: diet-associated gut microflora. PMID- 21542069 TI - Adalimumab for ulcerative colitis: a little is better than none? PMID- 21542070 TI - Phase clusters in large populations of chemical oscillators. PMID- 21542071 TI - 8-Vinyl-2'-deoxyguanosine as a fluorescent 2'-deoxyguanosine mimic for investigating DNA hybridization and topology. PMID- 21542073 TI - Surface functionalization by strain-promoted alkyne-azide click reactions. PMID- 21542072 TI - Light-triggered myosin activation for probing dynamic cellular processes. PMID- 21542074 TI - Micelle-based brain-targeted drug delivery enabled by a nicotine acetylcholine receptor ligand. PMID- 21542075 TI - Soluble synthetic analogues of malaria pigment: structure of mesohematin anhydride and its interaction with chloroquine in solution. PMID- 21542076 TI - A mitochondrial surface-specific fluorescent probe activated by bioconversion. PMID- 21542077 TI - Asymmetric hydrocyanation of alpha,beta-unsaturated ketones into beta-cyano ketones with the [Ru(phgly)2(binap)]/C6H5OLi catalyst system. PMID- 21542078 TI - Fullerene C72Cl4: the exception that proves the rule? PMID- 21542079 TI - In situ generated (hypo)iodite catalysts for the direct alpha-oxyacylation of carbonyl compounds with carboxylic acids. PMID- 21542080 TI - Well-defined bifunctional iron catalysts for the hydrogenation of ketones: iron, the new ruthenium. PMID- 21542081 TI - Generation of hot spots with silver nanocubes for single-molecule detection by surface-enhanced Raman scattering. PMID- 21542085 TI - Gernot Boche (1938-2011). PMID- 21542088 TI - Accessing the hidden majority of marine natural products through metagenomics. AB - Tiny marine animals represent an untapped reservoir for undiscovered, bioactive natural products. However, their small size and extreme chemical variability preclude traditional chemical approaches to discovering new bioactive compounds. Here, we use a metagenomic method to directly discover and rapidly access cyanobactin class natural products from these variable samples, and provide proof of-concept for genome-based discovery and supply of marine natural products. We also address practical optimization of complex, multistep ribosomal peptide pathways in heterologous hosts, which is still very challenging. The resulting methods and concepts will be applicable to ribosomal peptide and other biosynthetic pathways. PMID- 21542089 TI - Highly specific targeting and imaging of live cancer cells by using a peptide probe developed from rationally designed peptides. AB - Specific detection and in vivo tracing of cancer biomarkers are important for cancer analysis. In this work, a simple and effective strategy for developing peptide probes was established. Peptides were rationally designed by using an antisense peptide approach directed towards an extracellular fragment (EL2) of a novel tumor-related protein LAPTM4B. Positional-scanning and stepwise affinity screening was employed to obtain an optimal peptide AP2H (IHGHHIISVG). The dissociation constant between the two small peptides, AP2H and the target EL2, was 5.51 MUM under physiological conditions. Fluorescence imaging assays indicated that AP2H can recognize live hepatoma cells by targeting the LAPTM4B protein on the cell surface with high specificity, low cytotoxicity and desirable cell penetrability. Compared to negative control cells, AP2H could differentiate cells with different expression levels of LAPTM4B. The screened peptide probe for molecular signatures of cancer cells, based on targeting the LAPTM4B protein, has potential applications in cancer diagnosis and targetable drug delivery. PMID- 21542093 TI - The interplay between pipi*/npi* excited states in gas-phase thymine: a quantum dynamical study. AB - A quantum mechanical study of the interplay between the bright pipi*(S(pi)) and the dark npi*(S(n)) excited states of thymine in the gas phase is reported. TD PBE0 calculations indicate that within a relevant region of the S(pi) surface, connecting the Franck-Condon point with the planar and non-planar S(pi) plateau, S(pi) and S(n) are almost isoenergetic and that a S(pi)->S(n) population transfer is therefore likely. This latter process has been studied by two complementary quantum dynamical approaches, a three-dimensional anharmonic (quartic) model, and a full-dimensional harmonic linear vibronic coupling model. Although providing slightly different quantitative indications, both approaches predict a very fast and effective S(pi)->S(n) population transfer: already at 50 fs the S(n) state is significantly populated (20-40%) and this population persists or even increases on a longer time scale. PMID- 21542094 TI - A confidence level algorithm for the determination of absolute configuration using vibrational circular dichroism or Raman optical activity. AB - Spectral comparison is an important part of the assignment of the absolute configuration (AC) by vibrational circular dichroism (VCD), or equally by Raman optical activity (ROA). In order to avoid bias caused by personal interpretation, numerical methods have been developed to compare measured and calculated spectra. Using a neighbourhood similarity measure, the agreement between a computed and measured VCD or ROA spectrum is expressed numerically to introduce a novel confidence level measure. This allows users of vibrational optical activity (VOA) techniques (VCD and ROA) to assess the reliability of their assignment of the AC of a compound. To that end, a database of successful AC determinations is compiled along with neighbourhood similarity values between the experimental spectrum and computed spectra for both enantiomers. For any new AC determination, the neighbourhood similarities between the experimental spectrum and the computed spectra for both enantiomers are projected on the database allowing an interpretation of the reliability of their assignment. PMID- 21542090 TI - Some phorbol esters might partially resemble bryostatin 1 in their actions on LNCaP prostate cancer cells and U937 leukemia cells. AB - Phorbol 12-myristate 13-acetate (PMA) and bryostatin 1 are both potent protein kinase C (PKC) activators. In LNCaP human prostate cancer cells, PMA induces tumor necrosis factor alpha (TNFalpha) secretion and inhibits proliferation; bryostatin 1 does not, and indeed blocks the response to PMA. This difference has been attributed to bryostatin 1 not localizing PKCdelta to the plasma membrane. Since phorbol ester lipophilicity influences PKCdelta localization, we have examined in LNCaP cells a series of phorbol esters and related derivatives spanning some eight logs in lipophilicity (logP) to see if any behave like bryostatin 1. The compounds showed marked differences in their effects on proliferation and TNFalpha secretion. For example, maximal responses for TNFalpha secretion relative to PMA ranged from 97 % for octyl-indolactam V to 24 % for phorbol 12,13-dibenzoate. Dose-response curves ranged from monophasic for indolactam V to markedly biphasic for sapintoxin D. The divergent patterns of response, however, correlated neither to lipophilicity, to plasma membrane translocation of PKCdelta, nor to the ability to interact with model membranes. In U937 human leukemia cells, a second system in which PMA and bryostatin 1 have divergent effects, viz. PMA but not bryostatin 1 inhibits proliferation and induces attachment, all the compounds acted like PMA for proliferation, but several induced a reduced level or a biphasic dose-response curve for attachment. We conclude that active phorbol esters are not all equivalent. Depending on the system, some might partially resemble bryostatin 1 in their behavior; this encourages the concept that bryostatin-like behavior may be obtained from other structural templates. PMID- 21542095 TI - Hole-burning spectra of m-fluorophenol/ammonia (1:3) clusters and their excited state hydrogen transfer dynamics. AB - Hole-burning spectra of m-fluorophenol/ammonia (1:3) clusters are measured by four-color UV-near IR-UV-UV hole-burning spectroscopy. Cis and trans isomers of the cluster are clearly distinguished in the (1:3) cluster. Picosecond time evolutions of the excited state hydrogen transfer (ESHT) reaction in the (1:3) clusters are measured by the ion depletion due to 3p-3s Rydberg transition of reaction products ?NH(4)(NH(3))(2) lying in the near infrared region. From the wavelength dependence of the time evolution, we have concluded 1) the initial formation of a metastable ?NH(4)-NH(3)-NH(3) radical and 2) successive isomerization to the most stable NH(3)-?NH(4) -NH(3) radical in both cis and trans isomers. The reaction lifetimes of ESHT are determined by the rate equation analysis as 32.4 and 31.8 ps for the cis and trans isomer, respectively, and the isomerization and its back-reaction lifetime of both isomers are determined to be 3.3 ps and 11.2 ps. The almost same reaction rates are consistent with the similarity of the hydrogen bond networks in both clusters. PMID- 21542096 TI - Dilemmas of dye-sensitized solar cells. PMID- 21542097 TI - A technique to access difficult to find upper extremity veins for right heart catheterization: the levogram technique. AB - Upper extremity venous access provides a safer alternative for performance of right heart catheterization compared to femoral venous access. We describe a technique to access deep veins of the upper extremity, in patients undergoing transradial catheterization, using levophase contrast venography. This technique allows the operator to access deep veins of the upper extremity without the need for additional equipment, staff or training, using traditional basic catheterization laboratory skills and equipment. PMID- 21542098 TI - Bilateral coronary ostial stenoses post-Bentall procedure causing hemodynamic collapse and requiring mechanical assist device placement: successful intervention using the Szabo technique. AB - Despite surgical advances, the Bentall procedure still carries a 2-6% rate of acute complications involving the coronary vessels, including ostial stenoses, kinking or pseudoaneurysm formation. We report an unusual case of a patient who developed acute cardiogenic shock within hours following a Bentall procedure, requiring urgent mechanical assist device support. Coronary angiography revealed significant bilateral coronary ostial stenoses; suggesting global cardiac hypoperfusion as the cause for this acute hemodynamic collapse. Given the disturbed coronary anatomy, the novel Szabo technique was used to accurately position and deploy an ostial right and then an ostial left main coronary stent, with excellent angiographic results. We conclude that even in situations with altered coronary anatomy, the Szabo technique should be considered for any patient requiring precise aorto-ostial stent placement. PMID- 21542099 TI - Trans catheter aortic valve implantation with core valve revalving system in uncoiled (horizontal) aorta. Overcoming anatomical and technical challenges for successful deployment. AB - Uncoiling of the aortic root (horizontal aorta) offers a considerable technical challenge in successful deployment of core valve prosthesis. The problem is compounded in the presence of significant calcification of the ascending aorta that limits the capability to control the tension on delivery catheter during device release and may lead to implant failure. Recognition of adverse anatomical features and use of proximal access sites such as subclavian artery are likely to attenuate the degree of technical difficulty in these cases. Familiarity and facility with retrieval techniques using a snare catheter is desirable in cases of implant failure. PMID- 21542100 TI - Feasibility of complex coronary and peripheral interventions by trans-radial approach using large sheaths. AB - BACKGROUND: Trans-radial approach (TRA) reduces vascular access-site complications but has some technical limitations. Usually, TRA procedures are performed using 5 Fr or 6 Fr sheaths, whereas complex interventions requiring larger sheaths are approached by trans-femoral access. METHODS: During 4 years, at two Institutions with high TRA use, we have attempted to perform selected complex coronary or peripheral interventions by TRA using sheaths larger than 6 Fr. Clinical and procedural data were prospectively collected. Attempt to place a 7 Fr or 8 Fr sheath (according to the planned strategy of the procedure) was performed after 5-6 Fr sheath insertion, administration of intra-arterial nitrates and radial artery angiography. Late (>3 months) patency of the radial artery was checked (by angiography in the case of repeated procedures or by palpation + reverse Allen test). RESULTS: We collected 60 patients in which TRA large sheath insertion was attempted. The large sheath (87% 7 Fr, 13% 8 Fr) was successfully placed in all cases. Most of the procedures were complex coronary interventions (bifurcated or highly thrombotic or calcific chronic total occlusive lesions), whereas 8.3% were carotid interventions. Procedural success rate was 98.3% (1 failure to reopen a chronic total occlusion). No access-site related complication occurred. In 57 (95%) patients, late radial artery patency was assessed and showed patency in 90% of the cases, the remaining patients having asymptomatic collateralized occlusion. CONCLUSIONS: In selected patients, complex percutaneous interventions requiring 7-8 Fr sheaths can be successfully performed by RA approach without access-site clinical consequences. PMID- 21542101 TI - Perioperative rupture of the LIMA graft leading to cardiogenic shock, emergency angiography, and stenting with a polytetrafluoroethylene-covered stent. AB - A 58-year-old man underwent an elective coronary bypass graft for severe four vessel stenosis. Cardiogenic shock developed just after coronary bypass grafting with a left internal mammary artery (LIMA) to left anterior descending (LAD) artery and superficial venous graft to 1st and 2nd obtuse marginal (OM1/OM2) arteries the posterior descending artery (PDA) was too small to graft. Despite significant inotropes and an intra-aortic balloon pump, the patient deteriorated in intensive care unit with cardiogenic shock and ventricular arrhythmia. Urgent coronary angiography revealed a rupture or torn LIMA graft with extravasation of contrast into the left pleural cavity. There was no distal LIMA to LAD flow probably due to graft thrombosis. Revascularisation was performed on the severe ostial native LAD stenosis with a drug eluting stent. The rupture graft was then stented with a polytetrafluoroethylene-covered stent, which stopped the bleeding, and latter, led to total graft thrombosis. The patient improved significantly and supportive inotropes could be weaned down. At 11 month follow-up, the patient had mild left ventricular dysfunction, widely patent ostial LAD stent and thrombosed LIMA graft. PMID- 21542102 TI - Left atrial appendage closure with AMPLATZER cardiac plug for stroke prevention in atrial fibrillation: initial Asia-Pacific experience. AB - BACKGROUND: Left atrial appendage (LAA) is the main source of left atrial thrombus that causes stroke in patients with non-valvular atrial fibrillation (NVAF). This study reported the initial safety, feasibility, and 1-yr clinical outcomes following AMPLATZER cardiac plug (ACP) implantation in Asia-Pacific region. METHODS: Twenty NVAF patients (16 males, age 68 +/- 9 yr) with high risk for developing cardioembolic stroke (CHADS(2) score: 2.3 +/- 1.3) and contraindications to warfarin received ACP implants from June 2009 to May 2010. Patients received general anesthesia (n = 9) or controlled propofol sedation (n = 11) and the procedures were guided by fluoroscopy and transesophageal echocardiography (TEE). Clinical follow-up was arranged at 1 month and then every 3 months after implantation, whereas, a TEE was scheduled at 1 month upon completion of dual anti-platelet therapy. RESULTS: The LAA was successfully occluded in 19/20 patients (95%) at two Asian centers. One procedure was abandoned because of catheter-related thrombus formation. Other complications included coronary artery air embolism (n = 1) and TEE-attributed esophageal injury (n = 1). The median procedural and fluoroscopic times were 79 (IQR: 59 100) and 18 (IQR 12-27) minutes, respectively. The mean size of implant was 23.6 +/- 3.1 mm. The average hospital stay was 1.8 +/- 1.1 days. Follow-up TEE showed all the LAA orifices were sealed without device-related thrombus formation. No stroke or death occurred at a mean follow-up of 12.7 +/- 3.1 months. CONCLUSIONS: Our preliminary data suggested LAA closure with ACP is safe, feasible with encouraging 1-yr clinical outcomes. Further large-scaled trials are needed to confirm the efficacy of this device. PMID- 21542103 TI - Pioneer re-entry device for iliac chronic total occlusion: truly a paradigm shift. AB - The number of percutaneous revascularization procedures performed for symptomatic peripheral arterial disease has significantly increased over the past several years. Traditionally, the use of percutaneous techniques were limited to certain anatomic subsets, such as stenosis or focal occlusions, with surgical treatment preferred for more extensive disease. More recently, endovascular specialists are facing the challenge of peripheral chronic total occlusions. Furthermore, unlike the coronary circulation, these occlusions are often very long and associated with other features of complexity such as severe calcifications. One of the primary issues concerning these lesions is the ability to safely achieve initial angiographic success. This article focus indeed on the Pioneer catheter, a new lumen re-entry device exploiting intravascular ultrasound imaging that was used in a case of totally occluded left common iliac artery with favorable results. The details of this technique, and how this catheter helped in re-entering the true lumen at the aortic bifurcation after subintimal dissection, are thoroughly discussed. PMID- 21542104 TI - Noncalcified plaque: relationship between results of multislice computed tomography, risk factors, and late clinical outcome. AB - BACKGROUND: Contrast-enhanced multislice computed tomographic angiography (MSCTA) detects noncalcified plaque (NCP) in coronary arteries and associated coronary stenoses. However, the clinical relevance of NCP is poorly defined. OBJECTIVES: Our goal was to examine the relationship NCP, risk factors (RFs), and clinical follow-up in unselected outpatients undergoing MSCTA. METHODS: Five hundred six patients undergoing contrast MSCTA were evaluated for NCP (intraluminal density 25 < Hounsfield units < 130). One hundred twenty-four patients (24.5%) had calcium scores (CAC) of zero. Of these, 111 patients were examined for RFs and followed clinically for a mean of 34 months. RESULTS: Of 124 patients with zero CAC, 111 (89.5%) included 52 (46.8%) with no NCP, 40 (36.0%) with NCP, and mild luminal stenosis, 14 (12.6%) and 5 (4.5%) with NCP causing significant and severe stenosis, respectively. Patients in each group were similar in age but differed significantly in number of RFs. Current or former smokers, hypertensive, and obese patients had more NCP and associated stenosis. At a mean of 34 months, there were no events in the no NCP group, 2/54 (3.7%) events in the NCP without severe stenosis group (one sudden cardiac death and one ventricular tachycardia), and 2/5 (40.0%) patients had revascularization in the NCP with severe stenosis group. CONCLUSIONS: (1) In patients with zero CAC, presence of NCP on MSCTA was associated with more RFs, especially smoking, obesity, and hypertension. (2) NCP can result in severe coronary stenosis. (3) NCP detected by MSCTA in patients with zero CAC may identify patients with late cardiac events. PMID- 21542105 TI - Subintimal guidewire tracking during successful percutaneous therapy for chronic coronary total occlusions: insights from an intravascular ultrasound analysis. AB - OBJECTIVES: We sought to determine the frequency of subintimal guidewire tracking during successful percutaneous coronary intervention (PCI) for chronic coronary total occlusions (CTOs) and to better understand the procedural implications of this event. BACKGROUND: Successful PCI for chronic CTO is associated with improved outcomes in patients with ischemia. While subintimal guidewire tracking resulting in failure to cross is recognized as the major mode of failure for CTO PCI, the implications of subintimal guidewire tracking during successful CTO PCI are unknown. METHODS: Between March 2007 and October 2007, 26 consecutive patients, each with one de-novo CTO lesion successfully crossed with a guidewire were included in the analysis. Intravascular ultrasound (IVUS) was performed in each CTO vessel after guidewire crossing. Cases were classified as having definite subintimal wire tracking or no clear evidence of subintimal wire tracking based on analysis of IVUS images. RESULTS: Subintimal wire tracking occurred in 45% of cases. In cases where subintimal wire tracking was present, a previous attempt at CTO PCI was more common (42% vs. 7%, P <= 0.05). Subintimal wire tracking was also associated with significantly longer final mean stent length (71 vs. 50 mm), procedure time (122 vs. 69 min), fluoroscopy time (47 vs. 22 min), and contrast dose (300 vs. 199 mL, P <= 0.05 for all). There was one perforation in the subintimal group which was successfully treated with stent placement. CONCLUSIONS: Subintimal wire tracking occurs frequently during successful PCI for CTO and is associated with increased lesion and procedural complexity. PMID- 21542106 TI - Retrograde recanalization of chronic total occlusions from the transradial approach; early Canadian experience. AB - BACKGROUND: Retrograde approach for chronic total occlusions (CTO) improves recanalization success rates. Eight French (Fr) catheters and the femoral approach are advocated. OBJECTIVES: Evaluate whether transradial operators can achieve similar success rates using smaller catheters. METHODS: This is a single operator series of 42 consecutive cases performed between January and December 2010, including 13 while demonstrating CTO recanalization. Patients were referred because of complexity of the CTO or after failed attempt. RESULTS: Most frequent indications for recanalization were CCS 3-4 angina (52%) and CCS 1-2 in 21%. Eighteen (43%) patients underwent previous failed attempts. CTO was in the right coronary in 74%, left anterior descending in 24%, and a left main in 1. Most lesions (88%) were >=20 mm long and 52% were calcified. We used septal collateral channels (CC) in 33 (79%), epicardial CC in 8 (20%), and a saphenous vein graft in one case. Radial access was used in all patients and was bilateral in 37 (88%). Five cases required one radial and one femoral access. Six French guides were used in 91% for the retrograde side and 71% for the antegrade side. Otherwise, 7 Fr guides were used. The Corsair((r)) was used in 38 (90%). Procedural success was achieved in 37 (88%), mostly using reverse controlled antegrade-retrograde tracking (60%) or retrograde crossing (29%). The average <24 h Hb drop was 0.75 +/- 0.84 g/dl. No in-hospital major cardiac events occurred. CONCLUSION: Transradial retrograde CTO recanalization is feasible, safe, and still associated with high success rates despite the use of smaller guide catheters. PMID- 21542107 TI - The "bladder sign"--an important early marker of retroperitoneal hemorrhage. AB - Retroperitoneal hemorrhage remains one of the major complications of cardiac and peripheral vascular catheterization. Its high associated morbidity and mortality require vigilance and early intervention. We report six cases of retroperitoneal hemorrhage featuring a "bladder sign." The compression of the bladder described in this series can be visualized on the incidental cystogram that results from contrast given during catheterization. Its significance as a highly specific marker of retroperitoneal hemorrhage should be appreciated. PMID- 21542108 TI - Catheter conversion of classic Glenn to bidirectional Glenn with closure of left central shunt years after surgical attempts. AB - Bidirectional Glenn shunt is usually performed in patients with single ventricle in preparation for a total cavo-pulmonary connection. We present a patient born with complex congenital heart disease consisting of single ventricle, pulmonary atresia, non confluent pulmonary arteries, and anomalous pulmonary venous return in whom surgical bidirectional Glenn was attempted. After multiple surgical attempts she was converted to a Classic Glenn and a central ascending aorta to left pulmonary artery shunt. Several years later by the aid of radiofrequency wire the occluded pulmonary artery segment was canalized establishing continuity between the two pulmonary artery branches with stenting of the intervening segment. The central shunt to the left pulmonary artery was subsequently embolized. Thus this patient was converted in the catheterization laboratory from the physiology of a classic Glenn to the more preferred bidirectional Glenn physiology. PMID- 21542109 TI - Two-year follow-up of the GenousTM endothelial progenitor cell capturing stent versus the Taxus Liberte stent in patients with de novo coronary artery lesions with a high-risk of restenosis: a randomized, single-center, pilot study. AB - BACKGROUND: In the prospective randomized TRIAS pilot study, the bio-engineered GenousTM endothelial progenitor cell capturing stent was compared with the Taxus LiberteTM SR paclitaxel-eluting stent. At 1 yr, a statistically nonsignificant difference in the rates of target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) was observed. We have evaluated the safety and efficacy up to 2 yr. METHODS: A total of 193 patients with de novo coronary artery lesions carrying a high risk of restenosis were randomized to a Genous stent versus a Taxus stent. Dual antiplatelet therapy was prescribed for >=1 month after Genous stent implantation and for >=6 months after a Taxus stent. RESULTS: Between 1 and 2 yr, patients treated with the Genous stent tended to have fewer episodes of target lesion revascularization (2.0% versus 5.3%), but nearly similar rates of cardiac death (1.0% versus 0%), myocardial infarction (0% versus 1.1%), and stent thrombosis (0% versus 1.1%) when compared with the Taxus stent. As a result, at 2-yr follow-up treatment with the Genous stent compared with the Taxus stent resulted in a nonsignificant difference in target vessel failure (TVR) (20.4% versus 15.8%; risk difference 4.6%, 95% CI -6.2-15.5%). No stent thrombosis was observed in the Genous group compared to five cases (in four patients) in the Taxus group, resulting in a difference as compared with the Taxus stent (risk difference -4.2%; 95%CI -8.2% to -0.2%). CONCLUSIONS: In the TRIAS pilot study, treatment of coronary artery lesions carrying a high risk of restenosis with the Genous compared with the Taxus stent resulted in a nonsignificant difference of TVR at 2-yr follow-up, with convergence of the Kaplan-Meier curves between 1 and 2 yr. Stent thrombosis was only observed after Taxus stent implantation. PMID- 21542110 TI - Mid-term outcomes of carotid artery stenting in patients with angiographic string sign. AB - OBJECTIVES: To report on early and mid-term outcomes of carotid artery stenting (CAS) in patients with angiographic string sign (SS). BACKGROUND: Little is known about the prognosis of patients with carotid SS treated by CAS. METHODS: We retrospectively evaluated early and mid-term outcomes, together with ultrasound findings, in patients with SS treated by CAS at our institution. RESULTS: Of 308 CAS procedures, SS was diagnosed in 6.2% (19 patients, 58% symptomatic). Carotid stent implantation was successful in 18 patients (success rate 95%). There were no peri-procedural adverse events. One patient suffered from a transient ischemic attack during hospitalization and died of pneumonia. All remaining patients completed a 30-day follow-up, and no complications were reported (asymptomatic restenosis was diagnosed in 1 patient and successfully redilated). Six patients died of causes unrelated to CAS (pneumonia, decompensated heart failure, and contralateral stroke) before completing a 6-month follow-up. However, these patients presented with more pronounced, unfavorable clinical and angiographic characteristics compared to the rest of the patients. CONCLUSIONS: We suggest that CAS might be performed with acceptable procedural risk in patients presenting with SS, which is unsuitable for surgery. However, patients' clinical and angiographic characteristics must be carefully evaluated when considering interventional therapy, regardless of the favorable procedural outcomes. PMID- 21542111 TI - Seven-year safety and efficacy of the unrestricted use of drug-eluting stents in saphenous vein bypass grafts. AB - OBJECTIVES: The aim was to investigate the 7-year clinical outcomes of patients treated with either drug-eluting stents (DES) or bare-metal stents (BMS) for saphenous vein graft disease (SVG). BACKGROUND: Atherosclerotic disease in SVG has several peculiarities which make it difficult to extrapolate outcomes of the use of DES as compared to BMS, from outcomes observed in native coronary arteries. To date no long-term safety and efficacy results for DES in SVG have been published. METHODS: Between January, 2000 and December, 2005 a total of 250 consecutive patients with saphenous vein graft disease were sequentially treated with DES (either sirolimus- or paclitaxel-eluting stents) or with BMS. Yearly follow-up was performed. RESULTS: At 87 months (7.25 years), a total of 101 patients died (58 [46%] in the BMS group and 43 [42%] in the DES group, P-value= 0.4). There was no significant difference in the combined endpoint mortality or myocardial infarction. Cumulative target vessel revascularisation (TVR) was higher in the BMS group compared to the DES group (41% vs. 29%, respectively; adjusted hazard ratio [HR] 0.63, 95% confidence interval [CI]: 0.39-1.0). The cumulative incidence of major adverse cardiac events was 73% vs. 68% in the BMS and DES groups, respectively (adjusted HR 0.93, 95% CI: 0.67-1.3). CONCLUSIONS: In the present study, the unrestricted use of DES for SVG lesions appeared safe and effective up to 7.25 years- and the use of DES resulted in a clinically relevant lower rate of TVR. PMID- 21542112 TI - Recanalization and reuse of early occluded radial artery within 6 days after previous transradial diagnostic procedure. PMID- 21542113 TI - Economic outcomes of percutaneous coronary intervention with drug-eluting stents versus bypass surgery for patients with left main or three-vessel coronary artery disease: one-year results from the SYNTAX trial. AB - OBJECTIVES: To evaluate the cost-effectiveness of alternative approaches to revascularization for patients with three-vessel or left main coronary artery disease (CAD). BACKGROUND: Previous studies have demonstrated that, despite higher initial costs, long-term costs with bypass surgery (CABG) in multivessel CAD are similar to those for percutaneous coronary intervention (PCI). The impact of drug-eluting stents (DES) on these results is unknown. METHODS: The SYNTAX trial randomized 1,800 patients with left main or three-vessel CAD to either CABG (n = 897) or PCI using paclitaxel-eluting stents (n = 903). Resource utilization data were collected prospectively for all patients, and cumulative 1-year costs were assessed from the perspective of the U.S. healthcare system. RESULTS: Total costs for the initial hospitalization were $5,693/patient higher with CABG, whereas follow-up costs were $2,282/patient higher with PCI due mainly to more frequent revascularization procedures and higher outpatient medication costs. Total 1-year costs were thus $3,590/patient higher with CABG, while quality adjusted life expectancy was slightly higher with PCI. Although PCI was an economically dominant strategy for the overall population, cost-effectiveness varied considerably according to angiographic complexity. For patients with high angiographic complexity (SYNTAX score > 32), total 1-year costs were similar for CABG and PCI, and the incremental cost-effectiveness ratio for CABG was $43,486 per quality-adjusted life-year gained. CONCLUSIONS: Among patients with three vessel or left main CAD, PCI is an economically attractive strategy over the first year for patients with low and moderate angiographic complexity, while CABG is favored among patients with high angiographic complexity. PMID- 21542114 TI - Prevention of contrast-induced acute kidney injury in patients with stable chronic renal disease undergoing elective percutaneous coronary and peripheral interventions: randomized comparison of two preventive strategies. AB - OBJECTIVE: We compared use of intravenous (IV) normal saline (NS) to sodium bicarbonate (NaHCO(3)) with or without oral N-acetylcysteine (NAC) for prevention of contrast-induced acute kidney injury (CI-AKI). BACKGROUND: CI-AKI is associated with significant adverse clinical events. Use of NAC has produced variable results. Recently, intravenous hydration with NaHCO(3) for CI-AKI prophylaxis has been adopted as standard treatment for patients with stable chronic renal disease undergoing catheterization procedures. METHODS: We prospectively enrolled 320 patients with baseline renal insufficiency scheduled to undergo catheterization. Patients were randomly assigned to receive either IV NS +/- NAC (n = 161) or IV dextrose 5% in water containing 154 mEq/l of NaHCO(3) +/- NAC (n = 159). IV NS was administered at 1 ml/kg body weight for 12 hr preprocedure and 12 more hr postprocedure. IV NaHCO(3) was administered at 3 ml/kg body weight for 1 hr preprocedure followed by 1 ml/kg body weight postprocedure. A 1,200 mg oral dose of NAC was given 2-12 hr preprocedure and 6 12 hr postprocedure in 50% of patients in each study arm. CI-AKI was defined as an increase of >0.5 mg/dl or >25% above baseline creatinine. RESULTS: Overall incidence of CI-AKI was 10.3%. There was no significant difference in incidence among the two groups (NS +/- NAC 11.8% vs. NaHCO(3) +/- NAC 8.8%, p = ns). Incidence of CI-AKI increased with increasing age (p = 0.001), contrast agent use >3 ml/kg body weight (p = 0.038) and diuretic use (p = 0.005). CONCLUSION: Incidence of CI-AKI was no different in the NaHCO(3) group compared to NS group, and NAC did not reduce CI-AKI in the two study arms. PMID- 21542115 TI - Hybrid peratrial double device closure of a patent foramen ovale and sinus venosus defect in an infant with vein of Galen malformation. AB - Vein of Galen aneurysmal malformation is the most common cerebral arteriovenous malformation in children. Neurointerventional embolization has improved outcomes with this lesion. An association with cardiac defects has been recognized and can increase the risk of systemic embolic events during treatment. Cardiopulmonary bypass (CPB) to correct the cardiac defect before repair of the malformation may be associated with compromised cerebral perfusion and possible neurologic injury. We describe a successful hybrid peratrial closure of two intracardiac shunts (a patent foramen ovale and a sinus venosus ASD) before neurointervention, avoiding CPB, and eliminating the intracardiac embolic risk during treatment of the vein of Galen malformation. PMID- 21542116 TI - Mid-term follow up of perventricular device closure of muscular ventricular septal defects. AB - BACKGROUND: Surgical and transcatheter management of muscular ventricular septal defects (MVSD) have independent drawbacks. Hybrid procedures are becoming increasingly utilized to manage congenital cardiac lesions including MVSDs. This report describes the mid-term results of perventricular device closure of MVSDs at a single institution. METHODS: The cardiology database of patients who underwent attempted perventricular MVSD closure from a single institution was reviewed. RESULTS: Between January 2004 and December 2009, six patients underwent attempted perventricular MVSD closure in the operating room. Mean age was 9.8 +/- 9.1 months; mean weight was 7.2 +/- 3.7 kg. In five patients, closure was successful without use of bypass. In one patient, the device embolized to the left ventricle after release and patch closure of the MVSD was performed on cardiopulmonary bypass. The mean interval from the procedure to the most recent echocardiogram for the patients with successful perventricular closure was 39.8 +/- 25.2 months. Three patients demonstrated no residual shunt at the last echocardiogram. Two patients had mild, hemodynamically insignificant shunting; one had a left ventricular pseudoaneurysm that was embolized during repeat catheterization. CONCLUSIONS: Perventricular closure of MVSDs is attractive because it overcomes the limitations of surgery and catheterization. Additionally, it spares the need for cardiopulmonary bypass and its comorbidities. In some instances, however, successful deployment of the device is not possible. Our mid-term results demonstrate overall success but identify possible complications that are not immediately identified in the short term. PMID- 21542117 TI - Incidence and treatment of local stenosis or occlusion at the vascular access site leading to limb ischemia and new-onset intermittent claudication after percutaneous interventions: implications of vascular closure devices. AB - OBJECTIVE: Vascular access site complications (ASCs) are an ongoing hazard of percutaneous interventions (PI). We analyzed incidence, indication, and results of operative repair of access site complications leading to acute limb ischemia (ALI) or new-onset severe claudication (CI) in our institution during an 8-year period. METHODS: Retrospective analysis: demographic parameters, details of coronary or vascular intervention, use of a vascular closure device (VCD), clinical presentation, diagnosis and therapy. ENDPOINTS: perioperative outcome (death, limb loss, and need for re-operation/intervention) and length of hospital stay. For comparison of annual operation rates, patients were grouped by the years 2001 to 2004 (no use of VCD) and 2005 to 2008 (selective use of a VCD; in all cases: Angio-Seal), and Chi-Square-test was applied. RESULTS: Fifty-one patients (19 female; median age: 64.5 years) underwent repair of arterial ASCs causing ALI (n = 32) or new-onset severe CI (n = 19) after 58,453 catheter interventions (overall rate: 0.087%; ALI: 0.055%; CI: 0.032%). Corresponding with more widespread VCD use, the annual number of ALI and new onset CI increased significantly (P < 0.001). PERIOPERATIVE OUTCOME: 30 day mortality was 4%. No limb loss occurred. Re-operations were indicated in 10 patients (20%) for: hematoma (n = 5), local infection (n = 3), revision of fasciotomy (n = 1), and repeated thrombectomy (n = 1). Median length of postoperative hospital stay: 7 days (range: 1-28). CONCLUSION: ALI and new-onset severe CI due to access site complications after PI are rare, however, they are potentially threatening life and limb. The use of VCDs results in an overall increase of ischemic complications. PMID- 21542118 TI - Antegrade rewiring of the retrograde Corsair catheter during revascularization of chronic total coronary occlusions: a simple alternative to guidewire exteriorization. AB - Chronic total occlusions prevent a significant challenge to interventional cardiologists. Successful opening of chronically occluded vessels has been shown to be associated with decreased mortality and morbidity. Recently, the retrograde approach to chronic total occlusion intervention has been developed. In this case series, we present a novel technique to assist with this procedure involving antegrade wiring of a retrograde microcatheter. PMID- 21542119 TI - Idiopathic mediastinal fibrosis with involvement of the pulmonary vessels and left main coronary artery. AB - Idiopathic mediastinal fibrosis (IMF) is an uncommon clinical condition and the manifestations of this disease vary from a relatively benign disorder with minor symptoms to severe pulmonary vascular occlusion leading to mortality, commonly presenting a diagnostic and therapeutic challenge. Here, we present the case of a Taiwanese woman with obstruction of the left pulmonary veins and artery and stenosis of the left main coronary artery (LMCA) resulting from IMF. To our knowledge, this is the first reported case of IMF successfully treated with percutaneous balloon angioplasty with stent placement for the LMCA stenosis. PMID- 21542120 TI - Rescue "valve in valve" implantation after late onset CoreValve cusp rupture leading to acute massive aortic insufficiency. AB - Transcatheter aortic valve implantation (TAVI) has emerged as a feasible and effective alternative to aortic valve replacement in patients at high surgical risk, and is associated with a lower risk of death at 1 year follow-up when compared with standard therapy. In a recent large study, enrolling 663 high risk patients with symptomatic severe aortic stenosis TAVI with the use of CoreValve system has been associated with early and sustained clinical and hemodynamic benefits, with a cumulative mortality of 15.0% at 1 year follow-up. This study has shown that paravalvular aortic regurgitation after successful TAVI is a frequent finding, being of mild entity in the vast majority of cases, whereas valvular regurgitation is almost entirely absent or mild. Of note, no cases of structural valve deterioration were reported. We report a case of a successful implantation of a CoreValve that complicated with late onset massive intravalvular aortic regurgitation, due to CoreValve cusp rupture, leading to low output state with acute pulmonary edema, which was successfully treated with "valve in valve" implantation. PMID- 21542121 TI - Duration of dual antiplatelet therapy and outcomes after coronary stenting with the GenousTM bio-engineered R stentTM in patients from the e-HEALING registry. AB - OBJECTIVE: We investigated the relation between duration of dual antiplatelet therapy (DAPT) and clinical outcomes up to 12 months after GenousTM endothelial progenitor cell capturing R stentTM placement in patients from the e-HEALING registry. BACKGROUND: Cessation of (DAPT) has been shown to be associated with the occurrence of stent thrombosis (ST). After Genous placement, 1 month of DAPT is recommended. METHODS: Patients were analyzed according to continuation or discontinuation of DAPT at a 30-day and 6-month landmark, excluding patients with events before the landmark. Each landmark was a new baseline, and outcomes were followed up to 12 months after stenting. The main outcome for our current analysis was target vessel failure (TVF), defined as target vessel-related cardiac death or myocardial infarction and target vessel revascularization. Secondary outcomes included ST. (Un)adjusted hazard ratios (HR) for TVF were calculated with Cox regression. RESULTS: No difference was observed in the incidence of TVF [HR: 1.03; 95% confidence intervals (CI): 0.65-1.65, P = 0.89] in patients continuing DAPT (n = 4,249) at 30 days versus patients stopped (n = 309), and HR: 0.82 (95% CI: 0.55-1.23, P = 0.34) in patients continuing DAPT (n = 2,654) at 6 months versus patients stopped [n = 1,408] DAPT). Furthermore, no differences were observed in ST. Even after addition of identified independent predictors for TVF, adjusted TVF hazards were comparable. CONCLUSIONS: In a post hoc analysis of e-HEALING, duration of DAPT was not associated with the occurrence of the outcomes TVF or ST. The Genous stent may be an attractive treatment especially in patients at increased risk for (temporary) cessation of DAPT or bleeding. PMID- 21542122 TI - A randomized trial of intravenous n-acetylcysteine to prevent contrast induced nephropathy in acute coronary syndromes. AB - BACKGROUND: Pharmacokinetic data suggests that the intravenous form of n acetylcysteine (NAC) may be more effective than the oral formulation in preventing contrast induced nephropathy (CIN). NAC owing to its anti-oxidant properties might be beneficial for patients with acute coronary syndromes (ACS) who are at increased risk for CIN. The aim of this prospective randomized, single center, double-blind, placebo controlled trial (NCT00939913) was to assess the effect of high-dose intravenous NAC on CIN in ACS patients undergoing coronary angiography and/or percutaneous coronary intervention (PCI). METHODS: We randomized 398 ACS patients scheduled for diagnostic angiography +/- PCI to an intravenous regimen of high-dose NAC (1,200 mg bolus followed by 200 mg/hr for 24 hr; n = 206) or placebo (n = 192). The primary end-point was incidence of CIN defined as an increase in serum creatinine concentration >= 25% above the baseline level within 72 hr of the administration of intravenous contrast. RESULTS: There was no difference found for the primary end point with CIN in 16% of the NAC group and in 13% of the placebo group (p = 0.40). Change in serum cystatin-C, a sensitive marker for renal function, was 0.046 +/- 0.204 in the NAC group and 0.002 +/- 0.260 in the control group (p = 0.07). CONCLUSION: In ACS patients undergoing angiography +/- PCI, high-dose intravenous NAC failed to reduce the incidence of CIN. PMID- 21542123 TI - A single center experience with same-day transradial-PCI patients: a contrast with published guidelines. AB - OBJECTIVES: Our goal was to compare recently published Consensus Statement from the SCAI/ACC on appropriateness for same-day PCI with patient characteristics from a real-world same-day PCI experience in the United States. BACKGROUND: Recent practice statement published by the SCAI /ACC in 2009 describes patients suitable for outpatient PCI procedures. Whether this practice statement reflects actual real-world practice in the setting of advances in transradial catheterization needs further exploration. METHODS: Pre-existing, deidentified, quality assurance data from 100 sequential patients undergoing transradial PCI, and same-day discharge were compared with criteria in SCAI/ACC statement on outpatient PCI. Each had been identified post-PCI as uncomplicated and therefore eligible for same day discharged. Specific attention was placed on whether the patients carried any exclusion to same-day discharge. RESULTS: One hundred six procedures were recorded in 100 patients including 11 women and 89 men, median age 62 (55,71) years all with stable ischemia. Early follow up was done for medication compliance. None were readmitted nor had post-PCI complications. Only 15% met appropriateness criteria for same-day discharge. Older age, distance from the hospital, greater than simple PCI, and the need for specific antiplatelet therapy represented the dominant contraindications to discharge. CONCLUSIONS: Using transradial approaches and structured early follow up by advance practice nurses, same-day discharge can be accomplished successfully in a broad range of patients outside of those suggested by the SCAI/ACC 2009 Consensus Document. Confirmation of these results could result in shorter hospitalizations for US patients and align advances in catheterization technology to optimize heath care delivery. PMID- 21542124 TI - Hybrid therapy for interrupted aortic arch with aortopulmonary window in a low birth weight infant. AB - Interrupted aortic arch (IAA) is rarely associated with aortopulmonary window. Single-stage total correction is the preferred therapeutic option. When total correction is unfeasible, staged repair could be the therapeutic choice. Here, we presented a low birth weight infant who underwent bilateral pulmonary arteries banding and stenting ductus arteriosus by hybrid procedure. Hybrid procedure avoids long-term central line insertion and guarantees ductal flow. It also avoids the side effects from prostaglandin infusion. PMID- 21542125 TI - A new strategy for septal ablation with transendocardial ethanol injection using a multifunctional intracardiac echocardiography catheter: a feasibility study in canines. AB - OBJECTIVES: To evaluate the feasibility and safety of a novel multifunctional intracardiac echocardiography catheter for target septal ablation with transendocardial ethanol injection in canines. BACKGROUND: Percutaneous transluminal septal myocardial ablation has been the primary catheter-based strategy for the treatment of hypertrophic obstructive cardiomyopathy (HOCM). However, inherent limitations of the technique have reduced its therapeutic efficacy. METHODS: A new catheter (10 F), integrated with a nitinol needle (29 G) and a 6.5-10-MHz, 32-element, side-fire ultrasound imaging transducer, was delivered into the right ventricle in nine canines and the left ventricle in three canines. A 0.3-ml microbubble and 0.5-1.5 ml absolute ethanol were sequentially injected into the interventricular septum. Electrocardiograph recordings were obtained during the whole procedure. Three hours after this operation, the heart was harvested for gross and histological examination. RESULTS: In all canines, the catheter provided the structural support and helped guide proper needle position within the septum. The microbubble further allowed the confirmation of the needle location through focal echo-density enhancement. Different amounts of ethanol infusion produced a dose-related effect on myocardial ablation. Macroscopic examination showed that the target myocardium became pale with a distinct border between lesions and normal tissue. Hematoxylin and eosin staining further confirmed necrosis within the injection region. CONCLUSIONS: Transendocardial ethanol injection at the interventricular septum resulted in controlled myocardial infarction. In addition, the injection depth could be visually followed using this new system, which may provide a safer and more intuitive method for the treatment of HOCM or other cardiomyopathies. PMID- 21542126 TI - Transcatheter closure of a mechanical perivalvular leak using real-time three dimensional transesophageal echocardiography guidance. AB - A 47-year-old female with symptomatic mitral stenosis from a prior undersized mitral annuloplasty ring underwent mitral valve replacement with a mechanical valve. Later, she developed heart failure from a severe paravalvular leak (PVL). Because of the excessive mortality risks from a possible third open heart procedure, the patient was instead referred for transcatheter PVL closure. Standard fluoroscopy, invasive hemodynamics, and two-dimensional (2D) and three dimensional (3D) transesophageal echocardiography (TEE) imaging were performed during device placement with excellent image quality. The case highlights the unique benefit of 3D TEE imaging for preprocedure sizing, guidance of device deployment intraprocedure, and confirmation of PVL closure. PMID- 21542127 TI - Complement C4d immunohistochemistry in the assessment of liver allograft biopsy samples: applications and pitfalls. PMID- 21542128 TI - Beneficial effects of supplementation with branched-chain amino acids on postoperative bacteremia in living donor liver transplant recipients. AB - The aim of this study was to investigate the effects of preoperative oral supplementation with branched-chain amino acids (BCAAs) on postoperative bacteremia after living donor liver transplantation (LDLT) for chronic liver failure. Two hundred thirty-six patients who underwent adult-to-adult LDLT were evaluated in this retrospective study. The patients were divided into 2 groups: those who received oral supplementation with BCAAs before transplantation (the BCAA group; n = 129) and those who did not (the non-BCAA group; n = 107). Before the LDLT indication was determined, BCAA supplementation was prescribed by a hepatologist to preserve hepatic reserves. The clinical characteristics and the incidence of bacteremia were compared between the 2 groups. As for clinical characteristics, the Child-Pugh scores (P = 0.0003) and the Model for End-Stage Liver Disease scores (P = 0.0008) were significantly higher in the BCAA group versus the non-BCAA group. The incidence of bacteremia for Child-Pugh class C patients was significantly lower in the BCAA group (6/90 or 6.7%) versus the non BCAA group (11/50 or 22.0%, P = 0.0132). In a multivariate analysis, non-BCAA supplementation was an independent risk factor for bacteremia. In conclusion, preoperative BCAA supplementation might reduce the incidence of bacteremia after LDLT. Nevertheless, this is a preliminary report, and further studies, such as randomized, prospective studies, are necessary to clarify the beneficial effects of BCAA supplementation on postoperative bacteremia after liver transplantation. PMID- 21542129 TI - Growth of hepatocellular carcinoma in the regenerating liver. AB - Liver resection and liver transplantation are the treatment modalities with the greatest potential for curing hepatocellular carcinoma (HCC). Tumor recurrence after resection for HCC is, however, a major problem, and an increased rate of recurrence after living donor transplantation versus cadaveric whole liver transplantation has been suggested. Factors involved in liver regeneration may stimulate the growth of occult tumors. The aim of this project was to test the hypothesis that a microscopic HCC tumor in the setting of partial hepatectomy would show enhanced growth and signs of increased invasiveness corresponding to the size of the liver resection. Hepatectomy was performed to various degrees in groups of Buffalo rats with the concomitant implantation of a fixed number of hepatoma cells in the remnant liver; a control group underwent only resection. After 21 days, the sizes and numbers of the tumors and the expression of alpha fetoprotein (AFP), cyclin D1, calpain small subunit 1 (CAPNS1), CD34 (a microvessel density marker), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor 2 (VEGFR2) were evaluated and compared between the groups. The tumor volume and number increased significantly with the size of the partial hepatectomy (P < 0.05). The largest resections were also associated with increased hepatoma cell infiltration in the lungs and significant up-regulation of cyclin D1, AFP, CAPNS1, CD34, VEGF, and VEGFR2. The results suggest that liver regeneration after partial hepatectomy facilitates the growth and malignant transformation of microscopic HCC, and this could be significant for liver resection and partial liver transplantation strategies for HCC. PMID- 21542130 TI - Impact of portal venous hemodynamics on indices of liver function and graft regeneration after right lobe living donor liver transplantation. AB - The aim of this study was to evaluate the effects of portal hemodynamics on indices of liver function and graft regeneration in patients after adult right lobe living donor liver transplantation (R-LDLT). Sixty-four patients who underwent R-LDLT and had an uneventful postoperative course were enrolled in this study. The contribution of portal flow was greater to the recipient grafts versus the donor livers (90.74% versus 69.12%, P < 0.0001). Portal flow variations decreased significantly during the first 10 days after R-LDLT (P < 0.0001); variations in the hepatic arterial flow were more constant during this period (P = 0.812). The mean portal venous pressure (PVP) before recipient hepatectomy (the initial PVP) was 23.1 +/- 4.0 mm Hg; the mean PVP after reperfusion (the final PVP) was 15.0 +/- 4.3 mm Hg (P < 0.0001). Furthermore, the mean hepatic portal venous gradient (ie, PVP - central venous pressure) before recipient hepatectomy was 17.1 +/- 4.3 mm Hg; it decreased to 10.6 +/- 4.5 mm Hg after reperfusion (P < 0.0001). These findings suggest that after graft reperfusion, the vascular resistance of the hepatic parenchyma decreased, and there was an associated mild decrease in the portal hypertension. Multiple regression analysis indicated that PVPs correlated significantly with indices of liver function after living donor liver transplantation (P < 0.05). Patients were separated into 4 groups according to their PVP values: group A (initial PVP >= 23 mm Hg, final PVP >= 15 mm Hg), group B (initial PVP < 23 mm Hg, final PVP >= 15 mm Hg), group C (initial PVP >= 23 mm Hg, final PVP < 15 mm Hg), and group D (initial PVP < 23 mm Hg, final PVP < 15 mm Hg). Immediately after R-LDLT, the peak values for aspartate aminotransferase, alanine aminotransferase, the international normalized ratio and the average ascites production varied appreciably in these groups. The regeneration rate of the liver graft 3 months after R-LDLT was significantly greater in group A versus the other groups. In conclusion, PVP is a significant hemodynamic factor that influences the functional status of the liver and graft regeneration after R-LDLT. PMID- 21542131 TI - Beyond the GWAS in schizophrenia. PMID- 21542133 TI - Novel 2-substituted quinolin-4-yl-benzenesulfonate derivatives: synthesis, antiproliferative activity, and inhibition of cellular tubulin polymerization. AB - A series of 2-substituted quinolin-4-yl-benzenesulfonate derivatives were synthesized for the purpose of evaluating antiproliferative activity. Structure activity relationships of the newly synthesized compounds against human lymphoblastic leukemia and various solid tumor cell growths in culture are discussed. Of these derivatives, 2-phenyl-6-pyrrolidinyl-4-quinoline sulfonate analogues 10 f, 10 g, and 10 k, and 4'-nitrophenyl sulfonate 10 m exhibit superior cytotoxicity over other sulfonates. The antiproliferative activities of these compounds correlate well with their abilities to induce mitotic arrest and apoptosis. Mechanistic studies indicate that they target the vinblastine binding site of tubulin and inhibit cellular tubulin polymerization. Hence, these compounds induce the formation of aberrant mitotic spindles and mitotic arrest, resulting in intensive apoptosis. The tested compounds were shown to be poor substrates for membrane multidrug resistance transporters. The present studies suggest that these newly synthesized compounds are promising tubulin polymerization inhibitors and are worthy of further investigation as antitumor agents. PMID- 21542132 TI - SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing. AB - The stratum corneum (SC), the outermost layer of the epidermis, acts as a barrier against the external environment. It is hydrated by endogenous humectants to avoid desiccation. However, the molecular mechanisms of SC hydration remain unclear. We report that skin-specific retroviral-like aspartic protease (SASPase) deficiency in hairless mice resulted in dry skin and a thicker and less hydrated SC with an accumulation of aberrantly processed profilaggrin, a marked decrease of filaggrin, but no alteration in free amino acid composition, compared with control hairless mice. We demonstrated that recombinant SASPase directly cleaved a linker peptide of recombinant profilaggrin. Furthermore, missense mutations were detected in 5 of 196 atopic dermatitis (AD) patients and 2 of 28 normal individuals. Among these, the V243A mutation induced complete absence of protease activity in vitro, while the V187I mutation induced a marked decrease in its activity. These findings indicate that SASPase activity is indispensable for processing profilaggrin and maintaining the texture and hydration of the SC. This provides a novel approach for elucidating the complex pathophysiology of atopic dry skin. PMID- 21542134 TI - Expression and rapid experience-dependent regulation of type-A GABAergic receptors in the songbird auditory forebrain. AB - GABAergic transmission influences sensory processing and experience-dependent plasticity in the adult brain. Little is known about the functional organization of inhibitory circuits in the auditory forebrain of songbirds, a robust model extensively used in the study of central auditory processing of behaviorally relevant communication signals. In particular, no information is currently available on the expression and organization of GABAA receptor-expressing neurons. Here, we studied the distribution and regulation of GABAA receptors in the songbird auditory forebrain, with a specific focus on alpha5, a subunit implicated in tonic inhibition and sensory learning. We obtained a zebra finch cDNA that encodes the alpha5-subunit (GABRA5) and carried out a detailed analysis of its expression via in situ hybridization. GABRA5 was highly expressed in the caudomedial nidopallium (NCM), caudomedial mesopallium, and field L2. Using double fluorescence in situ hybridization, we demonstrate that a large fraction of GABRA5-expressing neurons is engaged by auditory experience, as revealed by the song-induced expression of the activity-dependent gene zenk. Remarkably, we also found that alpha5 expression is rapidly regulated by sensory stimulation: 30 min of conspecific song playbacks significantly increase the number of GABRA5 expressing neurons in NCM, but not in other auditory areas. This effect is selective for alpha5, but not gamma2 transcripts. Our results suggest that alpha5 containing GABAA receptors likely play a key role in central auditory processing and may contribute to the experience-dependent plasticity underlying auditory learning. PMID- 21542135 TI - Ectoplasm, ghost in the R cell machine? AB - Drosophila photoreceptors (R cells) are an extreme instance of sensory membrane amplification via apical microvilli, a widely deployed and deeply conserved operation of polarized epithelial cells. Developmental rotation of R cell apices aligns rhabdomere microvilli across the optical axis and enables enormous membrane expansion in a new, proximal distal dimension. R cell ectoplasm, the specialized cortical cytoplasm abutting the rhabdomere is likewise enormously amplified. Ectoplasm is dominated by the actin-rich terminal web, a conserved operational domain of the ancient vesicle-transport motor, Myosin V. R cells harness Myosin V to move two distinct cargoes, the biosynthetic traffic that builds the rhabdomere during development, and the migration of pigment granules that mediates the adaptive "longitudinal pupil" in adults, using two distinct Rab proteins. Ectoplasm further shapes a distinct cortical endosome compartment, the subrhabdomeral cisterna (SRC), vital to normal cell function. Reticulon, a protein that promotes endomembrane curvature, marks the SRC. R cell visual arrestin 2 (Arr2) is predominantly cytoplasmic in dark-adapted photoreceptors but on illumination it translocates to the rhabdomere, where it quenches ongoing photosignaling by binding to activated metarhodopsin. Arr2 translocation is "powered" by diffusion; a motor is not required to move Arr2 and ectoplasm does not obstruct its rapid diffusion to the rhabdomere. PMID- 21542136 TI - Dicer is required for the maintenance of notch signaling and gliogenic competence during mouse retinal development. AB - MicroRNAs (miRNAs) are 19-25 nucleotide RNAs that regulate messenger RNA translation and stability. Recently, we performed a conditional knockout (CKO) of the miRNA-processing enzyme Dicer during mouse retinal development and showed an essential role for miRNAs in the transition of retinal progenitors from an early to a late competence state (Georgi and Reh [2010]: J Neurosci 30:4048-4061). Notably, Dicer CKO progenitors failed to express Ascl1 and generated ganglion cells beyond their normal competence window. Because Ascl1 regulates multiple Notch signaling components, we hypothesized that Notch signaling is downregulated in Dicer CKO retinas. We show here that Notch signaling is severely reduced in Dicer CKO retinas, but that retinal progenitors still retain a low level of Notch signaling. By increasing Notch signaling in Dicer CKO progenitors through constitutive expression of the Notch intracellular domain (NICD), we show that transgenic rescue of Notch signaling has little effect on the competence of retinal progenitors or the enhanced generation of ganglion cells, suggesting that loss of Notch signaling is not a major determinant of these phenotypes. Nevertheless, transgenic NICD expression restored horizontal cells, suggesting an interaction between miRNAs and Notch signaling in the development of this cell type. Furthermore, while NICD overexpression leads to robust glial induction in control retinas, NICD overexpression was insufficient to drive Dicer-null retinal progenitors to a glial fate. Surprisingly, the presence of transgenic NICD expression did not prevent the differentiation of some types of retinal neurons, suggesting that Notch inactivation is not an absolute requirement for the initial stages of neuronal differentiation. PMID- 21542138 TI - Improved assessment of ex vivo brainstem neuroanatomy with high-resolution MRI and DTI at 7 Tesla. AB - The aim of the present work was to provide the topography of the main gray nuclei and white matter tracts of the human brainstem at 7 Tesla (7 T) high-field magnetic resonance imaging (MRI) using structural imaging (T1) and diffusion tensor imaging (DTI). Both imaging techniques represent a new field of increasing interest for its potential neuroanatomic and neuropathologic value. Brainstems were obtained postmortem from human donors, fixated by intracarotid perfusion of 10% neutral buffered formalin, and scanned in a Bruker BioSpec 7 T horizontal scanner. 3D-data sets were acquired using the modified driven equilibrium Fourier transform (MDEFT) sequence and Spin Echo-DTI (SE-DTI) sequence was used for DTI acquisition. High-resolution structural MRI and DTI of the human brainstem acquired postmortem reveals its basic cyto- and myeloar-chitectonic organization, only visualized to this moment by histological techniques and higher magnetic field strengths. Brainstem structures that are usually not observed with lower magnetic fields were now topographically identified at midbrain, pons, and medullar levels. The application of high-resolution structural MRI will contribute to precisely determine the extension and topography of brain lesions. Indeed, the current findings will be useful to interpret future high-resolution in vivo MRI studies in living humans. PMID- 21542139 TI - Intracellular trafficking of histone deacetylase 4 regulates long-term memory formation. AB - Histone acetylation is important for gene transcription, which is controlled by the balance between two kinds of opposing enzymes: histone acetyltransferases and histone deacetylases (HDACs). HDACs repress gene transcription by decreasing histone acetylation levels. Our hypothesis was that shuttling of Class II HDACs, such as HDAC4, between the nucleus and cytoplasm is critical for its function. We constructed mutants of mammalian HDAC4 that had different cellular locations and checked their function during memory formation using Caenorhabditis elegans as a model. The deletion of hda4, a homolog of HDAC4, was able to enhance learning and long-term memory (LTM) in a thermotaxis model. Transgenic experiments showed that mammalian wild-type HDAC4 rescued the phenotype of hda4-deleted worms but impaired LTM formation in wild-type worms. The cytosol-localized HDAC4 mutant was not able to alter the phenotype of knock-out worms but led to enhanced LTM formation in wild-type worms similar to hda4-deletion mutants. Constitutive nuclear localization of HDAC4 rescued the phenotype of deletion worms similar to wild-type HDAC4 but had no effect on wild-type worms. These results support our hypothesis that HDAC4's biological function is regulated by its intracellular distribution. PMID- 21542137 TI - Developmental mechanisms that regulate retinal ganglion cell dendritic morphology. AB - One of the fundamental features of retinal ganglion cells (RGCs) is that dendrites of individual RGCs are confined to one or a few narrow strata within the inner plexiform layer (IPL), and each RGC synapses only with a small group of presynaptic bipolar and amacrine cells with axons/dendrites ramified in the same strata to process distinct visual features. The underlying mechanisms which control the development of this laminar-restricted distribution pattern of RGC dendrites have been extensively studied, and it is still an open question whether the dendritic pattern of RGCs is determined by molecular cues or by activity dependent refinement. Accumulating evidence suggests that both molecular cues and activity-dependent refinement might regulate RGC dendrites in a cell subtype specific manner. However, identification of morphological subtypes of RGCs before they have achieved their mature dendritic pattern is a major challenge in the study of RGC dendritic development. This problem is now being circumvented through the use of molecular markers in genetically engineered mouse lines to identify RGC subsets early during development. Another unanswered fundamental question in the study of activity-dependent refinement of RGC dendrites is how changes in synaptic activity lead to the changes in dendritic morphology. Recent studies have started to shed light on the molecular basis of activity-dependent dendritic refinement of RGCs by showing that some molecular cascades control the cytoskeleton reorganization of RGCs. PMID- 21542140 TI - Overexpression of Lewis(y) antigen protects ovarian cancer RMG-1 cells from carboplatin-induced apoptosis by the upregulation of Topo-I and Topo-II beta. AB - Lewis (y) antigen, a difucosylated oligosaccharide, has been shown to be associated with malignant properties of ovarian carcinomas. In this study, we have investigated the potential role of Lewis (y) antigen, which was stably transfected into ovarian cancer RMG-1 cells, on carboplatin-induced apoptosis. Overexpression of Lewis (y) antigen effectively protected vitronectin-adherent RMG-1 cells from carboplatin-induced apoptosis as assessed by Hoechst 33258 staining and flow cytometry. Treatment with anti-Lewis (y) antigen, anti-integrin alphav, or anti-integrin beta3 antibody partially abolished the protective effect on apoptosis and markedly inhibited the expression of Topo-II beta in cells overexpressing Lewis (y) antigen (all P < 0.01). Moreover, elevated expression of Topo-I and Topo-II beta was found in Lewis (y) antigen-overexpressing cells (P < 0.01). However, no obvious changes in Topo-II alpha were observed throughout the study (P > 0.05). Taken together, these data suggest that the overexpression of Lewis (y) antigen confers cell adhesion-mediated drug resistance to apoptosis in ovarian cancer cells by the upregulation of Topo-I and Topo-II beta. Therefore, the inhibition of Lewis (y) antigen may be a novel strategy of cancer chemotherapy. PMID- 21542142 TI - National center offers HIV clinical consultation. PMID- 21542141 TI - A comparative assessment of the size of the frontal air sinus in the giraffe (Giraffa camelopardalis). AB - The current study examines the frontal air sinus of the giraffe (Giraffa camelopardalis) cranium with the aim of evaluating previously offered hypotheses as to why they have such an atypically voluminous frontal sinus relative to other artiodactyls. To date, no quantification of the frontal sinus in the adult or developing giraffe has been undertaken or compared to other artiodactyl species. Crania from eight species of adult artiodactyls, and giraffes varying in age from newborn to adult, were studied using CT scans to provide a volumetric assessment of the frontal sinus. Sinus volume was strongly correlated to cranial mass in the male giraffe ontogenetic series. The adult giraffe of both sexes were found to possess a far larger than predicted sinus volume relative to the relationship between frontal sinus volume and cranial mass observed in the other adult artiodactyls. Our results suggest that the volume of the frontal sinus in the giraffe is likely to be unique among artiodactyls, and the potential function and evolution we consider in light of several previously articulated hypotheses. PMID- 21542143 TI - Research. Nonwhites, southerners experience greater morbidity from HIV/AIDS. PMID- 21542144 TI - Prisons. Antiretroviral restrictions did not violate inmate's rights. PMID- 21542145 TI - Court affirms jury's ruling for criminal transmission of HIV. PMID- 21542147 TI - Marathon run is an important stress to muscle and brain functions. PMID- 21542148 TI - Wealth and athletic records. PMID- 21542149 TI - Maturity effect of training. PMID- 21542150 TI - Implications of the critical speed and slow component of Vo2 for the 2-hour marathon. PMID- 21542151 TI - The 2-h marathon--running from east. PMID- 21542152 TI - The two-hour marathon--who and when? And in what environmental conditions? PMID- 21542153 TI - The 2-hour marathon--more than physiology. PMID- 21542154 TI - The 2-hour marathon: Olympian vs. Paralympian. PMID- 21542155 TI - The 2-hour marathon: will women close the gap on men? PMID- 21542156 TI - Feasiblity of the two-hour marathon is a burning issue. PMID- 21542157 TI - The two-hour marathon: how important is age? PMID- 21542158 TI - The two-hour marathon: through a highly individualized training process? PMID- 21542159 TI - What for nature, and who to nurture? PMID- 21542160 TI - Physiological determinants of best performance in marathon running. PMID- 21542161 TI - Influence of early life factors on elite performance. PMID- 21542162 TI - Two-hour marathon: Bayes takes a day off? PMID- 21542163 TI - The two-hour marathon: running economy and lower body flexibility. PMID- 21542164 TI - Is the men's marathon world record 25 years behind the women's record? PMID- 21542165 TI - Role of altitude training and the two-hour marathon. PMID- 21542166 TI - A small body mass and higher muscle recruitment strategy is the key. PMID- 21542167 TI - Two-hour marathon and running economy. PMID- 21542168 TI - Oxidative stress: friend and foe of the elite marathoner. PMID- 21542169 TI - Critical velocity and maximal lactate steady state: better determinants of 2-hour marathon. PMID- 21542170 TI - The two-hour marathon, who and when? Haile Gebrselassie in 2000. PMID- 21542171 TI - The two-hour marathon: genetics will become increasingly important. PMID- 21542172 TI - The two-hour marathon: physiological and biochemical factors determinants running economy. PMID- 21542173 TI - What is coefficient of speed endurance to achieve two-hour marathon? PMID- 21542174 TI - Low pulmonary vascular resistance breaks the two-hour marathon limit. PMID- 21542175 TI - Genetic information will influence but not predict the first two-hour marathon. PMID- 21542176 TI - Two-hour marathon requires Mother Nature's help. PMID- 21542177 TI - The highest possible skeletal muscle metabolic stability as a key factor for breaking the 2-hour marathon barrier. PMID- 21542178 TI - The two-hour marathon: the importance of breathing economy. PMID- 21542179 TI - The two-hour marathon: how? PMID- 21542180 TI - The athlete with maintained cerebral oxygenation breaks the record. PMID- 21542181 TI - Do not underplay the roles of Vo2max and central fatigue in the 2-h marathon. PMID- 21542182 TI - Mechanisms of self-optimized pacing. PMID- 21542183 TI - [Comment to an editorial]. PMID- 21542184 TI - Optimizing strategies for the marathon. PMID- 21542185 TI - The advent of laparoscopic pancreatic surgery using the robot. PMID- 21542186 TI - Too much of a good thing? Multi-tasking and distraction in quality improvement. PMID- 21542187 TI - Peaceful rest vs rest in peace. PMID- 21542188 TI - Is time on the side of diversity in lung transplantation? PMID- 21542189 TI - Improving outcomes: the importance of data monitoring and ongoing educational interventions. PMID- 21542190 TI - Appendicitis equals diverticulitis: a challenge to traditional dogma. PMID- 21542191 TI - Diverticulitis: something new under the sun? PMID- 21542192 TI - Doctor, how many have you done? PMID- 21542193 TI - Proceedings of the First International Youth Mental Health Conference. Melbourne, Australia. July 29-30, 2010. PMID- 21542194 TI - Proceedings of the 3rd International Conference on Movement Dysfunction. Edinburgh, Scotland. October 30-November 1, 2009. PMID- 21542195 TI - Abstracts of lectures and posters: European Orthodontic Society, 86th Congress Portoroz, Slovenia 2010, 15-19 June. PMID- 21542196 TI - [The Tower of Babel]. PMID- 21542197 TI - Improved survival in second-line advanced prostate cancer treated with cabazitaxel. PMID- 21542198 TI - Panitumumab improves PFS in mCRC with wild-type KRAS. PMID- 21542199 TI - Identity, gender, and subjective well-being. AB - Using the self-reported level of happiness as a measure of subjective well-being, this study examines the relationship between gender identity and subjective well being with data from Taiwan. The findings suggest that an individual's perceptions about the ideals of women's gender roles in the labor market, the family, and politics are strongly related to his or her assigned social category, the prescriptions and characteristics associated with the social category, and the actions taken to match the ideals of gender identity. Consistent with Akerlof and Kranton's (2000) identity model, it is also found that an individual's gains or losses in gender identity lead to increases or decreases in the level of happiness. PMID- 21542200 TI - The genealogy of personal names: towards a more productive method in historical onomastics. AB - It is essential to combine genealogical and collective biographical approaches with network analysis if one wants to take full advantage of the evidence provided by (hereditary) personal names in historical and linguistic onomastic research. The naming practices of rural families and clans from the 18th to the 20th century can bring us much fresh information about their enduring attitudes and values, as well as about other mentalities of everyday life. Personal names were cultural symbols that contained socially shared meanings. With the help of genealogical method it is possible to obtain a more nuanced understanding of these past naming practices, for example by comparing the conventions of different communities. A long-term and systematic empirical research also enables us to dispute certain earlier assumptions that have been taken for granted in historical onomastics. Therefore, the genealogical method is crucial in studying the criteria for the choices of personal names in the past. PMID- 21542201 TI - Slumdog cities: rethinking subaltern urbanism. AB - This article is an intervention in the epistemologies and methodologies of urban studies. It seeks to understand and transform the ways in which the cities of the global South are studied and represented in urban research, and to some extent in popular discourse. As such, the article is primarily concerned with a formation of ideas - "subaltern urbanism" - which undertakes the theorization of the megacity and its subaltern spaces and subaltern classes. Of these, the ubiquitous 'slum' is the most prominent. Writing against apocalyptic and dystopian narratives of the slum, subaltern urbanism provides accounts of the slum as a terrain of habitation, livelihood, self-organization and politics. This is a vital and even radical challenge to dominant narratives of the megacity. However, this article is concerned with the limits of and alternatives to subaltern urbanism. It thus highlights emergent analytical strategies, utilizing theoretical categories that transcend the familiar metonyms of underdevelopment such as the megacity, the slum, mass politics and the habitus of the dispossessed. Instead, four categories are discussed - peripheries, urban informality, zones of exception and gray spaces. Informed by the urbanism of the global South, these categories break with ontological and topological understandings of subaltern subjects and subaltern spaces. PMID- 21542202 TI - Democracy on the edge: limits and possibilities in the implementation of an urban reform agenda in Brazil. AB - The 1990s in Brazil were a time of institutional advances in the areas of housing and urban rights following the signing of the new constitution in 1988 that incorporated the principles of the social function of cities and property, recognition of the right to ownership of informal urban squatters and the direct participation of citizens in urban policy decision processes. These propositions are the pillars of the urban reform agenda which, since the creation of the Ministry of Cities by the Lula government, has come under the federal executive branch. This article evaluates the limitations and opportunities involved in implementing this agenda on the basis of two policies proposed by the ministry - the National Cities Council and the campaign for Participatory Master Plans - focusing the analysis on government organization in the area of urban development in its relationship with the political system and the characteristics of Brazilian democracy. PMID- 21542203 TI - Social mix policies in Paris: discourses, policies and social effects. AB - Since the 1980s, the issue of social mix has become a public policy category in France. Enshrined in legislation, yet remaining controversial, it represents a major premise on which housing policies have been reconfigured. The concept of social mix is essentially based on who lives where, but it is also evoked in the context of urban renewal schemes for social housing estates, as well as in relation to new-build developments. A study of the bases of social mix policies conducted in Paris since 2001 in the context of the embourgeoisement of the capital shows the fundamental role of social housing stock. The City Council has become involved in policy decisions about both the location and the allocation of social housing. Particular attention has been paid to the middle classes in the name of the principle of 'balancing the population'. In order to measure the effects of the policy, this article relies on an analysis of two City of Paris schemes that have the stated intent of creating social mix. One of these schemes consists of redeveloping a working-class neighbourhood, Goutte d'Or, while the other involves the new acquisition of social housing in various more affluent neighbourhoods in the capital. This comparative study of the population shows that, whether in a neighbourhood poised for gentrification or in a more affluent neighbourhood, this policy has major effects on forms of local social cohesion, setting in motion individual trajectories and reshaping social and/or ethnic identities. PMID- 21542204 TI - Towards a phenomenology of civil war: Hobbes meets Benjamin in Beirut. AB - Based on interviews with Beirut intellectuals and architects, this essay endeavours to trace the contours for a phenomenology or anthropology of civil war. Thomas Hobbes serves as a guide, with his idea of civil war representing a relapse into the 'state of nature'; as absence of sovereignty resulting in a 'war of everybody against everybody'. The effects of ever-latent civil war in Beirut are far-reaching: the fragmentation of urban space and the disappearance of public space, the loss of memory and the fragmentation of time, even the reification of language. In the collective imagination and in the arts, Beirut appears as a ghost town, a spectral city with a spectral civility. What we discover is a city, its inhabitants, its social behaviour, but also its art and literature, in the grip of post-traumatic stress syndrome. From all this, we take home two things: first, any city can (at least in principle) relapse into a similar state of nature - Beirut can become a paradigm of latent civil war; and second, the traumatic modernity of Beirut mirrors the traumatic artistic expressions of modernism - the shock of modernity is also always a modernity of shock. PMID- 21542205 TI - LGBTQs in the city, queering urban space. AB - Since the 1960s, lesbian, gay, bisexual, transgender and queer (LGBTQ) culture has developed in big cities and metropolises everywhere (not only in the West, but also in Asia, Latin America and indeed Africa). This essay examines how cities provide the spatial conditions necessary for the formation of such emancipatory movements based on identity politics and strategies which transcend binary gender dualism. The starting point of this investigation is my thesis that only urban life enables LGBTQ individuals to live their lives fully, realize their (sexual) identities, and furthermore organize themselves collectively, become publicly visible, and appropriate urban, societal and political spaces. PMID- 21542206 TI - Don't ask me where I'm from: thoughts of immigrants to Catalonia on social integration and cultural capital. AB - Once you get here, you realize that thinking Foucault was writing for you was terribly naive, since in reality I did not exist as a subject for anyone like Foucault, or if I did it was only as an object of study', recalls one of the protagonists in this essay, a collage of fragments of interviews with foreign immigrants from impoverished countries who have settled in Barcelona and other Catalan towns in recent years. Widespread prejudice in the host society dictates that these people are generalized as being on a lower cultural level, anonymous members of the growing mass of immigrants prepared to work at any price. The prejudice seems to be confirmed by the fact that the great majority of them do low-skilled or unskilled work in sectors such as the building trade, hotels and restaurants and domestic service. The reality, however, is very different. The average level of formal education of these immigrants is similar to that of the host population. It is the precariousness of their legal status or the often insurmountable barriers preventing recognition of their academic and/or professional qualifications, or simply cultural prejudice, that condemn them to accept jobs well below their personal potential. Thus, the host society wastes social and cultural capital of the first order, and lays foundations for a permanent division between 'us' and 'them'. This essay offers a modest but revealing sample of the quality and diversity of the ideas and viewpoints of the immigrants themselves, an asset we continue to at best underestimate or more often ignore altogether. PMID- 21542207 TI - The bones of the body politic: thoughts on the Savorgnan de Brazza Mausoleum. AB - This essay examines three examples of political treatment of the dead (specifically their bones) in the Republic of the Congo: the return of the remains of its capital's founder, Savorgnan de Brazza; the disappearance of the body of Andre Matswa, hailed by the people as their messianic 'saviour' guardian; and finally, the treatment of unidentified victims of the various armed conflicts that occurred during the years 1990-2002. These events can be analysed through the prism of two different historical perspectives: in terms of the moyenne duree, the treatment of Matswa's bones paved the way for the subsequent occurrences by creating a precedent; in the context of the 'present of history', the construction of a Brazza mausoleum is contemporaneous with official denial of the presence of human remains scattered across the capital city of Brazzaville as a result of armed conflicts. The comparative analysis of these historical configurations posits a set of circumstances whereby the bones become a symbolic buttress of the capital. The historical puzzle here is to understand how that which came together in claiming Matswa's bones becomes, in the context of democratization of the regime, an aesthetic sense of the 'beauty of death' as expressed by people when they see the shrine as their country's finest architectural accomplishment. Through the splendour of the monument, this aesthetic sense articulates the denial of the presence of the nameless dead. PMID- 21542208 TI - Spatial collisions and discordant temporalities: everyday life between camp and checkpoint. AB - How do we make sense of the colonial subject that is neither in revolt nor in open crisis? How do people reproduce their lives, fashion routines, etch out some meaning when the political is evacuated, when time is on hold? These questions loom over a contemporary disjuncture in Palestine, marked in part by the splintering and opening up of the field of subjective bonds, attachments and associations to new modalities of production, less circumscribed by previous normative parameters and engendering a host of complexities and ambivalences in politico-social relationalities. Yet most scholarship on Palestine remains caught up in reductive binaries of violence versus resistance and heavily reliant on rigid and aggregated categories, the bulk of it unable to capture entire assemblages of action, subjective dissonance, productive ambiguities and contingent vitalities that inflect so much of contemporary quotidian life. The refugee in particular has emerged as a destabilizing figure, capable of subversively using the spatio-temporality of the camp as the very resource through which to disturb ascribed categorizations. Reading the paradoxical multiplicity of actions that refugees - women, children and the elderly - perform in the space between Qalandia camp and its checkpoint provides an insight into some of what defines contemporary refugee subjectivities - flexibility, a readiness to take risks, an ability to maneuver through different temporal orders and instrumentalize the spatial fragmentation. These subjects, traversing and negotiating liminality in everyday life, point to lived and bodied affirmations of presence and visibility that cannot be understood through frameworks of recognition and rights. PMID- 21542209 TI - Intensity-based climate change policies in Canada. AB - To reduce greenhouse gas emissions from large industries the Canadian government proposed using a tradable emissions performance standard approach, where the intensity of emissions, rather than the absolute level, is regulated. Unlike a cap and trade system, an emissions performance standard does not guarantee a certain overall level of emission reductions, a fact that has led to significant criticism. However, because of the dynamics of performance standards, they may reduce concerns over reductions in international competitiveness in cases where a country has climate policies that are more aggressive than those of some of its trade partners. Likewise, a performance standard may mesh more efficiently with existing taxes and therefore cause less overall economic impact than an absolute cap and trade system. This paper considers the theoretical arguments for and against such a performance standard system and evaluates it in comparison to a cap and trade system using a dynamic general equilibrium model applied to Canada. PMID- 21542210 TI - A curious jumble: the Canadian approach to online consumer health information. AB - As part of a larger e-health strategy, Canadian governments have invested millions in online health information services for the lay public. These services are intended to reduce demands on the primary health care system by encouraging greater individual responsibility for health and are often promoted using the language of personal empowerment. In this paper, we describe how lay searchers generally look for online health information and discuss the disempowering challenges they are likely to face in (a) locating Canadian government-sponsored health information sites and (b) finding useful information on these sites to address everyday health concerns. We conclude with several recommendations for policy changes. PMID- 21542211 TI - Prescribing pork in Israel. AB - Both Judaism and Islam have prohibited eating pork and its products for thousands of years. Scholars have proposed several reasons for the ban to which both religions almost totally adhere. Pork, and the refusal to eat it, possesses powerful cultural baggage for Jews. Israel has legislated two related laws: the Pork Law in 1962, that bans the rearing and slaughter of pigs across the country, and the Meat Law of 1994, prohibiting all imports of nonkosher meats into Israel. While not abounding, Israeli pork-eaters certainly exist, and a small number of pig-breeding farms operate in the country, mostly in Christian villages. The influx of Russian immigrants in the 1990s helped boost sales of pork, but the force of the taboo remains so powerful that many secular Israelis still eschew pork dishes, while willing to eat less charged nonkosher items such as shellfish. A porchetta feast recently held in the Muslim-Jewish town of Jaffa, defied the religious and cultural taboo. It was a celebration of a book by Dr. Eli Landau, The White Book, which is the first Hebrew-language collection of pork recipes. Fearing repercussions, Israeli publishers unanimously refused to publish it and the book chain stores declined to display it. As a result, Landau published it himself. PMID- 21542212 TI - Emmanuel Levinas and the ontology of eating. AB - This essay examines the existential philosophy of Emmanuel Levinas in relation to issues of food and eating. I argue that for Levinas, the act of eating is central to founding the ethical self, and that any understanding of Levinas's approach to embodiment must begin with what it means for us to ingest the outside world. Even in Levinas's earliest work, food is already a freighted ontological category. As his ideas mature, eating is transformed from the grounding for an ethical system to the system itself. The act of giving bread to another person takes its place as the ethical gesture par excellence. The story is not that we eat. The story is that we eat and develop a relationship to eating, and that relationship in turn helps determine our sense of ourselves in the world. Eating is the ethical event. The essay ends by asking how Levinas can help us answer the question, what would it mean to imagine every bite I take, or give to another, as a direct engagement with my own and my neighbor's existence? PMID- 21542213 TI - A journey into the imaginary of Sicilian pastry. AB - This article is an anthropological archeology of Sicilian confectionery, from the prehistoric-like assemblage of sesame seeds and honey (giurgiulena) to the extravagant gelato di campagna and the baroque-rustic cassata. Sweets are analyzed as architectural constructions that rely on newly discovered ingredients and techniques to create edible edifices that amazed the eye as much as the palate. They emerge from their historical and social context and affirm themselves as moments of innovation in the culinary art. On a deeper level, the art of pasticceri bears the marks of an existential quest that constantly redefines man's symbolic relation to the forces and contrasts of life. PMID- 21542215 TI - Retraction and apology. PMID- 21542214 TI - Reviving red snapper. AB - Red snappers in the Gulf of Mexico once hovered on the brink of extinction, their population having dropped to 2 percent of what had historically swum in the Gulf. But thanks to a recently introduced plan that turns the conventional wisdom of fisheries management on its head, the picture has begun to change. Called Individual Fishing Quotas (IFQs), the new regulations, which give a guaranteed allotment of fish to each participant instead of applying industry-wide quotas, went into effect for Gulf of Mexico Red Snapper (Lutjanus campechanus) in early 2007. The results were immediate and so profound that the Gulf Fishery Management Council voted earlier this year to increase the annual limit on red snapper to nearly 7 million pounds from 5 million. PMID- 21542216 TI - [Establishment of a 3D finite element model of human skull using MSCT images and mimics software]. AB - OBJECTIVE: To establish a human 3D finite element skull model, and to explore its value in biomechanics analysis. METHODS: The cadaveric head was scanned and then 3D skull model was created using Mimics software based on 2D CT axial images. The 3D skull model was optimized by preprocessor along with creation of the surface and volume meshes. The stress changes, after the head was struck by an object or the head hit the ground directly, were analyzed using ANSYS software. RESULTS: The original 3D skull model showed a large number of triangles with a poor quality and high similarity with the real head, while the optimized model showed high quality surface and volume meshes with a small number of triangles comparatively. The model could show the local and global stress changes effectively. CONCLUSION: The human 3D skull model can be established using MSCT and Mimics software and provides a good finite element model for biomechanics analysis. This model may also provide a base for the study of head stress changes following different forces. PMID- 21542217 TI - [Estimation of early postmortem interval using beta-actin mRNA in rat's brain, heart and kidney]. AB - OBJECTIVE: To explore the relationship between beta-actin mRNA degradation in SD rat's brain, heart and kidney and early postmortem interval (PMI) in order to find new markers for estimating early PMI. METHODS: Rats were sacrificed and kept in the place at a temperature of 20 degrees C. The total RNA were extracted from the brain, heart and kidney at different PMI points. Real time RT-PCR was applied to determine beta-actin mRNA levels in total RNA and the results were given in the form of Ct values. Linear relationships between PMI and Ct values were obtained and the functions of linear regression were established. RESULTS: The great decrease of beta-actin mRNA level were observed in the three organs. The degradation rate was obviously higher in 24 hours after death in the heart and kidney. However, there were no significant changes in the brain. The changes of Ct values and PMI showed a good linear relationship. CONCLUSION: beta-actin mRNA in rat's brain, heart and kidney degrades obviously after death and can be used for estimating early PMI by its degradation rules. PMID- 21542218 TI - [Concentration changes of potassium and hypoxanthine in vitreous humor of swine and its application to postmortem interval estimation]. AB - OBJECTIVE: To investigate the relationship between postmortem interval (PMI) and concentration changes of components in swine vitreous humor. METHODS: Ninety-six porcine eyes from swine dying from acute massive hemorrhage, being randomly divided into 24 groups, were stored in dark situation, at temperature of (15 +/- 2) degrees C and humidity of (50 +/- 5)% for 2-96 hours separately. The vitreous humor was collected. Concentrations of K+, Na+, Cl- and hypoxanthine (Hx) were analyzed by automatic biochemical analyzer and ultra performance liquid chromatograph (UPLC). The data were statistically analyzed by SPSS software. RESULTS: Linear regression analysis showed that concentrations of vitreous K+ and Hx were positively correlated with PMI(R2=0.767 and R2 = 0.793, respectively). Binary linear regression showed a higher correlation for K+ and Hx with PMI estimation (R2 = 0.866). PMI was not significantly correlated with vitreous Na+ and Cl- concentrations. CONCLUSION: Vitreous K+ and Hx concentrations can be used as the objective markers for PMI estimation. The binary linear regression functions of vitreous K+ and Hx concentrations with PMI are more accurate for estimating the PMI. PMID- 21542219 TI - [Forensic identification by coding of frontal sinus characteristics of CT]. AB - OBJECTIVE: To explore observing parameters of frontal sinus using reconstructive coronal nose bone sections of the head CT images and to establish the special identification codes. METHODS: CT images of the frontal sinus were analyzed by using distance measurement and morphological description. The discrimination codes of frontal sinus identification were: the number of right partial septa, shape-the location of the central septa, shape-the number of left partial septa, shape; the number of arches of right upper scalloping (the location of the right highest scalloping, the location of the right lowest scalloping)-the number of arches of left upper scalloping (the location of the left highest scalloping, the location of the left lowest scalloping); the width, height of the right sinus-the total width of sinus-the width, height of the left sinus. RESULTS: The identification codes of the frontal sinus were highly variable individually, but the codes were not statistically differences between males and females (P > 0.05). CONCLUSION: The identification codes of frontal sinus could be used for forensic individual identification, but not for sex determination. PMID- 21542220 TI - [A primary study for criteria of full sibling determination with Identifiler system]. AB - OBJECTIVE: To investigate the criteria of the number of identical allele (IAn) and the number of matched STR locus with 2 identical alleles (A2) for full sibling (FS) determination with Identifiler system. METHODS: According to the limited distribution of IAn. and A2, all of the 31 potential values of IAn. were substituted into the published discriminant functions to obtain the cut-off values of IAn and A2 for FS determination, and then 4 different criteria were determined to distinguish 280 FS pairs from 2283 individual pairs, respectively, which had been genotyped with Identifiler system. Cumulative full sibling index (CFSI) of the samples were calculated with ITO method, and 4 different criteria of CFSI (>1, > or =5, > or =20 and > or =100) were also utilized to determinate FS, respectively. Indices including sensitivity (SEN), specificity (SPE), accuracy(AC), positive predictive value(PPV) and negative predictive value (NPV) of the 8 different criteria for FS determination were calculated, respectively. Concordance of FS determination between the criteria based on IAn and A2 and that of CFSI were statistically tested with Kappa index. RESULTS: All the individual pairs, which meet the requirement of (I) IAn > or =15 and A2 > or =4, or (II) IAn > or =16 and A2 > or =3, or (III) IAn > or = 17 and A2 > or =3, or (IV) IAn > or =18 and A2 > or =3, could been concluded as FS. AC, SPE and NPV of the 4 criteria mentioned above and the 4 criteria of CFSI were all over 0.9500 in FS determination. Indices between criterion II and CFSI > or =5, criterion III and CFSI > or =20, criterion IV and CFSI > or =100 were similar with each other and the Kappa indexes of the 3 groups were 0.9049, 0.9204 and 0.9083, respectively. PPV and NPV of criterion III and CFSI > or =20 were all over 0.9500. CONCLUSION: The criterion of IAn > or =17 and A2 > or =3 was feasible and efficient for FS determination with Identifiler system, power of which was similar with the criterion of CFSI > or =20. PMID- 21542221 TI - [Relationship between cholecystokinin gene -45C/T polymorphism and schizophrenia and its application in forensic medicine]. AB - OBJECTIVE: To investigate the polymorphism of cholecystokinin (CCK) gene -45C/T of schizophrenia and its application in forensic medicine. METHODS: Bidirectional allele specific PCR was used to detect CCK gene -45C/T polymorphisms in 207 schizophrenic patients (case group) and 202 healthy individuals (control group) of the Han population in northern China. The chi2 test was used to identify Hardy Weinberg equilibrium of the genotype distribution in control group. The differences of genotype and allele frequencies distributions were compared between two groups. RESULTS: Distributions of the genotype frequencies satisfied the law of Hardy-Weinberg equilibrium in control group. The differences between genotypic frequencies and allele frequencies were not statistical significance in case group and control groups (P > 0.05). Gender-stratified analysis showed that frequency of allele T in female case group was statistically higher than that in female control group (P = 0.044). CONCLUSION: CCK gene -45C/T locus T allele may be positively associated with schizophrenia in female population and useful in schizophrenia identification. PMID- 21542222 TI - [Simultaneous determination of sixteen antibiotics in human urine with ultra performance liquid chromatography-tandem mass spectrometry]. AB - OBJECTIVE: To develop a method for simultaneous determination of sixteen antibiotics in human urine by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: With Piperacillin as an internal standard, the target antibiotics in urine samples were enriched and purified by Oasis HLB solid phase extraction (SPE) cartridges, then separated in a ZORBAX SB-C18 column with a gradient elution of mobile phase of 0.1% formic acid water and acetonitrile, finally analyzed with multiple reaction monitoring (MRM) mode. RESULTS: The limits of detection (LOD) for these sixteen antibiotics were in the range of 0.05-10.0 ng/mL and the limits of quantification (LOQ) in the range of 0.25-20.0 ng/mL. Within the related linear range, the related coefficient (r) of sixteen antibiotics were all more than 0.995. Accuracies for these antibiotics were ranged from 82.0%-119.3%, the within-day precision were less than 13.9%. CONCLUSION: The developed method is sensitive, specific and appropriate for the analysis of antibiotics in forensic toxicology and therapeutic drugs monitoring. PMID- 21542223 TI - [Analysis of 158 forensic identification cases involved with peripheral nerve injury]. AB - OBJECTIVE: To study the characteristics of forensic identification cases involved with peripheral nerve injury, and to discuss how to apply the clinical information, forensic examination and neurophysiological testing. METHODS: One hundred and fifty-eight cases which were diagnosed peripheral nerve injury in clinic, were collected. Then the individual characteristics, injuries, identification results, exaggeration or camouflage were analysed. RESULTS: The male, the unemployed, and the young and middle-aged were common in our cases. The main reasons of "peripheral nerve injury" were traffic accidents and sharp injuries. Most wounded parts were in limbs. Also the exaggeration and camouflage accounted for a considerable proportion in our cases. CONCLUSION: The forensic identification of "peripheral nerve injury" cases should be evaluated with clinical information, forensic examination and electrophysiological testing comprehensively. PMID- 21542224 TI - [Isolating sperm cells by laser capture microdissection technique from mixture sample]. AB - OBJECTIVE: To assess the application value of laser capture microdissection (LCM) technique for isolating a small number of sperm cells from mixture sample. METHODS: Mixture samples were prepared with sperm cells and vaginal epithelia at different concentrations. Both LCM technique and the differential lysis method were employed to obtain sperm cells from the mixture samples, and DNA was extracted by magnetic beads method. STR genotyping was determined using Identifiler kit. RESULTS: The successful STR genotype rate of sperm cells isolated from mixture samples with LCM technique was 92.86% (13/14). The rate of differential lysis method was 7.14% (1/14). The successful rates between the two methods were statistically different (P < 0.05). CONCLUSION: LCM technique can effectively exclude the interference of female cell component and isolate a small number of sperm cells to obtain a single male STR genotyping. LCM technique is obviously better than the differential lysis method. PMID- 21542225 TI - [Genetic polymorphisms of 21 non-CODIS STR loci]. AB - OBJECTIVE: To investigate genetic polymorphisms of 21 non-CODIS STR loci in Han population from the east of China and to explore their forensic application value. METHODS: Twenty-one non-CODIS STR loci, were amplified with AGCU 21+1 STR kit and DNA samples were obtained from 225 unrelated individuals of the Han population from the east of China. The PCR products were analyzed with 3130 Genetic Analyzer and genotyped with GeneMapper ID v3.2 software. The genetic data were statistically analyzed with PowerStats v12.xls and Cervus 2.0 software. RESULTS: The distributions of 21 non-CODIS STR loci satisfied the Hardy-Weinberg equilibration. The heterozygosity (H) distributions were 0.596-0.804, the discrimination power (DP) were 0.764-0.948, the probability of exclusion of duo testing (PEduo) were 0.176-0.492, the probability of exclusion of trios-testing (PEtrio) were 0.334-0.663, and the polymorphic information content (PIC) were 0.522-0.807. The cumulative probability of exclusion (CPE) of duo-testing was 0.999707, the CPE of trios-testing was 0.9999994, and the cumulated discrimination power (CDP) was 0.99999999999999999994. CONCLUSION: Twenty-one non CODIS STR loci are highly polymorphic. They can be effectively used in personal identification and paternity testing in trios cases. They can also be used as supplement in the difficult cases of diad paternity testing. PMID- 21542226 TI - [Comparison of four imaging examinations of shoulder joint injury in forensic expertise]. AB - OBJECTIVE: To compare the value of four imaging examinations, including the X ray, CT, MRI and gas-iodine double contrast CT analyses, in the forensic expertise of shoulder joint injury. METHODS: Imaging data of shoulder joint injury, by the X-ray, CT, MRI and gas-iodine double contrast CT were retrieved and analyzed. RESULTS: The correct diagnosis rates of fracture and soft tissue injury by X-ray, CT and MRI were 52.8%, 72.0% and 63.2%, as well as 0.0%, 32.9% and 82.5%, respectively. The correct diagnosis rate of soft tissue injury by gas iodine double contrast CT was 100%. CONCLUSION: X-ray is a useful screening method, CT is better for diagnosis of fracture, and MRI is fit for diagnosis of soft tissue injury. Gas-iodine double contrast CT can reflect not only the soft tissue injury but also its severity. Thus, combined application of X-ray, CT, MRI and gas-iodine double contrast CT can provide important imaging information for forensic expertise in shoulder joint injury. PMID- 21542227 TI - [Advancement in methods of evaluation on bone fracture healing and its application in forensic medicine]. AB - It is frequently encountered to identify the time of bone fracture in forensic medicine. Hence it is important to develop the methods for evaluating the time of bone fracture. This article reviews the applications and values of the methods such as ultrasonic evaluation, impulse measurement, digital imaging technology and bone mineral density testing technology, etc. It is proposed that to use these methods jointly may provide more scientific evidence in determine the time of bone fracture. PMID- 21542228 TI - [Progress on DNA quantification in estimation of postmortem interval]. AB - Estimation of postmortem interval (PMI) is one of the difficult problems in forensic medicine. With the development of molecular biological techniques, DNA quantification methods were widely applied in estimating PMI. The postmortem degradation of DNA in different tissues and organs was discussed in this article and the recent DNA quantitative techniques being used for estimating PMI were reviewed. These techniques included single cell gel electrophoresis, Feulgen staining image analysis, flow cytometry. PMID- 21542229 TI - [Application of nucleic acids and proteins in estimation of postmortem interval]. AB - Accurate estimation of postmortem interval (PMI) is one of the most important and difficult issues in forensic medicine. After death, the tissues autolyze and biomacromolecules degrade. DNA concentration decreases gradually with linear relationship with PMI. The housekeeping gene mRNA, for example beta-actin, GAPDH, has certain stability and can be used to PMI estimation as internal standard. This paper reviews the research progress and problems about DNA, RNA and proteins in the estimation of PMI in order to provide guidance for forensic pathology. PMID- 21542230 TI - [Interpretation of the susceptibility test results in enterobacteria producing 3rd- and 4th-generation cephalosporin- or carbapenem-hydrolyzing beta lactamases]. AB - The interpretation of the susceptibility of Gram-negative rods to beta-lactams is currently under discussion in CLSI and EUCAST--two authorities on determination of clinical breakpoints. This article summarizes the current knowledge about clinical breakpoints in enterobacteria and proposes guidance for clinical microbiology laboratories in the Czech Republic. PMID- 21542231 TI - [Antibiotic resistance of Streptococcus pneumoniae and Streptococcus pyogenes in 1996-2009]. AB - STUDY OBJECTIVES: To analyze trends in the resistance of Streptococcus pneumoniae to penicillin and macrolides and of S. pyogenes to macrolides over a 14-year period and to determine serotypes and molecular characteristics in a selected group of S. pneumoniae strains resistant to these antibiotics. MATERIAL AND METHODS: Susceptibility to antibiotics was tested by the participating laboratories by the disk diffusion method in isolates of both bacterial species from the lower and upper respiratory tract from 1996-2009. The National Reference Laboratory for Antibiotics (NRL/ATB) determined the minimal inhibitory concentrations of penicillin and erythromycin for invasive pneumococcal isolates from 2000-2009 and performed multilocus sequence analysis of selected resistant strains. RESULTS: Over the 14-year period monitored, penicillin resistance of S. pneumoniae isolates from the upper and lower respiratory tract showed a slightly downward trend similarly to blood isolates monitored since 2000. Resistance to macrolides in S. pneumoniae isolates was lower than penicillin resistance, regardless of the sample origin until 2005, but became higher than penicillin resistance in 2006 to follow a continuously upward trend since then. In 2009, the penicillin resistance rates of S. pneumoniae isolates from the upper respiratory tract, lower respiratory tract and blood were 3.5%, 5.1% and 4.7%, respectively, while the respective erythromycin resistance rates reached 8.4%, 12.2% and 5.5%. When using the new clinical breakpoints for pneumococci from pneumonia cases depending on penicillin dose and administration interval, only two (0.1%) of 1528 strains from the blood were confirmed as penicillin resistant (MIC 4 mg/l). Resistance of S. pyogenes to macrolides, reported in 16.5% of strains in 2001, sharply decreased to 9% in 2003 as a result of an intervention to promote the use of penicillin for the treatment of tonsillopharyngitis, and reached 11.1% in 2009. Among penicillin resistant strains of S. pneumoniae, the spread of clone Spain9V-3 (ST156) was confirmed, and among S. pneumoniae strains resistant to erythromycin alone, the spread of clones Poland6B-20 (ST315) and England9V-14 (ST9) was found. CONCLUSIONS: The favourable low prevalence of penicillin resistance among S. pneumoniae strains, which in addition is negligible in the light of the new clinical breakpoints for penicillin resistance in strains from patients with pneumonia, contrasts with the ever increasing resistance of this species to macrolides. The highest rates of resistance to macrolides found in the strains isolated mainly from the sputum of adult patients confirm the preference for macrolides over the drugs of choice amoxicillin or penicillin G in the treatment of adults with pneumococcal pneumonia. Further spread of successful multiresistant clones of S. pneumoniae, the presence of which has been revealed in the Czech Republic, can only be prevented by a radical reduction in overuse or misuse of antibiotics. PMID- 21542232 TI - [Residential care for substance users and addicts in the Czech Republic according to the health statistics since 1959]. AB - Similarly to the prevalence of disorders related to the use of addictive substance, the system of medical care for patients with addictive disorders, including the residential treatment, has changed dramatically in the Czech Republic in the last 50 years. GOAL: To perform descriptive analysis of historical data gathered, analysed and published by the Institute for Health Information and Statistics since 1959 on the inpatient psychiatric facilities, and numbers and characteristics of patients hospitalised due to addictive disorders in 1959-2008. RESULTS: The number of episodes of hospitalisation due to alcohol-related conditions was increasing throughout the whole monitored period since the end of the 1950s. After a short decrease at the turn of the 1980s and 1990s, the alcohol-related hospitalisations increased again to the historical peak of 11,691 episodes in 2005. As compared to alcohol-related admissions, the number of hospitalisations due to other (non-alcoholic) addictive disorders was 5 10 times lower until 1993 (60-1,000 episodes annually); however, a sharp increase was observed since 1994, to 5,264 episodes in 2008. The proportion of males among hospitalised alcohol users is currently about 70% in comparison with approximately 95 % at the very beginning of the study period, with most hospitalised persons being aged 40-49 years. Users of sedatives and hypnotics are more often females (approximately 65%), with the highest proportion of them being also aged 40-49 years. From 70 to 90% of hospitalised users of other addictive substances, i. e. illicit drugs and volatile substances, the percentage varying with the substance, are males and the highest proportion of cases is reported in the age group 20-29 years. In the last 15 years, the highest relative rates of hospitalisations for alcohol-related conditions were recorded in the Zlin, Olomouc and Moravian-Silesian Regions and for non-alcohol substance abuse in Prague and the Usti Region. The inpatient psychiatric bed capacity considerably decreased after 1989, which contrasts with the increasing number of alcohol related and particularly non-alcohol substance-related hospitalisations since the 1990s. CONCLUSION: The data on hospitalised users of addictive substances are a valuable contribution to the body of information about drug use and its consequences in the Czech Republic and are complementary to the description of the epidemiological situation and trends seen in other data sources. They are of crucial relevance to the study of alcohol abuse due to the scarcity of other data sources in the Czech Republic. PMID- 21542233 TI - [Laboratory diagnosis of pandemic influenza at the Department of Medical Microbiology of the Regional Authority of Public Health based in Banska Bystrica in the season 2009-2010]. AB - The Department of Medical Microbiology of the Regional Authority of Public Health (RAPH) in Banska Bystrica serves as a catchment laboratory of virology for the Central Slovakia Region, and in the influenza season 2009/10, it also served as such for the East Slovakia Region. MATERIAL AND METHODS: Specimens (nasopharyngeal swabs and post-mortem specimens) from patients with suspected influenza were obtained from both sentinel and non-sentinel physicians. The specimens were analyzed by a rapid test, followed by real-time PCR (RT-PCR) for influenza A or B diagnosis. RT-PCR subtyping for pandemic influenza A/H1N1 was performed. RESULTS: From May 2009 to June 2010, 2497 specimens were analyzed for the presence of influenza A and B viruses and in particular for the presence of pandemic influenza A/H1N1 virus. As many as 537 of 589 influenza A-positive specimens, i.e. 21.5% of all specimens analyzed and 91.2% of influenza A-positive specimens, were subtyped as pandemic influenza A/H1N1. CONCLUSION: In the influenza season 2009/10, the new pandemic influenza A/H1N1 clearly predominated in Central and Eastern Slovakia. PCR tests have played a key role in diagnosing patients with suspected pandemic influenza in the laboratory participating in the surveillance of influenza and influenza-like illness in the Slovak Republic. PMID- 21542234 TI - [Polio news]. AB - Although the Word Health Organization (WHO) launched the global polio eradication initiative 22 years ago, reports of new cases of this serious disease from various parts of the world are far from being uncommon. Former Czechoslovakia became the first country in the world to achieve polio eradication at the nationwide level. Since summer 1960, no case of non-imported paralytic poliomyelitis has been reported since 1961, Czechoslovakia has been the first country in the world to control permanently the spread of wild poliovirus strains. PMID- 21542235 TI - [In vitro efficacy of three novel delousing formulations against the head louse (Pediculus capitis L.)]. AB - A total of 498 head lice (2nd and 3rd instar larvae, females and males) combed out of the hair of 38 children, were exposed to the delousing formulations Diffusil H Forte Spray (carbaryl 1%), Diffusil Care (isopropyl myristate, cyclomethicone, and dimethiconol) and Paranit (coconut oil, anise oil, and ylang ylang oil) in in vitro tests. The first two formulations, i. e. Diffusil H Forte Spray and Diffusil Care, caused 100% mortality of exposed lice, while Paranit only killed 12.2% of exposed lice. PMID- 21542236 TI - [Lyme borreliosis and demyelinating disease of the central nervous system]. AB - A case report is presented of a 55-year-old patient diagnosed with a demyelinating disease of unclear etiology. The patient had Lyme borreliosis in 2004. Specific IgG antibodies against B. burgdorferi s. l. were detected in the serum. Intrathecal antibodies were not found in the cerebrospinal fluid, but the presence of B. garinii DNA was confirmed by PCR analysis. It can be hypothesized that the borrelial persistence in the body may have been one of the triggers of the autoimmune process resulting in demyelination of the central nervous system (CNS). PMID- 21542237 TI - [Novel controllers of airway obstruction in COPD patients]. AB - For improving effectiveness of chronic obstructive pulmonary disease (COPD) therapy is necessary to influence on pharmacologic receptors in the complementary way and to reduce the dose frequency. The once-daily dose administration is an important step which may allow to enhance of patients compliance. Novel long acting bronchodilators--beta2-agonists or ultra long-acting beta2-agonists (LABAs) such as indacaterol and carmoterol--are under clinical application for the treatment of COPD patients. Moreover, some new long-acting antimuscarinic agents (LAMA) (aclidinium, glycopyrrolate) and dual-action ultra LABA+LAMA combination products are under development. The main target of therapeutic research is to produce a dimmer molecule known as M3 antagonist-beta2 agonist (MABA) bronchodilators which will open the door for a new range of combination products. PMID- 21542238 TI - [The impact of prior revascularization procedures on outcome of percutaneous coronary intervention in ACS]. AB - Development of interventional cadriology is cause of increasing number of acute coronary syndrome (ACS) patients with prior revascularization procedures in the past. THE AIM OF THE STUDY: To evaluate the clinical feature of ACS patients with and without prior revascularization procedures and to compare in-hospital and long-term outcome following percutaneous coronary intervention (PCI) in these groups. MATERIAL AND METHODS: There were 325 ACS consecutive patients included to the study who underwent PCI procedures. There were 175 patients after PCI or coronary artery by-pass grafting in the past. Control group consisted of 150 subjects with ACS with no history of PCI procedures. We analyzed baseline characteristic as well as the inhospital, 30- and 180-day outcomes. RESULTS: The baseline characteristic revealed higher rate of patients with heart failure in case-history (18.0% vs. 26.9%, p = 0.03), diabetes (16.0% vs. 25.1%, p = 0.04), and multi-vessels coronary disease (85.2% vs. 60.6%, p = 0.003) in the subgroup of prior revascularization. The rate of non-STEMI was higher (28.0% vs. 40.6%, p = 0.02) and the rate of STEMI was lower (47.4% vs. 63.3%, p = 0.004) as a form of ACS in previously revascularized subjects. The analysis of inhospital outcome revealed significantly longer time of hospitalization of the patients with prior revascularization (7.7 +/- 4.6 vs. 5.4 +/- 4.1, p < 0.0001). There were no significant differences in clinical characteristics at 6-months after ACS. CONCLUSION: Patients undergoing PCI in ACS with prior revascularization procedures are characterized by a higher level of atherosclerosis risk factors, more advanced changes in coronary arteries and higher NSTEMI occurance than ACS patients without PCI history. Baseline and long-term results of revascularization, frequency and nature of complications are comparable in both groups, but length of hospitalization period and significantly longer in patients with revascularization in the past. PMID- 21542239 TI - [The assessment of influence of long-term exercise training on autonomic nervous system activity in young athletes preparing for competitions]. AB - The exercise training has positive impact on autonomic nervous system (ANS) activity. However, specific type of these changes significantly depends on intensity of used physical exertion. THE AIM OF THE STUDY: To assess the influence of long-term and single moderate physical exertion on ANS function in young athletes. MATERIAL AND METHODS: Sixteen middle-aged, 19-34 years old (24 +/ 5) athletes were included in the study. Assessment of ANS parameters (baroreflex sensitivity--BRS-WBA, heart rate variability--HRV) and mean heart rate period (mean HP) were calculated three times: recording 1--during the final stage of training period, recording 2--60 minutes after single moderate exertion, recording 3--after 2 months of training before competitions. RESULTS: In the whole group, significant increase of TP, HF SDNN and rMSSD indices was found in recording 2 comparing to recording 1, whereas after 2 months of intensive training no statistically significant changes were observed. In the group of athletes training only endurance sport (12 persons) in recording 2 the significant increase of TP, HF, SDNN, rMSSD and BRS-WBA was found. After 2 months of intensive training, no changes of these parameters were observed. CONCLUSIONS: In response to long-term training cycle with increasing intensity, preparing athletes for competitions, no significant changes of measured ANS parameters were found, which may indicate lack of overtraining during such a high intensity of training, and its safety. The changes of ANS parameters indicating increase of parasympathetic nervous system function after single exertion with moderate intensity (65% of maximum heart rate) were observed. PMID- 21542240 TI - [Posttraumatic stress disorder in patients with psoriasis]. AB - Posttraumatic stress disorder (PTSD) is an increasingly common medical condition. This anxiety disorder affects not only post war veterans but also those who suffered for extremely shocking situations, fear and hopelessness. Fundamental features of PTSD include the following: the symptoms are linked to the traumatic event and are not random, the symptoms were not present prior to the traumatic event, and the symptoms are present 1 month or later than completion of the traumatic event. There are some reports about the relatively frequent occurrence of PTSD in the case of psoriasis and some hypothesis about interactions between those two diseases. THE AIM OF THE STUDY: To assess the stress and increase of occurrence of PTSD symptoms in the group of patients suffering from psoriasis. MATERIAL AND METHODS: 20 patients (10 males and 10 females) aged 40.9 with psoriasis and PTSD were examined by the questionnaire Mississippi-C Scale. In addition, 20 patients, including 9 males and 11 females, aged 39.6 were also examined and formed the control group. RESULTS: It was observed significant relationship between PTSD and psoriasis. CONCLUSIONS: The article also emphasize the early intervention role in preventing the negative effects of stress, especially in patients suffering from psoriasis. PMID- 21542241 TI - [Venous thromboembolism triggered by spinning in a young woman with thrombophilia]. AB - Although regular sports activities decrease the risk of venous thromboembolism (VTE), VTE cases have been observed among professional and amateur athletes practicing various disciplines. The authors describe a case of a 25-year-old woman in whom calf pain, as popliteal vein thrombosis manifestation--preceding pulmonary embolism, occurred after she took up spinning, a popular form of indoor cycling. There was no history of leg injury. In hemostasis work up, factor V Leiden mutation and acquired low antithrombin activity-related to oral contraceptives use, were found. Strenuous exercise in an untrained woman might augment prothrombotic hemostasis profile. Vigorous cycling in standing position in the last phase of spinning, seems to be most unfavorable for patients with high VTE risk. PMID- 21542242 TI - [The role of dronedarone in the contemporary atrial fibrillation treatment]. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in the daily medical practice associated with increased cardiovascular mortality and stroke. Till now amiodarone is generally considered as the agent with the best efficacy for maintaining sinus rhythm. Despite its efficacy, amiodarone use is often limited by its extensive side effect profile. Dronedarone is benzofuran derivative structurally similar to amiodarone. Due to modification of the chemical structure of amiodarone the new pharmacokinetic properties provide with safety of the treatment. The ATHENA trial showed significant reductions in all cause mortality and cardiovascular hospitalization with dronedarone use. A post hoc analysis of the ATHENA data also suggested a decrease in stroke risk with this agent. Dronedarone is efficient in the controlling of ventricular rate as well as maintaining sinus rhythm in AF contraindicated in patients with NYHA class III/IV heart failure. Dronedarone use is significantly safer however is less effective in maintaining sinus rhythm than amiodarone. The European Society of Cardiology recommends dronedarone in new Guidelines for the Management of AF as a drug of fist-line treatment, what means the new interesting and safe alternative in the treatment of AF. PMID- 21542243 TI - [Clinical drug trials in elderly persons]. AB - Older people belong to the social group who is the largest consumer of drugs. But despite this commonly known statement, the evidence base for the pharmacotherapy of older patients is small and insufficient. Elderly persons are often excluded from many clinical drug trials, which are used to determine the effectiveness and safety of drugs. The reasons to exclude the elderly patients from randomised controlled drug trials are: the age-related changes in different body functions, coexisting morbidities, drug complications connected with polypharmacotherapy, poor cognitive functions, inability to consent or even death. Mentioned reasons make more likely that included old frail patients will be unable to complete the trial. However in the context of growing old the population of many countries, it is imperative to find new ways in order to enhance participation of older people in clinical drug trials which allow to avoid dangerous risk of pharmacotherapy. The examples of recommended ways are: minimalization or avoidance of traditional exclusion criteria; inclusion larger sample sizes of the elderly into the population trials, the usage of short, simple, understandable and adaptable for this special group of persons, information and consent forms; using a measure, such as CGA-comprehensive geriatric assessment, for multidimensional evaluation of old patient status. Mentioned recommendations may enhance the objectivization of clinical research outcomes in the old age persons. PMID- 21542244 TI - [Death of tumor cells. Photodynamic reaction in apoptosis induction in cancer cells]. AB - The main purpose of current anticancer methods is to initiate intracellular mechanisms leading to cell death (apoptosis or necrosis). The most required way of cell death is apoptosis. It is genetically caused process of active cell destruction. Cells undergo apoptosis without losing integrity, lysis, inflammation and damage of neighboring cells. There are formed apoptotic bodies from death cells. Apoptotic bodies are taken up by phagocytes and neighboring cells, which may also activate an anti-inflammatory response, at least in macrophages. There are three stages of apoptosis: decision, commitment and execution phase with inner and outer pathways. The significant role play cysteine proteases called caspases. Caspases are proteolytically activated heterodimer enzymes. The cascade of caspases play the key role in executive phase of apoptosis. However, p53 also is crucial in cell death. Is protein as a transcription factor can modulate gene expression coding proteins involved in apoptosis regulation. Photodynamic therapy (PDT) is a promising technique in anticancer therapies. It requires three crucial components for initiation of photodynamic reaction: a photosensitizer that selectively bounds with tumor cells; oxygen and a source of proper light for dye excitation. In many studies are shown that photosensitizers localized in mitochondria induced are apoptosis inductors, in contrast to these dyes localized in lysosomes and cytoplasmatic membrane. PMID- 21542245 TI - [Food-dependent exercise-induced anaphylaxis--current concepts in pathogenesis, diagnostics and treatment]. AB - Food-dependent exercise-induced anaphylaxis (FDEIA) is a rare syndrome, with symptoms caused by both ingestion of food allergen and physical exercise. The main purpose of this paper is to present current knowledge about FDEIA, focus on therapeutic possibilities, as well as to call attention to this uncommon and potentially life-threatening disease. The authors critically reviewed the data from available publications, including recent observations regarding pathomechanism, clinical history, severity-based classification of anaphylaxis symptoms, diagnostics and treatment options, including pharmacological prophylaxis. PMID- 21542246 TI - [Alterations of proteins and lipids glycosylation in pancreatic diseases]. AB - Proteins and lipids undergo the post- or co-translation modification, which changes their physiochemical and functional properties. The most common modification is glycosylation. The alterations of glycosylation appear following the course of various diseases. The results of these alterations are the structural and functional changes in tissues and organs. The alterations of proteins and lipids glycosylation occur also during the course of pancreatic diseases. These involve glycoconjugates of membranes, as well as glycolipids (gangliosides) located in the cells of the pancreas and in pancreatic islets. The structure of these compounds is dependent on the localization in the organ, and the changes in its structure can be monitored by the determination of carbohydrate levels in the blood. In pancreas diseases the alteration of glycosylation of plasma glycoproteins are also important. Some of them may be a prognostic markers of the disease. PMID- 21542247 TI - [Mechanisms of protective action of erythropoietin in cells]. AB - Cytokine and growth factor--erythropoietin (EPO)--apart from it's hematopoietic function is now considered to be a cytoprotective agent in a variety of vascular diseases, nervous system disorders and metabolic impairments. Recent work has elucidated that erythropoietin controls a variety of signal transduction pathways involving Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription, Wnt proteins, forkhead transcription factors, caspases, and nuclear factor kappaB. Further investigations of cellular pathways controlled by erythropoietin can be the base for therapeutic applicability of this cytokine throughout the body. PMID- 21542248 TI - [Genetically based states of elevated quantity of foetal haemoglobin (Hb F) in healthy individuals and patients]. AB - During human development, the switch from foetal gamma- to adult beta-globin on chromosome 11p is not complete resulting in the residual gamma-globin expression in a modest subpopulation of erythrocytes termed "F-cells". Genetic determinants that are responsible for higher level of Hb F include various mutations within the beta-globin gene cluster as well as singular nucleotide polymorphisms in other loci associated with Hb F quantitative trait, and also epigenetic mechanisms. All these molecular conditions may drive to hereditary persistence of foetal haemoglobin (HPFH). Taking into account a morphologic criterion, HPFH is called pancellular (p-) HPFH, if the increased Hb F is distributed in a uniform fashion among all of the red cells. When the Hb F distribution is restricted, the syndrome is referred to as heterocellular (h-) HPFH. The Hb F persistence rarely occurs in healthy adults or accompanies certain hemoglobinopathies changing substantially phenotypic diversity of sickle cell disease and beta-thalassaemia. PMID- 21542249 TI - [The role of ethanol in pathogenesis of pancreatitis]. AB - Alcohol consumption is associated with pancreatitis, but the mechanism inducing this injury is not fully understood. The pancreas can metabolize ethanol via oxidative pathway involving alcohol dehydrogenase (ADH), cytochrome P-450 2E1 and the nonoxidative pathway. Injury to the pancreas due to its capacity to metabolize ethanol may be mediated by direct effects of both fatty acid ethyl esters (FAEEs) and acetaldehyde and by alterations induced within the cells during ethanol metabolism, such as changes in the intracellular redox state and the generation of oxidative stress. These processes induce changes in pancreatic digestive enzymes secretion, what contributes to development of pancreatitis. PMID- 21542251 TI - [Cyclooxygenases inhibitors and other compounds with antiinflammatory potential in osteoarthrosis--part I]. AB - Nonsteroidal antiinflammatory drugs (NSAIDs) contain conventional nonselective drugs and selective inhibitors cyclooxygenase-2 (ICOX-2). NSAIDs frequently cause adverse effects tied with cyclooxygenases (COX, COXs) inhibition and prostaglandins (PG, PGs) synthesis, which exerts different physiological effects and are involved in the patophysiology of osteoarthritis. NSAIDs don't inhibit leucotriens (LT LTs) generation. Nonselective drugs cause detrimental results in the gastrointestinal tract. Selective COX-2 inhibitors exert thrombotic cardiovascular events and other negative effects in cardiovascular system. NSAIDs can intensify symptoms of OA and accelerate its progress. Analgetic and antiinflammatory properties possess also licofelone, a competitive inhibitor of cyclooxygenases and 5-lipooxygenase (5-LOX), which presents well gastrointestinal tract tolerability in contrast to NSAIDs. Licofelone decreases the production of proinflammatory leucotrienes and prostaglandins. Moreover inhibition of 5 lipooxygenase activity can delay of cartilago degradation. PMID- 21542250 TI - [The influence of alcohol on the oral cavity, salivary glands and saliva]. AB - Ethanol diffuses rapidly into saliva during the drinking, and immediately after its salivary concentration is temporarily much higher than in plasma. Within 30 minutes, salivary ethanol concentration equilibrates with the plasma level, thus suggesting that ethanol easily penetrates the whole body, including oral cavity tissues and salivary glands. After alcohol intake, the level of acetaldehyde in saliva strikingly exceeds the level in systemic blood. From saliva, acetaldehyde and ethanol easily reach all local tissues. Damage to the oral tissues seems to be ascribed mostly to the action of acetaldehyde, although some acute effects depend on a direct action of ethanol and formation of reactive oxygen species (ROS) and fatty acid ethyl esters (FAEEs). It is known that the oral mucosal surface is the home of numerous normal flora microorganisms and is the portal of entry for the majority of pathogens. The oral cavity and salivary antimicrobial immune defense systems eliminate pathogens and prevent massive overgrowth of microorganisms. An oral defense system participate in the protection of not only oral tissues, but also in the protection of upper digestive and respiratory tracts, against a number of microbial pathogens. Saliva plays the role in the oral cavity lubrication, maintenance of mucosal and tooth integrity, esophageal physiology, digestion and gastric cytoprotection. As alcohol abuse affects the structure and function of oral cavity mucosa, salivary glands and saliva, the maintenance of oral and general health under normal conditions is seriously impaired during the drinking. The severe tissue damage occurs in particular when alcohol abuse coincides with smoking. PMID- 21542252 TI - [Cyclooxygenases inhibitors and other compounds with antiinflammatory potential in osteoarthrosis--part II]. AB - NO-NSAIDs (or CINODs that is COX-inhibiting nitric oxide donors) are new class of antiinflammatory drugs and have a multi-pathway mechanism of action that involves cyclooxygenases (COXs) inhibition and nitric oxide (NO) donation. The first drug of this group is naproxcinod, which exerts rarely adverse effects of stomach, gut and less cardiovascular toxicity with naproxen. NO is an important mediator of endothelial function acting as a vasodilator and plays role in inflammation and pain perception that may be of relevance in osteoarthritis and in healing injures in stomach and gut. Lipoxins (LX, LXs): LXA4, LXB4 are group of lipid mediators leading to resolution of inflammation and protective influence on gastrointestinal mucosa. ATL (AT mean aspirin triggered therefore "depend on aspirin") synthesis, via COX-2, reduces the severity of damage gastrointestinal tract induced by NSAIDs. ATL also plays role in gastric adaptation during chronic aspirin administration. Antiinflammatory drugs hydrogen sulfide-releasing (H2S) (ATB-337 that consist of diclofenac linked to a hydrogen sulfide-releasing moiety) may show better efficacy and less toxicity. COX/5-LOX inhibitors and NO NSAIDs heals symptoms of osteoarthrosis. PMID- 21542253 TI - [Adequate solutions]. PMID- 21542254 TI - [Abuse of addictive drugs by nursing personnel. Neither punishment nor compassion but reliable solutions]. PMID- 21542255 TI - [Close monitoring in addiction recovery]. PMID- 21542256 TI - [Exercise and promoting motor activity in nursing. A mainstay in the nursing process]. PMID- 21542257 TI - [Animal assisted therapy. Respectful interaction behind bars]. PMID- 21542258 TI - [Interdisciplinary collaboration. Curiosity and respect assumed]. PMID- 21542259 TI - [New network. Engagement for excellent transplantation nursing]. PMID- 21542260 TI - [Liberia. Light again in the hospital]. PMID- 21542261 TI - [Settimio Monteverde. "There is no ethics free space" (interview by Urs Luthi)]. PMID- 21542262 TI - [Gaining clarity for the future]. PMID- 21542263 TI - [More and more vulnerable people]. PMID- 21542264 TI - [Dysfunctional situations at work. Co-dependence: no thank you!]. PMID- 21542265 TI - [Citizen psychiatry. All invited to the banquet]. PMID- 21542266 TI - [Nurse shortage and immigrants. Why not a bi-national training]. PMID- 21542267 TI - [Pediatric nursing. Addressing vulnerability]. PMID- 21542268 TI - [Caring for caregivers. A ritual of mourning for the team]. PMID- 21542269 TI - [Unfair dismissal. When the employer fails his responsibilities]. PMID- 21542270 TI - [The syndrome of 3 D]. PMID- 21542271 TI - [Basal cell carcinoma of the skin--biological behaviour of the tumor and a review of the most important molecular predictors of disease progression in pathological practice]. AB - Basal cell carcinoma of the skin is currently the most frequent malignancy in human population. Basal cell carcinoma represents a heterogeneous group of tumors with a variable clinical and morphological picture. Based on its biological behaviour, we generally differentiate between indolent (superficial and nodular) and aggressive type (infiltrative, micronodular, and metatypical) of basal cell carcinoma. Because of the different biological characteristics of these tumors, it is questionable whether they are a part of a continuous spectrum of carcinogenesis, starting with indolent and ending with aggressive forms, or they represent separate developmental lines. In the current clinical practice, there is an increasing demand for identification of tumors that are prognostically more adverse and their impact on the overall health status of patients is more serious. Recent advances in pathology and molecular medicine allow identification of various biomarkers from tumor tissue that are significantly involved in the mechanisms of malignant cell transformation. Detection of these biomarkers is of great importance in predicting further clinical behaviour of the cancer. The authors of the paper present basic information about biological behaviour of cutaneous basal cell carcinoma and provide an overview of the most important biomarkers that influence the clinical outcome and disease progression and are detectable through a routine biopsy tissue examination. It is now necessary to search for novel histological and molecular parameters that, in the future, could have a prognostic value in diagnostic and therapeutic process of this disorder. PMID- 21542272 TI - [Coronary heart disease and hypertension as late effects of testicular cancer treatment--a minireview]. AB - The modern treatment of testicular cancer has led to notable improvement in the prognosis of these patients. A significant number of testicular cancer survivors suffer from late effects of their treatment that can occur several years after the treatment. Cardiovascular late effects represent one of the most serious effects with respect to their life-threatening potential. Considering the higher risk of coronary heart disease, numerous studies have investigated the prevalence of cardiovascular risk factors in patients treated for testicular cancer. Higher prevalence of hypertension in patients after treatment for testicular cancer may be one of the reasons for their serious cardiovascular morbidity and mortality.The aim of this is to summarize the current knowledge on the impact of review treatment modalities used in testicular cancer therapy on prevalence of hypertension and its pathogenetic context. Both chemotherapy and radiotherapy are associated with increased prevalence of hypertension several years after completing the treatment. In patients treated with chemotherapy, hypertension is associated with administration of cisplatin. Cisplatin remains in organism for up to 20 years after administration and may lead to endothelial dysfunction. Regular and long-term monitoring of cardiovascular risk should be introduced to ensure better quality of life in these patients. PMID- 21542273 TI - [The use of PET/CT fusion in radiotherapy treatment planning of non-small-cell lung cancers]. AB - BACKGROUNDS: Lung cancer is currently the most frequently diagnosed malignant disease worldwide and radiotherapy has a fundamental and irreplaceable role in the therapeutic algorithm of this disease. Conventionally, radiotherapy is planned using CT alone. However, this could be a source of many inaccuracies and errors in the process of contouring the target volumes, the likelihood of which could be decreased by using the data from PET imaging and, ideally, from a fusion of PET and CT (as has already been proven in the diagnosis of lung cancer). CASE: This review is devoted to all important aspects related to the use of PET/CT imaging in radiotherapy treatment planning of non-small-cell lung cancer and to the advantages resulting from its use. CONCLUSION: Investigation of PET/CT imaging is a useful tool leading to increased accuracy of contouring of the target volumes. The integration of both diagnostic modalities reduces the limitations of these modalities if used separately. The use of combined PET/CT imaging often leads to an identification of a change in tumor size (it also often uncovers distant metastases) resulting in a change of treatment intention. The change of the target volume size and thus the change of irradiated volume of critical structures could lead to an increase of the dose delivered to the tumor in situations when a reduction of these volumes was reached. Investigation of PET/CT imaging also has a positive impact on subjective approach to contouring by different radiation oncologists. PMID- 21542274 TI - [Plasma cell separation algorithm from bone marrow samples]. AB - BACKGROUNDS: The aim of this paper is to present an algorithm for plasma cell separation from bone marrow samples of multiple myeloma patients. The main prerequisite for applying modern research methods in this disease is gaining pure cell populations. MATERIAL AND METHODS: Bone marrow samples were collected from outpatients or inpatients of the Internal Haematology and Oncology Clinic of the Faculty Hospital Brno, after they had signed an Informed Consent Form. The bone marrow was first depleted of red cells (by density gradient centrifugation or erythrolysis), plasma cells were labelled by monoclonal antibody against syndecan 1 (CD138) and separated either magnetically or by cell sorter. The purity of separated population was evaluated by flow cytometry or, alternatively, morfologically. RESULTS: We processed 28 bone marrow samples, in parallel, by magnetic or fluorescence-based separation, and we evaluated the purity of the separated fractions. Based on a statistical evaluation of resulting purities in the entire sample set as well as the individual groups divided according to the initial plasma cell content, a separation algorithm was proposed with a cut-off value of 5% of plasma cells in mononuclear fraction of bone marrow: samples with less than 5% of plasma cells are henceforth separated on cell sorter, samples with more than 5% are separated magnetically.The effectiveness of this algorithm was evaluated after the first year of its application on a dataset of 210 bone marrow samples: median purity of the separated plasma cells increased from 62.4% (0.4-99.6%) to 94.0% (23.9-100%). CONCLUSION: The introduction of a fluorescence based separation markedly increased the effectiveness of plasma cell separation from bone marrow samples, mainly in samples with low plasma cell content where magnetic separation used thus far is not sufficient. This finding also opened a door for plasma cell separation of bone marrow samples from patients with monoclonal gammopathy of undetermined significance, where plasma cell count is typically below or just over one percent. PMID- 21542275 TI - [Opportunistic infections in patients after complex therapy of cancer]. AB - BACKGROUNDS: An opportunistic infection is an infection caused by pathogens, such as Toxoplasma gondii, that usually are not pathogenic in a healthy host but may cause an infection in immunocompromised patients. Although the most frequent cause of an opportunistic infection is immunodeficiency due to HIV infection, the immunodeficiency induced by anticancer treatment cannot be ignored. DESIGN: A 56 year old female patient after a comprehensive treatment of breast cancer underwent a stereotactic biopsy of MR-verified multiple brain lesions suspected to be of metastatic aetiology. The histology report unexpectedly concluded that the lesion was brain toxoplasmosis confirmed by detection of IgM specific antibody in cerebrospinal fluid. Immunology examination has proven a deficit of cell-mediated immunity. The symptoms (cephalea, cerebellar symptomatology with vertigo) and MR findings disappeared following 6-month treatment with a combination of pyrimethamin, sulfadiazin and leucovorin. CONCLUSION: Since neoplastic duplicities and brain lesions of non-neoplastic aetiology are found in about 11% of oncology patients, histological verification of aetiology of intracranial lesions is essential for targeted therapy of these patients. Our case of brain toxoplasmosis documents the role of opportunistic infections in differential diagnosis of brain lesions in patients who underwent anticancer treatment. PMID- 21542276 TI - [Vulvar intraepithelial neoplasia]. AB - HPV infections of the lower genital tract are associated with the increasing incidence of vulvar intraepithelial neoplasia. The new classification divides vulvar intraepithelial neoplasia according to its incidence into two groups: usual and differentiated type. The usual type occurs mainly in young women and is associated with HPV infection, the differentiated type is HPV-negative and occurs in older women. The diagnosis is based on biopsy from a suspicious lesion. The standard treatment involves surgical excision. Topical treatment is now being preferred in young women in order to preserve appearance of the genitalia and sexual function. The high risk of recurrence is the reason for strict monitoring of patients after treatment completion. PMID- 21542277 TI - [The current development of new drugs for solid tumors--change of view on the optimal design of clinical trials]. PMID- 21542278 TI - [The role of avastin in the treatment of breast carcinoma in Europe and the United States]. PMID- 21542279 TI - [18th oncology forum--report from the meeting in Brno November 5 2010]. PMID- 21542280 TI - [Application of small molecule compounds inducing differentiation of stem cells]. AB - With the development of stem cells and regenerative medicine (treatment of various diseases using stem cells) research, the induction of differentiation of human stem cell technology has also made significant progress. The development of chemical biology offers a variety of small biological molecules for stem cell biology. This review focuses on how small molecule compounds (natural and synthetic) induce differentiation of stem cells. PMID- 21542281 TI - [Application of nuclear magnetic resonance to the determination of the configuration of glycoside bond]. AB - In the structural determination of natural glycosides, nuclear magnetic resonance (NMR) is an important approach in determining the configuration of glycoside bond. The test of coupling constant of the anomeric proton and chemical shift of the anomeric carbon are two common methods, but these methods are not suitable for some sugars. For those sugars, detailed 13C NMR analysis is an alternative choice. This paper summarizes the characteristics of 1H and 13C NMR data of the common monosaccharides published in the literatures, in order to search an approach to determine the configuration of glycoside bond. PMID- 21542282 TI - [Recent advances and perspective in the study of the molecular imprinting of proteins]. AB - Molecular imprinting technique (MIT) involves the synthesis of polymer in the presence of a template to produce complementary binding sites in terms of its size, shape, and functional group orientation. Such kind of polymer possesses specific recognition ability towards its template molecule. Despite the rapid development of MIT over the years, the majority of the template molecules that have been studied are small molecules, while molecular imprinting of proteins remains a significant yet challenging task due to their large size, structural flexibility and complex conformation. In this review, we summarize the research findings over the past five years, and discuss the characteristics of the technique, the most recent progress and the perspective in the field of molecular imprinting of proteins. PMID- 21542283 TI - [Knock-down of apollon gene by antisense oligodeoxynucleotide inhibits the proliferation of Lovo cells and enhances chemo-sensitivity]. AB - In this study, the effects of apollon antisense oligodeoxynucleotide (ASODN) on the proliferation and apoptosis of human Lovo cells in vitro were investigated. Apollon ASODN was incubated with human colorectal Lovo cells for 48 h, the proliferation inhibition and the clone forming rates were detected by WST method and clone formation assay, respectively. The expression of apollon mRNA was analyzed by real time fluorescent quantitative reverse transcription polymerase chain reaction. The percentage of apoptotic cells and cell cycle distribution were determined by flow cytometry. The morphology of apoptotic cells was examined by fluorescence microscope. Lovo cells incubated with apollon ASODN combined with 5-fluorouracil (5-FU), cisplatin (DDP) or epirubicin (EPI) of different concentrations, cell proliferation inhibition rates were detected with WST method and IC50 was calculated. It was found that ASODN targeting apollon gene could all suppress the growth of Lovo cells and induce apoptosis of these cells significantly (P < 0.05). After Lovo cells treated with apollon ASODN for 48 hours, the expression of the apollon mRNA level was suppressed significantly. And a marked concentration-dependent decline of cell proliferation and clone forming, increasing of cell apoptosis levels were observed. The percentage of G0/G1 phage cells was abated and that of S phage cells was increased and the Lovo cells arrested at S phage of the cell cycle detected with flow cytometry. Many Lovo cells stained with Hoechst 33258 exhibited apoptotic morphology such as cell shrinkage, nuclear condensation and nuclear fragmentation. Cell proliferation inhibition was detected and their chemo-therapeutic effects of 5-FU, DDP and EPI on Lovo cells combined with apollon ASODN (0.08 micromol x L(-1)) were enhanced independently compared with single 5-FU, DDP and EPI groups, and the sensitivity enhanced about 2.58, 4.47, and 5.33 times respectively. It can be concluded that ASODN targeting apollon can suppress the expression of apollon mRNA, and inhibit the proliferation, induce apoptosis, arrest cell cycle at S phase of colorectal cancer Lovo cells in vitro and enhance the chemo-sensitivity to 5-FU, DDP and EPI. PMID- 21542284 TI - [Role of nuclear factor-kappaB on emodin-induced sensitization of pancreatic cancer to gemcitabine]. AB - In view of gemcitabine resistance has limited clinical activity of gemcitabine as a cellulotoxic drug in pancreatic cancer patients, this study is designed to investigate the effect of emodin on the sensitivity of pancreatic cancer to gemcitabine as well as its mechanism. After gemcitabine-resistant pancreatic cancer cell line (SW1990/GZ) was established by escalating doses of gemcitabine serially in pancreatic cancer cell line (SW1990). The cellular proliferation was detected by cell counting kit-8 (CCK-8) assay. Flow cytometry (FCM) was used to determine apoptosis of pancreatic cancer cells. The activity of NF-kappaB in pancreatic cancer cells was measured by electrophoretic mobility shift assay (EMSA). Western blotting was used to detect the protein expression of Bcl-2 and Survivin in SW1990/GZ cells. Metastatic model simulating human pancreatic cancer was established by orthotopic implantation of histologically intact human tumor tissue into pancreatic wall of nude mice. Also, immunohistochemistry was used to detect the positive expression of Ki-67, NF-kappaB, Bcl-2 and Survivin in the tumors. The results show that pretreatment of cells with emodin followed by gemcitabine induced a higher percentage of growth inhibition and apoptosis of pancreatic cancer cells than that of gemcitabine alone. In addition to in vitro results, emodin in combination with gemcitabine is much more effective as an antitumor agent compared to either agent alone in the orthotopic tumor model. Further study showed that the emodin with or without gemcitabine significantly down-regulates NF-kappaB and its regulated molecules such as Bcl-2 and Survivin proteins both in vitro and in vivo. It is concluded that inactivation of NF kappaB signaling pathway by emodin resulting in the chemosensitization of pancreatic cancer to gemcitabine, which is likely to be an important and novel strategy for the treatment of pancreatic cancer. PMID- 21542285 TI - [Inhibitory effect of hydroxysafflor yellow A against PMN activation induced by LPS]. AB - Carthamus tinctorius L. is a traditional Chinese medicine with the effect of promoting blood circulation and removing blood stasis. HSYA (hydroxysafflor yellow A) is the main effective component of Carthamus tinctorius L. In order to study the inhibitory effects of HSYA against PMN (polymorphonuclear) activation induced by LPS (lipopolysaccharide), rabbit PMN adhesion potency which was activated by LPS through colorimetry method was observed. Cellular free calcium concentration was determined by fluorescence spectrophotometry. RT-PCR was applied to study the effect of HSYA on PMN TNF-alpha and IL-6 mRNA expression; The inhibition of HSYA on NF-kappaB activation was monitored with immunofluorescence. The results showed that after treated with HSYA, the increase of adhesion potency (HSYA dose 1.01 x 10(-4) mol x L(-1)), free calcium concentration (HSYA dose 3.1 x 10(-5) mol x L(-1)), TNF-alpha and IL-6 mRNA expression elevation (HSYA dose 5.2 x 10(-1) mol x L(-1)) induced by LPS were inhibited. HSYA can inhibit NF-kappaB p65 subgroup nuclear translocation (HSYA dose 5.2 x 10(-5) mol x L(-1)). It is suggested that HSYA is effective in PMN activation induced by LPS. PMID- 21542286 TI - [Mechanism of the reduction of cerebral ischemic-reperfusion injury through inhibiting the activity of NF-kappaB by propyl gallate]. AB - The probable mechanism of the reduction of rat cerebral ischemic-reperfusion injury by propyl gallate was studied. Intraluminal suture middle cerebral artery occlusion model of rat was employed. Propyl gallate was injected immediately after the ischemia was happened. The activity of NF-kappaB, and the expression of COX-2 and HSP70 on the peripheral ischemia were determined by Western blotting. The expression of TNF-alpha was determined by ELISA assay. RT-PCR and immunofluorescence staining were employed to detect the transcription and expression of TLR-4. Results showed that propyl gallate could inhibit the activity of NF-kappaB in the peripheral ischemia, and reduce the expression of COX-2 and TNF-alpha. As the upstream of NF-kappaB, the transcription and expression of TLR-4 decreased, as well as HSP70, the endogenic ligand of TLR-4. As an antioxidant, propyl gallate could reduce the cerebral ischemic-reperfusion injury through inhibiting the activity of NF-kappaB and decreasing the COX-2 and TNF-alpha in the peripheral ischemia. It also could influence HSP70 and TLR-4. PMID- 21542287 TI - [Study of a novel compound 2460A with activities produced by fungus]. AB - With IL-6R as target, a new compound 2460A was identified from fungus using HTS screening model. The taxonomics of the produced strain was confirmed to be Trichoderma hazianum rifai after sequencing analysis of rDNA-ITS (internal transcribed spacer). Results showed that this compound has a binding activity on IL-6R competed with IL-6, thus it is a new ligand of IL-6R originating from microbe. With MTT assay, the anti-tumor activities of 2460A were demonstrated on CM126 and HT-29 cell lines separately, the IC50 are 2.17 x 10(-5) mol x L(-1) and 1.8 x 10(-5) mol x L(-1) respectively. The compound affected lightly the HT-29 cell cycle at S phase. Studies for the anti-tumor activity of 2460A in vivo are in progress in our lab. PMID- 21542288 TI - [The design of muti-target antitumor drugs affecting on FTase and Raf-1 kinase]. AB - Ras/Raf/MEK/ERK singal transduction plays an important role in cell proliferation, differentiation, apoptosis, metastasis and metabolism. This investigation focused on this signal pathway and chose farnesyl transferase (FTase) as the main target and Raf-1 kinase as the second target. A lot of compounds were selected to construct the pharmacophore models of farnesyl transferase inhibitors (FTIs) and Raf-1 kinase inhibitors by using computer-aided drug design (CADD). The pharmacophore of FTIs is constituted by a hydrogen bonding acceptor, an aromatic ring, a positive ionizable and two hydrophobic regions; the pharmacophore of Raf-1 kinase is constituted by a hydrogen donor, a hydrogen acceptor, a hydrophobic regions and an aromatic ring. There are some similarities between the two pharmacophores. After analysis of the constructions of these two pharmacophores, some new aminomethylbenzoic acid derivatives with good forecasting activity against both of FTase and Raf-1 kinase were designed with these new pharmacophore models. PMID- 21542289 TI - [Two new phragmalin-type limonoid orthesters from Chukrasia tabularis var. velutina]. AB - As a part of our ongoing research program to isolate novel phragmalin limonoids from the stem bark of Chukrasia tabularis var. velutina, two new phragmalin limonoids orthesters, tabularin Q (1) and tabulalide O (4), along with two known compounds tabularin C (2) and tabularin H (3) were isolated. Their structures were elucidated by means of extensive 1D and 2D spectroscopic analyses which included HSQC, HMBC, and ROESY experiments and HR-ESI-MS. PMID- 21542290 TI - [A new aristolochic acid derivative from Asarum himalaicum]. AB - To study the chemical constituents of Asarum himalaicum, fifteen compounds were isolated from a 70% ethanol extract by using a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, and semi-preparative HPLC. By spectroscopic techniques including 1H NMR, 13C NMR, and HR-ESI-MS, these compounds were identified as 4 demethoxyaristolochic acid BII (1), aristolochic acid I (2), aristolochic acid Ia (3), 7-hydroxyaristolochic acid I (4), aristolochic acid IV (5), aristolic acid II (6), debilic acid (7), aristololactam I (8), 9-hydroxyaristololactam I (9), 7 methoxyaristololactam IV (10), (2S)-narigenin-5, 7-di-O-beta-D-pyranosylglucoside (11), 4-hydroxybenzoic acid (12), 3, 4-dihydroxybenzoic acid (13), 4 hydroxycinnamic acid (14), and beta-sitosterol (15). All of these compounds (1 15) were obtained from A. himalaicum for the first time. Among them, 1 was identified as a new compound, and compounds 3-6, 9, 12-14 were isolated from Asarum genus for the first time. Since the kidney toxicity of aristolochic acids and aristololactams has been reported, the result of this investigation suggests that it should be cautioned to use A. himalaicum as a medicine. PMID- 21542291 TI - [Microcalorimetric study on the metabolism of Staphylococcus aureus affected by qingkailing injection]. AB - This paper is to report the investigation on the metabolic behavior of Staphylococcus aureus (S. aureus) after given Qingkailing injection, and with the aim of seeking for a new quality control method based on biological assessment. The growth thermogenic curves of S. aureus were determined by microcalorimetry and analyzed by computer. The results showed that in the concentration range of (0-5.00%), the growth thermogenic curves of S. aureus were declined and removed back with increasing dosage of Qingkailing injection; the main parameters (T1, T2, k1, P1, P2 and I) and the dosage of Qingkailing injection have good correlation. The 50% inhibiting dosage is 3.26 %, and the optimal inhibiting dosage is 5.47%. Difference could be detected among the Qingkailing injection samples from different factories and different batches. It is proved that Qingkailing injection could inhibit the metabolic behavior of S. aureus, and microcalorimetry might be applied in the quality assessment of Qingkailing injection. PMID- 21542292 TI - [HPLC-UV-ELSD characteristic figure and chemical pattern recognition of Panacis Quinquefolii Radix]. AB - The paper is to report the establishment of a method of characteristic figure analysis for the quality control of Panacis Quinquefolii Radix. Application of HPLC-UV-ELSD techniques was connected in series and applied. The separation was carried out on the Agilent Extend-C18 (250 mm x 4.6 mm, 5 microm) column. The mobile phase consisted of water and acetonitrile with gradient elution. The flow rate was 1.0 mL x min(-1) and the wavelength of measurement was 203 nm. The temperature of drift tube was maintained at 106.5 degrees C and the flow rate of air was set at 2.9 L x min(-1). Twenty batches of the Panacis Quinquefolii Radix were determined. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) were applied to study on the HPLC characteristic figure and chemical pattern recognition. The HPLC-UV and HPLC-ELSD characteristic figure of Panacis Quinquefolii Radix was developed, the ginsenosides Rg1, Re, Rb1, Rc, Rb2, Rb3, Rd and the pseudoginsenoside F11 were identified. This method is accurate and reliable, and it can be used to control the quality of the Panacis Quinquefolii Radix. PMID- 21542293 TI - [Rapid analysis of metronidazole tablets by optic-fiber sensing technologies and the similarity of ultraviolet spectra]. AB - The paper is to report the development of an optic-fiber sensing technology method to analyze metronidazole tablets rapidly. In this fiber-optic sensing system, the light from source delivering to probe can be dipped into simple handling sample solution, absorbed by the solution and reflected to the fiber optic and detected in the detection system at last. Then the drug content can be shown in the screen from the ultraviolet absorption spectra and the consistency between that obtained by this method and that in China Pharmacopoeia can be compared. With regard to data processing, a new method is explored to identify the authenticity of drugs using the similarity between the sample map and the standard pattern by full ultraviolet spectrum. The results indicate that ultraviolet spectra of tablets can be obtained from this technology and the determination results showed no significant difference as compared with the method in China Pharmacopoeia (P > 0.05), and the similarity can be a parameter to identify the authenticity of drugs. PMID- 21542294 TI - [CYP2D6*1, CYP2D6*10 co-expressed with CYPOR in Bac-to-Bac expression system and activity determination]. AB - CYP2D6 is an important drug-metabolizing enzyme. The polymorphism of CYP2D6 leads to metabolism difference and the different reactions of drugs in the individuals and different races are normal phenomenon in clinical medication. CYP2D6*10 is an important subtype in Asian people and 51.3% Chinese are classified with this subtype. To obtain recombinant active CYP2D6*1/CYP2D6*10 in baculovirus system by optimizing coexpression with CYPOR, and detect their activity to catalyze dextromethorphan, three recombinants pFastBac-CYP2D6*1, pFastBac-CYP2D6*10 and pFastBac-CYPOR were constructed and transformed into DH10Bac cell to obtain the recombinant Bacmid-CYPOR, Bacmid-CYP2D6*1 and Bacmid-CYP2D6*10. And then the recombinant CYP2D6*1 and CYP2D6*10 virus were obtained by transfecting Sf9. Then homogenate protein activity was determined with dextromethorphan as substrate. The multiple of infection (MOI) and its ratio of recombinant CYP2D6 virus to CYPOR virus were adjusted by detecting the activity of the homogenate protein. The Km and Vmax are 26.67 +/- 2.71 micromol x L(-1) (n=3) and 666.7 +/- 56.78 pmol x nmol(-1) (CYP2D6) x min(-1) (n=3) for CYP2D6*1 to catalyze dextromethaphan. The Km and Vmax are 111.36 +/- 10.89 micromol x L(-1) (n=3) and 222.2 +/- 20.12 pmol x nmol(-1) (CYP2D6) x min(-1) (n=3) for CYP2D6*10 to catalyze dextromethorphan. There is significant difference between CYP2D6*1 and CYP2D6*10 for Vmax and Km (P < 0.01). The clearance ratio of CYP2D6*1 is 25.0 and the clearance ratio of CYP2D6*10 is 2.0. The expressed CYP2D6*1 and CYP2D6*10 are useful tools to screen the metabolism profile of many xenobiotics and endobiotics in vitro, which are benefit to understand individual metabolism difference. PMID- 21542295 TI - [Rheological properties of poloxamer 407 aqueous solutions]. AB - Rheological properties of poloxamer 407 (brand named Pluronic F127) were examined by changing shear rate, temperature and the recovery properties of apparent viscosity after heating for several times. The results indicated that poloxamer 407 aqueous solution showed a Newtonian behavior at a low concentration while it might be a pseudoplastic fluid when the concentration reached a certain point. The thixotropy and the sol-gel transition temperature decreased with increasing the concentration (it could be an in situ gel at body temperature when the concentration of poloxamer 407 up to 15.25%). The results that obtained from the theological data would be useful in the application of poloxamer 407 such as in situ gel preparation. PMID- 21542296 TI - [The enhancing effect of Angelica dahurica extracts on absorption of baicalin- the active composition of Scutellaria]. AB - To explore the mechanism of the absorption enhancement of Angelica dahurica extract (Ade), the absorption mechanism of baicalin in the Scutcllaria water extraction as well as the effect of Angelica dahurica extract on absorption of baicalin were investigated. In order to determine the main absorption site, everted intestinal sac model was used to study the effect of Angelica dahurica extract on the absorption of baicalin at duodenum, jejunum, ileum and colon. In situ single pass intestinal perfusion model was performed to study the absorption of various concentrations of baicalin and the effect of Angelica dahurica extract on the absorption of baicalin at the main absorption site. To authenticate the consequence of perfusion by getting the blood from the hepatic portal vein and determine the concentration of the baicalin in the blood. The result showed that baicalin could be absorbed at all of the four intestinal segments with increasing absorption amount per unit as follows: ileum > colon > jejunum > duodenum. The absorption ofbaicalin in the duodenum significantly increased with Angelica dahurica extract, thus, duodenum was chosen to be the studying site. Apparent permeability values (Papp) and absorption rate constant (Ka) of baicalin in the duodenum increased gradually with higher concentrations. When the concentration of baicalin rises to a certain degree, the absorption increase had a saturable process, the absorption of baicalin may be an active transportation. Baicalin may be not a substrate of P-gp as verapamil which had not significantly affected the Papp and Ka of baicalin. The absorption of baicalin in the duodenum significantly increased (P < 0.01) in the two models with Angelica dahurica extract and the concentration of baicalin in the blood from the hepatic portal vein showed that the Angelica dahurica extract can increase the absorption of baicalin. PMID- 21542297 TI - [CYP2D6 genotypes and phenotypes in Chinese Han, Uygur and Kazakh populations]. AB - This study is to compare the influence of CYP2D6 *3 and *4 genotypes and phenotypes on the metabolic activity of CYP2D6 in Chinese Han, Uygur and Kazakh ethnic groups. Allele specific amplification (ASA) was used to determine the CYP2D6*3 and CYP2D6*4 genotypes. Phenotypes of CYP2D6 in all subjects were determined using dextromethorphan as probe drug by HPLC methods. Among the 132 Han subjects, one subject (0.76%) exhibited the *1/*3 combination, and one (0.76%) exhibited the *1/*4. Among the 136 Uygur subjects, 4 subjects (2.94%) showed the *1/*3 combination, 12 (8.82%) showed *1/*4, 4 (2.94%) showed *4/*4, and one (0.74%) showed *3/*4. Among the 116 Kazakh subjects, 2 (1.72%) exhibited the *1/*3 combination, 7 (6.03%) exhibited *1/1*4, and one (0.86%) showed *4/*4. This research revealed significant differences in the occurrence frequencies of the CYP2D6 genotype between Han and Uygur ethnic groups, as well as between Uygur and Kazakh populations. However, no difference was found between Han and Kazakh populations. In addition, the prevalence of PMs of the Uygur is comparable to that of the Caucasians. However, the molecular mechanism underlying the poor metabolism is different in these two populations. PMID- 21542298 TI - [Determination of protein binding rate of oleanolic acid in human plasma and serum albumin]. AB - A LC-MS method was established for the determination of the protein binding rates of oleanolic acid in human plasma and serum albumin. The equilibrium dialysis combined with LC-MS to determine the total concentration in plasma and free drug concentration of oleanolic acid was carried out. The human plasma protein binding rates of oleanolic acid at three concentrations were 79.6%, 81.9% and 63.3%, respectively. The human serum albumin protein binding rates of oleanolic acid at three concentrations were 53.5%, 56.6% and 47.7%, respectively. The method is shown to be simple, accurate, sensitive and specific for the determination of biological samples. The protein binding rates in human plasma and serum albumin were of high strength. PMID- 21542299 TI - [Cyanobacterial cell division: genetics and comparative genomics of cyanobacterial cell division]. AB - Division of cyanobacteria serves as a model for studying division of plant chloroplasts. Analysis of mutants obtained by methods of "forward" and "reverse" genetics underlies effective vertical strategy for studying genetics of cell division in these photoautotrophic prokaryotes. Comparative genomic analysis indicates that some cyanobacterial genes involved in the control of cell division have homologs among cyanobacteria, green algae, and higher plants, some others, only in bacteria, whereas the remaining genes are specific only for cyanobacteria. PMID- 21542300 TI - [Molecular genetic determinants of intraspecific polymorphism of the phytopathogenic fungus Cryphonectria parasitica]. AB - The review summarizes the current evidence on the phytopathogenic fungus Cryphonectria parasitica, which is a classic object for studying hypovirulence. Phenotypic manifestations of hypovirulence and themolecular mechanisms of action of the mycovirus Cryphonectria hypovirus (CHV) infecting the fungus are described in detail. Genetic determinants of vegetative incompatibility in C. parasitica (a phenomenon increasing polymorphism of the fungus and preventing CHV expansion) are considered. The data on C. parasitica polymorphism are correlated with the data on the distribution of different CHV species in the European, American, and Asian populations of the fungus. PMID- 21542301 TI - [Investigation of pseudoautosomal and bordering regions in avian Z and W chromosomes with the use of large insert genomic BAC clones]. AB - To study pseudoautosomal and bordering regions in the avian Z and W chromosomes, we used seven BAC clones from genomic libraries as DNA probes of fragments of different gametologs of the ATP5A1 gene located close to the proximal border of the pseudoautosomal region (PAR) of sex chromosomes of domestic chicken and Japanese quail. Localization of BAC clones TAM31-b100C09, TAM31-b99N01, TAM31 b27P16, and TAM31-b95L18 in the short arm of Z chromosomes of domestic chicken and Japanese quail (region Zp23-p22) and localization of the BAC clones CHORI-261 CH46G16, CHORI-261-CH33F10, and CHORI-261-CH64F22 on W chromosomes of these species and in the short arm of Z chromosomes (region Zp23-p22) were determined by fluorescence in situ hybridization with the use of W-specific probes. The difference in the localization of the BAC clones on the Z and W chromosomes is probably explained by divergence of the nucleotide sequences of different sex chromosomes located beyond the pseudoautosomal region. PMID- 21542302 TI - [Is the cytosine DNA methyltransferase gene MET1 regulated by DNA methylation in Arabidopsis thaliana plants?]. AB - The methylation patterns of the MET1 gene in organs of Arabidopsis thaliana were studied by Southern blot hybridization of DNA samples hydrolyzed with differentially methylation-sensitive restriction endonucleases. A highly methylated on internal cytosine residue CCGG site was found 1.5 kb upstream of the gene, whereas CCGG sites located in more proximal parts of the 5'-flanking region and the gene itself are essentially unmethylated. This methylation pattern was observed in different organs of plants belonging to two different ecotypes as well as in different transgenic plant lines. The methylation level ofa CCGG site in exon 3 (2.1 kb from the gene's 5'-end) occurred to be variable between different transgenic plant lines and two ecotypes studied. Transcription levels of the MET1 gene vary slightly in organs of wild-type plants without any obvious correlation with its methylation. The transgenic antisense MET1 constructs expressed in plant genome do affect both MET1 methylation and its transcription but again without any obvious correlation. The comparative investigation of transcription levels of different genes of cytosine DNA methyltransferase family MET (MET1, MET2a, MET2b, MET3) and their methylation patterns shows that there may exist some mechanisms defending the most actively transcribed gene MET1 of this family from methylation mediated silencing. In contrast to DRM2 gene we could not find any adenine methylated GATC sites in the MET1 gene. PMID- 21542303 TI - [Genetic bases of methionine dependence in Yersinia pestis strains of major and non-major subspecies]. AB - Structural and functional organization of genes responsible for biosynthesis of amino acid methionine, which plays a leading role in cellular metabolism of bacteria, was studied in 24 natural Yersinia pestis strains of the major and minor subspecies from various natural plague foci located in the territory of Russian Federation and neighbouring foreign countries, and also in Y. pestis and Y. pseudotuberculosis strains recorded in the files of NCBI GenBank database. Conservatism of genes metA, metB, metC, metE, and metH as well as regulatory genes metR and metJ involved in biosynthesis of this amino acid was established. Sequencing of the variable locus of gene metB in natural Y. pestis strains of major and minor subspecies revealed that the reason for the methionine dependence of strains belonging to the major subspecies is a deletion of a single nucleotide (-G) in the 988 position from the beginning of the gene, whereas this dependence in strains belonging to subspecies hissarica results from the appearance of a single nucleotide (+G) insertion in the 989 position of gene metB. These mutations are absent in strains of the caucasica, altaica, and ulegeica subspecies of the plague agent and in strains of pseudotuberculosis microbe, which correlates with their capacity for methionine biosynthesis. PMID- 21542304 TI - [Study of genetic diversity and spatial structure of the wild soybean (Glycine soja Sieb. & Zucc.) population from the Ekaterinovka in the south of Primorskii krai]. AB - Data are presented on the genetic diversity and spatial structure of the natural wild soybean population from the neighborhood of the settlement of Ekaterinovka in Primorskii krai and on the relationship between the genetic structure of this population and its spatial organization. These data are discussed in comparison with the results of studies of wild soybean populations in the Far East region of the Russian Federation and China. Recommendations are given concerning the collection of genetic wild soybean resources. PMID- 21542305 TI - [Polymorphism of SSR alleles in pear cultivars grown in Belarus]. AB - Using SSR markers designed for Malus x domestica Borkh, genetic polymorphism of 43 pear accessions cultivated in Belarus was examined. A total of 217 alleles were identified with the mean number of 12.8 alleles per marker. The mean PIC value was 0.81; the mean number of informative alleles, 6.49. The heterozygosity level ranged from 0.30 to 0.84. Genetic diversity of SSR alleles in pear and apple genomes was compared. A method of identification of commercial pear cultivars using a set of six SSR markers was suggested. PMID- 21542306 TI - [Phylogenetic relationships of silver crucian carp Carassius auratus gibelio, C. auratus cuvieri, crucian carp C. carassius, and common carp Cyprinus carpio as inferred from mitochondrial DNA variation]. AB - PCR-RFLP analysis of the ND3/ND4L/ND4 and 12S/16S rRNA regions and nucleotide sequence variation of the cytochrome b gene were used to study the mtDNA divergence in species of the family Cyprinidae, to examine the phylogenetic relationships of the species, and to identify their taxonomic status. The results indicated that an ancestral form diverged into silver crucian carp and crucian carp after its separation from the common carp lineage. The divergence of continental Carassius auratus gibelio and Japanese C. auratus cuvieri occurred more recently. Two well distinguishable mtDNA phylogroups, suggesting divergent evolution, were observed in continental C. auratus gibelio populations. The divergence was possibly related to the formation of two silver crucian carp groups with different types of reproduction, triploid gynogenetic and diploid gonochoric. At the same time, the results supported the high probability of current genetic exchange between the forms. In view of these findings and high morphological similarity of the two forms, they were not considered to be separate species. PMID- 21542307 TI - [Allozyme variation in pygmy wood mouse Apodemus uralensis (Rodenita, Muridae) in the Ural region]. AB - Variation of 17 allozyme loci was examined in 530 Apodemus uralensis individuals caught in the Ural region in 2005 through 2007. In the populations examined, the mean value of the population genetic differentiation index F(ST) constituted 0.169. It was demonstrated that F(ST) values for the samples obtained from the 1 km2 plot in different years, as well as for the samples trapped at a distance from 0.3 to 5 km during one year, could be remarkably higher than the mean value, pointing to their high, statistically significant differentiation. It seems likely that this differentiation was caused by spatial population subdivision, associated with the mice migrations, temporal change of the population structure, and the gene drift. In A. uralensis, inhabiting the zone of East Ural radioactive trace, no differences in the allozyme sets and their frequencies were observed. PMID- 21542308 TI - [Population structure of Volga Tatars inferred from the mitochondrial DNA diversity data]. AB - The data on mitochondrial DNA (mtDNA) variation in two populations of Volga Tatars, representing the population of Buinsk and Aznakaevo districts of the Republic of Tatarstan are presented. Comparative analysis of the data on mtDNA variation in the populations of Eastern Europe showed that Volga Tatars were characterized by low interpopulation differentiation (F(ST) = 0.33%), while the level of interethnic differentiation in Eastern Europe is 1.8%. Genetic similarity of Tatars from the eastern regions of Tatarstan to Bashkirs, as well as of Tatars from western regions to Chuvashes, with whom they share territorial borders, was revealed. Positive correlation between population genetic structure in Eastern Europe and linguistic affiliation of the ethnic groups studied was observed. PMID- 21542309 TI - [Skewed X-chromosome inactivation in human embryos with mosaic trisomy 16]. AB - The sex ratio and X-chromosome inactivation were analyzed in placental tissues of human spontaneous abortuses with pure and mosaic forms of chromosome 16 trisomy. The sex ratio value was found to decrease with an increase in the share of cells with the trisomic karyotype, which suggests differential survival of embryos belonging to different sexes. The pattern of X-chromosome inactivation in cells of extraembryonic mesoderm in the control group of embryos and in spontaneous abortuses with the level of trisomy 16 below 80% corresponded to random X inactivation, whereas in most embryos with a frequency of trisomy 16 exceeding 80% skewed inactivation was observed. Our results support the hypothesis about the existence of an autosomal transfactor influencing the initiation of X chromosome inactivation and suggest its possible localization on chromosome 16. PMID- 21542310 TI - [Evolution of legume-rhizobium symbiosis for an improved ecological efficiency and genotypic specificity of partner interactions]. AB - Mathematical simulation of the evolution of polymorphic legume-rhizobium symbiosis showed that co-evolution of the partners for an improved ecological efficiency of symbiosis is greatly stimulated when low-active N2-fixing and non N2-fixing strains of nodule bacteria are prohibited from colonizing nodules. The results of analysis of the model were collated with the comparative morphology of the infection process in various legumes, and its was assumed that mechanisms controlling bacterial reproduction in nodules arose in early evolution of symbiosis in primitive legumes owing to a transition from mixed to clonal infection. The development of such mechanisms was associated with adaptively valuable macroevolutionary transformations of symbiosis and directed its microevolution towards a parallel increase in the specificity and efficiency of mutualism. The increase was due to a reorganization of selective processes in endosymbiotic bacterial populations, which was based on changes in their genetic and spatial structures and optimized metabolic feedbacks between the partners (preferential allocation of photosynthesis products to the most active N2-fixing strains). PMID- 21542311 TI - [Study of a mtDNA deletion in BALB/c mice exposed to ionizing radiation]. AB - A novel large mtDNA deletion of 5914 bp was detected in mice exposed to X radiation. The regions flanking the deleted fragment were characterized by the method of sequencing. The possibility of using a minimum sample of the mouse auricle tissue for detecting mtDNA deletions in the same animals at different postradiation times is demonstrated. PMID- 21542312 TI - [Changes in face expression recognition caused by additional visual-spatial load]. AB - Changes in face expression recognition and EEG synchronization arising from additional load on working memory were studied in healthy adults. Two types of additional task--semantic and visuospatial--were used to load working memory in an experiment with a visual set, formed to facial stimuli. During perception of new facial stimuli, both these types of additional task caused an increase of erroneous face expression recognitions in the form of assimilative illusions. Alpha-band (8-10 Hz) EEG synchronization analysis revealed that additional memory load causes a decrease of frontal attention system input in set-forming and set shifting. As for theta-band (4-7 Hz) synchronization, it changed ambiguously at additional memory load--in right fronto-temporal region coherence function decreased; other coherence connections, especially intra-hemispheric and in the left hemisphere, increased. At issue is the crucial role of fronto-thalamic and cortico-hippocampal systems in plasticity of visual sets formed to facial expressions. PMID- 21542313 TI - [Selection of visual hierarchical stimuli between global and local aspects in men and women]. AB - Sex differences in global-local hemispheric selective processing were examined by hierarchical letter presenting in conditions of their perception and comparison. Fifty-six right-handed males and 68 females (aged 17-22 years) participated in the experiment. During interference between global and local aspects of stimuli the mean reaction times for correct global responses was quicker than local responses, and the right hemisphere has been dominated during global selective processing independently from the sex. Sex differences in perception of visual hierarchical stimuli were more pronounced than in comparison condition: men prefer mostly the right-hemispheric global strategy of information processing, but women--the left-hemispheric local one. Dominance of global strategy in men and local strategy in women during visual hierarchical stimuli perception together with no sex differences in correct responses indicates possibility of similar results in cognitive activity by different ways. PMID- 21542314 TI - [Identification of the images of gradually transforming geometrical figures]. AB - The effect changing of dependence of distance, on which subject move the optic mouse, on presented geometrical figure has been studied in psychophysiological experiments by transformation of quadrat in triangle by exclusion of one of figures of representations row. It has been found 75% authentic effects. The findings are discussed in connection with the phenomena of lateral inhibition, including possible neuronal mechanisms. PMID- 21542315 TI - [Features of brain mechanisms of regulation of the level of wakefulness, organization of cognitive functions and adaptive reactions in children with attention deficit with hyperactivity syndrome and healthy children]. AB - In work results of research of features of infringement superslow cortical truncal, limbic-reticular and upsegmentary mechanisms of regulation of a level of wakefulness at children of 6-7 years with a syndrome of deficiency of attention and hyperactivity and healthy children, pupils of 1 class of a comprehensive school with different type of psychological adaptation are generalized. At use system-integrativity psychophysiology the approach features are established: a) organization emotional-motivational and cognitive spheres; b) psychophysiology mechanisms of formation of adaptive reactions at tactile interaction about earlier unknown alive object--a dolphin at the surveyed contingent of healthy and ill children. PMID- 21542316 TI - [Age-related changes in saccadic eye movements in healthy subjects and patients with Parkinson's disease]. AB - Age-related changes in characteristics of saccadic eye movements (latency, duration and percentage of multistep saccades) in healthy subjects and patients with Parkinson's disease were evaluated. Healthy volunteers were divided into 6 age groups (17-20 years, 21-30 years, 31-40 years, 41-50 years, 51-60 years, 61 75 years), parkinsonian patients into 3 age groups (41-50 years, 51-60 years, 61 75 years). According to our data, saccade characteristics depend upon age in both healthy subjects and parkinsonian patients. In healthy volunteers the percentage of multistep saccades and the mean saccade latency increase significantly after the age of 60. Values of these characteristics in patients with Parkinson's disease significantly exceed the values in the corresponding age groups of healthy subjects. The "disease" factor (MANOVA) has a greater influence on saccade latency and percentage of multistep saccades then the "age" factor. The duration of single saccades depends on age to a smaller extent and does not change in patients with Parkinson's disease. The peculiarities of neurodegenerative processes during normal aging and aging with Parkinson's disease are discussed. PMID- 21542317 TI - [Influence of an additional movement task for the upper extremities on equilibrium maintenance in frontal and sagittal level in standing man]. AB - The postural oscillations of standing man were studied during additional manual motor task that consisted of maintaining of the moving ball in the center of flat box. The movement of a center of pressure (CP) in frontal and sagittal plane were analyzed during standing on stable rigid support and on moving unstable support. The influence of the additional motor task on CP movement depend on level of support stability. Sagittal CP movement increased while the additional task was executed during standing on moving support but it did not when the support was stable. Frontal CP movement decreased when the additional task was executed during standing on stable support but it did not while the support was unstable. Thus execution of the additional motor task execution led to the reduction of efficacy of the postural control on the moving unstable support. This result suggests that the cortical influence on the postural mechanism was stronger during standing on moving support in comparison to the standing on the stable support. PMID- 21542318 TI - [Effect of head-down tilt on respiratory responses and human inspiratory muscles activity]. AB - The effect of head-down tilt on respiration and diaphragmal and parasternal muscles activity was investigated in 11 healthy subjects. The short-time (30 min) head-down tilt posture (-30 degrees relatively horizont) increased the inspiratory time (P < 0.05), decreased breathing frequency (P < 0.05), inspiratory and expiratory flow rate (P < 0.05) and increased the airway resistance (P < 0.05) compared with values in vertical posture. There were no significant changes in tidal volume and minute ventilation. Constant values of tidal volume and minute ventilation during head-down tilt were provided by increasing in EMG activity of parasternal muscles more then twice. It was established that the contribution of chest wall inspiratory muscles increased while the diaphragm's contribution decreased during head-down spontaneous breathing. Maximal inspiratory effort (Muller's maneuver) during head-down tilt evoked the opposite EMG-activity pattern: the contribution of inspiratory thoracic muscles was decreased and diaphragm's EMG-activity was increased compared with vertical posture. These results suggest that coordinate modulations in inspiratory muscles activity allows to preserve the functional possibility of human inspiratory muscles during short-time head-down tilt. PMID- 21542319 TI - [Antioxidant activity of blood plasma of south Altai's indigenous population of low and medium height altitude areas]. AB - Due to the fact that age change theories are still under discussion a study has been conducted on the estimation of antioxidant and antiradical activity of blood plasma. For the experiment was taken a homogeneous group of people which separate populations differ in geographical and climatic parameters of their living conditions. As a result there has been discovered a dependence of Altaians' antioxidant system upon geographical and climatic conditions, and age. PMID- 21542320 TI - [Lipids and their correlation with vitamin D in the indigenous populations of Russia European North]. AB - The aim of our research was to investigate the level of 25-OH vitamin D in blood plasma of indigenous inhabitants of Russia European North. The study showed that there was wide spreading of vitamin D deficiency among northerners especially in teenager. The significant reduction of 25-OH vitamin D3 was revealed in the inhabitants of Far North in March. It is shown that there is correlation of the vitamin D with total cholesterol, apolipoprotein A, high and low density lipoproteins and vitamin A and E. PMID- 21542321 TI - [Relationship of single-nucleotide polymorphism rs11562975 in thermo-sensitive ion channel TRPM8 gene with human sensitivity to cold and menthol]. AB - The examination of people belonging to the Russian ethnic group revealed that 20.3% of subjects had heterozygous genotype, containing the C-allele in single nucleotide polymorphism rs11562975, located in exon 7 of the gene encoding the temperature-sensitive ion channel TRPM8. Functional differences, associated with sensitivity to cold and menthol were identified between subjects with different genotypes of the polymorphism rs11562975 (GG and GC). Subjects with heterozygous genotype GC were characterized by increased sensitivity to cold and reduced sensitivity to menthol, agonist of the ion channel TRPM8, compared with subjects with homozygous genotype GG. PMID- 21542322 TI - [Variability in low-molecular subproteome of blood serum of healthy man in normal life conditions]. AB - For analysis of inter-individual variability in low-molecular serum subproteome proteome profiles of healthy men at the age of 20-30 years (36 subjects), 30-40 years (11 subjects) and 40-50 years (11 subjects) were obtained. Serum samples were fractionated on magnetic beads MB WCX using ClinProt robot prior to mass spectrometry based profiling. Mass-spectra were obtained with time-of-flight mass spectrometer Autoflex III ("Bruker Daltonics") in automatic mode. It was shown that low-molecular serum subproteome of healthy humans was characterized by significant inter-individual variability. 21% of all peaks in proteome profiles had coefficient of variation more than 50% and 29% of all peaks had low dispersion (CV < 30%).Therefore majority of peaks in proteome profile were peaks with moderate inter-individual variability (CV from 30% to 50%). Fragments of high-molecular kininogen, inter-alpha-trypsin inhibitor, complement components C3 and C4a, apolipoprotein CI, platelet factor IV, beta2-microglobulin and cystatin C showed wide variation among examined groups of healthy men. Dispersion of high molecular kininogen, inter-alpha-trypsin inhibitor, apolipoproteins AII and CIII peaks increased with age. PMID- 21542323 TI - [Acute and remote biochemical and physiological effects of exhaustive weightlifting exercise]. AB - The goal of the work was a study of exhaustive weightlifting exercise effect on prolonged changes in physiological and biochemical variables characterized functional status of skeletal muscles. An exercise gave rise to significant blood lactate concentration increase that was indicative of an anaerobic metabolism to be a predominant mechanism of muscle contraction energy supply. A reduction of m. rectus femoris EMG activity (amplitude and frequency), tonus of tension and an increase in tonus of relaxation were found immediately after exercise. Both EMG amplitude and frequency were increased 1 day post-exercise. However, after 3 days of recovery, EMG amplitude and frequency were decreased again and, in parallel, blood serum creatine kinase (CK) activity was significantly increased. After 9 recovery days, all measured variables with the exception of CK were normalized. A significant reverse correlation was found between blood serum lactate concentration and m. rectus femoris EMG activity at the same time points. Blood serum CK activity and m. rectus femoris EMG and tonus variables were observed to be significantly reversely correlated on the 3rd post-exercise day. Presented data demonstrate that exhaustive exercise-induced muscle injury resulted in phase alterations in electrical activity and tonus which correlated with lactate concentration and CK activity in blood serum. PMID- 21542324 TI - [Effect of steam bath on gastric secretion and some endocrine changes of athlete fighters]. AB - The issues of adaptation of the gastric glands to thermal load (steam bath) of athlete-fighters. The differences in adaptation to thermal load of gastric glands in connection with a weight category, seniority and age of athletes. Discovered the relationship in reaction to thermal load of gastric and endocrine glands. The stability of steam bath of gastric glands in the middle weight class athlete fighters combined with the preservation of endocrine homeostasis. The high sensitivity of athlete-fighters of light and middleweight category combined with an authentic increase in serum of blood the concentrations of gastric and aldosterone, and with decrease the concentrations of cortisol. PMID- 21542325 TI - [Regularity of changes in amplitude characteristics of electrohysterography of healthy pregnant women during third trimester]. AB - This research is aimed to establish regularity of changes of the peak characteristics of uterus bioelectric activity according to outside multichannel electrohysterography of healthy pregnant women in the third trimester. The research of uterus bioelectric activity of women with physiological pregnancy at 28 to 40 weeks of gestation was carried out with use of electrophysiological methods. Three groups of women were distinguished according to their pregnancy duration. The first group included 12 women with pregnancy duration for 26-28 weeks, the second group--49 women with duration of gestation for 29-37 weeks, the third group--48 women with pregnancy duration for 38-40 weeks. The result of this research is receiving of preliminary specifications of peak electrogisterogramme characteristics and establishing the fact that the later pregnancy is, the bigger the average amplitude of electrogisterogramme is. PMID- 21542326 TI - [Cardiovascular effects of nerve growth factor (analytical literature review) Part I. NGF-indirect intracellular signal pathways]. AB - Traditionally, nerve growth factor (NGF) is considered as chemoattractant that participates in the regulation of cell proliferation, differentiation and myelination of neurons. However, currently available data suggest that the physiological role of NGF in the organism is much wider. This review discusses the features of the influence of NGF on the functional activity of the cardiovascular system, as well as signaling pathways by which activated NGF TrkA and p75(ntr) receptors regulate the functional state of endothelial and vascular smooth muscle cells and cardiomyocytes. In addition, the review observes the theoretical perspectives of agonists and antagonists of TrkA and p75(ntr) receptors for the treatment of various diseases of the heart and blood vessels. PMID- 21542327 TI - [Intersystem interaction of the respiration and blood circulation]. AB - The review includes modern data about the functional interaction of respiratory and bloods circulatory systems in different conditions. The special attention is given to adaptive changes of respiratory and haemodynamic indices in extreme conditions. Based on the own researches physiological parallels between intersystem correlation of respiratory biomechanics and haemodynamics in the conditions of normal gravitation and weightlessness are drawn. PMID- 21542328 TI - [EEG changes with unblocking of acoustic and visual sensory canals]. AB - Modally specific and supramodal components of EEG dynamics, related to involuntary reorientation of anticipatory attention from internal into external, were studied using unblocking of either visual or acoustic apparatus. EEG registration took place while the examinees were in the resting states: with opened eyes; with closed eyes; with closed eyes and inserted noise-protective earplugs. Averaged values of EEG power in each of the derivations and of EEG coherence in each of the derivation pairs were calculated for an every examinee and for each of the states. The estimations were done in delta, theta, alphal, alpha2, beta1, beta2, gamma frequency bands. The received results support an idea about manifestation of both supramodal and modally specific components in brain mechanisms of involuntary anticipatory attention. These results seem to be of certain interest for existing discussion on divergence and convergence between systemic mechanisms of visual and auditory attention. PMID- 21542329 TI - [The influence of afferent inputs from the foot load receptors onto spinal alpha motoneurons excitability in air-stepping condition]. AB - We investigated excitability of alpha-motoneurons during voluntary and passive locomotor-like movements under air-stepping conditions during the imitation of foot loading. Limb loading notably inhibited the H-reflex during both static condition and active or passive stepping. Thus, load-related afferent inputs play an essentially role in phase-dependence H-reflex modulation. The excitability of alpha-motoneurons in the most degree is influenced by afferent inflow from foot receptors. PMID- 21542330 TI - [Intestinal endotoxin in induction of type 1 diabetes]. AB - We studied serum level of intestinal flora endotoxin (LPS) in 45 children and adolescents aged 3-17 years old with diabetes mellitus type 1. Levels of endotoxin, were significantly elevated in type 1 diabetic patients (2.89 +/- 0.33 Eu/ml) compared with control (0.4 +/- 0.03 Eu/ml). There was significant difference in serum LPS levels in patients with type 1 diabetes onset (3.93 +/- 0.79 Eu/ml) compared with children and adolescent with old time diabetes (2.37 +/ 0.27 Eu/ml). These results have a major implication on our understanding of the role of gut flora endotoxin in pathogenesis of type 1 diabetes. PMID- 21542331 TI - [Effect of music on the latency recognition of even and odd numbers]. AB - Studied influence of music of certain intensity on latency recognition of even and odd numbers with participation of the left and right hand accordingly. Music accompaniment decreased the latency recognition more pronounced with participation of the left hand that, apparently, is connected with activated influence of music on the right hemisphere at the people who are not professional musicians. Increase of efficiency of recognition in music accompaniment is considered as realisation of a principle of a dominant. PMID- 21542332 TI - [Analysis of cyclic fluctuations in larch bud moth populations by means of discrete-time dynamic models]. AB - Analysed are the data of larch bud moth (Zeiraphera diniana Gn.) fluctuations in Swiss Alps. The analysis applies simplest mathematical models of isolated population dynamics (in particular, Kostitzin model, Skellam model, the discrete logistic model, and some other ones), which include the minimal number of unknown parameters. The parameters have been estimated, for all the models in hand, by the least-squares method, to fit certain data from the Global Population Dynamics Database (N 1407 and N 6195), the sequences of the data deviations from the model trajectories being treated as well. The best approximations are shown to be achieved with Moran-Ricker model and the discrete logistic model. Statistical criteria (Kolmogorov-Smirnov and Shapiro-Wilk tests) reveal that the hypotheses of normal distribution of residuals must be rejected for one of the time series (N 1407); some models demonstrate serial correlations in the sequence of residuals (according to Durbin-Watson test). This leads to the conclusion that periodic fluctuations in the larch bud moth population (N 1407) can hardly be explained by self-regulation mechanisms alone. For another time series (N 6195), the modified discrete logistic model has appeared to be acceptable as a mode of fluctuations. PMID- 21542333 TI - [The prospects of using transgenic insects in biocontrol programs]. AB - Methods of biocontrol are widely used for suppression of pests and human disease vectors. One of the key methods is insects sterilization (sterile insect technique--SIT), which currently is accomplished by irradiation. Radiation exposed insects have reduced fitness so theis competitive abilities are diminished as compared to insects from wild populations. Modern bioengineering is capable of producing transgenic insects with predetermined traits, and by now the schemes for getting sterile insects without exposure to radiation are developed. Another area of modern studies is producing insects that are unable to transmit diseases malaria, for example. In the present review the implementation and perspectives are outlined for replacement of Anopheles wild populations with transgenic mosquitos. The main way for delivering the genetic material to recipient's genome is using transposon-based constructs. The markers of transgenesis are described. The potential danger for the environment of transgenic constructs remobilization and the necessity of their stabilization within the genome are emphasized. The existing methods of stabilization which involve the deletion of transposon terminal inverted repeats are described. PMID- 21542334 TI - [Relationship between dominance and richness of local species: an analysis of the underlying reasons with arboreal and avian communities of the West Caucasus as an example]. AB - Dominance level is traditionally expressed as a ratio between the number of individuals belonging to the most abundant species and the total number of individuals in a biological community. It is known that local species richness is usually higher in biological communities with high dominance level than in communities with low one. Taking into account a complex nature of the dominance phenomenon, the underlying reasons (or mechanisms) may be diverse: 1. Dominance level may be determined by bioecological traits of the most abundant species as well as stochastic impacts. The more abundant is dominant species, the fewer amount of resources goes to concomitant species and, therefore, the lower is community species richness. 2. The part of community resources used by the dominant species may be not a special case but can be a reflection of general pattern of resources distribution among species under specific environmental conditions. Correspondingly, in communities with higher dominance level there might be more "strict" distribution of resources among concomitant species, which, in turn, might influence community species richness. 3. The relationship between dominance level and community species richness may be caused by their dependence on the third variable, namely regional species pool. In the present paper we tackle the problem using arboreal and insectivorous bird communities of the West Caucasus as a case study. The data were collected in different altitudinal belts on both macroslopes of the western part of the Main Caucasian Ridge. The number of tree species and individual trees was counted within homogenous patches of arboreal phytocenoses 300 m2 in area. Species richness and numbers of insectivorous birds were estimated in course of route surveys with a route length being about 5 km. An analysis of empirical data was carried out using univariate and multiple correlation-regression techniques. The results indicate that the relationship between dominance and local species richness is determined to a large extent (by 50-60%) by a dominant taking over greater or lesser amount of the resources (mechanism 1). The role of two other mechanisms (2 and 3) is not so prominent--together, they are responsible for 25-40% of the relationship power. Relative contribution of different mechanisms to the relationship under consideration depends on conformity of species abundance rank structure with the geometric series model. At those sites where this conformity is manifested, the relationship between dominance level and species richness is due mainly to mechanisms 1 and 2, i.e., is determined by local processes. At other sites, where the conformity of species abundance rank structure with the geometric series model is not so good, a certain role belongs to the size of regional species pool (mechanism 3). PMID- 21542335 TI - [The structure of morphological variability (with the masticatory surface morphotypes of the lower first molar in voles as an example)]. AB - An analysis of morphotypical variability of the lower first molar in twelve species of Microtus genus revealed similarity in patterns of variability, consisting in two-three homologous series of three morphotypes of one class of rugosity in each series. In the majority of species, morphotypes are located in a single plane. In some species, morphotypes of other class of rugosity form the homologous series of a second plane so that the structure of the variability takes on a three-dimensional form. The variability spectrum is limited by molars design; at the different trends in complication of a masticatory surface have taxonomic weight of subgenus or species rank. Thus, incompleteness of homologous series is caused by taxonomic specificity and is nonrandom in essence. PMID- 21542336 TI - [Thermoresistance in Saccharomyces cerevisiae yeasts]. AB - Under natural conditions, yeast Saccharomyces cerevisiae reproduce, as a rule, on the surface of solid or liquid medium. Thus, life cycle of yeast populations is substantially influenced by diurnal changes in ambient temperature. The pattern in the response of unrestricted yeast S. cerevisiae culture to changes in the temperature of cultivation is revealed experimentally. Yeast population, in the absence of environmental constraints on the functioning of cell chemosmotic bioenergetic system, demonstrates the ability of thermoresistance when the temperature of cultivation switches from the range of 12-36 degrees C to 37.5-40 degrees C. During the transient period that is associated with the temperature switching and lasts from 1 to 4 turnover cycles, yeast reproduction rate remains 1.5-2 times higher than under stationary conditions. This is due to evolutionary acquired adaptive activity of cell chemosmotic system. After the adaptive resources exhausting, yeast thermoresistance fully recovers at the temperature range of 12-36 degrees C within one generation time under conditions of both restricted and unrestricted nourishment. Adaptive significance of such thermoresistance seems obvious enough--it allows maintaining high reproduction rate in yeast when ambient temperature is reaching a brief maximum shortly after noon. PMID- 21542337 TI - [Asymmetric cell division in the morphogenesis of Drosophila melanogaster macrochaetae]. AB - Asymmetric cell division (ACD) is the basic process which creates diversity in the cells of multicellular organisms. As a result of asymmetric cell division, daughter cells acquire the ability to differentiate and specialize in a given direction, which is different from that of their parent cells and from each other. This type of division is observed in a wide range of living organisms from bacteria to vertebrates. It has been shown that the molecular-genetic control mechanism of ACD is evolutionally conservative. The proteins involved in the process of ACD in different kinds of animals have a high degree of homology. Sensory organs--setae (macrochaetae)--of Drosophila are widely used as a model system for studying the genetic control mechanisms of asymmetric division. Setae located in an orderly manner on the head and body of the fly play the role of mechanoreceptors. Each of them consists of four specialized cells--offspring of the only sensory organ precursor cell (SOPC), which differentiates from the imaginal wing disc at the larval stage of the late third age. The basic differentiation and further specialization of the daughter cells of SOPC is an asymmetric division process. In this summary, experimental data on genes and their products controlling asymmetric division of SOPC and daughter cells, and also the specialization of the latter, have been systemized. The basic mechanisms which determine the time cells enter into asymmetric mitosis and which provides the structural characteristics of the asymmetric division process--the polar distribution of protein determinants Numb and Neuralized--the orientation of the mitotic spindle in relation to these determinants, and the uneven segregation of the determinants into the daughter cells that determines the direction of their development have been discussed. PMID- 21542338 TI - [Dynamics of energy metabolism in ontogenesis of striped shield bug (Graphosoma lineatum L.) and cabbage moth (Mamestra brassicae L.)]. AB - Dynamics of growth and oxygen consumption during ontogenesis of insects with direct (striped shield bug Graphosoma lineatum L.) and indirect (cabbage moth Mamestra brassicae L.) development have been compared. The correlation between a character of energy metabolism alteration and peculiarities of development of the insects has been shown. Cyclic decrease of oxygen consumption during molt and sharp dropping during metamorphosis have been observed in insects with indirect development. The decrease of oxygen consumption has been observed in insects with direct development only during molts. The coefficient a of allometric dependence of oxygen consumption on body weight of imago for cabbage moth was two times higher than that for striped shield bug. PMID- 21542339 TI - [Antipodal complex development in the embryo sac of wheat]. AB - Dynamics of an antipodal complex formation in wheat (Triticum aestivum L.) has been observed in detail using a reconstruction of serial semifine sections. Three consecutive crucial stages have been identified in the development of the antipodal complex: (1) proliferation of initial cells, (2) growth and functional differentiation of antipodal cells, and (3) cell apoptosis. Specific features of the mitotic division of antipodal cells have been characterized. It has been shown that the structure of interphase nuclei and mitotic chromosomes of proliferating antipodal cells is similar to that of nucellar cells surrounding the embryo sac. According to the reconstruction of appropriately oriented serial sections, the division of antipodal cells is asynchronous. DNA content in differentiated antipodal cells has been determined by a cytophotometric analysis; in the case of a mature embryo sac, the ploidy of antipodal cells varied from 8 to 32C. Proliferation and DNA endoreduplication processes in the antipodal complex proceed at different time; the second process starts only after the termination of the first one. DNA endoreduplication is accompanied by total chromatin remodeling; as a result, giant chromosomes are formed in the nuclei of antipodal cells. The final stage of the antipodal complex development is programmed cell death or apoptosis. A model for the structural organization of an antipodal complex has been proposed based on the layer arrangement of cells. The secretory activity of antipodal cells directed towards the endosperm syncytium has been detected for the first time. The analysis of "truncated" ovules with an undeveloped endosperm has shown that developing endosperm can be a possible inductor, which stimulates the functional activity of antipodal cells and triggers their terminal differentiation. The obtained results evidence the functional role of antipodal cells in the development of the endosperm and embryo. PMID- 21542340 TI - [Inductive activity of the posterior tip of planula in the marine hydroid Dynamena pumila]. AB - Activity of organizer regions is required for body plan formation in the developing organism. Transplanting a fragment of such a region to a host organism leads to the formation of a secondary body axis that consists of both the donor's and the host's tissues (Gerhart, 2001). The subject of this study, the White Sea hydroid cnidarian Dynamena pumila L. (Thecaphora, Sertulariidae), forms morphologically advanced colonies in the course of complex metamorphosis of the planula larva. To reveal an organizer region, a series of experiments has been performed in which small fragments of donor planula tissues were transplanted to embryos at the early and late gastrula stage, as well as to planulae. Only transplantations of a posterior tip fragment of a donor planula to a host planula of the same age led, in the course of metamorphosis, to the formation of a secondary shoot, which involved up to 50% of the host's tissues. After transplantations of tissue fragments of the anterior tip and the middle of the planula body, the formation of any ectopic structures was never observed. It was concluded that the posterior tip of the planula has organizer properties in Dynamena. PMID- 21542341 TI - [Passive and active reactions of embryonic tissues to the action of dosed mechanical forces]. AB - With the help of a suction manometric device, the relation between the deformation of Xenonus laevis embryo at the gastrula and neurula stages and the value of the applied force has been studied. Stiffness modules of embryonic tissues were in the order of several dozens of Pascal and they were inversely proportional during deformation from 40 to 20%. At the gastrula stage, a uniform or an increasing rate of expansion of the embryo body in the suction capillary with the diameter of approximately half that of the embryo was observed for 30 min after the action of the suction forces. The length of the stretched portion of the embryo correlates with the value of its deformation at the first minute. As a result of the expansion, the total body surface area of the deformed embryo increases more than twice compared to intact embryos. After expelling the embryo from the capillary, its surface reduced and the deformation became smoothened within 5 min, which indicates the existence of tensional force in the expanded embryo. These data confirm that, at the embryo gastrula stage, external mechanical forces do not only passively deform the embryo but also initiate the active expansion of the embryo which takes place at zero external force and overcomes the tensional resistance of tissues. The mechanism of active expansion and its link with the processes of normal morphogenesis are discussed. PMID- 21542342 TI - [Dispermic androgenesis in sturgeons with the help of cryopreserved sperm: production of androgenetic hybrids between Siberian and Russian sturgeons]. AB - Dispermic androgenesis was used to produce, for the first time, an androgenetic progeny of the Siberian sturgeon (Acipenser baerii) and the androgenetic nuclear cytoplasmic hybrids (Siberian sturgeon, A. baerii x Russian sturgeon, A. gueldenstaedtii) using cryopreserved sperm. Microsatellite DNA analysis confirmed exclusively paternal inheritance in the androgenetic progeny of Siberian sturgeon. Heterozygotes for certain microsatellite loci were detected among the androgenetic hybrids, thereby confirming a dispermic nature of androgenesis. According to the data of comparative morphological analysis, the obtained androgenetic hybrid, by the age of 15 months old, was completely identical to the paternal species. Both a female and a male were detected in the androgenetic sturgeon progenies, which is of interest for producing bisexual progenies via androgenesis. The data of this study confirm the feasibility of dispermic androgenesis using cryopreserved sperm to preserve and recover the gene pools of endangered sturgeon species. PMID- 21542343 TI - [Interaction between the PINOID/ABRUPTUS gene with the AGAMOUS gene: the negative regulator of stem cells in the meristem of Arabidopsis thaliana flower]. AB - Complementary interaction between the AGAMOUS and PINOID/ABRUPTUS genes was revealed. In double mutant abr ag-1, there is a significant increasing proliferation of cells of the floral meristem and formation of branching bine like flowers. This data indicate the participation of the PID/ABR gene in limitation of proliferating stem cells of the floral meristem. The revealed increase of transcription level of WUS gene in flowers of the abr mutant, as well as distortion of auxin distribution, allows us to suggest that the PID/ABR gene controls auxin transport and participates in detection of expression domains for the WUS gene. PMID- 21542344 TI - [Arabidopsis thaliana FIMBRIATA PETIOLES gene, controlling cell division and growth in floral organs]. AB - A new mutant, fimbriata petioles (fip), of Arabidopsis thaliana was obtained by chemical mutagenesis. The mutant is characterized by unusual anomalies of floral organs. Clusters of very large cells formed in the distal region of sepals and petals, which created fringed edges of these organs. An analysis of the morphology of the floral organs and leaves of the fip as 1 double mutant revealed a complementary interaction of the ASYMMETRIC LEAVES1 (AS1) and FIMBRIATA PETIOLES (FIP) genes. It was assumed that the FIP gene, together with the AS1 gene, controls cell proliferation, preventing their premature entry into endocycle. PMID- 21542345 TI - [The paper titled Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation by the research team headed by Mathias Treier was published in December in the Cell, vol. 139, issue 6, pp. 1130-1142]. PMID- 21542346 TI - [Effect of acetone and the probe 1-anilino-8-naphthalenesulfonate on water as estimated by fluorescence in the UV region]. AB - For investigation of influence of reactive oxygen species on biological systems the peculiarities of light scattering and fluorescence spectra of aqueous solutions in the presence of photoactive additions of acetone (5 x 10(-4) - 30) and anionic probe ANS (5 microg/l-10 mg/l) have been considered. In water and diluted aqueous acetone and ANS solutions, long-term spontaneous variations in parameters of light scattering and fluorescence spectra have been detected. It has been found that the spectral parameters and the character of ANS influence changed drastically at acetone concentrations of approximately 0.1%, approximately (0.2-0.3)%, and approximately 0.8%. The results can be explained by rearrangement of solvent structure in the surrounding of admixture molecules, photochemical processes with the participation of acetone and reactive oxygen species, as well secondary reactions with their involvement in gas-vapor and acetone bubbles. PMID- 21542347 TI - [Calcium-dioxolene complexes: rate constants of pyrocatechol oxidation in the presence of Ca2+]. AB - The effect of calcium ions on the rate of pyrocatechol autoxidation at pH 9.0 has been studied by mathematical modeling. The effect of Ca2+ on the oxygen absorption rate has been studied, and a kinetic model has been suggested, which takes different stages of interaction of pyrocatechol and its radical form with oxygen into account. It has been shown that the prooxidant action of Ca2+ is related to an abrupt increase (approximately by three orders of magnitude) in the rate constant of comproportionation (reaction of chain branching and formation of o-semiquinonates) and a marked decrease (by two orders of magnitude, from 1.4 10(7) to 0.6 10(5) M(-1)s(-1)) in the rate constant of disproportionation of o semiquinones. The system can be used as a model for studying the prooxidant action of calcium ions. PMID- 21542348 TI - [A study of bulky nanotube composites based on albumin by high-resolution microscopy]. AB - The structure of biocompatible nanocomposites formed by the action of laser radiation on an aqueous dispersion of albumin with carbon nanotubes has been studied by the high-resolution methods of atomic force and transmitting electron microscopy. It has been shown that the nanocomposites have a bulky structure consisting of conglomerates of nanotubes uniformly distributed in the albumin matrix. The results of the study may be useful in the production of filling nanomaterials for implants of biological tissues and organs and the control of their quality. PMID- 21542349 TI - [Spin polymerization of DNA/RNA nucleotides]. AB - The Car-Parrinello molecular dynamics (CPMD) has been used to study the ion radical (IR) polymerization (triplet (T) and singlet (S/TO) states) of adenine mononucleotides upon interaction with Mg2+(H2O)2-ATP(4-). It has been found that the IR polymerization occurs only upon Mg2+(H2O)2-ATP(4-) excitation into a T state (the Franck-Condon or femtosecond laser excitation); it naturally occurs in the dark with DNA polymerase or another Mg-holoenzyme upon interaction of Mg with two Asp residues. The IR path affects only the HO-C3' group of ribose, leaving the HO-C2' group inactive. The IR polymerization starts with the homolytic removal of the hydrogen atom from the HO-C3' group and its transfer onto the hydroxyl radical *OH, a product of the ATP cleavage, which yields a water molecule. A further progress of the reaction involves interaction between two ion radicals *AMP. The reaction is sensitive to the recombination of *OH and *AMP. It is mostly suppressed by the appearance of identically directed electron spins on both radicals (the radical pair in the T-state) in the vicinity of the HO-C3' group and not suppressed in the vicinity of the HO-C2' group (the spins in the radical pair are oppositely directed, the radical pair in the To state), making the latter inert on the IR polymerization, but allowing it to be active in the ionic (hydrolytic) polymerization. PMID- 21542350 TI - [Quantum theory of the hydrogen key in DNA]. AB - A quantum theory of the redistribution of the hydrogen atom that links nucleotide bases between two DNA strands at the moment of its untwisting has been advanced, which is based on two tunneling mechanisms: the Andreev-Meierovich mechanism of tunneling with spontaneous emission of a phonon and the Kagan-Maksimov mechanism of tunneling during the scattering of the phonon. It was shown that the probability for the hydrogen atom to be in a foreign pit, i.e., in the mutated form, decreases as the rate of untwisting increases. According to the model, the probability of mutation smoothly increases with temperature to a value of 1/2. PMID- 21542351 TI - [On the possibility of bipolaronic states in DNA]. AB - The possibility of the occurrence of bipolaronic states in homogeneous polynucleotide chains has been considered on the basis of the Holstein-Hubbard model. A phase diagram of the stability of bipolaronic states has been calculated for these chains. It was shown that, with the parameters characteristic for DNA, DNA can exhibit superconductivity with a transition temperature Tc approximately 6 K. The results obtained can serve as the basis for explaining the experiments with DNA superconductivity. PMID- 21542352 TI - [Thermodynamic analysis of complex formation of ethidium bromide with DNA in water solutions]. AB - A thermodynamic analysis of two types of binding of ethidium bromide with DNA: intercalation and binding to the outer surface of a biopolymer has been performed by spectrophotometry. It has been shown that the dominant contribution to the energy of external binding of the ligand to DNA is made by hydrophobic interactions, which lead to less negative values of enthalpy and entropy and more severe negative changes in the heat capacity of complex formation as compared with the intercalation type of binding. PMID- 21542353 TI - [A molecular dynamics study of the interaction between domain I-BAR of the IRSp53 protein and negatively charged membranes]. AB - The methods of computer simulation in full-atomic and large-grain approximations have been used to study specific interactions of the isolated domain I-BAR of the actin-binding protein IRSp53 and model membranes containing neutral phospholipids, as well as membranes containing high amounts of negatively charged PI(4,5)P2 phospholipids. It has been shown that the I-BAR domain does not interact with neutral lipids but induces the bending of the synthetic membrane rich in negatively charged phospholipids. A clusterization of charged lipids on the surface of the membrane at the sites of its interaction with the protein has been observed. This indicates that the interaction of the I-BAR protein with negatively charged lipids is of electrostatic and hydrophobic nature. PMID- 21542354 TI - [On the influence of local molecular environment on the redox potential of electron transfer cofactors in bacterial photosynthetic reaction centers]. AB - The addition of cryosolvents (glycerol, dimethylsulfoxide) to a water solution containing bacterial photosynthetic reaction centers changes the redox potential of the bacteriochlorophyll dimer, but does not affect the redox potential of the quinone primary acceptor. It has been shown that the change in redox potential can be produced by changes of the electrostatic interactions between cofactors and the local molecular environment modified by additives entered into the solution. The degree of influence of a solvent on the redox potential of various cofactors is determined by degree of availability of these cofactors for molecules of solvent, which depends on the arrangement of cofactors in the structure of reaction centers. PMID- 21542355 TI - [Molecular dynamics simulation of packing and mobility of lipids in bilayer membranes]. AB - A model of DSPC lipid membrane in gel and liquid-crystalline states has been developed. The parameters have been determined that enable one to calculate the molecular dynamics of lipid bilayers in the full-atromic approximation. The parameters of packing and mobility of lipid molecules for the liquid crystalline state of the bilayer have been calculated. The values agree well with experimental data. Based on the model of the liquid crystalline state of the membrane, a system in the gel-like state has been constructed. The model of the gel-like state reproduces well the packing of lipids in real bilayers, whereas the mobility of molecules in the gel-like state was found to be overestimated. PMID- 21542356 TI - [Regulation of the functional and mechanical properties of platelet and red blood cells by nitric oxide donors]. AB - The effect of NO donors (sodium nitroprusside, S-nitrosoglutathione, dinitrosyl iron complexes) on the functional and mechanical properties of human platelets and red blood cells has been investigated. It has been established by atomic force microscopy that NO donor-induced platelet disaggregation is accompanied by changes in the elastic properties of cells. It has been shown that, in the presence of NO donors, the detergent-induced hemolysis of red blood cells is delayed, and the elasticity modulus of these cells decreases. The results obtained indicate that NO donors regulate the structural and functional properties of platelets and red blood cells. PMID- 21542357 TI - [In vitro fluorescence assay to study the folding of Kv ion channels]. AB - A fluorescence assay to check the folding of potassium Kv channels expressed in vitro has been developed. For this aim, the fluorescently labeled channel blocker, recombinant agitoxin of yellow scorpion was employed. The level of expression of various Kv channels in vitro has been tested. It has been demonstrated that Kv2 channels form clusters on the cell surface, which are not associated with actin filaments. On the other hand, Kv10 channels form larger clusters, which are associated with actin, indicating the principal differences in the organization of cytoplasmic domains of Kv2 and Kv10 channels. PMID- 21542358 TI - [Estimation of luminescent properties of the derivatives of polymethine probes on their interaction with cells of different types]. AB - The spectral and luminescent properties of the derivatives of polymethine probes based on 3,3'-dialkyloxacarbocyanine bromide (H-510) and 1,1'-dialkyl-3,3, 3',3' tetramethylindodicarbocyanine bromide (D-307) (where alkyl is ethyl or octadecyl groups) on accumulation in bone marrow and liver cells of rats have been compared. The general regularities in the interaction between the probes and the membrane microenvironment have been revealed for each type of the cells. It was found that the structural features of membranes and the length of the chains of alkyl substitutes essentially affect the redistribution of dye molecules in the binding censers of particular types, as evidenced by changes in the spectral characteristics of probes. It has been shown by microfluorimetry that the accumulation of short-chain derivatives in single cells is representative of the distinctions in the parameters of their functional metabolic state, which coincides with the present view of the heterogeneous structure of these cellular populations. The hormonal action and the influence of incubation without serum on the intensity of cellular processes were accompanied by changes in the fluorescence of cells stained with the ethyl derivatives of the probes H-510 and D-307. This fact allows us to consider them as optical indicators of the cellular activity. The dye D-307 was found to be more resistant to photodestruction than H 510 both in single cells and model system. PMID- 21542359 TI - [Atomic force microscopy of living cells: advances and future outlooks]. AB - The advances of the method of atomic force microscopy for investigating the animal cells and an analysis of its development have been reviewed, with much attention being given to studies of living cells. The features and problems of the method have been considered, and a number of special methods based on the use of atomic force microscopy have been analyzed. The problems of choosing the geometry of probes for studies of animal cells, determination of cell adhesion on substrate, mapping of the cell surface using chemically modified cantilevers, and the distribution of molecular components inside the cell with the use of micro- and nanosurgical approaches have been discussed. The problems of combining the atomic force microscopy with optical and laser scanning confocal microscopy have been considered. Possible applications of the method in biotechnology and medicine are discussed. PMID- 21542360 TI - [Prospects of designing the medicines with diverse therapeutic activity on the basis of dinitrosyl iron complexes with thiol-containing ligands]. AB - A stable hypotensive preparation (Oxacom) based on dinitrosyl iron complexes (DNIC) with glutathione has been developed. The preparation has successfully passed through pharmacological trials. The tests on volunteers have shown a high hypotensive activity of the preparation: a single intravenous infusion of its aqueous solution at a dose of 0.2 microM per kg of body weight led to a 20-30% decrease in arterial pressure, which persisted for a period of 15-20 h. Similar experiments on the animals demonstrated that aqueous solutions of DNIC with cysteine or glutathione exert also the hypotensive action due to their vasodilatory activity. Besides, these complexes accelerate wound healing and produce a potent erective action. There is reason to suggest that DNIC with thiol containing ligands as NO donors can produce the cytotoxic action on the pathogenic mycobacteria Mycobacterium tuberculosis and, after respective treatment, inhibit cancer cell proliferation. These complexes can be used as analgetics, for inhibiting the adhesion process, in the therapy of preexplampsia, spermatogenesis pathologies, and in cosmetology for the treatment of skin injury. PMID- 21542361 TI - [Antiradical and NO-inhibiting activities of bet-hydroxy(ethoxy) derivatives of nitrous heterocycles]. AB - The antiradical and NO-inhibiting activities of beta-hydroxy(ethoxy) derivatives of nitrous heterocycles (3-hydroxypyridine, 5-hydroxybenzimodazole, and 6 hydroxy(alkoxy)-benzothiazole) have been studied. The antiradical activity has been studied using a homogeneous hydrophilic chemiluminescent system, and the quenching constants (Ki) have been determined. For the most reactive compound, 4 methylthiobenzimidazolyl-3-hydroxypyridine, Ki = 4.5 x 105 M(-1). The NO inhibiting activity was estimated on a model of the endotoxin shock of experimental animals using a spin trap of nitric oxide radicals based on complexes of iron with sodium diethyldithiocarbamate. It was found that the compounds at doses of 0.25-1 mmol/kg have both the inhibitory and stimulating action on the production of nitric oxide in the liver of animals. The results obtained suggest that some derivatives of nitrous heterocycles can be used as effective antioxidant preparations. PMID- 21542362 TI - [Computer modeling of nonlinear heart rate dynamics during train extracardial impulsation in the sinoatrial node]. AB - A computer model of excitation conduction in the heart has been employed to study the nonlinear heart rate dynamics under stress loads. The modeling was aimed to test the hypothesis explaining changes in the heart rate dynamics during nociceptive stress loads by the occurrence of train extracardial impulsation arriving at the sinoatrial node. The computer simulation shows that, with a particular set of parameters, the model imitates the dynamics of RR intervals observed in experiments. The present model provides a unified theoretical basis for further simulation of various types of ventricular disturbances under external extreme loads. PMID- 21542363 TI - [Factor analysis of the heart rate spectrum]. AB - The methodical problems of the factor analysis of the heart rate spectrum have been considered: the multi-variate normal assumption, factorability of the intercorrelation matrix, criteria for determining the number of factors, and the validity of the factor analysis model. Unnormalized and normalized variables, the matrices of Pearson's and Spearman's correlation coefficients were used. In the process of the factor analysis (principle components method, Varimax Rotation), the restrictions and the possibility of different statistical criteria and procedures were explored. The meaning of the selected factors and the possibility of using the intercorrelation matrix of Spearman coefficients for unnormalized variables were considered. PMID- 21542364 TI - [To the analytical theory of the supercompensation phenomenon]. AB - The effect of supercompensation and the conditions of its origination have been analyzed using a special analytical solution of the equation of the overdamped Duffing oscillator. The threshold values of the functional shift after the exposure of a living organism to intensive external load have been found. If these values are exceeded, the restoration process goes through the stages of enhanced and lowered working capacity. Expressions for the times of transition to these phases after the onset of recovery and for the time of occurrence of the maxima of these phases have been obtained and analyzed. PMID- 21542365 TI - [Noninvasive estimation of the oxygen state of experimental tumor by diffuse optical spectroscopy]. AB - The potentialities of diffuse optical spectroscopy for the noninvasive estimation of the oxygen state of experimental tumors have been demonstrated. The distribution of total, oxygenated and deoxygenated hemoglobin, as well as the level oxygen saturation of blood have been shown using two tumor models differing in the histological structure and functional characteristics. The results obtained by the optical method have been verified by immunohistochemical examination of tissue specimens with the exogenous hypoxia marker pimonidazole. PMID- 21542366 TI - [Consequences of plant tissue cryopreservation (phenotype and genome)]. AB - The question about the correspondence of regenerants after cryopreservation to the initial organisms has been the focus of attention of cryobiologists. The correspondence has been established for morphological and physiological characteristics and the content of DNA fragment in flowering plants and algae. But no less investigations point to some changes in the phenotype and the appearance of DNA polymorphism in specimens of both plant sections. Changes in DNA methylation at cytosine after cryopreservation of flower plant tissues have attracted considerable interest. Thus, after freezing and thawing, changes in the phenotype and genome may occur, and the latter changes proceed by two mechanisms: mutations and modifications of DNA methylation. PMID- 21542367 TI - [Accumulation of magnetic nanoparticles in plants grown on soils of Apsheron peninsula]. AB - The disclosure of magnetic nanoparticles in five plant species growing in Apsheron peninsula have been detected by the EPR method. The EPR spectra of these nanoparticles proved to be similar to those of synthesized magnetic nanoparticles. The result demonstrated that plants are capable of absorbing magnetic nanoparticles from the soil. The accumulation of nanoparticles in plants is confirmed by the presence of a broad EPR signal whose maximum position of the low-field component changes from g = 2.38 and halfwidth of the signal of 32 mT at room temperature to g = 2.71 and 50-55 mT at 80 K. The intensity of the broad EPR signal for plants grown in radioactively contaminated areas (170-220 mkR per h) was substantially lower compared with plants grown on clean soil. The parameters of the broad EPR signal and its dependence on the temperature of recording were identical with those for synthetic magnetic nanoparticles. The photosynthetic activity and changes in the genome of irradiated plants by the analysis of PCR products were studied. PMID- 21542368 TI - [Modification of the structure of plasmatic membranes of the liver by the action of alpha-tocopherol in vitro]. AB - The effect of the natural antioxidant alpha-tocopherol in a broad concentration range (10(-4) - 10(-25) M) on the viscosity characteristics and thermally induced structural transitions of a lipid bilayer of plasma membranes of murine hepatocytes in vitro has been studied. Changes in the rigidity of surface (approximately Abb) of the lipid bilayer were measured on a Bruker EMX EPR spectrometer (Germany) by the method of spin probes. Stable nitroxyl radicals of 5- and 16-doxylstearic acid, localized at different depth in the membrane served as spin probes. It was shown that the concentration dependence of the effect of alpha-tocopherol is linear and polymodal with three statistically significant increases in three ranges of its concentration: (1) in the range of traditional physiological concentrations 10(-4)-10(-9) M, (2) in the range of superlow doses 10(-9) - 10(-17) M, and (3) in the range of "imaginary" concentrations 10(-17) - 10(-25) M. The mechanisms of action of alpha-tocopherol in each of the three ranges are discussed. When studying the temperature dependences of viscous characteristics, a new thermally induced structural transition in the range of "physiological" temperatures 309-313 K for those alpha-tocopherol concentrations (including superlow ones) to which the maxima on the dose dependence curves at constant temperature of 293 K corresponded. PMID- 21542369 TI - [The development and application of solid-phase ELISA for the identification of avian influenza virus and its subtypes H5 and N3 in different biological samples]. AB - The paper presents the results of research on the development of effective solid phase ELISA methods for the identification of avian influenza virus (AIV) and typing its H5 and N3 subtypes in different biological samples. Optimized schemes for the production of goat antisera to matrix protein, hemagglutinin H5 and neuraminidase N3 of AIV were proposed. They were used to produce active and specific immunoglobulins and conjugates. Conditions of performing solid-phase ELISA with use of these preparations were optimized. PMID- 21542370 TI - [Evolution of the epidemic process under current conditions]. AB - The on-going evolution of the epidemic process is under active influence of a new regulatory risk factor, environmental pollution of technogenic origin. The negative influence of ecological pressure on the manifestations of infectious diseases is apparent as destabilization of the epidemic processes, increased severity of infections, impaired epidemiological and immunological efficacy of vaccine prophylaxis in the child population. The most vulnerable component in the epidemic process is the minimal period of infectious morbidity. As shown in an epidemiological experiment, it is in this period that especially active preventive measures must be taken to ensure efficacious management of infection. PMID- 21542371 TI - [Predictors of the patients' satisfaction with the quality of hospital-based medical care]. AB - The paper reports results of sociological analysis of satisfaction of the patients with the medical care provided in in-patient facilities of Arkhangelsk and Vologda regions and Komi Republic. The authors distinguish three groups of factors (professional, organizational, informational) that determine the patients' content with the quality of medical services. The study revealed the generally low level of patients' satisfaction estimated based on selected criteria for medical aid and services. PMID- 21542372 TI - [On the measures for environmental and health safety in the development and implementation of nanotechnologies and nanomaterials]. AB - Nanotechnologies find wide application in industry and medicine. The Russian market of nanotechnologies is at the very beginning of development. Rospotrebnadzor has amassed a wealth of experience in the creation of efficacious systems for estimation and sanitary-epidemiological control of the safety of goods and foodstuffs. The assessment of the safety of nanoparticles and nanomaterials has been carried out since 2007. In 2008-2009, a survey was initiated with a view to developing safety criteria for nanoproducts, nanomaterials, and nanotechnologies. In 2010, research institutions of Rospotrebnadzor were engaged in investigations aimed to develop relevant regulatory and procedural documentation. Studies are underway to work out new highly sensitive methods for the detection, identification and qualitative determination of nanomaterials in the environment, food-staffs, and biological media. PMID- 21542373 TI - [The safety of selective serotonin reuptake inhibitors: hemostasis]. AB - The literature data of the reaction of haemostatic system to antidepressants from the group of selective inhibitors of serotonin reuptake are summarized. The development of haemorrhagic complications is analyzed. The risk/benefit ratio is estimated for the treatment of depression in patients with acute myocardial infarction and stroke. A differential approach to indication of antidepressants is substantiated for the treatment of comorbid depressive disorders in different types of somatic pathology. PMID- 21542374 TI - [Markers of endocrine system and inflammation as prognostic risk factors of vascular complications of type 2 diabetes mellitus]. AB - The high risk of cardiovascular complications in patients with type 2 diabetes mellitus is a key problem in modern medicine. In this review, the basic risk factors of vascular complications in diabetes mellitus are described and their prognostic value analysed. Special attention is paid to the evaluation of the role of adipose tissue hormone adiponectin. The anti-inflammatory properties of adiponectin suggest its protective action against atherosclerosis and cardiovascular complications. In this article, we review a number of studies on the relationship between adiponectin and the main cardiovascular risk factors in patients with type 2 diabetes mellitus. PMID- 21542376 TI - [Sexuality and emotions]. PMID- 21542375 TI - [Nervous regulation of bone metabolism]. AB - This review is focused on the issues pertaining to the control of bone metabolism by adrenergic and serotoninergic regions of the vegetative nervous system. It is shown that mediators, enzymes, and receptors of these regions regulate bone remodeling processes. Data on the effects of regulatory peptides and nitric oxide on bone cells are presented. PMID- 21542377 TI - [In depth study of troubles in sexual development and behavior associated with anorexia nervosa]. AB - A group of 200 girls suffering from mental anorexia have been systematically studied, including the consequences of this illness on their psychosocial behaviour. The psychotherapeutic approach was completely indirect, concerning only all forms of sexual problems related with the alimentary dysfunctions in mental anorexia. PMID- 21542378 TI - [Estrogens and male sexuality: efficiency of antiestrogens in case of hypothalamic hypogonadism and late onset hypogonadism]. AB - Estrogen treatment in eugonadal men diminishes libido, whereas libido is preserved by estrogens in orchidectomized transsexuals as well as in cases of aromatase deficiency. Hypothalamic hypogonadism can be caused by stress, depression, anorexia or excessive exercise. It may result in erectile dysfunction and decreased libido. A 7 day trial of clomiphen (25 mg/day) can be used to test the responsiveness of the axis and may be continued for up to 6 months as a means to stimulation endogenous LH and testosterone secretion. Other antiestrogens such as raloxifen or anastrazol may have similar effects in obese men and in aging men with late onset hypogonadism (LOH). PMID- 21542379 TI - [Sexual problems in patients with prostate cancer and those with benign prostatic hypertrophy]. AB - We use the word "tumour" both for a benign prostatic hypertrophy and for a prostatic cancer. The psycho-emotional reactions from a man suffering from these illnesses could be different depending on the kind of tumour, but could be similar especially concerning sexual problems connected with the specific affliction. Hence the necessity also to consider beneficial a psychotherapeutic and sexotherapeutic intervention. PMID- 21542380 TI - [Neuropsychiatry of sexual desire]. AB - Inspired by the basic concepts of neuroscience, neuropsychiatry is a discipline at the interface between psychiatry, psychology, neurology and neuropathology. Interestingly, neuropsychiatry can also include specialized disciplines, such as developmental psychology, endocrinology and sexology. In this article, we describe the neuropsychiatric approach and present how it may be related to social neuroscience, and apply to sexual medicine by describing its importance for sexual dysfunctions and sexual desire. PMID- 21542381 TI - [Onirism, a renewal of sexual identity]. AB - Unity in complementarities of genders represents an almost universal sexual fantasy between man and woman, hardly ever object of scientific discussion. In line with tradition, medical education loses indeed insight into the evolutionary nature of sexuality. Sexologists do actually stress the importance of the struggle for pleasure in the healing processes, but too often neglect the nocturnal and the subconscious mind. An "avant-garde" medical approach, based on medical onirologie, could develop a critical approach to overidealization and promote multiple "erotic mind-body experiences", i.e., sources of renewed identities. PMID- 21542382 TI - [Sexuality and violence]. AB - Violence is only a form of excessive aggressiveness, hence we ask ourselves if it is something naturel or if it is something produced by society. Sexual violence in particular could express a sort of vehemence as well as attain a destructive intention, losing even any eroticism, as observed very frequently in rape. Instead of describing different manifestations of violence, it is more profitable to try to explain the deep origin of violence itself. PMID- 21542383 TI - [From aviation to surgery: the challenge of safety]. AB - Medical errors result in 44,000 to 98,000 deaths per year in the United States of America. Within the surgical specialties, half of these errors occur in the operating room. The origin of these errors is multifactorial, and is generally associated with problems in communication and teamwork. In order to improve safety in the operating room, many hospitals now propose to the medical staff "crew resource management" (CRM) training programs inspired by the aviation industry. This approach favors a better utilization of surgical checklists, improves efficiency during chirurgical interventions, and reduces patient mortality. In October 2009 we introduced a CRM course within the department of surgery at the Geneva University Hospitals. We are presenting this program as well as the first results following its application. PMID- 21542384 TI - [AIDS, tuberculosis, malaria, transparency]. PMID- 21542385 TI - [Effectiveness of "supervised" heroin]. PMID- 21542386 TI - ["Men in white" to "Dr. House" (1)]. PMID- 21542387 TI - [Nuclear interlocking lies]. PMID- 21542388 TI - Stability of beta-carotene under different laboratory conditions. PMID- 21542389 TI - Characterization of a Helical Morphological Mutant of Caulobacter crescentus. AB - Screening of poorly growing colonies following EMS treatment of Caulobacter crescentus culture revealed several mutants with altered cell morphology. One of these (CB15-UW.5) grew as elongated, helically twisted cells which were more susceptible to autolysis than the wild type. The mutant cells were found to have higher transglycosylase activity, this being reflected by shorter chain length of their murein. A second difference between the murein of the mutant and the parent was lower trimer content in the former, although in both cases the degree of crosslinkage was similar. PMID- 21542390 TI - Mutants of Caulobacter crescentus resistant to beta-lactam antibiotics. AB - A number of mutants of Caulobacter crescentus CB15 resistant ot ampicillin were isolated. The mutants differred in their resistance to several beta-lactam antibiotics. No differences in composition of the penicillin-binding proteins of the mutants compared to the parental strain, or in the affinity of these proteins to penicillin or ampicillin were found. The mutants were found to differ from the parent and also in many cases from each other in outer membrane protein composition. PMID- 21542391 TI - Characterization of the cell wall murein of Thiobacillus versutus. AB - Amino acid analysis of pure murein isolated from cells of Thiobacillus versutus grown in complex medium revealed the typical constituents of most mureins from gram-negative cells, i.e. muramic acid, glucosamine, glutamic acid, alanine and diaminopimelic acid in molecular ratio of 0.58: 0.79: 1.0: 1.76:1.07, respectively. The presence of glycine and leucine was also demonstrated (0.20 and 0.08 compared to glutamic acid). Glycine was also present in the murein of cells grown in chemically defined synthetic medium. The crosslinkage of T. versutus murein was approximately 36% --much higher than for most other gram-negative species. High pressure liquid chromatography analysis of muropeptide composition following muramidase digestion of T. versutus murein revealed essentially the same pattern as for Escherichia coli under similar conditions of digestion and separation with, however, some differences in the minor peaks. PMID- 21542392 TI - The murein of Thiobacillus neapolitanus. AB - Amino acid analysis of pure murein isolated from cells of T. neapolitanus revealed the typical constituents of most mureins form Gram-negative bacteria. i.e. glutamic acid, alanine and diaminopimelic acid, but the molecular ratio ot these was unusual, being approximately 1: 1: 1. The reduced amount of alanine was explained by the absence of monomers containing tetrapeptide side chains, as revealed by h. p. 1. c. analysis, [(3)H]glutamic acid, [(3)H]diaminopimelic acid and [(3)H]N-acetylglucosamine were incorporated into the murein and allowed to determine the degree of its crosslinkage (28%) and the occurrence of turnover. PMID- 21542393 TI - Changes in murein composition during the cell cycle of Caulobacter crescentus. AB - The amino acid and muropeptide compositions of murein (peptidoglycan) isolated from populations of Caulobacter crescentus predominantly composed of swarmer or stalked cells were determined and compared with the structure of murein sacculi obtained from a population of unsegregated cells. It appears that in spite of vast morphological alterations in the course of the cell cycle, the murein composition of the various cell types is not markedly different. PMID- 21542394 TI - Stephen Hales, an unrecognized giant of medicine. PMID- 21542395 TI - Samuel John Stratford (1802-1871). PMID- 21542396 TI - Eliminating the Decision Review Board. Final rules. AB - We are eliminating the Decision Review Board (DRB) portions of part 405 of our rules, which we currently use as the final step in our administrative review process for adjudicating initial disability claims in our Boston region. As of the effective date of this regulation, we will replace the DRB step with review by the Appeals Council. The Appeals Council will follow most of the rules in parts 404 and 416 that we use in the rest of the country to adjudicate disability claims at the Appeals Council level, with some differences needed to accommodate the rules that govern administrative law judge (ALJ) hearings in the Boston region. We will also authorize attorney advisors in the Boston region to conduct certain prehearing proceedings and make fully favorable decisions as they do in the rest of the country. We are making these changes to improve service to claimants and to increase consistency in our program rules. PMID- 21542397 TI - The role of colonic stents in 2010. PMID- 21542398 TI - Incidence and histological features of colorectal cancer in the Northern Cape Province, South Africa. AB - AIM: The purpose of this study was to determine the incidence of colorectal cancer (CRC) in the Northern Cape province of South Africa, and to identify patients with histological and demographic features suggestive of hereditary non polyposis colon cancer (HNPCC). METHOD: This is a retrospective review of all cases of primary adenocarcinoma of the colon or rectum diagnosed by the two pathology laboratories operating in the Northern Cape between January 2002 and February 2009. Demographic data were collected, as well as pathological staging of the tumours and histological features suggestive of HNPCC (according to the revised Bethesda guidelines for microsatellite instability testing). Population census data for the Northern Cape were obtained from Statistics South Africa. RESULTS: The annual incidence of CRC in the Northern Cape was 3.7/100,000 population (3.5/100,000 for men and 3.9/100,000 for women). The median age at which colorectal cancer was diagnosed was 59 years (range 16-90 years). On pathological and demographic criteria, 75/206 (36%) of the patients met at least one of the criteria of the revised Bethesda guidelines for microsatellite instability testing. CONCLUSION: CRC is rare in the Northern Cape, and one-third of the patients had demographic or tumour histological features suggestive of HNPCC. PMID- 21542399 TI - Vacuum-assisted closure of the open abdomen in a resource-limited setting. AB - AIM: We describe our experience of developing a modified vacuum-assisted closure (VAC) dressing for open abdomens. BACKGROUND: We see a high volume of trauma in our department. Massive delays in presentation of patients with acute abdomen are common. Closure at initial laparotomy is not possible in many cases, either because the patient has or will develop abdominal compartment syndrome, or because several re-look laparotomies will be required. A significant proportion of our patients who have undergone laparotomy therefore spend some of their stay in hospital with an open abdomen. The management of these patients is particularly labour intensive for nursing staff. The Opsite sandwich or Bogota bag invariably leaks, and sometimes needs changing daily. If a patient also has a temporary ileostomy, application can be difficult. The commercial VAC dressing is an improvement on the Opsite sandwich, but is prohibitively expensive. Financial constraints and the volume of abdominal trauma and sepsis we see mean that commercial VAC dressings for laparostomy are not affordable in our setting. METHODS/RESULTS: We describe our adapted VAC dressing. It is inexpensive and easy to apply, has made a big difference in the nursing of patients with an open abdomen, and has enabled us to increase the rate of delayed primary closure (i.e., we have reduced the rate of ventral hernia). CONCLUSION: The modified VAC dressing is now our department's method of choice for temporary abdominal closure. PMID- 21542400 TI - One-stage excision of inflamed sebaceous cyst versus the conventional method. AB - OBJECTIVE: The aim of this trial was to determine whether one-stage excision of inflamed sebaceous cysts is preferable to the conventional method. METHODS: A group of 166 patients underwent primary resection of an inflamed sebaceous cyst followed by 5 days' administration of antibiotics. A further 185 patients underwent conventional treatment consisting of initial antibiotic administration and incision and drainage of the lesion, followed by elective surgical excision 1 2 months later when the inflammation had subsided. Duration of antibiotic exposure, morbidity and cost were compared between the two groups. RESULTS: One stage excision of inflamed sebaceous cysts decreased the duration of antibiotic exposure, reduced morbidity and is more economical. CONCLUSION: This study strongly suggests that, provided cases are appropriately selected, primary resection of inflamed sebaceous cysts has advantages over conventional treatment. PMID- 21542401 TI - Is transdermal nitroglycerin application effective in preventing and healing flap ischaemia after modified radical mastectomy? AB - OBJECTIVE: We evaluated the efficacy of local nitroglycerin application in preventing and treating flap complications after modified radical mastectomy in a large patient cohort. PATIENTS AND METHODS: Between 1993 and 2008, 6426 patients undergoing surgery for stage II breast cancer were enrolled in this prospective study. Patients were randomised into treatment and control groups. In the treatment group a nitroglycerin preparation (Nitroderm) was applied to the flap area. Major complications, recovery periods, menopausal status, additional diseases (diabetes mellitus, hypertension, atherosclerotic heart disease) and adverse effects related to nitroglycerin use were recorded. RESULTS: The recovery rate without major complications was statistically significantly higher in the nitroglycerin-treated group than in the controls (p < 0.001). CONCLUSION: Our results indicate that topical nitroglycerin reduces flap complications after breast surgery. PMID- 21542402 TI - Prospective audit of mandibular fractures at the Charlotte Maxeke Johannesburg Academic Hospital. AB - OBJECTIVE: This study was a prospective cross-sectional clinical audit of patients with mandibular fractures at the Charlotte Maxeke Johannesburg Academic Hospital. METHODS: Between 1 March and 31 August 2004, patients with mandibular fractures seen by one clinician had their details recorded. RESULTS: The female:male ratio of the study sample of 133 patients was 1:6. Seventy-seven per cent were aged 20-39 years. Most fractures (86%) were the result of interpersonal violence, and 65% were alcohol-associated. Open reduction (75%) was the most common treatment. CONCLUSION: This study had the highest interpersonal violence and open reduction rates of all the studies reviewed. PMID- 21542403 TI - Chasing the ubiquitous RET proto-oncogene in South African MEN2 families- implications for the surgeon. AB - The RET proto-oncogene (REarranged during Transfection; RET) plays an important role in the causation of many thyroid tumours. Germline RET proto-oncogene missense mutations have been clearly linked to medullary thyroid carcinoma (MTC) and the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2A, MEN2B). METHODS: We investigated a cohort of MEN2-related patients referred to Tygerberg Hospital, W Cape (2003-2009). The study cohort was divided into three groups based on pathology (viz. MEN/MTC, phaeochromocytoma, and a miscellaneous group of MEN pathologies). Families with identified high-risk factors were recalled. Serum calcitonin levels were monitored where indicated. DNA was extracted from whole blood by standard techniques and polymerase chain reaction (PCR) products screened for RET gene variations by heteroduplex single-strand duplication techniques (heteroduplex single-strand conformation polymorphism analysis) being validated with automated sequencing techniques showing conformational variants in acrylamide gel. RESULTS: We screened 40 persons, male/female ratio 1:1.5. Three ethnic groups were represented (white (12), black (11) and mixed race (17)). Nine were index MTC cases, 5 phaeochromocytoma, 3 Hirschsprung's disease-MEN associations and 2 miscellaneous (1 neuroblastoma, 1 intestinal neuronal dysplasia), while 1 fell into the MEN2B category. The remaining 19 were unaffected relatives screened for carrier status, among whom afamilial recurrence was observed in 7. On genetic testing, an RET point mutation at the high-risk 634 cysteine allele was identified in 11 cases. A further cysteine radical mutation at the 620 position was related to MEN2 in 3 families plus 1 other family referred from elsewhere. Other less-recognised gene variations were detected throughout the RET gene in 70% of cases and included the 691 position on codon 11 (11 cases); the 432 position (4 cases, 1 homozygous) intronic mutations on exon 4 (1 case); and an IVS19-37G/C and a D1017N variation in exon 19 in 2 MEN families. Fifteen MTC patients have had thyroidectomies, of which 2 were prophylactic (C-cell hyperplasia; early occult MTC). A further 3 are awaiting prophylactic surgery. CONCLUSION: RET gene mutation carries a risk of MEN2 and MTC in all ethnic groups in South Africa. Prophylactic surgery may prevent MTC, so genetic screening is important to identify and treat high-risk patients. PMID- 21542404 TI - Popliteal vein aneurysm. PMID- 21542405 TI - Bouveret's syndrome with cholecysto-colic fistula. PMID- 21542406 TI - Successful medical management of postoperative parastomal hernia prosthesis infection after Hartmann restoration. PMID- 21542407 TI - Holistic quarterbacking and the 80/20 rule. PMID- 21542408 TI - Personality disorders in the oncology setting. AB - This paper reviews differential diagnosis of the difficult oncology patient, focusing on how the patient, the physician, the patient-physician relationship, and the cancer setting may all contribute to clinicians' experiences of difficulty. Because many difficult patients have personality disorders, we then review assessment and treatment of the personality disorders that tend to be most problematic in the cancer setting, suggesting a team-based approach for management. PMID- 21542409 TI - Personality disorders in the clinical setting. PMID- 21542410 TI - Challenging personalities in the oncology setting. PMID- 21542411 TI - Recognizing depression in patients with cancer. PMID- 21542412 TI - EvaIuating the "good death" concept from Iranian bereaved family members' perspective. AB - Improving end-of-life care demands that first you define what constitutes a good death for different cultures. This study was conducted to evaluate a good death concept from the Iranian bereaved family members' perspective. A descriptive, cross-sectional study was designed using a Good Death Inventory (GDI) questionnaire to evaluate 150 bereaved family members. Data were analyzed by SPSS. Based on the results, the highest scores belonged to the domains "being respected as an individual," "natural death," "religious and spiritual comfort," and "control over the future." The domain perceived by family members as less important was "unawareness of death." Providing a good death requires professional caregivers to be sensitive and pay attention to the preferences of each unique person's perceptions. In order to implement holistic care, caregivers must be aware of patients' spiritual needs. Establishing a specific unit in a hospital and individually treating each patient as a valued family member could be the best way to improve the quality of end-of-life care that is missing in Iran. PMID- 21542413 TI - Symptom experience in patients with gynecological cancers: the development of symptom cIusters through patient narratives. AB - The vast majority of the increasing cancer literature on physical and psychological symptom clusters is quantitative, attempting either to model clusters through statistical techniques or to test priori clusters for their strength of relationship. Narrative symptom clusters can be particularly sensitive outcomes that can generate conceptually meaningful hypotheses for symptom cluster research. We conducted a study to explore the explanation of patients about the development and coexistence of symptoms and how patients at tempted to self-manage them. We collected 2-month qualitative longitudinal data over four assessment points consisting of 39 interview data sets from 10 participants with gynecological cancer. Participants' experiences highlighted the presence of physical and psychological symptom clusters, complicating the patients 'symptom experience that often lasted 1 year. While some complementary and self-management approaches were used to manage symptoms, few options and interventions were discussed. The cancer care team maybe able to develop strategies for a more thorough patient assessment of symptoms reported as the most bother so mean and patient-centered sensitive interventions that encompass the physiological, psychological, sociocultural, and behavioral components of the symptom experience essential for effectives symptom management. PMID- 21542414 TI - Estimating minimally important differences for the worst pain rating of the Brief Pain Inventory-Short Form. AB - The Brief Pain Inventory-Short Form (BPI-SF) is widely used for assessing pain in clinical and research studies. The worst pain rating is often the primary outcome of interest; yet, no published data are available on its minimally important difference (MID). Breast cancer patients with bone metastases enrolled in a randomized, double-blind, phase III study comparing denosumab with zoledronic acid for preventing skeletal related events and completed the BPI-SF, FACT-B, and EQ-5 Datbaseline, week 5, and monthly through the end of the study. Anchor-and distribution-based MID estimates were computed. Data from 1,564 patients were available. Spearman correlation coefficients for anchors ranged from 0.33-0.65. Mean change scores for worst pain ratings corresponding to one-category improvement in each anchor were 0.26-1.04 for BPI-SF current pain, -1.40 to -2.42 for EQ-5D Index score, 1.71-1.98 for EQ-5D Pain item, -2.22 to -0.51 for FACT BTOI, -1.61 to -0.16 for FACT-G Physical, and -1.31 to -0.12 for FACT-G total. Distribution-based results were ISEM = 1.6, 0.5 effect size = 1.4, and Guyatt's statistic = 1.4. Combining anchor-and distribution-based results yielded a two point MID estimate. An MID estimate of two points is useful for interpreting how much change in worst pain is considered clinically meaningful. PMID- 21542415 TI - A pilot trial of decision aids to give truthful prognostic and treatment information to chemotherapy patients with advanced cancer. AB - Most cancer patients do not have an explicit discussion about prognosis and treatment despite documented adverse outcomes. Few decision aids have been developed to assist the difficult discussions of palliative management. We developed decision aids for people with advanced in curable breast, colorectal, lung, and hormone-refractory prostate cancers facing first-, second-, third-, and fourth-line chemotherapy. We recruited patients from our urban oncology clinic after gaining the permission of their treating oncologist. We measured knowledge of curability and treatment benefit before and after the intervention. Twenty-six of 27 (96%) patients completed the aids, with ameanage of 63, 56% female, 56% married, 56% African American, and 67% with a high school education or more. Most patients (14/27, 52%) thought a person with their advanced cancer could be cured, which was reduced (to 8/26, 31%, P = 0.15) after the decision aid. Nearly all overestimated the effect of palliative chemotherapy. No distress was noted, and hope did not change. The majority (20/27, 74%) found the information helpful to them, and almost all (25/27, 93%) wanted to share the information with their family and physicians. It is possible to give incurable patients their prognosis, treatment options, and options for improving end-of-life care without causing distress or lack of hope. Almost all find the information helpful and want to share it with doctors and family. Research is needed to test the findings in a larger sample and measure the outcomes of truthful information on quality of life, quality of care, and costs. PMID- 21542416 TI - Caco-2 cells, biopharmaceutics classification system (BCS) and biowaiver. AB - Almost all orally administered drugs are absorbed across the intestinal mucosa. The Caco-2 monolayers are used as an in vitro model to predict drug absorption in humans and to explore mechanism of drug absorption. The Caco-2 cells are derived from a human colon adenocarcinoma and spontaneously differentiate to form confluent monolayer of polarized cells structurally and functionally resembling the small intestinal epithelium. For studying drug permeability, Caco-2 cells are seeded onto the Transwell inserts with semipermeable membrane and grown to late confluence (21 days). After determination of cell viability, the integrity of monolayer is checked by phenol red permeability and by 14C-mannitol permeability. The transport from apical to basolateral (AP-BL) and basolateral to apical (BL AP) is studied by adding the diluted drug on the apical or basolateral side and withdrawing the samples from the opposite compartment, respectively, for HPLC analysis or liquid scintillation spectrometry. Ca2+ -free transport medium is used to determine paracellular component of the drug transport. On the basis of permeability and solubility, drugs can be categorized into four classes of Biopharmaceutics Classification System (BCS). For certain drugs, the BCS-based biowaiver approach can be used which enables to reduce in vivo bioequivalence studies. PMID- 21542417 TI - Comparison of duplex ultrasonography and magnetic resonance imaging in the detection of significant renal artery stenosis. AB - OBJECTIVE: The aim of our study was to evaluate duplex ultrasonography (DUS) and magnetic resonance angiography (MRA) in detection of haemodynamically significant renal artery stenosis (RAS). METHODS: The study included patients with high clinical suspicion of renovascular hypertension (RVH). The imaging of renal arteries was performed by DUS, MRA and digital subtraction angiography (DSA). Significant RAS was defined as maximum systolic velocity > or =180 cm/sec (DUS) or as 60% reduction of the endoluminal arterial diameter (MRA, DSA). The results of DUS and MRA were assessed in respect to the results of DSA. RESULTS: Arterial supply of 186 kidneys in 94 patients was evaluated. DSA revealed significant RAS in 61 kidneys evaluated. DUS was not able to examine arterial supply in 18 kidneys of 13 patients. In the detection of significant RAS, DUS was characterized by sensitivity and specificity of 85% and 84%. MRA achieved satisfactory imaging quality in all but one kidney evaluated. The sensitivity and specificity of MRA in the detection of significant RAS was 93% and 93%, respectively. CONCLUSION: In patients with high clinical probability of RVH, MRA proved to be more reliable and superior in both sensitivity and specificity to DUS in the detection of significant RAS. PMID- 21542418 TI - Surgical treatment of periodontal intrabony defects with calcium sulphate in combination with beta-tricalcium phosphate: clinical observations two years post surgery. AB - The study was designed to evaluate the clinical outcome of a composite material, beta-tricalcium phosphate in combination with calcium sulphate, in the treatment of periodontal intrabony defects. The combination of these materials is believed to aid in guided tissue regeneration owing to their properties. A total of 47 teeth with intrabony defects in 26 periodontitis patients were treated with Fortoss Vital (Biocomposites, Staffordshire, U.K.). Clinical parameters were evaluated which included changes in probing depth, clinical attachment level/loss and gingival recession at the baseline and 2 years postoperatively. The mean differences in measurements between the baseline and 2 years postoperatively were a reduction of 2.07 +/- 1.14 mm (p = 0.000) in case of probing depth and a gain of 1.93 +/- 1.36 mm (p = 0.000) in clinical attachment level; but an increase of 0.14 +/- 0.73 mm (p = 0.571) in gingival recession. The study results show that the treatment with a combination of beta tricalcium phosphate and calcium sulphate led to a significantly favorable clinical improvement in periodontal intrabony defects 2 years after the surgery. PMID- 21542419 TI - Gestational diabetes mellitus in primigravidae: a mild disease. AB - This prospective observational study was done to analyse the prevalence of gestational diabetes mellitus (GDM) among primigravidae and its outcome. All healthy primigravidae with singleton pregnancies were offered universal glucose tolerance testing between 16 and 28 weeks gestation. GDM and non GDM groups were managed according to hospital protocol. The antenatal features and pregnancy outcomes were analysed. Out of 616 primigravidae, 113 (18.34%) were GDM with slightly older (27.9 +/- 4.2 versus 26.32 +/- 3.3, p < 0.001) age. The mean fasting and two hours postprandial blood glucose in both groups were 4.99 +/- 1.08 mmol/l, 8.86 +/- 1.41 mmol/l(GDM) and 4.36 +/- 0.43 mmol/l, 5.71 +/- 1.11 mmol/l (Non GDM), respectively. Maternal family history of diabetes mellitus, weight exceeding 80 Kg, polyhydramnios (2.65% versus 0.2%, p = 0.028) and neonatal hyperbilirubinaemia (9.73% versus 2.98%, p = 0.01) occurred significantly more frequent in the GDM group compared to normal. There was no significant difference in other pregnancy outcomes and complications between the two groups. In conclusion GDM in primigravidae was detected at a relatively young age with more frequent maternal family history of DM, weight exceeding 80 Kg, polyhydromnions and neonatal hyperbilirubinaemia. The degree of disease was mild and treatment led to no significant complication. PMID- 21542420 TI - Case 1-2011: small intestinal diffuse large B-cell lymphoma in a 58-year-old patient with coeliac disease. PMID- 21542421 TI - Atopy patch test in diagnosis of food allergy to egg in adult patients suffering from atopic eczema. Three case reports. PMID- 21542422 TI - Chylothorax--a rare complication after cardiac surgery (a case report). AB - Chylothorax is a rare but severe complication of cardiac surgery. The authors present the case of a 76-year-old woman suffering from ischemic heart disease, after coronary artery bypass grafting that included a left internal mammary artery pedicle graft. On the ninth postoperative day the left-sided fluidothorax developed. The results of biochemical analysis were consistent with the chyle. Combined treatment with pleural drainage and total parenteral nutrition was effective. PMID- 21542423 TI - Laryngeal granular cell tumor; rare location. AB - Granular cell tumors are benign subcutaneous or submucosal lesions of neurogenic origin. In this case study one patient was diagnosed and treated successfully with complete surgical resection of a laryngeal granular cell tumor that was originated from the left arytenoid region that very rare location. There is no evidence of recurrence 2 years after surgery. Granular cell tumors should be considered in the differential diagnosis of laryngeal masses, particularly in the posterior glottis. PMID- 21542424 TI - Chronic eosinophilic pneumonia with subpleural curvilinear shadow. AB - We report a rare case of chronic eosinophilic pneumonia with subpleural curvilinear shadow. CT scan showed a patchy consolidation in the bilateral upper lungs. In addition, subpleural curvilinear shadow was found in the bilateral upper lungs. A bronchoalveolar lavage obtained from the right middle lobe showed 25 % eosinophils. Although very rare, we should therefore keep in mind that patients, who have patchy consolidation with areas of subpleural curvilinear shadow in the bilateral upper lungs, may have chronic eosinophilic pneumonia. PMID- 21542425 TI - Selection criteria towards competent and caring doctors. PMID- 21542426 TI - A randomised double-blind placebo-controlled study on the effects of a herbal toothpaste on gingival bleeding, oral hygiene and microbial variables. AB - INTRODUCTION: Different systems of traditional medicine of the Indian subcontinent, have used Acacia chundra Willd, Adhatoda vasica Nees., Mimusops elengi L., Piper nigrum L., Pongamia pinnata L. Pirerre, Quercus infectoria Olivier., Syzygium aromaticum L., Terminalia chebula Retz., Zingiber officinale Roscoe., individually or in combinations, to cure oral diseases. OBJECTIVE: To investigate the oral hygiene and gingival health benefits of toothpaste formulated with a mixture of the above herbs (15% w/w). METHODS: Sixty participants (test n = 30, control n = 30, mean age 23.6 +/- 2.25 vs 23.9 +/- 3.2 years) who fulfilled the selection criteria and had similar plaque (1.734 +/- 0.29 vs 1.771 +/- 0.33) and percentage of sites with gingival bleeding (19.6 +/- 7 vs 20.7 +/- 8) were studied in a double blind randomised clinical trial. Brushing instructions to all and a scaling for those with calculus were provided two weeks before baseline examination. One ml of resting saliva was collected to ascertain anaerobic (SAnB) and aerobic (SAB) bacterial counts, plaque index (PI), percentage sites with bleeding on probing (BOP) and pocket depth (PD) (at 6 sites/tooth) were recorded at baseline, followed by home use of the allocated toothpaste (test or placebo) twice a day for 12 weeks. Measurements were repeated at 4, 8, and 12 weeks. RESULTS: PI, BOP and SAnB decreased significantly in the test group at 4, 8, and 12 weeks compared to baseline measurements (Wilcoxon Signed Rank Test, p < 0.01). There was no statistically significant improvement in PI, BOP, and SAnB in the placebo group. CONCLUSIONS: Our study indicates the beneficial effects of this herbal toothpaste (Sudantha) on oral hygiene and gingival health variables when compared with the placebo. Further clinical trials using patients with gingivitis are necessary to confirm the therapeutic benefits of this herbal toothpaste. PMID- 21542427 TI - A trial of expectant management in incomplete miscarriage. AB - INTRODUCTION: Incomplete miscarriage is often treated with surgical evacuation in Sri Lanka. Expectant management, which is an alternative treatment, was assessed for efficacy and safety in a local setting. METHODS: Randomised clinical trial of two treatment groups of expectant and surgical management with 71 and 69 participants, respectively, was done at the University Gynaecology Unit of the Colombo North Teaching Hospital, Ragama, from December 2007 to July 2009. Women with incomplete miscarriage at a period of amenorrhoea of < 14 weeks and retained products of conception of < 50mm were included. Expectant management involved in ward treatment till resolution of heavy bleeding and pain and follow up for two weeks. In surgical treatment, evacuation was undertaken and the patient sent home from hospital after bleeding settled with follow up. The maximum anteroposterior diameter of the endometrial cavity was measured with transvaginal ultrasonography and a diameter < 15mm was considered as complete miscarriage. RESULTS: Expectant management had a treatment success of 90.1% at one week and 94.4% at two weeks. For surgical treatment this was 95.7%. Infection was noted in one subject from the surgical group and none in the expectant group. Fall in the haemoglobin concentration in the two groups was clinically not significant. The expectantly managed group had a shorter hospital stay than the surgically managed group (1.58 vs 2.57 days, p = 0.008). CONCLUSIONS: Expectant management is an effective and safe alternative to surgical evacuation in management of incomplete miscarriage in the local setting. It relieves the burden on the healthcare provider by shortening the hospital stay and avoiding the need for evacuation of retained products of conception under anaesthesia. PMID- 21542428 TI - Fetal acoustic stimulation test for early intrapartum fetal monitoring. AB - INTRODUCTION: The fetal acoustic stimulation test (FAST) is a simple cost effective screening test for antenatal fetal monitoring. The aim of the study was to evaluate the FAST as a screening test for early intrapartum fetal well being. METHODS: An initial non stress test (NST) followed by a FAST using corometric model 146 was carried out in 486 participants in early labour with uncomplicated singleton pregnancies and > 32 weeks gestation. A repeat NST was recorded in the participants who had an initial non reactive NST. The results of the NST and FAST were compared with fetal outcome. Maternal perception of fetal movements after FAST, results of NST before and after FAST, and the babies' 5 minute APGAR scores were measured. RESULTS: Of the 486 participants 413 (85%) noticed fetal movements after FAST. Initial NST was non reactive in 203 (42%) but 149 (31%) became reactive after FAST. Compared to the NST, FAST had a better sensitivity (97% vs 62%, p < 0.001), specificity (100% vs 87%, p = 0.017), positive predictive value (100% vs 98%, p = 0.024), negative predictive value (79% vs 17%, p < 0.001) and accuracy (99%vs 64%, p < 0.001) in predicting 5 minute APGAR < 7 in the baby. CONCLUSIONS: FAST is a reliable screening test for assessing fetal well being in early labour. It complements the NST and is better than the NST alone. PMID- 21542429 TI - Validation study of Sinhala version of the dermatology life quality index (DLQI). AB - INTRODUCTION: The effect of dermatological disease on patients' quality of life is a minimally addressed issue in Sri Lanka. One reason is the unavailability of a standardised measuring tool. This study was done to produce and validate a Sinhala version of the Dermatology Life Quality Index (DLQI), which is an internationally accepted quality of life measuring instrument. METHODS: The English version of the DLQI was translated according to standard procedures and the translated version was validated among 200 outpatients attending the dermatology clinics at the National Hospital of Sri Lanka and 30 healthy volunteers. The SF-36 was administered simultaneously to a random subsample of 125 participants to test for criterion validity. Intemal consistency and the test retest reliability were assessed separately for the translated DLQI. RESULTS: The Sinhala version of DLQI takes 3-5 minutes to be completed on average and had no confusing, embarrassing or difficult to answer questions. Except for personal relationship domain (0.442) all other domains demonstrated high Cronbach's alpha values suggesting satisfactory internal consistency within the domains. The DLQI demonstrated good test-retest reliability with all Kappa values above 0.83. In comparison with the relevant domains of the SF-36, the DLQI demonstrated greater than 0.4 (Pearson r) suggesting an acceptable criterion validity. The Sinhala version of the DLQI appears to discriminate well between disease status and disease severity (F = 31.09, p < 0.001, n = 240). CONCLUSIONS: The DLQI (Sinhala) version is a simple, acceptable and reliable tool to measure the effect of dermatological diseases on quality of life. PMID- 21542430 TI - Selection of medical students in Sri Lanka: time to re-think criteria? AB - OBJECTIVE: To examine the validity of selected entry level characteristics in relation to the GCE A/L examination as independent predictors of performance of students in medical school. METHODS: A retrospective, analytical study was done at the Faculty of Medicine, University of Kelaniya. Student characteristics at entry were described by sex, the average z-score, General English grade and attempt at GCE A/L examination, and average mark obtained at the English placement test on registration to medical school. Average marks at three summative examinations were used as indicators of performance in medical school. Multivariate analysis using multiple linear regression was carried out using these three outcome measures in relation to four entry point variables as predictors of performance in medical school. Causal path diagrams were constructed using standardised regression coefficients for the whole group and for male and female students separately. RESULTS: The A/L z-score, A/L attempt and English placement test marks were all significant predictors of outcome at the First Examination. Of the variables relating to the A/L examination, the attempt had a much higher path coefficient with performance at the First Examination than the A/L z-score, as did the English marks. Separate path analyses for male and female students showed that while the significance of the relationships remained the same, the magnitude of the correlation was different. CONCLUSIONS: Students who gain admission on their 3rd attempt at the AL examination fare much worse than those admitted to medical school on their 1st attempt. Differences between sexes in examination performance are probably linked to both A/L attempt and English language proficiency. PMID- 21542431 TI - Hidden and informal curricula in medical schools: impact on the medical profession in Sri Lanka. PMID- 21542432 TI - The Sri Lankan prototype of a negative pressure wound therapy device. PMID- 21542433 TI - Congenital urethral fistula. PMID- 21542434 TI - Severe anaphylaxis following ant bites. PMID- 21542435 TI - Isolated congenital foramen transversarium abnormality causing occipital headache. PMID- 21542436 TI - Update on contraception--4. PMID- 21542437 TI - Perception of pain during episiotomy in a tertiary care centre in Sri Lanka. PMID- 21542438 TI - A case of Behcet's disease complicated with intra cardiac thrombus and Budd Chiari syndrome. PMID- 21542439 TI - Poncet's disease or tuberculous rheumatism. PMID- 21542440 TI - Everything old is new again. PMID- 21542441 TI - Review of intermittent catheterization and current best practices. AB - Intermittent catheterization is the insertion and removal of a catheter several times a day to empty the bladder. This type of catheterization Is used to drain urine from a bladder that is not emptying adequately or from a surgically created channel that connects the bladder with the abdominal surface (such as Mitrofanoff continent urinary diversion). Intermittent catheterization is widely advocated as an effective bladder management strategy for patients with incomplete bladder emptying due to idiopathic or neurogenic bladder dysfunction. Urologic nurses are at the forefront of educating and teaching patients how to self-catheterize. Catheterizations performed in institutions, such as acute and rehabilitation hospitals and nursing homes, are done aseptically. Historically, however, intermittent catheterization has been performed by the patient in the home environment using a clean technique involving the re-use of catheters. New guidelines released in the past three years have recommended changes to the practice of re-using catheters. Currently, nurses use their clinical judgment to determine which technique and type of catheter to use, in conjunction with patient preference. Differential costs and insurance coverage of catheters/echniques may also influence decision making. The authors provide an overview of the indications, use, and complications associated with intermittent catheterization, present current guidelines on self-catheterization and treatment of catheter-associated complications, detail types of catheters, and review clinical practice of intermittent catheterization. PMID- 21542442 TI - Traces: making sense of urodynamics testing--part 3: electromyography of the pelvic floor muscles. AB - Electromyography (EMG) of the pelvic floor muscles is a valuable but challenging component of urodynamics testing. Optimal assessment relies on thoughtful selection of needle, wire, or surface patch electrodes; consistent display of EMG tracings simultaneously with pressure and flow tracings; and minimization of technical and environmental artifacts. This article reviews technical aspects of EMG, including the selection of the best electrodes for a given clinical scenario, minimization of environmental and technical artifacts, and clinical measurement during the filling cystometrogram and voiding pressure flow study. PMID- 21542443 TI - Urinary tract infection rates associated with re-use of catheters in clean intermittent catheterization of male veterans. AB - Clean intermittent catheterization used to manage urinary retention can be complicated by urinary tract infection (UTI). This retrospective study describes the frequency of antibiotic-treated UTI in patients undergoing intermittent catheterization. Most patients did not have UTI; this supports findings in previous studies. PMID- 21542444 TI - The causes and prevalence of vestibulodynia: a vulvar pain disorder. AB - Vestibulodynia is a chronic type of vulvar pain that affects at least 16% of women in the United States. The condition is often misdiagnosed or not diagnosed at all due to a lack of knowledge among health care professionals. Delayed diagnosis puts a woman at risk for sexual dysfunction, decreased quality of life, and relationship conflict. PMID- 21542445 TI - The prevalence of anxiety and depression in palliative care patients with cancer in Western Australia and New South Wales. AB - OBJECTIVES: To examine the prevalence and predictors of depression and anxiety in palliative care patients with cancer in Western Australia and New South Wales. DESIGN, SETTING AND PARTICIPANTS: A descriptive study of 266 consecutive patients at a range of inpatient and outpatient settings including home care, hospices, and private and tertiary care hospitals in WA and NSW from 1 March to 30 June 2002. MAIN OUTCOME MEASURES: Self-reported anxiety and depression using the Hospital Anxiety and Depression Scale (HADS) at a cut-off score of > or = 8 on each subscale (depression and anxiety) for possible cases, and of > or = 11 for probable cases; a cut-off score of > or = 19 was used for probable combined depression and anxiety. RESULTS: Patients included 200 in WA and 66 in NSW. For the whole sample, 45.8% of patients were possibly depressed and 22.7% probably depressed; 36.9% were possibly anxious and 19.8% probably anxious. About 25% of patients had probable combined depression and anxiety. Logistic regression analyses indicated that past anxiety in the family predicted probable depression, while age, marital status and past depression predicted probable anxiety. Age and past depression predicted probable combined depression and anxiety. CONCLUSIONS: These findings underscore the need for routine screening for anxiety and depression in palliative care settings, including questions about past personal and family history of anxiety and depression, and the need for a range of interventions and support services. PMID- 21542446 TI - Psychological distress (depression and anxiety) in people with head and neck cancers. AB - OBJECTIVE: To assess symptoms of depression and anxiety in patients with head and neck cancers (HNCs) before and after radiotherapy. DESIGN, PARTICIPANTS AND SETTING: Prospective observational study of 102 outpatients with HNCs at a tertiary cancer centre in Melbourne between 1 May 2008 and 30 May 2009. Eligibility criteria were a first-time diagnosis of HNC, age over 17 years, and agreement to undergo cancer treatment involving radiotherapy with curative intent. Data were collected before commencement of radiotherapy and again 3 weeks after completing treatment. MAIN OUTCOME MEASURES: Symptoms of depression and anxiety as assessed by the Hospital Anxiety and Depression Scale (HADS); physical and psychosocial aspects of quality of life as assessed by the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N). RESULTS: Seventy-five participants completed pretreatment and posttreatment questionnaires. Mean depression scores increased significantly from before to after treatment, while anxiety scores decreased significantly over the same period. The prevalence of mild to severe depression was 15% before treatment and 31% after treatment. The prevalence of mild to severe symptoms of anxiety was 30% before treatment, reducing to 17% after treatment. Posttreatment depression was predicted by pretreatment depression and receiving chemotherapy. Posttreatment anxiety was predicted by pretreatment anxiety and male sex. CONCLUSIONS: These findings suggest that rates of depression in patients with HNCs increase after cancer treatment, with a third of patients experiencing clinically significant symptoms of depression after radiotherapy. PMID- 21542448 TI - Predictors of psychosocial distress 12 months after diagnosis with early and advanced prostate cancer. AB - OBJECTIVE: To assess psychosocial distress in patients with early (localised) and advanced (metastatic) prostate cancer (PCA) at diagnosis (Time 1) and 12 months later (Time 2), and identify psychosocial factors predictive of later distress. DESIGN, PARTICIPANTS AND SETTING: Observational, prospective study of 367 men with early (211) or advanced (156) PCA recruited as consecutive attendees at clinics at seven public hospitals and practices in metropolitan Melbourne between 1 April 2001 and 30 December 2005. Both groups completed questionnaires at Time 1 and Time 2. MAIN OUTCOME MEASURES: Health-related quality of life as assessed by the Short Form 36-item Health Survey; psychological distress, including depression and anxiety as assessed by the Brief Symptom Inventory; and coping patterns as assessed by the Mini-Mental Adjustment to Cancer scale. RESULTS: Over the 12 months, both the early and advanced PCA group showed reduced vitality and increased depression and anxiety; this effect was greater in the advanced PCA group. Mental health, social functioning and role-emotional functioning also deteriorated in the advanced group. Predictors of depression at Time 2 for the early PCA group were depression, vitality and a fatalistic coping pattern at Time 1; anxiety at Time 2 was predicted by anxiety and vitality at Time 1. In the advanced PCA group, depression at Time 2 was predicted by depression and mental health at Time 1; anxiety at Time 2 was predicted by anxiety, mental health, cognitive avoidance and lower anxious preoccupation at Time 1. CONCLUSIONS: Men with early PCA experience decreasing vitality and increasing psychological distress over the 12 months following diagnosis; this trend is accelerated after diagnosis with advanced PCA. A fatalistic coping pattern at diagnosis of early PCA predicts later depression while cognitive avoidance and lower anxious preoccupation at diagnosis of advanced PCA predict later anxiety. PMID- 21542447 TI - Prevalence and predictors of anxiety and depression in women with invasive ovarian cancer and their caregivers. AB - OBJECTIVES: To assess the prevalence and predictors of depression and anxiety in women with ovarian cancer and their caregivers, to compare levels of depression and anxiety with community norms, and to explore the relationship between patients and their nominated caregivers. DESIGN, SETTING AND PARTICIPANTS: Prospective cohort study of 798 women with invasive ovarian cancer recruited between 1 January 2002 and 30 June 2006 through the nationwide Australian Ovarian Cancer Study, and 373 of their caregivers. MAIN OUTCOME MEASURES: Depression and anxiety as assessed with the Hospital Anxiety and Depression Scale, and the role of demographic variables, disease and treatment variables, psychosocial variables, and use of mental health and support services as potential predictors. RESULTS: Rates of anxiety and depression among patients were significantly lower than in previous reports, although clinical depression rates (5.9%) were significantly higher than community norms (3.0%; chi2 = 24.0; P < 0.001). Caregivers also reported higher levels of depression (chi2 = 21.1; P < 0.001) and anxiety (chi2 = 17.6; P < 0.001) compared with norms. There was no difference within patient-caregiver pairs for depression (P = 0.1), while caregivers reported significantly higher anxiety than patients (P < 0.01). In patients, higher symptom burden, lower optimism and current specialist mental health treatment all significantly predicted both depression and anxiety, while lower social support was a significant predictor of patient anxiety only. In caregivers, lower social support and lower optimism were significant predictors of depression and anxiety. Patients being treated for mental health was also a predictor of their caregiver's depression. CONCLUSIONS: While depression is significantly more common in women with ovarian cancer than in the general population, it is caregivers of such patients who report much higher levels of both subclinical and clinical depression and anxiety. PMID- 21542449 TI - Is psychological distress in people living with cancer related to the fact of diagnosis, current treatment or level of disability? Findings from a large Australian study. AB - OBJECTIVE: To investigate whether the observed elevated levels of psychological distress in cancer survivors relate specifically to aspects of cancer diagnosis, to treatment or to disability. DESIGN, PARTICIPANTS AND SETTING: Self-reported questionnaire data on demographic, health and lifestyle factors and mental health from 89574 Australian men and women aged 45 years or older, sampled from the Medicare database for the 45 and Up Study from 1 February 2006 to 30 April 2008. Logistic regression was used to examine the risk of high levels of psychological distress in relation to cancer diagnosis and disability, adjusting for age, sex, income and education. MAIN OUTCOME MEASURE: High psychological distress (Kessler Psychological Distress Scale score > or = 22). RESULTS: Overall, 7.5% of participants had high levels of psychological distress. Among cancer survivors, the median time since diagnosis was 7.3 years. Compared with people without cancer, the odds ratios (95% CIs) for psychological distress were: 1.17 (1.09 1.26) in people reporting having had any cancer apart from non-melanoma skin cancer; 1.34 (1.08-1.67) in those with cancer diagnosed in the previous year; 1.53 (1.33-1.76) for those reporting treatment for cancer in the previous month and 1.11 (1.03-1.19) for those with cancer but without recent treatment. Using individuals with neither cancer nor disability as the reference group, the adjusted odds ratio (95% CI) for psychological distress was 6.51 (5.95-7.12) in those reporting significant disability but no cancer, 1.14(1.04-1.24) in those without disability but with cancer and 5.81(4.88-6.91) in those with both cancer and disability. CONCLUSION: The risk of psychological distress in individuals with cancer relates much more strongly to their level of disability than it does to the cancer diagnosis itself. PMID- 21542450 TI - A randomised controlled trial to evaluate the effects of a self-help workbook intervention on distress, coping and quality of life after breast cancer diagnosis. AB - OBJECTIVE: To evaluate the efficacy of an interactive self-help workbook in reducing distress, and improving quality of life (QOL) and coping for women recently diagnosed with breast cancer. DESIGN: Randomised controlled trial comparing the use of the workbook and that of an information booklet. PARTICIPANTS AND SETTING: 49 women with Stage 0 to II breast cancer diagnosed in the previous month and recruited from 1 February 2007 to 1 February 2008, in two urban Australian public hospitals. MAIN OUTCOME MEASURES: The primary outcome measures were depression, anxiety, and posttraumatic stress. Secondary outcomes included QOL, body image, and the coping styles helplessness/hopelessness, cognitive avoidance and anxious preoccupation. RESULTS: After controlling for baseline levels, interactions at 3-month follow-up showed that participants in the workbook group had significantly lower levels of posttraumatic stress (F[1,89] = 7.01; P = 0.01), helplessness/hopelessness (F [1,89] = 4.75; P = 0.03), and cognitive avoidance (F [1,89] = 4.95; P = 0.03) than those in the control (information booklet) group. However, women in the workbook group had significantly poorer body image than those in the control group (F [1,89] = 6.43; P = 0.01). At 6 months, only the body image interaction remained significant (F [1,93] = 7.44; P = 0.01). CONCLUSION: These results suggest that a self-help workbook can be an effective, short-term intervention for improving posttraumatic stress, cognitive avoidance, and certain depressive symptoms in women recently diagnosed with breast cancer. However, issues related to body image need to be dealt with differently. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry PMID- 21542451 TI - Routine screening for psychological distress on an Australian inpatient haematology and oncology ward: impact on use of psychosocial services. AB - OBJECTIVE: To describe the outcomes and clinical experience of a 12-week pilot study of routine distress screening of newly admitted patients to an acute haematology and oncology ward. DESIGN, PATIENTS AND SETTING: Bedside measurement of psychological distress, and collection of demographic and clinical data for 115 newly admitted patients in an acute haematology and oncology ward of The Alfred hospital in Melbourne between 5 June and 25 August 2006. MAIN OUTCOME MEASURES: Psychosocial distress as measured by the Distress Thermometer and Problem Checklist, and 18-item Brief Symptom Inventory; rate of referral to psychology and social work services in the 12 weeks before and 12 weeks during the pilot study; ward staff feedback on the benefits and challenges associated with routine distress screening. RESULTS: 51% of patients were identified as being significantly distressed, of whom 47% had not received psychosocial support before screening. A significantly higher number of emotional and physical problems were reported by significantly distressed patients. Referrals to psychology and social work services during the pilot study increased, highlighting that screening directed more patients into care. Staff were generally positive about the ability of routine screening to help them care for their patients, and most agreed that some form of routine screening should continue. CONCLUSION: The use of routine distress screening by inpatient cancer services can significantly improve their capacity to offer psychosocial care. PMID- 21542452 TI - Mindfulness-based cognitive therapy: an efficacious community-based group intervention for depression and anxiety in a sample of cancer patients. AB - OBJECTIVE: To assess the impact of an 8-week structured mindfulness-based cognitive therapy (MBCT) program on individuals experiencing distress as a consequence of cancer. DESIGN, SETTING AND PARTICIPANTS: Prospective study of 16 participants with a history of cancer and five carers of people with cancer recruited from August 2008 to February 2009 through calls to the Cancer Council South Australia Helpline. Participants were assessed for anxiety and depression before and after undergoing a course in MBCT between 30 September and 18 November 2008 and 20 February and 10 April 2009. MAIN OUTCOME MEASURES: Depression, anxiety and mindfulness as measured by the Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory (STAI), and Freiburg Mindfulness Inventory (FMI), respectively, and a consumer-centred evaluation. RESULTS: There were significant reductions in depression (F[1,24] = 6.37; P = 0.012; partial-eta2 = 0.27) and anxiety (F[2,34] = 9.43; P = 0.001, partial-eta2 = 0.36) and mindfulness (F[2,32] = 8.36; P = 0.001; partial-eta2 = 0.34) following the intervention, and these effects were sustained at the 3-month follow-up. Reliable change indices further support these findings. Participants' scores on measures of depression and anxiety decreased as a function of increased mindfulness, as reflected by significant (P < 0.05) negative correlations between FMI scores and BDI-II scores (ranging from r = -0.46 to r = -0.79) and STAI scores (ranging from r = -0.46 to r = -0.50) scores at all time points. CONCLUSION: The MBCT program appears to be an efficacious intervention for use among people affected by cancer who also experience symptoms of depression and anxiety. PMID- 21542453 TI - A nurse-assisted screening and referral program for depression among survivors of colorectal cancer: feasibility study. AB - OBJECTIVE: To test the feasibility and acceptability of a telephone-based program to screen survivors of colorectal cancer (CRC) for distress, and to refer distressed patients to their treating health service. DESIGN, SETTING AND PARTICIPANTS: A prospective, multicentre study involving 59 patients with CRC recruited from six public and private health services in Melbourne, Victoria, from 15 June 2008 to 22 September 2009. Patients who had completed adjuvant chemotherapy for CRC were contacted (7-10 days after recruitment [outcall one] and again 4 weeks later [outcall two]) by the Cancer Council Victoria's helpline nurse, and screened for distress with the Distress and Impact Thermometer (DIT); participants were given tailored information and support and those with distress scores of > or = 5, and impact scores of > or = 4, were referred for follow-up. Telephone interviews were conducted 4 weeks after outcall two. Participating helpline and health service staff were surveyed on the feasibility and acceptability of the service. MAIN OUTCOME MEASURE: Anxiety and depression, measured by the Hospital Anxiety and Depression Scale (HADS). RESULTS: Of the 59 patients (87%) who agreed to participate, 63% were men; their mean age was 59 years (SD, 9.5 years). HADS depression decreased significantly from baseline (mean score, 4.93; SD, 4.22) to follow-up (mean score, 3.84; SD, 4.10; Z = 2.375; P = 0.02). However, there was no significant difference in HADS anxiety between baseline (mean score, 5.29; SD, 4.11) and follow-up (mean score, 4.78; SD, 3.65). Outcall one generated two referrals (4% of participants) and outcall two generated four referrals (8%); five of these six participants took up the referrals. Satisfaction with the program among participants was high; 82% found outcall one "quite or very helpful" and 79% found outcall two "quite or very helpful". Helpline and health service staff reported a straightforward process that did not adversely affect workloads. CONCLUSION: This model of care carries the potential to meet ongoing psychosocial needs of survivors of CRC. PMID- 21542454 TI - Azadirachta indica exerts chemopreventive action against murine skin cancer: studies on histopathological, ultrastructural changes and modulation of NF kappaB, AP-1, and STAT1. AB - The present study reports the histopathological, ultrastructural changes and modulation of NF-kappaB, AP-1, and STAT 1 during skin carcinogenesis in LACA mice and its intervention with Azadirachta indica. Skin tumors were induced by topical application of 7,12-dimethylbenz(a)anthracene (DMBA) (500 nmol/100 microl for 2 weeks) followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 microl of acetone, twice weekly) as a promoter. Male LACA mice were divided into four groups: Control, DMBA/TPA, aqueous Azadirachta indica leaf extract (AAILE), and AAILE + DMBA/TPA. AAILE was administered orally at a dose level of 300 mg/kg body weight three times a week for 20 weeks. Topical application of DMBA/ TPA to the skin resulted in well-developed squamous cell carcinomas characterized by hyperproliferation, hyperkeratosis, and corrugation of the epidermis. Degenerative changes were observed in the tumors of AAILE + DMBA/TPA-treated animals. Scanning electron microscopy revealed surface disruptions and certain rounded structures on the skin tumors of DMBA/TPA-treated animals. Topographical changes were also observed in the tumors of AAILE + DMBA/TPA-treated animals, which resembled regions of degeneration. Tumors obtained in DMBA/TPA group were associated with enhanced expression of NF-kappaB and AP-1 when compared to the control counterparts. Inhibition in tumorigenesis in response to A. indica treatment was accompanied by an overexpression of STAT 1 and AP-1 and decrease in NF-kappaB expression. The results of the present study provide a basis for the chemopreventive potential of A. indica against murine skin carcinogenesis. PMID- 21542455 TI - Knockdown of MED19 by lentivirus-mediated shRNA in human osteosarcoma cells inhibits cell proliferation by inducing cell cycle arrest in the G0/G1 phase. AB - MED 19 is a subunit of the mediator complex, which is a coactivator of RNA polymerase II and also interacts with the downstream coding region of many genes. However, the role of MED19 in osteosarcoma is unknown. In the present study, we applied lentivirus-mediated short hairpin RNA (shRNA)-triggered RNA interference to downregulate MED19 expression in human osteosarcoma SaOS-2 and U2OS cells. Knockdown of MED19 expression was confirmed by real-time PCR and Western blot. It was found that silencing of MED19 resulted in decreased cell viability, colony formation capacity, and DNA synthesis ability in both cells, as well as the G0/G1 phase cell cycle arrest. These results implied that MED19 played an important role in cell growth and cell cycle progression of human osteosarcoma cells. MED19 may be an attractive candidate for the therapeutic target in osteosarcoma. PMID- 21542456 TI - Anticancer effects of fullerene [C60] included in polyethylene glycol combined with visible light irradiation through ROS generation and DNA fragmentation on fibrosarcoma cells with scarce cytotoxicity to normal fibroblasts. AB - Fullerene [C60] included in polyethylene glycol (PEG) at a composing ratio of 1:350 w/w was examined for anticancer effects upon photodynamic therapy (PDT). Human connective tissue-derived fibrosarcoma cells HT1080 were decreased for a viability of 50% or 30%, by 3-h administration with PEG-fullerene [C60] at 50 or 100 ppm fullerene [C60] equivalent, respectively, subsequent rinsing out and irradiation with visible light (400-600 nm, 140 J/cm2: 450-fold as intense as in average outdoor), whereas the same tissue type-derived normal fibroblastic cells DUMS16 retained a viability of 93% or 85% under the same conditions. Anticancer effects were dependent on PEG-fullerene [C60] concentrations and irradiation doses, and scarcely exerted by PEG-fullerene [C60] alone, irradiation alone, or by fullerene [C60]-free PEG combined with irradiation, suggesting that the active principle may be fullerene [C60] as small as 0.0028 wt% versus the whole compound. Irradiation with PEG-fullerene [C60] occurred in intracellular DNA fragmentation according to TUNEL assay, and produced reactive oxygen species (ROS) such as hydroperoxides and peroxyl radicals or superoxide anion radicals in HT1080 cells as demonstrated by CDCFH-DA assay or nitroblue tetrazolium assay, respectively. Thus, PEG-fullerene [C60] is expected to be applied to anticancer PDT with scarce side effects on normal cells. PMID- 21542457 TI - Antitumor effect of suberoylanilide hydroxamic acid and topotecan in renal cancer cells. AB - The treatment modality for advanced renal cancer is limited. The development of novel systemic therapies has long been waited for. Suberoylanilide hydroxamic acid (SAHA) is one of the most potent histone deacetylase (HDAC) inhibitors, which are promising novel anticancer agents. SAHA has already been tested in phase II clinical trials; however, its effectiveness has been found to be limited. Recently, the combination of SAHA and topoisomerase I inhibitor, topotecan, was shown to be effective, but this treatment strategy has not been tested in renal cancer cells. In the present study, we found that the combination of SAHA and topotecan effectively inhibited the growth of renal cancer cells by suppressing the expression of cyclin-dependent kinase (CDK) 4 and cyclin D1, and promoting retinoblastoma protein (Rb) dephosphorylation. Furthermore, the combination therapy was found to inhibit both the function and expression of HDACs, which may be one of the main mechanisms of the combination therapy. To the best of our knowledge, this is the first report that has revealed the combined beneficial effect of SAHA and topotecan on renal cancer cells. Combining SAHA and topotecan is thus a promising approach to the treatment of renal cancer. PMID- 21542458 TI - Three-dimensional conformal radiation therapy of spontaneous benign prostatic hyperplasia in canines. AB - The purpose of this study was to determine the effect and possible mechanism of three-dimensional conformal stereotactic radiation therapy (3D-CRT) for the treatment of spontaneous benign prostatic hyperplasia (BPH) in a canine model. Eight canines (7-15 years old) with spontaneous benign prostatic hyperplasia (prostate volume >18 cm3) were used as experimental models. The prostates were directly exposed to 3D-CRT at a total dose of 14 Gy. Serum prostate-specific antigen (PSA) and prostate acid phosphatase (PAP), prostate volume (measured by transrectal ultrasound), apoptosis index [AI, measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)], proliferation index [PI, measured by proliferating cell nuclear antigen (PCNA) expression], alpha SMA, Bax, and bFGF were measured before and after radiation therapy. Histopathology of the prostate, rectum, and bladder tissue was also examined before and after irradiation. 3D-CRT treatment significantly decreased prostate volume, and the PI, PSA, and alpha-SMA, but significantly increased the AI, and had no effect on PAP. There was no evidence of Bax expression before or after irradiation. Irradiation led to no detectable symptoms of diarrhea or changes in stool, but did lead to minor bladder injury, based on light microscopy, scanning electron microscopy, and transmission electron microscopy. In our canine model, 3D-CRT is an effective, noninvasive treatment of BPH that is associated with minimal side effects. Our treatment appeared to reduce prostate size by treatment of the underlying pathological processes. PMID- 21542459 TI - Indole-3-carbinol inhibits prostate cancer cell migration via degradation of beta catenin. AB - We determined whether indole-3-carbinol (I3C) could affect DU145 human prostate carcinoma cell migration to prevent the development and progression of prostate cancer. Although previous studies have shown anticancer properties of I3C in various cancer cell lines, it has not been determined how I3C regulates epidermal growth factor (EGF)-induced migration and related signaling pathways. DU145 cells were treated with I3C (100 microM) in the absence or presence of EGF (10 ng/ml). Our results showed that I3C significantly inhibited DU145 cell migration with and without EGF stimulation. It has been reported that the beta-catenin signaling pathway controls androgen receptor (AR)-mediated prostate cancer progression, which plays a key role in the metastasis of prostate cancer. Western blot analysis demonstrated that I3C led to the phosphorylation of beta-catenin and subsequent degradation of beta-catenin in the absence and presence of EGF. In contrast, I3C did not have any effect on the expression of beta-catenin mRNA. From these results, we suggest that I3C inhibits EGF (dependent or independent) induced DU145 cell migration through beta-catenin degradation. PMID- 21542460 TI - Key organizational commitment antecedents for nurses, paramedical professionals and non-clinical staff. AB - PURPOSE: The purpose of this paper is to develop a causal model that explains the antecedents and mediating factors predicting the organizational commitment of healthcare employees in different work roles. DESIGN/METHODOLOGY/APPROACH: This study tests an integrative causal model that consists of a number of direct and indirect relationships for antecedents of organizational commitment. It is proposed that the relationship between job satisfaction and organizational commitment is best understood by focusing on the three interrelated facets of job satisfaction, i.e. satisfaction with career advancement, satisfaction with supervisor, and satisfaction with co-workers. However, the model also advances that these job satisfaction facets have different mediating effects for other antecedents of organizational commitment. FINDINGS: The Structural Equation Modeling (SEM) path analysis showed that the job satisfaction facets of career advancement and satisfaction with supervisor had a direct impact on organizational commitment. Employee empowerment, job-motivating potential, effective leadership, acceptance by co-workers, role ambiguity and role conflict were also important determinants of organizational commitment. Interestingly, post hoc analyses showed that satisfaction with co-workers only had an indirect impact on organizational commitment. ORIGINALITY/VALUE: While there has been extensive research on organizational commitment and its antecedents in healthcare organizations, most previous studies have been limited either to a single employee group or to a single time frame. This study proposes a practical causal model of antecedents of organizational commitment that tests relationships across time and across different healthcare employee groups. PMID- 21542461 TI - Valuation and handling of dialogue in leadership: a grounded theory study in Swedish hospitals. AB - PURPOSE: Leadership can positively affect the work environment and health. Communication and dialogue are an important part in leadership. Studies of how dialogue is valued and handled in first-line leadership have not so far been found. The aim of this study is to develop a theoretical understanding of how first-line leaders at hospitals in western Sweden value and handle dialogue in the organisation. DESIGN/METHODOLOGY/APPROACH: The study design was explorative and based on grounded theory. Data collection consisted of interviews and observations. A total of 11 first-line leaders at two hospitals in western Sweden were chosen as informants, and for four of them observation was also used. FINDINGS: One core category emerged in the analysis: leaders' communicative actions, which could be strategically or understanding-oriented, and experienced as equal or unequal and performed equitably or inequitably, within a power relationship. Four different types of communicativeactions emerged: collaborative, nurturing, controlling, and confrontational. Leaders had strategies for creating arenas and relationships for dialogue, but dialogue could be constrained by external circumstances or ignorance of the frameworks needed to conduct and accomplish dialogue. PRACTICAL IMPLICATIONS: First-line leaders should be offered guidance in understanding the consequences of consciously choosing and strengthening the communication component in leadership. ORIGINALITY/VALUE: The positive valuation of dialogue was not always manifest in practical action. One significant consequence of not using dialogue was that information with impact on organisational efficiency and finances was communicated upwards in the management system. PMID- 21542462 TI - A new workforce in the making? A case study of strategic human resource management in a whole-system change effort in healthcare. AB - PURPOSE: This paper seeks to describe the exploration of human resource issues in one large-scale program of innovation in healthcare. It is informed by established theories of management in the workplace and a multi-level model of diffusion of innovations. DESIGN/METHODOLOGY/APPROACH: A realist approach was used based on interviews, ethnographic observation and documentary analysis. FINDINGS: Five main approaches ("theories of change") were adopted to develop and support the workforce: recruiting staff with skills in service transformation; redesigning roles and creating new roles; enhancing workforce planning; linking staff development to service needs; creating opportunities for shared learning and knowledge exchange. Each had differing levels of success. PRACTICAL IMPLICATIONS: The paper includes HR implications for the modernisation of a complex service organisation. ORIGINALITY/VALUE: This is the first time a realist evaluation of a complex health modernisation initiative has been undertaken. PMID- 21542463 TI - Redrawing medical professional domains: new doctors, shifting boundaries, and traditional force fields. AB - PURPOSE: This paper aims to investigate the forces that influence the shifting of professional boundaries on the entry of a new medical occupation in Dutch hospitals - non-specialist emergency physicians. DESIGN/METHODOLOGY/APPROACH: Five case studies of Dutch hospitals were conducted and the emergency physicians' implementation process was analyzed by means of force field analysis. FINDINGS: Emergency physicians were conceptualized as being the answer to unequivocal contextual changes. However, their contribution to better performance varies due to problems in the implementation process. Strong socio-political forces between traditional specialties and these new doctors mediate the intended improvement. The emergency physicians aim to establish their own organizational-, patient- and knowledge-domain by redrawing professional boundaries but they are not on a par with the specialists who set these boundaries. Consequently, emergency physicians only gradually redraw the existing boundaries, resulting in limited added value. Their reaction is to obtain power by striving to develop into a recognized specialty; ironically, by becoming an additional layer in the traditional medical hierarchy they might lose their envisaged added value. RESEARCH LIMITATIONS/IMPLICATIONS: This paper is based on the first Dutch hospitals that implemented emergency physicians. The number of cases is therefore limited. Moreover, the study took place at an early stage of emergency physician implementation. PRACTICAL IMPLICATIONS: The extent of successful redrawing depends on the implementation's transition logic, the existing degree of differentiation and boundary permeability and on the ideological power developed by the leaders. ORIGINALITY/VALUE: The introduction of emergency physicians is currently being discussed in many countries worldwide, and some countries consider following the Dutch example of non-specialist doctors. This paper supports health professionals and hospital managers in not falling prey to the same pitfalls as some Dutch hospitals. PMID- 21542464 TI - Offshoring of healthcare services: the case of US-India trade in medical transcription services. AB - PURPOSE: - The issue of offshore outsourcing of healthcare services is a critical but little-examined problem in healthcare research. The purpose of this study is to contribute to filling this void. DESIGN/METHODOLOGY/APPROACH: A library-based study was carried out of the development of the Indian medical transcription offshoring industry. Findings- Cost-saving potential and the degree of outsourceability are higher for medical transcription compared with most services. Offshoring experience, typically in a low-value BPO, helps to enhance productivity and international linkages required for the success of medical transcription. Research limitations/implications - An important area of future research concerns comparing India's factor endowments in medical transcription outsourcing with other services. Further research is also needed to examine how India differs from its regional competitors in terms of factors endowments associated with these services. Another extension would be to investigate the drivers of offshoring of higher value services such as radiological readings. Practical implications - ICT infrastructures needed for outsourcing require much less investment compared with leading capital-intensive industries. The development patterns of the Indian medical and offshoring industries indicate that India may attract higher skilled medical functions in the future. The Indian offshoring industry is shifting its focus from BPO to knowledge process outsourcing (KPO). Developing countries need to shift to greater automation and greater levels of skill training to retain and reinforce their comparative advantages. ORIGINALITY/VALUE: This paper's greatest value stems from the fact that it examines the drivers of a new but rapidly growing healthcare industry. PMID- 21542465 TI - Connecting organisational culture and quality of care in the hospital: is job burnout the missing link? AB - PURPOSE: To date, relatively little evidence has been published as to what represents an effective and efficient way to improve quality of care and safety in hospitals. In addition, the initiatives that do exist are rarely designed or developed with regard to the individual and organisational factors that determine the success or failure of such initiatives. One of the challenges in linking organisational culture to quality of care is to identify the focal point at which a deficient hospital culture and inadequate organisational resources are most evident. The accumulated evidence suggests that such a point is physician burnout. This paper sets out to examine this issue. DESIGN/METHODOLOGY/APPROACH: The paper reviews the existing literature on organisational culture, burnout and quality of care in the healthcare sector. A new conceptual approach as to how organisational culture and quality of care can be more effectively linked through the physician experience of burnout is proposed. FINDINGS: Recommendations are provided with regard to how future research can approach quality of care from a bottom-up organisational change perspective. In addition, the need to widen the debate beyond US and North European experiences is discussed. ORIGINALITY/VALUE: The present paper represents an attempt to link organisational culture, job burnout and quality of care in a more meaningful way. A conceptual model has been provided as a way to frame and evaluate future research. PMID- 21542466 TI - Integrated weed management (IWM): will it reduce herbicide use? AB - The Sustainable Use of Pesticides Directive (2009/128/EC), part of the EU Thematic Strategy for Pesticides, requires Integrated Pest Management (IPM) to be actively promoted. A key objective is to give greater priority to non-chemical methods of plant protection to reduce the impact of pesticides on human health and the environment. Integrated Weed Management (IWM) can be considered part of IPM, and many non-chemical methods are available. For example, a recent review of methods for control of Alopecurus myosuroides (black-grass) in winter wheat found the following mean annual levels of control: ploughing 67%; delayed drilling 37%; fallowing 70%; higher seed rates 30%; competitive cultivars 27%. In comparison with herbicides these efficacy levels are mediocre, and A. myosuroides would be classified as resistant (R) or moderately resistant (MR) to all these methods if the criteria used by the Chemicals Regulation Directorate in the UK for assigning ratings to herbicide efficacy were used. It is, therefore, not surprising that farmers are reluctant to embrace IWM and continue to place greater.reliance on herbicides as a more reliable and cost effective method of weed control. While non-chemical methods will not replace herbicides on most farms, reduced reliance on herbicides will be necessary both for practical (increasing resistance, lack of new herbicides) and political reasons (complying with EU legislation). Farmers will use nonchemical control methods when they have a major weed problem, and have no alternative, but they must be encouraged to adopt IWM at an earlier stage. Research into IWM must be relevant and practical, and not simply conducted as some sort of 'academic' exercise. More effective knowledge transfer is vital, and this is a challenge due to the decline in independent, state funded, advisory services in many European countries. The question arises; is it possible to achieve reductions in pesticide use by simply promoting non-chemical methods of weed control, or will statutory limits on pesticides be needed to achieve this goal? PMID- 21542467 TI - Arabidopsis thaliana, a new tool to investigate Polymyxa betae-host interactions. AB - Little is known about the genome of Polymyxa betae and its interactions with sugar beet, due partly to the obligate nature of the protist and the patents on Beta vulgaris sequences. The identification of an ecotype of Arabidopsis thaliana compatible with the protist would help to improve this knowledge. The infection and development of P. betae in 14 worldwide ecotypes of A. thaliana were studied. The detection of plasmodia and resting spores and the production of zoospores in the roots of A. thaliana were obtained in three bioassays, using automatic immersion systems and individual glass tubes. Detection was done using molecular detection and microscopy. Compatible interactions were established between 13 A. thaliana ecotypes of the 14 that were tested and the monosporosoric Belgian strain of P. betae, A26-41. The ecotype Cvi-0 (N1096), from the Cape Verde Islands, was the most compatible with the protist. This ecotype is also susceptible to Plasmodiophora brassicae, another plasmodiophorid. Polymyxa betae infection in A. thaliana was relatively very low compared with B. vulgaris, but every stage of the life cycle of the protist was present. The spore-forming phase was promoted at the expense of the sporangial phase, probably caused by the stress of this new environment. In addition, the protist revealed a new phenotype. This new model study will allow molecular tools available for A. thaliana to be used in order to gain a better understanding of the P. betae-plant interaction during the spore-forming phase. PMID- 21542468 TI - Pre symptomatic detection of wheat leaf rust in the susceptible cv Skalmeje and the resistant cv Esket by means of UV laser-induced fluorescence. AB - In modern agriculture there is a great demand for a rapid and objective screening method for stress resistance, because so far, the resistance of new cultivars is tested in time- and money consuming field experiments. Based on fluorescence ratios, and lifetime of fluorophores measured by fluorescence spectroscopy, we have postulated that an early discrimination of susceptible and resistant wheat cultivars to the leaf rust pathogen Puccinia triticina can be accomplished. As representative for leaf rust resistant and leaf rust susceptible wheat genotypes the cultivars Esket and Skalmeje, respectively, were chosen. Plants were grown under controlled environment conditions and inoculated with the leaf rust pathogen at the second-leaf-stage by single-droplet application. Fluorescence measurements were carried out from two to four days after inoculation (dai) by using a compact fibre-optic fluorescence spectrometer with nanosecond time resolution. Experimental results indicated that UV laser-induced spectral characteristics as well as determination of fluorescence lifetime are suited to detect leaf rust two dai. For this purpose several ratios and wavelength can be considered. In general, the tested cultivars showed distinct responses to the pathogen development. In this context the ratio F451/F687 measured three dai and mean lifetimes at 500 nm and 530 nm are suited to differentiate the resistant Esket from the susceptible Skalmeje genotypes. PMID- 21542469 TI - Distribution of metamitron-resistant Chenopodium album L. in Belgian sugar beet. AB - Chenopodium album L. (fat-hen) with a Ser264-Gly mutation is resistant to photosystem II-inhibiting herbicides like the triazinone metamitron, a key herbicide in sugar beet. In recent years, this resistant biotype may cause unsatisfactory weed control in Belgian sugar beet. However, the dimension of the problem was yet unknown. Therefore, a survey was conducted in 2008 covering the whole Belgian sugar beet area. In randomly selected fields, C. album plants surviving weed control were counted and sampled. First, the number of surviving plants was used to estimate the prevalence of fields with unsatisfactory control and to classify the surveyed fields. Then, the share of the resistant biotype in each field was determined with cleaved amplified polymorphic sequence-analysis (CAPS-analysis) on sampled leaves. Finally, all results were visualised on the map of Belgium. Twenty percent of the fields had more than 500 surviving plants per hectare and were thus classified as fields with unsatisfactory C. album control. The resistant biotype was present in 95% of these fields and even in 74% of the sampled fields with good weed control. No pattern was found during mapping. These results indicate that the metamitron-resistant biotype has spread over the whole sugar beet area but that it is not (yet) causing severe problems in every field. To get a more accurate estimation of the portion of resistant plants in the field and the effect of herbicide treatment on this biotype, an elaborate survey will be conducted in 2010 on fields that have both untreated and treated plots installed. PMID- 21542470 TI - Weed seed bank response to 12 years of different fertilization systems. AB - Fertilizer amendments can impact weed populations in a variety of ways. This study evaluated the effects of 12 year-long applications of different fertilization systems on size and composition of the weed seed bank in a conventionally managed maize monoculture field. Fertilization systems included all factorial combinations of two dairy cattle slurry rates, three vegetable, fruit and garden waste (VFG) compost rates, and three synthetic N fertilizer rates. Soil samples were taken in each subplot in May 2008 after sowing and prior to herbicide application. Residues recovered from soil samples were tested for weed seedling emergence to characterize soil seed banks. Total weed seed bank density was affected by mineral N fertilization but not by compost or animal slurry application. Weed seed bank composition was related to compost amendment and mineral N fertilization. Annual compost amendments reduced seed bank density of some persistent species (e.g., Chenopodium album and Solanum nigrum) irrespective of mineral N fertilization. Compost is a promising tool for incorporation into integrated weed control strategies aimed at reducing weed seed bank persistence. PMID- 21542471 TI - Chlorophyll fluorescence protocol for quick detection of triazinone resistant Chenopodium album L. AB - Sugar beet growers in Europe are more often confronted with an unsatisfactory control of Chenopodium album L. (fat-hen), possibly due to the presence of a triazinone resistant biotype. So far, two mutations on the psbA-gene, i.e. Ser264 Gly and Ala251-Val, are known to cause resistance in C. album to the photosystem II-inhibiting triazinones metamitron, a key herbicide in sugar beet, and metribuzin. The Ser264-Gly biotype, cross-resistant to many other photosystem II inhibitors like the triazines atrazine and terbuthylazine, is most common. The second resistant C. album biotype, recorded in Sweden, is highly resistant to triazinones but only slightly cross-resistant to terbuthylazine. Since farmers should adapt their weed control strategy when a resistant biotype is present, a quick and cheap detection method is needed. Therefore, through trial and error, a protocol for detection with chlorophyll fluorescence measurements was developed and put to the test. First, C. album leaves were incubated in herbicide solution (i.e. 0 microM, 25 microM metribuzin, 200 microM metamitron or 25 microM terbuthylazine) during three hours under natural light. After 30 minutes of dark adaptation, photosynthesis yield was measured with Pocket PEA (Hansatech Instruments). In Leaves from sensitive C. album, herbicide treatment reduces photosynthesis yield due to inhibition of photosynthesis at photosystem II. This results in a difference of photosynthesis yield between the untreated control and herbicide treatment. Based on the relative photosynthesis yield (as a percentage of untreated), a classification rule was formulated: C. album is classified as sensitive when its relative photosynthesis yield is less than 90%, otherwise it is resistant. While metribuzin, and to a lesser extent, metamitron treatment allowed a quick detection of triazinone resistant C. album, terbuthylazine treatment was able to distinguish the Ser264-Gly from the Ala251-Val biotype. As a final test, 265 plants were classified with the protocol. Simultaneously, a CLeaved Amplified Polymorphic Sequence (CAPS)-analysis was conducted on the same plants to verify the presence of the Ser264-Gly mutation. Only one mismatch was found when results of both detection methods were compared. The test results illustrate that this protocol provides a reliable, quick and cheap alternative for DNA-analysis and bio-assays to detect the triazinone resistant C. album biotypes. PMID- 21542472 TI - Weed control in conventional and transgenic maize with resistance to glyphosate. AB - The researches were conducted in order to observe the behaviour of conventional and glyphosate resistant transgenic maize to different weed control methods. In this paper, the obtained results are presented. The study was conducted in experimental years 2008-2009 in the frame of Didactical Station USAMVB Timisoara. In order to conduct this study, 4 variants cultivated with conventional maize DKC 5143 and 8 variants cultivated with transgenic maize DKC-MON88017 with resistance against Diabrotica virgifera virgifera and to glyphosate. The efficacy of weed control methods was assessed, as well as the herbicide selectivity to cultivated maize hybrid. The weed coverage degree in control plot (V2) was 304 weeds/sqm in the first year and 465 weeds/sqm in the second year. In the variants cultivated with transgenic maize the control was up to 90% much more than control percent achieved in conventional variants. Although, in order to achieve an efficient control (higher than 95%), even to transgenic maize, two glyphosate sequential treatments has to be done. The yield results were positive correlated to the different control methods. However those were affected by climatic conditions recorded in experimental years. PMID- 21542473 TI - Determination of fungal pathogens of common weed species in the vicinity of Tokat, Turkey. AB - This study was carried out to determine the fungal pathogens on Chenopodium album L., Cirsium arvense (L.) Scop., Convolvulus arvensis L., Cynodon dactylon (L.) Pers., Delphinium consolida L., Portulaca oleracea L., Rumex crispus L., Solanum nigrum L., Sorghum halepense (L.) Pers. and Xanthium strumarium L. which were common weed species of agricultural areas. Surveys were conducted in May-June and August-September in 2004-2005 growing seasons. During the surveys density and frequency of the above mentioned weed species were also determined and number of infected plants was counted in each sampling area. Infected weed samples were collected from each sampling point and brought to the laboratory in polyethylene bags and the pathogens were identified at genus or species level. As a result of two year surveys, ten fungal pathogens were determined on eight weed species. The most important fungal pathogens determined on common weed species were as follow; Peronospora farinosa (Fr.) Fr. on C. album, and Septoria convolvuli DC., Erysiphe convolvuli DC., and Puccinia punctiformis (Strauss) Roehrl. on C. arvensis. These fungal diseases were observed mainly on the weeds located at the borders of fields. Infection rates of these pathogens reached up to 21.2% in some of the survey areas. Further studies should be conducted to evaluate the efficacy of these pathogen under in vitro and in vivo conditions. PMID- 21542474 TI - Examination of common ragweed's (Ambrosia artemisiifolia L.) allelopathic effect on some weed species. AB - In the last decades the importance of some weed species increased in Hungary. The common ragweed (Ambrosia artemisiifolia L.) also belongs to this group. The allelopathic effect of watery extract made from different plant parts of common ragweed (air dried leafy shoots, seeds) were studied on the germination and growth of some weed species. The extracts were prepared with tap water, chopped dry plant materials were added to water and 24 hours later the material was filtered. The germination took place in a Binder KBW type thermostat in dark. 25 seeds were put into one Petri-dish, adding 15 ml plant extract to each in four repeats. The timing of germination was checked in every two days and the rate of growth was estimated after a week, by counting the numbers of germinated seeds and measuring the length of the radicle and plumula. The measured data were statistically analysed and the effect of extracts on germinating ratio and seedling length were evaluated. PMID- 21542475 TI - Effect of seed depth on germination and growth of velvetleaf (Abutilon theophrasti Medic.). AB - Importance of several weed species has been considerably increased during the last few decades in Hungary. Velvetleaf (Abutilon theophrasti Medic.) belongs to this spreading weed group as well. This weed species was in the 27th position in the course of the fourth Hungarian weed survey, but at the time of the fifth weed survey in 2007-2008 it stepped forward to the 10th position in the cornfields of Zala County. Requiring a warm climate, global climate warming plays a significant role in its rapid spread. Moreover, its effective reproduction strategy supports its occurrence and continuous spread in almost all field crops. Protection against velvetleaf can only be successful, if we know its biological and ecological characteristics. Comprehensive knowledge of the plant and selection of a proper application of weed control methods together can result velvetleaf free crop fields. The experiment was set up on the 29th of April 2009 at Keszthely where fifty seeds were sown into 50 litres volume plastic pots, in four replications with fifty pieces of seed per each plot. Germination percent of velvetleaf seeds and several growth indexes of seedlings (stem- and root length, leaf area, number of leaves, stem- and root fresh and dry weight) were measured on three different sampling dates. PMID- 21542476 TI - Dominant species of dicot-weeds and weed biodiversity in spring barley in Latvia. AB - The composition of weed species in spring barley and weed biodiversity was evaluated in experiments in different growing seasons and with different previous crops. The aim of the experiments was to evaluate the composition of weed species in spring barley during a four year period in weather conditions of different growing seasons and with different previous crop as well as to assess the biodiversity in the experiments where the different groups of herbicides were applied. Over years and previous crops, the dicotyledonous weed community was dominated by Chenopodium album, followed by Viola arvensis. The herbicides from different groups had significant influences on the biodiversity of weeds. PMID- 21542477 TI - Effect of spray application technology on the biological control of aphids in Brussels sprouts. AB - A field trial was carried out to evaluate different application techniques for crop penetration and biological efficacy of aphid control in Brussels sprouts. Six different application techniques were tested at a pressure of 4.0 bar in a field trial in 3 parallels at the Provincial Vegetable Research Centre in Kruishoutem (PCG): a standard ISO 02 flat fan nozzle (at 200 l/ha), an ISO 04 twin air inclusion nozzle (at 800 l/ha), an ISO 03 drift reducing nozzle, an air injection nozzle (Airjet,) droplegs in combination with an ISO 03 drift reducing nozzle and an ISO 03 air inclusion nozzle (all at 400 l/ha). Best biological control of the aphids and spray distribution was found for the twin air inclusion nozzle, the air inclusion nozzle and the airjet-system. These are all drift reducing techniques because of their coarse droplet size spectrum or the effect of air support which makes the droplets faster. Both effects improve crop penetration. No added value was found for the droplegs for this type of spray treatments. Fine droplets, produced by a standard flat fan, did not give good results on biological control or penetration into the crop. PMID- 21542478 TI - Optimization of the spraying equipment and technology used in ornamental crops. AB - In 2006, a research project concerning the optimization of the spraying equipment and technology used in ornamental crops was started. First, several greenhouse growers were surveyed on the spray equipment and technology they were using for their plant protection. Later on, different parts of their equipment were evaluated. It this way, we could advice the connected growers on how to improve their own techniques and equipment. Additionally, the survey showed that growers predominantly use knapsack sprayers and lances for crop protection purposes. These techniques are often proven to be less effective compared to spray booms, which could explain the high application rates (up to 6650 L ha(-1)) used by most growers. Since spray boom equipment could enhance spray distribution and minimize labour cost, operator exposure; the usability of this technique in ornamental crops was studied by means of laboratory tests, field trials and bio-efficacy experiments. PMID- 21542479 TI - Effect of glyphosate on the microbial activity of two Romanian soils. AB - Glyphosate applied to soils potentially affect microbial activity. A series of field and laboratory experiments assessed the effect of this herbicide on soil microorganisms. The aim of experiments was to evaluate the effect of glyphosate application on the soil microbial community structure, function and their activity. We studied "in vitro", changes in the microbial activity of typical Chernozem and Gleysol soils, with and without applied glyphosate. The herbicide was applied at a rate of 2, respectively 4 mg kg(-1) of soil and microbial activity were measured by fluorescein diacetate (FDA) hydrolysis. We found an increase of 9 to 13% in FDA hydrolyses in the presence of glyphosate in rate of 2 mg kg (-1) compared with the same type of soil which had never received herbicide. The double quantity of glyphosate decrease soil microbial activity; the amount of hydrolyzed fluorescein is lower than the addition of 2 ppm. The greater decrease was observed in the Gleysol type where the fluorescein hydrolyzed is with 4, 85% lower than version control without glyphosate. Chemical characters of soil, influence soil biological activity when herbicide is added. In Chemozem case, rich in humus, whose predominant micro flora is represented by actinomycetes through glyphosate treatment these organisms growths of as major producers of antibiotics actinomycetes determine an inhibitory effect on eubacteria and micromycetes growth, which is highlighted by estimating a relatively small number of them. After 10 days, once with decreasing of glyphosate content in soil, decreases the number of active actinomycetes, therefore we are witnessing to a numerical growth of bacterial population. In Gleysol type the indigenous micro flora is represented by eubacteria, so when the glyphosate is added it was registered a high growth of these organisms fraction. PMID- 21542480 TI - 14C tebuconazole degradation in Colombian soils. AB - Tebuconazole is a fungicide used on onion crops (Allium Fistulosum L) in Colombia. Persistence of pesticides in soils is characterized by the half-life (DT50), which is influenced by their chemical structure, the physical and chemical properties of the soil and the previous soil history. Based on its structural and chemical properties, tebuconazole should be expected to be relatively persistent in soils. Laboratory incubation studies were conducted to evaluate persistence and bond residues of 14C tebuconazole in three soils, two inceptisol (I) and one histosol (H). Textural classifications were: loam (101), loamy sand (102) and loam (H03), respectively. Data obtained followed a first order degradation kinetics (R2 > or = 0.899) with DT50 values between 158 and 198 days. The production of 14CO2 from the 14C-ring-labelled test chemicals was very low and increased slightly during 63 days in all cases. The methanol extractable 14C-residues were higher than aqueous ones and both decreased over incubation time for the three soils. The formation of bound 14C-residues increased with time and final values were 11.3; 5.55 and 7.87% for 101, 102 and H03 respectively. Soil 101 showed the lowest mineralization rate and the highest bound residues formation, which might be explained by the clay fraction content. In contrast, an inverse behavior was found for soils 102 and H03, these results might be explained by the higher soil organic carbon content. PMID- 21542481 TI - Levels of hexachlorocyclohexanes in agricultural environment of Sacco river valley. AB - Aim of this trial was to verify the occurrence and the distribution of hexachlorocyclohexanes (HCHs) in soil, sediment, straw, alfalfa, other animal feed grown in farms with contaminated soil. In the present study two years of monitoring activity in the province of Roma and Frosinone was reported. Experimental trial in two contaminated sites was carried out on uptake and translocation of HCHs in maize and alfalfa. In 19 sites soil, forage and weed has been collected for two years, soil samples consisted in cores of 40 cm to test the presence of HCHs at different deep. The analytical determinations in soil and plant samples were carried out by gas liquid chromatography with electron capture detector and confirmed by mass detector. In the first year (2005- 2006) 68% of soil samples were contaminated (HCHs > LOQ) and 3% of vegetable samples. In the second year (2006- 2007) 42% of soil samples resulted positive and 26% of vegetable matrix. In particular B hexacyclohexane was detected in wheat stem (0.037 mg/kg) with a soil contamination of 0.039 mg/kg and in alfalfa (0.012 mg/kg) with presence in soil of 0.004 mg/kg. Experimental trials on maize evidenced a translocation factor for this isomer stem/soil of 0.006 mg/kg ? and for grain of 0.005 mg/kg. On alfalfa translocation factor root/soil was 0.01 and shot/soil 0.009. A propose to calculate the threshold value of soil contamination to admit crop grown destined to animal feed, would be based on HCHs LOD values weighted with translocation factor. PMID- 21542482 TI - Toxicity of botanical insecticides on golden apple snail (Pomacea canaliculata). AB - The molluscicidal activity of crude extracts from five highly potential plants, Annona squamosa seed, Nerium indicum Leaves, Stemona tuberose root, Cyperus rotundus corm and Derris elliptica root was assessed to Pomacea canaliculata. D. elliptica root and C. rotundus corm extracts showed the highest toxicity against 3-month old snails which have LC50 as 23.68 +/- 2.96 mg/l and 133.20 +/- 7.94 mg/l, respectively. The C. rotundus corm extracts were chosen for detoxification enzyme in vivo assay which shows esterase and glutathione S-transferase activity in stomach, intestinal tracts and digestive glands of survival treated P. canaliculata were inhibited. PMID- 21542483 TI - Acute toxicity of Amanranthus viridus extract on guppies, Poecilia reticulata. AB - Many Thai plant species shows the responsible for controlling insects from the host plants. To avoid potential toxic pollutant contaminating aquatic ecosystems, this present study was investigated for acute toxicity from Amaranthus viridis to Guppy fish (Poecilia reticulata) were selected for the bioassay experiments. The experiments were repeated 5 times and the 1-, 3- and 24-h LC50 was determined for the guppies. The acute toxicity experiments were carried out by static method and behavioral changes in guppies were determined for Amaranthus viridis concentration extract which extracted by Soxhlet's extraction method with ethanol as solvent. Water temperature was regulated at 20 +/- 1 degrees C. Data obtained from the acute toxicity tests were evaluated using the Probit analysis statistical method. The 24-h LC50 value for guppy was estimated as ca. 947 mg L( 1) (r2 = 0.95). However, in this concentration, no mortality was observed at higher concentration for 30 second. PMID- 21542484 TI - Biochemical, hematological and histological parameters induced by cypermetherin toxicity in domestic rabbits. AB - Cypermetherin is widely used in Algeria; this insecticide belongs to the group of pyrethroids classified by the World Health Organization as moderately harmful class II (WHO, 2005). This study was conducted to search the effect of non lethal dose on biochemical parameters, hematological and histological parts of the organs. Male of domestic rabbits Oryctolagus cuniculus (1 kg) received per week and per gavage 1/10 LD50 of Cypermetherin (ARRIVO 25%, active substance of Cypermetherin 250 g/l). blood was collected 72 hours after the treatment. Enzyme activities were assayed in the plasma samples for Glutamate oxalo acetate transaminase (GOT), Glutamate pyruvate transaminase (GPT), Alcaline phosphatase (AlcP), creatinine (Crea) and glucose. Red blood (RBC) cells and white blood cells (WBC) were calculated too. The results indicated a significant increase in transaminases GOT and GPT, and AlcP explain a high energy generating product and dysfunction of the liver. A decline in Crea, Hb, RBC and WBC which is related to the immunity, this is probably due to cell lyses explain the effect of Cypermetherin on erythropoeisis. Histological examination confirmed the biochemical tests by the observation of inflammatory infiltrate and perilobular fibrosis. In conclusion, Cypermetherin with used dose affects biochemical, hematological and histological parameters of the rabbits. PMID- 21542485 TI - Cypermetherin toxic effects on spermatogenesis and male mouse reproductive organs. AB - Cypermetherin has been implicated in the development of a variety of reproductive disorders in humans and infertility in wild life, where it increases the death rate of the offspring and induces aggressiveness (Elbetieha et al., 2001). Studies in workers exposed to handling of agro pesticides indicate that they have defects in their reproduction capabilities characterized by infertility and/or a decrease in the fertilizing potential, fetal death. In this study, mice weighing 30-35 g were used, separated in 3 groups, (1) control (2) vehicle (oil) and (3) experimental (Cypermetherin and oil). The animals were gavaged by 1/5, 1/20 LD50 for 2 and 4 weeks respectively, and with 1/5 LD50 for 12 weeks, then sacrificed. Epididymal spermatozoa were evaluated with respect to quantity, motility and morphology. The histology of testis and epididymis was also studied. Sperm count decreased by around 20% in treated animals compared with control. Teratology observations showed a clear modification of sperm morphology, especially the flagella. Testicular and epididymal morphology was also impaired. It is concluded that Cypermetherin may cause morphological and functional alteration of the male reproductive tract. PMID- 21542486 TI - Investigation on possible ecotoxicological risk of carbofuran insecticides. AB - Carbofuran-containing insecticides are widely used agents in plant protection. Their use may pose considerable environmental risk for both the protected and non protected predator and plantivorous birds. For defence of wild birds a model experiment was carried out on broiler chickens. In the study, eight animals were treated orally by gastric tube with a carbofuran-containing insecticide at a single dose of 2.5 mg/kg b.w. One animal served as untreated control specimen. Forage and drinking water were provided ad libitum. After the treatment, the possible clinical signs were observed carefully, blood samples were obtained from each bird and after exsanguinations liver, breast and leg muscle samples and stomach content were taken. The carbofuran concentration in blood, tissues and stomach content was determined by gas chromatographic method. Thirty minutes after poisoning, the average carbofuran concentration in breast muscle of chickens exceeded the maximum level of 0.1 mg/kg permitted in edible tissues, whereas ninety minutes after poisoning the concentration of one sample was still above the limit value. In the liver, leg-muscle and blood samples, the measured carbofuran concentration was lower than the permitted maximum value, except in the blood of two animals. The carbofuran concentration of the stomach content markedly exceeded the limit value. The sublethal concentration of the pesticides can reduce the capable of living of wild animals. Due to the sub toxic dose the poisoned birds can survive; however, the residue of insecticides can lead to secondary toxicosis of other animals. PMID- 21542487 TI - Study of the toxic effects of an insecticide and copper sulphate on chicken embryos. AB - The toxic effects of the BI 58 EC insecticide (38% dimethoate) applied alone or in combination with copper sulphate were studied on chicken embryo in the early phase of development. The test materials were injected in 0.1-0.1 ml volume into the air chamber of eggs on the first day of incubation. Subsequently, on days 2 and 3 of incubation permanent preparations were made from the embryo in order to study the early developmental stage. Embryos fixed on slides and stained with osmium tetroxide solution were studied under light microscope. According to the result of the statistical evaluation, to sum up, we can say that the simultaneous administration of the test materials did not result in a significant increase in the embryo mortality, but after the combined administration the rate of embryonic mortality markedly increased. As a result of combined administrations the developmental anomalies included the apperance of a blood ring, poor development or absence of somites, the retarted development of the vascular system, the head and the body, irregular differentiation of the brain vesicles. Summarising the findings, it can be established that the insecticide treatment combined with heavy metal resulted in enhanced embryotoxicity in the case of both combinations, which was primarily manifested in an increased embryonic mortality rate. PMID- 21542488 TI - Preliminary note on potential use of forage crops for soil phytoremediation of dieldrin. AB - The aim of this trial was to evaluate the feasibility of using tall fescue (Festuca arundinacea) and alfalfa (Medicago sativa) for phytoremediation of dieldrin. Experimental trial was carried out in greenhouse with temperature and light control. Each tested crop were seeded in individual pots (10 plants/pot) filled with contaminated soil (47 microg/kg dieldrin) and uncontaminated soil collected in sites located in the province of Latina (Italy). Samples of soil, root, and aerial part of plants were analysed at 3 and 6 months after seeding. The analytical determinations in soil and plant samples were carried out by GLC ECD and confirmed by GLC-MS. After 6 months in the greenhouse, recoveries of dieldrin from soil planted with tall fescue and alfalfa were significantly lower than recoveries in unplanted control soil. Dieldrin residue values in root did not differ between the two different sampling times for each forage crop tested, but they were always higher in fescue than in alfalfa. Residue levels in aerial part were low (< 10 microg/kg) in the two forage crops. Preliminary results seem to confirm the ability of tested plants to enhance dissipation of dieldrin in soil at low level of contamination. PMID- 21542489 TI - Let the RB set nurses' pay. PMID- 21542490 TI - Nurses' knowledge of basic care will be assessed by online tests. PMID- 21542491 TI - Regulator to pilot safer system of checking nurses' credentials. PMID- 21542492 TI - Why the NHS should cut drug waste before cutting jobs. PMID- 21542493 TI - Unfair wage deal could fuel tension between nursing staff and HCAs. PMID- 21542494 TI - The heart and soul of nursing. Interview by Adele Waters. AB - Nursing is concerned with the spiritual as well as the physical, argues Stephen Wright. Nurses who are valued in their work are best placed to provide 'soul care'. PMID- 21542495 TI - Stroke of genius. AB - Nurses at St. George's Hospital explain how they deliver top quality patient care after stroke. PMID- 21542496 TI - Back support. AB - An updated guide to manual handling has been produced by the charity BackCare to reduce the problems nurses experience. PMID- 21542497 TI - Cutting edge scheme. AB - In a bid to reduce knife crime in Merseyside, nurse Rob Jackson does not pull his punches when talking to young offenders and schoolchildren. PMID- 21542498 TI - Safety: principle of nursing practice C. AB - This is the fourth article in a nine-part series describing the Principles of Nursing Practice developed by the Royal College of Nursing (RCN) in collaboration with patient and service organisations, the Department of Health, the Nursing and Midwifery Council, nurses and other healthcare professionals. This article discusses Principle C, the provision of safe and effective care. PMID- 21542499 TI - Practice development in community nursing: opportunities and challenges. AB - Practice development has evolved as an activity in health care that is committed to supporting evidence-based practice, person-centered care and quality care. This article seeks to place the emerging evidence for the need for new approaches to practice development in the context of primary care and current health policy. The literature related to community practice development is reviewed and potential opportunities and challenges are discussed. An overview of some work from a practice development unit based in a primary care trust setting is highlighted. PMID- 21542500 TI - An overview of the menopause: assessment and management. AB - This article provides an overview of the menopause, including symptom management with medical and non-medical treatments. The article also examines the particular needs of women undergoing early menopause. It discusses the nurse's role in promoting health and providing appropriate and evidence-based advice to enable women to make informed decisions. PMID- 21542501 TI - Pulmonary embolism. PMID- 21542502 TI - Better safe than sorry. PMID- 21542503 TI - Bright new future. PMID- 21542504 TI - High-tech progression. PMID- 21542505 TI - GAO looks at bundling outside ESRD. PMID- 21542506 TI - State of the states: Medicaid raided to close budget gaps. PMID- 21542507 TI - States may avoid health-law mandates by matching coverage. PMID- 21542508 TI - The new CKD nutrition practice guidelines. PMID- 21542509 TI - New UNOS center to study and model deceased donor potential. PMID- 21542510 TI - Streamlining the future: exploring data submission solutions for the small provider. PMID- 21542511 TI - What can we expect down the road? PMID- 21542512 TI - A glimmer of hope for rural dialysis units. PMID- 21542513 TI - How will small providers fare under the bundle? PMID- 21542514 TI - Fluid and electrolyte balance in tennis players. PMID- 21542515 TI - Tennis and transplantation: a personal journey. PMID- 21542516 TI - HCAHPS: how the OR's scores affect your whole organization. PMID- 21542517 TI - Building resilience in the face of stress. PMID- 21542518 TI - How clinics help the preop process. PMID- 21542519 TI - Turnover? Focus on everything else. PMID- 21542520 TI - CMS updates anesthesia guidelines. PMID- 21542521 TI - Communication reduces cancellations. PMID- 21542522 TI - A few scope details still need attention. PMID- 21542523 TI - The 2011 Retirement Confidence survey: confidence drops to record lows, reflecting "the new normal". PMID- 21542524 TI - Association of gestational weight gain with cesarean delivery rate after labor induction. AB - OBJECTIVE: To evaluate the association of gestational weight gain with the cesarean delivery (CD) rate in term women undergoing induction of labor (IOL). STUDY DESIGN: This is a retrospective cohort study of 2,495 consecutive term women from May 2005 to June 2008 admitted for IOL between 37 and 42 completed weeks of gestation. Labor induction ending in cesarean delivery was defined as a binary outcome. Weight gain during pregnancy was calculated by subtracting prepregnancy weight from weight recorded at delivery. Multiple gestation, malpresentation, stillbirth, planned CD and women with prior CD were excluded. Maternal and obstetric characteristics were examined as predictors of CD using multivariable logistic regression analyses. RESULTS: The risk of CD increased by 13% (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.05-1.23) for each 5 kg increase in gestational weight gain. Other factors associated with an increased risk of CD included maternal age (OR per year 1.05, 95% CI 1.03-1.06), neonatal birth weight (OR 1.06 per 100 g, 95% CI 1.03-1.08), nulliparity (OR 9.13, 95% CI 7.00-11.90), Bishop score at admission < or = 5 (OR 2.3, 95% CI 1.90-2.90), male infant (OR 1.37, 95% CI 1.10-1.70) and unit increase in prepregnancy body mass index (OR 1.08, 95% CI 1.06-1.10). CONCLUSION: The CD rate following labor induction increases significantly with increasing gestational weight gain even after controlling for possible confounding variables. PMID- 21542525 TI - Peritoneal adhesion prevention at cesarean section: an analysis of the effectiveness of an absorbable adhesion barrier. AB - OBJECTIVE: To evaluate the effectiveness of an absorbable adhesion barrier utilized at cesarean delivery. STUDY DESIGN: We performed a retrospective, two arm cohort, chart review of primary and subsequent first repeat cesarean sections from January 1, 2006-December 31, 2009. Exclusion criteria were incomplete operative report, history of prior abdominal-pelvic surgery, pelvic inflammatory disease, chorioamnionitis, emergency cesarean delivery or use of corticosteroids within 2 weeks. Adhesion incidence/severity as well as skin incision to newborn delivery times were analyzed. Effects of peritoneal closure and suture types were examined. RESULTS: Of 262 primary cesareans performed, 43% (N= 112) had repeat cesarean section. With barrier, 74% had no adhesions at repeat surgery, versus 22% in the no barrier group (p = 0.011). Eleven percent had grade 2 adhesions with barrier, while 64% had grade 2-3 in the no barrier group (p = 0.012). The barrier group had no grade 3 adhesions. Those with parietal peritoneal closure had less incidence (p = 0.02) and mean adhesion severity (p = 0.03); no significant difference was found per suture type. No statistical difference in time from skin incision to newborn delivery was noted between primary and barrier group (p = 0.006); those without barrier had a statistically longer delivery interval (p = 0.35). CONCLUSION: Use of an absorbable adhesion baooorrier reduces the incidence and severity of adhesions at cesarean. PMID- 21542526 TI - Body mass index of patients with endometrial hyperplasia: comparison to patients with proliferative endometrium and abnormal bleeding. AB - OBJECTIVE: Endometrial hyperplasia is a known risk factor for the development of endometrial cancer, particularly atypical hyperplasia, with a subsequent risk of up to 30%. Of the known risk factors for endometrial hyperplasia, obesity is the most preventable, but there is a paucity of data addressing the association. We tested the hypothesis that patients with endometrial hyperplasia have a higher body mass index (BMI) than patients with abnormal bleeding who are found to have proliferative endometrium. STUDY DESIGN: This was an Institutional Review Board approved retrospective study using University Hospital Department of Pathology records. All patients who had endometrial sampling performed between January 1, 2001, and July 30, 2008, were included. The experimental group consisted of patients with endometrial hyperplasia including simple, complex and atypical hyperplasia. The control group consisted of patients who underwent endometrial sampling for abnormal bleeding during the same time period and were diagnosed with proliferative endometrium. BMI was calculated based on documented height and weight within 30 days of endometrial sampling. RESULTS: Forty-two patients with hyperplasia and 103 patients with proliferative endometrium met inclusion criteria, including documented height and weight and nonexposure to hormones. The median BMI in the hyperplasia group was 38 kg/m2 (95% CI 34.8-42.4) and 30 kg/m2 (95% CI 29.9-33.3) in the proliferative group (p < 0.0001). CONCLUSION: These data suggest that higher BMI is associated with endometrial hyperplasia as compared to women with lower BMIs and abnormal bleeding. PMID- 21542527 TI - Are age cutoffs still used to identify candidates for invasive testing for chromosomal abnormalities? AB - OBJECTIVE: Our objective was to determine whether women > or = age 35 are more likely to undergo invasive testing after risk adjustment as compared with younger women at similar adjusted risk. STUDY DESIGN: Results of first-trimester combined aneuploidy risk assessment of singleton pregnancies from 2007-2008 were reviewed. For each level of adjusted risk, the rate of invasive testing (CVS or amniocentesis) was compared for those < age 35 and those > or = age 35. Spearman correlation, Fisher's exact test, and chi2 for trend were used for statistical comparison. RESULTS: For all categories except adjusted risk of 1 in < or = 250, women > or = age 35 were significantly more likely to undergo invasive testing as compared with younger women of similar risk. In women > or = age 35 with low adjusted risk, we observed a trend towards lower rates of invasive testing over time. CONCLUSION: The higher rate of invasive testing in those > or = 35 indicates that women are still being categorized based on age, though our data suggest this may be decreasing. PMID- 21542528 TI - Pelvic floor muscle examination in female chronic pelvic pain. AB - OBJECTIVE: To determine if women with self-reported chronic pelvic pain (CPP) were more likely to have positive findings on two vaginal pelvic floor muscle (PFM) tests compared to women without CPP when the examiner was blinded to pain status. STUDY DESIGN: This was a prospective, cross-sectional study. Blinded examiners performed two vaginal pelvic floor tests (tenderness and strength) on 48 participants: 19 with self-reported CPP and 29 who were pain-free. Relative frequency of positive findings between groups and the total number of positive physical examination findings were calculated. RESULTS: Women with self-reported CPP were more likely to have PFM tenderness (63.2% with physician [M.D.] examiners [board certified in physical medicine and rehabilitation] and 73.7% with physical therapist [P.T.] examiners) as compared to pain-free participants (Fisher's exact test [FET]), 48 p < 0.001 with M.D., p < 0.001 with P.T.). PFM weakness was not more likely in women with CPP (31.6% with M.D., 42.1% with P.T.) as compared with pain-free participants (48.3% with M.D., 17.2% with P.T.) (FET, 48 p = 0.37 with M.D., p = 0.096 with P.T.). CONCLUSION: PFM tenderness is found more frequently in women with self-reported CPP than in pain-free women. PFM strength did not differentiate CPP from pain-free participants. Improved standardization of the PFM examination across disciplines may be helpful in distinguishing subgroups and treating women with CPP. PMID- 21542529 TI - Patient beliefs about pain diagnosis in chronic pelvic pain: relation to pain experience, mood and disability. AB - OBJECTIVE: To examine the contribution of pain beliefs (fear regarding pain diagnosis) in understanding pain experience, mood, affective distress, marital interactions surrounding pain, and functional disability among women with chronic pelvic pain (CPP). STUDY DESIGN: One hundred forty-nine consecutive females with CPP presenting to a university hospital Chronic Pain Clinic completed self-report inventories assessing demographic status, pain-related morbidity, depressive symptoms and global affective distress. Pain beliefs were assessed by subject response to the question "Do you think your pain is due to something more serious or different from what doctors have told you?" and subjects were categorized into "Yes More Serious" (n = 77) and "Not More Serious" (n = 72) groups. RESULTS: Subjects who believed they had "something more serious" as a cause for their pain reported more severe pain intensity (p < 0.05) and pain experience (p < 0.05), greater suffering due to pain (p = 0.01), a less attentive spouse/family member when in pain (p < 0.05), more severe pain disability (p < 0.05), and greater affective distress (p < 0.001). CONCLUSION: These findings provide further evidence for the psychological distress and functional disability that may result when CPP patients possess concerns,fears and possible misattributions regarding the cause of their pelvic pain. PMID- 21542530 TI - Validity of retrospectively reported behaviors during the periconception window. AB - OBJECTIVE: To assess the validity of retrospectively reported maternal behaviors while attempting pregnancy. STUDY DESIGN: Participants in a prospective pregnancy cohort study with periconception enrollment were queried about use of cigarettes, alcohol, vitamins and caffeine and the consumption of sport fish while attempting pregnancy. Prospective longitudinal data reported in daily diaries (gold standard) were compared with data obtained a decade later using a self administered questionnaire. Agreement was assessed by percent agreement and Kappa coefficients. RESULTS: Among the 82 participating women, percent agreement ranged from 54-74% for the 5 behaviors. Validity was highest for smoking (Kappa = 0.43, 95% confidence interval [CI]: 0.22, 0.65) followed by fish consumption (Kappa = 0.32, 95% CI: 0.09, 0.55), caffeine (Kappa = 0.21, 95% CI: 0.09, 0.51) and alcohol (Kappa = 0.20, 95% CI: 0.08, 0.33). There were no systematic differences in agreement by time to pregnancy or pregnancy outcome. Associations between smoking and alcohol consumption and pregnancy outcomes were highly sensitive to the levels of misclassification observed in this study. CONCLUSION: Validity was poor to moderate for the 5 behaviors, though higher for more regular behaviors such as smoking and caffeine consumption. The potential for misreporting of periconception behaviors can affect inferences, and thus efforts to capture information prospectively should be promoted. PMID- 21542531 TI - Clinical antibiotic response of mycoplasma and ureaplasma in patients with symptomatic recurrent vulvovaginal colonization. AB - OBJECTIVE: To assess the prevalence of mycoplasmas in symptomatic patients diagnosed with recurrent vulvovaginitis and to assess the response to doxycycline and ciprofloxacin. STUDY DESIGN: We conducted a retrospective medical records review of patients who consulted our private referral center for vulvovaginal disease between January 2004 and December 2008. The study included all the patients with positive culture for mycoplasma, ureaplasma or both and who received oral antibiotic therapy. The initial antibiotic therapy was with doxycycline, and persistent positivity was treated with ciprofloxacin. The center's Institutional Review Board approved the study. RESULTS: The condition was assessed in 225 patients; 47 (24.4%) had a positive culture as follows: ureaplasma, 34 (72.3%), mycoplasma, 3 (6.4%) and both cultures positive was found in 10 (21.3%) of the patients. The initial clinical and bacteriologic response to doxycycline was observed in 25 (73.5%) patients, while 9 (26.5%) remained persistent positive (p = 0.03). Of the nonresponders 7 (77.8%) became bacteriologic negative with ciprofloxacin, and 2 (22.2%) remained positive (p = 0.23). The cost of each antibiotic was comparable: doxycycline at $12.33 per course and ciprofloxacin at $13.02 per course. CONCLUSION: The prevalence of mycoplasma was 1.3%, ureaplasma 15.1% and both cultures positive 4.4%. The most effective response in our patients was with doxycycline. PMID- 21542532 TI - Impaired delivery outcomes in pregnancies following myomectomy compared to myoma complicated pregnancies. AB - OBJECTIVE: To compare obstetric and delivery outcomes between myoma-complicated pregnancies and pregnancies that follow myomectomy. STUDY DESIGN: Among the 7,589 deliveries performed in the Department of Obstetrics and Gynecology of the Osaka University Hospital, Osaka, Japan, from 1994 to 2007, women with a past history of myomectomy and those with myoma during their pregnancy were enrolled in this study. Their clinical records were reviewed retrospectively. RESULTS: The frequency of myomas detected during pregnancy significantly increased by 1.8-fold during the first 7-year period as compared with the latter 7-year period of the study (p < 0.001). The obstetric and delivery outcomes, including the rate of cesarean section, the rate of preterm delivery and the amount of blood loss at delivery, were better in pregnancies complicated with current myoma than those in pregnancies which had undergone previous myomectomy (p < 0.001, p = 0.002 and p = 0.005, respectively), with the exception of an increased need for analgesic medication. CONCLUSION: Myomectomy of large asymptomatic myomas does not improve future obstetric and delivery outcomes, indicating that most asymptomatic myomas should be managed conservatively in women still considering childbearing. PMID- 21542533 TI - Live delivery and implantation rates of donor oocyte recipients in their late forties are similar to younger recipients. AB - OBJECTIVE: To determine if there is a certain age when the uterus is somewhat less receptive to successful pregnancy despite the transfer of embryos from donated oocytes. STUDY DESIGN: We conducted a retrospective evaluation of donor oocyte recipient cycles according to specific ages. The recipients used an oral/vaginal graduated estradiol regimen followed by intramuscular and vaginal progesterone. Only recipients sharing oocytes with either the donor or another recipient were included. RESULTS: Evaluating the pregnancy rate by each year of age from 40-49 following transfer of embryos derived from donor oocytes showed no trend for lower pregnancy rates up to age 49. In fact the highest live delivery pregnancy rates (though not significant) were found at ages 47 (64.3%) and 49 (63.6%). The live delivered pregnancy rates for recipients < or = 39 was 52.5% vs. 55.6% for women > or = age 46. The live delivered pregnancy rate was 34.6% for women > or = age 50. The pregnancy and implantation rates were similar whether the source was infertile women sharing half their oocytes or compensated donors. CONCLUSION: The uterus does not seem to have a diminished capacity for implantation up to the age of 49, but it may be slightly less receptive after age 50. PMID- 21542534 TI - Transverse myelitis with urinary retention and clean, intermittent catheterization treated with neuromodulation. AB - OBJECTIVE: Transverse myelitis is a chronic, debilitating neurologic disease with numerous urological manifestations, including urinary detrusor overactivity, detrusor sphincter dyssynergia and urinary retention. We review our results with sacral neuromodulation for urinary retention in female patients with transverse myelitis. STUDY DESIGN: A retrospective, observational study was conducted among female patients with transverse myelitis and urinary retention hospitalized between January 2002 and January 2009. Five of seven consecutive women underwent Stage 1 and 2 sacral neuromodulation under general anesthesia. RESULTS: Four ambulatory patients (57%) were successfully implanted, while three nonambulatory patients did not achieve implantation, with a mean follow-up of 3.87 +/- 2.11 years and mean postoperative postvoid residual of 72.5 +/- 45.6 mL (p < 0.001). Postoperative uroflowmetry revealed a mean maximum uroflow of 16.7 +/- 5.9 mL/sec (preoperative max flow was 0.0 mL/sec) (p < 0.001). Two implanted patients required revisional surgeries for lead migration and increased impedance. CONCLUSION: Ambulatory female patients with transverse myelitis and urinary retention may be successfully treated with sacral neuromodulation. Insignificant improvements in postvoid residual urine/maximum uroflow were attained with nonambulatory and assisted ambulatory patients. PMID- 21542535 TI - Mindfulness meditation for women with chronic pelvic pain: a pilot study. AB - OBJECTIVE: Chronic pelvic pain (CPP) is a common condition that can be difficult to treat. Mindfulness meditation improves outcomes in patients with cancer pain, low back pain and migraine headaches. This study evaluates feasibility and efficacy of mindfulness for patients with CPP. STUDY DESIGN: Women with CPP were enrolled in an 8-week mindfulness program. Pre-assessments and post-assessments included daily pain scores, the Short Form-36 Health Status Inventory, Kentucky Inventory of Mindfulness Score and the Inventory of Depressive Symptomatology. RESULTS: Twelve out of 22 enrolled subjects completed the program and had significant improvement in daily maximum pain scores (p = 0.02), physical function (p = 0.01), mental health (p = 0.01) and social function (p = 0.02). The mindfulness scores improved significantly in all measures (p < 0.01). CONCLUSION: Data from this pilot study show the feasibility of mindfulness meditation in women with CPP. Initial pilot data suggest that quality of life and mindfulness outcomes may improve with mindfulness meditation and justify further investigation with a randomized, controlled trial. PMID- 21542536 TI - Immune thrombocytopenic purpura in pregnancy: a reappraisal of obstetric management and outcome. AB - OBJECTIVE: To evaluate the complications of pregnancy and perinatal outcome in women with idiopathic thrombocytopenic purpura (ITP). STUDY DESIGN: A retrospective analysis of 38 singleton pregnancies, their course, obstetric management and perinatal outcome of 32 patients with known ITP was undertaken. RESULTS: No major antenatal complications were noted among the patients. There were no maternal deaths, and only 1 stillbirth occurred in the series. Fourteen infants were delivered by cesarean section and 24 by vaginal delivery. Neonatal cord blood platelet count was performed in each of the live-born infants and revealed thrombocytopenia in 16 infants, but in only 6 (16.2%) of them was the cord blood platelet count < 50 x 10(9)/L. There was no neonatal death in the study, although 6 infants required supportive treatment with corticosteroids and intravenous immunoglobulin G. No maternal features could be used to predict the neonatal platelet count at birth. These results are comparable with other studies in the recent literature. CONCLUSION: Due to the low incidence of poor neonatal outcome in mothers with ITP, obstetric intervention based solely on their platelet count is not justified. Every patient with ITP should be managed individually, and the routine use of cesarean section should be abandoned. PMID- 21542537 TI - Thrombotic thrombocytopenic purpura with complete molar pregnancy: a case report. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is extremely rare. This disease and its prompt diagnosis are important because TTP in pregnancy carries a 90% mortality rate. CASE: A 21-year-old woman underwent suction dilation and curettage for molar pregnancy. Postoperatively the patient developed severe hypertension, microangiopathic anemia, thrombocytopenia and chest pain associated with ischemic cardiac changes. Despite blood and plasma transfusions and steroid therapy, the patient continued to have worsening hemolysis and thrombocytopenia. TTP was diagnosed, and plasmapheresis led to a rapid recovery. CONCLUSION: TTP can occur with molar pregnancy. Making this diagnosis in a timely manner is crucial to ensure that potentially life-saving plasmapheresis is initiated in a timely manner. To our knowledge, this is the first reported case of thrombotic thrombocytopenic purpura with molar pregnancy. PMID- 21542538 TI - Bladder calculus presenting as recurrent urinary tract infections: a late complication of cervical cerclage placement: a case report. AB - BACKGROUND: A cervical cerclage is often placed for women with cervical shortening or insufficiency. There are early and late complications of cervical cerclage placement, but they rarely involve the lower urinary tract. We present a case of a lower urinary tract complication from this procedure presenting as recurrent urinary tract infections. CASE: A 43-year-old woman with a history of cerclage placement during her second pregnancy (10 years prior) presented with recurrent urinary tract infections and hematuria. Radiologic imaging and cystoscopy revealed a 2-cm bladder stone attached to suture that was subsequently removed during cystoscopy. CONCLUSION: Retained suture from a cervical cerclage can act as a nidus for bladder stone formation. PMID- 21542539 TI - Malignant female adnexal tumor of probable Wolffian origin: a case report. AB - BACKGROUND: Female adnexal tumor of probable Wolffian origin (FATWO) is a rare tumor arising in locations with Wolffian remnants, such as the broad ligament. It is thought to be a benign lesion, although this is not always the case, with scattered case reports of more aggressive behavior, sometimes years later. CASE: A rare case of disseminated malignant FATWO is presented and the literature reviewed. CONCLUSION: FATWO has the potential for malignant behavior. Familiarity with this lesion will enhance recognition. Patients need long-term follow-up. PMID- 21542540 TI - Severe shoulder dystocia with a small-for-gestationaI-age infant: a case report. AB - BACKGROUND: Severe shoulder dystocia is disproportionately associated with large for-gestational-age infants. CASE: A nulliparous patient at 38 weeks' gestation had an uncomplicated antenatal course. Clinical pelvimetry revealed an acute angle pubic arch but otherwise normal diameters, conjugate and sacral concavity. Pre-pregnancy BMI was 20.8 and she had had a 14-pound (6.4 kg) weight gain. She presented in labor and, with oxytocin augmentation, progressed to full dilation over 6 hours, followed by an 18-minute second stage. Severe shoulder dystocia was encountered, necessitating multiple maneuvers, and was resolved after 2 minutes with delivery of the posterior arm. The healthy infant weighed 2,289 g (< 5th percentile) and exhibited only transient shoulder weakness, which resolved completely within 1 hour of life. With informed consent, CT pelvimetry was performed within 24 hours postpartum for investigative purposes, revealing small pelvic inlet and at-threshold interischial diameter. CONCLUSION: Geometric analysis reveals that borderline adequate pelvimetry likely played a significant role in severe shoulder dystocia etiology, even with a small-for-gestational-age infant. We alert obstetric providers to the possibility of severe shoulder dystocia in patients with borderline adequate pelves on clinical examination, even when estimated fetal weight makes cephalopelvic disproportion unlikely. PMID- 21542541 TI - Deliberate posterior low transverse incision at cesarean section of a gravid uterus in 180 degrees of torsion: a case report. AB - BACKGROUND: Torsion of the term gravid uterus is a rare, potentially serious, unexpected obstetric pathology and is almost always diagnosed at cesarean section. We report a case of deliberate posterior low transverse segment hysterotomy in irreducible uterine torsion at 41 weeks' gestation, CASE: A 29 year-old nullipara with a 15-cm uterine fibroid was admitted at 41 weeks' gestation with regular uterine contractions. Cesarean delivery was carried out for obstructed labor. Intraoperatively, 1800 levotorsion of the uterus was diagnosed. Following unsuccessful attempts at detorsioning the uterus, a posterior low transverse hysterotomy was performed for delivery. CONCLUSION: Delivery by a posterior low transverse hysterotomy may be feasible in uterine torsion after unsuccessful attempts at detorsioning the uterus during cesarean section at term. ( PMID- 21542562 TI - Novel lipophilic acetohydroxamic acid derivatives based on conformationally constrained spiro carbocyclic 2,6-diketopiperazine scaffolds with potent trypanocidal activity. AB - We describe novel acetohydroxamic acid derivatives with potent activity against cultured bloodstream-form Trypanosoma brucei and selectivity indices of >1000. These analogues were derived from conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds by attaching acetohydroxamic acid moieties to the imidic nitrogen. Optimal activity was achieved by placing benzyl groups adjacent to the basic nitrogen of the 2,6-DKP core. S-Enantiomer 7d was the most active derivative against T. brucei (IC(50) = 6.8 nM) and T. cruzi (IC(50) = 0.21 MUM). PMID- 21542563 TI - Baeyer-Villiger monooxygenases: more than just green chemistry. PMID- 21542564 TI - All-optical control of a single plasmonic nanoantenna-ITO hybrid. AB - We demonstrate experimentally picosecond all-optical control of a single plasmonic nanoantenna embedded in indium tin oxide (ITO). We identify a picosecond response of the antenna-ITO hybrid system, which is distinctly different from transient bleaching observed for gold antennas on a nonconducting SiO(2) substrate. Our experimental results can be explained by the large free carrier nonlinearity of ITO, which is enhanced by plasmon-induced hot-electron injection from the gold nanoantenna into the conductive oxide. The combination of tunable antenna-ITO hybrids with nanoscale plasmonic energy transfer mechanisms, as demonstrated here, opens a path for new ultrafast devices to produce nanoplasmonic switching and control. PMID- 21542565 TI - Structure of mixed phosphatidylethanolamine and cholesterol monolayers in a supported hybrid bilayer membrane studied by sum frequency generation vibrational spectroscopy. AB - The structure of hybrid bilayer membranes (HBMs) containing either a pure cholesterol or mixed cholesterol/dipalmitoylphosphatidylethanolamine (DPPE) proximal layer adsorbed onto an octadecanethiol (ODT) self-assembled monolayer (SAM) on a gold substrate have been investigated by sum frequency generation (SFG) spectroscopy. The HBMs were formed by the adsorption of either a pure cholesterol or mixed DPPE/cholesterol monolayer from the air/water interface of a Langmuir-Blodgett trough at surface pressures of 1, 20, or 40 mN.m(-1). SFG spectra were also recorded of HBMs where cholesterol was replaced by cholesterol d(7), in which the terminal isopropyl group of the alkyl chain of cholesterol was isotopically labeled. In order to isolate the contribution to the SFG spectra from the cholesterol in the mixed cholesterol/phospholipid films, DPPE-d was used, in which the alkyl chains of the phospholipid were deuterated. The infrared spectra of solvent-cast cholesterol and cholesterol-d(7) films were recorded to aid with assignment of the SFG spectra of the HBMs. Features corresponding to methyl, methylene, and methine stretches of cholesterol were identified in the SFG spectra. Information on the polar orientation of SFG-active groups was obtained from the phases of the spectral features. The structure of the HBMs showed little dependence on the surface pressure at which they were formed. SFG spectra of HBMs with a mixed cholesterol/DPPE proximal layer were very similar to the spectra of HBMs with a pure cholesterol proximal layer, although the features in the spectra were more intense than anticipated for a film with half the number of cholesterol molecules, indicating that DPPE did have some effect on the orientation of cholesterol molecules in the film. PMID- 21542566 TI - Effect of surfactants on shear-induced gelation and gel morphology of soft strawberry-like particles. AB - The role of surfactant type in the aggregation and gelation of strawberry-like particles induced by intense shear without any electrolyte addition is investigated. The particles are composed of a rubbery core, partially covered by a plastic shell, and well stabilized by fixed (sulfate) charges in the end group of the polymer chains originating from the initiator. In the absence of any surfactant, after the system passes through a microchannel at a Peclet number equal to 220 and a particle volume fraction equal to 0.15, not only shear-induced gelation but also partial coalescence among the particles occurs. The same shear induced aggregation/gelation process has been carried out in the presence of an ionic (sulfonate) surfactant or a nonionic (Tween 20) steric surfactant. It is found that for both surfactants shear-induced gelation does occur at low surfactant surface density but the conversion of the primary particles to the clusters constituting the gel decreases as the surfactant surface density increases. When the surfactant surface density increases above certain critical values, shear-induced gelation and eventually even aggregation do not occur any longer. For the sulfonate surfactant, this was explained in the literature by the non-DLVO, short-range repulsive hydration forces generated by the adsorbed surfactant layer. In this work, it is shown that the steric repulsion generated by the adsorbed Tween 20 layer can also protect particles from aggregation under intense shear. Moreover, the nonionic steric surfactant can also protect the strawberry-like particles from coalescence. This implies a decrease in the fractal dimension of the clusters constituting the gel from 2.76 to 2.45, which cannot be achieved using the ionic sulfonate surfactant. PMID- 21542567 TI - Simultaneous immobilization of lead and atrazine in contaminated soils using dairy-manure biochar. AB - Biochar produced from waste biomass is increasingly being recognized as a green, cost-effective amendment for environmental remediation. This work was to determine the ability of biochar to immobilize heavy metal Pb and organic pesticide atrazine in contaminated soils. Biochar prepared from dairy manure was incubated with contaminated soils at rates of 0, 2.5, and 5.0% by weight for 210 d. A commercial activated carbon (AC) was included as a comparison. The AC was effective in immobilizing atrazine, but was ineffective for Pb. However, biochar was effective in immobilizing both atrazine and Pb and the effectiveness was enhanced with increasing incubation time and biochar rates. After 210 d, soils treated with the highest rate of 5.0% biochar showed more than 57% and 66% reduction in Pb and atrazine concentrations in 0.01 M CaCl(2) extraction, respectively. Lead and atrazine concentrations in the toxicity characteristic leaching procedure solutions were reduced by 70-89% and 53-77%, respectively. Uptake of Pb and atrazine by earthworms (Eisenia fetida) was reduced by up to 79% and 73%. Phosphorus originally contained in biochar reacted with soil Pb to form insoluble hydroxypyromorphite Pb(5)(PO(4))(3)(OH), as determined by X-ray diffraction, which was presumably responsible for soil Pb immobilization, whereas atrazine stabilization may result from its adsorption by biochar demonstrated by the significant exponential decrease of extractable atrazine with increasing organic C in biochar (r(2) > 0.97, p < 0.05). The results highlighted the potential of dairy-manure biochar as a unique amendment for immobilization of both heavy metal and organic contaminants in cocontaminated soils. PMID- 21542568 TI - Reliable measurements of interfacial slip by colloid probe atomic force microscopy. II. Hydrodynamic force measurements. AB - Here we report a new study on the boundary conditions for the flow of a simple liquid in a confined geometry obtained by measuring hydrodynamic drainage forces with colloid probe atomic force microscopy (AFM). In this work, we provide experimental data obtained using a best practice experimental protocol and fitted with a new theoretical calculation (Zhu, L.; Attard, P.; Neto, C. Langmuir 2010, submitted for publication, preceding paper). We investigated the hydrodynamic forces acting on a silica colloid probe approaching a hydrophobized silicon surface in a single-component viscous Newtonian liquid (di-n-octylphthalate), a partially wetting system. The measured average slip lengths were in the range of 24-31 nm at approach velocities of between 10 and 80 MUm/s. Using our experimental approach, the presence of nanoparticle contaminants in the system can be indentified, which is important because it has been shown that nanoparticles lead to a large apparent slip length. Under our stringent control of experimental conditions, the measurement of the slip length is reproducible and independent of the spring constant of the cantilever. PMID- 21542569 TI - Reliable measurements of interfacial slip by colloid probe atomic force microscopy. I. Mathematical modeling. AB - We developed a stable spread-sheet algorithm for the calculation of the hydrodynamic forces measured by colloid probe atomic force microscopy to be used in investigations of interfacial slip. The algorithm quantifies the effect on the slip hydrodynamic force for factors commonly encountered in experimental measurements such as nanoparticle contamination, nonconstant drag force due to cantilever bending that varies with different cantilevers, flattening of the microsphere, and calibration at large separations. We found that all of these experimental factors significantly affect the fitted slip length, approximately in the order listed. Our modeling is applied to fit new experimental data reproducibly. Using this new algorithm, it is shown that the fitting of hydrodynamic theories to experimental data is reliable and the fitted slip length is accurate. A "blind test" protocol was developed that produces a reliable estimate of the fitting error in the determination of both the slip length and spring constant. By this blind test, we estimate that our modeling determines the fitted slip length with an average systematic error of 2 nm and the fitted spring constant with a 3% error. Our exact calculation of the drag force may explain previous reports that the fitted slip length depends upon the shape and spring constant of the cantilever used to perform the measurements. PMID- 21542570 TI - Study of energetics and structure of 1,2,3-benzotriazin-4(3H)-one and its 1H and enol tautomers. AB - This paper reports an experimental and computational study on the energetics of 1,2,3-benzotriazin-4(3H)-one. The standard (p degrees = 0.1 MPa) molar enthalpy of formation of solid 1,2,3-benzotriazin-4(3H)-one, at T = 298.15 K, was derived from its standard massic energy of combustion measured by static bomb combustion calorimetry in oxygen. The Calvet high-temperature vacuum sublimation technique was used to measure the respective standard molar enthalpy of sublimation at T = 298.15 K. From these two experimentally determined thermodynamic parameters, we have calculated the standard molar enthalpy of formation of 1,2,3-benzotriazin 4(3H)-one in the gas phase at T = 298.15 K, (200.9 +/- 3.8) kJ.mol(-1). Interrelations between structure and energy for 1,2,3-benzotriazin-4(3H)-one, the tautomer 1,2,3-benzotriazin-4(1H)-one, and the enol tautomer 1,2,3-benzotriazin-4 ol were discussed based on density functional theory (DFT) calculations with the B3LYP hybrid functional and the 6-311++G(d,p) basis set. The gas-phase enthalpy of formation of 1,2,3-benzotriazin-4(3H)-one was estimated from quantum chemical calculations using the G3(MP2)//B3LYP composite method. Nucleus-independent chemical shifts (NICS) were also calculated with the purpose of analyzing the aromaticity of the benzenic and heterocyclic rings of the title molecule and others related tautomerically to it. PMID- 21542571 TI - Solubilities and thermodynamic properties of SO2 in ionic liquids. AB - Task-specific ionic liquids (TSILs) have been experimentally demonstrated to absorb more sulfur dioxide (SO(2)) than normal ILs from gas mixtures with low SO(2) concentrations; however, the differences of SO(2) solubilities in the two kinds of ILs at given temperatures and pressures have not been studied systematically. Moreover, the mechanism of the interaction between SO(2) and ILs still remains unclear. In this work, the solubilities of SO(2) in TSILs (1,1,3,3 tetramethylguanidinium lactate and monoethanolaminium lactate) and normal ILs (1 butyl-3-methylimidazolium tetrafluoroborate and 1-butyl-3-methylimidazolium hexafluorophosphate) were determined. The solubilities of SO(2) are correlated by a modified Redlich-Kwong equation of state (RK EoS). The chemical absorption and physical absorption are differentiated, and the absorption mechanism has been proposed with the aid of the modified RK EoS. SO(2) absorption capacity in TSILs is contributed from both chemical interaction and physical interaction. Two TSIL molecules chemically absorb one SO(2) molecule, and the chemical absorption amount follows the chemical equilibrium. Normal ILs only physically absorb SO(2) following Henry's law. The chemical equilibrium constant, reaction enthalpy, Gibbs energy of reaction, reaction entropy, and Henry's law constant of SO(2) absorbed in ILs have been calculated. The present model can predict SO(2) absorption capacity for capture and SO(2) equilibrium concentration in IL for recovery. PMID- 21542572 TI - Thermal decomposition of condensed-phase nitromethane from molecular dynamics from ReaxFF reactive dynamics. AB - We studied the thermal decomposition and subsequent reaction of the energetic material nitromethane (CH(3)NO(2)) using molecular dynamics with ReaxFF, a first principles-based reactive force field. We characterize the chemistry of liquid and solid nitromethane at high temperatures (2000-3000 K) and density 1.97 g/cm(3) for times up to 200 ps. At T = 3000 K the first reaction in the decomposition of nitromethane is an intermolecular proton transfer leading to CH(3)NOOH and CH(2)NO(2). For lower temperatures (T = 2500 and 2000 K) the first reaction during decomposition is often an isomerization reaction involving the scission of the C-N bond the formation of a C-O bond to form methyl nitrate (CH(3)ONO). Also at very early times we observe intramolecular proton transfer events. The main product of these reactions is H(2)O which starts forming following those initiation steps. The appearance of H(2)O marks the beginning of the exothermic chemistry. Recent quantum-mechanics-based molecular dynamics simulations on the chemical reactions and time scales for decomposition of a crystalline sample heated to T = 3000 K for a few picoseconds are in excellent agreement with our results, providing an important, direct validation of ReaxFF. PMID- 21542573 TI - Comment on "Comparative tissue distribution, biotransformation and associated biological effects by decabromodiphenyl ethane and decabrominated diphenyl ether in male rats after a 90-day oral exposure study". PMID- 21542574 TI - Monitoring of perfluorinated compounds in aquatic biota: an updated review. AB - The goal of this article is to summarize new biological monitoring information on perfluorinated compounds (PFCs) in aquatic ecosystems (post-2005) as a followup to our critical review published in 2006. A wider range of geographical locations (e.g., South America, Russia, Antarctica) and habitats (e.g., high-mountain lakes, deep-ocean, and offshore waters) have been investigated in recent years enabling a better understanding of the global distribution of PFCs in aquatic organisms. High concentrations of PFCs continue to be detected in invertebrates, fish, reptiles, and marine mammals worldwide. Perfluorooctane sulfonate (PFOS) is still the predominant PFC detected (mean concentrations up to 1900 ng/g ww) in addition to important concentrations of long-chain perfluoroalkyl carboxylates (PFCAs; sum PFCAs up to 400 ng/g ww). More studies have evaluated the bioaccumulation and biomagnification of these compounds in both freshwater and marine food webs. Several reports have indicated a decrease in PFOS levels over time in contrast to PFCA concentrations that have tended to increase in tissues of aquatic organisms at many locations. The detection of precursor metabolites and isomers has become more frequently reported in environmental assessments yielding important information on the sources and distribution of these contaminants. The integration of environmental/ecological characteristics (e.g., latitude/longitude, salinity, and/or trophic status at sampling locations) and biological variables (e.g., age, gender, life cycle, migration, diet composition, growth rate, food chain length, metabolism, and elimination) are essential elements in order to adequately study the environmental fate and distribution of PFCs and should be more frequently considered in study design. PMID- 21542576 TI - Novel computational identification of highly selective biomarkers of pollutant exposure. AB - The use of in vivo biosensors to acquire environmental pollution data is an emerging and promising paradigm. One major challenge is the identification of highly specific biomarkers that selectively report exposure to a target pollutant, while remaining quiescent under a diverse set of other, often unknown, environmental conditions. This study hypothesized that a microarray data mining approach can identify highly specific biomarkers, and, that the robustness property can generalize to unforeseen environmental conditions. Starting with Arabidopsis thaliana microarray data measuring responses to a variety of treatments, the study used the top scoring pair (TSP) algorithm to identify mRNA transcripts that respond uniquely to phenanthrene, a model polycyclic aromatic hydrocarbon. Subsequent in silico analysis with a larger set of microarray data indicated that the biomarkers remained robust under new conditions. Finally, in vivo experiments were performed with unforeseen conditions that mimic phenanthrene stress, and the biomarkers were assayed using qRT-PCR. In these experiments, the biomarkers always responded positively to phenanthrene, and never responded to the unforeseen conditions, thereby supporting the hypotheses. This data mining approach requires only microarray or next-generation RNA-seq data, and, in principle, can be applied to arbitrary biomonitoring organisms and chemical exposures. PMID- 21542577 TI - Detection and structural identification of dissolved organic matter in Antarctic glacial ice at natural abundance by SPR-W5-WATERGATE 1H NMR spectroscopy. AB - Dissolved organic matter (DOM) is ubiquitous in aquatic ecosystems and is derived from various inputs that control its turnover. Glaciers and ice sheets are the second largest water reservoir in the global hydrologic cycle, but little is known about glacial DOM composition or contributions to biogeochemical cycling. Here we employ SPR-W5-WATERGATE (1)H NMR spectroscopy to elucidate and quantify the chemical structures of DOM constituents in Antarctic glacial ice as they exist in their natural state (average DOC of 8 mg/L) without isolation or preconcentration. This Antarctic glacial DOM is predominantly composed of a mixture of small recognizable molecules differing from DOM in marine, lacustrine, and other terrestrial environments. The major constituents detected in three distinct types of glacial ice include lactic and formic acid, free amino acids, and a mixture of simple sugars and amino sugars with concentrations that vary between ice types. The detection of free amino acid and amino sugar monomer components of peptidoglycan within the ice suggests that Antarctic glacial DOM likely originates from in situ microbial activity. As these constituents are normally considered to be biologically labile (fast cycling) in nonglacial environments, accelerated glacier melt and runoff may result in a flux of nutrients into adjacent ecosystems. PMID- 21542578 TI - Effects of metal chelator, sodium azide, and superoxide dismutase on the oxidative stability in riboflavin-photosensitized oil-in-water emulsion systems. AB - The effects of riboflavin photosensitization on the oxidative stability of oil-in water (O/W) emulsions were determined using lipid hydroperoxides and headspace volatile analyses. The influences of a metal chelator, sodium azide, and superoxide dismutase (SOD) on oxidation pathways were tested to gain a better understanding of the role of transition metals, singlet oxygen, and superoxide anion, respectively. Emulsions with riboflavin and visible light irradiation had significantly higher lipid hydroperoxides and volatiles (p < 0.05) as compared to samples without light irradiation or riboflavin. The addition of ethylenediammetetraacetic acid (EDTA) decreased the formation of lipid hydroperoxides, hexanal, 2-heptenal, and 1-octen-3-ol in a concentration dependent manner. Sodium azide, a singlet oxygen physical quencher, only inhibited the formation of 2-heptenal and 1-octen-3-ol. Overall, photosensitized riboflavin participated in both type I and type II pathways in O/W emulsions, and these pathways enhance the prooxidant activity of metals through their ability to produce lipid hydroperoxides and superoxide anion. PMID- 21542579 TI - Solvation of electrolytes and nonelectrolytes in aqueous solutions. AB - A new theory of electrolyte and nonelectrolyte solutions has been developed which, unlike the Debye-Huckel method applicable for small concentrations only, makes it possible to estimate thermodynamic properties of a solution in a wide range of state parameters. One of the main novelties of the proposed theory is that it takes into account the dependence of solvation numbers upon the concentration of solution, and all changes occurring in the solution are connected with solvation of the stoichiometric mixture of electrolyte ions or molecules. The present paper proposes a rigorous thermodynamic analysis of hydration parameters of solutions. Ultrasound and densimetric measurements in combination with data on isobaric heat capacity have been used to study aqueous solutions of electrolytes NaNO3, KI, NaCl, KCl, MgCl2, and MgSO4 and of nonelectrolytes urea, urotropine, and acetonitrile. Structural characteristics of hydration complexes have been analyzed: hydration numbers h, the proper volume of the stoichiometric mixture of ions without hydration shells V(2h), compressibility beta(1h), and the molar volume of water in hydration shells V(1h), their dependencies on concentration and temperature. It has been shown that for aqueous solutions the electric field of ions and molecules of nonelectrolytes has a greater influence on the temperature dependence of the molar volume of solution in hydration shells than a simple change of pressure. The cause of this effect may be due to the change in the dielectric permeability of water in the immediate vicinity of hydrated ions or molecules. The most studied compounds (NaCl, KCl, KI, MgCl2) have been studied in a wider range of solute concentrations of up to 4-5 mol/kg. Up to the complete solvation limit (CSL), the functions V(1h) = f(T) and beta(1h) = f(T) are linear with a high correlation factor, and the dependence Y(K,S) = f(beta1V1*) at all investigated concentrations of electrolytes and nonelectrolytes up to the CSL enables h and beta(h)V(h) to be determined on the basis of relationships obtained in the study. The behavior of nonelectrolyte solutions is no different from that of electrolyte solutions, although it is possible to trace the difference between hydrophobic and hydrophilic interactions. PMID- 21542580 TI - Nanocavity effect on photophysical properties of colchicine: a proof by circular dichroism study and picosecond time-resolved analysis in various reverse micellar assemblies. AB - In August 2009, colchicine won Food and Drug Administration (FDA) approval in the United States as a stand-alone drug for the treatment of acute flares of gout and familial Mediterranean fever. Recently, it is now the center of attraction in medicinal research. In this present paper, we have employed two other analogues of colchicine for exploring the photophysical properties inside nanocavity environment in details. Here we have a series of interesting results that have interesting similarity with the colchinoid-tubulin interaction. To monitor fluorescence properties of colchinoids, we have used absorption, emission, and time-resolved spectroscopy and to monitor structural properties we have measured circular dichroism. Steady-state anisotropy and dynamic light scattering results give an idea about the microenvironment sensed by the colchinoids molecules. A sharp increment for colchicine, very small increment for isocolchicine and no increment for colcemid in fluorescence and different circular dichroism (CD) spectra of all of these colchinoids upon embedment inside nanocavity of reverse micelle made a supposition that all these changes of fluorescence properties and CD results of colchinoids is not solely due to viscosity effect but also the constraint, that is, very narrow space to spread over, given by the nanocavity of reverse micelle. Moreover, we have noticed that the B ring of the colchinoids also have a pronounced effect on the interaction nature as well as on conformational change of these compounds after entrapment. PMID- 21542581 TI - Geometrical embedding governs a dramatic variation of electron paramagnetic resonance hyperfine coupling constants of disulfide radical anions. AB - Among the large variety of experimental techniques amenable to probe disulfide radical anions, electron paramagnetic resonance (EPR) spectroscopy provides the most definitive assignment of these versatile transient intermediates in biochemistry [Stubbe et al. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 8979-84; J. Am. Chem. Soc. 2009, 131, 200-211]. EPR parameters along both a series of 12 aliphatic 1,2-dithia-cycloalkane radical anions and a representative set of 18 short-loop peptides are investigated by means of density functional theory. While the g-tensor remains quasi-isotropic (with diagonal terms very close to 2.0, as expected for a sigma* singly occupied orbital), we evidence a dramatic conformational dependence of isotropic sulfur hyperfine coupling constants (hcc). Potential energy surface exploration of the prototypical dimethyldisulfide rationalizes their 3-4-fold amplitude, with values ranging between 10 and 29 G for aliphatic moieties. Sulfur hcc's are readily decomposed into three geometrical components: intersulfur distance, dihedral, and valence angles, with the latter being predominant. Increasing (respectively decreasing) contribution of sulfur atomic s orbital to the sigma* molecular orbital, with a concomitant higher (respectively weaker) density around the sulfur nuclei, can be monitored on Walsh diagrams along each degree of motion. In peptidic disulfide radical anionic systems, sulfur hcc's are dissymmetrized and span an even larger range of values, from 14 to 40 G. Again, dependence is governed by the mechanical embedding of the -CH(2)-S?S-CH(2)- motif, this time with a noticeable contribution from the hemibond lenghtening and some punctual short-range additive electrostatic contributions. This analysis comes within the scope of a unified picture of both spectroscopy and reactivity of the mechanochemistry of disulfide hemibonds. PMID- 21542582 TI - Phosphorylation-dependent perturbations of the 4.1R-associated multiprotein complex of the erythrocyte membrane. AB - The bulk of the red blood cell membrane proteins are partitioned between two multiprotein complexes, one associated with ankyrin R and the other with protein 4.1R. Here we examine the effect of phosphorylation of 4.1R on its interactions with its partners in the membrane. We show that activation of protein kinase C in the intact cell leads to phosphorylation of 4.1R at two sites, serine 312 and serine 331. This renders the 4.1R-associated transmembrane proteins GPC, Duffy, XK, and Kell readily extractable by nonionic detergent with no effect on the retention of band 3 and Rh, both of which also interact with 4.1R. In solution, phosphorlyation at either serine suppresses the capacity of 4.1R to bind to the cytoplasmic domains of GPC, Duffy, and XK. Phosphorylation also exerts an effect on the stability in situ of the ternary spectrin-actin-4.1R complex, which characterizes the junctions of the membrane skeletal network, as measured by the enhanced competitive entry of a beta-spectrin peptide possessing both actin- and 4.1R-binding sites. Thus, phosphorylation weakens the affinity of 4.1R for beta spectrin. The two 4.1R phosphorylation sites lie in a domain flanked in the sequence by the spectrin- and actin-binding domain and a domain containing the binding sites for transmembrane proteins. It thus appears that phosphorylation of a regulatory domain in 4.1R results in structural changes transmitted to the functional interaction centers of the protein. We consider possible implications of our findings for the altered membrane function of normal reticulocytes and sickle red cells. PMID- 21542583 TI - Optical tweezers for synchrotron radiation probing of trapped biological and soft matter objects in aqueous environments. AB - Investigations of single fragile objects manipulated by optical forces with high brilliance X-ray beams may initiate the development of new research fields such as protein crystallography in an aqueous environment. We have developed a dedicated optical tweezers setup with a compact, portable, and versatile geometry for the customary manipulation of objects for synchrotron radiation applications. Objects of a few micrometers up to a few tens of micrometers size can be trapped for extended periods of time. The selection and positioning of single objects out of a batch of many can be performed semi-automatically by software routines. The performance of the setup has been tested by wide-angle and small-angle X-ray scattering experiments on single optically trapped starch granules, using a synchrotron radiation microbeam. We demonstrate here for the first time the feasibility of microdiffraction on optically trapped protein crystals. Starch granules and insulin crystals were repeatedly raster-scanned at about 50 ms exposure/raster-point up to the complete loss of the structural order. Radiation damage in starch granules results in the appearance of low-angle scattering due to the breakdown of the polysaccharide matrix. For insulin crystals, order along the densely packed [110] direction is preferentially maintained until complete loss of long-range order. PMID- 21542584 TI - Analysis of the mechanism of lysozyme pressure denaturation from Raman spectroscopy investigations, and comparison with thermal denaturation. AB - Pressure denaturation of lysozyme dissolved in H(2)O and D(2)O was analyzed using Raman investigations in a wide frequency range. The simultaneous analysis of regions corresponding to the molecular fingerprint of the protein (500-1800 cm( 1)), and the low- (50-450 cm(-1)) and high- (2600-3800 cm(-1)) frequency spectra, allow us to probe protein denaturation and the organization of water molecules. The pressure- and heat-induced transformations are compared. Both pressure- and heat-denatured states are obtained through an intermediate state characterized by intact secondary structure and enhanced water penetration in the tertiary structure. As a consequence of a weaker penetration upon pressurizing, it was found that the pressure-denatured state was partially unfolded compared with the heat-denatured state. The mechanism of pressure denaturation was related to the disruption of the hydrogen-bond network of water onto a set of clusters characterized by strengthened O - H interactions, inducing a hardening of protein dynamics. The mechanism is opposite to that observed upon heating, i.e., the softening of the hydrogen bond network of water inducing a softer protein dynamics. The analysis of the intramolecular O-H stretching reveals that pressurizing lysozyme aqueous solution favors the development of low-density water from the protein surface to the bulk, contrasting to the compression of pure water leading to crystallization of high-density ice-VI. PMID- 21542585 TI - Growth and organization of an organic molecular monolayer on TiO2: catechol on anatase (101). AB - Anatase TiO(2) is a widely used photocatalytic material, and catechol (1,2 benzendiol) is a model organic sensitizer for dye-sensitized solar cells. The growth and the organization of a catecholate monolayer on the anatase (101) surface were investigated with scanning tunneling microscopy and density functional theory calculations. Isolated molecules adsorb preferentially at steps. On anatase terraces, monodentate ('D1') and bidentate ('D2') conformations are both present in the dilute limit, and frequent interconversions can take place between these two species. A D1 catechol is mobile at room temperature and can explore the most favorable surface adsorption sites, whereas D2 is essentially immobile. When a D1 molecule arrives in proximity of another adsorbed catechol in an adjacent row, it is energetically convenient for them to pair up in nearest-neighbor positions taking a D2-D2 or D2-D1 configuration. This intermolecular interaction, which is largely substrate mediated, causes the formation of one-dimensional catecholate islands that can change in shape but are stable to break-up. The change between D1 and D2 conformations drives both the dynamics and the energetics of this model system and is possibly of importance in the functionalization of dye-sensitized solar cells. PMID- 21542586 TI - Enzyme molecular mechanism as a starting point to design new inhibitors: a theoretical study of O-GlcNAcase. AB - O-Glycoprotein 2-acetamino-2-deoxy-beta-D-glucopyranosidase (O-GlcNAcase) hydrolyzes O-linked 2-acetamido-2-deoxy-beta-D-glucopyranoside (O-GlcNAc) residues from post-translationally modified serine/threonine residues of nucleocytoplasmic protein. The chemical process involves substrate-assisted catalysis, where two aspartate residues have been identified as the two key catalytic residues of O-GlcNAcase. In this report, the first step of the catalytic mechanism used by O-GlcNAcase involving substrate-assisted catalysis has been studied using a hybrid quantum mechanical/molecular mechanical (QM/MM) Molecular Dynamics (MD) calculations. The free energy profile shows that the formation of the oxazoline intermediate in the O-GlcNAcase catalytic reaction takes place by means of a stepwise mechanism. The first step would be a cyclization of the acetomide group, which seems to be dependent on the proton transfer from a conserved aspartate, Asp298 in Clostridium perfringens O GlcNAcase. From this new intermediate, a proton is transferred from the azoline ring to another conserved aspartate (Asp297) thus forming the oxazoline ion and departure of the aglycone. In addition, averaged values of protein-substrate interaction energy along the reaction path shows that, in fact, the transition states present the highest binding affinities. A deeper analysis of the binding contribution of the individual residues shows that Asp297, Asp298, and Asp401 are basically responsible of the stabilization of these complexes. These results would explain why O-(2-acetamido-2deoxy-d-glucopyranosylidene)amino-N phenycarbamate (PUGNAc), 1,2-dideoxy-2'-methyl-alpha-D-glucopyranoso-[2,1-d] Delta2'-thiazoline (NAG-thiazoline), and GlcNAcstatin derivatives are potent inhibitors of this enzyme, resembling the two transition states of the O GlcNAcase catalytic reaction path. These results may be useful to rational design compounds with more interesting inhibitory activity. PMID- 21542587 TI - Hexadentate terephthalamide(bis-hydroxypyridinone) ligands for uranyl chelation: structural and thermodynamic consequences of ligand variation. AB - Several linear, hexa- and tetradentate ligands incorporating a combination of 2,3 dihydroxy-terephthalamide (TAM) and hydroxypyridinone-amide (HOPO) moieties have been developed as uranyl chelating agents. Crystallographic analysis of several {UO(2)[TAM(HOPO)(2)]}(2-) complexes revealed a variable and crowded coordination geometry about the uranyl center. The TAM moiety dominates the bonding in hexadenate complexes, with linker rigidity dictating the equality of equatorial U O bonding. Hexadentate TAM(HOPO)(2) ligands demonstrated slow binding kinetics with uranyl affinities on average 6 orders of magnitude greater than those of similarly linked bis-HOPO ligands. Study of tetradentate TAM(HOPO) ligands revealed that the high uranyl affinity stems primarily from the presence of the TAM moiety and only marginally from increased ligand denticity. Uranyl affinities of TAM(HOPO)(2) ligands were within experimental error, with TAM(o-phen-1,2 HOPO)(2) exhibiting the most consistent uranyl affinity at variable pH. PMID- 21542588 TI - New insights into the substrate-plasma polymer interface. AB - We describe a new method to characterize the underside (substrate interface) of plasma polymer (PP) thin films via their simple delamination from a sodium chloride single crystal substrate. By depositing the PP film onto an ionic bonded surface such as a sodium chloride crystal, the PP films investigated were easily delaminated from the substrate. Two plasma polymer films deposited from 1 bromopropane (BrPP) and allylamine (AAPP) were used to exemplify this new technique. The top- and underside (substrate-plasma polymer interface) of the films were examined by X-ray photoelectron spectroscopy (XPS) and synchrotron based near edge X-ray adsorption fine structure (NEXAFS) spectroscopy. The results demonstrate that both films exhibit heterogeneous film structures with their chemical composition and levels of unsaturated species. The underside of both the BrPP and the AAPP films exhibited higher concentrations of oxygen, while their topsides contained higher levels of unsaturated species. These results provide useful insights into the BrPP and AAPP film formation and the chemistry. The delamination technique provides a simple method to analyze the early stages of film chemistry for plasma polymer thin films. Furthermore, this approach opens new opportunities for additional studies on the mechanisms and fundamentals of plasma polymer thin film formation with various monomers. PMID- 21542589 TI - Selective and random syntheses of [n]cycloparaphenylenes (n=8-13) and size dependence of their electronic properties. AB - [n]Cycloparaphenylenes (n = 8-13, CPPs) were synthesized, and their physical properties were systematically investigated. [8] and [12]CPPs were selectively prepared from the reaction of 4,4'-bis(trimethylstannyl)biphenyl and 4,4'' bis(trimethylstannyl)terphenyl, respectively, with Pt(cod)Cl(2) (cod = 1,5 cyclooctadiene) through square-shaped tetranuclear platinum intermediates. A mixture of [8]-[13]CPPs was prepared in good combined yields by mixing biphenyl and terphenyl precursors with platinum sources. Products were easily separated and purified by using gel permeation chromatography. In (1)H NMR spectra, the proton of the CPPs shifts to a lower field as n increased due to an anisotropic effect from the nearby PP moieties. Although the UV-vis spectra were rather insensitive to the size of the CPPs, the fluorescence spectra changed significantly in relation to their size. A larger Stokes shift was observed for the smaller CPPs. Redox properties of the CPPs were measured for the first time by using cyclic voltammetry, and the smaller CPPs had lower oxidation potentials. The results are consistent with the HOMO energies of CPPs, of which the smaller CPPs had higher energies. PMID- 21542590 TI - Acoustically mounted microcrystals yield high-resolution X-ray structures. AB - We demonstrate a general strategy for determining structures from showers of microcrystals. It uses acoustic droplet ejection to transfer 2.5 nL droplets from the surface of microcrystal slurries, through the air, onto mounting micromesh pins. Individual microcrystals are located by raster-scanning a several micrometer X-ray beam across the cryocooled micromeshes. X-ray diffraction data sets merged from several micrometer-sized crystals are used to determine 1.8 A resolution crystal structures. PMID- 21542591 TI - Structure of monolayers formed from neurotensin and its single-site mutants: vibrational spectroscopic studies. AB - The human, pig, and frog neurotensins and four single-site mutants of human neurotensin (NT), having the following modifications, [Gln(4)]NT, [Trp(11)]NT, [D Trp(11)]NT, and [D-Tyr(11)]NT, were immobilized onto an electrochemically roughened silver electrode surface in an aqueous solution. The orientation of adsorbed molecules was determined from surface-enhanced Raman scattering (SERS) measurements. A comparison was made between these structures to determine how the change upon the mutation of the neurotensin structure influences its adsorption properties. The SERS patterns were correlated with the contribution of the structural components of the aforementioned peptides to the ability to interact with the NTR1 G-protein receptor. Briefly, the SERS spectra revealed that the substitution of native amino acids in investigated peptides influenced slightly their adsorption state on an electrochemically roughened silver surface. Thus, human, pig, and frog neurotensins and [Gln(4)]NT and [D-Tyr(11)]NT tended to adsorb to the surface via the tyrosine ring, the oxygen atom of the deprotonated phenol group of Tyr(11), and the -CH(2)- unit(s), most probably of Tyr(11), Arg(9), and/or Leu(13). The observed changes in the enhancement of the deprotonated Tyr residue SERS signals indicated a further parallel orientation of a phenol-O bond with regard to the silver surface normal for pig NT, [Gln(4)]NT, and [D-Tyr(11)]NT, whereas the orientation was slightly tilted for human and frog NT. In the case of [Trp(11)]NT and [D-Trp(11)]NT, the formation of a peptide/Ag complex was confirmed by strong SERS bands involving the phenyl co-ring of Trp(11)/d-Trp(11) and -CH(2)- vibrations and the tilted and flat orientations of the two compounds with respect to the surface substrate. The spectral features were accompanied by a SERS signal caused by vibrations of the carboxyl group of C terminal Leu(13) and the guanidine group of Arg(9). Reported changes in SERS spectra of L and D isomers were fully supported by generalized two-dimensional correlation analysis. Additionally, a combination of mutation-labeling and vibrational spectroscopy (Fourier-transform Raman and absorption infrared) was used to investigate the possible peptide conformations and environments of the tyrosine residues. PMID- 21542592 TI - Cloning and characterization of an environmental DNA-derived gene cluster that encodes the biosynthesis of the antitumor substance BE-54017. AB - Soil is predicted to contain thousands of unique bacterial species per gram. Soil DNA libraries represent large reservoirs of biosynthetic diversity from which diverse secondary metabolite gene clusters can be recovered and studied. The screening of an archived soil DNA library using primers designed to target oxytryptophan dimerization genes allowed us to identify and functionally characterize the first indolotryptoline biosynthetic gene cluster. The recovery and heterologous expression of an environmental DNA-derived gene cluster encoding the biosynthesis of the antitumor substance BE-54017 is reported here. Transposon mutagenesis identified two monooxygenases, AbeX1 and AbeX2, as being responsible for the transformation of an indolocarbazole precursor into the indolotryptoline core of BE-54017. PMID- 21542593 TI - Nonequilibrium effects in DNA microarrays: a multiplatform study. AB - It has recently been shown that in some DNA microarrays the time needed to reach thermal equilibrium may largely exceed the typical experimental time, which is about 15 h in standard protocols (Hooyberghs et al. Phys. Rev. E2010, 81, 012901). In this paper we discuss how this breakdown of thermodynamic equilibrium could be detected in microarray experiments without resorting to real time hybridization data, which are difficult to implement in standard experimental conditions. The method is based on the analysis of the distribution of fluorescence intensities I from different spots for probes carrying base mismatches. In thermal equilibrium and at sufficiently low concentrations, log I is expected to be linearly related to the hybridization free energy DeltaG with a slope equal to 1/RT(exp), where T(exp) is the experimental temperature and R is the gas constant. The breakdown of equilibrium results in the deviation from this law. A model for hybridization kinetics explaining the observed experimental behavior is discussed, the so-called 3-state model. It predicts that deviations from equilibrium yield a proportionality of log I to DeltaG/RT(eff). Here, T(eff) is an "effective" temperature, higher than the experimental one. This behavior is indeed observed in some experiments on Agilent arrays [Hooyberghs et al. Phys. Rev. E2010, 81, 012901 and Hooyberghs et al. Nucleic Acids Res. 2009, 37, e53]. We analyze experimental data from two other microarray platforms and discuss, on the basis of the results, the attainment of equilibrium in these cases. Interestingly, the same 3-state model predicts a (dynamical) saturation of the signal at values below the expected one at equilibrium. PMID- 21542594 TI - Binding of cationic lipids to milk beta-lactoglobulin. AB - We determined the bindings of several lipids such as cholesterol (CHOL), 1,2 dioleoyl-3-trimethylammonium-propane (DOTAP), dioctadecyldimethyl-ammoniumbromide (DDAB), and dioleoylphosphatidylethanolamine (DOPE) to beta-lactoglobulin (beta LG) at physiological conditions. FTIR, CD, and fluorescence spectroscopic methods as well as molecular modeling were used to determine the binding of lipid-protein complexes. Structural analysis showed that lipids bind beta-LG via both hydrophilic and hydrophobic interactions with overall binding constants of K(CHOL beta-LG) = 6.0 (+/-0.6) * 10(3) M(-1), K(DOPE-beta-LG) = 6.5 (+/-0.7) * 10(3) M( 1), K(DDAB-beta-LG) = 1.6 (+/-0.3) * 10(4) M(-1), and K(DOTAP-beta-LG) = 2.2 (+/ 0.67) * 10(4) M(-1). The number of lipid bound per protein molecule (n) was 0.8 (CHOL), 0.7 (DOPE), 1.0 (DDAB), and 1.3 (DOTAP). Molecular modeling showed the participation of several amino acid residues in lipid-protein complexation with the order of binding DOTAP > DDAB > DOPE > CHOL. Alterations of the protein conformation were observed in the presence of lipids with a minor decrease in beta-sheet and an increase in turn structure. PMID- 21542595 TI - Intermolecular electron density modulations in water and their effects on the far infrared spectral profiles at 6 THz. AB - The modulations in the electron density induced by molecular motions are analyzed theoretically for tetrahedrally hydrogen-bonded water molecules. Those modulations are represented as the electron density derivatives, and their forms are examined by the use of the one- and two-dimensional integrated plots. It is shown that intermolecular flux of electrons, called intermolecular charge flux, is induced by the molecular translation modes in water, leading to the infrared intensity at 6 THz. This means that the molecular translational and electronic motions are strongly coupled, and this coupling is observable through this vibrational band. A comparison is made with the case of the OH stretching mode. A method to incorporate this effect in spectral simulations based on classical molecular dynamics is also shown. These results provide a way to correct understanding of dynamics in, for example, aqueous solutions of biomolecules from analyses of their vibrational spectra in the terahertz frequency region. A general idea on how we can perform reasonable calculations and analyses of the vibrational spectral profiles of liquid systems is also discussed. PMID- 21542596 TI - Thermal stability and structural variations of survivin and its deletants in aqueous solution as revealed by spectroscopy. AB - Survivin exists as a homodimeric conformation to act as a suppressor of apoptosis in organisms. Previously, we found that the deletants with truncations of N terminal residues up to Arg18 lost the binding ability to Smac/DIABLO but not the binding force of homodimers. In order to establish the relationship between function and structural stability, thermal unfolding of SurF and its deletants in buffer have been studied in the present paper. The fluorescent results indicated that with the removal of the N-terminus, the thermal stability of the tertiary structure dropped vigorously, especially for SurDeltaN18. However, using circular dichroism (CD) spectroscopy, we observed that the main unfolding of the secondary structures was not affected very much with N-terminus deletion. Fourier transform infrared (FT-IR) spectroscopy and two-dimensional (2D) correlation analysis were further used to provide structural information that occurred in the main transitions, which were associated with conformational changes of several beta components and alpha-helix, followed by the gain of some aggregations and random coils at high temperature. In addition, more aggregates were found to form for the longer N-terminal deletants during the main unfolding. PMID- 21542597 TI - Antitubercular chromones and flavonoids from Pisonia aculeata. AB - Three new chromones, pisonins A (1), B (2), and D (4), two new flavonoids, pisonivanone [(2S)-5,7,2'-trihydroxy-8-methylflavanone] (7) and pisonivanol [(2R,3R)-3,7-dihydroxy-5,6-dimethoxyflavanone] (8), one new isoflavonoid, pisonianone (5,7,2'-trihydroxy-6-methoxy-8-methylisoflavone) (9), and five compounds first isolated from nature, namely, pisonins C (3), E (5), and F (6), pisoniamide (10), and pisonolic acid (11), together with 18 known compounds have been isolated from the methanol extract of the combined stem and root of Pisonia aculeata. Among these isolates, 2, 7, 14, 16, and 19 exhibited antitubercular activities (MICs<=50.0 MUg/mL) against Mycobacterium tuberculosis H37Rv in vitro. PMID- 21542598 TI - Combining magnetic field induced locomotion and supramolecular interaction to micromanipulate glass fibers: toward assembly of complex structures at mesoscale. AB - The formation of ordered complex structures is one of the most challenging fields in the research of biomimic materials because those structures are promising with respect to improving the physical and mechanical properties of man-made materials. In this letter, we have developed a novel approach to fabricating complex structures on the mesoscale by combining magnetic-field-induced locomotion and supramolecular-interaction-assisted immobilization. We have employed a magnetic field to locomote the glass fiber, which was modified by the layer-by-layer self-assembly of magnetic nanoparticles, to desired positions and have exploited the supramolecular interaction to immobilize glass fiber onto the appointed position. By magnetically induced micromanipulation, we can drive another fiber across the former one and finally obtain a crossing structure, which can lead to more complex structures on the mesocale. Moreover, we have constructed a mesoscale structure, termed "CHEM", to demonstrate further the application of this method. PMID- 21542599 TI - Stimulus-responsive hydrogels made from biosynthetic fibrinogen conjugates for tissue engineering: structural characterization. AB - Nanostructured hydrogels based on "smart" polymer conjugates of poloxamers and protein molecules were developed in order to form stimulus-responsive materials with bioactive properties for 3-D cell culture. Functionalized Pluronic F127 was covalently attached to a fibrinopeptide backbone and cross-linked into a structurally versatile and mechanically stable polymer network endowed with bioactivity and temperature-responsive structural features. Small angle X-ray scattering and transmission electron microscopy combined with rheology were used to characterize the structural and mechanical features of this biosynthetic conjugate, both in solution and in hydrogel form. The temperature at which the chemical cross-linking of F127-fibrinopeptide conjugates was initiated had a profound influence on the mechanical properties of the thermo-responsive hydrogel. The analysis of the scattering data revealed modification in the structure of the protein backbone resulting from increases in ambient temperature, whereas the structure of the polymer was not affected by ambient temperature. The hydrogel cross-linking temperature also had a major influence on the modulus of the hydrogel, which was rationally correlated to the molecular structure of the polymer network. The hydrogel structure exhibited a small mesh size when cross-linked at low temperatures and a larger mesh size when cross linked at higher temperatures. The mesh size was nicely correlated to the mechanical properties of the hydrogels at the respective cross-linking temperatures. The schematic charts that model this material's behavior help to illustrate the relationship that exists between the molecular structure, the cross-linking temperature, and the temperature-responsive features for this class of protein-polymer conjugates. The precise control over structural and mechanical properties that can be achieved with this bioactive hydrogel material is essential in designing a tissue-engineering scaffold for clinical applications. PMID- 21542600 TI - Inverse virtual screening of antitumor targets: pilot study on a small database of natural bioactive compounds. AB - An inverse virtual screening in silico approach has been applied to natural bioactive molecules to screen their efficacy against proteins involved in cancer processes, with the aim of directing future experimental assays. Docking studies were performed on a panel of 126 protein targets extracted from the Protein Data Bank, to analyze their possible interactions with a small library of 43 bioactive compounds. Analysis of the molecular docking results was performed through the use of tables containing energy data organized in a matrix. The application of this approach may facilitate the prediction of the activity of unknown ligands for known targets involved in the development of cancer and could be applied to other models based on different libraries of ligands and different panels of targets. PMID- 21542601 TI - Ionic diamine rhodium complex catalyzed reductive N-heterocyclization of 2 nitrovinylarenes. AB - Ionic diamine rhodium complex (1) catalyzes the reductive N-cyclization of 2 vinylnitroarenes using carbon monoxide as a reducing agent to afford functionalized indoles. The catalytic system allows direct access to indoles with ester and ketone groups at the 2- or 3-position, in good yields. PMID- 21542602 TI - Brominated arginine-derived alkaloids from the red sea sponge Suberea mollis. AB - Investigation of a new collection of the Red Sea sponge Suberea mollis afforded two new brominated arginine-derived alkaloids, subereamines A (1) and B (2), a new brominated phenolic compound, subereaphenol D (3), and the known compounds dichloroverongiaquinol (4), aerothionin (5), and purealdin L (6). The structures of the isolated compounds were assigned using one- and two-dimensional NMR spectra and HRFABMS data. The absolute configurations of subereamines A (1) and B (2) were determined by acid hydrolysis followed by chiral-phase LC-MS. The antimicrobial and antioxidant activities of the isolated compounds have been evaluated. Dichloroverongiaquinol and subereaphenol D displayed significant antimicrobial activity. Using the DPPH TLC autographic rapid screen for free radical scavenging effects, subereaphenol D displayed a significant antioxidant effect. In addition, the cytotoxic activities of the isolated compounds were investigated. PMID- 21542603 TI - Efficient photoelectrochemical water splitting by anodically grown WO3 electrodes. AB - The potentiostatic anodization of metallic tungsten has been investigated in different solvent/electrolyte compositions with the aim of improving the water oxidation ability of the tungsten oxide layer. In the NMF/H(2)O/NH(4)F solvent mixture, the anodization leads to highly efficient WO(3) photoanodes, which, combining spectral sensitivity, an electrochemically active surface, and improved charge-transfer kinetics, outperform, under simulated solar illumination, most of the reported nanocrystalline substrates produced by anodization in aqueous electrolytes and by sol-gel methods. The use of such electrodes results in high water electrolysis yields of between 70 and 90% in 1 M H(2)SO(4) under a potential bias of 1 V versus SCE and close to 100% in the presence of methanol. PMID- 21542604 TI - Triple helical polysaccharide-induced good dispersion of silver nanoparticles in water. AB - Silver nanoparticles were constructed by using triple helical polysaccharide (lentinan) dissolved in water as matrix for the first time. The structure, morphology, and size of the nanocomposites in the polysaccharide aqueous solutions were investigated with UV-visible spectroscopy (UV-vis), transmission electron microscopy (TEM), and dynamic laser light scattering (DLS). The results revealed that the silver nanoparticles were attached to the polysaccharide chains through the strong noncovalent interactions, leading to the good dispersion of silver nanoparticles with mean radius of 6 nm in water. The silver nanoparticles were stable in the lentinan aqueous solution for 9 months. However, with an addition of NaOH, the polysaccharide with the imperfect helical structure broken partially by NaOH could aggregate in the alkali aqueous solution. The aggregation of the lentinan-bonded silver nanoparticles increased with an increase in the NaOH concentration, whereas the size of the silver nanoparticles barely changed, further confirming that the Ag nanoparticles were stable in this system. The aggregation was related to the conformation transition of the polysaccharide from the triple helix to random coil in the solution. A new method to detect the aggregates and aggregation rate was established according to the intensity of the maximum absorption peaks of the polysaccharide labeled by Ag nanoparticles in the UV spectrum. PMID- 21542605 TI - Effect of polypeptide sequence on polypeptide self-assembly. AB - This study represents a unique example where the self-assembly of five amphiphilic polypeptides was monitored as a function of their hydrophilic-to lipophilic balance (HLB). The HLB was tuned by preparing a series of polypeptides with aspartic acid (Asp) and phenylalanine (Phe) according to the sequence (Asp(x)Phe(y)) where x and y vary from 1 to 3. The self-assembly of the (Asp(x)Phe(y))(n) polypeptides with M(w) values ranging from 8 to 12 K was studied in solution by fluorescence quenching and nonradiative energy transfer (NRET) fluorescence experiments. Dynamic (DLS) and static (SLS) light scattering studies were used to complement the results obtained. The fluorescence quenching experiments conducted with the chromophore pyrene used as a free probe, physically bound to the polypeptides via hydrophobic interactions, demonstrated that the chromophore was less exposed to the solution for the sequences having a higher hydrophobic character. Protective quenching was also observed for those polypeptides randomly labeled with pyrene where the phenylalanine content was high, whereas pyrene was found to be fully exposed to the quencher for the polypeptides having more hydrophilic sequences. NRET used to probe interpolymeric association was not observed between a naphthalene and a pyrene labeled polypeptide for the polypeptide sequences which were richer in aspartic acid, whereas energy transfer took place with the more hydrophobic polypeptides. This observation led to the conclusion that those sequences with a higher content of aspartic acid essentially generate unimolecular polymeric micelles, whereas those with a higher content of phenylalanine generate polymeric aggregates which offer protection from the solvent to their hydrophobic cargo. The presence of these polymeric aggregates was also confirmed by DLS and SLS studies which suggest that species 100-200 nm in diameter are present in solution. PMID- 21542608 TI - Observation of negative charge trapping and investigation of its physicochemical origin in newly synthesized poly(tetraphenyl)silole siloxane thin films. AB - A new kind of organic-inorganic hybrid polymer, poly(tetraphenyl)silole siloxane, was invented and synthesized for realization of its unique charge trap properties. The organic portions consisting of (tetraphenyl)silole rings were responsible for negative charge trapping, while the Si-O-Si inorganic linkages provided the intrachain energy barrier for controlling electron transport. The polysilole siloxane dielectric thin films were fabricated by spin-coating and curing of the polymers, followed by characterization with spectroscopic ellipsometry (SE), near edge X-ray absorption fine structure spectroscopy (NEXAFS), and photoemission spectroscopy (PES). The abrupt increase in density and decrease in thickness of the thin film at a curing temperature of 100 degrees C was attributed to a thermodynamically preferred state in the nanoscopic arrangement of the polymer chains; this was due to cofacial pi-pi interactions in a skewed manner between peripheral phenyl groups of the (tetraphenyl)silole rings of the adjacent polymer chains. Using the NEXAFS spectrum to assess high electron affinity, the LUMO energy level of the dielectric thin film cured at 150 degrees C was positioned 1 eV above the Fermi energy level (E(F)). The electron trapping of the dielectric thin films was confirmed from the positive flat band shift (DeltaV(FB)) in the capacitance-voltage (C-V) measurements performed within the metal-insulator-semiconductor (MIS) device structure, which strongly verified the polymer design concept. From the simple kinetics model of the electron transport, it was proposed that the flat band shift (DeltaV(FB)) or trap density of the negative charges (|rho|) was logarithmically proportional to the decay constant (beta) for the electron-tunneling process. When a phenyl group of a silole ring in a polymer chain was inserted into the two available phenyl groups of another silole ring in another polymer chain, the electron transfer between the groups was enhanced, decreasing the trap density of the negative charges (|rho|). For the thermodynamically preferred state generating the high refractive index, the distance between the two phenyl groups of the adjacent polymer chains was estimated to be in the range of 0.27-0.36 nm. PMID- 21542606 TI - Linking of sensor molecules with amino groups to amino-functionalized AFM tips. AB - The measuring tip of an atomic force microscope (AFM) can be upgraded to a specific biosensor by attaching one or a few biomolecules to the apex of the tip. The biofunctionalized tip is then used to map cognate target molecules on a sample surface or to study biophysical parameters of interaction with the target molecules. The functionality of tip-bound sensor molecules is greatly enhanced if they are linked via a thin, flexible polymer chain. In a typical scheme of tip functionalization, reactive groups are first generated on the tip surface, a bifunctional cross-linker is then attached with one of its two reactive ends, and finally the probe molecule of interest is coupled to the free end of the cross linker. Unfortunately, the most popular functional group generated on the tip surface is the amino group, while at the same time, the only useful coupling functions of many biomolecules (such as antibodies) are also NH(2) groups. In the past, various tricks or detours were applied to minimize the undesired bivalent reaction of bifunctional linkers with adjacent NH(2) groups on the tip surface. In the present study, an uncompromising solution to this problem was found with the help of a new cross-linker ("acetal-PEG-NHS") which possesses one activated carboxyl group and one acetal-protected benzaldehyde function. The activated carboxyl ensures rapid unilateral attachment to the amino-functionalized tip, and only then is the terminal acetal group converted into the amino-reactive benzaldehyde function by mild treatment (1% citric acid, 1-10 min) which does not harm the AFM tip. As an exception, AFM tips with magnetic coating become demagnetized in 1% citric acid. This problem was solved by deprotecting the acetal group before coupling the PEG linker to the AFM tip. Bivalent binding of the corresponding linker ("aldehyde-PEG-NHS") to adjacent NH(2) groups on the tip was largely suppressed by high linker concentrations. In this way, magnetic AFM tips could be functionalized with an ethylene diamine derivative of ATP which showed specific interaction with mitochondrial uncoupling protein 1 (UCP1) that had been purified and reconstituted in a mica-supported planar lipid bilayer. PMID- 21542609 TI - Controlling assembly of paired gold clusters within apoferritin nanoreactor for in vivo kidney targeting and biomedical imaging. AB - Functional nanostructures with high biocompatibility and stability, low toxicity, and specificity of targeting to desired organs or cells are of great interest in nanobiology and medicine. However, the challenge is to integrate all of these desired features into a single nanobiostructure, which can be applied to biomedical applications and eventually in clinical settings. In this context, we designed a strategy to assemble two gold nanoclusters at the ferroxidase active sites of ferritin heavy chain. Our studies showed that the resulting nanostructures (Au-Ft) retain not only the intrinsic fluorescence properties of noble metal, but gain enhanced intensity, show a red-shift, and exhibit tunable emissions due to the coupling interaction between the paired Au clusters. Furthermore, Au-Ft possessed the well-defined nanostructure of native ferritin, showed organ-specific targeting ability, high biocompatibility, and low cytotoxicity. The current study demonstrates that an integrated multimodal assembly strategy is able to generate stable and effective biomolecule-noble metal complexes of controllable size and with desirable fluorescence emission characteristics. Such agents are ideal for targeted in vitro and in vivo imaging. These results thus open new opportunities for biomolecule-guided nanostructure assembly with great potential for biomedical applications. PMID- 21542611 TI - Background correction and multivariate curve resolution of online liquid chromatography with infrared spectrometric detection. AB - The use of multivariate curve resolution-alternating least-squares (MCR-ALS) in liquid chromatography-infrared detection (LC-IR) is troublesome due to the intense background absorption changes during gradient elution. Its use has been facilitated by previous removal of a significant part of the solvent background IR contributions due to common mobile phase systems employed during reversed phase gradient applications. Two straightforward background correction approaches based on simple-to-use interactive self-modeling mixture analysis (SIMPLISMA) and principal component analysis (PCA) are proposed and evaluated on reversed phase gradient LC-IR data sets obtained during the analysis of carbohydrate and nitrophenol mixtures. After subtraction of the calculated background signal, MCR ALS provided improved signal-to-noise ratios, removed remaining mobile phase and background signal contributions, and resolved overlapping chromatographic peaks. The present approach tends to enable easy-to-use background correction to facilitate the use of MCR-ALS in online LC-IR, even in challenging situations when gradient conditions are employed and only poor chromatographic resolution is achieved. It, therefore, shows great potential to facilitate the full exploitation of the advantages of simultaneous quantification and identification of a vast amount of analytes employing online IR detection, making new exciting applications more accessible. PMID- 21542610 TI - Biochemical characterization of the O-linked glycosylation pathway in Neisseria gonorrhoeae responsible for biosynthesis of protein glycans containing N,N' diacetylbacillosamine. AB - The O-linked protein glycosylation pathway in Neisseria gonorrhoeae is responsible for the synthesis of a complex oligosaccharide on undecaprenyl diphosphate and subsequent en bloc transfer of the glycan to serine residues of select periplasmic proteins. Protein glycosylation (pgl) genes have been annotated on the basis of bioinformatics and top-down mass spectrometry analysis of protein modifications in pgl-null strains [Aas, F. E., et al. (2007) Mol. Microbiol. 65, 607-624; Vik, A., et al. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 4447-4452], but relatively little biochemical analysis has been performed to date. In this report, we present the expression, purification, and functional characterization of seven Pgl enzymes. Specifically, the enzymes studied are responsible for synthesis of an uncommon uridine diphosphate (UDP)-sugar (PglD, PglC, and PglB-acetyltransferase domain), glycan assembly (PglB-phospho glycosyltransferase domain, PglA, PglE, and PglH), and final oligosaccharide transfer (PglO). UDP-2,4-diacetamido-2,4,6-trideoxy-alpha-d-hexose (DATDH), which is the first sugar in glycan biosynthesis, was produced enzymatically, and the stereochemistry was assigned as uridine diphosphate N'-diacetylbacillosamine (UDP diNAcBac) by nuclear magnetic resonance characterization. In addition, the substrate specificities of the phospho-glycosyltransferase, glycosyltransferases, and oligosaccharyltransferase (OTase) were analyzed in vitro, and in most cases, these enzymes exhibited strong preferences for the native substrates relative to closely related glycans. In particular, PglO, the O-linked OTase, and PglB(Cj), the N-linked OTase from Campylobacter jejuni, preferred the native N. gonorrhoeae and C. jejuni substrates, respectively. This study represents the first comprehensive biochemical characterization of this important O-linked glycosylation pathway and provides the basis for further investigations of these enzymes as antibacterial targets. PMID- 21542612 TI - High-sensitivity analysis of six synthetic musks by ultra-performance liquid chromatography-atmospheric pressure photoionization-tandem mass spectrometry. AB - The occurrence and potential toxicity of synthetic musks in environmental media have aroused concerns for the impacts of these chemicals on ecosystems and human health. Here, we present the first method using ultra-performance liquid chromatography-atmospheric pressure photoionization-tandem mass spectrometry (UPLC-APPI-MS/MS) for analysis of the six most important synthetic musks. Analysis was performed on an API 3000 triple quadrupole equipped with a PhotoSpray APPI source. Two pairs of precursor/product ions are presented that are essential for confirmation. Chromatographic separation is completed in 7 min in the positive mode and 5.1 min in the negative mode. Furthermore, three dopant solutions (0.5% anisole in toluene, 0.5% 2,4-difluoroanisole (DFA) in bromobenzene, and 0.5% DFA in chlorobenzene) are compared in terms of sensitivity, linearity, precision, and accuracy. The best sensitivity is associated with 0.5% anisole in toluene as the dopant; all LODs are below 6 pg. The linear range is 5 to 500 ppb with fairly good precision and accuracy. This analytical method has also proven its applicability by analyzing real air samples. In summary, we present a fast, sensitive, and reliable UPLC-APPI-MS/MS method for six important synthetic musks; it can be readily applied to environmental studies. PMID- 21542613 TI - Palladium-catalyzed oxidative cyclization of 3-phenoxyacrylates: an approach to construct substituted benzofurans from phenols. AB - In this paper, a novel and applicable synthesis of benzofurans from commercially available phenols and propiolate through the direct oxidative cyclization has been developed. In the presence of Pd(OAc)(2)/PPh(3) and CF(3)CO(2)Ag, (E)-type 3 phenoxyacrylates underwent reaction smoothly to generate the corresponding benzofurans in good yields in benzene at 110 degrees C under the air pressure. In addition, this transformation of phenols into benzofurans can also be carried out in one pot. The process was simple and efficient. A tentative mechanism of palladium-catalyzed oxidative cyclization of 3-phenoxyacrylates was proposed. PMID- 21542614 TI - Highly regioselective carbonylation of unactivated C(sp3)-H bonds by ruthenium carbonyl. AB - The regioselective carbonylation of unactivated C(sp(3))-H bonds of aliphatic amides was achieved using Ru(3)(CO)(12) as a catalyst. The presence of a 2 pyridinylmethylamine moiety in the amide is crucial for a successful reaction. The reaction shows a preference for C-H bonds of methyl groups as opposed to methylene C-H bonds and tolerates a variety of functional groups. The stoichiometric reaction of an amide with Ru(3)(CO)(12) gave a dinuclear ruthenium complex in which the 2-pyridinylmethylamino moiety was coordinated to the ruthenium center in an N,N manner. PMID- 21542615 TI - Solvent-induced crystallization of poly(3-dodecylthiophene): morphology and kinetics. AB - We report on the self-assembly of poly(3-dodecylthiophene) (P3DDT) into nanowhiskers for the first time via addition of the marginal solvent anisole into its well-dissolved solution. By controlling the solvent composition and aging time, we observed a morphology evolution from nanowhiskers to two-dimensional nanoribbons and foliated aggregates, which was ascribed to diverse driving forces for self-assembly in the process of crystallization. UV-vis absorption spectroscopy and dynamic lighting scattering (DLS) measurements were employed to in situ monitor crystallization kinetics of P3DDT induced by mixed solvents. It has been shown that conformational transition serves as a critical factor for P3AT to perform pi-pi stacking to form nanowhiskers. From a thermodynamic point of view, P3AT dispersion dissolved in mixed solvents is actually not a thermodynamic equilibrium system, but a multicomponent and multiphase case whose phase composition and properties evolve with time. The understanding in morphology transition mechanisms and crystallization kinetics of P3DDT can provide guidelines for optimization of processing parameters and enhance performance of photovoltaic devices. PMID- 21542618 TI - In situ measurement of reaction volume and calculation of pH of weak acid buffer solutions under high pressure. AB - Direct measurements of reaction volume, so far, have been limited to atmospheric pressure. This study describes a method for in situ reaction volume measurements under pressure using a variable volume piezometer. Reaction volumes for protonic ionization of weak acid buffering agents (MES, citric acid, sulfanilic acid, and phosphoric acid) were measured in situ under pressure up to 400 MPa at 25 degrees C. The methodology involved initial separation of buffering agents within the piezometer using gelatin capsules. Under pressure, the volume of the reactants was measured at 25 degrees C, and the contents were heated to 40 degrees C to dissolve the gelatin and allow the reaction to occur, and cooled to 25 degrees C, where the volume of products was measured. Reaction volumes were used to calculate pH of the buffer solutions as a function of pressure. The results show that the measured reaction volumes as well as the calculated pH values generally quite agree with their respective theoretically predicted values up to 100 MPa. The results of this study highlight the need for a comprehensive theory to describe the pressure behavior of ionization reactions in realistic systems especially at higher pressures. PMID- 21542616 TI - Encapsulation of carbon chain molecules in single-walled carbon nanotubes. AB - The vacuum space inside carbon nanotubes offers interesting possibilities for the inclusion, transportation, and functionalization of foreign molecules. Using first-principles density functional calculations, we show that linear carbon based chain molecules, namely, polyynes (C(m)H(2), m = 4, 6, 10) and the dehydrogenated forms C(10)H and C(10), as well as hexane (C(6)H(14)), can be spontaneously encapsulated in open-ended single-walled carbon nanotubes (SWNTs) with edges that have dangling bonds or that are terminated with hydrogen atoms, as if they were drawn into a vacuum cleaner. The energy gains when C(10)H(2), C(10)H, C(10), C(6)H(2), C(4)H(2), and C(6)H(14) are encapsulated inside a (10,0) zigzag-shaped SWNT are 1.48, 2.04, 2.18, 1.05, 0.55, and 1.48 eV, respectively. When these molecules come inside a much wider (10,10) armchair SWNT along the tube axis, they experience neither an energy gain nor an energy barrier. They experience an energy gain when they approach the tube walls inside. Three hexane molecules can be encapsulated parallel to each other (i.e., nested) inside a (10,10) SWNT, and their energy gain is 1.98 eV. Three hexane molecules can exhibit a rotary motion. One reason for the stability of carbon chain molecules inside SWNTs is the large area of weak wave function overlap. Another reason concerns molecular dependence, that is, the quadrupole-quadrupole interaction in the case of the polyynes and electron charge transfer from the SWNT in the case of the dehydrogenated forms. The very flat potential surface inside an SWNT suggests that friction is quite low, and the space inside SWNTs serves as an ideal environment for the molecular transport of carbon chain molecules. The present theoretical results are certainly consistent with recent experimental results. Moreover, the encapsulation of C(10) makes an SWNT a (purely carbon made) p-type acceptor. Another interesting possibility associated with the present system is the direction-controlled transport of C(10)H inside an SWNT under an external field. Because C(10)H has an electric dipole moment, it is expected to move under a gradient electric field. Finally, we derive the entropies of linear chain molecules inside and outside an open-ended SWNT to discuss the stability of including linear chain molecules inside an SWNT at finite temperatures. PMID- 21542619 TI - On the role of nonbonded interactions in vibrational energy relaxation of cyanide in water. AB - The vibrationally excited cyanide ion (CN(-)) in H2O or D2O relaxes back to the ground state within several tens of picoseconds. Pump-probe infrared spectroscopy has determined relaxation times of T1 = 28 +/- 7 and 71 +/- 3 ps in H2O and D2O, respectively. Atomistic simulations of this process using nonequilibrium molecular dynamics simulations allow determination of whether it is possible at all to describe such a process, what level of accuracy in the force fields is required, and whether the information can be used to understand the molecular mechanisms underlying vibrational relaxation. It is found that, by using the best electrostatic models investigated, absolute relaxation times can be described rather more qualitatively (T1(H2O) = 19 ps and T1(D2O) = 34 ps) whereas the relative change in going from water to deuterated water is more quantitatively captured (factor of 2 vs 2.5 from experiment). However, moderate adjustment of the van der Waals ranges by less than 20% (for NVT) and 7.5% (for NVE), respectively, leads to almost quantitative agreement with experiment. Analysis of the energy redistribution establishes that the major pathway for CN(-) relaxation in H2O or D2O proceeds through coupling to the water-bending plus libration mode. PMID- 21542623 TI - Atmospheric deposition of halogenated flame retardants at urban, e-waste, and rural locations in southern China. AB - Measurements of atmospheric deposition fluxes and temporal variation of halogenated flame retardants (HFRs) from 2007 to 2008 at urban, electronic waste (e-waste), and rural sites in southern China are presented. The deposition fluxes of total HFRs at the urban (99.3-1327 ng m(-2) day(-1)) and e-waste (79.1-1200 ng m(-2) day(-1)) sites were much higher than at the rural site (9.27-79.5 ng m(-2) day(-1)), demonstrating that e-waste recycling and industrial activities in southern China are two important sources of HFRs in the environment. The urban deposition profile was dominated by current-use HFRs (decabrominated diphenyl ether and decabromodiphenyl ethane), whereas the profile at the e-waste site reflects the past when significant amounts of PBDEs and Dechlorane Plus were used. Source apportionment estimated by principal component analyses with multiple linear regression analysis showed that deposition HFRs at the rural site were primarily contributed by the urban and e-waste sources (45% and 38%, respectively) compared to the contribution from local emission (17%). Our results suggest that the HFRs that are readily present in gas or sorbed onto fine particle phases have enhanced potential for long-range atmospheric transport. PMID- 21542624 TI - Effects of income and urban form on urban NO2: global evidence from satellites. AB - Urban air pollution is among the top 15 causes of death and disease worldwide, and a problem of growing importance with a majority of the global population living in cities. A important question for sustainable development is to what extent urban design can improve or degrade the environment and public health. We investigate relationships between satellite-derived estimates of nitrogen dioxide concentration (NO(2), a key component of urban air pollution) and urban form for 83 cities globally. We find a parsimonious yet powerful relationship (model R(2) = 0.63), using as predictors population, income, urban contiguity, and meteorology. Cities with highly contiguous built-up areas have, on average, lower urban NO(2) concentrations (a one standard deviation increase in contiguity is associated with a 24% decrease in average NO(2) concentration). More-populous cities tend to have worse air quality, but the increase in NO(2) associated with a population increase of 10% may be offset by a moderate increase (4%) in urban contiguity. Urban circularity ("compactness") is not a statistically significant predictor of NO(2) concentration. Although many factors contribute to urban air pollution, our findings suggest that antileapfrogging policies may improve air quality. We find that urban NO(2) levels vary nonlinearly with income (Gross Domestic Product), following an "environmental Kuznets curve"; we estimate that if high-income countries followed urban pollution-per-income trends observed for low-income countries, NO(2) concentrations in high-income cities would be ~10* larger than observed levels. PMID- 21542620 TI - Emissive iridium(III) diimine complexes formed by double cyclometalation of coordinated triphenylphosphite. AB - We report on the synthesis of a new series of iridium(III) complexes functionalized with various diimine chromophores, together with a facially coordinated dicyclometalated phosphite chelate and a monodentate anionic ancillary. This conceptual design presents a novel strategy in obtaining a new class of iridium(III) diimine complexes without employment of traditional nitrogen-containing polyaromatic cyclometalates. Additionally, we discuss the basic charactersistics of the ground and lower-lying excited states involved, as documented by crystal structural, photophysical studies, and density functional theory calculations. Fabrication of the green-emitting organic light-emitting diodes with one such dopant, [Ir(dbbpy)(tpit)NCS] (2b), where dbbpy and tpit represent di-tert-butyl-2,2'-bipyridine and dicyclometalated triphenylphosphite, respectively, was successfully made, attaining a peak external quantum efficiency (eta(ext)), a luminance efficiency (eta(l)), and a power efficiency (eta(p)) of 14.1%, 46.6 cd A(-1), and 39.9 lm W(-1), respectively. PMID- 21542621 TI - Contribution of active site residues to substrate hydrolysis by USP2: insights into catalysis by ubiquitin specific proteases. AB - The ubiquitin-specific protease (USP) structural class represents the largest and most diverse family of deubiquitinating enzymes (DUBs). Many USPs assume important biological roles and emerge as potential targets for therapeutic intervention. A clear understanding of USP catalytic mechanism requires a functional evaluation of the proposed key active site residues. Crystallographic data of ubiquitin aldehyde adducts of USP catalytic cores provided structural details on the catalytic triad residues, namely the conserved Cys and His, and a variable putative third residue, and inferred indirect structural roles for two other conserved residues (Asn and Asp), in stabilizing via a bridging water molecule the oxyanion of the tetrahedral intermediate (TI). We have expressed the catalytic domain of USP2 and probed by site-directed mutagenesis the role of these active site residues in the hydrolysis of peptide and isopeptide substrates, including a synthetic K48-linked diubiquitin substrate for which a label-free, mass spectrometry based assay has been developed to monitor cleavage. Hydrolysis of ubiquitin-AMC, a model substrate, was not affected by the mutations. Molecular dynamics simulations of USP2, free and complexed with the TI of a bona fide isopeptide substrate, were carried out. We found that Asn271 is structurally poised to directly stabilize the oxyanion developed in the acylation step, while being structurally supported by the adjacent absolutely conserved Asp575. Mutagenesis data functionally confirmed this structural role independent of the nature (isopeptide vs peptide) of the bond being cleaved. We also found that Asn574, structurally located as the third member of the catalytic triad, does not fulfill this role functionally. A dual supporting role is inferred from double-point mutation and structural data for the absolutely conserved residue Asp575, in oxyanion hole formation, and in maintaining the correct alignment and protonation of His557 for catalytic competency. PMID- 21542617 TI - Switchable supramolecular polymers from the self-assembly of a small monomer with two orthogonal binding interactions. AB - The low molecular weight heteroditopic monomer 1 forms supramolecular polymers in polar solution as shown, for example, by infrared laser-based dynamic light scattering (DLS), small-angle neutron scattering (SANS), electron microscopy (TEM, cryo-TEM), and viscosity measurements. Self-assembly of 1 is based on two orthogonal binding interactions, the formation of a Fe(II)-terpyridine 1:2 metal ligand complex and the dimerization of a self-complementary guanidiniocarbonyl pyrrole carboxylate zwitterion. Both binding interactions have a sufficient stability in polar (DMSO) and even aqueous solutions to ensure formation of linear polymers of considerable length (up to 100 nm). The supramolecular polymerization follows a ring-chain mechanism causing a significant increase in the viscosity of the solutions at millimolar concentrations and above. The linear polymers then further aggregate in solution into larger globular aggregates with a densely packed core and a loose shell. Both binding interactions can be furthermore switched on and off either by adding a competing ligand to remove the metal ion and subsequent readdition of Fe(II) or by reversible protonation and deprotonation of the zwitterion upon addition of acid or base. The self-assembly of 1 can therefore be switched back and forth between four different states, the monomer, a metal-complexed dimer or an ion paired dimer, and finally the polymer. PMID- 21542626 TI - Microbially mediated abiotic transformation of the antimicrobial agent sulfamethoxazole under iron-reducing soil conditions. AB - Large quantities of antimicrobial agents used in livestock production are released to soils by land application of manure, but only limited information is available on mechanisms that contribute to antimicrobial fate in soils under variable biogeochemical conditions. Dissipation of the sulfonamide antimicrobial sulfamethoxazole was examined in soil microcosms incubated under different terminal electron-accepting conditions (aerobic, nitrate-reducing, Fe(III) reducing, and sulfate-reducing). Somewhat unexpectedly, sulfamethoxazole dissipation was fastest under Fe(III)-reducing conditions, with concentrations decreasing by >95% within 1 day. The rapid transformation was attributed to abiotic reactions between sulfamethoxazole and Fe(II) generated by microbial reduction of Fe(III) soil minerals. Separate experiments demonstrated that sulfamethoxazole was abiotically transformed in Fe(II)-amended aqueous suspensions of goethite (alpha-FeOOH((s))), and observed rate constants varied with the extent of Fe(II) sorption to goethite. Sulfamethoxazole transformation is initiated by a 1-electron reductive cleavage of the N-O bond in the isoxazole ring substituent, and observed products are consistent with Fe(II)-mediated reduction and isomerization processes. These findings reveal potentially important, but previously unrecognized, pathways that may contribute to the fate of sulfamethoxazole and related chemicals in reducing soil environments. PMID- 21542625 TI - Stereolability of dihydroartemisinin, an antimalarial drug: a comprehensive kinetic investigation. Part 2. AB - Artemisinin or qinghaosu has now largely given way to the more potent dihydroartemisinin (DHA, 1) and its derivatives in the treatment of drug resistant malaria, in combination with other classical antimalarial drugs. DHA is obtained by NaBH(4) reduction of artemisinin and contains a stereochemically labile center at C-10, which provided two lactol hemiacetal interconverting epimers, namely 1alpha and 1beta. In the solid state, the drug consists exclusively of the beta-epimer; however, upon dissolution, the two epimers equilibrate, reaching different solvent-dependent ratios with different rates. Such equilibration also occurs in vivo, irrespective of the isomeric purity at which the drug would have been administered. The aim of this study was then to achieve an in-depth understanding of the kinetic features of the alpha/beta equilibration. To this purpose, free energy activation barriers (DeltaG(?)) of the interconversion were determined as a function of both general and specific acid and base catalysts, ionic strength, and temperature in different solvents by dynamic HPLC (DHPLC). In hydro-organic media, the dependence of DeltaG(?) on temperature led to the evaluation of the related enthalpic and entropic contributions. Theoretical calculations suggested that the rate-determining step of the interconversion is not the ring-opening of the cyclic hemiacetal but the previous reversible deprotonation of the individual epimers (base-catalyzed mechanism). The whole findings may contribute to shed some light on the mechanism of action and/or bioavailability of the drug at the molecular level. PMID- 21542622 TI - Enantioselective dichlorination of allylic alcohols. AB - The development of an enantioselective allylic alcohol dichlorination catalyzed by dimeric cinchona alkaloid derivatives and employing aryl iododichlorides as chlorine sources is reported. Reaction optimization, exploration of the substrate scope, and a model for stereoinduction are presented. PMID- 21542627 TI - Understanding and harnessing the health effects of rapid urbanization in China. AB - China is undergoing a rapid transition from a rural to an urban society. This societal change is a consequence of a national drive toward economic prosperity. Rapid urbanization impacts on infrastructure, environmental health and human wellbeing. Unlike many cases of urban expansion, Chinese urbanization has led to containment, rather than to increase, in the spread of infectious diseases. Conversely, the incidence of chronic conditions such as cardiovascular and metabolic diseases has risen, with higher rates occurring in urban regions. This rural-urban gradient in disease incidence seems not to be a reflection simply of more aggressive diagnosis or healthcare access. Other diseases exhibit little rural versus urban differences (e.g., liver cancer or respiratory disease), or even occur at a higher rate in the rural population (e.g., esophageal cancer). This article examines the impact of this changing demographic on environmental health and human wellbeing in China. Lessons learned from epidemiological studies mostly carried out in Europe and the U.S. may not be directly transferable to China. We advocate that there is now a need to establish robust systems of accurate data collection, a Chinese biobank network to facilitate the profiling of human health effects, and relevant randomized controlled trials to identify effective interventions in the Chinese urbanized setting. Such studies could allow for the future implementation of disease-preventive strategies. PMID- 21542628 TI - Oxidatively induced concurrent cationic and radical polymerization of isobutylene in the presence of LiCB11Me12. AB - A solution of a mechanistic puzzle is reported: upon initiation with air at 25 degrees C or with di-tert-butyl peroxide at 80 degrees C, isobutylene (IB) polymerizes at 1 atm in weakly coordinating solvents containing 10 wt % LiCB(11)(CH(3))(12) to a mixture of highly branched (b-PIB) and linear (l-PIB) polyisobutylene. The former polymer is separable by solvent extraction and is identical with the b-PIB that is produced from IB as a sole product under similar conditions under nonoxidizing radical initiation with azo-tert-butane. The latter polymer differs from standard l-PIB in that it carries a carborane anion attached at the chain end. The molecular weight of b-PIB ranges up to 26,000, and that of l-PIB, up to 50,000. Evidence is presented that the concurrent polymerization of IB to b-PIB and l-PIB is launched by an initial oxidation of the CB(11)(CH(3))(12)(-) anion to a neutral radical CB(11)(CH(3))(12)(*). This radical is proposed to subsequently transfer a methyl radical to IB, thus launching the formation of b-PIB by the radical mechanism while leaving behind the borenium ylide CB(11)(CH(3))(11), which is a strong Lewis acid and induces simultaneously the formation of l-PIB by the cationic mechanism. PMID- 21542629 TI - Fluorescence microscopy of the pressure-dependent structure of lipid bilayers suspended across conical nanopores. AB - Glass and fused-quartz nanopore membranes containing a single conically shaped pore are promising solid supports for lipid bilayer ion-channel recordings due to the high inherent stability of lipid bilayers suspended across the nanopore orifice, as well as the favorable electrical properties of glass and fused quartz. Fluorescence microscopy is used here to investigate the structure of the suspended lipid bilayer as a function of the pressure applied across a fused quartz nanopore membrane. When a positive pressure is applied across the bilayer, from the nanopore interior relative to the exterior bulk solution, insertion or reconstitution of operative ion channels (e.g., alpha-hemolysin (alpha-HL) and gramicidin) in the bilayer is observed; conversely, reversing the direction of the applied pressure results in loss of all channel activity, although the bilayer remains intact. The dependence of the bilayer structure on pressure was explored by imaging the fluorescence intensity from Nile red dye doped into suspended 1,2-diphytanoyl-sn-glycero-3-phosphocholine bilayers, while simultaneously recording the activity of an alpha-HL channel. The fluorescence images suggest that a positive pressure results in compression of the bilayer leaflets and an increase in the bilayer curvature, making it suitable for ion channel formation and activity. At negative pressure, the fluorescence images are consistent with separation of the lipid leaflets, resulting in the observed loss of the ion-channel activity. The fluorescence data indicate that the changes in the pressure-induced bilayer structure are reversible, consistent with the ability to repeatedly switch the ion-channel activity on and off by applying positive and negative pressures, respectively. PMID- 21542630 TI - Discovery of dual target inhibitors against cyclooxygenases and leukotriene A4 hydrolyase. AB - Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activities using enzyme assays and human whole blood assay. Introduction of small electron withdrawing groups like NO(2) and CF(3) in the ortho-position of the terminal phenyl ring was found to change the original single target LTA(4)H inhibitor to dual target LTA(4)H and COX-2 inhibitors. Compound 5a and 5m showed dual LTA(4)H and COX-2 inhibition activities in the enzyme assays and the HWB assay with IC(50) values in the micromolar to submicromolar range. As their activities in HWB assay were comparable to the two starting single target inhibitors, the two compounds are promising for further studies. The strategy used in the current study may be generally applicable to other dual target drug designs. PMID- 21542631 TI - Chemistry of Ni2+ in urease: sensing, trafficking, and catalysis. AB - Transition metals are both essential to enzymatic catalysis and limited in environmental availability. These two biological facts have together driven organisms to evolve mechanisms for selective metal ion sensing and utilization. Changes in metal ion concentrations are perceived by metal-dependent transcription factors and transduced into appropriate cellular responses, which regulate the machineries of competitive metal ion homeostasis and metallo-enzyme activation. The intrinsic toxicity of the majority of metal ions further creates a need for regulated intracellular trafficking, which is carried out by specific chaperones. The Ni(2+)-dependent urease enzymatic system serves as a paradigm for studying the strategies that cells use to handle an essential, yet toxic, metal ion. Although the discovery of urease as the first biological system for which nickel is essential for activity dates to 1975, the rationale for Ni(2+) selection, as well as the cascade of events involving metal-dependent gene regulation and protein-protein interactions leading to enzyme activation, have yet to be fully unraveled. The past 14 years since the Account by Hausinger and co-workers (Karplus, P. A.; Pearson, M. A.; Hausinger, R. P. Acc. Chem. Res. 1997, 30, 330-337) have witnessed impressive achievements in the understanding of the biological chemistry of Ni(2+) in the urease system. In our Account, we discuss more recent advances in the comprehension of the specific role of Ni(2+) in the catalysis and the interplay between Ni(2+) and other metal ions, such as Zn(2+) and Fe(2+), in the metal-dependent enzyme activity. Our discussion focuses on work carried out in our laboratory. In particular, the structural features of the enzyme bound to inhibitors, substrate analogues, and transition state or intermediate analogues have shed light on the catalytic mechanism. Structural and functional information has been correlated to understand the Ni(2+) sensing effected by NikR, a nickel-dependent transcription factor. The urease activation process, involving insertion of Ni(2+) into the urease active site, has been in part dissected and analyzed through the investigation of the molecular properties of the accessory proteins UreD, UreF, and UreG. The intracellular trafficking of Ni(2+) has been rationalized through a deeper understanding of the structural and metal-binding properties of the metallo-chaperone UreE. All the while, a number of key general concepts have been revealed and developed. These include an understanding of (i) the overall ancillary role of Zn(2+) in nickel metabolism, (ii) the intrinsically disordered nature of the GTPase responsible for coupling the energy consumption to the carbon dioxide requirement for the urease activation process, and (iii) the role of the accessory proteins regulating this GTPase activity. PMID- 21542632 TI - All-plasmonic modulation via stimulated emission of copropagating surface plasmon polaritons on a substrate with gain. AB - We experimentally demonstrate suppressed absorption and stimulated emission of surface plasmon polaritons (SPP) leading to all-plasmonic modulation of an SPP signal propagating at the interface between a metal and a gain medium; these observations are supported by the developed theory. The use of copropagating signal and control waves can provide more than 10 times more efficient SPP stimulated emission compared to out-of-plane pumping and opens up the possibility to realize integratable plasmonic components for active nanophotonic circuitry. PMID- 21542634 TI - Dielectric spectroscopy of proteins as a quantitative experimental test of computational models of their low-frequency harmonic motions. AB - Decades of molecular dynamics and normal mode calculations suggest that the largest-scale collective vibrational modes of proteins span the picosecond to nanosecond time scale. Experimental investigation of these harmonic, low amplitude motions, however, has proven challenging. In response, we have developed a vector network analyzer-based spectrometer that supports the accurate measurement of both the absorbance and refractive index of solvated biomolecules over the corresponding gigahertz to terahertz frequency regime, thus providing experimental information regarding their largest-scale, lowest frequency harmonic motions. We have used this spectrometer to measure the complex dielectric response of lysozyme solutions over the range 65 to 700 GHz and an effective medium model to separate the dielectric response of the solvated protein from that of its buffer. In doing so, we find that each lysozyme is surrounded by a tightly bound layer of 165 +/- 15 water molecules that, in terms of their picosecond dynamics, behave as if they are an integral part of the protein. We also find that existing computational descriptions of the protein's dynamics compare poorly with the results of our experiment. Specifically, published normal mode and molecular dynamics simulations do not explain the measured dielectric response unless we introduce a cutoff frequency of 250 GHz below which the density of vibrational modes drops to zero. This cutoff is physically plausible, given the known size of the protein and the known speed of sound in proteins, raising questions as to why it is not apparent in computational models of the protein's motions. PMID- 21542633 TI - Near-infrared light-responsive core-shell nanogels for targeted drug delivery. AB - A near-infrared light-responsive drug delivery platform based on Au-Ag nanorods (Au-Ag NRs) coated with DNA cross-linked polymeric shells was constructed. DNA complementarity has been applied to develop a polyacrylamide-based sol-gel transition system to encapsulate anticancer drugs into the gel scaffold. The Au Ag NR-based nanogels can also be readily functionalized with targeting moieties, such as aptamers, for specific recognition of tumor cells. When exposed to NIR irradiation, the photothermal effect of the Au-Ag NRs leads to a rapid rise in the temperature of the surrounding gel, resulting in the fast release of the encapsulated payload with high controllability. In vitro study confirmed that aptamer-functionalized nanogels can be used as drug carriers for targeted drug delivery with remote control capability by NIR light with high spatial/temporal resolution. PMID- 21542635 TI - Total synthesis of optically active lycopladine A by utilizing diastereoselective protection of carbonyl group in a 1,3-cyclohexanedione derivative. AB - We successfully synthesized two enantiomers of bicyclic enones, (7R,7aR)- and (7S,7aS)-9, from the hemiacetal 2a, which we first synthesized from the symmetrical diketone 1a via diastereoselective carbon-oxygen bond formation between one of the carbonyl groups and the chiral alcohol on the C2 side chain in a 2,2-disubstituted 1,3-cycloalkanedione derivative. We also report the total synthesis of natural (+)-lycopladine A [(+)-6] from (7R,7aR)-9 and the formal synthesis of unnatural (-)-lycopladine A [(-)-6] from (7S,7aS)-9. PMID- 21542636 TI - Plasmons in strongly coupled metallic nanostructures. PMID- 21542637 TI - Quantitatively interpreted enhanced inhibition of cytochrome P450s by heteroaromatic rings containing nitrogen. AB - It has been known for a long time that certain substructures bind to the heme iron in cytochromes P450. Detection of spectroscopic changes and crystal structures of protein ligand complexes have provided qualitative evidence, including for aromatic nitrogen-containing ligands. Compounds containing these same substructures are more likely to inhibit cytochrome P450s than expected due to lipophilicity. These two sets of observations are not easily linked by experiment, because binding to the iron atom alone is not readily measured. Quantum mechanical (density functional) calculations of binding energies for a number of different aromatic heterocycles to heme iron in a range of oxidation and spin states can provide a quantitative link between the observed structures and the biochemical inhibition that is measured. The studies reported here for a set of heteroaromatic rings containing nitrogen begin with quantum mechanical calculations which provide geometries and binding energies. Subsequently, AstraZeneca's database of cytochrome P450 inhibition assays has been searched to find data that are relevant to the same set of heteroaromatic compounds. These data have been analyzed in a number of fashions to account for both the narrow dynamic range of the assays and the lipophilicity dependence of this kind of inhibition. Finally, crystal structures have provided experimental geometric information. Taken together these different sources suggest that binding to the metal in our inhibition assays is dominated by Fe(III) in its doublet state, most likely occurring when the iron is pentavalent. Computed binding energies to this state contrast with the hydrogen-bond acceptor ability and basicity of the compounds, neither of which are able to correctly account for the effect of the particular environment in which the iron is found. This highlights the value of modeling biochemical events as closely as can be computationally afforded. The computational protocol devised was used to make predictions about a set of as yet unknown heteroaromatic compounds suggested by Pitt et al. PMID- 21542638 TI - Adsorption behavior of 4-methoxypyridine on gold nanoparticles. AB - We demonstrate a phase transfer method to create stable colloidal solutions of Au nanoparticles with 4-methoxypyridine ligands. We then investigate the adsorption behavior of 4-methoxypyridine onto gold surfaces by Raman spectroscopy, DFT calculations, and (1)H NMR. In contrast to unsubstituted pyridine and the frequently used (N,N-dimethylamino)pyridine (DMAP), a flat adsorption of 4 methoxypyridine on gold was found. PMID- 21542639 TI - Controlled electrochemically-assisted deposition of sol-gel biocomposite on electrospun platinum nanofibers. AB - The modification of platinum nanofibers by silica using the electrochemically assisted deposition is reported here. Pt nanofibers are obtained by electrospinning and deposited on a glass substrate. The electrochemically assisted deposition of the sol-gel material then gives the unique possibility to finely tune the silica film thickness around these nanofibers. It also allows the successful encapsulation of a biomolecule (glucose oxidase was chosen here as a model) while retaining its biological activity, as pointed out via the electrochemical monitoring of H(2)O(2) produced upon addition of glucose in the medium. This silica-glucose oxidase composite offers the possibility of comparing systematically the influence of the deposition time on the bioelectrode response and to compare it with the particular features of the deposits. It was found that the film first grew uniformly around the nanofibers and then started to deposit between them, covering the whole sample (fibers and glass substrate), and tended to fully embed the nanofibers for prolonged deposition. The thickness of the silica film is critical for the electroactivity of the biocomposite, the best response being obtained for a silica layer thickness in the range of the fiber diameter (~50 nm). PMID- 21542640 TI - Proline 68 enhances photoisomerization yield in photoactive yellow protein. AB - In proteins and enzymes, the local environment of an active cofactor plays an important role in controlling the outcome of a functional reaction. In photoactive yellow protein (PYP), it ensures photoisomerization of the chromophore, a prerequisite for formation of a signaling state. PYP is the prototype of a PAS domain, and the preferred model system for the studies of molecular mechanisms of biological light sensing. We investigated the effect of replacing proline-68, positioned near but not in direct contact with the chromophore, with other neutral amino acids (alanine, glycine, and valine), using ultrafast spectroscopy probing the visible and the mid-IR spectral regions, and molecular simulation to understand the interactions tuning the efficiency of light signaling. Transient absorption measurements indicate that the quantum yield of isomerization in the mutants is lower than the yield observed for the wild type. Subpicosecond mid-IR spectra and molecular dynamics simulations of the four proteins reveal that the hydrogen bond interactions around the chromophore and the access of water molecules in the active site of the protein determine the efficiency of photoisomerization. The mutants provide additional hydrogen bonds to the chromophore, directly and by allowing more water molecules access to its binding pocket. We conclude that proline-68 in the wild type protein optimizes the yield of photochemistry by maintaining a weak hydrogen bond with the chromophore, at the same time restraining the entrance of water molecules close to the alkylic part of pCa. This study provides a molecular basis for the structural optimization of biological light sensing. PMID- 21542641 TI - Molecular modeling of organophosphorous agents and their aqueous solutions. AB - Using molecular dynamics simulations, we modeled solvation and diffusion in aqueous solutions of organophosphorous compounds, including nerve G-agents sarin and soman (methylphosphonofluoridates) and their common simulants DMMP (dimethyl methylphosphonate) and DIFP (diisopropyl fluorophosphate). The aqueous solutions of the organophosphorous compounds were found to display complex molecular scale structures and dynamic properties due to competing interactions between strongly hydrophobic and hydrophilic groups. The mixing of agents with water was proved to be exothermic with negative excess mixing volume, indicating a strongly hydrophilic solvation. This effect was confirmed in a specially performed experiment. We discuss to what extent DMMP and DIFP are suitable simulants for G agents in experimental studies, as far as their interactions with water are concerned. We also focus on the relevance of the structural features and mobilities of agents in water to their interactions with permselective polyelectrolyte membranes that may be employed as protective barriers against chemical warfare agents. PMID- 21542642 TI - Controlling the lithiation-induced strain and charging rate in nanowire electrodes by coating. AB - The advanced battery system is critically important for a wide range of applications, from portable electronics to electric vehicles. Lithium ion batteries (LIBs) are presently the best performing ones, but they cannot meet requirements for more demanding applications due to limitations in capacity, charging rate, and cyclability. One leading cause of those limitations is the lithiation-induced strain (LIS) in electrodes that can result in high stress, fracture, and capacity loss. Here we report that, by utilizing the coating strategy, both the charging rate and LIS of SnO(2) nanowire electrodes can be altered dramatically. The SnO(2) nanowires coated with carbon, aluminum, or copper can be charged about 10 times faster than the noncoated ones. Intriguingly, the radial expansion of the coated nanowires was completely suppressed, resulting in enormously reduced tensile stress at the reaction front, as evidenced by the lack of formation of dislocations. These improvements are attributed to the effective electronic conduction and mechanical confinement of the coatings. Our work demonstrates that nanoengineering the coating enables the simultaneous control of electrical and mechanical behaviors of electrodes, pointing to a promising route for building better LIBs. PMID- 21542643 TI - Photoswitchable intramolecular through-space magnetic interaction. AB - The interaction between two TEMPO spin centers connected to a photoswitchable overcrowded alkene changes from noncoupled (three-line EPR spectrum) in the trans state, where the two spin centers are separated by ~22 A, to strongly coupled (five-line EPR spectrum) in the cis state, where the separation is ~7 A, upon photoswitching. Importantly, the performance of the alkene switching unit is essentially unaffected by the spin centers. PMID- 21542644 TI - Side chain effect on the double helix formation of ethynylhelicene oligomers. AB - Three series of ethynylhelicene oligomers with different side chains were synthesized: (P)-bD-n (n = 2-6) with branched alkyloxycarbonyl side chains; (P)-S n (n = 2-7) with decylsulfanyl side chains; and (P)-DF-n (n = 4, 6, 8, 10) with alternating decyloxycarbonyl and perfluorooctyl side chains. The double helix formation of these side chain derivatives was compared to that of (P)-D-n with decyloxycarbonyl side chains. CD, UV-vis, and vapor pressure osmometry (VPO) studies showed that (P)-bD-n formed double helices as well as (P)-D-n. CD studies in trifluoromethylbenzene at different temperatures and concentrations indicated that the stability of the aggregate of (P)-bD-6 was similar to that of (P)-D-6. Bulkiness of side chains had little effect on aggregation, which indicated that pi-pi interactions of the aromatic moiety were essential for double helix formation. (P)-S-n were random coils in all solvents examined except in trifluoromethylbenzene. Whereas (P)-D-7 formed a double helix at 1 * 10(-3) M in toluene, (P)-S-7 was a random coil. This result indicated that the double helix forming ability of (P)-S-n was substantially lower than that of (P)-D-n. Based on the previous observation that (P)-F-n formed a more stable double helix than (P) D-n, the order of stability may be summarized as follows: (P)-F-n > (P)-D-n and (P)-bD-n >(P)-S-n. The lower stability of (P)-S-n compared to that of (P)-F-n was ascribed to the softness and/or the electron-rich nature at the m-phenylene moiety. (P)-DF-n did not form a stable double helix. It was speculated that a regular alternating arrangement of soft/hard or electron-rich/deficient moieties is important for stable double helix formation. Side chains of ethynylhelicene oligomers can play significant roles in determining the stability of double helices. PMID- 21542646 TI - Triplet exciton generation in bulk-heterojunction solar cells based on endohedral fullerenes. AB - Organic bulk-heterojunctions (BHJ) and solar cells containing the trimetallic nitride endohedral fullerene 1-[3-(2-ethyl)hexoxy carbonyl]propyl-1-phenyl Lu(3)N@C(80) (Lu(3)N@C(80)-PCBEH) show an open circuit voltage (V(OC)) 0.3 V higher than similar devices with [6,6]-phenyl-C[61]-butyric acid methyl ester (PC(61)BM). To fully exploit the potential of this acceptor molecule with respect to the power conversion efficiency (PCE) of solar cells, the short circuit current (J(SC)) should be improved to become competitive with the state of the art solar cells. Here, we address factors influencing the J(SC) in blends containing the high voltage absorber Lu(3)N@C(80)-PCBEH in view of both photogeneration but also transport and extraction of charge carriers. We apply optical, charge carrier extraction, morphology, and spin-sensitive techniques. In blends containing Lu(3)N@C(80)-PCBEH, we found 2 times weaker photoluminescence quenching, remainders of interchain excitons, and, most remarkably, triplet excitons formed on the polymer chain, which were absent in the reference P3HT:PC(61)BM blends. We show that electron back transfer to the triplet state along with the lower exciton dissociation yield due to intramolecular charge transfer in Lu(3)N@C(80)-PCBEH are responsible for the reduced photocurrent. PMID- 21542645 TI - Structure and mutational analysis of the archaeal GTP:AdoCbi-P guanylyltransferase (CobY) from Methanocaldococcus jannaschii: insights into GTP binding and dimerization. AB - In archaea and bacteria, the late steps in adenosylcobalamin (AdoCbl) biosynthesis are collectively known as the nucleotide loop assembly (NLA) pathway. In the archaeal and bacterial NLA pathways, two different guanylyltransferases catalyze the activation of the corrinoid. Structural and functional studies of the bifunctional bacterial guanylyltransferase that catalyze both ATP-dependent corrinoid phosphorylation and GTP-dependent guanylylation are available, but similar studies of the monofunctional archaeal enzyme that catalyzes only GTP-dependent guanylylation are not. Herein, the three dimensional crystal structure of the guanylyltransferase (CobY) enzyme from the archaeon Methanocaldococcus jannaschii (MjCobY) in complex with GTP is reported. The model identifies the location of the active site. An extensive mutational analysis was performed, and the functionality of the variant proteins was assessed in vivo and in vitro. Substitutions of residues Gly8, Gly153, or Asn177 resulted in >=94% loss of catalytic activity; thus, variant proteins failed to support AdoCbl synthesis in vivo. Results from isothermal titration calorimetry experiments showed that MjCobY(G153D) had 10-fold higher affinity for GTP than MjCobY(WT) but failed to bind the corrinoid substrate. Results from Western blot analyses suggested that the above-mentioned substitutions render the protein unstable and prone to degradation; possible explanations for the observed instability of the variants are discussed within the framework of the three dimensional crystal structure of MjCobY(G153D) in complex with GTP. The fold of MjCobY is strikingly similar to that of the N-terminal domain of Mycobacterium tuberculosis GlmU (MtbGlmU), a bifunctional acetyltransferase/uridyltransferase that catalyzes the formation of uridine diphosphate-N-acetylglucosamine (UDP GlcNAc). PMID- 21542647 TI - Induced pluripotent stem (iPS) cells repair and regenerate infarcted myocardium. AB - Cardiac myocyte differentiation reported thus far is from iPS cells generated from mouse and human fibroblasts. However, there is no article on the generation of iPS cells from cardiac ventricular specific cell types such as H9c2 cells. Therefore, whether transduced H9c2 cells, originally isolated from embryonic cardiac ventricular tissue, will be able to generate iPS cells and have the potential to repair and regenerate infarcted myocardium remains completely elusive. We transduced H9c2 cells with four stemness factors, Oct3/4, Sox2, Klf4, and c-Myc, and successfully reprogrammed them into iPS cells. These iPS cells were able to differentiate into beating cardiac myocytes and positively stained for cardiac specific sarcomeric alpha-actin and myosin heavy chain proteins. Following transplantation in the infarcted myocardium, there were newly differentiated cardiac myocytes and formation of gap junction proteins at 2 weeks post-myocardial infarction (MI), suggesting newly formed cardiac myocytes were integrated into the native myocardium. Furthermore, transplanted iPS cells significantly (p < 0.05) inhibited apoptosis and fibrosis and improved cardiac function compared with MI and MI+H9c2 cell groups. Moreover, our iPS cell derived cardiac myocyte differentiation in vitro and in vivo was comparable to embryonic stem cells in the present study. In conclusion we report for the first time that we have H9c2 cell-derived iPS cells which contain the potential to differentiate into cardiac myocytes in the cell culture system and repair and regenerate infarcted myocardium with improved cardiac function in vivo. PMID- 21542648 TI - Bovine serum albumin nanoparticle promotes the stability of quercetin in simulated intestinal fluid. AB - Quercetin (Que) is a flavonoid widely distributed in vegetables and fruits and exhibits strong antioxidant activity, but the poor stability of Que limits its function and application. The present study developed a nanoparticle (NP) using bovine serum albumin (BSA) as a matrix to encapsulate Que. The stability of encapsulated Que by BSA NP was tracked in a simulated intestinal fluid (SIF). The antioxidant activity of encapsulated Que was evaluated by the 2,2-diphenyl-1 picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assays. Furthermore, the stabilizing mechanism of Que by BSA NP was investigated, using scanning transmisson electron microscopy (STEM), dynamic light scattering (DLS), UV-vis, fluorescence spectrometry, and circular dichroism (CD). The results revealed that Que was effectively encapsulated by BSA and formed spherical NP (<10 nm). BSA NP not only promoted the stability of encapsulated Que but also kept the antioxidant activity of encapsulated Que. The driving forces for BSA-Que association were hydrophobic interaction and hydrogen bond, and the latter was involved in the mechanism of Que stabilization. This suggested that BSA NP could be a good carrier to deliver hydrophobic flavonols. PMID- 21542649 TI - Comparison of the alpha-amylase inhibitor-1 from common bean (Phaseolus vulgaris) varieties and transgenic expression in other legumes--post-translational modifications and immunogenicity. AB - The seeds of peas (Pisum sativum) and chickpeas (Cicer arietinum) expressing a gene for alpha-amylase inhibitor-1 (alphaAI) from the common bean (Phaseolus vulgaris) are protected from damage by old world bruchids (pea and cowpea weevils). Here, we used electrospray ionization time-of-flight mass spectrometry to compare the post-translational modifications of alphaAI from transgenic sources with the processed forms of the protein from several bean varieties. All sources showed microheterogeneity with differences in the relative abundance of particular variants due to differences in the frequency of addition of glycans, variable processing of glycans, and differences of C-terminal exopeptidase activity. The structural variation among the transgenics was generally within the range of the bean varieties. Previously, mice showed allergic reactions following ingestion of transgenic pea alphaAI but not bean alphaAI. Here, only minor differences were observed following intraperitoneal sensitization. Both of the transgenic pea and bean forms of alphaAI elicited Th1 and Th2 antibody isotype responses, suggesting that both proteins are immunogenic and could potentially be allergenic. PMID- 21542650 TI - Tribute to Shaul Mukamel. PMID- 21542651 TI - Autobiography of Shaul Mukamel. PMID- 21542654 TI - Publications of Shaul Mukamel. PMID- 21542655 TI - Oxygen vacancy formation and migration in Ce(x)Th(1-x)O2 solid solution. AB - A local-density approximation with the Hubbard U correction (LDA+U) method has been employed to investigate oxygen vacancy formation and migration in Ce(x)Th(1 x)O(2). The addition of CeO(2) into ThO(2) significantly decreases the oxygen vacancy formation and migration energies. ThO(2) containing 50% CeO(2) exhibits the lowest calculated formation energy, 3.7 eV, and the lowest calculated migration energy, 0.2 eV, occurs for a CeO(2) content of 75%, suggesting that introducing CeO(2) into ThO(2) promotes the formation of mobile oxygen vacancies. If the ceria content is less than about 35%, the reduced Ce(x)Th(1-x)O(2) becomes antiferromagnetic (AFM), whereas the ferromagnetic (FM) state dominates for x values above about 35%, which may allow the tailoring of magnetic properties by varying the CeO(2) content. PMID- 21542656 TI - Formation of hydroxyl radical from the photolysis of salicylic acid. AB - Photodissociation dynamics of salicylic acid (SA) in the gas phase at different photolysis wavelengths (266, 315-317 nm) is investigated by probing the nascent OH photoproduct employing the single-photon laser-induced fluorescence (LIF) technique. At all the photolysis wavelengths it is found that the nascent OH radicals are produced mostly in a vibrationally ground state (upsilon'' = 0) and have similar rotational state distributions. The two spin-orbit and Lambda doublet states of the OH fragment formed in the dissociation are measured to have a nonstatistical distribution at each photolysis wavelength. The LIF signal of the OH could be observed upon photolysis at 317 nm but not at 317.5 nm. The threshold of OH formation from SA photodissociation is estimated to be 98.2 +/- 0.9 kcal/mol. The effect of the phenolic OH group on the dissociation of SA is discussed. PMID- 21542657 TI - Efficacy of cardioprotective 'conditioning' strategies in aging and diabetic cohorts: the co-morbidity conundrum. AB - Evidence obtained in multiple experimental models has revealed that cardiac 'conditioning' strategies--including ischaemic preconditioning, postconditioning, remote conditioning and administration of pharmacological conditioning mimetics- are profoundly protective and significantly attenuate myocardial ischaemia reperfusion injury. As a result, there is considerable interest in translating these cardioprotective paradigms from the laboratory to patients. However, the majority of studies investigating conditioning-induced cardioprotection have utilized healthy adult animals devoid of the risk factors and co-morbidities associated with cardiovascular disease and acute myocardial infarction. The aim of this article is to summarize the growing consensus that two well established risk factors, aging and diabetes mellitus, may render the heart refractory to the favourable effects of myocardial conditioning, and discuss the clinical implications of a loss in efficacy of cardiac conditioning paradigms in these patient populations. PMID- 21542659 TI - Impact of abciximab in elderly patients with high-risk acute coronary syndrome undergoing percutaneous coronary intervention: an observational registry study. AB - BACKGROUND: An increasing proportion of patients with acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI) are classified as elderly (aged >=70 years). The glycoprotein IIb/IIIa inhibitor abciximab is known to reduce adverse outcomes in patients aged <70 years with high-risk ACS undergoing PCI, but conflicting findings relating to its effects in the elderly have been reported. OBJECTIVE: The aim of this study was to evaluate the effect of abciximab in elderly high-risk ACS patients undergoing PCI. METHODS: From our dedicated PCI registry we identified 2068 ACS patients with high-risk lesions that were treated with PCI. Baseline data were collected prospectively. All-cause mortality, target vessel revascularization (TVR), myocardial infarction (MI), and the combination of these were primary study endpoints. All endpoints within 1 year after PCI were registered and validated. The population was subsequently stratified according to age and use of abciximab. RESULTS: Elderly patients constituted 42% of the total population. They presented with more co-morbidities, were less frequently treated with abciximab and had a higher risk of reaching the combined endpoint and higher all-cause mortality than younger patients. The age/abciximab stratified analysis revealed no effect of abciximab on any of the endpoints in elderly patients (combined endpoint: no abciximab 22.6% vs abciximab 23.4%, p=0.85; all-cause mortality: no abciximab 15.4% vs abciximab 15.9%, p=0.91; TVR: no abciximab 3.4% vs abciximab 5.5%, p=0.21; MI: no abciximab 7.0% vs abciximab 8.5%, p=0.54), whereas all-cause mortality and the risk of reaching the combined endpoint were significantly reduced in younger patients (combined endpoint: no abciximab 14.0% vs abciximab 9.4%, p=0.03; all-cause mortality: no abciximab 4.5% vs abciximab 1.7%, p=0.02; TVR: no abciximab 5.5% vs abciximab 4.3%, p=0.39; MI: no abciximab 7.2% vs abciximab 6.6%, p=0.80). These findings were confirmed in our adjusted analyses. CONCLUSIONS: In this large observational study we found no benefit of abciximab treatment in elderly high-risk ACS patients who underwent PCI. These findings should be taken into consideration when deciding on the treatment strategy for elderly ACS patients undergoing PCI. PMID- 21542658 TI - Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients. AB - Among the antidepressants, the selective serotonin reuptake inhibitors (SSRIs) are often preferred to other classes of antidepressants in the treatment of depression in the elderly because of their better safety profile. Most of the known effects of SSRIs, either beneficial or adverse, are linked to their inhibitory action on the serotonin reuptake transporter (5-HTT). This reuptake mechanism is present not only in neurons but also in other cells such as platelets. Serotoninergic mechanisms seem to play an important role in haemostasis, and their importance in this regard has long been underestimated. Abnormal activation may lead to a pro-thrombotic state, as may occur in patients with major depressive disorder, whilst downregulation, as occurs in patients treated with SSRIs, may have two clinical consequences, both of particular interest in the elderly. On the one hand, there may be an increased risk of bleeding; on the other hand, a reduction in thrombotic risk may be possible. Polymorphism in the promoter region of the gene that transcribes the 5-HTT has been shown to have a relevant impact on its function and, in turn, on the beneficial and adverse effects of SSRIs. Bleeding has been a concern since the introduction of SSRIs, with multiple case reports published and communicated to the pharmacovigilance systems. The first epidemiological study was published in 1999 and since then, 34 epidemiological studies from different areas, most of them including elderly patients in their study populations, have been published with a variety of results. Broadly, the epidemiological evidence supports a moderately increased risk of bleeding associated with the use of SSRIs, which may be critically dependent on patient susceptibility and the presence of risk factors. The impairment of primary haemostasis induced by SSRIs may result, as a beneficial counterpart, in a reduction in the thrombotic risk. A small number of clinical trials and an increasing number of epidemiological studies that include elderly patients have been conducted to clarify whether SSRIs reduce the risk of primary and secondary ischaemic disorders. However, the results have been inconclusive with some studies suggesting a preventive effect and others no effect or even an increased risk. Behind such contradictory results may be the role of depression itself as a cardiovascular risk factor and, therefore, a major confounding factor. How to disentangle its effect from that of the antidepressants is the methodological challenge to be overcome in future studies. In this complex scenario, the elderly seem to be at a crossroads, because they are the group in which both the risks and the benefits can be the greatest. Studies performed to date have provided us with some clues that can help orient clinicians in taking the most appropriate course of action. For instance, as the gastrointestinal bleeding risk appears to increase with age, prudent advice in patients with a previous history of upper-gastrointestinal bleeding or peptic ulcer, and in those who take NSAIDs, oral anticoagulants, antiplatelet drugs or corticosteroids, would be to suggest addition of an acid-suppressing agent to the drug regimen in those elderly patients in whom SSRIs are indicated. PMID- 21542660 TI - Association between glomerular filtration rate and adverse drug reactions in elderly hospitalized patients: the role of the estimating equation. AB - BACKGROUND: Reduced renal function increases the risk of adverse drug reactions (ADRs) to hydrosoluble drugs (hADRs). However, the ability of different equations to calculate estimated glomerular filtration rate (eGFR) or estimated creatinine clearance (eCCr) and thereby predict the risk of developing hADRs has not previously been compared. OBJECTIVE: The aim of this study was to investigate which of three different equations for estimating renal function (Cockcroft-Gault [CG], Modification of Diet in Renal Disease [MDRD] and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) was the most effective at predicting incident hADRs. METHODS: This multicentre study had an observational design and included 81 acute-care general (internal) or geriatric medicine wards in academic hospitals throughout Italy. Our series consisted of 10,442 hospitalized patients with a mean +/- SD age of 70.2 +/- 14.9 years enrolled in the GIFA study. The main outcome measures were incident ADRs during hospital stay. Data on these were collected and classified as hADRs or ADRs to liposoluble drugs (lADRs). Patients were grouped according to their eGFR (mL/min/1.73 m2) or eCCr (mL/min): >=90, 60 89.9, 45-59.9, 30-44.9 or <30. RESULTS: The multivariable adjusted risk of hADRs progressively increased with decreasing eGFR as determined by estimates of mL/min/1.73 m2 calculated using CKD-EPI (60-89.9: hazard ratio [HR]=1.07 [95% CI 0.70, 1.72]; 45-59.9: HR=1.62 [95% CI 1.0, 2.69]; 30-44.9: HR=2.13 [95% CI 1.24, 3.64]; <30: HR=2.30 [95% CI 1.28, 4.14]) and, to a lesser extent, MDRD (60-89.9: HR=1.15 [95% CI 0.75, 1.76]; 45-59.9: HR=1.73 [95% CI 1.09, 2.73]; 30-44.9: HR=2.14 [95% CI 1.30, 3.53]; <30: HR=1.99 [95% CI 1.11, 3.57]) equations. The risk of hADRs also increased with lower eCCr, but only at CG eCCr <45 mL/min (30 44.9: HR=1.61 [95% CI 0.96, 2.77]; <30: HR=1.76 [95% CI 1.0, 3.18]). Neither eGFR nor eCCr were associated with lADRs. CONCLUSIONS: CKD-EPI-based estimates of eGFR outperformed MDRD-based estimates of eGFR and CG-based estimates of eCCr as a predictor of hADRs. PMID- 21542661 TI - Criteria for drug selection in frail elderly persons. AB - BACKGROUND: Elderly patients with multiple morbidities and polypharmacy are at an increased risk of adverse drug events (ADEs). Appropriate prescribing, preserving the balance between drug effectiveness and safety, and treatment adherence may prevent these ADEs. In this study, we investigated which drug properties, such as effectiveness, safety, clinical experience and convenience, are relevant to the choice of medicine most appropriate for frail elderly patients. OBJECTIVES: The primary aim of this study was to develop a set of criteria to assist in the selection of the most appropriate drug within a drug class for the treatment of frail elderly patients. A secondary goal was to test the usefulness of the set of criteria in the prescription of antipsychotics for delirium and behavioural and psychological symptoms of dementia (BPSD). METHODS: Thirty-one criteria potentially relevant to the choice of appropriate drugs for frail elderly patients were selected on the basis of a literature search in MEDLINE (1966 2008), EMBASE (1947-2008) and the Cochrane Library (1993-2008). This list was reviewed by 46 experts (24 physicians, 22 pharmacists), who scored each item for relevance in clinical practice on a scale from 1 to 10 (where 1 is not important and 10 is very important). By consensus, the authors selected the most relevant criteria for the final set of criteria. The usefulness of the final set of criteria was assessed with regard to the prescription of antipsychotics for delirium and BPSD. RESULTS: The final set of 23 items consisted of 3 items on effectiveness, 14 on safety, including pharmacokinetic and pharmacodynamic criteria, 3 on clinical experience and 3 on convenience. Assessment using these criteria of the appropriateness of antipsychotics prescribed for delirium and BPSD revealed that certain drugs should be prescribed with caution to patients with Parkinson's disease and Lewy body dementia. CONCLUSIONS: The criteria identified in this study, selected on the basis of a literature review and clinical expert opinion, represent a promising approach for determining the appropriateness of a drug for use in frail elderly individuals relative to alternative drugs for the same indication or from the same class. PMID- 21542662 TI - How do the attitudes and beliefs of older people and healthcare professionals impact on the use of multi-compartment compliance aids?: a qualitative study using grounded theory. AB - BACKGROUND: Low adherence of older people to multiple medicine regimens is of widespread concern, and multi-compartment compliance aids are frequently supplied to older people in an attempt to improve their ability to take all their medicines at home. However, the evidence base for the use of such aids is very limited, and there is some evidence that they are used inappropriately. OBJECTIVE: We aimed to determine how the attitudes and beliefs of older people and healthcare professionals impacted on the use of multi-compartment compliance aids by older people living at home. METHOD: This was a qualitative study using grounded theory. Semi-structured interviews were conducted with 15 older people (mean age 82 [range 72-92] years) living independently in the community and receiving primary healthcare from two health service organizations in a large northern UK city. We then interviewed 17 healthcare professionals working in primary, secondary or intermediate care and involved in the provision of multi compartment compliance aids. RESULTS: Maintaining independence and remaining in control was important for all the older people interviewed, and professionals supported the view that this influenced patients' attitudes towards using their aid. Some patients saw the aids as helping to maintain independence, others as casting doubt on their independence. The aids were often issued without discussion with the patient. The patients largely agreed that the aids did not help with memory problems and that the decision to issue an aid could be seen as paternalistic. A minority of patients had difficulties using the aids. CONCLUSIONS: Careful multi-disciplinary assessment of older people is required before a compliance aid is provided. The views of the older person must be considered and respected. Further research is required to produce an evidence base for the use of such aids in this group of people. PMID- 21542663 TI - Spotlight on dabigatran etexilate in the prevention of stroke and systemic embolism in patients with atrial fibrillation. AB - The need for safe, effective and easily administered and monitored antithrombotic treatments that do not have the issues common to warfarin treatment has led to the development of new anticoagulant drugs. Dabigatran etexilate (Pradaxa(r), PradaxTM) is a prodrug of the direct thrombin inhibitor dabigatran, a direct, reversible, potent inhibitor of thrombin. Dabigatran does not interact with food, and is associated with very few known drug interactions. Dabigatran etexilate, at dosages of 110 and 150 mg twice daily, was shown to be noninferior to warfarin with regard to the incidence of stroke or systemic embolism in a large, randomized, partially blinded, multicentre study in a wide spectrum of patients with atrial fibrillation. Moreover, the higher dosage was associated with significantly greater efficacy than warfarin in this regard. These results were supported by secondary endpoints and subgroup analyses. In general, dabigatran etexilate is well tolerated, although it is associated with a higher rate of dyspepsia than warfarin. Major bleeding was as common in recipients of the higher dosage as, and less common in recipients of the lower dosage of dabigatran etexilate than, that in recipients of warfarin, and intracranial bleeding, life threatening major bleeding and total bleeding were less common in recipients of either dabigatran etexilate dosage than in warfarin recipients. However, the higher dosage of dabigatran etexilate was associated with a higher rate of gastrointestinal bleeding than warfarin was. The incidence of hepatotoxicity did not significantly differ across treatment groups. In conclusion, dabigatran etexilate 150 mg twice daily is more effective than warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation, and is generally well tolerated, particularly with regard to bleeding endpoints compared with warfarin. It requires more frequent administration than warfarin, but provides multiple improvements to various issues associated with warfarin administration. Direct comparisons with other new anticoagulant drugs would be beneficial, as would further investigation into the effects in different patient populations, long-term effects, and the gastrointestinal bleeding and dyspepsia observed with dabigatran etexilate treatment. Dabigatran etexilate is a promising new option for the prevention of stroke and systemic embolism in patients with atrial fibrillation. PMID- 21542664 TI - Abuse potential and psychoactive effects of delta-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. AB - INTRODUCTION: There is a growing consensus that cannabis dependence is a substantial and underappreciated problem. The key component responsible for the euphoric effects of cannabis and its dependence potential is delta-9 tetrahydrocannabinol (THC). THC-containing cannabinoid medicines theoretically pose a risk of abuse and dependence. AREAS COVERED: In order to evaluate the potential of Sativex to cause cannabis-like psychoactivity, abuse or dependence relevant data from all published papers have been reviewed along with the integrated safety analysis for Sativex use in multiple sclerosis (MS) patients on file at GW Pharmaceuticals. EXPERT OPINION: In clinical trials, intoxication scores have been low and euphoria reported by only 2.2% of patients. Tolerance has not occurred, abrupt withdrawal has not resulted in a formal withdrawal syndrome, and no cases of abuse or diversion have been reported to date. A formal abuse liability study of Sativex in experienced cannabis smokers showed some abuse potential in comparison with placebo at higher doses, but scores were consistently lower than equivalent doses of THC. Evidence to date suggests that abuse or dependence on Sativex is likely to occur in only a very small proportion of recipients. PMID- 21542665 TI - A critical evaluation of clinical decision support for the detection of drug-drug interactions. AB - INTRODUCTION: Incorporation of clinical decision support systems (CDSSs) into computerized physician order entry assists prescribers with medication dosing, identification of duplicate therapies, drug-allergy alerts and drug-drug interactions (DDIs). The generation of DDI alerts is one aspect of CDSS that may improve patient safety and reduce adverse drug events. AREAS COVERED: Currents issues with the generation of DDI alerts, such as alert fatigue, unclear clinical significance and database inconsistencies are a few of the problems that have been identified with DDI alerting. Research has shown that DDI alerting may be improved through the tiering of alerts, generation of patient-specific alert and directing some alerts to clinicians other than physicians. More research in this area, such as how to decrease the variability of database rating systems, improve the identification of clinically significant alerts and increase the patient specificity of the generated DDI alerts, should be conducted. EXPERT OPINION: DDI knowledgebases need to take into account more patient-specific information. Strategies to avoid alert fatigue, such as DDI tiering and reducing signal:noise ratios, are important areas for future study. End-user participation and clinician feedback should be incorporated in the development of DDI knowledgebases to increase alert compliance. PMID- 21542667 TI - Kidney spheroids recapitulate tubular organoids leading to enhanced tubulogenic potency of human kidney-derived cells. AB - Cell-based approaches utilizing autologous human renal cells require their isolation, expansion in vitro, and reintroduction back into the host for renal tissue regeneration. Nevertheless, human kidney epithelial cells (hKEpCs) lose their phenotype, dedifferentiate, and assume the appearance of fibroblasts after relatively few passages in culture. We hypothesized that growth conditions may influence hKEpC phenotype and function. hKEpCs retrieved from human nephrectomy tissue samples showed the ability to reproducibly form kidney spheres when grown in suspension culture developed in nonadherent conditions. Genetic labeling and time-lapse microscopy indicated, at least in part, the aggregation of hKEpCs into 3D spheroids rather than formation of pure clonally expanded spheres. Characterization of hKEpC spheroids by real-time polymerase chain reaction and FACS analysis showed upregulation of some renal developmental and "stemness" markers compared with monolayer and mostly an EpCAM(+)CD24(+)CD133(+)CD44(+) spheroid cell phenotype. Oligonucleotide microarrays, which were used to identify global transcriptional changes accompanying spheroid formation, showed predominantly upregulation of cell matrix/cell contact molecules and cellular biogenesis processes and downregulation of cell cycle, growth, and locomotion. Accordingly, hKEpC spheroids slowly proliferated as indicated by low Ki-67 staining, but when grafted in low cell numbers onto the chorioallantoic membrane (CAM) of the chick embryo, they exclusively reconstituted various renal tubular epithelia. Moreover, efficient generation of kidney spheroids was observed after long-term monolayer culture resulting in reestablishment of tubulogenic capacity upon CAM grafting. Thus, generation of a tubular organoid in hKEpC spheroids may provide a functional benefit for kidney-derived cells in vivo. PMID- 21542668 TI - Repair of rat sciatic nerve gap by a silk fibroin-based scaffold added with bone marrow mesenchymal stem cells. AB - Tissue-engineered nerve grafts (TENGs), typically consisting of a neural scaffold included with support cells and/or growth factors, represent a promising alternative to autologous nerve grafts for surgical repair of large peripheral nerve gaps. Here, we developed a new design of TENGs by introducing bone marrow mesenchymal stem cells (MSCs) of rats, as support cells, into a silk fibroin (SF) based scaffold, which was composed of an SF nerve guidance conduit and oriented SF filaments as the conduit lumen filler. The biomaterial SF had been tested to possess good biocompatibility and noncytoxicity with MSCs before the TENG was implanted to bridge a 10-mm-long gap in rat sciatic nerve. Functional and histological assessments showed that at 12 weeks after nerve grafting, TENGs yielded an improved outcome of nerve regeneration and functional recovery, which was better than that achieved by SF scaffolds and close to that by autologous nerve grafts. During 1-4 weeks after nerve grafting, MSCs contained in the TENG significantly accelerated axonal growth, displaying a positive reaction to S-100 (a Schwann cell marker). During 1-3 weeks after nerve grafting, MSCs contained in the TENG led to gene expression upregulation of S100 and several growth factors (brain-derived neurotrophic factor, ciliary neurotrophic factor, and basic fibroblast growth factor). These results suggest that the cell behaviors and neurotrophic functions of MSCs might be responsible for their promoting effects on peripheral nerve regeneration. PMID- 21542666 TI - Emerging drugs for osteoarthritis. AB - INTRODUCTION: Osteoarthritis (OA), the most prevalent form of joint disease, affects as much as 13% of the world's population. In the USA, it is the leading cause of disability in people over age 65 and is characterized by progressive cartilage loss, bone remodeling, osteophyte formation and synovial inflammation with resultant joint pain and disability. There are no treatments marketed for structural disease modification; current treatments mainly target symptoms, with > 75% of patients reporting need for additional symptomatic treatment. AREAS COVERED: Drugs in later development (Phase II - III) for OA pain and joint structural degeneration are reviewed. Topics that are not covered in this article are procedural-based (e.g., arthrocentesis, physical therapy), behavioral-based (e.g., weight loss, pain coping techniques) or device-based (e.g., knee braces, surgical implants) treatments. EXPERT OPINION: More in-depth understanding of the pathophysiology of the disease, as well as elucidation of the link between clinical symptomatology and structural changes in the joint will likely lead to the development of novel target classes with promising efficacy in the future. Efficacy notwithstanding, there remain significant hurdles to overcome in clinical development of these therapeutics, inherent in the progression pattern of the disease as well as challenges with readouts for both pain and structure modification trials. PMID- 21542669 TI - Cardiac gene transfer of short hairpin RNA directed against phospholamban effectively knocks down gene expression but causes cellular toxicity in canines. AB - Derangements in calcium cycling have been described in failing hearts, and preclinical studies have suggested that therapies aimed at correcting this defect can lead to improvements in cardiac function and survival. One strategy to improve calcium cycling would be to inhibit phospholamban (PLB), the negative regulator of SERCA2a that is upregulated in failing hearts. The goal of this study was to evaluate the safety and efficacy of using adeno-associated virus (AAV)-mediated cardiac gene transfer of short hairpin RNA (shRNA) to knock down expression of PLB. Six dogs were treated with self-complementary AAV serotype 6 (scAAV6) expressing shRNA against PLB. Three control dogs were treated with empty AAV6 capsid, and two control dogs were treated with scAAV6 expressing dominant negative PLB. Vector was delivered via a percutaneously inserted cardiac injection catheter. PLB mRNA and protein expression were analyzed in three of six shRNA dogs between days 16 and 26. The other three shRNA dogs and five control dogs were monitored long-term to assess cardiac safety. PLB mRNA was reduced 16 fold, and PLB protein was reduced 5-fold, with treatment. Serum troponin elevation and depressed cardiac function were observed in the shRNA group only at 4 weeks. An enzyme-linked immunospot assay failed to detect any T cells reactive to AAV6 capsid in peripheral blood mononuclear cells, heart, or spleen. Microarray analysis revealed alterations in cardiac expression of several microRNAs with shRNA treatment. AAV6-mediated cardiac gene transfer of shRNA effectively knocks down PLB expression but is associated with severe cardiac toxicity. Toxicity may result from dysregulation of endogenous microRNA pathways. PMID- 21542670 TI - Heterotopic pregnancy following bilateral tubal ligation: case report. AB - CASE REPORT: A 38-year-old woman presented, one year after bilateral tubal ligation, with vaginal bleeding, vomiting, and stupor. Ten days earlier, she had submitted to a dilatation and curettage for an unexpected intrauterine pregnancy. At the time of this presentation there was rebound tenderness and guarding on abdominal examination, and a 2.5 cm right adnexal mass was detected on transvaginal ultrasound together with free fluid in the pelvis. The serum level of beta-hCG was 8522 mIU/ml. At laparoscopy a right tubal pregnancy and a large haematocele in the pouch of Douglas were detected. A right salpingectomy and a bipolar electrocoagulation of the left tubo-cornual junction were performed laparoscopically. CONCLUSION: Pregnancy after tubal sterilisation may be heterotopic and this possibility should be considered in the differential diagnosis. PMID- 21542671 TI - Case-finding and risk-group screening for depression in primary care. AB - OBJECTIVE. Central health organizations suggest routine screening for depression in high-risk categories of primary care patients. This study compares the effectiveness of high-risk screening versus case-finding in identifying depression in primary care. DESIGN. Using an observational design, participating GPs included patients from 13 predefined risk groups and/or suspected of being depressed. Patients were assessed by the Major Depression Inventory (MDI) and ICD 10 criteria. Setting. Thirty-seven primary care practices in Mainland Denmark. Main outcome measures. Prevalence of depression, diagnostic agreement, effectiveness of screening methods, risk groups requiring special attention. RESULTS. A total of 37 (8.4%) of 440 invited GP practices participated. We found high-risk prevalence of depression in 672 patients for the following traits: (1) previous history of depression, (2) familial predisposition to depression, (3) chronic pain, (4) other mental disorders, and (5) refugee or immigrant. In the total sample, GPs demonstrated a depression diagnostic sensitivity of 87% and a specificity of 67% using a case-finding strategy. GP diagnoses of depression agreed well with the MDI (AUC values of 0.91-0.99). The potential added value of high-risk screening was 4.6% (31/672). Patients with other mental disorders were at increased risk of having an unrecognized depression (PR 3.15, 95% CI 1.91 5.20). If patients with other mental disorders were routinely tested, then 42% more depressed patients (14/31) would be recognized. CONCLUSIONS. A broad case finding approach including a short validation test can help GPs identify depressed patients, particularly by including patients with other mental disorders in this strategy. This exploratory study cannot support the screening strategy proposed by central health organizations. PMID- 21542672 TI - Oxidative stress in spiral ganglion cells of pigmented and albino guinea pigs exposed to impulse noise. AB - CONCLUSIONS: The results suggest that melanin inhibits formation of reactive oxygen species (ROS) and prevents apoptosis in spiral ganglion cells (SGCs) of pigmented guinea pigs following impulse noise. OBJECTIVE: The stria vascularis of pigmented guinea pig cochlea contains melanocytes that produce melanin, which has a protective effect on noise-induced hair cell damage through its antioxidant property. ROS are involved in cochlear damage induced by impulse noise trauma. The purpose of the present study was to investigate the oxidative stress in SGCs of pigmented and albino guinea pigs after exposure to impulse noise. METHODS: Pigmented and albino guinea pigs were exposed to impulse noise. Auditory thresholds were assessed by sound-evoked auditory brainstem response (ABR) before impulse noise exposure and 72 h after impulse noise exposure. 4-Hydroxynonenal (HNE) was used as a histochemical marker of ROS formation, and active-caspase-3 (cas-3) served as a marker for apoptosis. 4-HNE and cas-3 were determined immunohistochemically. Hair cell damage was analyzed by scanning electron microscopy. RESULTS: The rates of 4-HNE-positive and cas-3-positive SGCs in pigmented guinea pigs were much less than those for albino guinea pigs. Correspondingly, there was less hair cell damage and reduced ABR threshold shifts in pigmented guinea pigs. PMID- 21542673 TI - Increased incidence of oropharyngeal cancer and p16 expression. AB - CONCLUSIONS: The incidence of oropharyngeal squamous cell cancer (OPSCC) in Finland has increased during the past decades. A similar change has been seen in the relative frequency of p16-positive head and neck squamous cell carcinoma (HNSCC). As p16 is a surrogate marker for human papilloma virus (HPV) infection, and as most p16-positive HNSCCs are OPSCC, HPV infection may have had a role in the observed increased incidence of OPSCC. OBJECTIVES: Numerous studies have shown that HPV is an independent risk factor for OPSCC. We aimed to use p16 as a surrogate marker of HPV infection to study its role as a possible risk factor in OPSCC. Furthermore, the change in the incidence of OPSCC in Finland was studied. METHODS: HPV status was determined by p16 immunohistochemistry of 135 HNSCC tumour specimens retrieved from patients treated at the Helsinki University Central Hospital. Incidence data on OPSCC were obtained from the Finnish Cancer Registry. RESULTS: The incidence of OPSCC in Finland increased from 0.66/100 000 person-years during 1989-1993 to 1.36 during 2004-2008. During the same period a significant increase in the relative frequency of p16 positive HNSCC tumours from 22% during 1990-1999 to 41% during 2000-2007 could be seen at our institution. In all, 85% of the p16-positive specimens were OPSCC. PMID- 21542674 TI - Palonosetron versus other 5-HT3 receptor antagonists for prevention of chemotherapy-induced nausea and vomiting in patients with hematologic malignancies treated with emetogenic chemotherapy in a hospital outpatient setting in the United States. AB - OBJECTIVE: This study evaluated the rate of uncontrolled chemotherapy-induced nausea and vomiting (CINV) after initiating antiemetic prophylaxis with palonosetron versus other 5-HT3 receptor antagonists (RAs) in patients diagnosed with hematologic malignancies (lymphoma and leukemia) and receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) in a hospital outpatient setting. METHODS: Patients aged >= 18 years and diagnosed with hematologic malignancies initiating HEC or MEC and antiemetic prophylaxis with palonosetron (Group 1) and other 5-HT3 RAs (Group 2) for the first time in a hospital outpatient setting between 4/1/2007 and 3/31/2009 were identified from the Premier Perspective Database. Within each cycle, CINV events were identified (in the hospital outpatient, inpatient, and emergency room settings) through ICD 9 codes for nausea, vomiting, and/or volume depletion (from each CT administration day 1 until the end of the CT cycle), or use of rescue medications (day 2 until the end of the CT cycle). Negative binomial distribution generalized linear multivariate regression model estimating the CINV event rate on CT, specific CT cycles, and cancer diagnosis (leukemia/lymphoma)-matched groups in the follow-up period (first of 8 cycles or 6 months) was developed. RESULTS: Of 971 identified patients, 211 initiated palonosetron (Group 1). Group 1 patients comprised of more females [50.2 vs. 41.4%; p = 0.0226], Whites [74.4 vs. 70.4%, and Hispanics [7.6 vs. 6.3%; all races p = 0.0105], received more HEC treatments [89.6 vs. 84.2%; all CT types p = 0.0129], and had more lymphoma diagnosed patients [89.6 vs. 76.3%; all cancer types p = 0.0033] at baseline. After controlling for differences in several demographic and clinical variables, the regression model predicted a 20.4% decrease in CINV event rate per CT cycle for Group 1 versus Group 2 patients. Study limitations include potential lack of generalizability, absence of data on certain confounders including alcohol consumption and prior history of motion sickness, potential underestimation of incidence of uncontrolled CINV, and inability to draw conclusions pertaining to cause and effect relationship. CONCLUSION: In this retrospective hospital study, patients with hematologic malignancies treated with HEC or MEC and initiated on antiemetic prophylaxis with palonosetron in the hospital outpatient setting were more likely to experience significantly lower CINV event rates (in the hospital outpatient, inpatient, and emergency room settings) versus patients initiated on other 5-HT3 RAs. PMID- 21542675 TI - Estimation of resource utilisation difference between lithium and valproate treatment groups from the VALID study. AB - OBJECTIVE: To assess the difference in resource utilisation between lithium and valproate treatment groups from the VALID study. METHODS: A modelled economic study was conducted as an appendage to the VALID study, an international, randomised, open-label, parallel-group, 12-week, equivalence study in patients with bipolar I disorder experiencing a manic/mixed episode, compared the efficacy and safety of valproate against that of lithium. The difference in health resource utilisation between the treatment groups was analysed based on information collected from a standardised questionnaire. RESULTS: Efficacy and tolerability of valproate and lithium were shown to be comparable in the management of bipolar disorder in the VALID study. Cost analysis was based on information for 138 (35.5% male, mean age: 37.73 years) and 131 (45.8% male, mean age: 38.98 years) patients from lithium and valproate treatment groups, respectively. The groups differed in the number of hospital visits (503 vs. 421), outpatient visits (15 vs. 2), and number of work days lost (907 vs. 514.5) due to bipolar disorder. All differences were in favour of the valproate treatment group. In the modelled analysis and subsequent sensitivity analyses, the total cost saving was calculated to be US$199,322 (range: US$37,629-$226,903). This would translate into a cost saving of US$1444 per patient, or a cost saving of US$6278 per patient per year (range: US$1185-$7145 per patient per year). LIMITATIONS: The present study suffers from the limitations inherent in any economic evaluation that uses data from multicentre clinical trials with potential variations in treatment provision as well as the theoretical bias from an open-label study design. The study sample size had also limited statistical power to detect moderate differences in total medical costs, given the large variances often observed on cost variables. CONCLUSIONS: The use of valproate over lithium is likely to result in substantial cost savings to the healthcare system and reduce the financial burden to patients. PMID- 21542677 TI - Development of a short-form assessment for detection of subtle activity limitations: can use of everyday technology distinguish between MCI and Alzheimer's disease? AB - Research demonstrates that people with mild cognitive impairment (MCI) do have limitations in instrumental activities of daily living, social and other complex activities, but there is still a lack of knowledge on how such functional limitations are best detected and evaluated in the heterogeneous MCI population. In general, existing functional assessments lack sufficient sensitivity to detect subtle changes or differences in this population. Therefore, further development of valid, up-to-date, sensitive assessments is needed. Interestingly, activities that involve the use of everyday technology (e.g., using telephone or household equipment, managing finances and transportation) have demonstrated the best sensitivity to detect differences between people with MCI, people with early stage dementia and controls. This article introduces the development of assessments of the ability to use everyday technology, and presents empirical material describing the procedures of developing the Short-form Everyday Technology Use Questionnaire (S-ETUQ), a screening tool that distinguishes MCI from controls and Alzheimer's disease, intended to complement other functional assessments. PMID- 21542676 TI - Systemic adeno-associated virus-mediated gene therapy preserves retinal ganglion cells and visual function in DBA/2J glaucomatous mice. AB - A slow progressive death of neurons is the hallmark of neurodegenerative diseases, such as glaucoma. A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well. PMID- 21542678 TI - Nanomedicine for oral chemotherapy. PMID- 21542679 TI - Role of nanobiotechnology in the personalized management of glioblastoma multiforme. PMID- 21542681 TI - FeCo/graphite nanocrystals for vascular inflammation imaging. PMID- 21542682 TI - Investigation on mechanisms of glycopeptide nanoparticles for drug delivery across the blood-brain barrier. AB - AIM: Nanoneuroscience, based on the use polymeric nanoparticles (NPs), represents an emerging field of research for achieving an effective therapy for neurodegenerative diseases. In particular, poly-lactide-co-glycolide (PLGA) glyco heptapetide-conjugated NPs (g7-NPs) were shown to be able to cross the blood brain barrier (BBB). However, the in vivo mechanisms of the BBB crossing of this kind of NP has not been investigated until now. This article aimed to develop a deep understanding of the mechanism of BBB crossing of the modified NPs. MATERIALS & METHODS: Loperamide and rhodamine-123 (model drugs unable to cross the BBB) were loaded into NPs, composed of a mixture of PLGA, differently modified with g7 or with a random sequence of the same aminoamids (random-g7). To study brain targeting of these model drugs, loaded NPs were administered via the tail vein in rats in order to perform both pharmacological studies and biodistribution analysis along with fluorescent, confocal and electron microscopy analysis, in order to achieve the NP BBB crossing mechanism. Computational analysis on the conformation of the g7- and random-g7-NPs of the NP surface was also developed. RESULTS: Only loperamide delivered to the brain with g7-NPs created a high central analgesia, corresponding to the 14% of the injected dose, and data were confirmed by biodistribution studies. Electron photomicrographs showed the ability of g7-NPs in crossing the BBB as evidenced by several endocytotic vesicles and macropinocytotic processes. The computational analysis on g7 and random-g7 showed a different conformation (linear vs globular), thus suggesting a different interaction with the BBB. CONCLUSION: Taken together, this evidence suggested that g7-NP BBB crossing is enabled by multiple pathways, mainly membrane-membrane interaction and macropinocytosis-like mechanisms. The results of the computational analysis showed the Biousian structure of the g7 peptide, in contrast to random-g7 peptide (globular conformation), suggesting that this difference is pivotal in explaining the BBB crossing and allowing us to hypothesize regarding the mechanism of BBB crossing by g7-NPs. PMID- 21542683 TI - Antitumor efficacy, tumor distribution and blood pharmacokinetics of chitosan/glyceryl-monooleate nanostructures containing paclitaxel. AB - AIMS: This investigation compared the tumor distribution, efficacy, blood pharmacokinetic parameters and hematological alterations following treatment with chitosan/glyceryl-monooleate (GMO) nanostructures containing paclitaxel (PTX) to a conventional formulation of PTX (Taxol((r))) in BALB/c female mice. MATERIALS & METHODS: The tumor and blood concentrations of PTX were evaluated by HPLC and the pharmacokinetic parameters were determined through noncompartmental methods. Tumor development was evaluated by histopathological methods and hematological composition was monitored through differential white blood cells counts. RESULTS: Lower localized or intravenous doses of PTX-chitosan/GMO nanostructures significantly increased the antitumor activity of paclitaxel. The tumor distribution studies showed effective concentrations in the tumors with the chitosan/GMO formulation while systemic blood levels remained lower than after administration of the conventional formulation. CONCLUSION: Delivery systems consisting of chitosan/GMO and PTX are safe and effective administered locally (intratumorally) or intravenously. PMID- 21542684 TI - Conjugation of functionalized gadolinium metallofullerenes with IL-13 peptides for targeting and imaging glial tumors. AB - BACKGROUND: Glioblastoma multiforme is the most common and most lethal primary brain tumor in humans, with median survival of approximately 1 year. Owing to the ability of glioma cells to aggressively infiltrate normal brain tissue and survive exposure to current adjuvant therapies, there is a great need for specific targeted nanoplatforms capable of delivering both therapeutic and imaging agents directly to invasive tumor cells. METHOD: Gadolinium-containing endohedral fullerenes, highly efficient contrast agents for MRI, were functionalized and conjugated with a tumor-specific peptide and assessed for their ability to bind to glioma cells in vitro. RESULTS: We report the successful conjugation of the carboxyl functionalized metallofullerene Gd(3)N@C(80)(OH)( 26)(CH(2)CH(2)COOH)(-16) to IL-13 peptides and the successful targeting ability towards brain tumor cells that overexpress the IL-13 receptor (IL-13Ralpha2). CONCLUSION: These studies demonstrate that IL-13 peptide-conjugated gadolinium metallofullerenes could serve as a platform to deliver imaging and therapeutic agents to tumor cells. PMID- 21542687 TI - Targeted nutlin-3a loaded nanoparticles inhibiting p53-MDM2 interaction: novel strategy for breast cancer therapy. AB - AIM: The objective of the present study is to prepare and characterize nutlin-3a loaded polymeric poly(lactide-co-glycolide) nanoparticles (NPs) surface functionalized with transferrin ligand, to deliver the encapsulated drug in a targeted manner to its site of action and to evaluate the efficacy of the nanoformulation in terms of its cellular uptake, cell cytotoxicity, cell cycle arrest, apoptosis and activation of p53 pathway at molecular level in MCF-7 breast cancer cell line. METHOD: Nutlin-3a loaded poly(lactide-co-glycolide) NPs were prepared following the single oil-in-water emulsion method. Physicochemical characterization of the formulation included size and surface charge measurement, transmission electron microscopy characterization, study of surface morphology using scanning electron microscopy, Fourier-transform infrared spectral analysis and in vitro release kinetics studies. Furthermore, targeting ability of the conjugated system was assessed by cellular uptake and cell cytotoxicity studies in an in vitro cell model. Molecular basis of nutlin-3a-mediated p53 activation pathway was investigated by western blot analysis. Inhibition of cell cycle progression and apoptosis was evaluated by flow cytometry. RESULTS: Physiochemical characterization of the formulations revealed that nutlin-3a was efficiently encapsulated in the nanoparticulate system, reaching an encapsulation efficiency of approximately 80% with size of approximately 220 nm and negative zeta potential of approximately -10.4 mV. Higher cellular uptake efficiency of the conjugated system proved the effectiveness of targeted therapy. IC(50) values, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, showed superior antiproliferative activity of transferrin-conjugated NPs over unconjugated NPs and native nutlin-3a, owing to enhanced cellular uptake by cancer cells. At the molecular level the conjugated system showed enhanced activation of p53 pathway in comparison to native drug as evident from western blot analysis. Augmented cell cycle arrest and apoptosis was exhibited by the conjugated system. Thus, our results suggest that transferrin-conjugated nutlin 3a loaded NPs could be a potential drug carrier system for targeted delivery of potent anticancer drug nutlin-3a for breast cancer therapy. PMID- 21542685 TI - Synergistic administration of photothermal therapy and chemotherapy to cancer cells using polypeptide-based degradable plasmonic matrices. AB - AIM: Resistance of cancer cells to hyperthermic temperatures and spatial limitations of nanoparticle-induced hyperthermia necessitates the identification of effective combination treatments that can enhance the efficacy of this treatment. Here we show that novel polypeptide-based degradable plasmonic matrices can be employed for simultaneous administration of hyperthermia and chemotherapeutic drugs as an effective combination treatment that can overcome cancer cell resistance to hyperthermia. METHOD: Novel gold nanorod elastin-like polypeptide matrices were generated and characterized. The matrices were also loaded with the heat-shock protein (HSP)90 inhibitor 17-(allylamino)-17 demethoxygeldanamycin (17-AAG), currently in clinical trials for different malignancies, in order to deliver a combination of hyperthermia and chemotherapy. RESULTS: Laser irradiation of cells cultured over the plasmonic matrices (without 17-AAG) resulted in the death of cells directly in the path of the laser, while cells outside the laser path did not show any loss of viability. Such spatial limitations, in concert with expression of prosurvival HSPs, reduce the efficacy of hyperthermia treatment. 17-AAG-gold nanorod-polypeptide matrices demonstrated minimal leaching of the drug to surrounding media. The combination of hyperthermic temperatures and the release of 17-AAG from the matrix, both induced by laser irradiation, resulted in significant (>90%) death of cancer cells, while 'single treatments' (i.e., hyperthermia alone and 17-AAG alone) demonstrated minimal loss of cancer cell viability (<10%). CONCLUSION: Simultaneous administration of hyperthermia and HSP inhibitor release from plasmonic matrices is a powerful approach for the ablation of malignant cells and can be extended to different combinations of nanoparticles and chemotherapeutic drugs for a variety of malignancies. PMID- 21542686 TI - Evaluation of bacteriochlorophyll-reconstituted low-density lipoprotein nanoparticles for photodynamic therapy efficacy in vivo. AB - AIM: To evaluate the novel nanoparticle reconstituted bacteriochlorin e6 bisoleate low-density lipoprotein (r-Bchl-BOA-LDL) for its efficacy as a photodynamic therapy agent delivery system in xenografts of human hepatoblastoma G2 (HepG2) tumors. MATERIALS & METHODS: Bchl-BOA was encapsulated in the nanoparticle low-density lipoprotein (LDL), a native particle whose receptor's overexpression is a cancer signature for a number of neoplasms. Evaluation of r Bchl-BOA-LDL as a potential photosensitizer was performed using a tumor response and foot response assay. RESULTS & DISCUSSION: When compared with controls, tumor regrowth was significantly delayed at injected murine doses of 2 umole/kg r-Bchl BOA-LDL after illumination at fluences of 125, 150 or 175 J/cm(2). Foot response assays showed that although normal tissue toxicity accompanied the higher fluences it was significantly reduced at the lowest fluence tested. CONCLUSION: This research demonstrates that r-Bchl-BOA-LDL is an effective photosensitizer and a promising candidate for further investigation. PMID- 21542688 TI - Nitroxyl radical-containing nanoparticles for novel nanomedicine against oxidative stress injury. AB - This article discusses the preparation and characterization of pH-sensitive nitroxyl radical-containing nanoparticles (RNPs) possessing nitroxyl radicals in the core and reactive groups on the periphery, and its biomedical application. The RNPs prepared by a self-assembling amphiphilic block copolymers composed of a hydrophilic poly(ethylene glycol) (PEG) segment and a hydrophobic poly(chloromethylstyrene) (PCMS) segment in which the chloromethyl groups were converted to 2,2,6,6-tetramethylpiperidinyloxyls (TEMPOs) via an amination of PEG b-PCMS block copolymer with 4-amino-TEMPO are initially described. The cumulant average diameter of an RNP is approximately 40 nm, and the RNP has intense electron paramagnetic resonance signals. RNPs show a prolonged blood circulation time by the compartmentalization of nitroxyl radicals into the hydrophobic core, and disintegrate in response to a low pH environment, such as ischemic tissue, resulting in effectively scavenging reactive oxygen species due to an exposure of nitroxyl radicals from the RNP core. Thus, the RNP prepared was found to be effective for cerebral ischemia-reperfusion injury. Therefore, RNPs are promising as high-performance therapeutic nanomedicine for oxidative stress injuries. PMID- 21542689 TI - Superparamagnetic nanosystems based on iron oxide nanoparticles for biomedical imaging. AB - Magnetic iron oxide nanoparticles and their dispersion in various mediums are of wide interest for their biomedical applications and physicochemical properties. MFe(2)O(4) or MOFe(2)O(3) (where M = Co, Li, Ni or Mn, for example) can be molecularly engineered to provide a wide range of magnetic properties. In this article, we survey the literature, integrating the results of our work to give a rational view on the synthesis, physicochemical properties and applications of MFe(2)O(4), especially for MRI. However, retrieving detailed biological information on a subcellular level is difficult, owing to the limited resolution and low sensitivity of the MRI technique. Thus, this article also concentrates on the development of a magnetic iron oxide nanoparticles/quantum dot hybrids, as a dual-mode magnetic-fluorescent probe. The synthesis and physicochemical properties of the magnetic iron oxide nanoparticles/quantum dot hybrids and, especially, its application as an MRI-fluorescent probe, will also be described. PMID- 21542690 TI - Magnetoliposomes as multimodal contrast agents for molecular imaging and cancer nanotheragnostics. AB - In the emerging field of molecular and cellular imaging, flexible strategies to synthesize multimodal contrast agents with targeting ligands are required. Liposomes have the ability to combine with a large variety of nanomaterials, including superparamagnetic iron oxide nanoparticles, to form magnetoliposomes (MLs). MLs can be used as highly efficient MRI contrast agents. Owing to their high flexibility, MLs can be associated with other imaging modality probes to be used as multimodal contrast agents. By using a thermosensitive lipid bilayer in the ML structure, these biocompatible systems offer many possibilities for targeting and delivering therapeutic agents for 'theragnostics', a coincident therapy and diagnosis strategy. This article deals with the fast-growing field of MLs as biomedical diagnostic tools. Different kinds of MLs, their preparation methods, as well as their surface modification with different imaging probes, are discussed. ML applications as multimodal contrast agents and in theragnostics are reviewed. Some important issues for the biomedical uses of magnetic liposomes, such as toxicity, are summarized. PMID- 21542692 TI - Realizing the biological and biomedical potential of nanoscale imaging using a pipette probe. AB - Cells naturally operate on the nanoscale level, with molecules combining together to form complex molecular machines, which can work together to enable normal cell function or go wrong as in the case of many diseases. Visualizing these key processes on the nanoscale has been difficult and two main approaches have been used to date; nanometer resolution imaging of fixed cells using electron microscopy, or imaging live cells using optical or fluorescence microscopy, with a resolution of a few hundred nanometers. Scanning probe microscopy has the potential to allow live cells to be imaged at nanoscale resolution and a noncontact method based on the use of a nanopipette probe has been developed over the last 10 years that allows both topographic and functional imaging. The rapid progress in this area of research over the last 4 years is reviewed in this article, which shows that imaging of complex cellular structures and tissues is now possible and that these methods are now sufficiently mature to provide new insights into important diseases. PMID- 21542694 TI - Assessing disability in morbidly obese individuals: the Italian Society of Obesity test for obesity-related disabilities. AB - PURPOSE: To validate a new obesity-specific disability assessment test: the Obesity-related Disability test (Test SIO Disabilita Obesita Correlata, TSD-OC). METHODS: Adult obese individuals were assessed with the TSD-OC, 36-Item Short Form Health Survey (SF-36), 6-min walking test (6MWT) and grip strength. The TSD OC is composed of 36 items divided into seven sections (pain, stiffness, activities of daily living and indoor mobility, housework, outdoor activities, occupational activities and social life). Statistical correlations between the TSD-OC, functional assessment (6MWT and grip strength) and quality of life parameters (SF-36) were analysed. Internal consistency was assessed with Cronbach's alpha test. Test-retest reliability was evaluated in a subgroup of 30 individuals. A linking exercise between TSD-OC items and categories of the International Classification of Functioning, Disability and Health was performed. RESULTS: Test-retest showed excellent stability (r = 0.90) and excellent internal consistency was reported (Cronbach's alpha > 0.90). Significant low to moderate correlations between TSD-OC, SF-36 scores, 6MWT and grip strength were observed. A total of 26 ICF categories were linked, mostly related to the area of mobility. CONCLUSIONS: The TSD-OC is a reliable and valid instrument for measuring self reported disability in obese subjects. It may represent an important tool for establishing rehabilitation needs in individuals with obesity-related disability, for planning appropriate rehabilitation programmes and for evaluating their effectiveness. PMID- 21542695 TI - Arrangement of type IV collagen and laminin on substrates with controlled density of -OH groups. AB - Collagen IV (Col IV) and laminin (Lam) are the main structural components of the basement membrane where they form two overlapping polymeric networks. We studied the adsorption pattern of these proteins on five model surfaces with tailored density of -OH groups obtained by copolymerization of different ratios ethyl acrylate (EA) and hydroxyl EA (HEA): X(OH)=0, X(OH)=0.3, X(OH)=0.5, X(OH)=0.7, and X(OH)=1 (where X refers the ratio of HEA). Atomic force microscopy revealed substratum-specific adsorption patterns of Col IV and Lam, ranging from single molecules deposition on more hydrophilic substrata to the formation of complex networks on hydrophobic ones. Human umbilical endothelial cells were used to study the biological performance of adsorbed proteins, following the overall cell morphology, the quantities for cell adhesion and spreading, and the development of focal adhesion complexes and actin cytoskeleton. Surprisingly, two optima in the cellular interaction were observed-one on the most hydrophilic X(OH)=1 and other on the relatively hydrophobic X(OH)=0.3 substrate-valid for both Col IV and Lam. When the proteins were adsorbed consecutively, a hydrophobic shift to X(OH)=0 substratum was obtained. Collectively, these data suggest that varying with the density of -OH groups one can tailor the conformation and the functional activity of adsorbed basement membrane proteins. PMID- 21542691 TI - Nanoparticle preconditioning for enhanced thermal therapies in cancer. AB - Nanoparticles show tremendous promise in the safe and effective delivery of molecular adjuvants to enhance local cancer therapy. One important form of local cancer treatment that suffers from local recurrence and distant metastases is thermal therapy. In this article, we review a new concept involving the use of nanoparticle-delivered adjuvants to 'precondition' or alter the vascular and immunological biology of the tumor to enhance its susceptibility to thermal therapy. To this end, a number of opportunities to combine nanoparticles with vascular and immunologically active agents are reviewed. One specific example of preconditioning involves a gold nanoparticle tagged with a vascular targeting agent (i.e., TNF-alpha). This nanoparticle embodiment demonstrates preconditioning through a dramatic reduction in tumor blood flow and induction of vascular damage, which recruits a strong and sustained inflammatory infiltrate in the tumor. The ability of this nanoparticle preconditioning to enhance subsequent heat or cold thermal therapy in a variety of tumor models is reviewed. Finally, the potential for future clinical imaging to judge the extent of preconditioning and thus the optimal timing and extent of combinatorial thermal therapy is discussed. PMID- 21542696 TI - Functional modules distinguish human induced pluripotent stem cells from embryonic stem cells. AB - It has been debated whether human induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) express distinctive transcriptomes. By using the method of weighted gene co-expression network analysis, we showed here that iPSCs exhibit altered functional modules compared with ESCs. Notably, iPSCs and ESCs differentially express 17 modules that primarily function in transcription, metabolism, development, and immune response. These module activations (up- and downregulation) are highly conserved in a variety of iPSCs, and genes in each module are coherently co-expressed. Furthermore, the activation levels of these modular genes can be used as quantitative variables to discriminate iPSCs and ESCs with high accuracy (96%). Thus, differential activations of these functional modules are the conserved features distinguishing iPSCs from ESCs. Strikingly, the overall activation level of these modules is inversely correlated with the DNA methylation level, suggesting that DNA methylation may be one mechanism regulating the module differences. Overall, we conclude that human iPSCs and ESCs exhibit distinct gene expression networks, which are likely associated with different epigenetic reprogramming events during the derivation of iPSCs and ESCs. PMID- 21542697 TI - Purification and long-term expansion of multipotent endothelial-like cells with potential cardiovascular regeneration. AB - Endothelial progenitor cells (EPC) represent a relatively rare cell population, and expansion of sufficient cell numbers remains a challenge. Nevertheless, human adipose-derived stem cells (hASC) can be easily isolated and possess the ability to differentiate into endothelial cells. Here, we propose the isolation and characterization of multipotent endothelial-like cells (ME-LC) with the capacity to maintain their vascular progenitor properties for long periods. hASC were isolated from lipoaspirates and cultured through distinct consecutive culture stages for 2 months to enrich ME-LC: first in Dulbecco's modified Eagle's medium fetal bovine serum (stage I), followed by a stage of culture in absent of fetal bovine serum (stage II), a culture in SFO3 medium (stage III), and, finally, the culture of ME-LC into collagen IV-coated flasks in endothelial growth medium (EGM 2) (stage IV). ME-LC display increased expression levels of endothelial and hematopoietic lineage markers (CD45, KDR, and CXCR4) and EPC markers (CD34 and CD133), whereas the expression of CD31 was barely detectable. Reverse transcription (RT)-polymerase chain reaction assays showed expression of genes involved in early stages of EPC differentiation and decreased expression of genes associated to differentiated EPC (TIE-2, DLL4, and FLT-1). ME-LC formed capillary like structures when grown on Matrigel, secreted increased levels of stromal cell derived factor-1 (SDF-1), and showed the ability to migrate attracted by SDF-1, vascular endothelial growth factor, and hematopoietic growth factor cytokines. Importantly, ME-LC retained the capacity to differentiate into cardiomyocyte-like cells. We present a simplified and efficient method to generate large numbers of autologous ME-LC from lipoaspirates-derived hASC, opening up potential cell-based therapies for cardiovascular regenerative medicine. PMID- 21542698 TI - Development of myocardial constructs using modulus-matched acrylated polypropylene glycol triol substrate and different nonmyocyte cell populations. AB - Tissue engineering approaches are currently being investigated for the restoration of myocardial function in heart failure patients, most commonly by combining cells with a substrate to form myocardial-like constructs (MCs). The final properties of these constructs are dependant on the characteristics of both the substrate and the cells used for fabrication. To create a construct with the appropriate mechanical properties required for any future therapeutic, we tailored an acrylated polypropylene glycol triol (aPPGT) substrate to the elastic modulus of heart tissue and then investigated the fabrication of MCs. We first assessed the aPPGT substrate alone in vivo, both under normal conditions and in an infarct model in mice, and found that there was a mild foreign body response with good integration of the substrate into the epicardial surface in mice hearts. We next studied the fabrication and properties of MCs by culturing mouse embryonic cardiomyocytes on the aPPGT substrate. To achieve myocardial-like concentrically contractile constructs, cocultures with supportive stromal cells were found to be essential and both mouse heart-derived stromal cells or bone derived mouse mesenchymal stromal progenitor cells (mMSCs) could be used. These different stromal cell types produced MCs with different properties. The average beating rate of the constructs formed from mouse heart-derived stromal cells was significantly higher those constructs formed using mMSCs. Conversely, the constructs formed using mMSCs had reduced fibrotic extracellular matrix secretion and increased hepatocyte growth factor expression. Both of these mMSC construct properties may enhance integration and therapeutic efficacy of the construct postimplantation on the surface of the infarcted heart. This study thus demonstrates the formation of MCs using mechanically tailored aPPGT substrate and also demonstrates the effects of different stromal cell populations have on the properties of the resultant MCs, both of which are critical for future applications of tissue engineering in heart failure patients. PMID- 21542699 TI - Nanomedicine's promising therapy: magnetic drug targeting. PMID- 21542700 TI - Robotic versus laparoscopic surgery: perspectives for tailoring an optimal surgical option. PMID- 21542702 TI - The Integrity bare-metal stent made by continuous sinusoid technology. AB - The Integrity Coronary Stent System (Medtronic Vascular, CA, USA) is a low profile, open-cell, cobalt-chromium-alloy advanced bare-metal iteration of the well-known Driver/Micro-Driver Coronary Stent System (Medtronic Vascular). The Integrity stent is made with a process called continuous sinusoid technology. This process allows stent construction via wrapping a single thin strand of wire around a mandrel in a sinusoid configuration, with laser fusion of adjacent crowns. The wire-forming process and fusion pattern provide the stent with a continuous preferential bending plane, intended to allow easier access to, and smoother tracking within, distal and tortuous vessels while radial strength is maintained. Continuous sinusoid technology represents innovation in the design of stent platforms and will provide a future stent platform for newer technology, including drug-eluting stent platforms, drug-filled stents and core wire stents. PMID- 21542703 TI - Assessment of a novel lung sealant for performing endoscopic volume reduction therapy in patients with advanced emphysema. AB - AeriSeal Emphysematous Lung Sealant is a novel endoscopic lung-volume reduction therapy designed to reduce hyperinflation and improve pulmonary function and quality of life in patients with advanced emphysema. The device is administered to the subsegmental bronchus via a catheter as a 20 ml volume of liquid-foam. It flows into the peripheral airways and alveoli where it polymerizes and functions as a tissue glue, forming a film of material on the lung surface that seals the target region to cause durable absorption atelectasis. The AeriSeal System received CE mark approval for the treatment of patients with advanced upper lobe predominant and homogeneous emphysema based upon favorable results from clinical studies, and is commercially available in Europe. Patient and treatment site selection algorithms have been developed to simplify product use and optimize outcomes. This manuscript summarizes how the device is used, its mechanism of action and clinical trial results supporting its safety and efficacy. PMID- 21542704 TI - Cardiac resynchronization therapy for mild-to-moderate heart failure. AB - Cardiac resynchronization therapy (CRT) is recognized as a class I indication according to American and European practice guidelines since 2005 in selected patients with systolic heart failure and New York Heart Association (NYHA) III/IV symptoms. There is growing evidence that CRT may also benefit patients who are less symptomatic, as it may delay or even reverse the disease process. In the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT), Tang et al. randomized 1798 patients with left ventricular ejection fraction of <= 30%, QRS duration of >= 120 ms (or paced QRS >= 200 ms), and NYHA class II or III heart failure to receive an implantable cardioverter-defibrillator (ICD) or an ICD-CRT. After a mean follow-up of 40 months, there was a 25% relative reduction both in the primary outcome of death or heart failure hospitalization (p < 0.001), as well as in the secondary outcome of total mortality (p = 0.003). This landmark trial adds evidence to the efficacy of CRT in selected patients with mild-to-moderate heart failure, at the time of implementation of new guidelines. PMID- 21542705 TI - Safe use of ultrasonically activated devices based on current studies. AB - Ultrasonically activated devices (USADs) are a widely used alternative to suture ligation and clips in open and laparoscopic surgery because of their fast and easy control of bleeding without significant complications. By inducing protein denaturation and forming coaptive coagulation to seal vessels for cutting tissue, USADs result in reduced operating time, blood loss and hospital stay. Recently, various other types of vessel sealers have become available. In this article, we summarize the mechanism, efficacy and the advantages and disadvantages of USADs for appropriate use in surgery. PMID- 21542706 TI - Quality of life for patients supported on a left ventricular assist device. AB - Left ventricular assist devices (LVADs) are mechanical pumps implanted into patients at risk of dying from Stage D heart failure. These devices not only increase survival time, they also significantly improve quality of life. Implantation of a LVAD improves hemodynamics and reduces congestion in both the pulmonary and peripheral vasculature. Improvements in forward blood flow are probably responsible for the significant reduction in the severity of dyspnea and fatigue postimplant. Quality of life is a subjective evaluation and includes aspects of physical, mental and social functioning. Quality of life is significantly improved after implantation of a LVAD, changes little over the duration of support and improves again following heart transplantation. Patients who are discharged home on support report significantly better quality of life than patients who remain in hospital. At home patients can resume physical, mental and social activities that were compromised preimplant. A significant decline in functional ability while on support may be a trigger for patients to initiate discussions regarding LVAD withdrawal. While the bulk of evidence was generated during the era of pulsatile support, preliminary information suggests similar results can be anticipated for patients supported on continuous-flow devices. PMID- 21542707 TI - Surgical implants and technologies for cartilage repair and preservation of the knee. AB - Focal lesions of the articular cartilage of the knee can be managed with a variety of products and technologies in an attempt to restore function to the afflicted joint and forestall the need for possible total knee arthroplasty. Among these approaches are non-implant-based procedures (arthroscopic chondroplasty and microfracture), grafting procedures (autografts/mosaicplasty and allografts), cell-based procedures (autologous chondrocyte implantation) and nonbiologic implants (metallic plugs and cell-free polymers). For each clinically established procedure there are also a number of investigational variations that aim to improve the in vivo quality of the regenerated/restored cartilage surface. This article analyzes existing and developing non-implant- and graft-based technologies for the repair or restoration of the articular cartilage of the knee based on a review of the published literature. PMID- 21542708 TI - Intervertebral disc properties: challenges for biodevices. AB - Intervertebral disc biodevices that employ motion-preservation strategies (e.g., nucleus replacement, total disc replacement and posterior stabilization devices) are currently in use or in development. However, their long-term performance is unknown and only a small number of randomized controlled trials have been conducted. In this article, we discuss the following biodevices: interbody cages, nuclear pulposus replacements, total disc replacements and posterior dynamic stabilization devices, as well as future biological treatments. These biodevices restore some function to the motion segment; however, contrary to expectations, the risk of adjacent-level degeneration does not appear to have been reduced. The short-term challenge is to replicate the complex biomechanical function of the motion segment (e.g., biphasic, viscoelastic behavior and nonlinearity) to improve the quality of motion and minimize adjacent level problems, while ensuring biodevice longevity for the younger, more active patient. Biological strategies for regeneration and repair of disc tissue are being developed and these offer exciting opportunities (and challenges) for the longer term. Responsible introduction and rigorous assessment of these new technologies are required. In this article, we will describe the properties of the disc, explore biodevices currently in use for the surgical treatment of low back pain (with an emphasis on lumbar total disc replacement) and discuss future directions for biological treatments. Finally, we will assess the challenges ahead for the next generation of biodevices designed to replace the disc. PMID- 21542709 TI - Arthroscopic rotator cuff repair: suture anchor properties, modes of failure and technical considerations. AB - Rotator cuff injury and tears are a common source of shoulder pain, particularly among the elderly. Arthroscopic repair has now become the mainstay in the treatment of significant injuries that have failed conservative therapy. Compared with the traditional open technique, arthroscopic repair offers patients smaller incisions and less soft-tissue trauma, which result in improved postoperative pain and rehabilitation. The advances that have made arthroscopic repairs a reality includes improvement in arthroscopic rotator cuff instrumentation, particularly suture anchors. Suture anchors are used to reattach the torn rotator cuff tissue back onto the bone. Current rotator cuff anchors vary by design, anchor composition and suture materials. A treating physician should be aware of the advantages and limitations of these implants, which may influence the choice of one anchor over another. In addition to anchor variables, other factors that may affect the success of the repair include the local environment and surgical technique. In this article, various aspects of anchor design will be discussed. In addition, a concise review of technical considerations will also be discussed. PMID- 21542710 TI - Cochlear implants: current status and future potential. AB - This article reviews the current status of cochlear implantation in both adults and children, including expanding candidacy groups, bilateral implantation, advances in speech processing software, internal and external device hardware, surgical techniques and outcomes. Promising advances, novel therapies and evolving concepts are also highlighted in terms of their future impact on clinical outcomes. PMID- 21542713 TI - The survey on cellular and engineered tissue therapies in Europe in 2009. AB - Thanks to the coordinated efforts of four major scientific organizations, this report describes the "novel cellular therapy" activity in Europe for the year 2009. Fifty teams from 22 countries reported data on 814 patients using a dedicated survey, which were combined to additional 328 records reported by 55 teams to the standard European Blood and Marrow Transplantation (EBMT) database. Indications were cardiovascular (37%; 64% autologous), graft-vs.-host disease (27%; 7% autologous), musculoskeletal (17%; 98% autologous), epithelial/parenchymal (8%; 73% autologous), autoimmune (9%; 84% autologous), or neurological diseases (3%; 50% autologous). Autologous cells were used predominantly for cardiovascular (42%) and musculoskeletal (30%) disorders, whereas allogeneic cells were used mainly for graft-vs.-host disease (58%) and cardiovascular (30%) indications. Reported cell types were mesenchymal stem/stromal cells (MSC) (46%), hematopoietic stem cells (27%), chondrocytes (7%), keratinocytes (5%), dermal fibroblast (13%), and others (2%). In 59% of the grafts, cells were delivered after expansion; in 2% of the cases, cells were transduced. Cells were delivered intraorgan (46%), on a membrane or gel (29%), intravenously (16%) or using 3D scaffolds (8%). As compared to last year, the number of teams adopting the dedicated survey was 1.7-fold higher, and, with few exceptions, the collected data confirmed the captured trends. This year's edition specifically describes and discusses the use of MSC for the treatment of autoimmune diseases, due to the scientific, clinical, and economical implications of this topic. PMID- 21542715 TI - The impact of stress amongst health professionals. PMID- 21542714 TI - Growth factor priming of synovium-derived stem cells for cartilage tissue engineering. AB - This study investigated the potential use of synovium-derived stem cells (SDSCs) as a cell source for cartilage tissue engineering. Harvested SDSCs from juvenile bovine synovium were expanded in culture in the presence (primed) or absence (unprimed) of growth factors (1 ng/mL transforming growth factor-beta(1), 10 ng/mL platelet-derived growth factor-betabeta, and 5 ng/mL basic fibroblast growth factor-2) and subsequently seeded into clinically relevant agarose hydrogel scaffolds. Constructs seeded with growth factor-primed SDSCs that received an additional transient application of transforming growth factor beta(3) for the first 21 days (release) exhibited significantly better mechanical and biochemical properties compared to constructs that received sustained growth factor stimulation over the entire culture period (continuous). In particular, the release group exhibited a Young's modulus (267+/-96 kPa) approaching native immature bovine cartilage levels, with corresponding glycosaminoglycan content (5.19+/-1.45%ww) similar to native values, within 7 weeks of culture. These findings suggest that SDSCs may serve as a cell source for cartilage tissue engineering applications. PMID- 21542716 TI - Doctors vulnerable to psychological distress and addictions: treatment from the Practitioner Health Programme. AB - BACKGROUND: The Practitioner Health Programme (PHP) is a service set up to provide expert assessment and support to health professionals with mental and physical health problems affecting their ability to work. AIMS: The aim of this article is to examine the demographic and clinical characteristics of doctor patients utilising PHP. METHOD: We report on scores for the CORE-OM, the Work and Social Adjustment Scale and the FAST for the first 200 patients seen by PHP. RESULTS: Prevalent conditions included depression and alcohol dependence. Patients with co-morbid disorders showed severe distress and impairment of functioning. Ages ranged between 24 and 67, with 33.5% of the cohort aged between 30 and 39. Patients aged below 50 showed greater impairment of social functioning. CONCLUSIONS: The needs of doctors are profound, with young doctors particularly vulnerable. Measures should be put in place to ensure that doctors at an early stage of their careers are aware of help available to them. The results highlight the importance of a service such as PHP. PMID- 21542717 TI - Work related stress and European policy--a comparative exploration of contextual stressors in the rehabilitation sector in five European countries. AB - BACKGROUND: Dealing with work related stress is a declared priority of European Union mental health policy. A particularly under-researched sector in this regard is the community vocational support sector for people with mental health and intellectual disability problems. AIMS: To report on the organisational profile of the vocational support and rehabilitation sector for people with mental health and intellectual disabilities as this relates to occupational stress, in five European countries (Austria, Ireland, Italy, Romania and UK). METHODS: A sector profile questionnaire was distributed to representative organisations in five countries and a short face-to-face survey was conducted with 25 local managers (five from each country) to draw up a profile and facilitate a comparative description and analysis. RESULTS: It was found that there is no national and European data collected at any level in this sector upon which to base effective policy interventions to combat occupational stress specific to professionals working in this sector. Results indicate that the sector in a number of the countries sampled does not have effective mechanisms in place to deal with occupational stress. CONCLUSION: Developing effective transnational occupational stress management policy that supports staff working in this sector and measuring its success is greatly impaired by a failure to effectively define the purpose of the sector and collect and collate national data to support it. PMID- 21542718 TI - Mental health promotion policies in Europe. AB - There is little evidence that systematic mental health promotion (MHP) policies exist in the countries of the European Union (EU). In order to explore this, a sample of public health stakeholders in ten European regions was selected. Each region was asked to complete a postal questionnaire about structural indicators of those environmental factors that might have an impact on mental health; stakeholders were also provided with information on MHP concepts and strategies. Subsequently the regions were visited, and stakeholders were interviewed on their MHP policies using an open-ended questionnaire. It was found that there were no existing procedures or plans that could support the hope that systematic MHP policies would be developed in the next years in the EU. Only three of the ten regions had started to develop such policies. An 8-item questionnaire on the framework and process of MHP policy development was developed and used in the present study. This questionnaire may be a useful instrument in future studies on structural indicators of mental health. PMID- 21542720 TI - Expression of Th17 and Treg lymphocyte subsets in hypertrophied adenoids of children and its clinical significance. AB - Adenoid hypertrophy is the most common cause of upper airway obstruction and sleep-disordered breathing in children, yet its pathogenesis remains unclear. The identification of the novel helper T cell subsets, Th17 cells and regulatory T cells (Tregs) could provide new insight into our understanding of the mechanisms involved in the development of this condition. The purpose of this study is to evaluate the adenoidal lymphocyte subsets to describe the percentage of various lymphocyte subsets in hypertrophied adenoids and correlate them with symptom severity. Twenty consecutive children undergoing adenoidectomy were included, and lymphocytes were isolated from their adenoids. T cell subpopulations were detected by flow cytometry using a fluoresceinated monoclonal antibody directed against a number of cell markers (CD4+, CD8+, CD25+, FOXP3 IL17+, and others). We found a significant negative linear correlation between the Th17/Treg ratio and the patients' clinical scores (R = -0.71 p < 0.005). The correlation was independent of age and gender. Decreased ratios of Th17/Treg subpopulations may play a role in the pathogenesis of adenoid hypertrophy. PMID- 21542721 TI - Therapeutic effect of vitamin D3 in multiple sclerosis patients. AB - Multiple sclerosis (MS) is an inflammatory disease in which the myelin sheaths around the axons of the central nervous system are damaged. The damage leads to demyelination and scarring as well as a broad spectrum of signs and symptoms. The epidemiological data suggest a possible influence of vitamin D as an immunomodulatory agent on multiple sclerosis susceptibility as well as on clinical course of the disease. We investigated the effects of short-term vitamin D3 therapy on Iranian patients with MS. In a prospective randomized controlled trial study, 62 MS patients received 300,000 IU/month vitamin D3 or placebo as intramuscular injection for 6 months. Our results showed no significant difference between the treatment and the control groups in the expanded disability status scale scores and number of gadolinium-enhancing lesions during the 6-month treatment period. After 6 months, the levels of cell proliferation in the vitamin D treatment group were significantly lower than the control group. Also, the levels of transforming growth factor-beta and interleukin-10 in the vitamin D treatment group were significantly higher than the control group. This result suggests that vitamin D therapy may help prevent the development of MS and could be a useful addition to the therapy. PMID- 21542722 TI - Comparative analysis of long-term biofilm formation on metal and ceramic brackets. AB - OBJECTIVE: To test the null hypothesis that stainless steel and ceramic brackets show no differences in biofilm adhesion. MATERIALS AND METHODS: Twenty adolescents (6 boys, 14 girls) who had received fixed orthodontic therapy for 18.9 +/- 3.2 months were divided into a metal and a ceramic bracket group. Thirty brackets per group were taken from central incisors, canines, and second premolars and quantitatively analyzed for biofilm coverage with the Rutherford backscattering detection method. Five micrographs were obtained per bracket with views from the buccal, mesial, distal, gingival, and occlusal aspects, resulting in a total of 300 images. Biofilm formation between groups was compared using the Mann-Whitney U-test (alpha = .05). RESULTS: Total biofilm formation was 12.5% +/- 5.7% (3.3 +/- 1.6 mm(2)) of the surface on metal and 5.6% +/- 2.4% (1.5 +/- 0.6 mm(2)) on ceramic brackets. Differences between groups were statistically significant (P < .05). A pairwise comparison of biofilm formation revealed significantly lower biofilm formation on ceramic brackets with respect to intraoral location (central incisor, canine, second premolar) and bracket surface (buccal, mesial, distal). CONCLUSIONS: The hypothesis was rejected. The results indicate that ceramic brackets exhibit less long-term biofilm accumulation than metal brackets. PMID- 21542723 TI - Reliability of the integrated radiograph-photograph method to obtain natural head position in cephalometric diagnosis. AB - OBJECTIVE: To introduce a simple and reliable method to reorient lateral radiographs to the natural head position (NHP) according to standardized photographs made at NHP. MATERIAL AND METHODS: The study has two parts. In the first part, 45 patients were randomly selected from a patient cohort. Photographs (at NHP) and cephalograms from each patient were taken and assessed in two sessions by two observers. The time between the first and the second session was 5 weeks. The repeatability of profile measurements on cephalograms compared with standardized photographs of the same patient was determined; in the second part, the repeatability of three superimposing protocols (ie, the soft tissue N/subnasale line [V-line], the esthetic line [E-line], and a proposed nose best fit line [N-line]) was compared for the reorientation of the cephalogram according to the photographs made at the NHP. RESULTS: Our results showed that the integration of radiographs and photographs is an objective and reliable method to obtain NHP in lateral cephalograms. The N-line is a reproducible and stable reference line for the reorientation of radiographs to obtain NHP. CONCLUSION: Reorientation of radiographs according to standardized photographs made at the NHP is a reliable and objective method to standardize the radiographs at the NHP for cephalometric analysis. The N-line is a reproducible and stable reference line for the reorientation. It is preferred over the V-line or even E line, especially when the radiographs and photographs are taken at different sessions or at different treatment stages. PMID- 21542724 TI - Robotic-assisted transaxillary parathyroidectomy of an atypical adenoma. AB - The advancement of minimally invasive surgical technologies over the past several years has led to improved surgical outcomes and greater patient satisfaction. Particularly for patients undergoing parathyroidectomies, endoscopic surgeries resulted in smaller surgical scars when compared with the open approach. Early endoscopic methods, however, were still restricted in their ability to provide adequate dexterity, two-dimensional views of the operative field; and while smaller than open surgeries, still left the presence of a small cervical scar. The limitations of endoscopic surgery led to application of the da Vinci S surgical robot system (Intuitive Surgical, Sunnyvale, CA, USA) and a novel transaxillary approach for parathyroidectomy. This surgical technique and approach is ideal for patients with primary hyperparathyroidism. This case report demonstrates that parathyroidectomy with en bloc thyroid lobectomy for atypical parathyroid adenomas using robotic- assisted transaxillary surgery is safe and feasible. PMID- 21542725 TI - How experienced speech-language pathologists learn to work on teams. AB - This study sought to understand how 10 speech-language pathologists (SLPs) learned to work on teams with other disciplines. Team-work skills are cited by universities as a generic skill their graduate possess and by professional speech language pathology organizations as an important skill for clinicians. Few allied health curriculums, including speech-language pathology, teach explicit team-work skills. Which leads to the question: Where have experienced SLPs learned these skills? Interviews from 10 practicing SLPs determined where and how they learned to work on teams as well as team-skills that entry-level SLPs should possess. Only two of the 10 participants had any formal team training during university study and nine out of 10 participants described learning "on the job" during their first professional job with assistance from a workplace mentor. All participants believed that training in team-work with other disciplines is important to learn during university study. The needed attitudes, knowledge, and skills described for entry-level SLPs reflects similar characteristics listed by the World Health Organization's 2010 recommendation for inter-professional education. These findings support the inclusion of inter-professional education learning opportunities in the speech-language pathology curriculum. PMID- 21542726 TI - Adolescents in The Netherlands underestimate risk for sexually transmitted infections and deny the need for sexually transmitted infection testing. AB - Worldwide, adolescents are at risk for sexually transmitted infections (STI). In The Netherlands, test rates among young heterosexual people are low and knowledge on the behavioral determinants of testing is scarce. In this study, we investigated STI testing in more detail with two independent samples of 16-25 year old vocational school students (n = 756/n = 1302). The aim of this study was to examine risk perceptions in relation to STI testing among lower educated adolescents in order to inform the development of an intervention promoting STI testing. We compared multiple measures of risk perception, fear of testing, self efficacy for testing, and risk knowledge between groups of adolescents engaging and not engaging in risk behavior. The results show that at least half of the participating students with sexual experience underestimated their susceptibility for STI and showed an optimistic bias. Students with sexual experience also considered STI very severe but lacked self-efficacy for testing. This combination can yield a defensive reaction to the threat of STI that, in turn, results in the underestimation of personal risks. However, self-efficacy did not mediate the relationship between intention to test and perceived relative risk. In conclusion, our findings show underestimation of personal risks by vocational school students, a high perceived severity of STI and low self-efficacy for testing. A low level of knowledge regarding sexual risks and symptoms of STI might have contributed to low risk perceptions. Self-efficacy did not change the relation of intention-to-test to perceived risk. PMID- 21542728 TI - Factors associated with the interdental papilla height between two maxillary central incisors: a radiographic study. AB - BACKGROUND: Various factors affect the central maxillary incisor papilla height (PH) and central clinically observable PH (COPH) such that a study of these factors and their interactions is needed. This study reports on an investigation of the factors associated with PH and COPH in patients with and without papilla recession. METHODS: The central papilla was visually assessed in 450 adults using standardized periapical radiographs of maxillary central incisors. Various vertical and horizontal distances were measured including the lengths from the proximal cemento-enamel junction (pCEJ) to apical contact point (CP), bone crest (BC) to CP (BC-CP), BC to pCEJ (BC-pCEJ), and papilla tip (PT) to CP (PT-CP) and the interdental width at the pCEJ level (IW), width at the BC level (crest width [CW]), and width at the PT level (PTW). PH was defined as the length from the PT to BC, and COPH was defined as the length from the PT to pCEJ. Simple analyses for PH and COPH were performed, and significant variables were entered into multiple linear regression models. RESULTS: Among all study patients, papilla recession status and PT-CP were significant independent predictors of PH (both P <0.001). Age, papilla recession status, PT-CP, and BC-pCEJ were significant independent predictors of COPH (all P <0.001). Among patients with papilla recession, CW and PT-CP independently predicted PH (both P <0.001). All variables tested (except sex and CW) were significantly associated with COPH in patients with papilla recession, especially IW, PTW, PT-CP, and BC-pCEJ (P <0.001 for these variables). CONCLUSIONS: The effects of age and BC-pCEJ on COPH change differed in patients without and with recession, suggesting that the initial change in COPH was large but later slowed after recession occurred while there was no severe interdental bone loss progression. However, additional clinical study is needed to find out other variables that may decrease or ameliorate the severity of central papilla recession by restorative/prosthetic or orthodontic intervention and to confirm this possibility. PMID- 21542729 TI - Gingival blood glucose estimation with reagent test strips: a method to detect diabetes in a periodontal population. AB - BACKGROUND: Periodontal disease is considered the sixth complication of diabetes. Therefore, as a foremost responsibility of the periodontist, the present study was carried out to screen an unsuspecting periodontal population for the presence of diabetes with the help of gingival blood glucose and reagent test strips. METHODS: A total of 356 patients with no known medical history of diabetes visiting the outpatient Department of Periodontics, at the Government Dental College and Hospital, Nagpur, Maharashtra, India, were divided into 3 groups: group 1 included patients with a healthy periodontium; group 2, patients with gingivitis; and group 3, patients with periodontitis. Gingival blood, formed by puncturing the interdental papilla of the upper anterior teeth with a lancet, was allowed to fall onto a test reagent strip, where the color change was noted, and corresponding glucose values recorded. Patients with glucose values >120 gm% (per manufacturer provided chart) were sent for glucose tolerance tests to confirm their glycemic status. Patients with abnormal glucose tolerance values were further referred to a physician for the confirmation of diabetes. RESULTS: Diabetes was detected in 19.1% of the survey population, of which 3.9% of patients belonged to group 1, 7.8% of patients belonged to group 2, and 7.3% of patients belonged to group 3. Diabetes was detected in 40.8% of patients with hyperglycemia, of which 8.4% of patients belonged to group 1, 16.8% of patients belonged to group 2, and 15.6% of patients belonged to group 3. A total of 10.11% of the survey population who tested positive for diabetes were females and 8.99% were males. CONCLUSIONS: The use of reagent strips for the estimation of gingival blood glucose seemed to be a suitable option for the screening of an unsuspecting periodontal population for the presence of diabetes; however, additional studies in a larger population are needed to confirm their suitability. PMID- 21542730 TI - Immediate loading of implants placed with the osteotome technique: one-year prospective case series. AB - BACKGROUND: There is limited information regarding marginal bone-level changes around immediately loaded implants placed with the osteotome technique. The aim of this case series is to prospectively evaluate the clinical and radiographic outcome of immediately loaded implants placed with the osteotome technique over a 12-month period. METHODS: Eighteen patients in need of oral prosthetic rehabilitation that included single implant placement in positions #4 to #13 and/or #20 to #29 participated in this prospective trial. A modified implant installation procedure with an under preparation of the implant bed using the osteotome technique and immediate loading of the implant was performed. Clinical examinations were performed at 2 weeks, 6 months, and 12 months of follow-up. Radiographic examinations were performed at implant installation and at the 6- and 12-month follow-up visits. RESULTS: One implant failed to integrate and was removed at 3 months after implant installation. Four of 20 implants had insertion torque value >35 Ncm. The mean marginal bone loss was -0.09 mm at the 6-month and -0.19 mm at the 12-month follow-up visits. CONCLUSION: The present case series indicates that implants placed with the osteotome technique and immediately loaded did not demonstrate a high insertion torque and exhibited minimal marginal bone loss. PMID- 21542731 TI - Biomimetic surface modification using synthetic oligopeptides for enhanced guided bone regeneration in beagles. AB - BACKGROUND: In previous studies, oligopeptide corresponding to the cell-binding domains of bone morphogenetic proteins that bind to bone morphogenetic protein receptor enhanced the bone regenerative capacity of bovine bone minerals (BBM). The aim of this study is to evaluate the ability of BBM coated with oligopeptide to promote periodontal regeneration in a 1-wall intrabony defect model in dogs. METHODS: The second and third mandibular premolars and first molars of six adult beagles were extracted bilaterally, and the extraction sites were allowed to heal for 10 weeks. The 1-wall intrabony defects were prepared bilaterally on the mesial and distal side of the fourth mandibular premolars. Twenty-four intrabony defects were assigned to four treatment groups: 1) open flap debridement; 2) guided tissue regeneration (GTR); 3) GTR with a collagen membrane and BBM; and 4) GTR with a collagen membrane and BBM coated with the oligopeptide (Pep-BBM). The animals were sacrificed 10 weeks after surgery. For the histometric analysis, defect height, junctional epithelium migration, new cementum, new bone height, and new bone area were measured. New bone volume was measured using microcomputed tomography. RESULTS: Wound healing was generally uneventful. For junctional epithelium migration, the BBM and Pep-BBM groups exhibited mean (+/- SE) values of 0.53 +/- 0.41 and 0.48 +/- 0.30 mm, and for new cementum height, 1.71 +/- 0.46 and 2.50 +/- 2.00 mm, respectively. For junctional epithelium migration and cementum regeneration, there were no significant differences between the two groups. The mean (+/- SE) values of new bone height and new bone volume in the Pep-BBM group (3.88 +/- 0.31 mm and 32.35% +/- 9.60%) were significantly greater than the mean values for the BBM group (2.60 +/- 0.41 mm and 20.56% +/- 1.89%). For bone regeneration, the Pep-BBM group showed superior results compared to the BBM group with statistically significant differences. CONCLUSIONS: Through various parameters to evaluate periodontal regeneration, this oligopeptide coating influenced only the ability of BBM to promote bone regeneration in 1-wall intrabony defects in beagles. Junctional epithelium migration and cementum regeneration were not affected by this oligopeptide coating, and further investigations with special focus on regeneration of the periodontal ligament are necessary. PMID- 21542732 TI - Radiographic considerations for the regional anatomy in the posterior mandible. AB - BACKGROUND: Previous studies of the inferior alveolar nerve have used cadaveric specimens in small patient groups. The purpose of this study was to describe the anatomy in the posterior mandible with respect to the inferior alveolar nerve (IAN) using computed tomography (CT) images in a large patient population. We hypothesize that CT scans are an important component of a thorough treatment plan for minimizing risk to the IAN and optimizing surgical outcomes. METHODS: CT scans of 195 patients (62 males and 133 females; age range: 22 to 88 years) were evaluated retrospectively. With the aid of computer software, cross-sectional images were examined at 5-mm increments distal to the mental foramen to the ascending ramus. Four measurements were made at each cross-sectional image. The distances from the IAN to the: 1) alveolar crest (CN); 2) buccal cortical plate (BN); 3) lingual cortical plate (LN); and 4) inferior border (IN) were measured. RESULTS: Most measurements for males and females were significantly different. Mean values were as follows (males/females): CN, 13.85 +/- 0.43/11.98 +/- 0.40 mm (P <0.01); BN, 4.98 +/- 0.15/4.47 +/- 0.11 mm (P <0.01); LN, 2.93 +/- 0.12/3.19 +/- 0.10 mm (P <0.10); and IN, 7.76 +/- 0.16/7.00 +/- 0.15 mm (P <0.01). The 95% confidence intervals indicated that many patients had limited bone volume in the buccal shelf or ascending ramus. CONCLUSION: Given the high degree of variability in mandibular bone volume surrounding the IAN and the position of the IAN, the use of CT scans should be considered for surgical procedures in the posterior mandible when there is risk of injury to the IAN. PMID- 21542733 TI - Radiographic analysis of a transalveolar sinus-lift technique: a multipractice retrospective study with a mean follow-up of 5 years. AB - BACKGROUND: Various sinus-lift techniques have been described in the literature. The aim of this retrospective study is to evaluate the efficacy of a transalveolar sinus-lift technique in terms of implant survival, marginal bone loss, and complications. METHODS: A total of 538 patient records were examined, and after applying exclusion and inclusion criteria, a sample of patients was included with a mean follow-up of 5 years. Implants with a smooth or tapered surface were considered. Therefore, only sinus lifts with inorganic bovine bone matrix or demineralized bone matrix were included, and 1,536 periapical radiographs were analyzed. Outcome measures were implant success, implant failure (peri-implantitis and loss of osseointegration), marginal bone resorption, and biologic complications (membrane perforations, sinusitis, and intraoperative and/or postoperative hemorrhage). Periapical radiographs were evaluated before surgery, post-surgery, and after 6 months and 1, 3, and 5 years. We analyzed the residual crestal bone height under the sinus, the amount (mm) of height increase after surgery, and values of implant marginal bone resorption for considered follow-ups. RESULTS: Two hundred eighty-two (282) patients were excluded. Therefore, 256 patients treated with the transalveolar sinus-lift technique were included. A total of 376 dental implants and 323 sinus lifts were analyzed. The overall rates of implant success and failure were 94.9% and 5.1%, respectively. The mean bone loss around implants was 1.98 mm (mean follow-up of 5 years). Patients treated with inorganic bovine bone matrix showed a better implant success rate (P = 0.03) than did patients treated with demineralized human matrix. Three Schneiderian membrane perforations occurred in the 323 sinus lifts. In these cases, the surgeon performed another surgical operation after 3 months. Postoperative complications were peri-implantitis (six cases) and osseointegration losses (13 cases). CONCLUSIONS: The transalveolar sinus-lift technique was a safe, minimally invasive technique with an implant success rate comparable to traditional implantology. The implant success rate was positively affected by the low-resorption graft material, and a low bone-resorption rate around implants was found. PMID- 21542734 TI - Clinical efficacy of 1% alendronate gel as a local drug delivery system in the treatment of chronic periodontitis: a randomized, controlled clinical trial. AB - BACKGROUND: Alendronate (ALN), an aminobisphosphonate, is known to inhibit osteoclastic bone resorption and was proposed to have osteostimulative properties in vivo and in vitro as shown by an increase in matrix formation. The present study aims to explore the efficacy of a 1% ALN gel compared to a placebo gel as a local drug delivery system in adjunct to scaling and root planing (SRP) for the treatment of intrabony defects in patients with chronic periodontitis. METHODS: A total of 66 intrabony defects were treated with a 1% ALN or placebo gel. The ALN gel was prepared by adding ALN to a polyacrylic acid-distilled water mixture. Clinical parameters (modified sulcus bleeding index, plaque index, probing depth [PD], and clinical attachment level [CAL]) were recorded at baseline and 2 and 6 months, and radiographic parameters at baseline and 6 months. The defect fill at baseline and 6 months was calculated on standardized radiographs by using image analysis software. RESULTS: The mean PD reduction and CAL gain were greater in the ALN group than in the placebo group at 2 and 6 months. Furthermore, a significantly greater mean percentage of bone fill was found in the ALN group (40.4% +/- 11.71%) than in the placebo group (2.5% +/- 1.02%). CONCLUSIONS: Results of the present study shows that the local delivery of 1% ALN into the periodontal pocket stimulated a significant increase in PD reduction, CAL gain, and improved bone fill compared to a placebo gel as an adjunct to SRP. These results can provide a new direction in the field of periodontal healing. PMID- 21542735 TI - Non-carious cervical lesions associated with gingival recessions: a decision making process. AB - BACKGROUND: A method to predetermine the maximum root coverage level (MRC) was recently demonstrated to be reliable in predicting the position of the soft tissue margin after root coverage surgery. The aim of the present study is to suggest a decision-making process for treating non-carious cervical lesions (NCCLs) associated with gingival recessions based upon the topographic relationship between the MRC and NCCL and to assess patient and independent periodontist esthetic evaluations. METHODS: Five treatments were performed in 94 patients with NCCLs associated with a single gingival recession: 1) coronally advanced flap (CAF); 2) bilaminar procedure; 3) coronal odontoplasty plus restoration plus root odontoplasty plus CAF; 4) restoration plus CAF; and 5) restorative therapy. Clinical and esthetic evaluations made by the patient and an independent periodontist were done 1 year after treatments. RESULTS: The satisfaction of the patient and periodontist with esthetics was very high in all NCCL treatments and Miller Class gingival recessions. The patient satisfaction and evaluation of root coverage and the periodontist evaluation of root coverage were statistically correlated with color-match evaluations and not with the amount of root coverage clinically achieved in each patient. CONCLUSION: The proposed approaches provided good esthetic appearance and correct emergence profile for the great majority of NCCLs associated with gingival recessions. PMID- 21542736 TI - A lost opportunity for public health--the FDA advisory committee report on menthol. PMID- 21542737 TI - The threat of menthol cigarettes to U.S. public health. PMID- 21542738 TI - Images in clinical medicine. Hutchinson's nail sign. PMID- 21542739 TI - Pragmatic trials--guides to better patient care? PMID- 21542740 TI - The loneliness of visiting. PMID- 21542741 TI - Leukotriene antagonists as first-line or add-on asthma-controller therapy. AB - BACKGROUND: Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS: We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2) agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score <=6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score >=1). We randomly assigned patients to 2 years of open label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS: Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS: Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group. (Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others; Controlled Clinical Trials number, ISRCTN99132811.). PMID- 21542743 TI - Bisphosphonate use and atypical fractures of the femoral shaft. AB - BACKGROUND: Studies show conflicting results regarding the possible excess risk of atypical fractures of the femoral shaft associated with bisphosphonate use. METHODS: In Sweden, 12,777 women 55 years of age or older sustained a fracture of the femur in 2008. We reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft fracture and identified 59 patients with atypical fractures. Data on medications and coexisting conditions were obtained from national registries. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had ordinary subtrochanteric or shaft fractures. RESULTS: The age-adjusted relative risk of atypical fracture was 47.3 (95% confidence interval [CI], 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). CONCLUSIONS: These population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small. (Funded by the Swedish Research Council.). PMID- 21542742 TI - Radical prostatectomy versus watchful waiting in early prostate cancer. AB - BACKGROUND: In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results. METHODS: From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model. RESULTS: During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4). CONCLUSIONS: Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment. (Funded by the Swedish Cancer Society and the National Institutes of Health.). PMID- 21542744 TI - Sentinel-lymph-node biopsy for cutaneous melanoma. PMID- 21542745 TI - The hemostatic system as a modulator of atherosclerosis. PMID- 21542746 TI - Images in clinical medicine. Fat embolism syndrome. PMID- 21542747 TI - Clinical problem-solving. A sweet source of abdominal pain. PMID- 21542748 TI - Asthma treatment guidelines meet the real world. PMID- 21542749 TI - Effective treatment for early-stage prostate cancer--possible, necessary, or both? PMID- 21542750 TI - Leishmania--a parasitized parasite. PMID- 21542751 TI - Treatment of acute otitis media in children. PMID- 21542752 TI - Treatment of acute otitis media in children. PMID- 21542753 TI - Treatment of acute otitis media in children. PMID- 21542754 TI - Treatment of acute otitis media in children. PMID- 21542755 TI - Treatment of acute otitis media in children. PMID- 21542756 TI - Treatment of acute otitis media in children. PMID- 21542758 TI - Dialysis catheters and recombinant tissue plasminogen activator. PMID- 21542760 TI - Iniparib in metastatic triple-negative breast cancer. PMID- 21542762 TI - Glycerol kinase deficiency in adult hypoglycemic acidemia. PMID- 21542766 TI - Invasion by invitation: rhizobial infection in legumes. AB - Nodulation of legume roots typically begins with rhizobia attaching to the tip of a growing root-hair cell. The attached rhizobia secrete Nod factors (NF), which are perceived by the plant. This initiates a series of preinfection events that include cytoskeletal rearrangements, curling at the root-hair tip, and formation of radially aligned cytoplasmic bridges called preinfection threads (PIT) in outer cortical cells. Within the root-hair curl, an infection pocket filled with bacteria forms, from which originates a tubular invagination of cell wall and membrane called an infection thread (IT). IT formation is coordinated with nodule development in the underlying root cortex tissues. The IT extends from the infection pocket down through the root hair and into the root cortex, where it passes through PIT and eventually reaches the nascent nodule. As the IT grows, it is colonized by rhizobia that are eventually released into cells within the nodule, where they fix nitrogen. NF can also induce cortical root hairs that appear to originate from PIT and can become infected like normal root hairs. Several genes involved in NF signaling and some of the downstream transcription factors required for infection have been characterized. More recently, several genes with direct roles in infection have been identified, some with roles in actin rearrangement and others with possible roles in protein turnover and secretion. This article provides an overview of the infection process, including the roles of NF signaling, actin, and calcium and the influence of the hormones ethylene and cytokinin. PMID- 21542767 TI - Use of a secretion trap screen in pepper following Phytophthora capsici infection reveals novel functions of secreted plant proteins in modulating cell death. AB - In plants, the primary defense against pathogens is mostly inducible and associated with cell wall modification and defense-related gene expression, including many secreted proteins. To study the role of secreted proteins, a yeast based signal-sequence trap screening was conducted with the RNA from Phytophthora capsici-inoculated root of Capsicum annuum 'Criollo de Morelos 334' (CM334). In total, 101 Capsicum annuum secretome (CaS) clones were isolated and identified, of which 92 were predicted to have a secretory signal sequence at their N terminus. To identify differences in expressed CaS genes between resistant and susceptible cultivars of pepper, reverse Northern blots and real-time reverse transcription polymerase chain reaction were performed with RNA samples isolated at different time points following P. capsici inoculation. In an attempt to assign biological functions to CaS genes, we performed in planta knock-down assays using the Tobacco rattle virus-based gene-silencing method. Silencing of eight CaS genes in pepper resulted in suppression of the cell death induced by the non-host bacterial pathogen (Pseudomonas syringae pv. tomato T1). Three CaS genes induced phenotypic abnormalities in silenced plants and one, CaS259 (PR4 l), caused both cell death suppression and perturbed phenotypes. These results provide evidence that the CaS genes may play important roles in pathogen defense as well as developmental processes. PMID- 21542768 TI - Absorbable versus nonabsorbable mesh repair of congenital diaphragmatic hernias in a growing animal model. AB - INTRODUCTION: The repair of large congenital diaphragmatic hernia frequently results in patch disruption and recurrence as patients grow in size. Absorbable meshes allow for ingrowth of endogenous tissue as they are degraded, providing a more natural and durable repair. The aim of this study was to compare the characteristics of the new diaphragmatic tissue between an absorbable biologic mesh and a nonabsorbable mesh for repairing diaphragmatic hernia in a growing animal model. METHODS: The left hemi-diaphragm of twenty 2-month-old Yucatan pigs was nearly completely resected. Small intestinal submucosa (SIS; Cook Biotech, Lafayette, IN) and expanded polytetrafluoroethylene (ePTFE; W.L. Gore & Associates, Flagstaff, AZ) were randomly assigned to cover the defect in 10 animals each, and were survived for 6 months. During necropsy, newly formed diaphragmatic tissue was evaluated and compared between the two groups. RESULTS: At necropsy, the animals had tripled their weight. Patch disruption and herniation occurred in 3 animals in the ePTFE group and none in the SIS group. The SIS mesh had better integration to the chest wall (2.8 +/- 0.2 versus 1.3 +/- 0.3), more muscle growth within the newly formed diaphragmatic tissue (1.9 +/- 0.2 versus 0.4 +/- 0.2), and less fibrotic tissue (2.1 +/- 0.5 versus 3.4 +/- 0.4) than ePTFE. There was no difference between SIS and ePTFE in terms of adhesion scores to the lung (2 +/- 0.4 versus 2.4 +/- 0.4) and liver (1.8 +/- 0.3 versus 2.2 +/- 0.5). CONCLUSION: SIS allows for tissue ingrowth from surrounding tissue as it degrades, providing a more durable repair with 30% less incidence of herniation in a porcine model. As the diaphragm grows, SIS resulted in a more natural repair of the defect with more tissue growth, better tissue integration, and a comparable adhesion formation to ePTFE. PMID- 21542769 TI - Genetic characterization of non-O157 verocytotoxigenic Escherichia coli isolated from raw beef products using multiple-locus variable-number tandem repeat analysis. AB - Verocytotoxigenic Escherichia coli (VTEC) can produce serious human illness linked to the consumption of contaminated food, mainly of bovine origin. There is growing concern about non-O157 VTEC serotypes, which in some countries cause severe infections in a proportion similar to O157:H7 strains. As several epidemiological studies indicated the important role of meat as the major vehicle in the transmission of this pathogen to human consumers, our aim was to investigate the genetic diversity among non-O157:H7 VTEC isolated from raw beef products. We performed a multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA), and to our knowledge, this is the first time that VTEC serotypes O8:H19, O112:H2, O113:NM, O171:NM, ONT:H7, ONT:H19, and ONT:H21 were typed by this method. MLVA typing grouped the total number of strains from this study (51) into 21 distinct genotypes, and 11 of them were unique. Several MLVA profiles were found in different serotypes, O178:H19 being the most variable. The isolates could be principally discriminated by alleles of three of seven loci studied (CVN001, CVN004, and CVN014), and on the other hand, CVN003 rendered null alleles in all the isolates. As some VNTR markers might be serotype specific, it is possible that the implementation of new VNTR loci will increase intraserotype discrimination. PMID- 21542770 TI - Prevalence of metabolic syndrome among human immunodeficiency virus-infected subjects is widely influenced by the diagnostic criteria. AB - BACKGROUND: The aim of this study was to compare the prevalence of metabolic syndrome in human immunodeficiency virus (HIV)-infected patients treated with highly active antiretroviral therapy (HAART), using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), European Group for the Study of Insulin Resistance (EGIR), and International Diabetes Federation (IDF) definitions. METHODS: A cross-sectional study was carried out with 159 consecutive adult HIV-infected subjects (120 males and 39 females) under HAART. Anthropometric and laboratory parameters were measured by standard methods. Hyperinsulinemia was defined by a fasting concentration >75th percentile of values obtained in healthy individuals (107.5 pmol/L). RESULTS: The prevalence of ATP III-defined metabolic syndrome was 10.1%; it was 28.3% according to EGIR criteria and 15.1% using the IDF definition. The concordance between the definitions was low (kappa coefficient ranging between 0.134 and 0.296). All subjects with EGIR-defined metabolic syndrome had hyperinsulinemia, but only 50% of those with ATP III-defined metabolic syndrome and 62.5% in the IDF metabolic syndrome population had hyperinsulinemia. CONCLUSIONS: The inclusion of hyperinsulinemia as a criterion in the EGIR metabolic syndrome definition made it more discriminative than the ATP III definition, both in men and women, and than the IDF definition in men to identify metabolic syndrome in HIV-infected subjects under HAART. PMID- 21542771 TI - Combined low-dose oral propranolol and oral prednisolone as first-line treatment in periocular infantile hemangiomas. AB - PURPOSE: The purpose of this report was to describe 2 cases of periocular infantile hemangiomas (IHs) that were successfully treated with low-dose oral propranolol alone and in combination with oral prednisolone. METHODS: Two infants aged 3 months and 6 weeks, respectively, were referred for management of vision threatening periocular IHs causing ocular displacement and obscuration of the visual axis. The first infant had a superficial left upper eyelid capillary hemangioma with extraconal extension and the second infant had a deep preseptal capillary hemangioma in the right lower eyelid with intraconal extension. Both cases were started on oral propranolol 0.5 mg/kg/day in divided doses and titrated up to 1.5 mg/kg/day as first-line therapy. The first infant was also given oral prednisolone 2 mg/kg/day during the initial first month of treatment. RESULTS: Rapid regression in sizes of the hemangiomas was seen within the first 3 days of treatment. By 2 months of therapy, both infants had achieved normal ocular alignment. The second infant experienced a transient period of hypotension after the first dose of propranolol was started but recovered spontaneously. Both infants did not experience any adverse effects of propranolol throughout the treatment period. CONCLUSIONS: Low-dose oral propranolol is an effective first line therapy for the management of vision-threatening IH. Dose escalation in combination with oral prednisolone after pediatric assessment might be useful in avoiding adverse effects of propranolol in young infants. PMID- 21542772 TI - Laparoendoscopic single-site extraperitoneal inguinal hernia repair: initial experience in 10 patients. AB - BACKGROUND AND PURPOSE: Recent technical advances and a trend toward laparoscopic single incision surgery have led us to explore the feasibility of laparoendoscopic single-site (LESS) hernia repair. PATIENTS AND METHODS: We present our technique and initial experience with LESS extraperitoneal inguinal hernia repair in 10 consecutive men with unilateral inguinal hernias. Age range was 43.7 (28-64) years. Mean body mass index was 28 (range 24-30). Six were left inguinal hernias. There were six indirect and four direct hernias. Three patients had undergone previous open appendectomy. Incarcerated or bilateral hernias were excluded from our initial series. All cases were performed by three surgeons who were experienced in conventional totally extraperitoneal laparoscopic hernia repair as well as experienced in LESS. A literature review of current single-port inguinal hernia repair data is also presented. RESULTS: The mean operative time was 53 minutes (range 45-65 min). The average length of skin incision was 2.8 cm (range 2.3-3.2 cm). No drain was necessary in any of the patients, while no recordable bleeding was observed. There were no intraoperative or immediate postoperative complications. Hospitalization period was 2 days for all patients. After a limited follow-up of 1 month, there have been no recurrences and no complaints of testicular pain. The results of the current series compare favorably with those found in a literature review. CONCLUSION: LESS extraperitoneal inguinal hernia repair is both feasible and safe, although more technically demanding than its conventional laparoscopic counterpart. Although the cosmetic result with the former approach may prove superior, there are standing questions regarding the complications and long-term outcome. Randomized and if possible blinded trials that compare conventional and single-incision laparoscopic hernia repair may help to distinguish the most advantageous technique. PMID- 21542773 TI - FloSeal reduces the incidence of lymphoceles after lymphadenectomies in laparoscopic and robot-assisted extraperitoneal radical prostatectomy. AB - PURPOSE: To evaluate the efficacy and cost-effectiveness of FloSeal((r)) hemostatic matrix in preventing lymphocele development after pelvic lymphadenectomy (PLA). MATERIALS AND METHODS: This was a single-center, matched comparison of lymphadenectomies in laparoscopic and robot-assisted extraperitoneal radical prostatectomy (ERP) performed with and without FloSeal between January 2008 and October 2009. FloSeal was applied topically in the lymphadenectomy zone immediately after node resection. Cost analysis for lymphocele treatment was performed. RESULTS: A total of 142 patients underwent PLA with ERP (32 with FloSeal, 110 without FloSeal). The mean number of lymph nodes removed was 6.5+/-4.5 (range 2-20). Median prostate-specific antigen concentration was 8.5 ng/mL (range 1.5-24 ng/mL). There was one (3.1%) symptomatic lymphocele in the FloSeal group compared with 16 (14.5%) in the non FloSeal group. The median number of lymph nodes removed was 8 (range 5-20) in the FloSeal group and seven (range 3-25) in the non-FloSeal group. The only lymphocele in the FloSeal group was treated with percutaneous drainage alone. In the non-FloSeal group, six symptomatic lymphoceles were managed conservatively four with percutaneous puncture and six with fenestration after percutaneous drainage. The mean cost per patient of treating symptomatic lymphoceles was ?327 ($455) in the FloSeal group (total costs ?10,481 [$14,559]) vs ?553 ($769) (total costs ?60,870 [$84,551]) in the non-FloSeal group. CONCLUSIONS: These preliminary data suggest that the use of FloSeal after lymphadenectomy can reduce the number of symptomatic lymphoceles and is cost-effective. PMID- 21542774 TI - Renal parenchymal damage after percutaneous nephrolithotomy with one-stage tract dilation technique: a randomized clinical trial. AB - PURPOSE: To compare the effects of one-stage vs gradual dilation techniques during percutaneous nephrolithotomy (PCNL) on postoperative renal scar formation and overall renal function. PATIENTS AND METHODS: Of 152 adult patients who underwent surgery during the study period, 48 were randomized into two groups. In group 1 (n=19), gradual tract dilation with Alken metallic dilators was used, and in group 2 (n=29), one-stage tract dilation was used. We compared patient demographics, intraoperative and preoperative parameters, postoperative overall renal function, and renal scar formation on the target renal pole. RESULTS: Access time (P=0.001; 95% confidence interval [CI]: 3.19-6.30) and radiation exposure during access (P=0.03; 95% CI: 0.03-0.66) were significantly shorter in group 2. In group 1, the decrease in mean technetium-99m dimercaptosuccinic acid (99m-Tc DMSA) uptake from 44.1+/-20.1% to 43.4+/-19.6% 4 weeks postoperatively ( 0.7%+/-0.5%; P=0.27; 95% CI: -0.56-1.93) was not significant. In group 2, however, there was a significant decrease in post-PCNL 99m-Tc DMSA uptake 2 ( 2.4+/-0.3%, from 50.1+/-13.5% to 47.7+/-13.8%; P=0.001; 95% CI: 1.13-3.66). Four weeks after surgery, new scar formation or progression of the preoperative scar at the site of access were seen in 14 of 29 (48.3%) patients who were treated with one-stage dilation whereas only 2 of 19 (11.0%) patients who were treated with gradual dilation developed new scarring at the access site (P=0.007). CONCLUSION: Although the one-stage tract dilation technique reduced radiation exposure and access time, in the short term, it may cause more parenchymal damage than the gradual dilation technique. PMID- 21542775 TI - Laparoendoscopic single-site surgery for left adrenalectomy: standardization of technique. AB - PURPOSE: We developed step-by-step standardization of left adrenalectomy using laparoendoscopic single-site surgery (LESS) and evaluated the efficacy and safety of this surgical procedure. PATIENTS AND METHODS: To simplify the procedure, we used a technique that involved handling one straight operating instrument and crossing over another articulated assistant instrument intracorporeally. We classified the reciprocal positions of the two instruments into four types. The surgical procedures were divided into six steps, and we applied one of the four types of position to each step. RESULTS: Seven patients with left adrenal tumor underwent LESS by two operators. Five received left total adrenalectomy, one left partial adrenalectomy, and one bilateral total adrenalectomy. Mean operative time was 178 minutes. Blood loss was minimal (<=50 mL), and convalescence was uneventful in all patients. CONCLUSIONS: Although there is inevitably a learning curve, LESS left adrenalectomy can be safely introduced by beginners using a step by-step standardized technique. PMID- 21542776 TI - Heat adaptation and survival of Cronobacter spp. (formerly Enterobacter sakazakii). AB - Adaptation to sublethal stress can confer increased survival capability on foodborne pathogens. In this article, we report on the adaptive response of Cronobacter spp. to heat and compare the survival of heat adapted to unadapted Cronobacter spp. Five different isolates, representing at least three different Cronobacter spp., were adapted at 46 degrees C for 30 min and subjected to a lethal stress at 52 degrees C. All showed increased survival upon adaptation. Survival was greater in milk-grown cells, but broth-grown cells showed a higher degree of adaptation. The survival potential acquired following adaptation was not transferred to survival in a dry environment or to survival during reconstitution of artificially contaminated milk powder by conventional or microwave heat. The ratio of membrane unsaturated to saturated fatty acids decreased, possibly resulting in a more rigid membrane in adapted cells. Heat adapted cells showed increased survival potential to lethal heat stress, but not to dry stress. Alterations in the ratio of fatty acids in the membrane may explain this adaptation. PMID- 21542778 TI - The ups and downs of social participation: experiences of wheelchair users in Norway. AB - PURPOSE: The primary aim of the study was to explore how people with a disability experience participation in society. A secondary aim was to contribute to the understanding of the concept of participation in terms of the International Classification of Functioning, Disability and Health (ICF). METHOD: Six people with disabilities participated in focus group discussions. The data were analysed following the guidelines for the constant comparative method. RESULTS: Three main categories emerged with regard to the participants' experiences of participation in society. These included: (1) being engaged, (2) being a member of society and (3) interacting as a citizen. Furthermore, a sense of 'climbing up and sliding down the participation ladder' emerged as a core category of participation. This image reflected the dynamic interaction between individual and society; between, on one hand, an individual' attitude, engagement, motivation, interest and capacity, as well as their sense of responsibility vis-a-vis an activity or a social group; and, on the other hand, the opportunities that society and their immediate social worlds offer them. CONCLUSIONS: The fact that participants experience social participation as 'climbing up and sliding down the participation ladder' is important as it enables service providers, managers and policy makers to identify which intrapersonal and environmental factors operate together to limit or enhance the social participation of people with disabilities. This also implies that there is a need for a committed relationship in issues concerning participation for all in society, between people with disabilities and urban planners, and service providers. Findings also imply that participation means being autonomous and making decisions about one's own life and that the subjective dimension of participation must be considered in the revision of the ICF model. Another consideration is to separate activity and participation into two dimensions; i.e. to render more visible the fact that participation is related to environmental, as well as to personal, factors. PMID- 21542777 TI - Peroxisome proliferator-activated receptor gamma/signal transducers and activators of transcription 5A pathway plays a key factor in adipogenesis of human bone marrow-derived stromal cells and 3T3-L1 preadipocytes. AB - Adipogenesis is largely dependent on the signal transducers and activators of transcription (STAT) pathway. However, the molecular mechanism of the STAT pathway in the adipogenesis of human bone marrow-derived stromal cells (hBMSCs) remains not well understood. The purpose of this research was to characterize the transcriptional regulation involved in expression of STAT5A and STAT5B during adipogenesis in hBMSCs and 3T3-L1 cells. The expression of STAT5A and STAT5B increases with the onset of adipogenesis in hBMSCs and 3T3-L1 cells. The PPAR response elements regulatory element of STAT5A exists at a promoter region ranging from -346 to -101, and the CCAAT/enhancer-binding protein (C/EBP) regulatory element is located at -196 to -118 of the STAT5B promoter. C/EBPbeta and C/EBPalpha bound to the STAT5B promoter region, whereas peroxisome proliferator-activated receptor gamma (PPARgamma) bound to STAT5A. RNA interference of STAT5A completely blocked differentiation, whereas the inhibition of STAT5B only partially blocked differentiation. We propose that C/EBPalpha, C/EBPbeta, and PPARgamma control adipogenesis by regulating STAT5B and STAT5A and that STAT5A is necessary, whereas STAT5B plays a supplementary role during adipogenesis. Further, the regulation of PPARgamma-STAT5 by C/EBPbeta signaling seems to be the crucial adipogenesis pathway-initiating cascade of the various adipogenic genes. PMID- 21542779 TI - On total disc replacement. AB - Low back pain consumes a large part of the community's resources dedicated to health care and sick leave. Back disorders also negatively affect the individual leading to pain suffering, decreased quality-of-life and disability. Chronic low back pain (CLBP) due to degenerative disc disease (DDD) is today often treated with fusion when conservative treatment has failed and symptoms are severe. This treatment is as successful as arthroplasty is for hip arthritis in restoring the patient's quality of life and reducing disability. Even so, there are some problems with this treatment, one of these being recurrent CLBP from an adjacent segment (ASD) after primarily successful surgery. This has led to the development of alternative surgical treatments and devices that maintain or restore mobility, in order to reduce the risk for ASD. Of these new devices, the most frequently used are the disc prostheses used in Total Disc Replacement (TDR). This thesis is based on four studies comparing total disc replacement with posterior fusion. The studies are all based on a material of 152 patients with DDD in one or two segments, aged 20-55 years that were randomly treated with either posterior fusion or TDR. The first study concerned clinical outcome and complications. Follow-up was 100% at both one and two years. It revealed that both treatment groups had a clear benefit from treatment and that patients with TDR were better in almost all outcome scores at one-year follow-up. Fusion patients continued to improve during the second year. At two-year follow-up there was a remaining difference in favour of TDR for back pain. 73% in the TDR group and 63% in the fusion group were much better or totally pain-free (n.s.), while twice as many patients in the TDR group were totally pain free (30%) compared to the fusion group (15%). Time of surgery and total time in hospital were shorter in the TDR group. There was no difference in complications and reoperations, except that seventeen of the patients in the fusion group were re-operated for removal of their implants. The second study concerned sex life and sexual function. TDR is performed via an anterior approach, an approach that has been used for a long time for various procedures on the lumbar spine. A frequent complication reported in males when this approach is used is persistent retrograde ejaculation. The TDR group in this material was operated via an extra-peritoneal approach to the retroperitoneal space, and there were no cases of persistent retrograde ejaculation. There was a surprisingly high frequency of men in the fusion group reporting deterioration in ability to have an orgasm postoperatively. Preoperative sex life was severely hampered in the majority of patients in the entire material, but sex life underwent a marked improvement in both treatment groups by the two-year follow-up that correlated with reduction in back pain. The third study was on mobility in the lumbar spinal segments, where X-rays were taken in full extension and flexion prior to surgery and at two-year follow-up. Analysis of the films showed that 78% of the patients in the fusion group reached the surgical goal (non-mobility) and that 89% of the TDR patients maintained mobility. Preoperative disc height was lower than in a normative database in both groups, and remained lower in the fusion group, while it became higher in the TDR group. Mobility in the operated segment increased in the TDR group postoperatively. Mobility at the rest of the lumbar spine increased in both treatment groups. Mobility in adjacent segments was within the norm postoperatively, but slightly larger in the fusion group. In the fourth study the health economics of TDR vs Fusion was analysed. The hospital costs for the procedure were higher for patients in the fusion group compared to the TDR group, and the TDR patients were on sick-leave two months less. In all, these studies showed that the results in the TDR group were as good as in the fusion group. Patients are more likely to be totally pain-free when treated with TDR compared to fusion. Treatment with this new procedure seems justified in selected patients at least in the short-term perspective. Long-term follow-up is underway and results will be published in due course. PMID- 21542780 TI - Engineering cell platforms for myocardial regeneration. AB - INTRODUCTION: Various engineered 'cell-platforms' have been reported in recent years for the possible treatment of myocardial infarction (MI) and end-stage heart failure. These engineered platforms rely on two key factors: cells and/or biomaterial scaffolds for the regeneration of the infarcted heart tissue. AREAS COVERED: Two major cell-platform approaches are described and broadly categorized as 'injectable cell platforms' and 'patch-based cell platforms'. The recent advancements in these cell-platforms in terms of their relative successes in-vivo as well as their clinical feasibility are summarized. Natural as well as synthetic scaffolds, with or without the cellular component, are compared with cell based therapy alone. This review focuses on achievements, as well as the gaps that are presently checking any progress towards producing clinically relevant panacea for myocardial regeneration. EXPERT OPINION: Cardiac and induced pluripotent stem cells will probably be the focus of future research. The combined cell-biomaterial scaffold therapy is superior to cell therapy alone. Nevertheless, encouraging pre-clinical successes have limited translation into clinical practice due to limited cell survival post transplantation, inadequate construct thicknesses for human-sized hearts and the traditional use of 'flat (2D) tissue culture' techniques. The development of complementary dynamic 3D cultivation platforms will probably lead to improved outcomes and enable fast screening of various therapeutic approaches. PMID- 21542781 TI - Transgender late onset psychosis: the role of sex hormones. PMID- 21542782 TI - Analysis of the bacterial community within carrot wash water. AB - Vegetables are washed after harvest to remove unwanted organic and inorganic particles, but wash water contaminated with certain pathogenic microorganisms can potentially contaminate produce. In this study, the microbial diversity of wash water was analyzed in samples taken from a carrot-processing facility. A 16S rRNA gene library with 427 clones was constructed and analyzed by amplified rDNA restriction analysis. For taxonomic classification, the 16S rRNA gene nucleotide sequences of 94 amplified rDNA restriction analysis fingerprints were determined. Each fingerprint indicates a distinct group of microorganisms. The nucleotide sequences were assigned to corresponding reference species. The most prevalent genus was Tolumonas , with 26% of the clones, followed by Acinetobacter and Flacobacterium , with 11% each. The latter two genera contain species that are known to cause nosocomial infections. The fourth most common genus was Arcobacter , comprising 9% of all clones. Some species of Arcobacter are considered to be emerging food pathogens, mainly associated with the contamination of meat products. So far, they have not been considered as contaminants of fresh produce. Based on the sequence data, an Arcobacter-specific PCR assay was developed to facilitate the detection of vegetable-associated Arcobacter strains. PMID- 21542783 TI - Early gene response of human brain microvascular endothelial cells to Listeria monocytogenes infection. AB - The gene expression of human brain microvascular endothelial cells (HBMEC) in response to 4 h of infection by Listeria monocytogenes was analyzed. Four hours after infection, the expression of 456 genes of HBMEC had changed (p < 0.05). We noted that many active genes were involved in the formyl-methionyl-leucyl phenylalanine pathway in infected HBMEC. In the upregulated genes, mRNA levels of interleukin-8 and interleukin-15 in infected cells increased according to microarray and real-time reverse transcription - PCR analyses. Since both cytokines are regarded as potent chemotactic factors, the results suggest that HBMEC are capable of recruiting cells of innate and adaptive immune responses during early L. monocytogenes infection. PMID- 21542784 TI - Local bacteriophage isolates showed anti- Escherichia coli O157:H7 potency in an experimental ligated rabbit ileal loop model. AB - Escherichia coli O157:H7 is considered among the most important recently emerged food-borne bacteria causing severe hemorrhagic diarrhea. Antibiotic treatment is not recommended as a prospective curative agent against this pathogen. Therefore, potency assessment of the local lytic phage isolates infecting E. coli O157:H7 as an alternate remedy to antibiotics was the principal concern of this study. Phage isolates against E. coli O157:H7 were checked by polymerase chain reaction for the presence of the virulence genes stx1 and stx2, and the safe phages were further screened in vitro for their capacity as biocontrol agents. Two bacteriophage strains, namely PAH6 and P2BH2, that had expressed potential antibacterial activity (P < 0.05) in vitro were selected for in vivo testing in ligated rabbit ileal loop models. Both phage isolates were capable of decreasing fluid accumulation in rabbit ileal loops along with reducing bacterial growth (r = 0.992). Combined application of the phages was found most satisfactory, reducing seven log cycles of bacterial growth. Consistent results in both in vivo and in vitro experiments demonstrate the applicability of bacteriophages as a rapid response tool against E. coli O157:H7. To our knowledge, this is the first successful application of the rabbit ileal loop test for therapeutic evaluation of bacteriophages. PMID- 21542785 TI - Cdr2p contributes to fluconazole resistance in Candida dubliniensis clinical isolates. AB - The development of resistance to azole antifungals used in the treatment of fungal infections can be a serious medical problem. Here, we investigate the molecular mechanisms associated with reduced susceptibility to fluconazole in clinical isolates of Candida dubliniensis , showing evidence of the trailing growth phenomenon. The changes in membrane sterol composition were studied in the presence of subinhibitory fluconazole concentrations. Despite lanosterol and eburicol accumulating as the most prevalent sterols after fluconazole treatment, these ergosterol precursors still support growth of Candida isolates. The overexpression of ABC transporters was demonstrated by immunoblotting employing specific antibodies against Cdr1p and Cdr2p. The presence of a full-length 170 kDa protein Cdr1p was detected in two isolates, while a truncated form of Cdr1p with the molecular mass of 85 kDa was observed in isolate 966/3(2). Notably, Cdr2p was detected in this isolate, and the expression of this transporter was modulated by subinhibitory concentrations of fluconazole. These results suggest that C. dubliniensis can display the trailing growth phenomenon, and such isolates express similar molecular mechanisms like that of fluconazole-resistant isolates and can therefore be associated with recurrent infections. PMID- 21542786 TI - A new method for multiple gene inactivations in Bacillus subtilis 168, producing a strain free of selectable markers. AB - This study describes a novel method for repeated gene inactivation in Bacillus subtilis 168. A B. subtilis strain (BS-PS) that is conditionally auxotrophic for lysine was obtained by replacing the PlysA promoter with the Pspac promoter. The homologous recombination integration vector PLC-T was constructed to contain lacI, which encodes a Pspac promoter repressor, and the chloromycetin resistance gene. Target genes were manipulated by generating an insertion sequence with two homologous arms and the target gene in PLC-T to create a specific integrating vector. Integration into the BS-PS chromosome occurred by a single crossover at either of the two homologous arms. The resulting transitional strain (BS-PS-PI) was chloromycetin resistant and lysine auxotrophic and had an unstable genome structure because of the duplication. Excision of lacI and chloromycetin resistance gene was achieved by a second single crossover at the duplication. Recovery of a lysine prototroph functioned as counter-selection and was identified by PCR. In this work, we inactivated nprE and aprE, two protease genes secreted by B. subtilis 168 free of selectable markers. PMID- 21542788 TI - B-cell defects in common variable immunodeficiency: BCR signaling, protein clustering and hardwired gene mutations. AB - Common variable immunodeficiency (CVID) is the most frequently diagnosed symptomatic primary immunodeficiency. CVID develops as a consequence of absence or malfunction of proteins involved with immunoglobulin production by plasma and memory B-cells. The last decade has brought us clarification of several genetic predispositions to the development of CVID. Despite considerable effort, however, for eighty-five percent of CVID patients, disease etiology remains undefined. We propose that in subsets of patients, CVID may involve defective assembly of protein complexes, which is crucial for example for B cell activation upon antigen triggering of the B cell receptor/co-receptor complex. Such defective protein-protein interactions may not be uncovered by standard gene sequencing methods, and may involve epigenetic or post-transcriptional regulation. In this review, we summarize recent developments in CVID research and propose additional approaches to the clarification of etiology of CVID patient groups, necessary for development of tailored treatment options. PMID- 21542787 TI - Activation of Akt rescues endoplasmic reticulum stress-impaired murine cardiac contractile function via glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeation pore opening. AB - AIMS: The present study was designed to examine the impact of chronic Akt activation on endoplasmic reticulum (ER) stress-induced cardiac mechanical anomalies, if any, and the underlying mechanism involved. RESULTS: Wild-type and transgenic mice with cardiac-specific overexpression of the active mutant of Akt (Myr-Akt) were subjected to the ER stress inducer tunicamycin (1 or 3 mg/kg). ER stress led to compromised echocardiographic (elevated left ventricular end systolic diameter and reduced fractional shortening) and cardiomyocyte contractile function, intracellular Ca(2+) mishandling, and cell survival in wild type mice associated with mitochondrial damage. In vitro ER stress induction in murine cardiomyocytes upregulated the ER stress proteins Gadd153, GRP78, and phospho-eIF2alpha, and promoted reactive oxygen species production, carbonyl formation, apoptosis, mitochondrial membrane potential loss, and mitochondrial permeation pore (mPTP) opening associated with overtly impaired cardiomyocyte contractile and intracellular Ca(2+) properties. Interestingly, these anomalies were mitigated by chronic Akt activation or the ER chaperon tauroursodeoxycholic acid (TUDCA). Treatment with tunicamycin also dephosphorylated Akt and its downstream signal glycogen synthase kinase 3beta (GSK3beta) (leading to activation of GSK3beta), the effect of which was abrogated by Akt activation and TUDCA. The ER stress-induced cardiomyocyte contractile and mitochondrial anomalies were obliterated by the mPTP inhibitor cyclosporin A, GSK3beta inhibitor SB216763, and ER stress inhibitor TUDCA. INNOVATION: This research reported the direct relationship between ER stress and cardiomyocyte contractile and mitochondrial anomalies for the first time. CONCLUSION: Taken together, these data suggest that ER stress may compromise cardiac contractile and intracellular Ca(2+) properties, possibly through the Akt/GSK3beta-dependent impairment of mitochondrial integrity. PMID- 21542789 TI - Non-major histocompatibility complex rheumatoid arthritis susceptibility genes. AB - Recent results from genetic and treatment studies have shed new light on chronic inflammatory and autoimmune diseases such as rheumatoid arthritis (RA). In particular, genome-wide association studies (GWAS) have provided supportive evidence that RA is a disease with a strong genetic background. Interestingly, a series of candidate genes have been identified outside of the classical major histocompatibility (MHC) locus, which had long been regarded as the major contributor to the pathogenesis of this disease. Among these genes, PTPN22 plays an outstanding role. CD40, STAT4, PRM1, and TNFAIP3 also seem to be of relevance. Interestingly, there is a significant overlap between RA susceptibility genes and those of other autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes, which suggests common pathogenic mechanisms. Genetic analyses may not only provide new insights into the pathogenesis of RA, but may also open new avenues for therapeutic approaches, because overactive immune-signaling pathways might specifically be addressed by biologic therapies. However, the predictive value of many of the recent findings of large-scale genetic analyses in identifying new genetic polymorphisms remains low. We describe the current knowledge about the role of non-MHC genes in the pathogenesis of rheumatoid arthritis. PMID- 21542790 TI - Expression and immune function of tenascin-C. AB - Our immune system is designed to protect us from danger. Upon pathogen invasion and tissue injury, activation of both innate and adaptive immunity enables us to combat infection and to repair tissue damage. Tenascin-C is a large, extracellular matrix glycoprotein that has a very tightly controlled pattern of expression. Little or no tenascin-C is expressed in most healthy adult tissues; however, it is rapidly and transiently induced at sites of tissue injury and infection. Persistent tenascin-C expression is associated with pathologies such as chronic, non-healing wounds, autoimmune diseases, cancer, and fibrotic diseases. We discuss the myriad roles that this multifunctional molecule plays during the immune response, with a focus on how tissue levels of tenascin-C are regulated and the consequences of misregulated tenascin-C expression in immune regulated disease pathogenesis. PMID- 21542791 TI - Novel regulators of lymphocyte trafficking across high endothelial venules. AB - The physiological recruitment of circulating lymphocytes from the blood into secondary lymphoid tissues is an essential homeostatic mechanism for the immune system because it allows lymphocytes to encounter efficiently both their specific cognate antigen and the regulatory cells with which they need to interact, to initiate, maintain, and terminate immune responses appropriately. This constitutive lymphocyte trafficking is mediated by high endothelial venules (HEVs), which are present in secondary lymphoid tissues other than the spleen. There is growing evidence that lymphocyte trafficking across HEVs involves at least three steps, namely, (i) tethering/rolling, (ii) arrest/firm adhesion/intraluminal crawling, and (iii) transendothelial migration (TEM). Although the mechanisms underlying the first two steps have been determined relatively well, the mechanism regulating TEM is only partially understood. In particular, the molecular mechanism driving lymphocyte movement from the apical to the basolateral surface of the endothelial cells (ECs) of HEVs remains ill defined. This step is crucial for successful lymphocyte extravasation, and is thus an important target for therapeutic intervention in various immunological diseases. Here, we review the molecular mechanisms governing lymphocyte-HEV interactions, and highlight possible roles for two HEV proteins, i.e., nepmucin/CD300g and autotaxin, in lymphocyte TEM. PMID- 21542792 TI - Comparison of QSARs and characterization of structural basis of bioactivity using partial order theory and formal concept analysis: a case study with mutagenicity. AB - Fifteen quantitative structure-activity relationship (QSAR) models developed by various authors for the prediction of mutagenicity of aromatic and heteroaromatic amines were analyzed and thirteen of them, based on 95 amines, were compared using their respective statistics and order theory (Hasse Diagram Technique, HDT) to obtain an ordering of QSAR models. The technique of Formal Concept Analysis (FCA) was applied to the set of 95 amines to extract concepts and, in general, knowledge about the relationship between structural attributes and mutagenicity. HDT may be useful as a general tool for the comparison of different classes of QSAR models. FCA turns out to be a novel mathematical technique for seeking for relationships between molecular structure and activity. PMID- 21542793 TI - Characterization of a recombinant influenza vaccine candidate using complementary LC-MS methods. AB - Influenza vaccination is recognized as the most effective method for reducing morbidity and mortality due to seasonal influenza. To improve vaccine supply and to increase flexibility in vaccine manufacturing, cell culture-based vaccine production has emerged to overcome limitations of egg-based production. The switch of production system and the need for annual re-evaluation of vaccines for the effectiveness due to frequent viral antigenic changes call for methods for complete characterization of the hemagglutinin (HA) antigens and the final vaccine products. This study describes advanced liquid chromatography-mass spectrometry (LC-MS) methods for simultaneous identification of HA proteins and process-related impurities in a trivalent influenza candidate vaccine, comprised of purified recombinant HA (rHA) antigens produced in an insect cell-baculovirus expression vector system (BEVS). N-linked glycosylation sites and glycoforms of the three rHA proteins (corresponding to influenza A subtypes H1N1 and H3N2 and B virus, respectively) were profiled by peptide mapping using reversed-phase (RP) LC-MS(E) (data independent acquisition LC-MS using an alternating low and elevated collision energy scan mode). The detected site-specific glycoforms were further confirmed and quantified by hydrophilic interaction LC (HILIC)-multiple reaction monitoring (MRM) assays. LC-MS(E) was used to characterize the vaccine candidate, providing both protein identities and site-specific information of glycosylation and degradations on each rHA protein. HILIC-MRM methodology was used for rapid confirming and quantifying site-specific glycoforms and potential degradations on each rHA protein. These methods can contribute to the monitoring of vaccine quality especially as it pertains to product comparability studies to evaluate the impact of production process changes. PMID- 21542794 TI - Capturing and amplifying impurities from recombinant therapeutic proteins via combinatorial peptide libraries: a proteomic approach. AB - The technique of combinatorial peptide ligand libraries (CPLL), for capturing and amplifying low-abundance proteins in r-DNA products as well as in a number of other biological systems, is here analyzed in depth and reviewed. This methodology is based on a creation of several millions of bio-specific ligands composed of hexapeptides produced in a combinatorial way. When acting on an overloading and saturation principle, high-abundance species are captured in limited amounts, whereas low-abundance ones keep being concentrated on their bio specific ligand till substantial harvesting from solution (the capture process occurring in general from ca. 50% up to 90% efficiency). Examples are given on tracking host-cell impurities present in, e.g., recombinant albumin or monoclonal antibodies. Additionally, other examples of detecting traces of additives and fining agents in such beverages as white and red wines are presented. The unique mechanisms underlying the protein capture in the CPLL methodology, as opposed to capture by homogeneous beads, as represented by ion-exchangers and by hydrophobic resins, are discussed in depth. PMID- 21542795 TI - Analytical approaches for assessing aggregation of protein biopharmaceuticals. AB - Production of protein-based pharmaceuticals is a major issue in conventional pharmacology, biomedicine and nanomedicine. Being mostly obtained by genetic engineering, the quality and activity of protein drugs is a steady matter of concern. Although the physiology of the host recombinant cells, mostly mammalian and microbial, is progressively understood, the complexity of the cellular quality control systems escapes rational protein and process engineering, and recombinant proteins are often unstable, aggregate and/or do not reach the fully native conformation compatible with proper biological activity. In this review, we summarize the main biological aspects of protein folding and misfolding, mainly focusing in microbial cells, the newest insights in the biological control of protein quality and the main and analytical approaches that are suitable for the fast evaluation of the conformational quality and aggregation of recombinant drugs, even if showing apparent solubility. PMID- 21542796 TI - Electron transfer dissociation of modified peptides and proteins. AB - Mass spectrometry is the method of choice for sequencing peptides and proteins and is the preferred choice for characterizing post-translational modifications (PTMs). The most commonly used dissociation method to characterize peptides (i.e. collision-induced dissociation (CID)), however, has some limitations when it comes to analyzing many PTMs. Because CID chemistry is influenced by amino acid side-chains, some modifications can alter or inhibit dissociation along the peptide backbone, thereby limiting sequence information and hindering identification of the modification site. Electron transfer dissociation (ETD) has emerged as an alternate dissociation technique that, in most cases, overcomes these limitations of CID because it is less affected by side chain chemistry. Here, we review recent applications of ETD for characterizing peptide and protein PTMs with a particular emphasis on the advantages of ETD over CID, the ways in which ETD and CID have been used in a complementary manner, and how peptide modifications can still influence ETD dissociation pathways. PMID- 21542798 TI - Mass spectrometric strategies and their applications for molecular mass determination of recombinant therapeutic proteins. AB - Molecular weight determination of intact recombinant therapeutic proteins is a challenging analytical tool which furnishes valuable information not only for protein structure characterization but also to assess purity and heterogeneity. Up to now several mass spectrometric (MS) approaches have been reported for the measurement of monoisotopic or average masses of intact recombinant therapeutic protein. The choice of a suitable approach depends on several factors, among which are the sample complexity and homogeneity and the size of the target protein. MALDI-TOF, since it is rapid, simple and adaptable for automation has been found suitable for in-process monitoring quality of low/middle protein. High resolution MS such as Q-TOF, orbitrap and FT-ICR are excellent analytical tools for assessing protein heterogeneity and for structural characterization, in some cases without the need for proteolytic digestion and analysis of resulting products. High resolution techniques such as capillary electrophoresis (CE) and UPLC have been successfully coupled to high resolution MS analyzers in cases where the sample is complex and highly heterogeneous. The paper is a review of the most used and advanced MS strategies so far reported as well as of their applications in the biopharmaceutical field. PMID- 21542797 TI - Advanced mass spectrometry-based methods for the analysis of conformational integrity of biopharmaceutical products. AB - Mass spectrometry has already become an indispensable tool in the analytical armamentarium of the biopharmaceutical industry, although its current uses are limited to characterization of covalent structure of recombinant protein drugs. However, the scope of applications of mass spectrometry-based methods is beginning to expand to include characterization of the higher order structure and dynamics of biopharmaceutical products, a development which is catalyzed by the recent progress in mass spectrometry-based methods to study higher order protein structure. The two particularly promising methods that are likely to have the most significant and lasting impact in many areas of biopharmaceutical analysis, direct ESI MS and hydrogen/deuterium exchange, are focus of this article. PMID- 21542799 TI - Structural characterization of recombinant therapeutic proteins by circular dichroism. AB - Most of the protein therapeutics are now produced by recombinant DNA technology. The advantages of recombinant proteins are related to their higher specificity and to their safety as exposure to animal or human diseases. However, several problems are still present in development of recombinant proteins as therapeutics, such as low bioavailability, short serum half-life, and immune response. Their successful application hinges on the protein stereochemical stability, and on the folding and the tendency to aggregate induced by purification steps and storage. All these aspects determine the failure of many potential protein therapies, and limitations in the development of the formulation. The application of multiple analytical techniques is important in order to obtain a detailed product profile and to understand how manufacturing can influence product structure and activity. Surely the protein conformation is a key aspect to be assessed, because a specific conformation is often essential for the biological function of the protein. Thus, there is a growing need to perform structural studies under the conditions in which the proteins operate, and to monitor the structural changes of the protein. Circular dichroism has been increasingly recognised as a valuable and reliable technique to get this information. In particular, examples will be here reported on the use of circular dichroism spectroscopy in the structural characterization of free and formulated recombinant proteins, looking at the prediction of the secondary structure, propensity to conformational changes, stability, and tendency to aggregate. PMID- 21542800 TI - Development of a STAT5 phosphorylation assay as a rapid bioassay to assess interleukin-7 potency. AB - Interleukin (IL)-7 is a cytokine inducing the Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway. As a consequence of IL 7 activating this pathway, STAT5 is phosphorylated. In pharmaceutical quality control, the potency of biopharmaceuticals is commonly assessed by proliferation assays. This is also possible for IL-7 conjugates. However, the disadvantage of these classical "endpoint-assays" is that they require very long incubation times, up to several days, since they measure the downstream events of a cellular response. As an alternative to this, we developed a rapid intracellular phosphorylation assay, measuring IL-7 induced STAT5 phosphorylation in Kit 225 cells. The Kit 225 human T cell line expresses the IL-7 receptor and is responsive to IL-7, therefore making it a good candidate cell line for assay development. Like the Kinase receptor activation (KIRA) assay, developed by Sadick et al. [1], the STAT5 phosphorylation assay was performed using two separate microtiter plates: the first one for cell stimulation and lysis, the second one for enzyme-linked immuno sorbent assay (ELISA). The assay showed a high accuracy and precision with a mean recovery of 102% and a mean coefficient of variation of 9%. In comparison to the classical proliferation assay, the phosphorylation assay is much faster. Thus, the assay procedure time can at least be reduced from six to three days by using STAT5 phosphorylation instead of proliferation as an endpoint due to the shorter incubation time with IL-7. Moreover, the phosphorylation assay shows a wider dynamic range and higher signal to noise ratios and is thus more robust than the proliferation assay.mAs a consequence, this assay could serve as reliable, accurate, precise and fast alternative to the classical proliferation assay for IL-7. This study also serves as an example for the typical steps during development and qualification / validation of a potency assay for quality control testing. PMID- 21542801 TI - Advanced analytical strategies for recombinant therapeutic proteins. PMID- 21542803 TI - Bone marrow mesenchymal stem cells can differentiate into type II alveolar epithelial cells in vitro. AB - In this study, we demonstrate that BMSCs (bone marrow mesenchymal stem cells) can be successfully differentiated into type II alveolar epithelial cells in vitro under mimic pulmonary microenvironment. BMSCs were co-cultured with MRC-5 cells in modified SAGM (small airway growth medium). The BMSC-derived type II alveolar epithelial cells morphologically resemble human lung epithelial cells. They began to appear after 10 days in co-culture and became morphologically dominant after day 15. Correspondingly, SPC (surfactant protein C), a specific functional marker of human type II alveolar epithelial cells, was detected in differentiated cells by RT-PCR (reverse transcription-PCR) analysis after day 15. Immunostaining analysis revealed the present of scattered SPC-positive cells with a differentiation efficiency of 2.43-4.21%. Our study further showed that the SPC gene expression level in differentiated cells was related to the ratio of BMSCs to MRC-5 cells and the components of modified SAGM. PMID- 21542802 TI - Forebrain striatal-specific expression of mutant huntingtin protein in vivo induces cell-autonomous age-dependent alterations in sensitivity to excitotoxicity and mitochondrial function. AB - HD (Huntington's disease) is characterized by dysfunction and death of striatal MSNs (medium-sized spiny neurons). Excitotoxicity, transcriptional dysregulation and mitochondrial abnormalities are among the mechanisms that are proposed to play roles in HD pathogenesis. To determine the extent of cell-autonomous effects of mhtt (mutant huntingtin) protein on vulnerability to excitotoxic insult in MSNs in vivo, we measured the number of degenerating neurons in response to intrastriatal injection of QA (quinolinic acid) in presymptomatic and symptomatic transgenic (D9-N171-98Q, also known as DE5) mice that express mhtt in MSNs but not in cortex. After QA, the number of degenerating neurons in presymptomatic DE5 mice was not significantly different from the number in WT (wild-type) controls, suggesting the early, increased vulnerability to excitotoxicity demonstrated in other HD mouse models has a largely non-cell-autonomous component. Conversely, symptomatic DE5 mice showed significantly fewer degenerating neurons relative to WT, implying the resistance to excitotoxicity observed at later ages has a primarily cell-autonomous origin. Interestingly, mitochondrial complex II respiration was enhanced in striatum of symptomatic mice, whereas it was reduced in presymptomatic mice, both relative to their age-matched controls. Consistent with the QA data, MSNs from symptomatic mice showed decreased NMDA (N-methyl-d aspartate) currents compared with age-matched controls, suggesting that in addition to aging, cell-autonomous mechanisms mitigate susceptibility to excitotoxicity in the symptomatic stage. Also, symptomatic DE5 mice did not display some of the electrophysiological alterations present in other HD models, suggesting that blocking the expression of mhtt in cortical neurons may restore corticostriatal function in HD. PMID- 21542804 TI - Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. AB - AT1R (angiotensin type 1 receptor) and AT2R (angiotensin type 2 receptor) are well known to be involved in the complex cardiovascular actions of AngII (angiotensin II). However, shorter peptide fragments of AngII are thought to have biological activity in their own right and elicit effects that oppose those mediated by AngII. In the present study, we have used HEK (human embryonic kidney)-293 cells stably transfected with either AT1R or AT2R to perform a systematic analysis of binding affinities of all the major angiotensin peptides. Additionally, we tested the novel AT2R agonist Compound 21, as well as the MasR (Mas receptor) agonist and antagonist AVE0991 and A-779 respectively, for their ability to bind to AT1R or AT2R. Candesartan, CGP42214 and PD123319 were used as reference compounds. Binding studies using 125I-[Sar1Ile8]AngII on the AT1R transfected HEK-293 cells revealed only AngII, AngIII [angiotensin III; angiotensin-(2-8)] and candesartan to have high affinity for AT1R. In the AT2R transfected HEK-293 cells, competition for 125I-[Sar1Ile8]AngII binding was observed for all ligands except candesartan, AVE0991 and A-779, the latter two compounds having negligible affinity at either AT1R or AT2R. The rank order of affinity of ligands at AT2R was CGP42112>AngII>=AngIII>Compound 21>=PD123319?AngIV [angiotensin IV; angiotensin-(3-8)]>Ang-(1-7) [angiotensin-(1 7)]. Of note, although AngIV and Ang-(1-7) exhibited only modest affinity at AT2R compared with AngII, these two angiotensin peptides, together with AngIII, had substantial AT2R selectivity over AT1R. Collectively, our results suggest that shorter angiotensin peptides can act as endogenous ligands at AT2R. PMID- 21542806 TI - Photodynamic therapy-induced killing is enhanced in depigmented metastatic melanoma cells. AB - The resistance of pigmented human melanomas over their unpigmented counterparts to a number of therapies has suggested that the presence of intracellular melanin plays a role in rendering these cells less susceptible to cell death, probably through the ability of this pigment to act as an intracellular antioxidant, thus neutralizing chemotherapeutic-induced ROS (reactive oxygen species). PDT (photodynamic therapy) was recently suggested as an attractive, adjunctive therapy owing to its cellular specificity and limited side effects. In the present study, we propose that first depigmenting melanomas with a reversible TYR (tyrosinase) inhibitor such as PTU (phenylthiourea) increases their susceptibility to HYP-PDT (hypericin-mediated PDT). Pigmented [UCT Mel-1 (University of Cape Town melanoma cell line 1)] and unpigmented (A375) melanomas were first characterized with respect to their TYR activities and melanin quantities and then treated with a TYR inhibitor for 48 h. Cell viability assays after treatment with 3 MUM HYP-PDT showed a significant increase in cell death in depigmented melanomas compared with untreated melanomas that returned to the level of untreated melanoma cells on removing the TYR inhibitor. The present study supports the hypothesis that combining the inhibition of melanogenesis with PDT should be explored as a valid therapeutic target for the management of advanced melanoma. PMID- 21542805 TI - Oestrogen causes degradation of KLF5 by inducing the E3 ubiquitin ligase EFP in ER-positive breast cancer cells. AB - KLF5 (Kruppel-like factor 5) is a multifunctional transcription factor involved in cell proliferation, differentiation and carcinogenesis. In addition to frequent inactivation in different types of human cancers, including breast cancer, KLF5 has been identified as an essential co-factor for the TGF-beta (transforming growth factor beta) tumour suppressor. In our previous study demonstrating a negative regulation of ER (oestrogen receptor alpha) function by KLF5 in breast cancer cells [Guo, Dong, Zhao, Sun, Li and Dong (2010) Int. J. Cancer 126, 81-89], we noticed that oestrogen reduced the protein level of KLF5. In the present study, we have tested whether and how oestrogen/ER signalling regulates KLF5 protein. We found that oestrogen caused the degradation of KLF5 protein, and the degradation was sensitive to proteasome inhibitors, but not other inhibitors. The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked. EFP-mediated degradation impaired the function of KLF5 in gene transcription. Although only unubiquitinated EFP interacted with KLF5, overexpression of EFP appeared to prevent the ubiquitination of KLF5, while resulting in heavy ubiquitination of the E3 itself. Furthermore, ubiquitination of EFP interrupted its interaction with KLF5. Although the mechanism for how EFP degrades KLF5 remains to be determined, the results of the present study suggest that oestrogen causes the degradation of KLF5 protein by inducing the expression of EFP in ER-positive breast cancer cells. PMID- 21542807 TI - Distribution of killer cell immunoglobulin-like receptor genes and combinations with HLA-C ligands in an isolated Han population in southwest China. AB - Human natural killer cells express killer cell immunoglobulin-like receptors (KIRs), which interact with human leukocyte antigen (HLA) class I molecules. KIR/HLA combinations play an important role in innate and adaptive immunity. In the current study, 16 KIR genes were analyzed in an isolated Han group living in the Fengyandong (FYDH) region in the Yunnan province of southwest China. The framework KIR genes 3DL2, 3DL3, 3DP1, and 2DL4 were found in all individuals. A total of 22 distinct KIR genotypes were observed, four of which were unknown previously. Genotype 1 (N = 52, 55.9%) was the predominant genotype. Analysis of inhibitory and activating KIR and HLA-C ligands showed that all individuals displayed at least one inhibitory or activating KIR/HLA-C pair. One KIR/HLA-C pair was the most frequent (67/93), followed by two pairs (21/93), and three pairs (6/93). The comparison of KIR and HLA frequencies between FYDH and a local Han population showed that the two populations showed similar frequencies for the KIR genes. In contrast, the distribution of HLA alleles and haplotypes showed significant differences between them. PMID- 21542808 TI - Cesarean section after induction of labor compared with expectant management: no added risk from gestational week 39. AB - OBJECTIVE: To compare induction of labor and expectant management by gestational week with regard to the need for cesarean section (CS) in labor. DESIGN: Cohort study. SETTING: National study based on the Danish Birth Registry. POPULATION: Aggregated data from 230 528 deliveries from 2004 until mid-year 2009. Women with cesarean section before labor, previous cesarean, preterm birth, breech presentation, multiple pregnancy and specified medical illnesses in pregnancy were excluded. METHODS: We compared by gestational week nulliparous and parous women who were either induced or had expectant management until later spontaneous or induced labor. For each of five comparisons, we conducted multivariable logistic regression analysis, controlling for body mass index, age, smoking in pregnancy and use of epidural analgesia during labor. MAIN OUTCOME MEASURE: Rate of CS in labor. RESULTS: From gestational week 39 and thereafter, there was no difference with regard to CS rates in labor among nulliparous and parous women when comparing women with induced labor and those women who waited for a later labor, either induced or spontaneous. The odds ratios (with confidence intervals) for CS in labor in nulliparous women were 0.99 (0.84-1.17), 1.16 (1.04-1.30), 1.04 (0.94-1.15), 1.00 (0.92-1.10) and 0.97 (0.88-1.07) for weeks 37-41, respectively. For parous women the corresponding figures were 1.72 (1.35-2.20), 1.27 (1.04-1.55), 1.15 (0.95-1.39), 1.18 (0.99-1.40) and 1.07 (0.87-1.32), respectively. CONCLUSIONS: Induction of labor provides a sound tool when counseling a woman either going past term or presenting with a problem, even if it is not a severe medical illness. PMID- 21542809 TI - Deep pelvic endometriosis negatively affects ovarian reserve and the number of oocytes retrieved for in vitro fertilization. AB - OBJECTIVE: Endometriosis-associated infertility results in reduced ovarian response, fewer oocytes available for fertilization, compromised oocyte quality and higher miscarriage rates. A consistent proportion of women with endometriosis require in vitro fertilization. We sought to clarify the impact of deep infiltrating pelvic disease on antral follicle count and ovarian response to follicle-stimulating hormone (FSH) stimulation in patients with severe endometriosis. DESIGN: Retrospective cohort study. SETTING: University hospital. POPULATION: Patients with severe endometriosis (stages III-IV; n=51) were divided into two groups regarding localization of endometriosis during surgical staging: ovarian (n=27) and both ovarian and deep infiltrating disease (n=24). METHODS: A total of 73 long-protocol ovulation induction cycles with recombinant FSH for an intracytoplasmic sperm injection program were given. On day 3 of the cycle, measurements of FSH and luteinizing hormone and an ultrasound evaluation of antral follicle count were performed. MAIN OUTCOME MEASURES: Number of oocytes collected at ovum pick up, number of mature oocytes, number of embryos transferred and clinical pregnancy rate. RESULTS: Ovarian reserve in terms of antral follicle count was damaged in both groups but, if adjusted for age, it was significantly lower in the ovarian and pelvic infiltrating group compared with patients having only ovarian endometriosis. Pelvic deep infiltrating disease significantly impacted on the number of oocytes collected at pick up when adjusted for age. CONCLUSIONS: Deep infiltrating pelvic disease can negatively affect ovarian reserve in terms of antral follicle count and number of oocytes retrieved. Mechanisms underlying this phenomenon need to be elucidated. PMID- 21542810 TI - Surgical outcome of obstetric fistula: a retrospective analysis of 595 patients. AB - OBJECTIVE: The aim of the study was to investigate obstetric fistula in terms of patient demographics, fistula characteristics and predictors of surgical outcome. DESIGN: Retrospective cross-sectional study. SETTING: Fistula referral hospital in eastern Democratic Republic of Congo. Population. Five hundred and ninety-five women receiving fistula repair from November 2005 to November 2007. METHODS: Review of patient records for information on patient demographics, obstetric history, clinical data for index pregnancy, fistula characteristics and surgical information. Cross-tabulations and multivariate logistic regression models were used to predict surgical outcome. MAIN OUTCOME MEASURES: Fistula closure and incontinence despite fistula closure. Results. 82.9% had developed fistula following obstructed labor, 17.1% after medical interventions of which 71.1% involved cesarean section or peripartum hysterectomy. Median age at fistula development was 23 years; 40.8% were primiparous and 43.2% were parity three or more. Women took a median of two years to seek treatment. Closure rate was 87.1%, with 15.6% remaining incontinent. Failure to close the fistula was significantly associated with previous repairs, amount of fibrosis and fistula size. Compared with primary repairs, the odds ratio of failure was almost five times greater for three or more repairs (odds ratio 4.7, 95% confidence interval 2.2-10.0). Incontinence was significantly associated with previous repairs, amount of fibrosis and fistula location. Compared with fistulas with a high location, the odds ratio of incontinence for low, circumferential fistulas was 6.3 (95% confidence interval 2.5-16.4). CONCLUSIONS: Fistula in Democratic Republic of Congo was found in both primiparous and multiparous women, indicating a need for increased access to obstetric care for all pregnant women. Fistulas repaired for the first time, with no fibrosis and size <2 cm, had the best surgical outcome. PMID- 21542811 TI - Home birth in women who have given birth at least once in a health facility: contributory factors in a developing country. AB - OBJECTIVE: To study the link between patients' satisfaction about received services in health facilities and the choice of future delivery place of women who had delivered at least once in a facility. DESIGN: Cross-sectional study. SETTING: Health district Gossas in Senegal. SAMPLE: Three hundred and seventy three women who gave birth in the last 12 months. METHODS: Data were collected using a questionnaire during an interview. Logistic regression was used to explore the determinants of childbirth at home using the Andersen behavioral model. MAIN OUTCOME MEASURES: Place of delivery and satisfaction at reception and conduct of delivery. RESULTS: The average age was 28+/-6years. Among the women interviewed, 97% were married, 53% being in a polygamous system, and 18% were educated. Forty-seven per cent of them were satisfied with the quality of the last delivery made within a health facility. The prevalence of home birth was 22%. Home births were more frequent among women in a polygamous marriage [odds ratio (OR) 1.85; 95% confidence interval (CI) 1.01-3.14], with no means of transportation (OR 1.68; 95% CI 1.02-3.95) and who lived more than 5km from a health facility (OR 2.24; 95% CI 1.21-4.15). Poor quality of delivery in a health facility (OR 2.52; 95% CI 1.36-4.65) or a delivery done by a male provider (OR 3.90; 95% CI 2.30-6.65) were also risk factors for the choice of home delivery. CONCLUSIONS: Particular emphasis should be placed on training healthcare providers to improve the quality of service provided to patients in health facilities. PMID- 21542812 TI - Excretion patterns of large and small proteins in pre-eclamptic pregnancies. AB - OBJECTIVE: Pre-eclampsia is a serious pregnancy complication causing both fetal and maternal distress. Proteinuria is a diagnostic criterion frequently determined by albuminuria. We determined the protein excretion pattern of additional proteins, immunoglobulin G, transferrin, alpha1-microglobulin and beta2-microglobulin, in urine samples collected prospectively during pre eclamptic and healthy pregnancies. DESIGN: A prospective cohort study of 1,631 consecutive pregnant women. SETTING: A Danish regional hospital. SAMPLE: Thirty two women with pre-eclampsia and 185 healthy control women were identified from the cohort. Urine samples were obtained from the 18th week until delivery and divided into six gestational intervals. METHODS: Protein analyses of urine immunoglobulin G, transferrin, alpha1-microglobulin and beta2-microglobulin were done with a sandwich ELISA method. MAIN OUTCOME MEASURES: Urine levels of specific proteins during pre-eclamptic and healthy pregnancies. RESULTS: Immunoglobulin G and transferrin were significantly increased in pre-eclampsia after the 30th week of pregnancy. alpha(1)-Microglobulin and beta(2) microglobulin were differently excreted and found to be higher after the 36(th) week of pregnancy in pre-eclampsia, but only alpha1-microglobulin increased significantly. CONCLUSIONS: Immunoglobulin G, transferrin, alpha1- and beta2 microglobulin excretion patterns indicate initial glomerular damage followed by altered tubular handling of proteins. PMID- 21542813 TI - Unsafe abortion and postabortion care - an overview. AB - Forty per cent of the world's women are living in countries with restrictive abortion laws, which prohibit abortion or only allow abortion to protect a woman's life or her physical or mental health. In countries where abortion is restricted, women have to resort to clandestine interventions to have an unwanted pregnancy terminated. As a consequence, high rates of unsafe abortion are seen, such as in Sub-Saharan Africa where unsafe abortion occurs at rates of 18-39 per 1 000 women. The circumstances under which women obtain unsafe abortion vary and depend on traditional methods known and types of providers present. Health professionals are prone to use instrumental procedures to induce the abortion, whereas traditional providers often make a brew of herbs to be drunk in one or more doses. In countries with restrictive abortion laws, high rates of maternal death must be expected, and globally an estimated 66 500 women die every year as a result of unsafe abortions. In addition, a far larger number of women experience short- and long-term health consequences. To address the harmful health consequences of unsafe abortion, a postabortion care model has been developed and implemented with success in many countries where women do not have legal access to abortion. Postabortion care focuses on treatment of incomplete abortion and provision of postabortion contraceptive services. To enhance women's access to postabortion care, focus is increasingly being placed on upgrading midlevel providers to provide emergency treatment as well as implementing misoprostol as a treatment strategy for complications after unsafe abortion. PMID- 21542814 TI - Peer relationships and adolescents' academic and non-academic outcomes: same-sex and opposite-sex peer effects and the mediating role of school engagement. AB - BACKGROUND: The literature has documented theoretical/conceptual models delineating the facilitating role of peer relationships in academic and non academic outcomes. However, the mechanisms through which peer relationships link to those outcomes is an area requiring further research. AIMS: The study examined the role of adolescents' perceptions of their relationships with same-sex and opposite-sex peers in predicting their academic performance and general self esteem and the potentially mediating role of school engagement in linking these perceived peer relationships with academic and non-academic outcomes. SAMPLE: The sample comprised 1,436 high-school students (670 boys, 756 girls; 711 early adolescents, 723 later adolescents). METHOD: Self-report measures and objective achievement tests were used. Structural equation modelling (SEM) was performed to test the hypothesized model and its invariance across gender and age groups. RESULTS: Perceived same-sex peer relationships yielded positive direct and indirect links with academic performance and general self-esteem. Perceived opposite-sex peer relationships yielded positive direct and indirect links with general self-esteem and an indirect positive link with academic performance, but mediation via school engagement was not as strong as that of perceived same-sex peer relationships. These findings generalized across gender and age groups. CONCLUSION: Adolescents' same-sex and opposite-sex peer relationships seem to positively impact their academic performance and general self-esteem in distinct ways. It appears that school engagement plays an important role in mediating these peer relationship effects, particularly those of same-sex peer relationships, on academic and non-academic functioning. Implications for psycho educational theory, measurement, and practice are discussed. PMID- 21542815 TI - Academic self-handicapping: relationships with learning specific and general self perceptions and academic performance over time. AB - BACKGROUND: Academic self-handicapping (ASH) tendencies, strategies students employ that increase their chances of failure on assessments while protecting self-esteem, are correlated with classroom goal structures and to learners' general self-perceptions and learning strategies. In particular, greater ASH is related to poorer academic performance but has yet to be examined with respect to learners' performance across a series of tests. AIMS: This research was designed to examine the relationship between students' ASH tendencies and their self concept clarity, learning strategies, and performance on a series of tests in a university course. SAMPLE: A total of 209 (153 female; 56 male) Canadian university psychology students participated in this study. METHODS: Participants' ASH tendencies, self-concept clarity, approaches to learning, and self-regulatory learning strategies were assessed along with expected grades and hours of study in the course from which they were recruited. Finally, students' grades were obtained for the three tests for the course from which they were recruited. RESULTS: Students reporting greater self-handicapping tendencies reported lower self-concept clarity, lower academic self-efficacy, greater test anxiety, more superficial learning strategies, and scored lower on all tests in the course. The relationships of ASH scores and learner variables with performance varied across the three performance indices. In particular, ASH scores were more strongly related to second and third tests, and prior performances were accounted for. ASH scores accounted for a relatively small but significant proportion of variance for all three tests. CONCLUSIONS: These results showed that ASH is a unique contributing factor in student performance outcomes, and may be particularly important after students complete the initial assessment in a course. PMID- 21542816 TI - Antecedents and trajectories of achievement goals: a self-determination theory perspective. AB - BACKGROUND: Research has shown that both achievement goal theory and self determination theory (SDT) are quite useful in explaining student motivation and success in academic contexts. However, little is known about how the two theories relate to each other. AIM: The current research used SDT as a framework to understand why students enter classes with particular achievement goal profiles, and also, how those profiles may change over time. SAMPLE: One hundred and eighty four undergraduate preservice teachers in a required domain course agreed to participate in the study. METHOD: Data were collected at three time points during the semester, and both path modelling and multi-level longitudinal modelling techniques were used. RESULTS: Path modelling techniques with 169 students, results indicated that students' autonomy and relatedness need satisfaction in life predict their initial self-determined class motivation, which in turn predicts initial mastery-approach and -avoidance goals. Multi-level longitudinal modelling with 108 students found that perceived teacher autonomy support buffered against the general decline in students' mastery-approach goals over the course of the semester. CONCLUSIONS: Data provide a promising integration of SDT and achievement goal theory, posing a host of potentially fruitful future research questions regarding goal adoption and trajectories. PMID- 21542817 TI - Assessing pupil concerns about transition to secondary school. AB - BACKGROUND: The primary-secondary transition can negatively affect pupils' emotional and psychological adjustment. However, methods for assessing concerns regarding secondary school are limited. A reliable and valid measure of transition-related concerns would be useful both in evaluating and shaping the content and delivery of universal and targeted transition support programmes. AIMS: To assess the validity of a quantitative self-report measure of school concerns as an assessment tool during the primary-secondary school transition. SAMPLE: A UK sample of 147 Year 6 primary school pupils and 263 Year 7 secondary school pupils. METHOD: Self-reports of school concerns and school liking as well as self-reported and peer assessments on a range of psychological adjustment measures were collected. RESULTS: The School Concerns Questionnaire (SCQ) showed good reliability at primary and secondary school. Secondary concerns reduced significantly post-transition. Three factors emerged from an exploratory factor analysis of the SCQ and the pattern of results was replicated for post-transition concerns. Pupils with higher school concerns at secondary school reported reduced liking of school and reduced trust and respect for teachers. The SCQ was associated with generalized anxiety and female gender both pre-and post transition. Peer problems and depression were associated with pre- and post transition concerns, respectively. CONCLUSIONS: The SCQ is a simple to complete, reliable, and valid tool for assessing primary-secondary transition concerns. It could serve a valuable role in the evaluation and development of universal and targeted school-based initiatives that aim to promote positive secondary transition. PMID- 21542818 TI - Test expectancy affects metacomprehension accuracy. AB - BACKGROUND: Theory suggests that the accuracy of metacognitive monitoring is affected by the cues used to judge learning. Researchers have improved monitoring accuracy by directing attention to more appropriate cues; however, this is the first study to more directly point students to more appropriate cues using instructions regarding tests and practice tests. AIMS: The purpose of the present study was to examine whether the accuracy metacognitive monitoring was affected by the nature of the test expected. SAMPLE AND METHOD: Students (N= 59) were randomly assigned to one of two test expectancy groups (memory vs. inference). Then after reading texts, judging learning, completed both memory and inference tests. RESULTS: Test performance and monitoring accuracy were superior when students received the kind of test they had been led to expect rather than the unexpected test. CONCLUSION: Tests influence students' perceptions of what constitutes learning. Our findings suggest that this could affect how students prepare for tests and how they monitoring their own learning. PMID- 21542819 TI - The influence of prior knowledge on the retrieval-directed function of note taking in prior knowledge activation. AB - BACKGROUND: Prior knowledge activation facilitates learning. Note taking during prior knowledge activation (i.e., note taking directed at retrieving information from memory) might facilitate the activation process by enabling learners to build an external representation of their prior knowledge. However, taking notes might be less effective in supporting prior knowledge activation if available prior knowledge is limited. AIMS: This study investigates the effects of the retrieval-directed function of note taking depending on learners' level of prior knowledge. It is hypothesized that the effectiveness of note taking is influenced by the amount of prior knowledge learners already possess. SAMPLE: Sixty-one high school students participated in this study. A prior knowledge test was used to ascertain differences in level of prior knowledge and assign participants to a low or a high prior knowledge group. METHOD: A 2*2 factorial design was used to investigate the effects of note taking during prior knowledge activation (yes, no) depending on learners' level of prior knowledge (low, high) on mental effort, performance, and mental efficiency. RESULTS: Note taking during prior knowledge activation lowered mental effort and increased mental efficiency for high prior knowledge learners. For low prior knowledge learners, note taking had the opposite effect on mental effort and mental efficiency. CONCLUSIONS: The effects of the retrieval-directed function of note taking are influenced by learners' level of prior knowledge. Learners with high prior knowledge benefit from taking notes while activating prior knowledge, whereas note taking has no beneficial effects for learners with limited prior knowledge. PMID- 21542820 TI - Gender differences in variance and means on the Naglieri Non-verbal Ability Test: data from the Philippines. AB - BACKGROUND: Research on gender differences in intelligence has focused mostly on samples from Western countries and empirical evidence on gender differences from Southeast Asia is relatively sparse. AIMS: This article presents results on gender differences in variance and means on a non-verbal intelligence test using a national sample of public school students from the Philippines. SAMPLE: More than 2,700 sixth graders from public schools across the country were tested with the Naglieri Non-verbal Ability Test (NNAT). METHODS: Variance ratios (VRs) and log-transformed VRs were computed. Proportion ratios for each of the ability levels were also calculated and a chi-square goodness-of-fit test was performed. An analysis of variance was performed to determine the overall gender difference in mean scores as well as within each of three age subgroups. RESULTS: Our data show non-existent or trivial gender difference in mean scores. However, the tails of the distributions show differences between the males and females, with greater variability among males in the upper half of the distribution and greater variability among females in the lower half of the distribution. Descriptions of the results and their implications are discussed. CONCLUSIONS: Results on mean score differences support the hypothesis that there are no significant gender differences in cognitive ability. The unusual results regarding differences in variance and the male-female proportion in the tails require more complex investigations. PMID- 21542821 TI - The effect of directive tutor guidance on students' conceptual understanding of statistics in problem-based learning. AB - BACKGROUND: Education is aimed at students reaching conceptual understanding of the subject matter, because this leads to better performance and application of knowledge. Conceptual understanding depends on coherent and error-free knowledge structures. The construction of such knowledge structures can only be accomplished through active learning and when new knowledge can be integrated into prior knowledge. AIMS: The intervention in this study was directed at both the activation of students as well as the integration of knowledge. SAMPLE: Undergraduate university students from an introductory statistics course, in an authentic problem-based learning (PBL) environment, were randomly assigned to conditions and measurement time points. METHOD: In the PBL tutorial meetings, half of the tutors guided the discussions of the students in a traditional way. The other half guided the discussions more actively by asking directive and activating questions. To gauge conceptual understanding, the students answered open-ended questions asking them to explain and relate important statistical concepts. RESULTS AND CONCLUSIONS: Results of the quantitative analysis show that providing directive tutor guidance improved understanding. Qualitative data of students' misconceptions seem to support this finding. Long-term retention of the subject matter seemed to be inadequate. PMID- 21542822 TI - In-group and role identity influences on the initiation and maintenance of students' voluntary attendance at peer study sessions for statistics. AB - BACKGROUND: Although class attendance is linked to academic performance, questions remain about what determines students' decisions to attend or miss class. AIMS: In addition to the constructs of a common decision-making model, the theory of planned behaviour, the present study examined the influence of student role identity and university student (in-group) identification for predicting both the initiation and maintenance of students' attendance at voluntary peer assisted study sessions in a statistics subject. SAMPLE: University students enrolled in a statistics subject were invited to complete a questionnaire at two time points across the academic semester. A total of 79 university students completed questionnaires at the first data collection point, with 46 students completing the questionnaire at the second data collection point. METHOD: Twice during the semester, students' attitudes, subjective norm, perceived behavioural control, student role identity, in-group identification, and intention to attend study sessions were assessed via on-line questionnaires. Objective measures of class attendance records for each half-semester (or 'term') were obtained. RESULTS: Across both terms, students' attitudes predicted their attendance intentions, with intentions predicting class attendance. Earlier in the semester, in addition to perceived behavioural control, both student role identity and in group identification predicted students' attendance intentions, with only role identity influencing intentions later in the semester. CONCLUSIONS: These findings highlight the possible chronology that different identity influences have in determining students' initial and maintained attendance at voluntary sessions designed to facilitate their learning. PMID- 21542823 TI - The development of comprehension and reading-related skills in children learning English as an additional language and their monolingual, English-speaking peers. AB - BACKGROUND: A significant number of pupils in UK schools learn English as an additional language (EAL). Relative differences between the educational attainment of this group and monolingual, English-speaking pupils call for an exploration of the literacy needs of EAL learners. AIMS: This study explores the developmental progression of reading and listening comprehension skills and a range of reading-related skills in EAL learners, whose first language is of South Asian origin, and their monolingual peers. SAMPLE: Participants were 39 children learning EAL and 39 monolingual, English-speaking children who were all in school Year 3 at the start of the study. METHOD: Children completed standardized measures of comprehension, vocabulary, reading accuracy, and reading fluency in school Year 3 and again in Year 4. RESULTS: The results suggest that, although children learning EAL often demonstrate fast and accurate reading accuracy skills, lower levels of vocabulary knowledge place significant constraints on EAL learners' comprehension of spoken and written texts. CONCLUSIONS: Reciprocal relationships between vocabulary and comprehension may lead to increasing gaps in reading comprehension between monolingual and EAL pupils over time. It is proposed that support for the development of vocabulary skills in children learning EAL is needed in early years' classrooms. PMID- 21542825 TI - Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. AB - MYH9-related disease (MYH9-RD) is one of the most frequent forms of inherited thrombocytopenia. It is transmitted in an autosomal dominant fashion and derives from mutations of MYH9, the gene for the heavy chain of non-muscle myosin IIA. Patients present with congenital macrothrombocytopenia with mild bleeding tendency and may develop kidney dysfunction, deafness and cataracts later in life. The term MYH9-RD encompasses four autosomal-dominant thrombocytopenias that were previously described as distinct disorders, namely May-Hegglin Anomaly, Sebastian, Fechtner and Epstein syndromes. Thrombocytopenia is usually mild and derives from complex defects of megakaryocyte maturation and platelet formation. It is easily diagnosed, in that the presence of giant platelets in peripheral blood raises the suspicion of MYH9-RD and a simple immunofluorescence test on blood films confirms the diagnostic hypothesis. However, genotype/phenotype correlations have been recognized and mutation screening is therefore required to define the risk of acquiring extra-haematological defects. Results of a small clinical study suggested that a non-peptide thrombopoietin mimetic might greatly benefit both thrombocytopenia and bleeding tendency of MYH9-RD patients. PMID- 21542824 TI - Chromosome damage and repair in children with sickle cell anaemia and long-term hydroxycarbamide exposure. AB - Hydroxycarbamide (hydroxyurea) provides laboratory and clinical benefits for adults and children with sickle cell anaemia (SCA). Given its mechanism of action and prior reports of genotoxicity, concern exists regarding long-term toxicities and possible carcinogenicity. We performed cross-sectional analyses of chromosome stability using peripheral blood mononuclear cells (PBMC) from 51 children with SCA and 3-12 years of hydroxycarbamide exposure (mean age 13.2 +/- 4.1 years), compared to 28 children before treatment (9.4 +/- 4.7 years). Chromosome damage was less for children receiving hydroxycarbamide than untreated patients (0.8 +/- 1.2 vs. 1.9 +/- 1.5 breaks per 100 cells, P = 0.004). There were no differences in repairing chromosome breaks after in vitro radiation; PBMC from children taking hydroxycarbamide had equivalent 2 Gy-induced chromosome breaks compared to untreated patients (30.8 +/- 16.1 vs. 31.7 +/- 8.9 per 100 cells, P = not significant). Radiation plus hydroxycarbamide resulted in similar numbers of unrepaired breaks in cells from children on hydroxycarbamide compared to untreated patients (95.8 +/- 44.2 vs. 76.1 +/- 23.1 per 100 cells, P = 0.08), but no differences were noted with longer exposure (97.9 +/- 42.8 breaks per 100 cells for 3-6 years of hydroxycarbamide exposure vs. 91.2 +/- 48.4 for 9-12 years of exposure). These observations provide important safety data regarding long term risks of hydroxycarbamide exposure for children with SCA, and suggest low in vivo mutagenicity and carcinogenicity. PMID- 21542826 TI - 'Oxidation stress index' as a possible clinical marker for the evaluation of non Hodgkin lymphoma. PMID- 21542827 TI - Impaired immune function in children with Fanconi anaemia. AB - Fanconi anaemia is an autosomal recessive or X-linked disease characterized by progressive bone marrow failure, variable congenital abnormalities and a predisposition to malignancy. Reports of immune function in this population are limited, and include only specific areas of immune performance, showing variable defects. We report a cross-sectional immunological assessment in 10 children with FA. Absolute numbers of B cells and natural killer (NK) cells were reduced compared to controls (P = 0.048 and P = 0.0002, respectively), while absolute number of T cells were within normal range. Perforin and granzyme content of NK cells was reduced (P < 0.00001 and P = 0.0057, respectively) along with the NK cell cytotoxicity (P < 0.001). Antigen proliferation in response to tetanus was decreased (P = 0.008) while responses to candida and phytohaemagglutinin were not. Cytotoxic T cell function was also reduced (P < 0.0001). Immunoglobulin G levels were normal in those evaluated. Our series represents the first attempt at a comprehensive quantitative and functional evaluation of immune function in this rare group of patients and demonstrates a significant deficit in the NK cell compartment, a novel quantitative B cell defect, along with abnormal cytotoxic function. These findings may be especially relevant in this patient population with known predisposition to DNA damage and malignancy. PMID- 21542828 TI - Effects of metoprolol therapy on cardiac gap junction remodelling and conduction in human chronic atrial fibrillation. AB - BACKGROUND AND PURPOSE: We investigated the influence of metoprolol on gap junction proteins connexin43 (Cx43) and connexin40 (Cx40) in atrial tissue from patients with/without atrial fibrillation (AF). EXPERIMENTAL APPROACH: Left atrial tissue samples from 160 patients with AF or sinus rhythm (SR) with or without metoprolol (mean daily dose: 65.2 +/- 9.1 mg.day-1) were analysed for Cx43 and Cx40 by Western blot and immunohistology. Transverse and longitudinal conduction velocities were determined by 64 multi-electrode mapping. KEY RESULTS: Both Cx43 and Cx40 expression were significantly increased in patients with AF versus SR. Cx43-expression in AF was significantly higher in patients receiving metoprolol, while Cx40 expression was unaffected by metoprolol treatment. In AF, the ratio of lateral/polar expression of Cx43 and Cx40 was enhanced due to increased expression at the sides of the cells (lateral) and a loss at the cell poles. This AF-induced increase in lateral/polar expression of Cx43, but not of Cx40, was significantly antagonized by metoprolol treatment. Functionally, in AF patients, transverse conduction velocity in atrial samples was significantly enhanced and this change was also significantly antagonized by metoprolol. CONCLUSIONS AND IMPLICATIONS: AF induced enhanced lateral expression of Cx43 and Cx40 together with enhanced transverse conduction velocity in left atrial tissue. Alterations in localization of Cx43 and conduction changes were both antagonized by metoprolol, showing that pharmacological modulation of gap junction remodelling seems, in principle, possible. This finding may open new approaches to the development of anti-arrythmic drugs. PMID- 21542829 TI - Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Delta9-tetrahydrocannabinol in BV-2 microglial cells. AB - BACKGROUND AND PURPOSE: Apart from their effects on mood and reward, cannabinoids exert beneficial actions such as neuroprotection and attenuation of inflammation. The immunosuppressive activity of cannabinoids has been well established. However, the underlying mechanisms are largely unknown. We previously showed that the psychoactive cannabinoid Delta(9) -tetrahydrocannabinol (THC) and the non psychoactive cannabidiol (CBD) differ in their anti-inflammatory signalling pathways. EXPERIMENTAL APPROACH: To characterize the transcriptional effects of CBD and THC, we treated BV-2 microglial cells with these compounds and performed comparative microarray analysis using the Illumina MouseRef-8 BeadChip platform. Ingenuity Pathway Analysis was performed to identify functional subsets of genes and networks regulated by CBD and/or THC. KEY RESULTS: Overall, CBD altered the expression of many more genes; from the 1298 transcripts found to be differentially regulated by the treatments, 680 gene probe sets were up-regulated by CBD and 58 by THC, and 524 gene products were down-regulated by CBD and only 36 by THC. CBD-specific gene expression profile showed changes associated with oxidative stress and glutathione depletion, normally occurring under nutrient limiting conditions or proteasome inhibition and involving the GCN2/eIF2alpha/p8/ATF4/CHOP-TRIB3 pathway. Furthermore, CBD-stimulated genes were shown to be controlled by nuclear factors known to be involved in the regulation of stress response and inflammation, mainly via the (EpRE/ARE)-Nrf2/ATF4 system and the Nrf2/Hmox1 axis. CONCLUSIONS AND IMPLICATIONS: These observations indicated that CBD, but much less than THC, induced a cellular stress response in microglial cells and suggested that this effect could underlie its anti inflammatory activity. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. PMID- 21542830 TI - Methylene blue inhibits function of the 5-HT transporter. AB - BACKGROUND AND PURPOSE: Methylene blue (MB) is commonly employed as a treatment for methaemoglobinaemia, malaria and vasoplegic shock. An increasing number of studies indicate that MB can cause 5-HT toxicity when administered with a 5-HT reuptake inhibitor. MB is a potent inhibitor of monoamine oxidases, but other targets that may contribute to MB toxicity have not been identified. Given the role of the 5-HT transporter (SERT) in the regulation of extracellular 5-HT concentrations, the present study aimed to characterize the effect of MB on SERT. EXPERIMENTAL APPROACH: Live cell imaging, in conjunction with the fluorescent SERT substrate 4-(4-(dimethylamino)-styryl)-N-methylpyridinium (ASP(+) ), [(3) H]5-HT uptake and whole-cell patch-clamp techniques were employed to examine the effects of MB on SERT function. KEY RESULTS: In EM4 cells expressing GFP-tagged human SERT (hSERT), MB concentration-dependently inhibited ASP(+) accumulation (IC(50) : 1.4 +/- 0.3 uM). A similar effect was observed in N2A cells. Uptake of [(3) H]5-HT was decreased by MB pretreatment. Furthermore, patch-clamp studies in hSERT expressing cells indicated that MB significantly inhibited 5-HT-evoked ion currents. Pretreatment with 8-Br-cGMP did not alter the inhibitory effect of MB on hSERT activity, and intracellular Ca(2+) levels remained unchanged during MB application. Further experiments revealed that ASP(+) binding to cell surface hSERT was reduced after MB treatment. In whole-cell radioligand experiments, exposure to MB (10 uM; 10 min) did not alter surface binding of the SERT ligand [(125) I]RTI-55. CONCLUSIONS AND IMPLICATIONS: MB modulated SERT function and suggested that SERT may be an additional target upon which MB acts to produce 5 HT toxicity. PMID- 21542831 TI - Ligand binding and activation of the secretin receptor, a prototypic family B G protein-coupled receptor. AB - The secretin receptor is a prototypic member of family B G protein-coupled receptors that binds and responds to a linear 27-residue peptide natural ligand. The carboxyl-terminal region of this peptide assumes a helical conformation that occupies the peptide-binding cleft within the structurally complex disulphide bonded amino-terminal domain of this receptor. The amino terminus of secretin is directed toward the core helical bundle domain of this receptor that seems to be structurally distinct from the analogous region of family A G protein-coupled receptors. This amino-terminal region of secretin is critical for its biological activity, to stimulate Gs coupling and the agonist-induced cAMP response. While the natural peptide ligand is known to span the two key receptor domains, with multiple residue-residue approximation constraints well established, the orientation of the receptor amino terminus relative to the receptor core helical bundle domain is still unclear. Fluorescence studies have established that the mid-region and carboxyl-terminal end of secretin are protected by the receptor peptide-binding cleft and the amino terminus of secretin is most exposed to the aqueous milieu as it is directed toward the receptor core, with the mid-region of the peptide becoming more exposed upon receptor activation. Like other family B peptide hormone receptors, the secretin receptor is constitutively present in a structurally specific homo-dimeric complex built around the lipid-exposed face of transmembrane segment four. This complex is important for facilitating G protein association and achieving the high affinity state of this receptor. PMID- 21542834 TI - DFNB93, a novel locus for autosomal recessive moderate-to-severe hearing impairment. PMID- 21542832 TI - Paeoniflorin suppresses the expression of intercellular adhesion molecule-1 (ICAM 1) in endotoxin-treated human monocytic cells. AB - BACKGROUND AND PURPOSE: Paeoniflorin (PF) has ameliorative effects on learning and memory impairment and cerebral ischaemia in rats and has protective effects against the degeneration of dopaminergic neurons in substantia nigra. The neuroprotective effects of PF are most probably derived from its anti inflammatory property. Abnormally high levels of intercellular adhesion molecule 1 (ICAM-1) have been found to be associated with a wide range of inflammatory and immune responses. Here we studied whether PF regulates the levels of ICAM-1 elevated in LPS-activated differentiated human monocytic U937 cells and TNF-alpha stimulated human umbilical vein endothelial cells (HUVECs). EXPERIMENTAL APPROACH: mRNA levels were evaluated by RT-PCR. Protein levels were evaluated by Western blot analysis. An immunofluorescence technique was used to estimate NF kappaB translocation, and NF-kappaB binding to nuclear DNA was determined by EMSA. KEY RESULTS: PF inhibited ICAM-1 expression elevated in LPS-induced U937 cells and TNF-alpha-stimulated HUVECs. Although previous reports showed that PF's action is mediated by activating adenosine A1 receptors, application of a selective adenosine A1 receptor antagonist did not change the inhibitory effect of PF in our experiments. To elucidate the underlying mechanisms of the effect of PF, we studied its effect on signalling pathways upstream of ICAM-1 expression. PF suppressed the activation of the NF-kappaB pathway, which regulates the expression of ICAM-1. The TLR4 and MAPK pathways were shown not to be involved in the effects of PF in these cells. CONCLUSIONS AND IMPLICATIONS: PF inhibits ICAM 1 expression in LPS-treated U937 cells and TNF-alpha-stimulated HUVECs by suppressing the activation of the NF-kappaB pathway. PMID- 21542833 TI - 5alpha-reduced glucocorticoids exhibit dissociated anti-inflammatory and metabolic effects. AB - BACKGROUND AND PURPOSE: Dissociating anti-inflammatory efficacy from the metabolic side effects of glucocorticoids is an attractive therapeutic goal. 5alpha-Tetrahydro-corticosterone (5alphaTHB), produced from corticosterone by 5alpha-reductases, activates glucocorticoid receptors. This study compares the effects of 5alphaTHB on inflammation and metabolism in vitro and in vivo. METHODS: Suppression of cytokine release by 5alphaTHB and corticosterone were studied following LPS activation of mouse bone marrow derived macrophages. In vivo the efficacy of these steroids to dysregulate metabolic homeostasis and modulate immune suppression and the responses to thioglycollate-induced peritonitis in C57BL/6 mice were studied following acute injection (1.5-15 mg) and chronic infusion (50 ug.day(-1) , 14 days). RESULTS: In macrophages, 5alphaTHB increased secretion of IL-10 similarly to corticosterone (180%, 340%; data are % vehicle, treated with 5alphaTHB and corticosterone, respectively) and suppressed LPS-induced secretion of TNF-alpha (21.9%, 74.2%) and IL-6 (16.4%, 69.4%). In mice with thioglycollate-induced peritonitis, both 5alphaTHB and corticosterone reduced the numbers of neutrophils (58.6%, 49.9%) and inflammatory monocytes (69.5%, 96.4%), and also suppressed MCP-1 (48.7%, 80.9%) and IL-6 (53.5%, 86.7%) in peritoneal exudate. In mice chronically infused with 5alphaTHB and corticosterone LPS-induced production of TNF-alpha from whole blood was suppressed to the same degree (63.2%, 37.2%). However, in contrast to corticosterone, 5alphaTHB did not induce body weight loss, increase blood pressure or induce hyperinsulinaemia. CONCLUSIONS: 5alphaTHB has anti inflammatory effects in vitro and in vivo. At doses with equivalent anti inflammatory efficacy to corticosterone, 5alphaTHB did not induce metabolic toxicity and thus may be a prototype for a safer anti-inflammatory drug. PMID- 21542835 TI - The reliability of death certification in patients dying with mucopolysaccharidosis type II (Hunter syndrome). PMID- 21542836 TI - Addendum to 'Recent advances in the genetics of distal hereditary motor neuropathy give insight to a disease mechanism involving copper homeostasis that may extend to other motor neuron disorders'. PMID- 21542837 TI - DNA methylation in neurodegenerative disorders: a missing link between genome and environment? AB - The risk of developing neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease is influenced by genetic and environmental factors. Environmental events occurring during development or later in life can be related to disease susceptibility. One way by which the environment may exert its effect is through epigenetic modifications, which might affect the functioning of genes. These include nucleosome positioning, post-translational histone modifications, and DNA methylation. In this review we will focus in the potential role of DNA methylation in neurodegenerative disorders and in the approaches to explore such epigenetic changes. Advances in deciphering the role of epigenetic modifications in phenotype are being uncovered for a variety of diseases, including cancer, autoimmune, neurodevelopmental and cognitive disorders. Epigenetic modifications are now being also associated with cardiovascular and metabolic traits, and they are expected to be especially involved in learning and memory processes, as well as in neurodegenerative disease. The study of the role of methylation and other epigenetic modifications in disease development will provide new insights in the etiopathogenesis of neurodegenerative disorders, and should hopefully shape new avenues in the development of therapeutic strategies. PMID- 21542838 TI - The pivotal role of immunity and inflammatory processes in epilepsy is increasingly recognized: introduction. PMID- 21542839 TI - Immune-mediated epilepsies. AB - A pathogenic role of immunity in epilepsies has long been suggested based on observations of the efficacy of immune-modulating treatments and, more recently, by the finding of inflammation markers including autoantibodies in individuals with a number of epileptic disorders. Clinical and experimental data suggest that both innate and adaptive immunity may be involved in epilepsy. Innate immunity represents an immediate, nonspecific host response against pathogens via activation of resident brain immune cells and inflammatory mediators. These are hypothesized to contribute to seizures and epileptogenesis. Adaptive immunity employs activation of antigen-specific B and T lymphocytes or antibodies in the context of viral infections and autoimmune disorders. In this article we critically review the evidence for pathogenic roles of adaptive immune responses in several types of epilepsy, and discuss potential mechanisms and therapeutic targets. We highlight future directions for preclinical and clinical research that are required for improved diagnosis and treatment of immune-mediated epilepsies. PMID- 21542840 TI - Systemic and neurologic autoimmune disorders associated with seizures or epilepsy. AB - In this article, we review the incidence and significance of seizures in well established autoimmune disorders, including multiple sclerosis (MS), diabetes mellitus, celiac disease, thyroid disease, and systemic lupus erythematosus (SLE). The five following presentations discuss the incidence and possible pathogenesis of epilepsies that are found in these well-known autoimmune conditions. There is a large body of evidence describing the clinical presentation of seizures with MS and SLE, and showing that refractory epilepsy can complicate these already challenging disorders. However, the mechanisms involved are complex and generally not well understood. Neurologic syndromes, including seizure disorders, can also be a feature of celiac disease (CD) or subclinical CD, sometimes associated with cerebral calcification. The association between type-1 diabetes mellitus (T1DM) and epilepsy is unclear and requires more definitive epidemiologic analysis, despite the fact that antibodies to glutamic acid decarboxylase may provide a link between the two conditions. The association between thyroid disorders and encephalopathies, often termed Hashimoto's encephalopathy, is well known but the pathogenic significance of antithyroid antibodies in this condition is still debated. In general, the relationships between autoimmune mechanisms and seizures in these conditions are unclear; the seizures are likely to be caused by a variety of mechanisms, including ischemia, neuronal damage, and specific and nonspecific immunity. PMID- 21542841 TI - Autoantibodies and epilepsy. AB - In a substantial number of patients with epilepsy, the etiology of the seizure disorder remains unknown. In recent years, the detection of autoantibodies has contributed to the etiologic understanding of a substantial number of so far unexplained epilepsies. The associated syndromes are mainly related to the temporal lobes (with presentation as limbic encephalitis or chronic mediotemporal lobe epilepsy) or to extended brain areas (presenting as diffuse encephalopathies with seizures). However, the full spectrum of autoantibody-associated epilepsies is about to be determined. A promising example for this incipient expansion of the clinical spectrum is the description of a novel seizure type found in patients with antibodies to the voltage-gated potassium channel (VGKC) complex. At present, the antibodies most relevant in epileptology are those directed to molecules on the surface of neurons, namely to components of the VGKC complex and to the N-methyl-d-aspartate-receptor; other antigenic targets located on the surface of neurons are the gamma-aminobutyric acid (GABA)(B) -receptor and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor. There are several reasons to believe that these antibodies are directly pathogenic to the brain. Other autoantibodies target intracellular antigens like those directed to the enzyme glutamic acid decarboxylase (GAD) and the onconeural antibodies. Most researchers think that these antibodies are markers of the immunopathological process rather than being pathogenically active by themselves. Especially the epilepsies associated with antibodies to surface antigens seem to respond to immunotherapies. This offers novel promising therapeutic avenues for the epileptologist. The precise pathogenic effects of autoantibodies still need to be elucidated. PMID- 21542842 TI - Vaccinations and febrile seizures. AB - The occurrence of seizures related to fever results from complex interactions among genetic and environmental factors. The issue of the relationship between vaccination and febrile seizures is complex. It is difficult to identify whether the febrile seizures result from a nonspecific fever caused by vaccination or if these are secondary to an encephalitis or encephalopathy caused by the vaccine. There is evidence showing that vaccination does trigger the onset of febrile seizures in one third of patients with Dravet syndrome. In general, febrile seizures that occur after vaccination do not seem to be different from febrile seizures from other causes, thus advances in knowledge about febrile seizures in general should be relevant to vaccine-associated febrile seizures. PMID- 21542843 TI - Inflammation in epilepsy: clinical observations. AB - Over the past decade, an increasing number of observations indicate that activation of inflammatory processes occurs in variety of focal epilepsies. Understanding the feature and consequences of neuroinflammation, including the contribution to development and perpetuation of seizures, as well as to mood or cognitive dysfunction, is a major requisite for delineating its role in epilepsy. The present article discusses the most recent observations supporting the involvement of the inflammatory response in human focal epilepsy. It also evaluates emerging evidence concerning the possibility to identify epilepsy associated inflammatory biomarkers in cerebrospinal fluid and serum, as well as the potential application of neuroimaging approaches to study the inflammatory reactions in chronic epilepsy patients in vivo, aiming to improve the recognition of appropriate patient populations who might benefit from antiinflammatory or immunomodulatory therapies. PMID- 21542844 TI - Molecular cascades that mediate the influence of inflammation on epilepsy. AB - Experimental evidence strongly indicates a significant role for inflammatory and immune mediators in initiation of seizures and epileptogenesis. Here we will summarize data supporting the involvement of IL-1beta, TNF-alpha and toll-like receptor 4 in seizure generation and the process of epileptogenesis. The physiological homeostasis and control over brain immune response depends on the integrity of the blood-brain barrier, transforming growth factor (TGF)-beta signaling and leukocyte migration. To what extent targeting the immune system is successful in preventing epileptogenesis, and which signaling pathway should be beleaguered is still under intensive research. PMID- 21542845 TI - Antiepileptic drugs and the immune system. AB - Data on the effects of antiepileptic drugs on the immune system are frequently inconsistent and sometimes conflicting because the effects of drugs cannot be separated from those of seizures, first-generation drugs have been most intensively investigated, the patient's genetic background, the mechanism of action and the pharmacokinetic profile of AEDs and the concurrent use of immunosuppressant drugs may act as confounders. Valproate, carbamazepine, phenytoin, vigabatrin, levetiracetam, and diazepam have been found to modulate the immune system activity by affecting humoral and cellular immunity. AEDs are associated with pharmacokinetic interactions (most frequently occurring with carbamazepine, phenytoin, phenobarbital and valproate). Hepatic metabolism is the primary site of interaction for both AEDs and immunotherapies (ACTH, dexamethasone, hydrocortisone, methylprednisolone, cyclophosphamide, methotrexate, rituximab), which entail induction or inhibition of drug effects. However, the clinical importance of these drug interactions is still far from defined. An important adverse effect of the action of AEDs on the immune system is antiepileptic hypersensitivity syndrome (AHS), a life-threatening, idiosyncratic cutaneous reaction to aromatic AEDs resulting in end organ damage. Phenytoin, carbamazepine, phenobarbital, lamotrigine, oxcarbazepine, felbamate, and zonisamide have been implicated. The pathogenic mechanisms of AHS are incompletely understood. PMID- 21542846 TI - Immuno- and antiinflammatory therapies in epileptic disorders. AB - Several experimental and clinical studies demonstrated an immunologic basis for different forms of epilepsy. A wide range of immune abnormalities have been reported suggesting the existence of various subtypes of epileptic syndromes with different immunopathogenetic mechanisms. This evidence gives rise to the development of immunologic and immunomodulatory treatments such as usage of steroids, plasmapheresis, and intravenous immunoglobulins, which will be discussed briefly in this article. PMID- 21542847 TI - General conclusions. PMID- 21542848 TI - MRP8/14 is associated with systemic inflammation in stable coronary atherosclerosis in men. AB - BACKGROUND: MRP8/14, a secreted heterodimeric protein complex secreted upon phagocyte activation, plays an important role in atherogenesis and vascular injury. Phagocyte activation is crucially involved in the development of atherosclerotic processes, and MRP8/14 levels have also been linked to acute cardiovascular events. We investigated whether circulating MRP8/14 correlates to chronic coronary artery disease (CAD) stages in this observational, cross sectional study. METHODS AND RESULTS: A total of 240 male subjects undergoing elective coronary angiography were included in the study. CAD was present in 166 individuals, whereas 74 subjects were classified without prevalent CAD (control subjects). The atherosclerotic burden was obtained by three independent angiographic scores: the Severity, Gensini and Extent Score. Serum MRP8/14 levels were measured by ELISA. They were associated with hs-CRP, IL-6 and fibrinogen levels (r = 0.43, r = 0.40 and r = 0.44, respectively; all P < 0.001). However, MRP8/14 was neither associated with any other cardiovascular disease risk factor nor did serum levels differ between patients with stable CAD [0.82 (0.55-1.14) MUg mL(-1) ] and control subjects [0.91 (0.63-1.30) MUg mL(-1) ; P = 0.69]. Moreover, atherosclerotic wall irregularities did not demonstrate any association with circulating MRP8/14. CONCLUSIONS: The phagocyte activation marker MRP8/14 is significantly associated with markers of systemic inflammation in male patients with CAD. However, we were unable to find a correlation between circulating MRP8/14 complex and stable CAD. PMID- 21542849 TI - Pre-emptive morphine treatment abolishes nerve injury-induced lysophospholipid synthesis in mass spectrometrical analysis. AB - We have previously demonstrated that lysophosphatidic acid (LPA) production in the spinal cord following partial sciatic nerve injury (SCNI) and its signaling initiate neuropathic pain. In order to examine whether LPA production depends on the intense nociceptive signal, we have attempted to see suppression by pre emptive treatment with centrally administered morphine, which mainly inhibits nociceptive signal at the level of spinal cord. In the present study, we developed a quantitative mass spectrometry assay to simultaneously analyze several species of lysophosphatidyl choline (LPC). The levels of 16:0-, 18:0- and 18:1-LPC in the spinal cord and dorsal root were maximally increased at 75 min after SCNI and then declined, as LPC is converted to LPA by autotaxin (ATX). In atx(+/-)-mice, on the other hand, these levels were similar to wild-type mice at 75 min, but maximal at 120 min, suggesting that this difference is partly due to the low conversion of LPC to LPA in atx(+/-)-mice. When morphine was centrally administered before SCNI, the injury-induced increase of LPC was completely abolished. These results suggest that LPC (or LPA) is produced by injury-induced nociceptive signal, which is effectively and pre-emptively suppressed by central morphine, possibly through known descending anti-nociceptive pathways. PMID- 21542850 TI - How we treat: transfusion medicine support of obstetric services. AB - BACKGROUND: Obstetric services depend on the transfusion service (TS) to provide diagnostic testing and blood component therapy for clinical care pathways. STUDY DESIGN AND METHODS: We describe three quality improvement (QI) initiatives implemented to improve TS support of obstetric services. RESULTS: We implemented a pathway for patients requiring an ABO/Rh order for every admission to obstetric services, along with reconciliation of the daily hospital birth manifest and TS umbilical cord log to identify every woman eligible for RhIG. After assessment over 6 months, 21 (1%) of 2041 women lacked an admission ABO/Rh; all subsequently had ABO/Rh determinations. Umbilical cords were missing for eight (0.4%) mothers; four were D- and received RhIG. We developed algorithms for diagnostic blood ordering for patients deemed at "low,""moderate," or "high" risk of blood transfusion. A 27% reduction in total diagnostic test volumes and 24% reduction in charges was documented after compared to before implementation. We analyzed the impact of our massive transfusion protocol (MTP) on blood inventory management for 31 (0.25%) women undergoing 12,945 deliveries, representing 11% of 286 MTPs for all clinical services over a 32-month interval. O- uncrossmatched red blood cells (RBCs) represented 103 (24%) of 421 RBC units issued. Wastage rates of RBCs, plasma, and platelets ordered and issued in the MTPs were 0.7, 16, and 3%, respectively. CONCLUSION: QI initiatives for RhIG prophylaxis, diagnostic blood test ordering, and MTP improve TS support of obstetric services. PMID- 21542851 TI - Transfusion medicine in American undergraduate medical education. AB - BACKGROUND: Blood transfusion is the most common procedure performed in American hospitals, and transfusions are commonly ordered by physicians without formal training in transfusion medicine. Several transfusion medicine curricula have been proposed, including those developed through the Transfusion Medicine Academic Awards (TMAA). To our knowledge, no comprehensive study has assessed how transfusion medicine is incorporated into undergraduate medical education. STUDY DESIGN AND METHODS: We conducted an online survey to determine the manner in which transfusion medicine is incorporated into American undergraduate medical education. The survey was e-mailed to administrators of medical education at all of the 129 American medical schools accredited by the Association of American Medical Colleges. RESULTS: Eighty-six (67%) of the 129 identified medical school administrators responded. Seventy-one (83%) of the 86 administrators reported that their undergraduate medical education curriculum provides didactic lectures in transfusion medicine, with 48% of medical schools providing 1 or 2 hours of lecture-based instruction. A minority reported small group sessions devoted to transfusion medicine topics. While a slim majority reported the availability of transfusion medicine electives, only one of 84 administrators reported that such a rotation is required. Seventy-six of 83 (92%) administrators were unfamiliar with either the 1989 or the 1995 TMAA transfusion medicine curricula. CONCLUSION: Transfusion medicine content in American undergraduate medical education is variable and the influence of the TMAA program on contemporary medical school curricula is questionable. Future efforts in this area should focus on standardizing and improving undergraduate medical education in transfusion medicine. PMID- 21542852 TI - A Phase II study on the safety and efficacy of a single dose of pegfilgrastim for mobilization and transplantation of autologous hematopoietic stem cells in pediatric oncohematology patients. AB - BACKGROUND: Limited data are available on the use of pegfilgrastim in pediatric patients as a mobilizing agent in association with chemotherapy. STUDY DESIGN AND METHODS: This was a prospective, multicenter, Phase II study to evaluate the safety and efficacy of a single dose of 100 ug/kg pegfilgrastim in mobilizing peripheral blood stem cells (PBSCs) in pediatric patients. The primary endpoint of the study was the percentage of good mobilizers with pegfilgrastim (blood peak of CD34+ cells >= 20 * 10(6) /L). The results were compared with a historical control group. RESULTS: Thirty of 36 recruited patients were classified as good mobilizers (83%). The median value of circulating CD34+ at leukapheresis was 143 * 10(6) /L (range, 20 * 10(6) -1988 * 10(6) /L). No significant adverse effects were associated with the use of pegfilgrastim and no patient was withdrawn from using the drug. A blood peak of 20 * 10(6) /L or more CD34+ was observed in 33 of 36 control patients (92%) and the median CD34+ count at leukapheresis was 158 * 10(6) /kg (range, 28 * 10(6) -4529 * 10(6) /kg; p = 0.7). No significant differences were found between the two groups in terms of toxicity or other variables of mobilization. As at October 2008, 23 patients of the pegfilgrastim group and 32 patients of the filgrastim group underwent autologous transplant. No significant differences were found in terms of early toxicity, myeloid recovery, and Day 100 survival. CONCLUSION: A single dose of 100 ug/kg pegfilgrastim was safe and effective for PBSC collection in pediatric patients. We suggest that these results support the use of pegfilgrastim for pediatric patients. PMID- 21542853 TI - Alpha-generation as basic response-signature to transcranial magnetic stimulation (TMS) targeting the human resting motor cortex: a TMS/EEG co-registration study. AB - The effects of repetitive transcranial magnetic stimulation (rTMS) on cortical excitability are usually inferred from indirect indexes, such as EMG responses. It has now become possible to directly evaluate rTMS impact by means of concurrent EEG recording. The aim of this study was to examine the modulation induced by high frequency rTMS (20 Hz) over left primary motor cortex on the ongoing oscillatory activity. Thirteen subjects underwent two sham and a real rTMS session while acquiring EEG. Event-related desynchronization/synchronization was calculated for the alpha and beta bands. rTMS induced a dose-dependent increase in synchronization in both bands over central and parietal sites. The strongest effect found for the alpha band outlasted the end of the stimulation. Considering previous studies, our data suggest that alpha generation may represent an intrinsic induced response and a basic response signature to TMS targeting the human resting motor cortex. PMID- 21542854 TI - Structural model of the gas vesicle protein GvpA and analysis of GvpA mutants in vivo. AB - Gas vesicles are gas-filled protein structures increasing the buoyancy of cells. The gas vesicle envelope is mainly constituted by the 8 kDa protein GvpA forming a wall with a water excluding inner surface. A structure of GvpA is not available; recent solid-state NMR results suggest a coil-alpha-beta-beta-alpha coil fold. We obtained a first structural model of GvpA by high-performance de novo modelling. Attenuated total reflection (ATR)-Fourier transform infrared spectroscopy (FTIR) supported this structure. A dimer of GvpA was derived that could explain the formation of the protein monolayer in the gas vesicle wall. The hydrophobic inner surface is mainly constituted by anti-parallel beta-strands. The proposed structure allows the pinpointing of contact sites that were mutated and tested for the ability to form gas vesicles in haloarchaea. Mutations in alpha-helix I and alpha-helix II, but also in the beta-turn affected the gas vesicle formation, whereas other alterations had no effect. All mutants supported the structural features deduced from the model. The proposed GvpA dimers allow the formation of a monolayer protein wall, also consistent with protease treatments of isolated gas vesicles. PMID- 21542855 TI - Characterization of Bacillus subtilis uracil-DNA glycosylase and its inhibition by phage phi29 protein p56. AB - Uracil-DNA glycosylase (UDG) is a conserved DNA repair enzyme involved in uracil excision from DNA. Here, we report the biochemical characterization of UDG encoded by Bacillus subtilis, a model low G+C Gram-positive organism. The purified enzyme removes uracil preferentially from single-stranded DNA over double-stranded DNA, exhibiting higher preference for U:G than U:A mismatches. Furthermore, we have identified key amino acids necessary for B. subtilis UDG activity. Our results showed that Asp-65 and His-187 are catalytic residues involved in glycosidic bond cleavage, whereas Phe-78 would participate in DNA recognition. Recently, it has been reported that B. subtilis phage phi29 encodes an inhibitor of the UDG enzyme, named protein p56, whose role has been proposed to ensure an efficient viral DNA replication, preventing the deleterious effect caused by UDG when it eliminates uracils present in the phi29 genome. In this work, we also show that a phi29-related phage, GA-1, encodes a p56-like protein with UDG inhibition activity. In addition, mutagenesis analysis revealed that residue Phe-191 of B. subtilis UDG is critical for the interaction with phi29 and GA-1 p56 proteins, suggesting that both proteins have similar mechanism of inhibition. PMID- 21542856 TI - Assembly of the Caulobacter cell division machine. AB - Cytokinesis in Gram-negative bacteria is mediated by a multiprotein machine (the divisome) that invaginates and remodels the inner membrane, peptidoglycan and outer membrane. Understanding the order of divisome assembly would inform models of the interactions among its components and their respective functions. We leveraged the ability to isolate synchronous populations of Caulobacter crescentus cells to investigate assembly of the divisome and place the arrival of each component into functional context. Additionally, we investigated the genetic dependence of localization among divisome proteins and the cell cycle regulation of their transcript and protein levels to gain insight into the control mechanisms underlying their assembly. Our results revealed a picture of divisome assembly with unprecedented temporal resolution. Specifically, we observed (i) initial establishment of the division site, (ii) recruitment of early FtsZ binding proteins, (iii) arrival of proteins involved in peptidoglycan remodelling, (iv) arrival of FtsA, (v) assembly of core divisome components, (vi) initiation of envelope invagination, (vii) recruitment of polar markers and cytoplasmic compartmentalization and (viii) cell separation. Our analysis revealed differences in divisome assembly among Caulobacter and other bacteria that establish a framework for identifying aspects of bacterial cytokinesis that are widely conserved from those that are more variable. PMID- 21542857 TI - Haemophilus influenzae protein E recognizes the C-terminal domain of vitronectin and modulates the membrane attack complex. AB - Haemophilus influenzae protein E (PE) is a 16 kDa adhesin that induces a pro inflammatory immune response in lung epithelial cells. The active epithelial binding region comprising amino acids PE 84-108 also interferes with complement mediated bacterial killing by capturing vitronectin (Vn) that prevents complement deposition and formation of the membrane attack complex (MAC). Here, the interaction between PE and Vn was characterized using site-directed mutagenesis. Protein E variants were produced both in soluble forms and in surface-expressed molecules on Escherichia coli. Mutations within PE(84-108) in the full-length molecule revealed that K85 and R86 residues were important for the Vn binding. Bactericidal activity against H. influenzae was higher in human serum pre-treated with full-length PE as compared with serum incubated with PE(K85E, R86D) , suggesting that PE quenched Vn. A series of truncated Vn molecules revealed that the C-terminal domain comprising Vn(353-363) harboured the major binding region for PE. Interestingly, MAC deposition was significantly higher on mutants devoid of PE due to a decreased Vn-binding capacity when compared with wild-type H. influenzae. Our results define a fine-tuned interaction between H. influenzae and the innate immune system, and identify the mode of control of the MAC that is important for pathogen complement evasion. PMID- 21542859 TI - Substrate recognition by the POTRA domains of TpsB transporter FhaC. AB - Widespread in Gram-negative bacteria, the two-partner secretion (TPS) pathway mediates the secretion of large, beta-helical 'TpsA' proteins with various functions. TpsA proteins harbour a conserved, N-proximal TPS domain essential for secretion. TpsB transporters specifically recognize their TpsA partners in the periplasm and mediate their translocation across the outer membrane through a hydrophilic channel. The FHA/FhaC pair of Bordetella pertussis represents a model TPS system. FhaC is composed of a beta barrel preceded by two periplasmic POTRA domains in tandem. Here we show that both POTRAs are involved in FHA recognition. Surface plasmon resonance analyses indicated an interaction of micromolar affinity between the POTRAs and the TPS domain with fast association and dissociation steps, consistent with the transient character of this interaction in vivo. Major interaction sites in POTRAs correspond to hydrophobic grooves formed by a beta sheet edge and the flanking alpha helix, well-suited to accommodate extended, amphipathic strands of the substrate and consistent with beta augmentation. The initial recruitment of the TPS domain to POTRAs appears to be facilitated by electrostatic attractions. A domain corresponding to the first part of the repeat-rich central region of FHA is also recognized by the POTRAs, suggesting successive interactions in the course of secretion. PMID- 21542858 TI - A sigmaW-dependent stress response in Bacillus subtilis that reduces membrane fluidity. AB - Bacteria respond to physical and chemical stresses that affect the integrity of the cell wall and membrane by activating an intricate cell envelope stress response. The ability of cells to regulate the biophysical properties of the membrane by adjusting fatty acid composition is known as homeoviscous adaptation. Here, we identify a homeoviscous adaptation mechanism in Bacillus subtilis regulated by the extracytoplasmic function sigma factor sigma(W). Cell envelope active compounds, including detergents, activate a sense-oriented, sigma(W) dependent promoter within the first gene of the fabHa fabF operon. Activation leads to a decrease in the amount of FabHa coupled with an increase in FabF, the initiation and elongation condensing enzymes of fatty acid biosynthesis respectively. Downregulation of FabHa results in an increased reliance on the FabHb paralogue leading to a greater proportion of straight chain fatty acids in the membrane, and the upregulation of FabF increases the average fatty acid chain length. The net effect is to reduce membrane fluidity. The inactivation of the sigma(W)-dependent promoter within fabHa increased sensitivity to detergents and to antimicrobial compounds produced by other Bacillus spp. Thus, the sigma(W) stress response provides a mechanism to conditionally decrease membrane fluidity through the opposed regulation of FabHa and FabF. PMID- 21542860 TI - The two faces of ToxR: activator of ompU, co-regulator of toxT in Vibrio cholerae. AB - ToxR of Vibrio cholerae directly activates the ompU promoter, but requires a second activator, TcpP to activate the toxT promoter. ompU encodes a porin, while toxT encodes the transcription factor, ToxT, which activates V. cholerae virulence genes including cholera toxin and the toxin co-regulated pilus. Using an ompU-sacB transcriptional fusion, toxR mutant alleles were identified that encode ToxR molecules defective for ompU promoter activation. Many toxR mutants defective for ompU activation affected residues involved in DNA binding. Mutants defective for ompU activation were also tested for activation of the toxT promoter. ToxR-F69A and ToxR-V71A, both in the alpha-loop of ToxR, were preferentially defective for ompU activation, with ToxR-V71A nearly completely defective. Six mutants from the ompU-sacB selection showed more dramatic defects in toxT activation than ompU activation. All but one of the affected residues map to the wing domain of the winged helix-turn-helix of ToxR. Some ToxR mutants preferentially affecting toxT activation had partial DNA-binding defects, and one mutant, ToxR-P101L, had altered interactions with TcpP. These data suggest that while certain residues in the alpha-loop of ToxR are utilized to activate the ompU promoter, the wing domain of ToxR contributes to both promoter binding and ToxR/TcpP interaction facilitating toxT activation. PMID- 21542861 TI - The biological activity of botulinum neurotoxin type C is dependent upon novel types of ganglioside binding sites. AB - The seven botulinum neurotoxins (BoNT) cause muscle paralysis by selectively cleaving core components of the vesicular fusion machinery. Their extraordinary activity primarily relies on highly specific entry into neurons. Data on BoNT/A, B, E, F and G suggest that entry follows a dual receptor interaction with complex gangliosides via an established ganglioside binding region and a synaptic vesicle protein. Here, we report high resolution crystal structures of the BoNT/C cell binding fragment alone and in complex with sialic acid. The WY-motif characteristic of the established ganglioside binding region was located on an exposed loop. Sialic acid was co-ordinated at a novel position neighbouring the binding pocket for synaptotagmin in BoNT/B and G and the sialic acid binding site in BoNT/D and TeNT respectively. Employing synaptosomes and immobilized gangliosides binding studies with BoNT/C mutants showed that the ganglioside binding WY-loop, the newly identified sialic acid-co-ordinating pocket and the area corresponding to the established ganglioside binding region of other BoNTs are involved in ganglioside interaction. Phrenic nerve hemidiaphragm activity tests employing ganglioside deficient mice furthermore evidenced that the biological activity of BoNT/C depends on ganglioside interaction with at least two binding sites. These data suggest a unique cell binding and entry mechanism for BoNT/C among clostridial neurotoxins. PMID- 21542862 TI - The novel Listeria monocytogenes bile sensor BrtA controls expression of the cholic acid efflux pump MdrT. AB - Mammalian bile has potent anti-microbial activity, yet bacterial pathogens of the gastrointestinal tract and hepatobiliary system nonetheless persist and replicate within bile-rich environments. Listeria monocytogenes, a Gram-positive pathogen, encounters bile at three stages throughout its infectious cycle in vivo: in the gut during initial infection, in the liver where it replicates robustly and in the gallbladder, from which it can return to the intestine and thence to the environment. The mechanisms by which L. monocytogenes senses mammalian bile and counteracts its bactericidal effects are not fully understood. In this report, we have determined the L. monocytogenes bile-induced transcriptome, finding that many critical virulence factors are regulated by bile. Among these, the multidrug efflux pumps MdrM and MdrT, previously shown to be critical for the bacterial provocation of a pathogenesis-promoting host innate immune response, are robustly and specifically induced by the bile component cholic acid. This induction is mediated by BrtA, the first identified L. monocytogenes sensor of bile, which loses the ability to bind to and repress the mdrT promoter in the presence of cholic acid. We show that MdrT can export cholic acid, and that DeltamdrT bacteria are significantly attenuated both in vitro when exposed to cholic acid or bile, and in vivo in the gallbladders and livers of infected mice. PMID- 21542863 TI - Acquisition of VanB-type vancomycin resistance by Bacillus subtilis: the impact on gene expression, cell wall composition and morphology. AB - The vancomycin resistance operons from Enterococci, Staphylococci and Actinomycetes encode a VanRS two-component signal transduction system (TCS) and a suite of enzymes to modify the peptidoglycan biosynthetic precursor lipid II and to eliminate the D-Ala-D-Ala from the cell. Commingling of these regulatory and enzymatic activities with host functions has the potential to significantly impact host gene expression and cell wall metabolism. Here we report the effects of individually expressing the VanR(B) S(B) TCS and the VanY(B) WH(B) BX(B) resistance proteins in Bacillus subtilis. VanY(B) WH(B) BX(B) expression confers resistance to 2 ug ml(-1) of vancomycin with concomitant reduced Van-FL staining and leads to a cell division defect. In contrast to E. faecalis and S. aureus, VanS(B) is active in B. subtilis without vancomycin addition. Individual expression of the VanR(B) S(B) TCS and the VanY(B) WH(B) BX(B) resistance proteins repress and increase, respectively, expression of PhoPR regulon genes in the phosphate-limited state. When vancomycin-resistant cells are exposed to elevated vancomycin levels, mutant strains with increased resistance to vancomycin and a growth dependency on vanY(B) WH(B) BX(B) expression frequently arise. Mutation of the endogenous Ddl ligase is the necessary and sufficient cause of both phenotypes. We discuss how these effects may influence establishment of van operons in new host bacteria. PMID- 21542864 TI - Transcription of the plasmid-encoded toxin gene from enteroaggregative Escherichia coli is regulated by a novel co-activation mechanism involving CRP and Fis. AB - Enteroaggregative Escherichia coli (EAEC) is a major cause of diarrhoea in developing countries. EAEC 042 is the prototypical strain. EAEC 042 secretes the functionally well-characterized Pet autotransporter toxin that contributes to virulence through its cytotoxic effects on intestinal epithelial cells. Following a global transposon mutagenesis screen of EAEC 042, the transcription factors, CRP and Fis, were identified as essential for transcription of the pet gene. Using both in vivo and in vitro techniques, we show that the pet promoter is co dependent on CRP and Fis. We present a novel co-activation mechanism whereby CRP is placed at a non-optimal position for transcription initiation, creating dependence on Fis for full activation of pet. This study complements previous findings that establish Fis as a key virulence regulator in EAEC 042. PMID- 21542865 TI - Role for Golgi reassembly and stacking protein (GRASP) in polysaccharide secretion and fungal virulence. AB - Secretion of virulence factors is a critical mechanism for the establishment of cryptococcosis, a disease caused by the yeast pathogen Cryptococcus neoformans. One key virulence strategy of C. neoformans is the release of glucuronoxylomannan (GXM), a capsule-associated immune-modulatory polysaccharide that reaches the extracellular space through secretory vesicles. Golgi reassembly and stacking protein (GRASP) is required for unconventional protein secretion mechanisms in different eukaryotic cells, but its role in polysaccharide secretion is unknown. This study demonstrates that a C. neoformans functional mutant of a GRASP orthologue had attenuated virulence in an animal model of cryptococcosis, in comparison with wild-type (WT) and reconstituted cells. Mutant cells manifested altered Golgi morphology, failed to produce typical polysaccharide capsules and showed a reduced ability to secrete GXM both in vitro and during animal infection. Isolation of GXM from cultures of WT, reconstituted or mutant strains revealed that the GRASP orthologue mutant produced polysaccharides with reduced dimensions. The mutant was also more efficiently associated to and killed by macrophages than WT and reconstituted cells. These results demonstrate that GRASP, a protein involved in unconventional protein secretion, is also required for polysaccharide secretion and virulence in C. neoformans. PMID- 21542866 TI - The diguanylate cyclase, Rrp1, regulates critical steps in the enzootic cycle of the Lyme disease spirochetes. AB - Rrp1 is the sole c-di-GMP-producing protein (diguanylate cyclase) of Borrelia burgdorferi. To test the hypothesis that Rrp1 regulates critical processes involved in the transmission of spirochetes between ticks and mammals, an rrp1 deletion mutant (B31-Deltarrp1) and a strain that constitutively produces elevated levels of Rrp1 (B31-OV) were constructed. The strains were assessed for progression through the enzootic cycle using an Ixodes tick/C3H-HeJ mouse model and tick immersion feeding methods. B31-Deltarrp1 infected mice as efficiently as wild type but had altered motility, decreased chemotactic responses to N acetylglucosamine (NAG) and attenuated ability to disseminate or colonize distal organs. While this strain infected mice, it was not able to survive in ticks. In contrast, B31-OV displayed normal motility patterns and chemotactic responses but was non-infectious in mice. Using immersion feeding techniques, we demonstrate that B31-OV can establish a population in ticks and survive exposure to a natural bloodmeal. The results presented here indicate Rrp1, and by extension, c-di-GMP, are not strictly required for murine infection, but are required for the successful establishment of a productive population of B. burgdorferi in ticks. These analyses provide significant new insight into the genetic regulatory mechanisms of the Lyme disease spirochetes. PMID- 21542867 TI - The oxidative stress response in yeast cells involves changes in the stability of Aft1 regulon mRNAs. AB - Saccharomyces cerevisiae can import iron through a high-affinity system consisting of the Ftr1/Fet3-mediated reductive pathway and the siderophore mediated non-reductive one. Expression of components of the high-affinity system is controlled by the Aft1 transcriptional factor. In this study we show that, upon oxidative stress, Aft1 is transitorily internalized into the nucleus, followed by transcription activation of components of its regulon. In these conditions, the mRNA levels of the genes of the non-reductive pathway become increased, while those of FTR1 and FET3 remain low because of destabilization of the mRNAs. Consequently, the respective protein levels also remain low. Such mRNA destabilization is mediated by the general 5'-3' mRNA decay pathway and is independent of the RNA binding protein Cth2. Yeast cells are hypersensitive to peroxides in growth conditions where only the high-affinity reductive pathway is functional for iron assimilation. On the contrary, peroxide does not affect growth when iron uptake occurs exclusively through the non-reductive pathway. This reinforces the idea that upon oxidative stress S. cerevisiae cells redirect iron assimilation through the non-reductive pathway to minimize oxidative damage by the ferrous ions, which are formed during iron import through the Ftr1/Fet3 complexes. PMID- 21542870 TI - Psychological intervention to prevent ICU-related PTSD: who, when and for how long? AB - Experiencing treatment on a modern intensive care unit (ICU) is a potentially traumatic event. People who experience traumatic events have an increased risk of depression, anxiety disorders and post-traumatic stress disorder (PTSD). Extended follow-up has confirmed that many patients suffer physical and psychological consequences of the ICU treatment up to 12 months after hospital discharge. PTSD in particular has become increasingly relevant in both the immediate and longer term follow-up care of these patients. The extent to which the consequences of critical illness and the treatments received in the ICU contribute to the development of PTSD is poorly understood and more rigorous studies are needed. Understanding the factors associated with a poor psychological recovery after critical illness is essential to generate models of causality and prognosis, and to guide the delivery of effective, timely interventions. PMID- 21542868 TI - A central metabolic circuit controlled by QseC in pathogenic Escherichia coli. AB - The QseC sensor kinase regulates virulence in multiple Gram-negative pathogens, by controlling the activity of the QseB response regulator. We have previously shown that qseC deletion interferes with dephosphorylation of QseB thus unleashing what appears to be an uncontrolled positive feedback loop stimulating increased QseB levels. Deletion of QseC downregulates virulence gene expression and attenuates enterohaemorrhagic and uropathogenic Escherichia coli (EHEC and UPEC), Salmonella typhimurium, and Francisella tularensis. Given that these pathogens employ different infection strategies and virulence factors, we used genome-wide approaches to better understand the role of the QseBC interplay in pathogenesis. We found that deletion of qseC results in misregulation of nucleotide, amino acid, and carbon metabolism. Comparable metabolic changes are seen in EHEC DeltaqseC, suggesting that deletion of qseC confers similar pleiotropic effects in these two different pathogens. Disruption of representative metabolic enzymes phenocopied UPEC DeltaqseC in vivo and resulted in virulence factor downregulation. We thus propose that in the absence of QseC, the constitutively active QseB leads to pleiotropic effects, impairing bacterial metabolism, and thereby attenuating virulence. These findings provide a basis for the development of antimicrobials targeting the phosphatase activity of QseC, as a means to attenuate a wide range of QseC-bearing pathogens. PMID- 21542872 TI - Blood transfusion and the lung: first do no harm? AB - Marked variability in transfusion practice exists in cardiac surgical patients, with consumption of approximately 20% of the worldwide allogeneic blood supply. Observational studies have reported an association between red blood cell transfusion and adverse outcome, including pulmonary complications, in cardiac surgery. Tuinman and colleagues report that transfusions were associated with activation of pulmonary inflammation and coagulation by measurement of biomarkers in bronchoalveolar lavage fluid, and suggest that transfusion may be a mediator of acute lung injury. This study provides interesting preliminary data, but is limited by multiple confounding variables (plasma transfusion, use of anticoagulants and heparin antagonists) and the small sample size. A large multicenter, prospective, randomized clinical trial regarding the safety (inclusive of pulmonary complications) and efficacy of red blood cell transfusion in cardiac surgery is needed. PMID- 21542873 TI - Inspiratory muscle training in difficult to wean patients: work it harder, make it better, do it faster, makes us stronger. AB - Weaning from prolonged mechanical ventilation is a complex, time-consuming process that involves the loss of force/generating capacity of the inspiratory muscle. In their study 'Inspiratory muscle strength training improves the outcome in failure to wean patients: a randomized trial', Martin and colleagues showed that the use of an inspiratory muscle strength program increased the maximal inspiratory pressure and improved weaning success compared to a control group. The study was performed mainly in post-surgical patients, however, and the results, therefore, may not be generalizable to other subsets of patients, such as those with chronic obstructive pulmonary disease or congestive heart failure. Indeed, the study applied so-called 'strength training' and not 'endurance training', which may be more appropriate in certain circumstances. PMID- 21542874 TI - The challenges and hopes of personalized cancer medicine. AB - A report on the Genome Institute of Singapore and the Fritz Bender Stiftung joint meeting on 'Personalized Cancer Medicine: Towards Individualized Cancer Treatments', Singapore, 21-23 February 2011. PMID- 21542876 TI - Diversity and flexibility of Th17 effector functions. AB - IL-17-producing CD4+ T-helper cells (Th17 cells) have been recognised as important drivers of pathogenesis in a multitude of inflammatory diseases, including arthritis. The cytokines and transcription factors that instruct and execute Th17 lineage differentiation have been identified. This has induced hopes that targeting Th17 cells might yield a magic bullet against autoimmune diseases. A new wave of published reports shows that matters are more complicated: Th cells can coexpress IL-17 with a variety of other cytokines, including IFNgamma, IL-4, or IL-10, with different functional consequences. Moreover, IL-17 memory is not stable--Th17 cells can be instructed to express other lineage-defining cytokines and to halt IL-17 expression. Finally, Th17 cells may exert tissue-protective effects, even in the context of some inflammatory diseases. Manipulating Th17 cells or IL-17 effects may be more difficult than initially appreciated. Notwithstanding these facts, IL-17 remains a valuable and even more interesting therapeutic target. PMID- 21542875 TI - Chromatin as a target antigen in human and murine lupus nephritis. AB - The present review focuses on pathogenic molecular and transcriptional events in patients with lupus nephritis. These factors are renal DNaseI, exposed chromatin fragments and the corresponding chromatin-reactive autoantibodies. Lupus nephritis is the most serious complication in human systemic lupus erythematosus, and is characterised by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes. The latter deposition defines end-stage disease. This event is stringently linked to a renal-restricted shutdown of expression of the DNaseI gene, as determined by loss of DNaseI mRNA level and DNaseI enzyme activity. The major aim of the present review is to generate new therapeutic strategies based on new insight into the disease pathogenesis. PMID- 21542877 TI - Response to 'Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial'. PMID- 21542878 TI - Chemerin/ChemR23 pathway: a system beyond chemokines. AB - Chemerin is a chemokine that, through the engagement of its counter-receptor, ChemR23, attracts pro-inflammatory cells. However, chemerin has been shown to play other functions and a recent study by Berg and colleagues demonstrates that chemerin/ChemR23 is a system beyond chemokines. Human articular chondrocytes produce chemerin and express ChemR23, and upon stimulation with recombinant chemerin increase the production of pro-catabolic cytokines and metalloproteinases. The latter are up-regulated in osteoarthritic cartilage and cause extracellular matrix breakdown. Since an increase of chemerin in fat tissue and serum of obese patients has been reported, this new feature of chemerin may represent a functional link between obesity and osteoarthritis. PMID- 21542879 TI - Genome interrupted: sequencing of prostate cancer reveals the importance of chromosomal rearrangements. AB - A recent study involving whole genome sequencing of seven prostate cancers has provided the first comprehensive assessment of genomic changes that underlie this common malignancy. Point mutations were found to be infrequent but changes in chromosome structure were common. Rearrangements were linked to chromatin organization and associated with regions involved in transcription factor binding. Novel candidate prostate cancer genes were also identified, highlighting the importance of genome sequencing to identify oncogenic changes that are otherwise invisible to detection. PMID- 21542880 TI - European legislation impedes critical care research and fails to protect patients' rights. AB - The European Clinical Trials Directive requires an informed consent from the patient or a proxy in drug trials. Although informed consent is a valuable tool to protect patients' rights in clinical trials, this requirement largely impedes research in critical care settings, and if pursued in this context, it does not provide the patient with adequate protection. Instead of insisting on informed consent, we suggest that the focus should be shifted towards two other ethically relevant elements in human experimentation: risk assessment and selection of research subjects. When reviewing protocols in which a waiver of consent is deemed necessary, the Ethical Review Board should ensure that non-therapeutic risks are minimal, that the research is specifically designed to benefit critically ill patients, and that it cannot be conducted under circumstances where an informed consent can be obtained. If the European Directive is changed accordingly, this permits clinical trials in critical care settings, while adequate protection from risky non-therapeutic procedures is ensured and exploitation of the patient as an easily accessible research subject is prevented. PMID- 21542881 TI - Epigenetic regulation of satellite cell activation during muscle regeneration. AB - Satellite cells are a population of adult muscle stem cells that play a key role in mediating muscle regeneration. Activation of these quiescent stem cells in response to muscle injury involves modulating expression of multiple developmentally regulated genes, including mediators of the muscle-specific transcription program: Pax7, Myf5, MyoD and myogenin. Here we present evidence suggesting an essential role for the antagonistic Polycomb group and Trithorax group proteins in the epigenetic marking of muscle-specific genes to ensure proper temporal and spatial expression during muscle regeneration. The importance of Polycomb group and Trithorax group proteins in establishing chromatin structure at muscle-specific genes suggests that therapeutic modulation of their activity in satellite cells could represent a viable approach for repairing damaged muscle in muscular dystrophy. PMID- 21542882 TI - Knee osteoarthritis, lumbar-disc degeneration and developmental dysplasia of the hip--an emerging genetic overlap. AB - Genetics highlights relationships between biological systems, and as the number of defined osteoarthritis susceptibility alleles increases, there is the natural tendency to assess whether the alleles influence other musculoskeletal phenotypes. That has proven to be the case for the GDF5 polymorphism rs143383, a risk factor for knee osteoarthritis and several other common conditions, including lumbar-disc degeneration and developmental dysplasia of the hip. Another interesting example has recently emerged in the repeat polymorphism of the asporin gene, ASPN, which is also associated with these three phenotypes. Such discoveries increase our understanding of shared disease etiology but also emphasize the complexity of common genetic risk. PMID- 21542883 TI - Can ultrasonography make identification of asymptomatic hyperuricemic individuals at risk for developing gouty arthritis more crystal clear? AB - Hyperuricemia is the most important risk factor for gouty arthritis. The quandary is how to predict which patient with asymptomatic hyperuricemia will develop gouty arthritis. Can ultrasonography help identify hyperuricemic individuals at risk for developing gouty arthritis? In the previous issue of Arthritis Research & Therapy, Pineda and colleagues found ultrasonography changes suggestive of gouty arthritis in 25% of hyperuricemic individuals. These were found exclusively in hyperuricemic individuals but not in normouricemic patients. Ultrasonography may serve as a noninvasive means to diagnose gouty arthritis in hyperuricemic individuals who have yet to develop symptomatic gouty arthritis. PMID- 21542884 TI - Therapeutic hypothermia post out-of-hospital cardiac arrest - more questions than answers? AB - Nearly a decade since the introduction of therapeutic hypothermia to the ICU for cooling out-of-hospital cardiac arrest patients, key questions remain unanswered: when should cooling be initiated, how rapidly should the patient be cooled and using which device? The Time to Target Temperature study group provides important baseline data on the striking direct relationship between body temperature and survival from out-of-hospital cardiac arrest. PMID- 21542885 TI - What can we learn from study of Alzheimer's disease in patients with Down syndrome for early-onset Alzheimer's disease in the general population? AB - The clinical and scientific study of dementia in adults with Down syndrome led to the development of the amyloid hypothesis as a fundamental concept in Alzheimer's disease pathogenesis. The journey started with the discovery of the structure and metabolic processing of beta-amyloid brain deposits associated with Alzheimer's dementia in adults with Down syndrome, and then the prediction and confirmation of the amyloid precursor protein gene on chromosome 21. The processes and genes responsible for tau hyperphosphorylation contributing to toxic brain deposits were additionally identified. With increasing sophistication in genetic experimental techniques, additional mechanisms associated with excessive amyloid deposits were postulated and tested in brains of people with Down syndrome and Alzheimer's disease and in those with early-onset Alzheimer's disease. This in turn led to the proposal and testing for particular genetic defects associated with familial early-onset Alzheimer's disease. Nearly 200 genetic causes of early onset types of Alzheimer's disease have since been identified. Only a minority of these causes are on chromosome 21, although the aetiology of excess amyloid production remains fundamental to their pathogenesis. Knowledge of the pathogenic mechanisms of Alzheimer's disease in predisposed families and in people with Down syndrome is a step closer to prevention or cure of this devastating disease. PMID- 21542886 TI - What do measurements of molecular biomarkers in different body fluids really tell us? AB - Molecular or biochemical biomarkers of joint metabolism offer promise in helping us understand joint pathology, its detection and treatment. But they have often been studied alone and in only one body fluid. Although the synovial joint is usually the focus of most arthritis pathology, it is often difficult, for a variety of reasons, to obtain synovial fluid that should best reflect changes in biomarkers related to pathology. It is therefore very important to see whether analyses of more readily obtainable sera and urine also reflect changes in synovial fluid. Catterall and colleagues, in a paper in Arthritis Research & Therapy that examines very early biomarker changes following joint injury, provide us with some insights into these important questions. As the study was very small and examined very early changes following joint injury, prior to onset of any recognisable pathology, we look forward to future larger biomarker studies of this kind in patients with clinically defined arthritic changes to which we can relate biomarker data. PMID- 21542887 TI - Response to 'Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomized study over 21 months'. PMID- 21542888 TI - Testing for rare variant associations in complex diseases. AB - The study of rare variants holds the promise of accounting for some of the missing heritability in complex traits. Next-generation sequencing technologies enable probing of variation across the full spectrum of allele frequencies. Multiple methods for the analysis of rare variants have been proposed and, recently, Ionita-Laza et al. have presented an approach with the theoretical capacity to detect risk and protective variants. The identification of rare risk variants could have major implications in understanding complex disease etiopathogenesis. PMID- 21542889 TI - Methods for the de-identification of electronic health records for genomic research. AB - Electronic health records are increasingly being linked to DNA repositories and used as a source of clinical information for genomic research. Privacy legislation in many jurisdictions, and most research ethics boards, require that either personal health information is de-identified or that patient consent or authorization is sought before the data are disclosed for secondary purposes. Here, I discuss how de-identification has been applied in current genomic research projects. Recent metrics and methods that can be used to ensure that the risk of re-identification is low and that disclosures are compliant with privacy legislation and regulations (such as the Health Insurance Portability and Accountability Act Privacy Rule) are reviewed. Although these methods can protect against the known approaches for re-identification, residual risks and specific challenges for genomic research are also discussed. PMID- 21542890 TI - Soluble IL-18 receptor complex: a new star in the firmament of rheumatoid arthritis diagnosis? AB - It has long been recognized that laboratory tests are useful in the diagnosis of disease and to monitor treatment outcome. Their performance has become even more demanding with the development of personalized medicine. In patients with rheumatoid arthritis (RA) the standard biochemical tests measure serological markers of disease, such as C-reactive protein, and RA-associated auto antibodies, such as rheumatoid factor and anti-citrullinated protein antibodies. The information obtained from these markers does not, however, provide a complete picture of the disease and treatment efficacy. New biomarkers based on cytokine receptor complexes are promising for RA theragnostics. PMID- 21542891 TI - Older patients in the ICU: a cautious analysis of epidemiologic data is required. PMID- 21542892 TI - Predicting treatment outcome in classical Hodgkin lymphoma: genomic advances. AB - Classical Hodgkin lymphoma is considered a highly curable disease; however, 20% of patients cannot be cured with standard first-line chemotherapy and have a dismal outcome. Current clinical parameters do not allow accurate risk stratification, and personalized therapies are lacking. In fact, Hodgkin lymphoma (HL) is often over- or undertreated because of this lack of accurate risk stratification. In recent years, the early detection of chemoresistance by fluorodeoxyglucose positron emission tomography has become the most important prognostic tool in the management of HL. However, to date, no prognostic scores or molecular markers are available for the early identification of patients at very high risk of failure of induction therapy. In the last decade, many important advances have been made in understanding the biology of HL. In particular, the development of new molecular profiling technologies, such as SNP arrays, comparative genomic hybridization, and gene-expression profiling, have allowed the identification of new prognostic factors that may be useful for risk stratification and predicting response to chemotherapy. In this review, we focus on the prognostic tools and biomarkers that are available for newly diagnosed HL, and we highlight recent advances in the genomic characterization of classical HL and potential targets for therapy. PMID- 21542893 TI - The role of the central nervous system in the generation and maintenance of chronic pain in rheumatoid arthritis, osteoarthritis and fibromyalgia. AB - Pain is a key component of most rheumatologic diseases. In fibromyalgia, the importance of central nervous system pain mechanisms (for example, loss of descending analgesic activity and central sensitization) is well documented. A few studies have also noted alterations in central pain processing in osteoarthritis, and some data, including the observation of widespread pain sensitivity, suggest that central pain-processing defects may alter the pain response in rheumatoid arthritis patients. When central pain is identified, different classes of analgesics (for example, serotonin-norepinephrine reuptake inhibitors, alpha2delta ligands) may be more effective than drugs that treat peripheral or nociceptive pain (for example, nonsteroidal anti-inflammatory drugs and opioids). PMID- 21542894 TI - Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines. AB - The peripheral nociceptor is an important target of pain therapy because many pathological conditions such as inflammation excite and sensitize peripheral nociceptors. Numerous ion channels and receptors for inflammatory mediators were identified in nociceptors that are involved in neuronal excitation and sensitization, and new targets, beyond prostaglandins and cytokines, emerged for pain therapy. This review addresses mechanisms of nociception and focuses on molecules that are currently favored as new targets in drug development or that are already targeted by new compounds at the stage of clinical trials--namely the transient receptor potential V1 receptor, nerve growth factor, and voltage-gated sodium channels--or both. PMID- 21542895 TI - Diagnosis of invasive bronchial-pulmonary aspergillosis in patients with chronic obstructive respiratory diseases. PMID- 21542896 TI - In critically ill patients the procalcitonin level can be misleading. PMID- 21542897 TI - Trapped in a vicious loop: Toll-like receptors sustain the spontaneous cytokine production by rheumatoid synovium. AB - Synovial tissue of patients with rheumatoid arthritis (RA) spontaneously produces several cytokines, of which a fundamental role in joint inflammation and destruction has been established. However, the factors sustaining this phenomenon remain poorly understood. In a recent report, blockade of Toll-like receptor 2 (TLR2) was found to inhibit the spontaneous release of inflammatory cytokines by intact RA synovial explant cultures. Adding to the recent evidence implicating other TLRs (in particular, TLR4), this observation highlights the potential of TLRs as therapeutic targets to suppress the local production of multiple cytokines and to control the chronic inflammatory loop in RA. PMID- 21542898 TI - Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications. AB - INTRODUCTION: Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers. METHODS: In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method. RESULTS: We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels.Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. CONCLUSIONS: We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation. PMID- 21542899 TI - Lack of neuroprotection in the absence of P2X7 receptors in toxin-induced animal models of Parkinson's disease. AB - BACKGROUND: Previous studies indicate a role of P2X7 receptors in processes that lead to neuronal death. The main objective of our study was to examine whether genetic deletion or pharmacological blockade of P2X7 receptors influenced dopaminergic cell death in various models of Parkinson's disease (PD). RESULTS: mRNA encoding P2X7 and P2X4 receptors was up-regulated after treatment of PC12 cells with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). P2X7 antagonists protected against MPTP and rotenone induced toxicity in the LDH assay, but failed to protect after rotenone treatment in the MTT assay in PC12 cells and in primary midbrain culture. In vivo MPTP and in vitro rotenone pretreatments increased the mRNA expression of P2X7 receptors in the striatum and substantia nigra of wild type mice. Basal mRNA expression of P2X4 receptors was higher in P2X7 knockout mice and was further up-regulated by MPTP treatment. Genetic deletion or pharmacological inhibition of P2X7 receptors did not change survival rate or depletion of striatal endogenous dopamine (DA) content after in vivo MPTP or in vitro rotenone treatment. However, depletion of norepinephrine was significant after MPTP treatment only in P2X7 knockout mice. The basal ATP content was higher in the substantia nigra of wild-type mice, but the ADP level was lower. Rotenone treatment elicited a similar reduction in ATP content in the substantia nigra of both genotypes, whereas reduction of ATP was more pronounced after rotenone treatment in striatal slices of P2X7 deficient mice. Although the endogenous amino acid content remained unchanged, the level of the endocannabinoid, 2-AG, was elevated by rotenone in the striatum of wild-type mice, an effect that was absent in mice deficient in P2X7 receptors. CONCLUSIONS: We conclude that P2X7 receptor deficiency or inhibition does not support the survival of dopaminergic neurons in an in vivo or in vitro models of PD. PMID- 21542900 TI - CompaGB: An open framework for genome browsers comparison. AB - BACKGROUND: Tools to visualize and explore genomes hold a central place in genomics and the diversity of genome browsers has increased dramatically over the last few years. It often turns out to be a daunting task to compare and choose a well-adapted genome browser, as multidisciplinary knowledge is required to carry out this task and the number of tools, functionalities and features are overwhelming. FINDINGS: To assist in this task, we propose a community-based framework based on two cornerstones: (i) the implementation of industry promoted software qualification method (QSOS) adapted for genome browser evaluations, and (ii) a web resource providing numerous facilities either for visualizing comparisons or performing new evaluations. We formulated 60 criteria specifically for genome browsers, and incorporated another 65 directly from QSOS's generic section. Those criteria aim to answer versatile needs, ranging from a biologist whose interest primarily lies into user-friendly and informative functionalities, a bioinformatician who wants to integrate the genome browser into a wider framework, or a computer scientist who might choose a software according to more technical features. We developed a dedicated web application to enrich the existing QSOS functionalities (weighting of criteria, user profile) with features of interest to a community-based framework: easy management of evolving data, user comments... CONCLUSIONS: The framework is available at http://genome.jouy.inra.fr/CompaGB. It is open to anyone who wishes to participate in the evaluations. It helps the scientific community to (1) choose a genome browser that would better fit their particular project, (2) visualize features comparatively with easily accessible formats, such as tables or radar plots and (3) perform their own evaluation against the defined criteria. To illustrate the CompaGB functionalities, we have evaluated seven genome browsers according to the implemented methodology. A summary of the features of the compared genome browsers is presented and discussed. PMID- 21542901 TI - Capability and dependency in the Newcastle 85+ cohort study. Projections of future care needs. AB - BACKGROUND: Little is known of the capabilities of the oldest old, the fastest growing age group in the population. We aimed to estimate capability and dependency in a cohort of 85 year olds and to project future demand for care. METHODS: Structured interviews at age 85 with 841 people born in 1921 and living in Newcastle and North Tyneside, UK who were permanently registered with participating general practices. Measures of capability included were self reported activities of daily living (ADL), timed up and go test (TUG), standardised mini-mental state examination (SMMSE), and assessment of urinary continence in order to classify interval-need dependency. To project future demand for care the proportion needing 24-hour care was applied to the 2008 England and Wales population projections of those aged 80 years and over by gender. RESULTS: Of participants, 62% (522/841) were women, 77% (651/841) lived in standard housing, 13% (106/841) in sheltered housing and 10% (84/841) in a care home. Overall, 20% (165/841) reported no difficulty with any of the ADLs. Men were more capable in performing ADLs and more independent than women. TUG validated self-reported ADLs. When classified by 'interval of need' 41% (332/810) were independent, 39% (317/810) required help less often than daily, 12% (94/810) required help at regular times of the day and 8% (67/810) required 24-hour care. Of care-home residents, 94% (77/82) required daily help or 24-hour care. Future need for 24-hour care for people aged 80 years or over in England and Wales is projected to increase by 82% from 2010 to 2030 with a demand for 630,000 care home places by 2030. CONCLUSIONS: This analysis highlights the diversity of capability and levels of dependency in this cohort. A remarkably high proportion remain independent, particularly men. However a significant proportion of this population require 24-hour care at home or in care homes. Projections for the next 20 years suggest substantial increases in the number requiring 24-hour care due to population ageing and a proportionate increase in demand for care-home places unless innovative health and social care interventions are found. PMID- 21542902 TI - Tumor necrosis factor-alpha enhances hyperbaric oxygen-induced visfatin expression via JNK pathway in human coronary arterial endothelial cells. AB - BACKGROUND: Visfatin, a adipocytokine with insulin-mimetic effect, plays a role in endothelial angiogenesis. Hyperbaric oxygen (HBO) has been used in medical practice. However, the molecular mechanism of beneficial effects of HBO is poorly understood. We sought to investigate the cellular and molecular mechanisms of regulation of visfatin by HBO in human coronary arterial endothelial cells (CAECs). METHODS: Human CAECs were exposed to 2.5 atmosphere absolute (ATA) of oxygen in a hyperbaric chamber. Western blot, real-time polymerase chain reaction, and promoter activity assay were performed. In vitro glucose uptake and tube formation was detected. RESULTS: Visfatin protein (2.55-fold) and mRNA (2.53 fold) expression were significantly increased after exposure to 2.5 ATA HBO for 4 to 6 h. Addition of SP600125 and JNK siRNA 30 min before HBO inhibited the induction of visfatin protein. HBO also significantly increased DNA-protein binding activity of AP-1 and visfatin promoter activity. Addition of SP600125 and TNF-alpha monoclonal antibody 30 min before HBO abolished the DNA-protein binding activity and visfatin promoter activity induced by HBO. HBO significantly increased secretion of TNF-alpha from cultured human CAECs. Exogenous addition of TNF-alpha significantly increased visfatin protein expression while TNF-alpha antibody and TNF-alpha receptor antibody blocked the induction of visfatin protein expression induced by HBO. HBO increased glucose uptake in human CAECs as HBO and visfatin siRNA and TNF-alpha antibody attenuated the glucose uptake induced by HBO. HBO significantly increased the tube formation of human CAECs while visfatin siRNA, TNF-alpha antibody inhibited the tube formation induced by HBO. CONCLUSIONS: HBO activates visfatin expression in cultured human CAECs. HBO induced visfatin is mediated by TNF-alpha and at least in part through JNK pathway. PMID- 21542903 TI - Decrease of physical activity level in adolescents with limb fractures: an accelerometry-based activity monitor study. AB - BACKGROUND: Immobilization and associated periods of inactivity can cause osteopenia, the physiological response of the bone to disuse. Mechanical loading plays an essential role in maintaining bone integrity. Skeletal fractures represent one cause of reduction of the physical activity (PA) level in adolescents. The purpose of this study was to quantify the reduction of PA in adolescents with limb fractures during the cast immobilization period compared with healthy controls. METHODS: Two hundred twenty adolescents were divided into three groups: those with upper limb fractures (50 cases); lower limb fractures (50 cases); and healthy cases (120 cases). Patients and their healthy peers were matched for gender, age, and seasonal assessment of PA. PA level was assessed during cast immobilization by accelerometer. Time spent in PA in each of the different intensity levels - sedentary, light, moderate, and vigorous - was determined for each participant and expressed in minutes and as a percentage of total valid time. RESULTS: Reduction in PA during cast immobilization was statistically significant in patients with limb fractures compared to healthy controls. The total PA count (total number of counts/min) was significantly lower in those with upper and lower limb fractures (-30.1% and -62.4%, respectively) compared with healthy controls (p < 0.0001 and p = 0.0003, respectively). Time spent in moderate-to-vigorous PA by patients with upper and lower limb injuries decreased by 36.9% (p = 0.0003) and 76.6% (p < 0.0001), respectively, and vigorous PA was reduced by 41.4% (p = 0.0008) and 84.4% (p < 0.0001), respectively. CONCLUSIONS: PA measured by accelerometer is a useful and valid tool to assess the decrease of PA level in adolescents with limb fractures. As cast immobilization and reduced PA are known to induce bone mineral loss, this study provides important information to quantify the decrease of skeletal loading in this patient population. The observed reduction of high intensity skeletal loading due to the decrease in vigorous PA may explain osteopenia due to disuse, and these data should be kept in mind by trauma practitioners to avoid any unnecessary prolongation of the cast immobilization period. PMID- 21542904 TI - A snapshot of the organization and provision of primary care in Turkey. AB - BACKGROUND: This WHO study aimed to support Turkey in its efforts to strengthen the primary care (PC) system by implementing the WHO Primary Care Evaluation Tool (PCET). This article provides an overview of the organization and provision of primary care in Turkey. METHODS: The WHO Primary Care Evaluation Tool was implemented in two provinces (Bolu and Eskisehir) in Turkey in 2007/08. The Tool consists of three parts: a national questionnaire concerning the organisation and financing of primary care; a questionnaire for family doctors; and a questionnaire for patients who visit a family health centre. RESULTS: Primary care has just recently become an official health policy priority with the introduction of a family medicine scheme. Although the supply of family doctors (FDs) has improved, they are geographically uneven distributed, and nationwide shortages of primary care staff remain. Coordination of care could be improved and quality control mechanisms were lacking. However, patients were very satisfied with the treatment by FDs. CONCLUSIONS: The study provides an overview of the current state of PC in Turkey for two provinces with newly introduced family medicine, by using a structured approach to evaluate the essential functions of PC, including governance, financing, resource generation, as well as the characteristics of a "good" service delivery system (as being accessible, comprehensive, coordinated and continuous). PMID- 21542905 TI - Teaching tools in evidence based practice: evaluation of reusable learning objects (RLOs) for learning about meta-analysis. AB - BACKGROUND: All healthcare students are taught the principles of evidence based practice on their courses. The ability to understand the procedures used in systematically reviewing evidence reported in studies, such as meta-analysis, are an important element of evidence based practice. Meta-analysis is a difficult statistical concept for healthcare students to understand yet it is an important technique used in systematic reviews to pool data from studies to look at combined effectiveness of treatments. In other areas of the healthcare curricula, by supplementing lectures, workbooks and workshops with pedagogically designed, multimedia learning objects (known as reusable learning objects or RLOs) we have shown an improvement in students' perceived understanding in subjects they found difficult. In this study we describe the development and evaluation of two RLOs on meta-analysis. The RLOs supplement associated lectures and aim to improve students' understanding of meta-analysis in healthcare students. METHODS: Following a quality controlled design process two RLOs were developed and delivered to two cohorts of students, a Master in Public Health course and Postgraduate diploma in nursing course. Students' understanding of five key concepts of Meta-analysis were measured before and after a lecture and again after RLO use. RLOs were also evaluated for their educational value, learning support, media attributes and usability using closed and open questions. RESULTS: Students rated their understanding of meta-analysis as improved after a lecture and further improved after completing the RLOs (Wilcoxon paired test, p < 0.01 in all cases) Whilst the media components of the RLOs such as animations helped most students (86%) understand concepts including for example Forest plots, 93% of students rated usability and control as important to their learning. A small number of students stated they needed the support of a lecturer alongside the RLOs (7% 'Agreed' and 21% 'Neutral'). CONCLUSIONS: Meta-analysis RLOs that are openly accessible and unrestricted by usernames and passwords provide flexible support for students who find the process of meta-analysis difficult. PMID- 21542906 TI - Lack of global meiotic sex chromosome inactivation, and paucity of tissue specific gene expression on the Drosophila X chromosome. AB - BACKGROUND: Paucity of male-biased genes on the Drosophila X chromosome is a well established phenomenon, thought to be specifically linked to the role of these genes in reproduction and/or their expression in the meiotic male germline. In particular, meiotic sex chromosome inactivation (MSCI) has been widely considered a driving force behind depletion of spermatocyte-biased X-linked genes in Drosophila by analogy with mammals, even though the existence of global MCSI in Drosophila has not been proven. RESULTS: Microarray-based study and qRT-PCR analyses show that the dynamics of gene expression during testis development are very similar between X-linked and autosomal genes, with both showing transcriptional activation concomitant with meiosis. However, the genes showing at least ten-fold expression bias toward testis are significantly underrepresented on the X chromosome. Intriguingly, the genes with similar expression bias toward tissues other than testis, even those not apparently associated with reproduction, are also strongly underrepresented on the X. Bioinformatics analysis shows that while tissue-specific genes often bind silencing-associated factors in embryonic and cultured cells, this trend is less prominent for the X-linked genes. CONCLUSIONS: Our data show that the global meiotic inactivation of the X chromosome does not occur in Drosophila. Paucity of testis-biased genes on the X appears not to be linked to reproduction or germline specific events, but rather reflects a general underrepresentation of tissue biased genes on this chromosome. Our analyses suggest that the activation/repression switch mechanisms that probably orchestrate the highly biased expression of tissue-specific genes are generally not efficient on the X chromosome. This effect, probably caused by dosage compensation counteracting repression of the X-linked genes, may be the cause of the exodus of highly tissue biased genes to the autosomes. PMID- 21542907 TI - EphA4 expression promotes network activity and spine maturation in cortical neuronal cultures. AB - BACKGROUND: Neurons form specific connections with targets via synapses and patterns of synaptic connectivity dictate neural function. During development, intrinsic neuronal specification and environmental factors guide both initial formation of synapses and strength of resulting connections. Once synapses form, non-evoked, spontaneous activity serves to modulate connections, strengthening some and eliminating others. Molecules that mediate intercellular communication are particularly important in synaptic refinement. Here, we characterize the influences of EphA4, a transmembrane signaling molecule, on neural connectivity. RESULTS: Using multi-electrode array analysis on in vitro cultures, we confirmed that cortical neurons mature and generate spontaneous circuit activity as cells differentiate, with activity growing both stronger and more patterned over time. When EphA4 was over-expressed in a subset of neurons in these cultures, network activity was enhanced: bursts were longer and were composed of more spikes than in control-transfected cultures. To characterize the cellular basis of this effect, dendritic spines, the major excitatory input site on neurons, were examined on transfected neurons in vitro. Strikingly, while spine number and density were similar between conditions, cortical neurons with elevated levels of EphA4 had significantly more mature spines, fewer immature spines, and elevated colocalization with a mature synaptic marker. CONCLUSIONS: These results demonstrate that experimental elevation of EphA4 promotes network activity in vitro, supporting spine maturation, producing more functional synaptic pairings, and promoting more active circuitry. PMID- 21542908 TI - Rostral growth of commissural axons requires the cell adhesion molecule MDGA2. AB - BACKGROUND: Long-distance axonal growth relies on the precise interplay of guidance cues and cell adhesion molecules. While guidance cues provide positional and directional information for the advancing growth cone, cell adhesion molecules are essential in enabling axonal advancement. Such a dependence on adhesion as well as guidance molecules can be well observed in dorsal commissural interneurons, which follow a highly stereotypical growth and guidance pattern. The mechanisms and molecules involved in the attraction and outgrowth towards the ventral midline, the axon crossing towards the contralateral side, the rostral turning after midline crossing as well as the guidance along the longitudinal axis have been intensely studied. However, little is known about molecules that provide the basis for commissural axon growth along the anterior-posterior axis. RESULTS: MDGA2, a recently discovered cell adhesion molecule of the IgCAM superfamily, is highly expressed in dorsolaterally located (dI1) spinal interneurons. Functional studies inactivating MDGA2 by RNA interference (RNAi) or function-blocking antibodies demonstrate that either treatment results in a lack of commissural axon growth along the longitudinal axis. Moreover, results from RNAi experiments targeting the contralateral side together with binding studies suggest that homophilic MDGA2 interactions between ipsilaterally projecting axons and post-crossing commissural axons may be the basis of axonal growth along the longitudinal axis. CONCLUSIONS: Directed axonal growth of dorsal commissural interneurons requires an elaborate mixture of instructive (guidance) and permissive (outgrowth supporting) molecules. While Wnt and Sonic hedgehog (Shh) signalling pathways have been shown to specify the growth direction of post crossing commissural axons, our study now provides evidence that homophilic MDGA2 interactions are essential for axonal extension along the longitudinal axis. Interestingly, so far each part of the complex axonal trajectory of commissural axons uses its own set of guidance and growth-promoting molecules, possibly explaining why such a high number of molecules influencing the growth pattern of commissural interneurons has been identified. PMID- 21542909 TI - Association of daily tar and nicotine intake with incident myocardial infarction: results from the population-based MONICA/KORA Augsburg Cohort Study 1984-2002. AB - BACKGROUND: Cigarette smoking has been shown to be one of the most important risk factors for cardiovascular diseases. However, little is known about cumulative effects of daily tar and nicotine intake on the risk of incident myocardial infarction (MI) so far. To bridge this gap, we conducted an analysis in a large prospective study from Southern Germany investigating associations of daily tar and nicotine intake with an incident MI event. METHODS: The study was based on 4,099 men and 4,197 women participating in two population-based MONICA Augsburg surveys between 1984 and 1990 and followed up within the KORA framework until 2002. During a mean follow-up of 13.3 years, a number of 307 men and 80 women developed an incident MI event. Relative risks were calculated as hazard ratios (HRs) estimated by Cox proportional hazards models adjusted for cardiovascular risk factors. RESULTS: In the present study, male regular smokers consumed on average more cigarettes per day than female regular smokers (20 versus 15) and had a higher tar and nicotine intake per day. In men, the MI risk compared to never-smokers increased with higher tar intake: HRs were 2.24 (95% CI 1.40-3.56) for 1-129 mg/day, 2.12 (95% CI 1.37-3.29) for 130-259 mg/day and 3.01 (95% CI 2.08-4.36) for >= 260 mg/day. In women, the corresponding associations were comparable but more pronounced for high tar intake (HR 4.67, 95% CI 1.76-12.40). Similar associations were observed for nicotine intake. CONCLUSIONS: The present study based on a large population-based sample adds important evidence of cumulative effects of tar and nicotine intake on the risk of incident MI. Even low or medium tar and nicotine intake revealed substantial risk increases as compared to never-smokers. Therefore, reduction of tar and nicotine contents in cigarettes cannot be seen as a suitable public health policy in preventing myocardial infarction. PMID- 21542910 TI - Volume, patterns, and types of sedentary behavior and cardio-metabolic health in children and adolescents: a cross-sectional study. AB - BACKGROUND: Cardio-metabolic risk factors are becoming more prevalent in children and adolescents. A lack of moderate-to-vigorous intensity physical activity (MVPA) is an established determinant of cardio-metabolic risk factors in children and adolescents. Less is known about the relationship between sedentary behavior and cardio-metabolic health. Therefore, the objective was to examine the independent associations between volume, patterns, and types of sedentary behavior with cardio-metabolic risk factors among children and adolescents. METHODS: The results are based on 2527 children and adolescents (6-19 years old) from the 2003/04 and 2005/06 National Health and Nutrition Examination Surveys (NHANES). A cardio-metabolic risk score (CRS) was calculated based on age- and sex-adjusted waist circumference, systolic blood pressure, non-high-density lipoprotein cholesterol, and C-reactive protein values. Volume and patterns of sedentary behavior and moderate-to-vigorous physical activity (MVPA) were measured objectively using accelerometers. Types of sedentary behavior were measured by questionnaire. A series of logistic regression models were used to examine associations. RESULTS: Volume and patterns of sedentary behavior were not predictors of high CRS after adjusting for MVPA and other confounders (P > 0.1). For types of sedentary behavior, high TV use, but not high computer use, was a predictor of high CRS after adjustment for MVPA and other confounders. Children and adolescents who watched >=4 hours per day of TV were 2.53 (95% confidence interval: 1.45-4.42) times more likely to have high CRS than those who watched <1 hour per day. MVPA predicted high CRS after adjusting for all sedentary behavior measures and other confounders. After adjustment for waist circumference, MVPA also predicted high non-obesity CRS; however, the same relationship was not seen with TV use. CONCLUSION: No association was observed between overall volume and patterns of sedentary behavior with cardio-metabolic risk factors in this large sample of children and adolescents. Conversely, high TV use and low MVPA were independently associated with cardio-metabolic risk factors. However, the association between high TV use and clustered cardio-metabolic risk factors appears to be mediated or confounded by obesity. Thus, TV and MVPA appear to be two separate behaviors that need to be targeted with different interventions and policies. PMID- 21542911 TI - Assessment of psychosocial functioning and its risk factors in children with pectus excavatum. AB - BACKGROUND: Psychosocial functioning is poor in patients with pectus excavatum (PE). However, a comprehensive understanding of this issue does not exist. The aim of this study was to assess the severity of psychosocial problems as associated with PE, as well as to identify its risk factors. METHODS: A comparative study was performed at the Sichuan Academy of Medical Sciences/Sichuan Provincial People's Hospital in Chengdu, China. Patients age 6 to 16 who admitted to the outpatient department for the evaluation or treatment for PE were included in the study. In addition to parental reports of child psychosocial problems on the Achenbach Child Behavior Checklist (CBCL), parents also filled in other structured questionnaires, including socio-demographic variables, patients' medical and psychological characteristics. The severity of malformation was assessed by CT scan. For comparison, an age- and gender- matched control group was recruited from the general population. The socio-demographic and scores on CBCL were compared between patients and control subjects. Univariate and multivariate analysis were performed to examine risk factors for psychosocial problems in patients. RESULTS: No statistically significant differences were found with respect to social-demographic variables between children with PE and control subjects. Compared with control subjects, children with PE displayed higher prevalence of psychosocial problems in the different scales of the CBCL questionnaire such as 'withdraw', 'anxious-depressed', 'social problems' and 'total problems'. Both univariate and multivariate analyses suggested that age, severity of malformation, and being teased about PE were significantly associated with patients' psychosocial problems. CONCLUSIONS: The information derived from this study supports the opinion that children with PE have more psychosocial problems than children from the general population. Multiple medical and psychosocial factors were associated with patients' impairment of psychosocial functioning. PMID- 21542912 TI - Differential DNA extraction of challenging simulated sexual-assault samples: a Swiss collaborative study. AB - In sexual-assault cases, autosomal DNA analysis of gynecological swabs is a challenge, as the presence of a large quantity of female material may prevent detection of the male DNA. A solution to this problem is differential DNA extraction, but there is no established best practice for this. We decided to test the efficacy of a number of different protocols on simulated casework samples. Four difficult samples were sent to the nine Swiss laboratories active in forensic genetics. In each laboratory, staff used their routine protocols to separate the epithelial-cell fraction, enriched with the non-sperm DNA, from the sperm fraction. DNA extracts were then sent to the organizing laboratory for analysis. Estimates of male:female DNA ratio without differential DNA extraction ranged from 1:38 to 1:339, depending on the semen used to prepare the samples. After differential DNA extraction, most of the ratios ranged from 1:12 to 9:1, allowing detection of the male DNA. Compared with direct DNA extraction, cell separation resulted in losses of 94-98% of the male DNA. As expected, more male DNA was generally present in the sperm than in the epithelial-cell fraction. However, for about 30% of the samples, the reverse trend was seen. The recovery of male and female DNA was highly variable, depending on the laboratory involved. An experimental design similar to the one used in this study may be of assistance for local protocol testing and improvement. PMID- 21542913 TI - The Reversal Intervention for Metabolic Syndrome (TRIMS) study: rationale, design, and baseline data. AB - BACKGROUND: Recent attention has focused on strategies to combat the forecast epidemic of type-2 diabetes (T2DM) and its major vascular sequelae. Metabolic syndrome (MetS) comprises a constellation of factors that increase the risk of cardiovascular disease (CVD) and T2DM. Our study aims to develop a structured self-management education programme for people with MetS, which includes management of cardiovascular and diabetes risk factors, and to determine its impact. This paper describes the rationale and design of the TRIMS study, including intervention development, and presents baseline data. METHODS: Subjects recruited from a mixed-ethnic population with MetS were randomised to intervention or control arms. The intervention arm received structured group education based on robust psychological theories and current evidence. The control group received routine care. Follow-up data will be collected at 6 and 12 months. The primary outcome measure will be reversal of metabolic syndrome in the intervention group subjects compared to controls at 12 months follow-up. RESULTS: 82 participants (44% male, 22% South Asian) were recruited between November 2009 and July 2010. Baseline characteristics were similar for both the intervention (n = 42) and control groups (n = 40). Median age was 63 years (IQR 57 - 67), mean waist size 106 cm (SD +/- 11), and prescribing of statins and anti-hypertensives was 51% in each case. CONCLUSION: Results will provide information on changes in diabetes and CVD risk factors and help to inform primary prevention strategies in people with MetS from varied ethnic backgrounds who are at high risk of developing T2DM and CVD. Information gathered in relation to the programme's acceptability and effectiveness in a multi-ethnic population would ensure that our results are widely applicable. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov, study identifier: NCT01043770. PMID- 21542914 TI - Non-surgical treatment of hip osteoarthritis. Hip school, with or without the addition of manual therapy, in comparison to a minimal control intervention: protocol for a three-armed randomized clinical trial. AB - BACKGROUND: Hip osteoarthritis is a common and chronic condition resulting in pain, functional disability and reduced quality of life. In the early stages of the disease, a combination of non-pharmacological and pharmacological treatment is recommended. There is evidence from several trials that exercise therapy is effective. In addition, single trials suggest that patient education in the form of a hip school is a promising intervention and that manual therapy is superior to exercise. METHODS/DESIGN: This is a randomized clinical trial. Patients with clinical and radiological hip osteoarthritis, 40-80 years of age, and without indication for hip surgery were randomized into 3 groups. The active intervention groups A and B received six weeks of hip school, taught by a physiotherapist, for a total of 5 sessions. In addition, group B received manual therapy consisting of joint manipulation and soft-tissue therapy twice a week for six weeks. Group C received a self-care information leaflet containing advice on "live as usual" and stretching exercises from the hip school. The primary time point for assessing relative effectiveness is at the end of the six weeks intervention period with follow-ups after three and 12 months.Primary outcome measure is pain measured on an eleven-point numeric rating scale. Secondary outcome measures are the hip dysfunction and osteoarthritis outcome score, patient's global perceived effect, patient specific functional scale, general quality of life and hip range of motion. DISCUSSION: To our knowledge this is the first randomized clinical trial comparing a patient education program with or without the addition of manual therapy to a minimal intervention for patients with hip osteoarthritis. TRIAL REGISTRATION: ClinicalTrials NCT01039337. PMID- 21542915 TI - Cancer stem cell subsets and their relationships. AB - Emerging evidence suggests that cancer stem cells account for the initiation and progression of cancer. While many types of cancer stem cells with specific markers have been isolated and identified, a variety of differences among them began to be appreciated. Cancer stem cells are hierarchical populations that consist of precancerous stem cells, primary cancer stem cells, migrating cancer stem cells and chemoradioresistant cancer stem cells, playing different roles in cancer initiation and progression. Here we propose a new concept "horizontal hierarchy of cancer stem cells" to distinguish them from vertical hierarchy cancer stem cells, cancer transient-amplifying cells and cancer differentiated cells, and summarize our current understanding of these subsets of cancer stem cells with the aim to open up novel therapeutic strategies for cancer based on this understanding. PMID- 21542916 TI - Challenges of maintaining research protocol fidelity in a clinical care setting: a qualitative study of the experiences and views of patients and staff participating in a randomized controlled trial. AB - BACKGROUND: Trial research has predominantly focused on patient and staff understandings of trial concepts and/or motivations for taking part, rather than why treatment recommendations may or may not be followed during trial delivery. This study sought to understand why there was limited attainment of the glycaemic target (HbA(1c) <=6.5%) among patients who participated in the Treating to Target in Type 2 Diabetes Trial (4-T). The objective was to inform interpretation of trial outcomes and provide recommendations for future trial delivery. METHODS: In depth interviews were conducted with 45 patients and 21 health professionals recruited from 11 of 58 trial centres in the UK. Patients were broadly representative of those in the main trial in terms of treatment allocation, demographics and glycaemic control. Both physicians and research nurses were interviewed. RESULTS: Most patients were committed to taking insulin as recommended by 4-T staff. To avoid hypoglycaemia, patients occasionally altered or skipped insulin doses, normally in consultation with staff. Patients were usually unaware of the trial's glycaemic target. Positive staff feedback could lead patients to believe they had been 'successful' trial participants even when their HbA(1c) exceeded 6.5%. While some staff felt that the 4-T automated insulin dose adjustment algorithm had increased their confidence to prescribe larger insulin doses than in routine clinical practice, all described situations where they had not followed its recommendations. Staff regarded the application of a 'one size fits all' glycaemic target during the trial as contradicting routine clinical practice where they would tailor treatments to individuals. Staff also expressed concerns that 'tight' glycaemic control might impose an unacceptably high risk of hypoglycaemia, thus compromising trust and safety, especially amongst older patients. To address these concerns, staff tended to adapt the trial protocol to align it with their clinical practices and experiences. CONCLUSIONS: To understand trial findings, foster attainment of endpoints, and promote protocol fidelity, it may be necessary to look beyond individual patient characteristics and experiences. Specifically, the context of trial delivery, the impact of staff involvement, and the difficulties staff may encounter in balancing competing 'clinical' and 'research' roles and responsibilities may need to be considered and addressed. PMID- 21542917 TI - A comparative study on long-term evoked auditory and visual potential responses between Schizophrenic patients and normal subjects. AB - BACKGROUND: The electrical signals measuring method is recommended to examine the relationship between neuronal activities and measure with the event related potentials (ERPs) during an auditory and a visual oddball paradigm between schizophrenic patients and normal subjects. The aim of this study is to discriminate the activation changes of different stimulations evoked by auditory and visual ERPs between schizophrenic patients and normal subjects. METHODS: Forty-three schizophrenic patients were selected as experimental group patients, and 40 healthy subjects with no medical history of any kind of psychiatric diseases, neurological diseases, or drug abuse, were recruited as a control group. Auditory and visual ERPs were studied with an oddball paradigm. All the data were analyzed by SPSS statistical software version 10.0. RESULTS: In the comparative study of auditory and visual ERPs between the schizophrenic and healthy patients, P300 amplitude at Fz, Cz, and Pz and N100, N200, and P200 latencies at Fz, Cz, and Pz were shown significantly different. The cognitive processing reflected by the auditory and the visual P300 latency to rare target stimuli was probably an indicator of the cognitive function in schizophrenic patients. CONCLUSIONS: This study shows the methodology of application of auditory and visual oddball paradigm identifies task-relevant sources of activity and allows separation of regions that have different response properties. Our study indicates that there may be slowness of automatic cognitive processing and controlled cognitive processing of visual ERPs compared to auditory ERPs in schizophrenic patients. The activation changes of visual evoked potentials are more regionally specific than auditory evoked potentials. PMID- 21542918 TI - Seroprevalence of Toxoplasma gondii infection in pet dogs in Lanzhou, Northwest China. AB - BACKGROUND: In recent years, surveys of Toxoplasma gondii infection in dogs have been reported worldwide, including China. However, little is known about the prevalence of T. gondii in pet dogs in Northwest China. In the present study, the prevalence of T. gondii in pet dogs in Lanzhou, China was investigated using the modified agglutination test (MAT). RESULTS: In this survey, antibodies to T. gondii were found in 28 of 259 (10.81%) pet dogs, with MAT titers of 1:20 in 14 dogs, 1:40 in nine, 1:80 in four, and 1:160 or higher in one dog. The prevalence ranged from 6.67% to 16.67% among dogs of different ages, with low rates in young pet dogs, and high rates in older pet dogs. The seroprevalence in dogs >3 years old was higher than that in dogs <=1 years old, but the difference was not statistically significant (P >0.05). The seroprevalence in male dogs was 12.50% (17 of 136), and in female dogs it was 8.94% (11 of 123), but the difference was not statistically significant (P >0.05). CONCLUSIONS: A high prevalence of T. gondii infection was found in pet dogs in Lanzhou, Northwest China, which has implications for public health in this region. In order to reduce the risk of exposure to T. gondii, further measures and essential control strategies should be carried out rationally in this region. PMID- 21542919 TI - Delay in diagnosis of muscle disorders depends on the subspecialty of the initially consulted physician. AB - BACKGROUND: New therapeutic strategies in muscular dystrophies will make a difference in prognosis only if they are begun early in the course of the disease. Therefore, we investigated factors that influence the time to diagnosis in muscle dystrophy patients. METHODS: A sample of 101 patients (mean age 49 years; range 19-80; 44% women) with diagnosed muscle dystrophies from neurological practices and the neuromuscular specialty clinic in Berlin, Germany, was invited to participate. Time from first consultation to diagnosis, subspecialty of physician, and sociodemographic data were assessed with self report questionnaires. The association between time to diagnosis and potential predictors (subspecialty of initially consulted physician, diagnoses, gender, and age at onset) was modeled with linear regression analysis. RESULTS: The mean time span between first health-care contact and diagnosis was 4.3 years (median 1). The diagnostic delay was significantly longer if patients were initially seen by a non-neurological specialist compared to a general practitioner (5.2 vs. 3.5 years, p = 0.047). Other factors that were independently associated with diagnostic delay were female gender and inherited muscle disease. CONCLUSION: Action to improve clinical awareness of muscle diseases in non-neurological specialists is needed. PMID- 21542920 TI - GC/MS based metabolomics: development of a data mining system for metabolite identification by using soft independent modeling of class analogy (SIMCA). AB - BACKGROUND: The goal of metabolomics analyses is a comprehensive and systematic understanding of all metabolites in biological samples. Many useful platforms have been developed to achieve this goal. Gas chromatography coupled to mass spectrometry (GC/MS) is a well-established analytical method in metabolomics study, and 200 to 500 peaks are routinely observed with one biological sample. However, only ~100 metabolites can be identified, and the remaining peaks are left as "unknowns". RESULT: We present an algorithm that acquires more extensive metabolite information. Pearson's product-moment correlation coefficient and the Soft Independent Modeling of Class Analogy (SIMCA) method were combined to automatically identify and annotate unknown peaks, which tend to be missed in routine studies that employ manual processing. CONCLUSIONS: Our data mining system can offer a wealth of metabolite information quickly and easily, and it provides new insights, particularly into food quality evaluation and prediction. PMID- 21542921 TI - Genetic variation and population structure of Sudanese populations as indicated by 15 Identifiler sequence-tagged repeat (STR) loci. AB - BACKGROUND: There is substantial ethnic, cultural and linguistic diversity among the people living in east Africa, Sudan and the Nile Valley. The region around the Nile Valley has a long history of succession of different groups, coupled with demographic and migration events, potentially leading to genetic structure among humans in the region. RESULT: We report the genotypes of the 15 Identifiler microsatellite markers for 498 individuals from 18 Sudanese populations representing different ethnic and linguistic groups. The combined power of exclusion (PE) was 0.9999981, and the combined match probability was 1 in 7.4 * 1017. The genotype data from the Sudanese populations was combined with previously published genotype data from Egypt, Somalia and the Karamoja population from Uganda. The Somali population was found to be genetically distinct from the other northeast African populations. Individuals from northern Sudan clustered together with those from Egypt, and individuals from southern Sudan clustered with those from the Karamoja population. The similarity of the Nubian and Egyptian populations suggest that migration, potentially bidirectional, occurred along the Nile river Valley, which is consistent with the historical evidence for long-term interactions between Egypt and Nubia. CONCLUSION: We show that despite the levels of population structure in Sudan, standard forensic summary statistics are robust tools for personal identification and parentage analysis in Sudan. Although some patterns of population structure can be revealed with 15 microsatellites, a much larger set of genetic markers is needed to detect fine-scale population structure in east Africa and the Nile Valley. PMID- 21542922 TI - A revised nomenclature for transcribed human endogenous retroviral loci. AB - BACKGROUND: Endogenous retroviruses (ERVs) and ERV-like sequences comprise 8% of the human genome. A hitherto unknown proportion of ERV loci are transcribed and thus contribute to the human transcriptome. A small proportion of these loci encode functional proteins. As the role of ERVs in normal and diseased biological processes is not yet established, transcribed ERV loci are of particular interest. As more transcribed ERV loci are likely to be identified in the near future, the development of a systematic nomenclature is important to ensure that all information on each locus can be easily retrieved. RESULTS: Here we present a revised nomenclature of transcribed human endogenous retroviral loci that sorts loci into groups based on Repbase classifications. Each symbol is of the format ERV + group symbol + unique number. Group symbols are based on a mixture of Repbase designations and well-supported symbols used in the literature. The presented guidelines will allow newly identified loci to be easily incorporated into the scheme. CONCLUSIONS: The naming system will be employed by the HUGO Gene Nomenclature Committee for naming transcribed human ERV loci. We hope that the system will contribute to clarifying a certain aspect of a sometimes confusing nomenclature for human endogenous retroviruses. The presented system may also be employed for naming transcribed loci of human non-ERV repeat loci. PMID- 21542923 TI - Properties of metabolic graphs: biological organization or representation artifacts? AB - BACKGROUND: Standard graphs, where each edge links two nodes, have been extensively used to represent the connectivity of metabolic networks. It is based on this representation that properties of metabolic networks, such as hierarchical and small-world structures, have been elucidated and null models have been proposed to derive biological organization hypotheses. However, these graphs provide a simplistic model of a metabolic network's connectivity map, since metabolic reactions often involve more than two reactants. In other words, this map is better represented as a hypergraph. Consequently, a question that naturally arises in this context is whether these properties truly reflect biological organization or are merely an artifact of the representation. RESULTS: In this paper, we address this question by reanalyzing topological properties of the metabolic network of Escherichia coli under a hypergraph representation, as well as standard graph abstractions. We find that when clustering is properly defined for hypergraphs and subsequently used to analyze metabolic networks, the scaling of clustering, and thus the hierarchical structure hypothesis in metabolic networks, become unsupported. Moreover, we find that incorporating the distribution of reaction sizes into the null model further weakens the support for the scaling patterns. CONCLUSIONS: These results combined suggest that the reported scaling of the clustering coefficients in the metabolic graphs and its specific power coefficient may be an artifact of the graph representation, and may not be supported when biochemical reactions are atomically treated as hyperedges. This study highlights the implications of the way a biological system is represented and the null model employed on the elucidated properties, along with their support, of the system. PMID- 21542924 TI - The burden of physical activity on type 2 diabetes public healthcare expenditures among adults: a retrospective study. AB - BACKGROUND: Determinants of public healthcare expenditures in type 2 diabetics are not well investigated in developing nations and, therefore, it is not clear if higher physical activity decreases healthcare costs. The purpose of this study was to analyze the relationship between physical activity and the expenditures in public healthcare on type 2 diabetes mellitus treatment. METHODS: Cross-sectional study carried out in Brazil. A total of 121 type 2 diabetics attended to in two Basic Healthcare Units were evaluated. Public healthcare expenditures in the last year were estimated using a specific standard table. Also evaluated were: socio demographic variables; chronological age; exogenous insulin use; smoking habits; fasting glucose test; diabetic neuropathy and anthropometric measures. Habitual physical activity was assessed by questionnaire. RESULTS: Age (r = 0.20; p = 0.023), body mass index (r = 0.33; p = 0.001) and waist-to-hip ratio (r = 0.20; p = 0.025) were positively related to expenditures on medication for the treatment of diseases other than diabetes. Insulin use was associated with increased expenditures. Higher physical activity was associated with lower expenditure, provided medication for treatment of diseases other than diabetes (OR = 0.19; p = 0.007) and medical consultations (OR = 0.26; p = 0.029). CONCLUSIONS: Type 2 diabetics with higher enrollment in physical activity presented consistently lower healthcare expenditures for the public healthcare system. PMID- 21542925 TI - Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980-2006 in France. AB - BACKGROUND: Neurofibromatosis 1 (NF1), a common autosomal dominant disorder, was shown in one study to be associated with a 15-year decrease in life expectancy. However, data on mortality in NF1 are limited. Our aim was to evaluate mortality in a large retrospective cohort of NF1 patients seen in France between 1980 and 2006. METHODS: Consecutive NF1 patients referred to the National French Referral Center for Neurofibromatoses were included. The standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated as the ratio of observed over expected numbers of deaths. We studied factors associated with death and causes of death. RESULTS: Between 1980 and 2006, 1895 NF1 patients were seen. Median follow-up was 6.8 years (range, 0.4-20.6). Vital status was available for 1226 (65%) patients, of whom 1159 (94.5%) survived and 67 (5.5%) died. Overall mortality was significantly increased in the NF1 cohort (SMR, 2.02; CI, 1.6-2.6; P < 10-4). The excess mortality occurred among patients aged 10 to 20 years (SMR, 5.2; CI, 2.6-9.3; P < 10-4) and 20 to 40 years (SMR, 4.1; 2.8-5.8; P < 10-4). Significant excess mortality was found in both males and females. In the 10-20 year age group, females had a significant increase in mortality compared to males (SMR, 12.6; CI, 5.7-23.9; and SMR, 1.8; CI, 0.2-6.4; respectively). The cause of death was available for 58 (86.6%) patients; malignant nerve sheath tumor was the main cause of death (60%). CONCLUSIONS: We found significantly increased SMRs indicating excess mortality in NF1 patients compared to the general population. The definitive diagnosis of NF1 in all patients is a strength of our study, and the high rate of death related to malignant transformation is consistent with previous work. The retrospective design and hospital-based recruitment are limitations of our study. Mortality was significantly increased in NF1 patients aged 10 to 40 years and tended to be higher in females than in males. PMID- 21542926 TI - Management of esophageal stricture after complete circular endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) permits removal of esophageal epithelial neoplasms en bloc, but is associated with esophageal stenosis, particularly when ESD involves the entire circumference of the esophageal lumen. We examined the effectiveness of systemic steroid administration for control of postprocedural esophageal stricture after complete circular ESD. METHODS: Seven patients who underwent wholly circumferential ESD for superficially extended esophageal squamous cell carcinoma were enrolled in this study. In 3 patients, prophylactic endoscopic balloon dilatation (EBD) was started on the third post ESD day and was performed twice a week for 8 weeks. In 4 patients, oral prednisolone was started with 30 mg daily on the third post-ESD day, tapered gradually (daily 30, 30, 25, 25, 20, 15, 10, 5 mg for 7 days each), and then discontinued at 8 weeks. EBD was used as needed whenever patients complained of dysphagia. RESULTS: En bloc ESD with tumor-free margins was safely achieved in all cases. Patients in the prophylactic EBD group required a mean of 32.7 EBD sessions; the postprocedural stricture was dilated up to 18 mm in diameter in these patients. On the other hand, systemic steroid administration substantially reduced or eliminated the need for EBD. Corticosteroid therapy was not associated with any adverse events. Post-ESD esophageal stricture after complete circular ESD was persistent, requiring multiple EBD sessions. CONCLUSIONS: Use of oral prednisolone administration may be an effective treatment strategy for reducing post-ESD esophageal stricture after complete circular ESD. PMID- 21542927 TI - Sedation and renal impairment in critically ill patients: a post hoc analysis of a randomized trial. AB - INTRODUCTION: Not sedating critically ill patients reduces the time patients receive mechanical ventilation, decreases the time in the intensive care department and reduces the total hospital length of stay. We hypothesized that no sedation improves hemodynamic stability, decreases the need for vasoactive drugs, diminishes the need for extra fluids and lowers the risk of acute kidney injury. METHODS: We performed an evaluation on the database from our previous trial of 140 patients randomized to either no sedation vs. sedation with a daily interruption of sedatives. A total of 113 patients were included in the previous statistical analysis. Ten patients had pre-existing renal impairments and were excluded. Data were collected from observational cards and blood samples. RESULTS: A total of 103 patients were included in this retrospective review. We registered an increased urine output in the group receiving no sedation compared to the sedated control group (1.15 ml/kg/hour (0.59 to 1.53) vs. 0.88 ml/kg/hour (0.052 to 1.26), P = 0.03). In addition we saw a decrease in the number of patients with renal impairment according to the RIFLE classification (indicating Risk of renal dysfunction; Injury to the kidney; Failure of kidney function, Loss of kidney function and End-stage kidney disease) in the group receiving no sedation compared to the sedated control group (25 (51%) vs. 41 (76%), P = 0.012). The difference in the two groups with respect to mean arterial blood pressure, fluid balance and use of vasoactive drugs was not significant. CONCLUSIONS: A no sedation strategy to patients undergoing mechanical ventilation increases the urine output and decreases the number of patients with renal impairments. PMID- 21542928 TI - Complement C3 serum levels in anorexia nervosa: a potential biomarker for the severity of disease? AB - BACKGROUND: Anorexia nervosa carries the highest mortality rate of any psychiatric disorder. Even the most critically ill anorexic patients may present with normal 'standard' laboratory values, underscoring the need for a new sensitive biomarker. The complement cascade, a major component of innate immunity, represents a driving force in the pathophysiology of multiple inflammatory disorders. The role of complement in anorexia nervosa remains poorly understood. The present study was designed to evaluate the role of complement C3 levels, the extent of complement activation and of complement hemolytic activity in serum, as potential new biomarkers for the severity of anorexia nervosa. PATIENTS AND METHODS: This was a prospective cohort study on 14 patients with severe anorexia nervosa, as defined by a body mass index (BMI) <14 kg/m2. Serum samples were obtained in a biweekly manner until hospital discharge. A total of 17 healthy subjects with normal BMI values served as controls. The serum levels of complement C3, C3a, C5a, sC5b-9, and of the 50% hemolytic complement activity (CH50) were quantified and correlated with the BMIs of patients and control subjects. RESULTS: Serum C3 levels were significantly lower in patients with anorexia nervosa than in controls (median 3.7 (interquartile range (IQR) 2.5-4.9) vs 11.4 (IQR 8.9-13.7, P <0.001). In contrast, complement activation fragments and CH50 levels were not significantly different between the two groups. There was a strong correlation between index C3 levels and BMI (Spearman correlation coefficient = 0.71, P <0.001). CONCLUSIONS: Complement C3 serum levels may represent a sensitive new biomarker for monitoring the severity of disease in anorexia nervosa. The finding from this preliminary pilot study will require further investigation in future prospective large-scale multicenter trials. PMID- 21542929 TI - Validation of brief screening tools for depressive and alcohol use disorders among TB and HIV patients in primary care in Zambia. AB - BACKGROUND: This study was conducted to evaluate the diagnostic accuracy and determine the optimum cut-off scores for clinical use of the Center for Epidemiological Studies Depression scale (CES-D) and Alcohol Use Disorders Identification Test (AUDIT) against a reference psychiatric diagnostic interview, in TB and anti-retroviral therapy (ART) patients in primary care in Zambia. METHODS: This was a cross-sectional study in 16 primary level care clinics. Consecutive sampling was used to select 649 participants who started TB treatment or ART in the preceding month. Participants were first interviewed using the CES D and AUDIT, and subsequently with a psychiatric diagnostic interview for current major depressive disorder (MDD) and alcohol use disorders (AUDs) using the Mini International Neuropsychiatric Interview (MINI). The diagnostic accuracy was calculated using the Area Under the Receiver Operating Characteristic curve (AUROC). The optimum cut-off scores for clinical use were calculated using sensitivity and positive predictive value (PPV). RESULTS: The CES-D and AUDIT had high internal consistency (Cronbach's alpha = 0.84; 0.98 respectively). Confirmatory factor analysis showed that the four-factor CES-D model was not a good fit for the data (Tucker-Lewis Fit Index (TLI) = 0.86; standardized root mean square residual (SRMR) = 0.06) while the two-factor AUDIT model fitted the data well (TFI = 0.99; SRMR = 0.04). Both the CES-D and AUDIT demonstrated good discriminatory ability in detecting MINI-defined current MDDs and AUDs (AUROC for CES-D = 0.78; AUDIT = 0.98 for women and 0.75 for men). The optimum CES-D cut-off score in screening for current MDD was 22 (sensitivity 73%, PPV 76%) while that of the AUDIT in screening for AUD was 24 for women (sensitivity 60%, PPV 60%), and 20 for men (sensitivity 55%, PPV 50%). CONCLUSIONS: The CES-D and AUDIT showed high discriminatory ability in measuring MINI-defined current MDD and AUD respectively. They are suitable mental health screening tools for use among TB and ART patients in primary care in Zambia. PMID- 21542930 TI - Building a model: developing genomic resources for common milkweed (Asclepias syriaca) with low coverage genome sequencing. AB - BACKGROUND: Milkweeds (Asclepias L.) have been extensively investigated in diverse areas of evolutionary biology and ecology; however, there are few genetic resources available to facilitate and compliment these studies. This study explored how low coverage genome sequencing of the common milkweed (Asclepias syriaca L.) could be useful in characterizing the genome of a plant without prior genomic information and for development of genomic resources as a step toward further developing A. syriaca as a model in ecology and evolution. RESULTS: A 0.5* genome of A. syriaca was produced using Illumina sequencing. A virtually complete chloroplast genome of 158,598 bp was assembled, revealing few repeats and loss of three genes: accD, clpP, and ycf1. A nearly complete rDNA cistron (18S-5.8S-26S; 7,541 bp) and 5S rDNA (120 bp) sequence were obtained. Assessment of polymorphism revealed that the rDNA cistron and 5S rDNA had 0.3% and 26.7% polymorphic sites, respectively. A partial mitochondrial genome sequence (130,764 bp), with identical gene content to tobacco, was also assembled. An initial characterization of repeat content indicated that Ty1/copia-like retroelements are the most common repeat type in the milkweed genome. At least one A. syriaca microread hit 88% of Catharanthus roseus (Apocynaceae) unigenes (median coverage of 0.29*) and 66% of single copy orthologs (COSII) in asterids (median coverage of 0.14*). From this partial characterization of the A. syriaca genome, markers for population genetics (microsatellites) and phylogenetics (low-copy nuclear genes) studies were developed. CONCLUSIONS: The results highlight the promise of next generation sequencing for development of genomic resources for any organism. Low coverage genome sequencing allows characterization of the high copy fraction of the genome and exploration of the low copy fraction of the genome, which facilitate the development of molecular tools for further study of a target species and its relatives. This study represents a first step in the development of a community resource for further study of plant-insect co-evolution, anti herbivore defense, floral developmental genetics, reproductive biology, chemical evolution, population genetics, and comparative genomics using milkweeds, and A. syriaca in particular, as ecological and evolutionary models. PMID- 21542931 TI - The PathOlogist: an automated tool for pathway-centric analysis. AB - BACKGROUND: The PathOlogist is a new tool designed to transform large sets of gene expression data into quantitative descriptors of pathway-level behavior. The tool aims to provide a robust alternative to the search for single-gene-to phenotype associations by accounting for the complexity of molecular interactions. RESULTS: Molecular abundance data is used to calculate two metrics- 'activity' and 'consistency'--for each pathway in a set of more than 500 canonical molecular pathways (source: Pathway Interaction Database, http://pid.nci.nih.gov). The tool then allows a detailed exploration of these metrics through integrated visualization of pathway components and structure, hierarchical clustering of pathways and samples, and statistical analyses designed to detect associations between pathway behavior and clinical features. CONCLUSIONS: The PathOlogist provides a straightforward means to identify the functional processes, rather than individual molecules, that are altered in disease. The statistical power and biologic significance of this approach are made easily accessible to laboratory researchers and informatics analysts alike. Here we show as an example, how the PathOlogist can be used to establish pathway signatures that robustly differentiate breast cancer cell lines based on response to treatment. PMID- 21542932 TI - Alcohol outlets and clusters of violence. AB - BACKGROUND: Alcohol related violence continues to be a major public health problem in the United States. In particular, there is substantial evidence of an association between alcohol outlets and assault. However, because the specific geographic relationships between alcohol outlets and the distribution of violence remains obscured, it is important to identify the spatial linkages that may exist, enhancing public health efforts to curb both violence and morbidity. METHODS: The present study utilizes police-recorded data on simple and aggravated assaults in Cincinnati, Ohio. Addresses of alcohol outlets for Cincinnati, including all bars, alcohol-serving restaurants, and off-premise liquor and convenience stores were obtained from the Ohio Division of Liquor Control and geocoded for analysis. A combination of proximity analysis, spatial cluster detection approaches and a geographic information system were used to identify clusters of alcohol outlets and the distribution of violence around them. RESULTS: A brief review of the empirical work relating to alcohol outlet density and violence is provided, noting that the majority of this literature is cross sectional and ecological in nature, yielding a somewhat haphazard and aggregate view of how outlet type(s) and neighborhood characteristics like social organization and land use are related to assaultive violence. The results of the statistical analysis for Cincinnati suggest that while alcohol outlets are not problematic per se, assaultive violence has a propensity to cluster around agglomerations of alcohol outlets. This spatial relationship varies by distance and is also related to the characteristics of the alcohol outlet agglomeration. Specifically, spatially dense distributions of outlets appear to be more prone to clusters of assaultive violence when compared to agglomerations with a lower density of outlets. CONCLUSION: With a more thorough understanding of the spatial relationships between alcohol outlets and the distribution of assaults, policymakers in urban areas can make more informed regulatory decisions regarding alcohol licenses. Further, this research suggests that public health officials and epidemiologists need to develop a better understanding of what actually occurs in and around alcohol outlets, determining what factors (whether outlet, neighborhood, or spatially related) help fuel their relationship with violence and other alcohol-related harm. PMID- 21542933 TI - Integration Host Factor (IHF) binds to the promoter region of the phtD operon involved in phaseolotoxin synthesis in P. syringae pv. phaseolicola NPS3121. AB - BACKGROUND: Pseudomonas syringae pv. phaseolicola, the causal agent of halo blight disease in beans, produces a toxin known as phaseolotoxin, in whose synthesis participate a group of genes organized within the genome in a region known as the "Pht cluster". This region, which is thought to have been acquired by horizontal gene transfer, includes 5 transcriptional units, two monocistronic (argK, phtL) and three polycistronic (phtA, phtD, phtM), whose expression is temperature dependent. So far, the regulatory mechanisms involved in phaseolotoxin synthesis have not been elucidated and the only well-established fact is the requirement of low temperatures for its synthesis. In this work, we searched for regulatory proteins that could be involved in phaseolotoxin synthesis, focusing on the regulation of the phtD operon. RESULTS: In this study we identified the global regulator IHF (Integration Host Factor), which binds to the promoter region of the phtD operon, exerting a negative effect on the expression of this operon. This is the first regulatory protein identified as part of the phaseolotoxin synthesis system. Our findings suggest that the Pht cluster was similarly regulated in the ancestral cluster by IHF or similar protein, and integrated into the global regulatory mechanism of P. syringae pv. phaseolicola, after the horizontal gene transfer event by using the host IHF protein. CONCLUSION: This study identifies the IHF protein as one element involved in the regulation of phaseolotoxin synthesis in P. syringae pv. phaseolicola NPS3121 and provides new insights into the regulatory mechanisms involved in phaseolotoxin production. PMID- 21542934 TI - Treatment success in pragmatic randomised controlled trials: a review of trials funded by the UK Health Technology Assessment programme. AB - BACKGROUND: Previous research reviewed treatment success and whether the collective uncertainty principle is met in RCTs in the US National Cancer Institute portfolio. This paper classifies clinical trials funded by the UK HTA programme by results using the method applied to the US Cancer Institute trials, and compares the two portfolios. METHODS: Data on all completed randomised controlled trials funded by the HTA programme 1993-2008 were extracted. Each trial's primary results was classified into six categories; 1) statistically significant in favour of the new treatment, 2) statistically significant in favour of the control treatment 3) true negative, 4) truly inconclusive, 5) inconclusive in favour of new treatment or 6) inconclusive in favour of control treatment. Trials were classified by comparing the 95% confidence interval for the difference in primary outcome to the difference specified in the sample size calculation. The results were compared with Djulbegovic's analysis of NCI trials. RESULTS: Data from 51 superiority trials were included, involving over 48,000 participants and a range of diseases and interventions. 85 primary comparisons were available because some trials had more than two randomised arms or had several primary outcomes. The new treatment had superior results (whether significant or not) in 61% of the comparisons (52/85 95% CI 49.9% to 71.6%). The results were conclusive in 46% of the comparisons (19% statistically significant in favour of the new treatment, 5% statistically significant in favour of the control and 22% true negative). The results were classified as truly inconclusive (i.e. failed to answer the question asked) for 24% of comparisons (20/85). HTA trials included fewer truly inconclusive and statistically significant results and more results rated as true negative than NCI trials. CONCLUSIONS: The pattern of results in HTA trials is similar to that of the National Cancer Institute portfolio. Differences that existed were plausible given the differences in the types of trials -HTA trials are more pragmatic. The results indicate HTA trials are compatible with equipoise. This classification usefully summarises the results from clinical trials and enables comparisons of different portfolios of trials. PMID- 21542935 TI - A library of protein surface patches discriminates between native structures and decoys generated by structure prediction servers. AB - BACKGROUND: Protein surfaces serve as an interface with the molecular environment and are thus tightly bound to protein function. On the surface, geometric and chemical complementarity to other molecules provides interaction specificity for ligand binding, docking of bio-macromolecules, and enzymatic catalysis.As of today, there is no accepted general scheme to represent protein surfaces. Furthermore, most of the research on protein surface focuses on regions of specific interest such as interaction, ligand binding, and docking sites. We present a first step toward a general purpose representation of protein surfaces: a novel surface patch library that represents most surface patches (~98%) in a data set regardless of their functional roles. RESULTS: Surface patches, in this work, are small fractions of the protein surface. Using a measure of inter-patch distance, we clustered patches extracted from a data set of high quality, non redundant, proteins. The surface patch library is the collection of all the cluster centroids; thus, each of the data set patches is close to one of the elements in the library.We demonstrate the biological significance of our method through the ability of the library to capture surface characteristics of native protein structures as opposed to those of decoy sets generated by state-of-the art protein structure prediction methods. The patches of the decoys are significantly less compatible with the library than their corresponding native structures, allowing us to reliably distinguish native models from models generated by servers. This trend, however, does not extend to the decoys themselves, as their similarity to the native structures does not correlate with compatibility with the library. CONCLUSIONS: We expect that this high-quality, generic surface patch library will add a new perspective to the description of protein structures and improve our ability to predict them. In particular, we expect that it will help improve the prediction of surface features that are apparently neglected by current techniques.The surface patch libraries are publicly available at http://www.cs.bgu.ac.il/~keasar/patchLibrary. PMID- 21542936 TI - In vivo activity of Sapindus saponaria against azole-susceptible and -resistant human vaginal Candida species. AB - BACKGROUND: Study of in vivo antifungal activity of the hydroalcoholic extract (HE) and n-BuOH extract (BUTE) of Sapindus saponaria against azole-susceptible and -resistant human vaginal Candida spp. METHODS: The in vitro antifungal activity of HE, BUTE, fluconazole (FLU), and itraconazole (ITRA) was determined by the broth microdilution method. We obtained values of minimal inhibitory concentration (MIC) and minimum fungicide concentration (MFC) for 46 strains of C. albicans and 10 of C. glabrata isolated from patients with vulvovaginal candidiasis (VVC). VVC was induced in hyperestrogenic Wistar rats with azole susceptible C. albicans (SCA), azole-resistant C. albicans (RCA), and azole resistant C. glabrata (RCG). The rats were treated intravaginally with 0.1 mL of HE or BUTE at concentrations of 1%, 2.5% and 5%; 100 MUg/mL of FLU (treatment positive control); or distilled water (negative control) at 1, 24, and 48 h after induction of the infection, and the progress of VVC was monitored by culturing and scanning electron microscopy (SEM). The toxicity was evaluated in cervical cells of the HeLa cell line. RESULTS: The extracts showed in vitro inhibitory and fungicidal activity against all the isolates, and the MIC and MFC values for the C. glabrata isolates were slightly higher. In vivo, the SCA, RCA, and RCG infections were eliminated by 21 days post-infection, with up to 5% HE and BUTE, comparable to the activity of FLU. No cytotoxic action was observed for either extract. CONCLUSIONS: Our results demonstrated that HE and BUTE from S. saponaria show inhibitory and fungicidal activity in vitro, in addition to in vivo activity against azole-resistant vaginal isolates of C. glabrata and azole-susceptible and resistant isolates of C. albicans. Also considering the lack of cytotoxicity and the low concentrations of the extracts necessary to eliminate the infection in vivo, HE and BUTE show promise for continued studies with purified antifungal substances in VVC yeast isolates. PMID- 21542937 TI - A human-mouse conserved sex bias in amygdala gene expression related to circadian clock and energy metabolism. AB - BACKGROUND: Major depression affects twice as many women as men, but the underlying molecular mechanisms responsible for the heightened female vulnerability are not known. The amygdala, composed of heterogeneous subnuclei, participates in multiple functional circuits regulating emotional responses to stress. We hypothesized that sex differences in molecular structure may contribute to differential mood regulation and disease vulnerability. FINDINGS: Using gene arrays followed by quantitative PCR validation, we compared the transcriptome profiles between sexes in human and mouse amygdala. We now report sexually dimorphic features of transcriptomes in the basolateral nucleus of the amygdala, and these features are highly conserved across species. A functional analysis of differential gene expression showed that mitochondrial-related gene groups were identified as the top biological pathways associated with sexual dimorphism in both species. CONCLUSIONS: These results suggest that the basolateral amygdala is a sexually dimorphic structure, featuring a regulatory cascade of mitochondrial function and circadian rhythm, potentially linked through sirtuins and hormone nuclear receptors. Hence, baseline differences in amygdalar circadian regulation of cellular metabolism may contribute to sex related differences in mood regulation and vulnerability to major depression. PMID- 21542938 TI - Primary appendiceal mucinous adenocarcinoma in two first-degree relatives: case report and review. AB - Carcinomas of the appendix are exceedingly rare tumors and have an annual age adjusted incidence of around 0.4 cases per 100,000. Appendiceal adenocarcinoma accounts for < 0.5% of all gastrointestinal neoplasms and, of these, mucinous adenocarcinomas account for the majority. Published accounts of familial instances of primary appendiceal tumors are strikingly rare. We report two siblings who both developed primary mucinous adenocarcinomas. A genetics evaluation was conducted to determine if there was a recognizable underlying single gene disorder; no DNA mismatch repair defect was evident, and no other diagnosis was apparent. A review of appendiceal cancers seen at Mayo Clinic from l997 to the present was conducted to search for additional familial cases. Among 316 cases of primary appendiceal cancer of any histologic type, this sib pair was the only family reporting a second affected family member. The occurrence of appendiceal cancer in siblings may represent a random occurrence. An exceedingly rare predisposition syndrome cannot be ruled out. PMID- 21542939 TI - Evaluation of a community-based randomized controlled prenatal care trial in rural China. AB - BACKGROUND: A community-based randomized control prenatal care trial was performed in a rural county of China during 2000-2003. The purpose of this paper is to describe the trial implementation and the impact of the trial on the utilization of prenatal care and perinatal outcomes. MATERIALS AND METHODS: In the study county, 10 townships (from a total of 55) were each paired with a control (20 study townships in total), with the criteria for pairing being the township's socioeconomic development, perinatal health, and maternal care utilization and provision. One of each township pair was randomly allocated to the intervention or control groups. The trial interventions were: 1) training township hospital midwives and instructing them in how to provide systematic maternal care, 2) informing women in the community of the importance of prenatal care, 3) if needed, providing basic medical instruments to the hospitals. A variety of data sources were used to describe the trial implementation (observations, group discussions, field notes, survey to women). The data on pregnancy and perinatal outcomes were from the original hand-written work-records in the village family planning centers of the study townships. RESULTS: Implementation of the intervention was deficient. The factors hindering the trial implementation included poor coordination between midwives and family planning officers, broader policy changes implemented by the provincial government during the trial, the decentralization of county governance, and the lack of government funding for maternal care. There was only little difference in the use of maternal care, in women's opinions related to maternal care or content of prenatal care, and no difference in the perinatal outcomes between the intervention and control townships. CONCLUSIONS: A community based randomized controlled trial could not be fully carried out in rural China as planned due to the changing political landscape, the complexity of the socio-economic situation and a lengthy planning stage. The study could not answer if perinatal outcomes could be improved by increased use of prenatal care. TRIAL REGISTRATION: NCT 01054235. PMID- 21542940 TI - A comparison of the Giardia lamblia trophozoite and cyst transcriptome using microarrays. AB - BACKGROUND: Compared with many protists, Giardia lamblia has a simple life cycle alternating between cyst and trophozoite. Most research on the molecular biology of Giardia parasites has focused on trophozoites and the processes of excystation and encystation, whereas cysts have attracted less interest. The striking morphological differences between the dormant cyst and the rapidly dividing and motile trophozoite implies profound changes in the metabolism as the parasite encysts in the host's intestine and excysts upon ingestion by a new host. RESULTS: To investigate the magnitude of the transcriptional changes occurring during the G. lamblia life cycle we compared the transcriptome of G. lamblia trophozoites and cysts using single-color oligonucleotide microarrays. Cysts were found to possess a much smaller transcriptome, both in terms of mRNA diversity and abundance. Genes encoding proteins related to ribosomal functions are highly over-represented. The comparison of the transcriptome of cysts generated in culture or extracted from feces revealed little overlap, raising the possibility of significant biological differences between the two types of cysts. CONCLUSIONS: The comparison of the G. lamblia cyst and trophozoite transcriptome showed that transcripts of most genes are present at a lower level in cysts. This global view of the cyst and trophozoite transcriptome complements studies focused on the expression of selected genes during trophozoite multiplication, encystation and excystation. PMID- 21542941 TI - Characterization of a cryptic plasmid pSM429 and its application for heterologous expression in psychrophilic Pseudoalteromonas. AB - BACKGROUND: Pseudoalteromonas is an important genus widespread in marine environment, and a lot of psychrophilic Pseudoalteromonas strains thrive in deep sea and polar sea. By now, there are only a few genetic systems for Pseudoalteromonas reported and no commercial Pseudoalteromonas genetic system is available, which impedes the study of Pseudoalteromonas, especially for psychrophilic strains. The aim of this study is to develop a heterologous expression system for psychrophilic Pseudoalteromonas. RESULTS: A cryptic plasmid pSM429 isolated from psychrophilic Pseudoalteromonas sp. BSi20429 from the Arctic sea ice, was sequenced and characterized. The plasmid pSM429 is 3874 bp in length, with a G+C content of 28%. Four putative open reading frames (ORFs) were identified on pSM429. Based on homology, the ORF4 was predicted to encode a replication initiation (Rep) protein. A shuttle vector (Escherichia coli, Pseudoalteromonas), pWD, was constructed by ligating pSM429 and pUC19 and inserting a chloramphenicol acetyl transferase (CAT) cassette conferring chloramphenicol resistance. To determine the minimal replicon of pSM429 and to check the functionality of identified ORFs, various pWD derivatives were constructed. All derivatives except the two smallest ones were shown to allow replication in Pseudoalteromonas sp. SM20429, a plasmid-cured strain of Pseudoalteromonas sp. BSi20429, suggesting that the orf4 and its flanking intergenic regions are essential for plasmid replication. Although not essential, the sequence including some repeats between orf1 and orf2 plays important roles in segregational stability of the plasmid. With the aid of pWD-derived plasmid pWD2, the erythromycin resistance gene and the cd gene encoding the catalytic domain of a cold-adapted cellulase were successfully expressed in Pseudoalteromonas sp. SM20429. CONCLUSIONS: Plasmid pSM429 was isolated and characterized, and the regions essential for plasmid replication and stability were determined, helping the development of pSM429-based shuttle vectors. The shuttle vectors pWD and its derivatives could be used as cloning vectors for Pseudoalteromonas, offering new perspectives in the genetic manipulation of Pseudoalteromonas strains. With the aid of pWD-derived vector and its host, the erythromycin resistance gene and the cd gene of a cold-adapted protein were successfully expressed, indicating that the potential use of this system for recombinant protein production, especially for cold-adapted proteins. PMID- 21542942 TI - Early detection of secondary damage in ipsilateral thalamus after acute infarction at unilateral corona radiata by diffusion tensor imaging and magnetic resonance spectroscopy. AB - BACKGROUND: Traditional magnetic resonance (MR) imaging can identify abnormal changes in ipsilateral thalamus in patients with unilateral middle cerebral artery (MCA) infarcts. However, it is difficult to demonstrate these early changes quantitatively. Diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (MRS) are potentially sensitive and quantitative methods of detection in examining changes of tissue microstructure and metabolism. In this study, We used both DTI and MRS to examine possible secondary damage of thalamus in patients with corona radiata infarction. METHODS: Twelve patients with unilateral corona radiata infarction underwent MR imaging including DTI and MRS at one week (W1), four weeks (W4), and twelve weeks (W12) after onset of stroke. Twelve age-matched controls were imaged. Mean diffusivity (MD), fractional anisotropy (FA), N-acetylaspartate (NAA), choline(Cho), and creatine(Cr) were measured in thalami. RESULTS: T1-weighted fluid attenuation inversion recovery (FLAIR), T2-weighted, and T2-FLAIR imaging showed an infarct at unilateral corona radiate but no other lesion in each patient brain. In patients, MD was significantly increased at W12, compared to W1 and W4 (all P< 0.05). NAA was significantly decreased at W4 compared to W1, and at W12 compared to W4 (all P< 0.05) in the ipsilateral thalamus. There was no significant change in FA, Cho, or Cr in the ipsilateral thalamus from W1 to W12. Spearman's rank correlation analysis revealed a significant negative correlation between MD and the peak area of NAA, Cho, and Cr at W1, W4, and W12 and a significant positive correlation of FA with NAA at W1. CONCLUSIONS: These findings indicate that DTI and MRS can detect the early changes indicating secondary damage in the ipsilateral thalamus after unilateral corona radiata infarction. MRS may reveal the progressive course of damage in the ipsilateral thalamus over time. PMID- 21542943 TI - Efficient induction of CD25- iTreg by co-immunization requires strongly antigenic epitopes for T cells. AB - BACKGROUND: We previously showed that co-immunization with a protein antigen and a DNA vaccine coding for the same antigen induces CD40 low IL-10 high tolerogenic DCs, which in turn stimulates the expansion of antigen-specific CD4+CD25-Foxp3+ regulatory T cells (CD25- iTreg). However, it was unclear how to choose the antigen sequence to maximize tolerogenic antigen presentation and, consequently, CD25- iTreg induction. RESULTS: In the present study, we demonstrated the requirement of highly antigenic epitopes for CD25- iTreg induction. Firstly, we showed that the induction of CD25- iTreg by tolerogenic DC can be blocked by anti MHC-II antibody. Next, both the number and the suppressive activity of CD25- iTreg correlated positively with the overt antigenicity of an epitope to activate T cells. Finally, in a mouse model of dermatitis, highly antigenic epitopes derived from a flea allergen not only induced more CD25- iTreg, but also more effectively prevented allergenic reaction to the allergen than did weakly antigenic epitopes. CONCLUSIONS: Our data thus indicate that efficient induction of CD25- iTreg requires highly antigenic peptide epitopes. This finding suggests that highly antigenic epitopes should be used for efficient induction of CD25- iTreg for clinical applications such as flea allergic dermatitis. PMID- 21542945 TI - Sex, sex chromosomes and gene expression. AB - The X chromosome has fewer testis-specific genes than autosomes in many species. This bias is commonly attributed to X inactivation in spermatogenesis but a recent paper in BMC Biology provides evidence against X inactivation in Drosophila and proposes that somatic tissue- and testis- but not ovary-specific genes tend not to be located on the X chromosome. Here, we discuss possible mechanisms underlying this bias, including sexual antagonism and dosage compensation. PMID- 21542944 TI - Metabolic syndrome: definitions and controversies. AB - Metabolic syndrome (MetS) is a complex disorder defined by a cluster of interconnected factors that increase the risk of cardiovascular atherosclerotic diseases and diabetes mellitus type 2. Currently, several different definitions of MetS exist, causing substantial confusion as to whether they identify the same individuals or represent a surrogate of risk factors. Recently, a number of other factors besides those traditionally used to define MetS that are also linked to the syndrome have been identified. In this review, we critically consider existing definitions and evolving information, and conclude that there is still a need to develop uniform criteria to define MetS, so as to enable comparisons between different studies and to better identify patients at risk. As the application of the MetS model has not been fully validated in children and adolescents as yet, and because of its alarmingly increasing prevalence in this population, we suggest that diagnosis, prevention and treatment in this age group should better focus on established risk factors rather than the diagnosis of MetS. PMID- 21542946 TI - Optimized labeling of bone marrow mesenchymal cells with superparamagnetic iron oxide nanoparticles and in vivo visualization by magnetic resonance imaging. AB - BACKGROUND: Stem cell therapy has emerged as a promising addition to traditional treatments for a number of diseases. However, harnessing the therapeutic potential of stem cells requires an understanding of their fate in vivo. Non invasive cell tracking can provide knowledge about mechanisms responsible for functional improvement of host tissue. Superparamagnetic iron oxide nanoparticles (SPIONs) have been used to label and visualize various cell types with magnetic resonance imaging (MRI). In this study we performed experiments designed to investigate the biological properties, including proliferation, viability and differentiation capacity of mesenchymal cells (MSCs) labeled with clinically approved SPIONs. RESULTS: Rat and mouse MSCs were isolated, cultured, and incubated with dextran-covered SPIONs (ferumoxide) alone or with poly-L-lysine (PLL) or protamine chlorhydrate for 4 or 24 hrs. Labeling efficiency was evaluated by dextran immunocytochemistry and MRI. Cell proliferation and viability were evaluated in vitro with Ki67 immunocytochemistry and live/dead assays. Ferumoxide-labeled MSCs could be induced to differentiate to adipocytes, osteocytes and chondrocytes. We analyzed ferumoxide retention in MSCs with or without mitomycin C pretreatment. Approximately 95% MSCs were labeled when incubated with ferumoxide for 4 or 24 hrs in the presence of PLL or protamine, whereas labeling of MSCs incubated with ferumoxide alone was poor. Proliferative capacity was maintained in MSCs incubated with ferumoxide and PLL for 4 hrs, however, after 24 hrs it was reduced. MSCs incubated with ferumoxide and protamine were efficiently visualized by MRI; they maintained proliferation and viability for up to 7 days and remained competent to differentiate. After 21 days MSCs pretreated with mitomycin C still showed a large number of ferumoxide labeled cells. CONCLUSIONS: The efficient and long lasting uptake and retention of SPIONs by MSCs using a protocol employing ferumoxide and protamine may be applicable to patients, since both ferumoxides and protamine are approved for human use. PMID- 21542947 TI - Fracture prevention in postmenopausal women. AB - INTRODUCTION: The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of bisphosphonates to prevent fractures in postmenopausal women? What are the effects of pharmacological treatments other than bisphosphonates to prevent fractures in postmenopausal women? What are the effects of non-pharmacological treatments to prevent fractures in postmenopausal women? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: alendronate, calcitonin, calcium, calcium plus vitamin D, clodronate, denosumab, etidronate, exercise, hip protectors, hormone replacement therapy, ibandronate, multifactorial non-pharmacological interventions, pamidronate, parathyroid hormone, raloxifene, risedronate, strontium ranelate, vitamin D, vitamin D analogues, and zoledronate. PMID- 21542949 TI - Diagnostic imaging in AIDS in China: current status and clinical application. PMID- 21542950 TI - Radiologic diagnosis for AIDS patients complicated with candidal esophagitis. AB - BACKGROUND: Candidal esophagitis is the primary infection among all digestive tract opportunistic ones in acquired immunodeficiency syndrome (AIDS) cases. X ray manifestation reports of it are still rare. This study aimed to conduct a retrospective analysis on the X-ray data of 6 AIDS cases complicated with candidal esophagitis, and to study the X-ray characteristics of it combined with the findings from gastroscopy. METHODS: Among 6 cases in this series, all cases were confirmed by Shenzhen Center for Disease Control and Prevention (CDC) to be HIV positive and all of them had CD4 cell counts less than 150 * 10(6)/L. All cases underwent X-ray and gastroscopy, and mycelium were found in the mucous membrane of the esophagus. RESULTS: In this series, the findings of the X-ray were as follows: (1) Affected areas: Four cases in the whole esophagus, 2 cases in the middle and lower part of esophagus; (2) Abnormal motivity: Six cases had decreased tension, loose walls, weakened peristalsis, decreased number of peristalsis waves and delayed emptying of barium; (3) Abnormal contour: Six cases had the sign of "decorative border" or "brush", two cases had narrowed canal; (4) Abnormal membrane and "cobblestone sign": Six cases had thickened membrane and "cobblestone sign" on the surface of the abnormal membrane. The hyperemia of mucosa was covered tightly with yellow-white pseudomembrane spots. This was in accordance with the small cobblestone-like filling defect found by X-ray. CONCLUSIONS: If the AIDS cases have dysphagia, and X-ray shows that more than two sections of the esophagus are affected, with decreased motility, the walls in the sign of "brush" or "decorative edges", thickened membrane with "cobblestone sign", candidal esophagitis is highly possible. PMID- 21542948 TI - Determination of fetal chromosome aberrations from fetal DNA in maternal blood: has the challenge finally been met? AB - The analysis of cell-free fetal nucleic acids in maternal blood for prenatal diagnosis has been transformed by several recent profound technology developments. The most noteworthy of these are 'digital PCR' and 'next-generation sequencing' (NGS), which might finally deliver the long-sought goal of noninvasive detection of fetal aneuploidy. Recent data, however, indicate that NGS might even be able to offer a much more detailed appraisal of the fetal genome, including paternal and maternal inheritance of point mutations for mendelian disorders such as beta-thalassaemia. Although these developments are very exciting, in their current form they are still too complex and costly, and will need to be simplified considerably for their optimal translation to the clinic. In this regard, targeted NGS does appear to be a step in the right direction, although this should be seen in the context of ongoing progress with the isolation of fetal cells and with proteomic screening markers. PMID- 21542951 TI - Imaging and pathological findings of AIDS complicated by pulmonary Rhodococcus equi infection. AB - BACKGROUND: Rhodococcus equi (R. equi) infection commonly occurs in grazing areas, especially in patients with AIDS or with T-lymphocyte immuno-deficiencies. Literature reviews revealed that cases radiologically and pathologically diagnosed of AIDS complicated by R. equi infection are rare. This study aimed to investigate the imaging features and pathological basis of AIDS complicated by pulmonary R. equi infection. METHODS: A total of 13 cases of AIDS complicated by pulmonary R. equi infection were retrospectively analyzed based on their imaging, bacterial culture and pathological data, including 10 cases by chest CT scanning and X-ray radiology and 3 cases by only X-ray radiology. All 13 cases were definitely diagnosed by bacterial culture, including one by CT-guided pulmonary puncture with following H&E staining and periodic acid-Schiff (PAS) staining for diagnostic biopsy and another one by bronchial biopsy with following H&E staining and PAS staining for pathological diagnosis. The imaging findings and the pathological findings of AIDS complicated by pulmonary R. equi infection were compared and evaluated. RESULTS: Totally 9 subjects (70%) had radiological demonstrations of central ball liked high density shadows in unilateral pulmonary hilus areas; 10 (77%), cavities and liquefied levels; 3 (23%), pleural effussion. The foci were found in pulmonary inner zone in 10 subjects (77%) and in pulmonary outer zone in one subject (7%). The pathological findings included intra-alveolar hemorrhage, lymphocyte infiltration and granulation tissue proliferation, which were in line with the pathological process of necrotic pneumonia. After 8-month follow-up of anti-R. equi therapy of these 13 cases, 9 cases had obviously decreased or shrunk pulmonary cavities, one died, one missed follow-up, one completely absorbed foci and one did not receive reexaminations. CONCLUSIONS: The radiological demonstrations of AIDS complicated by pulmonary R. equi infection are central ball liked high density areas in unilateral pulmonary hilus area, parenchymal changes, secondary cavities, ground glass liked changes in the lung fields, nodules and treeinbuds sign, which are characteristic rather than specific. PMID- 21542952 TI - Using intra-operative GeneSearchTM Breast Lymph Node Assay to detect breast cancer metastases in sentinel lymph nodes: results from a single institute in China. AB - BACKGROUND: Sentinel lymph node (SLN) biopsy has become a common procedure for early breast cancer patients. The GeneSearch(TM) Breast Lymph Node (BLN) Assay is a real-time RT-PCR assay for the detecting nodal metastases larger than 0.2 mm. China Breast Cancer Clinical Study Group (CBCSG)-001a is a prospective multi center clinical trial that was conducted to validate the GeneSearch(TM) BLN Assay in China. METHODS: The SLNs from 90 consecutive patients were identified and dissected, and then sectioned along the short axis into multiple blocks. Intra operatively, the odd blocks were tested by BLN assay and the even ones were used for frozen section, while all the blocks were evaluated by touch imprint cytology. Post-operatively, the remaining tissues were assessed by histological evaluation. RESULTS: A total of 189 SLNs was tested by BLN assay. The sensitivity, specificity, positive predictive value, and negative predictive value were 88.9%, 97.4%, 88.9% and 97.4%, respectively, for BLN assay, 75.0%, 100%, 100% and 94.4%, respectively, for frozen section, and 63.9%, 100%, 100% and 92.2%, respectively, for touch imprint cytology. The sensitivity of BLN assay was higher than that of touch imprint cytology (P = 0.01) and frozen section (P = 0.13). When assessing the nodes with micro-metastases, BLN assay had a significant higher sensitivity than frozen section (P = 0.023) and touch imprint cytology (P = 0.005). CONCLUSION: The GeneSearch(TM) BLN Assay is an accurate and rapid intra-operative assay for breast SLNs and it is suitable for application in general medical practice. PMID- 21542953 TI - Lung transplantation in a Chinese single center: 7 years of experience. AB - BACKGROUND: Lung transplantation (LT) is a viable option for patients with end stage lung diseases, but in China, the supply is limited, and the experience with LT is rare too. This study aimed to evaluate the survival and postoperative complications of recipients undergone LT. METHODS: From January 2003 to May 2010, all patients who underwent LT were included. The clinical data of recipients were analyzed retrospectively, including demographic characteristics, survival rate, and the occurrences of postoperative complications, acute rejection and bronchiolitis obliterans syndrome. RESULTS: In total, 37 patients underwent LT. The early mortality (<= 30 days) was 14% (5/37). Cumulative survival rate was 78%, 70%, 70% and 42% at 1, 3, 5 and 6 years, respectively. In 37 patients, 5 (14%) developed fungal infections, 9 (24%) pulmonary bacterial infections, and 6 (16%) had bronchial anastomosis complications after LT. At three months post transplantation, a significant improvement was observed in lung function (P < 0.05). Fifteen recipients (41%) developed acute rejection within the first year. Freedom from bronchiolitis obliterans syndrome was 89%, 85% and 80% at 1, 2 and 3 years after transplantation. CONCLUSIONS: Despite the limited number of cases, the survival and occurrences of complications after LT were comparable to the international experience. Single LT may be a reasonable option for some patients with end-stage pulmonary diseases. PMID- 21542954 TI - Analysis of inborn errors of metabolism: disease spectrum for expanded newborn screening in Hong Kong. AB - BACKGROUND: Data of classical inborn errors of metabolism (IEM) of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area. METHODS: The laboratory records of plasma amino acids, plasma acylcarnitines and urine organic acids analyses from year 2005 to 2009 inclusive in three regional chemical pathology laboratories providing biochemical and genetic diagnostic services for IEM were retrospectively reviewed. RESULTS: Among the cohort, 43 patients were diagnosed of IEM, including 30 cases (69%) of amino acidemias (predominantly citrin deficiency, hyperphenylalaninemia due to 6-pyruvoyl tetrahydropterin synthase deficiency and tyrosinemia type I), 5 cases (12%) of organic acidemias (predominantly holocarboxylase synthetase deficiency) and 8 cases (19%) of fatty acid oxidation defects (predominantly carnitine acylcarnitine translocase deficiency). The incidence of classical IEM in Hong Kong was roughly estimated to be at least 1 case per 4122 lives births, or 0.243 cases per 1000 live births. This incidence is similar to those reported worldwide, including the mainland of China. The estimated incidence of hyperphenylalaninemia was 1 in 29 542 live births. CONCLUSIONS: Our data indicate that it is indisputable for the introduction of expanded newborn screening program in Hong Kong. Since Hong Kong is a metropolitan city, a comprehensive expanded newborn screening program and referral system should be available to serve the neonates born in the area. PMID- 21542955 TI - Comparison of long-term clinical outcome after successful implantation of FIREBIRD and CYPHER sirolimus-eluting stents in daily clinical practice: analysis of a large single-center registry. AB - BACKGROUND: Recent data have shown that sirolimus-eluting stents (SES) reduced not only the incidences of restenosis but also of target vessel revascularization (TVR). CYPHER and FIREBIRD stents are both widely used SES in China. However, comparative data concerning differences in long-term safety and efficacy regarding CYPHER and FIREBIRD stents in the Chinese population are still not available. METHODS: From April 2004 to October 2006, 3979 consecutive patients who underwent successful SES (FIREBIRD 2274; CYPHER 1705) implantation were prospectively enrolled into this study. All enrolled patients were divided into two groups based on stent type. Follow-up data, including death, myocardial infarction (MI), thrombosis, target lesion revascularization (TLR), TVR, and major adverse cardiac events (MACE, the composite of death, MI, and TVR) were obtained at 24 months. Cox's proportional-hazards models were used to assess relative risks of all the outcome measures between the two groups before and after propensity match. RESULTS: Unadjusted clinical outcomes demonstrated higher TVR (hazard ratio (HR) 1.78, 95%CI 1.26 - 2.50) and MACE (HR 1.40, 95%CI 1.08 - 1.82) for patients treated with FIREBIRD SES. After propensity match, the results showed a non-significant trend towards superiority of the CYPHER stent in all the analyzed parameters, however, no significant differences were found for all events at 24 months between FIREBIRD and CYPHER groups, and all thrombosis rates by Academic Research Consortium (ARC) definition were comparable between the two groups. CONCLUSIONS: In this large, real-world population, the use of domestic FIREBIRD SES in China was associated with nearly the same safety and efficacy versus the imported CYPHER SES. FIREBIRD SES can be taken as an alternative for CYPHER SES in daily practice. PMID- 21542956 TI - Calculated plasma medial effective concentration of propofol with and without magnesium sulfate at loss of consciousness. AB - BACKGROUND: Perioperative disorder of magnesium, an important cation in the human body, may affect clinical anesthesia. The pharmacological data of propofol use, which is popularly used in the anesthesiology department and intensive care unit, is incomplete in Chinese patients. This study aimed to assess the effect of magnesium sulfate on the calculated plasma medial effective concentration (Cp50cal) of propofol at loss of response to command in Chinese females. METHODS: Fifty patients undergoing gynecological laparoscopic surgery were randomly divided into the control group and the magnesium group. Before induction, magnesium sulfate (30 mg/kg) or placebo (equal volume of 0.9% saline) was given to patients in the magnesium group or the control group, respectively. Propofol was infused using a target-controlled infusion system, with a target concentration for each patient decided by up-and-down sequential allocation. After the equilibration between target plasma concentration and effective-site concentration, the state of consciousness was assessed. For determination of serum magnesium and calcium concentration, blood samples were taken before induction, after induction and at the end of surgery. RESULTS: The Cp50cal was 2.52 ug/ml (2.47 - 2.57 ug/ml) for patients in the control group, and 2.46 ug/ml (2.41 - 2.51 ug/ml) for those in the magnesium group. A significant reduction of Cp50cal was observed (P = 0.021). There was a significant difference between the serum magnesium concentrations after induction and at the end of the surgery (P < 0.05). In the magnesium group, there was a trend toward decreasing after surgery, while in the control group, Cp50cal decreased significantly (P < 0.01). CONCLUSIONS: Cp50cal of propofol at loss of response to command was 2.52 ug/ml (2.47 - 2.57 ug/ml) for Chinese female adults in this study. Infusion of 30 mg/kg magnesium sulfate may reduce the Cp50cal of propofol at loss of consciousness, which implies that magnesium may enhance the pharmacological effects of propofol. PMID- 21542957 TI - Risk factors of positive surgical margin and biochemical recurrence of patients treated with radical prostatectomy: a single-center 10-year report. AB - BACKGROUND: Many studies have shown that positive surgical margin and biochemical recurrence could impact the life of patients with prostate cancer treated with radical prostatectomy. With more and more patients with prostate cancer appeared in recent 20 years in China, it is necessary to investigate the risk of positive surgical margin and biochemical recurrence, and their possible impact on the prognosis of patients treated with radical prostatectomy. In this study, we analyzed the characteristics of patients with prostate cancer who had undergone radical prostatectomy in Macau area and tried to find any risk factor of positive surgical margin and biochemical recurrence and their relationship with the prognosis of these patients. METHODS: From 2000 to 2009, 149 patients with prostate cancer received radical prostatectomy and were followed up. Among these patients, 111 received retropubic radical prostatectomies, 38 received laparoscopic radical prostatectomies. All patients were followed-up on in the 3rd month, 6th month and from that point on every 6 months after operation. At each follow-up a detailed record of any complaint, serum prostate-specific antigen (PSA), full biochemical test and uroflowmetry was acquired. RESULTS: The average age was (69.0 +/- 6.1) years, preoperative average serum PSA was (10.1 +/- 12.1) ng/ml and average Gleason score was 6.4 +/- 1.3. The incidence of total complications was about 47.7%, the incidence of the most common complication, bladder outlet obstruction, was about 26.8%, and that of the second most common complication, urinary stress incontinence, was about 16.1% (mild 9.4% and severe 6.7%). The incidence of positive surgical margin was about 38.3%. The preoperative serum PSA ((13.4 +/- 17.6) ng/ml), average Gleason score (7.1 +/- 1.3) and pathological T stage score (7.0 +/- 1.4) were higher in patients with positive surgical margins than those with negative margins ((8.0 +/- 5.8) ng/ml, 6.0 +/- 1.2 and 5.4 +/- 1.4, respectively) (P = 0.004, P = 0.001 and P = 0.001, respectively). A univariate analysis showed that positive surgical margin had a positive statistical association with serum PSA (P = 0.007), Gleason score (P < 0.001), pathological T stage score (P < 0.001) and biochemical recurrence (BCR) (P = 0.035). The most common location of a positive surgical margin was in the apex of the prostate, which was about 63% (36/57). Sixty-four percent (23/36) of patients with positive surgical margin in apex were also involved in prostate lobe; other locations were prostate lobe (23%, 13/57), seminal vesicle (9%, 5/57). The multivariate analysis showed that positive surgical margin had a positive statistical association with Gleason score (P = 0.03) and pathological T stage score (P = 0.02). Neither univariate analysis or multivariate analysis showed any statistical relationship between BCR and any other risk factors covered in this study. CONCLUSIONS: Positive surgical margin is associated with pre-operative PSA, Gleason score, pathological T stage and biochemical recurrence. Earlier diagnosis and improved techniques of dissection of prostate apex could decrease the incidence of positive surgical margins. PMID- 21542958 TI - Radiofrequency treatment on respiratory symptoms due to gastroesophageal reflux disease. AB - BACKGROUND: Diagnosis and treatment for respiratory symptoms (RSs) of gastroesophageal reflux disease (GERD) is more difficult than that for common esophageal symptoms. The goal of this study was to evaluate the efficacy and safety of radiofrequency (RF) treatment on RSs of GERD in a preliminary 12-month follow-up observation. METHODS: From April 2006 to October 2008, 505 GERD patients with mainly respiratory presentations such as wheezing, chronic cough or hoarseness, were treated by endoscopic RF. A questionnaire was completed before and after treatment, using a six-point scale ranging from 0 to 5 to assess symptom severity and frequency. The symptom score was the sum of frequency and severity. RESULTS: Symptom scores were significantly improved at the end of the follow-up period. The mean heartburn score decreased from 5.31 to 1.79. The mean regurgitation score decreased from 5.02 to 1.64; mean cough score decreased from 6.77 to 2.85; mean wheezing score decreased from 7.83 to 3.07; and mean hoarseness score decreased from 5.13 to 1.81 (P < 0.01). No major complications or deaths occurred. Minor complications included temporary post-procedural retrosternal unease or pain (n = 106; 21.0%), mild fever (n = 86; 17.0%), transient nausea/vomiting (n = 97; 19.2%), and transient dysphagia (n = 42; 9.3%). Thirty-five (6.9%) patients had recurrence of symptoms. Endoscopic RF treatment was repeated in six patients, and laparoscopic fundoplication was performed in seven. CONCLUSION: Endoscopic RF is an effective and safe means to treat RSs in patients with GERD. PMID- 21542959 TI - Clinical applications of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in carcinoma of unknown primary. AB - BACKGROUND: Carcinoma of unknown primary (CUP) encompasses a heterogeneous group of tumors with varying clinical features. The management of patients of CUP remains a clinical challenge. The purpose of this study was to evaluate the clinical applications of integrated (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) information in patients with CUP, including detecting the occult primary tumor and effecting on disease therapy. METHODS: One hundred and forty-nine patients with histologically-proven metastases of CUP were included. For all patients, the conventional diagnostic work-up was unsuccessful in localizing the primary site. Whole-body PET/CT images were obtained approximately 60 minutes after intravenous injection of 350 - 425 MBq of (18)F-FDG. RESULTS: In 24.8% of patients, FDG PET/CT detected primary tumors that were not apparent after conventional workup. In this group of patients, the overall sensitivity, specificity, and accuracy rates of FDG PET/CT in detecting unknown primary tumors were 86.0%, 87.7%, and 87.2%, respectively. FDG PET/CT imaging also led to the detection of previously unrecognized metastases in 29.5% of patients. Forty-seven (31.5%, 47 of 149) patients underwent a change in therapeutic management. CONCLUSIONS: FDG PET/CT is a valuable tool in patients with CUP, because it assisted in detecting unknown primary tumors and previously unrecognized distant metastases, and optimized the management of these patients. PMID- 21542960 TI - Diagnosis and treatment of fungal infection after liver transplantation. AB - BACKGROUND: Liver transplantation is the most effective treatment for end-stage liver diseases; however, infections after transplantation can seriously affect the patient's health. The aim of this research was to investigate the diagnosis and treatment of fungal infection following liver transplantation. METHODS: Clinical data for 232 liver transplant patients at risk of fungal infection were examined for the presence of fungus in the blood, fluid, sputum, urine and stools of patients and by chest or abdominal CT scans. Patients diagnosed with a fungal infection were treated with Fluconazole or, if this was not effective, Voriconazole or Amphotericin B. Immunosuppressive therapy was also reviewed. RESULTS: Thirty-seven of 232 (15.9%) patients were diagnosed with a fungal infection, which occurred 4 to 34 days post-transplantation. Candida infections were diagnosed in 23 cases (62.2%) and Aspergillus infections in 12 cases (32.4%). Twenty-one cases were effectively treated with Fluconazole, 11 cases with Voriconazole, and two cases with Amphotericin B; however, three cases were not effectively treated with any of the antifungal agents. Overall, treatment was effective in 91.9% of patients. CONCLUSIONS: Fungal infection has a significant influence on survival rate after liver transplantation. Imaging studies, and pathogenic and biopsy examinations can diagnose fungal infections, which can be effectively treated with antifungal agents such as Fluconazole, Voriconazole or Amphotericin B. PMID- 21542961 TI - Application of purse-string suture for management of duodenal stump in radical gastrectomy. AB - BACKGROUND: Gastric cancer (GC) is the second leading cause of cancer mortality worldwide, and surgical resection is currently the only possible curative approach. Duodenal stump leakage is the most serious complication after radical gastrectomy, and optimal treatment is still lacking. METHODS: We retrospectively reviewed 2034 cases of total or subtotal gastrectomy for GC from January 1995 to December 2009, including 465 cases of duodenal stump closure using purse-string suture (group A), 835 cases of duodenal stump treated with linear cutting stapler and seromuscular layer suture (group B), and 734 cases of duodenal stump closure using full-thickness and seromuscular layer suture (group C). We evaluated the surgical cost, operative time for duodenal stump closure, short-term postoperative complications, perioperative blood loss, and postoperative recovery. RESULTS: There was no perioperative mortality in any group. Ninety-four postoperative (within 1 month) complications occurred: 18 abdominal bleeding, 14 anastomotic leakage, 15 abdominal infection, 36 wound infection, and 11 duodenal stump leakage. There was no significant difference among the groups in intra abdominal hemorrhage, anastomotic leakage, abdominal infection and wound infection. No postoperative duodenal stump leakage occurred in group A, which had a significant difference compared with groups B and C (6 cases in group B and 5 cases in group C suffered duodenal stump leakage. P < 0.01). The surgical cost in groups A and C was significantly lower than in group B (P < 0.01), with no significant difference between groups A and C. The processing time for duodenal stump closure in groups A and B was significantly shorter than in group C (P < 0.01), with no significant difference between groups A and B. There was no significant difference in blood loss and postoperative recovery among the groups. CONCLUSIONS: Duodenal stump closure using purse-string suture seems to be a promising approach with shorter operative time, and lower cost and incidence of duodenal stump leakage in radical gastrectomy. PMID- 21542962 TI - Multivariable analysis of factors associated with hospital readmission following pancreaticoduodenectomy for malignant diseases. AB - BACKGROUND: Readmission rates after pancreaticoduodenectomy (PD) for malignant diseases have a significant impact on survival rate. Identification of risk factors for readmission may improve discharge plans and postoperative care. Data exist on the morbidity and mortality of patients undergoing PD, but there are few reports about hospital readmissions after this procedure. Our aims were to evaluate the proportion and reasons for readmissions after PD for malignant diseases, the factors influencing readmissions, and to analyze the relationship between readmission rate and survival rate. METHODS: Four hundred and thirty-six patients, who had undergone PD for malignant diseases in our centre from October 1999 to October 2009, a 10-year period, excluding perioperative (30-day) mortality, were identified. All readmissions within 1 year following PD were analyzed with respect to timing, location, reasons for readmission and outcome. We reviewed the hospitalization and readmissions for patients undergoing PD, and compared patients requiring readmission to patients that did not require readmission. RESULTS: One hundred and forty-five patients (33.26%) were readmitted within 1 year following PD, for further treatment or complications. In those cases, diagnoses associated with high rates of readmission included radiation and/or chemotherapy (48.96%), progression of disease (11.72%), infection (11.72%), gastrointestinal dysfunction/obstruction (6.20%), surgery related complications (2.76%) and pain (4.14%). The proportion of T4 in readmission group was lower than no readmission group (P < 0.05). The proportion of node positive cases in readmission group was much higher than no readmission group (P < 0.01). The number of readmission for complications reduced gradually in the first three months, and reached a second peak in the sixth and seventh month. Median survival was lower for the readmission group compared with the no readmission group (21 versus 46 months, P = 0.024). CONCLUSION: These results may assist in both anticipating and facilitating postoperative care as well as managing patient expectations. PMID- 21542963 TI - Clinical and prognostic characteristics of pulmonary mucosa-associated lymphoid tissue lymphoma: a retrospective analysis of 23 cases in a Chinese population. AB - BACKGROUND: Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is the most frequent type of non-Hodgkin's lymphoma (NHL) that primarily involves the lungs. It represents a rare entity accounting for less than 1% of all NHLs and the clinical features have yet to be clearly elucidated. METHODS: The clinicopathological features and radiological data of 23 patients with pulmonary MALT lymphoma confirmed by biopsy in Peking Union Medical College Hospital from January 2001 to December 2010 were retrospectively analyzed. RESULTS: At diagnosis, there were 15 women and 8 men. The median age was 55.1 years (range, 37 - 73 years). One patient had a history of primary Sjoren's syndrome, another patient had a history of systemic lupus erythematosus (SLE) and secondary Sjoren's syndrome. One patient had a history of previous hematological malignancy (lymphomatoid papulosis in complete remission). In addition, one patient had simultaneous gastric and pulmonary involvement and one patient had simultaneous parotid gland and pulmonary involvement. The other 21 patients had disease localized within the lungs at the initial diagnosis. Among them, 10 patients were asymptomatic while two had non-specific pulmonary symptoms. There were six patients with fever, four patients had low grade fever and two patients had moderate-high fever. The most common manifestations were cough (n = 10), expectoration (n = 8), exertional dyspnea (n = 8), fatigue (n = 7), body weight loss (n = 6) and crackles (n = 6). Blood tests showed low to moderate anemia in six cases, elevated erythrocyte semimentation rate (ESR) in 10 cases and only one patient had elevated lactate dehydrogenase (LDH). High resolution computed tomography (HRCT) of the chest revealed bilateral disease in 13 patients, air space consolidation with or without air bronchogram in 15 patients, lung nodules in 15 patients, patchy opacities in eight patients, lung mass in three patients and pleural effusion in five patients. Flexible fiberoptic bronchoscopy showed multiple nodules in five patients and almost normal morphology in 18 patients. Pathological diagnosis was obtained by bronchial biopsies in three cases, by CT guided percutaneous lung biopsies in 11 cases and by surgical biopsies in nine cases. Of the 23 patients, one remained untreated, while 22 received various combinations of treatment (surgery alone in three patients, surgery plus chemotherapy in six patients, and chemotherapy alone in 13 patients). Twenty-one patients remained alive during the median follow-up of 23 (0.25 - 84) months, while one patient died from unknown causes, one patient died from lung infection. CONCLUSIONS: Pulmonary MALT lymphoma tends to occur in old-aged females and to be limited to the lungs on the initial diagnosis and LDH's level was normal in most patients. Lung nodules, patchy opacities and air space consolidation were the main HRCT manifestations. Association with immunohistochemical studies, CT-guided percutaneous lung biopsies and surgical biopsies were helpful to the diagnosis. Prognosis for this lymphoma tends to be indolent. PMID- 21542964 TI - Disease distribution and medical resources during the Beijing 2008 Olympic and Paralympic Games. AB - BACKGROUND: Appropriate planning and staffing for medical services at large-scale athletic events is essential to provide for a safe and successful competition. There are few well-documented accounts describing the demand for such services. The present study provided the data from the Beijing 2008 Olympics and Paralympics, with a view to provide the guidance for planning future events. METHODS: A total of 22 029 and 8046 patients, who received medical care from a physician at an Olympic or Paralympic medical station, were included. The patient proportion among different personnel, various disease proportions at different kinds of venues, and the disease spectrum at specified venues at the Olympics and Paralympics were analyzed. RESULTS: At both games, the patient proportion varied by accreditation status. The staff accounted for the largest number of visits at the Olympics (44.83%) and Paralympics (36.95%), with respiratory diseases the most common. Various disease spectrums were discovered at the different kinds of venues. Surgical diseases were the most frequently listed reason for visits, both at competition and non-competition venues, especially during the Paralympics. The sport-related injuries accounted for a majority of the surgical cases during both games. At training venues, ear nose and throat diseases accounted for the greatest number of visits during both games. CONCLUSIONS: During both games, people contracted different diseases at different venues. Adequate surgeons should be designated to offer assistance mostly in trauma situations. Appropriate numbers of physicians in respiratory diseases and otorhinolaryngology is of great importance. PMID- 21542965 TI - Derivation and characterization of Chinese human embryonic stem cell line with high potential to differentiate into pancreatic and hepatic cells. AB - BACKGROUND: Human embryonic stem cells have prospective uses in regenerative medicine and drug screening. Every human embryonic stem cell line has its own genetic background, which determines its specific ability for differentiation as well as susceptibility to drugs. It is necessary to compile many human embryonic stem cell lines with various backgrounds for future clinical use, especially in China due to its large population. This study contributes to isolating new Chinese human embryonic stem cell lines with clarified directly differentiation ability. METHODS: Donated embryos that exceeded clinical use in our in vitro fertilization-embryo transfer (IVF-ET) center were collected to establish human embryonic stem cells lines with informed consent. The classic growth factors of basic fibroblast growth factor (bFGF) and recombinant human leukaemia inhibitory factor (hLIF) for culturing embryonic stem cells were used to capture the stem cells from the plated embryos. Mechanical and enzymetic methods were used to propagate the newly established human embryonic stem cells line. The new cell line was checked for pluripotent characteristics with detecting the expression of stemness genes and observing spontaneous differentiation both in vitro and in vivo. Finally similar step-wise protocols from definitive endoderm to target specific cells were used to check the cell line's ability to directly differentiate into pancreatic and hepatic cells. RESULTS: We generated a new Chinese human embryonic stem cells line, CH1. This cell line showed the same characteristics as other reported Chinese human embryonic stem cells lines: normal morphology, karyotype and pluripotency in vitro and in vivo. The CH1 cells could be directly differentiated towards pancreatic and hepatic cells with equal efficiency compared to the H1 cell line. CONCLUSIONS: This newly established Chinese cell line, CH1, which is pluripotent and has high potential to differentiate into pancreatic and hepatic cells, will provide a useful tool for embryo development research, along with clinical treatments for diabetes and some hepatic diseases. PMID- 21542966 TI - Determining of migraine prognosis using latent growth mixture models. AB - BACKGROUND: This paper presents a retrospective study to classify patients into subtypes of the treatment according to baseline and longitudinally observed values considering heterogenity in migraine prognosis. In the classical prospective clinical studies, participants are classified with respect to baseline status and followed within a certain time period. However, latent growth mixture model is the most suitable method, which considers the population heterogenity and is not affected drop-outs if they are missing at random. Hence, we planned this comprehensive study to identify prognostic factors in migraine. METHODS: The study data have been based on a 10-year computer-based follow-up data of Mersin University Headache Outpatient Department. The developmental trajectories within subgroups were described for the severity, frequency, and duration of headache separately and the probabilities of each subgroup were estimated by using latent growth mixture models. SAS PROC TRAJ procedures, semiparametric and group-based mixture modeling approach, were applied to define the developmental trajectories. RESULTS: While the three-group model for the severity (mild, moderate, severe) and frequency (low, medium, high) of headache appeared to be appropriate, the four-group model for the duration (low, medium, high, extremely high) was more suitable. The severity of headache increased in the patients with nausea, vomiting, photophobia and phonophobia. The frequency of headache was especially related with increasing age and unilateral pain. Nausea and photophobia were also related with headache duration. CONCLUSIONS: Nausea, vomiting and photophobia were the most significant factors to identify developmental trajectories. The remission time was not the same for the severity, frequency, and duration of headache. PMID- 21542967 TI - Degradation products of different water content sevoflurane in carbon dioxide absorbents by gas chromatography-mass spectrometry analysis. AB - BACKGROUND: Sevoflurane is currently used as a volatile inhalation anesthetic with many clinical advantages. A representative degradation product, compound A, was quantitatively measured to investigate whether there are different reactions between two kinds of water content sevoflurane formulations with different carbon dioxide (CO2) absorbents. METHODS: A closed-circle breathe bag with the Drager Fabius GS anesthesia apparatus was used as an artificial rubber lung. The experiments were grouped according to different sevoflurane formulations: group A: higher-water sevoflurane (Ultane); group B: lower-water sevoflurane (Sevoness). During the experiment, CO2 (200 ml/min) was continually perfused to keep the end-tidal pressure of CO2 (P(ET)CO2) at 35 - 45 mmHg. The artificial ventilation was set to 6 L/min, and the breathing rate at 12 breaths/min. The circuit was operated with constant fresh gas flow rate (1 L/min) and the sevoflurane concentration was kept at 1.0 minimum alveolar concentration (MAC) for 240 minutes. At 0, 10, 20, 30, 60, 90, 120, 180 and 240 minutes, gas was collected from the Y-piece. Gas chromatography/mass spectrometry (GC/MS) was used to quantify the major degradation product, compound A, with different water content sevoflurane. PETCO2 and sevoflurane concentration, and the temperature of the canister were continuously monitored during the experiment. RESULTS: There were no significant differences in P(ET)CO2 and sevoflurane concentrations between the two groups. Dragersorb 800 plus produced the highest concentrations of compound A compared with other sodalimes, and Sevoness in Dragersorb 800 plus generated more compound A than Ultane (P < 0.05). There were significant differences in the peak and average compound A concentrations between Ultane and Sevoness with Dragersorb 800 plus (P < 0.05), while the compound A concentration produced by Sodasorb grase and sofonolime in the two groups showed no significant difference (P > 0.05). In the same group, the peak and average of compound A concentration produced by Sodasorb grase and sofonolime showed significant difference with Dragersorb 800 plus (P < 0.05). CONCLUSION: The water content of sevoflurane and potassium hydroxide in CO2 absorbent can influence compound A production. PMID- 21542968 TI - Chemoresistance of CD133+ cancer stem cells in laryngeal carcinoma. AB - BACKGROUND: Mounting evidence suggests that tumors are histologically heterogeneous and are maintained by a small population of tumor cells termed cancer stem cells. CD133 has been identified as a candidate marker of cancer stem cells in laryngeal carcinoma. This study aimed to analyze the chemoresistance of CD133(+) cancer stem cells. METHODS: The response of Hep-2 cells to different chemotherapeutic agents was investigated and the expression of CD133 was studied. Fluorescence-activated cell sorting analysis was used to identify CD133, and the CD133(+) subset of cells was separated and analyzed in colony formation assays, cell invasion assays, chemotherapy resistance studies, and analyzed for the expression of the drug resistance gene ABCG2. RESULTS: About 1% - 2% of Hep-2 cells were CD133(+) cells, and the CD133(+) proportion was enriched by chemotherapy. CD133(+) cancer stem cells exhibited higher potential for clonogenicity and invasion, and were more resistant to chemotherapy. This resistance was correlated with higher expression of ABCG2. CONCLUSIONS: This study suggested that CD133(+) cancer stem cells are more resistant to chemotherapy. The expression of ABCG2 could be partially responsible for this. Targeting this small population of CD133(+) cancer stem cells could be a strategy to develop more effective treatments for laryngeal carcinoma. PMID- 21542970 TI - Yohimbine protects against endotoxin-induced acute lung injury by blockade of alpha 2A adrenergic receptor in rats. AB - BACKGROUND: Alpha 2A adrenergic receptor (AR) is a subtype of alpha2 AR belonging to G protein-coupled receptors, and exerts a variety of biological effects. Recent studies have demonstrated that the alpha2A AR activation was closely related with inflammatory reaction. The present study aimed to investigate the influence of alpha2A AR antagonist, yohimbine, on the severity of endotoxin induced acute lung injury in rats. METHODS: A total of 72 male Sprague-Dawley rats were randomly divided into three groups: control group, lipopolysaccharide (LPS) group and LPS + yohimbine group. Rats were intratracheally administrated with normal saline or LPS (300 ug), and the rats in the LPS + yohimbine group were treated with additional yohimbine (2 mg/kg, i.p) soon after LPS administration. Six, 24 and 48 hours after treatment, arterial blood gas analysis was carried out, and optical microscopy was performed to evaluate pathological changes in the lung, and lung injury score was assessed. The count of white blood cells in bronchoalveolar lavage fluid (BALF) was determined. The levels of norepinephrine, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL 6 in BALF were measured with enzyme-linked immunosorbent assay. Immunocytochemistry was performed for the detection of alpha2A AR on inflammatory cells in BALF. RESULTS: When compared with the control group, the oxygenation index in the LPS group was significantly decreased, and white blood cell count, the lung histopathological scores, levels of norepinephrine and IL-6 as well as alpha2A AR expression on inflammatory cells in the BALF were dramatically increased at different time points, and the concentrations of TNF-alpha and IL 1beta were also increased except at 48 hours after LPS administration. The oxygenation index decreased while white blood cell count in BALF and the lung histopathological scores were obviously increased in the LPS + yohimbine group. The level of norepinephrine in BALF was increased at each time interval in the LPS + yohimbine group, and so did the levels of TNF-alpha, IL-1beta and IL-6 at 6 and 48 hours after LPS administration respectively. When compared with the LPS group, the oxygenation index, white blood cell count, the lung histopathological scores and the level of IL-6 in the LPS + yohimbine group were significantly improved at each time interval, and the concentrations of TNF-alpha and IL-1beta were also lower at 24 hours of LPS administration (all P < 0.05). Correlation analysis indicated the level of norepinephrine was related to the levels of TNF alpha, IL-1beta and IL-6 in the BALF and the lung histopathological scores (r = 0.703, r = 0.595, r = 0.487 and r = 0.688, respectively, P < 0.001) and the intensity scores of immunoreactivity to alpha2A AR on inflammatory cells were also associated with the levels of TNF-alpha, IL-1beta and IL-6 as well as the lung histopathologial scores (r = 0.803, r = 0.978, r = 0.716 and r = 0.808, respectively, P < 0.001). CONCLUSIONS: Yohimbine can inhibit TNF-alpha, IL-1beta and IL-6 overproduction and relieve the severity of pulmonary inflammation induced by endotoxin, which is maybe mediated by blockade of alpha2A AR on inflammatory cells. PMID- 21542969 TI - Silencing of high mobility group A1 enhances gemcitabine chemosensitivity of lung adenocarcinoma cells. AB - BACKGROUND: The high mobility group A1 (HMGA1) proteins are architectural transcription factors found to be overexpressed in lung adenocarcinoma. Lentivirus-mediated RNA interference (RNAi) technology is a powerful tool for silencing endogenous or exogenous genes in human cancer cells. Our preliminary study shows that gemcitabine inhibits growth of the human lung cancer cell line SPCA-1 and induces apoptosis, and this effect might link with down-regulation of HMGA1 expression. This study aimed to investigate the chemosensitivity change of the lung adenocarcinoma cells SPCA-1 after HMGA1 inhibition by lentivirus mediated RNAi. METHODS: We studied a highly malignant lung adenocarcinoma cell line (SPCA-1 cells). Lentiviral short-hairpin RNA (shHMGA1) expression vectors targeting HMGA1 were used for generation of lentiviral particles. After being transfected into the lung adenocarcinoma cell line SPCA-1, the expression of HMGA1 was determined by retrotranscriptase polymerase chain reaction (RT-PCR) and Western blotting. The effect of gemcitabine on proliferation of positive and negative cells was observed by methyl thiazolyl tetrazolium (MTT) assay and clonogenic survival assay. Apoptosis was observed by flow cytometery. Chemosensitivity to gemcitabine was determined by IC50 analysis. Caspase activity was quantitated by a caspase colorimetric protease assay kit. RESULTS: HMGA1 siRNA silenced its target mRNA specifically and effectively in SPCA-1 cells. The apoptotic rates of the scramble control group were (7.43 +/- 0.21)%, (11.00 +/- 0.20)%, and (14.93 +/- 0.31)%, and the apoptotic rates in the silenced group were (9.53 +/- 0.42)%, (16.67 +/- 0.45)%, and (25.40 +/- 0.79)% under exposure to 0.05, 0.5 and 5.0 ug/ml of gemcitabine (P < 0.05). The IC(50) of the silenced group was (0.309 +/- 0.003) ug/ml which was significantly lower than in the scramble control group, (0.653 +/- 0.003) ug/ml (P < 0.05). It reduced cancer cell proliferation and increased apoptotic cell death after being treated with gemcitabine compared with the scramble control group. HMGA1 silencing resulted in reduction in the phosphorylation of Akt, and promoted the activation of caspases 3, 8 and 9 upon exposure to gemcitabine. CONCLUSIONS: Lentivirus-mediated RNA interference of HMGA1 enhanced chemosensitivity to gemcitabine in lung adenocarcinoma cells. The mechanism may be associated with the PI-3K/Akt signal pathway. HMGA1 may represent a novel therapeutic target in lung cancer. PMID- 21542971 TI - Effects of aging on time course of neovascularization-related gene expression following acute hindlimb ischemia in mice. AB - BACKGROUND: Molecular analysis of neovascularization related genes by time course in response to ischemia has not been described in the context of aging. We aimed to provide a progressively deeper understanding of how aging compromises neovascularization. METHODS: Young (3-month) and old (18-month) C57Bl mice were subjected to left hindlimb ischemia. Necrosis score was evaluated in calf muscles. Calf muscles, peripheral blood, bone marrow were harvested at different time points. The expressions of matrix metalloproteiniase-9 (MMP9), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), stromal derived growth factor-1 (SDF1), hypoxia inducible factor-1alpha (HIF1alpha), VEGF receptor-1 (Flt1), VEGF receptor-2 (Flk1), angiopoietin-1 (Ang1), CD133, CD26 were detected by RT-PCR or Western blotting. White blood cells were counted in the peripheral blood. Gene expression data were compared by two-way analysis of variance. RESULTS: MMP9, HIF-1alpha and SDF-1 were more upregulated during acute ischemia in old vs. young mice, reflecting increased ischemia in aging mice. However VEGF and eNOS exhibited lower expression in old vs. young mice, despite greater ischemia intensity. Ang1 and Flk1 showed similar expression in old vs. young mice. MMP9 peaked earlier in peripheral blood in young vs. old mice. Concurrent decreasing CD26 and increasing CD133 expression in aging bone marrow suggest aging impairs progenitor cell mobilization, CONCLUSIONS: Our results indicate that a complex array of defects occur with aging that interfere with optimal neovascularization. These include potential impaired mobilization of progenitor cells to ischemic tissue, decreased levels of eNOS and VEGF and delayed responses to ischemia. PMID- 21542972 TI - E1A, E1B double-restricted adenovirus enhances the cytotoxicity and antitumor activity of gemcitabine to renal cell carcinoma. AB - BACKGROUND: Our previous studies have demonstrated potent oncolysis efficacy of the E1A, E1B double-restricted replication-competent oncolytic adenovirus AxdAdB 3 for treatment of bladder cancer. Here, we reported the feasibility and efficacy of AxdAdB-3 alone, or in combination with gemcitabine for treating renal cell carcinoma. METHODS: Cytopathic effects of AxdAdB-3 were evaluated in human renal cell carcinoma cell lines TOS-1, TOS-2, TOS-3, TOS-3LN, SMKT-R3, SMKT-R4 and ACHN, and in normal human renal proximal tubule epithelial cells (RPTEC). AxdAdB 3 induced down-regulation of the cell cycle was determined by flow cytometry. Combination therapies of AxdAdB-3 with gemcitabine were evaluated in vitro and in vivo on subcutaneous TOS-3LN tumors in a severe combined immunodeficiency disease (SCID) mouse model. RESULTS: AxdAdB-3 was potently cytopathic against the tested most renal cell carcinoma cell lines including TOS-2, TOS-3, TOS-3LN, SMKT-R3 and SMKT-R4, while normal human RPTEC were not destroyed. AxdAdB-3 effectively induced cell cycle S-phase entry. Combined therapy of AxdAdB-3 with gemcitabine demonstrated stronger antitumor effects in vitro and in vivo compared with either AxdAdB-3 or gemcitabine alone. CONCLUSION: AxdAdB-3 alone, or in combination with gemcitabine may be a promising strategy against renal cell carcinoma. PMID- 21542973 TI - Citation analysis of meta-analysis articles on posttraumatic stress disorder. AB - BACKGROUND: In the past two decades enormously scientific researches on posttraumatic stress disorder (PTSD) have been undertaken and many related meta analyses have been published. Citation analysis was used to get comprehensive perspectives of meta-analysis articles (MA articles) on PTSD for the purpose of facilitating the researchers, physicians and policy-makers to understand the PTSD. METHODS: MA articles on PTSD in any languages from January 1980 to March 2009 were included if they presented meta-analytical methods and received at least one citation recorded in the Web of Science (WoS). Whereas studies, in which any effect sizes of PTSD were not distinguished from other psychological disorders, were excluded. Citations to and by identified MA articles were documented basing on records in WoS. Citation analysis was used to examine distribution patterns of characteristics and citation impact of MA articles on PTSD. Canonical analysis was used to explore the relationship between the characteristics of MA articles and citation impact. RESULTS: Thirty-four MA articles published during 1998 and 2008 were identified and revealed multiple study topics on PTSD: 10 (29.4%) were about epidemiology, 13 (38.2%) about treatment or intervention, 6 (17.6%) about pathophysiology or neurophysiology or neuroendocrine, 3 (8.8%) about childhood and 2 (5.9%) about psychosocial adversity. Two articles cited most frequently with 456 and 145 counts were published in Journal of Consulting and Clinical Psychology by Brewin (2000) and Psychological Bulletin by Ozer (2003), respectively. Mean cited count was 7.48 +/ 10.56 and mean age (year 2009 minus article publication year) was (4.24 +/- 2.91) years. They had been cited approximately by 67 disciplines and by authors from 42 countries or territories. Characteristics of meta-analysis highly correlated with citation impact and reflected by canonical correlation of 0.899 (P < 0.000 01). CONCLUSIONS: The age of MA articles predicted their citation impact. Citation analysis would serve to capture the global perspectives and topics of MA articles on PTSD. PMID- 21542974 TI - Clinical characteristics and therapeutic strategies of atypical meningioma. AB - BACKGROUND: Atypical meningioma accounts for about 4.7% to 7.2% of all kinds of meningiomas, which is invasive with a relatively high recurrence and mortality. The objective of this study was to investigate the clinical manifestations and therapeutic strategies of atypical meningioma. METHODS: A total of 74 patients who underwent surgical treatment and pathologically confirmed for atypical meningioma in Neurosurgery Department of Beijing Tiantan Hospital from January 2003 to December 2008 were enrolled in this study. The characteristics of the tumors as well as therapeutic regimens and follow-up data were reviewed. After surgery, 56 patients underwent radiotherapy. Patients were followed up for about 3.5 years (range, 0.5 - 6.0 years), and 58 patients completed follow-up. RESULTS: Of the 58 patients who completed follow-up, good recovery was found in 30, neurological dysfunction in 15, and death in 13. Of the 58 patients, 21 had recurrent meningioma and 18 underwent a second surgery. CONCLUSIONS: Atypical meningioma is difficult to manage, with a high recurrence rate and poor survival. The extent of tumor resection and histological grade are the key determinants of outcome. Radiation therapy can be used as an adjunctive treatment after total or partial resection. PMID- 21542975 TI - Patterns in the occurrence and development of tumors. AB - Although we have made great progress in understanding tumor pathogenesis through studies on gene mutation and cancer stem cells, the clinical outcome continues to be unfavorable for many cancers. The biological characteristics of cancers including autonomous proliferation, invasion, metastasis, and post-treatment recurrence result from interactions between cancers and their microenvironment, which involves complex molecular interactions. However, the patterns underlying these complex mechanisms are still unclear. In this review, several potential patterns in the occurrence and development of cancers were elucidated. The core relationship between a tumor and its host microenvironment is the nutritional and signal interactions between cancer stem cells and endothelial cells. The nutritional interaction between the cancer and the host triggers the invasion and metastasis of cancers; the imbalance between tissue responses of cancer stem cells and the feedback regulation of self-renewal or post-injury repair leads to the autonomous proliferation of cancers. Cancers can restore the growth balance and maintain homeostasis, depending on residual nutritional factors, and these abilities are the determinants of therapeutic efficacy. These findings have been beneficial to developing novel strategies for cancer therapies. PMID- 21542976 TI - Successful treatment with biventricular pacing in a patient with hypertrophic obstructive cardiomyopathy. AB - We report the effects of biventricular pacing in a patient with hypertrophic obstructive cardiomyopathy (HOCM) refractory to medical therapy. A 58-year-old man with HOCM had suffered from dyspnea, chest pain and palpitation for 5 years. Cardiac catheterization showed a left ventricular outflow tract (LVOT) gradient of 80 mmHg. He refused septal myomectomy and the septal ablation was not available. Based on intraoperative pressure measurements, he was implanted with biventricular pacing and LVOT gradient decreased to 10 mmHg. During the follow-up period of 6 months, the patient's symptoms were markedly improved. Biventricular pacing may be an alternative therapy for patients with HOCM. PMID- 21542977 TI - Twin delivery of a 46,XY gonadal dysgenetic woman following vitrified oocytes donation. AB - A 46,XY gonadal dysgenetic woman gave birth to two healthy girls following vitrified oocytes donation. The loss of SRY gene was considered as the cause of this patient. Although similar cases have been reported about pregnancies of 46,XY pure gonadal dysgenetic women, successful delivery from vitrified oocytes has been hardly reported yet. Oocytes vitrification technique provides a beneficial way by saving superfluous oocytes from the pregnancy patients to these women who need. PMID- 21542978 TI - Subcutaneous implantation of benign thyroid tissue: a rare complication after thyroidectomy. AB - Subcutaneous implantation of benign thyroid tissue is a rare complication of thyroid surgery. Here the authors report two cases of subcutaneous implantation of benign thyroid tissue following conventional thyroid surgery. The diagnosis and differential diagnosis of cervical subcutaneous thyroid tissue implantation, and their clinical pathological characteristics are retrospectively investigated. The mechanism of the implantation process is analyzed. The management of patient with cervical subcutaneous soft tissue implantation is also discussed. PMID- 21542979 TI - Temporal lobe epilepsy with hypothalamic hamartoma: a rare case. AB - Refractory gelastic seizure is one of the most common clinical manifestations in patients with hypothalamic hamartoma (HH) and HH is usually regarded as the epileptogenic focus. A young female patient with a small HH and refractory seizures is reported here. However, both the seizure semiology and results of electroencephalogram monitoring indicated the right temporal region was the epileptogenic focus. Thus a standard right anterior temporal lobectomy was performed while the hamartoma preserved. There was a marked improvement in both seizure frequency and quality of life during a 13-month follow-up. The outcome supported the concept that independent epileptogenic focus outside of the hypothalamus might occur in patients with HH. PMID- 21542980 TI - An independent prognostic factor for heart failure: sympathetic hyperactivity. PMID- 21542981 TI - Criteria for microscopic review following automated hematology analysis. PMID- 21542982 TI - Retraction. Tenascin-C as a prognostic biomarker in osteosarcoma? Chinese Medical Journal 2009; 122(22): 2737-2743. PMID- 21542983 TI - Situation of low vision and blindness in China and their prevention. PMID- 21542984 TI - Comparison of FP-7 and S-2 Ahmed glaucoma valve implantation in refractory glaucoma patients for short-term follow-up. AB - BACKGROUND: Ahmed glaucoma valves (AGV) has been used for decades, but there is no detailed report about the efficacy of AGV in Chinese glaucoma patients. This study aimed to compare the intraocular pressure (IOP) lowering efficacy and side effects of S-2 polypropylene and PF-7 silicone AGV implantation in Chinese refractory glaucoma patients. METHODS: Patients were divided into S-2 model AGV group and FP-7 model AGV group. The complete and qualified surgical success rate, change of IOP, number of anti-glaucoma medications used and postoperative complications were recorded and analyzed. RESULTS: Average follow-up time was comparable between two groups. IOP was reduced from (37.9 +/- 12.7) mmHg preoperatively to (17.3 +/- 5.3) mmHg at the last follow-up in S-2 group and reduced from (39.9 +/- 14.4) mmHg to (17.7 +/- 4.9) mmHg in FP-7 group. Anti glaucoma medications were reduced from 3.8 +/- 0.2 to 1.5 +/- 0.2 in S-2 group, and 3.5 +/- 0.2 to 0.7 +/- 0.2 in FP-7 groups. The cumulative success rates were comparable in two groups, which were 61.2% and 72.1% in S-2 group and FP-7 group respectively. When IOP reduction criteria was used, complete success rates were 30.6% and 51.2% for S-2 and FP-7 groups, and qualified success rates were 86.1% and 92.7% separately. In both groups, the major complication was hypotony, and the previous trabeculectomy of patients was the major risk factor for surgery failure. CONCLUSIONS: In this short-term retrospective study, S-2 AGV is showed at least as effective as FP-7 AGV in IOP reduction, but associated with higher rate of complications. Previous trabeculectomy is a principle risk factor for AGV implantation failure. These clinical outcomes are important for converting use of the FP-7 silicon AGV in Chinese refractory glaucoma patients. PMID- 21542985 TI - Cytomegalovirus retinitis associated with acquired immunodeficiency syndrome. AB - BACKGROUND: Cytomegalovirus (CMV) retinitis is the most severe intraocular complication that results in total retinal destruction and loss of visual acuity in patients with acquired immunodeficiency syndrome (AIDS). This study aimed to investigate the fundus characteristics, systemic manifestations and therapeutic outcomes of CMV retinitis associated with AIDS. METHODS: It was a retrospective case series. CMV retinitis was present in 39 eyes (25 patients). Best corrected visual acuities, anterior segment, fundus features, fundus fluorescence angiography (FFA) and CD4(+) T-lymphocyte counts of the patients with CMV retinitis associated with AIDS were analyzed. Intravitreal injections of ganciclovir (400 ug) were performed in 4 eyes (2 patients). RESULTS: Retinal vasculitis, dense, full-thickness, yellow-white lesions along vascular distribution with irregular granules at the border, and hemorrhage on the retinal surface were present in 28 eyes. The vitreous was clear or mildly opaque. Late stage of the retinopathy was demonstrated in 8 eyes characterized as atrophic retina, sclerotic and attenuated vessels, retinal pigment epithelium (RPE) atrophy, and optic nerve atrophy. Retinal detachment was found in 3 eyes. The average CD4(+) T-lymphocyte count in peripheral blood of the patients with CMV retinitis was (30.6 +/- 25.3) * 10(6)/L (range, (0 - 85) * 10(6)/L). After intravitreal injections of ganciclovir, visual acuity was improved and fundus lesions regressed. CONCLUSIONS: CMV retinitis is the most severe and the most common intraocular complication in patients with AIDS. For the patients with yellow-white retinal lesions, hemorrhage and retinal vasculitis without clear cause, human immunodeficiency virus (HIV) serology should be performed. Routine eye examination is also indicated in HIV positive patients. PMID- 21542986 TI - Expression of adenosine receptors in human retinal pigment epithelium cells in vitro. AB - BACKGROUND: Adenosine receptors (ADORs) have been reported to play a role in experimental myopia. This study aimed to determine the distribution of ADORs in human retinal pigment epithelium (RPE) cells cultured in vitro. METHODS: Human RPE cells (cell line D407) were cultured in vitro. ADOR mRNA in RPE was detected by reverse transcription polymerase chain reaction. ADOR protein expression in RPE was confirmed by Western blotting analysis of cell lysates. Confocal fluorescence microscopy was used to study the subcellular distribution of ADORs. RESULTS: All four subtypes of ADORs mRNA and protein were expressed in human RPE. This was confirmed by Western blotting analysis. The ADOR subtypes were differently distributed within the cells. ADORA1 was expressed in nucleus, perinucleus and cytoplasm of RPE. ADORA2A was concentrated mainly in one side of the perinucleus and cytoplasm of RPE. ADORA2B was strongly expressed in the nucleus, perinucleus and the cytoplasm, and ADORA3 was expressed weakly in the cytoplasm of RPE. CONCLUSIONS: ADORs are expressed in human RPE. The different distribution at the subcellular level suggests different functions of ADOR subtypes. PMID- 21542987 TI - Gene expression profile changes caused by the dysfunction of Mer during retinal pigment epithelium phagocytosis. AB - BACKGROUND: Studies indicated that Mer might be the main contributor to the specific internalization of photoreceptor outer segments (POS) in retinal pigment epithelium (RPE). It is very important to understand the mechanism of POS phagocytosis under the pathway of Mer and its ligands. The objective of this study was to identify changes in gene expression profiles caused by Mer gene knockout (Mer-/-) during phagocytosis of POS in RPE. METHODS: RPE from both Mer-/ and wild-type (WT) mice were isolated and cultured to the 3rd passage. POS were subjected to culture medium with 20 nmol/L Gas6 and protein S to activate specific mer-mediated phagocytosis. RPE phagocytosis was evaluated by phagocytosis assays and differential gene expression identified by microarray at 3 and 12 hours; the 0-hour time point served as the control. Three independent samples for each Mer-/- or WT RPE were subjected to the same protocol of microarray. Five genes were confirmed by real-time quantitative PCR (QPCR). RESULTS: The Mer-/- RPE had less internalized POS than WT RPE after both 3 and 12 hours in phagocytosis assay. Compared to WT RPE and the 0-hour control, 38 and 45 different known genes were increased and 68 and 59 known genes were decreased in Mer-/- RPE after 3 and 12 hours, respectively. Abnormal POS phagocytosis in Mer-/ RPE was associated with significant gene expression changes in, for example, signal transduction (WNT, MAPK), phagocytosis (Vav3, Hsd11b1), cytoskeleton components (Myo7a), and metabolism, in a time-specific manner. QPCR results showed Vav3, Hsd11b1, Myo7a, Rtn2 and Itga8 in those independent samples were consistent with microarray. CONCLUSION: Gene expression profiles modulated in a time-specific manner in Mer-/- RPE indicate a possible internalization mechanism for abnormal POS phagocytosis, which gives insight into the mechanism of retinitis pigmentosa caused by the mutation of MerTK in humans. PMID- 21542989 TI - Fluorescence in situ hybridization in uncultured amniocytes for detection of aneuploidy in 4210 prenatal cases. AB - BACKGROUND: Almost all reported fluorescence in situ hybridization (FISH) kits for prenatal diagnosis use probes from foreign (non-Chinese) countries. The aim of this study was to analyze the reliability of domestic (Chinese) FISH probe sets to detect aneuploidies of chromosomes 13, 18, 21, X, and Y related to prenatal diagnosis in 4210 cases. METHODS: Cytogenetic karyotyping was carried out as a standard prenatal diagnostic test, and amniotic fluid cell interphase FISH analysis was performed using two sets of probes (centromeric probes for chromosomes 18, X, and Y, and locus-specific probes for chromosomes 13 and 21) provided by GP Medical Technologies, Beijing, China. Then we compared the two results and found the performance characteristics for informative FISH results of aneuploidies by the domestic kit probes. RESULTS: In 4210 cases, 4126 cases generated karyotype results and 133 abnormal karyotypes (including 97 aneuploidies) were found. The FISH results of 98 cases (among them, 31 cases gave normal cytogenetic results) were uninformative. The rate of abnormal cases was 3.2% (133/4126). For the abnormal karyotypes, the rate of aneuploidy was 72.9% (97/133). Among the 97 aneuploidies, there were 58 cases of trisomy 21 (58/97, 59.8%), four cases of trisomy 13, 23 cases of trisomy 18, and 12 cases of sex chromosomal aneuploidies. The total concordance of the two methods was 97.9% (95/97; two cases were mosaics that had a low percentage of abnormal cells), and the concordance of trisomy 21, 13, and 18 by the two methods was 100%. CONCLUSIONS: The two sets of the domestic FISH kit probes are reliable for prenatal diagnosis. The results demonstrate that FISH is a rapid and accurate clinical method for prenatal identification of chromosome aneuploidies. PMID- 21542988 TI - Effects of inhaled nitric oxide in neonatal hypoxemic respiratory failure from a multicenter controlled trial. AB - BACKGROUND: Hypoxemic respiratory failure (HRF) is one of the most common causes for neonatal infants requiring aggressive respiratory support. Inhaled nitric oxide (iNO) has been established routinely as an adjunct to conventional respiratory support in developed countries. The aim of this study was to investigate effects of iNO in neonates with HRF in resource limited condition with no or limited use of surfactant, high frequency oscillatory ventilation (HFOV) and extracorporeal membrane oxygenation. METHODS: A non-randomized, open, controlled study of efficacy of iNO was conducted over 18 months. Eligible term and near-term neonates from 28 hospitals with HRF (oxygenation index > 15) were enrolled prospectively into two groups as either iNO or control. Oxygenation improvement and mortality as primary endpoint were determined in relation with dosing and timing of iNO, severity of underlying diseases, complications and burden. Intention-to-treat principle was adopted for outcome assessment. Response to iNO at 10 or 20 parts per million (ppm) was determined by oxygenation in reference to the control (between-group) and the baseline (within-group). RESULTS: Compared to 93 controls, initial dose of iNO at 10 ppm in 107 treated infants significantly improved oxygenation from first hour (P = 0.046), with more partial- and non-responders improved oxygenation with subsequent 20 ppm NO (P = 0.018). This effect persisted on days 1 and 3, and resulted in relatively lower mortalities (11.2% vs. 15%) whereas fewer were treated with surfactant (10% vs. 27%), HFOV (< 5%) or postnatal corticosteroids (< 10%) in both groups. The overall outcomes at 28 days of postnatal life in the iNO-treated was not related to perinatal asphyxia, underlying diseases, severity of hypoxemia, or complications, but to the early use of iNO. The cost of hospital stay was not significantly different in both groups. CONCLUSIONS: With relatively limited use of surfactant and/or HFOV in neonatal HRF, significantly more responders were found in the iNO-treated patients as reflected by improved oxygenation in the first three days over the baseline level. It warrants a randomized, controlled trial for assessment of appropriate timing and long-term outcome of iNO. PMID- 21542990 TI - Comparison of drug eluting stent implantation with coronary artery bypass surgery in the treatment of patients with chronic total occlusion and multiple vessel disease. AB - BACKGROUND: In patients with chronic total occlusion (CTO) and multivessel coronary artery disease, the comparison of surgical and the percutaneous revascularization strategies has rarely been conducted. The aim of this study was to compare long term clinical outcomes of drug eluting stent (DES) implantation with coronary artery bypass surgery (CABG) in the patients with CTO and multivessel disease. METHODS: From a prospective registry of 6000 patients in our institution, we included patients with CTO and multivessel coronary artery disease who underwent either CABG (n = 679) or DES (n = 267) treatment. Their propensity risk score was used for adjusting baseline differences. RESULTS: At a median follow-up of three years, propensity score adjusted Cox regression analysis showed that the rate of major adverse cardiac cerebrovascular events (MACCE) was lower in CABG group (12.7% vs. 24.3%, hazard ratio (HR) 1.969, 95%CI 1.219 - 3.179, P = 0.006) mainly due to lower rate of target vessel revascularization in CABG group than in DES group (3.1% vs. 17.2%, HR 16.14, 95%CI 5.739 - 45.391, P < 0.001). The incidence of cardiac death or myocardial infarction (composite end point) was not significantly different between these two groups. On multivariate analysis, the significant predictors of MACCE were only the type of revascularization. Age, left ventricular ejection fraction (LVEF), and complete revascularization were identified as significant predictors of composite end points. CONCLUSIONS: Our study shows that in patients with CTO and multivessel coronary disease, DES can offer comparable long term outcomes in cardiac death and myocardial infraction free survival in comparison with CABG. However, there is an increased rate of MACCE which results from more repeat revascularizations. Obtaining a complete revascularization is crucial for decreasing adverse cardiac events. PMID- 21542991 TI - Laparoscopic splenectomy for immune thrombocytopenic purpura at a teaching institution. AB - BACKGROUND: High anatomic location, fragility, and generous blood supply of the spleen makes laparoscopic splenectomy (LS) difficult to master, and few patients need splenectomy for benign disorders. The aim of this research was to assess operative outcomes and hematological results of a large series of patients treated with LS for chronic immune thrombocytopenic purpura (ITP) and to determine which clinical variables predict favorable hematological outcome. METHODS: LS was successfully performed for 154 patients with chronic ITP from September 1999 to April 2009 at the First Affiliated Hospital of Sun Yat-sen University. Operative outcomes were assessed retrospectively. Long-term follow-up data were obtained from outpatient medical records and phone interviews. Clinical and laboratory variables (including gender, age, disease duration before surgery, previous response to steroids, preoperative platelet count, and postoperative peak platelet count) were evaluated by univariate analysis to identify potential predictors of hematological outcome. Multivariate Logistic regression model was used to determine independent predictors of hematological outcome. RESULTS: One patient died from subphrenic abscess and postoperative sepsis. The overall major morbidity rate was 8.4%. None of the patients required a second surgery for complications. Of the 127 patients available for a mean follow-up of 43.6 months (range 9 - 114 months), the overall initial response (i.e., at two months after LS) and long-term response to LS were achieved in 89.0% and 80.3%, respectively. Five patients (3.9%) developed pneumonia 3 - 35 months after LS. Univariate analysis showed a significant difference in mean age between responders (29.1 years) and nonresponders (38.8 years; P < 0.05). Patients who responded to steroid therapy had better hematological outcome than those who did not respond (P < 0.05). Compared to nonresponders, responders to LS had a significantly higher postoperative peak platelet count (404 * 10(9)/L versus 213 * 10(9)/L, P < 0.001). Multivariate Logistic regression analysis identified postoperative peak platelet count as the only independent predictor of favorable response to LS (P < 0.001). CONCLUSIONS: LS is a safe and effective treatment for chronic ITP. Postoperative peak platelet count may serve as a major predictor of long-term response. PMID- 21542992 TI - Factors affecting the long-term renal allograft survival. AB - BACKGROUND: In the past decades, the one-year graft survival of cadaveric renal allografts has been markedly improved, but their long-term survival has not kept pace. The attrition rate of renal allografts surviving after one year remains almost unchanged. The causes for late graft loss are multiple. The aim of this study was to analyze the predictive factors that impact long-term survival of grafts after kidney transplantation. METHODS: We retrospectively analyzed 524 kidney transplantation patients who were treated in our hospital between January 1991 and January 2000, including 254 patients who had lived more than 10 years with normal graft function (long survival group), and 270 cases whose renal graft had survived less than 10 years (control group). Specifically, we analyzed 10 factors that may potentially affect graft survival by both univariate and Logistic model multivariate analyses to pinpoint the independent risk factors. RESULTS: Univariate analyses showed that no significant differences existed in the age or gender of recipients, dialysis time, lymphotoxin levels, or cold ischemia time between the two groups. However, the ratio of delayed graft function and acute rejection, and the uric acid levels of patients in the long survival group were significantly lower than those in the control group (P < 0.01). Furthermore, we found that the concentration of cyclosporin A at one year after transplantation and the histocompatibility antigen match of donor recipients for patients within the long survival group were significantly higher than those in the control group (P < 0.01). Furthermore, multivariate analyses showed that these four factors were independent risk factors that impact patient survival. CONCLUSIONS: The ratios of delayed graft function and acute rejection, the concentration of cyclosporin A at one year after transplantation, and serum uric acid levels are very important factors that affect the long-term survival of renal grafts. PMID- 21542993 TI - Clinical experience in the use of marginal donor hearts. AB - BACKGROUND: Although heart transplantation has become a standard therapy for end stage heart disease, there are few published studies regarding the use of transplant organs from marginal donors. Here we describe the clinical outcome we have obtained using marginal donor hearts. METHODS: We analyzed 21 cases of orthotopic heart transplantation for end-stage heart disease performed in our department between September 2008 and July 2010. Of these patients, six received hearts from marginal donors and the remainder received standard-donor hearts. The two groups were compared in terms of both mortality and the incidence of perioperative complications such as infection, acute rejection, and right heart insufficiency. RESULTS: The 1-year survival rate of both groups was 100%. Only one death was recorded in standard-donor group during follow-up. Patients who received marginal donor hearts (83%) experienced more early complications than did the standard-donor-heart group (13%), but the mortality of the two groups was the same. The duration of post-ICU stay was greater in the marginal donor group than in the standard-donor group, (35.5 +/- 17.4) days and (21.7 +/- 2.6) days, respectively (P < 0.05). CONCLUSIONS: The use of marginal donor hearts increases the number of patients who can receive and benefit from transplants. However, it may introduce an increased risk of early complications, thus care should be taken both in the choice of patients who will receive marginal donor hearts and in the perioperative treatment of those for whom the procedure is performed. PMID- 21542994 TI - Distribution of serum prostate-specific antigen in Chinese healthy men: a population-based study. AB - BACKGROUND: The morbidity and mortality of prostate cancer have been increasing rapidly in recent China. There were few studies investigating prostate-specific antigen (PSA) values ranges in the healthy Chinese population. We performed this study to determine the distribution of serum PSA in a large healthy Chinese population. METHODS: From January 2001 to May 2008, 11 150 healthy Chinese men aged 30 - 79 years came to our hospital for routine health check-up. All subjects without a previous diagnosis of prostate cancer, a history of prostate surgery, or urogenital tract infection were proposed to undergo systematic serum PSA measurement and digital rectal examination (DRE). Men with normal DRE and PSA <= 4.0 ng/ml and those PSA > 4.0 ng/ml or abnormal DRE but without adverse findings on prostate biopsy were included (n = 9358). Age and serum PSA concentration were recorded and correlated through Logistic regression analysis. RESULTS: The 95th percentile serum PSA concentration was 1.89 ng/ml for men aged 30 to 39 years, 2.19 ng/ml for men aged 40 to 49 years, 2.88 ng/ml for men aged 50 to 59 years, 4.42 ng/ml for men aged 60 to 69 years, and 6.52 ng/ml for men aged 70 to 79 years. The serum PSA concentration correlated with age (P < 0.0001) with an annual increase of 0.97% for men in 40 years, 1.58% for men in 50 years, 3.04% for men in 60 years, and 3.99% for men in 70 years. CONCLUSIONS: The serum PSA level correlates directly with age in Chinese men older than 40 years, not in Chinese men younger than 40 years old. Chinese men have lower PSA level compared with white men above 60 years of age, not in those under 60 years of age. PMID- 21542995 TI - Microwave induces apoptosis in A549 human lung carcinoma cell line. AB - BACKGROUND: Microwaves have other biological effects on cancer as well besides killing tumor cells by coagulation. Some studies showed that microwaves may induce apoptosis in some tumor cells. The apoptotic effect of microwaves may help in clinic to remove residual malignant cells nearby the primary lesion and avoid relapse subsequently. However, there is little evidence on this subject from lung cancer. We studied the effect of microwaves on inducing apoptosis in the human lung carcinoma cell line A549 cells, aiming to identify its effect on apoptosis. METHODS: A549 cells were radiated by various intensities and durations of microwaves. Apoptosis induction in A549 cells was analyzed by morphological observations, tetrazolium blue color method (MTT) assays, flow cytometry, immunohistochemistry, and image analyses. RESULTS: Morphological changes in A549 cells, including cell shrinking and nuclear pyknosis, were observed after microwave radiation. Microwaves significantly inhibited metabolic activities and induced apoptosis in A549 cells. The results of the MTT assay showed a significant decrease of cell activities in all the radiation groups compared with the normal control (P < 0.01). The low point of cell activities often appeared at 6 - 12 hours after radiation. Apoptosis was also confirmed by flow cytometry. The early stage apoptotic rate reached 6.10% - 17.98% and the advanced stage apoptotic rate + necrosis rate reached 8.04% - 44.06% at 6 hours after microwave irradiation, in contrast to 2.32% and 4.10% in the respective control groups. Down-regulation of Bcl-2 expression and up-regulation of p53 expression were observed by immunohistochemistry after radiation. In most treated groups, the down-regulation of Bcl-2 expression reached its lowest level at 3 - 6 hours after radiation (integrated optical density (IOD)-6 hours: 2.13 +/- 0.08 - 5.14 +/- 0.13 vs. control: 5.79 +/- 0.10, P < 0.01) and the up-regulation of P53 expression peaked at about 3 hours (IOD-3 hours: 2.61 +/- 0.13 - 8.07 +/- 0.11 vs. control: 1.29 +/- 0.07, P < 0.01). Cell damage, apoptosis, and protein expression levels in the samples differed depending on the radiation intensity and duration. CONCLUSIONS: Microwaves can promote apoptosis in A549 cells. The effect depends on the duration and dosage of microwave radiation. Bcl-2 and p53 proteins may be involved in the apoptotic process of A549 cells induced by microwaves. PMID- 21542996 TI - Efficiently tracking of stem cells in vivo using different kinds of superparamagnetic iron oxide in swine with myocardial infarction. AB - BACKGROUND: Superparamagnetic iron oxide (SPIO) particles have shown much promise as a means to visualize labeled cells using molecular magnetic resonance imaging (MRI). Micrometer-sized superparamagnetic iron oxide (MPIO) particles and nanometer-sized ultrasmall superparamagnetic iron oxide (USPIO) are two kinds of SPIO widely used for monitoring stem cells migration. Here we compare the efficiency of two kinds of SPIO during the use of stem cells to treat acute myocardial infarction (AMI). METHODS: An AMI model in swine was created by 60 minutes of balloon occlusion of the left anterior descending coronary artery. Two kinds of SPIO particles were used to track after intracoronary delivered 10(7) magnetically labeled mesenchymal stem cells (MR-MSCs). The distribution and migration of the MR-MSCs were assessed with the use of 3.0T MR scanner and then the results were confirmed by histological examination. RESULTS: MR-MSCs appeared as a local hypointense signal on T2*-weighted MRI and there was a gradual loss of the signal intensity after intracoronary transplantation. All of the hypointense signals in the USPIO-labeled group were found on T2*-weighted MRI, contrast to noise ratio (CNR) decreased in the MPIO-labeled group (16.07 +/- 5.85 vs. 10.96 +/- 1.34) and USPIO-labeled group (11.72 +/- 1.27 vs. 10.03 +/- 0.96) from 4 to 8 weeks after transplantation. However, the hypointense signals were not detected in MPIO-labeled group in two animals. MRI and the results were verified by histological examination. CONCLUSIONS: We demonstrated that two kinds of SPIO particles in vitro have similar labeling efficiency and viability. USPIO is more suitable for labeling stem cells when they are transplanted via a coronary route. PMID- 21542997 TI - Correlation between coagulation function, tumor stage and metastasis in patients with renal cell carcinoma: a retrospective study. AB - BACKGROUND: The coagulation function in carcinoma patients is abnormal, but in renal cell carcinoma the extent and relationships of coagulation function remain unclear. This study retrospectively investigated the relationships between coagulation function, clinical stage and metastasis in patients with renal cell carcinoma. METHODS: A total of 350 consecutive patients admitted to our Urology Department from 2004 to 2010 were diagnosed with renal cell carcinoma by histopathologic examination and were included in this study. A total of 231 cases of renal benign tumors were considered as the control group. Fibrinogen, prothrombin time, activated partial thromboplastin time and international normalized ratio were evaluated in all subjects. Tumor size, clinical stage, lymph node metastasis, and distant metastasis were evaluated using radiologic imaging, intraoperative findings, and histological studies. RESULTS: The preoperative plasma fibrinogen levels of patients with renal cell carcinoma ((383.9 +/- 146.7) mg/dl) were significantly higher than those of the control group ((316.7 +/- 62.0) mg/dl) (P < 0.01). We divided the renal cell carcinoma group into stages Ia, Ib, II, III, and IV. The fibrinogen values were (315.6 +/- 64.6) mg/dl, (358.3 +/- 91.1) mg/dl, (465.6 +/- 164.7) mg/dl, (500.0 +/- 202.1) mg/dl, and (585.8 +/- 179.7) mg/dl, respectively. There were no significant differences in fibrinogen values between stage Ia and control groups. However, results of other stages showed significant differences when compared to control group values (P < 0.01). Using the cutoff value of 440 mg/dl, which defines hyperfibrinogenemia, plasma fibrinogen levels had a positive predictive value of 39.8% and a negative predictive value of 93.3% for predicting distant metastasis, with a sensitivity of 64.7% and specificity of 83.3%. CONCLUSIONS: Preoperative plasma fibrinogen levels are elevated in patients with renal cell carcinoma with distant metastasis or lymph node metastasis. Potential metastasis is more likely if the tumor size larger than 4 cm. Increased preoperative plasma fibrinogen levels, especially hyperfibrinogenemia, may be an indicator of metastasis. PMID- 21542998 TI - Use of the Attain Select II catheter delivery system to improve. AB - BACKGROUND: Despite technical advances in tools used to facilitate implantation of cardiac resynchronization therapy (CRT) devices, there are many hurdles related mainly to the variation in the anatomy of the coronary veins. One such difficulty is the presence of a very sharply-angulated or tortuous of the lateral or posterolateral cardiac vein. METHODS: Totally 44 patients, 28 males and 16 females, with congestive heart failure and intraventricular conduction delay were studied retrospectively. There were 23 patients who had left ventricular (LV) lead implantation using standard techniques and equipment. For the other 21 patients with LV lead implantation we used the Attain Select II catheter delivery system. The patients were seen every 3 - 6 months for 12 months and the efficacy of the primary procedure, LV lead implantation time, procedure and fluoroscopy time and the complications associated with the two techniques were evaluated. RESULTS: There were no significant differences in the age, gender, New York Heart Association (NYHA) functional class, ischemic etiology, QRS duration, left ventricular ejection fraction, left ventricular end-diastolic diameter, left ventricular end-systolic diameter and LV dyssynchrony between the two groups. The LV lead implantation time, procedure time and fluoroscopy time were significantly shorter in the group using the Attain Select II catheter delivery system; LV lead implantation time from (51 +/- 7) minutes to (40 +/- 7) minutes (P < 0.001), procedure time from (143 +/- 17) minutes to (124 +/- 18) minutes (P = 0.001), and fluoroscopy time from (45 +/- 7) minutes to (35 +/- 6) minutes (P < 0.001). A successful procedure of LV lead implantation was significantly improved from 17/23 (74%) patients using the standard techniques and equipment, to 20/21 (95.3%) patients using the Attain Select II catheter delivery system (P = 0.06) CONCLUSION: It is feasible and safe to implant LV leads through the coronary sinus using the Attain Select II catheter delivery system. PMID- 21542999 TI - Effect of pre-transplantation hemoglobin concentration on prognosis of renal transplant recipients. AB - BACKGROUND: For the renal transplant recipients, anemia is one of the common complications and becomes a major medical issue before transplantation. Haemoglobin (Hb) is used as a prognostic indicator, although the optimal pre transplantation Hb concentration associated with positive prognosis is still controversial. The aim of this study was to detect the optimal Hb concentration on predicting the graft survival and function. METHODS: A retrospective cohort study was conducted by reviewing the medical records of the patients who received renal transplantations at our center from January 2004 to June 2008. Patients were divided into two groups: high Hb group (>= 100 g/L, n = 79) and low Hb group (< 100 g/L, n = 63). There was no significant difference between the two groups regarding sex, age, blood type and tissue types. Renal function among the two groups was measured and compared. Panel reacting antigens (PRA) of all the recipients were negative. The effect of preoperative hemoglobin concentration on the postoperative renal function recovery in both groups was further analyzed. RESULTS: A total of 14 acute rejection episodes occurred, including 5 patients in the high Hb group (7.9%) and 9 in the low Hb group (11.4%, P > 0.05). The serum creatinine level at one-year post-transplantation of the low Hb group was significantly higher than that of the high Hb group ((117.8 +/- 36.3) umol/L vs. (103.1 +/- 35.5) umol/L, P < 0.05). For one-year actuarial patient and graft survival, incidence of delayed graft function (DGF), serum creatinine concentrations at 1, 3, 6 months post-transplantation, the incidence of cytomegalovirus (CMV) infection, post-transplantation anemia (PTA) and post transplantation diabetes mellitus (PTDM) of both groups, there were no statistically significant differences. CONCLUSION: Pre-transplantation Hb concentration has significant effect on one-year creatinine concentration, but can not significantly affect acute rejection episodes, DGF, PTA, CMV infection and PTDM. PMID- 21543000 TI - Spleen-preserving distal pancreatectomy with conservation of the spleen vessels. AB - BACKGROUND: Distal pancreatectomy traditionally included splenectomy; the spleen, however, is an important organ in the immunologic defense of the host and is worthy of preservation. The aim of this research was to study the feasibility, safety and clinical effects of spleen and splenic vessel-preserving distal pancreatectomy. METHODS: A retrospective review was performed for 26 patients undergoing distal pancreatectomy for benign or low grade malignant disease with splenectomy (n = 13) or splenic preservation (n = 13) at the First Hospital of Sun Yat-sen University and Guangdong General Hospital in Southern China from May 2002 to April 2009. RESULTS: All 26 pancreatectomies with splenectomy or splenic preservation were performed successfully. There was no statistically significant difference between two groups in mean operative time ((172 +/- 47) minutes vs. (157 +/- 52) minutes, P > 0.05), intraoperative estimated blood loss ((183 +/- 68) ml vs. (160 +/- 51) ml, P > 0.05), incidence of noninfectious and infection complication and mean length of postoperative hospital stay ((10.1 +/- 2.2) days vs. (12.1 +/- 4.6) days, P > 0.05). The platelet counts examined one week after operation were significantly higher in the distal pancreatectomy with splenectomy group than the other group ((37.3 +/- 12.8) * 10(9)/L vs. (54.7 +/- 13.2) * 10(9)/L, P < 0.05). CONCLUSIONS: Spleen-preserving distal pancreatectomy appears to be a feasible and safe procedure. In selected cases of benign or low-grade malignant disease, spleen-preserving distal pancreatectomy is recommended. PMID- 21543001 TI - Berberine potentizes apoptosis induced by X-rays irradiation probably through modulation of gap junctions. AB - BACKGROUND: Clinical combination of some traditional Chinese medical herbs, including berberine, with irradiation is demonstrated to improve efficacy of tumor radiotherapy, yet the mechanisms for such effect remain largely unknown. The present study investigated the effect of berberine on apoptosis induced by X rays irradiation and the relation between this effect and gap junction intercellular communication (GJIC). METHODS: The role of gap junctions in the modulation of X-rays irradiation-induced apoptosis was explored by manipulation of connexin (Cx) expression, and gap junction function, using oleamide, a GJIC inhibitor, and berberine. RESULTS: In transfected HeLa cells, Cx32 expression increased apoptosis induced by X-rays irradiation, while inhibition of gap junction by oleamide reduced the irradiation responses, indicating the dependence of X-rays irradiation-induced apoptosis on GJIC. Berberine, at the concentrations without cytotoxicity, enhanced apoptosis induced by irradiation only in the presence of functional gap junctions. CONCLUSIONS: These results suggest that berberine potentizes cell apoptosis induced by X-rays irradiation, probably through enhancement of gap junction activity. PMID- 21543002 TI - Differential temporal neural responses of pain-related regions by acupuncture at acupoint ST36: a magnetoencephalography study. AB - BACKGROUND: Previous neuroimaging studies primarily focused on the spatial distribution of acupuncture needling stimulation. However, a salient feature of acupuncture was its long-lasting effect. This study attempted to detect the spatial-temporal neural responses evoked by acupuncture at an analgesia acupoint ST36 by using magnetoencephalography. To further verify its functional specificity, we also adopted acupuncture at Pericardium 6 and nonacupoint as separated controls. METHODS: Forty-two college students, all right-handed and acupuncture naive, participated in this study. Every participant received only one acupoint stimulation, resulting in 14 subjects in one group. Both magnetoencephalography data (151-channel whole-head system) and structural functional magnetic resonance imaging data (3D sequence with a voxel size of 1 mm(3) for anatomical localization) were collected for each subject. All processing procedures were performed in BrainStorm Toolbox. RESULTS: Acupuncture at ST36 showed a significantly time-varied brain activities with different onset time. Our results presented that acupuncture at different acupoints (or comparing with nonacupoint) can specifically induce neural responses in different brain areas-acupuncture at ST36 can specifically induce the neural responses of pain inhibition areas, while acupuncture at PC6 can specifically induce the activities of the insula and amygdala. CONCLUSIONS: In the present study, we attempted to detect the temporal neural responses underlying the functional specificity of acupuncture at ST36, using acupoint belonging to different meridians and non acupoint with efficacy-irreverent as separate controls. The specific neural substrates involving acupuncture at different acupoints may be related to its functional specificity in clinical settings. PMID- 21543003 TI - Gap between evidence and physicians' knowledge and practice regarding hypertension and its drug treatment: a survey in a Chinese city. AB - BACKGROUND: Evidence-based medicine has come into its second decade. How prepared clinicians are in practicing it in particular in developing countries remains unclear. Thus we conducted this survey of physicians in urban hospitals in China to determine the size of the gap between research evidence and physicians' knowledge and practice regarding antihypertensive drugs for primary prevention of cardiovascular diseases in China. METHODS: A cross sectional survey by a face-to face interview was conducted in 20 tertiary general hospitals in China in 2005. A total of 444 physicians (mostly cardiologists) in internal medicine who had treated at least one hypertensive patient in the past 12 months were invited for the interview on their perception of the cardiovascular risk of hypertension, the magnitude of the benefit of antihypertensive drugs, knowledge on the overall risk approach, first-line drugs used, the risk above which drug treatment is recommended, and knowledge on evidence-based medicine. RESULTS: A total of 444 of the 468 eligible physicians were successfully interviewed with a response rate of 94.9%. They estimated that a hypertensive man with an actual 5-year cardiovascular risk of 8.4% would have a 5-year cardiovascular risk of 40% (95%CI: 38% to 42%) if not treated, and have an absolute risk reduction and relative risk reduction from drug treatment by 20% (95%CI: 18% to 22%) and 39% (95%CI: 37% to 42%) respectively, as compared to 3.3% and 33% respectively shown in research evidence. On average, the physicians would recommend drug treatment at a number needed to treat (NNT) of 368 or smaller, as compared to the actual NNT of 50 for drug treatment in an average hypertensive Chinese. Fifty-five percent (95%CI: 50% to 59%) of them had never intently used the national hypertension guidelines. The majority still prescribed drugs primarily based on blood pressure alone by ignoring other risk factors or the overall risk and 78% (95 % CI: 76% to 83%) used new expensive drugs such as calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors as first-line treatment. Only 13% (95%CI: 9% to 18%) could correctly interpret the NNT. Forty-three percent (95%CI: 39% to 48%) did not know the randomized controlled trial was scientifically the most rigorous among other study designs for evaluating the effectiveness of anti-hypertensive drugs. Ninety-two percent (95%CI: 90% to 94%) did not know they could start by searching systematic reviews when looking for evidence on the effectiveness of anti-hypertensive drugs as opposed to trials. Ninety-six percent (95%CI: 94% to 98%) did not know the Cochrane Library was an important source of systematic reviews. CONCLUSIONS: The surveyed physicians significantly over-estimated the cardiovascular risk of hypertension and the benefit of drug treatment, and had insufficient knowledge on the overall risk approach. They recommended drug treatment at a cardiovascular risk which was even much lower than the cutoff suggested for western populations, which would make many more people eligible for drug treatment. They also tended to prescribe new expensive drugs although the older cheaper ones may be more appropriate in many patients. They showed inappropriate knowledge on the basics of evidence-based medicine. PMID- 21543004 TI - A single institution experience using the LigaSure vessel sealing system in laparoscopic nephrectomy. AB - BACKGROUND: Vascular control and tissue dissection are crucial steps in successful laparoscopic surgery. Recently, a new commercially available vessel sealing technology, the LigaSure vessel sealing system (Valleylab, Boulder, USA), has been introduced. The aim of the present study was to evaluate the benefits of the LigaSure in laparoscopic nephrectomy. METHODS: From January 2005 to March 2010, 170 laparoscopic nephrectomies were performed with the LigaSure vessel sealing system, including simple and radical nephrectomy and nephroureterectomy. In a retrospective study, the laparoscopic operating time, estimated intraoperative blood loss, duration of postoperative drainage, total amount of postoperative drainage, as well as postoperative hospital stay, were recorded and studied. RESULTS: All 170 laparoscopic nephrectomies using LigaSure were accomplished successfully without conversion to open surgery. There was no severe vascular complication or other serious complications. The mean laparoscopic operating time was 124.2 minutes (range, 14 - 230 minutes); mean blood loss was 148.6 ml (range, 20 - 540 ml); mean time for postoperative drainage was 3.1 days (range, 1 - 7 days); mean amount of postoperative drainage was 206.5 ml (range, 27 - 435 ml) and mean postoperative hospital stay was 6.9 days (range, 3 - 18 days). CONCLUSIONS: Laparoscopic nephrectomy using LigaSure appears technically feasible and easy, and produces satisfactory results. The LigaSure provides a safe and fast way to seal vessels and tissue bundles during nephrectomy. PMID- 21543005 TI - Predictors of postoperative myasthenic crisis in patients with myasthenia gravis after thymectomy. AB - BACKGROUND: Thymectomy is considered the most effective treatment in patients with myasthenia gravis. This study aimed to explore the predictors of postoperative myasthenic crisis in patients with myasthenia gravis after thymectomy. METHODS: Clinical records of 243 patients with myasthenia gravis who underwent thymectomy were reviewed retrospectively. The following factors were analyzed in relation to the occurrence of myasthenic crisis after thymectomy: gender, age, duration of symptoms, Osserman stage, history of myasthenic crisis, concomitant diseases, preoperative pyridostigmine dose, preoperative steroid therapy, operation approach, operation time, presence of thymoma, major postoperative complications. RESULTS: Forty-four patients experienced postoperative myasthenic crisis during the first month after thymectomy. Univariate analysis revealed that Osserman stage (RR = 0.0976, P = 0.000), history of myasthenic crisis (RR = 0.2309, P = 0.012), preoperative pyridostigmine dose (RR = 0.4349, P = 0.016), thymoma (RR = 0.0606, P = 0.000), and major postoperative complications (RR = 0.1094, P = 0.000) were significantly related to postoperative myasthenic crisis. Multivariate Logistic regression analysis showed that Osserman stage (IIb + III + IV) (RR = 0.0953, P = 0.000), thymoma (RR = 0.0294, P = 0.000), and major postoperative complications (RR = 0.0424, P = 0.000) independently predict postoperative myasthenic crisis. CONCLUSION: Osserman stage (IIb + IIIb + IV), thymoma and major postoperative complications are independent predictors of postoperative myasthenic crisis in patients with myasthenia gravis who underwent thymectomy. PMID- 21543006 TI - Reproducibility and accuracy of quantitative assessment of articular cartilage volume measurements with 3.0 Tesla magnetic resonance imaging. AB - BACKGROUND: Quantitative magnetic resonance imaging (qMRI) of articular cartilage represents a powerful tool in osteoarthritis research, but has so far been confined to a field strength of 1.5 T. The aim of the study was to determine the reproducibility and accuracy of qMRI assessments of the knee cartilage volume by comparing quantitative swine cartilage volumes of the sagittal (sag) multi echo data imagine combination water-excitation (MEDICwe) sequence and the fast low angle shoot water-excitation (FLASHwe) sequence at 3.0-T MRI to directly measured volumes (DMV) of the surgically removed articular cartilage. METHODS: Test-retest MRI was acquired in 20 swine knees. Two sag FLASHwe sequences and two sag MEDICwe sequences (spatial resolution 0.4 mm * 0.4 mm * 1.0 mm of 3-dimension (3D) were acquired at 3-T MRI in a knee. Articular cartilage volume was calculated from 3D reformations of the MRI by using a manual program. Calculated volumes were compared with DMV of the surgically removed articular cartilage. Knee joint cartilage plates were quantified paired in order. RESULTS: In the knee joint of swine, reproducibility errors (paired analysis) for cartilage volume were 2.5% to 3.2% with sag FLASHwe, and 1.6% to 3.0% with sag MEDICwe. Correlation coefficients between results obtained with qMRI and DMV ranged from 0.90 to 0.98 for cartilage volume. Systematic pairwise difference between results obtained with qMRI and DMV ranged from -1.1% to 2.8%. Random pairwise differences between results obtained with qMRI and DMV ranged from (2.9 +/- 2.4)% to (6.8 +/- 4.5)%. CONCLUSIONS: FLASHwe and MEDICwe sequences permit highly accurate and reproducible analysis of cartilage volume in the knee joints of swine at 3-T MRI. Cartilage volume reproducibility for the MEDICwe data is slightly higher than the FLASHwe data. PMID- 21543007 TI - Serum HBV DNA level at week 24 as a proper predictor for the effect of 2-year lamivudine treatment. AB - BACKGROUND: Lamivudine is the first L-nucleoside analogue approved for the treatment of the patients with chronic hepatitis B (CHB) for over 10 years. The aim of this study was to evaluate the virologic responses at weeks 12 and 24 for the prediction of therapeutic effect and virologic breakthrough after 2 years of lamivudine treatment in the patients with CHB. METHODS: A retrospective study was conducted with 255 hepatitis B e antigen (HBeAg) positive and 122 HBeAg-negative CHB patients treated with lamivudine (100 mg, daily) and duration of treatment was 6 to 72 months. The levels of serum hepatitis B virus (HBV)-DNA at weeks 12 and 24 were evaluated for the predictive value of therapeutic effect and drug resistance after 2 years of lamivudine treatment. RESULTS: HBeAg seroconversion was closely correlated with levels of serum HBV DNA at week 12 (P = 0.000, OR = 0.394) and 24 (P = 0.019, OR = 0.442), while virologic breakthrough was more correlated with baseline levels of serum HBV DNA (P = 0.019, OR = 1.484) and at week 12 (P = 0.049, OR = 1.398) and 24 (P = 0.012, OR = 2.025). At year 2, the virologic response at week 24 was more sensitive compared with week 12 when it was used to predict the efficacy and virologic breakthrough, but was less specific compared with those at week 12. There were no significant differences in terms of predicting positive and negative values of HBV DNA between week 12 and 24 for efficacy and drug resistance at year 2 in both HBeAg positive and HBeAg negative patients. CONCLUSION: Level of serum HBV DNA at 24-week is a proper predictor for the therapeutic effect and virologic breakthrough at year 2 of lamivudine treatment. PMID- 21543008 TI - A case of aggravation of hemolytic anemia, elevated liver enzymes and low platelet count syndrome after delivery. AB - BACKGROUND: Hemolytic anemia, elevated liver enzymes and low platelet count (HELLP) syndrome is a severe obstetric complication which usually resolves in most patients after delivery. METHODS: We report a rare case of aggravation of HELLP syndrome after delivery. RESULTS: The patient underwent the treatment for HELLP syndrome, including glucocorticoid therapy. The symptoms of HELLP syndrome reappeared and became more severe than before the termination of pregnancy. The patient also had severe and persistent hypoproteinemia, hyponatremia and hypocalcemia. CONCLUSIONS: HELLP syndrome is an acute and critical obstetric syndrome which can have heterogeneous presentations and variable prognosis. We should be fully aware of the diverse clinical characteristics of this condition. PMID- 21543009 TI - Effect of surgery on delayed inhaled foreign body: a case report. AB - The occurrence of foreign body is uncommon in youths and adults. We report here a case of 16-year-old boy who inhaled a foreign body which was overlooked for 6 months. The patient suffered productive cough and received antibiotic treatment for 10 days. But the symptoms did not improve. Chest radiography and CT scan revealed a 1-cm-long needle-like foreign object in the right inferior lobar bronchus. Wedge resection of lung was finally performed because of severe hemorrhage caused by prior bronchoscopy. PMID- 21543010 TI - Breast metastases from rectal carcinoma. AB - Metastases to the breast from extramammary neoplasms are very rare, constituting 2.7% of all malignant breast tumours. The most common primary tumor metastatic to the breast is primary breast cancer. Rectal cancer metastasizing to the breast is extremely rare. We report a case of aggressive rectal carcinoma with metastasis to the breast. PMID- 21543011 TI - Clinical evidence in concurrence of retinitis pigmentosa and glaucoma. AB - Glaucoma is rarely complicated by retinitis pigmentosa (RP). To provide clinical evidences for this rare situation, we report the concurrence of these two diseases in two children of a Chinese family. In the present two-child Chinese family without positive history, the older sister presented with bilateral sector RP and coexisting chronic angle-closure glaucoma, and the brother with bilateral whole RP but without coexisting glaucoma. Clinical evidences in concurrence of variants of RP and glaucoma because of possible different gene mutations from the same genetic background represent a rare situation, which may provide clues for future researches in molecular pathogenesis of these rare diseases. PMID- 21543012 TI - Acute right ventricular myocardial injury and sudden cardiac arrest in a patient with persistent spontaneous coronary vasospasm. AB - Coronary vasospasm is a rare diagnosis resulting in sudden arrhythmic cardiac arrest. We report a case of a healthy, non-smoking elderly woman resuscitated from arrhythmic cardiac arrest. She had persistent spontaneous coronary vasospasm, leading to right ventricular myocardial injury and failure, and shock. She responded quickly to intravenous normal saline bolus infusion, but had irreversible neurological sequelae. Additionally, she had atrial fibrillation preceding ischemic ventricular fibrillation, a rare finding in coronary vasospasm related cardiac arrest. We suggest immediate coronary angiography of patients in sudden arrhythmic cardiac arrest with acute right ventricular failure for a prompt, accurate diagnosis and appropriate management of the coronary vasospasm. PMID- 21543013 TI - Multiple primary malignant neoplasms of three early cancer lesions: a case report. AB - Multiple primary malignant neoplasms (MPMNs) are rarely reported and it is important to give early diagnosis and proper therapy for these patients. Here reported a case of 62-year-old man with concomitant three early stage cancer lesions in upper gastrointestinal tract, all of which were detected by endoscopy. The first one was an IIc-type lesion at angular part of stomach under endoscopy, which was histologically confirmed to be a mucosal well-differentiated adenocarcinoma. The patient underwent a standard radical gastrectomy for the lesion after the failure of endoscopic treatment. The other two neoplasms were observed during follow-up and were indicated as early stage lesions by synthesizing information from endoscopy, endoscopic ultrasonography, computed tomography and biopsy. One displayed as a hyperemic patch (3 cm*4 cm in size) located at the part of esophagus 27 cm away from the incisor teeth and was proved to be moderately differentiated squamous cancer by histopathological examination. The other was an IIc-type lesion (3.0 cm*3.5 cm in size) located at the part of esophagus 36 cm away from the incisor teeth, and the biopsy result showed a poorly differentiated squamous carcinoma. Both the two lesions were treated with radical radiation because the patient refused surgery management. No recurrence of former lesions or occurrence of novel lesions were observed during post treatment follow-up, suggesting radical radiation might be effective for this patient. PMID- 21543017 TI - Fetuin-A, coronary artery calcification and outcome in maintenance hemodialysis patients. AB - BACKGROUND/AIMS: Previous studies have suggested that serum fetuin-A, a calcification inhibitor, predicts mortality in dialysis patients. This study investigated the relationships between fetuin-A, vascular calcification, and outcome in such patients. METHODS: 58 patients on maintenance hemodialysis underwent multirow spiral computed tomography to determine baseline coronary artery calcification (CAC) score. Serum fetuin-A was measured repeatedly over time. RESULTS: Time-averaged fetuin-A inversely correlated with age and baseline CAC score. After partial correlation analysis controlling for age, the association between fetuin-A and CAC became insignificant. During the study, 27 of 58 patients died and 26 experienced at least one cardiovascular event. Low fetuin-A was associated with a significant increase in all-cause mortality and the occurrence of a cardiovascular event. The association of fetuin-A with mortality and cardiovascular event remained significant even when adjusting for confounding factors, including age and CAC score. CONCLUSION: Time-averaged fetuin-A was associated with survival and cardiovascular outcome, independent of vascular calcification. PMID- 21543018 TI - Interleukin 10 and residual kidney function are associated with risk of vascular calcification in patients undergoing peritoneal dialysis. AB - AIMS: Vascular calcification is a common complication among dialysis patients and its pathogenesis involves a variety of factors. The roles of pro-inflammatory cytokines and residual kidney function (RKF) in peritoneal dialysis (PD) patients with vascular calcification have not been investigated. MATERIALS AND METHODS: 157 stable PD patients were enrolled. All patients had plain X-ray film examination including chest (posterior-anterior view, CXR) and pelvis. Vascular calcification was interpreted as calcified deposit over aortic arch and linear calcification of pelvic arteries. Relevant biochemical data, pro-inflammatory markers, and PD-related factors were measured and collected. RESULTS: Vascular calcification prevalence in CXRs was higher than that in pelvis films (38.2% vs. 22.3%, p < 0.05). Patients with vascular calcification in CXR had higher incidence of calcification in pelvis films (p < 0.05). Only a minor portion (14.6%) had two calcification sites. Regression analysis revealed that age, PD duration, body mass index, and RKF were independent factors associated with vascular calcification in CXR. Age, diabetes, IL-10 and RKF were factors associated in pelvis films. Factors independently related to vascular calcification in both films were age, duration, diabetes, IL-10, and RKF. CONCLUSIONS: Besides traditional risk factors, IL-10 and RKF were important factors associated with vascular calcification in PD patients. PMID- 21543019 TI - Impact of renal failure on metabolic bone parameters in a vitamin D-deficient patient cohort. AB - INTRODUCTION: Chronic renal failure is associated with major changes in bone metabolism, but studies evaluating bone metabolism with mild or moderate renal failure are rare. Moreover, the study populations were often heterogenous and/or patients were pretreated with calcium and vitamin-D preparations. Therefore, we prospectively evaluated metabolic bone parameters in patients with renal insufficiency (Stage 1 - 4) on their first visit to outpatient nephrologists. PATIENTS AND METHODS: 285 patients were prospectively evaluated regarding renal function, serum phosphorous, plasma parathyroid hormone (PTH), serum 25-OH vitamin-D and serum bone specific alkaline phosphatase (BAP) concentrations. Patients were subdivided according to the stages of chronic kidney disease. RESULTS: Hypocalcemia occurred in only 10% of patients in Stage 4, whereas serum phosphorous was elevated at the same stage in 40% of the patients. PTH increased from Stage 1 to 4 continually with a high prevalence of elevated PTH levels (> 65 pg/ml) in Stage 1: 44%; Stage 4: 84%. Serum 25-OH-vitamin-D levels were very low irrespective of renal function: < 15 ng/dl, i.e., 37.5 nmol/l in 70% of all patients. 25-OH-D was negatively correlated with PTH (r = 0.3, p < 0.0002). BAP was within the normal range in all stages but with a high prevalence of BAP values < 7.5 ng/ml in up to 25% in Stage 4. Only 6.5% of patients had features of classical renal hyperparathyroidism. Nearly 20% had low BAP levels in the presence of normal (9.5%) or increased (9.6%) PTH levels. CONCLUSION: This study demonstrates a high prevalence of hyperphosphatemia in patients with moderate renal failure. Hyperparathyroidism was present even in earlier stages and was aggravated by a high prevalence of vitamin D deficiency. However, also in the presence of elevated PTH levels, there is indication of low bone turnover as evidenced by low BAP levels, suggesting adynamic bone disease. PMID- 21543020 TI - Mineral metabolism management in Canadian peritoneal dialysis patients. AB - BACKGROUND: Abnormal mineral metabolism is associated with increased morbidity and mortality in dialysis patients. Therefore, the goal of this study was to compare a) mineral metabolism control among a cohort of Canadian peritoneal dialysis (PD) patients to K/DOQI-defined targets and b) the effect of different treatment strategies on mineral metabolism parameters. METHODS: We looked at a cohort of 317 Canadian PD patients from 9 clinics that used the PhotoGraphTM software program which tracks mineral metabolism management. Serum phosphorus (P), calcium (Ca) and intact parathyroid hormone (iPTH) values were collected for the patients. Data were categorized and analyzed by the type of phosphate binder prescribed, vitamin D use, and dosing and reimbursement criteria for the phosphate binder, sevelamer. RESULTS: The majority of patients achieved K/DOQI set targets for serum P. Patients who resided in Quebec (QC), which had greater access to sevelamer, had lower mean concentrations of P and Ca, were less likely to take Ca-based phosphate binders (CBBs) exclusively and were exposed to less exogenous Ca than in Ontario (ON). CONCLUSION: Availability of the phosphate binder sevelamer and reduced doses of elemental Ca were associated with more mineral metabolism parameters within suggested target ranges. Further studies that focus on patient outcomes are warranted. PMID- 21543021 TI - Evolution of microbiological trends and treatment outcomes in peritoneal dialysis related peritonitis. AB - BACKGROUND AND AIM: Peritoneal dialysis (PD)-related peritonitis is a major risk factor of technique failure and contributes to significant mortality in patients undergoing PD. The aim of this study was to examine the evolution of microbiological trends and treatment outcomes of PD-related peritonitis in our hospital over the past 26 years. METHODS: A total of 630 patients entered our CAPD program from February 1984 to June 2010. Among them, 119 patients (18.9%) experienced 599 episodes of peritonitis. Microbiological trends, treatment responses, techniques and patient survival were analyzed. RESULTS: The incidence rate of total peritonitis showed a steady decline from 1.08 episodes/patient-year in 1984 to 0.25 episode/ patient-year in 2009 (p < 0.001). A similar trend was found in gram-positive (p < 0.001) and gram-negative peritonitis (p = 0.015). In contrast, there was a trend toward an increased proportion of gram-negative peritonitis. This increase was not due to an increased rate of gram-negative peritonitis but to the more dramatic fall in gram-positive peritonitis. Treatment of peritonitis resulted in a complete cure in 78.0% of patients, while 16.7% of patients required catheter removal and 5.3% died. Gram-positive organisms were associated with a more favorable outcome compared to gram-negative pathogens as manifested by a higher cure rate (p = 0.023). The patient survival and technique survival were much improved after 2000 compared to that before 2000 (p < 0.0001). CONCLUSION: A remarkable improvement in the outcome of PD-related peritonitis has been achieved in the past 26 years in our hospital. To further decrease peritonitis rates, attention needs to be directed at reducing gram-negative peritonitis. PMID- 21543022 TI - Postdialysis fatigue is associated with sedentary behavior. AB - Postdialysis fatigue (PDF) is a common and debilitating phenomenon that adversely affects the quality of life of hemodialysis patients. Excessive ultrafiltration and rapid osmolar flux are implicated in the pathogenesis of PDF, but simple adjustments do not always ameliorate this symptom. Increased physical activity has long been associated with reduced fatigue in sedentary fatigued patients. The aim of the study was to examine the extent to which physical activity is associated with PDF. This was a retrospective cross-sectional study of hemodialysis patients (n = 58, age 55 +/- 13 years, 38 M, 20 F). Physical activity was measured by self-report using the Human Activity Profile (HAP) (n = 58) and accelerometry (n = 26). Postdialysis fatigue was assessed by a questionnaire rating frequency, severity, and duration of symptoms. 86% (50/58) of patients reported PDF ranging from mild to severe. The PDF index was inversely correlated with the adjusted score of the HAP (p < 0.05). Least squares linear regression was used to assess the association of physical activity with PDF, controlling for Kt/V and dialysis vintage. In the adjusted model (R2 = 0.40), physical activity remained the most significant predictor (p < 0.01) of PDF after adjusting for Kt/V and/or vintage. Further studies are needed to evaluate whether increasing habitual physical activity can mitigate PDF symptoms. PMID- 21543023 TI - Dialysis-associated morbidity, ultrafiltration, and cardiovascular variables in children with HIV infection. AB - Children infected with HIV on maintenance hemodialysis (HD) have increased mortality with adequate single pool Kt/V, as compared to non-HIV children on HD. It is unclear if HIV subjects on HD have similar dialysis-associated morbidity (DAM) and blood volume changes (dBV) as non-HIV subjects. It is also unclear how those variables are related to left ventricular mass index (LVMI), shortening fraction (SF), pre- and postdialysis blood pressure and mortality. METHODS: We investigated the relationship between LVMI, SF and dBV and DAM using noninvasive monitoring of hematocrit in HIV vs. non-HIV subjects and their association with mortality. We used a cross-sectional study design and analyzed 18 pediatric subjects (9 had vertically transmitted HIV) on HD over a 17-month period. HIV subjects tolerated fluid removal during HD treatments as well as non-HIV subjects. RESULTS: In our study we confirmed an association of LVMI with DAM in subjects on HD. We found that HIV subjects who did not survive had a significantly lower SF and similar viral load as compared to subjects who survived. CONCLUSIONS: Noninvasive monitoring of hematocrit in HIV subjects with compromised heart function allows effective ultrafiltration. Routine echocardiography should be periodically performed in all HIV-infected children on renal replacement therapy because subclinical abnormalities, i.e. increased LVMI or reduced SF in this population can be predictors of mortality. PMID- 21543024 TI - Renin angiotensin system blockade and activated vitamin D as a means of preventing deep vein thrombosis in renal transplant recipients. AB - BACKGROUND: Venous thromboembolism (VTE) is one of the thrombotic complications that occur in renal transplant recipients (RTR). The observation that vitamin D receptor activators, angiotensin-converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARBs) have a protective effect against protrombotic state suggests that their possible combination could reduce the incidence of VTE in RTR. OBJECTIVES: to evaluate the incidence of VTE in RTR and the timing of occurrence after renal transplantation (Tx); to compare the incidence of VTE in our RTR and RTR on calcitriol, ACEi, ARBs and their combination therapy. Risk factors were also evaluated. RESULTS: During follow-up, 96 of 769 RTRs, 73 males 23 females, developed a first episode of VTE: 23 in the first 3 months after Tx; 15 from 3 to 6 months; 9 from 6 to 12 months; 13 from 12 to 48 months and 36 after more than 48 months. The incidence was significantly lower in RTR on treatment with a combination of calcitriol 0.25 ug/day, an ACEi and an ARB and in RTR on treatment with only calcitriol 0.5 ug/day (9.4% and 9%, respectively, vs. 14.5% (p < 0.05)). However, the most decreased rate (5.6% vs. 14.5% (p < 0.01)) was in patients treated with a combination of calcitriol 0.5 ug/day, an ACEi and an ARB. CONCLUSION: A combination therapy with calcitriol 0.5 ug/day, ACEi, and ARB is associated with a 60% lower rate risk of VTE. PMID- 21543025 TI - Cytochrome P450 polymorphisms and the response of lupus nephritis to cyclophosphamide therapy. AB - BACKGROUND AND AIMS: The addition of cyclophosphamide to corticosteroids significantly improves the prognosis of severe kidney involvement in systemic lupus erythematosus (SLE). However, not all patients respond to cyclophosphamide. It has been suggested that genetic variations that reduce the metabolism of cyclophosphamide reduce its effectiveness. Cyclophosphamide is metabolized and activated by the cytochrome P450 (CYP) system and in particular CYP enzymes 2B6 and 2C19. Both CYP2B6 and CYP2C19 have variant alleles (CYP2B6*5 and CYP2C19*2) that attenuate or eliminate enzymatic activity. This investigation was done to determine the impact of CYP2B6*5 and CYP2C19*2 on the renal response in cyclophosphamide-treated lupus nephritis (LN) patients. METHODS: Patients with SLE (n = 237), unclassified autoimmune disease (n = 51), and healthy controls (n = 294) were genotyped for CYP2B6*5 and CYP2C19*2. Associations between these alleles and achievement of complete or partial response, development of end-stage renal disease, and time to remission were determined. RESULTS: The frequencies of the variant alleles CYP2B6*5 and CYP2C19*2 were 6.3 % and 15.9%, respectively. CYP2C19*2 genotypes were more frequent among African Americans than European Americans, and CYP2B6*5 genotypes were more frequent among European Americans than African Americans. Among LN patients treated with cyclophosphamide (n = 36), there were no differences between those with or without these genotypes relative to the frequency of complete or partial remissions or time to remission. CONCLUSION: This retrospective analysis failed to show an association between CYP2B6*5 and CYP2C19*2 and treatment outcomes in LN. This suggests that genotyping for these CYP450 variants may not be useful in individualizing treatment for severe LN. PMID- 21543026 TI - Higher serum beta2-microglobulin levels are associated with better survival in chronic hemodialysis patients: a reverse epidemiology. AB - AIMS: beta2-Microglobulin (beta2-M) has been considered a surrogate marker of putative mid-molecular weight (MW) uremic toxins, compounds difficult to dialyze by low-flux dialysis membranes. This study was performed to evaluate the relationship between serum beta2-M and survival of chronic hemodialysis (CHD) patients and the association of beta2-M levels and factors associated with mortality. METHODS: Part I of this study is a retrospective cohort evaluation that determined the relationship between beta2-M and mortality, and Part II is a cross-sectional study that evaluated the relationship between beta2-M and factors associated with mortality. Laboratory parameters, including beta2-M, albumin, prealbumin, creatinine, blood urea nitrogen (BUN), high-sensitivity C-reactive protein (hs-CRP), lipid battery, KT/V, and normalized protein nitrogen appearance (nPNA), were reviewed in Part I and measured in Part II. Clinical and demographic data, including age, sex, duration of hemodialysis, presence of cardiovascular disease, and presence of diabetes mellitus, were also recorded. RESULTS: Part I: During the follow-up period of 5 years, there were 95 all-cause deaths among the 289 patients. Comparison of survivors and non-survivors indicated that serum beta2-M was higher in survivors (36.8 +/- 12.3 vs. 32.6 +/- 13.2 ug/ml, p = 0.009). Kaplan-Meier analysis indicated that all-cause mortality in the lower beta2-M group was significantly higher compared to the higher beta2-M group (p < 0.0001). Multivariate Cox regression analyses indicated elevated beta2-M levels were significantly associated with lower mortality rate (relative risk: 0.608; 95% CI: 0.37 to 0.99; p = 0.046). Part II: The mean serum beta2-M concentration was 37.1 +/- 14.4 ug/ml. Univariate analysis indicated that beta2-M was positively correlated with nPNA, duration of HD, BMI, and the concentrations of creatinine, albumin, BUN, and hs-CRP, but was negatively correlated with HDL-C concentration. Multiple regression analysis indicated that levels of nPNA (p < 0.001), duration of hemodialysis (p < 0.001), creatinine (p < 0.001), albumin (p = 0.006), BUN (p = 0.011), and HDL-C (p = 0.038) were independently associated with serum beta2-M concentration. CONCLUSION: Our results showed that higher serum beta2-M levels are associated with better survival in CHD patients and that nutritional status might be an independent predictor of serum beta2-M concentration in these patients. PMID- 21543027 TI - Idiopathic hypercalcemia in infants with renal dysplasia. AB - BACKGROUND: We have observed infants with renal dysplasia who developed sustained hypercalcemia, without vitamin D or calcium supplementation (idiopathic). This has not been previously described. OBJECTIVES: 1) Define incidence, severity and duration of idiopathic hypercalcemia in infants with renal dysplasia below 12 months of age. 2) Evaluate phosphate, parathyroid hormone (PTH) and vitamin D levels in these infants. METHODS: A retrospective study was conducted from June 2005 to June 2008. Patients receiving calcium-containing phosphate binders or daily supplemental vitamin D in excess of 400 IU were excluded. Hypercalcemia was defined as at least three corrected calcium values above normal lab values for age, in a one-week interval. RESULTS: 15 of 99 (15%) infants with renal dysplasia had hypercalcemia. All were males; 10/15 (67%) were below one month of age at presentation; 9/15 (60%) had posterior urethral valves (PUV). Mean hypercalcemia duration was 5.2 +/- 6.0 months. Mean corrected calcium was 3.07 mmol/l (12.3 mg/dl). Only 3/10 infants had elevated PTH levels. None had elevated phosphate levels and only 1/8 patients who had 25-hydroxyvitamin D measured had an elevated level. CONCLUSIONS: Idiopathic hypercalcemia in infants with renal dysplasia is common. Neonates and those with PUVs are at greatest risk. Most have normal levels of 25-hydroxyvitamin D, phosphate and PTH. PMID- 21543028 TI - The effects of oral iron supplementation on the progression of anemia and renal dysfunction in patients with chronic kidney disease. AB - AIMS: Oral iron traditionally has been administered to patients with chronic kidney disease (CKD). However, there are limited data on the effect of oral iron in CKD patients. Here, we evaluate the effects of oral iron therapy on renal anemia and progression of renal disease in CKD patients. METHODS: Anemic patients with nondialytic CKD who were naive to erythropoiesis-stimulating agents (ESAs) were recruited for the prospective observational study. The participants were classified into oral iron or control group, and they were asked to keep their treatment status for 1 year. The primary outcomes were change in Hb and estimated glomerular filtration rate (eGFR). RESULTS: A total of 182 participants were enrolled and 138 completed a 12-month follow-up. No change in Hb level was observed during the follow-up period in the iron group, whereas a significant decrease in Hb was observed in the control group. Oral iron supplementation was effective, especially in patients with eGFR < 30 ml/min/1.73 m2. The changes in eGFR did not differ between the two groups. The incidences of drug-related adverse events were equivalent in two groups. CONCLUSIONS: Oral iron supplementation might attenuate the progression of anemia in nondialytic CKD patients without ESAs and not impact kidney function. PMID- 21543029 TI - Acute renal failure and nephrotic syndrome due to membranoproliferative nephritis during the second trimester of pregnancy. AB - We report the case of a patient with acute renal failure and nephrotic syndrome during the second trimester of an otherwise uncomplicated pregnancy. Despite pregnancy, percutaneous renal biopsy was performed to evaluate the etiology, showing Type I membranoproliferative glomerulonephritis. Two therapeutic options were considered: pregnancy termination, suggested by the gynecologists, and our proposal of starting steroid therapy, in order to reduce proteinuria and improve renal function. The patient refused pregnancy termination. She received i.v. methylprednisolone boluses, followed by maintenance oral prednisone and aspirin, with prompt acute renal failure resolution and reduced proteinuria. At Week 34 + 5 days of gestation, cesarean section was performed, without intra- and postoperative complications both for mother and newborn. Clinical maternal and fetal outcomes were excellent. One-year follow-up showed normal renal function and absence of proteinuria. Lacking guidelines concerning treatment of acute renal failure due to primary nephropathy in pregnancy, we consider this case of interest for our decision-making process and for the favorable outcome. PMID- 21543030 TI - Hyperkeratotic pruritic papules in a hemodialysis patient. PMID- 21543031 TI - Are statins really useless in "primary prevention"? Recent Cochrane meta-analysis revisited. PMID- 21543032 TI - Clarithromycin-induced hypersomnia in children. AB - Two cases of hypersomnia in children caused by therapeutic doses of oral clarithromycin are presented. Clarithromycin-induced hypersomnia in children has not been reported before. A 4-year-old girl and 13-year-old boy received clarithromycin as monotherapy. The girl fell into a deep sleep after every dose of the antibiotic. The boy reported daytime sleepiness and prolongation of night time sleep during the antibiotic therapy. In both cases the hypersomnia receded after cessation of clarithromycin therapy. The onset of hypersomnia after clarithromycin intake, its remission once the drug was stopped, and the absence of other possible causative factors favored the diagnosis of clarithromycin induced hypersomnia, further supported by the scores on Naranjo's Adverse Drug Reaction Probability Scale in both cases. Clinicians evaluating children receiving clarithromycin and exhibiting suddenly changed behavior should keep in mind that the antibiotic can produce uncommon adverse reactions. PMID- 21543033 TI - Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. AB - OBJECTIVE: To investigate the effect of the estimated highest therapeutic dose of linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate. SUBJECTS AND METHODS: This open-label, 2-period, fixed-sequence trial enrolled 18 healthy male volunteers, 17 of whom were homozygous for CYP2C9*1/*1. Subjects received a single oral dose of warfarin (10 mg) followed by a washout period of at least 14 days. Subjects then received oral linagliptin 5 mg once daily for 12 days (i.e. steady state) with a single dose of warfarin (10 mg) on Day 6. R(+) warfarin, S(-) warfarin, prothrombin time (PT) and international normalized ratio (INR) were assayed pre-dose and up to 168 h post dose. RESULTS: The geometric mean ratios (GMRs) (90% confidence interval (CI)) of AUC0-infinity and Cmax for (linagliptin + warfarin)/warfarin were 98.5 (95.7 - 101.5) and 99.7 (94.7 - 104.9), respectively, for R-warfarin; 103.0 (99.1 - 107.0) and 100.9 (93.7 - 108.6), respectively, for S-warfarin. Concomitant administration of linagliptin and warfarin had o clinically relevant effect on the AUC0-168 for INR or PT. The GMRs (90% CI) of INR nd PT AUC0-168 for (linagliptin + warfarin)/ warfarin were 93.4 (86.2 - 101.1) and 103.2 (95.4 - 111.6), respectively. The corresponding Eax values for both INR and PT were slightly increased after co-administration of linagliptin and warfarin compared with warfarin alone, being 104.3 (85.2 - 127.6) and 15.1 (94.3 -140.6), respectively, reflecting the higher variability of these endpoints. Co administration of linagliptin and warfarin was well tolerated. CONCLUSIONS: Coadministration of linagliptin did not alter the pharmacokinetics or pharmacodynamics of R- or S-warfarin, indicating that no dosage adjustment for warfarin is necessary when co-administered with linagliptin. PMID- 21543034 TI - Cyclosporine A area-under-time-concentration-curve in rheumatologic patients after the first dose. Which of the sparse sampling strategies will predict the best? AB - OBJECTIVE: The aim of the present study was to validate the limited sampling strategies (LSS:s) for prediction of AUC of cyclosporine A (CsA) after the first dose in rheumatologic patients. METHODS: 22 patients suffering from rheumathoid arthritis, systemic lupus erythematodus, ankylosing spondylitis dermato(poly)myositis or seronegative spondylarthritis were treated with Neoral(r) (female/male: 11/3, mean +/- SD: age 49 +/- 14 y, body weight 75 +/- 12 kg, height 166 +/- 7 cm, dose 71 +/- 25 mg, dose per kg 1.0 +/- 0.3 mg/kg), or Consupren(r) (7/1, 78 +/- 36, 175 +/- 8, 82 +/- 22, 1.1 +/- 0.3). Two patients whose C12h were missing were excluded from the AUC0-12 calculation. Whole blood levels of CsA were analyzed with HPLC. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after taking the first dose. Altogether 115 LSS:s obtained from the literature were validated. A linear trapezoidal rule was used as a reference method. Mean percentage prediction error (%PE) < +/- 15% and maximal one value of absolute %PE > 30% were considered to be acceptable. The root mean squared error (RMSE) was evaluated for equations that passed the criteria. RESULTS: The best performance with all values of the absolute %PE < 30% was found in three LSS:s for AUC0-12 and two for AUC0-8: AUC0-12 = 123.792 + 1.165 * C1h + 3.021 * C3h + 7.33 * C8h; 97.6 + 1.27 * C1h + 3.14 * C3h + 4.06 * C6h; or 124.3 + 1.34 * C1h - 0.16 * C2h + 3.27 * C3h + 3.96 * C6h; AUC0-8 = -19.8 + 1.99 * C2h + 2.38 * C4h + 3.15 * C6h or -22.4 + 2.51 * C2h + 5.49 * C6h. Validation criteria were further fulfilled in AUC0-12 = 24 + 3.66 * C0h + 2.11 * C1.5h + 4.54 * C4h or 0.2 + 2 * C2h + 10.2 * C6h; AUC0-8 = 55.37 + 2.89 * C0h + 1.08 * C1 + 0.9 * C2h + 2.23 * C3h; and AUC0-4 = -41 + 1.17 * C1h + 1.85 * C2h. Only one equation proposed for AUC0-6 did not pass the validation criteria. CONCLUSIONS: Equations validated for prediction of AUC0-12, AUC0-8 and AUC0-4 might be used for LSS:s of CsA independently of the length of treatment, indication, dosage or galenic formulation. PMID- 21543035 TI - Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers. AB - Fimasartan (BR-A-657) is an angiotensin II receptor antagonist, recently approved as an antihypertensive agent. OBJECTIVE: This study aimed to investigate whether administration of fimasartan has an effect on the steady-state pharmacokinetics of digoxin. METHODS: An open-label, two-period, two-treatment, single-sequence, crossover study was conducted in 14 healthy male volunteers. On the first day of each 7-day treatment period, subjects received a loading dose of digoxin 0.5 mg, either alone or together with fimasartan 240 mg in the morning, followed by an additional dose of digoxin 0.25 mg after 6 h. On the subsequent 6 days, digoxin 0.25 mg, either alone or with fimasartan 240 mg was administered once daily. Serial blood samples for pharmacokinetics were collected up to 24 h after the last administration in each period. RESULTS: The geometric mean ratio and 90% confidence intervals (CI) for the Cmax,ss and AUCtau,ss of digoxin (with/without fimasartan) were 1.307 (1.123 - 1.520) and 1.087 (1.015 - 1.165), respectively. Study medications were well-tolerated without serious adverse events or clinically meaningful changes. CONCLUSIONS: Coadministration of fimasartan with digoxin does not result in clinically significant changes of digoxin pharmacokinetics at steady-state in healthy subjects. PMID- 21543036 TI - Coagulation status in patients with coronary artery disease taking 100 mg aspirin and healthy volunteers using PFA-100(r) and ROTEM(r). AB - Previous investigation revealed that age is a major risk factor for thomboembolic events. Earlier studies with thrombelastography have demonstrated procoagulant activity in elderly patients with coronary artery disease. The aim of the present study was to investigate age-related differences in the coagulation status of patients with documented coronary artery disease, healthy elderly and healthy young volunteers with the rotation thrombelastography (ROTEM(r)) and PFA-100(r). Measured with ROTEM(r), mean clot formation time (CFT (EXTEM)) in healthy young volunteers (120.8 +/- 73.5 s) was significantly longer than in healthy elderly (78.3 +/- 36.7 s, p < 0.05) and in patients with coronary artery disease (74.3 +/ 59.1 s, p < 0.05). No difference was found between healthy elderly and patients with coronary artery disease. The lowest value for mean maximum clot formation (MCF (EXTEM)) was seen in healthy young volunteers (57.0 +/- 6.1 mm) which was significantly different to healthy elderly (61.9 +/- 4.8 mm, p < 0.05) and patients with coronary artery disease (65.3 +/- 8.4 mm, p < 0.05). No difference could be found between healthy elderly and patients with coronary artery disease, although a trend to higher mean MCF (EXTEM) and lower mean CFT (EXTEM)in patients with coronary artery disease was found. Measured with the collagen/epinephrine cartridge of the PFA-100(r), healthy young volunteers (166.4 +/- 59.5 s) had numerical but insignificantly longer mean closure times compared to healthy elderly (138.5 +/- 53.3 s). These findings point to agerelated differences in thrombelastographic parameters. The ROTEM(r) analysis indicates an increased coagulability in patients with coronary artery disease and healthy elderly compared to healthy young volunteers. PMID- 21543037 TI - Fatal lithium toxicity with therapeutic levels--a case report. AB - For nearly five decades now, lithium has been used as a drug for treatment of bipolar affective disorder [1]. Adverse effects of lithium have been reported, but still lithium continues to be an effective prophylactic agent for bipolar disorder. Serious and fatal toxicity can occur with levels of lithium considered to be in the therapeutic range [2, 3, 4, 5, 6]. We are reporting a patient who was on lithium for bipolar disorder and was admitted with a history of sudden collapse following vomiting, and sinus bradycardia with ST-T changes. The patient expired with levels of lithium being within therapeutic range. PMID- 21543038 TI - The persistence of drug-induced fever by teicoplanin--a case report. AB - OBJECTIVE: It was reported that the drug-induced fever of teicoplanin tended to persist after cessation of treatment. It is considered that the long half-life of teicoplanin causes the phenomenon. However there was no detailed report regarding plasma concentration of teicoplanin during onset of drug induced-fever. Therefore we investigated the relation between persistence of drug-induced fever and plasma concentration of teicoplanin. CASE: A 38-year-old male patient on the Left Ventricular Assist System (LVAS) was treated with teicoplanin for methicillin resistant Staphylococcus aureus (MRSA) and he experienced drug-induced fever. Plasma concentrations of teicoplanin were measured not only during the treatment with the drug but also after it was discontinued. As such, plasma concentration was measured even when the fever had subsided. RESULTS: On Day 9 of treatment, the dose was increased from 400 to 600 mg, but the patient had a fever of about 38 - 39 degrees C. When the treatment was discontinued, it took 9 days for the fever to subside to a temperature of about 37 degrees C. The half-life of elimination of teicoplanin in the elimination phase is about 108 h, which is long. The fever persisted until the plasma concentration decreased to below 10 ug/ml, which is the effective trough concentration, and subsided when the estimated blood concentration was 7.5 ug/ml. CONCLUSIONS: We suggest that there is the possibility that the drug-induced fever due to teicoplanin persisted until the plasma concentration had decreased adequately. Close monitoring of plasma concentration is necessary, particularly when teicoplanin clearance is decreased such as in patients with renal dysfunction. PMID- 21543042 TI - European institutes for disease prevention and control collaborate to improve public health surveillance. PMID- 21543043 TI - Innovations in communication: the Internet and the psychology of vaccination decisions. AB - This paper provides a psychological perspective on the possible effect of the Internet on the decision against vaccination. The reported importance of the Internet in health decisions is still low, but rising; especially the amount of interactive use of the Internet is increasing, e.g. due to the use of social media. It is argued that the fact that individuals do not report the Internet to be an important source of information does not necessarily mean that the information obtained in their Internet searches is not influential in their decisions. Evidence is summarised here regarding the (anti-)vaccination information on the Internet, and its influence on risk perceptions and on vaccination intentions and behaviour in relation to the encoded information. The conclusion suggests that scholars should strive to explain the underlying processes and potential mediators of vaccination decisions to increase the effectiveness of health communication. In reference to a definition of evidence based medicine, a great future challenge lies in evidence-based public health communication based on interdisciplinary research involving public health, medical research, communication science and psychology. PMID- 21543044 TI - The impact of the 2009 influenza A(H1N1) pandemic on attitudes of healthcare workers toward seasonal influenza vaccination 2010/11. AB - The emergence of the influenza A(H1N1)2009 virus provided a major challenge to health services around the world. However, vaccination rates for the public and for healthcare workers (HCWs) have remained low. We performed a study to review the reasons put forward by HCWs to refuse immunisation with the pandemic vaccine in 2009/10 and characterise attitudes in the influenza season 2010/11 due to the emergence of influenza A(H1N1)2009. A survey among HCWs and medical students in the clinical phase of their studies was conducted, using an anonymous questionnaire, at a German university hospital during an influenza vaccination campaign. 1,366 of 3,900 HCWs (35.0%) were vaccinated in the 2010/11 influenza season. Of the vaccinated HCWs, 1,323 (96.9%) completed the questionnaire in addition to 322 vaccinated medical students. Of the 1,645 vaccinees who completed the questionnaire, 712 had not been vaccinated against the influenza A(H1N1)2009 virus in the 2009/10 season. The main reason put forward was the objection to the AS03 adjuvants (239/712, 33.6%). Of the HCWs and students surveyed, 270 of 1,645 (16.4%) stated that the pandemic had influenced their attitude towards vaccination in general. Many German HCWs remained unconvinced of the safety of the pandemic (adjuvanted) influenza vaccine. For this reason, effective risk communication should focus on educating the public and HCWs about influenza vaccine safety and the benefits of vaccination. PMID- 21543046 TI - Are European immunisation programmes recession proof? PMID- 21543045 TI - Appearance of a novel measles G3 strain in multiple European countries within a two month period, 2010. AB - During late 2010, a previously unrecognised strain of measles genotype G3 virus was identified in five different European countries by the World Health Organization Measles and Rubella Laboratory Network.Apart from one, none had a travel history to south-east Asia, the usual source of G3 viruses, although epidemiological links could be established between some of the cases. This case series illustrates the value of genotyping and sequencing in tracking measles infections, and identifying otherwise unrecognised chains of transmission. PMID- 21543047 TI - Impacts of ambient salinity and copper on brown algae: 2. Interactive effects on phenolic pool and assessment of metal binding capacity of phlorotannin. AB - The aim of this study was to establish in laboratory experiments a quantitative link between phenolic pool (production, composition and exudation) in Ascophyllum nodosum and Fucus vesiculosus and their potential to bind metals. Additionally, the copper binding capacity of purified phlorotannin was investigated. A reduction in salinity decreased total phenolic contents, altered phenolic composition by increasing proportion of cell-wall phenolics, and also increased phenolic exudation of the two seaweed species. After 15 days at a salinity of 5, the inhibition of photosynthesis observed previously for A. nodosum coincided with the high exudation of phenolic compounds into the surrounding water of the seaweed tips which resulted in a significant reduction of phenolic contents. Increased copper concentration also reduced total phenolic contents, changed phenolic composition (increase in proportion and level of cell-wall phenolics), and positively affected phenolic exudation of A. nodosum and F. vesiculosus. A decrease in salinity enhanced the copper toxicity and caused the earlier impact on the physiology of seaweed tips. An involvement of phlorotannins in copper binding is also demonstrated; purified phlorotannins from A. nodosum collected from a site with little anthropogenic activity contained all four metals tested. When placed in copper-enriched water, as for the seaweed material, copper contents of the phenolics increased, zinc and cadmium contents decreased, but no change in chromium content was observed. The use of cell-wall phenolic content as biomarker of copper contamination seems promising but needs further investigation. PMID- 21543048 TI - Characterization and expression of cytochrome P4501A in Atlantic sturgeon and shortnose sturgeon experimentally exposed to coplanar PCB 126 and TCDD. AB - The AHR pathway activates transcription of CYP1A and mediates most toxic responses from exposure to halogenated aromatic hydrocarbon contaminants such as PCBs and PCDD/Fs. Therefore, expression of CYP1A is predictive of most higher level toxic responses from these chemicals. To date, no study had developed an assay to quantify CYP1A expression in any sturgeon species. We addressed this deficiency by partially characterizing CYP1A in Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) and shortnose sturgeon (Acipenser brevirostrum) and then used derived sturgeon sequences to develop reverse transcriptase (RT)-PCR assays to quantify CYP1A mRNA expression in TCDD and PCB126 treated early life-stages of both species. Phylogenetic analysis of CYP1A, CYP1B, CYP1C and CYP3A deduced amino acid sequences from other fishes and sturgeons revealed that our putative Atlantic sturgeon and shortnose sturgeon CYP1A sequences most closely clustered with previously derived CYP1A sequences. We then used semi-quantitative and real time RT-PCR to measure CYP1A mRNA levels in newly hatched Atlantic sturgeon and shortnose sturgeon larvae that were exposed to graded doses of waterborne PCB126 (0.01-1000 parts per billion (ppb)) and TCDD (0.001-10 ppb). We initially observed significant induction of CYP1A mRNA compared to vehicle control at the lowest doses of PCB126 and TCDD used, 0.01 ppb and 0.001 ppb, respectively. Significant induction was observed at all doses of both chemicals although lower expression was seen at the highest doses. We also compared CYP1A expression among tissues of i.p. injected shortnose sturgeon and found significant inducibility in heart, intestine, and liver, but not in blood, gill, or pectoral fin clips. For the first time, our results indicate that young life-stages of sturgeons are sensitive to AHR ligands at environmentally relevant concentrations, however, it is yet to be determined if induction of CYP1A can be used as a biomarker in environmental biomonitoring. PMID- 21543049 TI - Elucidating the toxicity targets of beta-ionone on photosynthetic system of Microcystis aeruginosa NIES-843 (Cyanobacteria). AB - In order to explore the potential targets of toxicity of beta-ionone on the photosynthetic system of Microcystis aeruginosa, the polyphasic rise in chlorophyll a (Chl a) fluorescence transient and transcript expression for key genes in photosystem II (PSII) of M. aeruginosa NIES-843 were studied. The EC50 value of beta-ionone on M. aeruginosa NIES-843 was found to be 21.23+/-1.87 mg/L. It was shown that beta-Ionone stress can lead to a decrease in pigment content of M. aeruginosa NIES-843 cells, and that carotenoids were more sensitive to beta ionone stress than Chl a. The normalized Chl a fluorescence transients were slightly decreased at 6.67 and 10 mg/L beta-ionone, but significantly increased at 15, 22.5 and 33.75 mg/L. There was no significant variation on transcript expression of psbA and psbO at a concentration of 6.67 mg/L beta-ionone, but they were down-regulated at 22.5 mg/L. Ultrastructural examination by transmission electron microscopy indicated that the thylakoids were distorted, and the thylakoid membrane stacks began to collapse when M. aeruginosa NIES-843 was exposed to beta-ionone at a concentration of 22.5 and 33.75 mg/L. Our results indicate that the reaction centre of PS II and the electron transport at the acceptor side of PS II are the targets responsible for the toxicity of beta ionone on the PS II of M. aeruginosa NIES-843. PMID- 21543050 TI - Effects of the pyrethroid fenvalerate on the alarm response and on the vulnerability of the mosquito larva Culex pipiens molestus to the predator Notonecta glauca. AB - Previous studies have shown that mosquito larvae retreat from the surface of water as an alarm response to sudden changes in light intensity. We investigated the effects of the insecticide fenvalerate on this alarm response in larvae of the mosquito Culix pipiens molestus and on the related vulnerability of these larvae to the predator Notonecta glauca. For the alarm response, after 1h of exposure to fenvalerate, no immediate effects were observed. However, after a 5-h postexposure period following 1h of exposure, the proportion of larvae that showed the alarm response decreased with increasing fenvalerate concentration. The median effective concentration (EC50) was 0.1 MUg/L. After 6h of continuous exposure, the EC50 decreased to 0.06 MUg/L. In addition, vulnerability to the predator N. glauca increased after 6h of continuous exposure. The median time needed for N. glauca to prey 50% of the larvae (PT50) decreased from 5h 48 min in the control to 3h 8 min at 0.3 MUg/L fenvalerate. No mortality occurred after 48 h when larvae were exposed for 6h in the absence of N. glauca. The median lethal concentration (LC50) was 0.3 MUg/L after 48 h of continuous exposure. The decrease in the PT50 was related strongly to the increase in the proportion of larvae that did not exhibit an alarm response. These results show that the alarm response can be inhibited by low levels of fenvalerate, and this inhibition seems to increase larval mortality due to predation. PMID- 21543051 TI - On the origins and biosynthesis of tetrodotoxin. AB - The potent neurotoxin tetrodotoxin (TTX) has been identified from taxonomically diverse marine organisms. TTX possesses a unique cage-like structure, however, its biosynthesis has yet to be elucidated. Biosynthetic studies in the TTX producing newt Taricha torosa, and in bacterial genera, including Vibrio, have proven inconclusive. Indeed, very few studies have been performed that address the cellular production of TTX. Here we review the sources of TTX described to date and provide evidence for the biosynthesis of TTX by symbiotic microorganisms in higher taxa. Chemical and genetic based biosynthesis studies of TTX undertaken thus far are discussed and we outline approaches which may be useful for expanding upon the current body of knowledge. The complex biosynthesis of structurally similar toxins, that reveal clues into the biosynthetic pathway of TTX, is also presented. PMID- 21543053 TI - Valproic acid induces apoptosis in differentiating hippocampal neurons by the release of tumor necrosis factor-alpha from activated astrocytes. AB - Human studies of neurodevelopment suggest that children exposed in utero to certain antiepileptic drugs (AEDs) suffer a variety of brain-behavior sequelae, such as neural tube defects, developmental delays, cognitive deficits, etc. Valproic acid (VPA), a commonly used AED, has greater risk for these side effects compared with other AEDs. However, the detailed molecular mechanisms underlying this developmental neurotoxicity of VPA is unclear despite previous research demonstrating that VPA could induce widespread apoptotic neurodegeneration in developing brains of animal models. This study characterizes the role of astrocytes in VPA-induced neurodegeneration. In developing brains, we evaluated the developmental neurotoxicity of VPA on differentiating neurons and astrocytes from neural progenitor cells cultured from the hippocampus of human fetuses. Exposure of a neuron-enriched culture to VPA at 250MUM or 500MUM did not cause neuronal apoptosis, but at 1mM and 7 days exposure, a slight increase in the percentage of apoptotic cells was observed. In contrast, VPA at 250MUM to 1mM, selectively induced neuronal apoptosis in a neuron-astrocyte mixed cell culture model. The VPA-treated astrocytes showed morphological changes, and the level of tumor necrosis factor-alpha (TNF-alpha) was elevated in the supernatant. Both neuronal apoptosis and TNF-alpha release from astrocytes increased with concentration and exposure time to VPA, suggesting a synergism between the two cell types. Treatment of the neuron-astrocyte mixed culture exposed to VPA with TNF-alpha antibody partly prevented neuronal apoptosis, while the addition of exogenous TNF-alpha induced apoptosis in both cultures. Moreover, this pro apoptotic effect was specific to VPA, as another AED, valpromide, failed to mimic this pro-apoptotic effect, nor did an inhibitor of histone deacetylase (iHDAC), sodium butyrate (NaB). We report a novel finding that astrocytes participate in VPA induced neurodegeneration by releasing TNF-alpha. PMID- 21543052 TI - Individual and combined effects of heat stress and aqueous or dietary copper exposure in fathead minnows (Pimephales promelas). AB - Despite its role as an essential micronutrient, copper (Cu) can be present in aquatic ecosystems at concentrations able to cause adverse health effects on aquatic organisms. Although Cu is acquired by fish by either water or diet, studies that have investigated Cu impacts in fish have mainly focused on the toxicity of waterborne Cu. Moreover, as the majority of experiments were carried out under simplified conditions, little is known about the effects of natural factors other than competitive ions on Cu toxicity in fish. As temperature is a primary factor that affects the physiological state of poikilotherm organisms, we investigated the individual and combined effects of temperature and waterborne or dietary Cu on fathead minnows (Pimephales promelas). Fish were exposed to environmentally realistic concentrations of waterborne or dietary Cu at 20 degrees C and 32 degrees C. Transcriptional and enzymatic responses of various indicators of metabolic capacities as well as indicators of heat, oxidative and metal stresses were measured in fish muscle. Under our experimental conditions, temperature was the most important factor affecting the general condition of fish. Although no significant Cu accumulation was observed in the muscle of Cu exposed fish, at 20 degrees C, waterborne and dietary Cu triggered significant changes in the transcription level of genes encoding for proteins involved in energy metabolism, metal detoxification and protein protection. Moreover, the response was quantitatively more important for dietary Cu than for waterborne Cu. Combined exposure to heat and Cu triggered the most significant changes in gene transcription levels and enzyme activities. During combined exposure to heat and Cu, in addition to synergistic effects of the two factors, both waterborne and dietary Cu impaired the adaptive response developed by fish to curb heat stress. Reciprocally, temperature impaired the adaptive response developed by fish to combat Cu toxicity. These results suggest that wild fish populations subjected to elevated temperatures due to seasonal warming or global climate change may become more susceptible to Cu pollution, and vice versa. PMID- 21543054 TI - [Acquired nonfacial dermal melanocytosis]. PMID- 21543055 TI - [Papular elastorrhexis: a case report and principal differential diagnoses]. PMID- 21543056 TI - Crystal structures of rare disaccharides, alpha-D-glucopyranosyl beta-D psicofuranoside, and alpha-D-galactopyranosyl beta-D-psicofuranoside. AB - The crystal structures of alpha-D-glucopyranosyl beta-D-psicofuranoside and alpha D-galactopyranosyl beta-D-psicofuranoside were determined by a single-crystal X ray diffraction analysis, refined to R(1)=0.0307 and 0.0438, respectively. Both disaccharides have a similar molecular structure, in which psicofuranose rings adopt an intermediate form between (4)E and (4)T(3). Unique molecular packing of the disaccharides was found in crystals, with the molecules forming a layered structure stacked along the y-axis. PMID- 21543057 TI - Invariant chain processing is independent of cathepsin variation between primary human B cells/dendritic cells and B-lymphoblastoid cells. AB - As part of the endocytic antigen processing pathway, proteolytic cleavage of the invariant chain (Ii) is important for the generation of class II-associated invariant chain peptide (CLIP). CLIP remains associated with the major histocompatibility complex (MHC) class II molecule to prevent premature loading of antigenic peptides. Cysteine proteases, such as Cathepsin S (CatS), CatL, or CatV, play a pivotal role in the final stage of Ii degradation depending on the cell type studied. Less is known regarding the early stages of Ii processing. We therefore explored whether the serine protease CatG is involved in the initial step of Ii degradation in primary antigen presenting cells (APC), since the cathepsin distribution differs between primary APC and cell lines. While primary human B cells and dendritic cells (DC) do harbor CatG, this protease is absent in B-lymphoblastoid cells (BLC) or monocyte-derived DC generated in vitro. In addition, other proteases, such as CatC, CatL, and the asparagine endoprotease (AEP), are active in BLC and monocyte-derived DC. Here we demonstrate that CatG progressively degraded Ii in vitro resulting in several intermediates. However, pharmacological inhibition of CatG in primary B cells and DC did not alter Ii processing, indicating that CatG is dispensable in Ii degradation. Interestingly, stalling of cysteine proteases by inhibition in BLC vs. primary B cells and DC did not result in any differences in the generation of distinct Ii intermediates between the cells tested, suggesting that Ii processing is independent of the cathepsin variation within professional human APC. PMID- 21543058 TI - Re: CT colonography training for radiographers -- a formal evaluation. PMID- 21543059 TI - Gender balance in Cortex acceptance rates. PMID- 21543060 TI - [Metabolic syndrome in the urban population of Malaga]. PMID- 21543061 TI - [Febrile syndrome as a presentation form of pituitary adenoma]. PMID- 21543062 TI - [Fever in a patient with a central vein catheter]. AB - A 75-year old male, operated on three weeks earlier due to descending colon cancer and reoperated 9 days later due to suture dehiscence, began with fever without clinical focality suggestive of surgical bed infection. The patient has a bilumen catheter in the right jugular vein, through which he receives different medications and parenteral nutrition. How can catheter-related infection be diagnosed? What should be done with the catheter? When and which antibiotics are appropriate to begin treatment? What risk factors for resistant bacteria should be considered? How should S. aureus bacteraemia be treated? Is it possible to reduce the rates of catheter-related infection? These and other questions are answered in this article and a working algorithm is presented. PMID- 21543063 TI - [Adrenoleukodystrophy. An inusual cause of primary adrenal insufficiency]. PMID- 21543064 TI - [Usefulness of blood cultures in the emergency services]. PMID- 21543065 TI - [Aseptic necrosis of the cutaneous fat and fascia after administration of intravenous cocaine]. PMID- 21543066 TI - [Hemorrhagic/ischemic stroke? The answer is in the heart]. PMID- 21543067 TI - [Shewanella algae bacteremia after contact with seawater in an immunocompromised patient]. PMID- 21543068 TI - Masquelet technique for the treatment of bone defects: tips-tricks and future directions. AB - Reconstruction of diaphyseal bone defects still represents a major clinical challenge. Several approaches are used with the common objective to regenerate bone loss and restore function. The methods most commonly used are the vascularised fibula autograft and the Ilizarov bone transfer technique. Recently, Masquelet proposed a procedure combining induced membranes and cancellous autografts. The aim of this article was to briefly describe the technique, to review the current evidence and to discuss the tips and tricks that could help the surgeons to improve outcome. Future directions to increase its effectiveness and expand its application are also being discussed. However, predicting the outcome of reconstruction of bone defects remains difficult; and the patient should always be informed that, although potential complications are mostly predictable, in most of the cases the reconstruction process is long and difficult. PMID- 21543069 TI - Knowledge about emergency contraception among family-planning providers in urban Ghana. AB - OBJECTIVE: To assess the theoretical and practical knowledge about emergency contraception (EC) among family-planning (FP) providers in Ghana and to examine the association between FP providers' theoretical and practical knowledge. METHODS: Data on 600 FP providers were collected through a census of facilities offering FP services in Kumasi, Ghana, in 2008. Nested linear multivariate regression analysis was used to identify sociodemographic, facility-related, and work-related variables associated with FP providers' theoretical and practical knowledge about EC. RESULTS: On average, FP providers gave 4.1 correct answers to the 11 questions assessing theoretical knowledge and 5.6 correct answers to the 8 questions assessing their practical ability to provide EC. The FP providers seemed to learn provision-related aspects through practice without having a particularly good theoretical knowledge on EC as a contraceptive method. The health sector in which FP providers worked, their education and having received EC-specific training, the number of services offered, and the number of women seen during a week were all significant correlates of both theoretical and practical knowledge about EC. The 2 knowledge domains were significantly and positively associated. CONCLUSION: There is need to improve knowledge about EC among FP providers in Ghana through in-service training. PMID- 21543070 TI - Anatomic variation in the elastic inhomogeneity and anisotropy of human femoral cortical bone tissue is consistent across multiple donors. AB - Numerical models commonly account for elastic inhomogeneity in cortical bone using power-law scaling relationships with various measures of tissue density, but limited experimental data exists for anatomic variation in elastic anisotropy. A recent study revealed anatomic variation in the magnitude and anisotropy of elastic constants along the entire femoral diaphysis of a single human femur (Espinoza Orias et al., 2009). The objective of this study was to confirm these trends across multiple donors while also considering possible confounding effects of the anatomic quadrant, apparent tissue density, donor age, and gender. Cortical bone specimens were sampled from the whole femora of 9 human donors at 20%, 50%, and 80% of the total femur length. Elastic constants from the main diagonal of the reduced fourth-order tensor were measured on hydrated specimens using ultrasonic wave propagation. The tissue exhibited orthotropy overall and at each location along the length of the diaphysis (p < 0.0001). Elastic anisotropy increased from the mid-diaphysis toward the epiphyses (p < 0.05). The increased elastic anisotropy was primarily caused by a decreased radial elastic constant (C(11)) from the mid-diaphysis toward the epiphyses (p < 0.05), since differences in the circumferential (C(22)) and longitudinal (C(33)) elastic constants were not statistically significant (p > 0.29). Anatomic variation in intracortical porosity may account for these trends, but requires further investigation. The apparent tissue density was positively correlated with the magnitude of each elastic constant (p < 0.0001, R(2) > 0.46), as expected, but was only weakly correlated with C(33)/C(11) (p < 0.05, R(2) = 0.04) and not significantly correlated with C(33)/C(22) and C(11)/C(22). PMID- 21543071 TI - Preparative separation of alkaloids from Gelsemium elegans Benth. using pH-zone refining counter-current chromatography. AB - Alkaloids in Gelsemium elegans possess a variety of therapeutic properties, including tumor suppression, analgesic and anti-inflammatory effects. In China, G. elegans has been used for centuries to treat a variety of medical conditions, including chronic pain and skin ulcer. Methods currently used to separate the active components of G. elegans are time-consuming and have low recovery. In the present study, we used pH-zone-refining counter-current chromatography to separate major alkaloids from a crude extract of G. elegans. The two-phase solvent system was methyl tert-butyl ether (MtBE)/acetonitrile/water (3:1.5:4, v/v). Triethylamine (20 mM) was added to the upper organic stationary phase as a retainer. Hydrochloric acid (10 mM) was added to the lower aqueous phase as an eluter. From 1.5 g of crude extract, we obtained 312 mg gelsemine, 420 mg koumine and 195 mg gelsevirine, with purities at 94.8%, 95.9% and 96.7%, respectively, which were determined by HPLC at 256 nm. The chemical identity of the isolated compounds was verified by electrospray ionization-mass spectrometry (ESI-MS), 1H NMR and 13C NMR. These results demonstrated that pH-zone-refining counter-current chromatography is an effective method to separate and purify major alkaloids from G. elegans. PMID- 21543072 TI - The design and use of a simple System Suitability Test Mix for generic reverse phase high performance liquid chromatography-mass spectrometry systems and the implications for automated system monitoring using global software tracking. AB - The development of a seven-component test mixture designed for use with a generic gradient and a reversed-phase high performance liquid chromatography-mass spectrometry (RP-HPLC-MS) system is discussed. Unlike many test mixtures formulated in order to characterise column quality at neutral pH, the test mixture reported here was designed to permit an overall suitability assessment of the whole liquid chromatography-mass spectrometry (LCMS) system. The mixture is designed to test the chromatographic performance of the column as well as certain aspects of the performance of the individual instrumental components of the system. The System Suitability Test Mix can be used for low and high pH generic reverse phase LCMS analysis. Four phthalates are used: diethyl phthalate (DEP), diamyl phthalate (DAP), di-n-hexyl phthalate (DHP) and dioctyl phthalate (DOP). Three other probes are employed: 8-bromoguanosine (8-BG), amitryptyline (Ami), and 4-chlorocinnamic acid (4-CCA). We show that analysis of this test mixture can alert the user when any part of the system (instrument or column) contributes to loss of overall performance and may require remedial action and demonstrate that it can provide information that enables us to document data quality control. PMID- 21543073 TI - Simple models for the effect of aliphatic alcohol additives on the retention in reversed-phase liquid chromatography. AB - Four retention models for the effect of aliphatic alcohol additives on the retention of analytes in reversed-phase liquid chromatography have been developed following either a semi-thermodynamic treatment or an empirical approach. Their performance was tested using the experimental retention times of six non-polar analytes (alkylbenzenes) and ten o-phthalaldehyde derivatives of amino acids under different isocratic chromatographic runs when a small amount of ethanol, 1 propanol, 1-butanol, 1-pentanol, 1-hexanol or 1-heptanol was added to methanol/water mixtures containing a constant amount of methanol. It was shown that for the structurally simple alkylbenzenes all the models can be adopted for retention prediction with good results. In contrast, just one out of four models, that with the fewest approximations, predicts satisfactorily the retention properties of amino acids derivatives. However, the most interesting feature is that this model can predict the effect of an alcohol-additive on the retention properties of solutes, even if this additive was not used in chromatographic runs done for the fitting procedure, provided that it belongs to the same homologous series of alkanols. This feature is also observed in all models described the retention of alkylbenzenes. PMID- 21543074 TI - Ionic liquids-assisted fabrication of silica-based monolithic columns. AB - The mesopores of a monolithic silica column are very important and useful for chromatographic separation since they can offer sufficiently large surface area. In this paper, a novel method with the assistance of an ionic liquid (1-butyl-3 methylimidazolium tetrafluoroborate ([bmin]BF4) was developed for the preparation of a C18-modified monolithic silica column for the first time, in which, the through pores and mesopores were formed simultaneously during the sol-gel reaction. The method is effective to simplify the preparation process of the silica-based monolithic columns. The factors influencing the sol-gel process, including the content of methanol and pH, were studied. The chromatographic performance of the prepared monolithic column was evaluated by the separation of alkylbenzenes. PMID- 21543075 TI - Imidazoline type stationary phase for hydrophilic interaction chromatography and reversed-phase liquid chromatography. AB - An imidazoline was prepared by solvent-free microwave-assisted organic synthesis and immobilized on porous silica particles by polymerization. The resulting material was composed of both hydrophobic alkyl ester chains and hydrophilic imidazoline rings, which gave it both hydrophilic interaction and reversed-phase characteristics. The titration curve suggests that the new material has buffering capacity and acquires increasing positive charge over the pH range 9-4, and is "zwitterionic" in the upper part of this pH range. Through investigating the effect of column temperature, the water content, pH and ion strength of mobile phase on the retention time of polar compounds in highly organic eluents, it was found that the new material could be used as a hydrophilic interaction liquid chromatography (HILIC) stationary phase which involved a complex retention process consisting of partitioning, surface adsorption and electrostatic interactions. In addition, the retention behavior of aromatic compounds in different mobile phase conditions was also studied, which showed the new material mainly exhibited a partitioning mechanism in the reversed-phase liquid chromatography (RPLC) mode. The separation of six water-soluble vitamins and five aromatic compounds were achieved by using the new material in the HILIC and RPLC modes, respectively. PMID- 21543076 TI - Carbon nanofibers extracted from soot as a sorbent for the determination of aromatic amines from wastewater effluent samples. AB - The isolation and characterization of carbon nanofibers from soot obtained by burning natural oil is reported. The fibers were extracted from the soot with tetrahydrofuran followed by sonication. The carbon nanofibers were mixed with poly(vinyl alcohol) and electrospun to get the nanofiber mat. The extraction ability of electrospun nanofibers for the separation and preconcentration of aromatic compounds such as 3-nitroaniline, 4-chloroaniline, 4-bromoaniline and 3,4-dichloroaniline were tested and efficiently evaluated using high performance liquid chromatography. Under optimized conditions, the method showed good linearity in a range of 0.5-50 MUg L-1 with correlation coefficient ranging from 0.989 to 0.998. High precision of the extraction with RSD values of 4.5-5.8% and low LOD value in a range of 0.009-0.081MUg L-1 for all aniline compounds were achieved. The proposed microextraction method offers advantages such as easy operation, high recovery, fast extraction, minimal use of organic solvent and elimination of tedious solvent evaporation and reconstitution steps. PMID- 21543077 TI - Electrosonic spray ionization--an ideal interface for high-flow liquid chromatography applications. AB - Electrosonic spray ionization (ESSI) has been studied as an interface between high-performance liquid chromatography (HPLC) and mass spectrometry (MS), using sample flow rates up to 3.0 ml min-1. This ionization interface was compared with pneumatically assisted electrospray ionization (ESI) using mass spectrometry for detection. For experiments that did not involve direct comparison of different flow rates, the ESI experiments were performed using post column splitting to work at optimal conditions. ESSI allows the interfacing of conventional or high resolution liquid chromatography (LC) methods to mass spectrometry without post column splitting. High sample flow rates could be handled without a significant loss of signal intensity using a nebulization gas flow rate of 5.5 L min-1. Since ESI needs to be operated with lower sample flow rates, it is limited to micro/nano LC systems, or post column splitting must be used. In particular, nano LC systems have to be treated with great care and require constant maintenance. When using post-column splitting, the increased diffusion can become a problem especially when using systems with very small void volumes. In all experiments ESSI showed better signal intensities than a commercially available, pneumatically assisted ESI source. ESSI does not require heating of the nebulizer gas, which should help to preserve the original structure of thermally unstable molecules. Therefore, ESSI is presented as an alternative to the commercially available heated ESI sources of AB SCIEX, Thermo Fischer, Agilent and Waters. The observed LC-ESSI-MS ion chromatograms are shown to be very stable even when using flow rates higher than 1.0 ml min-1, which could be very suitable for ultra high performance LC, where sample flow rates up to 2.0 mL min-1 with backpressures up to 1200 bar are used. Also, a difference in the relative intensities of singly and doubly protonated peptide monomers and dimers was observed between the two ionization methods. The coefficients of determination for the calibration of instrument response for Val-Tyr-Val and Met-Enkephalin showed excellent linearity over a wide concentration range (0.1-100 MUM), while ESI results were only linear over a much smaller range (0.1-20 MUM). The observed behavior is thought to be caused by insufficient ionization efficiency of solutions above ~20 MUM by ESI, exemplifying the robustness of ESSI as an interface between LC and MS. PMID- 21543078 TI - Ion-pairing reversed-phase liquid chromatography fractionation in combination with isotope labeling reversed-phase liquid chromatography-mass spectrometry for comprehensive metabolome profiling. AB - We report a novel two-dimensional (2D) separation strategy aimed at improving the detectability of liquid chromatography mass spectrometry (LC-MS) for metabolome analysis. It is based on the use of ion-pairing (IP) reversed-phase (RP) LC as the first dimension separation to fractionate the metabolites, followed by isotope labeling of individual fractions using dansylation chemistry to alter the physiochemical properties of the metabolites. The labeled metabolites having different hydrophobicity from their unlabeled counterparts are then separated and analyzed by on-line RPLC Fourier-transform ion-cyclotron resonance mass spectrometry (FTICR-MS). This off-line 2D-LC-MS strategy offers significant improvement over the one-dimensional (1D) RPLC MS technique in terms of the number of detectable metabolites. As an example, in the analysis of a human urine sample, 3564 13C-/12C-dansylated ion pairs or metabolites were detected from seven IP RPLC fractions, compared to 1218 metabolites found in 1D-RPLC-MS. Using a library of 220 amine- and phenol-containing metabolite standards, 167 metabolites were positively identified based on retention time and accurate mass matches, which was about 2.5 times the number metabolites identified by 1D-RPLC MS analysis of the same urine sample. PMID- 21543079 TI - New model describing adsorption from liquid binary mixtures of nonelectrolytes with limited and unlimited miscibility of components. AB - Using the thermodynamic idea of complementary systems, and based on fundamental concepts of the theory of volume filling of micropores, we derived a new universal model describing adsorption from solutions with limited and unlimited miscibility of components. The model takes into account the differences in collision diameters of adsorbed molecules as well as the competitive nature of adsorption from solutions. The applicability of this new approach is tested against experimental data. PMID- 21543080 TI - Adsorption of heavy metal ions from aqueous solution by polyrhodanine encapsulated magnetic nanoparticles. AB - Polyrhodanine-coated gamma-Fe(2)O(3) nanoparticles, synthesized by one-step chemical oxidation polymerization, were applied to the process of removal of heavy metal ions from aqueous solution. Factors influencing the uptake of heavy metal ions such as solution pH, initial metal ion concentration, contact time, and species of metal ions were investigated systematically by batch experiments. The adsorption equilibrium study exhibited that the Hg(II) ion adsorption of polyrhodanine-coated magnetic nanoparticles followed a Freundlich isotherm model than a Langmuir model. The kinetic data of adsorption of Hg(II) ion on the synthesized adsorbents were best described by a pseudo-second-order equation, indicating their chemical adsorption. In addition, the synthesized nano adsorbents can be repeatedly used with help of an external magnetic field due to their magnetic properties. This work demonstrates that the magnetic polyrhodanine nanoparticles can be considered as a potential recyclable adsorbent for hazardous metal ions from wastewater. PMID- 21543081 TI - Synergism and foaming properties in binary mixtures of a biosurfactant derived from Camellia oleifera Abel and synthetic surfactants. AB - A biosurfactant, named tea saponin (TS), was isolated and purified from the defatted seed of Camellia oleifera Abel. The characterization of TS including molecular weight, glycosyl composition, and thermal behavior as well as the surface and foaming properties was conducted. The synergistic interactions of binary systems of CTAB-TS, SDS-TS, and Brij35-TS were investigated. The results show that TS had a weight-average molecular weight of 809.12 g mol(-1) and contained four aglycones of L-rhamnose, D-galactose, D-glucose, and D-glucuronic acid. The critical micelle concentration (cmc) of 2.242 mmol L(-1) and the minimum surface tension (gamma(cmc)) of 43.5 mN m(-1) were determined for TS. Synergisms in surface tension reduction efficiency, in mixed micelle formation, and in surface tension reduction effectiveness were observed in CTAB-TS and SDS TS systems, whereas that was not shown in Brij35-TS mixtures. The mixtures of TS with CTAB and SDS showed synergism in foaming efficiency, but this synergism did not exist in Brij35-TS system with respect to the surface properties. Nevertheless, there appears to be no significant correlation between foam stability and the surface properties. PMID- 21543082 TI - Kinetics of bacterial potentiometric titrations: the effect of equilibration time on buffering capacity of Pantoea agglomerans suspensions. AB - Several recent studies have made use of continuous acid-base titration data to describe the surface chemistry of bacterial cells as a basis for accurately modelling metal adsorption to bacteria and other biomaterials of potential industrial importance. These studies do not share a common protocol; rather they titrate in different pH ranges and they use different stability criteria to define equilibration time during titration. In the present study we investigate the kinetics of bacterial titrations and test the effect they have on the derivation of functional group concentrations and acidity constants. We titrated suspensions of Pantoea agglomerans by varying the equilibration time between successive titrant additions until stability of 0.1 or 0.001 mV s(-1) was attained. We show that under longer equilibration times, titration results are less reproducible and suspensions exhibit marginally higher buffering. Fluorescence images suggest that cell lysis is not responsible for these effects. Rather, high DOC values and titration reversibility hysterisis after long equilibration times suggest that variability in buffering is due to the presence of bacterial exudates, as demonstrated by titrating supernatants separated from suspensions of different equilibration times. It is recommended that an optimal equilibration time is always determined with variable stability control and preliminary reversibility titration experiments. PMID- 21543083 TI - Supercrystal structures of polyhedral PbS nanocrystals. AB - The construction of supercrystals with non-spherical building blocks has attracted increasing attention due to their potential applications in the fabrication of novel devices. In this study, we report the large-scale preparation of dimension-controllable supercrystals of polyhedral PbS nanocrystals through a solvent evaporation approach. Because of the capillary flow of the drying droplet on the substrate, nanocrystals self-assemble into three distinct types of supercrystals on specific regions of the substrate during the solvent evaporation: two-dimensional supercrystals appear in the central region; three-dimensional faceted supercrystals and three-dimensional bulk supercrystals are found near the edge of the substrate. Moreover, the formation of superlattice structure of each type of supercrystals can be tuned by changing the shape of building blocks. The influences of experimental factors on self assembly are investigated as well. We anticipate that our research can provide some new insights into the construction of supercrystals with novel structures and large sizes. PMID- 21543084 TI - Adsorption of benzoic acid from aqueous solution by three kinds of modified bentonites. AB - Benzoic acid removal is important for the water treatment, and adsorption is an efficient treatment process. Three kinds of modified bentonites, hydroxy-aluminum pillared bentonite (Al(OH)-Bent), octadecyl trimethyl ammonium chloride modified bentonite (OTMAC-Bent), and both octadecyl trimethyl ammonium chloride and hydroxy-aluminum modified bentonite (Al(OH)-OTMAC-Bent) were prepared and characterized by XRD, FTIR, and BET analysis. Experiments were conducted on the adsorption of benzoic acid by the prepared modified bentonites at different temperatures in batch experiments. The results show benzoic acid adsorption capabilities of Na-Bent and Al(OH)-Bent are even low, but high for OTMAC-Bent and Al(OH)-OTMAC-Bent. Optimal conditions for the adsorption of benzoic acid on OTMAC Bent and Al(OH)-OTMAC-Bent were as follows: pH of 3.5, 0.04 g/mL adsorbent, and contact time of 90 min. Increased adsorption with temperature indicates that the adsorptions of benzoic acid onto Al(OH)-OTMAC-Bent and OTMAC-Bent are spontaneous and endothermic. The adsorption data could be well interpreted by the Langmuir model and Temkin Equation. The adsorption efficiency was higher than 85%, suggesting that OTMAC-Bent and Al(OH)-OTMAC-Bent are excellent adsorbents for effective benzoic acid removal from water. PMID- 21543085 TI - Prolonged bottle use and obesity at 5.5 years of age in US children. AB - OBJECTIVE: To examine the association between prolonged bottle use and the risk of obesity at 5.5 years of age. STUDY DESIGN: Data from the Early Childhood Longitudinal Study, Birth Cohort were analyzed for 6750 US children born in 2001. The outcome was obesity (body mass index >= 95 th percentile) at 5.5 years, and the exposure was parental report of the child using a bottle at 24 months. RESULTS: The prevalence of obesity at 5.5 years was 17.6%, and 22.3% of children were using a bottle at 24 months. The prevalence of obesity at 5.5 years was 22.9% (95% CI, 19.4% to 26.4%) in children who at 24 months were using a bottle and was 16.1% (95% CI, 14.9% to 17.3%) in children who were not. Prolonged bottle use was associated with an increased risk of obesity at 5.5 years (OR, 1.33; 95% CI, 1.05 to 1.68) after controlling for potential confounding variables (sociodemographic characteristics, maternal obesity, maternal smoking, breastfeeding, age of introduction of solid foods, screen-viewing time, and the child's weight status at birth and at 9 months of age). CONCLUSIONS: Prolonged bottle use was associated with obesity at 5.5 years of age. Avoiding this behavior may help prevent early childhood obesity. PMID- 21543087 TI - Thoracic surgery skill proficiency with chest wall tumor simulator. AB - OBJECTIVES: Inclusion of specialized simulation into surgery training may enhance the educational experience of residents. We set out to develop a simulated chest wall tumor model to teach the specifics skills needed for chest wall tumor resection with prosthetic reconstruction. METHODS: The model was constructed from porcine rib blocs and additional materials (Fig. 1A and B). Thirteen general surgery residents were asked to perform en bloc tumor resection with "mesh sandwich" reconstruction of the chest wall defect (Fig. 2A and B). Evaluation consisted of knowledge-based examination, operative time, and skill assessment with an objective checklist and subjective global rating scale. A thoracic surgeon proctored and evaluated the practice sessions. RESULTS: Scores on the knowledge-based examination suggested no association with resident training year. More time was needed by junior level residents to complete the simulated operative task, even though the average time improved with repetitive practice. Average task-specific scores were comparable amongst the resident groups. The mid level residents demonstrated the greatest improvement in skill proficiency; however, scores were consistently highest amongst the PGY-5s CONCLUSIONS: Our data suggest simulation is an effective teaching tool and training module for skill development needed for rarely performed procedures. The incorporation of this and similar simulation trainers is likely to improve surgical education and patient safety. PMID- 21543086 TI - Increasing blood glucose variability heralds hypoglycemia in the critically ill. AB - BACKGROUND: Control of hyperglycemia improves outcomes, but increases the risk of hypoglycemia. Recent evidence suggests that blood glucose variability (BGV) is more closely associated with mortality than either isolated or mean BG. We hypothesized that differences in BGV over time are associated with hypoglycemia and can be utilized to estimate risk of hypoglycemia (<50 mg/dL). MATERIALS AND METHODS: Patients treated with intravenous insulin in the Surgical Intensive Care Unit of a tertiary care center formed the retrospective cohort. Exclusion criteria included death within 24 h of admission. We describe BGV in patients over time and its temporal relationship to hypoglycemic events. The risk of hypoglycemia for each BG measurement was estimated in a multivariable regression model. Predictors were measures of BGV, infusions of dextrose and vasopressors, patient demographics, illness severity, and BG measurements. RESULTS: A total of 66,592 BG measurements were collected on 1392 patients. Hypoglycemia occurred in 154 patients (11.1%). Patient BGV fluctuated over time, and increased in the 24 h preceding a hypoglycemic event. In crude and adjusted analyses, higher BGV was positively associated with a hypoglycemia (OR 1.41, P < 0.001). Previous hypoglycemic events and time since previous BG measurement were also positively associated with hypoglycemic events. Severity of illness, vasopressor use, and diabetes were not independently associated with hypoglycemia. CONCLUSIONS: BGV increases in the 24 h preceding hypoglycemia, and patients are at increased risk during periods of elevated BG variability. Prospective measurement of variability may identify periods of increased risk for hypoglycemia, and provide an opportunity to mitigate this risk. PMID- 21543088 TI - Use of a third-generation perfluorocarbon for preservation of rat DCD liver grafts. AB - BACKGROUND: Cold storage in any of the commonly used preservation solutions is not always adequate for donation after cardiac death (DCD) liver grafts due to prolonged warm ischemic time. In this study, we used a third-generation perfluorocarbon (PFC), Oxycyte, for DCD liver graft preservation in a rat model. MATERIALS AND METHODS: Twenty-eight rats (14 in each group) were used. Thirty minutes after cardiopulmonary arrest, livers were harvested and flushed with a cold and pre-oxygenated solution of either University of Wisconsin (UW) or UW + 20% PFC. After 8 h of cold preservation in either of the investigated solutions, liver graft specimens were analyzed for evidence of ischemic injury. Hemotoxylin and eosin staining (H and E), as well as immunohistochemical analysis with anti cleaved caspase 3 antibody, was performed. Levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the preservation solution were analyzed at 1 and 8 h during preservation. RESULTS: In the PFC group, the degree of cell congestion, vacuolization and necrosis were all significantly less than in the UW group (P = 0.002-0.004). The number of cells with a positive cleaved caspase 3 antibody reaction was reduced by about 50% in comparison with the UW group (P < 0.006). The AST level in the PFC group was significantly less than in the UW group after 8 h of preservation (P < 0.048). CONCLUSION: The addition of PFC to UW solution significantly decreases the degree of histologic damage in rat DCD liver grafts. This preservation strategy can be potentially helpful for organ preservation after prolonged warm ischemia. PMID- 21543089 TI - Ischemic dose-response in the spinal cord: both immediate and delayed paraplegia. AB - BACKGROUND: Paraplegia remains a significant complication of thoracoabdominal aortic surgery. The study of this spinal cord ischemia and reperfusion injury (SCIR) has been stifled by the constraints of current models. Large animal models are costly and restricting with regard to mechanisms of both injury and protection. While few studies of a murine model of SCIR have been published, the dose-response curve of the ischemic injury has not yet been published. We hypothesized that a viable dose-response curve of the neurological injury relative to the ischemic time could be developed. MATERIALS AND METHODS: Through a cervicothoracic approach, the aortic arches of C57bl/6 mice were exposed to the origins of the left common carotid and the left subclavian arteries. The aorta was clamped between these two vessels with additional occlusion of the left subclavian artery. Ischemic times ranged from 3 to 12 min. Hindlimb motor function was observed for 48 h. Survival and motor function were evaluated. Spinal cord tissue was preserved for histologic analysis. RESULTS: Survival curves showed increasing mortality with increasing spinal cord ischemia. This model reproduced spinal cord injury ranging from immediate paraplegia to progressive paraparesis depending on the ischemic time. Spinal cord histology mirrored the extent of functional deficits. CONCLUSIONS: Reproducible spinal cord ischemic injury is possible in a murine model and is directly translatable to thoracoabdominal surgery. The dose-response curve demonstrates that different degrees of injury can be studied from dense paraplegia to delayed onset injury depending on the ischemic insult. PMID- 21543090 TI - [Anti-synthetase syndrome]. PMID- 21543092 TI - [Alendronate and resorptive hypercalciuria]. PMID- 21543091 TI - [Salvage treatment with infliximab of steroid-resistant graft-versus-host disease in allogeneic transplanted patients]. AB - BACKGROUND AND OBJECTIVE: Severe acute graft versus host disease (GVHD) and extensive chronic GVHD not responding to steroids have poor prognosis. Infliximab has reported to be effective in some of these patients. The efficacy of infliximab for the treatment of patients with steroid-resistant GVHD was evaluated. PATIENTS AND METHODS: Retrospective analysis to evaluate the activity and toxicity of infliximab in 9 patients with acute or chronic steroid resistant GVHD. RESULTS: Six patients had acute GVHD and 3 chronic GVHD. The source of progenitors was peripheral blood in all patients except one. Six received matched related SCT and 3 unrelated SCT. Patients received between 2 and 7 doses of infliximab, and 5 achieved a partial response. All patients presented infections: 4 developed Pseudomonas aeruginosa septicemia and 5 probable or confirmed infection by Aspergillus fumigatus. CONCLUSIONS: Infliximab provides transient response in steroid-resistant GVHD. However, it is associated with a high rate of infections. Earlier administration of infliximab should be explored to reduce the frequency of infections. PMID- 21543093 TI - [What should be done in the event of incidental meningioma?]. AB - BACKGROUND AND PURPOSE: The growing use of magnetic resonance and computed tomography imaging has facilitated the diagnosis of brain tumours even before the presence of clinical signs. A significant proportion of incidental lesions identified will be meningiomas, i.e. more than 40% of the diagnosed meningiomas are not associated with clinical signs. The natural history of incidental asymptomatic intracranial meningiomas must be known to develop the optimal therapeutic strategy: what is the tumor growth rate? How many asymptomatic tumours eventually become symptomatic? METHOD: The literature was reviewed in an attempt to answer these questions. RESULTS: In cases of incidental meningioma, its location, size and radiological aspect, the patient's age, the eventual unknown symptoms and the multiplicity of the lesions must all be considered. The radiological characteristics associated with low tumoral growth rate are the existence of calcifications and hypointense regions on T2-weighted MR images. On the radiological aspect, more than 60% of asymptomatic meningiomas will not grow in size. However, some meningiomas, even small in size, must be treated because of their location or the risk of producing neurological deficits. CONCLUSION: We recommend neurosurgical consultation for all patients with an incidental meningioma. PMID- 21543094 TI - Diverse facets of plant proteomics. PMID- 21543095 TI - Characterisation of the arabinose-rich carbohydrate composition of immature and mature marama beans (Tylosema esculentum). AB - Marama bean (Tylosema esculentum) is an important component of the diet around the Kalahari Desert in Southern Africa where this drought resistant plant can grow. The marama bean contains roughly 1/3 proteins, 1/3 lipids and 1/3 carbohydrates, but despite its potential as dietary supplement little is known about the carbohydrate fraction. In this study the carbohydrate fraction of "immature" and "mature" marama seeds are characterised. The study shows that the marama bean contains negligible amounts of starch and soluble sugars, both far less than 1%. The cell wall is characterised by a high arabinose content and a high resistance to extraction as even a 6M NaOH extraction was insufficient to extract considerable amounts of the arabinose. The arabinose fraction was characterised by arabinan-like linkages and recognised by the arabinan antibody LM6 and LM13 indicating that it is pectic arabinan. Two pools of pectin could be detected; a regular CDTA (1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid) or enzymatically extractable pectin fraction and a recalcitrant pectin fraction containing the majority of the arabinans, of which about 40% was unextractable using 6M NaOH. Additionally, a high content of mannose was observed, possibly from mannosylated storage proteins. PMID- 21543096 TI - Vaccine immune response and interference of colostral antibodies in calves vaccinated against rabies at 2, 4 and 6 months of age born from antirabies revaccinated females. AB - Considering the high prevalence of rabies in cattle, we aimed to evaluate the interference of colostral antibodies transferred to calves after birth and the benefit of administering an antirabies vaccination in two-month-old calves compared to vaccinating at 4 and 6 months of age. Calves born from females revaccinated against rabies during the third trimester of pregnancy were studied. Forty-eight hours after parturition, blood samples from dams and offspring were collected, and antirabies neutralizing antibody titers were analyzed using the Rapid Focus Fluorescent Inhibition Test. We found that all calves had similar titers of antibodies transferred through the colostrum. Furthermore, none of the calves presented a satisfactory serological response after the first vaccination, but all had an appropriate response after revaccination. This study demonstrates that antirabies vaccination should be recommended for calves at two months of age in endemic and epizootic situations. PMID- 21543097 TI - Manipulation of the gut microbiota in C57BL/6 mice changes glucose tolerance without affecting weight development and gut mucosal immunity. AB - Inflammatory diseases such as type 2 diabetes (T2D) in humans and mice are under the influence of the composition of the gut microbiota (GM). It was previously demonstrated that treating Lep(ob) mice with antibiotics improved glucose tolerance. However, wild type C57BL/6J mice may also exhibit plasma glucose intolerance reminiscent of human T2D. We hypothesized that antibiotic treatment in C57BL/6 mice would have an impact on glucose tolerance without affecting weight and gut immunology. When compared to mice treated with erythromycin or the controls, treatment for five weeks with ampicillin improved glucose tolerance without significantly affecting the weight or the number of gut mucosal regulatory T cells, tolerogenic dendritic cells or T helper cells type 1. 16S rRNA gene based denaturing gradient gel electrophoresis profiles clearly clustered according to treatment and showed that antibiotic treatment reduced GM diversity. It is concluded that antibiotic treatment changes glucose metabolism as well as the composition of the GM in C57BL/6 mice, and that this does not seem to be correlated to weight development in the mice. PMID- 21543098 TI - Seroprevalence of Leishmania infantum in a rural area of Senegal: analysis of risk factors involved in transmission to humans. AB - Whereas Leishmania infantum, the agent of visceral leishmaniasis (VL), is well known in North Africa, very limited data exist on its spread in West Africa, where mainly cutaneous leishmaniasis has been widely reported. Nevertheless, dogs infected with L. infantum were recently found in the Mont Rolland District in Senegal. To provide a better understanding of L. infantum epidemiology in this area, clinical and serological surveys were carried out to determine the seroprevalence of L. infantum-specific antibodies in the human population. In parallel, an analysis of environmental and individual factors associated with Leishmania antigen seropositivity was conducted to identify potential risk factors for exposure. Although no cases of VL were detected within this study, a large part of the population (73/315; 23%) was exposed to infection, with a strong age effect (being >40 years old increased the risk of being seropositive). Moreover, the presence of Nebedaye trees (Moringa oleifera) and infected dogs in the household were factors increasing the risk of exposure in household members. These results may provide important information to identify the still unknown sandfly species involved in transmission. PMID- 21543099 TI - Improved culture-based detection and quantification of Burkholderia pseudomallei from soil. AB - Environmental surveillance of the Gram-negative soil bacterium Burkholderia pseudomallei, the aetiological agent of melioidosis, is important in order to define human populations and livestock at risk of acquiring the infection. This study aimed to develop a more sensitive method for the detection of B. pseudomallei from soil samples in endemic areas compared with the currently used culture method based on soil dispersion in water. We report the development of a new protocol that involves soil dispersion in a polyethylene glycol (PEG) and sodium deoxycholate (DOC) solution to increase the yield of viable B. pseudomallei from soil samples. Comparative testing of soil samples from Northeast Thailand covering a wide range of B. pseudomallei concentrations demonstrated a significantly higher recovery (P<0.0001) of B. pseudomallei colony forming units by the new method compared with the conventional method. The data indicate that using the detergents PEG and DOC not only results in a higher recovery of viable B. pseudomallei but also results in a shift in the bacterial species recovered from soil samples. Future studies on the geographical distribution and population structure of B. pseudomallei in soil are likely to benefit from the new protocol described here. PMID- 21543100 TI - Structure of nitrifying biofilms in a high-rate trickling filter designed for potable water pre-treatment. AB - This study examined the composition and structure of nitrifying biofilms sampled from a high-rate nitrifying trickling filter which was designed to pre-treat raw surface water for potable supply. The filter was operated under a range of feed water ammonia and organic carbon concentrations that mimicked the raw water quality of poorly protected catchments. The biofilm structure was examined using a combination of fluorescence in situ hybridisation and scanning electron microscopy. Biopolymers (carbohydrate and protein) were also measured. When the filter was operated under low organic loads, nitrifiers were abundant, representing the majority of microorganisms present. Uniquely, the study identified not only Nitrospira but also the less common Nitrobacter. Small increases in organic carbon promoted the rapid growth of filamentous heterotrophs, as well as the production of large amounts of polysaccharide. Stratification of nitrifiers and heterotrophs, and high polysaccharide were observed at all filter bed depths, which coincided with the impediment of nitrification throughout most of the filter bed. Observations presented here specifically linked biofilm structure with filter functionality, physically validating previous empirical modelling hypotheses regarding competitive interactions between autotrophic and heterotrophic bacteria in biofilms. PMID- 21543101 TI - Influence of GSTM1 and GSTT1 genotypes and confounding factors on the frequency of sister chromatid exchange and micronucleus among road construction workers. AB - In the present study, we have investigated the influence of polymorphism of GSTM1 and GSTT1 genes and confounding factors such as age, sex, exposure duration and consumption habits on cytogenetic biomarkers. Frequency of sister chromatid exchanges (SCEs), high frequency cell (HFC) and cytokinesis blocked micronuclei (CBMN) were evaluated in peripheral blood lymphocytes of 115 occupationally exposed road construction workers and 105 unexposed individuals. The distribution of null and positive genotypes of glutathione-S transferase gene was evaluated by multiplex PCR among control and exposed subjects. An increased frequency of CBMN (7.03+/-2.08); SCE (6.95+/-1.76) and HFC (6.28+/-1.69) were found in exposed subjects when compared to referent (CBMN - 3.35+/-1.10; SCE - 4.13+/-1.30 and HFC - 3.98+/-1.56). These results were found statistically significant at p<0.05. When the effect of confounding factors on the frequency of studied biomarkers was evaluated, a strong positive interaction was found. The individuals having GSTM1 and GSTT1 null genotypes had higher frequency of CBMN, SCE and HFC. The association between GSTM1 and GSTT1 genotypes and studied biomarkers was found statistically significant at p<0.05. Our findings suggest that individuals having null type of GST are more susceptible to cytogenetic damage by occupational exposure regardless of confounding factors. There is a significant effect of polymorphism of these genes on cytogenetic biomarkers which are considered as early effects of genotoxic carcinogens. PMID- 21543102 TI - Effects of solids retention time on the performance of bioreactors bioaugmented with a 17beta-estradiol-utilizing bacterium, Sphingomonas strain KC8. AB - This study investigated the performance of lab-scale sequencing batch reactors (SBRs) that were inoculated with nitrifying activated sludge and bioaugmented with a Sphingomonas strain KC8 (a 17beta-estradiol-degrading bacterium). The bioaugmented SBRs were supplied with synthetic wastewater (average initial total organic carbon (TOC)=175 mgL(-1) and average initial ammonia-N=25 mgL(-1)) and daily dose of 17beta-estradiol (1mgL(-1)) and operated under three solid retention times (SRTs) of 5, 10, and 20 d. After three times periods of the operating SRTs, the overall removal of TOC (>87%) and ammonia (>91%) was similar in all the SBRs. Higher 17beta-estradiol removals (>99%) were observed for the SBRs. Neither estrogens nor estrogenic activity was detected in the treated water, except some samples from the SBR operating under 5d of SRT. The ratios of known estrogen degraders (Sphingomonas strain KC8 and ammonia-oxidizing bacteria) and amoA gene to the total bacterial population decreased as SRT increased, suggesting the presence of unknown estrogen-degraders in SBRs operating at SRT=10 and 20 d. Real-time-terminal-restriction fragment length polymorphism analysis showed that the evenness of microbial community structures was not affected by the SRT; while, the diversity indices suggest that longer SRTs might lead to more diverse microbial community structure. Overall, the results suggested that bioaugmented bioreactors operating at long SRTs (10 and 20 d) were effective in removing 17beta-estradiol to the non-estrogenic treatment endpoint. PMID- 21543103 TI - Dental clinics: a point pollution source, not only of mercury but also of other amalgam constituents. AB - Current literature suggests that amalgam waste from dental clinics is a point source of mercury pollution in the environment. However, apart from mercury, other amalgam constituents (e.g. Ag, Sn, Cu, and Zn) in dental clinics' wastewater have not been reported in the literature before. The objective of this study was to evaluate the concentrations of mercury and other metals in the wastewater of some dental clinics and the influent of a wastewater treatment plant in Al-Madinah Al-Munawarah (KSA). Samples were collected over a 2-month period from three dental clinics and analyzed for metals using ICP-MS. The mean concentrations of Hg, Ag, Sn, Cu, and Zn in the samples were 5.3+/-11.1, 0.49+/ 0.96, 3.0+/-10.7, 10.0+/-14.5, and 76.7+/-106 mg L(-1), respectively. Additionally, high concentrations of other metals such as Mg (14.4+/-15.2 mg L( 1)), Mn (3.0+/-4.6 mg L(-1)), Fe (3.0+/-4.5 mg L(-1)), Sr (1.6+/-2.4 mg L(-1)), and Ba (6.9+/-10.3 mg L(-1)) were also found. These values are much higher than the local permissible limits. Most of the metals of interest were also detected in the influent of the wastewater treatment plant. This renders dental clinics wastewater a hazardous waste which should be properly treated before it is discharged into the environment. PMID- 21543104 TI - Effects of black carbon on bioturbation-induced benthic fluxes of polychlorinated biphenyls. AB - It is unknown whether carbonaceous geosorbents, such as black carbon (BC) affect bioturbation by benthic invertebrates, thereby possibly affecting sediment-water exchange of sediment-bound contaminants. Here, we assess the effects of oil soot on polychlorinated biphenyl (PCB) mass transfer from sediment to overlying water, for sediments with and without tubificid oligochaeta as bioturbators. PCB levels were so low that toxicity to the oligochaeta played no role, whereas soot levels and binding affinity of PCBs to soot were so low that pore water PCB concentrations were not significantly affected by binding of PCBs to soot. This setup left direct effects of BC on bioturbation activity as the only explanation for any observed effects on mass transfer. Mass transfer coefficients (KL) for benthic boundary layer transport were measured by a novel flux method using EmporeTM disks as a sink for PCBs in the overlying water. For the PCBs studied (logKow 5.2-8.2), KL values ranged from 0.2 to 2 cm*d(-1) in systems without tubificids. Systems with tubificids showed KL values that were a factor of 10-25 higher. However, in the presence of oil soot, tubificids did not cause an increase in mass transfer coefficients. This suggests that at BC levels as encountered under field conditions, the mechanism for reduction of sediment-water transfer of contaminants may be twofold: (a) reduced mass transfer due to strong binding of the contaminants to BC, and (b) reduced mass transfer of contaminants due to a decrease in bioturbation activity. PMID- 21543105 TI - Derivation of aquatic predicted no-effect concentration (PNEC) for 2,4 dichlorophenol: comparing native species data with non-native species data. AB - 2,4-Dichlorophenol (2,4-DCP) is known as an important chemical intermediate and an environmental endocrine disruptor. There is no paper dealing with the predicted no-effect concentration (PNEC) of 2,4-DCP, mainly due to shortage of chronic and site-specific toxicity data. In the present study, toxicity data was obtained from the tests using six Chinese native aquatic species. The HC(5) (hazardous concentration for 5% of species) was derived based on the constructed species sensitivity distribution (SSD), which was compared with that derived from literature toxicity data of non-native species. For invertebrates, the survival no-observed effect concentrations (NOECs) were 0.05 and 1.00 mg L(-1) for Macrobrachium superbum and Corbicula fluminea, respectively. NOECs based on fishes' growth were 0.10, 0.20 and 0.40 mg L(-1) for Mylopharyngodon piceus, Plagiognathops microlepis and Erythroculter ilishaeformis, respectively. For aquatic plant Soirodela polyrhiza, NOEC based on concentration of chlorophyll was 1.00 mg L(-1). A final PNEC calculated using the SSD approach with a 50% certainty based on different taxa ranged between 0.008 and 0.045 mg L(-1). There is no significant difference between HC(5) derived from native and that from non native taxa. PMID- 21543106 TI - Clinicopathologic significance of minichromosome maintenance protein 2 and Tat interacting protein 30 expression in benign and malignant lesions of the gallbladder. AB - Gallbladder cancers are aggressive tumors with a poor prognosis and high mortality rate. To find specific biological markers for early diagnosis and prognosis and to develop possible alternative treatment strategies, we examined minichromosome maintenance protein 2 (MCM2) and Tat-interacting protein 30 (TIP30) expression in 108 gallbladder adenocarcinomas, 15 gallbladder polyps, 35 chronic cholecystitis tissues, and 46 peritumoral tissues using immunohistochemistry. Expression of MCM2 was significantly higher in adenocarcinomas than in peritumoral tissues (chi2 = 8.41; P < .01), adenomatous polyps (chi2 = 6.81; P < .01), and chronic cholecystitis (chi2 = 21.00; P < .01). In contrast, Tat-interacting protein 30 expression was significantly less in adenocarcinomas than in peritumoral tissues (chi2 = 13.26; P < .01), adenomatous polyps (chi2 = 4.76; P < .05), and chronic cholecystitis (chi2 = 18.93; P < .01). The benign lesions in gallbladder epithelium with positive MCM2 or negative Tat interacting protein 30 expression showed moderate to severe atypical hyperplasia. Expression of MCM2 and absence of Tat-interacting protein 30 were significantly associated with poor differentiation, large tumor mass, lymph node metastasis, and invasion of adenocarcinoma. Univariate Kaplan-Meier analysis showed that either elevated MCM2 (P = .006) or lowered Tat-interacting protein 30 (P = .006) expression was closely associated with shorter overall survival. Multivariate Cox regression analysis revealed that expression of MCM2 (P = .007) or nonexpression of Tat-interacting protein 30 (P = .009) was an independent predictor of a poor prognosis in adenocarcinoma. Our results suggest that overexpression of MCM2 or loss of expression of Tat-interacting protein 30 is closely related to carcinogenesis, progression, biological behavior, and prognosis of gallbladder adenocarcinoma. PMID- 21543107 TI - Influence of Klotho genotypes on plasma NO(x) levels in South Indian population. AB - INTRODUCTION: Despite experimental evidences of the influence of the aging suppressor gene Klotho, on the modulation of endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production, the contribution of its variants to the phenotypic variance of plasma nitrite and nitrate (NO(x)) has not been addressed to date. In the present study, we aimed to determine the influence of two exonic variants, KL-VS and C1818T of Klotho, on circulating NO(x) levels in South Indian population. MATERIALS AND METHODS: We genotyped the two Klotho KL VS and C1818T variants in 429 healthy South Indians and measured their plasma NO(x) concentrations by the Griess method. RESULTS: Genotype frequencies were compared in subjects with low and high NO(x) levels. An age-specific association of the Klotho C1818T variant was found with plasma NO(x) levels in subjects aged >40 years (p=0.027); the CC homozygotes were more prevalent in the low compared to the high plasma NO(x) group. However, the variant was not associated with plasma NO(x) levels in subjects aged<=40 years (p=0.799). The KL-VS variant did not have any influence on plasma NO(x) status (p=0.260). CONCLUSIONS: Our results suggest that the effect of Klotho C1818T variant on levels of plasma NO(x) becomes pronounced with age probably implying the adaptive capability of Klotho alleles to meet the age-related increasing physiological load. PMID- 21543108 TI - New recommendations for thromboelastography reference ranges for pregnant women. AB - INTRODUCTION: The target of this study was to compare thromboelastography coagulation parameters in pregnant and non-pregnant women. If appropriate, we would propose recommendations for new reference ranges for pregnant women in their third trimester. MATERIALS AND METHODS: Prospective observational study, comparing, by using thromboelastography, the blood samples of 60 healthy women in third trimester of pregnancy (group GRAV) to the samples of the control group of 43 healthy non-pregnant fertile women (group NON-GRAV). Selective percentiles were used to determine new reference limits. RESULTS: Mean values and standard deviations (SD) in both groups were as follows (GRAV vs NON-GRAV): time r 4.7 min (SD 1.7) vs. 7.8 (SD 2.8); time k1.5 min (SD 0.5) vs. 2,7 (SD 0,9); alpha angle 69.6 degrees (SD 5.5) vs. 54.4 (SD 11.5); maximum amplitude 71.3mm (SD 4.5) vs. 63.1 (SD 5.4); coagulation index 2.7 (SD 1.8) vs. -1.9 (SD 3.0); LY60 1.1% (SD 1.8) vs. 4.8 (SD 3.6). Due to statistically significant differences between both groups, we established, based on our results, these new thromboelastography reference limits for pregnant women: time r 2-8 min ("common" range 4-8 min), time k 1-3 min ("common" range 1-4 min), alpha angle 60-77 degrees ("common" range 47-74 degrees ), maximum amplitude 64-76 mm ("common" range 55-73 mm), LY60 0-3% ("common" range 0-15%), coagulation index 0-5 ("common" range (-3) - (+3)). CONCLUSIONS: It may not be suitable to use the same reference ranges for pregnant women as for the general population. Therefore, we suggest new reference limits for thromboelastography in pregnant women. PMID- 21543109 TI - Poor aspirin response in diabetic patients presenting with acute coronary syndromes: results using a near patient test. PMID- 21543110 TI - Progestins possess poor anti-estrogenic activity on murine hepatic coagulation gene transcription despite evident anti-estrogenic activity on uterine tissue. PMID- 21543111 TI - Evaluation of Fanconi anaemia genes FANCA, FANCC and FANCL in cervical cancer susceptibility. AB - OBJECTIVE: Disrupting the function of any of the 13 Fanconi anaemia (FA) genes causes a DNA repair deficiency disorder, with patients being susceptible to a number of cancer types. Variation in the family of FA genes has been suggested to affect risk of cervical cancer. The current study evaluates the influence of three genes in the FA pathway on cervical cancer risk in Swedish women. METHODS: TagSNPs in FANCA, FANCC and FANCL were selected using the Tagger algorithm in Haploview. A total of 81 tagSNPs were genotyped in 782 cases (CIN3 or ICC) and 775 controls using the Illumina GoldenGate Assay and statistically analyzed for association with cervical cancer. RESULTS: 72 SNPs were successfully genotyped in >98% of the samples. Nominal associations were detected for FANCA rs11649196 (p=0.05) and rs4128763 in FANCC (p=0.02). The associations did not withstand correction for multiple testing. CONCLUSIONS: The current study does not support that genetic variation in FANCA, FANCC or FANCL genes affects susceptibility to cervical cancer in the Swedish population. PMID- 21543112 TI - HIPEC in recurrent ovarian cancer patients: morbidity-related treatment and long term analysis of clinical outcome. AB - OBJECTIVE: To evaluate morbidity and mortality rates associated with the use of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) after optimal cytoreduction (CRS) in a large single-institutional series of platinum-sensitive recurrent ovarian cancer patients. Moreover, disease free (DFS) and overall survival (OS) of previously studied patients have been assessed after a longer follow-up period. METHOD: From May 2005 to October 2010, recurrent ovarian cancer patients with a platinum-free interval of at least 6 months have been prospectively enrolled in a protocol of CRS plus HIPEC with oxaplatinum (460 mg/m(2)) heated to 41.5 degrees C for 30 min, followed by 6 cycles of systemic chemotherapy with taxotere 75 mg/m(2) and oxaliplatin 100 mg/m(2). RESULTS: Forty one patients experienced 43 procedures (CRS+HIPEC). An optimal cytoreduction was achieved in all cases (CC-0 95.3%; CC-1 4.7%). A complication rate of 34.8% was registered, with no case of intraoperative death or within 30 days after surgery. Survival curves have been calculated in a group of 25 patients with a minimum follow-up of 18 months, obtaining a median DFS and OS of 24 (range 6-60) and 38 months (range 18-60), respectively. CONCLUSION: In recurrent platinum-sensitive ovarian cancer patients, the use of CRS plus HIPEC represents a safe treatment, able to significantly influence the survival rates compared to chemotherapy alone or surgery plus standard chemotherapy. PMID- 21543113 TI - Social context in school: its relation to adolescents' depressive mood. AB - This study examined the impact of various school-related factors on adolescents' depressive mood, including prosocial behavior, verbal aggression, and relationships with teachers. The data used in this study were collected in the context of a larger survey on victimization in secondary schools from the French Community of Belgium. Participants were 2896 secondary school students (1520 males; 1376 females) aged 12-18 years. Results showed that for both genders, the three strongest predictors of depressive mood were age, feeling of exclusion, and verbal aggression. This study focusing on school-related predictors of depressive mood confirmed the importance of the social context in school as a predictor of depression in both girls and boys. PMID- 21543114 TI - Tissue-engineered bone formation using periosteal-derived cells and polydioxanone/pluronic F127 scaffold with pre-seeded adipose tissue-derived CD146 positive endothelial-like cells. AB - The aim of this study was to generate tissue-engineered bone formation using periosteal-derived cells seeded into a polydioxanone/pluronic F127 (PDO/Pluronic F127) scaffold with adipose tissue-derived CD146 positive endothelial-like cells. Considering the hematopoietic and mesenchymal phenotypes of adipose tissue derived cells cultured in EBM-2 medium, CD146 positive adipose tissue-derived cells was sorted to purify more endothelial cells in characterization. These sorted cells were referred to as adipose tissue-derived CD146 positive endothelial-like cells. Periosteum is a good source of osteogenic cells for tissue-engineered bone formation. Periosteal-derived cells were found to have good osteogenic capacity in a PDO/Pluronic F127 scaffold, which could provide a suitable environment for the osteoblastic differentiation of these cells. Through the investigation of capillary-like tube formation on matrigel and the cellular proliferation of adipose tissue-derived CD146 positive endothelial-like cells cultured in different media conditions, we examined these cells could be cultured in EBM-2 with osteogenic induction factors. We also observed that the osteogenic activity of periosteal-derived cells could be good in EBM-2 with osteogenic induction factors, in the early period of culture. The experimental results obtained in the miniature pig model suggest that tissue-engineered bone formation using periosteal-derived cells and PDO/Pluronic F127 scaffold with pre-seeded adipose tissue-derived CD146 positive endothelial-like cells can be used to restore the bony defects of the maxillofacial region when used in clinics. PMID- 21543115 TI - Genomic instability of gold nanoparticle treated human lung fibroblast cells. AB - Gold nanoparticles (AuNPs) are one of the most versatile and widely researched materials for novel biomedical applications. However, the current knowledge in their toxicological profile is still incomplete and many on-going investigations aim to understand the potential adverse effects in human body. Here, we employed two dimensional gel electrophoresis to perform a comparative proteomic analysis of AuNP treated MRC-5 lung fibroblast cells. In our findings, we identified 16 proteins that were differentially expressed in MRC-5 lung fibroblasts following exposure to AuNPs. Their expression levels were also verified by western blotting and real time RT-PCR analysis. Of interest was the difference in the oxidative stress related proteins (NADH ubiquinone oxidoreductase (NDUFS1), protein disulfide isomerase associate 3 (PDIA3), heterogeneous nuclear ribonucleus protein C1/C2 (hnRNP C1/C2) and thioredoxin-like protein 1 (TXNL1)) as well as proteins associated with cell cycle regulation, cytoskeleton and DNA repair (heterogeneous nuclear ribonucleus protein C1/C2 (hnRNP C1/C2) and Secernin-1 (SCN1)). This finding is consistent with the genotoxicity observed in the AuNP treated lung fibroblasts. These results suggest that AuNP treatment can induce oxidative stress-mediated genomic instability. PMID- 21543117 TI - KLFs and ATRA-induced differentiation: new pathways for exploitation. PMID- 21543116 TI - Alginate oligosaccharide protects against endoplasmic reticulum- and mitochondrial-mediated apoptotic cell death and oxidative stress. AB - Oxidative stress is a major component of harmful cascades activated in neurodegenerative disorders. We sought to elucidate possible effects of alginate oligosaccharide (AOS) on H(2)O(2)-induced cell death and to determine the underlying molecular mechanisms in neuron-like PC12 cells. We found that AOS treatment protected PC12 cells against H(2)O(2)-induced endoplasmic reticulum (ER) and mitochondrial-dependent apoptotic cell death. AOS promoted Bcl-2 expression, while blocked Bax expression and inhibited H(2)O(2)-induced caspase-3 activation. It also blocked PARP cleavage. AOS acted on key molecules in apoptotic cell death pathway and reduced p53, p38, c-June NH2-terminal kinase phosphorylations, inhibited NFkB, and enhanced Nrf2 activation. These results suggest that treatment of PC12 cells with AOS can block H(2)O(2)-induced oxidative stress and caspase-dependent apoptotic cascades originating from both ER and mitochondria. Our in vivo experiments further confirm the neuroprotective potential of AOS against Abeta-induced neural damage. According to our data, the involvement of caspase-independent pathway in AOS-induced protection appears to be unlikely. PMID- 21543118 TI - Field-scale dissipation of tebuconazole in a vineyard soil amended with spent mushroom substrate and its potential environmental impact. AB - The persistence, mobility and degradation of tebuconazole were assessed under field conditions in a sandy clay loam soil amended with spent mushroom substrate (SMS) at two rates. The aim was to evaluate the environmental impact of the simultaneous application of SMS and fungicide in a vineyard soil. SMS is the pasteurized and composted organic material remaining after a crop of mushroom is produced. SMS is generated in increasing amounts in La Rioja region (Spain), and could be used as soil amendment in vineyard soils, where fungicides are also applied in large amounts. The study was carried out in 18 experimental plots (6 treatments and 3 replicates per treatment) over one year. Laboratory experiments were also conducted to verify the changes over time in the adsorption of fungicide by soils and in soil dehydrogenase activity caused by the fungicide and/or SMS. Tebuconazole dissipation followed biphasic kinetics with a rapid dissipation phase, followed by a slow dissipation phase. Half-life (DT50) values ranged from 8.2 to 12.4 days, with lower DT50 for amended soils when compared to the non-amended controls. The distribution of tebuconazole through the soil profile (0-50 cm) determined at 124, 209 and 355 days after its application indicated the higher mobility of fungicide to deeper soil layers in amended soils revealing the influence of solid and dissolved organic matter from SMS in this process. Tebuconazole might be available for biodegradation although over time only chemical or photochemical degradation was evident in surface soils. The results obtained highlight the interest of field and laboratory data to design rational applications of SMS and fungicide when they are jointly applied to prevent the possible risk of water contamination. PMID- 21543119 TI - Systemic and mucosal immunity induced by attenuated Salmonella enterica serovar Typhimurium expressing ORF7 of porcine reproductive and respiratory syndrome virus. AB - Oral administration of attenuated Salmonella vaccine may provide valuable advantages such as low cost, easy preparation, and safety. Attenuated Salmonella vaccines also serve as carriers of foreign antigens and immunomodulatory cytokines. Presently, an attenuated Salmonella enterica serovar Typhimurium strain was used as a carrier for open reading frame 7 (ORF7) protein of porcine reproductive and respiratory syndrome virus (PRRSV), a swine pathogen of significant global economic importance. Initially, an attenuated S. enterica serovar Typhimurium expressing ORF7 gene derived from PRRSV Korean isolate was constructed. Following oral administration of a single dose of the attenuated Salmonella vaccine expressing PRRSV ORF7, humoral and cell-mediated immune responses specific for ORF7 were induced at both systemic and mucosal sites including spleen, mesenteric lymph node, Peyer's patch, and laminar propria, as evaluated by determining serum ORF7-specific IgG and mucosal IgA responses, as well as Th1- and Th2-type cytokine production from antigen-stimulated T cells. The induced humoral responses were sustained for at least 12weeks post immunization. In particular, the immunized mice displayed immune responses to both the foreign ORF7 antigen and Salmonella itself. The results indicate the value of attenuated S. enterica serovar Typhimurium as an oral carrier of PRRSV antigenic proteins to induce effective systemic and mucosal immunity. PMID- 21543120 TI - Epidemiological studies on primipaternity and immunology in preeclampsia--a statement after twelve years of workshops. AB - Hypertensive disorders of pregnancy (HDP) represent 10% of human births globally and the major complication preeclampsia has a 3-5% prevalence. The etiology of HDP remains uncertain; however, major advances have been made over the last 25 years. The Seventh International Workshop on Reproductive Immunology, Immunological Tolerance and Immunology of Preeclampsia 2010 celebrated its 12th Anniversary in Tioman Island in 2010. Over this period, these seven workshops have contributed extensively to immunological, epidemiological, anthropological, and even vascular debates. The defect of trophoblastic invasion encountered in preeclampsia, intra-uterine growth restriction, and to some extent preterm labor, was understood only at the end of the 1970s. On the other hand, clinical and epidemiological findings at the end of the 20th century permitted us to apprehend that "preeclampsia, the disease of primiparae" may well be a disease of first pregnancy for a couple. Among the important advances, reproductive immunology is certainly the topic where knowledge has exploded in the last decade. This paper relates some major steps in the comprehension of this disease and provides a review of epidemiological studies on the "primipaternity paradigm". It focuses on the relevance of new developments and new concepts in immunology. At the beginning of the 21st century we are possibly closer than ever to understanding the etiology of this obstetrical enigma and also the pathophysiology of global endothelial inflammation in preeclamptic women. In this quest, reproductive immunology will certainly emerge as one of the main players. PMID- 21543121 TI - Recombination mapping of the susceptibility region for sporadic inclusion body myositis within the major histocompatibility complex. AB - Susceptibility to sporadic inclusion body myositis (sIBM) in Caucasians has been consistently associated with alleles of the major histocompatibility complex (MHC) 8.1 ancestral haplotype (AH) (defined by HLA-B*0801 and HLA-DRB1*0301). In this study recombination mapping was utilised to further refine the known 8.1AH susceptibility region near HLA-DRB1*0301. Caucasian sIBM patients carrying part of the 8.1AH were genotyped for a selection of 8.1AH-haplotypic polymorphisms. A common 8.1AH-specific susceptibility region was defined, spanning 172 kb and encompassing three genes--HLA-DRB3, HLA-DRA and BTNL2. It is thus likely that 8.1AH-derived susceptibility to sIBM originates from at least one of these genes. PMID- 21543122 TI - An encephalomyelitis-specific locus on chromosome 16 in mouse controls disease development and expression of immune-regulatory genes. AB - A locus on mouse chromosome 16 was found to control experimental autoimmune encephalomyelitis (EAE) in studies using congenic mice. Genes within the congenic region control encephalomyelitis but not arthritis, indicating the presence of genes in this region involved in central nervous system (CNS) specific mechanisms. Flow cytometry analyses of expression of two candidate genes within the linked locus, Cd200 and Btla, demonstrated a significantly lower expression of CD200 on CD4+ T cells and higher expression of BTLA on B cells from the congenic mice. These results suggest that genes within this mouse chromosome 16 locus specifically control EAE development possibly through immune-regulatory cell-surface molecules. PMID- 21543123 TI - Stem cell genes are poorly expressed in chondrocytes from microtic cartilage. AB - OBJECTIVES: This study was aimed to see the difference between chondrocytes from normal cartilage compared to chondrocytes from microtic cartilage. Specific attentions were to characterize the growth of chondrocytes in terms of cell morphology, growth profile and RT-PCR analysis. STUDY DESIGN: Laboratory experiment using auricular chondrocytes. METHODS: Chondrocytes were isolated from normal and microtic human auricular cartilage after ear reconstructive surgeries carried out at the Universiti Kebangsaan Malaysia Medical Centre. Chondrocytes were cultured in vitro and subcultured until passage 4. Upon confluency, cultured chondrocytes at each passage (P1, P2, P3 and P4) were harvested and subjected to growth profile and gene expression analyses. Comparison was made between the microtic and normal chondrocytes. RESULTS: For growth profile analysis cell viability did not show significant differences between both samples. There are no significance differences between both samples in terms of its growth rate, except in passage 1 where microtic chondrocytes were significant lower in their growth rate. Population doubling time and total number of cell doubling of all samples also did not show any significant differences. Gene expression is measured using Real Time-Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). There is no significant differences in the expression of collagen type I, collagen type II, collagen type X, aggrecan core protein, elastin and sox9 genes in both samples. There are significant lower in the expression of sox2, nestin, BST-1 and OCT-4 gene in microtic chondrocytes compared to the normal chondrocytes. Stem cells markers are included in this study as stemness in cells may imply a greater proliferative potential and plasticity in vitro. CONCLUSION: Chondrocytes from microtic samples have the same properties as chondrocytes from normal samples and hold promises to be used as a starting material in the reconstruction of the external ear in future clinical application. The reduction in sox2, nestin, BST-1 and OCT-4 gene expression in microtic samples could be the possible cause of the arrested development of the external ear. PMID- 21543124 TI - Pediatric invasive sinonasal Scopulariopsis brevicaulis--a case report and literature review. AB - OBJECTIVE: Acute invasive fungal sinusitis (AIFS) appears mainly in immunocompromized patients and may be caused by various pathogens. We describe a teenager with invasive sinonasal Scopulariopsis brevicaulis and review all the reports on this rare pathogen. METHODS: A literature search on Scopulariopsis sinonasal invasive infections was performed and clinical data including age, gender, co-morbidities, treatment and prognosis was collected on all the patients. RESULTS: A 17 years old boy with acute myelocytic leukemia and Scopulariopsis brevicaulis sinonasal infection was successfully treated at our department with a combination of extensive surgical debridement and antifungal antibiotics. We found six articled describing six patients with AIFS due to Scopulariopsis species. Four patients were adults and two were children, 3 males and 3 females. Two had an infection with Scopulariopsis acremoium, one with Scopulariopsis candida and for 3 patients no data was given on the specific Scopulariopsis species. All the patients except one were immunocompromized. One patient was treated with antifungal drugs, 2 with surgery and 4 patients received antifungals and were operated. One patient died due to the fungal infection and two patients died due to other causes. CONCLUSIONS: Scopulariopsis AIFS is a life threatening disease affecting mainly immunocompromized patients, both children and adults. No clear treatment regimen has been established yet. We describe the first case of a teenager with Scopulariopsis brevicaulis sinonasal infection treated successfully with a combination of wide local excision and antifungal therapy. PMID- 21543125 TI - Suction cautery adenoidectomy (SCA): is the additional cost justified? PMID- 21543126 TI - Association of ischemic stroke to coronary artery disease using computed tomography coronary angiography. AB - BACKGROUND: While patients with coronary artery disease (CAD) and cerebrovascular disease share similar risk factor profiles, data on whether IS can be considered a "CAD equivalent" are limited. We aimed to determine whether ischemic stroke is an independent predictor of CAD by using cardiac computed tomography angiography (CTA). METHODS: We analyzed the CTA in 392 patients with no history of CAD (24 patients with acute IS and 368 patients with acute chest pain). Extent of plaque burden was additionally dichotomized into 0-4 versus >4 segments. RESULTS: Patients with IS had a near 5-fold increase odds of having coronary artery plaque (odds ratio [OR] 4.9, P<0.01) as compared to those without IS. After adjustment for age, gender, and traditional cardiac risk factors, there remained a near 4 fold increase odds for coronary plaque (adjusted OR 3.7, P=0.04). When stratified by extent of plaque, patients with IS had over 18-fold increase odds of having >4 segments of plaque than 0-4 segments as compared to patients without stroke (OR 18.3, P<0.01), which remained significantly associated in adjusted analysis (adjusted OR 12.1, P<0.001). CONCLUSION: Acute IS is independently associated with higher risk and greater extent of CAD compared to patients with acute chest pain at low-to-intermediate risk for acute coronary syndrome. PMID- 21543127 TI - Plaque volume derived from three-dimensional reconstruction of coronary angiography predicts the fractional flow reserve. AB - OBJECTIVES: To compare the data calculated from the three dimensional (3D) reconstruction of a coronary stenosis with the fractional flow reserve (FFR) values measured on the same coronary segment. METHODS: Multiple projections of 22 patients (7 female, 15 male, age: 61 +/- 9.73 years) were evaluated by the IC30 software of the Axiom Artis X-ray machine. 3D reconstruction was successfully carried out on 23 coronary arteries (14 LAD, 4 CX and 5 RCA). RESULTS: Regression analysis demonstrated significant relationship between the cross-sectional area percentage stenosis (AS) calculated based on the 3D measurement and the FFR (r: 0.566, p: 0.008), as well as between the 3D derived plaque volume (PV) and the FFR (r: -0.501, p: 0.018). On the other hand, the diameter stenosis (DS) and the minimal lumen diameter (MLD) did not correlate with the FFR values. According to the Receiver Operating Characteristic (ROC) analysis the rank of the areas under the ROC curves (AUC) was the following: 1. PV (0.76), 2. AS (0.74), 3. DS (0.62), 4. MLA (0.55), and 5. MLD (0.51). The difference between the AUC of the PV and MLA was found to be significant (p=0.02). The best agreement with the FFR was found when the PV was >44% (sensitivity 66.67%, specificity 82.35%) and the 3D AS was >60% (sensitivity 100%, specificity 47%). CONCLUSION: Besides the 3D AS the calculated PV characterizing the entire lesion is also an important predictor of the flow consequence of the stenosis. PMID- 21543128 TI - Common functional principal components analysis: a new approach to analyzing human movement data. AB - In many human movement studies angle-time series data on several groups of individuals are measured. Current methods to compare groups include comparisons of the mean value in each group or use multivariate techniques such as principal components analysis and perform tests on the principal component scores. Such methods have been useful, though discard a large amount of information. Functional data analysis (FDA) is an emerging statistical analysis technique in human movement research which treats the angle-time series data as a function rather than a series of discrete measurements. This approach retains all of the information in the data. Functional principal components analysis (FPCA) is an extension of multivariate principal components analysis which examines the variability of a sample of curves and has been used to examine differences in movement patterns of several groups of individuals. Currently the functional principal components (FPCs) for each group are either determined separately (yielding components that are group-specific), or by combining the data for all groups and determining the FPCs of the combined data (yielding components that summarize the entire data set). The group-specific FPCs contain both within and between group variation and issues arise when comparing FPCs across groups when the order of the FPCs alter in each group. The FPCs of the combined data may not adequately describe all groups of individuals and comparisons between groups typically use t-tests of the mean FPC scores in each group. When these differences are statistically non-significant it can be difficult to determine how a particular intervention is affecting movement patterns or how injured subjects differ from controls. In this paper we aim to perform FPCA in a manner allowing sensible comparisons between groups of curves. A statistical technique called common functional principal components analysis (CFPCA) is implemented. CFPCA identifies the common sources of variation evident across groups but allows the order of each component to change for a particular group. This allows for the direct comparison of components across groups. We use our method to analyze a biomechanical data set examining the mechanisms of chronic Achilles tendon injury and the functional effects of orthoses. PMID- 21543129 TI - Differentiation of acetic acid bacteria based on sequence analysis of 16S-23S rRNA gene internal transcribed spacer sequences. AB - The 16S-23S gene internal transcribed spacer sequence of sixty-four strains belonging to different acetic acid bacteria genera were analyzed, and phylogenetic trees were generated for each genera. The topologies of the different trees were in accordance with the 16S rRNA gene trees, although the similarity percentages obtained between the species was shown to be much lower. These values suggest the usefulness of including the 16S-23S gene internal transcribed spacer region as a part of the polyphasic approach required for the further classification of acetic acid bacteria. Furthermore, the region could be a good target for primer and probe design. It has also been validated for use in the identification of unknown samples of this bacterial group from wine vinegar and fruit condiments. PMID- 21543130 TI - Use of continuous intravenous insulin infusion in type 1 diabetic pregnancy complicated by nephrotic syndrome. AB - We report a case of nephrotic syndrome complicating pregnancy in a woman with CSII-treated type 1 diabetes. This was associated with deteriorating glycaemic control which was successfully managed with continuous intravenous insulin for the two weeks before delivery. PMID- 21543131 TI - Avoiding the fate of Troy: response to Arlettaz et al. AB - We agree entirely with Arlettaz et al. that we face an environmental crisis of extraordinary proportions. However, their analysis of how to respond perfectly illustrates our point. In particular, we would transpose their statement 'Although we agree that communication strategies must accommodate human psychology to succeed, we believe that neglecting or euphemizing the dramatic impact that humans have on the biosphere, just through fear of the Cassandra syndrome when addressing an inconvenient truth, is not an acceptable alternative discourse.' to 'Although acknowledging the dramatic impact humans exert on the biosphere, there is no acceptable alternative discourse; to adopting communication strategies that accommodate human psychology.' PMID- 21543132 TI - Functional significance of cleavable signal peptides of G protein-coupled receptors. AB - About 5-10% of the G protein-coupled receptors (GPCRs) contain N-terminal signal peptides that are cleaved off by the signal peptidases of the endoplasmic reticulum (ER) during the translocon-mediated receptor insertion into the ER membrane. The reason as to why only a subset of the GPCRs requires these additional signal peptides was addressed in the past decade only by a limited number of studies. Recent progress suggests that signal peptides of GPCRs do not only serve the classical ER targeting and translocon gating functions as described for the signal peptides of secretory proteins. In the case of GPCRs, uncleaved pseudo signal peptides may regulate receptor expression at the plasma membrane and may also influence G protein coupling. Moreover, signal peptides of GPCRs seem to match functionally with sequences of the mature N tails. In this review, we summarize the current knowledge about cleavable signal peptides of GPCRs and address the question whether these sequences may be future drug targets in pharmacology. PMID- 21543133 TI - [Novelties in advanced life support]. AB - We present some of the most important developments in advanced life support incorporating the new international recommendations for resuscitation 2010. The study highlights aspects related to prevention and early detection of in-hospital cardiac arrest, resuscitation in the hospital, the new advanced life support algorithm, the techniques and devices for cardiopulmonary resuscitation, post resuscitation care, assessment of the prognosis of patients who survive initially, and specific aspects of non-beating heart organ donation and the creation of cardiac arrest referral centers. PMID- 21543134 TI - [Novelities in resuscitation training methods]. AB - The importance of cardiac arrest as a health problem makes training in resuscitation a topic of great interest. It is necessary to enhance resuscitation training for all citizens, starting in schools and institutes, targeting teachers and nurses for training, to in turn become future trainers. The model of short courses with video-instruction and the use of mannequins is useful for the dissemination of resuscitation techniques. Liberalization of the use of automated external defibrillators (AED) and reduction of the training requirements in basic life support and AED for those non-health professionals who can use them, seems appropriate. Training must be improved in schools of medicine and nursing schools at undergraduate level. Health professionals should be trained according to their needs, with emphasis on non-technical skills such as leadership and teamwork. The model based on the use of trainers and low-fidelity mannequins remains a basic and fundamental element in training. Training through performance evaluation is a technique that should be implemented in all areas where cases of cardiac arrest are seen and the healthcare team has intervened. Simulation appears to be defined as the current and future modality for training in various medical areas, including of course the important field of resuscitation. Lastly, research in resuscitation training should be considered an example of translational science, where rigorous studies of skill acquisition with outcome measures serve to transfer the results to the clinical environment for analysis of their impact upon patient care. PMID- 21543136 TI - [Smoke-free school environments: between health protection and health promotion]. AB - Tobacco control policies have undergone a major boost in terms of protecting people from involuntary exposure to environmental tobacco smoke, but less progress has been made in the denormalization of smoking behaviour. We describe an experience focused on the educational environment, which included marking the waiting areas (streets) of primary schools in the city of Terrassa as "Smoke-free environments". We placed a placard with the inscription "Smoke-free environment. We educate together" on the front of 50 out of 54 primary schools in the city. The proposal was well accepted. Our experience highlights the possibility of carrying out actions, based on local initiatives, that help to denormalize smoking without the need for legislative enforcement. PMID- 21543135 TI - Prevalence of transmitted antiretroviral resistance and distribution of HIV-1 subtypes among patients with recent infection in Catalonia (Spain) between 2003 and 2005. AB - OBJECTIVES: The objectives of this study were to assess the prevalence of transmitted HIV-1 drug resistances (TDR) and HIV-1 subtypes in recently infected patients in Catalonia between 2003 and 2005 and to describe the characteristics of these patients according to the presence or absence of TDR and HIV-1 subtype. METHODS: After application of the Serological Testing Algorithm for Recent HIV Seroconversion (STARHS), residual aliquots of serum samples from recently infected antiretroviral-naive individuals were genotyped. FASTA sequences were analyzed using the HIVDB Program. The World Health Organization 2009 List of Mutations for Surveillance of Transmitted HIV-1 Drug Resistant HIV Strains was used to estimate the prevalence of TDR. RESULTS: Of 182 recently infected patients, 14 (7.7%) presented TDR. Seven (3.8%) had genotypic evidence of TDR against non-nucleoside reverse transcriptase inhibitors, 6 (3.3%) against nucleoside reverse transcriptase inhibitors, 3 (1.6%) against protease inhibitors (PIs), and only 2 individuals (1.1%) presented TDR against more than one class of drugs. Thirty-five (19.2%) patients were infected with a non-B HIV-1 subtype. CONCLUSION: This is the first study to estimate the prevalence of TDR in recently infected patients in Catalonia. The results are similar to those of studies performed in other Spanish regions. Correct monitoring of these parameters requires systematic epidemiologic surveillance of transmitted resistance. PMID- 21543137 TI - [Validity of self-reported metabolic syndrome components in a cohort study]. AB - OBJECTIVES: To assess the accuracy of self-reported data needed to constitute the metabolic syndrome in the University of Navarra Follow-Up [Seguimiento Universidad de Navarra (SUN)] cohort. METHODS: The SUN project is a multi-purpose prospective cohort, formed by more than 20,000 university graduates, followed-up using surface mail questionnaires every 2 years. In a sample of 287 cohort participants, self-reported data on the criteria needed to define the metabolic syndrome (waist circumference, blood pressure, triglycerides, high-density lipoprotein-cholesterol and glucose) were compared with the same biometric data obtained by blood tests or measured by trained medical staff. Intra-class correlation coefficients with 95% confidence intervals (95% CI), relative mean error and agreement limits according to the method proposed by Bland and Altman were calculated for each variable studied. RESULTS: High intraclass correlations were found for the values of waist circumference (r=0.86, 95% CI: 0.80-0.90) and triglycerides (r=0.71, 95%CI: 0.61-0.79). Moderate intraclass correlations were found (between 0.46 and 0.63) for the other factors. Relative mean errors were always<2.5%, and >91% of values were within the limits of agreement for all variables. CONCLUSIONS: The results suggest that self-declared data on the criteria of metabolic syndrome obtained in the SUN cohort, though with some caution, are sufficiently accurate to be used in epidemiological studies. PMID- 21543138 TI - [Transmissibility and severity of the pandemic influenza A (H1N1) 2009 virus in Spain]. AB - OBJECTIVES: To estimate the value of the basic reproduction number for the pandemic wave of influenza A (H1N1) 2009 in Spain and to assess its impact on morbidity and mortality in the Spanish population compared with those in the previous influenza season. METHODS: Data on the incidence of influenza and viral detections were obtained from the Spanish Influenza Surveillance System. Deaths from pandemic influenza were obtained from the Coordinating Center for Health Alerts and Emergencies of the Spanish Ministry of Health and Social Policy, and deaths from seasonal influenza during the period 2003-2008 were obtained from the National Statistics Institute. The reproduction number was estimated by two methods: firstly, by using the growth rate of the cumulative incidence of influenza during the exponential growth phase of the pandemic wave, and secondly (maximum likelihood estimation), through analysis the dates of onset of symptoms observed in pairs of cases based on generation time distribution. We calculated the fatality rate and mortality from influenza by comparing potential years of life lost in the pandemic season with those in previous interpandemic seasons. RESULTS: The start of the pandemic wave occurred in Spain earlier in week 40/2009 (from 4 to 10 October), with an absolute predominance of the new strain in the pattern of circulating viruses. The value of R(0) in the growth phase of the wave was 1.29 (95% CI: 1.25-1.33), estimated with the first method, and was 1.01 (95% CI: 0.99-1.03) with the second method. During the pandemic season, there were 318 deaths from pandemic influenza, affecting younger age groups than in previous interpandemic seasons. Consequently, the number of potential years of life lost in the pandemic season (11,612) was estimated at six times the adjusted annual average of the interpandemic influenza seasons for comparison (1,802). CONCLUSIONS: The estimates of R(0) for the growth phase of the pandemic wave were in the lower range of estimates of this parameter in previous pandemics. Mortality indicators calculated in the pandemic period showed an increase in deaths compared with previous interpandemic seasons, which was most pronounced in young patients. PMID- 21543139 TI - [Transparency and good healthcare governance: an aid to overcoming the crisis]. AB - Countries thrive on an economic foundation capable of facilitating the fulfillment of human potential in a society that does not renounce major achievements such as the welfare state. A necessary condition is that the "rules of the game", formal and informal institutions, make what is socially desirable individually attractive. Improving health governance, including its dimension of controlling corruption, and helping Spain out of the current economic crisis are two sides of the same coin. Characterization of health system governance in Spain and analysis of the impact of this governance on health policy, management of healthcare organizations and clinical practice allows an ambitious and feasible agenda to be drawn up of the remaining tasks that health professionals -broadly defined- and social actors should undertake with the support of citizens. PMID- 21543140 TI - Synthesis and antimicrobial activities of hexahydroimidazo[1,5-a]pyridinium bromides with varying benzyl substituents. AB - Variously substituted benzyl bromides were employed to quaternize hexahydrobenzylimidazo[1,5-a]pyridine (A) and the resulting bromides (1-11) were evaluated for their in vitro antimicrobial activity against 10 pathogenic microorganisms: Staphylococcus aureus, Staphylococcus epidermidis, Bacillus cereus, Micrococcus luteus, Proteus vulgaris, Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia, Candida albicans and Candida krusei. Antimicrobial activities were surprisingly high (MIC: 0.78-400 MUg/mL) and the sensitivity of the salts tested has been found to depend strongly both on the benzyl substituents and the microorganisms used. However, the correlation observed between antimicrobial activity and calculated partition coefficient (ClogP) was poor. Acute toxicity assessment of these salts showed LD(50) of 757 2000 mg/kg, after oral administration in mice in 24h. PMID- 21543141 TI - Synthesis and biological evaluation of novel aliphatic amido-quaternary ammonium salts for anticancer chemotherapy: part I. AB - We synthesized novel aliphatic amido-quaternary ammonium salts in an effort to discover anticancer agents that increase Ras homolog gene family, member B, (RhoB) levels. These compounds exert anti-proliferative activities against several human cancer cell types. Seventeen compounds, varying in aliphatic carbon chain length and N-substituents, were synthesized and their biological activities were evaluated. Of these 17 compounds, compound 3i emerged as the most promising anticancer compound by promoting apoptosis through the RhoB mediated pathway. Potent biological activities observed for these novel aliphatic amido-quaternary ammonium salt analogues support their potential as anticancer, chemotherapeutic agents. PMID- 21543142 TI - Factors affecting nursing students' intention to work with older people in China. AB - BACKGROUND: In Western countries, caring for older people was viewed as an unattractive area by nursing students. The literature reported a number of barriers, including ageism that contributed to this undesirable situation. AIM: The purpose of this study was to explore factors affecting nursing students' intention to work with older people in a university in China. METHOD: A cross sectional survey was conducted with 622 nursing students enrolled in a 4-year Bachelor of Nursing programme at the university. Data analysis methods mainly included Chi-Square test, Mann-Whitney test, factor analysis and logistical regression. RESULTS: Working with older people was ranked as the second to least preferred area by nursing students. Ageist attitudes described as Prejudice was negatively associated with intention to work with older people; while students aged under-20 were more positively associated with an intention to work with older people. CONCLUSION: Nursing curriculum should be designed to target ageist attitude, by promoting socialisation with older people and creating more supportive learning environments in the care setting of older people. PMID- 21543143 TI - The inflow of (238)Pu and (239+240)Pu from the Vistula River catchment area to the Baltic Sea. AB - The aim of the work was to estimate plutonium inflow from the Vistula River's catchments area to the Baltic Sea. There were differences in plutonium activities depending on season and sampling site. The highest activities of (238)Pu and (239+240)Pu were transported from the Vistula River watershed to the Baltic Sea in spring and the lowest in summer. Annually, the southern Baltic Sea is enriched via the Vistula River with 10.3 MBq of (238)Pu and 89.0MBq of (239+240)Pu. The enhanced concentration of plutonium in water from the Vistula River is the result of its runoff from the Vistula drainage area, mostly from snowmelt, enhanced rainfalls and leached materials from river bed. PMID- 21543144 TI - Hamstrings loading contributes to lateral patellofemoral malalignment and elevated cartilage pressures: an in vitro study. AB - BACKGROUND: Hamstrings loading has previously been shown to increase tibiofemoral posterior translation and external rotation, which could contribute to patellofemoral malalignment and elevated patellofemoral pressures. The current study characterizes the influence of forces applied by the hamstrings on patellofemoral kinematics and the pressure applied to patellofemoral cartilage. METHODS: Ten knees were positioned at 40 degrees , 60 degrees and 80 degrees of flexion in vitro, and loaded with 586 N applied through the quadriceps, with and without an additional 200 N applied through the hamstrings. Patellofemoral kinematics were characterized with magnetic sensors fixed to the patella and the femur, while the pressure applied to lateral and medial patellofemoral cartilage was measured with pressure sensors. A repeated measures ANOVA with three levels, combined with paired t-tests at each flexion angle, determined if loading the hamstrings significantly (P<0.05) influenced the output. FINDINGS: Loading the hamstrings increased the average patellar flexion, lateral tilt and lateral shift by approximately 1 degrees , 0.5 degrees and 0.2mm, respectively. Each increase was significant for at least two flexion angles. Loading the hamstrings increased the percentage of the total contact force applied to lateral cartilage by approximately 5%, which was significant at each flexion angle, and the maximum lateral pressure by approximately 0.3 MPa, which was significant at 40 degrees and 60 degrees . INTERPRETATION: The increased lateral shift and tilt of the patella caused by loading the hamstrings can contribute to lateral malalignment and shifts pressure toward the lateral facet of the patella, which could contribute to overloading of lateral cartilage. PMID- 21543145 TI - Manipulation of vascular function by blood flukes? AB - Schistosomes (blood flukes) are long lived, intravascular parasites that afflict ~200 million people worldwide. Here we review the potential ability of these parasites to exert control on local vascular physiology. We examine schistosome kallikrein-like proteins that drive vasodilation. We review biogenic amine metabolism in the parasites that involve the vasodilator histamine and its receptors and the vasoconstrictor serotonin and its receptor. Schistosomes can trigger the release of histamine from host cells and can import serotonin. We consider the ability of schistosomes to generate and release the eicosanoid vasodilators PGD(2) and PGE(2) and the vasoconstrictors LTB(4) and LTC(4). The literature on nitric oxide metabolism in these blood flukes is assessed. Finally the potential impact of other schistosome metabolic processes (e.g. exogenous adenosine generation and acetylcholine degradation) on vascular function is appraised. An increased understanding of these processes could lead to novel anti parasitics as well as new therapies to treat vascular dysfunction. PMID- 21543146 TI - Association of out-of-hospital cardiac arrest with prior activity and ambient temperature. AB - OBJECTIVE: Little is known about triggers of sudden cardiac arrest. This study aimed to analyze the association of the occurrence of out-of-hospital cardiac arrest (OHCA) with patient activities just before the arrest and ambient temperature as one of the major environmental factors. METHODS: This prospective, population-based cohort study enrolled all person aged 18 years or older with OHCA of presumed cardiac origin in Osaka Prefecture, Japan, from 2005 through 2007. Patient activities before arrest were divided into six categories: sleeping, bathing, working, exercising, non-specific activities, and unknown. Age adjusted annual incidence rate of OHCA according to their prior activity and an hourly event rate in each activity by temperature were calculated. RESULTS: Among 19,303 OHCAs, 10,723 were presumed to be of cardiac etiology. The event rate of OHCA was 6.22, 54.49, 1.15, and 10.11 per 10,000,000 population per hour for sleeping, bathing, working, and exercising, respectively. Among patients who suffered OHCA during bathing, the event rate of OHCA per 10,000,000 per hour increased with decreasing temperature from 18.27 (>=25.1 degrees C) to 111.42 (<=5.0 degrees C) (odds ratio [OR] for 1 degrees C increase in temperature, 0.915; 95% confidence interval [CI], 0.907-0.923), while it was almost constant among those who were working (OR for 1 degrees C increase, 0.994; 95% CI, 0.981 1.007) or exercising (OR for 1 degrees C increase, 1.004; 95% CI, 0.971-1.038) before arrest. CONCLUSION: Both activities before cardiac arrest and ambient temperature were associated with the occurrence of OHCA. Preventive measures against OHCA should be enveloped considering these behavioral and environmental factors. PMID- 21543147 TI - Do not prime too much: Prime frequency effects of masked affective stimuli on effort-related cardiovascular response. AB - This experiment investigated the prime frequency effect of masked affective stimuli on effort-related cardiovascular response. Cardiovascular reactivity was recorded during a baseline period and an attention task in which either 1/3, 2/3, or 3/3 of the trials included the presentation of masked emotional facial expressions (sad vs. happy). In the resting trials participants were exposed to masked neutral expressions. As expected, and replicating previous findings (Gendolla and Silvestrini, in press), participants in the 1/3 priming condition showed stronger systolic blood pressure reactivity--indicating more effort--when they were exposed to masked sad faces than when they were exposed to masked happy faces. This effect disappeared in the 2/3 and 3/3 conditions. Findings are interpreted as demonstrating habituation effects of masked affective stimuli on effort mobilization. PMID- 21543148 TI - Expression of beta defensins 1, 3 and 4 in chorioamniotic membranes of preterm pregnancies complicated by chorioamnionitis. AB - OBJECTIVE: To quantify the expression of human beta-defensins (HBDs) 1, 3 and 4 in chorioamniotic membranes in pregnancies complicated by prematurity associated with histologic chorioamnionitis. STUDY DESIGN: The study group included 23 fragments of chorioamniotic membranes with histologic chorioamnionitis from women with preterm premature rupture of membranes (PPROM) and preterm labor (PTL) with intact membranes, who had preterm deliveries. As a control group, 30 chorioamniotic membranes without chorioamnionitis at the same gestational age as those in the study group were included. Chorioamniotic membranes were collected for histopathological analyses, and HBD mRNA expression quantification was analyzed by real time PCR. Comparisons were performed using the Mann-Whitney or Kruskal-Wallis tests and all the women were informed and provided written consent. RESULTS: The expression of HBDs mRNA in the fetal membranes was similar in patients without histologic chorioamnionitis (HBD1: 0.7-fold, HBD3: 0.9-fold, HBD4: 0.3-fold) compared to patients with chorioamnionitis (HBD1: 1.1-fold, HBD3: 0.9-fold, HBD4: 0.4-fold; p>0.05). Regarding the gestational complications that resulted in premature delivery, PPROM or PTL, the relative quantification of HBD1, HBD3 and HBD4 showed no statistically significant differences in either the absence or presence of chorioamnionitis. Among patients with histologic chorioamnionitis, patients with PPROM (HBD1: 2.7-fold, HBD3: 0.3-fold, HBD4: 0.7 fold) presented similar mRNA expression to those with PTL (HBD1: 0.7-fold, HBD3: 1.2-fold, HBD4: 0.13-fold; p>0.05). CONCLUSIONS: Chorioamniotic membranes are sources of beta defensins 1, 3 and 4; however, considering the sample size and the methodology applied, mRNA concentrations were not related to the presence of histologic chorioamnionitis. PMID- 21543149 TI - Alterations of follicular microcirculation and apex structure during ovulation in the rat. AB - OBJECTIVE: We utilized methods for intravital microscopy and microcirculation measurements to study changes during ovulation. STUDY DESIGN: Immature gonadotrophin-primed rats were laparotomized and one ovary was examined for morphological alterations during a 3 h period (covering a period from 1h before to 27 h after hCG) through water-immersion lenses (maximum magnification 812*). Microcirculatory blood flow was assessed by measurements of blood cell velocity and laser Doppler flowmetry. RESULTS: Follicular hyperaemia was observed 30 min after hCG and then vasomotion was observed. A gradual decline of apical blood flow was seen, which later was associated with an avascular area over the top of the apex. Cells from the surface over the follicular apex were then detached from the exterior of the follicle and this phenomenon was initiated more than one hour prior to follicular rupture. The subsequent structural alterations varied with or without formation of a cone over the stigma. In ovulations with a stigma-cone, a translucent, irregular mass formed over the stigma. Prior to follicular rupture, granulosa cells and follicular fluid were extruded from the follicular cavity at a velocity of around 70 MUm/s. Occasionally, intra-antral haemorrhage occurred prior to or during follicular rupture. CONCLUSION: Characteristic features of ovulation in the rat are microcirculatory vasomotion, gradual formation of apical avascular area, specific changes of the stigma, and extrusion of the oocyte granulosa cell complex with or without haemorrhage. PMID- 21543150 TI - Bone turnover and maternal 25(OH) vitamin D3 levels during pregnancy and the postpartum period: should routine vitamin D supplementation be increased in pregnant women? AB - OBJECTIVE: To investigate the relationship between 25(OH) vitamin D3 levels and maternal bone turnover during pregnancy and lactation. STUDY DESIGN: Thirty pregnant women and 30 healthy non-pregnant controls were included the study. The pregnant women were examined in the 12th, 25th and 32nd gestational weeks and 6 weeks after delivery. The controls were examined once. Serum concentrations of 25(OH) vitamin D3, parathyroid hormone (PTH), cross-linked C-terminal telopeptide of type I collagen (CTX), calcium, and phosphate were measured. RESULTS: In the 32nd week and the postpartum period, 25(OH) vitamin D3 deficiency rates were 13.3% and 33.3%, respectively. Serum 25(OH) vitamin D3 levels were below the detection limit in 10% and 33%, respectively, of the same subjects. In the control group, rates of 25(OH) vitamin D3 deficiency and "below detection limit" were 30% and 23%, respectively. While 25(OH) vitamin D3 and CTX levels were not correlated to each other in the first trimester, a negative correlation was found in the 2nd and 3rd trimesters and the postpartum period between 25(OH) vitamin D3 and CTX levels (r=-0.472, p=0.048; r=-0.893, p<0.0001, r=-0.881, p<0.001, respectively). No correlation between 25(OH) vitamin D3 and CTX levels was found in controls. CONCLUSION: We consider that 25(OH) vitamin D3 supplementation of women could both decrease maternal bone resorption and lead to enhanced bone mass in offspring during later life. Since women are prone to 25(OH) vitamin D3 insufficiency, we suggest higher doses of 25(OH) vitamin D3 should be given to pregnant subjects. PMID- 21543151 TI - Structural basis for the role of LYS220 as proton donor for nucleotidyl transfer in HIV-1 reverse transcriptase. AB - Biochemical studies by Castro et al. have recently revealed a crucial role for a general acid in the catalysis of nucleic acid transfer in distinct classes of polymerases. For HIV-RT LYS220 was identified as proton donor. This was unanticipated from a structural point of view, since in all ternary crystal structures of HIV-RT LYS220 are too distant from the active site to fulfill this role. In this work molecular dynamics simulations were used to reveal the dynamics of HIV-RT and to provide structural evidence for the role of LYS220. During a 1MUs molecular dynamics simulation LYS220 migrates toward the active site and occupies several positions enabling direct and water mediated proton transfer towards pyrophosphate. A combination of quantum mechanical and molecular mechanics methods was used to validate the different modes of interaction. PMID- 21543152 TI - Thirty-five years of intravesical bacillus Calmette-Guerin for bladder cancer: where now? PMID- 21543153 TI - HIV-associated myasthenia gravis and impacts of HAART: one case report and a brief review. PMID- 21543154 TI - Cerebral blood flow measurement following extreme blood pressure reduction in an acute intracerebral hemorrhage patient. PMID- 21543155 TI - Monoacylglycerol lipase (MAGL) knockdown inhibits tumor cells growth in colorectal cancer. AB - OBJECTIVES: Obesity has been reported to increase the risk of colorectal cancer, which may due to aberrant lipid metabolism. And recently findings of monoacylglycerol lipase provide a novel evidence in the correlation of obesity and cancer. So in this study, we investigated the effect of MAGL in regulation of tumor growth in colorectal cancer. METHODS: MAGL expression in tumor tissues was estimated, and then JZL184 and siRNA were used to knockdown the expression of MAGL in colorectal cancer cells. Cell viability and invasion were detected to estimate the influence of MAGL knocked down in vitro and vivo. Then cell proliferation, apoptosis, cell cycle transition and screening of candidate genes were performed for further exploring of the effect mediated by MAGL knocked down. RESULTS: It was noted that the expression of MAGL was highly elevated in tumor tissues, however, it was found only significantly correlated with the BMI index. Tumor cells' growth and invasion was significantly inhibited in vitro and in vivo induced by pharmacological and siRNA mediated MAGL knocked down. Cell proliferation was reduced and apoptosis was increased. And two target genes Cyclin D1 and Bcl-2 seemed to be repressed by MAGL knocked down. CONCLUSIONS: This study demonstrated colorectal cancer cells growth can be inhibited via knockdown of MAGL, which manipulate tumor cells proliferation and apoptosis by downregulation of Cyclin D1 and Bcl-2. It provides a novel therapeutic target in treatment of colorectal cancer and a further support for the correlation of obesity and colorectal cancer. PMID- 21543156 TI - Pilot scale treatment of chromite ore processing residue using sodium sulfide in single reduction and coupled reduction/stabilization processes. AB - Single Cr(VI) reduction and coupled reduction/stabilization (R/S) processes were evaluated at pilot scale to determine their effectiveness to treat chromite ore processing residue (COPR). Sodium sulfide was used as the reducing agent and cement, gypsum and lime were tested as the stabilizing agents. The pilot experiments were performed in a helical ribbon blender mixer with batches of 250 kg of COPR and mixing time up to 30 min. Na2S/Cr(VI) mass ratios of 4.6, 5.7 and 6.8 were evaluated in the single reduction process to treat COPR with Cr(VI) concentration of ~4.2 g/kg. The R/S process was tested with a Na2S/Cr(VI) mass ratio of 5.7 and including stabilizing agents not exceeding 5% (w/w(COPR)), to treat COPR with a Cr(VI) content of ~5.1g/kg. The single reduction process with a ratio of 6.8, reached Cr(VI) reduction efficiencies up to 97.6% in the first days, however these values decreased to around 93% after 380 days of storage. At this point the total Cr level was around 12.5 mg/L. Cr(VI) removal efficiencies exceeding 96.5% were reached and maintained during 380 days when the coupled R/S process was evaluated. Total Cr levels lower than 5 mg/l were attained at the initials days in all R/S batch tested, however after 380 days, concentrations below the regulatory limit were only found with gypsum (2%) as single agent and with a blend of cement (4%) and lime (1%). These results indicated that the coupled R/S process is an excellent alternative to stabilize COPR. PMID- 21543157 TI - A preliminary investigation of the reinnervation and return of sensory function in burn patients treated with INTEGRA(r). AB - BACKGROUND: Loss of sensory function in scar after burn is common, although the basis for this loss is not clear. Additionally, little is known about the effects of different treatment modalities on sensory function and neuroanatomical outcomes in burn patients. Here, we investigated the effects of the use of the INTEGRA((r)) dermal scaffold on neuroanatomy and sensory function in acute burn patients. HYPOTHESIS AND OBJECTIVES: We hypothesized that the use of artificial dermal templates would inhibit or reduce reinnervation after excision, since regrowth of nerves requires complex molecular interactions. Therefore the primary objective of this study was to identify whether there is regrowth of nerve fibres in the INTEGRA((r)) dermal scaffold. The secondary objective was to identify whether the INTEGRA((r)) dermal scaffold reduced nerve regrowth or limited sensory function outcomes in acute burn patients. METHODS: Five patients treated with INTEGRA((r)), cultured epithelial autograft spray (prepared using ReCell((r)) (CEA)) and split skin graft (SSG) were assessed for sensory function in scar and uninjured contralateral control skin. Neuroanatomy of scar and control sites was assessed using immunohistochemistry for PGP9.5, CGRP and substance P neuronal markers. Nerve density and sensory function was also assessed in a comparative group (n=8) treated with CEA and SSG only. RESULTS: Neuroanatomy was not significantly different in the INTEGRA((r)) patients when compared to the CEA/SSG group only. The patients treated with INTEGRA((r)) had worse sensory function than those with CEA/SSG only. CONCLUSIONS: Peripheral nerves do reinnervate the INTEGRA((r)) dermal scaffold. There is no statistically significant reduction in reinnervation observed when compared to a control group. It is possible that the use of artificial dermal constructs, while permissive for nerve regrowth, limit functionality when compared to nerves that regrow through dermal tissue. Further research to understand the causes of this, and into enhancing reinnervation in dermal scaffolds may improve sensory outcome in the most severely burned patients. PMID- 21543158 TI - Acute effects of moderate intensity aerobic exercise on affective withdrawal symptoms and cravings among women smokers. AB - A growing number of laboratory studies have shown that acute bouts of aerobic exercise favorably impact affect and cravings among smokers. However, randomized trials have generally shown exercise to have no favorable effect on smoking cessation or withdrawal symptoms during quit attempts. The purpose of the present study was to explore this apparent contradiction by assessing acute changes in affect and cravings immediately prior to and following each exercise and contact control session during an eight-week smoking cessation trial. Sixty previously low-active, healthy, female smokers were randomized to an eight-week program consisting of brief baseline smoking cessation counseling and the nicotine patch plus either three sessions/week of moderate intensity aerobic exercise or contact control. Findings revealed a favorable impact of exercise on acute changes in positive activated affect (i.e., energy), negative deactivated affect (i.e., tiredness), and cigarette cravings relative to contact control. However, effects dissipated from session to session. Results suggest that aerobic exercise has potential as a smoking cessation treatment, but that it must be engaged in frequently and consistently over time in order to derive benefits. Thus, it is not surprising that previous randomized controlled trials-in which adherence to exercise programs has generally been poor-have been unsuccessful in showing effects of aerobic exercise on smoking cessation outcomes. PMID- 21543159 TI - The effect of renin angiotensin system on tamoxifen resistance. AB - Breast cancer is one of the most common forms of cancer observed in women and endogenous estrogens are thought to play a major role in its development. Tamoxifen is a selective estrogen receptor (ER) modulator which is widely used to treat and prevent breast cancer. Tamoxifen is an ER antagonist in the breast but an ER agonist in cardiovascular system (CVS) and some other tissues. Many patients experience resistance to tamoxifen. Several studies have indicated various mechanisms in tamoxifen resistance. Growth factors and their receptors, extracellular proteins, transcription factors, cell-cycle regulators, and signal transduction molecules have been identified as being potentially involved in tamoxifen resistance. The aim of the present hypothesis is to provide evidences that may lead to this suggestion that renin-angiotensin system (RAS) may have a role in tamoxifen resistance. It has been established in numerous studies that RAS play a role in the progression of various cancers such as breast cancer. Besides, other studies have indicated that estrogen has an inhibitory effect on the RAS components levels in CVS and various tissues such as the adrenal and the pituitary. Therefore, it can be suggested that tamoxifen may increase RAS components levels in the breast tissue by its antagonistic effect on ER and causes resistance. Confirmation of this theory by experimental investigations may lead to this suggestion that combination of angiotensin-converting enzyme inhibitors or angiotensin receptor-1 blockers with tamoxifen may have a preventive effect on development of acquired tamoxifen resistance. PMID- 21543160 TI - European consumer response to packaging technologies for improved beef safety. AB - Beef packaging can influence consumer perceptions of beef. Although consumer perceptions and acceptance are considered to be among the most limiting factors in the application of new technologies, there is a lack of knowledge about the acceptability to consumers of beef packaging systems aimed at improved safety. This paper explores European consumers' acceptance levels of different beef packaging technologies. An online consumer survey was conducted in five European countries (n=2520). Acceptance levels among the sample ranged between 23% for packaging releasing preservative additives up to 73% for vacuum packaging. Factor analysis revealed that familiar packaging technologies were clearly preferred over non-familiar technologies. Four consumer segments were identified: the negative (31% of the sample), cautious (30%), conservative (17%) and enthusiast (22%) consumers, which were profiled based on their attitudes and beef consumption behaviour. Differences between consumer acceptance levels should be taken into account while optimising beef packaging and communicating its benefits. PMID- 21543161 TI - The effect of feeding system in the expression of genes related with fat metabolism in semitendinous muscle in sheep. AB - The effect of feeding system on the expression of LPL, ACACA, FASN, FABP4, DGAT1, SCD, CPT1B, PRKAA2, LEP, SREBP1, PPARG, PPARA and CEBPB genes in semitendinous muscle was studied. Forty-four single born male lambs of the Rasa Aragonesa breed, allocated to four different dietary treatments, were used: grazing alfalfa, grazing alfalfa with supplement for lambs, indoor lambs with grazing ewes and drylot. Significant differences were found in the expression of genes LPL, ACACA, FASN, FABP4, CPT1B and SCD. Genes related to adipogenesis (LPL, ACACA, FASN, FABP4, and SCD) are up-regulated in the intensive groups. In grazing groups CPT1B gene expression, related to beta-oxidation process, is up-regulated. The relative expression of CPT1B was 1.54 fold higher in ALF+S, and 0.43 and 0.37 fold lower in IND- GRE and IND, respectively. The results support the hypothesis that changes in fatty acid profile due to feeding system implicate changes in the mRNA expression level of genes related with fat metabolism. Feeding strategy is an important tool to manipulate intramuscular fatty acid profile in meat through altering gene expression of enzymes related with fat metabolism. PMID- 21543162 TI - Proton beam therapy for hepatocellular carcinoma located adjacent to the alimentary tract. AB - PURPOSE: To evaluate the safety and effectiveness of proton beam therapy for hepatocellular carcinoma (HCC) located adjacent to the alimentary tract. PATIENTS AND METHODS: Forty-seven patients (median age, 69 years; range, 43-82 years) who had HCC located within 2 cm of the alimentary tract underwent proton beam therapy. Liver damage according to the Child-Pugh classification was Class A in 35 patients, Class B in 9, and Class C in 3. Treatment protocols of the early 16 patients and the late 31 patients were 72.6 GyE in 22 fractions and 77 GyE in 35 fractions, respectively. RESULTS: During the median follow-up period of 23 months, 24 patients died; the remaining 23 patients were alive until September 2008. The median overall survival was 33.9 months (95% confidence interval [CI], 10.8-57.0 months). Actuarial overall and local progression-free survival rates at 3 years were 50.0% and 88.1%, respectively. Grade 2 and 3 alimentary tract hemorrhage was observed in 3 (6.4%) and 1 (2.1%) patients, respectively. CONCLUSIONS: Our proton beam therapy strategy for HCC located adjacent to the alimentary tract seems to be effective but should be performed with caution. PMID- 21543163 TI - Computed tomography appearance of early radiation injury to the lung: correlation with clinical and dosimetric factors. AB - PURPOSE: To systematically assess the spectrum of radiologic changes in the lung after radiation therapy for non-small-cell lung cancer. METHODS AND MATERIALS: We reviewed the cases of 146 patients treated with radical radiotherapy at our institution. All patients had computed tomography (CT) scans performed 3 months after completion of therapy. Radiographic appearances were categorized using a standard grading system. The association of these abnormalities with pretreatment factors and clinical radiation pneumonitis (RP) was investigated. RESULTS: New intrapulmonary abnormalities were seen in 92 patients (63%). These were ground glass opacity in 16 (11%), patchy consolidation in 19 (13%), and diffuse consolidation in 57 (39%). Twenty-five patients (17%) developed clinical symptoms of RP. Although 80% of the patients with RP had areas of consolidation seen on the posttreatment CT scan, the majority (74%) of patients with such radiographic changes were asymptomatic. For patients with lung infiltrates, the minimum isodose encompassing the volume of radiologic abnormality was usually >=27 Gy. Traditional dose-volume metrics, pulmonary function tests, and the coadministration of angiotensin converting enzyme inhibitors (ACE-I) were all strongly correlated with the presence of radiologic injury on univariate analysis (p<=0.002). There was also an inverse correlation between prior smoking history and CT scan changes (p=0.02). On multivariate analysis, dosimetric parameters and the use of ACE-I retained significance (p=0.005). CONCLUSIONS: Our findings suggest that there is substantial interindividual variation in lung radiosensitivity. ACE-I prevented the radiologic changes seen after high-dose radiation therapy, and their role as radioprotectants warrants further investigation. PMID- 21543164 TI - Assessing the role of volumetric modulated arc therapy (VMAT) relative to IMRT and helical tomotherapy in the management of localized, locally advanced, and post-operative prostate cancer. AB - PURPOSE: To quantify differences in treatment delivery efficiency and dosimetry between step-and-shoot intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT) for prostate treatment. METHODS AND MATERIALS: Twenty-five prostate cancer patients were selected retrospectively for this planning study. Treatment plans were generated for: prostate alone (n = 5), prostate + seminal vesicles (n = 5), prostate + seminal vesicles + pelvic lymph nodes (n = 5), prostate bed (n = 5), and prostate bed + pelvic lymph nodes (n = 5). Target coverage, dose homogeneity, integral dose, monitor units (MU), and sparing of organs at risk (OAR) were compared across techniques. Time required to deliver each plan was measured. RESULTS: The dosimetric quality of IMRT, VMAT, and HT plans were comparable for target coverage (planning target volume V95%, clinical target volume V100% all >98.7%) and sparing of organs at risk (OAR) for all treatment groups. Although HT resulted in a slightly higher integral dose and mean doses to the OAR, it yielded a lower maximum dose to all OAR examined. VMAT resulted in reductions in treatment times over IMRT (mean = 75%) and HT (mean = 70%). VMAT required 15-38% fewer monitor units than IMRT over all treatment volumes, with the reduction per fraction ranging from 100-423 MU from the smallest to largest volumes. CONCLUSIONS: VMAT improves efficiency of delivery for equivalent dosimetric quality as IMRT and HT across various prostate cancer treatment volumes in the intact and postoperative settings. PMID- 21543165 TI - An improved model for predicting radiation pneumonitis incorporating clinical and dosimetric variables. AB - PURPOSE: Single dose-volume metrics are of limited value for the prediction of radiation pneumonitis (RP) in day-to-day clinical practice. We investigated whether multiparametric models that incorporate clinical and physiologic factors might have improved accuracy. METHODS AND MATERIALS: The records of 160 patients who received radiation therapy for non-small-cell lung cancer were reviewed. All patients were treated to the same dose and with an identical technique. Dosimetric, pulmonary function, and clinical parameters were analyzed to determine their ability to predict for the subsequent development of RP. RESULTS: Twenty-seven patients (17%) developed RP. On univariate analysis, the following factors were significantly correlated with the risk of pneumonitis: fractional volume of lung receiving >5-20 Gy, absolute volume of lung spared from receiving >5-15 Gy, mean lung dose, craniocaudal position of the isocenter, transfer coefficient for carbon monoxide (KCOc), total lung capacity, coadministration of angiotensin converting enzyme inhibitors, and coadministration of angiotensin receptor antagonists. By combining the absolute volume of lung spared from receiving >5 Gy with the KCOc, we defined a new parameter termed Transfer Factor Spared from receiving >5 Gy (TFS(5)). The area under the receiver operator characteristic curve for TFS(5) was 0.778, increasing to 0.846 if patients receiving modulators of the renin-angiotensin system were excluded from the analysis. Patients with a TFS(5) <2.17 mmol/min/kPa had a risk of RP of 30% compared with 5% for the group with a TFS(5) >= 2.17. CONCLUSIONS: TFS(5) represents a simple parameter that can be used in routine clinical practice to more accurately segregate patients into high- and low-risk groups for developing RP. PMID- 21543166 TI - On-board imaging validation of optically guided stereotactic radiosurgery positioning system for conventionally fractionated radiotherapy for paranasal sinus and skull base cancer. AB - PURPOSE: To evaluate the positioning accuracy of an optical positioning system for stereotactic radiosurgery in a pilot experience of optically guided, conventionally fractionated, radiotherapy for paranasal sinus and skull base tumors. METHODS AND MATERIALS: Before each daily radiotherapy session, the positioning of 28 patients was set up using an optical positioning system. After this initial setup, the patients underwent standard on-board imaging that included daily orthogonal kilovoltage images and weekly cone beam computed tomography scans. Daily translational shifts were made after comparing the on board images with the treatment planning computed tomography scans. These daily translational shifts represented the daily positional error in the optical tracking system and were recorded during the treatment course. For 13 patients treated with smaller fields, a three-degree of freedom (3DOF) head positioner was used for more accurate setup. RESULTS: The mean positional error for the optically guided system in patients with and without the 3DOF head positioner was 1.4 +/- 1.1 mm and 3.9 +/- 1.6 mm, respectively (p <.0001). The mean positional error drifted 0.11 mm/wk upward during the treatment course for patients using the 3DOF head positioner (p = .057). No positional drift was observed in the patients without the 3DOF head positioner. CONCLUSION: Our initial clinical experience with optically guided head-and-neck fractionated radiotherapy was promising and demonstrated clinical feasibility. The optically guided setup was especially useful when used in conjunction with the 3DOF head positioner and when it was recalibrated to the shifts using the weekly portal images. PMID- 21543167 TI - Hyperbilirubinemia in infants with Gram-negative sepsis does not affect mortality. AB - BACKGROUND: Sepsis is associated with an increased production of oxidant species and a decrease in endogenous antioxidant defenses. Mortality is high, especially when endotoxins are involved, e.g., in infants with Gram-negative sepsis. Yet, chronic as well as acute unconjugated hyperbilirubinemia has been shown to protect against endotoxin-induced shock in vivo in rats and in mice. We hypothesized that hyperbilirubinemia in infants with Gram-negative sepsis improves survival and/or mitigates the inflammatory response. OBJECTIVE: To assess the relationships between serum bilirubin concentrations on the one hand, and leukocyte count, C-reactive protein and survival on the other hand, in infants with Gram-negative sepsis. METHODS: Retrospectively, we retrieved clinical and biochemical data from infants less than 90 days of age with a blood culture-proven Gram-negative sepsis between January 1998 and December 2005. RESULTS: We identified 92 infants with Gram-negative sepsis in the indicated period. Median gestational age was 29 (24-42) weeks. 22 Patients died. Preceding sepsis, median total serum bilirubin concentrations were below 150 MUmol/L. Median concentrations of conjugated bilirubin concentrations increased (+63%, p<0.05), and median concentrations of unconjugated bilirubin decreased (-36%, p<0.05) in infants with Gram-negative sepsis. Median total bilirubin concentrations before and during sepsis were not significantly different between survivors and non-survivors. Changes in bilirubin concentrations were not significantly correlated with changes in either white blood cell count or C reactive protein. CONCLUSION: Present data do not support the concept that bilirubin positively affects survival or the inflammatory response in infants with Gram-negative sepsis. PMID- 21543168 TI - Detection of the synthetic drug 4-fluoroamphetamine (4-FA) in serum and urine. AB - 4-Fluoroamphetamine (4-FA) was detected in the blood and urine of two individuals suspected for driving under the influence (DUI). The test for amphetamines in urine subjected to immunoassay screening using the CEDIA DAU assay proved positive. Further investigations revealed a 4-FA cross-reactivity of about 6% in the CEDIA amphetamine assay. 4-FA was qualitatively detected in a general unknown screening for drugs using GC/MS in full scan mode. No other drugs or fluorinated phenethylamines were detected. A validated GC/MS method was established in SIM mode for serum analysis of 4-FA with a limit of detection (LOD) of 1 ng/mL and a lower limit of quantification (LLOQ) of 5 ng/mL. Intra-assay precision was approx. 4% and inter-assay precision approx. 8%. Applying this method, the 4-FA serum concentrations of the two subjects were determined to be 350 ng/mL and 475 ng/mL, respectively. Given the pharmacological data of amphetamine, 4-FA psychoactive effects are to be expected at these serum levels. Both subjects exhibited sympathomimetic effects and psychostimulant-like impairment accordingly. PMID- 21543169 TI - Detection of marine and freshwater bacterioplankton in immersed victims: Post mortem bacterial invasion does not readily occur. AB - We previously applied our method of detecting marine or freshwater bacterioplankton (bacteria) in the blood of immersed victims as a marker of drowning. However, we did not confirm the absence of post-mortem bacterial invasion during immersion. Here we examined the nature of bacterioplankton in blood samples from 21 immersed and 4 non-immersed cadavers. We found only freshwater bacterioplankton in the blood of two victims that were retrieved from the sea or an estuary inhabited by marine bacterioplankton even though one victim was highly putrefied. The results of diatom testing suggested that these two victims had drowned in fresh or brackish water with low salinity and then flowed out to the estuary or the sea. Two others were submerged in water, but representative bacterioplankton were undetectable in their blood although one victim was highly putrefied. Autopsy findings and the results of diatom tests did not indicate that the cause of death was drowning. As in previous studies, we identified freshwater bacterioplankton in the blood of seven other victims that had drowned in freshwater, marine bacterioplankton in the blood of four victims that had drowned in seawater and none in four victims found on land that had died by means other than drowning. Bacterioplankton in the blood of drowned victims appears to reflect the type of water aspirated and blood does not become easily contaminated with bacteria post-mortem even in decomposed bodies. PMID- 21543170 TI - Comments on "Analysis of 50 SNPs in CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP1A2 by MALDI-TOF mass spectrometry in Chinese Han population". PMID- 21543171 TI - Predicting volumes of metabolically important whole-body adipose tissue compartments in overweight and obese adolescents by different MRI approaches and anthropometry. AB - OBJECTIVES: To evaluate 5-slice stack/single-slice MRI approaches and anthropometric measures as predictors for metabolically relevant whole-body adipose tissue (AT) compartments in overweight/obese adolescents. METHODS: Forty adolescents (22 males, age 11.4-16.1 years) were included with a BMI above the 90th percentile. Volumes of whole-body AT compartments, i.e. total AT (TAT), subcutaneous AT (SCAT) and visceral AT (VAT), were determined using a breath-hold T1-weighted-FSE-MR-sequence and semi-automated segmentation serving as the gold standard. SCAT, VAT and TAT was estimated by either axially oriented single slices or 5-slice-stacks centred at specific anatomic landmarks (umbilicus, head of femur and humerus). Furthermore, anthropometric measures were also evaluated as predictors of whole-body AT compartments. RESULTS: Strong correlations were found for both genders between TAT/SCAT and single-slice evaluation (e.g. whole body SCAT-SCAT at umbilicus level: r = 0.91 (m), r = 0.92 (f)) or anthropometry (SCAT-BMI: r = 0.93 (m, f)). VAT was correlated to VAT at umbilicus (r = 0.71 (m), r = 0.94 (f)) but only weakly to anthropometry. CONCLUSIONS: Anthropometric measures and single-slice MRI can accurately predict TAT/SCAT which cannot be improved by evaluation of 5-slice stacks. Prediction of VAT by 5-slice stack/single-slice MRI protocols seems only to be accurate in females. Anthropometry cannot be reliably used for prediction of VAT in both genders. Thus, MRI seems to be necessary for quantification of VAT in overweight/obese adolescents of both genders. PMID- 21543172 TI - Safety of sonographically guided aspiration of intramuscular, bursal, articular and subcutaneous hematomas. AB - OBJECTIVE: To evaluate the safety and efficacy of sonographically guided aspiration of intramuscular, bursal and subcutaneous hematomas. MATERIALS AND METHODS: One hundred eleven interventions were performed in 75 patients at a single institution from January 2005 to December 2009. In all cases the target of interest was identified with ultrasonography. RESULTS: Ninety-six procedures (87.3%) were successful, 14 procedures (12.7%) were unsuccessful due to excessive density and/or viscosity of the content. No significant complications were encountered during or immediately after any procedure. Clinical follow-up records were available for 73 (75%) procedures in 45 (66%) patients, 30 patients did not return for follow-up after hematoma evacuation. No septic or hemorrhagic complications or cases of neurovascular compromise were recorded. CONCLUSIONS: Sonographically guided hematoma evacuation is a safe procedure. However, the proportion of unsuccessful evacuations and hematoma recurrence is substantial. PMID- 21543173 TI - Role of perfusion-weighted imaging at 3T in the histopathological differentiation between astrocytic and oligodendroglial tumors. AB - OBJECTIVE: The differentiation of oligodendroglial tumors from astrocytic tumors is important clinically, because oligodendroglial tumors are more chemosensitive than astrocytic tumors. This study was designed to clarify the usefulness of 3T MR perfusion imaging (PWI) in the histopathological differentiation between astrocytic and oligodendroglial tumors. This is because there is a growing interest in the diagnostic performance of 3T MR imaging, which has the advantages of a higher signal-to-noise ratio (SNR) and greater spatial and temporal resolution. MATERIALS AND METHODS: This study retrospectively included 24 consecutive patients with supratentorial, WHO grade II and III astrocytic and oligodendroglial tumors (7 astrocytic, 10 oligoastrocytic, and 7 oligodendroglial tumors) that were newly diagnosed and resected between November 2006 and December 2009 at Hiroshima University Hospital. These patients underwent dynamic susceptibility contrast-enhanced (DSC) PWI relative cerebral blood volume (rCBV) measurements before treatment. Astrocytic tumors were designated as the astrocytic group, and oligoastrocytic and oligodendroglial tumors as the oligodendroglial group. The regions of interest with the maximum rCBV values within the tumors were normalized relative to the contra-lateral white matter (rCBVmax). RESULTS: The average rCBVmax of astrocytic tumors (2.01+/-0.68) was significantly lower than that of the oligoastrocytic (4.60+/-1.05) and oligodendroglial tumors (6.17+/-0.867) (P<0.0001). A cut-off value of 3.0 allowed to differentiate the oligodendroglial group from the astrocytic group at 100% sensitivity and 87.5% specificity. CONCLUSION: The rCBVmax values obtained from 3T MR PWI may be useful as an adjunct to the postoperative histopathological diagnosis of glioma patients. PMID- 21543174 TI - Iterative reconstruction reduces abdominal CT dose. AB - OBJECTIVE: In medical imaging, lowering radiation dose from computed tomography scanning, without reducing diagnostic performance is a desired achievement. Iterative image reconstruction may be one tool to achieve dose reduction. This study reports the diagnostic performance using a blending of 50% statistical iterative reconstruction (ASIR) and filtered back projection reconstruction (FBP) compared to standard FBP image reconstruction at different dose levels for liver phantom examinations. METHODS: An anthropomorphic liver phantom was scanned at 250, 185, 155, 140, 120 and 100 mAs, on a 64-slice GE Lightspeed VCT scanner. All scans were reconstructed with ASIR and FBP. Four readers evaluated independently on a 5-point scale 21 images, each containing 32 test sectors. In total 672 areas were assessed. ROC analysis was used to evaluate the differences. RESULTS: There was a difference in AUC between the 250 mAs FBP images and the 120 and 100 mAs FBP images. ASIR reconstruction gave a significantly higher diagnostic performance compared to standard reconstruction at 100 mAs. CONCLUSION: A blending of 50-90% ASIR and FBP may improve image quality of low dose CT examinations of the liver, and thus give a potential for reducing radiation dose. PMID- 21543175 TI - Automated volumetric assessment of the Achilles tendon (AVAT) using a 3D T2 weighted SPACE sequence at 3T in healthy and pathologic cases. AB - PURPOSE: Achilles tendinopathy has been reported to be frequently associated with increasing volume of the tendon. This work aims at reliable and accurate volumetric quantification of the Achilles tendon using a newly developed contour detection algorithm applied on high resolution MRI data sets recorded at 3T. MATERIALS AND METHODS: A total of 26 healthy tendons and 4 degenerated tendons were examined for this study. Automated identification (AI) of tendon boundaries was performed in transverse slices with isotropic resolution (0.8mm) gained with a T2-weighted SPACE sequence at 3T. For AI a snake algorithm was applied and compared to manual tracing (MT). RESULTS: AI was feasible in all examined tendons without further correction. AI of both tendons was performed in each participant within 2 min (2 * 37 slices) compared to MT lasting 20 min. MT and AI showed excellent agreement and correlation (R(2) = 0.99, p<0.0001). AI provided a reduction of measurement error (0.4 cm(3) vs. 0.5 cm(3)) and coefficient of variation (1% vs. 2%). DISCUSSION: Compared to MT the AI allows assessment of tendon volumes in highly resolved MRI data in a more accurate and reliable time saving way. Therefore automated volume detection is seen as a helpful clinical tool for evaluation of small volumetric changes of the Achilles tendon. PMID- 21543176 TI - Analysis of deep inferior epigastric perforator (DIEP) arteries by using MDCTA: Comparison between 2 post-processing techniques. AB - PURPOSE: Our purpose was to compare two post-processing techniques, Maximum Intensity-Projection (MIP) and Volume Rendering (VR) for the study of perforator arteries. METHODS: Thirty patients who underwent Multi-Detector-Row CT Angiography (MDCTA) between February 2010 and May 2010 were retrospectively analyzed. For each patient and for each reconstruction method, the image quality was evaluated and the inter- and intra-observer agreement was calculated according to the Cohen statistics. The Hounsfield Unit (HU) value in the common femoral artery was quantified and the correlation (Pearson Statistic) between image quality and HU value was explored. RESULTS: The Pearson r between the right and left common femoral artery was excellent (r=0.955). The highest image quality score was obtained using MIP for both observers (total value 75, with a mean value 2.67 for observer 1 and total value of 79 and a mean value of 2.82 for observer 2). The highest agreement between the two observers was detected using the MIP protocol with a Cohen kappa value of 0.856. The ROC area under the curve (Az) for the VR is 0.786 (0.086 SD; p value=0.0009) whereas the ROC area under the curve (Az) for the MIP is 0.0928 (0.051 SD; p value=0.0001). CONCLUSION: MIP showed the optimal inter- and intra-observer agreement and the highest quality scores and therefore should be used as post-processing techniques in the analysis of perforating arteries. PMID- 21543177 TI - Hemodynamic analysis of bladder tumors using T1-dynamic contrast-enhanced fast spin-echo MRI. AB - OBJECTIVES: To evaluate the hemodynamics of bladder tumors, we developed a method to calculate change in R(1) value (DeltaR(1)) from T(1)-dynamic contrast-enhanced fast spin-echo magnetic resonance imaging (T(1)DCE-FSE-MRI). MATERIALS AND METHODS: On a 1.5-T MR system, T(1)DCE-FSE-MRI was performed. This study was applied to 12 patients with urinary bladder tumor, i.e. urothelial carcinoma. We compared DeltaR(1)-time and DeltaSI-time between a peak in the DeltaR(1)-time and DeltaSI-time curve occurred during the first pass within 60s. Next, we assessed the slope of increase for 180s after CA injection (Slope(0-180)). RESULTS: The mean slope of the first pass was significantly higher for bladder tumors on both the DeltaR(1)-time and the DeltaSI-time curve compared with normal bladder walls. Moreover, a significant difference was apparent between bladder tumors and normal bladder walls on the mean Slope(0-180) in the DeltaR(1)-time curve. However, no significant difference in the mean Slope(0-180) was observed on the DeltaSI-time curve between bladder tumors and normal bladder walls. CONCLUSION: T(1)DCE-FSE MRI offers three advantages: quantitative analysis; high-quality (i.e., artifact free) images; and high temporal resolution even for SE images. Use of DeltaR(1) analysis with T(1)DCE-FSE-MRI allows more detailed information on the hemodynamics of bladder tumors to be obtained and assists in differentiation between bladder tumors and the normal bladder wall. PMID- 21543178 TI - Multislice CT angiography assessment of left coronary artery: correlation between bifurcation angle and dimensions and development of coronary artery disease. AB - PURPOSE: To investigate the relationship between left coronary bifurcation and dimensional changes and development of coronary artery disease using multislice CT angiography. MATERIALS AND METHODS: 30 patients (18 men, 12 women, mean age, 56 years +/- 8) suspected of coronary artery disease undergoing 64- and 256-slice CT angiography were included in the study. Left bifurcation angle and left coronary diameter were measured to determine the relationship between angulation and plaque formation and subsequent dimensional changes. RESULTS: Plaques were present in the left coronary artery in 22 patients with variable angulations and dimensional changes. The mean bifurcation angle between left anterior descending and left circumflex arteries was measured 89.1 degrees +/- 13.1 degrees (range, 55.3 degrees , 134.5 degrees ) among all patients. The mean bifurcation angle measured in patients with normal and diseased left coronary artery was 75.5 degrees +/- 19.8 degrees (range, 60 degrees , 96.1 degrees ), and 94 degrees +/- 19.7 degrees (range, 55.3 degrees , 134.5 degrees ), respectively, with significant difference between these two groups (p=0.02). Similarly, there is a significant difference in the mean diameters of left anterior descending and left circumflex between patients with normal and diseased left coronary artery (p<0.001), which were measured 2.8 +/- 0.3mm (range, 2.2, 3.2mm) and 2.1 +/- 0.4mm (range, 1.9, 2.9 mm) for the normal left coronary arteries, 4.0 +/- 0.8mm (range, 2.5, 6.1mm) and 2.9 +/- 0.5mm (range, 1.6, 3.9 mm) for the diseased left coronary arteries, respectively. CONCLUSION: There is a direct correlation between left bifurcation angle and dimensional changes and formation of plaques. Multislice CT angiography can be used to provide relevant features of left coronary atherosclerosis. PMID- 21543179 TI - Acute chest pain: the role of MR imaging and MR angiography. AB - MR imaging (MRI) and MR angiography (MRA) have gained a high level of diagnostic accuracy in cardiovascular disease. MRI in cardiac disease has been established as the non-invasive standard of reference in many pathologies. However, in acute chest pain the situation is somewhat special since many of the patients presenting in the emergency department suffer from potentially life-threatening disease including acute coronary syndrome, pulmonary embolism, and acute aortic syndrome. Those patients need a fast and definitive evaluation under continuous monitoring of vital parameters. Due to those requirements MRI seems to be less suitable compared to X-ray coronary angiography and multislice computed tomography angiography (CTA). However, MRI allows for a comprehensive assessment of all clinically stable patients providing unique information on the cardiovascular system including ischemia, inflammation and function. Furthermore, MRI and MRA are considered the method of choice in patients with contraindications to CTA and for regular follow-up in known aortic disease. This review addresses specific features of MRI and MRA for different cardiovascular conditions presenting with acute chest pain. PMID- 21543180 TI - Volume perfusion-CT of the liver: insights and applications. AB - The purpose of this article is to provide an up-to-date view on the spectrum of applications of volume perfusion-CT in the liver. Volume perfusion-CT yields important information on liver architecture and function by enabling quantification of dual liver parenchymal blood supply. Additional characterization of diffuse and focal liver diseases by illustration of distinct flow dynamics and permeability may become an important adjunct in the CT evaluation of liver pathologies. PMID- 21543181 TI - The relationship between BOLD signal and autonomic nervous system functions: implications for processing of "physiological noise". AB - Functional magnetic resonance imaging (fMRI) research has revealed not only important aspects of the neural basis of cognitive and perceptual functions, but also important information on the relation between high-level brain functions and physiology. One of the central outstanding questions, given the features of the blood oxygenation level-dependent (BOLD) signal, is whether and how autonomic nervous system (ANS) functions are related to changes in brain states as measured in the human brain. A straightforward way to address this question has been to acquire external measurements of ANS activity such as cardiac and respiratory data, and examine their relation to the BOLD signal. In this article, we describe two conceptual approaches to the treatment of ANS measures in the context of BOLD fMRI analysis. On the one hand, several research lines have treated ANS activity measures as noise, considering them as nothing but a confounding factor that reduces the power of fMRI analysis or its validity. Work in this line has developed powerful methods to remove ANS effects from the BOLD signal. On the other hand, a different line of work has made important progress in showing that ANS functions such as cardiac pulsation, heart rate variability and breathing rate could be considered as a theoretically meaningful component of the signal that is useful for understanding brain function. Work within this latter framework suggests that caution should be exercised when employing procedures to remove correlations between BOLD data and physiological measures. We discuss these two positions and the reasoning underlying them. Thereafter, we draw on the reviewed literature in presenting practical guidelines for treatment of ANS data, which are based on the premise that ANS data should be considered as theoretically meaningful information. This holds particularly when studying cortical systems involved in regulation, monitoring and/or generation of ANS activity, such as those involved in decision making, conflict resolution and the experience of emotion. PMID- 21543182 TI - Education level, not health literacy, associated with information needs for patients with cancer. AB - OBJECTIVE: Cancer patients receiving adjuvant therapy encounter increasingly complex situations and decisions with each new procedure and therapy. To make informed decisions about care, they need to be able to access, process, and understand information. Individuals with limited health literacy may not be able to obtain or understand important information about their cancer and treatment. The rate of low health literacy has been shown to be higher among African Americans than among non-Hispanic Whites. This study examined the associations between race, health literacy, and self-reported needs for information about disease, diagnostic tests, treatments, physical care, and psychosocial resources. METHODS: Measures assessing information needs were administered to 138 newly diagnosed cancer patients. Demographics were assessed by survey and health literacy was assessed with two commonly used measures: the Rapid Estimate Adult Literacy in Medicine (REALM) and the Short Test of Health Literacy in Adults (STOFHLA). RESULTS: Study findings indicate that educational attainment, rather than health literacy, is a significant predictor of information needs. CONCLUSION: Overcoming barriers to information needs may be less dependent on literacy considerations and more dependent on issues that divide across levels of educational attainment. PRACTICE IMPLICATIONS: Oncologists and hospital staff should be attentive to the fact that many patients require additional assistance to meet their information needs. PMID- 21543183 TI - Back to basics: Re-examining the role of patient empowerment in diabetes. PMID- 21543184 TI - Decision aids for surgical treatment of early stage breast cancer: a narrative review of the literature. AB - OBJECTIVE: To review and critique the published empirical research on decision aids for women actually facing surgical treatment of early stage breast cancer, synthesize findings across studies related to outcomes of decision aids use with specific attention to the influence of system and client characteristics, and identify opportunities for further research. METHODS: A systematic and reproducible search was carried out to identify studies evaluating decision aids for women making breast cancer surgical treatment decisions. All included studies were appraised. RESULTS: Most studies evaluated the outcomes of decision aids use in terms of final treatment decisions, patients' knowledge of treatment options, anxiety, decisional conflict, satisfaction and quality of life. Included studies varied in design, measures used to assess effectiveness, format of the aids, patient populations and clinical settings. Studies yielded mixed results related to the effect of the decision aids on the outcomes measured. CONCLUSION: Despite the mixed findings of the studies, some support exists for the use of decision aids with women diagnosed with early stage breast cancer. PRACTICE IMPLICATIONS: To ensure successful implementation of decision aids in clinical practice, healthcare providers should be educated on their use. Greater allocation of time, space and access to decision aids is also needed. PMID- 21543185 TI - The challenge of estimating PTSD prevalence in the context of ongoing trauma: the example of Israel during the Second Intifada. AB - Many studies attempt to gauge population prevalence of post traumatic stress disorder (PTSD) following a major catastrophe. However, little is known about the validity of these estimates in the increasingly common situation of ongoing trauma. During the period of the Second Intifada in Israel, which involved frequent and widespread terrorist attacks, several studies generated estimates of PTSD prevalence in the Israeli population, but yielded widely discrepant findings. A number of focused surveys using symptom checklists estimated population prevalence of PTSD or probable PTSD diagnosis at about 9%. However a large population health study conducted during this same time period using a structured diagnostic interview yielded a very low estimated prevalence of PTSD (0.5%). We examine methodological differences that might account for these striking discrepancies. Inherent limitations of both checklist and structured interview methods may be especially problematic in the context of ongoing trauma. Findings regarding PTSD and associated factors obtained during ongoing trauma should be interpreted with caution. PMID- 21543186 TI - Fluctuation of lacosamide serum concentrations during the day and occurrence of adverse drug reactions--first clinical experience. AB - PURPOSE: To obtain better understanding of the effect of lacosamide (LCM) in clinical practice, laboratory and clinical data of 17 patients under treatment with LCM as an add-on antiepileptic drug (AED) were retrospectively evaluated. METHODS: Total LCM serum concentrations were obtained at hourly intervals for up to 5h and 8h after morning dose. Adverse drug reactions (ADR) were assessed. RESULTS: LCM serum concentrations showed high fluctuations during the day with a steep increase within the first 3h after intake (mean 87.8%; range: 44.4-149.0%) under b.i.d. Mean trough and peak concentrations of LCM were 5.0 MUg/ml (range: 1.8-9.5 MUg/ml) and 9.7 MUg/ml (range: 4.0-18.3 MUg/ml), respectively; mean dose 353 mg/d (range: 200-600mg/d). Twelve patients showed ADRs. After conversion to t.i.d. or dose reduction LCM serum concentration showed lower fluctuations during the day and a lower increase after intake (mean: 50.0%, range: 27.1-66.7%); peak LCM was 9.4 MUg/ml (range: 4.7-11.6 MUg/ml), mean dose 388 mg/d (range: 300-500 mg/d). These interventions led to amelioration of the ADR. CONCLUSION: Changing the dose regimen from two to three times daily could reduce fluctuations of LCM during the day and improve tolerability of LCM in patients with ADR. PMID- 21543187 TI - Maternal reactions to a child with epilepsy: Depression, anxiety, parental attitudes and family functions. AB - OBJECTIVE: The goal of this study was to investigate how the disease and treatment of epilepsy affected the psychological profile (depression and anxiety) of mothers whose children had epilepsy, as well as these mothers' attitudes towards their children and their family relationships. METHODS: Both the case and control groups consisted of 50 children and their mothers. All mothers were asked to complete the Beck Depression Inventory, State-Trait Anxiety Inventory, Parental Attitude Research Instrument and Family Assessment Device. RESULTS: Mothers whose children had epilepsy scored significantly higher in depression and state anxiety compared to the mothers of the control group. The mothers of children diagnosed with epilepsy also failed to develop supportive and friendly relationships with their children. In addition, these mothers scored significantly higher in the Attitude of Hostility and Rejection, Marital Discordance and Authoritarian Attitude as compared to the mothers of the control group. CONCLUSION: This cross-sectional study demonstrated that, for the mothers of children who had epilepsy, the illness might have an adverse effect on their lives and their family relationships. PMID- 21543188 TI - Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan. AB - BACKGROUND: Recent findings in psoriasis research have shown that psoriasis is frequently associated with systemic comorbidities. OBJECTIVES: This study aims to describe the epidemiology of psoriasis and the prevalence of comorbidities in patients with psoriasis in Taiwan. METHODS: Patients who had at least one outpatient visit or admission with ICD-9-CM diagnosis code 696.0-1 in the Taiwan National Health Insurance (NHI) claims database during 2006 were identified as psoriasis cases. The cases were further classified into moderate to severe psoriasis (sPsO) for those who had previously received systemic therapy during the study period and mild psoriasis (mPsO) for those who had not. The cases were matched in a 1:4 ratio with controls from a sample cohort of 997,771 enrolees representative of the Taiwan population. Matching variables included age, gender and residential area. Prevalence of comorbidities was assessed using prevalence relative risk (RR) based upon a Cox proportional regression model. RESULTS: 51,800 psoriasis cases were identified (prevalence=0.235%; mean age=46.4+/-18.6; male:female=1.6:1) and 17.5% of cases were sPsO type. Psoriasis was associated with a significantly increased prevalence ratio (RR; [95% confidence interval]) for hypertension (1.51; [1.47, 1.56]), diabetes (1.64; [1.58, 1.70]), hyperglyceridaemia (1.61; [1.54, 1.68]), heart disease (1.32; [1.26, 1.37]), hepatitis B viral infection (1.73; [1.47, 2.04]), hepatitis C viral infection (2.02; [1.67, 2.44]), rheumatoid arthritis (3.02; [2.68, 3.41]), systemic lupus erythematosus (6.16; [4.70, 8.09]), vitiligo (5.94; [3.79, 9.31]), pemphigoid (14.75; [5.00, 43.50]), pemphigus (41.81; [12.41, 140.90]), alopecia areata (4.71; [2.98, 7.45]), lip, oral cavity and pharynx cancer (1.49; [1.22, 1.80]), digestive organs and peritoneum cancer (1.57; [1.41, 1.74]), depression (1.50; [1.39, 1.61]), fatty liver (2.27; [1.90, 2.71]), chronic airways obstruction (1.47; [1.34, 1.61]), sleep disorder (3.89; [2.26, 6.71]), asthma (1.29; [1.18, 1.40]), and allergic rhinitis (1.25; [1.18, 1.33]). Conversely, psoriasis was not associated with an increased risk of Crohn's disease. CONCLUSIONS: Psoriasis was associated with a significantly increased risk of comorbidities, especially for those patients with moderate to severe disease. These health associations should be taken into consideration when evaluating the burdens of psoriasis and designing effective treatment plans. PMID- 21543189 TI - Improved social interaction and increased anterior cingulate metabolism after group reminiscence with reality orientation approach for vascular dementia. AB - A group reminiscence approach (GRA) with reality orientation (RO) is widely used as a psychosocial intervention for dementia. Since clinical effectiveness was reported for the intervention, interest has been directed toward areas of the neuronal network that might be being stimulated. We hypothesized that the frontal lobe associated with social interaction was being stimulated. To test this hypothesis, we studied 24 patients with vascular dementia. In addition to conventional care, a 1-h session of GRA with RO was provided once a week for 3 months in the GRA-RO arm (n=12). Only supportive care was provided in the control arm (n=12). Before and after the interventions, cognitive function, depressive state, and social activities were assessed. Since glucose metabolism is associated with brain function, cerebral glucose metabolism was measured by positron emission tomography (PET). Regarding behavioral improvement, 10 patients in the GRA-RO arm showed improvement compared with only two patients in the control arm, a significant difference. PET demonstrated that metabolism in the anterior cingulate was increased in the GRA-RO arm, whereas no significant changes were observed in the control arm. These results suggest that GRA-RO stimulates the anterior cingulate and has a positive effect on social interaction. PMID- 21543190 TI - Midsagittal structural differences and sexual dimorphism of the corpus callosum in obsessive-compulsive disorder. AB - Neurobiological abnormalities in various brain regions, including the orbitofrontal cortex, basal ganglia, and thalamus, have been found in patients with obsessive-compulsive disorder (OCD), and impairment in white matter connectivity in these regions has recently been suggested. To investigate structural connectivity in OCD, we used the midsagittal area and thickness to assess the morphology of the corpus callosum (CC), the largest connecting fiber tract in the human brain. Midsagittal magnetic resonance images of the CC were acquired from 69 adult patients with OCD and 69 matched normal controls. We calculated and compared the total area and the areas of five subregions of the CC as well as the distances between 200 equidistant points on the top and bottom of lines on the surface of the CC in the two groups. The absolute total area of the CC was significantly larger in OCD patients than in controls when brain size, age, gender, and IQ were controlled. Significant enlargements in CC1, CC2, and CC5 were seen in OCD patients before correction for multiple comparisons. The thickness of the caudal part of the splenium was greater in OCD patients than in controls. The analysis according to gender showed that only male OCD patients differed from male controls with respect to the area of the CC. These findings reflect structural abnormalities in the CC, and especially in the splenium, in adult patients with OCD. Abnormal interhemispheric connectivity, including the parietotemporal and occipital areas, may affect the pathophysiology of OCD. Sexual dimorphism in the CC of OCD patients should be considered. PMID- 21543191 TI - How can cognitive remediation therapy modulate brain activations in schizophrenia? An fMRI study. AB - Cognitive remediation therapy (CRT) is a non biological treatment that aims to correct cognitive deficits through repeated exercises. Its efficacy in patients with schizophrenia is well recognized, but little is known about its effect on cerebral activity. Our aim was to explore the impact of CRT on cerebral activation using functional magnetic resonance imaging (fMRI) in patients with schizophrenia. Seventeen patients and 15 healthy volunteers were recruited. Patients were divided into two groups: one group received CRT with Rehacom(r) software (n=8), while a control group of patients (non-CRT group) received no additional treatment (n=9). The three groups underwent two fMRI sessions with an interval of 3months: they had to perform a verbal and a spatial n-back task at the same performance level. Patients were additionally clinically and cognitively assessed before and after the study. After CRT, the CRT group exhibited brain over-activations in the left inferior/middle frontal gyrus, cingulate gyrus and inferior parietal lobule for the spatial task. Similar but nonsignificant over activations were observed in the same brain regions for the verbal task. Moreover, CRT patients significantly improved their behavioural performance in attention and reasoning capacities. We conclude that CRT leads to measurable physiological adaptation associated with improved cognitive ability. Trial name: Cognitive Remediation Theraphy and Schizophrenia. http://clinicaltrials.gov/ct2/show/NCT01078129. REGISTRATION NUMBER: NCT01078129. PMID- 21543192 TI - Solid state NMR strategies for the structural characterization of new hybrid materials based on the intercalation of nitroxide radicals into CdPS3. AB - The radical cations 2-(3-N-butylpyridinium)-4,4,5,5-tetramethyl-4,5-dihydro-1H imidazol-1-oxyl-3-N-oxide (m-BuPYNN) and 4-(ethylammonium)-2,2,6,6 tetramethylpiperidin-1-oxide (EATEP) are successfully intercalated into the layered host structure of CdPS(3) via ion exchange. The reaction proceeds either directly from ethanolic solutions of the radical iodide salt or via a two-stage process involving first the formation of an intermediate tetramethylammonium intercalate. The resulting materials, which are described by the compositional formula Cd(1-x)PS(3){Rad}(2x), are characterized by chemical analysis, X-ray powder diffraction, bulk susceptibility measurements and EPR spectroscopy. Modern single and double resonance solid state NMR techniques are introduced successfully to study the structural modifications of the host lattice and the details of the intermolecular guest/host interactions. (1)H MAS-NMR spectra reveal substantial differences in the unpaired electron spin density distributions within the radical ions intercalated into the host lattice compared to those obtained for the pure radical ion salts, leading to different bulk magnetic properties. The results of (1)H/(31)P double resonance experiments indicate that the orientation of the guest molecules is dominated by Columbic interactions between the radical cations and the negatively charged cadmium vacancies in the host lattice. PMID- 21543193 TI - DNA condensation and its thermal stability influenced by phospholipid bilayer and divalent cations. AB - We studied the effect of divalent alkaline earth metal cations Ca2+, Mg2+ and transition metals Co2+, Ni2+, Cu2+ and Zn2+ on DNA condensation and its protection against thermal denaturation in presence of dioleoylphosphatidylcholine liposomes (DOPC). Experimental results have shown that Ca2+ and Mg2+ as well as Zn2+ mediate DNA condensation. Cu2+ causes DNA double helix destabilization, and does not mediate binding between DNA and DOPC liposomes. Co2+ and Ni2+ can interact with DNA on both ways mentioned above. Static light scattering was use to follow the size of aggregates in DNA condensation process. Phospholipid bilayer and divalent cations protect condensed DNA against thermal destabilization. The highest stabilization effect was found in aggregates with Ca2+ and Zn2+, whereas in presence of either Co2+ or Ni2+ some volume fraction of DNA is denatured. PMID- 21543194 TI - Direct electrochemistry and voltammetric determination of midecamycin at a multi walled carbon nanotube coated gold electrode. AB - Macrolide antibiotics generally shows slow electron-transfer rate and produces insensitive redox peaks at conventional electrodes. In this paper, we studied the electrochemical behavior of midecamycin, one of macrolide antibiotics, at a multi walled carbon nanotube (MWNT) modified gold electrode. It was found that MWNT could adsorb midecamycin and promote its direct electron-transfer. Hence midecamycin exhibited a more sensitive anodic peak at the modified electrode. The electrochemical process showed the feature of a mixed-control system of diffusion and adsorption. Under the optimized conditions (i.e. pH 7.0 phosphate supporting electrolyte, 5 MUl 0.5 mg ml-1 multi-walled carbon nanotube suspension for O = 2.0 mm electrode, accumulation at -0.8 V for 150 s), the anodic peak current was linear to midecamycin concentration in the range of 5 * 10-7 to 2 * 10-5M, with a correlation coefficient of 0.998. For a 5*10-6 M midecamycin solution, ten repetitive measurements gave a relative standard deviation of 2.2%. This method was successfully applied to the determination of midecamycin in medicine tablet and the recovery was 97.5-104.0%. PMID- 21543195 TI - Mimicking the fibrinolytic system on material surfaces. AB - Clotting and thrombosis remain the most serious problems in the development of blood contacting devices such as heart valves, vascular stents, grafts and catheters. No material exists that does not provoke these phenomena and coagulation appears to be inevitable when a foreign (i.e. non-endothelial) surface is in contact with blood. As an alternative to a surface that prevents coagulation, the concept of a clot-lysing or fibrinolytic surface is attractive. By designing the surface effectively to mimic the fibrinolytic system in the vasculature, it may be possible for clots to be lysed (effectively dissolved) as they form. In this review we elaborate on this concept and discuss ways in which such a surface could be realized. Developments in this area to the present time are reviewed, and some perspectives for future research are presented. PMID- 21543196 TI - Polymorphism, crystallinity and hydrophilic-lipophilic balance of stearic acid and stearic acid-capric/caprylic triglyceride matrices for production of stable nanoparticles. AB - There is an increasing interest in lipid nanoparticles because of their suitability for several administration routes. Thus, it becomes even more relevant the physicochemical characterization of lipid materials with respect to their polymorphism, lipid miscibility and stability, as well as the assessment of the effect of surfactant on the type and structure of these nanoparticles. This work focuses on the physicochemical characterization of lipid matrices composed of pure stearic acid or of mixtures of stearic acid-capric/caprylic triglycerides, for drug delivery. The lipids were analyzed by Differential Scanning Calorimetry (DSC), Wide Angle X-ray Diffraction (WAXD), Polarized Light Microscopy (PLM) and hydrophilic-lipophilic balance (HLB) in combination with selected surfactants to determine the best solid-to-liquid ratio. Based on the results obtained by DSC and WAXD, the selected qualitative and quantitative composition contributed for the production of stable nanoparticles, since the melting and the tempering processes provided important information on the thermodynamic stability of solid lipid matrices. The best HLB value obtained for stearic acid-capric/caprylic triglycerides was 13.8, achieved after combining these lipids with accepted surfactants (trioleate sorbitan and polysorbate 80 in the ratio of 10:90). The proposed combinations were shown useful to obtain a stable emulsion to be used as intermediate form for the production of lipid nanoparticles. PMID- 21543197 TI - Birth weight, current body mass index, and insulin sensitivity and secretion in young adults in two Latin American populations. AB - BACKGROUND AND AIMS: Although studies have shown association of birth weight (BW) and adult body mass index (BMI) with insulin sensitivity in adults, there is limited evidence that BW is associated with insulin secretion. We assessed the associations between BW and current BMI with insulin sensitivity and secretion in young Latin American adults. METHODS AND RESULTS: Two birth cohorts, one from Ribeirao Preto, Brazil, based on 1984 participants aged 23-25 years, and another from Limache, Chile, based on 965 participants aged 22-28 years were studied. Weight and height at birth, and current fasting plasma glucose and insulin levels were measured. Insulin sensitivity (HOMA%S) and secretion (HOMA%beta) were estimated using the Homeostatic Model Assessment (HOMA2). Multiple linear regression analyses were carried out to test the associations between BW and adult BMI z-scores on log HOMA%S and log HOMA%beta. BW z-score was associated with HOMA%S in the two populations and HOMA%beta in Ribeirao Preto when adult BMI z-score was included in the model. BW z-score was associated with decreasing insulin secretion even without adjusting for adult BMI, but only in Ribeirao Preto. BMI z-score was associated with low HOMA%S and high HOMA%beta. No interactions between BW and BMI z-scores on insulin sensitivity were shown. CONCLUSIONS: This study supports the finding that BW may affect insulin sensitivity and secretion in young adults. The effect size of BW on insulin status is small in comparison to current BMI. PMID- 21543198 TI - Lipids in metabolic health and disease. PMID- 21543200 TI - Dietary saturated fat, gender and genetic variation at the TCF7L2 locus predict the development of metabolic syndrome. AB - Transcription factor 7-like 2 (TCF7L2) is the strongest genetic determinant of type 2 diabetes (T2DM) and insulin-related phenotypes to date. Dietary fat is a key environmental factor which may interact with genotype to affect risk of metabolic syndrome (MetS) and T2DM. This study investigated the relationship between the TCF7L2 rs7903146 polymorphism, insulin sensitivity/resistance and MetS in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n=1754) and determined potential interactions with dietary fat intake. Female minor T allele carriers of rs7903146 had increased MetS risk (odds ratio [OR] 1.66, confidence interval [CI] 1.02-2.70, P=.04) and displayed elevated insulin concentrations (P=.005), impaired insulin sensitivity (P=.011), increased abdominal obesity (P=.008) and body mass index (P=.001) and higher blood pressure (P<.05) compared to the CC homozygotes. Metabolic syndrome risk was also modulated by dietary saturated fat (SFA) intake (P=.035 for interaction). High dietary SFA intake (>=15.5% energy) exacerbated MetS risk (OR 2.35, 95% CI 1.29 4.27, P=.005) and was associated with further impaired insulin sensitivity in the T allele carriers relative to the CC homozygotes (P=.025) and particularly to the T allele carriers with the lowest SFA intake (P=.008). No significant genotype effect on MetS risk or insulin sensitivity was evident among low-SFA consumers. In conclusion, the TCF7L2 rs7903146 polymorphism influences MetS risk, which is augmented by both gender and dietary SFA intake, suggesting novel gene-diet gender interactions. PMID- 21543201 TI - Tools for the identification of bioactives impacting the metabolic syndrome: screening of a botanical extract library using subcutaneous and visceral human adipose-derived stem cell-based assays. AB - Plant extracts continue to represent an untapped source of renewable therapeutic compounds for the treatment and prevention of illnesses including chronic metabolic disorders. With the increase in worldwide obesity and its related morbidities, the need for identifying safe and effective treatments is also rising. As such, use of primary human adipose-derived stem cells represents a physiologically relevant cell system to screen for bioactive agents in the prevention and treatment of obesity and its related complications. By using these cells in a primary screen, the risk and cost of identifying artifacts due to interspecies variation and immortalized cell lines is eliminated. We demonstrate that these cells can be formatted into 384-well high throughput screens to rapidly identify botanical extracts that affect lipogenesis and lipolysis. Additionally, counterscreening with human primary stem cells from distinct adipose depots can be routinely performed to identify tissue specific responses. In our study, over 500 botanical extracts were screened and 16 (2.7%) were found to affect lipogenesis and 4 (0.7%) affected lipolysis. PMID- 21543202 TI - Ethanol extract of Portulaca oleracea L. protects against hypoxia-induced neuro damage through modulating endogenous erythropoietin expression. AB - In addition to its role in erythropoiesis, erythropoietin is also appreciated for its neuroprotective effects, and it has been suggested for treatment of some ischemic-hypoxic neurovascular diseases. The protective effects of endogenous erythropoietin in the brain give rise to the hypothesis that modulating erythropoietin expression might be a better way for treatment of ischemia-hypoxia neurovascular diseases. We have found that ethanol extract of Portulaca oleracea L. (EEPO) could increase erythropoietin expression in hypoxic mouse brain in our previous study. The present study is to investigate whether EEPO exerts its neuroprotective effects against hypoxia injury through regulating endogenous erythropoietin expression. The results demonstrated that EEPO decreased the serum neuron specific enolase level in hypoxia mice and the activity of caspase-3 in neuron, increased the neuron viability and attenuated the pathological damages caused by the hypoxia condition. Importantly, we also found that EEPO stimulated the endogenous erythropoietin expression at both mRNA and protein levels. Using the conditioned medium containing soluble erythropoietin receptor, we found that the neuroprotective effects of EEPO were dependent, at least partly, on erythropoietin expression. Although EEPO did not affect transcription of hypoxia inducible factor-1alpha (HIF-1alpha), it did stabilize expression of HIF-1alpha. It is concluded that EEPO has neuroprotective effects against hypoxia injury, which is at least partly through stimulating endogenous erythropoietin expression by stabilizing HIF-1alpha. PMID- 21543199 TI - Towards a whole-body systems [multi-organ] lipidomics in Alzheimer's disease. AB - Preclinical and clinical evidence suggests that docosahexaenoic acid (DHA), an omega-3 fatty acid derived from diet or synthesized in the liver, decreases the risk of developing Alzheimer's disease (AD). DHA levels are reduced in the brain of subjects with AD, but it is still unclear whether human dementias are associated with dysregulations of DHA metabolism. A systems biological view of omega-3 fatty acid metabolism offered unexpected insights on the regulation of DHA homeostasis in AD [1]. Results of multi-organ lipidomic analyses were integrated with clinical and gene-expression data sets to develop testable hypotheses on the functional significance of lipid abnormalities observed and on their possible mechanistic bases. One surprising outcome of this integrative approach was the discovery that the liver of AD patients has a limited capacity to convert shorter chain omega-3 fatty acids into DHA due to a deficit in the peroxisomal d-bifunctional protein. This deficit may contribute to the decrease in brain DHA levels and contribute to cognitive impairment. PMID- 21543203 TI - Flavokawain B inhibits growth of human squamous carcinoma cells: Involvement of apoptosis and cell cycle dysregulation in vitro and in vivo. AB - Flavokawain B is a natural chalcone isolated from the rhizomes of Alpenia pricei Hayata. In the present study, we have investigated the antiproliferative and apoptotic effect of flavokawain B (5-20 MUg/ml; 17.6-70.4 MUM) against human squamous carcinoma (KB) cells. Exposure of KB cells with flavokawain B resulted in apoptosis, evidenced by loss of cell viability, profound morphological changes, genomic DNA fragmentation and sub-G1 phase accumulation. Apoptosis induced by flavokawain B results in activation of caspase-9, -3 and -8, cleavage of poly ADP ribose polymerase (PARP) and Bid in KB cells. Flavokawain B also down regulate Bcl-2 with concomitant increase in Bax level, which resulted in release of cytochrome c. Taken together, the induction of apoptosis by flavokawain B involved in both death receptor and mitochondrial pathway. We also observed that flavokawain B caused the G2/M phase arrest that was mediated through reductions in the levels of cyclin A, cyclin B1, Cdc2 and Cdc25C and increases in p21/WAF1, Wee1 and p53 levels. Moreover, flavokawain B significantly inhibits matrix metalloproteinase-9 and urokinase plasminogen activator expression, whereas tissue inhibitor of matrix metalloproteinase-1 and plasminogen activator inhibitor-1 were increased, which are playing critical role in tumor metastasis. In addition, flavokawain B treatment significantly inhibited in vivo growth of human KB cell-derived tumor xenografts in nude mice, which is evidenced by augmentation of apoptotic DNA fragmentation, as detected by in situ terminal deoxynucleotidyl transferase-meditated dUTP nick end-labeling staining. The induction of cell cycle arrest and apoptosis by flavokawain B may provide a pivotal mechanism for its cancer chemopreventive action. PMID- 21543204 TI - Ferulic acid, a phenolic phytochemical, inhibits UVB-induced matrix metalloproteinases in mouse skin via posttranslational mechanisms. AB - Matrix metalloproteinases MMP-2 and -9 are known to be overexpressed in ultraviolet B (UVB)-irradiated skin tissues and contribute to the acceleration of photoaging and the development of skin cancer. But the specific molecular mechanisms that can control or interfere with the expression and regulation of these MMP-2 and -9 activities in skin are not clearly understood. The aim of the present study was to analyze the suppressive effects of ferulic acid (FA), an abundant phenolic compound present in various dietary and medicinal plants, on UVB radiation-induced MMP-2 and -9 activities in mouse skin. For attenuation of chronic UVB irradiation damage to skin, inhibition of MMP-2 and -9 protein expression was detected using immunohistochemistry analysis. However, the in situ suppressive effects of FA did not interfere with the transcription or translation of MMP-2 and -9, suggesting that its action could be mediated via the proteasome pathway. Histological analyses showed that FA attenuates the degradation of collagen fibers, abnormal accumulation of elastic fibers and epidermal hyperplasia induced by UVB, demonstrating the functional and physiological relevance of FA effects in UVB-irradiated skin tissues. Together, our findings provide a novel and increased insight into the in vivo action of FA and suggest a possible clinical application in skin pathophysiological conditions associated with overexpression of MMP-2 and -9. PMID- 21543205 TI - Purple corn anthocyanins dampened high-glucose-induced mesangial fibrosis and inflammation: possible renoprotective role in diabetic nephropathy. AB - Purple corn has been classified as a functional food rich in anthocyanins possessing potential disease-preventive properties. This study examined whether purple corn anthocyanins (PCA) mainly comprised cyanidin 3-glucoside and cyanidin 3-(6"-malonylglucoside) can attenuate high-glucose (HG)-promoted mesangial cell (MC) proliferation and matrix accumulation, major features of diabetic glomerulosclerosis. Human renal MC were cultured for 3 days in media containing 5.5 mM glucose plus 27.5 mM mannitol as osmotic controls or media containing 33 mM glucose in the absence and presence of 1-20 MUg/ml PCA. The HG exposure of MC caused substantial increases in connective tissue growth factor (CTGF) expression and collagen IV secretion with mesangial hyperplasia, which were repealed by adding PCA. PCA boosted HG-plummeted membrane type-1 matrix metalloproteinase expression and dampened HG-elevated tissue inhibitor of matrix metalloproteinase 2 expression through disturbing transforming growth factor beta (TGF-beta)-SMAD signaling, facilitating extracellular matrix degradation. This study further revealed that PCA ameliorated HG-inflamed mesangial inflammation accompanying induction of intracellular cell adhesion molecule-1 and monocyte chemoattractant protein-1 (MCP-1) responsible for CTGF expression. The induction of intracellular cell adhesion molecule-1 and MCP-1 was mediated via TGF-beta signaling, which was suppressed by PCA. In addition, the HG-promoted CTGF expression entailed nuclear factor kappaB (NF-kappaB) signaling involved in MCP-1 transcription. The HG-TGF beta induction was blocked in the presence of a NF-kappaB inhibitor, and the nuclear NF-kappaB translocation was blunted by a TGF-beta receptor 1 inhibitor. PCA dampened NF-kappaB translocation in HG-exposed MC. These results demonstrate that there was a crosstalk between TGF-beta-SMAD and NF-kappaB pathways in the diabetes-associated mesangial fibrosis and inflammation, which appeared to be severed by PCA. PMID- 21543206 TI - Resveratrol regulates lipolysis via adipose triglyceride lipase. AB - Resveratrol has been reported to increase adrenaline-induced lipolysis in 3T3-L1 adipocytes. The general aim of the present work was to gain more insight concerning the effects of trans-resveratrol on lipid mobilization. The specific purpose was to assess the involvement of the two main lipases: adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in the activation of lipolysis induced by this molecule. For lipolysis experiments, 3T3-L1 and human SGBS adipocytes as well as adipose tissue from wild-type, ATGL knockout and HSL knockout mice were used. Moreover, gene and protein expressions of these lipases were analyzed. Resveratrol-induced free fatty acids release but not glycerol release in 3T3-L1 under basal and isoproterenol-stimulating conditions and under isoproterenol-stimulating conditions in SGBS adipocytes. When HSL was blocked by compound 76-0079, free fatty acid release was still induced by resveratrol. By contrast, in the presence of the compound C, an inhibitor of adenosine monophosphate-activated protein kinase, resveratrol effect was totally blunted. Resveratrol increased ATGL gene and protein expressions, an effect that was not observed for HSL. Resveratrol increased fatty acids release in epididymal adipose tissue from wild-type and HSL knockout mice but not in that adipose tissue from ATGL knockout mice. Taking as a whole, the present results provide novel evidence that resveratrol regulates lipolytic activity in human and murine adipocytes, as well as in white adipose tissue from mice, acting mainly on ATGL at transcriptional and posttranscriptional levels. Enzyme activation seems to be induced via adenosine monophosphate-activated protein kinase. PMID- 21543207 TI - Apple procyanidins induce hyperpolarization of rat aorta endothelial cells via activation of K+ channels. AB - Apple procyanidins (AP), one of the polyphenol-rich compounds, showed an endothelial-dependent vasorelaxation in rat aorta, but the mechanisms of beneficial effects are still unclear. The present study was designed to clarify the potential role of AP in rat aorta endothelial cells (RAECs). The treatment of RAECs with AP (1-10 MUg/ml) resulted in a dose-dependent hyperpolarization with a maximum effect at 10 MUg/ml, and for this reason, AP (10 MUg/ml) was used in all the following experiments. AP-induced hyperpolarization was significantly inhibited by pretreatment of nonspecific K(+) inhibitor, tetraethyl ammonium chloride or specific K(+) channel inhibitors, iberiotoxin, glibenclamide, 4 aminopyridine and BaCl(2), as well as by high KCl or Ca(2+)-free solution. AP induced hyperpolarization was also proved using 64-channel multielectrode dish system that can monitor a direct and real-time change of membrane potential. Furthermore, AP treatment caused a significant increase of nitric oxide (NO) production and cyclic guanosine monophosphate levels via endothelial NO synthase messenger RNA expression. The NO production was inhibited by N(G)-monoethyl-l arginine or Ca(2+)-free solution and was completely abolished by their combination. Also, AP inhibited endothelial proliferation, while the effect was significantly abolished by N(G)-monoethyl-l-arginine or tetraethyl ammonium chloride. These findings suggest that AP induces both hyperpolarization of RAECs via multiple activation of K(+) channels and activation of NO/cyclic guanosine monophosphate pathway via increasing NO production or is responsible for antiangiogenic effect. Diminishment of hyperpolarization as well as NO production of AP in Ca(2+)-free solution implicated that AP would play a crucial role in promoting Ca(2+) influx into endothelial cells so as to promote both actions. PMID- 21543208 TI - Intake of trans fatty acids during gestation and lactation leads to hypothalamic inflammation via TLR4/NFkappaBp65 signaling in adult offspring. AB - We examined whether feeding pregnant and lactating rats with hydrogenated vegetable fats rich in trans fatty acids led to an increase in serum endotoxin levels and inflammation and to impaired satiety-sensing pathways in the hypothalamus of 90-day-old offspring. Pregnant and lactating Wistar rats were fed either a standard chow (Control) or one enriched with hydrogenated vegetable fat (Trans). Upon weaning, the male offspring were divided in two groups: Control Control (CC), mothers and offspring fed the control diet; and Trans-Control (TC), mothers fed the trans diet, and offspring fed the control diet. The offspring's food intake and body weight were quantified weekly and the offspring were killed on the 90th day of life by decapitation. The blood and hypothalamus were collected from the offspring. Food intake and body weight were higher in the TC rats than in the CC rats. TC rats had increased serum endotoxin levels and increased hypothalamic cytokines, IL-6, TNF-alpha and IL1-beta, concentrations (P<.05). TLR4, NFkappaBp65 and MyD88 were higher (P<.05) in the TC rats than in the CC rats. AdipoR1 was lower in the TC rats than in the CC rats. Thus, the present study shows that the mothers' hydrogenated vegetable fat intake during pregnancy and lactation led to hypothalamic inflammation and impaired satiety sensing, which promotes deleterious metabolic consequences such as obesity, even after the withdrawal of the causal factor. In other words, the effect remains after the consumption of the standard chow by offspring. PMID- 21543209 TI - Role of G1359A polymorphism of the cannabinoid receptor gene on weight loss and adipocytokines levels after two different hypocaloric diets. AB - BACKGROUND: A silent intragenic polymorphism (1359 G/A) of the cannabinoid receptor 1 gene resulting in the substitution of the G to A at nucleotide position 1359 in codon 435 (Thr) was reported as a common polymorphism in Caucasian populations. Intervention studies with this polymorphism have not been realized. OBJECTIVE: We decide to investigate the role of missense polymorphism (G1359A) of cannabinoid receptor 1 gene on adipocytokines response and weight loss secondary to a low-fat versus a low-carbohydrate diet in obese patients. DESIGN: A population of 249 patients was analyzed. A nutritional evaluation was performed at the beginning and at the end of a 3-month period in which subjects received one of two diets (diet I: low fat vs. diet II: low carbohydrate). RESULTS: One hundred forty three patients (57.4%) had the genotype G1359G (wild type group), and 106 (42.6%) patients had G1359A (92 patients, or 36.9%) or A1359A (14 patients, or 5.6%; mutant-type group). With both diets in wild-type and mutant-type groups, body mass index (BMI), weight, fat mass, waist circumference and systolic blood pressure levels decreased. With both diets and in wild-type group, glucose, total cholesterol and insulin levels and homeostasis model assessment test score decreased. No metabolic effects were observed in mutant-type group. Leptin levels decreased significantly in the wild-type group with both diets (diet I: 10.8% vs. diet II: 28.9%; P<.05). CONCLUSION: The novel finding of this study is the lack of metabolic improvement of the mutant-type groups G1359A and A1359A after weight loss with both diets. Decrease in leptin level was higher with low-carbohydrate diet than low-fat diet. PMID- 21543210 TI - gamma-Tocopherol abolishes postprandial increases in plasma methylglyoxal following an oral dose of glucose in healthy, college-aged men. AB - Postprandial hyperglycemia contributes to the risk of cardiovascular disease in part by increasing concentrations of the reactive dicarbonyl methylglyoxal (MGO), a byproduct of glucose metabolism. Oxidative stress increases MGO formation from glucose in vitro and decreases its glutathione-dependent detoxification to lactate. We hypothesized that the antioxidant gamma-tocopherol, a form of vitamin E, would decrease hyperglycemia-mediated postprandial increases in plasma MGO in healthy, normoglycemic, college-aged men. Participants (n=12 men; 22.3+/-1.0 years; 29.3+/-2.4 kg/m(2)) received an oral dose of glucose (75 g) in the fasted state prior to and following 5-day ingestion of a vitamin E supplement enriched in gamma-tocopherol (500 mg/day). gamma-Tocopherol supplementation increased (P<.0001) plasma gamma-tocopherol from 2.22+/-0.32 to 7.06+/-0.71 MUmol/l. Baseline MGO concentrations and postprandial hyperglycemic responses were unaffected by gamma-tocopherol supplementation (P>.05). Postprandial MGO concentrations increased in the absence of supplemental gamma-tocopherol (P<.05), but not following gamma-tocopherol supplementation (P>.05). Area under the curve for plasma MGO was significantly (P<.05) smaller with the supplementation of gamma-tocopherol than without (area under the curve (0-180 min), -778+/-1010 vs. 2277+/-705). Plasma concentrations of gamma-carboxyethyl-hydroxychroman, reduced glutathione and markers of total antioxidant capacity increased after supplementation, and these markers and plasma gamma-tocopherol were inversely correlated with plasma MGO (r=-0.48 to -0.67, P<.05). These data suggest that short-term supplementation of gamma-tocopherol abolishes the oral glucose mediated increases in postprandial MGO through its direct and indirect antioxidant properties and may reduce hyperglycemia-mediated cardiovascular disease risk. PMID- 21543211 TI - Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepatic steatosis in high-fat diet-fed and db/db mice via the transcription factor FoxO1. AB - Obesity is a major risk factor for the development of type 2 diabetes, and both conditions are now recognized to possess significant inflammatory components underlying their pathophysiologies. Here, we hypothesized that cyanidin 3 glucoside (C3G), a typical anthocyanin reported to possess potent anti inflammatory properties, would ameliorate obesity-associated inflammation and metabolic disorders, such as insulin resistance and hepatic steatosis in mouse models of diabesity. Male C57BL/6J obese mice fed a high-fat diet for 12 weeks and genetically diabetic db/db mice at an age of 6 weeks received dietary C3G supplementation (0.2%) for 5 weeks. We found that dietary C3G lowered fasting glucose levels and markedly improved the insulin sensitivity in both high-fat diet fed and db/db mice as compared with unsupplemented controls. White adipose tissue messenger RNA levels and serum concentrations of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein 1) were reduced by C3G, as did macrophage infiltration in adipose tissue. Concomitantly, hepatic triglyceride content and steatosis were alleviated by C3G. Moreover, C3G treatment decreased c-Jun N-terminal kinase activation and promoted phosphorylation and nuclear exclusion of forkhead box O1 after refeeding. These findings clearly indicate that C3G has significant potency in antidiabetic effects by modulating the c-Jun N-terminal kinase/forkhead box O1 signaling pathway and the related inflammatory adipocytokines. PMID- 21543213 TI - Taurine supplementation restores glucose and carbachol-induced insulin secretion in islets from low-protein diet rats: involvement of Ach-M3R, Synt 1 and SNAP-25 proteins. AB - Isolated islets from low-protein (LP) diet rats showed decreased insulin secretion in response to glucose and carbachol (Cch). Taurine (TAU) increases insulin secretion in rodent islets with a positive effect upon the cholinergic pathway. Here, we investigated the effect of TAU administration upon glucose tolerance and insulin release in rats fed on a normal protein diet (17%) without (NP) or with 2.5% of TAU in their drinking water (NPT), and LP diet fed rats (6%) without (LP) or with TAU (LPT). Glucose tolerance was found to be higher in LP, compared to NP rats. However, plasma glucose levels, during ipGTT, in LPT rats were similar to those of controls. Isolated islets from LP rats secreted less insulin in response to increasing glucose concentrations (2.8-22.2 mmol/L) and to 100 MUmol/L Cch. This lower secretion was accompanied by a reduction in Cch induced internal Ca(2+) mobilization. TAU supplementation prevents these alterations, as judged by the higher secretion induced by glucose or Cch in LPT islets. In addition, Ach-M3R, syntaxin 1 and synaptosomal associated protein of 25 kDa protein expressions in LP were lower than in NP islets. The expressions of these proteins in LPT were normalized. Finally, the sarcoendoplasmatic reticulum Ca(2+)-ATPase 3 protein expression was higher in LPT and NPT, compared with controls. In conclusion, TAU supplementation to LP rats prevented alterations in glucose tolerance as well as in insulin secretion from isolated islets. The latter effect involves the normalization of the cholinergic pathway, associated with the preservation of exocytotic proteins. PMID- 21543212 TI - Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by proinflammatory enzymes. AB - Oxidative and nitrative stress responses resulting from inflammation exacerbate liver injury associated with nonalcoholic steatohepatitis (NASH) by inducing lipid peroxidation and protein nitration. The objective of this study was to investigate whether the anti-inflammatory properties of green tea extract (GTE) would protect against NASH by suppressing oxidative and nitrative damage mediated by proinflammatory enzymes. Obese mice (ob/ob) and their 5-week-old C57BL6 lean littermates were fed 0%, 0.5% or 1% GTE for 6 weeks (n=12-13 mice/group). In obese mice, hepatic lipid accumulation, inflammatory infiltrates and serum alanine aminotransferase activity were markedly increased, whereas these markers of hepatic steatosis, inflammation and injury were significantly reduced among obese mice fed GTE. GTE also normalized hepatic 4-hydroxynonenal and 3-nitro tyrosine (N-Tyr) concentrations to those observed in lean controls. These oxidative and nitrative damage markers were correlated with alanine aminotransferase (P<.05; r=0.410-0.471). Improvements in oxidative and nitrative damage by GTE were also associated with lower hepatic nicotinamide adenine dinucleotide phosphate oxidase activity. Likewise, GTE reduced protein expression levels of hepatic myeloperoxidase and inducible nitric oxide synthase and decreased the concentrations of nitric oxide metabolites. Correlative relationships between nicotinamide adenine dinucleotide phosphate oxidase and hepatic 4-hydroxynonenal (r=0.364) as well as nitric oxide metabolites and N-Tyr (r=0.598) suggest that GTE mitigates lipid peroxidation and protein nitration by suppressing the generation of reactive oxygen and nitrogen species. Further study is warranted to determine whether GTE can be recommended as an effective dietary strategy to reduce the risk of obesity-triggered NASH. PMID- 21543214 TI - Maternal high-fat feeding through pregnancy and lactation predisposes mouse offspring to molecular insulin resistance and fatty liver. AB - The exposure to an increased supply of nutrients before birth may contribute to offspring obesity. Offspring from obese dams that chronically consume a high-fat diet present clinical features of metabolic syndrome, liver lipid accumulation and activation of c-Jun N-terminal kinases (JNK) consistent with the development of nonalcoholic fatty liver disease (NAFLD). However, in spite of the importance of the resistance to insulin for the development of NAFLD, the molecular alterations in the liver of adult offspring of obese dams are yet to be investigated. In this study, we tested the hypothesis that the consumption of excessive saturated fats during pregnancy and lactation contributes to adult hepatic metabolic dysfunction in offspring. Adult male offspring of dams fed a high-fat diet (HN) during pregnancy and lactation exhibited increased fat depot weight; increased serum insulin, tumor necrosis factor alpha and interleukin 1beta; and reduced serum triglycerides. Liver showed increased JNK and I kappa B kinase phosphorylation and PEPCK expression in the adult. In addition, liver triglyceride content in the offspring 1 week after weaning and in the adult was increased. Moreover, basal ACC phosphorylation and insulin signaling were reduced in the liver from the HN group as compared to offspring of dams fed a standard laboratory chow (NN). Hormone-sensitive lipase phosphorylation (Ser565) was reduced in epididymal adipose tissue from the HN group as compared to the NN group. It is interesting that all changes observed were independent of postweaning diet in 14-week-old offspring. Therefore, these data further reinforce the importance of maternal nutrition to adult offspring health. PMID- 21543216 TI - Fish oil supplementation of maternal rats on an n-3 fatty acid-deficient diet prevents depletion of maternal brain regional docosahexaenoic acid levels and has a postpartum anxiolytic effect. AB - Docosahexaenoic acid (DHA) and arachidonic acid (AA) are the major polyunsaturated fatty acids (PUFA) in the neuronal membrane. Most DHA and AA accumulation in the brain occurs during the perinatal period via placenta and milk. This study examined whether maternal brain levels of DHA and AA are depleted during pregnancy and lactation due to meeting the high demand of the developing nervous system in the offspring and evaluated the effects of the reproductive cycle on serotonin metabolism and of fish oil (FO) on postpartum anxiety. Pregnant rats were fed during pregnancy and lactation with a sunflower oil-based n-3 PUFA-deficient diet without or with FO supplementation, which provided 0.37% of the energy source as n-3 PUFA, and the age-matched virgin rats were fed the same diets for 41 days. In both sets of postpartum rats, decreased DHA levels compared to those in virgin females were seen in the hypothalamus, hippocampus, frontal cortex, cerebellum, olfactory bulb and retina, while AA depletion was seen only in the hypothalamus, hippocampus and frontal cortex. Serotonin levels were decreased and turnover increased in the brainstem and frontal cortex in postpartum rats compared to virgin rats. FO supplementation during pregnancy and lactation prevented the decrease in maternal brain regional DHA levels, inhibited monoamine oxidase-A activity in the brainstem and decreased anxiety-like behavior. We propose that the reproductive cycle depletes maternal brain DHA levels and modulates maternal brain serotonin metabolism to cause postpartum anxiety and suggest that FO supplementation may be beneficial for postpartum anxiety in women on an n-3 PUFA-deficient diet. PMID- 21543217 TI - Evolution of heavy metals in municipal solid waste during bio-drying and implications of their subsequent transfer during combustion. AB - Bio-drying has been applied to improve the heating value of municipal solid waste (MSW) prior to combustion. In the present study, evolution of heavy metals in MSW during bio-drying and subsequent combustion was studied using one aerobic and two combined hydrolytic-aerobic scenarios. Heavy metals were concentrated during bio drying and transformed between different metal fractions, namely the exchangeable, carbonate-bound, iron- and manganese-oxides-bound, organic-matter bound and residual fractions. The amounts of heavy metals per kg of bio-dried MSW transferred into combustion flue gas increased with bio-drying time, primarily due to metals enrichment from organics degradation. Because of their volatility, the partitioning ratios of As and Hg in flue gas remained stable so that bio drying and heavy metal speciation had little effect on their transfer and partitioning during combustion. In contrast, the partitioning ratios of Pb, Zn and Cu tended to increase after bio-drying, which likely enhanced their release potential during combustion. PMID- 21543215 TI - Dietary cystine level affects metabolic rate and glycaemic control in adult mice. AB - Plasma total cysteine (tCys) is strongly and independently associated with obesity in large human cohorts, but whether the association is causal is unknown. Dietary cyst(e)ine increases weight gain in some rodent models. We investigated the body composition, metabolic rate and metabolic phenotype of mature C3H/HeH mice assigned to low-cystine (LC) or high-cystine (HC) diets for 12 weeks. Compared to LC mice, HC mice gained more weight (P=.004 for 12-week weight gain %), with increased fat mass and lean mass, and lowered O2 consumption and CO2 production by calorimetry. The HC mice had 30% increase in intestinal fat/body weight % (P=.003) and ~twofold elevated hepatic triglycerides (P=.046), with increased expression of hepatic lipogenic factors, peroxisome proliferator activated receptor-gamma and sterol regulatory element binding protein-1. Gene expression of both basal and catecholamine-stimulated lipolytic enzymes, adipose triglyceride lipase and hormone-sensitive lipase was inhibited in HC mice adipose tissue. The HC mice also had elevated fasting glucose (7.0 vs. 4.5 mmol/L, P<.001) and a greater area under the curve (P<.001) in intraperitoneal glucose tolerance tests, with enhanced expression of the negative regulator of insulin signaling, protein tyrosine phosphatase-1B, in liver and adipose tissue. Overall, high cystine intake promotes adiposity and an adverse metabolic phenotype in mice, indicating that the positive association of plasma tCys with obesity in humans may be causal. PMID- 21543218 TI - Catalytic pyrolysis of car tire waste using expanded perlite. AB - In this study, the non-catalytic and catalytic pyrolysis experiments were conducted on the sample of tire waste using expanded perlite as an additive material to determine especially the effect of temperature and catalyst-to-tire ratio on the products yields and the compositions and qualities of pyrolytic oils (NCPO and CPO). Non-catalytic studies, which were carried out under the certain conditions (a nitrogen flow of 100mL/min and a heating rate of 10 degrees C/min), showed that the highest yield of pyrolytic oil (NCPO) was 60.02wt.% at 425 degrees C. Then, the catalytic pyrolysis studies were carried out at catalyst-to tire ratio range of 0.05-0.25 and the highest catalytic pyrolytic oil (CPO) yield was 65.11wt.% at the ratio of 0.10 with the yield increase of 8.48wt.% compared with the non-catalytic pyrolysis. Lastly, the pyrolytic oils were characterized with applying a various techniques such as elemental analyses and various chromatographic and spectroscopic techniques (GC-MS, (1)H NMR, FT-IR, etc.). The characterization results revealed that the pyrolytic oils which were complex mixtures of C(5)-C(15) organic compounds (predominantly aromatic compounds) and also the CPO compared to the NCPO was more similar to conventional fuels in view of the certain fuel properties. PMID- 21543219 TI - Colorimetric detection of mercury, lead and copper ions simultaneously using protein-functionalized gold nanoparticles. AB - A simple, cost-effective and rapid colorimetric method for any or all of Hg(2+), Pb(2+) and Cu(2+) detection using papain-functionalized gold nanoparticles (P AuNPs) has been developed. Papain is a protein with seven cystein residues, which can selectively bind with Hg(2+), Pb(2+) and Cu(2+). We functionalized gold nanoparticles with papain. The P-AuNPs could be used to simultaneously detect Hg(2+), Pb(2+) and Cu(2+), and showed different responses to the three ions in an aqueous solution based on the aggregation-induced color change of gold nanoparticles. The P-AuNPs displayed the most obvious response to mercury ions in water in contrast to lead and copper ions, and the real water sample analysis verified the conclusion. The sensitivity of the detection system was influenced by the pH of the P-AuNPs solution, the concentration of P-AuNPs and the size of gold nanoparticles, and we found that larger gold nanoparticles contributed to more sensitive results. The detection system can detect as low as 200 nM Hg(2+), Pb(2+) or Cu(2+) using 42 nm gold nanoparticles. We expect our approach to have wide-ranging applications in the developing region for monitoring water quality in some areas. PMID- 21543220 TI - Electrochemical aptameric sensor based on the Klenow fragment polymerase reaction for cocaine detection. AB - An electrochemical aptasensor based on Klenow fragment (KF) polymerase reaction that combines the aggregation of ferrocene-functionalized oligonucleotide has been developed successfully for cocaine detection. In the presence of cocaine, the recognition probe changed its hairpin conformation into the tripartite complex. The aptamer-cocaine complex gave a 3'-single-stranded tail sequence complementary to the surface-tethered capture probe. In KF polymerase reaction, the recognition probe served as a template for the extension of a capture probe. It requires a sample volume of 2 MUL and is complete within 1 h. The ferrocene appended oligonucleotide incorporated into the newly synthesized complementary probe leads to an electrochemical response. This sensitive detection of cocaine is due to a very low background signal and large signal enhancement up to 9-fold upon addition of analyte. It permits detection of as low as 200 MUM cocaine. The simple and isothermal procedure does not require thermal cycling or special laboratory conditions, which makes it adaptable to low-cost and robust biosensing. PMID- 21543221 TI - Electrochemical measurement of the flux of hydrogen peroxide releasing from RAW 264.7 macrophage cells based on enzyme-attapulgite clay nanohybrids. AB - Determination of cellular ROS (reactive oxygen species) could lead to a better understanding of the clinical consequences of the enhancement in ROS concentration, and assisting in studies of the biological effect of ROS in cells. This work developed an electrochemical approach for measuring the flux of H(2)O(2) (a major ROS in living organisms) releasing from RAW 264.7 macrophage cells. This approach is based on the electrocatalytic reduction of the releasing H(2)O(2) at the biosensor of HRP-attapulgite/GC, which was fabricated by depositing the horseradish peroxidase-attapulgite nanohybrids on the glassy carbon (GC) electrode. The biosensor exhibited a rapid response, a wide linear range, a high sensitivity, a low detection limit, as well as good stability and repeatability due to using the natural mineral (attapulgite) as the enzyme immobilization substrate. In addition, some common coexisting ROS and compounds in biological system such as hypochlorite (OCl(-)), nitric oxide (NO), peroxynitrite (ONOO(-)), and ascorbic acid (AA) etc., did not cause any interference due to the use of a low operating potential (-400mV, versus SCE). Moreover, the developed approach can also be used for studying the effects of the stimulator loading and a variety of stimuli on the generation of H(2)O(2) in cells and the release flux of H(2)O(2) from cells. Therefore, this work has demonstrated a simple and effective sensing platform for detection of cellular H(2)O(2) released from cells such as RAW 264.7 cells, which has potential utility to cellular biology and pathophysiology. PMID- 21543222 TI - A highly efficient buckypaper-based electrode material for mediatorless laccase catalyzed dioxygen reduction. AB - The redox enzyme laccase from Trametes versicolor efficiently catalyzes the oxygen reduction reaction (ORR) in mediatorless biofuel cell cathodes when adsorbed onto multi-walled carbon nanotubes (MWCNTs). In this work we demonstrate that the fabrication of MWCNTs in form of buckypaper (BP) results in an excellent electrode material for laccase-catalyzed cathodes. BPs are mechanically stable, self-entangling mats with high dispersion of MWCNTs resulting in easy to handle homogeneous layers with highly mesoporous structures and excellent electrical conductivities. All biocathodes have been electrochemically investigated in oxygen-saturated buffer at pH 5 by galvanostatic polarization and potentiodynamic linear sweep voltammetry. Both methods confirm an efficient direct interaction of laccase with BP with a high open circuit potential of 0.882 V vs. normal hydrogen electrode (NHE). The high oxygen reduction performance leads to high current densities of 422+/-71 MUA cm(-2) at a typical cathode potential of 0.744 V vs. NHE. When the current density is normalized to the mass of the electrode material (mass activity), the BP-based film electrodes exhibit a 68-fold higher current density at 0.744 V vs. NHE than electrodes fabricated from the same MWCNTs in a non-dispersed agglomerated form as packed electrodes. This clearly shows that MWCNTs can act more efficiently as cathode when prepared in form of BP. This can be attributed to reduced diffusional mass transfer limitations and enhanced electrical conductivity. BP is thus a very promising material for the construction of mediatorless laccase cathodes for ORR in biofuel cells. In addition we demonstrated that these electrodes exhibit a high tolerance towards glucose, the most common bioanode fuel. PMID- 21543224 TI - Evaluating industrial symbiosis and algae cultivation from a life cycle perspective. AB - A comparative life cycle assessment (LCA) was conducted on 20 scenarios of microalgae cultivation. These scenarios examined the utilization of nutrients and CO(2) from synthetic sources and waste streams as well as the materials used to construct a photobioreactor (PBR). A 0.2-m(3) closed PBR of Chlorella vulgaris at 30%-oil content by weight with the productivity of 25 g/m(2) * day was used as a case study. Results of the study show that the utilization of resources from waste streams mainly avoided global warming potential (GWP) and eutrophication impacts. Impacts from the production of material used to construct the PBR dominate total impacts in acidification and ozone depletion categories, even over longer PBR lifetimes; thus, the choice of PBR construction materials is important. PMID- 21543225 TI - 2-Arylmethylaminomethyl-5,6-dihydroxychromone derivatives with selective anti-HCV activity. AB - Anti-HCV activity of aryl diketoacid (ADK) has been characterized by its two pharmacophoric elements, alpha,beta-diketo acid moiety and substituted aryl ring. In this study, as a part of our ongoing efforts to discover a novel anti-HCV compound mimicking the ADK scaffold, we designed 2-arylmethylaminomethyl-5,6 dihydroxychromone derivatives of which the dihydroxychromone moiety as well as the arylmethylaminomethyl substituent (R-PhCH(2)NHCH(2)-) were anticipated in exact match with the pharmacophore model of the ADK. The dihydroxychromone derivatives (3a-3u), thus prepared, showed biological activity in a substituent dependent fashion, thereby leading to selective anti-HCV effect (EC(50)=2.0-14.0 MUM, CC(50) >100 MUM) with the substituent groups such as Cl, Br, I, and Me specifically at the 3-position of the aromatic ring. PMID- 21543223 TI - The cancerous translation apparatus. AB - Deregulations in translational control are critical features of cancer initiation and progression. Activation of key oncogenic pathways promotes rapid and dramatic translational reprogramming, not simply by increasing overall protein synthesis, but also by modulating specific mRNA networks that promote cellular transformation. Additionally, ribosomopathies caused by mutations in ribosome components alter translational regulation leading to specific pathological features, including cancer susceptibility. Exciting advances in our understanding of translational control in cancer have illuminated a striking specificity innate to the translational apparatus. Characterizing this specificity will provide novel insights into how cells normally utilize translational control to modulate gene expression, how it is deregulated in cancer, and how these processes can be targeted to develop new cancer therapies. PMID- 21543226 TI - Design and synthesis of 5,6-fused heterocyclic amides as Raf kinase inhibitors. AB - Two scaffolds based on 5,6-fused heterocyclic backbones were designed and synthesized as Raf kinase inhibitors. The scaffolds were assessed for in vitro pan-Raf inhibition, activity in cell proliferation and target modulation assays, and pharmacokinetic parameters. PMID- 21543227 TI - Myotonic dystrophy type 2 (DM2) and related disorders report of the 180th ENMC workshop including guidelines on diagnostics and management 3-5 December 2010, Naarden, The Netherlands. PMID- 21543228 TI - Hairpin conformation of an 11-mer peptide. AB - An 11-mer peptide taken from a subsequence of the human protein ubiquitin was synthesized. The peptide has been fully characterized by NMR spectroscopy using chemical shift analysis and by NOE measurements. The conformation was calculated using state of the art MD methods of protein chemistry. A hairpin conformation was found which is to a large part identical with the structure of this peptide fragment within the human ubiquitin. The surprising result that already an 11-mer peptide adopts a hairpin conformation in aqueous solution is discussed in terms of initials sites for protein folding. PMID- 21543229 TI - Ultrastructural description of spermiogenesis within the Mediterranean Gecko, Hemidactylus turcicus (Squamata: Gekkonidae). AB - We studied spermiogenesis in the Mediterranean Gecko, Hemidactylus turcicus, at the electron microscope level and compared to what is known within other Lepidosaurs. In H. turcicus germ cells are connected via cytoplasmic bridges where organelle and cytoplasm sharing is observed. The acrosome develops from merging transport vesicles that arise from the Golgi and subsequently partition into an acrosomal cap containing an acrosomal cortex, acrosomal medulla, perforatorium, and subacrosomal cone. Condensation of DNA occurs in a spiral fashion and elongation is aided by microtubules of the manchette. A nuclear rostrum extends into the subacrosomal cone and is capped by an epinuclear lucent zone. Mitochondria and rough endoplasmic reticulum migrate to the posterior portion of the developing germ cell during the cytoplasmic shift and the flagellum elongates. Mitochondria surround the midpiece as the anlage of the annulus forms. The fibrous sheath begins at mitochondrial tier 3 and continues into the principal piece. Peripheral fibers associated with microtubule doublets 3 and 8 are grossly enlarged. During the final stages of germ cell development spermatids are wrapped with a series of Sertoli cell processes, which exhibit ectoplasmic specializations and differing cytoplasmic consistencies. The results observed here corroborate previous studies, which show the conservative nature of sperm morphology. However, ultrastructural character combinations specific to sperm and spermiogenesis seem to differ among taxa. Further studies into sperm morphology are needed in order to judge the relevance of the ontogenic changes recorded here and to determine their role in future studies on amniote evolution. PMID- 21543230 TI - Ultrastructural architecture of colonies of different morphologies produced by phenotypic switching of a clinical strain of Candida tropicalis and biofilm formation by variant phenotypes. AB - Candida tropicalis has been identified as one of the most prevalent pathogenic yeast species of the Candida-non-albicans (CNA) group. Study of switching in C. tropicalis has not been the subject of extensive research. Therefore, we investigated switching event and characterized the ultrastructural architecture of different phenotypes and biofilm produced in a C. tropicalis clinical strain. Cells switched heritably, reversibly, and at a high frequency between four phenotypes readily distinguishable by the shape of colonies formed on agar at 25 degrees C. SEM analysis was used to verify the architecture of whole Candida colonies at ultrastructural level. The smooth phenotype (parental phenotype) colony showed a hemispherical shape character, while the semi-smooth was characterized by the presence of shallow marginal depressions. The ring and rough phenotypes exhibited more complex architecture and were characterized by the presence of deep central and peripheral depressions areas. The biofilm-forming ability varied among the switch phenotypes. After 12h incubation, the smooth phenotype formed less biofilm compared to the other phenotypes (P<0.05). The electron microscopy analysis revealed that filamentation (pseudohyphae) was associated with ring and rough colonies. The ultrastructural analysis allowed the observation of the arrangement of individual cells within the colonies. At the deep central and peripheral depressions areas of the ring and rough colonies extracellular material was seen in different arrangements. The data presented here open new avenues to study a possible role for extracellular material in the formation and maintenance of the architecture of switch phenotypes in C. tropicalis. It is therefore essential that more strains be investigated to determine the biological significance of extracellular material in C. tropicalis phenotypic switching phenomenon. PMID- 21543231 TI - Energy deposition by a 106Ru/106Rh eye applicator simulated using LEPTS, a low energy particle track simulation. AB - The present study introduces LEPTS, an event-by-event Monte Carlo programme, for simulating an ophthalmic (106)Ru/(106)Rh applicator relevant in brachytherapy of ocular tumours. The distinctive characteristics of this code are the underlying radiation-matter interaction models that distinguish elastic and several kinds of inelastic collisions, as well as the use of mostly experimental input data. Special emphasis is placed on the treatment of low-energy electrons for generally being responsible for the deposition of a large portion of the total energy imparted to matter. PMID- 21543232 TI - Biological evaluation of dopamine analogues containing phenylboronic acid group as new boron carriers. AB - As new BNCT reagents, we designed and synthesized dopamine analogues containing phenylboronic acid group, N-3,4-dihydroxyphenethyl-4-dihydroxyborylbenzamide (dopamine-PCBA) and N-[2-(3,4-dihydroxyphenetyl)ethyl]-3-(4 dihydroxyborylphenyl)promionamide (dopamine-CEBA). The efficacies of these compounds have not been investigated for biological samples. Therefore we have carried out experiments with cultured tumor cells and tumor-bearing mice, and evaluated possibility of these compounds as boron carriers. Dopamine-PCBA and dopamine-CEBA were synthesized by coupling between p-carboxyphenylboronic acid (PCBA) or 4-(2-carboxyethyl)benzeneboronic acid (CEBA) and 3,4 (dibenzyloxy)phenethylamine hydrochloride (DBPA-HCl) followed by catalytic hydrogenation using Pd catalyst. The effect of compounds on cell vitality was determined by MTT assay in various cells. In vivo biodistribution of compounds was determined in Balb/c and DDY mice in bearing implanted CT26 cells. These results have demonstrated that dopamine-CEBA was less toxic. PMID- 21543233 TI - The radiobiological principles of boron neutron capture therapy: a critical review. AB - The radiobiology of the dose components in a BNCT exposure is examined. The effect of exposure time in determining the biological effectiveness of gamma rays, due to the repair of sublethal damage, has been largely overlooked in the application of BNCT. Recoil protons from fast neutrons vary in their relative biological effectiveness (RBE) as a function of energy and tissue endpoint. Thus the energy spectrum of a beam will influence the RBE of this dose component. Protons from the neutron capture reaction in nitrogen have not been studied but in practice protons from nitrogen capture have been combined with the recoil proton contribution into a total proton dose. The relative biological effectiveness of the products of the neutron capture reaction in boron is derived from two factors, the RBE of the short range particles and the bio-distribution of boron, referred to collectively as the compound biological effectiveness factor. Caution is needed in the application of these factors for different normal tissues and tumors. PMID- 21543234 TI - Editorial comment Improving the quality of care in cardiac surgery--the role of the 'mortality' meeting. PMID- 21543235 TI - Structure of the catalytic, inorganic core of oxygen-evolving photosystem II at 1.9 A resolution. AB - The catalytic center for photosynthetic water-splitting consists of 4 Mn atoms and 1 Ca atom and is located near the lumenal surface of photosystem II. So far the structure of the Mn(4)Ca-cluster has been studied by a variety of techniques including X-ray spectroscopy and diffraction, and various structural models have been proposed. However, its exact structure is still unknown due to the limited resolution of crystal structures of PSII achieved so far, as well as possible radiation damages that might have occurred. Very recently, we have succeeded in solving the structure of photosystem II at 1.9 A, which yielded a detailed picture of the Mn(4)CaO(5)-cluster for the first time. In the high resolution structure, the Mn(4)CaO(5)-cluster is arranged in a distorted chair form, with a cubane-like structure formed by 3 Mn and 1 Ca, 4 oxygen atoms as the distorted base of the chair, and 1 Mn and 1 oxygen atom outside of the cubane as the back of the chair. In addition, four water molecules were associated with the cluster, among which, two are associated with the terminal Mn atom and two are associated with the Ca atom. Some of these water molecules may therefore serve as the substrates for water-splitting. The high resolution structure of the catalytic center provided a solid basis for elucidation of the mechanism of photosynthetic water splitting. We review here the structural features of the Mn(4)CaO(5) cluster analyzed at 1.9 A resolution, and compare them with the structures reported previously. PMID- 21543236 TI - Maternal severity of illness across levels of care: a prospective, cross sectional study. AB - BACKGROUND: The severity of illness of women experiencing severe maternal morbidity has not been quantified outside of the intensive care setting yet is likely to have a bearing on clinical needs. AIM: To examine severity of illness in women with severe maternal morbidity. METHODS: A prospective observational study of critically ill pregnant and postpartum women was undertaken in intensive care units (ICU), high dependency units (HDU) and delivery suites (DS) of seven tertiary-level hospitals in Melbourne, during 2002-2004. Severity of illness was scored using the Acute Physiology and Chronic Health Evaluation version II (APACHE II) and Therapeutic Intervention Scoring System 28 items (TISS 28). RESULTS: 137 women participated in the study: ICU (n=33), HDU (n=46) and DS (n=58). The mean APACHE II score was 8.6 (95% CI 7.7-9.5) and mean TISS 28 score was 22.5 (95% CI 21.2-23.9). Women in ICU were sicker according to both APACHE II (mean 12.6, 95% CI 8.3-16.9) and TISS 28 (mean 31.5, 95% CI 28.2-35.5) compared to women not admitted to ICU (p<.005). There was no difference in the mean APACHE II scores of women in HDU (7.7, 95% CI 5.5-9.9) and DS (7.0, 95% CI 5.2-8.8; p=.20). Women born outside of Australia were more likely to be admitted to ICU (OR 3.27, 95% CI 1.19-8.97). Known risk factors like multiple pregnancy, age>=35 years and nulliparity were not associated with ICU admission. CONCLUSIONS: There was no difference in the severity of illness in women cared for in HDU and DS. It was not possible to predict which women would require ICU admission. Measurement of severity of illness adds a valuable dimension to the study of severe maternal morbidity. PMID- 21543237 TI - Quining diet qualia. AB - This paper asks whether we can identify a neutral explanandum for theories of phenomenal consciousness, acceptable to all sides. The 'classic' conception of qualia, on which qualia are intrinsic, ineffable, and subjective, will not serve this purpose, but it is widely assumed that a watered-down 'diet' conception will. I argue that this is wrong and that the diet notion of qualia has no distinctive content. There is no phenomenal residue left when qualia are stripped of their intrinsicality, ineffability, and subjectivity. Thus, if we reject classic qualia realism, we should accept that all that needs explaining are 'zero' qualia - our dispositions to judge that our experiences have classic qualia. Diet qualia should, in Dennett's phrase, be quined. PMID- 21543238 TI - MTHFR, MTR, and MTHFD1 gene polymorphisms compared to homocysteine and asymmetric dimethylarginine concentrations and their metabolites in epileptic patients treated with antiepileptic drugs. AB - PURPOSE: The purpose of the study was to determine the frequency of occurrence of polymorphisms of genes MTHFR (C677T), MTR (A2756G), and MTHFD1 (G1958A), as well as to analyze the concentration of homocysteine (Hcy), methionine (Met), asymmetric dimethylarginine (ADMA), and arginine (Arg) in epileptics treatment with antiepileptic drugs (AEDs), and controls. METHOD: The study included 65 epileptic patients treated with variable AEDs and 61 controls. The levels of Hcy and Met were determined by HPLC/EC, ADMA and Arg by HPLC with fluorescence detection. Polymorphisms of the studied genes were determined by PCR-RFLP. RESULTS: The study demonstrates that AEDs treatment in epileptics leads to increase in Hcy (p<0.05) and ADMA (p<0.01) concentrations. Greater increases in Hcy concentration during AEDs treatment appear to occur in individuals with the MTHFR CT (C677T) and MTHFD1 GG (G1958A) genotypes. Genetic conditions also appear to be related with changes in the ratios of Hcy, Met, Arg, and ADMA. It seems that in cases of AEDs treatment's effect on hyperhomocysteinemia, epileptic individuals appear to have a disturbed control of Hcy over ADMA. CONCLUSIONS: It is possible, that polymorphisms of genes related to Hcy-to-Met metabolism, in epileptics treated with AEDs may have an effect on the regulation of levels of risk factors of vascular diseases, Hcy and ADMA. PMID- 21543239 TI - Comparative trial of low- and high-dose zonisamide as monotherapy for childhood epilepsy. AB - PURPOSE: To evaluate the effectiveness of zonisamide (ZNS) as monotherapy in children with newly diagnosed epilepsy. METHODS: This randomized, multicenter trial included a 2-4-week titration and a 24-week maintenance phase after randomization to low-(3-4 mg/kg/day) or high-(6-8 mg/kg/day) dose groups as target maintenance dosages. The primary outcome measure was the seizure-free rate over 6 months, while a secondary measure was the change in cognition and behavior from screening to the end of the maintenance phase. RESULTS: Out of 125 patients enrolled, 90 (49 low-dose and 41 high-dose) completed the study. Forty-one patients (63.1%) in the low-dose group and 34(57.6%) in the high-dose group achieved 6 months' freedom from seizures (p=0.66). After treatment, the picture arrangement subtest improved in the low-dose group (p=0.047) while the vocabulary subtest worsened in the high-dose group (p=0.020). Comparing between the two groups, the vocabulary subtest in the high-dose group was significantly worse than that in the low-dose group (p=0.002). Social competence, somatic complaints, depression/anxiety and delinquent and aggressive behavior in the low-dose group were significantly improved (p<0.05). Moreover, total social competence, somatic complaints, delinquent behavior, externalizing, and total behavior problems were significantly more improved in the low-dose group than the high-dose group (p<0.05). CONCLUSIONS: ZNS is an effective monotherapy for newly diagnosed childhood epilepsy. Lower doses of ZNS have a similar efficacy and more beneficial neurocognitive effects compared to higher doses. When prescribing higher doses of ZNS, one must be aware of the possible manifestation of problems associated with language development, such as those affecting vocabulary acquisition. PMID- 21543240 TI - The effects of magnetically labeled rat spleen-originated endothelial progenitor cells on growth of glioma in vivo an experimental study. AB - RATIONALE AND OBJECTIVES: The aim of this study was to investigate the effects of exogenous endothelial progenitor cells (EPCs) on the growth and invasiveness of glioma in vivo to provide an experimental basis for the value and safety of using magnetically labeled EPCs as target vectors to detect early infiltration of glioma. MATERIALS AND METHODS: EPCs were collected from the spleens of healthy Sprague-Dawley rats, made EPCs conditioned medium after identification. Four models of Sprague-Dawley rat glioma (60 rats in total) were established as a control and three experimental groups (group A, B, and C). In the control group, orthotopic transplantation of C6 glioma cells was performed. Compared to the control group, EPCs conditioned medium was added in group A and P7228-labeled EPCs were added in group B. In group C, P7228-labeled EPCs were transplanted via the tail vein. Magnetic resonance imaging and perfusion-weighted imaging were performed on several days. Tumor microvascular density and vascular endothelial growth factor expression were determined through immunohistochemistry. RESULTS: In group C, hypointense areas were detected at the periphery of the tumor on the first day after transplantation of EPCs, and more hypointense areas were found inside the tumor over time. Tumor size in all four groups developed significantly with increasing time (P < .01), but there was no marked difference among these groups at the same time (P > .05). No remarkable differences in microvascular density and cells positive for vascular endothelial growth factor were found at the same time among the four groups (P > .05). CONCLUSIONS: Both magnetic resonance imaging and immunohistochemical findings confirmed that exogenous EPCs could not affect the biologic behavior of C6 glioma cells in vivo through a paracrine effect or by direct cellular interaction. Therefore, exogenous EPCs could not exert significant promoting effects on glioma growth. PMID- 21543241 TI - Ultrasound assessment of increased capsular width in temporomandibular joint internal derangements: relationship with joint pain and magnetic resonance grading of joint effusion. AB - OBJECTIVE: The relationship between radiologic evidence of effusion in the temporomandibular joint (TMJ) and the occurrence of clinical symptoms (e.g., pain) is still unclear. Increased capsular width (CW) measured in ultrasonographic imaging (USI) of the TMJ was considered to be an indirect marker of TMJ effusion. The purpose of this study was to evaluate the relationship between the grades of magnetic resonance imaging (MRI)-depicted joint effusion (JE), increased CW measured in USI, and joint pain in TMJ internal derangement (ID) patients. STUDY DESIGN: During a 4-year period, 91 patients clinically diagnosed with TMJ ID according to the Research Diagnostic Criteria for Temporomandibular Disorders classification were included in the study. Those with mainly myogenic complaints were excluded. In clinical examination, the severity of pain was assessed by visual analog scale (VAS, 0 to 10). All TMJs (n = 182) were evaluated to detect the presence of joint effusion by means of USI and MRI. MRI-depicted effusion was classified as no effusion, moderate effusion, and severe effusion. Receiver operating characteristic curve analysis was performed to depict the critical cutoff value for TMJ CW. USI sensitivity was evaluated by means of MRI effusion, and a cutoff value was depicted that was considered to be the threshold to discriminate the TMJs with and without effusion. The relationship between the joint pain and USI and MRI findings of effusion were evaluated with Friedman and Wilcoxon tests. RESULTS: The average VAS scores of the TMJs without effusion was found to be 2.55, with moderate effusion 2.92, and with severe effusion 4.80. A significant positive correlation was found between the VAS scores and the intensity of MRI JE (P = .003). The most accurate cutoff value of CW is found to be 1.65 mm. The average VAS score with CW <1.65 was found to be 2.10 and the average VAS score with CW >1.65 was found to be 3.75. A significant positive correlation was found between the clinical pain scores and CW measured in USI (P = .001). CONCLUSIONS: Both MRI-depicted effusion and USI assessment of CW were found to be related to the pain in TMJ ID patients. PMID- 21543243 TI - The effects on cardio-respiratory and acid-base variables of the anaesthetic alfaxalone in a 2-hydroxypropyl-beta-cyclodextrin (HPCD) formulation in sheep. AB - The objective of this study was to determine the pharmacodynamic effects in sheep of the anaesthetic alfaxalone in a 2-hydroxypropyl-beta-cyclodextrin formulation. Seven Ripollesa sheep, weighing 43.0+/-6.6 kg, were used in the study. Twenty four hours after instrumentation, the sheep were anesthetised with alfaxalone (2 mg/kg bodyweight IV) in cyclodextrin. Heart rate, arterial blood pressure, respiratory rate and arterial blood gases were recorded. Alfaxalone administration resulted in minimal cardio-respiratory depression. Time to standing from anaesthesia was 22.0+/-10.6 min. Apnoea was not observed in any of the sheep. Significant differences from baseline were not observed in respiratory rate or arterial blood pressure. Heart rate increased significantly (P<0.05) immediately after administration, returning to control values at 20 min. The calculated haemoglobin saturation (SO2) decreased significantly during the first 15 min after alfaxalone administration. The arterial pH decreased significantly during the first 30 min of the study, although no significant differences from basal values were observed in the arterial partial pressure of carbon dioxide (PaCO2). The results showed that alfaxalone in 2-hydroxypropyl-beta-cyclodextrin administered as an IV bolus at 2 mg/kg produced minimal adverse effects and an uneventful recovery from anaesthesia in sheep. PMID- 21543244 TI - 1H assisted 13C/15N heteronuclear correlation spectroscopy in oriented sample solid-state NMR of single crystal and magnetically aligned samples. AB - (1)H-irradiation under mismatched Hartmann-Hahn conditions provides an alternative mechanism for carrying out (15)N/(13)C transfers in triple-resonance heteronuclear correlation spectroscopy (HETCOR) on stationary samples of single crystals and aligned samples of biopolymers, which improve the efficiency especially when the direct (15)N-(13)C dipolar couplings are small. In many cases, the sensitivity is improved by taking advantage of the (13)C(alpha) labeled sites in peptides and proteins with (13)C detection. The similarities between experimental and simulated spectra demonstrate the validity of the recoupling mechanism and identify the potential for applying these experiments to virus particles or membrane proteins in phospholipid bilayers; however, further development is needed in order to derive quantitative distance and angular constraints from these measurements. PMID- 21543245 TI - Response of women with Fabry disease to enzyme replacement therapy: comparison with men, using data from FOS--the Fabry Outcome Survey. AB - Fabry disease (alpha-galactosidase A deficiency) is an X-linked disorder. Women who are heterozygous for disease-causing mutations often manifest signs and symptoms of Fabry disease, but most studies of the effects of enzyme replacement therapy (ERT) have included only men. To date, no direct comparison has been made of the relative effectiveness of long-term ERT between men and women. The aim of this analysis was to report the effectiveness of agalsidase alfa in a cohort of 78 women treated for 4 years and to compare outcomes with those of 172 men. All data were obtained from the Fabry Outcome Survey--an international database of patients with Fabry disease sponsored by Shire Human Genetic Therapies. Quantifiable clinical parameters were assessed at baseline and the 4-year time point. Measures of pain, health-related quality of life, cardiac structure and function, and renal function changed to a similar extent in women and men during treatment, with the exception of left ventricular mass, which only reduced significantly in women. Changes in the presence of each of 27 clinical features after 4 years of ERT were evaluated in two subpopulations: patients with and patients without clinical features at baseline. It was clear for most types of clinical features that a number of women with a feature at baseline were no longer reported to have it at the 4-year time point, and that clinical features were observed in only a small percentage of women in whom they had been absent at baseline. The percentage of patients who were symptomatic at the 4-year time point was calculated for each type of clinical feature. The results showed no significant differences between men and women for most clinical features evaluated. Overall, both sexes responded to agalsidase alfa in a similar way, suggesting there should be no difference in the criteria for assessment of treatment in women and men. PMID- 21543246 TI - Toxicity profile and adherence to the pharmacotherapeutic regimen of gemcitabine carboplatin in non-small cell lung cancer. AB - OBJECTIVE: To analyse the relationship between doses of gemcitabine-carboplatin (GEM-CARBO) administered and incidence and level of haematological and renal toxicity, and the adherence to the treatment in patients with non-small cell lung cancer. METHODS: Retrospective study which lasted for 37 months. We were able to obtain the minimum set of data needed to carry out the follow-up with the help of Farmis-Oncofarm((r)) software and the medical and pharmacotherapeutic records. The haematological toxicity was assessed in accordance with the Common Toxicity Criteria 3.0. Renal toxicity was evaluated using serum creatinine levels and creatinine clearance. RESULTS: Thirty-one patients were included in the study who were administered a total of 122 cycles. There was a 34.0% and 30.8% incidence of anaemia and grade 3 neutropaenia, respectively. There was also a 3.8% and 7.7% incidence of grade 3 and grade 4 thrombocytopaenia, respectively. No cases of renal toxicity were found. 65.0% of patients received more than 85.0% of the planned theoretical dosage of carboplatin and 58% of patients received more than 85.0% of the planned theoretical dosage of gemcitabine. Administration was delayed in 18.0% of the cycles prescribed. CONCLUSIONS: The indication and prescription of the GEM-CARBO regimen was adjusted in accordance with solid scientific evidence, but its haematological toxicity limited its use and made it difficult to maintain the dose intensity foreseen in the study. This compromised the effectiveness of the treatment. PMID- 21543247 TI - [Conscientious objection in the clinical setting. A proposal for its appropriate use]. AB - Social changes and new technologies have brought new problems in doctor-patient relationships. In many clinical contexts conscientious objection is misused, with negative effects for patients, healthcare professionals and institutions. The paper aims to clarify what conscientious objection means in a plural society based on a deliberative democracy and to show the different ways of understanding this society in order to respect both the ethical reasons of individuals and the compulsory normative framework of the Rule of Law. Furthermore, the paper identifies some clinical settings where conscientious objection is often invoked by healthcare professionals, and points out and analyses the arguments that explain why this appeal for conscientious objection is neither legitimate nor correct. Finally, it provides examples of the legal basis and Spanish jurisprudence, as well as the relevant clinical and ethical literature on this topic. PMID- 21543248 TI - [Conscientious objection in the clinical setting. A proposal for its appropriate use (II)]. AB - Social changes and new technologies have brought new problems in doctor-patient relationship. In many clinical contexts conscientious objection is misused, with negative effects for patients, healthcare professionals and institutions. In this article an attempt will be made to clarify the problem from a clinical point of view, assessing the increase in risks in clinical praxis due to patient choice, the complexity of current clinical praxis, and the appropriate use of life support measures. Likewise, it analyses socially controversial ethical values and professional practices with no curative value and with no clinical indication in the physiological sense. PMID- 21543250 TI - Risk factors of surgical site infection in patients undergoing major oncological surgery for head and neck cancer. AB - We assessed the risk factors associated with surgical site infection (SSI) in 697 patients who underwent major oncological surgery for head-and-neck cancer (HNC). SSIs within 30days were classified as incision, space, or leakage/fistula. Preoperative and operative risk factors for SSIs were assessed by univariate and multivariate analyses. Of these 697 patients, 128 (18.4%) had SSIs. Univariate analysis showed that SSIs were associated with tumor location, advanced tumor stage, smoking and alcohol habits, diabetes, history of prior radiotherapy or chemotherapy, anemia, hypoalbuminemia, mandible cutting, flap reconstruction, tracheotomy, clean-contaminated wounds, blood transfusion, and operation times. Multivariate analysis showed that independent risk factors for developing SSIs were oral cavity cancer (odds ratio [OR]: 6.06, 95% confidence interval [CI]: 1.209-30.378), history of prior radiotherapy (OR: 2.85, 95% CI: 1.172-6.931), tracheotomy (OR: 9.757, 95% CI: 2.609-36.491), and clean-contaminated wounds (OR: 13.953, 95% CI: 2.231-87.275). In contrast, thyroid malignancy was an independent predictor of not developing SSI (OR: 0.152, 95% CI: 0.035-0.658). High-risk patients of SSIs after major HNC surgery are predicted. Preventive measures or close monitoring in these patients may be required to reduce the likelihood of postoperative SSIs. Our data may help identify and properly manage high-risk patients. PMID- 21543249 TI - Allostatic load in an environmental riskscape: the role of stressors and gender. AB - Stressors are theorized to be associated with higher allostatic load (AL), a concept of physiological wear measured as a composite of physical biomarkers. Risk of high AL may vary by gender and may be intensified in places with significant environmental risks, otherwise known as 'environmental riskscapes'. Yet, no study has examined the relationship between stressors, gender, and allostatic load in an environmental riskscape. Using primary data collected in a sample (N=1072) exposed to various environmental and social stressors, we find that long-term residence in Texas City (30 or more years), residential proximity to petrochemical plants, perceived poor neighborhood conditions, and daily hassles are associated with higher allostatic load components. Variation in AL differs by gender and the types of biomarkers examined. Gender moderates the effect of length of residence in Texas City on cardiovascular health risk. We discuss our findings in light of current research on stressors, gender, allostatic load, and double jeopardy within environmental riskscapes. PMID- 21543251 TI - Cell cycles and cell division in the archaea. AB - Until recently little was known about the cell cycle parameters and division mechanisms of archaeal organisms. Although this is still the case for the majority of archaea, significant advances have been made in some model species. The information that has been gleaned thus far points to a remarkable degree of diversity within the archaeal domain of life. More specifically, members of distinct phyla have very different chromosome copy numbers, replication control systems and even employ distinct machineries for cell division. PMID- 21543252 TI - Theoretical studies of molecular structures and properties of platinum (II) antitumor drugs. AB - The molecular structure and vibration spectra of carboplatin were investigated by the different density functional models (mPW1PW, BPV86, HCTH, PBEPBE, LSDA and PBE1PBE) using several basis sets including LANL2DZ, SDD, LANL2MB, CEP-4G, CEP 31G and CEP-121G. The results indicate that LSDA/SDD and LSDA/LANL2DZ levels are clearly superior to all the remaining density functional methods in predicting the structures of carboplatin. Mean absolute deviation between the calculated harmonic and observed fundamental vibration frequencies for each method indicates that PBE1PBE/CEP-121G and PBE1PBE/SDD methods are sufficient to predict vibration spectrum of carboplatin comparing with other DFT methods. PMID- 21543253 TI - A cautionary note on the interpretation of phase-locking estimates with concurrent changes in power. PMID- 21543254 TI - Intermittent theta burst stimulation over primary motor cortex enhances movement related beta synchronisation. AB - OBJECTIVE: The objective of this study is to investigate how transcranial magnetic intermittent theta burst stimulation (iTBS) with a prolonged protocol affects human cortical excitability and movement-related oscillations. METHODS: Using motor-evoked potentials (MEPs) and movement-related magnetoencephalography (MEG), we assessed the changes of corticospinal excitability and cortical oscillations after iTBS with double the conventional stimulation time (1200 pulses, iTBS1200) over the primary motor cortex (M1) in 10 healthy subjects. Continuous TBS (cTBS1200) and sham stimulation served as controls. RESULTS: iTBS1200 facilitated MEPs evoked from the conditioned M1, while inhibiting MEPs from the contralateral M1 for 30 min. By contrast, cTBS1200 inhibited MEPs from the conditioned M1. Importantly, empirical mode decomposition-based MEG analysis showed that the amplitude of post-movement beta synchronisation (16-26 Hz) was significantly increased by iTBS1200 at the conditioned M1, but was suppressed at the nonconditioned M1. Alpha (8-13 Hz) and low gamma-ranged (35-45 Hz) rhythms were not notably affected. Movement kinetics remained consistent throughout. CONCLUSIONS: TBS1200 modulated corticospinal excitability in parallel with the direction of conventional paradigms with modestly prolonged efficacy. Moreover, iTBS1200 increased post-movement beta synchronisation of the stimulated M1, and decreased that of the contralateral M1, probably through interhemispheric interaction. SIGNIFICANCE: Our results provide insight into the underlying mechanism of TBS and reinforce the connection between movement-related beta synchronisation and corticospinal output. PMID- 21543255 TI - Effects of probiotic fermentation on the enhancement of biological and pharmacological activities of Codonopsis lanceolata extracted by high pressure treatment. AB - This study was designed to evaluate the enhancement of antioxidant, antimicrobial, enzymatic, cytotoxic, and cognitive activities of Codonopsis lanceolata extracted by high pressure treatment followed by probiotic fermentation. Dried C. lanceolata samples were subjected to 400 MPa for 20 min and then fermented with Bifidobacterium longum B6 (HPE-BLF) and Lactobacillus rhamnosus (HPE-LRF) at 37 degrees C for 7 days. Compared to conventional extraction (CE-NF, 6.69 mg GAE/g), the phenol amounts of HPE-BLF and HPE-LRF were significantly increased to more than 8 mg GAE/g, while the lowest flavonoid contents were observed for HPE-BLF (0.44 mg RE/mL) and HPE-LRF (0.45 mg RE/mL) (p<0.05). Cinnamic acid was the most abundant phenolic acid in the fermented C. lanceolata. The highest DPPH scavenging activities were observed for HPE-BLF and HPE-LRF, with minimum EC(50) values of 1.26 and 1.18 mg/mL, respectively. The HPE BLF and HPE-LRF samples exhibited the most noticeable antimicrobial activities against Staphylococcus aureus, Listeria monocytogenes, Salmonella Typhimurium, and Shigella boydii (MICs<15 mg/mL). The fermented C. lanceolata samples effectively inhibited alpha-glucosidase and tyrosinase activities and potentially improved a scopolamine-induced memory deficit in mice. The application of a fermentation process can effectively improve the biological and pharmacological activities of high-pressure-extracted C. lanceolata by increasing the extraction efficacy and inducing probiotic conversion. The results suggest that the combined treatment of HPE and a fermentation process could be used as alternative extraction method over CE. PMID- 21543256 TI - High-yields heterologous production of the novel Aspergillus fumigatus elastase inhibitor AFUEI in Aspergillus oryzae. AB - AFUEI, an elastase inhibitor produced by Aspergillus fumigatus strongly inhibits the elastolytic activity of A. fumigatus etc. To purify AFUEI, we constructed a strain that overproduces AFUEI by introducing the gene encoding AFUEI (Genbank accession no. AB546725) under control of the amyB promoter into the heterologous host Aspergillus oryzae. A. oryzae TF-4 displayed strong elastase inhibitory activity and produced considerably more AFUEI than that of A. fumigatus. Furthermore, AFUEI could be purified using culture broth and single ultrafiltration (UF) treatment, allowing for the effective production of AFUEI for use in clinical trials. PMID- 21543257 TI - Robust industrial Saccharomyces cerevisiae strains for very high gravity bio ethanol fermentations. AB - The application and physiological background of two industrial Saccharomyces cerevisiae strains, isolated from harsh industrial environments, were studied in Very High Gravity (VHG) bio-ethanol fermentations. VHG laboratory fermentations, mimicking industrially relevant conditions, were performed with PE-2 and CA1185 industrial strains and the CEN.PK113-7D laboratory strain. The industrial isolates produced remarkable high ethanol titres (>19%, v/v) and accumulated an increased content of sterols (2 to 5-fold), glycogen (2 to 4-fold) and trehalose (1.1-fold), relatively to laboratory strain. For laboratory and industrial strains, a sharp decrease in the viability and trehalose concentration was observed above 90 g l-1 and 140 g l-1 ethanol, respectively. PE-2 and CA1185 industrial strains presented important physiological differences relatively to CEN.PK113-7D strain and showed to be more prepared to cope with VHG stresses. The identification of a critical ethanol concentration above which viability and trehalose concentration decrease significantly is of great importance to guide VHG process engineering strategies. This study contributes to the improvement of VHG processes by identifying yeast isolates and gathering yeast physiological information during the intensified fermentation process, which, besides elucidating important differences between these industrial and laboratory strains, can drive further process optimization. PMID- 21543259 TI - Clinical and radiographic results of endoscopic injection for vesicoureteral reflux: defining measures of success. AB - OBJECTIVE: Criteria for success following endoscopic vesicoureteral reflux (VUR) surgery vary greatly. We sought to define outcomes based on radiographic and long term clinical follow up. METHODS: We reviewed the charts and interviewed parents of children who underwent endoscopic treatment for primary VUR (grades I-IV). All patients had a postoperative voiding cystourethrogram (VCUG) at mean of 3 months (1-21 months) and all cases of postoperative febrile urinary tract infection (FUTI) prompted repeat VCUG. Radiographic success was defined as no VUR on postoperative VCUG and clinical success as no FUTIs during follow up of 12-36 months. To demonstrate how criteria for success can affect outcomes, we calculated the success rates using different definitions. RESULTS: In 2004-2008, 336 patients (296 female and 40 male, mean age 4 years) were treated with dextranomer/hyaluronic acid via the Double-HIT method. Initial radiographic success was 90% (302/336). Of these, 19 (6%) developed FUTIs, 12 (4%) of whom had recurrent VUR, and 5 (2%) went on to open surgery. Of the radiographic failures, 18% were observed with no further treatment. Success defined clinically was 94% (281/300), and as 'radiographic cure and no clinical evidence of FUTIs' it was 82% (275/336). CONCLUSIONS: It is important to agree on a universal definition of success for VUR interventions to compare across studies and across therapies. Clinical success is more meaningful to the patient, and initial radiographic success could be followed by UTI necessitating further intervention. We question the need for routine postoperative VCUG. PMID- 21543258 TI - Airway irritation and cough evoked by acid: from human to ion channel. AB - Inhalation or aspiration of acid solution evokes airway defense responses such as cough and reflex bronchoconstriction, resulting from activation of vagal bronchopulmonary C-fibers and Adelta afferents. The stimulatory effect of hydrogen ion on these sensory nerves is generated by activation of two major types of ion channels expressed in these neurons: a rapidly activating and inactivating current mediated through ASICs, and a slow sustaining current via activation of TRPV1. Recent studies have shown that these acid-evoked responses are elevated during airway inflammatory reaction, revealing the potential convergence of a wide array of inflammatory signaling on these ion channels. Since pH in the airway fluid drops substantially in patients with inflammatory airway diseases, these heightened stimulatory effects of acid on airway sensory nerves may play a part in the manifestation of airway irritation and excessive cough under those pathophysiological conditions. PMID- 21543260 TI - Rating scale for psychogenic nonepileptic seizures: scale development and clinimetric testing. AB - Our aim was to develop a clinimetric scale evaluating motor phenomena, associated features, and severity of psychogenic nonepileptic seizures (PNES). Sixty video/EEG-recorded PNES induced by suggestion maneuvers were evaluated. We examined the relationship between results from this scale and results from the Clinical Global Impression (CGI) scale to validate this technique. Interrater reliabilities of the PNES scale for three raters were analyzed using the AC1 statistic, Kendall's coefficient of concordance (KCC), and intraclass correlation coefficients (ICCs). The relationship between the CGI and PNES scales was evaluated with Spearman correlations. The AC1 statistic demonstrated good interrater reliability for each phenomenon analyzed (tremor/oscillation, tonic; clonic/jerking, hypermotor/agitation, atonic/akinetic, automatisms, associated features). KCC and the ICC showed moderate interrater agreement for phenomenology, associated phenomena, and total PNES scores. Spearman's correlation of mean CGI score with mean total PNES score was 0.69 (P<0.001). The scale described here accurately evaluates the phenomenology of PNES and could be used to assess and compare subgroups of patients with PNES. PMID- 21543261 TI - Frontal lobe nonconvulsive status epilepticus: a case of epileptic stuttering, aphemia, and aphasia--not a sign of psychogenic nonepileptic seizures. AB - Stuttering is a repetitive, iterative disfluency of speech, and is usually seen as a developmental problem in childhood. Acquired causes in adults include strokes and medications. When stuttering occurs with seizure-like events, it is usually attributed to psychogenic nonepileptic seizures. We describe an elderly man who experienced personality change and bouts of stuttering, followed by anarthria with preserved writing and then aphasia affecting written and uttered language, and ending with confusion. EEG recordings showed nonconvulsive status epilepticus (NCSE) with focality in the left frontal region followed by bifrontal NCSE. This case enlarges our understanding of the behavioral correlates of focal frontal seizures to include simple partial seizures with speech and then language output disturbances (aphemia, then aphasia), progressing to complex partial phenomenology in the setting of frontal NCSE. PMID- 21543262 TI - Abnormalities of cortical thickness in postictal psychosis. AB - Postictal psychosis (PIP), the occurrence of psychotic episodes following a seizure, is a common and serious comorbidity in patients with epilepsy. Yet, the anatomical correlates remain poorly defined. Here, we used quantitative MRI morphometry to identify structural abnormalities in the cortex of patients with PIP relative to patients with epilepsy without PIP and age- and gender-matched normal healthy controls. Comparison of patients with epilepsy and PIP with patients with epilepsy without PIP revealed increased cortical thickness in the right lateral prefrontal cortex, right anterior cingulate cortex, and right middle temporal gyrus. The PIP group was distinguished from the EC and NC groups by thicker cortex in the right rostral anterior cingulate cortex and thinner cortex in the right angular gyrus and the left middle temporal region. Findings indicate that PIP is associated with thickening of the right anterior cingulate cortex, which may serve as a marker for patients at risk for developing PIP. PMID- 21543263 TI - Episodic and semantic memory in children with mesial temporal sclerosis. AB - The aim of this study was to analyze semantic and episodic memory deficits in children with mesial temporal sclerosis (MTS) and their correlation with clinical epilepsy variables. For this purpose, 19 consecutive children and adolescents with MTS (8 to 16 years old) were evaluated and their performance on five episodic memory tests (short- and long-term memory and learning) and four semantic memory tests was compared with that of 28 healthy volunteers. Patients performed worse on tests of immediate and delayed verbal episodic memory, visual episodic memory, verbal and visual learning, mental scanning for semantic clues, object naming, word definition, and repetition of sentences. Clinical variables such as early age at seizure onset, severity of epilepsy, and polytherapy impaired distinct types of memory. These data confirm that children with MTS have episodic memory deficits and add new information on semantic memory. The data also demonstrate that clinical variables contribute differently to episodic and semantic memory performance. PMID- 21543264 TI - Steroid-induced ocular hypertension with loteprednol etabonate 0.2%--a case report. AB - PURPOSE: The aim of this study was to present a case of a patient who showed a significant increase in intraocular pressure (IOP) with topical administration of loteprednol etabonate 0.2%. CASE REPORT: A 29-year-old man administered 1 drop of loteprednol etabonate 0.2% (Alrex((r))) to both eyes 4 times a day for 3 days as an off-label treatment for chronic red eye. By the third day of treatment, IOPs increased to 50 mmHg in each eye. The patient had no previous history of glaucoma. Gonioscopy found open angles in each eye. IOP returned to normal levels after discontinuation of Alrex. Steroid response in the same patient was confirmed on a second trial of Alrex. CONCLUSIONS: Although loteprednol etabonate has been shown to have a minimal effect on IOP in most patients, close follow-up is necessary whenever therapy is initiated. PMID- 21543265 TI - Sex differences in associations between psychosocial factors and aberrant crypt foci among patients at risk for colon cancer. AB - BACKGROUND: Psychosocial factors may impact cancer risk but sex differences in this domain are understudied. Examining psychosocial factors, such as depression and social support, among colon cancer patients allows for a unique opportunity to study sex differences in the association between psychosocial factors and colon cancer risk in this population. OBJECTIVE: The primary aim of this study was to evaluate sex differences in the association between key psychosocial factors and aberrant crypt foci (ACF), a putative biomarker of colon cancer risk. We hypothesized that higher levels of depression in women and lower levels of social support in men were associated with greater numbers of ACF among individuals at heightened risk for colon cancer. METHODS: Participants were self referred or referred by physicians for routine colonoscopy. Within 2 weeks before colonoscopy, participants completed standardized measures assessing psychosocial factors. At colonoscopy, individuals were examined for ACF frequency in the distal 20 cm of the colorectum. Regression beta weights were used to examine the association between the psychosocial factors and ACF. RESULTS: A total of 93 individuals (51% women, 49% men) consented to the study. Among women, higher levels of depressive symptoms were associated with greater numbers of ACF; among men, lower levels of social support were associated with greater numbers of ACF. CONCLUSIONS: These results suggest that although colon cancer affects men and women equally with regard to morbidity and mortality rates, there were important sex differences in how psychosocial variables were related to colon cancer risk. Psychosocial interventions aimed at targeting these types of factors are warranted but need to consider the role of sex. PMID- 21543266 TI - Centrally administered ghrelin activates cardiac vagal nerve in anesthetized rabbits. AB - Although central ghrelin has cardioprotective effect through inhibiting sympathetic nerve activity, the effects of central ghrelin on cardiac vagal nerve remain unknown. We investigated the effects of centrally administered ghrelin on cardiac autonomic nerve activities using microdialysis technique. A microdialysis probe was implanted in the right atrial wall adjacent to the sinoatrial node of an anesthetized rabbit and was perfused with Ringer's solution containing a cholinesterase inhibitor, eserine. After injection of ghrelin (1 nmol) into the right lateral cerebral ventricle, norepinephrine (NE) and acetylcholine (ACh) concentrations in the dialysate samples were measured as indices of NE and ACh release from nerve endings to the sinoatrial node using high-performance liquid chromatography. Heart rate was 270+/-4 bpm at baseline and decreased gradually after ghrelin injection to 234+/-9 bpm (P<0.01) at 60-80 min, followed by gradual recovery. Dialysate ACh concentration was 5.5+/-0.8 nM at baseline and increased gradually after ghrelin injection to 8.8+/-1.2 nM (P<0.01) at 60-80 min; the concentration started to decrease gradually from 100 to 120 min after injection reaching 5.6+/-0.8 nM at 160-180 min. Central ghrelin did not change mean arterial pressure or dialysate NE concentration. The elevated dialysate ACh concentration declined rapidly after transection of cervical vagal nerves. These results indicate that centrally administered ghrelin activates cardiac vagal nerve. PMID- 21543267 TI - The budding yeast Mei5-Sae3 complex interacts with Rad51 and preferentially binds a DNA fork structure. AB - Meiotic homologous recombination in Saccharomyces cerevisiae involves formation of nucleoprotein filaments of Rad51 and Dmc1 that mediate DNA strand exchange between homologous chromosomes. The Mei5-Sae3 protein complex functions as a recombination mediator to promote nucleation of the Dmc1 recombinase onto replication protein A-coated single-stranded DNA. Here, we have expressed and purified the Mei5 protein, Sae3 protein and the Mei5-Sae3 complex for biochemical studies. We show the Mei5-Sae3 complex preferentially binds a fork-like DNA substrate to 3' overhanging DNA, single-stranded DNA or double-stranded DNA. We demonstrate that Mei5 confers DNA binding activity to the Mei5-Sae3 complex. We determined Mei5-Sae3 interacts with the Rad51 recombinase through the N-terminal domain of Mei5. Unlike Rad52, Mei5-Sae3 lacks recombination mediator activity for Rad51. Importantly, we find that the Mei5-Sae3 complex does not harbor single strand DNA annealing activity. These properties of the Mei5-Sae3 complex distinguishes it from the Rad52 protein, which serves as the mediator of Rad51 and is involved in the single-strand DNA annealing pathway of homologous recombination. PMID- 21543268 TI - The fate of micronucleated cells post X-irradiation detected by live cell imaging. AB - Micronuclei are closely related to DNA damage. The presence of micronuclei in mammalian cells is a common phenomenon post ionizing radiation. The level of micronucleation in tumor cells has been used to predict prognosis after radiotherapy in many cancers. In order to understand how irradiation-induced micronuclei affect cell fate, we performed extensive long-term live cell imaging on X-irradiated nasopharyngeal carcinoma (NPC) cells. To visualize the dynamics of micronuclei more clearly, chromosomes were stably labeled with red fluorescent protein (RFP) by targeting to human histone H2B. Initially, significantly more micronuclei were observed in radiosensitive cells than in radioresistant cells post irradiation. Additionally, cells with micronuclei were found to be more likely to die or undergo cell cycle arrest when compared with micronucleus-free cells after irradiation, and the more micronuclei the cells contained the more likely they would die or undergo arrest. Moreover, micronucleated cells showed predisposition to produce daughter cells with micronuclei through chromosome lagging. Fluorescence in situ hybridization using human pan-centromeric probes revealed that about 70% of these micronuclei and lagging chromosomes did not contain centromeric signals. Finally, DNA damage was more severe and p38 stress kinase activity was higher in micronucleated cells than in micronucleus-free cells as shown by phospho-H2AX and phospho-p38 immunofluorescence staining. Altogether, our observations indicated that the presence of micronuclei coupled with activated DNA damage response could compromise the proliferation capacity of irradiated cells, providing the evidence and justification for using micronucleus index as a valuable biomarker of radiosensitivity. PMID- 21543269 TI - Research on the adsorption property of supported ionic liquids for ferulic acid, caffeic acid and salicylic acid. AB - In this paper, the preparation of new supported ionic liquids (SILs) composed of the N-methylimidazolium cation and the quinoline cation is described. They have been confirmed and evaluated by infrared spectroscopy, elemental analysis and thermogravimetric analysis. Six kinds of different SILs included SiO(2).Im(+).Cl( ), SiO(2).Im(+).BF(4)(-), SiO(2).Im(+).PF(6)(-), SiO(2).Qu(+).Cl(-), SiO(2).Qu(+).BF(4)(-) and SiO(2).Qu(+).PF(6)(-). The adsorption characteristics of ferulic acid (FA), caffeic acid (CA) and salicylic acid (SA) on SILs were investigated by static adsorption experiments. It was found that SiO(2).Qu(+).Cl( ) had excellent adsorption and desorption capacity to three tested phenolic compounds. The dynamic adsorption characteristics of FA, CA and SA on SiO(2).Qu(+).Cl(-) were also studied. The saturated adsorption capacity of FA, CA and SA using SiO(2).Qu(+).Cl(-) as adsorbent was 64.6 mg/g, 53.2 mg/g and 72.2 mg/g respectively. Using 70% ethanol as eluent, the saturated desorption efficiencies of FA, CA and SA were 97.2%, 90.3% and 96.5% respectively. Thus, SiO(2).Qu(+).Cl(-) had strong adsorption and separation capacity for FA, CA and SA. PMID- 21543270 TI - Analysis of hSCOMT adsorption in bioaffinity chromatography with immobilized amino acids: the influence of pH and ionic strength. AB - In the last years, chromatographic supports with amino acids as immobilized ligands (AAILs) were been used successfully for isolation of several biomolecules, such as proteins. In this context and based on specific properties of human soluble cathecol-O-methyltransferase (hSCOMT), we screened and analyzed the effect of experimental conditions, such as pH and ionic strength manipulation for hSCOMT adsorption, over six different AAIL commercial supports. Typically, the proteins adsorption on AAIL chromatographic supports is around their pI. While hSCOMT isoelectric point is around 5.5, this parameter leads us to design new adsorption strategies with several acid buffers for the chromatographic process. In terms of the ionic strength manipulation strategy, the results suggest that the AAILs-hSCOMT interaction is strongly affected by the intrinsic hSCOMT hydrophobic domains. On the other hand, the interaction mechanism of hSCOMT on amino acid resins appears to be highly dependent on the binding pH. Consequently the retention mechanism of the target enzyme on the AAILs can be as either in typical hydrophobic or ionic chromatographic supports, so long as selecting various mobile phases and separation conditions. In spite of these mixed-mode interactions and operation strategies, the elution of interferent's proteins from recombinant host can be achieved only with suitable adjusts in pH mobile phase set point. This lead to a new approach in biochromatographic COMT retention, while possess a higher specificity than other chromatographic methods reported in literature. PMID- 21543271 TI - Development of a liquid chromatography-tandem mass spectrometry with pressurized liquid extraction method for the determination of benzimidazole residues in edible tissues. AB - A confirmatory and quantitative method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with a pressure liquid extraction (PLE) was developed for the determination of 11 benzimidazole and 10 metabolites of albendazole, fenbendazole and mebendazole in the muscles and livers of swine, cattle, sheep and chicken. For sample preparation, we used an automated technique of PLE method. The optimum extraction conditions were obtained using an 11 ml Accelerated Solvent Extraction (ASE) cells, acetonitrile/hexane as the extraction solvent. HPLC analysis was performed on a C18 column with gradient elution using acetonitrile and 5 mmol l(-1) formic ammonium as mobile phase. The analytes were detected in the positive ion multiple reaction monitoring (MRM) mode by the LC ESI-MS/MS analysis. The recoveries of benzimidazole (BZDs) spiked at the levels of 0.5 MUg kg(-1) ranged from 70.1% to 92.7%; the between-day relative standard deviations were no more than 10%. The limits of quantification were 0.02-0.5 MUg kg(-1). The optimized method was successfully applied to monitor real samples containing BZDs, demonstrating the method to be simple, fast, robust and suitable for identification and quantification of BZDs residues in animal products. PMID- 21543272 TI - Development and validation of a quantitative assay for the determination of tamoxifen and its five main phase I metabolites in human serum using liquid chromatography coupled with tandem mass spectrometry. AB - A sensitive bioanalytical assay for the quantitative determination of tamoxifen and five of its phase I metabolites (N-desmethyltamoxifen, N-desmethyl-4 hydroxytamoxifen, N-desmethyl-4'-hydroxytamoxifen, 4-hydroxytamoxifen and 4' hydroxytamoxifen) in serum is described. The method has been fully validated at ranges covering steady-state serum concentrations in patients receiving therapeutic dosages of tamoxifen. The bioanalytical assay is based on reversed phase liquid chromatography coupled with tandem mass spectrometry in the positive ion mode using multiple reaction monitoring for drug (-metabolite) quantification. The sample pretreatment consists of protein precipitation with acetonitrile using only 50 MUL of serum. In the past, numerous assays have been developed by other groups for the quantification of tamoxifen and its phase I metabolites. However, the number of metabolites included in these studies is very limited and only very few of these assays have been fully validated. A liquid chromatography tandem mass spectrometry assay for the quantification of tamoxifen and four phase I metabolites in human serum that was previously developed by our group is now explicitly improved and described herein. Time of analysis has been reduced by 50% and sensitivity was increased by a reduction of the lower limit of quantification from 1.0 to 0.2 ng/mL for 4-hydroxytamoxifen and 4' hydroxytamoxifen. Additionally, two phase I metabolites that have never been quantified in human serum hitherto, namely 4'-hydroxytamoxifen and N-desmethyl-4' hydroxytamoxifen, were included in this assay. Validation results demonstrate an accurate and precise quantification of tamoxifen, N-desmethyltamoxifen, N desmethyl-4-hydroxytamoxifen, N-desmethyl-4'-hydroxytamoxifen, 4-hydroxytamoxifen and 4'-hydroxytamoxifen in human serum. The applicability of the assay was demonstrated and it is now successfully used to support clinical studies in which patient-specific dose optimization is performed based on serum concentrations of tamoxifen metabolites. PMID- 21543273 TI - Differentiating size-dependent responses of juvenile pink salmon (Oncorhynchus gorbuscha) to sea lice (Lepeophtheirus salmonis) infections. AB - Salmon infected with an ectoparasitic marine copepod, the salmon louse Lepeophtheirus salmonis, incur a wide variety of consequences depending upon host sensitivity. Juvenile pink salmon (Oncorhynchus gorbuscha) migrate from natal freshwater systems to the ocean at a young age relative to other Pacific salmon, and require rapid development of appropriate defenses against marine pathogens. We analyzed the early transcriptomic responses of naive juvenile pink salmon of sizes 0.3 g (no scales), 0.7 g (mid-scale development) and 2.4 g (scales fully developed) six days after a low-level laboratory exposure to L. salmonis copepodids. All infected size groups exhibited unique transcriptional profiles. Inflammation and inhibition of cell proliferation was identified in the smallest size class (0.3 g), while increased glucose absorption and retention was identified in the middle size class (0.7 g). Tissue-remodeling genes were also up regulated in both the 0.3 g and 0.7 g size groups. Profiles of the 2.4 g size class indicated cell-mediated immunity and possibly parasite-induced growth augmentation. Understanding a size-based threshold of resistance to L. salmonis is important for fisheries management. This work characterizes molecular responses reflecting the gradual development of innate immunity to L. salmonis between the susceptible (0.3 g) and refractory (2.4 g) pink salmon size classes. PMID- 21543275 TI - Expanding the CODIS core loci in the United States. PMID- 21543274 TI - [Characteristics of chronic renal failure in black adult patients hospitalized in the Internal Medicine department of Treichville University Hospital]. AB - OBJECTIVE: To describe the epidemiological, clinical, biological aspects, treatment and outcome of chronic renal failure. METHODS: A retrospective study was conducted on medical data of 301 inpatients with chronic renal failure from January 1, 2004 to December 31, 2008 in the internal medicine department of Treichville university hospital. RESULTS: The hospital prevalence of chronic renal failure was 7.5%. The average patient age was 44+/-10 years [range : 16-86 years] and sex ratio was 1.3. The main medical histories were self-medication (38.5%) and hypertension (33.5%). In 82.4% cases, it was the end-stage renal disease. Biological abnormalities were important. The causes were dominated by nephroangiosclerosis noted in 25.3%, followed by HIV-associated nephropathy in 17% and chronic interstitial nephritis in 10.3%. Treatment consisted of transfusion in 71% and dialysis in 16%. Lethality was 54%. CONCLUSION: The chronic renal failure is a fairly common cause of hospitalization in our department. His prognosis is terrible. The main causes are nephroangiosclerosis and HIV-associated nephropathy. Accent should be placed on preventive measures of hypertension and AIDS. PMID- 21543276 TI - Amplification volume reduction on DNA database samples using FTATM Classic Cards. AB - The DNA forensic community always strives towards improvements in aspects such as sensitivity, robustness, and efficacy balanced with cost efficiency. Therefore our laboratory decided to study the feasibility of PCR amplification volume reduction using DNA entrapped in FTATM Classic Card and to bring cost savings to the laboratory. There were a few concerns the laboratory needed to address. First, the kinetics of the amplification reaction could be significantly altered. Second, an increase in sensitivity might affect interpretation due to increased stochastic effects even though they were pristine samples. Third, statics might cause FTA punches to jump out of its allocated well into another thus causing sample-to-sample contamination. Fourth, the size of the punches might be too small for visual inspection. Last, there would be a limit to the extent of volume reduction due to evaporation and the possible need of re-injection of samples for capillary electrophoresis. The laboratory had successfully optimized a reduced amplification volume of 10 MUL for FTA samples. PMID- 21543277 TI - Interspecies chimera between primate embryonic stem cells and mouse embryos: monkey ESCs engraft into mouse embryos, but not post-implantation fetuses. AB - Unequivocal evidence for pluripotency in which embryonic stem cells contribute to chimeric offspring has yet to be demonstrated in human or nonhuman primates (NHPs). Here, rhesus and baboons ESCs were investigated in interspecific mouse chimera generated by aggregation or blastocyst injection. Aggregation chimera produced mouse blastocysts with GFP-nhpESCs at the inner cell mass (ICM), and embryo transfers (ETs) generated dimly-fluorescencing abnormal fetuses. Direct injection of GFP-nhpESCs into blastocysts produced normal non-GFP-fluorescencing fetuses. Injected chimera showed >70% loss of GFP-nhpESCs after 21 h culture. Outgrowths of all chimeric blastocysts established distinct but separate mouse- and NHP-ESC colonies. Extensive endogenous autofluorescence compromised anti-GFP detection and PCR analysis did not detect nhpESCs in fetuses. NhpESCs localize to the ICM in chimera and generate pregnancies. Because primate ESCs do not engraft post-implantation, and also because endogenous autofluorescence results in misleading positive signals, interspecific chimera assays for pluripotency with primate stem cells is unreliable with the currently available ESCs. Testing primate ESCs reprogrammed into even more naive states in these inter-specific chimera assays will be an important future endeavor. PMID- 21543278 TI - Painful medial knee compartment syndrome in over-45 year-olds: I--medical or surgical management: a series of 174 patients. AB - INTRODUCTION: There is at present no consensus on the management of degenerative medial meniscus lesions in patients aged over 45 years without proven osteoarthritis, especially given that the causal relation between degenerative meniscal lesion and osteoarthritis remains controversial. A prospective multicenter non randomized study was therefore performed. The principal objective was to assess surgeons' practice in the management of degenerative medial meniscus lesions. The secondary objectives were to identify predictive and prognostic factors and to compare medical versus surgical attitudes so as to draw up an adapted treatment strategy. PATIENTS AND METHOD: One hundred and seventy four patients were included between September 2008 and February 2010, and distributed between a surgical (n=104) and a medical group (n=70). Minimum follow up was 6 months. Patient satisfaction and health-related quality of life on the SF-36 questionnaire were assessed at 6 months. RESULTS: No difference emerged between the surgical and medical groups. However, predictive factors for poor results were identified: overweight (p=0.005), cartilage lesions (p=0.035) and meniscus extrusion (p=0.006). DISCUSSION: Results clarified the relation between degenerative meniscus lesions and osteoarthritis, in terms of meniscal incompetence. Meniscal extrusion should be seen as an arthrogenic degenerative meniscus lesion. We recommend a management strategy based on terrain and imaging data (X-ray and MRI), with the aim of providing patient relief while conserving cartilage. PMID- 21543279 TI - Has rare case of paraplegia complicating a lumbar epidural infiltration been reported? PMID- 21543280 TI - Relation between methylmercury exposure and plasma paraoxonase activity in inuit adults from Nunavik. AB - BACKGROUND: Methylmercury (MeHg) exposure has been linked to an increased risk of coronary heart disease (CHD). Paraoxonase 1 (PON1), an enzyme located in the high density-lipoprotein (HDL) fraction of blood lipids, may protect against CHD by metabolizing toxic oxidized lipids associated with low-density liproprotein and HDL. MeHg has been shown to inhibit PON1 activity in vitro, but this effect has not been studied in human populations. OBJECTIVES: This study was conducted to determine whether blood mercury levels are linked to decreased plasma PON1 activities in Inuit people who are highly exposed to MeHg through their seafood based diet. METHODS: We measured plasma PON1 activity using a fluorogenic substrate and blood concentrations of mercury and selenium by inductively coupled plasma mass spectrometry in 896 Inuit adults. Sociodemographic, anthropometric, clinical, dietary, and lifestyle variables as well as PON1 gene variants (rs705379, rs662, rs854560) were considered as possible confounders or modifiers of the mercury-PON1 relation in multivariate analyses. RESULTS: In a multiple regression model adjusted for age, HDL cholesterol levels, omega-3 fatty acid content of erythrocyte membranes, and PON1 variants, blood mercury concentrations were inversely associated with PON1 activities [beta-coefficient = -0.063; 95% confidence interval (CI), -0.091 to -0.035; p < 0.001], whereas blood selenium concentrations were positively associated with PON1 activities (beta-coefficient = 0.067; 95% CI, 0.045-0.088; p < 0.001). We found no interaction between blood mercury levels and PON1 genotypes. CONCLUSIONS: Our results suggest that MeHg exposure exerts an inhibitory effect on PON1 activity, which seems to be offset by selenium intake. PMID- 21543281 TI - An approach for quantitatively balancing methylmercury risk and omega-3 benefit in fish consumption advisories. AB - BACKGROUND: Nearly all fish consumption advisories for methylmercury (MeHg) are based only on risk. There is a need to also address benefits, especially those from polyunsaturated fatty acids (PUFAs), in neurodevelopmental function and cardiovascular health. However, because MeHg and PUFA generally act on these same end points, disentangling risk and benefit is challenging. OBJECTIVES: We propose an approach for balancing risk and benefit that is based on the use of statistically dissociated measures of risk and benefit. DISCUSSION: Because of mutual coexposure of MeHg and PUFAs in population-based studies and their opposite effect on many of the same end points, MeHg risk and PUFA benefit are tightly linked statistically, which results in mutual (negative) confounding. Thus, neither MeHg risk nor PUFA benefit can be accurately quantified without taking the other into account. A statistical approach that generates unconfounded risk and benefit coefficients for each end point can permit their subsequent recombination to describe the overall risk-benefit profile of each species of fish or fish diet. However, it appears that some end points may be adversely affected by MeHg without experiencing counterbalancing benefit from PUFAs. Such end points may drive consumption advisories and may preclude balancing of risk and benefit on the basis of other end points. CONCLUSIONS: Our thinking about fish consumption advisories now recognizes the need to balance risk and benefit. However, although statistical analysis of the appropriate data can eliminate mutual confounding, care is required to address the most sensitive end points that may be sensitive to risk and not benefit. PMID- 21543282 TI - Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. AB - BACKGROUND: The large and increasing number of chemicals released into the environment demands more efficient and cost-effective approaches for assessing environmental chemical toxicity. The U.S. Tox21 program has responded to this challenge by proposing alternative strategies for toxicity testing, among which the quantitative high-throughput screening (qHTS) paradigm has been adopted as the primary tool for generating data from screening large chemical libraries using a wide spectrum of assays. OBJECTIVES: The goal of this study was to develop methods to evaluate the data generated from these assays to guide future assay selection and prioritization for the Tox21 program. METHODS: We examined the data from the Tox21 pilot-phase collection of approximately 3,000 environmental chemicals profiled in qHTS format against a panel of 10 human nuclear receptors (AR, ERalpha, FXR, GR, LXRbeta, PPARgamma, PPARdelta, RXRalpha, TRbeta, and VDR) for reproducibility, concordance of biological activity profiles with sequence homology of the receptor ligand binding domains, and structure activity relationships. RESULTS: We determined the assays to be appropriate in terms of biological relevance. We found better concordance for replicate compounds for the agonist-mode than for the antagonist-mode assays, likely due to interference of cytotoxicity in the latter assays. This exercise also enabled us to formulate data-driven strategies for discriminating true signals from artifacts, and to prioritize assays based on data quality. CONCLUSIONS: The results demonstrate the feasibility of qHTS to identify the potential for environmentally relevant chemicals to interact with key toxicity pathways related to human disease induction. PMID- 21543283 TI - Identification of candidate genes downstream of TLR4 signaling after ozone exposure in mice: a role for heat-shock protein 70. AB - BACKGROUND: Toll-like receptor 4 (TLR4) is involved in ozone (O3)-induced pulmonary hyperpermeability and inflammation, although the downstream signaling events are unknown. OBJECTIVES: The aims of our study were to determine the mechanism through which TLR4 modulates O3-induced pulmonary responses and to use transcriptomics to determine potential TLR4 effector molecules. METHODS: C3H/HeJ (HeJ; Tlr4 mutant) and C3H/HeOuJ (OuJ; Tlr4 normal) mice were exposed continuously to 0.3 ppm O3 or filtered air for 6, 24, 48, or 72 hr. We assessed inflammation using bronchoalveolar lavage and molecular analysis by mRNA microarray, quantitative RT-PCR (real-time polymerase chain reaction), immunoblots, immunostaining, and ELISAs (enzyme-linked immunosorbent assays). B6 Hspa1a/Hspa1btm1Dix/NIEHS (Hsp70-/-) and C57BL/6 (B6; Hsp70+/+ wild-type control) mice were used for candidate gene validation studies. RESULTS: O3-induced TLR4 signaling occurred through myeloid differentiation protein 88 (MyD88)-dependent and -independent pathways in OuJ mice and involved multiple downstream pathways. Genomewide transcript analyses of lungs from air- and O3-exposed HeJ and OuJ mice identified a cluster of genes that were significantly up-regulated in O3-exposed OuJ mice compared with O3-exposed HeJ mice or air-exposed controls of both strains; this cluster included genes for heat-shock proteins (e.g., Hspa1b, Hsp70). Moreover, O3-induced inflammation, MyD88 up-regulation, extracellular signal-related kinase-1/2 (ERK1/2) and activator protein-1 (AP-1) activation, and kerotinocyte-derived chemokine (KC) protein content were significantly reduced in Hspa1a/Hspa1btm1Dix (Hsp70-/-) compared with Hsp70+/+ mice (p < 0.05). CONCLUSIONS: These studies suggest that HSP70 is an effector molecule downstream of TLR4 and is involved in the regulation of O3-induced lung inflammation by triggering similar pathways to TLR4. These novel findings may have therapeutic and preventive implications for inflammatory diseases resulting from environmental exposures. PMID- 21543284 TI - Cadmium, lead, and mercury in relation to reproductive hormones and anovulation in premenopausal women. AB - BACKGROUND: Metals can interfere with hormonal functioning by binding at the receptor site and through indirect mechanisms; thus, they may be associated with hormonal changes in premenopausal women. OBJECTIVES: We examined the associations between cadmium, lead, and mercury, and anovulation and patterns of reproductive hormones [estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone] among 252 premenopausal women 18-44 years of age who were enrolled in the BioCycle Study in Buffalo, New York. METHODS: Women were followed for up to two menstrual cycles, with serum samples collected up to eight times per cycle. Metal concentrations were determined at baseline in whole blood by inductively coupled mass spectroscopy. Marginal structural models with stabilized inverse probability weights and nonlinear mixed models with harmonic terms were used to estimate the effects of cadmium, lead, and mercury on reproductive hormone levels during the menstrual cycle and anovulation. RESULTS: Geometric mean (interquartile range) cadmium, lead, and mercury levels were 0.29 (0.19 0.43) MUg/L, 0.93 (0.68-1.20) MUg/dL, and 1.03 (0.58-2.10) MUg/L, respectively. We observed decreases in mean FSH with increasing cadmium [second vs. first tertile: -10.0%; 95% confidence interval (CI), -17.3% to -2.5%; third vs. first tertile: -8.3%; 95% CI, -16.0% to 0.1%] and increases in mean progesterone with increasing lead level (second vs. first tertile: 7.5%; 95% CI, 0.1-15.4%; third vs. first tertile: 6.8%; 95% CI, -0.8% to 14.9%). Metals were not significantly associated with anovulation. CONCLUSIONS: Our findings support the hypothesis that environmentally relevant levels of metals are associated with modest changes in reproductive hormone levels in healthy, premenopausal women. PMID- 21543285 TI - [Survival of breast cancers patients with meningeal carcinoma]. AB - PURPOSE: Among all solid tumors breast cancer is the most common cause of meningeal carcinomatosis (MC). The purpose of this study was to analyze clinical and biological responses as well as overall survival in MC patients (pts) of breast primary treated with intrathecal methotrexate (MTX). METHODS AND MATERIALS: Single-center retrospective series of MC pts treated between 2000 and 2007. Chemotherapy regimen was: MTX (15 mg/day; day 1-5) and depomedrol (40 mg, day 1) plus leucoverin (12 mg IV or 25 mg PO; day 1-5). Treatment cycles were repeated every 2 weeks. The survival was analyzed according to the characteristics of the tumor considering clinical and cytological response rates to treatment. RESULTS: The median survival was 4.5 months (range 0-53). In multivariate analysis, poor prognostic factors at diagnosis were: Performans status greater than 2 [P = 0.006, RR = 0.33 (0.15-0.71)], more than three chemotherapy regimens before MC diagnosis [P = 0.03, RR = 0.40 (0.19-0.93)], negative hormone receptor status [P = 0.02, RR = 0.4 (0.19-0.90)] and high Cyfra 21-1 level [P = 0.048, RR = 0.09-0.99]. The clinical progression after one cycle and the biological response after two cycles were independently correlated with OS [P<0.001, RR = 0.09 (0.02-0.37) and P = 0.003, RR = 3.6 (1.5-8.5), respectively]. A prognostic score designed to define three groups of patients is proposed. CONCLUSION: Although prognosis of patients with MC is poor, 1-year overall survival rate is 25%. The proposed prognostic score may be helpful in decision but warrants further assessment and validation in prospective trials. PMID- 21543286 TI - Occipital bone dysplasia associated with diffuse plexiform neurofibroma. PMID- 21543287 TI - Antibodies to pilosebaceous units along their neurovascular supply routes in a new variant of endemic pemphigus foliaceus in Colombia, South America. AB - Senear Usher syndrome is a variant of pemphigus foliaceus, confined to seborrheic sites and considered to be a clinical overlap syndrome, with features of both pemphigus foliaceus and lupus erythematosus. We recently described autoantibodies to skin eyelid meibomian glands in patients with a new variant of endemic pemphigus foliaceus (El Bagre EPF) in South America. We tested for El Bagre EPF patient sera autoreactivity to pilosebaceous units utilizing direct and indirect immunofluorescence, confocal microscopy, immunohistochemistry and immunoelectron microscopy. Hematoxylin and eosin staining of skin biopsies revealed that one third of the patients affected by El Bagre-EPF demonstrated some histologic alteration of the pilosebaceous units. By immunohistochemistry, most El Bagre EPF biopsies demonstrated evidence of an autoimmune response along the neural and vascular supply routes of the pilosebaceous units. An active immune response was seen with antibodies such as anti-human mast cell tryptase, myeloid/histoid antigen, CD8, CD20, CD68, CD117/c-kit, ZAP-70 and vimentin. Immunoelectron microscopy demonstrated autoantibodies within the hair follicle and at the basement membrane area of the sebaceous glands. El Bagre-EPF patients have autoantibodies to pilosebaceous units and to their surrounding neurovascular packages. Our results warrant further characterization and may explain the loss of hair described in severe endemic pemphigus foliaceus before the therapeutic steroid era. PMID- 21543288 TI - Granuloma annulare of the penis - subcutaneous presentation. PMID- 21543289 TI - Modified shark island flap for combined nasal ala-perialar defects. PMID- 21543290 TI - Etanercept in the treatment of psoriasis and psoriatic arthritis with concomitant hepatitis C virus infection: clinical and virological study in three patients. AB - Treatment of patients with psoriasis and concomitant hepatitis-C virus (HCV) infection poses a therapeutic challenge because most systemic drugs are associated with potential hepatotoxicity, either due to direct liver damage or to immunosuppression. Among newly available drugs for the treatment of psoriasis and psoriatic arthritis, studies investigating the effect of anti-tumour necrosis factor-alpha in such patients are still limited. We describe three psoriatic patients with HCV, one with concomitant alcoholic hepatitis, who were treated with etanercept monotherapy for six months. We obtained good clinical responses for both psoriasis and arthritis in all three patients. While no significant changes in viral load and transaminases were observed in two patients, alanine aminotrasferase and gamma-glutamyltransferase levels were raised during treatment in the patient with concomitant alcoholic hepatitis. At baseline, one patient was negative and two were positive for mixed-type cryoglobulins. During treatment, none of the patients developed cryoglobulinemia-related clinical symptoms, and one of the two patients positive at baseline was negative for cryoglobulins at the end of follow-up. Our results add to accumulating data suggesting that etanercept represents a valuable therapeutic option for treatment of HCV-positive psoriatic patients, with an acceptable safety profile in the short-term. However, etanercept treatment of HCV cases with concomitant alcoholic hepatitis must be undertaken with caution. PMID- 21543291 TI - Refractory leg ulcer successfully treated with hyperbaric oxygen therapy. PMID- 21543292 TI - Presence of a D8/17 B lymphocyte marker and HLA-DR subgroups in patients with rheumatic heart disease. AB - OBJECTIVE: The aim of our study was to investigate the association of HLA antigens and a non-HLA protein D8/17 with rheumatic heart disease and its pattern of cardiac involvement. METHODS: This cross- sectional observational study included 35 children and 12 adult patients who have rheumatic heart disease and 35 healthy children and 12 healthy adult controls. After physical examination, all patients and control group members were evaluated with 2D and color-coded echocardiography. B- lymphocyte D8/17 expression was tested by a flow cytometry assay. HLA genotyping was performed using polymerase chain reaction sequence specific primers. In statistical analysis, Chi-square, unpaired t and Mann Whitney U tests were used for comparison groups. RESULTS: The percentage of the D8/17-expressing B lymphocytes of the patient group was significantly higher than of the control group (77.3+/-15.6% vs. 67.7+/-20.0%, p=0.013). When compared with the control group, the HLA DRB5 (38.6% vs. 13.6%, p=0.007) and HLA DRB1*15 (31.8% vs. 9.0%, p=0.008) expression levels of the patient group were significantly higher and the DRB4 expression of the patient group was significantly lower (29.5% vs. 50.0%, p=0.049). CONCLUSION: Our findings support the association between HLA Class 2 subgroups and rheumatic heart disease, and an association between D8/17 expression and rheumatic heart disease. Further studies including higher number of patients and control group members should be performed for the confirmation of our results. PMID- 21543293 TI - Comparison of antihypertensive efficacy of carvedilol and nebivolol in mild-to moderate primary hypertension: a randomized trial. AB - OBJECTIVE: The aim of the present study is to compare the antihypertensive effects of carvedilol and nebivolol in mild-to-moderate hypertensive patients. METHODS: It is a prospective; placebo-controlled, cross-over, double-blind, randomized, single-center clinical trial. Patients (n=20) who were first diagnosed with mild to moderate systemic hypertension according to mean ambulatory blood pressure measurements > 130/85 mmHg and no previous antihypertensive therapy were prospectively enrolled into the study. After 10 days of placebo run-in period, they were randomized within the same group as cross-over design to one month carvedilol 25 mg and one month nebivolol 5 mg regimen given once daily in the morning. The primary outcome variables were systolic and diastolic blood pressures determined by 24-hour ambulatory blood pressure measurements. Mutlivariate analysis of variance for repeated measurements with 3x2 factorial design was used for statistical analysis of results. RESULTS: The study group consisted of 6 women and 14 men whose mean age was 42.9+/-12.8 years (range 19-63 years). Mean heart rate was significantly decreased after commencing both carvedilol (70.2+/-5.2 bpm) and nebivolol (64.9+/ 3.9 bpm) treatments compared to placebo (78.8+/-5.2 bpm) (p<0.05). Both carvedilol (133.8+/-9/86.6+/-8.6 mmHg) and nebivolol (134+/-8.7/85.6+/-7.4 mmHg) significantly decreased mean systolic and diastolic blood pressures compared to placebo (143.9+/-8.9/94.4+/-9.2 mmHg), respectively (p<0.05). However, there was no significant difference in decreasing either systolic or diastolic blood pressure between nebivolol and carvedilol therapies (p>0.05). No side effects were recorded during both carvedilol and nebivolol treatments. CONCLUSION: Although both carvedilol and nebivolol effectively decreased blood pressure compared to placebo, they showed similar efficacy for lowering blood pressure. PMID- 21543294 TI - N-3 polyunsaturated fatty acids administration does not reduce the recurrence rates of atrial fibrillation and inflammation after electrical cardioversion: a prospective randomized study. AB - OBJECTIVE: The purpose of the present prospective randomized study was to evaluate the effects of n-3 polyunsaturated fatty acids on recurrence rates of atrial fibrillation (AF) and inflammation after electrical cardioversion. METHODS: Calculation of the number of patients needed was based on the assumption of 20% and 65% chance of maintaining sinus rhythm with amiodarone and with polyunsaturated fatty acids, respectively. To observe a significant difference with an alpha level of 0.05 and a power of 0.80 it was necessary to include 22 patients in each group. A total of 47 patients were randomized to amiodarone (n=24) and amiodarone plus n-3 polyunsaturated fatty acids (n=23) groups before scheduled electrical cardioversion. The end-point was the recurrence of AF during 12-month follow-up. Effect of n-3 polyunsaturated fatty acids on inflammation was evaluated with high sensitivity C-reactive protein level measurements. Statistical analysis was performed using unpaired Student' t, Mann Whitney U and Chi-square tests. We analyzed the recurrence of AF using the Cox proportional hazards regression model to control for potentially confounding factors. RESULTS: Nine patients in the amiodarone group (37.5%), and 9 patients in the amiodarone plus n-3 polyunsaturated fatty acids group (39.1%) had recurrence of AF during follow-up (p=1). With the Cox proportional model, risk factors for the recurrence of AF were previous electrical cardioversion (HR 10.33, 95% CI 1.74 to 61.10, p=0.01) and high sensitivity C-reactive protein levels (HR 1.07, 95% CI 1.02 to 1.38, p=0.007). High sensitivity C-reactive protein levels at baseline, at day 15 and during AF recurrence were similar between two groups (p > 0.05 for all). CONCLUSION: N-3 polyunsaturated fatty acids administration does not reduce the recurrence rates of atrial fibrillation and inflammation. PMID- 21543295 TI - Relation between fragmented QRS and collateral circulation in patients with chronic total occlusion without prior myocardial infarction. AB - OBJECTIVE: It has been shown that the fragmented QRS (fQRS) on electrocardiogram (ECG) signifies regional myocardial scar in patients with non-Q-wave myocardial infarction (MI). We hypothesized that presence of fQRS on ECG may be related with poorly-grown collateral coronary circulation (CCC) in patients with chronic total coronary occlusion (CTO) without prior MI. METHODS: This retrospective observational study is included 56 patients (mean age 61.73+/-7.96 years; 67.9% men) with CTO in one of the major coronary arteries. Collateral circulation was graded according to Rentrop's classification. The fQRS was defined as the presence of an additional R wave or notching of R or S wave or the presence of fragmentation in two contiguous ECG leads corresponding to a major coronary artery territory. Patients with pathological Q-wave or history of MI, typical bundle brunch blocks (BBB) and incomplete right BBB were excluded from study. Statistical analysis was performed using Chi-square test, Student's t-test and logistic regression analysis. RESULTS: Fifteen patients had Rentrop grade 1, 15 patients had grade 2 and 26 patients had grade 3 CCC. Five (19%) of the patients who have grade 3 CCC, seven (47%) of the patients who had grade 2 CCC, ten (67%) of the patients who had grade 1 CCC had fQRS (p=0.002). Logistic regression analysis showed high predictive value of the presence of fQRS for Rentrop 1 CCC (OR=8.4, 95% CI 1.97-35.7; p=0.004). CONCLUSION: Results of our study may implicate the presence of fQRS on electrocardiogram as a predictor of a poorly grown CCC in patients with chronic total occlusion without prior MI. PMID- 21543296 TI - Endothelial progenitor cells (CD34+KDR+) and monocytes may provide the development of good coronary collaterals despite the vascular risk factors and extensive atherosclerosis. AB - OBJECTIVE: Endothelial progenitor cells (EPC) have a regenerative role in the vascular system. In this study, we aimed to evaluate simultaneously the effects of EPC and inflammatory cells on the presence and the extent of coronary artery disease (CAD) and the grade of coronary collateral growth in patients with clinical suspicion of CAD. METHODS: This study has a cross-sectional and observational design. We enrolled 112 eligible patients who underwent coronary angiography consecutively (mean age: 59+/-9 years). The association of circulating inflammatory cells and EPC (defined by CD34+KDR+ in the lymphocyte and monocyte gate) with the presence, severity and extent of CAD and the degree of collateral growth were investigated. Logistic regression analysis was used to define the predictors of collateral flow. RESULTS: Of 112 patients 30 had normal coronary arteries (NCA, 27%, 55+/-9 years) and 82 had CAD (73%, 61+/-8 years). Among the patients with CAD, the percent degree of luminal stenosis was <50% in 12 patients; 50-90% in 35 patients; and >=90% in the other 35 patients. Circulating inflammatory cells were higher (leukocytes, 7150+/-1599 vs 8163+/ 1588 mm(-3), p=0.001; neutrophils, 4239+/-1280 vs 4827+/-1273 mm(-3), p=0.021; monocytes, 512+/-111 vs 636+/-192 mm(-3), p=0.001) and EPCs were lower (0.27+/ 0.15% vs 0.17+/-0.14%, p<0.001; 21+/-15 vs 13+/-12 mm(-3), p=0.004) in CAD group than NCA group. When we investigated the collateral growth in patients having >=90% stenosis in at least one major coronary artery, we found that the patients with good collateral growth had significantly higher EPC (0.22+/-0.17% vs 0.10+/ 0.05%, p=0.009; 18+/-15 vs 7+/-3 mm(-3), p=0.003) in comparison to patients with poor collateral growth. Presence of EPC was associated with reduced risk for coronary artery disease (OR: 0.934, 95%CI: 0.883-0.998, p=0.018) and was an independent predictor for good collateral growth (OR: 1.295, 95%CI: 1.039-1.615, p=0.022). A sum of CD34+KDR-, CD34+KDR+ and CD34-KDR+ cells (192+/-98 mm(-3)), and a CD34-KDR- cell subpopulation within monocyte gate (514+/-173 mm(-3)) reached to highest counts in good collateral group among all study population. CONCLUSION: Endothelial progenitor cells can be mobilized from bone marrow to induce the coronary collateral growth in case of myocardial ischemia even in presence of the vascular risk factors and extensive atherosclerosis. This finding may be supportive to investigate the molecules, which can specifically mobilize EPC without inflammatory cells. PMID- 21543297 TI - The effect of interleukin-10 gene promoter polymorphisms on early-onset coronary artery disease. AB - OBJECTIVE: We assessed the association between interleukin-10 (IL-10) -1082G/A and -592C/A polymorphisms, and coronary heart disease (CHD). METHODS: A cross sectional, observational study included 86 patients (mean age 43.36+/-4.930 years) diagnosed to have CHD and 88 healthy controls (mean age 47.07+/-8.135 years). IL-10 -1082G/A and -592C/A polymorphisms were analyzed using restriction fragment length polymorphism (RFLP) and agarose gel electrophoresis methods in both patient and control groups. Genotype distributions of the polymorphisms between CHD patients and controls were assessed by Chi-square analysis. RESULTS: The genotype distribution of the -1082 G/A polymorphism was not different in premature CHD patients (GG: 38.3%; GA: 51.1%; AA: 10.6%) and controls (GG: 43.1%; GC: 43.1%; CC: 13.8%) (p=0.57). The prevalence of the A allele at -1082G/A polymorphism was 36.6% in patients and 35.3% in controls. Both allele and genotype frequencies of -592C/A polymorphism did not also differ significantly between patients with CHD and controls. We did not observe relationships between polymorphism-specific haplotypes and adverse angiographic and clinical outcomes. We have observed a significant difference of IL-10 -592C/A allelic frequency (OR=2.00 95% CI=0.9434-4.2579) between the younger CHD patients (<45 years, Group 2) and matched controls. CONCLUSION: Our study suggests that IL-10-592C/A polymorphism may play a role in susceptibility to CHD in younger patients. PMID- 21543298 TI - [Coronary artery ectasia: its frequency and relationship with atherosclerotic risk factors in patients undergoing cardiac catheterization]. AB - OBJECTIVE: Coronary artery ectasia (CAE) is defined as local or generalized aneurysmal dilatation of the coronary arteries. We aimed to determine the frequency of CAE at our center and to compare clinical and angiographic characteristics between patients with isolated CAE and CAE with coronary artery disease (CAD). METHODS: From February 2004 to December 2005, 12.514 patients were retrospectively analyzed by two independent operators who underwent coronary angiography. Coronary artery diameters were measured using qualitative computed angiography. CAD risk factors were recorded for all patients. Unpaired Student's t-test and Chi-square test were used for statistical analysis. RESULTS: CAE was diagnosed in 201 patients (1.59%). The majority (78%) were male. The mean age was 61+/-10.8 years (range, 25 to 82 years). The cases were divided into 2 groups as isolated CAE (Group 1) (14.9%) and CAE with CAD (Group 2) (85.1%). The risk factors of CAD were similar between two groups. The frequency of arterial involvement was: the right coronary artery (RCA) 54.3%; circumflex artery (Cx), 48.3%; the left anterior descending artery (LAD), 40.4%. CAE affected only one major vessel in 64.2% of cases and all 3 vessels in 9%. Isolated CAE was most commonly detected in Cx (47%). The type of CAE was determined according to Markis and Harikrishnan classification. The most prevalent involvement was Markis type 4 and Harikrishnan type 4a. Although atypical angina was the most common clinical presentation in both groups, acute coronary syndrome was more frequent in Group 2 (p=0.018). CONCLUSION: The risk factors of CAD and the manner of clinical presentation were considerably similar in both groups and this situation was consistent with similar etiopathogenesis of two diseases. PMID- 21543299 TI - Waiting for children's surgery in Canada: the Canadian Paediatric Surgical Wait Times project. AB - BACKGROUND: In addition to possibly prolonged suffering and anxiety, extended waits for children's surgery beyond critical developmental periods has potential for lifelong impact. The goal of this study was to determine the duration of waits for surgery for children and youth at Canadian paediatric academic health sciences centres using clinically-derived access targets (i.e., the maximum acceptable waiting periods for completion of specific types of surgery) as used in this Canadian Paediatric Surgical Wait Times project. METHODS: We prospectively applied standardized wait-time targets for surgery, created by nominal-group consensus expert panels, to pediatric patients at children's health sciences centres across Canada with decision-to-treat dates of Sept. 1, 2007 or later. From Jan. 1 to Dec. 30, 2009, patients' actual wait times were compared with their target wait times to determine the percentage of patients receiving surgery after the target waiting period. RESULTS: Overall, 27% of pediatric patients from across Canada (17,411 of 64,012) received their surgery after their standardized target waiting period. Dentistry, ophthalmology, plastic surgery and cancer surgery showed the highest percentages of surgeries completed past target. INTERPRETATION: Many children wait too long for surgery in Canada. Specific attention is required, in particular, in dentistry, ophthalmology, plastic surgery and cancer care, to address children's wait times for surgery. Improved access may be realized with use of national wait-time targets. PMID- 21543300 TI - [Frederick Banting and the opportunities for research for general practitioners]. PMID- 21543301 TI - United States menu labelling requirements to include exemptions for alcohol and popcorn. PMID- 21543302 TI - Empirically derived maximal acceptable wait time for surgery to treat adolescent idiopathic scoliosis. AB - BACKGROUND: Prioritizing patients using empirically derived access targets can help to ensure high-quality care. Adolescent scoliosis can worsen while patients wait for treatment, increasing the risk of adverse events. Our objective was to determine an empirically derived access target for scoliosis surgery and to compare this with consensus-based targets. METHODS: Two-hundred sixteen sequential patients receiving surgery for adolescent idiopathic scoliosis were included in the study. The main outcome was need for additional surgery. Logistic regression modeling was used to evaluate the relation between surgical wait times and adverse events and chi2 analysis was used as the primary analysis for the main outcome. RESULTS: Of the 88 patients who waited longer than six months for surgery, 13 (14.8%) needed additional surgery due to progression of curvature versus 1.6% (2 of 128 patients) who waited less than six months for surgery (chi2 analysis, p=0.0001). Patients who waited longer than six months for surgery had greater progression of curvature, longer surgeries and longer stays in hospital. These patients also had less surgical correction than patients who waited less than six months for surgery (Wilcoxon-Mann-Whitney test, p=0.011). All patients requiring additional surgeries waited longer than three months for their initial surgery. A receiver-operator characteristic curve also suggested a three-month wait as an access target. The adjusted odds ratio for an adverse event for each additional 90 days of waiting from time of consent was 1.81 (95% confidence interval 1.34-2.44). The adjusted odds ratio increased with skeletal immaturity and with the size of the spinal curvature at the time of consent. INTERPRETATION: A prolonged wait for surgery increased the risk of additional surgical procedures and other adverse events. An empirically derived access target of three months for surgery to treat adolescent idiopathic scoliosis could potentially eliminate the need for additional surgery by reducing progression of curvature. This is a shorter access target than the six months determined by expert consensus. PMID- 21543304 TI - [Did Abraham Flexner cause the creation of the JAMC?]. PMID- 21543305 TI - CMAJ 2011 election survey: transparency. PMID- 21543306 TI - Streptococcus pneumoniae meningitis in an adult with normal cerebrospinal fluid. PMID- 21543307 TI - CMAJ 2011 election survey: electronic health records. PMID- 21543309 TI - Do Canadian researchers have "blood on their hands"? PMID- 21543310 TI - CMAJ 2011 election survey: food safety. PMID- 21543311 TI - Central pontine myelinolysis. PMID- 21543312 TI - CMAJ 2011 election survey: patient safety. PMID- 21543313 TI - CMAJ 2011 election survey: public health. PMID- 21543314 TI - Lipids trigger a conformational switch that regulates signal recognition particle (SRP)-mediated protein targeting. AB - Co-translational protein targeting to the membrane is mediated by the signal recognition particle and its receptor (FtsY). Their homologous GTPase domains interact at the membrane and form a heterodimer in which both GTPases are activated. The prerequisite for protein targeting is the interaction of FtsY with phospholipids. However, the mechanism of FtsY regulation by phospholipids remained unclear. Here we show that the N terminus of FtsY (A domain) is natively unfolded in solution and define the complete membrane-targeting sequence. We show that the membrane-targeting sequence is highly dynamic in solution, independent of nucleotides and directly responds to the density of anionic phospholipids by a random coil-helix transition. This conformational switch is essential for tethering FtsY to membranes and activates the GTPase for its subsequent interaction with the signal recognition particle. Our results underline the dynamics of lipid-protein interactions and their importance in the regulation of protein targeting and translocation across biological membranes. PMID- 21543315 TI - Structural and thermodynamic basis for weak interactions between dihydrolipoamide dehydrogenase and subunit-binding domain of the branched-chain alpha-ketoacid dehydrogenase complex. AB - The purified mammalian branched-chain alpha-ketoacid dehydrogenase complex (BCKDC), which catalyzes the oxidative decarboxylation of branched-chain alpha keto acids, is essentially devoid of the constituent dihydrolipoamide dehydrogenase component (E3). The absence of E3 is associated with the low affinity of the subunit-binding domain of human BCKDC (hSBDb) for hE3. In this work, sequence alignments of hSBDb with the E3-binding domain (E3BD) of the mammalian pyruvate dehydrogenase complex show that hSBDb has an arginine at position 118, where E3BD features an asparagine. Substitution of Arg-118 with an asparagine increases the binding affinity of the R118N hSBDb variant (designated hSBDb*) for hE3 by nearly 2 orders of magnitude. The enthalpy of the binding reaction changes from endothermic with the wild-type hSBDb to exothermic with the hSBDb* variant. This higher affinity interaction allowed the determination of the crystal structure of the hE3/hSBDb* complex to 2.4-A resolution. The structure showed that the presence of Arg-118 poses a unique, possibly steric and/or electrostatic incompatibility that could impede E3 interactions with the wild type hSBDb. Compared with the E3/E3BD structure, the hE3/hSBDb* structure has a smaller interfacial area. Solution NMR data corroborated the interactions of hE3 with Arg-118 and Asn-118 in wild-type hSBDb and mutant hSBDb*, respectively. The NMR results also showed that the interface between hSBDb and hE3 does not change significantly from hSBDb to hSBDb*. Taken together, our results represent a starting point for explaining the long standing enigma that the E2b core of the BCKDC binds E3 far more weakly relative to other alpha-ketoacid dehydrogenase complexes. PMID- 21543316 TI - NMR solution structure of human vaccinia-related kinase 1 (VRK1) reveals the C terminal tail essential for its structural stability and autocatalytic activity. AB - Vaccinia-related kinase 1 (VRK1) is one of the mitotic kinases that play important roles in cell cycle, nuclear condensation, and transcription regulation. Kinase domain structures of two other VRK family members (VRK2 and VRK3) have been determined previously. However, the structure of VRK1, the most extensively studied and constitutively active VRK member, is yet to be characterized. Here, we present the nuclear magnetic resonance (NMR) solution structure of a catalytically active form of human VRK1 with its extended C terminal tail (residues 1-361). The NMR structure of human VRK1 reveals that the C-terminal tail orients toward the catalytic site and forms a number of interactions that are critical for structural stability and catalysis. The role of this unique C-terminal tail was further investigated by deletion mutant studies where deletion of the terminal tail resulted in a dramatic reduction in the autocatalytic activity of VRK1. NMR titration studies carried out with ATP or an ATP analog confirm that ATP/ATP analogs interact with all of the crucial residues present in important motifs of the protein kinase such as the hinge region, catalytic loop, DYG motif, and thereby suggest that the catalytic domain of VRK1 is not atypical. In addition to the conventional interactions, some of the residues present on the extended C-terminal tail also interact with the ligands. These observations also substantiate the role of the extended C-terminal tail in the biological activity of VRK1. PMID- 21543317 TI - Oxidation state-dependent protein-protein interactions in disulfide cascades. AB - Bacterial growth and pathogenicity depend on the correct formation of disulfide bonds, a process controlled by the Dsb system in the periplasm of Gram-negative bacteria. Proteins with a thioredoxin fold play a central role in this process. A general feature of thiol-disulfide exchange reactions is the need to avoid a long lived product complex between protein partners. We use a multidisciplinary approach, involving NMR, x-ray crystallography, surface plasmon resonance, mutagenesis, and in vivo experiments, to investigate the interaction between the two soluble domains of the transmembrane reductant conductor DsbD. Our results show oxidation state-dependent affinities between these two domains. These observations have implications for the interactions of the ubiquitous thioredoxin like proteins with their substrates, provide insight into the key role played by a unique redox partner with an immunoglobulin fold, and are of general importance for oxidative protein-folding pathways in all organisms. PMID- 21543318 TI - Structure and function of the RedJ protein, a thioesterase from the prodiginine biosynthetic pathway in Streptomyces coelicolor. AB - Prodiginines are a class of red-pigmented natural products with immunosuppressant, anticancer, and antimalarial activities. Recent studies on prodiginine biosynthesis in Streptomyces coelicolor have elucidated the function of many enzymes within the pathway. However, the function of RedJ, which was predicted to be an editing thioesterase based on sequence similarity, is unknown. We report here the genetic, biochemical, and structural characterization of the redJ gene product. Deletion of redJ in S. coelicolor leads to a 75% decrease in prodiginine production, demonstrating its importance for prodiginine biosynthesis. RedJ exhibits thioesterase activity with selectivity for substrates having long acyl chains and lacking a beta-carboxyl substituent. The thioesterase has 1000-fold greater catalytic efficiency with substrates linked to an acyl carrier protein (ACP) than with the corresponding CoA thioester substrates. Also, RedJ strongly discriminates against the streptomycete ACP of fatty acid biosynthesis in preference to RedQ, an ACP of the prodiginine pathway. The 2.12 A resolution crystal structure of RedJ provides insights into the molecular basis for the observed substrate selectivity. A hydrophobic pocket in the active site chamber is positioned to bind long acyl chains, as suggested by a long-chain ligand from the crystallization solution bound in this pocket. The accessibility of the active site is controlled by the position of a highly flexible entrance flap. These data combined with previous studies of prodiginine biosynthesis in S. coelicolor support a novel role for RedJ in facilitating transfer of a dodecanoyl chain from one acyl carrier protein to another en route to the key biosynthetic intermediate 2-undecylpyrrole. PMID- 21543319 TI - Structural and biochemical characterization of Staphylococcus aureus clumping factor B/ligand interactions. AB - Clumping factor B (ClfB) from Staphylococcus aureus is a bifunctional protein that binds to human cytokeratin 10 (K10) and fibrinogen (Fg). ClfB has been implicated in S. aureus colonization of nasal epithelium and is therefore a key virulence factor. People colonized with S. aureus are at an increased risk for invasive staphylococcal disease. In this study, we have determined the crystal structures of the ligand-binding region of ClfB in an apo-form and in complex with human K10 and Fg alpha-chain-derived peptides, respectively. We have determined the structures of MSCRAMM binding to two ligands with different sequences in the same site showing the versatile nature of the ligand recognition mode of microbial surface components recognizing adhesive matrix molecules. Both ligands bind ClfB by parallel beta-sheet complementation as observed for the clumping factor A.gamma-chain peptide complex. The beta-sheet complementation is shorter in the ClfB.Fg alpha-chain peptide complex. The structures show that several residues in ClfB are important for binding to both ligands, whereas others only make contact with one of the ligands. A common motif GSSGXG found in both ligands is part of the ClfB-binding site. This motif is found in many human proteins thus raising the possibility that ClfB recognizes additional ligands. PMID- 21543320 TI - First structural glimpse of CCN3 and CCN5 multifunctional signaling regulators elucidated by small angle x-ray scattering. AB - The CCN (cyr61, ctgf, nov) proteins (CCN1-6) are an important family of matricellular regulatory factors involved in internal and external cell signaling. They are central to essential biological processes such as adhesion, proliferation, angiogenesis, tumorigenesis, wound healing, and modulation of the extracellular matrix. They possess a highly conserved modular structure with four distinct modules that interact with a wide range of regulatory proteins and ligands. However, at the structural level, little is known although their biological function(s) seems to require cooperation between individual modules. Here we present for the first time structural determinants of two of the CCN family members, CCN3 and CCN5 (expressed in Escherichia coli), using small angle x-ray scattering. The results provide a description of the overall molecular shape and possible general three-dimensional modular arrangement for CCN proteins. These data unequivocally provide insight of the nature of CCN protein(s) in solution and thus important insight into their structure-function relationships. PMID- 21543321 TI - Protein-disulfide isomerase displaces the cholera toxin A1 subunit from the holotoxin without unfolding the A1 subunit. AB - Protein-disulfide isomerase (PDI) has been proposed to exhibit an "unfoldase" activity against the catalytic A1 subunit of cholera toxin (CT). Unfolding of the CTA1 subunit is thought to displace it from the CT holotoxin and to prepare it for translocation to the cytosol. To date, the unfoldase activity of PDI has not been demonstrated for any substrate other than CTA1. An alternative explanation for the putative unfoldase activity of PDI has been suggested by recent structural studies demonstrating that CTA1 will unfold spontaneously upon its separation from the holotoxin at physiological temperature. Thus, PDI may simply dislodge CTA1 from the CT holotoxin without unfolding the CTA1 subunit. To evaluate the role of PDI in CT disassembly and CTA1 unfolding, we utilized a real time assay to monitor the PDI-mediated separation of CTA1 from the CT holotoxin and directly examined the impact of PDI binding on CTA1 structure by isotope edited Fourier transform infrared spectroscopy. Our collective data demonstrate that PDI is required for disassembly of the CT holotoxin but does not unfold the CTA1 subunit, thus uncovering a new mechanism for CTA1 dissociation from its holotoxin. PMID- 21543322 TI - Genetic and biochemical characterization of a pathway for the degradation of 2 aminoethylphosphonate in Sinorhizobium meliloti 1021. AB - A variety of microorganisms have the ability to use phosphonic acids as sole sources of phosphorus. Here, a novel pathway for degradation of 2 aminoethylphosphonate in the bacterium Sinorhizobium meliloti 1021 is proposed based on the analysis of the genome sequence. Gene deletion experiments confirmed the involvement of the locus containing phnW, phnA, and phnY genes in the conversion of 2-aminoethylphosphonate to inorganic phosphate. Biochemical studies of the recombinant PhnY and PhnA proteins verified their roles as phosphonoacetaldehyde dehydrogenase and phosphonoacetate hydrolase, respectively. This pathway is likely not limited to S. meliloti as suggested by the presence of homologous gene clusters in other bacterial genomes. PMID- 21543323 TI - N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation. AB - Among human N-formyl peptide chemoattractant receptors, FPR2/ALX and FPR3 share the highest degree of amino acid identity (83%), and trigger similar cell responses upon ligand binding. Although FPR2/ALX is a promiscuous receptor, FPR3 has only one specific high affinity ligand, F2L, and a more restricted tissue/cell distribution. In this study, we showed that FPR2/ALX behaved as the prototypical receptor FPR1. The agonist-dependent phosphorylation used a hierarchical mechanism with a prominent role of Ser(329), Thr(332), and Thr(335). Phosphorylation of FPR2/ALX was essential for its desensitization but the lack of phosphorylation did not result in enhanced or sustained responses. In contrast, resting FPR3 displayed a marked level of phosphorylation, which was only slightly increased upon agonist stimulation. Another noticeable difference between the two receptors was their subcellular distribution in unstimulated cells. Although FPR2/ALX was evenly distributed at the plasma membrane FPR3 was localized in small intracellular vesicles. By swapping domains between FPR2/ALX and FPR3, we uncovered the determinants involved in the basal phosphorylation of FPR3. Experiments aimed at monitoring receptor-bound antibody uptake showed that the intracellular distribution of FPR3 resulted from a constitutive internalization that was independent of C terminus phosphorylation. Unexpectedly, exchanging residues 1 to 53, which encompass the N-terminal extracellular region and the first transmembrane domain, between FPR2/ALX and FPR3 switched localization of the receptors from the plasma membrane to intracellular vesicles and vice versa. A clathrin-independent, possibly caveolae-dependent, mechanism was involved in FPR3 constitutive internalization. The peculiar behavior of FPR3 most probably serves distinct physiological functions that remain largely unknown. PMID- 21543324 TI - Structure of the autocatalytic cysteine protease domain of potyvirus helper component proteinase. AB - The helper-component proteinase (HC-Pro) of potyvirus is involved in polyprotein processing, aphid transmission, and suppression of antiviral RNA silencing. There is no high resolution structure reported for any part of HC-Pro, hindering mechanistic understanding of its multiple functions. We have determined the crystal structure of the cysteine protease domain of HC-Pro from turnip mosaic virus at 2.0 A resolution. As a protease, HC-Pro only cleaves a Gly-Gly dipeptide at its own C terminus. The structure represents a postcleavage state in which the cleaved C terminus remains tightly bound at the active site cleft to prevent trans activity. The structure adopts a compact alpha/beta-fold, which differs from papain-like cysteine proteases and shows weak similarity to nsP2 protease from Venezuelan equine encephalitis alphavirus. Nevertheless, the catalytic cysteine and histidine residues constitute an active site that is highly similar to these in papain-like and nsP2 proteases. HC-Pro recognizes a consensus sequence YXVGG around the cleavage site between the two glycine residues. The structure delineates the sequence specificity at sites P1-P4. Structural modeling and covariation analysis across the Potyviridae family suggest a tryptophan residue accounting for the glycine specificity at site P1'. Moreover, a surface of the protease domain is conserved in potyvirus but not in other genera of the Potyviridae family, likely due to extra functional constrain. The structure provides insight into the catalysis mechanism, cis-acting mode, cleavage site specificity, and other functions of the HC-Pro protease domain. PMID- 21543325 TI - Contribution of conserved lysine residues in the alpha2-antiplasmin C terminus to plasmin binding and inhibition. AB - alpha(2)-Antiplasmin is the physiological inhibitor of plasmin and is unique in the serpin family due to N- and C-terminal extensions beyond its core domain. The C-terminal extension comprises 55 amino acids from Asn-410 to Lys-464, and the lysine residues (Lys-418, Lys-427, Lys-434, Lys-441, Lys-448, and Lys-464) within this region are important in mediating the initial interaction with kringle domains of plasmin. To understand the role of lysine residues within the C terminus of alpha(2)-antiplasmin, we systematically and sequentially mutated the C-terminal lysines, studied the effects on the rate of plasmin inhibition, and measured the binding affinity for plasmin via surface plasmon resonance. We determined that the C-terminal lysine (Lys-464) is individually most important in initiating binding to plasmin. Using two independent methods, we also showed that the conserved internal lysine residues play a major role mediating binding of the C terminus of alpha(2)-antiplasmin to kringle domains of plasmin and in accelerating the rate of interaction between alpha(2)-antiplasmin and plasmin. When the C terminus of alpha(2)-antiplasmin was removed, the binding affinity for active site-blocked plasmin remained high, suggesting additional exosite interactions between the serpin core and plasmin. PMID- 21543326 TI - Rab13-dependent trafficking of RhoA is required for directional migration and angiogenesis. AB - Angiogenesis requires concomitant remodeling of cell junctions and migration, as exemplified by recent observations of extensive endothelial cell movement along growing blood vessels. We report that a protein complex that regulates cell junctions is required for VEGF-driven directional migration and for angiogenesis in vivo. The complex consists of RhoA and Syx, a RhoA guanine exchange factor cross-linked by the Crumbs polarity protein Mupp1 to angiomotin, a phosphatidylinositol-binding protein. The Syx-associated complex translocates to the leading edge of migrating cells by membrane trafficking that requires the tight junction recycling GTPase Rab13. In turn, Rab13 associates with Grb2, targeting Syx and RhoA to Tyr(1175)-phosphorylated VEGFR2 at the leading edge. Rab13 knockdown in zebrafish impeded sprouting of intersegmental vessels and diminished the directionality of their tip cells. These results indicate that endothelial cell mobility in sprouting vessels is facilitated by shuttling the same protein complex from disassembling junctions to the leading edges of cells. PMID- 21543327 TI - Identification of dihydroceramide desaturase as a direct in vitro target for fenretinide. AB - The dihydroceramide desaturase (DES) enzyme is responsible for inserting the 4,5 trans-double bond to the sphingolipid backbone of dihydroceramide. We previously demonstrated that fenretinide (4-HPR) inhibited DES activity in SMS-KCNR neuroblastoma cells. In this study, we investigated whether 4-HPR acted directly on the enzyme in vitro. N-C8:0-d-erythro-dihydroceramide (C(8)-dhCer) was used as a substrate to study the conversion of dihydroceramide into ceramide in vitro using rat liver microsomes, and the formation of tritiated water after the addition of the tritiated substrate was detected and used to measure DES activity. NADH served as a cofactor. The apparent K(m) for C(8)-dhCer and NADH were 1.92 +/- 0.36 MUm and 43.4 +/- 6.47 MUm, respectively; and the V(max) was 3.16 +/- 0.24 and 4.11 +/- 0.18 nmol/min/g protein. Next, the effects of 4-HPR and its metabolites on DES activity were investigated. 4-HPR was found to inhibit DES in a dose-dependent manner. At 20 min, the inhibition was competitive; however, longer incubation times demonstrated the inhibition to be irreversible. Among the major metabolites of 4-HPR, 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo 4-HPR) showed the highest inhibitory effect with substrate concentration of 0.5 MUm, with an IC(50) of 1.68 MUm as compared with an IC(50) of 2.32 MUm for 4-HPR. N-(4-Methoxyphenyl)retinamide (4-MPR) and 4-Oxo-N-(4-methoxyphenyl)retinamide (4 oxo-4-MPR) had minimal effects on DES activity. A known competitive inhibitor of DES, C(8)-cyclopropenylceramide was used as a positive control. These studies define for the first time a direct in vitro target for 4-HPR and suggest that inhibitors of DES may be used as therapeutic interventions to regulate ceramide desaturation and consequent function. PMID- 21543328 TI - Teashirt-3, a novel regulator of muscle differentiation, associates with BRG1 associated factor 57 (BAF57) to inhibit myogenin gene expression. AB - In adult muscles and under normal physiological conditions, satellite cells are found in a quiescent state but can be induced to enter the cell cycle by signals resulting from exercise, injury-induced muscle regeneration, or specific disease states. Once activated, satellite cells proliferate, self-renew, and differentiate to form myofibers. In the present study, we found that the zinc finger-containing factor Teashirt-3 (TSHZ3) was expressed in quiescent satellite cells of adult mouse skeletal muscles. We showed that following treatment with cardiotoxin TSHZ3 was strongly expressed in satellite cells of regenerating muscles. Moreover, immunohistochemical analysis indicated that TSHZ3 was expressed in both quiescent and activated satellite cells on intact myofibers in culture. TSHZ3 expression was maintained in myoblasts but disappeared with myotube formation. In C2C12 myoblasts, we showed that overexpression of Tshz3 impaired myogenic differentiation and promoted the down-regulation of myogenin (Myog) and up-regulation of paired-box factor 7 (Pax7). Moreover, knockdown experiments revealed a selective effect of Tshz3 on Myog regulation, and transcriptional reporter experiments indicated that TSHZ3 repressed Myog promoter. We identified the BRG1-associated factor 57 (BAF57), a subunit of the SWI/SNF complex, as a partner of TSHZ3. We showed that TSHZ3 cooperated with BAF57 to repress MYOD-dependent Myog expression. These results suggest a novel mechanism for transcriptional repression by TSHZ3 in which TSHZ3 and BAF57 cooperate to modulate MyoD activity on the Myog promoter to regulate skeletal muscle differentiation. PMID- 21543329 TI - Crystal structure of the cytoplasmic phosphatase and tensin homolog (PTEN)-like region of Ciona intestinalis voltage-sensing phosphatase provides insight into substrate specificity and redox regulation of the phosphoinositide phosphatase activity. AB - Ciona intestinalis voltage-sensing phosphatase (Ci-VSP) has a transmembrane voltage sensor domain and a cytoplasmic region sharing similarity to the phosphatase and tensin homolog (PTEN). It dephosphorylates phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate upon membrane depolarization. The cytoplasmic region is composed of a phosphatase domain and a putative membrane interaction domain, C2. Here we determined the crystal structures of the Ci-VSP cytoplasmic region in three distinct constructs, wild type (248-576), wild-type (236-576), and G365A mutant (248-576). The crystal structure of WT-236 and G365A-248 had the disulfide bond between the catalytic residue Cys-363 and the adjacent residue Cys-310. On the other hand, the disulfide bond was not present in the crystal structure of WT-248. These suggest the possibility that Ci-VSP is regulated by reactive oxygen species as found in PTEN. These structures also revealed that the conformation of the TI loop in the active site of the Ci-VSP cytoplasmic region was distinct from the corresponding region of PTEN; Ci-VSP has glutamic acid (Glu-411) in the TI loop, orienting toward the center of active site pocket. Mutation of Glu-411 led to acquirement of increased activity toward phosphatidylinositol 3,5-bisphosphate, suggesting that this site is required for determining substrate specificity. Our results provide the basic information of the enzymatic mechanism of Ci-VSP. PMID- 21543330 TI - Atomic force microscopy of Connexin40 gap junction hemichannels reveals calcium dependent three-dimensional molecular topography and open-closed conformations of both the extracellular and cytoplasmic faces. AB - Atomic force microscopy was used to study the three-dimensional molecular topography and calcium-sensitive conformational changes of Connexin40 hemichannels (connexons) reconstituted in 1,2-dioeloyl-sn-glycero-3 phosphatidylcholine lipid bilayers. Two classes of objects were observed that differed in their protrusion heights above the bilayer (2.6 versus 4.2 nm). Comparison to reconstituted connexons containing Connexin40 truncated to eliminate most of its C-terminal cytoplasmic domain showed that the two height classes corresponded to the shorter extracellular and taller cytoplasmic aspects of the hemichannels and that the C-terminal tail of Connexin40 contributes ~1.6 nm in thickness. Hemichannels imaged in solutions containing < 10 MUm Ca(2+) showed 3.1-3.2 nm depressions (openings) in 30% of the cytoplasmic faces and 65% of the extracellular faces, and high-resolution three-dimensional topography of extracellular or cytoplasmic aspects of some connexons was observed. After addition of 3.6 mm Ca(2+), > 75% of the connexons in either orientation adopted closed conformations. In contrast, hemichannels imaged in the presence of 0.1 mm EDTA showed large (5.6- to 5.8-nm diameter) openings in nearly all hemichannels regardless of orientation, and detailed topography was visible in many connexons. Real-time imaging following the addition of 3.6 mm Ca(2+) showed transitions of both extracellular and cytoplasmic orientations from "open" into "closed" conformations within several minutes. These studies provide the first high resolution topographic information regarding a connexin with a large cytoplasmic domain and suggest that the extramembranous portions of Connexin40 contribute to a channel entrance that is relaxed by chelation of residual divalent cations. PMID- 21543331 TI - Inactivation kinetics of a new target of beta-lactam antibiotics. AB - Peptidoglycan is predominantly cross-linked by serine DD-transpeptidases in most bacterial species. The enzymes are the essential targets of beta-lactam antibiotics. However, unrelated cysteine LD-transpeptidases have been recently recognized as a predominant mode of peptidoglycan cross-linking in Mycobacterium tuberculosis and as a bypass mechanism conferring resistance to all beta-lactams, except carbapenems such as imipenem, in Enterococcus faecium. Investigation of the mechanism of inhibition of this new beta-lactam target showed that acylation of the E. faecium enzyme (Ldt(fm)) by imipenem is irreversible. Using fluorescence kinetics, an original approach was developed to independently determine the catalytic constants for imipenem binding (k(1) = 0.061 MUM(-1) min( 1)) and acylation (k(inact) = 4.5 min(-1)). The binding step was limiting at the minimal drug concentration required for bacterial growth inhibition. The Michaelis complex was committed to acylation because its dissociation was negligible. The emergence of imipenem resistance involved substitutions in Ldt(fm) that reduced the rate of formation of the non-covalent complex but only marginally affected the efficiency of the acylation step. The methods described in this study will facilitate development of new carbapenems active on extensively resistant M. tuberculosis. PMID- 21543332 TI - Idas, a novel phylogenetically conserved geminin-related protein, binds to geminin and is required for cell cycle progression. AB - Development and homeostasis of multicellular organisms relies on an intricate balance between cell proliferation and differentiation. Geminin regulates the cell cycle by directly binding and inhibiting the DNA replication licensing factor Cdt1. Geminin also interacts with transcriptional regulators of differentiation and chromatin remodelling factors, and its balanced interactions are implicated in proliferation-differentiation decisions during development. Here, we describe Idas (Idas being a cousin of the Gemini in Ancient Greek Mythology), a previously uncharacterised coiled-coil protein related to Geminin. We show that human Idas localizes to the nucleus, forms a complex with Geminin both in cells and in vitro through coiled-coil mediated interactions, and can change Geminin subcellular localization. Idas does not associate with Cdt1 and prevents Geminin from binding to Cdt1 in vitro. Idas depletion from cells affects cell cycle progression; cells accumulate in S phase and are unable to efficiently progress to mitosis. Idas protein levels decrease in anaphase, whereas its overexpression causes mitotic defects. During development, we show that Idas exhibits high level expression in the choroid plexus and the cortical hem of the mouse telencephalon. Our data highlight Idas as a novel Geminin binding partner, implicated in cell cycle progression, and a putative regulator of proliferation differentiation decisions during development. PMID- 21543333 TI - Mind molecules. AB - Scientific styles vary tremendously. For me, research is largely about the unfettered pursuit of novel ideas and experiments that can test multiple ideas in a day, not a year, an approach that I learned from my mentor Julius "Julie" Axelrod. This focus on creative conceptualizations has been my metier since working in the summers during medical school at the National Institutes of Health, during my two years in the Axelrod laboratory, and throughout my forty five years at Johns Hopkins University School of Medicine. Equally important has been the "high" that emerges from brainstorming with my students. Nothing can compare with the eureka moments when, together, we sense new insights and, better yet, when high-risk, high-payoff experiments succeed. Although I have studied many different questions over the years, a common theme emerges: simple biochemical approaches to understanding molecular messengers, usually small molecules. Equally important has been identifying, purifying, and cloning the messengers' relevant biosynthetic, degradative, or target proteins, at all times seeking potential therapeutic relevance in the form of drugs. In the interests of brevity, this Reflections article is highly selective, and, with a few exceptions, literature citations are only of findings of our laboratory that illustrate notable themes. PMID- 21543334 TI - Beta-arrestin-1 protein represses diet-induced obesity. AB - Diet-related obesity is a major metabolic disorder. Excessive fat mass is associated with type 2 diabetes, hepatic steatosis, and arteriosclerosis. Dysregulation of lipid metabolism and adipose tissue function contributes to diet induced obesity. Here, we report that beta-arrestin-1 knock-out mice are susceptible to diet-induced obesity. Knock-out of the gene encoding beta-arrestin 1 caused increased fat mass accumulation and decreased whole-body insulin sensitivity in mice fed a high-fat diet. In beta-arrestin-1 knock-out mice, we observed disrupted food intake and energy expenditure and increased macrophage infiltration in white adipose tissue. At the molecular level, beta-arrestin-1 deficiency affected the expression of many lipid metabolic genes and inflammatory genes in adipose tissue. Consistently, transgenic overexpression of beta-arrestin 1 repressed diet-induced obesity and improved glucose tolerance and systemic insulin sensitivity. Thus, our findings reveal that beta-arrestin-1 plays a role in metabolism regulation. PMID- 21543335 TI - Modulation of the transactivation function and stability of Kruppel-like zinc finger protein Gli-similar 3 (Glis3) by Suppressor of Fused. AB - Glis3 is a member of the Glis subfamily of Kruppel-like zinc finger transcription factors. Recently, Glis3 has been linked to both type I and type II diabetes and shown to positively regulate insulin gene expression. In this study, we have identified a region within the N terminus of Glis3 that shares high levels of homology with the Cubitus interruptus (Ci)/Gli family of proteins. We demonstrated that Glis3 interacts with Suppressor of Fused (SUFU), which involves a VYGHF motif located within this conserved region. We further showed that SUFU is able to inhibit the activation of the insulin promoter by Glis3 but not the activation by a Glis3 mutant deficient in its ability to bind SUFU, suggesting that the inhibitory effect is dependent on the interaction between the two proteins. Exogenous SUFU did not affect the nuclear localization of Glis3; however, Glis3 promoted the nuclear accumulation of SUFU. Additionally, we demonstrated that SUFU stabilizes Glis3 in part by antagonizing the Glis3 association with a Cullin 3-based E3 ubiquitin ligase that promotes the ubiquitination and degradation of Glis3. This is the first reported instance of Glis3 interacting with SUFU and suggests a novel role for SUFU in the modulation of Glis3 signaling. Given the critical role of Glis3 in pancreatic beta-cell generation and maintenance, the elevated Glis3 expression in several cancers, and the established role of SUFU as a tumor suppressor, these data provide further insight into Glis3 regulation and its function in development and disease. PMID- 21543336 TI - The ectodomain of the Toll-like receptor 4 prevents constitutive receptor activation. AB - Toll-like receptor 4 (TLR4) is involved in activation of the innate immune response in a large number of different diseases. Despite numerous studies, the role of separate domains of TLR4 in the regulation of receptor activation is poorly understood. Replacement of the TLR4 ectodomain with LPS-binding proteins MD-2 or CD14 resulted in a robust ligand-independent constitutive activation comparable with the maximal stimulation of the receptor with LPS. The same effect was achieved by the replacement of the ectodomain with a monomeric fluorescent protein or a 24-kDa gyrase B fragment. This demonstrates an intrinsic dimerization propensity of the transmembrane and cytoplasmic domains of TLR4 and reveals a previously unknown function of the ectodomain in inhibiting spontaneous receptor dimerization. Constitutive activation was abolished by the replacement of the ectodomain by a bulkier protein ovalbumin. N-terminal deletion variants of TLR4 revealed that the smallest segment of the ectodomain that already prevents constitutive activity comprises only 90 residues (542 to 631) of the total 608 residues. We conclude that TLR4 represents a receptor with a low threshold of activation that can be rapidly activated by the release of inhibition exerted by its ectodomain. This is important for the sensitivity of TLR4 to activation by different agonists. The TLR4 ectodomain has multiple roles in enabling ligand regulated activation, providing proper localization while serving as an inhibitor to prevent spontaneous, ligand-independent dimerization. PMID- 21543337 TI - Regulation of Src family kinases involved in T cell receptor signaling by protein tyrosine phosphatase CD148. AB - CD148 is a receptor-like protein-tyrosine phosphatase known to inhibit transduction of mitogenic signals in non-hematopoietic cells. Similarly, in the hematopoietic lineage, CD148 inhibited signal transduction downstream of T cell receptor. However, it also augmented immunoreceptor signaling in B cells and macrophages via dephosphorylating C-terminal tyrosine of Src family kinases (SFK). Accordingly, endogenous CD148 compensated for the loss of the main SFK activator CD45 in murine B cells and macrophages but not in T cells. Hypothetical explanations for the difference between T cells and other leukocyte lineages include the inability of CD148 to dephosphorylate a specific set of SFKs involved in T cell activation or the lack of CD148 expression during critical stages of T cell development. Here we describe striking differences in CD148 expression between human and murine thymocyte subsets, the only unifying feature being the absence of CD148 during the positive selection when the major developmental block occurs under CD45 deficiency. Moreover, we demonstrate that similar to CD45, CD148 has both activating and inhibitory effects on the SFKs involved in TCR signaling. However, in the absence of CD45, activating effects prevail, resulting in functional complementation of CD45 deficiency in human T cell lines. Importantly, this is independent of the tyrosines in the CD148 C-terminal tail, contradicting the recently proposed phosphotyrosine displacement model as a mechanism of SFK activation by CD148. Collectively, our data suggest that differential effects of CD148 in T cells and other leukocyte subsets cannot be explained by the CD148 inability to activate T cell SFKs but rather by its dual inhibitory/activatory function and specific expression pattern. PMID- 21543338 TI - The small GTPase Cdc42 is necessary for primary ciliogenesis in renal tubular epithelial cells. AB - Primary cilia are found on many epithelial cell types, including renal tubular epithelial cells, where they participate in flow sensing. Disruption of cilia function has been linked to the pathogenesis of polycystic kidney disease. We demonstrated previously that the exocyst, a highly conserved eight-protein membrane trafficking complex, localizes to primary cilia of renal tubular epithelial cells, is required for ciliogenesis, biochemically and genetically interacts with polycystin-2 (the protein product of the polycystic kidney disease 2 gene), and, when disrupted, results in MAPK pathway activation both in vitro and in vivo. The small GTPase Cdc42 is a candidate for regulation of the exocyst at the primary cilium. Here, we demonstrate that Cdc42 biochemically interacts with Sec10, a crucial component of the exocyst complex, and that Cdc42 colocalizes with Sec10 at the primary cilium. Expression of dominant negative Cdc42 and shRNA-mediated knockdown of both Cdc42 and Tuba, a Cdc42 guanine nucleotide exchange factor, inhibit ciliogenesis in Madin-Darby canine kidney cells. Furthermore, exocyst Sec8 and polycystin-2 no longer localize to primary cilia or the ciliary region following Cdc42 and Tuba knockdown. We also show that Sec10 directly interacts with Par6, a member of the Par complex that itself directly interacts with Cdc42. Finally, we show that Cdc42 knockdown results in activation of the MAPK pathway, something observed in cells with dysfunctional primary cilia. These data support a model in which Cdc42 localizes the exocyst to the primary cilium, whereupon the exocyst then targets and docks vesicles carrying proteins necessary for ciliogenesis. PMID- 21543339 TI - Methods and strategies for gene structure curation in WormBase. AB - The Caenorhabditis elegans genome sequence was published over a decade ago; this was the first published genome of a multi-cellular organism and now the WormBase project has had a decade of experience in curating this genome's sequence and gene structures. In one of its roles as a central repository for nematode biology, WormBase continues to refine the gene structure annotations using sequence similarity and other computational methods, as well as information from the literature- and community-submitted annotations. We describe the various methods of gene structure curation that have been tried by WormBase and the problems associated with each of them. We also describe the current strategy for gene structure curation, and introduce the WormBase 'curation tool', which integrates different data sources in order to identify new and correct gene structures. Database URL: http://www.wormbase.org/. PMID- 21543340 TI - Aspirin and familial adenomatous polyposis: coming full circle. AB - This perspective discusses the clinical trial reported by Burn and colleagues in this issue of the journal (beginning on page 655), which assessed aspirin and resistant starch for the prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP). The findings are examined in the context of previous clinical trials of aspirin in patients with sporadic adenomas and of sulindac or celecoxib in patients with FAP. This newly reported work raises important considerations of a role for aspirin in the clinical management of FAP patients and adds to considerations of a role for aspirin in the chemoprevention of colorectal cancer among broader populations. PMID- 21543341 TI - Back to the future: mechanism-based, mutation-specific combination chemoprevention with a synthetic lethality approach. AB - There is an increasing recognition that the mutations accompanying carcinogenesis may provide a window of therapeutic advantage designated synthetic lethality, an example of which is reported in this issue of the journal by Huang and colleagues (beginning on page 666). First discovered and studied in yeast, synthetic lethality has basic principles that have encouraged its development for treatment and now prevention in animal models of human cancer, especially malignancies refractory to standard approaches. The pros and cons of this approach and challenges in implementing it clinically are discussed. PMID- 21543344 TI - Lung-cancer chemoprevention by induction of synthetic lethality in mutant KRAS premalignant cells in vitro and in vivo. AB - Lung cancer is the leading cause of cancer death in both men and women in the United States, with a low 5-year survival rate despite improved treatment strategies. These data underscore the great need for effective chemoprevention of this cancer. Mutations and activation of KRAS occur frequently in, and are thought to be a primary driver of the development of, non-small cell lung cancers (NSCLC) of the adenocarcinoma subtype. In this study, we developed a new approach for the chemoprevention of NSCLC involving specific targeting of apoptosis in mutant KRAS cells. This approach is based on a synthetic lethal interaction among TNF-related apoptosis-inducing ligand (TRAIL), the second mitochondria-derived activator of caspase Smac/DIABLO (Smac), and KRAS. Mutational activation of KRAS modulated the expression of TRAIL receptors by upregulating death receptors and downregulating decoy receptors. Furthermore, oncogenic KRAS repressed cellular FADD-like interleukin 1beta-converting enzyme (FLICE)-like inhibitory protein (c FLIP) expression through activation of Erk/mitogen-activated protein kinase (MAPK)-mediated activation of c-Myc. Smac overcame KRAS-induced cell-survival signaling by antagonizing X-linked inhibitor of apoptosis protein (XIAP). Therefore, the combination of TRAIL and a small molecule mimic of Smac induced apoptosis specifically in mutant KRAS cells without harming normal cells. We further showed that short-term, intermittent in vivo treatment with TRAIL and Smac mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of KRAS-induced lung cancer. These results reflect the potential benefit of a selective therapeutic approach for the chemoprevention of NSCLC. PMID- 21543343 TI - A randomized placebo-controlled prevention trial of aspirin and/or resistant starch in young people with familial adenomatous polyposis. AB - Evidence supporting aspirin and resistant starch (RS) for colorectal cancer prevention comes from epidemiologic and laboratory studies (aspirin and RS) and randomized controlled clinical trials (aspirin). Familial adenomatous polyposis (FAP) strikes young people and, untreated, confers virtually a 100% risk of colorectal cancer and early death. We conducted an international, multicenter, randomized, placebo-controlled trial of aspirin (600 mg/d) and/or RS (30 g/d) for from 1 to 12 years to prevent disease progression in FAP patients from 10 to 21 years of age. In a 2 * 2 factorial design, patients were randomly assigned to the following four study arms: aspirin plus RS placebo; RS plus aspirin placebo; aspirin plus RS; RS placebo plus aspirin placebo; they were followed with standard annual clinical examinations including endoscopy. The primary endpoint was polyp number in the rectum and sigmoid colon (at the end of intervention), and the major secondary endpoint was size of the largest polyp. A total of 206 randomized FAP patients commenced intervention, of whom 133 had at least one follow-up endoscopy and were therefore included in the primary analysis. Neither intervention significantly reduced polyp count in the rectum and sigmoid colon: aspirin relative risk = 0.77 (95% CI, 0.54-1.10; versus nonaspirin arms); RS relative risk = 1.05 (95% CI, 0.73-1.49; versus non-RS arms). There was a trend toward a smaller size of largest polyp in patients treated with aspirin versus nonaspirin--mean 3.8 mm versus 5.5 mm for patients treated 1 or more years (adjusted P = 0.09) and mean 3.0 mm versus 6.0 mm for patients treated more than 1 year (P = 0.02); there were similar weaker trends with RS versus non-RS. Exploratory translational endpoints included crypt length (which was significantly shorter in normal-appearing mucosa in the RS group over time) and laboratory measures of proliferation (including Ki67). This clinical trial is the largest ever conducted in the setting of FAP and found a trend of reduced polyp load (number and size) with 600 mg of aspirin daily. RS had no clinical effect on adenomas. PMID- 21543342 TI - Mitochondrial subversion in cancer. AB - Mitochondria control essential cellular activities including generation of ATP via oxidative phosphorylation. Mitochondrial DNA (mtDNA) mutations in the regulatory D-loop region and somatic mtDNA mutations are common in primary human cancers. The biological impact of a given mutation may vary, depending on the nature of the mutation and the proportion of mutant mtDNAs carried by the cell. Identification of mtDNA mutations in precancerous lesions supports their early contribution to cell transformation and cancer progression. Introduction of mtDNA mutations in transformed cells has been associated with increased ROS production and tumor growth. Studies reveal that increased and altered mtDNA plays a role in the development of cancer but further work is required to establish the functional significance of specific mitochondrial mutations in cancer and disease progression. This review offers some insight into the extent of mtDNA mutations, their functional consequences in tumorigenesis, mitochondrial therapeutics, and future clinical application. PMID- 21543345 TI - Epigenetic alteration of DNA in mucosal wash fluid predicts invasiveness of colorectal tumors. AB - Although conventional colonoscopy is considered the gold standard for detecting colorectal tumors, accurate staging is often difficult because advanced histology may be present in small colorectal lesions. We collected DNA present in mucosal wash fluid from patients undergoing colonoscopy and then assessed the methylation levels of four genes frequently methylated in colorectal cancers to detect invasive tumors. We found that methylation levels in wash fluid were significantly higher in patients with invasive than those with noninvasive tumors. Cytologic and K-ras mutation analyses suggested that mucosal wash fluid from invasive tumors contained greater numbers of tumor cells than wash fluid from noninvasive tumors. Among the four genes, levels of mir-34b/c methylation had the greatest correlation with the invasion and showed the largest area under the receiver operating characteristic curve (AUC = 0.796). Using cutoff points of mir-34b/c methylation determined by efficiency considerations, the sensitivity/specificity were 0.861/0.657 for the 13.0% (high sensitivity) and 0.765/0.833 for the 17.8% (well-balanced) cutoffs. In the validation test set, the AUC was also very high (0.915), the sensitivity/specificity were 0.870/0.875 for 13.0% and 0.565/0.958 for 17.8%. Using the diagnostic tree constructed by an objective algorithm, the diagnostic accuracy of the invasiveness of colorectal cancer was 91.3% for the training set and 85.1% for the test set. Our results suggest that analysis of the methylation of DNA in mucosal wash fluid may be a good molecular marker for predicting the invasiveness of colorectal tumors. PMID- 21543346 TI - Injection treatments for patellar tendinopathy. AB - OBJECTIVE: Injection treatments are increasingly used as treatment for patellar tendinopathy. The aim of this systematic review is to describe the different injection treatments, their rationales and the effectiveness of treating patellar tendinopathy. METHODS: A computerised search of the Medline, Embase, CINAHL and Web of Knowledge databases was conducted on 1 May 2010 to identify studies on injection treatments for patellar tendinopathy. RESULTS: 11 articles on seven different injection treatments (dry needling, autologous blood, high-volume, platelet-rich plasma, sclerosis, steroids and aprotinin injections) were found: 4 randomised controlled trials (RCTs), 1 non-RCT, 4 prospective cohort studies and 2 retrospective cohort studies. All studies reported positive results. The Delphi scores of the four RCTs ranged from 5 to 8 out of 9. Different and sometimes contradictory rationales were used for the injection treatments. CONCLUSION: All seven different injection treatments seem promising for treating patellar tendinopathy. Unlike the other injection treatments, steroid treatment often shows a relapse of symptoms in the long term. Results should be interpreted with caution as the number of studies is low, few high-quality studies have been conducted and the studies are hard to compare due to different methodology. More high-quality studies using the same cross-cultural reliable and valid outcome measure are needed, as well as further research into the pathophysiology. Finally, some implications are provided for clinicians who want to use injection treatments as a part of their treatment for patellar tendinopathy, distinguishing between reactive and degenerative phase of patellar tendinopathy. PMID- 21543348 TI - Distribution of radiocesium and stable elements within a pine tree. AB - Distributions of (137)Cs and stable elements in different parts of a pine tree collected in Chernobyl-contaminated area in Belarus were determined. Samples include annual tree rings of wood, branches and needles with different ages. The concentrations of (137)Cs and stable Cs in annual tree rings were the highest in cambium and decreased sharply towards inside. The youngest needles and branches contained higher (137)Cs and stable Cs than older ones. The concentration of (137)Cs being highest in growing parts suggests the highest radiation dose to the radiation-sensitive parts of tree. Distribution patterns of stable elements in pine tree differ among the elements. Distributions similar to those of Cs were observed for K and Rb, suggesting that alkaline metals tend to be translocated to young growing parts of pine tree. A similar distribution was also observed for phosphorus. Distributions of alkaline earth metals and several heavy metals were different from those of alkaline metals. PMID- 21543347 TI - Studies on possibility for alleviation of lifestyle diseases by low-dose irradiation or radon inhalation. AB - Our previous studies showed the possibility that activation of the antioxidative function alleviates various oxidative damages, which are related to lifestyle diseases. Results showed that, low-dose X-ray irradiation activated superoxide dismutase and inhibits oedema following ischaemia-reperfusion. To alleviate ischaemia-reperfusion injury with transplantation, the changes of the antioxidative function in liver graft using low-dose X-ray irradiation immediately after exenteration were examined. Results showed that liver grafts activate the antioxidative function as a result of irradiation. In addition, radon inhalation enhances the antioxidative function in some organs, and alleviates alcohol-induced oxidative damage of mouse liver. Moreover, in order to determine the most effective condition of radon inhalation, mice inhaled radon before or after carbon tetrachloride (CCl(4)) administration. Results showed that radon inhalation alleviates CCl(4)-induced hepatopathy, especially prior inhalation. It is highly possible that adequate activation of antioxidative functions induced by low-dose irradiation can contribute to preventing or reducing oxidative damages, which are related to lifestyle diseases. PMID- 21543349 TI - Nationwide survey on pediatric CT among children of public health and school nurses to examine a possibility for a follow-up study on radiation effects. AB - A nationwide survey was conducted in Japan on paediatric CT among children of public health and school nurses to examine a possibility for a follow-up study on radiation effects. A survey questionnaire was sent out to 3173 public primary and junior high schools and 317 public health centres during October to December in 2009. According to the collected responses, 410 (16.2 %) children received the CT scans and the total number of CT scans was 585. Most of respondents expressed a high interest in radiation health effects and an intent to participate in the epidemiological study that will follow-up the health conditions of children. This study provides information to discuss the feasibility of the epidemiological study on health effects in children who received CT scans. PMID- 21543350 TI - The rising tide of liver Cirrhosis mortality in the UK: can its halt be predicted? AB - AIM: To explore whether it is possible to predict future United Kingdom (UK) death rate of liver cirrhosis based on birth cohort models. METHOD: Routinely available mortality data were plotted graphically to display the trends in cirrhosis mortality by birth cohort in several countries. Data for Italy, France, Portugal, USA, Canada, Scotland and England & Wales were plotted by birth cohort. RESULTS: The current increase in cirrhosis mortality in the UK countries is being driven by a birth cohort effect. Later birth cohorts have much higher death rates than preceding ones. This pattern was seen in Western European and North American countries, which had also experienced increases in liver cirrhosis mortality. However, after the increases, those countries had sudden and persistent falls in death rates. For each country, the dramatic reversal of death rates occurred at a single calendar period and in every age group simultaneously. CONCLUSION: Prediction of future death rates using information from previous cohorts is not possible due to the occurrence of sudden reversals in death rates. The sudden fall in the death rates of several birth cohorts suggests that reversing the current UK trend of rising liver cirrhosis deaths is possible. PMID- 21543351 TI - Adjuvant properties of a biocompatible thermo-responsive polymer of N isopropylacrylamide in autoimmunity and arthritis. AB - To evaluate the thermo-responsive poly(N-isopropylacrylamide) (PNiPAAm) polymer as an adjuvant, we synthesized PNiPAAm through free radical polymerization and characterized it both in vitro and in vivo. The polymer when mixed with collagen type II (CII) induced antigen-specific autoimmunity and arthritis. Mice immunized with PNiPAAm-CII developed significant levels of CII-specific IgG response comprising major IgG subclasses. Antigen-specific cellular recall response was also enhanced in these mice, while negligible level of IFN-gamma was detected in splenocyte cultures, in vitro. PNiPAAm-CII-immunized arthritic mouse paws showed massive infiltration of immune cells and extensive damage to cartilage and bone. As determined by immunostaining, most of the CII protein retained its native configuration after injecting it with PNiPAAm in naive mice. Physical adsorption of CII and the high-molecular-weight form of moderately hydrophobic PNiPAAm induced a significant anti-CII antibody response. Similar to CII, mice immunized with PNiPAAm and ovalbumin (PNiPAAm-Ova) induced significant anti-ovalbumin antibody response. Comparable levels of serum IFN-gamma, IL-1beta and IL-17 were observed in ovalbumin-immunized mice with complete Freund, incomplete Freund (CFA and IFA) or PNiPAAm adjuvants. However, serum IL-4 levels were significantly higher in PNiPAAm-Ova and CFA-Ova groups compared with the IFA-Ova group. Thus, we show for the first time, biocompatible and biodegradable thermo-responsive PNiPAAm can be used as an adjuvant in several immunological applications as well as in better understanding of the autoimmune responses against self-proteins. PMID- 21543352 TI - Quantifying selection and diversity in viruses by entropy methods, with application to the haemagglutinin of H3N2 influenza. AB - Many viruses evolve rapidly. For example, haemagglutinin (HA) of the H3N2 influenza A virus evolves to escape antibody binding. This evolution of the H3N2 virus means that people who have previously been exposed to an influenza strain may be infected by a newly emerged virus. In this paper, we use Shannon entropy and relative entropy to measure the diversity and selection pressure by an antibody in each amino acid site of H3 HA between the 1992-1993 season and the 2009-2010 season. Shannon entropy and relative entropy are two independent state variables that we use to characterize H3N2 evolution. The entropy method estimates future H3N2 evolution and migration using currently available H3 HA sequences. First, we show that the rate of evolution increases with the virus diversity in the current season. The Shannon entropy of the sequence in the current season predicts relative entropy between sequences in the current season and those in the next season. Second, a global migration pattern of H3N2 is assembled by comparing the relative entropy flows of sequences sampled in China, Japan, the USA and Europe. We verify this entropy method by describing two aspects of historical H3N2 evolution. First, we identify 54 amino acid sites in HA that have evolved in the past to evade the immune system. Second, the entropy method shows that epitopes A and B on the top of HA evolve most vigorously to escape antibody binding. Our work provides a novel entropy-based method to predict and quantify future H3N2 evolution and to describe the evolutionary history of H3N2. PMID- 21543353 TI - A dimensionless number for understanding the evolutionary dynamics of antigenically variable RNA viruses. AB - Antigenically variable RNA viruses are significant contributors to the burden of infectious disease worldwide. One reason for their ubiquity is their ability to escape herd immunity through rapid antigenic evolution and thereby to reinfect previously infected hosts. However, the ways in which these viruses evolve antigenically are highly diverse. Some have only limited diversity in the long run, with every emergence of a new antigenic variant coupled with a replacement of the older variant. Other viruses rapidly accumulate antigenic diversity over time. Others still exhibit dynamics that can be considered evolutionary intermediates between these two extremes. Here, we present a theoretical framework that aims to understand these differences in evolutionary patterns by considering a virus's epidemiological dynamics in a given host population. Our framework, based on a dimensionless number, probabilistically anticipates patterns of viral antigenic diversification and thereby quantifies a virus's evolutionary potential. It is therefore similar in spirit to the basic reproduction number, the well-known dimensionless number which quantifies a pathogen's reproductive potential. We further outline how our theoretical framework can be applied to empirical viral systems, using influenza A/H3N2 as a case study. We end with predictions of our framework and work that remains to be done to further integrate viral evolutionary dynamics with disease ecology. PMID- 21543354 TI - Intercontinental dispersal of giant thermophilic ants across the Arctic during early Eocene hyperthermals. AB - Early Eocene land bridges allowed numerous plant and animal species to cross between Europe and North America via the Arctic. While many species suited to prevailing cool Arctic climates would have been able to cross throughout much of this period, others would have found dispersal opportunities only during limited intervals when their requirements for higher temperatures were met. Here, we present Titanomyrma lubei gen. et sp. nov. from Wyoming, USA, a new giant (greater than 5 cm long) formiciine ant from the early Eocene (approx. 49.5 Ma) Green River Formation. We show that the extinct ant subfamily Formiciinae is only known from localities with an estimated mean annual temperature of about 20 degrees C or greater, consistent with the tropical ranges of almost all of the largest living ant species. This is, to our knowledge, the first known formiciine of gigantic size in the Western Hemisphere and the first reported cross-Arctic dispersal by a thermophilic insect group. This implies intercontinental migration during one or more brief high-temperature episodes (hyperthermals) sometime between the latest Palaeocene establishment of intercontinental land connections and the presence of giant formiciines in Europe and North America by the early middle Eocene. PMID- 21543355 TI - The perception of self-agency in chimpanzees (Pan troglodytes). AB - The ability to distinguish actions and effects caused by oneself from events occurring in the external environment is a fundamental aspect of human cognition. Underlying such distinctions, self-monitoring processes are often assumed, in which predicted events accompanied by one's own volitional action are compared with actual events observed in the external environment. Although many studies have examined the absence or presence of a certain type of self-recognition (i.e. mirror self-recognition) in non-human animals, the underlying cognitive mechanisms remain unclear. Here, we provide, to our knowledge, the first behavioural evidence that chimpanzees can perform self/other distinction for external events on the basis of self-monitoring processes. Three chimpanzees were presented with two cursors on a computer display. One cursor was manipulated by a chimpanzee using a trackball, while the other displayed motion that had been produced previously by the same chimpanzee. Chimpanzees successfully identified which cursor they were able to control. A follow-up experiment revealed that their performance could not be explained by simple associative responses. A further experiment with one chimpanzee showed that the monitoring process occurred in both temporal and spatial dimensions. These findings indicate that chimpanzees and humans share the fundamental cognitive processes underlying the sense of being an independent agent. PMID- 21543356 TI - Postglacial migration supplements climate in determining plant species ranges in Europe. AB - The influence of dispersal limitation on species ranges remains controversial. Considering the dramatic impacts of the last glaciation in Europe, species might not have tracked climate changes through time and, as a consequence, their present-day ranges might be in disequilibrium with current climate. For 1016 European plant species, we assessed the relative importance of current climate and limited postglacial migration in determining species ranges using regression modelling and explanatory variables representing climate, and a novel species specific hind-casting-based measure of accessibility to postglacial colonization. Climate was important for all species, while postglacial colonization also constrained the ranges of more than 50 per cent of the species. On average, climate explained five times more variation in species ranges than accessibility, but accessibility was the strongest determinant for one-sixth of the species. Accessibility was particularly important for species with limited long-distance dispersal ability, with southern glacial ranges, seed plants compared with ferns, and small-range species in southern Europe. In addition, accessibility explained one-third of the variation in species' disequilibrium with climate as measured by the realized/potential range size ratio computed with niche modelling. In conclusion, we show that although climate is the dominant broad-scale determinant of European plant species ranges, constrained dispersal plays an important supplementary role. PMID- 21543357 TI - Volumetric imaging of shark tail hydrodynamics reveals a three-dimensional dual ring vortex wake structure. AB - Understanding how moving organisms generate locomotor forces is fundamental to the analysis of aerodynamic and hydrodynamic flow patterns that are generated during body and appendage oscillation. In the past, this has been accomplished using two-dimensional planar techniques that require reconstruction of three dimensional flow patterns. We have applied a new, fully three-dimensional, volumetric imaging technique that allows instantaneous capture of wake flow patterns, to a classic problem in functional vertebrate biology: the function of the asymmetrical (heterocercal) tail of swimming sharks to capture the vorticity field within the volume swept by the tail. These data were used to test a previous three-dimensional reconstruction of the shark vortex wake estimated from two-dimensional flow analyses, and show that the volumetric approach reveals a different vortex wake not previously reconstructed from two-dimensional slices. The hydrodynamic wake consists of one set of dual-linked vortex rings produced per half tail beat. In addition, we use a simple passive shark-tail model under robotic control to show that the three-dimensional wake flows of the robotic tail differ from the active tail motion of a live shark, suggesting that active control of kinematics and tail stiffness plays a substantial role in the production of wake vortical patterns. PMID- 21543358 TI - Bayesian phylogenetic analysis supports an agricultural origin of Japonic languages. AB - Languages, like genes, evolve by a process of descent with modification. This striking similarity between biological and linguistic evolution allows us to apply phylogenetic methods to explore how languages, as well as the people who speak them, are related to one another through evolutionary history. Language phylogenies constructed with lexical data have so far revealed population expansions of Austronesian, Indo-European and Bantu speakers. However, how robustly a phylogenetic approach can chart the history of language evolution and what language phylogenies reveal about human prehistory must be investigated more thoroughly on a global scale. Here we report a phylogeny of 59 Japonic languages and dialects. We used this phylogeny to estimate time depth of its root and compared it with the time suggested by an agricultural expansion scenario for Japanese origin. In agreement with the scenario, our results indicate that Japonic languages descended from a common ancestor approximately 2182 years ago. Together with archaeological and biological evidence, our results suggest that the first farmers of Japan had a profound impact on the origins of both people and languages. On a broader level, our results are consistent with a theory that agricultural expansion is the principal factor for shaping global linguistic diversity. PMID- 21543359 TI - An update of the evolving epidemic of blaKPC-2-carrying Klebsiella pneumoniae in Greece (2009-10). AB - OBJECTIVES: To follow the epidemic of KPC-2-producing Klebsiella pneumoniae in Greece. METHODS: KPC-2-producing isolates (n = 378) were collected during January 2009-April 2010 in 40 Greek hospitals. bla(KPC) and bla(VIM) were detected by PCR. Carbapenemase production was confirmed by spectrophotometry. Sequences flanking bla(KPC-2) and their plasmid carriers were studied. Isolates were typed by PFGE and multilocus sequence typing (MLST). RESULTS: All 378 isolates were bla(KPC-2) positive; 18 also carried bla(VIM-1/VIM-4). Higher isolation frequencies were observed in Athens and Crete. Isolates were classified into 13 PFGE types and 11 sequence types (STs). ST258 was predominant (n = 322), followed by ST147 (n = 20), ST383 (n = 9), ST133 (n = 6), ST274 (n = 4) and ST323 (n = 3). Of the remaining isolates, seven were distributed into five STs (11, 17, 340 and the novel 494 and 495) and seven were not typed. bla(KPC-2) could not be transferred from ST258 isolates, in contrast to isolates of ST17, ST133, ST147, ST274, ST494 and ST495. All bla(KPC-2)-encoding plasmids were of similar size (~100 kb) and showed indistinguishable restriction fragment length polymorphism (RFLP) patterns except those from the ST340 isolates. Sequences flanking bla(KPC 2) revealed that the Tn4401a isoform was present in plasmids from all STs except ST340 containing Tn4401b. Co-production of VIM enzymes was observed in isolates of ST147, ST323 and ST383. CONCLUSIONS: Apart from the epidemic of KPC-2 producing K. pneumoniae belonging to ST258 in Greece, diffusion of bla(KPC-2) to at least 10 additional STs has taken place. Notably, strains from three of the latter STs (147, 323 and 383) were found to carry both bla(KPC-2) and bla(VIM). PMID- 21543360 TI - Cryptococcus and Trichosporon spp. are susceptible in vitro to branched histidine and lysine-rich peptides (BHKPs). PMID- 21543361 TI - Family involvement, independence, and patient autonomy in practice. AB - The legal debate about patient autonomy focuses mainly on mental capacity and provision of information. The influence of the family on the decisions of the competent adult patient has scarcely been discussed in English medical law. Dominated by the bioethical principle of individual autonomy, the law concentrates on the patient and takes an exclusionary stand regarding relatives. Hence, the aim of this article is to examine the attitude of English law towards the involvement of relatives when patients make decisions, and to investigate the views and experiences of patients and their relatives in reality. To fulfil this aim, a qualitative study was carried out in six NHS trusts in England. The study was based on in-depth interviews conducted with patients who suffer from long term illnesses, and their relatives. In the interviews, patients stated that the relatives assisted them in making informed decisions about treatment. Patients said that relatives had an influence on the decision-making process and on the decision itself, but also reported that ultimately relatives left the final decision to the patient. The findings reflect a relational approach to patient autonomy. When making decisions about treatment, patients needed to know that their relatives would support them no matter what they decided. However, exceptional cases which demonstrated substantial familial influence suggest that the law should secure the patient's interest in making their own decisions. In light of these findings, it is argued that the current exclusionary attitude expressed in English medical law towards the role of relatives should be changed. PMID- 21543362 TI - Safeguarding reproductive health? The inherent jurisdiction, contraception, and mental incapacity. A local authority v A [2010] EWHC 1549 (Fam). PMID- 21543364 TI - The Novalung interventional lung assist as bridge to lung transplantation for self-ventilating patients - initial experience. AB - We report the use of the Novalung pumpless device in self-ventilating patients awaiting a lung transplantation. Two patients developed carbon dioxide retention with respiratory acidosis that did not respond to maximum medical therapy. The Novalung interventional lung assist was established as a bridge to lung transplantation. The first patient was successfully transplanted after 140 days, and this is the longest support that has been reported so far. The second patient was weaned off the Novalung after a short period. The Novalung is a valuable device for self-ventilating patients with carbon dioxide retention being bridged to lung transplantation. PMID- 21543363 TI - Repairing interatrial septal defects from the operating room to the cardiac catheterization laboratory: 2D or not 2D? AB - Uncorrected congenital interatrial septal defect can be found in nearly a third of all adults and are associated with significant morbidity, including pulmonary hypertension, right-heart failure, atrial arrhythmias, and paradoxical embolic stroke. With advancing technology, percutaneous closure of atrial septal defects has become a viable alternative to open surgical repair. In this review, the authors provide 3 examples in which 3-dimensional interventional transesophageal echocardiogram effectively provided more precise visualization of the dynamic surface and geometry of the atrial septum and related structures than 2 dimensional TEE, permitting accurate sizing and repair of the defects. PMID- 21543365 TI - The obesity paradox in elderly obese patients undergoing coronary artery bypass surgery. AB - We sought to determine whether the protective role of the 'obesity paradox' was present among elderly obese patients undergoing coronary artery bypass grafting (CABG) by median sternotomy. We retrospectively analyzed 1909 consecutive patients who underwent heart surgery between January 2006 and June 2009, and identified 396 patients who were >= 70 years of age and had isolated CABG. Subjects were divided into three groups according to their body mass index (BMI): obese (BMI >= 30 kg/m(2)), overweight (BMI 25-29.99 kg/m(2)) and normal (BMI 18.5 24.99 kg/m(2)). Of the 396 patients, 94 were obese, 167 were overweight, and 135 had a normal BMI. The composite of in-hospital complications and hospital mortality did not differ between the groups. Re-exploration for bleeding was required in none of the obese patients, which was statistically significant (P=0.05) compared to the other groups; otherwise there was no statistical difference for all other complications, including total length hospital stay and length of stay in the intensive care unit. Despite being labeled as higher risk candidates preoperatively, obese elderly patients undergoing CABG did not demonstrate an increased risk of postsurgical complications. We conclude that the 'obesity paradox' is present in this population, and they should not be excluded from receiving the benefits of CABG. PMID- 21543366 TI - Muscle flaps or omental flap in the management of deep sternal wound infection. AB - The primary question addressed was whether muscle flaps (MFs) offer a significant advantage over an omental flap (OF) in the management of deep sternal wound infection (DSWI) following cardiovascular surgery in terms of outcome (morbidity and mortality). Altogether, 333 citations (from PubMed and EMBASE and using a manual search, without language restriction) were identified using the reported strategy. Focusing on publications from single institutions with experience with both types of flap in the treatment of DSWI, 16 studies represented the best evidence on the topic. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. These 16 observational studies covered 1046 patients, and all reported mortality rates. Unadjusted data from five of six studies investigating a possible association between mortality and flap type suggested a higher mortality rate following reconstruction with MFs. A meta-analysis of all six studies indicates a slight, but not significant, survival advantage for reconstruction with an OF [overall relative risk 1.29 (95% confidence interval 0.58-2.88)]. Thirteen studies reported on the number of individual postoperative complications for a total of 964 patients. Data, unadjusted for potentially confounding surgical factors, on complications following flap closure, such as complete or partial flap loss, haematoma, arm or shoulder weakness and chronic chest wall pain, suggested that these complications were more common following MF reconstruction. Four studies evaluated patients with recurrent sternal wound infection (n=521). Two of these were associated with a high incidence (>17.5%) of re-exploration for recurrent sternal infection following MF reconstruction. The most commonly reported complications following an OF were abdominal or diaphragmatic hernias, with an incidence of <5%. We conclude that the weight of current evidence is insufficient to prove the superiority of reconstruction with MFs to a laparotomy-harvested, OF in the treatment of DSWI. The results suggest that use of the omentum may be associated with lower mortality and fewer complications. PMID- 21543367 TI - Sternotomy and crutches. AB - The use of crutches following a sternotomy raises the concern of sternal dehiscence. We discuss secure reinforced sternal closure, classify sternal distractional forces and discuss the postoperative mobilization process. PMID- 21543368 TI - Use of the titanium vertical ribs osteosynthesis system for reconstruction of large posterolateral chest wall defect in lung cancer. AB - We report a case of reconstruction of a large full-thickness posterolateral defect of the chest wall after resection of a stage III non-small cell lung carcinoma (NSCLC) using the combination of a vertical expandable prosthetic titanium device and a polytetrafluoroethylene (PTFE) mesh. A 40-year-old female presented with a NSCLC classified as type IIIA and required both neoadjuvant radiotherapy and chemotherapy. An en bloc resection including the left upper lobe, posterolateral segments of five ribs (K3-K7) and vertebral bodies (T3-T6) was performed through a posterior J-shaped approach. A vertical rib osteosynthesis system was used to ensure thoracic wall stability and mechanical organ protection, prevent ventilatory impairment, avoid incarceration of the tip of the scapula, and maintain an acceptable cosmetic aspect. The device was locked onto the middle arch of the second and eighth ribs. We hung the PTFE mesh from the titanium bars with multiple non-absorbable sutures under maximal tension. Final pathological classification was T4N0M0 with an R0 final resection status. After an uneventful course, the patient was discharged on postoperative day 10. This first experience indicates that vertical rib osteosynthesis combined with a PTFE mesh can be used safely and easily in a one-stage procedure for major posterior chest wall defects. PMID- 21543369 TI - Risk stratification analysis of operative mortality in isolated coronary artery bypass graft patients in Pakistan: comparison between additive and logistic EuroSCORE models. AB - We compared the performances of the additive and logistic EuroSCORE in predicting mortality in patients undergoing isolated coronary artery bypass grafting at a single institution in Pakistan. Both models were applied to 2004 patients, operated upon at the Aga Khan University Hospital from January 2006 to July 2010. The actual mortality (3.8%) was significantly different from the additive (4.35%) and the logistic (6.41%) estimates. On the basis of degree of risk, actual mortality was 0.6% in the low-risk (additive EuroSCORE 0-4), 4.2% in the medium risk (EuroSCORE 5-9) and 19.1% in the high-risk (EuroSCORE 10-19) group. With the low risks, both systems slightly overestimated mortality, with the logistic EuroSCORE being more accurate. At a EuroSCORE of between 10 and 19, the additive EuroSCORE underestimated and logistic EuroSCORE overestimated mortality. Both models satisfactorily discriminated outcomes (receiver operating characteristics areas of 0.866 and 0.859 for the additive and the logistic model, respectively). The Hosmer-Lemeshow test showed that calibration was good for the additive model (P=0.424) but turned out to be inadequate for the logistic model (P<0.001). We conclude that the additive EuroSCORE is a more accurate model for risk assessment compared to the logistics model in the Pakistani population. PMID- 21543370 TI - PPIs: too much of a good thing? PMID- 21543371 TI - Managing diffuse oesophageal spasm. AB - Non-cardiac chest pain is common,1 affecting around 25% of the population during their lifetime and accounting for about 2-5% of presentations to hospital accident and emergency departments.2 Around 10% of patients presenting with such pain, and up to 13% of those presenting with functional dysphagia, have diffuse oesophageal spasm (DOS), an oesophageal motility disorder.3,4 DOS is often recognised and treated only after patients have attended hospital emergency departments and specialist clinics for years, because of the non-specific nature of their symptoms and difficulty in diagnosis (features common to motility disorders).5 Here we discuss the diagnosis and further management of patients with DOS. PMID- 21543372 TI - Nanomedicines--what are they? AB - Nanomedicines are drug formulations based on tiny structures (nanoparticles) usually measuring between 1nanometre (nm) and 100nm. More broadly, the term nanotechnology encompasses the production and application of structures, devices or systems by controlling the shape and size of materials at the nanometre scale.1 Nanotechnologies are used in a wide range of applications, including aerospace materials, cosmetics and in medicine.1,2 Here we discuss the application of this increasingly important technology to drug therapy. PMID- 21543373 TI - Update: artemisinins in malaria treatment in the UK. PMID- 21543374 TI - Microvascular tissue perfusion is impaired in acutely decompensated heart failure and improves following standard treatment. AB - AIMS: Acutely decompensated heart failure (ADHF) leads to neurohumoral activation potentially affecting vascular tone and organ perfusion and may be linked to unfavourable outcome. Global haemodynamic, clinical, and laboratory parameters may severely underestimate tissue hypoperfusion. Therefore, the purpose of this study was to evaluate microvascular flow index (MFI) in patients with ADHF and to assess the effect of standard pharmacological therapy using Sidestream Dark Field (SDF) imaging. METHODS AND RESULTS: Twenty-seven patients (mean age 75.5 +/- 10.1 years, 48% male) with ADHF in New York Heart Association functional class >=III were included. Serum markers of neurohumoral activation [brain natriuretic peptide (BNP)], endothelin-1 (ET-1), noradrenaline (NA), and echocardiographic parameters of left ventricle-function were determined at hospital admission and the day before discharge. Using SDF imaging, MFI was evaluated at both time points in semi-quantitative vessel categories (small: 10-25 MUm; medium: 26-50 MUm; and large: 51-100 MUm). At admission, increased serum levels of BNP, NA, and ET-1 and a severely reduced MFI were observed in association with ADHF. Serum levels of BNP, NA, and ET-1 decreased significantly with standard pharmacological therapy (BNP: 2163 +/- 1577 vs.1006 +/- 945 pg/mL, P< 0.05; NA: 349 +/- 280 to 318 +/- 265 pg/mL, P< 0.05; ET-1: 5.08 +/- 0.72 to 4.81 +/- 0.59 pg/mL; P< 0.01). Standard pharmacological treatment also had a profound impact on tissue perfusion by significantly improving median MFI in small [2.6; inter-quartile range (IQR) 2.3-2.9 vs. 2.9; IQR 2.8-3.0; P= 0.01) and medium-sized (2.0; IQR 1.9-2.5 vs. 2.7; IQR 2.5-2.8; P< 0.01) vessels. CONCLUSION: In patients with ADHF, microvascular tissue perfusion is impaired even when global haemodynamic or laboratory signs of hypoperfusion are absent. Effective pharmacological treatment to decrease neurohumoral activation significantly improves microflow. Hypoperfusion in ADHF is potentially linked to neurohumoral activation with increased plasma levels of vasoconstrictors and sympatho-adrenergic activity. PMID- 21543375 TI - Vitamin D status and outcomes in heart failure patients. AB - AIMS: Vitamin D status has been implicated in the pathophysiology of heart failure (HF). The aims of this study were to determine whether a low vitamin D status is associated with prognosis in HF and whether activation of the renin angiotensin system (RAS) and inflammatory markers could explain this potential association. METHODS AND RESULTS: We measured 25-hydroxy-vitamin D (25(OH)D), plasma renin activity (PRA), interleukin-6 (IL-6), C-reactive protein (CRP), and the incidence of death or HF rehospitalization in 548 patients with HF. Median age was 74 (64-80) years, left ventricular ejection fraction was 30% (23-42), and mean follow-up was 18 months. Low 25(OH)D levels were associated with female gender (P< 0.001), higher age (P= 0.002), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P< 0.001). Multivariable linear regression analysis showed that PRA (P= 0.048), and CRP levels (P= 0.006) were independent predictors of 25(OH)D levels. During follow-up, 155 patients died and 142 patients were rehospitalized. Kaplan-Meier analysis showed that lower 25(OH)D concentration was associated with an increased risk for the combined endpoint (all-cause mortality and HF rehospitalization; log rank test P= 0.045) and increased risk for all-cause mortality (log rank test P= 0.014). After adjustment in a multivariable Cox regression analysis, low 25(OH)D concentration remained independently associated with an increased risk for the combined endpoint [hazard ratio (HR) 1.09 per 10 nmol/L decrease; 95% confidence interval (CI) 1.00-1.16; P= 0.040] and all-cause mortality (HR 1.10 per 10 nmol/L decrease; 95% CI 1.00 1.22; P= 0.049). CONCLUSION: A low 25(OH)D concentration is associated with a poor prognosis in HF patients. Activation of the RAS and inflammation may confer the adverse effects of low vitamin D levels. PMID- 21543376 TI - Association between serum TSH concentration within the normal range and adiposity. AB - BACKGROUND: Overt hypothyroidism is clearly related to body weight gain and greater adiposity, but the range of hormonal change in serum TSH concentration associated with weight gain remains a focus of debate. AIM: The aim of this review was to assess studies that evaluated the relationship between anthropometric measures and serum TSH concentration in euthyroid subjects. METHODS: Studies held on the Ovid MEDLINE database were searched and original articles published from 2000 to 2010 were included. The literature search was restricted to studies conducted in humans aged 18 years or older and written in English, Spanish, or Portuguese. Studies that evaluated the association between anthropometric measures and serum TSH within the normal range as the primary objective, as well as additional analysis, were included. RESULTS: A total of 29 studies met the inclusion criteria. Of the 29 studies, 18 showed a positive relationship between measures of adiposity and serum TSH. Despite the plausibility of this association, only two studies reported longitudinal findings. The influence of smoking on the association between serum TSH and anthropometric measures was evaluated in only three studies and remains unclear. CONCLUSION: Thus, further longitudinal studies are needed to better understand the mechanisms by which TSH concentration might impact body weight. PMID- 21543377 TI - Circulating platelet-derived microparticles are elevated in women with polycystic ovary syndrome diagnosed with the 1990 criteria and correlate with serum testosterone levels. AB - OBJECTIVE: Women with polycystic ovary syndrome (PCOS) appear to have higher cardiovascular risk than healthy population. Patients diagnosed with PCOS according to the 1990 criteria have a more adverse metabolic profile than those diagnosed with the 2003 criteria. Platelet-derived microparticles (PMPs) appear to contribute to atherosclerosis but have not been assessed in PCOS. The aim of this study was to determine plasma PMPs in PCOS patients. Design A cross sectional study. METHODS: We assessed plasma PMPs in 76 normal weight women with PCOS (39 belonging to the phenotypes 1 and 2 (group I) and 37 belonging to the phenotypes 3 and 4 (group II)) and 21 healthy normal weight women. RESULTS: Markers of obesity and insulin resistance did not differ between women with PCOS and controls. Serum testosterone levels and the free androgen index (FAI) were higher in group I than in group II and controls (P<0.001 for all comparisons) but did not differ between the latter two groups. Plasma PMPs were higher in group I than in controls (P=0.018) but did not differ between group II and controls or between groups I and II. In the total study population (n=97), plasma PMPs correlated with serum testosterone levels (r=0.207, P=0.042) and the FAI (r=0.207, P=0.042). CONCLUSIONS: Plasma PMPs are elevated in women with phenotypes 1 and 2 of PCOS compared with healthy controls, but not in women with phenotypes 3 and 4. Hyperandrogenemia, which is more pronounced in phenotypes 1 and 2, appears to be implicated in the increase in plasma PMPs. PMID- 21543378 TI - Mutational analysis of the necdin gene in patients with congenital isolated hypogonadotropic hypogonadism. AB - CONTEXT: Necdin activates GNRH gene expression and is fundamental for the development, migration, and axonal extension of murine GNRH neurons. In humans, necdin plays a potential role in the hypogonadotropic hypogonadism phenotype in patients with Prader-Willi syndrome. AIM: To investigate necdin gene (NDN) variants in patients with isolated hypogonadotropic hypogonadism (IHH). PATIENTS AND METHODS: We studied 160 Brazilian patients with IHH, which includes 92 with Kallmann syndrome and 68 with normosmic IHH. Genomic DNA was extracted and the single NDN exon was amplified and sequenced. To measure GNRH transcriptional activity, luciferase reporter plasmids containing GNRH regulatory regions were transiently transfected into GT1-7 cells in the presence and absence of overexpressed wild-type or mutant necdin. RESULTS: A heterozygous variant of necdin, p.V318A, was identified in a 23-year-old male with Kallmann syndrome. The p.V318A was also present in affected aunt and his father and was absent in 100 Brazilian control subjects. Previous FGFR1 gene analysis revealed a missense mutation (p.P366L) in this family. Functional studies revealed a minor difference in the activation of GNRH transcription by mutant protein compared with wild type in that a significant impairment of the necdin protein activity threshold was observed. CONCLUSION: A rare variant of necdin (p.V318A) was described in a family with Kallmann syndrome associated with a FGFR1 mutation. Familial segregation and in vitro analysis suggested that this non-synonymous variant did not have a direct causative role in the hypogonadism phenotype. NDN mutations are not a frequent cause of congenital IHH. PMID- 21543379 TI - Osteoblasts in osteoporosis: past, emerging, and future anabolic targets. AB - OBJECTIVE: Age-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration. METHODS: A limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010. RESULTS AND DISCUSSION: We present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population. PMID- 21543380 TI - Understanding phenomena in the real world: the case for real time data collection in health services research. AB - Understanding the environmental and behavioural predictors of wellbeing is a key driver of health and social care research. Research set in the social world examines the relationships between behavioural, cognitive, emotional and environmental factors, linking these to disease or social ills with the aim of providing better preventive or treatment services. Much of this research is based on retrospective measurement tools, such as questionnaires or interviews. However, retrospective accounts are prone to bias arising from the influence of the participant's current affective state on autobiographical memory and error inducing heuristic strategies related to memory. Participant introspection also biases self-reports of behaviour and symptoms. This essay offers a critical examination of the advantages of ecological momentary assessment (EMA) methods over retrospective accounts in understanding social phenomena. Advantages of EMA include collection of longitudinal data from a representative part of the participant's daily experience, in real time and in the participant's natural environment. EMA accounts are gathered more closely in time to the event and are less biased by heuristic, autobiographical memory strategies. Real-time longitudinal data may be combined from a range of devices or forms of data collection; for example, self-report can be linked with objective physiological data. EMA allows testing of within-person variation in variables of interest in a way that is difficult to achieve using retrospective measures and between-person (group level) designs. EMA approaches provide not just more data, but better data than previously, allowing the application of more powerful analytic techniques to critical, real life questions than ever before. PMID- 21543381 TI - Greening health care: how hard can that be? AB - There are two key policy questions when addressing climate change and health care: where do we start and how do we move forward? This pragmatic exploration of the climate change issue and its impact on health care delivery starts from the premise that a proper understanding of the scope of the problem and a focus for bringing a broad range of people together to develop solutions is the place to begin policy discussions. Far from a standing start, there is much work already underway at the global and local levels. What is recommended is a forum that can bring people and ideas together in a creative, engaged and cross-generational dialogue that prepares for change in health care to meet the challenge of climate change. PMID- 21543382 TI - Assessing the suitability of fractional polynomial methods in health services research: a perspective on the categorization epidemic. AB - OBJECTIVE: To show how fractional polynomial methods can usefully replace the practice of arbitrarily categorizing data in epidemiology and health services research. METHODS: A health service setting is used to illustrate a structured and transparent way of representing non-linear data without arbitrary grouping. RESULTS: When age is a regressor its effects on an outcome will be interpreted differently depending upon the placing of cutpoints or the use of a polynomial transformation. CONCLUSIONS: Although it is common practice, categorization comes at a cost. Information is lost, and accuracy and statistical power reduced, leading to spurious statistical interpretation of the data. The fractional polynomial method is widely supported by statistical software programs, and deserves greater attention and use. PMID- 21543383 TI - Statistical synthesis of contextual knowledge to increase the effectiveness of theory-based behaviour change interventions. AB - Tailored implementation strategies targeting health professionals' adoption of evidence-based recommendations are currently being developed. Research has focused on how to select an appropriate theoretical base, how to use that theoretical base to explore the local context, and how to translate theoretical constructs associated with the key factors found to influence innovation adoption into feasible and tailored implementation strategies. The reasons why an intervention is thought not to have worked are often cited as being: inappropriate choice of theoretical base; unsystematic development of the implementation strategies; and a poor evidence base to guide the process. One area of implementation research that is commonly overlooked is how to synthesize the data collected in a local context in order to identify what factors to target with the implementation strategies. This is suggested to be a critical process in the development of a theory-based intervention. The potential of multilevel modelling techniques to synthesize data collected at different hierarchical levels, for example, individual attitudes and team level variables, is discussed. Future research is needed to explore further the potential of multilevel modelling for synthesizing contextual data in implementation studies, as well as techniques for synthesizing qualitative and quantitative data. PMID- 21543384 TI - Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata. AB - AIMS: Increased sympathetic tone in obstructive sleep apnoea results from recurrent episodes of systemic hypoxia and hypercapnia and might be an important contributor to the development of cardiovascular disease. In this study, we re evaluated the role of a specific population of sympathoexcitatory catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata in the control of sympathetic vasomotor tone, arterial blood pressure, and hypercapnia-evoked sympathetic and cardiovascular responses. METHODS AND RESULTS: In anaesthetized rats in vivo and perfused rat working heart brainstem preparations in situ, C1 neurones were acutely silenced by application of the insect peptide allatostatin following cell-specific targeting with a lentiviral vector to express the inhibitory Drosophila allatostatin receptor. In anaesthetized rats with denervated peripheral chemoreceptors, acute inhibition of 50% of the C1 neuronal population resulted in ~50% reduction in renal sympathetic nerve activity and a profound fall in arterial blood pressure (by ~25 mmHg). However, under these conditions systemic hypercapnia still evoked vigorous sympathetic activation and the slopes of the CO(2)-evoked sympathoexcitatory and cardiovascular responses were not affected by inhibition of C1 neurones. Inhibition of C1 neurones in situ resulted in a reversible fall in perfusion pressure and the amplitude of respiratory-related bursts of thoracic sympathetic nerve activity. CONCLUSION: These data confirm a fundamental physiological role of medullary catecholaminergic C1 neurones in maintaining resting sympathetic vasomotor tone and arterial blood pressure. However, C1 neurones do not appear to mediate sympathoexcitation evoked by central actions of CO(2). PMID- 21543386 TI - Reflections from the antipodes on the English strategy to reduce health inequalities and Mackenbach's analysis. PMID- 21543385 TI - A novel catestatin-induced antiadrenergic mechanism triggered by the endothelial PI3K-eNOS pathway in the myocardium. AB - AIMS: Catestatin (CST) is a chromogranin A (CgA)-derived peptide (hCgA352-372) with three identified human variants (G364S/P370L/R374Q-CST) that show differential potencies towards the inhibition of catecholamine release. Although CST affects several cardiovascular parameters, the mechanisms underlying CST action in the heart have remained elusive. Therefore, we sought to determine the mechanism of action of CST and its variants on ventricular myocardium and endothelial cells. METHODS AND RESULTS: Contractile force and Ca(2+) transients were measured, respectively, on rat papillary muscles and isolated cardiomyocytes (CC) under basal conditions and after beta-adrenergic stimulation. Nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation (P(Ser1179)eNOS) were studied in bovine aortic endothelial (BAE-1) cells. Under basal conditions, wild-type CST (WT-CST, 10-50 nM) transiently enhanced myocardial contractility. CST variants (G364S and P370L) exerted a comparable positive inotropic effect. The H(1) histamine receptor antagonist mepyramine abolished the increase of contractile force induced by WT-CST. Moreover, WT-CST dose-dependently (5-50 nM) reduced the effect of beta-adrenergic stimulation. This anti-adrenergic effect was not mediated by a direct action on CC, but involved a PI3K-dependent NO release from endocardial endothelial cells. Indeed, CST induced a wortmannin-sensitive, Ca(2+)-independent increase in NO production and eNOS phosphorylation on BAE-1 cells. While the anti-adrenergic and NO release effects of P370L-CST were comparable with those of WT-CST, the G364S variant was ineffective on the same parameters. CONCLUSION: Our results suggest that the anti adrenergic action of CST depends on the endothelial PI3K-Akt-eNOS pathway and that its structural alterations entail functional features that correlate with the different anti-hypertensive potential described in humans. PMID- 21543387 TI - Explaining socioeconomic differences in adolescent self-rated health: the contribution of material, psychosocial and behavioural factors. AB - BACKGROUND: Efforts to explain social inequalities in health have mainly focused on adults. Few studies have systematically analysed different explanatory pathways in adolescence. This study is among the first to examine the contribution of material, psychosocial and behavioural factors in the explanation of inequalities in adolescent health. METHODS: Data were obtained from the German part of the cross-sectional 'Health Behaviour in School-aged Children' Survey in 2006, with a total of 6997 respondents aged 11-15 years (response rate 86%). Socioeconomic position was measured using the Family Affluence Scale. Multistage logistic regression models were used to assess the relative importance of explanatory factors. RESULTS: Compared with adolescents from high affluent backgrounds, the ORs of fair/poor self-rated health increased to 1.53 (95% CI 1.11 to 2.12) in low affluent boys and to 2.08 (95% CI 1.62 to 2.67) in low affluent girls. In the separate analyses, material, psychosocial and behavioural factors attenuated the OR by 30-50%. Together, the three explanatory factors reduced the OR by about 80% in low affluent boys and girls. The combined analyses illustrated that material factors contributed most to the differences in self rated health because of their direct and indirect effect (through psychosocial and behavioural factors). CONCLUSIONS: The findings show that the main explanatory approaches for adults also apply to adolescents. The direct and indirect contribution of material factors for inequalities in self-rated health was stronger than that of behavioural and psychosocial factors. Strategies for reducing health inequalities should primarily focus on improving material circumstances in lower affluent groups. PMID- 21543388 TI - Does housing policy influence health? PMID- 21543389 TI - Tilly's Durable Inequality and health inequality in USA: when the categories do not match and the mechanisms do not work. PMID- 21543392 TI - The predatory behaviour of the thylacine: Tasmanian tiger or marsupial wolf? AB - The extinct thylacine (Thylacinus cynocephalus) and the extant grey wolf (Canis lupus) are textbook examples of convergence between marsupials and placentals. Craniodental studies confirm the thylacine's carnivorous diet, but little attention has been paid to its postcranial skeleton, which would confirm or refute rare eyewitness reports of a more ambushing predatory mode than the pack hunting pursuit mode of wolves and other large canids. Here we show that thylacines had the elbow morphology typical of an ambush predator, and propose that the 'Tasmanian tiger' vernacular name might be more apt than the 'marsupial wolf'. The 'niche overlap hypothesis' with dingoes (Canis lupus dingo) as a main cause of thylacine extinction in mainland Australia is discussed in the light of this new information. PMID- 21543393 TI - Retraction. Variation in chimpanzee 'culture' is predicted by local ecology, not geography. PMID- 21543394 TI - Rain increases the energy cost of bat flight. AB - Similar to insects, birds and pterosaurs, bats have evolved powered flight. But in contrast to other flying taxa, only bats are furry. Here, we asked whether flight is impaired when bat pelage and wing membranes get wet. We studied the metabolism of short flights in Carollia sowelli, a bat that is exposed to heavy and frequent rainfall in neotropical rainforests. We expected bats to encounter higher thermoregulatory costs, or to suffer from lowered aerodynamic properties when pelage and wing membranes catch moisture. Therefore, we predicted that wet bats face higher flight costs than dry ones. We quantified the flight metabolism in three treatments: dry bats, wet bats and no rain, wet bats and rain. Dry bats showed metabolic rates predicted by allometry. However, flight metabolism increased twofold when bats were wet, or when they were additionally exposed to rain. We conclude that bats may not avoid rain only because of sensory constraints imposed by raindrops on echolocation, but also because of energetic constraints. PMID- 21543395 TI - Queen pheromone regulates egg production in a termite. AB - In social insects, resource allocation is a key factor that influences colony survival and growth. Optimal allocation to queens and brood is essential for maximum colony productivity, requiring colony members to have information on the total reproductive power in colonies. However, the mechanisms regulating egg production relative to the current labour force for brood care remain poorly known. Recently, a volatile chemical was identified as a termite queen pheromone that inhibits the differentiation of new neotenic reproductives (secondary reproductives developed from nymphs or workers) in Reticulitermes speratus. The same volatile chemical is also emitted by eggs. This queen pheromone would therefore be expected to act as an honest message of the reproductive power about queens. In this study, we examined how the queen pheromone influences the reproductive rate of queens in R. speratus. We compared the number of eggs produced by each queen between groups with and without exposure to artificial queen pheromone. Exposure to the pheromone resulted in a significant decrease in egg production in both single-queen and multiple-queen groups. This is the first report supporting the role of queen pheromones as a signal regulating colony level egg production, using synthetically derived compounds in a termite. PMID- 21543396 TI - Craniofacial form and function in Metriorhynchidae (Crocodylomorpha: Thalattosuchia): modelling phenotypic evolution with maximum-likelihood methods. AB - Metriorhynchid crocodylomorphs were the only group of archosaurs to fully adapt to a pelagic lifestyle. During the Jurassic and Early Cretaceous, this group diversified into a variety of ecological and morphological types, from large super-predators with a broad short snout and serrated teeth to specialized piscivores/teuthophages with an elongate tubular snout and uncarinated teeth. Here, we use an integrated repertoire of geometric morphometric (form), biomechanical finite-element analysis (FEA; function) and phylogenetic data to examine the nature of craniofacial evolution in this clade. FEA stress values significantly correlate with morphometric values representing skull length and breadth, indicating that form and function are associated. Maximum-likelihood methods, which assess which of several models of evolution best explain the distribution of form and function data on a phylogenetic tree, show that the two major metriorhynchid subclades underwent different evolutionary modes. In geosaurines, both form and function are best explained as evolving under 'random' Brownian motion, whereas in metriorhynchines, the form metrics are best explained as evolving under stasis and the function metric as undergoing a directional change (towards most efficient low-stress piscivory). This suggests that the two subclades were under different selection pressures, and that metriorhynchines with similar skull shape were driven to become functionally divergent. PMID- 21543398 TI - Plastered in pustules. PMID- 21543400 TI - Bad medicine: bipolar II disorder. PMID- 21543401 TI - Bahrain unrest. PMID- 21543403 TI - WHO urges the phasing out of artemisinin based monotherapy for malaria to reduce resistance. PMID- 21543404 TI - Artificial duplicate reads in sequencing data of 454 Genome Sequencer FLX System. AB - The 454 Genome Sequencer (GS) FLX System is one of the next-generation sequencing systems featured by long reads, high accuracy, and ultra-high throughput. Based on the mechanism of emulsion PCR, a unique DNA template would only generate a unique sequence read after being amplified and sequenced on GS FLX. However, biased amplification of DNA templates might occur in the process of emulsion PCR, which results in production of artificial duplicate reads. Under the condition that each DNA template is unique to another, 3.49%-18.14% of total reads in GS FLX-sequencing data were found to be artificial duplicate reads. These duplicate reads may lead to misunderstanding of sequencing data and special attention should be paid to the potential biases they introduced to the data. PMID- 21543405 TI - Making raw data more widely available. PMID- 21543406 TI - PCORI: odd name, important job, potential trouble. PMID- 21543407 TI - The A to Z of the wellbeing industry: from Angelic Reiki to patient centred care. Wellbeing is big business, but how much of it works? PMID- 21543408 TI - Medical team in a crisis zone: medical responses to a clear and present danger. PMID- 21543410 TI - US court says federal money can be used for embryonic stem cell research. PMID- 21543411 TI - Prevalence and determinants of undernutrition and its trends among pre-school tribal children of Maharashtra State, India. AB - A community-based cross-sectional study carried out in tribal areas of Maharashtra covering 1751 pre-school children to assess nutritional status. Nutritional status was assessed using new WHO Growth Standards. Household wealth index was constructed using principle component analysis. The prevalence of underweight, stunting and wasting was 64, 61 and 29%, respectively. There was a significant (p < 0.05) reduction in the prevalence of underweight and stunting over two time periods (1999 and 2008). Logistic regression showed that the risk of underweight was 1.7 times higher among children of illiterate mothers and those suffering from morbidities, while stunting was 1.4 times higher among children belonging to lowest and middle household's wealth indexes. Undernutrition is a public health problem and is associated with literacy of mother, household wealth index and morbidities. Therefore, improving socio economic condition along with literacy of mothers and preventing infections through personal hygiene might help in improving the nutritional status of children. PMID- 21543412 TI - Peer training increases the level of knowledge on sexual and reproductive health in adolescents. AB - To reach 'youth' and equip them with accurate information on sexual and reproductive health (SRH) is a very important issue. Forty one volunteer students from Mersin University School of Medicine were trained as peer trainers on SRH in Mersin, Turkey. Every peer trainer then trained 100 peers aged between 15 and 20 years about SRH. A total of 3941 students participated and answered a questionnaire consisting of 20 questions about SRH before and after the training sessions. The mean score before the training session was 13.6 +/- 3.2 and after the training session was 17.0 +/- 2.8. The posttraining test results were found to be significantly higher (p < 0.001). Having previous SRH information from any kind of source also was found to be effective on pretraining test results positively (p = 0.002). As adolescence is the most vulnerable period to sexual health problems, increasing the awareness of sexual health is very important. PMID- 21543413 TI - Differences in the substrate binding regions of renal organic anion transporters 1 (OAT1) and 3 (OAT3). AB - This study examined the selectivity of organic anion transporters OAT1 and OAT3 for structural congeners of the heavy metal chelator 2,3-dimercapto-1 propanesulfonic acid (DMPS). Thiol-reactive reagents were also used to test structural predictions based on a homology model of OAT1 structure. DMPS was near equipotent in its ability to inhibit OAT1 (IC(50) = 83 MUM) and OAT3 (IC(50) = 40 MUM) expressed in Chinese hamster ovary cells. However, removal of a thiol group (3-mercapto-1-propanesulfonic acid) resulted in a 2.5-fold increase in IC(50) toward OAT1 vs. a ~55-fold increase in IC(50) toward OAT3. The data suggested that compound volume/size is important for binding to OAT1/OAT3. The sensitivity to HgCl(2) of OAT1 and OAT3 was also dramatically different, with IC(50) values of 104 and 659 MUM, respectively. Consistent with cysteines of OAT1 being more accessible from the external medium than those of OAT3, thiol-reactive reagents reacted preferentially with OAT1 in cell surface biotinylation assays. OAT1 was less sensitive to HgCl(2) inhibition and less reactive toward membrane-impermeant thiol reactive reagents following mutation of cysteine 440 (C440) to an alanine. These data indicate that C440 in transmembrane helix 10 of OAT1 is accessible from the extracellular space. Indeed, C440 was exposed to the aqueous phase of the presumptive substrate translocation pathway in a homology model of OAT1 structure. The limited thiol reactivity in OAT3 suggests that the homologous cysteine residue (C428) is less accessible. Consistent with their homolog specific selectivities, these data highlight structural differences in the substrate binding regions of OAT1 and OAT3. PMID- 21543414 TI - Statins reverse renal inflammation and endothelial dysfunction induced by chronic high salt intake. AB - High salt intake (HS) is a risk factor for cardiovascular and kidney disease. Indeed, HS may promote blood-pressure-independent tissue injury via inflammatory factors. The lipid-lowering 3-hydroxy 3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors exert beneficial lipid-independent effects, reducing the expression and synthesis of inflammatory factors. We hypothesized that HS impairs kidney structure and function in the absence of hypertension, and these changes are reversed by atorvastatin. Four groups of rats were treated for 6 wk in metabolic cages with their diets: normal salt (NS); HS, NS plus atorvastatin and HS plus atorvastatin. We measured basal and final body weight, urinary sodium and protein excretion (U(Prot)V), and systolic blood pressure (SBP). At the end of the experimental period, cholesterolemia, creatinine clearance, renal vascular reactivity, glomerular volume, cortical and glomerular endothelial nitric oxide synthase (eNOS), and transforming growth factor (TGF)-beta1 expression were measured. We found no differences in SBP, body weight, and cholesterolemia. HS rats had increased creatinine clearence, U(Prot)V, and glomerular volume at the end of the study. Acetylcholine-induced vasodilatation decreased by 40.4% in HS rats (P < 0.05). HS decreased cortical and glomerular eNOS and caused mild glomerular sclerosis, interstitial mononuclear cell infiltration, and increased cortical expression of TGF-beta1. All of these salt-induced changes were reversed by atorvastatin. We conclude that long-term HS induces inflammatory and hemodynamic changes in the kidney that are independent of SBP. Atorvastatin corrected all, suggesting that the nitric oxide-oxidative stress balance plays a significant role in the earlier stages of salt induced kidney damage. PMID- 21543415 TI - Collecting duct expression of N-methyl-D-aspartate receptor subtype NR3a regulates urinary concentrating capacity. PMID- 21543416 TI - Regulation of Kir4.1 and AQP4 expression and stability at the basolateral domain of epithelial MDCK cells by the extracellular matrix. AB - The proper targeting of ion channels to specialized domains is crucial for cell function. Kir4.1, the inwardly rectifying potassium channel, and aquaporin-4 (AQP4), the type 4 water-permeable channel, are localized at the basolateral domain of polarized epithelial cells; however, the mechanisms involved in their localization have yet to be determined. In this study, we investigated the role of the extracellular matrix in the localization of these channels in polarized Madin-Darby canine kidney (MDCK) cells. MDCK cells expressing green fluorescent protein-Kir4.1 or -AQP4 were cultured on laminin-1 or fibronectin and examined by confocal microscopy and cell surface biotinylation to assess plasma membrane expression of Kir4.1 and AQP4. Our data show that laminin-1 and fibronectin induce a significant increase in cell surface expression of both channels at the basolateral domain. Using fluorescence recovery after photobleaching, we demonstrate that laminin-1 and fibronectin reduce the diffusion rates of these channels. Finally, we show that the laminin receptor dystroglycan is important for cell surface expression of Kir4.1 but not AQP4. However, laminin-1 increases cell surface expression of both channels in cells deficient for dystroglycan, indicating that other receptors are involved. Indeed, RGD-containing peptides, which inhibit fibronectin binding to certain integrins, prevent the fibronectin induced increase in Kir4.1 and AQP4 cell surface expression and reverse the laminin- and fibronectin-induced reduction in both channels' diffusion rates. Similarly, the alphavbeta3-integrin function-blocking antibody alters the reduction of AQP4 diffusion rates induced by both laminin and fibronectin, suggesting that alphavbeta3-integrin plays a role in the stabilization of APQ4 at the basolateral domain of epithelial cells. PMID- 21543417 TI - Renal inflammation and elevated blood pressure in a mouse model of reduced {beta} ENaC. AB - Previous studies suggest beta-epithelial Na(+) channel protein (beta-ENaC) may mediate myogenic constriction, a mechanism of blood flow autoregulation. A recent study demonstrated that mice with reduced levels of beta-ENaC (beta-ENaC m/m) have delayed correction of whole kidney blood flow responses, suggesting defective myogenic autoregulatory capacity. Reduced renal autoregulatory capacity is linked to renal inflammation, injury, and hypertension. However, it is unknown whether beta-ENaC m/m mice have any complications associated with reductions in autoregulatory capacity such as renal inflammation, injury, or hypertension. To determine whether the previously observed altered autoregulatory control was associated with indicators of renal injury, we evaluated beta-ENaC m/m mice for signs of renal inflammation and tissue remodeling using marker expression. We found that inflammatory and remodeling markers, such as IL-1beta, IL-6, TNF alpha, collagen III and transforming growth factor-beta, were significantly upregulated in beta-ENaC m/m mice. To determine whether renal changes were associated with changes in long-term control of blood pressure, we used radiotelemetry and found that 5-day mean arterial blood pressure (MAP) was significantly elevated in beta-ENaC m/m (120 +/- 3 vs. 105 +/- 2 mmHg, P = 0.016). Our findings suggest loss of beta-ENaC is associated with early signs of renal injury and increased MAP. PMID- 21543418 TI - Role of the USF1 transcription factor in diabetic kidney disease. AB - The predominant transcription factors regulating key genes in diabetic kidney disease have not been established. The transcription factor upstream stimulatory factor 1 (USF1) is an important regulator of glucose-mediated transforming growth factor (TGF)-beta1 expression in mesangial cells; however, its role in the development of diabetic kidney disease has not been evaluated. In the present study, wild-type (WT; USF1 +/+), heterozygous (USF1 +/-), and homozygous (USF1 -/ ) knockout mice were intercrossed with Akita mice (Ins2/Akita) to induce type 1 diabetes. Mice were studied up to 36 wk of age. The degree of hyperglycemia and kidney hypertrophy were similar in all groups of diabetic mice; however, the USF1 -/- diabetic mice had significantly less albuminuria and mesangial matrix expansion than the WT diabetic mice. TGF-beta1 and renin gene expression and protein were substantially increased in the WT diabetic mice but not in USF1 -/- diabetic mice. The underlying pathway by which USF1 is regulated by high glucose was investigated in mesangial cell culture. High glucose inhibited AMP-activated protein kinase (AMPK) activity and increased USF1 nuclear translocation. Activation of AMPK with AICAR stimulated AMPK activity and reduced nuclear accumulation of USF1. We thus conclude that USF1 is a critical transcription factor regulating diabetic kidney disease and plays a critical role in albuminuria, mesangial matrix accumulation, and TGF-beta1 and renin stimulation in diabetic kidney disease. AMPK activity may play a key role in high glucose induced regulation of USF1. PMID- 21543419 TI - Fetal uninephrectomy in male sheep alters the systemic and renal responses to angiotensin II infusion and AT1R blockade. AB - Fetal uninephrectomy (uni-x) at 100 days of gestation results in compensatory nephrogenesis in the remaining kidney, resulting in a 30% reduction in total nephron number in male sheep. Recently, we showed that uni-x males at 6 mo of age have elevated arterial pressure, reduced renal blood flow (RBF), glomerular filtration rate (GFR), and low plasma renin levels (Singh R, Denton K, Bertram J, Jefferies A, Head G, Lombardo P, Schneider-Kolsky M, Moritz K. J Hypertens 27: 386-396, 2009; Singh R, Denton K, Jefferies A, Bertram J, Moritz K. Clin Sci (Lond) 118: 669-680, 2010). We hypothesized this was due to upregulation of the intrarenal renin-angiotensin system (RAS). In this study, renal responses to ANG II infusion and ANG II type 1 receptor (AT1R) blockade were examined in the same 6-mo-old male sheep. Uni-x animals had reduced levels of renal tissue and plasma renin and ANG II. Renal gene expression of renin, and gene and protein levels of AT1R and AT2R, were significantly lower in uni-x animals. In response to graded ANG II infusion, sham animals had the expected decrease in conscious RBF and GFR. Interestingly, the response was biphasic in uni-x sheep, with GFR initially decreasing, but then increasing at higher ANG II doses (34 +/- 7%; P(group * treatment) < 0.001), due to a paradoxical decrease in renal vascular resistance (P(group * treatment) < 0.001). In response to AT1R blockade, while GFR and RBF responded similarly between groups, there was a marked increase in sodium excretion in uni-x compared with sham sheep (209 +/- 35 vs. 25 +/- 12%; P < 0.001). In conclusion, in 6-mo-old male sheep born with a single kidney, these studies demonstrate that this is a low-renin form of hypertension, in which responses to ANG II are perturbed and the intrarenal RAS is downregulated. PMID- 21543420 TI - Air pollution around schools is linked to poorer student health and academic performance. AB - Exposing children to environmental pollutants during important times of physiological development can lead to long-lasting health problems, dysfunction, and disease. The location of children's schools can increase their exposure. We examined the extent of air pollution from industrial sources around public schools in Michigan to find out whether air pollution jeopardizes children's health and academic success. We found that schools located in areas with the highest air pollution levels had the lowest attendance rates-a potential indicator of poor health-and the highest proportions of students who failed to meet state educational testing standards. Michigan and many other states currently do not require officials considering a site for a new school to analyze its environmental quality. Our results show that such requirements are needed. For schools already in existence, we recommend that their environmental quality should be investigated and improved if necessary. PMID- 21543421 TI - Reducing the staggering costs of environmental disease in children, estimated at $76.6 billion in 2008. AB - A 2002 analysis documented $54.9 billion in annual costs of environmentally mediated diseases in US children. However, few important changes in federal policy have been implemented to prevent exposures to toxic chemicals. We therefore updated and expanded the previous analysis and found that the costs of lead poisoning, prenatal methylmercury exposure, childhood cancer, asthma, intellectual disability, autism, and attention deficit hyperactivity disorder were $76.6 billion in 2008. To prevent further increases in these costs, efforts are needed to institute premarket testing of new chemicals; conduct toxicity testing on chemicals already in use; reduce lead-based paint hazards; and curb mercury emissions from coal-fired power plants. PMID- 21543422 TI - Fine particulate matter pollution linked to respiratory illness in infants and increased hospital costs. AB - There has been little research to date on the linkages between air pollution and infectious respiratory illness in children, and the resulting health care costs. In this study we used data on air pollutants and national hospitalizations to study the relationship between fine particulate air pollution and health care charges and costs for the treatment of bronchiolitis, an acute viral infection of the lungs. We found that as the average exposure to fine particulate matter over the lifetime of an infant increased, so did costs for the child's health care. If the United States were to reduce levels of fine particulate matter to 7 percent below the current annual standard, the nation could save $15 million annually in reduced health care costs from hospitalizations of children with bronchiolitis living in urban areas. These findings reinforce the need for ongoing efforts to reduce levels of air pollutants. They should trigger additional investigation to determine if the current standards for fine-particulate matter are sufficiently protective of children's health. PMID- 21543423 TI - Children's vulnerability to toxic chemicals: a challenge and opportunity to strengthen health and environmental policy. AB - A key policy breakthrough occurred nearly twenty years ago with the discovery that children are far more sensitive than adults to toxic chemicals in the environment. This finding led to the recognition that chemical exposures early in life are significant and preventable causes of disease in children and adults. We review this knowledge and recommend a new policy to regulate industrial and consumer chemicals that will protect the health of children and all Americans, prevent disease, and reduce health care costs. The linchpins of a new US chemical policy will be: first, a legally mandated requirement to test the toxicity of chemicals already in commerce, prioritizing chemicals in the widest use, and incorporating new assessment technologies; second, a tiered approach to premarket evaluation of new chemicals; and third, epidemiologic monitoring and focused health studies of exposed populations. PMID- 21543424 TI - Prevalence and incidence of diabetes mellitus in adult patients on growth hormone replacement for growth hormone deficiency: a surveillance database analysis. AB - CONTEXT: GH replacement in adult GH-deficient patients may cause insulin resistance, raising concerns of potential increased risk of developing diabetes mellitus (DM). OBJECTIVE: Our objective was to assess DM prevalence and incidence in the international Hypopituitary Control and Complications Study (HypoCCS) surveillance database. DESIGN AND PARTICIPANTS: GH-treated patients enrolled into HypoCCS (2922 U.S. and 3709 European patients) were assessed for DM, defined as recorded on the clinical report form, reported as adverse events, fasting glucose at least 7 mmol/liter recorded at least twice, or insulin treatment reported. RESULTS: DM prevalence was 8.2% [95% confidence interval (CI) = 7.6-8.9] overall, 11.3% in the United States and 5.7% in Europe. Incidence (n/1000 patient-years) was 9.7 (95% CI = 8.4-10.9) overall, 14.1 (11.5-16.7) in the United States, and 7.0 (5.6-8.3) in Europe. Overall incidence was 2.1 (0.9-3.3) for patients with body mass index (BMI) below 25 kg/m(2) increasing to 16.4 (13.7-19.1) for BMI over 30 kg/m(2). Obesity (BMI > 30 kg/m(2)) prevalence was higher in the United States than Europe and higher in U.S. patients than a U.S. reference population. After age, gender, and BMI adjustment, U.S. HypoCCS DM incidence was 10.6 (8.1 13.0), compared with 7.1 (6.0-8.1) in the National Health Interview Survey. In Europe, incidence for French and German patients was comparable to reference populations; for Sweden, the point estimate was higher than the reference population, but 95% CI overlapped. GH dose was not correlated with DM incidence. CONCLUSIONS: The present analysis showed no evidence for increased DM incidence in GH-treated adult hypopituitary patients. However, those more prone to develop DM exhibited a higher than normal prevalence of obesity. PMID- 21543425 TI - Determination of serum and plasma sclerostin concentrations by enzyme-linked immunoassays. AB - BACKGROUND: Sclerostin alters bone formation. The precise and reproducible measurement of sclerostin concentrations in biological samples is important for assessment of metabolic bone disease. We determined sclerostin concentrations in serum and plasma using two commercially available ELISA. METHODS: We measured sclerostin concentrations in serum or heparin-plasma obtained from 25 normal human subjects using two commercial ELISA available from Biomedica Medizinprodukte GmbH and TECOmedical AG. RESULTS: With the Biomedica assay, serum sclerostin concentrations were 0.99 +/- 0.12 ng/ml (mean +/- sem), and plasma concentrations were 1.47 +/- 0.13 ng/ml (paired t test, P < 0.001). With the TECO assay, serum sclerostin levels were 0.71 +/- 0.05 ng/ml, and plasma sclerostin concentrations were 0.80 +/- 0.06 ng/ml (paired t test, P < 0.001). Serum and plasma sclerostin concentrations were significantly different when determined by the two assays (serum, P = 0.015; plasma, P < 0.001). Recovery of added recombinant sclerostin to serum was less than expected with both Biomedica and TECO assays (P < 0.001, paired t test). CONCLUSIONS: The concentrations of sclerostin in serum and plasma are different when determined by the two assays. Serum or plasma sclerostin concentrations with current assays should be interpreted with caution. The data suggest that the same assay should be used for comparing groups of patients or patients being followed longitudinally. Standardization of sclerostin assays is required before being introduced into general clinical laboratory use. PMID- 21543426 TI - Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. AB - CONTEXT: Endocrine effects of gastric bypass (GBP) surgery for obesity on glucose homeostasis are not fully understood. MAIN OBJECTIVE: The main objective of the study was to assess the changes in plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), leptin, somatostatin, glucose-dependent insulinotropic peptide, enteroglucagon, and glucagon early after GBP. METHOD: Twelve obese subjects (body mass index 45.3 +/- 1.9 kg/m(2)) were subjected to a liquid meal without lipids before and 3 d, 2 months, and 1 yr after GBP. Plasma concentrations of glucose, insulin, leptin, and gut peptide hormones were assessed before and for 180 min after the meal. Satiety was measured with visual analog scales. The absorption rate of acetaminophen added to the liquid meal was measured. Insulin resistance was measured by the homeostasis model assessment of insulin resistance. RESULTS: All subjects lost weight (body mass index 30.3 +/- 1.8 kg/m(2) at 1 yr). Fasting glucose was significantly lower on d 3 (P < 0.05). There was a progressive decrease in the homeostasis model assessment of insulin resistance after 2 months postoperatively. Postprandially, there was a progressive rise of GLP-1 and enteroglucagon and a transient increase in pancreatic glucagon release over the study period. There was a leftward shift of the time course of plasma glucose and insulin. Somatostatin release was lower on d 3 (P < 0.05) but then unchanged. The absorption rate of acetaminophen was twice as fast after GBP compared with before surgery and did not change over time. Satiety scores increased markedly postoperatively. CONCLUSION: Both enhanced insulin sensitivity and incretin hormones, such as GLP-1, contribute to the early control of glucose homeostasis. Progressively increasing postprandial levels of enteroglucagon (oxyntomodulin) and GLP-1 facilitate weight loss and enhance insulin effectiveness. PMID- 21543427 TI - Mammalian target of rapamycin pathway activation is associated to RET mutation status in medullary thyroid carcinoma. AB - CONTEXT: The genetic pathways involved in medullary thyroid carcinomas (MTC), except for RET mutations, are largely unknown, as is the detailed mapping of proteins activated as a consequence of RET tyrosine kinase phosphorylation. OBJECTIVE: The present study was designed to screen for the presence of mutations in other genes downstream to RET activation and to detect the activation patterns of a panel of intracellular regulators of cell growth. DESIGN: Forty-nine cases of MTC were analyzed for mutations in RET, BRAF, N-, H-, and K-RAS, and phosphatidylinositol-3 (PI3) kinase genes. Immunohistochemical analysis was performed using antibodies against several intracellular transducers. The effect of mammalian target of rapamycin (mTOR) inhibition was assessed in vitro onto TT cells by means of methyl thiazolyl tetrazolium and Western blot assays. RESULTS: BRAF, K-, H-, and N-RAS, and PI3 kinase mutations were absent in all cases examined. Germline RET mutations were detected in 20% of cases overall, whereas somatic RET mutations represented 53% of sporadic tumors. RET mutational status was associated to age, presence of multifocal tumors, and nodal status, but not disease outcome. Protein expression of markers investigated was highly heterogeneous, with a strong association between phospho-mTOR, phospho-AKT, and phospho-p70S6K, positively correlated to the presence of germline RET mutations. Moreover, selective mTOR inhibition affected cell proliferation of RET-mutant TT cells. CONCLUSIONS: Taken together, our findings indicate that mTOR intracellular signaling pathway is functionally activated in MTC with a preferential expression in cases with germline RET mutations; genes downstream to RET tyrosine kinase such as BRAF, RAS isoforms, and PI3 kinase are not mutated in MTC. PMID- 21543428 TI - Identification of new biomarkers of low-dose GH replacement therapy in GH deficient patients. AB - CONTEXT: GH secretion peaks at puberty and continues to be secreted in adulthood, albeit at a declining rate. Profound GH deficiency (GHD) in adults with pituitary disease is associated with symptoms that improve with GH substitution, but it is important to tailor the GH dose to avoid overtreatment. Measurement of serum IGF I levels is an important clinical tool in this regard, but it is well recognized that some patients receiving GH treatment do not show an increase in IGF-I. OBJECTIVE: The objective of the study was to identify novel serum biomarkers of GH treatment in adults with GHD. DESIGN AND PATIENTS: Eight patients with profound GHD as a consequence of a pituitary adenoma or its treatment were evaluated before and 3 months after GH replacement therapy (0.2-0.4 mg/d). MAIN OUTCOME MEASURES: Serum proteomic changes were studied using two-dimensional gel electrophoresis and mass spectrometry. Protein profiles were analyzed and compared in serum samples obtained before and after GH treatment. RESULTS: The levels of six serum protein spots were significantly altered after GH substitution. These proteins were identified as five isoforms of haptoglobin (decreased in posttreatment samples) and one isoform of apolipoprotein A-I (increased in posttreatment samples). Importantly, changes in the levels of the identified proteins were associated with decreases in fat mass and increases in lean mass in all patients. These results were independent of serum IGF-I levels. CONCLUSIONS: Evaluation of the identified proteins provides a novel alternative to traditional markers of GH status, such as serum IGF-I levels, to assess GH therapy in GH deficient adults. PMID- 21543430 TI - Increased prevalence of gallbladder polyps in acromegaly. AB - INTRODUCTION: Several studies have suggested an increased prevalence of benign and malignant tumors in acromegaly, particularly colonic neoplasms. The gallbladder's epithelial similarity to the colon raises the possibility that gallbladder polyps (GBP) may occur more frequently in acromegaly. PATIENTS AND METHODS: Thirty-one patients with newly diagnosed acromegaly (14 females, 17 males; mean age 54.7 yr, range 27-76 yr) were referred to our center between 2004 and 2008. All had pituitary adenomas and were treated with somatostatin analogs prior to transsphenoidal surgery. Biliary ultrasonography was performed at the time of referral. In a retrospective case-cohort study, we compared the prevalence of GBP in these scans with those of 13,234 consecutive patients (age range 20-80 yr) presenting at the hospital for abdominal/biliary ultrasound during the same time interval. Associations between GH and IGF-I levels and GBP in acromegaly were also examined. RESULTS: There was a higher prevalence of GBP in patients with acromegaly compared with controls (29.03 vs 4.62%, P = 0.000008); relative risk was 6.29 (95% confidence interval 3.61-10.96). Eight of nine patients with acromegaly and GBP were older than 50 yr of age. GH levels were higher in those with GBP (median 30.8 MUg/liter, interquartile range 10.9 39.1) than those without (8.2 MUg/liter, interquartile range 6.0-16.0), but IGF-I levels were comparable. CONCLUSIONS: This is the first study to demonstrate an increased prevalence of GBP in patients with newly diagnosed acromegaly. Further studies are required to determine whether these patients are at increased risk of developing gallbladder carcinoma and to define the role, if any, of biliary ultrasound surveillance. PMID- 21543429 TI - Estrogen sulfotransferase is expressed in subcutaneous adipose tissue of obese humans in association with TNF-alpha and SOCS3. AB - CONTEXT AND OBJECTIVE: Estrogen sulfotransferase (EST) catalyzes the inactivation of estrone and estradiol in numerous tissues. Animal studies suggest that EST modulates glucose and lipid metabolism in adipose tissue, but it is unknown whether EST is expressed in human adipose tissue and, if so, how its expression relates to features of the metabolic syndrome. DESIGN AND PARTICIPANTS: Cross sectional data from 16 obese men and women with metabolic dysregulation were collected as part of a larger randomized trial at an academic medical center. OUTCOME MEASURES: Participants underwent assessment of body composition, oral glucose tolerance testing, measurement of serum hormones and inflammatory markers, and sc fat biopsy to assess adipose expression of TNF-alpha, suppressor of cytokine signaling 3 (SOCS3), leptin, adiponectin, and EST. RESULTS: EST expression was detectable in sc adipose tissue from both men and women. Log(10) EST mRNA was not significantly associated with age, race, sex or menopausal status, or circulating levels of estrogen or testosterone. In univariate analysis, log(10) EST mRNA was significantly associated with visceral adipose tissue area (r = 0.57, P = 0.02) as well as adipose tissue expression of TNF alpha (r = 0.94, P < 0.0001) and SOCS3 mRNA (r = 0.93, P < 0.0001). The associations between EST expression and TNF-alpha and SOCS3 held in multivariate modeling controlling for age, race, sex and menopausal status, and visceral adiposity. EST expression was not significantly associated with the adipose tissue levels of leptin or adiponectin expression. CONCLUSIONS: EST is expressed in abdominal sc adipose tissue of both obese males and females in association with expression of TNF-alpha and SOCS3, suggesting potential roles in inflammation. Further studies are needed to determine the specific metabolic roles of EST expression in human adipose tissue. PMID- 21543431 TI - Differential effects of progesterone on COX-2 and Mn-SOD expressions are associated with histone acetylation status of the promoter region in human endometrial stromal cells. AB - CONTEXT: Progesterone differently regulates TNFalpha-induced gene expression of cyclooxygenase-2 (COX-2) and manganese superoxide dismutase (Mn-SOD) in human endometrial stromal cells (ESC). OBJECTIVE: The present study investigated the mechanisms by which TNFalpha and progesterone affect the expressions of COX-2 and Mn-SOD in ESC. METHODS: ESC were incubated with TNFalpha and progesterone. COX-2 and Mn-SOD mRNA expression was determined by real-time RT-PCR. Nuclear factor (NF)-kappaB binding to the promoter region or histone acetylation status of the NF-kappaB response element was analyzed by a chromatin immunoprecipitation assay. RESULTS: TNFalpha increased COX-2 and Mn-SOD mRNA levels. Progesterone (10(-6) M) suppressed TNFalpha-induced COX-2 mRNA expression, whereas TNFalpha-induced Mn SOD expression was not inhibited by progesterone. The inhibitory effect of progesterone was abolished by knockdown of progesterone receptors by small interfering RNA. Chromatin immunoprecipitation assay revealed that TNFalpha increased NF-kappaB binding at both the COX-2 promoter and the Mn-SOD enhancer and that progesterone inhibited only the NF-kappaB binding at the COX-2 promoter. The histone acetylation level of the NF-kappaB response element of the Mn-SOD enhancer was lower than that of the COX-2 promoter. However, when histone acetylation was induced by histone deacetylase inhibitors, progesterone inhibited the TNFalpha-induced NF-kappaB binding to the Mn-SOD enhancer. CONCLUSIONS: TNFalpha increased COX-2 and Mn-SOD expression via NF-kappaB activation. Progesterone inhibited COX-2 expression by inhibiting the binding of NF-kappaB to its response element but did not inhibit TNFalpha-induced Mn-SOD expression. The gene-specific action of progesterone may be due to the difference in chromatin structure at the NF-kappaB response elements in the COX-2 promoter and Mn-SOD enhancer. PMID- 21543432 TI - Markers of bone turnover in Gaucher disease: modeling the evolution of bone disease. AB - CONTEXT: Gaucher disease (GD) is a lysosomal storage disorder characterized by abundant presence of macrophages. Bone complications and low bone density are believed to arise from enhanced bone resorption mediated through macrophage derived factors. OBJECTIVE: The objective of the study was to investigate the relationship between bone turnover and bone complications in GD. DESIGN: This was a retrospective cohort study and review of the literature. PATIENTS: Forty adult type I GD patients were included in the study. OUTCOME MEASURES: Levels of the bone-resorption marker, type 1 collagen C-terminal telopeptide, and two bone formation markers, N-terminal propeptide of type 1 procollagen and osteocalcin, were investigated in relation to clinical bone disease, measures of overall disease severity, and imaging data representing bone marrow infiltration. RESULTS: Osteocalcin was decreased in 50% of our patients (median 0.35 nmol/liter, normal 0.4-4.0), indicating a decrease of bone formation. Type 1 collagen C-terminal telopeptide and N-terminal propeptide of type 1 procollagen were within the normal range for most patients. Osteocalcin concentration was negatively correlated to measures of overall disease severity and positively correlated with imaging data (correlation coefficient 0.423; P = 0.025), suggesting a relation with disease severity. A review of the literature revealed variable outcomes on bone resorption markers but more consistent abnormalities in bone formation markers. Two of three reports conclude that bone-formation parameters increase in response to enzyme therapy, but none describes an effect on bone-resorption markers. CONCLUSIONS: In contrast to earlier hypotheses, we propose that in GD patients, primarily a decrease in bone formation causes an imbalance in bone remodeling. PMID- 21543433 TI - Patient information page from the Hormone Foundation. Amenorrhea. PMID- 21543434 TI - Approach to the patient with nontoxic multinodular goiter. AB - Thyroid nodules are very common, and although the majority are benign, approximately 5% may harbor malignancy. The evaluation of the patient with solitary thyroid nodule is generally straightforward and will typically include measurement of serum TSH to assess thyroid function and fine-needle aspiration biopsy of the nodule, with or without ultrasound (US) guidance. The approach to the patient with nontoxic multinodular goiter represents a more difficult problem for the clinician. All patients should have serum TSH measured to assess functional thyroid status and US examination to evaluate the number, size, and sonographic features of the nodules and assist in the selection of nodules that may need fine-needle aspiration biopsy. Patients with nodules yielding malignant cytology should be referred for surgery. Given the lack of reliable markers to predict biological behavior of nodules with suspicious (indeterminate) cytology, patients with such nodules are generally advised to have surgery, unless autonomous function of these nodules can be confirmed by scintigraphy. Most of these patients, however, will ultimately prove to have benign follicular tumors. Many patients with benign but large goiters may experience clinical symptoms of pressure, such as dysphagia, choking sensation, or airway obstruction. Such patients will often require surgery for alleviation of symptoms. In the absence of malignancy, asymptomatic patients may be observed. Radioactive iodine, commonly used in many parts of Europe, is safe and effective and may be a reasonable option for many patients. Periodic follow-up with neck palpation and US exam is recommended for all patients. PMID- 21543435 TI - Coronary bypass surgery: protective effects of insulin or of prevention of hyperglycemia, or both? PMID- 21543436 TI - Thyroglobulin antibodies--failing the test. PMID- 21543437 TI - More than inflammation: interleukin-1beta polymorphisms and the lipid metabolism. PMID- 21543440 TI - Treatment recommendations for cystic fibrosis-related diabetes: too little, too late? PMID- 21543441 TI - Mechanisms of neutrophil transmigration across the vascular endothelium in COPD. AB - Chronic obstructive pulmonary disease (COPD) is a common and important disease. Neutrophils have been shown to play a fundamental role in its development and progression. Understanding the mechanisms underlying the trafficking of neutrophils across the vascular endothelium into the lung could potentially allow the development of targeted biological treatments. The early stages of neutrophil tethering, adherence to and rolling on the endothelium have been determined. The later stages of diapedesis through the glycocalyx, endothelial cell (EC) layer and basement membrane, which are less well characterised, have been reviewed here. Evidence obtained from in vitro and in vivo work, concerning the implicated adhesion molecules on the neutrophil and endothelium, the mechanisms for neutrophil navigation through the EC junction (paracellular route) and evidence for transmigration through the body of an EC itself (transcellular route), is considered. The mechanisms are complex and are often disease and stimulus specific. There is evidence that a significant degree of redundancy occurs. Transmigration in the lung differs from that in other organs in that the neutrophil can exit the circulation either through the postcapillary venule in the systemic circulation or through the capillary in the pulmonary circulation. A number of factors make the mechanisms of transmigration within the lung and COPD model unique. These include physical differences between the flow through the capillary and the postcapillary venule, the modulating effect of the alveolar epithelium and other cells such as the macrophage, the presence of a 'diseased' neutrophil and indeed the presence or absence of acute, acute on chronic or chronic pulmonary disease. PMID- 21543442 TI - DREME: motif discovery in transcription factor ChIP-seq data. AB - MOTIVATION: Transcription factor (TF) ChIP-seq datasets have particular characteristics that provide unique challenges and opportunities for motif discovery. Most existing motif discovery algorithms do not scale well to such large datasets, or fail to report many motifs associated with cofactors of the ChIP-ed TF. RESULTS: We present DREME, a motif discovery algorithm specifically designed to find the short, core DNA-binding motifs of eukaryotic TFs, and optimized to analyze very large ChIP-seq datasets in minutes. Using DREME, we discover the binding motifs of the the ChIP-ed TF and many cofactors in mouse ES cell (mESC), mouse erythrocyte and human cell line ChIP-seq datasets. For example, in mESC ChIP-seq data for the TF Esrrb, we discover the binding motifs for eight cofactor TFs important in the maintenance of pluripotency. Several other commonly used algorithms find at most two cofactor motifs in this same dataset. DREME can also perform discriminative motif discovery, and we use this feature to provide evidence that Sox2 and Oct4 do not bind in mES cells as an obligate heterodimer. DREME is much faster than many commonly used algorithms, scales linearly in dataset size, finds multiple, non-redundant motifs and reports a reliable measure of statistical significance for each motif found. DREME is available as part of the MEME Suite of motif-based sequence analysis tools (http://meme.nbcr.net). PMID- 21543443 TI - Improved similarity scores for comparing motifs. AB - MOTIVATION: A question that often comes up after applying a motif finder to a set of co-regulated DNA sequences is whether the reported putative motif is similar to any known motif. While several tools have been designed for this task, Habib et al. pointed out that the scores that are commonly used for measuring similarity between motifs do not distinguish between a good alignment of two informative columns (say, all-A) and one of two uninformative columns. This observation explains why tools such as Tomtom occasionally return an alignment of uninformative columns which is clearly spurious. To address this problem, Habib et al. suggested a new score [Bayesian Likelihood 2-Component (BLiC)] which uses a Bayesian information criterion to penalize matches that are also similar to the background distribution. RESULTS: We show that the BLiC score exhibits other, highly undesirable properties, and we offer instead a general approach to adjust any motif similarity score so as to reduce the number of reported spurious alignments of uninformative columns. We implement our method in Tomtom and show that, without significantly compromising Tomtom's retrieval accuracy or its runtime, we can drastically reduce the number of uninformative alignments. AVAILABILITY AND IMPLEMENTATION: The modified Tomtom is available as part of the MEME Suite at http://meme.nbcr.net. PMID- 21543444 TI - Structural insights into parallel strategies for germline antibody recognition of lipopolysaccharide from Chlamydia. AB - The structure of the antigen-binding fragment from the monoclonal antibody S64-4 in complex with a pentasaccharide bisphosphate fragment from chlamydial lipopolysaccharide has been determined by x-ray diffraction to 2.6 A resolution. Like the well-characterized antibody S25-2, S64-4 displays a pocket formed by the residues of germline sequence corresponding to the heavy and light chain V gene segments that binds the terminal Kdo residue of the antigen; however, although S64-4 shares the same heavy chain V gene segment as S25-2, it has a different light chain V gene segment. The new light chain V gene segment codes for a combining site that displays greater affinity, different specificity, and allows a novel antigen conformation that brings a greater number of antigen residues into the combining site than possible in S25-2. Further, while antibodies in the S25-2 family use complementarity determining region (CDR) H3 to discriminate among antigens, S64-4 achieves its specificity via the new light chain V gene segment and resulting change in antigen conformation. These structures reveal an intriguing parallel strategy where two different combinations of germline-coded V gene segments can act as starting points for the generation of germline antibodies against chlamydial antigens and show how anti-carbohydrate antibodies can exploit the conformational flexibility of this class of antigens to achieve high affinity and specificity independently of CDR H3. PMID- 21543445 TI - The role of decorin and biglycan dermatan sulfate chain(s) in fibrosis-affected fascia. AB - Organ fibrosis is associated with excessive deposition of dermatan sulfate (DS) in the extracellular matrix (ECM) of the affected tissue. However, the significance of DS in fibrosis process is poorly known. Thus, we have analyzed both in vitro and in vivo the binding potential toward fibroblast growth factor 2, platelet-derived growth factor BB and fibronectin (FN) of DS representing glycosaminoglycan (GAG) chains of two proteoglycans decorin and biglycan derived from fascia undergoing fibrosis due to Dupuytren's disease. Moreover, to investigate the relation between DS structure and its binding properties to above ligands, we have also studied the interactions of the GAG chains from normal porcine skin decorin and biglycan. The examined interactions, especially those engaging extractable pool of both human and porcine decorin DS, are characterized by very high affinity and low capacity. Moreover, the presence of iduronate residues is not essential for the DS binding to all studied ligands and the interactions more strongly depend on the GAG sulfation pattern. All investigated interactions have biological relevance as judged from the coexistence of decorin (and biglycan) DS, both growth factors and FN in supra-molecular complexes localized in ECM of both fibrous and normal human fascia. Moreover, these complexes also include collagen type III. It seems that fascia fibrosis process when compared with physiological circumstances is associated with the preservation of at least some functions of decorin and biglycan DSs such as the regulation of growth factor bioavailability and most probably influence FN fibrillogenesis as well as coupling of various fibrilar matrix element assembly. PMID- 21543446 TI - Smallpox vaccination and all-cause infectious disease hospitalization: a Danish register-based cohort study. AB - BACKGROUND: There is growing evidence from observational studies and randomized trials in low-income countries that vaccinations have non-specific effects. Administration of live vaccines reduces overall child morbidity and mortality, presumably due to protection against non-targeted infections. In Denmark, the live vaccine against smallpox was phased out in the 1970s due to the eradication of smallpox. We used the phasing-out period to investigate the effect of smallpox vaccination on the risk of hospitalization for infections. METHODS: From the Copenhagen School Health Records Register, a cohort of 4048 individuals was sampled, of whom 3559 had information about receiving or not receiving smallpox vaccination. Infectious disease hospitalizations were identified in the Danish National Patient Register. RESULTS: During 87,228 person-years of follow-up, 1440 infectious disease hospitalizations occurred. Smallpox-vaccinated individuals had a reduced risk of all-cause infectious disease hospitalization compared with smallpox-unvaccinated individuals [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.72-0.98]. The reduced risk of hospitalizations was seen for most subgroups of infectious diseases. The effect may have been most pronounced after early smallpox vaccination (vaccination age <3.5 years: HR 0.81; 95% CI 0.69 0.95; vaccination age >= 3.5 years: HR 0.91 95% CI 0.76-1.10). Among the smallpox vaccinated, the risk of infectious disease hospitalization increased 6% with each 1-year increase in vaccination age (HR 1.06; 95% CI 1.02-1.10). CONCLUSION: Smallpox vaccination is associated with a reduced risk of infectious disease hospitalization in a high-income setting. PMID- 21543447 TI - Commentary: Being gay in straight places--exploring density effects on the mental health of homosexual and bisexual populations. PMID- 21543448 TI - The undesired fellow traveller. PMID- 21543449 TI - Advanced esophageal carcinoma with a metastatic cutaneous lesion. PMID- 21543450 TI - ST-elevation myocardial infarction caused by thromboembolism from the left atrial appendage. PMID- 21543451 TI - NOA: a novel Network Ontology Analysis method. AB - Gene ontology analysis has become a popular and important tool in bioinformatics study, and current ontology analyses are mainly conducted in individual gene or a gene list. However, recent molecular network analysis reveals that the same list of genes with different interactions may perform different functions. Therefore, it is necessary to consider molecular interactions to correctly and specifically annotate biological networks. Here, we propose a novel Network Ontology Analysis (NOA) method to perform gene ontology enrichment analysis on biological networks. Specifically, NOA first defines link ontology that assigns functions to interactions based on the known annotations of joint genes via optimizing two novel indexes 'Coverage' and 'Diversity'. Then, NOA generates two alternative reference sets to statistically rank the enriched functional terms for a given biological network. We compare NOA with traditional enrichment analysis methods in several biological networks, and find that: (i) NOA can capture the change of functions not only in dynamic transcription regulatory networks but also in rewiring protein interaction networks while the traditional methods cannot and (ii) NOA can find more relevant and specific functions than traditional methods in different types of static networks. Furthermore, a freely accessible web server for NOA has been developed at http://www.aporc.org/noa/. PMID- 21543452 TI - MemPype: a pipeline for the annotation of eukaryotic membrane proteins. AB - MemPype is a Python-based pipeline including previously published methods for the prediction of signal peptides (SPEP), glycophosphatidylinositol (GPI) anchors (PredGPI), all-alpha membrane topology (ENSEMBLE), and a recent method (MemLoci) that specifically discriminates the localization of eukaryotic membrane proteins in: 'cell membrane', 'internal membranes', 'organelle membranes'. MemLoci scores with accuracy of 70% and generalized correlation coefficient (GCC) of 0.50 on a rigorous homology-unbiased validation set and overpasses other predictors for subcellular localization. The annotation process is based both on inheritance through homology and computational methods. Each submitted protein first retrieves, when available, up to 25 similar proteins (with sequence identity >=50% and alignment coverage >=50% on both sequences). This helps the identification of membrane-associated proteins and detailed localization tags. Each protein is also filtered for the presence of a GPI anchor [0.8% false positive rate (FPR)]. A positive score of GPI anchor prediction labels the sequence as exposed to 'Cell surface'. Concomitantly the sequence is analysed for the presence of a signal peptide and classified with MemLoci into one of three discriminated classes. Finally the sequence is filtered for predicting its putative all-alpha protein membrane topology (FPR <1%). The web server is available at: http://mu2py.biocomp.unibo.it/mempype. PMID- 21543453 TI - Dynamic modification of the ETS transcription factor PEA3 by sumoylation and p300 mediated acetylation. AB - Transcription factor activity is often controlled through the dynamic use of post translational modifications. Two such modifications are acetylation and sumoylation, which both occur on lysine residues, providing the opportunity for cross-talk at the molecular level. Here, we focussed on the ETS-domain transcription factor PEA3 and studied the potential interplay between these two modifications. We demonstrate that PEA3 is acetylated in a p300-dependent manner. ERK MAPK pathway signalling potentiates acetylation of PEA3, and enhances its trans-activation capacity. However, the major acetylation and sumoylation events take place on the same sites in PEA3 making simultaneous modification impossible. Indeed, manipulation of either the sumoylation or acetylation pathways causes reciprocal changes in PEA3 acetylation and sumoylation respectively. However, despite the mutually exclusive nature of these modifications, both contribute to the trans-activation capacity of PEA3, implying that a dynamic series of modification events occurs during the activation process. PMID- 21543454 TI - Specific implications of the HIV-1 nucleocapsid zinc fingers in the annealing of the primer binding site complementary sequences during the obligatory plus strand transfer. AB - Synthesis of the HIV-1 viral DNA by reverse transcriptase involves two obligatory strand transfer reactions. The second strand transfer corresponds to the annealing of the (-) and (+) DNA copies of the primer binding site (PBS) sequence which is chaperoned by the nucleocapsid protein (NCp7). NCp7 modifies the (+)/( )PBS annealing mechanism by activating a loop-loop kissing pathway that is negligible without NCp7. To characterize in depth the dynamics of the loop in the NCp7/PBS nucleoprotein complexes, we investigated the time-resolved fluorescence parameters of a (-)PBS derivative containing the fluorescent nucleoside analogue 2-aminopurine at positions 6, 8 or 10. The NCp7-directed switch of (+)/(-)PBS annealing towards the loop pathway was associated to a drastic restriction of the local DNA dynamics, indicating that NCp7 can 'freeze' PBS conformations competent for annealing via the loops. Moreover, the modifications of the PBS loop structure and dynamics that govern the annealing reaction were found strictly dependent on the integrity of the zinc finger hydrophobic platform. Our data suggest that the two NCp7 zinc fingers are required to ensure the specificity and fidelity of the second strand transfer, further underlining the pivotal role played by NCp7 to control the faithful synthesis of viral HIV-1 DNA. PMID- 21543455 TI - Dimer formation and conformational flexibility ensure cytoplasmic stability and nuclear accumulation of Elk-1. AB - The ETS (E26) protein Elk-1 serves as a paradigm for mitogen-responsive transcription factors. It is multiply phosphorylated by mitogen-activated protein kinases (MAPKs), which it recruits into pre-initiation complexes on target gene promoters. However, events preparatory to Elk-1 phosphorylation are less well understood. Here, we identify two novel, functional elements in Elk-1 that determine its stability and nuclear accumulation. One element corresponds to a dimerization interface in the ETS domain and the second is a cryptic degron adjacent to the serum response factor (SRF)-interaction domain that marks dimerization-defective Elk-1 for rapid degradation by the ubiquitin-proteasome system. Dimerization appears to be crucial for Elk-1 stability only in the cytoplasm, as latent Elk-1 accumulates in the nucleus and interacts dynamically with DNA as a monomer. These findings define a novel role for the ETS domain of Elk-1 and demonstrate that nuclear accumulation of Elk-1 involves conformational flexibility prior to its phosphorylation by MAPKs. PMID- 21543456 TI - The adaptor protein APPL1 increases glycogen accumulation in rat skeletal muscle through activation of the PI3-kinase signalling pathway. AB - APPL1 is an adaptor protein that binds to both AKT and adiponectin receptors and is hypothesised to mediate the effects of adiponectin in activating downstream effectors such as AMP-activated protein kinase (AMPK). We aimed to establish whether APPL1 plays a physiological role in mediating glycogen accumulation and insulin sensitivity in muscle and the signalling pathways involved. In vivo electrotransfer of cDNA- and shRNA-expressing constructs was used to over-express or silence APPL1 for 1 week in single tibialis cranialis muscles of rats. Resulting changes in glucose and lipid metabolism and signalling pathway activation were investigated under basal conditions and in high-fat diet (HFD)- or chow-fed rats under hyperinsulinaemic-euglycaemic clamp conditions. APPL1 over expression (OE) caused an increase in glycogen storage and insulin-stimulated glycogen synthesis in muscle, accompanied by a modest increase in glucose uptake. Glycogen synthesis during the clamp was reduced by HFD but normalised by APPL1 OE. These effects are likely explained by APPL1 OE-induced increase in basal and insulin-stimulated phosphorylation of IRS1, AKT, GSK3beta and TBC1D4. On the contrary, APPL1 OE, such as HFD, reduced AMPK and acetyl-CoA carboxylase phosphorylation and PPARgamma coactivator-1alpha and uncoupling protein 3 expression. Furthermore, APPL1 silencing caused complementary changes in glycogen storage and phosphorylation of AMPK and PI3-kinase pathway intermediates. Thus, APPL1 may provide a means for crosstalk between adiponectin and insulin signalling pathways, mediating the insulin-sensitising effects of adiponectin on muscle glucose disposal. These effects do not appear to require AMPK. Activation of signalling mediated via APPL1 may be beneficial in overcoming muscle insulin resistance. PMID- 21543457 TI - Interferon-gamma release assay for the diagnosis of tuberculosis in children. AB - AIMS: To compare the QuantiFERON-TB GOLD In Tube test (QTF) and the tuberculin skin test (TST) in children. METHODS: A prospective study was carried out in nine hospitals in Madrid, Spain. TST and QTF were performed in immigrants, tuberculosis (TB) contacts and patients with TB disease (TBD). RESULTS: 459 children were included. Disagreement between the tests was more frequently observed among latent tuberculosis infection (LTBI) cases (54%; 38/70) than in non-infected or TBD cases (0.8%; 3/369) (p<0.01). There were more BCG-vaccinated children among LTBI cases with negative QTF (76%) than among LTBI cases with positive QTF (40%) (p<0.001). Agreement between tests in BCG-vaccinated children was lower than in non-vaccinated cases (p<0.05). Tests in TB exposed patients showed better agreement than in non-exposed children (p<0.05). CONCLUSIONS: Agreement of both tests was excellent in TBD cases, non-vaccinated children and non-infected patients. A significant number of QTF negative results were observed among LTBI cases, especially in BCG-vaccinated children. Agreement was better in exposed children. PMID- 21543458 TI - Proactive recruitment in clinical trials: an idea whose time has come. PMID- 21543459 TI - Individual patient meta-analysis of exercise training effects on systemic brain natriuretic peptide expression in heart failure. AB - BACKGROUND: Brain natriuretic peptide (BNP) predicts exercise performance and exercise training may modulate BNP and its N-terminal portion (NT-pro-BNP), we therefore conducted an individual patient analysis of exercise training effects on BNP and NT-pro-BNP. AIMS: To use an individual patient meta-analysis to relate changes in BNP, NT-pro-BNP, and peak VO(2); to link these changes to volume parameters of exercise training programmes (intensity etc.); and to identify patient characteristics likely to lead to greater improvements in BNP, NT-pro BNP, and peak VO(2). DESIGN: Individual patient meta-analysis. METHODS: A systematic search was conducted of Medline (Ovid), Embase.com, Cochrane Central Register of Controlled Trials, and CINAHL (until July 2008) to identify randomized controlled trials of aerobic and/or resistance exercise training in systolic heart failure patients measuring BNP and/or NT-pro-BNP. Primary outcome measures were change in BNP, NT-pro-BNP, and peak VO2. Subanalyses were conducted to identify (1) patient groups that benefit most and (2) exercise programme parameters enhancing favourable changes in primary outcome measures. RESULTS: Ten randomized controlled studies measuring BNP or NT-pro-BNP met eligibility criteria, authors provided individual patient data for 565 patients (313 exercise and 252 controls). Exercise training had favourable effects on BNP (-28.3%, p < 0.0001), NT-pro-BNP (-37.4%, p = < 0.0001), and peak VO(2) (17.8%, p < 0.0001). The analysis showed a significant change in primary outcome measures; moreover, change in BNP (r = -0.31, p < 0.0001) and NT-pro-BNP (r = -0.22, p < 0.0001) were correlated with peak VO(2) change. CONCLUSION: Exercise training has favourable effects on BNP, NT-pro-BNP, and peak VO(2) in heart failure patients and BNP/NT pro-BNP changes were correlated with peak VO(2) changes. PMID- 21543460 TI - A modulator against mercury chloride-induced genotoxic damage: Dermatocarpon intestiniforme (L.). AB - Mercury has been used in many domains of human activities for many years, although in any form mercury is reported to be toxic. On the other hand, lichens have been used in the treatment of several diseases such as tuberculosis, hemorrhoids, ulcer, dysentery and cancer. Animal investigations on some common lichen species have demonstrated their antioxidant and antimutagenic activity. However, there is very scarce data on the medical or biologic effects of specific lichen species. Therefore, in the present study, we assessed the cyotogenetic effects of mercuric chloride (HgCl(2)) and the role of aqueous Dermatocarpon intestiniforme lichen extracts in mercury-treated human blood cultures (n = 3). The sister chromatid exchange (SCE) and micronucleus (MN) assays were performed to assess DNA damages in lymphocytes. Our results clearly revealed that the SCE and MN rates induced by HgCl(2) were alleviated by the presence of D. intestiniforme. In conclusion, the results of the present study revealed for the first time that the lichen D. intestiniforme provided increased resistance of DNA against HgCl(2)-induced genetic damage on human lymphocytes. PMID- 21543461 TI - Endosulfan-induced hepatotoxicity is route of exposure independent in rats. AB - Endosulfan is an important hepatotoxic agent that generates free oxygen radicals in liver. With the widespread use of endosulfan in agriculture, human beings are most likely to be exposed to it by eating food contaminated with endosulfan, exposure to its low levels by skin contact with contaminated soil, smoking cigarettes made from tobacco that has endosulfan residues on it, or by nose and whole body inhalation exposure in the farms during its application. Since endosulfan is a frequently used pesticide, and the incidence of toxic injury to the liver tissue in relation to its widespread use reported in the literature, we considered it necessary to investigate whether endosulfan-induced liver injury could be route of exposure dependent. Eighteen mature male albino Wistar rats, weighing between 180 and 220 g, were used in this study. The hepatotoxic effects of oral administration of endosulfan (5 mg/kg body weight) daily for 30 days, and 30 days whole body inhalation exposure to ungraded concentration of endosulfan were investigated in rats using serum liver enzymes and histopathological assay. At the end of the experimental period, serum alanine aminotransferase, aspartate amino transferase, alkaline phosphatase, and creatine kinase activities obtained for the group of rats exposed orally to endosulfan were not significantly different (p >= 0.05) from the activities obtained for rats exposed by whole body inhalation. However, the activity of these enzymes obtained for the rats exposed to endosulfan by both oral and inhalation routes were significantly increased (p <= 0.05) compared, respectively, to the control. Also, on microscopic examination, the liver tissues of experimental groups exhibited severe damage histopathologically. The results of the enzyme and histological analyses showed that both oral and whole body inhalation exposure to endosulfan may cause liver tissue damage in rats. The exposure to endosulfan in rats caused liver tissue damage independent of the route of exposure. PMID- 21543462 TI - Paraphenylene diamine hair dye poisoning in an adolescent. AB - A 14-year-old female was referred to the pediatric nephrology unit with a short history of progressive angio-oedema of the face requiring tracheostomy. She ingested an unusual substance which caused swollen tongue, cervical oedema and dark coloured brown urine. These clinical features with the laboratory tests confirmed the diagnosis of paraphenylene diamine (PPD) poisoning. Psychological assessment confirmed that the child had severe depression. The suicide attempt was just immediately after failure in the final qualifying examination to secondary school. She did not have any family support but she used to be punished in different ways. In Sudan PPD in its pure form is available in the local market and until recently there was no restrictions for its use or trade. Adolescents are well aware of its toxic effects and it is commonly used to attempt suicide. Legislation and laws should prevent its use in different hair dye formulations and look for another substitute. Clinical management is hampered by the lack of a rapid diagnostic test; no other treatment other than supportive measures can be offered. PMID- 21543463 TI - The neuroprotective role of boric acid on aluminum chloride-induced neurotoxicity. AB - This study was designed to investigate the qualitative and quantitative changes in brain tissue following aluminum chloride (AlCl(3)) administration and to determine whether boric acid (BA) has a protective effect against brain damage induced by AlCl( 3). For this aim, Sprague-Dawley rats were randomly separated into eight groups: (1) control, (2) AlCl(3) (5 mg/kg/day), (3, 4 and 5) BA (3.25, 36 and 58.5 mg/kg/day), (6, 7 and 8) AlCl(3) (5 mg/kg/day) plus BA (3.25, 36 and 58.5 mg/kg/day). After the animals were killed, the total numbers of neuron in the brain of all groups were determined using an unbiased stereological analysis. In addition to the stereological analysis, all brains were examined histopathologically by using light and electron microscopy. The stereological and histopathological results indicated a high damage of the rat brain tissues in the AlCl(3) and AlCl(3) + high dose BA (36 and 58.5) treatment groups. However, protective effects on neuron were observed in the AlCl(3) + low dose BA (3.25) group when compared other AlCl(3) groups. Our stereological and histopathological findings show that low-dose BA, as a proteasome inhibitor, can decrease the adverse effects of AlCl(3) on the cerebral cortex. PMID- 21543464 TI - Oxidative stress induced by chromium (VI) in bone of suckling rats. AB - Exposure to hexavalent chromium Cr(VI) compounds is of concern in many Cr-related industries and their surrounding environments. K(2)Cr(2)O(7) is widely recognized as an animal and human carcinogen, mutagen, and teratogen. The present study investigated the bone maturity of suckling rats whose mothers were treated with K(2)Cr(2)O(7). Experiments were carried out on female Wistar rats given 700 ppm of K(2)Cr(2)O(7) in their drinking water from the 14th day of pregnancy until day 14 after delivery. Exposing dams to K(2)Cr(2)O(7) caused disorders in the bone of their progeny. As corollary to this, malondialdehyde levels increased, while glutathione, a non-protein thiol and vitamin C decreased. Alteration of the antioxidant system in the treated group was also confirmed by the significant decline of superoxide dismutase, catalase, and glutathione peroxidase activities. Furthermore, K(2)Cr(2)O(7) induced changes in bone mineralization, especially calcium and phosphorus levels, which decreased. Whereas, in plasma and urine, they increased and decreased inversely. These results suggest that K(2)Cr(2)O(7) accelerated bone resorption activity. In fact, in treated pups, total tartrate resistant acid phosphatase, which reflected bone resorption, was enhanced while total alkaline phosphatase, which reflected bone formation, was reduced. The impairment of bone function was corresponded histologically. PMID- 21543465 TI - Pre-existing liver cirrhosis reduced the toxic effect of diethylene glycol in a rat model due to the impaired hepatic alcohol dehydrogenase. AB - Hepatic metabolizing enzymes of diethylene glycol (DEG) are impaired in liver diseases. Thus, the purpose of this study was to increase our understandings in metabolism and toxicology of DEG by clarifying the influences of pre-existing liver disease. Forty Sprague-Dawley rats with carbon tetrachloride-induced liver cirrhosis and 20 control rats were intraperitoneally administered a single dose of DEG, and randomly killed 1, 2, 5 or 8 days following exposure. Compared with control rats, the model rats had significantly higher blood CO(2)-combining power, lower blood urine nitrogen, serum creatinine and alanine aminotransferase levels on the second day and a lower mortality rate on the eighth day following DEG exposure. Enlargements of liver and kidneys and degeneration and necrosis of hepatocytes and renal tubules in the model rats was also less serious than in the control rats. Urine DEG levels were significantly higher on the first day in the model rats than the control rats (46.65 +/- 8.79 mg vs 18.88 +/- 6.18 mg, p < 0.01), but DEG concentrations in the blood, liver and kidneys were lower. Hepatic alcohol dehydrogenase (ADH) activity in the model rats was significantly lower than that in the control rats, which was positively related to renal damage. The toxic effects of DEG in rats with pre-existing liver cirrhosis are significantly reduced, which may be due to the decreased hepatic ADH activity. It suggests that the metabolite of ADH is responsible for DEG poisoning, and this toxic metabolite may mainly originate in the liver. PMID- 21543466 TI - Subclinical abnormalities in workers with continuous low-level toluene exposure. AB - Short-term exposure to a high concentration (TWA > 100 ppm) of toluene can cause hepatotocixity and neurotoxicity in humans. Data on the effects of exposure to low levels of toluene, however, are controversial. In addition, few studies on the effects of toluene exposure on the autonomic nervous system have been conducted. Urine samples from 34 male factory workers in Taiwan who were exposed to low levels of toluene either intermittently (n = 13) or continuously (n = 21) were taken on a Monday morning after a 2-day hiatus and at the end of the workweek on Friday evening. Urinary hippuric acid levels were measured using high performance liquid chromatography (HPLC). A complete blood work-up was also performed for each subject. The prevalence and severity of neurotoxic symptoms were investigated by a self-reported questionnaire, a neuropsychiatric battery, and sympathetic and peripheral nerve function tests. The mean value of urinary hippuric acid corrected for creatinine (Cr) was 0.34 +/- 0.18 g/g Cr on Monday morning and 0.43 +/- 0.26 g/g Cr on Friday evening. The difference in the mean value of urinary hippuric acid between the two periods (p < 0.01) and the odds ratio of impairment of sympathetic (OR = 4.13, p = 0.11) and peripheral nerves (OR = 6.94, p = 0.074) were higher in workers continuously exposed to toluene. In addition, workers who were continuously exposed to toluene had a lower mean platelet count (216 +/- 41 * 10(6) /uL) than workers who were intermittently exposed (252 +/- 40 * 10(6)/uL), (p = 0.018). Furthermore, there was a positive relationship between neurological abnormalities and a self-reported neuropsychiatric measurement (r = 0.35-0.66, p < 0.05) in all workers. These data suggest that continuous exposure to low levels of toluene may be associated with sympathetic and peripheral nerve dysfunction and sub-clinical hematological damage. Further research needs to be carried out regarding how chronic exposure to low-levels of toluene affects workers. PMID- 21543467 TI - Diazinon-induced brain toxicity and protection by vitamins E plus C. AB - Diazinon (DI) is a widely used pesticide in agriculture, resulting in environmental deleterious effects on neural systems. The current study was performed to investigate the effects of treatment with vitamins E plus C on brain toxicity, which is possibly induced by DI. Twenty-one male rats were divided into three groups (n = 7/group) as follows: (1) control group (C); (2) DI-treated group (DI); (3) DI + vitamins E plus C-treated group (DI + Vit). In order to examine lipid peroxidation and antioxidant status in rats, the level of malondialdehyde (MDA), activities of two free radical scavanging enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) have been studied in brain of rat. The results showed that treatment with DI induced significant (p < 0.05) increases in the level of serum MDA in rat brain. The vitamins E plus C combination reduced lipid peroxidation in rat brain. The activity of SOD level was significantly higher in DI + Vit group, compared to the control group. GSH-Px, SOD and CAT values were not significantly different in the DI group than in control. Oxidative stress contributes to DI-induced brain toxicity. Our results suggested that vitamins E plus C combination may have a protective effect on DI-induced brain toxicity. PMID- 21543468 TI - Identification of amino acid residues important for heparan sulfate proteoglycan interaction within variable region 3 of the feline immunodeficiency virus surface glycoprotein. AB - Heparan sulfate proteoglycans (HSPGs) act as binding receptors or attachment factors for the viral envelope of many viruses, including strains of HIV and feline immunodeficiency virus (FIV). The FIV gp95 glycoprotein (SU) from laboratory-adapted strains (tissue culture adapted [TCA]) such as FIV-34TF10 can bind to HSPG, whereas SU from field strains (FS) such as FIV-PPR cannot. Previous studies indicate that SU-HSPG interactions occur within the V3 loop. We utilized a series of nested V3 peptides to further map the HSPG binding sites and found that both sides of the predicted V3 loop stem were critical for the binding but not the CXCR4 binding domain near the predicted tip of the V3 loop. Neutralization assays for TCA strain entry using the same set of V3 peptides showed that peptides targeting CXCR4 or HSPG binding sites can block infection, supporting the V3 loop as a critical neutralization target. Site-directed mutagenesis identified two highly conserved arginines, R379 and R389, on the N terminal side of the V3 stem as critical for the contact between SU and HSPG. Residues K407, K409, K410, and K412 on the C-terminal side of the V3 stem form a second nonconserved domain necessary for HSPG binding, consistent with the observed specificity distinctions with FS FIV. Our findings discriminate structural determinants important for HSPG and CXCR4 binding by FIV SU and thus further define the importance of the V3 loop for virus entry and infection. PMID- 21543469 TI - Host-based ribavirin resistance influences hepatitis C virus replication and treatment response. AB - Many individuals infected with hepatitis C virus (HCV) develop a chronic infection, and of those who are treated with pegylated interferon and ribavirin (RBV), many do not respond. While the nucleoside analog RBV improves treatment outcome, and will likely be an important component of therapy with next generation viral inhibitors, RBV's mechanism is controversial. Most of RBV's proposed mechanisms require RBV import into cells. Therefore, we explored whether host-based RBV resistance develops through reduced cellular uptake, akin to chemotherapy resistance in some cancers. We examined the effect of host-based RBV resistance on HCV replication in cultured hepatoma Huh7.5 liver cells and whether RBV resistance develops in HCV patients. When Huh7.5 cells were exposed to RBV, resistance developed through reduced RBV uptake via the ENT1 nucleoside transporter and antiviral efficacy was reduced. The uptake defect in RBV resistant cells was specific to RBV, since transport of another ENT1 substrate, cytidine, was unaffected. Importantly, RBV uptake significantly declined in HCV patient peripheral blood mononuclear cells (PBMCs) following 4 weeks of therapy. Furthermore, maintenance of RBV uptake correlated with rapid treatment response. Our results uncovered a novel form of antiviral drug resistance and suggest that host-based RBV resistance develops in HCV patients undergoing therapy and that maintenance of RBV uptake may contribute to rapid viral clearance. PMID- 21543470 TI - RNA sequence determinants of a coupled termination-reinitiation strategy for downstream open reading frame translation in Helminthosporium victoriae virus 190S and other victoriviruses (Family Totiviridae). AB - The genome-length, dicistronic mRNA of the double-stranded RNA fungal virus Helminthosporium victoriae virus 190S (genus Victorivirus, family Totiviridae) contains two long open reading frames (ORFs) that overlap in the tetranucleotide AUGA. Translation of the downstream ORF, which encodes the RNA-dependent RNA polymerase (RdRp), has been proposed to depend on ribosomal reinitiation following termination of the upstream ORF, which encodes the capsid protein. In the current study, we examined the RNA sequence determinants for RdRp translation in this virus and demonstrated that a coupled termination-reinitiation (stop restart) strategy is indeed used. Signals for termination-reinitiation are found within a 32-nucleotide stretch of RNA immediately upstream of the AUGA motif, including a predicted pseudoknot structure. The close proximity in which this predicted structure is followed by the upstream ORF's stop codon appears to be especially important for promoting translation of the downstream ORF. The normal strong preferences for an AUG start codon and the canonical sequence context to favor translation initiation appear somewhat relaxed for the downstream ORF. Similar sequence motifs and predicted RNA structures in other victoriviruses suggest that they all share a related stop-restart strategy for RdRp translation. Members of the genus Victorivirus thus provide new and unique opportunities for exploring the molecular mechanisms of translational coupling, which remain only partly understood in this and other systems. PMID- 21543471 TI - Heliothis zea nudivirus 1 gene hhi1 induces apoptosis which is blocked by the Hz iap2 gene and a noncoding gene, pag1. AB - Heliothis zea nudivirus 1 (HzNV-1 or Hz-1 virus), previously regarded as a nonoccluded baculovirus, recently has been placed in the Nudivirus genus. This virus generates HzNV-1 HindIII-I 1 (hhi1) and many other transcripts during productive viral infection; during latent viral infection, however, persistency associated gene 1 (pag1) is the only gene expressed. In this report, we used transient expression assays to show that hhi1 can trigger strong apoptosis in transfected cells, which can be blocked, at least partially, by the inhibitor of apoptosis genes Autographa californica iap2 (Ac-iap2) and H. zea iap2 (Hz-iap2). In addition to these two genes, unexpectedly, pag1, which encodes a noncoding RNA with no detectable protein product, was found to efficiently suppress hhi1 induced apoptosis. The assay of pro-Sf-caspase-1 processing by hhi1 transfection did not detect the small P12 subunit at any of the time intervals tested, suggesting that hhi1 of HzNV-1 induces apoptosis through alternative caspase pathways. PMID- 21543472 TI - Role of CD4+ and CD8+ T-cell responses against JC virus in the outcome of patients with progressive multifocal leukoencephalopathy (PML) and PML with immune reconstitution inflammatory syndrome. AB - Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the brain caused by JC virus (JCV). To assess the role of CD4(+) and CD8(+) T-cells against JCV in the clinical outcome of PML and PML in the setting of immune reconstitution inflammatory syndrome (IRIS), we tested gamma interferon (IFN-gamma) response by enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) in 117 subjects, including 66 PML patients with different clinical outcomes. Both assays were concordant and demonstrated that the cellular immune response against JCV is associated with better clinical outcome. PML survivors had an early CD8(+) T-cell response more frequently than PML progressors (100% versus 27.3%; P = 0.001), while only a trend was observed for the early CD4(+) T-cell response between these two groups (80% versus 45.5%; P = 0.18). Although IRIS itself was more frequent in the PML survivor group, there was no difference in IFN-gamma-producing CD4(+) and CD8(+) T-cells between IRIS and non-IRIS PML patients, suggesting that T-cells expressing other cytokines likely have a role in the immunopathogenesis of IRIS. ELISpot and ICS assays are useful prognostic markers of PML evolution and may help in the clinical management of these patients. PMID- 21543473 TI - Epstein-Barr virus Zta-induced immunomodulators from nasopharyngeal carcinoma cells upregulate interleukin-10 production from monocytes. AB - During lytic infection with Epstein-Barr virus (EBV), several viral lytic proteins function to evade immune recognition or to actively suppress immune cells. An EBV lytic transactivator, Zta, induces an immunosuppressive cytokine interleukin 10 (IL-10) in B cells, but whether it regulates IL-10 in the context of epithelial cells is unclear. In this study, we tested nasopharyngeal carcinoma (NPC) cell lines and found that Zta did not induce IL-10 in these epithelial cells. Interestingly, the conditioned medium of Zta-expressing NPC cells enhanced IL-10 production from monocytes. We further revealed that the IL-10-inducing effect involved at least two immunomodulators that were upregulated by Zta and secreted from NPC cells: granulocyte-macrophage colony-stimulating factor (GM CSF) and prostaglandin E(2) (PGE(2)). Zta was recruited to and activated the GM CSF promoter, thus upregulating GM-CSF expression. Zta also activated the promoter of cyclooxygenase-2 (COX-2), and Zta-induced COX-2 increased downstream PGE(2) production. Cotreatment with GM-CSF and PGE(2) synergistically induced IL 10 production from monocytes. The IL-10-inducing effect of the Zta-conditioned medium was reduced when GM-CSF or the COX-2/PGE(2) pathway was blocked. The conditioned medium of NPC cells with EBV lytic infection showed a similar increase of GM-CSF and PGE(2) levels as well as the IL-10-inducing effect on monocytes, and knockdown of Zta abolished all the effects. Therefore, through Zta induced immunomodulators, EBV lytic infection in NPC cells can direct bystander monocytes to produce IL-10, which may be a novel way of EBV to promote local immunosuppression. PMID- 21543474 TI - NS4B self-interaction through conserved C-terminal elements is required for the establishment of functional hepatitis C virus replication complexes. AB - Hepatitis C virus (HCV) is an important human pathogen, persistently infecting more than 170 million individuals worldwide. Studies of the HCV life cycle have become possible with the development of cell culture systems supporting the replication of viral RNA and the production of infectious virus. However, the exact functions of individual proteins, especially of nonstructural protein 4B (NS4B), remain poorly understood. NS4B triggers the formation of specific, vesicular membrane rearrangements, referred to as membranous webs, which have been reported to represent sites of HCV RNA replication. However, the mechanism of vesicle induction is not known. In this study, a panel of 15 mutants carrying substitutions in the highly conserved NS4B C-terminal domain was generated. Five mutations had only a minor effect on replication, but two of them enhanced assembly and release of infectious virus. Ten mutants were replication defective and used for selection of pseudoreversions. Most of the pseudoreversions also localized to the highly conserved NS4B C-terminal domain and were found to restore replication competence upon insertion into the corresponding primary mutant. Importantly, pseudoreversions restoring replication competence also restored heterotypic NS4B self-interaction, which was disrupted by the primary mutation. Finally, electron microscopy analyses of membrane alterations induced by NS4B mutants revealed striking morphological abnormalities, which were restored to wild-type morphology by the corresponding pseudoreversion. These findings demonstrate the important role of the C-terminal domain in NS4B self interaction and the formation of functional HCV replication complexes. PMID- 21543475 TI - Gene-specific contributions to mumps virus neurovirulence and neuroattenuation. AB - Mumps virus (MuV) is highly neurotropic and was the leading cause of aseptic meningitis in the Western Hemisphere prior to widespread use of live attenuated MuV vaccines. Due to the absence of markers of virus neuroattenuation and neurovirulence, ensuring mumps vaccine safety has proven problematic, as demonstrated by the occurrence of aseptic meningitis in recipients of certain vaccine strains. Here we examined the genetic basis of MuV neuroattenuation and neurovirulence by generating a series of recombinant viruses consisting of combinations of genes derived from a cDNA clone of the neurovirulent wild-type 88 1961 strain (r88) and from a cDNA clone of the highly attenuated Jeryl Lynn vaccine strain (rJL). Testing of these viruses in rats demonstrated the ability of several individual rJL genes and gene combinations to significantly neuroattenuate r88, with the greatest effect imparted by the rJL nucleoprotein/matrix protein combination. Interestingly, no tested combination of r88 genes, including the nucleoprotein/matrix protein combination, was able to convert rJL into a highly neurovirulent virus, highlighting mechanistic differences between processes involved in neuroattenuation and neurovirulence. PMID- 21543476 TI - Adaptation of Saffold virus 2 for high-titer growth in mammalian cells. AB - Saffold viruses (SAFV) are a recently discovered group of human Cardioviruses closely related to Theiler's murine encephalomyelitis viruses (TMEV). Unlike TMEV and encephalomyocarditis virus, each of which is monotypic, SAFV are genetically diverse and include at least eight genotypes. To date, only Saffold virus 3 (SAFV 3) has been grown efficiently in mammalian cells in vitro. Here, we report the successful adaptation of SAFV-2 for efficient growth in HeLa cells after 13 passages in the alpha/beta interferon-deficient human glial cell line U118 MG. Nine amino acid changes were found in the adapted virus, with single mutations in VP2, VP3, and 2B, while 6 mutations arose in VP1. Most capsid mutations were in surface loops. Analysis of SAFV-2 revealed virus growth and cytopathic effect only in human cell lines, with large plaques forming in HeLa cells, with minimal cell association, and without using sialic acid to enter cells. Despite the limited growth of SAFV-2 in rodent cells in vitro, BALB/c mice inoculated with SAFV-2 showed antibody titers of >1:10(6), and fluorescence-activated cell sorting (FACS) analysis revealed only minimal cross-reactivity with SFV-3. Intracerebral inoculation of 6-week-old FVB/n mice produced paralysis and acute neuropathological changes, including meningeal infiltrates, encephalitis, particularly of the limbic system, and spinal cord white matter inflammation. PMID- 21543477 TI - Peptides derived from a distinct region of GB virus C glycoprotein E2 mediate strain-specific HIV-1 entry inhibition. AB - The nonpathogenic human GB virus C (GBV-C), a member of the Flaviviridae, is highly prevalent in individuals with HIV-1 infections or with parenteral and sexual risk factors. Long-term GBV-C viremia has been associated with better survival or improved diagnosis in several epidemiological studies. In a previous study we reported that the E2 glycoprotein of GBV-C interferes with HIV-1 entry in vitro. To address the question what region of the E2 protein is involved in suppression of HIV-1 replication, we performed an E2-derived peptide scanning and determined the HIV-inhibitory activity of each peptide in HIV replication assays. We demonstrate here that peptides representing the N-terminal part of the E2 protein from amino acids (aa) 29 to 72 are able to inhibit efficiently HIV-1 replication in vitro. In particular, the peptides P6-2 (representing the E2 region from aa 45 to 64) and P4762 (aa 37 to 64) showed the highest potency in HIV replication assays performed on TZM-bl cells with 50% inhibitory concentrations between 0.1 and 2 MUM. However, primary HIV-1 isolates representing clades A to H showed a high variability in their sensitivity to E2 peptides. Pseudovirus inhibition assays revealed that the sensitivity is determined by the gp120/gp41 envelope proteins. Using HIV-1 BlaM-Vpr-based fusion assays, we demonstrate that the E2-derived peptides prevent HIV-1 binding or fusion, presumably via interaction with the HIV-1 particle. Together, these findings reveal a new mechanism of viral interference, suggesting that the envelope protein E2 of GBV-C target directly HIV-1 particles to avoid entry of these virions. PMID- 21543479 TI - Multiploid inheritance of HIV-1 during cell-to-cell infection. AB - During cell-to-cell transmission of human immunodeficiency virus type 1 (HIV-1), many viral particles can be simultaneously transferred from infected to uninfected CD4 T cells through structures called virological synapses (VS). Here we directly examine how cell-free and cell-to-cell infections differ from infections initiated with cell-free virus in the number of genetic copies that are transmitted from one generation to the next, i.e., the genetic inheritance. Following exposure to HIV-1-expressing cells, we show that target cells with high viral uptake are much more likely to become infected. Using T cells that coexpress distinct fluorescent HIV-1 variants, we show that multiple copies of HIV-1 can be cotransmitted across a single VS. In contrast to cell-free HIV-1 infection, which titrates with Poisson statistics, the titration of cell associated HIV-1 to low rates of overall infection generates a constant fraction of the newly infected cells that are cofluorescent. Triple infection was also readily detected when cells expressing three fluorescent viruses were used as donor cells. A computational model and a statistical model are presented to estimate the degree to which cofluorescence underestimates coinfection frequency. Lastly, direct detection of HIV-1 proviruses using fluorescence in situ hybridization confirmed that significantly more HIV-1 DNA copies are found in primary T cells infected with cell-associated virus than in those infected with cell-free virus. Together, the data suggest that multiploid inheritance is common during cell-to-cell HIV-1 infection. From this study, we suggest that cell-to cell infection may explain the high copy numbers of proviruses found in infected cells in vivo and may provide a mechanism through which HIV preserves sequence heterogeneity in viral quasispecies through genetic complementation. PMID- 21543478 TI - HIV-1 Nef disrupts intracellular trafficking of major histocompatibility complex class I, CD4, CD8, and CD28 by distinct pathways that share common elements. AB - The Nef protein is an important HIV virulence factor that promotes the degradation of host proteins to augment virus production and facilitate immune evasion. The best-characterized targets of Nef are major histocompatibility complex class I (MHC-I) and CD4, but Nef also has been reported to target several other proteins, including CD8beta, CD28, CD80, CD86, and CD1d. To compare and contrast the effects of Nef on each protein, we constructed a panel of chimeric proteins in which the extracellular and transmembrane regions of the MHC-I allele HLA-A2 were fused to the cytoplasmic tails of CD4, CD28, CD8beta, CD80, CD86, and CD1d. We found that Nef coprecipitated with and disrupted the expression of molecules with cytoplasmic tails from MHC-I HLA-A2, CD4, CD8beta, and CD28, but Nef did not bind to or alter the expression of molecules with cytoplasmic tails from CD80, CD86, and CD1d. In addition, we used short interfering RNA (siRNA) knockdown and coprecipitation experiments to implicate AP-1 as a cellular cofactor for Nef in the downmodulation of both CD28 and CD8beta. The interaction with AP-1 required for CD28 and CD8beta differed from the AP-1 interaction required for MHC-I downmodulation in that it was mediated through the dileucine motif within Nef (LL(164,165)AA) and did not require the tyrosine binding pocket of the AP-1 MU subunit. In addition, we demonstrate a requirement for beta-COP as a cellular cofactor for Nef that was necessary for the degradation of targeted molecules HLA-A2, CD4, and CD8. These studies provide important new information on the similarities and differences with which Nef affects intracellular trafficking and help focus future research on the best potential pharmaceutical targets. PMID- 21543480 TI - HIV Gag-leucine zipper chimeras form ABCE1-containing intermediates and RNase resistant immature capsids similar to those formed by wild-type HIV-1 Gag. AB - During HIV-1 assembly, Gag polypeptides multimerize to form an immature capsid and also package HIV-1 genomic RNA. Assembling Gag forms immature capsids by progressing through a stepwise pathway of assembly intermediates containing the cellular ATPase ABCE1, which facilitates capsid formation. The NC domain of Gag is required for ABCE1 binding, acting either directly or indirectly. NC is also critical for Gag multimerization and RNA binding. Previous studies of GagZip chimeric proteins in which NC was replaced with a heterologous leucine zipper that promotes protein dimerization but not RNA binding established that the RNA binding properties of NC are dispensable for capsid formation per se. Here we utilized GagZip proteins to address the question of whether the RNA binding properties of NC are required for ABCE1 binding and for the formation of ABCE1 containing capsid assembly intermediates. We found that assembly-competent HIV-1 GagZip proteins formed ABCE1-containing intermediates, while assembly-incompetent HIV-1 GagZip proteins harboring mutations in residues critical for leucine zipper dimerization did not. Thus, these data suggest that ABCE1 does not bind to NC directly or through an RNA bridge, and they support a model in which dimerization of Gag, mediated by NC or a zipper, results in exposure of an ABCE1-binding domain located elsewhere in Gag, outside NC. Additionally, we demonstrated that immature capsids formed by GagZip proteins are insensitive to RNase A, as expected. However, unexpectedly, immature HIV-1 capsids were almost as insensitive to RNase A as GagZip capsids, suggesting that RNA is not a structural element holding together immature wild-type HIV-1 capsids. PMID- 21543481 TI - Inhibition of human BK polyomavirus replication by small noncoding RNAs. AB - Small noncoding RNAs regulate a variety of cellular processes, including genomic imprinting, chromatin remodeling, replication, transcription, and translation. Here, we report small replication-regulating RNAs (srRNAs) that specifically inhibit DNA replication of the human BK polyomavirus (BKV) in vitro and in vivo. srRNAs from FM3A murine mammary tumor cells were enriched by DNA replication assay-guided fractionation and hybridization to the BKV noncoding control region (NCCR) and synthesized as cDNAs. Selective mutagenesis of the cDNA sequences and their putative targets suggests that the inhibition of BKV DNA replication is mediated by srRNAs binding to the viral NCCR, hindering early steps in the initiation of DNA replication. Ectopic expression of srRNAs in human cells inhibited BKV DNA replication in vivo. Additional srRNAs were designed and synthesized that specifically inhibit simian virus 40 (SV40) DNA replication in vitro. These observations point to novel mechanisms for regulating DNA replication and suggest the design of synthetic agents for inhibiting replication of polyomaviruses and possibly other viruses. PMID- 21543482 TI - The host phosphoinositide 5-phosphatase SHIP2 regulates dissemination of vaccinia virus. AB - After fusing with the plasma membrane, enveloped poxvirus virions form actin filled membranous protrusions, called tails, beneath themselves and move toward adjacent uninfected cells. While much is known about the host and viral proteins that mediate formation of actin tails, much less is known about the factors controlling release. We found that the phosphoinositide 5-phosphatase SHIP2 localizes to actin tails. Localization requires phosphotyrosine, Abl and Src family tyrosine kinases, and neural Wiskott-Aldrich syndrome protein (N-WASP) but not the Arp2/Arp3 complex or actin. Cells lacking SHIP2 have normal actin tails but release more virus. Moreover, cells infected with viral strains with mutations in the release inhibitor A34 release more virus but recruit less SHIP2 to tails. Thus, the inhibitory effects of A34 on virus release are mediated by SHIP2. Together, these data suggest that SHIP2 and A34 may act as gatekeepers to regulate dissemination of poxviruses when environmental conditions are conducive. PMID- 21543483 TI - Beta interferon controls West Nile virus infection and pathogenesis in mice. AB - Studies with mice lacking the common plasma membrane receptor for type I interferon (IFN-alphabetaR(-)(/)(-)) have revealed that IFN signaling restricts tropism, dissemination, and lethality after infection with West Nile virus (WNV) or several other pathogenic viruses. However, the specific functions of individual IFN subtypes remain uncertain. Here, using IFN-beta(-)(/)(-) mice, we defined the antiviral and immunomodulatory function of this IFN subtype in restricting viral infection. IFN-beta(-)(/)(-) mice were more vulnerable to WNV infection than wild-type mice, succumbing more quickly and with greater overall mortality, although the phenotype was less severe than that of IFN-alphabetaR( )(/)(-) mice. The increased susceptibility of IFN-beta(-)(/)(-) mice was accompanied by enhanced viral replication in different tissues. Consistent with a direct role for IFN-beta in control of WNV replication, viral titers in ex vivo cultures of macrophages, dendritic cells, fibroblasts, and cerebellar granule cell neurons, but not cortical neurons, from IFN-beta(-)(/)(-) mice were greater than in wild-type cells. Although detailed immunological analysis revealed no major deficits in the quality or quantity of WNV-specific antibodies or CD8(+) T cells, we observed an altered CD4(+) CD25(+) FoxP3(+) regulatory T cell response, with greater numbers after infection. Collectively, these results suggest that IFN-beta controls WNV pathogenesis by restricting infection in key cell types and by modulating T cell regulatory networks. PMID- 21543484 TI - Interleukin-6, produced by resident cells of the central nervous system and infiltrating cells, contributes to the development of seizures following viral infection. AB - Cells that can participate in an innate immune response within the central nervous system (CNS) include infiltrating cells (polymorphonuclear leukocytes [PMNs], macrophages, and natural killer [NK] cells) and resident cells (microglia and sometimes astrocytes). The proinflammatory cytokine interleukin-6 (IL-6) is produced by all of these cells and has been implicated in the development of behavioral seizures in the Theiler's murine encephalomyelitis virus (TMEV) induced seizure model. The assessment, via PCR arrays, of the mRNA expression levels of a large number of chemokines (ligands and receptors) in TMEV-infected and mock-infected C57BL/6 mice both with and without seizures did not clearly demonstrate the involvement of PMNs, monocytes/macrophages, or NK cells in the development of seizures, possibly due to overlapping function of the chemokines. Additionally, C57BL/6 mice unable to recruit or depleted of infiltrating PMNs and NK cells had seizure rates comparable to those of controls following TMEV infection, and therefore PMNs and NK cells do not significantly contribute to seizure development. In contrast, C57BL/6 mice treated with minocycline, which affects monocytes/macrophages, microglial cells, and PMNs, had significantly fewer seizures than controls following TMEV infection, indicating monocytes/macrophages and resident microglial cells are important in seizure development. Irradiated bone marrow chimeric mice that were either IL-6-deficient mice reconstituted with wild-type bone marrow cells or wild-type mice reconstituted with IL-6-deficient bone marrow cells developed significantly fewer behavioral seizures following TMEV infection. Therefore, both resident CNS cells and infiltrating cells are necessary for seizure development. PMID- 21543486 TI - A reassortment-incompetent live attenuated influenza virus vaccine for protection against pandemic virus strains. AB - Although live-attenuated influenza vaccines (LAIV) are safe for use in protection against seasonal influenza strains, concerns regarding their potential to reassort with wild-type virus strains have been voiced. LAIVs have been demonstrated to induce enhanced mucosal and cell-mediated immunity better than inactivated vaccines while also requiring a smaller dose to achieve a protective immune response. To address the need for a reassortment-incompetent live influenza A virus vaccine, we have designed a chimeric virus that takes advantage of the fact that influenza A and B viruses do not reassort. Our novel vaccine prototype uses an attenuated influenza B virus that has been manipulated to express the ectodomain of the influenza A hemagglutinin protein, the major target for eliciting neutralizing antibodies. The hemagglutinin RNA segment is modified such that it contains influenza B packaging signals, and therefore it cannot be incorporated into a wild-type influenza A virus. We have applied our strategy to different influenza A virus subtypes and generated chimeric B/PR8 HA (H1), HK68 (H3), and VN (H5) viruses. All recombinant viruses were attenuated both in vitro and in vivo, and immunization with these recombinant viruses protected mice against lethal influenza A virus infection. Overall, our data indicate that the chimeric live-attenuated influenza B viruses expressing the modified influenza A hemagglutinin are effective LAIVs. PMID- 21543485 TI - An HIV-1 gp120 envelope human monoclonal antibody that recognizes a C1 conformational epitope mediates potent antibody-dependent cellular cytotoxicity (ADCC) activity and defines a common ADCC epitope in human HIV-1 serum. AB - Among nonneutralizing HIV-1 envelope antibodies (Abs), those capable of mediating antibody-dependent cellular cytotoxicity (ADCC) activity have been postulated to be important for control of HIV-1 infection. ADCC-mediating Ab must recognize HIV 1 antigens expressed on the membrane of infected cells and bind the Fcgamma receptor (FcR) of the effector cell population. However, the precise targets of serum ADCC antibody are poorly characterized. The human monoclonal antibody (MAb) A32 is a nonneutralizing antibody isolated from an HIV-1 chronically infected person. We investigated the ability of MAb A32 to recognize HIV-1 envelope expressed on the surface of CD4(+) T cells infected with primary and laboratory adapted strains of HIV-1, as well as its ability to mediate ADCC activity. The MAb A32 epitope was expressed on the surface of HIV-1-infected CD4(+) T cells earlier than the CD4-inducible (CD4i) epitope bound by MAb 17b and the gp120 carbohydrate epitope bound by MAb 2G12. Importantly, MAb A32 was a potent mediator of ADCC activity. Finally, an A32 Fab fragment blocked the majority of ADCC-mediating Ab activity in plasma of subjects chronically infected with HIV-1. These data demonstrate that the epitope defined by MAb A32 is a major target on gp120 for plasma ADCC activity. PMID- 21543487 TI - Kaposi's sarcoma-associated herpesvirus infection of endothelial cells inhibits neutrophil recruitment through an interleukin-6-dependent mechanism: a new paradigm for viral immune evasion. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), an endothelial cell (EC) neoplasm characterized by dysregulated angiogenesis and inflammation. KSHV infection of EC causes production of proinflammatory mediators, regarded as possible initiators of the substantial mononuclear leukocyte recruitment seen in KS. Conversely, KSHV immune evasion strategies exist, such as degradation of EC leukocyte adhesion receptors by viral proteins. Here, we report the effects of KSHV infection of primary EC on recruitment of flowing leukocytes. Infection did not initiate adhesion of any leukocyte subset per se. However, on cytokine-stimulated EC, KSHV specifically inhibited neutrophil, but not PBL or monocyte, transmigration, an observation consistent with the inflammatory cell profile found in KS lesions in vivo. This inhibition could be recapitulated on uninfected EC using supernatant from infected cultures. These supernatants contained elevated levels of human interleukin 6 (hIL-6), and both the KSHV- and the supernatant-induced inhibitions of neutrophil transmigration were abrogated in the presence of a hIL-6 neutralizing antibody. Furthermore, preconditioning of EC with hIL-6 mimicked the effect of KSHV. Using RNA interference (RNAi), we show that upregulation of suppressor of cytokine signaling 3 (SOCS3) was necessary for this effect of hIL 6. These studies reveal a novel paracrine mode of KSHV immune evasion, resulting in reduced recruitment of neutrophils, a cell type whose antiviral and antitumor roles are becoming increasingly appreciated. Moreover, the findings have implications for our understanding of the contribution of hIL-6 to the pathogenesis of other inflammatory disorders and tumors in which this cytokine is abundant. PMID- 21543488 TI - Identification of a novel neuropathogenic Theiler's murine encephalomyelitis virus. AB - Theiler's murine encephalitis viruses (TMEV) are divided into two subgroups based on their neurovirulence. Persistent strains resemble Theiler's original viruses (referred to as the TO subgroup), which largely induce a subclinical polioencephalomyelitis during the acute phase of the disease and can persist in the spinal cord of susceptible animals, inducing a chronic demyelinating disease. In contrast, members of the neurovirulent subgroup cause an acute encephalitis characterized by the rapid onset of paralysis and death within days following intracranial inoculation. We report herein the characterization of a novel neurovirulent strain of TMEV, identified using pyrosequencing technology and referred to as NIHE. Complete coverage of the NIHE viral genome was obtained, and it shares <90% nucleotide sequence identity to known TMEV strains irrespective of subgroup, with the greatest sequence variability being observed in genes encoding the leader and capsid proteins. The histopathological analysis of infected brain and spinal cord demonstrate inflammatory lesions and neuronal necrosis during acute infection with no evidence of viral persistence or chronic disease. Intriguingly, genetic analysis indicates the putative expression of the L protein, considered a hallmark of strains within the persistent subgroup. Thus, the identification and characterization of a novel neurovirulent TMEV strain sharing features previously associated with both subgroups will lead to a deeper understanding of the evolution of TMEV strains and new insights into the determinants of neurovirulence. PMID- 21543489 TI - Viral replication and innate host responses in primary human alveolar epithelial cells and alveolar macrophages infected with influenza H5N1 and H1N1 viruses. AB - Highly pathogenic influenza H5N1 virus continues to pose a threat to public health. Although the mechanisms underlying the pathogenesis of the H5N1 virus have not been fully defined, it has been suggested that cytokine dysregulation plays an important role. As the human respiratory epithelium is the primary target cell for influenza viruses, elucidating the viral tropism and innate immune responses of influenza H5N1 virus in the alveolar epithelium may help us to understand the pathogenesis of the severe pneumonia associated with H5N1 disease. Here we used primary cultures of differentiated human alveolar type II cells, alveolar type I-like cells, and alveolar macrophages isolated from the same individual to investigate viral replication competence and host innate immune responses to influenza H5N1 (A/HK/483/97) and H1N1 (A/HK/54/98) virus infection. The viral replication kinetics and cytokine and chemokine responses were compared by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). We demonstrated that influenza H1N1 and H5N1 viruses replicated productively in type II cells and type I-like cells although with different kinetics. The H5N1 virus replicated productively in alveolar macrophages, whereas the H1N1 virus led to an abortive infection. The H5N1 virus was a more potent inducer of proinflammatory cytokines and chemokines than the H1N1 virus in all cell types. However, higher levels of cytokine expression were observed for peripheral blood monocyte-derived macrophages than for alveolar macrophages in response to H5N1 virus infection. Our findings provide important insights into the viral tropisms and host responses of different cell types found in the lung and are relevant to an understanding of the pathogenesis of severe human influenza disease. PMID- 21543490 TI - Mechanism of inhibition of retrovirus release from cells by interferon-induced gene ISG15. AB - Budding of retroviruses from cell membranes requires ubiquitination of Gag and recruitment of cellular proteins involved in endosome sorting, including endosome sorting complex required for transport III (ESCRT-III) protein complex and vacuolar protein sorting 4 (VPS4) and its ATPase. In response to infection, a cellular mechanism has evolved that blocks virus replication early and late in the budding process through expression of interferon-stimulated gene 15 (ISG15), a dimer homologue of ubiquitin. Interferon treatment of DF-1 cells blocks avian sarcoma/leukosis virus release, demonstrating that this mechanism is functional under physiological conditions. The late block to release is caused in part by a loss in interaction between VPS4 and its coactivator protein LIP5, which is required to promote the formation of the ESCRT III-VPS4 double-hexamer complex to activate its ATPase. ISG15 is conjugated to two different LIP5-ESCRT-III-binding charged multivesicular body proteins, CHMP2A and CHMP5. Upon ISGylation of each, interaction with LIP5 is no longer detected. Two other ESCRT-III proteins, CHMP4B and CHMP6, are also conjugated to ISG15. ISGylation of CHMP2A, CHMP4B, and CHMP6 weakens their binding directly to VPS4, thereby facilitating the release of this protein from the membrane into the cytosol. The remaining budding complex fails to release particles from the cell membrane. Introducing a mutant of ISG15 into cells that cannot be conjugated to proteins prevents the ISG15-dependent mechanism from blocking virus release. CHMP5 is the primary switch to initiate the antiviral mechanism, because removal of CHMP5 from cells prevents ISGylation of CHMP2A and CHMP6. PMID- 21543491 TI - Canonical NF-kappaB activation is essential for Epstein-Barr virus latent membrane protein 1 TES2/CTAR2 gene regulation. AB - Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) transforms rodent fibroblasts and is expressed in most EBV-associated malignancies. LMP1 (transformation effector site 2 [TES2]/C-terminal activation region 2 [CTAR2]) activates NF-kappaB, p38, Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinase (ERK), and interferon regulatory factor 7 (IRF7) pathways. We have investigated LMP1 TES2 genome-wide RNA effects at 4 time points after LMP1 TES2 expression in HEK-293 cells. By using a false discovery rate (FDR) of <0.001 after correction for multiple hypotheses, LMP1 TES2 caused >2 fold changes in 1,916 mRNAs; 1,479 RNAs were upregulated and 437 were downregulated. In contrast to tumor necrosis factor alpha (TNF-alpha) stimulation, which transiently upregulates many target genes, LMP1 TES2 maintained most RNA effects through the time course, despite robust and sustained induction of negative feedback regulators, such as IkappaBalpha and A20. LMP1 TES2-regulated RNAs encode many NF-kappaB signaling proteins and secondary interacting proteins. Consequently, many LMP1 TES2-regulated RNAs encode proteins that form an extensive interactome. Gene set enrichment analyses found LMP1 TES2 upregulated genes to be significantly enriched for pathways in cancer, B- and T cell receptor signaling, and Toll-like receptor signaling. Surprisingly, LMP1 TES2 and IkappaBalpha superrepressor coexpression decreased LMP1 TES2 RNA effects to only 5 RNAs, with FDRs of <0.001-fold and >2-fold changes. Thus, canonical NF kappaB activation is critical for almost all LMP1 TES2 RNA effects in HEK-293 cells and a more significant therapeutic target than previously appreciated. PMID- 21543492 TI - Sprouty 2 binds ESCRT-II factor Eap20 and facilitates HIV-1 gag release. AB - The four ESCRT (endocytic sorting complexes required for transport) complexes (ESCRT-0, -I, -II, and -III) normally operate sequentially in the trafficking of cellular cargo. HIV-1 Gag trafficking and release as virus-like particles (VLPs) require the participation of ESCRTs; however, its use of ESCRTs is selective and nonsequential. Specifically, Gag trafficking to release sites on the plasma membrane does not require ESCRT-0 or -II. It is known that a bypass of ESCRT-0 is achieved by the direct linkage of the ESCRT-I component, Tsg101, to the primary L domain motif (PTAP) in Gag and that bypass of ESCRT-II is achieved by the linkage of Gag to ESCRT-III through the adaptor protein Alix. However, the mechanism by which Gag suppresses the interaction of bound ESCRT-I with ESCRT-II is unknown. Here we show (i) that VLP release requires the steady-state level of Sprouty 2 (Spry2) in COS-1 cells, (ii) that Spry2 binds the ESCRT-II component Eap20, (iii) that binding Eap20 permits Spry2 to disrupt ESCRT-I interaction with ESCRT-II, and (iv) that coexpression of Gag with a Spry2 fragment that binds Eap20 increases VLP release. Spry2 also facilitated release of P7L-Gag (i.e., release in the absence of Tsg101 binding). In this case, rescue required the secondary L domain (YPX(n)L) in HIV-1 Gag that binds Alix and the region in Spry2 that binds Eap20. The results identify Spry2 as a novel cellular factor that facilitates release driven by the primary and secondary HIV-1 Gag L domains. PMID- 21543493 TI - Canine distemper virus matrix protein influences particle infectivity, particle composition, and envelope distribution in polarized epithelial cells and modulates virulence. AB - In paramyxoviruses, the matrix (M) protein mediates the interaction between the envelope and internal proteins during particle assembly and egress. In measles virus (MeV), M mutations, such as those found in subacute sclerosing panencephalitis (SSPE) strains, and differences in vaccine and wild-type M proteins can affect the strength of interaction with the envelope glycoproteins, assembly efficiency, and spread. However, the contribution of the M protein to the replication and pathogenesis of the closely related canine distemper virus (CDV) has not been characterized. To this end this, we generated a recombinant wild-type CDV carrying a vaccine strain M protein. The recombinant virus retained the parental growth phenotype in VerodogSLAMtag cells, but displayed an increased particle-to-infectivity ratio very similar to that of the vaccine strain, likely due to inefficient H protein incorporation. Even though infectious virus was released only from the apical surface, consistent with the release polarity of the wild-type CDV strain, envelope protein distribution in polarized epithelial cells reproduced the bipolar pattern seen in vaccine strain-infected cells. Most notably, the chimeric virus was completely attenuated in ferrets and caused only a mild and transient leukopenia, indicating that the differences in particle infectivity and envelope protein sorting mediated by the vaccine M protein contribute importantly to vaccine strain attenuation. PMID- 21543494 TI - NRIP, a novel calmodulin binding protein, activates calcineurin to dephosphorylate human papillomavirus E2 protein. AB - Previously, we found a gene named nuclear receptor interaction protein (NRIP) (or DCAF6 or IQWD1). We demonstrate that NRIP is a novel binding protein for human papillomavirus 16 (HPV-16) E2 protein. HPV-16 E2 and NRIP can directly associate into a complex in vivo and in vitro, and the N-terminal domain of NRIP interacts with the transactivation domain of HPV-16 E2. Only full-length NRIP can stabilize E2 protein and induce HPV gene expression, and NRIP silenced by two designed small interfering RNAs (siRNAs) decreases E2 protein levels and E2-driven gene expression. We found that NRIP can directly bind with calmodulin in the presence of calcium through its IQ domain, resulting in decreased E2 ubiquitination and increased E2 protein stability. Complex formation between NRIP and calcium/calmodulin activates the phosphatase calcineurin to dephosphorylate E2 and increase E2 protein stability. We present evidences for E2 phosphorylation in vivo and show that NRIP acts as a scaffold to recruit E2 and calcium/calmodulin to prevent polyubiquitination and degradation of E2, enhancing E2 stability and E2-driven gene expression. PMID- 21543495 TI - Neutralizing monoclonal antibodies against hepatitis C virus E2 protein bind discontinuous epitopes and inhibit infection at a postattachment step. AB - The E2 glycoprotein of hepatitis C virus (HCV) mediates viral attachment and entry into target hepatocytes and elicits neutralizing antibodies in infected patients. To characterize the structural and functional basis of HCV neutralization, we generated a novel panel of 78 monoclonal antibodies (MAbs) against E2 proteins from genotype 1a and 2a HCV strains. Using high-throughput focus-forming reduction or luciferase-based neutralization assays with chimeric infectious HCV containing structural proteins from both genotypes, we defined eight MAbs that significantly inhibited infection of the homologous HCV strain in cell culture. Two of these bound E2 proteins from strains representative of HCV genotypes 1 to 6, and one of these MAbs, H77.39, neutralized infection of strains from five of these genotypes. The three most potent neutralizing MAbs in our panel, H77.16, H77.39, and J6.36, inhibited infection at an early postattachment step. Receptor binding studies demonstrated that H77.39 inhibited binding of soluble E2 protein to both CD81 and SR-B1, J6.36 blocked attachment to SR-B1 and modestly reduced binding to CD81, and H77.16 blocked attachment to SR-B1 only. Using yeast surface display, we localized epitopes for the neutralizing MAbs on the E2 protein. Two of the strongly inhibitory MAbs, H77.16 and J6.36, showed markedly reduced binding when amino acids within hypervariable region 1 (HVR1) and at sites ~100 to 200 residues away were changed, suggesting binding to a discontinuous epitope. Collectively, these studies help to define the structural and functional complexity of antibodies against HCV E2 protein with neutralizing potential. PMID- 21543496 TI - Absence of XMRV retrovirus and other murine leukemia virus-related viruses in patients with chronic fatigue syndrome. AB - Chronic fatigue syndrome (CFS) is a multisystem disorder characterized by prolonged and severe fatigue that is not relieved by rest. Attempts to treat CFS have been largely ineffective primarily because the etiology of the disorder is unknown. Recently, CFS has been associated with xenotropic murine leukemia virus related virus (XMRV) as well as other murine leukemia virus (MLV)-related viruses, though not all studies have found these associations. We collected blood samples from 100 CFS patients and 200 self-reported healthy volunteers from the same geographical area. We analyzed these in a blind manner using molecular, serological, and viral replication assays. We also analyzed samples from patients in the original study that reported XMRV in CFS patients. We did not find XMRV or related MLVs either as viral sequences or infectious viruses, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies. Our findings do not support an association between CFS and MLV-related viruses, including XMRV, and the off label use of antiretrovirals for the treatment of CFS does not seem justified at present. PMID- 21543497 TI - Protective effects of broadly neutralizing immunoglobulin against homologous and heterologous equine infectious anemia virus infection in horses with severe combined immunodeficiency. AB - Using the equine infectious anemia virus (EIAV) lentivirus model system, we previously demonstrated protective effects of broadly neutralizing immune plasma in young horses (foals) with severe combined immunodeficiency (SCID). However, in vivo selection of a neutralization-resistant envelope variant occurred. Here, we determined the protective effects of purified immunoglobulin with more potent broadly neutralizing activity. Overall, protection correlated with the breadth and potency of neutralizing activity in vitro. Four of five SCID foals were completely protected against homologous challenge, while partial protection occurred following heterologous challenge. These results support the inclusion of broadly neutralizing antibodies in lentivirus control strategies. PMID- 21543498 TI - The domain I-domain III linker plays an important role in the fusogenic conformational change of the alphavirus membrane fusion protein. AB - The alphavirus Semliki Forest virus (SFV) infects cells through a low-pH dependent membrane fusion reaction mediated by the virus fusion protein E1. Acidic pH initiates a series of E1 conformational changes that culminate in membrane fusion and include dissociation of the E1/E2 heterodimer, insertion of the E1 fusion loop into the target membrane, and refolding of E1 to a stable trimeric hairpin conformation. A highly conserved histidine (H3) on the E1 protein was previously shown to promote low-pH-dependent E1 refolding. An SFV mutant with an alanine substitution at this position (H3A) has a lower pH threshold and reduced efficiency of virus fusion and E1 trimer formation than wild-type SFV. Here we addressed the mechanism by which H3 promotes E1 refolding and membrane fusion. We identified E1 mutations that rescue the H3A defect. These revertants implicated a network of interactions that connect the domain I-domain III (DI-DIII) linker region with the E1 core trimer, including H3. In support of the importance of these interactions, mutation of residues in the network resulted in more acidic pH thresholds and reduced efficiencies of membrane fusion. In vitro studies of truncated E1 proteins demonstrated that the DI-DIII linker was required for production of a stable E1 core trimer on target membranes. Together, our results suggest a critical and previously unidentified role for the DI-DIII linker region during the low-pH-dependent refolding of E1 that drives membrane fusion. PMID- 21543499 TI - Arginine methylation of the RGG box does not appear to regulate ICP27 import during herpes simplex virus infection. AB - Arginine methylation can regulate protein import and export and can modulate protein interactions. Herpes simplex virus 1 (HSV-1) ICP27 is a shuttling protein involved in viral mRNA export. We previously reported that ICP27 is methylated on three arginines within its RGG box and that arginine methylation regulates ICP27 export and its interaction with SRPK1 and Aly/REF. Here, we report that ICP27 was efficiently imported into the nucleus when hypomethylated as determined by Fluorescence Recovery After Photobleaching (FRAP). Furthermore, coimmunoprecipitation of ICP27 with beta-importin was not significantly affected by ICP27 hypomethylation. Thus, ICP27 import does not appear to be regulated by arginine methylation. PMID- 21543500 TI - Identification and expression analysis of herpes B virus-encoded small RNAs. AB - Herpes B virus (BV) naturally infects macaque monkeys and is genetically similar to herpes simplex virus (HSV). Zoonotic infection of humans can cause encephalitis and if untreated has a fatality rate of ~80%. The frequent use of macaques in biomedical research emphasizes the need to understand the molecular basis of BV pathogenesis with a view toward improving safety for those working with macaques. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of mRNAs bearing complementary target sequences and are employed by viruses to control viral and host gene expression. Using deep sequencing and validation by expression in transfected cells, we identified 12 novel BV-encoded miRNAs expressed in lytically infected cells and 4 in latently infected trigeminal ganglia (TG). Using quantitative reverse transcription-PCR (RT-qPCR), we found that most of the miRNAs exhibited a high level of abundance throughout infection. Further analyses showed that some miRNAs could be generated from multiple transcripts with different kinetic classes, possibly explaining detection throughout infection. Interestingly, miRNAs were detected at early times in the absence of viral gene expression and were present in purified virions. In TG, despite similar amounts of viral DNA per ganglion, it was notable that the relative amount of each miRNA varied between ganglia. The majority of the miRNAs are encoded by the regions that exhibit the most sequence differences between BV and HSV. Additionally, there is no sequence conservation between BV- and HSV-encoded miRNAs, which may be important for the differences in the human diseases caused by BV and HSV. PMID- 21543501 TI - Binding interactions between soluble HIV envelope glycoproteins and quaternary structure-specific monoclonal antibodies PG9 and PG16. AB - PG9 and PG16 are antibodies isolated from a subject infected with HIV-1 and display broad anti-HIV neutralizing activities. They recognize overlapping epitopes, which are preferentially expressed on the membrane-anchored trimeric form of the HIV envelope glycoprotein (Env). PG9 and PG16 were reported not to bind to soluble mimetics of Env. The engineering of soluble Env proteins on which the PG9 and PG16 epitopes are optimally exposed will support efforts to elicit broad anti-HIV neutralizing antibodies by immunization. Here, we identified several soluble gp140 Env proteins that are recognized by PG9 and PG16, and we investigated the molecular details of those binding interactions. The IgG versions of PG9 and PG16 recognize the soluble trimeric gp140 form less efficiently than the corresponding monomeric gp140 form. In contrast, the Fab versions of PG9 and PG16 recognized the monomeric and trimeric gp140 forms with identical binding kinetics and with binding affinities similar to the high binding affinity of the anti-V3 antibody 447D to its epitope. Our data also indicate that, depending on the Env backbone, the interactions of PG9 and PG16 with gp140 may be facilitated by the presence of the gp41 ectodomain and are independent of the proper enzymatic cleavage of gp140 into gp120 and gp41. The identification of soluble Env proteins that express the PG9 and PG16 epitopes and the detailed characterization of the molecular interactions between these two antibodies and their ligands provide important and novel information that will assist in improving the engineering of future Env immunogens. PMID- 21543502 TI - Entry of tiger frog virus (an Iridovirus) into HepG2 cells via a pH-dependent, atypical, caveola-mediated endocytosis pathway. AB - Tiger frog virus (TFV), in the genus Ranavirus of the family Iridoviridae, causes high mortality of cultured tiger frog tadpoles in China. To explore the cellular entry mechanism of TFV, HepG2 cells were treated with drugs that inhibit the main endocytic pathways. We observed that TFV entry was inhibited by NH(4)Cl, chloroquine, and bafilomycin, which can all elevate the pH of acidic organelles. In contrast, TFV entry was not influenced by chlorpromazine or overexpression of a dominant-negative form of Esp15, which inhibit the assembly of clathrin-coated pits. These results suggested that TFV entry was not associated with clathrin mediated endocytosis, but was related to the pH of acidic organelles. Subsequently, we found that endocytosis of TFV was dependent on membrane cholesterol and was inhibited by the caveolin-1 scaffolding domain peptide. Dynamin and actin were also required for TFV entry. In addition, TFV virions colocalized with the cholera toxin subunit B, indicating that TFV enters as caveola-internalized cargo into the Golgi complex. Taken together, our results demonstrated that TFV entry occurs by caveola-mediated endocytosis with a pH dependent step. This atypical caveola-mediated endocytosis is different from the clathrin-mediated endocytosis of frog virus 3 (FV3) by BHK cells, which has been recognized as a model for iridoviruses. Thus, our work may help further the understanding of the initial steps of iridovirus infection in lower vertebrates. PMID- 21543503 TI - Hepatitis C virus hijacks P-body and stress granule components around lipid droplets. AB - The microRNA miR-122 and DDX6/Rck/p54, a microRNA effector, have been implicated in hepatitis C virus (HCV) replication. In this study, we demonstrated for the first time that HCV-JFH1 infection disrupted processing (P)-body formation of the microRNA effectors DDX6, Lsm1, Xrn1, PATL1, and Ago2, but not the decapping enzyme DCP2, and dynamically redistributed these microRNA effectors to the HCV production factory around lipid droplets in HuH-7-derived RSc cells. Notably, HCV JFH1 infection also redistributed the stress granule components GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1), ataxin-2 (ATX2), and poly(A) binding protein 1 (PABP1) to the HCV production factory. In this regard, we found that the P-body formation of DDX6 began to be disrupted at 36 h postinfection. Consistently, G3BP1 transiently formed stress granules at 36 h postinfection. We then observed the ringlike formation of DDX6 or G3BP1 and colocalization with HCV core after 48 h postinfection, suggesting that the disruption of P-body formation and the hijacking of P-body and stress granule components occur at a late step of HCV infection. Furthermore, HCV infection could suppress stress granule formation in response to heat shock or treatment with arsenite. Importantly, we demonstrate that the accumulation of HCV RNA was significantly suppressed in DDX6, Lsm1, ATX2, and PABP1 knockdown cells after the inoculation of HCV-JFH1, suggesting that the P-body and the stress granule components are required for the HCV life cycle. Altogether, HCV seems to hijack the P-body and the stress granule components for HCV replication. PMID- 21543504 TI - Structures of the major capsid proteins of the human Karolinska Institutet and Washington University polyomaviruses. AB - The Karolinska Institutet and Washington University polyomaviruses (KIPyV and WUPyV, respectively) are recently discovered human viruses that infect the respiratory tract. Although they have not yet been linked to disease, they are prevalent in populations worldwide, with initial infection occurring in early childhood. Polyomavirus capsids consist of 72 pentamers of the major capsid protein viral protein 1 (VP1), which determines antigenicity and receptor specificity. The WUPyV and KIPyV VP1 proteins are distant in evolution from VP1 proteins of known structure such as simian virus 40 or murine polyomavirus. We present here the crystal structures of unassembled recombinant WUPyV and KIPyV VP1 pentamers at resolutions of 2.9 and 2.55 A, respectively. The WUPyV and KIPyV VP1 core structures fold into the same beta-sandwich that is a hallmark of all polyomavirus VP1 proteins crystallized to date. However, differences in sequence translate into profoundly different surface loop structures in KIPyV and WUPyV VP1 proteins. Such loop structures have not been observed for other polyomaviruses, and they provide initial clues about the possible interactions of these viruses with cell surface receptors. PMID- 21543505 TI - NSs protein of rift valley fever virus promotes posttranslational downregulation of the TFIIH subunit p62. AB - Rift Valley fever virus (RVFV; family Bunyaviridae, genus Phlebovirus) is an important emerging pathogen of humans and ruminants. Its NSs protein has previously been identified as a major virulence factor that suppresses host defense through three distinct mechanisms: it directly inhibits beta interferon (IFN-beta) promoter activity, it promotes the degradation of double-stranded RNA dependent protein kinase (PKR), and it suppresses host transcription by disrupting the assembly of the basal transcription factor TFIIH through sequestration of its p44 subunit. Here, we report that in addition to PKR, NSs also promotes the degradation of the TFIIH subunit p62. Infection of cells with the RVFV MP-12 vaccine strain reduced p62 protein levels to below the detection limit early in the course of infection. This NSs-mediated downregulation of p62 was posttranslational, as it was unaffected by pharmacological inhibition of transcription or translation and MP-12 infection had no effect on p62 mRNA levels. Treatment of cells with proteasome inhibitors but not inhibition of lysosomal acidification or nuclear export resulted in a stabilization of p62 in the presence of NSs. Furthermore, p62 could be coprecipitated with NSs from lysates of infected cells. These data suggest that the RVFV NSs protein is able to interact with the TFIIH subunit p62 inside infected cells and promotes its degradation, which can occur directly in the nucleus. PMID- 21543506 TI - Chemical induction of endogenous retrovirus particles from the vero cell line of African green monkeys. AB - Endogenous retroviral sequences are present in high copy numbers in the genomes of all species and may be expressed as RNAs; however, the majority are defective for virus production. Although virus has been isolated from various Old World monkey and New World monkey species, there has been no report of endogenous retroviruses produced from African green monkey (AGM) tissues or cell lines. We have recently developed a stepwise approach for evaluating the presence of latent viruses by chemical induction (Khan et al., Biologicals 37:196-201, 2009). Based upon this strategy, optimum conditions were determined for investigating the presence of inducible, endogenous retroviruses in the AGM-derived Vero cell line. Low-level reverse transcriptase activity was produced with 5-azacytidine (AzaC) and with 5'-iodo-2'-deoxyuridine (IUdR); none was detected with sodium butyrate. Nucleotide sequence analysis of PCR-amplified fragments from the gag, pol, and env regions of RNAs, prepared from ultracentrifuged pellets of filtered supernatants, indicated that endogenous retrovirus particles related to simian endogenous type D betaretrovirus (SERV) sequences and baboon endogenous virus type C gammaretrovirus (BaEV) sequences were induced by AzaC, whereas SERV sequences were also induced by IUdR. Additionally, sequence heterogeneity was seen in the RNAs of SERV- and BaEV-related particles. Infectivity analysis of drug-treated AGM Vero cells showed no virus replication in cell lines known to be susceptible to type D simian retroviruses (SRVs) and to BaEV. The results indicated that multiple, inducible endogenous retrovirus loci are present in the AGM genome that can encode noninfectious, viruslike particles. PMID- 21543507 TI - Oncolytic herpes simplex virus 1 encoding 15-prostaglandin dehydrogenase mitigates immune suppression and reduces ectopic primary and metastatic breast cancer in mice. AB - Oncolytic herpes simplex virus 1 (HSV-1) viruses armed with immunomodulatory transgenes have shown potential for enhanced antitumor therapy by overcoming tumor-based immune suppression and promoting antitumor effector cell development. Previously, we reported that the new oncolytic HSV-1 virus, OncSyn (OS), engineered to fuse tumor cells, prevented tumor growth and metastasis to distal organs in the 4T1/BALB/c immunocompetent breast cancer mouse model, suggesting the elicitation of antitumor immune responses (Israyelyan et al., Hum. Gen. Ther. 18:5, 2007, and Israyelyan et al., Virol. J. 5:68, 2008). The OSV virus was constructed by deleting the OS viral host shutoff gene (vhs; UL41) to further attenuate the virus and permit dendritic cell activation and antigen presentation. Subsequently, the OSVP virus was constructed by inserting into the OSV viral genome a murine 15-prostaglandin dehydrogenase (15-PGDH) expression cassette, designed to constitutively express 15-PGDH upon infection. 15-PGDH is a tumor suppressor protein and the primary enzyme responsible for the degradation of prostaglandin E2 (PGE2), which is known to promote tumor development. OSVP, OSV, and OS treatment of 4T1 tumors in BALB/c mice effectively reduced primary tumor growth and inhibited metastatic development of secondary tumors. OSVP was able to significantly inhibit the development and accumulation of 4T1 metastatic tumor cells in the lungs of treated mice. Ex vivo analysis of immune cells following treatment showed increased inflammatory cytokine production and the presence of mature dendritic cells for the OSVP, OSV, and OS viruses. A statistically significant decrease in splenic myeloid-derived suppressor cells (MDSC) was observed only for OSVP-treated mice. These results show that intratumoral oncolytic herpes is highly immunogenic and suggest that 15-PGDH expression by OSVP enhanced the antitumor immune response initiated by viral infection of primary tumor cells, leading to reduced development of pulmonary metastases. The availability of the OSVP genome as a bacterial artificial chromosome allows for the rapid insertion of additional immunomodulatory genes that could further assist in the induction of potent antitumor immune responses against primary and metastatic tumors. PMID- 21543509 TI - Combining emerging agents in advanced breast cancer. AB - Newer treatments have improved survival for patients with metastatic breast cancer over the last two decades, and a battery of new cytotoxic and targeted therapies is continuing to enhance this trend. This review outlines recent data and ongoing research in this area, by highlighting new developments (regarding approved but relatively new classes of cytotoxic and targeted agents) and also new classes of targeted therapy that are undergoing clinical evaluation. Mechanisms for synergy between agents are discussed where data are available, as is information on the rationale behind the development of agents that inhibit angiogenesis, DNA repair, histone deacetylases, heat shock proteins, or various signaling pathways in tumor proliferation. The abundance of clinical research surrounding anticancer agents, together with ongoing cancer biology research, is expected to further increase the available pool of therapeutic options for metastatic breast cancer. Concomitantly, in the absence of an effective targeted monotherapy, a better understanding of the interplay between biologic and cytotoxic anticancer agents will improve our ability to rationally design combination regimens with better efficacy and tolerability. PMID- 21543508 TI - Different regions of HIV-1 subtype C env are associated with placental localization and in utero mother-to-child transmission. AB - HIV infections are initiated by a limited number of variants that diverge into a diverse quasispecies swarm. During in utero mother-to-child transmission (IU MTCT), transmitted viral variants must pass through multiple unique environments, and our previously published data suggest a nonstochastic model of transmission. As an alternative to a stochastic model of viral transmission, we hypothesize that viral selection in the placental environment influences the character of the viral quasispecies when HIV-1 is transmitted in utero. To test this hypothesis, we used single-template amplification to isolate HIV-1 envelope gene (env) sequences from both peripheral plasma and the placentas of eight nontransmitting (NT) and nine IU-transmitting participants. Statistically significant compartmentalization between peripheral and placental HIV-1 env was detected in one of the eight NT cases and six of the nine IU MTCT cases. In addition, viral sequences isolated from IU MTCT placental tissue showed variation in env V1 loop lengths compared to matched maternal sequences, while NT placental env sequences did not. Finally, comparison of env sequences from NT and IU MTCT participants indicated statistically significant differences in Kyte-Doolittle hydropathy in the signal peptide, C2, V3, and C3 regions. Our working hypothesis is that the hydropathy differences in Env associated with IU MTCT alter viral cellular tropism or affinity, allowing HIV-1 to efficiently infect placentally localized cells. PMID- 21543510 TI - Pentazocine-induced antinociception is mediated mainly by MU-opioid receptors and compromised by kappa-opioid receptors in mice. AB - Pentazocine is a widely used mixed agonist-antagonist opioid. Previous animal studies have demonstrated that pentazocine-induced antinociception displayed a ceiling effect characterized by biphasic dose response with a increasing and then descending analgesia like a bell-shaped curve. This study attempted to clarify the mechanisms underlying such dose-response relationships. ddY and C57BL/6J mice received subcutaneous injection of saline or pentazocine (3, 10, 30, 56, or 100 mg . kg(-1)), at 120 min after subcutaneous injection of saline, a MU-opioid receptor antagonist clocinnamox mesylate (C-CAM) (5 mg . kg(-1)), a kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (10 mg . kg(-1)), or the combination of C-CAM and nor-BNI. The antinociceptive effects of pentazocine were evaluated using tail pressure, hot plate, tail flick, and acetic acid writhing tests. Without pretreatment with an opioid receptor antagonist, the antinociceptive effects of pentazocine exhibited biphasic bell-shaped dose response curves peaking at 30 mg . kg(-1). C-CAM completely and partly antagonized the antinociception induced by pentazocine at low (3-30 mg . kg(-1)) and high (56-100 mg . kg(-1)) doses, respectively. nor-BNI enhanced the antinociception by pentazocine at high doses and turned the later descending portion of the biphasic dose-response curves into a sigmoid curve. The combination of C-CAM and nor-BNI completely abolished the antinociception by pentazocine at all doses. Our results suggest pentazocine produces antinociception primarily via activation of MU-opioid receptors, but at high doses, this MU-opioid receptor-mediated antinociception is antagonized by concomitant activation of kappa-opioid receptors. This provides the first reasonable hypothesis to explain the ceiling effects of pentazocine analgesia characterized by a biphasic dose response. PMID- 21543511 TI - In vivo oocyte developmental competence is reduced in lean but not in obese superovulated dairy cows after intraovarian administration of IGF1. AB - The present study investigated the role of IGF1 in lactating lean and non lactating obese dairy cows by injecting 1 MUg IGF1 into the ovaries prior to superovulation. This amount of IGF1 has been linked with pregnancy loss in women with the polycystic ovary syndrome (PCOS) and was associated with impaired bovine oocyte competence in vitro. Transcript abundance and protein expression of selected genes involved in apoptosis, glucose metabolism, and the IGF system were analyzed. Plasma concentrations of IGF1 and leptin, and IGF1 in uterine luminal fluid (ULF), were also measured. IGF1 treatment decreased embryo viability in lean cows to the levels observed in obese cows. Obese cows were not affected by IGF1 treatment and showed elevated levels of IGF1 (in both plasma and ULF) and leptin. Blastocysts from lean cows treated with IGF1 showed a higher abundance of SLC2A1 and IGFBP3 transcripts. IGF1 treatment reduced protein expression of tumor protein 53 in blastocysts of lean cows, whereas the opposite was observed in obese cows. IGF1 in plasma and ULF was correlated only in the control groups. Blastocyst transcript abundance of IGF1 receptor and IGFBP3 correlated positively with IGF1 concentrations in both plasma and ULF in lean cows. The detrimental microenvironment created by IGF1 injection in lean cows and the lack of effect in obese cows resemble to a certain extent the situation observed in PCOS patients, where IGF1 bioavailability is increased in normal-weight women but reduced in obese women, suggesting that this bovine model could be useful for studying IGF1 involvement in PCOS. PMID- 21543512 TI - Late onset lupus nephritis in Chinese patients: classified by the 2003 International Society of Nephrology and Renal Pathology Society system. AB - AIM: The aim of this study was to assess clinicopathological characteristics and outcomes of a cohort of Chinese patients with late onset lupus nephritis. METHODS: Clinical, pathological and outcome data for patients with late onset lupus nephritis (onset at age >=50 years) and early onset lupus nephritis (onset at age <=40 years) were retrospectively analyzed and compared. RESULTS: Among 271 patients with renal biopsy-proven lupus nephritis, 30 were identified as having late onset lupus nephritis and 241 were identified as having early onset lupus nephritis. Lower female predominance was observed in the late onset patients (p = 0.06). The interval between presentation of lupus nephritis and diagnosis was significantly longer in the late onset group than in the early onset group (p = 0.003). In comparison with early onset group, patients in the late onset group had significantly lower scores for endocapillary hypercellularity (p = 0.041), subendothelial hyaline deposits (p = 0.022) and glomerular leukocyte infiltration (p = 0.032), but had significantly higher scores for tubular atrophy (p = 0.037) and interstitial fibrosis (p = 0.018). Regarding long-term survival and renal outcome, there was no significant difference between the two groups, although it seemed that the early onset group had a poorer renal outcome (p = 0.077, hazard ratio (HR) = 3.909, 95% CI: 0.862-17.726). CONCLUSIONS: Patients with late onset lupus nephritis were usually diagnosed later; they had milder active lesions and more severe chronic lesions in renal pathology. However, the renal outcome was similar between late and early onset patients. PMID- 21543513 TI - Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus. AB - Disease activity 6 months before pregnancy of patients with systemic lupus erythematosus (SLE) associated with adverse maternal and fetal outcomes is not well studied. The aim of the study was to identify predictors of adverse maternal and fetal outcomes in pregnant SLE patients, based on patients' background characteristics, clinical and laboratory data 6 months before pregnancy. Of 103 pregnancies, 55 pregnancies in 39 SLE patients were investigated. Clinical and laboratory data were recorded at regular intervals from 6 months before conception to 1 year after delivery. Primary outcomes included the predictors of combined adverse maternal and fetal outcomes. Potential explanatory variables included demographic, clinical and laboratory data 6 months before conception. Using logistic regression, history of nephritis (p = 0.001, odds ratio [OR] 13.3, 95% confidence interval [CI] 2.7-65.1) and a high SLE Disease Activity Index (SLEDAI) score 6 months before pregnancy (p = 0.015, OR 1.7, 95% CI 1.1-2.7) were associated with combined adverse maternal outcome, whereas flare during pregnancy (p = 0.003, OR 29.3, 95% CI 3.1-273.1) predicted combined adverse fetal outcome. The area under the curve for SLEDAI score of combined maternal outcome was 0.73 (95% CI 0.58-0.87). The optimal cut-off point according to the receiver operating characteristic curve was 4, with a sensitivity of 64% and a specificity of 75%. In conclusion, a history of nephritis or a SLEDAI score of 4 or more in SLE patients 6 months before conception predicts adverse maternal outcomes, while disease flare during pregnancy predicts adverse fetal outcomes. Pregnancies should be delayed until the disease has been in remission for 6 months. PMID- 21543514 TI - Association of the PTPN22 R620W polymorphism with increased risk for SLE in the genetically homogeneous population of Crete. AB - Autoimmune diseases affect approximately 5% of the population, but much work remains to define the genetic risk factors and pathogenic mechanisms underlying these conditions. There is accumulating evidence that common genetic factors might predispose to multiple autoimmune disorders. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune disorders with multiple susceptibility genes. The functional R620W (C1858T) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, a member of the PTPs that negatively regulate T-cell activation, has been recently associated with susceptibility to various autoimmune diseases. The aim of this study was to assess whether the C1858T polymorphism of PTPN22 also confers increased risk for SLE and RA in the genetically homogeneous population of Crete. It was found that the minor T allele of the PTPN22 C1858T SNP was more common in SLE patients than in control individuals (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.11 to 3.9, p = 0.017). No significant difference was observed in the frequency of this allele when RA patients were compared with controls (OR = 1.14, 95% CI = 0.65 to 1.9, p = 0.64). Although the PTPN22 1858 T allele is found at decreased frequency in Southern Europe, including Crete, an association was found between this allele and SLE in the population studied. PMID- 21543516 TI - Characterization of the single-cell transcriptional landscape by highly multiplex RNA-seq. AB - Our understanding of the development and maintenance of tissues has been greatly aided by large-scale gene expression analysis. However, tissues are invariably complex, and expression analysis of a tissue confounds the true expression patterns of its constituent cell types. Here we describe a novel strategy to access such complex samples. Single-cell RNA-seq expression profiles were generated, and clustered to form a two-dimensional cell map onto which expression data were projected. The resulting cell map integrates three levels of organization: the whole population of cells, the functionally distinct subpopulations it contains, and the single cells themselves-all without need for known markers to classify cell types. The feasibility of the strategy was demonstrated by analyzing the transcriptomes of 85 single cells of two distinct types. We believe this strategy will enable the unbiased discovery and analysis of naturally occurring cell types during development, adult physiology, and disease. PMID- 21543515 TI - Comparative genomics of citric-acid-producing Aspergillus niger ATCC 1015 versus enzyme-producing CBS 513.88. AB - The filamentous fungus Aspergillus niger exhibits great diversity in its phenotype. It is found globally, both as marine and terrestrial strains, produces both organic acids and hydrolytic enzymes in high amounts, and some isolates exhibit pathogenicity. Although the genome of an industrial enzyme-producing A. niger strain (CBS 513.88) has already been sequenced, the versatility and diversity of this species compel additional exploration. We therefore undertook whole-genome sequencing of the acidogenic A. niger wild-type strain (ATCC 1015) and produced a genome sequence of very high quality. Only 15 gaps are present in the sequence, and half the telomeric regions have been elucidated. Moreover, sequence information from ATCC 1015 was used to improve the genome sequence of CBS 513.88. Chromosome-level comparisons uncovered several genome rearrangements, deletions, a clear case of strain-specific horizontal gene transfer, and identification of 0.8 Mb of novel sequence. Single nucleotide polymorphisms per kilobase (SNPs/kb) between the two strains were found to be exceptionally high (average: 7.8, maximum: 160 SNPs/kb). High variation within the species was confirmed with exo-metabolite profiling and phylogenetics. Detailed lists of alleles were generated, and genotypic differences were observed to accumulate in metabolic pathways essential to acid production and protein synthesis. A transcriptome analysis supported up-regulation of genes associated with biosynthesis of amino acids that are abundant in glucoamylase A, tRNA-synthases, and protein transporters in the protein producing CBS 513.88 strain. Our results and data sets from this integrative systems biology analysis resulted in a snapshot of fungal evolution and will support further optimization of cell factories based on filamentous fungi. PMID- 21543517 TI - Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. AB - PURPOSE: Metformin is a widely used antidiabetic drug whose anticancer effects, mediated by the activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines. EXPERIMENTAL DESIGN: Human tumors were xenografted into severe combined immunodeficient (SCID) mice and the cancer cell lines were treated with only paclitaxel or only metformin, or a combination of both drugs. Western blotting, flow cytometry, and immunohistochemistry were then used to characterize the effects of the different treatments. RESULTS: The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G(2)-M phase of the cell cycle, and decreased the tumor growth and increased apoptosis in tumor bearing mice, when compared with individual drug treatments. CONCLUSION: We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism shows how different drugs may cooperate to augment antigrowth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment. PMID- 21543518 TI - Intratumoral administration of TLR4 agonist absorbed into a cellular vector improves antitumor responses. AB - PURPOSE: Because toll-like receptor (TLR) agonists have been well characterized as dendritic cell (DC) activators, we hypothesized that the admixture of TLR4 agonist into a cellular vector could improve the antitumor response in vivo. EXPERIMENTAL DESIGN: Granulocyte macrophage colony stimulating factor secreting whole cell tumor cell vector (GVAX) was formulated with lipopolysaccharide (LPS), a TLR4 agonist, and its intratumoral therapeutic efficacy was tested in three different murine models. We utilized immunohistochemistry, fluorescence-activated cell sorting, enzyme-linked immunosorbent spot (ELISPOT), and in vivo CTL analysis to assess both local innate immune responses within the tumor tissue as well as the downstream generation of antitumor T-cell responses. RESULTS: Intratumoral treatment of LPS-absorbed GVAX showed efficacy in improving an antitumor response in vivo in comparison with GVAX alone. Improved antitumor efficacy of this novel admixture was not present in TLR4 signaling impaired mice. In the CT26 model, 40% to 60% of the mice showed regression of the transplanted tumor. When rechallenged with CT26 tumor cells, these mice proved to be immunized against the tumor. Tumors treated with TLR4 agonist-absorbed GVAX showed increased infiltrating CD4 and CD8 T cells as well as increased numbers of CD86(+) cells in the tumor tissue. Draining lymph nodes from the treated mice had enhanced number of activated CD86(+), MHCII(+), and CD80(+) DCs in comparison with GVAX alone and mock-treated groups. ELISPOT assay and in vivo CTL assay showed increased numbers of CTLs specific for the AH1 tumor antigen in mice treated with LPS-absorbed GVAX. CONCLUSION: TLR4 on antigen-presenting cells in the tumor microenvironment may be targeted by using cell-based vectors for improved antitumor response in vivo. PMID- 21543519 TI - Ntann12 annexin expression is induced by auxin in tobacco roots. AB - Ntann12, encoding a polypeptide homologous to annexins, was found previously to be induced upon infection of tobacco with the bacterium Rhodococcus fascians. In this study, Ntann12 is shown to bind negatively charged phospholipids in a Ca(2+) dependent manner. In plants growing in light conditions, Ntann12 is principally expressed in roots and the corresponding protein was mainly immunolocalized in the nucleus. Ntann12 expression was inhibited following plant transfer to darkness and in plants lacking the aerial part. However, an auxin (indole-3 acetic acid) treatment restored the expression of Ntann12 in the root system in dark conditions. Conversely, polar auxin transport inhibitors such as 1 naphthylphthalamic acid (NPA) or 2,3,5-triiodobenzoic acid (TIBA) inhibited Ntann12 expression in light condition. These results indicate that the expression of Ntann12 in the root is linked to the perception of a signal in the aerial part of the plant that is transmitted to the root via polar auxin transport. PMID- 21543520 TI - Acyl substrate preferences of an IAA-amido synthetase account for variations in grape (Vitis vinifera L.) berry ripening caused by different auxinic compounds indicating the importance of auxin conjugation in plant development. AB - Nine Gretchen Hagen (GH3) genes were identified in grapevine (Vitis vinifera L.) and six of these were predicted on the basis of protein sequence similarity to act as indole-3-acetic acid (IAA)-amido synthetases. The activity of these enzymes is thought to be important in controlling free IAA levels and one auxin inducible grapevine GH3 protein, GH3-1, has previously been implicated in the berry ripening process. Ex planta assays showed that the expression of only one other GH3 gene, GH3-2, increased following the treatment of grape berries with auxinic compounds. One of these was the naturally occurring IAA and the other two were synthetic, alpha-naphthalene acetic acid (NAA) and benzothiazole-2-oxyacetic acid (BTOA). The determination of steady-state kinetic parameters for the recombinant GH3-1 and GH3-2 proteins revealed that both enzymes efficiently conjugated aspartic acid (Asp) to IAA and less well to NAA, while BTOA was a poor substrate. GH3-2 gene expression was induced by IAA treatment of pre-ripening berries with an associated increase in levels of IAA-Asp and a decrease in free IAA levels. This indicates that GH3-2 responded to excess auxin to maintain low levels of free IAA. Grape berry ripening was not affected by IAA application prior to veraison (ripening onset) but was considerably delayed by NAA and even more so by BTOA. The differential effects of the three auxinic compounds on berry ripening can therefore be explained by the induction and acyl substrate specificity of GH3-2. These results further indicate an important role for GH3 proteins in controlling auxin-related plant developmental processes. PMID- 21543521 TI - Plants contain two SCO proteins that are differentially involved in cytochrome c oxidase function and copper and redox homeostasis. AB - Two Arabidopsis thaliana genes (HCC1 and HCC2), resulting from a duplication that took place before the emergence of flowering plants, encode proteins with homology to the SCO proteins involved in copper insertion during cytochrome c oxidase (COX) assembly in other organisms. Heterozygote HCC1 mutant plants produce 25% abnormal seeds with defective embryos arrested at the heart or torpedo stage. These embryos lack COX activity, suggesting that the requirement of HCC1 during the early stages of plant development is related with its COX assembly function. Homozygote HCC2 mutant plants develop normally and do not show changes in COX2 levels. These plants display increased sensitivity of root growth to increased copper and a higher expression of miR398 and other genes that respond to copper limitation, in spite of the fact that they have a higher copper content than the wild type. HCC2 mutant plants also show increased expression of stress-responsive genes. The results suggest that HCC1 is the protein involved in COX biogenesis and that HCC2, that lacks the cysteines and histidine putatively involved in copper binding, functions in copper sensing and redox homeostasis. In addition, plants that overexpress HCC1 have an altered response of root elongation to changes in copper in the growth medium and increased expression of two low-copper-responsive genes, suggesting that HCC1 may also have a role in copper homeostasis. PMID- 21543523 TI - Visual detection of UV cues by adult zebrafish (Danio rerio). AB - Visual sensitivity to ultraviolet (UV) light is widespread in the animal kingdom. Many studies on UV vision have utilized physiological and/or anatomical methods to determine whether animals are visually sensitive to UV wavelengths. However, ultimately behavioral methods can reveal whether retinal UV sensitivity results in perceptual detection of UV stimuli. For the widely studied zebrafish (Danio rerio), the adult retina possesses cone photoreceptors that are sensitive to UV light. Here, we used a behavioral technique, the escape response assay, to test whether adult zebrafish can visually detect and behaviorally respond to visual cues that reflect UV. We found that adult zebrafish robustly respond to UV reflecting cues under UV light while showing no responses to the same cues under no UV light. From our results, we confirm that adult zebrafish can visually detect UV reflecting cues and show that UV perceptual sensitivity is functional in adult zebrafish. Our study highlights the utility of the fish escape response assay for UV visual behavior research. PMID- 21543522 TI - Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation. AB - At the dimer interface of the extracellular ligand-binding domain of alpha-amino 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors a hydrophilic pocket is formed that is known to interact with two classes of positive allosteric modulators, represented by cyclothiazide and the ampakine 2H,3H,6aH pyrrolidino(2,1-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1,4-dioxan-10-one (CX614). Here, we present structural and functional data on two new positive allosteric modulators of AMPA receptors, phenyl-1,4-bis-alkylsulfonamide (CMPDA) and phenyl 1,4-bis-carboxythiophene (CMPDB). Crystallographic data show that these compounds bind within the modulator-binding pocket and that substituents of each compound overlap with distinct moieties of cyclothiazide and CX614. The goals of the present study were to determine 1) the degree of modulation by CMPDA and CMPDB of AMPA receptor deactivation and desensitization; 2) whether these compounds are splice isoform-selective; and 3) whether predictions of mechanism of action could be inferred by comparing molecular interactions between the ligand-binding domain and each compound with those of cyclothiazide and CX614. CMPDB was found to be more isoform-selective than would be predicted from initial binding assays. It is noteworthy that these new compounds are both more potent and more effective and may be more clinically relevant than the AMPA receptor modulators described previously. PMID- 21543524 TI - Differential attentional modulation of cortical responses to S-cone and luminance stimuli. AB - Neural signals driven by short-wave-sensitive (S) cones are, to a large degree, anatomically and functionally separate from the achromatic luminance pathway until at least one synapse into V1. Attentional mechanisms that act at an anatomically early stage in V1 may, therefore, affect S-cone and luminance signals differently. Here, we used a steady-state visually evoked potential (SSVEP) paradigm combined with electrical source imaging to study the effects of contrast and attention on neural responses to both chromatic S-cone isolating and achromatic stimuli in five human visual areas including V1. The responses to these gratings were affected very differently by changes in contrast and attention. Increasing cone contrast increased the response amplitude for both types of stimulus. For the S-cone-defined stimuli, we also observed a systematic decrease in the response phase of the first harmonic with increasing stimulus contrast, but there was no corresponding change in phase for the first harmonic of the luminance probes. Attending to the contrast of the grating increased the amplitude and phase of luminance-driven responses but had no effect on S-cone driven responses. We conclude that while attentional modulation can be observed in achromatic pathways as early as V1, attention may not affect SSVEP signals generated by S-cone stimuli. PMID- 21543525 TI - Unmet needs of severely affected multiple sclerosis patients: the health professionals' view. AB - BACKGROUND: Research has only started recently to specifically concentrate on the group of patients severely affected by multiple sclerosis (MS). AIM: The aim of this study was to assess the perception on patients' unmet needs by healthcare professionals. METHODS: Focus groups and expert interviews were recorded, transcribed verbatim and analysed by qualitative content analysis. RESULTS: Unmet needs were identified in four main categories ('support from family/friends'; 'healthcare services'; 'managing everyday life'; 'maintaining biographical continuity'). Whereas physicians assessed most unmet needs in the category 'healthcare services', nurses and social workers focussed on unmet needs in the categories 'support from family/friends' and 'maintaining biographical continuity'. Although the study focused on unmet needs of patients, professionals also voiced their unmet needs when caring for these patients. The group of professionals identified more subcategories than patients and included unmet needs of relatives. CONCLUSION: Adding professionals' perspective to that of patients is essential to gain a holistic view on patients' unmet needs and to further optimize their care. The perspective of palliative care might contribute to meet unmet needs of severely affected MS patients. PMID- 21543526 TI - Dying cancer patients' own opinions on euthanasia: an expression of autonomy? A qualitative study. AB - INTRODUCTION: Deliberations on euthanasia are mostly theoretical, and often lack first-hand perspectives of the affected persons. METHOD: Sixty-six patients suffering from cancer in a palliative phase were interviewed about their perspectives of euthanasia in relation to autonomy. The interviews were transcribed verbatim and analysed using qualitative content analysis with no predetermined categories. RESULTS: The informants expressed different positions on euthanasia, ranging from support to opposition, but the majority were undecided due to the complexity of the problem. The informants' perspectives on euthanasia in relation to autonomy focused on decision making, being affected by (1) power and (2) trust. Legalization of euthanasia was perceived as either (a) increasing patient autonomy by patient empowerment, or (b) decreasing patient autonomy by increasing the medical power of the health care staff, which could be frightening. The informants experienced dependence on others, and expressed various levels of trust in others' intentions, ranging from full trust to complete mistrust. CONCLUSIONS: Dying cancer patients perceive that they cannot feel completely independent, which affects true autonomous decision making. Further, when considering legalization of euthanasia, the perspectives of patients fearing the effects of legalization should also be taken into account, not only those of patients opting for it. PMID- 21543527 TI - Infant mortality rates regressed against number of vaccine doses routinely given: is there a biochemical or synergistic toxicity? AB - The infant mortality rate (IMR) is one of the most important indicators of the socio-economic well-being and public health conditions of a country. The US childhood immunization schedule specifies 26 vaccine doses for infants aged less than 1 year--the most in the world--yet 33 nations have lower IMRs. Using linear regression, the immunization schedules of these 34 nations were examined and a correlation coefficient of r = 0.70 (p < 0.0001) was found between IMRs and the number of vaccine doses routinely given to infants. Nations were also grouped into five different vaccine dose ranges: 12-14, 15-17, 18-20, 21-23, and 24-26. The mean IMRs of all nations within each group were then calculated. Linear regression analysis of unweighted mean IMRs showed a high statistically significant correlation between increasing number of vaccine doses and increasing infant mortality rates, with r = 0.992 (p = 0.0009). Using the Tukey-Kramer test, statistically significant differences in mean IMRs were found between nations giving 12-14 vaccine doses and those giving 21-23, and 24-26 doses. A closer inspection of correlations between vaccine doses, biochemical or synergistic toxicity, and IMRs is essential. PMID- 21543528 TI - Gestational weight gain and later maternal health: are they related? PMID- 21543529 TI - Perinatal programming of body weight control by leptin: putative roles of AMP kinase and muscle thermogenesis. AB - Breastfeeding, compared with infant-formula feeding, confers later protection against obesity. Leptin represents a candidate for the programming of the lean phenotype as suggested by 1) the presence of leptin in breast milk and its absence in infant formula, 2) a human study that showed a negative correlation between leptin concentrations in breast milk and body weights of infants until 2 y of age, and 3) intervention studies in animals. Milk-borne leptin and leptin synthesized in adipose tissue and the stomach may contribute to leptinemia in newborns. Studies in rodents suggested that early leptin treatment may program either a lean or obese phenotype, probably depending on the dose, route of administration, and timing of exposure to high leptin concentrations, whereas these studies also suggested the importance of the physiologic postnatal surge in leptinemia for the programming effect. Leptin oral administration at physiologic doses to neonate rats during the entire lactation period had later positive effects that prevented the animals from overweight and obesity and other metabolic alterations, which were particularly associated with feeding of a high fat diet. High leptin sensitivity, which is associated with leanness, and leptin resistance in obesity may be programmed by the early life environment. The differential sensitivity to leptin implies a contribution of leptin-inducible energy expenditure to the adult phenotype. Available data have suggested the involvement of nonshivering thermogenesis induced by a leptin-AMP-activated protein kinase axis in oxidative muscles, which is based on lipid metabolism. Additional studies on the programming effects of leptin, mainly in response to the oral intake of leptin, are required. PMID- 21543530 TI - Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. AB - BACKGROUND: Studies in mice indicate that the gut microbiome influences both sides of the energy-balance equation by contributing to nutrient absorption and regulating host genes that affect adiposity. However, it remains uncertain as to what extent gut microbiota are an important regulator of nutrient absorption in humans. OBJECTIVE: With the use of a carefully monitored inpatient study cohort, we tested how gut bacterial community structure is affected by altering the nutrient load in lean and obese individuals and whether their microbiota are correlated with the efficiency of dietary energy harvest. DESIGN: We investigated dynamic changes of gut microbiota during diets that varied in caloric content (2400 compared with 3400 kcal/d) by pyrosequencing bacterial 16S ribosomal RNA (rRNA) genes present in the feces of 12 lean and 9 obese individuals and by measuring ingested and stool calories with the use of bomb calorimetry. RESULTS: The alteration of the nutrient load induced rapid changes in the gut microbiota. These changes were directly correlated with stool energy loss in lean individuals such that a 20% increase in Firmicutes and a corresponding decrease in Bacteroidetes were associated with an increased energy harvest of ~150 kcal. A high degree of overfeeding in lean individuals was accompanied by a greater fractional decrease in stool energy loss. CONCLUSIONS: These results show that the nutrient load is a key variable that can influence the gut (fecal) bacterial community structure over short time scales. Furthermore, the observed associations between gut microbes and nutrient absorption indicate a possible role of the human gut microbiota in the regulation of the nutrient harvest. This trial was registered at clinicaltrials.gov as NCT00414063. PMID- 21543531 TI - Dietary insulin index and insulin load in relation to biomarkers of glycemic control, plasma lipids, and inflammation markers. AB - BACKGROUND: Dietary glycemic index and load are widely used to estimate the effect of carbohydrate-containing foods on postprandial blood glucose concentrations and as surrogates for insulin response. The food insulin index (II) directly quantifies the postprandial insulin secretion of a food and takes into account foods with a low or no carbohydrate content. OBJECTIVE: We investigated the average dietary II and insulin load (IL) in relation to biomarkers of glycemic control, plasma lipids, and inflammation markers. DESIGN: In a cross-sectional setting and with the use of data from the Nurses' Health Study and the Health Professionals Follow-Up Study, we measured plasma concentrations of C-peptide, glycated hemoglobin (Hb A(1c)), HDL cholesterol, LDL cholesterol, triglycerides, C-reactive protein (CRP), and interleukin-6 (IL-6) in fasting blood samples of 4002 healthy men and women. The dietary II and IL were assessed from food-frequency questionnaires by using directly analyzed or published food II data. RESULTS: After multivariate adjustment, participants in the highest quintile of II had 26% higher triglyceride concentrations than did participants in the lowest quintile of II (P for trend < 0.0001). This association was strongest in obese [body mass index (in kg/m(2)) >=30] participants (difference between highest and lowest quintiles in the II: 72%; P for trend = 0.01). Dietary II was inversely associated with HDL cholesterol in obese participants (difference: -18%; P for trend = 0.03). Similar associations were seen for the IL. Dietary II and IL were not significantly associated with plasma C-peptide, Hb A(1c), LDL cholesterol, CRP, or IL-6. CONCLUSION: Dietary II and IL were not associated with fasting biomarkers of glycemic control but may be physiologically relevant to plasma lipids, especially in obese individuals. PMID- 21543532 TI - Fetal regulation of iron transport during pregnancy. AB - During pregnancy, iron is transported from mother to fetus across the placenta. Iron is essential for many biological processes, including the transfer of oxygen in blood, but it can also be toxic. Elaborate and elegant mechanisms have evolved to make sure that the potential for oxidative damage is minimized. In this article, we examine how iron is transferred from the maternal liver to the placenta, taken up, and transferred to the fetal liver. We consider the molecular mechanisms and how they are regulated. In addition, we use data from previously published articles to examine how the processes are regulated and what adaptations can occur to ameliorate the consequences of iron deficiency--an all too common problem in pregnancy, even in the developed world. Finally, we examine some of the many questions that remain about the transfer process and consider how nutrients interact and what the consequences of these interactions may be for the mother and her developing infant. PMID- 21543533 TI - Gut microbiota and probiotics in maternal and infant health. AB - The interplay between both heredity and environmental factors seems to affect every stage of development from conception to the early postnatal period with potential long-term effects on child and adult health. During pregnancy, immune and metabolic functions of the fetus are dependent on the mother; moreover, the refinement of these functions seems to commence inside the uterus and to be diet sensitive. The microbiota inhabiting the intestinal tract develop an array of physiologic roles within the human body, which influences both metabolic and immune functions, particularly during early neonatal life and possibly even in utero. Transmission of bacteria from the mother to the neonate through direct contact with maternal microbiota during birth and through breast milk during lactation also seems to influence the infant's gut colonization, with potential health consequences. In this context, intentional modulation of microbiota composition through the use of probiotics during the perinatal and early postnatal period has been proposed as a possible dietary strategy to reduce risk of disease. Herein, studies are reviewed on the composition of the intestinal microbiota during pregnancy and clinical trials evaluating the effects of perinatal administration of probiotics on different clinical outcomes. PMID- 21543534 TI - How can the Developmental Origins of Health and Disease (DOHaD) hypothesis contribute to improving health in developing countries? AB - The relevance of nutrition during pregnancy and early infancy in defining short term health and survival has been well established. However, the Developmental Origins of Health and Disease (DOHaD) paradigm provides a framework to assess the effect of early nutrition and growth on long-term health. This body of literature shows that early nutrition has significant consequences on later health and well being. In this article, we briefly present the main consequences of malnutrition that affect human growth and development and consider how the DOHaD paradigm, with its evolutionary implications, might contribute to better addressing the challenge of improving nutrition. We examine how this paradigm is particularly appropriate in understanding the health and nutrition transition in countries that face the double burden of nutrition-related diseases (acute malnutrition coexisting with obesity and other chronic diseases). We focus on stunting (low height-for-age) to examine the short- as well as long-term consequences of early malnutrition with a life-course, transgenerational, and multidisciplinary perspective. We present current global and regional prevalence of stunting and discuss the need to reposition maternal and infant nutrition not only in health and nutrition intervention programs but also in consideration of the emerging research questions that should be resolved to better orient program and policy decisions. PMID- 21543535 TI - Biomonitoring and biomarkers to unravel the risks from prenatal environmental exposures for later health outcomes. AB - An increasing number of studies have addressed the concern that environmental pollutants may contribute to the early origin of diseases. Epidemiologic studies suggest that prenatal exposure to air pollutants, several food contaminants, and chemicals present in consumer products are associated with nongenetically transmitted adverse health effects, which manifest after birth. Changes in neurobehavior, sexual development, the prevalence of asthma and allergy, and growth curves have been shown to be associated with pollutant exposure at early life stages. This review focuses on human molecular epidemiologic studies that contribute knowledge by introducing biomarker measurements to obtain a mechanistic understanding of the relation between early life exposures and health outcome. It has been hypothesized that subtle effects induced by pollutant exposure during development can lead to functional deficits and altered programming, which leads to increased disease or dysfunction risk later in life. Biomarker analysis may provide sensitive tools to trace these subtle changes and obtain mechanistic insight about the causal pathway between external exposure and health effects in human population studies. Biomarkers of exposure can be measured in mothers before conception, during pregnancy, or after birth. Different biological tissues-such as peripheral or cord blood samples, hair samples, meconium, and urine-provide specific information that reflects the actual dose during pregnancy or at birth. Biomarkers of effect may include changes in hormone concentrations, oxidative stress variables, changes in gene expression levels, and epigenetic changes. PMID- 21543536 TI - Mechanisms of early life programming: current knowledge and future directions. AB - It has been >20 y since epidemiologic studies showed a relation between patterns of early growth and subsequent risk of diseases, such as type 2 diabetes, cardiovascular disease, and the metabolic syndrome. Studies of identical twins, individuals who were in utero during periods of famine, and animal models have provided strong evidence that the early environment, including early nutrition, plays an important role in mediating these relations. The concept of early life programming is therefore widely accepted. However, the mechanisms by which a phenomenon that occurs in early life can have long-term effects on the function of a cell and therefore on the metabolism of an organism many years later are only starting to emerge. These mechanisms include 1) permanent structural changes in an organ resulting from suboptimal concentrations of an important factor during a critical period of development, eg, the permanent reduction in beta cell mass in the endocrine pancreas; 2) persistent alterations in epigenetic modifications (eg, DNA methylation and histone modifications) that lead to changes in gene expression (eg, several transcription factors are susceptible to programmed changes in gene expression through such mechanisms); and 3) permanent effects on the regulation of cellular aging (eg, increases in oxidative stress that lead to macromolecular damage, including that to DNA and specifically to telomeres, can contribute to such effects). Further understanding of such processes will enable the development of preventive and intervention strategies to combat the burden of common diseases such as type 2 diabetes and cardiovascular disease. PMID- 21543537 TI - Lycopene bioavailability and metabolism in humans: an accelerator mass spectrometry study. AB - BACKGROUND: To our knowledge, there is no direct information on lycopene metabolism in humans. OBJECTIVE: The objective of this study was to quantify the long-term human bioavailability of lycopene in plasma and skin after a single dose of (14)C-lycopene and to profile the metabolites formed. DESIGN: We preselected 2 male subjects as lycopene absorbers and gave them an oral dose of 10 mg synthetic lycopene combined with ~6 MUg [6,6',7,7'-(14)C]lycopene (~30,000 Bq; 92% trans lycopene). The appearance of (14)C in plasma, plasma triacylglycerol-rich lipoprotein (TRL) fraction, urine, expired breath carbon dioxide, and skin biopsies was measured over 42 d. The (14)C in lycopene-isomer fractions from plasma and TRL fraction was measured to assess the isomerization of lycopene in vivo. RESULTS: We quantified (14)C from (14)C-lycopene in plasma, the plasma TRL fraction, expired carbon dioxide, urine, and skin. The time to maximum concentration (t(max)) of total (14)C-lycopene in plasma was 6 h, and the elimination half-life (t(1/2)) was 5 d, which were different from the t(max) and t(1/2) of unlabeled lycopene (0.5 and 48 d, respectively). (14)C-Lycopene was extensively isomerized after dosing as a 92% all-trans isomer at dosing but changed to 50% trans, 38% 5 cis, 1% 9 cis, and 11% other cis isomers after 24 h. A similar pattern of isomerization was seen in plasma TRL fractions. CONCLUSIONS: Lycopene was extensively isomerized after dosing and rapidly metabolized into polar metabolites excreted into urine with the rapid peak of (14)CO(2) after dosing, which implies that beta-oxidation was involved in the lycopene metabolism. Lycopene or its metabolites were detected in skin for up to 42 d. PMID- 21543538 TI - Whole-body and muscle protein metabolism are not affected by acute deviations from habitual protein intake in older men: the Hormonal Regulators of Muscle and Metabolism in Aging (HORMA) Study. AB - BACKGROUND: Acute deviations in protein intake before the quantification of protein kinetics in older humans may explain the controversy over the effects of older age on muscle protein synthesis and proteolysis rates. OBJECTIVE: We hypothesized that an acute decrease in protein intake from the habitual intake is associated with lower muscle protein synthesis and higher proteolysis rates, whereas an acute increase in protein intake from the habitual intake is associated with higher muscle protein synthesis and lower proteolysis rates. DESIGN: In 112 community-dwelling healthy men aged 65-90 y, we quantified resting whole-body [1,2-(13)C(2)]leucine kinetics, muscle mixed protein fractional synthesis rates (FSRs), and muscle proteasome proteolytic enzyme activities after participants consumed for 3 d controlled research meals (0.9-1.1 g protein . kg( 1) . d(-1)) that contained more or less protein than that habitually consumed and that induced alterations in nitrogen balance. RESULTS: Protein kinetic parameters were not significantly different between the groups, despite controlled research protein intakes that were lower (-0.2 to -0.3 g . kg(-1) . d(-1)) or higher (+0.2 g . kg(-1) . d(-1)) than habitual intakes and that induced negative (-22 to -25 mg . kg(-1) . d(-1)) or positive (22-25 mg . kg(-1) . d(-1)) nitrogen balance. Within these acutely altered protein intake and nitrogen balance boundaries, a reduction in protein intake from habitual intake and induction of negative nitrogen balance were not associated with higher proteolysis or lower muscle FSR, and an acute increase in protein intake from habitual intake and induction of positive nitrogen balance were not associated with lower proteolysis or higher muscle FSR. A higher quantitative insulin sensitivity check index was associated with lower whole-body proteolysis rates. CONCLUSIONS: The practice of acutely controlling protein intake, even at intakes lower than habitual intakes that induce negative nitrogen balance, before quantifying human protein kinetics does not significantly reduce muscle protein synthesis or increase proteolysis. Factors other than protein intake explain lower muscle protein synthesis rates with advanced age. This trial is registered at clinicaltrials.gov as NCT00183040. PMID- 21543539 TI - The OBELIX project: early life exposure to endocrine disruptors and obesity. AB - The hypothesis of whether early life exposure (both pre- and early postnatal) to endocrine-disrupting chemicals (EDCs) may be a risk factor for obesity and related metabolic diseases later in life will be tested in the European research project OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life). OBELIX is a 4-y project that started in May 2009 and which has the following 5 main objectives: 1) to assess early life exposure in humans to major classes of EDCs identified as potential inducers of obesity (ie, dioxin-like compounds, non-dioxin-like polychlorinated biphenyls, organochlorine pesticides, brominated flame retardants, phthalates, and perfluorinated compounds) by using mother-child cohorts from 4 European regions with different food-contaminant exposure patterns; 2) to relate early life exposure to EDCs with clinical markers, novel biomarkers, and health-effect data related to obesity; 3) to perform hazard characterization of early life exposure to EDCs for the development of obesity later in life by using a mouse model; 4) to determine mechanisms of action of obesogenic EDCs on developmental programming with in vivo and in vitro genomics and epigenetic analyses; and 5) to perform risk assessments of prenatal exposure to obesogenic EDCs in food by integrating maternal exposure through food contaminant exposure and health-effect data in children and hazard data in animal studies. PMID- 21543540 TI - Placental transport in pregnancy pathologies. AB - The placenta is positioned between the maternal and fetal circulation and hence plays a key role in transporting maternal nutrients to the developing fetus. Fetal growth changes in the 2 most frequent pregnancy pathologies, gestational diabetes mellitus and fetal growth restriction, are predominantly characterized by an exaggerated and restricted fat accretion, respectively. Glucose, by its regulating effect on fetal insulin concentrations, and lipids have been strongly implicated in fetal fat deposition. Transplacental glucose flux is highly efficient and limited only by nutrient availability (flow-limited)--ie, driven by the maternal-fetal glucose concentration gradient and blood flow, with little, if any, effect of placental morphology, glucose consumption, and transporter expression. This explains why, despite changes in these determinants in both pathologies, transplacental glucose flux is unaltered. PMID- 21543541 TI - Effect of dietary factors in pregnancy on risk of pregnancy complications: results from the Norwegian Mother and Child Cohort Study. AB - There has been a thrilling development , as well as profound changes, in our understanding of the effect of fetal nutrition on the development and health of the child. The Norwegian Mother and Child Cohort Study (MoBa) is an ongoing nationwide population-based pregnancy cohort study that between 1999 and 2008 recruited 90,723 women with 106,981 pregnancies and 108,487 children. The objective of MoBa is to test specific etiologic hypotheses by estimating the association between exposures and diseases with a special focus on disorders that may originate in early life. An important aspect in this regard is maternal diet and nutritional status during pregnancy. Nutritional factors have long been considered to be important determinants of maternal and fetal health, and dietary information is currently being collected in a number of pregnancy cohorts in Europe and the United States. Thus far, pregnancy complications studied in MoBa are preterm birth, preeclampsia, and fetal growth; and the aim of this article is to report results of recently published studies of dietary factors in relation to these outcomes. Numerous studies are planned using MoBa data, and the aim is to add to the knowledge of the interplay between dietary factors, nonnutrients, and toxic dietary substances and epigenetic modulation on fetal development and health later in life. PMID- 21543542 TI - The early programming of metabolic health: is epigenetic setting the missing link? AB - Adult health is dependent, in part, on maternal nutrition and growth during early life, which may independently affect insulin sensitivity, body composition, and overall energy homeostasis. Since the publication of the "thrifty phenotype hypothesis" by Hales and Barker (Diabetologia 1992;35:595-601), animal experiments have focused on establishing the mechanisms involved, which include changes in fetal cortisol, insulin, and leptin secretion or sensitivity. Intrauterine growth retardation can be induced by either prolonged modest changes in maternal diet or by more severe changes in uterine blood supply near to term. These contrasting challenges result in different amounts of cellular stress in the offspring. In addition, shifts in the transcriptional activity of DNA may produce sustained metabolic adaptations. Within tissues and organs that control metabolic homeostasis (eg, hypothalamus, adipose tissue, stomach, skeletal muscle, and heart), a range of phenotypes can be induced by sustained changes in maternal diet via modulation of genes that control DNA methylation and by histone acetylation, which suggests epigenetic programming. We now need to understand how changes in maternal diet affect DNA and how they are conserved on exposure to oxidative stress. A main challenge will be to establish how the dietary environment interacts with the programmed phenotype to trigger the development of metabolic disease. This may aid in the establishment of nutrigenomic strategies to prevent the metabolic syndrome. PMID- 21543543 TI - Does early nutrition program later bone health in preterm infants? AB - Preterm infants are at risk of metabolic bone disease (MBD) because of an inadequate mineral intake. Although infants with MBD are frequently asymptomatic during the neonatal period, we previously reported that MBD predicted reduced linear growth in infancy and midchildhood. Nevertheless, some studies suggest that preterm infants undergo catch-up growth in bone mineralization during infancy. To examine the hypothesis that early nutrition programs affect later bone health and peak bone mass, we studied 20-y-old subjects who were born preterm and who were randomly assigned to a diet during the neonatal period; the diets used varied markedly in nutrient and mineral content, and phosphate supplements were not provided. Despite large variations in early nutrient and mineral intakes (and the occurrence of MBD) during the neonatal period, the randomly assigned diets did not influence peak bone mass or turnover. However, the proportion of (unsupplemented) human milk in the neonatal diet was significantly positively associated with later whole-body bone size and mineral content. Compared with population reference data, preterm subjects were significantly shorter and had lower lumbar spine bone mineral density; the deficits were greatest in those born small for gestational age (ie, a birth weight <1250 g). The lack of effect of the randomly assigned diets on peak bone mass suggests that the observed deficits in height and lumbar spine bone mass may not be related to suboptimal early nutrient or mineral intake. The higher whole body bone mass associated with human milk intake, despite its very low nutrient content, may instead reflect nonnutritive factors in breast milk. These findings are relevant to discussions on the mineral requirements of preterm infants. PMID- 21543544 TI - Early diet and the risk of allergy: what can we learn from the prospective birth cohort studies GINIplus and LISAplus? AB - Recently, the American Academy of Pediatrics and the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition published new guidelines on early nutrition and allergy prevention in infants and children. This article reviews epidemiologic evidence from 2 prospective German birth cohort studies, the GINIplus and the LISAplus, regarding maternal diet during pregnancy and feeding patterns in early life and the risk of allergy in light of the new recommendations. The 2 cohorts include a total of 9088 infants who were recruited within different regions of Germany between 1995 and 1999. A subgroup of 2252 infants with a hereditary risk of atopy was enrolled in a double-blind, randomized trial to investigate the effect of feeding regimen in infancy on the development of allergy with the strict recommendation that allergenic solid food be introduced late in the study. The results of the GINIplus and LISAplus studies mainly support the new finding regarding allergy prevention that a delayed introduction of solid foods or the avoidance of highly allergenic foods during the first year does not seem to be beneficial for allergy prevention. A very early introduction of solid foods and a high diversity before week 17 of age may increase the risk of later allergy. We showed that a high intake of margarine, vegetable oils, and some allergenic fruit and vegetables during pregnancy was associated with an increased risk of allergies, especially eczema. Because maternal diet during pregnancy is not reflected in the current recommendations, it should be the focus of future studies. PMID- 21543545 TI - Food reinforcement, energy intake, and macronutrient choice. AB - BACKGROUND: Food is a powerful reinforcer that motivates people to eat. The relative reinforcing value of food (RRV(food)) is associated with obesity and energy intake and interacts with impulsivity to predict energy intake. OBJECTIVE: How RRV(food) is related to macronutrient choice in ad libitum eating tasks in humans has not been studied; however, animal research suggests that sugar or simple carbohydrates may be a determinant of reward value in food. This study assessed which macronutrients are associated with food reinforcement. DESIGN: Two hundred seventy-three adults with various body mass indexes were assessed for RRV(food), the relative reinforcing value of reading, food hedonics, energy intake in an ad libitum taste test, and usual energy intake derived from repeated 24-h dietary recalls. Multiple regression was used to assess the relation between predictors of total energy and energy associated with macronutrient intake after control for age, sex, income, education, minority status, and other macronutrient intakes. RESULTS: The results showed that the relative proportion of responding for food compared with reading (RRV(prop)) was positively related to body mass index, laboratory-measured energy intake, and usual energy intake. In addition, RRV(prop) was a predictor of sugar intake but not of total carbohydrate, fat, or protein intake. CONCLUSION: These results are consistent with basic animal research showing that sugar is related to food reward and with the hypothesis that food reward processes are more strongly related to eating than are food hedonics. This trial was registered at clinicaltrials.gov as NCT00962117. PMID- 21543546 TI - Developmental programming of adult obesity and cardiovascular disease in rodents by maternal nutrition imbalance. AB - Studies on fetal undernutrition have generated the hypothesis that fetal programming corresponds to an attempt of the fetus to adapt to adverse conditions encountered in utero. These adaptations would be beneficial if these conditions prevail later in life, but they become detrimental in the case of normal or plentiful nutrition and favor the appearance of the metabolic syndrome. In this article, the discussion is limited to the developmental programming of obesity and cardiovascular disorders caused by an early mismatched nutrition, particularly intrauterine growth retardation followed by postnatal catch-up growth. Selected data in humans are reviewed before evoking some mechanisms revealed or suggested by experiments in rodents. A variety of physiologic mechanisms are implicated in obesity programming, 2 of which are detailed. In some, but not all observations, hyperphagia resulting namely from perturbed development of the hypothalamic circuitry devoted to appetite regulation may contribute to obesity. Another contribution may be the developmental changes in the population of fat cell precursors in adipose tissue. Even if the link between obesity and cardiovascular disease is well established, alteration of blood pressure regulation may appear independently of obesity. A loss of diurnal variation in heart rate and blood pressure in adulthood has resulted from maternal undernutrition followed by postnatal overnutrition. Further research should clarify the effect of mismatched early nutrition on the development of brain centers regulating energy intake, energy expenditure, and circadian rhythms. PMID- 21543547 TI - Does avoidant coping influence young adults' smoking?: a ten-year longitudinal study. AB - INTRODUCTION: Young adults who avoid their emotions may be at risk for starting smoking or not quitting smoking. This study investigated whether a preliminary measure of avoidant coping longitudinally predicts young adults' smoking escalation and cessation. METHODS: In a sample of the 3,305 participants, originally from Washington State, a preliminary measure of self-reported avoidant coping at age 18 was used to predict both smoking escalation and cessation at ages 20 and 28 with both probability and logistic regression models (10-year retention: 98.5%). RESULTS: Individuals who scored high on avoidant coping at 18 were 2.52 (p = .001) times more likely to acquire smoking by 20. However, there was no evidence that avoidant coping at age 18 predicted smoking escalation at 28 or cessation for 20- and 28-year-olds. CONCLUSIONS: An avoidant coping style may have a short-term effect on young adults' smoking acquisition. Future research using a precise and well-validated measure of avoidant coping is now needed to test this possibility. PMID- 21543548 TI - Did the introduction of varenicline in England substitute for or add to the use of other smoking cessation medications? AB - INTRODUCTION: Varenicline has recently been added to the market as a new drug for smoking cessation. The aim of the current study was to assess whether varenicline substituted for, or added to, the use of other smoking cessation medications. METHODS: We used data from 2,595 smokers taking part in monthly household surveys of representative samples of the English population. We analyzed the percentage of smokers attempting to quit in the past 3 months and using nicotine replacement therapy over the counter (NRT OTC), NRT on prescription (NRT Rx), bupropion, or varenicline from November 2006 to December 2009. This survey covered 3 periods: (a) after the launch of varenicline but before the publication of the National Institute of Health and Clinical Excellence guidance on varenicline in July 2007, (b) the first year following the guidance, and (c) more than 1 year after the guidance. RESULTS: Varenicline usage was negligible in the first period, increased steadily during the second period, and increased less rapidly in the third period to 5.3% of those making a quit attempt (p < .001 for the trend). The percentage of quit attempters using any smoking cessation medication increased nonsignificantly by 2.8 percentage points from 41.7% to 44.5% (p = .268). The use of NRT OTC decreased significantly by 6.2 percentage points from 35.2% to 29.0% (p = .029), whereas the use of NRT Rx increased significantly by 3.7 percentage points from 6.8% to 10.5% (p = .025), and use of bupropion remained unchanged. CONCLUSIONS: Increased use of varenicline in England following guidance from the National Institute for Clinical Excellence in 2007 did not appear to substitute for use of other prescription smoking cessation medication. An observed decline in NRT OTC is likely to have been due to other factors. PMID- 21543549 TI - Age at smoking onset and the onset of depression and anxiety disorders. AB - INTRODUCTION: Smoking is a known risk indicator for depression and some of the anxiety disorders. No data are available on the role of age at smoking onset in the development of depression and anxiety disorders. We examined the association of smoking onset age on the onset age of depression and anxiety disorders. METHODS: Participants of the Netherlands Study of Depression and Anxiety Disorders who developed psychopathology after starting smoking were selected (N = 1,055). The dependent variable was the time to onset of psychopathology after starting smoking, and the independent variable was age at smoking onset. RESULTS: The time period between smoking onset and the onset of depression and/or anxiety disorders was 5 years shorter for early-onset smokers than for late-onset smokers. Moreover, a greater percentage of early-onset smokers than late-onset smokers had the first onset of psychopathology within the first 5 years after starting smoking. Age at smoking onset predicted age at psychopathology onset after controlling for the effects of gender, education, and childhood trauma. When separate analyses were done for depression and anxiety disorders, this pattern of results was found only for anxiety disorders. CONCLUSIONS: A young age at smoking onset is associated with a shorter time to first onset of an anxiety disorder. This study with psychiatric patients extends previous findings in general population samples that smoking and depression and anxiety disorders are associated. PMID- 21543550 TI - The effects of the acute administration of low-dosage ethanol on the phasic neurochemical oscillations of the basal ganglia. AB - The effects of the acute ethanol consumption on the brain's neurochemistry are largely studied at the synaptic level. Here, the acute action of low dosages of ethanol, in terms of the inhibition of the glutamatergic system through antagonizing the N-methyl-D-aspartate receptors, on the neurochemical oscillations along the neurocircuitry of the basal ganglia is investigated by mathematical models. Substantial alterations in the dynamical behaviour of the neurochemical oscillations after single administration of low dosages of ethanol have been observed. Significant dynamical changes in the gamma-aminobutyric acid and glutamate systems along the subthalamic-pallidal feedback loop and the dopamine system of the striatal complex suggest new perspectives in the understanding of the ethanol-induced motor dysfunctions. PMID- 21543551 TI - Relevance of IL7R genotype and mRNA expression in Dutch patients with multiple sclerosis. AB - BACKGROUND: The interleukin 7 receptor (IL7R) has been recognized as a susceptibility gene for Multiple Sclerosis (MS). Analysis of rs6897932 (the most strongly MS-associated single nucleotide polymorphism (SNP)), showed effects of genotype on the relative expression of membrane-bound to total amount of IL7R mRNA. OBJECTIVE: We assessed the relevance of IL7R on MS phenotype (including clinical and magnetic resonance imaging (MRI) parameters) at DNA and mRNA level in Dutch patients with MS. METHODS: The genotype of rs6897932 was analyzed in 697 patients with MS and 174 healthy controls. The relevance of genotype and carriership of the C allele on MS phenotype (disease activity and severity, using clinical and MRI parameters) was assessed. In addition, relative gene expression of membrane-bound to total IL7R mRNA was analyzed with respect to disease phenotype in a subgroup of 95 patients with early relapsing MS. RESULTS: In particular, homozygosity for the risk allele is a risk factor for MS in our population (OR(CC vs CT and TT) = 1.65 (95% CI: 1.18-2.30), two-sided p = 0.004). However, no effect of genotype or the relative expression of membrane-bound IL7R (presence of exon 6-7) to total amount of IL7R mRNA (presence of exon 4-5) was found on MS phenotype. DISCUSSION: Homozygosity for the IL7R exon 6 rs6897932 C allele is associated with a higher risk for MS in our Dutch population. No effect was found of genotype or mRNA expression on disease phenotype. PMID- 21543552 TI - Intracortical lesions by 3T magnetic resonance imaging and correlation with cognitive impairment in multiple sclerosis. AB - BACKGROUND: Accurate classification of multiple sclerosis (MS) lesions in the brain cortex may be important in understanding their impact on cognitive impairment (CI). Improved accuracy in identification/classification of cortical lesions was demonstrated in a study combining two magnetic resonance imaging (MRI) sequences: double inversion recovery (DIR) and T1-weighted phase-sensitive inversion recovery (PSIR). OBJECTIVE: To evaluate the role of intracortical lesions (IC) in MS-related CI and compare it with the role of mixed (MX), juxtacortical (JX), the sum of IC + MX and with total lesions as detected on DIR/PSIR images. Correlations between CI and brain atrophy, disease severity and disease duration were also sought. METHODS: A total of 39 patients underwent extensive neuropsychological testing and were classified into normal and impaired groups. Images were obtained on a 3T scanner and cortical lesions were assessed blind to the cognitive status of the subjects. RESULTS: Some 238 cortical lesions were identified (130 IC, 108 MX) in 82% of the patients; 39 JX lesions were also identified. Correlations between CI and MX lesions alone (p = 0.010) and with the sum of IC + MX lesions (p = 0.030) were found. A correlation between severity of CI and Expanded Disability Status Scale was also seen (p = 0.009). CONCLUSION: Cortical lesions play an important role in CI. However, our results suggest that lesions that remain contained within the cortical ribbon do not play a more important role than ones extending into the adjacent white matter; furthermore, the size of the cortical lesion, and not the tissue-specific location, may better explain their correlation with CI. PMID- 21543553 TI - Frequency and syndrome specificity of antibodies to aquaporin-4 in neurological patients with rheumatic disorders. AB - BACKGROUND: A new autoantibody (termed NMO-IgG, or AQP4-Ab) has recently been described in patients with neuromyelitis optica (NMO) and its formes frustes, longitudinally extensive transverse myelitis (LETM) and recurrent optic neuritis (rON). However, AQP4-Ab has been found also in patients with co-existing rheumatic diseases such as systemic lupus erythematosus (SLE) or Sjogren's syndrome (SS), conditions which are characterized by broad, polyspecific B cell activation. OBJECTIVES: In this study, we aimed at evaluating the syndrome specificity and frequency of AQP4-Ab in patients with rheumatic diseases and neurological symptoms. METHODS: For this purpose, serum samples from 109 neurological patients with established connective tissue disorders (CTD) (n = 54), possible CTD (n = 42), or vasculitis (n = 13) were analysed for the presence of AQP4-Ab by a cell-based assay employing recombinant human AQP4. RESULTS: AQP4 Ab was detectable in 31/40 (78%) patients with CTD and NMO spectrum disorders (median titre, 1:1000) but in none of the samples obtained from patients with CTD or vasculitis and neurological disorders other than NMO, LETM, or rON (n = 69). CONCLUSION: The high syndrome specificity of the antibody for neuromyelitis optica spectrum disorders (NMOSDs) in patients with CTD supports the concept of AQP4-Ab being involved in the pathogenesis of these neurological conditions, and argues against AQP4-Ab simply being part of the polyclonal B cell activation generally associated with rheumatic diseases. Moreover, the finding that AQP4-Ab is present in patients with CTD and co-existing NMOSD with approximately the same frequency as in patients without CTD strengthens the case of CTD and AQP4-Ab positive NMOSD representing two co-existing yet distinct entities in the majority of patients. PMID- 21543554 TI - Brain abnormalities as an initial manifestation of neuromyelitis optica spectrum disorder. AB - BACKGROUND: Although brain abnormalities are being recognized more frequently in patients with neuromyelitis optica spectrum disorder (NMOSD), most brain lesions in previous reports have accompanied pre-existing NMOSD. Here, we describe clinical and imaging characteristics of patients with NMOSD who presented with brain symptoms as their first manifestation of the condition. METHODS: Anti aquaporin-4 antibody was measured using cell-based assays and/or enzyme-linked immunosorbent assay in the sera of 257 patients with inflammatory diseases of the central nervous system who attended the multiple sclerosis clinic of the National Cancer Center, Korea, between May 2005 and December 2009. Eighty-three were seropositive, and 15 of these who presented with brain symptoms were included in this study. We retrospectively reviewed these individuals' clinical and radiological findings. RESULTS: Patients with NMOSD were followed for a mean of 90 months. Median age at onset was 24 years (6-54 years) and there was a female preponderance (94%). The initial manifestation was classified into two groups according to clinical characteristics: encephalopathy mimicking acute disseminated encephalomyelitis or posterior reversible encephalopathy syndrome and characteristic brainstem symptoms such as intractable hiccup and vomiting. The majority of brain symptoms and lesions resolved. Intriguingly, eight patients (53%) experienced brain relapses that followed a similar pattern during the course of their disease. CONCLUSION: It is important to recognize that NMO or NMOSD can initially present with brain symptoms. PMID- 21543555 TI - Microsomal quercetin glucuronidation in rat small intestine depends on age and segment. AB - UDP-glucuronosyltransferase (UGT) activity toward the flavonoid quercetin and UGT protein were characterized in three equidistant small intestine (SI) segments from 4-, 12-, 18-, and 28-month-old male Fischer 344 rats (n = 8/age) using villin to control for enterocyte content. SI microsomal intrinsic clearance of quercetin was increased 3- to 9-fold from 4 months in the proximal and distal SI at 12 and 18 months. Likewise, at 30 MUM quercetin, SI microsomal glucuronidation activity was increased with age: 4.8- and 3.9-fold greater at 18 months than at 4 months. Quercetin UGT regioselectivity was not changed by age. The distal SI preferentially catalyzed glucuronidation at the 7-position, whereas the proximal SI produced the greatest proportion of 4'- and 3'-conjugates. Enterocyte UGT content in different SI segments was not consistently changed with age. In the proximal SI, UGT1A increased 64 and 150% at 12 and 18 months and UGT1A1, UGT1A7, and UGT1A8 were also increased at 12 and 18 months. However, age-related changes in expression were inconsistent in the medial and distal segments. Microsomal rates of quercetin glucuronidation and UGT expression were positively correlated with UGT1A1 content for all pooled samples (r = 0.467) and at each age (r = 0.538 0.598). UGT1A7 was positively correlated with total, 7-O- and 3-O-quercetin glucuronidation at 18 months. Thus, age-related differences in UGT quercetin glucuronidation depend on intestinal segment, are more pronounced in the proximal and distal segments and may be partially related to UGT1A1 and UGT1A7 content. PMID- 21543556 TI - Preclinical and clinical pharmacokinetics of PF-02413873, a nonsteroidal progesterone receptor antagonist. AB - The recently discovered selective nonsteroidal progesterone receptor (PR) antagonist 4-[3-cyclopropyl-1-(methylsulfonylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy 2,6-dimethylbenzonitrile (PF-02413873) was characterized in metabolism studies in vitro, in preclinical pharmacokinetics in rat and dog, and in an initial pharmacokinetic study in human volunteers. Clearance (CL) of PF-02413873 was found to be high in rat (84 ml . min(-1) . kg(-1)) and low in dog (3.8 ml . min( 1) . kg(-1)), consistent with metabolic stability determined in liver microsomes and hepatocytes in these species. In human, CL was low in relation to hepatic blood flow, consistent with metabolic stability in human in vitro systems, where identified metabolites suggested predominant cytochrome P450 (P450)-catalyzed oxidative metabolism. Prediction of CL using intrinsic CL determined in human liver microsomes (HLM), recombinant human P450 enzymes, and single species scaling (SSS) from pharmacokinetic studies showed that dog SSS and HLM scaling provided the closest estimates of CL of PF-02413873 in human. These CL estimates were combined with a physiologically based pharmacokinetic (PBPK) model to predict pharmacokinetic profiles after oral suspension administration of PF 02413873 in fasted and fed states in human. Predicted plasma concentration versus time profiles were found to be similar to those observed in human over the PF 02413873 dose range 50 to 500 mg and captured the enhanced exposure in fed subjects. This case study of a novel nonsteroidal PR antagonist underlines the utility of PBPK modeling techniques in guiding prediction confidence and design of early clinical trials of novel chemical agents. PMID- 21543557 TI - Complexity, case-mix and rehabilitation: the importance of a holistic model of illness. AB - Rehabilitation is not cheap. It depends upon personal interactions between rehabilitation staff and the patient and their families, and salaries for staff are always expensive. Rehabilitation depends upon learning, which takes time. The more complex the problems presented by patients the more resources are likely to be needed. This editorial reviews briefly the nature of complexity, emphasizing that it encompasses both the number of factors impinging upon the outcome of interest and the non-linear nature of many of the relationships between different factors and inputs. It describes briefly the holistic biopsychosocial model of illness that underlies much rehabilitation practice and a model of the rehabilitation process, and it then considers how complexity might be measured. It concludes that measures exist, such as the INTERMED, although they can probably be improved. But evidence derived using the INTERMED already both validates the biopsychosocial model of illness, and provides a sound basis for further developments. PMID- 21543558 TI - Pulmonary pathology of pandemic influenza A/H1N1 virus (2009)-infected ferrets upon longitudinal evaluation by computed tomography. AB - We investigated the development of pulmonary lesions in ferrets by means of computed tomography (CT) following infection with the 2009 pandemic A/H1N1 influenza virus and compared the scans with gross pathology, histopathology and immunohistochemistry. Ground-glass opacities observed by CT scanning in all infected lungs corresponded to areas of alveolar oedema at necropsy. These areas were most pronounced on day 3 and gradually decreased from days 4 to 7 post infection. This pilot study shows that the non-invasive imaging procedure allows quantification and characterization of influenza-induced pulmonary lesions in living animals under biosafety level 3 conditions and can thus be used in pre clinical pharmaceutical efficacy studies. PMID- 21543559 TI - Ultrasensitive detection of drug-resistant pandemic 2009 (H1N1) influenza A virus by rare-variant-sensitive high-resolution melting-curve analysis. AB - Oseltamivir (Tamiflu), an oral neuraminidase inhibitor, has been widely used to treat pandemic 2009 (H1N1) influenza A. Although a majority of 2009 (H1N1) influenza A virus remains oseltamivir susceptible, the threat of resistance due to the His275Tyr mutation is highlighted by the limitations of alternative therapies and the potential for rapid, global fixation of this mutation in the circulating influenza A virus population. In order to better understand the emergence of resistance, we developed a rare-variant-sensitive high-resolution melting-curve analysis method (RVS-HRM) that is able to detect the His275Tyr oseltamivir resistance mutation to 0.5% in a background of susceptible virus. We applied RVS-HRM to clinical specimens from patients who developed oseltamivir resistance and demonstrated the ultrasensitive detection of influenza A virus N1 neuraminidase quasispecies. Interestingly, we were unable to detect the oseltamivir resistance mutation in pretreatment samples, suggesting that resistant virus does not reach even this very low detection threshold until exposed to selective drug pressure. Thus, patients naive to oseltamivir are most likely to be susceptible when this drug is used as a first-line treatment modality. PMID- 21543560 TI - Complete genome analysis of coxsackievirus A2, A4, A5, and A10 strains isolated from hand, foot, and mouth disease patients in China revealing frequent recombination of human enterovirus A. AB - Coxsackievirus (CV) strains CVA2, CVA4, CVA5, and CVA10 were isolated from patients with hand, foot, and mouth disease during a 2009 outbreak in China. Full genome sequences for four representative strains, CVA2/SD/CHN/09 (A2SD09), CVA4/SZ/CHN/09 (A4SZ09), CVA5/SD/CHN/09 (A5SD09), and CVA10/SD/CHN/09 (A10SD09), were determined. Phylogenetic and recombination analyses of the isolates by comparison with human enterovirus A prototype strains revealed that genetic recombination occurred during cocirculation of the viruses. The A2SD09 and A4SZ09 strains were most closely related to their corresponding prototype strains in the capsid region but shared noncapsid sequences with each other. Similarly, strains A5SD09 and A10SD09 had serotype-specific homology for the capsid proteins but shared noncapsid sequences with each other. Phylogenetic analyses of the four isolates with homotypic strains showed that CVA2 strains were divided into five genotypes. The A2SD09 strain clustered with Mongolia strains isolated in 2003, forming genotype V. The A4SZ09 strain and other isolates from mainland China and Taiwan clustered with genotype III strains and are likely related to strains that circulated in Europe and Mongolia. The A5SD09 strain is closely related to other Chinese strains isolated in 2008. The A10SD09 isolate, together with other Chinese strains isolated since 2004, formed a distinct lineage that was likely imported from Japan and South Korea. This study shows that natural recombination is a frequent event in human enterovirus A evolution. More comprehensive surveillance of enteroviruses that focus not only on EV71 or CVA16 is needed for us to understand the molecular epidemiology of enteroviruses and to track recombination events which may ultimately affect the virulence of viruses during outbreaks. PMID- 21543561 TI - Identification of Toxoplasma gondii SUB1 antigen as a marker for acute infection by use of an innovative evaluation method. AB - By the separation of Toxoplasma lysate using two-dimensional gel electrophoresis and its analysis with human serum samples and mass spectrometry, the subtilisin like protein (SUB1) was identified to be a potential marker for acute toxoplasmosis. Following expression of the C-terminal domain of SUB1 in Escherichia coli, it was tested in a line blot assay using a total of 80 human serum samples. Two computer programs based on different evaluation strategies were used for judgment of the line blot results: (i) a time-dependent method with a predefined cutoff value and (ii) a fixed-time-point method with a calculated cutoff. Thereby, SUB1 was proven to be rather reactive with specific immunoglobulin A (IgA), IgM, and IgG of patients with an acute infection. This finding makes this antigen an attractive candidate for improving diagnosis of toxoplasmosis and demonstrates that not only the selection of respective antigens but also the evaluation method chosen are important for the evaluation of new diagnostic markers. PMID- 21543562 TI - Optimization of periprosthetic culture for diagnosis of Propionibacterium acnes prosthetic joint infection. AB - Propionibacterium acnes is increasingly recognized as an important agent of prosthetic joint infection (PJI). However, the optimum culture conditions for recovery of this organism from PJI specimens have not been determined. By applying a prolonged 28-day culture incubation to all periprosthetic specimens received for bacterial culture from 198 revision arthroplasty procedures, we retrospectively determined that a 13-day culture incubation period is necessary for the recovery of P. acnes from patients with PJI. Incubation beyond this period was associated with increasing recovery of nondiagnostic isolates: 21.7% of P. acnes isolates believed to be clinically unimportant were recovered after 13 days of incubation. Importantly, a diagnosis of P. acnes PJI would have been missed in 29.4% of patients had extended culture incubation been applied only to anaerobic culture media. Although specimens from P. acnes PJIs were more commonly associated with the presence of >= 2 culture media positive for growth, acute inflammation (>= 5 neutrophils/high-power field) was observed in only 40% of patients with PJIs that had more than one specimen submitted for bacterial culture. These results support the need for a minimum culture incubation period of 13 days to be applied to both aerobic and anaerobic culture media for all periprosthetic specimens. Optimal recovery of infecting organisms from PJI specimens will be an important component in generating a universal definition for PJI due to indolent agents of infection, such as P. acnes. PMID- 21543563 TI - RNA versus DNA (NucliSENS EasyQ HIV-1 v1.2 versus Amplicor HIV-1 DNA test v1.5) for early diagnosis of HIV-1 infection in infants in Senegal. AB - The objective of this study was to compare the performance of the NucliSENS EasyQ HIV-1 v1.2 platform (bioMerieux, France) to the Amplicor HIV-1 DNA test v1.5 (Roche Molecular Systems, Switzerland) in detecting HIV-1 infection in infants using venipuncture-derived whole blood in tubes and dried blood spots. A total of 149 dried blood spots and 43 EDTA-anticoagulated peripheral blood samples were collected throughout Dakar and other areas in Senegal from infants and children aged 3 weeks to 24 months who were born to HIV-1-infected mothers. Samples were tested using the NucliSENS and Amplicor technologies. The NucliSENS and Amplicor results were 100% concordant using either EDTA-anticoagulated peripheral blood or dried blood spots. Compared to Amplicor, the sensitivity and specificity of the NucliSENS test were 100%. The NucliSENS EasyQ HIV-1 RNA assay performed as well as the Amplicor HIV-1 DNA test in detecting HIV-1 infection in infants. In addition, this platform can give an indication of the viral load baseline. The NucliSENS EasyQ platform is a good alternative for early infant diagnosis of HIV 1 infection. PMID- 21543564 TI - Improved identification of yeast species directly from positive blood culture media by combining Sepsityper specimen processing and Microflex analysis with the matrix-assisted laser desorption ionization Biotyper system. AB - Current methods for identification of yeast from blood cultures may take several days after these microorganisms have been observed by Gram stain smears from positive blood cultures. We explored the use of a matrix-assisted laser desorption ionization (MALDI) Biotyper system in combination with Sepsityper specimen processing and Microflex analysis for improved detection and identification of yeast species directly from positive blood culture specimens demonstrating yeast-like organisms by Gram stain. The limit of detection of yeast species in blood culture medium was determined to be 5.9 * 10(5) CFU, with intra- and interstrain coefficients of variation of 1.8 to 3.6% and 2.9%, respectively. A total of 42 yeast-containing positive blood culture specimens were processed, and the identification results were compared to those obtained by routinely used phenotypic methods. Specimens with discrepant results between the Biotyper and phenotypic methods were identified on the basis of internal transcribed spacer region sequencing. The MALDI Biotyper system correctly identified the 42 specimens to species level, including 28 (66.7%) Candida albicans, 8 (19.0%) Candida parapsilosis, and 5 (11.9%) Candida tropicalis isolates and 1 (2.4%) Cryptococcus neoformans isolate. The entire procedure, from specimen extraction to final result reporting, can be completed within 1 h. Our data indicated that the Sepsityper specimen processing and Microflex analysis by the MALDI Biotyper system provide a rapid and reliable tool for yeast species identification directly from positive blood culture media. PMID- 21543565 TI - Reevaluation of the taxonomic status of recently described species of Enterococcus: evidence that E. thailandicus is a senior subjective synonym of "E. sanguinicola" and confirmation of E. caccae as a species distinct from E. silesiacus. AB - Several of the more recently proposed new species of Enterococcus are nearly identical based on 16S rRNA gene sequence analysis and phenotypic traits. In the present study, DNA-DNA reassociation experiments, in conjunction with sequencing of the 16S rRNA and rpoB genes, provided evidence that "Enterococcus sanguinicola" and Enterococcus thailandicus actually represent the same species. In contrast, Enterococcus caccae and Enterococcus silesiacus, two other species with nearly identical 16S rRNA gene sequences, were confirmed to be separate species. PMID- 21543566 TI - Evaluation of BacT/Alert 3D automated unit for detection of nontuberculous mycobacteria requiring incubation at 30 degrees C for optimal growth. AB - The reliability of the BacT/Alert 3D unit for automated detection of nontuberculous mycobacteria (NTM) that grow optimally at 30 degrees C was assessed. This system reliably maintained a temperature of 30 degrees C and detected 50% of the clinical NTM strains (5 Mycobacterium marinum and 3 Mycobacterium gordonae strains) faster than 37 degrees C culture. PMID- 21543567 TI - Lack of association of small-colony-variant Staphylococcus aureus strains with long-term use of azithromycin in patients with cystic fibrosis. PMID- 21543568 TI - Point: Should all stools be screened for Shiga toxin-producing Escherichia coli? AB - In October 2009, the Centers for Disease Control and Prevention recommended that clinical laboratories test all stools submitted for the detection of enteric bacterial pathogens for the presence of Shiga toxin-producing Escherichia coli (STEC). In order to do this, it is recommended that all stools be cultured for Escherichia coli O157:H7 on selective medium as well as that testing for the presence of Shiga toxin be done by immunoassay to detect non-O157 STEC (3). There are a variety of products that are FDA approved for detection of Shiga toxin. Further, it is recommended that Shiga toxin detection be done by testing overnight enrichment broth cultures of stools rather than directly examining stools for this toxin. This recommendation was made approximately 18 months ago. We have asked Mario Marcon of Nationwide's Children Hospital in Columbus, OH, to explain the rationale for his decision to follow this recommendation, while we have asked Deanna Kiska and Scott Riddell of Upstate University Hospital in Syracuse, NY, why these guidelines have not been adopted by their laboratory. PMID- 21543569 TI - Mechanical disruption of lysis-resistant bacterial cells by use of a miniature, low-power, disposable device. AB - Molecular detection of microorganisms requires microbial cell disruption to release nucleic acids. Sensitive detection of thick-walled microorganisms such as Bacillus spores and Mycobacterium cells typically necessitates mechanical disruption through bead beating or sonication, using benchtop instruments that require line power. Miniaturized, low-power, battery-operated devices are needed to facilitate mechanical pathogen disruption for nucleic acid testing at the point of care and in field settings. We assessed the lysis efficiency of a very small disposable bead blender called OmniLyse relative to the industry standard benchtop Biospec Mini-BeadBeater. The OmniLyse weighs approximately 3 g, at a size of approximately 1.1 cm(3) without the battery pack. Both instruments were used to mechanically lyse Bacillus subtilis spores and Mycobacterium bovis BCG cells. The relative lysis efficiency was assessed through real-time PCR. Cycle threshold (C(T)) values obtained at all microbial cell concentrations were similar between the two devices, indicating that the lysis efficiencies of the OmniLyse and the BioSpec Mini-BeadBeater were comparable. As an internal control, genomic DNA from a different organism was spiked at a constant concentration into each sample upstream of lysis. The C(T) values for PCR amplification of lysed samples using primers specific to this internal control were comparable between the two devices, indicating negligible PCR inhibition or other secondary effects. Overall, the OmniLyse device was found to effectively lyse tough-walled organisms in a very small, disposable, battery-operated format, which is expected to facilitate sensitive point-of-care nucleic acid testing. PMID- 21543570 TI - Sensitive and specific phenotypic assay for metallo-beta-lactamase detection in Enterobacteria by use of a moxalactam disk supplemented with EDTA. AB - Moxalactam is highly hydrolyzed by plasmid-mediated metallo-beta-lactamases (MBLs), whereas it is poorly inactivated by serine-active carbapenemases. This study demonstrated that moxalactam resistance constituted an effective screen for MBL expression in enterobacteria, which could be confirmed, even in low-MBL producing isolates, by a disk potentiation test using moxalactam and EDTA. PMID- 21543571 TI - Frequent detection of respiratory viruses without symptoms: toward defining clinically relevant cutoff values. AB - Highly sensitive techniques, such as PCR, have greatly improved the detection of respiratory viruses. However, the sensitivity of PCR tests also complicates clinical interpretation, as the presence of small amounts of viral targets may not necessarily have clinical relevance. We performed a prospective case-control study in asymptomatic and symptomatic young children. PCR detection of 14 respiratory viruses was performed in nasal washes, and results were quantified in copies per milliliter. A total of 141 cases and 157 controls were included. In 72% of the cases and 28% of the controls, at least one virus was identified. When stratified for age, at least one virus was identified in 47% of the controls younger than 1 year old. Rhinovirus (RV) was frequently detected in both symptomatic and asymptomatic individuals. Receiver operating characteristic analysis for quantitative rhinovirus detection showed that cutoff values for clinical relevance are feasible for RV. In contrast to rhinovirus, respiratory syncytial virus (RSV) was rarely detected in controls, suggesting that a positive RSV test result is almost always of clinical relevance, independent of viral quantity. In conclusion, our study shows that asymptomatic carriage of a respiratory virus occurs frequently in young children. However, significant differences in the amount of virus present were observed between cases and controls. This suggests that defining cutoff levels should be feasible and represents the next necessary step for diagnosing viral respiratory infections using molecular tests. PMID- 21543572 TI - Prospective study of congenital toxoplasmosis screening with use of IgG avidity and multiplex nested PCR methods. AB - Acute infection with Toxoplasma gondii during pregnancy can cause congenital toxoplasmosis. The aim of this study was to evaluate whether screening with the use of IgG avidity and multiplex nested PCR methods was effective to detect a high-risk pregnancy. In a prospective study, serum T. gondii IgG avidity was measured in consecutive 146 pregnant women testing positive for T. gondii antibody and either positive or equivocal for IgM. Multiplex nested PCR for T. gondii DNA on amniotic fluid, maternal blood, and umbilical cord blood were performed with informed consent. A total of 51 (34.9%) women presented with low IgG avidity (<30%), 15 (10.3%) presented with borderline avidity (30 to 35%), and 80 (54.8%) presented with high avidity (>35%) indices. Amniotic fluid obtained at amniocentesis or birth yielded positive PCR results in nine women with low IgG avidity indices. Of these nine women, three had congenital toxoplasmosis. None of women with high or border line IgG avidity indices had a positive PCR result in the amniotic fluid or congenital toxoplasmosis. No congenital toxoplasmosis was detected in women whose amniotic fluids yielded negative PCR results. Ingestion of raw or undercooked meat was found to be the main risk factor for acute T. gondii infection. Congenital toxoplasmosis screening with a combination of IgG avidity in the maternal blood and multiplex nested PCR in the amniotic fluid was useful for detecting a high risk pregnancy and diagnosing congenital toxoplasmosis. PMID- 21543573 TI - Combined deletions of pfhrp2 and pfhrp3 genes result in Plasmodium falciparum malaria false-negative rapid diagnostic test. AB - We report a case of misdiagnosis of Plasmodium falciparum malaria from Brazil with negative PfHRP2-based rapid diagnostic tests (RDTs), leading to inappropriate case management. Genetic tests showed the deletion of both pfhrp2 and pfhrp3 genes. The detection of two distinct P. falciparum target antigens is then advisable. PMID- 21543574 TI - Echinocandin susceptibility testing of Candida isolates collected during a 1-year period in Sweden. AB - The susceptibilities of Candida isolates to the echinocandins anidulafungin, caspofungin, and micafungin were determined by using the recently revised CLSI breakpoints and Etest on 238 clinical bloodstream Candida isolates collected between September 2005 and August 2006. The isolates represent approximately 95% of all non-albicans Candida bloodstream infections and one-third of Candida albicans bloodstream infections during this 1-year period in Sweden. The collection included 81 C. albicans, 81 C. glabrata, 36 C. parapsilosis, 14 C. dubliniensis, 8 C. tropicalis, 8 C. lusitaniae, 5 C. krusei, 2 C. guilliermondii and 2 C. inconspicua isolates as well as 1 C. pelliculosa isolate. The MICs were largely consistent with the global epidemiology of bloodstream Candida isolates. All C. albicans and C. glabrata isolates were susceptible to all 3 echinocandins (MIC <= 0.016 MUg/ml in all instances). Resistance (MIC >= 8 MUg/ml) to anidulafungin alone was observed for 4 (11.1%) C. parapsilosis isolates and for 1/2 C. guilliermondii isolates. Intermediate susceptibility to caspofungin alone was observed for 2/5 C. krusei isolates. One of the eight C. tropicalis isolates was classified as being intermediately susceptible to micafungin (MIC, 0.5 MUg/ml) and as being resistant to anidulafungin and caspofungin (MIC >= 1 MUg/ml). This isolate harbored a heterozygous FKS1 hot spot mutation (S80P) known to confer echinocandin resistance. This first study to apply the revised CLSI breakpoints for Etest endpoints showed that the breakpoints worked successfully in detecting an isolate with a hot spot mutation. Acquired echinocandin resistance is rare in Sweden. Echinocandin MICs against C. parapsilosis and C. guilliermondii were lowest for micafungin. PMID- 21543575 TI - Hematogenously disseminated skin disease caused by Mucor velutinosus in a patient with acute myeloid leukemia. AB - We report here a case of disseminated skin infection caused by Mucor velutinosus, a recently described new species. We believe this to be the first published report of a clinical case of mucormycosis due to M. velutinosus, as well as a rare case of dissemination from a deep site to skin. PMID- 21543576 TI - Adaptive evolution of diagnostic resistance. PMID- 21543577 TI - Avidity Index for anti-HIV antibodies: comparison between third- and fourth generation automated immunoassays. AB - The development of assays for detecting recent HIV infections has become crucial for analyzing trends in infection in different populations, both for surveillance and prevention activities. The anti-HIV avidity index (AI), measured with third generation immunoassays (which detect anti-HIV antibody), has been shown to be an accurate tool for discriminating recent HIV infections (<6 months) from established infections (>= 6 months). We compared a third-generation immunoassay (AxSYM HIV 1/2 gO; Abbott Diagnostics) to a fourth-generation immunoassay (Architect HIV Ag/Ab Combo; Abbott Diagnostics; which detects anti-HIV antibody and p24 antigen) in terms of AI performance in distinguishing between recent and established HIV infections. A total of 142 samples from 75 HIV-infected individuals with an estimated date of seroconversion were assayed. The two assays showed the same accuracy in identifying a recent infection (91.5%), using an AI cutoff of 0.80, although Architect HIV Ag/Ab Combo was slightly more sensitive (89.4% versus 84.8%; P > 0.05) and yet less specific (93.4% versus 97.4%; P > 0.05). The correlation between assays was high (r = 0.87). When 20 specimens falling in the gray zone around the cutoff point (0.75 <= AI <= 0.84) were excluded, the accuracy of AI with Architect HIV Ag/Ab Combo was 94.7%, and the concordance between the two assays was 99.2%. The anti-HIV AI is a serological marker that accurately discriminates recent from established HIV infections. It can be successfully applied on fully automated fourth-generation HIV Ab/Ag immunoassays, which have several advantages, including increased throughput, high reproducibility, no need for specific technical skills, and easy comparability of results obtained in different settings. PMID- 21543578 TI - Comparative evaluation of three commercial identification systems using common and rare bloodstream yeast isolates. AB - The commercial yeast identification systems API ID32C, Auxacolor, and Vitek were evaluated using 251 molecularly identified bloodstream isolates and 2 reference strains, representing a total of 35 species (6 common and 29 rare). Correct identification rates were higher for common species (Auxacolor, 95%; API ID32C, 94%; Vitek, 92%) than for rare species (Auxacolor, 43%; API ID32C, 56%; Vitek, 64%). All systems performed equally among the former, and Vitek performed best among the latter. PMID- 21543579 TI - Fatal invasive infection with fungemia due to Microascus cirrosus after heart and lung transplantation in a patient with cystic fibrosis. AB - Scopulariopsis species are rarely but increasingly recognized as opportunistic pathogens in immunocompromised patients. We report on a patient suffering from cystic fibrosis who developed disseminated fungal infection due to a rare Scopulariopsis species, Microascus cirrosus, after heart and lung transplantation. Despite antifungal combination therapy with voriconazole and caspofungin, the patient died 4 weeks after transplantation. Diagnostic difficulties and optimal management of disseminated Scopulariopsis/Microascus infections are discussed. PMID- 21543580 TI - Characterization of genomic island 3 and genetic variability of Chilean field strains of Brucella abortus. AB - One of the capabilities developed by bacteria is the ability to gain large fragments of DNA from other bacteria or to lose portions of their own genomes. Among these exchangeable fragments are the genomic islands (GIs). Nine GIs have been identified in Brucella, and genomic island 3 (GI-3) is shared by two pathogenic species, B. melitensis and B. abortus. GI-3 encodes mostly unknown proteins. One of the aims of this study was to perform pulsed-field gel electrophoresis (PFGE) on field isolates of B. abortus from Chile to determine whether these isolates are clonally related. Furthermore, we focused on the characterization of GI-3, studying its organization and the genetic conservation of the GI-3 sequence using techniques such as tiling-path PCR (TP-PCR) and restriction fragment length polymorphism-PCR (RFLP-PCR). Our results, after PFGE was performed on 69 field isolates of B. abortus from Chile, showed that the strains were genetically homogeneous. To increase the power of genetic discrimination among these strains, we used multiple locus variable-number tandem repeat (VNTR) analysis with 16 loci (MLVA-16). The results obtained by MLVA-16 showed that the strains of B. abortus were genetically heterogeneous and that most of them clustered according to their geographic origin. Of the genetic loci studied, panel 2B was the one describing the highest diversity in the analysis, as well as locus Bruce19 in panel 2A. In relation to the study of GI-3, our experimental analysis by TP-PCR identified and confirmed that GI-3 is present in all wild strains of B. abortus, demonstrating the high stability of gene cluster GI-3 in Chilean field strains. PMID- 21543581 TI - Quality control guidelines for amphotericin B, Itraconazole, posaconazole, and voriconazole disk diffusion susceptibility tests with nonsupplemented Mueller Hinton Agar (CLSI M51-A document) for nondermatophyte Filamentous Fungi. AB - Although Clinical and Laboratory Standards Institute (CLSI) disk diffusion assay standard conditions are available for susceptibility testing of filamentous fungi (molds) to antifungal agents, quality control (QC) disk diffusion zone diameter ranges have not been established. This multicenter study documented the reproducibility of tests for one isolate each of five molds (Paecilomyces variotii ATCC MYA-3630, Aspergillus fumigatus ATCC MYA-3626, A. flavus ATCC MYA 3631, A. terreus ATCC MYA-3633, and Fusarium verticillioides [moniliforme] ATCC MYA-3629) and Candida krusei ATCC 6258 by the CLSI disk diffusion method (M51-A document). The zone diameter ranges for selected QC isolates were as follows: P. variotii ATCC MYA-3630, amphotericin B (15 to 24 mm), itraconazole (20 to 31 mm), and posaconazole (33 to 43 mm); A. fumigatus ATCC MYA-3626, amphotericin B (18 to 25 mm), itraconazole (11 to 21 mm), posaconazole (28 to 35 mm), and voriconazole (25 to 33 mm); and C. krusei, amphotericin B (18 to 27 mm), itraconazole (18 to 26 mm), posaconazole (28 to 38 mm), and voriconazole (29 to 39 mm). Due to low testing reproducibility, zone diameter ranges were not proposed for the other three molds. PMID- 21543582 TI - Upgraded Cobas Ampliprep-Cobas TaqMan version 2.0 HIV-1 RNA quantification assay versus first version: correction of underestimations. AB - The large underestimations of HIV RNA quantification observed in 17 patients with the first version of Cobas TaqMan assay have been successfully corrected in the upgraded version 2.0. In comparison with the Abbott RealTime assay, the mean difference that was 1.18 log(10) copies/ml is now zero. The discrepancies have disappeared. PMID- 21543583 TI - Interleukin-12 treatment down-regulates STAT4 and induces apoptosis with increasing ROS production in human natural killer cells. AB - NK cells are prominent mediators of the immunomodulating and antiangiogenic activity of IL-12. However, the effect of prolonged IL-12 treatment on NK cells is unclear. In this study, we observed that IL-12 initially activates NK cells, but prolonged IL-12 treatment specifically down-regulates IL-12 signaling and induces NK cell apoptosis associated with a significant reduction in cytolytic activity and IFN-gamma production in response to further IL-12 stimulation. Further results demonstrate that prolonged IL-12 stimulation of NK cells specifically decreases the level of activated STAT4 protein, a critical IL-12 signaling component, through decreasing STAT4 mRNA and protein levels rather than inducing STAT4 protein degradation. IL-12 treatment induces NK cell activation as well as levels of ROS, but prolonged IL-12 treatment causes ROS accumulation, which in turn, results in the loss of Deltapsi(m), the release of cytochrome c, and the activation of caspase-3, resulting in NK cell apoptosis. These findings provide new insights into IL-12 regulation in human NK cells, where IL-12 initially promotes NK cell activation but subsequently limits this response through a negative-feedback mechanism. PMID- 21543584 TI - AP-1 protein induction during monopoiesis favors C/EBP: AP-1 heterodimers over C/EBP homodimerization and stimulates FosB transcription. AB - AP-1 proteins heterodimerize via their LZ domains to bind TGACGTCA or TGACTCA, whereas C/EBPs dimerize to bind ATTGCGCAAT. We demonstrate that intact C/EBPalpha also heterodimerizes with c-Jun or c-Fos to bind a hybrid DNA element, TGACGCAA, or more weakly to TGATGCAA. A 2:1 ratio of c-Jun:C/EBPalpha or c-Fos:C/EBPalpha was sufficient for preferential binding. Semiquantitative Western blot analysis indicates that the summation of c-Jun, JunB, and c-Fos levels in differentiating myeloid cells is similar to or exceeds the entirety of C/EBPalpha and C/EBPbeta, indicating the feasibility of heterodimer formation. Induction of AP-1 proteins during monocytic differentiation favored formation of C/EBP:AP-1 heterodimers, with C/EBPalpha homodimers more evident during granulopoiesis. Approximately 350 human and 300 murine genes contain the TGACGCAA motif between -2 kb and +1 kb of their transcription start sites. We focused on the murine Fosb promoter, which contains a C/EBP:AP-1 cis element at -56 and -253, with the hFOSB gene containing an identical site at -253 and a 1-bp mismatch at -56. C/EBPalpha:AP-1 heterodimers bound either site preferentially in a gel-shift assay, C/EBPalpha:c Fos ER fusion proteins induced endogenous Fosb mRNA but not in the presence of CHX, C/EBP and AP-1 proteins bound the endogenous Fosb promoter, mutation of the 56 cis element reduced reporter activity fivefold, and endogenous FosB protein was expressed preferentially during monopoiesis versus granulopoiesis. Increased expression of Jun/Fos proteins elevates C/EBP:AP-1 heterodimer formation to potentially activate novel sets of genes during monopoiesis and potentially during other biologic processes. PMID- 21543585 TI - Asbestos exposure affects poly(ADP-ribose) polymerase-1 activity: role in asbestos-induced carcinogenesis. AB - Asbestos is known to induce malignant mesothelioma (MM) and other asbestos related diseases. It is directly genotoxic by inducing DNA strand breaks and cytotoxic by promoting apoptosis in lung target cells. Poly(ADP-ribose) polymerase-1 (PARP1) is a nuclear zinc-finger protein with a function as a DNA damage sensor. To determine whether PARP1 is involved in asbestos-induced carcinogenesis, PARP1 expression and activity as well as DNA damage and repair were evaluated in circulating cells of asbestos-exposed subjects, MM patients and age-matched controls. PARP1 expression and activity were also evaluated in pleural biopsies of MM patients and compared with normal tissue. Accumulation of the pre-mutagenic 8-hydroxy-2'-deoxyguanosine and elevated PARP1 expression were found both in asbestos-exposed subjects and MM patients. Although PARP1 was highly expressed, its activity was relatively low. Low DNA repair efficiency was observed in lymphocytes from MM patients. High expression of PARP1 associated with low PARP activity was also found in MM biopsies. To mimic PARP1 dysfunction, PARP1 expression and activity were induced in immortalised mesothelial cells by their exposure to asbestos in the presence of a PARP1 inhibitor, which resulted in transformation of the cells. We propose that exposure to asbestos inhibits the PARP1 activity possibly resulting in higher DNA instability, thus causing malignant transformation. PMID- 21543586 TI - Elevated serum beta-D-glucan levels in immunocompromised children with clinical suspicion for Pneumocystis jirovecii pneumonia. PMID- 21543587 TI - Induction of B cell responses upon experimental infection of neonatal calves with Mycobacterium avium subsp. paratuberculosis. AB - The objective of this study was to determine if experimental infection of neonatal calves with Mycobacterium avium subsp. paratuberculosis would invoke changes in the percentages of total B cells in the peripheral blood mononuclear cell population and of subpopulations of B cells as determined by CD5, CD25, and CD45RO markers during a 12-month period. Experimental infection groups included control (noninfected), oral (infected with M. avium subsp. paratuberculosis strain K-10), oral/DXM (pretreatment with dexamethasone before oral inoculation), i.p. (intraperitoneal inoculation), and oral/M (oral inoculation with mucosal scrapings from a cow with clinical disease) groups. Over the course of the study, the percentages of total B cells in nonstimulated and antigen-stimulated cell cultures increased for oral and i.p. group calves, with the highest percentages noted at 3 and 6 months. Oral/M group calves had increased percentages of activated B cells, as determined by CD5(dim) and CD5(bright) markers, at 9 and 12 months. Experimental infection by all methods resulted in increased expression of CD25(+) and CD45RO(+) B cells early in the study, but the most significant results were observed at 12 months for oral/DXM and oral/M group calves. Immunoblot analyses with a whole-cell sonicate of M. avium subsp. paratuberculosis demonstrated the most reactivity with sera from i.p. group calves and the least reactivity with sera from oral group calves. Further evidence of M. avium subsp. paratuberculosis-specific antibody responses in the i.p. group calves was demonstrated using the ethanol vortex enzyme-linked immunosorbent assay (EvELISA) method. In summary, an induction of B cell responses was noted after experimental infection with M. avium subsp. paratuberculosis, with differences in responses noted according to the method of experimental inoculation. PMID- 21543589 TI - A fragile balance at synapses: new evidence supporting a role for FMRP in homeostatic plasticity. PMID- 21543588 TI - Intranasal immunization of ferrets with commercial trivalent influenza vaccines formulated in a nanoemulsion-based adjuvant. AB - NB-1008 is a surfactant-stabilized soybean oil-in-water nanoemulsion (NE) adjuvant with influenza virus antigen incorporated into the NE by simple mixing. Intranasal administration of the antigen with NE adjuvant efficiently produces both mucosal and serum antibody responses as well as a robust cellular Th1 immune response. To demonstrate the adjuvant effect of the W(80)5EC NE, a killed commercial influenza vaccine for intramuscular administration (Fluzone or Fluvirin) was mixed with the W(80)5EC NE adjuvant and administered intranasally to naive ferrets. After a single intranasal immunization, the adjuvanted influenza vaccine elicited elevated serum hemagglutination inhibition (HAI) geometric mean titers (GMTs) ranging from 196 to 905 for the three hemagglutinin (HA) antigens present in the vaccine, which are approximately 19- to 90-fold higher titers at 1/50 the standard intramuscular commercial nonadjuvanted influenza vaccine dose. Seroconversion rates of 67% to 100% were achieved against each of the three viral strains present. The adjuvanted nasal influenza vaccine also produced significant cross immunity to five other H3N2 influenza virus strains not present in the vaccine and produced sterile immunity after challenge with homologous live virus. No safety issues were observed in 249 ferrets receiving the adjuvanted influenza vaccine. These findings demonstrate the ability of W(80)5EC NE to adjuvant nasally administered influenza vaccine and provide a basis for studying the intranasal W(80)5EC-adjuvanted influenza vaccine in humans. PMID- 21543590 TI - Distractibility in daily life is reflected in the structure and function of human parietal cortex. AB - We all appreciate that some of our friends and colleagues are more distractible than others. This variability can be captured by pencil and paper questionnaires in which individuals report such cognitive failures in their everyday life. Surprisingly, these self-report measures have high heritability, leading to the hypothesis that distractibility might have a basis in brain structure. In a large sample of healthy adults, we demonstrated that a simple self-report measure of everyday distractibility accurately predicted gray matter volume in a remarkably focal region of left superior parietal cortex. This region must play a causal role in reducing distractibility, because we found that disrupting its function with transcranial magnetic stimulation increased susceptibility to distraction. Finally, we showed that the self-report measure of distractibility reliably predicted our laboratory-based measure of attentional capture. Our findings distinguish a critical mechanism in the human brain causally involved in avoiding distractibility, which, importantly, bridges self-report judgments of cognitive failures in everyday life and a commonly used laboratory measure of distractibility to the structure of the human brain. PMID- 21543592 TI - Hyperactivity in the ventral cochlear nucleus after cochlear trauma. AB - The emergence of hyperactivity in the form of elevated spontaneous firing rates after cochlear trauma has been well documented in a number of central auditory structures, including the auditory cortex, inferior colliculus, and dorsal subdivision of the cochlear nucleus. This hyperactivity is of interest as a possible neural substrate of tinnitus. Whether the ventral subdivision of the cochlear nucleus shows hyperactivity has never been investigated despite the fact that, like the dorsal division, it also receives direct input from the damaged cochlea and supplies major ascending inputs to brainstem and midbrain auditory centers. We investigated spontaneous neuronal firing rates in the ventral cochlear nucleus in a guinea pig model of cochlear trauma in which we have shown that hyperactivity consistently develops in the inferior colliculus (Mulders and Robertson, 2009). The mean spontaneous firing rates of ventral cochlear nucleus neurons was significantly elevated compared to sham controls. This hyperactivity was more evident in primary-like and onset categories of neurons. Hyperactivity in the ventral subdivision of cochlear nucleus therefore needs to be considered in relation to neural models of the genesis of tinnitus. PMID- 21543591 TI - Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. AB - In Alzheimer's disease (AD), dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal long-term potentiation (LTP) can be inhibited by soluble oligomers of amyloid beta-protein (Abeta), but the synaptic elements that mediate this effect remain unclear. We examined field EPSPs and whole-cell recordings in wild-type mouse hippocampal slices. Soluble Abeta oligomers from three distinct sources (cultured cells, AD cortex, or synthetic peptide) inhibited LTP, and this was prevented by the selective NR2B inhibitors ifenprodil and Ro 25-6981. Soluble Abeta enhanced NR2B-mediated NMDA currents and extrasynaptic responses; these effects were mimicked by the glutamate reuptake inhibitor dl-threo-beta benzyloxyaspartic acid. Downstream, an Abeta-mediated rise in p38 mitogen activated protein kinase (MAPK) activation was followed by downregulation of cAMP response element-binding protein, and LTP impairment was prevented by inhibitors of p38 MAPK or calpain. Thus, soluble Abeta oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity. PMID- 21543593 TI - Spinal protein kinase M zeta underlies the maintenance mechanism of persistent nociceptive sensitization. AB - Sensitization of the pain pathway is believed to promote clinical pain disorders. We hypothesized that the persistence of a sensitized state in the spinal dorsal horn might depend on the activity of protein kinase M zeta (PKMzeta), an essential mechanism of late long-term potentiation (LTP). To test this hypothesis, we used intraplantar injections of interleukin-6 (IL-6) in mice to elicit a transient allodynic state that endured ~3 d. After the resolution of IL 6-induced allodynia, a subsequent intraplantar injection of prostaglandin E(2) (PGE(2)) or intrathecal injection of the metabotropic glutamate receptor 1/5 (mGluR1/5) agonist DHPG (dihydroxyphenylglycol) precipitated allodynia and/or nocifensive responses. Intraplantar injection of IL-6 followed immediately by intrathecal injection of a PKMzeta inhibitor prevented the expression of subsequent PGE(2)-induced allodynia. Inhibitors of protein translation were effective in preventing PGE(2)-induced allodynia when given immediately after IL 6, but not after the initial allodynia had resolved. In contrast, spinal PKMzeta inhibition completely abolished both prolonged allodynia to hindpaw PGE(2) and enhanced nocifensive behaviors evoked by intrathecal mGluR1/5 agonist injection after the resolution of IL-6-induced allodynia. Moreover, spinal PKMzeta inhibition prevented the enhanced response to subsequent stimuli following resolution of hypersensitivity induced by plantar incision. The present findings demonstrate that the spinal cord encodes an engram for persistent nociceptive sensitization that is analogous to molecular mechanisms of late LTP and suggest that spinally directed PKMzeta inhibitors may offer therapeutic benefit for injury-induced pain states. PMID- 21543594 TI - Neuroanatomical phenotype of Klinefelter syndrome in childhood: a voxel-based morphometry study. AB - Klinefelter syndrome (KS) is a genetic disorder characterized by a supernumerary X chromosome. As such, KS offers a naturally occurring human model for the study of both X-chromosome gene expression and androgen on brain development. Previous neuroimaging studies have revealed neuroanatomical variations associated with KS, but have differed widely with respect to subject inclusion criteria, including mosaicism, pubertal status, and history of testosterone replacement therapy (TRT), all factors likely to influence neurodevelopment. We conducted a voxel based morphometry study of regional gray and white matter (GM and WM, respectively) volumes in 31 KS males (mean age, 9.69 +/- 1.70 years) and 36 typically developing (TD) male controls (10.99 +/- 1.72 years). None of the participants with KS had received TRT, and all were prepubertal and had nonmosaic 47,XXY karyotypes. After controlling for age, males with KS showed trends (0.05 < p < 0.10) for significantly reduced total gray matter volume (TGMV) and total white matter volume (TWMV), relative to TD males. After controlling for TGMV and age, the KS group had significantly increased sensorimotor and parietal-occipital GM and significantly reduced amygdalar, hippocampal, insular, temporal, and inferior frontal GM relative to TD controls. After controlling for TWMV and age, the KS group had significantly increased left parietal WM as well as significantly reduced frontal and temporal WM. These findings are indicative of a characteristic prepubertal neuroanatomical phenotype that may be associated with cognitive-behavioral features of KS. This work offers new insight into the relationships among X-chromosome gene expression, neuroanatomy, and cognitive behavioral functions impaired in KS, including language and attention. PMID- 21543595 TI - Heterogeneous representations in the superior parietal lobule are common across reaches to visual and proprioceptive targets. AB - The planning and control of sensory-guided movements requires the integration of multiple sensory streams. Although the information conveyed by different sensory modalities is often overlapping, the shared information is represented differently across modalities during the early stages of cortical processing. We ask how these diverse sensory signals are represented in multimodal sensorimotor areas of cortex in macaque monkeys. Although a common modality-independent representation might facilitate downstream readout, previous studies have found that modality-specific representations in multimodal cortex reflect upstream spatial representations. For example, visual signals have a more eye-centered representation. We recorded neural activity from two parietal areas involved in reach planning, area 5 and the medial intraparietal area (MIP), as animals reached to visual, combined visual and proprioceptive, and proprioceptive targets while fixing their gaze on another location. In contrast to other multimodal cortical areas, the same spatial representations are used to represent visual and proprioceptive signals in both area 5 and MIP. However, these representations are heterogeneous. Although we observed a posterior-to-anterior gradient in population responses in parietal cortex, from more eye-centered to more hand- or body-centered representations, we do not observe the simple and discrete reference frame representations suggested by studies that focused on identifying the "best-match" reference frame for a given cortical area. In summary, we find modality-independent representations of spatial information in parietal cortex, although these representations are complex and heterogeneous. PMID- 21543596 TI - Recalling and forgetting dreams: theta and alpha oscillations during sleep predict subsequent dream recall. AB - Under the assumption that dream recall is a peculiar form of declarative memory, we have hypothesized that (1) the encoding of dream contents during sleep should share some electrophysiological mechanisms with the encoding of episodic memories of the awake brain and (2) recalling a dream(s) after awakening from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep should be associated with different brain oscillations. Here, we report that cortical brain oscillations of human sleep are predictive of successful dream recall. In particular, after morning awakening from REM sleep, a higher frontal 5-7 Hz (theta) activity was associated with successful dream recall. This finding mirrors the increase in frontal theta activity during successful encoding of episodic memories in wakefulness. Moreover, in keeping with the different EEG background, a different predictive relationship was found after awakening from stage 2 NREM sleep. Specifically, a lower 8-12 Hz (alpha) oscillatory activity of the right temporal area was associated with a successful dream recall. These findings provide the first evidence of univocal cortical electroencephalographic correlates of dream recall, suggesting that the neurophysiological mechanisms underlying the encoding and recall of episodic memories may remain the same across different states of consciousness. PMID- 21543597 TI - The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers. AB - In a large-scale meta-analysis, it has been recently shown that the transcription factor 4 (TCF4) gene is among the most prominent susceptibility genes for schizophrenia. Moreover, transgenic mice overexpressing TCF4 in the brain display a reduction of sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is heritable and has been established as an important translational endophenotype of schizophrenia. We therefore investigated the impact of the schizophrenia susceptibility gene TCF4 (rs9960767) on sensorimotor gating of the ASR in healthy humans and in patients with a schizophrenia spectrum disorder. We assessed PPI, startle reactivity, and habituation of the ASR in two independent samples. The first sample consisted of 107 healthy volunteers from London, UK. The second sample was a schizophrenia spectrum group (n = 113) of 73 schizophrenia patients and 40 individuals at high risk for schizophrenia from Bonn, Germany (total sample n = 220). In both samples, PPI was strongly decreased in carriers of the schizophrenia risk allele C of the TCF4 gene (meta-analysis across both samples: p = 0.00002), whereas startle reactivity and habituation were unaffected by TCF4 genotype. Sensorimotor gating is modulated by TCF4 genotype, indicating an influential role of TCF4 gene variations in the development of early information-processing deficits in schizophrenia. PMID- 21543598 TI - Stress-related methylation of the catechol-O-methyltransferase Val 158 allele predicts human prefrontal cognition and activity. AB - DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val(158) allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val(158) allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val(158) allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation. PMID- 21543599 TI - The calyx of Held develops adult-like dynamics and reliability by hearing onset in the mouse in vivo. AB - The development of the auditory system has received increasing attention since the mechanisms of patterned, spontaneous activity in prehearing mammals were discovered. This early activity originates in the cochlea and is assumed to be of importance for the establishment and refinement of synaptic connections in the auditory system. In the present study we investigate synaptic transmission and its interplay with spontaneous discharges in the developing auditory system. We used the calyx of Held as a model system, where this question can be investigated in vivo over a broad range of ages [postnatal day 8 (P8)-P28]. To precisely quantify the timing and reliability of synaptic transmission, we developed a novel fitting approach which decomposes the extracellularly recorded signal into its presynaptic and postsynaptic components. In prehearing mice, we found signal transmission to be unreliable, with high variability in the transmission delay and in the amplitude of postsynaptic components. These timing and amplitude changes were strongly correlated with the preceding activity. Around hearing onset (P12-P14), the properties of signal transmission converged to the adult like state which was characterized by high transmission reliability as well as high consistency in timing and amplitude. Although activity-dependent depression was still found in action potentials, EPSP depression no longer played a prominent role. In conclusion, the maturation of synaptic transmission at the calyx of Held seems to be precisely timed to achieve its adult potential by the time acoustically evoked signal processing commences. PMID- 21543600 TI - Nicotine potentiation of excitatory inputs to ventral tegmental area dopamine neurons. AB - Drug-induced changes in synaptic strength are hypothesized to contribute to appetitive behavior and addiction. Nicotine, the major addictive substance in tobacco, activates nicotinic receptors (nAChRs) to initiate a series of adaptive changes at the cellular and circuit levels in brain, particularly the ventral tegmental area (VTA). Our laboratory previously reported that nicotine facilitates induction of long-term potentiation (LTP) in VTA dopamine (DA) neurons by increasing glutamate release via activation of alpha7 nAChRs on the glutamate terminals, suggesting a critical presynaptic contribution of nicotine in LTP induction. In the present study, we used an in vitro exposure paradigm to study the effect of nicotine on excitatory synaptic strength. Brief exposure of nicotine to brain slices from drug-naive adult rats followed by a period of recovery resulted in an NMDA receptor (NMDAR)-dependent increase of AMPA receptor/NMDAR ratio in VTA DA neurons, which is consistent with the induction of LTP. These effects are similar to that induced by a single in vivo nicotine injection intraperitoneally. The induction of synaptic potentiation required excitation of DA neurons mediated by somatodendritic alpha4beta2 nAChRs, as well as enhancement of NMDAR function via D(5) dopamine receptors, also on DA neurons. Nicotine-induced increase of presynaptic glutamate release also contributed to the induction of synaptic plasticity, likely through increased activation of NMDAR. These results identified important receptor systems involved in nicotine induced long-term changes in excitatory synaptic input to VTA DA neurons. The data also revealed remarkable similarity in the mechanisms underlying synaptic plasticity induced by nicotine and cocaine in the VTA. PMID- 21543601 TI - Study of novel selective mGlu2 agonist in the temporo-ammonic input to CA1 neurons reveals reduced mGlu2 receptor expression in a Wistar substrain with an anxiety-like phenotype. AB - Group II metabotropic receptors (mGluRs) regulate central synaptic transmission by modulating neurotransmitter release. However, the lack of pharmacological tools differentiating between mGlu2 and mGlu3 receptors has hampered identification of the roles of these two receptor subtypes. We have used LY395756 [(1SR,2SR,4RS,5RS,6SR)-2-amino-4-methylbicyclo[3.1.0]-hexane2,6-dicarboxylic], an agonist at mGlu2 receptors and an antagonist at mGlu3 receptors in cell lines, to investigate the roles of these receptors in the temporo-ammonic path from entorhinal cortex to CA1-stratum lacunosum moleculare in rat hippocampal slices. Surprisingly, the degree of inhibition of the field EPSP induced by LY395756 fell into two distinct groups, with EC(50) values of <1 MUm and >100 MUm. In "sensitive" slices, LY395756 had additive actions with a mixed mGlu2/mGlu3 agonist, DCG-IV [(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine], whereas in "insensitive" slices, LY395756 reduced the effect of DCG-IV, with an IC(50) of ~1 MUm. This separation into sensitive and insensitive slices could be explained by LY395756 acting as an mGlu2 agonist and mGlu3 antagonist, respectively, a finding supported by data from mice lacking these receptors. The heterogeneity was correlated with differences in expression levels of mGlu2 receptors within our Wistar colony and other Wistar substrains. The initial search for a behavioral correlate indicated that rats lacking mGlu2 receptors showed anxiety-like behavior in open-field and elevated plus maze assays. These findings have implications for rat models of psychiatric disease and are especially pertinent given that mGlu2 receptors are targets for compounds under development for anxiety. PMID- 21543602 TI - Dendrite-derived supernumerary axons on adult axotomized motor neurons possess proteins that are essential for the initiation and propagation of action potentials and synaptic vesicle release. AB - Axotomy can trigger profound alterations in the neuronal polarity of adult neurons in vivo. This can manifest itself in the development of new axon-like processes emanating from the tips of distal dendrites. Previously, these processes have been defined as axonal based on their axonal morphology. This study extends this definition to determine whether, more importantly, these processes possess the prerequisite molecular machinery to function as axons. Using a combination of intracellular labeling and immunohistochemistry, we demonstrate that the distribution of voltage-gated sodium channels on these processes matches the arrangement of these channels that is necessary for the initiation and conduction of action potentials. At terminal bouton-like structures they possess key proteins necessary for the release of synaptic vesicles (SV2 and synaptophysin). Thus, axon-like processes emanating from the tips of distal dendrites represent a rearrangement of neuronal polarity whereby axotomized neurons can develop additional functional axons in vivo. PMID- 21543603 TI - Transcription factor short stature homeobox 2 is required for proper development of tropomyosin-related kinase B-expressing mechanosensory neurons. AB - Dorsal root ganglia (DRG) contain somatosensory neurons of diverse sensory modalities. Among these different types of sensory neurons, the molecular mechanisms that regulate the development and specification of touch neurons are the least well understood. We took a candidate approach and searched for transcription factors that are expressed in subsets of DRG neurons, and found that the transcription factor Shox2 (short stature homeobox 2) is expressed in subpopulations of TrkB (tropomyosin-related kinase B)- and Ret-expressing neurons at neonatal stages. Since TrkB is a known marker that is selectively expressed in touch sensory neurons, we decided to examine the function of Shox2 in specifying TrkB-positive DRG neurons. Conditional deletion of Shox2 in neural crest cells (which give rise to all DRG neurons) caused a 60 ~ 65% reduction in the number of TrkB-expressing neurons. It also resulted in an increase in coexpression of TrkC in Ret-positive sensory neurons. Deletion of Shox2 in differentiating DRG neurons at later time points caused only a moderate reduction in TrkB expression. Overexpression of Shox2 in all neural crest cells resulted in a small increase in the number of TrkB-expressing neurons. Finally, Shox2 deletion also caused reduced touch sensory axonal innervation to layers III/IV of the spinal cord. Together, our findings identify Shox2 as an essential but not sufficient component of the transcription programs required in neural progenitor cells for the proper specification of subsets of TrkB-expressing touch/mechanosensory neurons. PMID- 21543604 TI - Selective movement preparation is subserved by selective increases in corticomuscular gamma-band coherence. AB - Local groups of neurons engaged in a cognitive task often exhibit rhythmically synchronized activity in the gamma band, a phenomenon that likely enhances their impact on downstream areas. The efficacy of neuronal interactions may be enhanced further by interareal synchronization of these local rhythms, establishing mutually well timed fluctuations in neuronal excitability. This notion suggests that long-range synchronization is enhanced selectively for connections that are behaviorally relevant. We tested this prediction in the human motor system, assessing activity from bilateral motor cortices with magnetoencephalography and corresponding spinal activity through electromyography of bilateral hand muscles. A bimanual isometric wrist extension task engaged the two motor cortices simultaneously into interactions and coherence with their respective corresponding contralateral hand muscles. One of the hands was cued before each trial as the response hand and had to be extended further to report an unpredictable visual go cue. We found that, during the isometric hold phase, corticomuscular coherence was enhanced, spatially selective for the corticospinal connection that was effectuating the subsequent motor response. This effect was spectrally selective in the low gamma-frequency band (40-47 Hz) and was observed in the absence of changes in motor output or changes in local cortical gamma-band synchronization. These findings indicate that, in the anatomical connections between the cortex and the spinal cord, gamma-band synchronization is a mechanism that may facilitate behaviorally relevant interactions between these distant neuronal groups. PMID- 21543605 TI - Auditory efferents facilitate sound localization in noise in humans. AB - The mammalian auditory system contains descending neural pathways, some of which project onto the cochlea via the medial olivocochlear (MOC) system. The function of this efferent auditory system is not entirely clear. Behavioral studies in animals with olivocochlear (OC) lesions suggest that the MOC serves to facilitate sound localization in noise. In the current work, noise-induced OC activity (the OC reflex) and sound-localization performance in noise were measured in normal hearing humans. Consistent with earlier studies, both measures were found to vary substantially across individuals. Importantly, significant correlations were observed between OC-reflex strength and the effect of noise on sound-localization performance; the stronger the OC reflex, the less marked the effect of noise. These results suggest that MOC activation by noise helps to counteract the detrimental effects of background noise on neural representations of direction dependent spectral features, which are especially important for accurate localization in the up/down and front/back dimensions. PMID- 21543606 TI - Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults. AB - There is a strong genetic risk for late-onset Alzheimer's disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk allele C of the clusterin (CLU) gene variant rs11136000 is carried by ~88% of Caucasians. The C allele confers a 1.16 greater odds of developing late-onset AD than the T allele. AD patients have reductions in regional white matter integrity. We evaluated whether the CLU risk variant was similarly associated with lower white matter integrity in healthy young humans. Evidence of early brain differences would offer a target for intervention decades before symptom onset. We scanned 398 healthy young adults (mean age, 23.6 +/- 2.2 years) with diffusion tensor imaging, a variation of magnetic resonance imaging sensitive to white matter integrity in the living brain. We assessed genetic associations using mixed-model regression at each point in the brain to map the profile of these associations with white matter integrity. Each C allele copy of the CLU variant was associated with lower fractional anisotropy--a widely accepted measure of white matter integrity--in multiple brain regions, including several known to degenerate in AD. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. Young healthy carriers of the CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life. PMID- 21543607 TI - A neural mechanism mediating the impact of episodic prospection on farsighted decisions. AB - Humans can vividly imagine possible future events. This faculty, episodic prospection, allows the simulation of distant outcomes and desires. Here, we provide evidence for the adaptive function of this capacity and elucidate its neuronal basis. Participants either imagined specific events of spending money (e.g., L 35 in 180 days at a pub), or merely estimated what the money could purchase in the scenario. Imagining the future biased subsequent monetary decisions toward choices associated with a higher long-term pay-off. It thus effectively attenuated temporal discounting, i.e., the propensity to devalue rewards with a delay until delivery. Using functional magnetic resonance imaging, we implicate the medial rostral prefrontal cortex (mrPFC) in this effect. Blood oxygen level-dependent signal in this region predicted future-oriented choices on a trial-by-trial basis. Activation reflected the reward magnitude of imagined episodes, and greater reward sensitivity was related to less discounting. This effect was also associated with increased mrPFC-hippocampal coupling. The data suggest that mrPFC uses information conveyed by the hippocampus to represent the undiscounted utility of envisaged events. The immediate experience of the delayed reward value might then bias toward farsighted decisions. PMID- 21543608 TI - Distribution of phosphorylated TrkB receptor in the mouse hippocampal formation depends on sex and estrous cycle stage. AB - Tropomyosin-related kinase B receptor (TrkB) is a neurotrophin receptor important for the synaptic plasticity underlying hippocampal-dependent learning and memory. Because this receptor is widely expressed in hippocampal neurons, the precise location of TrkB activation is likely important for its specific actions. The goal of this study was to identify the precise sites of TrkB activation in the mouse hippocampal formation and to determine any changes in the distribution of activated TrkB under conditions of enhanced brain-derived neurotrophic factor (BDNF) expression and hippocampal excitability. Using electron microscopy, we localized TrkB phosphorylated at tyrosine 816 (pTrkB) in the hippocampal formation of male and female mice under conditions of naturally low circulating estradiol and naturally high circulating estradiol, when BDNF expression, TrkB signaling, and synaptic plasticity are enhanced. To compare relative amounts of pTrkB in each group, we counted profiles containing pTrkB-immunoreactivity (pTrkB ir) in all hippocampal subregions. pTrkB-ir was in axons, axon terminals, dendrites, and dendritic spines of neurons in the hippocampal formation, but the majority of pTrkB-ir localized to presynaptic profiles. pTrkB-ir also was abundant in glial profiles, which were further identified as microglia using immunofluorescence and confocal microscopy. Axonal and glial pTrkB-ir and pTrkB ir in the CA1 stratum radiatum were more abundant in high-estradiol states (proestrus females) than low-estradiol states (estrus and diestrus females and males). These findings suggest that presynaptic TrkB is positioned to modulate estradiol-mediated and BDNF-dependent synaptic plasticity. Furthermore, they suggest a novel role for TrkB in microglial function in the neuroimmune system. PMID- 21543609 TI - Functional organization of the thalamic input to the thalamic reticular nucleus. AB - Most axons connecting the thalamus and cortex in both directions pass through the thalamic reticular nucleus (TRN), a thin layer of GABAergic cells adjacent to the thalamus, and innervate neurons there. The TRN, therefore, is in a strategic location to regulate thalamocortical communication. We recorded neurons of the somatosensory region of the TRN in a thalamocortical slice preparation and studied the spatial organization of their thalamic input using laser scanning photostimulation. We show that the thalamoreticular pathway is organized topographically for most neurons. The somatosensory region of the TRN can be organized into three tiers. From the inner (thalamoreticular) border to the outer, in a manner roughly reciprocal to the reticulothalamic pathway, each of these tiers receives its input from one of the somatosensory relays of the thalamus--the posterior medial, ventroposterior medial, and ventroposterior lateral nuclei. What is surprising is that approximately a quarter of the recorded neurons received input from multiple thalamic regions usually located in different nuclei. These neurons distribute evenly throughout the thickness of the TRN. Our results, therefore, suggest that there exist a subpopulation of TRN neurons that receive convergent inputs from multiple thalamic sources and engage in more complex patterns of inhibition of relay cells. We propose these neurons enable the TRN to act as an externally driven "searchlight" that integrates cortical and subcortical inputs and then inhibits or disinhibits specific thalamic relay cells, so that appropriate information can get through the thalamus to the cortex. PMID- 21543610 TI - PSD-95 and PSD-93 play critical but distinct roles in synaptic scaling up and down. AB - Synaptic scaling stabilizes neuronal firing through the homeostatic regulation of postsynaptic strength, but the mechanisms by which chronic changes in activity lead to bidirectional adjustments in synaptic AMPA receptor (AMPAR) abundance are incompletely understood. Furthermore, it remains unclear to what extent scaling up and scaling down use distinct molecular machinery. PSD-95 is a scaffold protein proposed to serve as a binding "slot" that determines synaptic AMPAR content, and synaptic PSD-95 abundance is regulated by activity, raising the possibility that activity-dependent changes in the synaptic abundance of PSD-95 or other membrane-associated guanylate kinases (MAGUKs) drives the bidirectional changes in AMPAR accumulation during synaptic scaling. We found that synaptic PSD 95 and SAP102 (but not PSD-93) abundance were bidirectionally regulated by activity, but these changes were not sufficient to drive homeostatic changes in synaptic strength. Although not sufficient, the PSD-95 MAGUKs were necessary for synaptic scaling, but scaling up and down were differentially dependent on PSD-95 and PSD-93. Scaling down was completely blocked by reduced or enhanced PSD-95, through a mechanism that depended on the PDZ1/2 domains. In contrast, scaling up could be supported by either PSD-95 or PSD-93 in a manner that depended on neuronal age and was unaffected by a superabundance of PSD-95. Together, our data suggest that scaling up and down of quantal amplitude is not driven by changes in synaptic abundance of PSD-95 MAGUKs, but rather that the PSD-95 MAGUKs serve as critical synaptic organizers that use distinct protein-protein interactions to mediate homeostatic accumulation and loss of synaptic AMPAR. PMID- 21543611 TI - Dorsally and ventrally derived oligodendrocytes have similar electrical properties but myelinate preferred tracts. AB - In the developing spinal cord, most oligodendrocyte precursors (OLPs) arise from the ventral ventricular zone (VZ) under the influence of Sonic Hedgehog, but a minority are generated from the dorsal VZ in a Hedgehog-independent manner. In the developing forebrain too, OLPs arise from both the ventral and the dorsal VZ. It is not known whether dorsally and ventrally derived oligodendrocyte (OL) lineage cells have different properties. We generated a dual reporter mouse line to color code ventrally and dorsally derived OLPs (vOLPs and dOLPs) and their differentiated oligodendrocyte progeny (vOLs and dOLs) for functional studies. We found that ~80% of OL lineage cells in the postnatal spinal cord and ~20% in the corpus callosum are ventrally derived. In both spinal cord and corpus callosum, vOLPs and dOLPs had indistinguishable electrical properties, as did vOLs and dOLs. However, vOLPs and dOLPs had different migration and settling patterns. In the spinal cord, vOLPs appeared early and spread uniformly throughout the cord, whereas dOLPs arrived later and remained mainly in the dorsal and dorsolateral funiculi. During adulthood, corticospinal and rubrospinal tracts became myelinated mainly by dOLs, even though vOLs dominated these tracts during early postnatal life. Thus, dOLPs are electrically similar to vOLPs but appear to outcompete them for dorsal axons. PMID- 21543612 TI - Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition. AB - The nucleus accumbens (NAc) is involved in many reward-related behaviors. The NAc has two major components, the core and the shell. These two areas have different inputs and outputs, suggesting that they contribute differentially to goal directed behaviors. Using a discriminative stimulus (DS) task in rats and inactivating the NAc by blocking excitatory inputs with glutamate antagonists, we dissociated core and shell contributions to task performance. NAc core but not shell inactivation decreased responding to a reward-predictive cue. In contrast, inactivation of either subregion induced a general behavioral disinhibition. This reveals that the NAc actively suppresses actions inappropriate to the DS task. Importantly, selective inactivation of the shell but not core significantly increased responding to the nonrewarded cue. To determine whether the different contributions of the NAc core and shell depend on the information encoded in their constituent neurons, we performed electrophysiological recording in rats performing the DS task. Although there was no firing pattern unique to either core or shell, the reward-predictive cue elicited more frequent and larger magnitude responses in the NAc core than in the shell. Conversely, more NAc shell neurons selectively responded to the nonrewarded stimulus. These quantitative differences might account for the different behavioral patterns that require either core or shell. Neurons with similar firing patterns could also have different effects on behavior due to their distinct projection targets. PMID- 21543613 TI - Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish. AB - Whether changes in neuronal excitability can cause neurodegenerative disease in the absence of other factors such as protein aggregation is unknown. Mutations in the Kv3.3 voltage-gated K(+) channel cause spinocerebellar ataxia type 13 (SCA13), a human autosomal-dominant disease characterized by locomotor impairment and the death of cerebellar neurons. Kv3.3 channels facilitate repetitive, high frequency firing of action potentials, suggesting that pathogenesis in SCA13 is triggered by changes in electrical activity in neurons. To investigate whether SCA13 mutations alter excitability in vivo, we expressed the human dominant negative R420H mutant subunit in zebrafish. The disease-causing mutation specifically suppressed the excitability of Kv3.3-expressing, fast-spiking motor neurons during evoked firing and fictive swimming and, in parallel, decreased the precision and amplitude of the startle response. The dominant-negative effect of the mutant subunit on K(+) current amplitude was directly responsible for the reduced excitability and locomotor phenotype. Our data provide strong evidence that changes in excitability initiate pathogenesis in SCA13 and establish zebrafish as an excellent model system for investigating how changes in neuronal activity impair locomotor control and cause cell death. PMID- 21543614 TI - Homeostatic plasticity in the visual thalamus by monocular deprivation. AB - Monocular deprivation (MD) is a classic paradigm for experience-dependent cortical plasticity. One form is known as homeostatic plasticity, in which neurons innervated by the deprived eye show a remarkable capacity to compensate for degraded visual signals in an attempt to stabilize network activity. Although the evidence supporting homeostatic plasticity in visual cortex is extensive, it remains unclear whether neurons in subcortical visual structures respond to MD in a similar manner. Here we examined whether cells in the dorsal lateral geniculate nucleus (dLGN), the thalamic relay between the retina and visual cortex, show similar forms of experience-dependent homeostatic plasticity following MD. Two week-old mice were monocularly deprived for a period of 5-7 d and miniature EPSCs (mEPSCs) were obtained from cells located in dLGN regions receiving input from the deprived or nondeprived eye. We found that MD promotes increases in the frequency and amplitude of mEPSCs and were restricted to the monocular segment contralateral to the deprived eye. These changes were accompanied by an increase in the probability of glutamate release at corticothalamic terminals that arise from the deprived visual cortex. Our findings indicate that homeostatic synaptic regulation from MD extends beyond cortical circuitry and shed light on how the brain modulates and integrates activity in the face of altered sensory experience. PMID- 21543615 TI - BACE1 activity is modulated by cell-associated sphingosine-1-phosphate. AB - Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a pluripotent lipophilic mediator implicated in a variety of cellular events. Here we show that the activity of beta-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-beta peptide (Abeta) production, is modulated by S1P in mouse neurons. Treatment by SphK inhibitor, RNA interference knockdown of SphK, or overexpression of S1P degrading enzymes decreased BACE1 activity, which reduced Abeta production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimer's disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer's disease. PMID- 21543616 TI - Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. AB - Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington's disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect. We identify several genes (Myc, c-Src, Hif1alpha, and p21(waf1/cip1)) involved in neoplastic transformation, whose altered expression correlates with protective doses of mithramycin or its analogs. Most interestingly, inhibition of one these genes, Myc, is neuroprotective, whereas forced expression of Myc induces Rattus norvegicus neuronal cell death. These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration. PMID- 21543617 TI - The requirement for enhanced CREB1 expression in consolidation of long-term synaptic facilitation and long-term excitability in sensory neurons of Aplysia. AB - Accumulating evidence suggests that the transcriptional activator cAMP response element-binding protein 1 (CREB1) is important for serotonin (5-HT)-induced long term facilitation (LTF) of the sensorimotor synapse in Aplysia. Moreover, creb1 is among the genes activated by CREB1, suggesting a role for this protein beyond the induction phase of LTF. The time course of the requirement for CREB1 synthesis in the consolidation of long-term facilitation was examined using RNA interference techniques in sensorimotor cocultures. Injection of CREB1 small interfering RNA (siRNA) immediately or 10 h after 5-HT treatment blocked LTF when measured at 24 and 48 h after treatment. In contrast, CREB1 siRNA did not block LTF when injected 16 h after 5-HT treatment. These results demonstrate that creb1 expression must be sustained for a relatively long time to support the consolidation of LTF. In addition, LTF is also accompanied by a long-term increase in the excitability (LTE) of sensory neurons (SNs). Because LTE was observed in the isolated SN after 5-HT treatment, this long-term change was intrinsic to that element of the circuit. LTE was blocked when CREB1 siRNA was injected into isolated SNs immediately after 5-HT treatment. These data suggest that 5-HT-induced CREB1 synthesis is required for consolidation of both LTF and LTE. PMID- 21543619 TI - Effective connectivity reveals important roles for both the hyperdirect (fronto subthalamic) and the indirect (fronto-striatal-pallidal) fronto-basal ganglia pathways during response inhibition. AB - Fronto-basal ganglia pathways play a crucial role in voluntary action control, including the ability to inhibit motor responses. Response inhibition might be mediated via a fast hyperdirect pathway connecting the right inferior frontal gyrus (rIFG) and the presupplementary motor area (preSMA) with the subthalamic nucleus or, alternatively, via the indirect pathway between the cortex and caudate. To test the relative contribution of these two pathways to inhibitory action control, we applied an innovative quantification method for effective brain connectivity. Functional magnetic resonance imaging data were collected from 20 human participants performing a Simon interference task with an occasional stop signal. A single right-lateralized model involving both the hyperdirect and indirect pathways best explained the pattern of brain activation on stop trials. Notably, the overall connection strength of this combined model was highest on successfully inhibited trials. Inspection of the relationship between behavior and connection values revealed that fast inhibitors showed increased connectivity between rIFG and right caudate (rCaudate), whereas slow inhibitors were associated with increased connectivity between preSMA and rCaudate. In compliance, connection strengths from the rIFG and preSMA into the rCaudate were correlated negatively. If participants failed to stop, the magnitude of experienced interference (Simon effect), but not stopping latency, was predictive for the hyperdirect-indirect model connections. Together, the present results suggest that both the hyperdirect and indirect pathways act together to implement response inhibition, whereas the relationship between performance control and the fronto-basal ganglia connections points toward a top down mechanism that underlies voluntary action control. PMID- 21543618 TI - Synaptic reorganization of inhibitory hilar interneuron circuitry after traumatic brain injury in mice. AB - Functional plasticity of synaptic networks in the dentate gyrus has been implicated in the development of posttraumatic epilepsy and in cognitive dysfunction after traumatic brain injury, but little is known about potentially pathogenic changes in inhibitory circuits. We examined synaptic inhibition of dentate granule cells and excitability of surviving GABAergic hilar interneurons 8-13 weeks after cortical contusion brain injury in transgenic mice that express enhanced green fluorescent protein in a subpopulation of inhibitory neurons. Whole-cell voltage-clamp recordings in granule cells revealed a reduction in spontaneous and miniature IPSC frequency after head injury; no concurrent change in paired-pulse ratio was found in granule cells after paired electrical stimulation of the hilus. Despite reduced inhibitory input to granule cells, action potential and EPSC frequencies were increased in hilar GABA neurons from slices ipsilateral to the injury versus those from control or contralateral slices. Furthermore, increased excitatory synaptic activity was detected in hilar GABA neurons ipsilateral to the injury after glutamate photostimulation of either the granule cell or CA3 pyramidal cell layers. Together, these findings suggest that excitatory drive to surviving hilar GABA neurons is enhanced by convergent input from both pyramidal and granule cells, but synaptic inhibition of granule cells is not fully restored after injury. This rewiring of circuitry regulating hilar inhibitory neurons may reflect an important compensatory mechanism, but it may also contribute to network destabilization by increasing the relative impact of surviving individual interneurons in controlling granule cell excitability in the posttraumatic dentate gyrus. PMID- 21543620 TI - Active and passive antennal movements during visually guided steering in flying Drosophila. AB - Insects use feedback from a variety of sensory modalities, including mechanoreceptors on their antennae, to stabilize the direction and speed of flight. Like all arthropod appendages, antennae not only supply sensory information but may also be actively positioned by control muscles. However, how flying insects move their antennae during active turns and how such movements might influence steering responses are currently unknown. Here we examined the antennal movements of flying Drosophila during visually induced turns in a tethered flight arena. In response to both rotational and translational patterns of visual motion, Drosophila actively moved their antennae in a direction opposite to that of the visual motion. We also observed two types of passive antennal movements: small tonic deflections of the antenna and rapid oscillations at wing beat frequency. These passive movements are likely the result of wing induced airflow and increased in magnitude when the angular distance between the wing and the antenna decreased. In response to rotational visual motion, increases in passive antennal movements appear to trigger a reflex that reduces the stroke amplitude of the contralateral wing, thereby enhancing the visually induced turn. Although the active antennal movements significantly increased antennal oscillation by bringing the arista closer to the wings, it did not significantly affect the turning response in our head-fixed, tethered flies. These results are consistent with the hypothesis that flying Drosophila use mechanosensory feedback to detect changes in the wing induced airflow during visually induced turns and that this feedback plays a role in regulating the magnitude of steering responses. PMID- 21543622 TI - Cornichon-2 modulates AMPA receptor-transmembrane AMPA receptor regulatory protein assembly to dictate gating and pharmacology. AB - Neuronal AMPA receptor complexes comprise a tetramer of GluA pore-forming subunits as well as accessory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon-2/3 (CNIH-2/3). The mechanisms that control AMPA receptor complex assembly remain unclear. AMPA receptor responses in neurons differ from those in cell lines transfected with GluA plus TARPs gamma-8 or gamma-7, which show unusual resensitization kinetics and non-native AMPA receptor pharmacologies. Using tandem GluA/TARP constructs to constrain stoichiometry, we show here that these peculiar kinetic and pharmacological signatures occur in channels with four TARP subunits per complex. Reducing the number of TARPs per complex produces AMPA receptors with neuron-like kinetics and pharmacologies, suggesting a neuronal mechanism controls GluA/TARP assembly. Importantly, we find that coexpression of CNIH-2 with GluA/TARP complexes reduces TARP stoichiometry within AMPA receptors. In both rat and mouse hippocampal neurons, CNIH-2 also associates with AMPA receptors on the neuronal surface in a gamma-8-dependent manner to dictate receptor pharmacology. In the cerebellum, however, CNIH-2 expressed in Purkinje neurons does not reach the neuronal surface. In concordance, stargazer Purkinje neurons, which express CNIH-2 and gamma-7, display AMPA receptor kinetics/pharmacologies that can only be recapitulated recombinantly by a low gamma-7/GluA stoichiometry. Together, these data suggest that CNIH-2 modulates neuronal AMPA receptor auxiliary subunit assembly by regulating the number of TARPs within an AMPA receptor complex to modulate receptor gating and pharmacology. PMID- 21543623 TI - Construct validity of Stable-2000 and Stable-2007 scores. AB - We addressed the construct validity of Stable-2000 and Stable-2007 scores by examining correlations between selected items and validated independent measures of relevant constructs in samples of convicted sex offenders. In Study 1, the Child Molester Attitudes item of the Stable-2000 shared 23% of the variance with a self-report measure of beliefs supportive of child molestation, r(19) = .48. The Deviant Sexual Interests items of the Stable-2000 and Stable-2007 shared 7% to 66% of the variance, respectively, with an offense-history-based measure of pedophilic interests, r(18) = .27 for the Stable-2000 and r(11) = .81 for the Stable-2007. In Study 2, the Lovers/Intimate Partners, General Social Rejection/Loneliness, Rapist Attitudes, and Child Molester Attitudes items of the Stable-2000 shared 4% to 19% of the variance with self-report measures of, respectively, intimacy, r(90) = -.44; loneliness, r(88) = .34; beliefs supportive of rape, r(72) = .21; and beliefs supportive of child molestation, r(78) = .36. The results generally suggest that the Stable items examined are associated with measures of similar constructs; however, the degree of convergence was lower than expected. More systematic and comprehensive research is needed to examine convergence of the Stable items with other relevant measures and additional aspects of construct validity. Such efforts will provide a clearer understanding of dynamic risk factors, appropriate areas of focus for treatment efforts, and, more generally, why some sex offenders recidivate. PMID- 21543621 TI - Neural crest and ectodermal cells intermix in the nasal placode to give rise to GnRH-1 neurons, sensory neurons, and olfactory ensheathing cells. AB - The origin of GnRH-1 cells and olfactory ensheathing cells has been controversial. Genetic Cre-lox lineage tracing of the neural crest (NC) versus ectodermal contribution to the developing nasal placode was performed using two complementary mouse models, the NC-specific Wnt1Cre mouse line and an ectodermal specific Crect mouse line. Using these lines we prove that the NC give rise to the olfactory ensheathing cells and subpopulations of GnRH-1 neurons, olfactory and vomeronasal cells. These data demonstrate that Schwann cells and olfactory ensheathing cells share a common developmental origin. Furthermore, the results indicate that certain conditions that impact olfaction and sexual development, such as Kallmann syndrome, may be in part neurocristopathies. PMID- 21543624 TI - Glenohumeral osteoarthritis after arthroscopic Bankart repair for anterior instability. AB - BACKGROUND: Few data on shoulder arthropathy in patients undergoing arthroscopic repair for glenohumeral instability are available. HYPOTHESIS: Arthroscopic stabilization of Bankart lesions does not prevent the development of postoperative glenohumeral osteoarthritis. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Clinical (Rowe and Constant scores) and radiographic preoperative and postoperative data from 60 patients who underwent arthroscopic Bankart repair were compared. Osteoarthritis was graded preoperatively and postoperatively with the Buscayret classification grading system. The average age at surgery was 27.6 years, and follow-up averaged 8.0 years. RESULTS: The postoperative incidence of osteoarthritis in patients with no preoperative degenerative changes was 21.8% (12 of 55 patients). The incidence of degenerative joint disease of the glenohumeral joint showed evidence of a statistically significant association with older age at first dislocation and at surgery, increased length of time from the first episode to surgery, increased number of preoperative dislocations, increased length of time from the initial dislocation until surgery, increased number of anchors used at surgery, and more degenerated labrum at surgery. A higher number of preoperative dislocations, a greater length of follow-up, and reduced external rotation in abduction influenced Rowe and Constant scores. CONCLUSION: The number of anchors used and the state of the labrum are the most important factors associated with a higher risk of radiographic degenerative changes. Longer follow-up investigations are needed to draw meaningful conclusions. PMID- 21543625 TI - Tumor markers in metastatic breast cancer subtypes: frequency of elevation and correlation with outcome. AB - BACKGROUND: Little is known about the correlations between tumor markers (TMs), breast cancer subtypes, site(s) of metastasis and prognosis. METHODS: Women diagnosed with metastatic breast cancer were included. Breast cancer subtypes were defined as LuminalA, LuminalB, LuminalHer2, Her2, Basal and non-Basal triple negative (TN). Levels of elevation of TM values [cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA 125)] among the subtypes were analyzed. Site(s) of metastasis and outcomes were captured. RESULTS: Eight hundred and ten patients were included. Luminal subtypes were associated with an elevation in at least one TM: 90.8% of LuminalHer2+, 90% of LuminalB and 88.6% of LuminalA. TMs were less frequently elevated in Basal (74.1%) and non-Basal TN (71.4%) cases (P < 0.001). CA 15-3 was the most frequently elevated TM. The incidence of TM elevation did not differ between patients with solitary versus multiple metastatic sites. Breast cancer-specific survival (BCSS) was significantly worse for patients with elevated TMs (P = 0.001). CONCLUSIONS: TM elevation of CA 15-3, CEA and/or CA 125 was documented in the majority of patients with metastatic breast cancer with CA 15-3 occurring most commonly. Luminal subtypes expressed elevated TMs significantly more frequently compared with the non-Luminal groups. TM elevation was not different between the different sites of metastasis. Overall, elevated TMs predicted a worse BCSS. PMID- 21543626 TI - Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. AB - BACKGROUND: Cisplatin-based chemotherapy is a standard treatment of metastatic urothelial carcinoma (UC), though carboplatin-based chemotherapy is frequently substituted due to improved tolerability. Because comparative effectiveness in clinical outcomes of cisplatin- versus carboplatin-based chemotherapy is lacking, a meta-analysis was carried out. METHODS: PubMed was searched for articles published from 1966 to 2010. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in patients with metastatic UC. Individual patient data were not available and survival data were inconsistently reported. Therefore, the analysis focused on overall response (OR) and complete response (CR) rates. The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RRs). RESULTS: A total of 286 patients with metastatic UC from four randomized trials were included. Cisplatin-based chemotherapy was associated with a significantly higher likelihood of achieving a CR [RR = 3.54; 95% confidence interval (CI) 1.48-8.49; P = 0.005] and OR (RR = 1.34; 95% CI 1.04-1.71; P = 0.02). Survival end points could not be adequately assessed due to inconsistent reporting among trials. CONCLUSIONS: Cisplatin-based, as compared with carboplatin-based, chemotherapy significantly increases the likelihood of both OR and CR in patients with metastatic UC. The impact of improved response proportions on survival end points could not be assessed. PMID- 21543627 TI - Intracranial hemorrhage in patients with cancer treated with bevacizumab: the Memorial Sloan-Kettering experience. AB - BACKGROUND: Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor approved for recurrent glioblastoma (GBM), metastatic breast, colorectal and non-small-cell lung cancers (NSCLC). There has been a potentially increased risk of intracranial hemorrhage (ICH) in patients receiving bevacizumab. METHODS: We retrospectively identified patients with ICH who received bevacizumab between 1 January 2001 and 10 January 2009. RESULTS: We identified 1024 patients with ICH, 4191 patients who received bevacizumab and 12 (0.3%) who met both our criteria. There were eight women and four men with a median age of 66 years. Primary cancers were ovarian (n = 3), NSCLC (n = 3), colon (n = 1), angiosarcoma (n = 1) and GBM (n = 4). Intracranial tumors were present in 9 of the 12 patients; the remaining three (25%) had no evidence of intracranial pathology. Two hundred and fifty-seven patients with these same primary pathologies and brain tumors were treated with bevacizumab; ICH was seen in nine (3.7%), which was comparable to the 3.6% frequency seen in comparable patients not receiving bevacizumab. CONCLUSIONS: ICH with bevacizumab treatment in this population is rare and does not appear to increase its frequency over the baseline rate of ICH in a comparable population. Most bevacizumab-related ICH occurs into central nervous system tumors but spontaneous hemorrhages were seen. PMID- 21543628 TI - Dietary cholesterol intake and cancer. AB - BACKGROUND: This study assesses the association between dietary cholesterol intake and the risk of various cancers. PATIENTS AND METHODS: Mailed questionnaires were completed between 1994 and 1997 in eight Canadian provinces by 1182 incident histologically confirmed cases of the stomach, 1727 of the colon, 1447 of the rectum, 628 of the pancreas, 3341 of the lung, 2362 of the breast, 442 of the ovary, 1799 of the prostate, 686 of the testis, 1345 of the kidney, 1029 of the bladder, 1009 of the brain, 1666 non-Hodgkin's lymphomas (NHL), 1069 leukemia and 5039 population controls. Information on dietary habits and nutrition intake were obtained using a food frequency questionnaire, which provided data on eating habits 2 years before the study. Odds ratios (ORs) were derived by unconditional logistic regression to adjust for total energy intake and other potential confounding factors. RESULTS: Dietary cholesterol was positively associated with the risk of cancers of the stomach, colon, rectum, pancreas, lung, breast (mainly postmenopausal), kidney, bladder and NHL: the ORs for the highest versus the lowest quartile ranged from 1.4 to 1.7. In contrast, cholesterol intake was inversely associated with prostate cancer. CONCLUSIONS: Our findings add to the evidence that high cholesterol intake is linked to increased risk of various cancers. A diet low in cholesterol may play a role in the prevention of several cancers. PMID- 21543629 TI - Massage therapy for breast cancer patients: a systematic review. PMID- 21543630 TI - Trends of cutaneous melanoma in The Netherlands: increasing incidence rates among all Breslow thickness categories and rising mortality rates since 1989. AB - BACKGROUND: It has been debated that the epidemic of melanoma is largely due to overdiagnosis, since increases in incidence were mainly among thin melanomas and mortality rates remained stable. Our objective was to examine this controversy in The Netherlands. PATIENTS AND METHODS: Information on newly diagnosed melanoma patients was obtained from The Netherlands Cancer Registry. European Standardized Rates and estimated annual percentage change were calculated for the period 1989 2008. Cohort-based, period-based and multivariate survival analyses were carried out. RESULTS: The incidence rate of melanoma increased with 4.1% (95% confidence interval 3.6-4.5) annually. Incidence rates of both thin melanomas (<= 1 mm) and thick melanomas (> 4 mm) increased since 1989. Mortality rates increased mainly in older patients (> 65 years). Ten-year relative survival of males improved significantly from 70% in 1989-1993 to 77% in 2004-2008 (P < 0.001) and for females the 10-year relative survival increased from 85% to 88% (P < 0.01). Recently diagnosed patients had a better prognosis even after adjusting for all known prognostic factors. CONCLUSION: Since incidence of melanomas among all Breslow thickness categories increased as well as the mortality rates, the melanoma epidemic in The Netherlands seems to be real and not only due to overdiagnosis. PMID- 21543631 TI - Relationship between surface area of nonperfused myocardium and extravascular extraction of contrast agent following coronary microembolization. AB - Myocardial microvascular permeability and coronary sinus concentration of muscle metabolites have been shown to increase after myocardial ischemia due to epicardial coronary artery occlusion and reperfusion. However, their association with coronary microembolization is not well defined. This study tested the hypothesis that acute coronary microembolization increases microvascular permeability in the porcine heart. The left anterior descending perfusion territories of 34 anesthetized pigs (32 +/- 3 kg) were embolized with equal volumes of microspheres of one of three diameters (10, 30, or 100 MUm) and at three different doses for each size. Electron beam computed tomography (EBCT) was used to assess in vivo, microvascular extraction of a nonionic contrast agent (an index of microvascular permeability) before and after microembolization with microspheres at baseline and during adenosine infusion. A high-resolution three dimensional microcomputed tomography (micro-CT) scanner was subsequently used to obtain ex vivo, the volume and corresponding surface area of the embolized myocardial islands within the perfusion territories of the microembolized coronary artery. EBCT-derived microvascular extraction of contrast agent increased within minutes after coronary microembolization (P < 0.001 vs. baseline and vs. control values). The increase in coronary microvascular permeability was highly correlated to the micro-CT-derived total surface area of the nonperfused myocardium (r = 0.83, P < 0.001). In conclusion, myocardial extravascular accumulation of contrast agent is markedly increased after coronary microembolization and its magnitude is in proportion to the surface area of the interface between the nonperfused and perfused territories. PMID- 21543632 TI - Gut sensing of dietary K+ intake increases renal K+excretion. AB - Dietary K(+) intake may increase renal K(+) excretion via increasing plasma [K(+)] and/or activating a mechanism independent of plasma [K(+)]. We evaluated these mechanisms during normal dietary K(+) intake. After an overnight fast, [K(+)] and renal K(+) excretion were measured in rats fed either 0% K(+) or the normal 1% K(+) diet. In a third group, rats were fed with the 0% K(+) diet, and KCl was infused to match plasma [K(+)] profile to that of the 1% K(+) diet group. The 1% K(+) feeding significantly increased renal K(+) excretion, associated with slight increases in plasma [K(+)], whereas the 0% K(+) diet decreased K(+) excretion, associated with decreases in plasma [K(+)]. In the KCl-infused 0% K(+) diet group, renal K(+) excretion was significantly less than that of the 1% K(+) group, despite matched plasma [K(+)] profiles. We also examined whether dietary K(+) alters plasma profiles of gut peptides, such as guanylin, uroguanylin, glucagon-like peptide 1, and glucose-dependent insulinotropic polypeptide, pituitary peptides, such as AVP, alpha-MSH, and gamma-MSH, or aldosterone. Our data do not support a role for these hormones in the stimulation of renal K(+) excretion during normal K(+) intake. In conclusion, postprandial increases in renal K(+) excretion cannot be fully accounted for by changes in plasma [K(+)] and that gut sensing of dietary K(+) is an important component of the regulation of renal K(+) excretion. Our studies on gut and pituitary peptide hormones suggest that there may be previously unknown humoral factors that stimulate renal K(+) excretion during dietary K(+) intake. PMID- 21543633 TI - mu-Opioid receptor stimulation in the nucleus accumbens elevates fatty tastant intake by increasing palatability and suppressing satiety signals. AB - Infusion of a MU-opioid receptor (MOR) agonist into the nucleus accumbens (NAcc) drives voracious food intake, an effect hypothesized to occur through increased tastant palatability. While intake of many palatable foods is elevated by MOR stimulation, this manipulation has a preferential effect on fatty food ingestion. Consumption of high-fat foods is increased by NAcc MOR stimulation even in rats that prefer a carbohydrate-rich alternative under baseline conditions. This suggests that NAcc MOR stimulation may not simply potentiate palatability signals and raises the possibility that mechanisms mediating fat intake may be distinct from those underlying intake of other tastants. The present study was conducted to investigate the physiological mechanisms underlying the effects of NAcc MOR stimulation on fatty food intake. In experiment 1, we analyzed lick microstructure in rats ingesting Intralipid to identify the changes underlying feeding induced by infusion of a MOR-specific agonist into the NAcc. MOR stimulation in the NAcc core, but not shell, increased burst duration and first minute licks, while simultaneously increasing the rate and duration of Intralipid ingestion. These results suggest that MOR activation in the core increases Intralipid palatability and attenuates inhibitory postingestive feedback. In experiment 2, we measured the effects of MOR stimulation in the NAcc core on consumption of nonnutritive olestra. A MOR-specific agonist dose dependently increased olestra intake, demonstrating that caloric signaling is not required for hyperphagia induced by NAcc MOR stimulation. Feeding induced by drug infusion in both experiments 1 and 2 was blocked by a MOR antagonist. In experiment 3, we determined whether MOR activation in the NAcc core could attenuate satiety related signaling caused by infusion of the melanocortin agonist MTII into the third ventricle. Suppression of intake caused by MTII was reversed by MOR stimulation. Together, our results suggest that MOR stimulation in the NAcc core elevates fatty food intake through palatability mechanisms dependent on orosensory cues and suppression of satiety signals inhibiting food intake. PMID- 21543634 TI - Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle. AB - Silent mating type information regulator 2 homolog 1 (SIRT1)-mediated peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) deacetylation is potentially key for activating mitochondrial biogenesis. Yet, at the whole muscle level, SIRT1 is not associated with mitochondrial biogenesis (Gurd, BJ, Yoshida Y, Lally J, Holloway GP, Bonen A. J Physiol 587: 1817-1828, 2009). Therefore, we examined nuclear SIRT1 protein and activity in muscle with varied mitochondrial content and in response to acute exercise. We also measured these parameters after stimulating mitochondrial biogenesis with chronic muscle contraction and 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) administration in rodents and exercise training in humans. In skeletal and heart muscles, nuclear SIRT1 protein was negatively correlated with indices of mitochondrial density (citrate synthase activity, CS; cytochrome oxidase IV, COX IV), but SIRT1 activity was positively correlated with these parameters (r > 0.98). Acute exercise did not alter nuclear SIRT1 protein but did induce a time dependent increase in nuclear SIRT1 activity. This increase in SIRT1 activity was temporally related to increases in mRNA expression of genes activated by PGC 1alpha. Both chronic muscle stimulation and AICAR increased mitochondrial biogenesis and muscle PGC-1alpha, but not nuclear PGC-1alpha. Concomitantly, muscle and nuclear SIRT1 protein contents were reduced, but nuclear SIRT1 activity was increased. In human muscle, training-induced mitochondrial biogenesis did not alter muscle or nuclear SIRT1 protein content, but it did increase muscle and nuclear PGC-1alpha and SIRT1 activity. Thus, nuclear SIRT1 activity, but not muscle or nuclear SIRT1 protein content, is associated with contraction-stimulated mitochondrial biogenesis in rat and human muscle, possibly via AMPK activation. PMID- 21543635 TI - Environmental factors responsible for switching on the SO42- excretory system in the kidney of seawater eels. AB - Eels are unique in that they maintain lower plasma SO(4)(2-) concentration in SO(4)(2-)-rich (~30 mM) seawater (SW) than in SO(4)(2-)-poor (<0.3 mM) freshwater (FW), showing drastic changes in SO(4)(2-) regulation between FW and SW. We previously showed that the expression of renal SO(4)(2-) transporter genes, FW specific Slc13a1 and SW-specific Slc26a6a, changes profoundly after transfer of FW eels to SW, which results in the decrease in plasma SO(4)(2-) concentration after 3 days in SW. In this study, we attempted to identify the environmental factor(s) that trigger the switching of SO(4)(2-) regulation using changes in plasma and urine SO(4)(2-) concentrations and expression of the transporter genes as markers. Transfer of FW eels to 30 mM SO(4)(2-) or transfer of SW eels to SO(4)(2-)-free SW did not change the SO(4)(2-) regulation. Major divalent cations in SW, Mg(2+) (50 mM) and Ca(2+) (10 mM), were also ineffective, but 50 mM NaCl was effective for switching the SO(4)(2-) regulation. Further analyses using choline-Cl and Na-gluconate showed that Cl(-) is a primary factor and Na(+) is permissive for the Cl(-) effect. Since plasma SO(4)(2-) and Cl(-) concentrations were inversely correlated, we injected various solutions into the blood and found that Cl(-) alone triggered the switching from FW to SW-type regulation. Furthermore, the inhibitor of Na-Cl cotransporter (NCC) added to media significantly impaired the expression of SW-specific Slc26a6a in 150 mM NaCl. In summary, it appears that Cl(-) ions in SW are taken up into the circulation via the NCC together with Na(+), and the resultant increase in plasma Cl(-) concentration enhances SO(4)(2-) excretion by the kidney through downregulation of absorptive Slc13a1 and upregulation of excretory Slc26a6a, resulting in low plasma SO(4)(2-) concentration in SW. PMID- 21543636 TI - Disruption of COX-2 and eNOS does not confer protection from cardiovascular failure in lipopolysaccharide-treated conscious mice and isolated vascular rings. AB - It was hypothesized that a serial stimulation of vascular cyclooxygenase-2 (COX 2) with subsequent activation of endothelial nitric oxide synthase (eNOS) is responsible for decrease in blood pressure, cardiac performance, and vascular reactivity in endotoxemia caused by LPS. The hypothesis was tested in catheterized, conscious, freely moving, wild-type mice and mice (C57BL/6J background) with targeted deletion of COX-2 and eNOS that were given an intravenous LPS bolus (2 mg/kg, 055:B5). In vitro studies were performed on murine aorta rings. LPS caused a concomitant decrease in mean arterial blood pressure (MAP) and heart rate (HR) that was significant after 3 h and was sustained throughout the experiment (8 h). The LPS-induced changes in MAP and HR were not different from control in COX-2(-/-) and eNOS(-/-) mice. A prostacyclin receptor antagonist (BR5064) blocked the hypotensive effect of a prostacyclin agonist (beraprost), but did not attenuate the LPS-induced decrease in MAP and HR. LPS decreased eNOS and neuronal NOS mRNA abundances in several organs, while inducible NOS mRNA was enhanced. In aortic rings, LPS suppressed alpha(1) adrenoceptor-mediated vascular tone. Inhibition of COX-2 activity (NS 398), disruption of COX-2, endothelium removal, or eNOS deletion (eNOS(-/-)) did not improve vascular reactivity after LPS, while the NO synthase blockers 1400W and N(G)-nitro-l-arginine methyl ester prevented loss of tone. COX-2 and eNOS activities are not necessary for LPS-induced decreases in blood pressure, heart rate, and vascular reactivity. Inducible NOS activity appears crucial. COX-2 and eNOS are not obvious therapeutic targets for cardiovascular rescue during gram negative endotoxemic shock. PMID- 21543637 TI - The therapeutic potential of hydrogen sulfide: separating hype from hope. AB - Hydrogen sulfide (H(2)S) has become the hot new signaling molecule that seemingly affects all organ systems and biological processes in which it has been investigated. It has also been shown to have both proinflammatory and anti inflammatory actions and proapoptotic and anti-apoptotic effects and has even been reported to induce a hypometabolic state (suspended animation) in a few vertebrates. The exuberance over potential clinical applications of natural and synthetic H(2)S-"donating" compounds is understandable and a number of these function-targeted drugs have been developed and show clinical promise. However, the concentration of H(2)S in tissues and blood, as well as the intrinsic factors that affect these levels, has not been resolved, and it is imperative to address these points to distinguish between the physiological, pharmacological, and toxicological effects of this molecule. This review will provide an overview of H(2)S metabolism, a summary of many of its reported "physiological" actions, and it will discuss the recent development of a number of H(2)S-donating drugs that show clinical potential. It will also examine some of the misconceptions of H(2)S chemistry that have appeared in the literature and attempt to realign the definition of "physiological" H(2)S concentrations upon which much of this exuberance has been established. PMID- 21543638 TI - Chronic intermittent hypoxia increases blood pressure and expression of FosB/DeltaFosB in central autonomic regions. AB - Chronic intermittent hypoxia (CIH) models repetitive bouts of arterial hypoxemia that occur in humans suffering from obstructive sleep apnea. CIH has been linked to persistent activation of arterial chemoreceptors and the renin-angiotensin system, which have been linked to chronic elevations of sympathetic nerve activity (SNA) and mean arterial pressure (MAP). Because Fos and FosB are transcription factors involved in activator protein (AP)-1 driven central nervous system neuronal adaptations, this study determined if CIH causes increased Fos or FosB staining in brain regions that regulate SNA and autonomic function. Male Sprague Dawley rats were instrumented with telemetry transmitters for continuous recording of MAP and heart rate (HR). Rats were exposed to continuous normoxia (CON) or to CIH for 8 h/day for 7 days. CIH increased MAP by 7-10 mmHg without persistently affecting HR. A separate group of rats was killed 1 day after 7 days of CIH for immunohistochemistry. CIH did not increase Fos staining in any brain region examined. Staining for FosB/DeltaFosB was increased in the organum vasculosum of the lamina terminalis (CON: 9 +/- 1; CIH: 34 +/- 3 cells/section), subfornical organ (CON: 7 +/- 2; CIH: 31 +/- 3), median preoptic nucleus (CON 15 +/- 1; CIH: 38 +/- 3), nucleus of the solitary tract (CON: 9 +/- 2; CIH: 28 +/- 4), A5 (CON: 3 +/- 1; CIH: 10 +/- 1), and rostral ventrolateral medulla (CON: 5 +/- 1; CIH: 17 +/- 2). In the paraventricular nucleus, FosB/DeltaFosB staining was located mainly in the dorsal and medial parvocellular subnuclei. CIH did not increase FosB/DeltaFosB staining in caudal ventrolateral medulla or supraoptic nucleus. These data indicate that CIH induces an increase in FosB/DeltaFosB in autonomic nuclei and suggest that AP-1 transcriptional regulation may contribute to stable adaptive changes that support chronically elevated SNA. PMID- 21543640 TI - Identification of a potential biomarker for FABP4 inhibition: the power of lipidomics in preclinical drug testing. AB - The fatty acid binding protein 4 (FABP4) belongs to the family of lipid chaperones that control intracellular fluxes and compartmentalization of their respective ligands (e.g., fatty acids). FABP4, which is almost exclusively expressed in adipocytes and macrophages, contributes to the development of insulin resistance and atherosclerosis in mice. Lack of FABP4 protects against the development of insulin resistance associated with genetic or diet-induced obesity in mice. Furthermore, total or macrophage-specific FABP4 deficiency is protective against atherosclerosis in apolipoprotein E-deficient mice. The FABP4 small-molecule inhibitor BMS309403 has demonstrated efficacy in mouse models for type 2 diabetes mellitus and atherosclerosis, resembling phenotypes of mice with FABP4 deficiency. However, despite the therapeutically attractive long-term effects of FABP4 inhibition, an acute biomarker for drug action is lacking. The authors applied mass spectrometry lipidomics analysis to in vitro and in vivo (plasma and adipose tissue) samples upon inhibitor treatment. They report the identification of a potential biomarker for acute in vivo FABP4 inhibition that is applicable for further investigations and can be implemented in simple and fast-flow injection mass spectrometry assays. In addition, this approach can be considered a proof-of-principle study that can be applied to other lipid-pathway targeting mechanisms. PMID- 21543639 TI - Vanilloid, purinergic, and CCK receptors activate glutamate release on single neurons of the nucleus tractus solitarius centralis. AB - Baroreceptor inputs to nucleus of the tractus solitarius medialis (mNTS) neurons can be differentiated, among other features, by their response to vanilloid or purinergic agonists, active only on C- or A-fibers, respectively. A major aim of this study was to examine whether neurons of NTS centralis (cNTS), a subnucleus dominated by esophageal inputs, exhibit a similar dichotomy. Since it has been suggested that cholecystokinin (CCK), exerts its gastrointestinal (GI)-related effects via paracrine activation of vagal afferent C-fibers, we tested whether CCK-sensitive fibers impinging upon cNTS neurons are responsive to vanilloid but not purinergic agonists. Using whole cell patch-clamp recordings from cNTS, we recorded miniature excitatory postsynaptic currents (mEPSCs) to test the effects of the vanilloid agonist capsaicin, the purinergic agonist alpha,beta-methylene ATP (alpha,beta-Met-ATP), and/or CCK-octapeptide (CCK-8s). alpha,beta-Met-ATP, capsaicin; and CCK-8s increased EPSC frequency in 37, 71, and 46% of cNTS neurons, respectively. Approximately 30% of cNTS neurons were responsive to both CCK-8s and alpha,beta-Met-ATP, to CCK-8s and capsaicin, or to alpha,beta-Met-ATP and capsaicin, while 32% of neurons were responsive to all three agonists. All neurons responding to either alpha,beta-Met-ATP or CCK-8s were also responsive to capsaicin. Perivagal capsaicin, which is supposed to induce a selective degeneration of C-fibers, decreased the number of cNTS neurons responding to capsaicin or CCK-8s but not those responding to alpha,beta-Met-ATP. In summary, GI inputs to cNTS neurons cannot be distinguished on the basis of their selective responses to alpha,beta-Met-ATP or capsaicin. Our data also indicate that CCK-8s increases glutamate release from purinergic and vanilloid responsive fibers impinging on cNTS neurons. PMID- 21543641 TI - Mitral and tricuspid annular velocities before and after pericardiectomy in patients with constrictive pericarditis. AB - BACKGROUND: Previous studies have demonstrated that mitral annulus early diastolic (e') velocity is increased in constrictive pericarditis (CP) and reduced in restrictive cardiomyopathy. However, those studies did not comprehensively evaluate mitral and tricuspid annular velocities before and after pericardiectomy. METHODS AND RESULTS: We performed comprehensive echocardiography before and after pericardiectomy in 99 patients with CP, 52 with primary (idiopathic or postpericarditis etiology) and 47 with secondary CP (due to surgery or radiation). Overall, mean +/- SD mitral medial, mitral lateral, and tricuspid lateral e' velocities were 12.2 +/- 4.2, 10.0 +/- 5.4, and 11.6 +/- 3.5 cm/s, respectively; annular late diastolic velocities were 10.3 +/- 4.3, 12.2 +/- 4.9, and 11.7 +/- 5.4 cm/s, respectively; and annular systolic (s') velocities were 7.8 +/- 2.8, 8.2 +/- 2.1, and 11.2 +/- 3.8 cm/s, respectively. Medial e' was equal to or greater than mitral lateral e' in 74% of analyzable cases. With the exception of tricuspid s', there were significant differences in all s' and e'velocities between primary and secondary CP before pericardiectomy. After pericardiectomy, all annular velocities decreased significantly (P < 0.02 for all comparisons). The reduction in medial e' velocity was greater than that of mitral lateral e' velocity (P < 0.0001 and P = 0.0004, respectively), and the mitral lateral/medial e' ratio normalized (P = 0.0002). CONCLUSIONS: The mitral lateral/medial e' ratio is reversed in three fourths of patients with CP. All annular velocities are lower in secondary compared to primary CP before pericardiectomy. After pericardiectomy, there is reduction of all annular velocities and normalization of the mitral lateral/medial e' ratio. PMID- 21543642 TI - Early repolarization pattern in competitive athletes: clinical correlates and the effects of exercise training. AB - BACKGROUND: Inferior lead early repolarization pattern (ERP) recently has been associated with sudden cardiac death. Although ERP is common among athletes, prevalence, ECG lead distribution, clinical characteristics, and effects of physical training remain uncertain. We sought to examine the nonanterior ERP in competitive athletes. METHODS AND RESULTS: ERP was assessed in a cross-sectional cohort of collegiate athletes (n = 879). The relationship between ERP and cardiac structure were then examined in a longitudinal subgroup (n = 146) before and after a 90-day period of exercise training. ERP was defined as J-point elevation >= 0.1 mV in at least 2 leads within a nonanterior territory (inferior [II, III, aVF] or lateral territory [I, aVL, V4-V6]). Nonanterior ERP was present in 25.1% (221/879) of athletes, including the inferior subtype in 3.8% (33/879). Exercise training led to significant increases in the prevalence of ERP and the inferior subtype, but there were no associations between ERP and echocardiographic measures of left ventricular remodeling. In a multivariable model, ERP was associated with black race (odds ratio [OR], 5.84; 95% CI, 3.54 to 9.61; P < 0.001), increased QRS voltage (OR, 2.08; 95% CI, 1.71 to 2.52; P < 0.001), and slower heart rate (OR, 1.54; 95% CI, 1.26 to 1.87; P < 0.001). CONCLUSIONS: Nonanterior ERP, including the inferior subtype, is common and has strong clinical associations among competitive athletes. The finding of increased ERP prevalence after intense physical training establishes a strong association between exercise and ERP. PMID- 21543643 TI - Identification of IDO-positive and IDO-negative human dendritic cells after activation by various proinflammatory stimuli. AB - Dendritic cells (DCs) can induce tolerance or immunity. We identified and characterized an IDO-expressing and an IDO-negative human DC population after stimulation by various proinflammatory stimuli. IDO expression was strongly dependent on the maturation status of the cells (CD83-positive cells only). The two DC subpopulations remained IDO positive and IDO negative, respectively, over a time period of at least 48 h. IDO enzyme activity of human DCs was highest during stimulation by strongly maturation-inducing TLR ligands such as highly purified LPS (TLR4 ligand) or polyriboinosinic-polyribocytidilic acid (TLR3 ligand); factors of the adaptive immune system such as IFN-gamma, a mixture of cytokines, and IFN-alpha had lesser stimulatory capacity for IDO induction and activity. After stimulation with CD40L, IDO-positive DCs expressed significantly increased levels of B7 family molecules such as CD40, CD80, CD86, ICOS ligand, as well as PD-L1 (B7-H1) and PD-L2 (B7-DC) compared with the IDO-negative DC subset. At the same time, the inhibitory receptors Ig-like transcripts 3 and 4 were significantly downregulated on IDO-positive cells. Functionally, IDO-positive DCs produced significantly more IL-1beta and IL-15 and less IL-10 and IL-6 than the IDO-negative subset after CD40L stimulation. These results show that IDO expression is associated with a distinctive phenotype and functional capacity in mature DCs. It seems likely that the IDO-positive DC subset possesses a regulatory function and might skew a T cell response toward tolerance. PMID- 21543644 TI - Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1. AB - Sle2c1 is an NZM2410- and NZB-derived lupus susceptibility locus that induces an expansion of the B1a cell compartment. B1a cells have a repertoire enriched for autoreactivity, and an expansion of this B cell subset occurs in several mouse models of lupus. A combination of genetic mapping and candidate gene analysis presents Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18(INK4c) (p18), as the top candidate gene for inducing the Slec2c1-associated expansion of B1a cells. A novel single nucleotide polymorphism in the NZB allele of the Cdkn2c promoter is associated with a significantly reduced Cdkn2c expression in the splenic B cells and peritoneal cavity B1a cells from Sle2c1-carrying mice, which leads to a defective G1 cell cycle arrest in splenic B cells and increased proliferation of peritoneal cavity B1a cells. As the cell cycle is differentially regulated in B1a and B2 cells, these results suggest that Cdkn2c plays a critical role in B1a cell self-renewal and that its impaired expression leads to an accumulation of these cells with high autoreactive potential. PMID- 21543645 TI - A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. AB - The nucleotide-binding oligomerization domain-like receptor (NLR) family member, Nlrp6, has been implicated in inflammasome signaling to activate caspase-1, which is essential for the production of mature IL-1beta and IL-18. However, a function for Nlrp6 in vivo has never been demonstrated. Due to the relative high expression of Nlrp6 in intestinal tissue, we hypothesized that Nlrp6 has a role in intestinal homeostasis. Indeed, Nlrp6-deficient mice are more susceptible to chemically induced colitis as well as colitis-induced tumorigenesis than wild type (WT) mice. Nlrp6-deficient mice exhibited significantly more inflammation within the colon than WT mice after dextran sulfate sodium treatment. Their inability to resolve inflammation and repair damaged epithelium as efficiently as WT mice resulted in prolonged increases in epithelial proliferative activity that likely underlie the increased propensity for tumors in these mice during chronic inflammation. We further show that the activity of Nlrp6 in hematopoietic cells is critical for protection against inflammation-related colon tumorigenesis. This study highlights the importance of NLR function in maintaining intestinal homeostasis to prevent the development of aberrant inflammation and tumor development within the colon. PMID- 21543647 TI - Chlamydia pneumoniae inhibits activated human T lymphocyte proliferation by the induction of apoptotic and pyroptotic pathways. AB - Chlamydia pneumoniae is an omnipresent obligate intracellular bacterial pathogen that infects numerous host species. C. pneumoniae infections of humans are a common cause of community acquired pneumonia but have also been linked to chronic diseases such as atherosclerosis, Alzheimer's disease, and asthma. Persistent infection and immune avoidance are believed to play important roles in the pathophysiology of C. pneumoniae disease. We found that C. pneumoniae organisms inhibited activated but not nonactivated human T cell proliferation. Inhibition of proliferation was pathogen specific, heat sensitive, and multiplicity of infection dependent and required chlamydial entry but not de novo protein synthesis. Activated CD4(+) and CD8(+) T cells were equally sensitive to C. pneumoniae antiproliferative effectors. The C. pneumoniae antiproliferative effect was linked to T cell death associated with caspase 1, 8, 9, and IL-1beta production, indicating that both apoptotic and pyroptotic cellular death pathways were activated after pathogen-T cell interactions. Collectively, these findings are consistent with the conclusion that C. pneumoniae could induce a local T cell immunosuppression and inflammatory response revealing a possible host-pathogen scenario that would support both persistence and inflammation. PMID- 21543646 TI - The CD3 zeta subunit contains a phosphoinositide-binding motif that is required for the stable accumulation of TCR-CD3 complex at the immunological synapse. AB - T cell activation involves a cascade of TCR-mediated signals that are regulated by three distinct intracellular signaling motifs located within the cytoplasmic tails of the CD3 chains. Whereas all the CD3 subunits possess at least one ITAM, the CD3 epsilon subunit also contains a proline-rich sequence and a basic-rich stretch (BRS). The CD3 epsilon BRS complexes selected phosphoinositides, interactions that are required for normal cell surface expression of the TCR. The cytoplasmic domain of CD3 zeta also contains several clusters of arginine and lysine residues. In this study, we report that these basic amino acids enable CD3 zeta to complex the phosphoinositides PtdIns(3)P, PtdIns(4)P, PtdIns(5)P, PtdIns(3,5)P(2), and PtdIns(3,4,5)P(3) with high affinity. Early TCR signaling pathways were unaffected by the targeted loss of the phosphoinositide-binding functions of CD3 zeta. Instead, the elimination of the phosphoinositide-binding function of CD3 zeta significantly impaired the ability of this invariant chain to accumulate stably at the immunological synapse during T cell-APC interactions. Without its phosphoinositide-binding functions, CD3 zeta was concentrated in intracellular structures after T cell activation. Such findings demonstrate a novel functional role for CD3 zeta BRS-phosphoinositide interactions in supporting T cell activation. PMID- 21543648 TI - The Ia.2 epitope defines a subset of lipid raft-resident MHC class II molecules crucial to effective antigen presentation. AB - Previous work established that binding of the 11-5.2 anti-I-A(k) mAb, which recognizes the Ia.2 epitope on I-A(k) class II molecules, elicits MHC class II signaling, whereas binding of two other anti-I-A(k) mAbs that recognize the Ia.17 epitope fail to elicit signaling. Using a biochemical approach, we establish that the Ia.2 epitope recognized by the widely used 11-5.2 mAb defines a subset of cell surface I-A(k) molecules predominantly found within membrane lipid rafts. Functional studies demonstrate that the Ia.2-bearing subset of I-A(k) class II molecules is critically necessary for effective B cell-T cell interactions, especially at low Ag doses, a finding consistent with published studies on the role of raft-resident class II molecules in CD4 T cell activation. Interestingly, B cells expressing recombinant I-A(k) class II molecules possessing a beta-chain tethered hen egg lysosome peptide lack the Ia.2 epitope and fail to partition into lipid rafts. Moreover, cells expressing Ia.2(-) tethered peptide-class II molecules are severely impaired in their ability to present both tethered peptide or peptide derived from exogenous Ag to CD4 T cells. These results establish the Ia.2 epitope as defining a lipid raft-resident MHC class II conformer vital to the initiation of MHC class II-restricted B cell-T cell interactions. PMID- 21543649 TI - Committed dis(s)idents: participation in radical collective action fosters disidentification with the broader in-group but enhances political identification. AB - The present research examined the hypothesis that participation in radical, but not moderate, action results in disidentification from the broader in-group. Study 1 (N = 98) was a longitudinal study conducted in the context of student protests against tuition fees in Germany and confirmed that participation in radical collective action results in disidentification with the broader in-group (students) whereas participation in moderate collective action does not. Both types of action increased politicized identification. Study 2 (N = 175) manipulated the normativeness of different types of imagined collective actions in the same context and replicated this disidentification effect for radical actions, but only when this action mismatched the broader in-group's norms. This study also indicated that these effects were partially mediated by perceived lack of solidarity and perceived lack of commitment to the cause among the broader in group. The implications of these findings for understanding radicalization within social movements are discussed. PMID- 21543650 TI - How shared preferences in music create bonds between people: values as the missing link. AB - How can shared music preferences create social bonds between people? A process model is developed in which music preferences as value-expressive attitudes create social bonds via conveyed value similarity. The musical bonding model links two research streams: (a) music preferences as indicators of similarity in value orientations and (b) similarity in value orientations leading to social attraction. Two laboratory experiments and one dyadic field study demonstrated that music can create interpersonal bonds between young people because music preferences can be cues for similar or dissimilar value orientations, with similarity in values then contributing to social attraction. One study tested and ruled out an alternative explanation (via personality similarity), illuminating the differential impact of perceived value similarity versus personality similarity on social attraction. Value similarity is the missing link in explaining the musical bonding phenomenon, which seems to hold for Western and non-Western samples and in experimental and natural settings. PMID- 21543651 TI - AA amyloidosis associated with hepatitis B. AB - We report a 13-year-old Indian boy with nephrotic syndrome caused by renal AA amyloidosis. Workup of the AA amyloidosis revealed chronic hepatitis B. Laser microdissection of the Congo-red-positive glomeruli and vessels followed by liquid chromatography and tandem mass spectrometry confirmed the presence of serum amyloid A (SAA) protein and ruled out hereditary and familial amyloidosis. Furthermore, mass spectrometry also detected a variant of SAA protein (SAA W71R). PMID- 21543652 TI - When to initiate dialysis--is early start always better? AB - The question when to initiate dialysis is attracting increasing attention. In recent years, there has been a tendency to initiate dialysis earlier in terms of estimated glomerular filtration rate (eGFR) in an attempt to achieve better patient outcomes. However, several observational studies and one randomized controlled trial have found no benefit for early dialysis initiation. On the contrary, they have found that starting dialysis with a higher eGFR is associated with increased mortality. These studies need to be carefully interpreted in light of their reliance on eGFR to estimate kidney function at dialysis initiation. The decision to start dialysis should not be based solely on a predefined eGFR value, but more importantly on a careful clinical assessment of the individual patient. PMID- 21543654 TI - Coronary artery calcification in renal transplant recipients: is it a strong predictor of cardiovascular events? PMID- 21543653 TI - Effects of atorvastatin on NGAL and cystatin C in chronic kidney disease: a post hoc analysis of the LORD trial. AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C are biomarkers of kidney injury and function, respectively. This study assessed whether plasma NGAL and/or serum cystatin C predicted baseline estimated glomerular filtration rate (eGFR) and urinary protein excretion, rate of change of eGFR and urinary protein excretion and whether atorvastatin influenced changes in these biomarkers in patients with chronic kidney disease (CKD). METHODS: This is a post hoc analysis of the Lipid Lowering and Onset of Renal Disease trial, a randomized double-blind, placebo-controlled trial where 88 patients with Stages 2 4 CKD received atorvastatin 10 mg/day (48) or placebo (40). Stored blood samples were analysed for NGAL and cystatin C at baseline and a mean of 1.5 and 2.9 years later. Serum creatinine and Modification of Diet in Renal Disease (MDRD) eGFR were obtained three monthly. RESULTS: There were negative associations between NGAL and cystatin C and eGFR (P = 0.025 and P < 0.001, respectively) at all time points. There were no associations between baseline NGAL and cystatin C and rate of change of eGFR (P = 0.44 and P = 0.49, respectively). Baseline NGAL but not cystatin C (P = 0.043 and P = 0.35, respectively) predicted rate of change of urinary protein excretion. In atorvastatin-treated patients, NGAL decreased (mean, -7.4 ng/mL/year; SD 128.4), whereas it increased in the placebo group [mean, 4.6 ng/mL/year; SD 56.6), the difference being statistically significant (P = 0.049). CONCLUSIONS: NGAL is a biomarker of existing CKD but did not predict CKD progression. Atorvastatin reduced plasma NGAL but the significance and mechanisms require further investigation. Atorvastatin had no significant effect on cystatin C. PMID- 21543655 TI - Long-term outcomes of patients with light chain amyloidosis (AL) after renal transplantation with or without stem cell transplantation. AB - BACKGROUND: Recent advances in the treatment of immunoglobulin light chain amyloidosis (AL) have dramatically improved survival. Kidney transplantation (KTx) has become more common but the long-term outcomes remain unknown and it is the objective of this study. METHODS: Nineteen patients with AL underwent living (n = 18) or deceased (n = 1) KTx at our institution from 1999 to 2008 (median age 57 years, six women). The primary end points were patient and kidney allograft survival and recurrence of AL in the allograft. The secondary end point was kidney transplant rejection. Outcome data were stratified according to three treatment modalities: renal transplantation followed by autologous stem cell transplantation (ASCT) (Group 1, n = 8), ASCT followed by renal transplantation (Group 2, n = 6) and renal transplantation after complete remission achieved with nonmyeloablative therapy (Group 3, n = 5). RESULTS: The median follow-up was 41.4 months. At the time of study, 79% were still alive. Median graft survival did not differ from median overall survival. There was no difference in survival rates between the treatment groups. Five patients had a cellular rejection. Two of the three patients with a rejection in Group 1 died but neither patient with rejection in Groups 2 and 3. Recurrent amyloidosis was diagnosed by biopsy in one patient in Group 2 (preceding ASCT) and in another patient in Group 3. CONCLUSIONS: KTx can be successfully performed in AL patients in complete hematologic response and meet the usual KTx selection criteria. Outcomes appear similar whether hematologic response was achieved with ASCT or by nonmyeloablative therapy. PMID- 21543656 TI - The effect of bicarbonate peritoneal dialysis solutions on cardiac structural and functional alterations. AB - BACKGROUND: The systemic effects of absorbed glucose degradation products (GDPs) contained within the conventional peritoneal dialysis solutions (cPDS) are largely unknown, while they appear to affect also cardiovascular function. The aim of the present study was to evaluate if the new bicarbonate-based less bioincompatible new peritoneal dialysis solutions ameliorate cardiac structural and functional status as well as the peritoneal net ultrafiltration (UF) and residual renal function. Patients and methods. This is a single centre, prospective cohort study of 12 stable continues ambulatory peritoneal dialysis patients (four women, eight men) mean aged 71.3 +/- of 6.01 years and mean peritoneal dialysis (PD) duration 31.9 +/- 21.33 months, treated with the usual cPDS (Medital Bieffe(r), with increased GDPs, low pH and lactate as a buffer system). The patients changed for a 6-month period to the newer biocompatible PD solutions (BicaVera, Fresenius(r) low GDPs, normal pH, bicarbonate as a buffer) and at the end of this time, they returned to their previous schema of conventional solutions, for another 6 months. During the study period, the left ventricle ejection fraction (EF), left ventricle end systolic and diastolic diameter (LVESD, LVEDD), left ventricle mass index (LVMI), glyoxal serum and peritoneal concentrations, net UF and 24 h urine volume were repeatedly estimated: at the beginning of the study (T0), after 6 months with the biocompatible solutions (T6) and at the end of study (T12), after the 6-month period using again the cPDS. The UF volume and glyoxal concentrations were estimated at end of a 4 h dwell of an exchange with a PD solution of 2.27 % glucose. RESULTS: There was a statistically significant difference between the mean levels of EF, LVESD, LVEDD, LVMI, UF and glyoxal serum and peritoneal concentrations at the beginning (T0) and in the middle of the study (T6) (for serum glyoxal P = 0.005, for peritoneal glyoxal P = 0.0004, for EF P = 0.0004, for LVESD P = 0.023, for LVEDD P = 0.002, for LVMI P = 0.0005 and for UF P = 0.005) as well as between the mean values in the middle (T6) and at the end of the evaluation period (T12) (for serum glyoxal P = 0.043, for peritoneal glyoxal P = 0.006, for EF P = 0.00009, for LVESD P = 0.012, for LVEDD P = 0.00014, for LVMI P = 0.00013 and for UF P = 0.048). On the other hand, no statistically significant difference was revealed between the T0 and T12 mean values of glyoxal (serum and peritoneal), EF, LVESD, LVEDD, LVMI and UF. During the study period, there was no statistically significant difference in daily urine volume and glomerular filtration rate. CONCLUSIONS: The use of bicarbonate-based PDS induced a statistically significant improvement of left ventricle structure (LVESD, LVEDD and LVMI) and functional (EF) indicators. These beneficial effects on left ventricle in combination with the improvement of net UF may designate a protective role of the newer bicarbonate peritoneal solutions on cardiovascular function morbidity and mortality risk of PD patients. PMID- 21543657 TI - Erythropoietic response to erythropoiesis-stimulating agents and outcome: should we give up the haemoglobin target approach? PMID- 21543658 TI - The potential roles of FGF23 and Klotho in the prognosis of renal and cardiovascular diseases. AB - Fibroblast growth factor (FGF) 23 and Klotho are two factors associated with several metabolic disorders. Similar to humans, accelerated aging processes characterized by chronic vascular disease, bone demineralization, skin atrophy and emphysema have been recognized in FGF23-null mice and Klotho-deficient mice. The role of these factors in the control of mineral metabolism homeostasis have been shown recently, particularly at the level of parathyroid cells and also in modulating active vitamin D production, two phenomena which are relevant in the presence of chronic kidney disease. In addition, the hormonal affect of circulating FGF23 and Klotho proteins on vascular reactivity, either directly on endothelial cell functions or indirectly by modulating the brain endothelin-1 dependent sympathetic nervous system activity, has contributed to understanding their role in the pathophysiology of hypertension and atherosclerotic vasculopathies. Consequently, very recent clinical investigations seem to confirm the involvement of Klotho in modulating the severity and prognosis of human cardiovascular (CV) disorders and longevity. The present review reports data related to the possible interactive effects of Klotho and FGF23 on the prognosis of renal and CV diseases. PMID- 21543659 TI - Acute kidney injury in hospitalized HIV-infected patients: a cohort analysis. AB - BACKGROUND: Acute kidney injury (AKI) in hospitalized human immunodeficiency virus (HIV)-infected patients in the highly active antiretroviral therapy (HAART) era has not been extensively addressed. The aim of the present study was to analyze the incidence, etiology, risk factors and the impact of AKI on in hospital mortality in this population. METHODS: A total of 489 HIV-infected patients hospitalized in the Department of Infectious Diseases of the Hospital de Santa Maria (Lisbon, Portugal) between January 2005 and December 2007 were retrospectively studied. AKI was defined by 'Risk Injury Failure Loss of kidney function End-stage kidney disease'(RIFLE) criteria based on serum creatinine. Comparisons between patients with and without AKI were performed using the Student's t-test or the chi2 test. Logistic regression method was used to determine predictors of AKI and in-hospital mortality. A two-tailed P-value <0.05 was considered significant. RESULTS: Eighty-eight patients (18%) had AKI within the hospitalization period. The most common etiologies of AKI were sepsis (59%), nephrotoxic drug administration (37.5%), volume depletion (21.6%) and radiocontrast use (20.5%). Preexisting hypertension [adjusted odds ratio (OR) 2.4, 95% confidence interval (CI) 1.04-5.6, P = 0.04], acquired immunodeficiency syndrome (adjusted OR 2.7, 95% CI 1.2-6, P = 0.02), sepsis (adjusted OR 23, 95% CI 11-45.3, P < 0.001) and nephrotoxic drug administration (adjusted OR 2.8, 95% CI 1.4-5.8, P = 0.004) were risk factors of AKI. Patients with AKI had higher in hospital mortality than patients without AKI (27.3 versus 8%, P < 0.001). In multivariate analysis, AKI was a risk factor of in-hospital mortality (adjusted OR 2.7, 95% CI 1.3-5.6, P = 0.008). CONCLUSION: AKI occurred in 18% of hospitalized HIV-infected patients and it was independently associated with increased in-hospital mortality. PMID- 21543660 TI - Impact of vitamin A on clinical outcomes in haemodialysis patients. AB - BACKGROUND: Patients on maintenance haemodialysis treatment experience an excessive risk of cardiovascular disease and mortality. The vitamin A concentration is known to be higher in these patients compared to the general population where elevated vitamin A concentrations are associated with adverse outcome. The impact of vitamin A on morbidity and mortality in end-stage renal disease patients is controversial and is the topic of this study. METHODS: We analysed plasma retinol and retinol-binding protein 4 (RBP4) in 1177 diabetic haemodialysis patients, who participated in the German Diabetes and Dialysis Study (median follow-up 4 years). By Cox regression analyses hazard ratios (HRs) were determined for pre-specified, adjudicated end points according to baseline concentrations. RESULTS: Patients had a mean age of 66 +/- 8 years, mean retinol and RBP4 concentrations of 3.28 (0.71-7.44) and 4.02 (1.28-10.1) MUmol/L, respectively. Patients with retinol concentrations in the first quartile (<2.6 MUmol/L) had an almost 2-fold increased risk of all-cause mortality compared to patients of the fourth quartile [>3.9 MUmol/L; HR 1.81, 95% confidence interval (CI) 1.43-2.30]. There was a strong association between low retinol and the risk of sudden cardiac death (SCD, HR 2.22, 95% CI 1.41-3.50) and fatal infection (HR 2.19, 95% CI 1.26-3.82). Patients with RBP4 concentrations in the lowest quartile (<3.0 MUmol/L) were more likely to die of any cause (HR 1.43, 95% CI 1.14-1.80), experience SCD (HR 1.97, 95% CI 1.28-3.03) and cardiovascular events (HR 1.43, 95% CI 1.10-1.85). CONCLUSION: This large cohort study shows a strong association of low retinol and RBP4 concentrations with SCD and all-cause mortality in diabetic haemodialysis patients. PMID- 21543661 TI - More may be less: increasing extracorporeal blood flow in an axillary arterio arterial access decreases effective clearance. AB - Axillary arterio-arterial graft interposition has been described as a reasonable haemodialysis access in selected patients. In a patient with this unusual access, we measured and calculated effective clearance at different extracorporeal blood flows (Q(b)). Effective clearance increased with increasing blood flow and reached a maximum at a Q(b) of ~200 mL/min but then decreased when Q(b) was increased further. As this type of access typically provides low access flow, one has to be aware that local recirculation will easily occur. Therefore, a Q(b) above access flow has to be avoided since any increase beyond that threshold reduces effective clearance. PMID- 21543662 TI - Pharmacokinetics, safety, and tolerability of atomoxetine and effect of CYP2D6*10/*10 genotype in healthy Japanese men. AB - Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration-time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant. PMID- 21543663 TI - SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitus. AB - The incidence of type 2 diabetes mellitus is increasing worldwide. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin-independent manner. Dapagliflozin, the most prominent molecule in this class, is currently in a phase III clinical trial. Other members of this class (eg, sergliflozin, remogliflozin) are also in different phases of clinical trials. This class of novel agents can effectively control blood sugar level without producing weight gain or hypoglycemia. Results of ongoing phase III clinical trials are crucial to determine whether the risk-benefit ratio will allow approval of this new class of drugs for the management of type 2 diabetes mellitus. PMID- 21543664 TI - Application of the optimal design approach to improve a pretransplant drug dose finding design for ciclosporin. AB - A time and sampling intensive pretransplant test dose design was to be reduced, but at the same time optimized so that there was no loss in the precision of predicting the individual pharmacokinetic (PK) estimates of posttransplant dosing. The following variables were optimized simultaneously: sampling times, ciclosporin dose, time of second dose, infusion duration, and administration order, using a published ciclosporin population PK model as prior information. The original design was reduced from 22 samples to 6 samples/patient and both doses (intravenous oral) were administered within 8 hours. Compared with the prior information given by the published ciclosporin population PK model, the expected standard deviations (SDs) of the individual parameters for clearance and bioavailability could be reduced by, on average, 40% under the optimized sparse designs. The gain of performing the original rich design compared with the optimal reduced design, considering the standard errors of the parameter estimates, was found to be minimal. This application demonstrates, in a practical clinical scenario, how optimal design techniques may be used to improve diagnostic procedures given available software and methods. PMID- 21543665 TI - Familial dystopic os odontoideum: a report of three cases. PMID- 21543666 TI - Aneurysmal bone cysts of soft tissue represent true neoplasms: a report of two cases. PMID- 21543667 TI - Multifocal osteomyelitis with Streptococcus pneumoniae in a patient with Waldenstrom macroglobulinemia: a case report. PMID- 21543668 TI - Femoral neck fracture after arthroscopic management of femoroacetabular impingement: a case report. PMID- 21543669 TI - Early versus delayed reconstruction of the anterior cruciate ligament: a decision analysis approach. AB - BACKGROUND: A recent randomized controlled trial compared early anterior cruciate ligament reconstruction with a program of initial rehabilitation, with delayed anterior cruciate ligament reconstruction if needed. The authors reported that the improvement in Knee Injury and Osteoarthritis Outcome Scores was nearly identical in both groups and concluded that in young, active adults with acute ACL (anterior cruciate ligament) tears, a strategy of rehabilitation plus early ACL reconstruction was not superior to a strategy of rehabilitation plus optional delayed ACL reconstruction. Yet, in making that assessment, the authors did not account for the fact that there were more meniscal injuries in the group with delayed anterior cruciate ligament surgery. Establishing the true superiority of one strategy requires consideration of meniscal injury, as well as a further determination if the apparent protective effect regarding meniscal tears found in the cohort of patients with early anterior cruciate ligament reconstruction is offset by the costs of additional reconstructive surgery. That analysis of offsetting utility, omitted in the randomized controlled trial noted above, is provided in the present study. METHODS: A decision analysis model considering the options and probabilities described in the randomized controlled trial was constructed: the functional outcome of all groups was assumed to be equal, the likelihood of a patient eventually needing surgery despite initially choosing a program of rehabilitation was 37%, and the likelihood of needing a meniscectomy was 23% for the early surgery group and 35% for the rehabilitation and deferred anterior cruciate ligament reconstruction group. RESULTS: The early surgery option is the preferable therapeutic approach as long as the costs of a potential meniscal tear are at least 5.25 times the costs of reconstructive surgery. CONCLUSIONS: Early surgery for anterior cruciate ligament tears may be the preferred approach for some patients, on the basis of the utility values they assign to the possible treatment outcomes. The reported randomized controlled trial did not establish a dominant strategy. Indeed, early surgery may be the more effective approach overall. PMID- 21543670 TI - An analysis of the musculoskeletal trauma section of the Orthopaedic In-Training Examination (OITE). PMID- 21543671 TI - Clinical comparisons of the anatomical reconstruction and modified biceps rerouting technique for chronic posterolateral instability combined with posterior cruciate ligament reconstruction. AB - BACKGROUND: The purpose of this study was to describe a one-stage operation for posterior cruciate ligament reconstruction with use of an Achilles tendon-bone allograft and a posterolateral corner reconstruction with use of two different methods, with a comparison of clinical outcomes in the two groups. METHODS: Our study included forty-six patients who had undergone posterior cruciate ligament reconstruction with use of an Achilles tendon-bone allograft and posterolateral corner reconstruction with either anatomical reconstruction of the lateral collateral ligament and popliteus tendon with use of a tibialis posterior tendon allograft (twenty-one patients; Group A) or the modified biceps rerouting tenodesis (twenty-five patients; Group B) in an alternating fashion. Patients were assessed for knee instability with use of the dial test at 30 degrees and 90 degrees , together with varus and posterior stress radiography. RESULTS: At the two-year follow-up evaluation, although no significant difference was found on posterior stress radiography (mean and standard error, 5.7 +/- 0.4 mm for Group A compared with 4.8 +/- 0.4 mm for Group B), Group A showed more improvement than Group B on the dial test (16 degrees +/- 1 degrees vs. 13 degrees +/- 1 degrees at 30 degrees and 17 degrees +/- 1 degrees vs. 14 degrees +/- 1 degrees at 90 degrees ; p = 0.001 for both) and varus stress radiography (3.6 +/- 0.3 mm vs. 2.6 +/- 0.3 mm; p = 0.024), in the Lysholm (29.5 +/- 2.4 vs. 22.3 +/- 2.3; p = 0.037) and the International Knee Documentation Committee knee scores (p = 0.041), and less terminal flexion loss (4.0 degrees +/- 1.2 degrees vs. 8.8 degrees +/- 1.3 degrees ; p = 0.013). CONCLUSIONS: Combined with posterior cruciate ligament reconstruction, anatomical posterolateral corner reconstruction of the popliteus tendon and lateral collateral ligament showed better outcomes compared with the modified biceps rerouting tenodesis, although the mean differences of varus and external rotatory stability between the groups were relatively small. However, the overall difference might have been reduced by the negative value caused by overcorrection in Group B. This study demonstrated that anatomical posterolateral corner reconstruction is a reliable alternative method in addressing posterolateral corner and posterior cruciate ligament insufficiency of the knee, a finding that ideally should be tested in a randomized controlled trial. PMID- 21543672 TI - Comparison of nerve transfers and nerve grafting for traumatic upper plexus palsy: a systematic review and analysis. AB - BACKGROUND: In treating patients with brachial plexus injury, there are no comparative data on the outcomes of nerve grafts or nerve transfers for isolated upper trunk or C5-C6-C7 root injuries. The purpose of our study was to compare, with systematic review, the outcomes for modern intraplexal nerve transfers for shoulder and elbow function with autogenous nerve grafting for upper brachial plexus traumatic injuries. METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for studies in which patients had surgery for traumatic upper brachial plexus palsy within one year of injury and with a minimum follow-up of twelve months. Strength and shoulder and elbow motion were assessed as outcome measures. The Fisher exact test and Mann-Whitney U test were used to compare outcomes, with an alpha level of 0.05. RESULTS: Thirty-one studies met the inclusion criteria. Two hundred and forty-seven (83%) and 286 (96%) of 299 patients with nerve transfers achieved elbow flexion strength of grade M4 or greater and M3 or greater, respectively, compared with thirty-two (56%) and forty-seven (82%) of fifty-seven patients with nerve grafts (p < 0.05). Forty (74%) of fifty-four patients with dual nerve transfers for shoulder function had shoulder abduction strength of grade M4 or greater compared with twenty (35%) of fifty-seven patients with nerve transfer to a single nerve and thirteen (46%) of twenty-eight patients with nerve grafts (p < 0.05). The average shoulder abduction and external rotation was 122 degrees (range, 45 degrees to 170 degrees ) and 108 degrees (range, 60 degrees to 140 degrees ) after dual nerve transfers and 50 degrees (range, 0 degrees to 100 degrees ) and 45 degrees (range, 0 degrees to 140 degrees ) in patients with nerve transfers to a single nerve. CONCLUSIONS: In patients with demonstrated complete traumatic upper brachial plexus injuries of C5-C6, the pooled international data strongly favors dual nerve transfer over traditional nerve grafting for restoration of improved shoulder and elbow function. These data may be helpful to surgeons considering intraoperative options, particularly in cases in which the native nerve root or trunk may appear less than optimal, or when long nerve grafts are contemplated. PMID- 21543673 TI - Bioactive coating of titanium surfaces with recombinant human beta-defensin-2 (rHubetaD2) may prevent bacterial colonization in orthopaedic surgery. AB - BACKGROUND: A promising strategy to prevent infections around orthopaedic titanium implants is to use naturally occurring cationic antimicrobial peptides (CAMPs) such as the human beta-defensin-2 as antibacterial coatings. Human antimicrobial peptides represent a part of the innate immune system and have a broad antimicrobial spectrum against bacteria, fungi, and viruses. METHODS: In the present study, titanium surfaces were functionalized by four different self assembled monolayers (SAMs) forming methoxy silanes: (1) hexadecyltrimethoxysilane, (2) dimethoxymethyloctylsilane, (3) allyltrimethylsilane, and (4) 3-aminopropyltrimethoxysilane. In addition, calf skin type-I collagen was cross-linked to the SAM surface 3 aminopropyltrimethoxysilane by means of two different treatments: (1) N hydroxysuccinimide and (2) glutaraldehyde. The functionalized titanium surfaces were coated with recombinant human beta-defensin-2 (rHubetaD2), an antimicrobial peptide, and were tested for antibacterial activity against Escherichia coli. The release of rHubetaD2 was quantified by means of enzyme-linked immunosorbent assay (ELISA). RESULTS: The coating of functionalized titanium surfaces with rHubetaD2 was successful. Recombinant HubetaD2 was eluted from the titanium surfaces continuously, yielding antimicrobial activity up to several hours. Antimicrobial activity with a killing rate of 100% was observed for all functionalized titanium surfaces after two hours of incubation. The dimethoxymethyloctylsilane functionalized titanium surface delivered 0.65 MUg of rHubetaD2 after six hours with a 60% bacterial killing rate. The silane-functionalized surfaces exhibited a faster release of antimicrobially active rHubetaD2 compared with collagen modifications. CONCLUSIONS: Natural antibiotics such as rHubetaD2 integrated into the metal surface of titanium implants may be a promising tool to prevent and control infections around orthopaedic implants. PMID- 21543674 TI - Incidence of symptomatic venous thromboembolism in oncologic patients undergoing lower-extremity endoprosthetic arthroplasty. AB - BACKGROUND: As both cancer and major orthopaedic surgery are risk factors for venous thromboembolism, patients undergoing lower-extremity oncologic endoprosthetic arthroplasty for neoplastic processes are at substantial risk of the development of symptomatic venous thromboembolism. Therefore, the primary purpose of this study was to determine the incidence of symptomatic venous thromboembolism in patients undergoing lower-extremity oncologic endoprosthetic arthroplasty. Secondary purposes were to assess whether chemoprophylaxis influenced the incidence of venous thromboembolism, surgical complications, or the incidence of local sarcoma recurrence. We also sought to determine whether any known risk factors for venous thromboembolism could be identified in this patient population. METHODS: We performed a retrospective comparative review of 423 patients who had undergone mega-endoprosthetic reconstruction following cancer resection. Univariate analysis was used to assess the association between chemoprophylaxis and the incidence of venous thromboembolism, to postulate the surgical complications associated with chemoprophylaxis, and to assess the rate of recurrence of local sarcoma as well the association between risk factors and venous thromboembolism. RESULTS: Seventeen patients (4.0%) (95% confidence interval: 2.5% to 6.3%) had a venous thromboembolic event, ten with deep venous thrombosis and seven with nonfatal pulmonary embolism. Risk factors and chemoprophylactic regimens were not statistically associated with the occurrence of venous thromboembolism. CONCLUSIONS: The incidence of symptomatic venous thromboembolism in our group of cancer patients who underwent lower-extremity endoprosthetic arthroplasty was lower than anticipated. A significant difference was not identified between the use of any or no chemoprophylactic agent and the incidence of venous thromboembolism or complication rates. No risk factors were associated with the incidence of symptomatic venous thromboembolism. PMID- 21543675 TI - Modified carpal stretch test as a screening test for detection of scapholunate interosseous ligament injuries associated with distal radial fractures. AB - BACKGROUND: Intra-articular distal radial fractures are frequently accompanied by a scapholunate interosseous ligament injury, which may adversely affect the outcomes. Arthroscopy may not be appropriate as a first-line evaluation method to diagnose these injuries because of time, expense, and availability issues. The purpose of this study was to evaluate the effectiveness of the modified carpal stretch test for screening for scapholunate interosseous ligament injuries in patients with an intra-articular distal radial fracture. METHODS: The carpal stretch test is a radiographic evaluation in which disruption of the smooth arc of the proximal carpal row joint line indicates a lack of integrity of the scapholunate interosseous ligament. We modified the original carpal stretch test and prospectively performed the modified test on forty-eight patients with a total of forty-nine unstable intra-articular distal radial fractures. With the patient under anesthesia, the injured wrist was evaluated with the modified carpal stretch test with fluoroscopy. The wrist was then examined arthroscopically to classify the scapholunate interosseous ligament injury. Three observers independently determined whether there was disruption of the proximal carpal row joint line (Gilula's arc II), used as an indicator of a grade-III or IV scapholunate interosseous ligament tear, on fluoroscopic images. The fluoroscopic results were compared with the arthroscopic findings. RESULTS: The average sensitivity of the modified carpal stretch test was 78%, the average specificity was 72%, the average positive predictive value was 60%, the average negative predictive value was 87%, and the average accuracy was 74%. The intraclass correlation coefficient (ICC) for interobserver agreement was 0.73, and the ICCs for intraobserver agreement were 0.86, 0.68, and 0.84 for the three observers. CONCLUSIONS: The modified carpal stretch test was useful to rule out grade-III or IV scapholunate interosseous ligament tears associated with intra articular distal radial fractures, but it was not as useful to confirm the presence of a tear. This test may reduce the necessity for arthroscopic assessment to identify scapholunate interosseous ligament injuries following distal radial fractures and may improve the rates of detection of important carpal ligament injuries accompanying intra-articular distal radial fractures. PMID- 21543676 TI - Provision of orthopaedic workforce and implications for access to orthopaedic services in Ontario. AB - BACKGROUND: The aging population and increasing obesity rates will increase the prevalence of musculoskeletal conditions. Reports of orthopaedic surgeon shortages raise concerns about the ability of the health-care system to meet current and future demand in orthopaedics. A survey of all orthopaedic surgeons in Ontario, Canada, was carried out in 2006 to (1) update provision estimates of orthopaedic surgeons; (2) examine practice characteristics and perceived barriers to service; and (3) relate geographic availability of surgeons to population utilization of office-based and surgical orthopaedic services. METHODS: A two part questionnaire was sent to all orthopaedic surgeons in Ontario in 2006. Provision data in hours per week and full-time equivalents and practice patterns were analyzed by health region. Population-based data on the use of orthopaedic services were obtained from health service administrative databases. RESULTS: There were 396 practicing orthopaedic surgeons in Ontario in 2006, equivalent to 2.43 full-time equivalents per 100,000 population, a finding similar to surveys in 1997 and 2000. Most surgeons were male, with a mean age of forty-nine years, with mainly adult practices; 48% reported having a subspecialty. Provision varied across Ontario, with an average of 112 hours per week of direct clinical time per 100,000 population (50% in the office, 30% in the operating room, 20% working on call). Many surgeons also reported time for administration, teaching, and research. Most respondents reported barriers to timely surgery, notably a lack of resources (operating room time, anesthesia, nursing, and/or bed capacity). Low orthopaedic provision was associated with lower utilization of office-based and surgical services, after controlling for neighborhood income and type of residence (urban or rural). CONCLUSIONS: Shortages and geographic variation in the supply of surgeons mean that access to care continues to be a challenge in Ontario. In regions with fewer surgeons, residents are more likely to be deprived of office-based services, potentially affecting access to surgery and to orthopaedic expertise. In light of a potential shortage of surgeons, alternative methods of service provision may be needed to respond to the aging of the baby boomer population and an anticipated growth in the demand for surgery. PMID- 21543677 TI - Recovery of elbow motion following pediatric lateral condylar fractures of the humerus. AB - BACKGROUND: Temporary elbow stiffness is often seen after a lateral condylar fracture of the distal end of the humerus in children. There are scant scientific data available to assess the expected time frame for return of elbow motion after these injuries. The purpose of this study is to provide a prospective, longitudinal evaluation of elbow motion in a large group of pediatric patients undergoing treatment for a lateral condylar fracture of the distal end of the humerus. METHODS: We prospectively evaluated 141 patients with lateral humeral condylar fractures at a mean age of 5.2 years and with a mean follow-up of twenty nine weeks. The patients were treated with cast immobilization, percutaneous pinning, or open reduction and internal fixation on the basis of the initial displacement. Elbow motion was followed longitudinally at clinic visits. Relative arc of motion was calculated as a percentage of the motion of the normal, contralateral elbow. RESULTS: The mean relative arc of motion at the time of cast removal was 44%, reaching 84% by week 12. By weeks 18, 24, 36, and 48, the relative arc of motion reached 87%, 90%, 93%, and 97%, respectively. Compared with fractures treated without surgery, those treated surgically had a significantly lower absolute arc of motion from the time of cast removal (p = 0.018) and up to eighteen weeks after the injury (p < 0.001); however, no significant difference was observed at eighteen weeks or beyond. For patients treated surgically, no significant difference in relative arc of motion was observed between the patients with closed or open reductions. The age of the patient (hazard ratio = 0.87, p = 0.008), length of immobilization (hazard ratio = 0.79, p = 0.03), and severity of the fracture (hazard ratio = 0.40, p < 0.0001) were independent predictors of recovery of elbow motion after a lateral humeral condylar fracture in children. CONCLUSIONS: An initial rapid recovery in elbow motion can be expected after a lateral humeral condylar fracture in a child, with progressive improvements for up to one year after the injury. This recovery is slower if the patient is older, has a longer period of immobilization, and has a more severe injury. PMID- 21543678 TI - Rotaglide total knee arthroplasty: a long-term follow-up study. AB - BACKGROUND: Mobile-bearing knee designs represent an alternative to conventional fixed-bearing implants in total knee arthroplasty. The purpose of this study was to determine the clinical results of a mobile-bearing knee implant. METHODS: From 1990 to 1998, 326 primary consecutive mobile-bearing total knee prostheses were implanted in 260 patients who had a mean age and standard deviation of 66.7 +/- 6.9 years. Femoral and tibial components were cemented in all knees, and the patella was resurfaced in 199 knees (61%). Patients were evaluated with the use of the Knee Society clinical rating system and radiographic examinations. Complications were noted, and survivorship of the prostheses was determined. RESULTS: The mean follow-up period was 156 +/- 27.3 months, with maximum follow up at eighteen years. The mean Knee Society knee score improved from 32.4 +/- 21.2 preoperatively to 92.6 +/- 10.0 at the time of the last follow-up (p = 0.00), and the mean Knee Society functional score improved from 39.3 +/- 18.7 preoperatively to 66.7 +/- 18.6 at the time of the last follow-up (p = 0.00). Mean knee flexion improved from 92.3 degrees +/- 14.5 degrees preoperatively to 112.1 degrees +/- 13.4 degrees at the time of the last follow-up (p = 0.00). There were twenty-four (7.4%) knees that required revision. In eighteen (5.5%) knees, worn out or broken polyethylene was found and a polyethylene-only exchange was done. Six knees (1.8%) were fully revised. The survival rate was 0.96 (95% confidence interval, 0.93 to 0.98) at ten years and 0.87 (95% confidence interval, 0.79 to 0.93) at eighteen years. CONCLUSIONS: A fully congruent, mobile bearing total knee prosthesis had excellent survivorship during the ten to eighteen-year follow-up interval. PMID- 21543679 TI - Management of glenohumeral arthritis in the young adult. AB - The majority of cases of glenohumeral arthritis in older adults are primary osteoarthritis and treatment algorithms are well defined, with shoulder arthroplasty providing reliable pain relief and functional improvement of satisfactorily duration. In younger adults, however, diagnoses are more complex and arthroplasty outcomes are less durable. Arthroscopy may be useful both as a diagnostic tool for characterizing lesions and as a therapeutic tool for debridement. Arthroscopic debridement is most likely to benefit patients with mild glenohumeral arthritis, small lesions, and involvement of only one side of the glenohumeral joint. Reconstruction of the humeral joint surface may consist of cartilage repair or reconstruction, resurfacing arthroplasty, or arthroplasty with a stemmed component. Patients treated with hemiarthroplasty avoid glenoid implant loosening, but the procedure provides less predictable pain relief than does total shoulder arthroplasty and may lead to increased postoperative glenoid erosion. PMID- 21543681 TI - Radiographic structural abnormalities associated with premature, natural hip joint failure. AB - BACKGROUND: Significant controversy exists regarding the causes of premature, natural hip-joint failure. Identification of these causes may guide future investigations targeting prevention of this disorder. The aims of this study were to: (1) determine and characterize structural abnormalities associated with premature, natural hip-joint failure, and (2) analyze disease progression in the contralateral hips of patients with femoroacetabular impingement deformities. METHODS: We analyzed 604 patients (710 hips) from three different medical centers who underwent primary total hip arthroplasty at or before fifty years of age (average age, forty years). Three hundred fourteen patients (52%) were male, and 290 patients (48%) were female. RESULTS: The diagnoses associated with premature hip failure varied, but osteoarthritis and osteonecrosis were most common. Radiographic abnormalities associated with developmental hip dysplasia and femoroacetabular impingement were associated with the majority of osteoarthritic hips. Hips with femoroacetabular impingement deformities demonstrated distinct structural anatomy relative to asymptomatic hips, with a high prevalence of bilateral deformities. In a subgroup of seventy patients with femoroacetabular impingement deformities, contralateral radiographic disease progression or the need for total hip arthroplasty was observed in 73% of hips. CONCLUSIONS: Osteoarthritis and osteonecrosis are the major causes of premature hip-joint failure in young patients. Femoroacetabular impingement abnormalities are usually bilateral and are commonly associated with progression of the disease to the contralateral hip. PMID- 21543682 TI - Bone apposition of the acetabular rim in deep hips: a distinct finding of global pincer impingement. AB - BACKGROUND: Hips with coxa profunda can develop a pincer-type impingement with linear impact between the proximal part of the femur and the acetabulum, leading to bone apposition on the acetabular rim. METHODS: Twenty hips with radiographic features of rim ossification were isolated from a pilot cohort of 220 patients for histologic assessment of the acetabular rim and the labrum. In the second part of the study, the prevalence of radiographic signs of bone apposition in a cohort of 148 hips treated for femoroacetabular impingement was assessed. RESULTS: Histologic analysis confirmed that the labrum may become displaced and replaced by the appositional bone formation. The double-line sign and the recess sign are suggestive of an ongoing process of this bone formation, and the described phenotypes of bone apposition indicate the site of the impingement problem. Morphological anomalies of the proximal part of the femur, such as a low neck-shaft angle or a short femoral neck, may further contribute to the mechanism of pincer impingement. CONCLUSIONS: In later stages, this bone formation cannot be distinguished from the native bone and the labrum may appear to be nearly absent on imaging studies. While the bone apposition on the rim is first reactive to chronic impingement, the impingement then increases and may lead to further bone apposition. PMID- 21543683 TI - Clinical presentation of symptomatic acetabular dysplasia in skeletally mature patients. AB - BACKGROUND: Acetabular dysplasia is recognized as a cause of early degenerative hip osteoarthritis. The purpose of this study was to prospectively determine the early clinical presentation of symptomatic acetabular dysplasia in skeletally mature patients. METHODS: Fifty-seven consecutive skeletally mature patients with a total of sixty-five symptomatic hips were diagnosed with symptomatic acetabular dysplasia on the basis of the history, physical examination, and radiographs. These fifty-seven patients were enrolled in this study and were followed prospectively for a minimum of twenty-four months postoperatively. RESULTS: The study group included forty-one female patients (72%) and sixteen male patients (28%) with a mean age of twenty-four years. All were treated with a periacetabular osteotomy and were followed for a minimum of twenty-four months. The initial presentation was insidious in 97% of the hips, and the majority (77%) of the hips were associated with moderate-to-severe pain on a daily basis. Pain was most commonly localized to the groin (72%) and/or the lateral aspect of the hip (66%). Activity-related hip pain was common (88%), and activity restriction frequently diminished hip pain (in 75% of the cases). On examination, thirty-one hips (48%) were associated with a limp; twenty-five (38%), with a positive Trendelenburg sign; and sixty-three (97%), with a positive impingement sign. The mean time from the onset of symptoms to the diagnosis of hip dysplasia was 61.5 months. The mean number of health-care providers seen prior to the definitive diagnosis was 3.3. The mean Harris hip score improved from 66.4 points preoperatively to 91.7 points at a mean of 29.2 months after the periacetabular osteotomy. CONCLUSIONS: The diagnosis of symptomatic acetabular dysplasia is commonly delayed, and procedures other than a pelvic reconstructive osteotomy are frequently recommended. The diagnosis of developmental dysplasia of the hip should be suspected and investigated when a skeletally mature, young, active patient has a predominant complaint of insidious activity-related groin pain and/or lateral hip pain. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions to Authors for a complete description of levels of evidence. PMID- 21543684 TI - The labro-acetabular complex. AB - The human hip is subjected to several hundred million loading cycles during a lifetime. Hip instability and femoro-acetabular impingement cause damage to the rim of the acetabulum. The acetabular rim is a highly specialized structure known as the labro-acetabular complex. A unidirectional flow of synovial fluid has been identified in this region. The synovial fluid circulation is driven by the bellows-like movement of the zona orbicularis and depends on hip flexion and extension. Surgical repair of the damaged labro-acetabular complex should satisfy two goals. First, the labrum should be preserved or reconstructed when possible. Second, the precipitating cause of the labro-acetabular damage must be addressed. PMID- 21543685 TI - Magnetic resonance imaging of acetabular labral tears. AB - The acetabular labrum plays an important role in hip biomechanical function and stability. Labral tears can result in appreciable clinical symptoms and joint dysfunction and may predispose the hip to chondral damage and osteoarthritis. Magnetic resonance imaging is an effective tool for detecting and characterizing labral tears. Direct magnetic resonance arthrography is the most commonly used and validated technique for evaluating the labrum. However, indirect magnetic resonance arthrography and non-arthrographic magnetic resonance imaging are two less invasive and less resource-intensive techniques that should also be considered. Orthopaedic surgeons and radiologists should strive to develop and implement minimally and noninvasive diagnostic magnetic resonance imaging protocols for the investigation of labral pathology. PMID- 21543686 TI - The Shenton line in the diagnosis of acetabular dysplasia in the skeletally mature patient. AB - BACKGROUND: Undetected developmental dysplasia of the hip can progress to hip instability, which can lead to the development of early osteoarthritis. The purpose of the present study was to determine the reliability and accuracy of the Shenton line in the diagnosis of acetabular dysplasia in the skeletally mature patient. METHODS: Supine anteroposterior pelvic radiographs were obtained for a total of 128 hips in patients with a diagnosis of developmental dysplasia of the hip prior to pelvic osteotomy (sixty-four hips, including thirty-two left and thirty-two right hips) and normal patients (sixty-four hips, including thirty-two left and thirty-two right hips). Six orthopaedic surgeons determined if the Shenton line was broken or intact to determine interobserver reliability. Four observers reviewed the randomized radiographs again after four weeks to determine intraobserver reliability. RESULTS: The mean intraclass kappa value was 0.90 (range, 0.79 to 0.97), indicating excellent agreement between each reviewer's primary and secondary reviews. The kappa estimate for interobserver reliability among all six reviewers was 0.80 (95% confidence interval, 0.75 to 0.84), indicating an excellent agreement. The determination of a normal or abnormal Shenton line had a mean sensitivity of 83.3% (range, 60.9% to 93.8%) and specificity of 98.4% (range, 92.2% to 100%). CONCLUSIONS: The Shenton line is a reliable and accurate radiographic marker to detect superior femoral head subluxation indicative of acetabular dysplasia. PMID- 21543687 TI - Preoperative and postoperative lower-extremity joint and pelvic kinematics during maximal squatting of patients with cam femoro-acetabular impingement. AB - BACKGROUND: Understanding how the function of the lower extremity joints during everyday movements following surgery to treat cam femoro-acetabular impingement is essential to assess whether surgical intervention effectively restores the normal biomechanics of the hip. The purpose of this study was to compare preoperative and postoperative lower-extremity joint and pelvic angular displacements during maximal depth squatting of patients with unilateral symptomatic cam femoro-acetabular impingement. METHODS: Ten participants were compared with respect to their preoperative and postoperative test results. The participants were between eighteen and fifty years of age and had a positive impingement test and visible cam deformity on anteroposterior and Dunn view radiographs. Postoperative testing for each participant occurred between eight and thirty-two months following surgical intervention. Three-dimensional lower limb joint and pelvic kinematics of participants were collected during maximal depth squats. RESULTS: Postoperatively, participants squatted to a greater mean maximal depth than they did preoperatively. Postoperative knee flexion and ankle dorsiflexion angles of the affected extremity at maximal depth were significantly greater than preoperative values. The postoperative sum of all joint angles of the affected limb at maximal squat depth was significantly larger than the preoperative sum. No significant differences were detected between the preoperative and postoperative measurements of the patients with cam impingement with respect to the kinematics of the affected hip at maximal squat depth, the pelvic angular displacements at maximal squat depth, or the overall pelvic range of motion during maximal deep squatting (p > 0.05). CONCLUSIONS: The squat performance improved postoperatively, likely because of the combined effects of increased knee and ankle angles as well as a greater acetabular opening and thus reduced anterior femoral head coverage, allowing increased posterior pelvic pitch during the descent phase of the squat. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence. PMID- 21543688 TI - In situ fixation for slipped capital femoral epiphysis: perspectives in 2011. AB - Slipped capital femoral epiphysis is usually treated with in situ fixation to prevent progression of deformity. However, slipped capital femoral epiphysis always is associated with structural risk factors for hip dysfunction in addition to the risk of slip progression. Femoro-acetabular impingement causes some mechanical abnormality in every hip affected by slipped capital femoral epiphysis, even when the slip is mild. The severity of femoro-acetabular impingement caused by slipped capital femoral epiphysis depends on several factors. Cumulative injury to the articular cartilage can result from impingement, and it is better to prevent this type of injury than to treat it later. In situ fixation alone rarely relieves femoro-acetabular impingement in slipped capital femoral epiphysis. Skillful and precise in situ fixation allows careful analysis of hip function in the stabilized slip by eliminating the major risk of acute instability. The more subtle risk of long-term articular damage caused by femoro-acetabular impingement must be considered. The treatment of femoro-acetabular impingement in patients who have slipped capital femoral epiphysis is a separate issue from instability of the proximal femoral physis. Femoro-acetabular impingement must be assessed in every hip that is affected by slipped capital femoral epiphysis, even when the deformity is mild. Several treatment options exist for treating femoro-acetabular impingement associated with slipped capital femoral epiphysis. PMID- 21543689 TI - Hip arthroscopy: analysis of a single surgeon's learning experience. AB - BACKGROUND: The aim of this study was to objectively quantify a surgeon's learning experience for hip arthroscopy. METHODS: We prospectively reviewed the first 100 hip arthroscopic procedures performed between 1999 and 2004 by a single experienced consultant orthopaedic surgeon. In the second part of the study, three groups of patients were sequentially analyzed: Group 1 included the first thirty patients treated by the surgeon; group 2, the sixty-first through ninetieth patients; and group 3, the 121st through 150th patients. The groups were compared with regard to the diagnosis, the duration of the central and peripheral compartment procedure, patient satisfaction, conversion to arthroplasty, and the nonarthritic hip score. RESULTS: There was a decrease in complications from the first thirty cases to the remaining seventy operations. There was an overall decrease in operative time over the 100 cases, representing a gradual learning process. A marked decrease in the operative time for central compartment arthroscopy was noted when we compared group 1 (mean, seventy minutes; range, forty-five to ninety-eight minutes), group 2 (mean, forty-eight minutes; range, twenty-six to fifty-nine minutes), and group 3 (mean, thirty seven minutes; range, eighteen to sixty-one minutes). The operative time for peripheral compartment arthroscopy also decreased from group 2 (mean, ninety-one minutes; range, sixty to 126 minutes) to group 3 (mean, forty-five minutes; range, thirty-six to sixty-two minutes). There was an overall decrease in operative time over the first 100 cases. No difference among groups was noted in the number of cases requiring a reoperation or conversion to arthroplasty. There was a higher complication rate in the first thirty cases. An increase in the nonarthritic hip scores was noted postoperatively in the two groups in which the preoperative score had been measured. The postoperative score improved from group 1 (mean, 69; range, 39 to 84) to group 2 (mean, 79; range, 58 to 92) to group 3 (mean, 86; range, 51 to 98). Patient satisfaction was highest in group 3. CONCLUSIONS: Hip arthroscopy is associated with high patient satisfaction and good short-term outcomes, but there is a learning curve that we estimate to be approximately thirty cases. PMID- 21543690 TI - Periacetabular osteotomy after failed hip arthroscopy for labral tears in patients with acetabular dysplasia. AB - BACKGROUND: Chronic mechanical overload of the acetabular rim may lead to acetabular labral disease in patients with hip dysplasia. Although arthroscopic debridement of the labrum may provide symptomatic relief, the underlying mechanical abnormality remains. There is little information regarding how the results of periacetabular osteotomy are affected by a prior primary treatment for labral disease in the presence of acetabular dysplasia. METHODS: In a retrospective matched-cohort study, seventeen patients who had arthroscopic labral debridement prior to periacetabular osteotomy (the arthroscopy group) were compared with a control group of thirty-four patients who did not undergo arthroscopic labral debridement prior to periacetabular osteotomy (the non arthroscopy group). Two control patients were randomly matched to each experimental patient from a pool of controls. Functional outcomes were assessed with use of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Failure of periacetabular osteotomy was defined as conversion to a total hip replacement. RESULTS: Changes in the preoperative and postoperative WOMAC scores of arthroscopy and non-arthroscopy patients were comparable, and the differences between the two treatment groups were not significant. We were unable to show a significant difference between the seventeen arthroscopy and thirty four non-arthroscopy patients with regard to the risk of having to undergo a total hip replacement. CONCLUSIONS: When arthroscopic labral debridement fails to improve symptoms in patients with labral disease secondary to acetabular dysplasia, periacetabular osteotomy may still be considered as a joint-preserving procedure that can achieve good functional results. PMID- 21543691 TI - Incidence of deep vein thrombosis and pulmonary embolus following periacetabular osteotomy. AB - BACKGROUND: Venous thromboembolism, a known complication of orthopaedic procedures, is thought to be more prevalent following hip surgery. Venous thromboembolism risk assessment and appropriate prophylaxis according to the American College of Chest Physicians guidelines has become the standard of care. However, it is accepted that venous thromboembolism prophylaxis is associated with potential adverse sequelae including hematoma, wound drainage, and infection. Little is known regarding the incidence of venous thromboembolism following periacetabular osteotomy and the necessity for and method of routine prophylaxis. METHODS: A total of 1067 periacetabular osteotomies performed at six North American centers utilizing different methods of prophylaxis against venous thromboembolism were analyzed for type of prophylaxis and incidence of clinically symptomatic venous thromboembolism. RESULTS: There were four cases of pulmonary embolus and seven cases of deep vein thrombosis. There were no reported deaths. The crude incidence of clinically symptomatic venous thromboembolism was 9.4 per 1000 procedures. CONCLUSIONS: The risk from chemoprophylaxis and the development of hematoma may be greater than the risk of clinically important venous thromboembolism in patients undergoing periacetabular osteotomy. PMID- 21543692 TI - Prevalence and impact of pain at the greater trochanter after open surgery for the treatment of femoro-acetabular impingement. AB - BACKGROUND: Femoro-acetabular impingement can cause pain and degenerative changes of the hip joint. Traditionally, surgical dislocation of the hip joint has been performed for correction of pathologic abnormalities in the proximal part of the femur and the acetabulum. Failures of surgical treatment are often related to postoperative pain in the groin or in the area of the greater trochanter, associated with this surgical approach. The aim of our study was to determine the prevalence and functional impact of pain at the greater trochanter after surgical dislocation of the hip. METHODS: Fifty consecutive patients in whom femoro acetabular impingement had been treated with surgical dislocation of the hip at our institution were seen for clinical and radiographic follow-up at one year. The Merle d'Aubigne score was calculated preoperatively and at the time of follow up. Pain in the groin or at the greater trochanter during activity and at rest was recorded. RESULTS: The mean Merle d'Aubigne score significantly improved from 14.4 points preoperatively to 17 points postoperatively. Preoperatively, eight patients (16%) had pain over the greater trochanter. At one year after surgery, twenty-three (46%) had such pain; these patients were primarily female (seventeen of the twenty-three). The mean Merle d'Aubigne score was 17.4 points for the patients without groin pain and 16.1 points for those with groin pain. The presence or absence of pain at the greater trochanter had no significant influence on the outcome, but groin pain was associated with inferior results. CONCLUSIONS: Tenderness or pain over the greater trochanter is frequent after osteotomy of the greater trochanter and has a distinct female predominance. However, it has no significant negative influence on outcome. This is in contrast to groin pain, which is associated with inferior results. PMID- 21543693 TI - Computer-assisted correction of cam-type femoroacetabular impingement: a Sawbones study. AB - BACKGROUND: Assessing the adequacy of bone resection when correcting cam-type femoroacetabular impingement can be difficult when the surgeon is inexperienced or when less-invasive arthroscopic surgical techniques are used. The primary purpose of the present study was to compare, using a Sawbones model, the results of computer-assisted navigated osteochondroplasty of the femoral neck junction with correction with use of femoral head spherometer gauges. The second objective was to compare the results of computer-assisted osteochondroplasty performed by surgeons who had varied experience with the procedure. METHODS: We calculated and compared the post-resection alpha angle in custom-molded Sawbones models with cam type impingement following both surgical techniques, performed by three surgeons with varied experience with the procedure. The alpha angle was measured at two positions (the three o'clock and one-thirty positions of the femoral head-neck junction) before and after resection. RESULTS: At the three o'clock position, there were no significant differences between the computer-navigation and spherometer groups (p = 0.83). There was undercorrection at the one-thirty position, with the median alpha angle being greater in the navigation group as compared with the spherometer group (71.0 compared with 58.6; p = 0.05). In the navigation group, there were no significant differences in the post-resection mean alpha angle among the three surgeons at either the one-thirty plane or the three o'clock plane. CONCLUSIONS: Navigation enabled the inexperienced surgeon to perform an equivalent amount of bone resection as the more experienced surgeons. However, all surgeons did not sufficiently resect the cam deformity as compared with the gold-standard open technique at the one-thirty position. PMID- 21543695 TI - Evolution in hip resurfacing design and contemporary experience with an uncemented device. AB - The concepts of surface replacement of the hip and metal-on-metal articulation date back to the 1930s, and recent hip resurfacing designs have been more successful than their predecessors. Experience with the Cormet device followed initial collaboration with Mr. Derek McMinn. Both hybrid implants (a cementless cup and a cemented head) and entirely cementless implants, inserted with use of a variety of surgical approaches, yielded good results, with the cementless option increasing in popularity. The indications for hip resurfacing have become better understood, with the procedure considered most suitable for young and middle-aged males with a high activity profile. In addition, revision surgery, if necessary, has been associated in most cases with bone and soft-tissue conservation. Caution should be exercised when treating small individuals (especially females) and individuals with accompanying diagnoses other than osteoarthritis (such as hip dysplasia), for whom other bone-conserving options may be more appropriate to avoid an adverse reaction to metal debris. Correct implant placement during hip resurfacing is of critical importance. PMID- 21543694 TI - New insights into wear and biological effects of metal-on-metal bearings. AB - BACKGROUND: Despite the renewed interest in metal-on-metal implants in the past two decades, the underlying wear mechanisms and biological effects are still not fully understood. METHODS: This paper first reviews the tribology of metal-on metal bearings, bringing new insights into the interaction of wear and corrosion, and putting the characteristics and the potential origin of wear particles in perspective with the proposed wear mechanisms. It then summarizes the current knowledge on the biological effects of particles and metal ions in relation to these wear mechanisms. RESULTS: Tribochemical reactions play an important role in the wear of metal-on-metal joints. The generated tribomaterial, which progressively forms by mechanical mixing of the uppermost nanocrystalline zone of the metal surface with proteins from the synovial fluid, governs the wear rate and influences the corrosive behavior of the bearing. Nanometer-sized wear particles may initially originate from the passivation layer covering the implant surface and then detach from this tribolayer. The inflammatory response observed surrounding metal-on-metal implants appears to be lower than that around metal-on polyethylene implants. However, metallic byproducts, which can complex with proteins, may lead to a T lymphocyte-mediated hypersensitivity response. CONCLUSIONS: The tribolayer appears to have beneficial effects on the wear rate. Much information has been gained on wear particle characteristics, but the exact mechanisms of particle detachment remain to be further elucidated. Excessive wear along with a hypersensitivity response may be at the origin of the early adverse tissue reactions that have been recently reported in some patients with metal-on metal implants. PMID- 21543696 TI - Unsatisfactory surgical learning curve with hip resurfacing. AB - BACKGROUND: Hip resurfacing is considered by many to be a conservative alternative to conventional total hip arthroplasty. There are advantages and drawbacks to any procedure, and there is a learning curve associated with the introduction of any new technology. The purpose of this study is to report the complication rate, types of complications, and outcomes of hip resurfacing during the early experience of two high-volume hip surgeons. METHODS: Seventy-three hip resurfacing procedures were performed in sixty-four patients between September 2006 and March 2009. These procedures represented 6% of all of the primary hip arthroplasty procedures performed by the two surgeons. RESULTS: After an average duration of follow-up of twenty-five months, there were six revisions--i.e., an early failure rate of 8%. These revisions were performed to treat two deep infections, two femoral neck fractures, one case of femoral implant loosening, and one failure of an acetabular implant. CONCLUSIONS: Because of a high early failure rate, we have reduced the utilization of hip resurfacing in our patients who are candidates for hip arthroplasty. PMID- 21543697 TI - Residual groin pain at a minimum of two years after metal-on-metal THA with a twenty-eight-millimeter femoral head, THA with a large-diameter femoral head, and hip resurfacing. AB - BACKGROUND: Groin pain may persist in up to 4.3% of patients after total hip arthroplasty and up to 18% of patients one year after hip resurfacing. The incidence of this problem after total hip arthroplasty with a large-diameter femoral head is unknown. METHODS: We analyzed the natural history of groin pain and its clinical consequences during the first two years after three types of hip arthroplasty. Data were collected prospectively on 279 patients. Eighty-five patients had a polyethylene sandwich metal-on-metal total hip arthroplasty with a 28-mm-diameter femoral head, 105 had hip resurfacing, and eighty-nine had a total hip arthroplasty with a large-diameter femoral head component with three other cup designs (forty-nine in this group had the same monoblock acetabular cup design as those who had hip resurfacing). RESULTS: At the twenty-four-month follow-up evaluation, seventy-seven patients (28%) reported at least one painful area around the hip and thirty-four patients (12.2%) had pain at more than one location. At three months, the incidence of groin discomfort was significantly increased in those who had hip resurfacing (30.5%) and in those who had total hip arthroplasty with a large-diameter femoral head (30%) compared with those who had total hip arthroplasty with a 28-mm femoral head (18.3%). This incidence decreased at two years (14.9%, 16.9%, and 12.9%, respectively). At twenty-four months postoperatively, eleven (four who had hip resurfacing, six who had total hip arthroplasty with the large-diameter head, and one who had total hip arthroplasty with the 28-mm head) of forty-one patients who had groin pain had not reported groin pain at previous follow-up evaluations. Of the forty-one patients reporting groin pain at the time of the last follow-up, twenty-three patients (56%) did not seek further evaluation or treatment, nine had revision surgery (22%), and the remaining nine patients thought the pain was substantial enough to warrant further evaluation and treatment. CONCLUSIONS: When the exact source of groin pain cannot be found after total hip arthroplasty, careful follow up should be done as local reactions to metal-on-metal implants and component loosening may take time to become apparent clinically or on imaging studies. PMID- 21543698 TI - Impingement between the acetabular cup and the femoral neck after hip resurfacing arthroplasty. AB - BACKGROUND: Loosening, femoral neck fracture, and metal ion release have been well documented after hip resurfacing arthroplasty, but impingement between the acetabular cup and the femoral neck has not. The goal of this study was to analyze radiographic findings that were presumed to represent impingement of the neck after hip resurfacing arthroplasty, and to describe the mechanism of impingement. METHODS: Of the 635 hips (579 patients) that underwent hip resurfacing arthroplasty between September 1998 and May 2008, forty hips (6.3%) with positive radiographic findings were available for this study. The mean age of the patients was 34.9 years and there were thirty-five men and five women. The average follow-up was sixty-eight months (twenty-four to 132 months). Radiographic evaluation included an analysis of neck-shaft angle, inclination of the acetabular cup, head-neck ratio, lateral protrusion of the cup, anterior protrusion of the cup, and stem angle to the axis of the femoral neck. RESULTS: Impingement between the acetabular cup and the femoral neck occurred in 6.3% of hips and appeared at an average of seven months after surgery. There was no further change two years postoperatively. The impingement findings did not correlate with the clinical outcome, but all instances of impingement were located in the lateral or anterolateral part of the femoral neck along the arc from the center of the femoral head to the lateral edge of the socket. No significant factors were found to be related to the occurrence of impingement. CONCLUSIONS: Femoral-neck impingement should be differentiated from notching, narrowing, stress-shielding, or osteolysis of the femoral neck. Although we found no significant factors to explain the impingement found in the hips in our study, it appears that repetitive extreme motion of the involved hip and malposition of the implants can cause impingement after hip resurfacing arthroplasty. PMID- 21543699 TI - Cobalt and chromium levels in blood and urine following hip resurfacing arthroplasty with the Conserve Plus implant. AB - BACKGROUND: The purpose of the present study was to determine cobalt and chromium ion levels in the blood and urine of patients in whom a modern-generation metal on-metal hip resurfacing device had been implanted. METHODS: A total of ninety seven patients with a Conserve Plus metal-on-metal hip resurfacing implant were followed prospectively for two years. Cobalt and chromium levels in erythrocytes, serum, and urine were measured preoperatively as well as three, six, twelve, and twenty-four months postoperatively. RESULTS: The median serum cobalt and chromium ion levels were 1.04 MUg/L (range, 0.31 to 7.42 MUg/L) and 2.00 MUg/L (range, 0.28 to 10.49 MUg/L), respectively, at one year after surgery and 1.08 MUg/L (range, 0.44 to 7.13 MUg/L) and 1.64 MUg/L (range, 0.47 to 10.95 MUg/L), respectively, at two years after surgery. The corresponding mean levels (and standard deviations) of serum cobalt and chromium were 1.68 +/- 1.66 MUg/L and 2.70 +/- 2.22 MUg/L, respectively, at one year after surgery and 1.79 +/- 1.66 MUg/L and 2.70 +/- 2.37 MUg/L, respectively, at two years after surgery. CONCLUSIONS: These levels compare favorably with other published ion results for metal-on-metal hip resurfacing and replacement implants. No pseudotumors or other adverse soft-tissue reactions were encountered in our study population. Further research is needed to determine the clinical importance of increased cobalt and chromium ion levels in serum and urine following metal-on-metal hip resurfacing. PMID- 21543700 TI - A survey on the prevalence of pseudotumors with metal-on-metal hip resurfacing in Canadian academic centers. AB - BACKGROUND: Metal-on-metal bearings for hip arthroplasty have been in clinical use for over twenty years with excellent clinical results reported worldwide. A small percentage (<1%) of patients have developed an inflammatory response, and a more severe inflammatory response termed pseudotumor has been more recently reported. The primary purpose of this study was to determine the prevalence of pseudotumor following metal-on-metal hip resurfacing in Canadian academic centers. METHODS: Nine of the fourteen centers that perform metal-on-metal hip resurfacings were surveyed. The number of metal-on-metal hip resurfacing arthroplasties performed at each center was determined, as was the number of patients who presented with a pseudotumor and subsequently required revision hip surgery between 2002 and December 2008. RESULTS: At the nine centers, 3432 hip resurfacing arthroplasties were performed; 76.9% of the patients were male, the mean age was 51.2 years (range, sixteen to eighty-three years), and the mean body mass index was 28.1 (range, 17 to 55). The mean length of follow-up was 3.4 years (range, two to nine years). A pseudotumor developed after four of the 3432 arthroplasties, for a prevalence of 0.10%. CONCLUSIONS: Although pseudotumors remain a concern after metal-on-metal hip resurfacing, the prevalence at short to midterm follow-up is very low in this multicenter survey. Continued close monitoring is required to determine what clinical factors are involved with the uncommon pseudotumor formation. PMID- 21543701 TI - A biomechanical comparison of epiphyseal versus metaphyseal fixed bone-conserving hip arthroplasty. AB - BACKGROUND: The Birmingham Mid-Head Resection (BMHR) is a bone-conserving, short stem alternative to hip resurfacing for patients with abnormal femoral head anatomy. METHODS: The current study examines whether a bone-preserving femoral component that is fixed into the femoral neck metaphysis provides a mechanical advantage in terms of resisting femoral neck fracture in comparison with a conventional hip resurfacing implant in a human cadaveric femoral model. RESULTS: Femora with a BMHR femoral component failed at an average of 23% less load than those prepared with a conventional hip resurfacing component (mean and standard deviation, 5434 +/- 2297 compared with 7012 +/- 2619 N; p < 0.001). CONCLUSIONS: An uncemented, metaphyseal fixed, bone-conserving femoral implant does not provide superior mechanical strength or increased resistance to femoral neck fracture in comparison with a conventional hip resurfacing arthroplasty. PMID- 21543702 TI - Comparison of whole-blood metal ion levels in four types of metal-on-metal large diameter femoral head total hip arthroplasty: the potential influence of the adapter sleeve. AB - BACKGROUND: Metal-on-metal bearings, as used in total hip arthroplasty prostheses that have a large-diameter femoral head, were proposed as an option for treating young and active patients with degenerative hip disorders. Despite the theoretical improved performance of large metal articulations with regard to wear, metal ion levels produced by total hip arthroplasty prostheses in which a large-diameter femoral head is used have not been thoroughly evaluated. METHODS: From 173 eligible patients, 144 patients were allocated to undergo a unilateral total hip arthroplasty with use of metal-on-metal components and a large-diameter femoral head. The purpose of this study was to compare the amount of metal ion release (chromium, cobalt, and titanium) from four different types of prostheses from four different implant manufacturers (Biomet, DePuy, Smith & Nephew, and Zimmer). RESULTS: For cobalt ion levels, a significant difference was found between the different types of total hip arthroplasty prostheses with a large diameter femoral head at three, six, twelve, and twenty-four months, but only in male patients or patients with a femoral head size of 50 mm or greater. The highest mean cobalt levels at all follow-up periods were observed with the Zimmer implant and the lowest with the Biomet implant. Titanium ion levels were highest in the Zimmer group at all follow-up periods, whereas no difference between groups was found for chromium. At the most recent follow-up, one hip was revised after the development of an adverse local tissue reaction. Of concern was the observation at the time of revision surgery of black metallic deposits inside the adapter sleeve and on the prosthetic femoral neck. CONCLUSIONS: This investigation revealed that metal ion release differs greatly between various total hip arthroplasty implants with a large-diameter femoral head. The sources of metal ion production are numerous, but it is hypothesized that wear and corrosion at the junction between the adapter sleeve and the femoral stem in some patients may be responsible for the elevated cobalt ion levels that were found in the Zimmer group. On the other hand, an adapter sleeve made of titanium, such as the one used with the Biomet large-diameter-head total hip arthroplasty, is an unlikely contributor to the release of cobalt ions. Current technology or design of some total hip arthroplasty systems that make use of a large-diameter femoral head may not yet allow the use of modular large heads with a metal-on-metal articulation, especially in young, active male patients whose activities generate high loads at the hip joint. Further research is needed to better understand the favorable design characteristics of modular junctions in metal-on-metal total hip arthroplasty implants that make use of large-diameter femoral heads. PMID- 21543703 TI - Cementless metal-on-metal versus ceramic-on-polyethylene hip arthroplasty in patients less than fifty years of age: a comparative study with twelve to fourteen-year follow-up. AB - BACKGROUND: We previously reported the outcomes of a case-control study, at a minimum of five years of follow-up, comparing metal-on-metal and ceramic-on polyethylene bearings for cementless primary hip arthroplasty in active patients below the age of fifty years. This report is an update on these groups after a minimum duration of follow-up of twelve years. METHODS: Thirty-nine metal-on metal cementless hip replacements with a 28-mm-diameter Metasul articulation were compared with a control group that included thirty-nine cementless ceramic-on polyethylene hip replacements performed with a 28-mm-diameter head. The Metasul group included thirty patients with a mean age of forty years (range, twenty three to forty-nine years), and the control group included thirty-two patients with a mean age of forty-one years (range, fifteen to forty-nine years). The groups were matched for age, activity level, preoperative Harris hip score, acetabular cup diameter, and indication for hip arthroplasty. All patients had a high level of activity, with 82% rated as grade IV or V according to the Devane scale. RESULTS: After a mean duration of follow-up of thirteen years (twelve to fourteen years), only one hip (3%) had asymptomatic acetabular osteolysis and no hip (0%) had been revised in the metal-on-metal group, whereas eighteen hips (46%) had osteolysis and eleven hips (28%) had been revised because of wear or osteolysis in the ceramic-on-polyethylene group (p < 0.003). In the metal-on metal group, the median Co concentration in the whole blood was 0.95 MUg/L (0.4 to 4.8 MUg/L) and the median Cr concentration was 1.2 MUg/L (0.1 to 5.6 MUg/L). The twelve-year survival rate (with reoperation for any reason as the end point) was 100% in the metal-on-metal group and 70% (95% confidence interval, 63% to 77%) in the ceramic-on-polyethylene group (p = 0.003). CONCLUSIONS: After twelve to fourteen years of follow-up, metal-on-metal implants demonstrated better radiographic and survival results than ceramic-on-polyethylene implants in young, very active patients. Current wrought metal-on-metal implants with a 28-mm diameter head and high carbide concentration did not produce the high rates of osteolysis and allergic reactions that may be observed with cast low-carbide metal-on-metal bearings after a shorter duration of follow-up. PMID- 21543704 TI - Revision total hip arthroplasty performed through the Hueter interval. AB - Revision total hip arthroplasty through the direct anterior approach is technically challenging but offers some advantages in exposure of the acetabulum. This study presents a retrospectively reviewed consecutive series of fifty-one patients who underwent revision total hip arthroplasty through the anterior approach utilizing various extensions of this technique. The anatomic approach is discussed as well as problems as encountered in our series. PMID- 21543705 TI - Breaking gridlock: the determinants of health policy change in Congress. AB - Prior to the 2010 health care reforms, scholars often commented that health policy making in Congress was mired in political gridlock, that reforms were far more likely to fail than to succeed, and that the path forward was unclear. In light of recent events, new narratives are being advanced. In formulating these assessments, scholars of health politics tend to analyze individual major reform proposals to determine why they succeeded or failed and what lessons could be drawn for the future. Taking a different approach, we examine all health policies proposed in the U.S. House of Representatives between 1973 and 2002. We analyze these bills' fates and the effectiveness of their sponsors in guiding these proposals through Congress. Setting these proposed policies against a baseline of policy advancements in other areas, we demonstrate that health policy making has indeed been far more gridlocked than policy making in most other areas. We then isolate some of the causes of this gridlock, as well as some of the conditions that have helped to bring about health policy change. PMID- 21543706 TI - Whom do physicians work for? An analysis of dual practice in the health sector. AB - This article presents a thorough analysis of dual practice among physicians who work in both the public and private sectors. A conceptual framework is presented to help the reader understand dual practice and the contexts where it takes place. The article reviews the existing theoretical and empirical literature on this form of dual practice among physicians. It analyzes the extent of this phenomenon, the underlying factors that motivate physicians to engage in dual practice, and the main implications of their decision to do so. It also examines and discusses current policies that address dual practice. In this regard, the article provides some qualified support for the use of "rewarding" policies to retain physicians in the public sectors of more developed countries, while "limiting" policies are recommended for developing countries - with the caveat that the policies should be accompanied by the strengthening of institutional and contracting environments. The article highlights the lack of quality evaluative evidence regarding the consequences of dual practice on the delivery of health care services. It concludes that the overall impact of dual practice remains an open question that warrants more attention from researchers and policy makers alike. PMID- 21543707 TI - Commercial importation of prescription drugs in the United States: short-run implications. AB - The option of legalizing the commercial importation of prescription drugs is of continued policy interest as a way to reduce U.S. drug spending. Using IMS data, we estimate potential savings from commercial drug importation under assumptions about percentage of drugs likely to attract imports; potential supply from foreign countries; and share of savings passed on to payers. Our base case estimate is that $1.7 billion per year, or 0.6 percent of total drug spending, would be saved by payers; sensitivity analyses range from 0.2 to 2.5 percent under plausible assumptions and up to 17.4 percent under unrealistic assumptions about unlimited foreign supply, costless trade, and zero profits for intermediaries. Estimated savings to payers are less than the average price differentials between the United States and foreign countries because proposed legislation exempts certain drugs from importation; foreign markets are small relative to the United States; regulatory and other constraints may limit the volume of exports; trade is costly; and intermediaries will retain some savings. Although savings to U.S. payers/consumers would likely be small and have minimal impact on total U.S. health care spending, costs to other countries could be significant, due to reduced access and possibly higher prices. In the long run, reduced investment in R&D could adversely affect consumers globally. PMID- 21543708 TI - How Brazil outpaced the United States when it came to AIDS: the politics of civic infiltration, reputation, and strategic internationalization. AB - Using a temporal approach dividing the reform process into two periods, this article explains how both Brazil and the United States were slow to respond to AIDS. However, Brazil eventually outpaced the United States in its response due to international rather than democratic pressures. Since the early 1990s, Brazil's success has been attributed to "strategic internationalization": the concomitant acceptance and rejection of global pressure for institutional change and antiretroviral treatment, respectively. The formation of tripartite partnerships among donors, AIDS officials, and nongovernmental organizations has allowed Brazil to avoid foreign aid dependency, while generating ongoing incentives for influential AIDS officials to incessantly pressure Congress for additional funding. Given the heightened international media attention, concern about Brazil's reputation has contributed to a high level of political commitment. By contrast, the United States' more isolationist relationship with the international community, its focus on leading the global financing of AIDS efforts, and the absence of tripartite partnerships have prevented political leaders from adequately responding to the ongoing urban AIDS crisis. Thus, Brazil shows that strategically working with the international health community for domestic rather than international influence is vital for a sustained and effective response to AIDS. PMID- 21543711 TI - Rapid search for specific sites on DNA through conformational switch of nonspecifically bound proteins. AB - We develop a theory for the rapid search of specific sites on DNA, via a mechanism in which a nonspecifically-bound protein can switch between two conformations. In the "inactive" conformation, the bound protein has favorable, nonspecific interactions with the DNA, but cannot be recognized by the target site. In the "active" conformation, the protein is recognized by the target site but has a very rugged energy surface elsewhere on the DNA. The rate constant for protein binding to the specific site is calculated by an approach in which the protein, after reaching the DNA surface via 3D diffusion, searches for the target site via 1D diffusion while being allowed to escape to the bulk solution. Mindful of the pitfalls of many previous approximate treatments, we validate our approach against a rigorous solution of the problem when the protein has a fixed conformation. In the 1D diffusion toward the specific site, a conformationally switchable protein predominantly adopts the inactive conformation due to the favorable nonspecific interactions with the DNA, thus maximizing the 1D diffusion constant and minimizing the chance of escape to the bulk solution. Once at the target site, a transition to the active conformation allows the protein to be captured. This induced-switch mechanism provides robust speedup of protein-DNA binding rates, and appears to be adopted by many transcription factors and DNA modifying enzymes. PMID- 21543712 TI - Water molecule reorganization in cytochrome c oxidase revealed by FTIR spectroscopy. AB - Although internal electron transfer and oxygen reduction chemistry in cytochrome c oxidase are fairly well understood, the associated groups and pathways that couple these processes to gated proton translocation across the membrane remain unclear. Several possible pathways have been identified from crystallographic structural models; these involve hydrophilic residues in combination with structured waters that might reorganize to form transient proton transfer pathways during the catalytic cycle. To date, however, comparisons of atomic structures of different oxidases in different redox or ligation states have not provided a consistent answer as to which pathways are operative or the details of their dynamic changes during catalysis. In order to provide an experimental means to address this issue, FTIR spectroscopy in the 3,560-3,800 cm(-1) range has been used to detect weakly H-bonded water molecules in bovine cytochrome c oxidase that might change during catalysis. Full redox spectra exhibited at least four signals at 3,674(+), 3,638(+), 3,620(-), and 3,607(+) cm(-1). A more complex set of signals was observed in spectra of photolysis of the ferrous-CO compound, a reaction that mimics the catalytic oxygen binding step, and their D(2)O and H(2)(18)O sensitivities confirmed that they arose from water molecule rearrangements. Fitting with Gaussian components indicated the involvement of up to eight waters in the photolysis transition. Similar signals were also observed in photolysis spectra of the ferrous-CO compound of bacterial CcO from Paracoccus denitrificans. Such water changes are discussed in relation to roles in hydrophilic channels and proton/electron coupling mechanism. PMID- 21543713 TI - Coincident mass extirpation of neotropical amphibians with the emergence of the infectious fungal pathogen Batrachochytrium dendrobatidis. AB - Amphibians highlight the global biodiversity crisis because ~40% of all amphibian species are currently in decline. Species have disappeared even in protected habitats (e.g., the enigmatic extinction of the golden toad, Bufo periglenes, from Costa Rica). The emergence of a fungal pathogen, Batrachochytrium dendrobatidis (Bd), has been implicated in a number of declines that have occurred in the last decade, but few studies have been able to test retroactively whether Bd emergence was linked to earlier declines and extinctions. We describe a noninvasive PCR sampling technique that detects Bd in formalin-preserved museum specimens. We detected Bd by PCR in 83-90% (n = 38) of samples that were identified as positive by histology. We examined specimens collected before, during, and after major amphibian decline events at established study sites in southern Mexico, Guatemala, and Costa Rica. A pattern of Bd emergence coincident with decline at these localities is revealed-the absence of Bd over multiple years at all localities followed by the concurrent emergence of Bd in various species at each locality during a period of population decline. The geographical and chronological emergence of Bd at these localities also indicates a southbound spread from southern Mexico in the early 1970s to western Guatemala in the 1980s/1990s and to Monteverde, Costa Rica by 1987. We find evidence of a historical "Bd epidemic wave" that began in Mexico and subsequently spread to Central America. We describe a technique that can be used to screen museum specimens from other amphibian decline sites around the world. PMID- 21543715 TI - Laboratory synthesis of an independently reproducing vertebrate species. AB - Speciation in animals commonly involves an extrinsic barrier to genetic exchange followed by the accumulation of sufficient genetic variation to impede subsequent productive interbreeding. All-female species of whiptail lizards, which originated by interspecific hybridization between sexual progenitors, are an exception to this rule. Here, the arising species instantaneously acquires a novel genotype combining distinctive alleles from two different species, and reproduction by parthenogenesis constitutes an effective intrinsic barrier to genetic exchange. Fertilization of diploid parthenogenetic females by males of sexual species has produced several triploid species, but these instantaneous speciation events have neither been observed in nature nor have they been reconstituted in the laboratory. Here we report the generation of four self sustaining clonal lineages of a tetraploid species resulting from fertilization of triploid oocytes from a parthenogenetic Aspidoscelis exsanguis with haploid sperm from Aspidoscelis inornata. Molecular and cytological analysis confirmed the genetic identity of the hybrids and revealed that the females retain the capability of parthenogenetic reproduction characteristic of their triploid mothers. The tetraploid females have established self-perpetuating clonal lineages which are now in the third generation. Our results confirm the hypothesis that secondary hybridization events can lead to asexual lineages of increased ploidy when favorable combinations of parental genomes are assembled. We anticipate that these animals will be a critical tool in understanding the mechanisms underlying the origin and subsequent evolution of asexual amniotes. PMID- 21543718 TI - Ancient starch: Cooked or just old? PMID- 21543717 TI - A cluster of coregulated genes determines TGF-beta-induced regulatory T-cell (Treg) dysfunction in NOD mice. AB - Foxp3(+) regulatory T cells (Tregs) originate in the thymus, but the Treg phenotype can also be induced in peripheral lymphoid organs or in vitro by stimulation of conventional CD4(+) T cells with IL-2 and TGF-beta. There have been divergent reports on the suppressive capacity of these TGF-Treg cells. We find that TGF-Tregs derived from diabetes-prone NOD mice, although expressing normal Foxp3 levels, are uniquely defective in suppressive activity, whereas TGF Tregs from control strains (B6g7) or ex vivo Tregs from NOD mice all function normally. Most Treg-typical transcripts were shared by NOD or B6g7 TGF-Tregs, except for a small group of differentially expressed genes, including genes relevant for suppressive activity (Lrrc32, Ctla4, and Cd73). Many of these transcripts form a coregulated cluster in a broader analysis of T-cell differentiation. The defect does not map to idd3 or idd5 regions. Whereas Treg cells from NOD mice are normal in spleen and lymph nodes, the NOD defect is observed in locations that have been tied to pathogenesis of diabetes (small intestine lamina propria and pancreatic lymph node). Thus, a genetic defect uniquely affects a specific Treg subpopulation in NOD mice, in a manner consistent with a role in determining diabetes susceptibility. PMID- 21543720 TI - The inflammasome in atherosclerosis and type 2 diabetes. AB - Atherosclerosis is the cause of morbiditiy for 70% of patients with type 2 diabetes. In both of these diseases, a protein complex known as the inflammasome is stimulated to activate interleukin-1beta (IL-1beta) and IL-18, which are pathogenic inflammatory cytokines. Triggers for the inflammasome are obesity related factors, such as cholesterol crystals in atherosclerosis, or hyperglycemia, ceramides, and islet amyloid polypeptide in type 2 diabetes. Therapeutics that target IL-1beta in clinical trials for type 2 diabetes might also decrease the incidence of atherosclerosis. PMID- 21543721 TI - A phosphorus-based dendrimer targets inflammation and osteoclastogenesis in experimental arthritis. AB - Dendrimers are highly branched "tree-like" polymers that have demonstrated therapeutic potential in drug delivery, medical imaging, and tissue engineering in recent years. In addition, we have shown that an azabisphosphonate (ABP) capped dendrimer selectively targets monocytes and directs them toward anti inflammatory activation. We explored this property to assess the therapeutic potential of dendrimer ABP in the treatment of an inflammatory disease, rheumatoid arthritis. Intravenous injections of dendrimer ABP inhibited the development of inflammatory arthritis in two animal models: IL-1ra(-/-) mice and mice undergoing K/BxN serum transfer. Suppression of disease was characterized by normal synovial membranes, reduced levels of inflammatory cytokines, and the absence of cartilage destruction and bone erosion. Dendrimer ABP also exhibited anti-osteoclastic activity on mouse and human cells, mediated by c-FMS (cellular feline McDonough strain sarcoma virus oncogene homolog) inhibition. These preclinical demonstrations suggest the potential use of dendrimer ABP as a nanotherapeutic for rheumatoid arthritis. PMID- 21543722 TI - Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys. AB - The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was about a one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01-negative monkeys challenged with SIVsmE660, no CD8(+) T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope specific CD4(+) T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanisms of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies. PMID- 21543723 TI - Semantic and pragmatic factors influencing deaf and hearing students' comprehension of english sentences containing numeral quantifiers. AB - This research contrasted deaf and hearing students' interpretive knowledge of English sentences containing numeral quantifier phrases and indefinite noun phrases. A multiple-interpretation picture task methodology was used to assess 305 participants' judgments of the compatibility of sentence meanings with depicted discourse contexts. Participants' performance was assessed on the basis of hearing level (deaf, hearing) and grade level (middle school, high school, college). The deaf students were predicted to have differential access to specific sentence interpretations in accordance with the relative derivational complexity of the targeted sentence types. Hypotheses based on the pressures of derivational economy on acquisition were largely supported. The results also revealed that the deaf participants tended to overactivate pragmatic processes that yielded principled, though non-target, sentence interpretations. Collectively, the results not only contribute to the understanding of English acquisition under conditions of restricted access to spoken language input, they also suggest that pragmatic factors may play a broad role in influencing, and compromising, deaf students' reading comprehension and written expression. PMID- 21543724 TI - Suppression of a NAC-like transcription factor gene improves boron-toxicity tolerance in rice. AB - We identified a gene responsible for tolerance to boron (B) toxicity in rice (Oryza sativa), named BORON EXCESS TOLERANT1. Using recombinant inbred lines derived from the B-toxicity-sensitive indica-ecotype cultivar IR36 and the tolerant japonica-ecotype cultivar Nekken 1, the region responsible for tolerance to B toxicity was narrowed to 49 kb on chromosome 4. Eight genes are annotated in this region. The DNA sequence in this region was compared between the B-toxicity sensitive japonica cultivar Wataribune and the B-toxicity-tolerant japonica cultivar Nipponbare by eco-TILLING analysis and revealed a one-base insertion mutation in the open reading frame sequence of the gene Os04g0477300. The gene encodes a NAC (NAM, ATAF, and CUC)-like transcription factor and the function of the transcript is abolished in B-toxicity-tolerant cultivars. Transgenic plants in which the expression of Os04g0477300 is abolished by RNA interference gain tolerance to B toxicity. PMID- 21543725 TI - A hormonal regulatory module that provides flexibility to tropic responses. AB - Plants orient their growth depending on directional stimuli such as light and gravity, in a process known as tropic response. Tropisms result from asymmetrical accumulation of auxin across the responding organ relative to the direction of the stimulus, which causes differential growth rates on both sides of the organ. Here, we show that gibberellins (GAs) attenuate the gravitropic reorientation of stimulated hypocotyls of dark-grown Arabidopsis (Arabidopsis thaliana) seedlings. We show that the modulation occurs through induction of the expression of the negative regulator of auxin signaling INDOLE-3-ACETIC ACID INDUCIBLE19/MASSUGU2. The biological significance of this regulatory mechanism involving GAs and auxin seems to be the maintenance of a high degree of flexibility in tropic responses. This notion is further supported by observations that GA-deficient seedlings showed a much lower variance in the response to gravity compared to wild-type seedlings and that the attenuation of gravitropism by GAs resulted in an increased phototropic response. This suggests that the interplay between auxin and GAs may be particularly important for plant orientation under competing tropic stimuli. PMID- 21543726 TI - Multiple roles of WIN3 in regulating disease resistance, cell death, and flowering time in Arabidopsis. AB - The salicylic acid (SA) regulatory gene HOPW1-1-INTERACTING3 (WIN3) was previously shown to confer resistance to the biotrophic pathogen Pseudomonas syringae. Here, we report that WIN3 controls broad-spectrum disease resistance to the necrotrophic pathogen Botrytis cinerea and contributes to basal defense induced by flg22, a 22-amino acid peptide derived from the conserved region of bacterial flagellin proteins. Genetic analysis indicates that WIN3 acts additively with several known SA regulators, including PHYTOALEXIN DEFICIENT4, NONEXPRESSOR OF PR GENES1 (NPR1), and SA INDUCTION-DEFICIENT2, in regulating SA accumulation, cell death, and/or disease resistance in the Arabidopsis (Arabidopsis thaliana) mutant acd6-1. Interestingly, expression of WIN3 is also dependent on these SA regulators and can be activated by cell death, suggesting that WIN3-mediated signaling is interconnected with those derived from other SA regulators and cell death. Surprisingly, we found that WIN3 and NPR1 synergistically affect flowering time via influencing the expression of flowering regulatory genes FLOWERING LOCUS C and FLOWERING LOCUS T. Taken together, our data reveal that WIN3 represents a novel node in the SA signaling networks to regulate plant defense and flowering time. They also highlight that plant innate immunity and development are closely connected processes, precise regulation of which should be important for the fitness of plants. PMID- 21543727 TI - Application of gene targeting to designed mutation breeding of high-tryptophan rice. AB - Site-directed mutagenesis via gene targeting (GT) based on homologous recombination is the ultimate mutation breeding technology because it enables useful information acquired from structural- and computational-based protein engineering to be applied directly to molecular breeding, including metabolic engineering, of crops. Here, we employed this rationale to introduce precise mutations in OASA2--an alpha-subunit of anthranilate synthase that is a key enzyme of tryptophan (Trp) biosynthesis in rice (Oryza sativa)--via GT, with subsequent selection of GT cells using a Trp analog. The expression level of OASA2 in plants homozygous and heterozygous for modified OASA2 was similar to that of nontransformants, suggesting that OASA2 transcription in GT plants was controlled in the same manner as endogenous OASA2, and that GT could lead to a lower risk of gene silencing than in conventional overexpression approaches. Moreover, we showed that enzymatic properties deduced from protein engineering or in vitro analysis could be reproduced in GT plants as evidenced by Trp accumulation levels. Interestingly, mature seeds of homozygous GT plants accumulated Trp levels 230-fold higher than in nontransformants without any apparent morphological or developmental changes. Thus, we have succeeded in producing a novel rice plant of great potential nutritional benefit for both man and livestock that could not have been selected using conventional mutagenesis approaches. Our results demonstrate the effectiveness of directed crop improvement by combining precision mutagenesis via GT with a knowledge of protein engineering. PMID- 21543728 TI - EXORDIUM-LIKE1 promotes growth during low carbon availability in Arabidopsis. AB - Little is known about genes that control growth and development under low carbon (C) availability. The Arabidopsis (Arabidopsis thaliana) EXORDIUM-LIKE1 (EXL1) gene (At1g35140) was identified as a brassinosteroid-regulated gene in a previous study. We show here that the EXL1 protein is required for adaptation to C- and energy-limiting growth conditions. In-depth analysis of EXL1 transcript levels under various environmental conditions indicated that EXL1 expression is controlled by the C and energy status. Sugar starvation, extended night, and anoxia stress induced EXL1 gene expression. The C status also determined EXL1 protein levels. These results suggested that EXL1 is involved in the C-starvation response. Phenotypic changes of an exl1 loss-of-function mutant became evident only under corresponding experimental conditions. The mutant showed diminished biomass production in a short-day/low-light growth regime, impaired survival during extended night, and impaired survival of anoxia stress. Basic metabolic processes and signaling pathways are presumed to be barely impaired in exl1, because the mutant showed wild-type levels of major sugars, and transcript levels of only a few genes such as QUA-QUINE STARCH were altered. Our data suggest that EXL1 is part of a regulatory pathway that controls growth and development when C and energy supply is poor. PMID- 21543729 TI - AtMYB2 regulates whole plant senescence by inhibiting cytokinin-mediated branching at late stages of development in Arabidopsis. AB - Whole plant senescence of monocarpic plants consists of three major processes: arrest of shoot apical meristem, organ senescence, and permanent suppression of axillary buds. At early stages of development, axillary buds are inhibited by shoot apex-produced auxin, a mechanism known as apical dominance. How the buds are suppressed as an essential part of whole plant senescence, especially when the shoot apexes are senescent, is not clear. Here, we report an AtMYB2-regulated post apical dominance mechanism by which Arabidopsis (Arabidopsis thaliana) inhibits the outgrowth of axillary buds as part of the whole plant senescence program. AtMYB2 is expressed in the compressed basal internode region of Arabidopsis at late stages of development to suppress the production of cytokinins, the group of hormones that are required for axillary bud outgrowth. atmyb2 T-DNA insertion lines have enhanced expression of cytokinin-synthesizing isopentenyltransferases genes, contain higher levels of cytokinins, and display a bushy phenotype at late stages of development. As a result of the continuous generation of new shoots, atmyb2 plants have a prolonged life span. The AtMYB2 promoter-directed cytokinin oxidase 1 gene in the T-DNA insertion lines reduces the endogenous cytokinin levels and restores the bushy phenotype to the wild type. PMID- 21543731 TI - Stroke centers and quality of stroke care: how are we doing? PMID- 21543730 TI - Incident lacunes influence cognitive decline: the LADIS study. AB - BACKGROUND: In cerebral small vessel disease, the core MRI findings include white matter lesions (WML) and lacunar infarcts. While the clinical significance of WML is better understood, the contribution of lacunes to the rate of cognitive decline has not been established. This study investigated whether incident lacunes on MRI determine longitudinal cognitive change in elderly subjects with WML. METHODS: Within the Leukoaraiosis and Disability Study (LADIS), 387 subjects were evaluated with repeated MRI and neuropsychological assessment at baseline and after 3 years. Predictors of change in global cognitive function and specific cognitive domains over time were analyzed with multivariate linear regression. RESULTS: After controlling for demographic factors, baseline cognitive performance, baseline lacunar and WML lesion load, and WML progression, the number of new lacunes was related to subtle decrease in compound scores for executive functions (p = 0.021) and speed and motor control (p = 0.045), but not for memory or global cognitive function. Irrespective of lacunes, WML progression was associated with decrease in executive functions score (p = 0.016). CONCLUSION: Incident lacunes on MRI parallel a steeper rate of decline in executive functions and psychomotor speed. Accordingly, in addition to WML, lacunes determine longitudinal cognitive impairment in small vessel disease. Although the individual contribution of lacunes on cognition was modest, they cannot be considered benign findings, but indicate a risk of progressive cognitive impairment. PMID- 21543732 TI - Lacunes and cognitive decline: little things matter. PMID- 21543733 TI - Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. AB - BACKGROUND: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies. OBJECTIVES: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS. METHODS: Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005. RESULTS: Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted. CONCLUSIONS: Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound. PMID- 21543734 TI - Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy. AB - Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and is not rare. The NIH and National Institute of Neurological Disorders and Stroke sponsored a 3-day multidisciplinary workshop to advance research into SUDEP and its prevention. Parallel sessions were held: one with a focus on the science of SUDEP, and the other with a focus on issues related to the education of health care practitioners and people with epilepsy. This report summarizes the discussions and recommendations of the workshop, including lessons learned from investigations of sudden infant death syndrome (SIDS), sudden cardiac death, autonomic and respiratory physiology, medical devices, genetics, and animal models. Recommendations include educating all people with epilepsy about SUDEP as part of their general education on the potential harm of seizures, except in extenuating circumstances. Increasing awareness of SUDEP may facilitate improved seizure control, possibly decreasing SUDEP incidence. There have been significant advances in our understanding of the clinical and physiologic features of SIDS, sudden cardiac death, and SUDEP in both people and animals. Research should continue to focus on the cardiac, autonomic, respiratory, and genetic factors that likely contribute to the risk of SUDEP. Multicenter collaborative research should be encouraged, especially investigations with direct implications for the prevention of SUDEP. An ongoing SUDEP Coalition has been established to facilitate this effort. With the expansion of clinical, genetic, and basic science research, there is reasonable hope of advancing our understanding of SUDEP and ultimately our ability to prevent it. PMID- 21543735 TI - Interruption of natalizumab therapy for multiple sclerosis: what are the risks? PMID- 21543736 TI - Outcomes after ischemic stroke for hospitals with and without Joint Commission certified primary stroke centers. AB - BACKGROUND: The Joint Commission (JC) began certifying primary stroke centers (PSCs) in the United States in 2003. We assessed whether 30-day risk-standardized mortality (RSMR) and readmission (RSRR) rates differed between hospitals with and without JC-certified PSCs in 2006. METHODS: The study cohort included all fee-for service Medicare beneficiaries >=65 years old discharged with a primary diagnosis of ischemic stroke (International Classification of Diseases, ninth revision, Clinical Modification 433, 434, 436) in 2006. Hierarchical linear regression models calculated hospital-level RSMRs and RSRRs, adjusting for patient demographics, comorbid conditions, and hospital referral region. Hospitals were categorized as being higher than, no different from, or lower than the national average. RESULTS: There were 310,381 ischemic stroke discharges from 315 JC certified PSC and 4,231 noncertified hospitals. Mean overall 30-day RSMR and RSRR were 10.9% +/- 1.7% and 12.5% +/- 1.4%, respectively. The RSMRs of hospitals with JC-certified PSCs were lower than in noncertified hospitals (10.7% +/- 1.7% vs 11.0% +/- 1.7%), but the RSRRs were comparable (12.5% +/- 1.3% vs 12.4% +/- 1.7%). Almost half of JC-certified PSC hospitals had RSMRs lower than the national average compared with 19% of noncertified hospitals, but 13% of JC certified PSC hospitals had lower RSRRs vs 15% of noncertified hospitals. CONCLUSIONS: Hospitals with JC-certified PSCs had lower RSMRs compared with noncertified hospitals in 2006; however, differences were small. Readmission rates were similar between the 2 groups. PSC certification generally identified better-performing hospitals for mortality outcomes, but some hospitals with certified PSCs may have high RSMRs and RSRRs whereas some hospitals without PSCs have low rates. Unmeasured factors may contribute to this heterogeneity. PMID- 21543737 TI - Vascular risk factors and longitudinal changes on brain MRI: the ARIC study. AB - OBJECTIVE: To evaluate associations between vascular risk factors and changes in burden of infarcts, ventricular size (VS), sulcal widening (SW), and white matter hyperintensities (WMH) in an initially middle-aged, biracial cohort from the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Initial brain magnetic resonance (MR) scans and evaluations for vascular risk factors were performed in 1,812 ARIC participants in 1994-1995. In 2004-2006, 1,130 ARIC participants underwent repeat MR scans. MR scans were rated using a validated 9-point scale for VS, SW, and WMH. Infarcts were recorded. Multiple logistic regression analysis was used to assess associations between vascular risk factors and change between MR scans of one or more grades in VS, SW, WMH, or appearance of new infarcts, controlling for age, sex, and race. RESULTS: At baseline, the 1,112 participants with usable scans (385 black women, 200 black men, 304 white women, 223 white men) had a mean age of 61.7 +/- 4.3 years. In adjusted models, diabetes at baseline was associated with incident infarcts (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.29-2.95) and worsening SW (OR 2.10, 95% CI 1.36-3.24). Hypertension at baseline was associated with incident infarcts (OR 1.73, 95% CI 1.23-2.42). In subjects with the highest tertile of fasting blood sugar and systolic blood pressure at baseline, the risk of incident infarcts was 3.68 times higher (95% CI 1.89-7.19) than those in the lowest tertile for both. CONCLUSION: Both atrophic and ischemic imaging changes were driven by altered glycemic and blood pressure control beginning in midlife. PMID- 21543738 TI - Unforeseen decreases in dissolved oxygen levels affect tube formation kinetics in collagen gels. AB - The availability of oxygen (O(2)) is a critical parameter affecting vascular tube formation. In this study, we hypothesize that dissolved oxygen (DO) levels in collagen gels change during the three-dimensional (3D) culture of human umbilical vein endothelial cells (HUVECs) in atmospheric conditions and that such changes affect the kinetics of tube formation through the production of reactive oxygen species (ROS). We demonstrate a decrease in O(2) tension during 3D cultures of HUVECs. Noninvasive measurements of DO levels during culture under atmospheric conditions revealed a profound decrease that reached as low as 2% O(2) at the end of 24 h. After media replacement, DO levels rose rapidly and equilibrated at ~15% O(2), creating a reoxygenated environment. To accurately estimate DO gradients in 3D collagen gels, we developed a 3D mathematical model and determined the Michaelis-Menten parameters, V(max) and K(m), of HUVECs in collagen gels. We detected an increase in ROS levels throughout the culture period. Using diphenyliodonium to inhibit ROS production resulted in the complete inhibition of tube formation. Interference RNA studies further showed that hypoxia-inducible factors (HIFs)-1alpha and -2alpha are not involved in the formation of 3D tubes in collagen gels. We conclude that ROS affect the tubulogenesis process through HIFalpha-independent pathways, where the levels of ROS are influenced by the uncontrolled variations in DO levels. This study is the first demonstration of the critical and unexpected role of O(2) during 3D in vitro culture models of tubulogenesis in atmospheric conditions. PMID- 21543739 TI - Dual functional significance of calcineurin homologous protein 1 binding to Na(+)/H(+) exchanger isoform 1. AB - Calcineurin homologous protein 1 (CHP1) binds to the hydrophilic tail of the Na(+)/H(+) exchanger isoform 1 (NHE1). Previous gene knockout of CHP1 revealed that the loss of CHP1 caused a decrease in the total amount of NHE1, suggesting the destabilization of NHE1 molecules without CHP1 (Matsushita et al., Am J Physiol Cell Physiol 293: C246-C254, 2007). However, Pang et al. (J Biol Chem 276: 17367-17372, 2001) reported that NHE1 without a CHP1 binding site was found in the plasma membrane, suggesting no requirement of CHP1 binding for plasma membrane localization of NHE1. Here, the functional significance of CHP1 binding to NHE1 was examined to resolve these contradictory results. In CV1 cells, which overexpressed wild-type NHE1, overexpression of CHP1 caused an increase in both the total amount of NHE1 and the colocalization of NHE1 and CHP1 at the plasma membrane. This provided new visual evidence of the localization of NHE1 from endoplasmic reticulum to the plasma membrane upon CHP1 binding. An immunoprecipitation assay showed that the expression of CHP1 reduced the ubiquitination of NHE1 and/or its associated proteins. Mutant NHE1s without CHP1 binding site exhibited a modest localization to the plasma membrane. After reaching the plasma membrane, these mutant NHE1s exhibited shorter half-lives than the wild-type NHE1 with CHP1. The results suggest a dual functional significance of CHP1 and its binding region: 1) binding of CHP1 stabilizes NHE1 and increases its plasma membrane localization by masking a NHE1 disposal signal, and 2) CHP1 binding is required for the antiporter activity. PMID- 21543741 TI - Rho rocks H+-ATPases. Focus on "Regulation of V-ATPase recycling via a RhoA- and ROCKII-dependent pathway in epididymal clear cells". PMID- 21543740 TI - Ion channels and transporters [corrected] in cancer. 2. Ion channels and the control of cancer cell migration. AB - A hallmark of high-grade cancers is the ability of malignant cells to invade unaffected tissue and spread disease. This is particularly apparent in gliomas, the most common and lethal type of primary brain cancer affecting adults. Migrating cells encounter restricted spaces and appear able to adjust their shape to accommodate to narrow extracellular spaces. A growing body of work suggests that cell migration/invasion is facilitated by ion channels and transporters. The emerging concept is that K(+) and Cl(-) function as osmotically active ions, which cross the plasma membrane in concert with obligated water thereby adjusting a cell's shape and volume. In glioma cells Na(+)-K(+)-Cl(-) cotransporters (NKCC1) actively accumulate K(+) and Cl(-), establishing a gradient for KCl efflux. Ca(2+)-activated K(+) channels and voltage-gated Cl(-) channels are largely responsible for effluxing KCl promoting hydrodynamic volume changes. In other cancers, different K(+) or even Na(+) channels may function in concert with a variety of Cl(-) channels to support similar volume changes. Channels involved in migration are frequently regulated by Ca(2+) signaling, most likely coupling extracellular stimuli to cell migration. Importantly, the inhibition of ion channels and transporters appears to be clinically relevant for the treatment of cancer. Recent preclinical data indicates that inhibition of NKCC1 with an FDA approved drug decreases neoplastic migration. Additionally, ongoing clinical trials demonstrate that an inhibitor of chloride channels may be a therapy for the treatment of gliomas. Data reviewed here strongly indicate that ion channels are a promising target for the development of novel therapeutics to combat cancer. PMID- 21543742 TI - An intramolecular transport metabolon: fusion of carbonic anhydrase II to the COOH terminus of the Cl(-)/HCO(3)(-)exchanger, AE1. AB - Anion exchanger 1 (AE1) is the plasma membrane Cl(-)/HCO(3)(-) exchanger of erythrocytes. Carbonic anhydrases (CA) provide substrate for AE1 by catalyzing the reaction, H(2)O + CO(2) <-> HCO(3)(-) + H(+). The physical complex of CAII with AE1 has been proposed to maximize anion exchange activity. To examine the effect of CAII catalysis on AE1 transport rate, we fused either CAII-wild type or catalytically inactive CAII-V143Y to the cytoplasmic COOH terminus of AE1 to form AE1.CAII and AE1.CAII-V143Y, respectively. When expressed in transfected human embryonic kidney 293 cells, AE1.CAII had a similar Cl(-)/HCO(3)(-) exchange activity to AE1 alone, as assessed by the flux of H(+) equivalents (87 +/- 4% vs. AE1) or rate of change of intracellular Cl(-) concentration (93 +/- 4% vs. AE1), suggesting that CAII does not activate AE1. In contrast, AE1.CAII-V143Y displayed transport rates for H(+) equivalents and Cl(-) of 55 +/- 2% and of 40 +/- 2%, versus AE1. Fusion of CAII to AE1 therefore reduces anion transport activity, but this reduction is compensated for during Cl(-)/HCO(3)(-) exchange by the presence of catalytically active CAII. Overexpression of free CAII-V143Y acts in a dominant negative manner to reduce AE1-mediated HCO(3)(-) transport by displacement of endogenous CAII-wild type from its binding site on AE1. To examine whether AE1.CAII bound endogenous CAII, we coexpressed CAII-V143Y along with AE1 or AE1.CAII. The bicarbonate transport activity of AE1 was inhibited by CAII-V143Y, whereas the activity of AE1.CAII was unaffected by CAII-V143Y, suggesting impaired transport activity upon displacement of functional CAII from AE1 but not AE1.CAII. Taken together, these data suggest that association of functional CAII with AE1 increases Cl(-)/HCO(3)(-) exchange activity, consistent with the HCO(3)(-) transport metabolon model. PMID- 21543743 TI - Cholinergic and glutamatergic agonists induce gamma frequency activity in dorsal subcoeruleus nucleus neurons. AB - The dorsal subcoeruleus nucleus (SubCD) is involved in generating two signs of rapid eye movement (REM) sleep: muscle atonia and ponto-geniculo-occipital (PGO) waves. We tested the hypothesis that single cell and/or population responses of SubCD neurons are capable of generating gamma frequency activity in response to intracellular stimulation or receptor agonist activation. Whole cell patch clamp recordings (immersion chamber) and population responses (interface chamber) were conducted on 9- to 20-day-old rat brain stem slices. All SubCD neurons (n = 103) fired at gamma frequency when subjected to depolarizing steps. Two statistically distinct populations of neurons were observed, which were distinguished by their high (>80 Hz, n = 24) versus low (35-80 Hz, n = 16) initial firing frequencies. Both cell types exhibited subthreshold oscillations in the gamma range (n = 43), which may underlie the gamma band firing properties of these neurons. The subthreshold oscillations were blocked by the sodium channel blockers tetrodotoxin (TTX, n = 21) extracellularly and N-(2,6 dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314) intracellularly (n = 5), indicating they were sodium channel dependent. Gamma frequency subthreshold oscillations were observed in response to the nonspecific cholinergic receptor agonist carbachol (CAR, n = 11, d = 1.08) and the glutamate receptor agonists N-methyl-d-aspartic acid (NMDA, n = 12, d = 1.09) and kainic acid (KA, n = 13, d = 0.96), indicating that cholinergic and glutamatergic inputs may be involved in the activation of these subthreshold currents. Gamma band activity also was observed in population responses following application of CAR (n = 4, P < 0.05), NMDA (n = 4, P < 0.05) and KA (n = 4, P < 0.05). Voltage sensitive, sodium channel-dependent gamma band activity appears to be a part of the intrinsic membrane properties of SubCD neurons. PMID- 21543744 TI - Paving new paths for neuregulin-1-assisted cardiac regenerative medicine. Focus on "Improving murine embryonic stem cell differentiation into cardiomyocytes with neuregulin-1: differential expression of microRNA". PMID- 21543745 TI - NP603, a novel and potent inhibitor of FGFR1 tyrosine kinase, inhibits hepatic stellate cell proliferation and ameliorates hepatic fibrosis in rats. AB - Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of alpha-smooth muscle actin (alpha-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 MUM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg.kg( 1).day(-1)) administration significantly decreased hepatic collagen deposition and alpha-SMA expression in CCl(4)-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis. PMID- 21543746 TI - Altered attainment of developmental milestones influences the age of diagnosis of rett syndrome. AB - The early developmental history prior to the manifestation of Rett syndrome features is of clinical interest. This study describes the attainment of gross developmental milestones and regression, and assesses the relationships between genotype and age at diagnosis. The Australian Rett Syndrome Database and International Rett Syndrome Phenotype Database were used to source a total of 293 confirmed female subjects. Most girls learned to sit, were able to babble or use words, and approximately half learned to walk. Altered milestone attainment was associated with earlier diagnosis. There was variation in the acquisition of milestones, the age of regression, and the age of diagnosis by genotype. Most parents expressed concerns about unusual behaviors or development during infancy, and a more subtle atypical development during infancy was reported for most girls. It is important for clinicians to be aware of variable early development in Rett syndrome and that timely genetic testing is not precluded on this account. PMID- 21543747 TI - Task- and time-dependent modulation of Ia presynaptic inhibition during fatiguing contractions performed by humans. AB - Presynaptic modulation of Ia afferents converging onto the motor neuron pool of the extensor carpi radialis (ECR) was compared during contractions (20% of maximal force) sustained to failure as subjects controlled either the angular position of the wrist while supporting an inertial load (position task) or exerted an equivalent force against a rigid restraint (force task). Test Hoffmann (H) reflexes were evoked in the ECR by stimulating the radial nerve above the elbow. Conditioned H reflexes were obtained by stimulating either the median nerve above the elbow or at the wrist (palmar branch) to assess presynaptic inhibition of homonymous (D1 inhibition) and heteronymous Ia afferents (heteronymous Ia facilitation), respectively. The position task was briefer than the force task (P = 0.001), although the maximal voluntary force and electromyograph for ECR declined similarly at failure for both tasks. Changes in the amplitude of the conditioned H reflex were positively correlated between the two conditioning methods (P = 0.02) and differed between the two tasks (P < 0.05). The amplitude of the conditioned H reflex during the position task first increased (129 +/- 20.5% of the initial value, P < 0.001) before returning to its initial value (P = 0.22), whereas it increased progressively during the force task to reach 122 +/- 17.4% of the initial value at failure (P < 0.001). Moreover, changes in conditioned H reflexes were associated with the time to task failure and force fluctuations. The results suggest a task- and time-dependent modulation of presynaptic inhibition of Ia afferents during fatiguing contractions. PMID- 21543749 TI - The effect of TMS on visual motion sensitivity: an increase in neural noise or a decrease in signal strength? AB - The underlying mechanisms of action of transcranial magnetic stimulation (TMS) are still a matter of debate. TMS may impair a subject's performance by increasing neural noise, suppressing the neural signal, or both. Here, we delivered a single pulse of TMS (spTMS) to V5/MT during a motion direction discrimination task while concurrently manipulating the level of noise in the motion stimulus. Our results indicate that spTMS essentially acts by suppressing the strength of the relevant visual signal. We suggest that TMS may induce a pattern of neural activity that complements the ongoing activation elicited by the sensory signal in a manner that partially impoverishes that signal. PMID- 21543748 TI - Trial type probability modulates the cost of antisaccades. AB - The antisaccade task, where eye movements are made away from a target, has been used to investigate the flexibility of cognitive control of behavior. Antisaccades usually have longer saccade latencies than prosaccades, the so called antisaccade cost. Recent studies have shown that this antisaccade cost can be modulated by event probability. This may mean that the antisaccade cost can be reduced, or even reversed, if the probability of surrounding events favors the execution of antisaccades. The probabilities of prosaccades and antisaccades were systematically manipulated by changing the proportion of a certain type of trial in an interleaved pro/antisaccades task. We aimed to disentangle the intertwined relationship between trial type probabilities and the antisaccade cost with the ultimate goal of elucidating how probabilities of trial types modulate human flexible behaviors, as well as the characteristics of such modulation effects. To this end, we examined whether implicit trial type probability can influence saccade latencies and also manipulated the difficulty of cue discriminability to see how effects of trial type probability would change when the demand on visual perceptual analysis was high or low. A mixed-effects model was applied to the analysis to dissect the factors contributing to the modulation effects of trial type probabilities. Our results suggest that the trial type probability is one robust determinant of antisaccade cost. These findings highlight the importance of implicit probability in the flexibility of cognitive control of behavior. PMID- 21543750 TI - Live imaging of bulk endocytosis in frog motor nerve terminals using FM dyes. AB - We observed endocytosis in real time in stimulated frog motor nerve terminals by imaging the growth of large membrane infoldings labeled with a low concentration of FM dye. The spatial and temporal information made available by these experiments allowed us to image several new aspects of this synaptic vesicle recycling pathway. Membrane infoldings appeared near synaptic vesicle clusters and grew rapidly during long-duration, high-frequency stimulation. In some cases, we observed large, elongated infoldings growing laterally into the terminal. We used these observations to calculate infolding growth rates. A decrease in stimulation frequency caused a decrease in growth rates, but the overall length of these structures was unaffected by frequency changes. Attempts to wash the dye from these infoldings after stimulation were unsuccessful, demonstrating that the fluorescent structures had been endocytosed. We also used this technique to trigger and image infoldings during repeated, short trains. We found that membrane uptake occurred repeatedly at individual endocytosis sites, but only during a portion of the total number of trains delivered to the terminal. Finally, we showed that phosphatidylinositol 3-kinase, but not actin, was involved in this endocytosis pathway. The ability to monitor many individual bulk endocytosis sites in real time should allow for new types of endocytosis measurements and could reveal novel and unexpected mechanisms for coordinating membrane recovery during synaptic activity. PMID- 21543751 TI - The long-latency reflex is composed of at least two functionally independent processes. AB - The nervous system counters mechanical perturbations applied to the arm with a stereotypical sequence of muscle activity, starting with the short-latency stretch reflex and ending with a voluntary response. Occurring between these two events is the enigmatic long-latency reflex. Although researchers have been fascinated by the long-latency reflex for over 60 years, some of the most basic questions about this response remain unresolved and often debated. In the present study we help resolve one such question by providing clear evidence that the human long-latency reflex during a naturalistic motor task is not a single functional response; rather, it appears to reflect the output of (at least) two functionally independent processes that overlap in time and sum linearly. One of these functional components shares an important attribute of the short-latency reflex (i.e., automatic gain scaling, sensitivity to background load), and the other shares a defining feature of voluntary control (i.e., task dependency, sensitivity to goal target position). We further show that the task-dependent component of long-latency activity reflects a feedback control process rather than the simplest triggered reaction to a mechanical stimulus. PMID- 21543752 TI - Anesthetic state modulates excitability but not spectral tuning or neural discrimination in single auditory midbrain neurons. AB - The majority of sensory physiology experiments have used anesthesia to facilitate the recording of neural activity. Current techniques allow researchers to study sensory function in the context of varying behavioral states. To reconcile results across multiple behavioral and anesthetic states, it is important to consider how and to what extent anesthesia plays a role in shaping neural response properties. The role of anesthesia has been the subject of much debate, but the extent to which sensory coding properties are altered by anesthesia has yet to be fully defined. In this study we asked how urethane, an anesthetic commonly used for avian and mammalian sensory physiology, affects the coding of complex communication vocalizations (songs) and simple artificial stimuli in the songbird auditory midbrain. We measured spontaneous and song-driven spike rates, spectrotemporal receptive fields, and neural discriminability from responses to songs in single auditory midbrain neurons. In the same neurons, we recorded responses to pure tone stimuli ranging in frequency and intensity. Finally, we assessed the effect of urethane on population-level representations of birdsong. Results showed that intrinsic neural excitability is significantly depressed by urethane but that spectral tuning, single neuron discriminability, and population representations of song do not differ significantly between unanesthetized and anesthetized animals. PMID- 21543753 TI - Behavioral training enhances cortical temporal processing in neonatally deafened juvenile cats. AB - Deaf humans implanted with a cochlear prosthesis depend largely on temporal cues for speech recognition because spectral information processing is severely impaired. Training with a cochlear prosthesis is typically required before speech perception shows improvement, suggesting that relevant experience modifies temporal processing in the central auditory system. We tested this hypothesis in neonatally deafened cats by comparing temporal processing in the primary auditory cortex (AI) of cats that received only chronic passive intracochlear electric stimulation (ICES) with cats that were also trained with ICES to detect temporally challenging trains of electric pulses. After months of chronic passive stimulation and several weeks of detection training in behaviorally trained cats, multineuronal AI responses evoked by temporally modulated ICES were recorded in anesthetized animals. The stimulus repetition rates that produced the maximum number of phase-locked spikes (best repetition rate) and 50% cutoff rate were significantly higher in behaviorally trained cats than the corresponding rates in cats that received only chronic passive ICES. Behavioral training restored neuronal temporal following ability to levels comparable with those recorded in naive prior normal-hearing adult deafened animals. Importantly, best repetitition rates and cutoff rates were highest for neuronal clusters activated by the electrode configuration used in behavioral training. These results suggest that neuroplasticity in the AI is induced by behavioral training and perceptual learning in animals deprived of ordinary auditory experience during development and indicate that behavioral training can ameliorate or restore temporal processing in the AI of profoundly deaf animals. PMID- 21543754 TI - Stability in a frontal plane model of balance requires coupled changes to postural configuration and neural feedback control. AB - Postural stability depends on interactions between the musculoskeletal system and neural control mechanisms. We present a frontal plane model stabilized by delayed feedback to analyze the effects of altered stance width on postural responses to perturbations. We hypothesized that changing stance width alters the mechanical dynamics of the body and limits the range of delayed feedback gains that produce stable postural behaviors. Surprisingly, mechanical stability was found to decrease as stance width increased due to decreased effective inertia. Furthermore, due to sensorimotor delays and increased leverage of hip joint torque on center-of-mass motion, the magnitudes of the stabilizing delayed feedback gains decreased as stance width increased. Moreover, the ranges of the stable feedback gains were nonoverlapping across different stance widths such that using a single neural feedback control strategy at both narrow and wide stances could lead to instability. The set of stable feedback gains was further reduced by constraints on foot lift-off and perturbation magnitude. Simulations were fit to experimentally measured kinematics, and the identified feedback gains corroborated model predictions. In addition, analytical gain margin of the linearized system was found to predict step transitions without the need for simulation. In conclusion, this model offers a method to dissociate the complex interactions between postural configuration, delayed sensorimotor feedback, and nonlinear foot lift-off constraints. The model demonstrates that stability at wide stances can only be achieved if delayed neural feedback gains decrease. This model may be useful in explaining both expected and paradoxical changes in stance width in healthy and neurologically impaired individuals. PMID- 21543755 TI - Locomotor adaptations and aftereffects to resistance during walking in individuals with spinal cord injury. AB - Muscle activity during the swing phase of walking is influenced by proprioceptive feedback pathways. Previous studies have shown that feedback and anticipatory motor commands contribute to locomotor adaptive strategies to prolonged exposure to a resistance against leg movements during walking. The purpose of this study was to determine whether people with motor-incomplete spinal cord injuries (SCI) modulate flexor muscle activity in response to different levels of resistance in a similar way as uninjured controls. A second purpose was to determine whether people with motor-incomplete SCI have the capacity to form anticipatory motor commands following exposure to resistance. Subjects walked on a treadmill with the Lokomat robotic gait orthosis. The Lokomat applied different levels of a velocity-dependent resistance, normalized to each subject's maximum voluntary contraction of the hip flexors. Each condition consisted of 20 steps against resistance followed by 20 steps without. Electromyography and kinematics of the lower limb were recorded. Although both groups responded to the resistance with an overall increase in rectus femoris activity during swing, the SCI group showed weak modulation of muscle activity to different levels of resistance. Following removal of the resistance, both groups showed aftereffects, but they were manifested differently. Controls responded to the removal of resistance with a high step, whereas the SCI subjects exhibited increased step length. The size of the aftereffect was related to the amount of added resistance. In addition, the SCI group showed a negative relationship between the size of the aftereffect and locomotor function. PMID- 21543757 TI - Concordance between perceptual and categorical repetition effects in the ventral visual stream. AB - The process of object categorization is an integral part of human cognition. In the present study, we have used a repetition suppression paradigm to determine the degree to which the ventral visual cortex is sensitive to categorical relationships. By using images of animals and tools, suppression across perceptual (stimulus level) and categorical repetitions (basic level and domain level) was compared and contrasted across the domain-selective and hierarchical organization of the ventral visual stream. Both perceptual and categorical repetition effects were insensitive to domain-selective tuning, with suppression most prominent in regions responding maximally to images, irrespective of stimulus domain. Likewise, both perceptual and categorical repetition produced overlapping suppression across multiple regions of the visual hierarchy. Some divergent patterns were observed. The right superior temporal sulcus demonstrated repetition suppression only at the basic level (different examples of the same basic object), and the right anterior fusiform gyrus was sensitive to direct stimulus repetition but not basic-level categorical repetition. Because of the high concordance between the response profiles of perceptual and categorical repetition effects, we conclude they arise from a common cognitive mechanism. PMID- 21543756 TI - The speed of context integration in the visual cortex. AB - The observation of figure-ground selectivity in neurons of the visual cortex shows that these neurons can be influenced by the image context far beyond the classical receptive field. To clarify the nature of the context integration mechanism, we studied the latencies of neural edge signals, comparing the emergence of context-dependent definition of border ownership with the onset of local edge definition (contrast polarity; stereoscopic depth order). Single neuron activity was recorded in areas V1 and V2 of Macaca mulatta under behaviorally induced fixation. Whereas local edge definition emerged immediately (<13 ms) after the edge onset response, the context-dependent signal was delayed by about 30 ms. To see if the context influence was mediated by horizontal fibers within cortex, we measured the latencies of border ownership signals for two conditions in which the relevant context information was located at different distances from the receptive field and compared the latency difference with the difference predicted from horizontal signal propagation. The prediction was based on the increase in cortical distance, computed from the mapping of the test stimuli in the cortex, and the known conduction velocities of horizontal fibers. The measured latencies increased with cortical distance, but much less than predicted by the horizontal propagation hypothesis. Probability calculations showed that an explanation of the context influence by horizontal signal propagation alone is highly unlikely, whereas mechanisms involving back projections from other extrastriate areas are plausible. PMID- 21543758 TI - Changes in the neural control of a complex motor sequence during learning. AB - The acquisition of complex motor sequences often proceeds through trial-and-error learning, requiring the deliberate exploration of motor actions and the concomitant evaluation of the resulting performance. Songbirds learn their song in this manner, producing highly variable vocalizations as juveniles. As the song improves, vocal variability is gradually reduced until it is all but eliminated in adult birds. In the present study we examine how the motor program underlying such a complex motor behavior evolves during learning by recording from the robust nucleus of the arcopallium (RA), a motor cortex analog brain region. In young birds, neurons in RA exhibited highly variable firing patterns that throughout development became more precise, sparse, and bursty. We further explored how the developing motor program in RA is shaped by its two main inputs: LMAN, the output nucleus of a basal ganglia-forebrain circuit, and HVC, a premotor nucleus. Pharmacological inactivation of LMAN during singing made the song-aligned firing patterns of RA neurons adultlike in their stereotypy without dramatically affecting the spike statistics or the overall firing patterns. Removing the input from HVC, on the other hand, resulted in a complete loss of stereotypy of both the song and the underlying motor program. Thus our results show that a basal ganglia-forebrain circuit drives motor exploration required for trial-and-error learning by adding variability to the developing motor program. As learning proceeds and the motor circuits mature, the relative contribution of LMAN is reduced, allowing the premotor input from HVC to drive an increasingly stereotyped song. PMID- 21543759 TI - Stimulus-dependent changes in optical responses of the dorsal cochlear nucleus using voltage-sensitive dye. AB - Optical imaging with voltage-sensitive dye was used to examine the spatiotemporal dynamics of stimulus-driven activity on the surface of the dorsal cochlear nucleus (DCN). Stimulation with tones at low to moderate levels produced localized regions of activation that were most commonly elongated rostrocaudally. The size of these activation areas expanded with increases in sound level, while their centers shifted from the lateral direction to the medial direction with increases in stimulus frequency. In contrast to the tonotopic patterns of activation evoked by tones, electrical stimulation of the DCN surface resulted in bands of activation that were elongated along the medial-lateral axis; response latencies increased with distance along these bands from the point of stimulation. Shifting the site of electrical stimulation from the rostral direction to the caudal direction induced corresponding shifts in the rostrocaudal location of the activation band; moving the electrode tip to subsurface depths resulted in loss of the elongated band. Transecting the DCN along the rostrocaudal axis midway between its medial and lateral extremities blocked propagation of the response to the half of the DCN distal to but not proximal to the stimulating electrode. The results suggest that the two modes of stimulation activated two distinct populations of neurons, one involving primarily tonotopically organized cells and the other crossing these tonotopic zones and likely representing the activation of parallel fibers. These results reveal a number of new features in the spatial patterns of tone-elicited activation that are not readily predicted by responses recorded electrophysiologically. PMID- 21543760 TI - Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG. AB - The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus-driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAP(G466X)) that cosegregated with a rare polymorphism in CD40LG (CD40 ligand(G219R)). These genes are involved in the X linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAP(G466X) or CD40L(G219R) had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes. PMID- 21543761 TI - Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas. AB - APRIL (A proliferation-inducing ligand) is a TNF family member that binds two TNF receptor family members, TACI and BCMA. It shares these receptors with the closely related TNF family member, B-cell activating factor (BAFF). Contrary to BAFF, APRIL binds heparan sulfate proteoglycans (HSPGs), which regulates cross linking of APRIL and efficient signaling. APRIL was originally identified as a growth promoter of solid tumors, and more recent evidence defines APRIL also as an important survival factor in several human B-cell malignancies, such as chronic lymphocytic leukemia (CLL). To target APRIL therapeutically, we developed two anti-human APRIL antibodies (hAPRIL.01A and hAPRIL.03A) that block APRIL binding to BCMA and TACI. Their antagonistic properties are unique when compared with a series of commercially available monoclonal anti-human APRIL antibodies as they prevent in vitro proliferation and IgA production of APRIL-reactive B cells. In addition, they effectively impair the CLL-like phenotype of aging APRIL transgenic mice and, more importantly, block APRIL binding to human B-cell lymphomas and prevent the survival effect induced by APRIL. We therefore conclude that these antibodies have potential for further development as therapeutics to target APRIL-dependent survival in B-cell malignancies. PMID- 21543762 TI - Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity. AB - Females are more susceptible than males to many autoimmune diseases. The processes causing this phenomenon are incompletely understood. Here, we demonstrate that aged female mice acquire a previously uncharacterized population of B cells that we call age-associated B cells (ABCs) and that these cells express integrin alpha(X) chain (CD11c). This unexpected population also appears in young lupus-prone mice. On stimulation, CD11c(+) B cells, both from autoimmune prone and healthy strains of mice, secrete autoantibodies, and depletion of these cells in vivo leads to reduction of autoreactive antibodies, suggesting that the cells might have a direct role in the development of autoimmunity. We have explored factors that contribute to appearance of ABCs and demonstrated that signaling through Toll-like receptor 7 is crucial for development of this B cell population. We were able to detect a similar population of B cells in the peripheral blood of some elderly women with autoimmune disease, suggesting that there may be parallels between the creation of ABC-like cells between mice and humans. PMID- 21543763 TI - Functional interaction of heat shock protein 90 and Beclin 1 modulates Toll-like receptor-mediated autophagy. AB - Autophagy is one of the downstream effector mechanisms for elimination of intracellular microbes following activation of the Toll-like receptors (TLRs). Although the detailed molecular mechanism for this cellular process is still unclear, Beclin 1, a key molecule for autophagy, has been suggested to play a role. Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates the stability of signaling proteins. Herein, we show that Hsp90 forms a complex with Beclin 1 through an evolutionarily conserved domain to maintain the stability of Beclin 1. In monocytic cells, geldanamycin (GA), an Hsp90 inhibitor, effectively promoted proteasomal degradation of Beclin 1 in a concentration-dependent (EC(50) 100 nM) and time-dependent (t(50) 2 h) manner. In contrast, KNK437/Hsp inhibitor I had no effect. Hsp90 specifically interacted with Beclin 1 but not with other adapter proteins in the TLR signalsome. Treatment of cells with GA inhibited TLR3 and TLR4-mediated autophagy. In addition, S. typhimurium infection-induced autophagy was blocked by GA treatment. This further suggested a role of the Hsp90/Beclin 1 in controlling autophagy in response to microbial infections. Taken together, our data revealed that by maintaining the homeostasis of Beclin 1, Hsp90 plays a novel role in TLR-mediated autophagy. PMID- 21543764 TI - Ghrelin-induced adiposity is independent of orexigenic effects. AB - Ghrelin is a hormone produced predominantly by the stomach that targets a number of specific areas in the central nervous system to promote a positive energy balance by increasing food intake and energy storage. In that respect, similarities exist with the effects of consuming a high-fat diet (HFD), which also increases caloric intake and the amount of stored calories. We determined whether the effects of ghrelin on feeding and adiposity are influenced by the exposure to an HFD. Chronic intracerebroventricular ghrelin (2.5 nmol/d) increased feeding in lean rats fed a low-fat control diet (CD) [192 +/- 5 g (ghrelin+CD) vs. 152 +/- 5 g (control i.c.v. saline+CD), P<0.001], but the combination of ghrelin plus HFD did not result in significantly greater hyperphagia [150 +/- 7 g (ghrelin+HFD) vs. 136 +/- 4 g (saline+HFD)]. Despite failing to increase food intake in rats fed the HFD, ghrelin nonetheless increased adiposity [fat mass increase of 14 +/- 2 g (ghrelin+HFD) vs. 1 +/- 1 g (saline+HFD), P<0.001] up-regulating the gene expression of lipogenic enzymes in white adipose tissue. Our findings demonstrate that factors associated with high fat feeding functionally interact with pathways regulating the effect of ghrelin on food intake. We conclude that ghrelin's central effects on nutrient intake and nutrient partitioning can be separated and suggest an opportunity to identify respective independent neuronal pathways. PMID- 21543765 TI - The laminin-induced acrosome reaction in human sperm is mediated by Src kinases and the proteasome. AB - The aim of this work was to determine whether laminin (Ln), an extracellular matrix protein, induces the intracellular events that may be involved in producing the acrosome reaction in human sperm. To this end, we evaluated the effect of Ln on tyrosine phosphorylation, intracellular calcium concentration, proteasome activity, and phosphorylation in human sperm. Aliquots of highly motile sperm selected with a Percoll gradient, were incubated with different concentrations of Ln (0-20 MUg/ml) for different periods (0-18 h). The percentage of viable acrosome-reacted sperm was evaluated using fluorescein isothiocyanate labeled Pisum sativum agglutinin and Hoechst 33258 DNA dye. Tyrosine phosphorylation was evaluated by Western blot analysis. The chymotrypsin-like activity of the proteasome was evaluated with a fluorogenic peptide, and intracellular calcium concentration was measured with fura-2. The results indicate that Ln stimulated the acrosome reaction of human sperm in a dose dependent manner. This increase was drastically inhibited in the presence of herbimycin A, SU6656, and epoxomicin. In addition, Ln increased proteasome activity and phosphorylation; both events were inhibited by herbimycin A and SU6656. Finally, Ln induced an increase in intracellular calcium concentration, which was inhibited by SU6656 and epoxomicin. These results suggest that Ln is able to induce the acrosome reaction. This effect may be mediated by Src kinase and the proteasome, with the consequent induction of a calcium influx. PMID- 21543766 TI - Kruppel-like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen. AB - Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Kruppel-like factor 9 (KLF9), a member of the evolutionarily conserved Sp family of transcription factors, is expressed in uterine stroma and glandular epithelium, where it affects cellular proliferation, differentiation, and apoptosis. Deregulated expression of a number of Sp proteins has been associated with multiple types of human tumors, but a role for KLF9 in endometrial cancer development and/or progression is unknown. Here, we evaluated KLF9 expression in endometrial tumors and adjacent uninvolved endometrium of women with endometrial carcinoma. KLF9 mRNA and protein levels were lower in endometrial tumors coincident with decreased expression of family member KLF4 and growth-regulators FBJ murine osteosarcoma viral oncogene homolog (FOS) and myelocytomatosis viral oncogene homolog (MYC) and with increased expression of telomerase reverse transcriptase (TERT) and the chromatin-modifying enzymes DNA methyltransferase 1 (DNMT1) and histone deacetylase 3 (HDAC3). Expression of estrogen receptor alpha (ESR1) and the tumor-suppressor phosphatase and tensin homolog deleted in chromosome 10 (PTEN) did not differ between tumor and normal tissue. The functional relevance of attenuated KLF9 expression in endometrial carcinogenesis was further evaluated in the human endometrial carcinoma cell line Ishikawa by siRNA targeting. KLF9 depletion resulted in loss of normal cellular response to the proliferative effects of estrogen concomitant with reductions in KLF4 and MYC and with enhancement of TERT and ESR1 gene expression. Silencing of KLF4 did not mimic the effects of silencing KLF9 in Ishikawa cells. We suggest that KLF9 loss-of-expression accompanying endometrial carcinogenesis may predispose endometrial epithelial cells to mechanisms of escape from estrogen mediated growth regulation, leading to progression of established neoplasms. PMID- 21543768 TI - Discovery of candidate genes and pathways regulating oviduct development in chickens. AB - Estrogen is a key regulator in the development of the female reproductive system. It also stimulates oviduct development in immature chicks. We identified candidate genes and pathways associated with the development of chicken oviducts. A pellet containing the synthetic estrogen analog diethylstilbestrol (DES) was implanted subcutaneously in 1-wk-old female chicks for 10 days. The pellet was removed from half the group for 10 days, and an additional dose was given for a further 10 days. Total RNA was extracted from the oviducts of DES-treated and untreated chicks and subjected to an Affymetrix chicken GeneChip analysis. We found differential expression of 2290 and 1745 transcripts from the oviducts that were treated with DES once and twice, respectively. We also found a twofold or greater change in the expression of 77 and 390 transcripts between the two control and DES-treated time points, respectively, while we found a change in the expression of 10 transcripts that were common to all groups. Analyses of real time PCR and in situ hybridization of selected genes confirmed the validity of the gene expression patterns observed in the microarray analysis. In particular, CCRN4L, FAM26F, HAS2, NELF, and NTM were up-regulated in the DES-treated chicken oviducts. High-throughput analysis revealed that the differentially expressed genes were related to tubular formation, epithelial differentiation, hormone interactions, nerve development, and tissue remodeling in the chicken oviduct. This study provides novel insights into candidate genes regulating oviduct development and differentiation via estrogen. The identified genes may serve as biomarkers of reproductive tract development in chicks. PMID- 21543767 TI - Mice lacking the USP2 deubiquitinating enzyme have severe male subfertility associated with defects in fertilization and sperm motility. AB - The ubiquitin-proteasome system plays an important role in spermatogenesis. However, the functions of deubiquitinating enzymes in this process remain poorly characterized. We previously showed that the deubiquitinating enzyme USP2 is induced in late elongating spermatids. To identify its function, we generated mice lacking USP2. Usp2 -/- mice appeared normal, and the weights of major organs, including the testis, did not differ from wild type (Usp2 +/+). However, although the numbers of testicular spermatids and epididymal spermatozoa were normal in Usp2 -/- males, these animals had a severe defect in fertility, yielding only 12% as many offspring as Usp2 +/+ littermates. Spermatogenesis in Usp2 -/- mice was morphologically normal except for the presence of abnormal aggregations of elongating spermatids and formation of multinucleated cells in some tubules. The epididymal epithelium was morphologically normal in Usp2 -/- mice, but some abnormal cells other than sperm were present in the lumen. Usp2 -/ epididymal spermatozoa manifested normal motility when incubated in culture media, but rapidly became immotile when incubated in PBS in contrast to Usp2 +/+ spermatozoa, which largely maintained motility under this condition. Usp2 -/- and +/+ spermatozoa underwent acrosome reactions in vitro with similar frequency. In vitro fertilization assays demonstrated a severe defect in the ability of Usp2 -/ spermatozoa to fertilize eggs. This could be bypassed by intracytoplasmic sperm injection or removal of the zona pellucida, which resulted in fertilization rates similar to that of Usp2 +/+ mice. We demonstrate for the first time, using mouse transgenic approaches, a role for the ubiquitin system in fertilization. PMID- 21543769 TI - Sox2 modulates reprogramming of gene expression in two-cell mouse embryos. AB - Sox2 is a key gene that controls transcriptional networks required for pluripotency. The role of Sox2 in the developmental transition of a highly differentiated oocyte to totipotent blastomeres of the early preimplantation embryo, however, is not known. We report that Sox2, which is localized in the nucleus, is first zygotically expressed during the 2-cell stage and that its expression dramatically increases between the morula and blastocyst stages. Injecting a cRNA encoding Sox2 into 1-cell embryos resulted in overexpression of SOX2 by approximately 70% and developmental arrest at the 2-cell stage, whereas injecting cRNAs encoding Pou5f1, Myc (also known as c-Myc), or Klf4 has little effect on the ability of 2-cell embryos to cleave to the 4-cell stage. Global transcription assessed by bromo uridine triphosphate incorporation is reduced by approximately 15%, and transcript profiling revealed that approximately 15% of zygotically expressed genes are dramatically repressed in 2-cell embryos overexpressing SOX2. Furthermore, overexpressing a dominant-negative SOX2 perturbs reprogramming of gene expression in 2-cell embryos, though to a much lesser extent than that observed following overexpression of SOX2, and leads to developmental failure after the 2-cell stage but before the 8-cell stage. Results of these experiments implicate Sox2 as a critical transcriptional regulator in the oocyte-to-embryo transition that entails formation of totipotent blastomeres and indicate that the amount of Sox2 is critical for successful execution of this transition. PMID- 21543770 TI - Inhibitor of DNA binding 4 is expressed selectively by single spermatogonia in the male germline and regulates the self-renewal of spermatogonial stem cells in mice. AB - Continual spermatogenesis at a quantitatively normal level is required to sustain male fertility. The foundation of this process relies on maintenance of an undifferentiated spermatogonial population consisting of spermatogonial stem cells (SSCs) that self-renew as well as transient amplifying progenitors produced by differentiation. In mammals, type A(single) spermatogonia form the SSC population, but molecular markers distinguishing these from differentiating progenitors are undefined and knowledge of mechanisms regulating their functions is limited. We show that in the mouse male germline the transcriptional repressor ID4 is expressed by a subpopulation of undifferentiated spermatogonia and selectively marks A(single) spermatogonia. In addition, we found that ID4 expression is up-regulated in isolated SSC-enriched fractions by stimulation from GDNF, a key growth factor driving self-renewal. In mice lacking ID4 expression, quantitatively normal spermatogenesis was found to be impaired due to progressive loss of the undifferentiated spermatogonial population during adulthood. Moreover, reduction of ID4 expression by small interfering RNA treatment abolished the ability of wild-type SSCs to expand in vitro during long-term culture without affecting their survival. Collectively, these results indicate that ID4 is a distinguishing marker of SSCs in the mammalian germline and plays an important role in the regulation of self-renewal. PMID- 21543771 TI - Sertoli cell-specific deletion of the androgen receptor compromises testicular immune privilege in mice. AB - In the mammalian testis, meiotic and postmeiotic germ cell antigens are granted immune privilege. Both local immune suppression and specialized intercellular junctions between somatic Sertoli cells have been proposed to contribute to a highly restricted and effective blood-testis barrier (BTB) that helps maintain tolerance to germ cell antigens. Several studies have suggested that androgens play a role in immune suppression, although direct evidence for this is lacking. We previously reported that Sertoli cell-specific ablation of the androgen receptor (Ar) decreases expression of Cldn3, an androgen-regulated gene and component of Sertoli cell tight junctions, and increases the permeability of the BTB to biotin, a small-molecular-weight tracer. The physiological consequences of Sertoli cell-specific Ar (S-Ar) ablation on immune privilege are unknown. Here we show that in the testes of S-Ar mutant mice, the ultrastructure of Sertoli cell tight junctions is defective and testicular IgG levels are elevated. The interstitium of S-Ar mutant testes becomes populated with macrophages, neutrophils, plasma cells, and eosinophils, and serum samples of mutant mice contain antibodies against germ cell antigens. Together, these results suggest that Sertoli cell-specific deletion of the androgen receptor results in loss of testicular immune privilege. Suppressed levels of androgen signaling may be a contributing factor in idiopathic male infertility. PMID- 21543772 TI - Seminal advances in immunology of reproduction. PMID- 21543774 TI - Iron replacement therapy in cancer-related anemia: introduction. PMID- 21543775 TI - Iron replacement therapy in cancer-related anemia. AB - PURPOSE: The incidence, etiology, and management of cancer-related anemia is reviewed and the role of i.v. iron therapy in its treatment is described. SUMMARY: Between 30% and 90% of patients with cancer develop anemia due to direct effects of the disease, its treatment, underlying nutritional deficiencies, and the inflammation that characterizes chronic disease. Although the use of erythropoiesis-stimulating agents (ESAs) increases hemoglobin levels and decreases the need for transfusions, up to 50% of patients do not to respond to these drugs, usually due to the presence of absolute or functional iron deficiency. Multiple clinical trials have demonstrated that i.v. iron supplementation in patients with cancer-related anemia improves the response rate to ESAs, reduces the time to target hemoglobin levels, decreases ESA requirements, reduces costs, and is more efficacious than oral iron. These benefits are seen without increased toxicity. Nonetheless, i.v. iron remains underused in patients with cancer, partly due to misinformation and misinterpretation of the clinical nature of adverse events. CONCLUSION: Intravenous iron is underutilized in patients with cancer-related anemia. Based on published evidence, i.v. iron supplementation in patients with absolute or functional iron deficiency can improve patient responses to ESAs and reduce ESA requirements and may also reduce the need for transfusions and improve quality of life. PMID- 21543776 TI - The effect of lung deflation on the position and size of the subclavian vein in mechanically ventilated infants and children. AB - BACKGROUND: If lung deflation increases the distance from the subclavian vein (SCV) to the pleura and the diameter of the vein, it might decrease the risk of pneumothorax and increase the success rate of subclavian venous cannulation. We evaluated the effect of lung deflation on the distance from the SCV to the pleura (SCV-pleura distance) and on the cross-sectional area (CSA) of the SCV in mechanically ventilated pediatric patients. METHODS: Fifty patients (25 infants younger than 1 year and 25 children aged 1 to 8 years) were placed supine over a shoulder roll, and their lungs were ventilated with a tidal volume of 6 to 7 mL/kg. Lung deflation was achieved by opening the endotracheal tube to the atmosphere. The SCV-pleura distances and the SCV CSAs were measured using ultrasound at the end of inflation and 0, 30, 60, 90, and 120 seconds after lung deflation. A P value <0.05 was considered statistically significant. Increases of 5% in the distance and 25% in the CSA were defined as clinically relevant. RESULTS: The available data from 43 patients, 22 infants and 21 children, were analyzed. No clinically relevant changes in the SCV-pleura distance or in the SCV CSA were induced by lung deflation. Neither the SCV-pleura distance nor the CSA showed any further increase with time. CONCLUSIONS: Lung deflation failed to increase the SCV-pleura distance and the CSA of the SCV. Its application is unlikely to be advantageous in avoiding pneumothorax or improving the success rate of subclavian venous cannulation. PMID- 21543777 TI - Accounting for inpatient wards when developing master surgical schedules. AB - BACKGROUND: As the demand for health care services increases, the need to improve patient flow between departments has likewise increased. Understanding how the master surgical schedule (MSS) affects the inpatient wards and exploiting this relationship can lead to a decrease in surgery cancellations, a more balanced workload, and an improvement in resource utilization. We modeled this relationship and used the model to evaluate and select a new MSS for a hospital. METHODS: An operational research model was used in combination with staff input to develop a new MSS. A series of MSSs were proposed by staff, evaluated by the model, and then scrutinized by staff. Through iterative modifications of the MSS proposals (i.e., the assigned operating time of specialties), insight is obtained into the number, type, and timing of ward admissions, and how these affect ward occupancy. RESULTS: After evaluating and discussing a number of proposals, a new MSS was chosen that was acceptable to operating room staff and that balanced the ward occupancy. After implementing the new MSS, a review of the bed-use statistics showed it was achieving a balanced ward occupancy. The model described in this article gave the hospital the ability to quantify the concerns of multiple departments, thereby providing a platform from which a new MSS could be negotiated. CONCLUSION: The model, used in combination with staff input, supported an otherwise subjective discussion with quantitative analysis. The work in this article, and in particular the model, is readily repeatable in other hospitals and relies only on readily available data. PMID- 21543778 TI - Laboratory variables associated with low near-infrared cerebral oxygen saturation in icteric patients before liver transplantation surgery. AB - BACKGROUND: Although regional cerebral oxygen saturation (rSO2) measurements can detect disturbances in cerebral oxygenation, their usefulness is limited in patients with hyperbilirubinemia. We examined the relationship between rSO2 and other laboratory variables that may affect interpretation of low rSO2 in awake patients with end-stage liver disease before liver transplantation surgery. METHODS: Before induction of general anesthesia, rSO2 was measured in 164 patients with liver cirrhosis (Child class A/B/C = 19/41/104) and 8 with fulminant hepatic failure. Patients with West Haven hepatic encephalopathy of grade 3 or 4 were excluded. Relationships between rSO2 and laboratory variables were evaluated by correlation and multivariate regression, and by receiver operating characteristic curve analysis. RESULTS: Univariate analyses showed that rSO2 (median 58.5%, range 15% to 82%) correlated with serum total bilirubin, hemoglobin (Hb), creatinine, sodium, and magnesium concentrations, and prothrombin time (P < 0.001 each), but not with serum concentrations of glucose, albumin, potassium, and ammonia. Multiple logistic regression analysis showed that only elevated total bilirubin (range 0.4 to 66 mg/dL; odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.18 to 1.45) and low Hb (range 5.3 to 15.7 g/dL; OR = 0.21; 95% CI = 0.11 to 0.43) were independently related to rSO2 <50%. The optimum cutoff points for observing an rSO2 < 50% were total bilirubin >7.2 mg/dL (sensitivity 89%, specificity 90%) and Hb <9.6 g/dL (sensitivity 70%, specificity 82%). CONCLUSIONS: High total bilirubin and low Hb concentrations were independently associated with rSO2 values below 50% in end-stage liver disease patients awaiting liver transplantation. The results of this study identify patients in whom a low rSO2 may be an artifact rather than cerebral ischemia. PMID- 21543779 TI - Adenovirus-delivered angiopoietin 1 accelerates the resolution of inflammation of acute endotoxic lung injury in mice. AB - BACKGROUND: The immune system plays a key role in protecting the organism from infection. Timely resolution of the inflammatory response to infection plays a vital role in returning homeostasis and maintaining normal organ function. Angiopoietin1 prevents endothelial activation, part of the inflammatory response to a pathogen, and has an anti-inflammatory effect in acute lung injury. We designed this study to investigate whether increasing serum production of angiopoietin1 by IV administration of adenoviral-delivered angiopoietin1 could accelerate the resolution of inflammation in endotoxin-induced acute lung injury in mice. METHODS: Lipopolysaccharide was intratracheally instilled to induce acute lung injury in animals pretreated for 24 hours with adenoviral-GFP vector or adenoviral-GFP-angiopoietin1, respectively. An additional 6 mice in each pretreatment group were killed before lipopolysaccharide instillation to serve as controls. Indices of resolution of inflammation were analyzed. Apoptotic polymorphonuclear leukocytes and their phagocytosis by macrophages were determined by fluorescent activated cell sorter. The expression of angiopoietin1 in tissues and granulocyte macrophage colony-stimulating factor in the bronchoalveolar lavage fluid were measured. RESULTS: Lipopolysaccharide induced leukocyte infiltration into air spaces, with maximal infiltration 48 hours after lipopolysaccharide instillation. Pretreatment with adenovirus-GFP-angiopoietin1 markedly increased angiopoietin1 expression, reduced leukocyte, and neutrophil infiltration and shortened the duration of inflammation. Adenovirus-GFP angiopoietin1 pretreatment augmented the magnitude without altering the time course of granulocyte macrophage colony-stimulating factor. CONCLUSIONS: Our results suggest that angiopoietin1 pretreatment promotes resolution of inflammation in endotoxin-induced acute lung injury in mice by accelerating the apoptosis of neutrophils and their phagocytosis by macrophages. PMID- 21543780 TI - Adenosine triphosphate-sensitive potassium channel blockers attenuate the antiallodynic effect of R-PIA in neuropathic rats. AB - BACKGROUND: Nerve injury can generate neuropathic pain. The accompanying mechanical allodynia may be reduced by the intrathecal administration of adenosine. The neuroprotective effects of adenosine are mediated by the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel. We assessed the relationship between the adenosine A1 receptor agonist, N6-(R)-phenylisopropyl adenosine (R-PIA), and K(ATP) channels to determine whether the antiallodynic effects of R-PIA are also mediated through K(ATP) channels in a rat nerve ligation injury model of neuropathic pain. METHODS: Mechanical allodynia was induced by tight ligation of the left lumbar fifth and sixth spinal nerves. Mechanical allodynia in the left hindpaw was evaluated using von Frey filaments to measure withdrawal thresholds. R-PIA (0.5, 1, or 2 MUg) was administered intrathecally to induce antiallodynia. We assessed whether pretreatment with the K(ATP) channel blockers glibenclamide or 5-hydroxydecanoate reversed the antiallodynic effect of R-PIA. Also, we evaluated whether diazoxide, a K(ATP) channel opener, had an antiallodynic effect and promoted the antiallodynic effect of R-PIA. Lastly, we investigated whether the voltage-activated K channel blocker 4-aminopyridine attenuated the effect of R-PIA. RESULTS: Intrathecal R-PIA produced maximal antiallodynia at 2 MUg (P < 0.05). Intrathecal pretreatment with glibenclamide and intraperitoneal pretreatment 5-hydroxydecanoate significantly reduced the antiallodynic effect of R-PIA. Diazoxide produced an antiallodynic effect and also enhanced the antiallodynic action of R-PIA. 4-Aminopyridine had no effect on the antiallodynic action of R-PIA. CONCLUSIONS: The antiallodynic effects of adenosine A1 receptor stimulation may be related to K(ATP) channel activity in a rat model of nerve ligation injury. PMID- 21543782 TI - Workforce and finances of the United States anesthesiology training programs: 2009-2010. AB - Financial and workforce surveys were sent to 121 and 124 United States Anesthesiology training programs in 2009 and 2010, respectively. Seventy-two respondents (60%) and 81 respondents (65%) demonstrated median institutional support per faculty of $120,000 and $111,000; open faculty positions of 4% and 4.8%. Faculty billed an average of 11,050 units/year and collected $35.00/unit. In 2010, 56% of departments had installed anesthesia information management systems and 14% have signed a contract for an anesthesia information management system. PMID- 21543783 TI - Activated charcoal effectively removes inhaled anesthetics from modern anesthesia machines. AB - INTRODUCTION: If a malignant hyperthermia-susceptible patient is to receive an anesthetic, an anesthesia machine that has been used previously to deliver volatile anesthetics should be flushed with a high fresh gas flow. Conflicting results from previous studies recommend flush times that vary from 10 to 104 minutes. In a previously proposed alternative decontamination technique, other investigators placed an activated charcoal filter in the inspired limb of the breathing circuit. METHODS: We placed activated charcoal filters on both the inspired and expired limbs of several contaminated anesthesia machines and measured the time needed to flush the machine so that the delivered concentrations of isoflurane, sevoflurane, and desflurane would be <5 parts per million (ppm). We next simulated the case for which malignant hyperthermia is diagnosed 90 minutes after induction of anesthesia and measured how well activated charcoal filters limit further exposure. RESULTS: Activated charcoal filters decrease the concentration of volatile anesthetic delivered by a contaminated machine to an acceptable level in <2 minutes. The concentrations remained well below 5 ppm for at least 60 minutes. When malignant hyperthermia is diagnosed after induction of anesthesia, we found that with charcoal filters in place, the current anesthesia machine may be used for at least 67 minutes before the inspired concentration exceeds 5 ppm. CONCLUSIONS: Activated charcoal filters provide an alternative approach to the 10 to 104 minutes of flushing that are normally required to prepare a machine that has been used previously to deliver a volatile anesthetic. PMID- 21543784 TI - Statistical grand rounds: design and analysis of studies with binary- event composite endpoints: guidelines for anesthesia research. AB - Composite endpoints consisting of several binary events, such as distinct perioperative complications, are frequently chosen as the primary outcome in anesthesia studies (and in many other clinical specialties) because (1) no single outcome fully characterizes the disease or outcome of interest, and/or (2) individual outcomes are rare and statistical power would be inadequate for any single one. Interpreting a composite endpoint is challenging because components rarely meet the ideal criteria of having comparable clinical importance, frequency, and treatment effects. We suggest guidelines for forming composite endpoints and show advantages of newer versus conventional statistical methods for analyzing them. Components should be a parsimonious set of outcomes, which when taken together, well represent the disease of interest and are very plausibly related to the intervention. Adding components that are too narrow, redundant, or minimally influenced by the study intervention compromises interpretation of results and reduces power. We show that multivariate (i.e., multiple outcomes per patient) methods of analyzing a binary-event composite provide distinct advantages over standard methods such as any-versus-none, count of events, or evaluation of individual events. Multivariate methods can incorporate clinical importance weights, compensate for events occurring at varying frequencies, assess treatment effect heterogeneity, and are often more powerful than alternative statistical approaches. Methods are illustrated with an American College of Surgeons National Surgical Quality Improvement Program registry study that evaluated the effects of smoking on major perioperative outcomes, and with a clinical trial comparing the effects of crystalloids and colloids on major complications. Sample data files and SAS code are included for convenience. PMID- 21543785 TI - The mechanisms of propofol-induced vascular relaxation and modulation by perivascular adipose tissue and endothelium. AB - BACKGROUND: Propofol causes hypotension due to relaxation of vascular smooth muscle cells through its direct or indirect vasodilator effects. Perivascular adipose tissue (PVAT) and endothelium attenuate vascular contraction, and the function of PVAT is altered in hypertension and diabetes. Whether PVAT affects the action of anesthetics on vascular function is unknown. We studied the mechanisms of propofol-induced relaxation in relation to the involvement of PVAT and endothelium. METHODS: Thoracic aortic rings from Wistar rats were prepared with or without PVAT (PVAT+ and PVAT-), intact endothelium (E+), or both, or with the endothelium removed (E-) for functional studies. RESULTS: In phenylephrine precontracted vessels, propofol-induced relaxation was highest with both PVAT and E+ and lowest in vessels denuded of both PVAT and endothelium. Propofol-induced relaxation occurred via both endothelium-dependent and -independent mechanisms. The relaxation response induced by propofol was significantly reduced by nitric oxide synthase inhibitor (l-NNA), K(+) channel blockers (tetraethylammonium and glibenclamide) in E+ and E- vessels, and by soluble guanylyl cyclase inhibitor 1H (1,2,4) oxadiazolo (4,3-A) quinazoline-1-one and hydrogen peroxide scavenger (catalase) in E- vessels. The presence of PVAT significantly enhanced the relaxation response induced by propofol. In contrast to phenylephrine precontracted vessels in which the presence of PVAT or endothelium had an effect, in vessels precontracted with KCl, propofol-induced relaxation was similar among the 4 types of vessel preparation. CONCLUSIONS: PVAT enhances the relaxation effect induced by propofol in rat aorta through both endothelium-dependent and endothelium-independent pathways thus highlighting the clinical importance of PVAT. PMID- 21543786 TI - Low dose alpha-2 antagonist paradoxically enhances rat norepinephrine and clonidine analgesia. AB - Ultralow-dose opioid antagonists prolong opioid antinociception and block tolerance. In this study we determined whether low doses of the alpha-2 adrenergic receptor (A2-R) antagonist, atipamezole, similarly influenced A2-R induced antinociception and tolerance. In rats, intrathecal norepinephrine (NE) or clonidine in combination with atipamezole was tested using tail-flick and paw pressure tests. Acute tolerance to NE was induced by serial injections. Low-dose atipamezole significantly prolonged NE and clonidine-induced antinociception. Coadministration of atipamezole with A2-R agonists also prevented loss of agonist potency in the acute tolerance model. This study demonstrates paradoxical effects of low-dose A2-R antagonists augmenting A2-R agonist-induced analgesia. PMID- 21543787 TI - Postoperative mortality in children after 101,885 anesthetics at a tertiary pediatric hospital. AB - BACKGROUND: Mortality is a basic measure for quality and safety in anesthesia. There are few anesthesia-related mortality data available for pediatric practice. Our objective for this study was to determine the incidence of 24-hour and 30-day mortality after anesthesia and to determine the incidence and nature of anesthesia-related mortality in pediatric practice at a large tertiary institution. METHODS: Children <= 18 years old who had an anesthetic between January 1, 2003, and August 30, 2008, at the Royal Children's Hospital, Melbourne, Australia, were included for this study. Data were analyzed by merging a database for every anesthetic performed with an accurate electronic record of mortality of children who had ever been a Royal Children's Hospital patient. Cases of children dying within 30 days and 24 hours of an anesthetic were identified and the patient history and anesthetic record examined. Anesthesia related death was defined as those cases whereby a panel of 3 senior anesthesiologists all agreed that anesthesia or factors under the control of the anesthesiologist more likely than not influenced the timing of death. RESULTS: During this 68-month period, 101,885 anesthetics were administered to 56,263 children. The overall 24-hour mortality from any cause after anesthesia was 13.4 per 10,000 anesthetics delivered and 30-day mortality was 34.5 per 10,000 anesthetics delivered. The incidence of death was highest in children <= 30 days old. Patients undergoing cardiac surgery had a higher incidence of 24-hour and 30 day mortality than did those undergoing noncardiac surgery. From 101,885 anesthetics there were 10 anesthesia-related deaths. The incidence of anesthesia related death was 1 in 10,188 or 0.98 cases per 10,000 anesthetics performed (95%confidence interval, 0.5 to 1.8). In all 10 cases, preexisting medical conditions were identified as being a significant factor in the patient's death. Five of these cases (50%) involved children with pulmonary hypertension. CONCLUSIONS: Anesthesia-related mortality is higher in children with heart disease and in particular those with pulmonary hypertension. The lack of anesthetic-related deaths in children who did not have major comorbidities reinforces the safety of pediatric anesthesia in healthy children. PMID- 21543788 TI - Suppression of cautery-induced electromagnetic interference of cardiac implantable electrical devices by closely spaced bipolar sensing. AB - BACKGROUND: Electromagnetic interference (EMI) induced by electrocautery during surgery in patients with cardiac pacemakers or implanted cardioverter defibrillators (ICDs) may inhibit pacing and cause inappropriate tachyarrhythmia oversensing. In particular, susceptibility to EMI may be enhanced in ICDs by frequently used wide interelectrode sensing (i.e., integrated bipolar sensing). Consequently, ICD function is usually disabled preoperatively and restored later by noninvasive programming. Because sensing by closely spaced electrodes (i.e., true bipolar) may be less susceptible to EMI, preoperative programming to a true bipolar mode may minimize the need for perioperative programming while preserving device function. METHODS: Our study population consisted of 23 consecutive patients either receiving a new ICD or undergoing ICD pulse generator change. In each patient, electrocautery-induced EMI was initiated with the ICD in the closely spaced sensing configuration and again during widely spaced sensing. RESULTS: In comparing the 2 sensing modes, right ventricular electrogram amplitude was significantly greater and EMI noise amplitude tended to be greater with widely spaced bipolar sensing. Furthermore, widely spaced bipolar sensing was associated with ICD pacing inhibition in 22 of 23 patients and incorrect "ventricular fibrillation" detection in 17 of 23 patients. Conversely, closely spaced bipolar sensing was not accompanied by either pacing inhibition or incorrect ventricular fibrillation sensing. CONCLUSION: Closely spaced bipolar sensing (i.e., true bipolar) appropriately rejects electrocautery-induced EMI. Programming implanted devices to closely spaced bipolar sensing may minimize the need for perioperative reprogramming while preserving intraoperative device operation. PMID- 21543791 TI - Genetic studies of the etiology of asthma. AB - Asthma is a heterogeneous disease for which a strong genetic basis is firmly established. Although the generally accepted definition includes three domains of symptoms (variable airway obstruction, airway hyper-responsiveness, and airway inflammation), there is general agreement that, rather than being a single disease entity, asthma consists of related, overlapping syndromes. A considerable proportion of asthma is IgE-mediated, but the observation that not all individuals with asthma are atopic adds to the heterogeneity. Although a genetic basis for asthma is undeniable, elucidation of polymorphisms that are "causal" is greatly hampered by variability in the clinical phenotype, which is likely due to the multiple molecular mechanisms underlying the complex pathological processes involved in disease development and progression. One objective of this review is to consider progress that has been made to date in gene discovery in the field of asthma, with a focus on the evolution of molecular genetic methods that have led to the discoveries thus far, and with a particular focus on the major advances owed to the published genome-wide association studies (GWAS) on asthma to date. A second objective is to consider a Darwinian approach toward understanding the genetic underpinnings of asthma, including evidence supporting a modified Hygiene Hypothesis, which suggests that there are co-associations between asthma risk polymorphisms and polymorphisms associated with another IgE-mediated disease, schistosomiasis. The overall conclusion is that the huge research efforts and expense committed to asthma genetics have changed the perception about disease etiology in general and the functional relevance of the asthma genes identified thus far in particular. PMID- 21543789 TI - Oxidative stress-mediated regulation of proteasome complexes. AB - Oxidative stress has been implicated in aging and many human diseases, notably neurodegenerative disorders and various cancers. The reactive oxygen species that are generated by aerobic metabolism and environmental stressors can chemically modify proteins and alter their biological functions. Cells possess protein repair pathways to rescue oxidized proteins and restore their functions. If these repair processes fail, oxidized proteins may become cytotoxic. Cell homeostasis and viability are therefore dependent on the removal of oxidatively damaged proteins. Numerous studies have demonstrated that the proteasome plays a pivotal role in the selective recognition and degradation of oxidized proteins. Despite extensive research, oxidative stress-triggered regulation of proteasome complexes remains poorly defined. Better understanding of molecular mechanisms underlying proteasome function in response to oxidative stress will provide a basis for developing new strategies aimed at improving cell viability and recovery as well as attenuating oxidation-induced cytotoxicity associated with aging and disease. Here we highlight recent advances in the understanding of proteasome structure and function during oxidative stress and describe how cells cope with oxidative stress through proteasome-dependent degradation pathways. PMID- 21543792 TI - Genetics of complex airway disease. AB - The past 3 years have seen highly significant genetic effects identified for a wide variety of common complex diseases, including the airway disorders of asthma and chronic obstructive pulmonary disease. It appears that only a portion of the genetically mediated susceptibility to complex diseases has been identified, and there is much left to be discovered. This review briefly describes the results of the genome-wide association studies of asthma and gives an overview of the parallel and increasingly large-scale studies that are taking place with chronic obstructive pulmonary disease. The future impact is discussed of technological advances that allow increasingly large-scale gene expression studies, next generation sequencing, and genome-wide testing for epigenetic effects. The use of genetic technology to examine the airway microbiota that interact with the mucosa in health and disease is described. PMID- 21543793 TI - Pulmonary arterial hypertension: insights from genetic studies. AB - Familial pulmonary arterial hypertension (FPAH) was described 60 years ago, but real progress in understanding its origins and pathogenesis is just beginning. Germline mutations in bone morphogenetic protein receptor type 2 (BMPR2) are responsible for the disease in most families, and also in many sporadic cases of idiopathic PAH. Heritable PAH refers to patients with a positive family history, or with a responsible genetic mutation, and is an autosomal dominant disease that affects females disproportionately, may occur at any age, and is characterized by reduced penetrance and variable expressivity. These characteristics suggest that other endogenous or exogenous factors modify its expression. Several different factors have recently been demonstrated to modify the clinical expression of BMPR2 mutation, including estrogen metabolites and functional polymorphisms in transforming growth factor-beta1 and CYP1B1. Furthermore, a linkage study recently identified modifier loci for BMPR2 clinical expression, which suggests an oligogenic model. Clinical testing for BMPR2 mutations is available for families with heritable and idiopathic PAH, and is an evolving model of personalized medicine. Variable age of onset and decreased penetrance confound genetic counseling, because the majority of carriers of a BMPR2 mutation will never develop PAH, but often transmit the risk to their progeny. PMID- 21543794 TI - Idiopathic pulmonary fibrosis: update on genetic discoveries. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the lungs that increases in prevalence with advanced age. Recent evidence indicates that mutations in genes of two different biologic pathways lead to the common phenotype of familial pulmonary fibrosis (FPF) and sporadic IPF. Mutations in the genes encoding the lung surfactant proteins C and A2 (SFTPC and SFTPA2, respectively) cause increased endoplasmic reticulum stress in type II alveolar epithelial cells. Mutations in the genes encoding telomerase (TERT and TERC) cause IPF through shortening of telomere lengths and probable exhaustion of lung stem cells. All of the mutations are individually rare, but, collectively, TERT mutations are the most common genetic defect found in FPF. The overall penetrance of pulmonary fibrosis in TERT mutation carriers is 40% in subjects with a mean age of 51 years. Penetrance increases with advanced age, is greater in males than in females, and is positively associated with fibrogenic environmental exposures. Short telomere lengths are found in patients with FPF and sporadic IPF without mutations in telomerase, suggesting that the biologic pathway of telomerase dysfunction provides a biologic explanation for the age-related prevalence of IPF. The molecular data of two seemingly unrelated biologic pathways-alveolar epithelial endoplasmic reticulum stress and telomerase dysfunction-are beginning to elucidate the pathogenesis of IPF. These results have potentially predictive and therapeutic value. PMID- 21543795 TI - Toward a systematic understanding of mRNA 3' untranslated regions. AB - Messenger RNAs (mRNAs) contain prominent untranslated regions (UTRs) that are increasingly recognized to play roles in mRNA processing, transport, stability, and translation. 3' UTRs are believed to harbor recognition sites for a diverse set of RNA-binding proteins that regulate gene expression as well as most active microRNA target sites. Although the roles of 3' UTRs in the normal and diseased lung have not yet been studied extensively, available evidence suggests important roles for 3' UTRs in lung development, inflammation, asthma, pulmonary fibrosis, and cancer. Systematic, genome-wide approaches are beginning to catalog functional elements within 3' UTRs and identify the proteins and microRNAs that interact with these elements. Application of new data sets and experimental approaches should provide powerful insights into how 3' UTR-mediated regulatory events contribute to disease and may inspire novel therapeutic approaches. PMID- 21543796 TI - Genomic investigations into acute inflammatory lung injury. AB - Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome, are complex illnesses involving the interplay of both environmental (such as mechanical ventilation) and genetic factors. To understand better the underlying mechanisms of pathogenesis associated with ALI, we recently identified several candidate genes by global expression profiling in preclinical models of ALI and relevant single-nucleotide polymorphisms. We summarize here several strategies successfully used to identify novel ALI candidate genes and detail the validation of variants in these genes as contributing factors to ALI pathobiology, conclusions based on functional analyses, and specific genetic association studies conducted in ALI cohorts. Continued insights into ALI pathogenesis and identification of genetic variants, which confer ALI risk and severity, promise to reveal novel molecular therapeutic targets that can be translated into personalized treatments to reduce the very high, unacceptable mortality of this disorder. PMID- 21543797 TI - Transcriptomic studies of the airway field of injury associated with smoking related lung disease. AB - The "field of injury" hypothesis proposes that exposure to an inhaled insult such as cigarette smoke elicits a common molecular response throughout the respiratory tract. This response can therefore be quantified in any airway tissue, including readily accessible epithelial cells in the bronchus, nose, and mouth. High throughput technologies, such as whole-genome gene expression microarrays, can be employed to catalog the physiological consequences of such exposures in the airway epithelium. Pulmonary diseases such as chronic obstructive pulmonary disease, lung cancer, and asthma are also thought to be associated with a field of injury, and in patients with these diseases, airway epithelial cells can be a useful surrogate for diseased tissue that is often difficult to obtain. Global measurement of mRNA and microRNA expression in these cells can provide useful information about the molecular pathogenesis of such diseases and may be useful for diagnosis and for predicting prognosis and response to therapy. In this review, our aim is to summarize the history and state of the art of such "transcriptomic" studies in the human airway epithelium, especially in smoking and smoking-related lung diseases, and to highlight future directions for this field. PMID- 21543798 TI - Pathway-based classification of lung cancer: a strategy to guide therapeutic selection. AB - The critical challenge in virtually all cancer research is heterogeneity: "Breast cancer" and "lung cancer" are actually collections of disease with distinct molecular mechanisms and clinical characteristics. The challenge is evident in the complexity of most cancers with multiple mutations and alterations generating the cancer phenotype, requiring therapeutic strategies that can match the complexity with equally complex combination regimens. Substantial progress in treatment requires major advances in methods to define refined, "common mechanism" subgroups to allow development of combination therapeutics that target these individual mechanisms. Our work is on the use of genomic signatures of oncogenic signaling pathways that provide an opportunity to dissect the complexity of lung cancer and to serve as tools to direct the use of targeted therapeutic agents. PMID- 21543801 TI - Systems biology and personalized medicine: a network approach to human disease. AB - Human diseases have historically been classified on the basis of their end-organ manifestations, using a traditional clinicopathological approach dating to the 19th century. With the advent of rigorous molecular methodologies at the end of the 20th century, many specific disease determinants were identified and more targeted therapeutic strategies developed. Although the conventional reductionist approach underlying these strategies for understanding disease served us well in the pregenomic era, it hampers our understanding of the complex molecular networks within which disease develops that are increasingly manifest in the current era. This article presents a novel, holistic method for classifying human diseases that can serve as a template for understanding disease pathobiology, prognosis, and treatment. PMID- 21543799 TI - Advances in proteomic strategies toward the early detection of lung cancer. AB - Since the advent of the new proteomics era more than a decade ago, large-scale studies of protein profiling have been exploited to identify the distinctive molecular signatures in a wide array of biological systems spanning areas of basic biological research, various disease states, and biomarker discovery directed toward therapeutic applications. Recent advances in protein separation and identification techniques have significantly improved proteomics approaches, leading to enhancement of the depth and breadth of proteome coverage. Proteomic signatures specific for invasive lung cancer and preinvasive lesions have begun to emerge. In this review we provide a critical assessment of the state of recent advances in proteomic approaches and the biological lessons they have yielded, with specific emphasis on the discovery of biomarker signatures for the early detection of lung cancer. PMID- 21543802 TI - Aspen Lung Conference 2010: systems biology of lung diseases--progress in the omics era. AB - The 53rd annual Thomas L. Petty Aspen Lung Conference focused on the dramatic progress that has been made in the past several years in applying large-scale, unbiased data acquisition ("omics") to the study of lung biology and disease. The conference organizers, Mark Geraci, Ivor Douglas, Stephen Rennard, and David Schwartz, put together a terrific program, and the invited speakers and participants presented data describing the rapid evolution of experimental approaches that should encourage pulmonary scientists to begin to think about a true molecular systems biology of the lung. PMID- 21543800 TI - Proteostasis: a new therapeutic paradigm for pulmonary disease. AB - Among lung pathologies, alpha1AT, chronic obstructive pulmonary disease (COPD), emphysema, and asthma are diseases triggered by local environmental stress in the airway that we refer to herein collectively as airway stress diseases (ASDs). A deficiency of alpha-1-antitrypsin (alpha1AT) is an inherited genetic disorder that is a consequence of the misfolding of alpha1AT during protein synthesis in liver hepatocytes, reducing secretion to the plasma and delivery to the lung. Deficiency of alpha1AT in the lung triggers a similar pathological phenotype to other ASDs. Moreover, the loss of alpha1AT in the lung is a well-known environmental risk factor for COPD/emphysema. To date there are no effective therapeutic approaches to address ASDs, which reflects a general lack of understanding of their cellular basis. Herein, we propose that ASDs are disorders of proteostasis. That is, they are initiated and propagated by a common theme-a challenge to protein folding capacity maintained by the proteostasis network (PN) (see Balch et al., Science 2008;319:916-919). The PN is a network of chaperones and degradative components that generates and manages protein folding pathways responsible for normal human physiology. In ASD, we suggest that the PN system fails to respond to the increased burden of unfolded proteins due to genetic and environmental stresses, thus triggering pulmonary pathophysiology. We introduce the enabling concept of proteostasis regulators (PRs), small molecules that regulate signaling pathways that control the composition and activity of PN components, as a new and general approach for therapeutic management of ASDs. PMID- 21543822 TI - Psychiatric morbidity in prisoners with intellectual disabilities: analysis of prison survey data for England and Wales. AB - A substantial number of prisoners have intellectual disabilities. We analysed data on a sample drawn from all prisons in England and Wales. Intellectual disability was defined as Quick Test scores equivalent to an IQ of <=65. We found a significantly higher prevalence of probable psychosis, attempted suicide and cannabis use in prisoners with intellectual disabilities. Presence of intellectual disability was twice as likely to be associated with probable psychosis but the relationship was fully mediated by self-rated health status. It is important to identify this group as early as possible in order to provide timely interventions to cope in adverse environments and manage substance misuse. PMID- 21543823 TI - Effects of lowered serotonin transmission on cocaine-induced striatal dopamine response: PET [11C]raclopride study in humans. AB - BACKGROUND: Low serotonin transmission is thought to increase susceptibility to a wide range of substance use disorders and impulsive traits. AIMS: To investigate the effects of lowered serotonin on cocaine-induced (1.0 mg/kg cocaine, self administered intranasally) dopamine responses and drug craving. METHOD: In non dependent cocaine users, serotonin transmission was reduced using the acute tryptophan depletion method. Striatal dopamine responses were measured using positron emission tomography with [(11)C]raclopride. RESULTS: Acute tryptophan depletion increased drug craving and striatal dopamine responses to cocaine. These acute tryptophan depletion-induced increases did not occur in the absence of cocaine. CONCLUSIONS: The results suggest that low serotonin transmission can increase dopaminergic and appetitive responses to cocaine. These findings might identify a mechanism by which individuals with low serotonin are at elevated risk for both substance use disorders and comorbid conditions. PMID- 21543824 TI - Aging and osteoporosis in breast and prostate cancer. AB - As people with cancer survive longer, and as the US population ages, skeletal effects of cancer treatment are becoming more pronounced. This is particularly true for breast and prostate cancer survivors because of the high average age of patients with these malignancies, the propensity of older adults in general toward the development of osteoporosis, and the wide use of therapeutic agents in these cancers that negatively impact bone health. Various therapies used in the treatment and prevention of cancer may cause decreases in bone mineral density and an increased risk of debilitating fracture, even in the absence of bone metastases. Aging is both a baseline risk factor in the development of osteoporosis and bony fracture, as well as a predictor of poor outcome after fracture. A variety of mechanisms may be responsible for the development of bone loss in patients with breast or prostate cancer. Cytotoxic chemotherapy may directly exert long-term toxic effects on bone. Chemotherapy and endocrine therapy can induce hypogonadism, leading to an increased rate of bone loss. The risk of skeletal events in older adults due to cancer therapy should be appreciated by all oncologists, geriatricians, and internists. The following review may serve as a guide to the skeletal side effects of cancer therapy in older adults with breast or prostate cancer, how to screen for treatment-related bone loss, and how to best prevent and/or treat skeletal events. PMID- 21543825 TI - The management of cancer pain. AB - The experience of pain in cancer is widely accepted as a major threat to quality of life, and the relief of pain has emerged as a priority in oncology care. Pain is associated with both the disease as well as treatment, and management is essential from the onset of early disease through long-term survivorship or end of-life care. Effective relief of pain is contingent upon a comprehensive assessment to identify physical, psychological, social, and spiritual aspects and as a foundation for multidisciplinary interventions. Fortunately, advances in pain treatment and in the field of palliative care have provided effective treatments encompassing pharmacological, cognitive-behavioral, and other approaches. The field of palliative care has emphasized that attention to symptoms such as pain is integral to quality cancer care. PMID- 21543826 TI - Hierarchical, interface-induced self-assembly of diphenylalanine: formation of peptide nanofibers and microvesicles. AB - To gain insight into the hierarchical self-assembly of peptides and the surface effect on assembly formation, an aromatic peptide of diphenylalanine (FF) was used in this study as the model peptide. We found that the diphenylalanine peptide could self-assemble into a core-branched nanostructure through non covalent interactions in aqueous solution. The pre-assemblies further assembled into nanofibers and microvesicles on the glass surface and microporous membrane, respectively, showing a significant dependence on surface characteristics. The structural and morphological differences between nanofibers and microvesicles were investigated directly using several spectroscopy and microscopy techniques. Our results revealed a hierarchical and interface-induced assembly behavior of diphenylalanine peptide. The novel strategy based on the surface effect allows one to controllably fabricate various peptide-based nanostructures. PMID- 21543827 TI - Intrinsic DNA curvature of double-crossover tiles. AB - A theoretical model which takes into account the structural distortion of double crossover DNA tiles has been studied to investigate its effect on lattice formation sizes. It has been found that a single vector appropriately describes the curvature of the tiles, of which a higher magnitude hinders lattice growth. In conjunction with these calculations, normal mode analysis reveals that tiles with relative higher frequencies have an analogous effect. All the theoretical results are shown to be in good agreement with experimental data. PMID- 21543828 TI - Facile synthesis of zinc hydroxide carbonate flowers on zinc oxide nanorods with attractive luminescent and optochemical performance. AB - A simple synthesis route was designed to fabricate a functional composite, zinc hydroxide carbonate (ZHC) flowers on zinc oxide (ZnO) nanorods. The hydrolysis of hexamethylenetetramine (HMT) can generate various species which are slowly released and gradually change reaction modes in a Zn(NO(3))(2)/HMT solution. As a result, ZnO nanorods and ZHC flowers can be sequentially synthesized and connect very well under constant experimental conditions. The obtained composite has the advantages of both components and exhibits attractive properties. For instance, ZHC flowers on ZnO nanorods exhibit strong blue emission under the excitation of ultraviolet light, and dye-sensitized solar cells with the annealed composite as photoanode achieve much higher conversion efficiency than pure nanorod arrays. PMID- 21543829 TI - Influence of plasmon destructive interferences on optical properties of gold planar quadrumers. AB - Arrays of planar symmetric gold quadrumers consisting of a central nano-disc surrounded by three similar nano-discs belonging to the D(3h) point group were designed and fabricated. Since the geometrical configuration of quadrumers is the same as planar trigonal molecules, nano-discs can play the roles of artificial atoms to study the coupling trends among them. The plasmonic properties of the nano-disc structures are investigated by reflection spectrum measurement and finite-difference time-domain calculation with good agreement. Plasmon interaction among the nano-discs is also studied via a mass-spring coupled oscillator model. A pronounced Fano resonance (FR) is observed for the fabricated nano-discs with inter-disk gaps of around 18 nm during light irradiation at normal incidence. Although the obtained FR is independent of the excitation polarization, the near-field energy spatial distribution can be flexibly tuned by the polarization direction. This has potential applications in nano-lithography, optical switching and nonlinear spectroscopy. PMID- 21543830 TI - Piperidine induced polarity conversion in single-walled carbon nanotube field effect transistors. AB - Piperidine is found to be an efficient electron doping agent that converts as prepared p-type single-walled carbon nanotube (SWCNT) field effect transistors (FETs) into n-type SWCNT-FETs. Electron transfer from the amine group in piperidine to the SWCNTs is suggested to be the origin of the p- to n-type conversion. The effect of electron doping is further supported by the Raman tangential G(+) and G(-)-peak downshift up to 3 cm(-1) without the peak broadening. No detectable change in the Raman D-peak suggests non-covalent attachment of piperidine to the SWCNTs. A low temperature (110 degrees C) Si(3)N(4) passivation layer is used to maintain the long term air stability of the converted n-type devices. A complementary SWCNT inverter is demonstrated through integrating the n- and p-type SWCNT-FETs. PMID- 21543831 TI - Electrical properties of individual CoPt/Pt multilayer nanowires characterized by in situ SEM nanomanipulators. AB - Here we report for the first time accurate and comprehensive measurements of electrical properties of individual CoPt/Pt multilayer nanowires both with periodic and non-periodic layer structures. A remarkably high failure current density of 1.69 * 10(12) A m(-2) for the periodic MNW and a similar 1.76 * 10(12) A m(-2) for the non-homogeneous MNW has been measured. The resistance of both types of multilayer nanowire structures are well fitted by a series resistance model, determining the separate resistance contribution of the component layers and magnetic/nonmagnetic interfaces for a single multilayer nanowire. The field dependent interface resistance of both samples is calculated, 13.2 Omega for periodic layer structures and 4.84 Omega for non-periodic layer structures. The clear physical picture of the resistance distribution within individual multilayer nanowires is then determined. The accurate electrical testing of magnetic multilayer nanowires provides basic and necessary electrical parameters for their usage as building blocks or interconnects in nanoelectronics and nanosensors. PMID- 21543832 TI - Synthesis of copper nanoparticles by solid-state plasma-induced dewetting. AB - Copper nanoparticles were prepared by the plasma treatment of Cu thin films without extra heating. The Cu nanoparticles were formed through a solid-state dewetting process at temperatures of less than 450 K. The particle sizes, from 10 to 80 nm, were controlled by changing the thickness of the Cu film; the particle size increased linearly with the film thickness. The Cu nanoparticles produced by plasma treatment showed an excellent size uniformity compared to those prepared by heat treatment. In the early stage of the dewetting of the Cu film, uniformly distributed holes nucleated, and the holes grew and coalesced until the Cu nanoparticles were formed. The low operating temperatures used contributed to the production of uniform Cu nanoparticles. PMID- 21543833 TI - Crystalline structures and misfit strain inside Er silicide nanocrystals self assembled on Si(001) substrates. AB - The morphology and crystalline structure of Er silicide nanocrystals self assembled on the Si(001) substrate were investigated using scanning tunneling microscopy (STM) and transmission electron microscopy (TEM). It was found that the nanowires and nanorods formed at 630 degrees C has dominant hexagonal AlB(2) type structure, while inside the nanoislands self-organized at 800 degrees C the tetragonal ThSi(2)-type structure is prevalent. The lattice analysis via cross sectional high-resolution TEM demonstrated that internal misfit strain plays an important role in controlling the growth of nanocrystals. With the relaxation of strain, the nanoislands could evolve from a pyramid-like shape into a truncated hut-like shape. PMID- 21543834 TI - Human haptoglobin phenotypes and concentration determination by nanogold-enhanced electrochemical impedance spectroscopy. AB - Haptoglobin (Hp) is an acute phase protein that binds free hemoglobin (Hb), preventing Hb-induced oxidative damage in the vascular system. There are three phenotypes in human Hp, whose heterogeneous polymorphic structures and varying concentrations in plasma have been attributed to the cause of diseases and outcome of clinical treatments. Different phenotypes of Hp may be composed of the same subunits but different copy numbers, rendering their determination difficult by a single procedure. In this study, we have developed a simple, fast, reliable and sensitive method, using label-free nanogold-modified bioprobes coupled with self-development electrochemical impedance spectroscopy (EIS). By this method, probe surface charge transfer resistance is detected. The relative charge transfer resistance ratios for Hp 1-1, Hp 2-1 and Hp 2-2 were characterized. We were able to determine protein size difference within 3 nm, and the linear region of the calibration curve for Hp levels in the range of 90 pg ml(-1) and 90 ug ml( 1) (~1 fM to 1 pM). We surmise that similar approaches can be used to investigate protein polymorphism and altered protein-protein interaction associated with diseases. PMID- 21543835 TI - Triggering the volume phase transition of core-shell Au nanorod-microgel nanocomposites with light. AB - We have coated gold nanorods (NRs) with thermoresponsive microgel shells based on poly(N-isopropylacrylamide) (pNIPAM). We demonstrate by simultaneous laser heating and optical extinction measurements that the Au NR cores can be simultaneously used as fast optothermal manipulators (switchers) and sensitive optical reporters of the microgel state in a fully externally controlled and reversible manner. We support our results with optical modeling based on the boundary element method and 3D numerical analysis on the temperature distribution. Briefly, we show that due to the sharp increase in refractive index resulting from the optothermally triggered microgel collapse, the longitudinal plasmon band of the coated Au NRs is significantly red-shifted. The optothermal control over the pNIPAM shell, and thereby over the optical response of the nanocomposite, is fully reversible and can be simply controlled by switching on and off a NIR heating laser. In contrast to bulk solution heating, we demonstrate that light-triggering does not compromise colloidal stability, which is of primary importance for the ultimate utilization of these types of nanocomposites as remotely controlled optomechanical actuators, for applications spanning from drug delivery to photonic crystals and nanoscale motion. PMID- 21543836 TI - Metallic nanocone array photonic substrate for high-uniformity surface deposition and optical detection of small molecules. AB - Molecular probe arrays printed on solid surfaces such as DNA, peptide, and protein microarrays are widely used in chemical and biomedical applications especially genomic and proteomic studies (Pollack et al 1999 Nat. Genet. 23 41-6, Houseman et al 2002 Nat. Biotechnol. 20 270-4, Sauer et al 2005 Nat. Rev. Genet. 6 465-76) as well as surface imaging and spectroscopy (Mori et al 2008 Anal. Biochem. 375 223-31, Liu et al 2006 Nat. Nanotechnol. 1 47-52, Liu 2010 IEEE J. Sel. Top. Quantum Electron. 16 662-71). Unfortunately the printed molecular spots on solid surfaces often suffer low distribution uniformity due to the lingering 'coffee stain' (Deegan et al 1997 Nature 389 827-9) problem of molecular accumulations and blotches, especially around the edge of deposition spots caused by solvent evaporation and convection processes. Here we present, without any surface chemistry modification, a unique solid surface of high-aspect-ratio silver-coated silicon nanocone arrays that allows highly uniform molecular deposition and thus subsequent uniform optical imaging and spectroscopic molecular detection. Both fluorescent Rhodamine dye molecules and unlabeled oligopeptides are printed on the metallic nanocone photonic substrate surface as circular spot arrays. In comparison with the printed results on ordinary glass slides and silver-coated glass slides, not only high printing density but uniform molecular distribution in every deposited spot is achieved. The high-uniformity and repeatability of molecular depositions on the 'coffee stain'-free nanocone surface is confirmed by laser scanning fluorescence imaging and surface enhanced Raman imaging experiments. The physical mechanism for the uniform molecular deposition is attributed to the superhydrophobicity and localized pinned liquid solid-air interface on the silver-coated silicon nanocone surface. The unique surface properties of the presented nanocone surface enabled high-density, high uniformity probe spotting beneficial for genomic and proteomic microarrays and surface molecular imaging. PMID- 21543837 TI - A novel cationic liposome formulation for efficient gene delivery via a pulmonary route. AB - The clinical success of gene therapy for lung cancer is not only dependent on efficient gene carriers but also on a suitable delivery route. A pulmonary delivery route can directly deliver gene vectors to the lung which is more efficient than a systemic delivery route. For gene carriers, cationic liposomes have recently emerged as leading non-viral vectors in worldwide gene therapy clinical trials. However, cytotoxic effects or apoptosis are often observed which is mostly dependent on the cationic lipid used. Therefore, an efficient and safe cationic lipid, 6-lauroxyhexyl lysinate (LHLN), previously synthesized by our group was first used to prepare cationic liposomes. Physicochemical and biological properties of LHLN-liposomes were investigated. LHLN-liposome/DNA complexes showed positive surface charge, spherical morphology, a relatively narrow particle size distribution and strong DNA binding capability. Compared with Lipofectamine2000, the new cationic liposome formulation using LHLN exhibited not only lower cytotoxicity (P < 0.05) but also similar transfection efficiency in A549 and HepG2 lung cancer cells for in vitro tests. When administered by intratracheal instillation into rat lungs for in vivo evaluation, LHLN-liposome/DNA complexes exhibited higher pulmonary gene transfection efficiency than Lipofectamine2000/DNA complexes (P < 0.05). These results suggested that LHLN-liposomes may have great potential for efficient pulmonary gene delivery. PMID- 21543838 TI - Recruitment and blocking properties of the CardioFit stimulation lead. AB - The CardioFit vagal stimulation system has been developed as a proposed therapy for congestive heart failure (CHF). CardioFit is to be implanted in several hundred CHF patients enrolled in the INOVATE-HF clinical trial, an FDA approved study. The CardioFit stimulation lead (CSL), which is a cuff electrode that delivers stimulation pulses to the right cervical vagus, was designed to recruit efferent cardiac vagal fibers while minimizing unwanted recruitment of other fibers. This paper presents the CSL and measurements of its recruiting and blocking properties when placed on isolated porcine vagus nerves maintained at an elevated temperature in oxygenated artificial cerebrospinal fluid. Using charge balanced quasi-trapezoidal pulses driven through the CSL, we show in eight out of nine nerves a 63% +/- 13% (mean +/- SD) unidirectional attenuation of the A-fiber compound action potential attained at a current of 3.0 +/- 0.8 mA. The threshold for the activation of A- and B-fibers was found to be 0.3 +/- 0.17 mA and 2.5 +/- 1.1 mA, respectively. The results presented here should help to guide the optimal parameters used in the upcoming deployment of the CardioFit system. PMID- 21543839 TI - A chronic generalized bi-directional brain-machine interface. AB - A bi-directional neural interface (NI) system was designed and prototyped by incorporating a novel neural recording and processing subsystem into a commercial neural stimulator architecture. The NI system prototype leverages the system infrastructure from an existing neurostimulator to ensure reliable operation in a chronic implantation environment. In addition to providing predicate therapy capabilities, the device adds key elements to facilitate chronic research, such as four channels of electrocortigram/local field potential amplification and spectral analysis, a three-axis accelerometer, algorithm processing, event-based data logging, and wireless telemetry for data uploads and algorithm/configuration updates. The custom-integrated micropower sensor and interface circuits facilitate extended operation in a power-limited device. The prototype underwent significant verification testing to ensure reliability, and meets the requirements for a class CF instrument per IEC-60601 protocols. The ability of the device system to process and aid in classifying brain states was preclinically validated using an in vivo non-human primate model for brain control of a computer cursor (i.e. brain-machine interface or BMI). The primate BMI model was chosen for its ability to quantitatively measure signal decoding performance from brain activity that is similar in both amplitude and spectral content to other biomarkers used to detect disease states (e.g. Parkinson's disease). A key goal of this research prototype is to help broaden the clinical scope and acceptance of NI techniques, particularly real-time brain state detection. These techniques have the potential to be generalized beyond motor prosthesis, and are being explored for unmet needs in other neurological conditions such as movement disorders, stroke and epilepsy. PMID- 21543840 TI - Continuous neuronal ensemble control of simulated arm reaching by a human with tetraplegia. AB - Functional electrical stimulation (FES), the coordinated electrical activation of multiple muscles, has been used to restore arm and hand function in people with paralysis. User interfaces for such systems typically derive commands from mechanically unrelated parts of the body with retained volitional control, and are unnatural and unable to simultaneously command the various joints of the arm. Neural interface systems, based on spiking intracortical signals recorded from the arm area of motor cortex, have shown the ability to control computer cursors, robotic arms and individual muscles in intact non-human primates. Such neural interface systems may thus offer a more natural source of commands for restoring dexterous movements via FES. However, the ability to use decoded neural signals to control the complex mechanical dynamics of a reanimated human limb, rather than the kinematics of a computer mouse, has not been demonstrated. This study demonstrates the ability of an individual with long-standing tetraplegia to use cortical neuron recordings to command the real-time movements of a simulated dynamic arm. This virtual arm replicates the dynamics associated with arm mass and muscle contractile properties, as well as those of an FES feedback controller that converts user commands into the required muscle activation patterns. An individual with long-standing tetraplegia was thus able to control a virtual, two joint, dynamic arm in real time using commands derived from an existing human intracortical interface technology. These results show the feasibility of combining such an intracortical interface with existing FES systems to provide a high-performance, natural system for restoring arm and hand function in individuals with extensive paralysis. PMID- 21543841 TI - Structure of Greyhound hemoglobin: origin of high oxygen affinity. AB - This study presents the crystal structure of Greyhound hemoglobin (GrHb) determined to 1.9 A resolution. GrHb was found to crystallize with an alpha1beta1 dimer in the asymmetric unit and belongs to the R2 state. Oxygen-affinity measurements combined with the fact that GrHb crystallizes in the R2 state despite the high-salt conditions used for crystallization strongly indicate that GrHb can serve as a model high-oxygen-affinity hemoglobin (Hb) for higher mammals, especially humans. Structural analysis of GrHb and its comparison with the R2-state of human Hb revealed several regions that can potentially contribute to the high oxygen affinity of GrHb and serve to rationalize the additional stability of the R2-state of GrHb. A previously well studied hydrophobic cluster of bar-headed goose Hb near alpha119 was also incorporated in the comparison between GrHb and human Hb. Finally, a structural comparison with generic dog Hb and maned wolf Hb was conducted, revealing that in contrast to GrHb these structures belong to the R state of Hb and raising the intriguing possibility of an additional allosteric factor co-purifying with GrHb that can modulate its quaternary structure. PMID- 21543842 TI - Structural and functional studies of mycobacterial IspD enzymes. AB - A number of pathogens, including the causative agents of tuberculosis and malaria, synthesize isopentenyl diphosphate via the 2-C-methyl-D-erythritol 4 phosphate (MEP) pathway rather than the classical mevalonate pathway found in humans. As part of a structure-based drug-discovery program against tuberculosis, IspD, the enzyme that carries out the third step in the MEP pathway, was targeted. Constructs of both the Mycobacterium smegmatis and the Mycobacterium tuberculosis enzymes that were suitable for structural and inhibitor-screening studies were engineered. Two crystal structures of the M. smegmatis enzyme were produced, one in complex with CTP and the other in complex with CMP. In addition, the M. tuberculosis enzyme was crystallized in complex with CTP. Here, the structure determination and crystallographic refinement of these crystal forms and the enzymatic characterization of the M. tuberculosis enzyme construct are reported. A comparison with known IspD structures allowed the definition of the structurally conserved core of the enzyme. It indicates potential flexibility in the enzyme and in particular in areas close to the active site. These well behaved constructs provide tools for future target-based screening of potential inhibitors. The conserved nature of the extended active site suggests that any new inhibitor will potentially exhibit broad-spectrum activity. PMID- 21543843 TI - High-resolution structure of exo-arabinanase from Penicillium chrysogenum. AB - Arabinanase Abnx from Penicillium chrysogenum 31B, which belongs to the GH93 family, releases arabinobiose from the nonreducing terminus of alpha-1,5-L arabinan, which is distributed in the primary cell walls of higher plants. Crystal structures of Abnx and of its complex with arabinobiose were determined at the high resolutions of 1.14 A to an R(work) of 10.7% (R(free) = 12.8%) and 1.04 A to an R(work) of 10.4% (R(free) = 12.5%). Abnx has a six-bladed beta propeller fold with a typical ring-closure mode called 'Velcro', in which the last four-stranded beta-sheet is completed by the incorporation of a strand from the N-terminus. Catalytic residues which act as a nucleophile and an acid/base were proposed from the structures and confirmed by site-directed mutagenesis. The substrate-binding groove is enclosed at one end by two residues, Glu64 and Tyr66, which contribute to the recognition of the nonreducing chain end of the polysaccharide. A comparison with the related enzyme Arb93A which has a quite similar overall structure suggested that Abnx has different mechanisms to funnel substrates to the active site and/or to stabilize the transition state. PMID- 21543845 TI - Network approach for capturing ligand-induced subtle global changes in protein structures. AB - Ligand-induced conformational changes in proteins are of immense functional relevance. It is a major challenge to elucidate the network of amino acids that are responsible for the percolation of ligand-induced conformational changes to distal regions in the protein from a global perspective. Functionally important subtle conformational changes (at the level of side-chain noncovalent interactions) upon ligand binding or as a result of environmental variations are also elusive in conventional studies such as those using root-mean-square deviations (r.m.s.d.s). In this article, the network representation of protein structures and their analyses provides an efficient tool to capture these variations (both drastic and subtle) in atomistic detail in a global milieu. A generalized graph theoretical metric, using network parameters such as cliques and/or communities, is used to determine similarities or differences between structures in a rigorous manner. The ligand-induced global rewiring in the protein structures is also quantified in terms of network parameters. Thus, a judicious use of graph theory in the context of protein structures can provide meaningful insights into global structural reorganizations upon perturbation and can also be helpful for rigorous structural comparison. Data sets for the present study include high-resolution crystal structures of serine proteases from the S1A family and are probed to quantify the ligand-induced subtle structural variations. PMID- 21543844 TI - The structure of the PERK kinase domain suggests the mechanism for its activation. AB - The endoplasmic reticulum (ER) unfolded protein response (UPR) is comprised of several intracellular signaling pathways that alleviate ER stress. The ER localized transmembrane kinase PERK is one of three major ER stress transducers. Oligomerization of PERK's N-terminal ER luminal domain by ER stress promotes PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr980 on the kinase activation loop. Activated PERK phosphorylates Ser51 of the alpha-subunit of translation initiation factor 2 (eIF2alpha), which inhibits initiation of protein synthesis and reduces the load of unfolded proteins entering the ER. The crystal structure of PERK's kinase domain has been determined to 2.8 A resolution. The structure resembles the back to-back dimer observed in the related eIF2alpha kinase PKR. Phosphorylation of Thr980 stabilizes both the activation loop and helix alphaG in the C-terminal lobe, preparing the latter for eIF2alpha binding. The structure suggests conservation in the mode of activation of eIF2alpha kinases and is consistent with a 'line-up' model for PERK activation triggered by oligomerization of its luminal domain. PMID- 21543846 TI - X-ray crystal structure and small-angle X-ray scattering of sheep liver sorbitol dehydrogenase. AB - The X-ray crystal structure of sheep liver sorbitol dehydrogenase (slSDH) has been determined using the crystal structure of human sorbitol dehydrogenase (hSDH) as a molecular-replacement model. slSDH crystallized in space group I222 with one monomer in the asymmetric unit. A conserved tetramer that superposes well with that seen in hSDH (despite belonging to a different space group) and obeying the 222 crystal symmetry is seen in slSDH. An acetate molecule is bound in the active site, coordinating to the active-site zinc through a water molecule. Glycerol, a substrate of slSDH, also occupies the substrate-binding pocket together with the acetate designed by nature to fit large polyol substrates. The substrate-binding pocket is seen to be in close proximity to the tetramer interface, which explains the need for the structural integrity of the tetramer for enzyme activity. Small-angle X-ray scattering was also used to identify the quaternary structure of the tetramer of slSDH in solution. PMID- 21543847 TI - Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: insights into the role of HLA-A alleles in susceptibility to multiple sclerosis. AB - The structure of the human major histocompatability (MHC) class I molecule HLA A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 A resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease. PMID- 21543848 TI - Structure of a two-CAP-domain protein from the human hookworm parasite Necator americanus. AB - Major proteins secreted by the infective larval stage hookworms upon host entry include Ancylostoma secreted proteins (ASPs), which are characterized by one or two CAP (cysteine-rich secretory protein/antigen 5/pathogenesis related-1) domains. The CAP domain has been reported in diverse phylogenetically unrelated proteins, but has no confirmed function. The first structure of a two-CAP-domain protein, Na-ASP-1, from the major human hookworm parasite Necator americanus was refined to a resolution limit of 2.2 A. The structure was solved by molecular replacement (MR) using Na-ASP-2, a one-CAP-domain ASP, as the search model. The correct MR solution could only be obtained by truncating the polyalanine model of Na-ASP-2 and removing several loops. The structure reveals two CAP domains linked by an extended loop. Overall, the carboxyl-terminal CAP domain is more similar to Na-ASP-2 than to the amino-terminal CAP domain. A large central cavity extends from the amino-terminal CAP domain to the carboxyl-terminal CAP domain, encompassing the putative CAP-binding cavity. The putative CAP-binding cavity is a characteristic cavity in the carboxyl-terminal CAP domain that contains a His and Glu pair. These residues are conserved in all single-CAP-domain proteins, but are absent in the amino-terminal CAP domain. The conserved His residues are oriented such that they appear to be capable of directly coordinating a zinc ion as observed for CAP proteins from reptile venoms. This first structure of a two CAP-domain ASP can serve as a template for homology modeling of other two-CAP domain proteins. PMID- 21543849 TI - Pi sampling: a methodical and flexible approach to initial macromolecular crystallization screening. AB - The Pi sampling method is derived from the incomplete factorial approach to macromolecular crystallization screen design. The resulting 'Pi screens' have a modular distribution of a given set of up to 36 stock solutions. Maximally diverse conditions can be produced by taking into account the properties of the chemicals used in the formulation and the concentrations of the corresponding solutions. The Pi sampling method has been implemented in a web-based application that generates screen formulations and recipes. It is particularly adapted to screens consisting of 96 different conditions. The flexibility and efficiency of Pi sampling is demonstrated by the crystallization of soluble proteins and of an integral membrane-protein sample. PMID- 21543850 TI - Structure of human dual-specificity phosphatase 27 at 2.38 A resolution. AB - There are over 100 genes in the human genome that encode protein tyrosine phosphatases (PTPs) and approximately 60 of these are classified as dual specificity phosphatases (DUSPs). Although many dual-specificity phosphatases are still not well characterized, novel functions have been discovered for some of them that have led to new insights into a variety of biological processes and the molecular basis for certain diseases. Indeed, as the functions of DUSPs continue to be elucidated, a growing number of them are emerging as potential therapeutic targets for diseases such as cancer, diabetes and inflammatory disorders. Here, the overexpression, purification and structure determination of DUSP27 at 2.38 A resolution are presented. PMID- 21543851 TI - Structural basis for compound C inhibition of the human AMP-activated protein kinase alpha2 subunit kinase domain. AB - AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor to maintain energy balance at both the cellular and the whole-body levels and is therefore a potential target for drug design against metabolic syndrome, obesity and type 2 diabetes. Here, the crystal structure of the phosphorylated-state mimic T172D mutant kinase domain from the human AMPK alpha2 subunit is reported in the apo form and in complex with a selective inhibitor, compound C. The AMPK alpha2 kinase domain exhibits a typical bilobal kinase fold and exists as a monomer in the crystal. Like the wild-type apo form, the T172D mutant apo form adopts the autoinhibited structure of the 'DFG-out' conformation, with the Phe residue of the DFG motif anchored within the putative ATP-binding pocket. Compound C binding dramatically alters the conformation of the activation loop, which adopts an intermediate conformation between DFG-out and DFG-in. This induced fit forms a compound-C binding pocket composed of the N-lobe, the C-lobe and the hinge of the kinase domain. The pocket partially overlaps with the putative ATP-binding pocket. These three-dimensional structures will be useful to guide drug discovery. PMID- 21543852 TI - Involvement of the distal Arg residue in Cl- binding of midge larval haemoglobin. AB - Monomeric haemoglobin component V (Hb V) from the larva of the midge Propsilocerus akamusi shows high Cl- affinity under high salt concentrations at acidic pH. In order to understand the structural changes that depend on Cl- binding, crystal structures of Hb V were determined under acidic high-salt conditions and the structural changes arising from different haem-bound ligands were simulated. Crystal structures of Hb V under acidic high-salt conditions indicated that the side chain of ArgE10 on the distal face of the haem contributes to stabilizing haem-bound Cl-. The conformation of the Arg side chain in the Cl--bound form was almost identical to that in ligated Hb V at neutral pH but not to that in met Hb V under acidic salt-free conditions. Furthermore, preliminary molecular-dynamics simulations also indicated that the swinging of the Arg side chain into the haem pocket depends on Cl- ligation. This result suggests that, like pH change, Cl- binding affects the location of the distal Arg residue. Owing to the increased positive electrostatic potential observed in the haem pocket at acidic pH, it was concluded that electrostatic changes caused by pH change and anionic ligand binding may affect the behaviour of the polar Arg residue. PMID- 21543854 TI - Structure of CBM4 from Clostridium thermocellum cellulase K. AB - Here, a 2.0 A resolution X-ray structure of Clostridium thermocellum cellulase K family 4 carbohydrate-binding module (CelK CBM4) is reported. The resulting structure was refined to an R factor of 0.212 and an R(free) of 0.274. Structural analysis shows that this new structure is very similar to the previously solved structure of C. thermocellum CbhA CBM4. Most importantly, these data support the previously proposed notion of an extended binding pocket using a novel tryptophan containing loop that may be highly conserved in clostridial CBM4 proteins. PMID- 21543855 TI - Structure of the uncomplexed Neisseria meningitidis factor H-binding protein fHbp (rLP2086). AB - fHbp, a highly immunogenic outer membrane protein of Neisseria meningitidis, is responsible for binding to human factor H, a multi-domain protein which is the central regulator of the alternative complement pathway. Here, the crystal structure of mature fHbp determined at 2 A resolution is presented and is compared with the structure of the same protein in complex with factor H domains 6 and 7 recently solved using X-ray techniques. While the overall protein fold is well conserved, modifications are observed mainly in the loop regions involved in the interaction, reflecting a specific adaptation of fHbp in complexing factor H with high affinity. Such a comparison has to date been impaired by the fact that fHbp models determined by NMR show remarkable differences over the entire structure. PMID- 21543856 TI - Structural analysis of full-length Hfq from Escherichia coli. AB - The structure of full-length host factor Qbeta (Hfq) from Escherichia coli obtained from a crystal belonging to space group P1, with unit-cell parameters a = 61.91, b = 62.15, c = 81.26 A, alpha = 78.6, beta = 86.2, gamma = 59.9 degrees , was solved by molecular replacement to a resolution of 2.85 A and refined to R(work) and R(free) values of 20.7% and 25.0%, respectively. Hfq from E. coli has previously been crystallized and the structure has been solved for the N-terminal 72 amino acids, which cover ~65% of the full-length sequence. Here, the purification, crystallization and structural data of the full 102-amino-acid protein are presented. These data revealed that the presence of the C-terminus changes the crystal packing of E. coli Hfq. The crystal structure is discussed in the context of the recently published solution structure of Hfq from E. coli. PMID- 21543857 TI - Structure of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase in complex with the feedback inhibitor CoA reveals only one active-site conformation. AB - Phosphopantetheine adenylyltransferase (PPAT) catalyzes the penultimate step in the coenzyme A (CoA) biosynthetic pathway, reversibly transferring an adenylyl group from ATP to 4'-phosphopantetheine to form dephosphocoenzyme A (dPCoA). To complement recent biochemical and structural studies on Mycobacterium tuberculosis PPAT (MtPPAT) and to provide further insight into the feedback regulation of MtPPAT by CoA, the X-ray crystal structure of the MtPPAT enzyme in complex with CoA was determined to 2.11 A resolution. Unlike previous X-ray crystal structures of PPAT-CoA complexes from other bacteria, which showed two distinct CoA conformations bound to the active site, only one conformation of CoA is observed in the MtPPAT-CoA complex. PMID- 21543858 TI - Preliminary crystallographic analysis of the RNA-binding domain of HuR and its poly(U)-binding properties. AB - Human antigen R (HuR), a ubiquitously expressed member of the Hu protein family, is an important post-transcriptional regulator which has three RNA-recognition motif (RRM) domains. The two tandem N-terminal RRM domains can selectively bind to the AU-rich element (ARE), while the third one interacts with the poly(A) tail and other proteins. Here, the recombinant ARE-binding region of HuR (residues 18 186) was crystallized in space group P2(1)2(1)2, with unit-cell parameters a = 41.2, b = 133.1, c = 31.4 A. X-ray diffraction data were collected to a resolution of 2.8 A. Mutagenesis analysis and SPR assays revealed its poly(U) binding properties. PMID- 21543859 TI - Purification, crystallization and preliminary data analysis of the ligand receptor complex of the growth and differentiation factor 5 variant R57A (GDF5R57A) and BMP receptor IA (BRIA). AB - The binary ligand-receptor complex of human growth and differentiation factor 5 (GDF5) bound to its type I receptor BMP receptor IA (BRIA) was prepared and crystallized. By utilizing the GDF5 variant R57A, which exhibits a high affinity in the subnanomolar range for BRIA, the binary complex of GDF5R57A bound to the extracellular domain of BRIA could be produced and purified. Crystals of this complex belonged to a monoclinic space group: either I2, with unit-cell parameters a = 63.81, b = 62.85, c = 124.99 A, beta = 95.9 degrees , or C2, with unit-cell parameters a = 132.17, b = 62.78, c = 63.53 A, beta = 112.8 degrees . PMID- 21543860 TI - Crystallization of an engineered RUN domain of Rab6-interacting protein 1/DENND5. AB - Effectors of the Rab small GTPases are large multi-domain proteins which have proved difficult to express in soluble form in Escherichia coli. Generally, effectors are recruited to a distinct subcellular compartment by active (GTP bound) Rabs, which are linked to membranes by one or two prenylated Cys residues at their C-termini. Following recruitment via their Rab-binding domain (RBD), effectors carry out various aspects of vesicle formation, transport, tethering and fusion through their other domains. Previously, successful purification of the RUN-PLAT tandem domains (residues 683-1061) of the 1263-residue Rab6 interacting protein 1 (R6IP1) required co-expression with Rab6, as attempts to solubly express the effector alone were unsuccessful. R6IP1 is also known as DENN domain-containing protein 5 (DENND5) and is expressed as two isoforms, R6IP1A/B (DENND5A/B), which differ by 24 amino acids at the N-terminus. Here, a deletion in R6IP1 was engineered to enable soluble expression and to improve the quality of the crystals grown in complex with Rab6. A large 23-residue loop linking two alpha-helices in the RUN1 domain was removed and replaced with a short linker. This loop resides on the opposite face to the Rab6-binding site and is not conserved in the RUN-domain family. In contrast to wild-type R6IP1-Rab6 crystals, which took several weeks to grow to full size, the engineered R6IP1 (RPdel)-Rab6 crystals could be grown in a matter of days. PMID- 21543861 TI - Crystallization and preliminary X-ray diffraction analysis of the barley yellow dwarf virus cap-independent translation element. AB - Barley yellow dwarf virus (BYDV) RNA lacks a 5' m(7)GTP cap, yet it is translated efficiently because it contains a 105-base BYDV-like cap-independent translation element (BTE) in the 3' untranslated region (UTR). To understand how the BTE outcompetes the host mRNA for protein-synthesis machinery, its three-dimensional structure is being determined at high resolution. The purification using transcription from DNA containing 2'-O-methyl nucleotides and preliminary crystallographic analyses of the BTE RNA are presented here. After varying the BTE sequence and crystallization-condition optimization, crystals were obtained that diffracted to below 5 A resolution, with a complete data set being collected to 6.9 A resolution. This crystal form indexes with an R(merge) of 0.094 in the monoclinic space group C2, with unit-cell parameters a = 316.6, b = 54.2, c = 114.5 A, alpha = gamma = 90, beta = 105.1 degrees . PMID- 21543862 TI - Cloning, expression, purification, crystallization and preliminary crystallographic analysis of NifH1 from Methanocaldococcus jannaschii. AB - Nitrogen fixation is catalyzed by the nitrogenase complex in Azotobacter, which is composed of dinitrogenase and dinitrogenase reductase. Dinitrogenase is an alpha(2)beta(2) heterotetramer of the proteins NifD and NifK. Dinitrogenase reductase is a homodimer of the protein NifH. The expression of NifD/K and NifH nitrogenase homologues (named NflD/K and NflH for Nif-like D and H, respectively) has been detected in the non-nitrogen-fixing hyperthermophilic methanogen Methanocaldococcus jannaschii. Solving the structure of MjNifH1 may help in better understanding its function and may supply some clues to understanding the evolution of nitrogenase. The full-length protein with an additional His(6) tag at the C-terminus was expressed, purified and crystallized by the hanging-drop vapour-diffusion method at 287 K. An X-ray diffraction data set was collected to a resolution of 3.3 A. The crystal belonged to space group P4(1)32, with unit cell parameters a = b = c = 139.45 A, and was estimated to contain one protein molecule per asymmetric unit. PMID- 21543863 TI - Complex assembly, crystallization and preliminary X-ray crystallographic studies of the swine major histocompatibility complex molecule SLA-1*1502. AB - In order to illustrate the structure of the swine MHC class I (SLA-I) molecule and to evaluate the cytotoxic T lymphocyte (CTL) response against porcine reproductive and respiratory syndrome virus (PRRSV), the ternary complex of the SLA-I molecule termed SLA-1*1502 with beta(2)-microglobulin and the CTL epitope TMPPGFELY (PRRSV-NSP9(TY9)) derived from PRRSV nonstructural protein 9 (residues 198-206) was assembled and crystallized. The crystal diffracted X-rays to 2.2 A resolution and belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 66.1, b = 74.1, c = 98.6 A; it contained one molecule in the asymmetric unit. The Matthews coefficient and the solvent content were calculated to be 2.74 A(3) Da(-1) and 55.17%, respectively. The results will be helpful in obtaining insight into the structural basis of the presentation of viral epitopes by SLA-I. PMID- 21543864 TI - Crystallization and diffraction analysis of Sm23: an SGNH-family arylesterase from Sinorhizobium meliloti 1021. AB - Industrial demand for active biocatalysts with desirable biochemical properties is constantly increasing and the discovery and characterization of novel esterases is potentially useful for industrial processes. Here, X-ray crystallographic studies of an (R)-specific SGNH arylesterase (Sm23) from Sinorhizobium meliloti 1021 are reported. The recombinant protein was expressed in Escherichia coli with a His tag and purified to homogeneity. Sm23 was crystallized using 0.2 M magnesium formate as a precipitant and X-ray diffraction data were collected to a resolution of 2.2 A with an R(merge) of 6.9%. The crystals of SM23 belonged to the I-centred tetragonal space group I4(1)22, with unit-cell parameters a = b = 126.6, c = 190.9 A. A molecular-replacement solution was obtained using the crystal structure of arylesterase from Mycobacterium smegmatis as a template. PMID- 21543865 TI - Crystallization and preliminary X-ray crystallographic analysis of tyrosinase from the mushroom Agaricus bisporus. AB - Tyrosinase catalyzes the conversion of tyrosine to dihydroxyphenylalanine quinone, which is the main precursor for the biosynthesis of melanin. The enzyme from Agaricus bisporus, the common button mushroom, was purified and crystallized in two different space groups. Crystals belonging to space group P2(1) (unit-cell parameters a = 104.2, b = 105.0, c = 119.1 A, beta = 110.6 degrees , four molecules per asymmetric unit) diffracted to 3.0 A resolution. Crystals belonging to space group P2(1)2(1)2 (unit-cell parameters a = 104.0, b = 104.5, c = 108.4 A, two molecules per asymmetric unit) diffracted to 2.6 A resolution. It was essential to include 5 mM HoCl(3) in all crystallization conditions in order to obtain well diffracting crystals. PMID- 21543866 TI - Purification, crystallization and preliminary X-ray analysis of phycocyanin and phycoerythrin from Porphyra yezoensis Ueda. AB - Porphyra yezoensis is one of the most important and widely cultured seaweeds in China. Phycobiliproteins exhibit excellent spectroscopic properties and play versatile roles in the biomedical, food, cosmetics and chemical synthetic dye industries. Here, the purification and crystallization of phycoerythrin and phycocyanin, two phycobiliproteins extracted from P. yezoensis, are described. Using a novel protocol including co-precipitation with ammonium sulfate and hydroxyapatite column chromatography, both phycobiliproteins were produced on a large scale with improved quality and yield compared with those previously reported. Native PAGE analysis indicated that phycoerythrin and phycocyanin exist as (alphabeta)(3) heterohexamers in solution. The crystals of phycoerythrin diffracted to 2.07 A resolution and belonged to space group R3. The unit-cell parameters referred to hexagonal axes are a = b = 187.7, c = 59.7 A, with nine (alphabeta)(2) heterotetramers per unit cell. The crystals of phycocyanin diffracted to 2.70 A resolution in space group P2(1). Matthews coefficient analysis shows that 10-19 (alphabeta) heterodimers of phycocyanin in the asymmetric unit would be reasonable. A self-rotation function calculation clarified this ambiguity and indicated that 12 (alphabeta) heterodimers of phycocyanin are assembled in the asymmetric unit. PMID- 21543867 TI - Crystallization and preliminary X-ray diffraction analysis of transaldolase from Thermoplasma acidophilum. AB - The metabolic enzyme transaldolase from Thermoplasma acidophilum was recombinantly expressed in Escherichia coli and could be crystallized in two polymorphic forms. Crystals were grown by the hanging-drop vapour-diffusion method using PEG 6000 as precipitant. Native data sets for crystal forms 1 and 2 were collected in-house to resolutions of 3.0 and 2.7 A, respectively. Crystal form 1 belonged to the orthorhombic space group C222(1) with five monomers per asymmetric unit and crystal form 2 belonged to the monoclinic space group P2(1) with ten monomers per asymmetric unit. PMID- 21543869 TI - Superoxide reductase from Nanoarchaeum equitans: expression, purification, crystallization and preliminary X-ray crystallographic analysis. AB - Superoxide reductases (SORs) are the most recent oxygen-detoxification system to be identified in anaerobic and microaerobic bacteria and archaea. SORs are metalloproteins that are characterized by their possession of a catalytic nonhaem iron centre in the ferrous form coordinated by four histidine ligands and one cysteine ligand. Ignicoccus hospitalis, a hyperthermophilic crenarchaeon, is the only organism known to date to serve as a host for Nanoarchaeum equitans, a nanosized hyperthermophilic archaeon isolated from a submarine hot vent which completely depends on the presence of and contact with I. hospitalis cells for growth to occur. Similarly to I. hospitalis, N. equitans has a neelaredoxin (a 1Fe-type SOR) that keeps toxic oxygen species under control, catalysing the one electron reduction of superoxide to hydrogen peroxide. Blue crystals of recombinant N. equitans SOR in the oxidized form (12.7 kDa, 109 residues) were obtained using polyethylene glycol (PEG 2000 MME) as precipitant. These crystals diffracted to 1.9 A resolution at 100 K and belonged to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 51.88, b = 82.01, c = 91.30 A. Cell-content analysis suggested the presence of four monomers in the asymmetric unit. The Matthews coefficient (V(M)) was determined to be 1.9 A(3) Da(-1), corresponding to an estimated solvent content of 36%. Self-rotation function and native Patterson calculations suggested a tetramer with 222 point-group symmetry, similar to other 1Fe-SORs. The three-dimensional structure will be determined by the molecular-replacement method. PMID- 21543868 TI - Time-of-flight neutron diffraction study of bovine gamma-chymotrypsin at the Protein Crystallography Station. AB - The overarching goal of this research project is to determine, for a subset of proteins, exact hydrogen positions using neutron diffraction, thereby improving H atom placement in proteins so that they may be better used in various computational methods that are critically dependent upon said placement. In order to be considered applicable for neutron diffraction studies, the protein of choice must be amenable to ultrahigh-resolution X-ray crystallography, be able to form large crystals (1 mm(3) or greater) and have a modestly sized unit cell (no dimension longer than 100 A). As such, gamma-chymotrypsin is a perfect candidate for neutron diffraction. To understand and probe the role of specific active-site residues and hydrogen-bonding patterns in gamma-chymotrypsin, neutron diffraction studies were initiated at the Protein Crystallography Station (PCS) at Los Alamos Neutron Science Center (LANSCE). A large single crystal was subjected to H/D exchange prior to data collection. Time-of-flight neutron diffraction data were collected to 2.0 A resolution at the PCS with ~85% completeness. Here, the first time-of-flight neutron data collection from gamma-chymotrypsin is reported. PMID- 21543870 TI - Cloning, expression, purification, crystallization and preliminary X-ray studies of the mannose-binding lectin domain of MSMEG_3662 from Mycobacterium smegmatis. AB - The mannose-binding lectin domain of MSMEG_3662 from Mycobacterium smegmatis has been cloned, expressed, purified and crystallized and the crystals have been characterized using X-ray diffraction. The Matthews coefficient suggests the possibility of two lectin domains in the triclinic cell. The amino-acid sequence of the domain indicates structural similarity to well characterized beta-prism II fold lectins. PMID- 21543871 TI - Crystallization and preliminary diffraction analysis of the CAL PDZ domain in complex with a selective peptide inhibitor. AB - Cystic fibrosis (CF) is associated with loss-of-function mutations in the CF transmembrane conductance regulator (CFTR), which regulates epithelial fluid and ion homeostasis. The CFTR cytoplasmic C-terminus interacts with a number of PDZ (PSD-95/Dlg/ZO-1) proteins that modulate its intracellular trafficking and chloride-channel activity. Among these, the CFTR-associated ligand (CAL) has a negative effect on apical-membrane expression levels of the most common disease associated mutant DeltaF508-CFTR, making CAL a candidate target for the treatment of CF. A selective peptide inhibitor of the CAL PDZ domain (iCAL36) has recently been developed and shown to stabilize apical expression of DeltaF508-CFTR, enhancing net chloride-channel activity, both alone and in combination with the folding corrector corr-4a. As a basis for structural studies of the CAL-iCAL36 interaction, a purification protocol has been developed that increases the oligomeric homogeneity of the protein. Here, the cocrystallization of the complex in space group P2(1)2(1)2(1), with unit-cell parameters a = 35.9, b = 47.7, c = 97.3 A, is reported. The crystals diffracted to 1.4 A resolution. Based on the calculated Matthews coefficient (1.96 A(3) Da(-1)), it appears that the asymmetric unit contains two complexes. PMID- 21543872 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of the putative Vibrio parahaemolyticus resuscitation-promoting factor YeaZ. AB - Vibrio parahaemolyticus is a human pathogen associated with gastroenteritis caused by the ingestion of contaminated raw seafood. V. parahaemolyticus is able to survive exposure to low temperatures typical of those used for the refrigeration of foods by entering a viable but nonculturable (VBNC) state. The VBNC cells can regain culturability and renewed ability to cause infection upon temperature upshift. The resuscitation-promoting factor protein (Rpf, YeaZ) plays a key role in reactivation of growth. Crystals of V. parahaemolyticus YeaZ have been grown using the hanging-drop vapour-diffusion method with polyethylene glycol as a precipitating agent. The crystals belonged to the primitive monoclinic space group P2(1), with unit-cell parameters a = 81.7, b = 63.8, c = 82.3 A, beta = 105 degrees and four subunits in the asymmetric unit. A complete X-ray diffraction data set was collected from a single crystal to 3.1 A resolution. PMID- 21543873 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of MIL, a glycosylated jacalin-related lectin from mulberry (Morus indica) latex. AB - A quantitatively major protein has been purified from the latex of Morus indica. The purified previously uncharacterized protein, M. indica lectin (MIL), was further shown to be a glycosylated tetramer and belongs to the family of jacalin related lectins. Crystallization of MIL was also accomplished and the tetragonal crystals diffracted synchrotron X-rays to a resolution of 2.8 A. PMID- 21543874 TI - Crystallization and preliminary X-ray analysis of the N-terminal domain of human thioredoxin-interacting protein. AB - Thioredoxin-interacting protein (TXNIP) is a negative regulator of thioredoxin and its roles in the pathologies of diabetes and cardiovascular diseases have marked it out as a potential drug target. Expression of TXNIP is robustly induced under various stress conditions such as high glucose, heat shock, UV, H(2)O(2) and mechanical stress amongst others. Elevated levels of TXNIP result in the sequestration and inactivation of thioredoxin, leading to cellular oxidative stress. For some time, this was the only known function of TXNIP; however, more recently the protein has been shown to play a role in regulation of glucose uptake and activation of the inflammasome. Based on the primary sequence, TXNIP is remotely related to beta-arrestins, which include the visual arrestins. TXNIP has thus been classified as a member of the alpha-arrestin family, which to date includes five other members. None of the other alpha-arrestins are known to interact with thioredoxin, although curiously one has been implicated in glucose uptake. In order to gain insight into the structure-function relationships of the alpha-arrestin protein family, and particularly that of TXNIP, the N-terminal domain of TXNIP has been crystallized. The crystals belonged to a monoclinic space group and diffracted to 3 A resolution using synchrotron radiation. PMID- 21543875 TI - Molecular cloning, overexpression, purification, crystallization and preliminary X-ray diffraction analysis of a purine nucleoside phosphorylase from Bacillus subtilis strain 168. AB - Purine nucleoside phosphorylase (PNP; EC 2.4.2.1) is a key enzyme of the purine salvage pathway. Its ability to transfer glycosyl residues to acceptor bases is of great biotechnological interest owing to its potential application in the synthesis of nucleoside analogues used in the treatment of antiviral infections and in anticancer chemotherapy. Although hexameric PNPs are prevalent in prokaryotes, some microorganisms, such as Bacillus subtilis, present both hexameric and trimeric PNPs. The hexameric PNP from B. subtilis strain 168, named BsPNP233, was cloned, expressed and crystallized. Crystals belonging to different space groups (P32(1), P2(1)2(1)2(1), P6(3)22 and H32) were grown in distinct conditions with pH values ranging from 4.2 to 10.5. The crystals diffracted to maximum resolutions ranging from 2.65 to 1.70 A. PMID- 21543876 TI - Cloning, expression, purification, crystallization and preliminary X-ray diffraction data of the Pyrococcus horikoshii RadA intein. AB - The RadA intein from the hyperthermophilic archaebacterium Pyrococcus horikoshii was cloned, expressed and purified for subsequent structure determination. The protein crystallized rapidly in several conditions. The best crystals, which diffracted to 1.75 A resolution, were harvested from drops consisting of 0.1 M HEPES pH 7.5, 3.0 M NaCl and were cryoprotected with Paratone-N before flash cooling. The collected data were processed in the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 58.1, b = 67.4, c = 82.9 A. Molecular replacement with Rosetta using energy- and density-guided structure optimization provided the initial solution, which is currently under refinement. PMID- 21543877 TI - Cloning, expression, purification, crystallization and X-ray crystallographic analysis of Rv3168 from Mycobacterium tuberculosis H37Rv. AB - Tuberculosis is a widespread and deadly infectious disease, with one third of the human population already being infected. Aminoglycoside antibiotics have become less effective in recent years owing to antibiotic resistance, which arises primarily through enzymatic modification of the antibiotics. The gene product Rv3168, a putative aminoglycoside phosphotransferase (APH), from Mycobacterium tuberculosis was crystallized using the sitting-drop vapour-diffusion method in the presence of 0.2 M calcium acetate, 0.1 M Tris-HCl pH 7.0 and 20% PEG 3000 at 295 K. X-ray diffraction data were collected to a maximum resolution of 1.67 A on a synchrotron beamline. The crystal belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 56.74, b = 62.37, c = 103.61 A. With one molecule per asymmetric unit, the crystal volume per unit protein weight (V(M)) is 2.91 A(3) Da(-1). The structure was solved by the single-wavelength anomalous dispersion method and refinement of the selenomethionine structure is in progress. PMID- 21543878 TI - Crystallization and preliminary X-ray crystallographic studies of an oligomeric species of a refolded C39 peptidase-like domain of the Escherichia coli ABC transporter haemolysin B. AB - The ABC transporter haemolysin B (HlyB) from Escherichia coli is part of a type I secretion system that translocates a 110 kDa toxin in one step across both membranes of this Gram-negative bacterium in an ATP-dependent manner. Sequence analysis indicates that HlyB contains a C39 peptidase-like domain at its N terminus. C39 domains are thiol-dependent peptidases that cleave their substrates after a GG motif. Interestingly, the catalytically invariant cysteine is replaced by a tyrosine in the C39-like domain of HlyB. Here, the overexpression, purification and crystallization of the isolated C39-like domain are described as a first step towards obtaining structural insights into this domain and eventually answering the question concerning the function of a degenerated C39 domain in the ABC transporter HlyB. PMID- 21543879 TI - Crystallization and preliminary X-ray diffraction studies of the precursor protein of a thermostable variant of papain. AB - The crystallization of a recombinant thermostable variant of pro-papain has been carried out. The mutant pro-enzyme was expressed in Escherichia coli as inclusion bodies, refolded, purified and crystallized. The crystals belonged to space group P2(1), with unit-cell parameters a = 42.9, b = 74.8, c = 116.5 A, beta = 93.0 degrees , and diffracted to 2.6 A resolution using synchrotron radiation. Assuming the presence of two molecules in the asymmetric unit, the calculated Matthews coefficient is 2.28 A(3) Da(-1), corresponding to a solvent content of 46%. Initial attempts to solve the structure using molecular-replacement techniques were successful. PMID- 21543880 TI - Protein expression, crystallization and preliminary X-ray crystallographic studies of LidA from Legionella pneumophila. AB - LidA, a translocated substrate of the Legionella pneumophila Dot/Icm type IV secretion system, is associated with maintenance of bacterial integrity and interferes with the early secretory pathway. However, the precise mechanism of LidA in these processes remains elusive. To further investigate the structure and function of LidA, the full-length protein was successfully expressed in Escherichia coli and purified. LidA was crystallized using sitting-drop vapour diffusion and diffracted to a resolution of 2.75 A. The crystal belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 57.5, b = 64.5, c = 167.3 A, alpha = beta = gamma = 90 degrees . There is one molecule per asymmetric unit. PMID- 21543881 TI - Deferasirox lacks in vitro activity against Fusarium and Scedosporium species and black molds. PMID- 21543882 TI - Aspergillus terreus accessory conidia are multinucleated, hyperpolarizing structures that display differential dectin staining and can induce heightened inflammatory responses in a pulmonary model of aspergillosis. AB - In addition to phialidic conidia (PC), A. terreus produces accessory conidia (AC) both in vitro and in vivo. AC are distinct from PC in cell surface architecture, with the AC surfaces displaying more beta-glucan, a molecule that can be a trigger for the induction of inflammatory responses. The present study follows beta-glucan cell surface presentation throughout the course of germination of both types of conidia, and analyzes the differential capacity of AC and PC to elicit immune responses. Results show that AC display early, increased dectin-1 labeling on their cell surfaces compared to PC, and this differential dectin-1 labeling is sustained on the cell surface from the time of breaking dormancy through early germ tube emergence. Mouse alveolar macrophages showed a stronger inflammatory cytokine/chemokine response when challenged with AC than with PC in both ex vivo and in vivo experiments, correlating with the greater exposure of beta-glucan exhibited by AC. Further, histopathologic staining of the lungs from mice challenged with AC demonstrated heightened cell recruitment and increased inflammatory response compared to the lungs of mice challenged with PC. Our study also demonstrates that AC are multinucleate structures with the ability to germinate rapidly, polarizing in multiple directions and producing several hyphal extensions. We present evidence that A. terreus AC are phenotypically distinct from PC and can be potent activators of the innate immune mechanism thus possibly playing a role in this organism's pathogenesis. PMID- 21543883 TI - Knockout mutation of p27-p55 operon severely reduces replication of Mycobacterium bovis in a macrophagic cell line and survival in a mouse model of infection. AB - Integrity of p27-p55 operon has been demonstrated to be crucial for replication of Mycobacterium tuberculosis, the main agent of human tuberculosis, in the mouse model of infection. However, the individual contribution of each gene of the operon for the virulence of pathogenic Mycobacterium spp. still remains unclear. The operon is formed by two genes, p27 and p55. p27 gene encodes a lipoprotein that binds triacylated glycolipids and modulates the host immune responses by inhibiting the MHC-II Ag processing. Besides, p55 encodes an efflux pump that, together with P27, is involved in resistance to drugs. In this study, we evaluated the individual contribution of P27 and P55 to the virulence of Mycobacterium bovis, the etiological agent for bovine tuberculosis. Knockout mutation of p27-p55 operon in M. bovis severely decreased the virulence of the bacteria when assessed in a progressive model of pulmonary tuberculosis in Balb/c mice. In addition, the mutant strain showed poor replication in a murine macrophagic cell line. Virulence and intracellular replication were only restored when the mutant strain was complemented with a copy of the whole operon. The reintroduction of p55 into the mutant strain partially restored the virulence of the bacteria while no complementation was achieved with p27 individual gene. PMID- 21543884 TI - More (G-proteins) please! Identification of an elaborate network of G-proteins in soybean. AB - The studies performed in model plants Arabidopsis and rice have revealed a significantly simple repertoire of canonical G-protein components in plants, with the presence of only two possible heterotrimers versus hundreds of possible trimeric combinations in animal systems. Since a number of plant species are polyploid, we assessed if genome duplication events have resulted into multiplicity of G-protein components in such plants and whether the duplicated gene pairs have specific expression patterns or biochemical properties. Our analysis of soybean genome has identified four Galpha, four Gbeta and two Ggamma proteins, predicting thirty-two possible heterotrimeric combinations. All ten G protein genes are retained in soybean genome and ubiquitously expressed. The G protein genes have interesting expression profiles during seed developments and germination. The four Galpha proteins form two distinct groups based on their GTPase activity. Yeast-based interaction analyses predict that the proteins interact in most but not all of the possible combinations, and there is some degree of interaction specificity between duplicated gene pairs. This research, thus, identifies the most elaborate heterotrimeric G-protein network known to date in plants. PMID- 21543885 TI - Altered expression of auxin-related genes in the fatty acid elongase mutant oni1 of rice. AB - VLCFAs are the main components of cuticular wax, which covers and protects plants from physical and biological stresses. However, the effect of fatty acid composition or the physiological role of VLCFAs on plant development under normal growth conditions is not well understood. We analyzed loss-of-function mutants of ONION1 (ONI1) which encodes fatty acid elongase (beta-ketoacyl CoA synthase) catalyzing an elongation reaction of a carbon chain of VLCFAs. We showed that oni1 shoot contained a reduced amount of VLCFAs, and differentiation and functionality of an outermost cell layer (L1) were highly perturbed in oni1 shoot. In spite of the L1-specific expression of ONI1, the effects of the oni1 mutation were not restricted to L1, but expanded to inner cells, so that the entire shoot development was impaired including failure of the maintenance of the SAM and ectopic expression of SAM-specific KNOX genes in leaf. Thus, ONI1 function is cell non-autonomous, and signaling from L1 to inner cells may support proper development of inner cells. Here we report that expression of auxin related genes was affected in oni1 shoot, and we speculate the existence of improper auxin distribution due to a lack of normal L1 in oni1 shoot. PMID- 21543886 TI - Boundary genes in regulation and evolution of secondary growth. AB - Many extant land plants display secondary growth originating in a lateral meristem known as vascular cambium. A conspicuous product of secondary growth is wood which dominates terrestrial ecosystem biomass. Despite the economic and ecological significance of the process the underlying molecular mechanism are still poorly understood. We have recently shown that members of the LBD transcription factor family play function in control of secondary growth. Here we propose a mechanistic model of LBD regulatory roles. We also show how these roles may be linked to evolutionary changes in level and pattern of wood formation that provide structural and functional innovations in wood anatomy in relation to species growth habit and biology. PMID- 21543887 TI - How many E3 ubiquitin ligase are involved in the regulation of nodulation? AB - In plants, as in animals, recent work has established that many developmental and defence response pathways are regulated by E3 ubiquitin ligases which control the level or the activity of key proteins through ubiquitination. Nodule formation is a tightly regulated process that integrates specific signal exchange and the coordinated activation of developmental mechanisms to synchronize bacterial infection and organ development. In the last decade, the characterization of several E3 ubiquitin ligase with roles during nodulation has been reported. These are mainly RING-finger and U-Box proteins involved either in nodule organogenesis or in the infection process. In this review, we summarize the knowledge in this field and conclude that the major challenge will be the identification of the regulation and targets of these E3 ubiquitin ligases. PMID- 21543888 TI - Altered pattern of arbuscular mycorrhizal formation in tomato ethylene mutants. AB - Although no specific role has been demonstrated for ethylene during Arbuscular Mycorrhizal (AM) symbiosis, recent results suggest its participation in the regulation of the AM. Analysis of arbuscular mycorrhizal colonization in the abscisic acid (ABA)-deficient tomato sitiens mutant has shown that ABA deficiency induced ethylene production. It has also been suggested that one of the mechanisms used by ABA to determine susceptibility to fungal infection is negative modulation of the ethylene pathway. In this study, we describe the pattern of mycorrhization in mutant plants with altered ethylene biosynthesis and/or perception pathways. Epinastic (epi) plants with increased ethylene response were unaffected in terms of mycorrhizal frequency, although this mutation had a considerable negative impact on the intensity of mycorrhizal root colonization. The negative impact of the mutation in epi plants on the intensity of mycorrhizal root colonization was associated with a transitory increase in the transcript level of the LeETR6 ethylene receptor gene. On the other hand, ripenenig-inhibitor (rin) tomato mutant plants were positively affected in relation to all the mycorrhizal colonization parameters measured, suggesting that, at least in tomato plants, the regulation of AM formation is mediated by the RIN pathway. PMID- 21543889 TI - Eukaryotic initiation factor 6, an evolutionarily conserved regulator of ribosome biogenesis and protein translation. AB - We recently identified Receptor for Activated C Kinase 1 (RACK1) as one of the molecular links between abscisic acid (ABA) signaling and its regulation on protein translation. Moreover, we identified Eukaryotic Initiation Factor 6 (eIF6) as an interacting partner of RACK1. Because the interaction between RACK1 and eIF6 in mammalian cells is known to regulate the ribosome assembly step of protein translation initiation, it was hypothesized that the same process of protein translation in Arabidopsis is also regulated by RACK1 and eIF6. In this article, we analyzed the amino acid sequences of eIF6 in different species from different lineages and discovered some intriguing differences in protein phosphorylation sites that may contribute to its action in ribosome assembly and biogenesis. In addition, we discovered that, distinct from non-plant organisms in which eIF6 is encoded by a single gene, all sequenced plant genomes contain two or more copies of eIF6 genes. While one copy of plant eIF6 is expressed ubiquitously and might possess the conserved function in ribosome biogenesis and protein translation, the other copy seems to be only expressed in specific organs and therefore may have gained some new functions. We proposed some important studies that may help us better understand the function of eIF6 in plants. PMID- 21543890 TI - Identification of defense-related genes newly-associated with tomato flower abscission. AB - The current abscission model suggests the formation of a post-abscission trans differentiation of a protective layer as the last step of the process. The present report expands the repertoire of genes activated in the tomato flower abscission zone (AZ), which are likely to be involved in defense responses. We identified four different defense-related genes, including: Cysteine-type endopeptidase, alpha-Dioxygenase 1 (alpha-DOX1), HopW-1-1-Interacting protein2 (WIN2), and Stomatal-derived factor-2 (SDF2), that are newly-associated with the late stage of the abscission process. The late expression of these genes, induced at 8-14 h after flower removal when pedicel abscission was already in progress, was AZ-specific, and was inhibited by treatments that prevented pedicel abscission, including 1-methylcyclopropene pretreatment or IAA application. This information supports the activation of different defense responses and strategies at the late abscission stages, which may enable efficient protection of the exposed tissue toward different environmental stresses. PMID- 21543891 TI - Autophagy induction rescues muscular dystrophy. AB - Collagen VI is an extracellular matrix protein forming a microfibrillar network in the endomysium of skeletal muscles. In humans, mutations in any of the three genes coding for collagen VI cause several skeletal muscle diseases, including Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). Collagen VI null (Col6a1(-/-)) mice display a myopathic phenotype resembling that of BM and UCMD patients. Muscles lacking collagen VI are characterized by the presence of dilated sarcoplasmic reticulum and dysfunctional mitochondria, which triggers apoptosis and leads to muscle wasting. We have found that accumulation of abnormal organelles is due to an impairment of autophagy. Reactivation of the autophagic flux by either nutritional approaches or by pharmacological and genetics tools removes dysfunctional organelles and greatly ameliorates the dystrophic phenotype. PMID- 21543892 TI - E2F1: A new role in the DNA damage response. PMID- 21543893 TI - Defect of development of ocular vasculature in Glut1/SLC2A1 knockdown in vivo. PMID- 21543895 TI - WAVE2 regulates meiotic spindle stability, peripheral positioning and polar body emission in mouse oocytes. AB - During oocyte meiotic maturation, meiotic spindles form in the central cytoplasm and then migrate to the cortex to extrude a small polar body, forming a highly polarized cell through a process involving actin and actin-related molecules. The mechanisms underlying oocyte polarization are still unclear. The Arp2/3 complex regulates oocyte polarization but it is not known whether the WASP family of proteins, a known regulator of the Arp2/3 complex, is involved in this context. In the present study, the role of WASP family member WAVE2 in mouse oocyte asymmetric division was investigated. (1) WAVE2 mRNA and protein were detected during mouse oocyte meiosis. (2) siRNA-mediated and antibody-mediated disruption of WAVE2 resulted in the failure of chromosome congression, spindle formation, spindle positioning and polar body extrusion. (3) WAVE2 regulated actin-driven chromosome migration since chromosomes were arrested in the central cytoplasm by WAVE2 RNAi in the absence of microtubules. (4) Localization of gamma-tubulin and MAPK was disrupted after RNAi, confirming the effect of WAVE2 on spindle formation. (5) Actin cap and cortical granule-free domain (CGFD) formation was also disrupted, further confirming the failure of oocyte polarization. Our data suggest that WAVE2 regulates oocyte polarization by regulating meiotic spindle, peripheral positioning, probably via an actin-mediated pathway, and is involved in polar body emission during mouse oocyte meiotic maturation. PMID- 21543894 TI - MicroRNA signatures differentiate melanoma subtypes. AB - Melanoma is an aggressive cancer that is highly resistance to therapies once metastasized. We studied microRNA (miRNA) expression in clinical melanoma subtypes and evaluated different miRNA signatures in the background of gain of function somatic and inherited mutations associated with melanoma. Total RNA from 42 patient derived primary melanoma cell lines and three independent normal primary melanocyte cell cultures was evaluated by miRNA array. MiRNA expression was then analyzed comparing subtypes and additional clinicopathologic criteria including somatic mutations. The prevalence and association of an inherited variant in a miRNA binding site in the 3'UTR of the KRAS oncogene, referred to as the KRAS-variant, was also evaluated. We show that seven miRNAs, miR-142-3p, miR 486, miR-214, miR-218, miR-362, miR-650 and miR-31, were significantly correlated with acral as compared to non-acral melanomas (p < 0.04). In addition, we discovered that the KRAS-variant was enriched in non-acral melanoma (25%), and that miR-137 under expression was significantly associated with melanomas with the KRAS-variant. Our findings indicate that miRNAs are differentially expressed in melanoma subtypes and that their misregulation can be impacted by inherited gene variants, supporting the hypothesis that miRNA misregulation reflects biological differences in melanoma. PMID- 21543896 TI - Genetic control of susceptibility to carcinogen-induced colorectal cancer in mice: the Ccs3 and Ccs5 loci regulate different aspects of tumorigenesis. AB - Colorectal cancer (CRC) is a multistep disease that involves a two-way interaction between a complex genetic pre-disposition component, and a set of poorly understood extrinsic environmental factors. In mice, CRC can be induced by treatment with azoxymethane (AOM). Using a set of AcB/BcA recombinant congenic strains derived from CRC-susceptible A/J and CRC-resistant C57Bl/6J (B6) progenitors, we previously detected the Ccs3 locus (colon cancer susceptibility locus 3) as a major regulator of CRC susceptibility. Phenotyping of additional AcB/BcA strains for susceptibility to AOM-induced CRC has refined the Ccs3 interval to a 6.7 Mb segment on chromosome 3. In addition, the presence of intermediate susceptibility phenotypes in individual AcB/BcA strains suggested additional gene effects regulating CRC susceptibility in A/J and B6 strains. Those were investigated by linkage analysis and whole genome scanning in a set of 208 informative (B6 x A/J)F2 progeny, using tumor multiplicity as a quantitative measure of susceptibility. This analysis validated the important role of Ccs3 in regulating this trait, and additionally detected contribution from a second locus on the distal portion of chromosome 9 (LOD = 3.76), that was given the temporary designation of Ccs5. Ccs5 modulates tumor multiplicity in F2 animals bearing at least one A/J-derived susceptibility allele at Ccs3, with A/J-derived Ccs5 susceptibility alleles being inherited in a recessive manner. There is a strong additive effect of Ccs3 and Ccs5 on tumor multiplicity in F2 mice: mice doubly homozygotes for A/J or B6 alleles at Ccs3 and Ccs5 show tumor numbers similar to those of parental A/J and B6, respectively. Interestingly, the Ccs5 region overlaps several quantitative trait loci previously reported to regulate intestinal homeostasis and susceptibility to intestinal colitis in mice and humans. Our findings identify a novel two-locus system regulating CRC susceptibility in mice, of which the relevance to human CRC can now be tested experimentally. PMID- 21543898 TI - Function of S-nitrosoglutathione reductase (GSNOR) in plant development and under biotic/abiotic stress. AB - During the last decade, it was established that the class III alcohol dehydrogenase (ADH3) enzyme, also known as glutathione-dependent formaldehyde dehydrogenase (FALDH; EC 1.2.1.1), catalyzes the NADH-dependent reduction of S nitrosoglutathione (GSNO) and therefore was also designated as GSNO reductase. This finding has opened new aspects in the metabolism of nitric oxide (NO) and NO derived molecules where GSNO is a key component. In this article, current knowledge of the involvement and potential function of this enzyme during plant development and under biotic/abiotic stress is briefly reviewed. PMID- 21543899 TI - Phylogenetic analysis of GRAS proteins from moss, lycophyte and vascular plant lineages reveals that GRAS genes arose and underwent substantial diversification in the ancestral lineage common to bryophytes and vascular plants. AB - GRAS genes are a large family of streptophyte specific transcription factors that function in a diverse set of physiological and developmental processes. GRAS proteins of the HAIRY MERISTEM (HAM) sub-family are required for maintenance of shoot and root indeterminacy. The transcriptional targets of HAM proteins and the signaling inputs regulating HAM activity are completely unknown. Understanding the relationship of HAM proteins to other members of the GRAS family may inform hypotheses relating to cellular level HAM functions. I here report a phylogenetic analysis of GRAS proteins employing the complete set of known and probable GRAS proteins from the sequenced genomes of the flowering plants Arabidopsis and Rice, the lycophyte Selaginella moellendorffii, and the bryophyte Physcomitrella patens. HAM proteins are most closely related to DELLA proteins, key components of gibberellin perception. However, GRAS proteins diversified into a minimum of twelve discreet monophyletic lineages, including the HAM and DELLA subfamilies, prior to divergence of the moss and flowering plant lineages. Substantial diversification of GRAS proteins at so early a point in land plant evolution suggests that relative relatedness sequence homology among GRAS proteins sub families may not substantially reflect shared protein function. PMID- 21543897 TI - RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. AB - RON (MST1R) is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. RON has a putative role in several cancers, but its expression and function is poorly characterized in gastroesophageal adenocarcinoma. A recognized functional role of MET tyrosine kinase in gastroesophageal cancer has led to early phase clinical trials using MET inhibitors, with unimpressive results. Therefore, the role of RON in gastroesophageal cancer, as well as its role in cooperative signaling with MET and as a mechanism of resistance to MET inhibition, was studied in gastroesophageal tissues and cell lines. By IHC, RON was highly over-expressed in 74% of gastroesophageal samples (n=94), and over-expression was prognostic of poor survival (p=0.008); RON and MET co-expression occurred in 43% of samples and was prognostic of worst survival (p=0.03). High MST1R gene copy number by quantitative polymerase chain reaction, and confirmed by fluorescence in situ hybridization and/or array comparative genomic hybridization, was seen in 35.5% (16/45) of cases. High MST1R gene copy number correlated with poor survival (p=0.01), and was associated with high MET and ERBB2 gene copy number. A novel somatic MST1R juxtamembrane mutation R1018G was found in 11% of samples. RON signaling was functional in cell lines, activating downstream effector STAT3, and resulted in increased viability over controls. RON and MET co-stimulation assays led to enhanced malignant phenotypes over stimulation of either receptor alone. Growth inhibition as evidenced by viability and apoptosis assays was optimal using novel blocking monoclonal antibodies to both RON and MET, versus either alone. SU11274, a classic MET small molecule tyrosine kinase inhibitor, blocked signaling of both receptors, and proved synergistic when combined with STAT3 inhibition (combination index < 1). These preclinical studies define RON as an important novel prognostic marker and therapeutic target for gastroesophageal cancer warranting further investigation. PMID- 21543900 TI - Do some IAA proteins have two repression domains? AB - The plant hormone auxin regulates the transcription of specific genes through the interplay of Auxin Response Factors (ARFs) and Aux/IAA (IAA) repressors. We have recently shown that stabilized IAA repressors with identical amino acid substitutions in their conserved repression domains (i.e., domain I) confer either "low auxin" or "high auxin" phenotypes when the IAA proteins are constitutively expressed in transformed Arabidopsis plants. We have suggested that when domain I loses its capacity to repress, "high auxin" phenotypes generally result, but a subset of IAA proteins (e.g., IAA17) appear to contain a second repression domain resulting in the maintenance of "low auxin" phenotypes. Here we provide evidence for a second repression domain that lies between domains I and II in IAA7, an IAA repressor within the same clade as IAA17. PMID- 21543902 TI - Unexpected mobility of plant chromatin-associated HMGB proteins. AB - High mobility group (HMG) proteins of the HMGB family containing a highly conserved HMG box are chromatin-associated proteins that interact with DNA and nucleosomes and catalyze changes in DNA topology, thereby facilitating important DNA-dependent processes. The genome of Arabidopsis thaliana encodes 15 different HMG-box proteins that are further subdivided into four groups: HMGB-type proteins, ARID-HMG proteins, 3xHMG proteins that contain three HMG boxes and the structure-specific recognition protein 1 (SSRP1). Typically, HMGB proteins are localized exclusively to the nucleus, like Arabidopsis HMGB1 and B5. However, these Arabidopsis HMGB proteins showed a very high mobility within the nuclear compartment. Recent studies revealed that Arabidopsis HMGB2/3 and B4 proteins are predominantly nuclear but also exist in the cytoplasm, suggesting an as yet unknown cytoplasmic function of these chromosomal HMG proteins. PMID- 21543901 TI - MicroRNA-mediated establishment of transcription factor gradients controlling developmental phase transitions. AB - The juvenile-to-adult phase transition is an important and critical step during plant development to ensure maximum reproductivity. This transition is regulated by different pathways, in some of which microRNAs are considered to be essential key components. In seed plants, miR156 and miR172 act sequentially in well characterized pathways to induce the vegetative phase change and floral formation by the establishment of spatiotemporal gradients of their cognate target transcripts that encode master regulators of development. Recently, we reported on an unrelated, moss-specific miRNA that acts similarly in the control of the juvenile-to-adult phase transition in Physcomitrella patens. Physcomitrella miR534a defines the spatial expression of two transcripts encoding BLADE-ON PETIOLE (BOP) transcriptional coactivators in a cytokinin-dependent manner. We propose that this miRNA-mediated control is a major mechanism underlying the cytokinin-induced formation of the gametophore meristem in Physcomitrella. Furthermore, it suggests a convergent evolution of miRNA-controlled pathways regulating phase transitions in seed and non-seed plants. PMID- 21543903 TI - Does cell cycle arrest occur in plant under solar UV-B radiation? AB - UV-B radiation (280-315 nm) is an integral part of solar radiation and has many harmful effects on plant growth and development. However, the molecular mechanism for the inhibition of plant growth by UV-B remains largely unknown. UV-B radiation induces various responses such as growth inhibition, DNA damage and changes of gene expression. Recently, by using synchronous root tip culture, we found that UV-B modulates the expression of cell cycle regulatory genes through DNA damage. Western blotting analysis revealed that UV-B induced G1-to-S arrest did not correlate with the protein abundance of CDKB1;1 and CYCD3;1 gene regulating proteins, but may with the posttranslational control. We extended the expression analysis of cell cycle related genes based on the published microarray data and the results strengthen our assumption that cell cycle arrest could occur in plant under solar UV-B radiation. Further study is needed to elucidate the relationship between cell cycle regulation and protective pathway induced by low dose of UV-B radiation fundamental molecular mechanism for how plants respond to solar UV-B radiation. PMID- 21543904 TI - Auxin and cytokinin regulate each other's levels via a metabolic feedback loop. AB - The hormones auxin and cytokinin are key regulators of plant growth and development. As they are active at minute concentrations and regulate dynamic processes, cell and tissue levels of the hormones are finely controlled developmentally, diurnally, and in response to environmental variables. This fine control, along with a regulation of the capacity to respond ensures that the appropriate type, duration and intensity of responses are elicited. We have recently discovered that cytokinin and auxin regulate the synthesis of each other, demonstrating a mechanism for mutual feed back and feed forward control of auxin and cytokinin levels. This regulatory loop could be important for many developmental processes in plants, i.e., in fine-tuning plant hormone levels in the developing meristems of the root and shoot apex. These findings could also give a molecular explanation for earlier observations of auxin and cytokinin effects on cell cultures,1 where specific auxin and cytokinin ratios have been used to trigger different morphological events. PMID- 21543905 TI - Advanced Practice Registered Nursing Consensus model: where are we now? PMID- 21543906 TI - Intimate partner violence, depression, and substance abuse in women presenting to emergency departments for care. AB - The Research to Practice column is intended to elevate the research critique skills of the advanced practice nurse and to assist with the translation of research into practice. For each column, a topic and a particular research study are selected. The stage is set with a case presentation. The research paper is then reviewed and critiqued, and finally, the implications for translation into practice are discussed with particular attention to the case study. In this column, we address the topics of intimate partner violence and substance abuse, among African American women by presenting the following study: Hankin, A., Smith, L. S., Daugherty, J., & Houry, D. (2010). Correlation between intimate partner violence victimization and risk of substance abuse and depression among African American women in an urban emergency department. Western Journal of Emergency Medicine, 11(3), 252-256. PMID- 21543907 TI - Shoulder pain. AB - Shoulder pain is a frequent complaint encountered in the emergency setting. A brief review of shoulder anatomy and physical examination sets the foundation for evaluation of shoulder pain. Considerations of patient's age are helpful to predict injuries. Fractured clavicles are often seen in traumatic injuries in children and young adults, whereas fractures of the humeral head are more often seen in the elderly from traumatic injuries. Shoulder dislocations are more common in teens to fourth decade. This article reviews specific acute injuries, chronic conditions, and radiologic considerations of patients with shoulder complaints encountered in emergency settings. PMID- 21543908 TI - Management of hypertensive emergency and urgency. AB - Severe hypertension is a frequent condition among patients presenting to emergency departments. Historically, this has been referred to as a hypertensive crisis. In addition, these hypertensive crises have been further divided into either hypertensive emergencies or urgencies depending on the presence or absence of target organ damage, respectively. The management differs between these crises in both the rapidity of blood pressure correction and the medications used. Hypertensive emergencies must be treated immediately with intravenous antihypertensive medications. However, hypertensive urgencies may be treated with oral antihypertensive agents to reduce the blood pressure to baseline or normal over a period of 24-48 hr. Appropriate identification, evaluation, and treatment of these conditions are of great importance in the emergency department to prevent progression of organ damage and death. The purpose of this article is to provide an overview of the hypertensive crises and their management. PMID- 21543909 TI - Implementing the hypothermia protocol: a case study. AB - This case study describes a 72-year-old man who complained of epigastric abdominal pain, indigestion, fatigue, and shortness of breath for 2 days. He subsequently sustained a witnessed cardiac arrest with resuscitation and return of circulation. The patient was then placed on therapeutic hypothermia postresuscitation. The following case study incorporates an evidence-based practice protocol supporting the use of therapeutic hypothermia postresuscitation. This article discusses the pathophysiology, use of the hypothermia protocol and also inclusion and exclusion criteria. Educational information within the article provides guidelines for the advanced practice nurse regarding the use of therapeutic hypothermia in resuscitated patients. PMID- 21543911 TI - Pressure ulcer prevention in the emergency department. AB - Emergency nurses rescue patients from emergencies everyday through expert prioritization in a rapidly changing environment. After stabilization, the emergency nurse can focus attention on other risk factors that predispose the patient to unnecessary health care events. The demographics of patients visiting the emergency department have changed over the past 5 years, and the length of time spent in an emergency department has increased. A pressure ulcer can develop in several hours, depending upon risk factors and use of pressure ulcer prevention activities. The emergency nurse holds a key position in pressure ulcer prevention. However, the emergency nurse's role in preventing the development of a pressure ulcer warrants further delineation. This focused literature review intends to summarize and analyze pressure ulcer research pertinent to the emergency nurse as a starting point for developing emergency nurse pressure ulcer prevention guidelines. PMID- 21543910 TI - Health care in rural hospitals: a role for nurse practitioners. AB - Disparities in rural health care are associated with poor patient outcomes. There is a need to further evaluate opportunities to bridge the gaps and improve rural health care. This descriptive, exploratory study examined the current and potential expanded use of nurse practitioners (NPs) in rural hospitals of one Midwestern state. Surveys (N = 136) were mailed to chief executive officers (n = 68) and chief nursing officers (n = 68) of rural hospitals in Nebraska with a response rate of 57.3% and 80.8%, respectively. The majority of respondents represented critical access hospitals. A convenience sample of NPs (N = 19) who practiced in rural communities also completed written surveys. Findings identified potential opportunities to expand the use of NPs to provide emergency department coverage and inpatient hospital management of patients in rural hospitals. Education and training of NPs need to include the essential critical thinking and skill sets to manage these types of health care needs. PMID- 21543912 TI - An update on hereditary angioedema. AB - Hereditary angioedema affects approximately 1 in 50,000 individuals without gender or ethnic preference. Hereditary angioedema is caused by a decreased level (type I) or function (type II) of C1 inhibitor. Patients experience repeated episodes of angioedema involving sites that include the face, extremities, gastrointestinal tract, and larynx. Treatment involves measures to increase functioning levels of active C1 inhibitor through stimulation of endogenous pathways or exogenous supplementation. Additional therapies targeted at inhibition of bradykinin can also be used to treat episodes of angioedema. Treatment may be indicated for both acute episodes of angioedema and prevention of future episodes. PMID- 21543914 TI - Mild traumatic brain injury: a Midwest survey of discharge teaching practices of emergency department nurses. AB - Research indicates that the assessment and discharge teaching practices for persons with traumatic brain injury are more focused on ruling out severe brain injury and informing the person about "red flags" warranting a return visit to the medical provider. Our primary purpose was to determine the extent to which discharge practices were aligned with the Centers for Disease Control and Prevention guidelines contained within the Acute Concussion Evaluation care plan. Responses from 87 nurses (25.0% response rate) to a tailored survey were analyzed to determine emergency department nurses' discharge teaching practices for adults who experienced a mild traumatic brain injury (MTBI). Results indicated that nurses in general were focused on injury-specific information and less often provided information about MTBI, symptom management, or strategies for preventing future brain damage. System improvements are justified to provide injured persons with a clearly defined diagnosis and instructions for follow-up and symptom management. PMID- 21543915 TI - From the heart: thank you to home health, home care, and hospice aides! PMID- 21543917 TI - Creating and sustaining an effective coaching culture in home care: one organization's performance improvement related to aides and aide retention. AB - Relationships between aides and their supervisors are often challenging. Unproductive disciplinary conversations lead to increased dissatisfaction, low morale, high turnover, and stress levels among staff. This cycle can continue to spiral if not effectively addressed and aimed in a positive direction. This article shares the experience of an organization that addressed this concern through a performance improvement initiative. PMID- 21543918 TI - Keeping it in the family: when Mexican American older adults choose not to use home healthcare services. AB - Mexican American elders are more functionally impaired and chronically ill than Anglo elders, yet use home care services less. The purpose of this study was to describe the cultural norms that influence Mexican American elders and their caregivers not to use home care services. A secondary analysis using descriptive ethnography was conducted. Thematic analysis was used to analyze Mexican American elders' (N = 4) and family caregivers' (N = 3) individual interviews. The overall finding was the category, "We Take Care of our Own!" This finding represented how Mexican American families faced increasing needs of elders at home in the context of their cultural norm of familism. The cultural findings, "Taking Care of Our Own!" were similar to those by elders who had chosen to use home care services in a previous study. Recognizing the importance of this norm, which is central to the culture, may shape interdisciplinary interventions that support traditional Mexican American family values, yet bring skilled or supportive help into the home. Interventions to increase the use of home care services by Latino families can contribute solutions to the national agenda to reduce healthcare disparities. PMID- 21543919 TI - Do sleep dreams of palliative patients mean anything? PMID- 21543920 TI - Fecal ostomies: practical management for the home health clinician. AB - Ostomy creation is a common surgical procedure that affects more than 120,000 individuals annually in the United States. Ostomy patients require lifelong specialized support and care directed toward improving their health status, promoting self-care, and facilitating long-term adjustment. Home health clinicians are responsible for the assessment and management of the complex needs of the ostomy patient and must be able to identify and appropriately intervene when complications arise. This article will provide the home health clinician with an overview of fecal ostomy care and management, and review the role of the clinician in the management of the patient. PMID- 21543922 TI - Research on diabetes: prioritization, quality of life, medication adherence, and self-efficacy. AB - According to data provided by the Centers for Disease Control and Prevention, 7.8% of the population in the United States has diabetes, with 1.6 million new cases diagnosed in adults each year (CDC, 2008). The morbidity and mortality associated with diabetes is significant. This research brief column features four diabetes-related studies. The first article describes an examination of patient provider concordance in prioritizing health conditions in patients with diabetes with elevated blood pressure levels. The second write-up profiles a study investigating quality of life and depression in patients diagnosed with diabetes and patients at risk of developing diabetes. The third article discusses the role that disease and medication beliefs have on medication adherence. The last review provides information on a study that assesses the relationship between diabetes self-efficacy and glycemic control and other clinical parameters, and whether an intervention can affect changes in self-efficacy and, in turn, clinical outcomes. Each review describes how the study findings may have implications for home healthcare. Interested readers are encouraged to read the original articles for full information about the study methods and findings. PMID- 21543923 TI - Expansion in direct care industry emphasizes need for training standards. Interview by Emily Swanson. PMID- 21543925 TI - Neoadjuvant chemotherapy fails to improve survival in advanced ovarian cancer: but is it the real culprit? PMID- 21543926 TI - Vascular endothelial growth factor gene polymorphisms and risk of cervical intraepithelial neoplasia. AB - OBJECTIVE: To evaluate the association between 3 vascular endothelial growth factor (VEGF) gene polymorphisms and susceptibility of cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: This prospectively collected case-control study investigates three common VEGF gene polymorphisms (ie, VEGF -460 [rs833061], VEGF +405 [rs2010963], and VEGF +936 [rs3025039]) in 203 women with CIN and 209 healthy women by DNA pyrosequencing. Associations between polymorphisms and CIN risk are evaluated with univariate and multivariable models and haplotype analysis. RESULTS: In a multivariable regression model, the variant VEGF +405C allele was associated (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.2-5.1], P = 0.02) with increased susceptibility of CIN independent of number of sexual partners (OR, 2.2; 95% CI, 1.1-4.6; P = 0.03) and smoking (OR, 3.3; 95% CI, 1.6-6.6; P = 0.001). The haplotype VEGF -460C - +405C - +936C was associated with an OR of 5.2 (95% CI, 1.2-52.7) for the susceptibility of CIN. CONCLUSIONS: The presence of the variant VEGF +405C allele and the haplotype VEGF -460C - +405C - +936C are independently associated with higher susceptibility of CIN. PMID- 21543927 TI - AEG -1 overexpression: a novel indicator for peritoneal dissemination and lymph node metastasis in epithelial ovarian cancers. AB - OBJECTIVE: Despite advances in chemotherapy and cytoreductive surgery, ovarian cancer remains the most lethal gynecological malignancy with a 5-year survival rate of 25% to 30% in advanced stage disease. Our purpose is to evaluate whether astrocyte elevated gene-1 (AEG-1) is a novel predictor of peritoneal dissemination and lymph node metastasis in epithelial ovarian cancer (EOC), which was not previously studied by others. MATERIALS AND METHODS: Through immunohistochemical and Western blot analysis, AEG-1 expression was evaluated in 25 normal ovarian and 157 EOC specimens. The relationship between AEG-1 expression and EOC metastasis was determined by univariate and multivariate analyses. RESULTS: Western blotting analysis revealed that AEG-1 was overexpressed in metastatic tissues from patients with ovarian cancers. Immunohistochemistry results showed that 83 (95.4%) presented peritoneal dissemination; 41 (47.1%) had lymph node metastasis among 87 patients with AEG-1 overexpression. Univariate and multivariate logistic regression analyses demonstrated that AEG-1 overexpression correlated with peritoneal dissemination and lymph node metastasis in EOC. We further found that the positive and specificity predictive value of AEG-1 staining were better for peritoneal metastasis, whereas the negative and sensitivity predictive value of AEG-1 staining were better for lymph node metastasis. The odds ratio of high-to-low expression for peritoneal dissemination was 8.541 (95% confidence interval, 2.561 37.461), and that for lymph node metastasis was 9.581 (95% confidence interval, 2.613-23.214). CONCLUSIONS: The present findings indicate that AEG-1 is overexpressed in a great portion of EOC patients with peritoneal dissemination and/or lymph node metastasis and may be clinically useful for predicting metastasis in EOC. Our findings might provide some benefits for metastatic EOC patients in the clinic. PMID- 21543928 TI - Tissue factor-factor VIIa complex induces epithelial ovarian cancer cell invasion and metastasis through a monocytes-dependent mechanism. AB - OBJECTIVE: Tumor-associated macrophage infiltration and up-regulation of tissue factor-factor VII (TF-FVIIa) complex have been observed in the peritoneum and stroma of epithelial ovarian cancer (EOC). However, it is not clear how tumor associated macrophage and TF-FVIIa complex promotes EOC invasion. In the present study, we aimed to determine the mechanism by which interaction of TF-FVIIa and monocytes (MOs) promotes EOC metastasis. METHOD: Matrigel invasion assay was used to analyze the potential of EOC metastasis. Enzyme-linked immunosorbent assay and real-time polymerase chain reaction were used to detect expressions of cytokines and chemokines. Fluorescence-activated cell sorting was used to count the percentage of CD14, CD68, and CD163 of MOs. RESULTS: We found that the TF-FVIIa complex caused dynamic changes in MOs cytokine and chemokine expression. CD14 and CD163 were also upregulated on MOs by TF-FVIIa. Epithelial ovarian cancer cells were cocultured with TF-FVIIa-stimulated MOs, demonstrating increased invasion potential. Interleukin 8 (IL-8) was proposed as the major chemoattractant mediating EOC invasion based on MOs messenger RNA and protein expression profiles. Anti-IL-8 monoclonal neutralizing antibody attenuated EOC cell invasion in a concentration-dependent manner, and tumor necrosis factor alpha from TF FVIIa-stimulated MOs was observed to amplify IL-8 production. The following transcription factors in MOs were activated by TF-FVIIa and inhibited by the tissue factor pathway inhibitor: oncogenes HIF-1alpha, HIF-1beta, Oct I, Oct II, and Egr-1; inflammatory mediators c-Fos and c-Rel; and STAT family members STAT5A and STAT5B. CONCLUSIONS: Our study suggested that the interaction between the TF FVIIa complex might play a role in mediating EOC invasion and metastasis depending on MOs mechanism. PMID- 21543929 TI - Fertility-sparing surgery for borderline ovarian tumors: oncologic safety and reproductive outcomes. AB - INTRODUCTION: To evaluate the oncological safety and reproductive outcomes of patients with borderline ovarian tumors (BOTs) treated with fertility-sparing surgery. METHODS: Patients with BOTs who underwent radical or fertility-sparing surgery between 1997 and 2009 were identified from an institutional database. The recurrence rates were compared between the 2 surgery groups. To compare the reproductive outcomes, all patients who underwent fertility-sparing surgery were interviewed by telephone. RESULTS: One hundred forty-three patients underwent radical surgery, and 155 patients underwent fertility-sparing surgery. After a median interval of 38 months from the initial surgery (range, 10-77 months), 19 patients had a recurrence. The recurrence rate was similar in the radical and fertility-sparing surgery groups (4.9% and 7.7%, respectively; P = 0.280). In the fertility-sparing surgery group, however, the main site of recurrence was the remaining ovary that was successfully salvaged with a second round of fertility sparing surgery. Of 51 patients who attempted to conceive, 45 patients (88.2%) were successful and resulted in 54 term deliveries. CONCLUSIONS: Fertility sparing surgery for BOTs is safe and can result in future pregnancies, suggesting that such surgery should be considered for young patients who desire preservation of fertility. PMID- 21543930 TI - No supportive evidence for clinical benefit of routine follow-up in ovarian cancer: a Dutch multicenter study. AB - INTRODUCTION: Routine follow-up is standard medical practice in ovarian cancer patients treated with curative intent. However, no strong evidence exists indicating that prognosis is improved. The objective of this study was to evaluate the routine follow-up schedule for ovarian cancer patients regarding the adherence to the Dutch protocol, the detection of recurrences, and the follow up's impact on overall survival. METHODS: All 579 consecutive patients diagnosed with epithelial ovarian, primary peritoneal, or fallopian tube cancer in 4 Dutch hospitals between 1996 and 2006 were selected. Only patients in complete clinical remission after primary treatment were studied. Compliance to the Dutch follow-up guideline was assessed in a random sample of 68 patients. Of the 127 patients with recurrence, the mode of recurrence detection was addressed. Survival time since primary treatment was calculated using the Kaplan-Meier method. RESULTS: The patients received more follow-up visits than was recommended according to the guideline. The cumulative 5-year risk of recurrence was 55% (95% confidence interval [CI], 43%-67%). The survival of patients with recurrent ovarian cancer detected asymptomatically at a routine visit (n = 51) tended to be better compared with patients with symptomatic detection at a routine (n = 31) or diagnosed after an interval visit (n = 31). The median survival times were 44 (95% CI, 38-64), 29 (95% CI, 21-38), and 33 months (95% CI, 19-61), respectively (P = 0.08). The median time from primary treatment to recurrence was similar for the 3 groups: 14, 10, and 11 months, respectively (P = 0.26). CONCLUSIONS: Follow up in line with (inter)national guidelines yields a seemingly longer life expectancy if the recurrence was detected asymptomatically. However, this result is expected to be explained by differences in tumor biology and length-time bias. PMID- 21543931 TI - Prognosis and reproducibility of new and existing binary grading systems for endometrial carcinoma compared to FIGO grading in hysterectomy specimens. AB - BACKGROUND: The current International Federation of Gynecology and Obstetrics (FIGO) grade in endometrial carcinomas requires the evaluation of histologic features with proven prognostic value but with questionable reproducibility. This study tests the prognostic power and reproducibility of a new binary grading system. STUDY DESIGN: Specimens from 254 hysterectomies were graded according to the new 3- and 2-tiered FIGO grading systems described by Alkushi et al. The selected morphologic parameters for the new grading system included the presence of predominant solid or papillary architecture pattern, severe nuclear atypia, tumor necrosis, and vascular invasion. The Cox proportional hazards and kappa statistics were used for comparisons. RESULTS: On multivariate analysis, and looking at all tumor cell types, the 4 tested grading systems were independent predictors of survival, with the 3-tiered FIGO grading system being the most predictive (P = 0.005). In the subset of endometrioid tumors, the 3- and 2-tiered FIGO grading systems and the new grading system retained their statistical significance as predictors of survival (P = 0.004, P = 0.03, and P = 0.007, respectively), whereas the grading system of Alkushi et al did not (P = 0.1). In nonendometrioid tumors, the new grading system proved to be the best predictor of survival, reaching near statistical significance (P = 0.06). The new grading system had acceptable intraobserver and interobserver reproducibility assessment (kappa = 0.87 and kappa = 0.45, respectively). CONCLUSION: The 3-tiered FIGO grading system retained its superior prognostic power. However, available binary grading systems remain an attractive option by being highly reproducible and by eliminating the clinical ambiguity of intermediate grades of disease. PMID- 21543932 TI - A modified shortened administration schedule for neoadjuvant chemotherapy with irinotecan and cisplatin in locally advanced cervical cancer. AB - INTRODUCTION: The commonly used administration schedule of irinotecan in combination therapy with cisplatin in cervical cancer was once weekly for 3 weeks. To some extent, this administration schedule may be inconvenient for patients who were far from hospital. The aim of the current study is to investigate the efficacy and toxicities of a modified shortened administration schedule for neoadjuvant chemotherapy with irinotecan and cisplatin in locally advanced cervical cancer. METHODS: We retrospectively reviewed the clinical records of patients with cervical cancer who received neoadjuvant chemotherapy with irinotecan and cisplatin delivered by the modified administration schedule at Sun Yat-sen University Cancer Center from November 2005 to May 2010. Irinotecan was administrated by intravenous infusion for 1 hour at a dose of 80 mg/m on days 1 and 8. Cisplatin was administrated intravenously at a total dose of 60 to 70 mg/m, which was infused on day 1 or was divided into 2 or 3 doses and given on days 1 to 2 or 3. The treatment was repeated every 3 weeks. RESULTS: The total response rate was 78.8% (42/52), including a complete response and partial response rate of 11.5% (6/52) and 67.3% (35/52), respectively. Pathologically confirmed complete response was noted in 7.7% (4/52) of patients. Stable disease was observed in 17.3% (9/52) of patients and progression disease in 3.8% (2/52) of patients. Diarrhea and hematological toxicity were the major dose-limiting toxicities. Diarrhea occurred in 23.1% of patients with grades 1, 2, and 3 in 11.5%, 7.7%, and 3.8% of patients, respectively. No grade 4 diarrhea was noted. Grade 3/4 neutropenia developed in 7.7% (4/52) of patients. Grade 3/4 anemia occurred in 19.2% (10/52) of patients. CONCLUSIONS: The modified shortened administration schedule of combined therapy with irinotecan and cisplatin may be active against cervical cancer as neoadjuvant chemotherapy. The adverse effects could be controllable. PMID- 21543933 TI - Prognostic significance of CD4+ and CD8+ T cell infiltration within cancer cell nests in vulvar squamous cell carcinoma. AB - BACKGROUND: The clinicopathological significance of the local spontaneous immune reaction in vulvar squamous cell carcinoma remains unclear. The purpose of this study was to clarify the role of the subtypes of tumor-infiltrating lymphocytes, both individually and synergistically. METHODS: Seventy-six patients with verified histopathological data and complete clinical history were included into the study. We collected 76 paraffin-embedded samples of the primary tumor. The presence of CD4+ and CD8+ T cells was evaluated by immunohistochemistry and compared with commonly recognized prognostic factors. The primary end point analyzed was the overall survival. RESULTS: CD4+ and CD8+ T cells were detected both within the nests of carcinoma and in the stroma, but only the infiltration within cancer cell nests was further analyzed. There was significant positive correlation (Spearman rho test R = 0.282, P = 0.014) between the number of intratumoral CD4+ and CD8+ T cells. No correlation was observed between the number of tumor-infiltrating CD4+ and CD8+ T cells and the patients' survival. Patients were classified into the following 4 groups (CD4+/CD8+, CD4-/CD8- CD4+/CD8-, CD4-/CD8+), but none of them correlated with overall survival. CONCLUSIONS: These data support the statement that CD4- and CD8+ T cells cooperate within cancer cell nests, but this spontaneous immune reaction is an individual feature not influencing the prognosis. Intratumoral CD4+ T cells might control or reflect the immune responses against cancer cells, whereas CD8+ T cells do not seem to work as sufficient effectors in tumor tissues. PMID- 21543935 TI - The global impact of the Gynecologic Cancer InterGroup in enhancing clinical trials in ovarian cancer. AB - The Gynecologic Cancer InterGroup (GCIG) has developed from a small network of ovarian cancer researchers to a large international forum addressing multiple issues related to research in gynecologic cancers. Member groups of the GCIG have collaboratively conducted pivotal clinical trials in cancers of the ovary, endometrium, and cervix. The participation of operational and statistical personnel from the GCIG member groups has facilitated a collegial approach to international differences and restrictions.One of the powerful initiatives of the GCIG is the facilitation of the Ovarian Cancer Consensus Conference every few years. The 4th Ovarian Cancer Consensus Conference was held in Vancouver, Canada, in June 2010, and the resulting publications (herein) provide an invaluable resource to researchers in the field of gynecologic oncology. PMID- 21543936 TI - 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference. AB - 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer. This report provides the outcomes from the Fourth Ovarian Cancer Consensus Conference. PMID- 21543937 TI - First-line therapy in ovarian cancer trials. AB - At the 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG) held in Vancouver, Canada, in June 2010, representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. The process focused on 13 predetermined questions. Group A, 1 of the 3 discussion groups, addressed the first 5 questions, examining first-line therapies in newly diagnosed ovarian cancer patients. A1: What are the appropriate end points for different trials (maintenance, upfront chemotherapy trials including molecular drugs)? A2: Are there any subgroups defined by tumor biology who need specific treatment options/trials? A3: Is the 2004 GCIG recommended standard comparator arm still valid? A4: What is the role of modifying dose, schedule, and delivery of chemotherapy? A5: What role does surgery play today? PMID- 21543938 TI - Role of molecular agents and targeted therapy in clinical trials for women with ovarian cancer. AB - There is now a greater understanding of the molecular pathways in ovarian cancer, and using this knowledge, a large number of new therapeutic agents can be tested. The success of these drugs will depend on selecting drugs that target known key dysfunctional molecular pathways. To make best use of these compounds, prognostic and predictive biomarkers need to be identified. Novel methods of assessment such as functional imaging need to be developed as additional biological end points to evaluate these therapies. Promising antitumor activity has been observed with some drugs, and careful consideration is needed to determine in what circumstances new agents, such as antiangiogenic compounds, could be considered as a standard therapy. These areas were discussed at the 4th Ovarian Cancer Consensus Conference. PMID- 21543939 TI - Clinical trials in recurrent ovarian cancer. AB - The 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup was held in Vancouver, Canada, in June 2010. Representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. Group C, 1 of the 3 discussion groups, examined recurrent ovarian cancer, and we report the consensus reached regarding 4 questions. These included the following: (1) What is the role of cytoreductive surgery for recurrent ovarian cancer? (2) How do we define distinct patient populations in need of specific therapeutic approaches? (3) Should end points for trials with recurrent disease vary from those of first-line trials? (4) Is CA-125 progression alone sufficient for entry/eligibility into clinical trials? PMID- 21543940 TI - Clinical trials and treatment of the elderly diagnosed with ovarian cancer. AB - Elderly patients are more commonly diagnosed with advanced ovarian cancer and represent a growing proportion of all ovarian cancer cases. Despite this, the elderly have historically been underrepresented in clinical trials. Because clinical trials form the basis for most treatment guidelines and the elderly have been, to date, largely excluded from this process, little is known about the appropriate assessment and treatment of elderly ovarian cancer patients. Recognizing this knowledge deficit and the pressing need to correct it, this article aimed to summarize existing data and identify future areas of research focus. PMID- 21543941 TI - Patient-reported outcomes: clinical trials in ovarian cancer. PMID- 21543942 TI - Survivorship as an element of clinical trials in ovarian cancer. PMID- 21543943 TI - How to treat arterial stiffness beyond blood pressure lowering? PMID- 21543944 TI - Rate of blood pressure changes assessed by 24 h ambulatory blood pressure monitoring: another meaningful index of blood pressure variability? PMID- 21543945 TI - Precision, accuracy and added value of central pressure measurement. PMID- 21543946 TI - Revenge phenomena and posttraumatic stress disorder in former East German political prisoners. AB - To date, psychological revenge phenomena have not been investigated systematically as factors potentially contributing to posttraumatic stress disorder (PTSD). This follow-up study (1995: N = 146; 2008: N = 93) assessed the predictive power of revenge phenomena for current PTSD symptoms in a sample of former East German political prisoners some four decades after traumatization. As the results of multiple hierarchical regression analyses have revealed, revenge feelings and cognitions significantly contributed to the prediction of both self reported and clinician-rated PTSD symptoms above and beyond standard predictor variables. In contrast, revenge intentions did not contribute to the prediction of current PTSD. The findings suggest that revenge feelings and cognitions may be a maintaining factor for longtime PTSD. Identification and therapeutic modification of dysfunctional revenge phenomena may therefore enhance the effectiveness of psychotherapy for persistent PTSD. PMID- 21543947 TI - Recovery style predicts remission at one-year follow-up in outpatients with schizophrenia spectrum disorders. AB - Although people with schizophrenia use various coping strategies, it is largely unknown how their coping style contributes to remission of the illness. The concept of recovery style-either by sealing over or integrating-reflects an important distinction. We wanted to examine whether recovery style predicts remission at a 1-year follow-up. We examined the recovery style, insight, therapeutic alliance, and symptoms in 103 patients with psychotic disorders. To assess the remission status, the symptoms were measured at 6 and 12 months. Logistic regression analyses were used. Results showed that scoring an extra category toward integration (six categories exist) increased the odds of remission 1.84-fold (95% confidence interval, 1.11 to 3.03). Insight and therapeutic alliance were not predictive. Although remission was also predicted by positive symptom levels at baseline, this did not influence the effect of recovery style. In conclusion, independently of symptom levels, insight, or therapeutic alliance, an integrating recovery style increases the odds of remission at a 1-year follow-up. PMID- 21543948 TI - Mental health service utilization among college students in the United States. AB - We aimed to provide the most comprehensive picture, to date, of service utilization and help-seeking behavior for mental health problems among college students in the United States. We conducted online surveys in 2007 and 2009 of random samples of students in 26 campuses nationwide. Among students with an apparent mental health problem (32% of the weighted sample), 36% received any treatment in the previous year. The prevalence of psychotherapy and medication use was approximately equal. Treatment prevalence varied widely across campuses, with some campuses having prevalence 2 to 3 times higher than those of others. Apparent barriers to help-seeking included skepticism on treatment effectiveness and a general lack of perceived urgency. Overall, the findings indicate that help seeking for mental health varies substantially across student characteristics and across campuses. Strategies to address the low prevalence of treatment will need to be responsive to this diversity. PMID- 21543949 TI - Posttraumatic stress disorder in peacekeepers: a meta-analysis. AB - A meta-analysis was conducted to estimate the prevalence of posttraumatic stress disorder (PTSD) among peacekeepers. A systematic review was carried out using Medline, Institute for Scientific Information/Web of Science and Published International Literature on Traumatic Stress databases, leading to a total of 12 studies reporting PTSD estimates. Pooled current PTSD prevalence was 5.3%, ranging from 0.05% to 25.8%, and a metaregression was used to investigate the variables that could account for the lack of homogeneity. However, none of the extracted information was capable of explaining the heterogeneity of the estimates. Peacekeeping studies presented different methodologies such as several screening instruments and different times from the deployment to the moment of PTSD assessment. The wide difference found among those estimates highlights the importance of the creation of standards for PTSD evaluation among peacekeepers. PMID- 21543950 TI - The role of caregiver major depression in the relationship between anxiety disorders and asthma attacks in island Puerto Rican youth and young adults. AB - The goal of this study was to assess whether the association between asthma attacks and anxiety disorders in youth/young adults is reduced after adjusting for the caregivers' psychiatric disorders. An island-wide probability sample of 641 households in Puerto Rico with youth/young adults between ages 10 and 25 years participated along with their caregivers. The Diagnostic Interview Schedule for Children and the Composite International Diagnostic Interview were conducted to assess anxiety and depressive disorders. Youth/young adults with an anxiety disorder were more likely to have a lifetime history of asthma attacks versus youth/young adults without an anxiety disorder. Caregivers of participants with asthma attacks were more likely to have major depression than did the caregivers of participants without asthma attacks. The association between asthma attacks and anxiety disorders in youth was no longer significant after adjustment for caregiver major depression. It is important to consider the role of caregiver depression in asthma-anxiety comorbidity in youth/young adults. PMID- 21543951 TI - Randomized trial of dual-focused vs. single-focused individual therapy for personality disorders and substance dependence. AB - We conducted a randomized comparison of dual-focus schema therapy with individual drug counseling as enhancements to the residential treatment of 105 substance dependent patients with specific personality disorders versus those without. Both therapies were manual-guided and delivered for 6 months by experienced psychotherapists intensively trained and supervised with independent fidelity assessment. Using the Cox proportional hazards model, we found no psychotherapy differences in retention (days in treatment). Hierarchical linear modeling indicated that participants with personality disorders started with higher psychiatric, interpersonal, and dysphoria symptoms and that both therapies reduced symptoms in 6 months. Contrary to predictions, individual drug counseling resulted in more sustained reductions than did dual-focus schema therapy in several symptoms for several personality disorders. Our findings raised important questions about the added value of integrative or dual-focus therapies for co occurring personality disorders and substance dependence relative to empirically supported therapies focused more specifically on addiction symptoms. PMID- 21543952 TI - Determinants of depressive symptoms in narcoleptic patients with and without cataplexy. AB - The present prospective study assesses depressive symptoms in narcoleptic patients with (NC+) and without (NC-) cataplexy (46 women, 40 men) and age- and sex- matched healthy controls. Seventy patients were under treatment with stimulants and/or anticataplectics. All subjects completed the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale (SDS), the Global Impression of Severity of Depression (GSD), the Profile of Mood States (POMS) and Epworth Sleepiness Scale. Patients with narcolepsy were more depressed than controls (higher scores in BDI, GSD, SDS, and POMS [in the total score and in all subscale scores]); however, between the NC+ and NC- patient groups, no differences were found. Our study shows that the women and the patients using antidepressants and stimulants (combination) have a higher probability for depressive symptoms independent of the presence of cataplexy. The lack of difference between NC+ and NC- in the level of depression supports the assumption that the major psychosocial burden in narcolepsy is not necessarily associated with the presence of cataplexy. PMID- 21543953 TI - Effect of relocation and parental psychopathology on earthquake survivor children's mental health. AB - Earthquakes may increase the risk for psychopathology in children because the disaster may disrupt family functioning through causing psychopathology in the parents or disrupting social network through migration, school changes, or socioeconomic status changes caused by the job losses of the parents. This study aimed to investigate the effects of parental psychopathology on the traumatic stress and depression of earthquake survivor-children 4 years after the earthquake. A convenience sample of 104 earthquake survivor-children (43 boys, 61 girls) and their parents were assessed at their homes for earthquake experience and traumatic stress symptoms. The outcome variables were the factor scores of a child/adolescent traumatic stress questionnaire (Traumatic Stress Symptom Checklist for Children and Adolescents). The predictors of child's factor scores were examined using linear regression analyses. The traumatic stress factor score of the children was predicted two variables: the child's reported fear during the earthquake and the father's traumatic stress factor score. The depression factor score, on the other hand, was predicted using the depression factor score of the mother only. Demographic variables or relocation status were not predictive for either of children's factor scores. The results of the present study show that maternal and paternal psychopathologies have differential effects on the psychological status of earthquake survivor-children. Traumatic stress in the child is predicted using the traumatic stress of father, whereas depression in the child is predicted by mother's depression levels. Social network disruption does not seem to have a negative effect on children once parental psychopathology is taken into account. PMID- 21543954 TI - Threat/control-override symptoms and emotional reactions to positive symptoms as correlates of aggressive behavior in psychotic patients. AB - This cross-sectional multicenter study was carried out to examine whether the experience of threat/control-override symptoms and emotional reactions to positive symptoms (e.g., anger, anxiety) are related to aggressive behavior. Patients diagnosed with schizophrenia, delusional disorder, psychotic disorder not otherwise specified, or a schizoaffective disorder (N = 124) were interviewed and filled out self-report questionnaires. Results indicated that, in particular, threat/control-override symptoms were significantly related to aggressive behavior in psychotic patients. Further analysis revealed that the threat symptoms especially, but not the control-override symptoms, carried this effect. Anger disposition also accounted for a significant and unique proportion of the variance in the aggressive behavior of psychotic patients, whereas state anger and anxiety in reaction to positive symptoms did not. These results seem to suggest that feeling threatened by positive psychotic symptoms and anger disposition play a role in the origins of aggressive behavior of psychotic patients. PMID- 21543955 TI - An investigation of the relationship between cortical connectivity and schizotypy in the general population. AB - Recent neuroimaging investigations have identified a relationship between psychotic symptoms in schizophrenia and abnormal brain connectivity. On the basis of the continuum model of psychosis, it was hypothesized that schizotypal traits in healthy control participants would be associated with relatively impaired frontotemporal white matter health as assessed using diffusion tensor imaging. Twenty-one participants (12 women and 9 men aged 18 to 58 years) completed the Schizotypal Personality Questionnaire (SPQ) and underwent diffusion-weighted magnetic resonance imaging scanning as part of a larger study. White matter integrity for the major association fibre tracts was assessed using standard measures of diffusivity, specifically fractional anisotropy (FA) and axial and radial diffusivity. A series of negative binomial regressions yielded significant relationships between reduced FA in seven white matter tracts and increased scores on the SPQ cognitive-perceptual factor. These findings are consistent with research relating brain connectivity to the positive symptoms of schizophrenia, suggesting that the neurobiological bases of schizotypal personality in healthy controls may be analogous to the neurobiological bases of schizophrenia spectrum disorders. PMID- 21543956 TI - Evaluating psychological insight in a clinical sample using the Shedler-Westen assessment procedure. AB - Using the Shedler-Westen Assessment Procedure (SWAP)-200 Q-Sort items in a large clinical sample of outpatients (N = 105), we developed the SWAP insight scale. The rationale, psychometric properties, and convergent validity of this insight scale are reported. Through factor analysis, six of the SWAP-200 items were identified as psychometrically optimal in the assessment of insight (presence or absence) with an alpha coefficient of 0.78. We examined the construct validity of this SWAP insight scale using independent clinical videotape ratings of the Capacity for Dynamic Process Scale, specifically the items "appears introspective" and "manifests insight." We also examined the relationship between the SWAP insight scale using independent clinical videotape ratings of the Social Cognition and Object Relations Scale-Global Ratings, specifically ratings of "complexity of representations" and "social causality." The results demonstrated significant positive correlation between the SWAP insight scale and all five of these criterion measures. Partial correlations demonstrated that, even when the effects of global psychiatric severity are controlled for, the SWAP insight scale maintains a significant relationship with independent clinical videotape ratings of patients manifesting insight during sessions. Future research directions and clinical implications of the SWAP insight scale are discussed. PMID- 21543957 TI - Advancing nursing science through health trajectory research: an introduction. AB - The Minnesota Center for Health Trajectory Research has focused on developing ways to better understand how interventions influence health trajectories during transitional, acute, or chronic health challenges across the life span. The health trajectory perspective advances nursing science by providing a person centered point of view that emphasizes change in health over time within individuals, families, groups, or communities. Theoretical considerations and statistical modeling approaches used in studying health trajectories, along with exemplars from nursing research studies from this special issue of Nursing Research, are highlighted. PMID- 21543958 TI - Trajectories of parasympathetic nervous system function before, during, and after feeding in infants with transposition of the great arteries. AB - BACKGROUND: Compromised parasympathetic response to stressors may underlie feeding difficulties in infants with complex congenital heart defects, but little is known about the temporal pattern of parasympathetic response across phases of feeding. OBJECTIVES: The aim of this study was to describe initial data exploration of trajectories of parasympathetic response to feeding in 15 infants with surgically corrected transposition of the great arteries and to explore the effects of feeding method, feeding skill, and maternal sensitivity on trajectories. METHOD: In this descriptive, exploratory study, parasympathetic function was measured using high-frequency heart rate variability (HF HRV), feeding skill was measured using the Early Feeding Skills assessment, and maternal sensitivity was measured using the Parent-Child Early Relational Assessment. Data were collected before, during, and after feeding at 2 weeks and 2 months of age. Trajectories of parasympathetic function and relationships with possible contributing factors were examined graphically. RESULTS: Marked between infant variability in HF HRV across phases of feeding was apparent at both ages, although it was attenuated at 2 months. Four patterns of HF HRV trajectories across phases of feeding were identified and associated with feeding method, feeding skill, and maternal sensitivity. Developmental increases in HF HRV were apparent in most breast-fed, but not bottle-fed, infants. DISCUSSION: This exploratory data analysis provides critical information in preparation for a larger study in which varying trajectories and potential contributing factors can be modeled in relationship to infant outcomes. Findings support inclusion of feeding method, feeding skill, and maternal sensitivity in modeling parasympathetic function across feeding. PMID- 21543959 TI - Modeling trajectories and transitions: results from the New York University caregiver intervention. AB - BACKGROUND: Current research fails to capture the temporal dynamics of chronic disease in favor of cross-sectional snapshots of symptoms and outcomes. OBJECTIVE: The aim of this study was to estimate the effects of comprehensive psychosocial support on trajectories of spouse caregivers' well-being related to the nursing home placement transition. METHOD: Data from the New York University Caregiver Intervention, a randomized controlled trial of a comprehensive support program for spouse caregivers of persons with Alzheimer's disease, were utilized. A convenience sample of 406 spouse caregivers of community-dwelling persons with Alzheimer's disease was enrolled over a 9.5-year period in an Alzheimer's disease research center in New York City. Outcome measures, including the Zarit Burden Inventory and Geriatric Depression Scale, were used to assess the differential effects of nursing home placement and of the intervention on spouse caregivers. In-person interviews of spouse caregivers took place every 4 months during the first year of participation and every 6 months thereafter for up to 16 years; 385 caregivers provided sufficient follow-up data for all analyses. RESULTS: Longitudinal models found that wives were more likely than husbands to indicate reductions in burden in the months after placement in an institution. Wives also reported greater decreases in depressive symptoms after placement in an institution when compared with husbands. DISCUSSION: The inclusion of transitions and health trajectories in a randomized controlled trial offers an intriguing picture of how comprehensive psychosocial interventions can help families navigate the challenges of chronic disease care. The results also indicate how advances in nursing science can facilitate future research in the modeling of trajectories and transitions in the dementia care context. PMID- 21543960 TI - The pain trajectory during treadmill testing in peripheral artery disease. AB - BACKGROUND: Ischemia-induced pain associated with walking (claudication) in peripheral artery disease limits mobility and diminishes quality of life. Self reports of pain during standardized treadmill testing are used in clinical trials to assess the efficacy of interventions. OBJECTIVES: The aim of this study was to model pain trajectories during a peak walking test after 12 weeks of treatment in participants in four randomly assigned treatment groups (treadmill, arm ergometry, combination, and usual care) compared with baseline pain trajectories. METHODS: Self-reports of pain obtained at baseline and after 12 weeks of supervised exercise training for 41 participants (71% male; age, M = 64 years, SD = 8.6 years) were used. Pain was measured every 30 seconds with a numeric rating scale that had ordinal response options ranging from 0 (no pain) to 5 (severe pain). The test was continued until the maximum level of pain was reached and the participant could no longer walk. Observed responses from individual cases were plotted and patterns of pain were identified. A hierarchical generalized linear model for ordinal data was fit to compare baseline and postintervention trajectories. RESULTS: : Patterns in observed data reflected variations in time to onset of mild pain, acceleration to severe pain, and total walking time. All groups improved at 12 weeks; arm ergometry trajectories showed slower onset of pain, whereas treadmill training produced slower rates of increase to the maximum toward the end of the test. Effects for individuals appear as offsets from personal models at baseline. DISCUSSION: Change in the experienced claudication trajectory varied by type of exercise. Findings can inform design of future trials and aid decision making about exercise interventions for claudication. PMID- 21543961 TI - Health and illness over time: the trajectory perspective in nursing science. AB - BACKGROUND: Understanding change in health and illness over time is central to creating and evaluating interventions for individuals, families, and populations. The term health trajectory is a succinct and useful way to describe change in health status over time. OBJECTIVES: The aims of this article were to define the notion of a health trajectory; comment on the usefulness and current status of health trajectory research for nursing science and practice; and identify and illustrate the key elements of theory, design, and statistical models for health trajectory research. APPROACH: Constructs in theory about individual change are summarized, synthesized with characteristics of longitudinal design and statistical models for change, and discussed in light of current and emerging health care priorities and trends in nursing research. RECOMMENDATIONS: Health trajectory research is person focused and congruent with the person-centered emphasis of nursing practice. The contribution of nursing science to the overall effort to improve health will be enhanced when change over time is explicit in nursing theory, longitudinal designs are used, and contemporary statistical approaches for modeling change in health status are incorporated into research plans. PMID- 21543962 TI - Patterns of anxiety in critically ill patients receiving mechanical ventilatory support. AB - BACKGROUND: Mechanical ventilation is one of the most frequently used technological treatments in critical care units and induces great anxiety in patients. OBJECTIVES: Although mechanical ventilation and critical illness induce great anxiety and distress in hospitalized patients, little is known about anxiety ratings over the course of ventilatory support. Knowledge of anxiety ratings over time is needed to implement effective symptom management interventions. The purposes of this study were to describe anxiety ratings for a subgroup of mechanically ventilated patients over the duration of enrollment in a multisite clinical trial, to discern any pattern of change in anxiety ratings, to determine if anxiety decreases over time, and to explore the influence of sedative exposure on anxiety ratings. METHODS: Participants were 57 mechanically ventilated patients who were randomly assigned to the usual care group of a randomized controlled trial designed to assess the efficacy of music interventions on anxiety of mechanically ventilated patients in intensive care units. Anxiety ratings were obtained at study entry and daily for up to 30 days. A 100-mm visual analog scale was used to measure anxiety. Visual Analog Scale Anxiety scores were plotted as a function of study time in days for each participant to discern possible patterns of change. A mixed-models analysis was performed to assess the nature and magnitude of change over time (slope) using 251 observations on 57 patients. RESULTS: Results of the unconditional means model indicated that further modeling was appropriate. An autoregressive covariance structure with a random component for participant was chosen as the most appropriate covariance structure for modeling. An unconditional growth model indicated that the Visual Analog Scale-Anxiety ratings declined slowly over time: -.53 points per day (p = .09). DISCUSSION: Anxiety is an individual patient experience that requires ongoing management with appropriate assessment and intervention over the duration of mechanical ventilatory support. PMID- 21543963 TI - Symptoms associated with dietary fiber supplementation over time in individuals with fecal incontinence. AB - BACKGROUND: Knowledge about adverse symptoms over time from fiber supplementation is lacking. PURPOSE: The aim of this study was to compare the severity of adverse gastrointestinal (GI) symptoms during supplementation with dietary fiber or placebo over time in adults with fecal incontinence. A secondary aim was to determine the relationship between symptom severity and emotional upset and their association with study attrition and reducing fiber dose. METHODS: Participants (N = 189; 77% female; 92% White; age, M = 58 years, SD = 14 years) with fecal incontinence were randomly assigned to a placebo or a supplement of 16 g total dietary fiber per day from 1 of 3 sources: gum arabic, psyllium, or carboxymethylcellulose. They reported GI symptoms daily during baseline (14 days), incremental fiber dosing (6 days), and 2 segments of steady full fiber dose (32 days total). RESULTS: Severity of symptoms in all groups was minimal. Adjusting for study segment and day, a greater feeling of fullness in the psyllium group was the only symptom that differed from symptoms in the placebo group. The odds of having greater severity of flatus, belching, fullness, and bloating were 1.2-2.0 times greater in the steady dose segment compared with baseline. There was a positive association between symptom severity and emotional upset. Participants with a greater feeling of fullness or bloating or higher scores for total symptom severity or emotional upset were more likely to withdraw from the study sooner or reduce fiber dose. CONCLUSIONS: Persons with fecal incontinence experience a variety of GI symptoms over time. Symptom severity and emotional upset appear to influence fiber tolerance and study attrition. Supplements seemed well tolerated. PMID- 21543964 TI - Adolescent condom use consistency over time: global versus partner-specific measures. AB - BACKGROUND: The conundrum of measuring condom use consistency, particularly with adolescents, has left researchers with a cacophony of strategies, thereby limiting comparability and interpretation. OBJECTIVE: The aim of this analysis was to compare and contrast two measures of condom use consistency, global versus partner specific, and their relationships with key covariates, using trajectory groups differentiated by stability of condom use consistency over three time points. METHOD: Using self-report data from sexually active girls (aged 13-17 years) in a clinic-based intervention study aimed at lowering risk for early pregnancy, this analysis compared two measures of self-reported condom use consistency: (a) a global measure: overall condom use consistency in the past 6 months and (b) a partner-specific measure: condom use consistency with the most recent sex partner in the last 6 months. Using a subjective rule-based approach, the adolescent girls in the study (n = 151) were classified into trajectory groups representing their condom use consistency at three time points (baseline and 6 and 12 months). Then, using bivariate methods, trajectory groups were compared on four baseline covariates (age, treatment condition, hormonal use in the last 6 months, and number of sex partners in the last 6 months) and three time-varying covariates measured at baseline and at 6 and 12 months (hormonal use stability, stability of primary sex partner, and stability of number of sex partners). RESULTS: For the trajectory groups formed using the global measure of condom use consistency, stability of the primary sex partner differed significantly between trajectory groups. For the partner-specific trajectory groups, two baseline and one time-varying covariate relationships were significant: hormonal use in the 6 months prior to baseline, number of sex partners in the past 6 months (baseline), and stability of the primary sex partner (time varying), with hormonal use stability (time varying) trending toward significance. DISCUSSION: The larger number of significant covariate relationships with the partner-specific trajectory groups suggests greater utility in assessing partner-linked behavior rather than a global measure. Despite limitations of the analytic strategy, this study sheds light on a measurement conundrum that has been an obstacle to comparing and contrasting indicators of condom use consistency during adolescence. PMID- 21543965 TI - Health trajectory research: a call to action for nursing science. AB - The focus of health trajectory research is study of health over time for individual persons, families, or communities. The person-focused, time-based perspective reflects health as it is experienced over the life course and maps directly onto processes of care, contributing to ease in translation of results to practice. The agenda focuses on theoretical and empirical components needed to (a) build health trajectory science; (b) develop the scientific workforce to conduct health trajectory research; (c) integrate health trajectory research with other critical, emerging areas of nursing science (genomics and genetics, informatics, dynamic systems and communication); and (d) apply health trajectory research across the life span and continuum of care. Agenda items point the way toward a reorientation of nursing research that incorporates and emphasizes understanding of individual health trajectories. PMID- 21543966 TI - Overview of the Center for Health Trajectory Research. PMID- 21543967 TI - Depressive symptoms and risk for dementia: a 9-year follow-up of the Maastricht Aging Study. AB - OBJECTIVE: Depression relates to vascular disease and is a candidate risk factor for dementia. We assessed the risk associated with depressive symptoms for Alzheimer-type dementia and vascular dementia. METHODS: Depressive symptoms (SCL 90 depression subscale) were assessed in 771 community-dwelling individuals age 55 years and older. Onset of dementia (N = 37) was recorded at serial assessments 3, 6, and 9 years after baseline. RESULTS: Depressive symptom scores predicted all-type dementia (OR = 1.06, 95% CI = 1.01-1.10), and vascular dementia (OR = 1.11; 95% CI = 1.03-1.19), but not Alzheimer-type dementia (OR = 1.04; 95% CI = 0.98-1.09). People scoring in the upper quartile of the SCL-90 depression scale (N = 180) were at increased risk for dementia (OR = 2.06, 95% CI = 1.01-4.22). Results were unchanged after co-varying for baseline mini-mental state exam and presence of vascular disease. CONCLUSION: Depressive symptoms increase the risk for later dementia in community-dwelling older adults. PMID- 21543968 TI - Laparoscopic anterior versus posterior fundoplication for gastroesophageal reflux disease: systematic review and meta-analysis of randomized clinical trials. AB - OBJECTIVE: To compare short- and long-term outcome after laparoscopic anterior fundoplication (LAF) versus posterior fundoplication (LPF) through a systematic review and meta-analysis of randomized clinical trials (RCTs). SUMMARY OF BACKGROUND DATA: LPF is currently considered the surgical therapy of choice for gastroesophageal reflux disease (GERD). Alternatively, LAF has been alleged to reduce troublesome dysphagia and gas-related symptoms. METHODS: Four electronic databases (MEDLINE, EMBASE, Cochrane Library, and ISI web of Knowledge CPCI-S) were searched for RCTs comparing primary LAF versus LPF for GERD. The methodological quality was evaluated to assess bias risk. Primary outcomes were esophageal acid exposure time, heartburn, Dakkak dysphagia score (0-45) and reoperation rate. Short- and long-term results were pooled separately in meta analyses as risk ratios (RRs) and weighted mean differences (WMDs). RESULTS: Eleven reports on 7 eligible RCTs (anterior vs. posterior total [n = 5]; anterior vs. posterior partial [n = 2]) comparing LAF (n = 345) versus LPF (n = 338) were identified. Short-term (6-12 months) esophageal acid exposure time (3.3% vs. 0.8%: WMD 2.04; 95% confidence interval [CI] [0.84-3.24]; P < 0.001), heartburn (21% vs. 8%; RR 2.71; 95%CI [1.72-4.26]; P < 0.001) and reoperation rate (8% vs. 4%; RR 1.94; 95%CI [0.97-3.87]; P = 0.06) were higher after LAF. In contrast, the Dakkak dysphagia score was lower after LAF (2.5 vs. 5.7; WMD -2.87; 95%CI [-3.88 to -1.87]; P < 0.001). There were no short-term differences in prevalence of esophagitis, regurgitation and perioperative outcomes. The higher rate of heartburn after LAF persisted during long-term (2-10 years) follow-up (31% vs. 14%; RR 2.15; 95% CI [1.49-3.09]; P < 0.001) with more PPI use (25% vs. 10%; RR 2.53; 95% CI [1.40-4.45]; P = 0.002). The long-term reoperation rate was twice as high after LAF (10% vs. 5%; RR 2.12; 95% CI [1.07-4.21]; P = 0.03). Long-term Dakkak dysphagia scores, inability to belch, gas bloating and satisfaction were not different. CONCLUSIONS: Esophageal acid exposure time and the prevalence of heartburn are higher after LAF compared with LPF. In the short-term this is counterbalanced by less severe dysphagia. However, dysphagia scores become similar in the long-term, with a persistent substantial increase in prevalence of heartburn and PPI use after LAF. The reoperation rate is twice as high after LAF as well, mainly due to reinterventions for recurrent GERD. The prevalence of gas related symptoms is similar. These results lend level 1a support for the use of LPF as the surgical treatment of choice for GERD. PMID- 21543969 TI - Beta-lactam antibiotic decreases acquisition of and motivation to respond for cocaine, but not sweet food, in C57Bl/6 mice. AB - No medication is approved to treat cocaine addiction, but mounting evidence suggests that glutamate-directed approaches may reduce cocaine dependence and relapse. We tested the hypotheses that the glutamate transporter subtype 1 activator, ceftriaxone, disrupts acquisition of cocaine self-administration, motivation to self-administer cocaine, and conditioned place preference in mice. Repeated ceftriaxone (200 mg/kg) reduced the ability of mice to acquire cocaine and the motivation to self-administer cocaine after successful acquisition without affecting acquisition of or motivation for sweet food. Repeated ceftriaxone had no effect on cocaine-conditioned place preference. These results suggest that a beta-lactam antibiotic reduces the direct reinforcing strength of cocaine without producing nonspecific deficits in conditioned learning processes. PMID- 21543970 TI - Validation of the Medipro MediCare 100f upper arm blood pressure monitor, for self-measurement, according to the European Society of Hypertension International Protocol revision 2010. AB - OBJECTIVE: The validation of sphygmomanometer is important in accurate blood pressure measurement. This study presents the validation results by the Medipro MediCare 100f upper arm blood pressure monitor according to the European Society of Hypertension International Protocol (ESH-IP) revision 2010. METHODS: The ESH IP revision 2010 for the validation of blood pressure measuring devices in adults was followed precisely. A total of 99 couples of test device and reference blood pressure measurements were obtained during the study (three pairs for each of the 33 participants). RESULTS: The device produced 73, 93, and 98 measurements within 5, 10, and 15 mmHg for systolic blood pressure (SBP) and 79, 93, and 96 for diastolic blood pressure (DBP), respectively. The mean standard deviation device observer difference was 1.4 +/- 5.2 mmHg for SBP and 0.02+/-5.8 mmHg for DBP. The number of participants with two or three of the device-observer differences within 5 mmHg was 24 for SBP and 30 for DBP, whereas there was no participant with none of the device-observer differences within 5 mmHg. CONCLUSION: According to the results of the validation study based on the ESH-IP revision 2010, the Medipro MediCare 100f can be recommended for self-measurement in an adult population. PMID- 21543971 TI - Exploring nursing e-learning systems success based on information system success model. AB - E-learning is thought of as an innovative approach to enhance nurses' care service knowledge. Extensive research has provided rich information toward system development, courses design, and nurses' satisfaction with an e-learning system. However, a comprehensive view in understanding nursing e-learning system success is an important but less focused-on topic. The purpose of this research was to explore net benefits of nursing e-learning systems based on the updated DeLone and McLean's Information System Success Model. The study used a self-administered questionnaire to collected 208 valid nurses' responses from 21 of Taiwan's medium and large-scale hospitals that have implemented nursing e-learning systems. The result confirms that the model is sufficient to explore the nurses' use of e learning systems in terms of intention to use, user satisfaction, and net benefits. However, while the three exogenous quality factors (system quality, information quality, and service quality) were all found to be critical factors affecting user satisfaction, only information quality showed a direct effect on the intention to use. This study provides useful insights for evaluating nursing e-learning system qualities as well as an understanding of nurses' intentions and satisfaction related to performance benefits. PMID- 21543972 TI - A new instrument for measuring clinician satisfaction with electronic health records. AB - A new survey instrument was developed and validated to measure clinician (nurse) satisfaction with electronic health record impact on clinical process. The Health Information Technology Reference-Based Evaluation Framework guided the selection of evaluation dimensions for the survey. Survey questions were gathered from existing health information technology satisfaction surveys that reflected individual evaluation concepts, such as efficiency or benefits. Decisions about data-gathering methods (e.g., item selection) were made based on reviews of literature and surveys of clinician satisfaction with health information technology and expert input. Preliminary instrument validation was accomplished using qualitative and statistical analysis of five repeated sets of responses from clinicians at the pilot site and field administrations repeated twice at electronic health record implementation and paper-based comparison sites and by analyzing convergent evidence from observations and interviews. Reliability was assessed on one sample: 30 graduate nursing students at the single pilot site. Validity was assessed on three separate samples: (1) graduate nursing students (n = 30), (2) field test at a site with electronic health record (n = 39 participants), and (3) field test at a paper-based site (n = 17). The implementation and comparison sites are Program of All-Inclusive Care for the Elderly that provide managed day care for frail elderly. Survey responses were assessed for test-retest reliability, internal consistency, and content and construct validity. The instrument design enables its administration before and after electronic health record implementation. Work to date suggests the instrument is reliable and valid; it is offered to electronic health record evaluators for further testing and application. PMID- 21543973 TI - Levodopa induces synthesis of nerve growth factor and growth hormone in patients with Parkinson disease. AB - BACKGROUND: Polyneuropathy is observed in treated patients with Parkinson disease. Peripheral axonal degeneration is related to nerve growth factor metabolism. The causes for this axonal degeneration and the role of levodopa itself are not known. Levodopa may experimentally exert supportive effects on nerve growth factor synthesis and on growth hormone production, a hormonal compound with regenerative potential. OBJECTIVE: The objective of this study was to investigate the effects of soluble 250-mg levodopa/benserazide administration on plasma occurrence of levodopa, nerve growth factor, and growth hormone in patients with Parkinson disease over an interval of 60 minutes. RESULTS: Levodopa moderately increased bioavailability of nerve growth factor and growth hormone combined with the rise of levodopa. Nerve growth factor data and levodopa values correlated to each other. CONCLUSIONS: Axonal degeneration may not be due to levodopa itself, as levodopa supports production of nerve growth factor and of growth hormone. Both may complement each other for neuronal survival. PMID- 21543974 TI - Ruptured versus stable plaques in human coronary arteries. AB - OBJECTIVE: To derive a model for the identification of left anterior descending (LAD) coronary artery stenoses predisposed to plaque rupture and thrombosis. METHODS: Coronary angiograms of 186 consecutive patients (original sample) with an anterior ST elevation myocardial infarction (STEMI) and a recanalized LAD were reconstructed in the three-dimensional space. Culprit lesions were compared with 293 stable LAD coronary stenoses on the same patients. A model for predicting stenoses with a high probability of thrombosis was derived and validated in 50 subsequent patients with STEMI, and 50 patients with stable lesions (validation sample). RESULTS: The majority of culprit lesions occurred between 20 and 40 mm from the LAD ostium, whereas the majority of stable lesions were found in a distance of more than 60 mm (P<0.001). Culprit lesions were statistically significantly longer than stable ones (23.2 +/- 10.4 mm vs. 14.7 +/- 7.2 mm; P<0.001). Bifurcations on culprit lesions were significantly more frequent (86.6%) compared with stable lesions (41.3%, P<0.001). Lesion angulation was significantly sharper in culprit lesions, which were symmetrical whereas stable lesions resided in the inner vessel wall in respect to the local vessel curvature. A simple additive tool was developed by using these parameters in a multiple regression model. The discriminating ability of the proposed index was high in both the original [area under the receiver operating characteristic curve: 0.88 (95% confidence interval: 0.85-0.91)] and validation sample [area under the receiver operating characteristic curve: 0.69 (95% confidence interval: 0.59-0.78)]. CONCLUSION: Specific anatomic characteristics of LAD segments associated with STEMI can be identified on coronary angiograms and assist the risk stratification of coronary stenoses. PMID- 21543975 TI - Endoplasmic reticulum stress and glucose homeostasis. AB - PURPOSE OF REVIEW: Balancing glucose homeostasis is crucial to maintain appropriate energy and metabolic state. Chronic hyperglycemia with insulin resistance and development of type II diabetes mellitus is a growing health and health-economic threat. The unfolded protein response (UPR) is a mechanism by which the endoplasmic reticulum copes with diverse physiological and pathophysiological stress stimuli. Unresolved and chronic endoplasmic reticulum stress are important features in the development of diabetes mellitus. Understanding how the UPR impacts glucose balance and what disrupts this balance is critical for development of future therapies. RECENT FINDINGS: In pancreatic beta-cells, evidence is growing that the single branches of the UPR work in concert to supply insulin in response to acute glucose availability. Chronic glucose stimulation disrupts these primarily adaptive changes into an overwhelming UPR, which leads to reduced insulin supply and beta-cell mass due to apoptosis. In hepatocytes, the UPR interacts with key transcription factors to physiologically regulate glucose and lipid homeostasis. Prolonged endoplasmic reticulum stress disrupts these feedback loops and results in ongoing gluconeogenesis and steatosis. SUMMARY: Unraveling the molecular networks underlying the adaptive and contra-adaptive roles of the UPR in glucose metabolism will identify novel therapeutic approaches in the battle against diabetes mellitus. PMID- 21543976 TI - Is the obesity epidemic a national security issue around the globe? AB - PURPOSE OF REVIEW: To understand how obesity affects national security by focusing on three case study countries - the USA, China, and Mexico. RECENT FINDINGS: Whereas in the USA and Mexico, over two-thirds of adults are overweight and obese compared to about 29% of Chinese, large increases in the prevalence of overweight and obesity have occurred in all three countries in the past two decades. National security affected in the USA ranges both from an economic perspective - increasing healthcare problems and costs to the point where our labor costs have reached uncompetitive cost levels, and from a military preparedness perspective, namely our overweight soldiers are unable to perform normal activities and functions required of soldiers. In both Mexico and China, it is the economic and health system costs that are dominant concerns, both the costs of obesity-related medical care and the productivity of the work force are creating potential long-term effects on economic competitiveness. SUMMARY: Obesity is adversely affecting the welfare, economic, and in some cases military security of these three countries. PMID- 21543977 TI - Role of the lymphatic system in the pathogenesis of Crohn's disease. AB - PURPOSE OF REVIEW: Intestinal lymph containing interstitial fluid, proteins, immune cells, and digested lipids is actively transported back to the blood stream thanks to rhythmical contractions of the mesenteric lymphatic vessels. During this process, lymph flows through several lymph nodes, allowing antigens to be sampled by the immune system. Abnormalities in lymphatic drainage have been noted in the original descriptions of Crohn's disease, but essentially ignored since. The lymphatic system is re-emerging as a critical player in inflammatory and immune processes and the purpose of this review is to present and discuss new concepts related to the involvement of the lymphatic system in the development of inflammatory bowel diseases (IBDs) and more specifically Crohn's disease. RECENT FINDINGS: Recent studies reporting lymphangitis, lymphangiogenesis, bacterial infiltration and lymph node infection, immune cell trafficking, and fat-wrapping in Crohn's disease suggest altered lymph drainage and lymphatic pumping, implicating the lymphatic system as a likely player in inflammatory disorders and IBDs. SUMMARY: Improved knowledge and appreciation of the roles that the lymphatic system plays in immune cell trafficking, infection, fat transport, distribution and metabolism and, of course, edema resolution is necessary to better understand the pathogenesis of chronic inflammatory conditions such as Crohn's disease and may provide the basis for new therapeutic strategies. PMID- 21543978 TI - What the gastroenterologist needs to know about the histology of Barrett's esophagus. AB - PURPOSE OF REVIEW: The purpose of this review is to provide clinicians with an up to-date summary of the terminology, classification, biological characteristics, and limitations of pathology regarding Barrett's esophagus and associated neoplastic precursor lesions in order to optimize decision making when evaluating patients with this disorder. RECENT FINDINGS: This review summarizes some of the advancements and controversies regarding the definition and diagnostic criteria for Barrett's esophagus, difficulties that arise when trying to differentiate esophageal versus gastric epithelium in gastroesophageal junction (GEJ) biopsies, the histology and biology of nondysplastic Barrett's esophagus including columnar metaplasia without goblet cells, and the limitations and diagnostic variability in interpretation of conventional and nonconventional types of dysplasia in Barrett's esophagus. SUMMARY: The definition of Barrett's esophagus is controversial, particularly with regard to the need to identify goblet cells in esophageal biopsies. In most cases, morphologic evaluation of GEJ biopsies cannot help distinguish whether the columnar epithelium comes from the distal esophagus versus the proximal stomach. Metaplastic esophageal columnar epithelium that does not contain goblet cells nevertheless is biologically intestinalized, shows molecular abnormalities, and has been shown to be at risk for progression to cancer, but the magnitude of that risk is unknown. Interobserver agreement on the presence, grade, and type of dysplasia remains moderate at best, particularly in light of the recent recognition of nonconventional types of dysplasia, such as foveolar, serrated, and early crypt dysplasia, which make interpretation difficult. Close cooperation between clinicians and pathologists is essential in order to ensure proper interpretation of biopsy results and to provide optimal surveillance and treatment decisions. PMID- 21543979 TI - Infection prevention and control in cystic fibrosis. AB - PURPOSE OF REVIEW: This review will discuss recent studies of the virulence of cystic fibrosis (CF) pathogens, including epidemic strains, a more complex understanding of droplet transmission, bacterial contamination of CF clinics, and identifying and overcoming barriers to implementation of infection control guidelines. RECENT FINDINGS: Both morbidity and mortality are associated with methicillin-resistant Staphylococcus aureus (MRSA). Thus, clinicians are attempting eradication strategies for MRSA using combinations of oral, aerosolized, intravenous, and topical antibiotics, with some success. However, household contacts may be colonized with MRSA, which can impact the durability of eradication. Epidemic strains of Pseudomonas aeruginosa are also associated with increased morbidity and mortality and some clones are detected in CF patients throughout the world presumably due to social networks among patients. Recent experimental and clinical data have suggested that CF patients can generate droplet nuclei in the respirable range and that infectious particles can be cultured from room air minutes to hours after patients have left. SUMMARY: Although these observations regarding droplet nuclei have not been linked to transmission, they do challenge the safety of the '3-foot rule' and suggest the potential role of masks. Additional research is needed to develop strategies to improve infection control practices among healthcare professionals, CF patients, and families. PMID- 21543980 TI - The role of intraoperative hemodialysis in liver transplant patients. AB - PURPOSE OF REVIEW: Orthotopic liver transplant (OLT) is a major surgical procedure that can be both challenging and lengthy. One of the common findings in end-stage liver disease is renal failure, whether acute or chronic, which may complicate the intraoperative course. RECENT FINDINGS: The use of intraoperative hemodialysis is described by several centers to aid during OLT cases with impaired renal function or kidney failure. Unfortunately, there is a paucity of available data, which is limited to sporadic case reports, and only few structured studies in which continuous renal replacement therapy was used versus intraoperative hemodialysis, which is the main focus of this article. The rationale behind the use of intraoperative hemodialysis during OLT in patients with kidney dysfunction or failure is that the procedure is usually complicated by major hemodynamic changes, metabolic derangement, and coagulation abnormalities, which we think can be better managed intraoperatively using hemodialysis. In our institution, we performed over 140 cases of OLT using intraoperative hemodialysis since 2003 until the present. A retrospective cohort study is being conducted during the writing of this article. Preliminary data collection report zero percentage intraoperative mortality and 48 h postoperatively. SUMMARY: Hemodialysis is widely acknowledged as a treatment option to stabilize patients with renal failure, and one of the most challenging situations is during OLT in which the role of intraoperative hemodialysis is becoming more important today more than ever before. PMID- 21543981 TI - Pulmonary complications in cirrhosis. AB - PURPOSE OF REVIEW: To summarize the pulmonary complications seen in cirrhosis. RECENT FINDINGS: The definition of portopulmonary hypertension (POPH) has been refined to exclude cardiac disease. POPH may be treated with a variety of agents; inhaled agents are particularly useful in the peri-transplant period. Hepatopulmonary syndrome (HPS) remains refractory to medical therapy. SUMMARY: Cirrhosis may be complicated by one of two pulmonary vascular complications, portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS). POPH is a syndrome of increased vascular resistance, initiated by pulmonary vascular spasm. HPS is caused by intrapulmonary arteriovenous shunting with resultant hypoxemia. Both conditions are associated with portal hypertension, but are unrelated to the degree of portal hypertension, the nature or severity of the liver disease, and are associated with mortality in excess of the model for end-stage liver disease score. POPH is usually responsive to vasodilators, while HPS remains resistant to therapeutic agents. Both conditions are improved or cured by liver transplantation. PMID- 21543982 TI - Genetic causes of congenital hypothyroidism due to dyshormonogenesis. AB - PURPOSE OF REVIEW: Overview of congenital hypothyroidism caused by thyroid hormone synthesis defects, the current understanding of their pathophysiology, and clinical implications of molecular diagnoses. RECENT FINDINGS: Genetic defects in all known thyroid-specific factors required for thyroid hormone synthesis have been described. These include defects in iodide trapping (NIS), in the facilitated iodide efflux across the apical membrane (PDS), the organification of iodide within the follicular lumen (thyroid peroxidase, DUOX2, DUOXA2), the substrate for thyroid hormone synthesis (thyroglobulin) and the ability to recover and retain intrathyroidal iodine (iodotyrosine deiodinase). Clinical and biochemical evaluation aids in selecting the most appropriate candidate gene(s). A definite molecular diagnosis of thyroid dyshormonogenesis allows genetic counseling and has prognostic value in differentiating transient from permanent congenital hypothyroidism and predicting the response of patients to iodine supplementation as adjunct or alternative treatment to L-T4 replacement. SUMMARY: Congenital hypothyroidism due to thyroid dyshormonogenesis is a heterogenic disorder that may be caused by mutations in any of the known steps in the thyroid hormone biosynthesis pathway. An exact molecular diagnosis allows genetic counseling and the identification of asymptomatic mutation carriers at risk of recurrent hypothyroidism, and provides a rationale for adjunct iodide supplementation. PMID- 21543983 TI - Cross-linguistic comparison of frequency-following responses to voice pitch in American and Chinese neonates and adults. AB - OBJECTIVES: Cross-language studies, as reflected by the scalp-recorded frequency following response (FFR) to voice pitch, have shown the influence of dominant linguistic environments on the encoding of voice pitch at the brainstem level in normal-hearing adults. Research questions that remained unanswered included the characteristics of the FFR to voice pitch in neonates during their immediate postnatal period and the relative contributions of the biological capacities present at birth versus the influence of the listener's postnatal linguistic experience. The purpose of this study was to investigate the characteristics of FFR to voice pitch in neonates during their first few days of life and to examine the relative contributions of the "biological capacity" versus "linguistic experience" influences on pitch processing in the human brainstem. DESIGN: Twelve American neonates (five males, 1-3 days old) and 12 Chinese neonates (seven males, 1-3 days old) were recruited to examine the characteristics of the FFRs during their immediate postnatal days of life. Twelve American adults (three males; age: mean +/- SD = 24.6 +/- 3.0 yr) and 12 Chinese adults (six males; age: mean +/- SD = 25.3 +/- 2.6 yr) were also recruited to determine the relative contributions of biological and linguistic influences. A Chinese monosyllable that mimics the English vowel /i/ with a rising pitch (117-166 Hz) was used to elicit the FFR to voice pitch in all participants. RESULTS: Two-way analysis of variance (i.e., the language [English versus Chinese] and age [neonate versus adult] factors) showed a significant difference in Pitch Strength for language (p = 0.035, F = 4.716). A post hoc Tukey-Kramer analysis further demonstrated that Chinese adults had significantly larger Pitch Strength values than Chinese neonates (p = 0.024). This finding, coupled with the fact that American neonates and American adults had comparable Pitch Strength values, supported the linguistic experience model. On the other hand, Pitch Strength obtained from the American neonates, American adults, and Chinese neonates were not significantly different from each other, supporting the biological capacity model. CONCLUSIONS: This study demonstrated an early maturation of voice-pitch processing in neonates starting from 1 to 3 days after birth and a significant effect of linguistic experience on the neural processing of voice pitch at the brainstem level. These findings provide a significant conceptual advancement and a basis for further examination of developmental maturation of subcortical representation of speech features, such as pitch, timing, and harmonics. These findings can also be used to help identify neonates at risk for delays in voice-pitch perception and provide new directions for preventive and therapeutic interventions for patients with central auditory processing deficits, hearing loss, and other types of communication disorders. PMID- 21543984 TI - Month of conception and risk of autism. AB - BACKGROUND: Studies of season of birth or season of conception can provide clues about etiology. We investigated whether certain months or seasons of conception are associated with increased risk of autism spectrum disorders, for which etiology is particularly obscure. METHODS: The study population comprises 6,604,975 children born from 1990 to 2002 in California. Autism cases (n = 19,238) were identified from 1990 through 2008 in databases of the California Department of Developmental Services, which coordinates services for people with developmental disorders. The outcome in this analysis was autism diagnosed before the child's sixth birth date. The main independent variables were month of conception and season of conception (winter, spring, summer, and fall). Multivariate logistic regression models were used to estimate odds ratios (ORs) with their 95% confidence intervals (CIs) for autism by month of conception. RESULTS: Children conceived in December (OR = 1.09 [95% CI = 1.02-1.17]), January (1.08 [1.00-1.17]), February (1.12 [1.04-1.20]), or March (1.16 [1.08-1.24]) had higher risk of developing autism compared with those conceived in July. Conception in the winter season (December, January, and February) was associated with a 6% (OR = 1.06, 95% CI = 1.02-1.10) increased risk compared with summer. CONCLUSIONS: Higher risks for autism among those conceived in winter months suggest the presence of environmental causes of autism that vary by season. PMID- 21543985 TI - Left truncation, susceptibility, and bias in occupational cohort studies. AB - BACKGROUND: Left truncation occurs when subjects who otherwise meet entry criteria do not remain observable for a later start of follow-up. We investigated left truncation in occupational studies due to inclusion of workers hired before the start of follow-up in a simulation study. METHODS: Using Monte Carlo methods, we simulated null and positive associations between exposure (work duration) and mortality for 500 datasets of 5000 subjects, assuming the absence and presence of heterogeneity in susceptibility to disease and to the effect of exposure. We examined incident hires (followed since hire) and left-truncated prevalent hires (those hired before baseline and remained employed at baseline). We estimated the association (&OV0404;1*) as the mean slope using Cox proportional hazards with a linear term for exposure, under scenarios with and without susceptibility. RESULTS: With homogeneous susceptibility, there were no differences between incident and prevalent hires. Introducing only disease susceptibility did not change results. However, with heterogeneous susceptibility to the effect of exposure, downward bias was observed among prevalent hires under both the true null and positive exposure-response scenarios. The bias increased with time between hire and baseline (null: &OV0404;1* = 0.05 [SD = 0.08], &OV0404;1* = 0.08 [SD = 0.24], &OV0404;1* = -0.18 [SD = 0.98] if hired <15, 15 to <30, and >= 30 years before baseline, respectively), coincident with a decreasing percentage of susceptible subjects. CONCLUSIONS: Prevalent hires induce downward bias in an occupational cohort. This occurs because subjects who are less susceptible to the exposure remain exposed the longest, thereby underestimating the association. PMID- 21543986 TI - Caroli disease: review of eight cases with emphasis on magnetic resonance imaging features. AB - BACKGROUND: Caroli disease is a rare congenital disorder characterized by segmental, nonobstructive dilatation of intrahepatic bile ducts. The term Caroli syndrome is used for the association of Caroli disease with congenital hepatic fibrosis. STUDY AIMS: To provide an overview of the clinical presentation and imaging features of Caroli disease and syndrome, with an emphasis on magnetic resonance imaging. PATIENTS AND METHODS: Retrospective analysis of medical records on eight patients in whom a histologic diagnosis of Caroli disease or syndrome had been made. RESULTS: Presenting signs and symptoms were (hepato)splenomegaly, hematemesis and/or melena, cholangitis, jaundice, and recurrent fever. The central dot sign, defined in the literature as a dot or bundle of strong contrast enhancement within dilated intrahepatic ducts, was found in seven cases on various imaging modalities. A 'dot-like structure' was found in one case in which only unenhanced studies were available. There was a tendency toward a right hepatic-lobe predominance. CONCLUSION: There is an overlap between the imaging features of Caroli disease and Caroli syndrome. Our findings support earlier reports that the central dot sign is highly specific for the disease, and that it can be reliably detected by current imaging techniques. PMID- 21543987 TI - Cardiovascular abnormalities in late-onset Pompe disease and response to enzyme replacement therapy. AB - PURPOSE: We evaluated the prevalence of cardiovascular abnormalities and the efficacy and safety of enzyme replacement therapy in patients with late-onset Pompe disease. METHODS: Ninety patients were randomized 2:1 to enzyme replacement therapy or placebo in a double-blinded protocol. Electrocardiograms and echocardiograms were obtained at baseline and scheduled intervals during the 78 week study period. Baseline cardiovascular abnormalities, and efficacy and safety of enzyme replacement therapy were described. Three pediatric patients were excluded. RESULTS: Eighty-seven patients were included. Median age was 44 years; 51% were men. At baseline, a short PR interval was present in 10%, 7% had decreased left ventricular systolic function, and 5% had elevated left ventricular mass on echocardiogram (all in mild range). There was no change in cardiovascular status associated with enzyme replacement therapy. No significant safety concerns related to enzyme replacement therapy were identified. CONCLUSIONS: Although some patients with late-onset Pompe disease had abnormalities on baseline electrocardiogram or echocardiogram, those classically seen in infantile Pompe disease, such as significant ventricular hypertrophy, were not noted. Cardiovascular parameters were not impacted by enzyme replacement therapy, and there were no cardiovascular safety concerns. The cardiovascular abnormalities identified may be related to Pompe disease or other comorbid conditions. PMID- 21543988 TI - A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations. AB - PURPOSE: Cerebral cavernous malformations can occur sporadically or are caused by mutations in one of three identified genes. Cerebral cavernous malformations often remain clinically silent until a mutation carrier suffers a stroke or seizure. Presymptomatic genetic testing has been valuable to follow and manage cerebral cavernous malformation mutation carriers. During routine diagnostic testing, we identified a two base pair change in seven unrelated people of Ashkenazi Jewish heritage. Because of the location of the variant beyond the invariant splice donor sequence, the change was reported as a variant of unknown significance. In this study, we determined whether this change was a disease causing mutation and whether it represents a founder mutation in the Ashkenazi Jewish population. METHODS: Transcripts arising from the normal and mutant alleles were examined by reverse transcription-polymerase chain reaction from affected and unaffected Ashkenazi Jewish cerebral cavernous malformation family members. A synthetic splicing system using a chimeric exon was used to visualize the effects of the change on splice donor site utilization. RESULTS: The two base pair change in CCM2, c.30 + 5_6delinsTT, segregated with affected status in the study families. Reverse transcription-polymerase chain reaction revealed loss of the transcript allele that was in phase with the mutation. The two base pair change, when tested in an in vitro synthetic splicing system, altered splice donor site utilization. Resequencing of the genomic region proximal and distal to the CCM2 gene mutation revealed a common single-nucleotide polymorphism haplotype in affected individuals. CONCLUSIONS: The two base pair change in CCM2, c.30 + 5_6delinsTT, disrupted proper splice donor utilization leading to a degraded transcript. Single nucleotide polymorphism haplotype analysis demonstrated that this mutation was due to a founder in the Ashkenazi Jewish population. These data have the potential to simplify genetic testing for cerebral cavernous malformation in the Ashkenazi Jewish population. PMID- 21543989 TI - Implementation outcomes of a multiinstitutional web-based ethical, legal, and social implications genetics curriculum for primary care residents in three specialties. AB - PURPOSE: Medical genetics lends itself to disseminated teaching methods because of mismatches between numbers of physicians having patients with genetic disorders and availability of genetic specialists. METHOD: During 3 years, we implemented an interactive, web-based curriculum on ethical, legal, and social implications in medical genetics for primary care residents in three specialties at three institutions. Residents took five (of 10) cases and three (of five) tutorials that varied by specialty. We assessed changes in self-efficacy (primary outcome), knowledge, application, and viewpoints. RESULTS: Overall enrollment was 69% (279/403). One institution did not complete implementation and was dropped from pre-post comparisons. We developed a six-factor ethical, legal, and social implications self-efficacy scale (Cronbach alpha = 0.95). Baseline self-efficacy was moderate (71/115; range: 23-115) and increased 15% after participation. Pre post knowledge scores were high and unchanged. Residents reported that this curriculum covered ethical, legal, and social implications/genetics better than their usual curricula. Most (68-91%) identified advantages, especially in providing flexibility and stimulating self-directed learning. After participation, residents reported creating learning goals (66%) and acting on those goals (62%). CONCLUSIONS: Ethical, legal, and social implications genetics curricular participation led to modest self-efficacy gains. Residents reported that the curriculum covered unique content areas, had advantages over traditional curriculum, and that they applied ethical, legal, and social implications content clinically. We share lessons from developing and implementing this complex web based curriculum across multiple institutions. PMID- 21543990 TI - Robot-mediated upper limb physiotherapy: review and recommendations for future clinical trials. AB - Robot-mediated physiotherapy provides a new possibility for improving the outcome of rehabilitation of patients who are recovering from stroke. This study is a review of robot-supported upper limb physiotherapy focusing on the shoulder, elbow, and wrist. A literature search was carried out in PubMed, OVID, and EBSCO for clinical trials with robots providing shoulder, elbow, or wrist therapy. Results concerning motor control, spasticity, functional outcome, and the main features of the studies were evaluated. A total of 178 papers were found. On the basis of inclusion/exclusion criteria, 30 studies remained for evaluation. In these trials, a total of 493 patients received robot-aided therapy. The Fugl Meyer assessment was the most commonly used motor scale, and in 24 of 27 trials, motor function improved significantly. The application of the Modified Ashworth Scale showed that spasticity decreased significantly in nine of 21 trials. Functional scales were only examined in one-third of the studies with significant changes being found in half of them. The intensity and duration of the interventions as well as the elapsed time poststroke were varied. There are several scales, which were used in only a few trials. Unifying the methodology in robotic trials is desirable. Clarification of the acute/subacute/chronic categories, standardizing the application of certain scales for outcome measure in each trial, use of functional scales, and a clearer description of the interventions are recommended. PMID- 21543991 TI - Double use of corneal graft for Descemet stripping automated endothelial keratoplasty and coverage of glaucoma drainage device tube. AB - PURPOSE: To describe the efficacy and safety of using a single corneal graft for 2 different ocular surgeries, Descemet stripping automated endothelial keratoplasty in one patient and coverage of a glaucoma drainage device tube in another patient. MATERIALS AND METHODS: The records of 12 consecutive patients who underwent Ahmed glaucoma valve implantation using the anterior lamella of a donor cornea that had been previously used for Descemet stripping automated endothelial keratoplasty were reviewed. RESULTS: Nine eyes (75%) had superotemporal Ahmed valve implantation and 3 eyes (25%) had inferotemporal implantation. No intraoperative complications were encountered in any of these cases. During postoperative follow-up there were no graft rejections, wound dehiscences, tube exposures, or any glaucoma drainage device-related complications. In 1 patient, graft thinning was noticed 12 months after surgery, but without erosion of the conjunctiva or exposure of the tube. Mean intraocular pressure (IOP) before surgery was 32.8+/-9.3 mm Hg. The mean postoperative IOPs were 13.2+/-6.8 mm Hg (P<0.001) at day 1, 10.5+/-2.7 (P<0.001) at week 1, 12.2+/ 3.5 (P<0.001) at month 1, 12.9+/-3.0 (P<0.001) at month 3, 14.2+/-7.0 (P<0.001) at month 6, and 13.0+/-6.4 (P<0.001) at the final visit. The mean reduction in IOP was 59%. Mean follow-up time after surgery was 21.7+/-7.5 months. CONCLUSIONS: The use of the anterior corneal graft cap for patching a tube is safe and effective. The double use of a corneal graft is economically worthwhile and especially useful in countries where there is shortage of donor corneal tissues. PMID- 21543992 TI - Selective laser trabeculoplasty versus medical therapy as initial treatment of glaucoma: a prospective, randomized trial. AB - PURPOSE: To compare outcomes of selective laser trabeculoplasty (SLT) with drug therapy for glaucoma patients in a prospective randomized clinical trial. PATIENTS AND METHODS: Sixty-nine patients (127 eyes) with open-angle glaucoma or ocular hypertension were randomized to SLT or medical therapy. Target intraocular pressure (IOP) was determined using the Collaborative Initial Glaucoma Treatment Study formula. Patients were treated with SLT (100 applications 360 degrees) or medical therapy (prostaglandin analog). Six visits over 1 year followed initial treatment. If target IOP range was not attained with SLT, additional SLT was the next step, or in the medical arm additional medications were added. PRIMARY OUTCOME: IOP; secondary: number of steps. RESULTS: Sixty-nine patients were treated. Data collection terminated with 54 patients reaching 9 to 12-months follow-up. Twenty-nine patients were in the SLT group, 25 patients in the medical group. Baseline mean IOP for all eyes was 24.5 mm Hg in the SLT group, 24.7 mm Hg in the medical group. Mean IOP (both eyes) at last follow-up was 18.2 mm Hg (6.3 mm Hg reduction) in the SLT arm, 17.7 mm Hg (7.0 mm Hg reduction) in the medical arm. By last follow-up, 11% of eyes received additional SLT, 27% required additional medication. There was not a statistically significant difference between the SLT and medication groups. CONCLUSIONS: IOP reduction was similar in both arms after 9 to 12-months follow-up. More treatment steps were necessary to maintain target IOP in the medication group, although there was not a statistically significant difference between groups. These results support the option of SLT as a safe and effective initial therapy in open-angle glaucoma or ocular hypertension. PMID- 21543993 TI - Safety and efficacy of using off-label bevacizumab versus mitomycin C to prevent bleb failure in a single-site phacotrabeculectomy by a randomized controlled clinical trial. AB - PURPOSE: To analyze the safety and efficacy of bevacizumab (1.25 mg/0.05 mL) versus 0.03% mitomycin C (MMC) for preventing bleb failure in patients undergoing single-site phacotrabeculectomy for primary open-angle glaucoma or chronic angle closure glaucoma. MATERIALS AND METHODS: Thirty-eight consecutive patients with visually significant cataract and coexistent primary open-angle glaucoma or chronic angle-closure glaucoma were randomized into 3 groups. One group received conventional 0.03% MMC (n=13); the second group received 3 subconjunctival injections of bevacizumab (1.25 mg in 0.05 mL) (n=13); and the third group received bevacizumab soaked in sponges (1.25 mg in 0.05 mL) (n=12) intraoperatively on the sclera. Patients were followed up for 6 months. The primary outcome measure was treatment success and bleb morphology in the study eye at 6-month follow-up. RESULTS: All 3 groups showed significant reduction in mean intraocular pressure at 1 week after treatment, which was maintained at 6 months. However, the subconjunctival bevacizumab group had 90% patients with complete success as opposed to 60% in each of the other 2 groups (P=0.04). In both bevacizumab groups, bleb vascularity increased progressively over the 6 month follow-up. One patient in the subconjunctival bevacizumab group showed a local conjunctival necrosis. CONCLUSION: In this pilot study with a small number of subjects, short-term outcomes suggest that subconjunctival bevacizumab is equally effective in reducing intraocular pressure with a better safety profile compared with MMC in the dosing schedule studied. However, bevacizumab soaked in a sponge appears to have no advantages over MMC. Subconjunctival bevacizumab may be a useful agent for improving success and for limiting scar tissue after phacotrabeculectomy. PMID- 21543994 TI - Reduction of intraocular pressure using a modified 360-degree suture trabeculotomy technique in primary and secondary open-angle glaucoma: a pilot study. AB - PURPOSE: To investigate the effects of a modified 360-degree suture trabeculotomy technique for primary and secondary open-angle glaucoma (POAG and SOAG). METHODS: We modified the procedure for 360-degree trabeculotomy by using a 5-0 nylon suture, making a scleral flap to allow clear identification of Schlemm canal, and creating a corneal side port incision opposite to the scleral flap to retrieve the suture used to cannulate and cleave the canal. The modified 360-degree suture trabeculotomy (not combined with cataract surgery) was performed on 25 eyes with POAG and 18 eyes with SOAG, and the results were compared retrospectively with those of standard trabeculotomy with metal trabeculotomes (16 eyes with POAG and 19 eyes with SOAG). When the intraocular pressure (IOP) was reduced by 30% from the preoperative IOP and was also below 18 mm Hg at 3, 6, 9, 12, and 18 months after surgery and the patient was taking a similar number or fewer medications, the surgery was considered a "success." RESULTS: Using this modified technique, Schlemm canal was appropriately incised without resistance. At 12 months after the modified 360-degree suture trabeculotomy and trabeculotomy with metal trabeculotomes, the mean postoperative IOP values were 13.1 and 15.2 mm Hg, respectively, and the mean numbers of antiglaucoma medications were 0.5 and 1.4, respectively. The success rates of POAG at 12 months for the modified 360-degree suture trabeculotomy and trabeculotomy with metal trabeculotomes were 84% and 31%, respectively, and those of SOAG were 89% and 50%, respectively. The complications included a transient elevation of the IOP above 30 mm Hg in 22 eyes (47%) treated with the 360-degree suture trabeculotomy and 17 eyes (49%) treated with trabeculotomy with metal trabeculotomes. There was no significant difference between preoperative visual acuity and postoperative visual acuity in either procedure. CONCLUSIONS: This modified 360-degree suture trabeculotomy is a feasible surgical option for POAG and SOAG. PMID- 21543995 TI - Frequency doubling technology for earlier detection of functional damage in standard automated perimetry-normal hemifield in glaucoma with low-to-normal pressure. AB - PURPOSE: To compare the longitudinal change of frequency doubling technology (FDT) perimetry and standard automated perimetry (SAP) results in SAP-normal hemifield in open-angle glaucoma (OAG) eyes with low-to-normal intraocular pressure (IOP). MATERIALS AND METHODS: FDT perimetry with the N-30 full threshold protocol and SAP using the Humphrey Field Analyzer with the 30-2 Swedish Interactive Threshold Algorithm-standard protocol were periodically performed for at least 3 years in 39 eyes of 39 OAG patients with low-to-normal IOP and visual field damage confined to only one hemifield. The time courses of the mean of the threshold values of FDT and the mean of total deviations (TDs) in SAP-normal and SAP-abnormal fields were analyzed using a linear mixed model. RESULTS: The average follow-up was 4.9 years and the average IOP during follow-up was 12.6 mm Hg with or without medication. The aging effect-corrected rate of change in the mean FDT threshold values was significantly negative (P=0.004) in the SAP-normal hemifield, whereas that of mean of TD values by SAP did not significantly differ. In the SAP-abnormal hemifield, the rate of change was significantly negative for both tests (P<0.001). The mean of the slope of the mean TD values in the SAP abnormal hemifield was significantly more negative than that in the SAP-normal hemifield (P=0.011), whereas that of the mean FDT threshold values showed no significant difference between the 2 hemifields. CONCLUSIONS: FDT is useful for monitoring functional damage in the SAP-normal hemifield in OAG eyes with low-to normal IOP. PMID- 21543996 TI - Human papillomavirus in men: an update. PMID- 21543997 TI - Sclerotherapy of rectal venous malformations in a child with Klippel-Trenaunay syndrome. PMID- 21543998 TI - Pediatric lymphocytic colitis presenting with intractable diarrhea. PMID- 21543999 TI - Effects of long-term parenteral nutrition on serum lipids, plant sterols, cholesterol metabolism, and liver histology in pediatric intestinal failure. AB - BACKGROUND AND OBJECTIVE: Plant sterols (PS) in parenteral nutrition (PN) may contribute to intestinal failure-associated liver disease. We investigated interrelations between serum PS, liver function and histology, cholesterol metabolism, and characteristics of PN. PATIENTS AND METHODS: Eleven patients with intestinal failure (mean age 6.3 years) receiving long-term PN were studied prospectively (mean 254 days) and underwent repeated measurements of serum lipids, noncholesterol sterols, including PS, and liver enzymes. PS contents of PN were analyzed. Liver biopsy was obtained in 8 patients. Twenty healthy children (mean age 5.7 years) served as controls. RESULTS: Median percentage of parenteral energy of total daily energy (PN%) was 48%, including 0.9 g . kg(-1) . day(-1) of lipids. Respective amounts of PN sitosterol, campesterol, avenasterol, and stigmasterol were 683, 71, 57, and 45 MUg . kg(-1) . day(-1). Median serum concentrations of sitosterol (48 vs 7.5 MUmol/L, P < 0.001), avenasterol (2.9 vs 1.9, P < 0.01), stigmasterol (1.9 vs 1.2, P < 0.005), but not that of campesterol (9.8 vs 12, P = 0.22), were increased among patients in relation to controls, and correlated with PN% (r = 0.81-0.88, P < 0.005), but not with PN fat. Serum cholesterol precursors were higher in patients than in controls. Serum liver enzymes remained close to normal range. Glutamyl transferase correlated with serum PS (r = 0.61-0.62, P < 0.05). Liver fibrosis in 5 patients reflected increased serum PS (r = 0.55-0.60, P = 0.16-0.12). CONCLUSIONS: Serum PS moderately increase during olive oil-based PN, and correlate positively with PN% and glutamyl transferase. Despite well-preserved liver function, histology often revealed significant liver damage. PMID- 21544000 TI - Combination of general and specific warm-ups improves leg-press one repetition maximum compared with specific warm-up in trained individuals. AB - Accurate assessment of muscular strength is critical for exercise prescription and functional evaluation. The warm-up protocol may affect the precision of the 1 repetition maximum (1RM) test. Testing guidelines recommend performing both general and specific warm-ups before strength tests. The general warm-up intends to raise muscle temperature, whereas the specific warm-up aims to increase neuromuscular activation. Although there is scientific evidence for performing the specific warm-up, the effects of general warm-up on strength tests are still unclear. The purpose of this study was to investigate whether the combination of a general with a specific warm-up (G + SWU) protocol would improve leg press 1RM values compared with a specific warm-up (SWU) protocol. Thirteen participants were tested for leg-press 1RM under 2 warm-up conditions. In the first condition, participants performed the SWU only, which was composed of 1 set of 8 repetitions at approximately 50% of the estimated 1RM followed by another set of 3 repetitions at 70% of the estimated 1RM. In the second condition (G + SWU), participants performed the 1RM test after a 20-minute general warm-up on a stationary bicycle at 60% of HRmax and the same specific warm-up as in the SWU. Values of 1RM in SWU and in G + SWU were compared by a paired t-test, and significance level was set at p <= 0.05. Strength values were on average 8.4% (p = 0.002) higher in the G + SWU compared with the SWU. These results suggest that the G + SWU induced temperature-dependent neuromuscular adjustments that increased muscle force production capacity. Therefore, these results support the recommendations of the testing guidelines to perform a moderate intensity general warm-up in addition to the specific warm-up before maximum strength assessments. PMID- 21544002 TI - Medicare part D and changes in prescription drug use and cost burden: national estimates for the Medicare population, 2000 to 2007. AB - CONTEXT: The full effect of Medicare Part D, after the initial policy transition period and across the United States Medicare population, remains unclear. OBJECTIVE: To estimate nationally representative changes in prescription drug use and out-of-pocket drug costs 2 years after implementation of Part D. DESIGN, SETTING, AND PARTICIPANTS: We examined study outcomes over 8 years (2000 to 2007) and estimated changes after Part D, accounting for earlier trends. Our analyses used the community-dwelling sample of the Medicare Current Beneficiary Survey (unweighted unique n=38,798). Actual post-Part D outcomes were compared with projected values using 2000 to 2005 data. Subgroup analyses and standardization weights were used to address population-level shifts over time in health status and demographic characteristics. MAIN OUTCOME MEASURES: Annual prescription drug fills and out-of-pocket drug costs. RESULTS: We observed significant average per person increases of 1.8 prescription fills [95% confidence interval (CI), 1.1 2.5] in 2006 and 3.4 prescription fills (95% CI, 2.7-4.1) in 2007 above pre-Part D increases of 0.9 prescription fills per year. Average out-of-pocket drug costs decreased significantly by $143 (95% CI, -182.5--103.1) in 2006 and $148 (95% CI, -181.2--114.1) in 2007 above average pre-Part D increases of $12 per year. Prescription fills did not change for beneficiaries with fair to poor health until 2007 when large increases occurred (increases of 3.7 to 11.0 fills above pre-Part D trends). Significant reductions in OOP drug costs occurred in 2006 and persisted into 2007 across all groups except for sick and poor beneficiaries without Medicaid. CONCLUSIONS: After the transition year of 2006, the impact of Part D seemed larger and more consistent across the Medicare population. Of note, sick and poor beneficiaries experienced significant improvements in prescription drug use in 2007. PMID- 21544003 TI - Single-chain variable fragments antibody of CART inhibits the expression of cocaine-induced behavioral sensitization. AB - Cocaine and amphetamine-regulated transcript (CART) peptides are neurotransmitters with important roles in drug abuse. The increase of CART expression in the brain induced by psychostimulants is associated with changes of behavior in addicted animals. We expressed and purified the single-chain variable fragments antibody (scFv) against CART55-102, and observed the effect of CART scFv on the expression of cocaine-induced behavior sensitization in mice. Results showed that the titer of CART scFv was 1.6 MUg/ml. Single administration of CART scFv (intraperitoneal 0.04, 0.2, and 1 mg/kg) reduced the increasing locomotor activity induced by chronic cocaine intake in mice (P<0.05-0.01), but failed to affect the locomotor activity of naive mice. These results suggested that CART scFv may be a potential therapeutic tool to treat drug abuse. PMID- 21544001 TI - Health utilities for children and adults with type 1 diabetes. AB - OBJECTIVE: We studied health utilities in patients with type 1 diabetes to understand potential differences in health utilities as function of age, type of respondent (self report vs. proxy report), and method of assessment (direct vs. indirect). RESEARCH DESIGN AND METHODS: We elicited self-reported health utilities for adults (n=213) and children (n=238) with type 1 diabetes, and by parent proxy report (n=223) for overall quality of life [Health Utilities Index (HUI) Mark 3 and experienced time-trade-off (TTO) questions] and hypothetical complication states (TTO questions). RESULTS: Mean health utilities for overall quality of life (QOL) ranged from 0.81 to 0.91. Children had significantly higher overall QOL compared with adults (0.89 vs. 0.85, P<0.01) by HUI, but had no significant difference in QOL by TTO. There were no significant differences in QOL between child self report and parent proxy report. Utilities were higher for HUI versus TTO for parent proxy report (P<0.01) but not for adult or child self report. Utilities for hypothetical complication states were lower than for current QOL. Values were lower for stroke (0.34 to 0.53), end stage renal disease (0.47 to 0.55), and blindness (0.52 to 0.69) than for amputation (0.73 to 0.82) and angina (0.74 to 0.80). Complication utilities for parent proxy report were higher compared with adult self report for most hypothetical complication states. CONCLUSIONS: Individuals with type 1 diabetes with few complications report a relatively high QOL; however, future end stage complications are rated as having a significant impact on QOL. Differences in utilities by age, self report versus proxy report, and method raise important questions about whose utilities should be used in economic analyses. PMID- 21544004 TI - Wrestling and herpetic esophagitis. AB - Herpes simplex virus esophagitis has rarely been reported in immunocompetent children. We describe 2 immunocompetent wrestlers on the same team who presented with fever, odynophagia, and dysphagia. Histologic examination of the esophagus showed ulceration and exudate, herpes simplex virus was detected by polymerase chain reaction. We propose that wrestling may be a mode of transmission for this disease. PMID- 21544005 TI - Safety and pharmacokinetics of ribavirin for the treatment of la crosse encephalitis. AB - BACKGROUND: La Crosse viral encephalitis (LACVE) is associated with residual epilepsy and neurocognitive deficits in survivors. This report summarizes 3 phases of clinical studies of children treated with intravenous (IV) ribavirin (RBV), each one exploring a different phase (I, IIA, IIB) of clinical trial development. METHODS: In phase I, 7 children with life-threatening LACVE were treated with emergency use RBV using a moderate IV dose (8.33 mg/kg/dose q 8 hours day 1, 5 mg/kg/dose q 8 hours days 2-10). In phase IIA, 12 children with severe LACVE were enrolled: 8 treated with RBV (same dose as phase I) and 4 with placebo. In phase IIB an escalated dose was used (33 mg/kg dose 1, then 16 mg/kg/dose q 6 hours for 4 days, and 8 mg/kg/dose q 8 hours for 3 days). RESULTS: In a group of 15 children treated in phase I and phase IIA, RBV appeared safe at moderate dose, but based on steady-state RBV levels of 9.3 MUM, estimated cerebrospinal fluid levels were less than 20% of the EC50 of RBV for LACVE. At the escalated dose used in phase IIB, adverse events occurred, likely related to RBV, and therefore the trial was discontinued. Nevertheless, valuable pharmacokinetic (PK) and safety data were obtained at moderate dose, with potential treatment implications for other indications. CONCLUSIONS: Although the results do not support the use of RBV for LACVE, this nevertheless is the largest study of antiviral treatment for LACVE to date and the largest pharmacokinetic analysis of IV RBV in children for any indication. PMID- 21544006 TI - Improved cerebral oxygen saturation and blood flow pulsatility with pulsatile perfusion during pediatric cardiopulmonary bypass. AB - Brain monitoring techniques near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) ultrasound were used in pediatric patients undergoing cardiopulmonary bypass for congenital heart defect (CHD) repair to analyze the effect of pulsatile or nonpulsatile flow on brain protection. Regional cerebral oxygen saturation (rSO2) and cerebrovascular pulsatility index (PI) were measured by NIRS and TCD, respectively, in 111 pediatric patients undergoing bypass for CHD repair randomized to pulsatile (n = 77) or nonpulsatile (n = 34) perfusion. No significant differences in demographic and intraoperative data, including surgical risk stratification, existed between groups. Patients undergoing pulsatile perfusion had numerically lower decreases in rSO2 from baseline for all time points analyzed compared with the nonpulsatile group, with significant ~12% lower decreases at 40 and 60 min after crossclamp. Patients undergoing pulsatile perfusion had numerically lower decreases in PI from baseline for the majority of time points compared with the nonpulsatile group, with significant ~30% lower decreases between 5 and 40 min after crossclamp. Pulsatile flow has advantages over nonpulsatile flow as measured by NIRS and TCD, especially at advanced time points, which may improve postoperative neurodevelopmental outcomes. PMID- 21544007 TI - 11beta-Hydroxysteroid dehydrogenase type 1 activity in short small-for-GA children and in response to GH therapy. AB - Small for GA (SGA) children are at risk for developing the metabolic syndrome. Those who do not catch up, and remain short (SSGA), may benefit from GH therapy. 11beta Hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) is expressed in visceral fat and is implicated in metabolic morbidity. We hypothesized that SSGA children will have increased basal and glucocorticoid (GC)-stimulated 11beta-HSD 1 activity. Twenty SSGA children, aged 7.1 +/- 1 y (mean +/- SD), were studied before and while on GH therapy and compared with 12 normal age-matched controls. 11beta-HSD-1 activity was evaluated by gas chromatography mass spectrometry (GCMS) of urinary steroid product/substrate ratios. GC-stimulated 11beta-HSD-1 activity was assessed after overnight dexamethazone (DEX), by oral cortisone conversion to cortisol. In SSGA children, 11beta-HSD-1 activity was lower (p < 0.05) and GC-stimulated activity enhanced. SSGA children had maximal cortisol generation of 883 +/- 108 compared with 690 +/- 63 nmol/L in controls (p < 0.04). GH treatment suppressed 11beta-HSD-1 activity. GC-stimulated enzyme activity correlated negatively with GA (r = -0.53, p < 0.01) and birth weight (r = -0.55, p < 0.01). SSGA is associated with enhanced GC-stimulated 11beta-HSD-1 activity. This may be programmed in utero, as it is not a function of body composition or secondary metabolic derangement. GH therapy normalizes GC-stimulated 11beta-HSD-1 activity. PMID- 21544008 TI - Live colonocytes in newborn stool: surrogates for evaluation of gut physiology and disease pathogenesis. AB - Studies of gastrointestinal pathophysiology are not feasible by biopsies in human neonates. We examined the utility of live colonocytes in stool in studying cellular markers during early neonatal life. Expression of IgA, IgG, cluster of differentiation-45 cells (CD45), and toll-like receptors-2 and 4 (TLR2 and TLR4) were analyzed by flow cytometry. Colonocyte RNA extracts were used in quantitative real-time PCR (qRT-PCR) to examine the expression of cytokeratin-19, ribosomal protein-24, and tight-junction (Tj) protein zonula occludens-1 (ZO-1). Colonocyte yield varied between 5 * 104 to 2 * 106 cells/g of stool. Meconium samples yielded a highly enriched population of viable cells. Although low, all samples showed CD45-positive cells during the initial weeks of life. Starting as early as d 2, IgA expression was observed in 69% of the cells. Low to moderate expression of IgG was observed with a linear increase as the infants grew. There was an almost total lack of TLR2 staining; however, >55% of the colonocytes showed TLR4 expression. Although high levels of IgA in gut cells may serve as a natural protectant during neonatal period, increased TLR4 may provide a niche for lipopolysaccharide (LPS)-mediated epithelial damage. Use of stool colonocytes can be a valuable noninvasive approach for studying gut pathophysiology in the neonatal period. PMID- 21544010 TI - Designing and reporting case series in plastic surgery. AB - The case series is the most prevalent type of clinical research in the plastic surgery literature. However, this is a lower level study design in the hierarchy of evidence. The case series is nevertheless a useful hypothesis generator for future studies. These in turn can be tested with more robust study designs such as the randomized controlled trial. Because the case series remains the most common study design used to communicate our new innovations, there is a need to improve its reporting so that readers will know why the study was undertaken, what the results were, and how the results affect patient care. The authors provide a guide to help future investigators improve the conduct and the reporting of their case series. PMID- 21544009 TI - Magnetoencephalography reveals slowing of resting peak oscillatory frequency in children born very preterm. AB - Resting cortical activity is characterized by a distinct spectral peak in the alpha frequency range. Slowing of this oscillatory peak toward the upper theta band has been associated with a variety of neurological and neuropsychiatric conditions and has been attributed to altered thalamocortical dynamics. Children born very preterm exhibit altered development of thalamocortical systems. To test the hypothesis that peak oscillatory frequency is slowed in children born very preterm, we recorded resting magnetoencephalography (MEG) from school age children born very preterm (<= 32 wk gestation) without major intellectual or neurological impairment and age-matched full-term controls. Very preterm children exhibit a slowing of peak frequency toward the theta-band over bilateral frontal cortex, together with reduced alpha-band power over bilateral frontal and temporal cortex, suggesting that mildly dysrhythmic thalamocortical interactions may contribute to altered spontaneous cortical activity in children born very preterm. PMID- 21544011 TI - The dog as an animal model for intervertebral disc degeneration? AB - STUDY DESIGN: Prospective observational and analytic study. OBJECTIVE: To investigate whether spontaneous intervertebral disc degeneration (IVDD) occurring in both chondrodystrophic (CD) and nonchondrodystrophic dogs (NCD) can be used as a valid translational model for human IVDD research. SUMMARY OF BACKGROUND DATA: Different animal models are used in IVDD research, but in most of these models IVDD is induced manually or chemically rather than occurring spontaneously. METHODS: A total of 184 intervertebral discs (IVDs) from 19 dogs of different breeds were used. The extent of IVDD was evaluated by macroscopic grading, histopathology, glycosaminoglycan content, and matrix metalloproteinase 2 activity. Canine data were compared with human IVD data acquired in this study or from the literature. RESULTS: Gross pathology of IVDD in both dog types (CD and NCD) and humans showed many similarities, but the cartilaginous endplates were significantly thicker and the subchondral cortices significantly thinner in humans than in dogs. Notochordal cells were still present in the IVDs of adult NCD but were not seen in the CD breeds or in humans. Signs of degeneration were seen in young dogs of CD breeds (<1 year of age), whereas this was only seen in older dogs of NCD breeds (5-7 years of age). The relative glycosaminoglycan content and metalloproteinase 2 activity in canine IVDD were similar to those in humans: metalloproteinase 2 activity increased and glycosaminoglycan content decreased with increasing severity of IVDD. CONCLUSION: IVDD is similar in humans and dogs. Both CD and NCD breeds may therefore serve as models of spontaneous IVDD for human research. However, as with all animal models, it is important to recognize interspecies differences and, indeed, the intraspecies differences between CD and NCD breeds (early vs. late onset of IVDD, respectively) to develop an optimal canine model of human IVDD. PMID- 21544012 TI - Optimal trajectory for the occipital condylar screw. AB - STUDY DESIGN: Evaluation by simulation of screw insertion using fine-cut computed tomographic (CT) scans and screw trajectory software. OBJECTIVE: To evaluate the feasibility and optimal trajectory of the occipital condylar screw. SUMMARY OF BACKGROUND DATA: To the best of our knowledge, no large series examining the feasibility and optimal trajectory of occipital condylar screws have been published. METHODS: We simulated unicortical placement of a 4 * 18-mm screw using 1-mm sliced CT scans and 3-dimensional screw trajectory software in 314 occipital condyles of 157 patients. With the screw tip directed toward a point just below the tip of the basion on lateral fluoroscopy, 3 entry points were compared in view of success rate of screw placement, safe range of medial angulation in an axial plane, and maximum screw length. RESULTS: The lateral entry point had the highest success rate (93.0%) of screw placement, mean safe range of the medial angulation (10.9 degrees ), and maximum screw length (20.7 mm), followed by the middle (92.0%, 10.8 degrees , and 20.6 mm, respectively) and medial (74.2%, 7.7 degrees , and 19.7 mm, respectively) entry points. While the lateral and the middle entry points did not have any statistically significant difference in the 3 parameters, they were significantly better than the medial entry point. All 3 entry points had highly variable ranges of safe medial angulation, making it difficult to provide a single recommended value. CONCLUSION: Screw placement is feasible in up to 93% of the occipital condyles. The lateral and the middle entry points are significantly better than the medial entry point. Selection between the middle and the lateral entry points should be individualized taking into account local anatomic variation. Because the medial angulation of these screws is highly variable, preoperative 3-dimensional CT evaluation and possibly even intraoperative navigation may be required. PMID- 21544013 TI - Uni- and bilateral instrumented posterolateral fusion of the lumbar spine with local bone grafting: a prospective study with a 2-year follow-up. AB - STUDY DESIGN: Prospective trial. OBJECTIVE: To examine the bone union and clinical results after unilateral or bilateral instrumented posterolateral fusion surgery using a local bone graft. SUMMARY OF BACKGROUND DATA: The iliac crest bone graft technique for lumbar posterolateral fusion surgery is widely used; however, donor site problems such as pain and sensory disturbance have been reported. Local bone has been used for bilateral multisegment fusion surgery; however, outcomes have been poor because of insufficient amounts of local bone used. This study evaluated unilateral and bilateral posterolateral fusion at 3 levels using a local bone graft. METHODS: Sixty-two patients diagnosed with degenerated spondylolisthesis at 3 levels were divided into 2 groups. All underwent decompression and bilateral instrumented posterolateral fusion. However, a unilateral local bone graft was used in 32 patients and bilateral local bone graft was used in 30 patients. The amount of bone grafting, proportion of patients with bone union, duration of bone union, visual analog scale score, Japanese Orthopedic Association score, and Oswestry Disability Index were evaluated before and 2 years after surgery. RESULTS: Visual analog scale score, Japanese Orthopedic Association score, and Oswestry Disability Index were not significantly different between the 2 groups before and after surgery (P > 0.05). The amount of local bone graft used for each segment was significantly less in the bilateral group (P < 0.05). The proportion of patients with rates of bone union and instability were 86% and 9%, respectively, in the unilateral group, but significantly poorer at 60% and 34% in the bilateral group. CONCLUSION: If multisegment fusion (3-level fusion) is performed, bilateral local bone grafting results in a poor rate of bone union because of an insufficiency of local bone. Unilateral bone grafting is recommended because better rates of bone union and stability are achieved. PMID- 21544015 TI - Therapeutic monitoring and variability of atazanavir in HIV-infected patients, with and without HCV coinfection, receiving boosted or unboosted regimens. AB - BACKGROUND: Adequate plasma trough concentrations (Ctrough) of protease inhibitors are required to maintain antiviral activity throughout the dosing interval. Therapeutic drug monitoring is used in clinical practice to optimize dosage and avoid toxic or subtherapeutic drug exposure. The pharmacokinetic variability of Atazanavir (ATV) can be relatively large, as a result of several factors. One of the affecting factors may be hepatic impairment due to hepatitis C virus (HCV) coinfection. METHODS: We collected trough plasma samples from human immunodeficiency virus (HIV)-1-infected outpatients, with and without HCV coinfection and/or cirrhosis, receiving stable highly active antiretroviral therapy containing ATV. In the total population, we mainly compared the 2 regimens: 300ATV + 100RTV OD [ritonavir (RTV), once daily (OD)] versus 400ATV OD. We used a threshold value of 0.15 MUg/mL, based on the proposed therapeutic range (0.15-0.85 MUg/mL). Plasma concentrations of ATV were determined by a validated assay using high-performance liquid chromatography with ultraviolet detection. A total of 214 HIV-infected outpatients were included. For each regimen, we compared 3 groups of subjects: HIV+/HCV-, HIV+/HCV+, and HIV+/HCV+ with cirrhosis. RESULTS: In the whole study population, we observed a large variability and found suboptimal Ctrough levels (<0.15 MUg/mL) in 23 subjects (2 belonging to the 300/100 OD group and 21 to the 400 OD group). For the standard dosage regimen of 300ATV + 100RTV OD, we did not find a statistical difference between HIV-infected patients without HCV coinfection versus HIV-infected patients with HCV coinfection: median 0.85 (interquartile range 0.53-1.34) and 0.95 (0.70-1.36) MUg/mL, respectively. In HIV+/HCV+-infected patients with cirrhosis, we found a median Ctrough of 0.70 (0.43-1.0) MUg/mL, with no statistical difference when compared with HIV+/HCV- infected patients. For the 400ATV OD (n=90) dosage regimen, the total median ATV Ctrough was 0.40 (0.23-1.0) MUg/mL. In this group, we found a statistically significant difference between HIV+/HCV- and HIV+/HCV+-infected patients: median Ctrough was 0.23 (0.11-0.42) and 0.52 (0.20-1.0) MUg/mL, respectively. In HIV+/HCV+ subjects with cirrhosis, the Ctrough median value was 0.42 (0.13-0.75) MUg/mL, and there was a significant difference when compared with HIV patients without coinfection. CONCLUSIONS: Therapeutic drug monitoring of ATV in patients receiving unboosted regimen may be useful to identify those HIV-infected subjects, with or without HCV coinfection, who may benefit from adding low RTV doses, or the subset of patients in whom removal of RTV could be attempted without the risk of suboptimal plasma ATV exposure. PMID- 21544014 TI - Therapeutic drug monitoring of protease inhibitors and efavirenz in HIV-infected individuals with active substance-related disorders. AB - BACKGROUND: Achieving targeted antiretroviral (ARV) plasma concentrations during long-term treatment in human immunodeficiency virus (HIV)-infected patients with substance-related disorders (SRDs) may be challenging due to a number of factors, including medication adherence, coinfection with hepatitis B or C virus, medication intolerance, and drug interactions. One approach to investigate these factors is to conduct therapeutic drug monitoring to measure ARV exposure during treatment. The objective of this study was to utilize therapeutic drug monitoring to compare efavirenz (EFV) and protease inhibitor pharmacokinetics in patients with and without SRDs. METHODS: This was a multicenter, cross-sectional open label study in patients with HIV-1 infection receiving antiretroviral therapy (ART), with active (n=129) or without (n=146) SRD according to National Institute on Drug Abuse criteria. Two hundred seventy-five subjects who were receiving either protease inhibitor-based or EFV-based ART regimens for >6 months were enrolled at 4 HIV treatment centers with an equal distribution of SRD and non-SRD at each site. The patients were instructed during enrollment visits with regard to the importance of adherence before and after study visits. Demographics and routine clinical laboratory tests were recorded. RESULTS: Among the 275 patients, 47% had SRD with at least 1 substance. There were no significant differences between SRD and non-SRD groups for race, gender, age, or CD4 count at entry. A significantly higher proportion of patients with SRD had an entry HIV RNA plasma concentration>75 copies per milliliter compared with patients without SRD (40% vs 28%, P=0.044). Logistic regression modeling revealed an association between HIV RNA plasma concentration and African American race (P=0.017). A significantly higher proportion of SRDs also had an EFV or protease inhibitor trough concentration below the desired range (23% vs 9%, P=0.048). Significantly lower trough concentrations were noted in patients with SRDs receiving atazanavir (0.290 vs 0.976 MUg/mL) or lopinavir (3.75 vs 5.30 MUg/mL). CONCLUSIONS: The pharmacokinetic data indicate differences between HIV-infected patients with and without SRDs that may influence viral load suppression during long-term ART. These findings require additional investigation in a randomized design with more intensive pharmacokinetic assessment to identify individual factors that are contributing to suboptimal ARV exposure in patients with SRDs. PMID- 21544016 TI - Are benzo[a]pyrene-DNA adducts an accurate biomarker of long-term in utero exposure to smoking? AB - BACKGROUND: Maternal smoking during pregnancy is associated with adverse perinatal outcomes. In view of concerns about underreporting, benzo[a]pyrene (B[a]P)-DNA adducts could be used to provide information about long-term in utero exposure to smoking but have not previously been used with samples from neonates. This study aimed to verify whether B[a]P-DNA adducts could accurately assess tobacco smoke exposure during fetal life. The objectives were to correlate B[a]P DNA adduct levels with active maternal and passive smoking and to determine the sensitivity and specificity of smoking and nonsmoking status by comparing neonatal B[a]P-DNA adduct levels with those of maternal self-reports. MATERIALS AND METHODS: B[a]P-DNA adducts in neonatal buccal cell samples were determined by a competitive immunoassay. Three groups of neonates were constituted according to maternal self-reported smoking status during pregnancy: nonsmokers (n=25; control group), <10 cigarettes per day (n=18; S- group), or >10 cigarettes per day (n=21; S+ group). RESULTS: The mean B[a]P-DNA adduct level rose significantly when comparing the controls with the S- and S+ groups. Maternal active smoking had the strongest effect on B[a]P-DNA adduct levels in neonates. A cross analysis between B[a]P-DNA adduct levels and maternal self-reported levels revealed high sensitivity and specificity. CONCLUSIONS: This preliminary study suggests that B[a]P-DNA adducts are reliable biomarkers for the screening of long-term in utero exposure to smoking and are accurate when compared with maternal self-reported levels of active smoking. Detection of B[a]P-DNA adducts in neonates could provide a useful, noninvasive tool in clinical risk assessment studies but would benefit from further confirmation with another validated biomarker. PMID- 21544017 TI - Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis. AB - BACKGROUND: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug monitoring is not feasible in most settings. Developing a limited-sampling strategy based on population pharmacokinetics (PK) may help to overcome this problem. METHODS: Steady-state plasma concentrations after the administration of 400 mg of MFX once daily were determined in 21 patients with TB, using a validated liquid chromatography-tandem mass spectrometry method. A one-compartment population model was generated and crossvalidated. Monte Carlo data simulation (n=1000) was used to calculate limited-sampling strategies. The correlation between predicted MFX AUC0-24h (area under the concentration-time curve 0 to 24 hours) and observed AUC0-24h was investigated by Bland-Altman analysis. Finally, the predictive performance of the final model was tested prospectively using MFX profiles from patients with TB receiving 400, 600, or 800 mg once daily. RESULTS: Median minimum inhibitory concentration of Mycobacterium tuberculosis isolates was 0.25 mg/L (interquartile range: 0.25-0.5 mg/L). The geometric mean AUC0-24h was 24.5 mg.h/L (range: 8.5-72.2 mg.h/L), which resulted in a geometric mean AUC0 24h/minimum inhibitory concentration ratio of 72 (range: 21-321). PK analysis, based on PK profiles of 400 mg of MFX once daily, resulted in a crossvalidated population PK model with the following parameters: apparent clearance (Cl) 18.5+/ 8.6 L/h per 1.85 m, Vd 3.0+/-0.7 L/kg corrected lean body mass, Ka 1.15+/-1.16 h, and F was fixed at 1. After the Monte Carlo simulation, the best predicting strategy for MFX AUC0-24h for practical use was based on MFX concentrations 4 and 14 hours postdosing (r=0.90, prediction bias=-1.5%, and root mean square error=15%). CONCLUSIONS: MFX AUC0-24h in patients with TB can be predicted with acceptable accuracy for clinical management, using limited sampling. AUC0-24h prediction based on 2 samples, 4 and 14 hours postdose, can be used to individualize treatment. PMID- 21544018 TI - Association between adverse effects under azathioprine therapy and inosine triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease. AB - BACKGROUND: Inosine triphosphate pyrophosphatase (ITPA) catalyzes the pyrophosphohydrolysis of inosine triphosphate to inosine monophosphate. Recently, single-nucleotide polymorphisms in the ITPA gene, associated with decreased enzyme activity, have been reported. Some clinical studies have demonstrated that the 94C>A mutation is linked to flu-like symptoms, rash, and pancreatitis during azathioprine (AZA) therapy and to early AZA discontinuation. In this study, we investigated whether the enzyme phenotype is also related to adverse effects (AEs). METHODS: Patients suffering from inflammatory bowel disease who were treated with AZA (N=160; age 43+/-12 years) were included. Data were categorized into quartiles according to the ITPA activity. Information about the therapeutic regimen, AEs [leucopenia, increased hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase), flu-like symptoms, and pancreatitis], cotherapy, and comorbidity was obtained from the responsible clinicians and patients by using a standardized questionnaire. ITPA activity was measured by a validated high-performance liquid chromatography procedure. In patients with decreased ITPA activity, the 94C>A and IVS2+21A>C genotypes were determined. RESULTS: AEs were reported significantly more often for patients with low ITPA activity than for patients with high ITPA activity; the highest odds ratio for occurrence of AEs was found to be below a threshold of 59.9 MUmol/(gHb.h) [hemoglobin (Hb)]. Decreased ITPA activities [particularly <89.2 MUmol/(gHb.h)] were frequently accompanied by leucopenias, whereas very low enzyme activities [<37.3 MUmol/(gHb.h)] were associated with a higher incidence of increased liver enzymes. CONCLUSIONS: The results demonstrate a relationship between low ITPA activity and AEs and support the idea that the determination of ITPA phenotype might be an appropriate alternative to genotyping. PMID- 21544019 TI - An automated method for supporting busulfan therapeutic drug monitoring. AB - INTRODUCTION: Busulfan is a chemotherapeutic agent commonly used for myeloablative conditioning regimens such as in the treatment of chronic myelogenous leukemia. Busulfan dosing is complex due to wide interpatient variability in pharmacokinetics and a narrow therapeutic range. Although busulfan dose is normalized to body weight, therapeutic drug monitoring (TDM) using area under the plasma concentration curve is recommended after the first dose. A high busulfan area under the plasma concentration curve (>1500 MUM.min) is associated with an increased risk for sinusoidal obstruction syndrome, and a suboptimal area under the plasma concentration curve (<900 MUM.min) is associated with an increased risk for graft rejection or disease relapse. TDM of busulfan is not widely available due to the lack of commercially available and rapid methods to determine the area under the plasma concentration curve. METHODS: The purpose of this study was to evaluate the Roche cobas c 111 instrument, a photometric automated chemistry analyzer, using the Busulfan PCM assay from Saladax Biomedical Inc. The assay using this instrument was compared with an enzyme linked immunosorbent assay (ELISA) from Saladax Biomedical Inc and the Olympus AU400e. Linearity and accuracy were evaluated between 175 and 1750 ng/mL. Imprecision was determined by analyzing 5 concentrations of standards twice a day for 20 days. RESULTS: Linearity for the Roche method had a slope and y-intercept of 1.050 and -5.5, respectively, and percent recovery ranged between 95% and 105%. Correlation between the Roche and ELISA platforms was analyzed by linear regression on 26 frozen patient samples. The results from the comparison of the methods based on the Roche and ELISA platforms were as follows: coefficient of determination (R2) was 0.9684, with a slope and y-intercept of 0.752 and 108.41, respectively. Correlation between the Roche and Olympus instruments was analyzed by linear regression and Bland-Altman plots. The coefficient of determination (R2) was 0.9942, with a slope and y-intercept of 1.035 and -41.3326, respectively. CONCLUSIONS: Availability of TDM of busulfan can be improved by the use of commercially available reagents and automated platforms. PMID- 21544020 TI - Acupressure at acupoint P6 for prevention of postoperative nausea and vomiting: a randomised clinical trial. AB - BACKGROUND AND OBJECTIVE: Postoperative nausea and vomiting causes discomfort in many patients despite both antiemetic prophylactics and improved anaesthetic techniques. Stimulation of acupoint P6 is described as an alternative method for prophylaxis of postoperative nausea and vomiting.In a randomised, double-blinded study, we aimed to investigate the effect of P6 acupoint stimulation on the incidence of postoperative nausea and vomiting within 24 h postoperatively with an acupressure wristband: Vital-Band. METHODS: One hundred and thirty-four healthy, non-smoking women scheduled for breast surgery were randomised either to P6 stimulation or to sham control. Wristbands were applied and covered with a dressing before induction of anaesthesia. Follow-up was carried out three times within 24 h postoperatively. Primary outcomes were postoperative nausea and/or vomiting. RESULTS: One hundred and twelve patients completed the study. There were no statistically significant differences in the incidence of nausea [P6 stimulation, 35.1% (95% confidence interval, CI 22.7-47.5%) versus sham control, 43.1% (95% CI 29.5-56.7%; P = 0.433)] or vomiting [P6 stimulation, 25.9% (95% CI 14.6-37.2%) versus sham control, 26.9% (95% CI 14.8-39.0%; P = 1.000)]. Approximately, one third of the patients reported side effects caused by the wristband, for example, redness, swelling and tenderness. CONCLUSION: We did not find the Vital-Band effective in preventing either nausea or vomiting after operation in women undergoing breast surgery. PMID- 21544021 TI - Patients' experience of awake versus anaesthetised orotracheal intubation: a controlled study. AB - BACKGROUND AND OBJECTIVE: We investigated patients' self-reported experience following awake flexible fibreoptic tracheal intubation and compared this to the experience of matched patients who had undergone conventional tracheal intubation under general anaesthesia for the same type of surgical procedure. METHODS: Patients suspected of having, or known to have, a difficult airway underwent flexible fibreoptic orotracheal intubation with topical anaesthesia and sedation. A matched group of patients who underwent tracheal intubation conventionally following induction of general anaesthesia were identified in our database and questionnaires were mailed to the patients at a median of 15 months after the procedure. RESULTS: One hundred and ten patients completed the questionnaire. Feelings of discomfort, sensation of suffocation and hoarseness were reported by 14.6, 12.5, and 37.5%, respectively in the awake group and 0, 1.6, and 17.7%, respectively in the conventionally intubated group. No significant differences were reported between the groups with regard to sleeping disorders and the incidence of nightmares. CONCLUSION: Temporary discomfort is encountered more frequently following awake orotracheal intubation than after conventional intubation, but we did not find a difference in long-term problems such as sleeping disorders or nightmares. PMID- 21544022 TI - A simulated severe difficult airway does not alter the intubation performance with the SensaScope: a prospective randomised manikin study. AB - DESIGN: Prospective randomised controlled study. SETTING: Operation unit in a tertiary academic university hospital in a central European city. Period of the study was springtime and summer 2010. PATIENTS OR OTHER PARTICIPANTS: Twenty-four anaesthesiologists with various levels of professional experience were allocated to intubate an airway manikin either with the SensaScope (group S) or with the conventional Macintosh 3 laryngoscope (group L). INTERVENTIONS: Each participant performed three consecutive intubations with normal anatomy followed by three intubations with difficult anatomy. The airway difficulty was simulated by inflation of the manikin's tongue base with 40 ml of air. The times taken to view the larynx and to insert the tracheal tube were noted. The resulting tube position and the occurrence of dental damage were recorded. MAIN OUTCOME MEASURES: Those planned in the protocol. RESULTS: In normal anatomy, the laryngeal view (group L 5.9 +/- 4.2 s vs. group S 9.2 +/- 3.5 s) and intubation (group L 13.4 +/- 7.6 s vs. group S 23.3 +/- 8.6 s) was more rapidly obtained with conventional laryngoscopy (values presented as mean +/- SD). In difficult anatomy, only the SensaScope permitted successful laryngeal view (group L impossible vs. group S 9.9 +/- 4.8 s) and tracheal intubation (group L impossible vs. group S 23.4 +/- 8.8 s). The latter always enabled correct tracheal tube position, whereas with laryngoscopy alone either oesophageal intubation or aborted attempts resulted. In the difficult airway setting, the frequency of simulated tooth damage was also significantly higher with conventional laryngoscopy (group L 26 of 36 vs. group S 6 of 36). CONCLUSIONS: The SensaScope performed fairly well in normal intubation anatomy, although its use was more complex than with conventional laryngoscopy and it required a slightly longer time. In the difficult airway setting, the SensaScope performed as well as in normal anatomy, whereas intubation by direct laryngoscopy proved to be impossible. The SensaScope enables the user to overcome severe airway difficulties caused by large tissue masses at the level of the tongue base or mouth floor. PMID- 21544023 TI - EuSOS: European surgical outcomes study. PMID- 21544024 TI - OBTAIN: a study of the occurrence of bleeding and thrombosis during anti-platelet therapy in non-cardiac surgery. PMID- 21544025 TI - PERISCOPE study: predicting post-operative pulmonary complications in Europe. PMID- 21544026 TI - euCPSP: European observational study on chronic post-surgical pain. PMID- 21544027 TI - Forces applied by the laryngoscope blade onto the tongue during intubation attempts: a comparison between Mackintosh, AirTraq and Pentax AWS in a mannequin study. PMID- 21544028 TI - Optimal scoring methods of hand-strength tests in patients with stroke. AB - The purpose of this study was to determine the optimal scoring methods for measuring strength of the more-affected hand in patients with stroke by examining the effect of reducing measurement errors. Three hand-strength tests of grip, palmar pinch, and lateral pinch were administered at two sessions in 56 patients with stroke. Five scoring methods were used to present the strength scores. The smallest real difference was used to provide information on the measurement error. The smallest real difference percentage was used to compare the effect on minimizing the error. Using mean score of tests for nonspastic patients carried out at least twice was found to be advisable to minimize measurement errors in the grip, palmar pinch, and lateral pinch tests. However, the use of hand strength tests for patients with spasticity is limited because of the relatively high measurement errors. PMID- 21544029 TI - Approaching the promise of operational tolerance in clinical transplantation. AB - Long-term acceptance of transplanted organs without requirement for indefinite immunosuppression remains the ultimate goal of transplant clinicians and scientists. This clinical state of allograft acceptance termed "operational tolerance" has been elusive in routine practice. However, there are published reports of recipients where immunosuppression has been discontinued, by intention or patient noncompliance, in which the outcome is a nondestructive immune response and normal function. The question now arises how clinical operational tolerance might be achieved in the majority of recipients. This review provides an overview of current approaches to achieve operational tolerance, including the use of donor bone marrow and depletion of recipient T cells and the resistance of liver transplants to rejection. It also describes the key role of clinical immune monitoring and future approaches to tolerance induction including inhibition of T cell signaling, manipulation of costimulatory pathways, and expansion of regulatory T cells. The principles of these experimental approaches may ultimately be extended to provide safe and effective control of transplant rejection and induction of clinical operational tolerance. PMID- 21544030 TI - Prolonged xenograft survival induced by inducible costimulator-Ig is associated with increased forkhead box P3(+) cells. AB - BACKGROUND: Blockade of the inducible costimulator (ICOS) pathway has been shown to prolong allograft survival; however, its utility in xenotransplantation is unknown. We hypothesize that local expression of ICOS-Ig by the xenograft will suppress the T-cell response resulting in significant prolonged graft survival. METHODS: Pig iliac artery endothelial cells (PIEC) secreting ICOS-Ig were generated and examined for the following: (1) inhibition of allogeneic and xenogeneic proliferation of primed T cells in vitro and (2) prolongation of xenograft survival in vivo. Grafts were examined for Tregs by flow cytometry and cytokine levels determined by quantitative reverse-transcriptase polymerase chain reaction. RESULTS: Soluble ICOS-Ig markedly decreased allogeneic and xenogeneic primed T-cell proliferation in a dose-dependent manner. PIEC-ICOS-Ig grafts were significantly prolonged compared with wild-type grafts (median survival, 34 and 12 days, respectively) with 20% of PIEC-ICOS-Ig grafts surviving more than 170 days. Histological examination showed a perigraft cellular accumulation of Forkhead box P3 (Foxp3(+)) cells in the PIEC-ICOS-Ig grafts, these were also shown to be CD3(+)CD4(+)CD25(+). Survival of wild-type PIEC grafts in a recipient simultaneously transplanted with PIEC-ICOS-Ig were also prolonged, with a similar accumulation of Foxp3(+) cells at the periphery of the graft demonstrating ICOS Ig induces systemic graft prolongation. However, this prolongation was specific for the priming xenograft. Intragraft cytokine analysis showed an increase in interleukin-10 levels, suggesting a potential role in induction/function of CD4(+)CD25(+)Foxp3(+) cells. CONCLUSIONS: This study demonstrates prolonged xenograft survival by local expression of ICOS-Ig, we propose that the accumulation of CD4(+)CD25(+)Foxp3(+) cells at the periphery of the graft and secretion of interleukin-10 is responsible for this novel observation. PMID- 21544031 TI - Expression of CYP3A5 and P-glycoprotein in renal allografts with histological signs of calcineurin inhibitor nephrotoxicity. AB - BACKGROUND: Susceptibility to calcineurin inhibitor nephrotoxicity (CNIT) after solid organ transplantation could be related to an interindividual variability in renal expression and function of the metabolizing cytochrome P450 3A5 (CYP3A5) isoenzyme and of the multidrug efflux transporter P-glycoprotein (P-gp, ABCB1). METHODS: We compared renal expression of CYP3A5 and P-gp, measured by immunohistochemistry, in 32 renal allograft biopsies with de novo arteriolar hyalinosis as a sign of CNIT with a control group, consisting of normal protocol allograft biopsies (n=50) and protocol biopsies demonstrating alloimmune injury (n=21). In addition, we studied the association between renal expression and donor and recipient single-nucleotide polymorphisms CYP3A5 A6986G (rs776746), ABCB1 C3435T (rs1045642), and G2677T (rs2032582). RESULTS: CYP3A5 positivity at the brushborder of the proximal tubules was present in 47% of CNIT and 14% of control biopsies (P<0.01). In contrast, brushborder staining for CYP3A5 in distal tubules was present in 10% of CNIT and 39% of control biopsies (P<0.01). No significant association between tubular cell P-gp expression and CNIT was detected. The presence of genetic polymorphisms CYP3A5 A6986G and ABCB1 C3435T and G2677T in donors and recipients was not predictive of the renal expression profile of these molecules. CONCLUSIONS: Based on retrospectively collected data of 103 renal transplant recipients receiving tacrolimus in combination with mycophenolate mofetil and corticosteroids, we found that renal expression and localization of CYP3A5 but not P-gp is associated with the occurrence of CNIT. Common genetic polymorphisms in these proteins did not influence their expression profile as measured by immunohistochemistry. PMID- 21544032 TI - Genetic and clinical risk factors of new-onset diabetes after transplantation in Hispanic kidney transplant recipients. AB - BACKGROUND: New-onset diabetes after transplantation (NODAT) is one of the major complications after transplantation and is associated with reduced overall patient and graft survival. The objective of this study was to determine the genetic and clinical risk factors for NODAT in Hispanic kidney transplant recipients. METHODS: Hispanic kidney allograft recipients without evidence of preexisting diabetes who developed NODAT (n=133) were studied using Hispanic kidney transplant recipients with no evidence of diabetes as a control group (n=170). NODAT was defined as fasting glucose levels >=126 mg/dL on two or more occasions or patients taking any insulin or oral hypoglycemic agents 1 month or later after kidney transplantation. Fourteen alleles in nine genes were genotyped and other patients' clinical data with genotype data were analyzed by logistic regression. RESULTS: Among 14 alleles, hepatocyte nuclear factor 4 alpha (HNF4A) AA (rs2144908, odds ratio [OR]=1.96, confidence interval [CI]=1.08-3.50, P=0.010), HNF4A TT (rs1884614, OR=2.44, CI=1.42-4.48, P=0.002), and insulin receptor substrate 1 AA+AG (rs1801278, OR=2.71, CI=1.16-6.89, P=0.021) remained significant after logistic regression. Among the clinical factors, average age (OR=1.01, CI=1.00-1.08, P=0.048), sirolimus (OR=5.36, CI=3.02-10.4, P=0.001), deceased donor (OR=1.96, CI=1.16-2.94, P=0.015), and acute rejection (OR=2.92, CI=1.31-5.77, P=0.009) remained significant after logistic regression. CONCLUSION: This study indicates that polymorphism of two alleles of HNF-4A gene (rs2144908 and rs1884614) and insulin receptor substrate 1 (rs1801278) are significantly associated with NODAT in kidney transplant patients with Hispanic ethnicity. In the case of clinical factors, older age (>50 year), deceased donor type, acute rejection, and sirolimus use are associated with NODAT in Hispanic kidney transplant recipients. PMID- 21544033 TI - Immediate postoperative intensive care treatment of pediatric combined liver kidney transplantation: outcome and prognostic factors. AB - BACKGROUND: Studies reporting the immediate pediatric intensive care unit (PICU) treatment after combined liver-kidney transplantation (CLKT) are scarce, although this period is pivotal for survival and long-term outcome. METHODS: We retrospectively analyzed all pediatric CLKT performed in our center between 1998 and 2010. RESULTS: Sixteen patients underwent 17 CLKT at a median age of 5.3 years (range, 1.3-15.9 years). Median body weight at CLKT was 17.7 kg (range, 9.2 55 kg). Underlying diagnosis was primary hyperoxaluria type 1 in nine patients and autosomal recessive polycystic kidney disease in seven patients. Median time on PICU was 8.5 days (range, 3-68 days); however, patients with primary hyperoxaluria type 1 had a significantly longer stay (P=0.031). Median duration of ventilation was 1 day; however, five patients required ventilation for 25 to 52 days. Continuous veno-venous hemofiltration was applied in nine patients due to delayed kidney graft function, volume overload, or high plasma oxalate. Overall, the survival rate after CLKT was 100% and long-term outcome was very good at a mean follow-up of 3.6 years (range, 0.5-12.2 years). Waiting time, donor age, and donor-to-recipient weight ratio were found to be significant risk factors for an extended PICU stay (P=0.02, 0.0031, and 0.014, respectively). CONCLUSIONS: Immediate postoperative course after CLKT may be challenging and complex. However, excellent results can be achieved, even in small children. PMID- 21544034 TI - Liver transplant outcomes for patients with hepatorenal syndrome treated with pretransplant vasoconstrictors and albumin. AB - BACKGROUND: The combination of octreotide, midodrine, and albumin (triple therapy) is used to treat hepatorenal syndrome (HRS) often as a bridge to liver transplantation (LT). We examined post-LT outcomes in recipients with HRS, including the effect of pre-LT triple therapy. METHODS: Patients with HRS treated with triple therapy (cases) pre-LT were compared with a cohort that underwent LT in the immediate era before triple therapy was used (controls). RESULTS: Forty three patients with HRS underwent LT (27 cases and 16 controls). Twenty-one patients (49%) required hemodialysis (HD) pre-LT (48% of cases vs. 50% of controls, P=1.00). After LT, mean glomerular filtration rate (GFR) was similar between cases and controls at 1 month (56.9 vs. 52.6 mL/min/1.73 m(2), P=0.61) and at 1 year (P=0.13). Of the 27 cases, 11 responded to triple therapy pre-LT. Compared with nonresponders, there was no difference in GFR at 1 month (57.2 vs. 56.6 mL/min/1.73 m, P=0.96) or 1 year (P=0.48) post-LT. Long-term HD after LT was required in 7.7% of cases and 12.5% of controls (P=0.61). CONCLUSIONS: LT alone improved renal function in most patients with HRS, including those requiring short-term HD. Pre-LT treatment of HRS with triple therapy was not associated with additional benefit in GFR after LT. PMID- 21544035 TI - Current trends in living donor liver transplantation for primary sclerosing cholangitis. AB - BACKGROUND: Use of the Model for End-Stage Liver Disease (MELD) score has improved the efficiency of allocating deceased donor organs for liver transplant. However, its use may reduce access to deceased donor livers for patients with primary sclerosing cholangitis (PSC) due to the weighting of the MELD score variables. To overcome such barriers in the post-MELD era, clinicians might refer patients with PSC, relative to patients without PSC, for living donor transplants more frequently. METHODS: To test this hypothesis, we examined patients in the United Network for Organ Sharing database from December 1, 1994, to May 31, 2009. RESULTS: In multivariable models conditioned on transplant center, patients with PSC were significantly more likely to receive a living donor transplant in both the pre-MELD (odds ratio [OR]=2.75; 95% confidence interval [CI], 2.20-3.44) and post-MELD eras (OR=4.08; 95% CI, 3.45-4.82). There was a significant interaction between PSC and post-MELD era of transplantation (OR=1.48; 95% CI, 1.11-1.97), indicating that patients with PSC were more likely to receive living donor transplants at baseline relative to patients without PSC, and that this effect was magnified following the introduction of the MELD score. CONCLUSIONS: These findings raise the possibility that allocating livers on the basis of MELD score may have yielded the unintended consequence of increasing rates for living donor transplants for patients with PSC relative to patients with other forms of end stage liver disease. Future research is needed to determine whether the practice of selectively transplanting patients with PSC with living donor transplants is associated with differences in clinical outcomes. PMID- 21544036 TI - HLA and MICA: targets of antibody-mediated rejection in heart transplantation. AB - BACKGROUND: The goal of this study was to determine whether antidonor antibodies directed against human leukocyte antigen (HLA) or endothelial cells (ECs) expressed antigens, including major histocompatibility complex class I chain related antigens A (MICA) are associated with the diagnosis of antibody-mediated rejection (AMR) in heart transplant recipients. METHODS: We studied posttransplant antidonor HLA antibodies in 168 heart allograft recipients transplanted from October 2001 to December 2005. Among them, there were 37 AMR+ patients and 131 age- and sex- matched AMR- controls. Sera were collected at the time of protocol biopsies and tested for the presence of HLA antibodies. Seventy two of the 168 patients were genotyped for donor and recipient MICA alleles and were tested for the presence of anti-MICA antibodies. Thirty-one patients who never developed antibodies to HLA or MICA were further tested for anti-EC antibodies. RESULTS AND CONCLUSIONS: Of 37 AMR+ patients, 22 (60%) developed donor-specific antibodies (DSA) to HLA compared with 6 of 131(4%) AMR- patients (P<0.0001). Of the remaining 15 AMR+ patients, 5 had anti-HLA antibodies that were not donor specific and 10 did not show any HLA antibodies. In the subgroup of 72 patients, all 19 AMR+ patients had clearly demonstrable antibodies reactive with donor HLA, MICA or with nondonor-derived ECs, with 30% of them showed antibodies directed to non-HLA antigens. The incidence of transplant coronary artery disease was significantly higher in patients who had DSA to HLA and MICA compared with patients without DSA. PMID- 21544037 TI - Acylation of heteroaromatic amines: facile and efficient synthesis of a new class of 1,2,3-triazolo[4,5-b]pyridine and pyrazolo[4,3-b]pyridine derivatives. AB - 1,2,3-Triazolo[4,5-b]pyridines and pyrazolo[4,3-b]pyridines can be readily prepared via cyanoacetylation reactions of 5-amino-1,2,3-triazoles 1a,b and 4 amino- pyrazole 2 followed by subsequent cyclization of the formed cyanoacetamides. Reactions of amines 1a,b with a mixture of p-nitrophenylacetic acid and acetic anhydride under microwave irradiation conditions afforded the corresponding amides 15a,b that underwent cyclization to form 1,2,3-triazolo[4,5 b]pyridines 16a,b upon heating in DMF solutions containing sodium acetate. Reactions of 1a,b with active methylene compounds, including 17a-c, in the presence of zeolites as catalyst also afforded 1,2,3-triazolo[4,5-b]pyridine derivatives 20a-f via the intermediacy of triazole derivatives 19 and not 18. PMID- 21544038 TI - Crystallization products of risedronate with carbohydrates and their substituted derivatives. AB - The gastrointestinal absorption of bisphosphonates is in general only about 1%. To address this problem mixtures of risedronate monosodium salt with twelve varied sugar alcohols, furanoses, pyranoses and eight gluco-, manno- and galactopyranoside derivatives as counterions were designed in an effort to prepare co-crystals/new entities with improved intestinal absorption. Crystalline forms were generated by means of kinetically and/or thermodynamically controlled crystallization processes. One hundred and fifty-two prepared samples were screened by means of FT-NIR and FT-Raman spectroscopy. No co-crystal was prepared, but noteworthy results were obtained. A new solid phase of risedronate monosodium salt generated in the presence of phenyl-beta-d-galactopyranoside under thermodynamically controlled crystallization conditions was found and also characterized using solid state NMR spectroscopy, X-ray powder diffraction and differential scanning calorimetry. This new polymorph was named as form P. Interactions between risedronate monosodium salt and both carbohydrates were confirmed by means of molecular dynamics simulation. In the present study the relationships between the chemical structures of the studied compounds required for crystalline form change are discussed. PMID- 21544039 TI - Enhancement of leaf gas exchange and primary metabolites under carbon dioxide enrichment up-regulates the production of secondary metabolites in Labisia pumila seedlings. AB - A split plot 3 by 3 experiment was designed to investigate and distinguish the relationships among production of primary metabolites (soluble sugar and starch), secondary metabolites (total phenolics, TP; total flavonoids, TF) and leaf gas exchange of three varieties of the Malaysian medicinal herb Labisia pumila Blume, namely the varieties alata, pumila and lanceolata, under three levels of CO2 enrichment (400, 800 and 1,200 umol mol-1) for 15 weeks. The treatment effects were solely contributed by CO2 enrichment levels; no varietal differences were observed. As CO2 levels increased from 400 to 1,200 umol mol-1, the production of carbohydrates also increased steadily, especially for starch more than soluble sugar (sucrose). TF and TP content, simultaneously, reached their peaks under 1,200 umol exposure, followed by 800 and 400 umol mol-1. Net photosynthesis (A) and quantum efficiency of photosystem II (f(v)/f(m)) were also enhanced as CO2 increased from 400 to 1,200 umol mol-1. Leaf gas exchange characteristics displayed a significant positive relationship with the production of secondary metabolites and carbohydrate contents. The increase in production of TP and TFs were manifested by high C/N ratio and low protein content in L. pumila seedlings, and accompanied by reduction in cholorophyll content that exhibited very significant negative relationships with total soluble sugar, starch and total non structural carbohydrate. PMID- 21544040 TI - Asymmetric aldol reactions of alpha,beta-unsaturated ketoester substrates catalyzed by chiral diamines. AB - Highly efficient asymmetric aldol reactions between alpha,beta-unsaturated keto esters and acyclic ketones catalyzed by chiral diamines are reported. The corresponding products were obtained in excellent yields with excellent enantioselectivities. The absolute configuration for the product was determined by X-ray analysis. A variety of substrates were tolerable in the present catalytic system. PMID- 21544041 TI - Antihyperglycemic effect of orthosiphon stamineus benth leaves extract and its bioassay-guided fractions. AB - Preliminary investigations were carried out to evaluate the antidiabetic effects of the leaves of O. stamineus extracted serially with solvents of increasing polarity (petroleum ether, chloroform, methanol and water); bioassay-guided purification of plant extracts using the subcutaneous glucose tolerance test (SbGTT) was also carried out. Only the chloroform extract, given at 1 g/kg body weight (b.w.), significantly reduced (P < 0.05) the blood glucose level of rats loaded subcutaneously with 150 mg/kg (b.w.) glucose. The active chloroform extract of O. stamineus was separated into five fractions using a dry flash column chromatography method. Out of the five fractions tested, only chloroform fraction 2 (Cf2), at the dose of 1 g/kg (b.w.) significantly inhibited (P < 0.05) blood glucose levels in SbGTT. Active Cf2 was split into two sub-fractions Cf2-A and Cf2-B, using a dry flash column chromatography method. The activities Cf2-A and Cf2-B were investigated using SbGTT, and the active sub-fraction was then further studied for anti-diabetic effects in a streptozotocin-induced diabetic rat model. The results clearly indicate that Cf2-B fraction exhibited a blood glucose lowering effect in fasted treated normal rats after glucose-loading of 150 mg/kg (b.w.). In the acute streptozotocin-induced diabetic rat model, Cf2-B did not exhibit a hypoglycemic effect on blood glucose levels up to 7 hours after treatment. Thus, it appears that Cf2-B functions similarly to metformin, which has no hypoglycemic effect but demonstrates an antihyperglycemic effect only in normogycemic models. The effect of Cf2-B may have no direct stimulatory effects on insulin secretion or on blood glucose levels in diabetic animal models. Verification of the active compound(s) within the active fraction (Cf2-B) indicated the presence of terpenoids and, flavonoids, including sinensitin. PMID- 21544042 TI - Hepatitis C virus infection among adolescents and young adults:Massachusetts, 2002-2009. AB - Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma in the United States. Of the estimated 2.7--3.9 million persons with active HCV infection, most were born during 1945--1964 and likely were infected during the 1970s and 1980s, before the advent of prevention measures. Nationwide, rates of acute, symptomatic HCV infection declined during 1992--2005 and then began to level. Declines also were observed in rates of newly reported HCV infection in Massachusetts. Although these declines were evident among reported cases overall in Massachusetts during 2002--2006, an increase was observed among cases in the 15--24 year age group. In response to this increase, the Massachusetts Department of Public Health (MDPH) launched a surveillance initiative to collect more detailed information on cases reported during 2007- 2009 among this younger age group and to examine the data for trends through 2009. This report describes results of both efforts, which revealed continued increases in rates of newly reported HCV infection among persons aged 15--24 years. These cases were reported from all areas of the state, occurred predominantly among non-Hispanic white persons, and were equally distributed among males and females. Of cases with available risk data, injection drug use (IDU) was the most common risk factor for HCV transmission. The increase in case reports appears to represent an epidemic of HCV infection related to IDU among new populations of adolescents and young adults in Massachusetts. The findings indicate the need for enhanced surveillance of HCV infection and intensified hepatitis C prevention efforts targeting adolescents and young adults. PMID- 21544043 TI - Fatal injuries among grounds maintenance workers: United States, 2003--2008. AB - A total of 1,142 grounds maintenance workers (GMWs) were fatally injured at work during 2003--2008, an average of 190 each year. GMWs accounted for 3.4% of all occupational fatalities, and 31% of those GMWs were Hispanic or Latino. Approximately 83% of the Hispanic or Latino GMWs who died were born outside the United States. In 2008, approximately 1.52 million persons were employed as GMWs, constituting 1.0% of the U.S. workforce. During 2003--2007, an average of 13.3 per 100,000 employed GMWs died each year, compared with an overall rate of 4.0 fatalities per 100,000 U.S. workers. The rate of on-the-job fatal injuries among GMWs has remained elevated relative to other workers for >20 years. This report characterizes events leading to GMW fatalities and differences in fatality characteristics across demographic groups among GMWs, based on an evaluation of 2003--2008 data from the U.S. Department of Labor's Bureau of Labor Statistics (BLS) Census of Fatal Occupational Injuries (CFOI) program. The report also identifies workplace interventions that might reduce the incidence of fatal injuries. Major events leading to GMW occupational fatalities included transportation incidents (31%), contact with objects and equipment (25%), falls (23%), and traumatic acute exposures to harmful substances or environments (e.g., electrocution and drowning) (16%). To reduce the incidence of such fatalities, employers, trade and worker associations, and policy makers should focus on effective, targeted workplace safety interventions such as frequent hazard identification and training for specific hazards. Diversity among the populations of workers requires use of culture- and language-appropriate training techniques as part of comprehensive injury and illness prevention programs. PMID- 21544044 TI - Vital signs: asthma prevalence, disease characteristics, and self-management education: United States, 2001--2009. AB - BACKGROUND: Most persons with asthma can be symptom-free if they receive appropriate medical care, use inhaled corticosteroids when prescribed, and modify their environment to reduce or eliminate exposure to allergens and irritants. This report reviews recent progress in managing asthma and reducing its prevalence in the United States. METHODS: CDC analyzed asthma data from the 2001- 2009 National Health Interview Survey concerning children and adults, and from the 2001, 2005, and 2009 state-based Behavioral Risk Factor Surveillance System concerning adults. RESULTS: Among persons of all ages, the prevalence of asthma increased from 7.3% (20.3 million persons) in 2001 to 8.2% (24.6 million persons) in 2009, a 12.3% increase. Prevalence among children (persons aged <18 years) was 9.6%, and was highest among poor children (13.5%) and among non-Hispanic black children (17.0%). Prevalence among adults was 7.7%, and was greatest in women (9.7%) and in adults who were poor (10.6%). More uninsured persons with asthma than insured could not afford to buy prescription medications (40.3% versus 11.5%), and fewer uninsured persons reported seeing or talking with a primary care physician (58.8% versus 85.6%) or specialist (19.5% versus 36.9%). Among persons with asthma, 34.2% reported being given a written asthma action plan, and 68.1% had been taught the appropriate response to symptoms of an asthma attack. Only about one third of children or adults were using long-term control medicine such as inhaled corticosteroids at the time of the survey. CONCLUSIONS AND COMMENT: Persons with asthma need to have access to health care and appropriate medications and use them. They also need to learn self-management skills and practice evidence-based interventions that reduce environmental risk factors. PMID- 21544045 TI - Surveillance for traumatic brain injury-related deaths--United States, 1997-2007. AB - PROBLEM/CONDITION: Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Approximately 53,000 persons die from TBI related injuries annually. During 1989-1998, TBI-related death rates decreased 11.4%, from 21.9 to 19.4 per 100,000 population. This report describes the epidemiology and annual rates of TBI-related deaths during 1997-2007. REPORTING PERIOD: January 1, 1997-December 31, 2007. DESCRIPTION OF SYSTEM: Data were analyzed from the CDC multiple-cause-of-death public-use data files, which contain death certificate data from all 50 states and the District of Columbia. RESULTS: During 1997-2007, an annual average of 53,014 deaths (18.4 per 100,000 population; range: 17.8-19.3) among U.S. residents were associated with TBIs. During this period, death rates decreased 8.2%, from 19.3 to 17.8 per 100,000 population (p = 0.001). TBI-related death rates decreased significantly among persons aged 0-44 years and increased significantly among those aged >=75 years. The rate of TBI deaths was three times higher among males (28.8 per 100,000 population) than among females (9.1). Among males, rates were highest among non Hispanic American Indian/Alaska Natives (41.3 per 100,000 population) and lowest among Hispanics (22.7). Firearm- (34.8%), motor-vehicle- (31.4%), and fall related TBIs (16.7%) were the leading causes of TBI-related death. Firearm related death rates were highest among persons aged 15-34 years (8.5 per 100,000 population) and >=75 years (10.5). Motor vehicle-related death rates were highest among those aged 15-24 years (11.9 per 100,000 population). Fall-related death rates were highest among adults aged >=75 years (29.8 per 100,000 population). Overall, the rates for all causes except falls decreased. INTERPRETATION: Although the overall rate of TBI-related deaths decreased during 1997-2007, TBI remains a public health problem; approximately 580,000 persons died with TBI related diagnoses during this reporting period in the United States. Rates of TBI related deaths were higher among young and older adults and certain minority populations. The leading external causes of this condition were incidents related to firearms, motor vehicle traffic, and falls. PUBLIC HEALTH ACTIONS: Accurate, timely, and comprehensive surveillance data are necessary to better understand and prevent TBI-related deaths in the United States. CDC multiple-cause-of-death public-use data files can be used to monitor the incidence of TBI-related deaths and assist public health practitioners and partners in the development, implementation, and evaluation of programs and policies to reduce and prevent TBI related deaths in the United States. Rates of TBI-related deaths are higher in certain population groups and are primarily related to specific external causes. Better enforcement of existing seat belt laws, implementation and increased coverage of more stringent helmet laws, and the implementation of existing evidence-based fall-related prevention interventions are examples of interventions that can reduce the incidence of TBI in the United States. PMID- 21544046 TI - Device therapy. Meta-analysis demonstrates safety of pacemaker reutilization. PMID- 21544047 TI - Arrhythmias. A new hybrid ablation technique for AF. PMID- 21544048 TI - Interventional cardiology. The importance of patient-related factors on PCI outcomes. PMID- 21544049 TI - Diabetes: ACCORD: 5-year outcomes of intensive glycemic control. PMID- 21544050 TI - Neuroendocrinology: Kiss1 expressed in the amygdala in rodents. PMID- 21544051 TI - Epidemiology: Parkinson disease and diabetes. PMID- 21544052 TI - Diabetes: Diabetes mellitus and periodontal disease in youth. PMID- 21544053 TI - Radiotherapy: avoiding EBRT for those without high-risk endometrial cancer. PMID- 21544054 TI - Targeted therapies: evolve and ... surrender! PMID- 21544055 TI - Targeted therapies: resistance-SRC in the middle. PMID- 21544057 TI - Neurogastroenterology: A role for enteric glial cells in mucosal healing. PMID- 21544058 TI - Viral hepatitis: HAVCR1 variants underlie susceptibility to liver failure in hepatitis A infection--an unlikely link with allergy. PMID- 21544059 TI - Viral hepatitis: Mechanism of fatigue in patients with chronic hepatitis C involves carnitine. PMID- 21544060 TI - Binding of factor H to tubular epithelial cells limits interstitial complement activation in ischemic injury. AB - Factor H is a regulator of the alternative pathway of complement, and genetic studies have shown that patients with mutations in factor H are at increased risk for several types of renal disease. Pathogenic activation of the alternative pathway in acquired diseases, such as ischemic acute kidney injury, suggests that native factor H has a limited capacity to control the alternative pathway in the kidney. Here we found that an absolute deficiency of factor H produced by gene deletion prevented complement activation on tubulointerstitial cells after ischemia/reperfusion (I/R) injury, likely because alternative pathway proteins were consumed in the fluid phase. In contrast, when fluid-phase regulation by factor H was maintained while the interaction of factor H with cell surfaces was blocked by a recombinant inhibitor protein, complement activation after renal I/R increased. Finally, a recombinant form of factor H, specifically targeted to sites of C3 deposition, reduced complement activation in the tubulointerstitium after ischemic injury. Thus, although factor H does not fully prevent activation of the alternative pathway of complement on ischemic tubules, its interaction with the tubule epithelial cell surface is critical for limiting complement activation and attenuating renal injury after ischemia. PMID- 21544061 TI - The inducible deletion of Drosha and microRNAs in mature podocytes results in a collapsing glomerulopathy. AB - Micro-RNAs (miRNAs) are short (average 22 nucleotides) noncoding regulatory RNAs that inhibit gene expression by targeting complementary 3'-untranslated regions of protein-encoding mRNAs for translational repression or degradation. miRNAs play key roles in both the function and differentiation of many cell types. Drosha and Dicer, two RNAase III enzymes, function in a stepwise manner to generate a mature miRNA. Previous studies have shown that podocyte-specific deletion of Dicer during development results in proteinuric renal disease and collapsing glomerulopathy (CG); however, Dicer has functions other than the generation of miRNAs. Here we found that the podocyte-specific deletion of Drosha results in a similar phenotype to Dicer mutants, confirming that the Dicer mutant phenotype is due to the loss of miRNAs. Moreover, the inducible deletion of Drosha in 2- to 3-month-old mice (Tet-On system) resulted in CG. Thus, continuous generation of miRNAs are required for the normal function of mature podocytes and their loss leads to CG. Identifying these miRNAs may provide new insight into disease pathogenesis and novel therapeutic targets in various podocytopathies. PMID- 21544062 TI - Validation of the Oxford classification of IgA nephropathy. AB - The Oxford classification of IgA nephropathy (IgAN) identified four pathological elements that were of prognostic value and additive to known clinical and laboratory variables in predicting patient outcome. These features are segmental glomerulosclerosis/adhesion, mesangial hypercellularity, endocapillary proliferation, and tubular atrophy/interstitial fibrosis. Here, we tested the Oxford results using an independent cohort of 187 adults and children with IgAN from 4 centers in North America by comparing the performance of the logistic regression model and the predictive value of each of the four lesions in both data sets. The cohorts had similar clinical and histological findings, presentations, and clinicopathological correlations. During follow-up, however, the North American cohort received more immunosuppressive and antihypertensive therapies. Identifying patients with a rapid decline in the rate of renal function using the logistic model from the original study in the validation data set was good (c-statistic 0.75), although less precise than in the original study (0.82). Individually, each pathological variable offered the same predictive value in both cohorts except mesangial hypercellularity, which was a weaker predictor. Thus, this North American cohort validated the Oxford IgAN classification and supports its utilization. Further studies are needed to determine the relationship to the impact of treatment and to define the value of the mesangial hypercellularity score. PMID- 21544063 TI - The green tea polyphenol (-)-epigallocatechin-3-gallate ameliorates experimental immune-mediated glomerulonephritis. AB - The unchecked overproduction of reactive oxygen and nitrogen species by inflammatory cells can cause tissue damage, intensify inflammation, promote apoptosis, and accelerate the progression of immune-mediated glomerulonephritis (GN). Here we tested whether the anti-inflammatory and antioxidant properties of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) favorably affect the development of immune-mediated GN. Pretreatment of 129/svJ mice with EGCG from 2 days before to 2 weeks after the induction of GN led to reduced proteinuria and serum creatinine, and marked improvement in renal histology when compared with vehicle-pretreated diseased mice. This pretreatment reduced oxidative stress, and normalized osteopontin, p65/nuclear factor-kappaB, inducible nitric oxide synthase, nitric oxide metabolites, p-Akt, phosphorylated extracellular signal-regulated kinases 1 and 2, p47phox, and myeloperoxidase, all of which were elevated in vehicle-pretreated diseased mice. Levels of glutathione peroxidase and peroxisome proliferator-activated receptor-gamma (PPARgamma), both reduced in the vehicle-pretreated diseased mice, were normalized. This renoprotective effect was reversed by concomitant administration of the PPARgamma antagonist GW9662 throughout the EGCG pretreatment period. Importantly, mortality and renal dysfunction were significantly attenuated even when the polyphenol treatment was initiated 1 week after the onset of GN. Thus, EGCG reversed the progression of immune-mediated GN in mice by targeting redox and inflammatory pathways. PMID- 21544065 TI - Proteomic identification of vanin-1 as a marker of kidney damage in a rat model of type 1 diabetic nephropathy. AB - At present, the urinary albumin excretion rate is the best noninvasive predictor for diabetic nephropathy (DN) but major limitations are associated with this marker. Here, we used in vivo perfusion technology to establish disease progression markers in an animal model of DN. Rats were perfused with a reactive ester derivative of biotin at various times after streptozotocin treatment. Following homogenization of kidney tissue and affinity purification of biotinylated proteins, a label-free mass spectrometry-based proteomic analysis of tryptic digests identified and relatively quantified 396 proteins. Of these proteins, 24 and 11 were found to be more than 10-fold up- or downregulated, respectively, compared with the same procedure in vehicle-treated rats. Changes in the expression of selected differentially regulated proteins were validated by immunofluorescence detection in kidney tissue from control and diabetic rats. Immunoblot analysis of pooled human urine found that concentrations of vanin-1, an ectoenzyme pantetheinase, distinguished diabetic patients with macroalbuminuria from those with normal albuminuria. Uromodulin was elevated in the urine pools of the diabetic patients, regardless of the degree of albuminuria, compared with healthy controls. Thus, in vivo biotinylation facilitates the detection of disease-specific changes in the abundance of potential biomarker proteins for disease monitoring and/or pharmacodelivery applications. PMID- 21544064 TI - Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. AB - Tolvaptan and related V(2)-specific vasopressin receptor antagonists have been shown to delay disease progression in animal models of polycystic kidney disease. Slight elevations in serum creatinine, rapidly reversible after drug cessation, have been found in clinical trials involving tolvaptan. Here, we sought to clarify the potential renal mechanisms to see whether the antagonist effects were dependent on underlying renal function in 20 patients with autosomal dominant polycystic kidney disease (ADPKD) before and after 1 week of daily split-dose treatment. Tolvaptan induced aquaresis (excretion of solute-free water) and a significant reduction in glomerular filtration rate (GFR). The serum uric acid increased because of a decreased uric acid clearance, and the serum potassium fell, but there was no significant change in renal blood flow as measured by para aminohippurate clearance or magnetic resonance imaging (MRI). No correlation was found between baseline GFR, measured by iothalmate clearance, and percent change in GFR induced by tolvaptan. Blinded post hoc analysis of renal MRIs showed that tolvaptan significantly reduced total kidney volume by 3.1% and individual cyst volume by 1.6%. Preliminary analysis of this small cohort suggested that these effects were more noticeable in patients with preserved renal function and with larger cysts. No correlation was found between changes of total kidney volume and body weight or estimated body water. Thus, functional and structural effects of tolvaptan on patients with ADPKD are likely due to inhibition of V(2)-driven adenosine cyclic 3',5'-monophosphate generation and its aquaretic, hemodynamic, and anti-secretory actions. PMID- 21544066 TI - Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy. AB - Abnormal kidney function is common in the course of human immunodeficiency virus (HIV) infection. Here, we performed a cross-sectional analysis using 399 patients within the Aquitaine cohort (a hospital-based cohort of HIV-1-infected patients receiving routine clinical management) to estimate the prevalence of proximal renal tubular dysfunction (PRTD) associated with HIV infection. These patients did not differ statistically by sociodemographics, median age, years since HIV diagnosis, AIDS stage, or median CD4 cell count from the entire 3080 patient cohort. Antiretroviral therapy was received by 352 patients, with 256 given tenofovir (TDF); 325 had undetectable HIV plasma viral load, and 26 were diagnosed with PRTD. In multivariate analysis, significant independent associations were found between PRTD and age (odds ratio (OR) 1.28 per 5-year increase), atazanavir (OR 1.28 per year of exposure), and TDF (OR 1.23 per year) treatment. Among patients having received TDF-containing regimens over a 5-year period, PRTD remained significantly associated with TDF exposure when treatment was ongoing (OR 5.22) or had been discontinued (OR 11.49). Thus, cumulative exposure to TDF and/or atazanavir was associated with an increased risk of PRTD, with concern about its reversibility in patients with HIV. PMID- 21544067 TI - The involvement of Cdk5 activator p35 in social isolation-triggered onset of early Alzheimer's disease-related cognitive deficit in the transgenic mice. AB - Epidemiological studies indicate that isolated persons have increased risk of developing Alzheimer's disease (AD). This study investigated the cellular mechanisms of how social isolation influenced amyloid beta peptide (Abeta) accumulation and affected the severity of AD-associated cognitive decline in a mouse model of AD. Amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic (APP/PS1) mice were placed either in isolation or in group from postnatal day 28 and tested for cognitive performance at the age of 3 months with fear-conditioning paradigms. We found that social isolation accelerated impairment of contextual fear memory in the APP/PS1 mice. The magnitude of long term potentiation in the hippocampal CA1 neurons was significantly lower in the isolated APP/PS1 mice compared with group APP/PS1 and wild-type mice. Hippocampal level of Abeta was significantly elevated in the isolated APP/PS1 mice, which was accompanied by an increased calpain activity and p25/p35 ratio. In addition, surface expression of GluR1 subunit of AMPA receptor was decreased by social isolation. The association of p35, and alpha-CaMKII was significantly less in the isolated APP/PS1 mice indicating that their interaction was impaired. These results suggest that social isolation exacerbates memory deficit by increasing Abeta level, leading to the increased calpain activity, conversion of p35 to p25 and decrease in association of p35, alpha-CaMKII, and GluR1, resulting in the endocytosis of AMPA receptors. PMID- 21544068 TI - Hippocampal leptin signaling reduces food intake and modulates food-related memory processing. AB - The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 MUg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 MUg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing. PMID- 21544069 TI - Inhibition of beta-adrenergic receptors induces a persistent deficit in retrieval of a cocaine-associated memory providing protection against reinstatement. AB - Drug-seeking behavior is maintained by encounters with drug-associated cues. Preventing retrieval of drug-associated memories that these cues provoke would therefore limit relapse susceptibility; however, little is known regarding the mechanisms of retrieval. Here, we show that beta-adrenergic receptor activation is necessary for the retrieval of a cocaine-associated memory. Using a conditioned place preference (CPP) procedure, rats were conditioned to associate one chamber, but not another, with cocaine. When administered before a CPP trial, propranolol, but not saline, prevented retrieval of a cocaine-associated CPP. In subsequent drug-free trials, rats previously treated with propranolol continued to show a retrieval deficit, as no CPP was evident. This retrieval deficit was long lasting and robust, as the CPP did not re-emerge during a test for spontaneous recovery 14 days later or reinstate following a priming injection of cocaine. Moreover, the peripheral beta-adrenergic receptor antagonist sotalol did not affect retrieval. Thus, retrieval of cocaine-associated memories is mediated by norepinephrine acting at central beta-adrenergic receptors. Our findings support the use of propranolol, a commonly prescribed beta-blocker, as an adjunct to exposure therapy for the treatment of addiction by preventing retrieval of drug-associated memories during and long after treatment, and by providing protection against relapse. PMID- 21544070 TI - Neuromodulatory neurotransmitters influence LTP-like plasticity in human cortex: a pharmaco-TMS study. AB - Long-term potentiation (LTP) of synaptic efficacy is considered a fundamental mechanism of learning and memory. At the cellular level a large body of evidence demonstrated that the major neuromodulatory neurotransmitters dopamine (DA), norepinephrine (NE), and acetylcholine (ACh) influence LTP magnitude. Noninvasive brain stimulation protocols provide the opportunity to study LTP-like plasticity at the systems level of human cortex. Here we applied paired associative stimulation (PAS) to induce LTP-like plasticity in the primary motor cortex of eight healthy subjects. In a double-blind, randomized, placebo-controlled, crossover design, the acute effects of a single oral dose of the neuromodulatory drugs cabergoline (DA agonist), haloperidol (DA antagonist), methylphenidate (indirect NE agonist), prazosine (NE antagonist), tacrine (ACh agonist), and biperiden (ACh antagonist) on PAS-induced LTP-like plasticity were examined. The antagonists haloperidol, prazosine, and biperiden depressed significantly the PAS induced LTP-like plasticity observed under placebo, whereas the agonists cabergoline, methylphenidate, and tacrine had no effect. Findings demonstrate that antagonists in major neuromodulatory neurotransmitter systems suppress LTP like plasticity at the systems level of human cortex, in accord with evidence of their modulating action of LTP at the cellular level. This provides further supportive evidence for the known detrimental effects of these drugs on LTP dependent mechanisms such as learning and memory. PMID- 21544071 TI - Neural correlates of antidepressant-related sexual dysfunction: a placebo controlled fMRI study on healthy males under subchronic paroxetine and bupropion. AB - Sexual dysfunction is a common side effect of selective serotonin reuptake inhibitors (SSRIs) like paroxetine in the treatment of depression, imposing a considerable risk on medication adherence and hence therapeutic success. Bupropion, a norepinephrine and dopamine reuptake inhibitor, is recommended as an alternative treatment without adverse effects concerning sexual arousal and libido. We investigated the neural bases of paroxetine-related subjective sexual dysfunction when compared with bupropion and placebo. We scanned 18 healthy, heterosexual males in a randomized, double-blind, within-subject design while watching video clips of erotic and nonerotic content under steady-state conditions after taking 20 mg of paroxetine, 150 mg of bupropion, and placebo for 7 days each. Under paroxetine, ratings of subjective sexual dysfunction increased compared with placebo or bupropion. Activation along the anterior cingulate cortex (ACC), including subgenual, pregenual, and midcingulate cortices, in the ventral striatum and midbrain was decreased when compared with placebo. In contrast, bupropion let subjective ratings and ACC activations unchanged and increased activity of brain regions including posterior midcingulate cortex, mediodorsal thalamus, and extended amygdala relative to placebo and paroxetine. Brain regions that have been related to the processing of motivational (ventral striatum), emotional, and autonomic components of erotic stimulation (anterior cingulate) in previous studies showed reduced responsiveness under paroxetine in our study. Drug effects on these regions may be part of the mechanism underlying SSRI-related sexual dysfunction. Increased activation under bupropion may point to an opposite effect that may relate to the lack of impaired sexual functioning. PMID- 21544072 TI - The effects of nicotine replacement on cognitive brain activity during smoking withdrawal studied with simultaneous fMRI/EEG. AB - Impaired attention ('difficulty concentrating') is a cognitive symptom of nicotine withdrawal that may be an important contributor to smoking relapse. However, the neurobiological basis of this effect and the potentially beneficial effects of nicotine replacement therapy both remain unclear. We used functional MRI with simultaneous electroencephalogram (EEG) recording to define brain activity correlates of cognitive impairment with short-term smoking cessation in habitual smokers and the effects of nicotine replacement. We found that irrespective of treatment (ie nicotine or placebo) EEG alpha power was negatively correlated with increased activation during performance of a rapid visual information processing (RVIP) task in dorsolateral prefrontal, dorsal anterior cingulate, parietal, and insular cortices, as well as, caudate, and thalamus. Relative to placebo, nicotine replacement further increased the alpha-correlated activation across these regions. We also found that EEG alpha power was negatively correlated with RVIP-induced deactivation in regions comprising the 'default mode' network (ie angular gyrus, cuneus, precuneus, posterior cingulate, and ventromedial prefrontal cortex). These alpha-correlated deactivations were further reduced by nicotine. These findings confirm that effects of nicotine on cognition during short-term smoking cessation occur with modulation of neuronal sources common to the generation of both the blood oxygen-level-dependent and alpha EEG signals. Our observations thus demonstrate that nicotine replacement in smokers has direct pharmacological effects on brain neuronal activity modulating cognitive networks. PMID- 21544073 TI - The tale of TL1A in inflammation. AB - TL1A (also known as TNFSF15) is a tumor necrosis factor (TNF) family member expressed by monocytes, macrophages, dendritic cells (DCs), synovial fibroblasts, and endothelial cells in response to stimulation by cytokines, immune complexes, and microorganisms. Its cell surface receptor, DR3 (also known as TNFSF25, WSL-1, TRAMP, and LARD), is mainly expressed by T cells. PMID- 21544074 TI - A randomized study of the efficacy and safety of intravenous acetaminophen vs. intravenous placebo for the treatment of fever. AB - This randomized, double-blind, placebo-controlled study evaluated the antipyretic effect and safety of intravenous (i.v.) acetaminophen using an endotoxin-induced fever model. Subjects exhibiting sufficient fever response following administration of reference standard endotoxin (RSE) were randomly assigned to receive i.v. acetaminophen 1,000 mg (n = 31) or matching placebo (n = 29). The primary efficacy end point was the weighted sum of temperature differences from baseline through 6 h. Relative to placebo, i.v. acetaminophen administration produced a rapid decrease in temperature that persisted throughout the 6-h study period. The primary end point favored i.v. acetaminophen over placebo (P < 0.001). Temperature differences from baseline reached statistical significance at T30 min after endotoxin administration (15 min after completing the study medication infusion). Acetaminophen administered i.v. was well tolerated, and the frequency of adverse events was comparable to that after administration of i.v. placebo. This study shows that i.v. acetaminophen in a single 1,000-mg dose is safe and effective in reducing fever. PMID- 21544076 TI - Emerging technologies for improving phytochemical bioavailability: benefits and risks. PMID- 21544075 TI - Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study. AB - Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity. PMID- 21544077 TI - Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. AB - A microdose study of metformin was conducted to investigate the predictability of drug-drug interactions at the therapeutic dose (ThD). Healthy subjects received a microdose (100 ug) or ThD (250 mg) of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50 mg, p.o.), in a crossover fashion. Pyrimethamine significantly reduced the renal clearance of metformin by 23 and 35% at the microdose and ThD, respectively. At ThD, but not at microdose, it caused significant increases in the maximum concentration (C(max)) and area under the plasma concentration-time curve (AUC) of metformin (142 and 139% of control values, respectively). Human canalicular membrane vesicles showed pyrimethamine-inhibitable metformin uptake. Pyrimethamine did not affect plasma lactate/pyruvate after ThD of metformin but significantly reduced the renal clearance of creatinine, thereby causing elevation of plasma creatinine level. This microdose study quantitatively predicted a drug-drug interaction involving the renal clearance of metformin at ThD by pyrimethamine. Pyrimethamine is a useful in vivo inhibitor of MATE proteins. PMID- 21544078 TI - A phase I study evaluating tolerability, pharmacokinetics, and preliminary efficacy of L-menthol in upper gastrointestinal endoscopy. AB - Peppermint oil has been shown to relax gastrointestinal smooth muscle. In this randomized, placebo-controlled study, an L-menthol preparation, NPO-11, was assessed for tolerability and pharmacokinetics (PK) during gastrointestinal endoscopy. Single doses of NPO-11, as high as 320 mg, were well tolerated. NPO-11 was rapidly absorbed, with peak concentrations reached within 1 h after administration. Approximately 70% of the administered L-menthol and its metabolites were excreted in the urine, and this amount fluctuated with no change in the dose. The principal metabolite identified in plasma and urine was menthol glucuronide. The other metabolites include mono- or di-hydroxylated menthol derivatives, most of which are excreted, in part, as glucuronic acid conjugates. The pharmacokinetic data indicated that when NPO-11 is sprayed directly onto the gastric mucosa, it is rapidly metabolized to glucuronic acid conjugates that are excreted in urine. The findings from this study provide new data on the safety and PK of NPO-11 and support further trials. PMID- 21544080 TI - Pharmacokinetics of colistin and colistimethate sodium after a single 80-mg intravenous dose of CMS in young healthy volunteers. AB - Colistin pharmacokinetics (PK) was investigated in young healthy volunteers after a 1-h infusion of 80 mg (1 million international units (MIU)) of the prodrug colistin methanesulfonate (CMS). Concentration levels of CMS and colistin were determined in plasma and urine using a new chromatographic assay and analyzed simultaneously with a population approach after correcting the urine-related data for postexcretion hydrolysis of CMS into colistin. CMS and colistin have low volumes of distribution (14.0 and 12.4 liters, respectively), consistent with distribution being restricted to extracellular fluid. CMS is mainly excreted unchanged in urine (70% on average), with a typical renal clearance estimated at 103 ml/min-close to the glomerular filtration rate. Colistin elimination is essentially extrarenal, given that its renal clearance is 1.9 ml/min, consistent with extensive reabsorption. Colistin elimination is not limited by the formation rate because its half-life (3 h) is longer than that of CMS. The values of these pharmacokinetic parameters will serve as reference points for future comparisons with patients' data. PMID- 21544079 TI - Case definition and phenotype standardization in drug-induced liver injury. AB - Drug-induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH). PMID- 21544081 TI - Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations. AB - OBJECTIVE: Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among European populations. However, their contribution to obesity in other ethnicities is largely unknown. METHODS: We utilised five GWAS (N=10 482) from Chinese (three cohorts, including one with type 2 diabetes and another one of children), Malay and Indian ethnic groups from Singapore. Data sets were analysed individually and subsequently in combined meta-analysis for Z score body-mass index (BMI) associations. RESULTS: Variants at the FTO locus showed the strongest associations with BMI Z-score after meta-analysis (P-values 1.16 * 10(-7)-7.95 * 10(-7)). We further detected associations with nine other index obesity variants close to the MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B and TNKS/MSRA loci (meta-analysis P-values ranging from 3.58 * 10(-4)-1.44 * 10(-2)). Three other single-nucleotide polymorphisms (SNPs) from CADM2, PTBP2 and FAIM2 were associated with BMI (P-value <= 0.0418) in at least one dataset. The neurotrophin/TRK pathway (P-value=0.029) was highlighted by pathway-based analysis of loci that had statistically significant associations among Singaporean populations. CONCLUSION: Our data confirm the role of FTO in obesity predisposition among Chinese, Malays and Indians, the three major Asian ethnic groups. We additionally detected associations for 12 obesity-associated SNPs among Singaporeans. Thus, it is likely that Europeans and Asians share some of the genetic predisposition to obesity. Furthermore, the neurotrophin/TRK signalling may have a central role for common obesity among Asians. PMID- 21544082 TI - Effects of diet-induced obesity on colitis-associated colon tumor formation in A/J mice. AB - OBJECTIVE: Studies have indicated that obesity is associated with a higher risk of colorectal cancer. This study was performed to determine the effect of diet induced obesity on the formation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumors and to identify adiposity-related mechanisms. METHODS: Male A/J mice were placed on either a high-fat diet (HFD; 45% of total calories from fat) or a normal diet (ND; 15% of calories from fat) for 12 weeks. To induce colon tumors, AOM was administered at a dose of 10 mg/kg body weight, followed by two cycles of DSS supply. RESULTS: Study results indicated that the HFD group had twofold higher numbers of colonic tumors, as compared with the ND group. The HFD group also had significantly increased body weight and epididymal fat weight, which were associated with increases of serum insulin, insulin-like growth factor 1, leptin, epididymal fat pad leptin mRNA and colonic leptin receptor (Ob-R) mRNA. Animals on HFD showed higher expressions of Ob-R, insulin receptor, phosphorylated Akt, phosphorylated extracellular signal-regulated kinases, Bcl-xL and Cyclin D1 proteins in the colon. CONCLUSION: The results suggest that HFD induced obesity facilitates colon tumor formation, possibly by regulating downstream targets of circulating adiposity-related factors via receptor-mediated signaling of the phosphatidylinositol 3-kinase/Akt pathway. PMID- 21544084 TI - Effects of repeated dosing with Udenafil (Zydena) on cognition, somatization and erection in patients with erectile dysfunction: a pilot study. AB - The PDE5 inhibitors have recently been found to have cognitive-enhancing effects in animal models. To investigate the efficacy of repeated dosing with a PDE5 inhibitor on cognitive function and somatization in patients with erectile dysfunction, 27 patients with erectile dysfunction received udenafil (100 mg) at 3-day intervals for 2 months. The international index of erectile function-5 (IIEF-5), a cognitive battery (the Korean version of mini-mental state examination (K-MMSE), the frontal assessment battery (K-FAB), the Seoul verbal learning test) and a physical health questionnaire-15 (PHQ-15) were performed at baseline and at 2 months, following the administration of udenafil. The patients were divided on the basis of their IIEF-5 score into responders (change>7) and non-responders. The mean IIEF-5 score was significantly increased after treatment (7.92 +/- 3.83 to 16.33 +/- 4.75, P<0.001). The scores of K-MMSE (27.03 +/- 1.58 to 28.07 +/- 1.57, P=0.001), K-FAB (13.65 +/- 1.96 to 15.41 +/- 1.85, P<0.001) and PHQ-15 (18.92 +/- 4.96 to 17.63 +/- 4.75, P=0.003) were significantly improved after treatment. In addition, the responders (n=16) had more improved cognitive function (r=0.603, P=0.001) and somatization (r=-0.402, P=0.038) than non-responders (n=11). Repeated dosing with a PDE5 inhibitor seems to improve cognitive function and somatization, as well as erectile function in patients with erectile dysfunction. PMID- 21544083 TI - Four novel UCP3 gene variants associated with childhood obesity: effect on fatty acid oxidation and on prevention of triglyceride storage. AB - OBJECTIVE: The objective of the study was to look for uncoupling protein 3 (UCP3) gene variants in early-onset severe childhood obesity and to determine their effect on long-chain fatty acid oxidation and triglyceride storage. METHODS AND RESULTS: We identified four novel mutations in the UCP3 gene (V56M, A111V, V192I and Q252X) in 200 children with severe, early-onset obesity (body mass index standard deviation score >2.5; onset: <4 years) living in Southern Italy. We evaluated the role of wild-type (wt) and mutant UCP3 proteins in palmitate oxidation and in triglyceride storage in human embryonic kidney cells (HEK293). Palmitate oxidation was ~60% lower (P<0.05; P<0.01) and triglyceride storage was higher in HEK293 cells expressing the four UCP3 mutants than in cells expressing wt UCP3. Moreover, mutants V56M and Q252X exerted a dominant-negative effect on wt protein activity (P<0.01 and P<0.05, respectively). Telmisartan, an angiotensin II receptor antagonist used in the management of hypertension, significantly (P<0.05) increased palmitate oxidation in HEK293 cells expressing wt and mutant proteins (P<0.05; P<0.01), including the dominant-negative mutants. CONCLUSIONS: These data indicate that protein UCP3 affects long-chain fatty acid metabolism and can prevent cytosolic triglyceride storage. Our results also suggest that telmisartan, which increases fatty acid oxidation in rat skeletal muscle, also improves UCP3 wt and mutant protein activity, including the dominant negative UCP3 mutants. PMID- 21544085 TI - Assessment of arterial stiffness from ambulatory blood pressure monitoring in children with diabetes mellitus type-1 (DMT1). AB - Pulse pressure (PP) and ambulatory arterial stiffness index (AASI) can be calculated from ambulatory blood pressure (BP) monitoring (ABPM) and have been suggested as markers of arterial stiffness and predictors of cardiovascular mortality. We retrospectively evaluated PP and AASI from ABPM records in 84 children (43 boys) with diabetes mellitus type-1 (DMT1) compared with 27 non diabetic normotensive children. Based on office BP and ABPM, patients with DMT1 were divided into three groups: 24/84 (29%) had hypertension (DM HTN), 33/84 (39%) were normotensive (DM NT) and 27/84 (32%) had white-coat hypertension (DM WCH). DM WCH and DM HTN patients had significantly higher PP when compared with DM NT and NT patients alone (47.62 +/- 7.31 and 47.43 +/- 8.68 versus 41.45 +/- 4.44 and 42.18 +/- 5.97, respectively, P=0.0002). Similarly, AASI was significantly elevated in both DM WCH and DM HTN patients when compared with NT patients (0.35 +/- 0.14 and 0.36 +/- 0.15 versus 0.23 +/- 0.15, respectively, P=0.007). In conclusion, children with DMT1 and hypertension, including WCH, had significantly higher PP and AASI levels when compared with normotensive patients. This suggests that these children may be at an increased risk for developing cardiovascular complications later on in life. PMID- 21544086 TI - G-protein-coupled receptor kinase 4 polymorphisms predict blood pressure response to dietary modification in Black patients with mild-to-moderate hypertension. AB - Dopamine via G-protein-coupled receptor kinase 4 (GRK-4) regulates sodium (Na) balance in the proximal tubule of the kidney. Single-nucleotide polymorphisms of GRK-4 have been linked to impaired natriuresis and salt-sensitive hypertension. The purpose of this report was to determine the effect of GRK-4 gene polymorphisms on the blood pressure (BP) responses to dietary intervention. Black subjects aged 50-75 years with mild-to-moderate hypertension were randomised to an 8-week dietary intervention (n=40) or standard diet (n=40). BP was measured at baseline and at 8 weeks using 24-h ambulatory BP. All subjects underwent DNA analysis for the R65L and A142V polymorphisms. Data were analysed using generalised linear models. For the whole group, between-diet differences in mean 24-h ambulatory systolic BP was -4.53 mm Hg (95% confidence interval -9.05 to 0.01, P=0.05). In the intervention arm, the combined CC and CT group of the A142V showed a significant reduction in both systolic and diastolic ambulatory BP (-10 mm Hg, P=0.023 and -6.5 mm Hg, P=0.01, respectively), whereas the TT group demonstrated no reduction. Similarly, the combined GG and GT groups of the R65L showed a significant reduction in ambulatory BP (-10.6 mm Hg for systolic, P=0.004 and 5.8 mm Hg for diastolic, P=0.006). There was no response in the TT group. GRK-4 polymorphisms predict BP response to dietary modification in Black subjects with mild-to-moderate hypertension. These data may provide at least one among a range of clinical tools to target selected hypertensives to dietary intervention. PMID- 21544087 TI - Effects of anthocyanins on blood pressure and stress reactivity: a double-blind randomized placebo-controlled crossover study. AB - High intakes of flavonoids are associated with reduced cardiovascular risk, and flavonoids such as cocoa and soy protein isolate have shown beneficial effects on blood pressure (BP). Anthocyanins constitute a flavonoid subgroup consumed in regular diets, but few studies have assessed the antihypertensive potential of anthocyanins. We aimed to assess whether high concentrations of relatively pure anthocyanins reduce BP and alter cardiovascular and catecholamine reactivity to stress. A total of 31 healthy men between 35-51 years of age with screening BP >140/90 mm Hg, not on antihypertensive or lipid-lowering medication, were randomised in a double-blind crossover study to placebo versus 320-mg anthoycanins twice daily. Treatment duration was 4 weeks, with a 4-week washout. Sitting and supine BP measurements, ambulatory BP recording and stress reactivity were assessed and analyzed by a paired sample t-test. In all, 27 patients completed all visits. Sitting systolic BP (primary endpoint) was 133 mm Hg after placebo versus 135 mm Hg after anthocyanin treatment (P=0.25). Anthocyanins did neither affect semiautomatic oscillometric BP measurements in the sitting or supine position nor 24-h ambulatory BP. No significant differences in stress reactivity were found across treatment periods. Overall, we conclude that high concentrations of these relatively pure anthocyanins do not reduce BP in healthy men with a high normal BP. PMID- 21544088 TI - Behavioural and psychosocial correlates of nondipping blood pressure pattern among middle-aged men and women at work. AB - The underlying pathogenetic mechanisms of nondipping blood pressure (BP) pattern are not completely understood. Especially the role of psychosocial correlates remains unclear. The aim was to assess the association between nondipping BP pattern, behavioural and psychosocial factors in a sample of working men and women. The study sample included 167 working men and women aged 40-64 years from the BELSTRESS cohort. Socio-demographic, behavioural and psychosocial factors were assessed by self-administered questionnaires. Participants were medically examined and underwent an ambulatory BP monitoring during 24 h. Nondipping was defined when the average nocturnal decline in BP was <10%. The prevalence of nondipping for both systolic and diastolic BP was 7.8%. Nondipping was not significantly related to smoking, alcohol consumption and leisure time physical activity. A crude significant association was observed between nondipping and sleep problems. After adjusting for gender, education and body mass index, the risk for nondipping was associated with job strain, living alone, being unsatisfied about the contact with one's children, depressive symptoms and vital exhaustion. Nondipping BP pattern was consistently related to psychosocial factors in this study: positive associations were observed with measures of job strain, poor private life support (living alone and being unsatisfied about the contact with one's children) and mental health problems (depressive symptoms and vital exhaustion). PMID- 21544089 TI - Cardiovascular risk in subjects with left ventricular concentric remodeling: does meta-analysis help reconcile inconsistent findings? PMID- 21544090 TI - Non-dipping pattern relates to endothelial dysfunction in patients with uncontrolled resistant hypertension. AB - Resistant hypertension (RHTN) includes both patients whose blood pressure (BP) is uncontrolled on three or more medications (uncontrolled RHTN (UCRH)) and patients whose BP is controlled with use of four or more drugs (controlled RHTN (CRH)). It is unknown whether endothelial function and nocturnal drop demonstrate a similar pattern in patients with CRH and UCRH. We examined circadian BP patterns and vascular function in these patients. In all, 40 CRH and 26 UCRH patients, and 25 normotensives underwent biochemical testing, ambulatory BP monitoring, determination of brachial artery responses to endothelial-dependent (flow mediated; dilation (FMD)) and independent (nitroglycerin mediated) stimuli. The nighttime drop in systolic BP (SBP) and diastolic BP (DBP) was less pronounced in UCRH than in CRH (SBP, 1.9+/-1.6 versus 4.9+/-1.7%; DBP, 7.5+/-1.8 versus 10.9+/ 1.8%, UCRH and CRH, respectively; P<0.05). FMD was greater in control group compared with RHTN patients. Patients with UCRH had significantly impaired FMD compared with CRH (5.9+/-2.3% versus 7.1+/-5.1%; P<0.0001). Therefore, UCRH patients have less nocturnal dipping and a more impaired endothelial response compared with CRH patients. These findings suggest that important differences among patients with RHTN may allow identify subgroups with increased cardiovascular risk. PMID- 21544092 TI - Isthmin exerts pro-survival and death-promoting effect on endothelial cells through alphavbeta5 integrin depending on its physical state. AB - Isthmin (ISM) is a 60 kDa secreted-angiogenesis inhibitor that suppresses tumor growth in mouse and disrupts vessel patterning in zebrafish embryos. It selectively binds to alphavbeta5 (alphavbeta5) integrin on the surface of endothelial cells (ECs), but the mechanism of its antiangiogenic action remains unknown. In this work, we establish that soluble ISM suppresses in vitro angiogenesis and induces EC apoptosis by interacting with its cell surface receptor alphavbeta5 integrin through a novel 'RKD' motif localized within its adhesion-associated domain in MUC4 and other proteins domain. ISM induces EC apoptosis through integrin-mediated death (IMD) by direct recruitment and activation of caspase-8 without causing anoikis. On the other hand, immobilized ISM loses its antiangiogenic function and instead promotes EC adhesion, survival and migration through alphavbeta5 integrin by activating focal adhesion kinase (FAK). ISM unexpectedly has both a pro-survival and death-promoting effect on ECs depending on its physical state. This dual function of a single antiangiogenic protein may impact its antiangiogenic efficacy in vivo. PMID- 21544091 TI - Spatiotemporal firing patterns in the cerebellum. AB - Neurons are generally considered to communicate information by increasing or decreasing their firing rate. However, in principle, they could in addition convey messages by using specific spatiotemporal patterns of spiking activities and silent intervals. Here, we review expanding lines of evidence that such spatiotemporal coding occurs in the cerebellum, and that the olivocerebellar system is optimally designed to generate and employ precise patterns of complex spikes and simple spikes during the acquisition and consolidation of motor skills. These spatiotemporal patterns may complement rate coding, thus enabling precise control of motor and cognitive processing at a high spatiotemporal resolution by fine-tuning sensorimotor integration and coordination. PMID- 21544094 TI - Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1. AB - Oncolytic viruses have been combined with standard cancer therapies to increase therapeutic efficacy. Given the sequential activation of herpes viral genes (herpes simplex virus-1, HSV-1) and the temporal cellular changes induced by ionizing radiation, we hypothesized an optimal temporal sequence existed in combining oncolytic HSV-1 with ionizing radiation. Murine U-87 glioma xenografts were injected with luciferase encoding HSV-1, and ionizing radiation (IR) was given at times before or after viral injection. HSV-1 replication and tumor volume response were followed. Radiation given 6-9 h after HSV-1 injection resulted in maximal viral luciferase expression and infectious viral production in tumor xenografts. The greatest xenograft regression was also seen with radiation given 6 h after viral injection. We then tested if HSV-1 replication had a dose response to ionizing radiation. HSV-1 luciferase expression exhibited a dose response as xenografts were irradiated from 0 to 5 Gy. There was no difference in viral luciferase expression as IR dose increased from 5 Gy up to 20 Gy. These results suggest that the interaction of IR with the HSV-1 lytic cycle can be manipulated for therapeutic gain by delivering IR at a specific time within viral replicative cycle. PMID- 21544093 TI - The clinical efficacy of L-DOPA and STN-DBS share a common marker: reduced GABA content in the motor thalamus. AB - At odd with traditional views, effective sub-thalamic nucleus (STN) deep brain stimulation (DBS), in Parkinson's disease (PD) patients, may increase the discharge rate of the substantia nigra pars reticulata and the internal globus pallidus (GPi), in combination with increased cyclic guanosine monophosphate (cGMP) levels. How these changes affect the basal ganglia (BG) output to the motor thalamus, the crucial structure conveying motor information to cortex, is critical. Here, we determined the extracellular GABA concentration in the ventral anterior nucleus (VA) during the first delivery of STN-DBS (n=10) or following levodopa (LD) (n=8). Both DBS and subdyskinetic LD reversibly reduced (-30%) VA GABA levels. A significant correlation occurred between clinical score and GABA concentration. By contrast, only STN-DBS increased GPi cGMP levels. Hence, STN-ON and MED-ON involve partially different action mechanisms but share a common target in the VA. These findings suggest that the standard BG circuitry, in PD, needs revision as relief from akinesia may take place, during DBS, even in absence of reduced GPi excitability. However, clinical amelioration requires fast change of thalamic GABA, confirming, in line with the old model, that VA is the core player in determining thalamo-cortical transmission. PMID- 21544095 TI - Lineage- and stage-restricted lentiviral vectors for the gene therapy of chronic granulomatous disease. AB - Insertional mutagenesis represents a serious adverse effect of gene therapy with integrating vectors. However, although uncontrolled activation of growth promoting genes in stem cells can predictably lead to oncological processes, this is far less likely if vector transcriptional activity can be restricted to fully differentiated cells. Diseases requiring phenotypic correction only in mature cells offer such an opportunity, provided that lineage/stage-restricted systems can be properly tailored. In this study, we followed this reasoning to design lentiviral vectors for the gene therapy of chronic granulomatous disease (CGD), an immune deficiency due a loss of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes, most often secondary to mutations in gp91(phox). Using self-inactivating HIV1-derived vectors as background, we first expressed enhanced green fluorescent protein (eGFP) from a minimal gp91(phox) promoter, adding various natural or synthetic transcriptional regulatory elements to foster both specificity and potency. The resulting vectors were assessed either by transplantation or by lentiviral transgenesis, searching for combinations conferring strong and specific expression into mature phagocytic cells. The most promising vector was modified to express gp91(phox) and used to treat CGD mice. High-level restoration of NADPH activity was documented in granulocytes from the treated animals. We propose that this lineage-specific lentiviral vector is a suitable candidate for the gene therapy of CGD. PMID- 21544097 TI - Optimal conditions for lentiviral transduction of engrafting human CD34+ cells. AB - Cytokines are required for gamma-retroviral transduction of human CD34+ cells. However, cytokines may reduce engraftment of CD34+ cells and may not be necessary for their lentiviral transduction. We sought to optimize transduction and engraftment of human CD34+ cells using lentiviral vectors. Single 24 h transduction of human CD34+ cells with human immunodeficiency virus type 1 (HIV1) based lentiviral vectors in media containing stem cell factor (SCF), FMS-like tyrosine kinase 3 (FLT3) ligand, thrombopoietin (each 100 ng ml-1) and 10% fetal bovine serum was compared with various cytokine conditions during ex vivo culture and assayed using humanized xenograft mice for 6 months after transplantation. Serum-free media improved transduction efficiency of human CD34+ cells. Interleukin-3 (20 ng ml-1) had little effect on transduction efficiency or engraftment. Threefold higher cytokine mixture (each 300 ng ml-1) reduced engraftment of CD34+ cells. SCF alone (100 ng ml-1) proved insufficient for maintaining engraftment ability and reduced transduction efficiency. Short-term prestimulation had little effect on transduction efficiency or engraftment, yet 24 h prestimulation showed higher transduction efficiency, higher gene expression levels and lower engraftment. In summary, 24 h prestimulation followed by single 24-h lentiviral transduction in serum-free media with SCF, FLT3 ligand and thrombopoietin yields high transduction efficiency to engrafting human CD34+ cells, and is applicable in human clinical gene therapy trials. PMID- 21544096 TI - Molecular adjuvant HMGB1 enhances anti-influenza immunity during DNA vaccination. AB - DNA-based vaccines, while highly immunogenic in mice, generate significantly weaker responses in primates. Therefore, current efforts are aimed at increasing their immunogenicity, which include optimizing the plasmid/gene, the vaccine formulation and method of delivery. For example, co-immunization with molecular adjuvants encoding an immunomodulatory protein has been shown to improve the antigen (Ag)-specific immune response. Thus, the incorporation of enhancing elements, such as these, may be particularly important in the influenza model in which high titered antibody (Ab) responses are critical for protection. In this regard, we compared the ability of plasmid-encoded high-mobility group box 1 protein (HMGB1), a novel cytokine in which we have previously mutated in order to increase DNA vaccine immunogenicity, with boost Ag-specific immune responses during DNA vaccination with influenza A/PR/8/34 nucleoprotein or the hemagglutinin of A novel H1N1/09. We show that the HMGB1 adjuvant is capable of enhancing adaptive effector and memory immune responses. Although Ag-specific antibodies were detected in all vaccinated animals, a greater neutralizing Ab response was associated with the HMGB1 adjuvant. Furthermore, these responses improved CD8 T+-cell effector and memory responses and provided protection against a lethal mucosal influenza A/PR/8/34 challenge. Thus, co-immunization with HMGB1 has strong in vivo adjuvant activity during the development of immunity against plasmid-encoded Ag. PMID- 21544098 TI - Serum amyloid P component facilitates DNA clearance and inhibits plasmid transfection: implications for human DNA vaccine. AB - The demonstration that naked plasmid DNA can induce strong immune responses in mice has attracted considerable attention in the vaccine community. However, similar immunizations have been less/not effective in clinical trials during the past decade, and the underlying mechanisms remain unknown. In this study, we hypothesized that some DNA-binding proteins in human serum may serve as host barriers, responsible for the low efficiency of plasmids' transfection in vivo. Using proteomics, we showed that human serum amyloid P component (hSAP) is specifically present in human DNA-protein complexes. Further analysis indicated that hSAP effectively binds plasmid DNA, inhibits DNA transfection into somatic cells and facilitates the endocytosis of DNA by macrophages, whereas mouse SAP (mSAP) has similar, but much weaker, activities. In the presence of hSAP, the plasmid DNA expression in vivo and plasmid DNA-induced immune responses also significantly decreased. Therefore, our results suggest that hSAP contributes to extracellular DNA clearance and the inhibition of plasmid DNA transfection in vivo. This mechanism may be partly responsible for the insufficient immune responses to DNA vaccination in human beings; therefore, it may serve as a novel target for the improvement of DNA vaccines and DNA-based gene therapy. PMID- 21544099 TI - Cholera, canals, and contagion: Rediscovering Dr. Beck's report. AB - Cholera first appeared in North America (in Montreal and Quebec) in 1832 and spread rapidly across the eastern half of the continent. The dispatch of American disease control experts to Lower Canada in anticipation of cholera's spread implies that medical professionals expected spread, possibly from contagion, even though the notion that cholera was contagious was disparaged in medical writings of the time, and would be until John Snow's landmark work in London in the 1850s. Snow's insights derived largely from his observations on spatial and temporal patterns of cholera cases. We discuss a document from the 1832 epidemic, the report of Dr. Lewis Beck to New York's Governor Throop, which anticipates Snow in presenting geospatial data that imply cholera's contagiousness. Beck shows that the movements of immigrants along the newly completed New York state canal system resulted in sequential cholera outbreaks along the canal's path. Although aware of the degree to which this suggested contagion, Beck argues strenuously against the contagiousness of cholera. We explore the social context of early nineteenth century medicine that probably led Beck to disbelieve his own observations, and to favor a medical model inconsistent with his data. Themes that emerge from our inquiry include belief in disease as a physical manifestation of defective morality, stigmatization of the poor and immigrant groups, and reluctance to overturn prevailing medical models that themselves reflected the economic position of medical practitioners. We show that these themes continue to serve as obstacles to innovation in medical and public health practice today. PMID- 21544100 TI - Ultra-diffuse hydrothermal venting supports Fe-oxidizing bacteria and massive umber deposition at 5000 m off Hawaii. AB - A novel hydrothermal field has been discovered at the base of Loihi Seamount, Hawaii, at 5000 mbsl. Geochemical analyses demonstrate that 'FeMO Deep', while only 0.2 degrees C above ambient seawater temperature, derives from a distal, ultra-diffuse hydrothermal source. FeMO Deep is expressed as regional seafloor seepage of gelatinous iron- and silica-rich deposits, pooling between and over basalt pillows, in places over a meter thick. The system is capped by mm to cm thick hydrothermally derived iron-oxyhydroxide- and manganese-oxide-layered crusts. We use molecular analyses (16S rDNA-based) of extant communities combined with fluorescent in situ hybridizations to demonstrate that FeMO Deep deposits contain living iron-oxidizing Zetaproteobacteria related to the recently isolated strain Mariprofundus ferroxydans. Bioenergetic calculations, based on in-situ electrochemical measurements and cell counts, indicate that reactions between iron and oxygen are important in supporting chemosynthesis in the mats, which we infer forms a trophic base of the mat ecosystem. We suggest that the biogenic FeMO Deep hydrothermal deposit represents a modern analog for one class of geological iron deposits known as 'umbers' (for example, Troodos ophilolites, Cyprus) because of striking similarities in size, setting and internal structures. PMID- 21544101 TI - Linking phytoplankton community composition to seasonal changes in f-ratio. AB - Seasonal changes in nitrogen assimilation have been studied in the western English Channel by sampling at approximately weekly intervals for 12 months. Nitrate concentrations showed strong seasonal variations. Available nitrogen in the winter was dominated by nitrate but this was close to limit of detection from May to September, after the spring phytoplankton bloom. The (15)N uptake experiments showed that nitrate was the nitrogen source for the spring phytoplankton bloom but regenerated nitrogen supported phytoplankton productivity throughout the summer. The average annual f-ratio was 0.35, which demonstrated the importance of ammonia regeneration in this dynamic temperate region. Nitrogen uptake rate measurements were related to the phytoplankton responsible by assessing the relative abundance of nitrate reductase (NR) genes and the expression of NR among eukaryotic phytoplankton. Strong signals were detected from NR sequences that are not associated with known phylotypes or cultures. NR sequences from the diatom Phaeodactylum tricornutum were highly represented in gene abundance and expression, and were significantly correlated with f-ratio. The results demonstrate that analysis of functional genes provides additional information, and may be able to give better indications of which phytoplankton species are responsible for the observed seasonal changes in f-ratio than microscopic phytoplankton identification. PMID- 21544102 TI - Analysis of bacterial and archaeal diversity in coastal microbial mats using massive parallel 16S rRNA gene tag sequencing. AB - Coastal microbial mats are small-scale and largely closed ecosystems in which a plethora of different functional groups of microorganisms are responsible for the biogeochemical cycling of the elements. Coastal microbial mats play an important role in coastal protection and morphodynamics through stabilization of the sediments and by initiating the development of salt-marshes. Little is known about the bacterial and especially archaeal diversity and how it contributes to the ecological functioning of coastal microbial mats. Here, we analyzed three different types of coastal microbial mats that are located along a tidal gradient and can be characterized as marine (ST2), brackish (ST3) and freshwater (ST3) systems. The mats were sampled during three different seasons and subjected to massive parallel tag sequencing of the V6 region of the 16S rRNA genes of Bacteria and Archaea. Sequence analysis revealed that the mats are among the most diverse marine ecosystems studied so far and consist of several novel taxonomic levels ranging from classes to species. The diversity between the different mat types was far more pronounced than the changes between the different seasons at one location. The archaeal community for these mats have not been studied before and revealed a strong reaction on a short period of draught during summer resulting in a massive increase in halobacterial sequences, whereas the bacterial community was barely affected. We concluded that the community composition and the microbial diversity were intrinsic of the mat type and depend on the location along the tidal gradient indicating a relation with salinity. PMID- 21544105 TI - Flagship funding. PMID- 21544103 TI - Archaea in Yellowstone Lake. AB - The Yellowstone geothermal complex has yielded foundational discoveries that have significantly enhanced our understanding of the Archaea. This study continues on this theme, examining Yellowstone Lake and its lake floor hydrothermal vents. Significant Archaea novelty and diversity were found associated with two near surface photic zone environments and two vents that varied in their depth, temperature and geochemical profile. Phylogenetic diversity was assessed using 454-FLX sequencing (~51,000 pyrosequencing reads; V1 and V2 regions) and Sanger sequencing of 200 near-full-length polymerase chain reaction (PCR) clones. Automated classifiers (Ribosomal Database Project (RDP) and Greengenes) were problematic for the 454-FLX reads (wrong domain or phylum), although BLAST analysis of the 454-FLX reads against the phylogenetically placed full-length Sanger sequenced PCR clones proved reliable. Most of the archaeal diversity was associated with vents, and as expected there were differences between the vents and the near-surface photic zone samples. Thaumarchaeota dominated all samples: vent-associated organisms corresponded to the largely uncharacterized Marine Group I, and in surface waters, ~69-84% of the 454-FLX reads matched archaeal clones representing organisms that are Nitrosopumilus maritimus-like (96-97% identity). Importance of the lake nitrogen cycling was also suggested by >5% of the alkaline vent phylotypes being closely related to the nitrifier Candidatus Nitrosocaldus yellowstonii. The Euryarchaeota were primarily related to the uncharacterized environmental clones that make up the Deep Sea Euryarchaeal Group or Deep Sea Hydrothermal Vent Group-6. The phylogenetic parallels of Yellowstone Lake archaea to marine microorganisms provide opportunities to examine interesting evolutionary tracks between freshwater and marine lineages. PMID- 21544104 TI - Increase in Alphaproteobacteria in association with a polychaete, Capitella sp. I, in the organically enriched sediment. AB - We conducted bioremediation experiments on the organically enriched sediment on the sea floor just below a fish farm, introducing artificially mass-cultured colonies of deposit-feeding polychaete, Capitella sp. I. To clarify the association between the Capitella and bacteria on the efficient decomposition of the organic matter in the sediment in the experiments, we tried to identify the bacteria that increased in the microbial community in the sediment with dense patches of the Capitella. The relationship between TOC and quinone content of the sediment as an indicator of the bacterial abundance was not clear, while a significant positive correlation was found between Capitella biomass and quinone content of the sediment. In particular, ubiquinone-10, which is present in members of the class Alphaproteobacteria, increased in the sediment with dense patches of the Capitella. We performed denaturing gradient gel electrophoresis (DGGE) analyses to identify the alphaproteobacterial species in the sediment with dense patches of the worm, using two DGGE fragments obtained from the sediment samples and one fragment from the worm body. The sequences of these DGGE fragments were closely related to the specific members of the Roseobacter clade. In the associated system with the Capitella and the bacteria in the organically enriched sediment, the decomposition of the organic matter may proceed rapidly. It is very likely that the Capitella works as a promoter of bacteria in the organically enriched sediment, and feeds the increased bacteria as one of the main foods, while the bacteria decompose the organic matter in the sediment with the assistance of the Capitella. PMID- 21544106 TI - Storm warning. PMID- 21544107 TI - 2 degrees C or not 2 degrees C? That is the climate question. PMID- 21544120 TI - China unveils its space station. PMID- 21544119 TI - Antiuniverse here we come. PMID- 21544121 TI - Wayward whale not a fluke. PMID- 21544122 TI - A how-to for peer review. PMID- 21544124 TI - Space science: along for the ride. PMID- 21544125 TI - From isotopes to the stars. PMID- 21544131 TI - UNESCO helps manage tsunamis. PMID- 21544132 TI - NIH revamp: avoid a redundant revolution. PMID- 21544133 TI - NIH revamp: real issue is resources. PMID- 21544134 TI - NIH revamp: US health care at fault. PMID- 21544135 TI - It is rational to doubt Fukushima reports. PMID- 21544136 TI - Evolutionary biology: the origins of novelty. PMID- 21544137 TI - Biochemistry: life imitates art. PMID- 21544138 TI - Translational medicine: to the rescue of the failing heart. PMID- 21544140 TI - Metrology: filtering noise with a quantum probe. PMID- 21544141 TI - Materials chemistry: catalytic accordions. PMID- 21544142 TI - Single-ion quantum lock-in amplifier. AB - Quantum metrology uses tools from quantum information science to improve measurement signal-to-noise ratios. The challenge is to increase sensitivity while reducing susceptibility to noise, tasks that are often in conflict. Lock-in measurement is a detection scheme designed to overcome this difficulty by spectrally separating signal from noise. Here we report on the implementation of a quantum analogue to the classical lock-in amplifier. All the lock-in operations -modulation, detection and mixing--are performed through the application of non commuting quantum operators to the electronic spin state of a single, trapped Sr(+) ion. We significantly increase its sensitivity to external fields while extending phase coherence by three orders of magnitude, to more than one second. Using this technique, we measure frequency shifts with a sensitivity of 0.42 Hz Hz(-1/2) (corresponding to a magnetic field measurement sensitivity of 15 pT Hz( 1/2)), obtaining an uncertainty of less than 10 mHz (350 fT) after 3,720 seconds of averaging. These sensitivities are limited by quantum projection noise and improve on other single-spin probe technologies by two orders of magnitude. Our reported sensitivity is sufficient for the measurement of parity non conservation, as well as the detection of the magnetic field of a single electronic spin one micrometre from an ion detector with nanometre resolution. As a first application, we perform light shift spectroscopy of a narrow optical quadrupole transition. Finally, we emphasize that the quantum lock-in technique is generic and can potentially enhance the sensitivity of any quantum sensor. PMID- 21544143 TI - Convergence of electronic bands for high performance bulk thermoelectrics. AB - Thermoelectric generators, which directly convert heat into electricity, have long been relegated to use in space-based or other niche applications, but are now being actively considered for a variety of practical waste heat recovery systems-such as the conversion of car exhaust heat into electricity. Although these devices can be very reliable and compact, the thermoelectric materials themselves are relatively inefficient: to facilitate widespread application, it will be desirable to identify or develop materials that have an intensive thermoelectric materials figure of merit, zT, above 1.5 (ref. 1). Many different concepts have been used in the search for new materials with high thermoelectric efficiency, such as the use of nanostructuring to reduce phonon thermal conductivity, which has led to the investigation of a variety of complex material systems. In this vein, it is well known that a high valley degeneracy (typically <=6 for known thermoelectrics) in the electronic bands is conducive to high zT, and this in turn has stimulated attempts to engineer such degeneracy by adopting low-dimensional nanostructures. Here we demonstrate that it is possible to direct the convergence of many valleys in a bulk material by tuning the doping and composition. By this route, we achieve a convergence of at least 12 valleys in doped PbTe(1-x)Se(x) alloys, leading to an extraordinary zT value of 1.8 at about 850 kelvin. Band engineering to converge the valence (or conduction) bands to achieve high valley degeneracy should be a general strategy in the search for and improvement of bulk thermoelectric materials, because it simultaneously leads to a high Seebeck coefficient and high electrical conductivity. PMID- 21544144 TI - Depth-dependent extension, two-stage breakup and cratonic underplating at rifted margins. AB - Uniform lithospheric extension predicts basic properties of non-volcanic rifted margins but fails to explain other important characteristics. Significant discrepancies are observed at 'type I' margins (such as the Iberia-Newfoundland conjugates), where large tracts of continental mantle lithosphere are exposed at the sea floor, and 'type II' margins (such as some ultrawide central South Atlantic margins), where thin continental crust spans wide regions below which continental lower crust and mantle lithosphere have apparently been removed. Neither corresponds to uniform extension. Instead, either crust or mantle lithosphere has been preferentially removed. Using dynamical models, we demonstrate that these margins are opposite end members: in type I, depth dependent extension results in crustal-necking breakup before mantle-lithosphere breakup and in type II, the converse is true. These two-layer, two-stage breakup behaviours explain the discrepancies and have implications for the styles of the associated sedimentary basins. Laterally flowing lower-mantle cratonic lithosphere may underplate some type II margins, thereby contributing to their anomalous characteristics. PMID- 21544145 TI - Body plan innovation in treehoppers through the evolution of an extra wing-like appendage. AB - Body plans, which characterize the anatomical organization of animal groups of high taxonomic rank, often evolve by the reduction or loss of appendages (limbs in vertebrates and legs and wings in insects, for example). In contrast, the addition of new features is extremely rare and is thought to be heavily constrained, although the nature of the constraints remains elusive. Here we show that the treehopper (Membracidae) 'helmet' is actually an appendage, a wing serial homologue on the first thoracic segment. This innovation in the insect body plan is an unprecedented situation in 250 Myr of insect evolution. We provide evidence suggesting that the helmet arose by escaping the ancestral repression of wing formation imparted by a member of the Hox gene family, which sculpts the number and pattern of appendages along the body axis. Moreover, we propose that the exceptional morphological diversification of the helmet was possible because, in contrast to the wings, it escaped the stringent functional requirements imposed by flight. This example illustrates how complex morphological structures can arise by the expression of ancestral developmental potentials and fuel the morphological diversification of an evolutionary lineage. PMID- 21544146 TI - Enzyme-catalysed [4+2] cycloaddition is a key step in the biosynthesis of spinosyn A. AB - The Diels-Alder reaction is a [4+2] cycloaddition reaction in which a cyclohexene ring is formed between a 1,3-diene and an electron-deficient alkene via a single pericyclic transition state. This reaction has been proposed as a key transformation in the biosynthesis of many cyclohexene-containing secondary metabolites. However, only four purified enzymes have thus far been implicated in biotransformations that are consistent with a Diels-Alder reaction, namely solanapyrone synthase, LovB, macrophomate synthase, and riboflavin synthase. Although the stereochemical outcomes of these reactions indicate that the product formation could be enzyme-guided in each case, these enzymes typically demonstrate more than one catalytic activity, leaving their specific influence on the cycloaddition step uncertain. In our studies of the biosynthesis of spinosyn A, a tetracyclic polyketide-derived insecticide from Saccharopolyspora spinosa, we identified a cyclase, SpnF, that catalyses a transannular [4+2] cycloaddition to form the cyclohexene ring in spinosyn A. Kinetic analysis demonstrates that SpnF specifically accelerates the ring formation reaction with an estimated 500 fold rate enhancement. A second enzyme, SpnL, was also identified as responsible for the final cross-bridging step that completes the tetracyclic core of spinosyn A in a manner consistent with a Rauhut-Currier reaction. This work is significant because SpnF represents the first example characterized in vitro of a stand-alone enzyme solely committed to the catalysis of a [4+2] cycloaddition reaction. In addition, the mode of formation of the complex perhydro-as-indacene moiety in spinosyn A is now fully established. PMID- 21544149 TI - [The letters to the editor and their scientific support]. PMID- 21544148 TI - Arterial stiffness and bone demineralization: the Baltimore longitudinal study of aging. AB - BACKGROUND: Arterial stiffening is one of the hallmarks of vascular aging, and is an important risk factor for cardiovascular morbidity and mortality. Aging is also associated with bone demineralization. Accumulating evidence indicate that arterial stiffness and bone demineralization might share common pathways. The aims of this study were to evaluate whether the association between arterial stiffness and bone demineralization is independent of age, and to explore putative mechanisms that may mediate their relationship. METHODS: A cross sectional analysis was performed using data from 321 men (68 +/- 12 years) and 312 women (65 +/- 13 years) of the Baltimore Longitudinal Study of Aging. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) and cross-sectional cortical bone area (cCSA) was assessed at the level of the mid tibia with computed tomography (CT) imaging. RESULTS: Age was significantly correlated with PWV in men (r = 0.38, P < 0.0001) and women (r = 0.35, P < 0.0001). Age was associated with cCSA in women (r = -0.14, P = 0.0008), but not in men. Age-adjusted linear regression analysis showed a significant inverse association between PWV and cCSA, in women but not in men. The association between PWV and cCSA remained significant in women after adjusting for age, mean arterial pressure (MAP), obesity, menopause, drugs, alcohol intake, physical activity, renal function, serum calcium, and total estradiol concentration. CONCLUSIONS: Independent of age and other shared risk factors, arterial stiffness is inversely related to cortical bone area in women. The sex-specific signaling and molecular pathways that putatively underlie the cross-talk between central arteries and bone are not completely understood. PMID- 21544150 TI - [Evaluation of the diagnostic test of index platelet counts / size spleen, as a predictor of the presence of esophageal varices in cirrhosis]. AB - AIM: To evaluate the platelet count/spleen diameter (PC/SD) ratio as a non invasive diagnostic test to predict esophageal varices (VE) in patients with cirrhosis. METHODS: Diagnostic test study, retrospective analysis. Data was collected from patients with diagnosis of liver cirrhosis at gastrointestinal unit of Hospital Nacional Daniel Alcides Carrion between September 2010 and January 2011. Using a PC/SD ratio with a cut off value of 909, sensitivity, specificity, Positive and negative predictive values, positive and negative likelihood ratios were calculate. RESULTS: There were 47 patients; mean age of 60,74; etiology: alcoholic (25,5%); undeterminated (48,9%). Twenty-five percent patients had varices and 74,5% had no varices. The PC/SD ratio had a sensitivity of 40%, specificity of 75%, PPV of 82%, NPV 30%, LR (+) of 1,6 and LR (-) of 0,8. CONCLUSIONS: The PC/SD ratio was not an effective diagnostic test for esophageal varices. PMID- 21544151 TI - [Utility of urease rapid test for detection of Helicobacter pylori in patients with upper gastrointestinal bleeding from peptic ulcer]. AB - BACKGROUND: Peptic ulcer disease is the main cause of upper gastrointestinal bleeding and Helicobacter pylori is its principal etiology. The sensitivity of the diagnostics tests is low for the detection of H. pylori en the setting of bleeding peptic ulcer. In addition there are different results among them. GOAL: To validate the rapid urease test (RUT) in patients with bleeding peptic ulcer. STUDY: We prospectively included patients older than 14 years old who presented with bleeding peptic ulcer and performed diagnostic studies of RUT and histology for the detection of H. pylori. Two biopsies were taken (one from the antrum and another one from the corpus) for RUT and four biopsies (two from both antrum and corpus) for histology. RESULTS Ninety-three patients were included, gastric ulcer was the most frequent site of the bleeding. 48 patients were positive for H. pylori by histology studies and 55 patients were positive to H. pylori by RUT. The sensitivity and specificity of the RUT were 89.6% (IC 77.3-96.5) y 73.3% (IC 58.0-85.4) respectively. CONCLUSION: The RUT has a high sensitivity for the detection of H. pylori en the setting of bleeding peptic ulcer. PMID- 21544152 TI - ["Pilot study: sequential therapy in erradicating Helicobacter pylori in the Cayetano Heredia Hospital"]. AB - BACKGROUND: Sequential therapy is used as an alternative to growing antibiotic resistance of Helicobacter pylori to the standard triple therapy. Despite the success it had in Europe, we have no information regarding this therapy in our region. OBJECTIVES: To evaluate the eradication rate of Helicobacter pylori using sequential therapy and show its adverse effects. METHODS: We performed a prospective, observational, open descriptive study. 31 patients were evaluated who were treated with sequential therapy in the following way: the first 5 days omeprazole 20 mg and amoxicillin 1 g every 12 hours and following 5 days omeprazole 20 mg, clarithromycin 500 mg and tinidazole 500 mg every 12 hours. After four weeks of treatment, each patient had a C13 urea breath test to check for eradication. RESULTS: 31 patients were included, one patient was excluded from the protocol due to adverse drug react to amoxicillin. Of the remaining 30 patients who completed treatment, 22 (73%) were negative to breath test and 8 (27%) were positive. Of the patients who completed treatment, 10 had minor adverse events to treatment, the main symptoms were epigastralgia and nausea. CONCLUSIONS: Sequential therapy had an eradication rate of 73% which is much lower than that reported in European studies. However, therapy is easily accesible with lower cost and fewer side effects tan standard therapy. PMID- 21544153 TI - [Hemoconcentration, Apache II and Ranson as early predictors of severity in patients with acute pancreatitis in a hospital in Lima - Peru]. AB - OBJECTIVE: Compare hemoconcetration, APACHE II and Ranson scores as early predictors of severity defined by Atlanta criteria in patients with acute pancreatitis at Hospital Nacional Cayetano Heredia. MATERIALS AND METHODS: Retrospective descriptive study between December 2009 to November 2010 done using a data collection sheet to gather study relevant information. We classified acute pancreatitis into mild or severe according to Atlanta symposium criteria for organ failure and/or local complications. Comparison of hematocrit values was made using a t Student test to detect a significant difference and the area below the ROC curve was analyzed. RESULTS: Counting with 151 patients, 103 women (68.2%), with mean age of 45.5 +/- 19.17 years, 112 mild pancreatitis (74.2%) and 39 severe (25.8%). Mean hematocrit in mild cases was 38.40 +/- 4.77% and 39.78 +/ 7.35% in severe group with p equal to 0.182. Area below the ROC curve of 0.89 y 0.68 for APACHE II and Ranson scores respectively. CONCLUSION: Hemoconcentration and Ranson proved not to be as useful as APACHE II score in predicting severity in acute pancreatitis. PMID- 21544154 TI - [Gallbladder polyps: Clinical and pathological features in Cholecystectomy patients in the Anglo American clinic in the period of 1999-2007]. AB - OBJECTIVE: To describe the clinical and anatomopathologic characteristics of gallbladder polyps found in patients who underwent cholecystectomy at Clinica Anglo Americana for the 1999-2007 period. MATERIALS AND METHODS: Descriptive and retrospective study that started at Pathology Department where patients with anatomopathologic finding of gallbladder polyps who underwent cholecystectomy for the 1999-2007 period were selected. Clinical records were reviewed to take ultrasonographic, anatomopathologic and clinical characteristics, which were included and studied in a data base in Microsoft Excel. RESULTS: Gallbladder polyps were found in 172 (10%) of 1707 gallbladders that were analized. Cholesterolosic polyps were found in 95.4% of the cases, 4% were adenomas and 0.6% were hyperplasic polyps. Gallbladder polyps >= 10 mm were found in 32,25% of the cases. A 90% of these polyps were cholesterolosic and a 10% were adenomas. No malign polyps were found in this study. CONCLUSIONS: The vast majority of gallbladder polyps, including the >= 10 mm group, were cholesterolosic. The physician decision to remove the gallbladder must be individualized and discussed with each patient, considering gallbladder polyp characteristics such as size and growth rate of the lesion. PMID- 21544155 TI - [Gastritis and gastropathies]. AB - A review of the different types of gastritis, including features in which the edema and erythema can resemble the picture, but without the typical inflammatory reaction that is called gastropathy. A description of various epidemiological, aetiological, pathogenetic, are proposed. The review describes the diagnoses and treatment recommendations and prognosis of this common disorder. PMID- 21544156 TI - [Safety of the proton pump inhibitors]. AB - Proton Pump Inhibitors (PPI) are consumed by millions of people around the world, either by prescription or self-medication, some medications of this group are Over-the-counter (OTC) medicines. PPIs have been associated with hypergastrinemia, rebound acid hypersecretion, malabsorption, osteoporosis and infections. This is an updated review of clinical pharmacology aspects of IPBS, with emphasis on safety aspects. PMID- 21544157 TI - [Frantz tumor: a pancreatic pseudopapillary solid neoplasia]. AB - We report a case of solid and papillary epithelial neoplasm of the pancreas in a 35-year-old female. She presented with epigastric pain and weight loss, these symptoms developed 3 months before. Physical examination revealed mild pain on deep palpation of mesogastrium, without palpable abdominal mass; rest of the examination was normal. The laboratory data showed hemoglobin 13.3 gr/dl; WBC, platelets, blood coagulation test, blood biochemistry, electrolytes, liver function test were normals. Urine test: 14-16 leukocytes per field, urocultive negative, Ca 19.9: 21.2 (0-37). Her serology for hydatic cyst (arc V and inmunoblot) was negative.Abdominal ultrasound showed between body and tail of the pancreas a solid hypoechoic image. In abdominal CT was detected in the body of the pancreas the presence of two hypodense lesions with average density of 25 UH and mediate 50 and 22 mm in diameter. The nuclear magnetic resonance imaging identified the body of the pancreas, bilobed cyst of 45 and 25 mm in diameter, with isointensity in T1, hyperintensity in T2, unchanged after fat saturation, with peripheral contrast enhancement. Operation findings showed a cystic tumor in the body of pancreas without signs of infiltration to other organs. Therefore, distal pancreatectomy and splenectomy were carried out. The tumor was 60 x 46 x 35 mm and a half oval, encapsulated, irregular consistency, which the court left necrotic-looking material flow. The study showed the pattern typical hyalinized perivascular pseudopapillary with stroma, in immunohistochemical studies positive immunoreactivity was observed in cyclin D1 and progesterone receptor, also were positive for vimentin, enolase neuronoespecifica and CD-56. The proliferation index assessed by Ki-67 was less than 1% in tumor cells. The solid pseudopapillary neoplasm of the pancreas is a low-grade malignancy, relatively rare, representing between 0.9 and 2.7% of all pancreatic malignancies. It mainly affects young women (89% of cases), with a mean age at diagnosis of 28 years. Most have specific symptoms related to intra-abdominal mass and more than one third are usually discovered incidentally. PMID- 21544158 TI - [Solid pseudopapillary tumor of the pancreas: a neoplasm of low malignant potential?]. AB - BACKGROUND: Solid pseudo papillary tumor of the pancreas is considered a neoplasm of low malignant potential. The radicality of surgical approach is controversial. PATIENTS AND METHODS: We describe and analyze retrospectively the clinical, radiological, laboratory, operative report and pathology results of seven patients who were diagnosed and operated by solid pseudo papillary tumor of the pancreas in the period 2003 to 2010, in our institution. RESULTS: Six patients were female and one male. The median age was 35 years (range: 15-49). The most common symptom was abdominal pain (100%). Jaundice in one patient (14.3%). The radiological appearance mixed solid-cystic was the most common. We performed four Whipple procedures (57.1%), 2 distal pancreatectomy with splenectomy (28.6%), one by laparoscopy and the other by local resection. Morbidity presented in four patients. There was no postoperative mortality or reoperation. Five tumors were located in the pancreatic head (71.4%) and two in the tail (28.6%). The median tumor size was 93 mm (range: 20-150). Two (28.6%) were R1 resections. Four tumors showed malignant behavior (57.1%): splenic capsule and infiltration of metachronous liver metastases (1), infiltration of superior mesenteric artery (1), lymphatic metastasis (1) and synchronous liver metastases, and lymphovascular invasion duodenal infiltration (1). There was no mortality from the disease during the average follow-up of 26 months (range 6-70 months). CONCLUSION: Solid pseudo papillary tumor is a neoplasm with high malignant potential in our experience. We recommend an aggressive surgical approach with radical resection including lymphadenectomy. PMID- 21544159 TI - [Solid-pseudopapillary tumor of the pancreas. Presentation of 3 clinical cases]. AB - The solid-pseudopapillary tumors of the pancreas (TSPP) are a uncommon neoplasm (1- 2% of exocrine tumors). Are more frequent in young women and presents a low malignant potential (15% develop metastases). Its preoperative diagnosis is very difficult, because these tumors haven't radiological features that makes distinguish from the other pancreatic cysts tumors. Usually are a histopathological finding. Surgical therapy provides good survival, even in the presence of metastases. We present 3 cases with clinical, imaging, treatment and histopathology to provide more information about this rare disease. PMID- 21544160 TI - [Cecal solitary ulcer as a presentation of Crohn's disease]. AB - Crohn's Disease, is a rare inflammatory bowel disease in Peru. Incidence rates vary from 1,6 - 14,6 / 100,000 and prevalence rate is 140 / 100,000 in the western hemisphere. We report a case of 52 y.o male patient from Callao Peru, with a colonoscopy image of a solitary cecal ulcer and without other gastrointestinal findings and a histology suggestive of Crohn's Disease with a ASCA positive and p -ANCA negative. PMID- 21544161 TI - [Obscure digestive bleeding by ileal carcinoid tumor]. AB - The patient is an 82 year-old female with a history of osteoarthritis, hypothyroidism and anemia for 14 years (receiving blood transfusions). She was admited to our hospital with a nine months history of malaise, anorexia, fatigue and weakness, associated with intermitten episodes of abdominal pain. She was diagnosed anemia and occult blood positive stools. Physical examination revealed a patient in generally fair condition, obese, with mild edema of lower limbs, no changes in the evaluation of chest, cardiovascular, abdomen, etc. Laboratory data was unremarkable, except for iron deficiency anemia. The upper endoscopy showed duodenal ulcer scar, fundic polyposis and chronic gastritis. Colonoscopy revealed some diverticula, a small sessile polyp and internal hemorrhoids. The diagnosis of obscure gastrointestinal bleeding was made. The CT scan of the abdomen showed gallstones and fatty liver; a radiograph of intestinal transit detected a lesion apparently protruded intestinal loop for distal jejunum; enteroscopy was performed (with one team ball) anterograde and retrograde achieving assess distal jejunum and distal ileum without observing any injuries. The study of capsule endoscopy showed a polypoid tumor intestinal with evidence of having bleeding. Surgery detected the tumor in proximal ileum. The surgical specimen findings showed three tumors 0.7 mm, 10 mm and 15 mm on the proximal ileum. The microscopic examination revealed that these lesions were neuroendocrine tumors (carcinoid). The Ileal carcinoid tumor may rarely presented with obscure gastrointestinal bleeding. PMID- 21544162 TI - [Transvaginal notes Cholecystectomy in humans: first series of cases in Costa Rica]. AB - OBJECTIVES. To report the first case series of transvaginal NOTES cholecystectomy in humans in Costa Rica and its clinical potential in the treatment of abdominal diseases in this country. PATIENTS AND METHODS. We present a series of three cases of adult female patients of 44, 58 and 69 years of age (average 57 years), symptomatic, with a gall bladder polyp diagnosed by an abdominal ultrasound, who underwent a transvaginal cholecystectomy modified with laparoscopic technique. A 5 mm trocar was inserted through the umbilicus to create and to monitor the pneumoperitoneum, as well as to possibilitate endoscopic vision during the intravaginal introduction of an endoscope and a forceps device for cephalic retraction of the gall bladder. Through the intraumbilical trocar a conventional laparoscopic hook device was also inserted for dissection of the pedicle and hepatic bed, and also a laparoscopic clip applier for clipping of the cystic artery and duct. The gall bladder was extracted through the vagina. RESULTS. The three cases were successfully performed without intra- or postoperative complications. The average operative time was 107 minutes (range 100-115 minutes). The patients were discharged within 24 hours. At the 1-month follow-up, none of the patients complained neither of incisional pain nor dyspareunia. CONCLUSION. The transvaginal NOTES cholecystectomy combined with laparoscopic technique is feasible, safe, reproducible, and constitutes one step further in the development of pure NOTES procedures. More effort in technological investigation and dedication is to be required to apply this technique to other more complex procedures. PMID- 21544163 TI - [The research as fountain of perennial youth]. PMID- 21544165 TI - Structure based drug designing of a novel antiflaviviral inhibitor for nonstructural 3 protein. AB - Literature shows that Flaviviruses cause a variety of diseases, including fevers, encephalitis, and hemorrhagic fevers. NS3 is a multifunctional protein with an Nterminal protease domain (NS3pro) that is responsible for proteolytic processing of the viral polyprotein, and a C-terminal region that contains an RNA triphosphatase, RNA helicase and RNA-stimulated NTPase domain that are essential for RNA replication. Therefore, NS3 protein is the preferential choice for inhibition to stop the proteolytic processing. Hence, the 3D structure of NS3 protein was modeled using homology modeling by MODELLER 9v7. Evaluation of the constructed NS3 protein models were done by PROCHECK, VERYFY3D and through ProSA calculations. Ligands for the catalytic triad were designed using LIGBUILDER. The NS3 protein's catalytic triad was explored to find out the critical interactions pattern for inhibitor binding using molecular docking methodology using AUTODOCK Vina. It should be noted that these predicted data should be validated using suitable assays for further consideration. ABBREVIATIONS: DOPE - Discrete optimized protein energy, WHO - World Health Organization, ADME/T - Absorption, Distribution, Metabolism, Excretion and Toxicity. PMID- 21544164 TI - HIV-1 envelope accessible surface and polarity: clade, blood, and brain. AB - The human immunodeficiency virus type-1 (HIV-1) gp160 (gp120-gp41 complex) trimer envelope (ENV) protein is a potential vaccine candidate for HIV/AIDS. HIV-1 vaccine development has been problematic and charge polarity as well as sequence variation across clades may relate to the difficulties. Further obstacles are caused by sequence variation between blood and brain-derived sequences, since the brain is a separate compartment for HIV-1 infection. We utilize a threedimensional residue measure of solvent exposure, accessible surface area (ASA), which shows that major segments of gp120 and gp41 known structures are solvent exposed across clades. We demonstrate a large percent sequence polarity for solvent exposed residues in gp120 and gp41. The range of sequence polarity varies across clades, blood, and brain from different geographical locations. Regression analysis shows that blood and brain gp120 and gp41 percent sequence polarity range correlate with mean Shannon entropy. These results point to the use of protein modifications to enhance HIV-1 ENV vaccines across multiple clades, blood, and brain. It should be noted that we do not address the issue of protein glycosylation here; however, this is an important issue for vaccine design and development. ABBREVIATIONS: HIV-1 - human immunodeficiency virus type 1, AIDS - acquired immunodeficiency syndrome, ENV - envelope, gp160 - 160,000d glycoprotein, gp120 - 120,000d glycoprotein, gp41 - 41,000d glycoprotein, LANL - Los Alamos National Laboratories, PDB - Protein Data Bank, HVTN - STEP HIV vaccine trial, AA - amino acids, MSA - multiple sequence alignment, ASA - accessible surface area, SNPs- single nucleotide polymorphisms, HAART - Highly Active Antiretroviral Therapy, CCR5 - C-C chemokine receptor type 5, CNS - central nervous system, HIVE - HIV encephalitis, P - polarity, NP - non-polarity, CTL - cytotoxic T lymphocyte, NIAID - National Institute of Allergy and Infectious Diseases. PMID- 21544166 TI - Identification of the sequence motif of glycoside hydrolase 13 family members. AB - A bioinformatics analysis of sequences of enzymes of the glycoside hydrolase (GH) 13 family members such as alpha-amylase, cyclodextrin glycosyltransferase (CGTase), branching enzyme and cyclomaltodextrinase has been carried out in order to find out the sequence motifs that govern the reactions specificities of these enzymes by using hidden Markov model (HMM) profile. This analysis suggests the existence of such sequence motifs and residues of these motifs constituting the 1 to +3 catalytic subsites of the enzyme. Hence, by introducing mutations in the residues of these four subsites, one can change the reaction specificities of the enzymes. In general it has been observed that alpha -amylase sequence motif have low sequence conservation than rest of the motifs of the GH13 family members. PMID- 21544167 TI - PCR-based molecular characterization and insilico analysis of food-borne trematode parasites Paragonimus westermani, Fasciolopsis buski and Fasciola gigantica from Northeast India using ITS2 rDNA. AB - Food-borne fluke infections/trematodiases are emerging as a major public health problem worldwide with over 40 million people affected and over 10% of world population at risk of infection. The major concentration of these infections is in Southeast Asian and Western Pacific Regions, where the epidemiological factors (including the prevalent socio-cultural food habits) are conducive for transmission of these infections. The preponderance of these infections is usually in food deficit poor communities that lack access to proper sanitary infrastructure. While targeting health for all, especially the poor rural tribal communities, it is imperative to take these infections into account. Bayesian analysis phylogeny of food-borne trematode parasites under study showed that they are closely related phylogenetic groups. To focus the control strategies at the target populations, the aim of the present study was to establish molecular methods for accurate discrimination between common food-borne trematodes parasites Paragonimus (lung fluke), Fasciolopsis (giant intestinal fluke) and Fasciola (liver fluke), the infections of which commonly prevail in NE India. In the first step, we amplified and sequenced the second internal transcribed spacer (ITS2) region of ribosomal DNA, utilizing nucleotide differences between the multiple sequence alignments of the parasites under study. Based upon the differences in nucleotide sequences of conserved regions, we designed species specific primers that can unequivocally discriminate one species from another. ITS2 sequence motifs allowed an accurate in-silico distinction of the trematodes. The data indicate that ITS2 motifs (<= 50 bp in size) can be considered promising tool for trematode species identification. Using molecular morphometrics that is based on ITS2 secondary structure homologies, phylogenetic relationships with various isolates of several trematode species have been discussed. The present results suggest that the ITS2 specific primers can be used for epidemiological investigations of the prevalence of trematodiasis. PMID- 21544168 TI - DNA polymerase III alpha subunit from Mycobacterium tuberculosis H37Rv: Homology modeling and molecular docking of its inhibitor. AB - The alpha subunit of Mycobacterial DNA polymerase III holo enzyme catalyzes the polymerization of both DNA strands. The present investigation reports three dimensional (3-D) structure model of DNA polymerase III alpha subunit of Mycobacterium tuberculosis H37Rv (MtbDnaE1) generated using homology modeling with the backbone structure of DNA polymerase III alpha of Thermus aquaticus as a template. The model was evaluated at various structure verification servers, which assess the stereo chemical parameters of the residues in the model, as well as structural and functional domains. Comparative analysis of MtbDnaE1 structure reveals the structure of its catalytic domain to be unrelated to that of the human. Successful docking of known inhibitor of bacterial DNA polymerases, 251D onto the modeled MtbDnaE1 was also performed. Therefore, the structure model of MtbDnaE1, a potential anti-mycobacterial target, opens a new avenue for structure based drug designing against the pathogen. ABBREVIATIONS: aa - amino acid(s), PolIIIalpha - DNA polymerase III alpha subunit, Taq Pol IIIalpha - Pol IIIalpha of Thermus aquaticus, MtbDnaE1 - PolIIIalpha of Mycobacterium tuberculosis. PMID- 21544169 TI - Protein-Ligand interaction studies on 2, 4, 6- trisubstituted triazine derivatives as anti-malarial DHFR agents using AutoDock. AB - The dihydrofolate reductase (DHFR) domain of P. falciparum is one of the few well defined targets in malarial chemotherapy. The enzyme catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH) dependent reduction of dihydrofolate to tetrahydrofolate. Protein-ligand interactions were studied using DHFR protein 2BL9, extracted from PDB to evaluate the strength of affinity of various molecules towards ligand binding site and to study the extent of correlation between experimental values and computational dock scores. AutoDock runs resulted in binding energy scores from -7.14 to -10.72 kcal/mol. Among the five inhibitors (Bioorganic and Medicinal Chemistry Letters 15 2005 531-533) selected for docking studies, an excellent correlation was observed in all cases, for instance, experimentally reported most active molecule 2a (MIC: 1ug/ml) showed a high dock score (-10.72 kcal/mol) than the remaining inhibitors. Therefore, molecular docking using AutoDock suggests the importance of evaluating the prediction accuracy of various molecules as evidenced by a correlation coefficient of 0.961 between experimental activities and AutoDock binding energies. PMID- 21544170 TI - Molecular modeling of human alkaline sphingomyelinase. AB - Alkaline sphingomyelinase, which is expressed in the human intestine and hydrolyses sphingomyelin, is a component of the plasma and the lysosomal membranes. Hydrolase of sphingomyelin generates ceramide, sphingosine, and sphingosine 1-phosphate that have regulatory effects on vital cellular functions such as proliferation, differentiation, and apoptosis. The enzyme belongs to the Nucleotide Pyrophosphatase/Phosphodiesterase family and it differs in structural similarity with acidic and neutral sphingomyelinase. In the present study we modeled alkaline sphingomyelinase using homology modeling based on the structure of Nucleotide Pyrophosphatase/Phosphodiesterase from Xanthomonas axonopodis with which it shares 34% identity. Homology modeling was performed using Modeller9v7. We found that Cys78 and Cys394 form a disulphide bond. Further analysis shows that Ser76 may be important for the function of this enzyme, which is supported by the findings of Wu et al. (2005), that S76F abolishes the activity completely. We found that the residues bound to Zn(2+) are conserved and geometrically similar with the template. Molecular Dynamics simulations were carried out for the modeled protein to observe the effect of Zinc metal ions. It was observed that the metal ion has little effect with regard to the stability but induces increased fluctuations in the protein. These analyses showed that Zinc ions play an important role in stabilizing the secondary structure and in maintaining the compactness of the active site. PMID- 21544171 TI - The Booly aliasing resource: a database of grouped biological identifiers. AB - Redundancy among sequence identifiers is a recurring problem in bioinformatics. Here, we present a rapid and efficient method of fingerprinting identifiers to ascertain whether two or more aliases are identical. A number of tools and approaches have been developed to resolve differing names for the same genes and proteins, however, these methods each have their own limitations associated with their various goals. We have taken a different approach to the aliasing problem by simplifying the way aliases are stored and curated with the objective of simultaneously achieving speed and flexibility. Our approach (Booly-hashing) is to link identifiers with their corresponding hash keys derived from unique fingerprints such as gene or protein sequences. This tool has proven invaluable for designing a new data integration platform known as Booly, and has wide applicability to situations in which a dedicated efficient aliasing system is required. Compared with other aliasing techniques, Booly-hashing methodology provides 1) reduced run time complexity, 2) increased flexibility (aliasing of other data types, e.g. pharmaceutical drugs), 3) no required assumptions regarding gene clusters or hierarchies, and 4) simplicity in data addition, updating, and maintenance. The new Booly-hashing aliasing model has been incorporated as a central component of the Booly data integration platform we have recently developed and shoud be broadly applicable to other situations in which an efficient streamlined aliasing systems is required. This aliasing tool and database, which allows users to quickly group the same genes and proteins together can be accessed at: http://booly.ucsd.edu/alias. AVAILABILITY: The database is available for free at http://booly.ucsd.edu/alias. PMID- 21544172 TI - On experiences of i2b2 (Informatics for integrating biology and the bedside) database with Japanese clinical patients' data. AB - Informatics for Integrating Biology and the Bedside (i2b2) is a database system to facilitate sharing and reuse of clinical patients' data collected in individual hospitals. The i2b2 provides an ontology based object-oriented database system with highly simple and flexible database schema which enables us to integrate clinical patients' data from different laboratories and different hospitals. 392 patients' data including carcinoma and non-carcinoma specimens from cancer patients are transported from the Integrated Clinical Omics Database (iCOD) to the i2b2 database for a feasibility study to check applicability of i2b2 ontology and database schema on Japanese clinical patients' data. No modification is required for the i2b2 data model to deal with Japanese characters. Some modification of ontology is required to integrate biomedical information extracted from the cancer patients' data. We believe that the i2b2 system will be practical infrastructure to integrate Japanese clinical databases if appropriate disease ontology for Japanese patients is provided. PMID- 21544173 TI - ProViDE: A software tool for accurate estimation of viral diversity in metagenomic samples. AB - Given the absence of universal marker genes in the viral kingdom, researchers typically use BLAST (with stringent E-values) for taxonomic classification of viral metagenomic sequences. Since majority of metagenomic sequences originate from hitherto unknown viral groups, using stringent e-values results in most sequences remaining unclassified. Furthermore, using less stringent e-values results in a high number of incorrect taxonomic assignments. The SOrt-ITEMS algorithm provides an approach to address the above issues. Based on alignment parameters, SOrt-ITEMS follows an elaborate work-flow for assigning reads originating from hitherto unknown archaeal/bacterial genomes. In SOrt-ITEMS, alignment parameter thresholds were generated by observing patterns of sequence divergence within and across various taxonomic groups belonging to bacterial and archaeal kingdoms. However, many taxonomic groups within the viral kingdom lack a typical Linnean-like taxonomic hierarchy. In this paper, we present ProViDE (Program for Viral Diversity Estimation), an algorithm that uses a customized set of alignment parameter thresholds, specifically suited for viral metagenomic sequences. These thresholds capture the pattern of sequence divergence and the non-uniform taxonomic hierarchy observed within/across various taxonomic groups of the viral kingdom. Validation results indicate that the percentage of 'correct' assignments by ProViDE is around 1.7 to 3 times higher than that by the widely used similarity based method MEGAN. The misclassification rate of ProViDE is around 3 to 19% (as compared to 5 to 42% by MEGAN) indicating significantly better assignment accuracy. ProViDE software and a supplementary file (containing supplementary figures and tables referred to in this article) is available for download from http://metagenomics.atc.tcs.com/binning/ProViDE/ PMID- 21544174 TI - TTX, cations and spider venom modify avian muscle tone in vitro. AB - Agents that reduce skeletal muscle tone may have a number of useful clinical applications, e.g., for muscle spasticity and other muscle disorders. Recently, we reported that the venoms of two species of Australian theraphosid (Araneae, Theraphosidae) spiders (Coremiocnemis tropix and Selenotholus foelschei) reduced the baseline tension of chick biventer cervicis nerve-muscle preparation. The purpose of this study was to determine the underlying physiology mediating the change in muscle tension, which was addressed by conducting isometric tension experiments. We found that MgCl(2) (20mM), CaCl(2) (20mM), tetrodotoxin (1MUM) or C. tropix venom (2MUl/ml) produced a similar decrease in baseline tension, whereas d-tubocurarine (100MUM), gadolinium (1mM), verapamil (10mM), an increase in osmotic pressure by the addition of glucose (40mM), or the presence/absence of electrical stimulation did not produce a significant change in baseline tension. We suggest that mechanosensitive or muscle TTX-sensitive sodium channels are activated during muscle stretch. This may have implications for the treatment of stretch induced muscle damage. PMID- 21544175 TI - Suramin inhibits the early effects of PLA(2) neurotoxins at mouse neuromuscular junctions: A twitch tension study. AB - Several phospholipase A(2) (PLA(2)) neurotoxins from snake venoms can affect acetylcholine release at the neuromuscular junction. In isolated nerve-muscle preparations three distinct phases have been described for this phenomenon: An initial transient decrease in twitch tension; a second facilitatory phase during which twitch height is greater than control twitch height; and the last phase which causes a reduction in twitch height that finally results in paralysis. Suramin has been reported to inhibit the toxic effects of beta-bungarotoxin and another PLA(2) neurotoxin, crotoxin in vitro and in vivo. We have further examined the effects of suramin on the three phases of the effects of the presynaptic PLA(2) neurotoxins beta-bungarotoxin, taipoxin and ammodytoxin on mouse phrenic nerve-hemidiaphragm preparations. When preparations were pre treated with suramin (0.3mM), the early biphasic effects (depression followed by facilitation) were abolished, and the time taken for final blockade induced by beta-bungarotoxin, taipoxin and ammodytoxin A was significantly prolonged. In contrast, suramin did not significantly affect the facilitation induced by the potassium channel blocking toxin dendrotoxin I when applied under the same conditions. In addition, application of 0.3mM suramin did not prevent the facilitatory actions of 3,4-diaminopyridine (3,4-DAP) and tetraethylammonium chloride (TEA). Overall, the mechanism whereby suramin reduces the effects of PLA(2) neurotoxins remains elusive. Since suramin reduces both enzyme-dependent and enzyme-independent effects of the toxins, suramin is not acting as a simple enzyme inhibitor. Furthermore, the observation that suramin does not affect actions of standard K(+) channel blockers suggests that suramin does not stabilise nerve terminals. PMID- 21544176 TI - The inhibitory effect of Camellia sinensis extracts against the neuromuscular blockade of Crotalus durissus terrificus venom. AB - In geographically isolated populations where intensive medical care or serum therapy is not easily accessible snake envenomation is a major cause for concern. The aim of the present study was to test Camellia sinensis extracts, theaflavin and epigallocatechin (two of the main C. sinensis components) against the irreversible neuromuscular blockade induced by Crotalus durissus terrificus venom in mouse phrenic-nerve diaphragm preparations. A quantitative histological study was also performed. The venom (20ug/ml) completely decreased twitch tension after 70min and 5ug/ml venom abolished 50% of twitch amplitude after 60min. C. sinensis extract induced intense facilitatory effect in the preparation activity at 0.2mg/ml and slightly facilitatory effect at 0.05mg/ml. Both 0.05mg/ml C. sinensis extract and 0.05mg/ml commercial theaflavin maintained partial muscular activity in presence of 5ug/ml venom. The histological data confirms that Cs is able to protect the muscle from the myotoxic activity of the venom. Commercial epigallocatechin gallate did not show pre-synaptic nor post-synaptic activities. C. sinensis extract was able to protect the mouse phrenic-nerve diaphragm against the irreversible neuromuscular blockade induced by C. durissus terrificus venom. PMID- 21544177 TI - Antivenomics of Atropoides mexicanus and Atropoides picadoi snake venoms: Relationship to the neutralization of toxic and enzymatic activities. AB - Viperid snakes of the genus Atropoides are distributed in Mexico and Central America and, owing to their size and venom yield, are capable of provoking severe envenomings in humans. This study evaluated, using an 'antivenomics' approach, the ability of a polyspecific (polyvalent) antivenom manufactured in Costa Rica to recognize the proteins of Atropoides mexicanus and A. picadoi venoms, which are not included in the immunization mixture. In addition, the neutralization of lethal, hemorrhagic, myotoxic, coagulant, proteinase and phospholipase A(2) (PLA(2)) activities of these venoms by the antivenom was assessed. The antivenom was highly-effective in immunodepleting many venom components, particularly high molecular mass P-III metalloproteinases (SVMPs), L-amino acid oxidases, and some serine proteinases and P-I SVMPs. In contrast, PLA(2)s, certain serine proteinases and P-I SVMPs, and a C type lectin-like protein were only partially immunodepleted, and two PLA(2) molecules were not depleted at all. The antivenom was able to neutralize all toxic and enzymatic activities tested, although neutralization of lethality by A. nummifer venom was achieved when a challenge dose of 3 LD(50)s of venom was used, but was iffective when 4 LD(50)s were used. These results, and previously obtained evidence on the immunoreactivity of this antivenom towards homologous and heterologous venoms, revealed the low immunogenicity of a number of venom components (PLA(2)s, CRISPs, P-I SVMPs, and some serine proteinases), underscoring the need to search for innovative immunization protocols to improve the immune response to these antigens. PMID- 21544178 TI - Proteolytic activity of Elapid and Viperid Snake venoms and its implication to digestion. AB - Testing whether venoms may aid in digestion of the prey, eleven snake venoms were compared for the presence of proteases and endopeptidases that function in alkaline pH conditions. In vitro experiments examined the relative protease and endopeptidase activity of the venoms, which involved combining bovine muscle and snake venom in a buffered solution, encased within dialysis tubing. This mixture was then incubated at room temperature (~20 degrees C) for 24hr, with constant shaking. Bicinchoninic acid (BCA) assay and ninhydrin assay were used to determine peptide and amino acid concentrations. Histological and immunohistochemical investigations using N. kaouthia venom confirmed in vitro findings. Results show that B. arietans venom generated the highest amount of protein/peptides and amino acids in the dialysates, while O. scutellatus, N. ater niger and P. textilis venom did not show any significant protein degradation under alkaline conditions. Histological examination revealed varying degrees of muscle cell damage for each of the venom investigated, and the immunohistochemical study on N. kaouthia venom showed that the venom penetrated the muscle tissue to a significant degree. In vitro assays and histological results indicate that particular venoms may possess the ability to enhance digestion of bovine muscle tissue. PMID- 21544179 TI - Effect of honey bee venom on differentiation of cholinergic neurons. AB - Mouse P19 embryonic carcinoma (EC) cells are pluripotent and can differentiate into a population consisting largely of neurons and glia cells using a concentration of 5x10(-7)M of retinoic acid (RA). Thus, P19 EC cells are a good model system to study events occurring during the critical phases of neuronal differentiation, in vitro. Honey bee venom (BV) consists of mellitin, phospholipase A2, apamin and several other bioactive substances. Previous studies have shown that mellitin and phospholipase A2 - two major components of BV - play an important role in the differentiation of neurons. The purpose of this study was to examine effects of BV and RA on the differentiation of cholinergic neuron in P19 cell line. Preliminary results obtained from morphological examination showed that six days after treatment with 5x10(-7)M RA, P19 cells produced processes, and gradually obtained neuronal phenotype at approximately day-10. All cells then died at day-11. P19 cells treated with 1.3MUg/ml BV produced processes on day-6 and neurons appeared in the next four days. They then proceeded to total size until day-10 and produced elongated processes; however, all cells died on day-11. Using BV and RA together had the same effect but more pronounced differentiating results. It can be concluded that applying BV with RA has an additive effect on cell differentiation and proliferation. The presence of acetylcholinesterase (AChE), frequently used as a marker for neuronal differentiation, was also determined and found using DTNB. PMID- 21544180 TI - Non-covalent interaction of phospholipase A(2) (PLA(2)) and kaouthiotoxin (KTX) from venom of Naja kaouthia exhibits marked synergism to potentiate their cytotoxicity on target cells. AB - Present study shows that non-covalent interaction of kaouthiotoxin (KTX) with their respective pohospholipase A(2) (PLA(2)) from the venom of N. kaouthia displayed marked synergism to exert cytotoxicity without altering the biochemical properties of PLA(2). For example, although NK-PLA(2) or KTX alone did not induce appreciable hemolysis of washed human erythrocytes; however, the hemolytic potency of NK-PLA(2): KTX complex was significantly higher. Identically, selective lysis of virus infected Sf9 and normal Tn insect cells was further enhanced by the cognate NK-PLA(2): KTX complex as compared to individual components of the complex. Gas-chromatographic analysis of fatty acids released from intact erythrocytes by cytotoxic action of individual NK-PLA(2) and NK PLA(2): KTX complex demonstrated that ratio between saturated fatty acids (SFA) and unsaturated FA (UFA) was increasing with time of hydrolysis of RBC either in the case of NK-PLA(2) or NK-PLA(2)-KTX complex suggesting NK-PLA(2)-KTX complex apparently displayed the more preference for glycerophospholipids with SFAs on the sn-2 position. Therefore, it may be suggested that KTX first destabilize the target cell membrane followed by higher enzymatic activity of PLA(2) on dislocated and disorganized phospholipid bilayers resulting in a significantly higher (p < 0.05) membrane damage by NK-PLA(2)-KTX complex compared to individual components of the complex. PMID- 21544181 TI - A novel bioactive peptide from wasp venom. AB - Wasp venoms contain a number of pharmacologically active biomolecules, undertaking a wide range of functions necessary for the wasp's survival. We purified and characterized a novel bioactive peptide (vespin) from the venoms of Vespa magnifica (Smith) wasps with unique primary structure. Its amino acid sequence was determined to be CYQRRVAITAGGLKHRLMSSLIIIIIIRINYLRDNSVIILESSY. It has 44 residues including 15 leucines or isoleucines (32%) in the sequence. Vespin showed contractile activity on isolated ileum smooth muscle. The cDNA encoding vespin precursor was cloned from the cDNA library of the venomous glands. The precursor consists of 67 amino acid residues including the predicted signal peptide and mature vespin. A di-basic enzymatic processing site (-KR-) is located between the signal peptide and the mature peptide. Vespin did not show similarity with any known proteins or peptides by BLAST search, suggesting it is a novel bioactive peptide from wasp venoms. PMID- 21544182 TI - The pharmacokinetics of Iranian scorpion Odonthubuthus doriae venom and the available antivenom. AB - In Iran intramuscular (IM) administration of antivenoms is used for the treatment of human scorpion envenoming of six medically dangerous scorpion species, including Odonthubuthus doriae (O. doriae). The purpose of the current study is to investigate the efficiency of the intramuscular route and the delay of injection on the neutralizing effect of the available polyvalent antivenom. We compared the pharmacokinetics parameters of O. doriae venom and its antivenom. 5ug (131)I-labeled venom and 0.2ul of antivenom were administered via subcutaneous (SC) or IM into rats. Blood samples were taken at various predetermined time intervals during a 24hr period for the venom and a 360min period for the antivenom. The radio-iodination was carried out using the chloramin-T method. The results showed that pharmacokinetic parameters of the venom were T(1/2) = 496.53min; V(d) = 1522ml/kg; Cl = 2.12 ml/kg/min; mean resident residual time (MRT) = 555.77min, and for the antivenom T(1/2) = 902.13min, V(d) = 666.66 ml/kg , Cl = 0.512 ml/kg/min and MRT = 1292min. The total body clearance of the venom is relatively low in agreement with a high mean residence time. Higher AUC and C(max) values for the antivenom as well as its longer residence time indicate that the venom and antivenom are expected to have enough opportunity to interact in the tissue compartments. Over, this study suggests that the intramuscular administration of a single dose of antivenom (2 vials each of 5ml) based on current protocol in Iran is a suitable route for the treatment of envenomation with O. doriae. Prudently, further clinical studies with similar aims need to be carried out to confirm these findings in human victims. PMID- 21544183 TI - Heparin at low concentration acts as antivenom against Bothrops jararacussu venom and bothropstoxin-I neurotoxic and myotoxic actions. AB - Heparin has been shown to antagonize myotoxic effects of crotaline venoms. Here a very low heparin concentration (LHC) was examined in its ability to antagonize the neurotoxic/myotoxic effects of Bothrops jararacussu venom and its phospholipase A(2) myotoxin, bothropstoxin-I (BthTX-I), in an in vitroz nerve muscle preparation and in mice gastrocnemius. Normalization of results was done by assays with commercial antibothropic antivenom (CBA). LHC (1IU/ml) added to the incubation bath reduced by 4- and 4.5-fold (vs 2.8- and 2.5-fold by CBA) the neuromuscular paralysis, by 5.4 and 4.4-fold (vs 2.5- and 13.3-fold by CBA) the percentage of fibers damaged and by 6- and 1.7-fold (vs 30- and 1.6-fold by CBA) the CK activity induced by B. jararacussu and BthTX-I, respectively. Protamine sulphate added 15min after the incubation of the preparation with LHC+venom, avoided the LHC neutralizing effect against venom neurotoxicity. This strongly attests that given the polycationic nature of protamine, it probably complexed with the polyanionic heparin making it unattainable for binding to basic components of venom, reducing toxicity. Since heparin antagonism is generally stronger against venom effects than is myotoxin we discuss that other venom components than the BthTX-I are likely target for the antagonism promoted by the polyanionic heparin. PMID- 21544184 TI - Differences in venom toxicity and antigenicity between females and males Tityus nororientalis (Buthidae) scorpions. AB - Venom from male and female specimens of the medically important Venezuelan scorpion Tityus nororientalis have been compared. Males showed a significantly higher venom yield (2.39mg/individual) compared to female scorpions (0.98mg/individual). Female venom was significantly more toxic than that of males, with a median lethal dose (LD(50)) in C57BL/6 mice of 9.46 MUg venom protein/gm body weight [95% confidence interval (8.91-9.94)] whereas LD(50) for males was 13.36(12.58-14.03) MUg/gm. Mass spectral analyses by MALDI-TOF revealed differences in venom composition between males and females. From a clinical standpoint, the time course of toxicity course indicated a tendency, in the case of the female venom, to elicit the earlier occurrence of severe signs such as sialorrhea, dyspnea (bradypnea/apnea) and exophthalmus particularly in the late toxicity phase. Female venom was significantly less efficient than male venom to inhibit the binding of anti-T. discrepans antibodies to immobilized T. discrepans venom in ELISA assays, suggesting sex-related differences in the bioactive surfaces of T. nororientalis toxins. These results indicate that males and females of T. nororientalis produce venoms with different composition and activity which may have epidemiological implications. PMID- 21544185 TI - Deep coma and hypokalaemia of unknown aetiology following Bungarus caeruleus bites: Exploration of pathophysiological mechanisms with two case studies. AB - Bungarotoxin present in Bungarus caeruleus (BC) causes life threatening respiratory muscle paralysis. Deep coma and hypokalaemia have been observed in a significant proportion of patients, but the cause is unknown. We postulate the likely mechanism behind these two phenomena. We studied clinical details of two patients admitted with deep coma and performed electroencephalograms (EEG) and brain stem auditory and visual evoked potentials (BAEP and VEP). Daily serum potassium was measured along with urinary potassium excretion as a marker of total extracellular body potassium. Both patients had no brain stem reflexes on admission and the EEG revealed absent alpha and delta activity and presence of dominant theta activity. Alpha rhythm returned on the 3(rd) day in one patient, while in the other it did not, and the latter patient died on the 13(th) day due to disseminated intravascular coagulation. BAEP were delayed and VEP were absent in the deceased patient. Both had low serum potassium and low urinary potassium excretion. Replacement of potassium (up to 1.5mmol/kg/day) did not improve serum potassium and urinary potassium excretion. Absent alpha and delta activity in EEG and delayed BAEP and absent VEP are suggestive of a central action of the venom on both the cortical and brain stem neurones. Persistently low serum potassium and reduced urinary potassium excretion are suggestive of intracellular shift as the causative mechanism of hypokalaemia. PMID- 21544186 TI - Ontogenesis, gender, and molting influence the venom yield in the spider Coremiocnemis tropix (Araneae, Theraphosidae). AB - The demand for spider venom increases along with the growing popularity of venoms based research. A deeper understanding of factors that influence the venom yield in spiders would therefore be of interest to both commercial venom suppliers and research facilities. The present study addresses the influence of several factors on the venom yield by systematically analyzing the data obtained from 1773 electrical milkings of the Australian theraphosid spider Coremiocnemis tropix. Gender and ontogenesis were found to cause a major effect on the venom yield, as adult female C. tropix yielded significantly more venom than adult males. During ontogenesis, the venom yield increased with increasing size of the spiders. Furthermore, a significant reduction in the venom yield during the 50-day time interval preceding a molt was found. On the other hand, extended milking intervals (up to 449 days) and different states of nutrition (as an indication of how well the spider was fed) did not significantly affect the venom yield. Overall, the present findings suggest that venom production in spiders is carefully balanced between the demand for venom and the energy costs associated with its production. It can therefore be concluded that, in line with the venom optimization hypothesis, venom is a precious resource for spiders, which have implemented control mechanisms to ensure economical venom production and usage. PMID- 21544187 TI - Therapy-related myelodysplastic syndrome presenting as fulminant heart failure secondary to myeloid sarcoma. AB - Rapidly progressive heart failure is commonly caused by an extensive myocardial infarction, a mechanical complication of infarction, myocarditis, or acute valvular insufficiency. We present an unusual case that was caused by a diffuse infiltration of the myocardium with leukemic cells (myeloid sarcoma). The patient presented with episodic shortness of breath, he was anemic and thrombocytopenic, and his bone marrow biopsy revealed myelodysplastic syndrome from treatment for oligodendroglioma. His clinical course was characterized by a chronic leak of cardiac enzymes, a new right bundle branch block, and a large pericardial effusion causing tamponade and death from fulminant heart failure and ventricular arrhythmias within 2 weeks. At autopsy, the heart was massively infiltrated with myeloblasts and other immature myeloid cells. There was no evidence of acute leukemia in the bone marrow or peripheral blood. Cardiac infiltration in a patient with myelodysplastic syndrome is extremely rare, especially in the absence of bone marrow involvement by blasts. The recognition of this entity is becoming increasingly important as the incidence of cardiac myeloid sarcoma may be on the rise as the number of patients receiving chemotherapy increases. PMID- 21544188 TI - Spirulina (Arthrospira) industry in Inner Mongolia of China: current status and prospects. AB - This paper outlines an investigation on current situation of Spirulina (Arthrospira) industry in Inner Mongolia, an internal region of China with temperate continental climate. More than 20 Spirulina plants have been established in Inner Mongolia since 2001, most of which are located at Wulan Town in the Ordos Plateau. By the end of 2009, the total annual production of Spirulina in the Ordos Plateau surpassed 700 t (dw), which account for ca. 80% of the total productivity of Inner Mongolia, and ca. 20% of China. Besides abundant solar radiation and enough freshwater favorable for Spirulina production, the three technical strategies contribute to the prosperity and success of Spirulina industry in the region: (1) reducing the cost or investment by overall advantages of rich local natural resources with low cost for Spirulina production, such as alkaline lakes, coal, electricity, and sandy land; (2) controlling the culture temperature and to avoid contamination by building plastic greenhouses on raceway ponds, (3) reducing investment by simplifying the construction of the ponds and the greenhouses. As the result, the growth period of Spirulina has been prolonged from about 120 to about 165 days, the cost of Spirulina has decreased by 25-30%, and the quality of products has been enhanced substantially. Inner Mongolia is expected to become the largest base for Spirulina production not only in China, but also in the world in the near future. PMID- 21544189 TI - LC-MS-MS Method for the Analysis of New Non-Imidazole Histamine H(3) Receptor Antagonist 1-[3-(4-tert-Butylphenoxy)propyl]piperidine in Rat Serum-Application to Pharmacokinetic Studies. AB - A sensitive and specific liquid chromatography electrospray ionisation-tandem mass spectrometry method for determination of new non-imidazole histamine H(3) receptor antagonist 1-[3-(4-tert-butylphenoxy)propyl]piperidine (DL76) in rat serum has been developed and validated. Chromatography was performed on a XBridgeTM C18 analytical column (2.1 * 30 mm, 3.5 um, Waters, Ireland) with gradient elution using a mobile phase containing acetonitrile and water with an addition of 0.1% of formic acid. Detection was achieved by an Applied Biosystems MDS Sciex (Concord, Ontario, Canada) API 2000 triple quadrupole mass spectrometer. Electrospray ionization (ESI) was used for ion production. The limit of detection in the SRM mode was found to be 0.5 ng mL(-1). The limit of quantification was 1 ng mL(-1). The precision and accuracy for both intra- and inter-day determination of DL76 ranged from 1.65 to 15.09% and from 88.74 to 113.43%. The results of this analytical method validation allow to carry out pharmacokinetic studies in rats. The method was used for the pilot study of the pharmacokinetic behavior of DL76 in rats after intravenous administration. PMID- 21544190 TI - Development of a high-throughput Candida albicans biofilm chip. AB - We have developed a high-density microarray platform consisting of nano-biofilms of Candida albicans. A robotic microarrayer was used to print yeast cells of C. albicans encapsulated in a collagen matrix at a volume as low as 50 nL onto surface-modified microscope slides. Upon incubation, the cells grow into fully formed "nano-biofilms". The morphological and architectural complexity of these biofilms were evaluated by scanning electron and confocal scanning laser microscopy. The extent of biofilm formation was determined using a microarray scanner from changes in fluorescence intensities due to FUN 1 metabolic processing. This staining technique was also adapted for antifungal susceptibility testing, which demonstrated that, similar to regular biofilms, cells within the on-chip biofilms displayed elevated levels of resistance against antifungal agents (fluconazole and amphotericin B). Thus, results from structural analyses and antifungal susceptibility testing indicated that despite miniaturization, these biofilms display the typical phenotypic properties associated with the biofilm mode of growth. In its final format, the C. albicans biofilm chip (CaBChip) is composed of 768 equivalent and spatially distinct nano biofilms on a single slide; multiple chips can be printed and processed simultaneously. Compared to current methods for the formation of microbial biofilms, namely the 96-well microtiter plate model, this fungal biofilm chip has advantages in terms of miniaturization and automation, which combine to cut reagent use and analysis time, minimize labor intensive steps, and dramatically reduce assay costs. Such a chip should accelerate the antifungal drug discovery process by enabling rapid, convenient and inexpensive screening of hundreds-to thousands of compounds simultaneously. PMID- 21544191 TI - MassCode liquid arrays as a tool for multiplexed high-throughput genetic profiling. AB - Multiplexed detection assays that analyze a modest number of nucleic acid targets over large sample sets are emerging as the preferred testing approach in such applications as routine pathogen typing, outbreak monitoring, and diagnostics. However, very few DNA testing platforms have proven to offer a solution for mid plexed analysis that is high-throughput, sensitive, and with a low cost per test. In this work, an enhanced genotyping method based on MassCode technology was devised and integrated as part of a high-throughput mid-plexing analytical system that facilitates robust qualitative differential detection of DNA targets. Samples are first analyzed using MassCode PCR (MC-PCR) performed with an array of primer sets encoded with unique mass tags. Lambda exonuclease and an array of MassCode probes are then contacted with MC-PCR products for further interrogation and target sequences are specifically identified. Primer and probe hybridizations occur in homogeneous solution, a clear advantage over micro- or nanoparticle suspension arrays. The two cognate tags coupled to resultant MassCode hybrids are detected in an automated process using a benchtop single quadrupole mass spectrometer. The prospective value of using MassCode probe arrays for multiplexed bioanalysis was demonstrated after developing a 14plex proof of concept assay designed to subtype a select panel of Salmonella enterica serogroups and serovars. This MassCode system is very flexible and test panels can be customized to include more, less, or different markers. PMID- 21544192 TI - Novel, divergent simian hemorrhagic fever viruses in a wild Ugandan red colobus monkey discovered using direct pyrosequencing. AB - BACKGROUND: Simian hemorrhagic fever virus (SHFV) has caused lethal outbreaks of hemorrhagic disease in captive primates, but its distribution in wild primates has remained obscure. Here, we describe the discovery and genetic characterization by direct pyrosequencing of two novel, divergent SHFV variants co-infecting a single male red colobus monkey from Kibale National Park, Uganda. METHODOLOGY/PRINCIPAL FINDINGS: The viruses were detected directly from blood plasma using pyrosequencing, without prior virus isolation and with minimal PCR amplification. The two new SHFV variants, SHFV-krc1 and SHFV-krc2 are highly divergent from each other (51.9% nucleotide sequence identity) and from the SHFV type strain LVR 42-0/M6941 (52.0% and 51.8% nucleotide sequence identity, respectively) and demonstrate greater phylogenetic diversity within SHFV than has been documented within any other arterivirus. Both new variants nevertheless have the same 3' genomic architecture as the type strain, containing three open reading frames not present in the other arteriviruses. CONCLUSIONS/SIGNIFICANCE: These results represent the first documentation of SHFV in a wild primate and confirm the unusual 3' genetic architecture of SHFV relative to the other arteriviruses. They also demonstrate a degree of evolutionary divergence within SHFV that is roughly equivalent to the degree of divergence between other arterivirus species. The presence of two such highly divergent SHFV variants co infecting a single individual represents a degree of within-host viral diversity that exceeds what has previously been reported for any arterivirus. These results expand our knowledge of the natural history and diversity of the arteriviruses and underscore the importance of wild primates as reservoirs for novel pathogens. PMID- 21544193 TI - A novel DC therapy with manipulation of MKK6 gene on nickel allergy in mice. AB - BACKGROUND: Although the activation of dermal dendritic cells (DCs) or Langerhans cells (LCs) via p38 mitogen-activated protein kinase (MAPK) plays a crucial role in the pathogenesis of metal allergy, the in vivo molecular mechanisms have not been identified and a possible therapeutic strategy using the control of dermal DCs or LCs has not been established. In this study, we focused on dermal DCs to define the in vivo mechanisms of metal allergy pathogenesis in a mouse nickel (Ni) allergy model. The effects of DC therapy on Ni allergic responses were also investigated. METHODS AND FINDING: The activation of dermal DCs via p38 MAPK triggered a T cell-mediated allergic immune response in this model. In the MAPK signaling cascade in DCs, Ni potently phosphorylated MAP kinase kinase 6 (MKK6) following increased DC activation. Ni-stimulated DCs could prime T cell activation to induce Ni allergy. Interestingly, when MKK6 gene-transfected DCs were transferred into the model mice, a more pronounced allergic reaction was observed. In addition, injection of short interfering (si) RNA targeting the MKK6 gene protected against a hypersensitivity reaction after Ni immunization. The cooperative action between T cell activation and MKK6-mediated DC activation by Ni played an important role in the development of Ni allergy. CONCLUSIONS: DC activation by Ni played an important role in the development of Ni allergy. Manipulating the MKK6 gene in DCs may be a good therapeutic strategy for dermal Ni allergy. PMID- 21544194 TI - Isolation and mutagenesis of a capsule-like complex (CLC) from Francisella tularensis, and contribution of the CLC to F. tularensis virulence in mice. AB - BACKGROUND: Francisella tularensis is a category-A select agent and is responsible for tularemia in humans and animals. The surface components of F. tularensis that contribute to virulence are not well characterized. An electron dense capsule has been postulated to be present around F. tularensis based primarily on electron microscopy, but this specific antigen has not been isolated or characterized. METHODS AND FINDINGS: A capsule-like complex (CLC) was effectively extracted from the cell surface of an F. tularensis live vaccine strain (LVS) lacking O-antigen with 0.5% phenol after 10 passages in defined medium broth and growth on defined medium agar for 5 days at 32 degrees C in 7% CO2. The large molecular size CLC was extracted by enzyme digestion, ethanol precipitation, and ultracentrifugation, and consisted of glucose, galactose, mannose, and Proteinase K-resistant protein. Quantitative reverse transcriptase PCR showed that expression of genes in a putative polysaccharide locus in the LVS genome (FTL_1432 through FTL_1421) was upregulated when CLC expression was enhanced. Open reading frames FTL_1423 and FLT_1422, which have homology to genes encoding for glycosyl transferases, were deleted by allelic exchange, and the resulting mutant after passage in broth (LVSDelta1423/1422_P10) lacked most or all of the CLC, as determined by electron microscopy, and CLC isolation and analysis. Complementation of LVSDelta1423/1422 and subsequent passage in broth restored CLC expression. LVSDelta1423/1422_P10 was attenuated in BALB/c mice inoculated intranasally (IN) and intraperitoneally with greater than 80 times and 270 times the LVS LD50, respectively. Following immunization, mice challenged IN with over 700 times the LD50 of LVS remained healthy and asymptomatic. CONCLUSIONS: Our results indicated that the CLC may be a glycoprotein, FTL_1422 and -FTL_1423 were involved in CLC biosynthesis, the CLC contributed to the virulence of F. tularensis LVS, and a CLC-deficient mutant of LVS can protect mice against challenge with the parent strain. PMID- 21544195 TI - Analysis of wilms tumors using SNP mapping array-based comparative genomic hybridization. AB - Wilms tumor (WT) has been a model to study kidney embryogenesis and tumorigenesis and, although associated with hereditary, cancer predisposition syndromes, the majority of tumors occur sporadically. To analyze genetic changes in WT we have defined copy number changes and loss of heterozygosity in 56 Wilms tumors using high resolution oligonucleotide arrays at a average resolution of ~12 Kb. Consistent deletions were seen on chromosomes 1p, 4q, 7p, 9q, 11p, 11q, 14q, 16q, and 21q. High frequency gains were seen for 1q and lower frequency gains were seen on 7q and chromosomes 8, 12 and 18. The high resolution provided by the SNP mapping arrays has defined minimal regions of deletion for many of these LOH events. Analysis of CNAs by tumor stage show relatively stable karyotypes in stage 1 tumors and more complex aCGH profiles in tumors from stages 3-5. PMID- 21544196 TI - Exploring the diversity of plant DNA viruses and their satellites using vector enabled metagenomics on whiteflies. AB - Current knowledge of plant virus diversity is biased towards agents of visible and economically important diseases. Less is known about viruses that have not caused major diseases in crops, or viruses from native vegetation, which are a reservoir of biodiversity that can contribute to viral emergence. Discovery of these plant viruses is hindered by the traditional approach of sampling individual symptomatic plants. Since many damaging plant viruses are transmitted by insect vectors, we have developed "vector-enabled metagenomics" (VEM) to investigate the diversity of plant viruses. VEM involves sampling of insect vectors (in this case, whiteflies) from plants, followed by purification of viral particles and metagenomic sequencing. The VEM approach exploits the natural ability of highly mobile adult whiteflies to integrate viruses from many plants over time and space, and leverages the capability of metagenomics for discovering novel viruses. This study utilized VEM to describe the DNA viral community from whiteflies (Bemisia tabaci) collected from two important agricultural regions in Florida, USA. VEM successfully characterized the active and abundant viruses that produce disease symptoms in crops, as well as the less abundant viruses infecting adjacent native vegetation. PCR assays designed from the metagenomic sequences enabled the complete sequencing of four novel begomovirus genome components, as well as the first discovery of plant virus satellites in North America. One of the novel begomoviruses was subsequently identified in symptomatic Chenopodium ambrosiodes from the same field site, validating VEM as an effective method for proactive monitoring of plant viruses without a priori knowledge of the pathogens. This study demonstrates the power of VEM for describing the circulating viral community in a given region, which will enhance our understanding of plant viral diversity, and facilitate emerging plant virus surveillance and management of viral diseases. PMID- 21544197 TI - CORE: a phylogenetically-curated 16S rDNA database of the core oral microbiome. AB - Comparing bacterial 16S rDNA sequences to GenBank and other large public databases via BLAST often provides results of little use for identification and taxonomic assignment of the organisms of interest. The human microbiome, and in particular the oral microbiome, includes many taxa, and accurate identification of sequence data is essential for studies of these communities. For this purpose, a phylogenetically curated 16S rDNA database of the core oral microbiome, CORE, was developed. The goal was to include a comprehensive and minimally redundant representation of the bacteria that regularly reside in the human oral cavity with computationally robust classification at the level of species and genus. Clades of cultivated and uncultivated taxa were formed based on sequence analyses using multiple criteria, including maximum-likelihood-based topology and bootstrap support, genetic distance, and previous naming. A number of classification inconsistencies for previously named species, especially at the level of genus, were resolved. The performance of the CORE database for identifying clinical sequences was compared to that of three publicly available databases, GenBank nr/nt, RDP and HOMD, using a set of sequencing reads that had not been used in creation of the database. CORE offered improved performance compared to other public databases for identification of human oral bacterial 16S sequences by a number of criteria. In addition, the CORE database and phylogenetic tree provide a framework for measures of community divergence, and the focused size of the database offers advantages of efficiency for BLAST searching of large datasets. The CORE database is available as a searchable interface and for download at http://microbiome.osu.edu. PMID- 21544198 TI - Female resistance to invading males increases infanticide in langurs. AB - BACKGROUND: Infanticide by adult male occurs in many mammalian species under natural conditions, and it is often assumed to be a goal-directed action and explained predominately by sexual selection. Motivation of this behavior in mammals is limitedly involved. METHODOLOGY AND PRINCIPAL FINDINGS: We used long term reproductive records and direct observation in captivity and in the field of two snub-nosed langur species on the basis of individual identification to investigate how infanticide happened and to be avoided in nonhuman primates. Our observations suggested that infanticide by invading males might be more accidental than goal-directed. The invading male seemed to monopolize all the females including lactating mothers during takeovers. Multiparous mothers who accepted the invading male shortly after takeovers avoided infanticide in most cases. Our results conjectured primiparous mothers would decrease infanticidal possibility if they sexually accepted the invading male during or immediately after takeovers. In the studied langur species, voluntary abortion or mating with the invading male was evidently adopted by females to limit or avoid infanticide by takeover males. CONCLUSIONS AND SIGNIFICANCE: The objective of the invading male was to monopolize all adult females after his takeover. It appeared that the mother's resistance to accepting the new male as a mating partner was the primary incentive for infanticide. Motivation analysis might be helpful to further understand why infanticide occurs in primate species. PMID- 21544199 TI - Epigenetic inactivation of the miR-124-1 in haematological malignancies. AB - miR-124-1 is a tumour suppressor microRNA (miR). Epigenetic deregulation of miRs is implicated in carcinogenesis. Promoter DNA methylation and histone modification of miR-124-1 was studied in 5 normal marrow controls, 4 lymphoma, 8 multiple myeloma (MM) cell lines, 230 diagnostic primary samples of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), MM, and non-Hodgkin's lymphoma (NHL), and 53 MM samples at stable disease or relapse. Promoter of miR-124-1 was unmethylated in normal controls but homozygously methylated in 4 of 4 lymphoma and 4 of 8 myeloma cell lines. Treatment of 5-Aza-2'-deoxycytidine led to miR-124 1 demethylation and re-expression of mature miR-124, which also associated with emergence of euchromatic trimethyl H3K4 and consequent downregulation of CDK6 in myeloma cells harboring homozygous miR-124-1 methylation. In primary samples at diagnosis, miR-124-1 methylation was absent in CML but detected in 2% each of MM at diagnosis and relapse/progression, 5% ALL, 15% AML, 14% CLL and 58.1% of NHL (p<0.001). Amongst lymphoid malignancies, miR-124-1 was preferentially methylated in NHL than MM, CLL or ALL. In primary lymphoma samples, miR-124-1 was preferentially hypermethylated in B- or NK/T-cell lymphomas and associated with reduced miR-124 expression. In conclusion, miR-124-1 was hypermethylated in a tumour-specific manner, with a heterochromatic histone configuration. Hypomethylation led to partial restoration of euchromatic histone code and miR re expression. Infrequent miR-124-1 methylation detected in diagnostic and relapse MM samples showed an unimportant role in MM pathogenesis, despite frequent methylation found in cell lines. Amongst haematological cancers, miR-124-1 was more frequently hypermethylated in NHL, and hence warrants further study. PMID- 21544200 TI - Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network. AB - Cadmium (Cd), a toxic environmental contaminant, induces oxidative stress, leading to neurodegenerative disorders. Recently we have demonstrated that Cd induces neuronal apoptosis in part by activation of the mitogen-activated protein kineses (MAPK) and mammalian target of rapamycin (mTOR) pathways. However, the underlying mechanism remains elusive. Here we show that Cd elevated intracellular calcium ion ([Ca2+](i)) level in PC12, SH-SY5Y cells and primary murine neurons. BAPTA/AM, an intracellular Ca2+ chelator, abolished Cd-induced [Ca2+](i) elevation, and blocked Cd activation of MAKPs including extracellular signal regulated kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK) and p38, and mTOR mediated signaling pathways, as well as cell death. Pretreatment with the extracellular Ca2+ chelator EGTA also prevented Cd-induced [Ca2+](i) elevation, MAPK/mTOR activation, as well as cell death, suggesting that Cd-induced extracellular Ca2+ influx plays a critical role in contributing to neuronal apoptosis. In addition, calmodulin (CaM) antagonist trifluoperazine (TFP) or silencing CaM attenuated the effects of Cd on MAPK/mTOR activation and cell death. Furthermore, Cd-induced [Ca2+](i) elevation or CaM activation resulted in induction of reactive oxygen species (ROS). Pretreatment with BAPTA/AM, EGTA or TFP attenuated Cd-induced ROS and cleavage of caspase-3 in the neuronal cells. Our findings indicate that Cd elevates [Ca2+](i), which induces ROS and activates MAPK and mTOR pathways, leading to neuronal apoptosis. The results suggest that regulation of Cd-disrupted [Ca2+](i) homeostasis may be a new strategy for prevention of Cd-induced neurodegenerative diseases. PMID- 21544201 TI - Variation in array size, monomer composition and expression of the macrosatellite DXZ4. AB - Macrosatellites are some of the most polymorphic regions of the human genome, yet many remain uncharacterized despite the association of some arrays with disease susceptibility. This study sought to explore the polymorphic nature of the X linked macrosatellite DXZ4. Four aspects of DXZ4 were explored in detail, including tandem repeat copy number variation, array instability, monomer sequence polymorphism and array expression. DXZ4 arrays contained between 12 and 100 3.0 kb repeat units with an average array containing 57. Monomers were confirmed to be arranged in uninterrupted tandem arrays by restriction digest analysis and extended fiber FISH, and therefore DXZ4 encompasses 36-288 kb of Xq23. Transmission of DXZ4 through three generations in three families displayed a high degree of meiotic instability (8.3%), consistent with other macrosatellite arrays, further highlighting the unstable nature of these sequences in the human genome. Subcloning and sequencing of complete DXZ4 monomers identified numerous single nucleotide polymorphisms and alleles for the three microsatellite repeats located within each monomer. Pairwise comparisons of DXZ4 monomer sequences revealed that repeat units from an array are more similar to one another than those originating from different arrays. RNA fluorescence in situ hybridization revealed significant variation in DXZ4 expression both within and between cell lines. DXZ4 transcripts could be detected originiating from both the active and inactive X chromosome. Expression levels of DXZ4 varied significantly between males, but did not relate to the size of the array, nor did inheritance of the same array result in similar expression levels. Collectively, these studies provide considerable insight into the polymorphic nature of DXZ4, further highlighting the instability and variation potential of macrosatellites in the human genome. PMID- 21544202 TI - Short-term complexity of cardiac autonomic control during sleep: REM as a potential risk factor for cardiovascular system in aging. AB - INTRODUCTION: Sleep is a complex phenomenon characterized by important modifications throughout life and by changes of autonomic cardiovascular control. Aging is associated with a reduction of the overall heart rate variability (HRV) and a decrease of complexity of autonomic cardiac regulation. The aim of our study was to evaluate the HRV complexity using two entropy-derived measures, Shannon Entropy (SE) and Corrected Conditional Entropy (CCE), during sleep in young and older subjects. METHODS: A polysomnographic study was performed in 12 healthy young (21.1+/-0.8 years) and 12 healthy older subjects (64.9+/-1.9 years). After the sleep scoring, heart period time series were divided into wake (W), Stage 1-2 (S1-2), Stage 3-4 (S3-4) and REM. Two complexity indexes were assessed: SE(3) measuring the complexity of a distribution of 3-beat patterns (SE(3) is higher when all the patterns are identically distributed and it is lower when some patterns are more likely) and CCE(min) measuring the minimum amount of information that cannot be derived from the knowledge of previous values. RESULTS: Across the different sleep stages, young subjects had similar RR interval, total variance, SE(3) and CCE(min). In the older group, SE(3) and CCE(min) were reduced during REM sleep compared to S1-2, S3-4 and W. Compared to young subjects, during W and sleep the older subjects showed a lower RR interval and reduced total variance as well as a significant reduction of SE(3) and CCE(min). This decrease of entropy measures was more evident during REM sleep. CONCLUSION: Our study indicates that aging is characterized by a reduction of entropy indices of cardiovascular variability during wake/sleep cycle, more evident during REM sleep. We conclude that during aging REM sleep is associated with a simplification of cardiac control mechanisms that could lead to an impaired ability of the cardiovascular system to react to cardiovascular adverse events. PMID- 21544203 TI - Thyroid disruption by Di-n-butyl phthalate (DBP) and mono-n-butyl phthalate (MBP) in Xenopus laevis. AB - BACKGROUND: Di-n-butyl phthalate (DBP), a chemical widely used in many consumer products, is estrogenic and capable of producing seriously reproductive and developmental effects in laboratory animals. However, recent in vitro studies have shown that DBP and mono-n-butyl phthalate (MBP), the major metabolite of DBP, possessed thyroid hormone receptor (TR) antagonist activity. It is therefore important to consider DBP and MBP that may interfere with thyroid hormone system. METHODOLOGY/PRINCIPAL FINDINGS: Nieuwkoop and Faber stage 51 Xenopus laevis were exposed to DBP and MBP (2, 10 or 15 mg/L) separately for 21 days. The two test chemicals decelerated spontaneous metamorphosis in X. laevis at concentrations of 10 and 15 mg/L. Moreover, MBP seemed to possess stronger activity. The effects of DBP and MBP on inducing changes of expression of selected thyroid hormone response genes: thyroid hormone receptor-beta (TRbeta), retinoid X receptor gamma (RXRgamma), alpha and beta subunits of thyroid-stimulating hormone (TSHalpha and TSHbeta) were detected by qPCR at all concentrations of the compounds. Using mammalian two-hybrid assay in vitro, we found that DBP and MBP enhanced the interactions between co-repressor SMRT (silencing mediator for retinoid and thyroid hormone receptors) and TR in a dose-dependent manner, and MBP displayed more markedly. In addition, MBP at low concentrations (2 and 10 mg/L) caused aberrant methylation of TRbeta in head tissue. CONCLUSIONS: The current findings highlight potential disruption of thyroid signalling by DBP and MBP and provide data for human risk assessment. PMID- 21544204 TI - A soluble form of the high affinity IgE receptor, Fc-epsilon-RI, circulates in human serum. AB - Soluble IgE receptors are potential in vivo modulators of IgE-mediated immune responses and are thus important for our basic understanding of allergic responses. We here characterize a novel soluble version of the IgE-binding alpha chain of Fc-epsilon-RI (sFcepsilonRI), the high affinity receptor for IgE. sFcepsilonRI immunoprecipitates as a protein of ~40 kDa and contains an intact IgE-binding site. In human serum, sFcepsilonRI is found as a soluble free IgE receptor as well as a complex with IgE. Using a newly established ELISA, we show that serum sFcepsilonRI levels correlate with serum IgE in patients with elevated IgE. We also show that serum of individuals with normal IgE levels can be found to contain high levels of sFcepsilonRI. After IgE-antigen-mediated crosslinking of surface FcepsilonRI, we detect sFcepsilonRI in the exosome-depleted, soluble fraction of cell culture supernatants. We further show that sFcepsilonRI can block binding of IgE to FcepsilonRI expressed at the cell surface. In summary, we here describe the alpha-chain of FcepsilonRI as a circulating soluble IgE receptor isoform in human serum. PMID- 21544205 TI - Amino terminal domains of the NMDA receptor are organized as local heterodimers. AB - The N-methyl-D-aspartate (NMDA) receptor, an obligate heterotetrameric assembly organized as a dimer of dimers, is typically composed of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits. Despite the crucial role that the NMDA receptor plays in the nervous system, the specific arrangement of subunits within the dimer-of-dimer assemblage is not conclusively known. Here we studied the organization of the amino terminal domain (ATD) of the rat GluN1/GluN2A and GluN1/GluN2B NMDA receptors by cysteine-directed, disulfide bond mediated cross-linking. We found that GluN1 ATDs and GluN2 ATDs spontaneously formed disulfide bond-mediated dimers after introducing cysteines into the L1 interface of GluN2A or GluN2B ATD. The formation of dimer could be prevented by knocking out endogenous cysteines located near the L1 interface of GluN1. These results indicate that GluN1 and GluN2 ATDs form local heterodimers through the interactions in the L1-L1 interface and further demonstrate a dimer-of heterodimer arrangement in GluN1/GluN2A and GluN1/GluN2B NMDA receptors. PMID- 21544206 TI - Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum. AB - The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity. PMID- 21544207 TI - Multidimensional scaling reveals the main evolutionary pathways of class A G protein-coupled receptors. AB - Class A G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors in the human genome. Understanding the mechanisms which drove the evolution of such a large family would help understand the specificity of each GPCR sub-family with applications to drug design. To gain evolutionary information on class A GPCRs, we explored their sequence space by metric multidimensional scaling analysis (MDS). Three-dimensional mapping of human sequences shows a non-uniform distribution of GPCRs, organized in clusters that lay along four privileged directions. To interpret these directions, we projected supplementary sequences from different species onto the human space used as a reference. With this technique, we can easily monitor the evolutionary drift of several GPCR sub-families from cnidarians to humans. Results support a model of radiative evolution of class A GPCRs from a central node formed by peptide receptors. The privileged directions obtained from the MDS analysis are interpretable in terms of three main evolutionary pathways related to specific sequence determinants. The first pathway was initiated by a deletion in transmembrane helix 2 (TM2) and led to three sub-families by divergent evolution. The second pathway corresponds to the differentiation of the amine receptors. The third pathway corresponds to parallel evolution of several sub-families in relation with a covarion process involving proline residues in TM2 and TM5. As exemplified with GPCRs, the MDS projection technique is an important tool to compare orthologous sequence sets and to help decipher the mutational events that drove the evolution of protein families. PMID- 21544208 TI - A multiscale investigation of bicoid-dependent transcriptional events in Drosophila embryos. AB - BACKGROUND: Morphogen molecules form concentration gradients to provide spatial information to cells in a developing embryo. Precisely how cells decode such information to form patterns with sharp boundaries remains an open question. For example, it remains controversial whether the Drosophila morphogenetic protein Bicoid (Bcd) plays a transient or sustained role in activating its target genes to establish sharp expression boundaries during development. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we describe a method to simultaneously detect Bcd and the nascent transcripts of its target genes in developing embryos. This method allows us to investigate the relationship between Bcd and the transcriptional status of individual copies of its target genes on distinct scales. We show that, on three scales analyzed concurrently--embryonic, nuclear and local, the actively-transcribing gene copies are associated with high Bcd concentrations. These results underscore the importance of Bcd as a sustained input for transcriptional decisions of individual copies of its target genes during development. We also show that the Bcd-dependent transcriptional decisions have a significantly higher noise than Bcd-dependent gene products, suggesting that, consistent with theoretical studies, time and/or space averaging reduces the noise of Bcd-activated transcriptional output. Finally, our analysis of an X linked Bcd target gene reveals that Bcd-dependent transcription bursts at twice the frequency in males as in females, providing a mechanism for dosage compensation in early Drosophila embryos. CONCLUSION/SIGNIFICANCE: Our study represents a first experimental uncovering of the actions of Bcd in controlling the actual transcriptional events while its positional information is decoded during development. It establishes a sustained role of Bcd in transcriptional decisions of individual copies of its target genes to generate sharp expression boundaries. It also provides an experimental evaluation of the effect of time and/or space averaging on Bcd-dependent transcriptional output, and establishes a dosage compensation mechanism in early Drosophila embryos. PMID- 21544209 TI - Progression to AIDS in South Africa is associated with both reverting and compensatory viral mutations. AB - We lack the understanding of why HIV-infected individuals in South Africa progress to AIDS. We hypothesised that in end-stage disease there is a shifting dynamic between T cell imposed immunity and viral immune escape, which, through both compensatory and reverting viral mutations, results in increased viral fitness, elevated plasma viral loads and disease progression. We explored how T cell responses, viral adaptation and viral fitness inter-relate in South African cohorts recruited from Bloemfontein, the Free State (n = 278) and Durban, KwaZulu Natal (n = 775). Immune responses were measured by gamma-interferon ELISPOT assays. HLA-associated viral polymorphisms were determined using phylogenetically corrected techniques, and viral replication capacity (VRC) was measured by comparing the growth rate of gag-protease recombinant viruses against recombinant NL4-3 viruses. We report that in advanced disease (CD4 counts <100 cells/ul), T cell responses narrow, with a relative decline in Gag-directed responses (p<0.0001). This is associated with preserved selection pressure at specific viral amino acids (e.g., the T242N polymorphism within the HLA-B*57/5801 restricted TW10 epitope), but with reversion at other sites (e.g., the T186S polymorphism within the HLA-B*8101 restricted TL9 epitope), most notably in Gag and suggestive of "immune relaxation". The median VRC from patients with CD4 counts <100 cells/ul was higher than from patients with CD4 counts >= 500 cells/ul (91.15% versus 85.19%, p = 0.0004), potentially explaining the rise in viral load associated with disease progression. Mutations at HIV Gag T186S and T242N reduced VRC, however, in advanced disease only the T242N mutants demonstrated increasing VRC, and were associated with compensatory mutations (p = 0.013). These data provide novel insights into the mechanisms of HIV disease progression in South Africa. Restoration of fitness correlates with loss of viral control in late disease, with evidence for both preserved and relaxed selection pressure across the HIV genome. Interventions that maintain viral fitness costs could potentially slow progression. PMID- 21544210 TI - Sensitive dual color in vivo bioluminescence imaging using a new red codon optimized firefly luciferase and a green click beetle luciferase. AB - BACKGROUND: Despite a plethora of bioluminescent reporter genes being cloned and used for cell assays and molecular imaging purposes, the simultaneous monitoring of multiple events in small animals is still challenging. This is partly attributable to the lack of optimization of cell reporter gene expression as well as too much spectral overlap of the color-coupled reporter genes. A new red emitting codon-optimized luciferase reporter gene mutant of Photinus pyralis, Ppy RE8, has been developed and used in combination with the green click beetle luciferase, CBG99. PRINCIPAL FINDINGS: Human embryonic kidney cells (HEK293) were transfected with vectors that expressed red Ppy RE8 and green CBG99 luciferases. Populations of red and green emitting cells were mixed in different ratios. After addition of the shared single substrate, D-luciferin, bioluminescent (BL) signals were imaged with an ultrasensitive cooled CCD camera using a series of band pass filters (20 nm). Spectral unmixing algorithms were applied to the images where good separation of signals was observed. Furthermore, HEK293 cells that expressed the two luciferases were injected at different depth in the animals. Spectrally separate images and quantification of the dual BL signals in a mixed population of cells was achieved when cells were either injected subcutaneously or directly into the prostate. SIGNIFICANCE: We report here the re-engineering of different luciferase genes for in vitro and in vivo dual color imaging applications to address the technical issues of using dual luciferases for imaging. In respect to previously used dual assays, our study demonstrated enhanced sensitivity combined with spatially separate BL spectral emissions using a suitable spectral unmixing algorithm. This new D-luciferin-dependent reporter gene couplet opens up the possibility in the future for more accurate quantitative gene expression studies in vivo by simultaneously monitoring two events in real time. PMID- 21544211 TI - Patterns of plant biomass partitioning depend on nitrogen source. AB - Nitrogen (N) availability is a strong determinant of plant biomass partitioning, but the role of different N sources in this process is unknown. Plants inhabiting low productivity ecosystems typically partition a large share of total biomass to belowground structures. In these systems, organic N may often dominate plant available N. With increasing productivity, plant biomass partitioning shifts to aboveground structures, along with a shift in available N to inorganic forms of N. We tested the hypothesis that the form of N taken up by plants is an important determinant of plant biomass partitioning by cultivating Arabidopsis thaliana on different N source mixtures. Plants grown on different N mixtures were similar in size, but those supplied with organic N displayed a significantly greater root fraction. 15N labelling suggested that, in this case, a larger share of absorbed organic N was retained in roots and split-root experiments suggested this may depend on a direct incorporation of absorbed amino acid N into roots. These results suggest the form of N acquired affects plant biomass partitioning and adds new information on the interaction between N and biomass partitioning in plants. PMID- 21544213 TI - Thermal activation and saturation of ion beam sculpting. AB - We report a material-dependent critical temperature for ion beam sculpting of nanopores in amorphous materials under keV ion irradiation. At temperatures below the critical temperature, irradiated pores open at a rate that soon saturates with decreasing temperature. At temperatures above the critical temperature, the pore closing rate rises rapidly and eventually saturates with increasing temperature. The observed behavior is well described by a model based on adatom diffusion, but is difficult to reconcile with an ion-stimulated viscous flow model. PMID- 21544212 TI - Role of hypothalamic melanocortin system in adaptation of food intake to food protein increase in mice. AB - The hypothalamic melanocortin system--the melanocortin receptor of type 4 (MC4R) and its ligands: alpha-melanin-stimulating hormone (alpha-MSH, agonist, inducing hypophagia), and agouti-related protein (AgRP, antagonist, inducing hyperphagia)- is considered to play a central role in the control of food intake. We tested its implication in the mediation of the hunger-curbing effects of protein-enriched diets (PED) in mice. Whereas there was a 20% decrease in food intake in mice fed on the PED, compared to mice fed on an isocaloric starch-enriched diet, there was a paradoxical decrease in expression of the hypothalamic proopiomelanocortin gene, precursor of alpha-MSH, and increase in expression of the gene encoding AgRP. The hypophagia effect of PED took place in mice with invalidation of either MC4R or POMC, and was even strengthened in mice with ablation of the AgRP expressing neurons. These data strongly suggest that the hypothalamic melanocortin system does not mediate the hunger-curbing effects induced by changes in the macronutrient composition of food. Rather, the role of this system might be to defend the body against the variations in food intake generated by the nutritional environment. PMID- 21544214 TI - Oblique-incidence sputtering of Ru intermediate layer for decoupling of intergranular exchange in perpendicular recording media. AB - During the Ru deposition process for granular type perpendicular magnetic recording media, both a reduction in the Ru intermediate layer thickness and lowering of sputtering gas pressure were successfully achieved by focusing on a self-shadowing effect. Oblique-incidence sputtering with a 60 degrees incident angle under an Ar gas pressure of 0.6 Pa yielded (1) columnar Ru grains with a growth direction of 30 degrees from the film normal, (2) c-plane sheet texture by epitaxial growth on the Pt underlayer, and (3) a flat envelope of the surface and a deep gap at grain boundaries. This change in the Ru structure significantly contributes to reducing exchange coupling among magnetic grains, especially in the initial growth region in an overlying granular medium. PMID- 21544215 TI - Excitation of Cy5 in self-assembled lipid bilayers using optical microresonators. AB - Due to their sensitivity and temporal response, optical microresonators are used extensively in the biosensor arena, particularly in the development of label-free diagnostics and measurement of protein kinetics. In the present letter, we investigate using microcavities to probe molecules within biomimetic membranes. Specifically, a method for self-assembling lipid bilayers on spherical microresonators is developed and the bilayer-nature is verified. Subsequently, the microcavity is used to excite a Cy5-conjugated lipid located within the bilayer while the optical performance of the microcavity is characterized. The emission wavelength of the dye and the optical behavior of the microcavity agree with theoretical predictions. PMID- 21544216 TI - The Interconnection of MRI Scanner and MR-Compatible Robotic Device: Synergistic Graphical User Interface to Form a Mechatronic System. AB - MRI scanner and magnetic resonance (MR)-compatible robotic devices are mechatronic systems. Without an interconnecting component, these two devices cannot be operated synergetically for medical interventions. In this paper, the design and properties of a graphical user interface (GUI) that accomplishes the task is presented. The GUI interconnects the two devices to obtain a larger mechatronic system by providing command and control of the robotic device based on the visual information obtained from the MRI scanner. Ideally, the GUI should also control imaging parameters of the MRI scanner. Its main goal is to facilitate image-guided interventions by acting as the synergistic component between the physician, the robotic device, the scanner, and the patient. PMID- 21544218 TI - Children's Evaluative Categories and Inductive Inferences within the Domain of Food. AB - Evaluative categories include items that share the same value- laden assessment. Given that these categories have not been examined extensively within the child concepts literature, the present research explored evaluative categorization and induction within the domain of food as a test case. Specifically, two studies examined the categories of healthy and junky foods in children aged 4 and 7 years. Study 1 showed that by aged 4 years, children appropriately apply the evaluative categories of healthy and junky foods to a variety of different foods. Study 2 showed that by age 4 years, children also selectively use the evaluative categories of healthy and junky foods for inductive inferences about the human body, but not for arbitrary or unrelated inferences. Taken together, these results highlight the importance of evaluative processing in young children's categorization and induction. PMID- 21544219 TI - CIRCAMULTISEPTAN ASPECT OF SUDDEN DEATH: COMPETING SOCIO-ECOLOGICAL SYNCHRONIZERS: ALCOHOL AND MAGNETICS? AB - In order to investigate infradian aspects of sudden death, the daily incidence of 70,531 cases recorded in response to a call for an ambulance during 3 years (1979 1981) in Moscow, Russia, were re-analysed, focusing on multiseptans (components with periods of 7 days and/or multiples thereof). Apart from a prominent yearly and half-yearly variation in the daily incidence of sudden death, least squares spectra revealed the presence of about-weekly and two-weekly components. The about 15.2-day variation was validated by nonlinear least squares and shown to differ in period length from that found in the local index of geomagnetic activity, K. This result suggests that apart from any geomagnetic influence on sudden death, changes in lifestyle (such as alcohol consumption) associated with the twice-a-month salary schedule may affect the occurrence of sudden death. Such a component is not prominently seen for the incidence of other cardiovascular conditions recorded in the same database. The weekly pattern of sudden death, peaking on Saturdays, also differs from those of other cardiovascular conditions, characterized by a higher daily incidence on Mondays. The possibility to now record events in cardioverter-defibrillators offers an opportunity to explore broad chronomes of potentially lethal arrhythmia that may lead to a better understanding of underlying triggers, so that novel countermeasures may be designed and implemented. PMID- 21544217 TI - Physiological sensing of carbon dioxide/bicarbonate/pH via cyclic nucleotide signaling. AB - Carbon dioxide (CO(2)) is produced by living organisms as a byproduct of metabolism. In physiological systems, CO(2) is unequivocally linked with bicarbonate (HCO(3)(-)) and pH via a ubiquitous family of carbonic anhydrases, and numerous biological processes are dependent upon a mechanism for sensing the level of CO(2), HCO(3), and/or pH. The discovery that soluble adenylyl cyclase (sAC) is directly regulated by bicarbonate provided a link between CO(2)/HCO(3)/pH chemosensing and signaling via the widely used second messenger cyclic AMP. This review summarizes the evidence that bicarbonate-regulated sAC, and additional, subsequently identified bicarbonate-regulate nucleotidyl cyclases, function as evolutionarily conserved CO(2)/HCO(3)/pH chemosensors in a wide variety of physiological systems. PMID- 21544220 TI - Synthesis of Aminooxy End-functionalized pNIPAAm by RAFT Polymerization for Protein and Polysaccharide Conjugation. AB - A Boc-protected aminooxy end-functionalized poly(N-isopropylacrylamide) (pNIPAAm) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The monomer was polymerized in the presence of a Boc-protected aminooxy trithiocarbonate chain transfer agent (CTA) utilizing 2,2'-azobis(2 isobutyronitrile) (AIBN) as the initiator in DMF at 70 degrees C. The final polymer had a number-average molecular weight (M(n)) of 4,200 Da as determined by (1)H NMR spectroscopy and a narrow polydispersity index (1.14) by gel permeation chromatography (GPC). The Boc group was removed, and the polymer was then incubated with N(epsilon)-levulinyl lysine-modified bovine serum albumin (BSA). Gel electrophoresis confirmed that the conjugation was successful. The aminooxy end-functionalized pNIPAAm was also immobilized on a gold surface after reduction of the trithiocarbonate end-group. The pNIPAAm surface was then incubated with an aldehyde-modified heparin to yield the polysaccharide-functionalized surface. All surface modifications were monitored by FT-IR spectroscopy. PMID- 21544221 TI - Skin surface temperature rhythms as potential circadian biomarkers for personalized chronotherapeutics in cancer patients. AB - Chronotherapeutics involve the administration of treatments according to circadian rhythms. Circadian timing of anti-cancer medications has been shown to improve treatment tolerability up to fivefold and double efficacy in experimental and clinical studies. However, the physiological and the molecular components of the circadian timing system (CTS), as well as gender, critically affect the success of a standardized chronotherapeutic schedule. In addition, a wrongly timed therapy or an excessive drug dose disrupts the CTS. Therefore, a non invasive approach to accurately detect and monitor circadian rhythms is needed for a dynamic assessment of the CTS in order to personalize chronomodulated drug delivery schedule in cancer patients. Since core body temperature is a robust circadian biomarker, we recorded temperature at multiple locations on the skin of the upper chest and back of controls and cancer patients continuously. Variability in the circadian phase existed among patch locations in individual subjects over the course of 2-6 days, demonstrating the need to monitor multiple skin temperature locations to determine the precise circadian phase. Additionally, we observed that locations identified by infrared imaging as relatively cool had the largest 24 h temperature variations. Disruptions in skin temperature rhythms during treatment were found, pointing to the need to continually assess circadian timing and personalize chronotherapeutic schedules. PMID- 21544222 TI - Bioinspired Strong and Highly Porous Glass Scaffolds. AB - The quest for more efficient energy-related technologies is driving the development of porous and high-performance structural materials with exceptional mechanical strength. Natural materials achieve their strength through complex hierarchical designs and anisotropic structures that are extremely difficult to replicate synthetically. We emulate nature's design by direct-ink-write assembling of glass scaffolds with a periodic pattern, and controlled sintering of the filaments into anisotropic constructs similar to biological materials. The final product is a porous glass scaffold with a compressive strength (136 MPa) comparable to that of cortical bone and a porosity (60%) comparable to that of trabecular bone. The strength of this porous glass scaffold is ~100 times that of polymer scaffolds and 4-5 times that of ceramic and glass scaffolds with comparable porosities reported elsewhere. The ability to create both porous and strong structures opens a new avenue for fabricating scaffolds for a broad array of applications, including tissue engineering, filtration, lightweight composites, and catalyst support. PMID- 21544223 TI - Insights into the Mechanical Properties of the Kinesin Neck Linker Domain from Sequence Analysis and Molecular Dynamics Simulations. AB - The 14-18 amino acid kinesin neck linker domain links the core motor to the coiled-coil dimerization domain. One puzzle is that the neck linker appears too short for the 4 nm distance each linker must stretch to enable an 8 nm step - when modeled as an entropic spring, high inter-head forces are predicted when both heads are bound to the microtubule. We addressed this by analyzing the length of the neck linker across different kinesin families and using molecular dynamics simulations to model the extensibility of Kinesin-1 and Kinesin-2 neck linkers. The force-extension profile from molecular dynamics agrees with the Worm Like Chain (WLC) model for Kinesin-1 and supports the puzzling prediction that extending the neck linker 4 nm requires forces multiple times the motor stall force. Despite being 3 amino acids longer, simulations suggest that extending the Kinesin-2 neck linker by 4 nm requires similarly high forces. A possible resolution to this dilemma is that helix alpha-6 may unwind to enable the two head bound state. Finally, simulations suggest that cis/trans isomerization of a conserved proline residue in Kinesin-2 accounts for the differing predictions of molecular dynamics and the WLC model, and may contribute to motor regulation in vivo. PMID- 21544225 TI - Directionally Solidified Biopolymer Scaffolds: Mechanical Properties and Endothelial Cell Responses. AB - Vascularization is a primary challenge in tissue engineering. To achieve it in a tissue scaffold, an environment with the appropriate structural, mechanical, and biochemical cues must be provided enabling endothelial cells to direct blood vessel growth. While biochemical stimuli such as growth factors can be added through the scaffold material, the culture medium, or both, a well-designed tissue engineering scaffold is required to provide the necessary local structural and mechanical cues. As chitosan is a well-known carrier for biochemical stimuli, the focus of this study was on structure-property correlations, to evaluate the effects of composition and processing conditions on the three-dimensional architecture and properties of freeze-cast scaffolds; to establish whether freeze cast scaffolds are promising candidates as constructs promoting vascularization; and to conduct initial tissue culture studies with endothelial cells on flat substrates of identical compositions as those of the scaffolds to test whether these are biocompatible and promote cell attachment and proliferation. PMID- 21544224 TI - Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer. AB - Similar to genetic alterations, epigenetic aberrations contribute significantly to tumor initiation and progression. In many cases, these changes are caused by activation or inactivation of the regulators that maintain epigenetic states. Here we review our current knowledge on the KDM5/JARID1 family of histone demethylases. This family of enzymes contains a JmjC domain and is capable of removing tri- and di- methyl marks from lysine 4 on histone H3. Among these proteins, RBP2 mediates drug resistance while JARID1B is required for melanoma maintenance. Preclinical studies suggest inhibition of these enzymes can suppress tumorigenesis and provide strong rationale for development of their inhibitors for use in cancer therapy. PMID- 21544226 TI - F-Labeled GRPR Agonists and Antagonists: A Comparative Study in Prostate Cancer Imaging. AB - Radiolabeled bombesin analogs are promising probes for cancer imaging of gastrin releasing peptide receptor (GRPR). In this study, we developed (18)F-labeled GRPR agonists and antagonists for positron emission tomography (PET) imaging of prostate cancer. GRPR antagonists ATBBN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu NHCH(2)CH(3)) and MATBBN (Gly-Gly-Gly-Arg-Asp-Asn-D-Phe-Gln-Trp-Ala-Val-Gly-His Leu-NHCH(2)CH(3)), and agonists AGBBN (Gln-Trp-Ala-Val-Gly-His-Leu-MetNH(2)) and MAGBBN (Gly-Gly-Gly-Arg-Asp-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-MetNH(2)) were radiolabeled with (18)F via 4-nitrophenyl 2-(18)F-fluoropropionate. The in vitro receptor binding, cell uptake, and efflux properties of the radiotracers were studied on PC-3 cells. An in vivo PET study was performed on mice bearing PC-3 tumors. Direct (18)F-labeling of known GRPR antagonist ATBBN and agonist AGBBN did not result in good tumor targeting or appropriate pharmacokinetics. Modification was made by introducing a highly hydrophilic linker Gly-Gly-Gly-Arg Asp-Asn. Higher receptor binding affinity, much higher cell uptake and slower washout were observed for the agonist (18)F-FP-MAGBBN over the antagonist (18)F FP-MATBBN. Both tracers showed good tumor/background contrast, with the agonist (18)F-FP-MAGBBN having significantly higher tumor uptake than the antagonist (18)F-FP-MATBBN (P < 0.01). In conclusion, Gly-Gly-Gly-Arg-Asp-Asn linker significantly improved the pharmacokinetics of the otherwise hydrophobic BBN radiotracers. (18)F-labeled BBN peptide agonists may be the probes of choice for prostate cancer imaging due to their relatively high tumor uptake and retention as compared with the antagonist counterparts. PMID- 21544227 TI - Synthesis of Maleimide-End Functionalized Star Polymers and Multimeric Protein Polymer Conjugates. AB - Protein-polymer conjugates exhibit superior properties to unmodified proteins, generating a high demand for these materials in the fields of medicine, biotechnology, and nanotechnology. Multimeric conjugates are predicted to surpass the activity of monomeric conjugates. Herein, we report a straightforward method to synthesize multimeric polymer-conjugates. Four armed poly(N isopropylacrylamide) (pNIPAAm) was synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization in the presence of a tetra functionalized trithiocarbonate chain transfer agent (CTA). The polymer molecular weight, architecture and polydispersity index (PDI) were verified by gel permeation chromatography (GPC), dynamic light scattering gel permeation chromatography (DLS-GPC), and matrix-assisted laser desorption/ionization time-of flight (MALDI-TOF) mass spectrometry. This approach afforded well-defined polymers (PDI's < 1.06) and the ability to target various molecular weights. Maleimide functional groups were introduced at the chain ends by heating the polymers in the presence of a furan-protected azo-initiator. This allowed for site-specific conjugation of V131C T4 lysozyme to the polymers to generate multimeric protein-polymer conjugates. MALDI-TOF mass spectrometry, electrospray ionization gas-phase electrophoretic-mobility macromolecule analysis (ESI-GEMMA), gel electrophoresis, and liquid chromatography tandem mass spectrometry (LC MS/MS) of the trypsin digests demonstrated that multimeric protein-polymer conjugates had formed. This simple strategy provides ready access to star protein polymer conjugates for application in the fields of drug discovery, drug delivery, and nanotechnology. PMID- 21544228 TI - Assessing Homework Problems in Children with ADHD: Validation of a Parent-Report Measure and Evaluation of Homework Performance Patterns. AB - The factor structure of a parent-report measure of child homework problems, the Homework Problems Checklist, was examined in a geographically and ethnically diverse sample of children with Attention-Deficit/Hyperactivity Disorder (ADHD). This measure was completed by the parents of 579 children ages 7.0-9.9 diagnosed with ADHD Combined Type as part of the Multimodal Treatment Study of Children with ADHD (MTA). Results replicated previous work showing two salient factors that measure homework completion behaviors (Factor I) and homework management behaviors (Factor II). This two-factor solution remained consistent when examined across child sex and ethnicity subgroups. Analysis of patterns revealed that homework problems are greater for children in higher grades and that children with ADHD and comorbid Learning Disabilities experience significantly more homework problems than children with ADHD alone. This study also replicated previous work showing that homework problems and ADHD inattentive symptoms are highly correlated whereas correlations between homework problems and hyperactivity and impulsivity are low to moderate. Implications of the findings for the assessment of homework problems in children with ADHD and for intervention are discussed. PMID- 21544230 TI - Application of a fast proton dose calculation algorithm to a thorax geometry. AB - Treatment planning in proton therapy requires the calculation of absorbed dose distributions on beam shaping components and the patient anatomy. Analytical pencil-beam dose algorithms commonly used are not always accurate enough. The Monte Carlo approach is more accurate but extremely computationally intensive. The Fast Dose Calculator, a track-repeating algorithm, has been proposed as an alternative fast and accurate dose calculation. In this work FDC is applied to a proton therapy patient thoracic anatomy. PMID- 21544231 TI - Computational protein design: Advances in the design and redesign of biomolecular nanostructures. AB - Computational protein design facilitates the continued development of methods for the design of biomolecular structure, sequence and function. Recent applications include the design of novel protein sequences and structures, proteins incorporating nonbiological components, protein assemblies, soluble variants of membrane proteins, and proteins that modulate membrane function. PMID- 21544232 TI - Zernike phase contrast in scanning microscopy with X-rays. AB - Scanning X-ray microscopy focuses radiation to a small spot and probes the sample by raster scanning. It allows information to be obtained from secondary signals such as X-ray fluorescence, which yields an elemental mapping of the sample not available in full-field imaging. The analysis and interpretation from these secondary signals can be considerably enhanced if these data are coupled with structural information from transmission imaging. However, absorption often is negligible and phase contrast has not been easily available. Originally introduced with visible light, Zernike phase contrast(1) is a well-established technique in full-field X-ray microscopes for visualization of weakly absorbing samples(2-7). On the basis of reciprocity, we demonstrate the implementation of Zernike phase contrast in scanning X-ray microscopy, revealing structural detail simultaneously with hard-X-ray trace-element measurements. The method is straightforward to implement without significant influence on the resolution of the fluorescence images and delivers complementary information. We show images of biological specimens that clearly demonstrate the advantage of correlating morphology with elemental information. PMID- 21544229 TI - Why integrin as a primary target for imaging and therapy. AB - Integrin-mediated cell adhesion is involved in many essential normal cellular and pathological functions including cell survival, growth, differentiation, migration, inflammatory responses, platelet aggregation, tissue repair and tumor invasion. 24 different heterodimerized transmembrane integrin receptors are combined from 18 different alpha and 8 different beta subunits. Each integrin subunit contains a large extracellular domain, a single transmembrane domain and a usually short cytoplasmic domain. Integrins bind extracellular matrix (ECM) proteins through their large extracellular domain, and engage the cytoskeleton via their short cytoplasmic tails. These integrin-mediated linkages on either side of the plasma membrane are dynamically linked. Thus, integrins communicate over the plasma membrane in both directions, i.e., outside-in and inside-out signaling. In outside-in signaling through integrins, conformational changes of integrin induced by ligand binding on the extracellular domain altered the cytoplasmic domain structures to elicit various intracellular signaling pathways. Inside-out signaling originates from non-integrin cell surface receptors or cytoplasmic molecules and it activates signaling pathways inside the cells, ultimately resulting in the activation/deactivation of integrins. Integrins are one of key family proteins for cell adhesion regulation through binding to a large number of ECM molecules and cell membrane proteins. Lack of expression of integrins may result in a wide variety of effects ranging from blockage in pre implantation to embryonic or perinatal lethality and developmental defects. Based on both the key role they played in angiogenesis, leukocytes function and tumor development and easy accessibility as cell surface receptors interacting with extracellular ligands, the integrin superfamily represents the best opportunity of targeting both antibodies and small-molecule antagonists for both therapeutic and diagnostic utility in various key diseases so far. PMID- 21544233 TI - Quality Multi-domain Meshing for Volumetric Data. AB - Multi-domain meshing from volumetric data is of great importance in many fields like medicine, biology and geology. This paper proposes a new approach to produce a high quality mesh with separated multiple domains. A point cloud is generated from a preliminary mesh representing the boundary between different domains from the discrete volumetric representation used as input. A higher-order level-set method is employed to produce a quality sub-mesh from this point cloud and geometric flow is used as smoothing mechanism. A new approach to detect and curate intersections within an assembly of these 2-manifold sub-meshes by utilizing the intermediate volumetric representation is developed. The separation between sub-meshes can be controlled by the user using a gap threshold parameter. The resulting high quality multi-domain mesh is free from self- and inter-domain intersections and can be further utilized in finite element and boundary element computations. The proposed pipeline has been efficiently implemented and sample meshes have been provided for visualization. PMID- 21544234 TI - Constrained Maximum Likelihood Estimation for Two-level Mean and Covariance Structure Models. AB - Maximum likelihood is commonly used for estimation of model parameters in analysis of two-level structural equation models. Constraints on model parameters could be encountered in some situations such as equal factor loadings for different factors. Linear constraints are the most common ones and they are relatively easy to handle in maximum likelihood analysis. Nonlinear constraints could be encountered in complicated applications. In this paper we develop an EM type algorithm for estimating model parameters with both linear and nonlinear constraints. The empirical performance of the algorithm is demonstrated by a Monte Carlo study. Application of the algorithm for linear constraints is illustrated by setting up a two-level mean and covariance structure model for a real two-level data set and running an EQS program. PMID- 21544235 TI - Algorithms and Time Complexity of the Request-Service Problem. AB - Given a number of users each of which provides a set of services with a cost for each service and has a set of requests to be satisfied, the goal of the request service problem is to find a feasible solution that satisfies all requests of each user with minimum cost. In addition, a feasible solution must satisfy an additional constraint. Specifically, if user A provides a service to user B, B should provide a service back to A either directly or indirectly through other users. In this paper, we studied the complexity of this problem. We show that there exists a polynomial time algorithm that can compute a feasible solution with minimum cost if such a solution exists. However, if a feasible solution does not exist, the problem of maximizing the number of satisfied users (i.e., all requests of the users are satisfied) is NP-hard. PMID- 21544236 TI - Achieving a college education: The psychological experiences of Latina/o community college students. AB - This study examines the psychological and subjective experiences of Latina/o community college students. The impact of these experiences on their persistence toward achieving their education goals is also examined. Qualitative interviews with 15 community college students yielded eight themes: Overcoming personal and social challenges, maturation, self-discovery and college adjustment, self efficacy, continuously strategizing, sense of purpose, perception of faculty, perception of advisors, and guided and groomed by family to succeed. Implications for practice and recommendations for community colleges are discussed. PMID- 21544237 TI - Optical assessment of tumor resection margins in the breast. AB - Breast conserving surgery, in which the breast tumor and surrounding normal tissue are removed, is the primary mode of treatment for invasive and in situ carcinomas of the breast, conditions that affect nearly 200,000 women annually. Of these nearly 200,000 patients who undergo this surgical procedure, between 20 70% of them may undergo additional surgeries to remove tumor that was left behind in the first surgery, due to the lack of intra-operative tools which can detect whether the boundaries of the excised specimens are free from residual cancer. Optical techniques have many attractive attributes which may make them useful tools for intra-operative assessment of breast tumor resection margins. In this manuscript, we discuss clinical design criteria for intra-operative breast tumor margin assessment, and review optical techniques appied to this problem. In addition, we report on the development and clinical testing of quantitative diffuse reflectance imaging (Q-DRI) as a potential solution to this clinical need. Q-DRI is a spectral imaging tool which has been applied to 56 resection margins in 48 patients at Duke University Medical Center. Clear sources of contrast between cancerous and cancer-free resection margins were identified with the device, and resulted in an overall accuracy of 75% in detecting positive margins. PMID- 21544238 TI - Controlling droplet incubation using close-packed plug flow. AB - Controlling droplet incubation is critical for droplet-based microfluidic applications; however, current techniques are either of limited precision or place strict limits on the incubation times that can be achieved. Here, we present a simple technique to control incubation time by exploiting close-packed plug flow. In contrast to other techniques, this technique is applicable to very short and very long incubation times. PMID- 21544239 TI - Comparative analysis of cervical spine management in a subset of severe traumatic brain injury cases using computer simulation. AB - BACKGROUND: No randomized control trial to date has studied the use of cervical spine management strategies in cases of severe traumatic brain injury (TBI) at risk for cervical spine instability solely due to damaged ligaments. A computer algorithm is used to decide between four cervical spine management strategies. A model assumption is that the emergency room evaluation shows no spinal deficit and a computerized tomogram of the cervical spine excludes the possibility of fracture of cervical vertebrae. The study's goal is to determine cervical spine management strategies that maximize brain injury functional survival while minimizing quadriplegia. METHODS/FINDINGS: The severity of TBI is categorized as unstable, high risk and stable based on intracranial hypertension, hypoxemia, hypotension, early ventilator associated pneumonia, admission Glasgow Coma Scale (GCS) and age. Complications resulting from cervical spine management are simulated using three decision trees. Each case starts with an amount of primary and secondary brain injury and ends as a functional survivor, severely brain injured, quadriplegic or dead. Cervical spine instability is studied with one-way and two-way sensitivity analyses providing rankings of cervical spine management strategies for probabilities of management complications based on QALYs. Early collar removal received more QALYs than the alternative strategies in most arrangements of these comparisons. A limitation of the model is the absence of testing against an independent data set. CONCLUSIONS: When clinical logic and components of cervical spine management are systematically altered, changes that improve health outcomes are identified. In the absence of controlled clinical studies, the results of this comparative computer assessment show that early collar removal is preferred over a wide range of realistic inputs for this subset of traumatic brain injury. Future research is needed on identifying factors in projecting awakening from coma and the role of delirium in these cases. PMID- 21544240 TI - Hyperactive S6K1 mediates oxidative stress and endothelial dysfunction in aging: inhibition by resveratrol. AB - Mammalian target of rapamycin (mTOR)/S6K1 signalling emerges as a critical regulator of aging. Yet, a role of mTOR/S6K1 in aging-associated vascular endothelial dysfunction remains unknown. In this study, we investigated the role of S6K1 in aging-associated endothelial dysfunction and effects of the polyphenol resveratrol on S6K1 in aging endothelial cells. We show here that senescent endothelial cells displayed higher S6K1 activity, increased superoxide production and decreased bioactive nitric oxide (NO) levels than young endothelial cells, which is contributed by eNOS uncoupling. Silencing S6K1 in senescent cells reduced superoxide generation and enhanced NO production. Conversely, over expression of a constitutively active S6K1 mutant in young endothelial cells mimicked endothelial dysfunction of the senescent cells through eNOS uncoupling and induced premature cellular senescence. Like the mTOR/S6K1 inhibitor rapamycin, resveratrol inhibited S6K1 signalling, resulting in decreased superoxide generation and enhanced NO levels in the senescent cells. Consistent with the data from cultured cells, an enhanced S6K1 activity, increased superoxide generation, and decreased bioactive NO levels associated with eNOS uncoupling were also detected in aortas of old WKY rats (aged 20-24 months) as compared to the young animals (1-3 months). Treatment of aortas of old rats with resveratrol or rapamycin inhibited S6K1 activity, oxidative stress, and improved endothelial NO production. Our data demonstrate a causal role of the hyperactive S6K1 in eNOS uncoupling leading to endothelial dysfunction and vascular aging. Resveratrol improves endothelial function in aging, at least in part, through inhibition of S6K1. Targeting S6K1 may thus represent a novel therapeutic approach for aging-associated vascular disease. PMID- 21544241 TI - Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction. AB - Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-beta, collagen-1alpha or smooth muscle actin. Together, postobstructive renal interstitial fibrosis and tubular atrophy develop independent of SIGIRR, TLR2, TLR9, and MyD88. These data argue against a significant role of these molecules in renal fibrosis. PMID- 21544242 TI - MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1alpha expression. AB - MicroRNAs (miRNAs) are endogenous, small noncoding RNAs that play important roles in various cellular functions and tumor development. Recent studies have indicated that miR-21 is one of the important miRNAs associated with tumor growth and metastasis, but the role and molecular mechanism of miR-21 in regulating tumor angiogenesis remain to be elucidated. In this study, miR-21 was overexpressed by transfecting pre-miR-21 into human prostate cancer cells and tumor angiogenesis was assayed using chicken chorioallantoic membrane (CAM). We found that overexpression of miR-21 in DU145 cells increased the expression of HIF-1alpha and VEGF, and induced tumor angiogenesis. AKT and extracellular regulated kinases (ERK) 1/2 are activated by miR-21. Inhibition of miR-21 by the antigomir blocked this process. Overexpression of the miR-21 target, PTEN, also inhibited tumor angiogenesis by partially inactivating AKT and ERK and decreasing the expression of HIF-1 and VEGF. The AKT and ERK inhibitors, LY294002 and U0126, suppressed HIF-1alpha and VEGF expression and angiogenesis. Moreover, inhibition of HIF-1alpha expression alone abolished miR-21-inducing tumor angiogenesis, indicating that HIF-1alpha is required for miR-21-upregulated angiogenesis. Therefore, we demonstrate that miR-21 induces tumor angiogenesis through targeting PTEN, leading to activate AKT and ERK1/2 signaling pathways, and thereby enhancing HIF-1alpha and VEGF expression; HIF-1alpha is a key downstream target of miR-21 in regulating tumor angiogenesis. PMID- 21544243 TI - Fluctuations of epstein-barr virus serological antibodies and risk for nasopharyngeal carcinoma: a prospective screening study with a 20-year follow-up. AB - BACKGROUND: The impact of variation of Epstein-Barr virus (EBV) antibody titers before the development of nasopharyngeal carcinoma (NPC) is still unclear. We analyzed the fluctuations of antibodies against EBV before histopathological diagnosis to assess the risk of NPC and aimed to provide a reliable basis for screening in high risk populations. METHODS: This study was based on a population based screening program in Sihui County in Guangdong Province of China. A total of 18,986 subjects were recruited in 1987 and 1992, respectively. Baseline and repeated serological tests were performed for IgA antibodies against EBV capsid antigen (VCA/IgA) and early antigen (EA/IgA). Follow-up until the end of 2007 was accomplished through linkage with population and health registers. Cox proportional hazards regression model was used to estimate the relative risk of NPC in association with EBV antibodies. Time-dependent receiver operating characteristic curve (ROC) analysis was used to further evaluate the predictive ability. RESULTS: A total of 125 NPCs occurred during an average of 16.9 years of follow-up. Using baseline information alone or together with repeated measurements, serological levels of VCA/IgA and EA/IgA were significantly associated with increased risks for NPC, with a striking dose-response relationship and most prominent during the first 5 years of follow-up. Considering the fluctuant types of serological titers observed during the first three tests, relative risk was highest among participants with ascending titers of EBV VCA/IgA antibodies with an adjusted hazard ratio (HR) of 21.3 (95% confidence interval [CI] 7.1 to 64.1), and lowest for those with decreasing titers (HR = 1.5, 95% CI 0.2 to 11.4), during the first 5 years of follow-up. Time-dependent ROC analysis showed that VCA/IgA had better predictive performance for NPC incidence than EA/IgA. CONCLUSION: Our study documents that elevated EBV antibodies, particularly with ascending titers, are strongly associated with an increased risk for NPC. PMID- 21544244 TI - Kaposi's sarcoma-associated herpesvirus-encoded LANA down-regulates IL-22R1 expression through a cis-acting element within the promoter region. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is considered to be a necessary, but not sufficient, causal agent of Kaposi's sarcoma (KS). All forms of KS are characterized by the proliferation of spindle-shaped cells, and most (>90%) spindle cells from KS lesions are latently infected with KSHV. During KSHV latency, only a few viral genes are expressed. Among those latent genes, the ORF 73 gene encodes the latency-associated nuclear antigen (LANA), which is critical for the establishment and maintenance of the latent KSHV infection. Much evidence suggests that many cytokines can increase the frequency and aggressiveness of KS. In this study, a microarray analysis of KS and normal tissues revealed that multiple cytokines and cytokine receptors are regulated by KSHV latent infection. Of special interest, IL-22R1 transcript level was found to be down-regulated in the KS tissue. To study the possible regulation of IL-22R1 by LANA, the IL-22R1 promoter was constructed and found to contain a LANA-binding site (LBS). LANA was demonstrated to down-regulate IL-22R1 expression via direct binding to the LBS located within the IL-22R1 promoter region. Furthermore, KSHV latently infected cells showed an impaired response to IL-22 stimulation. These results suggest that LANA can regulate host factor expression by directly binding to a cis-acting element within the factor's promoter to benefit latent viral infection and suppression of the antiviral immune response. PMID- 21544245 TI - Deconstructing the late phase of vimentin assembly by total internal reflection fluorescence microscopy (TIRFM). AB - Quantitative imaging of intermediate filaments (IF) during the advanced phase of the assembly process is technically difficult, since the structures are several um long and therefore they exceed the field of view of many electron (EM) or atomic force microscopy (AFM) techniques. Thereby quantitative studies become extremely laborious and time-consuming. To overcome these difficulties, we prepared fluorescently labeled vimentin for visualization by total internal reflection fluorescence microscopy (TIRFM). In order to investigate if the labeling influences the assembly properties of the protein, we first determined the association state of unlabeled vimentin mixed with increasing amounts of labeled vimentin under low ionic conditions by analytical ultracentrifugation. We found that bona fide tetrameric complexes were formed even when half of the vimentin was labeled. Moreover, we demonstrate by quantitative atomic force microscopy and electron microscopy that the morphology and the assembly properties of filaments were not affected when the fraction of labeled vimentin was below 10%. Using fast frame rates we observed the rapid deposition of fluorescently labeled IFs on glass supports by TIRFM in real time. By tracing their contours, we have calculated the persistence length of long immobilized vimentin IFs to 1 um, a value that is identical to those determined for shorter unlabeled vimentin. These results indicate that the structural properties of the filaments were not affected significantly by the dye. Furthermore, in order to analyze the late elongation phase, we mixed long filaments containing either Alexa 488- or Alexa 647-labeled vimentin. The 'patchy' structure of the filaments obtained unambiguously showed the elongation of long IFs through direct end-to end annealing of individual filaments. PMID- 21544246 TI - Parkinson's disease permanent care unit: managing the chronic-palliative interface. AB - BACKGROUND: Parkinson's disease (PD) eventually leads to severe functional decline and dependence. Specialized care units for PD patients in need of permanent care are lacking. METHODS: Patients with severe PD are referred to the PD permanent care unit harboring 30 patients with specialized medical and health care provided by trained staff. Patients need to have intensive medical and care needs, and be no longer able to stay at home or at an ordinary institution. A written and continuously reviewed care plan is made for each patient at admission, with the overriding aim to preserve quality of life and optimize functionality. RESULTS: After five years, the PD permanent care unit has cared for 70 patients (36 men and 34 women) with a mean age of 76.6 years and a mean duration of Parkinsonism of 11.8 years. Hoehn and Yahr severity of disease was 3.7, cognition was 25.3 (Mini-Mental State Examination), and the mean daily levodopa dose was 739 mg. The yearly fatality rate was seven, and the mean duration of stay was 26.9 months. Only five patients moved out from the unit. CONCLUSION: A specially designed and staffed care unit for Parkinsonism patients seems to fill a need for patients and caregivers, as well as for social and health care authorities. This model is sensitive to the changing needs and capacities of patients, ensuring that appropriate services are available in a timely manner. There was a rather short duration of patient stay and remaining life span after admission to the unit. Despite the chronic/palliative state of patients at the PD permanent care unit, there are many therapeutic options, with the overriding objective being to allow the patients to end their days in a professional and comfortable environment. PMID- 21544247 TI - Self-management in heart failure: where have we been and where should we go? AB - Chronic conditions such as heart failure (HF) place a tremendous strain on patients, their families, the community, and the health care system because there are no real "cures". Adding to the burden are longer life expectancies and increased numbers of people living with multiple chronic conditions. Today, whether engaging in a health-promoting activity, such as exercise, or living with a chronic disease such as HF, the individual is responsible for actively managing day-to-day activities, a concept referred to as self-management. Self-management emerged as the cornerstone for chronic care models and multidisciplinary disease management strategies in chronic illness care. Moreover, self-management has been prioritized as a central pathway for improving the quality and effectiveness of most chronic HF care. Adherence to self-management is vital to optimize the treatment outcomes in HF patients, but implementing chronic disease self management (CDSM) strategies and identifying the difficulties in self-management has proved to be a challenge. Understanding both where we have been and the future direction of self-management in HF care is not only timely, but a crucial aspect of improving long-term outcomes for people with HF and other chronic diseases. PMID- 21544248 TI - Societal costs and burden of otitis media in Portugal. AB - This study aimed to estimate the resource consumption and societal impact of otitis media (OM) in children younger than five years of age in Portugal. An Internet survey on generic childhood symptoms and diseases was administered to a sample of parents. This self-report survey had been previously implemented in other European countries. Medically confirmed OM was defined as symptoms of earache or "running ear" and/or a diagnosis of OM provided by a medical doctor. Direct medical, nonmedical, and indirect nonmedical costs were calculated for individual cases. Mean total costs per OM episode were estimated at ?334. This corresponds to an estimated societal impact of 72 million ?/year, of which 39% were indirect nonmedical costs. An epidemiological study should help to confirm the results of this study, and evaluate whether an intervention to reduce the occurrence and/or duration of OM may have an impact on societal costs and quality of life for affected families. PMID- 21544249 TI - An exploratory qualitative study on perceptions about mosquito bed nets in the Niger Delta: what are the barriers to sustained use? AB - BACKGROUND: The effectiveness of malaria control programs is determined by an array of complex factors, including the acceptability and sustained use of preventative measures such as the bed net. A small-scale exploratory study was conducted in several locations in the Niger Delta region, Nigeria, to discover barriers against the use of bed nets, in the context of a current drive to scale up net use in Nigeria. METHODS: A qualitative approach with a convenience sample was used. One to one interviews with mostly male adult volunteers were undertaken which explored typical living and sleeping arrangements, and perceptions about and barriers against the use of the mosquito prevention bed net. RESULTS: Several key issues emerged from the qualitative data. Bed nets were not reported as widely used in this small sample. The reasons reported for lack of use included issues of convenience, especially net set up and dismantling; potential hazard and safety concerns; issues related to typical family composition and nature of accommodation; humid weather conditions; and perceptions of cost and effectiveness. Most barriers to net use concerned issues about everyday practical living and sleeping arrangements and perceptions about comfort. Interviewees identified were aware of malaria infection risks, but several also indicated certain beliefs that were barriers to net use. CONCLUSIONS: Successful control of malaria and scale up of insecticide-treated net coverage relies on community perceptions and practice. This small study has illuminated a number of important everyday life issues, which remain barriers to sustained net use, and has clarified further questions to be considered in net design and in future research studies. The study highlights the need for further research on the human concerns that contribute to sustained use of nets or, conversely, present significant barriers to their use. PMID- 21544250 TI - Physicians' perceptions, expectations, and experience with pharmacists at Hamad Medical Corporation in Qatar. AB - OBJECTIVES: The purpose of this study was to investigate the physicians' perceptions, and expectations of their experiences with the pharmacists at Hamad Medical Corporation (HMC) in Qatar. METHOD: A cross-sectional study was conducted at HMC between January and March 2006 using a validated questionnaire. The self administered questionnaire was distributed to 500 physicians who were working at HMC comprising Hamad General Hospital, Women's Hospital, Rumaila Hospital, Al Amal Hospital, Al Khor Hospital, and primary health centers. The questionnaire was composed of four parts, investigating the physicians' expectations, experiences, and perceptions of the pharmacists. RESULTS: A total of 205 questionnaires were completed (response rate 41%). A total of 183 physicians (89%) expected the pharmacist to educate patients about safe and appropriate use of drugs, whereas 118 (57%) expected the pharmacist to be available for health care team consultation during bedside rounds. The indices of physicians showing how comfortable they were with pharmacists, and their expectations of pharmacists, were 61% and 65%, respectively, whereas the index on experience of physicians with pharmacists was lower (15%). CONCLUSIONS: Physicians were comfortable with pharmacists and had high expectations of pharmacists in performing their duties. However, physicians reported a poor experience with pharmacists, who infrequently informed them about the effectiveness of alternative drugs, patients experiencing problems with prescribed medications, and who took personal responsibility to resolve any drug-related problem. PMID- 21544251 TI - Iron: A Pathological Mediator of Alzheimer Disease? AB - Metal-catalyzed oxidation and free radical formation are potent mediators of cellular injury to every category of macromolecule found in vulnerable neuronal populations and are thought to play an early and central role in Alzheimer disease (AD) pathogenesis. While metal-binding sites are present in proteins that accumulate in AD, metal-associated redox activity is primarily noted with nucleic acids, specifically with cytoplasmic RNA. Iron dyshomeostasis in AD is thought to arise from haem breakdown and mitochondrial turnover, and a reduction in microtubule density in vulnerable neurons increases redox-active metals, initiating a cascade of events culminating in characteristic pathologic features. Increased understanding of these early changes may be translated into more effective therapeutic modalities for AD than those currently in use. PMID- 21544252 TI - All Roads Lead to Rome: Update on Rome III Criteria and New Treatment Options. AB - The recently published Rome III criteria reflect current understanding of functional gastrointestinal disorders. These criteria include definitions of these conditions and their pathophysiologic subtypes and offer guidelines for their management. At the 2006 Annual Scientific Meeting of the American College of Gastroenterology, a panel of experts discussed these criteria as they pertain to irritable bowel syndrome, functional dyspepsia, and chronic constipation. This article reviews the panel's findings, highlights the differences between the Rome II and III criteria, and summarizes best treatment options currently available to practitioners and their patients. PMID- 21544253 TI - Maternal Variables Influencing Duration of Breastfeeding Among Low-Income Mothers. AB - This study used a retrospective comparison of 2 naturally occurring groups, first to examine how exclusive versus partial breastfeeding relates to duration of breastfeeding and, second, to determine if factors such as age and body mass index are associated with exclusive versus partial breastfeeding duration. These factors were hypothesized to influence the amount of breastfeeding in a sample of 42 low-income mothers enrolled in the Supplemental Nutrition Program for Women, Infants, and Children of a predominately rural, Midwestern county. This study examined de-identified data from a state database spanning a calendar year. Breastfeeding behavior, age, and body mass index measurements for mothers giving birth within the first 6 months of that year were analyzed. Exclusive breastfeeding mothers breastfed longer, were of older age, and had lower body mass indexes than partial breastfeeding mothers. These findings further describe characteristics of low-income breastfeeding women. Understanding how factors associated with exclusive versus partial breastfeeding affect breastfeeding duration may inform clinicians and researchers of areas for future interventions. PMID- 21544254 TI - Pseudomonas aeruginosa Biofilm Inactivation: Decreased Cell Culturability, Adhesiveness to Surfaces, and Biofilm Thickness Upon High-Pressure Nonthermal Plasma Treatment. AB - Bacterial biofilms are more resilient to standard killing methods than free living bacteria. Pseudomonas aeruginosa PAO1 biofilms grown on borosilicate coupons were treated with gas-discharge plasma for various exposure times. Almost 100% of the cells were inactivated after a 5-min plasma exposure. Atomic force microscopy was used to image the biofilms and study their micromechanical properties. Results show that the adhesiveness to borosilicate and the thickness of the Pseudomonas biofilms are reduced upon plasma treatment. PMID- 21544257 TI - Generalized and Heuristic-Free Feature Construction for Improved Accuracy. AB - State-of-the-art learning algorithms accept data in feature vector format as input. Examples belonging to different classes may not always be easy to separate in the original feature space. One may ask: can transformation of existing features into new space reveal significant discriminative information not obvious in the original space? Since there can be infinite number of ways to extend features, it is impractical to first enumerate and then perform feature selection. Second, evaluation of discriminative power on the complete dataset is not always optimal. This is because features highly discriminative on subset of examples may not necessarily be significant when evaluated on the entire dataset. Third, feature construction ought to be automated and general, such that, it doesn't require domain knowledge and its improved accuracy maintains over a large number of classification algorithms. In this paper, we propose a framework to address these problems through the following steps: (1) divide-conquer to avoid exhaustive enumeration; (2) local feature construction and evaluation within subspaces of examples where local error is still high and constructed features thus far still do not predict well; (3) weighting rules based search that is domain knowledge free and has provable performance guarantee. Empirical studies indicate that significant improvement (as much as 9% in accuracy and 28% in AUC) is achieved using the newly constructed features over a variety of inductive learners evaluated against a number of balanced, skewed and high-dimensional datasets. Software and datasets are available from the authors. PMID- 21544255 TI - Oscillators entrained by food and the emergence of anticipatory timing behaviors. AB - Circadian rhythms are adjusted to the external environment by the light-dark cycle via the suprachiasmatic nucleus, and to the internal environment of the body by multiple cues that derive from feeding/fasting. These cues determine the timing of sleep/wake cycles and all the activities associated with these states. We suggest that numerous sources of temporal information, including hormonal cues such as corticoids, insulin, and ghrelin, as well as conditioned learned responses determined by the temporal relationships between photic and feeding/fasting signals, can determine the timing of regularly recurring circadian responses. We further propose that these temporal signals can act additively to modulate the pattern of daily activity. Based on such reasoning, we describe the rationale and methodology for separating the influences of these diverse sources of temporal information. The evidence indicates that there are individual differences in sensitivity to internal and external signals that vary over circadian time, time since the previous meal, time until the next meal, or with duration of food deprivation. All of these cues are integrated in sites and circuits modulating physiology and behavior. Individuals detect changes in internal and external signals, interpret those changes as "hunger," and adjust their physiological responses and activity levels accordingly. PMID- 21544256 TI - Influenza A virus-specific CD8 T-cell responses: from induction to function. AB - Seasonal influenza virus infection is a leading cause of illness and mortality in young children and the elderly each year. Current influenza vaccines generate protective antibody responses; however, these must be given annually to provide protection against serologically distinct viruses. By contrast, CD8(+) T cells are capable of recognizing conserved antigenic determinants within the influenza virion and, as such, may provide protection against a number of variant strains of the virus. CD8(+) T cells play a critical key role in controlling and resolving influenza virus infections via the production of cytokines and cytolytic mediators. This article focuses on the induction of the influenza specific CD8(+) T-cell response and how these cells acquire and maintain effector function after induction. Moreover, we discuss how cytotoxic T-lymphocyte function correlates with protection following vaccination. PMID- 21544258 TI - Bringing proximate neighbours into the study of US residential segregation. AB - The race and ethnicity of neighbours are thought to be critical in shaping household mobility underlying residential segregation. However, studies on this topic have used data at the census-tract level of analysis rather than at the proximate-neighbour level. Using a non-publicly available version of the neighbour-cluster sample within the American Housing Survey, this study incorporates data on the race, ethnicity and socioeconomic characteristics of the proximate neighbours of White, Black and Latino households and examines their impact on household residential satisfaction, out- and in-mobility. Results indicate that proximate-neighbour race and ethnicity matter in influencing endpoints of the mobility process and do not necessarily parallel those at the census-tract level. Implications of these findings are discussed as they relate to the study of residential segregation. PMID- 21544259 TI - On Correcting Biases in Self-Reports of Age at First Substance Use with Repeated Cross-Section Analysis. AB - Household survey data on age at first use of alcohol, tobacco, marijuana, and hard drugs can be biased due to sample selection and inaccurate recall. One potential concern is attrition, whereby individuals who get involved with substance use at an early age become increasingly less likely to be surveyed in successive years. A comparison of data from the National Household Survey on Drug Abuse (NHSDA) with data from a longitudinal study suggested that attrition might have caused substantially less bias than did "forward telescoping," the inflating of age at first use over time. The evidence of forward telescoping was particularly pronounced with respect to age at first use of alcohol. This paper presents a procedure for correcting the distribution of age at first use for forward telescoping (but not attrition) by viewing a portion of the NHSDA data collected in successive years as constituting a cohort study. Results are presented from applying this procedure with NHSDA data collected from 1982 to 1995 for respondents born 1968-1973. The findings suggest that prevention programs need to be introduced at an earlier age than would be indicated by "uncorrected" retrospective data. Other implications are also highlighted. PMID- 21544260 TI - Visual speech primes open-set recognition of spoken words. AB - Visual speech perception has become a topic of considerable interest to speech researchers. Previous research has demonstrated that perceivers neurally encode and use speech information from the visual modality, and this information has been found to facilitate spoken word recognition in tasks such as lexical decision (Kim, Davis, & Krins, 2004). In this paper, we used a cross-modality repetition priming paradigm with visual speech lexical primes and auditory lexical targets to explore the nature of this priming effect. First, we report that participants identified spoken words mixed with noise more accurately when the words were preceded by a visual speech prime of the same word compared with a control condition. Second, analyses of the responses indicated that both correct and incorrect responses were constrained by the visual speech information in the prime. These complementary results suggest that the visual speech primes have an effect on lexical access by increasing the likelihood that words with certain phonetic properties are selected. Third, we found that the cross-modality repetition priming effect was maintained even when visual and auditory signals came from different speakers, and thus different instances of the same lexical item. We discuss implications of these results for current theories of speech perception. PMID- 21544261 TI - Synthetic studies on neoclerodane diterpenes from Salvia splendens: oxidative modifications of ring A. AB - Salvinorin A (1), a neoclerodane diterpene from the hallucinogenic mint Salvia divinorum, is the only known naturally occurring non-nitrogenous and specific kappa-opioid agonist. Some oxidative modifications of the A ring in the congeners of 1 isolated from Salvia splendens salviarin, splenolide B, splendidin and in the non-natural 8-epi-salviarin gave new derivatives, some of which were tested as agonists at opioid receptors. However, none of these compounds were active. The presence of the C-18, C-19 lactone could be at the origin of the observed lack of binding affinity. PMID- 21544262 TI - Crossmodal Source Identification in Speech Perception. AB - Four experiments examined the nature of multisensory speech information. In Experiment 1, participants were asked to match heard voices with dynamic visual alone video clips of speakers' articulating faces. This cross-modal matching task was used to examine whether vocal source matching can be accomplished across sensory modalities. The results showed that observers could match speaking faces and voices, indicating that information about the speaker was available for cross modal comparisons. In a series of follow-up experiments, several stimulus manipulations were used to determine some of the critical acoustic and optic patterns necessary for specifying cross-modal source information. The results showed that cross-modal source information was not available in static visual displays of faces and was not contingent on a prominent acoustic cue to vocal identity (f0). Furthermore, cross-modal matching was not possible when the acoustic signal was temporally reversed. PMID- 21544263 TI - PET imaging of CXCR4 using copper-64 labeled peptide antagonist. AB - Expression of CXCR4 in cancer has been found to correlate with poor prognosis and resistance to chemotherapy. In this study we developed a derivative of the CXCR4 peptide antagonist, T140-2D, that can be labeled easily with the PET isotope copper-64, and thereby enable in vivo visualization of CXCR4 in tumors. T140 was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N hydroxysuccinimide ester) (DOTA-NHS) to give T140-2D, which contains a DOTA molecule on each of the two lysine residues. (64)Cu-T140-2D was evaluated in vitro by migration and binding experiments, and in vivo by microPET imaging and biodistribution, in mice bearing CXCR4-positive and CXCR4-negative tumor xenografts. T140-2D was labeled with copper-64 to give (64)Cu-T140-2D in a high radiochemical yield of 86 +/- 3% (not decay-corrected) and a specific activity of 0.28 - 0.30 mCi/ug (10.36 - 11.1 MBq/ug). (64)Cu-T140-2D had antagonistic and binding characteristics to CXCR4 that were similar to those of T140. In vivo, (64)Cu-T140-2D tended to bind to red blood cells and had to be used in a low specific activity form. In this new form (64)Cu-T140-2D enabled specific imaging of CXCR4-positive, but not CXCR4-negative tumors. Undesirably, however, (64)Cu T140-2D also displayed high accumulation in the liver and kidneys. In conclusion, (64)Cu-T140-2D was easily labeled and, in its low activity form, enabled imaging of CXCR4 in tumors. It had high uptake, however, in metabolic organs. Further research with imaging tracers targeting CXCR4 is required. PMID- 21544264 TI - Facing the Music or Burying Our Heads in the Sand?: Adaptive Emotion Regulation in Midlife and Late Life. AB - Defenses that keep threatening information out of awareness are posited to reduce anxiety at the cost of longer-term dysfunction. By contrast, socioemotional selectivity theory suggests that preference for positively-valenced information is a late-life manifestation of adaptive emotion regulation. Using longitudinal data on 61 men, we examined links between emotion regulation indices informed by these distinct conceptualizations: defenses in earlier adulthood and selective memory for positively-valenced images in late-life. Use of avoidant defenses in midlife predicted poorer memory for positive, negative, and neutral images nearly 4 decades later. Late-life satisfaction was positively linked with midlife engaging defenses but negatively linked at the trend level with concurrent positive memory bias. PMID- 21544266 TI - Bayesian Peptide Peak Detection for High Resolution TOF Mass Spectrometry. AB - In this paper, we address the issue of peptide ion peak detection for high resolution time-of-flight (TOF) mass spectrometry (MS) data. A novel Bayesian peptide ion peak detection method is proposed for TOF data with resolution of 10 000-15 000 full width at half-maximum (FWHW). MS spectra exhibit distinct characteristics at this resolution, which are captured in a novel parametric model. Based on the proposed parametric model, a Bayesian peak detection algorithm based on Markov chain Monte Carlo (MCMC) sampling is developed. The proposed algorithm is tested on both simulated and real datasets. The results show a significant improvement in detection performance over a commonly employed method. The results also agree with expert's visual inspection. Moreover, better detection consistency is achieved across MS datasets from patients with identical pathological condition. PMID- 21544267 TI - Viscosity and interfacial properties in a mussel-inspired adhesive coacervate. AB - The chemistry of mussel adhesion has commanded the focus of much recent research activity on wet adhesion. By comparison, the equally critical adhesive processing by marine organisms has been little examined. Using a mussel-inspired coacervate formed by mixing a recombinant mussel adhesive protein (fp-151-RGD) with hyaluronic acid (HA), we have examined the nanostructure, viscosity, friction, and interfacial energy of fluid-fluid phase-separated coacervates using the surface forces apparatus and microscopic techniques. At mixing ratios of fp-151 RGD:HA resulting in marginal coacervation, the coacervates showed shear thickening viscosity and no structure by cryo-transmission electron microscopy (cryo-TEM). However, at the mixing ratio producing maximum coacervation, the coacervate showed shear-thinning viscosity and a transition to a bicontinuous phase by cryo-TEM. The shear-thinning viscosity, high friction coefficient (>1.2), and low interfacial energy (<1 mJ m(-2)) observed at the optimal mixing ratio for coacervation are promising delivery, spreading and adhesion properties for future wet adhesive and coating technologies. PMID- 21544268 TI - Understanding Random Effects in Group-Based Trajectory Modeling: An Application of Moffitt's Developmental Taxonomy. AB - The group-based trajectory modeling approach is a systematic way of categorizing subjects into different groups based on their developmental trajectories using formal and objective statistical criteria. With the recent advancement in methods and statistical software, modeling possibilities are almost limitless; however, parallel advances in theory development have not kept pace. This paper examines some of the modeling options that are becoming more widespread and how they impact both empirical and theoretical findings. The key issue that is explored is the impact of adding random effects to the latent growth factors and how this alters the meaning of a group. The paper argues that technical specification should be guided by theory, and Moffitt's developmental taxonomy is used as an illustration of how modeling decisions can be matched to theory. PMID- 21544269 TI - Rotavirus infection: optimal treatment and prevention. PMID- 21544270 TI - A rallying cry for the public health fund. PMID- 21544271 TI - PPI therapy: when to worry about fracture risk. PMID- 21544272 TI - Recent onset of confusion, limited mobility, and disturbed sleep-wake cycle. PMID- 21544273 TI - It's time to abandon the sliding scale. PMID- 21544274 TI - ACIP immunization update. PMID- 21544275 TI - Is your patient still using rosiglitazone? PMID- 21544276 TI - Returning traveler with painful penile mass. PMID- 21544277 TI - Clinical inquiries. What are the adverse effects of prolonged opioid use in patients with chronic pain? PMID- 21544278 TI - Clinical inquiries. Which oral antibiotics are best for acne? PMID- 21544279 TI - Clinical inquiries. Which treatments provide the most relief for pharyngitis pain? PMID- 21544280 TI - Clinical inquiries. When is the best time to clamp the umbilical cord after routine vaginal delivery? PMID- 21544281 TI - Clinical inquiries. How effective--and safe--are systemic steroids for acute low back pain? PMID- 21544282 TI - Kirkwood correlation factors in liquid mixtures from an extended Onsager-Kirkwood Frohlich equation. AB - Two approaches for applying the Onsager-Kirkwood-Frohlich equation to liquid mixtures are revisited at the light of recent developments leading to the estimation of relative permittivities and refractive indices of thermodynamically ideal liquid mixtures. From the one-liquid approach, the squared permanent dipole moment of the mixture molecular-equivalent species M is demonstrated to be a mole fraction average of squared permanent dipole moments of the components. An expression is obtained for calculating the ideal Kirkwood correlation factor of M at any composition by using only pure-constituent properties. From the two-liquid approach (Bottcher's equation), equations are obtained to describe the dependence on composition of the Kirkwood correlation factor of both components in the ideal mixture, even in mixtures of Onsager liquids. This dependency is tentatively ascribed to London dispersion forces acting between unlike molecules. It is demonstrated that Bottcher's equation can only be applied to mixtures where the relative permittivity of each component is larger than the squared refractive index of the other component. From the interplay of one- and two-liquid approaches, the ideal Kirkwood correlation factor of M and of both constituents are inter-related. Thermodynamic expressions are given for the calculation of excess Kirkwood correlation factors. In the case where permanent dipole moments are unknown, the ratio excess/ideal, termed the relative excess Kirkwood correlation factor for components and species M can still be evaluated. These ratios are related to more conventional excess properties. Density, relative permittivity and refractive index data are reported for binary mixtures of 2,2,2 trifluoroethanol with mono-, di-, tri- or tetra-glyme over the whole composition range at 288 K and 298 K. For these systems, ideal, excess and relative excess and Kirkwood correlation factors are calculated and discussed. In particular, by regarding Kirkwood correlation factors as a measure of order/molecular organisation in liquid mixtures, it is found that the formation of ideal mixtures entails a decrease of order which, for the present binary systems, is almost cancelled out upon passage to the corresponding real mixtures. It is concluded that the present formulation permits to estimate Kirkwood correlation factors of each constituent of liquid mixtures and thereby to draw information on their molecular organisation. PMID- 21544283 TI - Molecular spin crossover phenomenon: recent achievements and prospects. AB - Recently we assisted a strong renewed interest in the fascinating field of molecular spin crossover complexes by (1) the emergence of nanosized spin crossover materials through direct synthesis of coordination nanoparticles and nanopatterned thin films as well as by (2) the use of novel sophisticated high spatial and temporal resolution experimental techniques and theoretical approaches for the study of spatiotemporal phenomena in cooperative spin crossover systems. Besides generating new fundamental knowledge on size-reduction effects and the dynamics of the spin crossover phenomenon, this research aims also at the development of practical applications such as sensor, display, information storage and nanophotonic devices. In this critical review, we discuss recent work in the field of molecule-based spin crossover materials with a special focus on these emerging issues, including chemical synthesis, physical properties and theoretical aspects as well (223 references). PMID- 21544284 TI - Facile access to ultrasmall Eu2O3 nanoparticle-functionalized hollow silica nanospheres based on the spontaneous formation and decomposition of a cross linked organic/inorganic hybrid core. AB - We report a promising strategy for the facile synthesis of ultrasmall nanoparticle-functionalized hollow silica nanospheres by using a functional cross linked organic/inorganic hybrid core, which can be obtained simply through successive spontaneous reactions in water. PMID- 21544285 TI - High efficiency of cavity-based triaryl-phosphines in nickel-catalysed Kumada Tamao-Corriu cross-coupling. AB - Combining diaryl-calixarenyl phosphines with [Ni(cod)(2)] resulted in highly active Kumada-Tamao-Corriu cross-coupling catalysts. With one of the ligands, TOFs up to 439,000 mol(ArBr) mol(Ni)(-1) h(-1) were observed in the reaction of 1 bromonaphthalene with PhMgBr. The systems were also found to be active at room temperature with aryl chlorides. PMID- 21544286 TI - Weak molecular associations investigated by 1H-NMR spectroscopy on a neat organosiloxane-solvent mixture. AB - The rational design of new sensitive materials for chemical sensors relies on the knowledge of molecular interactions between the chemical species in question with compounds that may potentially be present in the gas phase. In this context, the intermolecular interactions between a family of functionalized polysiloxanes and a series of organic compounds have been investigated. This work addresses the problem of determining the association constant or energy by studying neat liquid mixtures without solvents. An original approach has been proposed to obtain such information from the excess function of the difference in chemical shifts between both interacting species. Data obtained as a function of the composition of the mixtures have been fitted according to two models: either by considering the formation of a 1:1 complex governed by an equilibrium constant or by the existence of a local composition following the Wilson model. Both methods have been tested on model compounds and the results have been compared with solubility enthalpies calculated using Hansen coefficients. PMID- 21544288 TI - Efficient white light emission by upconversion in Yb(3+)-, Er(3+)- and Tm(3+) doped Y2BaZnO5. AB - We report efficient white upconversion luminescence in Yb(3+)-, Er(3+)- and Tm(3+)-doped monophasic and biphasic Y(2)BaZnO(5) phosphors under 977 nm near infrared excitation and at low excitation power densities (down to ~25 mW mm( 2)). PMID- 21544287 TI - Sequencing nucleic acids: from chemistry to medicine. AB - Chemistry has played a vital role in making routine, affordable sequencing of human genomes a reality. This article focuses on the genesis and development of Solexa sequencing that originated in Cambridge, UK. This sequencing approach is helping transform science and offers intriguing prospects for the future of medicine. PMID- 21544289 TI - Highly ordered acid functionalized SBA-15: a novel organocatalyst for the preparation of xanthenes. AB - Post-synthesis modification of SBA-15 has been carried out to design highly ordered acid functionalized hybrid mesoporous organosilica, AFS-1. This material has been used as an efficient heterogeneous organocatalyst for the syntheses of xanthenes under mild conditions in the absence of any other metal co-catalyst. PMID- 21544290 TI - HO2 formation from the OH + benzene reaction in the presence of O2. AB - In this study we investigated the secondary formation of HO(2) following the benzene + OH reaction in N(2) with variable O(2) content at atmospheric pressure and room temperature in the absence of NO. After pulsed formation of OH, HO(x) (= OH + HO(2)) and OH decay curves were measured by means of a laser-induced fluorescence technique (LIF). In synthetic air the total HO(2) yield was determined to be 0.69 +/- 0.10 by comparison to results obtained with CO as a reference compound. HO(2) is expected to be a direct product of the reaction of the intermediately formed OH-benzene adduct with O(2). The HO(2) yield is slightly greater than the currently recommended yield of the proposed HO(2) co product phenol (~53%). This hints towards other, minor HO(2) forming channels in the absence of NO, e.g. the formation of epoxide species that was proposed in the literature. For other test compounds upper limits of HO(2) yields of 0.10 (isoprene) and 0.05 (cyclohexane) were obtained, respectively. In further experiments at low O(2) concentrations (0.06-0.14% in N(2)) rate constants of (2.4 +/- 1.1) * 10(-16) cm(3) s(-1) and (5.6 +/- 1.1) * 10(-12) cm(3) s(-1) were estimated for the OH-benzene adduct reactions with O(2) and O(3), respectively. The rate constant of the unimolecular dissociation of the adduct back to benzene + OH was determined to be (3.9 +/- 1.3) s(-1). The HO(2) yield at low O(2) was similar to that found in synthetic air, independent of O(2) and O(3) concentrations indicating comparable HO(2) yields for the adduct + O(2) and adduct + O(3) reactions. PMID- 21544291 TI - Blue-shifted A-H stretching frequencies in complexes with methanol: the decisive role of intramolecular coupling. AB - The presence of a blue shift of A-H stretching frequencies in intermolecular complexes is directly related to the intramolecular coupling between A-H and vicinal A-X bonds in isolated molecules. The intramolecular coupling between vicinal bonds is the decisive parameter that determines whether a general molecule is a candidate for displaying blue-shifted A-H stretching frequencies in intermolecular complexes, with or without hydrogen bonding. The structures and vibrational spectra of dimeric complexes of methanol with H(2)O, HF, HCN, HNC, HOF, HNO, and HSN are investigated at the MP2/6-311++G(2d,2p) approach. Blue- and red-shifts of the methyl C-H stretches of methanol and the various other A-H stretching frequencies in the complexes can be predicted by normal coordinate analyses of methanol and the partner molecules. It is, hence, suggested that conventional normal coordinate analysis is the appropriate predictive tool to decide beforehand whether a given molecule is a promising candidate for the observation of blue shifts in intermolecular complexes. PMID- 21544299 TI - Interface modification effects of 4-tertbutylpyridine interacting with N3 molecules in quasi-solid dye-sensitized solar cells. AB - In this paper, the interface modification effects of 4-tertbutylpyridine (TBP), especially the interaction with dye molecules, were discussed. The results of FTIR showed that TBP interacted with dye molecules, in addition to its interaction with the TiO(2) film. Reaction between N3 and TBP by the interaction force of the H atom in the -COOH group of N3 and the N atom of TBP could retard the aggregation of dye molecules, decreasing the electron quenching and charge recombination. Furthermore, the results of cyclic voltammograms and UV-vis absorption edge revealed the interaction between TBP and dye molecules could cause the energy level of the dye molecules to change, influencing the electron injection efficiency in DSCs. The IPCE results indicated that with TBP modification, the injection efficiency decreased, but the electron collection efficiency was enhanced. PMID- 21544300 TI - Fabrication of a novel cascade high-pressure electro-osmotic pump. AB - A novel cascade electro-osmotic pump (EOP) has been fabricated by alternately connecting a cation monolithic column and anion monolithic column in series. In this manner, the change of electric polarity between each stage of the cascade EOP is easily achieved and the pressure output of the EOP could be greatly enhanced without increase of the applied voltage. PMID- 21544301 TI - Thermo-switchable surfactant gel. AB - A thermo-switchable surfactant gel with the property of gelation on heating was developed for the first time based on palmitylamidosulfobetaine. Micellar growth from globular aggregates to entangled worms upon heating is responsible for the thermal gelation. PMID- 21544302 TI - Seebeck coefficients in ionic liquids--prospects for thermo-electrochemical cells. AB - Measurement of Seebeck coefficients in a range of ionic liquids (ILs) suggests that these electrolytes could enable the development of thermoelectric devices to generate electrical energy from low-grade heat in the 100-150 degrees C range. PMID- 21544303 TI - A copper(II) complex as an intermediate of copper(I)-catalyzed C-N cross coupling of N-phenylaniline with aryl halide by in situ ESI-MS study. AB - Complexes [Cu(NPh(2))(2)](-), [Cu(NPh(2))I](-) and K[Cu(phen)(NPh(2)) (p tolyl)](+) were observed by in situ electrospray ionization mass spectrometry (ESI-MS) analysis of the copper(I)-catalyzed C-N coupling reaction under the catalytic reaction condition indicating that they are intermediates in the reaction. A catalytic cycle composed of a free radical path and a 2e oxidative addition path is proposed based on these observations. PMID- 21544304 TI - Validation of the inhalable dust algorithm of the Advanced REACH Tool using a dataset from the pharmaceutical industry. AB - As it is often difficult to obtain sufficient numbers of measurements to adequately characterise exposure levels, occupational exposure models may be useful tools in the exposure assessment process. This study aims to refine and validate the inhalable dust algorithm of the Advanced REACH Tool (ART) to predict airborne exposure of workers in the pharmaceutical industry. The ART was refined to reflect pharmaceutical situations. Largely task based workplace exposure data (n = 192) were collated from a multinational pharmaceutical company with exposure levels ranging from 5 * 10(-5) to 12 mg m(-3). Bias, relative bias and uncertainty around geometric mean exposure estimates were calculated for 16 exposure scenarios. For 12 of the 16 scenarios the ART geometric mean exposure estimates were lower than measured exposure levels with on average, a one-third underestimation of exposure (relative bias -32%). For 75% of the scenarios the exposure estimates were, within the 90% uncertainty factor of 4.4, as reported for the original calibration study, which may indicate more uncertainty in the ART estimates in this industry. While the uncertainty was higher than expected this is likely due to the limited number of measurements per scenario, which were largely derived from single premises. PMID- 21544305 TI - Synthesis and reactivity of furoquinolines bearing an external methylene-bond: access to reduced and spirocyclic structures. AB - A family of furoquinolines were efficiently obtained through a tandem acetalization/cycloisomerization process catalyzed by (5 mol%) silver imidazolate polymer and triphenylphosphine, and diversity was brought by the use of 7 different alcohol groups. From these furoquinolines, 3 examples of reduced derivatives could be obtained (d.r. up to 94 : 6), 10 different spiroketal derivatives by hetero-Diels-Alder reaction (d.r. up to 20 : 1), 8 hetero-[5,5] spirocycles by cycloaddition with dibromoformaldoxime (d.r. up to 86 : 14) and finally 6 hetero-[5,6]-spirocycles by [4 + 2] cycloaddition with ethyl 3-bromo-2 (hydroxyimino)propanoate (d.r. up to 90 : 10). PMID- 21544306 TI - A theoretical study of the XP and NEXAFS spectra of alanine: gas phase molecule, crystal, and adsorbate at the ZnO(10 10) surface. AB - The adsorption of alanine on the mixed-terminated ZnO(10 10) surface is studied by means of quantum-chemical ab initio calculations. Using a finite cluster model and the adsorption geometry as obtained both by periodic CPMD and embedded cluster calculations, the C1s, N1s and O1s X-ray photoelectron spectra (XPS) and near-edge X-ray absorption fine structure (NEXAFS) spectra are calculated for single alanine molecules on ZnO(10 10). These spectra are compared with the spectra calculated for alanine in the gas phase and in its crystalline form and with experimental XPS and NEXAFS data for the isolated alanine molecule and for alanine adsorbed on ZnO(10 10) at multilayer and monolayer coverage. The excellent agreement between the experimental and calculated XP and NEXAFS spectra confirms the calculated adsorption geometry: A single alanine molecule is bound to ZnO(10 10) in a dissociated bidentate form with the two O atoms of the acid group bound to two Zn atoms of the surface and the proton transferred to one O atom of the surface. Other possible structures, such as adsorption of alanine in one of its neutral or zwitterionic forms in which the proton of the -COOH group remains at this group or is transferred to the amino group, can be excluded since they would give rise to quite different XP spectra. In the multilayer coverage regime, on the other hand, alanine is in its crystalline form as is also shown by the analysis of the XP spectra. PMID- 21544307 TI - Mechanistic analysis of trans C-N reductive elimination from a square-planar macrocyclic aryl-copper(III) complex. AB - A net trans C-N reductive elimination reaction is observed from a macrocyclic aryl-Cu(III) complex, and a mechanistic study of this reaction indicates that coordinating ligands play a role in mediating this unusual transformation. PMID- 21544308 TI - Bilirubin oxidase from Myrothecium verrucaria: X-ray determination of the complete crystal structure and a rational surface modification for enhanced electrocatalytic O2 reduction. AB - The blue multi-copper oxidase bilirubin oxidase (BOx) from the ascomycete plant pathogen Myrothecium verrucaria (Mv) efficiently catalyses the oxidation of bilirubin to biliverdin, with the concomitant reduction of O(2) to water, a reaction of considerable interest for low-temperature bio-fuel cell applications. We have solved the complete X-ray determined structure of Mv BOx at 2.4 A resolution, using molecular replacement with the Spore Coat Protein A (CotA) enzyme from Bacillus subtilis (PDB code 1GSK) as a template. The structure reveals an unusual environment around the blue type 1 copper (T1 Cu) that includes two non-coordinating hydrophilic amino acids, asparagine and threonine. The presence of a long, narrow and hydrophilic pocket near the T1 Cu suggests that structure of the substrate-binding site is dynamically determined in vivo. We show that the interaction between the binding pocket of Mv BOx and its highly conjugated natural organic substrate, bilirubin, can be used to stabilise the enzyme on a pyrolytic graphite electrode, more than doubling its electrocatalytic activity relative to the current obtained by simple adsorption of the protein to the carbon surface. PMID- 21544309 TI - Identification and characterisation of monoclonal antibodies that impair the activation of human thrombin activatable fibrinolysis inhibitor through different mechanisms. AB - Thrombin activatable fibrinolysis inhibitor (TAFI) forms a molecular link between coagulation and fibrinolysis and is a putative target to develop profibrinolytic drugs. Out of a panel of monoclonal antibodies (MA) raised against TAFI-ACIIYQ, we selected MA-TCK11A9, MA-TCK22G2 and MA-TCK27A4, which revealed high affinity towards human TAFI-TI-wt. MA-TCK11A9 was able to inhibit mainly plasmin-mediated TAFI activation, MA-TCK22G2 inhibited plasmin- and thrombin-mediated TAFI activation and MA-TCK27A4 inhibited TAFI activation by plasmin, thrombin and thrombin/thrombomodulin (T/TM) in a dose-dependent manner. These MA did not interfere with TAFIa activity. Using an eight-fold molar excess of MA over TAFI, all three MA were able to reduce clot lysis time significantly, i.e. in the presence of exogenous TM, MA-TCK11A9, MA-TCK22G2 and MA-TCK27A4 reduced clot lysis time by 47 +/- 9.1%, 80 +/- 8.6% and 92 +/- 14%, respectively, compared to PTCI. This effect was even more pronounced in the absence of TM i.e. MA-TCK11A9, MA-TCK22G2 and MA-TCK27A4 reduced clot lysis time by 90 +/- 14%, 140 +/- 12% and 147 +/- 29%, respectively, compared to PTCI. Mutagenesis analysis revealed that residues at position 268, 272 and 276 are involved in the binding of MA-TCK11A9, residues 147 and 148 in the binding of MA-TCK22G2 and residue 113 in the binding of MA-TCK27A4. The present study identified three MA, with distinct epitopes, that impair the activation of human TAFI and demonstrated that MA-TCK11A9 which mainly impairs plasmin-mediated TAFI activation can also reduce significantly clot lysis time in vitro. PMID- 21544311 TI - von Willebrand factor abnormalities in aortic valve stenosis: Pathophysiology and impact on bleeding. AB - Acquired von Willebrand syndrome (AVWS) may complicate severe aortic valve stenosis, due to a reduction in the haemostatically more efficient large von Willebrand factor (VWF) multimers. This study was designed to analyse the relevance of VWF abnormalities and haemorrhagic diathesis in severe aortic valve stenosis. Forty-one consecutive patients undergoing valve replacement were investigated: seven had minor bleeding symptoms in their recent history; 10 (24.3%) had a reduced VWF collagen binding (VWF:CB) to VWF antigen ratio, and 33 (80.5%) had a decrease in large VWF multimers. The shortage of large multimers was not associated with any accumulation of small VWF multimers (apparently ruling out any increased VWF proteolysis), nor was there any increase in VWF propeptide, which excludes a shorter VWF survival. The risk of developing VWF abnormalities was higher in patients with rheumatic valve disease than in degenerative cases (p=0.025) and in valves with <50% of residual endothelial cells (p=0.004). Bleeders differed from non-bleeders in that they had a higher mean transvalvular gradient and a more marked decrease in large VWF multimers. VWF abnormalities did not exacerbate peri-operative blood loss, however - a finding consistent with the full correction of these VWF abnormalities, seen already on the first postoperative day and persisting for up to six months after surgery. According to the data obtained in our cohort of patients VWF abnormalities are common in severe aortic stenosis, particularly in cases of rheumatic valve disease, but loss of the largest multimers does not seem to cause clinical bleeding in most patients. PMID- 21544310 TI - Interaction of high-molecular-weight kininogen with endothelial cell binding proteins suPAR, gC1qR and cytokeratin 1 determined by surface plasmon resonance (BiaCore). AB - The physiologic activation of the plasma kallikrein-kinin system requires the assembly of its constituents on a cell membrane. High- molecular-weight kininogen (HK) and cleaved HK (HKa) both interact with at least three endothelial cell binding proteins: urokinase plasminogen activator receptor (uPAR), globular C1q receptor (gC1qR,) and cytokeratin 1 (CK1). The affinity of HK and HKa for endothelial cells are KD=7-52 nM. The contribution of each protein is unknown. We examined the direct binding of HK and HKa to the soluble extracellular form of uPAR (suPAR), gC1qR and CK1 using surface plasmon resonance. Each binding protein linked to a CM-5 chip and the association, dissociation and KD (equilibrium constant) were measured. The interaction of HK and HKa with each binding protein was zinc-dependent. The affinity for HK and HKa was gC1qR>CK1>suPAR, indicating that gC1qR is dominant for binding. The affinity for HKa compared to HK was the same for gC1qR, 2.6-fold tighter for CK1 but 53-fold tighter for suPAR. Complex between binding proteins was only observed between gC1qR and CK1 indicating that a binary CK1-gC1qR complex can form independently of kininogen. Although suPAR has the weakest affinity of the three binding proteins, it is the only one that distinguished between HK and HKa. This finding indicates that uPAR may be a key membrane binding protein for differential binding and signalling between the cleaved and uncleaved forms of kininogen. The role of CK1 and gC1qR may be to initially bind HK to the membrane surface before productive cleavage to HKa. PMID- 21544312 TI - New oral anticoagulants in venous thromboembolism prophylaxis in orthopaedic patients: are they really better? AB - Prophylaxis against venous thromboembolism (VTE) is considered standard of care. Appropriate chemoprophylaxis for VTE has been mandated by the United States government agencies and consumer groups. However, controversies exist regarding the most clinically relevant and safe chemoprophylaxis protocols in patients undergoing joint replacement surgery. Thus, this paper reviews the clinical efficacy and safety of newer oral anticoagulants. A literature search was performed for oral anticoagulants in advanced stages of development using PubMed and abstracts from thrombosis meetings. Most clinical trial data have demonstrated equal or superior efficacy in venographic endpoints in comparison to low-molecular-weight heparins (LMWH). However, bleeding complications have been reported to occur with oral anticoagulants as frequently as or more frequently than with LMWH. Other potential complications reported include liver enzyme elevation and cardiac irregularities. It remains to be established whether newer oral anticoagulants will be better alternatives to the current standard-of-care in real-life medical clinical practice. PMID- 21544313 TI - Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux. AB - Edoxaban, an oral direct factor Xa (FXa) inhibitor, is in phase III clinical development for stroke prevention in atrial fibrillation and treatment of venous thromboembolism. The shed blood model allows for study of activated coagulation at a site of standardised tissue injury due to local release of tissue factor. The objective of this study was to evaluate the effect of three doses of edoxaban on markers of coagulation in shed and venous blood versus placebo and a standard prophylactic dose of fondaparinux. A total of 100 healthy male subjects were randomised to receive single doses of one of five treatments: subcutaneously administered fondaparinux 2.5 mg; orally administered edoxaban 30, 60, or 120 mg; or placebo. The primary objective was measurement of blood coagulation markers prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin (TAT) complex, and platelet activation marker beta-thromboglobulin (beta-TG), in venous and shed blood. Secondary objectives included pharmacokinetics, shed blood volume, and safety of edoxaban. Single doses of edoxaban caused rapid and significant decreases of F1+2, TAT, and beta-TG in the shed blood model, indicating inhibition of thrombin generation and platelet activation. Inhibition was significantly less for fondaparinux versus edoxaban. Baseline-corrected F1+2, TAT, and beta-TG values demonstrated sustained inhibition up to 24 hours for shed blood in the edoxaban groups but no significant inhibition in venous blood. Overall, edoxaban treatments were well tolerated. In conclusion, single oral doses of edoxaban 30, 60, or 120 mg caused rapid and sustained inhibition of coagulation up to 24 hours in the shed blood model. PMID- 21544314 TI - Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy. AB - Clopidogrel has become part of the mainstay of therapy for acute coronary syndromes and in patients post stenting. Clopidogrel is a pro drug and is metabolised by liver enzymes, particularly CYP2C19, into its active form. A considerable proportion of patients have a poor response to clopidogrel and this may be due to several factors. Genetic polymorphisms involved in clopidogrel's absorption, metabolism and activity at the platelet may interfere with its antiplatelet actions. Further, proton pump inhibitors (PPI) may interfere with clopidogrel's actions by functionally reducing the ability of CYP2C19 to convert clopidogrel to its active metabolite. By attenuating clopidogrel's actions, both polymorphisms and drug interactions may increase the risk of thrombotic events during clopidogrel therapy. This review will explore the current evidence relating to the association between PPIs, genetic polymorphisms and poor response to clopidogrel. Routine genetic testing cannot be recommended for patients receiving dual antiplatelet therapy (DAPT). However, it may have a role for patients with an episode of stent thrombosis, prior to planned high-risk stenting or major bleeding. Regarding concomitant clopidogrel and PPI therapy, it is recommended that only patients with previous gastrointestinal (GI) bleeding or multiple risk factors for GI bleeding should be prescribed gastroprotection. This is due to the uncertainty surrounding the clinical significance of this interaction given the discordant biochemical and clinical data, conflicting results from observational studies and the limitations of the COGENT study. Pantoprazole seems least likely to interact with clopidogrel and most suitable for use in patients receiving DAPT. PMID- 21544315 TI - Congenital combined deficiency of factor VII and X in a patient due to accidental diphacinone intoxication. PMID- 21544316 TI - Is CHA2DS2-VASc score a predictor of left atrial thrombus in patients with paroxysmal atrial fibrillation? PMID- 21544317 TI - Aspirin failure in patients presenting with acute cerebrovascular ischaemia. AB - Aspirin is the most commonly used antiplatelet drug for prevention of ischaemic stroke. In order to determine the prevalence and nature of aspirin failure, we studied 51 adults admitted with suspected ischaemic stroke and already prescribed daily aspirin. Within 48 hours (h) of onset, blood and urine samples were collected to assess platelet aggregation, activation and aspirin response by a range of methods. All tests were then repeated on a second sample taken 24 h after witnessed administration of 75 mg or 150 mg aspirin. At entry to the study, incomplete response to aspirin, measured by arachidonic acid (AA)-stimulated platelet aggregation, was found in 43% of patients. Following in-hospital aspirin administration, there was a significant decrease in AA-aggregation (p=0.001) suggesting poor adherence to therapy prior to admission. However, residual aggregation (10-15%) persisted in 11 subjects - suggesting alternative causes. In incomplete responders on admission, platelet aggregation with adenosine diphosphate (ADP) was significantly higher compared with responders (p<0.05) but there were no significant differences in collagen aggregation, platelet fibrinogen binding or P-selectin expression, plasma von Willebrand factor, fibrinogen, high-sensitivity C-reactive protein, or the urinary metabolite, 11 dehydro-TxB2. Incomplete platelet inhibition is common around the time of acute cerebrovascular ischaemic events in patients prescribed aspirin. Up to 50% of these observations appear due to incomplete adherence to aspirin therapy. Intervention studies are required to determine the clinical relevance of measured platelet response to aspirin in terms of outcome, and the effectiveness of improved pharmacotherapy for stroke prevention. PMID- 21544318 TI - Are P2Y12 reaction unit (PRU) and % inhibition index equivalent for the expression of P2Y12 inhibition by the VerifyNow assay? Role of haematocrit and haemoglobin levels. AB - The results of the whole blood VerifyNow P2Y12 assay can be expressed as platelet reaction units (PRU) or % inhibition index (%inh), but an optimal cut-off for the assessment of high on-treatment platelet reactivity (HPR) predictive of clinical events has been validated only for PRU. The aim of the study was to study the influence of haematological variables, such as platelet and leukocyte counts or haematocrit / haemoglobin, within the limits indicated by the manufacturer for assay validity, on the results of the test. We performed a comparison of PRU and %inh in a series 186 samples obtained from a clinical trial on patients under dual antiplatelet therapy. The results show that PRU significantly decreases with increasing haematocrit / haemoglobin, whereas %inh does not, due to a parallel change in PRU and iso-TRAP baseline value. PRU and % inhibition index are not equivalent for the definition of HPR, because of their different sensitivities to haematocrit / haemoglobin. PMID- 21544319 TI - Is increased platelet turnover responsible for low responsiveness to different thienopyridienes? A case report of recurrent stent thromboses. PMID- 21544320 TI - Immunity to thrombotic events is achievable if we stop the guessing game: is this the major hidden message from GRAVITAS? PMID- 21544321 TI - Higher mortality rate in patients hospitalised for acute pulmonary embolism during weekends. AB - The management of acute pulmonary embolism (PE) is often challenging and requires specific medical expertise, diagnostic techniques and therapeutic options that may not be available in all hospitals throughout the entire week. The aim of our study was to evaluate whether or not an association exists between weekday or weekend admission and mortality for patients hospitalised with acute PE. Using routinely collected hospital administrative data, we examined patients discharged with a diagnosis of PE from the hospitals of the Emilia- Romagna Region in Italy (January 1999-December 2009). The risk of in-hospital death was calculated for admissions at the weekend and compared to weekday admissions. Of a total of 26,560 PEs, 6,788 (25.6%) had been admitted during weekends. PE admissions were most frequent on Mondays (15.8%) and less frequent on Saturdays and Sundays/holidays (12.8%) (p<0.001). Weekend admissions were associated with significantly higher rates of in-hospital mortality than weekday admissions (28% vs. 24.8%) (p<0.001). The risk of weekend admission and in-hospital mortality was higher after adjusting for sender, hospital characteristics, and the Charlson co morbidity index. In conclusion, hospitalisation for PE on weekends seems to be associated with a significantly higher mortality rate than on weekdays. Further research is needed to investigate the reasons for this observed difference in mortality in order to try and implement future strategies that ensure an adequate level of care throughout the entire week. PMID- 21544322 TI - Impact of the type of centre on management of AF patients: surprising evidence for differences in antithrombotic therapy decisions. AB - Atrial fibrillation (AF) patients may receive treatment from specialists or from general medicine physicians representing different levels of care within a structured health care system. This "choice" is influenced by patient flow within a health care system, patient preference, and individual access to health care resources. We analysed how the postgraduate training and work environment of treating physicians affects management decisions in AF patients. Patient characteristics and treatment decisions were analysed at the time of enrolment into the registry of the German Atrial Fibrillation NETwork (AFNET). A total of 9,577 patients were enrolled from 2004 to 2006 in 191 German centres that belonged to the following four levels of care: 13 tertiary care centres (TCC) enrolled 3,795 patients (39.6%), 58 district hospitals (DH) enrolled 2,339 patients (24.4%), 62 office-based cardiologists (OC) enrolled 2,640 patients (27.6%), and 58 general practitioners or internists (GP) enrolled 803 patients (8.4%). Patients with new-onset AF were often treated in DH. TCC treated younger patients who more often presented with paroxysmal AF. Older patients and patients in permanent AF more often received outpatient care. Consistent with recommendations, younger patients and patients with non-permanent AF received rhythm control therapy more often. In addition, the type of centre affected the decision for rhythm control. Stroke risk was similar between centre types (mean CHADS2 scores 1.6 -1.9). TCC (68.8%) and OC (73.6%) administered adequate antithrombotic therapy more often than DH (55.1%) or GP (52.0%, p<0.001 between groups). Upon multivariate analysis, enrolment by TCC or OC was associated with a 1.60 (1.20-2.12, p=0.001) fold chance for adequate antithrombotic treatment. This difference between centre types was consistent irrespective of the type of stroke risk estimation (ESC 2001 guidelines, CHADS2 score), and also consistent when the recently suggested CHA2DS2-VASc score was used to estimate stroke risk. In conclusion, management decisions in AF are influenced by the education and clinical background of treating physicians in Germany. Inpatients receive more rhythm control therapy. Adequate antithrombotic therapy is more often administered in specialist (cardiologist) centres. PMID- 21544323 TI - Durable responses to rituximab in acquired factor VIII deficiency. PMID- 21544324 TI - Additive inhibitory effects of retinoids and interferon-alpha on the growth of human cervical carcinoma cells. AB - The combination of 13-cis retinoic acid (13CRA) and interferon-alpha (IFN-alpha) has shown marked antitumor activity against locally advanced cervical cancer in vivo. To begin to explore the mechanism and potential of the efficacy of this combination, the sensitivity of 9 cervical carcinoma cell lines to the growth inhibitory effects of these agents was examined after 1 to 7 days of treatment. IFN-alpha (100 U/ml) alone exerted variable effects. SiHa cell line was very sensitive showing 75% inhibition. ME180, CaSki, MS751, and C33-A cell lines were moderately inhibited (30-45% inhibition), and C41, HeLa, and HT-3 cell lines were poorly responsive (20% inhibition or less). 13CRA (10(-9) to 10(-6) M) alone also caused variable growth inhibitory effect. ME180, SiHa, and HT-3 exhibited considerable inhibition (IC(50)s of 9x10(-8), 4x10(-8), and 7x10(-8) M, respectively and maximal inhibition of 80%, 79%, and 83% at 10(-6) M) and the other cell lines showed minor responses (20-45% inhibition at 10(-6) M). ME180, MS751, C41, and HeLa demonstrated additive growth inhibitory effects of 13CRA and IFN-alpha whereas the other 4 cell lines showed no additive effects. All the cell lines expressed mRNAs for the nuclear retinoid receptors (RARs and RXRs) RAR alpha, RAR-gamma, and RXR-alpha, however, RAR-beta mRNA was detected only in ME180, MS751, C4I, and CaSki. Treatment with retinoic acid increased RAR-alpha level in C4I, HT-3, and CaSki; RAR-beta in HT-3; and RAR-gamma in HT-3 and C4I cells. IFN-alpha treatment did not exert any effect on the level of mRNA for any of the retinoid receptors in any of the cell lines or on the level of HPV18 E6 and E7 mRNA in HeLa cells. Treatment with the combination of RA and IFN-alpha did not affect the level of receptor mRNAs differently than RA alone did. There appeared to be no correlation between the responses of the cells to these agents and the presence or type of nuclear retinoid receptor, human papillomavirus, or mutant p53 in the cells. PMID- 21544325 TI - Dexniguldipine hydrochloride inhibits growth of human pancreatic adenocarcinoma cells and expression of protein kinase C isoforms alpha and zeta. AB - New therapeutic regimens are needed for the treatment of pancreatic cancer. In view of the importance of protein kinase C (PKC) in tumorigenesis, we evaluated the effects of dexniguldipine hydrochloride (DNIG) on the in vitro growth of CFPAC-1 human pancreatic adenocarcinoma cells and the expression of PKC isoforms. DNIG is a potent antineoplastic drug with well-established anti-PKC activity and the ability to reverse multidrug resistance. DNIG (1.6-25 mu M) decreased the number of cells in culture in a time- and dose-dependent manner with an EC(50) of 4.9 mu M on day 1 and 2.8 mu M on day 3. When PKC isoform expression in CFPAC-1 cells was analyzed by immunoblotting, the predominant isoforms were identified as alpha and zeta. The expression of PKC alpha and zeta was inhibited significantly by DNIG (0.63-2.5 mu M). These results suggest that DNIG suppresses the proliferation of CFPAC-1 pancreatic cancer cells, possibly by inhibiting the expression of specific PKC isoforms. PMID- 21544326 TI - Role of HPV in tumorigenesis of oral keratinocytes. AB - HPV-immortalized human oral keratinocytes can convert to tumorigenic cells by chemical carcinogens while normal human keratinocytes cannot. The different responses of these cells to chemical carcinogens may be due to their different genomic stability. Since the genomic stability of cells is closely associated with cell cycle control, we correlated cell cycle progression with the cellular levels or activities of key G(1) phase cell cycle regulatory proteins, p21(WAF/CIP1), cyclins (A, D1 and E), cdks (cdk2 and cdk4), gadd45 and PCNA proteins in normal and HPV-immortalized oral keratinocytes before and after treatment with a genotoxic agent, actinomycin D. Actinomycin D treatment in normal cells cause (i) an inhibition in the activity of cdk2 kinase, (ii) an increase in the level of WAF1/CIP1 mRNA and p21(WAF1/CIP1), (iii) an increase in the binding of the p21(WAF1/CIP1) protein with the cdk2 protein, (iv) a reduction in the transcription of cyclin A messages, (v) an increase in the p53 inducible gadd45 protein, and (vi) a significant decrease in the synthesis and level of the DNA replication protein, PCNA. However, actinomycin D failed to induce these changes in the HPV-immortalized cells. These results are consistent with the hypothesis that in HPV-immortalized oral keratinocytes, the key cell cycle regulatory components of the G(1) phase are significantly altered thereby making them prone to mutagenic damage when exposed to DNA damaging agents. PMID- 21544327 TI - Quantitative analysis of vascular endothelial growth factor expression in chronic lymphocytic leukaemia. AB - Vascular endothelial growth factor (VEGF) Flays a central role in solid tumour angiogenesis, although its expression has never been previously documented in circulating lymphoma or leukaemia cells. Here we have quantified mRNA encoding VEGF isoforms 121 and 165 in peripheral lymphocytes of 6/6 CLL patients using Northern blotting and quantitative reverse transcription-polymerase chain reaction (RT-PCR) techniques. No VEGF mRNA could be detected in control lymphocytes. VEGF expression in primary lymphoma cells was lower than in normoxic human colorectal carcinoma cells (LS174T), implying that VEGF expression within tumour cells must be regulated by a range of malignancy-associated factors. PMID- 21544328 TI - Down modulation of tumor-associated proteolytic activity by n-butanol in cultured murine mammary adenocarcinoma cells. AB - The extractive effects of n-butanol on the cell membrane have been extensively studied. Although shortterm effects of this alcohol were reported, a sustained action on tumor cells has not been described. It was previously shown that M3 mouse mammary adenocarcinoma cells pretreated with n-butanol exhibited a longer latency after subcutaneous inoculation into syngeneic mice. In the present study a short, 5-minute exposure of M3 cells to n-butanol (2.5% v/v) resulted in the complete inhibition of a secreted metalloproteinase activity of 105 kDa and a significant decrease in secreted urokinase (uPA) activity levels (p<0.01) measured in conditioned media after 72 hours of culture. Total cell-associated uPA activity of M3 control monolayers was composed of a membrane-bound (31%) and a cytoplasmic (69%) uPAfraction. In contrast, cell-associated uPA activity of n butanol pretreated M3 cells was mainly composed of a cytoplasmic uPA fraction and an extremely low membrane-bound uPA fraction (<5%). Further, an impaired uPA receptor binding capacity in these monolayers was also observed (p<0.05). These findings suggest that reduced proteolysis of extracellular matrix components may lead to local changes in tumor stroma composition, resulting in an altered behavior of M3 adenocarcinoma cells when inoculated in vivo. PMID- 21544329 TI - Simian virus 40-, but not human papillomavirus-, transformation of prostatic epithelial cells results in loss of growth-inhibition by 1,25-dihydroxyvitamin D 3. AB - In addition to its well known calcemic actions, 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D] exhibits differentiating and antiproliferative effects in several types of cancer cells. 1,25(OH)(2)D receptors (VDR) as well as 1,25(OH)(2)D mediated growth-inhibition have been demonstrated in human prostate cancer cell lines. In order to further develop model systems for the study of 1,25(OH)(2)D action and to elucidate the mechanism of growth-inhibition, we studied several human prostate cell lines immortalized with either simian virus 40 (SV40) or human papillomavirus type 18 (HPV). The SV40-transformed cell lines P69SV40-T and P153SV40-T were not growth-inhibited by 1,25(OH)(2)D at concentrations as high as 100 nM, whereas the HPV-transformed cells PZ-HPV-7 and CA-HPV-10 were growth inhibited. All cell lines expressed VDR, and VDR mRNA was demonstrated by Northern blot analysis. All cells exhibited induction of 24-hydroxylase mRNA, a 1,25(OH)(2)D responsive gene, after 1,25(OH)(2)D treatment. In an attempt to understand the apparent dissociation of 1,25(OH)(2)D actions in the SV40 transformed cells, we turned to the human prostate cancer cell line DU 145. These cells, like the SV40-transformed cells, are not growth-inhibited but demonstrate induction of 24-hydroxylase mRNA after 1,25(OH)(2)D treatment. DU 145 cells contain a mutated retinoblastoma gene (Rb) which contributes to their uncontrolled growth, analogous to the disruption of Rb by SV40 and HPV. We compared DU,145 cells to DU 145 cells transfected with normal Rb (DU 145/Rb). Similar to DU 145, DU 145/Rb cells were not growth-inhibited by 1,25(OH)(2)D, while 24-hydroxylase mRNA was induced. These results suggest that divergent pathways mediate the growth-inhibitory effect of 1,25(OH)(2)D and its induction of 24-hydroxylase. It also appears that the antiproliferative effect of 1,25(OH)(2)D is mediated by an Rb-independent mechanism. PMID- 21544330 TI - Analysis of cytokine gene expression in squamous cell carcinoma of the head and neck. AB - Cytokine production in squamous cell carcinoma (SCC) of the head and neck may directly influence the clinical behavior of this aggressive neoplasm since cytokines act as autocrine/paracrine growth factors, as well as immunomodulators. In the present study, the cytokine profiles of 16 SCCs of the head and neck and matched autologous, noncancerous mucosa were determined and compared to normal oral mucosa. Cytokine gene expression in noncancerous mucosa was similar to normal oral mucosa. Levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression were significantly increased in SCC relative to the mean +/- 2 SD of noncancerous mucosa or normal mucosa (p<0.05). Immunohistochemical analyses demonstrated that GM-CSF protein was produced by epithelial cells in the SCC. The overall mRNA expression relative to noncancerous-mucosa or normal mucosa of interleukin-1 beta, interleukin-1 alpha and tumor necrosis factor-alpha was not significantly increased in SCC, however, individual tumors did show selected increases in mRNA expression for these cytokines. These extensive differences in the levels of cytokine mRNA expression could modulate interactions between the tumor cells and the corresponding host cells affecting the behavior of head and neck SCC. PMID- 21544331 TI - Alteration of sensitivity to cis-diamine(glycolate)-platinum(II) (254-S) in oral tumor xenografts following multiple applications. AB - The emergence of resistance to platinum analogues is considered to be a major problem in the treatment of head and neck cancer. Therefore, it is important to clarify the mechanisms of resistance to these analogues and the mechanisms of the processes related to this resistance. The study of emergence of resistance in the solid tumors is particularly relevant. Ln the present study, the effect of a platinum analogue (254-S), on the response of an oral carcinoma cell line grown as a xenograft in nude mice, was studied. The effect of a full dose administered as a single intraperitoneal injection of 254-S (15 mg/kg X 1) on tumor growth was not significantly different from the effect of repeated intraperitoneal injections of 254-S, administered 3 times at 1/3 of this dose (5 mg/kg x3), or 5 times at 1/5 of this dose (3 mg/kg x5). However, when a single full-dose intraperitoneal injection of 254-S (15 mg/kg x1) was administered to each group of mice again at the 9th and 12th weeks after the initial treatment, different effects on tumor growth were observed among each group. The groups which received repeated treatment with 254-S (5 mg/kg, x3, or 3 mg/kg x5) showed a decrease in the inhibition of tumor growth, suggesting the emergence of resistance to 254-S. The study of platinum accumulation in the tumor tissues and a flow cytometric analysis of proliferating cell nuclear antigen (PCNA) supported the possibility that resistance to 254-S increases in tumor tissues treated repeatedly. These observations suggest that the potential use of this experimental assay as a model, may provide further insights into the therapeutic mechanisms of resistance to antineoplastic agents in the treatment of solid cancerous head and neck tumors. PMID- 21544332 TI - The non-uniform repair of active and inactive chromatin domains (review). AB - Substantial evidence demonstrates that DNA repair processes are not distributed homogeneously throughout the genome but that lesions are removed more efficiently and at higher rates from active than from inactive genes. Transcription-coupled repair (TCR) appears to be a sophisticated subpathway of nucleotide excision repair (NER) that targets the repair machinery to lesions present in the actively transcribed strand; TCR could explain the preferential repair of the transcribed over the nontranscribed strand in active genes and involves ERCC2 and ERCC3 helicases in human cells, integral components of TFIIH, as well as ERCCG. XPC protein is responsible for the repair of inactive regions. In S. cerevisiae RAD16 helicase as well as RAD9 and RAD24 proteins are involved in repairing nontranscribing regions whereas RAD3 and SSL2 helicases, homologs of the human ERCC2 and ERCC3, function for the repair of active regions. Unraveling the mechanisms that govern the heterogeneous repair rates among active and inactive parts of the genome is important in understanding mechanisms of carcinogenesis. PMID- 21544333 TI - A unified model explaining the preferential repair of active over inactive genes and of the transcribed over the nontranscribed strand. AB - DNA lesions are removed more efficiently and at higher rates from active than from inactive genes and from the transcribed compared with the nontranscribed strand. A unifying model is presented explaining the heterogeneity in DNA repair activities through the genome in terms of chromatin structure, nuclear matrix anchorage, transcription factor binding, protein phosphorylation mechanisms, and the linkage of repair mechanisms to other nuclear functions including transcription and replication. Transcription factors, preferentially assembled into complexes on the regulatory regions of active but not of inactive genes are proposed to contribute to repair differences. PMID- 21544334 TI - Comparative analysis of p16/CDKN2, p53 and ras gene alterations in human non small cell lung cancers, with and without associated pulmonary asbestosis. AB - To investigate genetic abnormalities in human non-small cell lung carcinomas (NSCLC) associated with pulmonary asbestosis as compared with nou-asbestos linked lung cancers, twenty-nine primary non-small cell lung carcinomas (NSCLC) were examined for genetic abnormalities of p16/CDKN2, p53 and ras genes by single strand conformation polymorphism analysis of polymerase chain reaction products (PCR-SSCP) and direct sequencing. Ten specimens were obtained from autopsies in which concurrent pulmonary asbestosis was present, while 19 samples were surgical specimens from asbestosis-free patients. K-ras mutations were detected in 10% each of the cancers from both asbestosis and non-asbestosis cases. p16/CDKN2 deletions or mutations and p53 aberrations were demonstrated in 20% and 10% of tumors from asbestosis cases, whereas, 32% and 21% of the cancers, respectively, from asbestosis-free patients were positive. In conclusion, it is suggested that the enhancement of neoplasia in the lung by asbestos is not dependent on suppression of p16/CDKN2 and p53 or ras activation and therefore, that asbestosis may activate alternate tumorigenic pathways in the development of NSCLC. PMID- 21544335 TI - Cell cycle dependence of drug initiated apoptosis in HL-60 cells. AB - The extent- and cell cycle specificity of apoptotic cell death were studied in human leukemia HL-60 cells treated with 1.25-20 mu M etoposide, 0.125-2.0 mu g/ml dactinomycin, 12.5-200 mu M 3-deazaadenosine (c(3)Ado) and 10-50 Gy gamma irradiation. Flow cytometry was used to measure the fraction of apoptotic cells and determining their cell cycle position. With all agents the extent of apoptotic cell death showed a clear dose- and time-dependency. Specific apoptosis of S-phase cells was found in cultures treated with 1.25-2.5 mu M etoposide. At 5 20 mu M etoposide, 0.125-2.0 mu g/ml dactinomycin and 50-200 mu M c(3)Ado cells from all cell cycle phases responded by apoptosis. Exposure of the cells to 10 Gy gamma-irradiation resulted in apoptosis of G(2)+M-phase cells. At 50 Gy cells from the S- and G(0)/G(1)-phases also entered apoptosis. Our findings indicate that the cell cycle specificity of an anti-cancer agent initiated apoptotic response depends upon the drug/irradiation dose and exposure time used. This demonstrates that the resistance of subpopulations of cells to apoptosis is relative. PMID- 21544336 TI - Relationship between expression of plasminogen activator system and metastatic ability in human cancers. AB - The gene expressions of urokinase-type plasminogen activator (u-PA), u-PA receptor (u-PR), and plasminogen activator inhibitor (PAI)-1 and -2 in human tumor cell lines and human gastric cancer tissues were analyzed using the reverse transcription (RT)-PCR. The expression patterns were compared with experimental metastatic ability in chick embryo or clinicopathological findings. The results indicate that the function of u-PA binding to u-PR and the diminished expression of PAI-2 are significantly involved in the process of cancer metastasis and PAI-2 may be more effective in regulating u-PA activity than PAI-1. PMID- 21544337 TI - Detection of RB, p16/CDKN2 and p15(INK4B) gene alterations with immunohistochemical studies in human prostate carcinomas. AB - To examine the status of cell cycle-inhibitory genes in human prostate carcinoma, we investigated alterations of RE (retinoblastoma), p16/CDKN2 and p15(INK4B) genes in 32 adenocarcinomas with immunohistochemistry. PCR-single-strand conformation polymorphism (SSCP) was used to examine all 27 exons of the RE gene, exons 1 to 3 of the p16/CDKN2 gene and exons 1 and 2 of the p15(INK4B) gene for mutations. Loss of heterozygosity (LOH) for the RE gene was probed by restriction fragment length polymorphism (RFLP) analysis. In addition, coordinate samples were subjected to immunohistochemical studies for reactivity to RE and p16 protein. The RE gene alterations were detected in 5 of the 32 tumors (16%); of these, only one mutation, a missense substitution, occurred within an exon. The remaining four single base insertions or deletions were found within introns of the RE gene and no mutational event was detected in its promoter region. LOH involving intron 17 of RB was detected in three cases of 10 informative tumors (30%). Intragenic mutations were also present in 3 of the 32 tumors in the p16/CDKN2 gene. In contrast, no mutational events were found in the p15(INK4B) gene in the tumors. Only one tumor had both a p16/CDKN2 mutation and LOH of the RE gene. Expression of pRB was absent or reduced in 16 cancers, while p16 expression was present in all cases to varying degrees. The results suggest that p16/CDKN2 gene mutations occur rarely and intragenic mutation, but not LOH,of the RE gene is not required in prostatic tumorigenesis. PMID- 21544338 TI - Flow cytometric DNA ploidy and recurrence development in squamous cell carcinoma of the oral cavity. AB - This prospective study on 348 patients with oral squamous cell carcinoma who underwent radical surgery established a close association between the DNA ploidy status of the primary tumor and the risk of local recurrence development. Nine percent of patients with flow cytometrically diploid tumors developed a recurrence compared to 46% of those with aneuploid tumors. This correlation held true even if evaluated with respect to tumor stage or histological grade. Thirteen percent of the diploid and 59% of the aneuploid group showed lymph node metastasis. These results provide substantial evidence that cytogenetic events that underlie aneuploidy formation from initially diploid progenitor cells are functionally linked to the development of tumor cell populations that have the capability to establish independently growing colonies in foreign tissues. PMID- 21544339 TI - Possible inhibitory effects of promotion stage treatment with thymosin fraction 5 on N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated urinary tract carcinogenesis in NON/Shi mice. AB - The modifying effects of thymosin fraction 5 (TF5), a dialyzable glycoprotein extract obtained from calf thymus, on second stage urinary tract carcinogenesis after N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) initiation were investigated in NON/Shi male mice. BBN was administered for 8 weeks and then TF5 was administered subcutaneously twice a week for 12 weeks. The incidence of urinary bladder carcinomas was decreased in the TF5 treatment group, but the malignancy of the renal pelvic carcinomas appeared to be enhanced. We repeated the experiment to obtain confirmatory evidence, but found no significant effect, although TF5 did stimulate the immune surveillance system. The reason why this discrepancy occurred might be related to the degree of hydronephrosis or the confounding influence of renal pelvic carcinomas. PMID- 21544340 TI - Screening of peptides which suppress the proliferation of transformed cells. AB - We have carried out three rounds of screening tests using 239 synthetic tripeptides for the growth-inhibitory activity toward tumor cells and found that those having amino acid sequences of Pro-Thr-Trp or Glu-Arg-Pro effectively inhibit proliferation of transformed cells. These peptides could be the fundamental structures of new types of anticancer drugs. PMID- 21544341 TI - Signaling pathways regulated by Rho-like proteins. AB - Small GTP-binding proteins of the Rho-subfamily, including Cdc42, Rac1 and RhoA, are key control molecules in the reorganization of the actin cytoskeleton induced by growth factors. Recent studies indicate that signal transduction pathways regulated by Rho-like GTPases are interconnected with the Ras-Raf-MAPkinase pathway, and play a role in several kinase pathways that lead to transcriptional activation and oncogenic transformation. Moreover, pathways regulated by Rac are involved in the acquisition of invasive and metastatic capacity of tumor cells. Aberrations in signaling pathways controlled by Rho-like GTPases may thus have consequences for tumor progression and metastasis. PMID- 21544342 TI - A comparison of the detection of activated c-Ki-ras genes by mismatch specific oligonucleotide hybridisation analysis and enriched PCR in colorectal adenocarcinomas. AB - We have examined 56 colorectal adenocarcinomas for activation of the c-Ki-ras proto-oncogene by two independent techniques, namely mismatch specific oligonucleotide hybridisation and an enriched PCR methodology. Biological significance of c-Ki-ras activation was assessed via Kaplan Meier analysis of patient survival. A total of 27% (15/56) of tumours were found to contain activated c-Ki-ras genes by mismatch specific oligonucleotide hybridisation and mutation was significantly associated with a poorer patient prognosis (p=0.018, log rank analysis). A total of 55% (31/56) of tumours were found to contain activated c-Ki-ras genes by enriched PCR, and again an association was noted between mutation and patient survival, but of a lower significance (p=0.029, log rank analysis). These results indicate that a high proportion of colorectal adenocarcinomas may contain low levels of activated c-Ki-ras genes, but this may be of limited biological significance. PMID- 21544343 TI - Effects of linoleic acid and eicosanoid synthesis inhibitors on the growth and c myc oncogene expression of human breast cancer cells. AB - We investigated the effects of linoleic acid and eicosanoid synthesis inhibitors on the growth, DNA synthesis, and c-myc oncogene expression of human breast cancer cell lines. The cell growth of all cell lines examined was stimulated by linoleic acid, although the optimal concentration of linoleic acid for the growth stimulation differed among the cell lines. The growth stimulation of MCF7 and MDA MB-435 cells was not dependent on the amount of released prostaglandin E(2) but their growth-concentration curve showed the same pattern as that of released leukotriene B-4. Moreover, linoleic acid stimulated the expression of c-myc mRNA in MCF7 cells without the presense of estrogen. Indomethacin as a cyclooxygenase inhibitor did not inhibit the c-myc expression in MCF7, but a lipoxygenase inhibitor, esculetin, markedly inhibited the c-myc expression in MCF7 affected by linoleic acid. These results suggest that linoleic acid has a direct mitogenic effect on breast cancer cells, and its mechanism is distinct from hormonal stimulation, Moreover, metabolites of lipoxygenase rather than those of cyclooxygenase may play an important role in the c-myc oncogene expression affected by linoleic acid. PMID- 21544344 TI - Serum levels of the type IV collagen 7s domain in patients with chronic viral liver diseases. AB - The serum levels of type IV collagen 7s domain (7s collagen) were determined in 80 patients with hepatocellular carcinoma (HCC) and in 105 with chronic liver disease without HCC. Among 86 patients with HCV infection, serum levels of the 7s collagen were significantly higher in those with HCC than-in those without HCC (p<0.05). In contrast, no significant differences were recognized between these two groups in 84 patients with HBV infection. Patients with HCV infection having high serum levels of the 7s collagen exceeding 7.0 ng/ml, were diagnosed as HCC with a sensitivity of 71.8%, a specificity of 74.5%, and a reliability of 77.9%. It was concluded that the progression of hepatic fibrosis plays an important role in the hepatocarcinogenesis of HCV, and that serum levels of the 7s collagen appeared to be useful as a risk factor of the development of HCV-related HCC. PMID- 21544345 TI - Characterisation of cellular changes which influence progression of human papillomavirus type-16 immortalised keratinocytes to anchorage-independent phenotype. AB - Cellular alterations which influence progression to an anchorage-independent phenotype are poorly understood. Few immortalised keratinocyte lines have been reported to form colonies in semi-solid medium, and the important role of the anchorage-dependence in controlling the behaviour of keratinocytes reflects the resistance of these cells to form colonies in soft agar. We describe here a model for studying in vitro the progression of human papillomavirus type-16 (HPV-16) immortalised keratinocytes from the early stages of immortalisation to an anchorage-independent phenotype. By an extensive selection procedure we have isolated three related cell lines, one immortalised, one weakly anchorage independent and one completely anchorage-independent. The comparison of these three lines gave a clear indication that this in vitro altered growth property is mainly correlated with a deregulation of the epidermal growth factor receptor (ECFR), leading to an increased proliferation rate of the cells coupled with changes in keratin expression. PMID- 21544346 TI - Resistance to tumor necrosis factor-induced apoptosis in mouse fibroblasts is a genetically dominant phenotype. AB - Although many tumor cells are sensitive to tumor necrosis factor (TNF)-induced cell death, most normal cells are resistant. To determine whether the sensitive phenotype or the resistant phenotype is genetically dominant, we constructed somatic cell hybrids of TNF-resistant (TNP) C3H mouse 10T1/2 fibroblasts and Ha ms-transformed TNF-sensitive (TNFs) 10T-EJ cells and then tested the sensitivity of those hybrids to TNF-induced cell death. All somatic cell hybrid cell lines tested were resistant to TNF-induced cell death. The TNFr 10T1/2 cells, however, exhibited sensitivity to TNF-induced cell death in the presence of cycloheximide (CHX), whereas TNFs 10T-EJ cells did not show any further increase in sensitivity to TNF-induced cell death in the presence of CHX. In addition, the killing of 1OT1/2 cells by TNF in the presence of CHX involved apoptosis. These results demonstrate that resistance to TNF-induced apoptosis is a genetically dominant phenotype and that certain protein(s) constitutively expressed or induced by TNF in resistant cells may confer protection against TNF-induced apoptosis. PMID- 21544347 TI - Pilot study of cytokine profiles in prostate cancer patients undergoing proton or conventional radiotherapy. AB - The mechanisms responsible for normal tissue late effects following radiotherapy are largely unknown and currently no method for predicting such risks is available. Abnormal levels of cytokine production induced by radiation has been suggested as a contributing factor by multiple investigators. The purpose of the present study was to evaluate plasma levels of transforming growth factor-beta 1 (TGF-beta 1), basic fibroblast growth factor (bFGF), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) in patients with prostate cancer scheduled for radiotherapy (protons, photons, or combination of both). It has been recently shown that ionizing radiation can increase expression of these cytokines and there are indications that they may be associated with morbidity. Blood samples were obtained from 20 subjects (age 51-80) before, during the first week, and immediately after the end of therapy; 3 healthy volunteers served as controls. Significant positive correlations (p<0.05) were obtained between bFGF, IL-1 beta, and TNF-alpha and the integral dose of radiation during the first week of treatment. Correlations approaching significance (p<0.1) were obtained with bFGF and acute treatment-related morbidity. A higher integral dose (due to larger irradiated volumes) was delivered with conventional photon compared to proton irradiation. No significance was obtained with any of the cytokines and pretreatment prostate specific antigen (PSA) levels, patient age, grade or stage of disease, or the integral dose by the end of radiation treatment. These results show that large changes occur in the plasma levels of certain cytokines early after initiation of radiotherapy and that treatment of larger volumes is more likely to induce these changes. Our data support further investigation of the role of cytokines during radiotherapy. PMID- 21544348 TI - Optimal therapy of malignant pleural effusions. AB - A randomized phase III trial of bleomycin, tetracycline and talc following chest tube drainage and a meta-analysis of relative benefit of bleomycin and tetracycline as sclerosing agents were performed to determine the optimal approach to malignant pleural effusion (MPE). Fifty patients were randomized to receive bleomycin (n=16), tetracycline (n=19) or talc (n=16) following chest tube drainage. Treatment groups were balanced for pretreatment characteristics. The study was ended prematurely because of the removal of parenteral tetracycline from the market. Overall, 52% of randomized patients had successful control of effusion 30 days after sclerosis. There were no differences between any of the three treatment groups in terms of 30 day control of effusion, overall survival (6 months), resclerosis rate, pain with sclerosis, fever, or duration of hospitalization (6 days). A meta-analysis was performed using the four previously reported trials of tetracycline vs. bleomycin and revealed a 20.6% advantage to the use of bleomycin (95% C.I. 7.9%-33.3%) (p=0.002). This phase III failed to demonstrate a significant difference between the three agents in terms of control of MPE at 30 days, side effects or survival. However, because of small sample size, this study lacks sufficient power to observe potentially clinically important differences between treatment groups. Inclusion of data from four previous trials in a meta-analysis showed that bleomycin may be superior. The median duration of hospitalization and the overall success rate of all three sclerosing agents in this study argue convincingly that new approaches to palliate MPE are needed. PMID- 21544349 TI - Expression of basic fibroblast growth factor in colorectal carcinoma. AB - Basic fibroblast growth factor (bFGF) has been shown to be a potent mitogen for a variety of cell types including colonic epithelial cells. Basic FGF has also been reported to have angiogenic activity. Thus, it has been proposed that bFGF expression might correlate with invasiveness and prognosis in human carcinomas. In the present study, bFGF expression has been evaluated in samples from 44 patients with large bowel carcinoma. Samples from the tumours and corresponding normal mucosae were collected at the time of surgery and frozen sections evaluated using a chick polyclonal antibody to bFGF and standard immunoperoxidase techniques. The expression of bFGF was significantly less within the tumours than in the corresponding normal mucosa (p<0.001). Five of the tumours were Dukes' stage A, 21 Dukes' stage B and 18 Dukes' stage C. Basic FGF expression tended to decrease with progression from Dukes' stage A to Dukes' stage C (p<0.05). This finding also paralleled loss of differentiation. Of the 44 patients, 8 have since died of their disease and only 3 of these had tumours which expressed bFGF. An attempt to correlate the expression of bFGF with that of another putative marker of colorectal disease progression, the cell-cell adhesion molecule E-cadherin, revealed no significant correlation. PMID- 21544350 TI - Characterization of the tumor-promoting activity of m-chloroperoxybenzoic acid in SENCAR mouse skin and its inhibition by gallotannin, oligomeric proanthocyanidin, and their monomeric units. AB - m-Chloroperoxybenzoic acid (CPBA),which induces ornithine decarboxylase activity as much as 12-O-tetradecanoylphorbol-13-acetate (TPA), was tested for its ability to induce DNA synthesis, hydroperoxide (HPx) production, and tumor promotion in mouse epidermis in vivo. After an early inhibition, CPBA stimulates DNA synthesis, a response which is maintained between 16 and 72 h and maximal after two treatments. CPBA at 0.6-5 mg stimulates DNA synthesis more than other organic peroxides, and nearly as much as TPA. The HPx-producing activity of the epidermis is maximally stimulated 48 h after two CPBA treatments at a 24-h interval. However, the HPx response to CPBA is much smaller than that to TPA. Aleppo gall tannic acid (AGTA) and loblolly pine bark condensed tannin (LPCT) inhibit both the DNA and HPx responses to CPBA. In contrast, their respective monomeric units, gallic acid (GA) and catechin (Cat) inhibit the DNA response to CPBA but fail to alter CPBA-stimulated HPx production. Although it is more potent than benzoyl peroxide, CPBA is a complete tumor promoter much weaker than TPA and even less effective than mezerein (MEZ). CPBA in stage 1 cannot enhance like TPA the tumor promoting activity of MEZ in stage 2. And in contrast to that of MEZ, the very weak tumor-promoting activity of CPBA is not enhanced after stage 1 treatment with TPA. At equal mg doses, AGTA, GA, LPCT, and Cat pretreatments all remarkably inhibit complete skin tumor promotion by CPBA. In spite of their antioxidant activities, AGTA post-treatments have no or very little inhibitory effects on the development of skin tumors by CPBA during 2-stage or complete tumor promotion. PMID- 21544351 TI - Tea in chemoprevention of cancer. AB - This review summarizes available information on epidemiological and experimental data showing an association of tea consumption with cancer prevention. Studies showing cancer risk associated with tea consumption are also summarized. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Experimental studies demonstrating the chemopreventive effects of tea have been conducted principally with green tea; limited studies have also assessed the usefulness of black tea. Majority of these studies have been carried out in skin tumor model system where consumption through drinking water of water extracts of tea or a polyphenolic fraction isolated from tea has been shown to afford protection against chemical carcinogen- or ultraviolet radiation-induced skin tumorigenesis. Tea consumption has also been shown to afford protection against chemical carcinogen-induced lung, forestomach, esophagus, duodenum, pancreas, liver, breast and colon carcinogenesis in specific bioassay models. Evidence has also accumulated showing that tea polyphenols prevent tumor promoter- and ultraviolet B-induced inflammatory responses in murine skin. The species and strains of animals, dose, route, frequency and duration of carcinogen administration, as well as types, route of administration and duration of tea or its polyphenolic component(s) treatment are described in detail. A brief description regarding mechanism(s) responsible for the broad chemopreventive effects of tea is provided. Epidemiologic studies, though inconclusive, in general suggest a possible preventive effect of tea consumption on human cancer. On the basis of available information, epidemiologic and experimental studies are ongoing to draw the possible relationship between tea consumption and cancer causation and prevention. Appropriate strategies for future clinical chemoprevention trials to translate animal data to human cancer risk are warranted. PMID- 21544352 TI - Modification of growth related enzymatic pathways and apparent loss of tumorigenicity of a ras-transformed bovine endothelial cell line by treatment with 5-iodo-6-amino-1,2-benzopyrone (INH2BP). AB - Bovine aortic endothelial cells were converted to a highly tumorigenic cell line by transfection with Ha-ras and stimulation with thrombin. Sustained pretreatment with a non-cytotoxic concentration (600 mu M) of 5-iodo-6-amino-1,2-benzopyrone (INH2BP), a lipophilic ligand of poly(ADP-ribose) polymerase, abrogated in vivo tumorigenicity, of 10(5) cells per inoculum an effect which developed progressively during 2 to 6 weeks of drug treatment. The initial action of the drug was cytostasis, consisting of an arrest in prophase, extreme cell enlargement consistent with cytoplasmic hypertrophy, as seen by EM, and dramatic morphologic changes. Although neither DNA, RNA or protein syntheses are directly affected by INH2BP, apparently newly synthesized cellular DNA is degraded by endonucleases, which are upregulated by the inhibition of their poly-ADP ribosylation. The drug treated cells exhibited greatly increased respiration and aerobic glycolysis, due to an augmentation of,glycolytic and respiratory enzymes in enlarged cells. These responses to the drug were reversible in cell cultures following drug removal, within 5-10 days drug exposure but the progressive loss of tumorigenicity in nude mice that developed after 3-6 weeks of drug exposure of cells, prior to inoculation to nude mice, was not reversible in vivo. Drug treatment produced a sustained 70-80% inhibition of pADPRT in intact cells at 600 mu M extracellular concentration of INH2BP. The prerequisite for the abrogation of tumorigenicity was the maintenance of pADPRT inhibition. The arrest of cell multiplication and a large decrease of Topo I, especially of Topo II and MAP kinase activities occurred without loss of enzyme protein as assayed in cell extracts of drug-treated cells. However INH2BP had no direct effect on these enzymes. Drug treatment down-regulated DNA-methyltransferase, PKC, ODC proteins, diminished cyclin A protein, but the hypophosphorylated form of Rb protein was significantly augmented. None of the enzymatic components of signal pathways so far studied, were directly affected by INH2BP. The inhibition of pADPRT by INH2BP coincided with an induction or activation of alkaline phosphatase and leucyl and glutamyl peptidase. The pADPRT content or the expression of pADPRT gene were not influenced by drug treatment, but the expression of ras gene was completely absent in nontumorigenic drug-treated cells, without a loss of ras gene from genomic DNA. Telomerase activity was not directly influenced by INH2BP treatment when assayed in diluted cell extracts, but the addition of homogeneous pADPRT to cell extracts, to approach physiological concentration of this protein in the cell, inhibited telomerase activity by binding of the polymer-free pADPRT to telomer templates. We conclude that inhibition of pADPRT indirectly down regulates growth stimulatory signal pathways and sustains growth-arrested cells in culture at a pre-apoptotic threshold which explains the absence of tumorigenicity in vivo. PMID- 21544353 TI - Expression of mRNA for gelatinase A and TIMP-2 in cell cultures and tissue samples derived from breast and lung carcinomas. AB - The aim of this study was to determine how closely expression of MMP-2 and TIMP-2 is associated with poor patient prognosis in breast and lung cancer. mRNA levels of MMP-2 and TIMP-2 were examined on dot blots in 34 cases of human breast carcinoma and in 13 cases of lung carcinoma. In breast carcinomas we found that high MMP-2 and/or low TIMP-2 expression did not consistently correspond to a poor clinical situation, while high MMP-2/TIMP-2 ratios were also found in subjects whose clinical status was relatively favorable. Statistical analysis did not show any significant association between MMP-2/TIMP-2 and the tumor markers examined. Regarding lung carcinomas, we did not find a correlation between the ratio and poor prognosis, whereas in lung carcinoma cells in vitro we found an enhancement in MMP-2 production. A possible explanation for these results is that in vivo, as opposed to in vitro, it appears that the stromal cells of the tumor and not the tumor cell itself, produce MMP-2. PMID- 21544354 TI - p53 levels in human mammary epithelial cells expressing wild-type and mutant human papillomavirus type 16 (HPV-16) E6 proteins. AB - Human fibroblast cells must overcome both the M1 and the M2 stages of cellular senescence to immortalize, at which point cells almost always express telomerase activity. The human papillomavirus (HPV) oncoproteins, HPV-16 E6 and E7, can block the progression to senescence in fibroblasts by associations with p53 and pRb, respectively. Human mammary epithelial (HME) cells require only HPV-16 E6 to bypass M1, suggesting that pRb may not have a direct role in HME cells senescence. In the present report, we show that only wild-type HPV-16 E6 allows complete degradation of p53, immortalization and reactivation of telomerase activity in HME cells. These results suggest that the ability of HPV-16 wild-type and mutant E6 proteins to degrade p53 in intact HME cells and keratinocytes does not completely correlate with their ability to degrade p53 in a cell-free system. This discrepancy between in vitro and in vivo p53 degradation may be biologically significant and may provide insight into the susceptibility of certain human cells and tissues for reactivation of telomerase and immortalization. PMID- 21544355 TI - The ganglioside GM(3) is raised in the sera and tissue of patients with bladder tumours. AB - An extraction procedure was developed which allowed the quantification of gangliosides from small volumes of sera (0.5 cm(3)) and samples of tissue (10 mg wet weight) from subjects with bladder cancer and from controls. The gangliosides were identified by high performance thin layer chromatography and mass spectrometry. In all samples the major ganglioside was GM(3) and amounts were elevated in both tissue and sera derived from tumour patients. The total lipid bound sialic acid was greater in tumour tissue than in healthy bladder but was below the level of detection in all sera. We suggest that serum GM(3) may be of prognostic value in bladder cancer. PMID- 21544356 TI - The ganglioside profile of human bladder cell lines and the effect of exogenous gangliosides on their growth. AB - The ganglioside composition of three human bladder cell lines, two tumourigenic (RT112 and EJ138) and one non-tumourigenic (Hu609) were analysed by thin-layer chromatography and mass spectroscopy. Sub-confluent cultures of the three cell lines expressed mainly monosialogangliosides. Xenografts of EJ138 cells expressed nearly twice as much GM(3) as tissue cultured cells. Proliferation of Hu609 and EJ138 cells measured by H-3-thymidine incorporation was increased by GM(3) and further enhanced by addition of EGF. Paradoxically the migration of all three cell lines was inhibited by a mixture of monosialogangliosides and the inhibition was abolished by EGF. PMID- 21544357 TI - Efficient adenovirus-mediated gene transfer into human cancer cell lines derived from digestive tract. AB - The efficiency of gene transfer into human cancer cells from digestive tract was evaluated using a replication-deficient recombinant adenovirus (Ad) vector harboring a lacZ gene of E. coli as a reporter gene (AxCALacZ). Average percent X gal staining of esophageal cancer cell lines was 46%, that of gastric cancer cell lines 82% and that of colon cancer cell lines 70% at 3 days after Ad vector infection. X-gal staining in vitro continued 2 months after infection. By the direct injection of adenovirus vector to the tumors in nude mice, a certain percentage of tumor cells was stained by the X-gal. Colon26 cell line infected with AxCALacZ was implanted in BALB/c mice immunized with AxCALacZ, and tumor growth was suppressed. We presume this was due to anti-adenoviral immunity. PMID- 21544358 TI - Heparin-binding EGF-like growth factor expression and biological action in human pancreatic cancer cells. AB - The epidermal growth factor (EGF) receptor is activated by EGF and other EGF-like growth factors, including heparin-binding epidermal growth factor-like growth factor (HB-EGF). We characterized the biological actions of HB-EGF in PANC-1 and COLO-357 human pancreatic cancer cell lines, and determined whether the presence of HB-EGF in human pancreatic carcinomas correlates with patient survival. HB-EGF enhanced the growth of both cell lines in a dose-dependent manner, with a potency that was generally similar to that of EGF and transforming growth factor-alpha (TGF-alpha). HB-EGF also readily induced tyrosine phosphorylation of the EGF receptor in these cells. Immunohistochemical analysis of 47 pancreatic cancer tissues revealed the presence of HB-EGF immunoreactivity in the cancer cells in 50% of the tumors. However, the presence of HB-EGF was not associated with a statistically significant decrease in the post-operative survival period. Furthermore, coexpression of HB-EGF and the EGF receptor was not associated with shorter patient survival. These findings suggest that HB-EGF activates the EGF receptor in human pancreatic cancer cells, but that it is not involved in enhancing the biological aggressiveness of this malignancy in vivo. PMID- 21544359 TI - Production of interleukin-6 by human osteoclast-like cells from giant cell tumor of bone. AB - Giant cell tumor (GCT) is a bone neoplasm which is characterized by the presence of large numbers of multinucleated osteoclast-like giant cells. Although GCT can be considered a benign lesion, it exhibits high local aggressiveness often associated with osteolytic properties. In this study, we used five different GCT primary cell cultures to evaluate whether osteoclast-like cells from GCT are able to produce interleukin-6 (IL-6), a cytokine strictly involved in the induction of osteoclast-mediated bone resorption. IL-6 assessment with ELISA revealed that osteoclast-like GCT cells produce low levels of this cytokine, which can be greatly increased after treatment with both lipopolysaccharide (LPS) or interleukin-1 beta (IL-1 beta). These data were confirmed by molecular analysis which revealed that GCT cells synthesize IL-6 mRNA and that the levels of IL-6 transcripts are greatly increased after treatment with both LPS and IL-1 beta. Moreover, by using a biologic assay with the 7TD1, a IL-6 dependent cell Line, we also determined that IL-6 synthesized by GCT cells is biologically active. This study supports the hypothesis that IL-6 locally released by GCT osteoclast-like cells may be involved in the induction of the osteolysis which is strictly associated with the biologic aggressiveness of GCT cells. PMID- 21544360 TI - Differential ability of 2,4-dinitrophenol to modulate etoposide cytotoxicity in mammalian tumor cell lines associated with inhibition of macromolecular synthesis. AB - The inhibitor of oxidative phosphorylation, 2,4-dinitrophenol (DNP), abrogates etoposide cytotoxicity in murine leukemia L1210 cells without affecting the quantity of drug-induced DNA lesions. Cell cycle arrest and events associated with cell death were followed in etoposide treated L1210 cells under conditions in which DNP reduced cytotoxicity greater than 100-fold. Micronucleation, associated with mitotic catastrophe, and apoptotic internucleosomal degradation of DNA, were both inhibited by DNP co-treatment to an extent consistent with clonogenic survival. However, the ability of etoposide to cause cell cycle arrest was minimally affected by DNP. For the same proportion of cells arresting in G(2), DNP co-treatment profoundly reduced etoposide cytotoxicity, suggesting a separation between etoposide-induced G(2) arrest and cell death. At the same concentration used to treat L1210 cells, DNP was unable to abrogate etoposide cytotoxicity in HeLa, Chinese hamster ovary or HL60 cells. The relationship between ongoing macromolecular synthesis during etoposide treatment and clonogenic survival was further studied in L1210 and HeLa cells. In general, L1210 cells were more sensitive than HeLa cells to inhibition of macromolecular synthesis by DNP. A higher DNP concentration did partially block etoposide cytotoxicity in HeLa cells, in association with increased inhibition of macromolecular synthesis. It was not possible to attribute the reduced cytotoxicity of etoposide in HeLa cells to inhibition of DNA or RNA synthesis alone, because inhibitors with greater specificity (aphidicolin and DRB) had no effect on clonogenic survival. However, aphidicolin partially abrogated etoposide cytotoxicity in L1210 cells, although to a lesser extent than DNP. These data indicate that inhibition of DNA or RNA synthesis alone during etoposide exposure is insufficient to abrogate killing of HeLa cells, that inhibition of etoposide cytotoxicity in HeLa cells may require the additional inhibition of protein synthesis, and that the modulating effects of ongoing DNA synthesis on etoposide cytotoxicity are cell line dependent. PMID- 21544361 TI - Platinum-sensitive and platinum-resistant ovarian cancer tissues show differences in the relationships between mRNA levels of p53, ERCC1 and XPA. AB - We investigated the association between p53 mRNA expression and clinically relevant surrogates of nucleotide excision repair (ERCC1 and XPA) in 28 ovarian cancer specimens. We observed that platinum-resistant tumors showed higher mRNA levels of p53, ERCC1, and XPA than platinum-sensitive tumors; mRNA expression patterns in responders differed substantially from nonresponders; and p53 expression showed a strong correlation with the expression of ERCC1, and of XPA in platinum-sensitive tumor tissues, but not with platinum-resistant tumors. 47% of the mutations from p53 sequence analysis were not related to clinical response to chemotherapy. We conclude that the p53 influence on DNA repair in human malignancy may vary substantially from tumor to tumor, and that such differences are not necessarily related to the mutational status of p53. PMID- 21544362 TI - Prediction of disease relapse in patients with breast cancer. AB - Among 157 breast cancer patients with median follow-up term of 120 months, we analyzed relationships of clinicopathologic factors and several prognostic factors determined histochemically with disease relapse, and we determined risk scores. Lymph-node status (p=0.0001) and microvessel count (MVC) (p=0.026) in all patients, p53 protein (p=0.0019) and MVC (p=0.001) in node-negative patients had independently significant prognostic value in predicting disease relapse. The risk scores based upon these factors had powerful predictive values for disease relapse (p=0.0001). Using these factors, we could simply and accurately identify patients with high-risk for relapse. Moreover, it might be useful for making decisions on adjuvant therapy. PMID- 21544363 TI - Dexamethasone inhibits invasiveness of a human pancreatic cancer cell line. AB - Recent studies have shown that dexamethasone inhibits gelatinases. We investigated the effect of dexamethasone on the invasiveness of a human pancreatic cancer cell line. Tumor cells were treated with dexamethasone at various concentrations for 24 h. Cells were examined in an invasion assay. The expression and activity of MMP-9 in culture media were quantitated by Western blotting and gelatin zymogram. The invasiveness of cancer cells and expression of MMP-9 were decreased by dexamethasone in a dose-dependent manner. Dexamethasone may be a useful therapeutic agent in the treatment of pancreatic cancer. PMID- 21544364 TI - Resistance-related proteins in initial and relapsed childhood acute lymphoblastic leukemia. AB - One hundred and eleven children with initial ALL and 28 children with relapsed ALL were analyzed immunohistochemically for expression of resistance-related proteins. P-glycoprotein (P-170) was found in 35% (initial ALL) vs 54% (relapsed ALL; p=0.07), glutathione S-transferase-pi (GST) in 49% vs 68% (p=0.07), thymidylate-synthase (TS) in 42% vs 64% (p=0.03), dihydrofolate-reductase (DHFR) in 20% vs 32% and metallothionein (MT) in 33% vs 32% of the cases. In initial ALL, the resistance proteins P-170 and GST were expressed more frequently in patients who relapsed under therapy and the frequency was similar to relapsed ALL. These results indicate that P-170 and GST-pi were already present before treatment. In contrast, expression of TS increased during treatment. PMID- 21544365 TI - Constitutive migration and expression of three protease systems define in vitro the malignant phenotype of Ha-ras transformed rat liver epithelial cells. AB - The analysis of migration and gene expression patterns of normal and Ha-ras transformed rat liver epithelial cells revealed differences of diagnostic relevance. The normal cells are induced to migrate by EGF/TGF alpha and to express a set of secreted proteins including fibronectin, EIP-1/PAI-1, and MEP cathepsin L, which the malignant, constitutively migratory cells express constitutively. Only the transformed cells produce proteins of Mr 58/60,000 identified by peptide sequencing as stromelysin-1. The constitutively migratory cells produce invasive tumors and, after intravenous injection, metastatic colonies in the lung ('experimental metastasis'). The results demonstrate specific differences between the migration/invasion of normal and malignant epithelial cells, with PAI-1 as a general biochemical marker for migration/invasion. Constitutive migration and the described gene expression pattern are proposed as in vitro indicators of an invasive phenotype. EGF inducibility of the transformed cells to maximal migration and to an increased expression of stromelysin indicates susceptibility to a paracrine stimulation of malignancy. PMID- 21544366 TI - Comparison of the prognostic significance of the Shimada classification and N-myc copy number in neuroblastoma. AB - This report outlines the experience with the first 20 patients (8 males and 12 females) enrolled in the Canadian National Neuroblastoma Diagnostic Laboratory, The study population ranged in age at diagnosis from one month to 11 years. Fourteen children had advanced (stage 3 or 4) disease. Tumors were sampled extensively and were classified, at the time of accession, according to the 'Shimada' histopathological scheme. A portion of each tumor was analyzed for N myc oncogene copy number. Nine tumors were classified as having 'favourable' histopathological features and 11 as 'unfavourable'. N-myc oncogene amplification, of 3 or more copies, was found in 2 of 9 tumors with 'favourable' histology and 5 of 11 with 'unfavourable' features. The follow-up interval was at least two years from initial diagnosis. The Shimada classification was more accurate than the N-myc oncogene copy number (p<0.01) in predicting clinical outcome. The sensitivity and specificity for Shimada histopathological classification were 100% and 92% respectively, while corresponding values were 75% and 42% for N-myc copy number. Our experience indicates that, when assessing prognosis in neuroblastoma, Shimada classification performs better than the N-myc copy number. PMID- 21544367 TI - In vivo and in vitro modulatory effect of human immunodeficiency virus type-1 (HIV-1) Tat protein on protein kinase C activity. AB - Extracellular HIV-1 Tat protein shows a pleiotropic activity on the survival/proliferation of different cell types, which may be relevant to the pathogenesis of the immune suppression as well as of the frequent neoplastic disorders observed during the course of HIV-1 disease. Therefore, we investigated the effect of recombinant Tat on the protein kinase C (PKC) activity in Jurkat CD4(+) T lymphoma cells by using a serine substituted specific PKC peptide substrate, which allowed the evaluation of the whole catalytic activity of both Ca++-dependent and Ca++-independent PKC isoforms. High concentrations of recombinant Tat (1 mu g/ml) induced an early (5 min) stimulation followed by a secondary (30-60 min) inhibition of PKC in whole Jurkat cell homogenates. Immuno localization experiments showed that recombinant Tat protein was rapidly taken up by Jurkat cells within the first 5 min from the addition in culture, thus suggesting the possibility that the secondary inhibitory phase of Tat on PKC activity in Jurkat cells could be due to a direct interaction between the two proteins. Consistently, PKC immunoprecipitated from Jurkat cells or purified from rat brain was significantly inhibited by the addition of high (0.1-1 mu g) but not low (1-10 ng) doses of Tat in a cell-free in vitro assay. The inhibition of PKC catalytic activity mediated by 1 mu g of Tat was at least partially due to competition among substrates. The present data may help in understanding the opposite effects on the survival/proliferation of different cell types observed in the presence of picomolar (stimulation) vs nanomolar (inhibition) concentrations of recombinant Tat. PMID- 21544368 TI - Immunohistochemical analysis of bcl-2 and p53 protein in breast carcinoma. AB - We analyzed the expression of bcl-2 and p53 in relation to clinicopathological features and estrogen receptor (ER) status in breast carcinomas from a series of 67 women who were treated surgically. Fifty and 23 cases showed positive immunostaining for bcl-2 and p53 protein, respectively. Thirty-five cases were ER positive. A positive relationship was observed between bcl-2 and ER (p<0.05). Furthermore, an inverse relationship was observed between bcl-2 and p53 (p<0.01), which suggests that overexpression of p53 may down-regulate bcl-2 expression in breast carcinoma tissue, as has been described in a breast carcinoma cell line. PMID- 21544369 TI - Relationship between oncogene amplification, aneuploidy and altered expression of p53 in breast cancer. AB - Many studies have noted an association between amplification of single oncogenes and poor prognosis in breast cancer. We are investigating whether measurement of amplification in a larger number of proto-oncogenes increases the reliability of the prognostic information provided. As the first stage of this investigation, amplification (of c-erbB-2, cycD1, int-2, c-myc and MDM2), aneuploidy and altered expression of p53, which all indicate genetic instability, were studied in 117 primary breast adenocarcinomas. Amplification was correlated with aneuploidy (p=0.002) but not with altered expression of p53 even though the tumours with p53 overexpression were all aneuploid. Our results suggest that measurement of amplification is a potentially valuable prognostic factor. PMID- 21544370 TI - Surgical procedures in gallbladder cancer with special reference to its macroscopic appearance. AB - To investigate the relationships of the gross appearance to cancer depth and microinvasion in gallbladder cancer, thirty-three cancers were macroscopically subgrouped: papillary (n=8), nodular (n=6), papillo-invasive (n=1), nodulo invasive (n=11), and invasive (n=7) type, respectively. Papillary type cancers were limited to the mucosa or the muscularis propria, without microinvasion. Most nodular type cancers infiltrated to the subserosa with moderate microinvasion. The other types of cancer frequently invaded the subserosa or more, with high incidence of microinvasion. Only the papillary type cancers indicated simple cholecystectomy, the other types should be operated in accordance with infiltration depth and degree of involvement. PMID- 21544371 TI - Comparative in vivo and in vitro proliferation of murine tumor cells in the bone microenvironment. AB - To examine the effect of bone microenvironmental factors on the growth of metastatic cells, the in vivo proliferative features of three murine cell lines were determined at skeletal metastatic sites and correlated with their ability to grow in vitro in the presence of bone-derived factors. Bones, ovaries, adrenals and the brain were most affected by metastasis, following an intraarterial injection of B16/F1 and B16/F10 melanoma and FS/L10 fibrosarcoma cells into C57BL/6 mice. Melanoma cells showed a marked metastatic preference for bone, while fibrosarcoma cells developed brain metastasis in all animals. Tumor burden in bones was highest (19+/-2%) for B16/F10 cells, compared to B16/F1 (10+/-2%) or FS/L10 (3+/-1%) cells. Autoradiographic studies demonstrated organ- and cell type specific differences in tumor cell proliferation, with B16/F10 cells displaying the lowest labelling indexes in bone (12+/-2% for B16/F10 vs 28+/-2% and 27+/-4% for B16/F1 and FS/L10 cells, respectively). To test if bone-derived factors differentially affected tumor cell growth in these three cell lines H-3-thymidine uptake by these tumor cells was assessed after in vitro incubation with bone derived conditioned medium. Under these conditions, we observed stimulation of B16/F10 cell proliferation, but inhibition of uptake in the other two cell lines. Thus, these results demonstrate that, in this in vivo experimental model, growth properties of metastatic cells are organ- and cell type-specific. Additionally, we show that the in vitro proliferative behavior of tumor cells in the presence of bone-derived factors correlates and may predict skeletal tumor growth properties in vivo. PMID- 21544372 TI - Expression of the fibroblast growth factor 4 (FGF-4) gene is regulated by serum in Tera-2 embryonal carcinoma cells. AB - Expression of the fibroblast growth factor 4 (FGF-4) gene is tightly regulated during mammalian development. Dysregulation of FGF-4 gene expression results in cell transformation and tumorigenesis. It is therefore pertinent to investigate the regulatory mechanisms which control expression of FGF-4. In an initial attempt to identify exogenous factors other than retinoic acid which might control FGF-4 expression, we have investigated the response of endogenous FGF-4 to serum in a number of embryonal carcinoma and embryonic stem cell lines. We have identified a human embryonal carcinoma cell line (Tera-2) in which the FGF-4 gene can be induced by serum. In Tera-2 cells made quiescent by serum deprivation, expression of the FGF-4 gene is repressed. Subsequent addition of serum reactivates FGF-LC expression and further addition of cycloheximide results in superinduction of mRNA suggesting that FGF-4 may be classified as an early response gene. It is suggested that this observation may be explained, at least in part, by the stage of differentiation of the Tera-2 cells. PMID- 21544373 TI - Lectin histochemistry, ploidy level, and proliferative activity in rhabdomyosarcoma subtypes. AB - The glycohistochemical expression of binding sites for eight lectins is characterized in a series of 8 embryonal, 4 alveolar and 4 pleomorphic rhabdomyosarcomas. The correlation between lectin staining and either the proliferation index or the ploidy level was also investigated. The data show that rhabdomyosarcomas exhibit heterogeneous lectin binding expressions. A comparable level of lectin labeling is observed in euploid and aneuploid tumours. In contrast to other neoplasms, lectin staining has proved to be of doubtful value in distinguishing between different RMS subtypes. The data also reveal that a significantly lower level of proliferative activity was observed in the pleomorphic group as compared to the alveolar one. PMID- 21544374 TI - Inhibitory effects of ascorbic acid on AP-1 activity and transformation of JB6 cells. AB - Ascorbic acid (vitamin C) has been reported as an anti-cancer agent. Previous in vitro studies using either primary cell cultures from cancer patients or tumor cell lines have indicated that different kinds of tumor cells may have different sensitivities to ascorbic acid for the inhibition of tumorigeneity or growth. Because the JB6 mouse epidermal cell system has been used extensively as an in vitro model for the study of tumor promotion and progression, we assessed the effects of ascorbic acid on transformation in JB6 cell variants. The results show that ascorbic acid could inhibit 5.5% to 97.1% of transformation of JB6 P+ cell Cl 41-19 induced by TPA, EGF or EGF + insulin, but has no effect on anchorage independent growth of JB6 transformed cell A33. Since our previous results indicated that induced AP-1 activity is required for tumor promoter induced transformation, we tested whether inhibition of tumor promoter-induced transformation by ascorbic acid is through an AP-1 inhibition mechanism. Our results indicated that ascorbic acid inhibited AP-I activity at the same dose range for inhibition of transformation. These results demonstrated that ascorbic acid has inhibitory effects on JB6 cell tumor promoter-induced transformation, but no influence on tumor cell phenotype expression and provided the basic knowledge for understanding of vitamin C action on tumor prevention. PMID- 21544375 TI - Identification of differentially expressed genes in breast cancer. AB - A number of genes differentially expressed in breast cancer were isolated using a subtractive cloning technique. DNA sequence analysis and GenBank searches of T4F10, T2H7, and T2E5 cDNA clones found them to be identical with E2A, MSS1, and SEC13R genes. Their expression in a variety of primary breast tumor and cancer cell lines was compared with c-ERB-B2 and pS2 by Northern blot analysis. In breast cancer cell lines, the genes that we isolated are more frequently expressed than the previously described c-ERB-B2 and pS2. PMID- 21544376 TI - Development of an immuno-lectin-enzymatic assay for the detection of serum cancer associated glycoproteins bearing Tn determinant. AB - We report the development of an immuno-lectin-enzymatic assay (CA83.4) with the purpose of quantifying serum glycoproteins bearing Tn determinant (GalNAc alpha-O Ser/Thr). An anti-Tn monoclonal antibody (83D4) is bound to the solid phase in order to capture glycoproteins. After the addition of a test sample, we used biotinylated isolectin B4 from Vicia villosa and avidin-peroxydase to act as a detection system. The linear relationship between CA83.4 determinations and the serum dilutions, the reproducibility of the dosage in intra- and inter-assay, and the specificity of the test for the N-acetylgalactosamine residue in a-glycosidic O-linkages, demonstrated the reliability of this trial. Self-recognition of Vicia villosa B4 molecules (K-D: 0.73x10(-6) M determined using biosensor technology) could determine an additional step of signal amplification in this assay. Using 0.25 units/ml of CA83.4 antigen as the cut-off level, higher values were found in 25/49 patients with breast cancer, 8/13 with colorectal carcinoma, 3/11 with lung cancer, but in none of the 49 patients with non-malignant diseases nor in 97 healthy controls. This first report on soluble Tn-glycoprotein detection assays suggests that Tn-glycoproteins are specific serological tumor markers and we believe that they could represent a valuable tool in the diagnosis of cancer. PMID- 21544377 TI - Telomerase reactivation in leukemia cells. AB - We utilized fluorescent-labeled primers and modified the telomeric repeal amplification protocol (TRAP) to assess telomerase activity during the process of in vitro establishment in four different leukemia cell lines. We demonstrate that three of four leukemia cell lines had elevated telomerase activity, shortened telomeres, and the appearance of either dicentric chromosomes or acentric fragments. By contrast, one leukemia cell line (HAL-01) had high levels of telomerase activity, stable telomeres, but no obvious additional cytogenetic rearrangements. These experiments indicate that there may be several pathways involving telomerase activity in the establishment of leukemia cell lines. PMID- 21544378 TI - Induction of c-fos expression following stimulation of pulmonary neuroendocrine cell proliferation by alterations in CO2/O-2 concentration. AB - Pulmonary neuroendocrine (PNE) cells were harvested and cultivated from peripheral lung tissue of 15 day old fetal hamsters under selective growth conditions, including a 10% CO2 atmosphere. Following 24 h of serum starvation under 10% CO2, PNE cells placed in a 5% CO2 atmosphere failed to proliferate over the next 24 h, while cells kept at 10% CO2 showed a 2.7-fold increase in cell number. Addition of nicotine to the cell culture medium resulted in an additional concentration-dependent increase in cell number under a 10% CO2 atmosphere, while nicotine did not stimulate the proliferation of cells maintained at 5% CO2. The nicotinic receptor antagonist hexamethonium completely blocked the stimulatory effect of nicotine on cell growth. As a first step towards determining the molecular mechanisms regulating the mitogenic stimulation of PNE cells by alterations in CO2/O-2 and nicotine, cells that had been serum starved under a 10% CO2 atmosphere for 24 h were removed from the incubator and either left untreated or treated with 1 mu M nicotine under ambient air. The cells were then returned to either a 5% or 10% CO2 atmosphere. Removal of the cells from a 10% CO2 environment and subsequent reintroduction to a high CO2 concentration resulted in a 3- to 4-fold increase in c-Sos RNA expression within 15-30 min upon return to the cell culture incubator. c-fos RNA levels their decreased back to control values by 1 h. Reintroduction into a 5% CO2 atmosphere, which failed to stimulate cell growth in the proliferation assay, caused only a 2-fold increase in the levels of c-fos transcripts. The CO2-mediated increases in c-Sos transcripts were observed both in the presence and absence of nicotine, suggesting that the effects of nicotine were mediated through a fos-independent pathway. Neither the alterations in CO2/O-2 concentration or treatment with nicotine altered the levels of c-myc or c-jun gene transcripts. Nicotine thus acts indirectly but synergistically with high CO2 concentrations to stimulate PNE cell proliferation. PMID- 21544379 TI - Modulation of growth and differentiation of human colon carcinoma cells by histone deacetylase inhibitory trichostatins. AB - Histone deacetylase inhibitors such as sodium butyrate or (R)-trichostatin A {(R) TSA; 7- [4-(dimethylamino) phenyl]-N-hydroxy-4,6-dimethyl-7-oxo-2, 4 heptadienamide} have been reported to modulate the proliferation and differentiation of certain cell types. In this study, we analyzed the effects of these agents on KM12 human colon carcinoma (HCC) cells in culture. We found that (R)-TSA induced cell flattening, inhibited anchorage-dependent and anchorage independent growth, increased the level of the differentiation marker carcinoembryonic antigen, and increased the expression of gelsolin, a candidate tumor suppressor, in these HCC cells. Cells treated with (R)-TSA for 3 h exhibited a high degree of histone (primarily H4) acetylation. (R)-TSA exerted these effects at concentrations in the range between 0.1 to 1 mu M that are at least 1,000 times lower than those required to achieve similar effects by n butyrate. Trichostatin C, which exhibits some histone deacetylase inhibitory activity but not the analogs (S)-TSA or (R)- or (S)-trichostatic acid, which lack histone deacetylase inhibitory activity, also showed some growth inhibitory activity. These results indicate that histone deacetylase inhibitors may lead to suppression of the transformed phenotype and enhanced differentiation in the KM12 HCC cells. PMID- 21544380 TI - Case-control study on colon cancer regarding previous diseases and drug intake. AB - Some diseases and drugs have previously been associated with increased risk for colon cancer. A case-control study on colon adenocarcinoma was conducted encompassing 329 cases and 658 controls. History of previous diseases and drug intake was assessed by questionnaire. Appendectomy was associated with a protective effect with odds ratio (OR) 0.5 and 95% confidence interval (CI) 0.2 0.9. Cholecystectomy was associated with increased risk, especially in females, for right sided and transverse colon cancer, OR 1.5 (CI 0.9-2.5) and OR 1.8 (CI 0.8-3.5), respectively. Ulcerative colitis increased the risk, OR 11 (CI 3.5-38). Also hyperplasia of the prostate gland and diabetes in men were related to an increased risk with OR 4.4 (CI 1.5-13) and OR 2.9 (CI 1.4-6.0), respectively. For men and women together diabetes mellitus yielded an increased OR of 1.7 (1.0 3.0). Regarding drugs somewhat increased risks were found for beta-2-stimulating agents, OR 1.9 (CI 0.6-5.4), benzodiazepine, OR 1.7 (CI 0.9-3.3), iron, OR 1.9 (CI 0.5-6.7), and paracetamol, OR 2.5 (0.6-8.5). Increased risks were found for hydralazine in men, OR 2.3 (CI 0.7-7.0), methyldopa in men, OR 4.3 (1.1-18), sulfonylurea, OR 2.9 (CI 1.2-6.7), and verapamil, OR 22 (CI 2.4-480). Somewhat decreased risk was found for indometacin, OR 0.6 (0.2-1.6). PMID- 21544381 TI - Selective suppression of nuclear retinoic acid receptor beta gene expression in human pancreatic carcinomas. AB - Retinoids restore normal cell growth and differentiation in malignant cells and are considered as potential therapeutic agents. Before using retinoids for the treatment of pancreatic cancer it is important to determine the expression of nuclear retinoid receptors, which mediate most actions of retinoids on gene expression in normal and malignant tissues. Digoxigenin-labeled antisense riboprobes of retinoic acid receptors (RARs) alpha, beta, and gamma, and retinoid X receptor (RXR) alpha were used for in situ hybridization to histological sections of-specimens from 24 human pancreatic carcinomas, 20 of which also contained adjacent normal tissue. All four receptors were detected in adjacent normal pancreatic tissue specimens and RAR-alpha, RAR-gamma, and RXR-alpha were also detected in all pancreatic carcinoma specimens. In contrast, RAR-beta mRNA transcripts were detected in only 67% of the malignant tissues and when expressed, the level of expression was significantly lower than that of the corresponding adjacent normal tissues. Decreased RAR-beta gene expression was especially noted in moderately- and poorly-differentiated cancers. These findings suggest that selective decrease or lass of RAR-beta gene expression in certain pancreatic carcinomas in vivo might be associated with the development or progression of pancreatic cancer. PMID- 21544382 TI - G-CSF accelerates the cell-cycling of hematopoietic progenitor cells and abrogates the deceleration by TNF alpha. AB - We examined the effects of granulocyte colony-stimulating factor (G-CSF) on cell cycling of hematopoietic progenitors in serum-free methylcellulose clonal cultures. Serial observations of the cultures showed hastening of growth of colonies by G-CSF, as determined by evaluating the time for individual colonies of 20 cells to reach 40 cells. G-CSF did not affect the incidence of proliferating cells in each developing colony. Cell-cycle analysis revealed that addition of G-CSF to cultures led to a decrease in the percentage of cells in the G1 phase of the cell-cycle, thereby indicating that G-CSF can modulate the cell cycle of hematopoietic progenitors mainly by shortening the period of the G1 phase. Tumor necrosis factor alpha (TNF alpha) exerted opposite effects on cell cycling of hematopoietic progenitors to those seen with G-CSF. G-CSF abolished the inhibitory effects of TNF alpha on the cell-cycling of hematopoietic progenitors. These observations indicate positive and negative regulatory roles of C-CSF and TNF alpha, respectively, and their interactions in the regulation of cell-cycling of hematopoietic progenitors. PMID- 21544383 TI - Sensitization of AIDS related non-Hodgkin's B lymphoma cell lines to cytotoxic drugs toxins by interferon-gamma. AB - AIDS-related lymphomas (ARL) progressively become resistant to conventional chemotherapy. We have developed three B cell lines from tumor biopsies of AIDS patients with non-Hodgkin's lymphoma (NHL). The ARL cell lines were shown to be resistant to a panel of cytotoxic cytokines, toxins and drugs such as tumor necrosis factor, diphteria toxin, ricin, adriamycin, cis-platinum and anti-Fas antibody. However, when these cell lines were pretreated with low concentrations of interferon-gamma (IFN-gamma), (50 U/ml or 150 U/ml) for 24 to 48 h, the tumor cells became sensitive to these cytotoxic agents. Pretreatment of ARL with IFN gamma stimulated proliferation while IFN-gamma inhibited the growth of ovarian tumor cell lines. Further, following treatment with IFN-gamma, the secretion of TNF-alpha by ARL lines was significantly decreased and TNF-alpha surface receptor expression was downregulated. The expression of several surface antigens on ARL was upregulated by IFN-gamma. These findings demonstrate that treatment of ARL with IFN-gamma stimulated cell proliferation, modulated several surface antigens, inhibited TNF-alpha secretion and sensitized the tumor cells to cytotoxicity by various drugs/toxins. These findings may be clinically relevant in the treatment of drug-refractory ARL. PMID- 21544384 TI - Autocrine transforming growth factor-beta (TGF beta) modulates the 120 kD and 105 kD retinoblastoma (RB) protein species in CBS colon carcinoma cells as revealed by an anti-sense TGF beta 1 expression vector. AB - Specific RE protein species modulated by autocrine TGF beta are unknown. CBS NEO (with autocrine TGF beta) and antisense TGF beta 1 transfected CBS RSVAS cells were compared for mitogenesis and RE species modulation. Significantly, high MW (120, 130 kD) were abundant relative to low MW (116, 110, 105 kD combined) RE species. CBS NEO required growth factors (GF) for maximal DNA synthesis (14 fold). 120 kD and 105 kD were significantly modulated in CBS NEO-GF. Nutrients (N) were an sufficient to maximally stimulate CBS RSVAS (8-fold). 130 kD and 116 110 low MW species were moderately induced by both N (CBS RSVAS-N) and GF (CBS NEO-GF), independent of autocrine TGF beta. In conclusion, autocrine TGF beta (CBS) has a role in modulation of 120 kD and 105 kD RE species which may play a role in the inhibitory action of autocrine TGF beta pathway. PMID- 21544385 TI - IL-2 as adjuvant for vaccination with cells malignantly converted by HPV 16 or 3 MC. AB - Experiments were designed to investigate the effects of murine recombinant IL-2 used as adjuvant for tumour vaccines in two model systems. The first system employed the Syrian hamster K3/II cell line transformed malignantly in vitro with DNA from E6-E7 oncogenes from HPV 16 and transplanted in Syrian hamsters. The second system made use of murine sarcoma Mc 12 induced with MC and transplanted in histocompatible mice. Both tumours were previously shown to express TRA capable of inducing transplantation resistance. It has been demonstrated here that the effect of the immunization in both tumour model systems could be substantially increased by IL-2 injected repeatedly at the site of vaccination. Some of the experimental mice were sacrificed after immunization and their spleen as well as regional lymph node cells were used for phenotypic analysis. IL-2 administration was found to be accompanied with an increase of TCR alpha beta(+), CD4(+) T cells in the spleen. Also in regional lymph nodes the T cell subsets showed a characteristic kinetics due to IL-2 administration. Following the IL-2 treatment, the percentage of lymph node TCR alpha beta(+), CD4(+) and CD8(+) cells dropped to less than half of the pretreatment values and then again gradually increased. No such kinetics was observed in vaccinated mice that did not receive IL-2. These results suggest that local administration of IL-2 at the site of vaccination elicits, in addition to the reaction in regional lymph nodes, a systemic reaction detectable in the spleen; they also suggest that the increase of CD4(+), TCR alpha beta(+) T splenocytes may play an important role in the mechanism of the observed adjuvant effect of IL-2. The adjuvant IL-2 effect augmenting the function of cell vaccines expressing HPV 16 E6-E7 oncoproteins deserves further studies, particularly with regard to its prospective utilization for treatment of human cervical carcinoma. PMID- 21544386 TI - Characterization by means of Delaunay triangulation and Voronoi paving of the influence of anti-hormone and/or anti-growth factor antibodies on the in vitro cell growth of human colorectal neoplastic cell lines. AB - A new tool is described which makes it possible to evaluate directly the influence of various growth factors on in vitro neoplastic cell growth on the one hand and to look at a concept of differentiation in terms of population dynamics, on the other. This tool relies upon the digital cell image analyses of Feulgen stained nuclei and the mathematical method of Voronoi paving. This technique enabled us to characterize the influence on the proliferation and the differentiation of the HCT-15 and LoVo colorectal cell lines of anti-gastrin (G), anti-estradiol (E(2)), anti-epidermal growth factor (EGF), anti-luteinizing hormone-releasing hormone (LHRH), and anti-transforming growth factor alpha (TGF alpha) and beta (TGF beta) antibodies. Two variants were set up with respect to each of the two cell lines, i.e, one growing in culture medium supplemented with 5% fetal calf serum (FCS) and another supplemented with 1% FCS+10 nM G+10 nM E(2). The data show that it is possible to characterize the cell clone structure and to assess growth rate concomitantly by direct cell counts. It further appears that while the anti-hormone and/or anti-growth factor antibody-induced effects on growth were relatively similar, these effects were in sharp contrast at the level of cell clone architecture. PMID- 21544387 TI - Increased monocyte chemoattractant protein-1 expression by tumor necrosis factor alpha can mediate macrophage infiltration in gliomas. AB - We compared the in vitro effects of various cytokines on the expression of monocyte chemoattractant protein-1 (MCP-1) in glioma cell lines and found that MCP-1 expression was highly induced by tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta. The intra-tumoral injection of TNF alpha in rat glioma model increased the in vivo expression of MCP-1 at 1 to 12 h after the injection and induced macrophage infiltration into tumor tissue. The injection of TNF alpha into post-operative tumor cavity of human malignant glioma also increased the concentration of MCP-1 in the cavity fluid at 24 to 38 h after injection. These data, together with the previous finding that the growth of transplanted MCP-1 transfected cells was significantly inhibited by infiltrated macrophages, suggest that injection of TNF alpha inhibits turner growth via the induction of MCP-1 expression. PMID- 21544388 TI - Combined evaluation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2 expression in gastric carcinoma. AB - Urokinase-type plasminogen activator (UPA) is a serine protease implicated in cancer invasion and metastasis. There are at least two kinds of specific inhibitor which act on UPA: plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2). It has been reported that both UPA and PAI-1 antigen levels are associated with short survival in patients with breast cancer. In this study, we investigated the correlation between the expression of UPA, PAI-2 and prognosis in gastric carcinoma. One hundred and twenty specimens resected from patients with gastric carcinoma were investigated by staining with monoclonal antibodies against UPA and PAI-2. UPA positive rate was significantly higher in patients with liver metastases than in those without such metastases, There was no significant association between PAI-2 expression and clinicopathologic factors. However, patients with UPA-positive and PAI-2-negative tumors had more advanced cancer than other patients. According to the prognosis, the patients with UPA-positive and PAI-2-negative tumors had a significantly poorer prognosis than other patients. In conclusion, the combined evaluation of UPA and PAI-2 expression is associated with tumor progression in gastric cancer. PMID- 21544389 TI - In vivo neutralization of vascular endothelial growth factor (VEGF) vascular permeability factor (VPF) inhibits ovarian carcinoma-associated ascites formation and tumor growth. AB - Vascular endothelial growth factor (VEGF)/ vascular permeability factor (VPF) is emerging as an important growth factor in a variety of tumor types. As a potent endothelial cell mitogen and vascular permeabilizing agent, VEGF/VPF has the unique functional capacity to mediate the component events of solid tumor neovascularization and ascites tumor growth. In the present series of investigations, our experimental hypothesis was that VEGF/VPF is a critical mediator of ovarian carcinoma-associated ascites formation and solid tumor growth. Athymic nude mice xenotransplanted with human ovarian carcinoma cell lines received either a preimmune rabbit serum or VEGF/VPF antiserum. Compared with the control group receiving the preimmune serum, the antiserum-treated animals displayed a 10- and 12-fold reduction in ascites accumulation and solid tumor growth, respectively. The administration of a neutralizing antiserum to VEGF/VPF conferred a modest survival advantage to animals harboring intraperitoneal tumors. These data demonstrate the significance of VEGF/VPF in the pathogenesis of ovarian carcinoma and suggest that interventions targeting this growth factor and/or its receptor may be of therapeutic value in the management of ovarian cancer. PMID- 21544390 TI - Establishment of a continuous cell line from a human carcinoid of the small intestine (KRJ-I). AB - A new continuous cell line from a human malignant carcinoid of the small intestine (KRJ-I) was established. The cells showed morphological and immunocytochemical features of the tumor of origin and expressed estrogen receptors. The cells are growing as a suspension, forming multicellular aggregates and spheroids. Electron microscopy confirmed the presence of neuroendocrine granules. Dose-dependent growth inhibition was observed after incubation with 5-azacytidine. Cytogenetic analyses of the tumor of origin, the cell line KRJ-I and a liver metastasis KRJ-II revealed clonal tetraploidy and clonal loss of the Y-chromosome and chromosome 19. PMID- 21544391 TI - Relation of protein kinase A and protein kinase C to signaling pathways of hematopoietic factors in leukemia cell lines. AB - In terms of growth, differentiation, and signaling pathways of hematopoietic factors, the effects of protein kinase C (PKC) activator, 12-O-tetradecanoyl phorbol-13-acetate (TPA) and protein kinase A(PKA) activator, dibutyryl cyclic adenosine monophosphate (dbcAMP) were examined in vitro using three factor responsive myeloid leukemia cell lines. TPA suppressed the growth of OCI/AML-1 and OCI/AML-5 cells but stimulated the proliferation of OCI/AML-4 cells. TPA differentiated OCI/AML-4 and OCI/AML-5 cells to macrophage-like cells. dbcAMP suppressed the growth of the three without differentiation. The stimulation of TPA induced tyrosine phosphorylation of some proteins in OCI/AML-4 and OCI/AML-5 cells. Their molecular weights were the same as those phosphorylated by hematopoietic factors. The patterns of phosphorylated proteins were different between the two. TPA induced the phosphorylation of MAP kinase, but not that of JAK2 protein in three cell lines. The stimulation of dbcAMP did not induce tyrosine phosphorylation in three cell lines. Overnight exposure of TPA inhibited the tyrosine phosphorylation induced by hematopoietic factors, although that of dbcAMP did not. We suggest a close relation of PKC to signaling pathways of hematopoietic factors, however, the ways of relation were diverse among the cell lines and the clear mechanism explaining its effects on growth and differentiation was not elucidated. PMID- 21544392 TI - Anthracyclines. AB - The genotoxicity and carcinogenicity data from in vitro and in vivo studies conducted during preclinical safety assessment of doxorubicin (DOXO), epirubicin (EPI) and idarubicin (IDA), are reviewed. The genotoxicity assays included a) gene mutation in Salmonella typhimurium with 5 tester strains; b) gene mutation in the V79 mammalian (lung) cell line; c) chromosome aberrations in human lymphocytes cultured in vitro; and d) chromosome aberrations in mouse bone marrow cells after intravenous (i.v.) administration in vivo. The long-term toxicity studies in the rat included a) single dose administration (3 mg/kg DOXO, 3.6 EPI and 0.75 IDA) to female rats of two different age groups, i.e. younger (7 weeks old at dosing) and older (13 weeks old), followed by one-year observation; and b) multiple dose administration to male and female rats (7 weeks old at dosing), consisting of i.v. administration of 0.25, 0.5 and 1 mg/kg DOXO or EPI and 0.06, 0.125 and 0.25 mg/kg IDA, once every 3 weeks for 10 cycles, followed by 18 months of observation. The genotoxicity studies revealed activity in gene mutation assays in bacterial and mammalian cells, and in chromosome aberration assays in human lymphocytes in vitro and in mouse bone marrow in vivo. In the two long-term studies in the rat, only mammary tumors were present. This finding was expected and, according to the literature, can be considered as species specific and not directly compound-related. The lack of tumor induction at the usual target organs for DNA reactive compounds, which are almost the same as those considered as target organs in anthracycline-exposed animals, indicates that the type and the extent of DNA damage precludes stimulation for proliferation and induction of neoplasia. Although an epigenetic mechanism can be hypothesized, support for such a mechanism is lacking. PMID- 21544393 TI - Comparison of the mRNA expression of factors related to drug resistance in lung tumors and adjacent normal tissue. AB - Drug resistance related proteins P-glycoprotein (P170), multidrug resistance associated protein (MRP), glutathione S-transferase-pi (GST-pi), glutathione peroxidase (GPX), topoisomerase II (Topo II), thymidylate synthase (TS), O-6 methylguanine-DNA-methyltransferase (MGMT), the heat shock proteins HSP27 and HSP70 and the protooncogenes Fos, Jun and EGFR were investigated in human lung carcinomas and matched normal tissues. We found that the mRNA expression of Topo II and TS were elevated in tumor tissue versus corresponding normal tissue. Additionally Topo II and TS correlated with the proliferating activity determined by expression of histone 3. P170, MRP, HSP70 and also EGFR mRNA were elevated in some tumor probes, but not GST-pi, GPX, MGMT and HSP27 mRNA. Additionally, we determined various values of Fos and Jun mRNA expression but there was no uniform pattern. The finding that some proteins were abnormally expressed in lung tumors compared to the adjacent normal tissue is an important finding for further investigations on the development of individualized chemotherapy but more samples should be examined to extend these observations. PMID- 21544394 TI - Antibody-dependent cytotoxic activity on human cancer cells expressing UK 114 tumor membrane antigen. AB - The monoclonal antibody (P-3 mAb) and the rabbit immune sera (RIS) recognizing a 14 kDa perchloric acid soluble protein extracted from goat liver (UK 114), locate this antigen on the cell membrane of several human cancer cell lines. UK 114 positive cells (e.g. HT 29 and KATO VI cells) undergo antibody-dependent cytolysis bl vitro. In nu/nu mice bearing xenografted HT 29 cells, tumor growth was markedly impaired by peri-tumoral injection of anti-UK 114 antibodies. These experiments suggest that human tumors expressing UK 114 over the cell membrane may undergo antibody-mediated cytolysis and growth control. PMID- 21544395 TI - Focal distribution of p16/CDKN2 gene mutations within individual prostate carcinomas. AB - To examine the potential role of pl6/CDKN2 gene mutations in prostate tumorigenesis, focal areas within individual tumors were investigated. Eleven cases of histologically heterogeneous prostate carcinomas obtained by radical prostatectomy were subjected to analysis of p16/CDKN2 gene mutations. DNA was extracted from 5 to 10 separate areas of each tumor with different growth or histological patterns. Exons 1 through 3 of the p16/CDKN2 gene were amplified using the polymerase chain reaction (PCR) and screened for homozygous deletions and mutations of this gene by single-strand conformation polymorphism (SSCP) analysis. No homozygous deletions were observed in any of the prostate carcinomas, but two of the eleven tumors demonstrated mutations in exon 2 of p16/CDKN2 gene. Missense mutations were detected in only one and two foci, respectively, out of six ana ten selected tumor areas. The present results suggest that p16/CDKN2 gene mutations, although they occur at a low incidence, are involved in prostate tumorigenesis, indicating a mutational heterogeneity in addition to morphological heterogeneity. PMID- 21544396 TI - Correlation between overexpression of c-met gene and the progression of gastric cancer. AB - The c-met oncogene encodes a receptor of hepatocyte growth factor (HGF), which has both mitogenic and motogenic activities. We have studied the c-met gene expression in gastric cancer by immunohistochemical method using an antibody specific to the c-met beta-chain. c-met immunoreactivity was preferentially localize on the cell membrane, and 55 (43%) of 127 primary gastric cancers showed c-met immunoreactivity. Strong correlation was found between c-met expression in large tumors, lymph node involvement, serosal invasion, as well as peritoneal dissemination. Furthermore, c-met positive tumors had a tendency to metastasize to more distant lymph node sites. Regarding the macroscopic type, Borrmann type 4 gastric cancer showed the highest incidence (12/16, 76%) of positive c-met expression. Patients with c-met positive tumor ran a significantly poorer prognosis than those with c-met negative one. These results indicate that the c met protein participates in the progression and invasion of stomach cancer, and that c-met tissue status is a useful biological marker in gastric cancer. PMID- 21544397 TI - Determination of vascularization of B-cell non-Hodgkin's lymphomas with four markers. AB - We evaluated the microvessel area (an index of angiogenesis) by using the factor VIII-related antigen (factor VIII-RA), and the expression of three components of the subendothelial basement membrane, namely: tenascin, laminin and type IV collagen. The four markers were assessed by immunohistochemical methods in 57 B cell non-Hodgkin's lymphomas (B-NHL) and 28 benign lymphadenopathies. We found that microvessel area and the basement membrane markers had a different distribution pattern in relation to the histological type and degree of malignancy. In reactive and atypical lymphoid hyperplasias and in follicular low- and intermediate-grade B-NHL, microvessels were distributed within the interfollicular zones. By contrast, diffuse intermediate-grade and high-grade B NHL were highly vascularized and microvessels were closely related to the neoplastic cells. Microvessel area was significantly associated with tenascin expression in all histological grades. Conversely, it was not correlated to laminin and type IV collagen expression, especially in diffuse intermediate-grade and high-grade B-NHL, where the expression of these markers was poor and fragmented. Our study suggests that angiogenesis and tenascin expression are associated phenomena in B-NHL, and that both increase with the malignancy grade. The prognostic value of angiogenesis and tenascin in B-NHL warrants further assessment in follow-up studies. PMID- 21544398 TI - Angiogenic phenotype induced by basic fibroblast growth factor transfection in brain microvascular endothelial cells. AB - Basic fibroblast growth factor (bFGF) is expressed in the vascular endothelium of human brain tumors. To investigate the biological consequences of a possible autocrine modality of microvascular endothelial cell activation by endogenous bFGF in these tumors, mouse brain microvascular endothelial cells were stably transfected with a retroviral expression vector harboring a human bFGF cDNA. When grown on tissue culture plastic, bFGF-transfected clones show a transformed morphology and increased saturation density. bFGF-transfectants have an invasive behavior when seeded on three-dimensional fibrin gel and originate endothelial cell sprouts when embedded within fibrin. Also, bFGF-transfected cells undergo morphogenetic organization and produce a complex network of branching cord-like structures connecting foci of infiltrating cells when seeded on Matrigel, a laminin-rich extracellular matrix material. In contrast, parental and mock transfected cells do not invade fibrin gels nor organize on Matrigel. These findings demonstrate that bFGF overexpression induces an angiogenic phenotype in brain microvascular endothelial cells characterized by an invasive behavior and morphogenic potential. They support the notion that neovascularization of brain tumors can be triggered by stimuli that induce vascular endothelium to produce its own autocrine factor(s). PMID- 21544399 TI - Effects of linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid on the growth and metastasis of MM48 mammary tumor transplants in mice. AB - In this study, we investigated the effects of linoleic acid (LA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) on the growth, metastasis and cell proliferation of a murine mammary tumor (MM48) transplanted into mice. We also examined the effect of these treatments on survival and tumor fatty acids. The growth of the primary tumor, number of metastatic tumors in the lung, and cell proliferation of the tumor were significantly inhibited in the EPA and DHA groups compared with the control and/or LA groups. Mice in the EPA group survived significantly longer than those in the control and LA groups, while mice in the DHA group survived longer than those in the control group. While the ratio of arachidonic acid (AA)/higher PUFAs (polyunsaturated fatty acids) in tumors correlated with tumor growth and lung metastases, the ratio of AA/LA did not. Therefore, it appears that both EPA and DHA exert their effects by competing with AA, thereby lowering the formation of AA metabolites. PMID- 21544400 TI - Gamma linolenic acid inhibits tyrosine phosphorylation of focal adhesion kinase and paxillin and tumour cell matrix interaction. AB - Gamma linolenic acid (GLA) is an anti-cancer agent recently reported to inhibit tumour cell-matrix attachment. This study examined the effects of GLA on the adhesion of two tumour cell lines, HT115 (human colon) and MDA MB 231 (human breast), to an extracellular matrix, Matrigel. The action of GLA on focal adhesion kinase(FAK) and paxillin was also investigated. Following cell adhesion to Matrigel in control experiments, both FAK and paxillin were quickly tyrosine phosphorylated and become concentrated at focal adhesion areas. Inclusion of GLA resulted in an inhibition of the tyrosine phosphorylation of both FAK and paxillin leading to a reduced attachment of both cell types to Matrigel. FAK and paxillin were also less well distributed in the focal adhesions compared with the controls. It is concluded, therefore, that GLA inhibits tumour-matrix adhesion via the inhibition of FAK and paxillin tyrosine phosphorylation. PMID- 21544401 TI - Growth inhibition of gastric cancer cell lines by the tyrphostin RG13022 and its effects on intracellular signalling. AB - Overexpression of EGFr and c-erbB-2 is related to poor prognosis in a variety of cancers including gastric cancer. Thus: the ability to modulate the functional activity of these receptors is an attractive target for diagnostic intervention. In this study we examined the effect of a well characterised tyrosine kinase inhibitor (RG13022) on the cellular proliferation and EGF activated tyrosine kinase signalling pathway of two primary gastric cell lines: MKN45 and N87. RG13022 has a dose dependent, antiproliferative effect on both gastric cell lines when grown either in serum-free conditions or in the presence of FCS. Western blotting revealed RG13022 caused an inhibition of EGF stimulated tyrosine phosphorylation of EGFr in A431 cells and both EGFr and c-erbB-2 in MKN45 cells. No clear modulation of EGFr or c-erbB-2 phosphorylation was observed in N87 cells. In both A431 cells and N87 cells (which overexpress EGFr and c-erbB-2 respectively) exposed to EGF, MAP2 kinase immunoblot analysis resulted in the detection of a second protein band with reduced migration in SDS-PAGE. In N87 cells, this protein appeared to co-mi,orate with a strongly tyrosine phosphorylated protein, which suggests that it is a hyper-phosphorylated form of MAP2 kinase. However, treatment with RG13022, whilst inhibiting phosphorylation of this protein, did not prevent a shift in gel mobility (suggestive of activation) of MAP2 kinase in response to EGF. These findings demonstrate that the tyrphostin RG13022 inhibits cell proliferation of two primary gastric cancer cell lines. Investigation of intracellular signalling pathways suggests that alterations in intracellular signalling are responsible for the actions of RG 13022 in these cells. The biochemical analysis revealed that in N87 and A431, cells which overexpress c-erbB-2 and EGFr respectively, the tyrphostin affects the MAP2 kinase immunoreactivity and migration on SDS gels but fails to affect this protein in the MKN45 cell line. This data questions the usefulness of MAP2 kinase gel shift assays as markers of activation but supports the further development of tyrosine kinase inhibitors as potential inhibitors of gastric tumour proliferation. PMID- 21544402 TI - Altered glucose metabolism and the invasive tumor phenotype. AB - Multiple genetic changes are necessary for carcinogenesis, yet a wide range of different genetic changes may give rise to malignant behavior and no set or sequence of defects is seen in all cancers. The similar pattern of invasive growth in malignancy despite the genotypic and phenotypic heterogeneity of tumor populations suggests that a final cellular state common to all cancers may exist. Such a state must be the sequela of many possible genetic changes, and the cellular properties of the state must promote malignant, invasive growth. It is hypothesized that the common denominator of the transformed state is reversion to primitive phenotype, and its invasive properties stem from alteration of metabolic pathways. Increased use of glycolysis and consequent production of acid have been consistently demonstrated in malignant cells in vitro and are seen in the vast majority of clinical tumors imaged with FDG Positron Emission Tomography (PET) and Magnetic Resonance Spectroscopy (MRS). Application of mathematical models from population ecology and competition theory demonstrates that these metabolic changes will alter the local microenvironment in ways that favor tumor growth but are lethal to normal cells. This phenomenon alone appears to provide a simple but sufficient mechanism for invasive tumor growth. This hypothesis is testable experimentally and suggests significant new approaches to tumor therapy. PMID- 21544403 TI - Differentiation of human fibroblasts to tissue macrophages by the Snyder-Theilen feline sarcoma virus (ST:FeSV). AB - We have previously reported the conversion of human fibroblasts (HF) to tissue macrophages (TM) by transduction with the Snyder-Theilen feline sarcoma virus [ST:FeSV(FeLV)]. Here, we have demonstrated macrophage mediated tumor cytotoxicity (MTC) of human teratocarcinoma cells (NTERA-2) by ST:FeSV-induced TM. Inclusion of the NTERA-2 specific antibody (SSEA-4), substantially increased antibody-dependent cellular cytotoxicity (ADCC) of the tumor cells by ST:FeSV induced TM. Tumor cell lysis by ST:FeSV-induced TM through either MTC or ADCC was especially effective at low serum concentrations (1%). The presence of cytokines during co-incubation, M-CSF in particular, enhanced the lysis of NTERA-2 cells by ST:FeSV-induced TM. Whereas pretreatment of the NTEBA-2 cells with all-trans retinoic acid (AtRA) enhanced MTC-induced lysis, it abrogated ADCC-induced lysis of the tumor cells by ST:FeSV-induced TM. Significantly, the co-incubation of NTERA-2 cells with ST:FeSV-induced TM in agar, resulted in a considerable stimulation of growth of untreated and TPA-pretreated NTERA-2 cells. In contrast, the growth of AtRA-pretreated NTERA-2 cells in agar was completely inhibited by ST:FeSV-induced TM. These results indicate that ST:FeSV-induced TM can produce potent growth-modulating cytokines, and that AtRA can modify their antitumor activity in monolayer cultures and in agar. The effects by AtRA, serum, and growth conditions (whether monolayers or agar) point to several levels of complexity regarding the interaction of tissue macrophages with tumor cells. PMID- 21544404 TI - Differentiation of human fibroblasts to tissue macrophages by the Snyder-Theilen feline sarcoma virus is accompanied by nuclear accumulation of the tumor suppressor p53. AB - Snyder-Theilen feline sarcoma virus (ST:FeSV)-transduced human fibroblasts differentiate into tissue macrophages with many of the properties of normal macrophages. These cells express high levels of the gag-fes tyrosine kinase fusion protein, p85(v-fes), and exhibit an elevated level of tyrosine phosphorylation. Expression of the macrophage phenotype is accompanied by increased levels of DNA-binding activity and nuclear accumulation of wild-type p53. The DNA-binding activity of the transcription factors Egr-1, CREB and Sp1, which are known to be involved in cell differentiation, is also increased in ST:FeSV-induced macrophages. These observations suggest that v-fes can activate signal transduction pathways normally involved in macrophage differentiation, and that transcription factors such as p53, further facilitate v-fes-induced terminal differentiation. PMID- 21544405 TI - Stereotactic radiosurgery for metastatic brain tumors. AB - We report on a prospective phase TI study utilizing stereotactic radiosurgery for patients with intracranial parenchymal metastases. Fifty patients ranging in age from 38 to 77 years with 1 to 3 intraparenchymal brain metastases were treated with stereotactic radiosurgery either immediately following whole brain radiotherapy or at the time of intracranial disease progression following failure of whole brain radiotherapy. Twenty patients treated with adjuvant therapy received a median radiosurgical dose of 20 Gy. Thirty patients treated with salvage therapy received a median radiosurgical dose of 20 Gy. No immediate neurotoxicity was seen following radiosurgery however, 4 patients (8%) developed symptomatic radiation necrosis. Median survival was 6.5 and 6.0 months for patients treated with adjuvant and salvage radiosurgery respectively. In patients with oligometastatic brain metastases manifesting intracranial disease progression after whole brain radiotherapy, salvage radiotherapy appears to offer improved palliation when compared to retreatment with whole brain radiotherapy. The results of patients treated with up-front adjuvant radiosurgery when compared to historical controls treated with whole brain radiotherapy only are less clear as to benefit and require a phase III study before definitive recommendations can be made. PMID- 21544406 TI - A statistical analysis of chromosome 11 and 17 loss of heterozygosity in epithelial ovarian cancer. AB - Many regions of the genome exhibit loss of heterozygosity (LOH) in epithelial ovarian cancer (EOC) suggesting sites of recessive genetic elements such as tumor suppressor genes. We performed detailed LOH studies of chromosomes 17 and 11 using 24 microsatellite repeat markers in a population of 47 patients with EOC. Univariate statistical analysis revealed that significant co-losses of chromosomal loci occurred between 17p and 17q whole arms (p=0.0003), NME1 (17q21) with D11S922 (11p15.5) (p=0.0067) and D11S912 (11q24) with D11S935 (11p13) (p=0.0073). Statistical analysis of the relationship between LOH on particular chromosomal arms and clinicopathological factors revealed a significant association between serous histological subtype of ovarian adenocarcinoma and chromosome 17p (p=0.0052) and telomeric 17q (p=0.0007) LOH. An analysis of specific polymorphic chromosomal loci demonstrated that adverse survival was significantly associated with LOH at 11q24 (p=0.0067) and 17q21 (p=0.0076). There were nonsignificant trends suggesting a relationship between chromosome 17p LOH and poorly differentiated (p=0.025) and advanced FIGO stage (p=0.031) tumours. Considering these statistical associations, a preliminary multistep model for involvement of chromosomes 11 and 17 in ovarian neoplasia can be constructed. PMID- 21544407 TI - Breast conserving surgery (BCS) in northern Norway. AB - Between 1986-1994, 66 patients were operated by 36 surgeons at 11 institutions. The majority were below the age of 50 years. Single women had a prolonged diagnostic delay (p = 0.025). During a median follow-up of 29 months, 13 patients relapsed and 5 died of progressive disease giving a 5-year disease-free survival of 51% and an overall survival of 77%. Relapse was correlated to lymph node status (pN(+)) at diagnosis (p = 0.024). There were no difference in clinical outcome between hospitals or surgeons. Multicenter studies and treatment protocols ensure a high cure rate and a low morbidity in small surgical units. PMID- 21544408 TI - Cell density-dependent modulation of basic fibroblast growth factor expression by human interferon-beta. AB - The production of basic fibroblast growth factor (bFGF) by human renal cell carcinoma (HRCC) is associated with induction of angiogenesis. Incubation of HRCC cells with human interferon alpha (IFN-alpha) or interferon beta (IFN-beta) downregulates the expression of bFGF and, hence, angiogenesis. The purpose of this study was to analyze the downregulation of the expression of bFGF in HRCC cells by IFN-alpha and IFN-beta. Human HRCC SN12PM6 cells cultured under sparse conditions expressed 3-7-fold higher levels of steady-state bFGF-specific mRNA transcripts and cellular bFGF protein than did confluent cultures. IFN-alpha or IFN-beta inhibited the steady-state expression of bFGF mRNA transcripts and cellular bFGF protein in a concentration-dependent manner in sparse but not confluent cultures. Moreover, IFN-beta downregulated the transcription rate of bFGF genes and inhibited the de novo synthesis of bFGF protein only in sparse cultures. The results demonstrate that the inhibitory effects of IFN- and -beta on bFGF expression are cell-density dependent. PMID- 21544409 TI - CD44 with variant exons 8-10 in colorectal tumors. AB - Using a fusion protein encoded by variant exon (v) 8-10 of CD44, a monoclonal antibody (mAb) 44-1V reactive with v9 product was generated. Western immunoblots and reverse transcriptase-polymerase chain reaction/Southern blot revealed that a 130 kilodalton component containing v8-10 products was specifically expressed in colorectal and gastric cancer cell lines. Immunohistological examination of 179 pairs of colorectal cancer and normal tissues revealed that about 47% of cancers expressed the CD44 variant (CD44v8-10), and its expression correlated with hematogenous and lymph node metastasis. These findings suggest the usefulness of CD44v8-10 in the prediction of colorectal cancer metastasis. PMID- 21544410 TI - Overexpression of RII beta regulatory subunit of protein kinase A induces growth inhibition and reverse-transformation in SK-N-SH human neuroblastoma cells. AB - SK-N-SH human neuroblastoma cell line was employed to test whether direct introduction of the RII beta subunit of PKA could induce growth inhibition and reverse-transformation of cancer cells. We infected SK-N-SH cells with an RII beta expression construct and the clonal line with the highest expression level was selected to examine the effect of RII beta overexpression. Elevation of RII beta was accompanied by marked reduction of RI alpha level and increase of C alpha level. Since the mRNA levels of RI alpha and C alpha were not altered by increased RII beta, the changes in the level of RI alpha and C alpha protein seem to be due to a post-transcriptional event. The RII beta-overexpressing cell line, SK-RII beta, exhibited retarded monolayer growth, decreased DNA synthesis, inability to grow in soft agar, and reduced viability in serum-free or low-serum condition as compared to parental cell, SK-N-SH. These characteristics of SK-RII beta disappeared when the RII beta expression was not fully induced. These results showed that the elevation of RII beta and/or the decrease of RI alpha is closely related to the suppression of cell proliferation and the status of transformation of SK-N-SH neuroblastoma cell line. PMID- 21544411 TI - Three cycles of ABDV plus extended field radiotherapy in patients with poor prognosis early-intermediate stage Hodgkin's disease. AB - The aim of the study was to verify the possibility of treating patients with poor prognosis early-intermediate Hodgkin's disease with a combined modality therapy consisting of three cycles of ABVD followed by extended field irradiation (EFRT). No patient had bulky mediastinum or had previously been administered chemo- or radiotherapy. At pathological restaging, 40/44 (91%) evaluable patients achieved complete responses (CR). After a ten-year followup, freedom from progression (FFP), relapse-free survival (RFS) and overall survival (OS) were 80%, 83% and 81%, respectively. Of the prognostic factors, univariate analysis showed that only stage III negatively influenced RFS, but not OS. Toxicity was mild except for subclinical mediastinal fibrosis in 32.5% of CR patients. No patient reported reduced fertility. Two cases of second neoplasms were recorded: one ameboid glioma and one thymoma, both occurring within five years after discontinuing chemo-radiotherapy. Our data suggest that three cycles of ABVD preceeding EFRT is an effective treatment for poor prognosis early-intermediate stage Hodgkin's disease; nevertheless, stage III patients and some stage II patients with unfavorable prognostic factors should be treated with a more aggressive approach. PMID- 21544412 TI - Accelerated neoadjuvant chemotherapy of non-small cell lung cancer (NSCLC). AB - Thirty patients with marginally resectable stage IIIA or stage IIIB NSCLC were treated with cisplatin (80 mg/ m(2)/i.v./dl), ifosfamide (4,000 mg/m(2)/i.v./dl) and vinorelbine (30 mg/m(2)/i.v./dl) plus G-CSF 300 mu g/s.c. on days 7-12 every 14 days for three cycles before surgery. In 26 evaluable patients, the radiographically assessed response rate to chemotherapy was 77% (8% complete). Three septic deaths (10%) occurred in spite of G-CSF and 1 patient refused to continue after the first cycle. Thoracothomy was performed in 23 patients including 19 complete resections. At 15 months median follow-up (range 10-22+), 11/19 (57%) completely resected patients relapsed. The overall median time to treatment failure was 11 months (range 0-17). Actuarial survival probability at 12, 18 and 24 months are 56%, 43% and 36%, respectively. In conclusion, the combination of cisplatin, ifosfamide and vinorelbine in full doses at a 14 day interval (accelerated chemotherapy) was very effective in neoadjuvant NSCLC setting. Nevertheless, relevant toxicity was demonstrated with a 10% death rate probably due to the overlapping toxicity of chemotherapy cycles, suggesting the need for a more intense supportive care or longer interval between cycles. PMID- 21544413 TI - Effect of inducer and inhibitor probes on DNA adduction of benzo[a]pyrene and 2 acetylaminofluorene and their roles in defining bioactivation mechanism(s). AB - In this study, we used DNA adducts as the endpoint to reflect on the type and amount of electrophilic metabolites formed in a cell-free system, which were 'trapped' with DNA and the resultant adducts analyzed by a highly sensitive (32)p postlabeling assay. Incubation of benzo[a]pyrene (BP) (10 mu M) with liver microsomes and S-9 fractions from uninduced and beta-naphthoflavone (beta-NF) induced rats and NADPH-generating system resulted in two major adducts, one derived from the interaction of benzo[a]pyrene diolepoxide with deoxyguanosine (BPDE-dG) and the other from further activation of 9-OH-BP. beta-NF treatment increased the microsomal DNA adduction capability: both BPDE-dG and 9-OH-BP adducts were enhanced to 19,600 and 26,600 adducts/10(9) nucleotides compared to 2,800 and 1,700 adducts/10(9) nucleotides with uninduced microsomes, respectively. An even greater enhancement of both adducts was observed when S-9 was substituted for microsomes. These results suggest the involvement of CYP1A1 in BP activation because of the known role of beta-NF in the induction of this enzyme. Further, evidence of the involvement of CYP1A1 was obtained by using alpha-naphthoflavone (alpha-NF), a known inhibitor of CYP1A family. Addition of alpha-NF (50 mu M) to the activation system almost completely (>95%) abolished both the adducts. These results are consistent with selective inhibition of CYP1A1, the isozyme involved in the conversion of BP to BP-7,8-diol. Further, cyclohexene oxide (Chox) (100 mu M), a known inhibitor of epoxide hydrolase reduced BPDE-dG adduct by 55% over that in the absence of the inhibitor, suggesting its epoxide origin; 9-OH-BP adduct was, however slightly increased. Enhanced DNA adduction of another class of carcinogen, 2-acetylaminofluorene (2 AAF) (20 mu M) with induced S-9 and microsomes, and inhibition in the presence of alpha-NF was also observed which is consistent with the involvement of CYP1A2 in the initial activation of aromatic amines. Results from these experiments suggest that the approach of using a battery of inducer/inhibitor probes and their influence on DNA adduction capability of subcellular fractions coupled with P-32 postlabeling can be fully exploited as important tools in defining metabolic pathway(s) that may be involved in the bioactivation of unknown compounds. PMID- 21544414 TI - Growth stimulatory effect and metabolism of testosterone in MCF-7 human breast cancer cells. AB - The purpose of our study was to evaluate the effect of testosterone and its metabolic pathway in MCF-7 cells in culture. Testosterone exhibited a dose dependent (from 0.1 to 10 nM) and time-dependent (from 3 to 9 days) growth stimulation. The metabolic pathway was investigated following treatment with two testosterone concentrations: one stimulating (10 nM) and one not affecting (0.1 nM) cell growth. Celite column chromatography was used to separate H-3 testosterone metabolites, whose identity was confirmed by gas chromatography-mass spectrometry analysis. The main findings of the metabolic study were: i) recovery of a large amount of untransformed testosterone; ii) a high conversion of testosterone to conjugated, biologically inactive metabolites; iii) the highest level of Sa-diol among the metabolites of testosterone; iv) a conversion (2%) of testosterone into oestradiol, which resulted in a growth stimulatory concentration when testosterone was used at 10 nM. We conclude that in our experimental conditions androgens and oestrogens can concur to stimulate MCF-7 cell growth through androgen receptor-mediated and oestrogen receptor-mediated mechanisms. PMID- 21544415 TI - Axillary lymph node metastases detection with nuclear medicine approaches in patients with newly diagnosed breast cancer. AB - Three different tracers, Tc-99m-Sesta MIBI, In-111-Pentetreotide and F-18-FDG, were evaluated in a preliminary study in three different groups of 10 breast cancer patients programmed for breast cancer resection and axillary dissection. Planar scintigraphy and single photon emission tomography (SPET) technique were used for imaging with Tc-99m-Sesta-MIBI and In-111-Pentetreotide, positron emission tomography (PET) was used for imaging with F-18-FDG. We studied 30 breast cancer patients; their clinical stage according to the TNM classification was 30 T1-T2, 1 T4 and 1 Tx (one patient had bilateral cancer and one had bifocal cancer). The lymph nodal status ranged from NO to N2 (14 NO, 16 N1, 1 N2). Tc-99m Sesta MIBI, In-111 Pentetreotide SPET and F-18-FDG PET were randomly performed before surgery to visualize the primary tumors and to detect axillary lymph node invasion. Tc-99m-Sesta MIBI correctly visualized 10 out of 11 primary cancers in 10 patients. In-111-Pentetreotide detected 9 out of 10 primary cancers. F-18-FDG imaged all the tumors (10). As regards the axillary nodes, Tc-99m-MIBI excluded axilla involvement in 7 out of 7 negative axillae (N-), while it was positive in 2 out of 3 positive cases (N+); In-111-Pentetreotide correctly identified 7 out of 8 negative axillae (N-), while it detected 2 of 3 positive sites. F-18-FDG visualized all positive axillary lymph nodes (4 out of 4 N+ patients) and correctly excluded involvement in all negative patients (6 out of 6 N- cases). This study demonstrated that all three tracers are adequate to be proposed as tumor seeking agents with the aim of developing non-invasive diagnostic methods for pre-operative detection of axillary metastases, so that surgical dissection can be limited to selected patients. The authors discuss the advantages and disadvantages of the different radiopharmaceuticals and conclude that in centers with PET facilities F-18-FDG is the best tumor seeking agent for the evaluation of axillary status. Between Tc-99m-Sesta MIBI and In-111-Pentetreotide the former seems to present more advantages in this kind of application, considering also its lower cost and easier availability. These results encourage further study, including the simultaneous comparison of these tracers in breast cancer staging. PMID- 21544416 TI - Site-dependent expression of vascular endothelial growth factor, angiogenesis and proliferation in human gastric carcinoma. AB - To determine the role of site of tumor implantation on tumor angiogenesis, we implanted gastric cancer cells in the orthotopic (stomach) and ectopic (subcutaneous) locations in nude mice. Tumors in the stomach demonstrated greater vascularization, higher levels of vascular endothelial growth factor (VEGF) expression, and greater proliferation compared with tumors in the subcutaneous tissues. These data suggest that the relationships among the expression of VEGF, vascularization, and proliferation of human gastric cancer cells are regulated by the organ microenvironment. In addition, VEGF may provide a target for anti angiogenic therapy for gastric cancers. PMID- 21544417 TI - Is chromosome in situ suppression (CISS) hybridization suited as a predictive test for intrinsic radiosensitivity in cancer patients? AB - Chromosome painting (chromosome in situ suppression hybridization, CISS) analyses were used to control in vitro radiosensitivity of peripheral blood lymphocytes of 70 cancer patients who were assigned to or had just undergone radiation therapy. This technique using three-colour detection of genomic DNA libraries of chromosomes 1, 2, and 4 was shown to uncover reliably radiation-induced chromosome damage in human peripheral blood lymphocytes. The lymphocytes of five out of the 70 cancer patients could be defined as to react hypersensitively to in vitro irradiation. This was particularly underlined not only by the mere increase of aberration rate but also by the quality of the induced abnormalities (e.g. incidence of complex chromosome rearrangements). The same patients were also characterized by extreme radiation reaction in clinical terms. In spite of some confounding factors, based on the presented observations, the CISS-technique can be proposed as a predictive technique for selecting radiosensitive patients and protecting them from undesired side effects of radiotherapy. A simplification of the screening procedure is proposed on the basis of the presented data. PMID- 21544418 TI - Overexpression of the ros1 gene in primary human gliomas may contribute to malignant progression. AB - Gliomas are malignant brain tumors thought to arise through multi-step tumorigenesis, involving both the activation of oncogenes and the loss of tumor suppressor genes. The ros1 gene encodes a proto-oncogenic protein which has been implicated, by in vitro studies, in the pathogenesis of several types of cancer, including gliomas. Northern blot analysis revealed expression of ros1 mRNA in 3 (30%) of 10 primary glioma specimens. In situ hybridization localized ros1 mRNA transcripts to GFAP positive tumor cells and pericytes around capillaries. Immunohistochemistry using an antibody specific for ros1 demonstrated strong positivity amongst neoplastic glial cells in the same glioma samples. No ros1 mRNA or protein was detected in 5 normal brain specimens. These data provide the first evidence for the overexpression of ros1 mRNA and protein in primary human gliomas, and are consistent with a proposed oncogenic role of ros1 in these tumors. PMID- 21544419 TI - The role of p53, bcl-2 and bax network in dexamethasone induced apoptosis in multiple myeloma cell lines. AB - The role of bcl-2 in protection against apoptosis is well established in a great variety of cells and has become a hallmark of drug-resistance in many tumor cell lines, notably in lymphomas and leukemias. Conflicting results have been reported as for the role of bcl-2 in spontaneous and drug induced apoptosis in multiple myeloma (MM), although high expression of bcl-2 was observed, in spite of relatively low frequency of t(14:18). We, therefore, decided to conduct a detailed study of the role of the bcl-2/bax/p53 network in dexamethasone (DEX) induced apoptosis in MM cells. Eight myeloma cell lines were screened for their expression of mRNA transcripts for p53, bcl-2 and bax, and the levels were correlated for sensitivity to DEX induced apoptosis. Two cell lines (HS-Sultan and ARH-77) expressed relatively high levels of bcl-2 transcripts, and were highly resistant to DEX induced apoptosis (up to 10 mu M). Two cell lines (8226 and ARP-1) expressed relatively low-levels of bcl-2 mRNA transcripts, and were highly sensitive to DEX (ID50= 0.1 mu M, at 24-48 h). Fax mRNA transcripts were abundant, were expressed ubiquitously in all cell lines, and, thus, did not correlate with sensitivity to DEX. The level of expression of mRNA transcripts for p53 varied among the various cell lines, and did not always correlate with resistance to DEX. Induction of apoptosis in 8226 and ARP-1 cells (DEX sensitive) resulted, within 24 h, in a transient but marked down-regulation of mRNA transcripts for bcl-2 and p53, whereas the level of expression of bax mRNA transcripts were unchanged, except for ARP-1 cells (lacking p53), where slight down-regulation of mRNA transcripts for bax, was observed. In contrast to the DEX sensitive cell lines, the level of expression of bcl-2, bax and p53 mRNA transcripts in the DEX resistant cell lines, were unchanged during 72 h of treatment with DEX (up to 10 mu M). We, therefore, conclude that bcl-2 and perhaps p53 are involved in resistance to DEX in myeloma cell lines. PMID- 21544420 TI - In vitro reversion of transformed phenotype in mouse C3H/10T1/2 cells. AB - Spontaneous tumor regression is still one of the most puzzling events in human cancer. A cell culture model of malignant transformation designed to permit the study of this phenomenon in vitro was applied to examine reversion and re expression of the transformed phenotype in two X-ray transformed mouse 10T1/2 cell clones. By alternating cell passages at low and high seeding density, the expression of cell contact inhibition and tumorigenic capacity were both reverted and restored. Growth of non-transformed wild-type cells was not affected by seeding density. This reversion of the transformed phenotype was associated with a modification in genomic 5-methylcytosine content. Initially, the transformed clones were hypomethylated, as occurs in most human tumors. After only four passages at low seeding density, the phenotype was reverted to that of non transformed 10T1/2 cells and genomic 5-methylcytosine content was significantly increased to levels measured in non-transformed C3H/10T1/2 mouse cells. Thus, hypomethylation induced by ionizing radiation was not a permanent feature of malignantly transformed 10T1/2 cells. Although genomic 5-methylcytosine content returned to normal levels during low density passaging, the methylation pattern of the c-myc gene specifically was not associated with cell passages either at low or high seeding density. In an attempt to identify genes involved in this process, expression of the tumor suppressor gene p53 was measured. Western blot analysis failed to detect any correlation between expression of p53 protein and reversion of the transformed phenotype. The results of this study indicate that the transformed phenotype is not permanently associated with the malignant transformation of C3H/1OT1/2 cells, and can be modulated by growth conditions in vitro. We propose that modulation of genomic 5-methylcytosine levels may be involved in this process. PMID- 21544421 TI - Urinary markers for prostate cancer. AB - Immunoglobulins (Igs), bombesin-like immunoreactivity (BLI), beta-2 microglobulin (beta-2m) and transferrin were measured by radioimmunoassay in the first voided urine of patients with advanced prostatic carcinoma. Compared to 16 age-matched, healthy subjects, urinary Igs were elevated in 19 (48%), BLI in 12 (30%), beta-2m in 29 (74%) and transferrin in 8 (20%) of 40 adenocarcinoma patients. Elevation in urinary Igs, BLI or beta-2m was associated with a significantly shorter survival. The four urine markers correlated well with serum chromogranin A but not with serum prostate-specific antigen. Results suggest that these urine markers are elevated with high frequency in advanced prostate cancer. PMID- 21544422 TI - Tenascin in human neoplasia. AB - Tenascin (TN), a recently characterized extracellular matrix protein, largely confined to the process with the development of embryo in areas of epithelial mesenchymal interactions, developing neural tissues, bone and cartilage where there are morphogenetic movements and tissue patterning, has a highly restricted expression in adult tissues. The function(s) and molecular mechanisms of enhanced expression of TN in neoplastic lesions, however, remain unclear. Tissue specimens of human neoplasia obtained from 1050 cases of biopsy or surgery and their representative fetal and normal adult tissues were evaluated for immunoreactivity of TN using seven different clones of monoclonal antibodies in a three stage streptavidin biotin immunoperoxidase method. The normal epithelial lined structures such as the mucous membrane and skin had a thin delicate immunoreactive band just beneath the basement membrane at the epithelial mesenchymal interface. Hyperplastic or dysplastic lesions of the epithelium, such as leukoplakia of the oral mucosa, senile keratosis and intraepithelial carcinoma of skin showed an enhanced expression of TN extending down into the connective tissue where the degree of enhanced expression correlated with increasing hyperplasia or dysplasia. The squamous cell carcinoma and adenocarcinoma of different organs, both at the primary site and in lymph node metastasis, showed a widespread stromal immunoreactivity and the expression was affected by infiltration of inflammatory cells, fibrous tissue reaction and tumor cell differentiation. There was heterogeneity in the expression of TN in benign epithelial neoplasms, squamous cell carcinoma and adenocarcinoma which varied in different areas of the same tumor specimen ranging from no reaction to intensely reactive areas. The undifferentiated carcinomas often had low expression in the stroma. The non-epithelial or mesenchymal tumors such as chondrogenic, osteogenic, myogenic, neurogenic, vascular and other miscellaneous neoplasms also had an enhanced expression of TN. When the immunoreactivity of seven different monoclonal antibodies to detect TN were compared, the pattern of expression of TN with different monoclonal antibody in majority of the cases were identical and equivocal, but there were slight differences in the intensity of staining. Using a single monoclonal antibody nearly 94% of the cases of human neoplasia showed an enhanced immunoreaction for TN. In conclusion, the results of the present study when combined with our previous in vitro study (Shrestha et al, Eur J Cancer Oral Oncol, in press) suggest that the enhanced expression of TN in vivo in a wide variety of neoplastic lesions of both epithelial and non-epithelial in origin may affect tumor growth, differentiation, vascularity, cellular adhesion, invasion and metastasis. PMID- 21544423 TI - Expression of urokinase and urinary trypsin inhibitor in metastatic and non metastatic murine Lewis lung carcinoma cells. AB - The murine Lewis lung carcinoma 3LL cells give rise to spontaneous and experimental lung metastasis in C57BL/6 mice. Tumor cells maintained by serial subcutaneous transplantation in mice retain their ability to form lung metastasis, while cells carried in vitro loose metastatic potential with time. In order to obtain the non-metastatic subline, 3LL cells selected for its high lung colonization potential was grown continuously in vitro for 24 weeks. The present study was undertaken to characterize the expression of both urokinase-type plasminogen activator (uPA) and urinary trypsin inhibitor (UTI) in the non metastatic (3LL(-)) and the metastatic (3LL(+)) cells. Both cells were tested on the Matrigel for invasive ability using a modified Boyden chamber and assayed for expression of uPA and UTI. The 3LL(+) cells secreted 5 times more uPA (6.25 mu g per 10(6) cells per 24 h) than the 3LL(-) cells (1.25 mu g per 10(6) cells per 24 h). The 3LL(+) cells, which expressed 2 times more cell-surface receptor-bound enzymatically active uPA (0.32 +/- 0.06 OD405) than the 3LL(-) cells (0.15 +/- 0.03 OD405), had larger amounts of cell-surface receptor-bound uPA. On the other hands, UTI levels in the conditioned media was decreased 25-fold in the 3LL(+) cells (0.05 mu g/10(6) cells/24 h) compared to the 3LL(-) cells (1.25 mu g/10(6) cells/24 h). The 3LL(-) cells expressed significantly higher levels of cell associated UTI as indicated by a cell ELISA (3LL(+), 0.30 +/- 0.04 OD450; 3LL(-), 1.30 +/- 0.21 OD450) and by Western blot analysis. Metastatic competence in the 3LL(+) tumor model is associated with increased expression and release of uPA, as well as decreased UTI production, consistent with a more invasive phenotype. These data support our hypothesis that UTI may contribute to the inhibition of uPA expression in tumor cells. PMID- 21544424 TI - Human lung carcinoma cells engineered to release IL2, IL7, GM-CSF and TNF alpha. AB - A human lung adenocarcinoma cell line (LC89) was transduced with the IL2, IL7, GM CSF and TNF alpha genes by retroviral vector mediated infection. This induced the constitutive and stable release of all cytokines. No difference or modulation was found in the parental and gene transduced LC89 cells with regard to cytokine receptor expression, in vitro cell growth and proliferation, nor in cell surface expression of different adhesion molecules. Following injection into immunosuppressed nu/nu mice, IL2 gene transduced LC89 cells lost their tumorigenic potential. LC89 cells engineered to release IL7 and TNF alpha grew in nu/nu mice, but in 40% of the animals tumor regression was observed. GM-CSF gene transduced LC89 cells showed a tumorigenic capacity identical to that of the parental clone. The levels of TGF beta(1) released by IL2, IL7 and GM-CSF gene transduced LC89 cells were markedly reduced compared to those of the parental and TNF alpha gene transduced cells. The results of this study support the concept that human lung cancer cells engineered with different cytokine genes maintain their intrinsic morphologic and proliferative features, while their tumorigenic and immunosuppressive capacities can be profoundly down-modulated. Both these effects are optimally achieved following insertion of the IL2 gene, suggesting that vaccination protocols with IL2 gene transduced tumor cells may be considered for the management of human lung cancer. PMID- 21544425 TI - Matrix metalloproteinase 2 and 9 in esophageal cancer. AB - To search for the biochemical properties of esophageal carcinoma relevant to its aggressive behavior, we studied metalloproteinases released from surgical specimens of the carcinoma. In an assay with [H-3]-labeled gelatin, esophageal carcinoma tissues showed gelatinolytic activities clearly higher than those of paired normal mucosae. EDTA and TIMP-1 could strongly suppress these activities, suggesting that the activities belong to metalloproteinases. In addition, levels of TIMP-1 expression did not show good correlation with these activities, suggesting that tumor-specific elevation of gelatinolytic activity depended on metalloproteinase per se rather than the suppression of TIMP-1-secretion. By zymographic analysis, two gelatinase bands of 82- and 62-kDa were found specifically in carcinoma tissues, in addition to the other 6 bands detected both in normal and carcinoma tissues. Immunoprecipitation and immunoblotting of gelatinases with anti-MMP-9 or anti-MMP-2 monoclonal antibody, and treatment of the enzymes with APMA showed that these 82- and 62-kDa gelatinases were cleaved products of MMP-9 and MMP-2, respectively. These results imply that enhanced secretion and proteolytic activation of MMP-2 and MMP-9 take place specifically in the esophageal carcinoma tissues. Moreover, the levels of gelatinolytic activity expressed good correlation with the organ metastasis rate of the carcinoma, suggesting that MMPs play an important role in tumor metastasis. PMID- 21544426 TI - Hepatitis B virus DNA integration frequently observed in the hepatocellular carcinoma DNA of hepatitis C virus-infected patients. AB - Human hepatitis B virus (HBV) and hepatitis C virus (HCV) are two major etiologic agents of chronic hepatitis, which is closely related to the development of hepatocellular carcinoma (HCC). We investigated the role of HBV coinfection in ongoing HCV-related liver diseases in HCV-infected patients. We found a high prevalence of anti-HBc in anti-HCV-positive/HBsAg-negative HCC patients and also found a close correlation between anti-HBc positivity and integration of HBV DNA into HCC DNA of anti-HCV-positive/HBsAg-negative patients. The present data suggest that integrated HBV DNA may play an important role in the development of HCC in the anti-HCV-positive/HBsAg-negative patients carrying the anti-HBc antibody. PMID- 21544427 TI - Postoperative immunocompetence and immunosuppressive effect of rat liver tumors. AB - To investigate the kinetics of postoperative immunocompetence and immunosuppressive effects of rat liver tumors, we examined natural killer cell cytotoxicity and blastogeneses to phytohemagllutinin-P, concanavalin A, and lipopolysaccharide on 1-, 2-, 3-, 5-, 7-, 9- and 14- postoperative days (-POD) after partial hepatectomy in tumor-bearing or healthy rats. The immunosuppressive effects of the tumor were observed on all the parameters examined, particularly from 1- to 3-POD and on 14-POD. Surgical stress induced immunosuppression in the early postoperative stage which lasted over 1 week, and the immunosuppression was seriously affected by the presence of the tumor. The present study suggests that surgery without curability is closely related to enhancement of the growth of the remaining or occult cancer, leading to worse survival. PMID- 21544428 TI - Pathological comparison between spontaneously developed and chemically induced liver cancers in LEC rats with hereditary hepatitis. AB - To investigate the pathological differences between spontaneously developed and chemically induced liver cancers in LEC rats with hereditary hepatitis, eight week-old LEC rats were fed 0.06% or 0.03% of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) for 12 weeks, and then fed basal diet. Spontaneous liver cancers occurred in 60.4% of the LEC rats, while 3'-Me-DAB induced cancers in all LEC rats. The survival periods of chemically (0.06%) treated LEC rats were significantly shorter than non-treated rats. The chemically-induced cancers were strongly related to Edmondson classification. Metastasis and transplantability of the chemically-induced cancers were higher than spontaneous cancers. LEC rats are highly susceptible to the chemical carcinogen with the initiated status of hepatocarcinogenesis. PMID- 21544429 TI - Mechanisms of the formation of the peritoneal dissemination in gastric cancer. AB - To clarify the mechanisms of the formation of peritoneal dissemination, a new animal model by the i.p. inoculation of highly metastatic gastric cancer cell line MKN-45-P was developed. Peritoneal dissemination with bloody ascites was found in 100% of nude mice, injected 1x10(7) MKN-45-P cells in suspension into the peritoneal cavity. By a highly sensitive method for specific detection of metastasized human tumor cells in nude mice using polymerase chain reaction, a human beta-globin-related sequence in the DNA from various parts of the peritoneum was specifically amplified and detected by gel electrophoresis and by a specific oligonucleotide probe. Greater omentum showed a strong signal of the amplified fragments of human beta-globin gene from the 1st day and the signals gradually increased. The signals in the gonadal fat, mesentery and ovarium could be weakly detected on the Ist day, transiently decreased on the 3rd day, and then increased from the 7th day. In the diaphragm, and abdominal wall, signals could be detected from the 7th day. In contrast, small intestine and colon did not show any human beta-globin signals. In greater omentum and gonadal fat, cancer cells were selectively detected in the milky spots stained by activated carbon on the 3rd day. In the diaphragm, cancer cells adhered to the small pores termed stomata, and invaded into the subdiaphragmatic lymphatic lacunae connected with stomata. From the 3rd day, mesothelial cells of the abdominal cavity became round and separated, resulting in the exposure of the underlying connective tissue. MKN 45-P cells were found to adhere to the naked areas of the submesothelial connective tissue. From these results, we conclude that the major metastatic route of the peritoneum may be firstly through milky spots, secondly through the diaphragmatic stomata, and thirdly by the adhesion to the naked connective tissue exposed after shrinkage of the mesothelial cells. The third process may be related to the interaction between some adhesion molecules and their ligands. PMID- 21544430 TI - Cell cycle-specific patterns of ADP-ribosylation and the effect of ionizing radiation. AB - The enzyme poly(ADP-ribose)polymerase (PARP) has been implicated in several cellular processes by the demonstration of ADP-ribosylation of proteins which play a role in cellular repair of DNA damage, response to ionizing radiation and apoptosis. In addition, ADP-ribosylation has been shown to play a role in cell cycle progression. To investigate the role of ADP-ribosylation in cell cycle progression, we have synchronized human squamous carcinoma cells (SQ-20B) and examined the changes in the pattern of ADP-ribosylation of proteins through the stages of the cell cycle. Moreover, synchronized SQ-20B cells were irradiated to determine the effects of irradiation on the patterns of ADP-ribosylation through the cell cycle phases. These studies showed the ADP-ribosylation of 3 specific proteins (70, 68 and 40 kDa) to change through the cell cycle. Furthermore, ionizing radiation altered the ADP-ribosylation patterns of these 3 proteins. Using a double antibody method, we determined that cyclins A, B1 and D1, cdc2 and PCNA are not modified by ADP-ribosylation. PMID- 21544431 TI - G(M3) inhibits murine MET-2 tumor invasion and growth. AB - G(M3) has some important roles in cell-to-cell interaction and has proved to have an optimal concentration for fibronectin mediated cell adhesion. G(M3) content in murine bladder tumor (MBT-2) assessed by thin-layer chromatography was similar to human invasive bladder tumor. From glycolipid composition also, MBT-2 is considered as an appropriate model for human invasive bladder tumor. Anti-tumor effect of locally administered G(M3) On MBT-2 tumor was investigated. MBT-2 cells were injected subcutaneously into the right hind limb of CH3/HeSlc female mice on day 1. Tumor bearing mice were randomly placed on day 8 into G(M3) treatment, G(D3) treament, sialic acid treament and control groups. G(M3) was administered between tumor and fascia at 10 mu g in 0.1 ml, 1 mu g in 0.1 ml from day 8 to day 20 every other day, 7 times in total. Control group was given 0.1 mi of saline. G(D3) group was given 12.5 mu g of G(D3), and sialic acid group 2.5 mu g of sialic acid. The relative growth rates of control group, G(M3) 1 mu g group, G(M3) 10 mu g group on day 22 were 139+/-74, 56+/-39, 22+/-14, respectively, and statistically significant among these three groups (Mann-Whitney's U test p<0.01). There were no significant difference between control and G(D3) or sialic acid group. All of the 15 control mice had muscle invasion, however, of the 19 G(M3) 10 mu g administered mice, only 4 had muscle invasion. The incidence of muscle invasion between these 2 groups was statistically significant in chi(2) test (p<0.001). Locally administered G(M3) inhibited both invasion and growth of MBT-2 tumor. This mechanism could be explained by an important role of G(M3) in cell adhesion mediated by integrin and fibronectin interaction. These results may be applied to antiadhesion therapy of human invasive bladder tumor. PMID- 21544432 TI - Oligonucleotides complementary to c-myb messenger RNA inhibit growth and induce apoptosis in human Burkitt lymphoma cells. AB - A 24-mer (antisense) phosphorothioate oligonucleotide (ODN) corresponding to the codons 2-9 of the c-myb gene was evaluated for its effects on the growth of a human Burkitt lymphoma cell line (Raji) in vitro. Raji cells incubated with different concentrations of c-myb antisense ODN (5-15 mu g/ml) for 24-72 h showed a significant dose-dependent decrease in growth. The same concentrations of control (sense) or scrambled c-myb phosphorothioate ODNs did not inhibit Raji cell growth. The c-myb antisense ODN, but not the control ODNs, significantly decreased c-myb mRNA levels in treated cells as determined by RT-PCR. Additionally, the c-myb antisense ODN induced apoptosis of Raji cells as demonstrated by i) flow cytometry to enumerate the A(o) (apoptotic cell population) population of propidium iodide stained cells; ii) electron microscopy to evaluate the cell morphology; and iii) DNA fragmentation pattern. Thus, an antisense c-myb ODN causes significant growth inhibition of Burkitt lymphoma cells, and one mechanism of growth inhibition is the induction of apoptosis of the lymphoma cells. In addition, antisense c-myb ODN did not reduce CFU-GM or BFU e colony-forming ability of normal hematopoietic stem/progenitor cells. Because the inhibition is sequence-specific and Burkitt lymphoma cell selective, evaluation of the therapeutic effects of c-myb antisense ODN against Burkitt lymphoma is warranted. PMID- 21544433 TI - Sequential expression of myc-, ras-, oncogene products and EGF receptor during DMBA-induced tongue carcinogenesis. AB - The mechanism leading to development of oral cancer has not been completely understood. It is currently believed that alternation of a number of genes can result in the development of epidermoid carcinomas. In this investigation, we used a 9,10-dimethyl 1,2-benzanthracene (DMBA)-induced carcinogenesis in a hamster tongue model to investigate the expression of c-myc, c-Ha-ms proteins and epidermal growth factor receptor (EGFr). During the DMBA-carcinogenesis of the tongue, the number of c-myc protein positive cells were increased in epithelial dysplasia and elevated throughout the process of tumorigenesis. The expression of c-Ha-ras protein was detected in normal epithelium. The level of c-Ha-ras protein expression was decreased in the dysplastic stage, and it was almost negative in squamous cell carcinomas. Detection of EGFr overexpression occurred only after 1 4 weeks of DMBA treatment, at a very early stage of tumor development, and increased through carcinogenesis varying individually within the malignant tissues. These results suggest that c-myc protein and c-Ha-ras protein expression may have an important role in malignant transformation, and the overexpression of EGFr can be correlated to very early stages of tumor development in the DMBA induced in vivo tongue carcinogenesis. PMID- 21544434 TI - Thymostimulin treatment of hepatocellular carcinoma on liver cirrhosis. AB - Hepatocellular carcinoma (HCC) on liver cirrhosis (LC) is a neoplasm with a poor prognosis. Only 10-36% of patients have resectable tumors at presentation, systemic chemotherapy is seldom useful and loco-regional treatments are feasible only in selected cases. On the basis of the possible role of depression of immune function in the pathogenesis of HCC on LC, we employed thymostimulin in the treatment of patients with unresectable HCC on LC, with the aim of influencing the course of the disease. Forty-six consecutive patients with HCC were enrolled from January 1987 to December 1993. All patients, 36 males and 10 females, with a median age of 67 years (range 58-82) had coexisting LC. All patients were treated with thymostimulin (TP-1 Serono) at doses of 70 mg/day i.m. five times a week until disease progression. Eleven patients achieved an objective response, with an overall response rate of 24%. Six patients obtained a CR (13.0%) with a median duration of 19+ months (range 5+/-23). Five patients (11%) achieved PR with a median duration of 10 months (range 7+/-22). Six patients (13.0%) presented MR (median duration: 12.5 months) and 12 (26.0%) had SD (median duration: 8 months). In 17 patients (36.9%) the disease progressed. Thymostimulin treatment was well tolerated and no major side effect was observed. Thymostimulin treatment can be considered a new promising therapy for advanced HCC. PMID- 21544435 TI - Pleiotropic functions of ETS-1 (Review). AB - ETS-1 is a cellular homologue of the viral ets oncogene of the E26 virus and functions as a sequence specific transcription factor. It plays an important role in cell proliferation, differentiation, lymphoid cell development, transformation, angiogenesis and apoptosis. ETS-1 may control the expression of critical genes involved in these processes by binding to ets binding sites present in their transcriptional regulatory regions. Recent progress in understanding the multiple functions of ETS-1 is summarized in this review. PMID- 21544436 TI - alpha-Interferon potentiates the growth inhibitory effects of anti-transferrin receptor monoclonal antibodies. AB - We have demonstrated that interferon-alpha 2 recombinant (IFN alpha) inhibits the growth and modulates the expression of the receptor for transferrin (TRF-R) in human epidermoid carcinoma KB cells. Receptor upregulation results in the reconstitution of intracellular iron levels in the IFN alpha-treated cells. Several anti-TRF-R murine monoclonal antibodies (MAbs) have been generated which induce tumor cell growth inhibition through blockade of receptor function. We have evaluated by MTT assay the effect of anti-TRF-R 42/6, E2.3, A27.15 and D65.30 MAbs given in combination with IFN alpha on the growth of human epidermoid carcinoma KB cells. We found that IFN alpha and A27.15 MAb induced a synergistic antiproliferative effect on these cells. These results suggest that IFN alpha may potentiate the antitumor efficacy of TRF-R-targeted therapy. PMID- 21544437 TI - New recurrent structural chromosome aberrations in non-Hodgkin's lymphoma. AB - Identification, and subsequent molecular dissection, of recurring structural chromosome aberrations has led to a substantial increase in our understanding of lymphomagenesis. Thus we have reviewed the published literature on cytogenetic findings in non-Hodgkin's lymphoma (NHL) in search of previously unrecognized recurring chromosome aberrations. Thirty-four balanced rearrangements, including 32 reciprocal translocations and two inversions, and 25 unbalanced translocations, each observed in at least two different cases of NHL and previously unrecognized as recurring, have been ascertained. Among the 32 reciprocal translocations, 10 involved bands harboring one of the immunoglobulin (Ig) genes. In nine of these, the following bands or regions may be sites of putative oncogenes that are activated through juxtaposition to Ig loci: 1p35-36, 5q11, 6q21, 9p24, 12q13, 13q11, 15p11, 15q21-22 and 15q23-24. In one instance, t(21;22)(q22;q11), Ig lambda chain gene involvement is unlikely, because the t(21;22) has been identified in two NHLs of T-cell lineage. An additional four reciprocal translocations and one inversion affected the band 3q27, containing the BCL6/LAZ3 gene, and one of the following bands: 1q25, 3q12, 6p21, 7p13, 12p13. Three other reciprocal translocations had the breakpoint at 11q13 known to harbor the BCL1 gene. Among the 16 remaining balanced rearrangements, one translocation involved a band containing a gene for a T-cell receptor, i.e. 7q35. Almost all chromosomes in the human karyotype (except 3, 8, 20 and 21) were implicated in at least one of the 25 recurrent unbalanced translocations. The distribution of resulting chromosomal imbalances is highly nonrandom, however, because 17 translocations involved the long arm of chromosome 1 (1q) invariably resulting in partial trisomy of 1q. We suggest that these unbalanced translocations of Iq are best regarded as non-specific secondary abnormalities that may contribute to lymphoma progression. PMID- 21544438 TI - Comparison of different antisense oligonucleotides against the BCR/ABL junction in chronic myelogenous leukemia. AB - The activity of the BCR/ABL hybrid gene is associated with a growth advantage of the chronic myelogenous leukemia (CML) stem cell. Suppression of BCR/ABL hybrid gene expression can be a valuable tool for leukemic cell purging. Antisense oligonucleotides (ODNs) have the capacity to specifically downregulate gene expression. Data reported on the effect they have on BCR/ABL hybrid gene expression are controversial. We present data illustrating that prolongation of ODN half-life by means of chemical or sequence modification has only limited specific growth suppressive effect on BCR/ABL-positive clonogenic cells in vitro. Compared to unmodified phosphodiester ODNs (PO-ODNs) spanning the BCR/ABL junctions, modified ODNs with either a 3'-GC-clamp (GC-ODNs) or ODNs with one 3' inverted nucleotide (3'-3' ODNs) to prevent 3'-exonuclease degradation, showed significantly prolonged extra- and intracellular half lives and different subcellular distributions in CML cell lines. In clonogenic assays from patients with CML, the modified ODNs were to some extent able to reduce colonies expressing BCR/ABL (GC-ODNs >3'-3'-ODNs >PO-ODNs). This difference did not become significant statistically. We demonstrate a substantially diminished hybridization efficacy of the modified antisense ODNs used, which may serve as a possible explanation for the failure to augment the leukemic cell purging efficacy. PMID- 21544439 TI - Relationship of cellular energy parameters to cytotoxicity for AG-17, lonidamine and cyclocreatine in four human tumor cell lines. AB - The cytotoxicity and effect on cellular energy parameters of AG-17, lonidamine and cyclocreatine were examined in four human tumor cell lines: MCF-7 breast carcinoma, SW2 small cell lung carcinoma, A2058 melanoma and A2058-055, a subline of A2058 transfected with the creatine kinase gene. Although these cell lines had widely differing levels of creatine kinase activity, there were no differences in their sensitivity to cyclocreatine. The MCF-7 cells were most sensitive to AG-17 and to lonidamine with 90% cell killing by 50 mu M and 115 mu M of the drugs after 72 h exposure, respectively. The percent of coupled respiration in the cells was 60-70% in the absence of drug exposure and was decreased to 30-40% after 24 h of exposure to each of the drugs. Cytochrome C oxidase activity was decreased by 8- to 9-fold in the high creatine kinase expressing cell lines (SW2 and A2058-055) after exposure to AG-17 (250 mu M) for 24 h. Lonidamine (250 mu M) exposure decreased hexokinase activity in the cells to 30-40% of normal in 24 h. Extra-cellular lactate levels increased most markedly in the media of the MCF-7 and SW2 cells exposed to AG-17 (100 and 250 mu M) for 24 h. Although no specific enzymatic target was effected, cyclocreatine exposure resulted in a decrease in the ATP content of the cells, especially in the MCF-7 cells where ATP was decreased to 30% of normal upon 24 h exposure to the drug. These results provide a rationale for the use of these agents in combination with each other or in combination with cytotoxic anticancer therapies targeted on cellular DNA. PMID- 21544440 TI - Early responses of SiHa human squamous carcinoma cells to hypoxic signals. AB - We compared the responses of c-Jun/AP-1 transcriptional complexes with those of NF-kappa B, an established hypoxia-inducible transcriptional complex, in hypoxic SiHa human squamous carcinoma cells. We observed that NF-kappa B was activated rapidly, while AP-1 activation was detectable only after prolonged hypoxia. However, in parallel with NF-kappa B activation, hypoxia induced a protein kinase activity that could phosphorylate the transactivation domain of the ATF-2 transcription factor in vitro. Taken together, these experiments indicate that NF kappa B can rapidly transduce hypoxic signals through increased DNA-binding and transactivation activities, whereas specific AP-1 (ATF-2/c-Jun) complexes may be activated under the same hypoxic conditions by a stress-reponsive MAPK pathway. PMID- 21544441 TI - Establishment of an in vitro cell model system to study human prostate carcinogenesis. AB - A positive family history of prostate cancer is a risk factor for this disease, suggesting that alterations of certain genes may play an important role in the development and progression of prostate cancer. However, genetic alterations responsible for initiation and acquisition of metastatic phenotypes by prostate cancer are not well defined. We have observed a consistent change in chromosome 5 in an in vitro cell model of human prostate carcinogenesis in which the near diploid cells from the surrounding tissue of an adenocarcinoma of the prostate obtained from a 42-year-old patient were subjected to in vitro cell culture and passages. We have examined three different passages of this cell strain by conventional and molecular cytogenetic methods and have seen an increased number of alterations in chromosome 5 in higher passage cells, with accompanying changes in cell morphology. In late passages of this cell line, no cell showed two normal copies of chromosome 5 as analyzed by G-banding and fluorecent in situ hybridization (FISH). The long arm (q) of chromosome 5 was either missing or involved in structural rearrangements. This observation suggests that the q arm of chromosome 5 may carry a tumor suppressor gene(s) that is well-expressed in normal prostate tissue, but when one of these tumor suppressor gene(s) is mutated or deleted and its encoded mRNA and protein are differentially expressed or not expressed at all in the prostate cells, then it may lead to initiation of tumor growth and development. Cytogenetic analyses of early passage cells in this cell strain revealed that approximately 78.8% of metaphases were normal, with a 46,XY chromosome constitution, and 21.2% of cells had clonal alterations mostly of chromosomes 5, 7, 8, 15, 16 and Y. In the middle passages, abnormal cells increased in number (78.26%) and also showed a large number of chromosomal changes. In the late passages, all cells showed structural and numerical abnormalities of the same chromosomes, in addition to some new markers; no cells were found to have a normal karyotype. These chromosomal aberrations could be considered early markers of prostate carcinogenesis. Some of the markers present in late passage cells were similar to those reported in a well-characterized prostate cancer cell line, LNCaP. PMID- 21544442 TI - Immunohistochemical detection of CDKN2, retinoblastoma and p53 gene products in primary astrocytic tumors. AB - The expressions of p16(INK4), retinoblastoma (RB) and p53 protein were immunohistochemically examined in 70 primary astrocytic tumors. In 58 patients with high grade astrocytoma (18 anaplastic astrocytomas and 40 glioblastomas), 30 (51.1%) and 15 (25.9%) cases were undetectable for p16(INK4) and pRB, respectively, but their lack occurred infrequently in 12 low grade astrocytomas. The expression of p16(INK4) was inversely correlated with that of PRB, especially in glioblastomas. Accumulation of p53 was detected in 32 (45.7%) of 70 cases without any dependence on the grade. A deregulation of three tumor suppressor gene products most often occurs singly. Only patients with negative staining for pRB were significantly associated with a shorter survival time. Our findings suggest that loss of functional pRB at the G1/S check point may represent an important step in glioblastoma development and have a stronger negative impact on clinical outcome than p16(INK4) or p53 aberrations. PMID- 21544443 TI - MDM2 overexpression in benign and malignant lesions of the human breast. AB - MDM2 overexpression has been detected in women with benign or cancerous lesions of the breast. Immunohistochemical methods were used to identify overexpression in 11 of 27 benign cases (41%) and 15 of 22 (68%) cancer cases. MDM2 overexpression correlated well with immunohistochemically detected estrogen receptor (ER), suggesting that expression of these proteins was coordinately regulated. To test this, the MCF-10A human breast cell line, negative for both ER and MDM2 expression, was transfected with a wild-type ER. Following transfection, both ER and MDM2 were strongly expressed in two independent clones. Expression of both was reduced in the presence of increasing concentrations of estradiol (10( 10)-10(-8) M) thus, estrogen may be involved in regulation of MDM2 expression in proliferative breast lesions. PMID- 21544444 TI - Differential expression between PAX-6 and EN proteins in medulloblastoma. AB - A collection of 28 medulloblastomas was analyzed for expression of the developmental control genes PAX-6 and EN by immunohistochemical staining. Sixteen medulloblastomas expressed both EN and PAX-6 but, when differentiation could be assessed in the positive areas, PAX-6 is expressed in the less differentiated cells. Since Drosophila en encodes a negative regulator, we overexpressed the chicken en-1 in retinal pigmented epithelium cells. This resulted in Pax-6 down regulation. These results suggest a regulatory loop between PAX-6 and EN, two molecular markers of medulloblastoma. PMID- 21544445 TI - Gastric leiomyosarcoma (Review). AB - Gastric leiomyosarcoma is a rare malignant tumor of the stomach which has seldom been described in the literature. Three patients, aged 47, 55, and 72 at time of presentation, were treated by the authors between 1985 and 1989. Clinical and pathological findings, treatment and outcome are discussed. A literature review is provided to establish a correlation between clinical and pathological findings, surgical and oncological treatment, and rate of survival. PMID- 21544446 TI - Expression of the FLT4/VEGFR3 receptor tyrosine kinase encoding gene in hepatic tumors. AB - The FLT4/VEGFR3 tyrosine kinase receptor belongs to a class of receptors for growth factors of the vascular endothelial growth factor family and is important for the biology of lymphatic endothelium. It may play an important role in tumor growth. We have looked for the expression of the FLT4 gene in tumors of various origins. FLT4 expression was not found except in some particular type of tumors: mouse hepatic tumors but not cell lines were shown to expressed Flt4 at a high frequency while Flt4 mRNA was absent or weakly expressed in normal liver, suggesting that Flt4 de novo expression in liver nonparenchymal cells participates in tumor development of this tissue. PMID- 21544447 TI - Roles of VLA-2 and VLA-3 on the formation of peritoneal dissemination in gastric cancer. AB - To clarify the mechanisms of the metastasis on the peritoneal surface from gastric cancer, a novel ex vivo co-culture system using human greater omentum and a highly metastatic cell line, MKN-45-P was developed. MKN-45-P was established from a gastric cancer cell line of MKN-45 by the progressive growing of the intraperitoneal passages. The differences of the expression of metastasis related genes between MKN-45 and MKN-45-P were examined by RT-PCR. Cancer cells adhered only to the naked area of the submesothelial basement membrane, which was exposed by the shrinkage and exfoliation of mesothelial cells of the omentum. The expressions of integrin alpha 2 and alpha 3 subunits in MKN-45-P were extremely elevated compared to those in MKN-45. Integrin beta 1 subunit expression did not change during the intraperitoneal passages. Anti-beta 1 integrin subunit antibody significantly inhibited the adherent number of MKN-45-P on the omentum. These results indicate that VLA-2 and VLA-3 may have an important role in the formation of the peritoneal dissemination from gastric cancer. PMID- 21544448 TI - The monetary costs of childhood cancer to the families of patients. AB - The medical costs of cancer treatment are well described, but there are few reports of expenses incurred by families of children with malignant disease. The objective of this study was to describe the monetary costs borne by families of patients with childhood cancer and to determine whether these costs represent an important component of the burden of illness. Families completed a prospective diary survey about daily expenses incurred during each sample week of therapy. We also undertook a retrospective, cross-sectional questionnaire survey about expenses, incurred during the entire duration of treatment, associated with major or one-time cost items. Seventy families of children treated for high risk acute lymphoblastic leukemia, 19 families of children treated for Wilms' tumor stages 2 5, and 16 families of children treated for neuroblastoma stages 3 and 4 completed diaries or questionnaires detailing the costs resulting from the diseases and their treatment. The mean total expenses (in 1986 Canadian dollars) incurred by families of childhood cancer patients over the entire course of therapy are $26,070 for acute lymphoblastic leukemia? $20,074 for Wilms' tumour, and $10,376 for neuroblastoma. On-going weekly costs rather than major one-time purchases account for the largest share of expenses. Overall, in spite of universal first dollar coverage for medical care in Canada, family-borne costs during the course of these illnesses are at least one-third of the average family's after-tax income. PMID- 21544449 TI - Predictors of the interval between onset of symptoms and first medical visit in patients with digestive tract cancer. AB - Lack of effective population screening programmes for digestive tract cancer makes a prompt diagnosis of symptomatic patients the primary option for early detection. The objective of the study was to analyze the characteristics and determinants of the interval between the first medical symptom and the first medical visit (ISV) in a sample of symptomatic patients of mid-low socioeconomic level admitted to hospital for a digestive tract cancer. During two years, 183 patients were personally interviewed with a structured questionnaire designed to elicit initial symptoms of digestive cancer. Fifty-seven percent consulted a physician during the first month after onset of symptoms, and over two-thirds did so within the first 2 months, but it took more than 3 months for 22.4% of the patients. In univariate analyses, the ISV was longer among patients illiterate, unemployed and in the lower social classes. The interval was also significantly longer when the physician-interviewer judged that the patient did not correctly identify the first symptom (p<0.05). In multivariate analyses, the chance of a longer ISV was 2.8 times higher in men; 16 times higher in unemployed patients; 9 times higher in patients with a first symptom of the lower digestive tract; and it increased 8-fold in subjects who attributed no importance to the first manifestation (all p<0.05). In spite of virtually universal health coverage, social factors seemed to act as barriers to seeking medical help in a subgroup of patients. Their procrastination was also related to the nature of the initial symptoms. Achieving an early clinical detection of digestive cancers may be difficult in some segments of the population, and may require substantial improvements in access to and the efficiency of the health system. PMID- 21544450 TI - P-glycoprotein-associated resistance to taxol and taxotere and its reversal by dexniguldipine-HCl, dexverapamil-HCl, or cyclosporin A. AB - A series of different human MDR (multidrug-resistant) cell lines including a HeLa MDR1 transfectant which exhibit high overexpression of the MDR1/P-glycoprotein gene, but no enhanced expression of the MRP (multidrug resistance associated protein) gene, showed different ratios of relative resistances to the taxanes taxol and taxotere. Using these cell lines the chemosensitizing efficacies of several structurally different chemosensitizers, i.e. the dihydropyridine dexniguldipine-HC1 (B8509-035), its main pyridine metabolite M1 (B8909-008), the cyclic peptide cyclosporin A, or the phenylalkylamine dexverapamil-HCl, were examined applying a 72 h tetrazolium based colorimetric MTT-assay, or a 96 h sulforhodamine B assay. Remarkably, we observed in some instances that the modulating efficacy of a particular chemosensitizer was strongly dependent on the cell line used for experimentation. Thus, dexniguldipine-HCl efficiently modulated taxane resistances of the ovarian carcinoma MDR cell line 2780AD in the submicromolar concentration range, whereas cyclosporin A and the other chemosensitizers were rather ineffective. Dexniguldipine-HCl or cyclosporin A, however, both showed a similarly strong modulating activity on the HeLa-MDR1 transfectant in clear contrast to the effects observed using the pyridine B8909 008, or dexverapamil-HCl, respectively, at the same final concentrations. Our results point to additional, as yet unidentified factors beyond the expression levels of P-glycoprotein which could contribute to the susceptibility of MDR cells to a combined treatment using taxanes and different chemosensitizing compounds. This result appears to be important considering the clinical application of chemosensitizers for combination therapy of tumors of different origin. PMID- 21544451 TI - HER-2/neu in bladder carcinoma. AB - A total of 66 bladder cancer patients were studied to verify possible relationships between HER-2/neu alterations and pathological characteristics, and to define a poor prognosis patient subgroup with respect to time to recurrence, time to progression and survival. Tumor and healthy tissue specimens were analyzed for HER-2/neu DNA amplification and protein overexpression by Southern and Western blot techniques and evaluated statistically. 13% of cases were amplified and 39% were overexpressed. HER-2/neu alterations were not significantly associated with pathological staging or tumor grading. Multifocal tumors had a higher percentage and overexpression with respect to monofocal tumors. Actuarial analyses did not show a significant statistical correlation between HER-2/neu amplification and overexpression and clinical outcome. Clinical evaluation of HER-2/neu status showed that this gene is not related to tumor relapse, progression or patient survival. PMID- 21544452 TI - Decreased expression of p16 gene in gastric cancer. AB - We analyzed gastric cancers for p16 gene alterations. Homozygous deletion of the p16 gene was found in 1 of 8 gastric cancer cell lines and none of 20 primary gastric cancers. Mutations of the p16 gene were not detected in exon 1-3. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed decreased or no expression of the p16 gene in 1 of 8 cell lines (12.5%) and in 8 of 20 tumors (40%), although no homozygous deletions or mutations within exon 1-3 were detected. These results suggest that the p16 gene may correlate to tumorigenesis due to decrease or loss of gene products in gastric cancers. PMID- 21544453 TI - Follicular thyroid cancer. AB - Patients with differentiated thyroid cancer generally have a good prognosis and high cure rates; however, subgroups of patients exist who develop progressive disease with significant morbidity and mortality. We analyzed the clinical outcome of patients with follicular thyroid cancer and distant metastases to define their presentation, impact of therapy and clinical outcome. A group of 44 patients with follicular thyroid cancer which had metastasized to the lungs or the skeleton was identified. All patients were treated at M.D. Anderson Cancer Center between 1965 and 1994. The group included 26 women and 18 men, with a median age of 56 years (range, 23 to 80 years). The primary tumor was limited to the thyroid in most cases. At the time of writing 13 patients were alive with metastatic disease a median of 43 months (range, 4 to 230 months) after diagnosis, while 27 patients died of thyroid cancer a median of 83 months (range, 4 to 238 months) after diagnosis. Bone pain was the chief complaint in almost all the 24 patients in whom distant metastases were present at diagnosis. In the 20 patients who initially presented with localized disease, distant metastases to the skeleton and/or lungs were detected after a median interval of 53 months (range, 8 to 216 months). Symptomatic spinal cord compression occurred in 13 patients and preceded their death by 4 to 34 months. Radioiodine uptake was seen in most bone metastases but in only about half of metastatic foci in the lungs. Radiotherapy was palliative and useful for bone metastases. We conclude that patients with follicular thyroid cancer and distant metastases have a distinct clinical profile that includes prominent skeletal and pulmonary involvement and substantial morbidity and mortality. Intensive multimodality therapy is required to optimize the clinical outcome. PMID- 21544454 TI - A morphometric study on the nuclear matrix of tumor cells in vitro. AB - Recently, we have demonstrated that two cervical carcinoma cell lines with different cell differentiation stages possessed different nuclear matrix stability. The nuclear matrix of poorly differentiated cells was more stable than that of the more differentiated one. In the present study, we further quantified the nuclear matrix density after treatment with different DNase I concentrations. Moreover, six more ovarian cell lines were also used to investigate the relationship between nuclear matrix stability and cell differentiation stages. Since the nuclear matrix is an important site for gene replication and transcription, the nuclear matrix stability can be used as an indicator to reflect these activities within the nucleus. PMID- 21544455 TI - HLA class I and neuroendocrine antigen expression in multidrug resistant small cell lung carcinoma cell lines. AB - Antigenic marker expression was studied in a series of eight small cell lung carcinoma (SCLC) cell lines, according to their histological subtype, classic or variant. These lines were obtained from human tumors xenografted into nude mice, originally derived from heterotransplanted tumor biopsy samples. We looked at an altered expression of HLA class I antigens, a battery of neuroendocrine antigens and the P-glycoprotein (Pgp) responsible for MDR1 encoded multidrug resistance, as markers of tumor malignancy. Three cell lines out of four of the classic subtype and two cell lines out of four of the variant subtype showed a lack or a low expression of HLA class I antigen. Recombinant interferon gamma (rIFN-gamma) treatment (100 U/ml, for 48 h) increased HLA class I expression of the cell lines differently, but did not induce an imbalance between HLA-A and HLA-B molecules as described in other tumor models. Neuroendocrine antigens were tested in six out of these eight lines, using a family of monoclonal antibodies developed against the cell membrane antigens of low passage cell lines derived from pleural effusions (de Leij et al, Cancer Res 45: 2192-2200, 1985). Globally, these antigens were more highly expressed in classic subtypes of SCLC. Neuroendocrine antigens corresponding to MOC-21 and MOC-32 monoclonal antibodies were weakly expressed in variant forms. Pgp expression was detectable with the JSB1 monoclonal antibody on the three variant SCLCs out of the six lines. Comparing two cell lines originated from the same patient before and after therapy, we showed that neuroendocrine reactivity to MOC-21 and MOC-32 was lost simultaneously with a gain of Pgp expression, and with a classic to variant histological transition. With regard to the clinical evolution, HLA class I expression and stimulation by rIFN-gamma was not related to malignancy. It appears that for variant forms, a low expression of neuroendocrine antigens detected by MOC-21 and MOC-32 monoclonal antibodies and a high level of Pgp predict for a poor prognosis. PMID- 21544456 TI - Antagonism of paclitaxel cytotoxicity by X-rays. AB - We have employed in vitro clonogenic assays and DNA flow cytometry to examine the effect of X-ray irradiation on the response of human tumor cells to paclitaxel. Irradiation caused the development of cell cycle delays in G1 and G2/M in the human breast MCF-7 and lung A549 adenocarcinoma cell lines. Irradiation given just prior to or concurrently with exposure to paclitaxel reduced cytotoxicity due to paclitaxel. For example, the surviving fraction of both MCF-7 and A549 cells was 0.03 after 24 h of exposure to 50 nM paclitaxel. However, if the cells were irradiated with 3 Gy just prior to the start of 24 h of paclitaxel exposure, the surviving fractions of MCF-7 and A549 cells were 0.08. Since 3 Gy alone reduced the survival of MCF-7 and A549 cells by 65% and 50%, respectively, the surviving fractions of MCF-7 and A549 cells were 7.6 and 5.3 fold higher after treatment with radiation and paclitaxel than would have been predicted if the cytotoxicities of the different treatments had been additive. Incubation of cells in 5 mM pentoxifylline after irradiation reduced the G2/M block induced by radiation and partially reversed the antagonism of paclitaxel cytotoxicity. These data show that radiation, by inducing cell cycle delays, can antagonize the cytotoxicity of paclitaxel. These results have implications for the development of clinical protocols which combine radiation and paclitaxel in treatment plans. PMID- 21544457 TI - Receptor status variation in primary breast cancer and subsequent accessible relapse. AB - To better understand the prognostic relevance of change in steroid receptor status, during the clinical course of breast cancer, we analysed the variation of estrogen and progesterone receptor (ER, PgR) status in a series of 532 primary tumors and metachronous accessible recurrences in individual patients. A more consistent variation was observed in patients with a receptor-positive primary (ER(+) or PgR(+)) than in those with a receptor-negative tumor (ER(-) or PgR(-)). Forty-four percent of PgR(+) and 24% of ER(+) tumors became negative, whereas only 20% of ER(-) or PgR(-) became positive. The changes were independent of tumor stage and menopausal status. However, steroid receptor variation appeared to be related to the interval between the primary tumor and relapse. In fact, the changes from ER(+) to ER(-) were more frequent in patients with a disease-free survival of less than 1 year, whereas changes from ER(-) to ER(+) occurred more often in patients with a disease-free survival of more than 3 years. Moreover, we observed a decrease in the number of ER(+) tumors following hormone treatment and a decrease in ER(-) tumors following chemotherapy. However, such variations did not reach statistical significance. Irrespective of the type of adjuvant therapy, the presence of at least one receptor (in particular, PgR) in the metachronous lesion was correlated with a long median time to relapse and to death. Our results confirmed the predictive relevance of receptor status of the primary lesion on relapse and survival and suggest the predictive relevance of receptor status of the metachronous lesion on post-relapse survival. PMID- 21544458 TI - A deletion map of chromosome 17q in sporadic human mammary carcinomas. AB - The long arm of chromosome 17 is a frequent target of allelic losses at multiple sites during breast cancer formation and progression. Several genes linked to breast carcinomas have been mapped on this chromosome such as BRCA1, NME and erbB2 genes. The aim of this work was to delineate a deletion map on chromosome 17q and to examine the role of loss of heterozygosity (LOH) during breast tumor development and progression looking for correlation between LOH on 17q and various histopathological parameters. A series of 71 human mammary carcinomas and the corresponding peripheral blood lymphocytes has been studied for loss of heterozygosity at 6 different polymorphic loci on chromosome 17q. 46 out of 71 (65%) tumors showed LOH on 17q. A positive correlation was found between allelic loss for BRCA1 flanking markers and young age at diagnosis. The absence of estrogen receptors was more frequently observed in tumors with deleted BRCA1 flanking markers. PMID- 21544459 TI - Stilbene estrogen-mediated enhanced tyrosine phosphorylation of the nuclear protein p53 by nuclear matrix associated tyrosine kinase(s). AB - We have previously shown that protein tyrosine kinases are present in the nuclei of hamster renal epithelial cells. In this study we have identified an endogenous, critically important nuclear matrix protein as a substrate for tyrosine phosphorylation by nuclear matrix tyrosine kinases (NM-PTKs) and its modulation by stilbene estrogen, diethylstilbestrol (DES). Analyses of tyrosine phosphorylation of nuclear matrix proteins by endogenous labeling revealed that NM-PTKs were able to phosphorylate the tyrosine residues of several proteins. Both amino acid analysis and immuno-precipitation of nuclear matrix proteins with the monoclonal antibody that recognizes wild-type p53 revealed that p53 was phosphorylated on its tyrosine residues by NM-PTK(s). Moreover, DES exposure resulted in the enhanced tyrosine phosphorylation of p53 to a tune of 3.6 fold. Several other proteins of the nuclear matrix were also differentially phosphorylated in response to DES exposure. The DES-mediated enhanced tyrosine phosphorylation of p53 coincided with increased cell proliferation of renal tubular epithelial cells of Syrian hamster. The results of this study suggest that p53 protein is phosphorylated at tyrosine residues and enhanced tyrosine phosphorylation of p53 by DES exposure may play a role in the proliferation of hamster renal tubular epithelial cells. PMID- 21544460 TI - Autocrine transforming growth factor-alpha is associated with modulation of a 130 kD RB protein species and 116/110 Rb as revealed by an antisense TGF alpha expression vector. AB - Specific RE protein species modulated by autocrine TGF alpha are unknown. HCT116 cells transfected with TGF alpha antisense expression vector were compared with control HCT116 NEO for mitogenesis and modulation of high MW (130, 120 kD) and low MW (116, 110, 105 kD) RE species. Nutrients alone (N) induced maximal mitogenesis in HCT116 NEO and modulated both 130 kD and 116 kD/110 kD RE species. TGF alpha antisense transfected clones required nutrients plus growth factors (GF) for maximal mitogenesis and both 130 kD/120 kD as well as 116 kD/110 kD species were modulated. Thus, autocrine TGF alpha (HCT116) was associated with 130 kD and 116/110 kD modulation while its suppression allowed modulation of a 120 kD species as well. PMID- 21544461 TI - Genetic separation of GvL and GvH reactivity in new recombinant-inbred tumor resistant mouse strains. AB - From a cross between a tumor-susceptible syngeneic mouse strain (DBA/2) and a tumor resistant MHC congenic strain (B10.D2) new recombinant inbred mouse strains were established over many generations of inbreeding and tumor resistance selection. The resistance selected against one DBA/2 derived malignant tumor (ESb) extended to other DBA/2 malignant tumors (SL 2, MDAY-D2) and was thus of more general significance. Since tumor resistance had an immunological basis and since the two parental strains differed in multiple minor histocompatibility antigens (H) as well as in viral superantigens (vSAGs) we determined specificities of cytotoxic T lymphocyte (CTL) responses in vitro. All CTL responses from tumor resistant strains showed not only antitumor reactivity but also rather strong anti-minor H reactivity. There was no relationship between cytolysis and the DBA/2 type vSAG-7 (Mls(a)) expression. We also tested the capacity of immune cells from 7 resistant lines to transfer graft versus leukemia and graft versus host reactivity to ESb tumor bearing DBA/2 mice. Immune cells from one subline were capable of transfering complete protection without development of chronic GVH over a period of 4 months. The resistant parental line B10.D2 and most of the other sublines also were able to transfer GvL reactivity but this was usually associated later with chronic GVH disease caused mortality. These results demonstrate the potential of this genetic approach to separate GvL from GvH reactivity. PMID- 21544462 TI - Irrelevance of the mutated p53 gene product to tumor rejection antigen in 3 methylcholanthrene-induced fibrosarcomas. AB - The relevance of mutated p53 to in vivo rejection of MC-induced fibrosarcomas and/or in vitro CTL activity against these tumors was investigated. p53 gene was found to be altered in nine MC-induced fibrosarcomas of BALB/c origin. The mutated p53 cDNA derived from several MC-induced fibrosarcomas was transduced into CMS8 which lacks p53 expression. Immunization of mice with these mutated p53 transfectants failed to protect them from original MC-induced fibrosarcomas from which mutated p53 genes were derived. CTL lines specific for these MC-induced fibrosarcomas destroyed the original MC-induced fibrosarcomas, but not CMS8 transduced with mutated p53 genes derived from the same lines. A series of 9mer peptides consisting of mutated amino acid residues of p53 of Meth A, CMS17 and CMS9 were prepared, and target P1HTR cells were pulsed with them. None of CTLs for these fibrosarcomas were reactive with P1HTR pulsed with these peptides. In conclusion, peptides derived from mutated p53 genes may serve as target antigens for CD8(+) MHC class I restricted CTL as reported, but may often not contribute as target antigens to the rejection of MC-induced fibrosarcomas. PMID- 21544463 TI - P53, Bcl-2 expression and cell proliferation in benign breast lesions. AB - The role of proliferation-related markers on breast cancer pathogenesis has been only occasionally investigated. The immunocytochemical expression of P53 and Bcl 2 (using PAb1801 and anti-bcl-2 monoclonal antibodies) and cell proliferation (evaluated as the H-3-thymidine labeling index [H-3-dT LI]) were determined on 62 benign breast lesions at different risk. Accumulation of the P53 protein was never observed; Bcl-2 was detected in 50% of cases and it was unrelated to biologic and clinicopathologic features. Median H-3-dT LI was about three times lower than that observed on large series of invasive breast cancer. It was only slightly higher in lesions from patients younger than 35 years or with a positive family history than in those under 35 or with a negative family history and appeared unrelated to histology or risk classification. Such findings indicate that the investigated biomarkers fail to identify women at increased risk for breast cancer. PMID- 21544464 TI - Sensitivity of hepatocellular carcinoma to nine anticancer drugs is unchanged after administration of epirubicin suspended in lipiodol. AB - Multidrug resistance is a major obstacle to the successful chemotherapy for human cancers. The chemosensitivities of hepatocellular carcinoma (HCC) treated with preoperative lipiodolization (LPD) to anticancer agents were compared to those without chemotherapy. Data on 22 patients with HCC treated with LPD (epirubicin, 20-70 mg/m(2) and lipiodol, 0.05-0.25 ml/kg) prior to hepatectomy (LPD group) and 77 with HCC treated by hepatic resection alone (control group) were compared. Chemosensitivities of resected tissues were tested by succinate dehydrogenase inhibition (SDI) tests for nine anticancer agents, epirubicin, adriamycin, mitomycin-C, cisplatin, carboquone, cyclophosphamide, 5-fluorouracil, etoposide, and vindesine. Among the anticancer agents studied, HCC was most sensitive (38% in the LPD group, 50% in the control) to cyclophosphamide and least sensitive (0% in LPD group, 2% in the control) to etoposide. There was no statistically significant difference in chemosensitivity between the two groups. As HCC does not seem to acquire multidrug resistance after single LPD with epirubicin, repeated LPD with epirubicin can be considered. PMID- 21544465 TI - Differential expression of P-glycoprotein in cord blood and peripheral blood lymphocyte subpopulations. AB - P-glycoprotein (P-gP) is a 170 kDa glycoprotein encoded by MDR1 that appears to be involved in the secretion of a large number of molecules including hormones, cyclosporin A (CSA) and cytokines. Cord blood lymphocytes are functionally immature and are sensitive to CSA. Therefore, we compared the surface expression and function of P-gP in cord blood and peripheral blood CD4(+) and CD8(+) T cells and their naive (CD45RA(+)) and memory (CD45RO(+)) subsets. We observed that only 1% of cord blood CD4(+) and 2% CD8(+) cells expressed P-gP as compared to 7% and 10% respectively of peripheral blood from young controls. In addition, MDR1 mRNA levels were also decreased in cord blood mononuclear cells as compared to peripheral blood from young controls. The efflux function of P-gP was measured by intracellular accumulation of rhodamine 123 (Rh123, a substrate for P-gP) in the presence or absence of CSA. A higher accumulation of Rh123 was observed in cord blood CD4(+) and CD8(+) and their naive and memory cell subtype as compared to those in peripheral blood. Furthermore, cord blood CD4(+) and CD8(+) T cell subsets exhibited greater sensitivity towards CSA (% increase: 119 and 188 respectively) as compared to peripheral blood (44 and 89 respectively). A physiological role of decreased P-gP expression and function in cord blood remains to be determined. PMID- 21544466 TI - Dehydroepiandrosterone reduces expression of glycolytic and gluconeogenic enzymes in the liver of male and female rats. AB - The in vivo effect of dehydroepiandrosterone (DHEA) on hepatic glycogen content and on glucose metabolizing enzymes was investigated in male and female Sprague Dawley rats treated with 0.6% (w/w) DHEA in the diet for 3, 7, 14, 28 and 140 days. The glycolytic enzymes studied (glucokinase, hexokinase, pyruvate kinase) showed a significant persistent decrease in activity in both sexes after 3-7 days of treatment. Gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6 bisphosphatase) were increased after 3 days, but decreased after 7-14 days. Glycolytic enzymes showed a stronger reduction than gluconeogenic enzymes. Females were slightly more affected than males. Glucose-6-phosphate dehydrogenase was unchanged in females, but increased in males. Glycogen content and the activity of glycogen phosphorylase were reduced after 3 days of treatment. mRNA analysis of glucokinase and phosphorylase indicated that these enzyme alterations were accompanied by reduced transcriptional expression, while glucose-6-phosphate dehydrogenase mRNA levels were unchanged. Withdrawal of DHEA from 4 week-treated rats was associated with an almost complete reversibility of the enzyme alterations after 2 weeks. After long-term treatment (140 days) glucokinase, glucose-6-phosphatase and fructose-1,6-bisphosphatase activities were no longer altered. Since DHEA treatment affects the key enzymes of glucose metabolic pathways in the same sense, it is suggested that DHEA does not regulate individual enzymes but rather common regulatory factors or signalling pathways. PMID- 21544467 TI - Protective effect of all trans retinoic acid against tumor promotion and progression in low- and high-risk protocols of mouse skin chemical carcinogenesis. AB - In this study, we assessed the protective effects of all trans retinoic acid (RA) against skin tumor promotion and progression in three different protocols of mouse skin multistage carcinogenesis. Under these protocols, where papillomas on the skin of SENCAR mice were induced for their low- and high-probability of conversion to malignant carcinomas, pre-application of RA (10 mu g/mouse/application) to that of tumor promoter 12-O-tetradecanoyl-phorbol-13 acetate (TPA) or mezerein (MEZ) in 7,12-dimethylbenz(a)anthracene (DMBA) initiated mouse skin resulted in a highly significant protection against skin tumor promotion. In terms of tumor incidence, multiplicity and volume/mouse, at the termination of the experiment at 20 weeks, RA showed 35-80%, 67-83% and 70 98% protection, respectively. While the effect of RA was profound in all the protocols, maximum affectivity was evident in high-risk papilloma induction protocol where DMBA was used as tumor initiator and one week later TPA was applied once a week for five weeks. In tumor progression studies, at 20 weeks of standard low- and high-risk protocols, when papilloma yield is stabilized, animals which did not receive RA in different protocols were divided into two groups and topically treated twice weekly either with acetone or RA (10 mu g). These treatments were continued for an additional 29 weeks. During these treatments, all suspected carcinoma formation was recorded and carcinomas were verified histologically at the termination of the experiment. In each case, RA showed remarkable protective effects against percentage of mice with carcinomas (35-45% protection), number of carcinomas per mouse (50-63% protection) and the rate of malignant conversion (50-63% protection). The results of the present study clearly demonstrate that irrespective of the risk for skin carcinogenesis, RA is capable of affording protection against the induction of nonmalignant lesions and their subsequent conversion to malignancy. PMID- 21544468 TI - Detection of human papilloma virus (HPV) and K-ras mutations in human lung carcinomas. AB - The purpose of our study was to assess the prevalence and prognostic significance of HPV infection as well as K-ras codon 12 point mutations in lung cancer. Patients diagnosed with lung carcinoma between 1988 and 1992 (N=99) were selected. HPV detection and typing was performed by PCR from paraffin-embedded tissues, while mutations in codon 12 of K-ras gene were detected using the restriction fragment length polymorphism (RFLP) analysis. The prevalence of HPV infection was 15%, while K-ras codon 12 point mutations were found in 18% of the specimens examined. In 50% of the HPV-positive cases, K-ras gene mutation coexisted. HPV 18 was the most frequent type. No correlation was found between K ras mutation and HPV infection with sex, age and clinical outcome of the patient, or the histological type and the differentiation grade of the tumor. An association was found between K-ms codon 12 point mutations and the stage of the tumor, occurring more frequently at stage III (p=0.037). Infection with potentially oncogenic HPV types could co-operate with K-ras gene activation in the progression of the disease, since K-ras activation by point mutations seems to be a late event in lung carcinogenesis. PMID- 21544469 TI - Anti-tumor ribonuclease, combined with or conjugated to monoclonal antibody MRK16, overcomes multidrug resistance to vincristine in vitro and in vivo. AB - Onconase, a ribonuclease isolated from Rana pipiens oocytes and early embryos, is a member of the RNase A superfamily. Onconase has anti-neoplastic properties both in vitro and in vivo, and is undergoing clinical evaluation. In the present study, Onconase was combined with or conjugated to MRK16, an anti-P-glycoprotein (Pgp) monoclonal antibody. The interaction of these combinations with vincristine (VCR) against parental and multidrug resistant (MDR), Pgp expressing, human colon carcinoma cells caused increased VCR cytotoxicity in vitro and enhanced survival of athymic nude mice given transplants of drug resistant HT-29(mdr1) cells in vivo. The results suggest that combination treatment with Onconase and other agents that modulate the chemosensitivity of Pgp-expressing human tumor cells has the potential to overcome MDR. PMID- 21544470 TI - Differential expression of platelet-derived endothelial cell growth factor (thymidine phosphorylase) in nonpolypoid and polypoid lesions of the colon. AB - To clarify the relationship between angiogenesis and the early development of colon cancer, expression of platelet-derived endothelial cell growth factor (PD ECGF), a known angiogenic and endothelial cell chemotactic factor, was examined in 119 human colon premalignant adenomas and colon carcinomas. Localization of PD ECGF was assessed by immunocytochemistry in 70 nonpolypoid growth (NPG) lesions that represented 29 carcinomas (NPG carcinomas) and 41 adenomas (NPG adenomas) and 49 polypoid growth (PC) lesions that included 15 carcinomas (PG carcinomas) and 34 adenomas (PC adenomas). Simultaneously, the expression of tranforming growth factor alpha (TGF alpha) and epidermal growth factor receptor (EGFR) were examined in serial sections from these lesions. Twenty (68.9%) of 29 NPC carcinomas and 20 (48.7%) of 41 NPC adenomas exhibited positive staining for PD ECGF, whereas 15 (100%) of 15 PG carcinomas and 27 (79.4%) of 34 PG adenomas expressed PD-ECGF. There was a statistically significant difference in the frequency of PD-ECGF expression between NPG adenomas and PG adenomas (p<0.01). In addition, the incidence of PD-ECGF expression was higher in PG carcinomas than in NPG carcinomas (p<0.05). Positive staining for TGF alpha and EGFR was detected in 14 (48.2%) and 10 (34.5%) of 29 NPG carcinomas, respectively, whereas, 17 (41.5%) and 13 (31.7%) of 41 NPG adenomas expressed TGF alpha and EGFR, respectively. A significant trend for coexpression of PD-ECGF and TGF alpha was detected in either NPG adenomas (p<0.05) or PG adenomas (p<0.01). These data demonstrate that PD-ECGF may be involved in the early stages of colon cancer development during the adenoma-carcinoma transition and additionally that angiogenesis which may be induced by PD-ECGF and/or TGF alpha could play an important role of colon cancer development. PMID- 21544471 TI - Detection of micro invasion during progression in preneoplastic human breast xenograft model. AB - Xenografted MCF10AT cell lines develop regions resembling human proliferative breast disease including atypical hyperplasia and carcinoma in situ (CIS). The lesions are truly preneoplastic because progression to invasive carcinoma occurs. Sporadic, stepwise progression produces xenografts in which relatively normal ducts, hyperplastic ducts, CIS, and invasive carcinoma may coexist. However, early invasive events are difficult to discern. A silver stain that identifies basement membrane due to the content of glycoprotein was used to define areas of invasiveness. The method confirms the progressive nature of the xenograft model, identifies micro invasive fronts, and allows definitive classification of lesion components. PMID- 21544472 TI - Immunohistochemical analysis of epidermal growth factor receptor (EGF-R) and c erbB-2 and correlation with pathological prognostic variables in endometrial carcinomas. AB - In this study the immunohistochemical expressions of epidermal growth factor receptor (EGF-R) and erbB-2 in endometrial carcinomas at different stages of disease progression were evaluated and correlated with clinicopathological prognostic variables. Our results indicate that EGF-R and erbB-2 molecules are expressed in normal endometrium as well as in the majority of the carcinomas evaluated (83% and 92% respectively). The intensity of the immunostaining varied greatly (1+ to 3+) in the different tumors. Within these tumors we focused on those characterized by high levels of expression (i.e. overexpression). Expression and overexpression of EGF-R has been associated with poorly differentiated tumors and with a 3.3 times higher risk of a more rapid disease relapse. Overexpression of the erbB-2 oncoprotein was significatively correlated with depth of myometrial invasion (M0-M1 vs M2-M3 p=0.05), pathological stage (stage I vs II-IV p=0.02) and grade of tumor differentiation (G1 vs G2-G3 p=0.001). In particular, c-erbB-2 overexpression was able to discriminate between the different subsets of stage I carcinomas. None of the IA tumors overexpressed the oncoprotein, as compared to IB and IC (41% and 100% respectively, p=0.04). This finding highlights a role for erbB-2 protein as a prognostic parameter in stage I endometrial carcinoma patients. PMID- 21544473 TI - Cell mediated cytotoxicity of human colon carcinoma cells by a monoclonal antibody (R4) recognizing the carcinoembryonic antigen (CEA) and CEA-related molecules. AB - We report a novel anti-CEA monoclonal antibody (MAb) designated R4, which mediates antibody-dependent cell-mediated cytotoxicity (ADCC) of human colon carcinoma cells and displays differential reactivity for human carcinomas versus the normal counterparts. R4 (IgG1) reacted with the cell surface of 6 colon carcinoma cell lines expressing CEA. Western blot analysis and epitope mapping using native and baculovirus recombinant CEA and non specific cross-reacting antigen (NCA) demonstrated that MAb R4 recognizes a proteinic epitope located on the 3' end of the domain I shared by CEA and NCA molecules. Immunohistochemical analysis demonstrated an intense staining of MAb R4 with the majority of the neoplastic tissues tested, including colon (13/13), stomach (2/2), breast (9/10), lung (7/10) and endometrial (2/4) carcinomas, whereas no reactivity with the correspondent normal tissues was observed. Using human PBLs from healthy donors as effector cells, we have shown that MAb R4 mediated antibody dependent-cell mediated cytotoxicity (ADCC) of human carcinoma cells LS-174T, CBS and WiDr. This activity was enhanced after PBLs activation with interleukin-2 (IL-2). The specificity of MAb R4 for an epitope shared by two tumor overexpressed antigens, CEA and NCA, resulting in an intense reactivity with neoplastic cells and the peculiar property to mediate ADCC, indicate that MAb R4 might be a novel powerful reagent for diagnostic and immunotherapy of carcinoma patients. PMID- 21544474 TI - Analysis of location and integrity of the human PITSLRE (p58(cdc2L1)) genes in neuroblastoma cell genomes. AB - The family of PITSLRE kinase genes, located in chromosome 1p36, has recently been associated with neuroblastoma tumorigenesis. In order to evaluate the role of these genes as putative tumor suppressor genes, we have analyzed the integrity of the coding region in primary tumors and its location relative to a neuroblastoma consensus deletion. A subset of aggressive neuroblastoma tumors with allelic loss of different parts of chromosome 1p were investigated. Single-strand conformation polymorphism (SSCP), heteroduplex (HD) and sequencing analysis of tumor DNA did not reveal any significant changes in the coding region. In particular, a primary tumor with an interstitial allelic deletion in 1p36 did not reveal concomitant loss of heterozygosity of the PITSLRE gene region when analyzed with a C/T DNA sequence polymorphism in exon 5 of PITSLRE1. FISH analysis on neuroblastoma cell lines with small interstitial deletions and with a balanced translocation in 1p36 revealed that the PITSLRE gene cluster was localized distal to the neuroblastoma consensus deletion. against an involvement of the PITSLRE genes in neuroblastoma tumorigenesis. PMID- 21544475 TI - The selective anticancer agents PB-100 and BG-8 are active against human melanoma cells, but do not affect non malignant fibroblasts. AB - When past the stage amenable to surgery, melanoma and its metastases are, as a rule, treated with chemotherapy, which is largely unsuccessful. In this report, experimental evidence is presented demonstrating that, in vitro, two selective anticancer agents, PB-100 and BG-8, dose dependently destroy human G-361 melanoma cells, but do not affect human non malignant CCD-974Sk fibroblasts used as controls. Trace metal compounds, present, often in abnormal amounts, in the cancer cell and/or its environment, are known to influence its proliferation. Assays were carried out using highly elevated amounts of ferritin, iron chloride or zinc chloride. Ferritin proved differentially mitogenic for melanoma cells and fibroblasts. Its activity was inhibited by both anticancer agents, which however tended to become less efficacious in its presence. FeCl3 was more moderately, but equally, mitogenic for malignant and normal cells, yet it impaired antiproliferative activity of PB-100 and inhibited that of BG-8. ZnCl2 exhibited a selective antiproliferative activity on the malignant melanoma cells; it did not compete with PB-100 or BG-8. Specific recognition and destruction of malignant cells by the two anticancer agents are discussed. PMID- 21544476 TI - Endometrial hyperplasia and endometrial carcinoma induce a vasoproliferative response in the chick embryo chorioallantoic membrane. AB - Ten specimens of endometrial adenocarcinoma, of endometrial hyperplasia and uterine prolapse (the latter used as controls), respectively, were grafted onto the chick embryo chorioallantoic membrane (CAM) to investigate their angiogenic activity. The vasoproliferative response was assessed four days after grafting on histologic sections by a planimetric point-count method. Microvessel counts in the CAM area under and around the implants were significantly higher in endometrial adenocarcinoma than in endometrial hyperplasia and in the latter over the controls. These findings show that endometrial hyperplasia and endometrial adenocarcinoma are angiogenic. These results confirm previous observation that angiogenic activity is both a marker of the passage between preneoplastic to neoplastic status and an event that influences tumour progression. PMID- 21544477 TI - Cumulative regional allelotyping of human breast carcinomas. AB - We have analyzed losses of heterozygosity (LOH) at markers from chromosomes 1, 2, 4 and 5 in a panel of 53 consecutive breast carcinomas. Together with a parallel analysis of LOH at chromosome 3, this allowed the identification of twenty-one regions of LOH. In contrast, in a comparative analysis of chromosome X, no region of loss could be defined. Cumulative regional allelotyping of 38 tumors with 71 markers from the five autosomes (37% of the genome) enabled the study of the respective distribution of regions of frequent loss, to identify associations of regions of LOH, and to distinguish tumors frequently affected by LOH such as lobular carcinomas. PMID- 21544478 TI - Point mutation of the c-Ki-ras proto-oncogene and the p53 tumour suppressor gene in distal colonic adenocarcinomas. AB - One hundred and twenty-seven monochronous primary colorectal adenocarcinomas were examined for both activation of the c-Ki-ras proto-oncogene by point mutation in codons 12 or 13 and inactivation of the p53 tumour suppressor gene by point mutation in exons four through nine. All of the carcinomas originated in the distal half of the colorectum. Activation of the c-Ki-ras proto-oncogene was detected in 23% (29/127) of adenocarcinomas, and p53 inactivation was detected in 63% (80/127) of adenocarcinomas. Only 16% (20/127) of cases exhibited both genetic changes, and no association was noted between the occurrence of these two changes. Individually, both ras activation and p53 inactivation were associated with a poorer patient prognosis (p=0.0009 and p=0.0159 respectively). In a Cox regression analysis both ras activation and p53 inactivation contributed independently towards patient mortality. These results suggest that mutations exert their effect independently of each other, and that it is the cumulative mutational load that determines a patient's prognosis. PMID- 21544479 TI - Cell proliferation and apoptosis in the exocrine pancreas of azaserine-treated rats and N-nitrosobis(2-oxopropyl)amine-treated hamsters. AB - Altered cell proliferation is an important characteristic of neoplastic development, hence the quantitation of cell growth in normal and (pre)neoplastic pancreatic tissue will provide useful information on the process (and modulation) of pancreatic tumour promotion in experimental animals. Cell proliferation was estimated by means of BrdU-incorporation in normal pancreatic tissue and in putative preneoplastic pancreatic tissue of azaserine-treated rats and of N nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters at 2, 6, 12, 26 and 52 weeks post-treatment. Furthermore, the effects of diets high in vegetable oil or fish oil on the BrdU labeling index, the Ki-67 labeling index as well as the apoptotic labeling index were determined in azaserine-induced atypical acinar cell foci (AACF) in the pancreas of rats. In saline- and azaserine-treated rats, the BrdU labeling index (LI) in normal pancreatic acinar cells showed a similar time related decrease. In azaserine-treated rats, the BrdU-LI in AACF was significantly higher than in normal acinar tissue. The BrdU, Ki-67 and apoptotic labeling indices in pancreatic AACF of rats fed diets high in vegetable oil versus fish oil were 24.8+/-1.7 vs 15.5+/-1.2 (BrdU; P<0.05), 9.9+/-0.8 vs 6.5+/ 0.5 (Ki-67; P<0.001) and 1.31+/-0.12 vs 0.97+/-0.11 (apoptosis; P<0.05), respectively. In hamsters, up to 26 weeks after BOP-treatment the BrdU-LI in acinar cells was significantly higher than in saline-treated animals. In BOP treated hamsters, ductal cells showed a significantly increased LI 2 weeks post treatment, whereas the LI in centroacinar cells had significantly increased 2 and 26 weeks post-treatment. In hamster pancreas the LI was significantly higher in tubular ductal complexes than in cystic ductal complexes and was highest in borderline lesions. It is concluded that (i) determination of BrdU-LI provides a reliable parameter to discriminate between putative preneoplastic lesions with a high or low growth potential, hence with a high or low potential to develop into ultimate carcinomas, (ii) BOP causes increased DNA synthesis in normal acinar cells, leading to increased risk of additional DNA damage, implicating the acinar cell to be putatively involved in the development of ductular adenocarcinomas in the hamster pancreas and (iii) quantitation of cell proliferation and apoptosis may be useful to determine the enhancing or inhibitory effects of life-style factors on pancreatic carcinogenesis. PMID- 21544480 TI - An alpha-fetoprotein-producing human gallbladder carcinoma cell line (KMG-C) shows more aggressive biologic behavior than an alpha-fetoprotein-non-producing cell line. AB - We have established a new human alphafetoprotein (AFP)-producing gallbladder carcinoma (GBC) cell line, termed KMG-C, from a 67-year-old Japanese male. KMG-C and its reconstituted tumors in nude mice showed the morphological features of an adenocarcinoma. Functionally, KMG-C secreted AFP, carcinoembryonic antigen, and carbohydrate antigen 19-9, as well as 7 serum proteins, including albumin and C reactive protein. KMG-C showed more malignant biological behavior than an AFP nonproducing GBC cell line, KMG-A, established originally from the tumor of the same patient; KMG-C had a shorter doubling time, higher tumorigenicity, and an aneuploid DNA index. Our results suggest that AFP-producing GBC cells may have more malignant biological characteristics than AFP-non-producing GBC cells in GBCs having both of these components. PMID- 21544481 TI - Characteristics of human tumour cell lines after induction of multidrug resistance. AB - A colorimetric technique was used to investigate some aspects of multidrug resistant (MDR)-induced cell lines. Continuous contact of the inducing agent with cells was necessary for MDR induction and this was followed by a series of phases i.e., a selection phase (ESP) lasted up to 6 days, a conditioning phase (CP) lasted up to 14 days and an expansion phase (EP) lasted up to 7 days. Gene transfection to correct missing MHC class I antigens on the Fen cell line did not affect cell behaviour. Of particular interest was the finding that the withdrawal of the MDR inducing agent did not reverse MDR phenotype immediately. PMID- 21544482 TI - Fluted serum relating to growth of both hepatocyte and hepatocellular carcinoma cells. AB - This study was undertaken to investigate a humoral substance contributing to both primary hepatocytes and hepatocellular carcinoma (HCC) cells in the primitive form. Peripheral blood from rat, 24 h after partial hepatectomy (PH) or sham operation, was eluted into 50 fractions using an HPLC, and each fraction was bio assayed. In vivo relationship between PH and tumor growth was also evaluated. Only one, approximately 100 kDa, of the 50 fractions from PH rat stimulated the growth of both types of cell, and the time-lag between PH and HCC injection also correlated significantly with tumor appearance and growth. Serum in PH rats contains certain humoral stimulator(s) contributing to growth of both hepatocyte and HCC cells. PMID- 21544483 TI - Suppression of cell growth by wild-type p53 in tumor-derived rat esophageal epithelial cells. AB - Our laboratory previously identified a frameshift mutation in codon 176 of the p53 gene in the cell line RE-149DHD derived from transformation of rat esophageal epithelial cells by benzo(a)pyrene dihydrodiol. This mutation correlated with tumorigenic potential of the cells. To investigate the effect of rat wt-p53 expression on cell growth we constructed a recombinant expression vector, pcDNA3 RP53, in which wt-p53 cDNA is under transcriptional control of a cytomegalovirus promoter, and introduced the vector into RE-149DHD cells. A stable clonal cell line was isolated from each of four colonies transfected by pcDNA3-RP53 vector. Exogenous p53 DNA fragments were successfully amplified from three of the four cell lines with the sense primer complementary to T7 promoter sequences downstream of the CMV promoter. Restriction digestion analysis of these amplified PCR fragments showed fragments of the expected size for exogenous p53 DNA, indicating successful introduction of the pcDNA3-RP53 vector into RE-149DHD cells. However, expression of exogenous p53 mRNA was not detected by RT-PCR in these cell lines. To further confirm absence of exogenous p53 expression, a different set of primers, spanning codon 176 of the p53 gene, was used to amplify a 183-bp fragment of p53 mRNA from all transfected cell lines, the parental RE 149DHD cell line and normal esophageal tissue. Subsequent SSCP analysis of the RT PCR products from all transfected cell lines and the parental cell line RE-149DHD showed the same mobility shift, indicating expression of endogenous mutant p53 alone, and no exogenous expression of p53 mRNA in all four stable clonal cell transfected with the pcDNA3-RP53 vector. This data suggests that wt-p53 may play a negative role in growth regulation of tumor-derived rat esophageal epithelial cells. PMID- 21544484 TI - Aspirin and aspirin-like drugs induce HLA-DR expression in HT29 colon cancer cells. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of colon cancer. The underexpression of HLA antigens during colon cancer development is suspected to be a mechanism by which malignant cells escape immune surveillance. We examined whether NSAIDs affect the expression of HLA-DR in HT29 human colon adenocarcinoma cells, which do not express HLA-DR. Aspirin, indomethacin and sulindac induced several-fold the expression of HLA-DR in these cells in a concentration- and time-dependent manner. Aspirin increased HLA-DR alpha steady state mRNA levels and HLA-DR alpha gene transcription rate. These findings raise the possibility that such a mechanism may be operative in vivo. PMID- 21544485 TI - In vivo monitoring of splenocytes in NMRI nu/nu- and nu/+,- mice during Lewis lung tumor progression or regression. AB - Splenocytes of T-cell deficient NMRI nu/nu- mice (n=15) and of inbred immunocompetent NMRI nu/+,littermates (n=18) significantly (p<0.05) increased during Lewis lung (LL) tumor growth and eventually decreased. Half of the heterozygous NMRI nu/+,- mice rejected the tumors (LL-regressors). Zymosan induced and lucigenin-amplified chemiluminescence (CL) of splenic polymorphonuclear leukocytes (PMN) and -precursors significantly (p<0.05) increased in NMRI nu/+,- mice with progressing tumors (LL-progressors) on the 3rd and in LL-regressors and nude mice on the 7th day after tumor inoculation. It subsequently decreased although numbers of PMN/- precursors further multiplied predominantly in the LL-progressors. Another peak of CL was found in those animals after the 20th day. Splenic lymphocytes significantly (p<0.05) increased in all mice from day 5 forward and dropped to original numbers between the 20th and 25th days. Maximal lymphocyte counts were significantly (p<0.05) lower in nude mice as compared to the NMRI nu/+,- littermates. The splenic T-/B-ratio significantly (p<0.005) correlated in LL-regressors and did not in LL progressors. This correlation could be a suitable marker for tumor progression in NMRI nu/+ mice bearing LL-tumors. PMID- 21544486 TI - Effect of photodynamic treatment of human endothelial cells on cell volume and cell viability. AB - Photodynamic therapy (PDT) has yielded promising results in the treatment of malignant tumors. However, the mechanisms leading to tumor destruction during PDT are still not completely understood. In addition to effects on the microcirculation, damage to cellular structures has been observed following exposure of cells to PDT. A phenomenon preceding these events might possibly be cell swelling. We therefore studied the influence of treatment with Photofrin(R) (PF) and laser light on volume changes and cell viability of endothelial cells. Endothelial cells were obtained from human umbilical cord veins (HUVEC) by an adaption of the method of Maruyama. After subcultivation the cells were harvested and transferred as a cell suspension into a specially designed incubation chamber. Cells received either PF in concentrations of 1.5 or 3.0 mu g/ml and laser illumination 60 min post incubation (630 nm; 40 mW/cm(2), 4 Joule), PF alone, or laser treatment only. Following start of PF incubation and after phototreatment cell samples were taken for volume measurements using flow cytometry, and for studies of cellular morphology using scanning electron microscopy. Simultaneously, cell viability was monitored by the trypan blue exclusion test and the colorimetric MTT assay. Both control groups, HUVEC receiving PF or laser treatment alone, revealed constant cell volumes and cell viability during the entire course of the experiment. After PDT (60 min post incubation) with 1.5 and 3.0 mu g PF/ml cell volume of HUVEC was increased at 15 min to 122%+/-6% and 140%+/-10% of baseline (100%), at 60 min to 152%+/-9% and 134%+/-18%, respectively (p<0.01). The number of viable cells was significantly reduced of samples treated with 1.5 and 3.0 mu g PF/ml at 15 min after PDT to 81%+/-3% and 76%+/-10% of baseline (100%), at 60 min after PDT to 32%+/-14% and 20%+/-15%, respectively (p<0.01). Scanning electron microscopy of cells exposed to PDT following 60 min incubation with Photofrin (3.0 mu g/ml) revealed significant cell damage. At the highest PF concentration HUVEC showed loss of microvilli and formation of blebs on the cellular surface. Our study demonstrates that PDT induces a significant increase in endothelial cell volume and a loss of cell viability. We suggest that swelling and damage of endothelial cells following PDT is a primary event finally contributing to cessation of blood flow and subsequent necrosis of tumors. PMID- 21544487 TI - Differentiation of primary human fibroblasts into tissue macrophages by the Snyder-Theilen strain of the feline sarcoma virus is associated with endoreduplication, a 1,9 translocation, phenotypic stability, and apoptosis. AB - We have previously reported the conversion of human fibroblasts to tissue macrophages by transduction with the Snyder-Theilen feline sarcoma virus [ST:FeSV (FeLV)]. The ST:FeSV-induced macrophages were largely configured as spherical cells, each with an extensive network of microvilli. Nuclear alterations included the appearance of three sub-populations within these mononucleated macrophages consisting of diploid (19%), tetraploid (43%), and octaploid (38%) cells. A karyotypic analysis revealed a 1,9 translocation in a small, dividing, subpopulation within the diploid fraction of the ST:FeSV-induced macrophages. Clonotypic assays demonstrated the conversion of all individually expanded, cloned fibroblasts, to macrophages following transduction with ST:FeSV. None of the converted macrophages reverted to the fibroblastic cell phenotype as determined by co-expression of v-fes and the receptor for the macrophage colony stimulating factor (CSF-IR). The ST:FeSV-induced macrophages did not form colonies in agar, nor did they form tumors in athymic mice. They appeared to undergo apoptosis after 4-6 weeks in culture. The findings pertain to the heterogeneous nature of tissue macrophages and their recruitment process during normal conditions, and in response to inflammatory stimuli. PMID- 21544488 TI - mRNA levels of molecular chaperones hsp27, hsp60 and hsp70 in cisplatin resistant squamous cell carcinomas. AB - The relationship between cisplatin (cDDP) resistance and the expression of the molecular chaperonins hsp70, 60 and 27 was studied in two head and neck squamous cell carcinoma cell lines (UM-SCC-5 and UM-SCC-10B). The cDDP resistant variants were obtained by continuous exposure to escalating doses of cDDP. The IC(50)s of the parent and resistant variants (15th selection) of the UM-SCC-5 and UM-SCC-10b were 7.2+/-1.5 mu M and 20.1+/-1.2 mu M, and 6.5+/-0.6 mu M and 40.1+/-1.2 mu M, respectively. The emergence of cDDP resistance was closely related to the increase in basal expression of hsp60 (r=0.85 and 0.91 for UM-SCC-5 and UM-SCC 10B, respectively) resulting in a 2 to 3-fold increase in hsp60 mRNA in the cDDP resistant variants (15th selection). Expression of hsp27 was increased at higher levels of resistance in the UM-SCC-10B variants only (3 to 5-fold), and not in the UM-SCC-5 variants. In contrast to hsp60 and hsp27, the emergence of cDDP resistance did not lead to higher hsp70 mRNA levels. In addition, we determined the ability of cDDP resistant variants to induce the hsps 27, 60 and 70 in response to cDDP treatment. In the parental cell lines, hsp27 and hsp60 were all slightly increased after cDDP treatment (IC70 dose). However, only hsp60 could be induced in the resistant variants. In summary, emergence of cDDP resistance is associated with increased levels of hsp60 mRNA in the resistant variants and an inhibition of the transcriptional activity of hsp27 and hsp70. PMID- 21544489 TI - Expression and sequence analysis of the SDI1/WAF1/CIP1/p21 tumor suppressor gene in prostate cancer cell lines. AB - The SDI1/WAF1/CIP1 gene encodes a M(r) 21,000 protein (p21) that can arrest cell growth by associating with and inhibiting cyclin-dependent kinase complexes necessary for cells to exit G(1). It is a critical downstream effector in the p53 growth control pathway and can be transcriptionally upregulated by increasing levels of wild-type p53 protein. Somatic mutations in the p21 gene have been detected in 17% of primary prostate cancers. In the current study, we examined four prostate cancer cell lines for expression of and mutations in the p21 gene. Transcripts for p21 mRNA were present in all PC cell lines; p21 protein was detected in androgen-dependent LNCaP cells, as well as in androgen-independent DU 145 and TSU-Pr1 cells but not in androgen-independent PC-3 cells. Examination of the entire coding region of the p21 gene by SSCP analysis and direct DNA sequencing did not detect mutations in the coding domains of the p21 gene. These data indicate that mutations of the SDI1/WAF1/CIP1/p21 gene are not present in cultured PC cells and suggest that defects in the p21 gene are infrequent in prostate cancers. PMID- 21544490 TI - HLA class I antigens are possible prognostic factors in hepatocellular carcinoma. AB - Thirty patients who underwent hepatectomy for the treatment of hepatocellular carcinoma (HCC) were examined for expression of HLA class I antigens on HCC cells by flow cytometry. The expression was found significantly lower in cases of stage IV compared with those of stage I or stage II (p<0.05), and in cases of intrahepatic metastases compared with those without metastases (p<0.001). In cases of non-curative hepatectomy, the expression of HLA class I antigens was lower compared with those treated by curative resection. Postoperative cumulative disease-free survival rates were well correlated with the expression rate of HLA class I antigens (p<0.05). Expression of HLA class I antigens on HCC may indicate low malignancy and better prognosis. PMID- 21544491 TI - HPLC determination of serum levels of soluble p53 antigen as a new method for colon cancer detection, and its clinical implication. AB - Previously, we have described a new modification of affinity chromatography columns for isolation of the cytoplasmic, soluble form of tumor-associated antigens (TAA) from the serum of colon cancer patients (Oncol Rep 2: 679-683, 1995). In this communication, we have shown that the main proteins of these TAA were p64 and p53. The correlation coefficient between each of these proteins and the total amount of TAA or total serum protein ranged from 0.55 to 0.93. The serum level of p53 antigen was shown to be related to the tumorigenicity: the correlation and regression coefficients between the serum level of p53 protein and the progress in colon cancer were 0.48 and 0.88, respectively, p<0.001. Therefore, the determination of serum concentration of this protein can serve as a screening tool for cancer detection. The serum level of p53 protein ranges between 0.24 to 0.94 mg/ml in patients with non cancer diseases, and between 1.0 to 2.0 mg/ml in patients with polyposis and in a high risk group, respectively, increases over 2.0 mg/ml in primary colon cancer patients and up to 5.0 mg/ml in cancer patients with metastases. The sensitivity and specificity of our method achieved 92% and 96%, respectively, and accuracy 88%. The presence of p53 protein in the cytoplasm of cells from patients with non cancer diseases may explain why p53 antigen is presented in their sera. Our method can be useful to detect cancer development either as a primary illness or as a recurrent disorder. It is possible to follow up patients with chronic diseases and to detect transformation of these diseases into cancer, or to follow up former cancer patients in order to detect as early as possible incidence of recurrent cancer. It should also be emphasized that our method allows the detection of patients with polyposis or those of high risk groups who exhibit a tendency to develop colon cancer. PMID- 21544492 TI - Assessment of apoptosis in relation to proliferation and mutational status of p53 gene in head and neck cancers. AB - The present studies were undertaken to determine the incidence of apoptosis in plastic embedded head and neck (HN) tumor biopsies (n=31) using in situ end labeling (ISEL) of fragmented DNA. The extent of spontaneous apoptosis in untreated tumors was correlated with histological grade, percent S-phase cells (Labeling Index, LI) and with the mutational status of p53 gene in these tumors. Additionally, the in vivo effects of chemo- and/or radiotherapy on apoptosis were evaluated in seven patients. In the majority of tumors studied (25/31) spontaneous apoptosis was virtually undetectable or was very low (1-15% positively labeled cells). Only 6 tumors showed intermediate to high apoptosis (>15% positively labeled cells). High apoptosis was more frequent in poorly differentiated tumors (similar to 50%), as compared to well and moderately differentiated tumors. The median LI for 31 tumors studied was 20.2%. The mean LI for moderately differentiated tumors (23.7+/-1.7%) was significantly higher than that in well differentiated (15.1+/-2.1%, p=0.005) and was comparable in poorly differentiated tumors (24.5%). Cytotoxic therapy significantly increased the degree of apoptosis in 5/7 specimens studied (p=0.03). Double labeling of 5 of these tumors before and after the therapy, combining ISEL with detection of IUdR/BrdU, showed compartmentalized apoptosis and proliferation with virtually no double labeled cells in any specimen. Interestingly, tumors with a mutated p53 gene (n=6) showed intermediate to high degree of pretherapy, baseline apoptosis in contrast to low or undetectable levels of apoptosis in tumors bearing wild type p53 (n=13, p=0.034). It appears that low levels of apoptosis and high proliferation may be characteristic of HN tumors. The spontaneous apoptosis in HN tumors seems unrelated to mutations in the p53 gene. Moreover, our data also show that despite overall increase in apoptosis induced by cytotoxic therapy, some proliferating tumor cells escaped the effects of therapy, which may contribute to the tumor relapse. PMID- 21544493 TI - Thermotolerance and sensitivity of human cancer cells to cisplatin and doxorubicin. AB - Testis tumour cells are more sensitive than most other types of cancer cell to heat, radiation and chemotherapeutic drugs, both in the clinic and in vitro. Since heat shock proteins (HSP) can protect cells from the cytotoxic effects of stress, we studied their role in the sensitivity of testis tumour cells to the frequently used cancer chemotherapeutic drugs, cisplatin and doxorubicin. Clonogenic assays of 3 testis tumour cell lines (833K, GCT27, GH) and 3 bladder cancer cell lines (RT112, HT1376, MGH-U1) following a 1 h exposure to the two drugs confirmed that the testis tumour cell lines were inherently more sensitive. Having shown previously that heat shock proteins were upregulated in both cell types following a heat shock, in this study no induction of HSP was seen following treatment for 1 h with cisplatin or doxorubicin (at concentrations reducing colony forming ability by 50%) in either cell type. In contrast, chronic exposure to cisplatin (at concentrations on the threshold of cytotoxicity), but not doxorubicin, resulted in upregulation of HSP 27, but not HSP73/72, in both cell types. Testis and bladder cancer cells with heat-induced increases in HSP were thermotolerant, and this was associated with increased resistance to doxorubicin, but not cisplatin. PMID- 21544494 TI - Bladder cancer cells do not express co-stimulatory molecules B7-1, B7-2 and B7-3. AB - It is widely established that BCG is an effective treatment for transitional cell carcinoma (TCC). Its clinical benefit might be attributable to effects both on immuno-competent cells themselves and the tumour, e.g., the induction of MHC Class II and ICAM-1 expression which are known to facilitate effector cell/ target cell interactions. It is of interest that the success of this therapy might be due in part to the induction of B7 molecules which could provide vital co-stimulatory signals to the host immune system. We showed that a panel of 8 TCC cell lines failed to express B7-1,-2,-3 molecules constitutively or after stimulation. Bladder cancer cells shed following immunotherapy also failed to express B7. After therapy B7 expression, however, was found on cells of lymphocytic and monocytic lineage produced locally. Of other co-stimulatory molecules examined (ICAM-3, HSP72, CD1b, VCAM) only CD40 appeared to be expressed on some of TCC cell lines. All cell lines failed to express previously predicted ICAM-3 indicating a possible existence of a novel ligand for LFA-1. PMID- 21544495 TI - Partitioning and sources of PAHs in wastewater receiving streams of Tianjin, China. AB - Polycyclic aromatic hydrocarbons (PAHs) partitioning among dissolved phase, suspended particulate matter, pore water, and sediment was studied in one moderately contaminated river (Yongding New River) and two highly contaminated drainage canals (South Drainage Canal and North Drainage Canal) of Tianjin, China. PAHs concentrations in sediment (ranged from 0.2 to 195 MUg/g) showed positive relations with both total organic carbon contents (ranged from 0.7% to 31.1%, dw) and black carbon contents (ranged from 0.1% to 2.1%, dw) in the sediments. Moreover, most of the measured organic carbon normalized partition coefficients of PAHs in the three streams were 0.76 to 1.54 log units higher than the predicted values. These indicated that strong and nonlinear sorption of PAHs by carbonaceous geosorbents such as black carbon (BC) existed in the streams, and BC was an important part of the carbonaceous particles controlling the partitioning of PAHs in the sediments of this study. PAH component ratio analyses suggested that PAHs in the three streams, effluent samples from wastewater treatment plants, and soil samples by the riverbank had similar main sources, which is coal/petroleum combustion. We suggested the transportation and transformation of both carbonaceous particles and PAHs during wastewater treatment process, surface runoff, etc, should be studied further in order to make decisions on PAHs controlling measures. PMID- 21544496 TI - Assessment of the quality of stormwater from an industrial park in central Taiwan. AB - The purposes of this study were to assess the quality of rainstorm runoffs from an industrial park developed to accommodate general industries in Taiwan and to investigate the possible contributors of pollutants in the runoffs. Rainstorm runoffs from this industrial park were found to contain COD and TSS with average event mean concentrations of two events of 2,202.6 +/- 1,356 and 784.7 +/- 409 mg/l, respectively. The pollution level of these runoffs was found to be tens of times higher than that which may be contributed by accumulation of pollutants in top soils. Other possible sources of the pollutants were those accumulated in rainwater discharge channels and those which overflow from individual pre treatment plants within the industrial lots. The assessment results are useful in devising the best management practices for the stormwater discharges. The heavy loadings suggest that installations of additional runoff pollution control practices at different zones are necessary at this and similar industrial parks. PMID- 21544497 TI - Organotin contamination in South American coastal areas. AB - Organotin compounds (OTs) were used in antifouling paints for more than four decades. However, due to their widespread intensive use and high toxicity, undesirable effects in non-target marine organisms have been detected since the early 1980s. Consequently, the International Maritime Organization banned new maritime applications of these products on January 1, 2003 and their presence on ship hulls from January 1, 2008. Although extensively studied in Europe, North America, Oceania, and Asia, environmental levels and effects of organotin contamination are still poorly known for South America. Thus, the current review aimed to present the actual status of this problem in South America by summarizing and comparing the available data in the literature. An overview of the OTs concentrations in sediment and biota and their effects, mainly imposex in marine gastropods, are presented. This work showed that in Atlantic coastal areas of South America there are "hot spots" of OTs contamination, similar to that observed in industrialized countries of Northern Hemisphere. On the other hand, the number of accomplished studies in the Pacific coast is extremely low. Despite the limitation on studies about OTs environmental levels and their related effects, the available data pointed out for a widespread TBT contamination along the South American coastal areas. Therefore, the establishment of baselines of organotin contamination in the Pacific coast and the implementation of temporal trend studies in the South American coastal areas is crucial to verify the effectiveness of local regulations and OTs global ban, and to map the most sensitive areas related to present and future antifouling impacts. PMID- 21544498 TI - Bioaccumulation of heavy metals in the wolf spider, Pardosa astrigera L. Koch (Araneae: Lycosidae). AB - Previous studies have proposed that Pardosa astrigera L. Koch (Lycosidae) can be used as a biological indicator of heavy metal contamination in soil. In this study, we estimated the bioaccumulation levels and the bioconcentration factors (BCF) of four heavy metals (Cd, Cu, Pb, and Zn) in adult female P. astrigera collected from various field sites according to heavy metal content gradient and broods. The relationship between heavy metal content in the soil and that in spiders was different depending on the heavy metals and the broods. However, heavy metal content in P. astrigera increased with increasing heavy metal content in the soil. While the heavy metal content in the soil was in the order of Zn > Pb > Cu > Cd, its content in P. astrigera was in the order Zn > Cu > Cd > Pb. The BCF for Cd in both of the broods was distinctly higher than those of the other heavy metals evaluated. These results indicate that P. astrigera may be useful as a biological indicator of Cd soil contamination. PMID- 21544499 TI - Dispersion model on PM2.5 fugitive dust and trace metals levels in Kuwait Governorates. AB - Frequent dust storms and recent environmental changes were found to affect the human health especially in residents of arid countries. Investigations on the PM(2.5) fugitive dust in six Kuwait Governorate areas using dispersion Gaussian plume modeling revealed significant relationship between low rate of pollutant emission, low wind velocity, and stable weather conditions' matrix causing high rate of dust deposition in summer than in winter. The rate of dust deposition and trace metals levels in PM(2.5) were in the sequence of G-VI > G-I > G-II > G-V > G-III > G-IV. Trace metals were observed in the sequence of Al > Fe > Zn > Ni > Pb > Cd irrespective of the Governorate areas and the two seasons. The high rate of dust deposition and trace metals in PM(2.5) was reflected by the vast open area, wind velocity, and rapid industrialization besides natural and anthropogenic sources. A combination of air dispersion modeling and nephalometric and gravimetric studies of this kind not only determines the seasonal qualitative and quantitative analyses on the PM(2.5) dust deposition besides trace metals apportionment in six Kuwait Governorate areas, but also characterizes air pollution factors that could be used by environmentalist to deduce preventive measures. PMID- 21544500 TI - Occurrences of six steroid estrogens from different effluents in Beijing, China. AB - Concentration levels of six natural and anthropogenic origin steroid estrogens, namely, diethylstilbestrol (DES), estrone (E1), estradiol (E2), estriol (E3), ethinylestradiol (EE2), and estradiol-17-valerate (Ev), from different effluents in Beijing were assessed. Sampling sites include two wastewater treatment plants (WWTPs), a chemical plant, a hospital, a pharmaceutical factory, a hennery, and a fish pool. In general, concentrations of estrogens in the effluents varied from no detection (nd) to 11.1 ng/l, 0.7 to 1.2 * 10(3) ng/l, nd to 67.4 ng/l, nd to 4.1 * 10(3) ng/l, nd to 1.2 * 10(3) ng/l, and nd to 11.2 ng/l for DES, E1, E2, EE2, E3, and Ev, respectively. The concentration levels of steroid estrogens from different effluents decreased in the order of pharmaceutical factory and WWTP inlets > hospital > hennery > chemical factory > fish pool. This study indicated that natural estrogens E1, E2, and E3 and synthetic estrogen EE2 are the dominant steroid estrogens found in the different Beijing effluents. For source identification, an indicator (hE = E3/(E1 + E2 + E3)) was used to trace human estrogen excretion. Accordingly, hE in effluents from the hospital and WWTP inlets exceeded 0.4, while much smaller values were obtained for the other effluents. Human excretions were the major contributor of natural estrogens in municipal wastewater. Estimation results demonstrated that direct discharge was the major contributor of steroid estrogen pollution in receiving waters. PMID- 21544501 TI - Effect of process conditions on the analysis of free and conjugated estrogen hormones by solid-phase extraction-gas chromatography/mass spectrometry (SPE GC/MS). AB - Simultaneous analysis of 11 free estrogen hormones and five conjugated estrogens in water and municipal wastewater was studied. The analytical method was developed and tested for different types of solid-phase extraction adsorbents, eluents, sample containers and storage conditions, derivatization, and matrix effects. Varian Bond Elut C-18 solid-phase extraction adsorbent cartridge was selected based on its high recoveries for both free and conjugated estrogens. Sample storage conditions, as well as selection and pretreatment of sample container materials, can affect the trace level analysis of estrogens. Silanization of glassware is observed to provide low relative standard deviation (RSD) in the analysis and less percentage loss due to contacting with sample container materials. Light exposure during the test can significantly impact the results. The derivatized samples stored at -20 degrees C for at least 6 days showed less than 10.5% average RSD in the analysis. The recovery efficiency in clean water varies from 72% to 101% for free estrogens and 78% to 82% for conjugated estrogens. The method detection limits (MDL) for most of the compounds range from 30 to 870 ng/L using a sample volume of 200 mL. With a sample volume of 3 L, the most sensitive compound produces a MDL of 0.03 ng/L. Dilute methanol is used to wash the loaded cartridge as a cleanup step in order to remove interfering species during analysis of wastewater samples. Using the optimized analytical methods, the concentration level of free estrogens in the influent and effluent municipal wastewaters is tested. PMID- 21544502 TI - Heavy metal concentration and speciation of seven representative municipal sludges from wastewater treatment plants in Northeast China. AB - The analysis of heavy metals is very important for assessing the feasibility of the agricultural utilization for the municipal sludge. In this paper, a four-step sequential extraction method was applied to extract heavy metals (Cu, Zn, Mn, Cr, and Ni) in municipal sludges from seven individual wastewater treatment plants located in Jilin and Heilongjiang Province, China, for estimating the mobility and bioavailability of the metal ions in the agricultural application. The total concentrations of heavy metals and their chemical fractions after the sequential extraction were determined. Principal component analysis (PCA) was applied to analyze the relations of heavy metals fractions in the municipal sludges. Experimental results indicated that the total concentrations of Cu, Zn, Cr, and Ni in all sludge samples were below the threshold values set out by the Chinese legislation (GB18918-2002). Specially, Zn had a high bioavailability and mobility, Cu and Cr had potential bioavailability, while Mn mainly existed in the residual fraction of municipal sludge. On the other hand, Ni had different mobility in different municipal sludge. PCA results were confirmed by the environmental behavior of heavy metals. PMID- 21544503 TI - Assessment of drinking water quality using ICP-MS and microbiological methods in the Bholakpur area, Hyderabad, India. AB - A total of 16 people died and over 500 people were hospitalized due to diarrhoeal illness in the Bholakpur area of Hyderabad, India on 6th May 2009. A study was conducted with immediate effect to evaluate the quality of municipal tap water of the Bholakpur locality. The study consists of the determination of physico chemical properties, trace metals, heavy metals, rare earth elements and microbiological quality of drinking water. The data showed the variation of the investigated parameters in samples as follows: pH 7.14 to 8.72, EC 455 to 769 MUS/cm, TDS 303.51 to 515.23 ppm and DO 1.01 to 6.83 mg/L which are within WHO guidelines for drinking water quality. The water samples were analyzed for 27 elements (Li, Be, B, Na, Mg, Al, Si, K, Ca, V, Cr, Mn, Fe, Ni, Co, Cu, Zn, As, Se, Rb, Sr, Mo, Ag, Cd, Sb, Ba and Pb) using inductively coupled plasma-mass spectrometry (ICP-MS). The concentrations of Fe (0.12 to 1.13 mg/L), Pb (0.01 to 0.07 mg/L), Cu (0.01 to 0.19 mg/L), Ni (0.01 to 0.15 mg/L), Al (0.16 to 0.49 mg/L), and Na (38.36 to 68.69 mg/L) were obtained, which exceed the permissible limits of the World Health Organization (WHO) for drinking water quality guidelines. The remaining elements were within the permissible limits. The microbiological quality of water was tested using standard plate count, membrane filtration technique, thermotolerant coliform (TTC), and most probable number (MPN) methods. The total heterotrophic bacteria ranged from 1.0 * 10(5) to 18 * 10(7 )cfu/ml. Total viable bacteria in all the water samples were found to be too numerable to count and total number of coliform bacteria in all water samples were found to be of order of 1,100 to >2,400 MPN index/100 ml. TTC tested positive for coliform bacteria at 44.2 degrees C. All the water samples of the study area exceeded the permissible counts of WHO and that (zero and minimal counts) of the control site (National Geophysical Research Institute) water samples. Excessively high colony numbers indicate that the water is highly contaminated with microorganisms and is hazardous for drinking purposes. Bacteriological pollution of drinking water supplies caused diarrhoeal illness in Bholakpur, which is due to the infiltration of contaminated water (sewage) through cross connection, leakage points, and back siphoning. PMID- 21544504 TI - Water quality and dissolved inorganic fluxes of N, P, SO4, and K of a small catchment river in the Southwestern Coast of India. AB - The southwestern coast of India is drained by many small rivers with lengths less than 250 km and catchment areas less than 6,500 km(2). These rivers are perennial and are also the major drinking water sources in the region. But, the fast pace of urbanization, industrialization, fertilizer intensive agricultural activities and rise in pilgrim tourism in the past four to five decades have imposed marked changes in water quality and solute fluxes of many of these rivers. The problems have aggravated further due to leaching of ionic constituents from the organic rich (peaty) impervious sub-surface layers that are exposed due to channel incision resulting from indiscriminate instream mining for construction-grade sand and gravel. In this context, an attempt has been made here to evaluate the water quality and the net nutrient flux of one of the important rivers in the southwestern coast of India, the Manimala river which has a length of about 90 km and catchment area of 847 km(2). The river exhibits seasonal variation in most of the water quality parameters (pH, electrical conductivity, dissolved oxygen, total dissolved solids, Ca, Mg, Na, K, Fe, HCO(3), NO(2)-N, NO(3)-N, P[Formula: see text], P[Formula: see text], chloride, SO(4), and SiO(2)). Except for NO(3)-N and SiO(2), all the other parameters are generally enriched in non-monsoon (December-May) samples than that of monsoon (June-November). The flux estimation reveals that the Manimala river transports an amount of 2,308 t y(-1) of dissolved inorganic nitrogen, 87 t y(-1) dissolved inorganic phosphorus, and 9246 t y(-1) of SO(4), and 1984 t y(-1) K into the receiving coastal waters. These together constitute about 23% of the total dissolved fluxes transported by the Manimala river. Based on the study, a set of mitigation measures are also suggested to improve the overall water quality of small catchment rivers of the densely populated tropics in general and the south western coast in particular. PMID- 21544505 TI - Sensitivity analysis of water quality for Delhi stretch of the River Yamuna, India. AB - Simulation models are used to aid the decision makers about water pollution control and management in river systems. However, uncertainty of model parameters affects the model predictions and hence the pollution control decision. Therefore, it often is necessary to identify the model parameters that significantly affect the model output uncertainty prior to or as a supplement to model application to water pollution control and planning problems. In this study, sensitivity analysis, as a tool for uncertainty analysis was carried out to assess the sensitivity of water quality to (a) model parameters (b) pollution abatement measures such as wastewater treatment, waste discharge and flow augmentation from upstream reservoir. In addition, sensitivity analysis for the "best practical solution" was carried out to help the decision makers in choosing an appropriate option. The Delhi stretch of the river Yamuna was considered as a case study. The QUAL2E model is used for water quality simulation. The results obtained indicate that parameters K(1) (deoxygenation constant) and K(3) (settling oxygen demand), which is the rate of biochemical decomposition of organic matter and rate of BOD removal by settling, respectively, are the most sensitive parameters for the considered river stretch. Different combinations of variations in K(1) and K(2) also revealed similar results for better understanding of inter-dependability of K(1) and K(2). Also, among the pollution abatement methods, the change (perturbation) in wastewater treatment level at primary, secondary, tertiary, and advanced has the greatest effect on the uncertainty of the simulated dissolved oxygen and biochemical oxygen demand concentrations. PMID- 21544506 TI - Extending large-scale forest inventories to assess urban forests. AB - Urban areas are continuously expanding today, extending their influence on an increasingly large proportion of woods and trees located in or nearby urban and urbanizing areas, the so-called urban forests. Although these forests have the potential for significantly improving the quality the urban environment and the well-being of the urban population, data to quantify the extent and characteristics of urban forests are still lacking or fragmentary on a large scale. In this regard, an expansion of the domain of multipurpose forest inventories like National Forest Inventories (NFIs) towards urban forests would be required. To this end, it would be convenient to exploit the same sampling scheme applied in NFIs to assess the basic features of urban forests. This paper considers approximately unbiased estimators of abundance and coverage of urban forests, together with estimators of the corresponding variances, which can be achieved from the first phase of most large-scale forest inventories. A simulation study is carried out in order to check the performance of the considered estimators under various situations involving the spatial distribution of the urban forests over the study area. An application is worked out on the data from the Italian NFI. PMID- 21544507 TI - [Antibiotic therapy for acute exacerbations of chronic obstructive pulmonary disease]. PMID- 21544508 TI - [Osteoporosis: prophylaxis, diagnostics and therapy according to the guidelines]. AB - Osteoporotic fractures are a frequent cause of functional disabilities and loss of quality of life. Preventive measurements need to focus on training of muscle function and coordination, and adequate daily calcium and vitamin D supplementation; furthermore a regular check up for drugs associated with falls and osteoporosis. The German guideline recommends that a specific osteoporosis medication should be initiated in individuals with a 10-year risk for hip and vertebral fractures of 30%. This article presents the current guideline for osteoporosis including the actual updates. PMID- 21544509 TI - Transcranial magnetic stimulation of macaque frontal eye fields decreases saccadic reaction time. AB - Transcranial magnetic stimulation (TMS) is increasingly used to perturb targeted human brain sites non-invasively, to test for causal effects on performance of cognitive tasks. TMS might also be used in non-human primates to complement invasive work and compare with human studies. Here, we targeted the frontal eye fields (FEF) in two macaques with a continuous theta-burst (cTBS) protocol, testing the impact on visually guided saccades. After unilateral cTBS over the FEF in either hemisphere, a small (mean 7 ms) but highly consistent decrease in saccadic reaction times (RTs) was observed. Lower latencies arose for saccades both contra- and ipsilateral to the stimulated FEF after cTBS. These results provide the first demonstration that TMS can be used to affect saccadic behavior in non-human primates. The unexpectedly bilateral impact on RTs may reflect an impact on 'fixation' neurons in the FEF and/or transcallosal modulation of both FEFs induced by unilateral cTBS. In either case, this study demonstrates a clear behavioral effect induced by TMS in awake behaving monkeys performing a cognitive task. This opens new opportunities for investigating the causal roles of targeted brain areas in behavior, for measuring physiological consequences of TMS in the primate brain, and ultimately for human-monkey comparisons. PMID- 21544510 TI - How two share two tasks: evidence of a social psychological refractory period effect. AB - A strong assumption shared by major theoretical approaches to cognition posits that the human cognitive system has a limited capacity for information processing. Evidence supporting this claim comes from the dual-task paradigm in which one cognitive system has to process two tasks simultaneously. In this study, we examined whether bottleneck-like processing can also be elicited when a dual task is shared between two individuals. Under dual-task instructions giving priority to Task 1, we found evidence of a psychological refractory period effect in dual-task and joint-task conditions. Under equal priority instructions, we replicated the finding of a psychological refractory period effect in the dual task, but not in the joint-task condition. These findings are in line with the assumption that a social psychological refractory period effect can be induced across two individuals. We suggest that this effect is due to task-specific monitoring requirements. We discuss our findings with respect to both dual-task and joint action theories. PMID- 21544512 TI - Discrepancies between prescribed and defined daily doses: a matter of patients or drug classes? AB - PURPOSE: Defined daily doses (DDD) are used for the measurement of drug utilisation. The aim of the study was to analyse whether differences between DDD and prescribed daily doses (PDD) exist for relevant drug classes such as antihypertensive drugs and, if so, whether they primarily depend on drug classes or patient-related factors. METHODS: Using the data of a large German statutory health insurance scheme, we analysed continuous prescriptions for the following antihypertensive drug classes: thiazide diuretics, beta-blockers, dihydropyridine calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs). We summed the doses of all dispensed drugs per person during a defined time frame. We calculated the PDD (= total dose divided by the number of days) and expressed them as the PDD:DDD ratio (= amount of DDD per day and person). RESULTS: During the study period, 149,704 patients continuously received an antihypertensive medication. The average PDD:DDD ratio ranged from 0.84 (beta-blockers) to 1.88 (ARBs) and 2.17 (ACEIs). The average prescribed dosage of each drug class remained unchanged, even if the patients had previously received another antihypertensive drug with another PDD:DDD ratio. For example, if patients were switched from a beta-blocker to an ACEI, the PDD:DDD ratio increased, on average, from 0.79 to 2.17. Vice versa, the ratio decreased for patients with a drug change from an ACEI to a beta-blocker from 2.06 to 0.75. CONCLUSIONS: Even large differences between DDD and PDD seem to be a matter of drug classes and not primarily of patient characteristics. PMID- 21544511 TI - Functional selectivity of adenosine receptor ligands. AB - Adenosine receptors are plasma membrane proteins that transduce an extracellular signal into the interior of the cell. Basically every mammalian cell expresses at least one of the four adenosine receptor subtypes. Recent insight in signal transduction cascades teaches us that the current classification of receptor ligands into agonists, antagonists, and inverse agonists relies very much on the experimental setup that was used. Upon activation of the receptors by the ubiquitous endogenous ligand adenosine they engage classical G protein-mediated pathways, resulting in production of second messengers and activation of kinases. Besides this well-described G protein-mediated signaling pathway, adenosine receptors activate scaffold proteins such as beta-arrestins. Using innovative and sensitive experimental tools, it has been possible to detect ligands that preferentially stimulate the beta-arrestin pathway over the G protein-mediated signal transduction route, or vice versa. This phenomenon is referred to as functional selectivity or biased signaling and implies that an antagonist for one pathway may be a full agonist for the other signaling route. Functional selectivity makes it necessary to redefine the functional properties of currently used adenosine receptor ligands and opens possibilities for new and more selective ligands. This review focuses on the current knowledge of functionally selective adenosine receptor ligands and on G protein-independent signaling of adenosine receptors through scaffold proteins. PMID- 21544514 TI - Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan. AB - AIMS/HYPOTHESIS: Studies on the link between diabetes and bladder cancer in Asians are rare. We investigated the association between diabetes and incidence of bladder cancer by using a large national insurance database. METHODS: A random sample of 1,000,000 individuals covered by the National Health Insurance was recruited. A total of 495,199 men and 503,748 women for all ages and 187,609 men and 189,762 women >=40 years old and without bladder cancer at recruitment were followed from 2003 to 2005. Cox regression evaluated the adjusted relative risk for all ages and for age >=40 years old. RESULTS: The results were similar for all ages and for age >=40 years. In Cox models, patients with diabetes consistently showed a significantly higher relative risk ranging from 1.36 to 1.51 after adjustment for age, sex and other potential confounders. Age, male sex, nephropathy, urinary tract diseases (infection and stone) and statin use were associated with bladder cancer, but occupation, hypertension, stroke, ischaemic heart disease, peripheral arterial disease, eye disease, dyslipidaemia and medications (oral glucose-lowering agents including sulfonylurea, metformin, acarbose and thiazolidinediones, insulin, fibrates, ACE inhibitors/angiotensin receptor blockers and calcium channel blockers) were not. Chronic obstructive pulmonary disease and living in regions other than Metropolitan Taipei were associated with lower risk. CONCLUSIONS: Patients with diabetes have a higher risk of bladder cancer. The association with urinary tract diseases suggests a complex scenario in the link between bladder cancer and diabetes at different disease stages. PMID- 21544513 TI - Dietary oxidized fat activates the oxidative stress-responsive transcription factors NF-kappaB and Nrf2 in intestinal mucosa of mice. AB - PURPOSE: Oxidized fats are known to induce oxidative stress resulting in the up regulation of antioxidant enzymes, with the underlying mechanism being unclear. It is known, however, that the response of tissues to oxidative stress is mediated by redox-sensitive transcription factors such as NF-kappaB and Nrf2. The aim of this study, therefore, was to test the hypothesis that ingestion of an oxidized fat causes activation of these transcription factors in the small intestinal mucosa. METHODS: Female mice were randomly assigned to 2 groups of 12 mice each and administered orally by gavage either oxidized or fresh fat once per day. RESULTS: After 6 days of treatment, mice were killed, intestinal mucosa was isolated, and nuclear concentration of NF-kappaB and Nrf2 and expression of NF kappaB- and Nrf2-regulated oxidative stress-responsive genes were determined. Oxidized fat markedly increased nuclear concentration of NF-kappaB and Nrf2 and transcript levels of oxidative stress-responsive genes, like aldo-keto reductase 1B8, vanin-1, glutathione peroxidase 1, and superoxide dismutase-1. In addition, oxidized fat increased the concentrations of PPAR-regulated genes. CONCLUSIONS: The activation of oxidative stress-sensitive pathways likely reflects an adaptive response of the intestinal mucosa to prevent oxidative damage to the intestinal mucosa. PMID- 21544515 TI - Transgenic expression of murine chemokine decoy receptor D6 by islets reveals the role of inflammatory CC chemokines in the development of autoimmune diabetes in NOD mice. AB - AIMS/HYPOTHESIS: Autoimmune diabetes results from a progressive destruction of insulin-producing beta cells in the pancreatic islets by chemokine-attracted lymphocytes. Because islet cells in NOD mice produce chemokines during the development of autoimmune diabetes, we investigated the role of inflammatory CC chemokines in disease progression in these mice. METHODS: We generated a transgenic NOD mouse model that overproduces the inflammatory CC chemokine decoy receptor D6 in pancreatic islets. RESULTS: The frequency of diabetes and insulitis scores of transgenic mice were decreased significantly, compared with non-transgenic control littermates. Transgenic expression of D6 (also known as Ccbp2) did not affect systemic lymphocyte development or alter: (1) the T cell subsets such as T helper (Th)1, Th2 and T regulatory cells; or (2) antigen presenting cells such as dendritic cells or macrophages. The percentages and numbers of T and B lymphocytes were decreased significantly in the pancreas. Activation status, autoantigen-specific proliferation and diabetogenicity of lymphocytes were also markedly reduced. CONCLUSIONS/INTERPRETATION: Inflammatory CC chemokines play a critical role in the development of autoimmune diabetes. Transgenic expression of D6 in pancreatic islets of NOD mice reduced this pathogenic process by suppressing activation of autoreactive lymphocytes and by reducing migration of lymphocytes to the pancreas. PMID- 21544517 TI - Relationship between Sloan-Kettering virus expression and mouse follicular development. AB - Sloan-Kettering virus gene product (Ski) is an unique nuclear pro-oncoprotein and belongs to the ski/sno proto-oncogene family. Ski plays multiple roles in a variety of cell types, it can induce both oncogenic transformation and terminal muscle differentiation when expressed at high levels. Ski/SnoN are important transcription regulators of the transforming growth factor-beta (TGF-beta) superfamily and function mainly through heterodimers. Since TGF-beta superfamily are key regulators of follicle development and it has been previously shown that SnoN is also vital to follicle development, this research was conducted to clarify the relationship between Ski expression and mouse follicular development, in ovaries of neonatal and gonadotropin-induced immature mice by immunohistochemical and real-time PCR techniques. In postnatal mice, positive staining for Ski was highly detected in oocyte nuclei at postnatal day 1. With follicular development, the localization moved gradually from oocyte nuclei to perinuclear space and the total levels decreased. During the estrous cycle, Ski expression was apparent at proestrus and estrus, faint at metestrus, highest at diestrus. After injection of gonadotropin, Ski was found in perinuclear space and weak in oocyte nuclei. Following the initiation of luteinization, the expression of Ski was found in corpus luteum. Real-time PCR results also showed that Ski mRNA expression was opposite to ovulation-related genes during the cumulus expansion, with the development of the follicles, its expression level decreased. Ski is expressed in a specific manner during follicle development, ovulation and luteinization. So Ski might play essential roles in these processes especially during early follicular development. PMID- 21544518 TI - The use of fibric Acid derivatives in cardiovascular prevention. AB - OPINION STATEMENT: Clinical trials have demonstrated the benefit of reduction of low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerotic cardiovascular disease. Evidence is less robust for the effect of reduction of triglyceride levels and increase of high-density lipoprotein (HDL) cholesterol levels. In spite of the decrease of cardiovascular events in trials of LDL cholesterol-lowering medications, considerable residual risk remains, even with the use of high-dose statins. The fibric acid derivatives or fibrates reduce triglyceride and increase HDL cholesterol levels, effects that would be expected to affect cardiovascular events. However, clinical outcomes trials with fibrates have shown mixed results. Post-hoc analyses of fibrate trials as well as several meta-analyses suggest an overall decrease in primarily non-fatal coronary events without decrease in total mortality. The effects are most apparent in patients with elevated triglycerides and low HDL cholesterol levels. Statin therapy is the treatment of choice for most patients with dyslipidemia. The addition of a fibrate appears to be most beneficial in high-risk patients who continue to have significant dyslipidemia on statin therapy, most notably patients with diabetes mellitus or the metabolic syndrome. Thus, fibrates are not first-line drugs, but they do have a place in the management of the atherogenic lipid profile. PMID- 21544516 TI - Permanent diabetes during the first year of life: multiple gene screening in 54 patients. AB - AIMS/HYPOTHESIS: The aim of this study was to investigate the genetic aetiology of permanent diabetes mellitus with onset in the first 12 months of age. METHODS: We studied 46 probands with permanent, insulin-requiring diabetes with onset within the first 6 months of life (permanent neonatal diabetes mellitus [PNDM]/monogenic diabetes of infancy [MDI]) (group 1) and eight participants with diabetes diagnosed between 7 and 12 months of age (group 2). KCNJ11, INS and ABCC8 genes were sequentially sequenced in all patients. For those who were negative in the initial screening, we examined ERN1, CHGA, CHGB and NKX6-1 genes and, in selected probands, CACNA1C, GCK, FOXP3, NEUROG3 and CDK4. The incidence rate for PNDM/MDI was calculated using a database of Italian patients collected from 1995 to 2009. RESULTS: In group 1 we found mutations in KCNJ11, INS and ABCC8 genes in 23 (50%), 9 (19.5%) and 4 (8.6%) patients respectively, and a single homozygous mutation in GCK (2.1%). In group 2, we identified one incidence of a KCNJ11 mutation. No genetic defects were detected in other loci. The incidence rate of PNDM/MDI in Italy is estimated to be 1:210,287. CONCLUSIONS/INTERPRETATION: Genetic mutations were identified in ~75% of non consanguineous probands with PNDM/MDI, using sequential screening of KCNJ11, INS and ABCC8 genes in infants diagnosed within the first 6 months of age. This percentage decreased to 12% in those with diabetes diagnosed between 7 and 12 months. Patients belonging to the latter group may either carry mutations in genes different from those commonly found in PNDM/MDI or have developed an early onset form of autoimmune diabetes. PMID- 21544519 TI - Educational paper: primary antibody deficiencies. AB - Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies and are characterized by a defect in the production of normal amounts of antigen-specific antibodies. PADs represent a heterogeneous spectrum of conditions, ranging from often asymptomatic selective IgA and IgG subclass deficiencies to the severe congenital agammaglobulinemias, in which the antibody production of all immunoglobulin isotypes is severely decreased. Apart from recurrent respiratory tract infections, PADs are associated with a wide range of other clinical complications. This review will describe the pathophysiology, diagnosis, and treatment of the different PADs. PMID- 21544520 TI - Post-ischemic early acidosis in cardiac postconditioning modifies the activity of antioxidant enzymes, reduces nitration, and favors protein S-nitrosylation. AB - Postconditioning (PostC) modifies the early post-ischemic pH, redox environment, and activity of enzymes. We hypothesized that early acidosis in PostC may affect superoxide dismutase (SOD) and catalase (CAT) activities, may reduce 3 nitrotyrosine (3-NT) protein levels, and may increase S-nitrosylated (SNO) protein levels, thus deploying its protective effects. To verify this hypothesis, we studied the early (7(th) min) and late (120(th) min) phases of reperfusion (a) endogenous SOD and CAT activities and (b) 3-NT protein levels and SNO protein levels. Isolated rat hearts underwent 30-min ischemia/120-min reperfusion (I/R) or PostC (5 cycles of 10-s I/R at the beginning of 120-min reperfusion) either with or without exogenous CAT or SOD infused during the initial 3 min of reperfusion. The effects of early reperfusion with acid buffer (AB, pH 6.8) on endogenous antioxidant enzymes were also tested. Pressure, infarct size, and lactate dehydrogenase release were also measured. At the 7(th) min, PostC induced a significant decrease in SOD activity with no major change both in Mn and Cu/Zn SOD levels and in CAT activity and level. PostC also reduced 3-NT and increased SNO levels. Exogenous SOD, but not CAT, abolished PostC cardioprotection. In late reperfusion (120-min), I/R increased SOD activity but decreased CAT activity and Cu/Zn SOD levels; these effects were reversed by PostC; 3-NT was not affected, but SNO was increased by PostC. AB reproduced PostC effects on antioxidant enzymes. The conclusions are as follows: PostC downregulates endogenous SOD and preserves CAT activity, thus increasing SNO and reducing 3-NT levels. These effects are triggered by early post-ischemic acidosis. Yet acidosis-induced SOD downregulation may limit denitrosylation, thus contributing to PostC triggering. Hence, exogenous SOD, but not CAT, interferes with PostC triggering. Prolonged SOD downregulation and SNO increase may contribute to PostC and AB beneficial effects. PMID- 21544521 TI - Influence of body weight and type of chow on the sensitivity of rats to the behavioral effects of the direct-acting dopamine-receptor agonist quinpirole. AB - RATIONALE: Amount and type of food can alter dopamine systems and sensitivity to drugs acting on those systems. OBJECTIVES: This study examined whether changes in body weight, food type, or both body weight and food type contribute to these effects. METHODS: Rats had free or restricted access (increasing, decreasing, or maintaining body weight) to standard (5.7% fat) or high-fat (34.3%) chow. RESULTS: In rats gaining weight with restricted or free access to high-fat chow, both limbs of the quinpirole yawning dose-response curve (0.0032-0.32 mg/kg) shifted leftward compared with rats eating standard chow. Restricting access to standard or high-fat chow (maintaining or decreasing body weight) decreased or eliminated quinpirole-induced yawning; within 1 week of resuming free feeding, sensitivity to quinpirole was restored, although the descending limb of the dose response curve was shifted leftward in rats eating high-fat chow. These are not likely pharmacokinetic differences because quinpirole-induced hypothermia was not different among groups. PG01037 and L-741,626 antagonized the ascending and descending limbs of the quinpirole dose-response curve in rats eating high-fat chow, indicating D3 and D2 receptor mediation, respectively. Rats eating high-fat chow also developed insulin resistance. CONCLUSIONS: These results show that amount and type of chow alter sensitivity to a direct-acting dopamine-receptor agonist with the impact of each factor depending on whether body weight increases, decreases, or is maintained. These data demonstrate that feeding conditions, perhaps related to insulin and insulin sensitivity, profoundly impact the actions of drugs acting on dopamine systems. PMID- 21544522 TI - West nile virus neuroinvasive disease. AB - West Nile virus (WNV), first recognized in North America in 1999, was responsible for the largest arboviral epidemic of human encephalitis in history and continues to be the most frequent cause of epidemic meningoencephalitis in North America. WNV neuroinvasive disease (WNND) occurs in fewer than 1% of infected individuals, with presentations including aseptic meningitis, encephalitis, and poliomyelitis. Between 1999 and 2009, over 12,000 cases of WNND were reported in the United States, with the peak annual incidence occurring in epidemics of 2002 and 2003. In this review, we first summarize the epidemiology of WNV over the past decade and the salient clinical features of WNND, including a discussion of laboratory and radiographic findings, risk factors, morbidity, and mortality. In addition, we review recent progress in our understanding of virus and host determinants of the pathogenesis of WNND, as well as the prospects for the development of specific therapeutic targets. PMID- 21544524 TI - New synthesis--plant defense signaling: new opportunities for studying chemical diversity. PMID- 21544523 TI - Reduction of myocardial infarct size by dronedarone in pigs--a pleiotropic action? AB - PURPOSE: Dronedarone is a first-line drug to prevent the recurrence of atrial fibrillation according to ESC guidelines. In the recent ATHENA trial, dronedarone reduced mortality and also hospitalization for acute coronary syndrome in patients with atrial fibrillation. This beneficial effect suggests that dronedarone might have also an impact on events associated with ischemia/reperfusion injury. METHODS: Fourteen anesthetized pigs received either dronedarone (2.5 mg/kg) or placebo. Effects of dronedarone on heart rate and blood pressure were reversed by atrial pacing and aortic constriction before pigs were subjected to 90 min regional low-flow myocardial ischemia and 2 h reperfusion. Regional myocardial blood flow was measured with microspheres and infarct size determined by TTC staining. RESULTS: With comparable heart rate and left ventricular pressure during ischemia, dronedarone reduced infarct size from 34 +/- 3% to 22 +/- 4% (p < 0.05) of the area at risk. Subendocardial blood flow during ischemia was not different between groups. The relationship between ischemic subendocardial blood flow in the area at risk and infarct size was displaced downwards, reflecting a direct cardioprotective action of dronedarone. CONCLUSION: The beneficial effect of dronedarone is attributed to cardioprotective properties, possibly through attenuation of calcium overload during myocardial ischemia/reperfusion. PMID- 21544525 TI - Italian toasted bread ('bruschetta') should be carefully evaluated by people with type 1 diabetes. PMID- 21544526 TI - A structurally diversified linker enhances the immune response to a small carbohydrate hapten. AB - The tether employed to covalently attach beta-mannan disaccharide glycoconjugates influences the specificity of rabbit antibodies that protect against Candida albicans. Two glycoconjugates containing (1 -> 2)-beta-mannan disaccharides linked to chicken serum albumin (CSA) either via a structurally uniform or via a stereodiversified spacer were prepared and evaluated in immunization trials in mice and rabbits. Immunization with conjugate vaccine possessing a structurally diversified linker induced higher IgG titers against Candida albicans cell wall phosphomannan than a conjugate with a structurally uniform linker. These results suggest that affinity maturation and the specific antibody response can be shifted towards recognition of the desired hapten by employing a linker with diversified configuration. PMID- 21544527 TI - Simple proposal for dosimetry with an Elekta iViewGTTM electronic portal imaging device (EPID) using commercial software modules. AB - BACKGROUND: An electronic portal imaging device (EPID) is used to control for patient setup and positioning during fractionated radiotherapy. Due to the rising complexity and conformity of irradiation techniques, the demand for an accurate verification of the dose delivered to the patient has also increased. The purpose of this study was to investigate a simple guidance for dosimetry with an Elekta iViewGTTM EPID using commercial software modules. MATERIAL AND METHODS: EPID measurements were performed using an Elekta iViewGTTM EPID on a linear accelerator with 6 MV x-ray beam. The EPID signal was studied for reproducibility, as well as characteristics as a function of dose, dose rate, and field size. A series of experiments, comparing the response of the flat panel imager and ionization chamber measurements of dose, determine the parameters for the calibration model. EPID measurements were also compared with calculations of the treatment planning system. RESULTS: We found a stable response of the EPID signal over a period of 14 months. It showed nonlinearity depending on dose up to 6.8%. There were low oscillations up to 1.2% depending on dose rate. For all fields, the calibrated flat panel profiles match the measured and calculated dose profiles with maximum deviation of 2-3% for the in-field region. In the high gradient areas, higher differences up to 6% were found. CONCLUSIONS: The gamma evaluation indicates good correlation between predicted and acquired EPID images. The EPID-based pretreatment IMRT verification method will help to improve the quality assurance procedure. PMID- 21544529 TI - Cigarette smoking and the risk of incident and fatal melanoma in a large prospective cohort study. AB - OBJECTIVE: Previous studies suggest that smoking may be inversely associated with risk of melanoma. We attempted to replicate this finding using data from the Cancer Prevention Study II (CPS-II) and CPS-II Nutrition cohort, two large prospective cohort studies of cancer mortality and incidence, respectively, with long-term follow-up. METHODS: Cox proportional hazards regression analysis was used to examine the association between smoking status and risk of melanoma mortality and incidence among Caucasians in these cohorts. Analyses were adjusted by age, occupation, latitude and educational status. RESULTS: The incidence rate of melanoma was lower in current than never smokers in both men [hazard ratio (HR): 0.70, 95% confidence interval (CI): (0.48-1.02)] and women [0.50 (0.30 0.83)]; incidence was not lower in former than in never smokers for either sex. The death rate from melanoma was lower in male current than never smokers [0.77 (0.62-0.94)], and in male and female former smokers [0.86 (0.73-1.01)] and [0.83 (0.65-1.06)], respectively. No trends in incidence or mortality were observed in male or female current smokers with years of smoking or cigarettes per day. CONCLUSIONS: This study provides limited support for the hypothesis that smoking reduces melanoma risk. The inconsistent results by smoking status and lack of clear dose-response relationships weaken the evidence for causality. PMID- 21544528 TI - Feasibility and toxicity of concomitant radio/immunotherapy with MabThera (Rituximab(r)) for patients with non-Hodkin's Lymphoma: results of a prospective phase I/II study. AB - PURPOSE: Non-Hodgkin's lymphomas (NHL) have a high radio- and chemosensitivity. Although initially responsive, approximately 50% of low grade B-cell lymphomas relapse after 10-15 years. Besides chemo- and radiotherapy, rituximab, a mouse/human chimeric antibody targeting CD20 antigen on the surface of B-cell lymphoma cells, is another treatment approach. In vitro data showed potentiation of radiation-induced apoptosis by addition of rituximab. The purpose of this study was to evaluate the feasibility and toxicity of radiotherapy with concomitant application of rituximab in NHL patients. PATIENTS AND METHODS: A total of 21 patients with B-cell lymphoma (stage I: n = 11; II: n = 5; III: n = 1; IV: n = 4) were included in this study, treated with radiotherapy of 30-40 Gy and weekly application of rituximab (375 mg/m2). Nine patients had R-CHOP chemotherapy previously, 1 patient leuceran chemotherapy, and 2 patients an initial treatment with 6 cycles of rituximab. Mean time of follow-up was 41.7 months. RESULTS: No grade 4 toxicity or treatment-related death was observed. In 1 patient, rituximab application had to be stopped after 3 cycles due to radiation-induced side effects. No late toxicities were reported. All patients were in complete remission after treatment. Progression or relapse was observed in 6 patients (28%); the mean time to progression was 27 months. The mean overall survival (OS) was 53 months. CONCLUSION: Combined radio/immunotherapy is feasible and safe. Treatment was well tolerated, no late toxicities were observed, and treatment outcome is promising. Randomized trials are necessary to clarify the benefit of this treatment approach and its applicability. PMID- 21544530 TI - Using factor analysis to identify dietary patterns in Iranian adults: Isfahan Healthy Heart Program. AB - OBJECTIVE: To identify dietary patterns of a representative sample of Iranian adults using factor analysis. METHODS: This study was conducted in 2000-2001 as the baseline survey of Isfahan Healthy Heart Program (IHHP). We studied 12,514 participants aged >=19 years who were randomly selected in three counties of Central Iran. A validated 48-item food frequency questionnaire was completed and factor analysis was used to identify dietary patterns. RESULTS: Four major dietary patterns were identified, namely "Western", "animal fat", "traditional" and "Mediterranean". In both men and women, we found a significant positive relationship between age and Mediterranean diet, and a negative relationship between age and the other three dietary patterns (P < 0.001). The Western and traditional dietary patterns showed a significant negative relationship with education in both genders (P < 0.01). The Western dietary pattern correlated positively with being single, widowed, or a divorced man (P < 0.001). CONCLUSIONS: We identified four major dietary patterns. As dietary pattern analysis is useful to identify dietary behaviors in relation to health risks, the results can be practical. PMID- 21544531 TI - Experiences of violence among adolescents: gender patterns in types, perpetrators and associated psychological distress. AB - PURPOSE: To explore the psychological distress associations of experiences of several types of violence and the victim-perpetrator relationship of physical violence, a gender analysis was applied. METHODS: Data were derived from a cross sectional questionnaire study among 17-year-old upper secondary school students (N = 1,663). Variables in focus were: self-reported psychological distress, experiences of physical violence, sexual assault, bullying and sexual harassment. Logistic regressions were used to examine associations. RESULTS: Experiences of physical violence, sexual assault, bullying and sexual harassment were associated with psychological distress in boys and girls. The perpetrators of physical violence were predominately males. Whether the perpetrator was unknown or known to the victim seem to be linked to psychological distress. Victimisation by a boyfriend was strongly related to psychological distress among girls. CONCLUSIONS: Experiences of several types of violence should be highlighted as factors associated with mental health problems in adolescents. The victim perpetrator relationships of violence are gendered and likely influence the psychological distress association. Gendered hierarchies and norms likely influence the extent to which adolescents experience violence and how they respond to it in terms of psychological distress. PMID- 21544532 TI - Biochemical diagnosis and assessment of disease activity in acromegaly: a two decade experience. AB - The objective of this study is to assess the secretory pattern of GH after Oral Glucose Tolerance Test (OGTT) or day-curve (DC), in relation with IGF-I and to evaluate the influence of therapy on OGTT. A retrospective analysis in 279 OGTTs performed in 93 acromegalic patients in our unit from January 1988 to December 2005, in 77 patients also DC data were retrived. GH concentration was evaluated by 3 different systems (RIA, IRMA and chemiluminescence assays), and IGF-I by two RIAs. About 12% of OGTT samples were discordant with the baseline, while discordance between nadir and 120th minute was much lower (5%), with all discordant values, except one, near the cut-off lines. Correlation between DC and OGTT data was around 0.99 among all values, discordance rate between nadir and minimum DC was much lower than that with mean DC. In almost 80% of cases there was a complete concordance between OGTT and DC results, and in about 30% IGF-I was discordant with GH. Correlation analysis between IGF-I and GH was highest with DC data and lowest with OGTT baseline (T0). Considering different treatments discrepancy rates between GH and IGF-I were comparable. The best GH parameter is the minimum GH DC, although in the clinical practice the evaluation of OGTT GH in association with IGF-I is the most practical approach. In this case, the basal and T120 GH values can replace multiple sampling. Different treatment modalities do not influence the discordance rate between GH and IGF-I. PMID- 21544533 TI - Skin testing and infliximab-specific antibodies detection as a combined strategy for preventing infusion reaction. PMID- 21544534 TI - Cardiovascular risk and dietary sugar intake: is the link so sweet? AB - Soft drinks and sugar-sweetened beverages have been targeted as one of the primary culprits in the escalating rates of obesity and diabetes and reduction of added sugars is considered between the goals to achieve in order to promote cardiovascular health and to reduce deaths from cardiovascular causes. Many reliable mechanisms, such as dislypidemia, inflammation and enhanced oxidative stress, have been proposed to support a causal link between sugar sweetened beverages intake and cardiovascular risk, but the ultimate underlying pathways remain to be determined in adequately designed studies. Furthermore, while epidemiological evidence strongly supports an association between sugar sweetened beverages consumption and obesity, type 2 diabetes mellitus or cardiovascular risk, incongruous findings yielded by clinical trials, or formal meta-analyses make difficult to draw firm conclusions in this regard. Further and rigorous studies are needed to better understand the role of sugar sweetened beverages in the etiology of cardiovascular diseases and to better address the warnings and decisions of regulatory authorities on public health worldwide. PMID- 21544535 TI - The role of statins in stroke. AB - Although evidence from epidemiological studies examining a relationship between cholesterol level and stroke is less than definitive, there is a compelling evidence from the clinical therapy trials primarily designed to examine the coronary benefits of statins that statin therapy also causes a reduction in the risk of stroke. Even though a stroke does not have the same exact pathophysiology as a heart attack, specific trials in stroke patients confirm advantages and risks of statin therapy in this kind of population. In primary prevention, statins are effective both when low-density lipoprotein (LDL) is raised and when hs-CRP is elevated. In secondary prevention, an absolute reduction of recurrent stroke can be obtained with statins, with a number needed to treat at 5 years of 45. PMID- 21544536 TI - Prevalence and prognostic role of anaemia in patients with acute heart failure and preserved or depressed ventricular function. AB - Observations available for patients with acute heart failure (HF) show conflicting results, and the prognostic role of anaemia ascertained on hospital admission is not well defined. We investigated the database of the Italian Survey on Acute Heart Failure (IS-AHF) to analyze prevalence, factors associated with and the prognostic role of anaemia (defined as haemoglobin < 12 g/dl) in patients hospitalized for acute HF with either depressed or preserved (>40%) ejection fraction (EF). The median haemoglobin level of the 2,318 patients considered in this analysis was 13 g/dl (inter-quartile range 11.5-14.3). The prevalence of anaemia was 31%. Patients who had anaemia were older, more frequently female gender, hospitalized for a chronic destabilized HF, had higher prevalence of preserved EF, hyponatremia, elevated troponin and other comorbidities (including diabetes, peripheral artery disease, chronic renal failure) than those who did not have anaemia. During the hospital stay, they were treated with higher doses of diuretics, and more frequently required mechanical ventilation and ultrafiltration, and less frequently received ACEi/ARB, aldosterone blockers and beta-blockers at hospital discharge. In-hospital mortality was 12.1 and 5.3% in patients with and without anaemia, respectively (p < 0.0001). In the multivariable analysis, anaemia was a significant independent predictor of in hospital mortality apart from age, low systolic blood pressure, impaired renal function, elevated troponin assay, the non use of beta-blocker and the requirement of inotropic drug. In conclusion, anaemia diagnosed at hospital admission for acute HF is a frequent comorbidity with meaningful implications on the clinical management and prognosis both in patients with reduced and preserved EF. PMID- 21544537 TI - Acute hyperglycemia and insulin resistance in acute heart failure syndromes without previously known diabetes. AB - No data is so far available on the relation between glucose values and insulin resistance and mortality, both at short- and long-term, in patients with acute heart failure syndromes (AHF). We prospectively assessed in 100 consecutive non diabetic AHF patients whether acute glucose metabolism, as indicated by fasting glycemia and insulin resistance (HOMA index) was able to affect short- and long term mortality. In the overall population, 51 patients showed admission glucose values >140 mg/dl. No significant difference was observed in admission and peak glycemia, insulin and C-peptide values and in HOMA-index between dead and survived patients. At multivariate logistic backward stepwise analysis the following variables were independent predictors for in-ICCU mortality (when adjusted for left ventricular ejection fraction): Fibrinogen (1 mg/dl increase) [OR (95% CI) 0.991 (0.984-0.997); p = 0.004]; NT-pro BNP (100 UI increase) [OR (95%CI) 1.005 (1.002-1.009); p = 0.004]; leukocyte count (1,000/MUl increase) [OR (95%CI) 1.252 (1.070-1.464); p = 0.005]. eGFR was independently correlated with long-term mortality (HR 0.96, 95%CI 0.94-0.98, p < 0.001). In consecutive patients with acute heart failure without previously known diabetes, we documented, for the first time, that fasting glucose and insulin values and insulin resistance do not affect mortality at short- and long-term. Inflammatory activation (as indicated by the leukocyte count and the fibrinogen) and NT-pro BNP levels are independent predictors for early death while the eGFR affects the long-term mortality. PMID- 21544538 TI - Statin therapy in patients with aortic stenosis after the ASTRONOMER trial: is there still any space? PMID- 21544539 TI - Computing spatial information from Fourier coefficient distributions. AB - The spatial relationships between molecules can be quantified in terms of information. In the case of membranes, the spatial organization of molecules in a bilayer is closely related to biophysically and biologically important properties. Here, we present an approach to computing spatial information based on Fourier coefficient distributions. The Fourier transform (FT) of an image contains a complete description of the image, and the values of the FT coefficients are uniquely associated with that image. For an image where the distribution of pixels is uncorrelated, the FT coefficients are normally distributed and uncorrelated. Further, the probability distribution for the FT coefficients of such an image can readily be obtained by Parseval's theorem. We take advantage of these properties to compute the spatial information in an image by determining the probability of each coefficient (both real and imaginary parts) in the FT, then using the Shannon formalism to calculate information. By using the probability distribution obtained from Parseval's theorem, an effective distance from the uncorrelated or most uncertain case is obtained. The resulting quantity is an information computed in k-space (kSI). This approach provides a robust, facile and highly flexible framework for quantifying spatial information in images and other types of data (of arbitrary dimensions). The kSI metric is tested on a 2D Ising model, frequently used as a model for lipid bilayer; and the temperature-dependent phase transition is accurately determined from the spatial information in configurations of the system. PMID- 21544540 TI - Cell membrane chromatography competitive binding analysis for characterization of alpha1A adrenoreceptor binding interactions. AB - A new high alpha(1A) adrenoreceptor (alpha(1A)AR) expression cell membrane chromatography (CMC) method was developed for characterization of alpha(1A)AR binding interactions. HEK293 alpha(1A) cell line, which expresses stably high levels of alpha(1A)AR, was used to prepare the stationary phase in the CMC model. The HEK293 alpha(1A)/CMC-offline-HPLC system was applied to specifically recognize the ligands which interact with the alpha(1A)AR, and the dissociation equilibrium constants (K (D)) obtained from the model were (1.87 +/- 0.13) * 10( 6) M for tamsulosin, (2.86 +/- 0.20) * 10(-6) M for 5-methylurapidil, (3.01 +/- 0.19) * 10(-6) M for doxazosin, (3.44 +/- 0.19) * 10(-6) M for terazosin, (3.50 +/- 0.21) * 10(-6) M for alfuzosin, and (7.57 +/- 0.31) * 10(-6) M for phentolamine, respectively. The competitive binding study between tamsulosin and terazosin indicated that the two drugs interacted at the common binding site of alpha(1A)AR. However, that was not the case between tamsulosin and oxymetazoline. The results had a positive correlation with those from radioligand binding assay and indicated that the CMC method combined modified competitive binding could be a quick and efficient way for characterizing the drug-receptor interactions. PMID- 21544541 TI - Intrinsic ratios of glucose, fructose, glycerol and ethanol 13C/12C isotopic ratio determined by HPLC-co-IRMS: toward determining constants for wine authentication. AB - High-performance liquid chromatography linked to isotope ratio mass spectrometry (HPLC-co-IRMS) via a Liquiface(c) interface has been used to simultaneously determine (13)C isotope ratios of glucose (G), fructose (F), glycerol (Gly) and ethanol (Eth) in sweet and semi-sweet wines. The data has been used the study of wine authenticity. For this purpose, 20 authentic wines from various French production areas and various vintages have been analyzed after dilution in pure water from 20 to 200 times according to sugar content. If the (13)C isotope ratios vary according to the production area and the vintage, it appears that internal ratios of (13)C isotope ratios (R((13)C)) of the four compounds studied can be considered as a constant. Thus, ratios of isotope ratios are found to be 1.00 +/- 0.04 and 1.02 +/- 0.08 for R((13)C(G/F)) and R((13)C(Gly/Eth)), respectively. Moreover, R((13)C(Eth/Sugar)) is found to be 1.15 +/- 0.10 and 1.16 +/- 0.08 for R((13)C(Gly/Sugar)). Additions of glucose, fructose and glycerol to a reference wine show a variation of the R((13)C) value for a single product addition as low as 2.5 g/L(-1). Eighteen commercial wines and 17 concentrated musts have been analyzed. Three wine samples are suspicious as the R((13)C) values are out of range indicating a sweetening treatment. Moreover, concentrated must analysis shows that (13)C isotope ratio can be also used directly to determine the authenticity of the matrix. PMID- 21544542 TI - MicroRNAs as biomarkers of disease onset. AB - MicroRNAs (miRNAs) are small, noncoding RNA molecules with the ability to posttranscriptionally regulate gene expression via targeting the 3' untranslated region of messenger RNAs. miRNAs are critical for normal cellular functions such as the regulation of the cell cycle, differentiation, and apoptosis, and they target genes during embryonal and postnatal development, whereas their expression is unbalanced in various pathological states. Importantly, miRNAs are abundantly present in body fluids (e.g., blood), which are routinely examined in patients. These molecules circulate in free and exosome encapsulated forms, and can be efficiently detected and amplified by means of molecular biology tools such as real-time PCR. Together with relative stability, specificity, and reproducibility, they are seen as good candidates for early recognition of the onset of disease. Thus, miRNAs might be considered as biomarkers for many pathological states. PMID- 21544543 TI - A deuterium-labelling mass spectrometry-tandem diode-array detector screening method for rapid discovery of naturally occurring electrophiles. AB - Because electrophiles regulate many signalling pathways in cells, by modifying cysteine residues in proteins, they have a wide range of biological activity. In this study, a deuterium-labelling mass spectrometry-tandem diode-array detector (MS-DAD) screening method was established for rapid discovery of naturally occurring electrophiles. Glutathione (GSH) was used as a probe and incubated with natural product extracts. To distinguish different types of electrophile, incubation was performed in two reaction solvents, H(2)O and D(2)O. Ten types of naturally occurring electrophile were chosen, on the basis of their properties, to undergo the screening assay. By using this screening method, we successfully discovered the bioactive electrophile 4-hydroxyderricin in an ethanol extract of Angelica keiskei. This electrophile had potent NAD(P)H:quinone oxidoreductase 1 (NQO1)-inducing activity at a concentration of 20 MUmol L(-1). PMID- 21544544 TI - Design and evaluation of a recombinant multi-epitope-based ELISA for the serological surveillance of HEV infection in northern China. AB - In this study, seven recombinant epitope peptides from within the ORF2 protein of the local genotype 4 swine hepatitis E virus (HEV) DQ strain were designed and analyzed. Then, a new multi-epitope-based ELISA was established. In comparison with a commercial kit, this test exhibited good specificity and sensitivity for anti-HEV genotype 4. Subsequently, this test was applied for analyzing serum samples from either swine herds or human populations in northern China. The overall seroprevalence rate of anti-HEV IgG reached up to 40.4% for swine and 8.1% for humans. A statistical difference was observed for humans in rural and urban areas, with a higher prevalence for people living in rural than urban areas. Moreover, sequencing confirmed that all RNA-positive samples belonged to genotype 4. PMID- 21544545 TI - Identification of three immediate-early genes of white spot syndrome virus. AB - Viral immediate-early (IE) genes generally encode regulatory proteins that are critical for viral replication. Their transcription, which is independent of de novo viral protein synthesis, is driven directly by host transcription factors. In this study, we examined promoter activities of 12 predicted regulatory genes of white spot syndrome virus (WSSV) belonging to the zinc finger protein family by EGFP-reporter assays in High Five cells. The results showed that the promoters of three genes (wsv056, wsv403 and wsv465) could drive reporter gene expression, and RT-PCR analysis revealed that their expression in WSSV-infected primary crayfish hemocytes was insensitive to the protein synthesis inhibitor cycloheximide (CHX). Therefore, they are IE genes of WSSV. PMID- 21544548 TI - Perforator-based propeller flaps treating loss of substance in the lower limb. AB - BACKGROUND: Local flaps based on perforator vessels are raising interest in reconstructive surgery of the limbs. These flaps allow efficient coverage of large wounds without the need to sacrifice a major vascular axis. The operative technique does not require microvascular anastomosis and allows reconstruction of soft tissue defects using nearby similar tissues. The aim of this study was to evaluate the clinical results of local perforator flaps in the treatment of complex lower-limb defects. MATERIALS AND METHODS: Twenty-two local perforator flaps were retrospectively studied. Loss of substance was due to postsurgical complications in seven cases, oncological resection in six, posttraumatic defect in five, pressure sores in three, and osteomyelitis in one. RESULTS: Postoperatively, two patients showed partial flap necrosis. In five patients, a superficial epidermolysis occurred. Minor complications were seen in three patients who showed transient venous congestion of the flap. Furthermore, transient leg edema was sometimes observed in patients with large propeller flaps. All but one patient healed without further major surgical procedures. In three cases, secondary skin grafts were performed. In most cases, the aesthetic result was optimal and patients were fully satisfied. CONCLUSIONS: When characteristics of the defect are suitable for treatment with a propeller-based local flap, this technique should be considered as one of reasonable options for surgical reconstruction. Microsurgical techniques facilitate the management of complex trauma in emergency and may allow planning reconstructive procedures and limb salvage in elective orthopedic surgery. PMID- 21544547 TI - Loss of huntingtin-associated protein 1 impairs insulin secretion from pancreatic beta-cells. AB - Hap1 was originally identified as a neuronal protein that interacts with huntingtin, the Huntington's disease (HD) protein. Later studies revealed that Hap1 participates in intracellular trafficking in neuronal cells and that this trafficking function can be adversely affected by mutant huntingtin. Hap1 is also present in pancreatic beta-cells and other endocrine cells; however, the role of Hap1 in these endocrine cells remains unknown. Using the Cre-loxP system, we generated conditional Hap1 knockout mice to selectively deplete the expression of Hap1 in mouse pancreatic beta-cells. Mutant mice with Hap1 deficiency in pancreatic beta-cells had impaired glucose tolerance and decreased insulin release in response to intraperitoneally injected glucose. Using cultured pancreatic beta-cell lines and isolated mouse pancreatic islets, we confirmed that decreasing Hap1 could reduce glucose-mediated insulin release. Electron microscopy suggested that there was a reduced number of insulin-containing vesicles docked at the plasma membrane of pancreatic islets in Hap1 mutant mice following intraperitoneal glucose injection. Glucose treatment decreased the phosphorylation of Hap1A in cultured beta-cells and in mouse pancreatic tissues. Moreover, this glucose treatment increased Hap1's association with kinesin light chain and dynactin p150, both of which are involved in microtubule-dependent trafficking. These studies suggest that Hap1 is important for insulin release from beta-cells via dephosphorylation that can regulate its intracellular trafficking function. PMID- 21544546 TI - The multiple roles of Notch signaling during left-right patterning. AB - The establishment of left-right (LR) asymmetry is regulated by intricate signaling mechanisms during embryogenesis and this asymmetry is critical for morphogenesis as well as the positioning of internal organs within the organism. Recent progress including elucidation of ion transporters, leftward nodal flow, and regulation of asymmetric gene expression contributes to our understanding of how the breaking of the symmetry is initiated and how this laterality information is subsequently transmitted to the organ primordium. A number of developmental signaling pathways have been implicated in this complex process. In this review, we will focus on the roles of the Notch signaling pathway during development of LR asymmetry. The Notch signaling pathway is a short-range communication system between neighboring cells. While Notch signaling plays essential roles in regulating the morphogenesis of the node and left-specific expression of Nodal in the lateral plate mesoderm, a hallmark gene in LR patterning, Notch signaling also suppresses the expression of Pitx2 that is a direct downstream target of Nodal during later stages of development. This negative activity of Notch signaling towards left-specific activity was recently shown to be inhibited by the B cell lymphoma 6 (BCL6)/BCL6 co-repressor (BcoR) transcriptional repressor complex in a target-specific manner. The complex regulation of Notch-dependent gene expression for LR asymmetry will be highlighted in this review. PMID- 21544549 TI - Healing of surgical site after total hip and knee replacements show similar telethermographic patterns. AB - BACKGROUND: Isolated reports indicate the efficacy of infrared thermography for monitoring wound healing and septic complications, but no long-term analysis has ever been performed on this, and there are no data on the telethermographic patterns of surgical site healing after uncomplicated total hip prosthesis and after knee prosthesis. MATERIALS AND METHODS: In this prospective, observational, nonrandomized cohort study, two groups with forty consecutive patients each, who were operated on respectively for total hip and for total knee replacements, underwent telethermographic examination of the operated and contralateral joints prior to and at fixed intervals for up to 1 year after uncomplicated surgery. A digital, portable telethermocamera and dedicated software were used for data acquisition and processing. RESULTS: No thermographic difference was observed preoperatively between the affected side and the contralateral side in both groups. After the intervention, a steep increase in the temperature of the operated joint was recorded after total hip replacement and after knee replacement, with a peak mean differential temperature measured three days postoperatively between the operated and unoperated joint of 3.1 +/- 0.8 degrees C after total hip replacement, and 3.4 +/- 0.7 degrees C after total knee replacement. Thereafter, the mean differential temperature declined slowly to 0.7 +/- 1.1 degrees C and to 0.5 +/- 1.3 degrees C at 60 days, and to 0.0 +/- 1.0 degrees C and -0.1 +/- 1.1 degrees C 90 days post-operatively, respectively. No further changes were observed for up to 1 year after surgery. Results were similar when comparing the average telethermographic values of an elliptical area where the main axis corresponded to the surgical wound. CONCLUSIONS: The surgical sites after uncomplicated total hip or total knee replacement show similar telethermographic patterns for up to 1 year from surgery, and can easily be monitored using a portable, digital, telethermocamera. PMID- 21544550 TI - Podcasting in medical education: can we turn this toy into an effective learning tool? AB - Advances in information technology have changed how we deliver medical education, sometimes for the better, sometimes not. Technologies that were designed for purposes other than education, such as podcasting, are now frequently used in medical education. In this article, the authors discuss the pros and cons of adapting existing technologies for medical education, caution against limiting evaluation of technologies to the level of rater satisfaction, and suggest a research agenda for formally evaluating the role of existing and future technologies in medical education. PMID- 21544551 TI - Self-reflection and academic performance: is there a relationship? AB - The purposes of the present study were two-fold: first, to evaluate whether reflection journal writing was effective in promoting self-reflection and learning, and whether students become better at self-reflection if they engage continuously in reflection journal writing. To that end, the reflection journals of 690 first-year applied science students at a local polytechnic were studied by means of an automated coding procedures using software. Data was collected twice, once at the beginning and again towards the end of an academic year. Outcomes of the textual content analyses revealed that students reflected on both the process and contents of their learning: critical review of past learning experiences, learning strategies and summaries of what was learned. Correlational analyses showed weak to moderate inter-relationships between the textual categories and their classroom and knowledge acquisition test grades. Taken together, the findings suggest that self-reflection on both how and what students have learned does lead to improvements in academic performance, although to a limited extent. PMID- 21544554 TI - Identification and Characterization of a Trypsin Inhibitor from Fagopyrum tataricum Seeds. AB - This study was aimed at investigating the purification and identification of serine protease inhibitors, F. tataricum trypsin inhibitor (FtTI) from tartary buckwheat (Fagopyrum tataricum) seeds. The FtTI was isolated by anion exchange chromatography, affinity chromatography, and centrifugal ultrafiltration. Under reducing and nonreducing conditions, an SDS-PAGE analysis showed that the isolated protein consists of a single polypeptide chain with a molecular mass of approximately 14 kDa. The two isoforms of FtTI were confirmed by the mass spectrometric profile where the two peaks corresponded to 11.487 and 13.838 kDa. The complete amino acid sequence of FtTI has been established by automatic Edman degradation and mass spectrometry. The molecule of FtTI consists of 86 amino acid residues containing two disulfide bonds which connect Cys8 to Cys65 and Cys49 to Cys58. The active site of FtTI contains an Asp66-Arg67 bond. The Ki value was calculated using the equation for slow tight binding inhibition which was 1.6 nM for trypsin. FtTI retained its inhibitory activity over a wide range of pH (3-10) and temperature (20-80 degrees C). FtTI can be rapidly inactivated by the combination of high temperature and high pressure. An analysis of the amino acid sequence suggests that FtTI is a member of the protease inhibitor Iota family. Furthermore, FtTI exhibited a strong inhibitory activity against phytopathogenic fungi. PMID- 21544552 TI - Combined use of anticancer drugs and an inhibitor of multiple drug resistance associated protein-1 increases sensitivity and decreases survival of glioblastoma multiforme cells in vitro. AB - Glioblastoma multiforme (GBM) is a brain tumour characterised by a remarkably high chemoresistance and infiltrating capability. To date, chemotherapy with temozolomide has contributed only poorly to improved survival rates in patients. One of the most important mechanisms of chemoresistance comes about through the activity of certain proteins from the ATP-binding cassette superfamily that extrudes antitumour drugs, or their metabolites, from cells. We identify an increased expression of the multiple drug resistance-associated protein 1 (Mrp1) in glioblastoma multiforme biopsies and in T98G and G44 cell lines. The activity of this transporter was also confirmed by measuring the extrusion of the fluorescent substrate CFDA. The sensitivity of GBM cells was low upon exposure to temozolomide, vincristine and etoposide, with decreases in cell viability of below 20% seen at therapeutic concentrations of these drugs. However, combined exposure to vincristine or etoposide with an inhibitor of Mrp1 efficiently decreased cell viability by up to 80%. We conclude that chemosensitization of cells with inhibitors of Mrp1 activity might be an efficient tool for the treatment of human GBM. PMID- 21544553 TI - Calpain modulates cyclin-dependent kinase inhibitor 1B (p27(Kip1)) in cells of the osteoblast lineage. AB - The ubiquitously expressed calpains-1 and -2 belong to a family of calcium dependent intracellular cysteine proteases. Both calpains are heterodimers consisting of a large catalytic subunit and a small regulatory subunit encoded by the gene Capn4. Ablation of the calpain small subunit eliminates calpain activity and leads to embryonic lethality. We previously created osteoblast-specific Capn4 knockout mice to investigate a physiological role for the calpain small subunit in cells of the osteoblast lineage. Deletion of Capn4 reduced trabecular and cortical bone, mainly due to impaired proliferation and differentiation of cells of the osteoblast lineage. To further investigate an underlining mechanism by which osteoblast-specific Capn4 knockout mice develop an osteoporotic bone phenotype, we established osteoblastic cell lines stably expressing either control or Capn4 RNA interference for this study. Capn4 knockdown cells showed reduced cell proliferation, accumulation of total and phosphorylated cyclin dependent kinase inhibitor 1B (p27(Kip1)) on serine 10, and reduced phosphorylation of retinoblastoma protein on threonine 821. Moreover, ablation of Capn4 increased 27 ( Kip1 ) mRNA levels, likely due to stabilized binding of Akt to protein phosphatase 2A, which presumably results in reduced phosphorylation of Akt on S473 and forkhead Box O (FoxO) 3A on T32. Collectively, calpain regulates cell proliferative function by modulating both transcription and degradation of p27(Kip1) in osteoblasts. In conclusion, calpain is a critical modulator for regulation of p27(Kip1) in cells of the osteoblast lineage. PMID- 21544555 TI - Growth inhibition and induction of stress protein, GroEL, of Bacillus cereus exposed to antibacterial peptide isolated from Bacillus subtilis SC-8. AB - This study was conducted to investigate the antibacterial effect of BSAP-254 on Bacillus cereus with the induced stress proteins. The BSAP-254 is an antimicrobial peptide isolated from soybean-fermenting bacteria, Bacillus subtilis SC-8. It had a narrow spectrum of activity against B. cereus group. The growth inhibitory effect of BSAP-254 (50 MUg/mL) reduced the population of B. cereus from >10(8) to 10(4) colony-forming units per milliliter within 30 min. In B. cereus exposed to BSAP-254, 14 intracellular proteins were differentially expressed as determined by 2-DE coupled with MS. Of the differentially expressed proteins identified, the stress protein GroEL, which is heat shock protein, was induced in B. cereus exposed to antibacterial peptide. PMID- 21544556 TI - Toxicity of cyanobacterial bloom extracts from Taihu Lake on mouse, Mus musculus. AB - The acute and sub-chronic toxicities of cyanobacterial extract from Taihu Lake (PR China) on mouse (Mus musculus) were investigated in this study via intraperitoneal (i.p.) injection. Increases in liver/body weight ratios and pathological changes in mouse liver showed adverse effects at the organ level. Images from transmission electron microscopy (TEM) indicated that abnormal membrane structure occurred and that the organelles were damaged severely in the cells of liver and testis. The high dose group received i.p. injection of 12 mg lyophilized algae cells/kg body weight. Malondialdehyde (MDA) levels increased significantly in the livers of this group, along with a significant decrease in catalase (CAT) activity. These results revealed the existence of obvious oxidative stress. Comet assay results also suggested a dose-dependent relationship between DNA damage in hepatocytes/testicular cells and the amount of bloom extract administered to the mice. There was a significant increase in DNA damage compared to the control group and the genotoxicity of the cyanobacterial bloom to testicular cells was higher than in hepatocytes. PMID- 21544557 TI - Baseline trace metals in bivalve molluscs from the Beagle Channel, Patagonia (Argentina). AB - In order to test the aptitude of individuals of Mytilus chilensis as biomonitors of heavy metals pollution in seawater, several samples of this mollusk together with surrounding seawater samples were collected along 170 km of the coastal area of the Beagle Channel (Tierra del Fuego, Argentina) in 2005 and 2007. The study, performed in seven locations strategically selected, involved the determination of Cd, Cr, Cu, Ni, Pb and Zn in seawaters and mollusks by atomic absorption spectrometry (AAS) and the calculation of the respective concentration factors (CFs). Obtained data were standardized and analyzed by multivariate techniques in order to establish differences between sampling sites and periods. Obtained results will be shown and the bioaccumulation ability of M. chilensis will be evaluated by comparison with results obtained for Mytilus species in different geographical marine areas. A fully discussion on the possibility of employing the results as background levels for comparative purposes in other marine waters of the world will be provided. The possible harm derived from human consumption of these mollusks will be also assessed. PMID- 21544558 TI - Practical implications for the administration of 13-cis retinoic acid in pediatric oncology. AB - Children with high-risk neuroblastoma are treated with polychemotherapy, surgery, radiotherapy and even autologous stem-cell transplantation. On top of this complex treatment, most children also receive 13-cis retinoic acid as differentiation agent. As no suitable pharmaceutical formulation is available so far, there are often problems with the administration of the product in children. The present report describes some practical recommendations for the administration of isotretinoin in children treated for high-risk neuroblastoma. PMID- 21544559 TI - Effect of a 36-month pharmaceutical care program on pharmacotherapy adherence in elderly diabetic and hypertensive patients. AB - OBJECTIVE: The primary objective of this study was to evaluate the effect of a pharmaceutical care program on pharmacotherapy adherence in elderly diabetic and hypertensive patients. The clinical outcomes of this pharmacotherapy adherence approach were the secondary objective of the study. SETTING: Public Primary Health Care Unit in a municipality in the Brazilian State of Sao Paulo. METHOD: A 36-month randomized, controlled, prospective clinical trial was carried out with 200 patients divided into two groups: control (n = 100) and intervention (n = 100). The control group received the usual care offered by the Primary Health Care Unit (medical and nurse consultancies). The patients randomized into the intervention group received pharmaceutical care intervention besides the usual care offered. MAIN OUTCOME MEASURE: Pharmacotherapy adherence (Morisky-Green test translated into Portuguese and computerized dispensed medication history) and clinical measurements (blood pressure, fasting glucose, A1C hemoglobin, triglycerides and total cholesterol) were evaluated at the baseline and up to 36 months. A P value <0.05 was considered statistically significant. RESULTS: A total of 97 patients from the intervention group and 97 patients from the control group completed the study (n = 194). Significant improvements in the pharmacotherapy adherence were verified for the intervention group according to the Morisky-Green test (50.5% of adherent patients at baseline vs. 83.5% of adherent patients after 36 months; P < 0.001) and the computerized dispensed medication history (52.6% of adherent patients at baseline vs. 83.5% of adherent patients after 36 months; P < 0.001); no significant changes were verified in the control group. Significant improvements in the number of patients reaching adequate values for their blood pressure (26.8% at baseline vs. 86.6% after 36 months; P < 0.001), fasting glucose (29.9% at baseline vs. 70.1% after 36 months; P < 0.001), A1C hemoglobin (3.3% at baseline vs. 63.3% after 36 months; P < 0.001), triglycerides (47.4% at baseline vs. 74.2% after 36 months; P < 0.001) and total cholesterol (59.8% at baseline vs. 80.4% after 36 months; P = 0.002) were verified in the intervention group, but remained unchanged in the control group. CONCLUSION: These results indicated the effectiveness of pharmaceutical care in improving pharmacotherapy adherence, with positive effects in the clinical outcomes of the patients studied. PMID- 21544560 TI - Impact of the FDA warning of potential ceftriaxone and calcium interactions on drug use policy in clinical practice. AB - OBJECTIVE: In September 2007, the FDA issued an alert recommending that ceftriaxone and calcium-containing solutions should not be administered to any patient within 48 h of each other. Due to the widespread use of ceftriaxone, significant concern was expressed by the greater healthcare community about the warning, which the FDA eventually retracted in April of 2009. We sought to quantify the impact of the warning on healthcare institutions. SETTING: A survey was administered to the membership of the Society of Infectious Diseases Pharmacists to quantify perceived changes in ceftriaxone use among healthcare institutions across the United States. METHOD: A survey of Infectious Diseases experts was conducted. Participants were queried for hospital policies/drug use statistics during two times: immediately after the FDA warning and approximately 13 months post warning (preceding the FDA retraction). MAIN OUTCOME MEASURE: Related changes in formulary, drug-use policy, and the number of employee hours that were devoted to addressing the FDA warning were assessed. RESULTS: Ninety four surveys representing 94 hospital systems were included in the analysis. Approximately half (n = 49, 52%) of respondent institutions enacted at least one drug-use policy change based on the warning; one institution removed ceftriaxone from a clinical protocol. Institutions' final interpretations of the warning differed slightly from initial understanding of the warning, and there was an overall minor decrease in the perceived use of ceftriaxone. The majority of those surveyed (n = 70, 74%) estimated that their respective institutions devoted between 1 and 49 employee hours to address the warning. CONCLUSION: Hospitals with ID pharmacists had minimal changes to ceftriaxone use after the 2007 FDA warning. Specialized pharmacists may be uniquely situated to help hospitals interpret global recommendations locally. PMID- 21544561 TI - [Reviews]. PMID- 21544562 TI - [Problems of the historiography of science in Islamic societies before 1700]. PMID- 21544563 TI - Medulla oblongata injury caused by an acupuncture needle; warning for serious complications due to a common method of alternative medicine. PMID- 21544564 TI - Presenilin 2 mutation R71W in an Italian early-onset sporadic Alzheimer's disease case. AB - Mutations in the presenilin 2 (PSEN2) gene are less commonly identified as genetic causes of early-onset familial Alzheimer's disease than mutations in the amyloid precursor protein (APP) and the presenilin 1 (PSEN1) genes. In fact, only 23 different mutations in the PSEN2 gene have been described in the literature. This paper deals with a sporadic case of a 55 year-old subject bearing an amino acid substitution from arginine to tryptophan at codon 71 of PSEN2 and presenting a peculiar early-onset Alzheimer's disease phenotype. PMID- 21544565 TI - Vascular function and multiple sclerosis. AB - Multiple sclerosis (MS) is a debilitating disease with an assumed autoimmune etiology which may lead to elevated oxidative stress, vascular dysfunction, and subsequent predisposition to cardiovascular disease. Therefore, the primary aim of this study was to evaluate vascular function and the potential role of oxidative stress in patients diagnosed with MS compared to healthy controls (C). Fourteen patients with relapsing-remitting MS (47 +/- 3 years) and 13 age- and activity-matched controls (44 +/- 5 years) underwent brachial artery flow mediated dilation (FMD) and reactive hyperemia testing using ultrasound Doppler. Venous blood was analyzed for C-reactive protein (CRP), lipid hydroperoxides (LH), the ferric reducing ability of plasma (FRAP), superoxide dismutase (SOD), and catalase activity. CRP [1.8 +/- 0.5 mg/L (MS), 1.0 +/- 0.5 mg/L (C)] and LH [1.2 +/- 0.2 MUmol/L (MS), 1.1 +/- 0.1 MUmol/L (C)] were not different between MS patients and controls. FMD [8.0 +/- 1.2% (MS) and 9.2 +/- 1.6% (C)] and reactive hyperemia [380 +/- 61 mL (MS) and 402 +/- 69 mL (C)] were also not different between groups. Vascular function, as assessed by both FMD and reactive hyperemia, was not impaired in patients with MS compared to controls. Further, there was no evidence of elevated systemic inflammation or oxidative stress in these patients, who were currently all in remission. These findings suggest that impaired vascular function, elevated inflammation and oxidative stress are not an obligatory accompaniment to MS. PMID- 21544566 TI - Functions of the nigrostriatal dopaminergic synapse and the use of neurotransplantation in Parkinson's disease. AB - While pharmaceutical options remain the overwhelmingly accepted treatment of choice for neurological and psychiatric diseases, significant accomplishments in regenerative neuroscience research have demonstrated the potential of cellular and synaptic functional repair in future therapies. Parkinson's disease stands out as an example in which repair by dopaminergic neurons appears a viable potential therapy. This article describes the basic neurobiological underpinnings of the rationale for cell therapy for Parkinson's disease and the challenges ahead for the use of regenerative medicine in the treatment for this disease. PMID- 21544567 TI - The phenotypic spectrum of neutral lipid storage myopathy due to mutations in the PNPLA2 gene. AB - Neutral lipid storage disease is caused by mutations in the CGI-58 or the PNPLA2 genes. Lipid storage can be detected in various cell types including blood granulocytes. While CGI-58 mutations are associated with Chanarin-Dorfman syndrome, a condition characterized by lipid storage and skin involvement (ichthyosis), mutations in the patatin-like phospholipase domain-containing protein 2 gene (PNPLA2) were reported with skeletal and cardiac muscle disease only. We describe clinical, myopathological, magnetic resonance imaging (MRI), and genetic findings of six patients carrying different recessive PNPLA2 mutations. Pulse-chase labeling of control and patient cells with supplementation of clenbuterol, salmeterol, and dexamethasone was performed in vitro. The patients share a recognizable phenotype with prominent shoulder girdle weakness and mild pelvic girdle and distal muscle weakness, with highly elevated creatine kinase (CK) and cardiomyopathy developing at later stages. Muscle histology invariably reveals massive accumulation of lipid droplets. New muscle or whole body MRI techniques may assist diagnosis and may become a useful tool to quantify intramuscular lipid storage. Four novel and two previously reported mutations were detected, affecting different parts of the PNPLA2 gene. Activation of hormone-sensitive lipase by beta-adrenergic substances such as clenbuterol appears to bypass the enzymatic block in PNPLA2-deficient patient cells in vitro. PNPLA2 deficiency is a slowly progressive myopathy with onset around the third decade. Cardiac involvement is relatively common at a later stage. Muscle MRI may detect increased lipid in a characteristic distribution, which could be used for monitoring disease progression. Beta-adrenergic agents may be beneficial in improving triacylglycerol breakdown in patients with PNPLA2 mutations. PMID- 21544568 TI - Is theory of mind related to social dysfunction and emotional problems in 22q11.2 deletion syndrome (velo-cardio-facial syndrome)? AB - Social dysfunction is intrinsically involved in severe psychiatric disorders such as depression and psychosis and linked with poor theory of mind. Children with 22q11.2 deletion syndrome (22q11DS, or velo-cardio-facial syndrome) have poor social competence and are also at a particularly high risk of developing mood (40%) and psychotic (up to 30%) disorders in adolescence and young adulthood. However, it is unknown if these problems are associated with theory of mind skills, including underlying social-cognitive and social-perceptual mechanisms. The present cross-sectional study included classic social-cognitive false-belief and mentalising tasks and social-perceptual face processing tasks. The performance of 50 children with 22q11DS was compared with 31 age-matched typically developing sibling controls. Key findings indicated that, while younger children with 22q11DS showed impaired acquisition of social-cognitive skills, older children with 22q11DS were not significantly impaired compared with sibling controls. However, children with 22q11DS were found to have social-perceptual deficits, as demonstrated by difficulties in matching faces on the basis of identity, emotion, facial speech and gaze compared with sibling controls. Furthermore, performance on the tasks was associated with age, language ability and parentally rated social competence and emotional problems. These results are discussed in relation to the importance of a better delineation of social competence in this population. PMID- 21544569 TI - Four weeks of training in a sledge jump system improved the jump pattern to almost natural reactive jumps. AB - In spite of extensive training regimens during long-term space missions with existing training devices, astronauts suffer from muscle and bone loss. It has been suggested that reactive jumps inducing high forces in the muscles consequently exposing the bones to high strains-help to counteract these degradations. In a previous study, a new sledge jump system (SJS) was found to allow fairly natural reactive jumps. The aim of the present study was to evaluate if training in the SJS would further reduce the differences between jumps in the SJS and normal jumps, particularly with respect to ground reaction forces (GRF) and rate of force development (RFD). Sixteen participants in a training group (TG) and 16 in a control group (CON) were tested before and after the TGs four week hopping training in the SJS. During the tests, kinetic, kinematic and electromyographic data were compared between hops on the ground and in the SJS. After the training period, the GRF, the RFD and the leg stiffness in the SJS significantly increased for the TG (but not for CON) by 10, 35 and 38%, respectively. The kinematic and electromyographic data showed no significant changes. A short training regimen in the SJS reduced the differences between jumps in the SJS and normal jumps. Considering that a natural movement that exposes the muscles and thus also the bones to high loads is regarded as important for the preservation of muscle and bone, the SJS seems to be a promising countermeasure. PMID- 21544570 TI - The effect of fixation transitions on quiet eye duration and performance in the soccer penalty kick: instep versus inside kicks. AB - Male goalkeepers of intermediate skill level attempted to stop penalty kicks executed with the instep and inside foot, in situ. A mobile eye tracker and an external camera were used to collect the gaze and motor behaviors of the goalkeepers, as well as the penalty takers' motor behaviors and flight of the ball. Percent saves was greater during instep (28%) than inside foot kicks (12%), but we detected few differences in fixation frequency, location, duration, or transitions that could be attributed to the type of kick used. Fixation transitions (or the frequency of gaze shifts between locations) were significantly higher on goals than on saves. During the final phase of the kicking action, the quiet eye was located on the visual pivot and was longer during saves than goals. Furthermore, when the final fixation on the ball exceeded approximately 1,100 ms, then the likelihood of goals increased. The results are discussed in light of past studies in goaltending and the dual demands of motor tasks that require information be fixated both early and late at spatial locations that exceed the limits of focal vision. PMID- 21544571 TI - Species traits predict assembly of mayfly and stonefly communities along pH gradients. AB - Much recent ecological research has centred on the interrelations between species diversity and ecological processes. In the present study, I show how species traits may aid in comprehending ecology by studying the link between an environmental variable and functional traits. I examined the composition of species traits with a theoretically underpinned relationship to ecological processes along a pH gradient. I focused on body size, reproductive output, life cycle length and feeding habit of mayflies and stoneflies. In mayfly assemblages, I found smaller body size, greater reproductive output, faster life cycles and a larger proportion of gathering collectors and scrapers with increasing pH. In stonefly assemblages, I found smaller body size, greater reproductive output and faster life cycles at sites with a history of long-term natural acidification, but no clear trends in feeding habits and in most traits where acidification is anthropogenic. The results suggest that mayflies and stoneflies exhibit different ecological functions following different ecological strategies. Mayflies follow an opportunistic strategy relative to stoneflies, likely facilitating high rates of ecological processes with respect to the autotrophic resource base at neutral sites. Relative to mayflies, stoneflies follow an equilibrium strategy contributing to ecological functioning in heterotrophic ecosystems and likely maintaining heterotrophic processes despite the erosion of species diversity in response to acidification. The rules governing an ecological community may be more readily revealed by studying the distribution of species traits instead of species diversity; by studying traits, we are likely to improve our understanding of the workings of ecological communities. PMID- 21544572 TI - Effects of nutrient addition on leaf chemistry, morphology, and photosynthetic capacity of three bog shrubs. AB - Plants in nutrient-poor environments typically have low foliar nitrogen (N) concentrations, long-lived tissues with leaf traits designed to use nutrients efficiently, and low rates of photosynthesis. We postulated that increasing N availability due to atmospheric deposition would increase photosynthetic capacity, foliar N, and specific leaf area (SLA) of bog shrubs. We measured photosynthesis, foliar chemistry and leaf morphology in three ericaceous shrubs (Vaccinium myrtilloides, Ledum groenlandicum and Chamaedaphne calyculata) in a long-term fertilization experiment at Mer Bleue bog, Ontario, Canada, with a background deposition of 0.8 g N m(-2) a(-1). While biomass and chlorophyll concentrations increased in the highest nutrient treatment for C. calyculata, we found no change in the rates of light-saturated photosynthesis (A(max)), carboxylation (V(cmax)), or SLA with nutrient (N with and without PK) addition, with the exception of a weak positive correlation between foliar N and A(max) for C. calyculata, and higher V(cmax) in L. groenlandicum with low nutrient addition. We found negative correlations between photosynthetic N use efficiency (PNUE) and foliar N, accompanied by a species-specific increase in one or more amino acids, which may be a sign of excess N availability and/or a mechanism to reduce ammonium (NH(4)) toxicity. We also observed a decrease in foliar soluble Ca and Mg concentrations, essential minerals for plant growth, but no change in polyamines, indicators of physiological stress under conditions of high N accumulation. These results suggest that plants adapted to low-nutrient environments do not shift their resource allocation to photosynthetic processes, even after reaching N sufficiency, but instead store the excess N in organic compounds for future use. In the long term, bog species may not be able to take advantage of elevated nutrients, resulting in them being replaced by species that are better adapted to a higher nutrient environment. PMID- 21544573 TI - A baker's dozen of ubiquitin. PMID- 21544574 TI - Streptomyces autolyticus JX-47 large-insert bacterial artificial chromosome library construction and identification of clones covering geldanamycin biosynthesis gene cluster. AB - Geldanamycin belongs to benzoquinone ansamycin antibiotic and has potent antitumor activities. In this study, a bacterial artificial chromosome (BAC) library with an average insert size of up to 150 kb was constructed from genomic DNA of Streptomyces autolyticus JX-47. A genetic-screening strategy was established using BAC end-sequencing and three pairs of primers designed to target the remote regions, gdmA1, gdmA3 and gdmRI, of the geldanamycin gene cluster. Three clones covering geldanamycin biosynthesis gene cluster were obtained, which together spanned a 250-kb genomic region, and a 150227-bp insert in the clone p4E9 was sequenced. Comparison with the reported geldanamycin gene cluster sequences from S. hygroscopicus revealed that it had the same gene arrangement and high gene homology in the polyketide synthase (PKS) region and its downstream with 84-100% DNA identity and 81-100% amino acid (AA) identity. Its DNA homology with the whole gene cluster sequence from S. hygroscopicus strain 17997 reached 99% identity. However, upstream of the PKS region exhibited great diversity, where only ORF16 was conserved, and the other genes including gdmL and gdmX were displaced. PMID- 21544575 TI - The self-compatibility mechanism in Brassica napus L. is applicable to F1 hybrid breeding. AB - Brassica napus, an allopolyploid species having the A genome of B. rapa and the C genome of B. oleracea, is self-compatible, although both B. rapa and B. oleracea are self-incompatible. We have previously reported that SP11/SCR alleles are not expressed in anthers, while SRK alleles are functional in the stigma in B. napus cv. 'Westar', which has BnS-1 similar to B. rapa S-47 and BnS-6 similar to B. oleracea S-15. This genotype is the most frequent S genotype in B. napus, and we hypothesized that the loss of the function of SP11 is the primary cause of the self-compatibility of 'Westar'. To verify this hypothesis, we transformed 'Westar' plants with the SP11 allele of B. rapa S-47. All the transgenic plants and their progeny were completely self-incompatible, demonstrating self compatibility to be due to the S haplotype having the non-functional SP11 allele in the A genome, which suppresses a functional recessive SP11 allele in the C genome. An artificially synthesized B. napus line having two recessive SP11 alleles was developed by interspecific hybridization between B. rapa and B. oleracea. This line was self-incompatible, but F(1) hybrids between this line and 'Westar' were self-compatible. These results suggest that the self-compatibility mechanism of 'Westar' is applicable to F(1) seed production in B. napus. PMID- 21544576 TI - Hormonal determinants and effect of ER22/23EK glucocorticoid receptor gene polymorphism on health status deterioration in the participants of the Mataro Ageing Study. AB - The purpose of this study is to assess the potential relationships of circulating IGF-I, adrenal and gonadal steroids, and polymorphism ER22/23EK of the glucocorticoid receptor (GC-R) gene with nutritional, functional and cognitive deterioration in a group of elderly people living independently. This is a population-based prospective study with 313 individuals (160 women and 153 men, 76.7 +/- 7 years) who participated. A physical exam, evaluation of functional capacity (Barthel scale), cognitive function (mini-mental state examination MMSE), geriatric depression scale (GDS), mininutritional assessment (MNA-SF) and cardiometabolic status were performed at basal time point and at 2 years of follow-up. Biological measurements included cortisol, dehydroepiandrosterone (DHEA), DHEA sulphate, testosterone, estradiol, IGF-I and polymorphism ER22/23EK of the GC-R gene. Estradiol was associated with MNA-SF decrease over time (p < 0.01, adjusted for age and gender, beta = -0.17, p = 0.03). Weight loss was related to testosterone in men (8.6 vs 12.1 pg/ml in no losers; p = 0.03), and in women with GDS (13.0% with depression vs 3.3% with no depression; p = 0.05) and MMSE (22.2% with cognitive deterioration vs 4.8% with no cognitive deterioration; p = 0.049). Barthel decrease was associated with testosterone (p = 0.02, after adjusting for age and gender, beta = -0.520, p < 0.001), and SHBG (p < 0.01, adjusted for age and gender, beta = 0.18, p < 0.01). DHEA was associated with deterioration in the MMSE (p = 0.01, after adjusting for age, gender, GDS scale and academic status, beta = -0.26, p = 0.01). Frailty development was related only in men with testosterone levels at the beginning of the study (p = 0.017). ER22/23EK was found in 3% of the subjects and carriers had a lower prevalence of hypertension. Adrenal and gonadal steroids are associated to impairment of the ageing health condition in elderly individuals living independently in Spain. ER22/23EK polymorphism of the GC-R gene has a low prevalence in our population. PMID- 21544577 TI - Red blood cell distribution width, multimorbidity, and the risk of death in hospitalized older patients. AB - We aimed to assess the association between red blood cell distribution width (RDW) and mortality in patients enrolled by a Geriatric Department. One hundred twenty-two patients were followed up during 5 years. The primary end point was all-cause mortality, and hazard ratios were estimated using a Cox proportional hazard model. Higher RDW values were strongly associated with an increased risk of death. Survival curves across RDW quartiles were statistically different according to the log-rank test (p = 0.017). The first quartile presented higher probability of survival compared to the last one. The gradient from lower to higher risk across quartiles was clear both in the 5-year mortality risk and in the mortality rate per 100 person-years, which ranged from 18.9 to 42.6. However, in the Cox regression model after adjusting for age, severity, and other factors, excess risk was only observed in the highest RDW quartile, with a hazard ratio of 2.24 (CI(95%) 1.13-4.42) vs the first quartile. RDW is a good predictor of mortality in hospitalized older adults beyond those with cardiovascular risk factors, and it could serve as an integrative measure of multiple clinical and subclinical processes simultaneously occurring in complex patients. PMID- 21544578 TI - NMDA and kainate receptor expression, long-term potentiation, and neurogenesis in the hippocampus of long-lived Ames dwarf mice. AB - In the current study, we investigated changes in N-methyl D-aspartate (NMDA) and kainate receptor expression, long-term potentiation (LTP), and neurogenesis in response to neurotoxic stress in long-living Ames dwarf mice. We hypothesized that Ames dwarf mice have enhanced neurogenesis that enables retention of spatial learning and memory with age and promotes neurogenesis in response to injury. Levels of the NMDA receptors (NR)1, NR2A, NR2B, and the kainate receptor (KAR)2 were increased in Ames dwarf mice, relative to wild-type littermates. Quantitative assessment of the excitatory postsynaptic potential in Schaffer collaterals in hippocampal slices from Ames dwarf mice showed an increased response in high-frequency induced LTP over time compared with wild type. Kainic acid (KA) injection was used to promote neurotoxic stress-induced neurogenesis. KA mildly increased the number of doublecortin-positive neurons in wild-type mice, but the response was significantly enhanced in the Ames dwarf mice. Collectively, these data support our hypothesis that the enhanced learning and memory associated with the Ames dwarf mouse may be due to elevated levels of NMDA and KA receptors in hippocampus and their ability to continue producing new neurons in response to neuronal damage. PMID- 21544579 TI - Cu to Zn ratio, physical function, disability, and mortality risk in older elderly (ilSIRENTE study). AB - Associations between copper to zinc ratio (CZr) and mortality have suggested CZr as a biomarker of aging. Nevertheless, very limited data exist on the association between serum CZr and physical or functional status of very old people. We examined the relationship between serum CZr and physical performance, muscle strength, functional status, and survival from the ilSIRENTE Study: a longitudinal study of persons aged 80 years or older (n = 346). An adjusted linear regression model was subsequently performed to calculate the regression coefficients of the associations between baseline physical and functional measures (dependent variable) with CZr or "Cu and Zn" alone taking also into account the influence of other relevant factors, including hematological (albumin, cholesterol, and urea) and inflammatory biomarkers (IL-6 and CRP) that were significantly different across CZr tertiles. CZr showed significant and stronger relationships than Cu or Zn alone with all baseline physical and functional measures in models that did not include adjustments for inflammatory parameters. CZr was also associated with physical decline, measured as "SPPB% decline" at 2 years of follow-up and mortality at 4 years of follow-up. Subjects in the high CZr tertile had a higher risk of death with an adjusted hazard ratio of 1.92 (95% CI, 1.12-3.29; p = 0.02). In conclusion, we have confirmed the role of CZr as a predictor of mortality, whereas the role of CZr as a biomarker or predictor of physical or functional performance seems to be the consequence of its strict relationships with inflammatory parameters. In this context, further investigations need to be carried out. PMID- 21544580 TI - Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model. AB - In this study, we performed an in-depth analysis of the neurologic and ophthalmologic phenotype in a patient with Pitt-Hopkins syndrome (PTHS), a disorder characterized by severe mental and motor retardation, carrying a uniallelic TCF4 deletion, and studied a zebrafish model. The PTHS-patient was characterized by high-resolution magnetic resonance imaging (MRI) with diffusion tensor imaging to analyze the brain structurally, spectral-domain optical coherence tomography to visualize the retinal layers, and electroretinography to evaluate retinal function. A zebrafish model was generated by knockdown of tcf4 function by injection of morpholino antisense oligos into zebrafish embryos and the morphant phenotype was characterized for expression of neural differentiation genes neurog1, ascl1b, pax6a, zic1, atoh1a, atoh2b. Data from PTHS-patient and zebrafish morphants were compared. While a cerebral MRI-scan showed markedly delayed myelination and ventriculomegaly in the 1-year-old PTHS-patient, no structural cerebral anomalies including no white matter tract alterations were detected at 9 years of age. Structural ocular examinations showed highly myopic eyes and an increase in ocular length, while retinal layers were normal. Knockdown of tcf4-function in zebrafish embryos resulted in a developmental delay or defects in terminal differentiation of brain and eyes, small eyes with a relative increase in ocular length and an enlargement of the hindbrain ventricle. In summary, tcf4-knockdown in zebrafish embryos does not seem to affect early neural patterning and regionalization of the forebrain, but may be involved in later aspects of neurogenesis and differentiation. We provide evidence for a role of TCF4/E2-2 in ocular growth control in PTHS-patients and the zebrafish model. PMID- 21544581 TI - The X-inactivation trans-activator Rnf12 is negatively regulated by pluripotency factors in embryonic stem cells. AB - X-inactivation, the molecular mechanism enabling dosage compensation in mammals, is tightly controlled during mouse early embryogenesis. In the morula, X inactivation is imprinted with exclusive silencing of the paternally inherited X chromosome. In contrast, in the post-implantation epiblast, X-inactivation affects randomly either the paternal or the maternal X-chromosome. The transition from imprinted to random X-inactivation takes place in the inner cell mass (ICM) of the blastocyst from which embryonic stem (ES) cells are derived. The trigger of X-inactivation, Xist, is specifically downregulated in the pluripotent cells of the ICM, thereby ensuring the reactivation of the inactive paternal X chromosome and the transient presence of two active X-chromosomes. Moreover, Tsix, a critical cis-repressor of Xist, is upregulated in the ICM and in ES cells where it imposes a particular chromatin state at the Xist promoter that ensures the establishment of random X-inactivation upon differentiation. Recently, we have shown that key transcription factors supporting pluripotency directly repress Xist and activate Tsix and thus couple Xist/Tsix control to pluripotency. In this manuscript, we report that Rnf12, a third X-linked gene critical for the regulation of X-inactivation, is under the control of Nanog, Oct4 and Sox2, the three factors lying at the heart of the pluripotency network. We conclude that in mouse ES cells the pluripotency-associated machinery exerts an exhaustive control of X-inactivation by taking over the regulation of all three major regulators of X-inactivation: Xist, Tsix, and Rnf12. PMID- 21544582 TI - Two novel mutations of the IRX4 gene in patients with congenital heart disease. AB - IRX4 was the first identified cardiac transcription factor that is restricted to the ventricles at all stages of heart development. Irx4-deficient mice show ventricular dysfunction and develop cardiomyopathy. To study the potential impact of sequence variations in IRX4 on congenital heart disease (CHD) in humans, we examined the coding region of IRX4 in a cohort of 698 Chinese people with congenital heart disease and 250 healthy individuals as the controls. We found two potential disease-causing mutations, p. Asn85Tyr and p. Glu92Gly. A mammalian two-hybrid assay showed that both of the mutations significantly affected the interaction between IRX4 and RXRA. It demonstrated that IRX4 had a potential causative impact on the development of congenital heart disease, particularly ventricular septal defect. PMID- 21544583 TI - Cardiac tamponade in a child with systemic-onset juvenile idiopathic arthritis: dramatic improvement after interleukin-1 blockade by anakinra. PMID- 21544584 TI - Accessory hepatic lobe. AB - PURPOSE: The aim of the present communication was to describe an accessory hepatic lobe in two patients and to outline the significance of the timely identification of this very rare anatomic variation for the clinical practice. METHODS: In the course of right hemihepatectomy, accessory liver lobes were detected in two patients. Their diagnosis was confirmed by histopathology and cholangiography. RESULTS: Both accessory hepatic lobes arose from the left liver segments. The first lobe was detected in a 56-year-old male operated on for a retroperitoneal liposarcoma. It amounted to 15% of the standard liver volume and was attached to liver segments 2 and 3 by a stalk. The second accessory lobe was found out in 45-year-old female operated on for a colon cancer and synchronous liver metastases. It was less than 15 g in weight and attached to the main liver by a mesentery as its bile duct drained into an extrahepatic duct. CONCLUSIONS: The accessory hepatic lobes require timely diagnosis. They should be kept in mind in cases with acute surgical abdomen. PMID- 21544585 TI - Clinical aspects of 2009 pandemic influenza A (H1N1) virus infection in Austria. AB - PURPOSE: To describe the clinical features, risk factors for severe disease and effectiveness of oseltamivir in patients with 2009 pandemic influenza A (H1N1) virus infection. METHODS: In a prospective, cross-sectional, multicentre study, data on 540 patients with confirmed 2009 H1N1 infection from seven Austrian hospitals were collected using a standardised online case-history form. RESULTS: The median age of the patients was 19.3 years (range 26 days-90.8 years); point of-care testing yielded false-negative results in 60.2% of the 176 cases tested. The most common symptoms were fever, cough, fatigue and headache. Overall, 343 patients (63.5%) were hospitalised, 49 (9.1%) were admitted to an intensive care unit (ICU) and 14 (4.1%) died. Case fatality rates were highest (9.1%) in those aged 65 years or older. Factors significantly associated with a higher risk for ICU admission included age, neurological disease, adipositas, and both interstitial pathology and lobular pathology on chest X-ray. No association with pregnancy, malignancy or immunosuppressive therapy was detected. Antiviral treatment significantly reduced the duration of fever by 0.66 days and lowered the risk of ICU admission, but had no significant benefit on survival. CONCLUSIONS: During the 2009 H1N1 influenza pandemic, elderly or obese patients and those with neurological disease had an increased risk for severe H1N1 infection in Austria. Pregnancy was not associated with a higher risk for severe disease in the later phase of the 2009 H1N1 pandemic. Antiviral treatment provided a minimal effect on the symptoms of influenza but reduced the risk of admission to an ICU. PMID- 21544586 TI - Development of immunity against hepatitis B virus after donor lymphocyte infusion in a peripheral blood stem cell transplantation recipient with chronic hepatitis B. AB - Hepatitis B virus (HBV) infection is one of the main concerns in blood and marrow transplantation (BMT) patients for possible breakthrough hepatitis. Active recipient immunization against HBV was found to be ineffective and many studies had showed that the adoptive transfer of immunity against hepatitis B virus would be possible by BMT with unknown duration and mechanism. A 46-year-old female patient with chronic hepatitis B had persistent detectable HBV DNA and positive serum hepatitis B e antigen (HBeAg), even while on long-term lamivudine and adefovir therapy. She received allogeneic matched unrelated donor peripheral blood stem cell transplantation (allo-MUD-PBSCT) for her refractory acute myeloid leukemia (AML). The HBV DNA became undetectable and she developed HBeAg seroconversion after PBSCT. Her hepatitis B surface antigen (HBsAg) remained positive, which disappeared later, along with the development of antibody to HBsAg after one shot of donor lymphocyte infusion (DLI) as a boost against her AML. In summary, BMT from an immunized donor would probably bring adoptive immunity against HBV. This adoptive immunity might be further enhanced by the subsequent DLI. PMID- 21544587 TI - Bilateral persistent trigeminal artery variants diagnosed by MR angiography. AB - A persistent trigeminal artery (PTA) is the most common anastomosis between the carotid and vertebrobasilar system. A PTA variant (PTAV) is a rare anomaly in which the cerebellar artery arises from the internal carotid artery (ICA) without connection with the basilar artery (BA). I present what I believe is the first report of bilateral PTAVs diagnosed using magnetic resonance (MR) angiography and briefly discuss the embryology of this rare anomaly. An 81-year-old woman with small infarctions underwent cerebral MR imaging and MR angiography with a 1.5 tesla imager for the evaluation of brain lesions. An MR angiography was obtained using the standard noncontrast three-dimensional time-of-flight technique. The MR angiographic demonstration of bilateral anterior inferior cerebellar arteries arising from the precavernous segment of the ICA without anastomosis to the BA indicated bilateral PTAVs. This is the first report of bilateral PTAVs diagnosed by MR angiography. The literature review indicates that an estimated prevalence of bilateral PTAVs is about 0.0012%. PMID- 21544588 TI - Increased obstacle clearance in people with ARCA-1 results in part from voluntary coordination changes between the thigh and shank segments. AB - Obstacle clearance can be a hazardous locomotor task if not coordinated with the utmost accuracy. The current study explored changes in leading limb segment coordination during obstacle clearance in a population with cerebellar ataxia using the planar law of intersegmental coordination. Eight participants with ARCA 1, caused by mutations in the SYNE-1 gene, and eight healthy adults stepped over obstacles. Healthy adults walked at natural speeds, as well as a velocity similar to the participants with cerebellar ataxia, resulting in three groups [healthy (H), matched velocity (MV) and cerebellar ataxia (CA)]. Elevation angles of the foot, shank and thigh in the sagittal plane were calculated. A principal component analysis was applied to limb segment trajectories, and a Fourier harmonic series was further used to determine temporal phase differences between adjacent segments. Although obstacle clearance was greater in the CA group, the planar nature of the 3D covariance plot of segment elevation angles, the covariance loop width and orientation did not differ between the CA, H and MV groups, suggesting that the planar patterns between elevation angles may not be heavily influenced by the cerebellum. Further analysis led to the observation of a nonlinear relationship between covariance loop width and thigh-shank fundamental harmonic phase difference, and a decrease in covariance loop width was observed when the fundamental harmonic phase difference between the thigh and shank segments is >90 degrees . This study supports previous work that a greater safety margin is used in people with cerebellar ataxia when stepping over obstacles, but reveals a mechanism of segmental coordination to facilitate this increase in toe clearance. Further work is required to determine whether ataxia severity has an effect on the observed coordination variables. PMID- 21544589 TI - theta-burst stimulation of the cerebellum interferes with internal representations of sensory-motor information related to eye movements in humans. AB - Continuous theta-burst stimulation (cTBS) applied over the cerebellum exerts long lasting effects by modulating long-term synaptic plasticity, which is thought to be the basis of learning and behavioral adaptation. To investigate the impact of cTBS over the cerebellum on short-term sensory-motor memory, we recorded in two groups of eight healthy subject each the visually guided saccades (VGSs), the memory-guided saccades (MGSs), and the multiple memory-guided saccades (MMGSs), before and after cTBS (cTBS group) or simulated cTBS (control group). In the cTBS group, cTBS determined hypometria of contralateral centrifugal VGSs and worsened the accuracy of MMGS bilaterally. In the control group, no significant differences were found between the two recording sessions. These results indicate that cTBS over the cerebellum causes eye movement effects that last longer than the stimulus duration. The VGS contralateral hypometria suggested that we eventually inhibited the fastigial nucleus on the stimulated side. MMGSs in normal subjects have a better final accuracy with respect to MGSs. Such improvement is due to the availability in MMGSs of the efference copy of the initial reflexive saccade directed toward the same peripheral target, which provides a sensory-motor information that is memorized and then used to improve the accuracy of the subsequent volitional memory-guided saccade. Thus, we hypothesize that cTBS disrupted the capability of the cerebellum to make an internal representation of the memorized sensory-motor information to be used after a short interval for forward control of saccades. PMID- 21544591 TI - The saga of zones in the cerebellar cortex as reflected in the corticonuclear system: a different approach, a specific hypothesis, and the proof begins (Voogd, 1969). PMID- 21544590 TI - Distribution and pattern of pathology in subjects with familial or sporadic late onset cerebellar ataxia as assessed by p62/sequestosome immunohistochemistry. AB - We investigated whether ubiquitin-binding protein p62/sequestosome-1 could be utilized to evaluate the pathology seen in patients with a clinical diagnosis of progressive late-onset cerebellar ataxia (LOCA). p62-immunoreactive (IR) lesions were assessed by means of immunohistochemistry in the brains of six LOCA cases, one with the spinocerebellar ataxia type 1 mutation (SCA1), ages at death ranging from 46 to 56 years. All cases fulfilled the criteria of olivopontocerebellar atrophy (OPCA), i.e., displaying cell loss in the predilection brain areas. One case, genetics unknown, exhibited p62-IR neuronal intranuclear inclusions (NIs). Similar NIs were labeled with the 1C2 antibody that recognizes proteins containing large polyglutamine stretches. In this case, also fused in sarcoma-IR NIs were seen. In the remaining LOCA cases, including the case with the SCA1 mutation, different kinds of nuclear and cytoplasmic p62 and 1C2 labeling but no NIs were seen. The immunoreactivity and distribution of lesions while applying p62 and 1C2 immunohistochemistry varied in our six LOCA cases fulfilling the criteria of OPCA. In all cases except in the SCA1, diffuse nuclear p62 labeling was seen, not previously reported in SCA or other neurodegenerative disorders. Due to the variability noted here as well as the limited number of cases, no assessment of progression and distributional pattern of pathology could be conducted. Based on a literature search, it is apparent that there is a need for clinico-pathologic-genetical studies of LOCA, especially to obtain a deeper understanding of the regional distribution and progression of pathology. PMID- 21544592 TI - Co-transplantation of fetal bone tissue facilitates the development and reconstitution in human B cells in humanized NOD/SCID/IL-2Rgammanull (NSG) mice. AB - BACKGROUND: In terms of the function and reconstitution efficacy of human immune cells, co-transplantation of human fetal tissues, such as thymus and liver, with CD34(+) hematopoietic stem cells (HSCs) has potential advantages in the generation of humanized mice. OBJECTIVE AND METHODS: To examine the effects of bone tissues in the reconstitution of human immune cells, particularly in B cells, we generated a new humanized mice co-transplanted with human fetal thymus (hFT)/fetal bone (hFB) tissues and human fetal liver-derived CD34(+) cells. RESULTS: Humanized mice exhibited effective reconstitution of human immune cells earlier compared to control humanized mice. In terms of quantity, the number of immune cells, such as human T, B, and monocyte/macrophages was significantly increased. Furthermore, significant increase of B cell progenitors and immature/naive B cells could be detected in the bone marrow and spleen of humanized mice. CONCLUSION: Our results demonstrate that co-transplantation of hFB tissue may facilitate the reconstitution of human B and T cells, and therefore the humanized model may be used to develop therapeutic human antibodies for clinical use. PMID- 21544593 TI - In vivo preclinical evaluation of the influence of osteoporosis on the anchorage of different pedicle screw designs. AB - We investigate the anchorage of pedicle screws with different surface treatments in osteoporotic bone. Eight ewes were divided into two groups of four animals each: four sheep underwent bilateral ovariectomy (OVX Group), whereas the operation was simulated in the remaining group (SHAM Group). Eighteen months after the first operation, the Dynesys((r)) System was fitted to the sheep using pedicle screws with three different surface treatments: untreated, rough blasted (uncoated) and bioactive coated (bioactive). Uncoated screws showed a significantly higher bone ingrowth value compared with the untreated screws in the OVX group (9.3%, p < 0.005) and a significantly lower bone ingrowth value in the SHAM group (-11.0%, p < 0.05). Furthermore, the bioactive pedicle screws had a significant lower bone ingrowth value than the untreated screws in the SHAM group (-12.1%, p < 0.05). These results suggest that both tested surface treatments of pedicular screws may provide an advantage in terms of bone quality and osseointegration, when implanted in osteoporotic vertebrae. PMID- 21544594 TI - Novel biodegradable alpha-TCP/poly(amino acid) composite artificial lamina following spinal surgery for prevention of intraspinal scar adhesion. AB - Biodegradable copolymer alpha-TCP/poly(amino acid) composite artificial lamina was prepared and used in goat cervical vertebra resection repair. Cervical 4 was removed by laminectomy, and a vertebra defect of 27 * 9 mm was made. alpha TCP/poly(amino acid) composite artificial lamina was inserted in the test group. The efficiency of the copolymer during repair and reconstruction of the goats' vertebra was tested by using X-ray, CT scanning, and histological and biomechanical measurements. In the 24 weeks following the operation, the artificial lamina refrained from shifting, and no dural adhesion pressure was observed. In contrast, the control group suffered from infiltration of soft tissue in the spinal canal, dural pressure and alpha-TCP/poly(amino acid) degradation. In conclusion, alpha-TCP/poly(amino acid) composite artificial lamina can significantly prevent scar tissue from infiltrating the spinal canal. PMID- 21544595 TI - The prevalence of MRI-defined spinal pathoanatomies and their association with modic changes in individuals seeking care for low back pain. AB - Modic changes are of increasing interest, however their age and gender prevalence are not well described. To date, the associations between Modic changes and other common vertebral pathologies have only been described in small samples (n < 100). Our aim was, in a large dataset of people with low back pain, to (1) describe the prevalence of a range of spinal pathoanatomies, and (2) examine the association between Modic changes and stages of intervertebral disc (IVD) pathology. Common pathologies were coded from the lumbar spine MRIs from 4,233 consecutive people imaged while attending a publicly-funded secondary care outpatient facility in Denmark. Prevalence data were calculated by pathology and by vertebral level. Prevalence was also calculated by age and gender categories for Modic changes. The association between stages of IVD pathology (degeneration, bulge, herniation) and Modic changes at L4/5 and L5/S1 was expressed using prevalence ratios (PR) and 95% confidence intervals. The prevalence of Modic changes and IVD pathology were greater in L4/5 and L5/S1, compared with the upper lumbar spine. There was no significant gender difference in prevalence of Modic changes (p = 0.11). The prevalence of IVD disc pathology occurring concurrently with Modic changes ranged from 11.5 to 17.5% (Type 1), 8.5 to 12.7% (Type 2) and 17.1 to 25.6% (Type 1 and/or 2) while the prevalence occurring in the absence of Modic changes ranged from 0.5 to 6.3% (Type 1), 0.3 to 4.9 (Type 2), 0.8 to 9.7% (Type 1 and/or 2). The associated PR for IVD pathology occurring concurrently with Modic changes ranged from 1.8 to 29.2 (p < 0.05). The highest PR (29.2) was between degeneration and Modic changes, indicating that it is rare for Modic changes to occur without disc degeneration. Spinal pathoanatomy was common in this population, particularly IVD pathologies, and a consistent trend of a relatively greater prevalence in the lower lumbar spine was identified. Modic changes were more likely to be present among individuals with IVD pathology than without, which may implicate mechanical factors as being one aetiological pathway for Modic changes, although other hypotheses may equally explain this association. PMID- 21544596 TI - Increased expression of transcription initiation factor IIB after rat traumatic brain injury. AB - The protein TFIIB is a general transcription initiation factor that plays a pivotal role in the preinitiation complex (PIC) and selects the transcription initiation site. However, its distribution and function in the central nervous system (CNS) remains unclear. In the present study, we mainly investigated the expression and cellular localization of TFIIB during traumatic brain injury (TBI). Western blot analysis revealed that TFIIB was present in normal rat brain cortex. It gradually increased, reached a peak at the 5th day after TBI, and then decreased. Importantly, more TFIIB was colocalized with astrocytes and microglia, which are largely proliferated. In addition, Western blot detection showed that the 5th day post injury was also the proliferation peak indicated by the elevated expression of PCNA. Importantly, injury-induced expression of TFIIB was colabelled by proliferating cell nuclear antigen (proliferating cells marker). These data suggested that TFIIB may be implicated in the proliferation of astrocytes and microglia and the recovery of neurological outcomes. But the inherent mechanisms remained unknown. Further studies are needed to confirm the exact role of TFIIB after brain injury. PMID- 21544598 TI - Long-term surgical outcomes of idiopathic spinal cord herniation. AB - BACKGROUND: Because of the lack of long-term postoperative follow-up studies of idiopathic spinal cord herniation (ISCH), there is little information about the long-term effectiveness and complications of the dural defect enlargement in patients with ISCH. The purpose of this study is to determine the long-term effectiveness of this procedure. METHODS: Sixteen patients with ISCH were treated surgically by enlargement of the dural defect. The patient's neurological status and surgical outcome were evaluated by the JOA scores for thoracic myelopathy and the recovery rate (mean follow-up period 9.6 years). Correlations between the surgical outcomes and patients' age and duration of disease were assessed retrospectively. The patients were also divided into two groups based on the location of the dural defect: the ventro-lateral (VL) group and the ventral (V) group. The difference in the duration of disease, preoperative JOA score, and the recovery rate were compared between the two groups. RESULTS: There was no recurrence of ISCH after surgery. The mean recovery rate was 42.6%. There was a significant correlation between the patient's age and the recovery rate, and between the duration of disease and the recovery rate. The median recovery rate was significantly lower in the V group than in the VL group. There were no complications related to CSF leakage after surgery. CONCLUSIONS: Long-term surgical outcomes of enlargement of the dural defect for ISCH were stable and favorable without recurrences or any complications. This procedure should be considered for patients with ISCH before their neurological deficit worsens, especially for the patients in whom the dural defect is located at the ventral part of the dural canal. PMID- 21544597 TI - Localization and subcellular distribution of prolyl oligopeptidase in the mouse placenta. AB - Prolyl oligopeptidase (POP) is a serine endopeptidase which selectively digests a -Pro-X- peptide bond. Our previous study showed that POP mRNA was strongly expressed in the spongiotrophoblast of the mouse placenta at E17.5, suggesting its importance in development. To gain more insight into POP's role during gestation, we investigated its expression using different developmental stages of placenta. As a result of in situ hybridization, we found that localization of POP mRNA changed at E12.5. POP mRNA was strongly expressed in the spongiotrophoblast and labyrinth at E10.5 and E11.5 but thereafter only in the spongiotrophoblast. Immunohistochemistry revealed that POP was present in the parietal trophoblast giant cell, the spongiotrophoblast cell, and the labyrinth at E11.5 but the strong expression in the labyrinth was maintained only in the canal-associated and sinusoidal trophoblast giant cells at E16.5 and E18.5. To determine subcellular distribution of the POP protein, we fractionated the placental extract into cytoplasmic, membrane, and nuclear subfractions. By Western blot analysis, POP was detected in the cytoplasmic and membrane fractions but not in the nuclear fraction at E11.5 and E16.5. Interestingly, the cytoplasmic POP exhibited higher enzymatic activity than the membrane-associated type. These data suggest that the cytoplasmic and membrane-associated POP have distinct roles in different types of placental cells. PMID- 21544599 TI - Influence of common variants in FTO and near INSIG2 and MC4R on growth curves for adiposity in African- and European-American youth. AB - Recent genome-wide association (GWA) studies identified several common variants for obesity: rs9939609 in FTO, rs7566605 near INSIG2 and both rs17782313 and rs17700633 near the MC4R gene. This study aimed to assess the influence of these polymorphisms on development of adiposity in European- (EA) and African-American (AA) youth in two ongoing longitudinal studies including 986 and 606 participants with age ranges of 10-25.8 and 4.0-23.9 years, respectively. Individual growth curve modeling was conducted separately in the two studies. We tested the effect of the SNPs on levels and increase with age (i.e., slope) of weight, body mass index (BMI), waist circumference and skinfolds from childhood to adulthood, and potential moderation by ethnicity or gender. Beta coefficients computed in the two studies were pooled using meta-analysis. Rs9939609 was associated with logtransformed levels of BMI (beta = 0.021, P = 0.01), weight (beta = 0.019, P = 0.04) and waist circumference (beta = 0.012, P = 0.04). Rs17782313 was associated with triceps (beta = 0.05, P = 0.02). Significant interactions of rs17700633 with gender were observed on subscapular-, suprailiac- and sum of skinfolds, with significant associations limited to males (P < 0.05). No significant interactions with ethnicity were found. Only one effect on the slope was observed, rs17700633 showed a significant interaction with age on triceps (beta = 0.004, P = 0.04). In two longitudinal studies of EA and AA youth, we replicated the effect of FTO and common variants near MC4R on general and central adiposity. These variants did not affect the increase with age of adiposity from childhood to adulthood with one exception. Common variants for obesity identified in GWA studies have detectable but modest effects on growth curves for adiposity in EA and AA youth. PMID- 21544600 TI - [Vertigo and fluctuating hearing-loss. Differential diagnosis: Meniere's disease, migraine, and psychogenic vertigo]. AB - We present the case of a female patient suffering from recurrent vertigo and low frequency hearing loss who was admitted for inpatient treatment with the diagnosis of Meniere's disease. After evaluation of all diagnostic examinations, including psychosomatic evaluation, a diagnosis of vestibular migraine with accompanying psychogenic vertigo could be confirmed and was treated accordingly. Neurotologic findings and the corresponding literature are reported. PMID- 21544601 TI - Delirium in patients with head and neck cancer in the outpatient treatment setting. AB - PURPOSE: Delirium is a common neurocognitive disorder among patients with cancer. In patients with head and neck cancer, delirium has been examined in the postoperative setting. Because no studies have reported on delirium during outpatient cancer treatment, we conducted a prospective study in 69 patients with head and neck cancer to examine neurocognitive function before, during, and after outpatient treatment. We also conducted a retrospective study in a subset of caregivers. In this paper, we report the prevalence and incidence of delirium and subsyndromal delirium (SSD) during outpatient treatment. METHODS: Assessments were conducted before treatment, at scheduled treatment visits, and at a 3-month post-treatment visit. Delirium and SSD were assessed using the Confusion Assessment Method (CAM). Following treatment, we retrospectively asked patients (n = 58) and a subset of caregivers (n = 23) whether patients experienced delirium during treatment. RESULTS: Based on CAM assessments at scheduled treatment visits, six patients (8.6%) developed delirium during treatment. Additionally, 31% of patients and 43.5% of caregivers retrospectively reported delirium. The prevalence and incidence of SSD were 7.2% and 45.3%, respectively. CONCLUSIONS: These data suggest that delirium and SSD are frequent in patients with head and neck cancer undergoing outpatient treatment. Delirium was often associated with medical complications. The potential impact of delirium and SSD on treatment outcomes, recovery, and caregiving are significant clinical concerns. PMID- 21544602 TI - Increased elongase 6 and Delta9-desaturase activity are associated with n-7 and n 9 fatty acid changes in cystic fibrosis. AB - Patients with cystic fibrosis, caused by mutations in CFTR, exhibit specific and consistent alterations in the levels of particular unsaturated fatty acids compared with healthy controls. Evidence suggests that these changes may play a role in the pathogenesis of this disease. Among these abnormalities are increases in the levels of n-7 and n-9 fatty acids, particularly palmitoleate (16:1n-7), oleate (18:1n-9), and eicosatrienoate or mead acid (20:3n-9). The underlying mechanisms of these particular changes are unknown, but similar changes in the n 3 and n-6 fatty acid families have been correlated with increased expression of fatty acid metabolic enzymes. This study demonstrated that cystic fibrosis cells in culture exhibit increased metabolism along the metabolic pathways leading to 16:1n-7, 18:1n-9, and 20:3n-9 compared with wild-type cells. Furthermore, these changes are accompanied by increased expression of the enzymes that produce these fatty acids, namely Delta5, Delta6, and Delta9 desaturases and elongases 5 and 6. Taken together, these findings suggest that fatty acid abnormalities of the n-7 and n-9 series in cystic fibrosis are as a result, at least in part, of increased expression and activity of these metabolic enzymes in CFTR-mutated cells. PMID- 21544603 TI - EPA or DHA supplementation increases triacylglycerol, but not phospholipid, levels in isolated rat cardiomyocytes. AB - It is well recognized that a high dietary intake of long-chain polyunsaturated fatty acids (LC-PUFA) has profound benefits on health and prevention of chronic diseases. In particular, in recent years there has been a dramatic surge of interest in the health effects of n-3 LC-PUFA derived from fish, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Notwithstanding, the metabolic fate and the effects of these fatty acids once inside the cell has seldom been comprehensively investigated. Using cultured neonatal rat cardiomyocytes as model system we have investigated for the first time, by means of high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy in combination with gas chromatography (GC), the modification occurring in the cell lipid environment after EPA and DHA supplementation. The most important difference between control and n-3 LC-PUFA-supplemented cardiomyocytes highlighted by HR-MAS NMR spectroscopy is the increase of signals from mobile lipids, identified as triacylglycerols (TAG). The observed increase of mobile TAG is a metabolic response to n-3 LC-PUFA supplementation, which leads to an increased lipid storage. The sequestration of mobile lipids in lipid bodies provides a deposit of stored energy that can be accessed in a regulated fashion according to metabolic need. Interestingly, while n-3 LC-PUFA supplementation to neonatal rat cardiomyocytes causes a huge variation in the cell lipid environment, it does not induce detectable modifications in water-soluble metabolites, suggesting negligible interference with normal metabolic processes. PMID- 21544604 TI - Alcohol use and mental distress as predictors of non-response in a general population health survey: the HUNT study. AB - PURPOSE: To investigate to what degree alcohol use and mental distress are associated with non-response in a population-based health study. METHODS: From 1995 to 1997, 91,488 persons were invited to take part in a health study at Nord Trondelag, Norway, and the response rate was 69.2%. Demographics were available for everyone. Survey answers from a previous survey were available for most of the participants and a majority of non-participants. In addition, the survey responses from spouses and children of the invitees were used to predict participation in the aforementioned study. Crude and adjusted ORs for a number of predictors, among these alcohol consumption and mental distress, are reported. RESULTS: Both heavy drinkers (OR = 1.27) and abstainers (OR = 1.64) had a higher probability of dropping out in comparison to people who usually do not drink. High levels of mental distress (OR = 1.84) also predicted attrition. CONCLUSION: Alcohol use and mental distress are moderately associated with non-response, though probably not a major cause, as controlling for other variables weakened the associations. Nevertheless, the moderate but clear underrepresentation at the crude level of people with high alcohol consumption, abstainers and people with poor mental health should be taken into consideration when interpreting results from health surveys. PMID- 21544605 TI - On the meaningfulness of testing preference axioms in stated preference discrete choice experiments. AB - A stream of studies on evaluation of health care services and public goods have developed tests of the preference axioms of completeness and transitivity and methods for detecting other preference phenomena such as unstability, learning- and tiredness effects, and random error, in stated preference discrete choice experiments. This methodological paper tries to identify the role of the preference axioms and other preference phenomena in the context of such experiments and discusses whether or how such axioms and phenomena can be subject to meaningful (statistical) tests. PMID- 21544606 TI - Effects of ammonium nitrate on larval survival and growth of four Iberian amphibians. AB - The purpose of this study was to understand the differences in tolerance to ammonium nitrate in four Iberian amphibians. Results showed a negative effect on amphibian survival and larvae total length. Three different tolerance groups on amphibian survival were established. The two first groups showed a higher reduction, around 90% and between 70 and 80% after 96 h exposition at the maximum concentration tested (180 mg NH4NO3/L), while the third group showed no mortality in any concentration tested. In addition, a reduction in larvae total length was also detected for all four species, with Bufo bufo as the most sensitive species. PMID- 21544607 TI - Production of phloroglucinol by Escherichia coli using a stationary-phase promoter. AB - Escherichia coli was metabolically engineered using a new host-vector system to produce phloroglucinol. The key biosynthetic gene phlD (encoding a type III polyketide synthase) from Pseudomonas fluorescens was expressed in E. coli using the stationary-phase promoter of the fic gene and a high-copy plasmid. In shake flasks, the engineered strain produced phloroglucinol up to 0.28 g/l with a productivity of 0.014 g/l h. About 9.2% of the glucose consumed was converted to phloroglucinol after 20 h. Compared with the widely used inducible T7 promoter system, this strain did not require IPTG induction and the final titer of phloroglucinol was 22% higher. PMID- 21544608 TI - Recombinant hBMP4 incorporated with non-canonical amino acid for binding to hydroxyapatite. AB - A novel growth factor containing non-canonical amino acids was designed and synthesized to enhance the binding to hydroxyapatite (HA). The designed protein was human bone morphogenetic protein 4 (hBMP4) incorporating diphosporylated serines (pSpS) that was found in salivary protein statherin and was reported to be responsible for binding to HA. Recombinant hBMP4 and a short peptide sequences containing pSpS were ligated by enzymatice reaction of sortase A, which exchanges the terminal amino acids of two polypeptides. Resulting hBMP4 containing pSpS (hBMP4-pSpS) bound HA more efficiently than hBMP-4 tagged with canonical serines (hBMP4-SS). The HA-bound hBMP-4-pSpS exhibited osteogenesis inducing activity to multipotential mesenchyme cells (C3H10T1/2) as evidenced by increased expression of osteogenic markers, which was not seen by hBMP4-SS. This novel protein with non-canonical serines will be applicable to bone regeneration materials in combination with HA. PMID- 21544609 TI - Secretion of biologically-active human interferon-beta by Bacillus subtilis. AB - Human interferon-beta (hIFN-beta) was used as a heterologous model protein to investigate the effects of the Bacillus subtilis AmyE propeptide and co expression of PrsA in enhancing the secretion of heterologous proteins in B. subtilis. Secretion and activity of hIFN-beta with AmyE propeptide increased by more than four-fold compared to that without AmyE propeptide. Moreover, under conditions of co-expressed PrsA, the secretion production and activity of hIFN beta with AmyE propeptide increased by more than 1.5-fold. AmyE propeptide and co expression of PrsA thus have an additive effect on enhancing the production of the hIFN-beta in B. subtilis. PMID- 21544610 TI - Substitution of Asp189 residue alters the activity and thermostability of Geobacillus sp. NTU 03 lipase. AB - Error-prone PCR was used to create more thermoactive and/or thermostable variants of thermoalkalophilic lipases. A variant of the alpha6 helix (lid domain), with an 189E to V substitution at residue 189, lost its thermostability but exhibited higher activity than that of its wild-type predecessor (r03Lip). Site-saturation mutagenesis was used to explore the sequence-function relationship. Five other mutants also lost thermostability (20-40%) but exhibited enhanced thermoactivity (6.3-79-fold). The mutant E189I showed the highest activity retaining 50% activity after maintaining it at 65 degrees C for 24 h. In comparison to r03Lip, the mutant E189I had a higher affinity for p-nitrophenyl palmitate and p nitrophenyl stearate (61 and 56% decreased Km) and catalytic efficiency (42-fold and 18-fold increased kcat/Km). The mutant lipase retained its tolerance to n hexane, but had an improved transesterification activity. The results suggest that residue Glu189 plays a significant role in the thermostability and activity of this thermoalkalophilic lipase. PMID- 21544611 TI - In vitro screening of ovarian tumor specific peptides from a phage display peptide library. AB - To develop more biomarkers for diagnosis and therapy of ovarian cancer, a 12-mer phage display library was used to isolate peptides that bound specifically to the human ovarian tumor cell line SK-OV-3. After five rounds of in vitro screening, the recovery rate of phages showed a 69-fold increase over the first round of washings and a group of phage clones capable of binding to SK-OV-3 cells were obtained. A phage clone named Z1 with high affinity and specificity to SK-OV-3 cells was identified in vitro. More importantly, the synthetic biotin-labeled peptide, ZP1 (=SVSVGMKPSPRP), which corresponded to the sequence of the inserted fragment of Z1, demonstrated a high specificity to SK-OV-3 cells especially when compared to other cell lines (A2780 and 3T3). ZP1 might therefore be a biomarker for targeting drug delivery in ovarian cancer therapy. PMID- 21544612 TI - Adenoviral delivered eGFP-intron splicing system for multiple gene RNAi. AB - An eGFP-intron splicing system that allows for co-ordinated expression of up to four siRNAs from a single adenoviral vector has been developed. In this splicing structure the intron, embedded by a multiple miR30-based shRNAs, is located between two incomplete eGFP domains which require successful splicing for functionality. To prove the principle of the method, an adenoviral vector delivering four transcripts targeting survivin, XIAP, Hec1, and VEGF was developed which enabled the knockdown of target genes by 70, 70, 54 and 44%, respectively, in HeLa cells. This is the first report of multi-siRNA engineering technology in the context of adenoviral vector which would enable concomitant knockdown of tumor-related target genes. The results provide a strategy for gene function analysis and cancer gene therapy. PMID- 21544613 TI - Catechin production in cultured cells of Taxus cuspidata and Taxus baccata. AB - The main polyphenols in callus and cell suspension cultures of Taxus cuspidata and T. baccata were (+)-catechin and (-)-epicatechin, while lignans, such as (+) taxiresinol, (+)-isotaxiresinol, (+)-isolariciresinol and (-) secoisolariciresinol, were present in trace amounts. T. cuspidata cells contained 1.7% (+)-catechin and 2.4% (-)-epicatechin on dry wt basis but when stimulated with methyl jasmonate produced 3.4% catechin and 5.2% epicatechin. These are the highest levels of these metabolites obtained in plant cell cultures. PMID- 21544614 TI - Expression of glr gene encoding glutamate racemase in Bacillus licheniformis WX 02 and its regulatory effects on synthesis of poly-gamma-glutamic acid. AB - The glr gene, which encodes glutamate racemase involved in the conversion of L glutamic acid to its D-isomer, was cloned and expressed in Bacillus licheniformis WX-02. Overexpression of the glr gene not only increased the production of poly gamma-glutamic acid (gamma-PGA) by 22.5% but also increased the proportion of D glutamate in gamma-PGA from 77 to 85%. The activity of glutamate racemase was higher than in the original strain throughout cultivation. This is the first report that overexpression of the glr gene could enhance the L- and D-glutamate conversion in B. licheniformis WX-02 and increase the proportion of D-glutamate in gamma-PGA and the yield of gamma-PGA. PMID- 21544615 TI - H2 inhibits TNF-alpha-induced lectin-like oxidized LDL receptor-1 expression by inhibiting nuclear factor kappaB activation in endothelial cells. AB - H(2) is a therapeutic antioxidant that can reduce oxidative stress. Oxidized low density lipoprotein, which plays roles in atherosclerosis, may promote endothelial dysfunction by binding the cell-surface receptor LOX-1. LOX-1 expression can be upregulated by various stimuli, including TNF-alpha. Thus, we aimed to examine whether the upregulation of LOX-1 by different stimuli could be blocked by H(2) in endothelial cells. H(2) significantly abolished the upregulation of LOX-1 by different stimuli, including TNF-alpha, at the protein and mRNA levels. The TNF-alpha-induced upregulation of LOX-1 was also attenuated by the NF-kappaB inhibitor N-acetyl-L-cysteine. H(2) inhibited the TNF-alpha induced activation of NF-kappaB and the phosphorylation of IkappaB-alpha. Furthermore, H(2) inhibited the expression of LOX-1 and the activation of NF kappaB in apolipoprotein E knockout mice, an animal model of atherosclerosis. Thus, H(2) probably inhibits cytokine-induced LOX-1 gene expression by suppressing NF-kappaB activation. PMID- 21544616 TI - Sucrose monolaurate synthesis with Protex 6L immobilized on electrospun TiO2 nanofiber. AB - TiO(2) nanofibers with uniform diameter about 125 nm were prepared based on sol gel process and electrospinning technology. Protex 6L, an industrial alkaline protease, was covalently immobilized on TiO(2) nanofiber through gamma aminopropyltriethoxysilane modification and glutaraldehyde crosslinking. With 2 (v/v)% glutaraldehyde as crosslinker, the enzyme loading is about 201 mg (g nanofiber membrane)(-1), and the specific activity of the immobilized Protex 6L is 2.45 MUmol h(-1) ml(-1) mg(-1) protein for synthesis of sucrose monolaurate from sucrose and vinyl laurate. The optimal condition for sucrose monolaurate production is 5% (v/v) water content in DMSO/2-methyl-2-butanol solvent mixture and 50 degrees C. Under this condition, 97% conversion was achieved within 36 h by nanofibrous Protex 6L, which is corresponding to a productivity 34 times higher than that of most widely used Novozym 435. After 10 cycles reuse, nanofibrous Protex 6L retained 52.4% of its original activity. PMID- 21544617 TI - Encoding of force increases and decreases by tibial campaniform sensilla in the stick insect, Carausius morosus. AB - Detection of force increases and decreases is important in motor control. Experiments were performed to characterize the structure and responses of tibial campaniform sensilla, receptors that encode forces through cuticular strains, in the middle leg of the stick insect (Carausius morosus). The sensilla consist of distinct subgroups. Group 6A sensilla are located 0.3 mm distal to the femoro tibial joint and have oval shaped cuticular caps. Group 6B receptors are 1 mm distal to the joint and have round caps. All sensilla show directional, phasico tonic responses to forces applied to the tibia in the plane of joint movement. Group 6B sensilla respond to force increases in the direction of joint extension while Group 6A receptors discharge when those forces decrease. Forces applied in the direction of joint flexion produce the reverse pattern of sensory discharge. All receptors accurately encode the rate of change of force increments and decrements. Contractions of tibial muscles also produce selective, directional sensory discharges. The subgroups differ in their reflex effects: Group 6B receptors excite and Group 6A sensilla inhibit tibial extensor and trochanteral depressor motoneurons. The tibial campaniform sensilla can, therefore, encode force increases or decreases and aid in adapting motor outputs to changes in load. PMID- 21544618 TI - Olfactory sensitivity to amino acids in the blackspot sea bream (Pagellus bogaraveo): a comparison between olfactory receptor recording techniques in seawater. AB - The current study investigated the olfactory sensitivity of the blackspot sea bream to amino acids, odorants associated with food detection in fish, and compared the efficacy of two different experimental methods: multi-unit recording from the olfactory nerve and the electro-olfactogram (EOG). Twenty essential amino acids plus L-DOPA evoked clear, concentration-dependent olfactory responses using both methods, with estimated thresholds of 10(-8.5)-10(-6.2) M (nerve recording) and 10(-7.5)-10(-4.8) M (EOG). The most potent amino acids were L cysteine, L-methionine (both sulphur-containing), L-alanine, L-leucine (both neutral), L-glutamine (amide-containing) and L-serine (hydroxyl-containing). The least potent were L-proline (secondary alpha-amino group), the aromatic amino acids and glycine (simplest). Although the rank order of olfactory potency was similar for the two methods used, and the calculated thresholds given by the two methods were positively correlated, the sensitivity of the EOG was consistently lower than multi-unit recording by approximately one order of magnitude, presumably due to the electrical shunting effect of seawater. As in freshwater, the EOG could be a valid method for comparing olfactory potency of different odorants in stenohaline marine fish; however, for absolute 'biological' thresholds, a more invasive recording technique, such as multi-unit recording from the olfactory nerve, should be used. PMID- 21544619 TI - Molecular and functional characterization of an endoglucanase in the phytopathogenic fungus Pyrenochaeta lycopersici. AB - Many fungal plant pathogens secrete an array of cell wall degrading enzymes mainly involved in the pathogenesis. In this work, a cDNA clone encoding an extracellular endo-1,4-beta-glucanase (named PlEGL1) from the causal agent of the Corky Root Rot of tomato, Pyrenochaeta lycopersici, was isolated and characterized, in order to understand its putative role in the pathogenesis and its mechanism of action. Multiple alignment of the deduced amino acidic sequence shows a high homology with other endoglucanases from different phytopathogenic fungi and detects a well-defined conserved domain of the Glycosyl Hydrolase family 61 (GH61). In vitro, Plegl1 gene transcription is correlated to a cellulolytic activity of the fungus, regulated, in its turn, by the presence of sugar and/or cellulose in the culture medium. In the infected plants, expression level of Plegl1 is positively correlated to the development of the disease. PlEGL1 was heterologously expressed in Escherichia coli and the recombinant protein was purified and tested for its cellulolytic ability, showing a very weak activity, in agreement with all the endoglucanases belonging to GH61 family. The finding in this paper will provide the basis for further determination of biochemical properties of the PlEGL1 protein and its possible involvement in the host-pathogen interaction. PMID- 21544620 TI - Gene fragmentation: a key to mitochondrial genome evolution in Euglenozoa? AB - Phylum Euglenozoa comprises three groups of eukaryotic microbes (kinetoplastids, diplonemids, and euglenids), the mitochondrial (mt) genomes of which exhibit radically different modes of organization and expression. Gene fragmentation is a striking feature of both euglenid and diplonemid mtDNAs. To rationalize the emergence of these highly divergent mtDNA types and the existence of insertion/deletion RNA editing (in kinetoplastids) and trans-splicing (in diplonemids), we propose that in the mitochondrion of the common evolutionary ancestor of Euglenozoa, small expressed gene fragments promoted a rampant neutral evolutionary pathway. Interactions between small antisense transcripts of these gene fragments and full-length transcripts, assisted by RNA-processing enzymes, permitted the emergence of RNA editing and/or trans-splicing activities, allowing the system to tolerate indel mutations and further gene fragmentation, respectively, and leading to accumulation of additional mutations. In this way, dramatically different mitochondrial genome structures and RNA-processing machineries were able to evolve. The paradigm of constructive neutral evolution acting on the widely different mitochondrial genetic systems in Euglenozoa posits the accretion of initially neutral molecular interactions by genetic drift, leading inevitably to the observed 'irremediable complexity'. PMID- 21544621 TI - A longitudinal study of maternal folate and vitamin B12 status in pregnancy and postpartum, with the same infant markers at 6 months of age. AB - Folate and vitamin B12 are involved in homocysteine metabolism and are critical to the methylation of DNA. We aimed to assess plasma vitamin B12 (pB12), plasma folate (pFol), and red cell folate (rcFol) in women and their infants during pregnancy and after birth. Maternal biomarkers were tested as predictors of infant biomarkers, including plasma homocysteine (pHcy), at age 6 months. Participants (n = 153) were recruited at the John Hunter Hospital, Australia. Maternal fasting blood samples were collected at 20 and 36 weeks gestation, and at 14 and 27 weeks postpartum. Fifty healthy, term infants provided non-fasting samples at age 6 months. Plasma homocysteine data were available for 16 infants at age 6 months. Maternal pB12 concentrations fell by 16% from 20 to 36 weeks gestation, but had recovered by 14 weeks postpartum. Maternal rcFol concentrations fell by 31% from 20 weeks gestation to 27 weeks postpartum. Infants breastfed at 6 months had lower pB12 (median 159 vs. 402 pmol/L, n = 23 vs. 18, P < 0.01) and folate (median folate z-score -0.58 vs. 0.85, n = 23 vs. 17, P < 0.01), and higher pHcy (median 11.9 vs. 7.3 MUmol/L, n = 8 vs. 6, P < 0.01), than those on infant formula. Maternal pregnancy pFol, but not pB12, inversely predicted infant pHcy, after adjustment for the infant's current pB12 (P = 0.04). Changes in maternal B12 and folate occur during pregnancy and after birth. Infant homocysteine metabolism may be regulated through maternal folate concentrations during pregnancy and postnatal feeding. PMID- 21544622 TI - Rational design, synthesis and biological evaluations of amino-noscapine: a high affinity tubulin-binding noscapinoid. AB - Noscapine and its derivatives are important microtubule-interfering agents shown to have potent anti-tumor activity. The binding free energies (DeltaG (bind)) of noscapinoids computed using linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model were in agreement with the experimental DeltaG (bind) with average root mean square error of 0.082 kcal/mol. This LIE-SGB model guided us in designing a novel derivative of noscapine, amino noscapine [(S)-3-((R)-9-amino-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxy isobenzo-furan-1(3H)-one] that has higher tubulin binding activity (predicted DeltaG (bind) = -6.438 kcal/mol and experimental DeltaG (bind) = -6.628 kcal/mol) than noscapine, but does not significantly change the total extent of the tubulin subunit/polymer ratio. The modes of interaction of amino-noscapine with the binding pocket of tubulin involved three hydrogen bonds and are distinct compared to noscapine which involved only one hydrogen bond. Also the patterns of non-bonded interactions are albeit different between both the lignads. The 'blind docking' approach (docking of ligand with different binding sites of a protein and their evaluations) as well as the reasonable accuracy of calculating DeltaG (bind) using LIE-SGB model constitutes the first evidence that this class of compounds binds to tubulin at a site overlapping with colchicine-binding site or close to it. Our results revealed that amino-noscapine has better anti-tumor activity than noscapine. PMID- 21544623 TI - Agrobacterium-mediated transformation of Australian rice varieties and promoter analysis of major pollen allergen gene, Ory s 1. AB - A simple protocol for Agrobacterium-mediated transformation of Australian rice using mature embryos is described. Transgenic plants of two commercial genotypes of Australian rice, Amaroo and Millin, were produced. Transgenic plants were obtained by applying selection pressure to callus and to the regenerated shoots. Exclusion of the selective agent (hygromycin) during plant regeneration was found to be critical for recovery of transgenic plants from these commercial varieties. Transgenic plants were produced after 3 months. The developed system was also used to study spatial and temporal expression of a rice pollen-specific gene, Ory s 1. Expression of pOry s 1::uidA in transgenic rice demonstrated GUS expression in mature pollen, hence indicating potential use of this promoter to direct pollen-specific gene expression. Further Ory s 1 5' deletion study indicated that the pollen-specificity element may reside within -405 bp to the start of the transcription, while the region upstream of -405 contained a cis-acting regulatory element(s) responsible for quantitative expression of this gene. PMID- 21544624 TI - A model to predict the frequency of integration of fitness-related QTLs from cultivated to wild soybean. AB - With the proliferation of genetically modified (GM) products and the almost exponential growth of land use for GM crops, there is a growing need to develop quantitative approaches to estimating the risk of escape of transgenes into wild populations of crop relatives by natural hybridization. We assessed the risk of transgene escape by constructing a population genetic model based on information on fitness-related QTLs obtained from an F (2) population of wild soybean G. soja * cultivated soybean Glycine max. Simulation started with ten F (1) and 990 wild soybeans reproducing by selfing or outcrossing. Seed production was determined from the genetic effects of two QTLs for number of seeds (SN). Each seed survived winter according to the maternal genotype at three QTLs for winter survival (WS). We assumed that one neutral transgene was inserted at various sites and calculated its extinction rate. The presence of G. max alleles at SN and WS QTLs significantly decreased the probability of introgression of the neutral transgene at all insertion sites equally. The presence of G. max alleles at WS QTLs lowered the risk more than their presence at SN QTLs. Although most model studies have concentrated only on genotypic effects of transgenes, we show that the presence of fitness-related domestication genes has a large effect on the risk of transgene escape. Our model offers the advantage of considering the effects of both domestication genes and a transgene, and they can be widely applied to other wild * crop relative complexes. PMID- 21544625 TI - Septin 6 regulates the cytoarchitecture of neurons through localization at dendritic branch points and bases of protrusions. AB - Septins, a conserved family of GTP-binding proteins with a conserved role in cytokinesis, are present in eukaryotes ranging from yeast to mammals. Septins are also highly expressed in neurons, which are post-mitotic cells. Septin6 (SEPT6) forms SEPT2/6/7 complexes in vivo. In this study, we produced a very specific SEPT6 antibody. Immunocytochemisty (ICC) of dissociated hippocampal cultures revealed that SEPT6 was highly expressed in neurons. Developmentally, the expression of SEPT6 was very low until stage 3 (axonal outgrowth). Significant expression of SEPT6 began at stage 4 (outgrowth of dendrites). At this stage, SEPT6 clusters were positioned at the branch points of developing dendrites. In maturing and mature neurons (stage 5), SEPT6 clusters were positioned at the base of filopodia and spines, and pre-synaptic boutons. Detergent extraction experiments also indicated that SEPT6 is not a post-synaptic density (PSD) protein. Throughout morphologic development of neurons, SEPT6 always formed tiny rings (external diameter, ~0.5 MUm), which appear to be clusters at low magnification. When a Sept6 RNAi vector was introduced at the early developmental stage (DIV 2), a significant reduction in dendritic length and branch number was evident. Taken together, our results indicate that SEPT6 begins to be expressed at the stage of dendritic outgrowth and regulates the cytoarchitecture. PMID- 21544626 TI - Regulation of vascular endothelial growth factor signaling by miR-200b. AB - Vascular endothelial growth factor (VEGF) signaling plays an important role in angiogenesis. In the VEGF signaling pathway, the key components are VEGF and its receptors, Flt-1 and KDR. In this study, we show that transfection of synthetic miR-200b reduced protein levels of VEGF, Flt-1, and KDR. In A549 cells, miR-200b targeted the predicted binding sites in the 3'-untranslated region (3'-UTR) of VEGF, Flt-1, and KDR as revealed by a luciferase reporter assay. When transfected with miR-200b, the ability of HUVECs to form a capillary tube on Matrigel and VEGF-induced phosphorylation of ERK1/2 were significantly reduced. Taken together, these results suggest that miR-200b negatively regulates VEGF signaling by targeting VEGF and its receptors and that miR-200b may have therapeutic potential as an angiogenesis inhibitor. PMID- 21544627 TI - A strong promoter activity of pre-B cell stage-specific Crlz1 gene is caused by one distal LEF-1 and multiple proximal Ets sites. AB - The promoter of pre-B cell stage-specific Crlz1 gene, whose protein translocates the cytoplasmic core binding factor beta (CBFbeta) into the nucleus and thereby allows its heterodimerization with Runx, has a very strong activity, which is about 25% of cytomegalovirus (CMV) promoter activity and comparable to the EF 1alpha promoter activity. Its transcription start site was mapped at 155 nt upstream of translation initiation codon. 5'-truncation analysis of charged amino acids rich leucine zipper 1 (Crlz1) promoter revealed that one distal region from -612 to -536 and one proximal region from -198 to -100 as numbered from the transcription start site were critical for the promoter activity. The 3' truncation analysis of the promoter revealed that the basal promoter sequence around the transcription start site, which should be necessary for the assembly of transcription initiation complex and the start of RNA polymerase II, was also essential, although not sufficient by itself. When transcription factor binding sites within those two critical regions were searched by in vivo footprinting, one distal LEF-1 and multiple proximal Ets consensus-like sites were found to be footprinted. Indeed, the protein causing a footprint over the distal region was found to be LEF-1, and the ones causing three footprints over the proximal region were found to be such Ets family members as Fli-1 and GABP, as verified by EMSA and ChIP analyses. Furthermore, those LEF-1 and Ets sites were shown to drive additively a strong transcription of Crlz1 gene. PMID- 21544628 TI - Frederick L. Whitam (1933-2009). PMID- 21544629 TI - Sorafenib augments cytotoxic effect of S-1 in vitro and in vivo through TS suppression. AB - PURPOSE: Sorafenib, a multikinase and tyrosine-kinase inhibitor, has anti-tumor activity in patients with advanced renal cell carcinoma (RCC). Recently, we reported that S-1 was active and well tolerated for the treatment of cytokine refractory metastatic RCC. Therefore, we hypothesized that S-1 might be a good candidate for combination therapy with molecular targeting agents. In this study, we examined the mechanisms underlying for the synergism between S-1 and Sorafenib for RCC treatment in vitro and in tumor-bearing murine models. METHODS: Human RCC cell lines were used for the in vitro cell proliferation assay. ACHN and 786-O tumors were subcutaneously transplanted into NCr-nu/nu-mice. Mice were treated with S-1 and/or Sorafenib, and tumor growth and side effects were monitored. RESULTS: Synergistic anti-proliferative effects of Sorafenib and S-1 were clearly demonstrated in ACHN and 786-O cell lines in vitro due to the suppression of TS and E2F-1 expression. In the NCr-nu/nu model, the synergistic anti-tumor effects of S-1 and Sorafenib were again clearly seen, indicating direct synergistic effects of each drug on tumor growth. CONCLUSIONS: Our results demonstrate the synergistic activity of S-1 and Sorafenib and provided the rationale for combination therapy with S-1 and Sorafenib for the treatment of patients with advanced RCC. PMID- 21544630 TI - Nitric oxide: role in tumour biology and iNOS/NO-based anticancer therapies. AB - PURPOSE: The diatomic radical nitric oxide (NO) has been the cause of intense debate with implication in carcinogenesis, tumour progression, invasion, angiogenesis and modulation of therapeutic responses. The tumour biology of NO is highly complex, and this review summarises the various protective and damaging mode of action of NO. METHODS: We reviewed all published literature addressing the complexities of the role of NO in the altered biology of cancer and evaluating promising therapeutic roles of NO/iNOS for anti-cancer therapy. RESULTS: The available experimental evidences highlight contrasting pro- and anti tumour effects of iNOS expression, which appear to be reconciled by consideration of the concentrations of NO involved, the temporo-spatial mode of NO action, intracellular targets, cellular redox state and the timing of an apoptotic stimulus. Several clinical and experimental studies indicate that the presence of NO in tumour microenvironment is detrimental to tumour cell survival and metastasis. In contrast, numerous reports suggest that NO can have tumour promoting effects. NO is a 'double-edged sword' in cancer, and this review offers insight into the dichotomous nature of NO and discuss the therapeutic gain that can be achieved by manipulating tumour NO. CONCLUSIONS: NO may exert a biphasic response, such that when NO levels go beyond a critical concentration that would be suitable for tumour growth and survival, growth arrest and/or apoptotic pathways are initiated. These characteristics of NO have been exploited therapeutically with impressive effects in pre-clinical models of cancer to slow tumour growth and to enhance the efficacy of both chemotherapy and radiotherapy. PMID- 21544631 TI - First patient treated with a re-challenge of catumaxomab in recurrent malignant ascites: a case report. AB - In the past, treatment for malignant ascites focussed on symptomatic relief or treatment of the underlying disease. A promising option evolved with catumaxomab (Removab((r))) in 2009. Since catumaxomab is a bispecific, trifunctional antibody with mouse-rat origin, so far repeated treatment cycles were not an option due to the occurrence of human anti-drug antibodies (HADA). Nevertheless, the good results obtained so far raised the question whether a repeated treatment cycle with catumaxomab could be feasible and effective. We report on a 74-year-old female patient with breast cancer and peritoneal carcinomatosis. To our knowledge, this is the first patient world-wide to be treated with a repeated cycle of catumaxomab. HAMA (human anti-mouse antibodies) values were identified in blood and ascites samples. Ascites samples were also stained to identify and quantify cells, positive for EpCAM (epithelial cell adhesion molecule) and CD45. The patient tolerated the second cycle without unexpected side effects and remained puncture-free for another 45 days. Analysis of blood and ascites revealed a quick increase in HAMA values in the blood samples after 1 week, but considerably lower HAMA values and delayed increase in the ascites samples. Also a distinct and continuous decrease of EpCAM-positive cells was observed in the ascites samples under treatment. A strong increase in CD45-positive cells was detected after the beginning of the second cycle, with a consecutive decline toward the end. This first experience suggests that a repeated cycle of catumaxomab might be feasible and effective. As a consequence, a phase II trial (SECIMAS) was initiated. PMID- 21544632 TI - Characterization of arsenic-induced cytogenetic alterations in acute promyelocytic leukemia cell line, NB4. AB - Gain or loss of genes plays important roles in leukemogenesis of APL via cooperation with PML-RARA. Fluorescence in situ hybridization (FISH) was applied to investigate the DNA copy number changes of hTERT, ERG, CDKN1B (P27), CDKN2A (P16), and TP53 genes in an acute promyelocytic leukemia (APL) cell line (NB4). Five bacterial artificial chromosome probes (BAC) for 9p21.3, 17p13.1, 12p13.2, 5p15.33, 21q22.2 regions were prepared using sequence independent amplification (SIA) and were hybridized to NB4 cells treated with different doses of arsenic trioxide (As(2)O(3); ATO) at various time intervals. NB4 cells were also karyotyped by G-banded chromosome analysis 24 h after culture initiation. FISH analysis prior to treatment showed CDKN1B, CDKN2A, and TP53 gene deletion but ERG and hTERT gene amplification. After treatment with ATO, the number of the NB4 cells with deleted CDKN1B and CDKN2A as well as the counts of the cells with hTERT amplification was significantly reduced in time- and does-dependent manners. In addition, we observed expressive increase in signal patterns of CDKN1B and CDKN2A along with significant decline in hTERT signal patterns in ATO treated cells as compared with the control group (in time- and dose-dependent manners). On the other hand, no difference in signal patterns for Erg and p53 was observed in response to ATO exposure. The results of the present study show the cytogenetic alteration in hTERT, CDKN1B, and CDKN2A in NB4 cells after treatment with ATO might introduce a new mechanism of antitumor activities of ATO in APL cell line, NB4. PMID- 21544633 TI - Normal range of spinal mobility for healthy young adult Turkish men. AB - Anthropometric characteristics may vary among human populations, especially with differences in race. The aim of the present study is to find normal values of some measures (chest expansion, Schober's test and modified Schober's test) frequently used in the assessment of patients with ankylosing spondylitis, in young adult Turkish men. Initial recruitment identified 2,925 healthy male participants aged 20-30 years, and the final study sample included 1,982 of them. Participants joined the research from all cities except one in Turkey. The measurements of chest expansion, Schober's test, and modified Schober's test were performed by the same researcher using a plastic measuring tape. The mean (+/ standard error) values of the chest expansion, Schober's test, and modified Schober's test were 6.11 (+/-0.02), 5.62 (+/-0.02), and 7.78 (+/-0.02) cm, respectively. The estimated normal lower bounds for chest expansion, Schober's test, and modified Schober's test may be between 3.71-3.86 cm, 3.86-3.97 cm, and 5.46-5.60 cm, respectively, for young adult Turkish men. No correlation was found between height and spinal mobility. The normal values for spinal mobility in this sample of healthy young adult Turkish men differed from those reported for other young adult male populations (chest expansion >=5 cm, Schober's test >5 cm, modified Schober's test >7 cm). It is thus useful to consider nationality in interpreting results of spinal mobility tests. PMID- 21544634 TI - G109T polymorphism of SLC22A12 gene is associated with serum uric acid level, but not with metabolic syndrome. AB - SLC22A12 gene, encoding urate transport 1, has been known to be responsible to urate metabolism. This study sought to determine the association between the novel G109T polymorphism in SLC22A12 with serum uric acid and the development of metabolic syndrome in Korean male subjects. A total of 132 healthy male subjects were enrolled in this study. Metabolic syndrome was determined using the modified guidelines for metabolic syndrome proposed by the National Cholesterol Education Program's Third Adult Treatment Panel. Genotyping for the SLC22A12 gene was assessed using denaturing high-performance liquid chromatography analysis. Serum uric acid and fractional excretion of uric acid (FEUA) from blood and urine samples were measured. Frequencies of the 109GG, 109GT, and 109TT genotypes were 57.6, 38.6, and 3.8%, respectively. Serum uric acid levels and FEUAs were significantly different among the three genotypes of the G109T polymorphism (P = 0.035 and P = 0.033, respectively). In addition, subjects of genotypes with the T allele had lower uric acid levels and higher FEUAs compared to those with the 109GG genotype (P = 0.007 and P = 0.031, respectively). The G109T polymorphism of the SLC22A12 gene has no association with metabolic syndrome. However, a number of metabolic syndrome components were related to serum uric acid level (r = 0.285, P = 0.001) and also significantly different between genotype with and without T allele (P = 0.008). The novel G109T polymorphism of the SLC22A12 gene is related to serum uric acid level, but not to the development of metabolic syndrome. PMID- 21544635 TI - TNF promoter -308 G>A and LTA 252 A>G polymorphisms in Portuguese patients with systemic lupus erythematosus. AB - The polymorphism of the tumor necrosis factor (TNF) promoter gene at position 308 and that of the lymphotoxin alpha (LTA) gene at position 252 have been implicated as genetic risk factors for systemic lupus erythematosus (SLE) in some populations. In a nested case-control study, we investigated the possible association of these polymorphisms with susceptibility to SLE and with phenotypic disease features in Portuguese Caucasian patients. TNF-308 G>A and LTA 252 A>G polymorphisms were determined by restriction fragment length polymorphism analysis in a cohort of 115 SLE patients and 152 unrelated healthy controls, and the magnitude of the association between genotypes and SLE diagnosis was calculated. For SLE patients, we also tested the association between disease characteristics and genotypes. No significant differences in genotype or allele frequencies could be identified between SLE cases and controls. Lupus nephritis (OR = 2.84; 95%CI 1.14-7.03, P = 0.02) and the presence of anti-Sm antibodies (OR = 3.11; 95%CI 1.08-8.94; P = 0.03) were significantly more prevalent among lupus patients possessing the TNF-308 A allele. The occurrence of nephritis was also higher in LTA 252 G allele carriers (OR = 2.90; 95%CI 1.12-7.54; P = 0.02). Our results do not support a major role of either the TNF-308 G>A or the LTA 252 A>G polymorphisms as genetic risk factors for SLE. Nevertheless, these polymorphisms appear to associate with the risk of renal lupus and distinct immunological features. PMID- 21544636 TI - Physical performance and knee osteoarthritis among community-dwelling women in Japan: the Hizen-Oshima Study, cross-sectional study. AB - Osteoarthritis (OA) is the most common chronic joint disorder. Relationships between knee OA and physical performance have been examined, but mainly in patients with knee OA. Clarifying the relationship between knee OA and physical performance among community-dwelling individuals is thus important. Subjects comprised 563 community-dwelling Japanese women. Radiographic knee OA was defined as Kellgren-Lawrence criteria grade 2 or higher. Painful knee OA was defined as radiographic OA combined with knee pain. We evaluated performance-based measures of physical functioning. Student's t tests were used to compare continuous variables. Adjusted means of performance-based measures were compared between groups using general linear modeling methods. Mean age was 64.3 years. Women with radiographic OA were older than those without OA (P < 0.0001). BMI was greater in women with radiographic OA than in women without OA (P < 0.0001). In univariate analysis, women with radiographic OA displayed worse physical functioning than women without OA, with longer chair stand time, longer walking time, and shorter functional reach. Performance-based measurements with painful OA resembled those with radiographic OA. Age- and BMI-adjusted means of chair stand time and walking time were longer in women with radiographic or painful knee OA than in women without OA (P < 0.0001 each). Furthermore, chair stand and walking took longer for women with painful knee OA than for women with radiographic knee OA. Women with knee OA showed deteriorated performance of chair stand and walking. Painful knee OA was associated with poorer performance than radiographic knee OA. PMID- 21544637 TI - CD28 proximal promoter polymorphisms in systemic lupus erythematosus susceptibility. AB - CD28 expression and serum levels are significantly increased in patients with SLE than in healthy controls (HC). Until now, there are no studies of proximal promoter polymorphisms of CD28 gene in SLE. Therefore, our objective was to investigate the polymorphisms present in the proximal promoter of CD28 in a group of SLE and HC and to associate the polymorphisms present with the CD28 serum levels of 40 patients and 40 controls. One hundred and seven patients as well as 108 controls matched by age range and genders were included. The 11 ACR criteria were analyzed on the clinical files, and the proximal promoter region of CD28 gene was analyzed by direct sequencing of a 489-basepair fragment. C28 serum levels (sCD28) were measured by ELISA technique in 40 patients and 40 controls. Only two of the eight reported polymorphisms were found, and they correspond to rs35593994 (-372 A/G) and rs56156157 (-145 -/C). The first had a prevalence of 41 and 36% in patients and controls respectively and the second of 1.4% in both groups. None of these polymorphisms were associated with SLE, and the polymorphism -372 A/G was not associated with the clinical features of disease. Likewise, the association with the sCD28 and the genotypes of -372 A/G polymorphism was not significant. The polymorphisms of the proximal promoter of CD28 are not associated with SLE, and the polymorphism -372 A/G is not associated with the diagnostic criteria of SLE or the sCD28. PMID- 21544638 TI - Mannose-binding lectin 2 gene haplotype analysis in Korean patients with ankylosing spondylitis. AB - Mannose-binding lectin (MBL) serum levels or genetic polymorphisms are known to be associated with autoimmune diseases. We investigated MBL2 genetic polymorphisms in 95 patients with ankylosing spondylitis (AS) and in 252 healthy controls. MBL2 promoter polymorphisms at -550 (H/L), -221 (Y/X), +4 (P/Q), and exon polymorphisms at codon 52 (Arg/Cys), 54 (Gly/Asp, or A/B), and 57 (Gly/Glu) were investigated using polymerase chain reaction and restriction fragment length polymorphism. Genetic polymorphisms were analyzed using SPSS (ver 12.0) and Haploview (ver 4.2). MBL2 single-nucleotide polymorphisms (SNPs) were not significantly different between patients with AS and controls. By haplotype analysis, LYPB frequency was significantly lower in AS (10.7% vs. 21.3%, OR 0.441, 95% CI: 0.266-0.733, P value = 0.001, Pc value = 0.008). The frequency of LYPA (15.4% vs. 9.2%, OR 1.802, 95% CI: 1.097-2.961, P value = 0.019, Pc value = 0.101) and HYPB (3.5% vs. 0.8%, OR 4.457, 95% CI: 1.289-15.409, P value = 0.011, Pc value = 0.060) tended to be higher in AS. Clinical characteristics of AS were not associated with any MBL2 SNP or haplotype. In summary, haplotypes of MBL2 genetic polymorphisms were found to be associated with AS, which suggests that MBL2 genetic polymorphisms may play a role during the development of AS. PMID- 21544639 TI - Evaluation of the effects of Global Postural Reeducation in patients with ankylosing spondylitis. AB - The objective of this study is to assess the effects of Global Postural Reeducation (GPR) in patients with ankylosing spondylitis and compare GPR with group conventional segmental self-stretching and breathing exercises. This is a controlled interventional study of 38 patients divided into 2 groups: a GPR group (n = 22) and a control group (n = 16). Both groups were treated for more than 4 months. With the GPR group patients, positions that stretched the shortened muscle chains were used. With the control group patients, conventional segmental self-stretching and breathing exercises were performed. The variables analyzed were pain intensity, morning stiffness, spine mobility, chest expansion, functional capacity (Health Assessment Questionnaire-Spondyloarthropathies-HAQ S), quality of life (Medical Outcome Study Short Form 36 Healthy Survey-SF-36), and disease activity (Bath Ankylosing Spondylitis Disease Activity Index-BASDAI). Statistical analysis was used with a significance level of P < 0.05. There was a statistically significant improvement for all the parameters analyzed between pre and post-treatment in both groups. In the intergroup comparison, the GPR group showed a significantly greater improvement in morning stiffness (P = 0.013), spine mobility parameters, except finger-floor distance (P = 0.118), in chest expansion (P = 0.028), and in the physical aspect component of the SF-36 (P = 0.001). The results of this study showed that individual treatment with GPR (overall stretching) seems to have better clinical outcomes than group treatment with conventional segmental self-stretching and breathing exercises for patients with ankylosing spondylitis. PMID- 21544640 TI - For many high anal fistulas, lay open is still a good option. PMID- 21544641 TI - How reliable are CT scans for the evaluation of calcaneal fractures? AB - INTRODUCTION: CT scans are deemed to be the gold standard for the evaluation of calcaneal fractures. However, the reliability of the interpretation has not been studied systematically. PATIENTS AND METHODS: In a prospective multicenter study, the CT data set of five different fractures was presented to 57 evaluators. The participating surgeons were asked to assess calcaneal fractures on the basis of a multiple choice questionnaire. The CT scans were validated by the intraoperative findings. The questionnaires were compared to the model solution of three foot and ankle surgeons. The intra- and interrater reliability was calculated. RESULTS: The proportion of intraobserver agreement was 82%. Cohen's kappa was kappa = 0.748 with P < 0.0001. In total, 61% of the items were answered similarly to the model answer. Only 27% of the evaluators were able to correctly classify the fracture according to Sanders and 63% of the evaluators agreed that surgical procedure was necessary. The more experienced the surgeon, the higher was the interrater agreement. CONCLUSION: This is the first study to systematically analyze the reliability of the interpretation of CT scans of calcaneal fractures. This was found to be unsatisfactory. Future studies must show, if specific interventions, e.g., teaching programs or image procession modalities (e.g., 3D reconstructions), are capable of improving the quality of interpretation of CT scans for calcaneal fractures. PMID- 21544642 TI - Presentation, microsurgical therapy, and clinical outcomes in three cases of expanding melanonychia of the nail unit in children. AB - The management of expanding melanonychia in childhood is controversial. Here, we present three cases and discuss their operating indications and reconstruction. Between January 1, 1995 and December 31, 2007, one boy and two girls, were operated for expanding melanonychia, involving the thumb, index finger or the middle finger. They were 2, 4, and 7 years at the time of surgery. A complete resection of the nail plate was performed followed by a direct finger reconstruction using a free short-pedicle vascularized nail flap of the toe. Histology showed a junctional nevus in all cases. The follow-ups were after 2, 3, and 5 years and without any complications or recurrence. Regarding reconstruction, the mean Foucher and Leclere score were, respectively, 17 and 16 points. It is concluded that for expanding melanonychia, in case of doubt, an examination of the entire lesion is necessary. Reconstruction of the nail unit after wide excision with nail plate ablation can be performed using microsurgery as discussed below. However, new guidelines on shave biopsy can make this microsurgical procedure obsolete. PMID- 21544643 TI - Evolution of apolar sporocytes in marchantialean liverworts: implications from molecular phylogeny. AB - In meiosis of basal land plants, meiotic division planes are typically predicted by quadri-lobing of the cytoplasm and/or quadri-partitioning of plastids prior to nuclear divisions. However, sporocytes of several marchantialean liverworts display no indication of premeiotic establishment of quadripolarity, as is observed in flowering plants. In these cases, the shape of sporocytes remains spherical or elliptical and numerous plastids are distributed randomly in the cytoplasm during meiosis. Through a survey of sporocyte morphology in marchantialean liverworts, we newly report the occurrence of apolar sporocytes in Sauteria japonica and Athalamia nana (Cleveaceae; Marchantiales). Molecular phylogenetic analyses revealed that the quadri-lobing of cytoplasm and quadri partitioning of plastids were lost independently several times during the evolution of marchantialean liverworts. In addition, our phylogenetic analyses indicate that the simplified sporophytes of several marchantialean liverworts are not a primitive condition but rather represent the result of reductive evolution. The loss of the quadripolarity of sporocytes appears to correlate with the evolutionary trend of the sporophyte towards reductions. Through the evolution of the simplified sporophytes, suppression of mitotic divisions of sporogenous cells might had caused not only the modification of sporophyte ontogeny but also the drastic cytological change of sporocyte. PMID- 21544644 TI - Non-hematological tumors of head and neck region in the pediatric age group in a tertiary care cancer center. AB - PURPOSE: To analyze the clinical profile, management and outcome of non hematological tumors in head and neck region in children less than 18 years of age. PATIENTS AND METHODS: Medical records of patients (0-18 years) presenting with non-hematological tumors of head and neck region from 2000 to 2010 were reviewed. RESULT: Out of the 78 patients identified, 50 were males with median age of 14 years (3 months to 18 years). Histologically, 58 out of the 78 patients had malignant tumors and 20 were metastatic at presentation. Common site of tumor origin was noted as thyroid (23/78), salivary glands (21/78) and nasopharynx (13/78). Out of 78 patients, 44 patients were treated by surgery, 26 patients received radiation and 13 patients received chemotherapy, while 9 patients received radio-iodine (I-131) treatment. Median follow up of all cases was 22 months (range 1 month to 8 years). The event free survival was 74.1% and overall survival was 89.6%. Subset analysis revealed patients with thyroid and salivary gland malignancies have excellent survival, while those with squamous cell carcinoma and high risk neuroblastoma had poor outcome. CONCLUSION: This study reveals the interesting profile of head and neck tumors in children, and important role of surgery for favorable outcome. PMID- 21544645 TI - High flow priapism: diagnosis and treatment in pediatric population. AB - PURPOSE: To present three cases of arterial high flow priapism (HFP) and propose a management algorithm for this condition. MATERIALS AND METHODS: We studied three children with post-traumatic arterial HFP (two patients with perineal trauma and one with penis trauma). RESULTS: Spontaneous resolution was observed in all the patients. The time of resolution by a return to a completely flaccid penis was different: 14, 27 and 36 days in each case. CONCLUSIONS: Absence of long-term damaging effects of arterial HFP on erectile tissue combined with the possibility of spontaneous resolution associated with blunt perineal trauma are suggestive signs for the introduction of an observation period in the management algorithm of HFP. Such a period may help to avoid unnecessary surgical intervention. Thus, these cases reinforce the decision to manage these patients conservatively and avoid angiographic embolization as a first therapeutic choice. PMID- 21544646 TI - Different transcription activity of HERV-K LTR-containing and LTR-lacking genes of the KIAA1245/NBPF gene subfamily. AB - Long terminal repeats (LTRs) of human endogenous retroviruses (HERVs) located near or within genes might affect their expression. We used the KIAA1245/NBPF human gene subfamily in an attempt to assess the regulatory potential of HERV LTRs. The subfamily includes five closely related paralogous genes: three of them contain an LTR in the second intron, and two genes lack it. Earlier we reported that the second and third exons of only LTR-containing genes of this subfamily could be detected in mature mRNAs of various cell lines and human tissues. The corresponding parts of mRNA of LTR-lacking genes analyzed in our study were absent from EST libraries, but other fragments of their mRNAs were available in EST databases. For a more unbiased view on the correlation between gene transcription and the intronic LTRs, in the present work we analyzed non-spliced pre-mRNA thus avoiding splicing effects. Based on RT-PCR analysis, we demonstrated that the KIAA1245/NBPF LTR-lacking gene AL592309/NBPF3 was transcriptionally active, but the LTR-containing genes showed significantly higher transcription levels. The data are in agreement with the suggestion that HERV-K LTRs within the second intron of the KIAA1245/NBPF subfamily genes might affect their transcriptional activity. However, it still remains to be investigated whether the revealed effect is due just to the LTR insertion or other factors are responsible for the difference. PMID- 21544647 TI - Clinical outcome of a headache-specific multidisciplinary treatment program and adherence to treatment recommendations in a tertiary headache center: an observational study. AB - This study investigated the outcome of a 5-day headache-specific multidisciplinary treatment program (MTP) and the adherence to treatment recommendations in 295 prospectively recruited consecutive headache patients [210 migraine, 17 tension-type headache (TTH), 68 combination headache, including 56 medication-overuse headache (MOH)]. Headache frequency decreased from 13.4 (+/ 8.8) to 8.8 (+/-8.0) days per month after 12-18 months. Forty-three percent of the participants fulfilled the primary outcome (reduction of headache frequency of >=50%), which was less likely in patients with combination of migraine and TTH compared to migraine (OR = 3.136, p = 0.002) or TTH (OR = 1.029, n.s.). Increasing number of headache days per month (OR = 1.092, p <= 0.0001) and adherence to lifestyle modifications (OR = 1.269, p = 0.004) predicted primary outcome. 51 of 56 MOH patients were treated successfully. Thirty-five percent of the patients were adherent to pharmacological prophylaxis, 61% to relaxation therapy, and 72% to aerobic endurance sports. MTP is effective in headache treatment. Adherence to therapy was associated with better outcome. PMID- 21544648 TI - Post-infectious headache: a reactive headache? AB - Post-infectious disease syndrome includes both neurological and non-neurological disorders. However, headache as an isolated or a presenting complaint of post infectious illness has not been well acknowledged in the literature. In this retrospective observation, patients having daily headache of more than 1 week and <4 weeks duration were included. We divided this group into patients having headache with preceding history of febrile illness in the recent past and patients without such history of febrile illness. We compared clinical features and therapeutic responses of various drugs between the groups. There were no significant differences in demographic features in these groups. However, associated neck pain, nausea, photophobia and meningeal signs were more prevalent in patients having history of preceding infection. A relatively lower proportion of subjects showed complete response to drugs at 3 months in post-infectious group. Good responses were noted to steroids in post-infectious group. In conclusion, a subset of patients with daily headache may be because of post infectious pathology and treatment in the early stage may prevent it from becoming chronic. Large prospective studies are required to confirm these observations. PMID- 21544649 TI - A transient third cranial nerve palsy as presenting sign of spontaneous intracranial hypotension. AB - Spontaneous intracranial hypotension is an uncommon cause of sudden and persistent headache: associated symptoms are common, among which there are cranial nerve palsies, especially of the abducens nerve. We report a case of a 21 year-old man with a transient and isolated third nerve palsy due to spontaneous intracranial hypotension. To our knowledge, there are only few reports in the literature of such association. PMID- 21544650 TI - Exploitation of differential homeostatic proliferation of T-cell subsets following chemotherapy to enhance the efficacy of vaccine-mediated antitumor responses. AB - The 5-year survival rate for stage IB-III non-small-cell lung cancer (NSCLC) remains 15%. Surgical resection followed by adjuvant chemotherapy with cisplatin and vinorelbine is one standard-of-care. We sought to determine in a preclinical model whether (a) the combination of cisplatin and vinorelbine could positively modulate components of the immune system independent of antitumor activity, and (b) there were synergistic effects of this drug combination and vaccine immunotherapy. We examined the effect of cisplatin/vinorelbine on gene expression, cell-surface phenotype, and CTL-mediated cytolysis of murine lung carcinoma cells in vitro; we also assessed the effects of cisplatin/vinorelbine on immune subsets and function of Tregs in vivo. Finally, we evaluated the potential synergy between chemotherapy and a recombinant yeast-CEA vaccine in a murine model transgenic for CEA with mice bearing lung tumors. These studies demonstrate that exposure of lung tumor cells to the platinum doublet cisplatin/vinorelbine modulates tumor cell phenotype and increases sensitivity to CTL-mediated cytolysis. These studies also demonstrate that cisplatin/vinorelbine (a) induces sub-myeloablative leucopenia that differentially modulates reconstitution of Treg versus effector T-cell subsets and (b) can be employed synergistically with vaccine, exploiting homeostatic peripheral expansion of T cells. Antitumor studies show for the first time that cisplatin/vinorelbine combined with vaccine increases the survival of mice with established NSCLC. These findings provide the rationale for the potential clinical benefit of the combined use of vaccine with cisplatin/vinorelbine chemotherapy regimens. PMID- 21544652 TI - Predictors for spontaneous stone passage in patients with renal colic secondary to ureteral calculi. AB - OBJECTIVES: To determine the clinical, laboratory, and imaging variables that can predict spontaneous stone passage in patients with renal colic secondary to ureteral calculi. METHODS: We prospectively analyzed the medical records of 114 patients who admitted to the emergency department for renal colic from June until November of 2010. Forty-six of them were excluded. The presence of ureteral calculi was confirmed by either a kidney-ureter-bladder plain film or an ultrasound or a computer tomography. In all patients, a second visit after 1 month was planned and the stone status was checked by the same imaging techniques. RESULTS: From the 68 patients, 16 had a calculus in the upper ureter, 10 in the mid ureter, and 42 in lower part. Stone size was ranged from 2.3 to 15 mm, 52.9% of them were located in the left ureter and 51.5% were radiopaque. Stones passed spontaneously in 36 patients. In multivariate analysis, serum white blood cell count found to be the most significant predictor (P = 0.028) for spontaneous passage followed by stone size (P = 0.037). In analysis of patients with stone size <10 mm, left side (P = 0.017) and serum white blood cell count (P= 0.032) found to be significant predictors. CONCLUSIONS: Serum white blood cell count is an easy to assay variable in everyday practice. This study showed that its value, at the acute phase of a renal colic, is a significant predictor for stone spontaneous passage and should be considered. Stone size remains a valuable predictor. Stones <10 mm on the left ureter have a higher likelihood to pass spontaneously. PMID- 21544651 TI - The role of obesity in kidney disease: recent findings and potential mechanisms. AB - Obesity epidemic is in rise in almost every industrialized country and continues to be a growing problem worldwide. In fact, obesity per se has been recognized as a chronic disease. Consequently, there has been a cascade of metabolic changes initiated by the markedly risen prevalence that contributes to the increased incidence of diabetes, hypertension, and cardiovascular disease. Moreover, obesity is also associated with an increased risk of chronic kidney disease (CKD). The majority of the studies indicate a direct relationship between body mass index (BMI) and CKD risk. Moreover, current evidence emphasized the fact that central obesity measurements, such as waist circumference, could be a better predictor of CKD progression and mortality than BMI. The detrimental effects of obesity on kidney outcome have been recognized in nondialysis-dependent (NDD)-CKD patients. However, survival in overweight or obese CKD patients undergoing maintenance hemodialysis is paradoxically opposed compared with the general population. This "reverse epidemiology," however, is valid mainly for the inflammated end-stage renal disease (ESRD) patients. In fact, renal transplant recipients with higher BMI have inferior patient and graft survival compared to patients with lower BMI. This review also provides perspectives concerning the mechanisms associated with obesity, such as the renin-angiotensin-aldosterone system (RAAS) activation, and the role of leptin, adiponectin, fetuin-A, and adipose tissue, as factors that contribute to the development of CKD. Prevention strategies for CKD patients are also discussed and should be considered by clinicians. PMID- 21544653 TI - Effects of the Er,Cr:YSGG laser on bone and soft tissue in a rat model. AB - The purpose of this study was to investigate the histological changes that occur in rat soft and hard tissues after Er,Cr:YSGG laser surgery. Each of 20 rats was submitted to four procedures which were randomly distributed to the right and left sides of the animal: procedure 1 dorsal incision with a scalpel; procedure 2 dorsal incision with a 2.0-W Er,Cr:YSGG laser; procedure 3 skull defect created with a diamond bur; procedure 4 skull defect created with a 3.0-W Er,Cr:YSGG laser. The animals were killed 3, 7, 15 and 30 days after surgery, and histological examinations were performed. The histometric analysis of the bone defects was evaluated using an unpaired t-test. Initially, the dorsum showed more histological signs of repair following procedure 1, although similar healing responses following procedures 1 and 2 were seen on day 30 after surgery. By day 30 the bone formation observed following procedure 4 was much more evident than following procedure 3. The unpaired t-test identified significant differences in bone formation on day 30 (p = 0.01), whereas a greater bone percentage was seen following procedure 4 than following procedure 3 (79.96 +/- 10.30% and 58.23 +/- 9.99%, respectively). Thus, histological repair of the Er,Cr:YSGG laser wounds was similar to that of the scalpel wounds. However, skull defects created with the Er,Cr:YSGG laser showed greater bone formation than defects created with the bur. Within the limitations of this study, we can conclude that the Er,Cr:YSGG laser is a promising surgical instrument in vivo, particularly for bone surgery. PMID- 21544654 TI - Features and applications of bacterial sialidases. AB - Sialidases, or neuraminidases (EC 3.2.1.18), belong to a class of glycosyl hydrolases that release terminal N-acylneuraminate residues from the glycans of glycoproteins, glycolipids, and polysaccharides. In bacteria, sialidases can be used to scavenge sialic acids as a nutrient from various sialylated substrates or to recognize sialic acids exposed on the surface of the host cell. Despite the fact that bacterial sialidases share many structural features, their biochemical properties, especially their linkage and substrate specificities, vary widely. Bacterial sialidases can catalyze the hydrolysis of terminal sialic acids linked by the alpha(2,3)-, alpha(2,6)-, or alpha(2,8)-linkage to a diverse range of substrates. In addition, some of these enzymes can catalyze the transfer of sialic acids from sialoglycans to asialoglycoconjugates via a transglycosylation reaction mechanism. Thus, some bacterial sialidases have been applied to synthesize complex sialyloligosaccharides through chemoenzymatic approaches and to analyze the glycan structure. In this review article, the biochemical features of bacterial sialidases and their potential applications in regioselective hydrolysis reactions as well as sialylation by transglycosylation for the synthesis of sialylated complex glycans are discussed. PMID- 21544655 TI - Naringinases: occurrence, characteristics, and applications. AB - Naringinase, an enzyme complex, is commercially attractive due to its potential usefulness in pharmaceutical and food industries. It is of particular interest in the biotransformation of steroids, antibiotics, and mainly of glycosides hydrolysis. Moreover, it can be used in citrus juices debittering and wine industries. Naringinase expresses activity on alpha-L-rhamnosidase and beta-D glucosidase. Many natural glycosides, including naringin, rutin, quercitrin, hesperidin, diosgene, and ter-phenyl glycosides, containing terminal alpha rhamnose and beta-glucose can act as substrates of naringinase. The sources, production, activity, biochemical properties, and substrate specificity of naringinase are reviewed, along with a description of the enzymatic deglycosylation systems and applications, concluding with the identification of areas which need further extensive studies. PMID- 21544656 TI - Adrenalectomy in older Americans has increased morbidity and mortality: an analysis of 6,416 patients. AB - BACKGROUND: The incidence of adrenal tumors increases with age. We examined the impact of older age (>60 years) on clinical and economic outcomes after adrenalectomy. METHODS: Adult patients who underwent adrenalectomy in the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (HCUP-NIS) from 2003-2008 were categorized into age groups: <=60 years, 61-70 years, and >70 years. Outcomes were compared using chi(2) and ANOVA; multivariate regression was used to assess the independent effect of older age on adrenalectomy outcomes. RESULTS: There were 6,416 patients: 21.9% were 61-70 years, and 12.9% were >70 years. Compared with patients <=60 years, patients 61-70 and >70 years had more complications (14.1% vs. 19.9 and 22.6%; p < 0.001) and mortality (0.4% vs. 1.3 and 2.3%; p < 0.001), longer mean length of stay (LOS) (3.3 vs. 4.0 and 4.9 days; p < 0.001), and higher mean costs ($12,307 vs. $13,226 and $14,649; p < 0.001). After adjustment, older age remained independently associated with sustaining one or more complications after adrenalectomy (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.1-1.7, for patients 61-70 years; OR 1.7, 95% CI 1.3-2.2 for patients >70 years) and longer adjusted LOS (1-day difference, p < 0.01). Age >70 years was independently associated with increased mortality after adrenalectomy (OR 2.8; 95% CI 1.4-5.6). Complications, LOS, and costs were reduced if patients underwent surgery by high-volume compared with low-volume surgeons. CONCLUSIONS: Older age seems to be independently associated with adverse short-term clinical and economic outcomes after adrenalectomy. Enhanced access to high-volume surgeons is a potentially modifiable factor of particular importance in these patients. PMID- 21544657 TI - Quality improvement of pancreatic surgery by centralization in the western part of the Netherlands. AB - BACKGROUND: Centralization of pancreatic surgery in high-volume hospitals is under debate in many countries. In the western part of the Netherlands, the professional network of surgical oncologists agreed to centralize all pancreatic surgery from 2006 in two high-volume hospitals. Our aim is to evaluate whether centralization of pancreatic surgery has improved clinical outcomes and has changed referral patterns. MATERIALS AND METHODS: Data of the Comprehensive Cancer Centre West (CCCW) of all 249 patients who had a resection for suspected pancreatic cancer between 1996 and 2008 in the western part of the Netherlands were analyzed. Multivariable modeling was used to evaluate survival for 3 time periods; 1996-2000, 2001-2005 (introduction of quality standards), and 2006-2008 (after centralization). In addition, the differences in referral pattern were analyzed. RESULTS: From 2006, all pancreatic surgery was centralized in 2 hospitals. The 2-year survival rate increased after centralization from 39% to 55% (P =.09) for all patients who had a pancreatic resection for pancreatic cancer. After adjustment for age, tumor location, stage, histology, and adjuvant treatment, the latter period was significantly associated with improved survival (hazard ratio [HR] 0.50; 95% confidence interval [95% CI] 0.34-0.73). CONCLUSIONS: Centralization of pancreatic surgery was successful and has resulted in improved clinical outcomes in the western part of the Netherlands, demonstrating the effectiveness of centralization. PMID- 21544658 TI - Scars and satisfaction: do smaller scars improve patient-reported outcome? AB - Thyroidectomy has few complications, as a result, many patients are concerned about the prominence of their scar. Performing thyroid surgery through excessively small incisions in order to maximise cosmesis may increase the likelihood of complications. This study investigates the relationship between conventional approach thyroidectomy scar length and patient satisfaction. A validation of self-measurement of neck circumference and thyroidectomy scar was carried out with the measurements taken by patients compared with those taken by an investigator. One hundred consecutive patients who had undergone conventional thyroidectomy and total thyroidectomy within 24 months were invited to measure their scars and neck circumference, and to score their satisfaction on a Likert scale of 1-10. Spearman's correlation was calculated for the relationship between absolute and relative scar length, and patient satisfaction. Thirty-four patients entered the preliminary study and 80 patients entered the main study (80% response rate). Measurements by patients and investigators were closely associated: Spearman's Rank correlation coefficient for neck circumference and for scar length were rho = 0.9, p < 0.0001 and rho = 0.93, p < 0.0001 respectively. No significant correlation was evident between scar length and patient satisfaction (rho = 0.068, p = 0.55), or between relative scar length ratio and patient satisfaction (rho = -0.045, p = 0.69). Mean scar length was 6.96 cm [standard deviation (SD) 2.70], and mean satisfaction score 8.62 (SD 2.04). Thyroidectomy scar length appears to have no association with patient satisfaction. Thyroid surgery should, therefore, not be performed through unnecessarily small incisions for purely aesthetic reasons. PMID- 21544659 TI - Mothers of infants with congenital heart defects: well-being from pregnancy through the child's first six months. AB - PURPOSE: This study compared the well-being among mothers of children with congenital heart defects (CHD) with mothers of children without CHD (controls), at pregnancy and at 6 months postpartum. METHODS: We linked prospective data from the Norwegian Mother and Child Cohort Study (MoBa), conducted by the Norwegian Institute of Public Health, with a nationwide medical CHD registry. In the MoBa cohort of 61,456 mothers, we identified 212 mothers of infants with mild (n = 92), moderate (n = 50), or severe CHD (n = 70). Subjective well-being was operationalized by means of maternal life satisfaction, joy, and anger at the 30th week of gestation and at 6 months postpartum. RESULTS: Subjective well-being in mothers of children with CHD remained unchanged and similar to that of controls on satisfaction with life (P = 0.120) and feelings of joy (P = 0.065). However, at child age 6 months, mothers of infants with severe CHD reported slightly elevated feelings of anger compared with controls (P = 0.006). CONCLUSIONS: Joy and life satisfaction remained intact among mothers of children with CHD. Yet, elevated feelings of anger in mothers of children with the most severe CHD suggest that they may experience more frustration. PMID- 21544660 TI - Response by authors re: Differentiation of oncocytoma and renal cell carcinoma in small renal masses (<4 cm): the role of 4-phase computerized tomography. PMID- 21544661 TI - Contemporary management of patients with high-risk non-muscle-invasive bladder cancer who fail intravesical BCG therapy. AB - It is advocated that patients with high-risk non-muscle-invasive bladder cancer (NMIBC) receive an adjuvant course of intravesical Bacille Calmette-Guerin (BCG) as first-line treatment. However, a substantial proportion of patients will 'fail' BCG, either early with persistent (refractory) disease or recur late after a long disease-free interval (relapsing). Guideline recommendation in the 'refractory' setting is radical cystectomy, but there are situations when extirpative surgery is not feasible due to competing co-morbidity, a patient's desire for bladder preservation or reluctance to undergo surgery. In this review, we discuss the contemporary management of NMIBC in patients who have failed prior BCG and are not suitable for radical surgery and highlight the potential options available. These options can be categorised as immunotherapy, chemotherapy, device-assisted therapy and combination therapy. However, the current data are still inadequate to formulate definitive recommendations, and data from ongoing trials and maturing studies will give us an insight into whether there is a realistic efficacious second-line treatment for patients who fail intravesical BCG but are not candidates for definitive surgery. PMID- 21544662 TI - Current evidence for transurethral laser therapy of non-muscle invasive bladder cancer. AB - INTRODUCTION: Bladder cancer is the second most common malignancy of urologic tumors. Back in 1976, lasers were added to the endourological armetarium for bladder tumor treatment. Despite nowadays' standard procedure for staging and treating non-muscle invasive bladder tumor by transurethral resection of bladder tumors (TURB) via a wire loop, laser resection techniques for bladder tumor came back in focus with the introduction of Ho:YAG and not to mention recently Tm:YAG lasers. This review aims to display the current evidence for these techniques. MATERIALS AND METHODS: Throughout April 2010, MEDLINE and the Cochrane central register of controlled trials were searched previously for the following terms: "Laser, resection, ablation, coagulation, Nd:YAG Neodym, HoYAG: Holmium, Tm:YAG Thulium and transitional carcinoma, bladder, intravesical." RESULTS: Eleven articles on Ho:YAG and 7 on Tm:YAG were identified. Searches by Cochrane online library resulted in no available manuscripts. CONCLUSION: Today, Nd:YAG does not play any role in treatment of lower urinary tract transitional cell carcinoma. Ho:YAG and Tm:YAG seem to offer alternatives in the treatment of bladder cancer, but still to prove their potential in larger prospective randomized controlled studies with long-term follow-up. Future expectations will show whether en bloc resection of tumors are preferable to the traditional "incise and scatter" resection technique, in which is contrary to all oncological surgical principles. For the primary targets, here are within first-time clearance of disease, in addition to low in-fields and out-of-fields recurrence rates. PMID- 21544663 TI - Synaptic organization of the rat thalamus: a quantitative study. AB - First-order thalamic nuclei receive driving afferents from ascending pathways and transmit processed information to the cortex. Higher-order thalamic nuclei receive driver messages from layer 5 of cortex and transmit information from one cortical area to the other. The different types of axon terminals RL (round vesicles, large terminals), RS (round vesicles, small terminals) and F (flattened vesicles) and their synaptic junctions have been here compared in three first order (ventrobasal, lateral geniculate and anteroventral) and three higher-order (posterior, lateral posterior and mediodorsal) thalamic nuclei of the rat. In the present study, the higher-order relays differ from first-order relays as in the cat, in having fewer driver terminals (RL) and synapses than do the first-order relays. However, the F terminals showed opposite ratios in the first versus higher-order thalamic nuclei. The majority of the terminals in all thalamic nuclei studied were RS terminals. The area measurements of the three types of terminals and synaptic lengths showed no significant differences between first and higher-order nuclei. The driver inputs represent the minority and the modulatory inputs represent the majority of the terminals and synapses in all thalamic nuclei. In conclusion, there is a relative paucity of driver inputs, whereas modulatory inputs establish more numerous synapses to achieve finer modulation. PMID- 21544664 TI - Anatomical variation of the vertebral artery clinically mimicking myasthenia gravis. AB - Cranial nerve palsy, most commonly trigeminal, abducens, or facial, caused by compression of an ectatic or elongated intracranial artery is a well-known phenomenon. Symptoms of brain stem compression by an abnormal artery have rarely been reported (Tomasello et al. Neurosurgery 56(suppl 1):117-124, 2005). The authors present a 59-year-old woman with intermittent ptosis of the right eye, diplopia and swallowing disturbances, enhanced after physical effort, implying myasthenia gravis. Typical diagnostic procedures, e.g. repetitive nerve stimulation tests, acetylcholine receptor antibodies level were within normal limit. Neurogenic changes from the orbicularis oculi muscle were found in EMG. MRI and angio-CT revealed anatomical variation of the vertebral artery (elongated and arcuate route), causing intermittent signs of brain stem lesion. We point out the similarity of the clinical symptoms of myasthenia gravis and vascular brain stem compression by abnormal vertebral artery. The two diseases require completely different therapeutic proceedings. PMID- 21544665 TI - The "eye of the tiger" sign in pure akinesia with gait freezing. AB - The "eye of the tiger" is a neuroradiologic sign due to iron deposition in the globus pallidus: it appears as diffuse low signal intensity with a central area of high signal intensity confined to the globus pallidus. The "eye of the tiger" sign has been associated with neurodegeneration with brain iron accumulation type 1 (NBIA1), a condition caused by mutations in the gene encoding pantothenate kinase 2 (PANK2). However, the specificity of this neuroradiologic sign has been already challenged and it has been described in other neurodegenerative diseases. Here, we report the first case of a patient suffering from pure akinesia with gait freezing with the "eye of the tiger" sign in T2-weighted MRI sequences. All clinical, laboratory and radiologic data excluded other diagnosis and genetic testing excluded PANK2 mutations suggesting that the "eye of the tiger" is not specific for NBIA1 and may also occur in other movement disorders. PMID- 21544667 TI - [Avoidance, diagnostics and therapy of nerve lesions after total hip arthroplasty]. AB - Nerve palsy following total hip arthroplasty is a rare complication. Developmental dysplasia of the hip, previous fracture treatment and medical comorbidities are characteristic risk factors. By accurate preparation of the patient and a careful operative technique nerve palsy can be avoided in most cases. Nerve palsy following poor patient positioning during the perioperative period should be avoided by close cooperation with anesthesiologists.In cases of postoperative nerve palsy correct diagnostics should be carried out immediately. Further treatment options should be considered to minimize the damage. For patients with definite nerve palsy, devices such as a foot drop splint are often necessary and should be carried out as soon as possible. PMID- 21544668 TI - The effects of real-time image navigation in operative liver surgery. AB - PURPOSE: In liver surgery, preoperative planning is usually performed by using CT scans. Ultrasonic probes are frequently used operatively to verify tissue deformations, for example when resecting a liver tumor with an ultrasonic dissector. Avoidance of dissecting vitally important hepatic vessels and the recrudescence of tumors are of crucial importance. The potential benefits of real time image navigation in operative liver surgery were investigated experimentally. METHODS: Four model tumors with realistic ultrasonic features have been embedded into a bowl filled with candle gel. The aim was to locate these tumors with the ultrasonic probe and to puncture them safely with the ultrasonic dissector. The experiment was performed four times, once completely without navigation and three times with ultrasonic-based navigation but under different preconditions. RESULTS: Less attempts are needed to puncture a certain tumor with real-time image navigation than without navigation (P<0.02%). The effectiveness of ultrasonic-based navigation varied with the surgical preconditions. CONCLUSIONS: The use of a suitable navigation system improves safety and effectiveness in liver surgery for intraoperative localization of key structures such as tumors. However, resecting hepatic tumors with appropriate safety margin demands for further enhancements concerning the proposed methods. PMID- 21544669 TI - Health and illness representations of workers with a musculoskeletal disorder related work disability during work rehabilitation: a qualitative study. AB - INTRODUCTION: Distinctions between disease and illness have been criticized for being too theoretical. In practice, however, it may help explain gaps in understanding and miscommunication between health care professionals and patients/injured workers, since each has their own perception of reality. To reduce the gap between health care professionals and patients in understanding the definition of disease, this paper documents general representations of health, illness and work-related musculoskeletal disorders and their influence on the work rehabilitation program. METHODS: A qualitative methodology was used. Semi-structured interviews were conducted with 16 participants (male, female) recruited when they were starting an intensive interdisciplinary work rehabilitation program for chronic pain due to a musculoskeletal disorder. Interviews were performed at three points during the program and 1 month after discharge. RESULTS: First, participants described health and illness in terms of: (1) illness prototype; (2) the absence or presence of symptoms; (3) physical health and capacities; (4) engaging in a healthy lifestyle; (5) maintaining independence; (6) preserving mental well-being; and (7) healing from accidents or injuries. A second observation was that rehabilitation success depended on workers transitioning from a less mechanistic to a more functional view of health. CONCLUSION: This study highlights the importance of identifying and acknowledging workers' health, illness and WRMSD representations to facilitate their return to work. PMID- 21544670 TI - Ictal and peri-ictal changes in cervical vagus nerve activity associated with cardiac effects. AB - The vagus nerves convey both afferent and efferent information about autonomic activity related to cardiovascular functions. Those functions have been shown to change due to epileptic seizures, which suggests that ictal events might be detected via the vagus electroneurogram (VENG). In this study, we characterize the association of ictal and peri-ictal VENG with cardiac parameters. The electrocorticogram (ECoG), electrocardiogram, and the VENG were recorded in anesthetized rats, which were intravenously infused with either a pentylenetetrazole (PTZ) solution (PTZ-lot, n = 11) or saline (control-lot, n = 6). Control animals were subsequently vagotomized and also infused with a PTZ solution (n = 5, V-PTZ-lot). Cardiac and VENG parameters were assessed during different ECoG stages of ictal activity. None of the parameters changed in the control-lot. PTZ infusion induced seizures in all rats. Cardiac-related VENG showed distinctive firing patterns for the left and right vagus nerves. Significant ictal and post-ictal changes were seen in both the left and the right VENG in association with cardiac changes and increased parasympathetic influence on the heart. Changes in VENG parameters might provide a new way to assess the ictal state of patients, which could be suitable for triggering on-demand vagus nerve stimulation. PMID- 21544671 TI - Development and implementation of an Internet-based survivorship care program for cancer survivors treated with hematopoietic stem cell transplantation. AB - INTRODUCTION: The Internet provides a widely accessible modality for meeting survivorship care needs of cancer survivors. In this paper, we describe the development and implementation of an Internet site designed as a base from which to conduct a randomized controlled trial to meet psycho-educational needs of hematopoietic stem cell transplantation (HSCT) survivors. METHODS: A cross disciplinary team designed, wrote content, and programmed an Internet site for online study registration, consent, assessment, and study implementation. All survivors who were 3-18 years after HSCT for hematologic malignancy and treated at one transplant center were approached by mail for participation. All study activities could be conducted without study staff contact. However, participants had options for phone or email contact with study staff as desired. RESULTS: Of 1,775 participants approached for the study, 775 (58% of those eligible) consented and completed baseline assessment. Mean age was 51.7 (SD, 12.5; age range, 18-79 years), with 56% male. Fifty-seven percent required staff contact one or more times; a majority were for minor technical issues or delays in completion of enrollment or baseline assessment. DISCUSSIONS/CONCLUSIONS: This study demonstrated the potential for providing Internet-based survivorship care to long-term survivors of HSCT. Although building a survivorship Internet site requires a team with diverse expertise, once built, these resources can be implemented rapidly with large numbers of survivors. IMPLICATIONS FOR CANCER SURVIVORS: While Internet-based services will not meet all the needs of cancer survivors, this methodology represents an important modality for augmenting onsite clinical services as a method for meeting psycho-educational, information, and resource needs of cancer survivors. PMID- 21544672 TI - Regulatory T cells but not T helper 17 cells are modulated in an animal model of Graves' hyperthyroidism. AB - Graves' disease (GD) involves auto-immunity against thyroid cell antigens, but the reasons for the induction of auto-immunity are uncertain. We wished to investigate the role of T helper 17 (Th17) and regulatory T cells (Treg) in a mouse model of Graves' hyperthyroidism. The model was generated by immunizing mice with adenovirus expressing the autoantigen thyroid-stimulating hormone receptor (Ad-TSHR289). The frequencies of splenic Th17 and Treg were determined by flow cytometry. The levels of interleukin-17(IL-17), forkhead box P3 (Foxp3), and orphan retinoic acid nuclear receptor (RORgammat) mRNA were determined by real-time PCR. The number of CD4(+)CD25(+)Foxp3(+) T lymphocyte was significantly reduced in the Ad-TSHR289 group compared with the Ad-control (P < 0.05). mRNA level for Foxp3 was less abundant in Ad-TSHR289 group compared with Ad-control (P < 0.05). However, CD4(+)IL-17(+) T-cell subpopulation and expression of RORgammat mRNA did not differ significantly between Ad-TSHR289 and Ad-control groups (P > 0.05). Nevertheless, in Ad-TSHR289 group, a profound increase in the Th17/Treg ratios was found. The present study demonstrates that Th17 is not involved in promoting Graves' hyperthyroidism, while Treg and the ratio of Th17/Treg might play a role in the pathogenesis of Graves' hyperthyroidism. PMID- 21544673 TI - Measurement of synchronous activity by microelectrode arrays uncovers differential effects of sublethal and lethal glutamate concentrations on cortical neurons. AB - We grew cultures of rat cortical cells on microelectrode arrays to investigate the effects of glutamate-mediated neurotoxicity as a model of traumatic brain injury. Treatment with two different concentrations of glutamate, 175 and 250 MUM, led to different outcomes. Cultures treated with 250 MUM glutamate suffered a loss in overall activity that was not seen in cultures treated with 175 MUM glutamate. An analysis of the changes in the synchronization of action potential firing between electrodes, however, revealed a loss of synchronization in subsets of electrode pairs treated with both the higher and lower concentrations of glutamate. We found that this loss of action potential synchronization was dependent on the initial amount of synchronization prior to injury. Finally, our data suggest that the synchronization of electrical activity as well as the susceptibility to loss of firing synchrony is independent of the distance between neurons in a network. PMID- 21544674 TI - Adaptive surrogate modeling for expedited estimation of nonlinear tissue properties through inverse finite element analysis. AB - Simulation-based prediction of specimen-specific biomechanical behavior commonly requires inverse analysis using geometrically consistent finite element (FE) models. Optimization drives such analyses but previous studies have highlighted a large computational cost dictated by iterative use of nonlinear FE models. The goal of this study was to evaluate the performance of a local regression-based adaptive surrogate modeling approach to decrease computational cost for both global and local optimization approaches using an inverse FE application. Nonlinear elastic material parameters for patient-specific heel-pad tissue were found, both with and without the surrogate model. Surrogate prediction replaced a FE simulation using local regression of previous simulations when the corresponding error estimate was less than a given tolerance. Performance depended on optimization type and tolerance value. The surrogate reduced local optimization expense up to 68%, but achieved accurate results for only 1 of 20 initial conditions. Conversely, up to a tolerance value of 20 N(2), global optimization with the surrogate yielded consistent parameter predictions with a concurrent decrease in computational cost (up to 77%). However, the local optimization method without the surrogate, although sensitive to the initial conditions, was still on average seven times faster than the global approach. Our results help establish guidelines for setting acceptable tolerance values while using an adaptive surrogate model for inverse FE analysis. Most important, the study demonstrates the benefits of a surrogate modeling approach for intensive FE based iterative analysis. PMID- 21544675 TI - Stress analysis of carotid atheroma in transient ischemic attack patients: evidence for extreme stress-induced plaque rupture. AB - Plaque rupture has been considered to be the result of its structural failure. The aim of this study is to suggest a possible link between higher stresses and rupture sites observed from in vivo magnetic resonance imaging (MRI) of transient ischemic attack (TIA) patients, by using stress analysis methods. Three patients, who had recently suffered a TIA, underwent in vivo multi-spectral MR imaging. Based on plaque geometries reconstructed from the post-rupture status, six pre rupture plaque models were generated for each patient dataset with different reconstructions of rupture sites to bridge the gap of fibrous cap from original MRI images. Stress analysis by fluid structure interaction simulation was performed on the models, followed by analysis of local stress concentration distribution and plaque rupture sites. Furthermore, the sensitivity of stress analysis to the pre-rupture plaque geometry reconstruction was examined. Local stress concentrations were found to be located at the plaque rupture sites for the three subjects studied. In the total of 18 models created, the locations of the stress concentration regions were similar in 17 models in which rupture sites were always associated with high stresses. The local stress concentration region moved from circumferential center to the shoulder region (slightly away from the rupture site) for a case with a thick fibrous cap. Plaque wall stress level in the rupture locations was found to be much higher than the value in non-rupture locations. The good correlation between local stress concentrations and plaque rupture sites, and generally higher plaque wall stress level in rupture locations in the subjects studied could provide indirect evidence for the extreme stress induced plaque rupture hypothesis. Local stress concentration in the plaque region could be one of the factors contributing to plaque rupture. PMID- 21544676 TI - Multigeneration reproduction ratios and the effects of clustered unvaccinated individuals on epidemic outbreak. AB - An SIR epidemiological community-structured model is constructed to investigate the effects of clustered distributions of unvaccinated individuals and the distribution of the primary case relative to vaccination levels. The communities here represent groups such as neighborhoods within a city or cities within a region. The model contains two levels of mixing, where individuals make more intra-group than inter-group contacts. Stochastic simulations and analytical results are utilized to explore the model. An extension of the effective reproduction ratio that incorporates more spatial information by predicting the average number of tertiary infections caused by a single infected individual is introduced to characterize the system. Using these methods, we show that both the vaccination coverage and the variation in vaccination levels among communities affect the likelihood and severity of epidemics. The location of the primary infectious case and the degree of mixing between communities are also important factors in determining the dynamics of outbreaks. In some cases, increasing the efficacy of a vaccine can in fact increase the effective reproduction ratio in early generations, due to the effects of population structure on the likely initial location of an infection. PMID- 21544677 TI - A case of obstruction due to jejunoileal diverticula. AB - OBJECTIVE: The objective of this study is to discuss the presentation and diagnosis of a complicated jejunoileal diverticuli. CASE REPORT: The case of a 94 year-old woman with small bowel obstruction secondary to an impacted enterolith from a jejunoileal diverticulum is presented to illustrate the clinical picture and radiographic findings of complicated small bowel diverticula. PMID- 21544678 TI - Surveillance data on pesticide and agricultural chemical releases and associated public health consequences in selected US states, 2003-2007. AB - BACKGROUND: While pesticides and agricultural chemicals are used to increase crop production and to reduce the spread of disease, their toxic nature also has the potential to threaten human health. Releases of pesticides and agricultural chemicals have resulted in human illness and death. This analysis examines releases of pesticides and agricultural chemicals and their associated injuries captured by the Hazardous Substances Emergency Events Surveillance (HSEES) system from 2003-2007. METHODS: Simple descriptive statistics are presented. Comparisons were made to data from all HSEES events when possible. RESULTS: Analysis of the data shows that farm workers are at particular risk for injury and that the most frequent months for releases of pesticides and agricultural chemicals were the spring planting months of April through June. Releases of pesticides and agricultural chemicals occurred more often during transport, had higher frequencies of patient decontamination associated with them, and lower frequencies of evacuation and shelter-in place orders compared with all HSEES events. CONCLUSION: Since exposures are precipitated by behavioral and environmental factors, especially in occupational settings, future interventions targeting employers, and transporters of agricultural chemicals, as well as physicians, are recommended. These interventions should be customized to fit local conditions. PMID- 21544679 TI - The functioning of hospital ethics committees: a multiple-case study of four Canadian committees. AB - A multiple-case study of four hospital ethics committees in Canada was conducted and data collected included interviews with key informants, observation of committee meetings and ethics-related hospital documents, such as policies and committee minutes. We compared the hospital committees in terms of their structure, functioning and perceptions of key informants and found variation in the dimensions of empowerment, organizational culture of ethics, breadth of ethics mandate, achievements, dynamism, and expertise. PMID- 21544681 TI - Remote ischaemic preconditioning of the heart: remote questions, remote importance, or remote preconditions? PMID- 21544680 TI - Quantitative assessment of trabecular bone micro-architecture of the wrist via 7 Tesla MRI: preliminary results. AB - OBJECT: The goal of this study was to determine the feasibility of performing quantitative 7 T magnetic resonance imaging (MRI) assessment of trabecular bone micro-architecture of the wrist, a common fracture site. MATERIALS AND METHODS: The wrists of 4 healthy subjects (1 woman, 3 men, 28 +/- 8.9 years) were scanned on a 7 T whole body MR scanner using a 3D fast low-angle shot (FLASH) sequence (TR/TE = 20/4.5 m s, 0.169 * 0.169 * 0.5 mm). Trabecular bone was segmented and divided into 4 or 8 angular subregions. Total bone volume (TBV), bone volume fraction (BVF), surface-curve ratio (SC), and erosion index (EI) were computed. Subjects were scanned twice to assess measurement reproducibility. RESULTS: Group mean subregional values for TBV, BVF, SC, and EI (8 subregion analysis) were as follows: 8489 +/- 3686, 0.27 +/- 0.045, 9.61 +/- 6.52; and 1.43 +/- 1.25. Within each individual, there was subregional variation in TBV, SC, and EI (>5%), but not BVF (<5%). Intersubject variation (>=12%) existed for all parameters. Within subject coefficients of variation were <=10%. CONCLUSION: This is the first study to perform quantitative 7T MRI assessment of trabecular bone micro-architecture of the wrist. This method could be utilized to study perturbations in bone structure in subjects with osteoporosis or other bone disorders. PMID- 21544682 TI - OxLDL and macrophage survival: essential and oxygen-independent involvement of the Hif-pathway. AB - Atherosclerotic plaques are characterized by hypoxic even anoxic areas and by high concentrations of oxidized lipoproteins. Moreover, unstable plaques attract a high number of macrophages despite the proapoptotic background within these plaques. Recently, it was shown that these macrophages are positive for Hif 1alpha. This subunit is a part of hypoxia-inducible factor 1 (Hif-1), a key transcriptional factor under hypoxia. Till date, it is not understood whether the Hif-system (consisting of Hif-1, Hif-2 and Hif-3) is involved in protection of macrophages under these proatherogenic conditions. The present study delineates that oxLDL causes fundamental changes in the regulation of the Hif-system in primary human macrophages. First, both oxLDL and hypoxia mediate accumulation of Hif-1alpha protein. Second, treatment with a combination of oxLDL and hypoxia is acting in an additive manner on Hif-1alpha protein content. Third, oxLDL alone does not increase Hif-2alpha protein, but abolishes the hypoxic induction of Hif 2alpha completely. OxLDL treatment alone was not toxic for macrophages under neither normoxia nor hypoxia. But, inhibition of Hif-pathway by adenoviral expression of a dominant-negative mutant combined with oxLDL treatment independently of the oxygen tension leads to apoptosis, as determined by caspase 3 activation and induction of DNA fragmentation. Furthermore, this inhibition also mediates the opening of the mitochondrial permeability transition pore. In conclusion, the present data show that Hif-1alpha regulation is essential for survival of oxLDL-treated macrophages independent of the oxygen tension. Therefore, this newly characterized mechanism might also have an important influence for the vulnerability of atherosclerotic plaques. PMID- 21544683 TI - Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation? AB - Perioperative myocardial ischemia contributes to postoperative morbidity and mortality. Remote intermittent ischemia (RI) has been shown to benefit patients undergoing coronary artery bypass graft (CABG) surgery by decreasing postoperative cardiac troponin levels. In addition, there is evidence that volatile anesthetics may provide myocardial protection. In this prospective randomized controlled trial we tested the hypothesis that RI is cardioprotective under a strict anesthetic regime with volatile anesthesia until cardiopulmonary bypass (CPB). We also assessed whether RI modulates postoperative cytokine and growth factor concentrations. Fifty-four patients referred for elective CABG surgery without concomitant valve or aortic surgery were randomized to three 5 min cycles of left upper limb ischemia by cuff inflation (RI) or placebo without cuff inflation (Plac). All patients received the volatile anesthetic isoflurane (1.15-1.5 vol%) before CPB and the intravenous anesthetic propofol (3-4 mg/kg/h) thereafter until the end of surgery. Cardiac arrest during CPB was induced by intermittent cross-clamp fibrillation, or by blood cardioplegia. We excluded patients older than 85 years, with unstable angina, significant renal disease, and those taking sulfonylureas. Troponin I (cTnI) was measured preoperatively and after 6, 12, 24 and 48 h. In addition, brain natriuretic peptide (BNP), creatine kinase (CKMB) and a panel of cytokines and growth factors were analyzed perioperatively. Although cTnI, BNP and CKMB all increased post-CABG, there were no significant differences between RI and Plac groups; area under the curve for cTnI 189.4 (183.6) ng/mL/48 h and 183.0 (155.2) ng/mL/48 h mean (SD), p = 0.90, respectively, despite a tendency to a shorter (p < 0.07) cross-clamp time in the treatment group. Similarly, there were no differences between groups in the central venous concentrations of numerous cytokines and growth factors. In patients undergoing CABG surgery RI does not provide myocardial protection under a strict anesthetic regime with volatile anesthesia until CPB, and RI was not associated with changes in cytokines. PMID- 21544684 TI - [Update Stroke Conference 2011: International Stroke Conference 2011, Los Angeles, USA]. PMID- 21544685 TI - Glycyrrhiza glabra (Linn.) and Lavandula officinalis (L.) cell suspension cultures-based biotransformation of beta-artemether. AB - The biotransformation of beta-artemether (1) by cell suspension cultures of Glycyrrhiza glabra and Lavandula officinalis is reported here for the first time. The major biotransformed product appeared as a grayish-blue color spot on thin layer chromatography (TLC) with transparent crystal-like texture. Based on its infrared (IR) and (1)H nuclear magnetic resonance (NMR) spectra, the product was characterized as a tetrahydrofuran (THF)-acetate derivative (2). The highest conversion efficiencies of 57 and 60% were obtained when 8-9-day-old cell suspensions of G. glabra and L. officinalis were respectively fed with 4-7 mg of compound 1 in 40 ml of medium per culture and the cells were harvested after 2-5 days of incubation. The addition of compound 1 at the beginning of the culture cycle caused severe growth depression in a dose-dependent manner, resulting in poor bioconversion efficiency of ~25% at 2-5 mg/culture dose only. PMID- 21544686 TI - Relationship between the GTPase, metal-binding, and dimerization activities of E. coli HypB. AB - Biosynthesis of the metallocenter in the active site of the [NiFe] hydrogenase enzyme requires the accessory protein HypB, which is a metal-binding GTPase. In this study, the interplay between the individual activities of Escherichia coli HypB was examined. The full-length protein undergoes nucleotide-responsive dimerization that is disrupted upon mutation of L242 and L246 to alanine. This mutant HypB is monomeric under all of the conditions investigated but the inability of L242A/L246A HypB to dimerize does not abolish its GTPase activity and the monomeric protein has metal-binding behavior similar to that of wild-type HypB. Furthermore, expression of L242A/L246A HypB in vivo results in hydrogenase activity that is approximately half of the activity produced by the wild-type control, suggesting that dimerization of HypB does not have a critical role in the hydrogenase maturation pathway. In contrast, the GTPase activity of HypB is modulated by metal loading of the protein. These results provide insight into the role of HypB in hydrogenase biosynthesis. PMID- 21544687 TI - Oxidized and aggregated recombinant human interferon beta is immunogenic in human interferon beta transgenic mice. AB - PURPOSE: To study the effect of oxidation on the structure of recombinant human interferon beta-1a (rhIFNbeta-1a) and its immunogenicity in wild-type and immune tolerant transgenic mice. METHODS: Untreated rhIFNbeta-1a was degraded by metal catalyzed oxidation, H(2)O(2)-mediated oxidation, and guanidine-mediated unfolding/refolding. Four rhIFNbeta-1a preparations with different levels of oxidation and aggregation were injected intraperitoneally in mice 15* during 3 weeks. Both binding and neutralizing antibodies were measured. RESULTS: All rhIFNbeta-1a preparations contained substantial amounts of aggregates. Metal catalyzed oxidized rhIFNbeta-1a contained high levels of covalent aggregates as compared with untreated rhIFNbeta-1a. H(2)O(2)-treated rhIFNbeta-1a showed an increase in oligomer and unrecovered protein content by HP-SEC; RP-HPLC revealed protein oxidation. Guanidine-treated rhIFNbeta-1a mostly consisted of dimers and oligomers and some non-covalent aggregates smaller in size than those in untreated rhIFNbeta-1a. All degraded samples showed alterations in tertiary protein structure. Wild-type mice showed equally high antibody responses against all preparations. Transgenic mice were discriminative, showing elevated antibody responses against both metal-catalyzed oxidized and H(2)O(2)-treated rhIFNbeta-1a as compared to untreated and guanidine-treated rhIFNbeta-1a. CONCLUSIONS: Oxidation-mediated aggregation increased the immunogenicity of rhIFNbeta-1a in transgenic mice, whereas aggregated preparations devoid of measurable oxidation levels were hardly immunogenic. PMID- 21544688 TI - Preparation of personalized-dose salbutamol sulphate oral films with thermal ink jet printing. AB - PURPOSE: To evaluate the use of thermal ink-jetting as a method for dosing drugs onto oral films. METHODS: A Hewlett-Packard printer cartridge was modified so that aqueous drug solutions replaced the ink. The performance of the printer as a function of print solution viscosity and surface tension was determined; viscosities between 1.1 and 1.5 mm(2) s(-1) were found to be optimal, while surface tension did not affect deposition. A calibration curve for salbutamol sulphate was prepared, which demonstrated drug deposition onto an acetate film varied linearly with concentration (r(2) = 0.9992). The printer was then used to deposit salbutamol sulphate onto an oral film made of potato starch. RESULTS: It was found that when doses were deposited in a single pass under the print head, then the measured dose was in good agreement with the theoretical dose. With multiple passes the measured dose was always significantly less than the theoretical dose. It is proposed that the losses arise from erosion of the printed layer by shearing forces during paper handling. The losses were predictable, and the variance in dose deposited was always less than the BP limits for tablet and oral syrup salbutamol sulphate preparations. CONCLUSIONS: TIJ printing offers a rapid method for extemporaneous preparation of personalized dose medicines. PMID- 21544689 TI - Classification of mesh fiber exposure: comment. PMID- 21544691 TI - The brain-lung-brain axis. PMID- 21544692 TI - Acute effects of intracranial hypertension and ARDS on pulmonary and neuronal damage: a randomized experimental study in pigs. AB - PURPOSE: To determine reciprocal and synergistic effects of acute intracranial hypertension and ARDS on neuronal and pulmonary damage and to define possible mechanisms. METHODS: Twenty-eight mechanically ventilated pigs were randomized to four groups of seven each: control; acute intracranial hypertension (AICH); acute respiratory distress syndrome (ARDS); acute respiratory distress syndrome in combination with acute intracranial hypertension (ARDS + AICH). AICH was induced with an intracranial balloon catheter and the inflation volume was adjusted to keep intracranial pressure (ICP) at 30-40 cmH2O. ARDS was induced by oleic acid infusion. Respiratory function, hemodynamics, extravascular lung water index (ELWI), lung and brain computed tomography (CT) scans, as well as inflammatory mediators, S100B, and neuronal serum enolase (NSE) were measured over a 4-h period. Lung and brain tissue were collected and examined at the end of the experiment. RESULTS: In both healthy and injured lungs, AICH caused increases in NSE and TNF-alpha plasma concentrations, extravascular lung water, and lung density in CT, the extent of poorly aerated (dystelectatic) and atelectatic lung regions, and an increase in the brain tissue water content. ARDS and AICH in combination induced damage in the hippocampus and decreased density in brain CT. CONCLUSIONS: AICH induces lung injury and also exacerbates pre-existing damage. Increased extravascular lung water is an early marker. ARDS has a detrimental effect on the brain and acts synergistically with intracranial hypertension to cause histological hippocampal damage. PMID- 21544693 TI - [Electrochemotherapy of skin tumors]. AB - Electrochemotherapy represents a new innovative technology using a combination of electroporation and application of very low dose cytotoxic drugs for the treatment of cutaneous and subcutaneous skin tumors and metastases. Based on a high number of preclinical and clinical studies this procedure has been established as a simple, safe and very effective tumor treatment whose costs are acceptable. The procedure can be performed as a single treatment of localized disease as well as a repeated palliative treatment of cutaneous metastases regardless of the tumor type. Because of the lack of significant side effects and of short duration the procedure can be performed on an out-patient basis. Several studies led to the validation of standard operating procedures for its use in daily clinical practice. This treatment has become established in many different European countries. PMID- 21544694 TI - Candida and invasive candidiasis: back to basics. AB - The ubiquitous Candida spp. is an opportunistic fungal pathogen which, despite treatment with antifungal drugs, can cause fatal bloodstream infections (BSIs) in immunocompromised and immunodeficient persons. Thus far, several major C. albicans virulence factors have been relatively well studied, including morphology switching and secreted degradative enzymes. However, the exact mechanism of Candida pathogenesis and the host response to invasion are still not well elucidated. The relatively recent discovery of the quorum-sensing molecule farnesol and the existence of quorum sensing as a basic regulatory phenomenon of the C. albicans population behavior has revolutionized Candida research. Through population density regulation, the quorum-sensing mechanism also controls the cellular morphology of a C. albicans population in response to environmental factors, thereby, effectively placing morphology switching downstream of quorum sensing. Thus, the quorum-sensing phenomenon has been hailed as the 'missing piece' of the pathogenicity puzzle. Here, we review what is known about Candida spp. as the etiological agents of invasive candidiasis and address our current understanding of the quorum-sensing phenomenon in relation to virulence in the host. PMID- 21544695 TI - Specific IgG antibody responses may be used to monitor leprosy treatment efficacy and as recurrence prognostic markers. AB - Although curable, leprosy requires better diagnostic and prognostic tools to accompany therapeutic strategies. We evaluated the serum samples of leprosy patients from Venezuela and Brazil for reactivity against the specific recombinant proteins, ML0405 and ML2331, and the LID-1 fusion protein that incorporates both of these antigens. Antigen-specific IgG was highest in lepromatous leprosy patients (LL) and decreased across the disease spectrum, such that only a small subset of true tuberculoid patients (TT) tested positive. The impact of multidrug therapy (MDT) on these antibody responses was also examined. Several years after treatment, the vast majority of Venezuelan patients did not possess circulating anti-LID-1, anti-ML0405, and anti-ML2331 IgG, and the seropositivity of the remaining cases could be attributed to irregular treatment. At discharge, the magnitude and proportion of positive responses of Brazilian patients against the proteins and phenolic glycolipid (PGL)-I were lower for most of the clinical forms. The monthly examination of IgG levels in LL patient sera after MDT initiation indicated that these responses are significantly reduced during treatment. Thus, responses against these antigens positively correlate with bacillary load, clinical forms, and operational classification at diagnosis. Our data indicate that these responses could be employed as an auxiliary tool for the assessment of treatment efficacy and disease relapse. PMID- 21544696 TI - A novel method to produce immobilised biomolecular concentration gradients to study cell activities: design and modelling. AB - It is well known that many cell functions are activated by chemical signals with a time and space-dependent profile. To mimic these profiles in vitro, it is necessary to develop a system that is able to generate concentration gradients with a resolution similar to that perceived by cells, which is around nanomolar with a spatial resolution of a few tens of microns. Many devices capable of generating steady-state concentration gradients have been developed using continuous flow micro-fluidic techniques. However, these systems cannot reproduce the immobilised concentration gradients that are present in the extracellular matrix. For this reason, we have developed a new gradient generator to enable precise and reproducible studies on the effects of immobilised concentration gradients on cell behaviour. A well-known gradient of a desired molecule was generated on the bottom surface of a hydrogel, which was then used as a stamp to immobilise the molecule on a functionalised substrate. A concentration gradient was thus obtained using a simple silane-based chemical reaction. To validate the method, image analysis was performed on glass slides printed with fluorescein isothiocyanate (FITC)- collagen and FITC-poly-lysine concentration gradients. Preliminary cell adhesion tests were also carried out by seeding NIH-3T3 and mesencephalic cells on lab-glass slides printed with concentration profiles of collagen and poly-lysine, respectively. PMID- 21544697 TI - Morphofunctional evaluation of the heart of obese patients before and after bariatric surgery. AB - BACKGROUND: This study aims to evaluate the effect of weight loss on the physical capacity and the structure and function of the heart after bariatric surgery. METHODS: Forty-three adult obese patients, 31 women (72.1%) and 12 men (27.9%), were submitted to electrocardiogram, ergometric test, and echo Doppler cardiogram at presurgical stage and 1 year after Roux-en-Y gastric bypass. The statistical analysis utilized the Wilcoxon, Student's t, and Shapiro-Wilk tests with 5% significance level. RESULTS: Weight was reduced from 116.5 +/- 21.5 to 80 +/- 15.9 kg and body mass index from 41.8 +/- 4.4 to 28.4 +/- 3.8 kg/m(2). Cardiac frequency was reduced from 77.9 +/- 9.6 to 70.9 +/- 7.8 bpm, systolic pressure from 130 +/- 20 to 120 +/- 10 mmHg, and diastolic pressure from 80 +/- 10 to 80 +/- 0 mmHg. Ergometric tests showed distance covered from 378.9 +/- 126.5 to 595 +/- 140.4 m, metabolic coefficient from 6.7 +/- 2.4 to 8.3 +/- 2.6 ml O(2)/kg/min, and oxygen consumption (VO(2)) from 23.1 +/- 8.4 to 30 +/- 10.3 metabolic equivalents of task. The echo Doppler cardiogram showed interventricular septum from 12 +/- 2 to 10 +/- 1 mm, posterior wall from 11 +/- 2 to 10 +/- 1 mm, and ventricular mass from 273 +/- 85 to 216 +/- 60 g. There was improvement in the diastolic function with an increase in the E'/A' and E/A relationship and the ejection fraction with an increase from 70.2 +/- 7.2% to 72.9 +/- 6.4%. CONCLUSIONS: Bariatric surgery improved physical capacity as well as structural and functional improvement of the heart. PMID- 21544698 TI - A mid-term experience with the Cousin Bioring--adjustable gastric band. AB - BACKGROUND: Since March 2003, we have used the Cousin Bioring in our laparoscopic gastroplasty procedures for morbid obesity. The Bioring belongs to the new generation of adjustable gastric bands. The aim of this study is to review our experience with this particular type of band. METHODS: Between March 2003 and March 2010, 316 patients had a laparoscopic implantation of the Cousin Bioring in our department. As many as 169 patients had the operation at least 5 years ago, of which 161 had a complete follow-up. Short- and long-term results were prospectively collected and analysed. RESULTS: There were no intra-operative and only two mild early post-operative complications. Mortality was zero. The mean percent of excess weight loss (%EWL) was 56% at 5 years, 55% at 6 years and 56% at 7 years. Of the 169 patients, four had a band removal for intolerance and/or insufficient weight loss and 11 (6.5%) developed late complications requiring surgery. We managed to solve all complications by minimally invasive procedures without loss of the device. Fifteen of the 169 patients suffered preoperatively from diabetes mellitus type 2. Ten of these had a remission after 5 years. The quality-of-life was assessed 3 years post-operatively for 164 patients and showed an improvement in 83.5% of them. CONCLUSION: Laparoscopic implantation of the Cousin Bioring is a straightforward and safe operation. Complications occur, but they are rather benign and easy to remediate. The mean weight loss is considered successful (%EWL > 50) and persists 5 to 7 years after the operation. PMID- 21544699 TI - Assessment of thermal load on transported goats administered with ascorbic acid during the hot-dry conditions. AB - The major factor in the induction of physiological stress during road transportation of livestock is the complex fluctuations of the thermal transport microenvironment, encountered when animals are transported across different ecological zones. Recommended guidelines on optimum "on-board" conditions in which goats should be transported are lacking, and there are no acceptable ranges and limits for the thermal loads to which goats may be subjected during long distance road transportation in hot-dry conditions. Panting score (PS), rectal temperature (RT), heart rate (HR) and respiratory rate (RR) were employed as reliable stress indices to assess the effects of different thermal loads, measured as temperature humidity index (THI), encountered in the vehicle during 12 h of road transportation of 40 goats, and to suggest the administration of 100 mg/kg body weight of ascorbic acid (AA) as an ameliorating agent. The results obtained showed that the PS, RT, HR and RR rose above normal reference values with increase in the THI and journey duration. The rise in PS value, which is a visual indicator of the severity of thermal load, was the most pronounced. The results suggest that values of THI in the vehicle up to 94.6 constitute no risk, while at of 100 it presents a moderate risk and above 100 may result in severe stress. The relationships between the thermal load and the physiological variables were positive and significant (P < 0.05). They reflect the degree of stress imposed by each THI value during the transportation, and may be used as recommended ranges and limit thermal load values in transported goats. The results demonstrated that administration of 100 mg/kg body weight of AA before road transportation mitigated the risk of adverse effects of high THI values and other stress factors due to road transportation in goats. PMID- 21544700 TI - And lead us (not) into persuasion...? Persuasive technology and the ethics of communication. AB - The paper develops ethical guidelines for the development and usage of persuasive technologies (PT) that can be derived from applying discourse ethics to this type of technologies. The application of discourse ethics is of particular interest for PT, since 'persuasion' refers to an act of communication that might be interpreted as holding the middle between 'manipulation' and 'convincing'. One can distinguish two elements of discourse ethics that prove fruitful when applied to PT: the analysis of the inherent normativity of acts of communication ('speech acts') and the Habermasian distinction between 'communicative' and 'strategic rationality' and their broader societal interpretation. This essay investigates what consequences can be drawn if one applies these two elements of discourse ethics to PT. PMID- 21544701 TI - Determinants of physical activity among people with spinal cord injury: a test of social cognitive theory. AB - BACKGROUND: Little theory-based research has focused on understanding and increasing physical activity among people with physical disabilities. Testing a social cognitive theory-based model of determinants is important for identifying variables to target in physical activity-enhancing interventions. PURPOSE: The aim of this study is to examine Social Cognitive Theory variables as predictors of physical activity among people living with spinal cord injury. METHODS: Structural equation modeling was used to test a model of Social Cognitive Theory predictors of physical activity (n=160). RESULTS: The model explained 39% of the variance in physical activity. Self-regulation was the only significant, direct predictor. Self-regulatory efficacy and outcome expectations had indirect effects, mediated by self-regulation. CONCLUSION: Social Cognitive Theory is useful for predicting physical activity in people with spinal cord injury. Self regulation is the most potent Social Cognitive Theory predictor of physical activity in people with spinal cord injury. Self-regulation and its determinants should be targeted in physical activity-enhancing interventions. PMID- 21544702 TI - Anger suppression and subsequent pain behaviors among chronic low back pain patients: moderating effects of anger regulation style. AB - BACKGROUND: Suppression of anger is linked to subsequent pain intensity among chronic low back patients, but it is not clear whether anger regulation style (trait anger-out, anger-in) moderates these effects or if aroused anger accounts for links between anger regulation style and pain. METHOD: Chronic low back pain patients (N=58) were assigned to Suppression or No Suppression conditions for a task with harassing confederate and then underwent structured pain behavior procedures. Spielberger Anger Expression Inventory tapped trait anger-out (AOS) and anger-in (AIS). RESULTS: Regressions tested Emotion Regulation condition * AOS and AIS effects on outcomes. AOS was related to grimacing and sighing for Suppression condition patients. AIS was related negatively to guarding and bracing for Suppression condition patients. Anger report partly mediated effects for AOS and AIS. CONCLUSIONS: Anger regulation style moderated effects of state anger suppression on subsequent pain behaviors, effects that were partly explained by aroused anger. PMID- 21544703 TI - Metastatic cerebral malignant fibrous histiocytoma masquerading as neurocysticercosis. PMID- 21544704 TI - The genetics of colour in fat-tailed sheep: a review. AB - Fat-tailed sheep come in various colours-most are either brown (tan) or black. In some, most of the body is white with the tan or black colour restricted to the front portion of the body or to just around the eyes, muzzle and parts of the legs. The Karakul breed is important for the production of lamb skins of various colours for the fashion industry. As well as the black and tan colours there are Karakuls bred for grey or roan shades, a white colour or one of the numerous Sur shades. In the Sur shades, the base of the birthcoat fibre is one of a number of dark shades and the tip a lighter or white shade. All these colours and many others are the result of the interaction of various genes that determine the specifics of the coat colour of the sheep. A number of sets of nomenclature and symbols have been used to represent the various loci and their alleles that are involved. In the 1980s and 1990s, a standardised set, based closely on those of the mouse and other species was developed. Using this as the framework, the alleles of the Extension, Agouti, Brown, Spotting, Pigmented Head and Roan loci are described using fat-tailed sheep (mainly Damara, Karakul and Persian) as examples. Further discussion includes other types of "white markings," the Ticking locus and the Sur loci. PMID- 21544707 TI - Paleozoological data suggest Euroamerican settlement did not displace ursids and North American elk from lowlands to highlands. AB - The hypothesis that Euroamerican settlement displaced some populations of large mammal taxa from lowland plains habitats to previously unoccupied highland mountain habitats was commonly believed in the late nineteenth and early twentieth centuries. By the middle twentieth century biologists had come to favor the hypothesis that Euroamerican colonization resulted in the extirpation of populations of large mammal in lowland habitats and those taxa survived in pre existing relict populations in the highlands. Why modern biologists changed their minds is unclear. There is no historical evidence that unequivocally favors one hypothesis over the other. The low-elevation Columbia Basin of eastern Washington state in the northwestern United States is surrounded by forested mountains. The majority of historical records (1850 AD or younger) of black bear (Ursus americanus), brown bear (Ursus arctos), and North American elk (Cervus elaphus) occur in mountainous, coniferous forest habitats. Paleozoological records of these taxa <= 10,000 year old and >160 year old in both highland and lowland habitats suggest the displacement hypothesis does not apply to ursids and elk in this area. These taxa seem to have been more or less ubiquitous in the area prior to Euroamerican colonization (ca. 1850 AD), and were extirpated from lowland habitats after colonization. Recent colonization of lowland shrub-steppe habitats by elk in particular, although historically unprecedented, must be categorized as recolonization rather than an invasion. Whether a species is classified as indigenous or nonindigenous may influence management activities focused on that species. The paleozoological record indicates ursids and elk are indigenous to the highland forest habitats of eastern Washington. PMID- 21544705 TI - Clinical factors related to brain structure in HIV: the CHARTER study. AB - Despite the widening use of combination antiretroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n = 251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression. PMID- 21544706 TI - From research to practice: an integrative framework for the development of interventions for children with fetal alcohol spectrum disorders. AB - Since fetal alcohol syndrome was first described over 35 years ago, considerable progress has been made in the delineation of the neurocognitive profile in children with prenatal alcohol exposure. Preclinical investigators have made impressive strides in elucidating the mechanisms of alcohol teratogenesis and in testing the effectiveness of pharmacological agents and dietary supplementation in the amelioration of alcohol-induced deficits. Despite these advances, only limited progress has been made in the development of evidence-based comprehensive interventions for functional impairment in alcohol-exposed children. Having performed a search in PubMed and PsycINFO using key words, interventions, treatment, fetal alcohol syndrome, prenatal alcohol exposure, and fetal alcohol spectrum disorders, we found only 12 papers on empirically-based interventions. Only two of these interventions had been replicated and none met the criteria of "well-established," as defined by Chambless and Hollon (Journal of Consulting and Clinical Psychology 66(1):7-18, 1998). There has been only limited cross fertilization of ideas between preclinical and clinical research with regard to the development of interventions. Therefore, we propose a framework that allows integrating data from preclinical and clinical investigations to develop comprehensive intervention programs for children with fetal alcohol spectrum disorders. This framework underscores the importance of multi-level evaluations and interventions. PMID- 21544708 TI - Adhesion of small cell lung cancer cells to E- and P-selectin under physiological flow conditions: implications for metastasis formation. AB - Haematogenous metastasis of small cell lung cancer (SCLC) is still a poorly understood process and represents the life threatening event in this malignancy. In particular, the rate-limiting step within the metastatic cascade is not yet clearly defined although, many findings indicate, that extravasation of circulating tumour cells is crucially important as most tumour cells within the circulation undergo apoptosis. If extravasation of SCLC tumour cells mimics leukocyte-endothelial interactions, SCLC cells should adhere to E- and P selectins expressed on the luminal surface of activated endothelium. The adhesion to E- and P-selectin under physiological shear stress with regard to adhesive events, rolling behaviour and rolling velocity was determined in the human SCLC cell lines SW2, H69, H82, OH1 and OH3. OH1 SCLC cells adhered best to recombinant human (rh) E-selectin FC-chimeras and human lung endothelial cells (HPMEC), H82 SCLC cells adhered best to activated human umbilical vein endothelial cells (HUVEC) under physiological shear stress. As OH1 cells had also produced by far the highest number of spontaneous lung metastases when xenografted into pfp/rag2 mice in previous experiments our findings implicate that adhesion of SCLC cells to E-selectin is of paramount importance in SCLC metastasis formation. PMID- 21544709 TI - Revision of Wenyonia Woodland, 1923 (Cestoda: Caryophyllidea) from catfishes (Siluriformes) in Africa. AB - Tapeworms of the genus Wenyonia Woodland, 1923 (Caryophyllidea: Caryophyllaeidae), parasites of catfishes in Africa, are revised. This revision is based on material from large-scale sampling, in the Democratic Republic of the Congo, Kenya, Senegal and the Sudan between 2006 and 2009, and the examination of all of the type-specimens available. The following six species are considered valid and their redescriptions are provided: Wenyonia virilis Woodland, 1923 (type-species; new synonym W. kainjii Ukoli, 1972); W. acuminata Woodland, 1923; W. longicauda Woodland, 1937; W. minuta Woodland, 1923 (new synonym W. mcconnelli Ukoli, 1972); W. synodontis Ukoli, 1972; and W. youdeoweii Ukoli, 1972. A key to the identification of Wenyonia spp. is provided and numerous new hosts and geographical records are reported. A comparative phylogenetic analysis of partial sequences of the 28S rRNA gene of four species divided the monophyletic genus into two lineages, one represented by W. acuminata and W. minuta and another one composed of W. virilis and W. youdeoweii. PMID- 21544710 TI - Histological and molecular studies of species of Myxobolus Butschli, 1882 (Myxozoa: Myxosporea) in the gills of Abramis, Blicca and Vimba spp. (Cyprinidae), with the redescription of M. macrocapsularis Reuss, 1906 and M. bliccae Donec & Tozyyakova, 1984. AB - Although Myxobolus spp. from cyprinid fishes are generally characterised by a strict host-specificity, this study has found that the breams Abramis brama (L.), Blicca bjoerkna (L.) and Vimba vimba (L.) may be infected by the same Myxobolus spp. It is demonstrated that M. macrocapsularis Reuss, 1906, a parasite of the gill filaments of B. bjoerkna, can also infect A. brama. In the same way, M. bliccae Donec & Tozyyakova, 1984, also a parasite of B. bjoerkna, can also occur in V. vimba. The molecular sequences of M. macrocapsularis spores from B. bjoerkna and A. brama were 100% identical. Two of the 18S rDNA sequences of three replicate samples of M. bliccae from B. bjoerkna were 100% identical, whereas the third sequence exhibited a 99.7% similarity with sequences from V. vimba. M. bliccae sequences of spores collected from V. vimba showed a 99.8% similarity to the first two isolates and 99.6% to the third. Data obtained by morphological, histological and molecular biological methods all suggest that Myxobolus spp., known for their strict host-specificity, may sometimes infect several closely related cyprinids. PMID- 21544711 TI - Bucephaline digeneans (Bucephalidae) in Sphyraena putnamae Jordan & Seale (Sphyraenidae) from the lagoon off New Caledonia. AB - Three species of bucephaline bucephalids are described from Sphyraena putnamae Jordan & Seale and distinguished from related forms using visual keys. Rhipidocotyle khalili Nagaty, 1937 is illustrated and measurements given. Rhipidocotyle bartolii n. sp. [syns R. longicirrus (Nagaty, 1937) of Bartoli & Bray (2005); and possibly Bucephalopsis arcuatus (Linton, 1900) of Manter (1940)] differs from R. longicirrus (sensu stricto) in width, pre-uterine distance, pre oral distance and cirrus-sac extent. Prosorhynchoides toomboensis n. sp. differs from similar species by combinations of characters presented in a table. The bucephalids of Sphyraena spp. are listed and discussed. PMID- 21544712 TI - Huffmanela plectropomi n. sp. (Nematoda: Trichosomoididae: Huffmanelinae) from the coralgrouper Plectropomus leopardus (Lacepede) off New Caledonia. AB - Huffmanela plectropomi n. sp. is described from eggs only, which were found in black spots in the mesentery of a coralgrouper, Plectropomus leopardus (Lacepede), caught near Noumea, New Caledonia, South Pacific. The eggs are 64-76 (mean 69) MUm in length and 29-35 (mean 32) MUm in width, with a thin shell. The surface of the eggs bears a thick, continuous layer of filaments. The species is distinguished from other members of the genus by the dimensions of its eggs and the characteristics of their surface. This is the first species of Huffmanela Moravec, 1987 to be described from a grouper (Serranidae, Epinephelinae). PMID- 21544713 TI - A new cryptic species of Aponurus Looss, 1907 (Digenea: Lecithasteridae) from Mediterranean goatfish (Teleostei: Mullidae). AB - The status of the trematode Aponurus laguncula Looss, 1907 in the western Mediterranean is re-assessed by means of a comparative morphological study and rDNA sequences based on newly collected material. A. laguncula (sensu stricto) is redescribed from Trachinus draco L. and a new cryptic species of the 'A. laguncula complex', Aponurus mulli n. sp., is described on the basis of abundant material from Mullus barbatus L. (type-host) and M. surmuletus L. off the Spanish Mediterranean coasts. The new species is differentiated from A. laguncula (sensu stricto) by its: significantly larger, elongate body, with maximum width at the level of the ventral sucker; shorter forebody; distinctly larger sinus-sac, seminal receptacle and seminal vesicle, with the latter also being more elongate; vesicular pars prostatica; more anteriorly located vitellarium, which consists of eight globular follicles; and distinctly smaller eggs, which are also smaller in relation to body size and have both their opercular and anopercular poles rounded. The variability and the allometric growth of the morphological characters in the new species were studied in detail, resulting in additional distinguishing features. Sequences of the large subunit rRNA (28S) gene (domains D1-D3) and ITS2 rRNA gene region for the new species have been submitted to GenBank in order to enhance future studies on species differentiation within the 'A. laguncula complex'. PMID- 21544714 TI - Formulation strategy to overcome multi-drug resistance (MDR). PMID- 21544715 TI - Discovery of an orally available PAR-1 antagonist as a novel antiplatelet agent. AB - Antiplatelet therapy is a key treatment in atherothrombotic disease and platelet is activated via multiple pathways. Current agents do not interfere with all pathways including the protease-activated receptor-1 (PAR-1) pathway stimulated by thrombin. New antiplatelet agents targeting PAR-1 are aimed to reduce thrombosis ideally without increasing bleeding risk. This article provides a review of the new class of agents, PAR-1 antagonists. PMID- 21544716 TI - Synthesis and cytotoxicity of novel 3-amino-4-indolylmaleimide derivatives. AB - In an attempt to develop potent and selective antitumor agents, a series of novel 3-amino-4-indolylmaleimides were designed and synthesized. The reaction showed high regioselectivity. The structure of compound 7a was determined by an X-ray single crystal diffraction method. The cytotoxicities of the title compounds were evaluated against HeLa, SMMC 7721 and HL 60 cancer cell lines by a standard MTT assay in vitro. The pharmacological results showed that some of the title compounds displayed moderate or high cytotoxic activity against the tested cell lines. Compound 7d was the most promising compound against the tested cancer cell lines. Structure-activity relationships are discussed based on the experimental data obtained. A hydroxyethylamino group at the 3-position in the side chain of indolylmaleimide is associated with an increase in cytotoxicity. PMID- 21544717 TI - C-7 oxygenated coumarins from the fruits of Micromelum minutum. AB - A new 7-oxygenated coumarin, 7-demethylmurralonginol isovalerate (1), and a new natural product, murralonginol (2), together with seven known 7-oxygenated coumarins, murralonginol isovalerate (3), murralongin (4), micromelin (5), scopoletin (6), microminutin (7), murrangatin (8), and minumicrolin (9), were isolated from the fruits of Micromelum minutum. The structures of these compounds were established on the basis of their 1D and 2D NMR spectroscopic data. Among these isolates, compounds 2 and 4 - 9 exhibited cytotoxicity against cholangiocarcinoma cell line, KKU-100. PMID- 21544718 TI - Isolation of megastigmane sesquiterpenes from the silkworm (Bombyx mori L.) droppings and their promotion activity on HO-1 and SIRT1. AB - The silkworm (Bombyx mori L.) droppings were extracted with 80% aqueous MeOH, and the concentrated extract was partitioned in succession with EtOAc, n-BuOH, and H(2)O. From the EtOAc fraction, five megastigmane sesquiterpenes were isolated through repeated silica gel and ODS column chromatography. According to the results of spectroscopic data, such as NMR, MS, and IR, the chemical structures of the isolated compounds were determined as (3S,5R,8R)-3,5-dihydroxymegastigma 6,7-dien-9-one (1), (S)-dehydrovomifoliol (2), (6R,7E,9R) -9-hydroxy-4,7 megastigmadien-3-one (3), (3S,5R,6S,7E)-3,5,6-trihydroxy-7-megastigmen-9-one (4), (6R,9R)-9-hydroxy-4-megastigmen-3-one (5). Compounds 2 through 5 were isolated for the first time from silkworm droppings. GC/MS analysis indicated silkworm powder contained compound 3, and mulberry leaves contained compound 4. Compounds 1 and 5 increased the expression of heme oxygenase-1 and SIRT1 in HepG2 and HEK239 cells, respectively. Heme oxygenase-1 is considered to be an antioxidant enzyme that catabolizes heme to carbon monoxide, free iron and biliverdin, while SIRT1 is the mammalian homologue of the yeast silent information regulator (Sir) 2, which are involved in the suppression of inflammatory mediators or factors that may be used to improve atopy-related symptoms. PMID- 21544719 TI - A dimeric triterpenoid glycoside and flavonoid glycosides with free radical scavenging activity isolated from Rubus rigidus var. camerunensis. AB - The aerial part of Rubus rigidus var. camerunensis (Rosaceae) is used to treat respiratory and cardiovascular disorders in the Cameroonian traditional medicine. The ethanol extract exhibited more potent antioxidant activity (E(max)s of 119% and 229% activity on DPPH and beta-carotene test) than aqueous extract. Bioactivity-guided fractionation of the ethanol extract based on free radical scavenging assay (DPPH assay) afforded five flavonoid glycosides (four flavonol glycosides and an anthocyanin) and three glucosides of 19alpha-hydroxyursane-type triterpenoid (two monomeric and one dimeric triterpenoids). The flavonoids were identified as kaempferol 3-O-(2"-O-E-p-coumaroyl)-beta-D-glucopyranoside (1), kaempferol-3-O-beta-D-glucopyranoside (astragalin, 2), kaempferol-3-O-alpha-L arabinofuranoside (juglanin, 3), quercetin-3-O-beta-D-glucopyranoside (isoquercitrin, 4), pelargonidin-3-O-beta-D-glucopyranoside (callistephin, 5). The three triterpenoids were 2alpha, 3beta, 19alpha, 23-tetrahydroxyurs-12-ene-28 O-beta-D-glucopyranosyl ester (nigaichigoside F(1), 6), 2alpha, 3beta, 19alpha trihydroxyurs-12-ene-23-carboxyl-28-O-beta-D-glucopyranosyl ester (suavissimoside R(1), 7) as monomeric triterpenoids and coreanoside F(1) (8) as a dimeric triterpenoid. The flavonoids exhibited potent antioxidant activities (66 to 93.56% against DPPH radical) and they were also active on beta-carotene test. Coreanoside F(1) exhibited a 63% antioxidant activity, meanwhile the other two triterpenoids showed a weak activity. Three important facts on structure-activity relationship were observed: Compound 8, a dimeric triterpenoid glycoside, strongly enhanced antioxidant activity of its monomers, compound 3 with 3-O-alpha L-arabinofuranyl has much more potent activity than compound 2 with 3-O-beta-D glucopyranosyl, and antocyanin (5) is more potent than its corresponding flavonol glycosides. PMID- 21544720 TI - A combination of a microemulsion and a phospholipid complex for topical delivery of oxymatrine. AB - Oxymatrine (OMT), a water-soluble drug, has a very low oral bioavailability because of its low membrane permeability and its biotransformation in the gastrointestinal tract. Formulated as an oxymatrine-phospholipid complex (OMT PLC) can improve the lipid solubility and effectiveness of OMT. The purpose of this study was to explore the utility of the combination of a microemulsion and an OMT-PLC as a topical delivery vehicle for enhancing the absorption and efficacy of OMT. The solubility of OMT-PLC was determined and phase diagrams of microemulsions were constructed. Various microemulsion formulations were developed and characterized by their physicochemical properties, and their in vitro and in vivo permeability through skin. An optimal microemulsion (ME4), which presented as spherical droplets and consisted of 10.0% OMT-PLC, 8.0% isopropyl myristate, 30.0% Cremophor RH40/polyethylene glycol 400 (1:1) and 52.0% water, was selected. It possessed an average droplet size of 32.4 nm, a low viscosity of 113.7 mPa . s, and a high cloud point of 88 degrees C. Compared to the control solution, ME4 provided better skin permeability in vitro and a higher retention ratio of OMT in skin in vivo. Moreover, ME4 significantly enhanced the antiproliferative activity of OMT on scar fibroblasts. These results indicate that the combination of a microemulsion and a phospholipid complex represents an effective vehicle for topical delivery of OMT. PMID- 21544721 TI - Biochemically altered human erythrocytes as a carrier for targeted delivery of primaquine: an in vitro study. AB - The aim of this study was to investigate human erythrocytes as a carrier for targeted drug delivery of primaquine (PQ). The process of PQ loading in human erythrocytes, as well as the effect of PQ loading on the oxidative status of erythrocytes, was also studied. At PQ concentrations of 2, 4, 6, and 8 mg/mL and an incubation time of 2 h, the ratios of the concentrations of PQ entrapped in erythrocytes to that in the incubation medium were 0.515, 0.688, 0.697 and 0.788, respectively. The maximal decline of erythrocyte reduced glutathione content was observed at 8 mg/mL of PQ compared with native erythrocytes p < 0.001. In contrast, malondialdehyde and protein carbonyl were significantly increased in cells loaded with PQ (p < 0.001). Furthermore, osmotic fragility of PQ carrier erythrocytes was increased in comparison with unloaded cells. Electron microscopy revealed spherocyte formation with PQ carrier erythrocytes. PQ-loaded cells showed sustained drug release over a 48 h period. Erythrocytes were loaded with PQ successfully, but there were some biochemical as well as physiological changes that resulted from the effect of PQ on the oxidative status of drug-loaded erythrocytes. These changes may result in favorable targeting of PQ-loaded cells to reticulo-endothelial organs. The relative impact of these changes remains to be explored in ongoing animal studies. PMID- 21544722 TI - Rheological and mucoadhesive characterization of poly(vinylpyrrolidone) hydrogels designed for nasal mucosal drug delivery. AB - Poly(vinylpyrrolidone) (PVP) hydrogels were crosslinked by gamma irradiation to add structure and rigidity, and then rheological and mucoadhesive properties were evaluated. The effects of PVP concentration, radiation dose, and additives, such as poly(ethylene glycol) (PEG) and glycerol, on rheological properties were investigated. In an oscillatory analysis, an increase in polymer concentrations increased the storage modulus (G') and the loss modulus (G") but decreased the loss tangent (tan delta < 1). The relationships between G'or G" and the frequency levelled off at higher frequencies, which is indicative of polymer chain entanglement and network formation. Each of the 6% PVP hydrogels exhibited plastic flow with rheopectic behavior. PVP concentration, radiation dose, and the presence of PEG or glycerol influenced the rheological and mucoadhesive properties of the hydrogels. However, adding acyclovir to the formulation did not have a profound effect on the rheological behavior of the hydrogels. The results suggest that a 3% PVP hydrogel with 1% PEG crosslinked with 20 kGy is the most appropriate hydrogel. The results demonstrated the successful complementary application of oscillatory and flow rheometry to characterize and develop a hydrogel for mucosal drug administration. PMID- 21544723 TI - Electrospray fabrication of doxorubicin-chitosan-tripolyphosphate nanoparticles for delivery of doxorubicin. AB - This work focused on a new technique for the preparation of doxorubicin (DOX) loaded chitosan (CS) nanoparticles (DOX-CS) - formation by electrospray ionization in the presence of tripolyphosphate (TPP) as the stabilizer. The working distance, needle gauge, flow rate, stirring rate, electrospraying voltage and DOX to CS molar ratio were sequentially and individually optimized and found to be a 26 gauge needle, an applied voltage of 13 kV, a flow rate of 0.5 mL/h, a working distance of 8 cm and a stirring rate of 400 rpm. The incorporation of chemically unchanged DOX with the CS into the particles was ascertained by Fourier transformed infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Under these optimized conditions, the DOX-CS particles were found to be nanoparticles of approximately 300-570 (dry particles) or 530-870 nm diameter (hydrated particles), with a PDI and SPAN polydispersity indices of 0.97-0.82 and 0.62-0.64, respectively, for initial DOX loading levels of 0.25-1%, as determined by SEM and particle size analyzer, respectively. Moreover, a high encapsulation efficiency (EE) of DOX into the nanoparticles was attained, ranging from 63.4 to 67.9% EE at 1 to 0.25% DOX loading. Finally, the in vitro DOX release behaviors of the DOX-CS particles revealed a prolonged release of DOX over at least seven hours. PMID- 21544724 TI - Feasibility of rat hair as a quality control material for the determination of methamphetamine and amphetamine in human hair. AB - A quality control material (QCM) is a necessity in hair drug analysis, but it is not always easy to have an authentic hair sample containing various target drugs and metabolites. In the present study, the feasibility of rat hair as a QCM was examined for its application in the determination of methamphetamine (MA) and amphetamine (AP) in human hair. MA was administered to lean Zucker rats, from which only pigmented hair was collected for the preparation of a QCM. The rat hair was then washed, homogenized and finally bottled. Both homogeneity and stability were examined in order to demonstrate the suitability of rat hair as a QCM in hair drug analysis. The concentrations of MA and AP in each bottle were determined using extraction with 1% HCl in methanol at 38 degrees C followed by gas chromatography/mass spectrometry after derivatization with trifluoroacetic anhydride. Furthermore, the prepared QCM was used in an inter-laboratory quality assurance program. In the homogeneity test, no significant difference was observed between bottles of the QCM. The statistical results also showed no significant trends in stability for three months at room temperature. An inter laboratory quality assurance program was also performed successfully using this material. Thus, rat hair will be useful as an alternative QCM sample for the determination of a variety of drugs and their metabolites in human hair. PMID- 21544725 TI - Characterization and biodistribution of human mesenchymal stem cells transduced with lentiviral-mediated BMP2. AB - Recently, the genetic modification of mesenchymal stem cells (MSCs) has led to increased differentiation potential. For the therapeutic application of genetically modified MSCs, it is crucial to evaluate their characteristics and safety. In this study, we investigated the effects of bone morphogenetic protein 2 (BMP2) gene transfer on the characteristics and biodistribution of human MSCs. Lentiviral-mediated BMP2 transduction to MSCs enhanced osteocyte differentiation and decreased adipocyte differentiation. Although there is no significant difference in cell proliferation capacity, MSCs transduced BMP2 proliferate somewhat higher than nontransduced or GFP transduced MSCs. No significant changes were observed in surface antigen expression in genetically modified MSCs. In vivo transplantation of lentiviral-mediated BMP2 gene transferred MSCs to nude mice did not result in tumor formation. To evaluate the biodistribution of genetically modified cells, MSCs carrying BMP2 were injected into the tail vein of femur fractured mice. The introduced MSCs were detected in the spleen, testis and fractured femur 28 days post-implantation. These findings suggest that diverse safety tests for genetically modified MSCs should be considered, particularly when a lentivirus mediated gene transfer method is used. PMID- 21544726 TI - Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin. AB - Quercetin, a flavonoid, is an inhibitor of P-glycoprotein-mediated efflux transport, and its oxidative metabolism is catalyzed by CYP enzymes. Thus, it is expected that the pharmacokinetics of both intravenous and oral doxorubicin can be changed by quercetin. The purpose of this study was to investigate the effect of oral quercetin on the bioavailability and pharmacokinetics of orally and intravenously administered doxorubicin in rats. The effects of quercetin on the P glycoprotein (P-gp) and CYP3A4 activities were also evaluated. Quercetin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC(50)) of 1.97 MUM. In addition, quercetin significantly enhanced the intracellular accumulation of rhodamine-123 in MCF 7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of doxorubicin were determined in rats after oral (50 mg/kg) or intravenous (10 mg/kg) administration of doxorubicin to rats in the presence and absence of quercetin (0.6, 3 or 15 mg/kg). Compared to control, quercetin significantly (p < 0.05 for 0.6 mg/kg, p < 0.01 for 3 and 15 mg/kg) increased the area under the plasma concentration-time curve (AUC(0-infinity), 31.2-136.0% greater) of oral doxorubicin. Quercetin also significantly increased the peak plasma concentration (C(max)) of doxorubicin, while there was no significant change in T(max) and T(1/2) of doxorubicin. Consequently, the absolute bioavailability of doxorubicin was increased by quercetin compared to control, and the relative bioavailability of oral doxorubicin was increased by 1.32 to 2.36 fold. In contrast, the pharmacokinetics of intravenous doxorubicin were not affected by quercetin. These results suggest that the quercetin-induced increase in bioavailability of oral doxorubicin can be attributed to enhanced doxorubicin absorption in the gastrointestinal tract via quercetin-induced inhibition of P-gp and reduced first pass metabolism of doxorubicin due to quercetin-induced inhibition of CYP3A in the small intestine and/or in the liver rather than reduced renal and/or hepatic elimination of doxorubicin. Therefore, it appears that the development of oral doxorubicin preparations is possible, which will be more convenient than the intravenous dosage forms. Therefore, concurrent use of quercetin provides a therapeutic benefit - it increases the bioavailability of doxorubicin administered orally. PMID- 21544727 TI - Synergistic improvement in insulin resistance with a combination of fenofibrate and rosiglitazone in obese type 2 diabetic mice. AB - Peroxisome proliferator-activated receptor (PPAR) alpha, which is abundant in the liver, increases lipoprotein lipase activity, resulting in a decrease of triglyceride (TG) levels. PPARgamma, which is abundant in adipose tissue, stimulates adipocyte differentiation and adipogenesis, and results in an increase in insulin sensitivity. Fenofibrate, a PPARalpha agonist, is commonly used to treat dyslipidemia, and rosiglitazone, a PPARgamma agonist, is effective in improving glycemic control. To examine the synergistic effects of rosiglitazone in combination with fenofibrate, an obese type 2 diabetes mellitus (DM) mouse model was established by the combined administration of streptozotocin and nicotinamide and fed on a high-fat diet (35% of energy as fat) for 3 weeks. The mice had significantly higher plasma glucose concentrations and insulin resistance, as examined by an oral glucose tolerance test and insulin challenge test compared with normal mice. After establishing a dose-response curve for each drug, the drugs were orally administered for 3 weeks either alone or in combination. After individual administration of fenofibrate, HDL cholesterol levels significantly increased, and plasma glucose and TG levels decreased in obese type 2 DM mice. The individual administration of rosiglitazone showed increased insulin resistance (QUICKI). However, HDL cholesterol and TG levels were not significantly changed. In a combination of fenofibrate at 25 mg/kg and rosiglitazone at 1.25 mg/kg there was a decrease in plasma glucose and TG levels, and a combination of fenofibrate at 50 mg/kg and rosiglitazone at 2.5 mg/kg showed an increase in plasma HDL cholesterol levels. Moreover, parameters related to insulin resistance (HOMA-IR) and insulin sensitivity (QUICKI) were improved significantly. Thus, our results show that combination therapy with lower doses of fenofibrate and rosiglitazone ameliorates the type 2 DM condition to a greater extent than high doses of either individual monotherapy. PMID- 21544728 TI - Anticancer potential of magnolol for lung cancer treatment. AB - Lung malignancy is a major cause of human mortality. As such, safe pharmacological agents that can detect lung cancer are urgently required. Magnolol has been reported to have anticancer property. However, it is still unclear whether magnolol induces apoptosis of lung carcinoma cells. In this study, magnolol inhibited cell growth, increased lactate dehydrogenase release, and modulated cell cycle in human lung carcinoma A549 cells. Magnolol induced the activation of caspase-3 and cleavage of Poly-(ADP)-ribose polymerase, and decreased the expression level of nuclear factor-kappaB/Rel A in the nucleus. In addition, magnolol inhibited basic fibroblast growth factor-induced proliferation and capillary tube formation of human umbilical vein endothelial cells. These data indicate that magnolol is a potential candidate for treating of human lung carcinoma. PMID- 21544729 TI - Contribution of Epstein-Barr virus infection to chemoresistance of gastric carcinoma cells to 5-fluorouracil. AB - Although Epstein-Barr virus (EBV) is associated with 6-16% of the gastric carcinoma (GC) cases, the effect of EBV infection on the tumorigenesis process and the responsiveness to chemotherapy remain unclear. We compared chemosensitivity of the EBV-positive GC (AGSEBV) and EBV-negative GC (AGS) cells to 5-fluorouracil (5-FU). Although 5-FU inhibited the growth of both cell lines in a dose- and time-dependent manner, the sensitivity of EBV-positive GC cells to 5-FU was lower than that of EBV-negative GC cells. The cleavage of PARP and caspase-3 was also lower in AGS-EBV cells than in AGS cells following 5-FU treatment. Both the level of Bcl-2 expression and the ratio of Bcl-2/Bax were higher in AGS-EBV than in AGS cells not only at basal state but also following 5 FU treatment. Moreover, p53 and p21 expression was enhanced further by 5-FU in AGS than in AGS-EBV cells. Immunofluorescence assay and Western blot showed that 5-FU induced the expression of EBV-lytic genes including BZLF1, BRLF1, BMRF1 and BHRF1. Our results suggest that latent and lytic EBV infection contributes to the chemoresistance to 5-FU in gastric carcinoma by modulating apoptosis related cellular genes. PMID- 21544730 TI - Protective effects of fucoidan against gamma-radiation-induced damage of blood cells. AB - Fucoidan, a sulfated polysaccharide purified from brown algae including Fucus vesiculosus and Laminaria japonica, has a variety of biological activities, including antioxidant and antitumor activities. Here, we investigated the radioprotective effects of fucoidan on human monoblastic leukemia cell line U937. Further, animal tests were carried out using Balb/c mice in order to determine the radiation-induced changes in the counts of blood cells, including thrombocytes, erythrocytes, leukocytes and hematocrit. Cell viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wherein fucoidan (1, 10, and 100 MUg/mL) was observed to improve recovery from damage caused by 8-Gy radiation in a dose dependent manner. The viability of U937 cells pre-treated with fucoidan also increased in a dose dependent manner. Furthermore, fucoidan at 100 mg/kg was found to protect against changes in the counts of blood cells as follows: on day 28 after irradiation, the thrombocyte count in the irradiated controls decreased to 45% compared with the non irradiated controls, while that in the fucoidan-treated group was 60%. The hematocrit in the fucoidan-treated group recovered to 75% on day 28, while that in the irradiated control was 68%. The erythrocyte count in the irradiated controls consistently ranged from 64% to 67% throughout the experiment, but that in the fucoidan-treated group increased gradually, ranging from 75% to 80%. The mean number of survival days and 50-day actuarial survival rate increased dose dependently in the fucoidan-treated group. The mean number of survival days and the 50-day actuarial survival rate in this group was 16, 21, and 29 days and 12%, 20%, and 30% at fucoidan doses of 1, 10, and 100 mg/kg. The values of these parameters in the control group were 9 days and 0%, although the difference between the test and control groups was not statistically significant. Our results may prove valuable in the field of radioprotection. PMID- 21544731 TI - Curculigo orchioides, natural compounds for the treatment of noise-induced hearing loss in mice. AB - Noise exposure is one of the most common causes of hearing loss. Noise-induced hearing loss (NIHL) is thought to primarily involve damage to the sensory hair cells of the cochlea via mechanical and metabolic mechanisms. Curculigo orchioides Gaerten (C. orchioides) is considered to have immunostimulant, hepatoprotective, antioxidative, anticancer, and antidiabetic activities. But the effect of C. orchioides on NIHL is not yet reported, this study focused on examining the therapeutic effects of C. orchioides on NIHL in a mouse model. Oral treatment with the extract of C. orchioides began 24 h following an examination that determined a shift in hearing threshold induced by noise exposure. Hearing threshold shifts were assessed by analyzing auditory brainstem responses at 1, 5, and 7 days following noise exposure. Central auditory function was evaluated using auditory middle latency responses, and cochlear function was determined based on transient-evoked otoacoustic emissions. C. orchioides reduced hearing threshold shifts, central auditory function damage, and cochlear function deficits. Our results suggest that C. orchioides can be utilized as a potential therapeutic natural product for NIHL. PMID- 21544732 TI - Cell growth inhibition and apoptosis by SDS-solubilized single-walled carbon nanotubes in normal rat kidney epithelial cells. AB - Carbon nanotubes (CNTs), promising novel nanomaterials, have been applied to drug delivery and bio-imaging; however, their potential harmful effects on human health and environment have gained much attention recently. In the present study, we investigated cytotoxic effect of solubilized single-walled CNTs (SWCNTs), which were dispersed in water by sodium dodesyl sulfate (SDS), in normal rat kidney epithelial cells (NRK-52E). SDS-SWCNT (0.125-10 MUg/mL)-treated NRK-52E cells showed decreased cell viability and enhanced cytotoxicity marker levels following 24-48 h incubation. In addition, SDS-SWCNT treatment evoked the cell growth inhibition: 8 MUg/mL SDS-SWCNT induced the growth arrest at G(0)/G(1) phase and levels of cell cycle-related proteins such as CDK2, CDK6 and phosphorylated-retinoblastoma (pRB) were significantly reduced by CNT. Whereas, at higher concentration of SDS-SWCNT, the percentage of cell numbers in apoptotic sub-G(1) phase was substantially increased. Along with these changes, SDS-SWCNT treatment elevated protein levels for p53 and p21 with a concomitant increase in the single strand DNA breakage. Taken together, these results suggest that SDS solubilized SWCNTs exert genotoxic effect in renal epithelial cells, and p53 dependent signaling can be associated with the growth arrest and apoptosis events upon CNT-induced DNA damage. PMID- 21544733 TI - Anti-inflammatory effects of eriodictyol in lipopolysaccharide-stimulated raw 264.7 murine macrophages. AB - Flavonoids have biological activities including anti-allergic, anti-inflammatory, antimicrobial and anticancer activities shown from in vitro studies. Of these biological activities, the anti-inflammatory capacity of flavonoids has long been emphasized in Chinese medicine. In this study, I investigated that what flavonoid can be applied to the suppression of lipopolysaccharide (LPS)-induced inflammatory responses in macrophages among the four similar structure flavonoids. Eriodictyol was found to reduce nitric oxide (NO) production from LPS stimulated Raw 264.7 cells in non-cytotoxic concentrations. Moreover, eriodictyol strongly suppressed the phagocytic activity of activated macrophages. Pre treatment of Raw 264.7 cells with eriodictyol reduced the expression of mRNA and the secretion of pro-inflammatory cytokines. These inhibitory effects were found to be caused by blockage of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activation and phosphorylation of p38 mitogen activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase (JNK). PMID- 21544734 TI - Inhibitory effect of ginsenosides from steamed ginseng-leaves and flowers on the LPS-stimulated IL-12 production in bone marrow-derived dendritic cells. AB - Interleukin-12, a heterodimeric cytokine comprising p40 and p35 subunits, plays an essential role in the regulating the differentiation of Th cells, which establish and maximize the capabilities of the immune system. The aim of present study is to screen the effect of 21 ginsenosides from steamed ginseng-leaves and flowers on IL-12 production in bone marrow-derived dendritic cells induced by lipopolysaccharide. Noticeably, ginsenoside Rg(6) (12) and ginsenoside F(4) (13) exhibited particularly inhibitory effect on LPS-induced IL-12 production with the inhibition values of 80 and 82%; and ginsenoside ST(1) (4), ginsenoside SL(2) (8), ginsenoside SL(3) (9), ginsenoside Rh(3) (14), ginsenoside Rk(2) (15), and ginsenoside Rs(4) (18) showed moderate effects with inhibition rates of 63, 65, 67, 68, 71, 73, and 67%, respectively. These results warrant further studies concerning potential of saponin extracts of steamed ginseng-leaves and flowers for medicinal uses. PMID- 21544735 TI - Role of metabolism by intestinal bacteria in arbutin-induced toxicity in vitro. AB - A possible role of metabolism by intestinal bacteria in arbutin-induced toxicity was investigated in mammalian cell cultures. Following an incubation of arbutin with intestinal bacteria, either Bifidobacterium longum HY81 or Bifidobacterium adolescentis, for 24 h, its aglycone hydroquinone could be produced and detected in the bacterial culture media. The bacterial growth was not affected up to 10 mM arbutin in the culture medium. When the toxicity of bacteria cultured medium with arbutin was tested in the HepG2 cell lines, the medium with arbutin was more toxic than either parent arbutin only or bacteria cultured medium without arbutin, indicating that metabolic activation might be required in arbutin induced toxicity. In addition, bacteria cultured medium with arbutin could suppress LPS and ConA mitogenicity in splenocyte cultures prepared from normal mice. The results indicate that the present toxicity testing system might be applied for assessing the possible role of metabolism by intestinal bacteria in certain chemical-induced toxicity in mammalian cell cultures. PMID- 21544736 TI - Changes in prepregnancy body mass index between pregnancies and risk of gestational and type 2 diabetes. AB - INTRODUCTION: We investigated whether changes in interpregnancy body mass index (BMI) influence the risk of gestational and type 2 diabetes among a cohort of women with two consecutive live, singleton births of 20-44 weeks gestation (n = 232,272). METHODS: Logistic regression models were used to examine the risk for development of gestational or type 2 diabetes during the second pregnancy. Mothers with normal weight for both pregnancies (normal-normal) served as the referent group. RESULTS: Across all BMI categories, mothers with significant weight gain (i.e., moving from a lower BMI category into a higher category) had an increased risk for the development of diabetes. Mothers who moved from normal prepregnancy weight (BMI = 18.5-24.9 kg/m2) in the first pregnancy to obese prepregnancy weight (BMI >= 30.0 kg/m2) in the second pregnancy showed the greatest increment in risk. These mothers exhibited a threefold risk for developing diabetes (OR = 3.21, 95% CI 2.76-3.73). Mothers who maintained their interpregnancy BMI weight category or who moved to a lower BMI category had reduced risk for gestational and type 2 diabetes. The risk associated with mothers who moved to a lower BMI category was approximately half that of the normal-normal BMI category. CONCLUSION: Interpregnancy weight gain is associated with a dose-response increase in risk of diabetes. Establishing a normal interpregnancy BMI may reduce the risk of diabetes. PMID- 21544737 TI - Cyclin D1 G870A polymorphism and colorectal cancer susceptibility: a meta analysis of 20 populations. AB - PURPOSE: Studies investigating the association between genetic polymorphism of cyclin D1 (CCND1) G870A and risk of colorectal cancer (CRC) reported conflicting results. In order to derive a more precise estimation of the relationship, a meta analysis was performed. MATERIALS AND METHODS: We performed an extensive search of relevant studies and carried out a meta-analysis, including 20 studies with 5,975 cases and 8,333 controls, to obtain a more precise estimate. RESULTS: Overall, significantly elevated colorectal cancer risk was associated with variant allele 870A when all studies were pooled (AA vs. GG: OR = 1.23, 95% CI = 1.04-1.44; GA vs. GG: OR = 1.13, 95% CI = 1.01-1.26; dominant model: OR = 1.16, 95% CI = 1.03-1.31). In the subgroup analysis by ethnicity, significantly increased risks were detected among Caucasians (AA vs. GG: OR = 1.27, 95% CI = 1.04-1.44; dominant model: OR = 1.17, 95% CI = 1.02-1.34).We also observed sporadic CRC with an increased cancer susceptibility (AA vs. GG: OR = 1.24, 95% CI = 1.04-1.48; dominant model: OR = 1.17, 95% CI = 1.04-1.33), when colorectal cancer was stratified into sporadic CRC and hereditary nonpolyposis colorectal cancer (HNPCC). However, no significant associations were found in both Asians and HNPCC patients for all genetic models. CONCLUSION: Result suggests that the cyclin D1 870A allele is a low-penetrant risk factor for developing sporadic colorectal cancer, especially among Caucasians. PMID- 21544738 TI - Backbone and Ile-delta1, Leu, Val methyl 1H, 13C and 15N NMR chemical shift assignments for human interferon-stimulated gene 15 protein. AB - Human interferon-stimulated gene 15 protein (ISG15), also called ubiquitin cross reactive protein (UCRP), is the first identified ubiquitin-like protein containing two ubiquitin-like domains fused in tandem. The active form of ISG15 is conjugated to target proteins via the C-terminal glycine residue through an isopeptide bond in a manner similar to ubiquitin. The biological role of ISG15 is strongly associated with the modulation of cell immune function, and there is mounting evidence suggesting that many viral pathogens evade the host innate immune response by interfering with ISG15 conjugation to both host and viral proteins in a variety of ways. Here we report nearly complete backbone (1)H(N), (15)N, (13)C', and (13)C(alpha), as well as side chain (13)C(beta), methyl (Ile delta1, Leu, Val), amide (Asn, Gln), and indole N-H (Trp) NMR resonance assignments for the 157-residue human ISG15 protein. These resonance assignments provide the basis for future structural and functional solution NMR studies of the biologically important human ISG15 protein. PMID- 21544739 TI - EATRIS, a vision for translational research in Europe. AB - Tremendous progress has been made in biomedical research in genomics, proteomics and metabolomics, which has led to an increasing insight into molecular mechanisms related to diseases. Yet the output of disease prevention, diagnosis and treatment solutions remains low. It is against this background that several European countries have gathered to take new actions for improving translational research from bench to bedside. Surveys were conducted to identify major bottlenecks and assess the situation of translational research in Europe. While the importance of translational research is already recognized and national governments have increased their efforts and academia more and more directs its research towards translation, there are still hurdles to overcome. Thus, a European research infrastructure-EATRIS-will be established to integrate basic and clinical research in dedicated translational centres. These EATRIS Centres will provide broad access to high-end pre-clinical and clinical facilities, including the necessary translational expertise for researchers from academia and industry. PMID- 21544740 TI - Pharmacopsychiatry. Editorial. PMID- 21544741 TI - Stress and affective disorders: animal models elucidating the molecular basis of neuroendocrine-behavior interactions. AB - Profound dysfunctions in several neuroendocrine systems have been described in patients suffering from affective disorders such as major depression. In order to elucidate the mechanisms underlying these functional alterations, animal models including mice genetically modified by either direct gene-targeting or by selective breeding approaches have been used exceedingly, revealing valuable insights into neuroendocrine pathways conserved between rodents and men. This review focuses on altered function and regulation of the hypothalamic-pituitary adrenocortical axis, including its involvement in emotionality and stress responsiveness. In this context, the corticotropin-releasing hormone system and disturbances in glucocorticoid receptor signaling seem to be of central importance. However, changes in the expression and release patterns of vasopressin, dopamine and serotonin have also been shown to contribute to variation in emotionality, stress coping, cognitive functions and social behaviors. Affective disorders show a high degree of complexity, involving a multitude of molecular, neuroendocrine, and behavioral alterations as well as an intense gene-environment interaction, making it difficult to dissociate the primary causes from secondary consequences of the disease. Thus, interdisciplinary research, as applied in the emerging field of systems biology, involving adequate animal models and combined methodologies can significantly contribute to our understanding regarding the transmission of genetic predispositions into clinically relevant endophenotypes. It is only with deep insight into the mechanisms by which the stress hormone systems are regulated that novel treatment strategies and promising targets for therapeutic interventions can be developed in the future. Such in-depth understanding is ultimately essential to realizing our goal of predictive, preventive, and personalized medicine. PMID- 21544742 TI - Affective disorders as complex dynamic diseases--a perspective from systems biology. AB - Understanding mental disorders and their neurobiological basis encompasses the conceptual management of "complexity" and "dynamics". For example, affective disorders exhibit several fluctuating state variables on psychological and biological levels and data collected of these systems levels suggest quasi chaotic periodicity leading to use concepts and tools of the mathematics of nonlinear dynamic systems. Regarding this, we demonstrate that the concept of "Dynamic Diseases" could be a fruitful way for theory and empirical research in neuropsychiatry. In a first step, as an example, we focus on the analysis of dynamic cortisol regulation that is important for understanding depressive disorders. In this case, our message is that extremely complex phenomena of a disease may be explained as resulting from perplexingly simple nonlinear interactions of a very small number of variables. Additionally, we propose that and how widely used complex circuit diagrams representing the macroanatomic structures and connectivities of the brain involved in major depression or other mental disorders may be "animated" by quantification, even by using expert-based estimations (dummy variables). This method of modeling allows to develop exploratory computer-based numerical models that encompass the option to explore the system by computer simulations (in-silico experiments). Also inter- and intracellular molecular networks involved in affective disorders could be modeled by this procedure. We want to stimulate future research in this theoretical context. PMID- 21544743 TI - Modulation of ligand-gated ion channels as a novel pharmacological principle. AB - The present study investigated the functional antagonism of different antidepressants on 5-HT (3) receptor function and the role of lipid rafts for these modulatory effects. Electrophysiological recordings of 5-HT evoked cation currents were recorded with N1E-115 and HEK-5-HT (3A) cells and hippocampal neurons. The characterization of the antagonism of antidepressants was made by the displacement of [ (3)H]GR65630 binding. For membrane fractionation, sucrose density gradient centrifugation was used. Gradient fractions were assayed for antidepressant concentrations by HPLC; 5-HT (3) receptor membrane distribution was determined by Western blot. Colocalization experiments were performed by means of immunocytochemistry. Most antidepressants acted as non-competitive antagonists at the 5-HT (3) receptor. Moreover, some of these compounds were enriched within lipid rafts. Cholesterol depletion impaired lipid raft integrity thereby affecting 5-HT (3) receptor function, whereas the antagonistic effects of antidepressants were not altered.In conclusion, most antidepressants directly antagonize 5-HT (3) receptor activity. 5-HT (3) receptor function PER SE appears to depend on lipid raft integrity, which is, however, not a prerequisite for the modulatory potency of antidepressants at this receptor. PMID- 21544744 TI - The clinical side of bipolar disorders. AB - This article summarizes key facts on the epidemiology, diagnosis and clinical treatment of bipolar disorder. Bipolar disorder is a common mental disorder with a high disease burden, but still does not get the attention it deserves in research and clinical training. The nature of the disorder is complex, but it is apparent that biological factors are decisive. Thus, understanding the biological systems and cycles affected will become crucial for developing more targeted interventions. Currently, standard treatments seem to have a low specificity for Bipolar Disorder, and only few experimental interventions target directly potential underlying disturbances as HPA axis or circadian clock dysregulation. Systemic analysing and modelling of bipolar disorder is a novel approach which might open up new ways in developing more selective therapies. PMID- 21544745 TI - Comparison of pre-episode and pre-remission states using mood ratings from patients with bipolar disorder. AB - Daily self-reported mood ratings from patients with bipolar disorder were analyzed to see if the 60 days before an episode of hypomania or depression (pre episode state) could be distinguished from the 60 days before a month of euthymia (pre-remission state), and if a pre-hypomanic state could be distinguished from a pre-depressed state. Data were available from 98 outpatients with bipolar disorder, who returned about one year of daily data, and received treatment as usual. The approximate entropy (ApEn), mean mood and mood variability (standard deviation) were determined for 53 pre-hypomanic states, 42 pre-depressive states, and 65 pre-remission states.There was greater serial irregularity (ApEn) and greater variability in mood in the pre-episode than the pre-remission state. There was greater serial irregularity (ApEn) but no difference in variability in mood in the pre-hypomanic state when compared to the pre-depressed state. ApEn can distinguish between the pre-episode, pre-remission, pre-hypomanic and pre depressive states. Using daily mood ratings, pre-episode changes were detected before the episode onset. Further investigation to relate the pre-episode and pre remission states to other clinical and biological data is indicated. PMID- 21544746 TI - Proteome-based pathway modelling of psychiatric disorders. AB - The etiopathogenesis of many psychiatric illnesses remains unclear and a variety of these diseases can coexist, partly mimicking each other while contributing to and distorting symptomatic expressions. To understand the processes involved, it is necessary to unravel signalling pathways, complex interaction networks and metabolic alterations involving a plethora of anatomical components. When addressing such largely obscure mechanisms, primary data mainly based on genomics and differential gene expression patterns turns out to be of limited usefulness. Numerous direct as well as very indirect processes modulate and dissociate gene expression from protein functions and physiological effects. Proteomics approaches that utilise metabolic labelling and high-throughput mass spectrometry to provide proteome dynamics data need to be utilised. However, the data thus gathered encompasses a complex assembly of numerous types of intermixed cells, representing biological processes that occur in both time and space across several scalar levels. The complexities represented are such that to analytically approach these diseases, a systems standpoint becomes necessary. This implies multiple experimental interrogations in an iterative interplay between experimentation and modelling. While this may be reasonably considered in the context of in vitro systems, it can hardly be contemplated when addressing CNS tissues from heterogeneous human origins, thereby imposing serious constraints upon the investigation of human cognitive disorders. In this article, the authors expose a paradigm that addresses and alleviates at least some of these major difficulties. Based on the reasoned utilisation of trait animal models and human material, this approach has already started to deliver novel and directly exploitable knowledge. PMID- 21544747 TI - Effects of dopamine and glutamate on synaptic plasticity: a computational modeling approach for drug abuse as comorbidity in mood disorders. AB - Major depressive disorder (MDD) affects about 16% of the general population and is a leading cause of death in the United States and around the world. Aggravating the situation is the fact that "drug use disorders" are highly comorbid in MDD patients, and VICE VERSA. Drug use and MDD share a common component, the dopamine system, which is critical in many motivation and reward processes, as well as in the regulation of stress responses in MDD. A potentiating mechanism in drug use disorders appears to be synaptic plasticity, which is regulated by dopamine transmission. In this article, we describe a computational model of the synaptic plasticity of GABAergic medium spiny neurons in the nucleus accumbens, which is critical in the reward system. The model accounts for effects of both dopamine and glutamate transmission. Model simulations show that GABAergic medium spiny neurons tend to respond to dopamine stimuli with synaptic potentiation and to glutamate signals with synaptic depression. Concurrent dopamine and glutamate signals cause various types of synaptic plasticity, depending on input scenarios. Interestingly, the model shows that a single 0.5 mg/kg dose of amphetamine can cause synaptic potentiation for over 2 h, a phenomenon that makes synaptic plasticity of medium spiny neurons behave quasi as a bistable system. The model also identifies mechanisms that could potentially be critical to correcting modifications of synaptic plasticity caused by drugs in MDD patients. An example is the feedback loop between protein kinase A, phosphodiesterase, and the second messenger cAMP in the postsynapse. Since reward mechanisms activated by psychostimulants could be crucial in establishing addiction comorbidity in patients with MDD, this model might become an aid for identifying and targeting specific modules within the reward system and lead to a better understanding and potential treatment of comorbid drug use disorders in MDD. PMID- 21544748 TI - The aims of systems biology: between molecules and organisms. AB - The systems approach to biology has a long history. Its recent rapid resurgence at the turn of the century reflects the problems encountered in interpreting the sequencing of the genome and the failure of that immense achievement to provide rapid and direct solutions to major multi-factorial diseases. This paper argues that systems biology is necessarily multilevel and that there is no privileged level of causality in biological systems. It is an approach rather than a separate discipline. Functionality arises from biological networks that interact with the genome, the environment and the phenotype. This view of biology is very different from the gene-centred views of neo-Darwinism and molecular biology. In neuroscience, the systems approach leads naturally to 2 important conclusions: first, that the idea of 'programs' in the brain is confusing, and second, that the self is better interpreted as a process than as an object. PMID- 21544749 TI - "Endoscopic resection" of superficial gastrointestinal neoplasia: a single key opening all the doors. PMID- 21544750 TI - [An anatomic facsimile model with origin inner ear structures for temporal bone preparations]. AB - BACKGROUND: Microsurgical dissection exercises are essential in otosurgery training. Human temporal bone specimens are rarely available for necessary extensive preparation steps up to the cochlea. This requires the development of new Anatomical Facsimile Models (AFM) of the temporal bone with its diffizil internal structures. MATERIAL AND METHODS: The construction of AFM was realized by rapid prototyping technologies. Data for processing come from high resolution CT-scans. RESULTS: With the production of AFM true to the original structures of the temporal bone by rapid prototyping methods it was possible to reproduce the very small cavity structures of the inner ear (cochlea, semicircular canals). All cavity structures of the temporal bone, including the middle ear, are constructed without solid support material. This allows the introduction of Cochlea-Implant electrodes into the cochlea. CONCLUSION: The use of modern rapid prototyping technologies enables us to produce any number of identical models of an original specimen. The preparation steps and the material properties correspond to those of the original temporal bone. Therefore AFM are excellent preparation models. PMID- 21544751 TI - [Smokers develop a nasal obstruction in supine position]. AB - BACKGROUND: We found in a previous study a healthy non-smoker nose does not develop obstruction lying in supine position . We examined whether a designated smoker nose behaves consistently. MATERIAL AND METHODS: 39 healthy young smokers participated. The daily consumption was O 21 cigarettes. 9 test positions have been realized. Acoustic rhinometry was used for the estimation of nasal volumes and the nasal minimum cross-sectional areas as parameters for nasal respiration. Additionally, blood pressure and heart rate were measured to control the cardiovascular behavior. RESULTS: The total nasal volume decreased significantly lying down. Only one third of the volunteers noticed this obstruction. Going upstairs all measured parameters increased. 2 min later all rhinometric parameters, the diastolic blood pressure and heart rate had reached its baseline level. Systolic blood pressure took about 4 min. CONCLUSIONS: A cigarette smoke induced nasal obstruction can be demonstrated during supine position using the acoustic rhinometry. One third of smokers noted a deterioration of nasal breathing. During stairs climbing the sympathic tone is increasing followed by nasal decongestion, raised blood pressure and heart rate. If smokers complaint of nasal obstruction in lying position - whether alert or during sleep - it is advisable to lift the bed-head. In medium term a therapy of chronic rhinitis with topical corticosteroids, in longer term a smoking cessation is recommended. PMID- 21544752 TI - [Diabetes insipidus due to neurosarcoidosis]. PMID- 21544753 TI - [Evidence based endoscopic ultrasound]. AB - In this overview the variety of current evidence based diagnostic options of EUS are discussed. PMID- 21544754 TI - [Incidence of, risk factors for, and prevention of intestinal leakage]. AB - BACKGROUND: Intestinal anastomotic leakage represents a major complication in visceral surgery with relevant morbidity and mortality. MATERIAL AND METHODS: Based on a literature -search in Medline / PubMed the available data are presented, critically reviewed and summarised. RESULTS AND CONCLUSION: Beside optimisation of surgical technique, patient-dependent risk factors - such as relevant comorbidity, certain medications or previous radiochemotherapy - play a major role in the development of anastomotic leak-age. The effort for optimisation of these patient-dependent risk factors is not incorporated within the compensation scheme in German hospitals. PMID- 21544755 TI - [Diverticulitis--conservative therapy]. AB - BACKGROUND: Diverticulitis due to diverticulosis of the colon is a common clinical problem with a high morbidity and socio-economic consequences. Frequent clinical signs are flatulence, abdominal pain, stool problems which may often be misinterpreted as the symptoms of an irritable bowel or a colitis. Accordingly, the diagnostic work-up must be adequate to allow for the stage-adapted planning and performance of the therapy. MATERIAL AND METHODS: The following questions will be addressed in this review: What do we need to clarify diagnosis? Which antibiotics should be used? What is the best conservative approach for treatment? RESULTS AND CONCLUSIONS: Basic conservative therapy consists of systemic antibiosis which can be extended by a topical antibiosis, and administration of aspirin as well as probiotics. The indications for a specific therapy is made on an individual basis according to stage (Hansen and Stock). Above all, a "team approach" and close communication between gastroenterologists and surgeons are mandatory for adequate treatment of these patients. PMID- 21544756 TI - [Diverticulitis of the small intestine as a rare differential diagnosis in patients with upper abdominal pain]. PMID- 21544757 TI - [What does the nephrologist expect from the invasive treatment of renal artery stenosis?]. PMID- 21544758 TI - [Problems in Psychiatric Classification]. PMID- 21544759 TI - [Symptoms and cognition in geriatric schizophrenia]. AB - From the first manifestation of schizophrenic psychosis onwards numerous psychopathological symptoms and cognitive impairments occur, which are affected by age and the aging process. Clinical trials report a pronounced incidence of positive symptoms in late-onset schizophrenia. Negative symptoms are often observed in chronic-course psychosis, but occur infrequently in late-onset schizophrenia. With respect to cognitive performance neuropsychological studies have shown a decrease in the test performance of permanently hospitalised patients with chronic schizophrenia as age and illness duration increased. Comparative studies of early and late-onset patients in most cases have reported no differing profiles of cognitive performance. Some investigators propose that late-onset schizophrenia may be a prodromal symptom of dementia. However, current studies show that late-onset schizophrenia is basically comparable to its early onset counterpart. The manifestation in youth and early adulthood may be prevented by specific protective factors until aging-related parameters lead to the onset of symptoms during late life. PMID- 21544760 TI - [Erik Essen-Moller and the roots of multiaxial classification in psychiatry]. AB - Against the background of the preparation of ICD-11 and DSM-V, the historical roots of a multiaxial diagnostic assessment in psychiatry are reviewed. The principles of such an approach are traced back to the Swedish psychiatrist Erik Essen-Moller who had proposed a distinction between aetiological and descriptive aspects in the classification of mental disorders. Furthermore, he suggested to break down the descriptive classification into the cross-sectional psychopathological picture and the clinical course. Nowadays, a multiaxial assessment is used in diagnostic systems such as DSM-IV. However, these current concepts differ considerably from Essen-Moller's suggestions. A return to the original approach of multiaxial diagnostic assessment comprising the axes "syndromes", "course types" and "aetiology" would be in line with current neurobiological findings and may provide a bridge between the traditional categorical diagnostic approach and dimensional models. PMID- 21544761 TI - [Autism spectrum disorders in adulthood: clinical and neuropsychological findings of Aspergers syndrome diagnosed late in life]. AB - INTRODUCTION: High-functioning autism (HFA) and Aspergers syndrome (AS) are autism spectrum disorders (ASD) characterised by disturbances in social interaction, both verbal and non-verbal communication and repetitive and/or restrictive behaviour since early childhood. Symptoms appear generally during early childhood and adolescence. The increasing need to clarify diagnostic queries in advanced age led to the constitution of specialised outpatient clinics for adults involving a growing amount of HFA/AS subjects diagnosed late in life. However, thus far neuropsychological data about this group are scarce. METHODS: We present a subgroup of 39 patients with HFA/AS (mean age at diagnosis 31.1 +/- 8.9 years) who were consecutively diagnosed at the autism outpatient clinic at the Department of Psychiatry at the University Hospital Cologne. Autistic symptoms (autism spectrum quotient; AQ), depressive symptoms (Beck depression inventory; BDI), general intelligence (HAWIE-R), social cognition ("theory of mind", ToM) and executive functioning (COWAT) were systematically studied in comparison to a control group matched for age, education, gender and intelligence (n = 39). RESULTS: HFA/AS subjects presented higher AQ scores (40.4 +/- 5.2) as opposed to the healthy controls (13.5 +/- 4.8). Neuropsychologically, patients showed deficits in social cognition, executive functions and in subtests of HAWIE R related to verbal comprehension and perceptual organisation as opposed to the healthy control group. DISCUSSION: The diagnosis of autistic disorders in adulthood basically relies on the clinical assessment of autistic core symptoms which were corroborated by high AQ values. The self-rating instrument AQ was found to be highly discriminative between the HFA/AS group and the healthy control group. The neuropsychological profile of adult HFA/AS patients diagnosed late in life is compatible with that of previously investigated HFA/AS populations. These findings show that such basic autism-associated deficits persist until adulthood, although patients are able to learn social rules. PMID- 21544762 TI - [Diagnostic work-up in Whipple's disease with cerebral involvement]. AB - The diagnostic work-up in the case of a suspected cerebral involvement of Whipple's disease involves neuroimaging and analysis of cerebrospinal fluid (CSF) including polymerase chain reaction (PCR) assays for Tropheryma whipplei. As neurological findings may be complex and unspecific, extracerebral symptoms often lead to the suspicion of Whipple's disease. We report the cases of two patients in whom the suspected diagnosis of Whipple's disease could not be proved either by endoscopy or by the analysis of CSF. Only by means of a cerebral biopsy was the diagnosis assumed and specific therapy was initiated. PMID- 21544763 TI - [Bilateral wrist drop - central or peripheral lesion?]. AB - The wrist drop, also called carpoptosis or drop hand, is a common clinical presentation in case of peripheral damage to the radial nerve. But what about the picture of a bilateral finger/wrist drop?! We report the case of a 61-year-old female patient who was admitted to the hospital for myocardial infarction. Subsequently she developed a right dominant bilateral wrist drop. Further neurological examination revealed a positive Wartenberg sign pointing towards a central motoric dysfunction. The following native cerebral CT scan demonstrated bilateral hypodense lesions in both hand knobs in the precentral gyri. Subsequent MRI confirmed acute cerebral infarction in these two but also several other, clinically silent, locations. Further diagnostic work-up revealed a hypokinetic cardiac apex suggesting cardiac embolism to be the cause for cerebral thrombembolism and the clinically leading symptom of right-dominant bilateral finger/wrist drop. Besides the case presentation also the differential diagnosis and clinical test for diagnostic work-up of wrist drops are presented and discussed. PMID- 21544764 TI - [Differential diagnosis and treatment of myalgias]. PMID- 21544765 TI - N-acetylaspartylglutamate in CNS hypomyelination. AB - CSF N-acetylaspartylglutamate (NAAG) has been found to be elevated in some hypomyelinating disorders. This study addressed the question whether it could be used as a marker for hypomyelination and as a means to distinguish between hypomyelinating disorders biochemically. We have measured CSF NAAG in a cohort of 28 patients with hypomyelination with known and unknown aetiology. NAAG was found to be elevated in 7 patients, but was normal in the majority, including patients with defined hypomyelinating disorders. CSF NAAG is not a universal marker of hypomyelination, and the mechanism of its elevation remains poorly understood. PMID- 21544766 TI - [Effects of inpatient treatment on eating disorder symptoms, health-related quality of life and personal resources in anorexia and bulimia nervosa]. AB - The aim of the present prospective-naturalistic study was the evaluation of psychosomatic inpatient treatment for anorexia nervosa (AN) and bulimia nervosa (BN). 128 patients with eating disorders (n=59 AN and n=69 BN) were investigated on admission and discharge using the following standardized questionnaires: eating disorder symptoms (EDI), general psychopathology (BSI), quality of life (SF-12), and personal resources (SOC-13, SWE). Moderate to large effect sizes were achieved for the eating disorder symptoms; in addition, general psychopathology was substantially reduced at the end of treatment, and quality of life as well as personal resources were enhanced. Personal resources were found to be the strongest predictors for therapy outcome. Based on our data, important insights and recommendations may be gained for the inpatient treatment of eating disorders, especially with regard to the potential influence of personal resources. PMID- 21544767 TI - [Examination of the stability of medically unexplained symptoms and somatoform disorders over time within the context of different diagnostic concepts]. AB - OBJECTIVE: The aim of this study was to determine and to compare the stability of medically unexplained symptoms and somatoform disorders within the context of different diagnostic concepts (SSI4/6, DSM-IV, DSM-V). METHOD: In a 2-stage follow-up study, 620 consecutive patients were first of all screened using the PHQ-15 questionnaire. In the second stage, 308 selected persons were then interviewed in detail. 12 months later, 89,9% of participants could be interviewed again. RESULTS: Medically unexplained symptoms and somatoform disorders showed weak stability coefficients. In regard to Complex Somatic Symptom Disorder (DSM-V), the prevalence rates were smaller than expected. Within a year, they declined drastically. CONCLUSION: The instability of Complex Somatic Symptom Disorder should be taken into account when revising somatoform disorder for DSM-V. In order to improve stability, the time criterion should be extended by the duration of mental preoccupation with the ailments. PMID- 21544769 TI - Rectovaginal Staphylococcus aureus colonization: is it a neonatal threat? AB - We sought to determine the rate of Staphylococcus aureus rectovaginal colonization and positive newborn blood cultures. Routinely obtained group B streptococcus (GBS) rectovaginal specimens were cultured for S. aureus using standard microbiology procedures. S. aureus- and GBS-positive blood cultures in infants less than 3 days old were determined from our microbiology database. Overall, 1488 rectovaginal cultures were obtained. Rates of positive GBS, S. aureus, and methicillin-resistant S. aureus (MRSA) cultures were 20.2%, 8.2%, and 1.7%, respectively. Cultures were positive for methicillin-susceptible S. aureus (MSSA) and GBS or MRSA and GBS in 1.6% and 0.3% of women, respectively. There was no association between GBS and MSSA or MRSA. From 1998 to 2008, there were four positive S. aureus blood cultures (0.4/10,000 live births). The rate of early onset GBS-positive blood cultures was 2.8/10,000 live births. S. aureus rectovaginal colonization at 35 to 37 weeks is relatively uncommon and currently does not appear to pose a significant risk of early onset neonatal sepsis. PMID- 21544770 TI - Perinatal outcome in the live-born infant with prenatally diagnosed omphalocele. AB - We compared perinatal outcomes between live-born nonisolated and isolated omphaloceles diagnosed during a prenatal ultrasound. Fetuses (n = 86) with omphalocele were identified between 1995 and 2007 at a single institution. Inclusion criteria were an omphalocele >14 weeks' gestation, available fetal and/or neonatal karyotype, and a live-born infant (n = 46). Perinatal outcomes were compared in nonisolated (n = 23) and isolated omphaloceles (n = 23). For all omphaloceles, the majority delivered after 34 weeks by cesarean. Mean birth weight (2782 versus 2704 g), median length of stay (27 versus 25 days), and mortality (two deaths in each group) were not different between the nonisolated and isolated groups (p > 0.05). In the nonisolated group, seven major anomalies were not confirmed postnatally. Of the prenatally diagnosed isolated omphaloceles, 8 (35%) were diagnosed with a syndrome or other anomalies after birth. The outcomes were similar in nonisolated and isolated prenatally diagnosed omphaloceles, but ultrasound did not always accurately determine the presence or absence of associated anomalies. PMID- 21544771 TI - Linking maternal platelet counts with neonatal platelet counts and outcomes using the data repositories of a multihospital health care system. AB - It is unclear whether neonates born to women with thrombocytopenia during pregnancy are themselves at increased risk for thrombocytopenia at birth. In the current retrospective study, platelet count reference ranges were developed for pregnant women according to trimester, and correlations were sought between the platelet counts of mothers at delivery and their neonates. During the study period, 92,518 platelet counts were recorded on 41,887 pregnant women. A progressive shift toward lower platelet counts in a similarly shaped histogram occurred during pregnancy, with the lower reference range (2.5 percentile) for platelets during the third trimester being 113 * 10(9)/L. Among 11,797 maternal neonatal pairs following delivery, no correlation was observed between maternal and neonatal counts. However, if the mother's lowest count was <50 * 10(9)/L, the relative risk of any degree of thrombocytopenia in their neonate was 4.6 (95% confidence interval [CI], 1.8 to 33.3) and the relative risk of severe neonatal thrombocytopenia was 7.8 (95% CI, 1.8 to 33.3). The results of the current study demonstrate that platelet counts >75 * 10(9)/L in pregnant women were not associated with an increased risk of neonatal thrombocytopenia, and maternal platelet counts of <50 * 10(9)/L were accompanied by an almost fivefold risk increase of neonatal thrombocytopenia. PMID- 21544772 TI - Effect of maternal age on the risk of stillbirth: a population-based cohort study on 37 million births in the United States. AB - The objective of our study was to evaluate the incidence and effect of maternal age on the risk of stillbirth. We conducted a population-based cohort study using the Centers for Disease Control and Prevention's "Linked Birth-Infant Death" and "Fetal Death" data files. We excluded all births of gestational age under 24 weeks and those with reported congenital malformations. We estimated the adjusted effect of maternal age on the risk of stillbirth using logistic regression analysis. There were 37,504,230 births that met study criteria, of which 130,353 (3.5/1,000) were stillbirths. Rates of stillbirth remained constant throughout the 10 years. As compared with women between the ages of 25 and 30, decreasing maternal age was associated with the following risk of stillbirth: odds ratio (OR) 0.95 (95% confidence interval [CI] 0.93 to 0.97) for ages 20 to 25; OR 0.97 (95% CI 0.94 to 0.99) for ages 15 to 20; and OR 1.32 (95% CI 1.18 to 1.47) for ages <15. Increasing maternal age was associated with an increasing risk of stillbirth: OR 1.02 (95% CI 0.99 to 1.04) for ages 30 to 35, OR 1.25 (95% CI 1.21 to 1.28) for ages 35 to 40, OR 1.60 (95% CI 1.53 to 1.67) for ages 40 to 45, and OR 2.22 (95% CI 1.91 to 2.53) for ages >45. Although the overall risk is low, the risk of stillbirth increases considerably in women at the extremes of the reproductive age spectrum. Antenatal surveillance may be justified in these women. PMID- 21544773 TI - [Physiology of the human corneal endothelium--new insights from electrophysiological investigations]. AB - Currently, the identification of apoptotic or damaged human corneal endothelial (HCE) cells is limited to a morphological assessment and vital staining. Specific electrophysiological investigations may prospectively help to identify damaged HCE cells at an earlier stage. Besides calcium imaging, the so-called patch-clamp technique is an important test method enabling one to assay the effect of various substances on ion channels and receptors of the cell membrane. First electrophysiological pilot experiments with cultivated and freshly isolated HCE cells have revealed promising results. In this way, the expression of certain transient receptor potential channels (TRPs) could be demonstrated. However, the function of these channels is still not fully elucidated. In humans, TRPs play a crucial role in the sense of taste, pheromones, temperature and pain and are involved in osmolarity. This review summarises the current literature on the electrophysiology of the human corneal endothelium and deduces potential approaches to a sensitive vitality and function test under utilisation of the electrophysiological properties of HCE cells. PMID- 21544774 TI - Metabolism of the lignan dehydrodiisoeugenol in rats. AB - Dehydrodiisoeugenol (DDIE), a major active lignan from the seed and aril of the fruit of Myristica fragrans Houtt., functions as a potential anti-inflammatory agent by inhibiting lipopolysaccharide-stimulated nuclear factor kappa B activation and cyclooxygenase-2 expression in macrophages. However, the metabolism of DDIE remains unknown. This report describes the metabolic fate of DDIE in liver microsomes, urine, and feces of rats treated with DDIE. DDIE metabolites were isolated by sequential column chromatography and high performance liquid chromatography from liver microsomes incubations, urine, and feces. Nine metabolites ( M-1 to M-9), including 5 new metabolites, were determined spectroscopically using ultra-violet (UV), mass spectrometry (MS), nuclear magnetic resonance (NMR), and circular dichroism (CD). Analysis of the isolated metabolites showed that DDIE undergoes four major pathways of metabolism in the rat: oxidation (including hydroxylation, hydroformylation, and acetylation), demethylation, ring-opening, and dehydrogenation. In contrast to the metabolites from liver microsomes, the major metabolites In vivo were generated from DDIE by multiple metabolic reactions. Given these results, we describe a metabolic pathway for DDIE in the rat that gives insight into the metabolism of DDIE and the mechanism of DDIE bioactivity in humans. PMID- 21544775 TI - Two pairs of epimeric indole alkaloids from Catharanthus roseus. AB - Two pairs of epimeric indole alkaloids (1- 4) with a chlorine atom were isolated from the aerial part of Catharanthus roseus. Their structures were established on the basis of the spectroscopic data including UV, IR, HRESIMS, NMR, and X-ray diffraction analyses. The cytotoxic activities of 1-4 against the HepG2 cell line were evaluated. PMID- 21544776 TI - The content of artemisinin in the Artemisia annua tea infusion. AB - The traditional use of the medicinal plant Artemisia annua for the treatment of malaria entails the preparation of a tea infusion. In the scientific literature there have been some discrepancies on the quantity of the active principle, artemisinin, in the tea infusion. Due to these discrepancies, we decided to quantify artemisinin in tea infusions prepared according to different methods. We also studied the water solubility of pure artemisinin at room temperature and at 100 degrees C and compared it to the solubility of artemisinin from the plant material. We found that the extraction efficiency is very sensitive to temperature and that efficiencies of above 90 % can be reached. We also showed that the solubility of artemisinin is not improved by other components in the extract but that a supersaturated solution of artemisinin might be formed, which is stable for at least 24 hours. PMID- 21544777 TI - New antimycobacterial triterpenoids from Rhus taitensis. AB - Two new triterpenoids were isolated from the leaves and twigs of Rhus taitensis. Their structures were elucidated by 1D and 2D NMR spectroscopic studies as 1,10,24,25,30-pentahydroxysqualene and dammar-20(22),24-diene-3 beta,26,27-triol. Both compounds exhibited moderate antimycobacterial activities with an MIC of 45 ug/mL. PMID- 21544778 TI - Long-term outcome after argon plasma coagulation of small-bowel lesions using double-balloon enteroscopy in patients with mid-gastrointestinal bleeding. AB - BACKGROUND AND STUDY AIMS: Vascular malformations are the most common sources of bleeding in the small bowel. They can be treated with argon plasma coagulation (APC) during double-balloon enteroscopy (DBE). This study aimed to evaluate the long-term follow-up of the effectiveness of APC for small-bowel bleeding by means of a single-center retrospective study. PATIENTS AND METHODS: Between June 2003 and December 2005, APC treatment for small-bowel lesions was carried out during DBE in 63 patients with known or suspected mid-gastrointestinal bleeding. Fifty patients were included in the analysis. Main outcome measurements were comparison of hemoglobin values and blood transfusion requirements before and after APC, and rebleeding rates. RESULTS: Twenty-nine patients (58%) had only oral DBE, whereas 21 patients (42%) underwent combined oral and anal approaches. The most frequent bleeding sources treated with APC were angiodysplasias in 44 patients (88%). Hemoglobin levels increased distinctly and stabilized after APC during a mean long-term follow-up of 55 +/- 7 months, with mean levels of 7.6 g/dL before APC and 11.0 g/dL afterwards. Blood transfusion requirements substantially declined, from 30 patients (60%) before APC to 8 (16%) afterwards. However, small-bowel bleeding recurred in 21 patients (42%), particularly in patients with Osler disease (6 of 8 patients, 75%). CONCLUSIONS: Bleeding sources in the small bowel can be effectively treated with APC using DBE, and long-term follow-up data show a clear increase in hemoglobin levels and reduced blood transfusion requirements after APC. Further efforts are needed to reduce the rebleeding rate, possibly through more intensive initial treatment. PMID- 21544779 TI - Ectopic thyroid with Hashimoto's thyroiditis presenting as goitrous hypothyroidism. PMID- 21544780 TI - Iatrogenic bladder rupture in a child following voiding cystourethrography and its laparoscopic management. PMID- 21544781 TI - Gastric bleeding induced by unusual hepatic portal and splenic venous cavernous malformation--report of a case. PMID- 21544782 TI - Multi-layer reconstruction of cloacal bladder exstrophy with a pedicled anterior lateral thigh perforator flap, vastus lateralis muscle and fascia lata. PMID- 21544783 TI - Surgical repair of Treves' field mesenteric hernia: use of the purse-string technique. PMID- 21544784 TI - [Sea voyages with urinal and vomit bucket - travel and medicinal utensils for crusades and pilgrimages to the holy land]. PMID- 21544785 TI - [Definition of the Diagnosis Osteomyelitis-Osteomyelitis Diagnosis Score (ODS)]. AB - AIM: The disease "osteomyelitis" is characterised by different symptoms and parameters. Decisive roles in the development of the disease are played by the causative bacteria, the route of infection and the individual defense mechanisms of the host. The diagnosis is based on different symptoms and findings from the clinical history, clinical symptoms, laboratory results, diagnostic imaging, microbiological and histopathological analyses. While different osteomyelitis classifications have been published, there is to the best of our knowledge no score that gives information how sure the diagnosis "osteomyelitis" is in general. METHOD: For any scientific study of a disease a valid definition is essential. We have developed a special osteomyelitis diagnosis score for the reliable classification of clinical, laboratory and technical findings. The score is based on five diagnostic procedures: 1) clinical history and risk factors, 2) clinical examination and laboratory results, 3) diagnostic imaging (ultrasound, radiology, CT, MRI, nuclear medicine and hybrid methods), 4) microbiology, and 5) histopathology. RESULTS: Each diagnostic procedure is related to many individual findings, which are weighted by a score system, in order to achieve a relevant value for each assessment. If the sum of the five diagnostic criteria is 18 or more points, the diagnosis of osteomyelitis can be viewed as "safe" (diagnosis class A). Between 8-17 points the diagnosis is "probable" (diagnosis class B). Less than 8 points means that the diagnosis is "possible, but unlikely" (class C diagnosis). Since each parameter can score six points at a maximum, a reliable diagnosis can only be achieved if at least 3 parameters are scored with 6 points. CONCLUSION: The osteomyelitis diagnosis score should help to avoid the false description of a clinical presentation as "osteomyelitis". A safe diagnosis is essential for the aetiology, treatment and outcome studies of osteomyelitis. PMID- 21544786 TI - [The treatment of patellar dislocation: a systematic review]. AB - AIM: The diagnosis and treatment of patellar dislocation is very complex. The aim of this study is to give an overview of the biomechanics of the patellofemoral joint and to point out the latest developments in diagnosis and treatment of patellar dislocation. METHOD: The authors electronically searched Medline, Cochrane and Embase for studies on the biomechanics of the patellofemoral joint and for conservative and surgical treatments after patellar dislocation. We extracted baseline demographics, biomechanical, conservation and surgical details. RESULTS: Understanding the biomechanics of the patellofemoral joint is necessary to understand the pathology of patellar dislocation. The patellofemoral joint consists of a complex system of static, active and passive stabilising factors. Patellar instability can result from osseous and soft-tissue abnormalities, such as trochlear dysplasia, patella alta, a high tibial tuberosity trochlear groove (TTTG) distance, weaknesses of the vastus medialis obliquus or a lesion of the medial retinaculum. Recent studies have focused on the medial patellofemoral ligament (MPFL) and have shown that the MPFL is the most significant passive stabiliser of the patella. Following patellar dislocation, an MRI should be standard practice to detect an MPFL rupture, osteochondral lesions or other risk factors for redislocation. An acute first time patellar dislocation without osteochondral lesions and without severe risk factors for a redislocation should follow a conservative treatment plan. If surgical treatment is required, the best postoperative results occur when the MPFL is reconstructed, leading to a redislocation rate of 5%, this includes cases that have a dysplastic trochlea. Duplication of the medial retinaculum show very inconsistent results in the literature, possibly due to the fact that the essential pathomorphology of patellar dislocation is not addressed. Addressing the exact location of the rupture of the MPFL with a suture is possibly more convenient, especially after first-time dislocation with associated risk factors for a redislocation. Recent literature does not encourage the use of lateral release, since this can increase patellar instability. Indications for lateral release include persistent patellar instability or pain reduction in an older arthritic subject. For correcting a patellofemoral malalignment, the TTTG distance should be measured and a medial transposition of the anterior tibial tubercle hinged on a distal periosteal attachment should be considered. Cartilage lesions on the medial facet of the patella are a contra-indication for medial tubercle transposition. For cartilage lesions of the lateral facet, antero medialization of the tibial tubercle can be successful. A tubercle osteotomy can be efficiently combined with MPFL reconstruction. We believe that patients with open epiphyseal plates should be treated with duplication of the medial retinaculum. In the presence of patellar maltracking, an additional subperiostal soft tissue release with medialisation of the distal part of the patellar tendon can be performed. CONCLUSION: It seems that the predominating factors for patellar dislocation are heterogenic morphology in combination with individual predisposition. Non-surgical treatment is typically recommended for primary patellar dislocation without any osteochondral lesions and in the absence of significant risk factors for redislocation. If surgical treatment is deemed necessary, addressing the essential pathomorphology has become the primary focus. PMID- 21544787 TI - Mitigation of occult lung injury by pneumonectomy via minithoracotomy in mice. AB - BACKGROUND: The systemic and pulmonary inflammatory response associated with pneumonectomy performed via minithoracotomy versus that after open posterolateral thoracotomy is uncertain. METHODS: Groups consisting of 7 randomly assigned mice underwent a) minithoracotomy (with 5-mm long incisions and sparing of the muscles) alone, b) posterolateral thoracotomy (with 20-mm long incisions) alone, c) pneumonectomy via minithoracotomy, or d) pneumonectomy via posterolateral thoracotomy. The animals' daily food intake, body weight changes and spontaneous activity were monitored for 10 days, and lung water accumulation and vascular hyperpermeability in the remaining right lung were measured at 24 h after surgery. Concentrations of high mobility group box 1 protein (HMGB1), a mediator of inflammation and shock, were measured in the bronchoalveolar lavage fluid. RESULTS: Compared with posterolateral thoracotomy, pneumonectomy via minithoracotomy was associated with significantly less weight loss (p < 0.05), despite a similar daily food intake among the groups. Spontaneous activity after pneumonectomy via minithoracotomy returned earlier than after posterolateral thoracotomy. Pulmonary vascular hyperpermeability and water retention in the residual lung were significantly less prominent after pneumonectomy performed via minithoracotomy than after pneumonectomy via posterolateral thoracotomy (both comparisons p < 0.05). HMGB1 concentrations in the bronchoalveolar lavage fluid collected from the residual lung were significantly lower (p < 0.05) after minithoracotomy than after posterolateral thoracotomy. CONCLUSIONS: Based on postoperative weight loss, spontaneous activity, and the degree of pulmonary capillary injury in the residual lung, pneumonectomy via minithoracotomy was less invasive than posterolateral thoracotomy. The lower increase in HMGB1 associated with minithoracotomy might result in lower pulmonary vascular hyperpermeability and reflect less surgical invasiveness. PMID- 21544788 TI - The dilemma of subaortic stenosis--a single center experience of 15 years with a review of the literature. AB - OBJECTIVE: The term "subaortic stenosis" includes a variety of obstructions of the left ventricular outflow tract (LVOT), ranging from a short (discrete) subvalvular membrane to long, tunnel-like narrowing. An association with other congenital lesions is frequent. We reviewed the reported literature and describe our results, analyzing the nomenclature of and risk factors for restenosis after surgical treatment. METHODS: From 1994 to 2009, 81 children (53 males, 28 females; median age: 57 months, range [ R]: 5-204) underwent surgical relief of a subaortic stenosis. Patients were divided, according to pathology, into short segment (group A, n = 42) and complex obstructions (group B, n = 39), with the latter including long segment stenosis and/or associated anomalies such as aortic coarctation, interrupted aortic arch or Shone's complex. RESULTS: Surgery resulted in a significant reduction of the gradient between the left ventricle and the aorta in both groups (Delta P group A: 51 +/- 28 mmHg, group B: 46 +/- 25 mmHg). There was no operative mortality. One patient died in the early postoperative period due to pericardial tamponade. Median follow-up was 90 months (R = 0.5-187). Twenty-five (31%) patients required reoperation because of recurrent stenosis after a median of 43 months (R = 0.5-128). Seven (16%) patients belonging to group A developed restenosis, and 18 (46%) in group B. Freedom from reoperation for all patients was 60% after 10 years. 10 (40%) of the patients of group B were ultimately treated with a Ross-Konno reconstruction of the LVOT. CONCLUSION: Despite adequate surgical resection, recurrence of subaortic stenosis within several years after initial surgical treatment is frequent, especially in patients with complex lesions. In cases requiring reoperation, the surgical therapy is often extensive, and even includes Ross Konno reconstruction of the LVOT. PMID- 21544789 TI - Influence of aortic dimensions on the hemodynamic performance of small aortic valve prostheses: impact on patient/prosthesis mismatch. AB - BACKGROUND: Since Doppler echocardiography takes no account of pressure recovery, the true hemodynamic burden of aortic valve prostheses remains vague. The purpose of this study was to elucidate the methodological error of Doppler gradient estimation by means of a model demonstrating the different influence of aortic root diameters on net and Doppler gradients, respectively. This matters especially in small valves and the related patient/prosthesis mismatch calculation. METHODS: Two bileaflet small aortic valve prostheses (19 mm SJM Regent(r) and On-X(r) valve) were tested using a pulsatile circulatory mock loop simulator with two different aortic models: one with statistically normal diameters according to annular size, another one simulating an aortic aneurysm of 50 mm. Doppler and simultaneously recorded net gradients as well as systolic energy losses were obtained for different hemodynamic conditions. RESULTS: In all measurements a significant amount of pressure recovery was observed. In cases of aortic aneurysm systolic energy loss increased significantly for each cardiac output at each heart rate ( P < 0.0028), reflected by a significant ( P < 0.0001) increase in net gradients. The corresponding Doppler gradients were unchanged. This indicates significantly less pressure recovery ( P < 0.0001) in the aneurysmatic aorta. CONCLUSIONS: Geometry of the ascending aorta considerably alters aortic valve hemodynamic parameters. The hemodynamic function of small aortic valve prostheses, especially with corresponding normal outflow dimensions, is much better than expected from Doppler gradients. Thus, calculation of a patient/prosthesis mismatch can be misleading. PMID- 21544790 TI - Long-term results of mechanical and biological heart valves in dialysis and non dialysis patients. AB - INTRODUCTION: We wanted to answer the question whether biological heart valves are inferior compared to mechanical heart valves in end-stage renal disease (ESRD) patients. METHODS: Between 01/1996 und 12/2006, 44 of 3293 patients undergoing aortic valve replacement (AVR) in a single institution suffered from dialysis-dependent ESRD and underwent a follow-up investigation after 1.9 years (median). Twelve (28.9 %) of these patients received a biological, 32 (71.1 %) of these patients a mechanical aortic valve prosthesis. To evaluate a possible influence of the valve type (biological/mechanical) on survival, uni- and multivariate logistic regression was used. RESULTS: ESRD patients after AVR had a relatively poor short-term (30-day mortality: 22.7 %) and long-term survival (median survival time: 24.7 months; 95 % CI: 0.2-47.7 months), irrespective of the type of heart valve prosthesis (hazard ratio for mortality depending on heart valve type in dialysis patients: 1.31, P = 0.400). Dialysis-dependent patients were not reoperated due to valve-related reasons. CONCLUSIONS: The long-term survival of dialysis-dependent patients after AVR is low (5-year survival: 29.5 %) irrespective of the type of heart valve prosthesis. Therefore, the use of biological AVR is not contraindicated in this group of patients. PMID- 21544791 TI - [Quality of life after fast track colorectal surgery]. AB - BACKGROUND: Fast track (enhanced recovery) surgery is a standardized concept of perioperative management, which is applied independently of the disease and the operative procedure. The implementation of this concept adjusts the quality of medical results and allows to analyse different factors and their impact on quality of life (QoL). The aim of this investigation was to assess the QoL of patients after elective colorectal surgery undergoing standardized perioperative fast track rehabilitation. MATERIAL AND METHODS: From December 2004 to May 2006 all patients undergoing elective colorectal surgery and fast track rehabilitation were included in this study. Quality of life was evaluated prospectively using the Gastrointestinal Quality of Life Index (GIQLI) according to Eypasch. QoL was analyzed pre- and postoperatively. Subgroup analyses were performed regarding age, malignant or non-malignant colorectal disease and surgical approach. Follow up was performed three months postoperatively. RESULTS: 124 patients underwent elective resection within a fast track program (age 64+/-10 years, 55 with benign disease, 69 with colorectal carcinoma; 67 men and 57 women). 62 patients (50 %) completed the follow-up examination (QoL evaluation three months postoperatively). Pre- and postoperative QoL did not differ significantly (98 [92 104] and 103 [98-109] points, respectively). Subgroup analyses revealed that patients having undergone colorectal resection for benign disease had significantly improved quality of life after surgery, but not so the patients treated for colorectal cancer. The QoL was 14 (2-26) and -1 (-9 - 5), respectively. Patients' age and surgical approach (minimally invasive or open) did not influence their QoL. CONCLUSION: Postoperative QoL after standarized fast track perioperative management was influenced mainly by the patients' disease (with potential QoL improvement in benign disorders), whereas age and the operative approach (minimally invasive or open) had little impact in this respect. PMID- 21544792 TI - [Evaluation of microcirculatory disorders in shock patients]. AB - The microcirculatory status depicts an indicator of organ perfusion in hemodynamic shock. Distribution pattern of microcirculatory disturbances reflects the underlying cause of shock: In septic shock, organ perfusion is severely impaired via arteriolo-venous shunting with shutting up small vessel perfusion; however, cardiogenic shock is characterized by a global impairment of microcirculation, involving all vascular beds. Hence, a differentiated evaluation of microcirculatory disturbances not only supports an early diagnosis of an imminent multiorgan dysfunction syndrome (MODS), but also allows a more accurate evaluation of severity of hemodynamic compromise in critical care medicine. Bedside sidestream darkfield (SDF) technique offers the opportunity to describe the microcirculatory status quo semiquantitatively and to evaluate the effect of novel therapeutic approaches on microcirculation. Further technical improvements of this technique may open new fields of diagnostic and therapeutic applications in intensive care medicine by supporting an early diagnosing of MODS, evaluating prognosis, and optimizing therapeutic measures . PMID- 21544793 TI - [Recent developments in genetic kidney diseases]. AB - The improved understanding of genetic kidney diseases has given rise to a more detailed understanding of kidney function within the last decade. Insights into the pathophysiological principles of frequent kidney diseases - partly inherited, partly acquired - have been obtained by the investigation of rare genetic disorders and can now serve as a starting point for the development of novel therapeutic strategies. In this way various clinical multicenter trials, which are based on the observations made in basic science have been established for the very common autosomal dominant polycystic kidney disease. Furthermore, the influence of genetic aspects on frequent kidney diseases, e. g. diabetic nephropathy, is becoming more obvious. This article aims to give an overview over essential recent development in the field of genetic kidney diseases. PMID- 21544794 TI - [Clinical guidelines and health services research]. AB - Doctors are bound to ensure and improve the quality of their own work. This is a significant part of medical professionalism and lasts one's entire working life. In this regard clinical guidelines provide valuable and helpful information because they give recommendations on prevention, diagnosis, treatment, and aftercare based on current evidence. However, in their medical work potential users widely ignore such guidelines. Hence it is necessary to discover barriers to compliance with the guidelines and, based on the findings, to investigate more effective strategies for implementing the guidelines. Analyses and evaluation can be performed by using health services research. Undesirable developments in doctors' daily routines, associated with negative consequences for healthy and ill people, as well as for the economics of health care, can be detected and improvements can be identified systematically. This branch of research has become ever more important - even necessary. It ist likely that the increasing demand for assessing the needs, costs, structural conditions, and quality of health care will confirm the significance of such evaluation. PMID- 21544796 TI - [Glycemic control and cardiovascular benefit: what do we know today?]. PMID- 21544797 TI - Prediction and analysis of protein methylarginine and methyllysine based on Multisequence features. AB - Protein methylation, one of the most important post-translational modifications, typically takes place on arginine or lysine residue. The reversible modification involves a series of basic cellular processes. Identification of methyl proteins with their sites will facilitate the understanding of the molecular mechanism of methylation. Besides the experimental methods, computational predictions of methylated sites are much more desirable for their convenience and fast speed. Here, we propose a method dedicated to predicting methylated sites of proteins. Feature selection was made on sequence conservation, physicochemical/biochemical properties, and structural disorder by applying maximum relevance minimum redundancy and incremental feature selection methods. The prediction models were built according to nearest the neighbor algorithm and evaluated by the jackknife cross-validation. We built 11 and 9 predictors for methylarginine and methyllysine, respectively, and integrated them to predict methylated sites. As a result, the average prediction accuracies are 74.25%, 77.02% for methylarginine and methyllysine training sets, respectively. Feature analysis suggested evolutionary information, and physicochemical/biochemical properties play important roles in the recognition of methylated sites. These findings may provide valuable information for exploiting the mechanisms of methylation. Our method may serve as a useful tool for biologists to find the potential methylated sites of proteins. PMID- 21544798 TI - The effects of shear flow on protein structure and function. AB - Protein molecules are subjected to potentially denaturing fluid shear forces during processing and in circulation in the body. These complex molecules, involved in numerous biological functions and reactions, can be significantly impaired by molecular damage. There have been many studies on the effects of hydrodynamic shear forces on protein structure and function. These studies are reviewed and the implications to bioprocessing and pathophysiology of certain diseases are discussed. PMID- 21544799 TI - Downregulation of breast cancer resistance protein in colon adenomas reduces cellular xenobiotic resistance and leads to accumulation of a food-derived carcinogen. AB - Several molecular changes in colorectal adenomas provide the basis of the adenoma carcinoma sequence. We investigated the expression of xenobiotic ATP-binding cassette (ABC) transporters in humans and in ApcMin mice and conducted functional studies estimating the importance of the expression changes. Twenty-nine adenomas from 21 patients and eight adenomas from four ApcMin mice were analyzed using Western blotting and quantitative Real-time polymerase chain reaction (RT-PCR). Adjacent healthy tissue served as control for each polyp. Breast cancer resistance protein (BCRP) was significantly downregulated in human colorectal adenomas (to 28 +/- 35% of adjacent healthy tissue). This was in line with data from ApcMin mice adenomas, where downregulation was significant as well (to 58 +/ 34%). In parallel, quantitative RT-PCR showed BCRP mRNA downregulation in human adenomas (to 17 +/- 31%). Basal multidrug resistance-associated protein 2 expression was low and did not change in adenomas; multidrug resistance transporter 1 expression also did not differ between adenomas and healthy tissue. In a functional study, ApcMin mice received radioactively labelled 2-amino-1 methyl-6-phenylimidazo[4,5-beta] pyridine (PhIP), a food colon carcinogen and substrate of BCRP, by oral gavage with analysis of PhIP accumulation and DNA adduct formation 48 hr later. In this setting, we could demonstrate a higher carcinogen concentration in adenomas of ApcMin mice (181 +/- 113% of normal tissue) including immunohistochemical detection of PhIP-DNA adducts. We conclude that significant transcriptional downregulation of BCRP/Bcrp leads to higher carcinogen concentrations in colorectal adenomas of mice and men. This might promote the adenoma-carcinoma sequence by higher genotoxic effects. The results indicate a possible role of transporter deficiencies in susceptibility for colon carcinoma. PMID- 21544800 TI - VEGFR-2 expression in human melanoma: revised assessment. AB - Vascular endothelial growth factor (VEGF) is an angiogenic factor that also functions as an autocrine growth factor for VEGF receptor (VEGFR)-2(+) melanomas. In multiple studies, VEGFR-2 was detected by immunostaining in 78-89% of human melanoma cells, suggesting that most patients with melanoma would benefit from anti-VEGF therapy. Here, we evaluated 167 human melanoma specimens in a tissue microarray to verify the presence of VEGFR-2, but found disparities in staining with commercial antibodies A-3 and 55B11. Antibody A-3 stained melanoma cells in 79% of specimens, consistent with published results; however, we noted extensive nonspecific staining of other cells such as smooth muscle and histiocytes. In contrast, antibody 55B11 stained melanoma cells in only 7% (95% confidence interval: 3.3-11.5) of specimens. As an internal positive control for VEGFR-2 detection, vascular endothelial cells were stained with antibody 55B11 in all specimens. We compared VEGFR-2(+) and VEGFR-2(-) melanoma cell lines by immunoblotting and immunohistochemistry after small interfering RNA (siRNA) knockdown and transient overexpression of VEGFR-2 to validate antibody specificity. Immunoblotting revealed that A-3 primarily cross-reacted with several proteins in both cell lines and these were unaffected by siRNA knockdown of VEGFR-2. In contrast, 55B11 staining of VEGFR-2(+) cells was mostly eliminated by siRNA knockdown of VEGFR-2 and increased in VEGFR-2(-) melanoma cell lines following transfection to express ectopic VEGFR-2. Our results show that relatively few melanoma cells (<10%) express detectable levels of VEGFR-2, and therefore, the majority of patients with melanoma are unlikely to benefit from antiproliferative effects of anti-VEGF therapy. PMID- 21544801 TI - Functional interrelationship between the WASF3 and KISS1 metastasis-associated genes in breast cancer cells. AB - Loss of WASF3 function in breast cancer cells results in loss of invasion phenotypes and reduced metastatic potential. By using oligonucleotide arrays, we now demonstrate that knockdown of WASF3 leads to the upregulation of the KISS1 metastasis suppressor gene with concomitant reduced invasion and loss of matrix metalloproteinases (MMP)-9 activity. Using a luciferase reporter, KISS1 transcription is significantly increased in the absence of WASF3. Knockdown of KISS1 in WASF3-silenced cells resulted in the recovery of the invasion phenotype. WASF3 knockdown also resulted in elevated IkappaBalpha levels in the cytoplasm and reduced levels of nuclear factor-kappa-B (NF-kappaB) p65/50 subunits in the nucleus. Tumor necrosis factor-alpha (TNF-alpha) has been associated with cell invasion through induction of MMP-9 production via KISS1 regulation of the NF kappaB pathway. When WASF3 knockdown cells are treated with TNF-alpha, no effect is seen on invasion or nuclear translocation of NF-kappaB. Thus, coordinated expression patterns of the WASF3 metastasis promoter gene and the KISS1 metastasis suppressor gene appear to exert their influence through inhibition of NF-kappaB signaling, which in turn regulates MMP-9 production facilitating invasion. PMID- 21544802 TI - Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer. AB - Circulating micro-RNA (miR) profiles have been proposed as promising diagnostic and prognostic biomarkers for cancer, including lung cancer. We have developed methods to accurately and reproducibly measure micro-RNA levels in serum and plasma. Here, we study paired serum and plasma samples from 220 patients with early stage nonsmall cell lung cancer (NSCLC) and 220 matched controls. We use qRT-PCR to measure the circulating levels of 30 different miRs that have previously been reported to be differently expressed in lung cancer tissue. Duplicate RNA extractions were performed for 10% of all samples, and micro-RNA measurements were highly correlated among those duplicates. This demonstrates high reproducibility of our assay. The expressions of miR-146b, miR-221, let-7a, miR-155, miR-17-5p, miR-27a and miR-106a were significantly reduced in the serum of NSCLC cases, while miR-29c was significantly increased. No significant differences were observed in plasma of patients compared with controls. Overall, expression levels in serum did not correlate well with levels in plasma. In secondary analyses, reduced plasma expression of let-7b was modestly associated with worse cancer-specific mortality in all patients, and reduced serum expression of miR-223 was modestly associated with cancer-specific mortality in stage IA/B patients. MiR profiles also showed considerable differences comparing African American and European Americans. In summary, we found significant differences in miR expression when comparing cases and controls and find evidence that expression of let-7b is associated with prognosis in NSCLC. PMID- 21544803 TI - Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? AB - Amiloride.HCl is clinically used as an oral potassium-sparing diuretic, but multiple studies in biochemical, cellular and animal models have shown that the drug also possesses anti-tumour and anti-metastasis activities. The additional effects appear to arise through inhibition of two discrete targets: (i) the sodium-hydrogen exchanger 1 (NHE1), a membrane protein responsible for the characteristically low extracellular pH of tumours and (ii) the urokinase-type plasminogen activator (uPA), a serine protease mediator of cell migration, invasion and metastasis and well-known marker of poor prognosis in cancer. This mini-review summarises for the first time the reported anti-tumour/metastasis effects of amiloride in experimental models, discusses the putative molecular mechanisms responsible for these effects and concludes by commenting on the pros and cons of trialling amiloride or one of its structural analogues as potential new anti-tumour/metastasis drugs. PMID- 21544804 TI - Serum enterolactone and postmenopausal breast cancer risk by estrogen, progesterone and herceptin 2 receptor status. AB - Lignans are a group of estrogenic compounds present in plants. Several epidemiological studies proposed that lignans may protect against breast cancer by exerting anticarcinogenic activity. Levels of enterolactone were determined in serum samples of 1,250 cases and 2,164 controls from a large population-based case-control study. We assessed the association between serum enterolactone and postmenopausal breast cancer risk using conditional logistic regression accounting for potential risk and confounding factors. Fractional polynomials were used to determine the function that best fitted the data. Moreover, we assessed heterogeneity by estrogen/progesterone/herceptin (ER/PR/HER2) status of the tumor. Additionally, a meta-analysis with seven further studies addressing enterolactone concentrations and breast cancer risk was performed. Postmenopausal breast cancer risk decreased with increasing serum enterolactone levels [highest compared to lowest quintile: [odds ratio = 0.65; 95% confidence interval (CI) 0.52-0.83, p(trend) = < 0.0001]. A significant inverse association for ER+/PR+ as well as ER-/PR- tumors was observed, with a significantly stronger association for ER-/PR- tumors (p(heterogeneity) = 0.03). The association for ER-/PR- tumors did not differ by expression of HER2 (p(heterogeneity) = 0.3). The meta-analysis yielded a significant reduced pooled risk estimate of: 0.66; 95% CI: 0.55-0.77) comparing the highest to the lowest quantiles of enterolactone levels. We found strong evidence for a significant inverse association between serum enterolactone and postmenopausal breast cancer risk, which was stronger for ER-PR- than for ER+PR+ tumors but not differential by further expression of HER2. The overall evidence together with other studies supports an inverse association between higher serum enterolactone levels and postmenopausal breast cancer risk. PMID- 21544805 TI - Quinacrine has anticancer activity in breast cancer cells through inhibition of topoisomerase activity. AB - The small molecule Quinacrine (QC, a derivative of 9-aminoacridine), an anti malaria drug, displays activity against cancer cell lines and can simultaneously suppress nuclear factor-kappaB (NF-kappaB) and activate p53 signaling. In this study, we investigated the anticancer mechanism underlying these drug activities in breast cancer cell lines. QC caused a dose-dependent decrease of both anchorage dependent and independent growth of breast cancer cells (MCF-7 and MDA MB-231) without affecting normal breast epithelial cells (MCF-10A), as evident from clonogenic cell survival, [3-(4,5-dimethylthiazol-2yl-)-2,5-diphenyl tetrazolium bromide] viability, wound healing and soft agar growth. QC activated the proapoptotic marker Bax, PARP cleavage, p53 and its downstream target, p21 (Cip1/Waf1) and downregulated the antiapoptotic marker Bcl-xL and relative luciferase activity of NF-kappaB in MCF-7 cells. Results of DAPI nuclear staining and FACS analysis show that QC increased apoptosis in a dose-dependent manner. QC caused apoptosis by increasing the cell population in S-phase and simultaneously decreasing the G1 and G2/M populations. A dose-dependent increase of DNA damage as measured by the comet assay was seen in MCF-7 cells after exposure to QC. With regards to the mechanism of DNA damage, we found that QC inhibited topoisomerase activity in MCF-7 cells by increasing the unwinding of supercoiled DNA. Collectively, the results demonstrate that QC has efficient anticancer potential against breast cancer cells via not only an induction of p53 and p21 but also an induction of S phase arrest, DNA damage and inhibition of topoisomerase activity. PMID- 21544806 TI - Humanized tumor mice--a new model to study and manipulate the immune response in advanced cancer therapy. AB - The immunological impact on antibody-based anticancer therapies remains incompletely understood due to the lack of appropriate animal models for in vivo analysis. Here, we present a novel humanized tumor mouse (HTM) model, generated by concurrent transplantation of human hematopoietic stem cells (HSCs) and human breast cancer cells in neonatal NOD-scid IL2Rgamma(null) mice. Five weeks after intrahepatic transplantation, a functional human immune system was developed in all organs, and, in addition, tumor cells were detectable in lung and bone marrow (early dissemination). After 3 months posttransplant, tumor-cell effusions and macroscopic tumors associated with liver or spleen were found. Furthermore, disseminated cells in different lymphoid and nonlymphoid organs were measurable. Tumor growth was accompanied by specific T-cell maturation and tumor cell specific T-cell activation. In addition, Natural-Killer cell accumulation and activation were observed in HTM, which was further enhanced upon IL-15 treatment facilitating the possibility of immune cell modulation in, e.g., antibody dependent cellular cytotoxicity-based immunotherapeutic approaches. This novel mouse model makes it possible to combine transfer of MHC mismatched tumor cells together with human HSCs resulting in a solid coexistence and interaction without evidence for rejection. Overall, humanized tumor mice represent a powerful in vivo model that for the first time permits the investigation of human immune system-related target cancer therapy and resistance. PMID- 21544807 TI - Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma. AB - Renal clear cell carcinoma (RCCC) is the most frequent subpopulation of renal cell carcinoma and is derived from the proximal uriniferous tubules. We have previously reported that an actin-binding protein, 4.1B/DAL-1, is expressed in renal proximal tubules, whereas it is inactivated in 45% of RCCC by promoter methylation. In the lung and several epithelial tissues, 4.1B is shown to associate with a tumor suppressor protein, CADM1, belonging to the immunoglobulin superfamily cell adhesion molecules. Here, we demonstrate by immunohistochemistry that another member of the CADM-family protein, CADM4, as well as 4.1B is expressed specifically in human proximal tubules, while CADM1 and 4.1N, another member of the 4.1 proteins, are expressed in the distal tubules. Immunoprecipitation analysis coupled with Western blotting revealed that CADM4 associated with 4.1B, while CADM1 associated with 4.1N in the lysate from normal human kidney, implicating that a cascade of CADM4 and 4.1B plays an important role in normal cell adhesion of the proximal tubules. On the other hand, CADM4 expression was lost or markedly reduced in 7 of 10 (70%) RCC cell lines and 28 of 40 (70%) surgically resected RCCC, including 10 of 16 (63%) tumors with T1a. CADM4 expression was more preferentially lost in RCCC with vascular infiltration (p = 0.04), suggesting that loss of CADM4 is involved in tumor invasion. Finally, introduction of CADM4 into an RCC cell line, 786-O, dramatically suppressed tumor formation in nude mice. These findings suggest that CADM4 is a novel tumor suppressor candidate in RCCC acting with its binding partner 4.1B. PMID- 21544808 TI - Body fat distribution, weight change during adulthood, and thyroid cancer risk in the NIH-AARP Diet and Health Study. AB - Body mass index (BMI) has been positively associated with thyroid cancer risk in several studies, but the underlying mechanisms remain unclear. We examined the associations for waist and hip circumference and weight change during adulthood with thyroid cancer risk among 125,347 men and 72,363 women in the NIH-AARP Diet and Health Study who completed a second mailed questionnaire in 1996-1997. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated separately by sex and adjusted for race/ethnicity, education and smoking status. During follow-up (median = 10.1 years), 106 men and 105 women were diagnosed with a first primary thyroid cancer, as identified through linkage to state cancer registries. Having a large waist circumference (above the clinical cutpoint for normal: > 102 cm in men and > 88 cm in women) was associated with increased risk in both men (HR = 1.79, 95% CI: 1.21-2.63) and women (HR = 1.54, 95% CI: 1.05-2.26). Having both a large waist and BMI in the obese range (>= 30 kg/m2) approximately doubled the risk of thyroid cancer (HR in men = 2.13, 95% CI: 1.18-3.85; HR in women = 1.91, 95% CI: 1.31-3.25) compared to having a normal waist circumference/normal BMI (18.5-24.9 kg/m2). We also observed positive association for weight gain between ages 18-35 in men (gained >= 10.0 kg vs. lost/gained < 5 kg, HR = 1.49, 95% CI: 0.93-2.39, p-trend = 0.03), but the association was less pronounced in women. No clear association for weight gain in later life was observed. These results support a potential role for hormonal and metabolic parameters common to central adiposity in thyroid carcinogenesis. PMID- 21544809 TI - Genetic variability in the metabolism of the tobacco-specific nitrosamine 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol (NNAL). AB - Urinary metabolites of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1 (3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, termed total NNAL, have recently been shown to be good predictors of lung cancer risk, years before diagnosis. We sought to determine the contribution of several genetic polymorphisms to total NNAL output and inter-individual variability. The study subjects were derived from the Harvard/Massachusetts General Hospital Lung cancer case-control study. We analyzed 87 self-described smokers (35 lung cancer cases and 52 controls), with urine samples collected at time of diagnosis (1992-1996). We tested 82 tagging SNPs in 16 genes related to the metabolism of NNK to total NNAL. Using weighted case status least squares regression, we tested for the association of each SNP with square-root (sqrt) transformed total NNAL (pmol per mg creatinine), controlling for age, sex, sqrt packyears and sqrt nicotine (ng per mg creatinine). After a sqrt transformation, nicotine significantly predicted a 0.018 (0.014, 0.023) pmol/mg creatinine unit increase in total NNAL for every ng/mg creatinine increase in nicotine at p < 10E-16. Three HSD11B1 SNPs and AKR1C4 rs7083869 were significantly associated with decreasing total NNAL levels: HSD11B1 rs2235543 (p = 4.84E-08) and rs3753519 (p = 0.0017) passed multiple testing adjustment at FDR q = 1.13E-05 and 0.07 respectively, AKR1C4 rs7083869 (p = 0.019) did not, FDR q = 0.51. HSD11B1 and AKR1C4 enzymes are carbonyl reductases directly involved in the single step reduction of NNK to NNAL. The HSD11B1 SNPs may be correlated with the functional variant rs13306401 and the AKR1C4 SNP is correlated with the enzyme activity reducing variant rs17134592, L311V. PMID- 21544810 TI - Variations in sex hormone metabolism genes, postmenopausal hormone therapy and risk of endometrial cancer. AB - We investigated whether variants in sex steroid hormone metabolism genes modify the effect of hormone therapy (HT) on endometrial cancer risk in postmenopausal non-Hispanic white women. A nested case-control study was conducted within the California Teachers Study (CTS). We genotyped htSNPs in six genes involved in the hormone metabolism in 286 endometrial cancer cases and 488 controls. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each haplotype using unconditional logistic regression, adjusting for age. The strongest interaction was observed between duration of estrogen therapy (ET) use and haplotype 1A in CYP11A1 (p(interaction) = 0.0027; p(interaction) = 0.010 after correcting for multiple testing within each gene). The OR for endometrial cancer per copy of haplotype 1A was 2.00 (95% CI: 1.05-3.96) for long-term ET users and 0.90 (95% CI: 0.69-1.18) for never users. The most significant interaction with estrogen progestin therapy (EPT) was found for two haplotypes on CYP19A1 and EPT use (haplotype 4A, p(interaction) = 0.024 and haplotype 3B, p(interaction) = 0.043). However, neither this interaction, nor the ET or EPT interactions for any other genes, was statistically significant after correction for multiple testing. Variations in CYP11A1 may modify the effect of ET use on risk of postmenopausal endometrial cancer; however, larger studies are needed to explore these findings further. PMID- 21544812 TI - Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. AB - In recent years, increasing evidence has suggested a strong association between diabetes mellitus (DM) and hepatocellular carcinoma (HCC). To provide a quantitative assessment of this association, we performed a systematic review and meta-analysis of cohort studies. We collected studies through a literature search of Medline from January 1, 1966 and EMBASE from January 1, 1974, through July 31, 2010. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. A total of 25 cohort studies that met our inclusion and exclusion criteria were included in our analysis. Among these, 18 studies showed that DM was associated with an increased incidence of HCC (SRRs = 2.01, 95% CI: 1.61-2.51), compared with individuals without DM. There was a statistically significant heterogeneity among these studies (Q = 136.68, p < 0.001, I(2) = 87.6%). Analyses subgrouped by controlling confounders revealed that the increased incidence of HCC was independent of geographic location, alcohol consumption, history of cirrhosis, or infections with hepatitis B (HBV) or hepatitis C virus (HCV). In addition, DM was also positively associated with HCC mortality (SRR = 1.56; 95% CI: 1.30-1.87), with no significant evidence of heterogeneity among studies (Q = 1.16, p = 0.56, I(2) =0%). There were no significant publication bias (p = 0.79 for Egger's regression asymmetry test). These findings strongly support a positive association between DM and increased risk of HCC in both males and females. PMID- 21544811 TI - Oncogenic KRAS-induced interleukin-8 overexpression promotes cell growth and migration and contributes to aggressive phenotypes of non-small cell lung cancer. AB - The CXC chemokine interleukin-8 (IL-8) is an angiogenic growth factor that is overexpressed in various cancers, including non-small cell lung cancer (NSCLC). Previously, IL-8 was shown as a transcriptional target of RAS signaling, raising the possibility of its role in oncogenic KRAS-driven NSCLC. Using microarray analysis, we identified IL-8 as the most downregulated gene by shRNA-mediated KRAS knockdown in NCI-H1792 NSCLC cells where IL-8 is overexpressed. NSCLC cell lines harboring KRAS or EGFR mutations overexpressed IL-8, while IL-8 levels were more prominent in KRAS mutants compared to EGFR mutants. IL-8 expression was downregulated by shRNA-mediated KRAS knockdown in KRAS mutants or by treatment with EGFR tyrosine kinase inhibitors and EGFR siRNAs in EGFR mutants. In our analysis of the relationship of IL-8 expression with clinical parameters and mutation status of KRAS or EGFR in 89 NSCLC surgical specimens, IL-8 expression was shown to be significantly higher in NSCLCs of males, smokers, and elderly patients and those with pleural involvement and KRAS mutated adenocarcinomas. In KRAS mutant cells, the MEK inhibitor markedly decreased IL-8 expression, while the p38 inhibitor increased IL-8 expression. Attenuation of IL-8 function by siRNAs or a neutralizing antibody inhibited cell proliferation and migration of KRAS mutant/IL-8 overexpressing NSCLC cells. These results indicate that activating mutations of KRAS or EGFR upregulate IL-8 expression in NSCLC; IL-8 is highly expressed in NSCLCs from males, smokers, elderly patients, NSCLCs with pleural involvement, and KRAS-mutated adenocarcinomas; and IL-8 plays a role in cell growth and migration in oncogenic KRAS-driven NSCLC. PMID- 21544813 TI - Aryl hydrocarbon receptor nuclear translocator is associated with tumor growth and progression of hepatocellular carcinoma. AB - bHLH/PAS proteins play important roles in tumor progression. Lost or reduced expression of single-minded homolog 2 (SIM) as well as aryl hydrocarbon receptor repressor (AHRR) has been observed in cancerous human tissues. Here, we investigated the role of aryl hydrocarbon receptor nuclear translocator (ARNT), another bHLH/PAS protein, in hepatocellular carcinoma (HCC). Using tissue microarray and immunohistochemistry, we found that intratumoral ARNT was inversely correlated with time to recurrence and overall survival of HCC patients after resection. Knockdown of ARNT in HepG2, HCCLM3 and HCCLM6 cells significantly shortened cell doubling time, increased S-phase cell populations and accelerated in vivo HCCLM6 growth and metastasis. After ARNT expression was rescued, prolonged cell doubling time and decreased S-phase cell populations were observed in HepG2, HCCLM3 and HCCLM6 cells. And, HCCLM6 growth and metastasis in vivo were remarkably inhibited. Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC. According to the results of immunoprecipitation assay, both ARNT/ARNT and ARNT/AHRR complexes were clearly formed in HCCLM6 xenograft with increased ARNT expression. In summary, ARNT is an important regulator of HCC growth and metastasis and could be a promising prognostic candidate in HCC patients. PMID- 21544814 TI - Candidate driver genes in microsatellite-unstable colorectal cancer. AB - Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in ~ 15% of all colorectal cancers (CRCs). Microsatellite mutations that drive tumourigenesis, typically inactivation of tumour suppressors, are selected for and are frequently detected in MSI cancers. Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6-10 bp in length. All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were identified in >20%, additional 70 samples were sequenced. To distinguish driver mutations from passengers, we similarly analyzed the occurrence of frameshift mutations in 121 intronic control repeats and utilized a statistical regression model to determine cut-off mutation frequencies for repeats of all types (A/T and C/G, 6-10 bp). Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9 of ABCC5, 43% in G8 of WDTC1, 33% in A8 of ROCK1, 30% in T8 of OR51E2, and 28% in A8 of TCEB3. Immunohistochemical staining of GLYR1 revealed defective protein expression in tumors carrying biallelic mutations, supporting a loss of function hypothesis. This is a large scale, unbiased effort to identify genes that when mutated are likely to contribute to MSI CRC development. PMID- 21544815 TI - Targeting of pancreatic and prostate cancer stem cell characteristics by Crambe crambe marine sponge extract. AB - Cancer stem cells (CSCs) are suggested as reason for resistance of tumors toward conventional tumor therapy including pancreatic and advanced prostate cancer. New therapeutic agents are urgently needed for targeting of CSCs. Marine sponges harbor novel and undefined compounds with antineoplastic activity but their potential to eliminate CSC characteristics is not examined so far. We collected 10 marine sponges and one freshwater sponge by diving at the seaside and prepared crude methanolic extracts. The effect to established pancreatic and prostate CSC lines was evaluated by analysis of apoptosis, cell cycle, side population, colony and spheroid formation, migratory potential in vitro and tumorigenicity in vivo. While each sponge extract at a 1:10 dilution efficiently diminished viability, Crambe crambe marine sponge extract (CR) still strongly reduced viability of tumor cells at a dilution of 1:1,000 but was less toxic to normal fibroblasts and endothelial cells. CR inhibited self-renewal capacity, apoptosis resistance, and proliferation even in gemcitabine-selected pancreatic cancer cells with acquired therapy resistance and enhanced CSC characteristics. CR pretreatment of tumor cells diminished tumorigenicity of gemcitabine-resistant tumor cells in mice and totally abolished tumor take upon combination with gemcitabine. Our data suggest that CR contains substances, which render standard cancer therapy more effective by targeting of CSC characteristics. Isolation of bioactive metabolites from CR and evaluation in mice are required for development of new CSC-specific chemotherapeutic drugs from a marine sponge. PMID- 21544816 TI - Clinical use of nomograms for breast cancer. PMID- 21544817 TI - A nomogram predicting the probability of primary breast cancer survival at 2- and 5-years using pathological and biological tumor parameters. AB - PURPOSE: Our objective was to develop a nomogram to predict individual overall survival (OS) for primary breast cancer, based on pathological and biological tumor parameters. METHODS: A retrospective study in a cohort of 180 patients with primary breast cancer was used to build the nomogram. Pathological factors and tumor proteases measured prospectively in primary tumors were used. A multivariate Cox proportional hazards model was used to explore the relationship with OS, and regression coefficients were used to build the nomogram. The nomogram was internally validated with 200 bootstrap re-samples. RESULTS: The final variables included in the nomogram comprised tumor size (P = 0.04), nodal pathological status (P = 0.01), estrogen receptor status (P = 0.04), urokinase plasminogen activator inhibitor-1 (PAI-1; P = 0.02), thymidine kinase (P = 0.03), and cathepsin D (P = 0.004). The predictive accuracy of the nomogram at estimating the probability of OS, at both 2 and 5 years, was respectively 0.874 and 0.832 before and after calibration. CONCLUSION: A nomogram to predict 2- and 5-year OS in BC, using histological and biological parameters was successfully developed. This prognostic tool should prove useful in decision-making and therapeutic research. PMID- 21544818 TI - The development of a brief acceptance and mindfulness-based program aimed at reducing sexual revictimization among college women with a history of childhood sexual abuse. AB - Women with a history of childhood sexual assault (CSA) are more likely to be revictimized; however, most existing programs aimed at reducing sexual victimization do not expressly address the issue of revictimization. The present study examined the efficacy of a brief mindfulness-based program in reducing rates of sexual assault and revictimization in college women over the course of an academic semester. Although the results were not statistically significant, a large-magnitude effect was noted, whereby women with a history of CSA who participated in the program were less likely to be sexually assaulted and raped at 2-month follow-up. PMID- 21544819 TI - Cast lipid implants for controlled drug delivery: importance of the tempering conditions. AB - Lipid implants prepared by melting and casting offer a great potential for advanced drug delivery. However, care must be taken with respect to the solid state of the lipid(s) and potential changes thereof during storage. Generally, a thermal aftertreatment is required. However, little is known about the impact of the curing time and temperature on drug release. The aim of this study was to better understand the importance of these parameters for different types of implants containing propranolol hydrochloride. Hydrogenated cottonseed oil and hydrogenated soybean oil were used as matrix formers. The implants were characterized with respect to their in vitro release kinetics, water uptake, thermal properties, and morphology. On the basis of these experimental results, a mechanistic mathematical model was used to gain further insight into the underlying mass transport mechanisms. Both the curing time and the temperature strongly affected the resulting drug release patterns. Importantly, in most cases, these effects could not be attributed to polymorph transformations but to changes in the implants' microstructure. The size of the lipid particles depended on both the curing time and the temperature, and determined the size of the pores/channels through which water and drug diffuse. The importance of this aspect is often underestimated. PMID- 21544820 TI - Reliability and robustness of simultaneous absolute quantification of drug transporters, cytochrome P450 enzymes, and Udp-glucuronosyltransferases in human liver tissue by multiplexed MRM/selected reaction monitoring mode tandem mass spectrometry with nano-liquid chromatography. AB - Mass spectrometry (MS)-based multiplexed multiple reaction monitoring quantification of proteins has recently evolved as a versatile tool for accurate, absolute quantification of proteins. The purpose of this study was to examine the validity of the present method with regard to standard bioanalytical criteria for drug transporters, cytochrome P450 (CYP) enzymes and uridine 5'-diphospho glucuronosyltransferases (UGTs). Membrane preparations from human liver tissue were used for target protein quantification. As a result, the determination coefficients (r(2)) of all targets were greater than 0.986. In the absence of matrix, inaccuracy values (expressed as % deviation) were -8.1% to 20.3%, whereas imprecision values (expressed as % coefficient of variation) were within 15.9%. In the presence of matrix, which consisted of digested plasma membrane fraction for transporters and digested microsomal membrane fraction for CYP enzymes and UGTs, respectively, the inaccuracy was -15.3%-8.1%, and the imprecision were within 18.9%. Sufficient sample stability of membrane fraction was shown for three freeze-thaw cycles, 32 days at -20 degrees C, and in processed samples for 7 days at 10 degrees C. In conclusion, this study demonstrated, for the first time, that the MS-based assay with nano-liquid chromatography provides adequate reliability and robustness for the quantification of selected drug transporters, P450 enzymes and UGTs. PMID- 21544821 TI - Two-dimensional pH mapping of release kinetics of silica-encapsulated drugs. AB - The encapsulation of pharmaceutical drug molecules in silica gels during the sol gel synthesis and their kinetic release profile in aqueous solutions were systematically investigated in dependence of synthesis pH(S) and extraction pH(E) values. Six pH values in the range from 1 to 6 were chosen in a 6 * 6 two dimensional matrix to screen the first-order initial dissolution rate constant and the total amount of released drug. Characteristic differences are discovered in such two-dimensional pH mapping profiles for the molecules with different ionization behavior and they are explained by surface imprinting and encapsulation processes. Remarkably, these encapsulations must occur either in the particles of the sol solutions or during the rapid liquid-solid transition of the spray-drying process employed in this study. This pH mapping method is suggested as a novel tool to probe noncovalent imprinting and encapsulation processes in sol-gel-derived materials with embedded guest molecules. PMID- 21544822 TI - Formulation optimization of estradiol microemulsion using response surface methodology. AB - The aim of the current study was to find an optimal estradiol-loaded microemulsion with higher permeation rate and shortened lag time (LT) for transdermal application by using a response surface methodology (RSM) and constrained mixture design. Isopropyl myristate (X1 ), distilled water (X2 ), and ethanol (X3 ) were selected as independent variables, whereas the viscosity of microemulsion and permeation parameters including the cumulative amount at 24 h (Q24h ) and LT of estradiol-loaded microemulsion through skin were set as dependent variables. The result showed that the three independent variables had a remarkable effect (p < 0.05) on the dependent variables. Moreover, the predicted and observed values of these three dependent variables of the optimal microemulsion formulations, which were produced by the RSM optimization technique, were close, demonstrating that RSM was a useful technique for optimizing pharmaceutical formulations. However, the experimental estradiol loaded microemulsion with higher permeation rate was expected to provide effective therapeutic concentration in a workable administration area. PMID- 21544823 TI - A randomized, quadruple crossover single-blind study on immediate action of chewed and unchewed low-dose acetylsalicylic acid tablets in healthy volunteers. AB - In the initial treatment of acute myocardial infarction, it is important to administer oral low-dose acetylsalicylic acid (ASA) within 10 min of arrival at the hospital. However, ASA is supplied as an enteric-coated tablet or buffered tablet to prevent gastric irritation. Although current guidelines recommended that patients should chew their initial dose of ASA, there is little evidence as to whether this is efficacious. Therefore, we aimed to make a direct comparison of the pharmacokinetics and pharmacodynamics of ASA after ingestion of intact and chewed nonenteric-coated buffered ASA tablet (NBA) and enteric-coated ASA tablet (ECA) in a quadruple crossover study in healthy volunteers. Chewing ECA accelerated t(max) of ASA absorption, which became equivalent to that after ingestion of intact or chewed NBA. A significant decrease in serum thromboxane B(2) was observed 20 min after ingestion of chewed ECA, or intact or chewed NBA, and inhibition of platelet aggregation was also observed within 20 min. Thus, chewing of the ECA appears to result in a similar timing of ASA action to that in the case of chewed or unchewed NBA. PMID- 21544824 TI - Preclinical prediction of human brain target site concentrations: considerations in extrapolating to the clinical setting. AB - The development of drugs for central nervous system (CNS) disorders has encountered high failure rates. In part, this has been due to the sole focus on blood-brain barrier permeability of drugs, without taking into account all other processes that determine drug concentrations at the brain target site. This review deals with an overview of the processes that determine the drug distribution into and within the CNS, followed by a description of in vivo techniques that can be used to provide information on CNS drug distribution. A plea follows for the need for more mechanistic understanding of the mechanisms involved in brain target site distribution, and the condition-dependent contributions of these mechanisms to ultimate drug effect. As future direction, such can be achieved by performing integrative cross-compare designed studies, in which mechanisms are systematically influenced (e.g., inhibition of an efflux transporter or induction of pathological state). With the use of advanced mathematical modeling procedures, we may dissect contributions of individual mechanisms in animals as links to the human situation. PMID- 21544825 TI - Pancreatic splenosis demonstrated by contrast-enhanced sonography. AB - Pancreatic splenosis is a very rare condition whose features on contrast-enhanced ultrasound (CEUS) have not, to our knowledge, been previously reported. We present the imaging findings in a case of pancreatic splenosis, in which a confident diagnosis was achieved with the use of CEUS and confirmed by a labeled heat denatured red cell scan. Accumulation of ultrasound contrast microbubbles in splenic tissue can be readily visualized on late-phase CEUS and this technique has already been used to confirm the nature of intrapancreatic accessory spleens. This case shows that it can also confirm the diagnosis of splenosis. PMID- 21544826 TI - Evolution of sonographic findings in a fetus with ileal atresia. AB - We report a case of a meconium pseudocyst secondary to ileal atresia and midgut volvulus. Initially, a single anechoic cyst was detected on prenatal sonography. The cyst gradually increased in size during the second trimester and eventually appeared as a large mass in the lower abdomen with echogenic content and associated with bowel dilatation. This case indicates that until the mid third trimester a single sonolucent cyst without signs of bowel obstruction may be associated with congenital intestinal obstruction. PMID- 21544827 TI - Characterization of nontraumatic focal splenic lesions using contrast-enhanced sonography. AB - PURPOSE: To compare contrast-enhanced sonography (CEUS) with contrast-enhanced CT in the assessment of nontraumatic focal lesions of the spleen. METHODS: CEUS and CT findings in 22 patients with fever of unknown origin and ultrasound-detected splenic focal lesions were analyzed retrospectively. CEUS was performed using an ultrasound unit equipped with a 3.6-MHz probe and contrast-specific software. A 4 ml bolus of second-generation contrast medium was used. The CEUS examinations included a 4-minute recording following injection of the contrast medium. MRI, splenic biopsy, or ultrasound follow-up were used if findings from CT were inconclusive. RESULTS: The final diagnoses were as follows: seven splenic infarcts, five hemangiomas, three lacerations, two benign cysts, one lymphoma, one granuloma, one abscess, and two lesions of unknown etiology. CEUS and CT had the same specificity (77.2%). Both CEUS and CT failed to characterize nodular hypovascular lesions with a hypoenhancing pattern. CONCLUSIONS: CEUS is as effective as CT for characterizing nontraumatic focal lesions of the spleen. If CEUS findings are consistent with a benign splenic lesion, CT seems to be of limited additional value. PMID- 21544828 TI - Sonographic measurement of cervical volume in nonpregnant women using the geometric formula for a cylinder versus the three-dimensional automated virtual organ computer-aided analysis (vocal). AB - BACKGROUND: To sonographically evaluate the volume of uterine cervix in nonpregnant women with use of the geometric formula for a cylinder and to assess agreement with the reference Virtual Organ Computer-Aided AnaLysis (VOCAL) method. METHODS: Three-dimensional ultrasound volume datasets of the uterine cervix from 81 women were obtained prospectively within a 1-year period. Volume measurements were performed using VOCAL and the geometric formula for a cylinder. Reliability was evaluated using intraclass correlation coefficient and Bland Altman plots were produced to examine intermethod agreement. Time needed to perform measurements was compared with Student's t test. RESULTS: There was good agreement between VOCAL and the geometric formula for a cylinder (mean percentage difference, -0.78%; 95% limits of agreement, -17.59-16.03%). Measurements made by the formula for a cylinder were slightly greater than VOCAL by a mean (+/-SE) of 0.78% (+/-0.95%). A high degree of reliability was observed between the two methods (intraclass correlation coefficient, 0.97; 95%CI, 0.95-0.98). Cervical volume estimation with the geometric formula for a cylinder was faster to obtain. CONCLUSIONS: This method comparison study shows that the geometric formula for a cylinder has good agreement with VOCAL and can determine the volume of the cervix in a faster way. PMID- 21544829 TI - Renal venous doppler ultrasonography in normal subjects and patients with diabetic nephropathy: value of venous impedance index measurements. AB - OBJECTIVES: To provide reference values of intrarenal venous impedance index (VII) measured with duplex Doppler ultrasonography in a healthy adult population and to assess the usefulness this index for evaluating the functional status of kidney in patients with diabetic nephropathy (DN). METHODS: Between May 2005 and December 2009, Doppler ultrasonography of both kidneys was performed in 164 healthy volunteers (controls) and 58 patients with DN. Renal interlobar and segmental vein Doppler waveforms and VII were obtained and compared between groups using the Student's t test. Correlation between VII and serum creatinine concentration (SCC) was calculated. RESULTS: In controls, the mean VII was lower in interlobar than in segmental renal veins (p < 0.01), without difference between the right and left kidneys. Waveform modulation was dampened in DN patients whose mean VII (0.32 +/- 0.18) was lower than in controls (0.38 +/- 0.18) (p < 0.01). SCC showed moderate correlations (r = 0.65) with intrarenal VII in the patient group. CONCLUSIONS: Renal VII is typically lower in DN than in controls and moderately correlated with SCC, which reflects renal function in DN, but does not offer a significant advantage over arterial resistance index. PMID- 21544830 TI - Assessment of right atrial pressure using echocardiography and correlation with catheterization. AB - PURPOSE: Right ventricular systolic pressure is crucial for both treatment and prognosis of cardiovascular and pulmonary diseases. The proper measurement of right ventricular systolic pressure depends on an accurate estimation of right atrial pressure (RAP). There is no standard method for estimating RAP noninvasively. The purpose of this study was to compare different noninvasive methods, namely, inferior vena cava (IVC) size and inspiratory collapse, tissue Doppler derived E/E' (TV E/E') for estimating RAP, and their correlation with catheter-based measurements in patients with mitral valve stenosis with atrial fibrillation (AF) or normal sinus rhythm (NSR). METHODS: The study group consisted of 39 patients (13 men, mean age 58.9 +/- 11.8 years) with rheumatic mitral valve stenosis. We performed cardiac catheterization and transthoracic echocardiography on all patients. RESULTS: Mean RAP measured by catheterization was 9.7 +/- 3.8 mmHg. No correlation was found between RAP and TV E/E' ratio, but there was a significant correlation between RAP and IVC diameter (r = 0.51, p < 0.05). Seventeen patients (43.6%) were in AF and 22 patients (56.4%) were in NSR. There was no correlation between TV E/E' ratio and RAP in patients with AF and in patients with NSR. RAP was correlated with collapsibility index in patients with AF (r = 0.56, p < 0.05). RAP was significantly correlated with IVC diameter (r = 0.62, p < 0.005) and collapsibility index (r = 0.49, p < 0.05) in patients with NSR. CONCLUSIONS: The combination of IVC diameter and collapsibility index is a simple a semiquantitative approach that might provide a better estimation of RAP. PMID- 21544831 TI - Developmental associations between externalizing behaviors, peer delinquency, drug use, perceived neighborhood crime, and violent behavior in urban communities. AB - This study examines the precursors of violent behavior among urban, racial/ethnic minority adults. Data are from an on-going study of male and female African Americans and Puerto Ricans, interviewed at four time waves, Time 1-Time 4 (T1 T4), from adolescence to adulthood. Structural Equation Modeling was used to analyze the developmental pathways, beginning in mid-adolescence (T1; age = 14.0 years), to violent behavior in adulthood (T4; age = 29.2 years). The variables assessed were: components of externalizing behaviors (i.e., rebelliousness, delinquency; T1, T3); illicit drug use (T2); peer delinquency (T2); perceived neighborhood crime (T4); and violent behavior (T3, T4). Results showed that the participants' externalizing behaviors (rebelliousness and delinquency) were relatively stable from mid-adolescence (T1; age = 14.0 years) to early adulthood (T3; age = 24.4 years). The participants' externalizing behaviors in mid adolescence also had a direct pathway to peer delinquency in late adolescence (T2; age = 19.1 years). Peer delinquency, in turn, had a direct pathway to the participants' illicit drug use in late adolescence (T2), and to externalizing behaviors in early adulthood (T3). The participants' illicit drug use (T2; age = 19.1 years) had both direct and indirect paths to violent behavior in adulthood (T4). The participants' externalizing behaviors in early adulthood (T3) were linked with violent behavior at T3, and perceived neighborhood crime (T4), both of which had direct pathways to violent behavior in adulthood (T4). The findings suggest developmental periods during which externalizing behaviors, exposure to delinquent peers, illegal drug use, and neighborhood crime could be targeted by prevention and intervention programs in order to reduce violent behavior. PMID- 21544832 TI - Label-free discrimination of normal and fibroadenomal breast tissues using second harmonic generation imaging. AB - Early detection of fibroadenoma (FA) is critical for preventing subsequent breast cancer. In this work, we show that label-free second harmonic generation (SHG) imaging is feasible and effective in quantitatively differentiating the fibroadenomal tissue from normal breast tissue. With the advent of the clinical portability of miniature SHG microscopy, we believe that the technique has great potential in offering a noninvasive in vivo imaging tool for early detection of FA and monitoring the treatment responses of FA in clinics. PMID- 21544835 TI - Electro- and liquid phase-separations. Part II. PMID- 21544836 TI - Therapeutic plasma proteins--application of proteomics in process optimization, validation, and analysis of the final product. AB - An overview is given on the application of proteomic technology in the monitoring of different steps during the production of therapeutic proteins from human plasma. Recent advances in this technology enable the use of proteomics as an advantageous tool for the validation of already existing processes, the development and fine tuning of new production steps, the characterization and quality control of final products, the detection of both harmful impurities and modifications of the therapeutic protein and the auditing of batch-to-batch variations. Further, use of proteomics for preclinical testing of new products, which can be either recombinant or plasma-derived, is also discussed. PMID- 21544837 TI - Lectin-based structural glycomics: a practical approach to complex glycans. AB - Glycans exist in nature in various forms of glycoconjugates, i.e., glycoproteins, glycolipids, and glycosaminoglycans, either in soluble or membrane-bound forms. One of their prominent properties distinguished from nucleic acids and proteins is "heterogeneity" largely attributed to their inherent features of biosynthesis. In general, various methods based on the physicochemical principles have been taken for their separation and structural determination although all of them require prior liberation of glycans and appropriate labeling. On the other hand, a series of carbohydrate-binding proteins, or "lectins," have extensively been used in a more direct manner for cell typing, histochemical staining, and glycoprotein fractionation. Although most procedures conventionally used are useful, unfortunately they lack "throughput" comparable to a performance required for current omics studies. Recently, a novel technique called lectin microarray has attracted increasing attention from not only glycoscientists but also researchers in other fields, because it is straightforward and also informative. The method is innovating in that it enables direct approach to glycoconjugates such as glycoproteins and even cells without liberation of glycans from the core substrate, and therefore can be effectively applied for the sake of differential profiling in various fields. Concept, strategy, and technical advancement of lectin microarray are described. Also, as an introduction to glycomics, the authors explain the motivation to challenge this theme. PMID- 21544838 TI - Ion-permeable membrane for on-chip preconcentration and separation of cancer marker proteins. AB - Cancer marker proteins have been electrophoretically concentrated and then separated in a microfluidic device. On-chip preconcentration was achieved using an ion-permeable membrane, consisting of acrylamide, N,N'-methylene-bisacrylamide and 2-(acrylamido)-2-methylpropanesulfonate. This negatively charged membrane was photopolymerized in the microdevice near the injection intersection. Anionic proteins were excluded from the porous membrane based on both size and charge, which concentrated target components in the injection intersection prior to separation by microchip capillary electrophoresis (MU-CE). Bovine serum albumin was used in the initial characterization of the system and showed a 40-fold enrichment in the MU-CE peak with 4 min of preconcentration. Adjustment of buffer pH enabled baseline resolution of two cancer biomarkers, alpha-fetoprotein (AFP) and heat shock protein 90 (HSP90), while fine control over preconcentration time limited peak broadening. Our optimized preconcentration and MU-CE approach was applied to AFP and HSP90, where enrichment factors of >10-fold were achieved with just 1 min of preconcentration. Overall, the process was simple and rapid, providing a useful tool for improving detection in microscale systems. PMID- 21544839 TI - Comparative NMR and MS studies on the mechanism of enantioseparation of propranolol with heptakis(2,3-diacetyl-6-sulfo)-beta-cyclodextrin in capillary electrophoresis with aqueous and non-aqueous electrolytes. AB - In our recent studies, the reversal of the enantiomer migration order (EMO) was observed with heptakis (2,3-dimethyl-6-sulfo)-beta-CD (HDMS-beta-CD) when aqueous electrolyte was changed with nonaqueous electrolyte in CE. One-dimensional rotating frame nuclear Overhauser effect spectroscopy experiments prevailed that an inclusion complex was formed between the analyte and the chiral selector in the aqueous buffer, whereas an external complex resulted when a methanolic electrolyte was employed. In the case of the similarly substituted heptakis (2,3 diacetyl-6-sulfo)-beta-CD (HDAS-beta-CD), the external complex was observed in the aqueous buffer but an inclusion complex was formed in methanolic electrolyte. In contrast to heptakis (2,3-dimethyl-6-sulfo)-beta-CD, no reversal of the enantiomer migration order was observed with HDAS-beta-CD. In the present study, further mechanisms of enantioselective recognition and separation of propranolol enantiomers with HDAS-beta-CD were investigated by using different techniques of nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. To the best of our knowledge, enantioselective nuclear Overhauser effect was observed for the first time in this study. PMID- 21544840 TI - Incorporation of guanosine gels into sieving matrices for length- and sequence based separation of DNA in capillary electrophoresis. AB - Sieving gels are used in capillary gel electrophoresis to resolve DNA strands of different lengths. For complex samples, however, such as those encountered in metagenomic analysis of microbial communities or biofilms, length-based separation may mask the true genetic diversity of the community since different organisms may contribute same-length DNA with different sequences. There is a need, therefore, for DNA separations based on both the length and sequence. Previous work has demonstrated the ability of guanosine gels (G-gels) to separate four single-stranded DNA 76-mers that differ by only a few A/G base substitutions. The goal of the present work is to determine whether G-gels could be combined with commercial sieving gels in order to simultaneously separate DNA based on both length and sequence. The results are given for the four 76-mers and for a standard dsDNA ladder. Commercial sieving gels were used alone and in combination with G-gels. For the 76-mers, the combined medium was less efficient than the G-gel alone but was able to achieve partial resolution. The combined medium was at least as effective as the sieving gel alone at resolving the denatured DNA ladder and showed indications of sequence-based resolution as well, as supported by MALDI-MS. The results show that the combined sieving gel/G-gel medium retains the selectivity of the individual media, providing a promising approach to simultaneous length- and sequence-based DNA separation for metagenomic analysis of complex systems. PMID- 21544841 TI - Molecular dynamics simulations of ionic and nonionic surfactant micelles with a generalized Born implicit-solvent model. AB - In recent years, all-atom and coarse-grained models have been developed and applied to simulations of micelles and biological membranes. Here, we explore the question of whether a combined all-atom representation of surfactant molecules and continuum description of solvent based on the generalized Born model can be used to study surfactant micelles. Specifically, we report the parameterization of the GBSW model with a surface-area dependent nonpolar solvation energy term for dodecyl sulfate, dodecyl tetramethylammonium, and dodecyl triethyleneglycol ether molecules. In the parameterization procedure,the atomic Born radii were derived from the radial distribution functions of solvent charge and refined targeting the potential of mean force of dimer interactions from explicit-solvent simulations. The optimized radii were then applied in molecular dynamics simulations of the ionic and nonionic micelles.We found that the micelles are stable but more compact and rigid than in explicit solvent as a consequence of the drastic reduction in solvation and mobility of surfactant monomers within the micelle. Based on these data and our previous work, we suggest that in addition to a more accurate description of the nonpolar solvation energy, the ruggedness in the short-range interactions due to solvent granularity is a critical feature that needs to be taken into account to accurately model processes such as micelle formation and protein folding in implicit solvent. Finally, the explicit-solvent data presented here offers new insights into different conformational behavior of ionic and nonionic micelles which is valuable for understanding hydrophobic assemblies and of interest to the detergent industry. PMID- 21544842 TI - Human cognitive performance in a 3 mT power-line frequency magnetic field. AB - Extremely low frequency (ELF, <300 Hz) magnetic fields (MF) have been reported to modulate cognitive performance in humans. However, little research exists with MF exposures comparable to the highest levels experienced in occupations like power line workers and industrial welders. This research aims to evaluate the impact of a 60 Hz, 3 mT MF on human cognitive performance. Ninety-nine participants completed the double-blind protocol, performing a selection of psychometric tests under two consecutive MF exposure conditions dictated by assignment to one of three groups (sham/sham, MF exposure/sham, or sham/MF exposure). Data were analyzed using a 3 * 2 mixed model analysis of variance. Performance between repetitions improved in 11 of 15 psychometric parameters (practice effect). A significant interaction effect on the digit span forward test (F = 5.21, P < 0.05) revealed an absence of practice effects for both exposure groups but not the control group. This memory test indicates MF-induced abolition of the improvement associated with practice. Overall, this study does not establish any clear MF effect on human cognition. It is speculated that an ELF MF may interfere with the neuropsychological processes responsible for this short-term learning effect supported by brain synaptic plasticity. PMID- 21544843 TI - Calibration and uncertainties in personal exposure measurements of radiofrequency electromagnetic fields. AB - In the past 5 years radiofrequency personal exposure meters have been used to characterize the exposure during daily activities. We found from calibration tests for the 12 frequency bands of the EME Spy 121 exposimeter in a Gigahertz Transverse Electromagnetic cell and an Open Area Test Site, that these measurements tend to underestimate the actual exposure. Therefore, a maximum frequency-dependent correction factor of 1.1-1.6 should be applied to the electric field. This correction factor consists of three multipliers correcting for calibration, elevation arrival angle, and influence of the body. The calibration correction factor should be determined per exposimeter, as the maximum range of response between exposimeters in a frequency band is 2.4 dB. Since the range of response for different elevation angles could reach 10.2 dB, a strict protocol for wearing the exposimeter during fieldwork should be followed to be able to compare and combine measurements made by different persons in the same microenvironments. Because the influence of the body depends on the azimuth angle of arrival, it may lead to an over- or underestimation. Thus, the body correction factor is an average over the angles and should only be applied in activities involving movement through the full 360 degrees range of random angles of arrival. PMID- 21544844 TI - On the border of the homeotic function: re-evaluating the controversial role of cofactor-recruiting motifs: the role of cofactor-recruiting motifs in conferring Hox evolutionary flexibility may critically depend on the protein environment. AB - In this review we present concepts that challenge a recently emerging paradigm explaining how similar Hox proteins perform different developmental functions across evolution, despite relatively limited sequence variability. This paradigm relates to the transcription factor, Fushi tarazu (Ftz), whose evolutionary plasticity has been shown to rely on the shuffling between two short protein recognition motifs. We discuss the Ftz paradigm and consider alternative interpretations to the evolutionary flexibility of this Hox protein. In particular, we propose that the protein environment might have played a critical role in the functional shuffling of Ftz during arthropod evolution. PMID- 21544845 TI - Regulation of cigarette smoke-mediated mucin expression by hypoxia-inducible factor-1alpha via epidermal growth factor receptor-mediated signaling pathways. AB - Cigarette smoking is strongly implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Mucus hypersecretion is the key manifestation in patients with COPD and mucin 5AC (MUC5AC) is a major component of airway mucus. Hypoxia inducible factor-1 (HIF-1) is a transcriptional factor which can be stimulated to bind to the MUC5AC promoter and induce MUC5AC promoter activation. Previous studies have reported that activation of HIF-1alpha pathways by cigarette smoke contributes to the development of COPD. We hypothesize that cigarette smoke up-regulates HIF-1alpha production and HIF-1 activity through epidermal growth factor receptor (EGFR)-activated signal cascades pathways, leading to mucin production in human airway epithelial cells (16HBE). We show that cigarette smoke increases HIF-1alpha production, HIF-1 activity and MUC5AC expression. These effects are prevented by small interfering RNA (siRNA) for HIF 1alpha, indicating that cigarette smoke-induced mucin production is HIF-1alpha dependent. Cigarette smoke activates extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K) signal pathways, both of which are inhibited by gefitinib (an inhibitor of EGFR), suggesting that cigarette smoke-activated signal pathways are mediated by EGFR in 16HBE cells. Furthermore, pretreatment with gefitinib and the pharmacological inhibitors of PI3K (LY294002) and ERK1/2 (PD98059) prevented cigarette smoke-mediated Akt and ERK1/2 phosphorylation responses, HIF-1alpha production, HIF-1 activity and MUC5AC expression. These observations demonstrate an important role for EGFR-mediated signaling pathways in regulating cigarette smoke-induced HIF-1 activation and MUC5AC expression. Our results suggest that cigarette smoke activates EGFR mediated signaling pathways, leading to HIF-1alpha production and HIF-1 activation, resulting in mucin expression in human airway epithelial cells. PMID- 21544846 TI - A mixture model for the joint analysis of latent developmental trajectories and survival. AB - A general joint modeling framework is proposed that includes a parametric stratified survival component for continuous time survival data, and a mixture multilevel item response component to model latent developmental trajectories given mixed discrete response data. The joint model is illustrated in a real data setting, where the utility of longitudinally measured cognitive function as a predictor for survival is investigated in a group of elderly persons. The object is partly to determine whether cognitive impairment is accompanied by a higher mortality rate. Time-dependent cognitive function is measured using the generalized partial credit model given occasion-specific mini-mental state examination response data. A parametric survival model is applied for the survival information, and cognitive function as a continuous latent variable is included as a time-dependent explanatory variable along with other explanatory information. A mixture model is defined, which incorporates the latent developmental trajectory and the survival component. The mixture model captures the heterogeneity in the developmental trajectories that could not be fully explained by the multilevel item response model and other explanatory variables. A Bayesian modeling approach is pursued, where a Markov chain Monte Carlo algorithm is developed for simultaneous estimation of the joint model parameters. Practical issues as model building and assessment are addressed using the DIC and various posterior predictive tests. PMID- 21544847 TI - Analysis of spontaneous adverse drug reaction (ADR) reports using supplementary information. AB - Assessment of safety of newly marketed drugs is an important public health issue. Once the drug is in the market, clinicians and/or health professionals are responsible for recognizing and reporting suspected side effects known as adverse drug reaction (ADR). Such reports are collected in a so-called spontaneous reporting (SR) system. The primary purpose of spontaneous ADR reporting is to provide early warnings or suspicions, which have not been recognized prior to marketing of a drug because of limitations of clinical trials. We shall discuss the existing work to analyze the SR database and their drawbacks and also suggest methodologies to tackle these drawbacks by defining a source population and considering the problem of under-reporting, with the help of supplementary data. Unbiased estimate of population odds-ratio has been obtained and the corresponding asymptotic results are derived. PMID- 21544848 TI - Urinary exosomes and proteomics. AB - A number of highly abundant proteins in urine have been identified through proteomics approaches, and some have been considered as disease-biomarker candidates. These molecules might be clinically useful in diagnosis of various diseases. However, none has proven to be specifically indicative of perturbations of cellular processes in cells associated with urogenital diseases. Exosomes could be released into urine which flows through the kidney, ureter, bladder and urethra, with a process of filtration and reabsorption. Urinary exosomes have been recently suggested as alternative materials that offer new opportunities to identify useful biomarkers, because these exosomes secreted from epithelial cells lining the urinary track might reflect the cellular processes associated with the pathogenesis of diseases in their donor cells. Proteomic analysis of such urinary exosomes assists the search of urinary biomarkers reflecting pathogenesis of various diseases and also helps understanding the function of urinary exosomes in urinary systems. Thus, it has been recently suggested that urinary exosomes are one of the most valuable targets for biomarker development and to understand pathophysiology of relevant diseases. PMID- 21544849 TI - Effects of second-generation tyrosine kinase inhibitors towards osteogenic differentiation of human mesenchymal cells of healthy donors. AB - The BCR-ABL inhibitor imatinib is a standard first-line therapy for patients with chronic myeloid leukemia. However, it has been demonstrated that this long-term treatment is associated with altered bone metabolism. The mechanisms of this effect are not fully understood, but an inhibition of the platelet-derived growth factor receptor (PDGF-R) beta axis has been suspected on the basis of some in vitro findings. We evaluated the osteoblastic differentiation of mesenchymal stem cells derived from bone marrow (hBM-MSCs) after in vitro treatment with dasatinib, nilotinib or bosutinib. Human bone marrow mesenchymal stem cells were induced to differentiate in osteoblastic cells by treatment with osteogenic medium with or without dasatinib, nilotinib or bosutinib. We found that the addition of dasatinib, and to a greater extend nilotinib, induced expression of osteogenic mRNA markers as compared with cultures with standard medium or osteogenic medium only. However, treatment with bosutinib did not induce an increase of osteogenic markers. In conclusion, we show that besides imatinib, other tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib, but not bosutinib, increase osteogenic markers in hBM-MSCs. Because bosutinib differs from the other TKIs because of its low affinity to other kinases such as PDGF-R, these experiments suggest that inhibition of PDGF-R may be involved in the induction of osteoblastogenesis by TKIs. PMID- 21544850 TI - From the liver to the blood-brain barrier: an interconnected system regulating brain amyloid-beta levels. PMID- 21544851 TI - A new specialization in astrocytes: glutamate- and ammonia-induced nuclear size changes. AB - We observed nuclear swelling in glutamate (Glu)-treated astrocytes that was concomitant with but independent of astrocytic cell swelling. We confirmed Glu induced nuclear swelling with nuclei isolated from astrocytes. Ammonia is metabolically related to Glu and could induce a nuclear swelling in intact astrocytes but shrinkage in isolated nuclei. Other compounds such as glutamine, aspartate, taurine, glycine, and ATP did not cause any nuclear swelling in isolated nuclei of astrocytes. Surprisingly, Glu and ammonia did not induce nuclear swelling in microglia, C6, HEK 293, or Hep G2 cell lines in cultures and their isolated nuclei. The Glu- and ammonia-induced nuclear size changes appear to be a specific response of astrocytes to these two closely related metabolic compounds. PMID- 21544852 TI - Interplay between glycogen synthase kinase-3beta and tau in the cerebellum of Hsp27 transgenic mouse. AB - The association between heat shock protein 27 (Hsp27) and hyperphosphorylated tau has gained attention for more than a decade, but it has never been explored in vivo. In the present study, we found that tau phosphorylated at S396/404 (PHF-1) and S262 sites was significantly increased in the cerebellum of Hsp27 transgenic mice, which was concomitant with increased glycogen synthase kinase-3beta (GSK3beta) phosphorylated at Y216 and decreased GSK3beta phosphorylated at S9. Neither 70-kDa ribosomal protein S6 kinase (p70S6K; total p70S6K, p70S6K at T389, and p70S6K at T421/S424) nor protein phosphatase PP2A (total PP2A, PP2A at Y307, methylated or demethylated PP2A) was changed. This suggests that the increased tau phosphorylation at S396/404 and S262 sites may be induced by Hsp27 through enhancement of GSK3beta activity in the mouse cerebellum. PMID- 21544853 TI - Transfection of Noggin in bone marrow stromal cells (BMSCs) enhances BMSC-induced functional outcome after stroke in rats. AB - Early intervention with intravenous administration of bone marrow stromal cells (BMSCs) reduces infarction size and ameliorates functional deficits in rat ischemia models. Noggin, an inhibitor of bone morphogenetic protein (BMP), has been demonstrated to provide protection from ischemic disease. In the present work, we hypothesize that administering Noggin-transfected BMSCs enhances BMSC induced brain repair after cerebral ischemia. We compared the effects of BMSCs alone and Noggin-transfected BMSCs (Noggin-BMSCs) systematically delivered into the middle cerebral artery occlusion (MCAo) rat model. Noggin expression in BMSCs was achieved using adenoviral infection together with a green fluorescent protein (GFP) vector to monitor transduction efficiency and facilitate posttransplantation tracking. BMSCs and Noggin-BMSCs were intravenously injected into the rats 6 hr after MCAo. At 7 days after MCAo, the GFP-expressing BMSCs and Noggin-BMSCs were found primarily in the ischemic penumbra, which indicated that the intravenously delivered cells survived and reached in the lesion site. Both BMSC and Noggin-BMSC treatment significantly promoted neurogenesis in the ipsilateral subventrical zone (SVZ), reduced infarct volume, and led to functional improvement compared with the control group. Moreover, these beneficial effects were significantly greater in the Noggin-BMSC-treated group compared with BMSCs alone treatment (P < 0.05). Noggin expression in the ischemic hemisphere was significantly increased in the Noggin-BMSC-treated group as revealed by enzyme-linked immunosorbent assay (ELISA) at 7 days after MCAo compared with BMSC-treated and control groups (P < 0.05). These results indicate that transfection of Noggin in BMSCs enhances BMSC-induced neuroprotective effects when administered intravenously during the acute phase after stroke. PMID- 21544854 TI - Thyroid abnormalities in patients treated with lenalidomide for hematological malignancies: results of a retrospective case review. AB - Lenalidomide is an antiangiogenic drug associated with hypothyroidism. We describe a case-series of lenalidomide use in hematological cancers and the prevalence of thyroid abnormalities. We reviewed medical records of patients treated with lenalidomide at a single center form 2005 to 2010 and extracted demographic, clinical, and laboratory data. Of 170 patients with confirmed lenalidomide use (age 64.9 +/- 15 years), 148 were treated for multiple myeloma and 6% had thyroid abnormalities attributable only to lenalidomide. In patients with a previous diagnosis of thyroid dysfunction, the addition of lenalidomide therapy was associated with a higher incidence of subsequent TFTF abnormality (17%) as compared to patients with no previous diagnosis of thyroid dysfunction (6%) (P=0.0001). Many patients (44%) with pre-existing disease and a change in thyroid function before or while on lenalidomide had no further follow-up of their thyroid abnormalities, Of 20 patients who did not undergo any thyroid function testing either before starting or while on lenalidomide for a median of 9.4 months (+/- 6.5), 35% developed new symptoms compatible with hypothyroidism, including worsened fating, constipation or cold intolerance. Symptoms of thyroid dysfunction overlap with side effects of lenalidomide. Thyroid hormone levels are not regularly evaluated in patients on lenalidomide. While on this treatment, thyroid abnormalities can occur in patients with no previous diagnoses and in patients with pre-existing abnormalities. Because symptoms of thyroid dysfunction could be alleviated by appropriate treatment, thyroid function should be evaluated during the course of lenalidomide to improve patients quality of life. PMID- 21544855 TI - Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management. AB - Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolytic anemia, increased susceptibility to infections and vaso-occlusion leading to a reduced quality of life and life expectancy. Oxidative stress is an important feature of SCD and plays a significant role in the pathophysiology of hemolysis, vaso-occlusion and ensuing organ damage in sickle cell patients. Reactive oxygen species (ROS) and the (end-)products of their oxidative reactions are potential markers of disease severity and could be targets for antioxidant therapies. This review will summarize the role of ROS in SCD and their potential implication for SCD management. PMID- 21544856 TI - Patterns of monoclonal immunoglobulins and serum free light chains are significantly different in black compared to white monoclonal gammopathy of undetermined significance (MGUS) patients. AB - Monoclonal gammopathy of undetermined significance (MGUS), the precursor to multiple myeloma, is more common in blacks than whites. The serum free light chain (sFLC) assay is an important prognostic test in MGUS, but no study has evaluated sFLC levels and ratios in black MGUS patients. One-hundred and twenty five black MGUS patients at two urban centers were compared to the white population of the Mayo Clinic. The median age for blacks was 73 years [41-94] and 75% were male. The M-protein isotype in blacks was 81% IgG, 13% IgA, 2% IgM, and 4% biclonal compared to 70%, 12%, 16%, and 2%, respectively, in whites, (P < 0.0005). The median M-protein concentration for blacks was 0.44 gm/dL (trace 2.33) compared to 1.2 gm/dl in whites. An abnormal sFLC ratio was present in 45% of black compared to 33% of white (P = 0.01) patients. Using the Mayo Clinic risk model, black patients had a significantly lower proportion of higher risk MGUS compared to whites: low 43%, low-intermediate 45%, high-intermediate 10%, and high 2% (P = 0.014). Black patients with MGUS have significantly different laboratory findings compared to whites. The biologic basis for these disparities and their effect on prognostic assessment is unknown. Prognostic models based on these biomarkers should be used cautiously in nonwhite populations. PMID- 21544857 TI - Interference of high concentrations of immunoglobulin on stained blood and bone marrow smears in a case of plasma cell myeloma. PMID- 21544858 TI - The impact of osteoporosis (as measured by lumbar spine quantitative computed tomography) on disease activity and survival in myeloma patients: a 13-year prospective study. PMID- 21544859 TI - Inhibitory effect of thrombin on the expression of secretory group IIA phospholipase A2. AB - It is well known that the expression level of secretory group IIA phospholipase A(2) (sPLA(2)-IIA) is elevated in inflammatory diseases and lipopolysaccharide (LPS) up-regulates the expression of sPLA(2)-IIA in human umbilical vein endothelial cells (HUVECs). Recently, lower concentration thrombin could elicit anti-inflammatory responses in HUVECs. Here, the effects of lower concentration thrombin on the expression of sPLA(2)-IIA in LPS-stimulated HUVECs were investigated. Prior treatment of cells with thrombin (25-75 pM) inhibited LPS induced sPLA(2)-IIA expression by activating its receptor, protease-activated receptor-1 (PAR-1). And pretreatment of cells with either PI3-kinase inhibitor (LY294002) or cholesterol depleting agent (methyl-beta-cyclodextrin, MbetaCD) abolished the inhibitory activity of thrombin against sPLA(2)-IIA expression. Therefore, these results suggest that PAR-1 activation by lower concentration thrombin inhibited LPS mediated expression of sPLA(2)-IIA by PAR-1 and PI3-kinase dependent manner in lipid raft on the HUVECs. PMID- 21544860 TI - Impact of HMG-CoA reductase inhibition on oxidant-induced injury in human retinal pigment epithelium cells. AB - In addition to cholesterol-lowering effect, HMG-CoA reductase inhibition by statins has been shown to have protective effect in many cells type. The loss of vision in retinal degeneration disease associates with oxidative stress and apoptosis in retinal pigment epithelium (RPE) cell. This study was designed to examine the effect of statins on oxidant-induced damage in human RPE cells. Cultured human ARPE-19 (ARPE) cells were challenged with hydrogen peroxide (H(2) O(2) ) plus tumor necrosis factor alpha (TNFalpha) in the presence or absence of statins or various stress signaling inhibitors, including anti-oxidants N-acetyl cysteine (NAC), the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI), and the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580. Apoptosis was evaluated by TUNEL analysis and cell viability was determined by MTT assay. Reactive oxygen species (ROS) were detected by 2',7'-dichlorodihydrofluorescein diacetate (H(2) DCFH-DA). Expression of p-p38 MAPK protein was measured by Western blot analysis. Our findings indicate that statins treatment significantly suppressed oxidant-induced ROS accumulation and RPE apoptosis. Statins increased cell viability in a dose dependent manner. In addition, statins treatment prevented the activation of NADPH oxidase and p38 MAPK signaling induced by oxidative stress. These results suggest that statins protects ARPE cells from oxidative stress via an NADPH oxidase and/or p38 MAPK-dependent mechanisms, which may contribute to statins induced beneficial effects on RPE function. PMID- 21544861 TI - 15-lipoxygenase-1 exerts its tumor suppressive role by inhibiting nuclear factor kappa B via activation of PPAR gamma. AB - 15-Lipoxygenase-1 (15-LOX-1) is an enzyme of the inflammatory eicosanoid pathway whose expression is known to be lost in colorectal cancer (CRC). We have previously shown that reintroduction of the gene in CRC cell lines slows proliferation and induces apoptosis (Cimen et al. [2009] Cancer Sci 100: 2283 2291). We have hypothesized that 15-LOX-1 may be anti-tumorigenic by the inhibition of the anti-apoptotic inflammatory transcription factor nuclear factor kappa B. We show here that ectopic expression of 15-LOX-1 gene in HCT-116 and HT 29 CRC cell lines inhibited the degradation of inhibitor of kappa B (IkappaBalpha), decreased nuclear translocation of p65 and p50, decreased DNA binding in the nucleus and decreased transcriptional activity of Nuclear factor kappa B (NF-kappaB). As the 15-LOX-1 enzymatic product 13(S)-HODE is known to be a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, and NF kappaB can be inhibited by PPARgamma, we examined whether activation of PPARgamma was necessary for the abrogation of NF-kappaB activity. Our data show that the inhibition of both early and late stages of NF-kappaB activation could rescued by the PPARgamma antagonist GW9662 indicating that the inhibition was most likely mediated via PPARgamma. PMID- 21544862 TI - Mercury bioaccumulation, speciation, and influence on web structure in orb weaving spiders from a forested watershed. AB - Atmospheric deposition is an important source of Hg in remote terrestrial ecosystems of northeastern North America. As high-level invertebrate consumers, orb-weaving spiders (family Araneidae) are excellent subjects for studying the impact of sublethal levels of Hg on forest animals because their webs provide snapshots of behavior and neurological function. Spiders of the diadematus group of the genus Araneus were collected from the Jeffers Brook watershed in the White Mountain National Forest, New Hampshire (USA), and analyzed for Hg content. Webs were photographed and measured to test for correlations between Hg body burden and web structure. Collected spiders contained concentrations of total Hg averaging 44.7 +/- 10.0 ng/g Hg (wet mass; mean +/- standard deviation), with 37 +/- 6% of the total Hg present in the methylmercury form. Mercury loads were likely accumulated through diet (potential prey items contained an average of 43% of the Hg load in collected spiders) and possibly web ingestion. The present study found no direct evidence that the web structure-and thus the prey-capture ability-of spiders in the study area was affected by their Hg body burden. PMID- 21544863 TI - Health status of native fish (Percilia gillissi and Trichomycterus areolatus) downstream of the discharge of effluent from a tertiary-treated elemental chlorine-free pulp mill in Chile. AB - Few data exist on the possible effects of pulp and paper effluent discharge on native fish populations in the Southern Hemisphere, relative to the research done in the Northern Hemisphere. The present research examined two native fish species (Trichomycterus areolatus and Percilia gillissi) for effects at both the molecular and individual level due to the discharge of effluent from a tertiary treated elemental chlorine-free pulp mill into a fluvial system in Central Chile over three seasons (February 2007, October 2007, January 2008). Different responses were observed between species and between sexes. There was an increase in the production of gonadal 17beta-estradiol in the females of both species but a drop in 11-ketotestosterone production in P. gillissi males. Female gonadal size was increased, especially during the summer period, with corresponding increases the frequency of advanced oocyte development, and in the oocyte diameter in both species. Hepatic ethoxyresorufin-O-deethylase (EROD) activity was elevated for both species downstream of the discharge point, although overall it was higher in P. gillissi than T. areolatus. Decreases in the frequency of smaller-sized fish for both species, as well as a drop in the size of the adults downstream of the discharge point, were observed. The present study is the first evidence of endocrine disruption in native freshwater fish associated with modern pulp mills in South America. This study establishes possible links in the reproductive alterations observed at the subindividual and individual levels that could explain the changes observed at the population level. PMID- 21544864 TI - Relationship between vitamin D status and bone mineralization, mass, and metabolism in children with osteogenesis imperfecta: histomorphometric study. AB - The effect of low vitamin D levels in children with bone fragility disorders has not been examined in detail. In this study, we evaluated the relationship between vitamin D status and parameters of skeletal mineralization, mass, and metabolism in a group of pediatric osteogenesis imperfecta (OI) patients. This retrospective study consisted of 71 patients with a diagnosis of OI type I, III, or IV (ages 1.4 to 17.5 years; 36 girls) who had not received bisphosphonate treatment before iliac bone biopsy. Serum 25-hydroxyvitamin D [25(OH)D] levels ranged from 13 to 103 nmol/L and were less than 50 nmol/L in 37 patients (52%). None of the OI patients had radiologic signs of rickets or fulfilled the histomorphometric criteria for the diagnosis of osteomalacia (ie, elevated results for both osteoid thickness and mineralization lag time). Serum 25(OH)D levels were negatively correlated with age and serum parathyroid hormone levels but were not correlated with any parameter of bone mineralization (ie, osteoid thickness, mineralization lag time, or bone-formation rate per bone surface) or bone mass (ie, lumbar spine areal bone mineral density, iliac bone volume per tissue volume, or iliac cortical width). We found no evidence that serum 25(OH)D levels in the range from 13 to 103 nmol/L were associated with measures of bone mineralization, metabolism, or mass in children with OI. PMID- 21544865 TI - Skeletal muscle fat content is inversely associated with bone strength in young girls. AB - Childhood obesity is an established risk factor for metabolic disease. The influence of obesity on bone development, however, remains controversial and may depend on the pattern of regional fat deposition. Therefore, we examined the associations of regional fat compartments of the calf and thigh with weight bearing bone parameters in girls. Data from 444 girls aged 9 to 12 years from the Jump-In: Building Better Bones study were analyzed. Peripheral quantitative computed tomography (pQCT) was used to assess bone parameters at metaphyseal and diaphyseal sites of the femur and tibia along with subcutaneous adipose tissue (SAT, mm(2) ) and muscle density (mg/cm(3) ), an index of skeletal muscle fat content. As expected, SAT was positively correlated with total-body fat mass (r = 0.87-0.89, p < .001), and muscle density was inversely correlated with total-body fat mass (r = -0.24 to -0.28, p < .001). Multiple linear regression analyses with SAT, muscle density, muscle cross-sectional area, bone length, maturity, and ethnicity as independent variables showed significant associations between muscle density and indices of bone strength at metaphyseal (beta = 0.13-0.19, p < .001) and diaphyseal (beta = 0.06-0.09, p < .01) regions of the femur and tibia. Associations between SAT and indices of bone strength were nonsignificant at all skeletal sites (beta = 0.03-0.05, p > .05), except the distal tibia (beta = 0.09, p = .03). In conclusion, skeletal muscle fat content of the calf and thigh is inversely associated with weight-bearing bone strength in young girls. PMID- 21544867 TI - The chronic administration of cerebrolysin induces plastic changes in the prefrontal cortex and dentate gyrus in aged mice. AB - Cerebrolysin (Cbl) is a mixture of neuropeptides with effects similar to the endogenous neurotrophic factors and is considered one of the best drugs used in the treatment of dementias such as Alzheimer's disease (AD). In brains with AD, morphological changes in the dendrites of pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of this drug on the dendrites of pyramidal neurons of the PFC and CA1 dorsal hippocampus and granule cells from the dentate gyrus (DG) and medium spiny neurons of the nucleus accumbens (NAcc) of aged mice. Cbl (5 ml kg( 1) , i.p.) was administered daily for 60 days to 6-month-old mice. Dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at 8 months ages. In all Cbl-treated mice a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC and granule cells of the DG was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC whereas in granule neurons of the DG the increase in dendritic length was further from the soma. Our results suggest that Cbl induces plastic modifications of dendritic morphology in the PFC and DG. These changes may explain the therapeutic effect seen in AD patients treated with Cbl. PMID- 21544866 TI - A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover. AB - Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed 7-day continuous-infusion models using human parathyroid hormone(1-34) [hPTH(1-34)] and human parathyroid hormone-related protein(1-36) [hPTHrP(1-36)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dL), with marked suppression of endogenous PTH(1-84). The maximal tolerated infused doses over a 7-day period (2 and 4 pmol/kg/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28 pmol/kg/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25 dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] and tubular maximum for phosphorus (TmP/GFR) remained unaltered with these low doses despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30% to 40% for the 7 days of the infusions. With cessation of PTH and PTHrP infusion, bone-formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone-resorption program but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions are reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT. PMID- 21544868 TI - The ultrastructure of lamellar stack astrocytes. AB - Astrocytes support neurons and map out nonoverlapping domains in grey matter of the brain. The astrocytes of the glia limitans, however, do overlap. Using ultrastructural tools and immunogold histochemistry a subtype of astrocyte able to assemble large lamellar stacks was investigated at the ventral surface of the brain near the hypothalamus. Lamellar stacks were subsequently discovered also in the internal glia limitans of the epithalamus. Circular lamellar stacks containing AQP4 water channels surround neuronal processes, and might serve as osmosensors. The lamellar stacks are well-organized and can form over 100 membrane layers between neuropil and the basal membrane, but a barrier function is not obvious from the noncontinuous character of the stacks along the glia limitans. PMID- 21544871 TI - Topography of the recurrent laryngeal nerve in relation to the thyroid artery, Zuckerkandl tubercle, and Berry ligament in Kenyans. AB - Injury to the recurrent laryngeal nerve (RLN) is an important but avoidable complication of thyroidectomy. This complication may be avoided by the identification of the nerve facilitated by important landmarks found along its course. The setting for this work is the Human Anatomy Laboratory of the University of Nairobi. The aim of this work is to determine the topographic relationship of the RLN with the inferior thyroid artery (ITA), the tubercle of Zuckerkandl (TZ), and the ligament of Berry (LB) in a Kenyan population. The relationship between the nerve and the above landmarks was determined during dissection of 146 right and left thyroid lobes. One right side of the neck had a nonrecurrent nerve. Of the specimens where relationship was determined, the nerve was anterior to the ITA in 37% of cases and posterior in 51.4%. In relation to the LB, 45.3% were superficial (dorsolateral). The TZ was clearly delineated in 86 of the 146 specimens. No nerve traversed the tubercle. The RLN exhibited variations similar to those in other populations. The TZ when present was a reliable landmark to the nerve. PMID- 21544869 TI - Astrocytic activation of A1 receptors regulates the surface expression of NMDA receptors through a Src kinase dependent pathway. AB - Chemical transmitters released from astrocytes, termed gliotransmitters, modulate synaptic transmission and neuronal function. Using astrocyte-specific inducible transgenicmice (dnSNARE mice), we have demonstrated that inhibiting gliotransmission leads to reduced activation of adenosine A1 receptors (A1R) and impaired sleep homeostasis (Halassa et al. (2009) Neuron 61:213-219); Pascual et al. (2005) Science 310:113-116). Additionally, synaptic N-methyl-D-aspartate receptor (NMDAR) currents are reduced in these astrocyte-specific transgenic animals (Fellin et al. (2009) Proc Natl Acad Sci USA 106:15037-15042). Because of the importance of adenosine and NMDA receptors to sleep processes we asked whether there is a causal linkage between changes in A1R activation and synaptic NMDA receptors. We show that astrocytic dnSNARE expression leads to reduced tyrosine phosphorylation of Srckinase and NR2 subunits concomitant with the decreased surface expression of the NR2 subunits. To test the role of A1R signaling in mediating these actions, we show that incubation of wildtype (WT) slices with an A1R antagonist reduces tyrosine phosphorylation of Src kinase and NR2B, decreases the surface expression of the NR2B subunits and leads to smaller NMDA component of miniature EPSCs. In dnSNARE mice we could rescue WT phenotype by incubation in an A1R agonist:activation of A1 receptor led to increased tyrosine phosphorylation of Src kinase and NR2B subunits as well as increased the surface expression of the NR2B subunit and increased NMDA component of the synaptic mEPSC. These results provide the first demonstration that astrocytes can affect neuronal excitability on a long time scale by regulating the surface expression of NMDA receptors through the activation of specific intracellular signaling pathways. PMID- 21544870 TI - Differentiation of postnatal cerebellar glial progenitors is controlled by Bmi1 through BMP pathway inhibition. AB - Bmi1 is a polycomb group (Pc-G) protein involved in heritable gene repression, maintenance of cell identity, and proliferation. During the development of the central nervous system, Bmi1 is crucial for self-renewal of neural stem cells and for proliferation of neuronal (granule cell) progenitors of the cerebellum. Here, we use loss of function mouse models and in vitro assays--granule cell cultures and glial-neuronal co-cultures--to show that Bmi1 plays a crucial role in specification of glial progenitors during postnatal cerebellar development. Moreover, we demonstrate in in vitro assays that Bmi1 exerts this novel function through repression of BMP pathway and that this is independent of its known role in mediating the cellular response to Shh signaling. Thus modulation of Bmi1 expression in glial progenitors may represent a key event in determining the differentiation potential of these cells. PMID- 21544872 TI - A salvage procedure for an accidentally twisted small bowel in orthotopic duodenal reconstruction after pylorus-preserving partial pancreatoduodenectomy. AB - A case of pylorus-preserving Whipple procedure with an accidentally clockwise 360 degrees rotated small bowel limb in orthotopic duodenal reconstruction is presented. A simple salvage procedure is proposed. PMID- 21544873 TI - The lymphatic system: a historical perspective. AB - The study of the lymphatic system has a lengthy history, with many notable medical minds making important contributions. We now appreciate that this system is an essential component of the immune system, as well as vital to the maintenance of fluid homeostasis within the body. A good knowledge of the lymphatic system is clinically important concerning cancer, edema, surgery, and the immune response. This article reviews the history of the evolution and discovery of the lymphatic system. PMID- 21544874 TI - Thoughts on human variations. AB - The article is an autobiographical sketch of the author and his extensive investigation of human variations. PMID- 21544875 TI - Physiological closure of the physeal plate of the distal radius: An MRI analysis. AB - To have knowledge of the physiological closure of a particular physeal plate is necessary to understand fractures close to the end of growth (transitional fractures). Most frequent fractures involve the distal radius in adolescents. However, there are no systematic investigations on the topic of growth plate closure concerning the distal radius plate, so far. Twenty-two healthy female volunteers underwent MRI investigations of their left wrist. Absolute width, percentage and localization of the physeal part, closed at the time of investigation were recorded. Sequential MRI scans were performed. In this series T1-weighted sequences were most useful to distinguish open and closed parts of the physis. Total area was 291-469 mm(2) (average, 399 mm(2) ). It did positively correlate with body height (P < 0.01), but not with weight (P = 0.241) or BMI (P = 0.394). Physeal closure took place at 15-18 years. There was no significant correlation between menarche and closure (P = 0.091). Bony bridging of the growth plate begins centroradial and ends with a small limbus dorsoradial. Sequential scans showed that there are only a few months from beginning to end of physeal closure. Physiological closure of the distal radius growth plate takes place in late adolescence, varying individually. There seems to be no influence of the menarche in female individuals. The process happens within a very short time of less than a year. This may be one rationale for the fact, that transitional fractures of the distal radius are rare. PMID- 21544876 TI - Three-dimensional analysis of deciduous maxillary anterior teeth using cone-beam computed tomography. AB - The recent introduction of cone-beam computed tomography (CBCT) into the medical field has allowed the nondestructive investigation of internal structures at relatively low cost and radiation exposure. The accuracy of CBCT in both two and three dimensions has been demonstrated, and CBCT has been used successfully for craniofacial anatomy. Knowing the anatomical structure of deciduous teeth is essential for clinical dentistry. However, the root structure of deciduous teeth is rarely reported because of the scarcity of intact deciduous teeth without root resorption. The aim of this study was to evaluate the intact root form of deciduous teeth using CBCT. Data from 38 young children was analyzed using an image-analyzing program. The degree of buccal dilacerations was 26.3 degrees for deciduous maxillary central incisors (DMA), 16.5 degrees for deciduous maxillary lateral incisors (DMB), and 17.5 degrees for deciduous maxillary canines (DMC) in about half of the root length. The crown-to-root ratios were 0.52 for DMA, 0.48 for DMB, and 0.52 for DMC. These data will be helpful for understanding the development of dentition, and for clinical dentistry. PMID- 21544877 TI - Topological insulator thin films of Bi2Te3 with controlled electronic structure. PMID- 21544878 TI - Contiguous metal-mediated base pairs comprising two Ag(I) ions. AB - The incorporation of transition-metal ions into nucleic acids by using metal mediated base pairs has proved to be a promising strategy for the site-specific functionalization of these biomolecules. We report herein the formation of Ag(+) mediated Hoogsteen-type base pairs comprising 1,3-dideaza-2'-deoxyadenosine and thymidine. By defunctionalizing the Watson-Crick edge of adenine, the formation of regular base pairs is prohibited. The additional substitution of the N3 nitrogen atom of adenine by a methine moiety increases the basicity of the exocyclic amino group. Hence, 1,3-dideazaadenine and thymine are able to incorporate two Ag(+) ions into their Hoogsteen-type base pair (as compared with one Ag(+) ion in base pairs with 1-deazaadenine and thymine). We show by using a combination of experimental techniques (UV and circular dichroism (CD) spectroscopies, dynamic light scattering, and mass spectrometry) that this type of base pair is compatible with different sequence contexts and can be used contiguously in DNA double helices. The most stable duplexes were observed when using a sequence containing alternating purine and pyrimidine nucleosides. Dispersion-corrected density functional theory calculations have been performed to provide insight into the structure, formation and stabilization of the twofold metalated base pair. They revealed that the metal ions within a base pair are separated by an Ag...Ag distance of about 2.88 A. The Ag-Ag interaction contributes some 16 kcal mol(-1) to the overall stability of the doubly metal mediated base pair, with the dominant contribution to the Ag-Ag bonding resulting from a donor-acceptor interaction between silver 4d-type and 4s orbitals. These Hoogsteen-type base pairs enable a higher functionalization of nucleic acids with metal ions than previously reported metal-mediated base pairs, thereby increasing the potential of DNA-based nanotechnology. PMID- 21544879 TI - Synthesis and ring-opening metathesis of tetraalkoxy-substituted [2.2]paracyclophane-1,9-dienes. AB - Tetraalkoxy-substituted [2.2]paracyclophane-1,9-dienes can be prepared in three steps from dithia[3.3]paracyclophanes. A mixture of pseudo-geminal and pseudo ortho diastereomers is produced and the pure compounds can be separated by fractional crystallization. The solid state structures of these diastereomers reveal strongly distorted aromatic rings consistent with high levels of ring strain. Reaction of these diastereomers with the second generation Grubbs catalyst shows that only the pseudo-geminal isomer can be ring opened to give cis,trans-distrylbenzenes. The origin of this selectivity is discussed and the photoisomerization of the as-formed cis,trans-product to the all trans isomer is demonstrated. PMID- 21544880 TI - Synthesis and reactivity of alkynyl-linked phosphonium borates. AB - The phosphine tBu(2 PC[triple bond]CH (1) was reacted with B(C(6)F(5)) to give the zwitterionic species tBu(2)P(H)C[triple bond]CB(C(6)F(5))(3) (2). The analogous species tBu(2)P(Me)C[triple bond]CB(C(6)F(5))(3) (3), tBu(2)P(H)C[triple bond]CB(Cl)(C(6)F(5))(2) (4), tBu(2)P(H)C[triple bond]CB(H)(C(6)F(5))(2) (5), and tBu(2)P(Me)C[triple bond]CB(H)(C(6)F(5))(2) (6) were also prepared. The salt [tBu(2)P(H)C[triple bond]CB(C(6)F(5))(2)(THF)][B(C(6)F(5))(4)] (7) was prepared through abstraction of hydride by [Ph(3)C][B(C(6)F(5))(4)]. Species 5 reacted with the imine tBuN=CHPh to give the borane-amine adduct tBu(2)PC[triple bond]CB[tBuN(H)CH(2)Ph](C(6)F(5))(2) (8). The related phosphine Mes(2)PC[triple bond]CH (9; Mes=C(6)H(2)Me(3)) was used to prepare [tBu(3)PH][Mes(2)PC[triple bond]CB(C(6)F(5))(3)] (10) and generate Mes(2)PC[triple bond]CB(C(6)F(5))(2). The adduct Mes(2)PC[triple bond]CB(NCMe)(C(6)F(5))(2) (11) was isolated. Reaction of Mes(2)PC[triple bond]CB(C(6)F(5))(2) with H(2) gave the zwitterionic product (C(6)F(5))(2)(H)BC(H)=C[P(H)Mes(2)][(C(6)F(5))(2)BC[triple bond]CP(H)Mes(2)] (12). Reaction of tBu(2)PC[triple bond]CB(C(6)F(5))(2), a phosphine-borane generated in situ from 5, with 1-hexene gave the species [tBu(2)PC[triple bond]CB(C(6)F(5))(2)](CH(2)CHnBu)[tBu(2)PC[triple bond]CB(C(6)F(5))(2)] (13) and subsequent reaction with methanol or hexene resulted in the formation of [tBu(2)P(H)C[triple bond]CB(C(6)F(5))(2)](CH(2)CHnBu)[tBu(2)PC[triple bond]CB(C(6)F(5))(2)](OMe) (14) or the macrocycle {[tBu(2)PC[triple bond]CB(C(6)F(5))(2)](CH(2)CH(2)nBu)}(2) (15), respectively. In a related fashion, the reaction of 13 with THF afforded the macrocycle [tBu(2)PC[triple bond]CB(C(6)F(5))(2)](CH(2)CHnBu)[tBu(2)PC[triple bond]CB(C(6)F(5))(2)][O(CH(2))(4)] (16), although treatment of tBu(2)PC[triple bond]CB(C(6)F(5))(2) with THF lead to the formation of {[tBu(2)[triple bond]CB(C(6)F(5))(2)][O(CH(2))(4)]}(2) (17). In a related example, the reaction of Mes(2)PC[triple bond]CB(C(6)F(5))(2) with PhC[triple bond]CH gave {[Mes(2)PC[triple bond]CB(C(6)F(5))(2)](CH[triple bond]CPh)}(2) (18). Compound 5 reacted with AlX(3) (X=Cl, Br) to give addition to the alkynyl unit, affording (C(6)F(5))(2)BC(H)=C[P(H)tBu(2)](AlX(3)) (X=Cl 19, Br 20). In a similar fashion, 5 reacted with [Zn(C(6)F(5))(2)]?C(7)H(8), [Al(C(6)F(5))(3)]?C(7)H(8), or HB(C(6)F(5))(2) to give (C(6)F(5))(3)BC(H)=C[P(H)tBu(2)][Zn(C(6)F(5))] (21), (C(6)F(5))(3)BC(H)=C[P(H)tBu(2)][Al(C(6)F(5))(2)] (22), or [(C(6)F(5))(2)B](2)HC=CH[P(H)tBu(2)] (23), respectively. The implications of this reactivity are discussed. PMID- 21544881 TI - Topical dermal application of essential oils attenuates the severity of adjuvant arthritis in Lewis rats. AB - This study was aimed at examining the effect of an ointment containing essential oils (EO) on the severity of adjuvant arthritis (AA), an experimental model of human rheumatoid arthritis (RA), in Lewis rats and to define the underlying mechanisms. At the onset of AA, the rats received topical application twice daily of an ointment containing 20% EO or placebo ointment. The synovial fluid (SF) and synovium-infiltrating cells (SIC) of rats were tested for pro-inflammatory cytokines TNF-alpha and IL-1beta. The hind paws and skin were examined histologically. The activity/level of matrix metalloproteinases (MMPs) and anti mycobacterial heat-shock protein 65 (Bhsp65) antibodies were tested. Arthritic rats treated with ointment containing EO developed less severe clinical arthritis compared with the controls, and this activity was attributable to EO and not to the carrier oil. The levels of TNF-alpha and IL-1beta, and the activity of MMPs in SF and SIC-lysate were significantly reduced in EO-treated arthritic rats compared with the controls. However, the levels of anti-Bhsp65 antibodies were unaffected by treatment. Thus, topical dermal delivery of EO-containing ointment down-modulates the severity of AA in Lewis rats by inhibiting defined mediators of inflammation. Such ointments should be tested in patients with RA and other arthritic conditions. PMID- 21544882 TI - Effect of Salvia miltiorrhiza hydrophilic extract on antioxidant enzymes in diabetic patients with chronic heart disease: a randomized controlled trial. AB - To investigate whether Salvia miltiorrhiza hydrophilic extract (SMHE) has the ability to ameliorate oxidative stress in diabetic patients with chronic heart disease (CHD), 62 patients with CHD were recruited. These patients were assigned randomly into two groups: (1) placebo group receiving hypoglycemic therapy; (2) treatment group receiving hypoglycemic therapy plus SMHE. The biological markers related to oxidative stress were measured to determine the effect of treatment. Thirty patients in the placebo group and 24 patients in the treatment group were followed to completion in this study. Overall, the malondialdehyde (MDA) level at day 30 in the treatment group was significantly lower than in the placebo group. However, no significant difference in the serum antioxidant enzymes activities was observed between the groups. At day 60, the serum glutathione (GSH) level, superoxide dismutase (SOD), Paraoxonase (PONase) and glutathione reductase (GSSG R) activities increased markedly in the treatment group compared with the placebo group. There was no significant difference in the level of lipid profile between the two groups. This study indicated that SMHE clearly reduced oxidative stress in diabetic patients with CHD. PMID- 21544883 TI - Pharmacokinetics of geniposide in Zhi-Zi-Hou-Pu decoction and in different combinations of its constituent herbs. AB - Zhi-Zi-Hou-Pu decoction (ZZHPD), a classic antidepressant formula, is composed of Gardenia jasminoides Ellis (ZZ), Fructus aurantii immaturus (ZS) and Cortex magnoliae officinalis (HP). ZZHPD has attracted a great deal of attention for its antidepressant effects. The aim of this study was to compare the pharmacokinetics of geniposide (one of the predominant active ingredients) after oral administration of different combinations of ZZHPD and to explore the influence of herb-herb interaction on the pharmacokinetics of geniposide. Twenty four rats were divided randomly into four groups and were administered one of the four extracts: ZZ, ZZ-HP, ZZ-ZS and ZZHPD (ZZ-HP-ZS) via intragastric gavage with approximately the same dose of 40.65 mg/kg geniposide (an effective human daily dose of ZZHPD). Plasma concentrations of geniposide were determined using an HPLC method. Pharmacokinetic parameters were calculated from the plasma concentration time data. Compared with ZZ alone, the ZZ-ZS combination delayed T(max) and ZZ HP, ZZ-ZS, ZZHPD remarkably shortened the T(1/2) of geniposide. In addition, ZZ HP, ZZ-ZS, ZZHPD obviously increased the AUC of geniposide. The result illustrated that the oral bioavailability of geniposide was dramatically enhanced when ZZ was combined with HP or/and ZS. It can be deduced that herb-herb interaction may increase the absorption, and significantly improve the oral bioavailability of geniposide in rats. PMID- 21544884 TI - Linalool from rosewood (Aniba rosaeodora Ducke) oil inhibits adenylate cyclase in the retina, contributing to understanding its biological activity. AB - Rosewood oil (RO) (Aniba rosaeodora Ducke) is rich in linalool, a monoterpene alcohol, which has well studied anxiolytic, sedative and anticonvulsant effects. The inhibition of the increases in cAMP protects against seizures in a diversity of models of epilepsy. In this paper, the principal aim was to investigate the effects of RO, (+/-)-linalool and (-)-linalool) on adenylate cyclase. They were tested in chick retinas and forskolin was used to stimulate the enzyme target. The phosphodiesterase inhibitor, 4-(3-butoxy-4-methoxybenzyl)-imidazolidin-2-one, and the non-selective adenosine receptor antagonist 3-isobutyl-methyl-xanthine (IBMX), were used to control the participation of phosphodiesterase and adenosine receptors in the resulting effects, respectively. The cAMP accumulation was measured by enzyme immune assay (EIA). Rosewood oil, (-)-linalool and (+/-) linalool inhibited exclusively the cAMP accumulation stimulated by forskolin, even when adenosine receptors were blocked with IBMX. The IC(50) values (in MU m concentration range) calculated from their concentration response-curves were not statistically different, however, the compounds presented a different relative efficacy. These results extend the range of subcellular mechanisms underlying the relaxant action of linalool on the central nervous system. PMID- 21544885 TI - The effects of the hydroalcohol extract of Rosa canina L. fruit on experimentally nephrolithiasic Wistar rats. AB - This research evaluated the possible therapeutic potential of Rosa canina (RC) as a preventive agent in experimentally induced calcium oxalate (CaOx) nephrolithiasis with ethylene glycol (1% EG) in rats. In this experiment, 50 Wistar rats were divided randomly into five groups (n = 10). These groups received tap drinking water (group I), 1% EG (group II), 250 mg/kg RC + 1% EG (group III), 500 mg/kg RC + 1% EG (group IV), or 2.5 g/kg potassium citrate + 1% EG (group V) for a period of 30 days. Blood and urine were collected for biochemical analysis, and the liver and kidneys were prepared for total lipid peroxides, calcium content and histological evaluation. The extract was analysed for total phenolics, flavonoids, ascorbic acid, citric acid and radical scavenger activity. The supplementation of the hydromethanol RC extract contributed to reducing the kidney and liver lipid peroxides to optimum levels in rats that had been treated with EG-induced CaOx lithiasis. The extract also decreased renal and urinary calcium contents, decreased the size and number of CaOx calculi in the kidneys, and significantly increased citrate excretion without changing the volume, pH, or urinary concentrations of oxalate in comparison with the control group. According to these results, RC can be useful as a preventive agent against the formation of CaOx kidney stones. PMID- 21544886 TI - Effects of licarin E on expression of matrix metalloproteinase-1 and type-1 procollagen in UVB-irradiated human skin fibroblasts. AB - Ultraviolet B (UVB) radiation induces photoaging by upregulating the expression of matrix metalloproteinase (MMP) and decreasing collagen synthesis in human skin cells. This study evaluated the effects of licarin E isolated from mace, the aril of Myristica fragrans Houtt., on MMP-1 and type-1 procollagen levels in UVB irradiated human skin fibroblasts. Powdered mace extracted with 95% ethanol was used and licarin E isolated by preparative high-performance liquid chromatography. In addition, western blot analysis, reverse transcription PCR and electrophoretic mobility shift assay were used to evaluate the effects of licarin E and its molecular mechanism. It was found that licarin E attenuated UVB-induced MMP-1 expression by inactivating mitogen-activated protein kinases (MAPKs), thereby inhibiting activator protein 1. Licarin E also increased type-1 procollagen expression by stimulating transforming growth factor beta (TGFbeta)/Smad signaling. The findings show that licarin E positively regulates the expression of MMP-1 and type-1 procollagen in UVB-irradiated human skin fibroblasts through MAPK and TGFbeta signaling, suggesting its potential as a potent antiphotoaging agent. PMID- 21544887 TI - Investigation of UDP-glucuronosyltransferases (UGTs) inhibitory properties of carvacrol. AB - UDP-glucuronosyltransferases (UGTs), the most important phase II drug metabolizing enzymes (DMEs), could metabolize many drugs and various endogenous substances including bilirubin, steroid hormones, thyroid hormones, bile acids and fat-soluble vitamins. Evaluation of the inhibitory effects of compounds on UGTs is clinically important because inhibition of UGT isoforms could not only result in serious drug-drug interactions (DDIs), but also induce metabolic disorders of endogenous substances. The aim of the present study was to investigate the inhibitory effects of carvacrol on major UGT isoforms. The results showed that carvacrol could inhibit the activity of UGT1A9 with negligible effects on other UGT isoforms. When 4-methylumbelliferone (4-MU) was used as a nonspecific probe substrate and recombinant UGT enzymes were utilized as an enzyme resource, the inhibition of UGT1A9 was best fit to the competitive type and the inhibition kinetic parameter (K(i)) was calculated to be 5.7 uM. Furthermore, another specific probe substrate, propofol, was employed to determine the inhibitory kinetics of UGT1A9, and the results demonstrated that the inhibitory type was noncompetitive. The inhibition kinetic parameter (K(i)) was determined to be 25.0 uM. Because this substrate-dependent inhibition of UGT1A9 might confuse the in vitro-in vivo extrapolation, these in vitro inhibition kinetic parameters should be interpreted with special caution. PMID- 21544888 TI - Detection of neuronal activity and metabolism in a model of dehydration-induced anorexia in rats at 14.1 T using manganese-enhanced MRI and 1H MRS. AB - In this study, hypothalamic activation was performed by dehydration-induced anorexia (DIA) and overnight food suppression (OFS) in female rats. The assessment of the hypothalamic response to these challenges by manganese-enhanced MRI showed increased neuronal activity in the paraventricular nuclei (PVN) and lateral hypothalamus (LH), both known to be areas involved in the regulation of food intake. The effects of DIA and OFS were compared by generating T-score maps. Increased neuronal activation was detected in the PVN and LH of DIA rats relative to OFS rats. In addition, the neurochemical profile of the PVN and LH were measured by (1) H MRS at 14.1T. Significant increases in metabolite levels were measured in DIA and OFS relative to control rats. Statistically significant increases in gamma-aminobutyric acid were found in DIA (p=0.0007) and OFS (p<0.001) relative to control rats. Lactate increased significantly in DIA (p=0.03), but not in OFS, rats. This work shows that manganese-enhanced MRI coupled to (1) H MRS at high field is a promising noninvasive method for the investigation of the neural pathways and mechanisms involved in the control of food intake, in the autonomic and endocrine control of energy metabolism and in the regulation of body weight. PMID- 21544891 TI - A superhydrophobic to superhydrophilic in situ wettability switch of microstructured polypyrrole surfaces. AB - We present an electrochemical layered system that allows for the fast, in situ wettability switch of microstructured PPy upon the application of an electric stimulus. We have eliminated the need for PPy to be immersed in an electrolyte to switch between wetting states, laying the groundwork for PPy to be used as a viable material in many applications, including microfluidics or smart textiles. The PPy surface was switched from the superhydrophobic state (contact angle=159) to the superhydrophilic state (contact angle=0) in 3 s. A wettability gradient was also created on a PPy surface using the layered system, causing a 3 uL droplet to travel approximately 2 mm in 0.8 s. PMID- 21544889 TI - A simple noniterative principal component technique for rapid noise reduction in parallel MR images. AB - The utilization of parallel imaging permits increased MR acquisition speed and efficiency; however, parallel MRI usually leads to a deterioration in the signal to-noise ratio when compared with otherwise equivalent unaccelerated acquisitions. At high accelerations, the parallel image reconstruction matrix tends to become dominated by one principal component. This has been utilized to enable substantial reductions in g-factor-related noise. A previously published technique achieved noise reductions via a computationally intensive search for multiples of the dominant singular vector which, when subtracted from the image, minimized joint entropy between the accelerated image and a reference image. We describe a simple algorithm that can accomplish similar results without a time consuming search. Significant reductions in g-factor-related noise were achieved using this new algorithm with in vivo acquisitions at 1.5 T with an eight-element array. PMID- 21544892 TI - Diels-Alder reactions as an efficient route to high purity cyclic polymers. AB - A simple and efficient route for the synthesis of cyclic polymer systems is presented. Linear furan protected alpha-maleimide-omega-cyclopentadienyl functionalized precursors (poly(methyl methacrylate) and poly(tert-butyl acrylate)) were synthesized via atom transfer radical polymerization (ATRP) and subsequent substitution of the bromine end-group with cyclopentadiene. Upon heating at high dilution, deprotection of the dieneophile occurs followed by an intramolecular Diels-Alder reaction yielding a high purity cyclic product. PMID- 21544893 TI - Distribution of Y-chromosome Q lineages in Native Americans. AB - OBJECTIVES: This investigation was performed to identify and evaluate the distribution of all 15 Y-chromosome lineages belonging to the Q clade in a sample of natives from South America. METHODS: One hundred and forty-eight individuals from 20 Native American populations, as well as 24 Asian samples including Eskimos, were tested with 18 biallelic loci that can identify all currently known lineages of the Y-Chromosome Q clade. Sequencing was performed in part of the sample (~180,000 nucleotides, which detected, for instance, several downstream markers related to the Q1a3a lineage). RESULTS: No new mutation was found and Q1a3a was consistently found in high frequencies in all populations, followed at a much lower frequency by Q1a3*, while Q1a3a derived-lineages are probably population/tribe/region-specific. CONCLUSION: The number of basal Y chromosome lineages in North America is apparently higher than in South America due probably to a bottleneck during the South American colonization and/or more recent Circum Arctic gene flow. PMID- 21544894 TI - Unexpected changes in maternal breast size during pregnancy in relation to infant sex: an evolutionary interpretation. AB - OBJECTIVES: This study evaluated changes in breast size during pregnancy depending on infant sex. Due to larger nutritional needs during lactation, male infants may stimulate greater changes in maternal breast size than female infants. METHODS: Data were collected by an online questionnaire survey of 120 women from Poland, who had at least one child. RESULTS: Changes in breast circumference during pregnancy were associated with the infant's gender. Surprisingly, mothers of female infants had greater breast circumference changes than the mothers of male infants (P = 0.03). CONCLUSION: The observed difference is surprising in the light of studies reporting that mothers of male infants produced milk that had greater energy content. However, breast size alone does not determine the quality and quantity of produced milk. It is suggested that the larger difference in breast size for mothers of female infants results from a trade-off between direct energy allocations to the growing fetus and to breast enlargement. Perhaps, as in other primates maintaining sexually attractive attributes during pregnancy, early breast enlargement in women is a primary sexual stimulus. The ultimate function of early breast enlargement may function to ensure greater involvement from partners, which is especially important to mothers expecting daughters, who might be in poorer nutritional condition, as predicted by Trivers-Willard hypothesis. PMID- 21544896 TI - Chondromyxoid fibroma of the nasal septum: case report and review of literature. AB - BACKGROUND: Chondromyxoid fibroma (CMF) is a rare bone tumor, accounting for less than 0.5% of all bone tumors, with a predilection for lower extremity bone metaphyses. Involvement of the head and neck is extremely rare, with only 3 cases reported in the nasal septum in world literature. METHODS: This is a case report of a CMF in the nasal septum of a 49-year-old woman with a 6-month history of congestion. MRI showed a bilobed mass originating from the nasal septum. Histologic and immunoperoxidase staining as well as electron microscopic studies were performed. A literature review was performed. RESULTS: The patient underwent a midface-degloving approach for surgical resection. The final pathology was prototypic of CMF. The patient was disease-free 16 months postoperatively. CONCLUSIONS: CMF is a rare, benign neoplasm occasionally occurring in the head and neck. Surgical resection is often curative. CMF must be differentiated from chondrosarcoma, given the substantial differences in treatment. PMID- 21544895 TI - Novel molecular targeted therapies for refractory thyroid cancer. AB - The incidence of thyroid cancer continues to increase and this neoplasia remains the most common endocrine malignancy. No effective systemic treatment currently exists for iodine-refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. RET (rearranged during transfection)/PTC (papillary thyroid carcinoma) gene rearrangements, B-Raf gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR-2) angiogenesis pathways are some of the known genetic alterations playing a crucial role in the development of thyroid cancer. Several novel agents have demonstrated promising responses. Of the treatments studied, multi-kinase inhibitors such as axitinib, sorafenib, motesanib, and XL-184 have shown to be the most effective by inducing clinical responses and stabilizing the disease process. Randomized clinical trials are currently evaluating these agents, results that may soon change the management of thyroid cancer. PMID- 21544897 TI - Patient versus clinician symptom reporting: how accurate is the detection of distress in the oncologic after-care? AB - OBJECTIVE: The high prevalence of psychosocial distress in cancer patients is well known. The objective of this study was to investigate the agreement between the self-report of patients and the detection of distress by the treating physicians. METHODS: The participating patients were all enrolled in a structured 5-year after-care program in Palatinate, Germany. All tumor-free patients with a scheduled follow-up exam in a 3-month time frame were asked to fill in a questionnaire regarding their psychosocial distress. The treating physicians participating in the program are family doctors or specialized physicians working in general practices. Their assessment of the patients' distress is part of the program. Agreement was evaluated using the kappa statistic. RESULTS: The levels of psychosocial distress were very high in the self-rating of 2642 patients. Low concordance was observed between the ratings of the patients and the physicians, with all kappa values below 0.1. Only about every 10th patient reporting weak to severe problems with depression or anxiety was identified as such. Detection of problems by physicians was somewhat better for female than male patients and highest among breast cancer patients. CONCLUSIONS: Overall the results of our study show that the need for psychosocial support extends past the acute treatment phase. The recognition of psychosocial distress in their patients seems to be extremely low in the outpatient, follow-on care phase. The application of an efficient rating method should become a routine part of the follow-up exams with physicians being trained to improve their abilities to detect the distress in the patient. PMID- 21544898 TI - Caregiving styles and attachment orientations in couples facing advanced cancer. AB - OBJECTIVE: This study examines associations between caregiving styles and caregivers' and patients' attachment orientations among couples facing advanced cancer. Four caregiving styles were examined: proximate, sensitive, controlling, and compulsive. METHOD: A total of 110 patients with advanced gastrointestinal or lung cancer and their spouse caregivers were recruited. Measures included: the Experiences in Close Relationships Inventory, the Caregiving Questionnaire, and the Demand Subscale from the Caregiving Burden Scale. RESULTS: Caregivers reported high levels of proximate and sensitive caregiving and moderate levels of controlling and compulsive caregiving. Hierarchical regressions were conducted to examine the contribution of caregivers' and patients' attachment orientations to each caregiving style while controlling for caregiving demands. Both caregiving proximity and sensitive caregiving were negatively associated with caregivers' avoidant attachment. Controlling caregiving was positively related to caregivers' avoidant and anxious attachment orientations. Compulsive caregiving was positively associated with caregiving demand and caregivers' attachment anxiety. In addition, compulsive caregiving was positively associated with patients' attachment avoidance and negatively associated with patients' attachment anxiety. CONCLUSIONS: The study demonstrated two clusters of ways to provide care: other oriented and self-oriented. The study revealed that both patients' and caregivers' attachment orientations contributed to caregivers' patterns of caregiving. Insecure attachment orientations and resulting couple interaction patterns of 'demand-withdrawal' and 'avoidance-pursuit' are potential sources of distress that may benefit from exploration in psychotherapeutic interventions for couples facing advanced cancer. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21544900 TI - Mitochondria determine the differentiation potential of cardiac mesoangioblasts. AB - An understanding of cardiac progenitor cell biology would facilitate their therapeutic potential for cardiomyocyte restoration and functional heart repair. Our previous studies identified cardiac mesoangioblasts as precommitted progenitor cells from the postnatal heart, which can be expanded in vitro and efficiently differentiated in vitro and in vivo to contribute new myocardium after injury.Based on their proliferation potential in culture, we show here that two populations of mesoangioblasts can be isolated from explant cultures of mouse and human heart.Although both populations express similar surface markers, together with a panel of instructive cardiac transcription factors, they differ significantly in their cellular content of mitochondria. Slow dividing (SD) cells, containing many mitochondria, can be efficiently differentiated with 5 azacytidine (5-aza) to generate cardiomyocytes expressing mature structural markers. In contrast, fast dividing (FD) mesoangioblasts, which contain decreased quantities of mitochondria, do not respond to 5-aza treatment.Notably, increasing mitochondrial numbers using pharmacological nitric oxide (NO) donors reverses the differentiation block in FD mesoangioblasts and leads to a progressive maturation to cardiomyocytes; conversely decreasing mitochondrial content, using respiratory chain inhibitors and chloramphenicol, perturbs cardiomyocyte differentiation in SD populations. Furthermore, isolated cardiac mesoangioblasts from aged mouse and human hearts are found to be almost exclusively mitochondria low FD populations, which are permissive for cardiomyocyte differentiation only after NO treatment. Taken together,this study illustrates a key role for mitochondria in cardiac mesoangioblast differentiation and raises the interesting possibility that treatments, which increase cellular mitochondrial content, may have utility for cardiac stem cell therapy. PMID- 21544899 TI - Concise review: adipocyte origins: weighing the possibilities. AB - Adipose tissue is the primary energy reservoir in the body and an important endocrine organ that plays roles in energy homeostasis, feeding, insulin sensitivity, and inflammation. While it was tacitly assumed that fat in different anatomical locations had a common origin and homogenous function, it is now clear that regional differences exist in adipose tissue characteristics and function. This is exemplified by the link between increased deep abdominal or visceral fat, but not peripheral adipose tissue and the metabolic disturbances associated with obesity. Regional differences in fat function are due in large part to distinct adipocyte populations that comprise the different fat depots. Evidence accrued primarily in the last decade indicates that the distinct adipocyte populations are generated by a number of processes during and after development. These include the production of adipocytes from different germ cell layers, the formation of distinct preadipocyte populations from mesenchymal progenitors of mesodermal origin, and the production of adipocytes from hematopoietic stem cells from the bone marrow. This review will examine each of these process and their relevance to normal adipose tissue formation and contribution to obesity-related diseases. PMID- 21544901 TI - Concise review: non-cell autonomous reprogramming: a nucleic acid-free approach to induction of pluripotency. AB - The reprogramming of somatic cells to a pluripotent state by the expression of a defined set of exogenous transcription factors represents a significant breakthrough for the use of stem cells in regenerative medicine. It has the potential to make autologous stem cell therapy practical and promote better understanding of the disease processes by generating patient specific stem cells. Several strategies have been used to generate induced pluripotent stem cells (iPSCs) that include nucleic acid and non-nucleic acid-based approaches, with and without epigenetic modifications. The purpose of these different approaches for generating iPSCs, besides understanding the underlying mechanism, is to develop a facile method for reprogramming without genetic alteration, suitable for clinical use. Here, we discuss different strategies for generating iPSCs, with an emphasis on a recent non-cell autonomous approach to reprogram somatic progenitors that regenerate cornea to a pluripotent state through the recruitment of endogenous transcription factors. PMID- 21544902 TI - Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice. AB - Bone marrow-derived mesenchymal stromal cells (BMSCs) mitigate inflammation in mouse models of acute lung injury. However, specific mechanisms of BMSC actions on CD4 T lymphocyte-mediated inflammation in vivo remain poorly understood. Limited data suggests promotion of Th2 phenotype in models of Th1-mediated diseases. However, whether this might alleviate or worsen Th2-mediated diseases such as allergic asthma is unknown. To ascertain the effects of systemic administration of BMSCs in a mouse model of Th2-mediated allergic airways inflammation, ovalbumin (OVA)-induced allergic airways inflammation was induced in wild-type C57BL/6 and BALB/c mice as well as in interferon-gamma (IFNgamma) receptor null mice. Effects of systemic administration during antigen sensitization of either syngeneic or allogeneic BMSC on airways hyperreactivity, lung inflammation, antigen-specific CD4 T lymphocytes, and serum immunoglobulins were assessed. Both syngeneic and allogeneic BMSCs inhibited airways hyperreactivity and lung inflammation through a mechanism partly dependent on IFNgamma. However, contrary to existing data, BMSCs did not affect antigen specific CD4 T lymphocyte proliferation but rather promoted Th1 phenotype in vivo as assessed by both OVA-specific CD4 T lymphocyte cytokine production and OVA specific circulating immunoglobulins. BMSCs treated to prevent release of soluble mediators and a control cell population of primary dermal skin fibroblasts only partly mimicked the BMSC effects and in some cases worsened inflammation. In conclusion, BMSCs inhibit Th2-mediated allergic airways inflammation by influencing antigen-specific CD4 T lymphocyte differentiation. Promotion of a Th1 phenotype in antigen-specific CD4 T lymphocytes by BMSCs is sufficient to inhibit Th2-mediated allergic airways inflammation through an IFNgamma-dependent process. PMID- 21544903 TI - Brief report: efficient generation of hematopoietic precursors and progenitors from human pluripotent stem cell lines. AB - By mimicking embryonic development of the hematopoietic system, we have developed an optimized in vitro differentiation protocol for the generation of precursors of hematopoietic lineages and primitive hematopoietic cells from human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSCs). Factors such as cytokines, extra cellular matrix components, and small molecules as well as the temporal association and concentration of these factors were tested on seven different human ESC and iPSC lines. We report the differentiation of up to 84% human CD45+ cells (average 41% +/- 16%, from seven pluripotent lines) from the differentiation culture, including significant numbers of primitive CD45+/CD34+ and CD45+/CD34+/CD38- hematopoietic progenitors. Moreover, the numbers of hematopoietic progenitor cells generated, as measured by colony forming unit assays, were comparable to numbers obtained from fresh umbilical cord blood mononuclear cell isolates on a per CD45+ cell basis. Our approach demonstrates highly efficient generation of multipotent hematopoietic progenitors with among the highest efficiencies reported to date (CD45+/CD34+) using a single standardized differentiation protocol on several human ESC and iPSC lines. Our data add to the cumulating evidence for the existence of an in vitro derived precursor to the hematopoietic stem cell (HSC) with limited engrafting ability in transplanted mice but with multipotent hematopoietic potential. Because this protocol efficiently expands the preblood precursors and hematopoietic progenitors, it is ideal for testing novel factors for the generation and expansion of definitive HSCs with long-term repopulating ability. PMID- 21544904 TI - Concise review: putting a finger on stem cell biology: zinc finger nuclease driven targeted genetic editing in human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) encompassing human embryonic stem cells and human induced pluripotent stem cells (hiPSCs) have a wide appeal for numerous basic biology studies and for therapeutic applications because of their potential to give rise to almost any cell type in the human body and immense ability to self-renew. Much attention in the stem cell field is focused toward the study of gene-based anomalies relating to the causative affects of human disease and their correction with the potential for patient-specific therapies using gene corrected hiPSCs. Therefore, the genetic manipulation of stem cells is clearly important for the development of future medicine. Although successful targeted genetic engineering in hPSCs has been reported, these cases are surprisingly few because of inherent technical limitations with the methods used. The development of more robust and efficient means by which to achieve specific genomic modifications in hPSCs has far reaching implications for stem cell research and its applications. Recent proof-of-principle reports have shown that genetic alterations with minimal toxicity are now possible through the use of zinc finger nucleases (ZFNs) and the inherent DNA repair mechanisms within the cell. In light of recent comprehensive reviews that highlight the applications, methodologies, and prospects of ZFNs, this article focuses on the application of ZFNs to stem cell biology, discussing the published work to date, potential problems, and future uses for this technology both experimentally and therapeutically. PMID- 21544905 TI - An evaluation of site-specific immune responses directed against first-generation adenoviral vectors administered by convection-enhanced delivery. AB - BACKGROUND: Direct adenoviral vector injections into the brain have been used in clinical trials to treat patients with high-grade gliomas. However, a recent phase 3 trial using first-generation vectors failed to demonstrate significant survival benefits. Malignant gliomas infiltrate extensively through the white matter, making them difficult to treat, and chemotherapy is at best partially effective. Convection enhanced delivery (CED) represents a rationale approach for achieving widespread targeting of infiltrating tumour cells. Previous studies have demonstrated that infusions of particle numbers above a threshold level [10(8) plaque-forming units (pfu)] are associated with a pronounced inflammatory response in rat grey matter, although no such comparisons have been made with CED infusions into the white matter. METHODS: In the present study, we investigated the distribution and immune response after the administration of 10(7) and 10(9) pfu of a first-generation adenoviral vector (Ad.CMV.EGFP) by CED in both small and large animal models. RESULTS: We show that Ad.CMV.EGFP can be efficiently distributed by CED over large volumes of brain. A threshold vector dose of between 10(7) and 10(9) pfu was seen in both rat striatum and white matter, above which transgene expression was lost at 30 days. Furthermore, all adenoviral infusions were associated with evidence of significant tissue damage, as demonstrated by loss of neurones and astrocytes or the presence of extensive astrocytosis. CONCLUSIONS: These results indicate that CED is capable of mediating widespread adenoviral vector distribution, although these vectors are associated with significant tissue toxicity that may render their safe application in clinical trials unfeasible. PMID- 21544909 TI - All-or-nothing cooperative self-assembly of an annulene sandwich. PMID- 21544908 TI - Synthesis of 64Cu(II)-bis(dithiocarbamatebisphosphonate) and its conjugation with superparamagnetic iron oxide nanoparticles: in vivo evaluation as dual-modality PET-MRI agent. PMID- 21544910 TI - "Triazole bridge": disulfide-bond replacement by ruthenium-catalyzed formation of 1,5-disubstituted 1,2,3-triazoles. PMID- 21544911 TI - Copper-catalyzed intramolecular dehydrogenative aminooxygenation: direct access to formyl-substituted aromatic N-heterocycles. PMID- 21544912 TI - A conformational switch underlies ClpP protease function. PMID- 21544913 TI - Organocatalytic chemoselective monoacylation of 1,n-linear diols. PMID- 21544914 TI - Controlled metalation of a single adsorbed phthalocyanine. PMID- 21544916 TI - Parent heavy methylenes: chemical tricks to access isolable complexes of elusive H2E: species (E=Ge and Sn). PMID- 21544917 TI - Study of cytoskeletal changes induced by okadaic acid in HL-7702 liver cells and development of a fluorimetric microplate assay for detecting diarrhetic shellfish poisoning. AB - Diarrhetic shellfish poisoning (DSP) is a gastrointestinal illness with symptoms such as diarrhea, nausea, vomiting, headache, chills and moderate to severe abdominal pain. DSP has been recognized as a worldwide public health problem, causing great concern to the shellfish industry. Accumulation of DSP in shellfish is an unpredictable phenomenon that necessitates the implementation of a widespread collection and thorough monitoring program for mollusk toxicity. Therefore, development of accurate analytical protocols for the rapid determination of toxicity levels would be necessary. In this study we investigated cytoskeletal changes induced by okadaic acid in HL-7702 Liver Cells and developed a new cytotoxicity assay for detection and quantitation of DSP. This assay is based on fluorometric of F-actin depolymerization induced by okadaic acid (OA) compounds in HL-7702 liver cell line. The measurable range of OA was 2.5 ~ 40 nmol/L. The detection limit of the F-actin assay for OA was 2.01 MUg/100 g muscles in shellfish extracts. The performance of this assay has been evaluated by comparative analysis of shellfish samples by the fluorescent assay, mouse bioassay, and ELISA assay. Comparison of the results by all three methods revealed excellent consistency, the results of fluorescent assay were in significant correlation with ELISA assay (R(2) = 0.830). Examination of F-actin assay is very convenient, rapid, and sensitive, which can be used to quantify the amount of OA in shellfish samples. PMID- 21544918 TI - Fetal adrenal development: comparing effects of combined exposures to PCB 118 and PCB 153 in a sheep model. AB - This study investigated the effects of exposure to the ubiquitous contaminants polychlorinated biphenyls (PCBs) on the fetal adrenal cortex and on plasma cortisol using the domestic sheep (Ovis aries) as a model. Pregnant ewes were intendedly subjected to oral treatment with PCB 153 (98 MUg/kg bw/day), PCB 118 (49 MUg/kg bw/day) or the vehicle corn oil from mating until euthanasia on gestation day 134 (+/-0.25 SE). However, because of accidental cross contamination occurring twice causing a mixed exposure scenario in all three groups, the focus of this paper is to compare three distinct groups of fetuses with different adipose tissue PCB levels (PCB 153high, PCB 118high and low, combined groups) rather than comparing animals exposed to single PCB congeners to those of a control group. When comparing endocrine and anatomical parameters from fetuses in the PCB 153high (n = 13) or PCB 118high (n = 14) groups with the low, combined group (n = 14), there was a significant decrease in fetal body weight (P < 0.05), plasma cortisol concentration (P < 0.001) and adrenal cortex thickness (P < 0.001). Furthermore, adrenal weight was decreased and plasma ACTH was increased only in the PCB 118high group. Expression of several genes encoding enzymes and receptors related to steroid hormone synthesis was also affected and mostly down-regulated in fetuses with high PCB tissue levels. In conclusion, we suggest that mono-and di-ortho PCBs were able to interfere with growth, adrenal development and cortisol production in the fetal sheep model. (c) 2011 Wiley Periodicals, Inc. Environ Toxicol, 2013. PMID- 21544919 TI - Effects of quercetin and chrysin on 2,3,7,8-tetrachlorodibenzo-p-dioxin induced hepatotoxicity in rats. AB - The objective of current study is to investigate the effects of the administration of chrysin (CH) and quercetin (Q) on rat liver in which oxidative and histological damage had been induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Rats were randomly divided into six equal groups. TCDD was orally administered at the dose of 2 MUg/kg/week, and Q and CH were orally administered at the doses of 20 mg/kg day and 50 mg/kg/day, respectively, by gavages dissolved in corn oil. The liver samples to be analyzed for the determination of oxidative and histological alternations were taken from rats at 60 days. The results indicated that although 2,3,7,8-TCDD significantly induced (P <= 0.01) lipid peroxidation (increase of MDA levels), it positively affected oxidant/antioxidant system (a decline in the levels of GSH, CAT, GSH-Px, and CuZn-SOD) in rats significantly. The histological changes observed in the liver correlated with the biochemical findings. However, these effects of TCDD on oxidative and histological changes were eliminated by Q and CH treatment. In conclusion, TCDD caused an adverse effect on rat's liver. When Q and CH were given together with TCDD, they prevented hepatotoxicty induced by TCDD. Thus, it is thought that Q and CH may be useful as a new category of anti-TCDD toxicity agent. PMID- 21544920 TI - Bacterial biosensors for evaluating potential impacts of estrogenic endocrine disrupting compounds in multiple species. AB - To study the effects and possible mechanisms of suspected endocrine disrupting compounds (EDCs), a wide variety of assays have been developed. In this work, we generated engineered Escherichia coli biosensor strains that incorporate the ligand-binding domains (LBDs) of the beta-subtype estrogen receptors (ERbeta) from Solea solea (sole), and Sus scrofa (pig). These strains indicate the presence of ligands for these receptors by changes in growth phenotype, and can differentiate agonist from antagonist and give a rough indication of binding affinity via dose-response curves. The resulting strains were compared with our previously reported Homo sapiens ERbeta biosensor strain. In initial tests, all three of the strains correctly identified estrogenic test compounds with a high degree of certainly (Z' typically greater than 0.5), including the weakly binding test compound bisphenol A (BPA) (Z' ~ 0.1-0.3). The modular design of the sensing element in this strain allows quick development of new species-based biosensors by simple LBD swapping, suggesting its use in initial comparative analysis of EDC impacts across multiple species. Interestingly, the growth phenotypes of the biosensor strains indicate similar binding for highly estrogenic control compounds, but suggest differences in ligand binding for more weakly binding EDCs. PMID- 21544921 TI - Effects of trifluralin on the mouse ovary. AB - Trifluralin, a herbicide used to protect many arable and horticultural crops, was evaluated for its potential toxicity on the mammalian ovary. To this end, adult female mice were fed or not (control) with a trifluralin-enriched diet (150 mg/kg body weight/day) during gestation and lactation. After weaning, 3-week-old female mice from either trifluralin-treated or control groups were used to evaluate whether the exposure to this herbicide in utero and during lactation could induce stress responses in the ovary. It was found that trifluralin exposure caused a significantly higher level of p53, but not of pRb, in the whole ovary, and in particular in granulosa cells. TUNEL staining showed that herbicide treatment did not increase the apoptotic index of the somatic compartment. Also oocyte fertilizability was unaffected, as metaphase II oocytes retrieved from treated mice were capable of forming male and female pronuclei after in vitro fertilization as control mice. However, trifluralin determined a slightly higher number of oocytes with cytoplasmic degeneration compared with control animals. In conclusion, our results suggest that exposure to a low trifluralin dose during pregnancy and lactation does not impair oocyte quality, but can induce a stress response in ovarian somatic cells. PMID- 21544922 TI - Acute toxicity and superficial damage to goldfish from the ionic liquid 1-methyl 3-octylimidazolium bromide. AB - In the present study, goldfish toxicity and superficial damage from 1-methyl-3 octylimidazolium bromide ([C8 mim]Br) exposure were evaluated by an acute toxicity test. These results show that the 24-h 50% lethal concentration for [C8 mim]Br in goldfish is 244 mg L(-1) , and this indicates that [C8 mim]Br is a chemical with moderate or low toxicity to organisms. Scanning electronic microscope and histological observations revealed that acute exposure to [C8 mim]Br induced obvious superficial damage to the skin, gill filaments, and intestinal villi of the goldfish, and this suggests that the skin, gills, and intestines may be the first direct targets of the ionic liquid in this fish. Histological examination also indicated that [C8 mim]Br-exposure caused damage to the goldfish's hepatopancreas and kidney, consisting mainly of hepatic cords in a loose connection, hepatic cytoplasmic vacuolation, renal parenchyma vacuolization, and intumescence of the renal tubule. In addition, we found that [C8 mim]Br caused a significant increase in malondialdehyde (MDA) level in the hepatopancreases from these goldfish, and thus we suggest that the MDA level may be a biomarker of [C8 mim]Br-toxicity in goldfish. PMID- 21544923 TI - Toxicologic and immunologic effects of perinatal exposure to the brominated diphenyl ether (BDE) mixture DE-71 in the Sprague-Dawley rat. AB - Brominated diphenyl ethers (BDEs) are persistent environmental contaminants found in human blood, tissues, and milk. To assess the impact of the commercial BDE mixture DE-71 on the developing immune system in relation to hepatic and thyroid changes, adult (F0) rats were exposed to DE-71 by gavage at doses of 0, 0.5, 5, or 25 mg/kg body weight (bw)/d for 21 weeks. F0 rats were bred and exposure continued through gestation, lactation and postweaning. F1 pups were weaned and exposed to DE-71 by gavage from postnatal day (PND) 22 to 42. On PND 42, half of the F1 rats were assessed for toxicologic changes. The remaining F1 rats were challenged with the T-dependent antigen keyhole limpet hemocyanin (KLH) and immune function was assessed on PND 56. Dose-dependent increases in total BDE concentrations were detected in the liver and adipose of all F0 and F1 rats. In F0 rats, increased liver weight, hepatocellular hypertrophy, and decreased serum thyroxine (T4) were characteristic of DE-71 exposure. In F1 rats perinatal DE-71 exposure caused a nondose-dependent increase in body weight and dose-dependent increases in liver weight and hepatocellular hypertrophy. Serum T3 and T4 levels were decreased. In spleen from DE-71 exposed rats the area occupied by B cells declined while the area occupied by T cells increased; however, cellular and humoral immune responses to KLH challenge were not altered. Thus hepatic and thyroid changes in rats exposed perinatally to DE-71 were associated with altered splenic lymphocyte populations, an effect which has been linked to hypothyroidism. PMID- 21544924 TI - PFOS and PCB 153 have direct adverse effects on neonatal testis modeled using a coculture of primary gonocyte and sertoli cells. AB - Perfluorooctane sulfonate (PFOS) is widely used in industry; it is nonbiodegradable and persistent in the human body and in the environment. Although reports have indicated that young people might have higher PFOS levels in serum or blood than do older people, its adverse effects on neonatal testicular cells had not been investigated previously. PCB 153 is one of the most prevalent polychlorinated biphenyl (PCB) congeners in biological tissues, but the direct adverse effect of PCB 153 on neonatal testis remains unclear. In this study, we exposed a neonatal Sertoli cell/gonocyte coculture system to PFOS and PCB 153 individually at concentrations of 0, 1, 10, 50, and 100 MUM for 24 h. Exposure to either compound reduced the cell viability and induced the production of reactive oxygen species (ROS) in dose-dependent manners, with PCB 153 having a greater effect than PFOS. Whereas PCB 153 induced apoptosis significantly from 10 MUM, PFOS induced no obvious change. Morphologically, both PCB 153 and PFOS induced changes in the vimentin and actin filaments in the Sertoli cells, as investigated using confocal argon ion laser scanning microscopy; here, PFOS exhibited a more dramatic effect than did PCB 153. Furthermore, doses of 50 MUM for PFOS and 10 MUM for PCB 153 were the key concentrations that produced significant differences between the control and exposure groups. We suggest that both PCB 153 and PFOS directly affect neonatal gonocyte and Sertoli cells; the production of ROS and the change in the cytoskeleton in Sertoli cells might be causes. PMID- 21544925 TI - Involvement of oxidative stress in methyl parathion and parathion-induced toxicity and genotoxicity to human liver carcinoma (HepG2) cells. AB - Methyl parathion (C8H10NO5PS) and parathion (C10H14 NO5PS) are both organophosphate insecticides (OPI) widely used for household and agricultural applications. They are known for their ability to irreversibly inhibit acetylcholinesterase which often leads to a profound effect on the nervous system of exposed organisms. Many recently published studies have indicated that human exposure to OPI may be associated with neurologic, hematopoietic, cardiovascular, and reproductive adverse effects. Studies have also linked OPI exposure to a number of degenerative diseases including Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. Also, oxidative stress (OS) has been reported as a possible mechanism of OPI toxicity in humans. Hence, the aim of the present investigation was to use human liver carcinoma (HepG2) cells as a test model to evaluate the role of OS in methyl parathion- and parathion-induced toxicity. To achieve this goal, we performed the MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide] assay for cell viability, lipid peroxidation assay for malondialdehyde (MDA) production, and Comet assay for DNA damage, respectively. Results from MTT assay indicated that methyl parathion and parathion gradually reduce the viability of HepG2 cells in a dose-dependent manner, showing 48 h-LD50 values of 26.20 mM and 23.58 mM, respectively. Lipid peroxidation assay resulted in a significant increase (P < 0.05) of MDA level in methyl parathion- and parathion-treated HepG2 cells compared with controls, suggesting that OS plays a key role in OPI-induced toxicity. Comet assay indicated a significant increase in genotoxicity at higher concentrations of OPI exposure. Overall, we found that methyl-parathion is slightly less toxic than parathion to HepG2 cells. The cytotoxic effect of these OPI was found to be associated, at least in part, with oxidative cell/tissue damage. PMID- 21544926 TI - Metiram-induced nephrotoxicity in albino mice: effect of licorice aqueous extract. AB - The present study was designed to estimate the effect of aqueous extract of licorice on metiram toxicity in mice. Treating mice with metiram at a dose level of [1/2] LD(50) daily for 3 weeks induced many histological changes in the kidney cortex. The renal tubules lost their characteristic appearance and their lining epithelial cells were degenerated. The glomeruli were atrophied and the renal blood vessels were congested. The intertubular spaces infiltrated by inflammatory leukocytic cells. Metiram caused an increase in proliferating cell nuclear antigen (PCNA) expression in nuclei of tubular epithelial cells. Metiram also caused marked elevation in serum creatinine and blood urea nitrogen. Treating animals with metiram and licorice aqueous extract led to an improvement, in both biochemical and histopathological alterations. These results proved that licorice had an ameliorative effect against kidney injury induced by metiram and this effect may be attributed to its antioxidant activity. PMID- 21544927 TI - Transradial arterial access for coronary and peripheral procedures: executive summary by the Transradial Committee of the SCAI. AB - In response to growing U.S. interest, the Society for Coronary Angiography and Interventions recently formed a Transradial Committee whose purpose is to examine the utility, utilization, and training considerations related to transradial access for percutaneous coronary and peripheral procedures. With international partnership, the committee has composed a comprehensive overview of this subject presented here-with. PMID- 21544928 TI - Seven useful designs. AB - When designing a clinical trial there is a need to design a study that achieves the objectives of a trial both efficiently and with minimum resources. This paper describes seven trial designs that could possibly be used in clinical development and highlights how a design although not optimal for an individual study may be optimal for a wider clinical program. PMID- 21544929 TI - Quantitative comparison of randomization designs in sequential clinical trials based on treatment balance and allocation randomness. AB - To evaluate the performance of randomization designs under various parameter settings and trial sample sizes, and identify optimal designs with respect to both treatment imbalance and allocation randomness, we evaluate 260 design scenarios from 14 randomization designs under 15 sample sizes range from 10 to 300, using three measures for imbalance and three measures for randomness. The maximum absolute imbalance and the correct guess (CG) probability are selected to assess the trade-off performance of each randomization design. As measured by the maximum absolute imbalance and the CG probability, we found that performances of the 14 randomization designs are located in a closed region with the upper boundary (worst case) given by Efron's biased coin design (BCD) and the lower boundary (best case) from the Soares and Wu's big stick design (BSD). Designs close to the lower boundary provide a smaller imbalance and a higher randomness than designs close to the upper boundary. Our research suggested that optimization of randomization design is possible based on quantified evaluation of imbalance and randomness. Based on the maximum imbalance and CG probability, the BSD, Chen's biased coin design with imbalance tolerance method, and Chen's Ehrenfest urn design perform better than popularly used permuted block design, EBCD, and Wei's urn design. PMID- 21544931 TI - Improved adhesion of human cultured periosteal sheets to a porous poly(L-lactic acid) membrane scaffold without the aid of exogenous adhesion biomolecules. AB - Human cultured periosteal sheets, which are developed from small excised periosteum tissue segments (PTSs) in culture dishes by simple expansion culture, have been applied as a promising autologous osteogenic grafting material for periodontal regenerative therapy. However, the weak initial adhesion of PTSs to dish surfaces often hampers cellular outgrowth and limits the number of preparations. To correct this weakness and still avoid the use of animal-derived adhesion biomolecules, we have developed a novel, biodegradable, porous poly(L lactic acid) (pPLLA) membrane. Freshly excised PTSs bound well to the highly porous pPLLA membrane, possibly due to the presence of semihemispheric 20-30 MUm diameter openings on the upper surface. Global gene expression analysis demonstrated that periosteal sheets cultured on pPLLA membranes upregulated expression of many adhesion molecules. Osteogenic induction stimulated the production of proteoglycans by these cells and concomitantly enhanced their expansion and penetration into the deep pore regions of the membrane in parallel with the progression of in vitro mineralization. These findings suggest that our pPLLA membranes not only facilitate initial adhesion, primarily mediated by adsorbed proteins, but also enhance biological adhesion by inducing endogenous adhesion molecules in periosteal sheet cultures. Therefore, the efficacy of periosteal sheets in therapy should be greatly enhanced by using this new pPLLA membrane. PMID- 21544932 TI - [Central and peripheral mu-opioid systems in the mechanisms of emotional stress]. AB - The aim of the work was to study effect of peripheral administration of mu-opioid receptor ligands unable to penetrate through the hematoencephalic barrier on the measures of emotionality in rats and on the release of beta-endorphins from nerve endings of the anterior cingulate cortex during emotional stress. The mu-opioid receptor agonist loperimide mostly acted as an anxiolytic whereas the receptor antagonist methylnaloxon showed depressive activity. Lifetime microdialysis and subsequent immunoenzyme assay demonstrated that intraventricular infusion of loperamide and methylnaloxon decreased and increased respectively the surge of beta-endorphin into the intercellular space. Immobilization-induced emotional stress insignificantly increased the beta-endorphin level in the cingulate cortex. Peripheral administration of loperamide but not methylnaloxon markedly increased the release of the neuropeptide during stress. These findings confirm the hypothesis of the authors about reciprocal interaction of central and peripheral components of the endogenous opioid system and explain the mechanism of antistress action of loperamide. PMID- 21544933 TI - [CYP2C9 and VKORC1 gene polymorphism and acenocoumarol anticoagulant activity in Russian patients at high risk of thromboembolic complications]. AB - The study included 25 patients at high risk of thromboembolic complications. All of them were treated with acenocoumarol for 6 months under control of the frequency of hemorrhage and episodes of severe hypocoagulation (a more than 3 fold rise in INR). All the patients underwent CYP2C9 and VKORC1 genotyping. It was shown that the presence of CYP2C9*2 and CYP2C9*3 alleles in the CYP2C9 locus and the AA genotype of the polymorphous G-1639(3673)A marker of the VKORC1 gene was not associated with the development of severe hypocoagulation episodes (p = 0.261--for CYP2C9, p = 0.616 and 0.361 for VKORC1 in the total group and a subgroup of patients having the CYP2C9*1/*1 genotype respectively and treated with acenocoumarol. The search for other genetic markers of efficacy and safety of this drug should be continued. PMID- 21544934 TI - [Physiological and hygienic rationale for the duration of exposure to the heating environment and comfortable thermal conditions during a workshift]. AB - The strain in different functional systems of human body maintaining thermal homeostasis that develops during work under heating conditions results in impaired working capacity and efficiency and may be harmful to health. One of the most efficacious measures is the reduction of exposure to the adverse conditions and its rational alternation with rest in the comfortable environment. Based on the mathematical and statistical analysis of the results of multiple-factor experiments, we derived a multiple regression equation describing the quantitative dependence of the integral index of human body thermal regime on the totality of factors responsible for thermal strain. The equation permits to determine the heat content in the human body formed by exothermal and endothermal strain, to estimate the contribution of each individual factor, and to predict the risk of overheating in order to take measures for reducing the thermal strain. Recommendations are proposed on the duration of thermal exposure during a workshift depending on the overheating risk level and on the optimal relationship between the duration of staying in the heating microclimate and the duration of the rest (work) in the comfortable environment. PMID- 21544935 TI - Canadian pioneers: Charles Leonard Huskins (1897-1953). PMID- 21544936 TI - Sporadic Creutzfeldt-Jakob disease mimicking nonconvulsive status epilepticus. PMID- 21544937 TI - Nursing diagnoses, interventions, and patient outcomes for hospitalized older adults with pneumonia. AB - A study was conducted by academic and community hospital partners with clinical information systems that included the standardized nursing language classifications of the North American Nursing Diagnosis Association International (NANDA-I), Nursing Interventions Classification (NIC), and Nursing Outcomes Classification (NOC). The aim of the study was to determine the frequency of NANDA-I, NIC, and NOC (NNN) terms documented for older adults with pneumonia who were discharged from three hospitals during a 1-year period. NNN terms were ranked according to frequency for each hospital, and then the rankings were compared with previous studies. Similarity was greater across hospitals in rankings of NANDA-I and NOC terms than in rankings of NIC terms. NANDA-I and NIC terms are influenced by reimbursement and regulatory factors as well as patient condition. The 10 most frequent NNN terms for each hospital accounted only for a small to moderate percentage of the terms selected. PMID- 21544938 TI - [In the 11- M terrorist tragedy in Madrid]. PMID- 21544939 TI - Isolated pulmonary langerhans cell histiocytosis in a 3-year-old girl with atypical radiologic findings. PMID- 21544940 TI - Long-term study of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. AB - The efficacy and safety of infliximab in patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis (excluding localized type) and psoriatic erythroderma were assessed in clinical practice. Without washout of the existing treatment of psoriasis, treatment was switched to infliximab, which was given at a dose of 5 mg/kg at weeks 0, 2 and 6 and then every 8 weeks up to week 46. The primary end-points were 75% improvement in Psoriasis Area and Severity Index score (PASI 75 response rate) for plaque psoriasis, 20% improvement in American College of Rheumatology criteria (ACR 20 response rate) for psoriatic arthritis, and global improvement in pustular psoriasis and psoriatic erythroderma. The PASI 75 response rate in plaque psoriasis was 72.2% at week 10 and 53.6% at week 50. The ACR 20 response rate in psoriatic arthritis was 66.7% at week 14 and 80.0% at week 46. The response defined as global improvement in pustular psoriasis was between 66.7% and 100.0% during the 2-50-week period. The response defined as global improvement in psoriatic erythroderma was between 75.0% and 100.0% during the week-2-50 period. There were 14 discontinued patients. The most frequently reported reason for discontinuation was the development of adverse events. However, there were no serious respiratory diseases, infections or infusion reactions. In patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma, infliximab was well tolerated, regardless of prior treatment, and also showed superior efficacy over a period of approximately 1 year. PMID- 21544941 TI - Enhanced expression of Toll-like receptor 2 in lesional tissues and peripheral blood monocytes of patients with oral lichen planus. AB - Some members of the Toll-like receptor (TLR) family, which plays key roles in both innate and adaptive immune responses, are involved in the pathogenesis of autoimmune, chronic inflammatory and infectious diseases. However, the role of TLR in the pathogenesis of oral lichen planus (OLP) has not been investigated. The aim of this study was to understand the roles of TLR in OLP. The expression of TLR genes in OLP tissues was analyzed by cDNA microarray and reverse transcription polymerase chain reaction, and TLR protein expression in OLP tissues and peripheral blood monocytes was examined by immunohistochemical analysis and flow cytometry, respectively. Furthermore, TLR ligand-induced cytokine production from peripheral blood monocytes was measured by enzyme-linked immunosorbent assay. Among 10 TLR genes, the average expression ratio of the genes for TLR1, 2, 3, 5, 6 and 10 in OLP tissues compared to that in the normal buccal mucosae was more than 1.0. In contrast, the average ratio of the genes for TLR7, 8 and 9 was less than 1.0. TLR2 but not TLR4 was highly expressed in the cells of the spinous layer and infiltrating monocytes in OLP tissues, and the mean fluorescence intensity of TLR2 on peripheral blood monocytes was significantly higher in OLP patients than in healthy controls. Furthermore, the peripheral blood monocytes from OLP patients produced considerably higher amounts of interleukin (IL)-12 and lower amounts of IL-10 than those from healthy controls. In OLP, the T-helper cell (Th)1/Th2 balance appears to shift toward Th1 dominance, probably depending on the upregulation of TLR2 expression and these alterations in TLR2-mediated immunity may be involved in the pathogenesis and maintenance of OLP. PMID- 21544942 TI - Catadromous eels continue to be slippery research subjects. AB - As adults, Atlantic eels (Anguilla rostrata in the Americas and Anguilla anguilla in Europe) are tubular slime-covered fish that spend most of their catadromous life-cycle in coastal environs before swimming far out to sea to reproduce, as part of an intergenerational migratory circuit that provides an interesting reversal of the pattern displayed by adult anadromous salmon that live mostly in the ocean but then migrate long distances to spawn in freshwater streams. Earlier genetic findings on Atlantic eels involved specimens collected across their broad continental ranges and generally indicated that conspecifics probably engage in panmictic or quasi-panmictic spawning,from which arise leaf-shaped leptocephaus larvae that then disperse back to coastal locations more or less at random with respect to the widespread geographical origins of the parental genes they carry. In this issue, Alset al. (2011) add exciting information about this peculiar life history pattern of catadromous Atlantic eels by extending the genetic analyses to eel larvae collected from the Sargasso Sea, the oceanic area where both species spawn. Results help to confirm standard textbook wisdom that these catadromous eels are nearly unique in the biological world by having both broad geographical distributions and yet displaying intraspecific near panmixia. PMID- 21544943 TI - Screening of marine algae for potential tyrosinase inhibitor: those inhibitors reduced tyrosinase activity and melanin synthesis in zebrafish. AB - In order to find new anti-browning and whitening agents in this study, we investigated 43 indigenous marine algae for tyrosinase inhibitory activity. The extracts from Endarachne binghamiae, Schizymenia dubyi, Ecklonia cava (EC) and Sargassum silquastrum (SS) evidenced potent tyrosinase inhibitory activity similar to that of positive control, kojic acid. Among those marine algae, EC and SS are distributed abundantly on Jeju Island. Therefore, we selected those two species for further studies. Our results evidenced that both species reduced cellular melanin synthesis and tyrosinase activity. On the other hand, we utilized zebrafish as an alternative in vivo model. All the tested samples evidenced excellent inhibitory effects on the pigmentation of zebrafish, most likely due to their potential tyrosinase inhibitory activity. In simultaneous in vivo toxicity tests, no toxicity was observed in either algal species, on the other hand, toxicity was observed in positive controls. These results provided that EC and SS extract could be used as an ingredient for whiting cosmetics and that zebrafish is an alternative in vivo model. PMID- 21544944 TI - Detecting gene expression profiles associated with environmental stressors within an ecological context. PMID- 21544945 TI - Successful treatment of multiple keratoacanthoma with topical imiquimod and low dose acitretin. PMID- 21544946 TI - Folliculosebaceous cystic hamartoma associated with melanocytic nevus. PMID- 21544947 TI - Unusual presentations of papular umbilicated granuloma annulare. PMID- 21544948 TI - Clinical features of acne vulgaris in 444 patients with ethnic skin. PMID- 21544949 TI - Follicular spicules associated with Propionibacterium acnes in response to erythromycin. PMID- 21544950 TI - A diabetes drug, sitagliptin, also has a potential to prevent diabetes. PMID- 21544951 TI - Predicting disease phenotypes based on the molecular networks with condition responsive correlation. AB - Network-based methods using molecular interaction networks integrated with gene expression profiles have been proposed to solve problems, which arose from smaller number of samples compared with the large number of predictors. However, previous network-based methods, which have focused only on expression levels of proteins, nodes in the network through the identification of condition-responsive interactions. We propose a novel network-based classification, which focuses on both nodes with discriminative expression levels and edges with Condition Responsive Correlations (CRCs) across two phenotypes. We found that modules with condition-responsive interactions provide candidate molecular models for diseases and show improved performances compared conventional gene-centric classification methods. PMID- 21544952 TI - Semi-automatic 3D segmentation of brain structures from MRI. AB - We present a semi-automatic 3D segmentation method for brain structures from Magnetic Resonance Imaging (MRI). There are three main contributions. First, our method combines boundary-based and region-based approaches but differs from previous hybrid methods in that we perform them in two separate phases. This allows for more efficient segmentation. Second, a probability map is generated and used throughout the segmentation to account for the brain structures with low intensity contrast to the background. Third, we develop a set of tools for manual adjustment after the segmentation. This is particularly important in clinical research because the reliability of the results can be ensured. The experimental results and validations on different data sets are shown. PMID- 21544953 TI - Predictions of flexible C-terminal tethers of bacterial proteins with the FLEXTAIL bioinformatics pipeline. AB - Proteins use conserved binding motifs associated with relatively unconserved flexible amino acid sequences as mobile tethers for interacting molecules, as exemplified by C-terminal sequences of bacterial chemotaxis receptors. The FLEXTAIL bioinformatics pipeline predicts flexible tethers and their binding motifs based on the properties of flexibility and sequence conservation. In four groups of bacterial genomes, the algorithm identified > 100 putative binding domains, including verifying the known bacterial chemotaxis receptor-- NWETF binding motif. Some potential C-terminal flexible regions that have not previously been recognised to function as protein tethers were found and should be investigated further for binding targets and flexibility. PMID- 21544954 TI - Improving accuracy of microarray classification by a simple multi-task feature selection filter. AB - Leveraging information from the publicly accessible data repositories can be very useful when training a classifier from a small-sample microarray data. To achieve this, we proposed a multi-task feature selection filter that borrows strength from auxiliary microarray data. It uses Kruskal-Wallis test on auxiliary data and ranks genes based on their aggregated p-values. The top-ranked genes are selected as features for the target task classifier. The multi-task filter was evaluated on microarray data related to nine different types of cancers. The results showed that the multi-task feature selection is very successful when applied in conjunction with both single-task and multi-task classifiers. PMID- 21544955 TI - Modelling gene and protein regulatory networks with answer set programming. AB - Recently, many approaches to model regulatory networks have been proposed in the systems biology domain. However, the task is far from being solved. In this paper, we propose an Answer Set Programming (ASP)-based approach to model interaction networks. We build a general ASP framework that describes the network semantics and allows modelling specific networks with little effort. ASP provides a rich and flexible toolbox that allows expanding the framework with desired features. In this paper, we tune our framework to mimic Boolean network behaviour and apply it to model the Budding Yeast and Fission Yeast cell cycle networks. The obtained steady states of these networks correspond to those of the Boolean networks. PMID- 21544956 TI - Medicinal chemistry by the numbers: the physicochemistry, thermodynamics and kinetics of modern drug design. PMID- 21544957 TI - The identification of and rationale for drugs which act at the motilin receptor. PMID- 21544958 TI - Progress in the design and development of phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of chronic diseases. PMID- 21544959 TI - Progress in the development of beta-secretase inhibitors for Alzheimer's disease. AB - Since the original identification of BACE in 1999 and until quite recently, BACE was often regarded as a "difficult" drug target, much as renin has proven to be. The reasons for this include the following. First, the long and shallow nature of the substrate binding pocket suggested that it would not be possible to identify small molecule drugs that could have adequate binding affinity. Second, functional groups that typically interact with the active site aspartates are usually highly polarized and, therefore, contribute to reduced CNS localization. Early BACE inhibitors were all designed using knowledge of the peptide substrates and usually contained some variation of a few well-known transition-state isosteres. While these had great impact on fundamental understanding of the enzyme structure and key interaction regions, they were very large, very polar, and had essentially no CNS availability. Continued progress by reducing the peptidic nature of these compounds resulted in incremental advances and has provided compounds that meet, or nearly meet, typical CNS drug-like criteria. The challenges associated with peptidic starting points inspired innovative new approaches to search for different starting points. Several groups employed high concentration screening (ligand concentration 100 microM and higher) to find weak hits after conventional screening (typically at 10 microM) failed to find more potent ones. Fragment-based methods have also been developed to identify even weaker hits (IC50 1 mM and greater). This was accomplished through the evolution and refinement of several detection methodologies including calorimetry, surface plasmon resonance, NMR, and crystallography. Coupled with detailed structural understanding of ligand-enzyme interactions and focus on maintaining ligand efficiency, these developments have resulted in several examples where potency was improved by 10,000-fold to afford compounds with IC50 values < 10 nM and promising drug-like characteristics. Together, all these efforts have afforded a diverse array of chemotypes as BACE inhibitors. Early work focused on improving BACE potency in isolated enzyme assays. However, most of these compounds showed potency reductions in cellular assays. Continued improvements in drug properties and in understanding of the physiologically relevant conditions have resulted in many compounds that show strong potency in both isolated and cellular assays. Several compounds have shown reduction of Abeta using rodent in-vivo models both peripherally and in the brain. Recently, one compound has demonstrated reduction of brain Abeta levels in a non-human primate. Phase I clinical trials were initiated on BACE inhibitor CTS-21166 from CoMentis in July of 2007. This compound derives from the earliest described peptidic inhibitors such as OM99-2 [58] but no details have been reported. In addition to strategies involving small molecule inhibitors of BACE and gamma-secretase to reduce Abeta levels, the application of biological agents has been under investigation since the identification of Abeta. The earliest efforts in this area failed. Despite encouraging results in preclinical models, immunization against Abeta by administration of AN-1792 from Elan led to development of aseptic meningoencephalitis in 6% of the patients receiving the drug. Nevertheless, continued efforts with other biological approaches appear encouraging. Most advanced in clinical trials is bapineuzumab from Elan, which is in Phase III clinical trials. This is a humanized monoclonal antibody against Abeta plaques. A recent monograph is devoted to progress in these areas. Taken together, considerable progress has been made in developing CNS-penetrant agents that reduce AP levels and in providing validation that such agents will be therapeutically beneficial for the treatment of Alzheimer's disease. PMID- 21544960 TI - Advances in the design of 5-HT6 receptor ligands with therapeutic potential. PMID- 21544961 TI - Delirium superimposed on dementia. Assessment and intervention. AB - Delirium remains a significant risk for hospitalized older adults and has been shown to be a persistent risk posthospitalization as well. Dementia is a risk factor for delirium. The prevalence of delirium superimposed on dementia (DSD) ranges from 22% to 89% in hospitalized and community-dwelling individuals 65 and older. Individuals with DSD have been found to have accelerated decline in cognitive and functional abilities, greater need for institutionalization, greater rehospitalization risk, and increased mortality. The purpose of this article is to define and describe DSD, outline assessment tools for its identification, and provide appropriate nursing interventions. PMID- 21544962 TI - Challenges and strategies for heart failure symptom management in older adults. AB - Heart failure (HF), predominant in adults older than 65, is a chronic and progressive syndrome frequently associated with the burden of distressing symptoms. HF symptom management is directed at treating the underlying causes of acute decompensation, which commonly relate to lack of medication adherence or dietary restriction. Therefore, for older adults capable of managing their health care needs, promotion of self-care is essential for symptom management. Using the Model of Heart Failure Self-Care as a guide, the purpose of this article is to discuss the relationship between self-care and HF symptom management and to provide nursing strategies for assessment and promotion of self-care in older adults with HF. PMID- 21544963 TI - Delirium in older cardiac surgery patients: directions for practice. AB - Delirium affects approximately 20% to 25% of patients undergoing cardiac surgery and is particularly common in older adults. This article reviews the etiology and risk factors for delirium associated with cardiac surgery in older adults. Delirium screening, prevention, and treatment strategies, including both pharmacological and nonpharmacological therapies, are presented. Interventions appropriate in both the intensive care unit and PMID- 21544965 TI - Handoffs: what ORs can learn from formula one race crews. PMID- 21544964 TI - Complementary and alternative medicine for older adults with venous leg ulcer pain. AB - Chronic pain management is an important, and often under-addressed, component in the care of older adults with venous leg ulcers (VLUs). Clinicians caring for older adults with VLUs must consider and address both the physiological and psychosocial aspects of chronic pain. Traditional pharmacological approaches to pain management are only part of the solution. One strategy is to adopt a more holistic approach to chronic pain management that includes complementary and alternative medicine (CAM) therapies. Unfortunately, there is a paucity of CAM research that focuses on the pain management of older adults with VLUs. Despite these limitations, pain management that includes discussion of relevant CAM modalities must be a priority for clinicians caring for older adults living with VLUs. PMID- 21544966 TI - Health tips. Controlling dandruff. PMID- 21544967 TI - Freezing out the pain of bone tumors. PMID- 21544968 TI - Coronary artery spasm. A trigger of trouble. PMID- 21544969 TI - Savvy salads. Create a healthy meal. PMID- 21544970 TI - I'm looking to taper off a medication that I'm taking. Should I just start taking it every other day? PMID- 21544971 TI - FDA limits prescription acetaminophen. But be vigilant about over-the-counter acetaminophen, too. PMID- 21544972 TI - Keeping up with your vaccinations. New guidelines include several changes. PMID- 21544973 TI - Minimally invasive treatments for bothersome leg veins. Treating enlarged leg veins can improve their appearance and reduce the risk of swelling, aching, and other problems. PMID- 21544974 TI - Mindfulness meditation practice changes the brain. PMID- 21544975 TI - Timing of hormone therapy influences breast cancer risk. PMID- 21544976 TI - Ask the doctor. I'm 50 years old and have never had an HPV test. Do I need one as part of my health screening? PMID- 21544977 TI - [Levofloxacin and other fluoroquinolones in therapy of respiratory tract infections]. AB - Levofloxacin, like other fluoroquinolones, acts as a antibacterial agent on bacterial topoisomerases. A broad range of Gram-positive and Gram-negative of levofloxacin was confirmed in clinical trials in patients with respiratory tract infections. In therapy of chronic diseases exacerbations of the respiratory tract, including community-acquired pneumonia, a high oral bioavailability allows to switch from intravenous to oral way of treatment. Although a high penetration degree of levofloxacin into serum and tissues gives possibility to control bacterial biofilm. For this reasons levofloxacin is recommended for therapy of respiratory tract infections as a second-line antibacterial agent, but in severe exacerbations may be considered as additional therapy, rarely as monotherapy. PMID- 21544978 TI - [Risk factors of death or re-hospitalization in acute coronary syndrome patients before and after earlier heart revascularization]. AB - Cardiovascular diseases including coronary artery disease and its complications- acute coronary syndromes (ACS) are the leading causes of mortality in developed countries. With the growing number of percutaneous revascularization procedures (PCI) patients with at least one prior revascularization procedure constitute a growing population. The aim of the study was to define the predictors of death and rehospitalization of patients treated for ACS before and after earlier heart revascularization. MATERIAL AND METHODS: The study group consisted of 325 patients admitted with the ACS symptoms, 147 patients with prior PCI, 28 patients with former surgical revascularization and 150 patients with no prior coronary artery revascularization procedure. Case-history acquisition, physical examination, ECG, ultrasound echocardiography, coronary angiography and angioplasty of the ACS related vessel as well as the laboratory assessment of morphology, creatinine, sodium, potassium, glucose, troponine I, creatine kinase and its MB isoenzyme serum levels were performed in all cases. RESULTS: The study revealed that cardiogenic shock at the baseline, non-successful PCI procedure, impaired < 45% left ventricle ejection fraction were the independent predictors for death or re-hospitalization due to ACS onset. CONCLUSIONS: Even though ACS patients with prior revascularization history have worse echocardiographic parameters which have determined prognostic value, compared with patients with no prior revascularization the prognosis for the 6-month follow-up in both groups remains comparable. PMID- 21544979 TI - [Venous thrombosis as a complication of pacemaker implantation--own observations]. AB - Thrombosis is a fairly rare, yet dangerous complication of pacemaker implantation. It may occur in various time intervals after the actual implantation procedure. The risk factors are as follows: inflammation or injury, vein anomalies, arrhythmia, venous stenosis. The aim of the study was to assess the risk factors for venous thrombosis, determine the interrelationship between venous thrombosis and the level of select inflammatory and pro-thrombotic factors, as well as to evaluate the actual impact of pacemaker implantation procedure within a group of patients with permanent heart stimulation system. MATERIAL AND METHODS: The study involved 48 patients with permanent heart stimulation system, divided into 2 groups. Group A (18 F, 20 M; mean age 71.7 +/- 13.6 years) consisted of patients who had up to 3 thrombotic risk factors, whereas group B (2 F, 8 M; mean age 71.6 +/- 7.5 years) comprised the patients with more than 5 thrombotic risk factors. All patients were subsequently followed up for 18 months. Prior to pacemaker implantation the following factors were assessed in each patient: specific indications for pacemaker implantation, overall clinical condition, coexisting diseases, history of tobacco smoking, medications used prior to the procedure (anti-platelet, anti-coagulation), history of thrombotic or infectious complications, previous temporary heart stimulation. A transthoracic echocardiogram (TTE) and an ultrasound examination of the veins in both upper extremities were carried out. The levels of: D-dimers, fibrinogen, interleukin-6 (IL-6), hsCRP, TF and PAI-1 were determined in the venous blood. During the pacemaker implantation procedure the actual access to the veins and possible venous anomalies were assessed. After the pacemaker implantation, the TTE and venous ultrasound examination were carried out after 6 and 12 months, blood analyses for up to 7 days after the implantation, and subsequently after 6 and 12 months. RESULTS: Patients in group B had significantly lower left ventricle ejection fraction and larger left ventricle end diastolic diameter than group A patients. In 3 patients in group B (which made up 6.25% of the study population), symptomatic venous thrombosis occurred after a 12-month observation period (mean 13.06 months). Initially, the levels of IL-6, hsCRP, TF, PAI-1, fibrinogen and D-dimers were considerably higher in group B, in comparison to group A. In all patients the levels of the above referenced factors kept on increasing for up to 7 days after the procedure. In group A they subsequently decreased, whereas in group B they kept on growing. In group B a significant negative correlation was observed between the left ventricle ejection fraction and the inflammatory and thrombotic factors under study. The lower the ejection fraction, the higher actually were their values. CONCLUSIONS: In patients with more than 5 thrombosis risk factors, the increased levels of IL-6, hsCRP, fibrinogen, D-dimers, TF and PAI-1 were observed. A pacemaker implantation procedure is believed to increase both thrombotic and inflammatory state in a patient for up to 7 days after the procedure. In patients prone to thrombosis, a negative correlation between the ejection fraction and the levels of hsCRP, D dimers, TF and PAI-1 were observed. PMID- 21544980 TI - [Subpopulation of CD14+CD16+ monocytes in the children with acute lymphoblastic leukemia treated with filgrastim]. AB - It is well known that patients with leucopenia are susceptible to life threatening infections due to chemotherapy. The number of neutrophils and monocytes is increasing after administration filgrastim (G-CSF) in patients with the acute lymphoblastic leukemia. CD16 expression was analyzed in order to determine whether monocytes function is also impaired by chemotherapy CD16. The aim of study was to compare the percentage of CD14+CD16+ monocytes in the group of children with the acute lymphoblastic leukemia after administration filgrastim with the group of children with inflammatory state and the group of the healthy children. MATERIALS AND METHODS: The cell surface expression of CD16 was analyzed by flow cytometry. The percentage of CD16 expression and the mean intensity fluorescence rate of CD16 receptor was studied. RESULTS: Monocytes showed increased CD16 expression in the group of the children with the acute lymphoblastic leukemia in comparison to the other two groups. There were no differences in the mean fluorescence intensity of the CD16 monocytes between groups. CONCLUSIONS: The present study demonstrated that G-CSF increased the percentage of monocytes with the CD16 expression, which could be beneficial to the immunological response of the children with the acute lymphoblastic leukemia. PMID- 21544981 TI - [Symptoms from the internal organs of patients with systemic sclerosis in the light of selected diagnostic tests]. AB - Systemic sclerosis (SSc) is a chronic, progressive connective tissue disease with the different clinical course characterized by a progressive fibrosis of the skin and internal organs, leading to their failure, changes in blood morphology and blood vessels disorders. The disease most often affects the skin, the osteoarticular system, the alimentary tract, the cardio-vascular system, lungs, kidneys and the nervous system. In involved systems and organs observed symptoms are able to develop gradually relatively to disease course, leading to a permanent and irreversible health damage. The aim of study was to identify major symptoms of SSc patients and to examine the relation between patients' complaints and the results of diagnostic tests: pulmonary artery pressure (PHT), lung image (X-ray and HRCT) and cytology of broncho-alveolar lavage (BAL), oesophagus X-ray and stress ECG. MATERIAL AND METHODS: The study group consisted of 63 patients with diagnosed SSc according to the ARA criteria: 47 with limited systemic sclerosis (ISSc) (74.6%) and 16 with diffuse systemic sclerosis (dSSc) (25.4%). The basic research tool was a survey questionnaire drafted for the needs of this study, assessing the health problems of patients. The examination was performed in all patients and the results of diagnostic tests were completed in selected groups according to therapeutic purposes. RESULTS: From the all identified symptoms from the alimentary tract the most characteristic was heartburn (in 71% cases). About 60% of subjects reported difficulties with swallowing, out of which 68% were ISSc patients (p < or = 0.05). The X-ray examination of the oesophagus showed a shallow peristaltic wave in 55% patients with this complaint, and it occurred significantly more often in patients who were diagnosed as ISSc for > or = 15 years (p < or = 0.05). A positive result of HRCT was more often obtained in the group of patients with dSSc (p < or = 0.05). It has been proved that there is a significant relation between fatigue reported by patients and a positive result of HRCT and BAL (p < or = 0.05). A positive result of exercise ECG was obtained in 69% of patients with dyspnoea and 61% with fatigue (p < or = 0.05). CONCLUSIONS: Disorders of the gastrointestinal tract demonstrated particular intensity in patients with ISSc, with known shall owing of the peristaltic wave in the X-ray of the esophagus. Pulmonary changes were observed in HRCT and BAL, concerned mostly dSSc patients in whom fatigue was the major symptom. Patients who declared fatigue and dyspnoea had changes in exercise ECG, with no relation to the clinical presentation of SSc. PMID- 21544982 TI - [Cultivated oral epithelial cells in oral cavity tissue losses treatment with autologous transplantation--case reports]. AB - The rapid development of bioengineering in recent years enables to search for new therapies involving the use of tissue cultures. The aim of this paper is to study and apply the method of keratinocytes culture of mucous membrane on amniotic membrane to cover the losses in the oral cavity. MATERIAL AND METHODS: In four cases keratinocytes culture on amniotic membrane was applied and transplanted to cover antro-oral fistulas and mucosal and mandibular bone losses. RESULTS: Histopathological and immunohistochemistrical examinations of the culture were performed. Cytokeratin 14, protein 63, conexin 43 and IgG were indicated. CONCLUSION: Autologous transplants of epithelial cells on amniotic membrane are a new effective method to cover unhealed tissue losses in oral cavity with the use of modern methods of tissue engineering. PMID- 21544983 TI - [The use of induced sputum examination in respiratory system diseases]. AB - Induced sputum is a valuable tool enabling thorough evaluation of respiratory system, and it has been increasingly used in pneumonology. The article presents the mechanism of sputum induction and basic differences between induced sputum and BALF. The usefulness of induced sputum in modern oncology and microbiology is discussed, from diagnosing lung cancer and tuberculosis to assessment and monitoring of respiratory tract bacterial flora in chronic lung diseases. The authors describe the role of sputum cell count and fluid-phase analysis in various conditions, like asthma, COPD, non-asthmatic eosinophilic bronchitis (NAEB) and interstitial lung diseases, as well as in estimating occupational exposure for diagnosing occupational respiratory disorders. Basic guidelines for sputum induction methodology are discussed, and indications, contraindications and safety issues presented. PMID- 21544984 TI - [Current views on the etiopathogenesis of autoimmune thyroiditis (Hashimoto's disease)]. AB - Autoimmune thyroiditis (Hashimoto's disease) is the most common type of inflammation of the thyroid gland. Although its etiopathogenesis is still unclear, it is defined as a polygenic disorder developing as the result of complex reactions between genetic and environmental factors. These factors lead to the breakdown of natural resistance to self-antigens and the development of auto-reactive lymphocytes and immunoglobulins. Environmental factors which play an important role in the development of autoimmune thyroiditis include iodine excess, interferon alpha and bacterial and viral infections. There are some genes whose polymorphisms have been confirmed as etiologic factors associated with the development of autoimmune thyroiditis. These are as follows: some variants of the HLA genes, PTPN and Tg genes and genes encoding proinflammatory cytokines such as: IFNgamma, TGFbeta, IL6 and IL4. Hitherto there has been no clear confirmation of the participation of the following genes polymorphisms in the development of autoimmune thyroiditis: IL, IL10, IL2beta, IL1R, IL4R, IL23R. PMID- 21544985 TI - [Cardiovascular complications of phosphodiesterase-5 inhibitors]. AB - Phosphodiesterase type 5 inhibitors increase the intracellular level of cyclic guanosine monophosphate that is a potent nitric oxide dependent vasodilatation and antiproliferation agent. Unlike vardenafil and tadalafil which are prescribed in the erectile dysfunction, sildenafil is also used in a treatment of the pulmonary arterial hypertension, both congenital and acquired. The drug administration may let to various side effects such epistaxis, headache, flushing, eye problem including blurry vision, retinal hemorrhage and nonarteritic anterior ischemic optic neuropathy. It may be also complicated by high reduction of blood pressure and syncope especially in patients concomitantly treated with oral nitrate medications. High caution should be also taken in patients with a heart failure. PMID- 21544986 TI - [Rare causes of hypoglycemia in adults--glycogen storage diseases]. AB - Metabolic diseases such as glycogen storage diseases, disorders of gluconeogenesis and fatty acid oxidation disorders belong to rare causes of hypoglycemia. Most of them are diagnosed in a childhood, but they can be also revealed in an adulthood. This paper discusses clinical and laboratory signs of glycogen storage diseases leading to hypoglycemia. It also presents cases of patients with such disorders diagnosed in adulthood and described in the literature. PMID- 21544987 TI - [Rare causes of hypoglycemia in adults--disorders of gluconeogenesis and fatty acid oxidation disorders]. AB - Disorders of gluconeogenesis and fatty acid oxidation disorders belong to rare causes of hypoglycemia. Most of them are diagnosed in a childhood, but they can be revealed also in an adulthood. This paper discusses clinical and laboratory signs of these disorders and presents cases of patients diagnosed in adulthood and described in the literature. PMID- 21544988 TI - [Glycated hemoglobin (HbA1c) as a standard diagnostic criterium for diabetes?]. AB - Glycated hemoglobin HbA1c is considered the gold standard for assessing the compensation and treatment of diabetes. After the success of the DCCT and UKPDS studies, which showed that HbA1c is an independent indicator of risk for the development of chronic vascular complications of diabetes, this parameter was used for routine monitoring of metabolic control. In 2010, the American Diabetes Association introduced HbA1c determined by HPLC or HPLC-standardized methods for the diagnosis of diabetes as a parameter more accurate and more stable than the determination of fasting plasma glucose or oral glucose tolerance test. HbA1c measurements can be performed by different analytical methods including HPLC, affinity chromatography, electrophoresis and immunoenzymatic and immunoturbidometric methods. Due to differences in the results of HbA1c determined by laboratories using various methods, it is extremely important to standardize methods for the results given by the HPLC method compared to the methods used in the DCCT and UKPDS studies. The problem is even greater as the large discrepancies are observed between the frequency of carbohydrate disorders diagnosed on the basis of determination of HbA1c and glucose, which raise important questions concerning the widespread introduction of HbA1c for the diagnosis of diabetes. PMID- 21544989 TI - [Aspects of the standardization of glycated hemoglobin (HbA1c) measurement]. AB - Glycated hemoglobin (HbA1c) is considered the gold standard for monitoring and the treatment of diabetes. After the success of the DCCT and UKPDS studies, which showed that HbA1c is an independent indicator for risk of developing chronic complications of diabetes, intensive work began on the standardization of this parameter. Currently, the process of standardization of HbA1c determination is being pursued by two independent international organizations: NGSP and IFCC. At present most HbA1c determinations carried out worldwide are done via a test which is performed using uniform and standardized methods, which have been certified by the NGSP. At the same time, the IFCC has created a new, more consistent and specific method of standardization, but this method is not used routinely. According to the IFCC standard, HbA1c values are significantly lower compared to the results obtained by NGSP. Moreover, the IFCC has introduced a new alternative unit of HbA1c mmol/mol. Discrepancies between the programs of the two organizations, their advantages and disadvantages, have led to the consensus on global standardization of HbA1c determinations. This paper presents aspects of the standardization of HbA1c determination methods, which takes into account the obtained values and recommended range of values for each group of diabetic patients, as well as the statement of the largest diabetological organization. PMID- 21544990 TI - [Emotional dysregulation in borderline personality disorder]. AB - Borderline personality disorder (BDP) concerns young people, because it surfaces to emerge in early adult age and it last up to forties. Approximately 2 people out of 100 suffer from this disorder and they are mainly women. Borderline personality projects unprofitable onto individual development, disturbs interpersonal relationships and exposes to untimely death, because of autodestructional behaviors and suicidal tendencies strongly connected with this issue. The only purpose of treatment is acceleration of natural process of recuperation by appeasement of symptoms and improvement of functioning, especially an elimination of autoaggression acts and rescue from suicidal. In order to achieve the effects, very essential is to choose appropriate methods for each patients. Borderline personality disorder prognosis are far more advantageous than in any other mental disorder. PMID- 21544991 TI - [Professional burnout among people suffer from psoriasis]. AB - Discussion in topic of professional burnout subject to discussion in Poland since 80'. Professional burnout is a state of emotional and physical exhaustion caused by excessive and prolonged stress. As the stress continues, you begin to lose the interest or motivation of job, additionally burnout reduces your productivity or energy. That's why it's important to recognize the early signs of burnout. Discriminate three phases of professional burnout: emotional exhaustion, depersonalization and reduced personal accomplishment. The risk of professional burnout involve especially people who suffer from psoriasis. The aim of this study was to discuss the problem about burnout among people suffer from psoriasis. PMID- 21544992 TI - [The current state of knowledge of pediatric sleep medicine. Report from the Congress of the International Pediatric Sleep Association (IPSA) joint meeting with Pediatric Sleep Medicine Conference (Rome, 2010)]. AB - The Congress of the International Pediatric Sleep Association joint meeting with Pediatric Sleep Medicine Conference was held in Rome on December 3-5, 2010. It was chaired by the president of IPSA, prof. O. Bruni. About 400 participants taking part in 20 sessions could listen to lectures delivered by the most prominent specialists in pediatric sleep medicine. The presented issues related to sleep development, sleep-disordered breathing, abnormal behaviors and movements during sleep (restless legs syndrome, periodic limb movement disorder, bruxism), epilepsy, narcolepsy, insomnia, infant apnea, arousals and SIDS, sleep problems in children with other diseases (cancer, autism, ADHD, obesity), pharmacological treatment of pediatric sleep disorders, sleep habits, sleep education programs for children and families. This paper reports on the latest findings in the field of sleep medicine presented at the Congress. Particular attention was paid to practical issues in daily clinical work. PMID- 21544993 TI - [Posttransfusion iron overload]. AB - Patients receiving red cell concentration regularly are liable to develop iron overload. The characteristic feature of this condition is higher than normal generalized iron depositing. Iron excess initially is deposited in the liver, reticuloendothelial system, and consequently in such organs as the heart and endocrine glands. Humans do not possess mechanisms to excrete the excess of this metal. Patients who have undergone long time hemotherapy develop manifestations of diabetes, liver cirrhosis or cardiomyopathy; the most common cause of death is heart failure. Posttransfusion iron overload is observed most often in patients with thalassemia, aplastic and hemolytic syndromes and with syderoplastic anemias. An interesting fact is that numerous and long time transfusions in patients with chronic bleeding do not results in iron overload. Each transfused unit of red cell concentrate delivers approximately 250 mg of iron, thus iron accumulation is an inevitable effect of long time red cell concentrate therapy. Excessive iron intake manifests clinically when the total iron level reaches 400 1000 mg/kg b.m. The clinical picture resulting from posttransfusion iron overload includes dark skin, liver cirrhosis and circulatory disorders in the form of arrhythmia and insufficiency (of left ventricle, particularly). Iron overload can be treated but it is better to prevent it by administering chelating drugs. These compounds have high affinity and specificity to iron. They eliminate it with urine in the form of a bound complex. The use of chelating drugs is recommended when around 20 red cell concentrate units have been transfused and the serum ferritin level is about 1000 microg/ml. PMID- 21544994 TI - [The epidemiological trends connected with detection of HIV, HCV, HBV and syphilis markers in blood donors in the years 2006-2009]. AB - In the recent years a great progress has been documented in infection prevention. There is more possibilities responsible for infection and its transmission. THE AIM OF THE STUDY: To analyze obtained epidemiological data concerned to detected infection in blood donors in the area of Blood Bank in Katowice in the years 2006 2009. MATERIAL AND METHODS: Statistic calculations taking account of confirmed infections in the years 2006-2009 were analyzed in first-time donors and multiple donors, and for all donors. RESULTS: Tests confirming infection were performed in the IHiT in Warsaw, in RBC in Katowice, confirmation test for syphilis in the RBC in Warsaw. Only the positive confirmed results are taken into account and presented in summary. In first-time donors more frequently the markers of infection: HCV and HBV dozens of times, HIV and syphilis several times were detected. In the group of first-time donors a downward trend was detected in the number of detected infections HBV and HCV In the group of multiple donors the downward trend was documented in the number of detected antibodies associated to syphilis. In the group of multiple donors the number of detected HIV infections has been increased in the years 2008 and 2009. CONCLUSIONS: For monitoring trends of each type of infections, a period of four-years is not sufficiently long. This data needs a further observations. PMID- 21544995 TI - [The quality of platelet concentrates in dependence on storage time before pathogen inactivation]. AB - Pathogen inactivation procedure performed just before distribution of platelet concentrates (PCs) may decrease costs caused by loss of these components due to relatively short expiry date. THE AIM OF STUDY: To evaluate the quality of PCs pathogen inactivated on the first or the fifth day of storage. MATERIAL AND METHODS: PCs preparated from buffy-coats were suspended in platelet additive solution (Intersol, Baxter Healthcare Corporation, Belgium). The photochemical pathogen inactivation was performed on the 1st or the 5th day of storage using amotosalen and UVA (Cerus, Europe BV). PCs were stored for 7 days. RESULTS: There were observed increased expression of CD62 and CD63, elevated activity of LDH and lower concentration of glucose in PCs pathogen inactivated on day 1 compare to the control group. PCs pathogen inactivated on day 5 showed decreased expression of CD62 and CD63 compare to the control group. There were no significant differences in platelet number, pH, lactate concentration, hypotonic shock response and release of platelet derived microparticles in both groups of pathogen inactivated PCs. CONCLUSIONS: Time of storage of PCs before pathogen inactivation has no significant impact on PCs quality. Pathogen inactivation procedure performed just after having received request for PCs is more cost effective than the routine pathogen inactivation in all PCs before storage. PMID- 21544996 TI - [Quality of buffy-coat-derived platelet concentrates prepared using automated system terumo automated centrifuge and separator integration (TACSI)]. AB - Platelet recovery, and viability, and function is strongly dependent on the method of the preparation of platelet concentrate (PC). The glucose consumption, decrease of pH, release of alpha granules during storage in platelet concentrate impair their clinical effectiveness. THE AIM OF STUDY: To compare of the quality of buffy-coat-derieved platelet concentrates prepared using automatic system terumo automated centrifuge and separator integration (TACSI) and stored over 7 days. MATERIAL AND METHODS: PCs were prepared from buffy coats using manual method (group I), or automatic system TACSI (group II). Fifteen PCs prepared from the 5 buffy coats each were stored over 7 days in 22-24 degrees C and tested. Samples were taken from the PCs container on days 1 and 7. The following laboratory tests were performed: number of platelets, platelets derived microparticles, CD62P expression, platelet adhesion, pH, glucose, lactate dehydrogenase activity. RESULTS: We have observed higher expression of CD62P in PCs prepared using manual method compared to the PCs produced automatically Platelet recovery was significantly higher in PCs prepared using automatic systems compare to manual method. CONCLUSION: Compared to manual methods, automatic system for preparation of buffy coats, is more efficient and enable production of platelets concentrates of higher quality. PMID- 21544997 TI - [The use of blood and its components in two gynecological-obstetrical wards of selected Silesian hospitals in years 1996-2002]. AB - Blood and its components are valuable medication that should be administered according to recommendation after consideration of expected benefits and adverse reactions to the patient. THE AIM OF STUDY: To analyze amount and form of blood components or whole blood transfused at gynecological-obstetrical wars of university hospital (UH) or regional hospital (RH). Age of the patients and clinical diagnosis were included into the analysis. MATERIAL AND METHODS: Two gynecological-obstetrical wards were investigated. The appropriate data were obtained from the hospital documentation (there was no electronic data system). Amount and form of transfused blood components or whole blood, diagnosis at admission, patient's age and number of the treated patients were collected from the hospital transfusion book. The final clinical diagnosis, age of the patient, and transfusion details were obtained from the patient's medical records. The diagnoses were presented according to the ICD-10 classification. UH patients (29,759 patients) and 13,540 patients from RH from 1996 to 2002 were investigated. RESULTS: Blood and its components were used for transfusion in 1150 women (3.8%) treated in UH, and in 206 women (1.5%) hospitalized in RH. In years 1996-2002, there were transfused 2746 units of blood and its components, including: 371 units of whole blood (13.5%), 2073 units of red blood cells (75.5%), 281 units of fresh frozen plasma (10.2%) and 21 units of therapeutic platelet concentrate (0.8%) in RH there were transfused 527 units of blood and its components, including: 8 units of whole blood (1.5%), 450 units of red blood cells (85.4%), 63 units of fresh frozen plasma (12%), and 6 units of therapeutic platelet concentrate (1.1%). The age of patients in UH was between 14 and 92 years and in RH between 18 and 79 years. CONCLUSIONS: The rate of patients with the same diagnosis in whom the transfusion was made, was higher in University Hospital. There were no differences between the number of transfused blood and its components between the two hospitals. The age of patients who had blood transfusion was higher for the University Hospital. Introduction of payment for blood and its components, resulted in decrease in percentage of the patients receiving transfusion as seen in comparison of the period 1999-2002 and 1996-1998 in both investigated hospital. The PRBC transfusion average rate units, increased in the period 1999-2002, compared to the 1996-1998. Presented method of analysis of use of blood and its components may reveal new aspects of the problem and may be helpful for planning of blood donation. PMID- 21544998 TI - [Health economics of inhibitor bypassing agents in haemophilia A-activated prothrombin complex concentrate (aPCC) and recombinant activated factor VIIa (rFVIIa)]. AB - Haemophilia A is a sex-linked recessive genetic disorder associated with haemorrhagic diathesis due to reduced plasma activity of coagulation factor VIII, i.e., below 50% of the normal value (< 0.5 IU/ ml). The treatment of haemophilia A-Inhibitor patients is bidirectional. Major issues with treatment are inhibitor eradication and control of haemorrhage. The aim of the analysis was to evaluate costs and effects of the use of aPCC and rFVIIa in haemophilia A-inhibitor patients in on-demand treatment, perioperative prophylaxis and long-term prophylaxis. MATERIALS AND METHODS: The cost analysis was performed from the payer's perspective for all treatment schemes. Dosage and duration of treatment were obtained from a systematic review of clinical trials, Summary of Product Characteristics and clinical practice guidelines. Analysis was conducted in accordance with the AHTAPol (Agency for Health Technology Assessment in Poland) guidelines. RESULTS: The use of aPCC in on-demand treatment of children and adults during one day or one episode of bleeding (irrespective of the intensity of bleeding: from mild to severe) reduced the payer's expenditures in comparison to the use of rFVIIa. The use of aPCC in perioperative prophylaxis of children and adults during minor and major surgical interventions and implantations of central venous access devices was associated with savings for the payer in comparison to the use of rFVIIa, irrespectively of dosage of both drugs. Break even point analysis showed that the use of aPCC in long-term prophylaxis may be less expensive than the use of aPCC in on-demand treatment if bleedings last for 2.5 days or more. Sensitivity analysis showed that assumptions concerning body weight of patients significantly influence expenses of the public payer. However, the use of aPCC was associated with lower costs than the use of rFVIIa, irrespectively of the patients' body weight. CONCLUSIONS: In order to demonstrate the actual size of expenditures on treatment of haemophilia A-Inhibitor patients, collection of data concerning real clinical practice in Poland is required. PMID- 21544999 TI - [Educated donor--safe patient]. AB - The safety of transfusion is still improving and very important is raising of education among donors. The important element is also awareness of the possibility of withdrawing themselves from the donation process when they know that their blood isn't suitable for recipients. AIM: The aim of this study was checked of donor's knowledge about the risk of transfusion transmitted infections. MATERIAL AND METHODS: The 581 regular donors (86.2% men, mean age 32 years) who answered of questions about tests which are performed in donation, and about their knowledge of transmission infections by transfusions. Donors gave blood average four times a year, for 11 years. RESULTS: Over 85% of respondents believed that blood is safe. More than half of donors knew that during donation can be detected anemia, syphilis, jaundice, but 50% believed that the hepatitis viruses can be detected after one week after infection. More than 80% of donors knew about the possibility of detecting of HIV infection, but 11% written that HIV can be detected after one day after infection. Approximately 50% of donors believed that can be detected diabetes during donation, and more than 12% of them -that can be detected thyropathy and cancer. The 30% of blood donors didn't know what tests were performed in the blood donations. Donors (80%) knew about the risk groups. Donors (50%) knew correct temporary disqualification periods after surgery and tattoo also, but 17% of them indicated a shorter period of disqualification. 43% of donors shortened the time after gastroscopy. Over 30% of donors didn't know about risks of infection in case of contact with alien blood. A lot of donors (63.3%) knew about the possibility of withdrawing themselves from the donation and 43.5% of them knew about this rule. CONCLUSION: The donor doesn't need to know the details of detection of infections in blood, but donor need to know that he should be aware that even a few months is needed to obtain a reliable result, which translates into transfusion safety. For this purpose, he should be given the appropriate information. Blood transfusion services should not only seek to increase the volume of donations, but to contribute to ensure that donors are given educational materials regarding infectious diseases transmitted by blood transfusion. PMID- 21545000 TI - [Prophylaxis in patients with haemophilia complicated by inhibitors]. AB - The occurrence of factor VIII or factor IX inhibitor following treatment of a haemophilia A or B patient with factor VIII/IX concentrates is a serious complication. In the presence of these inhibitors, bleeds cannot be treated with the missing factors. The treatment of haemophilia complicated by the presence of inhibitor has two aims. The most important aim is complete elimination of the inhibitor, and the other aim is to stop bleeding. The first aim can be achieved by regular administration of the missing factor in order to eliminate inhibitor from the patient's blood. This method is called--immune tolerance induction (ITI) The second method depends on the titer of the inhibitor, types of response and degree of bleeding. In treatment of bleeding episodes concentrates inducing thrombin generation in the plasma of patients with haemophilia complicated by inhibitor are used. This assures haemostasis, in spite of the presence of factor VIII or IX inhibitor. The concentrates used are called bypassing agents. If ITI is unsuccessful regular prophylaxis with bypassing concentrates is being introduced more and more often. According to literature this reduces the frequency of bleeds by as much as 85% and improves the quality of life of patients with severe haemophilia complicated by inhibitor. PMID- 21545001 TI - [Early prophylaxis of bleeding in haemophilia and a risk of inhibitor development]. AB - Prophylaxis of bleeding in severe haemophilia is defined as the regular administration of missing factor concentrates to prevent haemarthroses as well as other bleeding episodes. This management is the gold standard of treatment in children with severe haemophilia, however the optimal time of prophylaxis initiation as well as the intensity of therapy in young children remain a matter of controversy. There are several models of prophylaxis, e.g., Swedish (Malmoe), Canadian, French (COMETH recommendations) or proposed by Kumik et al. in 2009. The development of inhibitor is the most serious iatrogenic complication affecting children with haemophilia. Several data suggest that prophylaxis initiated at the early age may increase the risk of inhibitor formation, however recent studies (CANAL or made by Chambers et al.) showed that early exposure to factor VIII was not directly associated with higher incidence of inhibitor as compared to children treated later during the first year of life. On the other hand early prophylaxis (initiated between 6th and 12th month of life) can minimize the intensity of the exposure to FVIII and prevent the inhibitor development resulting in improvement of child's quality of life. Undisputable is that prophylaxis of haemophilia is associated with a lower risk of inhibitor development than on-demand therapy. PMID- 21545002 TI - [Foeto-maternal haemorrhage--detection and quantification]. AB - Quantification of foetal RBCs in maternal blood samples should be essential to establish the dose of prophylactic anti-RhD immunoglobulin. In practice, the volume of foetomaternal haemorrhage (FMH) is rarely calculated and routine anti RhD doses vary in the world from 100 microg to 300 microg. In Poland the postpartum dose of IgG anti-D is 150 microg, and there is no antepartum prophylaxis. The aim of this review paper is to present that detection and quantification of FMH are important and introduction of some tests for it evaluation is necessary in Poland. Taking into consideration many reports and our preliminary experiences we show principles of some methods and techniques, their advantages and limits. As immunohaematologists we indicate very important multidisciplinary problem which concerns transfusiologists, gynaecologists and haematologists. PMID- 21545003 TI - [Potentially pathogenic changes in red blood cells during their storage]. AB - Blood fractionation and storage improve the availability of blood products, e.g., packed red blood cells (RBCs) for transfusion. But the following question appears: how long-stored RBCs are safe and effective? In many clinical retrospective studies authors indicated risk of transfusion of stored RBCs, especially in critically ill patients eg. with acute myocardial infarction syndrome. They observed higher frequency of mortality, morbidity, infections, renal and lung failure, inflammation and thrombosis when RBC units were long stored and non-leucoreduced than when they were fresh and leucoreduced. Responsible mechanisms are unknown but some factors are suspected eg.: RBCs do not deliver oxygen, because they have low concentration of ATP and 2.3 DPG and their shape changes. Also cytokines, enzymes and ions (K, Ca) from white blood cells (WBCs) can influence RBCs and transfused patients. Changes involve some membrane molecules associated with adhesion, oxygen transport, complement regulation during the storage of RBCs. It is interesting how the long-period storage and presence of WBCs can influence the membrane surface of RBCs and then their biological functions. Proposed study can improve our knowledge about changes in RBCs during their storage and then may be safety of blood transfusion. PMID- 21545004 TI - [Calculation of feto-maternal haemorrhage volume using various morphological parameters and various formulas]. AB - Quantification of FMH is essential for determination of an accurate dose of anti RhD Ig in antepartum and postpartum immunoprophylaxis of HDFN. Doses of anti-RhD are established with reference to the volume of RhD positive foetal red blood cells in the circulation of RhD negative voluntaries. Results obtained from flow cytometry, microscopic Kleihauer-Betke test or serological test indicate percentage of these cells. THE AIM OF THE STUDY: To compare results of FMH volume calculation using various formulas. MATERIAL AND METHODS: EDTA blood samples from 51 mothers and 51 cord blood samples from their newborns were analyzed. Five formulas were based on following parameters: percentage of foetal red blood cells in the blood sample from mother, mother's body weight and Hct, maternal and foetal MCV. RESULTS: The range of maternal Hct was 25.7-46.2% (mean 34.3%), ratio of foetal MCV to maternal MCV was 1.09-1.41 (mean 1.19), body weight of mothers 56-99 kg (mean 73.5 kg) and calculated volume of their blood 3600-7425 mi (mean 5100 ml). For 0.4% FMH we predicted 2, 3 or 4 doses of anti-RhD Ig 500 IU (100 microg) and 1, 2 or 3 doses of anti-RhD Ig 750 IU (150 microg) depending on the woman. CONCLUSIONS: The formula with individual maternal and foetal morphological parameters is much more accurate for calculation of the volume of FMH and doses of anti-RhD Ig than often used formula with average values of the parameters. PMID- 21545005 TI - [Epilepsy in the elderly]. AB - The incidence of epilepsy is higher among the elderly, the most rapidly growing segment of the population, than in any other age group. New-onset seizures in elderly patients are typically symptomatic or cryptogenic partial seizures that require long-term treatment. Epilepsy in the elderly is a frequently occurring pathology, differing in etiology, clinical presentation and prognosis from those of young people. Establishing the diagnosis of epilepsy in old age can be more difficult than in younger patients due to the extensive range of differential diagnoses and a higher prevalence of concomitant disease. Beyond a certain age physiological and pathophysiological changes can affect the pharmacokinetics and pharmacodynamics of antiepileptic drugs(AEDs), increasing the risk of pharmacological interactions due to polypharmacy. Furthermore, the elderly people are sensitive to adverse events of AEDs, as for example, to cognitive disturbances, osteoporosis. Several of newer AEDs have good safety and cognitive effect profiles and have no interactions with other drugs. The treatment strategies are demanding: they must take into consideration the co-morbidity, co medication, alterations in drug metabolism, and the effects on aging body. These factors make the management of epilepsy in the elderly particulary challenging, but with appropriate pharmacological treatment most elderly people with epilepsy will remain seizure-free. PMID- 21545006 TI - [Cadasil and other hereditary small vessel diseases of the brain--increasingly diagnosed conditions underlying familial ischaemic stroke and dementia]. AB - CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) has recently gained great interest in vascular neurology as the most common heritable cause of stroke and vascular dementia in adults. This autosomal dominant small vessel disease of the brain--unlike the sporadic, hypertensive form--appears already in adult midlife in the absence of vascular risk factors with ischemic episodes and progressive dementia, its first manifestation can be migraine with aura, and is often associated with psychiatric disturbances. The magnetic resonance imaging (MRI) changes showing a characteristic pattern may precede symptoms by more than a decade. The identification of the mutation of the NOTCH 3 gene responsible for the disorder encoding a transmembrane receptor of vascular smooth muscle cells - has given great impetus on research to understand the molecular and vascular pathogenesis of the disease. The special importance of this latter lies in the fact that CADASIL provides a pure genetic model for subcortical cerebral ischemia and vascular dementia without the confounding factors of comorbidities and advanced age. Thus insights into CADASIL may help us better understand the more common sporadic forms as well. Moreover CADASIL is one of the best studied examples of secondary migraine. Currently we have far less knowledge on other forms of hereditary small vessel disease of the brain such as CARASIL, HERNS, CRV, HVR, PXE etc. Neurologists are becoming more and more familiar with CADASIL, and with the wider availability of MRI it is increasingly diagnosed. However the disorder is still probably underrecognised. This review aims to summarize our current knowledge on CADASIL with special emphasis on diagnostic and differential diagnostic points for the practising neurologist. PMID- 21545007 TI - [Interdisciplinary approach to vestibular system impairment]. AB - In the first part of this review the definition of vertigo/dizziness was discussed. The major difference between the two signs is the existence of the direction, which is specific for vertigo. Dizziness is a frequent complaint in the clinical practice. Its frequency is increasing with advance of age, to intimate the play of declining cognitive process in the pathogenesis of its. The popular health significance of vertigo is in the rowing number of the patients. The onset of the most cases with acute vertigo appears between secundums and minutes so the patients will be provided in circumstances of emergency department. First of all three form should be take into account: neuronitis vestibularis, benign paroxysmal positional vertigo and Meniere syndrome. Without typical periferal signs of vertigo, central cause should be searched, principally stroke (lysis possibility). The differential diagnose of the different dizziness/vertigo forms according to the elapsed time of the onset or congenital and acquired nystagmus was created in tables. The recommendations of the therapy of acute and chronic dizziness/vertigo syndromes are, lack of results of evidence based trials doubtful. The more often used drugs based on clinical trials are discussed as vinpocetine, betahistine and piracetam. The in vitro and in vivo data suggest that the last molecule is eligible to use both in periferal and central type of vertigo syndromes. PMID- 21545008 TI - [EEG source localization using LORETA (low resolution electromagnetic tomography)]. AB - Eledctroencephalography (EEG) has excellent temporal resolution, but the spatial resolution is poor. Different source localization methods exist to solve the so called inverse problem, thus increasing the accuracy of spatial localization. This paper provides an overview of the history of source localization and the main categories of techniques are discussed. LORETA (low resolution electromagnetic tomography) is introduced in details: technical informations are discussed and localization properties of LORETA method are compared to other inverse solutions. Validation of the method with different imaging techniques is also discussed. This paper reviews several publications using LORETA both in healthy persons and persons with different neurological and psychiatric diseases. Finally future possible applications are discussed. PMID- 21545009 TI - [Anti-NMDA-receptor encephalitis: description of the syndrome in connection with the first Hungarian patient]. AB - In the majority of cases, anti-NMDA (N-methyl-D-aspartate) receptor encephalitis is a severe, but treatable disorder, therefore early diagnosis and adequate therapy are very important. It should be suspected in children and young women, who develop acute psychiatric symptoms and seizures. During the course of the disease severe encephalopathy, agitation, hallucinations, orofacial dyskinesias, prolonged cognitive disturbance, autonomic symptoms can be observed and akinetic mutism develops. EEG shows diffuse slowing. Brain MRI is normal or unspecific. Elevated protein, pleiocytosis and oligoclonal bands can be present in the CSF Detection of NMDA-receptor antibodies in sera or CSF confirms diagnosis. We present the case of a 15-year-old girl, who fully recovered within two months after steroid treatment and repeated plasma exchange. Ovarian teratoma has not been detected. PMID- 21545010 TI - [Differentiation of deficit and non-deficit schizophrenia based on cognitive functions]. AB - Cognitive dysfunction is a core feature in schizophrenia and has a great impact on psychosocial functioning. Still it remains unclear, whether the different diagnostic subgroups have a specific cognitive profile. The topic of this research was to investigate the neurocognitive characteristics of deficit and non deficit schizophrenia, and to examine if the two diagnostic subgroups have a qualitative difference in cognitive functioning. In Study 1., 275 patient and 130 healthy controls completed the WCST (Wisconsin Card Sorting Test). We performed an exploratory factor analytic study on the variables for the total group and each subgroups, then we assessed the ability of the factors to distinguish between the deficit, non deficit and control groups. In Study 2., I used the Kilroy-test to investigate procedural and context-dependent learning. 78 patients and 30 healthy controls completed the test, which has two phases: while the training phase is dominantly related to basal ganglia circuits, the context dependent probe phase requires intact medial-temporal lobe functioning. Thus the two interactive memory systems can be examined separately within one test. Study 1.: Results of the exploratory factor analysis of the whole sample yielded two factors which together explained approximately 95% of the total variance. Comparison of the diagnostic groups on each of the factors revealed that both schizophrenia groups showed executive function impairment in comparison to controls. Deficit patients suffer from a more severe degree of impairment on the "General executive function" factor (conceptualization, flexibility, set shifting) than non-deficit patients. On the other hand, non-perseverative error type (factor 2.) seems to be less typical to deficit than to the non-deficit patients. Study 2.: Results revealed that deficit and non-deficit patients were similarly impaired on the probe phase compared with controls. However, the training phase was not compromised in non-deficit patients, but deficit patients showed a significant impairment. While context-dependent learning is uniformly impaired in schizophrenia, procedural learning remains relatively intact in non deficit patients. In conclusion, the two diagnostic subgroups seem to differ not only in the degree of cognitive impairment, but in the characteristics as well. The deficit-syndrome can be characterized by a specific profile regarding executive function, and shows greater impairment in procedural learning. PMID- 21545011 TI - [Role of carotid stents in stroke prevention]. PMID- 21545012 TI - [Why to say good-bye? Where are we going? Let us adapt!]. PMID- 21545013 TI - [About the future of neurology--answer to Csaba Ertsey]. PMID- 21545014 TI - [Reflections on the meditations about the future of neurology]. PMID- 21545015 TI - [Obesity, the stepchild of medicine]. PMID- 21545016 TI - [Understanding the life of the obese patient. A contribution to therapeutic patient education]. AB - This article presents an approach of obesity centered on patients' experience. How is obesity defined by these latter? Is it considered as a disease? Is it apprehended by them as an element to fight or as a potentially meaningful event? Has the sick person the feeling to suffer from obesity or to have resources to face it? At the crossroads of three human sciences (sociology, anthropology and education), this approach aims to enrich and increase the efficiency of therapeutic patient education for obese patients. Extended experience narration extracts are presented in this article, obtained from research interviews. They show the importance of taking into account the "subjective experience" of the disease when accompanying persons affected by obesity. PMID- 21545017 TI - [What is the evolution of metabolically normal obesity?]. AB - A subgroup of obese subjects which could be protected from the cardiometabolic complications of obesity is described in the literature as "metabolically normal obese subjects". However, the lack of a joint definition of metabolic normality makes the available data difficult to interpret and to compare. A recent analysis of more than 1200 subjects in a prospective study showed that 21% of obese metabolically normal subjects at baseline developed the metabolic syndrome after three years. The obese subjects who remained metabolically normal showed, at three years, significantly higher values of cardiometabolic parameters as compared to subjects with normal body weight. In conclusion, the obese subjects even without any metabolic abnormality should benefit of a closer medical monitoring as well as a regular follow-up to avoid further weight gain. PMID- 21545018 TI - [A new program of therapeutic education for obese patients]. AB - Obesity is a chronic disease which is increasing over the past thirty years. This disease is complex and its treatment is difficult and generally frustrating for the patients and the medical team because of a high risk of relapse. Indeed, a dietetic approach alone is most of the time not good enough to obtain a long lasting weight loss; the few drugs on the market should also be prescribed as a part of a more global approach. A multidisciplinary approach with a long-standing follow-up including a cognitive-behavioral therapy coupled to a diet and physical activity is mandatory to avoid any weight regain. We propose a new multidisciplinary program of two years with in hospital-stay and ambulatory follow-up which is showing some promising results (90% of success at one year). PMID- 21545019 TI - [New guidelines for bariatric surgery care: practical implications]. AB - From the 1st of January 2011, new conditions have been validated in which surgery for weight loss is borne by the basic insurance. These are very significant changes compared to the old criteria. Indeed, on one hand, patients with BMI > or = 35 kg/m2 may, without age limit and in the absence of comorbidities benefit from surgery without prior request to the medical council health insurance company concerned. On the other hand, the notion of a minimum casuistry is for the first time introduced in centers performing this type of intervention. In addition, certified centers are required to follow standard procedures for the patients' teaching and follow up. PMID- 21545020 TI - [Management of hyperinsulinemic hypoglycemia post-gastric bypass surgery]. AB - Gastric bypass surgery is an effective treatment for morbid obesity, allowing a substantial weight loss together with an improvement of the cardiovascular and metabolic comorbidities, particularly the glucose control. However, after gastric bypassing, an imbalance between sensitivity and insulin secretion may be observed. This disorder gives rise to hyperinsulinemic hypoglycemia (late dumping syndrome) and is characterized by a dizziness that can be disabling. This problem must be distinguished from conditions provoking similar symptoms, as for instance the early dumping syndrome and the food restriction-related hypoglycemia. Since all these conditions need a particular management, their distinction is essential. PMID- 21545021 TI - [Anorexia: somatic assessment and management]. AB - Anorexia nervosa, which affects about 2-3% of the general population, is the psychiatric illness with the highest rate of mortality. The management is often complex, requiring multiple stakeholders on the patient's physical and psychiatric. The new specialized centre "abC" (anorexia-bulimia, Centre vaudois) was created with the objective of providing quality services to patients involved and to provide a network facilitating the interaction between physicians and specialized institutions. This is an inter-institutional and interdisciplinary collaboration born of the CHUV and the eHnv (Hospitalized Institutions in Nord Vaudois). The abC includes an outpatient pole (CHUV) and a hospital unit on the site of Saint Loup. At term, it will include a day centre (CHUV). PMID- 21545022 TI - [Undocumented but not without the right to health]. PMID- 21545023 TI - [An intergenerational neighborhood: between utopia and reality]. PMID- 21545024 TI - [Usage of Facebook by adolescents aged 13-15 in Lausanne]. PMID- 21545025 TI - [Obsessive compulsive disorders: a "new disease?"]. PMID- 21545026 TI - [Parkinson disease: a new study promoting gene therapy]. PMID- 21545027 TI - ["Men in white" to "Dr. House" (2)]. ]. PMID- 21545028 TI - [Phasing out nuclear power?]. PMID- 21545029 TI - [Prison and brutality]. PMID- 21545030 TI - [Cryopreservation of teeth]. AB - After tooth loss dental implants or fixed prosthetic restorations are not indicated in children and adolescents due to incomplete maxillary and mandibular development. Cryopreservation is a method for long-term storage of healthy teeth which were removed for orthodontic reasons or due to traumatic origin. These preserved teeth can be used as autogenous replants or transplants after tooth loss. During transport to and from the freezing facilities prior to freezing the teeth are stored in a cell culture medium. The tooth is transferred into a freezing tube containing cell culture medium and cryoprotectant DMSO. Teeth autotransplanted after cryopreservation show vitality of the PDL cells. Usually no enamel and/or dentinal cracks can be observed. After tooth loss transplantation of cryopreserved teeth could be an effective and biological therapy for tooth replacement. PMID- 21545031 TI - [Periapical osseous dysplasia of the anterior maxilla--a case presentation]. AB - Osseous dysplasias (formerly cemento-osseous dysplasias/ CODs) represent a specific clinico-pathologic spectrum of related, non-neoplastic benign fibro osseous lesions. The most recent WHO classification (2005) defines them as bone related lesions (9262/0). The controversial presence of cementum was solved by complete removal of the term "cemento" in the revised classification of tumors. Normal bone architecture is replaced by fibroblasts and collagen fibers containing variable amounts of mineralized material. Osseous dysplasias are often identified as an incidental finding on standard dental radiographs of adults. They usually cause no specific symptoms or obvious clinical findings. Four different types of ODs can be distinguished: the periapical osseous dysplasia (POD), the focal osseous dysplasia (FocOD), the florid osseous dysplasia (FOD) and the familial gigantiform cementoma. This case report presents an unusual localization of a periapical osseous dysplasia (POD) in the anterior maxillary bone in a 33-year old female patient of Caucasian origin. Radiological, clinical and histopathological characteristics of the POD and similar benign lesions are defined and discussed. PMID- 21545032 TI - [Pandemic influenza 2009 in Russia. Characteristics of the isolation and biological properties of viruses]. AB - Research Institute of Influenza, Ministry of Health and Social Development of Russia, Saint Petersburg The characteristics of the isolation of pandemic influenza A(H1N1)v viruses were studied on chick embryos (CE) and MDCK cell culture. The materials (nasal swabs and autopsies) were collected in different regions Russia in the period from 20 July to 30 December 2009. The paper gives the data of the antigenic analysis of isolates, their capacity to multiply in different species-specific and tissue cell cultures. The viruses isolated on CE were shown to have higher hemagglutination titers and to be more stable. Isolation from the autopsies was effective only on CE. All the test cell lines other than MDCK were insensitive to the isolated pandemic influenza strains. The antigenic analysis showed no significant antigenic drift of the viruses isolated during the first wave of the pandemic in the Russian Federation. PMID- 21545033 TI - [The morphological and karyological characteristics of MDCK and vero (B) cells cultures on plant hydrolyzate-based nutrient media]. AB - MDCK and Vero (B) cell cultures were propagated during 10 passages in the experimental nutrient media containing the soybean powder hydrolyzate prepared using trypsin and bromelain enzymes and the rice powder hydrolysate prepared with trypsin and in the control DMEM and SFM4 MegaVir media. The karyological, morphological, and proliferative characteristics of continuous cultures were examined and compared. The experimental media supplied with 3% fetal bovine serum (FBS) (Gibco, U.S.A.) showed high growth-enhancing properties and failed to affect their morphology. After propagated during 10 passages in the experimental media preserved a stable karyotype. MDCK cell cultures in the nutrient media based on rice and soybean powder hydrolyzates low (2%) in FBS caused no substantial changes in the proliferation indices and morphological and karyological characteristics of cell cultures. PMID- 21545034 TI - [Detection of recombinations in tick-borne encephalitis virus by using computer analysis of viral genomes]. AB - Computer programs were used to search for tick-borne encephalitis (TBE) virus recombinants among the isolates whose complete nucleotide sequences are deposited in the GenBank database. The application of RDP, Chimaera, Maximum chi2, and TOPAL programs has revealed recombinant sites in a number of sequences, which indicates that TBE virus has recombinations and that the programs are suitable for their detection. PMID- 21545035 TI - [Interaction of the Siberian and Far Eastern subtypes of tick-borne encephalitis virus in mammals with mixed infection. I. Factors influencing the type of interaction]. AB - Polytypic strains containing the fragments of genes of Siberian and Far Eastern tick-borne encephalitis (TBE) virus subtypes were isolated from the brain of fatal TBE patients, the blood of TBE patients, and Ixodes persulcatus ticks in the foci of concomitant circulation of the two subtypes. The interaction of the Siberian and Far Eastern TBE virus subtypes was studied in the neural phase of the infection of albino mice and Syrian hamsters in order to understand conditions for formation of these strains and their role in the etiology of acute TBE. Their viral progeny was genotyped by reverse transcription-polymerase chain reaction and fluorescence hybridization assay with genotype-specific probes. Mixed infection showed an effect of synergism, independent reproduction of the two subtypes in the brain and spleen, competitive exclusion of one subtype from the viral population. The type of the Interaction depended on the species of animals, the properties of partner strains, and the target organ. PMID- 21545036 TI - [Detection of tick-borne encephalitis virus in Ixodes ticks collected in a natural focus of Gornyi Altai]. AB - Enzyme immunoassay of tick-borne encephalitis virus (TBE) in the samples of Ixodes ticks collected in the outskirts of the settlement of Manzherok, Maiminsk District, Republic of Altai, revealed TBE antigen in 16.9 +/- 1.9% of the talga ticks. Real-time reverse transcription-polymerase chain reaction (RT-PCR) with specific fluorescent probes and phylogenetic analysis of the nucleotide sequences of RT-RCR products corresponding to 5'-terminal fragment of the E gene of TBE, all the virus strains isolated from the ticks collected in Gomyi Altai were referred to as the Siberian genetic type that was dominant in virus-carrying ticks in the majority of endemic areas of Russia and near abroad. Viral load assays using the real-time RT-PCR with the probes indicated the threshold cycles Ct = 25.34-28.98, which, with regard to the efficiency of RNA identification and reverse transcription, was equal to about 10(4)-10(5) viral RNA copies per tick. PMID- 21545037 TI - [Prevalence of high- and low-risk oncogenic human papillomaviruses in patients with external genital pathology]. AB - The paper presents the results of examining 49 patients with genital papillomas, vulvar and vaginal leukoplakia, dysplasia, and cancer. The findings may suggest that human papillomavirus plays an important role in the development of vulvar and vaginal lesions and reconsider the importance of high- and low-risk oncogenic genotypes in the development of benign neoplasms, precancerous conditions, and malignant tumors of the vulva and vagina. PMID- 21545038 TI - [Phylogenetic analysis of cytomegaloviruses isolated from man and different primate species]. AB - Institute of Medical Primatology, Russian Academy of Medical Sciences, Sochi The conserved regions of nucleotide sequences were found in primate cytomegaloviruses (CMV). Universal primers were designed for the consensus sequence of a conservative region of the UL56 gene of the betaherpesvirinae subfamily. Amplification, sequencing, and phylogenetic analysis of the fragments of CMV strains isolated from man and different primate species were made. Analysis of sequenced gene fragments showed that the UL56 gene area is most suitable for the phylogenetic analysis of primate CMV and could identify several groups of clusters by the degree of relationship among the viruses of this family. PMID- 21545039 TI - [Analysis of the genetic constructs expressing antiviral siRNAs in the non-viral test system]. AB - The efficiency of RNA interference triggered by the genetic constructs encoding siRNAs and directed against human immunodeficiency virus type 1 (HIV-1) transcripts was investigated in the non-viral test system. The investigation showed 6 biologically active siRNAs attacking 6 conservative targets in the HIV-1 genome. Expression of these genetic constructs failed to induce a nonspecific interferon response. PMID- 21545040 TI - [New adamantane derivatives and ways of overcoming the resistance of influenza A viruses to rimantadine and amantadine]. AB - The amino acid and peptide derivatives of 1-adamantane carboxylic acid and rimantadine (18 compounds) have been first synthesized and investigated for their activity against influenza A virus (H1N1, H1N1v). In a series of obtained adamantine derivatives, some compounds have been found to be able to inhibit rimantadine-resistant influenza A virus strains. Thus, the antiviral properties of rimantadine can be restored. PMID- 21545041 TI - [Specific features of a change in some blood biochemical indicators in virus urogenital infections]. AB - Analysis of blood biochemistry in cytomegalovirus, papillomavirus infections and herpes simplex virus showed a significant decrease in blood albumins, a significant rise in total protein, the percentage of alpha2-globulins, and an increase in the activity of ALAT, aldolase 1.6. This reflects the activity of inflammation, reveals hepatic toxic activity, and indicates renal dysfunction and externally asymptomatic active processes in the liver. PMID- 21545042 TI - [Evaluation of the efficiency and reactogenicity of emulsion-based adjuvant systems in the manufacture of polyclonal enteroviral diagnostic sera]. AB - Whether various adjuvants might be used in the manufacture of commercial enteroviral diagnostic sera (EDS) was studied. The following adjuvants: Ribi, SAF 1, and TiterMax were compared; vaseline-lanoline emulsion used to prepare EDSs, as well as modified Freund's complete adjuvant served as controls. Chinchilla rabbits were intramuscularly injected enterovirus antigens (enterovirus 70 and ECHO 2) together with the adjuvant emulsions. TiterMax showed the highest efficiency comparable with the activity of Freund's adjuvant. The activities of Ribi, SAF-1, and vaseline-lanoline emulsion were 3-4 times lower. The neutralizing activity of the sera obtained after 2-3 (TiterMax) or 4-5 (Ribi, SAF 1) immunizations was maximal. Further immunizations resulted in a reduction in the titers of neutralizing antibodies. TiterMax and vaseline-lanoline emulsion caused minimal complications at the site of inoculation whereas SAF-1 and Ribi gave rise to severer inflammatory responses. PMID- 21545043 TI - [The specific features of the reproduction of the bovine coronavirus strain ARRIAH in the continuous RBT cell culture]. AB - Cultivation of the bovine coronavirus strain ARRHIAH in the continuous RBT versus MDBK and Taurus cell cultures made it possible to reduce the time taken to reproduce the virus and to increase its hemagglutination titer. The RBT cell line is suitable for determining the infectious activity of the coronavirus reproduced in the other cell cultures. Optimization of a manufacturing process for diagnostic agents and vaccines has been achieved while applying a roll tube method for both RBT cell cultivation and coronavirus reproduction. PMID- 21545044 TI - [Focal osteosclerotic lesions of the jaws--a review focusing on diagnostic and therpeutic aspects]. AB - The diagnosis of osteosclerotic lesions is sometimes quite challenging for the general dental practitioner. When having no clear reason for a sclerotic process in the jaw bone, the dentist is often left without a definite diagnosis and treatment plan. Additionally, the literature often mixes terms for sclerotic bone lesions in the mandible or maxilla, causing further confusion about classification, therapy and prognosis of these entities. Although osteosclerotic jaw lesions can arise in every decade of life, they often are encountered by chance on routine radiographic examinations. For further diagnosis these lesions are even referred for invasive procedures such as bone biopsies. Nevertheless, accurate knowledge about the pathogenesis, radiographic and clinical appearance of these lesions could already lead to a diagnosis without the need for further biopsies. The present review focuses on the focal osteosclerosis of the jaws, discussing diagnosis, treatment and important differential diagnoses. PMID- 21545045 TI - [Update on side effects of alcohol-containing antiseptic mouthwashes]. AB - Antiseptic mouthwashes are widely prescribed in odontostomatology. Also, they are increasingly integrated in routine oral hygiene programs. Graded ethanol is present in many of the available mouthwashes. This has continuously raised the concern about their safety and potential side effects of the alcohol in their composition. Alcohol was associated in many reports to cancers of the oral and pharyngeal region. Xerostomia was also suggested as a potential side effect of alcohol-containing mouthwashes. Although substantial evidence supports the association of ethanol to oral cancer, the supposed association lacks of consistency and scientific evidence. Future research is needed to determine the causal relationship of alcohol-containing mouthwashes and oral cancers. On the other hand, the benefit of alcohol in mouthwashes composition is not scientifically established. PMID- 21545046 TI - Medicare and Medicaid programs: changes affecting hospital and critical access hospital conditions of participation: telemedicine credentialing and privileging. Final rule. AB - This final rule will revise the conditions of participation (CoPs) for both hospitals and critical access hospitals (CAHs). The final rule will implement a new credentialing and privileging process for physicians and practitioners providing telemedicine services. Currently, a hospital or CAH receiving telemedicine services must go through a burdensome credentialing and privileging process for each physician and practitioner who will be providing telemedicine services to its patients. This final rule will remove this undue hardship and financial burden. PMID- 21545047 TI - Caregivers program. Interim final rule. AB - This document promulgates Department of Veterans Affairs (VA) interim final regulations concerning a new caregiver benefits program provided by VA. This rule implements title I of the Caregivers and Veterans Omnibus Health Services Act of 2010, which was signed into law on May 5, 2010. The purpose of the new caregiver benefits program is to provide certain medical, travel, training, and financial benefits to caregivers of certain veterans and servicemembers who were seriously injured in the line of duty on or after September 11, 2001. PMID- 21545048 TI - [Managed care and physician network - and everything will work out fine?]. PMID- 21545049 TI - Lessons from high- and low- performing states for raising overall health system performance. AB - The authors of this brief interviewed stakeholders in states with high-ranking and low-ranking health system performance, according to The Commonwealth Fund's State Scorecard on Health System Performance. Findings suggest there are market, political, and cultural characteristics that can help or hinder health system improvement. High-performing states are more likely to have: (1) a history of continuous reform and government leadership; (2) a culture of collaboration among stakeholders; transparency of price and quality information; and (3) a congruent set of policies that focus on system improvement. Regardless of starting point, state policymakers and proponents for health system improvement can work to align incentives to change provider, health plan, purchaser, and consumer behavior; frame health in terms of economic development to gain public and political support; engage purchasers and payers to drive value and quality improvement; bring stakeholders together to develop goals and build trust; and take advantage of federal funding, incentives, and reform opportunities. PMID- 21545050 TI - Physician practices, e-prescribing and accessing information to improve prescribing decisions. AB - Hoping to reduce medication errors and contain health care costs, policy makers are promoting electronic prescribing through Medicare and Medicaid financial incentives. Many e-prescribing systems provide electronic access to important information--for example, medications prescribed by physicians in other practices, patient formularies and generic alternatives--when physicians are deciding what medications to prescribe. However, physician practices with e prescribing face challenges using these features effectively, according to a new qualitative study by the Center for Studying Health System Change (HSC) funded by the Agency for Healthcare Research and Quality (AHRQ). While most of the 24 practices studied reported that physicians had access to patient formulary information, only slightly more than half reported physician access to patient medication histories, and many physicians did not routinely review these sources of information when making prescribing decisions. Study respondents highlighted two barriers to use: (1) tools to view and import the data into patient records were cumbersome to use in some systems; and (2) the data were not always perceived as useful enough to warrant the additional time to access and review them, particularly during time-pressed patient visits. To support generic prescribing, practices typically set their system defaults to permit pharmacist substitution of generics; many practices also used other tools to more proactively identify and select generic alternatives at the point of prescribing. Overall, physicians who more strongly perceived the need for third-party data, those in practices with greater access to complete and accurate data, and those with easier-to-use e-prescribing systems were more likely to use these features consistently. PMID- 21545052 TI - Scientists develop method to observe the migration of cancer cells. PMID- 21545051 TI - Co-crystallization may reduce bulkiness of pills. PMID- 21545053 TI - Innovative fluorine-addition process could enable faster drug design and manufacture. PMID- 21545054 TI - Immunization and the Affordable Care Act. PMID- 21545055 TI - Preventing pregnancy among older teens. PMID- 21545056 TI - Tapping school facilities for community health: joint-use agreements. PMID- 21545057 TI - Preventive surgery is associated with reduced cancer risk and mortality in women with BRCA1 and BRCA2 mutations. AB - Women who have inherited mutations in the BRCA1 or BRCA2 (BRCA1/2) genes have a substantially elevated risk of developing breast and ovarian cancer. For more than 10 years, researchers have studied whether preventive surgery (to remove breasts, ovaries, and/or fallopian tubes) can reduce the cancer and mortality risk in BRCA1/2 mutation carriers. This Issue Brief summarizes the results of the latest, largest, multinational study on the effects of preventive surgery in these women. The results are consistent with earlier studies and provide strong evidence for the use of preventive surgery as an effective approach to managing this genetic risk. PMID- 21545058 TI - The changing geography of outpatient procedures. AB - Since the early 80s, many surgical procedures have moved from the inpatient to outpatient setting. Outpatient surgical visits now account for about two-thirds of all surgical visits in the U.S. Over the same period, freestanding ambulatory surgery centers (ASCs) have arisen as alternatives to traditional hospital-based outpatient surgical departments. The number of ASCs grew from 240 in 1983 to 5,174 in 2008. The growth of ASCs raises safety concerns about the risk of complications and adequate access to emergency care. This Issue Brief summarizes evidence from one state about the changing geography of outpatient procedures and the possible risks associated with these changes. PMID- 21545059 TI - Whither medicine? The expansion of non-doctor practice. PMID- 21545060 TI - [Effects of continuous blood purification on plasma cytokines in patients with severe acute pancreatitis]. PMID- 21545061 TI - [Biological oscillations: clocks for all times]. PMID- 21545062 TI - Changes in spirometry over time in uremic patients receiving long-term hemodialysis therapy. AB - Complications of respiratory system in patients suffering from chronic renal failure who are treated with regular haemodialysis are well known. However, the influence of the duration of haemodialysis on pulmonary function is less understood. The aim of this study was to determine spirometry changes in patients on chronic haemodialysis over a five-year period. We tested 21 patients, out of which 11 female and 10 male, mean age of 50 (+/- 11) years. The mean duration of haemodialysis was 52.2 (+/- 44.7) months at the time of the inclusion. We performed spirometry testings in all patients, one hour before start and one hour after completion of haemodialysis. All parameters of spirometry recorded one hour after completion of haemodialysis (FVC, FEV1, FEF75, 50, 25, % of predicted), improved significantly (p < 0.01). After five years, only FVC demonstrated significant decline and none of the recorded spirometry parameters improved significantly one hour post haemodialysis compared to pre-haemodialysis period. Analysis of post-dialysis parameters of spirometry at the study onset and following five years of haemodialysis showed that all parameters, except FEF50 (p > 0.05), significantly deteriorated (p < 0.01). Patients who are on long-term haemodialysis show a significant decline in FVC following five years of treatment. Although the spirometry changes in observed population treated with chronic haemodialysis have reversible character during the first years of renal replacement therapy, five years after these changes become irreversible. PMID- 21545063 TI - The sensitivity of electromyoneurography in the diagnosis of diabetic polyneuropathy. AB - Diabetic polyneuropathy is a complex set of clinical syndromes, which deplete various regions of the nervous system. The process leading to diabetic neuropathy is multi-factorial. Its symptoms are paresthesia, dysesthesia and pain. The signs of damage to the peripheral neurons are hypoesthesia, hypoalgesia, hyperesthesia and hyperalgesia, decreased tendon reflexes, and, possibly, weakness and muscle atrophy. There is no universal classification. Electromyoneurography is indispensable in the diagnosis of diabetic polyneuropathy. However, there is no agreement on the most sensitive parameter for an early diagnosis. One hundred patients with diabetes mellitus were examined in order to investigate the sensitivity of different electromyographic parameters. Electromyographic techniques proved to be entirely sensitive for the early diagnosis of diabetic polyneuropathy. Some of the parameters are more suitable for an early detection of peripheral nerve damage, and others, which are not so sensitive but easy to use and stable, are suitable to follow up the course of diabetic polyneuropathy. PMID- 21545064 TI - Expression of vascular endothelial growth factor in melanocytic nevi. AB - Melanocytic nevi represent a benign neoplastic proliferation of melanocytes. The level of vascular endothelial growth factor expression in these proliferations is low in most cases; whereas an increased expression of this factor may be an indicator of pre-neoplastic changes in melanocyte lesions. We performed a semi quantitative assessment of the level of vascular endothelial growth factor expression (score 0 to 3) on samples taken from 34 patients with benign melanocyte alterations of the skin. Melanocytic nevi showed an expression of vascular endothelial growth factor in 79.41% of the cases. The low level of expression (score 1) was seen in 70.59% cases. The results showed no statistically significant difference in the presence and level of vascular endothelial growth factor expression in relation to the following morphological parameters: histological type, a defect in the surface, density of inflammation infiltrate, mitotic index, growth phase and cell type. PMID- 21545065 TI - Correlation between EuroSCORE and intensive care unit length of stay after coronary surgery. AB - During the last several years many authors have found that the European System for Cardiac Operative Risk Evaluation is useful in the prediction of not only postoperative mortality but also of the length of stay in the intensive care unit, complication rate and overall treatment expenses. This study included 329 patients who had undergone isolated surgical myocardial revascularization at our Department during the period from January 1st to June 6th, 2008. For the operative risk evaluation, the additive European System for Cardiac Operative Risk Evaluaion was used. In group I (low risk 0-2%) there were 144 patients (43.7%), whereas group II (medium risk 3-5%) and group III (high risk > or = 6%) included 141 (42.8%) and 44 (13.4%) patients, respectively. The length of stay in the intensive care unit was 25.56, 32.43 and 49.59 hours for groups I, II and III, respectively. The difference in the mean length of stay in the intensive care unit between the groups was highly statistically significant (p < 0.001) with a positive correlation (R = 0.193; p < 0.001). There is a positive correlation in patients who had undergone surgical myocardial revascularization in terms of operative risk expressed by the additive European System for Cardiac Operative Risk Evaluation and length of stay in the intensive care unit, total intubation period and development of early postoperative complications. PMID- 21545066 TI - Detection and treatment of amblyopia in children. AB - Refractive errors are a common cause of decreased visual acuity. They can be found in 2-4% of preschool children. If not discovered on time and not properly treated, they can lead to amblyopia and strabismus. The active participation of parents and paediatricians is of great importance in timely discovering and treatment of amblyopia. The most common causes of amblyopia are strabismus (50.1%) and refractive error (44.7%). The best treatment results are achieved in amblyopic children with strabismus. The cooperation of physicians of all specialties, above all paediatricians and ophthalmologists, as well as a good collaboration of parents based on their being well-informed, must exist in the process of timely diagnosing and treating of amblyopia. PMID- 21545067 TI - Statins and the lung: hope or hype? PMID- 21545068 TI - Sildenafil improves six-minute walk distance in chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Sildenafil has been found to improve exercise capacity and haemodynamic parameters in patients with various pulmonary disorders. This study was undertaken to evaluate its efficacy in severe chronic obstructive pulmonary disease (COPD). METHODS: In this double-blind, randomised, placebo-controlled study, 37 patients with severe COPD received either sildenafil or placebo for 12 weeks. Distance covered in six-minute walk test (6MWD) was taken as primary end point. Pulmonary artery pressure (PAP) was measured as secondary end point. RESULTS: Thirty-three patients (15 in sildenafil arm and 18 in placebo arm) completed the study. Non-parametric tests were used for comparison. There was significant increase in 6MWD from baseline after three months of follow-up in sildenafil users (median change in distance covered in six-minute walk test (delta6MWD) = 190m) as compared to placebo users (delta6MWD = 0m, p < 0.05). The PAP decreased significantly (chi2 = 14.94, p < 0.05) in sildenafil group after three months, while it did not change significantly among placebo group (chi2 = 3.84, p > 0.05). CONCLUSION: Sildenafil improved 6MWD and PAP in patients with severe COPD. PMID- 21545069 TI - Cardiopulmonary exercise testing in evaluation of patients of chronic obstructive pulmonary disease. AB - BACKGROUND: Objective assessment of severity in patients with chronic obstructive pulmonary disease (COPD) is mainly limited to pulmonary function testing performed at rest. But, accurate assessment of exercise capacity in patients with COPD may be possible with cardiopulmonary exercise testing (CPET). METHODS: Forty three patients with stable COPD were included and were divided into three groups based upon the spirometry data as per the Global Initiative for Obstructive Lung Disease (GOLD) guidelines as follows: Group A: mild COPD, Group B: moderately severe COPD and Group C: severe COPD. Symptom-limited CPET was performed using treadmill on incremental continuous ramp protocol in all of them. RESULTS: Five patients (11.6%) had mild COPD; 16 (37.2%) had moderately severe COPD and the remaining 22 (51.6%) patients had severe COPD. Anaerobic threshold was attained in all the 43 patients. The dominant symptom at peak exercise were dyspnoea (n = 19) and both dyspnoea and leg fatigue (n = 7). The other causes of exercise limitation included dyspnoea with significant oxygen desaturation (n = 6); and dyspnoea with severe oxygen desaturation (n = 2). Six patients complained only of leg fatigue at peak exercise. A significant correlation between forced expiratory volume in the first second (FEV1) percent predicted and the predicted maximum oxygen uptake (VO2 max % predicted) was observed in all the three groups (r = 0.39, p = 0.011) but with marked variability of peak VO2 for a given degree of airflow obstruction. Twenty-three (53.5%) patients with low anaerobic threshold (< 30%) were identified as potential group likely to benefit from exercise training for pulmonary rehabilitation. CONCLUSIONS: Cardiopulmonary exercise testing is useful to determine the causes of exercise limitation and to assess the maximal exercise capacity of patients with COPD. PMID- 21545070 TI - Initial experience of endobronchial silicon stents from a tertiary care centre in North India. AB - BACKGROUND: Central airway obstruction (CAO) is defined as obstruction of trachea and principal bronchi. Therapeutic rigid bronchoscopy with tracheobronchial stenting using silicon stents is a well established procedure in the management of such conditions. However, there is limited experience with this technique in India. METHODS: Between January 2010 and April 2010, Dumon stents were placed in four patients with CAO. Three patients had symptomatic tracheal stenosis while one patient had malignant obstruction at the carina. Rigid bronchoscopy under general anaesthesia was performed to relieve the CAO followed by placement of silicon stents. Pre- and post-stent placement symptom assessment was performed with a symptom-based visual analogue scale. RESULTS: Four patients underwent silicon stent placement in the tracheobronchial tree. Three patients had benign post-intubation tracheal stenosis and one had malignant tracheal obstruction at carina due to endobronchial growth. Significant improvement was achieved in all patients. There were no significant complications. CONCLUSIONS: Rigid bronchoscopy with silicon stent placement is an effective and suitable method of relieving the distressing symptoms due to benign or malignant airway obstruction. PMID- 21545071 TI - Bronchoscopy and endobronchial disease in patients with human immunodeficiency virus infection. AB - The natural history of human immunodeficiency virus (HIV) infection has been significantly altered since the advent of antiretroviral therapy (ART). However, lung diseases are still common in these patients. This makes flexible fibreoptic bronchoscopy a valuable diagnostic tool. Knowledge of the visual appearance of various diseases would be of utmost importance to the bronchoscopist. Timely recognition of the endobronchial appearance of these diseases can narrow the differential diagnosis and potentially mitigate an avoidable delay in the diagnosis. PMID- 21545072 TI - Metastatic pleural effusion: a rare presentation of salivary gland adenoid cystic carcinoma. AB - Adenoid cystic carcinoma, an uncommon malignant salivary gland neoplasm, is known for its long clinical course, indolent growth, local recurrence and late distant metastasis. We report an unusual case of adenoid cystic carcinoma of the palate in a 64-year-old woman, undiagnosed for more than 15 years, who presented as malignant pleural effusion. PMID- 21545073 TI - Fractured tracheostomy tube migrating into the tracheobronchial tree: a rare complication. AB - Tracheostomy is a life saving procedure and many patients are discharged with permanent tracheostomy tubes. We report the rare occurrence of a fractured tracheostomy tube migrating into the tracheobronchial tree and highlight the clinical manifestations of this uncommon complication that carries the potential risk of fatal respiratory obstruction. PMID- 21545074 TI - Chest wall metastasis of squamous cell carcinoma of larynx. AB - Distant metastases in squamous cell carcinoma of head and neck are most often to the lung, liver and bone. They rarely metastasise to chest wall. We report a 60 year-old male patient who initially presented with an abscess over the anterior chest wall that was initially treated for infective pathology. Due to lack of response, cytological examination was performed that turned out to be metastasis from carcinoma larynx. PMID- 21545075 TI - Rare presentation of spontaneous acquired diaphragmatic hernia. AB - Spontaneous acquired diaphragmatic hernia without any apparent history of trauma is a very rare condition and is very difficult to diagnose. We present a case of a 21-year-old male who presented with abdominal pain for one month and four episodes of vomiting for one day. Clinical suspicion, chest radiography with nasogastric tube in situ and computed tomography (CT) confirmed the diagnosis. The diaphragmatic defect was repaired surgically. The patient had an uneventful post-operative recovery. PMID- 21545076 TI - Effects of long-term supplementation of dairy cow diets with rumen-protected conjugated linoleic acids (CLA) on performance, metabolic parameters and fatty acid profile in milk fat. AB - The supplementation of conjugated linoleic acids (CLA) to the rations of dairy cows represents an opportunity to reduce the content of milk fat. Therefore, CLA have the potential beneficial effect of reducing energy requirements of the early lactating cow. The present study aimed at the examination of long-term and posttreatment effects of dietary CLA intake on performance, variables of energy metabolism-like plasma levels of non esterified fatty acids (NEFA) and beta hydroxybutyrate (BHB), and fatty acid profile in milk fat. Forty-six pregnant German Holstein cows were assigned to one of three dietary treatments: (1) 100 g/ d of control fat supplement (CON), (2) 50 g/d of control fat supplement and 50 g/ d of CLA supplement (CLA-1) and (3) 100 g/d of CLA supplement (CLA-2). The lipid encapsulated CLA supplement consisted of approximately 10% of trans-10, cis-12 CLA and cis-9, trans-11 CLA each. The experiment started 1 d after calving and continued for about 38 weeks, divided into a supplementation (26 weeks) and a depletion period (12 weeks). Over the first 7 weeks of treatment, 11 and 16% reductions in dry matter intake compared to control were observed for the cows fed CLA-1 and CLA-2 supplements respectively. Consequently, the calculated energy balance for these two CLA groups was lower compared to the control. Plasma levels of NEFA and BHB remained unaffected. Later in lactation the highest CLA supplementation resulted in a reduction of milk fat content of 0.7%. However, no reduction in milk fat yield, and accordingly no milk fat depression (MFD), could be shown. The trans-10, cis-12 CLA in milk fat increased with increasing dietary CLA supplementation in a dose-dependent manner. The proportion of C16 in milk fat was decreased by the highest CLA supplementation. With the exception of an increase in plasma glucose level in the CLA-2 group, no post-treatment effects were observed. Overall, under the conditions of the present study no improvement in the calculated energy balance by CLA supplementation could be shown for the entire evaluation period. PMID- 21545077 TI - Relationship between hydroxycinnamic acid content, lignin composition and digestibility of maize silages in sheep. AB - Cell wall-bound hydroxycinnamic acids and the composition of lignin were studied in relation to the digestibility of a collection of 91 maize silages in wethers. Total lignin and guaiacyl content showed the highest correlation coefficients with digestibility. Using the above-mentioned chemical parameters, eight equations were also developed to predict digestibility. The prediction of organic matter digestibility produced a high adjusted R2 value (0.487) using total lignin, guaiacyl, esterified ferulic acid and esterified p-coumaric acid content as predictors. The prediction of in vivo dry matter digestibility produced a higher adjusted R2 value (0.516) using the same variables as predictors. Cell wall digestibility depends on a multiplicity of factors and it is not possible to attribute a causal effect on in vivo digestibility to any single factor. However, total lignin, guaiacyl and p-coumaric acid content emerge as good predictors of digestibility. PMID- 21545078 TI - Effect of xylanase and glucanase supplementation to a cereal-based, threonine limited diet on the nitrogen balance of growing pigs. AB - In cereal-based diets, non-starch polysaccharides (NSP) lower precaecal nutrient absorption and increase endogenous protein and amino acid (AA) losses. Adding exogenous NSP-degrading enzymes aims amongst others to reduce these negative effects and to thereby improve protein and AA supply. However, biased results exist in the literature on their efficacy in growing pigs. Hence, the objective of this study was to analyse the effects of different levels of xylanase and beta glucanase supplementation. Nitrogen (N) retention from a threonine-limited diet was chosen as an indirect indicator for differences in praecaecal threonine absorption and endogenous protein and AA losses. During three balance periods, 12 male pigs with a bodyweight of 31-66 kg were used in a cross-over design. They received three different diets based on wheat, barley, rye, and soybean meal containing 0, 40 or 80 mg/kg of an enzyme preparation containing endo-1,4,-beta xylanase and endo-1,4-beta-glucanase. N excretion and retention were identical in animals of the different treatment groups, stressing that enzyme supplementation did not affect threonine absorption and/or endogenous protein and AA losses neither at medium nor at high supplementation level. Hence, in the present trial, beta-glucanase and xylanase addition to cereal diets did not improve protein and AA availability in growing pigs of a body weight > 30 kg. PMID- 21545079 TI - Effect of crude protein and phosphorus level on growth performance, bone mineralisation and phosphorus, calcium and nitrogen utilisation in grower finisher pigs. AB - Two experiments in a 2 x 2 factorial arrangement were conducted to evaluate the effect of crude protein (CP) (130 vs. 200 g/kg) and phosphorus (P) (4.0 vs. 6.0 g total P/kg) level in a phytase supplemented diet (500 FTU [phytase units]/kg) in grower-finisher pigs. Owing to the design of the experiment, as dietary P level increased, there was also an increase in dietary calcium (Ca) level in order to maintain a dietary Ca to P ratio of 1.6:1. In Experiment 1, four diets were fed to 56 pigs (n = 14, initial body weight [BW] 36.7 +/- 4.2 kg) to investigate the interaction between CP and P on growth performance, bone mineralisation and digesta pH. Experiment 2 consisted of 16 entire male pigs (n = 4; offered identical diets to that offered in Experiment 1) for the determination of total tract apparent digestibility and nitrogen (N), P and Ca utilisation. There was an interaction between CP and P level on bone ash, bone P and bone Ca concentrations (p < 0.05). Pigs offered low CP-low P diets had a higher bone ash, P and Ca concentrations than pigs offered high CP-low P diets. However, there was no effect of CP level at high P levels on bone ash, P and Ca concentrations. Pigs offered low P diets had a lower ileal pH compared with pigs offered high P diets (p < 0.05). In conclusion, offering pigs a high CP-low P, phytase-supplemented diet resulted in a decrease in bone mineralisation. PMID- 21545080 TI - Effects of high dietary levels of soybean meal and its constituents (potassium, oligosaccharides) on foot pad dermatitis in growing turkeys housed on dry and wet litter. AB - Soybean meal (SBM) is the main protein source in diets for turkeys. High dietary levels of SBM are thought to increase the incidence of foot pad dermatitis (FPD). Therefore, this study was conducted to test potential effects of high SBM and to elucidate which constituents in SBM might be associated with the development of FPD. Two week-old female turkeys were allotted to four groups of 29 birds each, and housed on dry wood shavings in floor pens over a period of three weeks. Four different diets were fed: control, high SBM, high potassium (K) or high oligosaccharide (OL) diet. Additionally, for only 8 h/d half of the animals in each group were exposed to wet litter (27% DM) in adjacent separate boxes. The foot pads of all birds were assessed on days 0, 7, 14 and 21 for external lesions. For the histopathology of the foot pads, on day 0 three birds from each group, and on days 7 and 14 six birds per feeding group were selected. The remaining birds in each group were sacrificed on day 21 and their pads were evaluated histologically. High dietary levels of SBM, potassium or oligosaccharides did not influence the severity of FPD on dry litter, but slightly increased the severity on wet litter. However, there were no histopathological differences in FPD severity between these dietary treatments within each litter form compared to the control. Nevertheless, the FPD severity was in general higher on wet litter. Thus, litter moisture appears to be one of the most important factors involved in FPD in turkeys. In addition, all nutritional factors which increase water intake and excreta or litter moisture may contribute to an increased development and severity of FPD in turkeys. PMID- 21545081 TI - Pantothenic acid supplementation to support rumen microbes? AB - Based on repeatedly reported extensive pantothenic acid disappearance in the rumen, the present study is aimed at examining if pantothenic acid is used for a more efficient ruminal fermentation and microbial growth in an artificial rumen (Rusitec). Three substrates differing in roughage/concentrate ratio were incubated with and without the addition of Ca-D-pantothenate. Pantothenic acid was extensively degraded without notably influencing fermentation, microbial protein synthesis and the status of other B-vitamins such as riboflavin, vitamin B6 and niacin. Therefore, pantothenic acid supplementation cannot be expected to contribute to microbial benefit for the ruminant animal. PMID- 21545082 TI - Giving advice to a diabetic patient. PMID- 21545083 TI - ABA-dependent and -independent G-protein signaling in Arabidopsis roots revealed through an iTRAQ proteomics approach. AB - Heterotrimeric G-proteins are important signal transducers in all eukaryotes. The plant hormone abscisic acid (ABA) has emerged as a key regulator of G-protein mediated signaling pathways in plants. ABA-regulation of G-protein signaling involves both conventional and novel mechanisms. We have utilized the null mutant of the Arabidopsis G-protein alpha subunit gpa1 to evaluate to what extent ABA dependent changes in the proteome are regulated by G-proteins. We used Arabidopsis root tissue as both ABA and G-proteins, individually and in combination, affect root growth and development. We identified 720 proteins, of which 42 showed GPA1-dependent and 74 showed ABA-dependent abundance changes. A majority of ABA-regulated proteins were also GPA1-dependent. Our data provide insight into how tissue specificity might be achieved in ABA-regulated G-protein signaling. A number of proteins related to ER body formation and intracellular trafficking were altered in gpa1 mutant, suggesting a novel role for GPA1 in these pathways. A potential link between ABA metabolism and ABA signaling was also revealed. The comparison of protein abundance changes in the absence of ABA offers clues to the role of GPA1 in ABA-independent signaling pathways, for example, regulation of cell division. These findings substantially contribute to our knowledge of G-protein signaling mechanisms in plants. PMID- 21545084 TI - Investigation at residue level of the early steps during the assembly of two proteins into supramolecular objects. AB - Understanding the driving forces governing protein assembly requires the characterization of interactions at molecular level. We focus on two homologous oppositely charged proteins, lysozyme and alpha-lactalbumin, which can assemble into microspheres. The assembly early steps were characterized through the identification of interacting surfaces monitored at residue level by NMR chemical shift perturbations by titrating one (15)N-labeled protein with its unlabeled partner. While alpha-lactalbumin has a narrow interacting site, lysozyme has interacting sites scattered on a broad surface. The further assembly of these rather unspecific heterodimers into tetramers leads to the establishment of well defined interaction sites. Within the tetramers, most of the electrostatic charge patches on the protein surfaces are shielded. Then, hydrophobic interactions, which are possible because alpha-lactalbumin is in a partially folded state, become preponderant, leading to the formation of larger oligomers. This approach will be particularly useful for rationalizing the design of protein assemblies as nanoscale devices. PMID- 21545085 TI - Solar energy demand (SED) of commodity life cycles. AB - The solar energy demand (SED) of the extraction of 232 atmospheric, biotic, fossil, land, metal, mineral, nuclear, and water resources was quantified and compared with other energy- and exergy-based indicators. SED represents the direct and indirect solar energy required by a product or service during its life cycle. SED scores were calculated for 3865 processes, as implemented in the Ecoinvent database, version 2.1. The results showed that nonrenewable resources, and in particular minerals, formed the dominant contribution to SED. This large share is due to the indirect solar energy required to produce these resource inputs. Compared with other energy- and exergy-based indicators, SED assigns higher impact factors to minerals and metals and smaller impact factors to fossil energetic resources, land use, and nuclear energy. The highest differences were observed for biobased and renewable energy generation processes, whose relative contribution of renewable resources such as water, biomass, and land occupation was much lower in SED than in energy- and exergy-based indicators. PMID- 21545086 TI - Palladium-catalyzed domino C-S coupling/carbonylation reactions: an efficient synthesis of 2-carbonylbenzo[b]thiophene derivatives. AB - A facile and selective palladium-catalyzed domino procedure has been developed for the preparation of 2-carbonylbenzo[b]thiophene derivatives from 2-gem dihalovinylthiophenols. This protocol involves intramolecular C-S coupling/intermolecular carbonylation cascade sequences and allows access to various highly functionalized benzo[b]thiophenes in moderate yields. PMID- 21545087 TI - The first [2]pseudorotaxane and the first pseudocryptand-type poly[2]pseudorotaxane based on bis(meta-phenylene)-32-crown-10 and paraquat derivatives. AB - By the self-assembly of a bis(meta-phenylene)-32-crown-10 bearing two electron donating groups (carbazoles) with electron-accepting paraquat derivatives, the first [2]pseudorotaxane and the first pseudocryptand-type poly[2]pseudorotaxane based on bis(meta-phenylene)-32-crown-10 were isolated as crystalline solids as shown by X-ray analyses. PMID- 21545088 TI - Flow dichroism as a reliable method to measure the hydrodynamic aspect ratio of gold nanoparticles. AB - Particle shape plays an important role in controlling the optical, magnetic, and mechanical properties of nanoparticle suspensions as well as nanocomposites. However, characterizing the size, shape, and the associated polydispersity of nanoparticles is not straightforward. Electron microscopy provides an accurate measurement of the geometric properties, but sample preparation can be laborious, and to obtain statistically relevant data many particles need to be analyzed separately. Moreover, when the particles are suspended in a fluid, it is important to measure their hydrodynamic properties, as they determine aspects such as diffusion and the rheological behavior of suspensions. Methods that evaluate the dynamics of nanoparticles such as light scattering and rheo-optical methods accurately provide these hydrodynamic properties, but do necessitate a sufficient optical response. In the present work, three different methods for characterizing nonspherical gold nanoparticles are critically compared, especially taking into account the complex optical response of these particles. The different methods are evaluated in terms of their versatility to asses size, shape, and polydispersity. Among these, the rheo-optical technique is shown to be the most reliable method to obtain hydrodynamic aspect ratio and polydispersity for nonspherical gold nanoparticles for two reasons. First, the use of the evolution of the orientation angle makes effects of polydispersity less important. Second, the use of an external flow field gives a mathematically more robust relation between particle motion and aspect ratio, especially for particles with relatively small aspect ratios. PMID- 21545090 TI - Facile and enantiospecific syntheses of (6S,7R)-6-chloro-7-benzyloxy-, (7S)-halo , and (7S)-hydroxy-cocaine and natural (-)-cocaine from D-(-)-ribose. AB - First syntheses of C6,7 and C7 enantiopure cocaine analogues were achieved from D (-)-ribose via a trans-acetonide controlled endo-selective intramolecular nitrone alkene cycloaddition (INAC) as the key step. This synthetic scheme allows practical preparation of cocaine analogues for bioevaluation as potential candidates for the treatment of cocaine addiction and as potential conjugates for immunotherapy. PMID- 21545089 TI - Rapid detection of urinary tract infections using isotachophoresis and molecular beacons. AB - We present a novel assay for rapid detection and identification of bacterial urinary tract infections using isotachophoresis (ITP) and molecular beacons. We applied on-chip ITP to extract and focus 16S rRNA directly from bacterial lysate and used molecular beacons to achieve detection of bacteria specific sequences. We demonstrated detection of E. coli in bacteria cultures as well as in patient urine samples in the clinically relevant range 1E6-1E8 cfu/mL. For bacterial cultures we further demonstrate quantification in this range. The assay requires minimal sample preparation (a single centrifugation and dilution), and can be completed, from beginning of lysing to detection, in under 15 min. We believe that the principles presented here can be used for design of other rapid diagnostics or detection methods for pathogenic diseases. PMID- 21545091 TI - A new organic-inorganic hybrid oxyfluorotitanate [Hgua]2.(Ti5O5F12) as a transparent UV filter. AB - A new generation UV absorber is obtained by microwave-heating-assisted hydrothermal synthesis: [Hgua](2).(Ti(5)O(5)F(12)). The structure of this hybrid titanium(IV) oxyfluoride is ab initio determined from powder X-ray data by combining a direct space method, Rietveld refinement [orthorhombic, Cmm2, a = 22.410(1) A, b = 11.191(1) A, c = 3.802(1) A], and density functional theory geometry optimization. The three-dimensional network is built up from infinite inorganic layers (infinity)(Ti(5)O(5)F(12)) separated by guanidinium cations. The theoretical optical gap (3.2 eV) estimated from density of state calculations is in good agreement with the experimental gap (3.3 eV) obtained by UV-vis diffuse reflectivity. The optical absorption is mainly due to O(2p) -> Ti(3d) and F(2p) > Ti(3d) transitions at higher energies. The refraction index is low in the visible range (n ~ 1.9) compared to that of TiO(2) and, consequently, [Hgua](2).(Ti(5)O(5)F(12)) shows a good transparency adapted to UV shielding. Under UV irradiation at 254 nm for 40 h, the white microcrystalline powder turns to light purple-gray. This color change is caused by the reduction of Ti(IV) to Ti(III), confirmed by magnetic measurements. PMID- 21545092 TI - Chemical vapor deposition-grown graphene: the thinnest solid lubricant. AB - As an atomically thin material with low surface energy, graphene is an excellent candidate for reducing adhesion and friction when coated on various surfaces. Here, we demonstrate the superior adhesion and frictional characteristics of graphene films which were grown on Cu and Ni metal catalysts by chemical vapor deposition and transferred onto the SiO(2)/Si substrate. The graphene films effectively reduced the adhesion and friction forces, and multilayer graphene films that were a few nanometers thick had low coefficients of friction comparable to that of bulk graphite. PMID- 21545093 TI - Coulometric detection of irreversible electrochemical reactions occurring at Pt microelectrodes used for neural stimulation. AB - The electrochemistry of 50 MUm diameter Pt electrodes used for neural stimulation was studied in vitro by reciprocal derivative chronopotentiometry. This differential method provides well-defined electrochemical signatures of the various polarization phenomena that occur at Pt microelectrodes and are generally obscured in voltage transients. In combination with a novel in situ coulometric approach, irreversible H(2) and O(2) evolution, Pt dissolution and reduction of dissolved O(2) were detected. Measurements were performed with biphasic, charge balanced, cathodic-first and anodic-first current pulses at charge densities ranging from 0.07 to 1.41 mC/cm(2) (real surface area) in phosphate buffered saline (PBS) with and without bovine serum albumin (BSA). The extent to which O(2) reduction occurs under the different stimulation conditions was compared in O(2)-saturated and deoxygenated PBS. Adsorption of BSA inhibited Pt dissolution as well as Pt oxidation and oxide reduction by blocking reactive sites on the electrode surface. This inhibitory effect promoted the onset of irreversible H(2) and O(2) evolution, which occurred at lower charge densities than those in PBS. Reduction of dissolved O(2) on Pt electrodes accounted for 19-34% of the total injected charge in O(2)-saturated PBS, while a contribution of 0.4-12% was estimated for in vivo stimulation. These result may prove important for the interpretation of histological damage induced by neural stimulation and therefore help define safer operational limits. PMID- 21545094 TI - Calixarene and resorcarene based receptors: from structural and thermodynamic studies to the synthesis of a new mercury(II) selective material. AB - Materials used in current technological approaches for the removal of mercury lack selectivity. Given that this is one of the main features of supramolecular chemistry, receptors based on calix[4]arene and calix[4]resorcarene containing functional groups able to interact selectively with polluting ions while discriminating against biologically essential ones were designed. Thus two receptors, a partially functionalized calix[4]arene derivative, namely, 5,11,17,23-tetra-tert-butyl [25-27-bis(diethyl thiophosphate amino)dihydroxy] calix[4]arene (1) and a fully functionalized calix[4]resorcarene, 4,6,10,12,16,18,22,24-diethyl thiophosphate calix[4]resorcarene (2) are introduced. Mercury(II) was the identified target due to the environmental and health problems associated with its presence in water Thus following the synthesis and characterization of 1 and 2 in solution ((1)HNMR) and in the solid state (X-ray crystallography) the sequence of experimental events leading to cation complexation studies in acetonitrile and methanol ((1)H NMR, conductance, potentiometric, and calorimetric measurements) with the aim of assessing their behavior as mercury selective receptors are described. The cation selectivity pattern observed in acetonitrile follows the sequence Hg(II) > Cu(II) > Ag(I). In methanol 1 is also selective for Hg(II) relative to Ag(I) but no interaction takes place between this receptor and Cu(II) in this solvent. Based on previous results and experimental facts shown in this paper, it is concluded that the complexation observed with Cu(II) in acetonitrile occurs through the acetonitrile receptor adduct rather than through the free ligand. Receptor 2 has an enhanced capacity for uptaking Hg(II) but forms metalate complexes with Cu(II). These studies in solution guided the inmobilization of receptor 1 into a silica support to produce a new and recyclable material for the removal of Hg(II) from water. An assessment on its capacity to extract this cation from water relative to Cu(II) and Ag (I) shows that the cation selectivity pattern of the inmobilized receptor is the same as that observed for the free receptor in methanol. These findings demonstrate that fundamental studies play a critical role in the selection of the receptor to be attached to silicates as well as in the reaction medium used for the synthesis of the new decontaminating agent. PMID- 21545095 TI - Characterizing DNA methyltransferases with an ultrasensitive luciferase-linked continuous assay. AB - DNA (cytosine-5)-methyltransferases (DNMTs) catalyze the transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) to the 5-position of cytosine residues and thereby silence transcription of regulated genes. DNMTs are important epigenetic targets. However, isolated DNMTs are weak catalysts and are difficult to assay. We report an ultrasensitive luciferase-linked continuous assay that converts the S-adenosyl-L-homocysteine product of DNA methylation to a quantifiable luminescent signal. Results with this assay are compared with the commonly used DNA labeling from [methyl-(3)H]AdoMet. A 5'-methylthioadenosine adenosylhomocysteine nucleosidase is used to hydrolyze AdoHcy to adenine. Adenine phosphoribosyl transferase converts adenine to AMP and pyruvate orthophosphate dikinase converts AMP to ATP. Firefly luciferase gives a stable luminescent signal that results from continuous AMP recycling to ATP. This assay exhibits a broad dynamic range (0.1-1000 pmol of AdoHcy). The rapid response time permits continuous assays of DNA methylation detected by light output. The assay is suitable for high-throughput screening of chemical libraries for DNMT inhibition activity. The kinetic properties of human and bacterial CpG methyltransferases are characterized using this assay. Human catalytic domain DNMT3b activation by DNMT3L is shown to involve two distinct kinetic states that alter k(cat) but not K(m) for AdoMet. The assay is shown to be robust in the presence of high concentrations of the pyrimidine analogues 5-azacytidine and 5-azacytosine. PMID- 21545096 TI - Theranostic nanomedicine. AB - Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically administered (chemo)therapeutic agents. Many different types of nanomedicines have been evaluated over the years, including for instance liposomes, polymers, micelles and antibodies, and a significant amount of evidence has been obtained showing that these submicrometer-sized carrier materials are able to improve the balance between the efficacy and the toxicity of therapeutic interventions. Besides for therapeutic purposes, nanomedicine formulations have in recent years also been increasingly employed for imaging applications. Moreover, paralleled by advances in chemistry, biology, pharmacy, nanotechnology, medicine and imaging, several different systems have been developed in the last decade in which disease diagnosis and therapy are combined. These so-called (nano) theranostics contain both a drug and an imaging agent within a single formulation, and they can be used for various different purposes. In this Account, we summarize several exemplary efforts in this regard, and we show that theranostic nanomedicines are highly suitable systems for monitoring drug delivery, drug release and drug efficacy. The (pre)clinically most relevant applications of theranostic nanomedicines relate to their use for validating and optimizing the properties of drug delivery systems, and to their ability to be used for pre-screening patients and enabling personalized medicine. Regarding the former, the combination of diagnostic and therapeutic agents within a single formulation provides real-time feedback on the pharmacokinetics, the target site localization and the (off-target) healthy organ accumulation of nanomedicines. Various examples of this will be highlighted in this Account, illustrating that by non-invasively visualizing how well carrier materials are able to deliver pharmacologically active agents to the pathological site, and how well they are able to prevent them from accumulating in potentially endangered healthy tissues, important information can be obtained for optimizing the basic properties of drug delivery systems, as well as for improving the balance between the efficacy and the toxicity of targeted therapeutic interventions. Regarding personalized medicine, it can be reasoned that only in patients which show high levels of target site accumulation, and which respond well to the first couple of treatment cycles, targeted therapy should be continued, and that in those in which this is not the case, other therapeutic options should be considered. Based on these insights, we expect that ever more efforts will be invested in developing theranostic nanomedicines, and that these systems and strategies will contribute substantially to realizing the potential of personalized medicine. PMID- 21545097 TI - Mechanisms of fibrinogen adsorption at solid substrates. AB - Adsorption of fibrinogen, modeled as a linear chain of touching beads of various sizes, was theoretically studied using the random sequential adsorption (RSA) model. The adsorption process was assumed to consist of two steps: (i) formation of an irreversibly bound fibrinogen monolayer under the side-on orientation, which is independent of the bulk protein concentration and (ii) formation of the reversibly bound, end-on monolayer, whose coverage was dependent on the bulk concentration. Calculation based on the RSA model showed that the maximum surface concentration of the end-on (reversible) monolayer equals N(?infinity) = 6.13 * 10(3) MUm(-2) which is much larger than the previously found value for the side on (irreversible) monolayer, equal to N(infinity) = 2.27 * 10(3) MUm(-2). Hence, the maximum surface concentration of fibrinogen in both orientations is determined to be 8.40 * 10(3) MUm(-2) corresponding to the protein coverage of 5.70 mg m(-2) assuming 20% hydration. Additionally, the surface blocking function (ASF) was determined for the end-on fibrinogen adsorption, approximated for the entire range of coverage by the interpolating polynomial. For the coverage approaching the jamming limit, the surface blocking function (ASF) was shown to vanish proportionally to (theta(?infinity) - theta(?))(2). These calculation allowed one to theoretically predict adsorption isotherms for the end-on regime of fibrinogen and adsorption kinetics under various transport conditions (diffusion and convection). Using these theoretical results, a quantitative interpretation of experimental data obtained by TIRF and ellipsometry was successfully performed. The equilibrium adsorption constant for the end-on adsorption regime was found to be 8.04 * 10(-3) m. On the basis of this value, the depth of the adsorption energy minimum, equal to -17.4 kT, was predicted, which corresponds to DeltaG = -41.8 kJ mol(-1). This is in accordance with adsorption energy derived as the sum of the van der Waals and electrostatic interactions. Besides having significance for predicting fibrinogen adsorption, theoretical results derived in this work also have implications for basic science providing information on mechanisms of anisotropic protein molecule adsorption on heterogeneous surfaces. PMID- 21545098 TI - Spatial and temporal presence of a wastewater-derived micropollutant plume in Lake Geneva. AB - This study discusses the occurrence and environmental risk associated with a micropollutant plume originating from the direct discharge of treated wastewater into the Vidy Bay of Lake Geneva, Switzerland. The temporal variations and spatial extent of the plume and its effect on the presence of 39 pharmaceuticals and other micropollutants in the Vidy Bay were assessed over a 10 month period. A pronounced plume was observed from April to October, leading to locally elevated (up to 70-fold) pharmaceutical concentrations compared to the surrounding water column. For three of the measured substances, these plume-associated concentrations were sufficiently high to pose an ecotoxicological risk. The plume depth followed the thermal lake stratification, which moved to lower depths over the course of the warm seasons. Pharmaceutical hotspots associated with the plume were detected as far as 1.5 km downstream of the effluent wastewater outfall, but concentrations typically decreased with increasing distance from the wastewater outfall as a result of dilution and photodegradation. From November to January, when uniform temperature prevailed throughout the water column, no micropollutant plumes were detected. In contrast to pharmaceuticals, most pesticides showed homogeneous concentrations throughout the Vidy Bay during the whole study period, indicating that the effluent wastewater was not their dominant source. A strong linear correlation between electrical conductivity and concentrations of wastewater-derived micropollutants was identified. This relation will allow future estimates of wastewater-derived micropollutant concentrations via simple conductivity measurements. PMID- 21545099 TI - Determining valine side-chain rotamer conformations in proteins from methyl 13C chemical shifts: application to the 360 kDa half-proteasome. AB - A method is presented for determining Val side-chain chi(1) rotamer distributions in proteins based exclusively on measured (13)C(gamma1) and (13)C(gamma2) chemical shifts. The approach selects an ensemble of 20 chi(1) values, calculates average methyl (13)C(gamma1,gamma2) chemical shifts via theoretical quantum chemical calculations and maximizes the agreement with the experimentally measured shifts using a genetic algorithm. The methodology is validated with an application involving six proteins for which (13)C(gamma) chemical shifts and three-bond methyl-backbone scalar couplings are available. The utility of the methodology is demonstrated with an application to the 360 kDa 'half-proteasome' where the chi(1) rotameric distributions of Val residues are calculated on the basis of chemical shifts. For the most part the chi(1) profiles so obtained compare very well with those generated from the high-resolution (2.3 A) X-ray structure of the proteasome. Both NMR and X-ray distributions are cross-validated by comparing calculated (1)H-(13)C methyl residual dipolar couplings with measured values, and the level of agreement is at least as good for the NMR derived chi(1) values. Notably, as the resolution of the X-ray data improves (rotamer distributions from 3.4 and 2.3 A X-ray structures are compared with the NMR data), the agreement with the NMR gets significantly better. This emphasizes the importance of NMR approaches for the study of high molecular weight complexes that can be recalcitrant to high resolution X-ray analysis. PMID- 21545100 TI - Anomalous contact angle hysteresis of a captive bubble: advancing contact line pinning. AB - Contact angle hysteresis of a sessile drop on a substrate consists of continuous invasion of liquid phase with the advancing angle (theta(a)) and contact line pinning of liquid phase retreat until the receding angle (theta(r)) is reached. Receding pinning is generally attributed to localized defects that are more wettable than the rest of the surface. However, the defect model cannot explain advancing pinning of liquid phase invasion driven by a deflating bubble and continuous retreat of liquid phase driven by the inflating bubble. A simple thermodynamic model based on adhesion hysteresis is proposed to explain anomalous contact angle hysteresis of a captive bubble quantitatively. The adhesion model involves two solid-liquid interfacial tensions (gamma(sl) > gamma(sl)'). Young's equation with gamma(sl) gives the advancing angle theta(a) while that with gamma(sl)' due to surface rearrangement yields the receding angle theta(r). Our analytical analysis indicates that contact line pinning represents frustration in surface free energy, and the equilibrium shape corresponds to a nondifferential minimum instead of a local minimum. On the basis of our thermodynamic model, Surface Evolver simulations are performed to reproduce both advancing and receding behavior associated with a captive bubble on the acrylic glass. PMID- 21545101 TI - Validation of speciation techniques: a study of chlorozincate(II) ionic liquids. AB - The speciation of chlorozincate(II) ionic liquids, prepared by mixing 1-octyl-3 methylimidazolium chloride, [C(8)mim]Cl, and zinc(II) chloride in various molar ratios, chi(ZnCl(2)), was investigated using Raman spectroscopy and differential scanning calorimetry; the Gutmann acceptor number, which is a quantitative measure of Lewis acidity, was also determined as a function of the composition. These results were combined with literature data to define the anionic speciation; in the neat liquid phase, the existence of Cl(-), [ZnCl(4)](2-), [Zn(2)Cl(6)](2-), [Zn(3)Cl(8)](2-), and [Zn(4)Cl(10)](2-) anions was confirmed. From two chlorozincate(II) ionic liquids with [C(2)mim](+) cations (chi(ZnCl(2)) = 0.33 and chi(ZnCl(2)) = 0.50), crystals have been obtained, revealing the structures of [C(2)mim](2)[ZnCl(4)] and [C(2)mim](2)[Zn(2)Cl(6)] forming three dimensional hydrogen-bond networks. The compound [C(2)mim](2){Zn(4)Cl(10)} was crystallized from the chi(ZnCl(2)) = 0.75 composition, showing an open-framework structure, with the first example of zinc in a trigonal-bipyramidal chloride coordination. Reinvestigation of the electrospray ionization mass spectrometry of these systems demonstrated that it is an unreliable technique to study liquid phase speciation. PMID- 21545102 TI - Swift heavy ion induced ordering and piezoelectric beta-phase in poly(vinylidene fluoride). AB - Ion flux dependent swift heavy ions (SHI) induced structural changes have been reported for pristine poly(vinylidene fluoride) (PVDF). Ordering phenomena has been observed first followed by its transformation from alpha to beta-form (polar metastable piezoelectric phase). The ordering of (020) plane become prominent at higher ion flux SHI irradiation and its further increase induces structural change from alpha to beta phase as revealed by XRD and FTIR analyses. Structural changes are also supported by morphological evidence and thermal studies before and after SHI irradiation. PMID- 21545103 TI - Stress delocalization in crack tolerant electrospun nanofiber networks. AB - The fracture toughness of a noncontinuum fibrous network produced by electrospinning polyamide 6 nanofibers is investigated. The mechanical properties of the nanofiber network is observed to be independent of various incorporated macroscopic crack lengths, resulting in an apparent increase in fracture toughness with increasing crack length as evaluated using conventional fracture mechanics. Strain mapping of the nanofiber network indicates stress delocalization mechanisms operating around these macroscopic cracks in the network. The deformation behavior of the nanofiber network will therefore depend on the volume of fibers being loaded in the network and not the number of fibers in the cross-sectional width defining continuum sample mechanics. These results indicate a propensity for both the synthetic electrospun nanofibrous network in this work and potentially other nanofibrous networks to resist failure from macroscopic cracks incorporated within the material. PMID- 21545105 TI - Use of electrical impedance spectroscopy as a practical method of investigating the formation of aggregates in aqueous solutions of dyes and surfactants. AB - Molecular aggregation plays a key role in the physicochemical properties of dyes and surfactants. In this work, we show that electrical impedance spectroscopy (EIS) provides a practical method for the investigation of processes such as micellization in surfactants and dye dimerization. The electrical characterization of the structural phase transitions associated with aggregation events in these systems allows an accurate and direct determination of relevant parameters such as the corresponding critical concentrations for micelle formation and dimerization of these types of molecules, without the need of recurring to the use of auxiliary probe or reporter molecules. Because of its competitive advantages with respect to currently used methods (such as conductimetry and spectroscopic techniques), we argue that when implemented along the procedures described in this work, EIS becomes a simple and convenient technique for the characterization of aggregation processes in soft matter. PMID- 21545106 TI - Quantifying water-mediated protein-ligand interactions in a glutamate receptor: a DFT study. AB - It is becoming increasingly clear that careful treatment of water molecules in ligand-protein interactions is required in many cases if the correct binding pose is to be identified in molecular docking. Water can form complex bridging networks and can play a critical role in dictating the binding mode of ligands. A particularly striking example of this can be found in the ionotropic glutamate receptors. Despite possessing similar chemical moieties, crystal structures of glutamate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in complex with the ligand-binding core of the GluA2 ionotropic glutamate receptor revealed, contrary to all expectation, two distinct modes of binding. The difference appears to be related to the position of water molecules within the binding pocket. However, it is unclear exactly what governs the preference for water molecules to occupy a particular site in any one binding mode. In this work we use density functional theory (DFT) calculations to investigate the interaction energies and polarization effects of the various components of the binding pocket. Our results show (i) the energetics of a key water molecule are more favorable for the site found in the glutamate-bound mode compared to the alternative site observed in the AMPA-bound mode, (ii) polarization effects are important for glutamate but less so for AMPA, (iii) ligand-system interaction energies alone can predict the correct binding mode for glutamate, but for AMPA alternative modes of binding have similar interaction energies, and (iv) the internal energy is a significant factor for AMPA but not for glutamate. We discuss the results within the broader context of rational drug-design. PMID- 21545108 TI - Synthesis of N-[(3S)-2,6-dioxo-1-(2-phenylethyl)-3-piperidinyl]-(2S)-2 methylbutanamide ((-)-julocrotine). AB - The total synthesis of (-)-julocrotine (1) starting from l-glutamic acid in 41% overall yield is described. The methodology utilizes protection, deprotection, and regioselection (carbonyl differentiation via oxazolidinone) protocols, and glutarimide ring formation is the key step. PMID- 21545107 TI - Synthesis and biological characterization of arylomycin B antibiotics. AB - Antibiotics are virtually always isolated as families of related compounds, but the evolutionary forces underlying the observed diversity are generally poorly understood, and it is not even clear whether they are all expected to be biologically active. The arylomycin class of antibiotics is comprised of three related families that are differentiated by nitration, glycosylation, and hydroxylation of a conserved core scaffold. Previously, we reported the total synthesis of an A series member, arylomycin A2, as well as the A series derivative arylomycin C16 and showed that both are active against a broader spectrum of bacteria than previously appreciated. We now report the total synthesis of a B series analogue, arylomycin B-C16, and its aromatic amine derivative. While the aromatic amine loses activity against all bacteria tested, the B series compound shows activities that are similar to the A series compounds, except that it also gains activity against the important pathogen Streptococcus agalactiae. PMID- 21545109 TI - Cytotoxic norsesquiterpene peroxides from the endophytic fungus Talaromyces flavus isolated from the mangrove plant Sonneratia apetala. AB - Four new norsesquiterpene peroxides, named talaperoxides A-D (1-4), as well as one known analogue, steperoxide B (5, or merulin A), have been isolated from a mangrove endophytic fungus, Talaromyces flavus. Their structures were elucidated mainly by 1D and 2D NMR. Structures of 1, 2, and 5 were further confirmed by single-crystal X-ray diffraction, and their absolute configurations were also determined using copper radiation. Cytotoxic activities of compounds 1-5 were evaluated in vitro against human cancer cell lines MCF-7, MDA-MB-435, HepG2, HeLa, and PC-3. Compounds 2 and 4 showed cytotoxicity against the five human cancer cell lines with IC50 values between 0.70 and 2.78 MUg/mL. PMID- 21545110 TI - How does a drug molecule find its target binding site? AB - Although the thermodynamic principles that control the binding of drug molecules to their protein targets are well understood, detailed experimental characterization of the process by which such binding occurs has proven challenging. We conducted relatively long, unguided molecular dynamics simulations in which a ligand (the cancer drug dasatinib or the kinase inhibitor PP1) was initially placed at a random location within a box that also contained a protein (Src kinase) to which that ligand was known to bind. In several of these simulations, the ligand correctly identified its target binding site, forming a complex virtually identical to the crystallographically determined bound structure. The simulated trajectories provide a continuous, atomic-level view of the entire binding process, revealing persistent and noteworthy intermediate conformations and shedding light on the role of water molecules. The technique we employed, which does not assume any prior knowledge of the binding site's location, may prove particularly useful in the development of allosteric inhibitors that target previously undiscovered binding sites. PMID- 21545111 TI - Palladium(II)-catalyzed direct alkenylation and arylation of arenes: removable 2 pyridylsulfinyl group assisted C-H bond activation. AB - Palladium-catalyzed C-H activation reactions directed by a removable 2 pyridylsulfinyl group were developed. Aromatic olefination products were formed in good yields on treatment of 2-(phenylsulfinyl)pyridines with alkenes in the presence of a Pd catalyst. The reaction tolerates a wide range of substituted alkenes, including various acrylates and styrenes. The controlled experiments indicated that the 2-pyridyl moiety, rather than the sulfinyl, played the role of ligand. The final reductive desulfonylation affords the stilbenes, sulfides, and disulfides with different reductive conditions, respectively. More importantly, this transformation could also be applied in arylation through dual C-H activation. PMID- 21545112 TI - Fast parallel tandem mass spectral library searching using GPU hardware acceleration. AB - Mass spectrometry-based proteomics is a maturing discipline of biologic research that is experiencing substantial growth. Instrumentation has steadily improved over time with the advent of faster and more sensitive instruments collecting ever larger data files. Consequently, the computational process of matching a peptide fragmentation pattern to its sequence, traditionally accomplished by sequence database searching and more recently also by spectral library searching, has become a bottleneck in many mass spectrometry experiments. In both of these methods, the main rate-limiting step is the comparison of an acquired spectrum with all potential matches from a spectral library or sequence database. This is a highly parallelizable process because the core computational element can be represented as a simple but arithmetically intense multiplication of two vectors. In this paper, we present a proof of concept project taking advantage of the massively parallel computing available on graphics processing units (GPUs) to distribute and accelerate the process of spectral assignment using spectral library searching. This program, which we have named FastPaSS (for Fast Parallelized Spectral Searching), is implemented in CUDA (Compute Unified Device Architecture) from NVIDIA, which allows direct access to the processors in an NVIDIA GPU. Our efforts demonstrate the feasibility of GPU computing for spectral assignment, through implementation of the validated spectral searching algorithm SpectraST in the CUDA environment. PMID- 21545113 TI - Fabrication of a highly sensitive aptasensor for potassium with a nicking endonuclease-assisted signal amplification strategy. AB - A novel strategy to fabricate an aptasensor for potassium with high sensitivity and selectivity by using nicking endonuclease is proposed in this work. A nicking endonuclease (Nt.CviPII), which may recognize specific nucleotide sequences in double-stranded DNA formed by a potassium-binding aptamer and a linker DNA but cleave only the linker strand, may transfer and amplify the quantitative information of the potassium detection to that of the linker DNA through elaborate strand-scission cycles. Since the technique for gene assay is much more mature, the linker DNA can thereby be detected by a number of available methods. Here, taking advantage of a simple and fast gold nanoparticles-based sensing technique, we are able to assay the linker and consequently potassium ion simply by UV-vis spectroanalysis and even with the naked eye. Results show that a 2 MUL sample containing 0.1 mM of potassium is enough to induce distinct color appearance of the nanoparticles, and the potassium ion can be easily distinguished from many other ions. The strategy proposed in this work shows some unique advantages over some traditional methods and may be further developed for the detection of some other chemicals in the future. PMID- 21545114 TI - Synthesis and development of a multifunctional self-decontaminating polyurethane coating. AB - A unique, durable, nonleaching antimicrobial urethane coating possessing energy dampening properties is reported. Five novel diol-functionalized quaternary ammonium bromide salts were designed, synthesized, and cross-linked with a commercial polyisocyanate to afford novel multifunctional self-decontaminating coatings. Leaching of the antimicrobial into the environment is eliminated because of the biocidal tether. The effectiveness of these molecules to self concentrate at the air-polymer interface without addition of other surface modifying additives proved extremely advantageous, and consequently resulted in microphase separation as confirmed by AFM. The coatings were designed to continuously decontaminate against a variety of pathogenic bacteria in addition to affording preliminary dampening properties. Minimum inhibitory concentration studies as well as surface antimicrobial evaluations were conducted using both Gram-positive and Gram-negative bacteria. Additionally, viscoelastic properties, hardness, tack, and surface energy measurements were used to correlate with coating performance. PMID- 21545115 TI - High surface area tapes produced with functionalized graphene. AB - We describe a scalable method for producing continuous graphene networks by tape casting surfactant-stabilized aqueous suspensions of functionalized graphene sheets. Similar to all other highly connected graphene-containing networks, the degree of overlap between the sheets controls the tapes' electrical and mechanical properties. However, unlike other graphene-containing networks, the specific surface area of the cast tapes remains high (>400 m(2).g(-1)). Exhibiting apparent densities between 0.15 and 0.51 g.cm(-3), with electrical conductivities up to 24 kS.m(-1) and tensile strengths over 10 MPa, these tapes exhibit the best combination of properties with respect to density heretofore observed for carbon-based papers, membranes, or films. PMID- 21545116 TI - Constructing metal-based structures on nanopatterned etched silicon. AB - Silicon surfaces with nanoscale etched patterns were obtained using polystyrene block-poly(4-vinylpyridine) (PS-b-P4VP) block copolymer films as templates, followed by brief immersion in HF(aq). The resulting interfaces were comprised of pseudohexagonal arrays of pits on the silicon, whose shapes depended upon the chosen silicon orientation. The top unetched face of silicon remains capped by the native oxide, and the pit interiors are terminated by Si-H(x). Selective chemical functionalization via these two chemical handles was demonstrated to be a viable approach toward building nanostructured metal oxide and metal features within these silicon pits and on the top face. Using a series of interfacial chemical reactions, including oxidation (of Si-H(x)-terminated regions), hydrosilylation, and alkoxysilane-based chemistry on silicon oxide, the growth of metal-based structures can be spatially controlled. In the first approach, titania nanobowls were grown within the etch pits, and in the second, galvanic displacement was used to produce gold nanoparticles either within the etch pits, on the top silicon face, or both. PMID- 21545117 TI - Thermal emission spectra from individual suspended carbon nanotubes. AB - We study the thermal emission spectra of individual suspended carbon nanotubes induced by electrical heating. Semiconducting and metallic devices exhibit different spectra, based on their distinctive band structures. These spectra are compared with the ideal blackbody emission spectrum. In the visible wavelength range, the thermal emission spectra of semiconducting devices agree well with Planck's law, while the spectra of metallic devices show an additional peak between 1.5 and 1.9 eV. In the near-infrared wavelength range, the semiconducting nanotubes exhibit a peak around 1 eV. These additional peaks are attributed to the E11M and E22SC transitions that are thermally driven under these high applied bias voltages. These peaks show a strong polarization dependence, while the blackbody tail is unpolarized, which provides further evidence for electron-hole recombination in thermal emission. For semiconducting devices, the temperature of the nanotube is fit to Planck's law and compared with the temperatures obtained from the G band and 2D band Raman downshifts, as well as the anti-Stokes/Stokes intensity ratio. For devices showing thermal non-equilibrium, the electron temperature agrees well with G+ downshift but deviates from G_ downshift. PMID- 21545118 TI - Kinetic isotope effects in the study of organometallic reaction mechanisms. PMID- 21545119 TI - Discrete, solvent-free alkaline-earth metal cations: metal...fluorine interactions and ROP catalytic activity. AB - Efficient protocols for the syntheses of well-defined, solvent-free cations of the large alkaline-earth (Ae) metals (Ca, Sr, Ba) and their smaller Zn and Mg analogues have been designed. The reaction of 2,4-di-tert-butyl-6 (morpholinomethyl)phenol ({LO(1)}H), 2-{[bis(2-methoxyethyl)amino]methyl}-4,6-di tert-butylphenol ({LO(2)}H), 2-[(1,4,7,10-tetraoxa-13-azacyclopentadecan-13 yl)methyl]-4,6-di-tert-butylphenol ({LO(3)}H), and 2-[(1,4,7,10-tetraoxa-13 azacyclo-pentadecan-13-yl)methyl]-1,1,1,3,3,3-hexafluoropropan-2-ol ({RO(3)}H) with [H(OEt(2))(2)](+)[H(2)N{B(C(6)F(5))(3)}(2)](-) readily afforded the doubly acidic pro-ligands [{LO(1)}HH](+)[X](-) (1), [{LO(2)}HH](+)[X](-) (2), [{LO(3)}HH](+)[X](-) (3), and [{RO(3)}HH](+)[X](-) (4) ([X](-) = [H(2)N{B(C(6)F(5))(3)}(2)](-)). The addition of 2 to Ca[N(SiMe(3))(2)](2)(THF)(2) and Sr[N(SiMe(3))(2)](2)(THF)(2) yielded [{LO(2)}Ca(THF)(0.5)](+)[X](-) (5) and [{LO(2)}Sr(THF)](+)[X](-) (6), respectively. Alternatively, 5 could also be prepared upon treatment of {LO(2)}CaN(SiMe(3))(2) (7) with [H(OEt(2))(2)](+)[X]( ). Complexes [{LO(3)}M](+)[X](-) (M = Zn, 8; Mg, 9; Ca, 10; Sr, 11; Ba, 12) and [{RO(3)}M](+)[X](-) (M = Zn, 13; Mg, 14; Ca, 15; Sr, 16; Ba, 17) were synthesized in high yields (70-90%) by reaction of 3 or 4 with the neutral precursors M[N(SiMe(3))(2)](2)(THF)(x) (M = Zn, Mg, x = 0; M = Ca, Sr, Ba, x = 2). All compounds were fully characterized by spectroscopic methods, and the solid-sate structures of compounds 1, 3, 7, 8, 13, 14, {15}(4).3CD(2)Cl(2), {16}(4).3CD(2)Cl(2), and {{17}(4).EtOH}.3CD(2)Cl(2) were determined by X-ray diffraction crystallography. Whereas the complexes are monomeric in the case of Zn and Mg, they form bimetallic cations in the case of Ca, Sr and Ba; there is no contact between the metal and the weakly coordinating anion. In all metal complexes, the multidentate ligand is kappa(6)-coordinated to the metal. Strong intramolecular M...F secondary interactions between the metal and F atoms from the ancillary ligands are observed in the structures of {15}(4).3CD(2)Cl(2), {16}(4).3CD(2)Cl(2), and {{17}(4).EtOH}.3CD(2)Cl(2). VT (19)F{(1)H} NMR provided no direct evidence that these interactions are maintained in solution; nevertheless, significant Ae...F energies of stabilization of 25-26 (Ca, Ba) and 40 kcal.mol(-1) (Sr) were calculated by NBO analysis on DFT-optimized structures. The identity and integrity of the cationic complexes are preserved in solution in the presence of an excess of alcohol (BnOH, (i)PrOH) or L-lactide (L-LA). Efficient binary catalytic systems for the immortal ring-opening polymerization of L-LA (up to 3,000 equiv) are produced upon addition of an excess (5-50 equiv) of external protic nucleophilic agents (BnOH, (i)PrOH) to 8-12 or 13-17. PLLAs with M(n) up to 35,000 g.mol(-1) were produced in a very controlled fashion (M(w)/M(n) ~ 1.10-1.20) and without epimerization. In each series of catalysts, the following order of catalytic activity was established: Mg ? Zn < Ca < Sr ~ Ba; also, Ae complexes supported by the aryloxide ligand are more active than their parents supported by the fluorinated alkoxide ancillary, possibly owing to the presence of Ae...F interactions in the latter case. The rate law -d[L-LA]/dt = k(p).[L-LA](1.0).[16](1.0).[BnOH](1.0) was established by NMR kinetic investigations, with the corresponding activation parameters DeltaH(++) = 14.8(5) kcal.mol(-1) and DeltaS(++) = -7.6(2.0) cal.K(-1).mol(-1). DFT calculations indicated that the observed order of catalytic activity matches an increase of the L-LA coordination energy onto the cationic metal centers with parallel decrease of the positive metal charge. PMID- 21545120 TI - Ab initio calculation of the adhesion and ideal shear strength of planar diamond interfaces with different atomic structure and hydrogen coverage. AB - We propose a method to calculate the ideal shear strength tau of two surfaces in contact by ab initio calculations. This quantity and the work of adhesion gamma are the interfacial parameters usually derived from tip-based friction force measurements. We consider diamond interfaces and quantitatively evaluate the effects of surface orientation and passivation. We find that in the case of fully passivated interfaces, gamma is not affected by the orientation and the alignment of the surfaces in contact. On the contrary, tau does show a dependence on the atomic-scale roughness of the interface. The surface termination has a major impact on the tribological properties of diamond. The presence of dangling bonds, even at concentrations low enough to prevent the formation of interfacial C-C bonds, causes an increase in the resistance to sliding by 2 orders of magnitude with respect to the fully hydrogenated case. We discuss our findings in relation to experimental observations. PMID- 21545121 TI - The adsorption and self-assembly of mixtures of alkylbenzene sulfonate isomers and the role of divalent electrolyte. AB - In this paper, the role of the different structural isomers of the anionic surfactant sodium para-dodecyl benzene sulfonate, LAS, on surface adsorption and solution self-assembly has been studied. Using a combination of neutron reflectivity, NR, and small angle neutron scattering, SANS, the effect of mixing an isomer with a short symmetric hydrocarbon chain with one which has an asymmetric hydrocarbon chain on both the equilibrium surface adsorption behavior and the solution microstructure of the mixtures, both in the presence and absence of a divalent cation (Ca(2+)), has been investigated. In the absence of electrolyte, the LAS isomer mixtures form small charged globular micelles throughout the composition range studied. The micelle aggregation number increases with the increase in the asymmetric isomer content, reflecting an increase in the packing efficiency within the micelle. The addition of calcium ions promotes the formation of planar aggregates, as multilamellar vesicles, but only when the symmetric LAS isomer is the major component of the mixture. At a surfactant concentration just above the critical micelle concentration, CMC, and in the absence of electrolyte, the variation in the surface composition is close to the solution composition. Regular solution theory, RST, calculations show that this variation is also close to what is expected for ideal mixing. The addition of Ca(2+) ions induces a different surface behavior, resulting in the formation of multilayer structures at the interface throughout the entire composition range. PMID- 21545122 TI - Predicting neopentane isosteric enthalpy of adsorption at zero coverage in MCM 41. AB - The isosteric enthalpy of adsorption for neopentane at relative pressures down to 3 * 10(-8) in MCM-41 was predicted for the temperature range from -15 to 0 degrees C. At such low pressures and temperatures, experimental measurements become problematic for this system. We used an atomistic model for MCM-41 obtained by means of a kinetic Monte Carlo method mimicking the synthesis of the material. The model was parametrized to represent experimental nitrogen adsorption isotherms at 77 K using grand canonical Monte Carlo simulations. The simulated isosteric enthalpy of adsorption shows very good agreement with available experimental data, demonstrating that GCMC simulations can predict heats of adsorption for conditions that are challenging for experimental measurements. Additional insights into the adsorption mechanisms, derived from energetic analysis at the molecular level, are also presented. PMID- 21545123 TI - Repellency of the lotus leaf: resistance to water intrusion under hydrostatic pressure. AB - In an attempt to better understand the repellency of the lotus leaf, a model was constructed from hydrophobic hemispheres arranged on a hexagonal array. Two scenarios were considered. In the first, the hemispheres were smooth. In the second, the hemispheres had a secondary roughness. The model shows that, without the secondary structure, the repellency of this surface geometry is relatively poor. The secondary structure directs the surface tension upward, allowing much greater resistance to penetration of water and prevents the loss of repellency. From the proposed model, the maximum intrusion pressure (or so-called Cassie Wenzel transition) of the lotus leaf is estimated to be 12-15 kPa. The predicted maximum pressure agrees well with reported values from experimental measurements. PMID- 21545124 TI - Influence of ferrite nanoparticle type and content on the crystallization kinetics and electroactive phase nucleation of poly(vinylidene fluoride). AB - This work reports on the nucleation of the beta-phase of poly(vinylidene fluoride) (PVDF) by incorporating CoFe(2)O(4) and NiFe(2)O(4) nanoparticles, leading in this way to the preparation of magnetoelectric composites. The fraction of filler nanoparticles needed to produce the same beta- to alpha-phase ratio in crystallized PVDF is 1 order of magnitude lower in the cobalt ferrite nanoparticles. The interaction between nanoparticles and PVDF chains induce the all-trans conformation in PVDF segments, and this structure then propagates in crystal growth. The nucleation kinetics is enhanced by the presence of nanoparticles, as corroborated by the increasing number of spherulites with increasing nanoparticle content and by the variations of the Avrami's exponent. Further, the decrease of the crystalline fraction of PVDF with increasing nanoparticle content indicates that an important fraction of polymer chains are confined in interphases with the filler particle. PMID- 21545125 TI - Thia-, aza-, and selena[3.3.1]bicyclononane dichlorides: rates vs internal nucleophile in anchimeric assistance. AB - Sulfur-, selenium-, and nitrogen-containing compounds bearing leaving groups in the beta-position undergo facile substitution chemistry enabled by anchimeric assistance. Here we provide direct comparisons between such systems in the rigid bicyclo[3.3.1]nonane framework easily derived from 1,5-cyclooctadiene. For a series of dichloride electrophiles of this type, the relative reactivities were found to be Se ? (alkyl)N > S >= (propargyl)N > (phenyl)N, with the reaction rates at the two extremes differing by more than 3 orders of magnitude. For the N alkyl case, substitution rates were largely independent of the trapping nucleophile but were strongly dependent on solvent, showing that the process is controlled by the formation of the high-energy three-membered cationic intermediate. PMID- 21545126 TI - Diamine-catalyzed conjugate addition to acrylate derivatives. AB - Diamines were found to promote catalytic conjugate addition of alpha-cyano active methine nucleophiles to various acrylate derivatives. PMID- 21545127 TI - Detailed atomistic analysis of the HIV-1 protease interface. AB - HIV-1 protease is a very attractive target for the development of new anti-HIV drugs and has been extensively studied over the past decades. In this study, we present a detailed atomic level characterization of the dimer interface in the enzyme HIV-1 protease through computational alanine scanning mutagenesis and molecular dynamics simulations. In addition to a full mapping of the amino acid residues present at the subunit interface, in terms of the corresponding energetic contribution for dimer formation and of their classification as hot spots, warm spots, and null spots, we trace a dynamic analysis of the subunit interacting and solvent accessible surface areas and of the most important hydrogen bonds between subunits. The results presented illustrate the high energetic importance for dimer formation of a small set of five amino acid residue pairs at the subunit interface-Leu5, Ile50, Arg87, Leu97, and Phe99-and provide important clues on the most important structural and energetic determinants for dimer formation. In addition, the results presented suggest several key targets at the subunit interface for the development of new molecules that aim to inhibit HIV-1 protease (PR) activity through blocking the formation of the fully active PR homodimeric form, providing important clues for drug design. PMID- 21545128 TI - Dynamics of a heparin-binding domain of VEGF(165) complexed with its inhibitor triamterene. AB - Vascular endothelial growth factor (VEGF), which has neurotrophic and neuroprotective effects in addition to its major role in angiogenesis, interacts with Abeta and accumulates in the senile plaques of Alzheimer's disease (AD) patients' brains. It is known that Abeta binds to the heparin-binding domain (HBD) of the 165-amino acid VEGF variant, VEGF(165). In this study, we showed that triamterene (Trm) inhibits VEGF--Abeta interaction without affecting other biological activities of VEGF or Abeta. We investigated the importance of structural and dynamic features of HBD for its molecular-recognition processes. The binding model of HBD and Trm was constructed based on measurements of chemical shift changes and docking study. The results showed that the loop region (S11-L17) and F18 at the beginning of the first beta-sheet in the HBD constitute the inhibitor binding site. The N1 atom of pteridine ring of Trm forms hydrogen bonding with backbone amide proton of R13, and the phenyl ring took part in a hydrophobic interaction with the aromatic ring of F18. To investigate the functional importance of the inherent structural flexibility of the HBD in VEGF, the dynamic properties of free HBD and HBD--Trm complex were assessed by measuring spin relaxation rates, and the backbone dynamics were investigated by model-free analysis. The residues in the disordered loop region of the N-terminus exhibited conformational exchanges in free HBD, and flexibility of this loop region decreased dramatically upon binding to Trm, suggesting that Abeta as well as inhibitor may recognize these unique dynamic features of the HBD. Furthermore, C-terminal residues continued to exhibit slow conformational motions, even in the HBD--Trm complex, implying that these motions at the C-terminus of the HBD might be important for interactions with heparin molecules. The flexibility of HBD demonstrated here should be essential for VEGF function and interaction with other protein partners. PMID- 21545129 TI - Facile reduction of a uranyl(VI) beta-ketoiminate complex to U(IV) upon oxo silylation. AB - Reaction of the uranyl beta-ketoiminate complex UO(2)((tBu)acnac)(2) (1) ((tBu)acnac = (t)BuNC(Ph)CHC(Ph)O) with Me(3)SiI, in the presence of Ph(3)P, results in the reductive silylation of the uranyl moiety and formation of the U(V) bis-silyloxide complex [Ph(3)PI][U(OSiMe(3))(2)I(4)] (2). Subsequent reaction of 2 with Lewis bases, such as 2,2'-bipyridine (bipy), 1,10 phenanthroline (phen), and tetrahydrofuran (THF), results in a further reduction of the metal center and isolation of the U(IV) complexes U(OSiMe(3))(2)I(2)(bipy)(2) (3), U(OSiMe(3))(2)I(2)(phen)(2) (4), and [U(OSiMe(3))(2)I(THF)(4)][I(3)] (5), respectively. PMID- 21545130 TI - Influence of the 316 L stainless steel interface on the stability and barrier properties of plasma fluorocarbon films. AB - Coatings are known to be one of the more suited strategies to tailor the interface between medical devices and the surrounding cells and tissues once implanted. The development of coatings and the optimization of their adhesion and stability are of major importance. In this work, the influence of plasma etching of the substrate on a plasma fluorocarbon ultrathin coating has been investigated with the aim of improving the stability and the corrosion properties of coated medical devices. The 316 L stainless steel interface was subjected to two different etching sequences prior to the plasma deposition. These plasma etchings, with H(2) and C(2)F(6) as gas precursors, modified the chemical composition and the thickness of the oxide layer and influenced the subsequent polymerization. The coating properties were evaluated using flat substrates submitted to deformation, aging into aqueous medium and corrosion tests. X-ray photoelectron spectroscopy (XPS), time of flight-secondary ion mass spectrometry (ToF-SIMS), ellipsometry, and atomic force microscopy (AFM) were performed to determine the effects of the deformation and the aging on the chemistry and morphology of the coated samples. Analyses showed that plasma etchings were essential to promote reproducible polymerization and film growth. However, the oxide layer thinning due to the etching lowered the corrosion resistance of the substrate and affected the stability of the interface. Still, the deformed samples did not exhibited adhesion and cohesion failure before and after the aging. PMID- 21545132 TI - Structural characteristics around the beta-ionone ring of the retinal chromophore in Salinibacter sensory rhodopsin I. AB - Organisms sense and respond to environmental stimuli through membrane-embedded receptors and transducers. Sensory rhodopsin I (SRI) and sensory rhodopsin II (SRII) are the photoreceptors for the positive and negative phototaxis in microorganisms, respectively. They form signaling complexes in the membrane with their cognate transducer proteins, HtrI and HtrII, and these SRI-HtrI and SRII HtrII complexes transmit a light signal through their cytoplasmic sensory signaling system, inducing opposite effects (i.e., the inactivation or activation of the kinase CheA). Here we found, by using Fourier transformed infrared spectroscopy, that a conserved residue, Asp102 in Salinibacter SRI (SrSRI), which is located close to the beta-ionone ring of the retinal chromophore, is deprotonated upon formation of the active M-intermediate. Furthermore, the D102E mutant of SrSRI affects the structure and/or structural changes of Cys130. This mutant shows a large spectral shift and is comparably unstable, especially in the absence of Cl(-). These phenomena have not been observed in the wild-type, or the N105Q and N105D mutants of Natronomonas pharaonis SRII (NpSRII), indicating differences in the structure and structural changes between SrSRI and NpSRII around the beta-ionone ring. These differences could also be supported by the measurements of the reactivity with the water-soluble reagent azide. On the basis of these results, we discuss the structure and structural changes around the retinal chromophore in SrSRI. PMID- 21545131 TI - 64Cu-labeled lissamine rhodamine B: a promising PET radiotracer targeting tumor mitochondria. AB - Enhanced mitochondrial potential in carcinoma cells is an important characteristic of cancer. It is of great current interest to develop a radiotracer that is sensitive to mitochondrial potential changes at the early stage of tumor growth. In this report, we present the synthesis and evaluation of (64)Cu-labeled Lissamine rhodamine B (LRB), (64)Cu(DOTA-LRB) (DOTA-LRB = 2-(6 (diethylamino)-3-(diethyliminio)-3H-xanthen-9-yl)-5-(N-(2-(2-(4,7,10 tris(carboxymethyl)-1,4,7,10-tetraazacyclo-dodecan-1 yl)acetamido)ethyl)sulfamoyl)benzenesulfonate) as a new radiotracer for imaging tumors in athymic nude mice bearing U87MG human glioma xenografts by positron emission tomography (PET). We also explored its localization mechanism using Cu(DOTA-LRB) as the fluorescent probe in both the U87MG human glioma cell line and the cultured primary U87MG glioma cells. It was found that (64)Cu(DOTA-LRB) had the highest tumor uptake (6.54 +/- 1.50, 6.91 +/- 1.26, 5.68 +/- 1.13, 7.58 +/- 1.96, and 5.14 +/- 1.50%ID/g at 0.5, 1, 2, 4, and 24 h postinjection, respectively) among many (64)Cu-labeled organic cations evaluated in the same animal model. The cellular staining study indicated that Cu(DOTA-LRB) was able to localize in mitochondria of U87MG glioma cells due to the enhanced negative mitochondrial potential. This statement is completely supported by the results from decoupling experiment with carbonylcyanide-m-chlorophenylhydrazone (CCCP). MicroPET data showed that the U87MG glioma tumors were clearly visualized as early as 30 min postinjection with (64)Cu(DOTA-LRB). (64)Cu(DOTA-LRB) remained stable during renal excretion, but underwent extensive degradation during hepatobiliary excretion. On the basis of the results from this study, it was concluded that (64)Cu(DOTA-LRB) represents a new class of promising PET radiotracers for noninvasive imaging of the MDR-negative tumors. PMID- 21545133 TI - A naphthodithiophene-diketopyrrolopyrrole donor molecule for efficient solution processed solar cells. AB - We report the synthesis, characterization, and first implementation of a naphtho[2,3-b:6,7-b']dithiophene (NDT)-based donor molecule in highly efficient organic photovoltaics (OPVs). When NDT(TDPP)(2) (TDPP = thiophene-capped diketopyrrolopyrrole) is combined with the electron acceptor PC(61)BM, a power conversion efficiency (PCE) of 4.06 +/- 0.06% is achieved-a record for a PC(61)BM based small-molecule OPV. The substantial PCE is attributed to the broad, high oscillator strength visible absorption, the ordered molecular packing, and an exceptional hole mobility of NDT(TDPP)(2). PMID- 21545134 TI - Rapid determination of carbohydrates, ash, and extractives contents of straw using attenuated total reflectance fourier transform mid-infrared spectroscopy. AB - Analysis of the chemical components of lignocellulosic biomass is essential to understanding its potential for utilization. Mid-infrared spectroscopy and partial least-squares regression were used for rapid measurement of the carbohydrate (total glycans; glucan; xylan; galactan; arabinan; mannan), ash, and extractives content of triticale and wheat straws. Calibration models for total glycans, glucan, and extractives showed good and excellent predictive performance on the basis of slope, r2, RPD, and R/SEP criteria. The xylan model showed good and acceptable predictive performance. However, the ash model was evaluated as providing only approximate quantification and screening. The models for galactan, arabinan, and mannan indicated poor and insufficient prediction for application. Most models could predict both triticale and wheat straw samples with the same degree of accuracy. Mid-infrared spectroscopic techniques coupled with partial least-squares regression can be used for rapid prediction of total glycans, glucan, xylan, and extractives in triticale and wheat straw samples. PMID- 21545135 TI - Quantum-yield-optimized fluorophores for site-specific labeling and super resolution imaging. AB - Single-molecule applications, saturated pattern excitation microscopy, and stimulated emission depletion (STED) microscopy demand bright as well as highly stable fluorescent dyes. Here we describe the synthesis of quantum-yield optimized fluorophores for reversible, site-specific labeling of proteins or macromolecular complexes. We used polyproline-II (PPII) helices as sufficiently rigid spacers with various lengths to improve the fluorescence signals of a set of different trisNTA-fluorophores. The improved quantum yields were demonstrated by steady-state and fluorescence lifetime analyses. As a proof of principle, we characterized the trisNTA-PPII-fluorophores with respect to in vivo protein labeling and super-resolution imaging at synapses of living neurons. The distribution of His-tagged AMPA receptors (GluA1) in spatially restricted synaptic clefts was imaged by confocal and STED microscopy. The comparison of fluorescence intensity profiles revealed the superior resolution of STED microscopy. These results highlight the advantages of biocompatible and, in particular, small and photostable trisNTA-PPII-fluorophores in super-resolution microscopy. PMID- 21545136 TI - Classical simulations with the POLIR potential describe the vibrational spectroscopy and energetics of hydration: divalent cations, from solvation to coordination complex. AB - POLIR, a polarizable water potential optimized for vibrational and intermolecular spectroscopy in pure water but not optimized for solvation, is used to describe solutions of the divalent metal cations Ca(2+), Mg(2+), and Cu(2+). The spectral shifts in the O-H stretch region obtained from classical simulations are in agreement with experiment. The water-ion binding energies are dominated by classical electrostatics, even though the Cu(2+) case might be considered to involve an intermediate-strength chemical bond. Three-body energies of the ion with the first solvation shell are in agreement with ab initio calculations. Our results indicate the importance of polarization in the development of accurate, transferable, force fields and the power of classical methods when it is carefully included. PMID- 21545137 TI - Genotoxicity of several polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs, and their mechanisms of toxicity. AB - Polybrominated diphenyl ethers (PBDEs) have been extensively utilized as flame retardants, and recently there has been concern about potential adverse effects in humans and wildlife. Their hydroxylated analogs (OH-BDEs) have received increasing attention due to their potential for endocrine and neurological toxicities. However, the potentials and mechanisms of genotoxicity of these brominated compounds have scarcely been investigated. In the present study, genotoxicity of tetra-BDEs, penta BDE, octa-BDE, deca-BDE, and tetra-OH-BDEs were investigated by use of chicken DT40 cell lines including wild-type cells and a panel of mutant cell lines deficient in DNA repair pathways. Tetra-BDEs have greater genotoxic potential than do the other BDEs tested. OH-tetra-BDEs were more genotoxic than tetra-BDEs. DT40 cells, deficient in base excision repair (Polbeta(-/-)) and translesion DNA synthesis (REV3(-/-)) pathways, were hypersensitive to the genotoxic effects of tetra-BDEs and OH-tetra-BDEs. The observation of chromosomal aberrations and gamma-H2AX assay confirmed that the studied brominated compounds caused double strand breaks. Pretreatment with N acetyl-l-cysteine (NAC) significantly rescued the Polbeta(-/-) and REV3(-/-) mutants, which is consistent with the hypothesis that PBDEs and OH-BDEs cause DNA damage mediated through reactive oxygen species (ROS). Some tetra-BDEs and OH tetra-BDEs caused base damage through ROS leading to replication blockage and subsequent chromosomal breaks. PMID- 21545138 TI - Enantioselectivity tuning of chiral herbicide dichlorprop by copper: roles of reactive oxygen species. AB - Reactive oxygen species (ROS) are considered to be the key players in cell toxicity. However, cross talk between the enantioselective toxicity of pesticides, heavy metals, and ROS is poorly understood. To decipher the puzzle, the effects of copper (Cu) on the enantioselective ecotoxicity of the chiral pesticide dichlorprop (DCPP) to Scenedesmus obliquus were investigated. The results showed that the presence of DCPP and Cu, both individually and in combination, caused a sudden increase of ROS. This in turn stimulated the response of antioxidant defenses, impaired subcellular structure and physiological function, and finally resulted in cell growth inhibition. In the absence of Cu, ROS production after exposure to the herbicidally active (R) enantiomer was higher than that of the (S)-enantiomer, suggesting a preference for an (R)-enantiomer-induced production of ROS. When DCPP and Cu were both added to algae simultaneously, (R)-DCPP preferentially induced production of ROS was observed. However, the enantioselective induced production of ROS was reversed when DCPP was mixed with Cu for 24 h prior to addition to the algae solution. It was also found that the generation of ROS, antioxidant response, and growth inhibition rate in Scenedesmus obliquus were all (R)-enantiomer preferentially induced. These findings implied that ROS play a primary role in chemical contaminant toxicity, and interactions between contaminants can tune the enantioselectivity of chiral herbicides, which should be considered in future risk assessment. PMID- 21545139 TI - 1-Palmitoyl-2-(9'-oxononanoyl)-sn-glycero-3-phosphocholine, an oxidized phospholipid, accelerates Finnish type familial gelsolin amyloidosis in vitro. AB - Finnish type familial amyloidosis (FAF) is a neurodegenerative disease, which involves the deposition of D187N or -Y mutant gelsolin fragments as amyloid in various tissues, accompanied by dermatologic, neurologic, and ophthalmologic disorders. Like the other amyloid diseases, FAF is associated with oxidative stress. The latter results in an extensive chemical modification of biomolecules, such as the formation of a myriad of phospholipids with oxidatively modified acyl chains containing various functional groups. Here we demonstrate that 1-palmitoyl 2-(9'-oxononanoyl)-sn-glycero-3-phosphocholine (PoxnoPC), a zwitterionic oxidized phospholipid bearing an aldehyde moiety at the end of its truncated sn-2 acyl chain, accelerates amyloidogenesis of FtG(179-194) (i.e., the core amyloidogenic segment of residues 179-194 of FAF gelsolin) as revealed by thioflavin T (ThT) fluorescence and electron microscopy. These techniques and Trp fluorescence show that the accelerated conversion of FtG(179-194) into amyloid fibrils consists of distinct consecutive phases. PoxnoPC at a close to critical micelle concentration (~22.5 MUM) causes a maximal increase in ThT fluorescence and the K(app) for fibril formation. The rates of fibril elongation and nucleation were proportional to PoxnoPC concentration, while the rates of nucleation were different below and above the critical micelle concentration. Our data also suggest an initial rapid formation of a 1:1 complex by PoxnoPC and FtG(179-194). The latter could involve a transient Schiff base and reside at the membrane hydrocarbon-water interface in the proximity of the phosphocholine headgroup. Subsequently, these profibrils insert into a more hydrophobic milieu and undergo a slow structural transition and assemble into amyloid fibers. Different phases can be expected when proteins aggregate on the phospholipid membrane surfaces, underlying the importance of a detailed kinetic analysis to fully understand the effects of oxidized phospholipids on amyloidogenesis. This study represents the first comprehensive analysis of the kinetics and mechanisms of amyloid formation in the presence of an oxidized phospholipid. PMID- 21545140 TI - Analyzing nanomaterial bioconjugates: a review of current and emerging purification and characterization techniques. PMID- 21545141 TI - Strand annealing and terminal transferase activities of a B-family DNA polymerase. AB - DNA replication polymerases have the inherent ability to faithfully and rapidly copy a DNA template according to precise Watson-Crick base pairing. The primary B family DNA replication polymerase (Dpo1) in the hyperthermophilic archaeon, Sulfolobus solfataricus, is shown here to possess a remarkable DNA stabilizing ability for maintaining weak base pairing interactions to facilitate primer extension. This thermal stabilization by Dpo1 allowed for template-directed synthesis at temperatures more than 30 degrees C above the melting temperature of naked DNA. Surprisingly, Dpo1 also displays a competing terminal deoxynucleotide transferase (TdT) activity unlike any other B-family DNA polymerase. Dpo1 is shown to elongate single-stranded DNA in template-dependent and template-independent manners. Experiments with different homopolymeric templates indicate that initial deoxyribonucleotide incorporation is complementary to the template. Rate-limiting steps that include looping back and annealing to the template allow for a unique template-dependent terminal transferase activity. The multiple activities of this unique B-family DNA polymerase make this enzyme an essential component for DNA replication and DNA repair for the maintenance of the archaeal genome at high temperatures. PMID- 21545142 TI - A route to nanoscopic materials via sequential infiltration synthesis on block copolymer templates. AB - Sequential infiltration synthesis (SIS), combining stepwise molecular assembly reactions with self-assembled block copolymer (BCP) substrates, provides a new strategy to pattern nanoscopic materials in a controllable way. The selective reaction of a metal precursor with one of the pristine BCP domains is the key step in the SIS process. Here we present a straightforward strategy to selectively modify self-assembled polystyrene-block-poly(methyl methacrylate) (PS b-PMMA) BCP thin films to enable the SIS of a variety of materials including SiO(2), ZnO, and W. The selective and controlled interaction of trimethyl aluminum with carbonyl groups in the PMMA polymer domains generates Al-CH(3)/Al OH sites inside the BCP scaffold which can seed the subsequent growth of a diverse range of materials without requiring complex block copolymer design and synthesis. PMID- 21545143 TI - Experimental and theoretical studies of the colloidal stability of nanoparticles a general interpretation based on stability maps. AB - The current work addresses the understanding of the stabilization of nanoparticles in suspension. Specifically, we study ZnO in ethanol for which the influence of particle size and reactant ratio as well as surface coverage on colloidal stability in dependence of the purification progress was investigated. The results revealed that the well-known zeta-potential determines not only the colloidal stability but also the surface coverage of acetate groups bound to the particle surface. The acetate groups act as molecular spacers between the nanoparticles and prevent agglomeration. Next to DLVO calculations based on the theory of Derjaguin, Landau, Verwey and Overbeek using a core-shell model we find that the stability is better understood in terms of dimensionless numbers which represent attractive forces as well as electrostatic repulsion, steric effects, transport properties, and particle concentration. Evaluating the colloidal stability in dependence of time by means of UV-vis absorption measurements a stability map for ZnO is derived. From this map it becomes clear that the dimensionless steric contribution to colloidal stability scales with a stability parameter including dimensionless repulsion and attraction as well as particle concentration and diffusivity of the particles according to a power law with an exponent of -0.5. Finally, we show that our approach is valid for other stabilizing molecules like cationic dendrons and is generally applicable for a wide range of other material systems within the limitations of vanishing van der Waals forces in refractive index matched situations, vanishing zeta-potential and systems without a stabilizing shell around the particle surface. PMID- 21545144 TI - Three-dimensional structure and catalytic mechanism of cytosine deaminase. AB - Cytosine deaminase (CDA) from E. coli is a member of the amidohydrolase superfamily. The structure of the zinc-activated enzyme was determined in the presence of phosphonocytosine, a mimic of the tetrahedral reaction intermediate. This compound inhibits the deamination of cytosine with a K(i) of 52 nM. The zinc and iron-containing enzymes were characterized to determine the effect of the divalent cations on activation of the hydrolytic water. Fe-CDA loses activity at low pH with a kinetic pK(a) of 6.0, and Zn-CDA has a kinetic pK(a) of 7.3. Mutation of Gln-156 decreased the catalytic activity by more than 5 orders of magnitude, supporting its role in substrate binding. Mutation of Glu-217, Asp 313, and His-246 significantly decreased catalytic activity supporting the role of these three residues in activation of the hydrolytic water molecule and facilitation of proton transfer reactions. A library of potential substrates was used to probe the structural determinants responsible for catalytic activity. CDA was able to catalyze the deamination of isocytosine and the hydrolysis of 3 oxauracil. Large inverse solvent isotope effects were obtained on k(cat) and k(cat)/K(m), consistent with the formation of a low-barrier hydrogen bond during the conversion of cytosine to uracil. A chemical mechanism for substrate deamination by CDA was proposed. PMID- 21545145 TI - Use of a QM/MM-based FEP method to evaluate the anomalous hydration behavior of simple alkyl amines and amides: application to the design of FBPase inhibitors for the treatment of type-2 diabetes. AB - Standard molecular mechanics (MM) force fields predict a nearly linear decrease in hydration free energy with each successive addition of a methyl group to ammonia or acetamide, whereas a nonadditive relationship is observed experimentally. In contrast, the non-additive hydration behavior is reproduced directly using a quantum mechanics (QM)/MM-based free-energy perturbation (FEP) method wherein the solute partial atomic charges are updated at every window. Decomposing the free energies into electrostatic and van der Waals contributions and comparing the results with the corresponding free energies obtained using a conventional FEP method and a QM/MM method wherein the charges are not updated suggests that inaccuracies in the electrostatic free energies are the primary reason for the inability of the conventional FEP method to predict the experimental findings. The QM/MM-based FEP method was subsequently used to evaluate inhibitors of the diabetes drug target fructose-1,6-bisphosphatase adenosine 5'-monophosphate and 6-methylamino purine riboside 5'-monophosphate. The predicted relative binding free energy was consistent with the experimental findings, whereas the relative binding free energy predicted using the conventional FEP method differed from the experimental finding by an amount consistent with the overestimated relative solvation free energies calculated for alkylamines. Accordingly, the QM/MM-based FEP method offers potential advantages over conventional FEP methods, including greater accuracy and reduced user input. Moreover, since drug candidates often contain either functionality that is inadequately treated by MM (e.g., simple alkylamines and alkylamides) or new molecular scaffolds that require time-consuming development of MM parameters, these advantages could enable future automation of FEP calculations as well as greatly increase the use and impact of FEP calculations in drug discovery. PMID- 21545146 TI - Flame preparation of visible-light-responsive BiVO4 oxygen evolution photocatalysts with subsequent activation via aqueous route. AB - Visible-light-active BiVO(4) photocatalyst prepared by a one-step flame spray pyrolysis demonstrates the structural evolution from amorphous to crystalline scheelite-tetragonal and further to scheelite-monoclinic (the photocatalytic active phase). Up to 95% scheelite-monoclinic content, the rest being scheelite tetragonal, can be achieved in situ by exposing the collection filter to higher flame temperature. Reasonable activity in terms of photocatalytic O(2) evolution was obtained with the increase in crystallinity and scheelite-monoclinic content. Although analogous postcalcination of BiVO(4) improves crystallization and phase transformation, it inevitably induces vacancy defects that are detrimental to the photocatalytic activity. Hence a facile aqueous acid treatment on the flame-made BiVO(4) is introduced, which in the presence of small addition of Bi and V promotes full transformation to scheelite-monoclinic and reduces charge trapping defects. As a result, the photocatalytic O(2) evolution activity was increased by a remarkable 5 folds compared to the best performing untreated flame-made BiVO(4). PMID- 21545147 TI - Gas-surface scattering dynamics of CO2, NO2, and O3 in collisions with model organic surfaces. AB - High-energy (70 kJ/mol) molecular beams of CO(2), NO(2), and O(3) were scattered from long-chain methyl (CH(3)-), hydroxyl (OH-), and perfluoro (CF(3)(CF(2))(8)-, or F-) omega-functionalized alkanethiol self-assembled monolayers (SAMs) on gold to study the dynamics of energy exchange and thermal accommodation of atmospherically important triatomic molecules on model organic surfaces. Overall, the extent of energy transfer in gas collisions with all of the surfaces studied was substantial. Specifically, the triatomics scatter from each surface only after dissipating greater than 80% of their incident energy. Furthermore, although the OH-SAM is a more rigid surface, the extent of energy transfer and accommodation of these molecules to the CH(3)- and OH-SAMs were approximately the same. The similar scattering dynamics are likely due to significant gas-surface attractive forces between the triatomics and the OH terminal groups, which compensate for the rigidity of this monolayer. In contrast to the OH- and CH(3) SAMs, the dominant pathway in collisions of the gases with the F-SAM was impulsive scattering. The portion of molecules that accommodated (<40%) to the F SAM was about half of the amount that accommodated (~70%) to the CH(3)- and OH SAMs. Although differences in the surface properties had a significant effect on the dynamics, variances in the chemical and physical properties of the three gases, CO(2), NO(2), and O(3), were found to have little effect on the extent of energy transfer and accommodation for collisions with any one surface. PMID- 21545148 TI - Direct spectrophotometric assay of laccase using diazo derivatives of guaiacol. AB - Laccase (EC 1.10.3.2) is a widespread cuproenzyme able to oxidize various types of phenols and similar aromatic compounds through a one-electron transfer mechanism. The enzyme has already found its way into the market as a biocatalyst. Because of its ability to be paired by electron mediators, the expectation for employing laccases in versatile processes is very high. There are a few spectrophotometric methods for assaying the laccase activity; however, all of them are based on the formation of product(s) resulting from the enzymatic and inevitable succeeding chemical reactions. Use of diazo derivatives of guaiacol (DdG) was developed as a new spectrophotometric method based on substrate depletion allowing direct assessment of enzyme activity has been introduced. This method allows accurate comprehensive kinetic studies of laccases and provides reliable information about the quality of docking of different substrates or one substrate to the active sites of different laccases. Using this method, the kinetic parameters of various DdG carrying different electron donating and withdrawing substituents were used to assay laccase from Neurospora crassa. 2 Methoxy-4-[(4-phenyl)azo]-phenol (K(m) = 93.5 MUM and V = 1.98 MUM/min) was identified as an appropriate substrate for the accurate and routine spectrophotometric based assay of laccases. PMID- 21545149 TI - Switching of molecular insertion in a cyclic molecule via photo- and thermal isomerization. AB - Two new cyclic ligands were synthesized: a ligand with two trans-azobenzene moieties and one bipyridine moiety, trans(2)-oAB-O13, and a ligand with two trans azobenzene moieties and two bipyridine moieties, trans(2)-oAB-bpy. Both ligands underwent reversible trans-cis isomerization at the azobenzene moieties. The mole ratios of the trans(2) form:trans-cis form:cis(2) form, evaluated by (1)H NMR spectroscopy of the photostationary states prepared by 1 h illumination, were 0.13:0.27:0.60 (365 nm irradiation) and 0.41:0.47:0.12 (436 nm irradiation) for oAB-O13, and 0.18:0.12:0.70 (365 nm irradiation) and 0.36:0.43:0.21 (436 nm irradiation) for oAB-bpy. When trans(2)-oAB-O13 was mixed with Cu(I), both the bipyridine units and the polyether chains coordinated to the copper center. Addition of a noncyclic bipyridine ligand, trans(2)-oAB-2OH, afforded a bis(bipyridine)copper(I) complex, [Cu(trans(2)-oAB-O13)(trans(2)-oAB-2OH)]BF(4). The bis(bipyridine) ligand, trans(2)-oAB-bpy, formed a 1:1 complex with Cu(I), [Cu(trans(2)-oAB-bpy)]BF(4). [Cu(cis(2)-oAB-bpy)]BF(4) did not undergo the ligand substitution reaction with a noncyclic ligand with two azobenzene moieties and one bipyridine moiety, oAB, whereas its thermal isomerization in the presence of oAB caused the formation of [Cu(trans(2)-oAB-bpy)(trans(2)-oAB)]BF(4), indicating that the isomerization and ligand exchange reactions synchronized via a conformational change of the cyclic ligand. PMID- 21545150 TI - Simultaneous determination and differentiation of glycidyl esters and 3 monochloropropane-1,2-diol (MCPD) esters in different foodstuffs by GC-MS. AB - The aim of this study was the development of a method for the simultaneous determination and differentiation of fatty acid esters of 3-monochloropropane-1,2 diol (3-MCPD esters) and glycidol (glycidyl esters) in different foodstuffs. The esters were isolated from fat-rich food samples using a single extraction step and separated from interfering substances. For differentiation of 3-MCPD esters and glycidyl esters the glycidol moiety was converted into 3-methoxypropane-1,2 diol (3-MPD) by acidic alcoholysis. Subsequent determination was achieved by isotope dilution GC-MS after transesterification using an isotope-labeled 3-MCPD ester as internal standard. During optimization of the procedure, critical parameters affecting simultaneous determination and differentiation of these analytes were investigated. Rapid ester cleavage and derivatization at ambient temperature proved to be essential for the simultaneous determination of these analytes. The method was validated for various fat-rich foodstuffs such as bakery products, sweets, gravy, and soup powders as well as edible fats and oils. LODs of 8 and 15 MUg/kg (fat-rich foodstuffs) as well as 50 and 65 MUg/kg (edible oils and fats) were obtained for 3-MCPD esters and glycidyl esters, respectively. Recoveries for 3-MCPD esters and glycidyl esters ranged within 98 +/- 4 and 88 +/ 2% in all tested foodstuffs (0.05-2.5 mg/kg) and within 99 +/- 16 and 93 +/- 13% for edible oils and fats (0.15-3 mg/kg) over a wide concentration range. These results proved an accurate and differentiated determination of 3-MCPD esters and glycidyl esters with successful application to the fast screening of samples, avoiding tedious and laborious sample preparation. PMID- 21545151 TI - Benthic microbial fuel cell as direct power source for an acoustic modem and seawater oxygen/temperature sensor system. AB - Supported by the natural potential difference between anoxic sediment and oxic seawater, benthic microbial fuel cells (BMFCs) promise to be ideal power sources for certain low-power marine sensors and communication devices. In this study a chambered BMFC with a 0.25 m(2) footprint was used to power an acoustic modem interfaced with an oceanographic sensor that measures dissolved oxygen and temperature. The experiment was conducted in Yaquina Bay, Oregon over 50 days. Several improvements were made in the BMFC design and power management system based on lessons learned from earlier prototypes. The energy was harvested by a dynamic gain charge pump circuit that maintains a desired point on the BMFC's power curve and stores the energy in a 200 F supercapacitor. The system also used an ultralow power microcontroller and quartz clock to read the oxygen/temperature sensor hourly, store data with a time stamp, and perform daily polarizations. Data records were transmitted to the surface by the acoustic modem every 1-5 days after receiving an acoustic prompt from a surface hydrophone. After jump-starting energy production with supplemental macroalgae placed in the BMFC's anode chamber, the average power density of the BMFC adjusted to 44 mW/m(2) of seafloor area which is better than past demonstrations at this site. The highest power density was 158 mW/m(2), and the useful energy produced and stored was >= 1.7 times the energy required to operate the system. PMID- 21545152 TI - Discovery and characterization of a nonphosphorylated cyclic peptide inhibitor of the peptidylprolyl isomerase, Pin1. AB - Phage panning led to the discovery of a disulfide-cyclized peptide CRYPEVEIC that inhibits Pin1 activity with a K(I) of 0.5 MUM. NMR chemical shift perturbation experiments show that cyclic CRYPEVEIC binds to the active site of Pin1. Pin1 residues K63 and R68, which bind the phosphate of substrate peptides, do not show a significant chemical shift change in response to binding of cyclic CRYPEVEIC, consistent with absence of phosphate on the peptide. Cyclic CRYPEVEIC adopts a stable conformation with the side chains of the Y, P, V, and I residues packed together on one side of the ring. Cyclic CRYPEVEIC in solution exists as a mixture of two species, with a 1:4 cis/trans ratio for the Y-P bond. This mixture is stabilized to a single conformation when bound to Pin1. The constrained structure of cyclic CRYPEVEIC apparently facilitates high affinity binding without the presence of a phosphate group. PMID- 21545154 TI - Contributions of natural emissions to ozone and PM2.5 as simulated by the Community Multiscale Air Quality (CMAQ) model. AB - The relative roles of natural and anthropogenic sources in determining ozone and fine particle concentrations over the continental United States (U.S.) are investigated using an expanded emissions inventory of natural sources and an updated version of the Community Multiscale Air Quality (CMAQ) model. Various 12 month CMAQ simulations for the year 2002 using different sets of input emissions data are combined to delineate the contributions of background pollutants (i.e., model boundary conditions), natural emissions, anthropogenic emissions, as well as the specific impacts of lightning and wildfires. Results are compared with observations and previous air quality model simulations. Wildfires and lightning are both identified as contributing significantly to ozone levels with lightning NO(x) adding as much as 25-30 ppbV (or up to about 50%) to surface 8-h average natural O(3) mixing ratios in the southeastern U.S. Simulated wildfire emissions added more than 50 ppbV (in some cases >90%) to 8-h natural O(3) at several locations in the west. Modeling also indicates that natural emissions (including biogenic, oceanic, geogenic and fires) contributed <= 40% to the annual average of total simulated fine particle mass over the eastern two-thirds of the U.S. and >40% across most of the western U.S. Biogenic emissions are the dominant source of particulate mass over the entire U.S. and wildfire emissions are secondary. Averaged over the entire modeling domain, background and natural ozone are dominant with anthropogenically derived ozone contributing up to a third of the total only during summer. Background contributions to fine particle levels are relatively insignificant in comparison. Model results are also contrasted with the U.S. Environmental Protection Agency (EPA) default values for natural light scattering particle concentrations to be used for regional haze regulatory decision-making. Regional differences in EPA guidance are not supported by the modeling and EPA uncertainty estimates for default values are far smaller than the modeled variability in natural particle concentrations. PMID- 21545153 TI - The suppressive tumor microenvironment: a challenge in cancer immunotherapy. AB - In this review, we introduce the changing public perception of vaccines and immunotherapy in cancer treatments. We discuss the roles that different immunosuppressive cells play in the tumor microenvironment. Tumor associated macrophages (TAMs) and M1 and M2 macrophage phenotypes are discussed in depth. Additionally, the role that myeloid derived suppressor cells (MDSC) and T regulatory cells (Tregs) play in the tumor microenvironment is addressed. Highlighted are examples of therapies used against each suppressive cell type, which vary from the hypothetical to the ineffective; the inefficient to the successful. A variety of treatments have been tried to combat this fundamental problem, indeed the cause that allows cancerous mutated cells to survive, multiply and overtake the body. Efficient methods to disable each particular suppressive type of cell have been introduced; this review summarizes the discussion with a table to guide future development. We see gene therapy as the most innovative and flexible method to lead the charge to specifically modifying the tumor microenvironment. PMID- 21545155 TI - Wormlike micelles formed by sodium erucate in the presence of a tetraalkylammonium hydrotrope. AB - Anionic wormlike micelles, particularly those formed by long-chain carboxylate surfactants, are relatively less documented though their cationic or zwitterionic counterparts are frequently reported. In this study, the wormlike micelles of sodium erucate (NaOEr), a C22-tailed anionic surfactant with a monounsaturated tail, in the presence of a tetraalkylammonium hydrotrope were investigated for the first time. The different effects of two hydrotropes, benzyl trimethyl ammonium bromide (BTAB) and tetramethyl ammonium bromide (TMAB), on the phase behavior and rheological behaviors were compared, and the influences of surfactant concentration and temperature on the rheological properties of NaOEr solutions were also examined. Both organic salts can lower the Krafft temperature of NaOEr solutions and thus improve its water solubility, but BTAB can make T(K) drop more sharply. At a fixed NaOEr concentration, less BTAB is demanded to induce the formation of viscoelastic solution and to obtain the maximum viscosity of NaOEr solution; at a constant salt concentration, with increasing NaOEr content, the NaOEr-BTAB system shows a larger zero-shear viscosity (eta(0)), relaxation time, and plateau modulus but lower overlapping concentration than those of the NaOEr-TMAB system. The occurrence of maximum eta(0) with increasing salt content for the NaOEr-BTAB system results from the formation of vesicles and L(3) phases, which were verified by cryo-TEM observations. eta(0) shows an exponential decrease with increasing temperature; nevertheless it still remains above 10(3) mPa.s even at 90 degrees C. PMID- 21545156 TI - Comparison of diffusivity data derived from electrochemical and NMR investigations of the SeCN-/(SeCN)2/(SeCN)3- system in ionic liquids. AB - Electrochemical studies in room temperature ionic liquids are often hampered by their relatively high viscosity. However, in some circumstances, fast exchange between participating electroactive species has provided beneficial enhancement of charge transport. The iodide (I-)/iodine (I(2))/triiodide (I(3)-) redox system that introduces exchange via the I- + I(2) ? I(3)- process is a well documented example because it is used as a redox mediator in dye-sensitized solar cells. To provide enhanced understanding of ion movement in RTIL media, a combined electrochemical and NMR study of diffusion in the {SeCN--(SeCN)(2)-(SeCN)(3)-} system has been undertaken in a selection of commonly used RTILs. In this system, each of the Se, C and N nuclei is NMR active. The electrochemical behavior of the pure ionic liquid, [C(4)mim][SeCN], which is synthesized and characterized here for the first time, also has been investigated. Voltammetric studies, which yield readily interpreted diffusion-limited responses under steady-state conditions by means of a Random Assembly of Microdisks (RAM) microelectrode array, have been used to measure electrochemically based diffusion coefficients, while self diffusion coefficients were measured by pulsed field gradient NMR methods. The diffusivity data, derived from concentration and field gradients respectively, are in good agreement. The NMR data reveal that exchange processes occur between selenocyanate species, but the voltammetric data show the rates of exchange are too slow to enhance charge transfer. Thus, a comparison of the iodide and selenocyanate systems is somewhat paradoxical in that while the latter give RTILs of low viscosity, sluggish exchange kinetics prevent any significant enhancement of charge transfer through direct electron exchange. In contrast, faster exchange between iodide and its oxidation products leads to substantial electron exchange but this effect does not compensate sufficiently for mass transport limitations imposed by the higher viscosity of iodide RTILs. PMID- 21545157 TI - Molecular conformations in the pentasaccharide LNF-1 derived from NMR spectroscopy and molecular dynamics simulations. AB - The conformational dynamics of the human milk oligosaccharide lacto-N fucopentaose (LNF-1), alpha-L-Fucp-(1 -> 2)-beta-D-Galp-(1 -> 3)-beta-D-GlcpNAc (1 -> 3)-beta-D-Galp-(1 -> 4)-D-Glcp, has been analyzed using NMR spectroscopy and molecular dynamics (MD) computer simulations. Employing the Hadamard (13)C excitation technique and the J-HMBC experiment, (1)H,(13)C trans-glycosidic J coupling constants were obtained, and from one- and two-dimensional (1)H,(1)H T ROESY experiments, proton-proton cross-relaxation rates were determined in isotropic D(2)O solution. In the lyotropic liquid-crystalline medium consisting of ditetradecylphosphatidylcholine, dihexylphosphatidylcholine, N-cetyl-N,N,N trimethylammonium bromide, and D(2)O, (1)H, (1)H and one-bond (1)H, (13)C residual dipolar couplings (RDCs), as well as relative sign information on homonuclear RDCs, were determined for the pentasaccharide. Molecular dynamics simulations with explicit water were carried out from which the internal isomerization relaxation time constant, tau(N), was calculated for transitions at the psi torsion angle of the beta-(1 -> 3) linkage to the lactosyl group in LNF 1. Compared to the global reorientation time, tau(M), of ~0.6 ns determined experimentally in D(2)O solution, the time constant for the isomerization relaxation process, tau(N(scaled)), is about one-third as large. The NMR parameters derived from the isotropic solution show very good agreement with those calculated from the MD simulations. The only notable difference occurs at the reducing end, which should be more flexible than observed by the molecular simulation, a conclusion in complete agreement with previous (13)C NMR relaxation data. A hydrogen-bond analysis of the MD simulation revealed that inter-residue hydrogen bonds on the order of ~30% were present across the glycosidic linkages to sugar ring oxygens. This finding highlights that intramolecular hydrogen bonds might be important in preserving well-defined structures in otherwise flexible molecules. An analysis including generalized order parameters obtained from nuclear spin relaxation experiments was performed and successfully shown to limit the conformational space accessible to the molecule when the number of experimental data are too scarce for a complete conformational analysis. PMID- 21545158 TI - Novel products from C6H5 + C6H6/C6H5 reactions. AB - To date only one product, biphenyl, has been reported to be produced from C(6)H(5) + C(6)H(6)/C(6)H(5) reactions. In this study, we have investigated some unique products of C(6)H(5) + C(6)H(6)/C(6)H(5) reactions via both experimental observation and theoretical modeling. In the experimental study, gas-phase reaction products produced from the pyrolysis of selected aromatics and aromatic/acetylene mixtures were detected by an in situ technique, vacuum ultraviolet (VUV) single photon ionization (SPI) time-of-flight mass spectrometry (TOFMS). The mass spectra revealed a remarkable correlation in mass peaks at m/z = 154 {C(12)H(10) (biphenyl)} and m/z = 152 {C(12)H(8) (?)}. It also demonstrated an unexpected correlation among the HACA (hydrogen abstraction and acetylene addition) products at m/z = 78, 102, 128, 152, and 176. The analysis of formation routes of products suggested the contribution of some other isomers in addition to a well-known candidate, acenaphthylene, in the mass peak at m/z = 152 (C(12)H(8)). Considering the difficulties of identifying the contributing isomers from an observed mass number peak, quantum chemical calculations for the above mentioned reactions were performed. As a result, cyclopenta[a]indene, as indacene, s-indacene, biphenylene, acenaphthylene, and naphthalene appeared as novel products, produced from the possible channels of C(6)H(5) + C(6)H(6)/C(6)H(5) reactions rather than from their previously reported formation pathways. The most notable point is the production of acenaphthylene and naphthalene from C(6)H(5) + C(6)H(6)/C(6)H(5) reactions via the PAC (phenyl addition-cyclization) mechanism because, until now, both of them have been thought to be formed via the HACA routes. In this way, this study has paved the way for exploring alternative paths for other inefficient HACA routes using the PAC mechanism. PMID- 21545159 TI - Jet-cooled rotational spectrum of laser-ablated phenylalanine. AB - The rotational spectrum of neutral phenylalanine has been recorded for the first time using laser-ablation molecular-beam Fourier transform microwave spectroscopy (LA-MB-FTMW). Two conformers stabilized by conjugative O-H...N and N-H...pi hydrogen bond interactions have been conclusively identified on the basis of experimental values of rotational and (14)N nuclear quadrupole coupling constants. The nonobservation of the rotational spectra of the other low-energy conformers has been attributed to the photofragmentation that takes place in the laser ablation process. Nuclear quadrupole coupling interactions have been used directly to determine the orientation of the amino group and to identify and experimentally characterize the N-H...pi interactions. PMID- 21545160 TI - Comparative assessment of the composition and charge state of nitrogenase FeMo cofactor. AB - A significant limitation in our understanding of the molecular mechanism of biological nitrogen fixation is the uncertain composition of the FeMo-cofactor (FeMo-co) of nitrogenase. In this study we present a systematic, density functional theory-based evaluation of spin-coupling schemes, iron oxidation states, ligand protonation states, and interstitial ligand composition using a wide range of experimental criteria. The employed functionals and basis sets were validated with molecular orbital information from X-ray absorption spectroscopic data of relevant iron-sulfur clusters. Independently from the employed level of theory, the electronic structure with the greatest number of antiferromagnetic interactions corresponds to the lowest energy state for a given charge and oxidation state distribution of the iron ions. The relative spin state energies of resting and oxidized FeMo-co already allowed exclusion of certain iron oxidation state distributions and interstitial ligand compositions. Geometry optimized FeMo-co structures of several models further eliminated additional states and compositions, while reduction potentials indicated a strong preference for the most likely charge state of FeMo-co. Mossbauer and ENDOR parameter calculations were found to be remarkably dependent on the employed training set, density functional, and basis set. Overall, we found that a more oxidized [Mo(IV) 2Fe(II)-5Fe(III)-9S(2-)-C(4-)] composition with a hydroxyl-protonated homocitrate ligand satisfies all of the available experimental criteria and is thus favored over the currently preferred composition of [Mo(IV)-4Fe(II)-3Fe(III)-9S(2-)-N(3 )] from the literature. PMID- 21545161 TI - 2-difluoromethylene-4-methylenepentanoic acid, a paradoxical probe able to mimic the signaling role of 2-oxoglutaric acid in cyanobacteria. AB - 2-Difluoromethylene-4-methylenepentanoic acid (DFMPA), a seemingly deviated analog of 2-oxoglutaric acid (2-OG), could surprisingly mimic its signaling function in cyanobacteria. Computer modeling revealed the favorable binding of DFMPA toward the 2-OG receptor, NtcA, via mutual conformational changes, suggesting that structural alteration of 2-OG is tolerated for it to exercise its signaling role. This extremely useful finding could be exploited for the design of affinity probes with which to study new 2-OG receptors in related signaling pathways. PMID- 21545162 TI - Direct atomic-scale imaging about the mechanisms of ultralarge bent straining in Si nanowires. AB - To safely and reliably use nanowires (NWs) for exploring new functions for different nanodevices, the mechanical properties and structural evolution of the nanowires under external stress become highly important. Large strain (up to 14%) bending experiments of Si NWs were conducted in a high-resolution transmission electron microscope at atomic resolution. The direct dynamic atomic-scale observations revealed that partial and full dislocation nucleation, motion, escape, and interaction were responsible for absorbing the ultralarge strain of up to 14% in bent Si nanowires. The prevalent full dislocation movement and interactions induced the formation of Lomer lock dislocations in the Si NWs. Finally, in contrast to the unlock process of Lomer dislocations that can happen in metallic materials, we revealed that the continuous straining on the Lomer dislocations induced a crystal-amorphous (c-a) transition in Si NWs. Our results provide direct explanation about the ultralarge straining ability of Si at the nanometer scale. PMID- 21545163 TI - Palladium-catalyzed decarboxylative arylation of potassium cyanoacetate: synthesis of alpha-diaryl nitriles from aryl halides. AB - A palladium-catalyzed decarboxylative coupling of potassium cyanoacetate with aryl bromides and chlorides is described. The reaction conditions feature the absence of additional strong inorganic bases and provide ester functional group tolerance. With Pd(dba)(2) and XPhos ligand as the catalyst system, alpha-diaryl nitriles can be obtained in good yields. PMID- 21545164 TI - Effect of surface modes on the six-dimensional molecule-surface scattering dynamics of H2-Cu(100) and D2-Cu(111) systems. AB - We include the phonon modes originating from the three layers of Cu(100)/Cu(111) surface atoms on the dynamics of molecular [H(2)(v,j)/D(2)(v,j)] degrees of freedom (DOFs) through a mean field approach, where the surface temperature is incorporated into the effective Hamiltonian (potential) either by considering Boltzmann probability (BP) or by including the Bose-Einstein probability (BEP) factor for the initial state distribution of the surface modes. The formulation of effective potential has been carried out by invoking the expression of transition probabilities for phonon modes known from the "stochastic" treatment of linearly forced harmonic oscillator (LFHO). We perform four-dimensional (4D?2D) as well as six-dimensional (6D) quantum dynamics on a parametrically time and temperature-dependent effective Hamiltonian to calculate elastic/inelastic scattering cross-section of the scattered molecule for the H(2)(v,j)-Cu(100) system, and dissociative chemisorption-physisorption for both H(2)(v,j)-Cu(100) and D(2)(v,j)-Cu(111) systems. Calculated sticking probabilities by either 4D?2D or 6D quantum dynamics on an effective potential constructed by using BP factor for the initial state distribution of the phonon modes could not show any surface temperature dependence. In the BEP case, (a) both 4D?2D and 6D quantum dynamics demonstrate that the phonon modes of the Cu(100) surface affect the state-to state transition probabilities of the scattered H(2) molecule substantially, and (b) the sticking probabilities due to the collision of H(2) on Cu(100) and D(2) on Cu(111) surfaces show noticeable and substantial change, respectively, as function of surface temperature only when the quantum dynamics of all six molecular DOFs are treated in a fully correlated manner (6D). PMID- 21545165 TI - Strong enhancement of solar cell efficiency due to quantum dots with built-in charge. AB - We report a 50% increase in the power conversion efficiency of InAs/GaAs quantum dot solar cells due to n-doping of the interdot space. The n-doped device was compared with GaAs reference cell, undoped, and p-doped devices. We found that the quantum dots with built-in charge (Q-BIC) enhance electron intersubband quantum dot transitions, suppress fast electron capture processes, and preclude deterioration of the open circuit voltage in the n-doped structures. These factors lead to enhanced harvesting and efficient conversion of IR energy in the Q-BIC solar cells. PMID- 21545166 TI - Local-mode approach to modeling multidimensional infrared spectra of metal carbonyls. AB - We present a general approach for modeling multidimensional infrared spectra based on a combination of phenomenological fitting and ab initio electronic structure calculations. The vibrational Hamiltonian is written in terms of bilinearly coupled Morse oscillators that represent local carbonyl stretches. This should be contrasted with the previous approach, where the anharmonic Hamiltonian was given in terms of normal-mode coordinates ( Baiz et al. J. Phys. Chem. A 2009 , 113 , 9617 ). The bilinearly coupled Morse oscillator Hamiltonian is parametrized such that the frequencies and couplings are consistent with experiment, and the anharmonicities are computed by density functional theory. The advantages of the local-mode versus normal-mode approaches are discussed, as well as the ability of different density functionals to provide accurate estimates of the model parameters. The applicability and usefulness of the new approach are demonstrated in the context of the recently measured multidimensional infrared spectra of dimanganese decacarbonyl. The shifts in local site frequencies, couplings, and anharmonicities due to hydrogen bonding to the individual carbonyls are explored. It is found that, even though the effect of hydrogen bonding is nonlocal, it is additive. PMID- 21545167 TI - Isothermal decomposition of hydrogen peroxide dihydrate. AB - We present a new method of growing pure solid hydrogen peroxide in an ultra high vacuum environment and apply it to determine thermal stability of the dihydrate compound that forms when water and hydrogen peroxide are mixed at low temperatures. Using infrared spectroscopy and thermogravimetric analysis, we quantified the isothermal decomposition of the metastable dihydrate at 151.6 K. This decomposition occurs by fractional distillation through the preferential sublimation of water, which leads to the formation of pure hydrogen peroxide. The results imply that in an astronomical environment where condensed mixtures of H(2)O(2) and H(2)O are shielded from radiolytic decomposition and warmed to temperatures where sublimation is significant, highly concentrated or even pure hydrogen peroxide may form. PMID- 21545168 TI - Rotational motion in LiBH4/LiI solid solutions. AB - We investigated the localized rotational diffusion of the (BH(4))(-) anions in LiBH(4)/LiI solid solutions by means of quasielastic and inelastic neutron scattering. The (BH(4))(-) motions are thermally activated and characterized by activation energies in the order of 40 meV. Typical dwell times between jumps are in the picosecond range at temperatures of about 200 K. The motion is dominated by 90 degrees reorientations around the 4-fold symmetry axis of the tetrahedraly shaped (BH(4))(-) ions. As compared to the pure system, the presence of iodide markedly reduces activation energies and increases the rotational frequencies by more than a factor of 100. The addition of iodide lowers the transition temperature, stabilizing the disordered high temperature phase well below room temperature. PMID- 21545169 TI - Spontaneous membrane-translocating peptides by orthogonal high-throughput screening. AB - Combinatorial peptide chemistry and orthogonal high-throughput screening were used to select peptides that spontaneously translocate across synthetic lipid bilayer membranes without permeabilization. A conserved sequence motif was identified that contains several cationic residues in conserved positions in an otherwise hydrophobic sequence. This 9-residue motif rapidly translocates across synthetic multibilayer vesicles and into cells while carrying a large polar dye as a "cargo" moiety. The extraordinary ability of this family of peptides to spontaneously translocate across bilayers without an energy source of any kind is distinctly different from the behavior of the well-known, highly cationic cell penetrating peptides, such as the HIV tat peptide, which do not translocate across synthetic bilayers, and enter cells mostly by active endocytosis. Peptides that translocate spontaneously across membranes have the potential to transform the field of drug design by enabling the delivery of otherwise membrane impermeant polar drugs into cells and tissues. Here we describe the chemical tools needed to rapidly identify spontaneous membrane translocating peptides. PMID- 21545170 TI - Antiangiogenic antitumor activity of HPMA copolymer-paclitaxel-alendronate conjugate on breast cancer bone metastasis mouse model. AB - Polymer therapeutics have shown promise as tumor-targeted drug delivery systems in mice. The multivalency of polymers allows the attachment of different functional agents to a polymeric backbone, including chemotherapeutic and antiangiogenic drugs, as well as targeting moieties, such as the bone-targeting agent alendronate (ALN). We previously reported the conjugation of ALN and the chemotherapeutic drug paclitaxel (PTX) with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. The in vitro physicochemical properties, cancer cytotoxicity and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate were extensively characterized. The reported results warranted in vivo evaluations of the conjugate. In this manuscript, we evaluated the in vivo anticancer and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate. The conjugate exhibited an antiangiogenic effect by decreasing microvessel density (MVD), and inducing apoptotic circulating endothelial cells (CEC) following treatment of the mice. Using intravital imaging system and mCherry-labeled breast cancer cell lines, we were able to monitor noninvasively the progression of orthotopic metastatic tumors injected into the tibia of the mice. HPMA copolymer-PTX-ALN conjugate showed the greatest antitumor efficacy on mCherry-labeled 4T1 mammary adenocarcinoma inoculated into the tibia, as compared with PTX alone or in combination with ALN. Treatment with the bone-targeted polymeric conjugate demonstrated improved efficacy, was better tolerated, and was more easily administered intravenously than the clinically used PTX formulated in Cremophor/ethanol. PMID- 21545171 TI - Chrysobactin siderophores produced by Dickeya chrysanthemi EC16. AB - The plant pathogen Dickeya chrysanthemi EC16 (formerly known as Petrobacterium chrysanthemi EC16 and Erwinia chrysanthemi EC16) was found to produce a new triscatecholamide siderophore, cyclic trichrysobactin, the related catecholamide compounds, linear trichrysobactin and dichrysobactin, and the previously reported monomeric siderophore unit, chrysobactin. Chrysobactin is comprised of L-serine, D-lysine, and 2,3-dihydroxybenzoic acid (DHBA). Trichrysobactin is a cyclic trimer of chrysobactin joined by a triserine lactone backbone. The chirality of the ferric complex of cyclic trichrysobactin is found to be in the Lambda configuration, similar to Fe(III)-bacillibactin, which contains a glycine spacer between the DHBA and L-threonine components and is opposite that of Fe(III) enterobactin, which contains DHBA ligated directly to L-serine. PMID- 21545172 TI - Machilusides A and B: structurally unprecedented homocucurbitane glycosides from the stem bark of Machilus yaoshansis. AB - Two structurally novel homocucurbitane triterpenoid glycosides, machilusides A (1) and B (2), possessing an unprecedented C(36) skeleton with a D-fructose moiety incorporated into a cucurbitane nucleus forming unique cage-like tricyclic ring moieties, were isolated from the stem bark of Machilus yaoshansis. Their structures were determined by spectroscopic methods. Both compounds exhibited nonselective cytotoxic activities against several human cancer cell lines. The biosynthetic pathway of 1 and 2 was postulated. PMID- 21545174 TI - Deciphering three beneficial effects of 2,2'-bipyridine-N,N'-dioxide on the luminescence sensitization of lanthanide(III) hexafluoroacetylacetonate ternary complexes. AB - Lanthanide hexafluoroacetylacetonate ternary complexes with 2,2'-bipyridine-N,N' dioxide, [Ln(hfa)(3)(bpyO2)], were synthesized for Ln = Eu, Gd, Tb, and Lu and fully characterized by elemental, thermal, and mass-spectrometric analyses. The X ray crystal structure of [Eu(hfa)(3)(bpyO2)].0.5C(6)H(6) reveals an octa coordinate metal ion lying in a severely distorted trigonal dodecahedron geometry; the Eu-O distances lie in the range 2.36-2.44 A with no significant difference between hfa(-) and bpyO2. A detailed comparative photophysical investigation has been carried out to determine the exact influence of the introduction of bpyO2 in the inner coordination sphere of the metal ion in replacement of the two water molecules in [Ln(hfa)(3)(H(2)O)(2)]. While this replacement is detrimental for Tb, it leads to a 15-fold increase in the overall quantum yield for Eu. This large improvement originates from (i) a better sensitization efficiency, the ancillary ligand being responsible for 3/4 of the energy transfer, (ii) elimination of nonradiative deactivation pathways through harmonics of O-H vibrations, and (iii) reduction in the radiative lifetime. The latter influence is rarely documented, but it accounts here for a ~25% increase in the intrinsic quantum yield, so that more attention should be given to this parameter when designing highly luminescent lanthanide complexes. PMID- 21545173 TI - Stereochemical basis for engineered pyrrolysyl-tRNA synthetase and the efficient in vivo incorporation of structurally divergent non-native amino acids. AB - Unnatural amino acids (Uaas) can be translationally incorporated into proteins in vivo using evolved tRNA/aminoacyl-tRNA synthetase (RS) pairs, affording chemistries inaccessible when restricted to the 20 natural amino acids. To date, most evolved RSs aminoacylate Uaas chemically similar to the native substrate of the wild-type RS; these conservative changes limit the scope of Uaa applications. Here, we adapt Methanosarcina mazei PylRS to charge a noticeably disparate Uaa, O methyl-l-tyrosine (Ome). In addition, the 1.75 A X-ray crystal structure of the evolved PylRS complexed with Ome and a non-hydrolyzable ATP analogue reveals the stereochemical determinants for substrate selection. Catalytically synergistic active site mutations remodel the substrate-binding cavity, providing a shortened but wider active site. In particular, mutation of Asn346, a residue critical for specific selection and turnover of the Pyl chemical core, accommodates different side chains while the central role of Asn346 in aminoacylation is rescued through compensatory hydrogen bonding provided by A302T. This multifaceted analysis provides a new starting point for engineering PylRS to aminoacylate a significantly more diverse selection of Uaas than previously anticipated. PMID- 21545175 TI - Hyphenated FT-IR-attenuated total reflection and electrochemical impedance spectroscopy technique to study the water uptake and potential stability of polymeric solid-contact ion-selective electrodes. AB - A new hyphenated method utilizing FT-IR-attenuated total reflection (ATR) and electrochemical impedance spectroscopy (EIS) is presented to correlate the water uptake with concomitant potential and impedance changes of polymeric coated-wire electrodes (CWEs) and solid-contact ion-selective electrodes (SCISEs). The Ca(2+) selective silicone rubber (RTV 3140) based SCISEs with poly(3-octylthiophene) (POT) as the solid-contact (SC) showed good correlation between a very low water content at the Pt-coated ZnSe substrate/SC interface and a superior potential stability. This is due to the hydrophobicity of both RTV 3140 and POT and the approximately 2 orders of magnitude lower water diffusion coefficients in POT compared to RTV 3140. Practically no potential drift could be observed during 24 h when unconditioned CaSCISEs were contacted with 10(-3) M CaCl(2), in contrast to the Ca(2+)-selective CWEs with considerably higher water uptake and potential drift. The CaSCISEs had a fast Nernstian response with a detection limit of 8 * 10(-9) M Ca(2+) and a good reproducibility and stability of the standard potential, which indicates that the CaSCISEs does not require any conditioning prior to use. PMID- 21545176 TI - Development of polymeric microbubbles targeted to prostate-specific membrane antigen as prototype of novel ultrasound contrast agents. AB - Ultrasound-targeted microbubbles (MBs) offer new opportunities to enhance the capabilities of diagnostic ultrasound (US) imaging to specific pathological tissue. Herein, we report on the design and development of a novel prototype of US contrast agent based on polymeric MBs targeted to prostate-specific membrane antigen (PSMA) for use in the diagnosis of prostate cancer (PCa). First, a set of air-filled MBs by a variety of biocompatible polymers were prepared and characterized in terms of morphology and echogenic properties after exposure to US. MBs derived from poly(D,L-lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG) copolymer resulted as the most effective in terms of reflectivity. Such polymer was therefore preconjugated with a urea-based PSMA inhibitor molecular probe (DCL), and the obtained MBs were investigated in vitro for their targeting efficacy toward PSMA positive PCa (LNCaP) cells. Fluorescence microscopy proved a specific and efficient adhesion of targeted MBs to LNCaP cells. To our knowledge, this work reports the first model of polymeric MBs appropriately engineered to target PSMA, which might be further optimized and used for PCa diagnosis and potential carriers for selective drug delivery. PMID- 21545177 TI - Generation of profluorescent isoindoline nitroxides using click chemistry. AB - Novel profluorescent nitroxides bearing a triazole linker between the coumarin fluorophore and an isoindoline nitroxide were prepared in good yields using the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (CuAAC). Nitroxides containing 7-hydroxy and 7-diethylamino substitution on their coumarin rings displayed significant fluorescence suppression, and upon reaction with methyl radicals, normal fluorescence emission was returned. The fluorescence emission for the 7-hydroxycoumarin nitroxide and its diamagnetic analogue was found to be strongly influenced by pH with maximal fluorescence emission achieved in basic solution. Solvent polarity was also shown to affect fluorescence emission. The significant difference in fluorescence output between the nitroxides and their corresponding diamagnetic analogues makes these compounds ideal tools for monitoring processes involving free-radical species. PMID- 21545178 TI - Food grade fungal stress on germinating peanut seeds induced phytoalexins and enhanced polyphenolic antioxidants. AB - The effects of food grade fungus Rhizopus oligosporus stress on phytochemicals and phytoalexins of germinating peanut seeds were investigated by comparing the metabolic profiles of ungerminated (UG), germinated (G), and germinated seeds under fungal stress (GS). Three types of peanut seeds with different skin color (red, reddish brown, and black) were compared in the process. The polyphenolic contents were analyzed and correlated with antioxidant capacity for specific free radicals including peroxyl radical ROO(*) (ORAC), hydroxyl radical HO(*) (HORAC), superoxide radical O(2)(*-) (SORAC), and DPPH radical. The polyphenolic fingerprints analyzed by HPLC and LC-MS(n) showed that phenolic acids (coumaric, sinapinic, and ferulic acids derivatives) were the major group of phenolic compounds in ungerminated seeds. G or GS increased the level of phenolic acids, phytoalexins, and antioxidant capacity values in reddish and red peanuts but not in black peanuts. From the LC-MS(n) spectral data, 45 compounds were identified tentatively in the germinated peanuts, including 14 coumaric acids, 3 ferulic acids, 4 sinapinic acids, 2 hydroxybenzoic acids, 1 caffeic acid, 2 flavonoids, and 19 stilbenoids derivatives. Reddish brown germinated peanuts produced the highest amount of phytoalexins after GS with 55 compounds detected. Forty-five of these compounds were suggested as stilbenoid phytoalexins derivatives. The high content of phytoalexins may enhance the bioactivity of peanut seeds as functional food ingredients. PMID- 21545179 TI - Preparation of SF5 aromatics by vicarious nucleophilic substitution reactions of nitro(pentafluorosulfanyl)benzenes with carbanions. AB - Vicarious nucleophilic substitutions (VNS) of hydrogen in 1-nitro-4 (pentafluorosulfanyl)benzene with carbanions provide 2-substituted 1-nitro-4 (pentafluorosulfanyl)benzenes in good to high yields. VNS of 1-nitro-3 (pentafluorosulfanyl)benzene gives a mixture of 6- and 4-substituted 1-nitro-3 (pentafluorosulfanyl)benzenes in 85:15 to >98:2 ratio and good to high yields. In basic media, the VNS reactions lead to the formation of carbanions that can be alkylated by alkyl halides affording the corresponding alkylated products in moderate yields. Transformation of primary products to substituted (pentafluorosulfanyl)anilines and 3- or 4-substituted (pentafluorosulfanyl)benzenes is also described. PMID- 21545180 TI - Targeting tumor cells through chitosan-folate modified microcapsules loaded with camptothecin. AB - Poly(vinyl alcohol) microcapsules have been tailored as carriers to deliver camptothecin, an anticancer drug poorly soluble in water. The capsules have been reacted with a chitosan--folate complex in order to selectively target cancer cells overexpressing the folic acid receptor. Microcapsules decorated with the chitosan--folate complex have been characterized in their uptake and release of camptothecin, following the absorption band at lambda = 370 nm diagnostic of the drug molecule. The selectivity of chitosan-folate microcapsules in targeting cancer cells has been demonstrated by fluorescence microscopy using HeLa cells, overexpressing the folate receptor and NIH3t3 fibroblasts as a negative control. The chitosan--folate microcapsules loaded with camptothecin significantly reduce the proliferation of HeLa tumor cells, while they have a negligible effect on fibroblasts. This work demonstrates that the chitosan--folate microcapsules represent a promising system to selectively target hydrophobic drugs, such as camptothecin, to tumor cells. PMID- 21545181 TI - Biodistribution study of nanometric hybrid gadolinium oxide particles as a multimodal SPECT/MR/optical imaging and theragnostic agent. AB - Nanometric hybrid gadolinium oxide particles (Gado-6Si-NP) for diagnostic and therapeutic applications (mean diameter 3-4 nm) were obtained by encapsulating Gd(2)O(3) cores within a polysiloxane shell, which carries organic fluorophore (Cy 5) and is derivatized by a hydrophilic carboxylic layer. As residency time in the living body and methods of waste elimination are crucial to defining a good nanoparticle candidate and moving forward with steps for validation, this study was aimed at evaluating the biodistribution of these multimodal Gado-6Si-NP in rodents. Gado-6Si-NP were imaged following intravenous injection in control Wistar rats and mice using MRI (7 T), optical fluorescent imaging, and SPECT. A clear correlation was observed among MRI, optical imaging, and SPECT regarding the renal elimination. Quantitative biodistribution using gamma-counting of each sampled organ confirmed that these nanoparticles circulated freely in the blood pool and were rapidly cleared by renal excretion without accumulation in liver and RES uptake. These results demonstrate that Gado-6Si-NP display optimal biodistribution properties, enabling them to be developed as multimodal agents for in vivo imaging and theragnostics, especially in oncological applications. PMID- 21545183 TI - Identification of a fungi-derived terrestrial halogenated natural product in wild boar (Sus scrofa). AB - In this study, we identified and quantitated a tetrachlorinated compound found at high concentrations in some samples of the meat of free-ranging wild boar (Sus scrofa) from Southern Germany. Mass spectrometric analysis indicated that the compound was a tetrachloromethoxyphenol isomer, and the subsequently synthesized tetrachloro-p-methoxyphenol was identical with the unknown compound in wild boar. Tetrachloro-p-methoxyphenol is a known secondary metabolite of basidiomycetous fungi, which in turn are regular feed items of the wild boar. It is extremely likely that the wild boar have accumulated tetrachloro-p-methoxyphenol by exploiting basidiomycetes. The highest concentration in the samples (n = 22) was ~1 mg/kg lipids tetrachloro-p-methoxyphenol. This concentration was higher than that of polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT) in any of the samples. Some samples did not contain tetrachloro-p methoxyphenol, which indicates varied preferences in fungi by wild boars. Our data suggest that during their entire evolution, humans have been in contact with the natural product tetrachloro-p-methoxyphenol by consuming wild boars. PMID- 21545182 TI - "Clickable", trifunctional magnetite nanoparticles and their chemoselective biofunctionalization. AB - A multifunctional iron oxide based nanoformulation for combined cancer-targeted therapy and multimodal imaging has been meticulously designed and synthesized using a chemoselective ligation approach. Novel superparamagnetic magnetite nanoparticles simultaneously functionalized with amine, carboxyl, and azide groups were fabricated through a sequence of stoichiometrically controllable partial succinylation and Cu (II) catalyzed diazo transfer on the reactive amine termini of 2-aminoethylphosphonate grafted magnetite nanoparticles (MNPs). Functional moieties associated with MNP surface were chemoselectively conjugated with rhodamine B isothiocyanate (RITC), propargyl folate (FA), and paclitaxel (PTX) via tandem nucleophic addition of amine to isothithiocyanates, Cu (I) catalyzed azide--alkyne click chemistry and carbodiimide-promoted esterification. An extensive in vitro study established that the bioactives chemoselectively appended to the magnetite core bequeathed multifunctionality to the nanoparticles without any loss of activity of the functional molecules. Multifunctional nanoparticles, developed in the course of the study, could selectively target and induce apoptosis to folate-receptor (FR) overexpressing cancer cells with enhanced efficacy as compared to the free drug. In addition, the dual optical and magnetic properties of the synthesized nanoparticles aided in the real-time tracking of their intracellular pathways also as apoptotic events through dual fluorescence and MR-based imaging. PMID- 21545184 TI - Correction to Copper-mediated coupling of 1,1-dibromo-1-alkenes with imidazoles: a general method for the synthesis of N-alkynylimidazoles. PMID- 21545185 TI - Secondary metabolites from Glycine soja and their growth inhibitory effect against Spodoptera litura. AB - The wild soybean (Glycine soja Sieb. et Zucc) has been reported to be relatively resistant to insect and pathogenic pests. However, the responsible secondary metabolites in the aerial part of this important plant are largely unknown. From the aerial part of G. soja, 13 compounds were isolated and identified, including seven isoflavonoids (1-7), a cyclitol (8), two sterol derivatives (9 and 10), and three triterpenoids (11-13). Compound 7 is a new isoflavonoid, and compounds 9 and 10 are reported as natural products for the first time. The growth inhibitory activity of 1, 3, 4, and 8 against the larvae of Spodoptera litura was investigated. The most abundant isoflavonoid in the aerial part of G. soja, daidzein (1), which could not be metabolized by S. litura, was found to inhibit the insect larvae growth significantly in 3 days after feeding diets containing the compound. Compounds 3, 4, and 8, which could be partially or completely metabolized, were inactive. Our results suggested that the isoflavonoid daidzein (1) might function as a constitutive defense component in G. soja against insect pests. PMID- 21545186 TI - One-pot synthesis of symmetrical and unsymmetrical aryl sulfides by Pd-catalyzed couplings of aryl halides and thioacetates. AB - Aryl sulfides were obtained from the coupling reaction of S-aryl (or S-alkyl) thioacetates and aryl bromides in the presence of palladium catalyst. This reaction method enables the one-pot synthesis of symmetrical and unsymmetrical diaryl sulfides by employing potassium thioacetate with aryl iodides and aryl bromides. PMID- 21545187 TI - Multivalent display of proteins on viral nanoparticles using molecular recognition and chemical ligation strategies. AB - Multivalent display of heterologous proteins on viral nanoparticles forms a basis for numerous applications in nanotechnology, including vaccine development, targeted therapeutic delivery, and tissue-specific bioimaging. In many instances, precise placement of proteins is required for optimal functioning of the supramolecular assemblies, but orientation- and site-specific coupling of proteins to viral scaffolds remains a significant technical challenge. We have developed two strategies that allow for controlled attachment of a variety of proteins on viral particles using covalent and noncovalent principles. In one strategy, an interaction between domain 4 of anthrax protective antigen and its receptor was used to display multiple copies of a target protein on virus-like particles. In the other, expressed protein ligation and aniline-catalyzed oximation was used to display covalently a model protein. The latter strategy, in particular, yielded nanoparticles that induced potent immune responses to the coupled protein, suggesting potential applications in vaccine development. PMID- 21545188 TI - Conformational role for the C-terminal tail of the intrinsically disordered high mobility group A (HMGA) chromatin factors. AB - The architectural factors HMGA are highly connected hubs in the chromatin network and affect key cellular functions. HMGA have a causal involvement in cancer development; in fact, truncated or chimeric HMGA forms, resulting from chromosomal rearrangements, lack the constitutively phosphorylated acidic C terminal tail and display increased oncogenic potential, suggesting a functional role for this domain. HMGA belong to the intrinsically disordered protein category, and this prevents the use of classical approaches to obtain structural data. Therefore, we combined limited proteolysis, ion mobility separation-mass spectrometry (IMS-MS), and electrospray ionization-mass spectrometry (ESI-MS) to obtain structural information regarding full length and C-terminal truncated HMGA forms. Limited proteolysis indicates that HMGA acidic tail shields the inner portions of the protein. IMS-MS and ESI-MS show that HMGA proteins can assume a compact form and that the degree of compactness is dependent upon the presence of the acidic tail and its constitutive phosphorylations. Moreover, we demonstrate that C-terminal truncated forms and wild type proteins are post-translationally modified in a different manner. Therefore, we propose that the acidic tail and its phosphorylation could affect HMGA post-translational modification status and likely their activity. Finally, the mass spectrometry-based approach adopted here proves to be a valuable new tool to obtain structural data regarding intrinsically disordered proteins. PMID- 21545191 TI - Potential role of the alcohol and smoking in the squamous cell carcinoma of the head and neck: review of the current literature and new perspectives. AB - Alcohol and tobacco are responsible for a very large proportion of chronic disease and some tumors in particular may be the result of interactions between the two risk factors. The present systematic literature review was conducted to judge combined effects of alcohol drinking and tobacco, as well as and genetic polymorphisms on alcohol-related cancer risk. We can conclude that the interaction of smoking and alcohol significantly increases the risk for aero digestive cancers. Unfortunately, little is known about mechanisms and details of interaction with regard to disease outcomes, which is why particular questions must be targeted in future research efforts. PMID- 21545190 TI - Ultrasound-guided injection of a corticosteroid and hyaluronic acid: a potential new approach to the treatment of trigger finger. AB - BACKGROUND AND OBJECTIVES: Stenosing tenosynovitis (trigger finger) is one of the most common causes of pain and disability in the hand, which may often require treatment with anti-inflammatory drugs, corticosteroid injection, or open surgery. However, there is still large room for improvement in the treatment of this condition by corticosteroid injection. The mechanical, visco-elastic, and antinociceptive properties of hyaluronic acid may potentially support the use of this molecule in association with corticosteroids for the treatment of trigger finger. This study examines the feasibility and safety of ultrasound-guided injection of a corticosteroid and hyaluronic acid compared, for the first time, with open surgery for the treatment of trigger finger. METHODS: This was a monocentric, open-label, randomized study. Consecutive patients aged between 35 and 70 years with ultrasound-confirmed diagnosis of trigger finger were included. Patients were randomly assigned to either ultrasound-guided injection of methylprednisolone acetate 40 mg/mL with 0.8 mL lidocaine into the flexor sheath plus injection of 1 mL hyaluronic acid 0.8% 10 days later (n = 15; group A), or to open surgical release of the first annular pulley (n = 15; group B). Clinical assessment of the digital articular chain was conducted prior to treatment and after 6 weeks, and 3, 6, and 12 months. The duration of abstention from work and/or sports activity, and any treatment complications or additional treatment requirements (e.g. physiotherapy, compression, medication) were also recorded. RESULTS: Fourteen patients (93.3%) in group A had complete symptom resolution at 6 months, which persisted for 12 months in 11 patients (73.3%), while three patients experienced recurrences and one experienced no symptom improvements. No patients in group A reported major or minor complications during or after corticosteroid injection, or required a compression bandage. All 15 patients in group B achieved complete resolution of articular impairment by 3 weeks after surgery, but ten patients were assigned to physiotherapy and local and/or oral analgesics for complete resolution of symptoms, which was approximately 30-40 days postsurgery. The mean duration of abstention from work and/or sport was 2-3 days in group A and 26 days in group B. CONCLUSIONS: Although the limited sample size did not allow any statistical comparison between treatment groups, and therefore all the findings should be regarded as preliminary, the results of this explorative study suggest that ultrasound-guided injection of a corticosteroid and hyaluronic acid could be a safe and feasible approach for the treatment of trigger finger. It is also associated with a shorter recovery time than open surgery, which leads to a reduced abstention from sports and, in particular, work activities, and therefore may have some pharmacoeconomic implications, which may be further explored. In light of the promising results obtained in this investigation, further studies comparing ultrasound-guided injection of corticosteroid plus hyaluronic acid with corticosteroid alone are recommended in order to clarify the actual benefits attributable to hyaluronic acid. PMID- 21545189 TI - Do productivity costs matter?: the impact of including productivity costs on the incremental costs of interventions targeted at depressive disorders. AB - BACKGROUND: When guidelines for health economic evaluations prescribe that a societal perspective should be adopted, productivity costs should be included. However, previous research suggests that, in practice, productivity costs are often neglected. This may considerably bias the results of cost-effectiveness studies, particularly those regarding treatments targeted at diseases with a high incidence rate in the working population, such as depressive disorders. OBJECTIVES: This study aimed to, first, investigate whether economic evaluations of treatments for depressive disorders include productivity costs and, if so, how. Second, to investigate how the inclusion or exclusion of productivity costs affects incremental costs. METHODS: A systematic literature review was performed. Included articles were reviewed to determine (i) whether productivity costs had been included and (ii) whether the studies adhered to national health economic guidelines about the inclusion or exclusion of these costs. For those studies that did include productivity costs, we calculated what proportion of total costs were productivity costs. Subsequently, the incremental costs, excluding productivity costs, were calculated and compared with the incremental costs presented in the original article, to analyse the impact of productivity costs on final results. Regression analyses were used to investigate the relationship between the level of productivity costs and the type of depressive disorder, the type of treatment and study characteristics such as time horizon used and productivity cost valuation method. RESULTS: A total of 81 unique economic evaluations of treatments for adults with depressive disorders were identified, 24 of which included productivity costs in the numerator and one in the denominator. Approximately 69% of the economic evaluations ignored productivity costs. Two-thirds of the studies complied with national guidelines regarding the inclusion of productivity costs. For the studies that included productivity costs, these costs reflected an average of 60% of total costs per treatment arm. The inclusion or exclusion of productivity costs substantially affected incremental costs in a number of studies. Regression analyses showed that the level of productivity costs was significantly associated with study characteristics such as average age, the methods of data collection regarding work time lost, the values attached to lost work time, the type of depressive disorder, the type of treatment provided and the level of direct costs. CONCLUSIONS: Studies that do not include productivity costs may, in many cases, poorly reflect full societal costs (or savings) of an intervention. Furthermore, when comparing total costs reported in studies that include productivity costs, it should be noted that study characteristics such as the methods used to assess productivity costs may affect their level. PMID- 21545192 TI - Improvement in survival of breast cancer patients - trends over two time periods in a single institution in an Asia Pacific country, Malaysia. AB - BACKGROUND: There is improvement in breast cancer survival in the developed world, but information on breast cancer survival trends in the Asia Pacific region is limited. The aim of the study was to evaluate survival trends and factors that affect survival in Malaysia. METHODS: Two prospective groups of 423 and 965 newly diagnosed breast cancer patients in University of Malaya Medical Centre, Kuala Lumpur, Malaysia diagnosed in two time periods ie. 1993 to 1997 and in 1998 to 2002 were studied. Vital status was obtained from the National Registry of Births and Deaths. The overall survival was calculated from the date of diagnosis to the date of death from any cause. The survival differences between the two groups were analysed using the log-rank or Peto-Wilcoxon method. Survival estimates and independent prognostic factors were estimated by the Kaplan-Meier method and multivariate analysis using Cox proportional hazard models. P values less than 0.05 were considered statistically significant. Analyses were performed using SPlus 2000 Professional Release 2. RESULTS AND DISCUSSION: Median follow-up for the two groups were 55 months (SD 29.2 months) in the first group and 52 months (SD 24.43) in the second group. There was improvement in 5-year observed survival from 58.4% (CI 0.54-0.63) to 75.7% (CI 0.73-0.79). The improvement in survival was significantly seen in all co-variates (p< 0.05) except for those aged 40 years and below (p= 0.27), tumour size 2 to 5 cm (p=0.11), grade 3 (p=0.32) and patients with Stage IV disease (p= 0.80). Stage of disease, lymph node (LN) involvement, size and grade were identified as independent prognostic factors in cohort one. For the second cohort; stage and LN involvement remained independent factors with the addition of ER status and ethnicity. CONCLUSIONS: There was improvement in 5-year observed survival. Besides known prognostic factors, Malay ethnicity was an independent prognostic factor. PMID- 21545193 TI - Microvessel density in follicular cysts, keratocystic odontogenic tumours and ameloblastomas. AB - PURPOSE: Multicystic ameloblastoma is a benign epithelial odontogenic tumor that exhibits a more aggressive behavior than follicular cyst and keratocystic odontogenic tumor (KCOT). The aim of this study was to perform an immunohistochemical evaluation of the mean microvessel density (MVD) effect on clinical behavior of odontogenic lesions and to determine whether peritumoral or intratumoral MVD has a more prominent role in clinical behavior of odontogenic lesions. METHODS: In a descriptive-analytic cross-sectional study, 45 paraffin blocks of mentioned lesions were selected and stained immunohistochemically with CD34. Mean MVD, peritumoral and intratumoral MVD for each odontogenic lesion was investigated and compared with each other. ANOVA and Kruskal Wallis were used for the statistical analysis of the results. RESULTS: Mean MVD was 40.8 +/- 15.9, 25.3 +/- 5.4, and 9.4 +/- 3.52 in ameloblastoma, keratocystic odontogenic tumor , and follicular cyst, respectively. Mean MVD difference between the above mentioned lesions was statistically significant. (p < 0.001) In all the odontogenic lesions, Intratumoral MVD was higher than peritumoral (pericystic) areas. (p = 0.001) CONCLUSION: There was an increase of mean MVD in multicystic ameloblastoma in comparison to keratocystic odontogenic tumor and follicular cyst and it may be concluded as one of the main factors in multicystic ameloblastoma aggressive behavior. Intratumoral (intracystic MVD) has a more prominent role in growth and clinical behavior of mentioned odontogenic lesions. This supports the hypothesis that the early stages of growth and development of follicular cyst, KCOT and multicystic ameloblastoma may share some similarities regarding angiogenesis. PMID- 21545194 TI - A case-control study of risk factors for lung cancer in Mumbai, India. AB - In the year 2010, it is estimated that nearly 1.35 million new cases and 1.18 million deaths with lung cancer occurred. In India, among males, lung cancer rates vary across the country which has encouraged us to conduct a case-control study to study the risk factors. The present unmatched hospital-based case control study conducted at Tata Memorial Hospital included subjects registered between the years 1997-99. There were 408 lung 'cancer cases' and 1383 'normal controls'. Data on age, tobacco habits, occupational history, dietary factors, tea, coffee were collected by the social investigators. Univariate and regression analysis were applied for obtaining the odds ratio for risk factors. In the study, cigarette smoking (OR=5.2) and bidi smoking (OR=8.3), as well as alcohol consumption (OR=1.8), demonstrated dose-response relationships with lung cancer risk. Among the dietary items, only red-meat consumption showed 2.2-fold significant excess risk. Consumption of milk showed a 60% reduction in risk; while coffee showed a 2-fold excess risk for lung cancer. In addition, exposure to use of pesticides showed a 2.5-fold significant excess risk for lung cancer. PMID- 21545195 TI - Prognostic factors in patients with malignant salivary gland neoplasms in a Brazilian population. AB - Due to the difficulty of follow-up for long periods, information about the survival rates of malignant salivary gland tumors is deficient in the global scientific literature. This study was aimed at investigating the epidemiological profile and prognostic factors that might affect survival in patients with primary malignant salivary gland tumors in Brazil. Patients were investigated regarding histopathological subtypes, age, gender, anatomic localization, smoking and alcohol intake, tumor size, clinical stage, histological grade, recurrence, metastasis, and treatment on clinicopathological outcomes. Survival curves were generated using the Kaplan-Meier method, and both univariate and multivariate analyses were performed using the log rank test and Cox regression, respectively. A total of 63 cases were analyzed, females being slightly predominant (50.8%), with ages ranging from 13 to 87 years. The most common diagnosis was adenoid cystic carcinoma and the most affected anatomical location was the parotid. Tumors were predominantly classified as stage I and high-grade at the diagnosis. The 5- and 10-year overall survival rates were 84.6% and 74.7%, respectively. Disease-free survival (DFS) rates were 71.6% (5 years) and 56.6% (10 years). Univariate analysis showed significant effects of tumor size and clinical stage on the DFS (P<0.0001 for both), and Cox regression analysis confirmed clinical stage as an independent prognostic factor (P = 0.035). Our results highlight the relevance of clinical stage as an independent prognostic parameter for malignant salivary gland tumors. PMID- 21545196 TI - Is breast self examination (BSE) still relevant? A study on BSE performance among female staff of University of Malaya. AB - OBJECTIVES: This study aimed to determine the rate of breast self examination (BSE) among the female staff of University of Malaya and to determine the role of BSE in detecting breast abnormalities. METHODS: A total of 1598 questionnaires were posted to all female staff, aged 35 years and above. Their knowledge on breast cancer, practice of BSE and detection rate of breast abnormality as confirmed by CBE was determined. RESULTS: The response rate for this study was 45 percent (714 respondents). The rate of respondents having awareness on breast cancer was 98.7 percent. Eighty four percent (598) of the respondents had performed BSE in their lifetime. However, in only 41% was it regular at the recommended time. Forty seven percent (334) had undergone CBE at least once in a lifetime but only 26% (185) had CBE at least once in the past 3 years, while 23% (165) had had a mammogram. There was a significant relationship between CBE and BSE whereby those who had CBE were twice more likely to do BSE. Nineteen percent (84 respondents) of those who did BSE claimed they had detected a breast lump. Of these, 87% (73) had gone for CBE and all were confirmed as such. CONCLUSION: BSE is still relevant as a screening tool of breast cancer since those who detect breast lump by BSE will most probably go for further check up. CBE should be done to all women, especially those at highest risk of breast cancer, to encourage and train for BSE. PMID- 21545197 TI - Diagnostic challenges and role of immunohistochemistry in metastatic liver disease. AB - OBJECTIVE: To evaluate the role of Immunohistochemistry (IHC) in the diagnosis of metastatic liver disease, with a descriptive, cross-sectional study at the Department of Histopathology, Armed Forces Institute of Pathology (AFIP), Rawalpindi. MATERIAL AND METHODS: A total of 130 cases of metastatic liver disease were retrieved from the tumor registry data. Eosin-haematoxylin stained sections and Immunohistochemistry panels applied to ascertain the site of primary tumor were evaluated. The panels of detailed immunohistochemical markers were applied. Frequency and percentages were calculated for qualitative variables. Mean and standard deviations were calculated for quantitative variables. RESULTS: Males were 87 (67%) and were females 43 (33.07%). The most common site of primary was in GIT (45%), followed by neuroendocrine carcinoma and gall bladder. The other less common sites were lung, breast, ovary and thyroid. CONCLUSION: There is no specific singular panel of immunohistochemistry markers which can be used in all cases of metastatic liver tumors. The best use and selection of IHC markers depend upon morphological features, clinical history and results of other relevant investigations. PMID- 21545198 TI - Expression of xenobiotic metabolizing genes in head and neck cancer tissues. AB - BACKGROUND: Xenobiotic metabolizing genes are involved in detoxification of carcinogens. Expression of these enzymes may be one of the reasons for interindividual differences in head and neck cancer risks. The aim of current study was first to evaluate the expression of CYP1A1, GSTM1, GSTT1 and GSTP1 and second to observe its relationship with stages of head and neck cancer in Pakistani population. METHODOLOGY: Fresh biopsy tissues were taken from oncology institutional hospitals. Semi quantitative reverse transcriptase polymerase chain reaction was used to investigate CYP1A1, GSTM1, GSTT1 and GSTP1 expression in 49 head and neck cancer tumor tissue and 49 normal healthy tissues. Statistical analysis was performed to explore its association with head and neck cancer risk. RESULTS: The current study revealed that the CYP1A1 mRNA expression was markedly reduced in tissues of head and neck carcinoma compared to adjacent normal tissue (OR 4.5, CI 1.5-13.4). CYP1A1 expression was downregulated in 62.5% tissues of stage 1, 72.7% tissues of stage 2, 60% tissues of stage 3 and 100% tissues of stage 4. Undetectable or partial loss of expression of GSTM1 and GSTT1 mRNA was also observed at a higher rate in head and neck cancer tissue compared to control (OR 4.5, CI 1.5- 13.4 and OR 3.2, CI 1.1- 9.6 respectively). GSTM1 and GSTT1 expression was also downregulated in stage wise pattern; stage 1 had 50% and 12.5% tissues showing down regulation of GSTM1 and GSTT1 genes respectively, both GSTM1 and GSTT1 had 55% tissues with down regulation in stage 2, similarly stage 3 had 60% tissues showing down regulation of these genes and stage 4 had 86% and 71% tumors. GSTP1 mRNA expression was significantly higher in cancer tissue as in control tissue (OR 4.2, CI 1.2- 15.3). GSTP1 over expression also revealed related to stages with 36.4%, 60% and 71% tumor of stage 2, 3 and 4 respectively. CONCLUSION: Our results revealed that CYP1A1, GSTM1 and GSTT1 are downregulated in the head and neck cancer progression while GSTP1 is upregulated. These down regulations and up regulation were more marked in advanced stages of head and neck cancer. Therefore, CYP and GST expression may be an important mechanism involved in the carcinogenesis but the underlying mechanisms leading to such regulations in expression deserve further investigations. PMID- 21545199 TI - Preliminary data about female malignant breast tumours in Cambodia. AB - BACKGROUND: Breast cancer is the most frequent cancer among women and the most frequent cause of cancer death in women in both developing and developed countries. However, little is known about the situation in Cambodian women living in Cambodia. OBJECTIVES: To describe the different histological types of invasive breast cancer, their frequency, grade and stage and their surgical management in Cambodia. MATERIALS AND METHODS: A retrospective study of female breast primary invasive malignant lesions processed during 2003 and 2004 in the pathology laboratory of the 'Institut Pasteur du Cambodge', in Phnom Penh, was carried out with conventional histology techniques. RESULTS: A total of 102 patients were included, with an average age of 47. Most specimens were tumour excisions or mastectomies. Tumours were generally large (37.5 % at least T3), distributed into carcinomas (94.2 %), phyllodes tumours (3.9 %) and lymphomas (1.9 %). Most cases of carcinoma presented with histological grade III (76.6%) and were invasive ductal (82.3%) or medullary (11.4%) in type. Lymphadenectomy was not systematic but nodal metastases were observed in 26 of 31 (83.9%). CONCLUSIONS: Late diagnosis of the disease is due to absence of systematic breast cancer screening and awareness. Apparent rarity of lobular carcinoma and over frequency of medullary carcinoma and phyllodes tumours should be confirmed on a larger series of patients using immunohistochemistry. Its use for other markers to help oncologists to decide whether anti-hormone treatment is indicated is also recommended, together with more standardized surgery. PMID- 21545200 TI - Risk of cancer development in India. AB - Incidence as a measure of risk for development of cancer is a well accepted epidemiological concept which can be precisely defined. The present communication documents an estimate of the current probability of development of cancer for specific age groups as well as for entire life time risk at the India country level for several cancers and 'all sites together'. The published data on age specific cancer incidence rates from 12 population based registries located at various parts of the country along with the abridged life tables relating to the Indian population formed the basic material for computation. Employing life table methodology for estimates, the current probability of developing cancer of all sites from 35-64 years is 4.67% in males and 6.55% in females while life time risk was found to be 9.05% and 10.2% respectively. The greater risk in females was mainly due to the high risk of development of cancer of the uterine cervix and breast. When the age-period of 35 to 70+ years were considered, the probability percentage was found to be 9.94 % in males whereas it was 11.6% in females. According to these estimates 1 in 10 men and 1 in 8 women in India can expect develop cancer of any form, in their life span after the age of 35 years. The probability of developing tobacco related cancers from 35 to 70+ years was found to be 4.75% and 2.16% in males and females respectively. Estimation in terms of probability will be useful in evaluating the changes in the disease spectrum as a result of change in mortality experience and population structure over a period of time. PMID- 21545201 TI - Establishment of a fluorescent implantation metastasis model of bladder cancer and real-time microscopic detection in nude mice. AB - OBJECTIVE: To establish a fluorescent implantation metastasis model of bladder carcinoma with high metastatic potential in nude mice and observe development and metastasis. METHODS: Human bladder cancer EJ cells with high invasive ability were screened and transfected with GFP plasmid to screen stable enhanced GFP expressing clones instilled into the bladders of nude mice. Subsequent growth, invasion, and metastasis of the implanted tumors were observed and evaluated with a whole-body fluorescence optical imaging system. RESULTS: The transfected bladder cancer EJ cells stably and efficiently expressed EGFP. The growth, invasion and metastasis of the implant bladder tumor were readily observed and accurately evaluated by fluorescent microscopy. In the bladders of nude mice, the rates of EGFP expression detected by flow cytometry at weeks 1-4 were 22.6%, 46.7%, 62.3% and 72.7%, respectively, with clear increase over time. CONCLUSION: GFP-labeled bladder cancer EJ cells display green fluorescence under fluorescent microscopy and show stable GFP expression. The model will provide a simple and reliable means for studying the mechanism of implantation metastasis of human bladder cancers in vivo. PMID- 21545202 TI - RNA interference of caveolin-1 via lentiviral vector inhibits growth of hypopharyngeal squamous cell carcinoma FaDu cells In Vitro and In Vivo. AB - OBJECTIVE: To investigate the effects of caveolin-1 (CAV1) on the growth of hypopharyngeal squamous cell carcinoma (HSCC) FaDu cells in vitro and in vivo. METHODS: A CAV1-RNAi-lentivirus construct was transfected into FaDu cells and expression of caveolin-1 was tested by RT-PCR and western blotting analysis. Cell apoptosis was analyzed by transferase-medisated dUTP nick-end labeling (TUNEL) assay. Tumor inhibition effects were investigated by injecting rCAV1-RNAi lentivirus construct into tumors created with FaDu cells in the HSCC mouse model, with the empty-vector lentivirus as a control. CAV1 expression in xenografts was tested by RT-PCR and immunohistochemistry. RESULTS: RT-PCR and western blot analysis demonstrated successful construction of the CAV1-RNAi-lentivirus construct producing small hairpin RNA. The average weights and volumes of tumor in mice treated with CAV1-RNAi-lentivirus were lower than in mice with control treatment (P < 0.05). RT-PCR revealed weak positive expression of CAV1 in CAV1 construct-treated xenografts and immunohistochemistry confirmed lower CAV1 expression than in controls.(P < 0.05). In addition, downregulation of CAV1 increased cell apoptosis in vitro. CONCLUSION: The growth of HSCCs could be inhibited by recombinant CAV1-RNAi-lentivirus in vitro and in vivo. PMID- 21545203 TI - Oleanolic acid from Prunella Vulgaris L. induces SPC-A-1 cell line apoptosis via regulation of Bax, Bad and Bcl-2 expression. AB - Prunella vulgaris L. (PV) has been used as a herb for chemoprevention of lung cancer. In this study, the main active compound, oleanolic acid (OA) was isolated from an ethanol extract and its chemical structure was identified according to the results of high performance liquid chromatography (HPLC), high performance thin layer chromatography (HPTLC) and liquid chromatography-mass spectrography (LC-MS). Results for cell viability indictated no notable differences between OA and ethanol extract of PV in lung adenocarcinoma SPC-A-1 cells measured by MTT assay. Consistent concentration-response curves. Fluorescence detection with acridine orange-ethidium bromide was used to evaluate apoptosis of SPC-A-1 cells. OA at 16 and 8 microM group increased significantly the apoptosis rate compared with normal and 1% DMSO groups (p<0.05). In addition, immunocytochemistry assays showed increase in Bax and Bad protein expression while Bcl-2 decreased. Moreover, the ratio of Bax/Bcl-2 was heightened by OA treatment. The results suggest OA induced apoptosis of lung adenocarcinoma cells through down-regulating Bcl-2 expression, and up-regulating Bax and Bad expression. PMID- 21545204 TI - Major cancer mortality and changes in Yanting, 2004-2009: introduction to cancer challenges in a high risk area. AB - Yanting County is one of high risk areas of esophageal cancer in China. Recently, the economic level has improved to a new standard, but cancer issues have not been updated. This study aimed to describe the main cancer mortalities and change from 2004 to 2009 and provide an evidence base for future active strategies. Yanting Cancer Research Institute provided all cancer mortality data and age standardized rates were calculated based on the world standard population 2000. Annual percentage change was used to estimate the time trend for each cancer. Mortality from upper gastrointestinal cancers, but not other cancers, was much higher than worldwide average figures. Rates for esophageal cancer declined over the 6 years, but lung cancer mortality showed an upward trend. For gastric and liver cancer, no obvious change was observed. Considering the high mortality from upper gastrointestinal cancers, it is necessary to take actions investigating the risk factors and addressing the issues of prevalent cancer challenges. PMID- 21545205 TI - Video-assisted thoracoscopic surgery for malignant pleural effusions. AB - AIM: To evaluate the efficacy of video-assisted thoracoscopic surgery (VATS) in the diagnosis and treatment of malignant pleural effusions (MPE) and to assess the results and complications of the procedure. METHODS: A total of 61 patients with the diagnosis of malignant pleural effusion were assessed retrospectively between 2004 - 2010, 25 women (40.9%) and 36 men (59.1%), with an age range of 18 78 (mean: 61.3). Video-thoracoscopic surgery was performed under general anesthesia or with local anesthesia in sedated patients. RESULTS: No intraoperative complications were observed. In 6 cases, prolonged air leak developed. Pleurodesis was successfully implemented in malignant cases. The chest tube was removed when the amount of fluid was less 50 cc/24 h. The duration of drainage was significantly shorter in patients in whom VATS was performed. CONCLUSION: We believe that VATS is an effective method in the diagnosis and palliative treatment of cases with malignant pleural effusions. PMID- 21545206 TI - Predictive role of adenosine deaminase for differential diagnosis of tuberculosis and malignant pleural effusion in Turkey. AB - Tuberculous pleural effusion (TPE) is a common problem for differential diagnosis from malignant effusion (MPE) in epidemic areas of tuberculosis (TB). Prediction based on adenosine deaminase (ADA) is dependent on age as well as the tuberculosis incidence. The aim of the study was to evaluate cutoff values for ADA with sensitivity and specificity results for the differential diagnosis of MPE and TPE in a population with intermediate incidence of TB. We retrospectively analysed 196 patients with a definitive diagnosis of TPE (n = 114) and MPE (n = 82). The optimal cutoff value of ADA was determined using the receiver operating characteristic (ROC) curve. There was a statistically significant difference according to the levels of pleural fluid ADA between TPE and MPE groups (p < 0.0001). The cutoff value for diagnosing TPE was > 55 U/L, with a sensitivity = 86.8%, specificity = 86.6%, positive predictive value (PPV) = 90%, negative predictive value (NPV) = 82.6% and accuracy = 82.6%. We then combined ADA > 55 U/L and age < 50 and were able to discriminate the TPE group with increased specifity (95.7 %) and PPV (98.8%) results. The model could correctly classify 21 MPE out of 23 and 82 TPE out of 94 patients. A pleural fluid ADA value < 31 U/L suggests that TPE is highly unlikely with a sensitivity = 43.9 %, specificity = 100%, PPV = 100%, NPV = 71.3% and accuracy = 76.6%. It can be concluded that ADA is a very useful parameter for the differential diagnosis of TPE and MPE, specifically in youngers with a higher incidence of tuberculosis. PMID- 21545207 TI - Turkish hysterectomy and mastectomy patients - depression, body image, sexual problems and spouse relationships. AB - The aim of this study was to compare hysterectomy and mastectomy patients in terms of depression, body image, sexual problems and spouse relations. The study group comprised 94 patients being treated in Ege University Radiation Oncology Clinic, Tulay Aktas Oncology Hospital, Izmir Aegean Obstetrics and Gynecology Training and Research Hospital for breast and gynecological cancer (42 patients underwent mastectomy, 52 patient underwent hysterectomy). Five scales were used in the study: Sociodemographic Data Form, Beck Depression Scale, Body Image Scale, Dyadic Adjustment Scale, Golombok Rust Sexual Functions Scale. Mastectomy patients were more depressive than hysterectomy patients (t = 2.78, p < 0.01). Body image levels of the patients were bad but there was no significant difference between the two patient groups (p > 0.05). Hysterectomy patients had more problems in terms of vaginismus (t = 2.32, p < 0.05), avoidance of sexual intercourse (t = 2.31, p < 0.05), communication (t = 2.06, p < 0.05), and frequency of sexual intercourse than mastectomy patients (t = 2.10, p < 0.05). As compared with compliance levels between patients and spouses; hysterectomy patients had more problems related to expression of emotions than mastectomy patients (t = 2.12, p < 0.05). In conclusion, body image was negative, mastectomy was associated with more depression and hysterectomy with greater sexual problems and difficulties with spouse relationships. PMID- 21545208 TI - Relationships between psychosocial adjustment and hopelessness in women with breast cancer. AB - OBJECTIVE: Several physical, psychological and social variables influence women with breast cancer. This study was designed to analyze the relationship between psychosocial adjustment and hopelessness in a group of such women in Turkey. METHOD: The subjects were 90 women with breast cancer recruited at Ege University School of Medicine Department of Radiation Oncology Nurse Counsellor Unit and Tulay Aktas Oncology Hospital Outpatient Chemotherapy Unit. Data were collected using an Introductory Information Form and Psychosocial Adjustment to the Illness Scale - Self-Report (PAIS-SR) and the Beck Hopelessness Scale (BHS) and analyzed by Pearson Correlation Analysis. RESULTS: The mean age of the women was 49.4 +/- 11.0. It was found that the level of psychosocial adjustment of 63.3% of the women was 'poor'. A positive relationship was determined between PAIS-SR mean score and BHS mean score of the women with breast cancer (r = 0.731, p < 0.01). CONCLUSION: It was observed that as the psychosocial adjustment worsens, as the level of hopelessness of the women increases. In the light of this relationship, it was concluded that the attempts to increase hope and therefore the support for the psychosocial adjustment of patients should play a vital role in increasing their quality of life. PMID- 21545209 TI - Information needs of patients with meningiomas. AB - The aim of this descriptive, cross-sectional study was to determine information requirements of patients with typical meningiomas after surgery. The study sample consisted of 20 patients who underwent surgery for brain tumours in neurosurgery clinics of a university hospital. Permission to conduct research was obtained from all patients and from the hospital. Before the surgery, a booklet was given to patients for training. Patients were followed up one, three, six and 12 months later by the phone after the surgery and asked to report their problems. All questions were recorded and answered. Data were collected by the socio demographic, patient symptom and health status questionnaire. Descriptive data were analyzed using percentage and arithmetic averages. Comparative statistics were evaluated using chi-square. Patients wanted information about diet, physical therapy and rehabilitation, quick thinking difficulties, fasting, headache, irritability, personality change, fatigue, driving, deep vein thrombosis during the follow up. There was a significant difference between their health status and fear of seizures and recurrent tumor, forgetfulness, lack of concentration (p < 0.05). Although they received health education and booklet, patients needed more information during the 12 months after surgery. Therefore it suggested that monitoring the patient's needs is necessary. PMID- 21545210 TI - Thyroid dysfunction following therapeutic external radiation to head and neck cancer. AB - AIM: The aim of the present study was to evaluate changes in thyroid function in patients with head and neck cancer treated with external beam radiotherapy (EBRT). MATERIALS AND METHODS: This prospective study was conducted on ninety patients with non-thyroid head and neck cancer who were referred to the department of radiotherapy. Thyroid function tests were conducted before, midway during and after EBRT, with follow up at monthly intervals up to 6 months after the completion of therapy. RESULTS: Serum T3 and T4 levels were decreased at completion of EBRT and remained so after 6 months follow up. However, serum TSH levels did not significantly vary. CONCLUSION: EBRT to the neck region for treatment of head and neck cancer induces hypothyroidism and therefore utmost care must be taken to exclude the thyroid from radiation beams without sparing the tumor as far as possible. The clinical protocol in such cases should include monitoring of T3, T4 and TSH levels during and after the EBRT. PMID- 21545211 TI - Trace elements, heavy metals and other biochemical parameters in malignant glioma patients. AB - AIM: We aimed to assess relevance of mineral, trace element and heavy metal levels in patients with malignant gliomas. METHODS: In this study, erythrocyte catalase (CAT), and carbonic anhydrase (CA), serum copper (Cu.), zinc (Zn), lead (Pb), iron (Fe), cadmium (Cd), cobalt (Co), manganese (Mn), and magnesium (Mg) levels were measured in 22 healthy humans and 22 malignant glioma patients. Metal concentrations were assessed by atomic adsorption spectrophotometry, while biochemical methods were used for CAT and CA. RESULTS: The Cd, Fe, Mg, Mn, Pb and Zn levels were significantly elevated in the patients as a whole compared to controls(P<0.05), while Cu was decreased and Co demonstrated no change. Although mean CAT activity were significantly lowered, CA exhibited significant increase. CONCLUSIONS: The results of the current study indicate that antioxidant enzymes may have a role in the genesis of considerable oxidative stress in patients with malignant glioma. CAT and CA seem to play particular roles in the pathophysiology of this disease. PMID- 21545212 TI - Marital adjustment and loneliness status of women with mastectomy and husbands reactions. AB - AIM: The present descriptive analysis of breast-cancer women with mastectomy surgery was conducted to assess husband partner compatibility and level of loneliness during the post-surgery period. MATERIALS AND METHODS: The study was carried out in Ondokuz Mays University, Medical Faculty surgical clinic. A sample of 48 women with mastectomy and 44 husbands were included in the study. A questionnaire form, the dyadic adjustment scale, and UCLA loneliness scale were used to process the data. Descriptive statistics, correlations, Mannhitney U and Kruskalallis tests were used for data analysis with the SPSS 13.0 statistical package for Windows. RESULTS: It was determined that the education background of husbands influenced marital adjustment, this being better with a high school or further diploma. Husbands who described their marriage as bad after the surgery had higher marital adjustment scores (p < 0.01). A connection was found between loneliness status of participant women and their marital adjustment (r = 0.373; p = 0.009). Similar findings were obtained for their husbands (r = 0.412; p = 0.005). CONCLUSION: At the end of this research, women with mastectomy and their husbands described their marital relations before the surgery as good but as bad after the surgery. Women with mastectomy and their husbands stated that they did not feel lonely before or after the surgery. It is critical that nursing initiatives be arranged in line with health training on marital adjustment and loneliness and psycho-social approaches and communications are adjusted to meet the needs of women and husbands. PMID- 21545213 TI - Cancer of corpus uteri in Tunisia: epidemiological and clinicopathological features. AB - INTRODUCTION: The aim of this study was to survey for the first time the burden and characteristics of corpus uteri cancers in Central Tunisia. DESIGN: Characteristics of all cancer cases diagnosed during a 15-year period were analyzed based on the data of the Cancer Registry of the Center of Tunisia. Five year age-specific rates, crude incidence rates, world age-standardized rates (ASR), and annual percent change (APC) were calculated using annual data on population size and its estimated age structure. RESULTS: A total of 218 new cases of corpus uteri cancer were recorded. The ASR was 3.1 per 100,000 with a significant increase over time (APC: +7.1%; 95% CI: 3.1%, 11.1%). The median age at diagnosis was 60 years and only 20.6% of patients were less than 50 years old. The tumor size was higher than 2 cm in 83.5% of cases. Stage I was the most frequent (59.9%) followed by advanced stages (23.2%). Endometrial adenocarcinoma was the most frequent histological type (62.8%) with grade II accounting for 48.5% of cases. CONCLUSION: Corpus uteri cancer is an important female cancer with increasing trend over time. These findings justify the need to plan and develop effective programs aiming at the control of the spread of cancer in Tunisia. PMID- 21545214 TI - Role of preoperative chemotherapy in squamous cell carcinoma of esophagus in kashmir, a cancer belt - a pilot study. AB - BACKGROUND: Esophageal carcinoma is the fifth leading gastrointestinal malignancy and is one of the leading causes of cancer related death. Despite improvements in surgical technique over the last few decades, the outcome has been dismal, with overall 5 year survival not exceeding 15%-25%. AIMS AND OBJECTIVES: To evaluate the effect of preoperative chemotherapy on resectability, complication rate and overall survival in patients with squamous cell carcinoma esophagus. MATERIALS AND METHODS: 50 patients with histologically confirmed squamous cell carcinoma (SCC), with localised or loco-regional disease (stage 4 excluded) were divided into 2 groups. Group A patients were subjected to 2-3 cycles of pre-operative chemotherapy (5FU-CDDP), whereas Group B patients were directly operated on. OBSERVATIONS: 3 (12%) patients in group A showed complete pathological response to chemotherapy and 18 (72%) showed a partial response, with four patients (16%) showing resistance to chemotherapy. There was no statistically significant difference in terms of response to chemotherapy with respect to degree of differentiation of tumor. There was no significant difference in the overall resectability rates between the two groups (p > 0.05), but R0 resection was achieved in 20 (80%) of group A and only 10 (40%) of group B, the difference being statistically significant (p < 0.05). The rate of overall complications was also much higher in the control group. Initially there was no significant difference in the survival between the two groups, but later (20 months) the study group showed a slight non-significant advantage. CONCLUSION: Preoperative chemotherapy significantly increases the rate of R0 resection without significantly increasing postoperative morbidity and mortality in patients with squamous cell carcinoma of esophagus. However, to assess the impact on survival the study period needs to be extended. PMID- 21545215 TI - Mutagenicity and mutagens of the red chili pepper as gallbladder cancer risk factor in Chilean women. AB - High consumption of red chili pepper has been shown to be a risk factor for gallbladder cancer (GBC) in Chilean women with gallstones, and included mutagens may be important in this context. We aimed to investigate the mutagenicity and mutagens in Chilean red chili pepper in the Ames test using Salmonella typhimurium strains TA98, TA1537, TA100, and TA1535 with and without metabolic activation (S9 mix). Pure capsaicin was tested for mutagenicity using strain TA98. The presence of aflatoxins was evaluated by two-dimensional thin layer chromatography, and then the concentrations of aflatoxins B1, B2, G1, and G2 were measured by an HPLC system. In strain TA98, the mean numbers of revertant colonies with and without the S9 mix were 2.5- and 2.2-fold higher than those of each negative control, respectively. However, pure capsaicin did not show mutagenic activity in strain TA98. Aflatoxin contamination of red chili pepper was confirmed, and the concentrations of aflatoxins B1 and G1 were 4.4 ng/g and 0.5 ng/g, respectively. Our findings suggest that low-level but protracted exposure to aflatoxins may be associated with the development of GBC in Chilean women who carry gallstones. PMID- 21545216 TI - Safety and efficacy of argon plasma coagulation for resection of lipomas and hamartomas in large airways. AB - AIMS: To describe the use of argon plasma coagulation (APC) for radical resection of lipomas and hamartomas in large airways. METHODS: Eight patients (7 males and 1 female) were retrospectively reviewed. Data extracted included patient demographic characteristics, type and location of lesion, type of anesthesia used, number of APC sessions required, complications, length of hospital stay, and outcomes. All patients were followed-up for a minimum of 24 months. RESULTS: The patients had a mean age of 54.6 +/- 13.5 years. Lipomas were diagnosed in five and hamartomas in three. Because complete removal of the tumor could not be achieved during one session, two additional APC treatments were carried out in one of the patients, and three in another. Duration of each procedure ranged from 90 to 120 minutes. For the six patients performed under general anesthesia, only one session was required, and the mean time was 110 min. All tumors were completely removed, and no perioperative or long-term complications occurred. During a minimum follow-up of 2 years, no recurrence was noted in any patient. CONCLUSIONS: Complete resection of lipomas and hamartomas inside large airways can be safely achieved via APC. Further studies regarding the use of this technique for other tumor types are warranted. PMID- 21545217 TI - Knowledge and applications of the midwives and nurses at an educational hospital on the early diagnosis of cervix cancer. AB - This descriptive study was made to determine the knowledge levels and application situations of 96 midwives and nurses at an educational hospital in Istanbul. Data were collected with the survey form and evaluated using frequency distribution and chi-square significance tests. Almost two-thirds of the midwives and nurses included stated that they never go for routine gynaecological tests without any sysmptoms, over 50% stated that they did not see themselves as being under risk in the aspect of cervix cancer, and 18.7% had no information about risk factors. While 54.2% had experienced at least one pap smear test, 20.8% stated that they did not see having a pap smear test as mandatory. Over 90.0 about the HPV vaccine, mostly from visual and published media, and 78.1% wanted to have HPV vaccination. A statistically significant difference was found between the the knowledge levels and application situations of the midwives and nurses and their age groups, educational status, and marital status (p<0.05). Participants in the age group 32 and over, with undergraduate or more education, and who were married, had more knowledge and practical experience. PMID- 21545218 TI - Phase II trial of irinotecan plus nedaplatin (INP) in treating patients with extensive stage small cell lung cancer. AB - PURPOSE: We conducted a phase II study of combination chemotherapy with irinotecan (CPT-11) and nedaplatin (NDP), (INP regimen), to determine the effects and toxicities in patients with extensive stage small cell lung cancer (SCLC). METHODS: From March 2005 to December 2010, 60 patients with histologically or cytologically confirmed extensive SCLC were enrolled into this study. All received treatment CPT-11 at a dose of 60 mg/m2 on days 1 and 8, and NDP 20 mg/m2 on days 1-5, every 3-4 weeks as a cycle. Patients were treated until tumor progression or unacceptable toxicity. RESULTS: Main toxicities included: myelosuppression, nausea or vomiting, diarrhea, elevation of alanine aminotransferase,and bilirubin. No treatment related death occurred in this study. Thirteen patients had complete response, forty-two had partial response, three remained stable, and two had progressive disease. Median progression-free survival was 13 months (95% confidence interval: 9-17) and median overall survival was 22 months (95% confidence interval: 19-25). CONCLUSION: INP is an effective and well tolerated regimen for treatment of extensive staged SCLC. PMID- 21545219 TI - Genetic variation in carcinogen metabolizing genes associated with oral cancer in pakistani population. AB - BACKGROUND: Xenobiotics are metabolized by either phase I enzymes like CYP1A1 or phase II enzymes like GSTs. Polymorphisms in the encoding genes (CYP1A1, GSTM1, GSTT1 and GSTP1) potentially may therefore contribute towards risk association for oral cancer. METHODOLOGY: These genes were investigated via a case control study consisting of 228 oral cancer patients and 150 cancer free normal individuals as controls. DNA was extracted from WBCs for genotyping. Polymerase chain reaction-single stranded conformational polymorphism (SSCP) was used for screening CYP1A1 and GSTP1 genes mutations. Deletion of GSTM1 and GSTT1 genes were analyzed by multiplex PCR. RESULTS: Two novel mutations were found in this study in relation to oral cancer. A substitution mutation of A2842 with C resulting in missense tyrosine to serine formation along with a frameshift mutation due to insertion of thymidine at nucleotide 2842 resulting in 495 nucleotide sequence to alter was found in oral cancer patients. GSTM1 and GSTT1 deletion polymorphism was found in significantly higher number of individuals (OR=2.08, CI 1.05-4.2; OR=1.5, CI 0.9-2.4 respectively) compared to controls. 10 patients had deletion of both GSTM1 and GSTT1 genes. GSTP1 gene was also found to have novel substitution mutations of A2848 to T and G2849 to A in exon 7 resulting in leucine to leucine and alanine to threonine formation respectively. Two intronic deletions of cytosine at positions 1074 and 1466 was found in intron 3 and 4 in patients and no control had these exonic or intronic variants in GSTP1 gene. CONCLUSION: These results suggest that accumulation of genetic changes in CYP1A1, GSTM1, GSTT1 and GSTP1 genes are associated with increased risk of oral cancer. PMID- 21545220 TI - Elevated serum thymidine kinase 1 predicts risk of pre/early cancerous progression. AB - BACKGROUND: Serological thymidine kinase 1 (STK1) is a reliable proliferation marker for prognosis, monitoring tumour therapy, relapse and detection of malignancies. In this study we investigate the use of STK1 in health screening. METHODS: The concentration of STK1 was determined by a sensitive dot blot ECL assay in 8,135 persons participating in a health screening program. RESULTS: The frequency of persons with elevated STK1 (<2.0 pM) was 1.1%, representing diseases linked to pre/early cancerous progression. One person with malignancy (gastric carcinoma) was found among persons with elevated STK1, but none of persons with normal STK1 values. There was a significantly higher frequency of persons with moderate/severe type of hyperplasia of breast and prostate expressing elevated STK1, compared to persons with normal STK1 values. No significant difference was found concerning mild hyperplasia. Of persons with elevated STK1, 89.2% had diseases linked to risk for pre/early cancerous progression, compared to 41.2% of persons with normal STK1 values. Among the persons with elevated STK1 values, one developed liver carcinoma after 13 months and five persons showed progression in their disease within 19 months (breast and prostate hyperplasia, HBV infection). CONCLUSION: Serological TK1 may be a reliable marker for risk assessment of pre/early cancerous progression. PMID- 21545221 TI - Expression pattern of tumor endothelial marker 8 protein in gallbladder carcinomas. AB - Tumor endothelial marker 8 protein (TEM8) is highly specific to tumor angiogenesis and is not required for normal adult angiogenesis and hence might prove to be a target for anti-angiogenic therapies in the future. We here evaluated protein and gene expression patterns in human endothelial cells of benign gallbladder - gallstone diseases (GSDs) and gallbladder carcinomas (GBCs) using immunostaining, immunofluorescence and western blotting techniques. Subjects comprised 175 GBC patients, 38 males and 137 females, aged 30-85 years (mean age 50.3 +/- 13.4 years) and twenty with GSDs, aged 30-75 years, (51.4 +/- 10.0 years) for comparison (male 4/20 and females 16/20). TEM8 protein expression increased significantly (p < 0.0001) with increasing stage of GBC and was mostly limited to endothelial cells, although there was no significant change with the grade. Interestingly, only 80-85 kDa and 60 kDa isoforms of TEM8 increased significantly whereas 45 kDa isoform was absent in GBCs. Conclusions- These results suggest that TEM8 plays an unknown important biological role to promote tumor angiogenesis in GBC. PMID- 21545222 TI - Cytotoxicity of a plant steroidal saponin on human lung cancer cells. AB - Trillium tschonoskii Maxim has been used to treat several diseases, including cancers, in folk medicine. The primary objective of the present study was to test whether TTB2, a steroidal saponin isolated from n-BuOH extracts, might exert effects on cell survival, morphology, cell cycle, reactive oxygen species (ROS) production and mitochondrial function in a lung cancer cell line. It was found that TTB2 had anti-proliferative and morphological influence, leading to the loss of mitochondrial membrane potential (MMP) in a dose-dependent manner. A significant increase in the level of intracellular ROS and an accumulation of cells in the G2/M phases of the cell cycle were also observed in treated cells. In summary, our results indicated that this compound might have potential use for the treatment of cancer. PMID- 21545223 TI - Hookah smoking and lung cancer in the Kashmir valley of the Indian subcontinent. AB - BACKGROUND: The literature about the causal relationship between lung cancer and tobacco smoking mostly concerns cigarettes. Hookah smoking is popular in the Kashmir valley of the Indian subcontinent, and is generally believed to be innocuous because of the passage of the smoke through water before inhalation. OBJECTIVE: To determine the relationship of hookah smoking to lung cancer in Kashmir. MATERIALS AND METHODS: In a case-control design, 251 cases of lung cancer and 500 age-matched controls were studied. A predefined questionnaire was administered through a personal interview regarding various smoking and dietary patterns and the results compared through statistical analyses. RESULTS: There were 194 (178 current) ever-smokers amongst the cases and 223 (134 current) amongst controls. Smokers had a 4.2 times risk of lung cancer compared to non smokers (OR 4.23, 95% CI 3.0-5.96, p < 0.0001). There were 120 hookah smokers amongst the cases and 100 amongst the controls and hookah smokers were nearly six times at risk for lung cancer as compared to nonsmokers (OR 5.83, (95% CI 3.95 8.60, p < 0.0001). Cigarette smokers were commoner amongst cases (46 vs 64 in controls; OR 3.49, 95% CI 2.18-5.60, p=0.000). The severity of smoking was associated with a higher risk of lung cancer (Chi-square 72.1, p 0.000).The practice of changing water of the hookah after each session proved non-existent. CONCLUSION: Hookah smoking is associated with a significantly higher risk for lung cancer in Kashmiri population, with about 6 fold elevated risk as compared to non-smoking controls. PMID- 21545224 TI - Anti-proliferative effects of organic extracts from root bark of Juglans Regia L. (RBJR) on MDA-MB-231 human breast cancer cells: role of Bcl-2/Bax, caspases and Tp53. AB - With increasing use of plant-based cancer chemotherapeutic agents, exploring the antiproliferative effects of phytochemicals has gained increasing momentum for anticancer drug design. The present study was undertaken to investigate the effect of root bark of Juglans regia (RBJR) organic extracts on cell proliferation, and to determine the molecular mechanism of RBJR-induced cell death by determining the expression of Bcl-2, Bax, caspases, Tp53, Mdm-2 and TNF alpha in MDA-MB-231 human breast cancer cells. The results demonstrate that WNRB suppressed proliferation and induced apoptosis in a dose and time dependent manner by modulating expression of key genes. This involved characteristic changes in cytoplasmic and nuclear morphology, DNA fragmentation (TUNEL assay), levels of mRNA and expression of corresponding proteins. Real Time PCR and western blot analysis revealed that the expression of of Bax, caspases, tp53, and TNF-alpha was markedly increased in MBA-MB-231 cells treated with the RBJR extract. In contrast Bcl2 and mdm-2 expression was down regulated after exposure. In summary, our data suggest the presence of bioactive compound(s) in WNRB capable of killing breast carcinoma cells through induction of apoptosis, and therefore a candidate source of anticancer drugs. PMID- 21545225 TI - Plantago major protective effects on antioxidant status after administration of 7,12-Dimethylbenz(a)anthracene in rats. AB - AIM: The present study was designed to evaluate effects of Plantago major extract on oxidative status in Wistar albino rats administrated 7,12 dimethylbenz(a)anthracene (DMBA). METHODS: Rats were divided into three equal groups of 6 animals each: Group 1 controls, group 2 treated with DMBA (100 mg/kg, single dose) and group 3 receiving the DMBA and the aqueous extract at 100 mg/kg/d for 60 days. RESULTS: Significant decrease in catalase (P < 0.05), carbonic anhydrase (p <= 0.01), reduced glutathione (GSH) (P < 0.01) and total protein (P < 0.01) values was observed in the DMBA group compared with the healthy controls and DMBA + Plantago major groups. CONCLUSION: The results suggest preventive effects of Plantago major on DMBA induced oxidative damage in Wistar albino rats that might be due to decreased free radical generation. PMID- 21545226 TI - Childhood cancer frequency in the center of Tunisia. AB - OBJECTIVE: In this paper, we analyzed the frequency of childhood cancer in the Center of Tunisia during 1993-2006. DESIGN: The different types of cancer were grouped according to the International Classification for Cancer in Children. The general and specific frequencies by age and by sex were analyzed. RESULTS: A total of 727 new cases of childhood cancer were registered, with a male to-female sex ratio of 1.7/1. Leukemias had the highest frequency (27%) and, of these, lymphoid leukemias were the most prevalent (73.5%). Thereafter, in descending order of frequency, were lymphomas (25.7%), tumors of the central nervous system (CNS, 9.2%), neuroblastomas (7.7%), sarcomas (6.9%), carcinomas (6.3%), bone tumors (5.8%), nephroblastomas (5.5%), and germinal cell tumors (2.6%). The highest frequency of cancer was found at age 10-14 years (34.9%). Leukemias were the most frequent in age groups 1-4 and 5-9 years, whereas, neuroblastomas and lymphomas were the most frequent at age under one year and 10-14 years, respectively. Of those cases of solid tumors, 55.8% were diagnosed as having advanced stages of the disease. CONCLUSION: Leukemias, lymphomas, and CNS tumors were the principal cancers in the Center of Tunisia. A childhood cancer registry with high-resolution data collection is advocated for in-depth analysis of pediatric malignancies. PMID- 21545227 TI - Primary pleuropulmonary neoplasms in childhood: fourteen cases from a single center. AB - BACKGROUND: We aimed to review clinical characteristics, treatment results and outcome of pediatric patients with primary pleuropulmonary neoplasms. METHODS: Medical records of 14 cases diagnosed between 1972-2009 were reviewed retrospectively. RESULTS: The male/female ratio was 5/9 and the mean age at diagnosis was 9.1 years (2-16). All but one were symptomatic, presenting with fever, coughing, dyspnea, or weight loss. One patient presented with hemoptysis, and another with digital clubbing. One mesothelioma was diagnosed incidentally. Some 8/14 patients were initially diagnosed as having pneumonia (median delay in diagnosis of 2.5 months). Diagnoses included pleuropulmonary blastoma (PPB, n = 5), inflammatory pseudotumor (n = 3), mesothelioma (n = 2), mucoepidermoid carcinoma (MEC, n = 2), and carcinoid tumor (n = 2). Patients with PPB underwent surgery and received chemotherapy with or without radiotherapy. Two carcinoid tumor cases underwent surgery, one further received chemotherapy. Patients with mesothelioma were treated with chemotherapy. Inflammatory pseudotumors were all resected. Two cases with MEC received chemotherapy, one after surgery. 2/5 PPB patients survived without recurrence, 3 died; all carcinoid tumors and inflammatory pseudotumors were alive; 1/2 MEC patients was alive after 252 months, the other one was lost without disease; 1/2 mesothelioma patients was alive without disease, the other was died. For all cases, median follow-up was 30.5 months (0.6-252). CONCLUSIONS: Primary pleuropulmonary tumors are rare but clinical presentation can be varied and delay in diagnosis is common. Children with persistent coughs, recurrent pneumonia or hemoptysis should be considered as indicators for early diagnosis, very important because the prognosis of these tumors varies with histology and stage. PMID- 21545228 TI - Survival of patients with transitional cell carcinoma of the urinary bladder in indonesia: a single institution review. AB - OBJECTIVE: To describe for the first time the survival of bladder transitional cell carcinoma (TCC) in Indonesia, according to clinicopathological characteristics. MATERIALS AND METHODS: Retrospective study of bladder TCC survival in a single institution, Cipto Mangunkusumo Hospital, Indonesia's national tertiary referral centre, between the years 1995 and 2005. The Kaplan Meier method was used to determine the overall survival (OS). RESULTS: The evaluable data covered 254 cases of primary bladder TCC, in which 95 (37.4%) were non muscle-invasive bladder cancer (NMIBC), and 159 cases (62.6%) were muscle invasive (MIBC). Of these, 105 cases (41.4%) with a follow-up period up to five years were eligible for survival analysis. The mean age was 56.5 +/- 12.1 years old, with a male to female ratio of 6:1. The 5-year OS for all bladder TCC was 27.6%, with a mean survival time of 32.6 months. For NMIBC, the 5-year OS was 53.8% with a mean survival of 54.5 months. For MIBC, the 5-year OS was 19% with a mean survival of 25.4 months. Regarding pathological stage, the 5-year OS for stage 0, I, II, III, and IV was 83.3%, 45%, 30%, 18.8%, and 9.1%, respectively. CONCLUSION: The overall survival of bladder TCC in Indonesia is low compared to other countries. Possible explanations include the high number of advanced-stage tumours at initial presentation, under-staging, significant number of treatment refusal by our patients, and the non-standardized use of adjuvant therapy in our centre. PMID- 21545229 TI - Monocyte chemoattractant protein-1 modulates invasion and apoptosis of PC-3M prostate cancer cells via regulating expression of VEGF, MMP9 and caspase-3. AB - Prostate cancer is a form of malignancy that is most likely to develop in older males, but because of the propensity to metastasize to parts of the body, particularly the bones, can have a deleterious impact on quality of life. Recently monocyte chemoattractant protein-1 (MCP-1) has been shown to play important role in prostate cancer progression and metastasi. In this study we aimed to investigate the mechanisms underlying its functional roles. In vitro transwell invasion assays with PC-3M prostate cancer cells demonstrated MCP-1 promotion of invasion, while annexin V-FITC and TUNEL confirmed inhibition of apoptosis. Treatment MCP-1 further led to significant upregulation of VEGF and MMP-9 and downregulation of Caspase-3 at both mRNA and protein levels compared with untreated control (P < 0.05), while siRNA mediated knockdown reversed these changes. Taken together, our results indicate important roles of MCP-1 in prostate cancer progression and metastasis and our finding of regulation of VEGF, MMP-9 and Caspase-3 expression open up new possibilities for targeted therapy. PMID- 21545230 TI - Cervical human papilloma virus infection among the general female population in Vietnam: a situation analysis. AB - Human papilloma virus (HPV) is the necessary cause of cervical cancer. This survey used a sample of 1,500 married women aged 15-69 to examine the prevalence of HPV infection and HPV specific types in Vietnam as well as risk factors of HPV infection. Results indicated that the prevalence of HPV infection in Hanoi and HCM was 6.13 and 8.27. The proportion of multiple HPV infection was also higher in HCM than in Hanoi (35.5% vs. 17.4%). Risk factors having significant associations with general HPV infection were early age at first sexual intercourse, number of life time sexual partners and period of use of oral contraceptives. Future implementation of HPV vaccine campaigns in Vietnam should consider the fact that HPV type 58 is common among both Hanoi and HCM populations, which none of the currently available vaccines target. PMID- 21545231 TI - Prevention of mammary carcinogenesis in C3H/OuJ mice by green tea and tamoxifen. AB - BACKGROUND: Tamoxifen (TAM) is useful in the chemoprevention of breast cancer, and green tea catechins, including (-)-epigallocatechin gallate (EGCG), may have similar actions. In this study, we investigated their effects, alone or in combination, on mammary carcinogenesis using breast cancer cells and preneoplastic lesions inC3H/OuJ mice. METHODS: Growth inhibitory effects of EGCG and TAM on MCF-7 cells were evaluated with the anchorage-independent colony forming assay. The effects on mammary tumor carcinogenesis and preneoplastic lesions were assessed in vivo using animals treated with GTE in drinking water (1%, 0.1%), or a tamoxifen pellet (10 mg/ animal, subcutaneously inoculated) or both agents in combination (1%GTE + 10 mg TAM). The number and size of mammary tumors were measured weekly during treatment. At 48 weeks of age, mice were sacrificed for the examination of hyperplastic alveolar nodules (HAN) and argyrophilic nucleolar organizer regions (AgNOR). RESULTS: In the anchorage independent growth assay, EGCG and TAM exhibited dose-dependent antiproliferative effects on MCF-7 cells. In the tumor formation assay, tumor incidences were decreased in the GTE, TAM, and GTE+TAM groups, particularly in the latter, in which no tumors developed. AgNOR counts were also significantly lower in the 1%GTE+TAM compared with the 1%GTE group, suggesting an additional anticarcinogenic effect. CONCLUSION: These data suggest that GTE and TAM, individually and in combination, have potential for chemoprevention of breast cancer. PMID- 21545232 TI - Frequency of genetic alterations observed in cell cycle regulatory proteins and microsatellite instability in gallbladder adenocarcinoma: a translational perspective. PMID- 21545233 TI - Two-layered dissolving microneedles for percutaneous delivery of sumatriptan in rats. AB - A novel transdermal delivery of sumatriptan (ST) was attempted by application of dissolving microneedle (DM) technology. Dextran DM (d-DM) and hyaluronate DM (h DM) were prepared by adding ST solution to dextran solution or hyaluronic acid solution. One DM chip, 1.0 * 1.0 cm, contains 100 microneedle arrays in a 10 * 10 matrix. The mean lengths of DMs were 496.6 +/- 2.9 MUm for h-DM and 494.5 +/- 1.3 MUm for d-DM. The diameters of the array basement were 295.9 +/- 3.9 MUm (d-DM) and 291.7 +/- 3.0 MUm (h-DM), where ST contents were 31.6 +/- 4.5 MUg and 24.1 +/ 0.9 MUg. These results suggest that ST was stable in h-DM. Each DM was administered to rat abdominal skin. The maximum plasma ST concentrations, Cmax, and the areas under the plasma ST concentration versus time curves (AUC) were 44.6 +/- 4.9 ng/ml and 24.6 +/- 3.9 ng . h/ml for h-DM and 38.4 +/- 2.7 ng/ml and 14.1 +/- 1.5 ng . h/ml for d-DM. The bioavailabilities of ST from DMs were calculated as 100.7 +/- 18.8% for h-DM and 93.6 +/- 10.2% for d-DM. Good dose dependency was observed on Cmax and AUC. The stability study of ST in DM was performed for 3 months under four different conditions, -80, 4, 23, and 50 degrees C. At the end of incubation period, they were, respectively, 100.0 +/- 0.3%, 97.8 +/- 0.2%, 98.8 +/- 0.2%, and 100.7 +/- 0.1%. These suggest the usefulness of DM as a noninvaisive transdermal delivery system of ST to migraine therapy. PMID- 21545234 TI - Clinical analysis of the treatment of spinocerebellar ataxia and multiple system atrophy-cerebellar type with umbilical cord mesenchymal stromal cells. AB - BACKGROUND AIMS: The aims of this study were to observe the safety and effectiveness of umbilical cord mesenchymal stromal cells (UC-MSC) in the treatment of spinocerebellar ataxia (SCA) and multiple system atrophy-cerebellar type (MSA-C). METHODS: From October 2009 to September 2010, 14 cases of SCA and 10 cases of MSA-C were given UC-MSC by weekly intrathecal injection, at a dose of 1 * 10(6)/kg four times as one course. All the patients received one course of treatment, except three patients who received two courses. The movement ability and quality of daily life were evaluated with the International Cooperative Ataxia Rating Scale (ICARS) and Activity of Daily Living Scale (ADL) and the scores compared with those before cell therapy. A follow-up of 6-15 months was carried out for all of the patients. RESULTS: The results showed that the ICARS and ADL scores were significantly decreased 1 month after treatment (P < 0.01). The symptoms, including unstable walking and standing, slow movement, fine motor disorders of the upper limbs, writing difficulties and dysarthria, were greatly improved except for one patient, who had no response. The observed side-effects included dizziness (four patients), back pain (two cases) and headache (one case), which disappeared within 1-3 days. During the follow-up, 10 cases remained stable for half a year or longer, while 14 cases had regressed to the status prior to the treatment within 1-14 months (an average of 3 months). CONCLUSIONS: Intrathecal injection of UC-MSC is safe and can delay the progression of neurologic deficits for SCA and MSA-C patients. PMID- 21545235 TI - Polycomb group protein Bmi1 promotes hematopoietic cell development from embryonic stem cells. AB - Bmi1 is a component of the Polycomb repressive complexes and essential for maintaining the pool of adult stem cells. Polycomb repressive complexes are key regulators for embryonic development by modifying chromatin architecture and maintaining gene repression. To assess the role of Bmi1 in pluripotent stem cells and on exit from pluripotency during differentiation, we studied forced Bmi1 expression in mouse embryonic stem cells (ESC). We found that ESC do not express detectable levels of Bmi1 RNA and protein and that forced Bmi1 expression had no obvious influence on ESC self-renewal. However, upon ESC differentiation, Bmi1 effectively enhanced development of hematopoietic cells. Global transcriptional profiling identified a large array of genes that were differentially regulated during ESC differentiation by Bmi1. Importantly, we found that Bmi1 induced a prominent up-regulation of Gata2, a zinc finger transcription factor, which is essential for primitive hematopoietic cell generation from mesoderm. In addition, Bmi1 caused sustained growth and a >100-fold expansion of ESC-derived hematopoietic stem/progenitor cells within 2-3 weeks of culture. The enhanced proliferative capacity was associated with reduced Ink4a/Arf expression in Bmi1 transduced cells. Taken together, our experiments demonstrate distinct activities of Bmi1 in ESC and ESC-derived hematopoietic progenitor cells. In addition, Bmi1 enhances the propensity of ESC in differentiating toward the hematopoietic lineage. Thus, Bmi1 could be a candidate gene for engineered adult stem cell derivation from ESC. PMID- 21545236 TI - A survey of stress among amyotrophic lateral sclerosis care providers. AB - Amyotrophic lateral sclerosis (ALS) is a uniformly fatal disease. In the US, care is concentrated in specialized clinics. ALS health care providers likely experience stress, but levels and associated factors and methods to manage them are not known. A questionnaire was designed to assess levels of emotional stress among ALS clinic providers (neurologists and clinic managers) at time of diagnosis, during care of the patient, and at time of the patient's death. Also included were questions about diagnostic practice patterns. Sixty-eight Muscular Dystrophy Association and ALS Association certified clinics were surveyed with a 47% response rate. Stress levels ranged from very severe to none at the various clinical stages but did not differ significantly between neurologists and managers. Stress tended to be lower in more experienced providers, although not uniformly so for all situations and time-points. Stress reduction techniques were rated as more effective for managers than for neurologists. Providers reported high levels of job satisfaction but a significant number gave consideration to leaving their positions due to stress and operational issues. In conclusion, stress is experienced by ALS clinic providers and managed by a variety of methods but with limited success. PMID- 21545237 TI - Sporadic motor neuron disease in a familial novel SOD1 mutation: incomplete penetrance or chance association? AB - Cu/Zn superoxide dismutase (SOD1) gene mutations have been reported in familial and sporadic amyotrophic lateral sclerosis (ALS). We report a novel G61R SOD1 mutation in a patient with a distinct phenotype including prominent lower motor neuron dysfunction, proximal weakness and atrophy with asymmetrical onset in the thigh and buttock and relentless clinical course. The G61R mutation segregated in three unaffected relatives including the 80-year-old mother and two of the proband's siblings. Potential mechanisms include an autosomal dominant condition with reduced penetrance or a chance association. PMID- 21545239 TI - Feasibility of FDG-PET/CT imaging during concurrent chemo-radiotherapy in patients with locally advanced pancreatic cancer. PMID- 21545238 TI - ALSUntangled No. 10: Luteolin and Lutimax. PMID- 21545240 TI - Dramatic changes in catestatin are associated with hemodynamics in acute myocardial infarction. AB - Acute myocardial infarction (AMI) is characterized by complex neuroendocrine activation. To investigate catestatin profiles, serial catestatin levels were determined by enzyme-linked immunosorbent assay in the first week after AMI in 50 patients. Catestatin levels reduced at admission and negatively correlated with heart rates; it increased significantly on the third day but remained decreased at 1 week and positively with blood pressure. In a subgroup of 20 patients admitted within 4 h after onset, circulating catestatin correlated inversely with norepinephrine. Catestatin might be involved in the course of AMI and act as a tool in monitoring the progression of AMI. PMID- 21545241 TI - Adverse reactions to duloxetine in depression. AB - INTRODUCTION: Untreated or inadequately treated depression is the largest risk factor for suicide. However, treatment with different antidepressants can have considerable adverse effects, including the increase of the frequency of suicidal thoughts and behavior. This review summarizes the frequency and severity of adverse events observed during the treatment of depression with duloxetine and considers their relevance to clinical practice. AREAS COVERED: A comprehensive review of the literature was conducted using PubMed and Medline databases listing data published until December 2010. Articles describing safety and tolerability of duloxetine were selected and reference lists of these articles were scrutinized for further relevant papers. In addition, US and EU Summaries of Product Characteristics were studied. EXPERT OPINION: Treatment with duloxetine was associated with mild to moderate adverse events; sexual dysfunction, nausea, headache, dry mouth, somnolence and dizziness being the most frequent among them. No increase in death from suicide and suicidal thoughts and behavior were detected as compared to placebo. So as to avoid discontinuation syndrome as a consequence of abrupt withdrawal of duloxetine, 2 weeks tapering has been recommended before discontinuation. Overall, duloxetine was found to be well tolerated and can be safely administered even in older patients and in those with concomitant illnesses. PMID- 21545242 TI - Antidepressant use in pregnancy. AB - INTRODUCTION: Depression during pregnancy can affect up to 20% of all women and may be treated effectively with antidepressants. Currently, information on > 20,000 women exposed to antidepressants with pregnancy outcomes is available in the literature. However, there is a continuing fear of physicians prescribing and women taking these drugs during pregnancy, probably due to many of the studies reporting conflicting outcomes and subsequently, the dissemination of these results. AREAS COVERED: The authors searched the literature using Medline, Embase and Reprotox followed by a manual search of retrieved articles and reviews of the topic. The authors then selected key publications in this field which they considered relevant to the subsequent discussion of this topic. EXPERT OPINION: In this review, the authors evaluate the safety of different classes of antidepressants and find no convincing evidence of an increased risk for any adverse outcomes in an appreciable fashion. The authors note that even in studies documenting a potential for harm, the risk is marginal with rarely an odds ratio above 2. Therefore, it is important that each woman discusses the risks/benefits of treatment with her healthcare provider to allow an informed decision to be made based on scientific evidence. PMID- 21545243 TI - Smooth pursuit and visual scanpaths: Independence of two candidate oculomotor risk markers for schizophrenia. AB - OBJECTIVES: Smooth pursuit and visual scanpath deficits are candidate trait markers for schizophrenia. It is not clear whether eye tracking dysfunction (ETD) and atypical scanpath behaviour are the product of the same underlying neurobiological processes. We have examined co-occurrence of ETD and scanpath disturbance in individuals with schizophrenia and healthy volunteers. METHODS: Eye movements of individuals with schizophrenia (N = 96) and non-clinical age matched comparison participants (N = 100) were recorded using non-invasive infrared oculography during smooth pursuit in both predictable (horizontal sinusoid) and less predictable (Lissajous sinusoid) conditions and a free viewing scanpath task. RESULTS: Individuals with schizophrenia demonstrated scanning deficits in both tasks. There was no association between performance measures of smooth pursuit and scene scanpaths in patient or control groups. Odds ratios comparing the likelihood of scanpath dysfunction when ETD was present, and the likelihood of finding scanpath dysfunction when ETD was absent were not significant in patients or controls in either pursuit variant, suggesting that ETD and scanpath dysfunction are independent anomalies in schizophrenia. CONCLUSION: ETD and scanpath disturbance appear to reflect independent oculomotor or neurocognitive deficits in schizophrenia. Each task may confer unique information about the pathophysiology of psychosis. PMID- 21545244 TI - Does exposure to maternal smoking during pregnancy affect the clinical features of ADHD? Results from a controlled study. AB - OBJECTIVES: Exposure to maternal smoking during pregnancy may be a significant risk factor for attention-deficit/hyperactivity disorder (ADHD) independently of family history of ADHD. The main aim of this study was to examine whether the clinical profile of ADHD differs between children with and without exposure to maternal smoking during pregnancy. METHODS: This was a case-control study of boys and girls with and without ADHD ascertained from psychiatric and paediatric sources. Maternal smoking during pregnancy was defined by interviews with subjects' mothers. Main outcome measures were ADHD symptoms and associated clinical features in children with and without exposure to maternal smoking during pregnancy. RESULTS: No significant differences were found between ADHD children with and without exposure to maternal smoking during pregnancy on clinical characteristics. When these analyses were repeated in the subgroup of subjects without parental history of ADHD, there were also no statistically significant differences found. CONCLUSIONS: Despite adequate statistical power, no significant differences were found between ADHD children with and without exposure in the clinical features of ADHD and associated disorders. Results provide support for the notion that ADHD cases resulting from exposure to maternal smoking during pregnancy have similar clinical profiles as other ADHD cases. PMID- 21545246 TI - Neonatal plasma TSH--estimated upper reference intervals for diagnosis and follow up of congenital hypothyroidism. AB - Age- and method-dependent plasma TSH reference intervals are essential for the diagnosis and management of congenital hypothyroidism. However, accurate reference intervals for plasma TSH have not been adequately defined due to the difficulties in obtaining samples from a healthy paediatric population. To overcome the difficulties in generating such intervals we estimated method dependent plasma TSH upper-reference intervals by determining the blood spot TSH upper-reference interval from newborn blood spot TSH screening data (N = 10,697) and then derived method-dependent conversion factors for blood spot TSH to plasma TSH concentration from paired-blood spot and plasma TSH measurements. The upper reference interval for blood spot TSH of 3.04 mU/L was obtained from the 97.5th centile of the selected data. Using experimentally-derived conversion factors, estimates of plasma TSH upper reference intervals of 7.6, 6.3, 7.3, 8.3 and 6.5 mU/L were obtained for the Siemens Centaur, Abbott Architect, Roche Elecsys E170, Siemens Immulite 2000 and Beckman access HYPERsensitive TSH assays respectively. These estimated method-dependent plasma TSH upper reference intervals will be of great practical use to clinicians to diagnose and to follow up infants found to have increased blood spot TSH concentrations identified by Newborn Screening programmes. PMID- 21545247 TI - Emerging therapies in metastatic bone pain. AB - INTRODUCTION: Current treatment for metastatic bone pain is mainly palliative. Recent insights into the molecular mechanisms involved in bone metastases have led to the identification of promising therapeutic targets. This review offers an update of preclinical and clinical data on new drugs for metastatic bone pain. AREAS COVERED: Biphosphonates are the gold standard of bone-targeted therapy in bone metastases, for their anti-resorptive and analgesic effects. New drugs aim at breaking the 'vicious cycle' of bone metastatic disease, due to the bidirectional interaction between cancer cells and bone microenvironment. Osteoprotegerin, RANK/RANKL interaction, cathepsin K, the Wnt/beta-catenin pathway and sclerostin are emerging targets for modulation of cancer-induced bone desorption. Other promising targets are those expressed in cancer cells that metastasize to bone, including Src, nerve growth factor, endothelin A, TGF-beta and CXCR4. Interesting therapeutic options include targets on nociceptors that innervate the bone, such as TPRV1, Trk and cannabinoid receptors. EXPERT OPINION: Emerging therapies promise, in the next 10 years, a significant expansion in the array of therapeutic options for bone metastases. Most of these drugs are still in an early phase of development. Further clinical trials are needed to support the evidence of their efficacy and tolerability profile. PMID- 21545245 TI - Reduced genual corpus callosal white matter integrity in pathological gambling and its relationship to alcohol abuse or dependence. AB - OBJECTIVE: Magnetic resonance imaging (MRI) studies have demonstrated functional prefrontal cortical (PFC) abnormalities in pathological gambling (PG) and other psychiatric disorders characterized by impaired impulse control; e.g., cocaine dependence and bipolar disorder. These abnormalities are accompanied by impairments in white matter microstructures in the anterior (genual) corpus callosum (CC) in cocaine dependence and bipolar disorder. Prior studies have not examined white matter integrity in PG. We predicted impairments in genual CC white matter in PG. METHODS: Nineteen participants with PG and 19 matched control participants underwent diffusion tensor imaging (DTI) to compare white matter integrity in the CC, as assessed using fractional anisotropy (FA). RESULTS: In PG subjects as compared to control subjects, reduced FA values in the left and right genu of the CC were observed. Multiple regression analyses confirmed that PG status - in addition to age and past alcohol abuse/dependence (AA/AD) - was a significant predictor of genual FA values. Among PG participants, left and right genu FA values were negatively correlated with scores on the Behavioral Activation System Fun-Seeking (BAS-FS) subscale. Limitations. Limitations include a reliance on self-report measures of impulsivity and related constructs and a relatively small sample of PG subjects with past AA/AD. CONCLUSION: Findings of decreased FA values in the genu of the CC in PG subjects suggest that, like with other disorders of behavioral dyscontrol, white matter microstructural abnormalities contribute to the pathophysiology of PG. These differences appear particularly relevant to individuals with remitted AA/AD, highlighting the importance of considering co-occurring substance use disorders when investigating PG. PMID- 21545248 TI - Factors associated with second-hand smoke exposure in young inner-city children with asthma. AB - OBJECTIVES: To examine the association of social and environmental factors with levels of second-hand smoke (SHS) exposure, as measured by salivary cotinine, in young inner-city children with asthma. METHODS: We used data drawn from a home based behavioral intervention for young high-risk children with persistent asthma post-emergency department (ED) treatment (N = 198). SHS exposure was measured by salivary cotinine and caregiver reports. Caregiver demographic and psychological functioning, household smoking behavior, and asthma morbidity were compared with child cotinine concentrations. Chi-square and ANOVA tests and multivariate regression models were used to determine the association of cotinine concentrations with household smoking behavior and asthma morbidity. RESULTS: Over half (53%) of the children had cotinine levels compatible with SHS exposure and mean cotinine concentrations were high at 2.42 ng/ml (SD 3.2). The caregiver was the predominant smoker in the home (57%) and 63% reported a total home smoking ban. Preschool aged children and those with caregivers reporting depressive symptoms and high stress had higher cotinine concentrations than their counterparts. Among children living in a home with a total home smoking ban, younger children had significantly higher mean cotinine concentrations than older children (cotinine: 3-5 year olds, 2.24 ng/ml (SD 3.5); 6-10 year olds, 0.63 ng/ml (SD 1.0); p < .05). In multivariate models, the factors most strongly associated with high child cotinine concentrations were increased number of household smokers (beta = 0.24) and younger child age (3-5 years) (beta = 0.23; p < .001, R(2) = 0.35). CONCLUSION: Over half of the young inner-city children with asthma were exposed to SHS, and caregivers are the predominant household smokers. Younger children and children with depressed and stressed caregivers are at significant risk of smoke exposures, even when a household smoking ban is reported. Further advocacy for these high-risk children is needed to help caregivers quit and to mitigate smoke exposure. PMID- 21545251 TI - Targeted next-generation sequencing: microdroplet PCR approach for variant detection in research and clinical samples. PMID- 21545249 TI - The efficacy and tolerability of inhaled montelukast plus inhaled mometasone compared with mometasone alone in patients with chronic asthma. AB - BACKGROUND: The efficacy of oral montelukast in chronic asthma is well established. Montelukast is also an effective adjunctive therapy to inhaled corticosteroids (ICS) in asthma uncontrolled on ICS alone. Inhaled montelukast was recently shown to provide significant bronchodilation compared with placebo in patients with chronic asthma. The purpose of this study was to evaluate the efficacy of inhaled montelukast added to inhaled mometasone. METHODS: This was an 8-week, multicenter, randomized, double-blind, placebo-controlled study comparing once-daily inhaled montelukast 1 mg plus inhaled mometasone 220 MUg (delivered by separate dry powder inhalers) with placebo plus inhaled mometasone 220 MUg. Men and women aged 15-85 years with chronic asthma, forced expiratory volume in 1 second (FEV(1)) 50-80% of the predicted value, and beta-agonist reversibility >=12% were eligible. Patients were required to meet a minimum symptom threshold while receiving open-label inhaled mometasone during a 3-week prestudy/run-in period. Patients received blinded (montelukast vs. placebo) treatment for 2 weeks, entered a 1-week washout period, then crossed over to the other treatment for 2 weeks. The primary endpoint was the average change from baseline in FEV(1) over the 2-week treatment period. Secondary endpoints included daytime and nighttime symptom scores. Other endpoints included short-acting beta-agonist (SABA) use, asthma exacerbations, asthma control, peak expiratory flow (PEF), and blood eosinophil count. RESULTS: A total of 134 patients were randomized. For the primary endpoint, change from baseline in FEV(1), inhaled montelukast plus inhaled mometasone was significantly more effective than placebo plus inhaled mometasone (least squares mean 0.22 L vs. 0.17 L; p = .033 [two-sided at alpha = 0.05]). Inhaled montelukast plus inhaled mometasone was also significantly more effective than placebo plus inhaled mometasone in improving daytime asthma symptom scores (p = .005) and nighttime asthma symptom scores (p = .015), increasing the percentage of days with asthma control (p = .004), decreasing the percentage of days with asthma exacerbations (p <= .001), and decreasing the blood eosinophil count (p = .013). Differences were not significant on AM or PM PEF or SABA use, although the latter approached significance (p = .073). Both treatments were well tolerated. CONCLUSION: Inhaled montelukast plus inhaled mometasone was significantly more effective than placebo plus inhaled mometasone in improving FEV(1), symptoms, asthma control, and blood eosinophil count. PMID- 21545252 TI - Helicobacter pylori molecular diagnosis. PMID- 21545253 TI - Transferrin crowned as new biomarker for sporadic Creutzfeldt-Jakob disease. PMID- 21545254 TI - Minimal residual disease testing to predict relapse following transplant for AML and high-grade myelodysplastic syndromes. AB - Evaluation of: Lange T, Hubmann M, Burkhardt R et al. Monitoring of WT1 expression in PB and CD34(+) donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning. Leukemia 25, 498-505 (2011). Early detection of relapse is critical for patients who have undergone hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) or high-grade myelodysplastic syndromes (MDS), since therapy can be initiated while disease burden remains low. As these neoplasms represent a heterogeneous group of malignancies with distinct underlying mutations, no single genetic marker exists that both defines AML/MDS and can be exploited for sensitive detection of neoplastic cells prior to overt hematologic relapse. Conversely, the Wilms' tumor gene (WT1) expression level is increased in blasts of most AML/MDS patients, and quantitative analysis of WT1 expression has been used to predict relapse following myeloablative HSCT. In this article, we review a recently published study evaluating the usefulness of multiple markers, including WT1 expression, for predicting relapse in AML/MDS patients following reduced-intensity conditioning nonmyeloablative HSCT. PMID- 21545255 TI - Regulating molecular diagnostic assays: developing a new regulatory structure for a new technology. AB - Molecular diagnostics are playing an increasingly important part in the practice of medicine. However, molecular diagnostics have not yet made the clinical impact that many had predicted. Multiple factors affect the uptake and utilization of molecular diagnostics, including government regulation. Current regulatory systems were not developed to optimize regulation of molecular diagnostics. This article recommends areas that should be carefully evaluated and appropriately revised, including risk assessment, review criteria and facilitating product improvements. The adoption of molecular diagnostics will be advanced as regulatory criteria become more predictable and their application becomes more consistent between products and over time. PMID- 21545256 TI - Urine molecular profiling distinguishes health and disease: new methods in diagnostics? Focus on UPLC-MS. AB - Urine may be a waste product, but it contains an enormous amount of information. Its role in diagnostics cannot be underestimated. The combination of high-end analytical technology with multivariate statistics allows differential analysis of replicate samples with applications for both high- and low-molecular-weight analytes, namely proteins and metabolites. Global urine profiles measured with NMR or mass spectrometry (MS)-based methods distinguish, for example, individuals, health status and hormonal changes. They do not necessarily discriminate between substance classes but investigate method-determined subgroups, such as all compounds separated by reversed-phase liquid chromatography. For diagnostics, the identification of those compounds is of secondary interest because the overall features of the profile itself are used for sample comparison. The potential of this simple approach for clinical diagnostics is huge, since only minimal urine preparation (e.g., centrifugation and filtration for liquid chromatography-MS) is necessary and the experimental execution using, for instance, technologies such as ultra-performance liquid chromatography coupled with high-end MS can be standardized. However, concerted collaborative efforts are required to generate comparable datasets and to create the profile database necessary for diagnostic applications. PMID- 21545257 TI - Applications of electrowetting-based digital microfluidics in clinical diagnostics. AB - Digital microfluidics based on electrowetting is a type of microfluidic platform in which liquids are processed as individual unit-sized droplets that are dispensed from a source, merged together, split apart or transported between locations on demand. These devices are implemented using arrays of surface electrodes to control the shape and position of droplets through the electrowetting effect. A major thrust of digital microfluidics research has been the development of integrated lab-on-a-chip devices to perform clinical in vitro diagnostic assays. A variety of preparatory and analytical processes have been implemented and feasibility has been demonstrated for test types ranging from clinical chemistries to immunoassays, nucleic acid tests and cell-based assays. In this article, the current state and future potential of digital microfluidics for clinical diagnostic testing is reviewed and evaluated. PMID- 21545258 TI - Expecting the unexpected: nucleic acid-based diagnosis and discovery of emerging viruses. AB - Extrapolation from recent disease history suggests that changes in the global environment, including virus, vector and human behavior, will continue to influence the spectrum of viruses to which humans are exposed. In this article, these environmental changes will be enumerated, and their potential impact on target-focused, nucleic acid-based diagnostic tests will be considered, followed by a presentation of some emerging technological responses. PMID- 21545259 TI - Next-generation sequencing applied to molecular diagnostics. AB - Next-generation sequencing technologies have begun to revolutionize the field of cancer genetics through rapid and accurate assessment of a patient's DNA makeup with minimal cost. These technologies have already led to the realization of the inter- and intra-tumor genetic heterogeneity and the identification of novel mutations and chimeric genes, however, several challenges lie ahead. Given the low number of recurrent somatic genetic aberrations in common types of cancer, the identification of 'driver' genetic aberrations has proven challenging. Furthermore, implementation of next-generation sequencing and/or some of its derivatives into routine practice as diagnostic tests will require in-depth understanding of the pitfalls of these technologies and a great degree of bioinformatic expertise. This article focuses on the contribution of next generation sequencing technologies to diagnosis and cancer prognostication and prediction. PMID- 21545260 TI - Implications of genomic instability in the diagnosis and treatment of breast cancer. AB - Tumorigenesis is a multistep process resulting from DNA mutations observed at the DNA sequence and chromosome level as well as epigenetic changes, which affect expression of oncogenes and tumor suppressor genes. Breast cancer is a very heterogeneous disease that manifests in various histological and clinical types. Defects in the biological action of the genome driven by various alterations, such as point mutations and chromosomal rearrangements, lead to the collapse of genome integrity, uncontrolled cell proliferation and failure in apoptotic cell death. Detailed profiling of breast cancer-associated genomic alterations is indispensable for the design of individualized anticancer therapy, by suggesting diagnostic and prognostic criteria as well as the outcome of applied treatment. Among various directions of cancer research, identification of genomic alterations in breast cancer and their translation into clinical applications is at the forefront. PMID- 21545262 TI - Severity of locomotor and cardiovascular derangements after experimental high thoracic spinal cord injury is anesthesia dependent in rats. AB - Anesthetics affect outcomes from central nervous system (CNS) injuries differently. This is the first study to show how two commonly used anesthetics affect continuously recorded hemodynamic parameters and locomotor recovery during a 2-week period after two levels of contusion spinal cord injury (SCI) in rats. We hypothesized that the level of cardiovascular depression and recovery of locomotor function would be dependent upon the anesthetic used during SCI. Thirty two adult female rats were subjected to a sham, 25-mm or 50-mm SCI at T3-4 under pentobarbital or isoflurane anesthesia. Mean arterial pressure (MAP) and heart rate (HR) were telemetrically recorded before, during, and after SCI. Locomotor function recovered best in the 25-mm-injured isoflurane-anesthetized animals. There was no significant difference in locomotor recovery between the 25-mm injured pentobarbital-anesthetized animals and the 50-mm-injured isoflurane anesthetized animals. White matter sparing and extent of intermediolateral cell column loss appeared larger in animals anesthetized with pentobarbital, but this was not significant. There were no differential effects of anesthetics on HR and MAP before SCI, but recovery from anesthesia was significantly slower in pentobarbital-anesthetized animals. At the time of SCI, MAP was acutely elevated in the pentobarbital-anesthetized animals, whereas MAP decreased in the isoflurane-anesthetized animals. Hypotension occurred in the pentobarbital anesthetized groups and in the 50-mm-injured isoflurane-anesthetized group. In pentobarbital-anesthetized animals, SCI resulted in acute elevation of HR, although HR remained low. Return of HR to baseline was much slower in the pentobarbital-anesthetized animals. Severe SCI at T3 produced significant chronic tachycardia that was injury severity dependent. Although some laboratories monitor blood pressure, HR, and other physiological variables during surgery for SCI, inherently few have monitored cardiovascular function during recovery. This study shows that anesthetics affect hemodynamic parameters differently, which in turn can affect functional outcome measures. This supports the need for a careful evaluation of cardiovascular and other physiological measures in experimental models of SCI. Choice of anesthetic should be an important consideration in experimental designs and data analyses. PMID- 21545263 TI - Black tea and theaflavins suppress various inflammatory modulators and i-NOS mediated nitric oxide synthesis during gastric ulcer healing. AB - The modulation of the cyclooxygenase-independent pathway by black tea (BT) and its constituent theaflavins (TFs) during their healing action against indomethacin-induced stomach ulceration in mice was investigated. On the 3(rd) day of its administration, indomethacin (18 mg/kg) induced maximum stomach ulceration, which was associated with increased myeloperoxidase (MPO) activity (93.3%, p<0.001), and inducible nitric oxide synthase (iNOS) expression (1.6 fold, p<0.001), along with augmented levels of serum nitrite (1.5-fold, p<0.001), selectins and cell adhesion molecules (CAMs), as well as reduced endothelial nitric oxide synthase (eNOS) expression (60%, p<0.001). Treatment with BT (40 mg/kg) and TF (1 mg/kg) for 3 days reversed these parameters and provided excellent (78-81%) ulcer healing. However, alterations of NOS expressions and levels of selectins and CAMs were only partially responsible for the excellent healing capacity (~80%) of omeprazole (3 mg/kg * 3 days). PMID- 21545264 TI - Neutrophil gelatinase-associated lipocalin: a new antioxidant that exerts its cytoprotective effect independent on Heme Oxygenase-1. AB - Neutrophil Gelatinase-Associated Lipocalin (NGAL/Lcn2), a member of the lipocalin family, has a variety of functions. There are extensive studies examining the expression of NGAL under harmful conditions. However, its precise function remains poorly understood. Heme Oxygenase 1 (HO-1) is an enzyme with well established cytoprotective effects. Previous work showed that NGAL induces expression of HO-1. Interestingly, the same stimuli induced the expression of both NGAL and HO-1. The current study was designed to (1) determine whether NGAL exerts its cytoprotective effect through HO-1 and (2) compare NGAL and HO-1 with each other in terms of their protective role against oxidative stress. The current data indicate that NGAL exerts its cytoprotective effect independent of HO-1 and protects cells against oxidative stress more efficiently than HO-1. The data also strongly suggest that induction of NGAL under harmful conditions is a compensatory response to ameliorate oxidative stress-mediated toxicity. These findings may suggest new applications of NGAL, particularly when oxidative stress is a major factor. PMID- 21545266 TI - Availability of O(2) and H(2)O(2) on pre-photosynthetic Earth. AB - Old arguments that free O(2) must have been available at Earth's surface prior to the origin of photosynthesis have been revived by a new study that shows that aerobic respiration can occur at dissolved oxygen concentrations much lower than had previously been thought, perhaps as low as 0.05 nM, which corresponds to a partial pressure for O(2) of about 4 * 10(-8) bar. We used numerical models to study whether such O(2) concentrations might have been provided by atmospheric photochemistry. Results show that disproportionation of H(2)O(2) near the surface might have yielded enough O(2) to satisfy this constraint. Alternatively, poleward transport of O(2) from the equatorial stratosphere into the polar night region, followed by downward transport in the polar vortex, may have brought O(2) directly to the surface. Thus, our calculations indicate that this "early respiration" hypothesis might be physically reasonable. PMID- 21545267 TI - Whole lichen thalli survive exposure to space conditions: results of Lithopanspermia experiment with Aspicilia fruticulosa. AB - The Lithopanspermia space experiment was launched in 2007 with the European Biopan facility for a 10-day spaceflight on board a Russian Foton retrievable satellite. Lithopanspermia included for the first time the vagrant lichen species Aspicilia fruticulosa from Guadalajara steppic highlands (Central Spain), as well as other lichen species. During spaceflight, the samples were exposed to selected space conditions, that is, the space vacuum, cosmic radiation, and different spectral ranges of solar radiation (lambda >= 110, >=200, >=290, or >=400 nm, respectively). After retrieval, the algal and fungal metabolic integrity of the samples were evaluated in terms of chlorophyll a fluorescence, ultrastructure, and CO(2) exchange rates. Whereas the space vacuum and cosmic radiation did not impair the metabolic activity of the lichens, solar electromagnetic radiation, especially in the wavelength range between 100 and 200 nm, caused reduced chlorophyll a yield fluorescence; however, there was a complete recovery after 72 h of reactivation. All samples showed positive rates of net photosynthesis and dark respiration in the gas exchange experiment. Although the ultrastructure of all flight samples showed some probable stress-induced changes (such as the presence of electron-dense bodies in cytoplasmic vacuoles and between the chloroplast thylakoids in photobiont cells as well as in cytoplasmic vacuoles of the mycobiont cells), we concluded that A. fruticulosa was capable of repairing all space-induced damage. Due to size limitations within the Lithopanspermia hardware, the possibility for replication on the sun-exposed samples was limited, and these first results on the resistance of the lichen symbiosis A. fruticulosa to space conditions and, in particular, on the spectral effectiveness of solar extraterrestrial radiation must be considered preliminary. Further testing in space and under space-simulated conditions will be required. Results of this study indicate that the quest to discern the limits of lichen symbiosis resistance to extreme environmental conditions remains open. PMID- 21545268 TI - Astrophysical ionizing radiation and Earth: a brief review and census of intermittent intense sources. AB - Cosmic radiation backgrounds are a constraint on life, and their distribution will affect the Galactic Habitable Zone. Life on Earth has developed in the context of these backgrounds, and characterizing event rates will elaborate the important influences. This in turn can be a base for comparison with other potential life-bearing planets. In this review, we estimate the intensities and rates of occurrence of many kinds of strong radiation bursts by astrophysical entities, ranging from gamma-ray bursts at cosmological distances to the Sun itself. Many of these present potential hazards to the biosphere; on timescales long compared with human history, the probability of an event intense enough to disrupt life on the land surface or in the oceans becomes large. Both photons (e.g., X-rays) and high-energy protons and other nuclei (often called "cosmic rays") constitute hazards. For either species, one of the mechanisms that comes into play even at moderate intensities is the ionization of Earth's atmosphere, which leads through chemical changes (specifically, depletion of stratospheric ozone) to increased ultraviolet B flux from the Sun reaching the surface. UVB is extremely hazardous to most life due to its strong absorption by the genetic material DNA and subsequent breaking of chemical bonds. This often leads to mutation or cell death. It is easily lethal to the microorganisms that lie at the base of the food chain in the ocean. We enumerate the known sources of radiation and characterize their intensities at Earth and rates or upper limits on these quantities. When possible, we estimate a "lethal interval," our best estimate of how often a major extinction-level event is probable given the current state of knowledge; we base these estimates on computed or expected depletion of stratospheric ozone. In general, moderate-level events are dominated by the Sun, but the far more severe infrequent events are probably dominated by gamma-ray bursts and supernovae. We note for the first time that so-called "short-hard" gamma-ray bursts are a substantial threat, comparable in magnitude to supernovae and greater than that of the higher-luminosity long bursts considered in most past work. Given their precursors, short bursts may come with little or no warning. PMID- 21545269 TI - From the love of peptides to the search for life on Mars, an astrobiology itinerary. PMID- 21545270 TI - A bacterial enrichment study and overview of the extractable lipids from paleosols in the Dry Valleys, Antarctica: implications for future Mars reconnaissance. AB - The Dry Valleys of Antarctica are one of the coldest and driest environments on Earth with paleosols in selected areas that date to the emplacement of tills by warm-based ice during the Early Miocene. Cited as an analogue to the martian surface, the ability of the Antarctic environment to support microbial life-forms is a matter of special interest, particularly with the upcoming NASA/ESA 2018 ExoMars mission. Lipid biomarkers were extracted and analyzed by gas chromatography--mass spectrometry to assess sources of organic carbon and evaluate the contribution of microbial species to the organic matter of the paleosols. Paleosol samples from the ice-free Dry Valleys were also subsampled and cultivated in a growth medium from which DNA was extracted with the explicit purpose of the positive identification of bacteria. Several species of bacteria were grown in solution and the genus identified. A similar match of the data to sequenced DNA showed that Alphaproteobacteria, Gammaproteobacteria, Bacteriodetes, and Actinobacteridae species were cultivated. The results confirm the presence of bacteria within some paleosols, but no assumptions have been made with regard to in situ activity at present. These results underscore the need not only to further investigate Dry Valley cryosols but also to develop reconnaissance strategies to determine whether such likely Earth-like environments on the Red Planet also contain life. PMID- 21545271 TI - Evolution of breast cancer incidence in relation to hormone replacement therapy use in Belgium. AB - BACKGROUND: Recent randomized studies concluded that an increased risk of breast cancer is associated with hormone replacement therapy (HRT). Since then, HRT use has decreased in many countries. Several studies have reported a subsequent decrease in breast cancer incidence. AIM: As Belgium has one of the highest incidences of breast cancer in Europe and has a high rate of HRT use, with differences between regions, we assessed the evolution of breast cancer incidence and HRT sales per region and per regimen. MATERIALS AND METHODS: Breast cancer incidence rates (provided by the Belgian Cancer Registry) and HRT sales data (provided by IMS Health(r)) were analyzed by region, age class and HRT regimens. We also calculated the correlation between breast cancer incidence and HRT sales. RESULTS: Breast cancer incidence decreased from 2003 onwards in Flanders, Brussels and Wallonia, especially in the age group 50-69 years. In the same three regions, HRT use decreased by half from 2002 onwards. Greater decreases were observed for estrogens combined with androgenic progestins, estrogens only and estrogens prescribed with a separate progestin. The correlation between breast cancer incidence rates and HRT sales in the previous year was 0.55 (p=0.04), but, when adjusted for the number of women in the age class 40-69 years in each region, the correlation was no longer statistically significant (r=0.39, p=0.17). CONCLUSION: Although many arguments support the hypothesis that the drop in breast cancer incidence can be partly explained by the decrease in HRT use, we were unable to find a strong association between the two in Belgium. PMID- 21545272 TI - Impact of surgical menopause on lipid and bone metabolism. AB - OBJECTIVE: To clarify the effects of ovariectomy on lipid and bone metabolism. METHODS: This study was a prospective study with a longitudinal design within 1 year after surgery. Sixty-two premenopausal women were recruited and divided into two groups: group M (preservation of ovary, n=27) and group BSO (bilateral ovariectomy, n=35). Serum lipid levels, urinary N-telopeptide of type I collagen (NTx) and bone mineral density (BMD) were measured. We also examined the number of postoperative episodes requiring pharmacological intervention. RESULTS: There was a significant elevation in the level of low density lipoprotein cholesterol in group BSO from 6 to 12 months compared with the baseline level; the level did not change in group M. The NTx level significantly increased from 6 to 12 months, and the BMD was significantly decreased by as much as 6.7% at 12 months in group BSO; these variables did not change in group M. The effect of lipid and bone metabolism in group BSO was observed when the ages of the two groups were matched. Carbohydrate metabolism and arterial stiffness, measured by pulse wave velocity, did not change throughout the study period in either group. No subjects in group M required medication expect for two patients whose ovarian function was diminished by postoperative radiation and by natural menopause. Eleven women received medication in group BSO: nine for climacteric disorders using hormone therapy (25.7%), and two for dyslipidemia using statins (5.7%). CONCLUSIONS: Bilateral ovariectomy seems to cause dyslipidemia and serious loss of bone mineral density within only 1 year, and patients who lose ovarian function may require careful medical care. PMID- 21545273 TI - Improvement in HDL cholesterol in postmenopausal women supplemented with pumpkin seed oil: pilot study. AB - OBJECTIVE: Pumpkin seed oil is rich in phytoestrogens and animal studies suggest that there is some benefit to supplementation in low estrogen conditions. This study is the first to evaluate the benefit of pumpkin seed oil in postmenopausal women. METHODS: This pilot study was randomized, double-blinded and placebo controlled. Study participants included 35 women who had undergone natural menopause or had iatrogenically entered the climacteric due to surgery for benign pathology. Wheat germ oil (placebo; n = 14) and pumpkin seed oil (n = 21) were administered to eligible participants over a 12-week period at a dose of 2 g per day. Serum lipids, fasting plasma glucose and blood pressure were measured and an 18-point questionnaire regarding menopausal symptoms was administered; the atherogenic index was also calculated. Differences between groups, as well as before and after the period of supplementation, were evaluated with Student's t test, Wilcoxon matched-pair signed-ranked test and Mann-Whitney test, as appropriate (Stata version 10.1). RESULTS: Women receiving pumpkin seed oil showed a significant increase in high density lipoprotein cholesterol concentrations (0.92 +/- 0.23 mmol/l vs. 1.07 +/- 0.27 mmol/l; p = 0.029) and decrease in diastolic blood pressure (81.1 +/- 7.94 mmHg vs. 75.67 +/- 11.93 mmHg; p < 0.046). There was also a significant improvement in the menopausal symptom scores (18.1 +/- 9.0 vs. 13.2 +/- 6.7; p < 0.030), with a decrease in severity of hot flushes, less headaches and less joint pains being the main contributors. Women in the group receiving wheat germ oil reported being more depressed and having more unloved feeling. CONCLUSION: This pilot study showed pumpkin seed oil had some benefits for postmenopausal women and provided strong evidence to support further studies. PMID- 21545274 TI - Mitochondrial mayhem: the mitochondrion as a modulator of iron metabolism and its role in disease. AB - The mitochondrion plays vital roles in various aspects of cellular metabolism, ranging from energy transduction and apoptosis to the synthesis of important molecules such as heme. Mitochondria are also centrally involved in iron metabolism, as exemplified by disruptions in mitochondrial proteins that lead to perturbations in whole-cell iron processing. Recent investigations have identified a host of mitochondrial proteins (e.g., mitochondrial ferritin; mitoferrins 1 and 2; ABCBs 6, 7, and 10; and frataxin) that may play roles in the homeostasis of mitochondrial iron. These mitochondrial proteins appear to participate in one or more processes of iron storage, iron uptake, and heme and iron-sulfur cluster synthesis. In this review, we present and critically discuss the evidence suggesting that the mitochondrion may contribute to the regulation of whole-cell iron metabolism. Further, human diseases that arise from a dysregulation of these mitochondrial molecules reveal the ability of the mitochondrion to communicate with cytosolic iron metabolism to coordinate whole cell iron processing and to fulfill the high demands of this organelle for iron. This review highlights new advances in understanding iron metabolism in terms of novel molecular players and diseases associated with its dysregulation. PMID- 21545276 TI - Human epigenome data reveal increased CpG methylation in alternatively spliced sites and putative exonic splicing enhancers. AB - The role of gene body methylation, which represents a major part of methylation in DNA, remains mostly unknown. Evidence based on the CpG distribution associates its presence with nucleosome positioning and alternative splicing. Recently, it was also shown that cytosine methylation influences splicing. However, to date, there is no methylation-based data on the association of methylation with alternative splicing and the distribution in exonic splicing enhancers (ESEs). We presently report that, based on the computational analysis of the Human Epigenome Project data, CpG hypermethylation (>80%) is frequent in alternatively spliced sites (particularly in noncanonical) but not in alternate promoters. The methylation frequency increases in sequences containing multiple putative ESEs. However, significant differences in the extent of methylation are observed among different ESEs. Specifically, moderate levels of methylation, ranging from 20% to 80%, are frequent in SRp55-binding elements, which are associated with response to extracellular conditions, but not in SF2/ASF, primarily responsible for alternative splicing, or in CpG islands. Finally, methylation is more frequent in the presence of AT repeats and CpGs separated by 10 nucleotides and lower in adjacent CpGs, probably indicating its dependence on helical formations and on the presence of nucleosome positioning-related sequences. In conclusion, our results show the regulation of methylation in ESEs and support its involvement in alternative splicing. PMID- 21545279 TI - New appointments to the Surgical Infections editorial board. PMID- 21545280 TI - Scoring system development and validation for initial treatment failure in suppurative kidney infections. AB - BACKGROUND: Suppurative kidney infections (SKIs) have potentially lethal implications and a high incidence of treatment-related morbidity and death. Until this point, there has been no study that has derived a prognostic model for adverse early outcomes in SKI. Therefore, our aim was to derive and validate a simple scoring system of early treatment failure in SKI. METHODS: Logistic regression and bootstrap methods were used to create an integer score for estimating the risk of early treatment failure using patient characteristics, severity of disease, bacterial etiology, type of pathology, initial antibiotic therapy, and early urologic procedures. RESULTS: This study included 92 adult patients with 104 SKIs. Early treatment failure was observed in 57 patients (54.8%). The length of the hospital stay and the treatment complications were significantly longer and more common, respectively, in patients with early treatment failure. The factors associated most strongly with early treatment outcome were whether there had been an early complete urologic procedure, the adequacy of early antibiotic therapy, and the presence or absence of sepsis syndrome. The total possible score ranged from 0 to 22 points, with a cut-off value of 5 points. A score of <= 5 points identified early success correctly in 85.3% of patients, whereas a score > 5 points correctly identified early failure in 93.2%. The scoring system retained its predictive ability on the validation set. CONCLUSION: A scoring system was created to predict early treatment failure for a given patient with SKI. Although the system has good performance characteristics and provides a possible intervention measure, further studies should be performed before widespread implementation. PMID- 21545277 TI - Re-orientation of clinical research in traumatic brain injury: report of an international workshop on comparative effectiveness research. AB - During the National Neurotrauma Symposium 2010, the DG Research of the European Commission and the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) organized a workshop on comparative effectiveness research (CER) in traumatic brain injury (TBI). This workshop reviewed existing approaches to improve outcomes of TBI patients. It had two main outcomes: First, it initiated a process of re-orientation of clinical research in TBI. Second, it provided ideas for a potential collaboration between the European Commission and the NIH/NINDS to stimulate research in TBI. Advances in provision of care for TBI patients have resulted from observational studies, guideline development, and meta-analyses of individual patient data. In contrast, randomized controlled trials have not led to any identifiable major advances. Rigorous protocols and tightly selected populations constrain generalizability. The workshop addressed additional research approaches, summarized the greatest unmet needs, and highlighted priorities for future research. The collection of high-quality clinical databases, associated with systems biology and CER, offers substantial opportunities. Systems biology aims to identify multiple factors contributing to a disease and addresses complex interactions. Effectiveness research aims to measure benefits and risks of systems of care and interventions in ordinary settings and broader populations. These approaches have great potential for TBI research. Although not new, they still need to be introduced to and accepted by TBI researchers as instruments for clinical research. As with therapeutic targets in individual patient management, so it is with research tools: one size does not fit all. PMID- 21545281 TI - Anaerobic coverage in intra-abdominal and biliary infections. PMID- 21545282 TI - Extracorporeal membrane oxygenation in the context of the 2009 H1N1 influenza A pandemic. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) incorporates surgical techniques as adjuncts in the management of refractory respiratory dysfunction. For many years, its primary application was for support of neonatal infants in cardiorespiratory failure. As the 2009 H1N1 influenza A pandemic developed, more reports came in of severe respiratory dysfunction and even death that seemed to be occurring preferentially in younger adults. Centers with the capability began to use ECMO to salvage these patients. RESULTS: The H1N1 virus is a subtype of influenza A. The hemagglutinin receptor binding is similar to that of the seasonal influenza virus, but 2009 H1N1 also binds to alpha2,3-linked receptors, which are found in the conjunctivae, distal airways, and alveolar pneumocytes. Influenza viruses elude host immune responses through drift and shift in the hemagglutinin (HA) and neuraminidase (NA) proteins. The incubation period ranges from 1-7 days. The majority of patients present with fever and cough, but a broad spectrum of clinical syndromes has been reported, and laboratory testing remains the mainstay of diagnosis. Most patients recover within a week without treatment. The H1N1 virus remains largely sensitive to the NA inhibitors but is resistant to the matrix protein-2 inhibitors. Extracorporeal membrane oxygenation provides continuous pulmonary (and sometimes cardiac) support and minimizes ventilator induced lung injury. The potential for life-threatening complications is high. In 2009, in the Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR) randomized trial of ECMO, the overall survival rate was 63% in the ECMO group compared with 47% in the control group (p = 0.03). Similar studies have been reported from Australia and New Zealand, Canada, and France. CONCLUSIONS: Supportive management is continued along with ECMO. Antiviral drugs and antimicrobial agents should be given as appropriate, as should nutritional support. Volume management should be used. Ventilator settings should be reduced as ECMO support allows, with a goal of reducing airway pressures, ventilator rate, and FiO(2). Complications of ECMO are common. Bleeding, the most common, can result in death, especially if it occurs intracranially. PMID- 21545283 TI - Respice, adspice, and prospice. AB - The title, "Look to the past, Look to the present, and Look to the future," the motto of City College of New York, expresses how my family life and education led me to an academic career in physical chemistry and ultimately to a study of proteins. The economic depression of the 1930s left a lasting impression on my outlook and career aspirations. With fortunate experiences at several stages in my life, I was able to participate in the great adventure of the last half of the twentieth century: the revolution in biology that advanced the field of protein chemistry to so great an extent. The future is bright and limitless, with greater understanding of biology yet to come. PMID- 21545285 TI - Proton-pumping mechanism of cytochrome C oxidase. AB - Cytochrome c oxidase (CcO), as the terminal oxidase of cellular respiration, coupled with a proton-pumping process, reduces molecular oxygen (O(2)) to water. This intriguing and highly organized chemical process represents one of the most critical aspects of cellular respiration. It employs transition metals (Fe and Cu) at the O(2) reduction site and has been considered one of the most challenging research subjects in life science. Extensive X-ray structural and mutational analyses have provided two different proposals with regard to the mechanism of proton pumping. One mechanism is based on bovine CcO and includes an independent pathway for the pumped protons. The second mechanistic proposal includes a common pathway for the pumped and chemical protons and is based upon bacterial CcO. Here, recent progress in experimental evaluations of these proposals is reviewed and strategies for improving our understanding of the mechanism of this physiologically important process are discussed. PMID- 21545284 TI - Decision making in living cells: lessons from a simple system. AB - The life cycle of bacteriophage lambda serves as a simplified paradigm for cell fate decisions. The ongoing quantitative, high-resolution experimental investigation of this life cycle has produced some important insights in recent years. These insights have to do with the way cells choose among alternative fates, how they maintain long-term memory of their gene-expression state, and how they switch from one stable state to another. The recent studies have highlighted the role of spatiotemporal effects in cellular processes and the importance of distinguishing chemical stochasticity from possible hidden variables in cellular decision making. PMID- 21545286 TI - Protein self-organization: lessons from the min system. AB - One of the most fundamental features of biological systems is probably their ability to self-organize in space and time on different scales. Despite many elaborate theoretical models of how molecular self-organization can come about, only a few experimental systems of biological origin have so far been rigorously described, due mostly to their inherent complexity. The most promising strategy of modern biophysics is thus to identify minimal biological systems showing self organized emergent behavior. One of the best-understood examples of protein self organization, which has recently been successfully reconstituted in vitro, is represented by the oscillations of the Min proteins in Escherichia coli. In this review, we summarize the current understanding of the mechanism of Min protein self-organization in vivo and in vitro. We discuss the potential of the Min oscillations to sense the geometry of the cell and suggest that spontaneous protein waves could be a general means of intracellular organization. We hypothesize that cooperative membrane binding and unbinding, e.g., as an energy dependent switch, may act as an important regulatory mechanism for protein oscillations and pattern formation in the cell. PMID- 21545287 TI - Amphipols from A to Z. AB - Amphipols (APols) are short amphipathic polymers that can substitute for detergents to keep integral membrane proteins (MPs) water soluble. In this review, we discuss their structure and solution behavior; the way they associate with MPs; and the structure, dynamics, and solution properties of the resulting complexes. All MPs tested to date form water-soluble complexes with APols, and their biochemical stability is in general greatly improved compared with MPs in detergent solutions. The functionality and ligand-binding properties of APol trapped MPs are reviewed, and the mechanisms by which APols stabilize MPs are discussed. Applications of APols include MP folding and cell-free synthesis, structural studies by NMR, electron microscopy and X-ray diffraction, APol mediated immobilization of MPs onto solid supports, proteomics, delivery of MPs to preexisting membranes, and vaccine formulation. PMID- 21545288 TI - Neuroprotection with an erythropoietin mimetic peptide (pHBSP) in a model of mild traumatic brain injury complicated by hemorrhagic shock. AB - Pyroglutamate helix B surface peptide (pHBSP) is an 11 amino acid peptide, designed to interact with a novel cell surface receptor, composed of the classical erythropoietin (EPO) receptor disulfide linked to the beta common receptor. pHBSP has the cytoprotective effects of EPO without stimulating erythropoiesis. Effects on early cerebral hemodynamics and neurological outcome at 2 weeks post-injury were compared in a rat model of mild cortical impact injury (3m/sec, 2.5 mm deformation) followed by 50 min of hemorrhagic hypotension (MAP 40 mm Hg for 50 min). Rats were randomly assigned to receive 5000 U/kg of EPO, 30 MUg/kg of pHBSP, or an inactive substance every 12 h for 3 days, starting at the end of resuscitation from the hemorrhagic hypotension, which was 110 min post-injury. Both treatments reduced contusion volume at 2 weeks post-injury, from 20.8+/-2.8 mm(3) in the control groups to 7.7+/-2.0 mm(3) in the EPO-treated group and 5.9+/-1.5 mm(3) in the pHBSP-treated group (p=0.001). Both agents improved recovery of cerebral blood flow in the injured brain following resuscitation, and resulted in more rapid recovery of performance on beam balancing and beam walking tests. These studies suggest that pHBSP has neuroprotective effects similar to EPO in this model of combined brain injury and hypotension. pHBSP may be more useful in the clinical situation because there is less risk of thrombotic adverse effects. PMID- 21545289 TI - Development and licensure of medical countermeasures for platelet regeneration after radiation exposure. PMID- 21545291 TI - Medical countermeasures for platelet regeneration after radiation exposure. Report of a workshop and guided discussion sponsored by the National Institute of Allergy and Infectious Diseases, Bethesda, MD, March 22-23, 2010. AB - The events of September 11, 2001 and their aftermath increased awareness of the need to develop medical countermeasures (MCMs) to treat potential health consequences of a radiation accident or deliberate attack. The medical effects of lethal exposures to ionizing radiation have been well described and affect multiple organ systems. To date, much of the research to develop treatments for mitigation of radiation-induced hematopoietic damage has focused on amelioration of radiation-induced neutropenia, which has long been considered to be the primary factor in determining survival after an unintentional radiation exposure. Consistent with historical data, recent studies have highlighted the role that radiation-induced thrombocytopenia plays in radiation mortality, yet development of MCMs to mitigate radiation damage to the megakaryocyte lineage has lagged behind anti-neutropenia approaches. To address this gap and to foster research in the area of platelet regeneration after radiation exposure, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored a workshop on March 22-23, 2010 to encourage collaborations between NIAID program awardees and companies developing pro-platelet approaches. NIAID also organized an informal, open discussion between academic investigators, product development contractors, and representatives from the U.S. Food and Drug Administration (FDA) and other relevant government agencies about drug development toward FDA licensure of products for an acute radiation syndrome indication. Specific emphasis was placed on the challenges of product licensure for radiation/nuclear MCMs using current FDA regulations (21 CFR Parts 314 and 601) and on the importance of animal efficacy model development, design of pivotal protocols, and standardization of irradiation and animal supportive care. PMID- 21545292 TI - Chasing free radicals in cells and tissues. PMID- 21545290 TI - AT1 receptor antagonism does not influence early radiation-induced changes in microglial activation or neurogenesis in the normal rat brain. AB - Blockers of the renin-angiotensin-aldosterone system (RAAS) ameliorate cognitive deficits and some aspects of brain injury after whole-brain irradiation. We investigated whether treatment with the angiotensin II type 1 receptor antagonist L-158,809 at a dose that protects cognitive function after fractionated whole brain irradiation reduced radiation-induced neuroinflammation and changes in hippocampal neurogenesis, well-characterized effects that are associated with radiation-induced brain injury. Male F344 rats received L-158,809 before, during and after a single 10-Gy dose of radiation. Expression of cytokines, angiotensin II receptors and angiotensin-converting enzyme 2 was evaluated by real-time PCR 24 h, 1 week and 12 weeks after irradiation. At the latter times, microglial density and proliferating and activated microglia were analyzed in the dentate gyrus of the hippocampus. Cell proliferation and neurogenesis were also quantified in the dentate subgranular zone. L-158,809 treatment modestly increased mRNA expression for Ang II receptors and TNF-alpha but had no effect on radiation-induced effects on hippocampal microglia or neurogenesis. Thus, although L-158,809 ameliorates cognitive deficits after whole-brain irradiation, the drug did not mitigate the neuroinflammatory microglial response or rescue neurogenesis. Additional studies are required to elucidate other mechanisms of normal tissue injury that may be modulated by RAAS blockers. PMID- 21545293 TI - A wearable respiratory biofeedback system based on generalized body sensor network. AB - Wearable medical devices have enabled unobtrusive monitoring of vital signs and emerging biofeedback services in a pervasive manner. This article describes a wearable respiratory biofeedback system based on a generalized body sensor network (BSN) platform. The compact BSN platform was tailored for the strong requirements of overall system optimizations. A waist-worn biofeedback device was designed using the BSN. Extensive bench tests have shown that the generalized BSN worked as intended. In-situ experiments with 22 subjects indicated that the biofeedback device was discreet, easy to wear, and capable of offering wearable respiratory trainings. Pilot studies on wearable training patterns and resultant heart rate variability suggested that paced respirations at abdominal level and with identical inhaling/exhaling ratio were more appropriate for decreasing sympathetic arousal and increasing parasympathetic activities. PMID- 21545294 TI - Molecular mechanisms underlying chemopreventive activities of glycyrrhizic acid against UVB-radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. AB - Glycyrrhizic acid has been shown to possess anti-inflammation, antiviral and chemoprotective activity against tumors. We evaluated the protective effects of glycyrrhizic acid in UVB-radiation-induced skin tumor formation in SKH-1 hairless mice and the early molecular biomarkers of these effects. Mice irradiated at 180 mJ/cm2 twice per week showed 100% tumor incidence in 20 weeks. Feeding with glycyrrhizic acid prior to UVB irradiation caused delays in tumor appearance, multiplicity and size. Feeding with glycyrrhizic acid for 2 weeks before a single UVB irradiation (180 mJ/cm2) resulted in significant decrease in UVB-radiation induced thymine dimer-positive cells, expression of proliferative cell nuclear antigen (PCNA), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, and apoptotic sunburn cells together with an increase in p53- and p21/Cip1-positive cell populations in epidermis. Simultaneously, glycyrrhizic acid also significantly inhibited NF-kappaB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and nitric oxide (NO) levels. Thus glycyrrhizic acid ameliorates UVB-radiation-induced tumorigenesis via downregulation of cell proliferation controls involving thymine dimer, PCNA, apoptosis and transcription factor NF-kappaB and of inflammatory responses involving COX-2, PGE2 and NO while upregulating of p53 and p21/Cip1 to prevent DNA damage and facilitate DNA repair. PMID- 21545295 TI - Concurrent validity of a computer-based cognitive screening tool for use in adults with HIV disease. AB - As the incidence of HIV-associated dementia has decreased, the survival of HIV infected individuals with milder forms of cognitive impairment has increased. Detecting this milder impairment in its earliest stages has great clinical and research importance. We report here the results of an initial evaluation of the Computer Assessment of Mild Cognitive Impairment (CAMCI((r))), a computerized screening tool designed to assess abnormal cognitive decline with reduced respondent and test administrator burden. Fifty-nine volunteers (29 HIV infected; age=50.9 years; education=14.9 years; 36/59 males) completed the CAMCI((r)) and a battery of neuropsychological tests. The CAMCI was repeated 12 and 24 weeks later. The results from the CAMCI were compared to Global and Domain Impairment scores derived from the full neuropsychological test battery. The CAMCI detected mild impairment (compared with normal and borderline test performance) with a sensitivity of 0.72, specificity of 0.97, positive predictive rate of 0.93, and a negative predictive rate of 0.89. Median stability over 12 and 24 weeks of follow up was 0.32 and 0.46, respectively. These rates did not differ as a function of serostatus. A discriminant function analysis correctly classified 90% of the subjects with respect to their overall Global Impairment Rating from six of the CAMCI scores. This preliminary study demonstrates that the CAMCI is sensitive to mild forms of cognitive impairment, and is stable over 24 weeks of follow-up. A larger trial to obtain risk-group appropriate normative data will be necessary to make the instrument useful in both clinical practice and research (e.g., clinical trials). PMID- 21545297 TI - Lentivirus-mediated RNA interference targeting Bax inhibitor-1 suppresses ex vivo cell proliferation and in vivo tumor growth of nasopharyngeal carcinoma. AB - Bax inhibitor-1 (Bi-1), an anti-apoptotic protein that belongs to the Bcl-2 family, plays an important role in the mitochondrial apoptosis pathway to suppress Bax-induced apoptosis. In several human cancers, including nasopharyngeal carcinoma, its expression was found to be increased; however, up regulated expression of this protein has been linked to increased cell proliferations. In this study, we down-regulated the gene expression of Bi-1 in nasopharyngeal carcinoma cells by using a lentivirus transfection system packed with short hairpin RNA targeting Bi-1 and used an in vivo model to assess its efficacy as a target in human gene therapy. The data indicated that human malignant nasopharyngeal carcinoma cells, CNE-1 and SUNE-1, transfected with lentiviral short hairpin RNA targeting Bi-1 grew more slowly and showed a higher degree of apoptosis. Moreover, the tumorigenicity of CNE-1 was significantly suppressed when inoculated mice were intratumorically injected with the same vector. Taken together, these data lead us to conclude that Bi-1 plays a crucial role in CNE-1 tumorigenesis and that Bi-1 may be a novel therapeutic target for nasopharyngeal carcinoma. PMID- 21545296 TI - Testing and linkage to care outcomes for a clinician-initiated rapid HIV testing program in an urban emergency department. AB - The urban emergency department is an important site for the detection of HIV infection. Current research has focused on strategies to increase HIV testing in the emergency department. As more emergency department HIV cases are identified, there need to be well-defined systems for linkage to care. We conducted a retrospective study of rapid HIV testing in an urban public emergency department and level I trauma center from June 1, 2008, to March 31, 2010. The objectives of this study were to evaluate the increase in the number of tests and new HIV diagnoses resulting from the addition of targeted testing to clinician-initiated diagnostic testing, describe the demographic and clinical characteristics of patients with newly diagnosed HIV infection, and assess the effectiveness of an HIV clinic based linkage to care team. Of 96,711 emergency department visits, there were 5340 (5.5%) rapid HIV tests performed, representing 4827 (91.3%) unique testers, of whom 62.4% were male and 60.8% were from racial/ethnic minority groups. After the change in testing strategy, the median number of tests per month increased from 114 to 273 (p=0.004), and the median number of new diagnoses per month increased from 1.5 to 4 (p=0.01). From all tests conducted, there were 65 new diagnoses of HIV infection (1.2%, 95% confidence interval [CI] 0.9%, 1.5%). The linkage team connected over 90% of newly diagnosed and out-of care HIV-infected patients to care. In summary, the addition of targeted testing to diagnostic testing increased new HIV case identification, and an HIV clinic based team was effective at linkage to care. PMID- 21545298 TI - A comprehensive evaluation of the toxicology of cigarette ingredients: inorganic compounds. AB - CONTEXT: Two ammonia compounds, diammonium phosphate and ammonium hydroxide, are typically used in the processing or flavoring of tobacco used in the manufacture of cigarettes. OBJECTIVE: A battery of tests was used to compare the toxicity of mainstream smoke from experimental cigarettes containing different added levels of diammonium phosphate (target maximal inclusion level, 50,000 ppm) or both ammonium hydroxide (target maximal inclusion level 11,160 ppm) and diammonium phosphate. MATERIALS AND METHODS: The tests included analytical chemistry, with over 40 constituents in mainstream cigarette smoke; in vitro bacterial (Salmonella) mutagenicity and cytotoxicity (neutral red uptake) assays, and 90 day smoke inhalation studies using rats. Diammonium phosphate acted as a burn retardant, and consequently, the highest planned inclusion level could not be used. Ammonium hydroxide could not be added to cigarettes at meaningfully different levels. RESULTS: Apart from a substantial reduction in smoke concentrations of formaldehyde seen in the smoke chemistry analysis and animal exposure characterization, there were very few endpoints in any of the analyses that showed significant differences as a result of the addition of either of the two ammonia compounds. These differences, when present, occurred only sporadically, with no evidence of any dose-response relationships. CONCLUSION: The results of these experiments show that the ammonia compounds, diammonium phosphate and ammonium hydroxide, when added to cigarette tobacco, even at high inclusion levels, have minimal toxicological sequelae. PMID- 21545299 TI - Insights from a multi-year program designed to test the impact of ingredients on mainstream cigarette smoke toxicity. AB - CONTEXT: Cigarette tobacco ingredients may alter the distribution of chemical constituents present in smoke. When considering the toxicological relevance of potential ingredient-related effects on chemical and biological measurements assessing cigarette smoke toxicity, it is critical to understand the intrinsic variability of tobacco and cigarette smoke that is influenced by the environmental conditions during growing, agricultural practices during preparation, cigarette manufacturing tolerances, and stability of the assay methods. OBJECTIVE: To understand possible effects of ingredients on cigarette smoke toxicity, various chemical and biological endpoints were measured in smoke from experimental cigarettes (added ingredient) to the intrinsic variability of control cigarettes (no added ingredient). MATERIALS AND METHODS: Data were collected during a multi-year program testing a variety of cigarette ingredients from several chemical classes. Chemical analysis of mainstream cigarette smoke,and biological procedures (Salmonella mutagenicity, cytotoxicity, and smoke inhalation) were performed using validated and controlled laboratory methods. The within-study and temporal variation of control cigarettes manufactured in parallel with experimental cigarettes was calculated and used to measure intrinsic variability. RESULTS: The overwhelming majority of data generated from experimental cigarettes fell within the experiment variability represented by the pooled standard error of the entire multi-year dataset for the control cigarettes. CONCLUSION: The results of this evaluation add to a growing body of the literature regarding a weight of evidence assessment of cigarette ingredient toxicity. When assessed against the variability of assay methodology, natural agricultural change, and manufacturing control, the ingredients studied here demonstrated little relevant influence on the mainstream cigarette smoke toxicity endpoints measured. PMID- 21545300 TI - Determinants of enamel decalcification during simulated orthodontic treatment. AB - OBJECTIVE: To determine the relative effects that phosphoric acid etching, metal brackets, composite resin adhesives, and filled resin sealants have on enamel decalcification. MATERIALS AND METHODS: One hundred and fifty teeth were randomly divided into six groups to test the effects of acid etching, brackets, and a composite resin adhesive. The right side of each tooth was sealed. The teeth were submitted to a simulated carious challenge by Streptococcus mutans in a nutritive media for 42 days. Scanning electron photomicrographs (SEMs) were used to qualitatively evaluate the tooth surfaces. DIAGNOdent laser fluorescence was used to quantify the decalcification changes that occurred. RESULTS: SEMs showed normal enamel on the control teeth, etching patterns on the acid-etched teeth, surface degradation on the teeth that had resin, and sealant tags on the sealed side. The untreated control group showed significantly less decalcification (P <= .05) than did all groups except the no etch+bracket group. The no etch+bracket group showed significantly less decalcification than did the etch+bracket, no etch+resin, and the etch+resin groups. Acid-etched teeth demonstrated significantly more decalcification (34%) than did those that were not etched. The teeth with resin showed significantly more decalcification (24%) than did those without resin. There was no significant difference between teeth that did and did not have brackets. The unsealed side of the teeth showed small amounts of--but significantly more--decalcification (5%) compared to the sealed side. CONCLUSIONS: Acid etching and composite resin adhesives increase enamel decalcification in vitro, while brackets do not. Filled resin sealants protect the teeth from decalcification. PMID- 21545301 TI - In vitro evaluation of self-etch bonding in orthodontics using cyclic fatigue. AB - OBJECTIVE: To evaluate the bond strength of a self-etch bonding system using static loading and cyclic fatigue with shear testing. This is a two-part evaluation; the first part will evaluate shear testing, the second part tensile testing. MATERIALS AND METHODS: Bovine teeth (n = 82) were randomly distributed to either a self-etch (Transbond Plus) or total-etch (37% phosphoric-acid + Transbond XT) group. The static shear (SSBS) and cyclic shear (CSBS) bond strengths were measured 24 hours after the bonding of mesh-based brackets. The adhesive remnant index (ARI) and failure sites were evaluated. RESULTS: The mean SSBS was 34.25 +/- 9.21 and 24.64 +/- 9.42 MPa for the total- and self-etch groups, respectively. CSBS was 24.07 +/- 0.65 MPa and 18.92 +/- 1.08 MPa for the total- and self-etch groups, respectively. Cyclic loading produced lower bond strengths compared to static testing for both adhesives; the difference was only statistically significant for the total-etch system. Comparison of the two materials showed a statistically significant difference between the two techniques. The total-etch had higher bond strengths than the self-etch bonding system. The samples showed a predominance of ARI scored of 2 and 1, and their bonding failure sites were cohesive within the composite. CONCLUSION: Cyclic loading, simulating occlusal forces, reduces the bond strength of both bonding systems. Even though the self-etch bonding system had lower shear bond strength than the total-etch system, both were still clinically acceptable. PMID- 21545303 TI - Abstracts of the Thirty-first Annual Meeting of the Surgical Infection Society. Palm Beach, Florida, USA. May 11-14, 2011. PMID- 21545304 TI - Genetics of Alzheimer's disease: an insight into presenilins and apolipoprotein E instigated neurodegeneration. AB - Alzheimer's disease (AD) has long been characterized primarily by extracellular deposition of Abeta protein. It is a genetically intricate neurodegenerative disorder. Presenilins (PSs) (presenilin 1 [ PS1] and presenilin 2 [PS2]) and apolipoprotein E (APOE) epsilon4 allele have been found to be potentially linked to Abeta accumulation and accrual in turn contributing for the AD pathology, despite their significant role in processing of amyloid precursor protein (APP) and lipid metabolism. In this review, the role of PSs and APOE in general physiology and AD pathology due to the mutations occurring in them has been discussed. In addition, a few animal models employed to study these mutations and a few therapeutic avenues studied were summarized. PMID- 21545305 TI - Role of cerebellohypothalamic GABAergic projection in mediating cerebellar immunomodulation. AB - Our previous studies have shown that the cerebellar interposed nucleus (IN) modulates lymphocyte functions. As the cerebellum does not have a direct contact with the immune system, it is required to explore the pathway mediating the cerebellar immunomodulation. In this study, both lymphocyte percentage in peripheral leukocytes and lymphocyte proliferation induced by concanavalin A were reduced by the bilateral IN lesions with kainic acid. Anterograde tracing of nerve tracts with biotinylated dextran amine (BDA) from the cerebellum to the hypothalamus revealed that the BDA-labeled fibers from the cerebellar IN neurons traveled through superior cerebellar peduncle (SCP), crossed in SCP decussation, and primarily terminated in lateral hypothalamic area (LHA). Retrograde tracing with wheat germ agglutinin-horseradish peroxidase from the LHA to the cerebellar IN combined with immunohistochemistry for gamma-aminobutyric acid (GABA) or glutamate in the cerebellar sections displayed that the neuronal projections from the cerebellar IN to the LHA mostly were GABAergic. Blockage of GABA(A) receptors in the LHA with hydrastine led to a reduction in the lymphocyte percentage and proliferation, similar to the IN lesions. These results show a direct GABAergic projection from cerebellar IN to LHA and suggest that the projection mediates cerebellar immunomodulation. PMID- 21545302 TI - Genetics of nonsyndromic orofacial clefts. AB - With an average worldwide prevalence of approximately 1.2/1000 live births, orofacial clefts are the most common craniofacial birth defects in humans. Like other complex disorders, these birth defects are thought to result from the complex interplay of multiple genes and environmental factors. Significant progress in the identification of underlying genes and pathways has benefited from large populations available for study, increased international collaboration, rapid advances in genotyping technology, and major improvements in analytic approaches. Here we review recent advances in genetic epidemiological approaches to complex traits and their applications to studies of nonsyndromic orofacial clefts. Our main aim is to bring together a discussion of new and previously identified candidate genes to create a more cohesive picture of interacting pathways that shape the human craniofacial region. In future directions, we highlight the need to search for copy number variants that affect gene dosage and rare variants that are possibly associated with a higher disease penetrance. In addition, sequencing of protein-coding regions in candidate genes and screening for genetic variation in noncoding regulatory elements will help advance this important area of research. PMID- 21545306 TI - Dendritic pathology and spinal loss in the visual cortex in Alzheimer's disease: a Golgi study in pathology. AB - Alzheimer's disease is a neurodegenerative disorder characterized by progressive decline in memory, loss of professional skills, impairment of judgement and behavior, and decline in social performances. In terms of neuropathology, the morphological hallmarks of the disease are the accumulation of alpha-beta peptide and the neurofibrillary degeneration, associated with synaptic alterations, involving mostly the dendritic spines. This study is based on the morphological analysis of 10 brains, 5 of which were obtained from patients who suffered from Alzheimer's disease and 5 from nondemented senile individuals used as control group. The segments taken in major from the occipital lobe were studied with the use of Golgi method, as well as Gallyas' and Bielschowski' s staining methods. In most of the pyramidal cells in the affected brains, there seems to be important spine loss and extensive dendrite pathology. Apical dendrites are distorted and tortuous. Horizontal dendritic arborization is severely decreased leading to an amputated, bell-shaped cell soma. Senile plaques have been often revealed, and neurofibrillary changes have also been noticed. PMID- 21545307 TI - Torque teno mini virus infection and multiple sclerosis. AB - Multiple sclerosis (MS) is a disease of young adults which is characterized by autoimmune demyelination of the central nervous system. Interaction of genetics and environmental factors are required to cause MS. Among the proposed environmental factors for MS, viral infections are thought to play a role in the pathogenesis of the disease. Torque teno mini virus (TTMV), which has recently been shown to infect humans, is a member of circoviridae, and has a circular DNA with 2860 nucleotides. Since there are a few data about the pathogenicity of this virus, this study sought to investigate the presence of TTMV in sera from MS patients and healthy individuals. We studied 149 serum samples from MS patients and 150 sera of healthy individuals. Serum DNA was extracted using phenol chloroform and was subjected to nested polymerase chain reaction. TTMV-DNA was detected in 24 (16%) sera of the healthy blood donors and in 21 (14.1%) samples of the MS patients, where the difference did not reach significance (p > .05). The result of this study could not establish an association between TTMV infection and MS. PMID- 21545308 TI - Acupressure for treating neurological disorders: a systematic review. AB - The objective of this review is to assess the clinical evidence for or against acupressure as a treatment for neurological disorders. We searched the literature from 12 databases from their inception to July 2010. We included any type of controlled clinical trial (CCT) in which patients with neurological disorders were treated with acupressure. The methodological quality of all clinical trials was assessed using the Cochrane risk of bias analysis. In total, two randomized clinical trials (RCTs) and four CCTs were included. Four studies (one RCT and three CCTs) compared the effects of acupressure with routine care or no treatment in patients with stroke and showed significant effects of acupressure on improving patient function and symptoms. One RCT, which compared acupressure with sham acupressure and no treatment in patients with headache, also showed that acupressure significantly reduced headache severity and pain. However, all trials were open to methodological limitations and a high risk of bias. In conclusion, current evidence showing that acupressure is an effective treatment for improving function and symptoms in patients with stroke is limited. However, the evidence is insufficient to draw conclusions concerning the effects of acupressure on other neurological disorders. More rigorous studies are warranted. PMID- 21545309 TI - Regulated hypoxia/reperfusion-dependent modulation of ERK1/2, cPLA2, and Bcl 2/Bax: a potential mechanism of neuroprotective effect of penehyclidine hydrochloride. AB - The activation of event-related kinase 1/2 (ERK1/2) and cytosolic phospholipaseA2 (cPLA2), which can aggravate hypoxia/reoxygenation (H/R) damage related to their downstream Bcl-2/Bax and Caspase-3 pathway, plays a key role in H/R. The M1 receptors could be responsible for activation of ERK1/2. Thus, it seems that the regulation of M1 receptors mediated the ERK1/2; cPLA2-mediated Bcl-2/Bax pathway may be a significant responsive signal in H/R. Penehyclidine hydrochloride (PHC) is an anticholinergic agent with high degree of selectivity for M1 and M3 receptor subtypes, it is reported that PHC has a protective effect against H/R damage. Here we hypothesize and demonstrate that PHC could downregulate the expression of pERK1/2, cPLA2, and Caspase-3, increased the ratio of Bcl-2/Bax. This study may widen the application of PHC and therapeutic agents of stroke. PMID- 21545310 TI - Polyneuropathy due to cyclosporine A in patients with renal transplantation: a case report. AB - BACKGROUND: Calcineurin inhibitor cyclosporine A (CsA) is a potent immunosuppressive agent. The side effects of CsA include nephrotoxicity, hypertension, hypertrichosis, infection, hyperpotassemia, and, to a lower extent, neuropathy. OBJECTIVES: In this case report, we aimed to present a renal transplant patient with polyneuropathy (PNP) due to the use of CsA and with improvement when switched to rapamycin. METHODS: In electromyography, axonal sensory PNP was detected. CsA was stopped and rapamycin was begun. RESULTS: His complaints rapidly improved after using rapamycin. CONCLUSIONS: Patients using CsA should be closely monitored for peripheral neuropathy and in case of toxicity, alternative immunosuppressive agents should be considered. PMID- 21545311 TI - IgA-dominant postinfectious glomerulonephritis: not peculiar to staphylococcal infection and diabetic patients. AB - BACKGROUND: IgA-dominant postinfectious glomerulonephritis (PIGN) is a unique form of PIGN. It has been linked to staphylococcal infection and underlying diabetic glomerulosclerosis. However, the significance of glomerular IgA-dominant deposition in PIGN remains unclear. METHODS: We reported 10 patients with IgA dominant PIGN encountered at a single center, each characterized by subepithelial humps. Their demographic, clinical, and renal biopsy findings were summarized and compared with the data of 32 patients with non-IgA-dominant PIGN. RESULTS: The mean age was 57 years. An immunocompromised background was present in 70% of patients; only one patient had diabetes mellitus. The causative infectious agents included Staphylococcus (30%), Streptococcus (20%), and gram-negative organisms (50%). Decreased serum complement was present in 60%. Increased serum IgA was noted in 75%. The mean peak serum creatinine was 5.1 mg/dL, and 20% required acute dialysis. Diffuse endocapillary-proliferative glomerulonephritis was found in all cases, and three patients also had crescentic glomerulonephritis. Electron microscopy revealed large subepithelial hump-shaped deposits in all cases. At the last follow-up, one patient had died, five had achieved complete recovery, three had persistent renal insufficiency, and one was on chronic dialysis. Compared to patients with non-IgA-dominant PIGN, increased serum IgA was more commonly present in IgA-dominant group (p = 0.007). There were no significant differences in other clinical parameters and outcome between the two groups. CONCLUSIONS: IgA dominant PIGN resembles poststreptococcal glomerulonephritis in its histological spectrum and ultrastructural appearance. Increasing serum IgA may be involved in the pathogenesis of this form of PIGN. Our data suggested that IgA-dominant PIGN was not peculiar to staphylococcal infection and diabetic patients. PMID- 21545312 TI - Prevalence of nasal Staphylococcus aureus carriage in the patients undergoing hemodialysis and evaluation of risk factors and laboratory parameters. AB - BACKGROUND: In this study, we aimed to determine the nasal carriage rate of Staphylococcus aureus and risk factors in hemodialysis (HD) patients. METHODS: One hundred eighty-four HD patients were evaluated. A second sample was taken from the subjects, the wipe samples of whom were isolated as S. aureus. And subjects whose second samples' results were the same were deemed as S. aureus carriers. RESULTS: Fifty-two (28.3%) patients were identified as S. aureus carriers. In the control group, S. aureus carriage has been found out as 14.9% in 116 healthy subjects. The isolation rate of S. aureus has been found statistically significantly high in the age group of 41-61 years. But, methicillin-resistant S. aureus (MRSA) isolation ratio has been statistically high in the group over the age of 61 years. Sepsis history and gastrointestinal system disease development is closely related to bacterial isolation. MRSA isolation ratios have been found high in chronic lung disease patients, diabetic patients, patients with infection history, and patients with impaired general state of health. The carriage ratios have been found higher in the patients who are settled in urban areas, are subjected to dialysis for more than 10 years, and are hospitalized in the past year. However, the difference between the other groups is not statistically significant. CONCLUSIONS: S. aureus carriage must be screened on regular intervals in HD patients. Nasal S. aureus carriage follow-up and treatment is a process that will protect patients from more severe clinical pictures. PMID- 21545313 TI - Beneficial effects of N-acetylcysteine and ebselen on renal ischemia/reperfusion injury. AB - INTRODUCTION: It has been demonstrated that peroxynitrite accompanies acute renal ischemia and contributes to the pathophysiology of renal damage. Therefore, we aimed to investigate the roles of N-acetylcysteine (NAC), a well-known powerful antioxidant, and ebselen (E), a scavenger of peroxynitrite, on renal injury induced by renal ischemia/reperfusion injury (IRI) of rat kidney. MATERIALS AND METHODS: Forty male Sprague-Dawley rats were divided into five groups: sham, renal IRI, renal IRI+NAC, renal IRI+E, and renal IRI+NAC+E. IR injury was induced by 60 min of bilateral renal ischemia followed by 6 h of reperfusion. After reperfusion, kidneys and blood samples were obtained for histopathological and biochemical evaluations. RESULTS: Renal IR resulted in increased malondialdehyde and nitrite/nitrate levels suggesting increased lipid peroxidation and peroxynitrite production and decreased superoxide dismutase and glutathione peroxidase activities. Both NAC and E alone significantly decreased malondialdehyde and nitrite/nitrate levels and increased superoxide dismutase and glutathione peroxidase activities. Additionally in the renal IRI+NAC+E group, all biochemical results were quite close to those of sham group. Histopathologically, the kidney injury in rats treated with combination of NAC and E was found significantly less than the other groups. CONCLUSIONS: Both NAC and E are able to ameliorate IRI of the kidney by decreasing oxidative and nitrosative stresses and increasing free radical scavenger properties. Additionally, combination of NAC and E prevents kidney damage more than when each drug is used alone, suggesting that scavenging peroxynitrite nearby antioxidant activity is important in preventing renal IRI. PMID- 21545314 TI - Induction of an in vitro reversible hypometabolism through chitosan-based nanoparticles. AB - OBJECTIVE: Chitosan-based nanoparticles (NPs) were prepared to promote intracellular sustained delivery of the synthetic delta opioid D-Ala(2)-D-Leu(5) enkephalin (DADLE), prolonging peptide activity and inducing a safe and reversible hypometabolic state. MATERIALS AND METHODS: NPs were prepared by combining ionotropic gelation and ultrasonication treatment. NP uptake studies and the effects of encapsulated DADLE on HeLa cells proliferation were tested by transmission electron microscopy (TEM) analysis, by immuno-fluorescence and immuno-cytochemistry. RESULTS: DADLE-loaded NPs are produced with suitable characteristics, a satisfactory process yield (55.4% +/- 2.4%) and encapsulation efficiency (64.6% +/- 2.1%). NPs are effective in inducing a hypometabolic stasis at a 10(-4) M DADLE concentration. Moreover, as seen from the immunofluorescence study, the effect persists through the recovery period (72 h). Indeed, NPs labelled by anti-enkephalin antibody inside cell nucleus reassert that the in vivo release of the peptide can be prolonged with respect to the case of free peptide supply. CONCLUSION: The nanoparticulate drug delivery system described seems to be effective in inducing and prolonging a sort of hibernation-like state in the cells. PMID- 21545315 TI - In-vitro cytotoxicity and cell uptake study of gelatin-coated magnetic iron oxide nanoparticles. AB - The aim of this study was to modify the surfaces of magnetic iron oxide nanoparticles (IOPs) with gelatin in order to reduce cytotoxicity and enhance cellular uptake. The gelatin-coated IOPs were characterized in terms of their functionalization, size, surface charge, morphology and crystalline structure using Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), dynamic light scattering (DLS), transmission electron microscopy (BIO-TEM) and x-ray diffraction (XRD) analysis. The cytotoxicity of the gelatin-coated IOPs to human fibroblasts was assessed using an MTT-assay and was compared with uncoated IOPs. Similarly, the cellular uptake of the coated and uncoated IOPs was visualized using BIO-TEM and quantified using inductively coupled plasma spectroscopy (ICPS). As shown by the Fourier emission scanning electron microscopy (FE-SEM) and viability test, the massive uptake of uncoated IOPs lead to reduced viability. However, gelatin coating lead to increased viability and slow uptake without any visible distortion to the cell morphology. PMID- 21545316 TI - Synthesis and characterization of new biopolymeric microcapsules containing DEHPA TOPO extractants for separation of uranium from phosphoric acid solutions. AB - A novel microcapsule adsorbent for separation of uranium from phosphoric acid solutions was developed by immobilizing the di(2-ethylhexyl) phosphoric acid trioctyl phosphine oxide extractants in the polymeric matrix of calcium alginate. Physical characterization of the microcapsules was accomplished by scanning electron microscopy and thermogravimetric techniques. Equilibrium experiments revealed that both ion exchange and solvent extraction mechanisms were involved in the adsorption of [Formula: see text] ions, but the latter prevailed in a wider range of acid concentration. According to the results of kinetics study, at low acidity level, the rate controlling step was slow chemical reaction of [Formula: see text] ions with the microdroplets of extractant, whereas it changed to intraparticle diffusion at higher acid concentration. The study also attempted identification of the diffusion paths of the ions within the microcapsules, and the mechanism of change of mass transfer rate during the uptake process. The prepared microcapsules preserved their entire capacity after three cycles of adsorption, and their breakthrough behaviour was well fitted by a new formula derived from shrinking core model. PMID- 21545317 TI - In vitro evaluation of the antioxidant activity of liposomal flavonols by the HRP H2O2-luminol system. AB - Considering that antioxidant flavonols have been reported to be beneficial to human health, but that their low water solubility and bioavailability limit their administration through systemic route, the development of suitable flavonol carriers is of great importance for clinical therapeutics. The aim of this study was to prepare liposomes containing flavonols or not and evaluate their antioxidant activity. Vesicles were obtained by ethanol injection method and characterized in terms of entrapment efficiency, size and zeta potential. Inhibitory activity of liposomal flavonols on reactive oxygen species generation was assessed in vitro using luminol-H(2)O(2)-horseradish peroxidase technique. Antioxidant activity of liposomal flavonols is dependent on concentration and chemical structure of active compound. Quercetin and myricetin are the most active flavonols (IC(50) = 0.6-0.9 umol/L), followed by kaempferol (IC(50) = 3.0 4.5 umol/L) and galangin (IC(50) = 4.0-7.0 umol/L). Our results suggest that antioxidant-loaded liposomes may be promising tools for therapy of diseases where oxidative stress is involved. PMID- 21545318 TI - Preparation, characterization and biodistribution of nanostructured lipid carriers for parenteral delivery of bifendate. AB - Nanostructured lipid carrier (NLC)-loaded bifendate (DDB) was prepared by melt emulsification method to improve drug payloads and liver targeting. The particle size of the prepared formulation analysed by photon correlation spectroscopy (PCS) was 217.4 nm with a narrow polydispersity index (PI) lower than 0.2, meanwhile the loading capacity increased from 4.3% to 15.7% in comparison with DDB-loaded SLN reported in previous study. The zeta potential value was -21.91 mV, and transmission electron microscopy studies revealed NLC of irregularly spherical shape. With respect to lipid polymorphism, a less ordered structure of NLC was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In addition, tissue distribution of DDB-loaded NLC and DDB solution were carried out in Kunming strain mice. In tested organs, the distribution of DDB-loaded NLC to liver was higher than that of free drug. These results support the potential applications of NLC for the delivery of DDB. PMID- 21545319 TI - In vitro anticancer activity of doxorubicin-loaded gelatin-coated magnetic iron oxide nanoparticles. AB - Magnetic drug targeting allows accumulation of drug at a defined target site with the help of an external magnetic field. Current research explored uptake and anticancer activity of doxorubicin-loaded gelatin-coated magnetic iron oxide particles (DXR-GIOPs) in order to investigate potential of gelatin-coated iron oxide particles (GIOPs) as a drug carrier in the field of magnetic drug targeting. The in vitro test was done using HeLa cells as a model cell and DXR as a model drug. The cytotoxicity and uptake of GIOPs were also studied and results were compared with that of DXR-GIOPs. The results indicated that GIOPs were not toxic to HeLa cells even at higher concentration of 1.2 mg/mL; however, DXR-GIOPs showed toxicity in time as well as dose-dependent manner. Furthermore, quantitative and qualitative uptake studies showed higher uptake of DXR-GIOPs compared to GIOPs in the identical condition by the cells. PMID- 21545320 TI - A novel microparticulate vaccine for melanoma cancer using transdermal delivery. AB - In this study, we formulated a microparticulate melanoma cancer vaccine via the transdermal route. The vaccine was delivered using microneedle-based Dermaroller(r) which is available for cosmetic purposes. Unlike subcutaneous injections, administration using microneedles is painless and in general can increase the permeability of many compounds ranging in size from small molecules to proteins and microparticles that do not normally penetrate the skin. The vaccine microparticles were taken up by the antigen presenting cells which demonstrated a strong IgG titre level of 930 ug/mL in serum samples. The formulation increased the immunogenicity of the vaccine by incorporating the antigen into an albumin matrix having a size range of around 0.63-1.4 um which acted as a synthetic adjuvant. The animals were vaccinated with 1 prime and 4 booster doses administered every 14 days over 8 weeks duration, followed by challenge with live tumour cells which showed protection after transdermal vaccination. PMID- 21545321 TI - Chitosan-based macrophage-mediated drug targeting for the treatment of experimental visceral leishmaniasis. AB - The potential of chitosan microparticles as a carrier of doxorubicin for the treatment of visceral leishmaniasis was evaluated by macrophage-mediated drug targeting approach. Cationic charge of doxorubicin was masked by complexing it with dextran sulphate (a poly anion) in order to facilitate its incorporation into cationic chitosan microparticles. Prior to in vitro and in vivo studies, characterization studies were carried out systematically: particle size (~1.049 um), surface morphology (fluorescence microscopy - spherical structured microparticles), Fourier transform infrared spectroscopy (to characterize effective cross-linking) and differential scanning calorimetry. In vitro studies were carried out in J774.1 in order to check the effective endocytotic uptake of microparticles by macrophages. In vivo studies were conducted in Syrian golden hamsters as per well-established protocols and the results drawn from in vivo studies displayed substantial reduction in leishmanial parasite load for doxorubicin-encapsulated chitosan microparticles: ~78.2 +/- 10.4%, when compared to the control (free doxorubicin): 33.3 +/- 2.4%. PMID- 21545322 TI - Effect of decisive formulation variables on bioencapsulation efficiency and integrity of yeast biocapsules for oral itraconazole delivery. AB - Reproducible delivery of drugs through bioencapsulation in cellular carriers is severely limited by biovariability in cellular carriers and effects of decisive formulation variables. Surmounting the constraints in reproducible results, our work explores optimization methodology for precise and reproducible cellular bioencapsulation technology for poorly water soluble drug. Active-dried baker's yeast cells were selected as cellular carriers for poorly soluble antimycotic agent itraconazole (ITZ). Pre-treatment of yeast cells with various techniques exhibited substantial augmentation in bioencapsulation efficiency (%BE). Sequentially optimized values of formulation variables like bioencapsulation temperature (40-50 degrees C), stirring rate (350 rpm) and time (5 h) exhibited highest %BE with desired reproducibility. In comparison with marketed product, bioencapsulated itraconazole demonstrated marked increase in solubility with more than 70% release in 10 min. Compression pressure equivalent to tablet hardness of 2.0-3.5 kg/cm(2) was optimum to maintain integrity of biocapsules. Resulting biocapsules exhibited safe residual solvent content, inertness for fermentation ability and excellent stability at accelerated conditions. PMID- 21545323 TI - The manufacturing techniques of drug-loaded polymeric nanoparticles from preformed polymers. AB - Over the past few decades, nanoparticle (NP) formulation has been the subject of extensive research. The choice of a suitable NP formulation technique is dependent on the physicochemical properties of the drug, such as solubility and chemical stability. Different NP manufacturing methods enable modification of the physicochemical characteristics such as size, structure, morphology and surface texture, but also affect the drug loading, drug entrapment efficiency and release kinetics. This review covers an update on the state of art of the manufacturing of polymeric NPs from preformed polymers. Both, conventional methods for NP preparation, such as spontaneous formulation and emulsification-based methods, and new approaches in NP technology are presented. A comparative analysis is given for polymer, drug and solvent nature, toxicity, purification, drug stability and scalability of the method. The information obtained allows establishing criteria for selecting a method for preparation of NPs according to its advantages and limitations. PMID- 21545326 TI - Ambroise Pare and 16th century neurosurgery. AB - The luminousness of Ambroise Pare, the surgeon-statesman, has withstood the ravages of time as the mark of a man, a hero, a surgeon-par-excellence, and above all, a benevolent philosopher. A self-made individual, his tryst with the art of surgery emanated from the literally non-stop battlefields of 16th century feudal Europe. Although a maverick in the medical world of his times; he rose from the humblest origins to the highest echelons solely as a result of his own genius and diligence. Among his mammoth contributions to the renaissance of surgery, Pare did perform many procedures which we see as neurosurgical, especially in the realms of neurotrauma and paediatric neurosurgery; the present vignette is an attempt to elucidate the same. PMID- 21545327 TI - Delays in treating patients with good grade subarachnoid haemorrhage in London. AB - BACKGROUND AND PURPOSE: Spontaneous aneurysmal subarachnoid haemorrhage (SAH) is managed as a neurosurgical priority with guidelines and published literature emphasising the identification and the treatment of the ruptured aneurysm within 48 h of ictus. We audited the timing of management of good grade (WFNS 1 & 2) SAH in a neurosurgical unit in Greater London. We also reviewed the available services for treating SAH within Greater London. MATERIALS AND METHODS: Retrospective audit of patients admitted with SAH to St. George's Hospital between 31 May 2007 and 31 May 2009 was performed. Prospective telephone and public record review of the catchment area and neurovascular provisions of the seven London neurosurgical units were assessed. RESULTS: There were 141 WFNS grade 1 and 2 SAH patients admitted. Only a quarter were treated within 48 h of ictus. Patients destined for endovascular treatment waited significantly longer periods until treatment when compared with that of clipping group patients. The day of the week on which diagnostic angiography occurred was critical in determining treatment delays, probably due to the lack of routine provision of clipping at weekends and next day coiling services. We estimated that 440 good grade SAH are admitted per annum in Greater London. There are 20 neurovascular surgeons and 16 interventional neuroradiologists across seven neurosurgical units that routinely treat SAH. CONCLUSIONS: We have identified significant delays in treating three quarters of good grade SAH patients in London. This appears to be due to a lack of next day treatment availability. A collaborative strategy between the seven London neurosurgical units could reduce treatment delays. PMID- 21545328 TI - Percutaneous glycerol rhizotomy for trigeminal neuralgia: safety and efficacy of repeat procedures. AB - Percutaneous glycerol rhizotomy (PGR) is an established technique to treat trigeminal neuralgia. Our aim was to establish how safe and efficacious repeat glycerol rhizotomies were on a study of 179 PGRs performed in our institution. There was an overall success rate of 92.1% in improvement of facial pain. Nine patients had reduced facial sensation post-operatively. There were no cases of anaesthesia dolorosa. The mean time to repeat injection was 22.9 months (1-108 months). Of those requiring repeat glycerol rhizotomies within 6 months, 23% had multiple sclerosis. There was no evidence that the number of repeat glycerol rhizotomies affects the probability of them having a complication (p = 0.87). Glycerol rhizotomy for trigeminal neuralgia is a safe and efficacious method of pain relief, which is particularly useful in the elderly. It can be repeated many times with no increase in morbidity and most importantly, in our practice, no anaesthesia dolorosa. PMID- 21545329 TI - An unusual complication following translabyrinthine resection of an acoustic neuroma. AB - We report the case of a 58-year old man who presented with a 4 cm right acoustic neuroma. He underwent a translabyrinthine resection. Two years later he presented with multiple strokes and progressive generalised deterioration. A cerebral angiogram demonstrated an extensive right side cerebellar dural arteriovenous fistula with retrograde flow causing corticovenous reflux. The fistula was treated successfully endovascularly. There is only one published report of a dural arteriovenous fistula occurring following acoustic neuromas surgery. The pathogenesis and management of this unusual complication is discussed. PMID- 21545331 TI - A journey--with acknowledgements. PMID- 21545330 TI - The Isadora syndrome: a case report of cervical, oesophageal and tracheal transection in a go-karting accident. AB - We report a case of cervical spine, tracheal and oesophageal trauma from a go karting injury caused by the patient's scarf catching in the vehicle's wheel. We discuss the significance of the pre-hospital and operative management of this potentially life-threatening injury by a multi-specialty surgical team. The importance of health and safety issues in recreational sports is highlighted in view of the increasing incidence of cervical spine trauma over past two decades. PMID- 21545334 TI - Intensive chemotherapy of metastatic colorectal cancer: weighing between safety and clinical efficacy: Evaluation of Masi G, Loupakis F, Salvatore L, et al. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol 2010;11:845-52. AB - This paper evaluates a recent study whereby a four-drug combination regimen adding bevacizumab to triplet fluorouracil, oxaliplatin and irinotecan chemotherapy is described for the first-line treatment of metastatic colorectal cancer. It extends the use of intensive medical treatments combining chemotherapy and the VEGF inhibitor bevacizumab, opening new perspectives for the design of four-drug intensive regimen-associating chemotherapy and targeted agents. In the future, these four-drug intensive regimens should be further improved for efficacy:toxicity ratio and verification in randomized trials. PMID- 21545335 TI - A new paradigm for the understanding of obesity: the role of stem cells. AB - Obesity is a pandemic disorder that can be defined as a chronic excess of adipose tissue that increases the risk of suffering chronic diseases such as, diabetes, arterial hypertension, stroke and some forms of cancer. We now know that adipose tissue, aside from being an energy store, is also an important endocrine and metabolic organ. Recently, new mechanisms that control obesity have been identified, such as the equilibrium between white and brown adipose tissue, the localization of adipose mass (visceral or ventral), and the presence of adipose and mesenchymal stem cells. In this review, we describe the implication of these stem cell types in the normal physiology and dysfunction of adipose tissue. These stem cells provide a potential target for modulating the response of the body to obesity and diabetes, as well as a potential tool for regenerative medicine. PMID- 21545336 TI - Preparation and characterization of galactose-modified liposomes by a nonaqueous enzymatic reaction. AB - In this study, NOH (NOH = N-octadecyl-4-[(D-galactopyranosyl)oxy]-2,3,5,6 tetrahydroxy hexanamide) was enzymatically synthesized as a targeting molecule and incorporated into liposomes to prepare a liposome surface modified with galactose. Glycyrrhetinic-acid-loaded liposome (GA-LP) and glycyrrhetinic-acid loaded liposome surface modified with galactose (NOH-GA-LP) were prepared by the ethanol-injection method. NOH-GA-LP was characterized by morphology, particle size, zeta potential, encapsulation efficiency, release in vitro, and stability. The size of spherical particles was in the range of 179-211 nm. Spherical particles exhibit a positive electrical charge (38.7 mV) and possess high encapsulation efficiency (91.3%) and show sustained release (72% over 48 hours) in vitro. This novel approach for the liposome surface modified with galactose by enzymatic synthesis is expected to provide potential application as a drug carrier for active targeted delivery to hepatocytes. PMID- 21545337 TI - Incurred sample reanalysis. AB - In this issue of Bioanalysis we have focussed on incurred sample reanalysis, with the aim of providing some examples of incurred sample reanalysis failures and ensuing investigations, to provide a greater shared experience. PMID- 21545338 TI - Incurred sample reanalysis: it is just a matter of good scientific practice. PMID- 21545339 TI - How to manage having no incurred sample reanalysis evaluation failures. PMID- 21545341 TI - Conference Report: Analytical challenges in the qualification and validation of pharmacodynamic biomarkers. AB - This 1-day workshop, held in association with the Royal Society of Chemistry Analytical Biosciences Group, discussed current concepts in the qualification and validation of biomarker assays for the measurement of pharmacodynamic responses to drugs and vaccines. The venue was Burlington House, the prestigious home of the Royal Society of Chemistry, with delegates drawn from academia, pharmaceutical companies and CROs. PMID- 21545342 TI - Bioanalysis Young Investigator: Sadagopan Krishnan. AB - Supervisor's supporting comments. I am pleased to recommend Sadagopan Krishnan for the Bioanalysis Young Investigator award. Sadagopan is a bright, creative and highly-motivated young bioanalytical chemist. His theses in our laboratory involved the development of electrochemiluminescent arrays for chemical toxicity screening utilizing cytochrome P450 metalloenzymes. He was senior author of a paper in Analytical Chemistry on this that was featured on the cover. He also investigated fundamental properties of human metabolic cytochrome P450s - research was carried out at his own initiative, and explains for the first time the role of iron spin state on enzyme electron transfer rates. He then developed thin films that mimic the natural cytochrome P450 redox cycle for the first time. He worked with several other group members to develop a superparamagnetic labeling scheme for immunosensing of proteins by surface plasmon resonance at unprecedented low levels, down to 10 fg/ml. Sadagopan has also demonstrated strong leadership skills. After his PhD, Sadagopan joined the group of Fraser Armstrong at Oxford University, UK, as a postdoctoral fellow. He is currently expanding his research horizons into the area of biofuel cells. His eventual goal is to join the faculty of a major university and build a world-class research group in bioanalytical chemistry. PMID- 21545343 TI - Impact of methylation of acyl glucuronide metabolites on incurred sample reanalysis evaluation: ramiprilat case study. AB - BACKGROUND: Reanalysis of incurred samples showed that the bioanalytical method for the quantification of ramipril and ramiprilat was generating irreproducible results for ramiprilat. RESULTS: An additional peak interfering with ramiprilat was observed in the incurred samples but not in the calibrant and quality control samples. A similar interference was detected for ramipril, but it was chromatographically separated. Interferences were produced during sample preparation, which involves strong cation exchanger cartridges. The interfering products corresponded to the methylation of ramipril and ramiprilat glucuronide. CONCLUSION: Following this discovery, a reproducible method was developed and successfully validated for ramipril and ramiprilat. Additional stability tests were performed in the presence of glucuronide and diketopiperazine metabolites of ramipril and ramiprilat to demonstrate the method specificity. PMID- 21545344 TI - An investigation of incurred human urine sample reanalysis failure. AB - BACKGROUND: In this case study, urine samples were collected and transferred before the presence of a small degree of nonspecific binding was identified for the analyte of interest in human urine. The approach taken to address the issue was to use standards and quality controls to mimic the study samples and use Tween-80 (0.5%) to retrieve the adsorbed analyte. The method was validated, however, the incurred sample reanalysis (ISR) failed. RESULTS: Investigation into the ISR failure unveiled ineffective mixing of the study samples, with almost no headspace left inside the sample tubes after the addition of the surfactant using a regular vortex mixer, as the cause of the ISR failure. All samples were reanalyzed using a modified sample mixing method, which resulted in two successful ISR runs. CONCLUSIONS: Thorough sample mixing after the addition of surfactant is one of the important steps in ensuring accurate and reproducible analyses of urine samples with a small degree of analyte nonspecific binding. PMID- 21545345 TI - Impact of oxcarbazepine sulfate metabolite on incurred sample reanalysis and quantification of oxcarbazepine. AB - BACKGROUND: Recently, incurred sample reanalysis (ISR) has become a requirement in bioanalysis. The general guidance recommends investigating ISR failure to evaluate the suitability of an analytical method. In the case of acceptable ISR evaluation, there were no precise recommendations for further testing when sporadic values were obtained. RESULTS: The ISR evaluation performed during a bioequivalence study for the anticonvulsant drug oxcarbazepine showed acceptable ISR results, but one particular chromatographic anomaly led to a thorough investigation. The finding of these tests showed that an oxcarbazepine phase II metabolite occasionally co-eluted with the drug and impacted oxcarbazepine's quantitation through in-source conversion. CONCLUSION: This paper demonstrates the necessity of rigorous interpretation of ISR results and close monitoring of all subject sample results. PMID- 21545346 TI - Incurred sample accuracy assessment: design of experiments based on standard addition. AB - It is commonly acknowledged that random and systematic analytical errors contribute to poor data quality, and moreover, to imprecise and inaccurate pharmacokinetic parameters. To investigate the random errors in GLP bioanalysis, common ground has been found in today's bioanalysis to assess the reproducibility of the method by reanalyzing part of the incurred samples. The undesired systematic errors in bioanalysis affecting the trueness of the method and leading to inaccurate data remain relatively unattended so far. In order to obtain both precise and accurate data it is suggested in this paper to apply standard addition experiments to calculate the relative systematic errors as an estimate for the incurred sample accuracy. This approach, which can be seen as an important extension to current guidelines in GLP bioanalysis, is illustrated by assessing the accuracy of the bioanalytical results for a bioequivalence study for alendronate. PMID- 21545347 TI - Investigation and resolution of incurred sample reanalysis failures: two case studies. AB - The reanalysis of incurred bioanalytical samples (incurred sample reanalysis) provides additional data that help us to ensure that a 'validated bioanalytical method' is reproducible. While the guidelines for the conduct of incurred sample reanalysis evaluations have been well described, published information pertaining to the occurrence of failures and the manner in which they are resolved has not received the same amount of attention. The purpose of this manuscript is to describe two case studies where incurred sample reanalysis failures were encountered for small molecules, the approaches that were taken to elucidate the root cause of the failures, and the remedial actions that were implemented to prevent such failures from recurring. PMID- 21545348 TI - Incurred sample reanalysis: failures in macromolecule analysis--insight into possible causes. AB - "Good people are good because they've come to wisdom through failure" - William Saroyan. Since the Crystal City III conference considerable effort has been spent defining what constitutes appropriate incurred sample reanalysis analysis. While what to do, such as the number of samples and acceptance criteria, is becoming generally recognized, it is important to step back and examine as a community what we are learning by this exercise. Through discussions with colleagues throughout the industry who specialize in macromolecule analysis, it was clear most incurred sample reanalysis testing passes without issue, but in some cases there are lessons to be learned. We thank all who would share, in confidence, their failures as well as their investigations so as a community we can learn. We would suggest scientist can be substituted for people in the quote from William Saroyan. PMID- 21545349 TI - Incurred sample reanalysis (ISR): a decisive tool in bioanalytical research. AB - The AAPS Workshop 2008 on Current Topics in GLP Bioanalysis: Assay Reproducibility for Incurred Samples was the defining moment in establishing incurred sample reanalysis (ISR) as a mandatory exercise in demonstrating assay reproducibility using incurred (study) samples. The importance of ISR can be envisaged from its role in clinical as well as non-clinical studies. Incurred samples can differ significantly in their composition when compared with the calibration standards and quality control samples that are used to validate the developed method. The present article attempts to summarize five troubleshooting cases encountered in the analyses of incurred samples for bioanalytical methods developed in our laboratory for mesalamine, hydrochlorothiazide, clopidogrel, sildenafil and rabeprazole. The issues identified were related to: sample inhomogeneity, sample processing error, impact of buffer pH during sample preparation, instability of metabolite and change in laboratory environment. The steps taken to trace and correct these incidents are discussed with adequate data. These examples will further broaden the scope and emphasize the significance of ISR. We believe this investigation will help to develop more reliable and efficient bioanalytical methods. PMID- 21545350 TI - GlaxoSmithKline's experience of incurred sample reanalysis for dried blood spot samples. AB - Dried blood spots are becoming a popular alternative to plasma for many different applications. This has been driven by animal ethics but also by ease of use and cost savings. Recent regulatory guidance now has a requirement for incurred sample reanalysis. This article details three examples of incurred sample reanalysis using dried blood spot samples. PMID- 21545351 TI - Beyond successful ISR: case-by-case investigations for unmatched reassay results when ISR passed. AB - Incurred sample reanalysis (ISR) is now commonly practiced in regulated bioanalytical laboratories. With an average ISR success rate of 95% or higher and an increasing number of ISR tests being conducted, more and more situations deserve scientific evaluation or investigation for the unmatched reassay results revealed in ISR tests even though they meet the acceptance criteria. First, should an investigation be initiated when an ISR test is acceptable? How large a discrepancy or what situation would warrant an investigation? What would be the impact on a study? How would investigations regarding unmatched reassay results be conducted? What are the main root causes identified? Can normal random errors cause a large discrepancy in unfavorable combinations? How could the timeline and cost be affected? All these questions are addressed in this paper with five real case examples. PMID- 21545353 TI - Baroreceptor sensitivity, cardiovascular responses and ECG left ventricular hypertrophy in men: the SABPA study. AB - AIM. Research has shown a significant relationship between hypertension and attenuated baroreceptor sensitivity (BRS), which in turn reflects alterations of autonomic control of the cardiovascular system. The objective of this study was to compare the BRS of African and Caucasian men and determine possible associations with blood pressure and left ventricular hypertrophy. MATERIALS AND METHODS. Participants included African (n = 82) and Caucasian (n = 100) male teachers, aged between 20 and 65 years, recruited in the North-West Province, South Africa. Ambulatory blood pressure monitoring was conducted for a 22-23-h period and, thereafter, cardiovascular parameters were recorded with a Finometer and 12-lead ECG during rest and while challenging the cardiovascular system with the cold pressor and Stroop color?word conflict tests. Spontaneous BRS was calculated as well as the Cornell product [marker of left ventricular hypertrophy (LVH)]. RESULTS. The African men had significantly lower BRS stress responses. Attenuated BRS coupled to an ?-adrenergic response pattern predicted elevation of blood pressure in the African men. BRS reduction did not prove to be a significant predictor of LVH. CONCLUSION. Lower BRS, especially during stress, may pose a significant health threat for African men regarding earlier development or promotion of alpha -adrenergic-driven hypertension and greater risk for cardiovascular disease. PMID- 21545354 TI - Dry age-related macular degeneration: recent progress of therapeutic approaches. AB - Age-related macular degeneration (AMD) is a progressive retinal degenerative disease and a common cause of blindness. In AMD, there are two phenotypes; "atrophic (dry)" and "neovascular (wet)". The former is characterized by the geographic atrophy due to death of retinal pigment epithelium, and the latter is developed due to choroidal neovascularization. While wet AMD can be treated by the inhibition of vascular endothelial growth factor or photodynamic therapy, so far there are no available treatments for dry AMD. Fortunately, understanding of pathogenesis in dry AMD has significantly been progressed and many candidates for the treatment of dry AMD have been introduced in clinical trials as well as preclinical stages. In this article, the progress of therapeutic approaches for dry AMD is reviewed. PMID- 21545355 TI - Syntaxin 17 cycles between the ER and ERGIC and is required to maintain the architecture of ERGIC and Golgi. AB - BACKGROUND INFORMATION: Syntaxin 17 is a SNARE (soluble N-ethylmaleimide sensitive-factor-attachment protein receptor) protein that predominantly localizes to the ER (endoplasmic reticulum) and to some extent in the ERGIC (ER Golgi intermediate compartment). Syntaxin 17 has been suggested to function as a receptor at the ER membrane that mediates trafficking between the ER and post-ER compartments. It has a unique 33 amino acid luminal tail whose function is not known. Here we have investigated the structural requirements for localization of syntaxin 17 to the ERGIC and its role in trafficking. RESULTS: Deletion analysis showed that syntaxin 17 required its cytoplasmic domain to exit the ER and localize to the ERGIC. Mutation of a conserved tyrosine residue in the cytoplasmic domain resulted in reduced localization of syntaxin 17 in the ERGIC and ER-exit sites, suggesting the presence of a tyrosine-based ER export motif. Syntaxin 17 also required its C-terminal tail to localize to the ERES (ER exit sites) and ERGIC. Knockdown of syntaxin 17 destabilized the ERGIC organization and also caused fragmentation of the Golgi complex. Syntaxin 17 showed direct interaction with transmembrane proteins p23 and p25 (cargo receptors that cycle between the ER and Golgi) with the help of its C-terminal tail. Overexpression of syntaxin 17 redistributed beta-COP (beta-coatomer protein) which required its C terminal tail. Overexpression of syntaxin 17 also blocked the anterograde transport of VSVG (vesicular stomatitis virus G-protein) in the ERGIC. CONCLUSIONS: We show that syntaxin 17 has a tyrosine-based motif which is required for its incorporation into COPII (coatomer protein II) vesicles, exit from the ER and localization to the ERGIC. Our results suggest that syntaxin 17 cycles between the ER and ERGIC through classical trafficking pathways involving COPII and COPI (coatomer protein I) vesicles, which requires its unique C terminal tail. We also show that syntaxin 17 is essential for maintaining the architecture of ERGIC and Golgi. PMID- 21545356 TI - A scaffold of accessory subunits links the peripheral arm and the distal proton pumping module of mitochondrial complex I. AB - Mitochondrial NADH:ubiquinone oxidoreductase (complex I) is a very large membrane protein complex with a central function in energy metabolism. Complex I from the aerobic yeast Yarrowia lipolytica comprises 14 central subunits that harbour the bioenergetic core functions and at least 28 accessory subunits. Despite progress in structure determination, the position of individual accessory subunits in the enzyme complex remains largely unknown. Proteomic analysis of subcomplex Idelta revealed that it lacked eleven subunits, including the central subunits ND1 and ND3 forming the interface between the peripheral and the membrane arm in bacterial complex I. This unexpected observation provided insight into the structural organization of the connection between the two major parts of mitochondrial complex I. Combining recent structural information, biochemical evidence on the assignment of individual subunits to the subdomains of complex I and sequence-based predictions for the targeting of subunits to different mitochondrial compartments, we derived a model for the arrangement of the subunits in the membrane arm of mitochondrial complex I. PMID- 21545358 TI - The impact of organisational culture on the delivery of person-centred care in services providing respite care and short breaks for people with dementia. AB - Ensuring the development and delivery of person-centred care in services providing respite care and short breaks for people with dementia and their carers has a number of challenges for health and social service providers. This article explores the role of organisational culture in barriers and facilitators to person-centred dementia care. As part of a mixed-methods study of respite care and short breaks for people with dementia and their carers, 49 telephone semi structured interviews, two focus groups (N= 16) and five face-to-face in-depth interviews involving front-line staff and operational and strategic managers were completed in 2006-2007. Qualitative thematic analysis of transcripts identified five themes on aspects of organisational culture that are perceived to influence person-centred care: understandings of person-centred care, attitudes to service development, service priorities, valuing staff and solution-focused approaches. Views of person-centred care expressed by participants, although generally positive, highlight a range of understandings about person-centred care. Some organisations describe their service as being person-centred without the necessary cultural shift to make this a reality. Participants highlighted resource constraints and the knowledge, attitudes and personal qualities of staff as a barrier to implementing person-centred care. Leadership style, the way that managers' support and value staff and the management of risk were considered important influences. Person-centred dementia care is strongly advocated by professional opinion leaders and is prescribed in policy documents. This analysis suggests that person-centred dementia care is not strongly embedded in the organisational cultures of all local providers of respite-care and short-break services. Provider organisations should be encouraged further to develop a shared culture at all levels of the organisation to ensure person-centred dementia care. PMID- 21545357 TI - Protein kinase Czeta phosphorylates occludin and promotes assembly of epithelial tight junctions. AB - Protein kinases play an important role in the regulation of epithelial tight junctions. In the present study, we investigated the role of PKCzeta (protein kinase Czeta) in tight junction regulation in Caco-2 and MDCK (Madin-Darby canine kidney) cell monolayers. Inhibition of PKCzeta by a specific PKCzeta pseudosubstrate peptide results in redistribution of occludin and ZO-1 (zona occludens 1) from the intercellular junctions and disruption of barrier function without affecting cell viability. Reduced expression of PKCzeta by antisense oligonucleotide or shRNA (short hairpin RNA) also results in compromised tight junction integrity. Inhibition or knockdown of PKCzeta delays calcium-induced assembly of tight junctions. Tight junction disruption by PKCzeta pseudosubstrate is associated with the dephosphorylation of occludin and ZO-1 on serine and threonine residues. PKCzeta directly binds to the C-terminal domain of occludin and phosphorylates it on threonine residues. Thr403, Thr404, Thr424 and Thr438 in the occludin C-terminal domain are the predominant sites of PKCzeta-dependent phosphorylation. A T424A or T438A mutation in full-length occludin delays its assembly into the tight junctions. Inhibition of PKCzeta also induces redistribution of occludin and ZO-1 from the tight junctions and dissociates these proteins from the detergent-insoluble fractions in mouse ileum. The present study demonstrates that PKCzeta phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions. PMID- 21545359 TI - Stigma by association: the effects of caring for HIV/AIDS patients in South Africa. AB - The shortage of healthcare workers caring for South Africa's 5-6 million persons living with HIV/AIDS (PLHA) calls for inquiry into workers' challenges and experiences. This exploratory study examines one little-studied challenge: stigmatisation of HIV/AIDS healthcare workers based on their association with PLHA. The authors tested the hypotheses that HIV/AIDS healthcare workers experience stigmatisation due to their association with PLHA, and that such association stigma is correlated with thoughts of leaving the HIV/AIDS field. A sample of 100 participants who provided direct care to PLHA was recruited from a variety of public and private HIV/AIDS care centres in Eastern Cape province, South Africa. Participants attended one of 12 focus groups held between June and August, 2008. They completed a 17-item questionnaire and discussed each item. Findings exhibit the presence of an adverse differentiation and labelling of HIV/AIDS healthcare workers, leading to status loss and discrimination, creating an impetus for HIV/AIDS healthcare workers to leave AIDS work altogether. A significant relationship (chi(2) (TREND) = 3.86, df = 1, P = 0.049) was found between contemplation of leaving AIDS work and perception of others' responses to their work with PLHA. In addition, associations emerged between type of AIDS worker and contemplation of working in AIDS care outside of South Africa (Kruskal Wallis chi(2) = 6.96, df = 2, P = 0.031), with doctors and nurses reporting higher frequency of contemplating leaving South Africa to work with PLHA elsewhere (Mann-Whitney z = -2.53, P = 0.011). The study lays the foundation for additional research on the effects of association stigma. In turn, increased efforts to retain and recruit new HIV/AIDS healthcare workers will expand the pool of healthcare personnel to PLHA. PMID- 21545360 TI - Increasing support for breastfeeding: what can Children's Centres do? AB - Britain has one of the lowest breastfeeding rates in Europe, with particularly low rates among White British families living in disadvantaged communities. As breastfeeding has important long-term health benefits for babies and their mothers, this represents a serious inequality in health. It is part of the remit of Sure Start Children's Centres which serve disadvantaged areas to offer child and family health services, including breastfeeding support. This study utilised an action research strategy to involve stakeholders in developing and extending breastfeeding promotion and support within three Children's Centres in Bristol. A total of 10 focus groups were conducted with Children's Centre staff and local parents between July 2008 and May 2009. Stakeholders' views were explored on current breastfeeding promotion and how Children's Centres could better support breastfeeding to meet local needs. Barriers to breastfeeding promotion were identified as latent hostility in the local community towards breastfeeding, and lack of knowledge about infant feeding among staff. Following implementation of the proposed changes, staff, parents and researchers shared their views on what had been achieved and on possible future initiatives. While there was variation in the extent to which Children's Centres engaged with the action research process, and in the extent to which change was made, all Centres did develop their breastfeeding promotion practice. Initiatives put into practice included strengthening links with health professionals, actively seeking to involve fathers, increasing the breastfeeding peer support offered locally and adopting a clear 'Breastfeeding Welcome' policy. This study has demonstrated that a collaborative action research approach can effectively stimulate the development of breastfeeding promotion and support within Children's Centres, leading to prompt and sustainable changes in practice. PMID- 21545361 TI - Concealed conduction. PMID- 21545362 TI - Narrow complex tachycardia with alternating cycle length: what is the mechanism? PMID- 21545363 TI - "ECG concealment" during left atrial flutter with 2:1 entrance block into the right atrium. PMID- 21545364 TI - Long-term follow-up in patients with presumptive Brugada syndrome treated with implanted defibrillators. AB - INTRODUCTION: Risk stratification for patients with suspected Brugada syndrome (BS) remains difficult. Implantation of cardioverter-defibrillators (ICDs) in high-risk patients provides continuous long-term arrhythmia protection. METHODS: Data of 33 consecutive patients undergoing ICD implantation after BS evaluation between 1995 and 2008 were reviewed. RESULTS: There were 30 (91%) men and 3 (9%) women (46.4 +/- 11.7 years). Type I Brugada was noted in 18 (54.5%), type II in 12 (36.4%) patients, and ST elevation after drug challenge in 3 patients (9.1%). Three patients had prior cardiac arrest; 70% a history of syncope; and 56% ventricular arrhythmias at the electrophysiology study. During 7.9 +/- 3.6 years of follow-up, 2 patients with prior arrest received appropriate ICD shocks. None of the 30 patients without prior arrest had a sustained arrhythmia detected. ICD related adverse effects occurred in 11 (33%) patients, including inappropriate shocks in 5 (15%). Eight patients (24%) developed 11 major device-related complications including subclavian vein thrombosis (1), pericardial effusion (1), lead fracture (2), and infection (2); in 4 patients the only complication was premature battery depletion that required early ICD replacement; however, some of these complications such as lead fractures and early battery depletion may not be specific for this patient cohort and may not repeat in the future. CONCLUSION: Risk stratification for patients with BS for primary prevention remains challenging. The low risk of arrhythmic events that is exceeded by ICD-related adverse effects should inform discussions with patients who do not have a prior history of cardiac arrest. PMID- 21545365 TI - Isolation of hofbauer cells from human term placentas with high yield and purity. AB - PROBLEM Placental villus macrophages (i.e., Hofbauer cells, HBCs) were identified more than 100 years ago. Alterations in their numbers and characteristics are associated with several complications of pregnancy. Although HBCs have previously been isolated and cultured, there is no consensus methodology to obtain these cells with high yield and purity for in vitro studies. METHOD OF STUDY Hofbauer cells were isolated from human term placentas using protocols in which cytotrophoblasts (CTs) and fibroblasts (FIBs), other major villous cell types, were isolated in parallel. Enzymatic digestion, Percoll gradients, and immunoselection were used to isolate the three cell types. Purity was assessed by morphology, flow cytometry, and phagocytosis assays. RESULTS Hofbauer cells were isolated with 98-99% purity and a yield of 130-200 * 10(6) cells/80-100 g of tissue. HBCs exhibited a pleiomorphic and vacuolated appearance for at least 5 days in culture medium with and without serum. High levels of phagocytosis in HBCs, but not in CTs or FIBs, confirmed macrophage function in HBCs. Phagocytotic activity was maintained across several days in culture. CONCLUSION Hofbauer cells were isolated from term placenta with high yield and purity using protocols in which CTs and FIBs were also obtained. This methodology will foster future studies that examine the role of HBCs in regulating villus function. PMID- 21545366 TI - Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin. AB - PROBLEM Women with antiphospholipid antibodies (aPL) are at risk of miscarriage and pre-eclampsia, obstetrical disorders associated with reduced trophoblast invasion and spiral artery transformation. aPL target the placenta by binding beta(2) -glycoprotein I (beta(2) GPI) on the trophoblast. In this study, we determined whether aPL alter the trophoblast secretion of angiogenic factors and evaluated the effect of low molecular weight heparin (LMWH) on this response. METHOD OF STUDY First-trimester trophoblast was treated with anti-beta(2) GPI antibodies with or without LMWH. Angiogenic factor secretion was measured by enzyme-linked immunosorbent assay. RESULTS Trophoblast cells produced more vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), and soluble endoglin following exposure to anti-beta(2) GPI Abs, and this occurred in both a MyD88-dependent and MyD88-independent manner. LMWH was unable to reverse the effects of the anti-beta(2) GPI Abs on trophoblast VEGF secretion, but enhanced PlGF. Strikingly, LMWH upregulated soluble fms-like tyrosine kinase receptor-1 (sFlt-1) secretion independently of aPL. CONCLUSION This study demonstrates that aPL perturb the secretion of trophoblast angiogenic factors. LMWH does not reverse this effect but exacerbates sFlt-1 secretion, a potent anti angiogenic factor. These findings may help to explain why women with antiphospholipid syndrome, who are treated with heparin to prevent early pregnancy loss, remain at increased risk of developing late obstetrical complications, such as pre-eclampsia. PMID- 21545367 TI - Pulmonary angiography with 64-multidetector-row computed tomography in normal dogs. AB - Pulmonary angiography using 64-multidetector-row computed tomography (MDCT) was used to evaluate pulmonary artery anatomy, and determine the sensitivity of pulmonary artery segment visualization in four Beagle dogs using images reconstructed to 0.625 mm and retro-reconstructed to 1.25 and 2.5 mm slice thickness. Morphologically, characteristic features included a focal narrowing in the right cranial pulmonary artery in all dogs, which should not be mistaken as stenosis. While the right cranial pulmonary artery divided into two equally sized branches that were tracked into the periphery of the lung lobe in all dogs, only a single left cranial (cranial portion) lobar artery was present. Compared with 1.25 and 2.5 mm retro-reconstructions, 0.625 mm reconstructions allowed for detection of significantly (P<=0.05) more pulmonary artery segments and sharper depiction of vessel margins. Clinical applications such as prevalence and significance of diameter changes, and detection of pulmonary arterial thrombembolism on lobar and sublobar level, using pulmonary angiography with 64 MDCT applying 0.625 mm reconstruction slice thickness remain to be established. PMID- 21545368 TI - Clinical relevance of abnormal scintigraphic findings of adult equine ribs. AB - Horses with cranial rib abnormalities may exhibit severe acute lameness and may have unusual gait deficits characterized by forelimb abduction during protraction at the walk. Horses with caudal rib abnormalities may resent being saddled and ridden. In a retrospective evaluation of 20 horses with a documented rib lesion, 25 sites of increased radiopharmaceutical uptake were found in one or more ribs. Thirteen (52%) scintigraphic lesions involved the first rib; four were located immediately dorsal to the sternal articulation, eight were near the costochondral junction and one was at the costovertebral junction. Six (24%) scintigraphic rib lesions involved ribs 2-8; one was located immediately dorsal to the sternal articulation, three were at the costovertebral junction and two were near the costochondral junction. Six (24%) scintigraphic rib lesions involved the mid portion (five) or costovertebral junction (one) of ribs 9-18. The 20 horses were divided into three groups based on the clinical relevance of the scintigraphic findings. Group 1 (n=3) horses had clinical signs attributed to a rib abnormality; Group 2 (n=6) horses had a rib abnormality that was a plausible explanation for clinical signs; Group 3 (n=11) horses had clinical signs that could not be attributed to a rib abnormality. For horses with cranial rib abnormalities, a modified lateral scintigraphic image with the ipsilateral limb pulled caudally and a left (right) 45 degrees caudal-right (left) radiograph facilitated the diagnosis. PMID- 21545369 TI - Comparison of point-of-care testing (POCT): i-STAT((r)) international normalized ratio (INR) vs reference laboratory INR in pediatric patients undergoing major surgery. AB - BACKGROUND: The aim of the study was to compare international normalized ratio (INR) results obtained by point-of-care testing (i-STAT(r) device) with the reference laboratory INR in children undergoing major surgery with expected significant blood loss. METHODS: Pediatric patients undergoing craniofacial, spine, hip, or cancer surgery were included. Blood samples for coagulation testing were tested at several intraoperative time points and generally withdrawn from the arterial catheter, if accessible. A volume of 1.4 ml citrated blood was used for the reference laboratory INR test, and 0.1 ml of blood was taken for the whole blood INR test using the i-STAT(r) device. Blood samples for both tests were withdrawn at the same time and immediately analyzed with both devices. RESULTS: A total of 169 paired blood samples were taken intraoperatively from 44 pediatric patients [IQR 0.9-10.7 years (median 3.3)]. Reference laboratory INR ranged from 0.96 to 3.43 (mean 1.40; sd 0.32) and INR of i-STAT(r) from 0.95 to 2.29 (mean 1.26; sd 0.22). The correlation coefficient was 0.83 (P < 0.001), and the bias values were 0.12 and 0.55 at the medical decision level of <=2.0 and >2.0, respectively. CONCLUSIONS: In the perioperative setting, point-of-care INR testing in children using the i-STAT(r) device is a reliable and easy-to-handle method for INR values <=2.0, while INR values >2.0 might be underestimated. PMID- 21545370 TI - Clinical features of healthcare-associated pneumonia (HCAP) in a Japanese community hospital: comparisons among nursing home-acquired pneumonia (NHAP), HCAP other than NHAP, and community-acquired pneumonia. AB - BACKGROUND AND OBJECTIVE: More than 100000 Japanese die of pneumonia every year. The number of people residing in nursing homes is increasing with the ageing of the population. In 2005, the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) published important guidelines for the management of healthcare-associated pneumonia (HCAP). In Japan, however, the optimum strategy for management of HCAP is still unclear. The purpose of this study was to clarify the clinical features of patients with HCAP. METHODS: Patients (n = 202) who were consecutively admitted with a diagnosis of acute pneumonia between October 2007 and September 2009 were retrospectively evaluated. Using the ATS/IDSA guidelines, patients were divided into three groups: a community acquired pneumonia (CAP) group (n = 123), a nursing home-acquired pneumonia (NHAP) group (n = 46) and a HCAP other than NHAP (O-HCAP) group (n = 33). These groups were then compared with respect to laboratory data, microbiological findings and mortality. RESULTS: Thirty-day mortality in the NHAP group (10.9%) tended to be higher than that in the CAP group (3.3%) or the O-HCAP group (0%). The pathogens most frequently identified were Streptococcus pneumoniae and Haemophilus influenzae in the CAP group, methicillin-resistant Staphylococcus aureus and Klebsiella pneumoniae in the NHAP group, and S. pneumoniae and K. pneumoniae in the O-HCAP group. CONCLUSIONS: The NHAP group was clinically different from the O-HCAP group, based on bacteriological examination and mortality rates. In order to accurately diagnose, and formulate optimum treatment strategies for Japanese patients, the categories of HCAP, as specified in the ATS/IDSA guidelines, should not be applied directly either to patients with NHAP or those with O-HCAP. PMID- 21545371 TI - Exhaled nitric oxide and exhaled breath condensate pH as predictors of sputum cell counts in optimally treated asthmatic smokers. AB - BACKGROUND AND OBJECTIVE: Smoking is thought to modify the pattern of airway inflammation. Induced sputum provides useful information on cellular phenotype in inflammatory airways disorders; however, it is time-consuming and difficult to implement in everyday clinical practice. The aim of this study was to determine whether exhaled NO (FeNO) and exhaled breath condensate (EBC) pH differed in asthmatic smokers compared with asthmatic non-smokers and healthy subjects, and to evaluate the performance of FeNO and EBC pH for predicting the cellular phenotype of induced sputum. METHODS: Asthmatic smokers (n = 40) and non-smoking asthmatic patients (n = 43) were recruited for the study. Healthy smoking (n = 30) or non-smoking (n = 30) subjects served as controls. FeNO and EBC pH were measured and all subjects underwent sputum induction for assessment of cell counts. RESULTS: EBC pH was significantly lower in asthmatic smokers compared with non-smokers (P < 0.01). FeNO levels were also significantly lower in asthmatic smokers compared with non-smokers (P < 0.001). EBC pH was inversely associated with sputum eosinophils in both asthmatic smokers and non-smokers (P < 0.001), whereas it was inversely associated with sputum neutrophils only in asthmatic smokers (P < 0.001). FeNO was positively associated with sputum eosinophils both in asthmatic smokers and non-smokers (P < 0.001) but was not associated with sputum neutrophils. In asthmatic smokers, FeNO was a better predictor of sputum eosinophilia, whereas EBC pH was a better predictor of sputum neutrophilia. A combination of FeNO <= 14 ppb together with EBC pH > 7.20 predicted the paucigranulocytic induced sputum phenotype. CONCLUSIONS: EBC pH and FeNO levels were significantly lower in asthmatic smokers compared with non smokers. Combined specific cut-off levels for FeNO and EBC pH may predict the paucigranulocytic phenotype in asthmatic smokers. PMID- 21545372 TI - Reversibility of impaired nasal mucociliary clearance in smokers following a smoking cessation programme. AB - BACKGROUND AND OBJECTIVE: Smoking cessation (SC) is recognized as reducing tobacco-associated mortality and morbidity. The effect of SC on nasal mucociliary clearance (MC) in smokers was evaluated during a 180-day period. METHODS: Thirty three current smokers enrolled in a SC intervention programme were evaluated after they had stopped smoking. Smoking history, Fagerstrom's test, lung function, exhaled carbon monoxide (eCO), carboxyhaemoglobin (COHb) and nasal MC as assessed by the saccharin transit time (STT) test were evaluated. All parameters were also measured at baseline in 33 matched non-smokers. RESULTS: Smokers (mean age 49 +/- 12 years, mean pack-year index 44 +/- 25) were enrolled in a SC intervention and 27% (n = 9) abstained for 180 days, 30% (n = 11) for 120 days, 49.5% (n = 15) for 90 days or 60 days, 62.7% (n = 19) for 30 days and 75.9% (n = 23) for 15 days. A moderate degree of nicotine dependence, higher education levels and less use of bupropion were associated with the capacity to stop smoking (P < 0.05). The STT was prolonged in smokers compared with non-smokers (P = 0.002) and dysfunction of MC was present at baseline both in smokers who had abstained and those who had not abstained for 180 days. eCO and COHb were also significantly increased in smokers compared with non-smokers. STT values decreased to within the normal range on day 15 after SC (P < 0.01), and remained in the normal range until the end of the study period. Similarly, eCO values were reduced from the seventh day after SC. CONCLUSIONS: A SC programme contributed to improvement in MC among smokers from the 15th day after cessation of smoking, and these beneficial effects persisted for 180 days. PMID- 21545373 TI - Pleural controversy: pleurodesis versus indwelling pleural catheters for malignant effusions. AB - Malignant pleural effusions (MPE) are a common complication of advanced malignancy. The treatment of MPE should be focused on palliation of associated symptoms. The traditional approach to MPE has been to attempt pleurodesis by introducing a sclerosant into the pleural space. A more recent development in the treatment of MPE has been the use of indwelling pleural catheters (IPC) for ongoing drainage of the pleural space. Controversy exists as to which approach is superior. Pleurodesis approaches will have the advantage of a time-limited course of treatment and high pleurodesis rate at the cost of a more invasive procedure requiring a general anaesthetic or conscious sedation (for thoracoscopic approaches) and an inpatient hospital stay. Use of IPC will allow the patient to be treated on an outpatient basis with a minimally invasive procedure, at the cost of long-term need for catheter drainage and care. Symptom control appears similar between techniques. Complication rates between the two approaches cannot be easily compared, but studies suggest more frequent severe complications such as respiratory failure, arrhythmias and even mortality following pleurodesis, with infection rates similar between the two approaches. IPC will likely see increasing utilization in the future but patient preference and local resources and expertise will continue to play a significant part in treatment decisions. Randomized trials directly comparing the two approaches are needed and some are underway. Novel combination approaches utilizing both IPC and pleurodesis agents have the potential to further improve the care of these patients. PMID- 21545374 TI - Reference values for spirometry: the way forward for our patients. PMID- 21545375 TI - Induction of antitumor immunity using dendritic cells electroporated with Polo like kinase 1 (Plk1) mRNA in murine tumor models. AB - Polo-like kinase 1 (Plk1), a serine-threonine kinase, plays a key role in the regulation of the cell cycle. Elevated Plk1 expression in various cancers is correlated with poor prognosis and poor patient survival rates. Several Plk1 inhibitors are currently being developed as potential treatments for cancer. In the present study, we investigated whether dendritic cells (DC) electroporated with mouse Plk1RNA (mPlk1RNA/DC) can induce Plk1-specific immune responses and exert antitumor effects in various murine tumor models. Overexpression of Plk1 protein was confirmed in several mouse and human tumor cell lines and various cancer tissues. Furthermore, Plk1-specific CD4(+) and CD8(+) T cells were induced by vaccination with mPlk1RNA/DC and the cytotoxic activity of the T cells was demonstrated against several Plk1-expressing tumor cell lines. Vaccination with mPlk1RNA/DC inhibited the growth of MC-38 and B16F10 tumors in C57BL/6 mice and the growth of CT26 tumors in BALB/c mice. Depletion of CD8(+) T cells reversed the inhibition of tumor growth by mPlk1RNA/DC vaccination. Homologous human Plk1RNA-electroporated DC also inhibited tumor growth in MC-38 tumor-bearing mice. In addition, Plk1-specific cytotoxic T lymphocytes from PBMC of healthy donors could be induced using autologous monocyte-derived DC electroporated with RNA encoding the whole gene of human Plk1. Taken together, the results of the present study suggest that Plk1 could be a universal tumor antigen recognized by cytotoxic T lymphocytes for cancer immunotherapy. PMID- 21545376 TI - Clinical severity of haemophilia A: does the classification of the 1950s still stand? AB - The classification of haemophilia originates from 1950s and has been adopted unchallengedly by the ISTH in 2001. The aim of this study was: does the current classification compare onset of bleeding and age at first treatment, as well as annual joint bleeding frequency according to baseline FVIII activity? Data on age and reason of diagnosis, onset of treatment, onset of bleeding and bleeding frequency from 411 patients with haemophilia A born after 1970 were collected. Data were analysed according to base-line FVIII activity levels. Age at diagnosis, onset of bleeding and start of treatment according to FVIII activity were compared with the current classification. Overall, the distinction between severe and non-severe haemophilia was clear. The distinction between mild and moderate haemophilia was more difficult, mostly due to the wide variability in the group of patients with moderate haemophilia. Patients with severe haemophilia experienced their milestones like diagnosis, first treatment and joint bleed earliest, mostly as infants aged 0-3 years, whereas patients with moderate haemophilia reached these milestones around toddler age, 2-7 years, and patients with mild haemophilia reached them when they were in elementary school, around the ages of 5-14 years. This study confirms the clinical distinction between severe and non-severe haemophilia A. However, the group of moderate haemophilia patients showed a wide variability, warranting close follow-up and individualized treatment. PMID- 21545377 TI - Thrombocytopenia and bleeding in dental procedures of patients with Gaucher disease. AB - The risk of bleeding during dental procedures may be increased in patients with Gaucher disease. We aimed to evaluate potential coagulation and platelet function abnormalities and targeted therapy accordingly. Patients with type 1 Gaucher disease who were treated at the Oral and Maxilo-Facial surgery clinic at Sheba Medical Center between 2003 and 2010 comprised the study cohort. Data collected included disease history, enzyme treatment, platelet counts, dental therapy and outcome. Bleeding was defined as excessive bleeding during or immediately following procedure. Coagulation studies and platelet function tests including aggregometry were performed on all patients. Dental procedures (n = 14, including eight teeth extractions, two crown lengthening procedures, one cyst enucleation and three deep dental scaling) of seven patients were studied. Mean platelet count prior to procedure was 73 K +/- 14.8 mm(3). Patients bleeding risk score was calculated according to previous history of bleeding tendency, degree of thrombocytopenia, presence of comorbid coagulopathy and the type of dental procedure. Two patients with highest risk score received prophylactic platelet transfusions, three patients (medium-risk) received DDAVP preprocedure and all received systemic tranexamic acid, which was the only systemic therapy for low risk patients. Meticulous surgical local haemostasis was applied. No excessive intra-operative or postoperative bleeding occurred. Patients with Gaucher disease who have thrombocytopenia and abnormal platelet function tests may be safely treated if meticulous haemostasis is applied along with systemic therapy as required. Platelet transfusions are not mandatory and should be applied considering the procedure-related risk and the patient's calculated haematological risk for bleeding. PMID- 21545378 TI - Factor IX replacement to cover total knee replacement surgery in haemophilia B: a single-centre experience, 2000-2010. AB - Total knee replacement (TKR) is a well recognized treatment for haemophilic arthropathy. Successful haemostasis can be achieved by bolus doses or continuous infusion (CI) using either recombinant (r) or plasma-derived (pd) factor IX (FIX). We retrospectively analysed our experience of factor replacement to cover TKR in haemophilia B patients and explored factors related to FIX use during surgery. Between 2000 and 2010, 13 primary TKRs were performed in 11 haemophilia B patients. Operations were performed by the same surgeon using standard techniques. Median age was 58 years (42-79). An adjusted CI protocol was used for 5 days followed by bolus doses. FIX:C was maintained at 100 IU dL(-1) in the immediate postoperative period. There was no excess haemorrhage. There was no evidence of thrombosis or infection. All patients received mechanical thromboprophylaxis and only one chemical. CI was used in seven cases. Ten patients received pdFIX. Median hospital stay was 14 days (8-17). Median factor usage was 999 IU kg(-1) (768-1248). During CI, factor consumption was 695 IU kg( 1), 691 IU kg(-1) and 495 IU kg(-1) for BeneFix(r), Replenine(r) and Haemonine, respectively. Clearance of both pdFIX and rFIX reduced during CI. All operations were uncomplicated. The decreased clearance in the CI setting reduced the amount of FIX required to maintain a therapeutic level. This reduction was greater with pdFIX and may be related to pharmacokinetic differences between pdFIX and rFIX. Given the excellent safety profile of the pdFIX products, CI of FIX and particularly pdFIX is safe, efficacious and convenient. PMID- 21545379 TI - Intentions and statins prescribing: can the theory of planned behaviour explain physician behaviour in following guideline recommendations? AB - OBJECTIVES: Few studies have assessed the utility of the Theory of Planned Behaviour (TPB) in explaining physicians' behaviour. This study uses the TPB for explaining physicians' implementation of guidelines' prescribing recommendations. METHODS: We developed the questionnaire via conducting qualitative interviews and pilot study. A random sample of 155 general practitioners (GPs) in England participated in the study. Prescribing and practice data were collected from routine sources. We analysed the data using regression methods. RESULTS: TPB explained 48% of variation in reported intentions to follow guidelines' prescribing recommendations. Attitude and perceived controls, but not subjective norms, were predictors of variation in intentions. TPB belief variables significantly explained variation in effective and efficient prescribing indicators (14% and 12% respectively). Normative, control and behavioural beliefs contributed to the models. Only for efficient prescribing, the TPB items retained their significance in presence of demographic variables. We found no significant relationship between intention and prescribing. CONCLUSIONS: TPB helped understanding of GPs prescribing behaviour and their intentions to implement a clinical guideline. Beliefs (e.g. normative beliefs) were better predictors of behaviour than the composite scores for their corresponding higher-level construct (e.g. indirect subjective norm). TPB models should be tested alongside randomized trials to test the assumption of causality that change in beliefs ultimately results in change in behaviour. PMID- 21545380 TI - Do Indonesian community pharmacy workers respond to antibiotics requests appropriately? AB - OBJECTIVE: To quantify antibiotics sales without a prescription and to explore provision of patient assessment and medicine information related to antibiotics requested with or without a prescription in Surabaya community pharmacies. METHODS: Scenarios of specific product requests (ciprofloxacin tablets and tetracycline capsules) and a request of amoxicillin dry syrups based on a new prescription were presented by simulated patients to 105 purposively selected pharmacies. Data were recorded by simulated patients after their purchase of each product. They documented the questions asked in patient assessment, the content of information given, recommendations provided and pharmacy workers' characteristics. RESULTS: Antibiotics requested without a prescription were sold in 80 (91%) pharmacies. Information related to ciprofloxacin tablets and tetracycline capsules was only provided when requested by the simulated patient in 69% and 68% of pharmacies for the two scenarios, respectively. Very few pharmacies assessed patients. Medicine information on indication, dosing, duration and direction for use was provided more frequently in all cases. Medicine information was more likely to be given when a new prescription of amoxicillin dry syrups being presented. Overall, the majority of sampled pharmacies responded antibiotics requests inappropriately. CONCLUSION: Inappropriate responses to antibiotic requests with or without a prescription remain an issue in Indonesia with pharmacy workers often failing to adequately assess patients. The illegality of delivering antibiotics without a prescription is of a considerable concern. Therefore, strategies to control antibiotics dispensing in community pharmacies should be seriously considered. PMID- 21545382 TI - Abstracts of the Royal Australasian College of Physicians Congress 2011. May 22 25, 2011. Darwin, Northern Territory, Australia. PMID- 21545381 TI - Outpatient treatment of children with severe pneumonia with oral amoxicillin in four countries: the MASS study. AB - OBJECTIVE: A recent randomized clinical trial demonstrated home-based treatment of WHO-defined severe pneumonia with oral amoxicillin was equivalent to hospital based therapy and parenteral antibiotics. We aimed to determine whether this finding is generalizable across four countries. METHODS: Multicentre observational study in Bangladesh, Egypt, Ghana and Vietnam between November 2005 and May 2008. Children aged 3-59 months with WHO-defined severe pneumonia were enrolled at participating health centres and managed at home with oral amoxicillin (80-90 mg/kg per day) for 5 days. Children were followed up at home on days 1, 2, 3 and 6 and at a facility on day 14 to look for cumulative treatment failure through day 6 and relapse between days 6 and 14. RESULTS: Of 6582 children screened, 873 were included, of whom 823 had an outcome ascertained. There was substantial variation in presenting characteristics by site. Bangladesh and Ghana had fever (97%) as a more common symptom than Egypt (74%) and Vietnam (66%), while in Vietnam, audible wheeze was more common (49%) than at other sites (range 2-16%). Treatment failure by day 6 was 9.2% (95% CI: 7.3-11.2%) across all sites, varying from 6.4% (95% CI: 3.1-9.8%) in Ghana to 13.2% (95% CI: 8.4-18.0%) in Vietnam; 2.7% (95% CI: 1.5-3.9%) of the 733 children well on day 6 relapsed by day 14. The most common causes of treatment failure were persistence of lower chest wall indrawing (LCI) at day 6 (3.8%; 95% CI: 2.6 5.2%), abnormally sleepy or difficult to wake (1.3%; 95% CI: 0.7-2.3%) and central cyanosis (1.3%; 95% CI: 0.7-2.3%). All children survived and only one adverse drug reaction occurred. Treatment failure was more frequent in young infants and those presenting with rapid respiratory rates. CONCLUSIONS: Clinical treatment failure and adverse event rates among children with severe pneumonia treated at home with oral amoxicillin did not substantially differ across geographic areas. Thus, home-based therapy of severe pneumonia can be applied to a wide variety of settings. PMID- 21545383 TI - Can the New Cooperative Medical Scheme promote rural elders' access to health care services? AB - The aim of the present study was to examine the impact of the New Cooperative Medical Scheme (NCMS) on rural elders' access to health-care services. Articles were identified from PubMed, Elsevier, Wiley, EBSCO, EMBASE, SCI Expanded, ProQuest, Google, and CNKI which is the most informative database in Chinese, with the search terms "rural", "China", "old", "older", or "elder", "elderly", or "aged", "aging", "medical insurance", or "community-based medical insurance", or "cooperative medical scheme". Related websites and yearbooks were searched as well. The NCMS has improved the health-care utilization of rural elders, and they have the highest satisfaction with it among all age groups. However, affordability difficulty remained the common barrier for the rural elderly to access quality health care, in spite of the special considerations given to the rural elderly, such as premium remission and free check-ups. Faced with ever growing health challenges, some impoverished rural elders with poor physical health and functional limitations may lack sufficient access to basic health-care services. Followed by the provider payment reform initiated by the NCMS, a stricter regulation for doctors' prescriptions, clinical practice and disease management is needed to promote rural elders' access to health-care services. Health management for rural elders can be expected for the NCMS to promote rural elders' health-care access once a better coordination between the NCMS and health care system can be achieved. PMID- 21545384 TI - Association of polypharmacy with fall risk among geriatric outpatients. AB - AIM: To investigate the association of fall risk with comorbidities and medications in geriatric outpatients in a cross-sectional design. METHODS: A total of 262 outpatients (84 men and 178 women, mean age 76.2+/-6.8years) were evaluated. Physical examination, clinical histories and medication profile were obtained from each patient. History of falls in the past year, 22-item fall risk index, 13-point simple screening test for fall, and time interval of one-leg standing test were examined as markers of fall risk. RESULTS: On univariate analysis, older age, female sex, hypertension, osteoporosis, history of stroke, number of comorbidities, use of antihypertensives, aspirin, bisphosphonates, hypnotics and number of prescribed drugs were significantly associated with either of four indices. On multiple regression analysis, the number of drugs was associated with all of the four indices, independent of other factors associated in the univariate analysis. The association of number of drugs with fall risk indices was stepwise. CONCLUSION: In geriatric outpatients, polypharmacy rather than number of comorbidities was associated with fall risk. Prospective and intervention studies are needed to clarify the causal relationship between polypharmacy, comorbidities and fall risk. PMID- 21545385 TI - Effects of exercise treatment with or without heat and steam generating sheet on urine loss in community-dwelling Japanese elderly women with urinary incontinence. AB - AIM: To determine the effects of exercise treatment with or without heat and steam generating sheet (HSGS) on reducing urine loss in community-dwelling elderly women with urinary incontinence (UI). METHODS: One hundred and forty seven community-dwelling women aged 70years and older with stress, urge and mixed UI were randomly assigned to exercise+HSGS (n=37), exercise only (n=37), HSGS only (n=37) or an education group (n=36). Exercise+HSGS, and exercise groups received exercise training twice a week for 3months. When the HSGS was placed on the lower back, the temperature of the skin surface rose to 38-40 degrees C and it continued to generate heat and steam for over 5h. The HSGS group used one sheet per day continuously for 3months. Urine loss and fitness data were collected at baseline and after intervention. RESULTS: The intervention groups showed significant improvements in muscle strength and walking speed compared to the education group. Exercise and HSGS showed urine loss cure rates of 54.1%, exercise 34.3% and HSGS 21.6% after treatment; whereas, the education group (2.9%) showed no significant improvement (chi(2) =21.89, P<0.001). Combining the HSGS to the exercise intervention showed a 61.5% cure rate for stress UI, 50.0% urge UI and 40.0% mixed UI. CONCLUSION: This data suggests that exercise treatment with HSGS is more effective for treating urine loss regardless of UI type. The HSGS can be used as a supplementary treatment method to enhance the effects of exercise on women with urge, mixed and stress UI. PMID- 21545386 TI - Prospective trial to identify optimal bladder cancer surveillance protocol: reducing costs while maximizing sensitivity. PMID- 21545387 TI - Filter-feeding in marine macro-invertebrates: pump characteristics, modelling and energy cost. PMID- 21545388 TI - Cold tolerance strategies in nematodes. PMID- 21545389 TI - Forthcoming reviews. PMID- 21545390 TI - Estimating genetic benefits of polyandry from experimental studies: a meta analysis. AB - The consequences of polyandry for female fitness are controversial. Sexual conflict studies and a meta-analysis of mating rates in insects suggest that there is a longevity cost when females mate repeatedly. Even so, compensatory material benefits can elevate egg production and fertility, partly because polyandry ensures an adequate sperm supply. Polyandry can therefore confer direct benefits. The main controversy surrounds genetic benefits. The argument is analogous to that surrounding the evolution of conventional female mate choice, except that with polyandry it is post-copulatory mechanisms that might bias paternity towards males with higher breeding values for fitness. Recent meta analyses of extra-pair copulations in birds have cast doubt on whether detectable genetic benefits exist. By contrast, another meta-analysis showed that polyandry elevates egg hatching success (possibly due to a fertilization bias towards sperm with paternal genes that elevate embryo survival) in insects. A detailed summary of whether polyandry elevates other components of offspring performance is lacking. Here we present a comprehensive meta-analysis of 232 effect sizes from 46 experimental studies. These experiments were specifically designed to try to quantify the potential genetic benefits of polyandry by controlling fully for the number of matings by females assigned to monandry and polyandry treatments. The bias-corrected 95% confidence intervals for egg hatching success (d = -0.01 to 0.61), clutch production (d = 0.07 to 0.45) and fertility (d = 0.04 to 0.40) all suggest that polyandry has a beneficial effect (although P values from parametric tests were marginally non-significant at P = 0.075, 0.052 and 0.058, respectively). Polyandry was not significantly beneficial for any single offspring performance trait (e.g. growth rate, survival, adult size), but the test power was low due to small sample sizes (suggesting that many more studies are still needed). We then calculated a composite effect size that provides an index of general offspring performance. Depending on the model assumptions, the mean effect of polyandry was either significantly positive or marginally non significant. A possible role for publication bias is discussed. The magnitude of the reported potential genetic benefits (d = 0.07 to 0.19) are larger than those from two recent meta-analyses comparing offspring sired by social and extra-pair mates in birds (d = 0.02 to 0.04). This difference raises the intriguing possibility that cryptic, post-copulatory female choice might be more likely to generate 'good gene' or 'compatible gene' benefits than female choice of mates based on the expression of secondary sexual traits. PMID- 21545391 TI - Ethics and prevention of overweight and obesity: an inventory. AB - Efforts to counter the rise in overweight and obesity, such as taxes on certain foods and beverages, limits to commercial advertising, a ban on chocolate drink at schools or compulsory physical exercise for obese employees, sometimes raise questions about what is considered ethically acceptable. There are obvious ethical incentives to these initiatives, such as improving individual and public health, enabling informed choice and diminishing societal costs. Whereas we consider these positive arguments to put considerable effort in the prevention of overweight indisputable, we focus on potential ethical objections against such an effort. Our intention is to structure the ethical issues that may occur in programmes to prevent overweight and/or obesity in order to encourage further debate. We selected 60 recently reported interventions or policy proposals targeting overweight or obesity and systematically evaluated their ethically relevant aspects. Our evaluation was completed by discussing them in two expert meetings. We found that currently proposed interventions or policies to prevent overweight or obesity may (next to the benefits they strive for) include the following potentially problematic aspects: effects on physical health are uncertain or unfavourable; there are negative psychosocial consequences including uncertainty, fears and concerns, blaming and stigmatization and unjust discrimination; inequalities are aggravated; inadequate information is distributed; the social and cultural value of eating is disregarded; people's privacy is disrespected; the complexity of responsibilities regarding overweight is disregarded; and interventions infringe upon personal freedom regarding lifestyle choices and raising children, regarding freedom of private enterprise or regarding policy choices by schools and other organizations. The obvious ethical incentives to combat the overweight epidemic do not necessarily override the potential ethical constraints, and further debate is needed. An ethical framework to support decision makers in balancing potential ethical problems against the need to do something would be helpful. Developing programmes that are sound from an ethical point of view is not only valuable from a moral perspective, but may also contribute to preventing overweight and obesity, as societal objections to a programme may hamper its effectiveness. PMID- 21545392 TI - Turning attention to the young. PMID- 21545393 TI - Obesity hypertension in adolescents: epidemiology, evaluation, and management. AB - The prevalence of hypertension among all adolescents is approximately 3.5%, with somewhat higher rates of prehypertension. Obesity affects approximately 20% of adolescents in the United States, and the prevalence of hypertension is much higher among obese adolescents compared with nonobese adolescents. As in other populations, the evaluation of elevated blood pressure in obese adolescents should begin with a confirmation of the blood pressure elevation, followed by a focused diagnostic work-up to detect possible secondary causes of hypertension. Primary therapy for obesity-related hypertension in adolescents begins with weight loss, and may include antihypertensive medications if target-organ damage or other indications for drug therapy are present. The emphasis of management should be reduction of future cardiovascular risk. PMID- 21545395 TI - Long-term effects of aerobic plus resistance training on the metabolic syndrome and adiponectinemia in obese adolescents. AB - The metabolic syndrome is an emerging clinical problem and different kinds of interventions have emphasized that healthy eating and exercise are crucial to its control. The aim of this study was to identify whether aerobic training plus resistance training (AT+RT) is more effective than AT on improving features of the metabolic syndrome and adiponectinemia in obese adolescents. A total of 30 adolescents (aged 15-19 years, body mass index >=95 percentile) were enrolled in the program. All patients were diagnosed with the metabolic syndrome and submitted to 1 year of interdisciplinary intervention. They were divided into two groups: AT (n=15) and AT+RT (n=15). Blood samples were collected to analyze glycemia and lipid profiles. Adiponectin was measured by enzyme-linked immunosorbent assay, and insulin resistance was measured by homeostasis model assessment of insulin resistance index. After short- and long-term intervention, both groups presented a significant reduction in body mass, body mass index, fat mass, and visceral fat. Indeed, the AT+RT group had significantly higher changes throughout the intervention in body composition, total cholesterol, waist circumference, glucose, and adiponectin. Although important clinical parameters were ameliorated with AT, the AT+RT group showed more effective improvements in metabolic profiles and adiponectinemia. These findings suggest a clinical role of AT+RT in the control of metabolic syndrome in pediatric populations. PMID- 21545394 TI - Cardiac and vascular consequences of pre-hypertension in youth. AB - Hypertension is associated with increased left ventricular mass (LVM) and carotid intima-media thickness (cIMT), which predict cardiovascular (CV) events in adults. Whether target organ damage is found in pre-hypertensive youth is not known. The authors measured body mass index, blood pressure, fasting glucose, insulin, lipids and C-reactive protein, LVM/height(2.7) (LVM index), diastolic function, cIMT, carotid stiffness, augmentation index, brachial artery distensibility, and pulse wave velocity (PWV) in 723 patients aged 10 to 23 years (29% with type 2 diabetes mellitus). Patients were stratified by blood pressure level (normotensive: 531, pre-hypertensive: 65, hypertensive: 127). Adiposity and CV risk factors worsened across blood pressure group. There was a graded increase in cIMT, arterial stiffness, and LVM index and decrease in diastolic function from normotension to pre-hypertension to hypertension. In multivariable models adjusted for CV risk factors, status as pre-hypertension or hypertension remained an independent determinant of target organ damage for LVM, diastolic function, internal cIMT, and carotid and arterial stiffness. Pre-hypertension is associated with cardiovascular target organ damage in adolescents and young adults. PMID- 21545396 TI - Impact of type 1 diabetes and body weight status on cardiovascular risk factors in adolescent children. AB - Type 1 diabetes (T1D) is a risk factor for cardiovascular disease. However, it is unclear whether increased body weight amplifies that risk in T1D patients. This is a cross-sectional study examining the presence of cardiovascular risk factors in normal and overweight children, both with and without T1D. Sixty-six children (aged 16+/-2.2 years) were included in one of the following groups: (T1D and normal weight, T1D and overweight, healthy and normal weight, and healthy and overweight). A fasting blood sample was analyzed for lipid profile (triglyceride, cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), apolipoprotein B (apoB), and apolipoprotein C-III (apoC-III) levels. Body composition was determined by dual energy x-ray absorptiometry and vascular elasticity by HDI/Pulsewave CR-2000 (Hypertension Diagnostics, Eagan, MN). Statistical analyses examined the effect of T1D and body weight status and their interactions on cardiovascular risk parameters. In this study, the authors were unable to demonstrate an additive effect of body weight status and T1D on cardiovascular risk profile. However, subgroup analysis of patients with T1D revealed higher apoC-III levels in overweight patients with T1D (P=.0453) compared with normal-weight diabetic children. Most notably, there was a direct relationship of small artery elasticity to body weight status. This seemingly paradoxical observation supports recent data and warrants further investigation. PMID- 21545398 TI - Peripheral and central blood pressure responses of combination aliskiren/hydrochlorothiazide and amlodipine monotherapy in African American patients with stage 2 hypertension: the ATLAAST trial. AB - Efficacy of antihypertensive agents on central blood pressure (BP) in African Americans is not well studied. The authors report on an 8-week double-blind, randomized study of African American patients with stage 2 hypertension that compared brachial and central BP responses (substudy of 53 patients) to combination aliskiren/hydrochlorthiazide (HCTZ) and amlodipine monotherapy. Following a 1- to 4-week washout, initial therapy was aliskiren/HCTZ 150/12.5 mg (n=166) or amlodipine 5 mg (n=166) for 1 week, forced-titrated to aliskiren/HCTZ 300/25 mg or amlodipine 10 mg for 7 weeks. Mean seated systolic BP reductions from baseline was similar with both treatments (-28.6 mm Hg with aliskiren/HCTZ vs -28.2 mm Hg with amlodipine). In the substudy, significantly greater reductions in central systolic BP was observed with aliskiren/HCTZ vs amlodipine (-30.1 mm Hg vs -21.2; P=.031), although 24-hour mean ambulatory BP reductions between the two groups were similar. Central pressure is considered an important risk factor in African Americans, and these findings may suggest a new treatment option for these patients. PMID- 21545397 TI - Effectiveness and safety of valsartan in children aged 6 to 16 years with hypertension. AB - The effectiveness and safety of valsartan have not been assessed in hypertensive children. Therefore, hypertensive patients aged 6 to 16 years (n=261) were randomized to receive weight-stratified low- (10/20 mg), medium- (40/80 mg), or high-dose (80/160 mg) valsartan for 2 weeks. After 2 weeks, patients were randomized to a 2-week placebo-controlled withdrawal phase. Dose-dependent reductions in sitting systolic blood pressure (SSBP) and sitting diastolic blood pressure (SDBP) were observed after 2 weeks (low dose, -7.9/-4.6 mm Hg; medium dose, -9.6/-5.8 mm Hg; high dose, -11.5/-7.4 mm Hg [P<.0001 for all groups]). During the withdrawal phase, SSBP and SDBP were both lower in the pooled valsartan group than in the pooled placebo group (SSBP, -2.7 mm Hg [P=.0368]; SDBP, -3.0 mm Hg [P=.0047]). Similar efficacy was observed in all subgroups. Valsartan was well tolerated and headache was the most commonly observed adverse event during both the double-blind and 52-week open-label phases. PMID- 21545399 TI - Blood pressure effects of naproxcinod in hypertensive patients. AB - The blood pressure (BP) effects of naproxcinod and naproxen were assessed in an 8 week, double-blind, crossover study in 131 hypertensive patients aged 50 to 74 years. Patients received naproxcinod 750 mg twice daily or naproxen 500 mg twice daily, then the alternate treatment, each for 14 days, with placebo run in/washout before each active treatment period and 24-hour ambulatory BP monitoring conducted before and after each active treatment period. Mean change from baseline in average 24-hour systolic BP (SBP) after 2 weeks of treatment numerically favored naproxcinod 750 mg twice daily (least-squares [LS] mean for naproxcinod minus naproxen: -1.6 mm Hg; P=.12). Post hoc analyses showed statistically significant SBP differences favoring naproxcinod for the 8 elapsed hours (LS mean: -4.4 mm Hg; P<.0001) and the 24 hours following morning dosing (LS mean: -2.4 mm Hg; P=.006). Naproxcinod may be a beneficial alternative for patients with osteoarthritis requiring nonsteroidal anti-inflammatory drugs. PMID- 21545401 TI - Leadership message. American Society of Hypertension-designated centers of excellence: a new initiative. PMID- 21545400 TI - Short Form (SF-36) Health Survey measures are associated with decreased adherence among urban African Americans with severe, poorly controlled hypertension. AB - The objective of this study was to determine whether an association exists between Short Form (SF-36) Health Survey measures and nonadherence among urban African Americans with poorly controlled hypertension. A total of 158 African Americans were admitted to an urban academic hospital for severe, uncontrolled hypertension. The main outcome measure was self-reported nonadherence to antihypertensive medications using a validated instrument. For every 10-point increase in Physical Component Summary (PCS) score, an individual was almost two times more likely to report being nonadherent (odds ratio, 1.94; 95% confidence interval, 1.30-2.90; P<.01). A significant interaction (P=.05) was observed between the physical functioning and mental health subscales. Individuals with high physical functioning and low mental health scores displayed the lowest adherence rate. These results suggest that high physical functioning, especially if associated with poor mental health, increases the likelihood of nonadherence to antihypertensive regimens among urban African Americans. The SF-36 may serve as an effective clinical tool that identifies patients at risk for nonadherence and, more importantly, may improve clinicians' understanding of nonadherence, allowing for discussions about antihypertensive medications to be tailored to individual patients. PMID- 21545404 TI - Schizophrenia-relevant behaviors in a genetic mouse model of constitutive Nurr1 deficiency. AB - Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the dopaminergic development and survival. Altered expression of Nurr1 has been suggested as a potential genetic risk factor for dopamine-related brain disorders, including schizophrenia. In support of this, recent experimental work in genetically modified mice shows that mice with a heterozygous constitutive deletion of Nurr1 show a facilitation of the development of schizophrenia-related behavioral abnormalities. However, the behavioral characterization of this Nurr1-deficient mouse model remains incomplete. This study therefore used a comprehensive behavioral test battery to evaluate schizophrenia-relevant phenotypes in Nurr1 deficient mice. We found that these mice displayed increased spontaneous locomotor activity and potentiated locomotor reaction to systemic treatment with the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). In addition, male but not female Nurr1-deficient mice showed significant deficits in the prepulse inhibition and prepulse-elicited reactivity. However, Nurr1 deletion did not induce overt abnormalities in other cardinal behavioral and cognitive functions known to be impaired in schizophrenia, including social interaction and recognition, spatial recognition memory or discrimination reversal learning. Our findings thus suggest that heterozygous constitutive deletion of Nurr1 results in a restricted phenotype characteristic of schizophrenia symptomatology, which primarily relates to motor activity, sensorimotor gating and responsiveness to the psychomimetic drug MK-801. This study further emphasizes a critical role of altered dopaminergic development in the precipitation of specific brain dysfunctions relevant to human psychotic disorder. PMID- 21545405 TI - The role of the toothbrush in the abrasion process. AB - AIM: To evaluate the relative abrasivity of different toothbrushes both qualitatively and quantitatively. MATERIALS AND METHODS: Acrylic plates were exposed to brushing in a brushing machine with ten different toothbrushes with water alone and with a toothpaste. The results were evaluated using a profilometer after one and 6 h of brushing (corresponding to 2000 and 12,000 double strokes, respectively). A surface roughness value (Ra-value) and also a volume loss value were calculated from the profilometer measurements. These values were then compared to each other. RESULTS: The results showed that brushing with water alone caused less abrasion than when a toothpaste was added. Six-hour brushing with water caused less abrasion than 1 h with a toothpaste. The number of filaments or filament diameter influenced the results in various ways. When brushing with water, the harder toothbrush (Jordan Medium) caused more abrasion (higher Ra-value), but when adding the toothpaste, the softer toothbrush (Jordan soft) caused more abrasion after 12,000 double strokes. CONCLUSION: Besides supporting the fact that a toothpaste is needed to create a significant abrasion, this study also showed that a softer toothbrush can cause as much and in some cases more abrasion than harder ones. When conducting abrasivity studies, it is important to look at both the quantitative and qualitative aspect of abrasivity. PMID- 21545406 TI - Brassinosteroid enhances jasmonate-induced anthocyanin accumulation in Arabidopsis seedlings. AB - Jasmonate (JA) regulates plant development, mediates defense responses, and induces anthocyanin biosynthesis as well. Previously, we isolated the psc1 mutant that partially suppressed coi1 insensitivity to JA, and found that brassinosteroid (BR) was involved in JA signaling and negatively regulated JA inhibition of root growth in Arabidopsis. In this study it was shown that JA induced anthocyanin accumulation was reduced in BR mutants or in wild type treated with brassinazole, an inhibitor of BR biosynthesis, whereas it was induced by an application of exogenous BR. It was also shown that the 'late' anthocyanin biosynthesis genes including DFR, LDOX, and UF3GT, were induced slightly by JA in the BR mutants relative to wild type. Furthermore, the expression level of JA-induced Myb/bHLH transcription factors such as PAP1, PAP2, and GL3, which are components of the WD-repeat/Myb/bHLH transcriptional complexes that mediate the 'late' anthocyanin biosynthesis genes, was lower in the BR mutants than that in wild type. These results suggested that BR affects JA induced anthocyanin accumulation by regulating the 'late' anthocyanin biosynthesis genes and this regulation might be mediated by the WD repeat/Myb/bHLH transcriptional complexes. PMID- 21545407 TI - Insensate foot of diabetic foot ulcer can have underlying silent neuropathic pain. AB - Subjects with diabetic foot ulcer (DFU) are believed to be less likely to complain of symptoms of painful diabetic peripheral neuropathy (PDPN). When we assessed this using Leeds Assessment of Neuropathic Symptoms and Signs questionnaire (s-LANSS) we found that out of total 44 subjects with DFU, 19 (43.2%) had possible neuropathic discomfort. s-LANSS score was significantly higher in DFU group (8.1 +/- 7.7 versus 4.7 +/- 4.6; P = 0.04). However, there was no difference in the perception of pain in 10-point Likert scale (3.9 +/- 3.6 versus 3.3 +/- 3.0; P = NS) between these two groups. This study suggests that subjects with DFU may suffer from PDPN, but do not perceive it. Further studies are needed to assess if treatment of PDPN in these subjects is beneficial. PMID- 21545408 TI - A study of HLA class I and class II 4-digit allele level in Stevens-Johnson syndrome and toxic epidermal necrolysis. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are represented by rare but life-threatening cutaneous adverse reactions to different drugs. Previous studies have found that in a Han Chinese population from Taiwan and other Asian Countries, a strong genetic association between HLA-class I alleles (B*15:02, B*58:01) and SJS and TEN was induced by carbamazepine and allopurinol, respectively. To identify genetic markers that covered the MHC region, we carried out a case-control association enrolling 20 Caucasian patients with SJS/TEN. Our patient series included 10 cases related to paracetamol, 7 to allopurinol and 3 to different drugs (plaquenil, itraconazol, nabumetone). Healthy controls were represented by 115 Caucasian bone marrow or stem cell donors. The HLA-A*, B*, C*, DRB1*, DQB1*, DQA1* and DPB1* genotyping were determined. The frequencies of HLA-A*33:03 as well as C*03:02 and C*08:01 were significantly higher in SJS/TEN patient subgroup showing allopurinol drug-induced severe cutaneous adverse reactions (SCAR) as compared to controls (28.6% vs 0%, P=0.00002, Pc=0.0011; 28.6% vs 0%, P=0.00002, Pc=0.001; 28.6% vs 0%, P=0.00002, Pc=0.001, respectively). In the same subgroup the frequencies of B*58:01, DRB1*15:02 and DRB1*13:02 alleles, although considerably higher than in control group (42.8% vs 5.2%, P=0.003; 28.6% vs 1.7%, P=0.005; 28.6% vs 3.5%, P=0.037, respectively), appeared no more statistically different after P correction (Pc=0.248; Pc=0.29; Pc=1.00, respectively). In addition, in 10 of the 20 SJS/TEN patient subgroup with paracetamol-induced SCAR no statistically significant association with HLA alleles could be found. However, in the same SJS/TEN patient subgroup showing allopurinol drug-induced SCAR, haplotype analysis indicated that B*58:01, DRB1*13:02 and DRB1*15:02 alleles, that in a single allele analysis lost statistical significance after P correction, may still confer susceptibility, because the B*58:01-DRB1*13:02 and DRB1*15:02-DQB1*05:02 are positively associated with the disease (14.2% vs 0.43%, P= 0.00001, Pc=0.00028; 14.2% vs 0.43%, P=0.00001, Pc=0.00028, respectively). Our results show that in contrast to SCAR-related to paracetamol, where HLA alleles do not appear to be involved, HLA molecules behave as a strong risk factor for SCAR-related to allopurinol even when a limited number of patients are considered. PMID- 21545409 TI - HLA-DQB1*06:41 shown by sequence-based typing may be associated with DRB1*13:02. AB - In this report we present DQB1*06:41, a novel allele probably associated with DRB1*13:02. PMID- 21545410 TI - Novel major histocompatibility complex class II alleles in a group of Chinese rhesus macaques (Macaca mulatta). AB - Seven novel MhcMamu-DQB1 alleles were observed in a population of rhesus macaques of Chinese origin. PMID- 21545411 TI - Translational neuropharmacology and the appropriate and effective use of animal models. AB - This issue of the British Journal of Pharmacology is dedicated to reviews of the major animal models used in neuropharmacology to examine drugs for both neurological and psychiatric conditions. Almost all major conditions are reviewed. In general, regulatory authorities require evidence for the efficacy of novel compounds in appropriate animal models. However, the failure of many compounds in clinical trials following clear demonstration of efficacy in animal models has called into question both the value of the models and the discovery process in general. These matters are expertly reviewed in this issue and proposals for better models outlined. In this editorial, we further suggest that more attention be made to incorporate pharmacokinetic knowledge into the studies (quantitative pharmacology). We also suggest that more attention be made to ensure that full methodological details are published and recommend that journals should be more amenable to publishing negative data. Finally, we propose that new approaches must be used in drug discovery so that preclinical studies become more reflective of the clinical situation, and studies using animal models mimic the anticipated design of studies to be performed in humans, as closely as possible. PMID- 21545413 TI - NPY receptors as potential targets for anti-obesity drug development. AB - The neuropeptide Y system has proven to be one of the most important regulators of feeding behaviour and energy homeostasis, thus presenting great potential as a therapeutic target for the treatment of disorders such as obesity and at the other extreme, anorexia. Due to the initial lack of pharmacological tools that are active in vivo, functions of the different Y receptors have been mainly studied in knockout and transgenic mouse models. However, over recent years various Y receptor selective peptidic and non-peptidic agonists and antagonists have been developed and tested. Their therapeutic potential in relation to treating obesity and other disorders of energy homeostasis is discussed in this review. PMID- 21545412 TI - The age of anxiety: role of animal models of anxiolytic action in drug discovery. AB - Anxiety disorders are common, serious and a growing health problem worldwide. However, the causative factors, aetiology and underlying mechanisms of anxiety disorders, as for most psychiatric disorders, remain relatively poorly understood. Animal models are an important aid in giving insight into the aetiology, neurobiology and, ultimately, the therapy of human anxiety disorders. The approach, however, is challenged with a number of complexities. In particular, the heterogeneous nature of anxiety disorders in humans coupled with the associated multifaceted and descriptive diagnostic criteria, creates challenges in both animal modelling and in clinical research. In this paper, we describe some of the more widely used approaches for assessing the anxiolytic activity of known and potential therapeutic agents. These include ethological, conflict-based, hyponeophagia, vocalization-based, physiological and cognitive based paradigms. Developments in the characterization of translational models are also summarized, as are the challenges facing researchers in their drug discovery efforts in developing new anxiolytic drugs, not least the ever-shifting clinical conceptualization of anxiety disorders. In conclusion, to date, although animal models of anxiety have relatively good validity, anxiolytic drugs with novel mechanisms have been slow to emerge. It is clear that a better alignment of the interactions between basic and clinical scientists is needed if this is to change. PMID- 21545414 TI - Endocannabinoid tone versus constitutive activity of cannabinoid receptors. AB - This review evaluates the cellular mechanisms of constitutive activity of the cannabinoid (CB) receptors, its reversal by inverse agonists, and discusses the pitfalls and problems in the interpretation of the research data. The notion is presented that endogenously produced anandamide (AEA) and 2-arachidonoylglycerol (2-AG) serve as autocrine or paracrine stimulators of the CB receptors, giving the appearance of constitutive activity. It is proposed that one cannot interpret inverse agonist studies without inference to the receptors' environment vis-a-vis the endocannabinoid agonists which themselves are highly lipophilic compounds with a preference for membranes. The endocannabinoid tone is governed by a combination of synthetic pathways and inactivation involving transport and degradation. The synthesis and degradation of 2-AG is well characterized, and 2 AG has been strongly implicated in retrograde signalling in neurons. Data implicating endocannabinoids in paracrine regulation have been described. Endocannabinoid ligands can traverse the cell's interior and potentially be stored on fatty acid-binding proteins (FABPs). Molecular modelling predicts that the endocannabinoids derived from membrane phospholipids can laterally diffuse to enter the CB receptor from the lipid bilayer. Considering that endocannabinoid signalling to CB receptors is a much more likely scenario than is receptor activation in the absence of agonist ligands, researchers are advised to refrain from assuming constitutive activity except for experimental models known to be devoid of endocannabinoid ligands. PMID- 21545415 TI - Prospects for cannabinoid therapies in basal ganglia disorders. AB - Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like Delta(9) tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB(1) and CB(2) receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB(2) receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB(2) receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB(2) receptor up regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB(2) receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB(2) receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation. PMID- 21545416 TI - Unraveling the mechanisms underlying the rapid vascular effects of steroids: sorting out the receptors and the pathways. AB - Aldosterone, oestrogens and other vasoactive steroids are important physiological and pathophysiological regulators of cardiovascular and metabolic function. The traditional view of the cardiovascular actions of these vasoactive steroids has focused on their roles as regulators of transcription via activation of their 'classical' receptors [mineralocorticoid receptors (MR) and oestrogen receptors (ER)]. However, based on a series of observations going back more than half a century, scientists have speculated that a range of steroids, including oestrogen and aldosterone, might have effects on regulation of smooth muscle contractility, cell growth and differentiation that are too rapid to be accounted for by transcriptional regulation. Recent studies performed in our laboratories (and those of others) have begun to elucidate the mechanism of rapid steroid-mediated cardiometabolic regulation. GPR30, now designated as GPER-1 (http://www.iuphar db.org/DATABASE/FamilyIntroductionForward?familyId=22), a newly characterized 'orphan receptor', has been implicated in mediating the rapid effects of estradiol and most recently those of aldosterone. Studies to date have taught us that to understand the rapid vascular mechanisms of steroids, one must (i) know which vascular 'compartment' the steroid is acting; (ii) know which receptor the steroid hormone is activating; and (iii) not assume the receptor specificity of a steroid receptor ligand based solely on its selectivity for its traditional 'transcriptional' steroid receptor. Our newfound appreciation of the rapid effects of steroids such as aldosterone and oestrogens opens up a new vista for advancing our understanding of the biology and pathobiology of vascular regulation. PMID- 21545418 TI - Bateman's principle and immunity in a sex-role reversed pipefish. AB - In diverse animal species, from insects to mammals, females display a more efficient immune defence than males. Bateman's principle posits that males maximize their fitness by increasing mating frequency whereas females gain fitness benefits by maximizing their lifespan. As a longer lifespan requires a more efficient immune system, these implications of Bateman's principle may explain widespread immune dimorphism among animals. Because in most extant animals, the provisioning of eggs and a higher parental investment are attributes of the female sex, sex-role reversed species provide a unique opportunity to assess whether or not immune dimorphism depends on life history and not on sex per se. In the broad-nosed pipefish Syngnathus typhle, males brood and nourish the eggs in a ventral pouch and thus invest more into reproduction than females. We found males to have a more active immune response both in field data from four populations and also in an experiment under controlled laboratory conditions. This applied to different measures of immunocompetence using innate as well as adaptive immune system traits. We further determined the specificity of immune response initiation after a fully factorial primary and secondary exposure to a common marine pathogen Vibrio spp. Males not only had a more active but also a more specific immune defence than females. Our results thus indeed suggest that the sex that invests more into the offspring has the stronger immune defence. PMID- 21545419 TI - Divergent host plant specialization as the critical driving force in speciation between populations of a phytophagous ladybird beetle. AB - Detecting the isolating barrier that arises earliest in speciation is critically important to understanding the mechanism of species formation. We tested isolating barriers between host races of a phytophagous ladybird beetle, Henosepilachna diekei (Coleoptera: Coccinellidae: Epilachnine), that occur sympatrically on distinct host plants. We conducted field surveys for the distribution of the beetles and host plants, rearing experiments to measure six potential isolating factors (adult host preference, adult and larval host performance, sexual isolation, egg hatchability, F(1) hybrid inviability, and sexual selection against F(1) hybrids), and molecular analyses of mitochondrial ND2 and the nuclear ITS2 sequences. We found significant genetic divergence between the host races, and extremely divergent host preference (i.e. habitat isolation) and host performance (i.e. immigrant inviability), but no other isolating barriers. The fidelity to particular host plants arises first and alone can prevent gene flow between differentiating populations of phytophagous specialists. PMID- 21545417 TI - Functional analysis of the Listeria monocytogenes secretion chaperone PrsA2 and its multiple contributions to bacterial virulence. AB - As an organism that has evolved to live in environments ranging from soil to the cytosol of mammalian cells, Listeria monocytogenes must regulate the secretion and activity of protein products that promote survival within these habitats. The post-translocation chaperone PrsA2 has been adapted to assist in the folding and activity of L. monocytogenes secreted proteins required for bacterial replication within host cells. Here we present the first structure/function investigation of the contributions of PrsA2 to protein secretion and activity as well as to bacterial virulence. Domain swap experiments with the closely related L. monocytogenes PrsA1 protein combined with targeted mutagenesis indicate distinct functional roles for the PrsA2 peptidyl-prolyl isomerase (PPIase) and the N- and C-terminal domains in pathogenesis. In contrast to other PrsA-like proteins described thus far in the literature, an absolute in vivo requirement for PrsA2 PPIase activity is evident in mouse infection models. This work illustrates the diversity of function associated with L. monocytogenes PrsA2 that serves to promote bacterial life within the infected host. PMID- 21545420 TI - Locally asymmetric introgressions between subspecies suggest circular range expansion at the Antirrhinum majus global scale. AB - Assessing processes of geographic expansion in contact zones is a crucial step towards an accurate prediction of the evolution of species genetic diversity. The geographic distribution of cytonuclear discordance often reflects genetic introgression patterns across a species geographic range. Antirrhinum majus pseudomajus and A. m. striatum are two interfertile subspecies that occupy nonoverlapping areas but enter in contact in many locations at the margin of their geographic distribution. We found that genetic introgression between both subspecies was asymmetric at the local scale and geographically oriented in opposite directions at both ends of their contact zone perimeter in the Pyrenees. Our results suggest that the geographic expansion of A. majus subspecies was circular around the perimeter of their contact zone and pinpoint the need to integrate different spatial scales to unravel complex patterns of species geographic expansion. PMID- 21545421 TI - Adaptation to marginal habitats by evolution of increased phenotypic plasticity. AB - In an island population receiving immigrants from a larger continental population, gene flow causes maladaptation, decreasing mean fitness and producing continued directional selection to restore the local mean phenotype to its optimum. We show that this causes higher plasticity to evolve on the island than on the continent at migration-selection equilibrium, assuming genetic variation of reaction norms is such that phenotypic variance is higher on the island, where phenotypes are not canalized. For a species distributed continuously in space along an environmental gradient, higher plasticity evolves at the edges of the geographic range, and in environments where phenotypes are not canalized. Constant or evolving partially adaptive plasticity also alleviates maladaptation owing to gene flow in a heterogeneous environment and produces higher mean fitness and larger population size in marginal populations, preventing them from becoming sinks and facilitating invasion of new habitats. Our results shed light on the widely observed involvement of partially adaptive plasticity in phenotypic clines, and on the mechanisms causing geographic variation in plasticity. PMID- 21545422 TI - Genetic and environmental sources of covariance among internal reproductive traits in the yellow dung fly. AB - Substantial inter- and intraspecific variation is found in reproductive traits, but the evolutionary implications of this variation remain unclear. One hypothesis is that natural selection favours female reproductive morphology that allows females to control mating and fertilization and that diverse male reproductive traits arise as counter adaptations to subvert this control. Such co evolution predicts the establishment of genetic correlations between male and female reproductive traits that closely interact during mating. Therefore, we measured phenotypic and genetic correlations between male and female reproductive tract characteristics in the yellow dung fly, Scathophaga stercoraria (Diptera: Scathophagidae), using a nested half-sib breeding experiment. We found significant heritabilities for the size of most reproductive tract traits investigated in both females (spermathecae and their ducts, accessory glands and their ducts) and males (testis size but not sperm length). Within the sexes, phenotypic and genetic correlations were mostly nil or positive, suggesting functional integration of or condition-dependent investment in internal reproductive traits. Negative intrasexual genetic correlations, potentially suggestive of resource allocation trade-offs, were not evident. Intersexual genetic correlations were mostly positive, reflecting expected allometries between male and female morphologies. Most interestingly, testis size correlated positively with female accessory gland size and duct length, potentially indicative of a co-evolutionary arms race. We discuss these and alternative explanations for these patterns of genetic covariance. PMID- 21545423 TI - Heritability of short-scale natal dispersal in a large-scale foraging bird, the wandering albatross. AB - Natal dispersal is a key life history trait for the evolution and adaptation of wild populations. Although its evolution has repeatedly been related to the social and environmental context faced by individuals, parent-offspring regressions have also highlighted a possible heritable component. In this study, we explore heritability of natal dispersal, at the scale of the sub-Antarctic Possession Island, for a large-scale foraging seabird, the Wandering albatross Diomedea exulans, exploiting a pedigree spanning over four decades and a maximum of four generations. The comparison of three different methods shows that heritability on the liability scale can vary drastically depending on the type of model (heritability from 6% to 86%), with a notable underestimation by restricted maximum likelihood animal models (6%) compared to Bayesian animal models (36%). In all cases, however, our results point to significant additive genetic variance in the individual propensity to disperse, after controlling for substantial effects of sex and natal colony. These results reveal promising evolutionary potential for short-scale natal dispersal, which could play a critical role for the long-term persistence of this species on the long run. PMID- 21545424 TI - Sexual conflict in Gerris gillettei (Insecta: Hemiptera): intraspecific intersexual correlated morphology and experimental assessment of behaviour and fitness. AB - The contemporary dynamics of sexually antagonistic coevolution caused by sexual conflicts have seldom been investigated at the intraspecific level. We characterized natural populations of Gerris gillettei and documented significant intersexual correlations for morphological traits previously related to sexual conflict in water striders. These results strongly indicate that sexually antagonistic coevolution contributed to population differentiation and resulted in different balances of armaments between the sexes within natural populations of this species. No-choice mating experiments further revealed that both male and male-female relative arms levels influence copulation duration. However, there were no asymmetries in reproductive behaviour and fitness between sympatric and allopatric mating pairs, suggesting that differentiation by sexual conflict was not sufficient to influence the outcome of mating interactions. Altogether, these results question the relative importance of female connexival spines vs. genitalia traits in mediating pre- and post-copulatory conflict in Gerris. PMID- 21545425 TI - A phylogeny of frugivorous hornbills linked to the evolution of Indian plants within Asian rainforests. AB - Understanding the origin and radiation of modern Asian hornbills and the influential ecological roles they play as seed dispersal agents within Asian rainforests should help reveal the evolution of these roles. We constructed a dated phylogeny of hornbills using mitochondrial DNA sequences of the cytochrome b gene and discovered that all clades leading to frugivorous hornbills originated in the mid-Eocene ~48 Ma. This 'explosive' radiation coincided with a remarkable floral invasion of Asian rainforests from the Indian microcontinent. Analysis of phylogenetic data, in conjunction with palaeontological events, suggests that the invasion of distinctive flora comprised two waves, one during the mid-Eocene, when India was offshore of the Sunda Shelf, and the other late Eocene, when India collided with the Asian mainland. We propose that frugivorous vertebrates, such as hornbills, were present during the first wave and assisted rapid colonization of the Asian flora. PMID- 21545426 TI - Intraspecific divergence in the lateral line system in the nine-spined stickleback (Pungitius pungitius). AB - The mechanosensory lateral line system of fishes is an important organ system conveying information crucial to individual fitness. Yet, our knowledge of lateral line diversity is almost exclusively based on interspecific studies, whereas intraspecific variability and possible population divergence have remained largely unexplored. We investigated lateral line system variability in four marine and five pond populations of nine-spined stickleback (Pungitius pungitius). We found significant differences in neuromast number between pond and marine fish. In particular, three of seventeen lateral line regions (viz. caudal peduncle superficial neuromasts; canal neuromasts from the anterior trunk and caudal peduncle) showed strong divergence between habitats. Similar results were obtained with laboratory-reared individuals from a subset of populations, suggesting that the patterns found in nature likely have a genetic basis. Interestingly, we also found habitat-dependent population divergence in neuromast variability, with pond populations showing greater heterogeneity than marine populations, although only in wild-caught fish. A comparison of neutral genetic (F(ST)) and phenotypic (P(ST)) differentiation suggested that natural selection is likely associated with habitat-dependent divergence in neuromast counts. Hence, the results align with the conclusion that the mechanosensory lateral line system divergence among marine and pond nine-spined sticklebacks is adaptive. PMID- 21545427 TI - Acute loss of lung function without wheezing during bee venom immunotherapy. PMID- 21545428 TI - Intracellular glutathione redox status in human dendritic cells regulates IL-27 production and T-cell polarization. AB - BACKGROUND: Glutathione redox status, changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione, plays a significant role in various aspects of cellular function. In this study, we examined whether intracellular glutathione redox status in human dendritic cells (DCs) regulates the polarization of Th1/Th2 balance. METHODS: Human monocyte-derived DCs (MD-DCs) treated with glutathione reduced form ethyl ester (GSH-OEt) or L-buthionine-(S,R)-sulfoximine (BSO) were stimulated by lipopolysaccharide (LPS), and the levels of polarization cytokines were measured. Next, DCs matured by LPS or thymic stromal lymphopoietin (TSLP) were cocultured with allogeneic CD4(+) naive T cells and Th1/Th2 balance was evaluated by cytokine production from the primed T cells. RESULTS: Monocyte derived DCs exposed to GSH-OEt and BSO had increased and decreased intracellular GSH contents, respectively. Lipopolysaccharide-induced interleukin (IL)-27 production was enhanced by GSH-OEt and suppressed by BSO, but neither GSH-OEt nor BSO affected the expression of HLA-DR, CD80, CD83, or CD86. Mature GSH-OEt treated MD-DCs enhanced interferon (IFN)-gamma production from CD4(+) T cells compared with nontreated MD-DCs, and small interfering RNA (siRNA) against IL-27 suppressed the effect of GSH-OEt on IFN-gamma production. Additionally, although human myeloid DCs activated by TSLP (TSLP-DCs) prime naive CD4(+) T cells to differentiate into Th2 cells, treatment of TSLP-DCs with GSH-OEt reduced IL-13 production and enhanced IFN-gamma production by CD4(+) T cells. Interleukin-27 siRNA attenuated the inhibitory effect of GSH-OEt on Th2 polarization. CONCLUSION: Our results reveal that Th1 and Th2 responses are controlled by intracellular glutathione redox status in DCs through IL-27 production. PMID- 21545429 TI - Histamine H4 receptors in normal conjunctiva and in vernal keratoconjunctivitis. AB - BACKGROUND: While it is known that histamine is the primary mediator of ocular allergy, the presence and distribution of histamine receptors are not well documented in the human eye. Our aim was to evaluate histamine receptor expression in normal and vernal keratoconjunctivitis conjunctiva. METHODS: Mucosal biopsies were obtained from conjunctiva of healthy donors and from tarsal conjunctiva of vernal patients. Immunostaining and semi-quantitative reverse transcriptase polymerase chain reaction for H(1), H(2), H(3), and H(4) receptors were performed. Histamine receptor expression was also evaluated in conjunctival cell cultures exposed to histamine, interleukin-4, interleukin-5, interferon gamma and tumor necrosis factor-alpha. RESULTS: Immunostaining for H(1) and H(2) receptors was slightly positive in normal and over-expressed in vernal tissues. H(3) receptors were rarely present in normal and inflamed conjunctiva. In striking contrast to control tissues, H(4) receptors were highly expressed in all inflamed tissues, particularly by stromal inflammatory cells. Semi-quantitative reverse-transcriptase polymerase chain reaction demonstrated an over-expression of H(1), H(2), and H(4) receptors in vernal vs control tissues. Notably, H(4) receptors were five times more expressed in vernal vs control tissues. In cell cultures, H(2) receptor expression was stimulated eight times the normal levels by interleukin-4 and three times by histamine, but the H(4) receptor was only slightly affected by stimulation with these mediators. CONCLUSIONS: Increased expression of H1, and particularly of H(2) and H(4) receptors in vernal keratoconjunctival tissues indicate their important role in the pathogenesis of this disease. H(4) receptors may be a target in the treatment of allergic inflammation. PMID- 21545430 TI - Newly appreciated roles for basophils in allergy and protective immunity. AB - Basophils are evolutionarily conserved in many animal species, in spite of the fact that they account for <1% of peripheral blood leukocyte. This suggests that basophils have an indispensable and nonredundant role in vivo, even though they show some phenotypic similarity with tissue-resident mast cells. However, their functional significance remained uncertain long after Paul Ehrlich discovered them as blood-circulating cells with basophilic granules more than 130 years ago. The study of basophils has been far behind that of mast cells, owing to the rarity of basophils and the paucity of tools for their detection and functional analysis. Recent development of novel analytical tools, including basophil depleting antibodies and genetically engineered mice deficient only in basophils, has greatly advanced basophil research and illuminated previously unrecognized roles of basophils. We now appreciate that basophils and mast cells play distinct roles in immune responses. Basophils have crucial roles in the development of acute and chronic allergic responses, the protective immunity against ecto- and endoparasites, and the regulation of acquired immunity, including the augmentation of humoral memory responses and the initiation of Th2 responses. Thus, basophils are no longer the neglected minority and are key players in the immune system. PMID- 21545431 TI - Varicocoele repair: the role of the duration of infertility. PMID- 21545432 TI - Achieving excellence as a breast health educator at a global level: a new initiative of the World Society for Breast Health. PMID- 21545433 TI - Predictors of invasion and axillary lymph node metastasis in patients with a core biopsy diagnosis of ductal carcinoma in situ: an analysis of 255 cases. AB - The diagnosis of ductal carcinoma in situ (DCIS) using core biopsy does not ensure the absence of invasion on final excision. We performed a retrospective analysis of 255 patients with DCIS who had subsequent excision. Clinical, radiologic, and pathologic findings were correlated with risk of invasion and sentinel lymph node (SLN) metastasis. Of 255 patients with DCIS, 199 had definitive surgery and 52 (26%) had invasive ductal carcinoma (IDC) on final excision. Extent of abnormal microcalcification on mammography, and presence of a radiologic/palpable mass and solid type of DCIS were significantly associated with invasion on final excision. Sentinel lymph node biopsy was performed in 131 (65.8%) patients of whom 18 (13.4%) had metastasis. Size of IDC and extent of DCIS on final pathology were significantly associated with positive SLN. Micrometastasis and isolated tumor cells comprised majority (71.4%) of the metastases in DCIS. SLN biopsy should be considered in those with high risk DCIS. PMID- 21545434 TI - Mammary myofibrosarcoma: case report and literature review. AB - A case of myofibrosarcoma of breast is reported. A female patient aged 81 years presented with a mammary mass lesion. Histologically, the tumor consisted of neoplastic spindle cells arranged in fascicles and with variably cellularity and hyalinization. Immunohistochemical studies showed expression of vimentin, smooth muscle actin, and Bcl-2, but not desmin, S-100, C-kit, or CD34. Proliferative index identified by Ki67 was approximately 30%. Electron microscopy revealed variable amount of rough endoplasmic reticulum, myofilaments, fibronexus junctions, and fibronectin fibrils. The histological, immunohistochemical, and ultrastructural features of this tumor were consistent with myofibrosarcoma. This case will be one of the very few cases of ultrastructurally confirmed mammary myofibrosarcoma reported in the literature and contributes to the recognition of this rare mammary malignant neoplasm. The literature on mammary myofibrosarcoma and its differential diagnosis is also reviewed. PMID- 21545435 TI - Pseudoangiomatous stromal hyperplasia of breast in man: a case report. PMID- 21545436 TI - Primary isolated hydatid cyst of breast. PMID- 21545437 TI - Large breast masses in young patients: a multi-disciplinary approach to an uncommon clinical scenario. PMID- 21545438 TI - Spraguea (Microsporida: Spraguidae) infections in the nervous system of the Japanese anglerfish, Lophius litulon (Jordan), with comments on transmission routes and host pathology. AB - Anglerfish from the genus Lophius are a globally important commercial fishery. The microsporidian Spraguea infects the nervous system of these fish resulting in the formation of large, visible parasitic xenomas. Lophius litulon from Japan were investigated to evaluate the intensity and distribution of Spraguea xenomas throughout the nervous system and to assess pathogenicity to the host and possible transmission routes of the parasite. Spraguea infections in L. litulon had a high prevalence; all fish over 403 mm in standard length being infected, with larger fish usually more heavily infected than smaller fish. Seventy percent of all fish examined had some gross visible sign of infection. The initial site of development is the supramedullary cells on the dorsal surface of the medulla oblongata, where all infected fish have parasitic xenomas. As the disease progresses, a number of secondary sites typically become infected such as the spinal, trigeminal and vagus nerves. Fish with infection in the vagus nerve bundles often have simultaneous sites of infection, in particular the spinal nerves and along the ventral nerve towards the urinary bladder. Advanced vagus nerve infections sometimes form xenomas adjacent to kidney tissue. Spraguea DNA was amplified from the contents of the urinary bladders of two fish, suggesting that microsporidian spores may be excreted in the urine. We conclude that supramedullary cells on the hindbrain are the primary site of infection, which is probably initiated at the cutaneous mucous glands where supramedullary cells are known to extend their peripheral axons. The prevalence of Spraguea infections in L. litulon was very high, and infections often extremely heavy; however, no associated pathogenicity was observed, and heavily infected fish were otherwise normal. PMID- 21545439 TI - An evaluation of the duration of efficacy of emamectin benzoate in the control of Caligus curtus Muller infestations in Atlantic cod, Gadus morhua L. AB - The duration of efficacy of emamectin benzoate in the control of Caligus curtus infestations in Atlantic cod, Gadus morhua L., was studied following an administration of 50 MUg kg-1 for seven consecutive days. No lice were found on medicated fish when challenged 1 week (challenge 1) or 5 weeks (challenge 2) following termination of medication, whereas the mean abundance of lice among the unmedicated fish was 17.9 and 19.3 lice per fish in challenge 1 and 2, respectively. Muscle concentrations of 19.5 +/- 8.2 ng g-1 and 3.4 +/- 0.9 ng g 1, respectively, and skin concentrations of 23.1 +/- 10.8 and 4.2 +/- 1.0 ng g-1, respectively, were found 27 and 55 days following the termination of medication. Tissue concentrations and the duration of efficacy indicate a dosing regime for emamectin in cod, similar to the regime used for Atlantic salmon, Salmo salar L. PMID- 21545440 TI - Chronic ulcerative dermatopathy in cultured marine fishes. Comparative study in sharpsnout sea bream, Diplodus puntazzo (Walbaum). AB - Chronic ulcerative dermatopathy (CUD) also known as chronic erosive dermatopathy, hole-in-the-head, head and lateral line erosion syndrome (HLLE) and lateral line depigmentation (LLD) is a chronic disease of unknown aetiology that affects the lateral line canals of the head and the trunk of various fish species. It has been described only in freshwater species although there are reports that it also affects marine fish. Here, we describe the disease in cultured sharpsnout sea bream using histology and scanning electron microscopy and identify several marine species as CUD sensitive. The results of this study correlate the development of the disease with the use of borehole water, indicating that the aetiology is probably associated with water quality rather than nutritional imbalance or infectious agents. PMID- 21545441 TI - Infections with Philometra sp. associated with mortalities in wild-hatched captive-raised striped bass, Morone saxatilis (Walbaum). AB - The striped bass, Morone saxatilis (Walbaum), once represented an important resource for fisheries in the St Lawrence River (Quebec, Canada). A restoration programme, involving captive propagation, was implemented with the objective of restocking the population, which had disappeared in the late 1960s. An unusually high rate of mortality was observed during the winter of 2006 in captive-raised fingerlings that were originally collected from the Miramichi River (New Brunswick, Canada) the previous summer. Post-mortem examinations revealed extensive granulomatous and hyperplastic peritonitis associated with numerous nematodes of the genus Philometra. Given the severity of the lesions, high intensity of infection by Philometra sp. was presumed to be the primary factor in the unusual mortalities reported that winter. Observations suggest that this nematode, which was acquired in the wild, cannot establish itself in a captive environment, most likely because of the absence of the obligate intermediate host. Examination of archived specimens of striped bass showed that this parasite was probably present in the St Lawrence River population prior to its extirpation. Consequently, the introduction of infected fish into this ecosystem should not be a concern. Nevertheless, infection-related mortalities of fingerlings might affect dynamics of wild striped bass populations. PMID- 21545442 TI - Pathogenic Gram-positive cocci in South African rainbow trout, Oncorhynchus mykiss (Walbaum). PMID- 21545443 TI - Understanding the gender disparity in HIV infection across countries in sub Saharan Africa: evidence from the Demographic and Health Surveys. AB - Women in sub-Saharan Africa bear a disproportionate burden of human immunodeficiency virus (HIV) infections, which is exacerbated by their role in society and biological vulnerability. The specific objectives of this article are to (i) determine the extent of gender disparity in HIV infection; (ii) examine the role of HIV/acquired immune deficiency syndrome (AIDS) awareness and sexual behaviour factors on the gender disparity and (iii) establish how the gender disparity varies between individuals of different characteristics and across countries. The analysis involves multilevel logistic regression analysis applied to pooled Demographic and Health Surveys data from 20 countries in sub-Saharan Africa conducted during 2003-2008. The findings suggest that women in sub-Saharan Africa have on average a 60% higher risk of HIV infection than their male counterparts. The risk for women is 70% higher than their male counterparts of similar sexual behaviour, suggesting that the observed gender disparity cannot be attributed to sexual behaviour. The results suggest that the risk of HIV infection among women (compared to men) across countries in sub-Saharan Africa is further aggravated among those who are younger, in female-headed households, not in stable unions or marital partnerships or had an earlier sexual debut. PMID- 21545444 TI - Scripting sexual function: a qualitative investigation. AB - The biomedical model assumes universal agreement in what it means to have a functioning sex life. In reality there is significant variation in the criteria that individuals employ in assessing their sex lives. We use a scripting approach to understand the meaning of sexual function from a lay perspective. Based on the accounts of 32 individuals representing a range of sexual function experience, we identified three scripts employed by participants to describe their sexual experiences: the biomedical script emphasised genital function and physical release (orgasm), the relational script focused on relational aspects of encounters and valued emotional intimacy and security; and the erotic script focused on pleasure and valued novelty and excitement. Respondent accounts usually contained elements of more than one script, but often one of these was prominent. At the intra-psychic level each script serves as a schema, comprising priorities, expectations and evaluative criteria. In the context of sex therapy, this scripting approach may help shed light on the sources of sexual difficulties. Our findings also challenge the current domination of the biomedical script in measuring, diagnosing and treating sexual dysfunction, since the construct does not adequately reflect the priorities of those who prioritise alternative scripts. PMID- 21545445 TI - An interactional approach to conceptualising small talk in medical interactions. AB - In medical interactions, it may seem straightforward to identify 'small talk' as casual or social talk superfluous to the institutional work of dealing with patients' medical concerns. Such a broad characterisation is, however, extremely difficult to apply to actual talk, and more specificity is necessary to pursue analyses of how small talk is produced and what it achieves for participants in medical interactions. We offer an approach to delineating a subgenre of small talk called topicalised small talk (TST), derived on the basis of conversation analytically-informed analyses of routine consultations involving orthopaedic surgeons and older patients. TST is a line of talk that is referentially independent from their institutional identities as patients or surgeons, oriented instead to an aspect of the personal biography of one (or both), or to some neutral topic available to interactants in any setting (e.g. weather). Importantly, TST is an achievement of both patient and surgeon in that generation and pursuit of topic is mutually accomplished. In an exploratory but systematic analysis, when this approach was applied to a purposive sample of surgeon-patient interactions, TST was much more prevalent in visits with White than African American patients. Accounts for possible ethnic differences in TST are suggested. PMID- 21545446 TI - Investigation into activation of dysfunctional schemas in euthymic bipolar disorder following positive mood induction. AB - OBJECTIVES. There are dysfunctional cognitions that may be characteristic of bipolar disorder (BD), and which may be mood-state dependent. However, it has been found that such cognitions may be resilient to minor positive mood increase. The aim of this study is to investigate whether positive mood-induction procedure has the effect of altering the availability of dysfunctional schemas in a group of individuals with BD. DESIGN. The sentence completion task was designed to assess the content of dysfunctional schemas: it was modified for use with positive mood-induction procedure in the current study so that more dysfunctional schematic models would lead to completion of sentence stems by negative constructs, whereas functional schematic models led to completion of sentence stems by positive constructs. METHODS. Using the modified sentence completion task, 30 participants with remitted bipolar I disorder were compared with 30 individuals with no history of affective disorder. Results. At baseline the bipolar group inserted significantly more dysfunctional completions than the control group. Following mood induction, the number of dysfunctional completions was reduced for both groups. The bipolar group still inserted significantly more dysfunctional completions relating to autonomy than the control group following mood induction. However, no significant group by time interactions were identified. CONCLUSIONS. As predicted, participants' reports of dysfunctional attitudes reduced following the mood-induction procedure, although no difference was identified between the groups in terms of the size of this reduction. The bipolar group continued to insert significantly more dysfunctional completions for the factor of autonomy, suggesting that this group has more access to autonomy schemas, regardless of change in mood. This finding may have implications in terms of focus of therapy and relapse prevention work. PMID- 21545447 TI - Confirmatory factor analysis and factorial invariance analysis of the adolescent self-report Strengths and Difficulties Questionnaire: how important are method effects and minor factors? AB - OBJECTIVES. This study examined the factor structure of the self-report Strengths and Difficulties Questionnaire, paying special attention to the number of factors and to negative effects of reverse-worded items and minor factors within the subscales on model fit. Furthermore, factorial invariance across gender, age, level of education, and ethnicity was investigated. DESIGN. Data were obtained from the Youth Health Monitor Rotterdam, a community-based health surveillance system. METHODS. The sample consisted of 11,881 pupils of 11-16 years old. Next to the original five-factor model, a factor model with the number of factors based on parallel analysis and scree test was investigated. Confirmatory factor analysis for ordered-categorical measures was applied to examine the goodness-of fit and factorial invariance of the factor models. RESULTS. After allowing reverse-worded items to cross-load on the prosocial behaviour factor and adding error correlations, a good fit to the data was found for the original five-factor model (emotional symptoms, conduct problems, hyperactivity-inattention, peer problems, prosocial behaviour) and a model with four factors (emotional symptoms and peer problems, conduct problems, hyperactivity-inattention, prosocial behaviour). Factorial invariance across gender, age, level of education, and ethnicity was found for the final five- and four-factor model, except for the prosocial factor of the four-factor model that showed partial invariance across gender. Conclusions. While support was found for both models, the final five factor model is theoretically more plausible and gained additional support as the original scales emotional problems and peer problems showed different relations with gender, educational level, and ethnicity. PMID- 21545448 TI - Clinical correlates of olfactory hallucinations in schizophrenia. AB - OBJECTIVES. Olfactory hallucinations (OHs) are underrepresented in conventional clinical instruments, infrequently researched, and poorly understood. To advance understanding of OHs, we examined their past-month prevalence and co-occurring symptoms in two datasets. DESIGN. One dataset comprised categorical codes and was examined using homogeneity analysis and logistic regression; the other dataset comprised numeric ratings and was examined using principal components analyses and linear regression. METHOD. The two datasets included: (1) 962 cases with Present State Examination - 9th Edition (PSE-9), codes (recoded present/absent) from the World Health Organization 10 Country (WHO-10) Study and (2) 265 cases with ratings on Scales for Assessing Positive/Negative Symptoms of Schizophrenia (SAPS/SANS). Two PSE-9 items (external- and self-smells) were recoded into a single OH item to examine consistency with the SAPS/SANS dataset, which contained a single OH item. RESULTS. Prevalence of OHs and hallucinations in other modalities differed according to the WHO-10 international centre. Across centres, OHs were present in 13% of the WHO-10 dataset, similar to the 17% prevalence rate in the SAPS/SANS dataset. Referential/control delusions and other hallucinations (particularly, somatic/tactile/gustatory hallucinations) were significant independent correlates of OHs in both datasets. OHs also co-occurred with social anxiety and depression in the WHO-10 dataset, with self-smells being particularly associated with self-depreciation. CONCLUSIONS. Sociocultural factors may modulate the self-reporting and/or detection of OHs and hallucinations in other modalities. Referential/control delusions promote the generation and/or maintenance of OHs independent of factors shared with other hallucinations. OHs and hallucinations of taste, touch, and bodily sensation frequently co-occur. Self-smells warrant sensitive probing. PMID- 21545449 TI - The clinical and occupational effectiveness of condition management for Incapacity Benefit recipients. AB - OBJECTIVES. The aim of the Condition Management Programme (CMP) is to help Incapacity Benefit recipients manage their health conditions more effectively and return to work. This paper seeks to examine the clinical and employment outcomes from a group-based and mixed-condition CMP. DESIGN. In a prospective cohort design, measures of employment status and psychological well-being were taken at three time points; pre-CMP, post-CMP, and at 3-month follow-up. METHOD. Participants (N= 2,064) with a variety of physical and mental health conditions voluntarily attended a seven session cognitive-behaviourally informed psychoeducational group intervention. The psychological measures used were the Clinical Outcomes in Routine Evaluation - Outcome Measure, Work and Social Adjustment Scale, Self-Efficacy Scale, and the Intrinsic Motivation Scale. The employment status of participants was also measured at the three time points of the evaluation. RESULTS. Following CMP, 50% of participants experienced a reliable improvement in psychological well-being and 26% had either taken some steps towards work or returned to work at follow-up. Participants with a mental health condition were more likely to experience a reliable improvement in psychological well-being compared to those with physical health conditions. CONCLUSIONS. The results suggest that participation in CMP may be helpful in facilitating more effective self-management of the health conditions contributing to unemployment. The results have implications for whether formal employment assistance should be available in mental health services. PMID- 21545450 TI - Emotions, self-esteem, and paranoid episodes: an experience sampling study. AB - OBJECTIVES. The evidence to date for a causal role of emotions in the generation of paranoid symptoms is scarce, mainly because of a lack of studies investigating the longitudinal association between emotional processes and paranoia. The primary aim of this study was to investigate whether momentary emotional experiences (anxiety, depression, anger/irritability) and self-esteem predicted the onset and duration of a paranoid episode. We also studied whether levels of emotional experiences and self-esteem were respectively higher and lower during a paranoid episode. DESIGN. A 1-week, prospective momentary assessment study. METHODS. Data were collected using the experience sampling method, a structured self-assessment diary technique. The sample consisted of 158 individuals who ranged across the paranoia continuum. Participants with a psychotic disorder were recruited from in-patient and out-patient mental health services. Participants without psychotic disorder were sampled from the general population. RESULTS. Specific aspects of emotional experience were implicated in the onset and persistence of paranoid episodes. Both an increase in anxiety and a decrease in self-esteem predicted the onset of paranoid episodes. Cross-sectionally, paranoid episodes were associated with high levels of all negative emotions and low level of self-esteem. Initial intensity of paranoia and depression was associated with longer, and anger/irritability with shorter duration of paranoid episodes. CONCLUSIONS. Paranoid delusionality is driven by negative emotions and reductions in self-esteem, rather than serving an immediate defensive function against these emotions and low self-esteem. Clinicians need to be aware of the central role of emotion-related processes and especially self-esteem in paranoid thinking. PMID- 21545451 TI - Motivation to change and pathological gambling: analysis of the relationship with clinical and psychopathological variables. AB - OBJECTIVES. The present study analyses the internal factor structure of the University of Rhode Island Change Assessment (URICA) Scale in pathological gambling (PG). The scale's association with the clinical profile of patients is also evaluated. METHOD. The factor analysis was based on a sample of 531 men with a DSM-IV diagnosis of pathological gambling. The statistical analysis included confirmatory factor analysis and linear correlation. RESULTS. The analyses confirmed the internal structure obtained for the URICA. The internal consistency was satisfactory (Cronbach's alpha between .74 and .85). The association between URICA scores and the socio-demographic and clinical profile of patients ranged between moderate and weak (R coefficients below .30). Lower motivation was present in 28.4% of cases and it was associated with shorter duration of the disorder, lower severity of the PG symptoms, and high psychopathology. Conclusions. The results support the validity and reliability of the URICA in a Spanish clinical population of pathological gamblers. PMID- 21545452 TI - Clinical presentation and early care relationships in 'poor-me' and 'bad-me' paranoia. AB - OBJECTIVE. To test the proposal that 'poor-me' (PM) and 'bad-me' (BM) paranoia can be differentiated in terms of (1) current emotional experience and presence of grandiose delusions and (2) early caregiving and threats to self-construction. METHOD. Participants experiencing persecutory delusions were separated into PM (N= 21) and BM (N= 15) groups on the basis of perceived deservedness of the persecution. The groups were compared on measures examining grandiose delusions, shame and depression, parental care, and threats of alienation and insecurity. RESULTS. As predicted, BM patients scored higher on shame and depression, and lower on grandiose delusions, than PM patients. BM patients reported higher levels of parental overprotection, but PM patients were not characterized by neglect, and the groups did not differ in type of threat to self-construction. Conclusion. The two paranoia types were differentiated on symptomatic and emotional presentation, but predicted differences in early relationships and self construction were not fully supported. PMID- 21545453 TI - The habitual use of emotion regulation strategies in schizophrenia. AB - OBJECTIVES. Although emotion dysregulation is regarded as a core feature of schizophrenia, the use of specific regulatory strategies remains poorly understood. The aim of this study, therefore, was to investigate the habitual use of suppression, reappraisal, and acceptance in this population. METHODS. Thirty three individuals with schizophrenia and 36 matched controls completed self report measures examining emotion regulation and psychosocial functioning. RESULTS. No group differences were found in terms of use of suppression or reappraisal, but clinical participants reported using less acceptance. Further, greater use of acceptance was associated with better psychosocial outcomes. CONCLUSIONS. Results highlight the potential utility of acceptance-based interventions for comorbid psychopathology in schizophrenia. PMID- 21545454 TI - The power of talk: developing discriminatory group norms through discussion. AB - Research has shown that group discussion can increase intergroup prejudice and discrimination. However, we know little about the process by which discussion has this effect. Therefore, four studies were conducted in a real-world context to investigate this process. Results suggest that discussing a negative societal stereotype (relative to individual rumination in Studies 1 and 3 and alternative discussions in Studies 2 and 3) increases intentions to engage in discrimination against the out-group target of the stereotype. This is mediated by the formation of an in-group norm which supports discrimination (Study 1) and the extent to which the discussion validates the stereotype (Study 2). A fourth study manipulated the extent to which consensus on the negative stereotype was reached through discussion. When the discussion ended in consensus, participants have greater intention to undertake collective action against the stereotyped out group, mediated by a congruent in-group norm. These results provide evidence that the process by which discussion increases intergroup discrimination is via the formation of discriminatory local group norms. PMID- 21545455 TI - How minority members' perceptions of majority members' acculturation preferences shape minority members' own acculturation preferences: evidence from Chile. AB - Two survey studies were conducted in Chile with members of the indigenous minority group Mapuche (Ns = 566; 394). The aim was to find predictors of minority members' acculturation preferences, especially integration. It was hypothesized that minority members' preferences would depend on their perceptions of what majority members want. Specifically, it was predicted that a perception that majority members want minority members to maintain their original culture would be associated with a greater desire for culture maintenance among minority participants. Further, it was predicted that a perception that majority members want intergroup contact would be associated with a greater desire for contact among minority participants. Finally, it was predicted that a perception that majority members are in favour of both culture maintenance and contact (i.e., integration) would be associated with more support for integration among minority participants. Results bore out these predictions. Theoretical and policy implications are discussed. PMID- 21545456 TI - Do memory-impaired individuals report stable attitudes? AB - This research explored whether individuals diagnosed with probable Alzheimer's disease report stable attitudes. Two groups of participants (16 memory-impaired individuals with dementia and 16 matched controls without memory impairment) were presented with photos of various common objects and asked to indicate their attitude towards each object. Participants completed this task on two occasions, separated by 1 week. The results of the experiment revealed that memory-impaired individuals showed significant stability across time in their attitudes, although their level of attitude stability was less pronounced than that demonstrated by the matched controls. Theoretical and applied implications of the results are discussed. PMID- 21545457 TI - 'They seem to think "we're better than you"': framing football support as a matter of 'national identity' in Scotland and England. AB - Within social psychology, studies of the nation have typically been understood in terms of national identity. Criticisms have been made of the tendency to conflate 'being' a member of a national category with psychological attachment to the group and its members. Furthermore, ethnomethodologically informed approaches have argued that little has been said about when and how social actors frame matters as one of national identity. Taking the example of national football support, this study considers the circumstances under which football may be cast as a matter of national identity, and when such ascriptions are resisted. Interviews were conducted with participants born and resident in England and Scotland, whereas in Scotland national football support is treated as a matter of national identity for Scottish and English people, in England it is separated from a collective sense of English identity. Adopting a discursive analytic stance, this study examines the internal and external attribution of national stereotypes and considers their role in managing issues of social causality, justification of in-group behaviour, and the differentiation of national groups. PMID- 21545458 TI - Mobilizing opposition towards Muslim immigrants: national identification and the representation of national history. AB - This research, conducted in the Netherlands, investigates whether people who do not feel strongly committed to their national in-group (i.e., lower identifiers) can be mobilized against expressive rights of Muslim immigrants when specific historical representations of the nation are made salient. Three experimental studies were conducted to examine whether a national identity presented as rooted in Christianity results in comparable levels of opposition towards Muslim expressive rights for lower and higher identifiers. Results in all three studies show that higher identifiers were more likely to oppose Muslim rights than lower identifiers when a tolerant or neutral historical national identity was salient. Yet, no differences in levels of opposition between lower and higher identifiers were observed in the Christian condition. These findings underline the importance of historical representations of the nation to understand the relationship between national identification and opposition to ethnic out-groups. PMID- 21545459 TI - The impact of rumination on aggressive thoughts, feelings, arousal, and behaviour. AB - Although rumination following a provocation can increase aggression, no research has examined the processes responsible for this phenomenon. With predictions derived from the General Aggression Model, three experiments explored the impact of two types of post-provocation rumination on the processes whereby rumination augments aggression. In Experiment 1, relative to distraction, self-focused rumination uniquely increased the accessibility of arousal cognition, whereas provocation-focused rumination uniquely amplified the accessibility of aggressive action cognition. In Experiment 2, provocation-focused rumination uniquely increased systolic blood pressure. In Experiment 3, both types of rumination increased aggressive behaviour relative to a distraction condition. Angry affect partially mediated the effects of both provocation- and self-focused rumination on aggression. Self-critical negative affect partially mediated the effect of self-focused rumination but not provocation-focused rumination. These findings suggest that provocation-focused rumination influences angry affect, aggressive action cognition, and cardiovascular arousal, whereas self-focused rumination increases self-critical negative affect, angry affect, and arousal cognition. These studies enhance our understanding of why two types of post-provocation rumination increase aggressive behaviour. PMID- 21545460 TI - Trust, cooperation, and equality: a psychological analysis of the formation of social capital. AB - Research suggests that in modern Western culture there is a positive relationship between the equality of resources and the formation of trust and cooperation, two psychological components of social capital. Two studies elucidate the psychological processes underlying that relationship. Study 1 experimentally tested the influence of resource distributions on the formation of trust and intentions to cooperate; individuals receiving a deficit of resources and a surplus of resources evidenced lower levels of social capital (i.e., trust and cooperation) than did individuals receiving equal amounts. Analyses revealed the process was affective for deficit participants and cognitive for surplus participants. Study 2 provided suggestive support for the affective-model of equality and social capital using proxy variables in the 1996 General Social Survey data set. Results suggest support for a causal path of unequal resource distributions generating affective experiences and cognitive concerns of justice, which mediate disengagement and distrust of others. PMID- 21545461 TI - In vitro elution of amikacin and ticarcillin from a resorbable, self-setting, fiber reinforced calcium phosphate cement. AB - OBJECTIVE: To determine in vitro elution characteristics of amikacin and ticarcillin from fiber reinforced calcium phosphate beads (FRCP). SAMPLE POPULATION: Experimental. METHODS: FRCP beads with water (A), amikacin (B), ticarcillin/clavulanate (C), or both amikacin and ticarcillin/clavulanate (D) were bathed in mL phosphate-buffered saline (PBS) at 37 degrees C, 5% CO(2) and 95% room air. PBS was sampled (eluent) and beads were placed in fresh PBS at time points 1 and 8 hours and 1, 2, 3, 4, 5, 6, 7, 10, 12, 14, 18, 21, 25, 28, 35, 42, 49, and 56 days. Antibiotic concentration and antimicrobial activity of eluent against Escherichia coli, Staphylococcus aureus, and Klebsiella pneumoniae were determined. RESULTS: Both antibiotics eluted in a bimodal pattern. Beads with a single antibiotic eluted 20.8 +/- 2.5% of amikacin and 29.5 +/- 0.8% of ticarcillin over 56 days. Coelution of the antibiotics resulted in a lower proportion (AUC(0-infinity) ) of antibiotics eluted for both amikacin (9.5 +/- 0.2%) and ticarcillin (21.7 +/- 0.09%). Bioassay of antimicrobial activity of the eluent (t = 1, 8, and 24 hours) established reduced antimicrobial activity of amikacin from combination beads (D). CONCLUSIONS: FRCP beads with amikacin or ticarcillin/clavulanate, but not the combination, are suitable carriers for wound implantation. CLINICAL RELEVANCE: Duration before complete resorption of FRCP beads in vivo should be determined before clinical use as a resorbable depot. The results of this study underscore the importance of testing drug combinations, despite success of the combination systemically, before their use in local applications. PMID- 21545462 TI - Postoperative mortality in cats after ureterolithotomy. AB - OBJECTIVE: To identify preoperative risk factors associated with mortality before discharge in cats having a single or multiple ureterotomy procedures to treat a ureteral obstruction. STUDY DESIGN: Case series. ANIMALS: Cats (n=47). METHODS: Data were obtained from the medical records (2002-2009) of cats that had undergone ureterolithotomy procedures. Multiple preoperative factors were evaluated for association of survival to discharge. RESULT: Survival to discharge after ureterolithotomy was 79% (37/47). Over 79% of cats were azotemic before surgery and 94% had chronic kidney disease changes at the time of ultrasonographic diagnosis. Six cats required an additional surgical procedure because of complications with ureterolithotomy. Overall prevalence of postoperative uroabdomen was 6% (3/47). On multivariate analysis, there were no preoperative variables significantly associated with survival to discharge. CONCLUSIONS: Ureterolithotomy in cats was associated with a 21% mortality rate before hospital discharge. No preoperative variables associated with mortality were identified; therefore, further studies are needed to identify more discriminating preoperative characteristics for mortality after ureterolithotomy in this population of cats. PMID- 21545463 TI - Internal fixation of a fractured axis in an adult horse. AB - OBJECTIVE: To report internal fixation of a fractured axis with a dynamic compression plate (DCP). STUDY DESIGN: Case report. ANIMALS: A 7-year-old Warmblood gelding. METHOD: Surgery was performed under anesthesia in sternal recumbency. After fracture reduction the complete transverse fracture in the cranial third of the axis was stabilized with a 7-hole 4.5 mm DCP. Optimal positioning of the plate and the length of the screws were facilitated by fluoroscopy. Recovery from anesthesia was supervised in a pool. RESULTS: The horse had an excellent outcome and returned to its previous activity level. CONCLUSION: Surgical treatment with fracture reduction and plate fixation enables normal bearing of the head and neck and improves neck flexibility soon after surgery. PMID- 21545464 TI - Remanence and survival of commercial yeast in different ecological niches of the vineyard. AB - The use of commercial wine yeast strains as starters has been grown extensively over the past three decades. Wine yeasts are annually released in winery environments; however, little is known about the fate of these strains in the vineyard. To evaluate the industrial starter yeasts' ability to survive in nature and become part of the natural microbiota of musts, commercial yeast was disseminated voluntarily in an experimental vineyard in the Madrid region (Spain). A large sampling plan was devised over 3 years, including samples of grapes, leaves, bark and soil. The disseminated yeast was well represented in the vineyard during the first 8 months. After 2 years, the commercial yeast strain had not survived in the sprayed plants, but a residual population was found in plants situated 50 m east of the sprayed area. After 3 years, commercial yeast disseminated was not found in the sampled vineyard. Grapes and soil showed the highest number of yeasts isolated in the vegetative period, the bark being the main natural reservoir during the resting stages. The result of analysis of population variations from year to year indicated that permanent implantation of commercial strain (K1M) in the vineyard did not occur and its presence was limited in time. PMID- 21545465 TI - Permanent transvenous left ventricular endocardial pacing in a patient with univentricular atrioventricular connection. AB - Chronotropic incompetence is associated with poorer effort tolerance and worse mortality outcomes, not only in the general cardiac population but also in patients with congenital heart disease. When present in complex patients, pacing options may be limited by difficult pacing access, and an open surgical approach for epicardial lead placement may not always be desirable. We describe a case of symptomatic chronotropic incompetence in a patient with tricuspid atresia, valvar and subpulmonary stenosis, normally related great vessels, and a modified Blalock Taussig shunt, awaiting cardiac transplantation, whom we palliated with a transvenous endocardial pacing strategy. This technique may provide an alternative pacing strategy for highly selected patients, where few other treatment options are available. PMID- 21545466 TI - The use of octreotide to successfully treat protein-losing enteropathy following the Fontan operation. AB - Octreotide has had limited use for the treatment of protein-losing enteropathy following the Fontan operation. We describe three cases where subcutaneous octreotide was successfully used to treat refractory protein-losing enteropathy following the Fontan operation. Patients received octreotide therapy for a period of 14-28 months. Octreotide was discontinued in one patient due to symptomatic cholelithiasis; this patient died 7 months after treatment was discontinued. Octreotide may be a useful treatment in these patients, but further study on its efficacy and mechanism of action is needed. PMID- 21545467 TI - Right ventricular endocarditis in a pregnant woman with a restrictive ventricular septal defect. AB - A 22-year-old woman with a restrictive unoperated perimembranous ventricular septal defect was diagnosed with staphylococcal endocarditis during her 14th week of pregnancy. Echocardiography revealed a long, thin, and mobile vegetation along the right ventricular free wall that increased to 8 cm in length, with systolic protrusion across the pulmonary valve. The vegetation subsequently embolized, resulting in a pulmonary abscess. She responded favorably to intravenous antibiotic therapy maintained for a total of 6 weeks, with resolution of the intracardiac mass and pulmonary abscess. The remaining peripartum and postpartum course was relatively unremarkable. Percutaneous closure of the ventricular septal defect was successfully performed postpartum. PMID- 21545468 TI - Root dilation in patients with truncus arteriosus. AB - OBJECTIVE: A dilated aortic root is a common finding in children and adults with some forms of congenital heart defects. No data exist on root dilation in truncus arteriosus. We sought to delineate root dimensions across a population of patients with truncus arteriosus. DESIGN: We performed a single-center retrospective review of all patients with truncus arteriosus. Demographic information, clinical history, and most recent echocardiographic data were evaluated. RESULTS: We identified 76 patients whose most recent study was at a median age of 5.4 years (range 0--32.7 years). Mean truncal root z-score was 5.1 +/- 2.3. All but three patients had truncal root z-scores greater than or equal to 2. Truncal root z-scores remained stable with increasing body surface area and age. There were no cases of dissection or rupture. Six patients underwent truncal root surgery, typically for indications of root dilation with significant truncal valve insufficiency and left ventricular dilation. CONCLUSIONS: In conclusion, mean truncal root z-score was 5, and all but three patients had truncal root z scores greater than or equal to 2. Although repeat surgical intervention was rare and major complications related to root dilation did not occur in our cohort, further studies with longitudinal follow-up into adulthood are needed. PMID- 21545469 TI - The perspective of patients with congenital heart disease: does health care meet their needs? AB - OBJECTIVE: A first step in the delivery of tailored care is answering the following question: does health care meet the needs of patients? Therefore patients' perspective on health care use and their needs was examined. The design used was cross-sectional questionnaire study. PATIENTS: A total of 1109 adult congenital heart defect (CHD) patients attending one of eight Dutch hospitals were randomly selected from a national database (10% of all registered patients). MAIN OUTCOME MEASURES: Patient reported questionnaires on in- and outpatient health care use during the past year and need for additional care. RESULTS: A total of 66% and 40% of patients had contact with their cardiologist and general practitioner, respectively. Six to 10 percent were hospitalized, operated upon, or visited the emergency room. For the majority, the amount of contact was sufficient. Most patients indicated that the communication skills and expertise of the cardiologist and general practitioner were sufficient, and health care improvements were not necessary. Frequent health care users had a poor functional status and frequent contact with their cardiologist and general practitioner. Patients who want more contact with their cardiologist rated the communication skills of the cardiologist as insufficient. CONCLUSIONS: For most patients, the amount and quality of care are both sufficient. Patients who rate the communication skills of the cardiologist as insufficient have need more contact. In addition to the recommended training program as described in the American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) guidelines, we recommend the incorporation of communication training. This is the first study to provide insight into health care use and needs of CHD patients in countries with a compulsory health insurance system from the patient perspective. PMID- 21545470 TI - The impact of obesity on early postoperative outcomes in adults with congenital heart disease. AB - BACKGROUND: As the prevalence of obesity continues to increase, it now includes the growing number of patients with congenital heart disease (CHD). This particular obese patient population may pose additional intraoperative as well as postoperative challenges that may contribute to poor outcomes. Our aims were to determine the influence of obesity on morbidity and mortality in adults with CHD undergoing surgical repair at a free standing children's hospital. METHODS: A retrospective analysis of adult (>=18 years) CHD surgery cases from 2002 to 2008 was performed. Congenital heart lesions were defined as mild, moderate, or complex. Patients were categorized by body mass index (BMI): underweight (BMI < 20 kg/m(2)), normal (BMI 20-24.9 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)), and obese (BMI >= 30 kg/m(2)). Demographics, incidence of mortality, or specific morbidities were statistically compared using Fisher's exact test and analyses of variance (anovas). RESULTS: In this population (n = 165), overweight (29%) and obese (22%) patients were prevalent. Hypertension (HTN) and pre-HTN were more prevalent in obese and overweight patients. Postoperative renal dysfunction was observed in obese patients with complex CHD (P = .04). Mortality was not different among groups. CONCLUSIONS: Obesity is becoming increasingly common among adults with CHD. Despite marginal evidence of postoperative renal complications in obese patients with CHD of severe complexity, the overall presence of obesity did not influence mortality or short term postoperative morbidities. PMID- 21545471 TI - A rapid DNA extraction method for PCR amplification from wetland soils. AB - AIMS: We tested a method of rapid DNA extraction from wetland soil samples for use in the polymerase chain reaction. METHODS AND RESULTS: The glass bead/calcium chloride/SDS method obtained in the present study was compared with the calcium chloride/SDS/enzymatic extraction method and the UltraCleanTM Soil DNA Isolation Kit. Rapid DNA extraction could be completed within about two hours without purification steps. CONCLUSIONS: This study succeeded in establishing a fast soil DNA extraction protocol that can be applied to various environmental sources that are rich in humic acid content. SIGNIFICANCE AND IMPACT OF THE STUDY: The method provides a technology with high-quality DNA extraction from soils for testing the diversity of AOB and AOA. PMID- 21545472 TI - Meta-analysis: Coeliac disease and hypertransaminasaemia. AB - BACKGROUND: There may be a positive association between coeliac disease and serum hypertransaminasaemia but evidence is conflicting. AIMS: To conduct a systematic review and meta-analysis to determine the prevalence of coeliac disease in adults presenting with cryptogenic serum hypertransaminasaemia and the prevalence of hypertransaminasaemia in patients with newly diagnosed coeliac disease. METHODS: MEDLINE and EMBASE were searched up to August 2010. Case series and case-control studies recruiting adults with either cryptogenic hypertransaminasaemia that applied serological tests for coeliac disease and/or distal duodenal biopsy to participants or newly diagnosed biopsy-proven coeliac disease that assessed serum transaminases were eligible. The pooled prevalence of coeliac disease in individuals presenting with abnormal serum transaminases and the pooled prevalence of hypertransaminasaemia in newly diagnosed coeliac disease were calculated with 95% confidence intervals (CI). RESULTS: Eleven eligible studies were identified. Pooled prevalences of positive coeliac serology and biopsy proven coeliac disease in cryptogenic hypertransaminasaemia were 6% (95% CI 3% to 10%) and 4% (95% CI 1% to 7%) respectively. Pooled prevalence of abnormal serum transaminases in newly diagnosed coeliac disease was 27% (95% CI 13% to 44%). Exclusion of gluten led to normalisation of serum transaminase levels in 63% to 90% of patients within 1 year. CONCLUSIONS: Undetected coeliac disease is a potential cause for cryptogenic hypertransaminasaemia in 3% to 4% of cases. More than 20% of individuals with newly diagnosed coeliac disease may have abnormal serum transaminases and these normalise on a gluten-free diet in the majority of cases. PMID- 21545473 TI - Review article: Microscopic colitis--lymphocytic, collagenous and 'mast cell' colitis. AB - BACKGROUND: Microscopic colitis is a relatively common cause of chronic diarrhoea in predominantly older adults, traditionally termed lymphocytic colitis and collagenous colitis. Increased mast cells found in the colonic biopsies of some patients with chronic diarrhoea may represent a distinct type of microscopic colitis. AIM: To provide an updated review of the epidemiology, diagnosis and treatment of microscopic colitis, and to discuss the role of mast cells in the gastrointestinal tract and their potential role in cases of functional diarrhoea. METHOD: A MEDLINE literature search was performed to identify pertinent articles. Relevant clinical abstracts were also reviewed. RESULTS: Incidence rates of microscopic colitis (lymphocytic and collagenous colitis) have increased over time, to levels comparable with other forms of inflammatory bowel disease. The possibility of drug-induced microscopic colitis and concomitant coeliac sprue are important considerations when evaluating these patients. There are few controlled treatment trials in microscopic colitis, with much of the data on treatment coming from retrospective studies. Mast cells have been implicated in functional bowel disorders, with increased mast cells possibly contributing to cases of otherwise unexplained chronic diarrhoea, although this concept requires further investigation. CONCLUSIONS: In patients with microscopic colitis, a systematic approach to therapy often leads to satisfactory control of symptoms. The role of mast cells in chronic diarrhoea represents an evolving field, with the potential to offer alternative treatment pathways in patients with otherwise unexplained functional diarrhoea. PMID- 21545474 TI - Polymorphism of ITPA 94C>A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine. AB - WHAT IS KNOWN AND OBJECTIVE: Genetic polymorphisms of thiopurine S methyltransferase (TPMT) and inosine triphosphate pyrophosphohydrolase (ITPA 94C>A) contribute to variable responses, including fatal adverse effects, among subjects treated with 6-mercaptopurine (6-MP). Our objectives were to investigate the distribution of specific TPMT and ITPA genotypes in healthy subjects and patients with acute lymphoblastic leukaemia (ALL) from the three main ethnic groups (Malays, Chinese and Indians) in Malaysia and the association of the polymorphisms with adverse effects of 6-MP. METHODS: Patients with ALL and healthy controls were recruited and genotyped for genetic variants of TPMT and ITPA 94C>A. The relationship between genotypes and clinical outcomes was investigated. RESULTS AND DISCUSSION: Acute lymphoblastic leukaemia patients with allele ITPA 94A were more likely to develop fever and liver toxicity with 6-MP. The prevalence of TPMT variants was low and this makes it unlikely that testing for them would be useful in our populations. Only patients heterozygous for TPMT*3C were detected. WHAT IS NEW AND CONCLUSION: Our results suggest that ITPA 94C>A testing, but not TPMT testing, may help in minimizing the adverse effects of 6-MP in Malaysian patients. However, whether this is true in clinical practice requires a larger study and formal randomized controlled evaluation. PMID- 21545475 TI - NICE - impact on glaucoma case detection. AB - AIM: To investigate the impact of publication of the National Institute of Clinical Excellence (NICE) guidelines ('Glaucoma: diagnosis and management of chronic open angle glaucoma and ocular hypertension') in April 2009, on the referrals for suspect glaucoma to Moorfields Community Eye Clinic (MCEC) at Ealing Hospital. METHODS: The clinical data from all optometrist initiated referrals for suspect glaucoma and ocular hypertension were scrutinised by a Consultant Ophthalmologist for a 2 month period, 6 months after the publication of the NICE guidance. Each was then categorised into the following groups: glaucoma positive; glaucoma suspect; glaucoma negative; ocular hypertension (OHT) requiring further follow up in clinic; ocular hypertension to be followed up by community optometrist; other. The positive predictive value (PPV) was then calculated and a historical comparison made with previous studies. RESULTS: A total of 110 new referrals were assessed during the collection period, which reflects a marked increase in numbers attending. However, there was no increase in absolute numbers of glaucoma and glaucoma suspects identified. The absolute numbers of ocular hypertensive patients rose. The PPV fell to 0.25, which is lower than found in previous studies. CONCLUSIONS: The rising number of new referrals and the unchanged absolute numbers of glaucoma and glaucoma suspects identified following publication of the NICE guidance, in addition to a lower PPV, makes us question what advantage in improved case detection this represents. Furthermore, is this a cost effective strategy? We believe the next step is to introduce a repeat review, with carefully considered clinical governance of any new scheme. PMID- 21545476 TI - The short-term influence of elevated intraocular pressure on axial length. AB - PURPOSE: To investigate the influence of a short period of elevated IOP (induced through the wearing of standard swimming goggles) upon axial length. METHODS: Forty young adult subjects (20 myopes and 20 emmetropes, mean age 22 +/- 2 years) had their IOP and axial length measured before, during and after a 3 min period of swimming goggle wear. IOP was measured using a non-contact tonometer, and axial length with an optical biometer based upon the principle of partial coherence interferometry. RESULTS: A 3-min period of swimming goggle wear was found to be associated with a significant increase in IOP (mean change 3.7 +/- 2.6 mmHg, p < 0.0001) and a significant axial elongation of the eye (mean change in axial length of 18 +/- 12 MUm, p < 0.0001). Both IOP and axial length were found to return to baseline levels upon removal of the swimming goggles. A significant positive association was found between the changes in IOP and axial length (r(2) = 0.37, p < 0.0001). There were no significant differences between the emmetropic and myopic subjects in terms of their magnitude of change in axial length and IOP during swimming goggle wear. CONCLUSIONS: A small magnitude of elevation in IOP, induced through mechanical means and imposed for a short period of time was associated with a small but statistically significant axial elongation of the eye. PMID- 21545477 TI - Dilated cardiomyopathy: a possibly underestimated presentation of Cushing's disease. PMID- 21545478 TI - Plasma vaspin concentrations are elevated in metabolic syndrome in men and are correlated with coronary atherosclerosis in women. AB - OBJECTIVE: Vaspin is visceral adipose-tissue-derived adipokine, which has an insulin-sensitizing effect in obese type 2 diabetic rodent models. As adipokines may serve as a link between visceral adiposity and atherosclerosis, we investigated whether plasma vaspin concentrations were associated with the metabolic syndrome and coronary atherosclerosis. DESIGN AND METHODS: We measured fasting plasma vaspin levels in 81 subjects with the metabolic syndrome and 241 age- and sex-matched control subjects without the metabolic syndrome using the enzyme-linked immunosorbent assay. Multi-detector row cardiac computed tomography was performed to evaluate coronary atherosclerosis. We analysed sex-specific plasma vaspin concentrations according to the presence of the metabolic syndrome and the severity of coronary atherosclerosis. RESULTS: Plasma vaspin concentrations were significantly higher in men with the metabolic syndrome compared with those without the metabolic syndrome [median 0.60 (inter-quartile range 0.40-0.99) ng/ml vs 0.40 (0.26-0.66) ng/ml, P = 0.002]. There was a positive correlation between plasma vaspin concentrations and body mass index, waist circumference, and per cent body fat in men. However, these relationships were not found in women. Plasma vaspin concentrations were associated with the presence and severity of coronary artery stenosis such as higher Agatstone calcium score, number of diseased vessels and characteristics of coronary artery plaque only in women. CONCLUSIONS: Higher plasma vaspin concentrations are significantly associated with metabolic syndrome in men. In women, vaspin concentrations are associated with coronary atherosclerosis. Further studies regarding the role of vaspin in the pathogenesis of obesity and atherosclerosis are required. PMID- 21545481 TI - The effects of age and gender on the pharmacokinetics and pharmacodynamics in healthy subjects of the plasminogen activator, lanoteplase. AB - AIMS: To investigate the influence of age and gender on the intravenous pharmacokinetics and pharmacodynamics of the plasminogen activator, lanoteplase. METHODS: Forty healthy subjects (10 each of young males, elderly males, young females and elderly females) received a single bolus 10 kU kg(-1) intravenous dose of lanoteplase. Plasma from blood serially collected for 24 h post-dose was analyzed for lanoteplase (antigen), fibrinogen, plasminogen and alpha2 antiplasmin concentrations, plasma plasminogen activation activity (PPAA) and rapid plasminogen activator inhibitor (PAI-1). RESULTS: Lanoteplase mean total systemic clearance (CL(t)) values ranged from 1.9 to 2.8 l h(-1) and mean steady state volume of distribution (V(ss)) values ranged from 12.3 to 15.6 l. Age-by gender interactions were observed for lanoteplase CL(t) (P= 0.04), but no differences were observed for V(ss) or elimination half-life. Elderly females had a 27% lower mean CL(t) than young females (95% CI for the difference 0.17, 1.27 l h(-1)) and 32% lower CL(t) than elderly males (95% CI for the difference 0.15, 1.65 l h(-1)). PPAA AUC/dose values did not show an age-by-gender interaction. Haemostasis parameters indicated only a slight degree of systemic plasminogen activation. CONCLUSIONS: Elderly females had a lower mean lanoteplase CL(t) than elderly males and young females. However, no difference was observed between young and elderly females for the AUC/dose of PPAA. In addition, there were no age-related or gender-related differences observed in the other pharmacodynamic parameters measured. PMID- 21545479 TI - Inhibitors of propagation of coagulation: factors V and X. AB - Cardiovascular diseases are still the most important cause of morbidity and mortality in western countries and antithrombotic treatment is nowadays widely used. Drugs able to reduce coagulation activation are the treatment of choice for a number of arterial and/or venous thromboembolic conditions. Some of the drugs currently used for this purpose, such as heparins (UFH or LMWH) and VKA, have limitations consisting of a narrow therapeutic window and an unpredictable response with the need of laboratory monitoring in order to assess their efficacy and safety. These drawbacks have stimulated an active research aimed to develop new drugs able to act on single factors involved in the coagulation network, with predictable response. Intense experimental and clinical work on new drugs has focused on synthetic agents, which could preferably be administered orally and at fixed doses. The most advanced clinical development with new anticoagulants has been achieved for those inhibiting FXa and some of them, like fondaparinux, are already currently used in clinical practice. Other agents, such as rivaroxaban, apixaban, otamixaban and edoxaban are under development and have already been studied or are currently under investigation in large scale phase III clinical trials for prevention and treatment of venous thromboembolism, atrial fibrillation and acute coronary syndromes. Some of them have proved to be more effective than conventional therapy. Data on some agents inhibiting FVa are still preliminary and some of these drugs have so far been considered only in patients with disseminated intravascular coagulation secondary to sepsis. PMID- 21545480 TI - How to manage hypertension in pregnancy effectively. AB - The hypertensive disorders of pregnancy (HDP) are a leading cause of maternal mortality and morbidity in both well and under-resourced settings. Maternal, fetal, and neonatal complications of the HDP are concentrated among, but not limited to, women with pre-eclampsia. Pre-eclampsia is a systemic disorder of endothelial cell dysfunction and as such, blood pressure (BP) treatment is but one aspect of its management. The most appropriate BP threshold and goal of antihypertensive treatment are controversial. Variation between international guidelines has more to do with differences in opinion rather than differences in published data. For women with severe hypertension [defined as a sustained systolic BP (sBP) of >=160 mmHg and/or a diastolic BP (dBP) of >=110 mmHg], there is consensus that antihypertensive therapy should be given to lower the maternal risk of central nervous system complications. The bulk of the evidence relates to parenteral hydralazine and labetalol, or to oral calcium channel blockers such as nifedipine capsules. There is, however, no consensus regarding management of non severe hypertension (defined as a sBP of 140-159 mmHg or a dBP of 90-109 mmHg), because the relevant randomized trials have been underpowered to define the maternal and perinatal benefits and risks. Although antihypertensive therapy may decrease the occurrence of BP values of 160-170/100-110 mmHg, therapy may also impair fetal growth. The potential benefits and risks do not seem to be associated with any particular drug or drug class. Oral labetalol and methyldopa are used most commonly, but many different beta-adrenoceptor blockers and calcium channel blockers have been studied in clinical trials. PMID- 21545482 TI - Selective serotonin re-uptake inhibiting antidepressants and the risk of overanticoagulation during acenocoumarol maintenance treatment. AB - AIM: The aim of this study was to investigate the effects of co-medication with selective serotonin re-uptake inhibitors (SSRIs) on overanticoagulation during acenocoumarol maintenance treatment. METHODS: All subjects from The Rotterdam Study who received acenocoumarol maintenance treatment between April 1 1991 and September 9 2009 were followed for the event of an international normalized ratio (INR) >=6, until death, end of treatment or end of the study period. With the Andersen-Gill extension of the Cox proportional hazards model, risks for repeated events of overanticoagulation in relation to concomitant SSRI use were calculated. RESULTS: The risk for overanticoagulation during acenocoumarol maintenance treatment was increased in combination with fluvoxamine (HR 2.63, 95% CI 1.49, 4.66) and venlafaxine (HR 2.19, 95% CI 1.21, 3.99). There was no increase in risk for the other SSRIs, but numbers of exposed cases were low for all SSRIs except paroxetine. CONCLUSION: Fluvoxamine and venlafaxine were associated with a more than double risk of INR values >=6 in acenocoumarol treated subjects. PMID- 21545483 TI - Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal. AB - AIMS: To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock. METHODS: Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling. RESULTS: The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h(-1) (49%), a mean half-life of 9.6 h (range 0.83-28.6 h) and a total volume of distribution of 19.5 l (range 6.48 35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low. CONCLUSIONS: Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (>1 mg l(-1)). PMID- 21545484 TI - Should monitoring of vancomycin be delayed? A case of likely nephrotoxicity occasioned by morbid obesity and minimal monitoring. PMID- 21545486 TI - Comprehension of argument structure and semantic roles: evidence from English learning children and the forced-choice pointing paradigm. AB - Research using the intermodal preferential looking paradigm (IPLP) has consistently shown that English-learning children aged 2 can associate transitive argument structure with causal events. However, studies using the same methodology investigating 2-year-old children's knowledge of the conjoined agent intransitive and semantic role assignment have reported inconsistent findings. The aim of the present study was to establish at what age English-learning children have verb-general knowledge of both transitive and intransitive argument structure using a new method: the forced-choice pointing paradigm. The results suggest that young 2-year-olds can associate transitive structures with causal (or externally caused) events and can use transitive structure to assign agent and patient roles correctly. However, the children were unable to associate the conjoined agent intransitive with noncausal events until aged 3;4. The results confirm the pattern from previous IPLP studies and indicate that children may develop the ability to comprehend different aspects of argument structure at different ages. The implications for theories of language acquisition and the nature of the language acquisition mechanism are discussed. PMID- 21545485 TI - Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Available data suggest that fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors, such as ketoconazole. Currently, no information is available on whether dose adjustment is necessary when fesoterodine is administered with a moderate CYP3A4 inhibitor. WHAT THIS STUDY ADDS: This study shows that adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor. AIMS: To assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine. METHODS: In this open-label, randomized, two-way crossover study, 28 healthy subjects (18-55 years) received single doses of fesoterodine 8 mg alone or with fluconazole 200 mg. PK endpoints, including the area under the plasma concentration-time curve from 0 to infinity (AUC(0,infinity)), maximum plasma concentration (C(max) ), time to C(max) (t(max) ), and half-life (t(1/2) ), were assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine. RESULTS: Concomitant administration of fesoterodine with fluconazole increased AUC(0,infinity) and C(max) of 5-HMT by approximately 27% and 19%, respectively, with corresponding 90% confidence intervals of (18%, 36%) and (11%, 28%). There was no apparent effect of fluconazole on 5-HMT t(max) or t(1/2) . Fesoterodine was generally well tolerated regardless of fluconazole co administration, with no reports of death, serious adverse events (AEs) or severe AEs. Following co-administration of fesoterodine with fluconazole, 13 subjects (48%) experienced a total of 40 AEs; following administration of fesoterodine alone, six subjects (22%) experienced a total of 19 AEs. The majority of AEs were of mild intensity. There were no clinically significant changes in laboratory or physical examination parameters. CONCLUSION: Fesoterodine 8 mg single dose was well tolerated when administered alone or with fluconazole. Based on the observed increase in 5-HMT exposures being within the inherent variability of 5-HMT pharmacokinetics, adjustment of fesoterodine dose is not warranted when co administered with a moderate CYP3A4 inhibitor provided they are not also inhibitors of transporters. PMID- 21545487 TI - Are people successful at learning sequences of actions on a perceptual matching task? AB - We report the results of an experiment in which human subjects were trained to perform a perceptual matching task. Subjects were asked to manipulate comparison objects until they matched target objects using the fewest manipulations possible. An unusual feature of the experimental task is that efficient performance requires an understanding of the hidden or latent causal structure governing the relationships between actions and perceptual outcomes. We use two benchmarks to evaluate the quality of subjects' learning. One benchmark is based on optimal performance as calculated by a dynamic programming procedure. The other is based on an adaptive computational agent that uses a reinforcement learning method known as Q-learning to learn to perform the task. Our analyses suggest that subjects were successful learners. In particular, they learned to perform the perceptual matching task in a near-optimal manner (i.e., using a small number of manipulations) at the end of training. Subjects were able to achieve near-optimal performance because they learned, at least partially, the causal structure underlying the task. In addition, subjects' performances were broadly consistent with those of model-based reinforcement-learning agents that built and used internal models of how their actions influenced the external environment. We hypothesize that people will achieve near-optimal performances on tasks requiring sequences of action-especially sensorimotor tasks with underlying latent causal structures-when they can detect the effects of their actions on the environment, and when they can represent and reason about these effects using an internal mental model. PMID- 21545488 TI - Acquiring contextualized concepts: a connectionist approach. AB - Conceptual knowledge is acquired through recurrent experiences, by extracting statistical regularities at different levels of granularity. At a fine level, patterns of feature co-occurrence are categorized into objects. At a coarser level, patterns of concept co-occurrence are categorized into contexts. We present and test CONCAT, a connectionist model that simultaneously learns to categorize objects and contexts. The model contains two hierarchically organized CALM modules (Murre, Phaf, & Wolters, 1992). The first module, the Object Module, forms object representations based on co-occurrences between features. These representations are used as input for the second module, the Context Module, which categorizes contexts based on object co-occurrences. Feedback connections from the Context Module to the Object Module send activation from the active context to those objects that frequently occur within this context. We demonstrate that context feedback contributes to the successful categorization of objects, especially when bottom-up feature information is degraded or ambiguous. PMID- 21545489 TI - Growth temperature regulation of some genes that define the superficial capsular carbohydrate composition of Escherichia coli K92. AB - We studied growth temperature as a factor controlling the expression of genes involved in capsular polymers of Escherichia coli K92. These genes are shown to be regulated by growth temperature. Expression levels of genes belonging to the kps cluster, responsible for polysialic acid (PA) biosynthesis, were significantly increased at 37 degrees C compared with at 19 degrees C, being up to 500-fold increased for neuE and neuS genes. Similarly, the genes for the nan operon, responsible for PA catabolism, also reached higher expression levels at 37 degrees C, although with slightly lower values (39-141-fold). In contrast, genes of the cps operon, which are implicated in colanic acid (CA) metabolism, were upregulated when the bacteria were grown at 19 degrees C, albeit to a much lesser extent (around twofold). This different regulation of genes involved in the biosynthesis of polysialic and CAs correlates with the reported maximal production temperatures for the two polymers. The results suggest that the metabolism of PA is predominantly regulated by changes in gene expression, while CA production may be regulated mainly by post-transcriptional processes such as phosphorylation-dephosphorylation reactions. PMID- 21545490 TI - A catabolic pathway for the degradation of chrysene by Pseudoxanthomonas sp. PNK 04. AB - The chrysene-degrading bacterium Pseudoxanthomonas sp. PNK-04 was isolated from a coal sample. Three novel metabolites, hydroxyphenanthroic acid, 1-hydroxy-2 naphthoic acid and salicylic acid, were identified by TLC, HPLC and MS. Key enzyme activities, namely 1-hydroxy-2-naphthoate hydroxylase, 1,2 dihydroxynaphthalene dioxygenase, salicylaldehyde dehydrogenase and catechol-1,2 dioxygenase, were noted in the cell-free extract. These results suggest that chrysene is catabolized via hydroxyphenanthroic acid, 1-hydroxy-2-naphthoic acid, salicylic acid and catechol. The terminal aromatic metabolite, catechol, is then catabolized by catechol-1,2-dioxygenase to cis,cis-muconic acid, ultimately forming TCA cycle intermediates. Based on these studies, the proposed catabolic pathway for chrysene degradation by strain PNK-04 is chrysene -> hydroxyphenanthroic acid -> 1-hydroxy-2-naphthoic acid -> 1,2 dihydroxynaphthalene -> salicylic acid -> catechol ->cis,cis-muconic acid. PMID- 21545491 TI - Hemophagocytic syndrome occurred in a patient with subcutaneous panniculitis-like T-cell lymphoma without overt skin lesion: successful treatment with steroid pulse therapy. PMID- 21545492 TI - False-negative sentinel lymph node biopsy resulting from obstruction of lymphatic basin by nodal metastasis: a case report of malignant melanoma. PMID- 21545493 TI - Cutaneous silica granuloma with generalized involvement of lymph nodes. AB - We report a case of cutaneous silica granuloma with generalized involvement of distal lymph nodes; no similar case has been reported in the published work. The 45-year-old man was a stonemason who had been incidentally sprayed with rock dust from a saw 22 years ago. The subject presented with nodules and erythematous areas on his face and chin. In addition, there was swelling in the cervical and inguinal lymph nodes. An excised lymph node had normal architecture with numerous non-caseating epithelioid cell granuloma and silicotic nodules which contained scattered, multinucleated, giant cells. There were particles in the granuloma exhibiting birefringence under polarized light microscopy. Elemental X-ray spectra of these lesions showed the presence of silica in these granulomas. PMID- 21545494 TI - Acquired reactive perforating collagenosis in dermatomyositis. PMID- 21545495 TI - Case of eosinophilic pustular folliculitis associated with pregnancy. PMID- 21545496 TI - Superficial granulomatous pyoderma accompanied with ulcerative colitis successfully treated with tacrolimus ointment. PMID- 21545497 TI - Livedo vasculopathy associated with methylenetetrahydrofolate reductase C677T homozygosity. PMID- 21545498 TI - Therapeutic effectiveness of botulinum toxin type A based on severity of palmar hyperhidrosis. AB - A dose of 60 units (U) of botulinum toxin type A (BT-A) has been confirmed to have efficacy for patients with palmoplantar hyperhidrosis. However, the effectiveness of this dose is limited in severe cases defined as sweat production of 2 mg/cm(2) per min or more (measured by the ventilated capsule method) and a Hyperhidrosis Disease Severity Scale (HDSS) grade of 3 or 4. An increased dose of 90 U of BT-A was found to reduce sweating for approximately 7 months. In a comparison of patients with sweat production of more than 2.5 mg/cm(2) per min and an HDSS grade of 4 and patients with sweat production of 2.5 mg/cm(2) per min or less and an HDSS grade of 3, there was no difference in the reduction of sweat production at 5 months, but the duration of the reduced sweating was shorter for the former group. This suggests that there are limits to the efficacy of BT-A for severe forms of the disease with sweat production of more than 2.5 mg/cm(2) per mL. PMID- 21545499 TI - Clinical effectiveness of once-daily levofloxacin for inflammatory acne with high concentrations in the lesions. PMID- 21545500 TI - Inflammatory myofibroblastic tumor of the skin grossly mimicking squamous cell carcinoma: a case report. PMID- 21545501 TI - Linear immunoglobulin A/immunoglobulin G bullous dermatosis associated with Vogt Koyanagi-Harada disease. AB - Vogt-Koyanagi-Harada disease is characterized by marked bilateral uveitis associated with symmetric vitiligo, alopecia, poliosis and dysacousia. Linear immunoglobulin (Ig)A bullous dermatosis (LABD) is characterized by small, tense, subepidermal bullae caused by IgA type autoantibody targeting the basal lamina. LABD patients sometimes show coexistence of IgG type autoantibody, termed linear IgA/IgG bullous dermatosis (LAGBD). We reported a 35-year-old Japanese male case of combined LAGBD and Vogt-Koyanagi-Harada disease. His human leukocyte antigen typing was -A24, B52, C*1202, DR*1502, DQ*0601. Immunoblot revealed that patient sera reacted to both 180- and 230-kDa proteins at the IgA and IgG level. Because Vogt-Koyanagi-Harada disease and LABD are reported to be associated with other autoimmune diseases, it is probable that Vogt-Koyanagi-Harada disease and LAGBD in our case may be associated with each other in the pathomechanism. However, we cannot exclude the possibility of this being mere coincidence. PMID- 21545502 TI - Short anagen syndrome successfully controlled with topical minoxidil and systemic cyclosporine A combination therapy. PMID- 21545503 TI - Clinical experience of ustekinumab in the treatment of erythrodermic psoriasis: a case series. PMID- 21545504 TI - Patterned pigmentation in a child: a case of segmental pigmentation disorder. PMID- 21545505 TI - Order and disorder in corneocyte adhesion. AB - Epidermal cornified cells are attached to each other with modified desmosomes, namely corneodesmosomes. Changes in the corneodesmosome degradation process influence the total thickness of the stratum corneum and surface appearance of the skin. The major extracellular constituents of corneodesmosomes are desmoglein 1, desmocollin 1 and corneodesmosin. The intracellular part of corneodesmosomes is cross-linked into cornified cell envelopes. Corneodesmosomes are degraded from the central surface area of each cell. Peripheral corneodesmosomes retain structural integrity up to the skin surface. A hypothesis where tight junctions in the stratum corneum play a role in this spatial difference in corneodesmosome degradation has recently been proposed. Genetic defects in corneodesmosin and inhibitors for proteases involved in corneodesmosome degradation result in accelerated desquamation and severe barrier impairment, presenting as the inflammatory type of peeling skin syndrome and Netherton syndrome, respectively. Abnormal corneodesmosome degradation is also found in more common skin diseases including ichthyosis vulgaris, atopic dermatitis, psoriasis vulgaris, lichen planus and soap-induced xerosis. PMID- 21545506 TI - Safety and efficacy of a fixed-dose cyclosporin microemulsion (100 mg) for the treatment of psoriasis. AB - Cyclosporin is a second-line modality for the treatment of psoriasis. The long term efficacy of cyclosporin and potential adverse side-effects, however, are a concern to patients. Therefore, a cyclosporin microemulsion (Neoral), which is steadily absorbed at an ultra-low dosage (1-2 mg/kg per day) or low dosage (2-3 mg/kg per day), is currently recommended. The dose must be calculated based on patient bodyweight and the blood concentration monitored regularly, which is time consuming. Furthermore, the concentration is related to the safety profile, but not to efficacy. We examined whether a fixed-dose cyclosporin microemulsion (100 mg/day) is effective for treating psoriasis. Enrolled patients (n = 40) were given either 100 mg cyclosporin emulsion once daily (group A) or 50 mg twice daily (group B), regardless of patient weight and condition, before meals in a randomized controlled study. Patient bodyweight ranged 50-80 kg. We assessed the serum cyclosporin concentration 1 h after administrating the medicine (C1 score), Psoriasis Area and Severity Index (PASI) score, quality of life, and the results of regular blood examinations. The improvement rate was 69.4 +/- 4.8% in group A and 73.4 +/- 4.3% in group B. PASI-50 was achieved by 82% in group A and 84% in group B. At 6 weeks, the number of patients with PASI-50 was significantly higher in group A than in group B. PASI-75 and -90 were also achieved in both groups with no significant difference between groups. Administration of a fixed-dose cyclosporin microemulsion (100 mg/day) is practical for second-line psoriasis treatment. PMID- 21545507 TI - Case of Ramsay-Hunt syndrome associated with dysphagia. PMID- 21545508 TI - Multicentric reticulohistiocytosis presenting with the cutaneous features of photosensitivity dermatitis. PMID- 21545509 TI - Detection of KI polyomavirus and WU polyomavirus DNA by real-time polymerase chain reaction in nasopharyngeal swabs and in normal lung and lung adenocarcinoma tissues. AB - Polyomaviruses KI (KIPyV) and WU (WUPyV) were detected from 7 (3.0%) and 38 (16.4%) of 232 children with respiratory tract infections by real-time PCR. The rates of infection by KIPyV and WUPyV alone were 3 of 7 (42.9%) and 20 of 38 (52.6%), respectively. In the other samples, various viruses (human respiratory syncytial virus, human metapneumovirus, human rhinovirus, parainfluenza virus 1 and human bocavirus) were detected simultaneously. One case was positive for KIPyV, WUPyV and hMPV. There was no obvious difference in clinical symptoms between KIPyV-positive and WUPyV-positive patients with or without coinfection. KIPyV was detected in one of 30 specimens of lung tissue (3.3%). Neither of the viruses was detected in 30 samples of lung adenocarcinoma tissue. PMID- 21545510 TI - A novel combination of selective agents for isolation of Leptospira species. AB - A novel combination of antimicrobial agents (sulfamethoxazole, 40 MUg/mL; trimethoprim, 20 MUg/mL; amphotericin B, 5 MUg/mL; fosfomycin, 400 MUg/mL; and 5 fluorouracil, 100 MUg/mL) was developed for selective isolation of leptospires from contaminated samples. The growth of 16 microorganisms considered as possible contaminants during isolation of Leptospira were inhibited by this antimicrobial cocktail. In contrast, the growth of a smaller inoculum (10(1) cells per mL) of 25 Leptospira strains (representing 18 serovars/serogroups of 5 species) was not suppressed by this antimicrobial combination. This cocktail, after being incorporated into Leptospira growth medium (Korthof's), successfully detected leptospires in environmental soil and water. Based on the results, this selective medium has the potential to meet the existing need for an effective selective medium for the isolation of Leptospira. PMID- 21545511 TI - Decreased plasma granulysin and increased interferon-gamma concentrations in patients with newly diagnosed and relapsed tuberculosis. AB - Granulysin and interferon-gamma (IFN-gamma) have broad antimicrobial activity which controls Mycobacterium tuberculosis (M. tuberculosis) infection. Circulating granulysin and IFN-gamma concentrations were measured and correlated with clinical disease in Thai patients with newly diagnosed, relapsed and chronic tuberculosis (TB). Compared to controls, patients with newly diagnosed, relapsed and chronic TB had lower circulating granulysin concentrations, these differences being significant only in newly diagnosed and relapsed TB (P < 0.001 and 0.004, respectively). Granulysin concentrations in patients with newly diagnosed and relapsed TB were significantly lower than in those with chronic TB (P= 0.003 and P= 0.022, respectively). In contrast, significantly higher circulating IFN-gamma concentrations were found in patients with newly diagnosed and relapsed TB compared to controls (P < 0.001). The IFN-gamma concentrations in newly diagnosed and relapsed patients were not significantly different from those of patients with chronic TB. However, in vitro stimulation of peripheral blood mononuclear cells (PBMCs) from patients with newly diagnosed, relapsed and chronic TB with purified protein derivative (PPD) or heat killed M. tuberculosis (H37Ra) enhanced production of granulysin by PBMCs. In vitro, stimulation of PBMCs of newly diagnosed TB patients with PPD produced greater amounts of IFN-gamma than did controls, while those stimulated with H37Ra did not. The results demonstrate that patients with active pulmonary TB have low circulating granulysin but high IFN gamma concentrations, suggesting possible roles in host defense against M. tuberculosis for these agents. PMID- 21545512 TI - Stability of recombinant bovine interferon-gamma antiviral activity in the absence of stabilizing additives. AB - The stability of recombinant bovine interferon-gamma (rbIFN-gamma) produced by a baculovirus expression system was investigated under different storage conditions: freezing-thawing and storage for 30 days at temperatures of -80, 4, 25, and 37 degrees C. Antiviral activity was not significantly decreased by freeze-thawing at least five times. Furthermore, although not statistically different, antiviral activity gradually decreased as temperature increased. These findings suggest that rbIFN-gamma possesses high thermal and freeze-thaw stability. PMID- 21545513 TI - Biomechanical characterisation of equine laryngeal cartilage. AB - REASONS FOR PERFORMING THE STUDY: Upper airway obstruction is a common problem in the performance horse as the soft tissues of the larynx collapse into the airway, yet there is a paucity of information on biomechanical properties for the structural cartilage components. OBJECTIVE: To measure the geometry and compressive mechanical properties of the hyaline cartilage to improve understanding of laryngeal function and morphology. METHODS: A total of 11 larynges were harvested from Thoroughbred and Standardbred racehorses. During gross dissection, linear dimensions of the cricoid were obtained. From both the cricoid and arytenoid, specimens were cored to obtain 6 mm disc samples from 3 sites within the dorsal cricoid (caudal, middle and rostral) and 2 central sites in the arytenoids (inner, outer). The specimens were mechanically tested using radial confined compression to calculate the aggregate modulus and permeability of the tissue. The biomechanical data were analysed using a nested mixed effects model. RESULTS: Geometrically, the cricoid has relatively straight walls compared to the morphology of human, ovine and canine larynges. There were significant observations of higher modulus with increasing age (0.13 MPa per year; P = 0.007) and stiffer cricoid cartilage (2.29 MPa) than the arytenoid cartilage (0.42 MPa; P<0.001), but no difference was observed between the left and right sides. Linear contrasts showed that the rostral aspect (2.51 MPa) of the cricoid was 20% stiffer than the caudal aspect (2.09 MPa; P = 0.025), with no difference between the arytenoid sites. CONCLUSIONS: The equine larynx is a well supported structure due to both the geometry and material properties of the cricoid cartilage. The hyaline structure is an order of magnitude higher in compressive modulus compared to the arytenoids and other hyaline-composed tissues. POTENTIAL RELEVANCE: These characterisations are important to understand the biomechanics of laryngeal function and the mechanisms involved with surgical interventions. PMID- 21545514 TI - The impact of body mass index on right ventricular systolic functions in normal and mildly obese healthy patients: a velocity vector imaging study. AB - BACKGROUND: Increasing prevalence of obesity is a significant problem in Western countries. Obesity has many effects on cardiovascular structure, function, and hemodynamics. Our aim was to compare the impact of body mass index (BMI) on right ventricular (RV) functions among healthy subjects with conventional echocardiography, tissue Doppler imaging (TDI), and velocity vector imaging (VVI). METHODS: Eighty-one healthy subjects divided into three group according to their BMI. All subjects were evaluated by conventional echocardiography, TDI, and VVI. A full polysomnogram were performed in subjects with BMI >= 30 km/m(2). RESULTS: RV end-diastolic and end-systolic diameters of patients in these three groups were similar (P > 0.05). There were no differences between each group in RV outflow tract fractional shortening (P = 0.52) and tricuspid annular plane systolic excursion (P = 0.94). No correlation observed between BMI and RV systolic parameters obtained with TDI. Longitudinal peak systolic strain and SRs were similar in all groups through each segment (P > 0.05). CONCLUSION: The results of our study show no changes in the RV functions in obese and overweight who were otherwise healthy subjects. We also revealed a significant correlation between BMI and left ventricular diameters and wall thickness but no relation with RV diameters or functions. PMID- 21545515 TI - Mitral valve diseases in Williams syndrome-case report and review of the literature. AB - Williams syndrome is a genetic syndrome involving an unusual facies, short stature, developmental delay and heart defects. There is a genetic marker for this disease. Williams syndrome is frequently associated with congenital heart defects. The most common cardiac diagnoses are supravalve aortic stenosis, supravalve pulmonic stenosis, and arterial hypertension. In contrast, the association of mitral valve prolapse with Williams syndrome is less well defined. We present a case of a 15-year-old girl with Williams syndrome who underwent successful mitral valve repair. Review of the echocardiographic database of our institution over a 10-year period identified 26 other patients with Williams syndrome. Overall, 10 of the 27 children with Williams syndrome had mitral valve disease (37%) including 9 patients with mitral valve prolapse and one with mitral insufficiency. In conclusion, patients with Williams syndrome should be examined for mitral valve disease. Mitral valve repair is feasible and may be considered in the growing child with Williams syndrome. PMID- 21545516 TI - Isolated left ventricular noncompaction mimicking ventricular mass. AB - Isolated left ventricular noncompaction is an inherited cardiomyopathy characterized by multiple prominent trabeculations with deep intertrabecular recesses. The diagnosis is often missed because echocardiography poses inherent problems of poor echo window in assessment of the LV apex, which is most commonly involved in noncompaction. We report a case in which conventional 2D echocardiography failed to demonstrate multiple prominent trabeculations. Contrast echocardiography confirmed the presence of multiple trabeculations with deep intertrabecular recesses. This report emphasizes the importance of contrast echocardiography in the diagnosis of ventricular noncompaction. PMID- 21545517 TI - Transesophageal echocardiographic detection of thrombus superimposed on metastatic left atrial tumor. AB - We present a 32-year-old male with metastatic thymic carcinoma invading the left atrium in whom two-dimensional transesophageal echocardiography was able to differentiate a thrombus superimposed on the tumor. PMID- 21545518 TI - Global and regional myocardial function quantification in Takotsubo cardiomyopathy in comparison to acute anterior myocardial infarction using two dimensional (2D) strain echocardiography. AB - AIMS: This study sought to compare global and regional myocardial function in Takotsubo cardiomyopathy (TC) to that in acute anterior myocardial infarction (AMI) using 2D strain imaging. METHODS: Twelve consecutive patients with TC (ten women, two men) and 12 patients with AMI (four women, eight men) underwent 2D echocardiography at initial presentation. 2D strain images were analyzed to measure longitudinal and radial strain. Global strain was calculated as the average longitudinal strain of the segments of two-, three-, and four-chamber views. Biplane ejection fraction was assessed using Simpson's biplane method. RESULTS: Significant differences in radial strain (TC vs. AMI) were found in lateral (13.5 +/- 10.1% vs. 25.1 +/- 11.2%, P = 0.035), posterior (15.2 +/- 14.5% vs. 51.4 +/- 14.2%, P < 0.001), and inferior (17.9 +/- 15.5% vs. 49.4 +/- 16.9%, P = 0.002) segments. Longitudinal strain was significantly lower in TC in basal inferior (-15.8 +/- 9.2% vs. -22.7 +/- 3.8%, P = 0.037), midinferior (-8.3 +/- 9.2% vs. -16.8 +/- 3.0%, P = 0.004), basal-posterior (-12.2 +/- 9.4% vs. -21.6 +/ 4.4%, P = 0.016), midposterior (-4.4 +/- 8.0% vs. -15.4 +/- 3.5%, P = 0.002), apical-posterior (2.3 +/- 6.7% vs. -6.4 +/- 10.1%, P = 0.023), and midlateral ( 3.4 +/- 6.9% vs. -9.5 +/- 5.8%, P = 0.028) segments. Global strain and ejection fraction were significantly higher in patients with AMI (-3.5 +/- 8.2% vs. -10.3 +/- 8.4%, P < 0.001 and 37 +/- 11% vs. 46 +/- 11%, P = 0.045). CONCLUSION: In TC, strain was reduced around the entire mid left-ventricular circumference, whereas in AMI it was predominantly reduced in the anterior and anteroseptal wall. These observed differences confirm the notion that TC affects myocardium beyond the territory of a single coronary artery. They may allow noninvasive distinction between both entities. PMID- 21545519 TI - A floating thrombus in sinus of valsalva complicated with cardiogenic shock in a patient with plasminogen activator inhibitor 1 4G/5G polymorphism. AB - Thrombus in sinus of Valsalva is unusual reason for acute myocardial infarction. We demonstrated a case with floating thrombus in sinus of Valsalva obstructing the right coronary ostium intermittently, and causing cardiogenic shock. The patient was diagnosed with multiplane transesophageal echocardiography and treated successfully with surgical removal of mass. A homozygote polymorphism of plasminogen activator inhibitor (PAI) 1 4G/5G was found. This is the first report demonstrating a patient with PAI 1 polymorphism and thrombus of Valsalva complicated with cardiogenic shock. PMID- 21545520 TI - Transesophageal echocardiographic finding of left atrial appendage lobe mimicking a mass lesion. AB - We describe an elderly patient undergoing ablation for atrial fibrillation in whom, two-dimensional transesophageal echocardiography showed a mass-like lesion in or adjacent to left atrial appendage (LAA). This mass-like effect was produced by en face visualization of the top of a LAA lobe in the presence of a small effusion in the transverse sinus of the pericardium. PMID- 21545521 TI - Melatonin attenuates brain contusion-induced oxidative insult, inactivation of signal transducers and activators of transcription 1, and upregulation of suppressor of cytokine signaling-3 in rats. AB - The induction of oxidative stress and inflammation has been closely linked in traumatic brain injury (TBI). Transcriptional factors of signal transducers and activators of transcription (STAT) proteins are redox sensitive and participate in the regulation of cytokine signaling. Previous studies demonstrated that melatonin protects neurons through its antioxidative and anti-inflammatory effects in various neuropathological conditions. However, the effect of melatonin on STAT activity after TBI has not yet been explored. In this study, we used a controlled weight-drop TBI model and found that brain contusion induced oxidative stress (a decreased level of total glutathione and an increased ratio of oxidized glutathione to total glutathione), a reduction in STAT1 DNA-binding activity, and consequently neuronal loss in a contusion depth-dependent manner. A significant increased mRNA expression of suppressor of cytokine signaling (SOCS3), inducible nitric oxide synthetase (iNOS), and interleukine-6 (IL-6), but a decreased protein expression of protein inhibitor of activated STAT (PIAS1), was found 24 hr after brain contusion. SOCS3 and PIAS1 are endogenous negative regulators of STAT1. Moreover, the combination of intraperitoneal and local (presoaked in gelfoam and placed on the traumatic cortex) administration of melatonin had the most pronounced influence in inhibiting all effects except the PIAS1 downregulation induced by brain contusion. The results suggest that SOCS-3 upregulation and oxidative stress may contribute to the STAT1 inactivation after TBI. Melatonin protects neurons from TBI by reducing oxidative stress, STAT1 inactivation, and upregulation of SOCS-3 and pro-inflammatory cytokines. PMID- 21545522 TI - Intracoronary melatonin increases coronary blood flow and cardiac function through beta-adrenoreceptors, MT1/MT2 receptors, and nitric oxide in anesthetized pigs. AB - Melatonin is involved in the regulation of the cardiovascular system through the modulation of sympathetic function and the nitric oxide (NO)-related pathway and interaction with MT1/MT2 receptors. However, information regarding its direct actions on coronary blood flow and cardiac function is scarce. This study therefore determined the primary in vivo effect of melatonin on cardiac function and perfusion and the involvement of the autonomic nervous system, MT1/MT2 receptors, and NO. In 35 pigs, melatonin infused into the coronary artery at 70 pg for each mL/min of coronary blood flow while preventing changes in heart rate and arterial pressure increased coronary blood flow, dP/dt(max), segmental shortening, and cardiac output by about 12%, 14%, 8%, and 23% of control values (P < 0.05), respectively. These effects were accompanied by an increase in coronary NO release of about 46% (P < 0.05) of control values. The aforementioned responses were graded in a further five pigs. Moreover, the blockade of muscarinic cholinoreceptors (n = 5) and alpha-adrenoreceptors (n = 5) did not abolish the observed responses to melatonin. After beta(1)-adrenoreceptors blocking (n = 5), melatonin failed to affect cardiac function, whereas beta(2) adrenoreceptors (n = 5) and NO synthase inhibition (n = 5) prevented the coronary response and the effect of melatonin on NO release. Finally, all effects were prevented by MT1/MT2 receptor inhibitors (n = 10). In conclusion, melatonin primarily increased coronary blood flow and cardiac function through the involvement of MT1/MT2 receptors, beta-adrenoreceptors, and NO release. These findings add new information about the mechanisms through which melatonin physiologically modulates cardiovascular function and exerts cardioprotective effects. PMID- 21545523 TI - Melatonin protects PLPC liposomes and LDL towards radical-induced oxidation. AB - This study investigated the in vitro protective effects of melatonin against oxidation of 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine (PLPC) liposomes [(PLPC) = 250 MUm] and low-density lipoproteins (LDL, 3 g/L total concentration) by hydroxyl radicals produced by water gamma radiolysis. Conjugated dienes (CD) and hydroperoxides from cholesteryl esters (CEOOH) and phospholipids (PCOOH) were measured as indices of lipid peroxidation. Protein (apoB) oxidation in LDL was assessed by carbonyl groups. Two LDL antioxidants (vitamin E and beta-carotene) were monitored as a function of the radiation dose. Three concentrations of melatonin were studied in PLPC liposomes, i.e., 20, 50 and 100 MUm, and one in LDL, i.e., 100 MUm. Melatonin consumption was also followed up in both lipid models upon irradiation, together with the residual PLPC concentration in liposomes. In PLPC liposomes, scavenging of lipid-derived peroxyl radicals was not the only phenomenon to explain the protective properties of melatonin towards lipid peroxidation. Indeed, melatonin also reacted with hydroxyl radicals generated in aqueous phase, which led us to suggest that hydroxyl radicals reacted relatively slowly with PLPC. Melatonin was efficient in lowering lipid peroxidation in LDL, as shown by the decrease in the formation of CDs and in hydroperoxides. Moreover, melatonin clearly slowed radio-induced apolipoprotein B carbonylation and protected alpha-tocopherol and beta-carotene in LDL. PMID- 21545524 TI - Pathogenesis of alcohol-induced liver disease: classical concepts and recent advances. AB - Alcoholic liver disease (ALD) is a primary consequence of heavy and prolonged drinking. ALD contributes to the bulk of liver disease burden worldwide. Progression of ALD is a multifactorial and multistep process that includes many genetic and environmental risk factors. The molecular pathogenesis of ALD involves alcohol metabolism and secondary mechanisms such as oxidative stress, endotoxin, cytokines and immune regulators. The histopathological manifestation of ALD occurs as an outcome of complex but controlled interactions between hepatic cell types. Hepatic stellate cells (HSCs) are the key drivers of fibrogenesis, but transformation of hepatocytes to myofibroblastoids also implicate parenchymal cells as playing an active role in hepatic fibrogenesis. Recent discoveries indicate that lipogenesis during the early stages of ALD is a risk for advancement to cirrhosis. Other recently identified novel molecules and physiological/cell signaling pathways include fibrinolysis, osteopontin, transforming growth factor-beta-SMAD and hedgehog signaling, and involvement of novel cytokines in hepatic fibrogenesis. The observation that ALD and non alcoholic steatohepatitis share common pathways and genetic polymorphisms suggests operation of parallel pathogenic mechanisms. Future research involving genomics, epigenomics, deep sequencing and non-coding regulatory elements holds promise to identify novel diagnostic and therapeutic targets for ALD. There is also a need for adequate animal models to study pathogenic mechanisms at the molecular level and targeted therapy. PMID- 21545525 TI - Emerging management concepts for eosinophilic esophagitis in children. AB - Eosinophilic esophagitis (EoE) is a newly recognized condition that appears to be increasing in incidence for as yet unknown reasons. It can occur at any age and presents both to gastroenterologists and allergists. Clinical manifestations range from gastrointestinal symptoms (vomiting, feeding difficulties, dysphagia or food bolus impaction) to co-existing atopic conditions (asthma, allergic rhinitis or eczema). The diagnosis requires demonstration of at least 15 eosinophils per high power field on esophageal histology, usually in the context of resistance to proton pump inhibitor treatment or a normal 24-h esophageal pH monitoring study. The differential diagnosis between EoE and gastroesophageal reflux disease (GERD) can be problematic as there is significant clinical overlap between both conditions. Although difficult-to-manage esophageal strictures are well recognized in patients with long-standing EoE, little is known about risk factors for the development of this complication. There is a paucity of data on both the natural history and optimal long-term management of EoE. Current treatment options include food allergen elimination diets, use of topical aerosolized corticosteroids, or a combination of the two. Pediatric case studies have been provided to illustrate the complexity of decision points that often arise in the management of these patients. This paper aims to discuss the various strategies currently available to clinicians in the management of EoE and highlights gaps in the current evidence base that urgently require further research. PMID- 21545526 TI - Transseptal left heart catheterization and the incidence of persistent iatrogenic atrial septal defects. AB - INTRODUCTION: Access to the left atrium for invasive and interventional cardiac procedures requires a transseptal (TS) puncture that creates an iatrogenic atrial septal defect (iASD). The utilization of TS access is increasing in cardiology, and the frequency of iASD is, therefore, likely to increase as well. Here, we discuss the TS technique, review existing series of iASD with regard to incidence and clinical significance of residual iASD, and present emerging techniques utilizing TS access where iASD may result. METHODS AND RESULTS: A PubMed search for "iatrogenic atrial septal defects" was performed to identify prospective series addressing the incidence of iASDs after TS procedures. We identified 10 series with primary attention to iASD. Cases involving TS access included electrophysiology ablation procedures, atrial appendage closure, and percutaneous balloon mitral valvuloplasty. Immediate postprocedural incidence of iASD was as high as 87%, with decreased incidence of residual iASD detected over time. At 18 months of follow-up, up to 15% of iASD cases persisted. Residual iASDs were not associated with clinical sequelae of embolism, cyanosis, or right heart failure. CONCLUSIONS: iASDs are frequent following TS access and a majority resolve over time. Available evidence suggests iASDs are well tolerated but late term follow up is limited. With the increased utilization of TS transcatheter procedures, the frequency and size of iASDs may rise. Understanding the rare but serious clinical implications of iASD and the need for systematic surveillance in the future is warranted. PMID- 21545527 TI - Physical activity for patients undergoing an allogeneic hematopoietic stem cell transplantation: benefits of a moderate exercise intervention. AB - An allogeneic hematopoietic stem cell transplantation (HSCT) can have profound and lasting adverse effects on a patient's physical and psychological well-being. So far, only few studies have investigated the effectiveness of physical activity over the entire inpatient phase of an allogeneic HSCT. PURPOSE: We performed a randomized controlled study to examine the influence of a controlled moderate exercise program starting parallel to chemotherapeutic conditioning and total body irradiation on the patient's physical and psychological constitution. PATIENTS AND METHODS: Forty-seven patients undergoing an allogeneic HSCT were randomly assigned to an exercise group (EG) or a control group (CG). While the EG took part in an endurance and activity of daily living-training twice a day, the CG received the clinic's standard physiotherapy program once a day. RESULTS: Significant differences and/or trends in favor of the EG were observed regarding the primary endpoint endurance performance (P=0.002), muscular strength (P=0.022), fatigue (P=0.046), and emotional state (P=0.028) without posing an additional risk for the individual. CONCLUSION: The results show that the training program is feasible and seems to have positive influences on physical performance and quality of life in patients undergoing an allogeneic HSCT. However, further studies are necessary to confirm these results. PMID- 21545528 TI - Levels of microbial agents in floor dust during remediation of a water-damaged office building. AB - We examined the effects of remediation on loads of culturable fungi in floor dust collected from a large water-damaged office building during four cross-sectional surveys (2002, 2004, 2005, and 2007, respectively). We created a binary remediation variable for each year for each sampled workstation using information on remediation associated with water damage obtained from building management and used generalized linear mixed-effects models. We found significantly lower levels of culturable total and hydrophilic fungi at remediated workstations than at non remediated workstations in 2004 and 2005 after completion of major remediation. The remediation effect, however, disappeared in 2007. The fraction of hydrophilic to total fungal concentrations was lowest in 2004, increased in 2005, and was highest in 2007. Our results indicate that the 2003 remediation lowered dust indices of dampness temporarily, but remediation was incomplete, consistent with a building assessment report of water infiltration. This study demonstrates the utility of longitudinal evaluation of microbial indices during remediation of water damage in this building, in which elimination of sources of moisture was not fully addressed. Our findings indicate that the fraction of hydrophilic fungi derived from concentrations of fungal species may be a useful index for assessing the long-term effectiveness of remediation. PRACTICAL IMPLICATIONS: This study demonstrates the utility of longitudinal evaluation of microbial indices during remediation of water damage in this building, in which elimination of sources of moisture was incomplete. Our findings indicate that the fraction of hydrophilic fungi derived from concentrations of fungal species may be a useful index for assessing the long-term effectiveness of remediation. PMID- 21545529 TI - Prevalence and location of maxillary sinus septa in the Taiwanese population and relationship to the absence of molars. AB - OBJECTIVES: Understanding the septum structure of the sinus is necessary for correct implant placement in the maxilla if sinus encroachment is required. The exact mechanism that controls septum development is unclear, although a role for the irregular pneumatization of the sinus floor following tooth loss has been suggested. The aims of this study were to examine the prevalence and location of sinus septa in the Taiwanese population and to determine whether there is a relationship between the presence of septa and the absence of molars. MATERIALS AND METHODS: Using computed tomography (CT) scans of sinuses obtained from 423 subjects (216 women and 207 men, mean age 53.65 years), septum morphology and its correlation with the presence of molars was examined. RESULTS: About 30% of subjects (124/423) had sinus septa, corresponding to 20.45% of all sinus segments detected (173/846). Fifty-nine patients had multiple septa, giving a prevalence of septa of 22.93%. Septa were located most frequently in the regions of the first and second molars. The prevalence was not related to tooth loss (edentulous, partially edentulous, or dentate maxillary segments). Logistic regression analysis showed that men were significantly more likely to have septa than were women (OR=1.67; P=0.019). CONCLUSIONS: In the 423 Taiwanese subjects tested, the prevalence of septum was 29.31% according to the subjects and 22.93% according to the sinus segments. The most frequent location of septa was in the region of the first and secondary molars. No correlation was observed between the presence of septa and the absence of molars. PMID- 21545530 TI - Prognostic parameters contributing to palatal implant failures: a long-term survival analysis of 239 patients. AB - OBJECTIVE: To evaluate the demographic, radiological and therapeutic parameters that influence the overall clinical performance of palatal implants subjected to orthodontic loading. PATIENTS AND METHODS: The data of all patients who had received an orthodontic palatal implant for skeletal anchorage between January 1998 and December 2007 were reviewed retrospectively. The primary endpoint was the implant loss. The following parameters were assessed by univariate (log-rank test) and multivariate (Cox's regression) analysis: (a) age and gender, (b) vertical bone height along the prospective implant axis, (c) surgeon's experience and (d) implant type. RESULTS: Two-hundred and thirty-nine palatal implants were inserted in patients aged between 10 and 65 years. In all, 11/239 (4.6%) implants were lost: nine during the healing phase and two under functional loading. On univariate analysis, "surgeon's experience" was associated with a better implant survival and vice versa (P=0.0005; log-rank test). The significance of "surgeon's experience" was confirmed by Cox's regression analysis (P=0.001; Wald test). All other parameters had no impact on implant loss. CONCLUSIONS: The survival probability of palatal implants is not related to demographic and radiological parameters. Implant losses mainly occurred early in the healing phase of the palatal implant. According to our data, "surgeon's experience" is the cornerstone of palatal implant success. PMID- 21545531 TI - The effect of smoking on survival and bone loss of implants with a fluoride modified surface: a 2-year retrospective analysis of 1106 implants placed in daily practice. AB - AIM: To compare the survival and peri-implant bone loss of implants with a fluoride-modified surface in smokers and nonsmokers. MATERIALS AND METHODS: Patient files of all patients referred for implant treatment from November 2004 to 2007 were scrutinized. All implants were placed by the same experienced surgeon (B. C.). The only inclusion criterion was a follow-up time of at least 2 years. Implant survival and bone loss were assessed by an external calibrated examiner (S. V.) comparing digital peri-apical radiographs taken during recall visits with the post-operative ones. Implant success was determined according to the international success criteria (Albrektsson et al. 1986). Survival of implants installed in smokers and nonsmokers was compared using the log-rank test. Both nonparametric tests and fixed model analysis were adopted to evaluate bone loss in smokers and nonsmokers. RESULTS: One-thousand one-hundred and six implants in 300 patients (186 females; 114 males) with a mean follow-up of 31 months (SD 7.15; range 24-58) were included. Nineteen implants in 17 patients failed, resulting in an overall survival rate of 98.3% at the implant level and 94.6% at the patient level. After a follow-up period of 2 years, the cumulative survival rates was 96.7% and 99.1% with the patient and implant as the statistical unit, respectively. Implant survival was significantly higher for nonsmokers compared with smokers (implant level P=0.025; patient level P=0.017). The overall mean bone loss was 0.34 mm (n=1076; SD 0.65; range 0-7.1). Smokers lost significantly more bone compared with nonsmokers in the maxilla (0.74 mm; SD 1.07 vs. 0.33 mm; SD 0.65; P<0.001), but not in the mandible (0.25 mm; SD 0.65 vs. 0.22 mm; SD 0.5; P=0.298). CONCLUSION: The present study is the first to compare peri-implant bone loss in smokers and nonsmokers from the time of implant insertion (baseline) to at least 2 years of follow-up. Implants with a fluoride modified surface demonstrated a high survival rate and limited bone loss. However, smokers are at a higher risk of experiencing implant failure and more prone to show peri-implant bone loss in the maxilla. Whether this bone loss is predicting future biological complications remains to be evaluated. PMID- 21545532 TI - Deproteinized bovine bone mineral in marginal defects at implants installed immediately into extraction sockets: an experimental study in dogs. AB - AIM: To evaluate the influence of deproteinized bovine bone mineral (DBBM) particles concomitant with the placement of a collagen membrane on alveolar ridge preservation and on osseointegration of implants placed into alveolar sockets immediately after tooth extraction. MATERIAL AND METHODS: The pulp tissue of the mesial roots of (3) P(3) was removed in six Labrador dogs and the root canals were filled. Flaps were elevated in the right side of the mandible, and the buccal and lingual alveolar bony plates were exposed. The third premolar was hemi sectioned and the distal root was removed. A recipient site was prepared and an implant was placed lingually. After implant installation, defects of about 0.6 mm wide and 3.1 mm depth resulted at the buccal aspects of the implant, both at the test and at the control sites. The same surgical procedures and measurements were performed on the left side of the mandible. However, DBBM particles with a size of 0.25-1 mm were placed into the remaining defect concomitant with the placement of a collagen membrane. RESULTS: All implants were integrated into mature bone. No residual DBBM particles were detected at the test sites after 4 months of healing. Both the test and the control sites showed buccal alveolar bone resorption, 1.8 +/- 1.1 and 2.1 +/- 1 mm, respectively. The most coronal bone-to implant contact at the buccal aspect was 2 +/- 1.1 an 2.8 +/- 1.3 mm, at the test and the control sites, respectively. This difference in the distance was statistically significant. CONCLUSION: The application of DBBM concomitant with a collagen membrane to fill the marginal defects around implants placed into the alveolus immediately after tooth extraction contributed to improved bone regeneration in the defects. However, with regard to buccal bony crest preservation, a limited contribution of DBBM particles was achieved. PMID- 21545533 TI - Relationship between the bone density estimated by cone-beam computed tomography and the primary stability of dental implants. AB - OBJECTIVES: The aims of this study were to objectively assess bone quality with density values obtained by cone-beam computed tomography (CBCT) and to determine the correlations between bone density and primary stability of dental implants. MATERIAL AND METHODS: Eighteen Straumann implants were inserted into 18 fresh femoral heads of swine. The bone densities of implant recipient sites were preoperatively determined by the density value using CBCT. The maximum insertion torque value of each implant was recorded using a digital torque meter. Resonance frequency, which represented a quantitative unit called the implant stability quotient (ISQ), was measured using an Osstell Mentor immediately after the implant placement. Spearman's correlation coefficient was calculated to evaluate the correlations among density values, insertion torques, and ISQs at implant placement. RESULTS: The density values ranged from 98 to 902. The mean density value, insertion torque, and ISQ were 591 +/- 226, 13.4 +/- 5.2 Ncm, and 67.1 +/- 8.1, respectively. Statistically significant correlations were found between the density values and insertion torque (r(s) =0.796, P<0.001), density values and ISQ (r(s) =0.529, P=0.024), and insertion torque and ISQ (r(s) =0.758, P<0.001). CONCLUSIONS: The bone quality evaluated by specific CBCT showed a high correlation with the primary stability of the implants. Hence, preoperative density value estimations by CBCT may allow clinicians to predict implant stability. Whether the density values obtained by the CBCT device used in the present study could be applied to other devices requires further elucidation. PMID- 21545534 TI - Correlation in the densities of augmented and existing bone in guided bone augmentation. AB - OBJECTIVES: Our previous work used a rabbit experimental model to investigate the effectiveness of guided bone augmentation (GBA). Although a density similar to that of existing bone is required for successful bone augmentation, few studies have compared the densities of augmented and existing bone. The purpose of the present study was to investigate the correlation in the densities of existing and augmented bone following GBA in rabbit calvaria. MATERIAL AND METHODS: The calvaria of 18 adult male Japanese white rabbits were exposed. A circular groove and nine small holes were drilled into the cortical surface of each left parietal bone. A customized, standardized, hemispherical titanium cap was press-fitted into each groove. Six animals were sacrificed after each healing period of 1, 3, and 6 months and histomorphometric analyses were conducted. RESULTS: Significant increases were observed in the area of augmented bone between 1 and 6 months (62.7 +/- 21.6% vs. 93.4 +/- 3.9%). In contrast, no significant differences among healing periods were observed in the density of augmented or existing bone. Regression analysis demonstrated a significant positive correlation between the densities of augmented and existing bone; the strength of this correlation increased with the length of healing (R(2) =0.97). CONCLUSIONS: These results suggest that the area of augmented bone increases significantly with the length of healing, filling the occlusive space after 6 months, and that the density of augmented bone depends on that of the existing bone, such that augmented bone has a density about half that of the existing bone. PMID- 21545535 TI - Failure analysis of fractured dental zirconia implants. AB - OBJECTIVES: The purpose of the present study was the macroscopic and microscopic failure analysis of fractured zirconia dental implants. METHODS: Thirteen fractured one-piece zirconia implants (Z-Look3) out of 170 inserted implants with an average in situ period of 36.75+/-5.34 months (range from 20 to 56 months, median 38 months) were prepared for macroscopic and microscopic (scanning electron microscopy [SEM]) failure analysis. These 170 implants were inserted in 79 patients. The patient histories were compared with fracture incidences to identify the reasons for the failure of the implants. RESULTS: Twelve of these fractured implants had a diameter of 3.25 mm and one implant had a diameter of 4 mm. All fractured implants were located in the anterior side of the maxilla and mandibula. The patient with the fracture of the 4 mm diameter implant was adversely affected by strong bruxism. By failure analysis (SEM), it could be demonstrated that in all cases, mechanical overloading caused the fracture of the implants. Inhomogeneities and internal defects of the ceramic material could be excluded, but notches and scratches due to sandblasting of the surface led to local stress concentrations that led to the mentioned mechanical overloading by bending loads. CONCLUSIONS: The present study identified a fracture rate of nearly 10% within a follow-up period of 36.75 months after prosthetic loading. Ninety-two per cent of the fractured implants were so-called diameter reduced implants (diameter 3.25 mm). These diameter reduced implants cannot be recommended for further clinical use. Improvement of the ceramic material and modification of the implant geometry has to be carried out to reduce the failure rate of small-sized ceramic implants. Nevertheless, due to the lack of appropriate laboratory testing, only clinical studies will demonstrate clearly whether and how far the failure rate can be reduced. PMID- 21545536 TI - Adipositas athletica: a group of neglected conditions associated with medical risks. AB - At the 2008 Olympics, the body weight of the athletes varied from 28 to 181 kg and many Olympic athletes therefore today have a stature far from the ancient Greek athletic ideals. Athletes and sports associated with leanness and their medical problems have been researched extensively. However, there has been less focus on those athletes, who may gain a competitive advantage by having excess body fat, being large or oversized. The present review introduces for the first time the concept of Adipositas athletica and gives a description and classification of these athletes. Adipositas athletica is defined as having a higher than "athletic normal" (Greek Olympic ideals) fat mass and being an elite athlete. The condition is divided into subgroups based on the intent or non intent to increase body fat per se. Another factor is the intent to increase body mass as well as increasing physiological factors such as strength or endurance. It is concluded that most of the sports-medicine community-physicians, researchers and nutritionists - has neglected these oversized and obese athletes, their long- and short-term morbidity and mortality, their eating problems and the use of performance-enhancing drugs. Although some data on overweight and obese athletes exist, the most remarkable finding when reviewing the literature is the paucity of data. Many unanswered questions remain and great strides remain to be made. PMID- 21545537 TI - Force interaction and 3D pole movement in double poling. AB - The aim of this study was to analyze double poling using combined kinetic and 3D kinematic analysis at high skiing speeds as regards pole force components, pole angles and pole behavior during the poling and swing phase. The hypothesis was that a horizontal pole force is more predictive for maximal skiing speed (V(max)) than the resultant pole force. Sixteen elite skiers performed a double-poling V(max) test while treadmill roller skiing. Pole forces and 3D kinematics of pole movement at a speed of 30 km/h were analyzed and related to V(max). The duration of the "preparation phase" showed the strongest relationship with V(max) (r=0.87, P<0.001). Faster skiers generated longer cycle lengths with longer swing and poling times, had less inclined pole angles at pole plant and a later peak pole force. Horizontal pole forces were not more highly related to V(max) compared with the resultant pole force. Impact force was not related to V(max). At high skiing speeds, skiers should aim to combine high pole forces with appropriate timing of pole forces and appropriate pole and body positions during the swing and poling phase. The emphasis in training should be on the development of specific strength capacities for pole force production and the utilization of these capacities in double-poling training sessions. PMID- 21545538 TI - Both poor cardiorespiratory and weak muscle fitness are related to a high concentration of oxidized low-density lipoprotein lipids. AB - Good physical fitness is associated with favorable serum lipids. Oxidized low density lipoprotein (ox-LDL) could be even more atherogenic than serum lipids. We studied the association of ox-LDL and serum lipids with physical fitness. Healthy young (mean age 25 years) men (n=846) underwent maximal oxygen uptake (VO(2max)) and muscle fitness index (MFI) tests and completed a leisure-time physical activity (LTPA) questionnaire. Age (ANCOVA1), age+waist circumference+systolic blood pressure+fasting blood glucose+smoking (ANCOVA3) were used as covariates. The groups with the lowest VO(2max), MFI and LTPA had 23%, 16% and 8% higher concentrations of ox-LDL than the groups with the highest VO(2max) (P<0.0001), MFI (P=0.022) and LTPA (P=0.039) groups, respectively. Subjects with poor fitness (low VO(2max) or low MFI) or low LTPA had elevated levels of ox-LDL/high-density lipoprotein (HDL)-cholesterol, total cholesterol, LDL-cholesterol, triglycerides and a low level of HDL-cholesterol (ANCOVA1, in all, P<0.05). Furthermore, low VO(2max) is associated with a high level of ox-LDL/HDL-cholesterol and triglycerides, and with a low level of HDL-cholesterol (ANCOVA3, in all, P<0.05). Also, subjects with low LTPA had a high ratio of ox-LDL/HDL-cholesterol (ANCOVA1, P=0.001). In conclusion, both poor fitness (both low VO(2max) and low MFI) and low LTPA are associated with a higher concentration of ox-LDL lipids and serum lipids, which may indicate a higher risk for atherosclerosis. PMID- 21545539 TI - Spatial mapping by imaging mass spectrometry offers advancements for rapid definition of human skin proteomic signatures. AB - Investigations into the human skin proteome by classical analytical procedures have not addressed spatial molecular distributions in whole-skin biopsies. The aim of this study was to develop methods for the detection of protein signatures and their spatial disposition in human skin using advanced molecular imaging technology based on mass spectrometry technologies. This technology allows for the generation of protein images at specific molecular weight values without the use of antibody while maintaining tissue architecture. Two experimental approaches were employed: MALDI-MS profiling, where mass spectra were taken from discrete locations based on histology, and MALDI-IMS imaging, where complete molecular images were obtained at various MW values. In addition, proteins were identified by in situ tryptic digestion, sequence analysis of the fragment peptides and protein database searching. We have detected patterns of protein differences that exist between epidermis and dermis as well as subtle regional differences between the papillary and reticular dermis. Furthermore, we were able to detect proteins that are constitutive features of human skin as well as those associated with unique markers of individual variability. PMID- 21545540 TI - Influence of severity of the cutaneous manifestations and age on the prevalence of several cardiovascular risk factors in patients with psoriasis. AB - INTRODUCTION: Psoriasis is a disease with proinflammatory state that has been associated with an increased risk of cardiovascular disease. METHOD: This is a cross-sectional, observational study, with analysis of 98 patients being treated for psoriasis. Several variables were analysed: gender, age, weight, height, Psoriasis Area and Severity Index (PASI), blood pressure, blood glucose, blood lipids, obesity, metabolic syndrome (MS) and Framingham score. RESULTS: Ninety eight patients were analysed (51 men; 52.0%). Age ranged from 12 years to 98 years. About 67% of the patients had dyslipidaemia, 14.3% had type 2 diabetes mellitus and 59.2% had systemic arterial hypertension. Forty-four percentage of patients had the MS and 27.6% had a body mass index >30 kg/m(2). The Psoriasis Area and Severiy Index were equal or over 10 in 27 patients, 18 of whom had dyslipidaemia (P = 0.929) and 14 of whom had the MS (P = 0.327). Seventy-four patients were over the age of 40 years and, of these, 56 had dyslipidaemia (P = 0.002) and 41 had the MS (P < 0.001). For 89 patients, whose cardiovascular risk was calculated according to the Framingham criteria, 71.4% at high or moderate risk had a PASI below 10 (P = 0.945) and 100% at high or moderate risk were over the age of 40 years (P = 0.001). CONCLUSION: There was strong evidence that psoriasis patients have an increased cardiovascular risk, chiefly those over the age of 40 years, probably because of the chronic inflammatory state. It seems that the severity of the cutaneous manifestations was not associated with a higher risk in these patients. PMID- 21545541 TI - Cutaneous lumbosacral Herpes simplex virus among patients hospitalized for an advanced disease. AB - BACKGROUND: Cutaneous Herpes simplex virus (HSV) infections are regularly observed in lumbosacral areas, and many are refractory to appropriate initial diagnosis and management. OBJECTIVE: We aimed to evaluate the incidence of lumbosacral HSV among advanced disease patients, to estimate their survival index from HSV onset, and to describe their clinical and virological characteristics. METHODS: A prospective, descriptive study was conducted in a palliative and continuous care centre, collecting patients with suspected cutaneous HSV lesions in the lumbosacral area. RESULTS: From 2008 to 2010, 24 patients were included: 19 had HSV-2 confirmed by at least one laboratory test. Incidence of HSV-2 was 2.67% (1.73-4.33%, 95% CI). No age, gender or survival differences were observed compared to the global population in the centre. Most lesions were detected early as vesicles (14/24) or small ulcers. Sensitivity was good for all diagnostic methods (62.5% for immunofluorescence and 79.2% for culture and/or PCR). Outcome was favourable under classical antiherpetic drugs and topical antiseptic dressing. CONCLUSIONS: Cutaneous lumbosacral HSV remains uncommon in patients hospitalized with advanced diseases. Most of these patients suffer from pressure ulcers or other dermatitis; we advocate increased attention of this diagnosis to avoid skin complications and added pain. PMID- 21545542 TI - Isotretinoin has no negative effect on attention, executive function and mood. AB - BACKGROUND: According to some animal data, impairments in learning and memory are seen with isotretinoin. Isotretinoin has been shown to affect human brain metabolism, but the data on human neural functions is lacking. OBJECTIVES: To evaluate whether isotretinoin treatment affects cognitive functions, causes depression and anxiety or alters anger level and anger expression. METHODS: Neuropsychological tests of attention and executive functions, behavioural tests measuring anger and depression and measures assessing acne severity were applied to 63 severe and/or resistant acne patients from four medical centres including one primary care institute and three university hospitals at the beginning, at the end of first month, third month and at end of treatment with isotretinoin. RESULTS: From a total of 63 patients, 15 missed the final visit and 48 were evaluated. Overall, 11 (six women, five men) and five (all women) patients reported anger and depression, respectively, during treatment. Eleven of these 16 patients improved spontaneously. No detrimental effects of isotretinoin treatment on either executive functions or mood were found. Several executive functions and control of anger trait were found to be improved. Clearing of acne was obtained in 94.6% of patients. LIMITATIONS: Improvement of several measures may be related to learning effect of repeated testing. Investigating brain functions is a complex process and various methods can be used. CONCLUSION: The test battery used in this study, which is commonly used to evaluate mental status both in adults and children, did not show any negative effect of isotretinoin on executive functional parameters in acne patients. PMID- 21545543 TI - Narrow-band UVB irradiation stimulates the migration and functional development of vitiligo-IgG antibodies-treated pigment cells. AB - BACKGROUND: The pathogenesis of vitiligo remains unclear. Most authorities favoured the autoimmune cause for the strong associations of vitiligo with multiple autoimmune diseases and the presence of autoantibodies in vitiligo patients. Narrow-band UVB (NBUVB) irradiation has been considered to be an effective treatment for vitiligo with simple treatment procedure and decreased accumulated ultraviolet exposure doses. OBJECTIVES: The aim this study was to investigate the effects of NBUVB irradiation on normal IgG antibodies (N-IgG) or vitiligo IgG antibodies (V-IgG)-treated NCCmelan5 cells in terms of proliferation, migration and melanin formation. METHODS: Cultured NCCmelan5 cells were treated with (i) NBUVB irradiation alone, (ii) N-IgG or V-IgG alone, and (iii) combination of N-IgG or V-IgG with NBUVB irradiation. The proliferation of NCCmelan5 cells were evaluated using BrdU incorporation assay. Western blotting was used to determine the expressions of phosphorylated p125(FAK) (pp125(FAK)) and tyrosinase in NCCmelan5 cells. The locomotion of NCCmelan5 cells was assessed using time-lapse assay and in vitro wound scratch assay. RESULTS: Neither N-IgG nor V-IgG significantly affected the proliferation of NCCmelan5 cells. The migration, melanin formation and tyrosinase expression in NCCmelan5 cells were decreased by V-IgG. NBUVB irradiation increased the proliferation of V-IgG treated NCCmelan5 cells. In addition, NBUVB irradiation enhanced the mobility of V-IgG-treated NCCmelan5 cells via upregulation of pp125(FAK). The melanogenesis and tyrosinase expression in V-IgG-treated NCCmelan5 cells were promoted using NBUVB irradiation. CONCLUSIONS: Our study demonstrated that the deleterious effects of V-IgG in the pathogenesis of vitiligo might be overcome by NBUVB irradiation. PMID- 21545544 TI - Effects of isotretinoin treatment on sleep in patients with severe acne: a pilot study. AB - BACKGROUND: There are a few case reports in literature that isotretinoin treatment may alter sleep architecture. Also studies in mice suggest a role of retinoids in the contribution of delta oscillations to the sleep electroencephalography. OBJECTIVES: The aim of this study was to investigate the effect of isotretinoin treatment on sleep architecture using polysomnography (PSG). PATIENTS AND METHODS: Twelve severe acne vulgaris patients without any psychiatric and sleep disorders were treated with 0.5 mg/kg of isotretinoin. Clinician-administered acne questionnaire, psychiatric examination, Epworth sleepiness scale and PSG recordings were performed after the first month of treatment. RESULTS: Sleep efficiency was increased from 83.5% (62.8-89.0%, quartiles) to 89.5% (81.5-93.5%, quartiles; P = 0.036) and sleep latency decreased from 18.0 min (11.1-36.3, quartiles) to 15.5 min (9.3-19.0, quartiles; P = 0.023) following 1-month isotretinoin treatment. There were no significant changes in other sleep parameters of PSG and scores of Epworth sleepiness scale. CONCLUSIONS: This study suggests that isotretinoin treatment slightly improves night-time sleep without any effects on sleep stages and daytime sleepiness. PMID- 21545545 TI - Successful treatment of vitiligo on the axilla in a 5-year-old child by cultured melanocyte transplantation. PMID- 21545546 TI - Margin involvement and clinical pattern of basal cell carcinoma with mixed histology. AB - BACKGROUND: Mixed basal cell carcinoma (BCC) has not been sufficiently and specifically studied. OBJECTIVE: The aim of this study was to estimate in adults the prevalence of mixed cases observed among primary BCCs and to compare clinical and anatomical features of mixed vs. single BCCs, with focus on the incomplete excision. PATIENTS AND METHODS: A total of 3636 histologically confirmed primary BCCs were examined. Data on gender, age, histological subtype, anatomical location and margin involvement were collected. Mixed type was defined as a combination of two or more single subtypes. RESULTS: Prevalence of single and mixed BCCs was 82.2% and 17.8% respectively. Prevalence of BCCs on the upper limbs was higher in mixed than single cases (8.8% vs. 4.0%; P<0.001) while prevalence on the back was lower (16.9% vs. 23.7%; P<0.001). Tumour was aggressive in 59.1% of mixed vs. 16.0% of single BCCs (P<0.001). Margin involvement was more prevalent in mixed than in single BCCs (16.7% vs. 9.6%; P<0.0001). At multivariate analysis being mixed vs. single BCC was associated with aggressiveness of tumour (OR=8.5, 95% CI, 6.9-10.4), lateral margin involvement (OR=1.98, 95% CI, 1.42-2.76) and subject being man (OR=1.31, 95% CI, 1.10-1.60) but not with deep involvement of margin or anatomical location. CONCLUSION: Among BCCs, the mixed type may be observed in adults with relatively high rate and may represent a complex and individual subset of BCCs with potential aggressive behaviour. PMID- 21545547 TI - Effects of oral supplementation with beta-carotene on concentrations of beta carotene, vitamin A and alpha-tocopherol in plasma, colostrum and milk of mares and plasma of their foals and on fertility in mares. AB - In this study, effects of oral beta-carotene supplementation to mares (beta carotene group: 1000 mg/day, n = 15; control group: n = 15) from 2 weeks before foaling until 6 weeks thereafter on concentrations of beta-carotene, vitamin A and alpha-tocopherol in plasma, colostrum and milk and plasma of their foals were determined. In addition, effects on fertility were studied. Beta-carotene concentrations increased in plasma and colostrum of beta-carotene-supplemented mares compared to control mares (p < 0.05). In mares of both groups, beta carotene concentrations were higher in colostrum than in milk (p < 0.05). In foals, beta-carotene concentrations increased with colostrum uptake and were higher in foals born to supplemented mares (p < 0.05; control group: 0.0003 +/- 0.0002 MUg/ml on day 0, 0.008 +/- 0.0023 MUg/ml on day 1; beta-carotene group: 0.0005 +/- 0.0003 MUg/ml on day 0, 0.048 +/- 0.018 MUg/ml on day 1). Concentrations of vitamin A and alpha-tocopherol were higher in colostrum than in milk (p < 0.05) but did not differ between groups. Concentration of alpha tocopherol in plasma of mares decreased over time and in foals, increased markedly within 4 days after birth. All but one mare (control group) showed oestrus within 2 weeks post-partum. Occurrence of oestrus did not differ between groups. More mares of the control group (7/7 vs. 5/12 in the beta-carotene group) became pregnant after being bred in first post-partum oestrus (p < 0.05). In conclusion, beta-carotene supplementation to mares increased beta-carotene concentrations in plasma, colostrum and milk of mares and plasma of their foals but had no positive effects on fertility. PMID- 21545548 TI - Rabbit anti-rat thymocyte immunoglobulin preserves renal function during ischemia/reperfusion injury in rat kidney transplantation. AB - Ischemia/reperfusion (I/R) injury is an important cause of renal graft dysfunction in humans. Increases in cold and warm ischemia times lead to a higher risk of early post-transplant complications including delayed graft function and acute rejection. Moreover, prolonged cold ischemia is a predictor of long-term kidney graft loss. The protective effect of rabbit anti-rat thymocyte immunoglobulin (rATG) was evaluated in a rat model of I/R injury following syngeneic kidney transplantation. Serum creatinine concentration was evaluated at 16 h and 24 h post-transplant. Animals were sacrificed 24 h post-transplant for evaluation of histology, infiltrating leukocytes, nitrotyrosine staining, and apoptosis. rATG was effective in preventing renal function impairment, tissue damage and tubular apoptosis associated with I/R only when was given 2 h before transplantation but not at the time of reperfusion. Pretransplant rATG treatment of recipient animals effectively reduced the amount of macrophages, CD4(+), CD8(+) T cells and LFA-1(+) cells infiltrating renal graft subjected to cold ischemia as well as granzyme-B expression within ischemic kidney. On the other hand, granulocyte infiltration and oxidative stress were not modified by rATG. If these results will be translated into the clinical setting, pretransplant administration of Thymoglobuline((r)) could offer the additional advantage over peri-transplant administration of limiting I/R-mediated kidney graft damage. PMID- 21545549 TI - Occupational sensitization to soy allergens in workers at a processing facility. AB - BACKGROUND: Exposure to soy antigens has been associated with asthma in community outbreaks and in some workplaces. Recently, 135 soy flake processing workers (SPWs) in a Tennessee facility were evaluated for immune reactivity to soy. Allergic sensitization to soy was common and was five times more prevalent than in health care worker controls (HCWs) with no known soy exposure. OBJECTIVE: To characterize sensitization to soy allergens in SPWs. METHODS: Sera that were positive to soy ImmunoCAP (n=27) were tested in IgE immunoblots. Wild-type (WT) and transgenic (TG) antigens were sequenced using nanoscale Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry (nanoUPLC MS/MS). IgE reactivity towards 5-enolpyruvylshikimate-3-phosphate synthase (CP4-EPSP), a protein found in TG soy, was additionally investigated. De-identified sera from 50 HCWs were used as a control. RESULTS: Immunoblotting of WT and TG soy flake extracts revealed IgE against multiple soy antigens with reactivity towards 48, 54, and 62 kDa bands being the most common. The prominent proteins that bound SPW IgE were identified by nanoUPLC MS/MS analysis to be the high molecular weight soybean storage proteins, beta-conglycinin (Gly m 5), and Glycinin (Gly m 6). No specific IgE reactivity could be detected to lower molecular weight soy allergens, Gly m 1 and Gly m 2, in soybean hull (SH) extracts. IgE reactivity was comparable between WT and TG extracts; however, IgE antibodies to CP4-EPSP could not be detected. CONCLUSIONS AND CLINICAL RELEVANCE: SPWs with specific IgE to soy reacted most commonly with higher molecular weight soybean storage proteins compared with the lower molecular weight SH allergens identified in community asthma studies. IgE reactivity was comparable between WT and TG soy extracts, while no IgE reactivity to CP4-EPSP was observed. High molecular weight soybean storage allergens, Gly m 5 and Gly m 6, may be respiratory sensitizers in occupational exposed SPWs. PMID- 21545550 TI - Allergic sensitization in kidney-transplanted patients prevails under tacrolimus treatment. AB - BACKGROUND: Type I allergies have repeatedly been reported after solid organ transplantation despite T cell-targeted immunosuppressive therapy. A causal relationship with tacrolimus has been proposed. OBJECTIVE: The present study directly compared the occurrence of allergic sensitization and disease under tacrolimus- vs. cyclosporin A-based immunosuppressive therapy. METHODS: The prevalences of IgE-mediated sensitization and allergy were assessed in a cross sectional study of kidney-transplanted adults receiving tacrolimus (n = 100) or cyclosporin A (n = 100). METHODS: included a standardized questionnaire, skin prick test and measurement of total and specific IgE against common nutritive and inhalant allergens. Results The prevalence of sensitization was significantly higher in the tacrolimus- than in the cyclosporin A-treated group (34%, n = 34, vs. 20%, n = 20; P = 0.026). The rate of clinically relevant allergy in patients receiving tacrolimus was twice that in patients receiving cyclosporin A (15%, n = 15, vs. 8%, n = 8; P = 0.12). No other factor (age, serum drug level, concomitant immunosuppressive medication, time since transplantation, underlying disease) was found to have an influence on sensitization or allergy prevalence (logistic regression). CONCLUSION AND CLINICAL RELEVANCE: Our results suggest that post transplant immunosuppression with tacrolimus is associated with an increased occurrence of IgE-mediated sensitization and probably manifestation of allergic disease, which has to be treated specifically despite immunosuppressive therapy. PMID- 21545551 TI - Why could passive Immunoglobulin E antibody therapy be safe in clinical oncology? PMID- 21545552 TI - Pharmaceutical drugs: the delicate balance between reducing pain and reducing harm. PMID- 21545553 TI - Definitions related to the use of pharmaceutical opioids: extramedical use, diversion, non-adherence and aberrant medication-related behaviours. AB - AIMS: This paper (i) reviews the language used to describe and manage those patient practices that fall outside standard medical models of opioid treatment (for pain and opioid dependence), and (ii) proposes a consistent terminology that can be applied across multiple healthcare settings. METHOD: Peer-reviewed and grey literature documenting empirical studies of (non-)adherence with opioid treatment, proposed definitions or other potentially important aspects of terminology were included in this review. RESULTS: There are international inconsistencies in the terminology used to describe the unintended consequences of opioid treatment, and the terms used often lack specificity. The terms 'hazardous use', 'extramedical use', 'opioid dependence', 'diversion', 'non adherence' and 'aberrant behaviours' are defined. We advocate for consistent application of these terms in the context of opioid treatment, and propose that care is taken to describe individual practices and intentions. CONCLUSIONS: The increasing global attention on the use and diversion of pharmaceutical opioids warrants a discussion of current terms and definitions. Exaggerated concerns regarding 'addiction potential' may result in restrictions in the supply of opioids and the under-treatment of legitimate medical conditions. Researchers, clinicians, policy-makers and patients need to ensure greater care is given to terminology, including detailed descriptions of patient practices, the context in which they occur and severity of associated harm. PMID- 21545554 TI - The availability, diversion and injection of pharmaceutical opioids in South Asia. AB - AIMS: To provide an overview of the availability of pharmaceutical opioids and the evidence on the extent of diversion and injection in South Asia. METHODS: This paper reviews existing peer-reviewed and 'grey' literature on the extramedical use and injection of pharmaceutical opioids in Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka. RESULTS: Reports indicate that prescribing for all types of pain is inadequate. There is a paucity of empirical data across South Asia regarding the mechanisms and extent of the diversion and misuse of pharmaceutical opioids, although the problem is widely acknowledged. India is believed to account for significant large-scale diversion within the region and further afield through poor regulation of licit opioid production and pharmacies. A recent decline in use of natural opiates has been accompanied by an increase in pharmaceutical opioid misuse and increasingly, injection, particularly in Bangladesh, India, Nepal and Pakistan. The medications are typically buprenorphine preparations and/or other lower potency opioids, such as codeine, nalbuphine and dextropropoxyphene. Opioid substitution treatment and needle-syringe programs are available in some countries, but better coverage is needed. Studies identify a lack of comprehensive knowledge regarding HIV and high prevalence of risk behaviours among at-risk populations in the region. CONCLUSIONS: It is imperative for the region to rapidly facilitate access to opioids for the treatment of pain and opioid dependence, ensuring effective systems that maintain quality care, regulate and monitor retail pharmacies, and minimise diversion. Prevention of HIV among people who inject pharmaceutical opioids is essential. PMID- 21545555 TI - Recent trends in pharmaceutical drug use among frequent injecting drug users, frequent methamphetamine users and frequent ecstasy users in New Zealand, 2006 2009. AB - AIMS: To examine the rates of pharmaceutical drug use, and level of prescription use and injection of pharmaceutical drugs, by frequent injecting drug users (IDU), frequent methamphetamine users and frequent ecstasy users in New Zealand for 2006-2009. DESIGN AND METHOD: The paper draws on findings from the 2006, 2007, 2008 and 2009 Illicit Drug Monitoring System (IDMS). The IDMS interviews three groups of frequent illegal drug users (i.e. IDU, methamphetamine users and ecstasy users) from the three main cities of New Zealand using purposive sampling and 'snowballing'. RESULTS: Pharmaceutical morphine rather than heroin was the principal opioid used by the IDU. Few of the IDU or frequent methamphetamine users had prescriptions to use morphine. A lower proportion of the IDU had a prescription to use morphine in 2009 compared to 2008. The injection of methadone by IDU and methamphetamine users was common. A higher proportion of the IDU had injected methadone in 2009 compared to previous years. A higher proportion of the IDU had used oxycodone in 2009 compared to 2008 and prescription use of oxycodone by IDU was very low. All three groups of frequent drug users were involved in the extra-medical use of methylphenidate and benzodiazepines. DISCUSSION AND CONCLUSION: Extra-medical use of pharmaceuticals occurred among all three groups of frequent illegal drug users to varying degrees. Differences between the three groups in the level and type of extra-medical pharmaceutical drug use suggest that different control strategies may be effective for each group. PMID- 21545556 TI - The prescription drug epidemic in the United States: a perfect storm. AB - INTRODUCTION AND AIMS: Abuse of prescription analgesics in the USA is increasing. The epidemic has been driven by many factors, including marketing strategies, incorrect prescribing practices, a variety of legal and illegal drug sources, belated governmental responses and increases in the number of prescriptions written. DESIGN AND METHODS: Data sources including surveys, emergency room visits, treatment admissions, overdose deaths, toxicology laboratory findings and journal articles were examined to identify trends. RESULTS: The surveys and emergency department visits show use lowest among young teenagers and highest among older teenagers and young adults, with significant increases among those aged 55 and older. The length of time between initial use of an opioid other than heroin and admission to treatment is shortening. Mortality data and toxicology exhibits confirm the increases and show the variation in the prevalence of various drugs across the USA. DISCUSSION AND CONCLUSIONS: Abuse is increasing, with varying patterns of use by high-risk groups and different geographic preferences. Prescription drug monitoring programs are being developed in each of the US states to deter 'doctor shopping'; the Food and Drug Administration has increased authority over manufacturers; and options for proper disposal of leftover medications exist. There is increased emphasis on responsible prescribing including risk assessments, prescribing agreements, treatment plans, and training for clinicians, as well as monitoring the interactions with benzodiazepines. However, unless these efforts decrease diversion, abuse and addiction, clinicians may lose the ability to use some of these opioids for effective pain management or so many barriers will be raised that pain will go undertreated or untreated. PMID- 21545557 TI - Trends over time in characteristics of pharmaceutical drug-related ambulance attendances in Melbourne. AB - INTRODUCTION AND AIMS: There is growing concern regarding pharmaceutical drug related harms. Evidence suggests increasing non-medical use of pharmaceutical drugs, along with associated morbidity and mortality. This paper explores trends of pharmaceutical-related ambulance attendances over the past decade in order to identify populations experiencing acute harm, and levels of harms in the community. DESIGN AND METHODS: A retrospective analysis of pharmaceutical drug related ambulance attendances in metropolitan Melbourne, Australia, is presented, with rates of attendances over the period 2000 to 2009 and change over time examined. Characteristics of attendances are explored to understand the nature of presentation and demographic characteristics. RESULTS: Benzodiazepines represented the drug group with the highest rates of attendances over the 10 year period. Rates of attendances increased significantly for opioid analgesics, while significant decreases were noted for benzodiazepines, antidepressant and anticonvulsants. While women represented the majority of patients for each drug category presented over the period examined, there was an increase in the proportion of men attended in relation to opioid analgesics. Alcohol involvement in presentations has increased significantly for all drug groups. DISCUSSION AND CONCLUSIONS: Increasing pharmaceutical-related ambulance attendances for opioid analgesics reflect increasing use, with the increase in other analgesic-related attendances also concerning. The overrepresentation of female patients reflects a population experiencing drug-related harm not reflected in illicit drug research. The rise of alcohol involvement represents heightened risk of adverse events including death, and suggests an area for public education to prevent alcohol and drug-related harms. PMID- 21545558 TI - Benzodiazepines, opioids and driving: an overview of the experimental research. AB - ISSUES: Road crashes contribute significantly to the total burden of injury in Australia, with the risk of injury being associated with the presence of drugs and/or alcohol in the driver's blood. Increasingly, some of the most commonly detected drugs include prescription medicines, the most notable of these being benzodiazepines and opioids. However, there is a paucity of experimental research into the effects of prescribed psychoactive drugs on driving behaviours. APPROACH: This paper provides an overview of experimental studies investigating the effects of prescribed doses of benzodiazepines and opioids on driving ability, and points to future directions for research. KEY FINDINGS: There is growing epidemiological evidence linking the therapeutic use of benzodiazepines and opioids to an increased crash risk. However, the current experimental literature remains unclear. Limitations to study methodologies have resulted in inconsistent findings. IMPLICATIONS: Limited experimental evidence exists to inform policy and guidelines regarding fitness-to-drive for patients taking prescribed benzodiazepines and opioids. CONCLUSION: Further experimental research is required to elucidate the effects of these medications on driving, under varying conditions and in different medical contexts. This will ensure that doctors prescribing benzodiazepines and opioids are well informed, and can appropriately advise patients of the risks associated with driving whilst taking these medications. PMID- 21545559 TI - Reducing harm from injecting pharmaceutical tablet or capsule material by injecting drug users. AB - BACKGROUND: It has long been known that drug users may use a variety of pharmaceutical preparations by injection, many of which are not intended for intravenous administration (e.g. buprenorphine, methylphenidate, oxycodone). The introduction of tablet fillers such as talc or starch, in the blood circulation may cause, besides local injection site complications, pulmonary emboli. To reduce the harmful consequences of injecting such solutions, drug users have been encouraged to use filters. This research studied the effectiveness of an injection drug user syringe filter (IDUSF) in eliminating these particles. METHODS: Generic buprenorphine and methylphenidate (Ritaline(r)), both containing talc, are frequently diverted for use by injection in France. The aim of our laboratory-based study was to compare the effectiveness of an IDUSF (Sterifilt(r), filter pore size = 10 um) versus no filtration, at reducing the number of particles in solutions of dissolved generic buprenorphine and Ritaline(r). RESULTS: Compared with a non-filtered solution drawn up through a 30G needle, filtering of the generic buprenorphine solution eliminated approximately 85% of all particles between 1 and 5 um in diameter and 97% of particles between 5 and 18 um. In the Ritaline(r) solution, these values were two thirds and 95%, respectively. CONCLUSION: Preliminary results indicate that IDUSF are effective in significantly filtering out large particles, which are responsible for major harms like pulmonary emboli. One strategy for alleviating these consequences is to promote the implementation of IDUSF in harm reduction programs, accompanied by training of social workers, peers and drug users. PMID- 21545560 TI - Pharmaceutical opioid analgesic and heroin dependence: how do treatment-seeking clients differ in Australia? AB - INTRODUCTION AND AIMS: Non-prescribed use of pharmaceutical opioid analgesics (POA) has been escalating internationally. In Australia, few studies have examined if POA users have similar characteristics and treatment needs to heroin users. The aim of this study was to compare those presenting for treatment where heroin versus POA were the primary drugs of concern. DESIGN AND METHODS: A convenience sample of 192 treatment entrants were recruited from alcohol and drug treatment services in four Australian jurisdictions. A structured interview collected data on demographic characteristics, substance use, self-perceived mental and physical health, crime and harms resulting from drug use. Multivariate analyses were performed to identify characteristics which may differentiate those seeking treatment for heroin compared with POA. RESULTS: Most treatment entrants sampled reported a history of injection drug use and use of both heroin and POA. However, those with primary POA problems were less likely to report an overdose history (adjusted odds ratio 0.90, 95% confidence interval 0.81-0.99) and more likely to initiate opioid use for pain (adjusted odds ratio 2.52, 95% confidence interval 1.04-6.12) than those with primary heroin problems. Latent Class Analysis found that, while most of the POA group were similar to heroin users in demographics, health and injecting drug use, there was a small, distinct group of primary POA problem users that did not typically inject and who commonly initiated opioid use for pain and also experienced elevated physical and mental health disability. DISCUSSION AND CONCLUSIONS: While some differences existed, this study of Australian treatment seekers found many similar characteristics between those with primary problems with heroin and POA. Few non-injecting POA were recruited in this sample. This finding contrasts with reports of a growing population of opioid-dependent people with characteristics that are distinct from traditional opioid-dependent populations, which may reflect the orientation of current treatment systems in Australia towards injection drug users. PMID- 21545561 TI - Prescription opioid abuse, pain and addiction: clinical issues and implications. AB - ISSUES: Prescription opioid misuse in the USA has increased over threefold since 1990 to epidemic proportions, with substantial increases in prescription opioid use also reported in other countries, such as Australia and New Zealand. The broad availability of prescription pain medications, coupled with public misconceptions about their safety and addictive potential, have contributed to the recent surge in non-medical use of prescription opioids and corresponding increases in treatment admissions for problems related to opioid misuse. Given competing pressures faced by physicians to both diagnose and treat pain syndromes and identify individuals at risk for addictive disorders, the use of opioids in the treatment of pain poses a significant clinical challenge. APPROACH: This paper reviews the interaction between pain and opioid addiction with a focus on clinical management issues, including risk factors for opioid dependence in patients with chronic pain and the use of assessment tools to identify and monitor at-risk individuals. Treatment options for opioid dependence and pain are reviewed, including the use of the partial u agonist buprenorphine in the management of concurrent pain and opioid addiction. IMPLICATIONS: Physicians should strive to find a reasonable balance between minimising potential adverse effects of opioid medications without diminishing legitimate access to opioids for analgesia. CONCLUSIONS: The article discusses the need to identify methods for minimising risks and negative consequences associated with opioid analgesics and poses research directions, including the development of abuse-deterrent opioid formulations, genetic risk factors for opioid dependence and opioid induced hyperalgesia as a potential target for medication therapy. PMID- 21545562 TI - Acceptability of cognitive-behaviour therapy via the Internet for cessation of benzodiazepine use. AB - INTRODUCTION AND AIMS: Long-term use of benzodiazepines remains common, and conveys significant risk. Providing psychological intervention in association with gradual dose reduction increases cessation rates above dose reduction alone, but appropriate psychological support is difficult to obtain. This study was undertaken to assess the outcomes of an uncontrolled case series of an Internet based cognitive-behaviour therapy for benzodiazepine cessation. DESIGN AND METHODS: Users of benzodiazepines for >3 months who wanted to reduce or cease benzodiazepines participated in the trial. They completed online assessments and accessed 13 newsletters on managing withdrawal symptoms and developing alternate ways to cope with life events. Therapist assistance was provided by email. Follow up was at 3 and 6 months and feedback was obtained via comments and emails. RESULTS: Program ratings and emailed comments of the program were positive. Thirty-two people registered for the program and 14 (44%) completed a 6 month follow up. Of these, eight (57%) reduced weekly intake by at least half, including five (36%) who ceased use. Shorter duration of use and birth outside Australia predicted greater percentage reductions at 3 months, while being living with a partner and being in paid employment predicted reductions at 6 months. DISCUSSION AND CONCLUSIONS: While results were encouraging, controlled research is required to confirm the efficacy of the program, and engagement of both users and prescribers needs further attention. PMID- 21545563 TI - Increasing the benefits and reducing the harms of prescription opioid analgesics. AB - ISSUES: Consumption of prescription opioid analgesics (POAs) in Australia has increased steadily in recent years, raising concerns of increasing harms including overdose and dependence, as has occurred in the USA. APPROACH: Exposition of the Royal Australasian College of Physicians Prescription Opioid Policy with reference to the published literature, drawing out principles for harm reduction for psychoactive pharmaceutical drugs. KEY FINDINGS: Complex professional, patient, regulatory and market factors influence health professionals balancing the benefits and harms of POAs. Owing to the potential for diversion, overlapping markets probably exist for pharmaceutical opioids used for populations with cancer pain, chronic non-cancer pain, and people dependent on pharmaceutical and illicit opioids (including those needing opioid substitution treatment). Attempts to reduce or restrict supply in one area may increase demand in others. There is a need to consider new harm reduction strategies for people with problematic pharmaceutical opioid use. These people are demographically not well characterised, and may be distinct from the more familiar population of injection drug users. IMPLICATIONS: Harm reduction is a valid approach for POAs. However, the role of health professionals as gatekeepers of opioid supply, the need to optimise health benefits of POAs, and the likely interplay of complex market forces among populations consuming opioids have no close parallel in harm reduction for other substances. This poses fundamentally different challenges. CONCLUSIONS: Reducing inappropriate supply and demand for POAs while maximising their benefits and minimising their harms may improve health outcomes. PMID- 21545564 TI - Managing the continuum between pain and dependency in general practice. PMID- 21545565 TI - Decreasing the harms of prescription opioids: a case for pharmacists. PMID- 21545566 TI - A harm reductionist response. PMID- 21545567 TI - Harms: How much, how many, how often? PMID- 21545568 TI - Gender differences in cancer carer psychological distress: an analysis of moderators and mediators. AB - Women cancer carers report higher rates of distress than men; however, there is little understanding of the mechanisms underlying these gender differences. The aim of this study was to examine the potential mediating roles of burden of care, unmet needs, self-silencing, self-efficacy and optimism, and the potential moderating influence of social support, cancer stage, patient gender, time spent caring and other responsibilities, on gender differences in carer distress. Of 329 informal cancer carers (245 women, 119 men), women reported significantly more anxiety, burden of care and unmet needs than men. In the mediation analysis, gender differences in anxiety were fully explained by both the independent contribution and combination of: Disrupted Schedule, Health Problems and Emotional and Spiritual Unmet Needs. Women cared for both men and women patients, across a broad range of relationships, whereas men predominantly cared for their female partner. There was no gender difference in number of hours spent caring or in companionship, amount of support received, and additional responsibilities for children, housework or studies, and none of these factors acted as moderators of gender differences in anxiety. It is concluded that women's gendered role is associated with unmet needs and burden of care, resulting in greater anxiety. PMID- 21545569 TI - Young adults' management of Type 1 diabetes during life transitions. AB - AIM: To identify life transitions likely to impact diabetes self-care among young adults with Type 1 diabetes and their coping strategies during transition events. BACKGROUND: Relationships among psychosocial stress, adjustment, coping and metabolic control affect clinical outcomes and mental health. Life transitions represent major change and are associated with stress that temporarily affects individuals' problem-solving, coping abilities and blood glucose levels. DESIGN: A qualitative interpretive inquiry. METHOD: Semi-structured interviews were conducted with 20 young adults with Type 1 diabetes and a constant comparative analysis method. Data and analysis was managed using QSR NVivo 7 software. RESULTS: Participants identified two significant transition groups: life development associated with adolescence, going through the education system, entering new relationships, motherhood and the workforce and relocating. Diabetes related transitions included being diagnosed, developing diabetes complications, commencing insulin pump treatment and going on diabetes camps. Participants managed transitions using 'strategic thinking and planning' with strategies of 'self-negotiation to minimise risks'; 'managing diabetes using previous experiences'; 'connecting with others with diabetes'; 'actively seeing information to 'patch' knowledge gaps'; and 'putting diabetes into perspective'. CONCLUSIONS: Several strategies are used to manage diabetes during transitions. Thinking and planning strategically was integral to glycaemic control and managing transitions. The impact of transitions on diabetes needs to be explored in larger and longitudinal studies to identify concrete strategies that assist diabetes care during life transitions. RELEVANCE TO CLINICAL PRACTICE: It is important for health professionals to understand the emotional, social and cognitive factors operating during transitions to assist young adults with Type 1 diabetes to achieve good health outcomes by prioritising goals and plan flexible, timely, individualised and collaborative treatment. PMID- 21545570 TI - The protective effects of resilience and hope on quality of life of the families coping with the criminal traumatisation of one of its members. AB - AIM: This paper investigated the possible predictive and mediating determinates of quality of life in this often forgotten population, focusing specifically on the role of sociodemographics, mental impairments, coping mechanisms, resilience and hope on subjective quality of life. BACKGROUND: The family members of survivors of man-made trauma are sometimes severely traumatised themselves and may suffer from post-traumatic stress disorder, depression and poor quality of life. Most studies focus on the victims and ignore the effect of the incidents on the victim's family members. METHOD: Data were collected between October 2007 March 2008, a self-report questionnaire incorporating seven scales was administrated to 175 family members of victims of man-made trauma. One-way anova was performed to compare the variance in the reported quality of life. The structural equation models of path analysis was used to evaluate the main effects and interactions and interrelations among variables. RESULTS: Of the psychosocial factors, having a personal previous traumatic experience was found to significantly affect post-traumatic stress disorder, depression and physical health. Post-traumatic stress disorder and depression were found to directly and indirectly affect quality of life. Coping mechanism, resilience and a hope state mediated the effect of post-traumatic stress disorder and depression making the three significant predictors of subjective quality of life. CONCLUSION: Based on these findings and the scores of the different scales, clinicians may be able to design treatment plans that encourage the poorly adapting family members of victims of trauma, especially those with symptoms of post-traumatic stress disorder or depression, to accept changes as a part of life, nurture a positive view of the self, make connections for better social support and maintain or re create a hopeful outlook towards life goals. RELEVANCE TO CLINICAL PRACTICE: Knowledge of the psychosocial factors associated with resistance to severe trauma can also help in the prevention and treatment of individuals at high risk for developing post-traumatic stress disorder or depression. PMID- 21545571 TI - Knowledge of using acetaminophen syrup and comprehension of written medication instruction among caregivers with febrile children. AB - AIM: This article aims to explore caregivers' knowledge of acetaminophen and comprehension of written medication instructions about acetaminophen syrup when administered to febrile children. BACKGROUND: Fever is one of the most common problems about which primary caregivers seek medical advice for their children. Administration of acetaminophen is the most common form of treatment for febrile children. Medication safety is of the upmost importance for medication administration in this patient group. DESIGN: A cross-sectional study design was used. METHODS: The study included 102 caregivers with febrile children under six years old. A self-designed questionnaire was used to solicit participants' responses concerning: (1) approaches to fever management prior to hospital admission; and (2) knowledge and comprehension of antipyretic medication administration. Caregivers were asked to answer specific questions about the instructions provided with the medication. Results. Antipyretic by oral (66%) and antipyretic suppository (60%) were the most commonly used forms of fever management in febrile children. After reading the written medication instructions, one-third of the participants had more than one misunderstanding of the instructions for medication with timing, time interval of administration and/or medication dosage. Almost two-thirds of the participants misunderstood the side effects of acetaminophen. Participants with a poorer academic background were associated with poorer comprehension of the provided instructions. CONCLUSION: Administration of antipyretic medication is the most common approach taken to reduce children's temperature. A significant percentage of primary caregivers appear to lack a thorough understanding of the instructions provided with antipyrexial medication. RELEVANCE TO CLINICAL PRACTICE: Written medication instruction is a major source of information for primary caregivers. Clinical nurses have a potentially important role to play to provide caregivers with legible and understandable medication instructions and to ensure that caregivers fully comprehend this information. PMID- 21545572 TI - The evaluation of depression, suicidal ideation and coping strategies in haemodialysis patients with renal failure. AB - AIM: This study aimed at evaluating depression and suicidal ideation and coping strategies with stress in patients receiving haemodialysis replacement therapy. BACKGROUND: Patients undergoing haemodialysis treatment may often experience depression and accompanying suicidal ideation. Coping strategies with depression related suicidal ideation may require regular evaluation of the patient and the support of nurses. DESIGN: A cross-sectional descriptive study. METHOD: The sample consisted of 92 adults with an age range of 19-65 who had chronic renal failure and consecutively admitted to the Dialysis Center of Kadikoy and Dialysis Center of Kahraman in Turkey. Four instruments were used: Socio-demographic Form, Beck Depression Inventory, Suicide Behaviors Questionnaire and Coping Strategies with Stress Inventory. RESULTS: The points obtained from Beck Depression Inventory were above 17 (the cut-off point) in 40.2% of the patients. There were positive correlations between depression and Suicide Behaviors Questionnaire (r = 0.469, p = 0.001), between patients' age and depression (r = 0.43, p = 0.00) and suicidal ideation (r = 0.27, p = 0.01). Depression and behavioural disengagement had a positive correlation (p = 0.001, r = 0.410). Depression and suicidal ideation increased with lower education status (F = 7.42, p = 0.001; F = 4.51, p = 0.014). CONCLUSION: Haemodialysis patients frequently experience depression. This study demonstrated that suicidal ideation increased as the severity of depression increased. Depression and suicidal ideation were increasing with age in patients with chronic renal failure. Therefore, it is considered necessary for dialysis patients to be under regular psychiatric evaluation with risk assessment. RELEVANCE TO CLINICAL PRACTICE: It is vitally important that nurses in dialysis centres evaluate the psychosocial conditions of patients with renal failure undergoing haemodialysis treatment so as to enhance the quality of nursing care. It is also fundamental for the success of holistic care that nurses properly assess the possibility of depression and suicide as well as coping strategies. This study sheds light on the holistic evaluations of dialysis patients. PMID- 21545573 TI - Range-wide population genetic structure of Symbiodinium associated with the Caribbean Sea fan coral, Gorgonia ventalina. AB - Numerous marine invertebrates form endosymbiotic relationships with dinoflagellates of the genus Symbiodinium, yet few studies have examined the population structure of these symbionts. Here, we elucidate the population genetic structure of Symbiodinium harboured by the Caribbean octocoral Gorgonia ventalina throughout the entire range of the host. We used ten microsatellite loci to survey 35 localities spanning 3124 km across the Caribbean and Western Atlantic. Diversity of Symbiodinium haplotypes was low within colonies of G. ventalina but high among colonies. Despite high haplotypic diversity, significant evidence of clonal reproduction in Symbiodinium was detected, and most clones occurred within localities, not among them. Pairwise measures of F(ST) illustrated significant differentiation in 98% of comparisons between localities, suggesting low levels of gene flow. Clustering analyses identified six genetic groups whose distribution delimited four broad biogeographic regions. There was evidence of some connectivity among regions, corresponding with known geographic and oceanographic features. Fine-scale spatial surveys of G. ventalina colonies failed to detect differentiation among Symbiodinium at the metre scale. However, significant differentiation was observed among Symbiodinium hosted by sympatric G. ventalina colonies of different size/age classes. This cohort effect suggests that Symbiodinium may have an epidemic population structure, whereby G. ventalina recruits are infected by the locally predominant symbiont strain(s), which change over time. PMID- 21545574 TI - Cardiac ventricular repolarization reserve: a principle for understanding drug related proarrhythmic risk. AB - Cardiac repolarization abnormalities can be caused by a wide range of cardiac and non-cardiac compounds and may lead to the development of life-threatening Torsades de Pointes (TdP) ventricular arrhythmias. Drug-induced torsades de pointes is associated with unexpected and unexplained sudden cardiac deaths resulting in the withdrawal of several compounds in the past. To better understand the mechanism of such unexpected sudden cardiac deaths, the concept of repolarization reserve has recently emerged. According to this concept, pharmacological, congenital or acquired impairment of one type of transmembrane ion channel does not necessarily result in excessive repolarization changes because other repolarizing currents can take over and compensate. In this review, the major factors contributing to repolarization reserve are discussed in the context of their clinical significance in physiological and pathophysiological conditions including drug administration, genetic defects, heart failure, diabetes mellitus, gender, renal failure, hypokalaemia, hypothyroidism and athletes' sudden deaths. In addition, pharmacological support of repolarization reserve as a possible therapeutic option is discussed. Some methods for the quantitative estimation of repolarization reserve are also recommended. It is concluded that repolarization reserve should be considered by safety pharmacologists to better understand, predict and prevent previously unexplained drug-induced sudden cardiac deaths. PMID- 21545575 TI - Nanomolar potency and selectivity of a Ca2+ release-activated Ca2+ channel inhibitor against store-operated Ca2+ entry and migration of vascular smooth muscle cells. AB - BACKGROUND AND PURPOSE: The aim was to advance the understanding of Orai proteins and identify a specific inhibitor of the associated calcium entry mechanism in vascular smooth muscle cells (VSMCs). EXPERIMENTAL APPROACH: Proliferating VSMCs were cultured from human saphenous veins. Intracellular calcium was measured using fura-2, whole-cell current was recorded using patch-clamp and cell migration quantified in modified Boyden chambers. Subcellular protein localization was determined by microscopy. Isometric tension was recorded from mouse aortic rings. KEY RESULTS: Molecular disruption and rescue experiments indicated the importance of Orai1 in calcium entry caused by store depletion evoked passively or by platelet-derived growth factor (PDGF), suggesting the presence of Ca(2+) release-activated Ca(2+) (CRAC) channels like those of the immune system. The CRAC channel blocker, S66, was a potent inhibitor of the VSMC signals, IC(50) 26 nM, which was almost two orders of magnitude greater than with leucocytes. S66 had no effect on PDGF- and ATP-evoked calcium release, overexpressed transient receptor potential canonical (TRPC)5 channels, native TRPC1/5-containing channels, stromal interaction molecule 1 clustering, non selective cationic current evoked by store depletion and phenylephrine-evoked aortic contraction. S66 reduced PDGF-evoked VSMC migration while having only modest effects on cell proliferation and no effect on cell viability. CONCLUSIONS AND IMPLICATIONS: The data suggest that Orai1 has a role in human VSMC migration, and that a CRAC channel inhibitor has high potency and selectivity for the associated calcium entry, suggesting a distinct characteristic of vascular CRAC channels and the potential for selective chemical suppression of vascular remodelling. PMID- 21545576 TI - Resistin: functional roles and therapeutic considerations for cardiovascular disease. AB - Resistin, originally described as an adipocyte-specific hormone, has been suggested to be an important link between obesity, insulin resistance and diabetes. Although its expression was initially defined in adipocytes, significant levels of resistin expression in humans are mainly found in mononuclear leukocytes, macrophages, spleen and bone marrow cells. Increasing evidence indicates that resistin plays important regulatory roles apart from its role in insulin resistance and diabetes in a variety of biological processes: atherosclerosis and cardiovascular disease (CVD), non-alcoholic fatty liver disease, autoimmune disease, malignancy, asthma, inflammatory bowel disease and chronic kidney disease. As CVD accounts for a significant amount of morbidity and mortality in patients with diabetes and without diabetes, it is important to understand the role that adipokines such as resistin play in the cardiovascular system. Evidence suggests that resistin is involved in pathological processes leading to CVD including inflammation, endothelial dysfunction, thrombosis, angiogenesis and smooth muscle cell dysfunction. The modes of action and signalling pathways whereby resistin interacts with its target cells are beginning to be understood. In this review, the current knowledge about the functions and pathophysiological implications of resistin in CVD development is summarized; clinical translations, therapeutic considerations and future directions in the field of resistin research are discussed. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. PMID- 21545577 TI - Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease. AB - Adipose tissue is an active endocrine and paracrine organ that may influence the development of atherosclerosis and vascular disease. In the setting of obesity, adipose tissue produces a variety of inflammatory cytokines (or adipokines) that are known to modulate key mechanisms of atherogenesis. In particular, adipose tissue located on the surface of the heart surrounding large coronary arteries (i.e. epicardial perivascular adipose tissue) has been implicated in the pathogenesis of coronary artery disease. The present review outlines our current understanding of the cellular and molecular links between perivascular adipose tissue and atherosclerosis with a focus on potential mechanisms by which epicardial perivascular adipose tissue contributes to obesity-related coronary disease. The pathophysiology of perivascular adipose tissue in obesity and its influence on oxidative stress, inflammation, endothelial dysfunction and vascular reactivity is addressed. In addition, the contribution of specific epicardial perivascular adipose-derived adipokines (e.g. leptin, adiponectin) to the initiation and expansion of coronary disease is also highlighted. Finally, future investigative goals are discussed with an emphasis on indentifying novel therapeutic targets and disease markers within perivascular adipose tissue. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. PMID- 21545580 TI - Two- to eight-month-old infants' perception of dynamic auditory-visual spatial colocation. AB - From birth, infants detect associations between the locations of static visual objects and sounds they emit, but there is limited evidence regarding their sensitivity to the dynamic equivalent when a sound-emitting object moves. In 4 experiments involving thirty-six 2-month-olds, forty-eight 5-month-olds, and forty-eight 8-month-olds, we investigated infants' ability to process this form of spatial colocation. Whereas there was no evidence of spontaneous sensitivity, all age groups detected a dynamic colocation during habituation and looked longer at test trials in which sound and sight were dislocated. Only 2-month-olds showed clear sensitivity to the dislocation relation, although 8-month-olds did so following additional habituation. These results are discussed relative to the intersensory redundancy hypothesis and work suggesting increasing specificity in processing with age. PMID- 21545581 TI - Transition from crawling to walking and infants' actions with objects and people. AB - Associations between infants' transition to walking and object activities were examined. Fifty infants were observed longitudinally during home observations. At 11 months, all infants were crawlers; at 13 months, half became walkers. Over age, infants increased their total time with objects and frequency of sharing objects with mothers. Bidirectional influences between locomotion and object actions were found. Walking was associated with new forms of object behaviors: Walkers accessed distant objects, carried objects, and approached mothers to share objects; crawlers preferred objects close at hand and shared objects while remaining stationary. Earlier object activities predicted walking status: Crawlers who accessed distant objects, carried objects, and shared objects over distances at 11 months were more likely to walk by 13 months. PMID- 21545582 TI - Hemoglobin, growth, and attention of infants in southern Ethiopia. AB - Male and female infants from rural Ethiopia were tested to investigate relations among hemoglobin (Hb), anthropometry, and attention. A longitudinal design was used to examine differences in attention performance from 6 (M = 24.9 weeks, n = 89) to 9 months of age (M = 40.6 weeks, n = 85), differences hypothesized to be related to changes in iron status and growth delays. Stunting (length-for-age z scores < -2.0) and attention performance, t(30) = -2.42, p = .022, worsened over time. Growth and Hb predicted attention at 9 months, R(2) = .15, p < .05, but not at 6. The study contributes to the knowledge base concerning the relations among Hb, early growth, and attention. PMID- 21545583 TI - Cytotoxic T lymphocyte antigen 4 immunoglobulin modified dendritic cells attenuate allergic airway inflammation and hyperresponsiveness by regulating the development of T helper type 1 (Th1)/Th2 and Th2/regulatory T cell subsets in a murine model of asthma. AB - T helper type 2 (Th2) and regulatory T cells (T(reg) ) have been postulated to have critical roles in the pathogenesis of allergic asthma. Cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) gene-modified dendritic cells (DC CTLA4Ig) have the potential to reduce Th2 cells and induce T(reg) cells. In the present study, we evaluated the therapeutic effects and potential mechanisms of the adoptive transfer of DC-CTLA4Ig into mice in an experimental model of asthma. BALB/c mice were sensitized with ovalbumin (OVA) and challenged with aerosolized OVA for 7 days. Just prior to the first challenge, DC-CTLA4Ig, DCs or DCs infected with DC-green fluorescent protein (GFP) were injected intravenously into mice. The administration of DC-CTLA4Ig reduced airway hyperresponsiveness, relieved asthmatic airway inflammation and decreased the numbers of esosinophils in the BALF in OVA-sensitized/challenged mice. In addition, DC-CTLA4Ig altered the balance of Th1/Th2 cytokine production in the lungs with increased interferon (IFN)-gamma levels and decreased interleukin (IL)-4 levels, decreased the percentage of Th2 and increased both the percentage of Th1 and T(reg) cells in the lungs of OVA-sensitized/challenged mice. This research demonstrates that DC CTL4Ig reduces airway hyperresponsiveness effectively and prevents airway inflammation in OVA-sensitized/challenged mice, which is due most probably to attenuated secretion of Th2 cytokines and increased secretion of Th1 cytokines in the local airway, and the correction of the pulmonary imbalance between Th1/Th2 cells and Th2/T(reg) cells. PMID- 21545584 TI - The in vivo immunomodulatory effect of recombinant tumour necrosis factor-alpha in guinea pigs vaccinated with Mycobacterium bovis bacille Calmette-Guerin. AB - Previous studies from our laboratory demonstrated that treatment in vitro with recombinant guinea pig tumour necrosis factor TNF (rgpTNF)-alpha-enhanced T cell and macrophage functions. Similarly, injection of Mycobacterium tuberculosis infected guinea pigs with anti-TNF-alpha altered splenic granuloma organization and caused inflammatory changes and reduced the cell-associated mycobacteria in the tuberculous pluritis model. In this study, rgpTNF-alpha was injected into bacille Calmette-Guerin (BCG)-vaccinated guinea pigs to modulate immune functions in vivo. Guinea pigs were vaccinated intradermally with BCG, 2 * 10(3) colony forming units (CFU) and injected intraperitoneally with either rgpTNF-alpha (25 ug/animal) or 1% bovine serum albumin (BSA) for a total of 12 injections given every other day. Treatment with rgpTNF-alpha significantly enhanced the skin test response to purified protein derivative (PPD), reduced the number of CFUs and increased the PPD-induced proliferation in the lymph nodes at 6 weeks after vaccination. The levels of interleukin (IL)-12 mRNA were increased in the lymph node and spleen cells stimulated with PPD. TNF-alpha treatment induced a decrease in TNF-alpha, IL-12p40 and IL-10 mRNA levels in peritoneal cells following PPD stimulation while live M. tuberculosis caused an increase in TNF-alpha mRNA and a decrease in the IL-10 mRNA expression. TNF-alpha injection also induced an increase in the infiltration of mononuclear cells and in the proportions of CD3(+) T cells in the lymph nodes. These results indicate that rgpTNF-alpha enhances some aspects of T cell immunity and promotes control of mycobacteria in the tissues. Future studies will address the role of TNF-alpha in BCG-vaccinated guinea pigs following low-dose pulmonary challenge with virulent M. tuberculosis. PMID- 21545586 TI - Stopover ecology of a migratory ungulate. AB - 1. Birds that migrate long distances use stopover sites to optimize fuel loads and complete migration as quickly as possible. Stopover use has been predicted to facilitate a time-minimization strategy in land migrants as well, but empirical tests have been lacking, and alternative migration strategies have not been considered. 2. We used fine-scale movement data to evaluate the ecological role of stopovers in migratory mule deer Odocoileus hemionus- a land migrant whose fitness is strongly influenced by energy intake rather than migration speed. 3. Although deer could easily complete migrations (range 18-144 km) in several days, they took an average of 3 weeks and spent 95% of that time in a series of stopover sites that had higher forage quality than movement corridors. Forage quality of stopovers increased with elevation and distance from winter range. Mule deer use of stopovers corresponded with a narrow phenological range, such that deer occupied stopovers 44 days prior to peak green-up, when forage quality was presumed to be highest. Mule deer used one stopover for every 5.3 and 6.7 km travelled during spring and autumn migrations, respectively, and used the same stopovers in consecutive years. 4. Study findings indicate that stopovers play a key role in the migration strategy of mule deer by allowing individuals to migrate in concert with plant phenology and maximize energy intake rather than speed. Our results suggest that stopover use may be more common among non-avian taxa than previously thought and, although the underlying migration strategies of temperate ungulates and birds are quite different, stopover use is important to both. 5. Exploring the role of stopovers in land migrants broadens the scope of stopover ecology and recognizes that the applied and theoretical benefits of stopover ecology need not be limited to avian taxa. PMID- 21545585 TI - Lactobacillus rhamnosus GG and Streptococcus thermophilus induce suppressor of cytokine signalling 3 (SOCS3) gene expression directly and indirectly via interleukin-10 in human primary macrophages. AB - In the present study we have characterized T helper type 2 (Th2) [interleukin (IL)-10]/Th1 (IL-12) cytokine expression balance in human primary macrophages stimulated with multiple non-pathogenic Gram-positive bacteria used in the food industry and as probiotic substances. Bacteria representing Lactobacillus, Bifidobacterium, Lactococcus, Leuconostoc, Propionibacterium and Streptococcus species induced anti-inflammatory IL-10 production, although quantitative differences between the bacteria were observed. S. thermophilus was able to induce IL-12 production, while the production of IL-12 induced by other bacteria remained at a low level. The highest anti-inflammatory potential was seen with bifidobacteria, as evidenced by high IL-10/IL-12 induction ratios. All studied non-pathogenic bacteria were able to stimulate the expression of suppressor of cytokine signalling (SOCS) 3 that controls the expression of proinflammatory cytokine genes. Lactobacillus and Streptococcus species induced SOCS3 mRNA expression directly in the absence of protein synthesis and indirectly via bacteria-induced IL-10 production, as demonstrated by experiments with cycloheximide (CHX) and anti-IL-10 antibodies, respectively. The mitogen activated protein kinase (MAPK) p38 signalling pathway played a key role in bacteria-induced SOCS3 gene expression. Enhanced IL-10 production and SOCS3 gene expression induced by live non-pathogenic Lactobacillus and Streptococcus is also likely to contribute to their immunoregulatory effects in vivo. PMID- 21545588 TI - Patient blood management: a growing challenge and opportunity. PMID- 21545589 TI - Cataracts and corticosteroids in granulocyte donors. PMID- 21545590 TI - Neonatal transfusion practice: should our policies mature with our patients? PMID- 21545591 TI - Transfusion medicine illustrated. A bloody mistake: unrecognized warm reactive anti-A1 resulting in acute hemolytic transfusion reaction. PMID- 21545593 TI - The lost (to follow-up) intervention. PMID- 21545595 TI - The Bavarian Red Cross Blood Donor BioBank: the first successful combination of blood donation and biobanking for medical research. PMID- 21545596 TI - Purported deleterious effects of "old" versus "fresh" red blood cells: an updated meta-analysis. PMID- 21545597 TI - Blood samples, repositories, and ethics. PMID- 21545600 TI - Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products. AB - BACKGROUND AND OBJECTIVES: The occurrence of thromboembolic events (TEEs) with intravenous immunoglobulin lots (IVIGs) raised the question of the causative agent for these adverse events. We investigated the predominant plasma proteases in 19 IVIG lots from five manufacturers including three lots associated with adverse events. MATERIAL AND METHODS: The inhibitor profile of the amidolytic activity in IVIG lots was investigated with substrates S-2302 and S-2288. In immunocapture assays, prekallikrein and FXI antigen and respective active proteases were quantified. Non-activated partial thromboplastin time (NAPTT) and a modified FXIa PTT served as global and FXIa-specific clotting assays, respectively. RESULTS: Kallikrein was identified as one major contaminant activity in IVIGs. A second activity was seen in some IVIGs with substrate S 2288, but not with S-2302. Inhibition studies excluded FXIIa, thrombin or plasmin as contaminant activity. FXI antigen was seen in all 19 IVIG lots, and FXIa activity was found as second major impurity in some IVIGs, including all lots involved in TEEs. FXIa highly correlated with a short clotting time in NAPTT. CONCLUSIONS: Kallikrein and FXIa are the major contaminants in IVIGs. FXIa was highly procoagulant, with highest level in TEE-associated IVIGs. Since the NAPTT unambiguously identified FXIa procoagulant activity in IVIGs, its implementation as a release test would improve the safety of IVIGs. PMID- 21545601 TI - Validation of self-reporting of hand eczema among Danish hairdressing apprentices. AB - BACKGROUND: Hairdressing apprentices have a high incidence of hand eczema. Most studies use self-reported hand eczema as a cost-effective method to estimate the prevalence of hand eczema. No validation studies on self-reported hand eczema among hairdressing apprentices exist. OBJECTIVES: To evaluate the validity of self-reporting of hand eczema among Danish hairdressing apprentices. METHODS: During their first 2 weeks of training, 502 hairdressing apprentices were enrolled in this study. All apprentices completed a self-administered questionnaire including questions regarding, for example, current hand eczema, and they were all clinically examined for hand eczema three times during the first part of their education by use of the Hand Eczema Severity Index. The validity of self-reporting of hand eczema was measured with the clinical examination as the gold standard. RESULTS: The sensitivity of self-reporting of hand eczema was 70.3%, and the specificity was 99.8%. The positive predictive value was 96.3%, and the negative predictive value was 98.5%. CONCLUSIONS: We found good agreement between self-reporting of hand eczema and clinical examination. There was good sensitivity and high specificity. Self-reporting of hand eczema among hairdressing apprentices is considered to be a valid method for estimating the prevalence of hand eczema, although it might underestimate the true prevalence. PMID- 21545602 TI - Patch testing with hydroxyethyl-p-phenylenediamine sulfate - cross-reactivity with p-phenylenediamine. AB - BACKGROUND: Adverse reactions to permanent hair dyes are frequent, and primarily result from sensitization to p-phenylenediamine (PPD). OBJECTIVES: To investigate the degree of cross-reactivity to a chemically similar dye, hydroxyethyl-p phenylenediamine sulfate (HPPS), and whether this might be a dyeing alternative for patients who are sensitive to PPD. METHOD: HPPS was patch tested in two concentrations in a total of 216 patients suspected of having contact dermatitis caused by hair dyes and/or hair cosmetics. A regular use test with a hair dye containing HPPS was suggested to every patient who had had an adverse reaction to a PPD hair dye in the past. RESULTS: Forty of 216 (19.9%) patients reacted to 1% PPD, whereas only 2/216 (0.9%) showed a positive reaction to 1% HPPS. Reactivity to 2% HPPS was only slightly higher (5/216, 2.3%). On the basis of the 43 PPD positive patients, the reactivity to 2% HPPS amounted to 12%; the corresponding figure for toluene-2,5-diamine was 15% (5/33). In a use test on two PPD-positive patients with a hair dye containing HPPS, no adverse reaction was seen, even after several years of regular dyeing. CONCLUSIONS. HPPS may be an alternative hair dye for individuals not tolerating PPD-containing dyes. However, cross reactivity with PPD and other aromatic amines may occur. HPPS is also a known sensitizer, and the risk of de novo sensitization can only be assessed by a controlled study on a large panel and under regular use conditions. PMID- 21545603 TI - Correlation between lesion site and concentration of dimethyl fumarate in different parts of shoes in patients with contact dermatitis caused by dimethyl fumarate in footwear. AB - BACKGROUND: Dimethyl fumarate (DMF) has been identified as being responsible for an outbreak of shoe contact dermatitis in Europe. All reported cases to date have involved the dorsa of the toes and the dorsa of the feet, sometimes in association with other areas. OBJECTIVES: To establish a correlation between the site of the lesions and the concentration of DMF in different parts of the footwear from patients suffering from shoe contact dermatitis. METHODS: We performed a retrospective study of 8 patients with shoe contact dermatitis caused by DMF. Clinical data and patch test results obtained with DMF were recorded. The contents of DMF in different parts of eight samples of shoes involved were analysed with gas chromatography-mass spectrometry. RESULTS: The chemical analysis of all samples studied showed the presence of DMF, both in the uppers and the soles of the shoes. A clinical-analytical correlation was found in all cases. The presence of DMF in a child's boot was detected 1 year after withdrawal of the sachet with DMF from the shoe box. CONCLUSIONS: A correlation exists between the concentrations of DMF in the different parts of the shoe and the localization of the lesions. Although DMF is a volatile substance, it can remain impregnated in shoes for a long period of time. PMID- 21545604 TI - Detection and isolation of chloromethane-degrading bacteria from the Arabidopsis thaliana phyllosphere, and characterization of chloromethane utilization genes. AB - Chloromethane gas is produced naturally in the phyllosphere, the compartment defined as the aboveground parts of vegetation, which hosts a rich bacterial flora. Chloromethane may serve as a growth substrate for specialized aerobic methylotrophic bacteria, which have been isolated from soil and water environments, and use cmu genes for chloromethane utilization. Evidence for the presence of chloromethane-degrading bacteria on the leaf surfaces of Arabidopsis thaliana was obtained by specific quantitative PCR of the cmuA gene encoding the two-domain methyltransferase corrinoid protein of chloromethane dehalogenase. Bacterial strains were isolated on a solid mineral medium with chloromethane as the sole carbon source from liquid mineral medium enrichment cultures inoculated with leaves of A. thaliana. Restriction analysis-based genotyping of cmuA PCR products was used to evaluate the diversity of chloromethane-degrading bacteria during enrichment and after strain isolation. The isolates obtained, affiliated to the genus Hyphomicrobium based on their 16S rRNA gene sequence and the presence of characteristic hyphae, dehalogenate chloromethane, and grow in a liquid culture with chloromethane as the sole carbon and energy source. The cmu genes of these isolates were analysed using new PCR primers, and their sequences were compared with those of previously reported aerobic chloromethane-degrading strains. The three isolates featured a colinear cmuBCA gene arrangement similar to that of all previously characterized strains, except Methylobacterium extorquens CM4 of known genome sequence. PMID- 21545605 TI - Evidence of compositional differences between the extracellular and intracellular DNA of a granular sludge biofilm. AB - AIMS: Extracellular polymeric substances (EPS) are an important component of microbial biofilms, and it is becoming increasingly apparent that extracellular DNA (eDNA) has a functional role in EPS. This study characterizes the eDNA extracted from the novel activated sludge biofilm process of aerobic granules. METHODS AND RESULTS: Exposing the sludge to cation exchange resin (CER) was used for the extraction of eDNA and intracellular DNA (iDNA) from aerobic granules. This was optimized for eDNA yield while causing minimal cell lysis. We then compared the DNA composition of these extractions using randomly amplified polymorphic DNA (RAPD) fingerprinting and PCR-based denaturing gradient-gel electrophoresis (DGGE). Upon the analysis of the genomic DNA and the 16S rRNA genes, differences were detected between the sludge biofilm eDNA and iDNA. CONCLUSIONS: Different bacteria within the biofilm disproportionally release DNA into the EPS matrix of the biofilm. SIGNIFICANCE AND IMPACT OF THE STUDY: The findings further the idea that eDNA has a functional role in the biofilm state, which is an important conceptual information for industrial application of biofilms. PMID- 21545606 TI - Randomised clinical trial: The ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation--a double-blind study. AB - BACKGROUND: One half of patients with constipation are not satisfied with available therapies, hence there is a need for more effective and well-tolerated drugs. AIM: To evaluate the effects of a specific inhibitor of the Ileal Bile Acid Transporter (IBAT; syn apical sodium-dependent bile acid transporter; ASBT) in patients with chronic idiopathic constipation (CIC) with focus on safety, colonic transit and efficacy signals. METHODS: This was a single-centre, prospective, randomised, double-blind, placebo-controlled study with a dose escalating design in patients with CIC. In addition to evaluation of conventional safety and tolerability parameters, (i) colonic transit time (CTT) was measured using radio-opaque markers, (ii) metabolic parameters [lipid profile, C4 (7alpha hydroxy-4-cholesten-3-one) and FGF19 (Fibroblast Growth Factor 19)] were evaluated, and (iii) constipation parameters, such as changes in stool frequency and consistency, were analysed. RESULTS: Thirty patients were randomised into five dose-levels (range: 0.1-10 mg/day) or to placebo. All patients completed a 14-day treatment period, and the safety/tolerability analysis was favourable. A3309, present in picomolar concentrations in plasma, induced up to a three-fold increase in bile acid synthesis (C4) and a reduction of plasma FGF19, as well as reduction in total and LDL cholesterol. CTT was reduced in the highest dose groups; the main acceleration was identified in the left colon. Efficacy parameters showed trends for increased number of spontaneous bowel movements and improved stool consistency. CONCLUSIONS: Ileal Bile Acid Transporter inhibition is a novel mechanism for treatment of patients with chronic idiopathic constipation and has additional benefits of improving metabolic parameters (EudraCT 2008-003255-72). PMID- 21545607 TI - How much is the life of a cancer patient worth? A pharmaco-economic perspective. AB - WHAT IS KNOWN AND OBJECTIVE: Countries struggle to accommodate the introduction of new effective cancer medicines, while containing costs. Our objective is to comment on several pharmaco-economic challenges involved in determining the value of cancer medicines by reviewing cost-effectiveness thresholds for cancer medicines in several countries and by discussing the cost-effectiveness of anti cancer biotechnology and orphan medicines. COMMENT: A literature search was carried out of PubMed, Centre for Reviews and Dissemination databases, Cochrane Database of Systematic Reviews and EconLit up to August 2009. Health technology assessment agencies in England and Scotland are willing to incur a higher cost per quality-adjusted life year for cancer medicines than for other medicines. Risk-sharing arrangements have been implemented to optimize the value of cancer medicines. The cost-effectiveness of biotechnology medicines in cancer care is challenged by their high price, and depends on the ability to identify the most responsive target population, through use of suitable biomarkers. The evaluation of orphan medicines in cancer care needs to balance the absence of an alternative therapy for a life-threatening disease against the high cost-effectiveness ratio, and usually weak clinical data. WHAT IS NEW AND CONCLUSION: Current strategies used to inform decisions on the funding of expensive anti-cancer medicines are commented on to highlight important issues and problems. Pharmaco-economic evaluation is an important tool for assessing the value of cancer medicines and to inform evidence-based decision making in cancer care. Value-judgments such as preferential consideration of anti-cancer medicines can then be made explicitly. PMID- 21545608 TI - A proposed mechanism for chemotherapy-related cognitive impairment ('chemo-fog'). AB - WHAT IS KNOWN AND OBJECTIVE: Chemotherapeutic drugs for cancer treatment are, of necessity, cytotoxic. Unintended damage to normal central nervous system neuronal structure or function might lead to deleterious adverse effects on cognitive function, a mild form of which is reported by some cancer survivors. Understanding the physiologic connection between cancer chemotherapy and the reported cognitive dysfunction, could help inform choice of drugs, treatment regimens and new drug development. Our objective is to comment on a proposed mechanism for 'chemo-fog'. COMMENT: An increasing number of patients are surviving cancer and are generating a new and rapidly growing category within the healthcare system. Some of these cancer survivors are reporting that they are experiencing residual and lingering effects from the cancer, or from its treatment, and that they now need care as survivors. This has given rise to the new field of 'survivor care'. Control of chemo-fog is an important aspect and understanding its mechanism, the basis for more rationale therapy. Such insight would also help direct drug-discovery efforts. WHAT IS NEW AND CONCLUSION: New evidence suggests that 'chemo-fog' may be due to excessive cytokine release by the cytotoxic agents. Control of the elevated levels of the blood-brain-barrier permeable pro-inflammatory cytokines, may help minimize this adverse effect. PMID- 21545609 TI - Liraglutide: once-daily GLP-1 agonist for the treatment of type 2 diabetes. AB - WHAT IS KNOWN AND OBJECTIVE: The prevalence of diabetes is increasing worldwide. Over the recent years, new discoveries have led to the development of new pharmacological agents targeting the incretin hormones gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1). These agents, called incretin mimetics, are the newest agents added to the diabetes treatment options. The purpose of this article is to review the relevant literature on the chemistry, pharmacology, pharmacokinetics, metabolism, clinical trials, safety, drug interactions and place in therapy of liraglutide in the treatment of type 2 diabetes. METHODS: An extensive search of the literature was performed with liraglutide and NN2211 as key terms. This article presents a review of the literature related to the chemistry, pharmacology, pharmacokinetics, drug interactions and safety and efficacy of liraglutide. RESULTS AND DISCUSSION: Liraglutide, a subcutaneously administered GLP-1 agonist, displays phamacodynamic and pharmacokinetic properties that allow for once-daily administration. The agent has been shown to be efficacious as monotherapy, as well as in combination with glimperide, metformin and/or rosiglitazone, reducing glycoslyated haemoglobin (A1C) between 0.84% and 1.5%. The primary adverse event reported with liraglutide is transient nausea. WHAT IS NEW AND CONCLUSION: Liraglutide has been well studied in dual and triple combination therapies with sulfonylureas, metformin and rosiglitazone and appears safe and effective. For patients who cannot tolerate first-line agents, metformin, insulin and sulfonylureas, liraglutide is a reasonable treatment option. PMID- 21545610 TI - Treatment of irritable bowel syndrome. AB - WHAT IS KNOWN AND OBJECTIVE: The complexity and diversity of irritable bowel syndrome's (IBS) presentation make treatment difficult. Although there are reviews and guidelines for treating IBS, they focus on the efficacy of medications for IBS symptoms using high-priority endpoints, leaving those of lower priority largely unreported. Therefore, the aim of this review is to provide a comprehensive evidence-based review of the efficacy of medications to treat IBS symptoms, reported by IBS subtype, including secondary symptom endpoints that are often underreported. METHODS: A review of PubMed for articles published through December 2009 using the keywords: 'irritable bowel syndrome', 'therapeutics', 'antidiarrhoeals', 'laxatives', 'loperamide', 'dietary fibre', 'psyllium', 'calcium polycarbophil', 'bulking agents', 'lubiprostone', 'antidepressant agents, tricyclics' and its representative entities, 'serotonin reuptake inhibitors' and its representative entities, 'dicyclomine', hyoscyamine', 'peppermint oil', 'parasympatholytics' and its representative entities, 'rifaximin', 'pregabalin', 'gabapentin', 'clonidine', 'octreotide', 'atropine' and 'probiotics' is provided. Placebo-controlled trials were evaluated for the strength of evidence supporting the efficacy of each medication for explicit IBS symptoms. The efficacy of each medication for the symptoms of abdominal pain, bloating, stool form, mucus, urgency, feeling of incomplete evacuation, flatulence, frequency, or borborgymi and overall symptoms are reported by IBS subtype. RESULTS AND DISCUSSION: The literature search identified 58 placebo-controlled trials of the efficacy of medications for treating IBS symptoms, which were critically evaluated and reported. The available studies suggest improvement in various IBS symptoms with loperamide, fibre supplements, lubiprostone, tricyclic antidepressants (TCAs), selective serotonin receptor inhibitors (SSRIs), antispasmotics, rifaximin, pregabalin, gabapentin, clonidine, octreotide and probiotic treatments. WHAT IS NEW AND CONCLUSION: This review is the first to compile the available evidence on the efficacy of the various pharmacological treatments for IBS on the basis of IBS subtype and specific symptoms. This evidence is limited and more well-designed studies are required to better inform therapeutic decision-making in the management of this difficult syndrome. PMID- 21545611 TI - Deciphering the mechanism(s) of action of natural products: analgesic peroxide oil as example. AB - BACKGROUND: There are multiple reports of natural products having therapeutic effect. In an era of evidence-based medicine, clinical trials inform clinical decisions regarding use of the product, but prevailing preference is to identify and use a single 'active ingredient'. Yet, the clinical benefit of a natural product might derive from the fortuitous combination of its multiple components. Therefore, the elucidation of the mechanism(s) of action of natural products is important, but presents significant challenges. This article examines this issue using peroxide oil (essential oxygen oil) as an illustrative example. OBJECTIVE: To review the published literature of a natural product in an effort to elucidate postulated mechanism(s) of action of a complex mixture. METHODS: The clinical and preclinical literature was reviewed from the perspective of its contribution to elucidating a mechanism of analgesic action of a natural product. RESULTS: Peroxide oil contains ingredients that are associated with analgesic mechanisms, such inhibition of lipid peroxidation and arachidonic acid metabolism and non opioid, glibenclamide-sensitive receptor-mediated and K(ATP) -NO-cGMP channel pathways. CONCLUSION: Although its exact mechanism remains unknown, peroxide oil provides an example of how a natural product can be evaluated for plausible mechanistic explanation of its purported therapeutic efficacy. Such an approach seems valuable, since, as in this case, the constituents appear to contribute in an additive or synergistic manner, something not possible with a single substance. PMID- 21545612 TI - Hepatotoxicity of therapeutic short-course paracetamol in hospital inpatients: impact of ageing and frailty. AB - BACKGROUND: Paracetamol, a commonly used simple analgesic, can be fatal in overdose. Case reports suggest liver damage may occur at therapeutic doses. In older and particularly frail patients, dose reduction of therapeutic paracetamol is recommended due to concerns of an increased risk of hepatotoxicity. AIMS: This study aimed to investigate the effects of ageing and frailty on the safety of paracetamol in hospital inpatients commenced on short courses of the drug. METHODS: An observational cohort study of young (18-55 years, n = 19), older (>= 70 years) fit (n = 24) and older frail (n = 28) hospital inpatients. Treatment group participants commenced regular paracetamol (3-4 g/day) during their hospital admission, whereas the control group was not exposed to paracetamol. In both groups, plasma alanine aminotransferase (ALT) was measured at baseline and day 5, and risk factors for raised ALT were recorded. A random serum paracetamol concentration was measured at day 5 in the treatment group. RESULTS: No older frail treatment participants had an abnormal day 5 ALT. Odds ratios for having a day 5 ALT above the upper limit of normal (ULN) with paracetamol use, compared with unexposed controls, were 3.7 [95% confidence intervals (CI): 0.32, 41.59] for older not frail participants and 2.5 (95% CI: 0.34, 18.3) for younger participants. Decreasing frailty score independently predicted a day 5 ALT above the ULN (P < 0.05). Day 5 serum paracetamol concentrations were highest in older frail participants (P < 0.005). CONCLUSION: Higher paracetamol concentrations observed in frail older patients after 5 days of therapeutic paracetamol do not necessarily indicate an increased risk of hepatotoxicity. PMID- 21545613 TI - Intravenous bisphosphonates for post-menopausal osteoporosis: adherence to a network guideline. AB - WHAT IS KNOWN AND OBJECTIVE: An evidence-based guideline on the use of intravenous (i.v.) bisphosphonates in post-menopausal osteoporosis was developed across a healthcare system and approved by clinical experts and Pharmacy and Therapeutics Committees. The objective of the study was to evaluate adherence to the guideline at hospitals in the healthcare system. METHODS: Post-menopausal women who received i.v. zoledronic acid or i.v. ibandronate for osteoporosis between September 2007 and October 2008 were identified through a data repository that provides patient-level longitudinal information on diagnoses, medications and laboratory tests. Manual review of electronic medical records supplemented the data capture. The guideline recommends use of i.v. bisphosphonates in patients: (i) who have had a recent vertebral or hip fracture; (ii) who cannot stand or sit upright for 30-60 min; (iii) who have oesophageal dysmotility or varices; (iv) who have documented adherence issues or, (v) who failed to tolerate oral bisphosphonates after 12 months. In addition, specific monitoring tests are recommended prior to administration. RESULTS AND DISCUSSION: Among the 220 women that received an i.v. bisphosphonate (hospitals A/B: n = 92 vs. hospital C: n = 128), 72% met the criteria for use. The results were similar when examined by institution (hospitals A/B 66% vs. hospital C 77%; P = 0.094). On review of the electronic medical records, an additional reason for using i.v. bisphosphonates was identified: persistent bone loss despite oral bisphosphonate therapy. When this criterion for use was included, the adherence rate increased to 80% (hospitals A/B 72% vs. hospital C 86%; P = 0.009). Serum calcium and 25-OH vitamin D were performed in 75% (hospitals A/B 77% vs. hospital C 73%; P = 0.53), and 86% (hospitals A/B 84% vs. hospital C 87%; P = 0.53) of patients respectively. WHAT IS NEW AND CONCLUSION: Adherence to an i.v. bisphosphonates evidence-based guideline was adequate (defined as at least 80%) although room for improvement in meeting the criteria for use at one hospital and for conducting baseline serum calcium levels was noted. A future project is warranted to re assesses adherence after the measures to improve guideline adherence are implemented. PMID- 21545614 TI - Perceived feasibility of a community pharmacy-based asthma intervention: a qualitative follow-up study. AB - WHAT IS KNOWN AND OBJECTIVE: Asthma is a National Health Priority Area in Australia; however, recent evidence suggests that its management remains suboptimal. Community pharmacists are in a unique position to help patients manage asthma, and a number of community pharmacy-based asthma interventions have demonstrated effectiveness with improved patient outcomes. This study aimed to explore the views of general practitioners (GPs), community pharmacists and patients towards a pharmacy-based intervention that saw patients with poorly managed asthma supplied with educational material and referred to their GP for an asthma management review. METHODS: A qualitative follow-up study of participants who had been involved in the intervention was conducted. A sample of six GPs, 10 community pharmacists and 10 patients participated in semi-structured face-to face interviews. Data were analysed using interpretive phenomenology. RESULTS AND DISCUSSION: General practitioners accepted the intervention process if they had positive relationships with pharmacists. There was also some hesitance of GPs towards the intervention, related to a perceived encroachment on their area of responsibility and a perceived conflict of interest of pharmacists in providing health care. GPs indicated the need to be more involved with the intervention process, and expressed that patients were rarely forthcoming about problems with their asthma. Community pharmacists felt that patients can be apathetic about asthma and often fail to seek medical advice. The intervention was implemented very easily, with minimal disruptions to the pharmacists' workflow, and pharmacists suggested that it would be better if GPs were more involved with the intervention process. Patients' general satisfaction with pharmacy services was high, but their expectations were quite low. Although there was an appreciation by patients of community pharmacists' interest in their health, this did not necessarily translate into appointments with GPs for an asthma management review. The reason for this related primarily to patients' under-estimation of their asthma severity. WHAT IS NEW AND CONCLUSION: A wider rollout of the asthma intervention, with an improved process for involving GPs, would be feasible and well accepted. Further research should determine the best approach in influencing patients' perceptions of asthma control and whether these perceptions are amenable to a more intensive educational intervention. This could result in more efficient asthma interventions, translating to improved patient outcomes. PMID- 21545615 TI - Doctors' beliefs and knowledge on corticosteroid-induced osteoporosis: identifying barriers to improve prevention. AB - WHAT IS KNOWN AND OBJECTIVE: Despite the availability of effective treatments for the management of corticosteroid-induced osteoporosis (CIOP), the condition is undertreated. Our objective was to assess prescribers' knowledge and likely prescribing patterns concerning the diagnosis and treatment of CIOP. Another goal was to identify key barriers to the use of preventive therapy in patients using long-term corticosteroids. METHODS: We used a postal survey of general practitioners (GPs) and specialists in the Netherlands. The survey comprised of questions on: demographic data, perceived barriers to the use of preventive therapy for CIOP, and knowledge of diagnosis and treatment of CIOP. Case scenarios were questioned to assess practice patterns. RESULTS: Responding prescribers correctly answered an average of 55% of knowledge questions and 69% of case scenarios. Multiple questions and cases showed that knowledge on the use of bone mineral density (BMD) determination was poor. BMD was determined in patients who, according to the national osteoporosis guideline, should be treated with bisphosphonates independent of BMD. Moreover, only 18% of doctors correctly answered that the BMD cutoff in CIOP patients is a T-score of <=-1 or <=-1.5. Key barriers identified were: (i) GPs, significantly more than specialists, consider prescription of preventive therapy the responsibility of another doctor; (ii) discontinuation of anti-resorptive medication due to adverse effects and (iii) the reluctance to prescribe preventive therapy in patients already prescribed multiple medications. WHAT IS NEW AND CONCLUSION: Doctors did not identify many barriers to the prescribing of anti-resorptive therapies. Lack of knowledge, especially concerning use of BMD-results, likely led to the under-treatment of the presented patients. PMID- 21545616 TI - Lay perspectives on the use of biologically based therapies in the context of cancer: a qualitative study from Sweden. AB - WHAT IS KNOWN AND OBJECTIVE: Biologically based therapies (BBTs) such as herbal medicines represent the most commonly used type of complementary and alternative medicine by cancer patients. There is a paucity of data regarding individuals' motives for starting and continuing use of BBTs in cancer. Our objective is to explore lay perspectives on use of BBTs in cancer. Our hope is that the data generated will support pharmacists and other professionals in improving their communication about BBTs with patients. METHODS: Interviews with 12 individuals with cancer who used BBTs were analyzed with interpretive description and framework analysis, to build on previous literature and gain new knowledge of clinical relevance. RESULTS: The findings suggest that users are motivated to continue to use BBTs when they experience these as both effective and harmless. Perceived effects of BBTs include a wide range of responses such as improved physical and psychological well-being, and cancer-related benefits. These experiences go beyond the legal health and medical claims for these products. The findings indicate that users' views of side-effects, ascribed to BBT use, are situation-dependent with the potential to either facilitate or hinder continued BBT use. WHAT IS NEW AND CONCLUSION: Our results indicate the importance of acknowledging users' own views of BBTs to improve patient-provider communication. This should aid the design of more effective BBT surveillance systems and hence increase patient safety and satisfaction. PMID- 21545617 TI - Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements. AB - WHAT IS KNOWN AND OBJECTIVE: The reported incidence of metformin associated lactic acidosis (MALA) in type 2 diabetes mellitus (DM) is 3-9 cases per 100,000 patient-years. In clinical practice, 22-94% of patients using metformin have contraindications to metformin, so the incidence of MALA may be higher than reported. AIM OF THE STUDY: To estimate the incidence of MALA in type 2 DM patients by means of metformin serum concentration measurements and investigate the correlation of metformin serum concentration with the clinical outcome of MALA. METHODS: MALA cases were identified by reviewing the medical records of patients with metformin serum concentrations measured between January 2000 and October 2008. MALA was defined as arterial pH <7.35 and lactate concentration >5.0 mmol/L in patients using metformin. The incidence of MALA was calculated from the number of cases and the at risk population. The correlation coefficient between the metformin and lactate concentration was calculated by linear regression. The relationship between metformin serum concentration, lactate concentration and outcome was examined by calculating the mean metformin and lactate concentration in patients who survived and those who died. The Student's t-test was used to compare groups. RESULTS AND DISCUSSION: In 29 patients metformin serum concentration was measured, 16 had MALA. Eleven of the 16 MALA cases (69%) had risk factors for lactic acidosis in their medical history, 13 cases (81%) had renal failure on admission. The incidence of MALA was estimated at 47 per 100,000 patient-years, this is 5-16 times higher than previously reported. This may be explained by the use of metformin in the presence of risk factors for lactic acidosis. Survivors had a higher metformin serum concentration (18.9 mg/L) than non-survivors (2.9 mg/L, P = 0.006) which can be explained by less severe underlying disease in patients who survived MALA, rather than an effect of metformin itself. WHAT IS NEW AND CONCLUSION: The incidence of MALA estimated from metformin serum concentration measurements in type 2 DM patients is 5-16 times higher than reported in literature. MALA is probably caused by the frequent use of metformin in the presence of risk factors for lactic acidosis. Metformin serum concentration measurements may aid in the timely diagnosis and therapy of MALA. The outcome of MALA is determined by the severity of the underlying disease, rather than by metformin itself. PMID- 21545618 TI - Modelling the atypical absorption of menatetrenone and the metabolism to its epoxide: effect of VKORC1 polymorphism. AB - WHAT IS KNOWN AND OBJECTIVE: This study aimed to model the atypical absorption of menatetrenone and its epoxide metabolite and to examine the influence of the single nucleotide polymorphism (SNP) of vitamin K2 epoxide reductase complex subunit 1 (VKORC1) on the pharmacokinetics. METHODS: After the administration of 30 mg of menatetrenone to 26 healthy subjects, the plasma concentrations of menatetrenone and its epoxide were measured using LC-MS/MS. For the haplotype analysis, the SNP of the VKORC1 gene was investigated in the 26 volunteers. The model parameters were estimated using the ADAPT II program. RESULTS AND DISCUSSION: A two-compartment model with Weibull-type absorption and saturable elimination described the pharmacokinetics of menatetrenone and its epoxide. The plasma concentrations of both tended to be lower in the H1/H7 genotype group than in the wild-type H1/H1 group. WHAT IS NEW AND CONCLUSION: We present the first detailed pharmacokinetic modelling of menatetrenone in relation to VKORC1 genotype. This study suggests that VKORC1 genotype is unlikely to be helpful in dose-selection because of the very high inter-individual variation in systemic exposure within each genotype group, and the small inter-group difference observed. PMID- 21545619 TI - Combined pharmacogenetic effect of ADCY9 and ADRB2 gene polymorphisms on the bronchodilator response to inhaled combination therapy. AB - WHAT IS KNOWN AND OBJECTIVE: Inhaled combination therapy composing of long-acting beta2-agonist and corticosteroid has been widely applied in the management of asthma, but observed treatment responses vary. The aim of this study was to evaluate the pharmacogenetic effect of the adenylyl cyclase type 9 (ADCY9) gene polymorphism on combination therapy. MATERIALS AND METHODS: Eighty-six mild to moderate Korean asthmatics were enrolled in this clinical trial. After the 2-week 'run-in' period, patients received budesonide (an inhaled corticosteroid) and formoterol (long-acting beta2-agonist) during the following 12-week active treatment period. Forced expiratory volume in 1 s (FEV(1) ) and maximum mid expiratory flow (MMEF) levels were measured at all visits as primary outcome. ADCY9 (Ile772Met, 150127 C/T, 150130 C/T, 150397 C/T, 150479 C/T, TTTA (5/4) ) and beta2-adrenergic receptor (ADRB2, Arg16Gly) gene polymorphisms were genotyped. RESULTS: Significant associations were observed between the ADCY9 single nucleotide polymorphisms and percent changes in FEV(1) (Ile772Met T/C, P = 0.030) and MMEF (150397 C/T, P = 0.016) after 8 weeks of combination therapy. Haplotype associations were also observed with respect to percent changes in FEV(1) after 8 weeks of therapy (Ht3[TTCC], P = 0.017). Additive therapeutic effect was observed in those with the ADCY9 Ile772Met and ADRB2 Arg16Gly gene polymorphisms in terms of percent change in FEV(1) after 8 and 12 weeks of therapy (P = 0.002 and P = 0.027 respectively). WHAT IS NEW AND CONCLUSION: Our results suggest that ADCY9 gene polymorphisms may alone, and in combination with ADRB2 gene polymorphisms, contribute to individual response to combination therapy in mild to moderate asthmatics. PMID- 21545620 TI - Pharmacokinetics of midazolam tablet in different Chinese ethnic groups. AB - WHAT IS KNOWN AND OBJECTIVES: Subjects of different ethnic groups may respond differently to drugs. The present study was conducted to compare the oral pharmacokinetics of midazolam among healthy volunteers from five different ethnic groups in China: Han, Mongolian, Uygur, Hui and Korean. METHODS: Healthy volunteers (10 Hans, 10 Mongolians, 10 Uygurs, 10 Huis and 9 Koreans) of Chinese nationality received a single oral tablet dose of 15 mg midazolam in an open label, parallel-group study. Blood samples were collected at intervals and analysed for midazolam by high performance liquid chromatography (HPLC). Ethnic differences in pharmacokinetic parameters of midazolam using non-compartmental methods and anova and Kruskal-Wallis rank test. RESULTS AND DISCUSSION: Midazolam maximum concentration (C(max) ) was significantly lower in Mongolians than that in Hans, Uygurs, Huis and Koreans (74.9 +/- 33.7, 103.1 +/- 26.4, 124.8 +/- 50.0, 130.0 +/- 38.3 and 189.0 +/- 82.1 MUg/L, respectively). C(max) for the Koreans were significantly greater, compared with Hans and Mongolians. The time to attain C(max) (t(max) ) for Hans was significantly longer as compared with Koreans and Uygurs (1.5 +/- 0.7, 0.8 +/- 0.5, 0.6 +/- 0.7 h, respectively). Midazolam terminal half-life (t(1/2z)) were 3.0 +/- 0.8, 2.2 +/- 0.7, 1.9 +/- 0.7, 3.5 +/- 1.9, 3.8 +/- 2.3 h for Hans, Mongolians, Uygurs, Huis and Koreans, respectively. The differences in half-life were significant between Koreans and Mongolians, Koreans and Uygurs, Uygurs and Huis, respectively. There were no differences between young males and females for all pharmacokinetic parameters. Double peaks in the concentration-time profiles were observed in some subjects. WHAT IS NEW AND CONCLUSION: There were some significant differences in midazolam pharmacokinetics between the five Chinese ethnic groups. However, the wide intra ethnic variability observed in PK parameters makes predictions of midazolam kinetics, using ethnicity as predictor, unreliable. PMID- 21545621 TI - Chronic cough associated with interferon/ribavirin therapy for hepatitis C. AB - WHAT IS KNOWN AND OBJECTIVE: The combination of pegylated interferon and ribavirin has become standard therapy for chronic hepatitis C infection. The occurrence of chronic cough associated with this treatment regimen has been reported, but the mechanism by which cough occurs has not previously been investigated. We measured cough reflex sensitivity, during and after completion of therapy, in four patients who developed chronic cough associated with interferon/ribavirin therapy. CASE SUMMARY: Four patients without history of respiratory symptoms developed chronic cough temporally related to initiation of therapy with pegylated interferon and ribavirin for chronic hepatitis C infection. Cough resolved within 2-6 weeks after completion of a 48-week course of therapy. To measure cough reflex sensitivity, capsaicin cough challenge testing was performed 1 month prior to cessation of therapy, and 1 and 2 months after completion of treatment. In all patients, cough reflex sensitivity, as measured by C(5) , the concentration of capsaicin inducing 5 or more coughs, was significantly enhanced during treatment compared to 1 month after completion of therapy (P = 0.016). WHAT IS NEW AND CONCLUSION: Previous studies have observed that cough occurs more commonly in patients receiving the combination of interferon and ribavirin compared to interferon alone, thus implicating ribavirin as the causal agent. Our data demonstrate that it does so by reversible enhancement of cough reflex sensitivity. Clinicians should be aware of this potential treatment-related effect, so as to avoid unnecessary and costly diagnostic evaluations seeking an alternative aetiology of cough. PMID- 21545622 TI - Simvastatin-induced myopathy, the role of interaction with diltiazem and genetic predisposition. AB - WHAT IS KNOWN AND OBJECTIVE: Diltiazem shows a pharmacokinetic interaction with statins that are CYP3A substrates but this may not result in myopathy unless additional genetic or clinical factors are present. Subsequent changes in treatment or underlying disease may result in a delayed onset of this adverse affect. Our objective is to report on two cases of statin-induced myopathy associated with concomitant use of diltiazem and other contributing factors, and to briefly review the related literature. COMMENT: A 63-year-old Chinese woman with hypertension and familial hypercholesterolaemia (FH) taking diltiazem 90 mg twice daily had elevation of creatine kinase (CK) to 4016 U/L and alanine aminotransferase (ALT) to 165 IU/L 4 weeks after increasing the dose of simvastatin from 40 to 80 mg daily. Another 80-year-old Chinese woman with FH, mild vascular dementia and hypertension was hospitalized with bilateral lower limb weakness associated with raised CK (8869 IU/L), lactate dehydrogenase (1384 IU/L) and ALT (288 IU/L) after taking diltiazem 60 mg twice daily with simvastatin 40 mg for 11 months. Statin-associated myopathy was suspected and simvastatin was stopped in both cases, and symptoms resolved and all laboratory parameters returned to normal in 2 weeks. The myopathy in both cases is likely to have resulted from an interaction of higher doses of simvastatin with diltiazem through inhibition of CYP3A enzymes and drug transporters. The strength of simvastatin-diltiazem interactions in the two cases estimated by the Drug Interaction Probability Scale (DIPS) indicated a possible association. WHAT IS NEW AND CONCLUSION: The two cases reported here and the brief literature review emphasize the potential interaction between two drugs frequently coadministered, simvastatin and diltiazem and we suggest that diltiazem should not be used with higher doses of those statins metabolized by CYP3A such as simvastatin or atorvastatin and even with lower doses caution should be exercised in patients who may have cause for impaired metabolism. PMID- 21545623 TI - Possible long-acting risperidone-induced hypothermia precipitating phenytoin toxicity in an elderly patient. AB - WHAT IS KNOWN AND OBJECTIVE: Thermodysregulation, including hypothermia, is recognized as a potential adverse effect secondary to atypical antipsychotics. We report the first known case of hypothermia possibly associated with long-acting risperidone depot injection, precipitating further adverse events secondary to supratherapeutic phenytoin concentrations. CASE SUMMARY: A 75-year-old African American female presented as a transfer from an outpatient psychiatric center with hypothermia (35.1 degrees C), bradycardia, altered mental status and a series of witnessed tonic-clonic seizures. The patient was discovered to be profoundly neutropenic (absolute neutrophil count = 266 * 10(9) /L) and a corrected phenytoin concentration was 147.708 MUm. During the 3 months preceding admission, phenytoin dosing was stable and consecutive therapeutic concentrations were documented. The only recent change in medication regimen was a switch from oral risperidone to the long-acting injectable formulation. Upon discontinuation of the risperidone and phenytoin, the patient's mental status and laboratory abnormalities returned to baseline. The patient did not experience additional seizure activity. WHAT IS NEW AND CONCLUSION: This unintentional significant drop in core body temperature may have resulted in altered metabolism of phenytoin leading to supratherapeutic concentrations and subsequent tonic-clonic seizures, bradycardia and neutropenia. Low core body temperatures can alter the pharmacokinetic profiles of hepatically metabolized medications, prompting careful patient assessment especially in those receiving medications with a narrow-therapeutic index. Hypothermia should be recognized as a potential adverse event with the long-acting injectable formulation of risperidone. PMID- 21545624 TI - Reversible parkinsonism and cognitive decline due to a possible interaction of valproic acid and quetiapine. AB - WHAT IS KNOWN AND OBJECTIVE: Combination therapy with valproic acid plus quetiapine is recommended as one of the first-line approaches to treatment of manic or mixed episodes in patients with bipolar disorder. CASE SUMMARY: A 66 year-old patient with this psychiatric disease developed parkinsonism and cognitive decline during concomitant treatment with both drugs. The rapid onset of symptoms soon after use of the combination suggested an interaction/using the Karch-Lasagna criteria, the interaction was judged to be definite. WHAT IS NEW AND CONCLUSION: Their evidence on a pharmacokinetic drug interaction between the two drugs is conflicting but possible underlying mechanisms proposed include CYP3A4 inhibition. As concomitant use of valproate and quetiapine is now quite frequent in bipolar disorder, this potential interaction should be closely monitored, especially in the elderly. PMID- 21545625 TI - Estimated rate of fatal automobile accidents attributable to acute solvent exposure at low inhaled concentrations. AB - Acute solvent exposures may contribute to automobile accidents because they increase reaction time and decrease attention, in addition to impairing other behaviors. These effects resemble those of ethanol consumption, both with respect to behavioral effects and neurological mechanisms. These observations, along with the extensive data on the relationship between ethanol consumption and fatal automobile accidents, suggested a way to estimate the probability of fatal automobile accidents from solvent inhalation. The problem can be approached using the logic of the algebraic transitive postulate of equality: if A=B and B=C, then A=C. We first calculated a function describing the internal doses of solvent vapors that cause the same magnitude of behavioral impairment as ingestion of ethanol (A=B). Next, we fit a function to data from the literature describing the probability of fatal car crashes for a given internal dose of ethanol (B=C). Finally, we used these two functions to generate a third function to estimate the probability of a fatal car crash for any internal dose of organic solvent vapor (A=C). This latter function showed quantitatively (1) that the likelihood of a fatal car crash is increased by acute exposure to organic solvent vapors at concentrations less than 1.0 ppm, and (2) that this likelihood is similar in magnitude to the probability of developing leukemia from exposure to benzene. This approach could also be applied to other potentially adverse consequences of acute exposure to solvents (e.g., nonfatal car crashes, property damage, and workplace accidents), if appropriate data were available. PMID- 21545626 TI - QRA model-based risk impact analysis of traffic flow in urban road tunnels. AB - Road tunnels are vital infrastructures providing underground vehicular passageways for commuters and motorists. Various quantitative risk assessment (QRA) models have recently been developed and employed to evaluate the safety levels of road tunnels in terms of societal risk (as measured by the F/N curve). For a particular road tunnel, traffic volume and proportion of heavy goods vehicles (HGVs) are two adjustable parameters that may significantly affect the societal risk, and are thus very useful in implementing risk reduction solutions. To evaluate the impact the two contributing factors have on the risk, this article first presents an approach that employs a QRA model to generate societal risk for a series of possible combinations of the two factors. Some combinations may result in F/N curves that do not fulfill a predetermined safety target. This article thus proposes an "excess risk index" in order to quantify the road tunnel risk magnitudes that do not pass the safety target. The two-factor impact analysis can be illustrated by a contour chart based on the excess risk. Finally, the methodology has been applied to Singapore's KPE road tunnel and the results show that in terms of meeting the test safety target for societal risk, the traffic capacity of the tunnel should be no more than 1,200 vehs/h/lane, with a maximum proportion of 18% HGVs. PMID- 21545627 TI - Optimal experimental design strategies for detecting hormesis. AB - Hormesis is a widely observed phenomenon in many branches of life sciences, ranging from toxicology studies to agronomy, with obvious public health and risk assessment implications. We address optimal experimental design strategies for determining the presence of hormesis in a controlled environment using the recently proposed Hunt-Bowman model. We propose alternative models that have an implicit hormetic threshold, discuss their advantages over current models, and construct and study properties of optimal designs for (i) estimating model parameters, (ii) estimating the threshold dose, and (iii) testing for the presence of hormesis. We also determine maximin optimal designs that maximize the minimum of the design efficiencies when we have multiple design criteria or there is model uncertainty where we have a few plausible models of interest. We apply these optimal design strategies to a teratology study and show that the proposed designs outperform the implemented design by a wide margin for many situations. PMID- 21545628 TI - Six distributional effects of environmental policy. AB - While prior literature has identified various effects of environmental policy, this note uses the example of a proposed carbon permit system to illustrate and discuss six different types of distributional effects: (1) higher prices of carbon-intensive products, (2) changes in relative returns to factors like labor, capital, and resources, (3) allocation of scarcity rents from a restricted number of permits, (4) distribution of the benefits from improvements in environmental quality, (5) temporary effects during the transition, and (6) capitalization of all those effects into prices of land, corporate stock, or house values. The note also discusses whether all six effects could be regressive, that is, whether carbon policy could place disproportionate burden on the poor. PMID- 21545629 TI - Adoptive parents' suspicion of preadoption abuse of their adopted children and the use of support services. AB - BACKGROUND: Adopted children have a higher risk of developmental, mental, behavioural and social problems compared with non-adopted children, and their use of postadoption support services is of interest. Little attention has been given to the impact of preadoption abuse on the use of these services, and therefore this study examines whether or not adoptive parents' suspicion of preadoption abuse has a significant impact on the use of support services by adopted children. METHODS: Data from the National Survey of Adoptive Parents, a US nationally representative survey of adopted children, were used to examine parents' suspicion of preadoption abuse and its effects on the use of postadoption support services by children aged 6-17 years (n = 1411). Statistical analyses were used to examine the relationship between suspected abuse and the use of support services while controlling for characteristics of the adopted child and adoptive parents/household. RESULTS: Seven out of 10 adopted children have used some form of support service, and a larger percentage of 6- to 12-year old children suspected of experiencing preadoption abuse used a support service compared with children not suspected of experiencing abuse. Significant relationships existed between various types of suspected preadoption abuse and the use of different types of postadoption support services. These relationships may go unaccounted for when only examining if any preadoption abuse occurred, or if any support service was used. CONCLUSIONS: The type of preadoption abuse suspected appears to play a modest role in predicting the type of postadoption support services used by an adopted child. Giving further attention to understanding the relationship between different types of preadoption abuse and types of postadoption support services may help better understand the problems and difficulties experienced by adopted children. PMID- 21545631 TI - Acetylcholine controls mouse oocyte maturation via downregulation of cAMP. AB - 1. In mice, acetylcholine (ACh) plays an important role in oocyte activation and embryonic development. However, the role of ACh in mouse oocyte maturation has not been investigated. 2. In the present study, the effects of 100 MUmol/L and 1 mmol/L ACh on maturation processes of murine germinal vesicle (GV) intact oocytes (GV oocytes) exposed to 10 and 100 MUmol/L 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of cyclic nucleotide phosphodiesterase, were evaluated morphologically and immunologically. It has been shown that IBMX inhibits the resumption of meiosis by preventing cAMP breakdown. 3. In the present study, at the start of in vitro culture 100% of oocytes were at the GV stage. After 18 h culture, 95 +/- 3, 0 and 85.8 +/- 10.2% of oocytes had passed the GV stage in the control, IBMX and IBMX + ACh groups, respectively. The IBMX-induced inhibition of the maturation process was significantly attenuated by approximately 90% by ACh in groups treated with 10 MUmol/L IBMX + 100 MUmol/L ACh and 100 MUmol/L IBMX + 1 mmol/L ACh. Although cAMP levels were high in oocytes treated with 100 MUmol/L IBMX, levels were reduced in groups treated simultaneously with 100 MUmol/L ACh. Furthermore, compared with mature oocytes, ACh-treated GV oocytes exhibited significantly lower (by approximately 2.3-fold) or absent Ca(2+) peaks. 4. The results of the present study indicate that maturation of GV oocytes, arrested by IBMX treatment, is resumed following ACh treatment and that this effect is due to downregulation of cAMP rather than changes in intracellular Ca(2+) levels. PMID- 21545630 TI - Renal tubulointerstitial hypoxia: cause and consequence of kidney dysfunction. AB - 1. Intrarenal oxygen availability is the balance between supply, mainly dependent on renal blood flow, and demand, determined by the basal metabolic demand and the energy-requiring tubular electrolyte transport. Renal blood flow is maintained within close limits in order to sustain stable glomerular filtration, so increased intrarenal oxygen consumption is likely to cause tissue hypoxia. 2. The increased oxygen consumption is closely linked to increased oxidative stress, which increases mitochondrial oxygen usage and reduces tubular electrolyte transport efficiency, with both contributing to increased total oxygen consumption. 3. Tubulointerstitial hypoxia stimulates the production of collagen I and alpha-smooth muscle actin, indicators of increased fibrogenesis. Furthermore, the hypoxic environment induces epithelial-mesenchymal transdifferentiation and aggravates fibrosis, which results in reduced peritubular blood perfusion and oxygen delivery due to capillary rarefaction. 4. Increased oxygen consumption, capillary rarefaction and increased diffusion distance due to the increased fibrosis per se further aggravate the interstitial hypoxia. 5. Recently, it has been demonstrated that hypoxia simulates the infiltration and maturation of immune cells, which provides an explanation for the general inflammation commonly associated with the progression of chronic kidney disease. 6. Therapies targeting interstitial hypoxia could potentially reduce the progression of chronic renal failure in millions of patients who are otherwise likely to eventually present with fully developed end-stage renal disease. PMID- 21545632 TI - Introduction: hearing footsteps of the future. PMID- 21545633 TI - Cola beverage and delayed elimination of methotrexate. AB - AIMS: To report a case of severe delayed methotrexate elimination attributable to consumption of a cola beverage. METHODS: To investigate unexplained low urinary pH in a lymphoma patient treated with high-dose methotrexate. RESULTS: Unexpected urinary acidity, despite administration of large amounts of sodium bicarbonate, could be attributed to repeated consumption of a cola beverage. It resulted in a delayed elimination of methotrexate and acute renal failure. Discontinuation of cola drinks, increase in calcium folinate rescue and in sodium bicarbonate allowed satisfactory elimination of methotrexate on day 12 after infusion and recovery from renal impairment without other severe toxicity. No other cause of delay in methotrexate elimination could be identified. CONCLUSIONS: Cola beverages have a low pH due to their phosphoric acid content that is excreted by renal route. We recommend patients receiving high dose methotrexate abstain from any cola drink within 24 h before and during methotrexate administration and until complete elimination of the drug. PMID- 21545634 TI - Readjusting one's life in the tension inherent in work and motherhood. AB - AIM: This paper is a report on a study undertaken to interpret employed first time mothers' experiences of returning to work after maternity leave, in a Norwegian context. BACKGROUND: Despite the increasing rate of employed fertile women and increasing welfare benefits to support the work-life balance, the first years after giving birth are described as being the most demanding on mothers' health. However, little is known about mothers' experiences of returning to work after maternity leave. METHODS: The study included nine Norwegian employees who were individually interviewed during the first months after their return to work following maternity leave. The interviews were conducted during 2009 and interpreted using a method grounded in hermeneutics. FINDINGS: Overall, the meaning of returning to work was interpreted as 'Readjusting one's life in the tension inherent in work and motherhood'. This comprehensive theme was based on three sub-themes: (a) Striving to manage the workload and taking responsibility for the best interests of the child, (b) Struggling with feelings of not being a good enough mother, and (c) Maintaining a balance between sensitivity and self confidence. CONCLUSION: Returning to work after maternity leave appears to be a transitional phase that can be critical to the well-being of first-time mothers. To support women during this phase, employers and public health nurses should monitor the work in relation to the women's capacity and value their competence both as employees and mothers. PMID- 21545635 TI - Multi-disciplinary perceptions of patient group directions as a replacement for the pro re nata prescribing of antipsychotic medications in acute mental health settings. AB - BACKGROUND: Patient group directions have been used in the NHS for 10 years. Despite high levels of reported use, few studies have examined staff perceptions or evaluated them in practice. In mental health services, pro re nata prescriptions continue to contribute to high doses and polypharmacy of antipsychotics. Replacing pro re nata with patient group directions might improve the quality and safety of care associated with this practice. AIMS: This study aimed to explore the acceptability of patient group directions in acute mental health services. METHOD: Qualitative methods were used. Data were analysed using thematic content analysis. Twenty-six members of the multi-disciplinary team (doctors, nurses and pharmacists) participated in either focus groups or individual interviews in 2009. RESULTS: A broad range of benefits were suggested, including improved safety and access to treatments, and the professional development of nurses. However, concerns also emerged about the need for a culture shift in thinking, and the danger of multiple systems for the supply of medicines. CONCLUSION: Despite the widespread use of patient group directions in clinical settings in the last 10 years, limited research has examined their development and potential. Patient group directions can potentially give a rigorous means of supplying or administering medicines. However, their development requires careful consideration. PMID- 21545636 TI - Suboptimal care of the acutely unwell ward patient: a concept analysis. AB - AIM: This paper presents a concept analysis of suboptimal care of the acutely unwell ward patient. BACKGROUND: Acutely unwell patients exhibit abnormal vital signs which are either not recognized or are treated inappropriately. This is frequently termed 'suboptimal care'. However, use of the term 'suboptimal care' is ambiguous and not clearly defined. Critical review of this concept is required to ensure nurses have a better understanding of why and how suboptimal care occurs. DATA SOURCES: Electronic databases (CINAHL, Medline, Cochrane) were searched for literature related to suboptimal care of acutely unwell ward patients. Reference lists from relevant publications were reviewed. No date or language restrictions were imposed. Only articles relevant to suboptimal care of the acutely unwell adult ward patient were included. All literature reviewed was in English and was published between 1990 and 2009. METHOD: The Walker and Avant approach was used. RESULTS: The attributes of suboptimal care are delays in diagnosis, treatment or referral, poor assessment and inadequate or inappropriate patient management. These attributes are preceded by contextual antecedents which can be categorized into patient complexity, healthcare workforce, organization and education factors. Suboptimal care may have catastrophic consequences for patients such as death, Intensive Care Unit admission or cardiac arrests which are preventable or avoidable. CONCLUSION: For future research, investigators need to develop more objective measures which capture delays in the treatment and inappropriate or inadequate management of acutely unwell patients. This should occur through critical focus on the antecedents to suboptimal care. PMID- 21545637 TI - Perinatal attachment in naturally pregnant and infertility-treated pregnant women in Taiwan. AB - AIM: This article is a report of a study of the differences in maternal-foetal attachment and maternal-infant attachment among naturally pregnant and infertility-treated pregnant women in Taiwan. BACKGROUND: Studies have shown that infertility treatment is likely to make up an increasing proportion in the coming years. As these experiences are unique, the attachment relationship may be affected. METHOD: The research data were collected from two obstetrics clinics which were located in central Taiwan. In 2008, all participants (n = 125) were asked to fill out the prenatal questionnaires at the beginning of the study and were followed up with postnatal questionnaires that were mailed to them 1-2 months after labour (n = 110). We used chi-square tests for categorical and t- tests for continuous variables. Multivariate analysis of variances was then performed, and changes in the maternal-foetal attachment and maternal-infant attachment Scales were assessed. FINDINGS: Women who became pregnant after fertility treatment had higher maternal-foetus and maternal-infant attachment scores, and this result was statistically significant; pregnancy mode and level of education are the main factors that have a significant effect on maternal foetus attachment; and pregnancy mode and participation in prenatal education have a main effect on maternal-infant attachment. CONCLUSION: Development of a specific support group for mothers, such as a group for prenatal education, and providing useful resources for pregnant women with a lower level of education are involved in the future research studies for therapeutic intervention. PMID- 21545638 TI - Working with culture: culturally appropriate mental health care for Asian Americans. AB - AIM: The aim of this study is to describe how mental healthcare providers adapted their practice to meet the unique needs of Asian Americans. BACKGROUND: As the number of ethnic minorities and multicultural patients and families rapidly increases, cultural competency becomes an essential skill for all healthcare providers. The lack of knowledge about how healthcare providers grapple with diverse cultures and cultural competency limits the ability of others to deliver patient-centred care across cultural lines. METHODS: Interpretive phenomenology guided the design and conduct of this study. Twenty mental healthcare providers who treated Asian Americans were recruited. Narrative data were collected through face-to-face, in-depth interviews between 2006 and 2007. RESULTS/FINDINGS: Three characteristics of culturally appropriate care for Asian Americans were identified. Cultural brokering: providers addressed issues stemming from cultural differences via bicultural skills education. Asian American patients generally received broader education than current literature recommended. Supporting families in transition: providers assisted Asian American families during transition from and to professional care. Using cultural knowledge to enhance competent care: providers' knowledge of Asian culture and flexible attitudes affected the care that they provided. Culturally competent providers were able to identify cultural issues that were relevant to the specific situation, and incorporated cultural solutions into the care provided. CONCLUSION: Culturally appropriate care is nuanced and context specific. Thus, more sophisticated and broader conceptualizations are necessary to prepare nurses for such complex practice. PMID- 21545639 TI - Developing a multi-systemic fall prevention model, incorporating the physical environment, the care process and technology: a systematic review. AB - AIMS: This paper reports a review that assessed the effectiveness and characteristics of fall prevention interventions implemented in hospitals. A multi-systemic fall prevention model that establishes a practical framework was developed from the evidence. BACKGROUND: Falls occur through complex interactions between patient-related and environmental risk factors, suggesting a need for multifaceted fall prevention approaches that address both factors. DATA SOURCES: We searched Medline, CINAHL, PsycInfo and the Web of Science databases for references published between January 1990 and June 2009 and scrutinized secondary references from acquired papers. REVIEW METHODS: Due to the heterogeneity of interventions and populations, we conducted a quantitative systematic review without a meta-analysis and used a narrative summary to report findings. RESULTS: From the review, three distinct characteristics of fall prevention interventions emerged: (1) the physical environment, (2) the care process and culture and (3) technology. While clinically significant evidence shows the efficacy of environment-related interventions in reducing falls and fall-related injuries, the literature identified few hospitals that had introduced environment-related interventions in their multifaceted fall intervention strategies. CONCLUSION: Using the multi-systemic fall prevention model, hospitals should promote a practical strategy that benefits from the collective effects of the physical environment, the care process and culture and technology to prevent falls and fall-related injuries. By doing so, they can more effectively address the various risk factors for falling and therefore, prevent falls. Studies that test the proposed model need to be conducted to establish the efficacy of the model in practice. PMID- 21545640 TI - Holistic concerns of Chinese stroke survivors during hospitalization and in transition to home. AB - AIM: This article is a report of a study conducted to explore the phenomenon of concerns as experienced by Chinese stroke survivors during hospitalization and in transition to home. BACKGROUND: Stroke is characterized by its sudden onset and prolonged residual problems, which affect survivors' holistic well-being. Many studies have focused on stroke consequences and their correlates with psychosocial outcomes. Very little is known about holistic concerns of stroke survivors, particularly in the transition from hospital to home. METHOD: We used purposive sampling of 15 stroke survivors who participated in semi-structured interviews after being discharged from stroke wards of a general hospital in Hong Kong from November 2008 to February 2009. The interviews were transcribed verbatim and analysed using Giorgi's phenomenological techniques. FINDINGS: Stroke survivors' physical, psychological, socio-cultural and spiritual concerns in hospital and transition to home emerged from the data analysis. The four major themes identified were: (a) dynamic interplay of holistic concerns, (b) cultural expression of illness experiences, (c) social support 'paradox' and (d) caring gaps in clinical management. CONCLUSION: Understanding the interwoven holistic concerns for the stroke survivors in hospital and after discharged home can help nurses to identify their health needs and plan for appropriate nursing interventions. The findings provide guidance for the development of culture sensitive holistic care interventions with family involvement in Chinese stroke populations. PMID- 21545641 TI - Does collective efficacy moderate the associations between physical work load and intention to leave or sickness absence? AB - AIM: This paper is a report of a study, which examines the moderating effect of collective efficacy on the associations between physical workload, intention to leave and sickness absence. BACKGROUND: The positive association between physical workload and both intention to leave and sickness absence in the healthcare sector is well-established. However, knowledge is limited with respect to how social contextual factors such as collective efficacy moderate these associations. METHODS: A questionnaire was distributed over a 4-month period in 2006/2007 to all employees at elderly care centres in 35 Danish municipalities who were asked to rate their groups' collective efficacy. The final sample consisted of 6929 female employees from 290 work groups. Employees were predominantly healthcare helpers and assistants, but also nurses and other healthcare professionals participated in the study. Information on collective efficacy was aggregated to work group level. RESULTS: Collective efficacy moderated the association between physical workload and intention to leave, i.e. employees with high levels of physical workload had lower intention to leave if they worked in a group with high levels of collective efficacy and higher intention to leave if they worked in a group with low levels of collective efficacy. No moderating effect of collective efficacy on the association between physical workload and sickness absence was found. CONCLUSION: Our findings suggest that enhancing the sense of collective efficacy might be a mean for organizations and managers to reduce intention to leave, but further research is needed. PMID- 21545642 TI - Medication administration technologies and patient safety: a mixed-method systematic review. AB - BACKGROUND: Healthcare leaders need evidence-based information on nursing medication administration technologies to guide the design of improvements to patient safety. AIM: The aim of this study was to evaluate the research evidence on relationships between the use of medication administration technologies and incidence of medication administration incidents and preventable adverse drug events to inform decision-making about existing technology options. DATA SOURCES: Thirteen electronic databases and seven relevant patient safety websites were searched for the years 1980-2009. REVIEW METHODS: A mixed-method systematic literature review of research on medication administration technologies and associated links to patient safety, operationalized as medication administration incidents and preventable adverse drug events, was conducted. RESULTS: Twelve studies (two qualitative, five pre- and postinterventions and five correlational) met the inclusion criteria. All were assessed as medium quality with low generalizability of study findings. Only two studies sampled more than one hospital and none of the studies was driven by an explicit theoretical framework. The studies included in this review are generally positive towards medication administration technologies and their potential benefits, yet the level of evidence overall is equivocal. The majority of studies pointed to the development of workarounds by nurses following medication administration technology implementation that could compromise patient safety. CONCLUSION: More theoretically driven research is needed to determine which medication administration technologies should be implemented in what ways to most effectively reduce medication administration incidents and preventable adverse drug events and minimize the development of potentially unsafe workarounds. Further evidence is required to accurately assess the actual contribution of medication administration technologies for improving patient safety. PMID- 21545643 TI - Immunohistochemical study of endocrine cells in the gastrointestinal tract of the barking deer, Muntiacus muntjak. AB - The morphology, distribution and relative frequencies of endocrine cells in the gastrointestinal tract of the barking deer (Muntiacus muntjak) were investigated. The immunohistochemical method employed used seven types of antisera against chromogranin, serotonin, gastrin, cholecystokinin, somatostatin, glucagon and insulin. Chromogranin and serotonin immunoreactive (IR) cells were found throughout the gastrointestinal tract. Conversely, gastrin-IR cells were only found in the oxyntic gland, pyloric gland and duodenum, while cholecystokinin-IR and somatostatin-IR cells were detected in the oxyntic gland, pyloric gland and small intestines. Somatostatin-IR cells were also seen in the caecum. Glucagon-IR cells were found in all parts of the gastrointestinal tract apart from the colon and rectum. No insulin-IR cells were found in the gastrointestinal tract of this species. The cells in the small intestine were generally spindle shaped with long cytoplasmic processes ending in the lumen (open type), while in the stomach and large intestine, they were occasionally round or spherical in shape (closed type). An uncommon distribution pattern of endocrine cells in the gastrointestinal tract of the barking deer was noted for cholecystokinin- and glucagon-IR cells. PMID- 21545644 TI - Morphological characteristics of pelves of estonian holstein and estonian native breed cows from the perspective of calving. AB - Dystocia is more common in Holstein-Friesian (HF) breed cows than in other dairy breeds. This is often caused by a disproportion between the birth canal of a female animal and the fetus. It is thought that the main determiners of unsuitability are the birth mass of the calf and the shape of the female pelvis. From the perspective of calving the cranial and caudal pelvic apertures are of great significance. This study focuses on pluriparous pelves of the Estonian Native Breed (EN) and the Estonian Holstein Breed (EHF). The longest measurement of the cranial pelvic aperture of an EHF cow is the conjugate diameter. The cranial pelvic aperture narrows slightly ventrally, being shaped like a trapezium with rounded angles. The longest measurement of the caudal aperture is its caudal transverse measurement. The aperture is flattened dorsoventrally. The cranial pelvic aperture of an EN cow is dorsally angular, but more oval ventrally, and is on the whole narrower and higher. By comparison with the EHF cow, the pelvic cavity of the EN cow widens caudally, and the height of the pelvic apertures contributes to ease of calving. It appears that the configuration of the pelvis of an EN cow is similar to the pelvis of the elk (Alces alces). The pelvis of the EHF cow has become unsuitable for easy calving, especially with regard to the caudal aperture. PMID- 21545645 TI - Pituitary adenylate cyclase-activating polypeptide-immunoreactive cells in the ageing gerbil hippocampus. AB - In the present study, we investigated age-related changes in pituitary adenylate cyclase-activating polypeptide (PACAP) immunoreactivity and its protein levels in the gerbil hippocampus at various ages using immunohistochemistry and western blot analysis. In the post-natal month 1 (PM 1) group, PACAP-immunoreactive cells were found in all hippocampal subregions. The number of PACAP-immunoreactive cells was decreased in the PM 3 group and was still more decreased in the PM 6 and 12 groups. Thereafter, in the PM 18 and 24 groups, PACAP-immunoreactive cells were significantly increased again. However, in the mossy fibre zone, PACAP immunostaining was very strong in the adult group, especially in the PM 6 group. In addition, PACAP protein level was highest at PM 6, showing a slight decrease at PM 24. These results indicate that PACAP-immunoreactive cells are lowest in the adult stage and highest in the aged stage. However, PACAP immunoreactivity in the mossy fibre zone and PACAP protein level in the hippocampus are highest in the adult stage. PMID- 21545646 TI - Overexpression and biochemical characterization of soluble pyridine nucleotide transhydrogenase from Escherichia coli. AB - The soluble pyridine nucleotide transhydrogenase (STH) is an energy-independent flavoprotein that directly catalyzes hydride transfer between NAD(H) and NADP(H) to maintain homeostasis of these two redox cofactors. The sth gene in Escherichia coli was cloned and expressed as a fused protein (EcSTH). The purified EcSTH displayed maximal activity at 35 degrees C, pH 7.5. Heat-inactivation studies showed that EcSTH retains 50% activity after 5 h at 50 degrees C. The enzyme was stable at 4 degrees C for 25 days. The apparent K(m) values of EcSTH were 68.29 MUM for NADPH and 133.2 MUM for thio-NAD(+) . The k(cat) /K(m) ratios showed that EcSTH had a 1.25-fold preference for NADPH over thio-NAD(+) . Product inhibition studies showed that EcSTH activity was strongly inhibited by excess NADPH, but not by thio-NAD(+) . EcSTH activity was enhanced by 2 mM adenine nucleotide and inhibited by divalent metal ions: Mn(2+) , Co(2+) , Zn(2+) , Ni(2+) and Cu(2+) . However, after preincubation for 30 min, most divalent metal ions had little effect on EcSTH activity, except Zn(2+) , Ni(2+) and Cu(2+) . The enzymatic analysis could provide the important basic knowledge for EcSTH utilizations. PMID- 21545647 TI - Patterns of scintigraphic uptake in the fetlock joint of Thoroughbred racehorses and the effect of increased radiopharmaceutical uptake in the distal metacarpal/tarsal condyle on performance. AB - REASONS FOR PERFORMING STUDY: The effect of palmar osteochondral disease lesions on performance of Thoroughbred (TB) racehorses is unclear. There is a need to describe patterns of radiopharmaceutical uptake (IRU) in fetlock joints of TB racehorses and to evaluate post scintigraphy performance. HYPOTHESES: IRU in the metacarpal (MC) and metatarsal (MT) condyles is more common than IRU in the parasagittal grooves and is associated with poorer post diagnosis performance than controls. METHODS: Location of IRU within the fetlock region was identified and graded subjectively in TB racehorses. Performance variables were determined from race records for horses with moderate/marked MC/MT condylar IRU (cases), other horses undergoing scintigraphy (scintigraphy controls) and age/sex matched controls from the last race in which a case participated (controls). Statistical analyses included quantile regression, Fisher's exact test, Kaplan-Meier survival curves, log-rank test and Cox regression. RESULTS: Metacarpal/MT condylar IRU was identified in 103/220 horses with only 3/220 having parasagittal IRU. Moderate/marked IRU was identified in the MC and MT condylar regions in 62 and 39 horses, respectively, with palmaromedial and plantarolateral IRU most common. Fore- and hindlimb cases had fewer starts, reduced earnings (P<0.001) and reduced earnings/start than controls respectively. Cases were more likely to return to racing later than controls following a rest period. Cases were older than scintigraphy controls. CONCLUSIONS: In TB racehorses presenting for lameness MC/MT condylar IRU is the most common abnormality identified within the fetlock joint. Racehorses with moderate/marked condylar IRU have a shortened racing career, are less successful than age/sex matched controls and are older than other racehorses presented for scintigraphy. POTENTIAL RELEVANCE: Overload of the MC/MT condyles is a common and significant problem in TB racehorses that is readily identified with scintigraphy. Scintigraphy of horses that are lame or performing poorly is less useful for screening for potential condylar fractures. PMID- 21545648 TI - Virological response to darunavir in patients infected with HIV is linked to darunavir resistance-associated mutations corrected by the count of mutations with positive impact and is not associated with pharmacological and combined virological/pharmacological parameters. AB - The relationships between virological (darunavir resistance-associated mutations), pharmacological (darunavir trough plasma concentration), combined virological/pharmacological [darunavir genotypic inhibitory quotient (GIQ)] parameters and virological response were evaluated in experienced patients infected with human immunodeficiency virus. In this retrospective study (48 patients), the relationship between these parameters and the virological response was investigated by multivariate logistic regression. Darunavir GIQ is defined as the ratio between darunavir trough plasma concentration and the count of darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V) corrected or not corrected by the count of mutations with positive impact (V82A and E35D). The pharmacological and combined virological/pharmacological parameters failed to predict virological response. The count of darunavir resistance-associated mutations corrected by the count of V82A and E35D mutations was the single parameter significantly (P = 0.027) associated with virological response. This result suggests that both negative and positive impacts of mutations including V82A and E35D should be considered to predict virological response in experienced patients. PMID- 21545649 TI - Using optical coherence tomography for the differential diagnosis of a pigmented choroidal lesion. PMID- 21545650 TI - Unsupervised sub-segmentation for pigmented skin lesions. AB - BACKGROUND: Early identification of malignant melanoma with the surgical removal of thin lesions is the most effective treatment for skin cancers. A computer aided diagnostic system assists to improve the diagnostic accuracy, where segmenting lesion from normal skin is usually considered as the first step. One of the challenges in the automated segmentation of skin lesions arises from the fact that darker areas within the lesion should be considered separate from the more general suspicious lesion as a whole, because these pigmented areas can provide significant additional diagnostic information. METHODS: This paper presents, for the first time, an unsupervised segmentation scheme to allow the isolation of normal skin, pigmented skin lesions, and interesting darker areas inside the lesion simultaneously. An adaptive mean-shift is first applied with a 5D spatial colour-texture feature space to generate a group of homogenous regions. Then the sub-segmentation maps are calculated by integrating maximal similarity-based region merging and the kernel k-means algorithm, where the number of segments is defined by a cluster validity measurement. RESULTS: The proposed method has been validated extensively on both normal digital photographs and dermoscopy images, which demonstrates competitive performance in achieving automatic segmentation. The isolated dark areas have proved helpful in the discrimination of malignant melanomas from atypical benign nevi. Compared with the results obtained from the asymmetry measure of the entire lesion, the asymmetry distribution of the isolated dark areas helped increase the accuracy of the identification of malignant melanoma from 65.38% to 73.07%, and this classification accuracy reached 80.77% on integrating both asymmetry descriptors. CONCLUSION: The proposed segmentation scheme gives the lesion boundary closed to the manual segmentation obtained by experienced dermatologists. The initial classification results indicate that the study of the distributions of darker areas inside the lesions is very promising in characterizing melanomas. PMID- 21545651 TI - Thermography-measured effect of capsaicin, methylprednisolone and mitomycin on the survival of random skin flaps in rats. AB - AIMS: This study was designed to determine if steroids, capsaicin and mitomycin improved skin flap survival in rats, and it has confirmed that thermography is an effective method to measured skin flap vitality. METHODS: Forty female Wistar rats were randomised into four groups. A standardised full thickness inferiorly based dorsal random-pattern skin flap was raised, and a gelatine sponge was placed before suturing between the flap and its recipient bed, soaked with 0.9 % saline in the control group and with capsaicin, methylprednisolone and mitomycin in the experimental groups. Vitality of the flap and of the survival area was measured by infrared thermography. RESULTS: Methylprednisolone statistically significant decrease skin flap necrosis, approximately 56%, when compared with controls (P< 0.05). CONCLUSION: Corticosteroids applied subcutaneously in a single dose on a gelatine sponge produced a statistically significant improvement of the survival of random skin flaps in rats, whereas capsaicin and mitomycin showed no improvement. PMID- 21545652 TI - Effect of periodontopathogen lipopolysaccharides and proinflammatory cytokines on CD46, CD55, and CD59 gene/protein expression by oral epithelial cells. AB - Membrane-anchored complement regulatory proteins (CRPs), including CD46, CD55, and CD59, protect host cells from complement attack. In the present study, we investigated whether periodontopathogen lipopolysaccharide and proinflammatory cytokines modulate CRP gene/protein expression in human oral epithelial cells. The lipopolysaccharide of Treponema denticola and Tannerella forsythia were the most potent for increasing the gene expression of CD55 and CD59, and to a lesser extent CD46, after a 48-h stimulation. An lipopolysaccharide-induced upregulation of epithelial cell-surface CRP was also demonstrated. The stimulation of epithelial cells with lipopolysaccharide was associated with interleukin-6 (IL-6) and IL-8 secretion. Although these two cytokines had no effect on CD46 and CD55 gene expression in epithelial cells, IL-1beta and tumor necrosis factor-alpha induced a significant upregulation. The cell-surface expression of CRP was also increased by the stimulation of epithelial cells with cytokines. The CD46, CD55, and CD59 gene/protein expression was upregulated by periodontopathogen lipopolysaccharide and proinflammatory cytokines. It can be hypothesized that, when faced with bacterial challenges and inflammatory conditions associated with active periodontal sites, oral epithelial cells may respond by increasing CRP gene/protein expression to avoid cell lysis by the complement system, which is activated during periodontitis. PMID- 21545653 TI - Effect of green buffer storage on the fertility of fresh camel semen after artificial insemination. AB - Artificial insemination (AI) is one of the most widely used reproductive technologies, and there is considerably interest in commercializing this technology in camels. Storage of semen extender frozen (at -20 degrees C) is of considerable interest to scientists working with camels, as transportation of diluents at refrigeration temperature is not always possible given the hot, arid and remote conditions that dromedary camels exist in. Therefore, this study was conducted to compare the fertility of fresh camel semen, after dilution in fresh or frozen-thawed green buffer (GB), after AI into single and multiple ovulating female camels. No differences were observed in any sperm characteristics (motility, membrane integrity, acrosome integrity or morphology) when semen was diluted in fresh or frozen-thawed GB (p>0.05). Sperm motility was increased by dilution (fresh: 70.7 +/- 4.9% and frozen: 68.8 +/- 3.1%) compared with the motility of sperm in neat semen (35 +/- 2.85%; p<0.05), and sperm motility changed from oscillatory to forward progressive after dilution. Pregnancy rates were higher (p<0.05) for single ovulating camels inseminated with semen diluted in fresh (72.7%) compared with frozen-thawed GB (27.3%), and fertilization rates were also higher (p<0.05) for multiple ovulating camels inseminated with semen diluted in fresh (83.3%) compared with frozen-thawed GB (11.1%). These results clearly demonstrate the detrimental effect of freezing and thawing semen diluent on the fertility of fresh camel semen. However, further studies are required to elucidate the mechanism responsible for this reduction in fertility. Moreover, these results demonstrate that the fertility of fresh camel semen diluted in fresh GB is high enough to be considered commercially viable. PMID- 21545654 TI - Uterine fibrosarcoma in a Warmblood mare. AB - This paper describes a case of uterine fibrosarcoma in an 18-year-old Warmblood mare. The mare had exhibited bloody fluid accumulation inside the uterus and vaginal haemorrhagic discharge since the previous foaling. The mare was euthanized, and on pathological examination, in addition to the uterine neoplasia, multiple metastases were found in the lungs, liver and spleen. The histological and immunohistochemical examination determined that the tumour was a fibrosarcoma. To our knowledge, this is the first paper to describe a uterine fibrosarcoma in a mare. PMID- 21545656 TI - Event-related potential evidence for the use of external coordinates in the preparation of tactile attention by the early blind. AB - Recent studies have suggested that visual experience in childhood is crucial for the automatic activation of an external spatial reference frame in tactile perception. These findings are largely based on behavioural work, with limited exploration using event-related potentials (ERPs). The present study examined the role of external spatial frameworks on tactile perception by recording ERP correlates of both preparatory processes and somatosensory processing during a tactile attention task for a group of early blind participants and age-matched sighted controls who carried out the task in darkness. Participants had to shift attention to one hand or the other as indicated by an auditory cue presented at the start of each trial, in order to detect infrequent tactile targets delivered to the attended hand. Spatial information about the external environment was acquired in advance during tactile exploration of the testing booth. ERPs measured during the cue-target interval indicated a conflict between anatomical and external spatial reference frames for both early blind and sighted participants, as marked by the delayed onset of the anterior directing attention negativity, although the delay was more pronounced in the sighted. A delay was also observed, irrespective of visual experience, on the onset of attentional modulations of somatosensory ERPs elicited by tactile stimuli. Although these results confirm that neither concurrent nor developmental vision is necessary for the default use of an external spatial framework in tactile attention, they suggest that the relative impact of an external vs. an anatomical spatial coordinate system may be affected by visual experience. PMID- 21545655 TI - Sortase independent and dependent systems for acquisition of haem and haemoglobin in Listeria monocytogenes. AB - We studied three Fur-regulated systems of Listeria monocytogenes: the srtB region, that encodes sortase-anchored proteins and a putative ABC transporter, and the fhu and hup operons, that produce putative ABC transporters for ferric hydroxamates and haemin (Hn)/haemoglobin (Hb) respectively. Deletion of lmo2185 in the srtB region reduced listerial [(59) Fe]-Hn transport, and purified Lmo2185 bound [(59) Fe]-Hn (K(D) = 12 nM), leading to its designation as a Hn/Hb binding protein (hbp2). Purified Hbp2 also acted as a haemophore, capturing and supplying Hn from the environment. Nevertheless, Hbp2 only functioned in [(59) Fe]-Hn transport at external concentrations less than 50 nM: at higher Hn levels its uptake occurred with equivalent affinity and rate without Hbp2. Similarly, deletion of sortase A had no effect on ferric siderophore or Hn/Hb transport at any concentration, and the srtA-independence of listerial Hn/Hb uptake distinguished it from comparable systems of Staphylococcus aureus. In the cytoplasmic membrane, the Hup transporter was specific for Hn: its lipoprotein (HupD) only showed high affinity for the iron porphyrin (K(D) = 26 nM). Conversely, the FhuD lipoprotein encoded by the fhu operon had broad specificity: it bound both ferric siderophores and Hn, with the highest affinity for ferrioxamine B (K(D) = 123 nM). Deletions of Hup permease components hupD, hupG or hupDGC reduced Hn/Hb uptake, and complementation of DeltahupC and DeltahupG by chromosomal integration of hupC(+) and hupG(+) alleles on pPL2 restored growth promotion by Hn/Hb. However, DeltahupDGC did not completely eliminate [(59) Fe] Hn transport, implying the existence of another cytoplasmic membrane Hn transporter. The overall K(M) of Hn uptake by wild-type strain EGD-e was 1 nM, and it occurred at similar rates (V(max) = 23 pmol 10(9) cells(-1) min(-1)) to those of ferric siderophore transporters. In the DeltahupDGC strain uptake occurred at a threefold lower rate (V(max) = 7 pmol 10(9) cells(-1) min(-1)). The results show that at low (< 50 nM) levels of Hn, SrtB-dependent peptidoglycan anchored proteins (e.g. Hbp2) bind the porphyrin, and HupDGC or another transporter completes its uptake into the cytoplasm. However, at higher concentrations Hn uptake is SrtB-independent: peptidoglycan-anchored binding proteins are dispensable because HupDGC directly absorbs and internalizes Hn. Finally, DeltahupDGC increased the LD(50) of L. monocytogenes 100-fold in the mouse infection model, reiterating the importance of this system in listerial virulence. PMID- 21545658 TI - Hemifield effects of spatial attention in early human visual cortex. AB - Early visual areas (V1, V2, V3/VP, V4v) contain representations of the contralateral hemifield within each hemisphere. Little is known about the role of the visual hemifields along the visuo-spatial attention processing hierarchy. It is hypothesized that attentional information processing is more efficient across the hemifields (known as bilateral field advantage) and that the integration of information is greater within one hemifield as compared with across the hemifields. Using functional magnetic resonance imaging we examined the effect of distance and hemifield on parallel attentional processing in the early visual areas (V1-V4v) at individually mapped retinotopic locations aligned adjacently or separately within or across the hemifields. We found that the bilateral field advantage in parallel attentional processing over separated attended locations can be assigned, at least partly, to differences in distractor position integration in early visual areas. These results provide evidence for a greater integration of locations between two attended locations within one hemifield than across both hemifields. This nicely correlates with behavioral findings of a bilateral field advantage in parallel attentional processing (when distractors in between cannot be excluded) and a unilateral field advantage if attention has to be shifted across separated locations (when locations in between were integrated). PMID- 21545657 TI - Targeted mutation of the calbindin D 28k gene selectively alters nonvisual photosensitivity. AB - Light intensity is an important determinant of diverse physiological and behavioral responses within the non-image-forming visual system. Thresholds differ among various photic responses, namely control of circadian rhythms, vigilance state, activity level and pupil constriction, but the mechanisms that regulate photosensitivity are not known. Calbindin D(28k) (CalB) is a calcium binding protein associated with light processing in the mammalian circadian clock. Loss-of-function studies indicate that CalB-deficient mice (CalB(-/-)) have deficits in their ability to entrain to light-dark cycles. To explore the role of CalB in modulating photosensitivity, thresholds for three behaviors mediated by the non-image-forming visual system (entrainment, masking and pupillary light reflex; PLR) were compared in CalB(-/-) and wildtype mice, and the localization of CalB protein in these circuits was examined in adult and juvenile mice. The results reveal a divergence in how CalB affects thresholds to photic cues among these responses. Entrainment and masking were 40- to 60-fold less sensitive in CalB(-/-) than in wildtype mice. On the other hand, the PLR in CalB(-/-) mice was 80- to 200-fold more sensitive. Though CalB is expressed in the retina and in brain circuits regulating entrainment we found no CalB expression in any component of the PLR pathway, namely the olivary pretectal nucleus, Edinger-Westphal nucleus and ciliary ganglion. The behavioral and anatomical data together suggest that, in normal animals, the retinal response to light is blunted in the presence of CalB, but responsiveness of the higher order processes that transduce afferent retinal input is enhanced. PMID- 21545659 TI - The World Association for Veterinary Dermatology (WAVD) (Formerly the World Congress of Veterinary Dermatology Association). PMID- 21545660 TI - Adverse events in 50 cats with allergic dermatitis receiving ciclosporin. AB - Ciclosporin is an immunosuppressive drug that has been used to treat allergies and other immune-mediated diseases in cats, dogs and humans. Information about the adverse effects of ciclosporin in cats has been limited to smaller studies and case reports. Adverse effects in dogs are mainly gastrointestinal in nature, but humans can also experience hypertension and altered renal function. The aim of this retrospective case series study was to document the occurrence and clinical appearance of adverse events in cats receiving ciclosporin to treat allergic skin disease. The medical records of 50 cats with allergic dermatitis treated with oral ciclosporin (1.9-7.3 mg/kg/day) were reviewed. Adverse events occurred in 66% (33 cats). Adverse events likely to be associated with ciclosporin included the following: vomiting or diarrhoea within 1-8 weeks of receiving ciclosporin (24%), weight loss (16%), anorexia and subsequent hepatic lipidosis (2%) and gingival hyperplasia (2%). Other adverse events less likely to be associated with ciclosporin therapy included the following: weight gain (14%), dental tartar and gingivitis (10%), otitis (4%), chronic diarrhoea (4%), inflammatory bowel disease with indolent gastrointestinal lymphoma (2%), urinary tract infection (2%), cataract (2%), elevated liver enzymes (2%), hyperthyroidism and renal failure (2%) and transient inappropriate urination (2%). Some cats experienced multiple adverse events. Case-control studies are needed to prove cause and effect of ciclosporin with regard to these adverse events. PMID- 21545663 TI - Exploring nursing staff's attitudes and use of music for older people with dementia in long-term care facilities. AB - AIMS: This study aimed to explore nursing staff's attitudes and use of music for older people with dementia in long-term care facilities. BACKGROUND: Music has shown positive outcomes in managing behavioural symptoms of older people with dementia. Older people living in long-term care facilities often do not have access to trained music therapists. Nursing staff provide the majority of direct care for institutionalised older people with dementia, therefore, will be the most appropriate personnel to learn and implement music therapy for those with dementia. To date, no studies have explored nursing staff's attitudes and use of music for those with dementia. DESIGN: A cross-sectional research design was used. METHODS: A convenience sample of 285 nursing staff caring for those with dementia in long-term care facilities in Taiwan were recruited. Participants received a self-administered questionnaire consisted of items exploring nursing staff's attitude and use of music for those with dementia. A total of 214 participants completed the questionnaires, giving a response rate of 75.1%. RESULTS: Most nursing staff held positive attitudes towards use of music for older people with dementia (mean=84.89, range 23-115), but only 30.6% (n=66) had used music for those with dementia in practice. The majority perceived that they had limited knowledge and skills about use of music (72.9%). Over half of the participants reported that they lacked resources and time to implement music therapy in practice. CONCLUSIONS: Nursing staff need more formal training to use music for those with dementia. Nursing staff can be the suitable personnel to learn easily and implement music therapy as a part of routine activity programmes for those with dementia. RELEVANCE TO CLINICAL PRACTICE: Appropriately trained nursing staff in long-term care facilities who use music therapy may help improve the mental health of older people with dementia. PMID- 21545664 TI - Understanding dietary decision-making in patients attending a secondary prevention clinic following myocardial infarction. AB - AIMS AND OBJECTIVES: This study aimed to explore the issues that influence the dietary choices made by patients attending a secondary prevention clinic following a myocardial infarction. BACKGROUND: Secondary prevention clinics play an important role in promoting dietary advice, yet evidence suggests that many individuals are neither implementing nor maintaining the lifestyle changes recommended. Research largely focuses on compliance to lifestyle changes in general, and only a small number of quantitative studies address the issues surrounding adherence to dietary advice. DESIGN: Phenomenology was selected as the most appropriate approach for this qualitative study, enabling patients' lived experiences of dietary decision-making to be explored. METHOD: A purposive sample of nine participants was selected from a cardiac secondary prevention clinic. Semi-structured interviews were taped, transcribed and analysed using an interpretative approach. RESULTS: Data analysis produced six central themes contributing to patients' decision-making. Fear, determination and self-control were enabling factors and poor recall of information, a need for additional support and a lack of will power were disabling factors. Findings suggest that patient motivation and ability to make sustainable dietary change can decline as disabling factors reduce determination and self-control, and initial fear of their heart condition subsides. CONCLUSION: In this study, patients' motivation regarding dietary decision-making changed over time and was strongly influenced by a fear of future heart problems. RELEVANCE TO CLINICAL PRACTICE: Health care professionals need to understand the temporal nature of decision-making postmyocardial infarction and adopt a wide repertoire of responsive strategies that support patients to follow a healthy diet in the longer term. PMID- 21545665 TI - Factors influencing iron nutrition among one-year-old healthy children in Sweden. AB - AIMS AND OBJECTIVES: To describe possible social, nutritional and biological factors influencing iron intake and iron status among healthy one-year-old children in southern Sweden. BACKGROUND: Iron deficiency is one of the most important nutritional disorders and increases the risk of delayed mental and motor development. Children are at risk because of rapid growth, which entails relatively high requirements of iron. DESIGN: A prospective study using survey methods. METHOD: Randomly selected one-year-old children (n = 90) and their parents participated. Parents answered a questionnaire enquiring about demographic data and the child's feeding and health during the first year. The child's total food intake and blood samples (haemoglobin, mean corpuscular volume, S-ferritin and transferring receptor) were obtained. Results. Twenty seven per cent of the children had an iron intake below the Nordic Nutrition Recommendations of 8 mg/day (NNR 2004). Follow-on formula and iron-fortified porridge contributed to 64% of the child's total iron intake. Partial breastfeeding and low maternal education correlated negatively with iron intake from complementary food. In total, 10.3% (n = 9) of the children were found to be iron-depleted (S-ferritin <= 12 MUg/l), and 2.3% (n = 2) had iron deficiency with or without anaemia (Hb <= 100 g/l). CONCLUSIONS: One-year-old children in Sweden may be at risk of developing iron deficiency, but information about iron-rich food can improve iron status. RELEVANCE TO CLINICAL PRACTICE: Knowledge about factors influencing children's iron intake and iron status may improve the nutritional advice and education from the Child Health Services to prevent or detect iron deficiency. PMID- 21545666 TI - Recent status scores for version 6 of the Addiction Severity Index (ASI-6). AB - AIMS: To describe the derivation of recent status scores (RSSs) for version 6 of the Addiction Severity Index (ASI-6). DESIGN: 118 ASI-6 recent status items were subjected to nonparametric item response theory (NIRT) analyses followed by confirmatory factor analysis (CFA). Generalizability and concurrent validity of the derived scores were determined. SETTING AND PARTICIPANTS: A total of 607 recent admissions to variety of substance abuse treatment programs constituted the derivation sample; a subset (n = 252) comprised the validity sample. MEASUREMENTS: The ASI-6 interview and a validity battery of primarily self-report questionnaires that included at least one measure corresponding to each of the seven ASI domains were administered. FINDINGS: Nine summary scales describing recent status that achieved or approached both high scalability and reliability were derived; one scale for each of six areas (medical, employment/finances, alcohol, drug, legal, psychiatric) and three scales for the family/social area. Intercorrelations among the RSSs also supported the multi-dimensionality of the ASI-6. Concurrent validity analyses yielded strong evidence supporting the validity of six of the RSSs (medical, alcohol, drug, employment, family/social problems, psychiatric). Evidence was weaker for the legal, family/social support and child problems RSSs. Generalizability analyses of the scales to males versus females and whites versus blacks supported the comparability of the findings, with slight exceptions. CONCLUSIONS: The psychometric analyses to derive Addiction Severity Index version 6 recent status scores support the multi dimensionality of the Addiction Severity Index version 6 (i.e. the relative independence of different life functioning areas), consistent with research on earlier editions of the instrument. In general, the Addiction Severity Index version 6 scales demonstrate acceptable scalability, reliability and concurrent validity. While questions remain about the generalizability of some scales to population subgroups, the overall findings coupled with updated and more extensive content in the Addiction Severity Index version 6 support its use in clinical practice and research. PMID- 21545667 TI - Extended telephone-based continuing care for alcohol dependence: 24-month outcomes and subgroup analyses. AB - AIMS: To determine whether 18 months of telephone continuing care improves 24 month outcomes for patients with alcohol dependence. Subgroup analyses were performed to identify patients who would benefit most from continuing care. DESIGN: Comparative effectiveness trial of continuing care that consisted of monitoring and feedback only (TM) or monitoring and feedback plus counseling (TMC). Patients were randomized to treatment as usual (TAU), TAU plus TM or TAU plus TMC, and followed quarterly for 24 months. SETTING: Publicly funded intensive out-patient programs (IOP). PARTICIPANTS: A total of 252 alcohol dependent patients (49% with current cocaine dependence) who completed 3 weeks of IOP. MEASUREMENTS: Percentage of days drinking, any heavy drinking and a composite good clinical outcome. FINDINGS: In the intent-to-treat sample, group differences in alcohol outcomes out to 18 months favoring TMC over TAU were no longer present in months 19-24. There was also a non-significant trend for TMC to perform better than usual care on the good clinical outcome measure (60% vs. 46% good clinical outcome in months 19-24). Overall significant effects favoring TMC and TM over TAU were seen for women; and TMC was also superior to TAU for participants with social support for drinking, low readiness to change and prior alcohol treatments. Most of these effects were obtained on at least two of three outcomes. However, no effects remained significant at 24 months. CONCLUSIONS: The benefits of an extended telephone-based continuing care programme to treat alcohol dependence did not persist after the end of the intervention. A post-hoc analysis suggested that women and individuals with social support for drinking, low readiness to change or prior alcohol treatments may benefit from the intervention. PMID- 21545668 TI - Nicotine dependence, abuse and craving: dimensionality in an Israeli sample. AB - AIMS: Evidence-based changes planned for Diagnostic and Statistical Manual 5th edition (DSM-5) substance use disorders (SUDs) include combining dependence and three of the abuse criteria into one disorder and adding a criterion indicating craving. Because DSM-IV did not include a category for nicotine abuse, little empirical support is available for aligning the nicotine use disorder criteria with the DSM-5 criteria for other SUDs. DESIGN: Latent variable analyses, bootstrap tests and likelihood ratio tests were used to explore the unidimensionality, psychometric properties and information of the nicotine criteria. SETTING AND PARTICIPANTS: A sample of household residents selected from the Israeli population register yielded 727 life-time cigarette smokers. MEASUREMENTS: DSM-IV nicotine dependence criteria and proposed abuse and craving criteria, assessed with a structured interview. FINDINGS: Three abuse criteria (hazardous use, social/interpersonal problems and neglect roles) were prevalent among smokers, formed a unidimensional latent trait with nicotine dependence criteria, were intermixed with dependence criteria across the severity spectrum and significantly increased the diagnostic information over the dependence-only model. A craving criterion was shown to fit well with the other criteria. CONCLUSION: Similar to findings from research on other substances, nicotine dependence, abuse and craving criteria appear to derive from a common underlying dimension. The results support alignment of nicotine criteria with those for alcohol and drug use disorders in Diagnostic and Statistical Manual 5th edition. PMID- 21545669 TI - The social norms of birth cohorts and adolescent marijuana use in the United States, 1976-2007. AB - AIMS: Studies of the relationship between social norms and marijuana use have generally focused on individual attitudes, leaving the influence of larger societal-level attitudes unknown. The present study investigated societal-level disapproval of marijuana use defined by birth cohort or by time-period. DESIGN: Combined analysis of nationally representative annual surveys of secondary school students in the United States conducted from 1976 to 2007 as part of the Monitoring the Future study. SETTING: In-school surveys completed by adolescents in the United States. PARTICIPANTS: A total of 986 003 adolescents in grades 8, 10 and 12. MEASUREMENTS: Main predictors included the percentage of students who disapproved of marijuana in each birth cohort and time-period. Multi-level models with individuals clustered in time-periods of observation and birth cohorts were modeled, with past-year marijuana use as the outcome. FINDINGS: Results indicated a significant and strong effect of birth cohort disapproval of marijuana use in predicting individual risk of marijuana use, after controlling for individual level disapproval, perceived norms towards marijuana and other characteristics. Compared to birth cohorts in which most (87-90.9%) adolescents disapproved of marijuana use, odds of marijuana use were 3.53 times higher in cohorts where fewer than half (42-46.9%) disapproved (99% confidence interval: 2.75, 4.53). CONCLUSIONS: Individuals in birth cohorts that are more disapproving of marijuana use are less likely to use, independent of their personal attitudes towards marijuana use. Social norms and attitudes regarding marijuana use cluster in birth cohorts, and this clustering has a direct effect on marijuana use even after controlling for individual attitudes and perceptions of norms. PMID- 21545670 TI - Hospital-reported data on the pneumonia quality measure "Time to First Antibiotic Dose" are not associated with inpatient mortality: results of a nationwide cross sectional analysis. AB - OBJECTIVES: Significant controversy exists regarding the Centers for Medicare & Medicaid Services (CMS) "time to first antibiotics dose" (TFAD) quality measure. The objective of this study was to determine whether hospital performance on the TFAD measure for patients admitted from the emergency department (ED) for pneumonia is associated with decreased mortality. METHODS: This was a cross sectional analysis of 95,704 adult ED admissions with a principal diagnosis of pneumonia from 530 hospitals in the 2007 Nationwide Inpatient Sample. The sample was merged with 2007 CMS Hospital Compare data, and hospitals were categorized into TFAD performance quartiles. Univariate association of TFAD performance with inpatient mortality was evaluated by chi-square test. A population-averaged logistic regression model was created with an exchangeable working correlation matrix of inpatient mortality adjusted for age, sex, comorbid conditions, weekend admission, payer status, income level, hospital size, hospital location, teaching status, and TFAD performance. RESULTS: Patients had a mean age of 69.3 years. In the adjusted analysis, increasing age was associated with increased mortality with odds ratios (ORs) of >2.3. Unadjusted inpatient mortality was 4.1% (95% confidence interval [CI] = 3.9% to 4.2%). Median time to death was 5 days (25th 75th interquartile range = 2-11). Mean TFAD quality performance was 77.7% across all hospitals (95% CI = 77.6% to 77.8%). The risk-adjusted OR of mortality was 0.89 (95% CI = 0.77 to 1.02) in the highest performing TFAD quartile, compared to the lowest performing TFAD quartile. The second highest performing quartile OR was 0.94 (95% CI = 0.82 to 1.08), and third highest performing quartile was 0.91 (95% CI = 0.79 to 1.05). CONCLUSIONS: In this nationwide heterogeneous 2007 sample, there was no association between the publicly reported TFAD quality measure performance and pneumonia inpatient mortality. PMID- 21545671 TI - Utilization of radiographs for the diagnosis of ankle fractures in Kingston, Ontario, Canada. AB - OBJECTIVES: This study assessed the utilization and clinical yield of radiographs ordered to assist in the diagnosis of acute ankle injuries presenting to two emergency departments (EDs) in Kingston, Ontario, Canada, over a 7-year period. METHODS: A large case series was assembled. Records of ankle injuries from the Kingston sites of the Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) were linked to hospital discharge records containing procedure codes. Utilization of radiographs and the clinical yield of these assessments were analyzed over time. RESULTS: Following exclusions, 7,706 acute ankle injuries were identified for analysis. Utilization of radiography increased modestly over time, to a high of 70.3% (95% confidence interval [CI] = 67.3% to 72.9%) in 2007. The percentage of cases positive for fracture remained consistent (18.3% to 21.9% annually). CONCLUSIONS: Explanations for the observed increase in utilization of radiographs remain uncertain. Increased use of clinical decision tools such as the Ottawa Ankle Rules (OAR) appear to be required to reduce procedure costs within the ED and to limit patient exposure to radiography. PMID- 21545672 TI - Emergency department operations dictionary: results of the second performance measures and benchmarking summit. AB - The public, payers, hospitals, and Centers for Medicare and Medicaid Services (CMS) are demanding that emergency departments (EDs) measure and improve performance, but this cannot be done unless we define the terms used in ED operations. On February 24, 2010, 32 stakeholders from 13 professional organizations met in Salt Lake City, Utah, to standardize ED operations metrics and definitions, which are presented in this consensus paper. Emergency medicine (EM) experts attending the Second Performance Measures and Benchmarking Summit reviewed, expanded, and updated key definitions for ED operations. Prior to the meeting, participants were provided with the definitions created at the first summit in 2006 and relevant documents from other organizations and asked to identify gaps and limitations in the original work. Those responses were used to devise a plan to revise and update the definitions. At the summit, attendees discussed and debated key terminology, and workgroups were created to draft a more comprehensive document. These results have been crafted into two reference documents, one for metrics and the operations dictionary presented here. The ED Operations Dictionary defines ED spaces, processes, patient populations, and new ED roles. Common definitions of key terms will improve the ability to compare ED operations research and practice and provide a common language for frontline practitioners, managers, and researchers. PMID- 21545673 TI - Mortality 6 years after inpatient treatment of female Japanese patients with eating disorders associated with alcoholism. AB - AIMS: This study was conducted to clarify the mortality of patients with eating disorders associated with alcoholism. We focused on the mortality rate 6 years after inpatient treatment of patients with eating disorders associated with alcoholism compared with eating disorder patients without alcoholism and alcoholic patients without eating disorders. METHODS: The subjects were 164 female Japanese patients 30 years of age or younger with eating disorders or alcoholism who were inpatients at some time during the period from 1990 to 1998 at the Japanese National Hospital Organization, Kurihama Alcoholism Center. A semi-structured interview concerning alcohol problems, eating problems, psychiatric disorders and other clinical characteristics was conducted at the time of the first admission. A survey concerning survival was conducted in October 2001, and 100% of the patients were followed up. RESULTS: The mortality of the 47 eating disorder patients with alcoholism, 86 eating disorder patients without alcoholism, and 31 alcoholics without eating disorders was 27.7%, 3.5%, and 19.4%, respectively, at 6 years after inpatient treatment, showing significant differences. On the Kaplan-Meier survival curves, the mortality of the eating disorder patients with alcoholism was significantly higher than that of the patients without alcoholism, but not significantly higher than that of young female alcoholics without eating disorders. The 13 eating disorder patients with alcoholism who had died were five anorexia nervosa and seven bulimia nervosa patients. CONCLUSION: The results of the study suggest that comorbid alcoholism is a major factor in the death of anorexia nervosa and bulimia nervosa patients. PMID- 21545674 TI - Screening for diabetes using Japanese monitoring guidance in schizophrenia patients treated with second-generation antipsychotics: a cross-sectional study using baseline data. AB - AIM: The Japanese blood glucose monitoring guidance for patients receiving second generation antipsychotics has been newly developed. We aimed to report a cross sectional study using the baseline data of the Japanese monitoring guidance to find undiagnosed hyperglycemia systematically as a routine clinical practice and to quantify the frequency of glucose abnormalities in schizophrenia patients treated with second-generation antipsychotics. METHODS: Data for 537 patients with schizophrenia, who had not been diagnosed as having diabetes prior to baseline screening and started the monitoring between June 2008 and January 2009, were collected from medical records in 25 hospitals. Blood glucose (fasting or casual), hemoglobin(A1c) , serum lipids, height/weight, clinical diabetic symptoms, and family history of diabetes were assessed. Patients were classified into normal, pre-diabetic or probable diabetic type based on their values of blood glucose or hemoglobin(A1c) , and various background characteristics and serum lipid values were compared among the three types. RESULTS: Out of 537 patients, 13 (2.4%) met criteria for probable diabetic type, 51 (9.5%) for pre diabetic type, and 473 (88.1%) for normal type. Individuals categorized as probable diabetic type had a higher body mass index and higher frequency of family history of diabetes mellitus than those with normal type. CONCLUSION: Glucose abnormalities were newly detected in 11.9% of schizophrenia patients treated with second-generation antipsychotics by the baseline monitoring. To assess the detective power and usefulness of the guidance, longitudinal investigations are necessary. PMID- 21545675 TI - Basal rates and circadian profiles in continuous subcutaneous insulin infusion (CSII) differ for preschool children, prepubertal children, adolescents and young adults. AB - OBJECTIVE: Initiation of continuous subcutaneous insulin therapy (CSII) requires an appropriate basal rate profile. Different approaches exist; however, there is a lack of evidence-based recommendations, especially in young children. STUDY DESIGN: In this large multicenter survey, 5941 CSII patients from the German/Austrian prospective documentation system (DPV) were analyzed. Patients were divided into four age groups: <6 yr (n = 837), 6 to <12 yr (n = 1739), 12 to <18 yr (n = 2985) and 18 to <25 yr (n = 380). Basal insulin requirement and diurnal distribution were evaluated based on the most recent documentation for each patient. RESULTS: Basal insulin requirement differed significantly between the four age groups (<6: 0.25 +/- 0.12; 6 to <12: 0.33 +/- 0.12; 12 to <18: 0.43 +/- 0.15; 18 to <25: 0.35 +/- 0.13 U/kg; p < 0.001). Circadian insulin profiles were markedly different between the younger and older age groups. In addition to age, longer diabetes duration, female gender, higher HbA1c and lower body mass index standard deviation score (BMI-SDS) were related to higher basal insulin requirement per kilogram of body weight. CONCLUSIONS: Age of the patient is the primary factor that influences both total daily requirement and circadian distribution of basal insulin in CSII. Experience from a large database may therefore facilitate the initiation of pump therapy in pediatric patients. PMID- 21545676 TI - Behavioral research in pediatric diabetes: putting the evidence to work for advocacy and education. AB - Dr Henri Lestradet was a founding member of the International Study Group for Diabetes (in childhood and adolescence) (ISGD), and his influence on the scope and vision of this organization was profound. A brief biography of Dr Lestradet and a summary of how his original ISGD evolved into the current International Society for Pediatric and Adolescent Diabetes (ISPAD) will be presented first. Second, consistent with Dr Lestradet's vision for children with diabetes worldwide, I will suggest five areas of behavioral research in diabetes in which there is strong evidence that can be used to create educational and advocacy initiatives for children with diabetes. Finally, I will recommend several priorities for behavioral research in the next decade which will help to strengthen Prof. Lestradet's legacy of support for children with diabetes and their families. PMID- 21545677 TI - Methylmalonic acidemia mimicking diabetic ketoacidosis in an infant. AB - Methylmalonic acidemia (MMA) is an inherited organic acidemia usually present with recurrent episodes of acute illness. A typical episode is ushered in with ketonuria and vomiting, followed by acidosis, dehydration, and lethargy, leading, in the absence of aggressive treatment, to coma and death. We report an infant with MMA presented with diabetes symptoms. A 13-month-old girl complained of polydipsia, diuresis, and loss of weight. She had clinical signs of diabetic ketoacidosis such as dehydration, deep sighing respiration, smell of ketones, lethargy, and vomiting. Laboratory analysis showed hyperglycemia with acidosis and ketonuria. She was treated with parenteral fluid, electrolyte, and insulin infusion. Two days after her discharge, after having a meal rich in protein, she was brought unconscious with hepatomegaly, severe acidosis, ketonuria, and mild hyperammonemia. The absence of hyperglycemia and the presence of neurologic findings suggested organic acidemia. MMA was diagnosed because of methylmalonic aciduria and elevated C3 carnitine esters. Cranial magnetic resonance imaging (MRI) showed increased uptake of radiocontrast material in the basal ganglia bilaterally. A homozygous mutation in exon 4 of the MMAA gene was found in mutation analysis and confirmed the diagnosis of cblA-deficient MMA. Neurologic regression was improved with treatment of low-protein diet, vitamin B12, and l carnitine. In patients born to consanguineous parents who admit during infancy with severe acidosis refractory to treatment, organic acidemias should be kept in mind, even they have high blood glucose. The definitive diagnosis is important because it may allow a specific treatment and a favorable evolution to prevent the sequelae. PMID- 21545681 TI - Preface: chloroplast biotechnology. PMID- 21545682 TI - Post-partum weight retention in women in Asia: a systematic review. AB - Obesity is a health issue for people in Asia, and many studies support that childbearing may contribute to women's obesity. However, most studies of post partum weight retention (PWR) focus on Western countries. This paper aimed to review recent data on PWR and discuss the related factors of PWR for women in Asia. Three electronic databases - MEDLINE, CINAHL and PsycINFO - were searched for data from January 1990 to August 2010. Twelve studies were identified as containing information related to PWR. Chinese, Taiwanese and Korean women tend to have higher gestational weight gain and PWR than women in other Asian countries in this review. The average reported gestational weight gain in these studies ranged from 8.3 kg to 18.0 kg, and the average weight retention at 6 months post partum in various countries ranged from 1.56 kg to 4.1 kg. Gestational weight gain had a positive effect on PWR, but there were no consistent conclusions for other factors. Only a few psychosocial and behavioural factors have been studied. Moreover, no one has assessed changes in waist circumference and waist-to-hip ratio for measuring central obesity and ensuring risk of chronic disease. Focusing on changes in maternal weight and body composition, and considering the impact of psychological and behavioural factors are suggested for future studies in Asia. PMID- 21545683 TI - Complete sequence and analysis of the mitochondrial genome of the methylotrophic yeast Hansenula polymorpha DL-1. AB - We determined the complete nucleotide sequence of the 41 719 bp mitochondrial genome of the methylotrophic yeast Hansenula polymorpha strain DL-1. It contains genes for three subunits of cytochrome oxidase (cox1, cox2 and cox3), three subunits of ATP synthase (atp6, atp8 and atp9), seven subunits of NADH dehydrogenase (nad1-6 and nad4L), apocytochrome b (cob), four endonuclease/maturase homologs, a ribosomal protein (rps3), large and small rRNAs and a complete set of tRNAs. The structural genes are organized in two major transcriptional units. Phylogenetic, gene content and gene order analyses revealed the close phylogenetic relationship between H. polymorpha and Brettanomyces custersianus, and support the assignment of strain DL-1 to a separate genus rather than including it in the polyphyletic genus Pichia. PMID- 21545685 TI - Proliferation and differentiation potential of human adipose-derived mesenchymal stem cells isolated from elderly patients with osteoporotic fractures. AB - Aging has less effect on adipose-derived mesenchymal stem cells (ADSCs) than on bone marrow-derived mesenchymal stem cells (BMSCs), but whether the fact holds true in stem cells from elderly patients with osteoporotic fractures is unknown. In this study, ADSCs and BMSCs of the same donor were harvested and divided into two age groups. Group A consisted of 14 young patients (36.4 +/- 11.8 years old), and group B consisted of eight elderly patients (71.4 +/- 3.6 years old) with osteoporotic fractures. We found that the doubling time of ADSCs from both age groups was maintained below 70 hrs, while that of BMSCs increased significantly with the number of passage. When ADSCs and BMSCs from the same patient were compared, there was a significant increase in the doubling time of BMSCs in each individual from passages 3 to 6. On osteogenic induction, the level of matrix mineralization of ADSCs from group B was comparable to that of ADSCs from group A, whereas BMSCs from group B produced least amount of mineral deposits and had a lower expression level of osteogenic genes. The p21 gene expression and senescence-associated beta-galactosidase activity were lower in ADSCs compared to BMSCs, which may be partly responsible for the greater proliferation and differentiation potential of ADSCs. It is concluded that the proliferation and osteogenic differentiation of ADSCs were less affected by age and multiple passage than BMSCs, suggesting that ADSCs may become a potentially effective therapeutic option for cell-based therapy, especially in elderly patients with osteoporosis. PMID- 21545686 TI - Proteomic analysis of metabolic, cytoskeletal and stress response proteins in human heart failure. AB - Human heart failure is a complex syndrome and a primary cause of morbidity and mortality in the world. However, the molecular pathways involved in the remodelling process are poorly understood. In this study, we performed exhaustive global proteomic surveys of cardiac ventricle isolated from failing and non failing human hearts, and determined the regulatory pathway to uncover the mechanism underlying heart failure. Two-dimensional gel electrophoresis (2-DE) coupled with tandem mass spectrometry was used to identify differentially expressed proteins in specimens from failing (n = 9) and non-failing (n = 6) human hearts. A total of 25 proteins with at least 1.5-fold change in the failing heart were identified; 15 proteins were up-regulated and 10 proteins were down regulated. The altered proteins belong to three broad functional categories: (i) metabolic [e.g. NADH dehydrogenase (ubiquinone), dihydrolipoamide dehydrogenase, and the cytochrome c oxidase subunit]; (ii) cytoskeletal (e.g. myosin light chain proteins, troponin I type 3 and transthyretin) and (iii) stress response (e.g. alphaB-crystallin, HSP27 and HSP20). The marked differences in the expression of selected proteins, including HSP27 and HSP20, were further confirmed by Western blot. Thus, we carried out full-scale screening of the protein changes in human heart failure and profiled proteins that may be critical in cardiac dysfunction for future mapping. PMID- 21545687 TI - Regulatory mechanisms of interleukin-8 production induced by tumour necrosis factor-alpha in human hepatocellular carcinoma cells. AB - Interleukin (IL)-8 plays the critical role in the initiation of micro environmental inflammation responsible for tumour growth and patient prognosis. This study aimed at investigating the molecular mechanisms of IL-8 production from human hepatocellular carcinoma (HCC) cells. The levels of IL-8 and phosphorylation of p38 mitogen-activated protein kinase (MAPK), ERK1/2 and Akt in MHCC-97H cells were measured by ELISA, Western blot and immunofluorescence. NF kappaB p65 protein nuclear translocation was determined by non-radioactive NF kappaB p50/p65 transcription factor activity kit and cell bio-behaviours were detected by the real-time cell-monitoring system. Tumour necrosis factor-alpha (TNF-alpha) significantly induced phosphorylation of p38 MAPK, ERK, Akt and production of IL-8 from HCC cells, which were prevented by SB203580 (p38 MAPK inhibitor), PD98059 (ERK inhibitor), LY294002 and Wortmannin (PI3K inhibitor) and SB328437 (CCR3 inhibitor). TNF-alpha could significantly increase the translocation of NF-kappaB p65 protein into the nucleus in a dose-dependent manner, while SB203580 partially inhibited. In inflammatory micro-environment, HCC auto-produced IL-8 through p38 MAPK, ERK and PI3K/Akt signalling pathways, where the p38 MAPK is a central factor to activate the NF-kappaB pathway and regulate the expression of IL-8 production. There was a potential cross-talking between receptors. PMID- 21545688 TI - Impact of sample volume and handling time during analysis on the in vitro quality measurements of platelet concentrates held in syringes. AB - INTRODUCTION: The determination of quality parameters is a necessity for monitoring the efficacy of platelet concentrates. During consolidated quality control studies, there may be a large number of samples to be analyzed at the same time. This common workflow setup triggered the question whether there is an influence of the number of samples to be analyzed on the accuracy of the test results. METHODS: Two different sample volumes of platelet concentrates, 1 ml and 50 ml, were analyzed for a set of standard in vitro parameters including pCO(2), pO(2), pH, glucose, and lactate as well as platelet activation via CD62P expression and responsiveness to adinosine diphosphate in an extent-of-shape change assay. To assess apoptotic mechanisms triggered by the hold time, changes in the phosphatidylserine exposure were monitored. RESULTS: In total, eleven time points were assessed over a 3-h period as well as an overnight point for assay evaluation. Except for pCO(2) and pO(2), all in vitro parameters analyzed were unaffected by a sample hold time of up to 3-h. CONCLUSION: Sampling for pO(2) determination should be carried out in small volumes and assessed within 30 min of collection to obtain reliable and comparable results. PMID- 21545689 TI - Differential results between self-report and interview-based ratings of risk symptoms of psychosis. AB - AIM: Assessing potential risk of developing psychosis has gained growing attention in recent literature. The selection of suitable assessment methods is the central question for this research endeavour. Whereas prodromal detection instruments are mostly interview-based instruments, there are short screening instruments for self-report use. METHODS: Difference in psychosis risk scores was tested between self-report results and interview results, with risk symptoms of psychosis included in PROD screening instrument. Subjects were recruited by an early intervention team in Finland. RESULTS: There was a significant difference between psychosis risk scores based on self-report versus interview in a sample of adolescents (n=87; P<0.001). CONCLUSIONS: Results suggest that when using screening instruments, risk scores and risk status may vary by the method the information is collected. Checking self-report results by an additional interview is recommended for both clinical and scientific uses. PMID- 21545690 TI - Foot-and-mouth disease control and eradication in the Bicol Surveillance Buffer Zone of the Philippines. AB - Following the onset of an epidemic of foot and mouth disease (FMD) commencing in 1994 and affecting mainly pigs in the Philippines, a National Plan for the Control and Eradication of the disease was initiated. A disease surveillance buffer zone in the southern Luzon region of Bicol was established to protect the Visayas and Mindanao from infection and enable eventual elimination of the disease in Luzon. With achievement of Office International Epizooties (OIE) certified FMD freedom with vaccination in the Philippines now imminent, the four components of the disease control strategy are reviewed, including quarantine and animal movement controls, strategic vaccination, surveillance and disease investigation, and enhanced public awareness with school on the air radio programmes. Although numbers of outbreaks declined following widespread vaccination, evaluation of serological responses in vaccinates suggested low levels of immune protection. The cessation of outbreaks was considered more likely a result of animal movement controls, improved surveillance and emergency response capability, and reduction in FMD-risk behaviours by livestock owners, particularly through efforts to enhance public awareness of biosecurity measures by the training of traders, livestock industry personnel and both commercial and smallholder farmers. A two-stage random sampling serosurveillance strategy enabled identification of residual infection that was not detected through opportunistic sampling and negative incident reporting. Intensive investigations of FMD outbreaks, particularly in Albay province in 1999, enabled improved understanding of the risk factors involved in disease transmission and implementation of appropriate interventions. The findings from this review are offered to assist development of FMD control and eradication programmes in other countries in south-east Asia that are now being encouraged to support the OIE goal of FMD freedom with vaccination by 2020. PMID- 21545691 TI - Salmonella control measures with special focus on vaccination and logistic slaughter procedures. AB - This study focussed on the effectiveness of Salmonella control measures to decrease Salmonella prevalence at slaughter. Considered measures were the control of hygiene and husbandry management as well as vaccination and logistic slaughter procedures. Results emphasized the capabilities of the farrowing stage to influence slaughter pig prevalence. Limited Salmonella entry by the implementation of hygiene control measures at farrowing farms obtained a significant decrease in prevalence after lairage at slaughterhouse. In contrast, hygiene control measures at finishing stage were less effective. Husbandry control measures, preventing physical contacts between pigs, were proved to decrease slaughter pig prevalence whether they were implemented at farrowing or finishing stage. Furthermore, the vaccination of sows and piglets was an appropriate control measure to decrease slaughter pig prevalence, if a large part of farms established this control measure. Simultaneous implementation of control measures showed that vaccination and especially hygiene measures are mutually supportive. Concerning logistic slaughter procedures it became obvious that with decreasing prevalence, infections at transport and lairage become more and more important. The herd status separation significantly decreased the percentage of infected pigs that became infected at lairage. PMID- 21545692 TI - Risk factors of highly pathogenic avian influenza H5N1 occurrence at the village and farm levels in the Red River Delta Region in Vietnam. AB - A case-control study at both village and farm levels was designed to investigate risk factors for highly pathogenic avian influenza H5N1 during the 2007 outbreaks in one province of Northern Vietnam. Data related to human and natural environments, and poultry production systems were collected for 19 case and 38 unmatched control villages and 19 pairs of matched farms. Our results confirmed the role of poultry movements and trading activities. In particular, our models found that higher number of broiler flocks in the village increased the risk (OR = 1.49, 95% CI: 1.12-1.96), as well as the village having at least one poultry trader (OR = 11.53, 95% CI: 1.34-98.86). To a lesser extent, in one of our two models, we also identified that increased density of ponds and streams, commonly used for waterfowl production, and greater number of duck flocks in the village also increased the risk. The higher percentage of households keeping poultry, as an indicator of households keeping backyard poultry in our study population, was a protective factor (OR = 0.95, 95% CI: 0.91-0.98). At the farm level, three risk factors at the 5% level of type I error were identified by univariate analysis: a greater total number of birds (P = 0.006), increase in the number of flocks having access to water (P = 0.027) and a greater number of broiler flocks in the farm (P = 0.049). Effect of vaccination implementation (date and doses) was difficult to investigate because of a poor recording system. Some protective or risk factors with limited effect may not have been identified owing to our limited sample size. Nevertheless, our results provide a better understanding of local transmission mechanisms of HPAI H5N1 in one province of the Red River Delta region in Vietnam and highlight the need to reduce at-risk trading and production practices. PMID- 21545693 TI - Editorial. Molecular Oral Microbiology (MOM) has been on the road now for a little over 15 months. PMID- 21545695 TI - Porphyromonas gingivalis mutY is involved in the repair of oxidative stress induced DNA mispairing. AB - The ability for DNA mismatch repair, after oxidative stress-induced DNA damage, is critical for the persistence of Porphyromonas gingivalis in the inflammatory environment of the periodontal pocket. Our previous report demonstrated that, in contrast to other organisms, the repair of oxidative stress-induced DNA damage involving 8-oxo-7,8-dihydroguanine (8-oxoG) may occur by a yet-to-be described mechanism in P. gingivalis. 8-oxoG does not block DNA replication; rather, it mispairs with adenine, which can be repaired by the MutY glycosylase. To determine the function of the P. gingivalis MutY homologue in DNA repair, it was insertionally inactivated using the ermF-ermAM antibiotic cassette and used to create a mutY-deficient mutant (FLL147) by allelic exchange mutagenesis. FLL147 had an increased rate of spontaneous mutation and was more sensitive to hydrogen peroxide compared with the wild-type W83 strain. DNA oligomers containing a site specific 8-oxoG:A mispair was repaired similarly in both the P. gingivalis mutY defective mutant and wild-type strains. The P. gingivalis mutY homologue was shown to complement the mutY mutation in Escherichia coli. In a gel mobility shift assay, the purified recombinant MutY is able to bind an oligo containing an 8-oxoG:A mispair. Taken together, MutY may play the expected role in oxidative stress resistance in P. gingivalis. However, there may exist other redundant mechanism(s) for the removal of 8-oxoG:A mismatch in this organism. PMID- 21545696 TI - Streptococcus mutans strains recovered from caries-active or caries-free individuals differ in sensitivity to host antimicrobial peptides. AB - Antimicrobial peptides (AMPs) are among the repertoire of host innate immune defenses. In the oral cavity, several AMPs are present in saliva and have antimicrobial activities against oral bacteria, including Streptococcus mutans, a primary etiological agent of dental caries. In this study, we hypothesized that unique S. mutans strains, as determined by DNA fingerprinting from sixty 13-year old subjects with or without experience of caries, would have different susceptibilities to alpha-defensins-1-3 (HNP-1-3), beta-defensins-2-3 (HBD-2-3) and LL-37. The salivary levels of these peptides in subjects were also measured by enzyme-linked immunosorbent assays. We found that S. mutans strains from children with active caries showed greater resistance to salivary HNP-1-2, HBD-2 3 and LL-37 at varying concentrations than those from caries-free subjects. In addition, combinations of these peptides increased their antimicrobial activity against S. mutans either additively or synergistically. The salivary levels of these peptides were highly variable among subjects with no correlation to host caries experience. However, the levels of a number of these peptides in saliva appeared to be positively correlated within an individual. Our findings suggest that the relative ability of S. mutans to resist host salivary AMPs may be considered a potential virulence factor for this species such that S. mutans strains that are more resistant to these peptides may have an ecological advantage to preferentially colonize within dental plaque and increase the risk of dental caries. PMID- 21545697 TI - Characterization of antigen-presenting cells induced by intragastric immunization with recombinant chimeric immunogens constructed from Streptococcus mutans AgI/II and type I or type II heat-labile enterotoxins. AB - Intragastric (i.g.) immunization with recombinant chimeric proteins constructed from the saliva-binding region (SBR) of Streptococcus mutans surface antigen AgI/II and the A2/B subunits of enterobacterial heat-labile enterotoxins has been successfully used to induce salivary and circulating antibodies against S. mutans that have protective potential against dental caries. To investigate the mode of action of these vaccine constructs, mice were immunized i.g. with chimeric proteins constructed from SBR and cholera toxin (CT) or the type II enterotoxins of Escherichia coli, LT-IIa and LT-IIb. Antigen-presenting cells (APC) in Peyer's patches (PP) and mesenteric lymph nodes (MLN) were characterized by flow cytometry. Compared with immunization with SBR alone, chimeric proteins SBR LTIIaA2/B and SBR-LTIIbA2/B increased the number of B cells and macrophages in PP and diminished B cell numbers in MLN, whereas SBR-CTA2/B diminished the numbers of B cells and macrophages in PP and MLN. Immunization with all three chimeric proteins led to upregulation of MHC class II molecules and co-stimulatory receptors CD40, CD80, and CD86 especially on dendritic cells in PP and also on APC in MLN. The results provide a molecular basis for the enhanced immune responses induced by chimeric proteins compared with uncoupled antigen, and for differential responses to chimeric proteins based on CT or type II enterotoxins. PMID- 21545698 TI - Interaction of oral bacteria with gingival epithelial cell multilayers. AB - Primary gingival epithelial cells were cultured in multilayers as a model for the study of interactions with oral bacteria associated with health and periodontal disease. Multilayers maintained at an air-liquid interface in low-calcium medium displayed differentiation and cytokeratin properties characteristic of junctional epithelium. Multilayers were infected with fluorescently labeled Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum or Streptococcus gordonii, and bacterial association was determined by confocal microscopy and quantitative image analysis. Porphyromonas gingivalis invaded intracellularly and spread from cell to cell; A. actinomycetemcomitans and F. nucleatum remained extracellular and showed intercellular movement through the multilayer; whereas S. gordonii remained extracellular and predominantly associated with the superficial cell layer. None of the bacterial species disrupted barrier function as measured by transepithelial electrical resistance. P. gingivalis did not elicit secretion of proinflammatory cytokines. However, A. actinomycetemcomitans and S. gordonii induced interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6 and IL-8 secretion; and F. nucleatum stimulated production of IL-1beta and TNF-alpha. Aggregatibacter actinomycetemcomitans, F. nucleatum and S. gordonii, but not P. gingivalis, increased levels of apoptosis after 24 h infection. The results indicate that the organisms with pathogenic potential were able to traverse the epithelium, whereas the commensal bacteria did not. In addition, distinct host responses characterized the interaction between the junctional epithelium and oral bacteria. PMID- 21545699 TI - Streptococcus anginosus l-cysteine desulfhydrase gene expression is associated with abscess formation in BALB/c mice. AB - Streptococcus anginosus, an anginosus group bacterium, is frequently isolated from odontogenic abscesses, and is the oral bacterium that is primarily responsible for producing hydrogen sulfide from l-cysteine through the action of its l-cysteine desulfhydrase (betaC-S lyase) enzyme. However, the relationship between its production of hydrogen sulfide and abscess formation has not been investigated. To elucidate the etiological role of hydrogen sulfide in abscess formation, we initially measured, using specific primers, expression of the lcd gene, which encodes betaC-S lyase, in the pus of abscesses that formed in BALB/c mice following subcutaneous injection of S. anginosus into the dorsa. Expression of lcd was >15-fold higher when l-cysteine was present than when it was absent. A mouse virulence assay revealed that the mean diameter of abscesses caused by S. anginosus FW73 plus l-cysteine was greater than that of abscesses caused by S. anginosus FW73 in the absence of l-cysteine. These findings demonstrate that the lcd gene of S. anginosus is upregulated in mouse abscesses and that hydrogen sulfide, the product of a reaction catalyzed by betaC-S lyase, plays an etiological role in odontogenic abscess formation. PMID- 21545701 TI - Experiences of doctors and nurses implementing nurse-delivered cardiovascular prevention in primary care: a qualitative study. AB - AIM: This paper reports on a study of the experiences of general practitioners and practice nurses implementing nurse-delivered cardiovascular prevention to high risk patients in primary care. BACKGROUND: Difficulties may arise when innovations are introduced into routine daily practice. Whether or not implementation is successful is determined by different factors related to caregivers, patients, type of innovation and context. METHODS: A qualitative study nested in a randomized trial (2006-2008) to evaluate the effectiveness of nurse-delivered cardiovascular prevention. Six primary health care centres in the Netherlands (25 general practitioners, 6 practice nurses) participated in the trial. Interviews were held on two occasions: at 3 and at 18 months after commencement of consultation. The first occasion was a group interview with six practice nurses. The second consisted of semi-structured interviews with one general practitioner and one practice nurse from each centre. FINDINGS: Main barriers to the implementation included: lack of knowledge about the guideline, attitudes towards treatment targets, lack of communication, insufficient coaching by doctors, content of life style advice. At the start of the consultation project, practice nurses expressed concern of losing nursing tasks. Other barriers were related to patients (lack of motivation), the guideline (target population) and organizational issues (insufficient patient recording and computer systems). CONCLUSIONS: Both general practitioners and practice nurses were positive about nurse-delivered cardiovascular prevention in primary care. Nurses could play an important role in successive removal of barriers to implementation of cardiovascular prevention. Mutual confidence between care providers in the healthcare team is necessary. PMID- 21545702 TI - Isolation of xylose isomerases by sequence- and function-based screening from a soil metagenomic library. AB - BACKGROUND: Xylose isomerase (XI) catalyses the isomerisation of xylose to xylulose in bacteria and some fungi. Currently, only a limited number of XI genes have been functionally expressed in Saccharomyces cerevisiae, the microorganism of choice for lignocellulosic ethanol production. The objective of the present study was to search for novel XI genes in the vastly diverse microbial habitat present in soil. As the exploitation of microbial diversity is impaired by the ability to cultivate soil microorganisms under standard laboratory conditions, a metagenomic approach, consisting of total DNA extraction from a given environment followed by cloning of DNA into suitable vectors, was undertaken. RESULTS: A soil metagenomic library was constructed and two screening methods based on protein sequence similarity and enzyme activity were investigated to isolate novel XI encoding genes. These two screening approaches identified the xym1 and xym2 genes, respectively. Sequence and phylogenetic analyses revealed that the genes shared 67% similarity and belonged to different bacterial groups. When xym1 and xym2 were overexpressed in a xylA-deficient Escherichia coli strain, similar growth rates to those in which the Piromyces XI gene was expressed were obtained. However, expression in S. cerevisiae resulted in only one-fourth the growth rate of that obtained for the strain expressing the Piromyces XI gene. CONCLUSIONS: For the first time, the screening of a soil metagenomic library in E. coli resulted in the successful isolation of two active XIs. However, the discrepancy between XI enzyme performance in E. coli and S. cerevisiae suggests that future screening for XI activity from soil should be pursued directly using yeast as a host. PMID- 21545703 TI - Markedly impaired bilateral coordination of gait in post-stroke patients: Is this deficit distinct from asymmetry? A cohort study. AB - BACKGROUND: Multiple aspects of gait are typically impaired post-stroke. Asymmetric gait is common as a consequence of unilateral brain lesions. The relationship between the resulting asymmetric gait and impairments in the ability to properly coordinate the reciprocal stepping activation of the legs is not clear. The objective of this exploratory study is to quantify the effects of hemiparesis on two putatively independent aspects of the bilateral coordination of gait to gain insight into mechanisms and their relationship and to assess their potential as clinical markers. METHODS: Twelve ambulatory stroke patients and age-matched healthy adults wore a tri-axial piezo-resistive accelerometer and walked back and forth along a straight path in a hall at a comfortable walking speed during 2 minutes. Gait speed, gait asymmetry (GA), and aspects of the bilateral coordination of gait (BCG) were determined. Bilateral coordination measures included the left-right stepping phase for each stride phii, consistency in the phase generation phi_CV, accuracy in the phase generation phi_ABS, and Phase Coordination Index (PCI), a combination of accuracy and consistency of the phase generation. RESULTS: Group differences (p < 0.001) were observed for gait speed (1.1 +/- 0.1 versus 1.7 +/- 0.1 m/sec for patients and controls, respectively), GA (26.3 +/- 5.6 versus 5.5 +/- 1.2, correspondingly) and PCI (19.5 +/- 2.3 versus 6.2 +/- 1.0, correspondingly). A significant correlation between GA and PCI was seen in the stroke patients (r = 0.94; p < 0.001), but not in the controls. CONCLUSIONS: In ambulatory post-stroke patients, two gait coordination properties, GA and PCI, are markedly impaired. Although these features are not related to each other in healthy controls, they are strongly related in stroke patients, which is a novel finding. A measurement approach based on body-fixed sensors apparently may provide sensitive markers that can be used for clinical assessment and for enhancing rehabilitation targeting in post stroke patients. PMID- 21545704 TI - Extensive epigenetic reprogramming in human somatic tissues between fetus and adult. AB - BACKGROUND: Development of human tissue is influenced by a combination of intrinsic biological signals and extrinsic environmental stimuli, both of which are mediated by epigenetic regulation, including DNA methylation. However, little is currently known of the normal acquisition or loss of epigenetic markers during fetal and postnatal development. RESULTS: The DNA methylation status of over 1000 CpGs located in the regulatory regions of nearly 800 genes was evaluated in five somatic tissues (brain, kidney, lung, muscle and skin) from eight normal second trimester fetuses. Tissue-specific differentially methylated regions (tDMRs) were identified in 195 such loci. However, comparison with corresponding data from trisomic fetuses (five trisomy 21 and four trisomy 18) revealed relatively few DNA methylation differences associated with trisomy, despite such conditions having a profound effect on development. Of interest, only 17% of the identified fetal tDMRs were found to maintain this same tissue-specific DNA methylation in adult tissues. Furthermore, 10% of the sites analyzed, including sites associated with imprinted genes, had a DNA methylation difference of >40% between fetus and adult. This plasticity of DNA methylation over development was further confirmed by comparison with similar data from embryonic stem cells, with the most altered methylation levels being linked to domains with bivalent histone modifications. CONCLUSIONS: Most fetal tDMRs seem to reflect transient DNA methylation changes during development rather than permanent epigenetic signatures. The extensive tissue-specific and developmental-stage specific nature of DNA methylation will need to be elucidated to identify abnormal patterns of DNA methylation associated with abnormal development or disease. PMID- 21545705 TI - Normal sex differences in prenatal growth and abnormal prenatal growth retardation associated with 46,XY disorders of sex development are absent in newborns with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. AB - BACKGROUND: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is the most common presentation of a disorder of sex development (DSD) in genetic females. A report of prenatal growth retardation in cases of 46,XY DSD, coupled with observations of below-optimal final height in both males and females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, prompted us to investigate prenatal growth in the latter group. Additionally, because girls with congenital adrenal hyperplasia are exposed to increased levels of androgens in the absence of a male sex-chromosome complement, the presence or absence of typical sex differences in growth of newborns would support or refute a hormonal explanation for these differences. METHODS: In total, 105 newborns with congenital adrenal hyperplasia were identified in our database. Gestational age (weeks), birth weight (kg), birth length (cm) and parental heights (cm) were obtained. Mid-parental height was considered in the analyses. RESULTS: Mean birth weight percentile for congenital adrenal hyperplasia was 49.26%, indicating no evidence of a difference in birth weight from the expected standard population median of 50th percentile (P > 0.05). The expected sex difference in favor of heavier males was not seen (P > 0.05). Of the 105 subjects, 44 (27%; 34 females, 10 males) had birth length and gestational age recorded in their medical chart. Mean birth length for this subgroup was 50.90 cm (63rd percentile), which differed from the expected standard population median of 50th percentile (P = 0.0082). The expected sex difference in favor of longer males was also not seen (P > 0.05). CONCLUSION: The prenatal growth retardation patterns reported in cases of 46,XY disorders of sex development do not generalize to people with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Sex differences in body weight and length typically seen in young infants were not seen in the subjects who participated in this study. We speculate that these differences were ameliorated in this study because of increased levels of prenatal androgens experienced by the females infants. PMID- 21545706 TI - Representation of less-developed countries in Pharmacology journals: an online survey of corresponding authors. AB - BACKGROUND: Scientists from less-developed countries (LDC) perceive that it is difficult to publish in international journals from their countries. This online survey was conducted with the primary aim of determining the opinion of corresponding authors of published papers in international Pharmacology journals regarding the difficulties in publications and their possible solutions. METHODS: The titles of all Pharmacology journals were retrieved from Pubmed. 131 journals were included in study. The latest issue of all journals was reviewed thoroughly. An online survey was conducted from the corresponding authors of the published papers who belonged to LDC. RESULTS: 584 out 1919 papers (30.4%) originated from the LDC. 332 responses (response rate; 64.5%) were received from the authors. Approximately 50% the papers from LDC were published in journals with impact factor of less than 2. A weak negative correlation (r = -0.236) was observed between journal impact factor and the percentage of publications emanating from LDC. A significant majority of the corresponding authors (n = 254; 76.5%) perceived that it is difficult to publish in good quality journals from their countries. According to their opinion, biased attitude of editors and reviewers (64.8%) is the most important reason followed by the poor writing skills of the scientists from LDC (52.8%). The authors thought that well-written manuscript (76.1%), improvement in the quality of research (69.9%) and multidisciplinary research (42.9%) are important determinants that may improve the chances of publications. CONCLUSIONS: The LDC are underrepresented in publications in Pharmacology journals. The corresponding authors of the published articles think that biased attitude of the editors as well as the reviewers of international journals and the poor writing skills of scientists are the major factors underlying the non-acceptance of their results. They also think that the improvement in the writing skills and quality of research will increase the chances of acceptance of their works in international journals. PMID- 21545707 TI - Terrestrial invasion of pomatiopsid gastropods in the heavy-snow region of the Japanese Archipelago. AB - BACKGROUND: Gastropod mollusks are one of the most successful animals that have diversified in the fully terrestrial habitat. They have evolved terrestrial taxa in more than nine lineages, most of which originated during the Paleozoic or Mesozoic. The rissooidean gastropod family Pomatiopsidae is one of the few groups that have evolved fully terrestrial taxa during the late Cenozoic. The pomatiopsine diversity is particularly high in the Japanese Archipelago and the terrestrial taxa occur only in this region. In this study, we conducted thorough samplings of Japanese pomatiopsid species and performed molecular phylogenetic analyses to explore the patterns of diversification and terrestrial invasion. RESULTS: Molecular phylogenetic analyses revealed that Japanese Pomatiopsinae derived from multiple colonization of the Eurasian Continent and that subsequent habitat shifts from aquatic to terrestrial life occurred at least twice within two Japanese endemic lineages. Each lineage comprises amphibious and terrestrial species, both of which are confined to the mountains in heavy-snow regions facing the Japan Sea. The estimated divergence time suggested that diversification of these terrestrial lineages started in the Late Miocene, when active orogenesis of the Japanese landmass and establishment of snowy conditions began. CONCLUSIONS: The terrestrial invasion of Japanese Pomatiopsinae occurred at least twice beside the mountain streamlets of heavy-snow regions, which is considered the first case of this event in the area. Because snow coverage maintains stable temperatures and high humidity on the ground surface, heavy-snow conditions may have paved the way for these organisms from freshwater to land via mountain streamlets by preventing winter desiccation in mountain valleys. The fact that the terrestrialization of Pomatiopsidae occurred only in year-round wet environments, but not in seasonally dried regions, provides new insight into ancient molluscan terrestrialization. PMID- 21545708 TI - Adolescent fertility and family planning in East Asia and the Pacific: a review of DHS reports. AB - BACKGROUND: Adolescent pregnancy has significant health and socio-economic consequences for women, their families and communities. Efforts to prevent too early pregnancy rely on accurate information about adolescents' knowledge, behaviours and access to family planning, however available data are limited in some settings. Demographic and Health Survey (DHS) reports are recognised as providing nationally representative data that are accessible to policymakers and programmers. This paper reviews DHS reports for low and lower middle income countries in East Asia and the Pacific to determine what information regarding adolescent fertility and family planning is available, and summarises key findings. METHODS: The most recent DHS reports were sought for the 33 low and lower middle income countries in the East Asia and Pacific region as defined by UNICEF and World Bank. Age-disaggregated data for all indicators relevant to fertility and current use, knowledge and access to family planning information and services were sought to identify accessible information. Reported data were analysed using an Excel database to determine outcomes for adolescents and compare with adult women. RESULTS: DHS reports were available for eleven countries: Cambodia, Indonesia, Marshall Islands, Nauru, Papua New Guinea, Philippines, Samoa, Solomon Islands, Timor-Leste, Tuvalu and Vietnam. Twenty seven of 40 relevant DHS indicators reported outcomes for adolescent women aged 15-19 years. There were limited data for unmarried adolescents. A significant proportion of women commence sexual activity and childbearing during adolescence in the context of low contraceptive prevalence and high unmet need for contraception. Adolescent women have lower use of contraception, poorer knowledge of family planning and less access to information and services than adult women. CONCLUSION: DHS reports provide useful and accessible data, however, they are limited by the failure to report data for unmarried adolescents and report age disaggregated data for some indicators. Further research is required to better understand the barriers that both married and unmarried adolescents face accessing reproductive health information and services, and their information and service delivery preferences. PMID- 21545709 TI - Somatic and germline expression of piwi during development and regeneration in the marine polychaete annelid Capitella teleta. AB - BACKGROUND: Stem cells have a critical role during adult growth and regeneration. Germline stem cells are specialized stem cells that produce gametes during sexual reproduction. Capitella teleta (formerly Capitella sp. I) is a polychaete annelid that reproduces sexually, exhibits adult growth and regeneration, and thus, is a good model to study the relationship between somatic and germline stem cells. RESULTS: We characterize expression of the two C. teleta orthologs of piwi, genes with roles in germline development in diverse organisms. Ct-piwi1 and Ct-piwi2 are expressed throughout the life cycle in a dynamic pattern that includes both somatic and germline cells, and show nearly identical expression patterns at all stages examined. Both genes are broadly expressed during embryonic and larval development, gradually becoming restricted to putative primordial germ cells (PGCs) and the posterior growth zone. In juveniles, Ct-piwi1 is expressed in the presumptive gonads, and in reproductive adults, it is detected in gonads and the posterior growth zone. In addition, Ct-piwi1 is expressed in a population of putative PGCs that persist in sexually mature adults, likely in a stem cell niche. Ct-piwi1 is expressed in regenerating tissue, and once segments differentiate, it becomes most prominent in the posterior growth zone and immature oocytes in regenerating ovaries of regenerating segments. CONCLUSIONS: In C. teleta, piwi genes may have retained an ancestral role as genetic regulators of both somatic and germline stem cells. It is likely that piwi genes, and associated stem cell co-regulators, became restricted to the germline in some taxa during the course of evolution. PMID- 21545710 TI - Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling. AB - BACKGROUND: Progressive remodeling of the left ventricle (LV) following myocardial infarction (MI) can lead to congestive heart failure, but the underlying initiation factors remain poorly defined. The objective of this study, accordingly, was to determine the key factors and elucidate the regulatory mechanisms of LV remodeling using integrated computational and experimental approaches. RESULTS: By examining the extracellular matrix (ECM) gene expression and plasma analyte levels in C57/BL6J mice LV post-MI and ECM gene responses to transforming growth factor (TGF-beta1) in cultured cardiac fibroblasts, we found that key factors in LV remodeling included macrophages, fibroblasts, transforming growth factor-beta1, matrix metalloproteinase-9 (MMP-9), and specific collagen subtypes. We established a mathematical model to study LV remodeling post-MI by quantifying the dynamic balance between ECM construction and destruction. The mathematical model incorporated the key factors and demonstrated that TGF-beta1 stimuli and MMP-9 interventions with different strengths and intervention times lead to different LV remodeling outcomes. The predictions of the mathematical model fell within the range of experimental measurements for these interventions, providing validation for the model. CONCLUSIONS: In conclusion, our results demonstrated that the balance between ECM synthesis and degradation, controlled by interactions of specific key factors, determines the LV remodeling outcomes. Our mathematical model, based on the balance between ECM construction and destruction, provides a useful tool for studying the regulatory mechanisms and for predicting LV remodeling outcomes. PMID- 21545711 TI - Safety and efficacy of the immunosuppressive agent 6-tioguanine in murine model of acute and chronic colitis. AB - BACKGROUND: Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD. METHODS: We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry. RESULTS: 6 TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 MUg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL 6 and IFN-gamma production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 MUg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-beta was observed only in colon of AZA-treated mice. CONCLUSIONS: Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities. PMID- 21545712 TI - SNiPlay: a web-based tool for detection, management and analysis of SNPs. Application to grapevine diversity projects. AB - BACKGROUND: High-throughput re-sequencing, new genotyping technologies and the availability of reference genomes allow the extensive characterization of Single Nucleotide Polymorphisms (SNPs) and insertion/deletion events (indels) in many plant species. The rapidly increasing amount of re-sequencing and genotyping data generated by large-scale genetic diversity projects requires the development of integrated bioinformatics tools able to efficiently manage, analyze, and combine these genetic data with genome structure and external data. RESULTS: In this context, we developed SNiPlay, a flexible, user-friendly and integrative web based tool dedicated to polymorphism discovery and analysis. It integrates:1) a pipeline, freely accessible through the internet, combining existing softwares with new tools to detect SNPs and to compute different types of statistical indices and graphical layouts for SNP data. From standard sequence alignments, genotyping data or Sanger sequencing traces given as input, SNiPlay detects SNPs and indels events and outputs submission files for the design of Illumina's SNP chips. Subsequently, it sends sequences and genotyping data into a series of modules in charge of various processes: physical mapping to a reference genome, annotation (genomic position, intron/exon location, synonymous/non-synonymous substitutions), SNP frequency determination in user-defined groups, haplotype reconstruction and network, linkage disequilibrium evaluation, and diversity analysis (Pi, Watterson's Theta, Tajima's D).Furthermore, the pipeline allows the use of external data (such as phenotype, geographic origin, taxa, stratification) to define groups and compare statistical indices.2) a database storing polymorphisms, genotyping data and grapevine sequences released by public and private projects. It allows the user to retrieve SNPs using various filters (such as genomic position, missing data, polymorphism type, allele frequency), to compare SNP patterns between populations, and to export genotyping data or sequences in various formats. CONCLUSIONS: Our experiments on grapevine genetic projects showed that SNiPlay allows geneticists to rapidly obtain advanced results in several key research areas of plant genetic diversity. Both the management and treatment of large amounts of SNP data are rendered considerably easier for end-users through automation and integration. Current developments are taking into account new advances in high-throughput technologies.SNiPlay is available at: http://sniplay.cirad.fr/. PMID- 21545713 TI - Vitamin D receptor gene polymorphisms in multiple sclerosis patients in northwest Greece. AB - BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been linked to both multiple sclerosis (MS) and osteoporosis. We examined the frequency of the Taq-I and Bsm-I polymorphisms of the vitamin D receptor (VDR) gene in 69 patients with MS and 81 age and sex-matched healthy individuals. Genotyping of Taq-I (rs731236) and Bsm-I (rs1544410) was performed using TaqMan SNP Genotyping Assay. All patients and controls had determination of body mass index (BMI), bone mineral density (BMD) and smoking history. RESULTS: The mean age of patients was 39 +/- 10.5 years compared to 38.7 +/- 10.7 years of the controls (p = 0.86), the BMI was 24.8 +/- 4.2 kg/m2 compared to 25.7 +/- 4.8 kg/m2 of the controls (p = 0.23), the BMD in the lumbar spine 0.981 +/- 0.15 compared to 1.025 +/- 013 of the controls (p = 0.06) and the total hip BMD was 0.875 +/- 0.14 compared to 0.969 +/- 0.12 of the controls (p < 0.001). There were no differences of the Taq I (TT, CT, CC) and Bsm-I genotypes (GG, GA, AA) and allelic frequencies between MS and control individuals. Multivariate analysis also failed to show any association of the Taq-I and Bsm-I polymorphisms and MS or sex, BMI, BMD and smoking history. CONCLUSIONS: This study suggests that the Taq-I and Bsm-I polymorphisms of the VDR gene are not associated with MS risk, BMI or BMD in the Greek population studied. PMID- 21545714 TI - Should a single blastocyst transfer policy be a clinical decision or should it depend on the embryological evaluation on day 3? AB - BACKGROUND: Single blastocyst transfer has the advantage of maximizing the fresh single pregnancy rate. However, in patients with a low number of good quality embryos on day 3, it remains unclear whether immediate embryo transfer or further embryo culture with blastocyst transfer is the most preferable option. METHODS: A retrospective cohort study was carried out in which the outcome of 590 fresh in vitro fertilization (IVF) cycles over a 15 months period and their cryo cycles were analyzed. A total of 341 patients cycles had an elective day 5 strategy independent of intermediate embryo evaluation while another 249 patients underwent a day 5 embryo transfer only if at least four embryos were available on day 3. Blastocyst vitrification was performed using a closed high security system. RESULTS: Demographics, stimulation parameters and embryological data were comparable in the two groups. Patients in the elective day 5 group had a lower fresh transfer rate (90.62% vs. 95.18%, p < 0.05) as compared to patients with a day 3 or day 5 embryo transfer policy. No difference was observed in the fresh live birth rate and multiple pregnancy rate per initiated cycle (32.84% vs. 28.92%; 1.17% vs 0%) The projected cumulative ongoing pregnancy rate compensating for double counting in case subjects have more than one pregnancy is not different (42.58% vs. 39.84%). CONCLUSIONS: Despite lower fresh transfer rates, elective single blastocyst transfer yields a similar projected cumulative ongoing pregnancy rate as in a policy with cleavage stage or blastocyst transfer depending on a good quality embryo count on day 3. PMID- 21545715 TI - A novel technique of differential lung ventilation in the critical care setting. AB - BACKGROUND: Differential lung ventilation (DLV) is used to salvage ventilatory support in severe unilateral lung disease in the critical care setting. However, DLV with a double-lumen tube is associated with serious complications such as tube displacement during ventilatory management. Thus, long-term ventilatory management with this method may be associated with high risk of respiratory incidents in the critical care setting. FINDINGS: We devised a novel DLV technique using two single-lumen tubes and applied it to five patients, two with severe unilateral pneumonia and three with thoracic trauma, in a critical care setting. In this novel technique, we perform the usual tracheotomy and insert two single-lumen tubes under bronchoscopic guidance into the main bronchus of each lung. We tie the two single-lumen tubes together and suture them directly to the skin. The described technique was successfully performed in all five patients. Pulmonary oxygenation improved rapidly after DLV induction in all cases, and the three patients with thoracic trauma were managed by DLV without undergoing surgery. Tube displacement was not observed during DLV management. No airway complications occured in either the acute or late phase regardless of the length of DLV management (range 2-23 days). CONCLUSIONS: This novel DLV technique appears to be efficacious and safe in the critical care setting. PMID- 21545716 TI - The effects of linkage disequilibrium in large scale SNP datasets for MDR. AB - BACKGROUND: In the analysis of large-scale genomic datasets, an important consideration is the power of analytical methods to identify accurate predictive models of disease. When trying to assess sensitivity from such analytical methods, a confounding factor up to this point has been the presence of linkage disequilibrium (LD). In this study, we examined the effect of LD on the sensitivity of the Multifactor Dimensionality Reduction (MDR) software package. RESULTS: Four relative amounts of LD were simulated in multiple one- and two locus scenarios for which the position of the functional SNP(s) within LD blocks varied. Simulated data was analyzed with MDR to determine the sensitivity of the method in different contexts, where the sensitivity of the method was gauged as the number of times out of 100 that the method identifies the correct one- or two locus model as the best overall model. As the amount of LD increases, the sensitivity of MDR to detect the correct functional SNP drops but the sensitivity to detect the disease signal and find an indirect association increases. CONCLUSIONS: Higher levels of LD begin to confound the MDR algorithm and lead to a drop in sensitivity with respect to the identification of a direct association; it does not, however, affect the ability to detect indirect association. Careful examination of the solution models generated by MDR reveals that MDR can identify loci in the correct LD block; though it is not always the functional SNP. As such, the results of MDR analysis in datasets with LD should be carefully examined to consider the underlying LD structure of the dataset. PMID- 21545717 TI - Antibiotic resistance and molecular epidemiology of Staphylococcus aureus in Nigeria. AB - BACKGROUND: Staphylococcus aureus is an important pathogen causing a wide range of infections in the hospital and community setting. In order to have adequate information for treatment of S. aureus infections, it is crucial to understand the trends in the antibiotic-resistance patterns. In addition, the occurrence and changes in types of S. aureus, clonal identities, and their geographic spread is essential for the establishment of adequate infection control programmes. In this study, 68 S. aureus isolates obtained from clinical and non-clinical sources in Nigeria between January and April 2009 were characterized using phenotypic and molecular methods. RESULTS: All the S. aureus isolates were susceptible to teicoplanin, vancomycin, phosphomycin, fusidic acid, rifampicin, daptomycin, mupirocin, linezolid and tigecycline. Sixteen percent of the isolates were resistant to oxacillin, while 55% and 72% of isolates were resistant to tetracycline and trimethoprim/sulphamethoxazole (cotrimoxazole), respectively (Table 1). There was excellent correlation between the broth microdilution assay and detection of antibiotic resistance genes by the multiplex PCR, in the determination of S. aureus resistance to erythromycin, gentamicin, methicillin and tetracycline. A total of 28 spa types were identified in the study, and the predominant spa type among the methicillin-susceptible S. aureus (MSSA) isolates was t084 (13 isolates). The t037-ST241-SCCmecIII type was the only clone identified in Maiduguri (North-East Nigeria) while in South-West Nigeria, diversity among the MRSA isolates (t451-ST8-SCCmecV; t008-ST94-SCCmecIV; t002-ST5 SCCmecV; t064-ST8-SCCmecV) was observed. The toxin genes seh and etd were detected in isolates affiliated with clonal complexes CC1, CC80 and sequence type ST25, respectively. The proportion of PVL-positive isolates among MSSA was high (40%). Most of the PVL-positive MSSA isolates were obtained from wound infections and associated with clonal complexes CC1, CC30, CC121 and with sequence type ST152. CONCLUSIONS: The use of phenotypic and molecular methods provided useful information on antibiotic resistance and molecular diversity of S. aureus in Nigeria. The high proportion of PVL-positive MSSA isolates affiliated to various clonal complexes and detected in all the health institutions is a major concern, both as a source of severe infections and as a potential reservoir that could lead to the emergence of PVL-positive MRSA. This study presents the first baseline information on the nature of the antibiotic resistance genes from S. aureus isolates in Nigeria. There is the need to curtail the spread and establishment of MRSA and PVL-positive MSSA clones in Nigerian health care institutions. PMID- 21545718 TI - Efficacy of mesenchymal stem cells in suppression of hepatocarcinorigenesis in rats: possible role of Wnt signaling. AB - BACKGROUND: The present study was conducted to evaluate the tumor suppressive effects of bone marrow derived mesenchymal stem cells (MSCs) in an experimental hepatocellular carcinoma (HCC) model in rats and to investigate the possible role of Wnt signaling in hepato-carcinogenesis. METHODS: Ninety rats were included in the study and were divided equally into: Control group, rats which received MSCs only, rats which received MSCs vehicle only, HCC group induced by diethylnitroseamine (DENA) and CCl(4), rats which received MSCs after HCC induction, rats which received MSCs before HCC induction. Histopathological examination and gene expression of Wnt signaling target genes by real time, reverse transcription-polymerase chain reaction (RT-PCR) in rat liver tissue, in addition to serum levels of ALT, AST and alpha fetoprotein were performed in all groups. RESULTS: Histopathological examination of liver tissue from animals which received DENA-CCl(4) only, revealed the presence of anaplastic carcinoma cells and macro-regenerative nodules type II with foci of large and small cell dysplasia. Administration of MSCs into rats after induction of experimental HCC improved the histopathological picture which showed minimal liver cell damage, reversible changes, areas of cell drop out filled with stem cells. Gene expression in rat liver tissue demonstrated that MSCs downregulated beta-catenin, proliferating cell nuclear antigen (PCNA), cyclin D and survivin genes expression in liver tissues after HCC induction. Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels. Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect. CONCLUSIONS: Administration of MSCs in chemically induced HCC has tumor suppressive effects as evidenced by down regulation of Wnt signaling target genes concerned with antiapoptosis, mitogenesis, cell proliferation and cell cycle regulation, with subsequent amelioration of liver histopathological picture and liver function. PMID- 21545719 TI - Estimation of affinities of ligands in mixtures via magnetic recovery of target ligand complexes and chromatographic analyses: chemometrics and an experimental model. AB - BACKGROUND: The combinatorial library strategy of using multiple candidate ligands in mixtures as library members is ideal in terms of cost and efficiency, but needs special screening methods to estimate the affinities of candidate ligands in such mixtures. Herein, a new method to screen candidate ligands present in unknown molar quantities in mixtures was investigated. RESULTS: The proposed method involves preparing a processed-mixture-for-screening (PMFS) with each mixture sample and an exogenous reference ligand, initiating competitive binding among ligands from the PMFS to a target immobilized on magnetic particles, recovering target-ligand complexes in equilibrium by magnetic force, extracting and concentrating bound ligands, and analyzing ligands in the PMFS and the concentrated extract by chromatography. The relative affinity of each candidate ligand to its reference ligand is estimated via an approximation equation assuming (a) the candidate ligand and its reference ligand bind to the same site(s) on the target, (b) their chromatographic peak areas are over five times their intercepts of linear response but within their linear ranges, (c) their binding ratios are below 10%. These prerequisites are met by optimizing primarily the quantity of the target used and the PMFS composition ratio.The new method was tested using the competitive binding of biotin derivatives from mixtures to streptavidin immobilized on magnetic particles as a model. Each mixture sample containing a limited number of candidate biotin derivatives with moderate differences in their molar quantities were prepared via parallel combinatorial-synthesis (PCS) without purification, or via the pooling of individual compounds. Some purified biotin derivatives were used as reference ligands. This method showed resistance to variations in chromatographic quantification sensitivity and concentration ratios; optimized conditions to validate the approximation equation could be applied to different mixture samples. Relative affinities of candidate biotin derivatives with unknown molar quantities in each mixture sample were consistent with those estimated by a homogenous method using their purified counterparts as samples. CONCLUSIONS: This new method is robust and effective for each mixture possessing a limited number of candidate ligands whose molar quantities have moderate differences, and its integration with PCS has promise to routinely practice the mixture-based library strategy. PMID- 21545720 TI - Inference of gene regulatory networks from time series by Tsallis entropy. AB - BACKGROUND: The inference of gene regulatory networks (GRNs) from large-scale expression profiles is one of the most challenging problems of Systems Biology nowadays. Many techniques and models have been proposed for this task. However, it is not generally possible to recover the original topology with great accuracy, mainly due to the short time series data in face of the high complexity of the networks and the intrinsic noise of the expression measurements. In order to improve the accuracy of GRNs inference methods based on entropy (mutual information), a new criterion function is here proposed. RESULTS: In this paper we introduce the use of generalized entropy proposed by Tsallis, for the inference of GRNs from time series expression profiles. The inference process is based on a feature selection approach and the conditional entropy is applied as criterion function. In order to assess the proposed methodology, the algorithm is applied to recover the network topology from temporal expressions generated by an artificial gene network (AGN) model as well as from the DREAM challenge. The adopted AGN is based on theoretical models of complex networks and its gene transference function is obtained from random drawing on the set of possible Boolean functions, thus creating its dynamics. On the other hand, DREAM time series data presents variation of network size and its topologies are based on real networks. The dynamics are generated by continuous differential equations with noise and perturbation. By adopting both data sources, it is possible to estimate the average quality of the inference with respect to different network topologies, transfer functions and network sizes. CONCLUSIONS: A remarkable improvement of accuracy was observed in the experimental results by reducing the number of false connections in the inferred topology by the non-Shannon entropy. The obtained best free parameter of the Tsallis entropy was on average in the range 2.5 <= q <= 3.5 (hence, subextensive entropy), which opens new perspectives for GRNs inference methods based on information theory and for investigation of the nonextensivity of such networks. The inference algorithm and criterion function proposed here were implemented and included in the DimReduction software, which is freely available at http://sourceforge.net/projects/dimreduction and http://code.google.com/p/dimreduction/. PMID- 21545721 TI - GenDrux: a biomedical literature search system to identify gene expression-based drug sensitivity in breast cancer. AB - BACKGROUND: This paper describes the development of a web-based tool, GenDrux, which extracts and presents (over the Internet) information related to the disease-gene-drug nexus. This information is archived from the relevant biomedical literature using automated methods. GenDrux is designed to alleviate the difficulties of manually processing the vast biomedical literature to identify disease-gene-drug relationships. GenDrux will evolve with the literature without additional algorithmic modifications. RESULTS: GenDrux, a pilot system, is developed in the domain of breast cancer and can be accessed at http://www.microarray.uab.edu/drug_gene.pl. GenDrux can be queried based on drug, gene and/or disease name. From over 8,000 relevant abstracts from the biomedical literature related to breast cancer, we have archived a corpus of more than 4,000 articles that depict gene expression-drug activity relationships for breast cancer and related cancers. The archiving process has been automated. CONCLUSIONS: The successful development, implementation, and evaluation of this and similar systems when created may provide clinicians with a tool for literature management, clinical decision making, thus setting the platform for personalized therapy in the future. PMID- 21545722 TI - Socioeconomic status and the incidence of non-central nervous system childhood embryonic tumours in Brazil. AB - BACKGROUND: Childhood cancer differs from most common adult cancers, suggesting a distinct aetiology for some types of childhood cancer. Our objective in this study was to test the difference in incidence rates of 4 non-CNS embryonic tumours and their correlation with socioeconomic status (SES) in Brazil. METHODS: Data was obtained from 13 Brazilian population-based cancer registries (PBCRs) of neuroblastoma (NB), Wilms'tumour (WT), retinoblastoma (RB), and hepatoblastoma (HB). Incidence rates by tumour type, age, and gender were calculated per one million children. Correlations between social exclusion index (SEI) as an indicator of socioeconomic status (SES) and incidence rates was investigated using the Spearman's test. RESULTS: WT, RB, and HB presented with the highest age adjusted incidence rates (AAIRs) in 1 to 4 year old of both genders, whereas NB presented the highest AAIR in <=11 month-olds. However, differences in the incidence rates among PBCRs were observed. Higher incidence rates were found for WT and RB, whereas lower incidence rates were observed for NB. Higher SEI was correlated with higher incidences of NB (0.731; p = 0.0117), whereas no SEI correlation was observed between incidence rates for WT, RB, and HB. In two Brazilian cities, the incidence rates of NB and RB were directly correlated with SEI; NB had the highest incidence rates (14.2, 95% CI, 8.6-19.7), and RB the lowest (3.5, 95% CI, 0.7-6.3) in Curitiba (SEI, 0.730). In Natal (SEI, 0.595), we observed just the opposite; the highest incidence rate was for RB and the lowest was for NB (4.6, 95% CI, 0.1-9.1). CONCLUSION: Regional variations of SES and the incidence of embryonal tumours were observed, particularly incidence rates for NB and RB. Further studies are necessary to investigate risk factors for embryonic tumours in Brazil. PMID- 21545723 TI - Arbuscular mycorrhizal symbiosis elicits shoot proteome changes that are modified during cadmium stress alleviation in Medicago truncatula. AB - BACKGROUND: Arbuscular mycorrhizal (AM) fungi, which engage a mutualistic symbiosis with the roots of most plant species, have received much attention for their ability to alleviate heavy metal stress in plants, including cadmium (Cd). While the molecular bases of Cd tolerance displayed by mycorrhizal plants have been extensively analysed in roots, very little is known regarding the mechanisms by which legume aboveground organs can escape metal toxicity upon AM symbiosis. As a model system to address this question, we used Glomus irregulare-colonised Medicago truncatula plants, which were previously shown to accumulate and tolerate heavy metal in their shoots when grown in a substrate spiked with 2 mg Cd kg(-1). RESULTS: The measurement of three indicators for metal phytoextraction showed that shoots of mycorrhizal M. truncatula plants have a capacity for extracting Cd that is not related to an increase in root-to-shoot translocation rate, but to a high level of allocation plasticity. When analysing the photosynthetic performance in metal-treated mycorrhizal plants relative to those only Cd-supplied, it turned out that the presence of G. irregulare partially alleviated the negative effects of Cd on photosynthesis. To test the mechanisms by which shoots of Cd-treated mycorrhizal plants avoid metal toxicity, we performed a 2-DE/MALDI/TOF-based comparative proteomic analysis of the M. truncatula shoot responses upon mycorrhization and Cd exposure. Whereas the metal responsive shoot proteins currently identified in non-mycorrhizal M. truncatula indicated that Cd impaired CO2 assimilation, the mycorrhiza-responsive shoot proteome was characterised by an increase in photosynthesis-related proteins coupled to a reduction in glugoneogenesis/glycolysis and antioxidant processes. By contrast, Cd was found to trigger the opposite response coupled the up accumulation of molecular chaperones in shoot of mycorrhizal plants relative to those metal-free. CONCLUSION: Besides drawing a first picture of shoot proteome modifications upon AM symbiosis and/or heavy metal stress in legume plants, the current work argues for allocation plasticity as the main driving force for Cd extraction in aboveground tissues of M. truncatula upon mycorrhization. Additionally, according to the retrieved proteomic data, we propose that shoots of mycorrhizal legume plants escape Cd toxicity through a metabolic shift implying the glycolysis-mediated mobilization of defence mechanisms at the expense of the photosynthesis-dependent symbiotic sucrose sink. PMID- 21545724 TI - Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder. AB - BACKGROUND: Serotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD). Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4) have been shown to modulate amygdala and prefrontal cortex (PFC) activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD but genetic factors influencing these activations have yet to be examined. METHODS: We investigated whether SLC6A4 promoter polymorphisms (5-HTTLPR, rs25531) and several downstream single nucleotide polymorphisms (SNPs) modulated activity of brain regions involved in the cognitive control of emotion in post-9/11 veterans with PTSD. We used functional MRI to examine neural activity in a PTSD group (n = 22) and a trauma exposed control group (n = 20) in response to trauma-related images presented as task-irrelevant distractors during the active maintenance period of a delayed response working memory task. Regions of interest were derived by contrasting activation for the most distracting and least distracting conditions across participants. RESULTS: In patients with PTSD, when compared to trauma-exposed controls, rs16965628 (associated with serotonin transporter gene expression) modulated task-related ventrolateral PFC activation and 5-HTTLPR tended to modulate left amygdala activation. Subsequent to combat-related trauma, these SLC6A4 polymorphisms may bias serotonin signaling and the neural circuitry mediating cognitive control of emotion in patients with PTSD. CONCLUSIONS: The SLC6A4 SNP rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD. Functional MRI may help identify intermediate phenotypes and dimensions of PTSD that clarify the functional link between genes and disease phenotype, and also highlight features of PTSD that show more proximal influence of susceptibility genes compared to current clinical categorizations. PMID- 21545725 TI - Adipose-derived mesenchymal stem cell protects kidneys against ischemia reperfusion injury through suppressing oxidative stress and inflammatory reaction. AB - BACKGROUND: Reactive oxygen species are important mediators exerting toxic effects on various organs during ischemia-reperfusion (IR) injury. We hypothesized that adipose-derived mesenchymal stem cells (ADMSCs) protect the kidney against oxidative stress and inflammatory stimuli in rat during renal IR injury. METHODS: Adult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus immediate intra-renal administration of 1.0 * 106 autologous ADMSCs, followed by intravenous ADMSCs at 6 h and 24 h after IR). The duration of ischemia was 1 h, followed by 72 hours of reperfusion before the animals were sacrificed. RESULTS: Serum creatinine and blood urea nitrogen levels and the degree of histological abnormalities were markedly lower in group 3 than in group 2 (all p < 0.03). The mRNA expressions of inflammatory, oxidative stress, and apoptotic biomarkers were lower, whereas the anti-inflammatory, anti-oxidative, and anti-apoptotic biomarkers were higher in group 3 than in group 2 (all p < 0.03). Immunofluorescent staining showed a higher number of CD31+, von Willebrand Factor+, and heme oxygenase (HO)-1+ cells in group 3 than in group 2 (all p < 0.05). Western blot showed notably higher NAD(P)H quinone oxidoreductase 1 and HO 1 activities, two indicators of anti-oxidative capacity, in group 3 than those in group 2 (all p < 0.04). Immunohistochemical staining showed higher glutathione peroxidase and glutathione reductase activities in group 3 than in group 2 (all p < 0.02) CONCLUSION: ADMSC therapy minimized kidney damage after IR injury through suppressing oxidative stress and inflammatory response. PMID- 21545726 TI - Causes and 3-year-incidence of blindness in Jing-An District, Shanghai, China 2001-2009. AB - BACKGROUND: Registered data can provide valuable information regarding blindness. The purpose of this study was to evaluate the main causes and 3-year incidence of registered blindness in Jing-An district in Shanghai, China. METHODS: Data from the blindness registry (age, gender and cause of visual disability) were collected and analyzed. The prevalence of blindness for 2003, 2007, 2009 and the 3-year incidence of blindness were calculated. RESULTS: The reported blindness increased significantly from 113.7 per 100,000 in 2003 to 145.8 per 100,000 in 2006 to 165.9 per 100,000 in 2009 (P < 0.05, P < 0.05, respectively). Age significantly affects prevalence; the odd ratios (OR) were 2.57 in the 30 y - 49 y range (P < 0.001), 7.27 in the 50 y - 69 y range (P < 0.001) and 21.2 in the >= 70 y (P < 0.001). The 3-year incidence increased from 32.3 per 100,000 in 2001 2003 to 34.2 per 100,000 in 2004-2006 to 40.8 per 100,000 in 2007-2009. The causes of new blindness registered in 2001-2009 were myopic macular degeneration (19.4%), followed by glaucoma (17.7%), age-related macular degeneration (11.8%), optical nerve atrophy (9.4%), retinitis pigmentosa (8.6%), diabetic retinopathy (7.8%) and corneal opacity (5.8%). CONCLUSIONS: The 3-year incidence and prevalence of registered blindness increased in the past 9 years. The leading causes of new blindness were myopic macular degeneration, glaucoma and age related macular degeneration. The pattern of causes has changed little in the past 9 years and is different from other locations in China. The pattern is similar to that of Taiwan, Hongkong, and Western countries. PMID- 21545727 TI - Emergency percutaneous needle decompression for tension pneumoperitoneum. AB - BACKGROUND: Tension pneumoperitoneum as a complication of iatrogenic bowel perforation during endoscopy is a dramatic condition in which intraperitoneal air under pressure causes hemodynamic and ventilatory compromise. Like tension pneumothorax, urgent intervention is required. Immediate surgical decompression though is not always possible due to the limitations of the preclinical management and sometimes to capacity constraints of medical staff and equipment in the clinic. METHODS: This is a retrospective analysis of cases of pneumoperitoneum and tension pneumoperitoneum due to iatrogenic bowel perforation. All patients admitted to our surgical department between January 2005 and October 2010 were included. Tension pneumoperitoneum was diagnosed in those patients presenting signs of hemodynamic and ventilatory compromise in addition to abdominal distension. RESULTS: Between January 2005 and October 2010 eleven patients with iatrogenic bowel perforation were admitted to our surgical department. The mean time between perforation and admission was 36 +/- 14 hrs (range 30 min - 130 hrs), between ER admission and begin of the operation 3 hrs and 15 min +/- 47 min (range 60 min - 9 hrs). Three out of eleven patients had clinical signs of tension pneumoperitoneum. In those patients emergency percutaneous needle decompression was performed with a 16G venous catheter. This improved significantly the patients' condition (stabilization of vital signs, reducing jugular vein congestion), bridging the time to the start of the operation. CONCLUSIONS: Hemodynamical and respiratory compromise in addition to abdominal distension shortly after endoscopy are strongly suggestive of tension pneumoperitoneum due to iatrogenic bowel perforation. This is a rare but life threatening condition and it can be managed in a preclinical and clinical setting with emergency percutaneous needle decompression like tension pneumothorax. Emergency percutaneous decompression is no definitive treatment, only a method to bridge the time gap to definitive surgical repair. PMID- 21545728 TI - Transcriptional robustness and protein interactions are associated in yeast. AB - BACKGROUND: Robustness to insults, both external and internal, is a characteristic feature of life. One level of biological organization for which noise and robustness have been extensively studied is gene expression. Cells have a variety of mechanisms for buffering noise in gene expression, but it is not completely clear what rules govern whether or not a given gene uses such tools to maintain appropriate expression. RESULTS: Here, we show a general association between the degree to which yeast cells have evolved mechanisms to buffer changes in gene expression and whether they possess protein-protein interactions. We argue that this effect bears an affinity to epistasis, because yeast appears to have evolved regulatory mechanisms such that distant changes in gene copy number for a protein-protein interaction partner gene can alter a gene's expression. This association is not unexpected given recent work linking epistasis and the deleterious effects of changes in gene dosage (i.e., the dosage balance hypothesis). Using gene expression data from artificial aneuploid strains of bakers' yeast, we found that genes coding for proteins that physically interact with other proteins show less expression variation in response to aneuploidy than do other genes. This effect is even more pronounced for genes whose products interact with proteins encoded on aneuploid chromosomes. We further found that genes targeted by transcription factors encoded on aneuploid chromosomes were more likely to change in expression after aneuploidy. CONCLUSIONS: We suggest that these observations can be best understood as resulting from the higher fitness cost of misexpression in epistatic genes and a commensurate greater regulatory control of them. PMID- 21545729 TI - Inorganic base-catalyzed formation of antivirally active N-substituted benzamides from alpha-amido sulfones and N-nucleophile. AB - BACKGROUND: Heteronucleophiles as well as carbanionic reagents can be used to react with alpha-amido sulfones, thus giving the opportunity to prepare a large array of amino derivatives. Since, novel 1,3,4-oxadiazole-2-thiol derivatives can serve as potent nucleophiles, we employed 5-subsititued phenyl-1,3,4-oxadiazole-2 thiols as the nucleophilic source of nitrogen in the reaction with alpha-amido sulfones. RESULTS: A series of N-substituted benzamides bearing 1,3,4-oxadiazol unit were prepared for the first time by the reaction of in situ generated protected imine from alpha-amido sulfones with 5-subsititued phenyl-1,3,4 oxadiazole-2-thiols as the source of nitrogen nucleophile. Some of the synthesized products displayed favourable antiviral activity against cucumber mosaic virus (CMV) in preliminary antiviral activity tests. The title compounds 5c, 5o and 5r revealed curative activity of 42.2%, 48.7% and 40.5%, respectively against CMV (inhibitory rate) compared to the commercial standard Ningnanmycin (53.4%) at 500 MUg/mL. CONCLUSION: A practical synthetic route to N-benzoyl-alpha amido sulfones by the reaction of 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the source of nitrogen nucleophiles with in situ generated protected imine from N-benzoyl-alpha-amido sulfones is presented. The reaction catalyzed by an inorganic base has considerable significance to exploit the potential of alpha amido sulfones in organic synthesis. PMID- 21545730 TI - Biofilm formation and adherence characteristics of an Elizabethkingia meningoseptica isolate from Oreochromis mossambicus. AB - BACKGROUND: Elizabethkingia spp. are opportunistic pathogens often found associated with intravascular device-related bacteraemias and ventilator associated pneumonia. Their ability to exist as biofilm structures has been alluded to but not extensively investigated. METHODS: The ability of Elizabethkingia meningoseptica isolate CH2B from freshwater tilapia (Oreochromis mossambicus) and E. meningoseptica strain NCTC 10016(T) to adhere to abiotic surfaces was investigated using microtiter plate adherence assays following exposure to varying physico-chemical challenges. The role of cell-surface properties was investigated using hydrophobicity (bacterial adherence to hydrocarbons), autoaggregation and coaggregation assays. The role of extracellular components in adherence was determined using reversal or inhibition of coaggregation assays in conjunction with Listeria spp. isolates, while the role of cell-free supernatants, from diverse bacteria, in inducing enhanced adherence was investigated using microtitre plate assays. Biofilm architecture of isolate CH2B alone as well as in co-culture with Listeria monocytogenes was investigated using flow cells and microscopy. RESULTS: E. meningoseptica isolates CH2B and NCTC 10016(T) demonstrated stronger biofilm formation in nutrient-rich medium compared to nutrient-poor medium at both 21 and 37 degrees C, respectively. Both isolates displayed a hydrophilic cell surface following the bacterial adherence to xylene assay. Varying autoaggregation and coaggregation indices were observed for the E. meningoseptica isolates. Coaggregation by isolate CH2B appeared to be strongest with foodborne pathogens like Enterococcus, Staphylococcus and Listeria spp. Partial inhibition of coaggregation was observed when isolate CH2B was treated with heat or protease exposure, suggesting the presence of heat-sensitive adhesins, although sugar treatment resulted in increased coaggregation and may be associated with a lactose-associated lectin or capsule-mediated attachment. CONCLUSIONS: E. meningoseptica isolate CH2B and strain NCTC 10016(T) displayed a strong biofilm-forming phenotype which may play a role in its potential pathogenicity in both clinical and aquaculture environments. The ability of E. meningoseptica isolates to adhere to abiotic surfaces and form biofilm structures may result from the hydrophilic cell surface and multiple adhesins located around the cell. PMID- 21545731 TI - Positional effect of phosphorylation sites 266 and 267 in the cytoplasmic domain of the E2 protein of hepatitis C virus 3a genotype: interferon resistance analysis via sequence alignment. AB - BACKGROUND: Interferon is well thought-out as the key defence against all infections including HCV. The only treatment for HCV infection is pegylated interferon alpha (IFN-alpha) but unluckily more than half of the infected individuals do not act in response to the cure and become chronic HCV carriers. The mechanism how HCV induce interferon resistance is still elusive. It is recently reported that HCV envelope protein 2 interacts with PKR which is the interferon-inducible protein kinase and which in turn blocks the activity of its target molecule called eukaryotic initiation factor elF2. Sequence analysis of Envelope protein reveals it contains a domain homologous to phosphorylation sites of PKR andthe translation initiation factor eIF2alpha. Envelope protein competes for phosphorylation with PKR. Inhibition of kinase activity of PKR is postulated as a mechanism of to interferon (IFN) resistance. RESULTS: Present study involves the insilico investigation of possible role of potential phosphorylation in envelope 2 protein of 3a genotype in interferon resistance. Envelope protein coding genes were isolated from local HCV isolates, cloned and sequenced. Phylogenetic analysis was done and tertiary structure of envelope gene was predicted. Visualization of phosphorylation in tertiary structure reveals that residue 266 and 267 of envelope gene 2 are surface exposed and their phosphorylation may compete with the phosphorylation of PKR protein and possibly involved in mediating Interferon Resistance. CONCLUSION: A hybrid in-silico and wet laboratory approach of motif prediction, evolutionary and structural analysis has pointed out serine 266 and 267 of the HCV E2 gene as a hopeful claimant for the serine phosphorylation. Recognition of these nucleotide variations may assist to propose genotype precise therapy to avoid and resolve HCV infections. PMID- 21545732 TI - Stanniocalcin 2 alters PERK signalling and reduces cellular injury during cerulein induced pancreatitis in mice. AB - BACKGROUND: Stanniocalcin 2 (STC2) is a secreted protein activated by (PKR)-like Endoplasmic Reticulum Kinase (PERK) signalling under conditions of ER stress in vitro. Over-expression of STC2 in mice leads to a growth-restricted phenotype; however, the physiological function for STC2 has remained elusive. Given the relationship of STC2 to PERK signalling, the objective of this study was to examine the role of STC2 in PERK signalling in vivo. RESULTS: Since PERK signalling has both physiological and pathological roles in the pancreas, STC2 expression was assessed in mouse pancreata before and after induction of injury using a cerulein-induced pancreatitis (CIP) model. Increased Stc2 expression was identified within four hours of initiating pancreatic injury and correlated to increased activation of PERK signalling. To determine the effect of STC2 over expression on PERK, mice systemically expressing human STC2 (STC2Tg) were examined. STC2Tg pancreatic tissue exhibited normal pancreatic morphology, but altered activation of PERK signalling, including increases in Activating Transcription Factor (ATF) 4 accumulation and autophagy. Upon induction of pancreatic injury, STC2Tg mice exhibited limited increases in circulating amylase levels and increased maintenance of cellular junctions. CONCLUSIONS: This study links STC2 to the pathological activation of PERK in vivo, and suggests involvement of STC2 in responding to pancreatic acinar cell injury. PMID- 21545733 TI - Patients visiting the complementary medicine clinic for pain: a cross sectional study. AB - BACKGROUND: Pain is one of the most common reasons for seeking medical care. The purpose of this study was to characterize patients visiting the complementary medicine clinic for a pain complaint. METHODS: This is a cross-sectional study. The study took place at Clalit Health Services (CHS) complementary clinic in Beer Sheva, Israel. Patients visiting the complementary clinic, aged 18 years old and older, Hebrew speakers, with a main complaint of pain were included. Patients were recruited consecutively on random days of the month during a period of six months. Main outcome measures were: pain levels, location of pain, and interference with daily activities. Once informed consent was signed patients were interviewed using a structured questionnaire by a qualified nurse. The questionnaire included socio-demographic data, and the Brief Pain Inventory (BPI). RESULTS: Three-hundred and ninety-five patients were seen at the complementary medicine clinic during the study period, 201 (50.8%) of them met the inclusion criteria. Of them, 163 (81.1%) agreed to participate in the study and were interviewed. Pain complaints included: 69 patients (46.6%) with back pain, 65 (43.9%) knee pain, and 28 (32.4%) other limbs pain. Eighty-two patients (50.3%) treated their pain with complementary medicine as a supplement for their conventional treatment, and 55 (33.7%) felt disappointed from the conventional medicine experience. Eighty-three patients (50.9%) claimed that complementary medicine can result in better physical strength, or better mental state 51 (31.3%). Thirty-seven patients (22.7%) were hoping that complementary medicine will prevent invasive procedures. CONCLUSION: Given the high proportion of patients with unsatisfactory pain relief using complementary and alternative medicine (CAM), general practitioners should gain knowledge about CAM and CAM providers should gain training in pain topics to improve communication and counsel patients. More clinical research to evaluate safety and efficiency of CAM for pain is needed to provide evidence based counseling. PMID- 21545734 TI - Characterization of age-related gene expression profiling in bone marrow and epididymal adipocytes. AB - BACKGROUND: While an increase in bone marrow adiposity is associated with age related bone disease, the function of bone marrow adipocytes has not been studied. The aim of this study was to characterize and compare the age-related gene expression profiles in bone marrow adipocytes and epididymal adipocytes. RESULTS: A total of 3918 (13.7%) genes were differentially expressed in bone marrow adipocytes compared to epididymal adipocytes. Bone marrow adipocytes revealed a distinct gene profile with low expression of adipocyte-specific genes peroxisome proliferator-activated receptor gamma (PPARgamma), fatty acid binding protein 4 (FABP4), perilipin (Plin1), adipsin (CFD) and high expression of genes associated with early adipocyte differentiation (CCAAT/enhancer binding protein beta (C/EBPbeta), regulator of G-protein signaling 2 (RGS2). In addition, a number of genes including secreted frizzled related protein 4 (SFRP4), tumor necrosis factor alpha (TNFalpha), transforming growth factor beta 1(TGFbeta1), G protein coupled receptor 109A (GPR109A) and interleukin 6 (IL-6), that could affect adipose-derived signaling to bone are markedly increased in bone marrow adipocytes. Age had a substantial effect on genes associated with mitochondria function and inflammation in bone marrow adipocytes. Twenty seven genes were significantly changed with age in both adipocyte depots. Among these genes, IL6 and GPR109A were significantly reduced with age in both adipocyte depots. CONCLUSIONS: Overall, gene profiling reveals a unique phenotype for primary bone marrow adipocytes characterized by low adipose-specific gene expression and high expression of inflammatory response genes. Bone marrow and epididymal adipocytes share a common pathway in response to aging in mice, but age has a greater impact on global gene expression in epididymal than in bone marrow adipocytes. Genes that are differentially expressed at greater levels in the bone marrow are highly regulated with age. PMID- 21545735 TI - Collapse-to-emergency medical service cardiopulmonary resuscitation interval and outcomes of out-of-hospital cardiopulmonary arrest: a nationwide observational study. AB - INTRODUCTION: The relationship between collapse to emergency medical service (EMS) cardiopulmonary resuscitation (CPR) interval and outcome has been well documented. However, most studies have only analyzed cases of cardiac origin and Vf (ventricular fibrillation)/pulseless VT (ventricular tachycardia). We sought to examine all causes of cardiac arrest and analyze the relationship between collapse-to-EMS CPR interval and outcome in a nationwide sample using an out-of hospital cardiac arrest (OHCA) registry. METHODS: This was a retrospective observational study based on a nationwide OHCA patient registry in Japan between 2005 and 2008 (n = 431,968). We included cases where collapse was witnessed by a bystander and where collapse and intervention time were recorded (n = 109,350). Data were collected based on the Utstein template. One-month survival and neurologically favorable one-month survival were used as outcome measures. Logarithmic regression and logistic regression were used to examine the relation between outcomes and collapse-to-EMS CPR interval. RESULTS: Among collapse-to-EMS CPR intervals between 3 and 30 minutes, the logarithmic regression equation for the relationship with one-month survival was y = -0.059 ln(x) + 0.21, while that for the relationship with neurologically favorable one-month survival was y = 0.041 ln(x) + 0.13. After adjusting for potential confounders in the logistic regression analysis for all intervals, longer collapse-to-EMS CPR intervals were associated with lower rates of one-month survival (odds ratio (OR) 0.93, 95% confidence interval (CI): 0.93 to 0.93) and neurologically favorable one-month survival (OR 0.89, 95% CI 0.89 to 0.90). CONCLUSIONS: Improving the emergency medical system and CPR in cases of OHCA is important for improving the outcomes of OHCA. PMID- 21545736 TI - Recombinant expression and functional analysis of proteases from Streptococcus pneumoniae, Bacillus anthracis, and Yersinia pestis. AB - BACKGROUND: Uncharacterized proteases naturally expressed by bacterial pathogens represents important topic in infectious disease research, because these enzymes may have critical roles in pathogenicity and cell physiology. It has been observed that cloning, expression and purification of proteases often fail due to their catalytic functions which, in turn, cause toxicity in the E. coli heterologous host. RESULTS: In order to address this problem systematically, a modified pipeline of our high-throughput protein expression and purification platform was developed. This included the use of a specific E. coli strain, BL21(DE3) pLysS to tightly control the expression of recombinant proteins and various expression vectors encoding fusion proteins to enhance recombinant protein solubility. Proteases fused to large fusion protein domains, maltosebinding protein (MBP), SP-MBP which contains signal peptide at the N terminus of MBP, disulfide oxidoreductase (DsbA) and Glutathione S-transferase (GST) improved expression and solubility of proteases. Overall, 86.1% of selected protease genes including hypothetical proteins were expressed and purified using a combination of five different expression vectors. To detect novel proteolytic activities, zymography and fluorescence-based assays were performed and the protease activities of more than 46% of purified proteases and 40% of hypothetical proteins that were predicted to be proteases were confirmed. CONCLUSIONS: Multiple expression vectors, employing distinct fusion tags in a high throughput pipeline increased overall success rates in expression, solubility and purification of proteases. The combinatorial functional analysis of the purified proteases using fluorescence assays and zymography confirmed their function. PMID- 21545737 TI - Chloroquine resistant vivax malaria in a pregnant woman on the western border of Thailand. AB - Chloroquine (CQ) resistant vivax malaria is spreading. In this case, Plasmodium vivax infections during pregnancy and in the postpartum period were not satisfactorily cleared by CQ, despite adequate drug concentrations. A growth restricted infant was delivered. Poor susceptibility to CQ was confirmed in-vitro and molecular genotyping was strongly suggestive of true recrudescence of P. vivax. This is the first clinically and laboratory confirmed case of two high grade CQ resistant vivax parasite strains from Thailand. PMID- 21545738 TI - Mycobacterial infections in a large Virginia hospital, 2001-2009. AB - BACKGROUND: In areas where both tuberculosis (TB) and nontuberculous mycobacteria (NTM) are prevalent, descriptive studies of the clinical features of individual mycobacteria are needed to inform clinical triage. METHODS: We queried the University of Virginia Clinical Data Repository for all mycobacterial infections from 2001-2009. RESULTS: Of 494 mycobacterial infections in 467 patients there were 22 species. Patients with pulmonary Tb were more likely to be reported as immigrants (p < 0.001) and less likely to have a predisposing risk factor for NTM (pre-existing lung disease or host predisposition; p = 0.002). Review of chest CT scans revealed that TB infection was more likely to exhibit cavities and pleural effusion than NTM infection (p < 0.05). Among NTM infections M. kansasii, M. xenopi, and M. fortuitum were more likely than MAC to have cavities. There were at least 83 patients that met criteria for NTM lung disease and these were caused by 9 species. M. abscessus infection was associated with cystic fibrosis and M. xenopi infection was associated with male gender. CONCLUSIONS: In our center mycobacterial infections were common and of diverse species. Immigrant status, cavities, and effusion were associated with TB vs. NTM. PMID- 21545739 TI - SNPs and real-time quantitative PCR method for constitutional allelic copy number determination, the VPREB1 marker case. AB - BACKGROUND: 22q11.2 microdeletion is responsible for the DiGeorge Syndrome, characterized by heart defects, psychiatric disorders, endocrine and immune alterations and a 1 in 4000 live birth prevalence. Real-time quantitative PCR (qPCR) approaches for allelic copy number determination have recently been investigated in 22q11.2 microdeletions detection. The qPCR method was performed for 22q11.2 microdeletions detection as a first-level screening approach in a genetically unknown series of patients with congenital heart defects. A technical issue related to the VPREB1 qPCR marker was pointed out. METHODS: A set of 100 unrelated Italian patients with congenital heart defects were tested for 22q11.2 microdeletions by a qPCR method using six different markers. Fluorescence In Situ Hybridization technique (FISH) was used for confirmation. RESULTS: qPCR identified six patients harbouring the 22q11.2 microdeletion, confirmed by FISH. The VPREB1 gene marker presented with a pattern consistent with hemideletion in one 3 Mb deleted patient, suggestive for a long distal deletion, and in additional five non-deleted patients. The long distal 22q11.2 deletion was not confirmed by Comparative Genomic Hybridization. Indeed, the VPREB1 gene marker generated false positive results in association with the rs1320 G/A SNP, a polymorphism localized within the VPREB1 marker reverse primer sequence. Patients heterozygous for rs1320 SNP, showed a qPCR profile consistent with the presence of a hemideletion. CONCLUSIONS: Though the qPCR technique showed advantages as a screening approach in terms of cost and time, the VPREB1 marker case revealed that single nucleotide polymorphisms can interfere with qPCR data generating erroneous allelic copy number interpretations. PMID- 21545740 TI - Deceased donor neutrophil gelatinase-associated lipocalin and delayed graft function after kidney transplantation: a prospective study. AB - INTRODUCTION: Expanding the criteria for deceased organ donors increases the risk of delayed graft function (DGF) and complicates kidney transplant outcome. We studied whether donor neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker for acute kidney injury, could predict DGF after transplantation. METHODS: We included 99 consecutive, deceased donors and their 176 kidney recipients. For NGAL detection, donor serum and urine samples were collected before the donor operation. The samples were analyzed using a commercial enzyme linked immunosorbent assay kit (serum) and the ARCHITECT method (urine). RESULTS: Mean donor serum NGAL (S-NGAL) concentration was 218 ng/mL (range 27 to 658, standard deviation (SD) 145.1) and mean donor urine NGAL (U-NGAL) concentration was 18 ng/mL (range 0 to 177, SD 27.1). Donor S-NGAL and U-NGAL concentrations correlated directly with donor plasma creatinine levels and indirectly with estimated glomerular filtration rate (eGFR) calculated using the modification of diet in renal disease equation for glomerular filtration rate. In transplantations with high (greater than the mean) donor U-NGAL concentrations, prolonged DGF lasting longer than 14 days occurred more often than in transplantations with low (less than the mean) U-NGAL concentration (23% vs. 11%, P = 0.028), and 1-year graft survival was worse (90.3% vs. 97.4%, P = 0.048). High U-NGAL concentration was also associated with significantly more histological changes in the donor kidney biopsies than the low U-NGAL concentration. In a multivariate analysis, U-NGAL, expanded criteria donor status and eGFR emerged as independent risk factors for prolonged DGF. U-NGAL concentration failed to predict DGF on the basis of receiver operating characteristic curve analysis. CONCLUSIONS: This first report on S-NGAL and U NGAL levels in deceased donors shows that donor U-NGAL, but not donor S-NGAL, measurements give added value when evaluating the suitability of a potential deceased kidney donor. PMID- 21545741 TI - Inpatient hospital complications and lengths of stay: a short report. AB - BACKGROUND: Increasingly, efforts are being made to link health care outcomes with more efficient use of resources. The current difficult economic times and health care reform efforts provide incentives for specific efforts in this area. FINDINGS: This study defined relationships between inpatient complications for urinary tract infection and pneumonia and hospital lengths of stay in three general hospitals in the metropolitan area of Syracuse, New York. It employed the Potentially Preventable Complications (PPC) software developed by 3MTM Health Information Services to identify lengths of stay for patients with and without urinary tract infection and pneumonia. The patient populations included individuals assigned to the same All Patients Refined Diagnosis Related Groups and severity of illness. The comparisons involved two nine month periods in 2008 and 2009.The study demonstrated that patients who experienced the complications had substantially longer inpatient hospital stays than those who did not. Patients with a PPC of urinary tract infection stayed a mean of 8.9 - 11.9 days or 161 - 216 percent longer than those who did not for the two time periods. This increased stay produced 2,020 - 2,427 additional patient days.The study demonstrated that patients who experienced the complications had substantially longer inpatient hospital stays than those who did not. Patients with a PPC of pneumonia stayed a mean of 13.0 - 16.3 days or 232 - 281 percent longer than those who did not for the two time periods. This increased stay produced 2,626 - 3,456 additional patient days. Similar differences were generated for median lengths of stay. CONCLUSIONS: The differences in hospital stays for patients in the same APR DRGs and severity of illness with and without urinary tract infection and pneumonia in the Syracuse hospitals were substantial. The additional utilization for these complications was valued at between $2,000,000 - $3,000,000 for a three month period. These differences in the use of hospital resources have important implications for reduction of health care costs among providers and payors of care. PMID- 21545743 TI - A computational model of the hypothalamic: pituitary: gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17alpha-ethynylestradiol and 17beta-trenbolone. AB - BACKGROUND: Endocrine disrupting chemicals (e.g., estrogens, androgens and their mimics) are known to affect reproduction in fish. 17alpha-ethynylestradiol is a synthetic estrogen used in birth control pills. 17beta-trenbolone is a relatively stable metabolite of trenbolone acetate, a synthetic androgen used as a growth promoter in livestock. Both 17alpha-ethynylestradiol and 17beta-trenbolone have been found in the aquatic environment and affect fish reproduction. In this study, we developed a physiologically-based computational model for female fathead minnows (FHM, Pimephales promelas), a small fish species used in ecotoxicology, to simulate how estrogens (i.e., 17alpha-ethynylestradiol) or androgens (i.e., 17beta-trenbolone) affect reproductive endpoints such as plasma concentrations of steroid hormones (e.g., 17beta-estradiol and testosterone) and vitellogenin (a precursor to egg yolk proteins). RESULTS: Using Markov Chain Monte Carlo simulations, the model was calibrated with data from unexposed, 17alpha-ethynylestradiol-exposed, and 17beta-trenbolone-exposed FHMs. Four Markov chains were simulated, and the chains for each calibrated model parameter (26 in total) converged within 20,000 iterations. With the converged parameter values, we evaluated the model's predictive ability by simulating a variety of independent experimental data. The model predictions agreed with the experimental data well. CONCLUSIONS: The physiologically-based computational model represents the hypothalamic-pituitary-gonadal axis in adult female FHM robustly. The model is useful to estimate how estrogens (e.g., 17alpha-ethynylestradiol) or androgens (e.g., 17beta-trenbolone) affect plasma concentrations of 17beta-estradiol, testosterone and vitellogenin, which are important determinants of fecundity in fish. PMID- 21545745 TI - What could infant and young child nutrition learn from sweatshops? AB - BACKGROUND: Adequate infant and young child nutrition demands high rates of breastfeeding and good access to nutrient rich complementary foods, requiring public sector action to promote breastfeeding and home based complementary feeding, and private sector action to refrain from undermining breastfeeding and to provide affordable, nutrient rich complementary foods. Unfortunately, due to a lack of trust, the public and private sectors, from both the North and the South, do not work well together in achieving optimal infant and young child nutrition. DISCUSSION: As the current debate in infant and young child nutrition is reminiscent of the "sweatshop" debate fifteen years ago, we argue that lessons from the sweatshops debate regarding cooperation between public and private sectors - and specific organizational experiences such as the Ethical Trading Initiative in which companies, trade unions, and civil society organizations work together to enhance implementation of labour standards and address alleged allegations - could serve as a model for improving cooperation and trust between public, civil society and private groups, and ultimately health, in infant and young child nutrition. SUMMARY: Lessons from the sweatshops debate could serve as a model to promote cooperation and trust between public and private groups, such that they learn to work together towards their common goal of improving infant and young child nutrition. PMID- 21545744 TI - Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition. AB - BACKGROUND: LINE-1s (L1, Long Interspersed Element-1) are the most abundant autonomous non-LTR retrotransposons in the human genome and replicate by reverse transcription of an RNA intermediate. Full-length L1 encodes two open reading frames (ORF1, ORF2) and ORF2 has reverse transcriptase activity. RESULTS: Here we expressed human L1 RT in E. coli and the purified protein displayed the same RT activity as that of ORF2p expressed in insect cells. We tested the effect of different reverse transcriptase inhibitors on L1 RT and found that all four tested nucleoside inhibitors efficiently inhibited L1 RT activity competitively. The Ki values of NRTIs were calculated (AZTTP, 16.4 +/- 4.21 nM; d4TTP, 0.73 +/- 0.22 nM; ddCTP, 0.72 +/- 0.16 nM; 3TCTP, 12.9 +/- 2.07 nM). L1 RT was less sensitive to non-nucleoside reverse transcriptase inhibitors, among these nevirapine had no effect, even at concentrations up to 500 MUM. We also examined the effect of RT inhibitors on L1 retrotransposition efficiency in vivo using a cell-based retrotransposition assay. Similarly, all analog inhibitors decreased L1 retrotransposition frequency with different potencies whereas nevirapine had little or no effect on L1 retrotransposition. For comparison, we also tested the same inhibitors to highly purified RT of an LTR-retrotransposon (Ty1) and found it was less sensitive to NRTIs than L1 RT and has the same inhibition profile as L1 RT to NNRTIs. CONCLUSIONS: These data indicate that bacterially expressed L1 RT is an active reverse transcriptase sensitive to nucleoside RT inhibitors but not to non-nucleoside inhibitors. PMID- 21545746 TI - Predicting the risk of end-stage renal disease in the population-based setting: a retrospective case-control study. AB - BACKGROUND: Previous studies of predictors of end-stage renal disease (ESRD) have limitations: (1) some focused on patients with clinically recognized chronic kidney disease (CKD); (2) others identified population-based patients who developed ESRD, but lacked earlier baseline clinical measures to predict ESRD. Our study was designed to address these limitations and to identify the strength and precision of characteristics that might predict ESRD pragmatically for decision-makers--as measured by the onset of renal replacement therapy (RRT). METHODS: We conducted a population-based, retrospective case-control study of patients who developed ESRD and started RRT. We conducted the study in a health maintenance organization, Kaiser Permanente Northwest (KPNW). The case-control study was nested within the adult population of KPNW members who were enrolled during 1999, the baseline period. Cases and their matched controls were identified from January 2000 through December 2004. We evaluated baseline clinical characteristics measured during routine care by calculating the adjusted odds ratios and their 95% confidence intervals after controlling for matching characteristics: age, sex, and year. RESULTS: The rate of RRT in the cohort from which we sampled was 58 per 100,000 person-years (95% CI, 53 to 64). After excluding patients with missing data, we analyzed 350 cases and 2,114 controls. We identified the following characteristics that predicted ESRD with odds ratios >= 2.0: eGFR<60 mL/min/1.73 m(2) (OR = 20.5; 95% CI, 11.2 to 37.3), positive test for proteinuria (OR = 5.0; 95% CI, 3.5 to 7.1), hypertension (OR = 4.5; 95% CI, 2.5 to 8.0), gout/positive test for uric acid (OR = 2.5; 95% CI, 1.8 to 3.5), peripheral vascular disease (OR = 2.2; 95% CI, 1.4 to 3.6), congestive heart failure (OR = 2.1; 95% CI, 1.4 to 3.3), and diabetes (OR = 2.1; 95% CI, 1.5 to 2.9). CONCLUSIONS: The clinical characteristics needed to predict ESRD--for example, to develop a population-based, prognostic risk score--were often documented during routine care years before patients developed ESRD and required RRT. PMID- 21545747 TI - WFDC1 expression identifies memory CD4 T-lymphocytes rendered vulnerable to cell cell HIV-1 transfer by promoting intercellular adhesive junctions. AB - BACKGROUND: Elucidating mechanisms that promote HIV-1 transfer between CD4+ T lymphocytes and their subsequent loss is of importance to HIV-1 pathogenesis. We recently reported that whey acidic protein, ps20, promotes cell-free HIV-1 spread through ICAM-1 modulation. Since ICAM-1 is pivotal in cell conjugation and intercellular HIV-1 transfer, this study examines ps20 effects on HIV-1 spread between T lymphocytes. RESULTS: We demonstrate intrinsic ps20 variability in primary CD4+ T-lymphocyte clonal populations and a significant positive correlation between endogenous ps20 levels and virus transfer involving fusion resulting in a spreading infection that could be reversed by the addition of reverse transcriptase inhibitors. Blocking anti-ps20 antibody or siRNA mediated ps20 knockdown, significantly reduced virus transfer. Conversely, virus transfer was promoted by ectopic ps20 expression or by exogenous addition of recombinant ps20. A higher frequency of virological synapse formation was evident in cocultures of HIV-1 infected donor T-cells with ps20high v ps20low/intermediate targets. Blocking ps20 inhibited T-lymphocyte conjugate formation and ICAM-1 expression, and was as potent as ICAM-1 in inhibiting HIV-1 transfer. CONCLUSIONS: Therefore ps20 is a novel marker of CD4+ T-cells rendered vulnerable to HIV-1 infection by regulating the fundamental biologic process of intercellular conjugate formation and consequently of potential importance in HIV 1 pathogenesis. PMID- 21545748 TI - Assessment of function and clinical utility of alcohol and other drug web sites: an observational, qualitative study. AB - BACKGROUND: The increasing popularity and use of the internet makes it an attractive option for providing health information and treatment, including alcohol/other drug use. There is limited research examining how people identify and access information about alcohol or other drug (AOD) use online, or how they assess the usefulness of the information presented. This study examined the strategies that individuals used to identify and navigate a range of AOD websites, along with the attitudes concerning presentation and content. METHODS: Members of the general community in Brisbane and Roma (Queensland, Australia) were invited to participate in a 30-minute search of the internet for sites related to AOD use, followed by a focus group discussion. Fifty one subjects participated in the study across nine focus groups. RESULTS: Participants spent a maximum of 6.5 minutes on any one website, and less if the user was under 25 years of age. Time spent was as little as 2 minutes if the website was not the first accessed. Participants recommended that AOD-related websites should have an engaging home or index page, which quickly and accurately portrayed the site's objectives, and provided clear site navigation options. Website content should clearly match the title and description of the site that is used by internet search engines. Participants supported the development of a portal for AOD websites, suggesting that it would greatly facilitate access and navigation.Treatment programs delivered online were initially viewed with caution. This appeared to be due to limited understanding of what constituted online treatment, including its potential efficacy. CONCLUSIONS: A range of recommendations arise from this study regarding the design and development of websites, particularly those related to AOD use. These include prudent use of text and information on any one webpage, the use of graphics and colours, and clear, uncluttered navigation options. Implications for future website development are discussed. PMID- 21545749 TI - Interferon signaling patterns in peripheral blood lymphocytes may predict clinical outcome after high-dose interferon therapy in melanoma patients. AB - BACKGROUND: High-dose Interferon (HDI) therapy produces a clinical response and achieves relapse-free survival in 20-33% of patients with operable high risk or metastatic melanoma. However, patients may develop significant side effects frequently necessitating dose reduction or discontinuation of therapy. We recently showed that peripheral blood lymphocytes (PBL) from some melanoma patients have impaired interferon (IFN) signaling which could be restored with high concentrations of IFN. This exploratory study evaluated IFN signaling in PBL of melanoma patients to assess whether the restoration of PBL IFN signaling may predict a beneficial effect for HDI in melanoma patients. METHODS: PBL from 14 melanoma patients harvested on Day 0 and Day 29 of neoadjuvant HDI induction therapy were analyzed using phosflow to assess their interferon signaling patterns through IFN-alpha induced phosphorylation of STAT1-Y701. RESULTS: Patients who had a clinical response to HDI showed a lower PBL interferon signaling capacity than non-responders at baseline (Day 0). Additionally, clinical responders and patients with good long-term outcome showed a significant increase in their PBL interferon signaling from Day 0 to Day 29 compared to clinical non-responders and patients that developed metastatic disease. The differences in STAT1 activation from pre- to post- HDI treatment could distinguish between patients who were inclined to have a favorable or unfavorable outcome. CONCLUSION: While the sample size is small, these results suggest that interferon signaling patterns in PBL correlate with clinical responses and may predict clinical outcome after HDI in patients with melanoma. A larger confirmatory study is warranted, which may yield a novel approach to select patients for HDI therapy. PMID- 21545750 TI - GIS measured environmental correlates of active school transport: a systematic review of 14 studies. AB - BACKGROUND: Emerging frameworks to examine active school transportation (AST) commonly emphasize the built environment (BE) as having an influence on travel mode decisions. Objective measures of BE attributes have been recommended for advancing knowledge about the influence of the BE on school travel mode choice. An updated systematic review on the relationships between GIS-measured BE attributes and AST is required to inform future research in this area. The objectives of this review are: i) to examine and summarize the relationships between objectively measured BE features and AST in children and adolescents and ii) to critically discuss GIS methodologies used in this context. METHODS: Six electronic databases, and websites were systematically searched, and reference lists were searched and screened to identify studies examining AST in students aged five to 18 and reporting GIS as an environmental measurement tool. Fourteen cross-sectional studies were identified. The analyses were classified in terms of density, diversity, and design and further differentiated by the measures used or environmental condition examined. RESULTS: Only distance was consistently found to be negatively associated with AST. Consistent findings of positive or negative associations were not found for land use mix, residential density, and intersection density. Potential modifiers of any relationship between these attributes and AST included age, school travel mode, route direction (e.g., to/from school), and trip-end (home or school). Methodological limitations included inconsistencies in geocoding, selection of study sites, buffer methods and the shape of zones (Modifiable Areal Unit Problem [MAUP]), the quality of road and pedestrian infrastructure data, and school route estimation. CONCLUSIONS: The inconsistent use of spatial concepts limits the ability to draw conclusions about the relationship between objectively measured environmental attributes and AST. Future research should explore standardizing buffer size, assess the quality of street network datasets and, if necessary, customize existing datasets, and explore further attributes linked to safety. PMID- 21545751 TI - Hydrophobic pulses predict transmembrane helix irregularities and channel transmembrane units. AB - BACKGROUND: Few high-resolution structures of integral membranes proteins are available, as crystallization of such proteins needs yet to overcome too many technical limitations. Nevertheless, prediction of their transmembrane (TM) structure by bioinformatics tools provides interesting insights on the topology of these proteins. METHODS: We describe here how to extract new information from the analysis of hydrophobicity variations or hydrophobic pulses (HPulses) in the sequence of integral membrane proteins using the Hydrophobic Pulse Predictor, a new tool we developed for this purpose. To analyze the primary sequence of 70 integral membrane proteins we defined two levels of analysis: G1-HPulses for sliding windows of n = 2 to 6 and G2-HPulses for sliding windows of n = 12 to 16. RESULTS: The G2-HPulse analysis of 541 transmembrane helices allowed the definition of the new concept of transmembrane unit (TMU) that groups together transmembrane helices and segments with potential adjacent structures. In addition, the G1-HPulse analysis identified helix irregularities that corresponded to kinks, partial helices or unannotated structural events. These irregularities could represent key dynamic elements that are alternatively activated depending on the channel status as illustrated by the crystal structures of the lactose permease in different conformations. CONCLUSIONS: Our results open a new way in the understanding of transmembrane secondary structures: hydrophobicity through hydrophobic pulses strongly impacts on such embedded structures and is not confined to define the transmembrane status of amino acids. PMID- 21545752 TI - On the curvature in logarithmic plots of rate coefficients for chemical reactions. AB - In terms of the reduced potential energy barrier zeta = DeltauTS/kT, the rate coefficients for chemical reactions are usually expressed as proportional to e zeta. The coupling between vibrational modes of the medium to the reaction coordinate leads to a proportionality of the regularized gamma function of Euler Q(a,zeta) = Gamma(a,zeta)/Gamma(a), with a being the number of modes coupled to the reaction coordinate. In this work, the experimental rate coefficients at various temperatures for several chemical reactions were fitted to the theoretical expression in terms of Q(a,zeta) to determine the extent of its validity and generality. The new expression affords lower deviations from the experimental points in 29 cases out of 38 and it accounts for the curvature in the logarithmic plots of rate coefficients versus inverse temperature. In the absence of tunneling, conventional theories predict the curvature of these plots to be identically zero. PMID- 21545754 TI - The local touch. PMID- 21545755 TI - Osteopontin in macrophage function. AB - The secreted phosphorylated protein osteopontin (OPN) is expressed in a variety of tissues and bodily fluids, and is associated with pathologies including tissue injury, infection, autoimmune disease and cancer. Macrophages are ubiquitous, heterogeneous cells that mediate aspects of cell and tissue damage in all these pathologies. Here, the role of OPN in macrophage function is reviewed. OPN is expressed in macrophage cells in multiple pathologies, and the regulation of its expression in these cells has been described in vitro. The protein has been implicated in multiple functions of macrophages, including cytokine expression, expression of inducible nitric oxide synthase, phagocytosis and migration. Indeed, the role of OPN in cells of the macrophage lineage might underlie its physiological role in many pathologies. However, there are numerous instances where the published literature is inconsistent, especially in terms of OPN function in vitro. Although the heterogeneity of OPN and its receptors, or of macrophages themselves, might underlie some of these inconsistencies, it is important to understand the role of OPN in macrophage biology in order to exploit its function therapeutically. PMID- 21545753 TI - Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-beta toxicity. AB - The pathology of Alzheimer's disease (AD) is characterized by amyloid plaques (aggregates of amyloid-beta (Abeta)) and neurofibrillary tangles (aggregates of tau) and is accompanied by mitochondrial dysfunction, but the mechanisms underlying this dysfunction are poorly understood. In this review, we discuss the critical role of mitochondria and the close inter-relationship of this organelle with the two main pathological features in the pathogenic process underlying AD. Moreover, we summarize evidence from AD post-mortem brain as well as cellular and animal AD models showing that Abeta and tau protein trigger mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. A vicious cycle as well as several vicious circles within the cycle, each accelerating the other, can be drawn, emphasizing the synergistic deterioration of mitochondria by tau and Abeta. PMID- 21545756 TI - Smith-Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways. AB - Smith-Magenis syndrome (SMS) is a complex neurobehavioural disorder characterised by intellectual disability, self-injurious behaviours, sleep disturbance, obesity, and craniofacial and skeletal anomalies. Diagnostic strategies are focused towards identification of a 17p11.2 microdeletion encompassing the gene RAI1 (retinoic acid induced 1) or a mutation of RAI1. Molecular evidence shows that most SMS features are due to RAI1 haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region for 17p11.2 deletion cases. The functional role of RAI1 is not completely understood, but it is probably a transcription factor acting in several different biological pathways that are dysregulated in SMS. Functional studies based on the hypothesis that RAI1 acts through phenotype-specific pathways involving several downstream genes have shown that RAI1 gene dosage is crucial for normal regulation of circadian rhythm, lipid metabolism and neurotransmitter function. Here, we review the clinical and molecular features of SMS and explore more recent studies supporting possible therapeutic strategies for behavioural management. PMID- 21545757 TI - Endometriosis: diagnosis and management. AB - OBJECTIVE: To improve the understanding of endometriosis and to provide evidence based guidelines for the diagnosis and management of endometriosis. OUTCOMES: OUTCOMES evaluated include the impact of the medical and surgical management of endometriosis on women's experience of morbidity and infertility. METHODS: Members of the guideline committee were selected on the basis of individual expertise to represent a range of practical and academic experience in terms of both location in Canada and type of practice, as well as subspecialty expertise along with general gynaecology background. The committee reviewed all available evidence in the English and French medical literature and available data from a survey of Canadian women. Recommendations were established as consensus statements. The final document was reviewed and approved by the Executive and Council of the SOGC. RESULTS: This document provides a summary of up-to-date evidence regarding diagnosis, investigations, and medical and surgical management of endometriosis. The resulting recommendations may be adapted by individual health care workers when serving women with this condition. CONCLUSIONS: Endometriosis is a common and sometimes debilitating condition for women of reproductive age. A multidisciplinary approach involving a combination of lifestyle modifications, medications, and allied health services should be used to limit the impact of this condition on activities of daily living and fertility. In some circumstances surgery is required to confirm the diagnosis and provide therapy to achieve the desired goal of pain relief or improved fecundity. Women who find an acceptable management strategy for this condition may have an improved quality of life or attain their goal of successful pregnancy. EVIDENCE: Medline and Cochrane databases were searched for articles in English and French on subjects related to endometriosis, pelvic pain, and infertility from January 1999 to October 2009 in order to prepare a Canadian consensus guideline on the management of endometriosis. VALUES: The quality of evidence was rated with use of the criteria described by the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described by the Task Force. See Table 1. BENEFITS, HARMS, AND COSTS: Implementation of the guideline recommendations will improve the care of women with pain and infertility associated with endometriosis. PMID- 21545758 TI - Evaluation of patient reporting of adverse drug reactions to the UK 'Yellow Card Scheme': literature review, descriptive and qualitative analyses, and questionnaire surveys. AB - BACKGROUND: The monitoring of adverse drug reactions (ADRs) through pharmacovigilance is vital to patient safety. Spontaneous reporting of ADRs is one method of pharmacovigilance, and in the UK this is undertaken through the Yellow Card Scheme (YCS). Yellow Card reports are submitted to the Medicines and Healthcare products Regulatory Agency (MHRA) by post, telephone or via the internet. The MHRA electronically records and reviews information submitted so that important safety issues can be detected. While previous studies have shown differences between patient and health-care professional (HCP) reports for the types of drugs and reactions reported, relatively little is known about the pharmacovigilance impact of patient reports. There have also been few studies on the views and experiences of patients/consumers on the reporting of suspected ADRs. OBJECTIVES: To evaluate the pharmacovigilance impact of patient reporting of ADRs by analysing reports of suspected ADRs from the UK YCS and comparing reports from patients and HCPs. To elicit the views and experiences of patients and the public about patient reporting of ADRs. DESIGN: (1) Literature review and survey of international experiences of consumer reporting of ADRs; (2) descriptive analysis of Yellow Card reports; (3) signal generation analysis of Yellow Card reports; (4) qualitative analysis of Yellow Card reports; (5) questionnaire survey of patients reporting on Yellow Cards; (6) qualitative analysis of telephone interviews with patient reporters to the scheme; (7) qualitative analysis of focus groups and usability testing of the patient YCS; and (8) national omnibus telephone survey of public awareness of the YCS. PARTICIPANTS: Patients (n = 5180) and HCPs (n = 20,949) submitting Yellow Card reports from October 2005 to September 2007. Respondents to questionnaire survey (n = 1362). Participants at focus groups and usability testing sessions (n = 40). National omnibus telephone survey (n = 2028). SETTING: The literature review included studies in English from across the world. All other components included populations from the UK; the omnibus survey was restricted to Great Britain. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Characteristics of patient reports: types of drug and suspected ADR reported; seriousness of reports; and content of reports. The relative contributions of patient reports and of HCP reports to signal generation. Views and experiences of patient reporters. Views of members of the public about the YCS, including user-friendliness and usability of different ways of patient reporting. Public awareness of the YCS. Suggestions for improving patient reporting to the YCS. RESULTS: Compared with HCPs, patient reports to the YCS contained a higher median number of suspected ADRs per report, and described reactions in more detail. The proportions of reports categorised as 'serious' were similar; the patterns of drugs and reactions reported differed. Patient reports were richer in their descriptions of reactions than those from HCPs, and more often noted the effects of ADRs on patients' lives. Combining patient and HCP reports generated more potential signals than HCP reports alone; some potential signals in the 'HCP-only' data set were lost when combined with patient reports, but fewer than those gained; the addition of patient reports to HCP reports identified 47 new 'serious' reactions not previously included in 'Summaries of Product Characteristics'. Most patient reporters found it fairly easy to make reports, although improvements to the scheme were suggested, including greater publicity and the redesign of web- and paper-based reporting systems. Among members of the public, 8.5% were aware of the YCS in 2009. CONCLUSIONS: Patient reporting of suspected ADRs has the potential to add value to pharmacovigilance by reporting types of drugs and reactions different from those reported by HCPs; generating new potential signals; and describing suspected ADRs in enough detail to provide useful information on likely causality and impact on patients' lives. These findings suggest that further promotion of patient reporting to the YCS is justified, along with improvements to existing reporting systems. In order of priority, future work should include further investigation of (1) the pharmacovigilance impact of patient reporting in a longer-term study; (2) the optimum approach to signal generation analysis of patient and HCP reports; (3) the burden of ADRs in terms of impact on patients' lives; (4) the knowledge and attitudes of HCPs towards patient reporting of ADRs; (5) the value of using patient reports of ADRs to help other patients and HCPs who are seeking information on patient experiences of ADRs; and (6) the impact of increasing publicity and/or enhancements to reporting systems on the numbers and types of Yellow Card reports from patients. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 21545759 TI - Solutes, surgery and the ocular surface. PMID- 21545760 TI - Criteria for diagnosis of Sjogren-Jones syndromes. PMID- 21545761 TI - A solute gradient in the tear meniscus. I. A hypothesis to explain Marx's line. AB - Marx's line is a line of mucosal staining behind the mucocutaneous junction. It can be demonstrated throughout life in all normal lids by staining with lissamine green and related dyes. Of all the body orifices, only the mucosae of the eye and mouth are directly exposed to the atmosphere. In this paper, we suggest that for the eye, this exposure leads to the formation of Marx's line. The tear meniscus thins progressively toward its apex, where it is pinned at the mucocutaneous junction of the lid. It also thins toward the black line, which segregates the meniscus from the tear film after the blink. We predict that, because of the geometry of the tear meniscus, evaporation generates a solute gradient across the meniscus profile in the anteroposterior plane, which peaks at the meniscus apices at the end of the interblink. One outcome would be to amplify the level of tear molarity at these sites so that they reach hyperosmolar proportions. Preliminary mathematical modeling suggests that dilution of this effect by advection and diffusion of solute away from the meniscus apex at the mucocutaneous junction will be restricted by spatial constraints, the presence of tear and surface mucins at this site, and limited fluid flow. We conclude that evaporative water loss from the tear meniscus may result in a physiological zone of hyperosmolar and related stresses to the occlusal conjunctiva, directly behind the mucocutaneous junction. We hypothesize that this stimulates a high epithelial cell turnover at this site, incomplete epithelial maturation, and a failure to express key molecules such as MUC 16 and galectin-3, which, with the tight junctions between surface epithelial cells, are necessary to seal the ocular surface and prevent penetration of dyes and other molecules into the epithelium. This is proposed as the basis for Marx's line. In Part II of this paper (also published in this issue of The Ocular Surface), we address additional pathophysiological consequences of this mechanism, affecting lid margins. PMID- 21545762 TI - A solute gradient in the tear meniscus. II. Implications for lid margin disease, including meibomian gland dysfunction. AB - We have hypothesized previously that evaporation from the tears generates a solute gradient across the tear meniscus, which delivers hyperosmolar stress to the mucocutaneous junction (MCJ) of the lid margin. This is proposed as the basis for Marx's line, a line of staining with topically applied dyes that lies directly behind the MCJ. In this article, we consider the implications of this hypothesis for progressive damage to the lid margin as an age-related phenomenon, its amplification in dry eye states, and its possible role in the etiology of meibomian gland dysfunction (MGD). It is suggested that a hyperosmolar or related stimulus, acting behind the MCJ over a lifetime, promotes the anterior migration of the MCJ, which is a feature of the aging lid margin. This mechanism would be amplified in dry eye states, not only by reason of increased tear molarity at the meniscus apex but also by raising the concentration of inflammatory peptides at this site. This could explain the increased width and irregularity of Marx's line in dry eye. While the presence of stem cells at the lid margin may equip this region to respond to such stress, their depletion could be the basis of irreversible lid margin damage. It is further proposed, given the proximity of the MCJ to the meibomian gland orifices, that the solute gradient mechanism could play a role in the initiation of MGD by delivering hyperosmolar and inflammatory stresses to the terminal ducts and orifices of the glands. By the same token, the presence of a zone of increased epithelial permeability in this region may provide a back door route for the delivery of drugs in the treatment of MGD. PMID- 21545763 TI - Evolution of deep anterior lamellar keratoplasty (DALK). AB - The concept of selective tissue transplantation was theorized over two centuries ago. However, deep anterior lamellar keratoplasty (DALK) was difficult to perform with the instruments available at that time, and visual acuity results were poor compared to those achieved by full-thickness transplantation. Recently, many technical improvements in surgical instrumentation and advances in eye bank technology have led to the re-emergence of DALK. Now, patients with stromal pathologies not affecting the corneal endothelium can benefit from this surgery, which allows total stromal replacement of the recipient's cornea, leaving an intact recipient Descemet membrane and endothelium. Along with the advances in surgical instrumentation, improvements in surgical techniques and imaging technology have contributed to improved visual outcomes obtained with DALK. DALK is now seen as a viable alternative to penetrating keratoplasty with equivalent visual results and better long-term graft survival. PMID- 21545764 TI - Withdrawal of approved drugs. PMID- 21545765 TI - Predicting binaural interference. PMID- 21545766 TI - Longitudinal infant speech perception in young cochlear implant users. AB - PURPOSE: This paper presents longitudinal case studies of children who received (cochlear implants) CIs and a controlled sample of children with normal hearing (NH). Phoneme discrimination (i.e., /sa-ma/, /a-i/, /a-u/, /u-i/, /ta-da/, /pa ka/) was assessed prior to receiving CIs and monthly for 3 mo following CI activation. RESEARCH DESIGN: Case studies. STUDY SAMPLE: Three cochlear implant recipients and seven NH control participants were recruited through the University of Colorado Hospital and the University of Colorado, Boulder. DATA COLLECTION AND ANALYSIS: The study utilized the visual reinforcement audiometry and interactive play assessment of speech pattern contrasts (VRASPAC) algorithm. A comparison of scoring was conducted using Cohen's kappa to determine interrater reliability. RESULTS: Findings from this study revealed that CI recipients could discriminate at least three out of five phoneme contrasts at mastery level (>=90%) by 2 mo of device use. None of the CI recipients reached mastery prior to implantation. Following 3 mo of CI use there was no difference in contrast discrimination performance between the CI users and their NH age-matched peers (with the exception of /pa-ka/ for one CI user. CONCLUSIONS: The CI users in this case study, who were implanted between 12 and 16 mo of age, were able to master the phoneme contrasts regardless of bilateral or unilateral CI, socioeconomic status, or language spoken at home. PMID- 21545767 TI - Use of 64-channel electroencephalography to study neural otolith-evoked responses. AB - BACKGROUND: The vestibular evoked myogenic potential (VEMP) is a myogenic response that can be used clinically to evaluate the function of the saccule. However, to date, little is known about the thalamo-cortical representation of saccular activation. It is important to understand all aspects of the VEMP, as this test is currently used clinically in the evaluation of saccular function. PURPOSE: To identify the areas of the brain that are activated in response to stimuli used clinically to evoke the VEMP. RESEARCH DESIGN: Electroencephalography (EEG) recordings combined with current density analyses were used to identify the areas of the brain that are activated in response to stimuli presented above VEMP threshold (500 Hz, 120 dB peak SPL [pSPL] tone bursts), as compared to stimuli presented below VEMP threshold (90 dB pSPL, 500 Hz tone bursts). Ten subjects without any history of balance or hearing impairment participated in the study. RESULTS: The neural otolith-evoked responses (NOERs) recorded in response to stimuli presented below VEMP threshold were absent or smaller than NOERs that were recorded in response to stimuli presented above VEMP threshold. Subsequent analyses with source localization techniques, followed by statistical analysis with SPM5 (Statistical Parametric Mapping), revealed several areas that were activated in response to the 120 dB pSPL tone bursts. These areas included the primary visual cortex, the precuneus, the precentral gyrus, the medial temporal gyrus, and the superior temporal gyrus. CONCLUSIONS: The present study found a number of specific brain areas that may be activated by otolith stimulation. Given the findings and source localization techniques (which required limited input from the investigator as to where the sources are believed to be located in the brain) used in the present study as well as the similarity in findings between studies employing galvanic stimuli, fMRI (functional magnetic resonance imaging), and scalp-recorded potentials in response to VEMP-eliciting stimuli, our study provides additional evidence that these brain regions are activated in response to stimuli that can be used clinically to evoke the VEMP. PMID- 21545768 TI - Working memory supports listening in noise for persons with hearing impairment. AB - BACKGROUND: Previous studies have demonstrated a relation between cognitive capacity, in particular working memory, and the ability to understand speech in noise with different types of hearing aid signal processing. PURPOSE: The present study investigates the relation between working memory capacity and the speech recognition performance of persons with hearing impairment under both aided and unaided conditions, following a period of familiarization to both fast- and slow acting compression settings in the participants' own hearing aids. RESEARCH DESIGN: Speech recognition was tested in modulated and steady state noise with fast and slow compression release settings (for aided conditions) with each of two materials. Working memory capacity was also measured. STUDY SAMPLE: Thirty experienced hearing aid users with a mean age of 70 yr (SD = 7.8) and pure-tone average hearing threshold across the frequencies 0.25, 0.5, 1, 2, 3, 4, and 6 kHz (PTA7) and for both ears of 45.8 dB HL (SD = 6.6. INTERVENTION: 9 wk experience with each of fast-acting and slow-acting compression. DATA COLLECTION AND ANALYSIS: Speech recognition data were analyzed using repeated measures analysis of variance with the within-subjects factors of material (high constraint, low constraint), noise type (steady state, modulated), and compression (fast, slow), and the between-subjects factor working memory capacity (high, low). RESULTS: With high constraint material, there were three-way interactions including noise type and working memory as well as compression, in aided conditions, and performance level, in unaided conditions, but no effects of either working memory or compression with low constraint material. Investigation of simple main effects showed a significant effect of working memory during speech recognition under conditions of both "high degradation" (modulated noise, fast-acting compression, low signal-to-noise ratio [SNR]) and "low degradation" (steady state noise, slow acting compression, high SNR). The finding of superior performance of persons with high working memory capacity in modulated noise with fast-acting compression agrees with findings of previous studies including a familiarization period of at least 9 wk, in contrast to studies with familiarization of 4 wk or less that have shown that persons with lower cognitive capacity may benefit from slow-acting compression. CONCLUSIONS: Working memory is a crucial factor in speech understanding in noise for persons with hearing impairment, irrespective of whether hearing is aided or unaided. Working memory supports speech understanding in noise under conditions of both "high degradation" and "low degradation." A subcomponent view of working memory may contribute to our understanding of these phenomena. The effect of cognition on speech understanding in modulated noise with fast-acting compression may only pertain after a period of 4-9 wk of familiarization and that prior to such a period, persons with lower cognitive capacity may benefit more from slow-acting compression. PMID- 21545769 TI - Transitioning hearing aid users with severe and profound loss to a new gain/frequency response: benefit, perception, and acceptance. AB - BACKGROUND: Adults with severe and profound hearing loss tend to be long-term, full-time users of amplification who are highly reliant on their hearing aids. As a result of these characteristics, they are often reluctant to update their hearing aids when new features or signal-processing algorithms become available. Due to the electroacoustic constraints of older devices, many severely and profoundly hearing-impaired adults continue to wear hearing aids that provide more low- and mid-frequency gain and less high-frequency gain than would be prescribed by the National Acoustic Laboratories' revised formula with profound correction factor (NAL-RP). PURPOSE: To investigate the effect of a gradual change in gain/frequency response on experienced hearing-aid wearers with moderately severe to profound hearing loss. RESEARCH DESIGN: Double-blind, randomized controlled trial. STUDY SAMPLE: Twenty-three experienced adult hearing aid users with severe and profound hearing loss participated in the study. Participants were selected for inclusion in the study if the gain/frequency response of their own hearing aids differed significantly from their NAL-RP prescription. Participants were assigned either to a control or to an experimental group balanced for aided ear three-frequency pure-tone average (PTA) and age. INTERVENTION: Participants were fitted with Siemens Artis 2 SP behind the-ear (BTE) hearing aids that were matched to the gain/frequency response of their own hearing aids for a 65 dB SPL input level. The experimental group progressed incrementally to their NAL-RP targets over the course of 15 wk, while the control group maintained their initial settings throughout the study. DATA COLLECTION AND ANALYSIS: Aided speech discrimination testing, loudness scaling, and structured questionnaires were completed at 3, 6, 9, 12, and 15 wk postfitting. A paired comparison between the old and new gain/frequency responses was completed at 1 and 15 wk postfitting. Statistical analysis was conducted to examine differences between the experimental and control groups and changes in objective performance and subjective perception over time. RESULTS: The results of the study showed that participants in the experimental group were subjectively accepting of the changes to their amplification characteristics, as evidenced by nonsignificant changes in the ratings of device performance over time. Perception of loudness, sound quality, speech intelligibility, and own voice volume did not change significantly throughout the study. Objectively, participants in the experimental group demonstrated poorer speech discrimination performance as the study progressed, although there was no change in objective loudness perception. According to the paired comparison, there was an overall subjective preference for the original gain/frequency response among all participants, although participants in the experimental group did show an increase in preference for the NAL-RP response by the end of the study. CONCLUSIONS: Based on the findings of this study, we suggest that undertaking a gradual change to a new gain/frequency response with severely and profoundly hearing-impaired adults is a feasible procedure. However, we recommend that clinicians select transition candidates carefully and initiate the procedure only if there is a clinical reason for doing so. A validated prescriptive formula should be used as a transition target, and speech discrimination performance should be monitored throughout the transition. PMID- 21545770 TI - Behavioral and electrophysiologic binaural processing in persons with symmetric hearing loss. AB - BACKGROUND: Binaural hearing improves our ability to understand speech and to localize sounds. Hearing loss can interfere with binaural cues, and despite the success of amplification, ~25% of people with bilateral hearing loss fit with two hearing aids choose to wear only one (e.g., Brooks and Bulmer, 1981). One explanation is reduced binaural processing, which occurs when the signal presented to one ear interferes with the perception of the signal presented to the other ear (e.g., Jerger et al, 1993). Typical clinical measures, however, are insensitive to binaural processing deficits. PURPOSE: The purpose of this study was to determine the extent to which behavioral measures of binaural performance were related to electrophysiological measures of binaural processing in subjects with symmetrical pure-tone sensitivity. RESEARCH DESIGN: The relationship between middle latency responses (MLRs) and behavioral performance on binaural listening tasks was assessed by Spearman's rho correlation analyses. Separate repeated measures analyses of variance (RMANOVAs) were performed for MLR latency and MLR amplitude. STUDY SAMPLE: Nineteen subjects were recruited for the present study based on a clinical presentation of symmetrical pure-tone sensitivity with asymmetrical performance on a word-recognition in noise test. This subpopulation of patients included both subjects with and subjects without hearing loss. DATA COLLECTION AND ANALYSIS: Monaural and binaural auditory processing was measured behaviorally and electrophysiologically in right-handed subjects. The behavioral tests included the Words-in-Noise test (WIN), the dichotic digits test (DDT), and the 500 Hz masking level difference (MLD). Electrophysiologic responses were measured by the binaural interaction component (BIC) of the MLR. The electrophysiological responses were analyzed to examine the effects of peak (Na, Pa, and Nb) and condition (monaural left, monaural right, binaural, and BIC) on MLR amplitude and latency. RESULTS: Significant correlations were found among electrophysiological measures of binaural hearing and behavioral tests of binaural hearing. A strong correlation between the MLD and the binaural Na-Pa amplitude was found (r = .816). CONCLUSIONS: The behavioral and electrophysiological measures used in the present study clearly showed evidence of reduced binaural processing in ~10 of the subjects in the present study who had symmetrical pure-tone sensitivity. These results underscore the importance of understanding binaural auditory processing and how these measures may or may not identify functional auditory problems. PMID- 21545771 TI - Clinical neuropathology 3/2011. PMID- 21545772 TI - Oculopharyngeal muscle dystrophy: fine structure and mRNA expression levels of PABPN1. AB - OBJECTIVE: The underlying molecular mechanism leading to the OPMD causing mutation in the PABPN1 gene has not been elucidated so far. Two models are under consideration: the first model is the polymerase slippage mechanism. The second model is unequal crossing over. The aim of the present study is to correlate clinical, fine structural, and molecular genetic data. MATERIAL AND METHODS: In 6 cases of OPMD, confirmed by electron microscopy, we analyzed mutations in exon 1 of the polyadenine binding protein nuclear1 (PABPN1) gene on chromosome 14q11.1 using DNA isolated from biopsied muscle tissue. Furthermore, the corresponding mRNA from frozen biopsies was analyzed. RESULTS: In addition to the usual expansion of the (GCG)6 sequence to the well known (GCG)8-13 trinucleotide repeats in 5 of the patients, we detected a novel (GCA)2(GCG) insertion in one patient. This mutation favors a pathomechanism of "unequal crossing over" instead of a "polymerase slippage" model. Tubulofilamentous (8.5 nm) nuclear inclusions were especially prominent in an isolated nucleus of a nuclear clump in a severely atrophic muscle fiber. However, no correlation was found between muscle weakness, the frequency of repeats, and the frequency and size of nuclear inclusions. CONCLUSIONS: Muscle weakness was not obviously correlated to the number of repeats, but it is suggested that it might be linked to an increase of the transcription rate representing the ratio between mutated versus normal RT-PCR products. PMID- 21545773 TI - Differential degeneration of the locus coeruleus in dementia subtypes. AB - OBJECTIVE: Neuronal loss in the locus coeruleus (LC) is common in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The aims of the present study were to investigate LC degeneration in different dementia disorders including vascular dementia (VaD) and frontotemporal lobar degeneration (FTLD), to compare LC degeneration with severity of pathology in AD and DLB/PDD, to further evaluate the usefulness of a previously presented scoring system and to examine the predictive value of macroscopic assessment of the LC. METHODS: A horizontal mid-level section of the pons was examined in 200 neuropathologically examined cases with clinical dementia. A previous macroscopic assessment of the LC was performed in 149 of the cases. RESULTS: Cases with DLB/ PDD and AD presented with the highest microscopic LC degeneration scores, with significant differences compared to combined AD + VaD, in turn with a higher score than VaD, FTLD and other dementia disorders. Interrater agreement (weighted kappa;) for LC degeneration scoring was 0.83 - 0.91. DLB/ PDD, AD and AD + VaD were the diagnoses for 85% of the cases with macroscopic LC depigmentation. CONCLUSION: LC degeneration, which may be macroscopically noted, often indicates synuclein and/or Alzheimer pathology among demented. When clinical information is scarce or inconsistent, a macroscopic assessment of the LC may facilitate focusing of the subsequent neuropathological investigation. Also, the semiquantitative scoring system is a reliable tool for histological assessment of LC degeneration. PMID- 21545774 TI - Concomitant CNS pathology in a patient with amyotropic lateral sclerosis following poliomyelitis in childhood. AB - Post-polio syndrome (PPS) develops in approximately 30% of polio survivors several decades after the acute attack of paralytic poliomyelitis. Some of these patients develop post-poliomyelitis muscular atrophy (PPMA) which is characterized by a slowly progressive muscle weakness. Due to its clinicopathological features, investigators have often studied PPS and PPMA in association with amyotrophic lateral sclerosis (ALS), the underlying hypothesis being an increased risk of developing ALS from a prior acute paralytic poliomyelitis. Various studies, however, have indicated that de novo ALS cases in patients with prior acute paralytic poliomyelitis are rare. Herein, we describe a rare case of a 75-year-old woman who at post-mortem examination presented a combination of a PPS with proven histopathological sporadic ALS features. Furthermore, neuropathology of this case also revealed several other histopathological findings reminiscent of a tauopathy, synucleinopathy and amyloid angiopathy and a large pituitary cyst. To our knowledge, this is the first reported case of PPS with clear pathological hallmarks of sporadic ALS, including ubiquitin-, TDP-43, phosphorylated TDP-43- and p62-positive inclusions, with accompanying features compatible with Alzheimer's and Parkinson's disease. PMID- 21545775 TI - Angiolipoma in sellar, suprasellar and parasellar region: report on two new cases and review of literature. AB - Angiolipomas of CNS are very rare; more than 90% involve the spinal canal. There are only a few case reports documenting the tumor in the sellar/suprasellar region. We report 2 cases of angiolipoma involving sellar/suprasellar and right parasellar region in two female patients. On histopathology the lesion was composed of vascular component which was of cavernous type in one patient and of capillary caliber in the other with admixture of mature adipocytes. The MRI findings were distinctive as the lesion was predominantly iso-to-hypointense on T1W sequence, hyperintense on T2WI and FLAIR sequence. In addition, a few small hyperintense areas were noted on plain T1W images which may represent intralesional fat. One of the cases also showed lipid lactate peak on MR spectroscopy. To the best of our knowledge only 8 other cases of sellar, parasellar angiolipomas have been reported in indexed literature. MRI with fat suppression sequences should be routinely performed in lesions in such locations with hyperintense areas on T1WI as the incidence of intraoperative blood loss is very high. A preoperative suspicion of the diagnosis might help in reducing the patient morbidity. PMID- 21545776 TI - Spinal solitary fibrous tumor mimicking hemangioma. PMID- 21545778 TI - Primary intracranial leiomyosarcoma in an immunocompetent patient. PMID- 21545777 TI - Primary B-cell lymphoma of choroid plexus in a 30-year-old immunocompetent male. PMID- 21545779 TI - Effects of nitrite exposure on functional haemoglobin levels, bimodal respiration, and swimming performance in the facultative air-breathing fish Pangasianodon hypophthalmus. AB - In this study we investigated nitrite (NO2-) effects in striped catfish, a facultative air-breather. Fish were exposed to 0, 0.4, and 0.9 mM nitrite for 0, 1, 2, 4, and 7 days, and levels of functional haemoglobin, methaemoglobin (metHb) and nitrosyl haemoglobin (HbNO) were assessed using spectral deconvolution. Plasma concentrations of nitrite, nitrate, chloride, potassium, and sodium were also measured. Partitioning of oxygen consumption was determined to reveal whether elevated metHb (causing functional hypoxia) induced air-breathing. The effects of nitrite on maximum oxygen uptake (MO(2max)) and critical swimming speed (U(crit)) were also assessed. Striped catfish was highly tolerant to nitrite exposure, as reflected by a 96 h LC50 of 1.65 mM and a moderate nitrite uptake into the blood. Plasma levels of nitrite reached a maximum after 1 day of exposure, and then decreased, never exceeding ambient levels. MetHb, HbNO and nitrate (a nitrite detoxification product) also peaked after 1 day and then decreased. Only high levels of nitrite and metHb caused reductions in MO(2max) and U(crit). The response of striped catfish contrasts with that seen in most other fish species and discloses efficient mechanisms of combating nitrite threats. Furthermore, even though striped catfish is an efficient air-breather, this species has the ability to sustain aerobic scope and swimming performance without air-breathing, even when faced with nitrite-induced reductions in blood oxygen carrying capacity. Our study is the first to confirm that high levels of nitrite and metHb reduce MO(2max) and thereby aerobic scope, while more moderate elevations fail to do so. Further studies are needed to elucidate the mechanisms underlying the low nitrite accumulation in striped catfish. PMID- 21545781 TI - The end of the primary outcome measure: a research agenda for constructing its replacement. AB - No definitive or gold standard outcome measure exists to test the efficacy of the mental disorder treatments examined within randomized controlled trials. As a result, researchers often evaluate efficacy via multiple outcome measures administered within a single controlled trial. This practice commonly yields inconsistent findings as to a treatment's efficacy. To address the issue of inconsistent findings, increasingly (and paradoxically) controlled trials include designations of a single measure as a primary outcome and other measures as secondary outcomes. In this paper, we review recent work highlighting the limitations of this approach to testing efficacy. In discussing how these limitations outweigh the strengths of the primary outcome method, we argue that this method needs to be replaced with an approach that addresses its limitations. In doing so, we outline the basic principles of a research agenda to develop such a replacement approach. The approach (Standardized Replication Rate [SRR] Approach) would focus on the extent to which multiple outcome measures within a controlled trial yield replicable effects, relative to the characteristics of the outcome measures and the treatment(s) examined within the trial. A research agenda focused on developing the SRR Approach would increase accountability for both reporting and interpreting controlled trials evidence. PMID- 21545780 TI - The emotional Stroop task and posttraumatic stress disorder: a meta-analysis. AB - Posttraumatic stress disorder (PTSD) is associated with significant impairment and lowered quality of life. The emotional Stroop task (EST) has been one means of elucidating some of the core deficits in PTSD, but this literature has remained inconsistent. We conducted a meta-analysis of EST studies in PTSD populations in order to synthesize this body of research. Twenty-six studies were included with 538 PTSD participants, 254 non-trauma exposed control participants (NTC), and 276 trauma exposed control participants (TC). PTSD-relevant words impaired EST performance more among PTSD groups and TC groups compared to NTC groups. PTSD groups and TC groups did not differ. When examining within-subject effect sizes, PTSD-relevant words and generally threatening words impaired EST performance relative to neutral words among PTSD groups, and only PTSD-relevant words impaired performance among the TC groups. These patterns were not found among the NTC groups. Moderator analyses suggested that these effects were significantly greater in blocked designs compared to randomized designs, toward unmasked compared to masked stimuli, and among samples exposed to assaultive traumas compared to samples exposed to non-assaultive traumas. Theoretical and clinical implications are discussed. PMID- 21545782 TI - A meta-analysis of treatments for perinatal depression. AB - This meta-analysis assessed efficacy of pharmacologic and psychological interventions for treatment of perinatal depression. A systematic review identified 27 studies, including open trials (n=9), quasi-randomized trials (n=2), and randomized controlled trials (n=16) assessing change from pretreatment to posttreatment or comparing these interventions to a control group. Uncontrolled and controlled effect sizes were assessed in separate meta-analyses. There was significant improvement in depressive symptoms from pretreatment to posttreatment, with an uncontrolled overall effect size (Hedges' g) of 1.61 after removal of outliers and correction for publication bias. Symptom levels at posttreatment were below cutoff levels indicative of clinically significant symptoms. At posttreatment, intervention groups demonstrated significantly greater reductions in depressive symptoms compared to control groups, with an overall controlled effect size (Hedges' g) of 0.65 after removal of outliers. Individual psychotherapy was superior to group psychotherapy with regard to changes in symptoms from pretreatment to posttreatment. Interventions including an interpersonal therapy component were found to have greater effect sizes, compared to control conditions, than interventions including a cognitive behavioral component. Implications of the findings for clinical practice and future research are discussed. PMID- 21545783 TI - Intracellular anion fluorescence assay for sodium/iodide symporter substrates. AB - The sodium/iodide symporter (NIS) is primarily responsible for iodide accumulation in the thyroid gland for the synthesis of thyroid hormones; however, it can also transport other lyotropic anions in the thyroid gland and nonthyroid tissues. Some NIS substrates have important physiological or clinical roles, and others are environmental contaminants with health-related consequences. The aim of this study was to assess the utility of a yellow fluorescent protein variant, YFP-H148Q/I152L, as a biosensor to monitor the cellular uptake of NIS substrates, including thiocyanate (SCN(-)), nitrate (NO(3)(-)), chlorate (ClO(3)(-)), perchlorate (ClO(4)(-)), and perrhenate (ReO(4)(-)). The fluorescence of purified YFP-H148Q/I152L was suppressed by anions with an order of potency of ReO(4)( )>ClO(4)(-)=I(-)=SCN(-)=ClO(3)(-)>NO(3)(-)?Cl(-). Anions also suppressed the fluorescence of YFP-H148Q/I152L expressed in FRTL-5, a thyroid cell line with high NIS expression. Quantitation of intracellular concentrations revealed differences among anions in the affinity and maximal velocity of NIS-mediated uptake as well as in the rate constant for passive efflux. These results suggest that YFP-H148Q/I152L can serve as an intracellular biosensor of NIS-transported anions and may be useful to study the physiology of endogenous anions as well as the health-related consequences of environmental anions. PMID- 21545784 TI - Microplate-based kinetic method for assay of mitochondrial NADH-- and succinate- cytochrome c reductase activities. AB - This article describes a microplate-based kinetic assay for mitochondrial NADH-- and succinate--cytochrome c reductase activities in rat brain mitochondria. The assay reported here is based on the conventional spectrophotometric method and involves substrate-driven reduction of exogenous cytochrome c. Conditions regarding linearity with respect to time and protein concentration have been standardized. Furthermore, the methods were tested for inhibition of respective activities by specific inhibitors. The microplate format described here can be employed for rapid and simultaneous measurements of mitochondrial NADH-- and succinate--cytochrome c reductase activities in a large number of samples. PMID- 21545785 TI - Use of ribozyme cleavage kinetics to measure salt-induced changes in solution pH. AB - Several ribozymes are active in molar concentrations of monovalent salts, and pH rate curves under such conditions are consistent with mechanisms involving general acid-base catalysis. Interpreting the apparent pK(a) values requires an accurate estimation of solution pH, which can be difficult to obtain using a typical glass pH electrode in the presence of high salt concentrations. In the current work we have used the VS ribozyme as a "biological pH meter" to evaluate the effects of molar concentrations of monovalent salts on changes in solution pH. We find that almost all of the measured change in pH observed in high concentrations of LiCl is due to a real change in solution pH. In contrast, high concentrations of NaCl cause errors in pH measurement in addition to changes in actual pH. Different buffer systems affect both the direction and the magnitude of pH changes: we observed changes in measured pH of up to 1 pH unit, which require proper interpretation to avoid adverse effects on the conclusions drawn from pH rate and other experiments that utilize very high salt concentrations. PMID- 21545786 TI - Detection of glutathione in whole blood after stabilization with N ethylmaleimide. AB - The measurement of glutathione is a challenging task in that, during sample manipulation, a large percentage of this compound can be artificially oxidized. Here a high-performance liquid chromatography (HPLC) method to measure reduced glutathione in blood, based on the analysis of its conjugate with N ethylmaleimide, has been developed and validated. The method is linear in the concentration range 0.1-2 mM, and the lower limit of quantification is 0.05 mM. Blood samples treated with N-ethylmaleimide are stable at -20 degrees C for 90 days. This method has simplicity and rapidity as its main advantages; therefore, it is particularly suitable for large-scale clinical studies. PMID- 21545787 TI - An unbiased approach for analysis of protein glycosylation and application to influenza vaccine hemagglutinin. AB - Here a mass spectrometry-based platform for the analysis of glycoproteins is presented. Glycopeptides and released glycans are analyzed, the former by quadrupole orthogonal time-of-flight liquid chromatography/mass spectrometry (QoTOF LC/MS) and the latter by permethylation analysis using matrix-assisted laser desorption/ionization (MALDI)-TOF MS. QoTOF LC/MS analysis reveals the stochastic distribution of glycoforms at occupied sequons, and the latter provides a semiquantitative assessment of overall protein glycosylation. Hydrophilic interaction chromatography (HILIC) was used for unbiased enrichment of glycopeptides and was validated using five model N-glycoproteins bearing a wide array of glycans, including high-mannose, complex, and hybrid subtypes such as sulfo and sialyl forms. Sialyl and especially sulfated glycans are difficult to analyze because these substitutions are labile. The conditions used here allow detection of these compounds quantitatively, intact, and in the context of overall glycosylation. As a test case, we analyzed influenza B/Malaysia/2506/2004 hemagglutinin, a component of the 2006-2007 influenza vaccine. It bears 11 glycosylation sites. Approximately 90% of its glycans are high mannose, and 10% are present as complex and hybrid types, including those with sulfate. The stochastic distribution of glycoforms at glycosylation sites is revealed. This platform should have wide applications to glycoproteins in basic sciences and industry because no apparent bias for any glycoforms is observed. PMID- 21545788 TI - All-or-none membrane permeabilization by fengycin-type lipopeptides from Bacillus subtilis QST713. AB - The fungicidal activity of Bacillus subtilis QST713 has been utilized for the highly effective and environmentally safe protection of crops against a variety of pathogens. It is based mainly on the production of cyclic lipopeptides of the fengycin (FEs), surfactin, and iturin families. The mixed population of native FEs forms micelles which solubilize individual FEs such as agrastatin 1 (AS1) that are otherwise rather insoluble on their own. Fluorescence lifetime-based calcein efflux measurements and cryo transmission electron microscopy show that these FEs show a unique scenario of membrane permeabilization. Poor miscibility of FEs with lipid probably promotes the formation of pores in 10% of the vesicles at only~1MUM free FE and in 15% of the vesicles at 10 MUM. We explain why this limited, all-or-none leakage could nevertheless account for the killing of virtually all fungi whereas the same extent of graded vesicle leakage may be biologically irrelevant. Then, crystallization of AS1 and micellization of plipastatins cause a cut-off in leakage at 15% that might regulate the biological activity of FEs, protecting Bacillus and plant membranes. The fact that FE micelles solubilize only about 10 mol-% fluid lipid resembles the behavior of detergent resistance. PMID- 21545789 TI - Mechanics and dynamics of triglyceride-phospholipid model membranes: Implications for cellular properties and function. AB - We demonstrate here that triolein alters the mechanical properties of phospholipid membranes and induces extraordinary conformational dynamics. Triolein containing membranes exhibit fluctuations up to size range of 100MUm and with the help of these are e.g. able to squeeze through narrow passages between neighbouring structures. Triolein-phosphatidylcholine membranes were found to have bending rigidity significantly lower than that of corresponding pure phosphatidylcholine membrane. Moreover, the triolein containing membranes were found to be reluctant to fuse, which is in good accordance with larger lamellar distances observed in the TOPOPC membranes. These findings suggest repulsion between adjacent membranes. We provide a comprehensive discussion on the possible explanations for the observed mechanics and dynamics in the TOPOPC system and on their potential cellular implications. PMID- 21545790 TI - Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation. AB - Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor beta1 (TGFbeta1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose dependent manner, and both were suppressed by blockade of LPAR1/3. The pro proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1/3 signaling system is involved in the development of RLF through promoting fibroblast proliferation in a CTGF-dependent manner. The LPA-LPAR1/3-CTGF pathway may be a potential target for RLF therapy. PMID- 21545792 TI - Lack of association between paraoxonase 1 Q192R polymorphism and multiple sclerosis in relapse phase: A case-control study. AB - OBJECTIVES: The aim of this study was to estimate the serum activity of paraoxonase 1(PON1) and assess the distribution of PON1 polymorphisms in MS patients in the relapse phase. DESIGN AND METHODS: PON1 and arylesterase (ARE) serum activities were measured in two equal groups (each group 63 cases) of relapsing-remitting MS patients and healthy individuals. RESULTS: Mean values for serum PON1 and ARE activities were 90.3+/-63.4 and 182.1+/-128.7IU/L for patients and 99.9+/-73.3 and 190.8+/-150.3IU/L for controls. Those values were not statistically significant (p=0.242 and p=0.378), respectively. Comparing genotype distributions and allele frequencies in both groups for PON1 Q192R and PON L55M polymorphisms did not show any statistical difference. CONCLUSION: In a selected group of MS patients in relapsing phase no statistically significant difference in PON1 and ARE activities was detected but the mean values for the serum enzyme activities were lower in MS patients. PMID- 21545791 TI - Combining anticancer agents photodynamic therapy and LCL85 leads to distinct changes in the sphingolipid profile, autophagy, caspase-3 activation in the absence of cell death, and long-term sensitization. AB - Two anticancer agents, LCL85 and photodynamic therapy (PDT) were combined to test whether the combination PDT/LCL85 evokes changes in the sphingolipid (SL) profile and promotes cell death. Treatment of SCCVII mouse squamous carcinoma cells using the silicone phthalocyanine Pc 4 for PDT induced increases in the prodeath global ceramides/dihydroceramides (DHceramides), and no changes in the prosurvival sphingosine-1-phosphate (S1P). In contrast, after LCL85, the levels of most ceramides and DHceramides were reduced, whereas the levels of S1P were increased. After PDT/LCL85 the levels of global ceramides and DHceramides, and of S1P, were restored to resting levels. PDT/LCL85 also enhanced the levels of C18-, C20-, and C20:1-ceramide, and C18-DHceramide. Treatment with PDT, with or without LCL85, led to substantial reductions in sphingosine levels. PDT/LCL85 induced enhanced autophagy and caspase-3 activation. None of the treatments affected short-term viability of cells. In contrast, long-term clonogenic survival was reduced not only after PDT or LCL85, but even more after PDT/LCL85. Overall, our data show that short-term exposure to PDT/LCL85 led to distinct signature effects on the SL profile, enhanced autophagy, and caspase-3 activation without cell death. Long term exposure to PDT/LCL85 enhanced overall cell killing, supporting translational potential of PDT/LCL85. PMID- 21545793 TI - Netrin1 is required for neural and glial precursor migrations into the olfactory bulb. AB - Netrin1 (NTN1) deficiency in mouse brain causes defects in axon guidance and cell migration during embryonic development. Here we show that NTN1 is required for olfactory bulb (OB) development at late embryogenesis and at early postnatal stages to facilitate the accumulation of proper numbers of granular and glomerular neuron subtypes and oligodendrocytes into the OB. In addition to the analysis of Ntn1-/- mice we made tissue and neurosphere cultures to clarify the role of NTN1 in the anterior forebrain. We propose that a subset of neural progenitors/precursors requires NTN1 to efficiently enter the rostral migratory stream to migrate into the OB. The analysis of postnatal Ntn1-/- OBs revealed a reduction of specific types of interneurons which have been shown to originate from particular subregions of the lateral ventricle walls. Based on Ntn1 expression in ventral parts of the ventricle walls, we observed a decrease in the mainly ventrally derived type II interneurons that express calcium-binding proteins calretinin and calbindin. Instead, no change in the numbers of dorsally derived tyrosine hydroxylase expressing interneurons was detected. In addition to the specific reduction of type II interneurons, our results indicate that NTN1 is required for oligodendroglial migration into the OB. Furthermore, we characterised the Ntn1 expressing subpopulation of neurosphere-forming cells from embryonic and adult brain as multipotent and self-renewing. However, NTN1 is dispensable for the proliferation of neurosphere forming progenitor cells and for their differentiation. PMID- 21545794 TI - Hedgehog signaling controls homeostasis of adult intestinal smooth muscle. AB - The Hedgehog (Hh) pathway plays multiple patterning roles during development of the mammalian gastrointestinal tract, but its role in adult gut function has not been extensively examined. Here we show that chronic reduction in the combined epithelial Indian (Ihh) and Sonic (Shh) hedgehog signal leads to mislocalization of intestinal subepithelial myofibroblasts, loss of smooth muscle in villus cores and muscularis mucosa as well as crypt hyperplasia. In contrast, chronic over expression of Ihh in the intestinal epithelium leads to progressive expansion of villus smooth muscle, but does not result in reduced epithelial proliferation. Together, these mouse models show that smooth muscle populations in the adult intestinal lamina propria are highly sensitive to the level of Hh ligand. We demonstrate further that Hh ligand drives smooth muscle differentiation in primary intestinal mesenchyme cultures and that cell-autonomous Hh signal transduction in C3H10T1/2 cells activates the smooth muscle master regulator Myocardin (Myocd) and induces smooth muscle differentiation. The rapid kinetics of Myocd activation by Hh ligands as well as the presence of an unusual concentration of Gli sties in this gene suggest that regulation of Myocd by Hh might be direct. Thus, these data indicate that Hh is a critical regulator of adult intestinal smooth muscle homeostasis and suggest an important link between Hh signaling and Myocd activation. Moreover, the data support the idea that lowered Hh signals promote crypt expansion and increased epithelial cell proliferation, but indicate that chronically increased Hh ligand levels do not dampen crypt proliferation as previously proposed. PMID- 21545795 TI - Essential roles of snap-29 in C. elegans. AB - SNARE domain proteins are key molecules mediating intracellular fusion events. SNAP25 family proteins are unique target-SNAREs possessing two SNARE domains. Here we report the genetic, molecular, and cell biological characterization of C. elegans SNAP-29. We found that snap-29 is an essential gene required throughout the life-cycle. Depletion of snap-29 by RNAi in adults results in sterility associated with endomitotic oocytes and pre-meiotic maturation of the oocytes. Many of the embryos that are produced are multinucleated, indicating a defect in embryonic cytokinesis. A profound defect in secretion by oocytes and early embryos in animals lacking SNAP-29 appears to be the underlying defect connecting these phenotypes. Further analysis revealed defects in basolateral and apical secretion by intestinal epithelial cells in animals lacking SNAP-29, indicating a broad requirement for this protein in the secretory pathway. A SNAP-29-GFP fusion protein was enriched on recycling endosomes, and loss of SNAP-29 disrupted recycling endosome morphology. Taken together these results suggest a requirement for SNAP-29 in the fusion of post-Golgi vesicles with the recycling endosome for cargo to reach the cell surface. PMID- 21545796 TI - A potential for granulocyte-colony stimulating factor for use as a prophylactic agent for heatstroke in rats. AB - Heatstroke is a form of excessive hyperthermia associated with a systemic inflammatory response that leads to multi-organ dysfunction in which central nervous system disorders predominate. Herein we determined to ascertain whether heat-induced multi-organ dysfunction in rats could be attenuated by granulocyte colony stimulating factor (G-CSF) preconditioning. Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline, 0.3 ml, subcutaneously) or G-CSF (50-200 MUg/kg body weight in 0.3 ml normal saline, subcutaneously) daily and consecutively for 5 days before the start of thermal experiments. They were exposed to an ambient temperature of 43 degrees C for 68 min to induce heatstroke. G-CSF preconditioning significantly prolonged the survival time in heatstroke rats in a dose-related way (82-98 min vs 127-243 min). The non-preconditioning heatstroke animals showed hyperthermia, arterial hypotension, increased serum levels of systemic inflammatory response molecules, increased hypothalamic apoptotic cell numbers as well as neuronal damage scores, and increased serum levels of renal and hepatic dysfunction indicators. These heatstroke syndromes could be significantly reduced by G-CSF preconditioning. Thus our results revealed a potential for G-CSF used as a prophylactic agent for heatstroke in rats. PMID- 21545797 TI - The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2 chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxamide (SCH 655842): comparison of efficacy and side effects across rodent species. AB - The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3 10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species. PMID- 21545798 TI - Induction of G1 cell cycle arrest and apoptosis by berberine in bladder cancer cells. AB - Bladder cancer is the ninth most common type of cancer, and its surgery is always followed by chemotherapy to prevent recurrence. Berberine is non-toxic to normal cells but has anti-cancer effects in many cancer cell lines. This study was aimed to determine whether berberine inhibits the cell proliferation and induces cell cycle arrest and apoptosis in BIU-87 and T24 bladder cancer cell line. The superficial bladder cancer cell line BIU-87 and invasive T24 bladder cancer cells were treated with different concentrations of berberine. MTT assay was used to determine the effects of berberine on the viability of these cells. The cell cycle arrest was detected through propidium iodide (PI) staining. The induction of apoptosis was determined through Annexin V-conjugated Alexa Fluor 488 (Alexa488) staining. Berberine inhibited the viability of BIU-87 and T24 cells in a dose- and time-dependent manner. It also promoted cell cycle arrest at G0/G1 in a dose-dependent manner and induced apoptosis. We observed that H-Ras and c-fos mRNA and protein expressionswere dose-dependently and time-dependently decreased by berberine treatment. Also, we investigated the cleaved caspase-3 and caspase-9 protein expressions increased in a dose-dependent manner. Berberine inhibits the cell proliferation and induces cell cycle arrest and apoptosis in BIU-87, bladder cancer cell line and T24, invasive bladder cancer cell line. Berberine can inhibit the oncogentic H-Ras and c-fos in T24 cells, and can induce the activation of the caspase-3 and caspase-9 apoptosis. Therefore, berberine has the potential to be a novel chemotherapy drug to treat the bladder cancer by suppressing tumor growth. PMID- 21545799 TI - Long-lasting, distinct changes in central opioid receptor and urinary bladder functions in models of schizophrenia in rats. AB - Ketamine treatments and social isolation of rats reflect certain features of schizophrenia, among them altered pain sensitivity. To study the underlying mechanisms of these phenomena, rats were either housed individually or grouped for 33 days after weaning, and treated with either ketamine or saline for 14 days. After one month re-socialization, the urinary bladder capacity by ultrasound examination in the anesthetized animals, and changes of MU-opioid receptors by saturation binding experiments using a specific MU-opioid agonist [(3)H]DAMGO were determined. G-protein signaling was investigated in DAMGO stimulated [(35)S]GTPgammaS functional assays. Ketamine treatment significantly decreased the bladder volume and isolation decreased the receptor density in cortical membranes. Among all groups, the only change in binding affinity was an increase induced by social isolation in the cortex. G-protein signaling was significantly decreased by either ketamine or social isolation in this tissue. Ketamine treatment, but not housing, significantly increased MU-opioid receptor densities in hippocampal membranes. Both ketamine and isolation increased the efficacy, while the potency of signaling was decreased by any treatment. Ketamine increased the receptor density and G-protein activation; while isolation decreased the efficacy of G-protein signaling in hippocampal membranes. The changes in the co-treated group were similar to those of the isolated animals in most tests. The distinct changes of opioid receptor functioning in different areas of the CNS may, at least partially, explain the augmented nociceptive threshold and morphine potency observed in these animals. Changes in the relative urinary bladder suggest a detrusor hyperreflexia, another sign of schizophrenia. PMID- 21545800 TI - Effect of the p38 MAPK inhibitor SB-239063 on Lipopolysaccharide-induced psychomotor retardation and peripheral biomarker alterations in rats. AB - Lipopolysaccharide (LPS) administration in rats induces a characteristic syndrome termed 'sickness behavior', including profound changes on locomotor activity and circulating stress and inflammatory mediators. The aim of the present investigation was to evaluate whether the behavioral and the peripheral biomarker responses induced by LPS could be modified by acute treatment with the p38 mitogen-activated protein kinase inhibitor SB-239063. Male Sprague-Dawley rats were treated orally either with vehicle or SB-239063 (3, 10 and 30 mg/kg) 1h before an intraperitoneal injection of either saline or LPS 125 MUg/kg. Two hours after LPS injection, rats were placed in a novel open field arena for locomotion assessment during both the light and dark periods. Inflammation and stress mediators were evaluated in plasma 2, 3, 5 or 14 h into the dark phase. Pre treatment with SB-239063 significantly reversed the locomotor deficits induced by LPS injection. Interleukin (IL)-1beta, IL-6, IL-10, Granulocyte-Macrophage-Colony Stimulating Factor, Interferon-gamma, and C-reactive-protein levels were increased significantly by LPS, but not when LPS was preceded by SB-239063 treatment. LPS significantly decreased growth-hormone and Prolactin, and this effect was attenuated by SB-239063. Tumor Necrosis Factor-alpha, Adrenocorticotropic Hormone and Corticosterone levels were significantly higher in LPS-treated rats and were not normalized by SB-239063. Thus, we demonstrate that acute treatment with SB-239063 may have ameliorating effects in early changes of LPS-induced sickness behavior and alteration in the peripheral cytokines/hormones. As such, our procedure may offer an opportunity to test the activity of novel anti-inflammatory compounds on specific symptoms of sickness associated with neuroimmune dysfunctions. PMID- 21545801 TI - Long-term estradiol-17beta administration reduces population of neurons in the sympathetic chain ganglia supplying the ovary in adult gilts. AB - Elevated levels of endogenous estrogens occurring in the course of pathological states of ovaries (follicular cysts, tumors) as well as xenoestrogens may result in hyperestrogenism. In rat, a close relationship between estrogens and sympathetic and sensory neurons supplying the genito-urinary system was reported. Recently, we have shown that long-term estradiol-17beta (E(2)) administration affected morphological and immunochemical organization of the sympathetic ovarian neurons in the caudal mesenteric ganglion of adult gilts. In this study, the influence of E(2) overdose on the number and distribution of neurons in the sympathetic chain ganglia (SChG) projecting to the ovary of adult pigs was investigated. The numbers of ovarian dopamine-beta-hydroxylase (DbetaH-), neuropeptide Y (NPY-), somatostatin (SOM-), galanin (GAL-) and estrogen receptors (ERs-) immunoreactive perikarya as well as the density of the intraganglionic nerve fibers containing DbetaH and/or NPY, SOM, GAL were also determined. On day 3 of the estrous cycle the ovaries of both the control and experimental gilts were injected with retrograde neuronal tracer Fast Blue, to identify the neurons innervating gonads. From day 4 of the estrous cycle to the expected day 20 of the second studied cycle, the experimental gilts were injected with E(2), while the control gilts were receiving oil. After the last E(2)/oil injection, the SChG Th16-S2 were collected and processed for double-labeling immunofluorescence. Injections of E(2): (1) increased the E(2) level in the peripheral blood ~4-5 fold, (2) reduced the total number of Fast Blue-positive postganglionic neurons in the ganglia under investigation, (3) decreased the number of perikarya in the L2-L4 ganglia, (4) reduced the number of perikarya in the ventral, dorsal and central regions of the SChG, (5) decreased the numbers of DbetaH(+)/NPY(+) and DbetaH(+)/GAL(+) perikarya and the numbers of DbetaH(+) but NPY(-), SOM(-) and GAL(-) perikarya in the SChG, (6) decreased the number of perikarya expressing ERs subtype alpha and beta, and (7) decreased the total number of the intraganglionic nerve fibers containing DbetaH and/or NPY. These results show that long-term E(2) treatment of adult gilts down-regulates the population of both noradrenergic and ERs expressing the SChG ovary supplying neurons. Our findings suggest also that elevated E(2) levels that occur during pathological states may regulate gonadal function(s) by affecting ovary supplying neurons. PMID- 21545802 TI - The CYP701B1 of Physcomitrella patens is an ent-kaurene oxidase that resists inhibition by uniconazole-P. AB - The moss Physcomitrella patens produces both ent-kaurene and ent-kaurenoic acid, which are intermediates of gibberellin biosynthesis in flowering plants. The CYP701 superfamily of cytochrome P450s functions as ent-kaurene oxidases in the biosynthesis of ent-kaurenoic acid. A candidate gene encoding ent-kaurene oxidase in P. patens, CYP701B1, was cloned and heterologously expressed in yeast to examine enzyme activities in vitro. The recombinant CYP701B1 protein catalyzed the oxidation reaction from ent-kaurene to ent-kaurenoic acid. CYP701B1 activity was highly resistant to the ent-kaurene oxidase inhibitor uniconazole-P (IC(50) 64 MUM), even though the activity of Arabidopsis ent-kaurene oxidase (CYP701A3) was sensitive (IC(50) 0.26 MUM). PMID- 21545803 TI - Reproductive plasticity in Polistes paper wasp workers and the evolutionary origins of sociality. AB - Regulatory pathways in solitary species provide the raw materials for the evolution of sociality. Therefore, comparing the mechanisms that mediate reproductive plasticity in social species and their solitary ancestors can provide insight into the evolutionary origin of sociality. In many solitary insects, the effect of juvenile hormone (JH) on fertility is mediated through the fat body; individuals in good physical condition show a stronger fertility response to JH than individuals in poor physical condition. Here, we test whether a similar, condition-dependent JH response mediates fertility in workers of the primitively eusocial Polistes dominulus wasps. We test how body weight, JH, and adult nutrition influence worker ovarian development. Both JH-treatment and adult nutrition dramatically increased ovarian development. Body weight also influenced ovarian development, as large workers developed more eggs than smaller workers. Body weight and fat are strongly linked in P. dominulus workers, so these results suggest that the fat-dependent JH responsiveness common in solitary insects is conserved in social wasps. The simple, ancestral relationship between reproductive investment and physical condition may facilitate cooperation by allowing workers to adaptively allocate energy into reproduction based on their probability of successfully becoming a queen. PMID- 21545804 TI - Survey of bumble bee (Bombus) pathogens and parasites in Illinois and selected areas of northern California and southern Oregon. AB - Pathogens have been implicated as potential factors in the recent decline of some North American bumble bee (Bombus) species, but little information has been reported about the natural enemy complex of bumble bees in the United States. We targeted bumble bee populations in a state-wide survey in Illinois and several sites in California and Oregon where declines have been reported to determine presence and prevalence of natural enemies. Based on our observations, most parasites and pathogens appear to be widespread generalists among bumble bee species, but susceptibility to some natural enemies appeared to vary. PMID- 21545806 TI - Azido analogs of neuroactive steroids. AB - Analogs of pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), modified in position 17 were prepared. Compounds with 20-keto pregnane side chain replaced completely by azide (17alpha- and 17beta-azido-5beta-androstan-3alpha-ol), compounds with its part replaced (20-azido-21-nor-5beta-pregnan-3alpha-ol), and compounds with keto group only replaced ((20R)- and (20S)-20-azido-5beta-pregnan 3alpha-ol) were synthesized using tosylate displacements with sodium azide or Mitsunobu reaction with azoimide. All five azido steroids were converted into corresponding sulfates. Subsequent tests for inhibition of glutamate induced response on NMDA receptors revealed that modification of pregnanolone sulfate side chain with azide did not disturb the activity and some of sulfates tested were more active than parent compound. PMID- 21545805 TI - Methylphenidate and MU opioid receptor interactions: a pharmacological target for prevention of stimulant abuse. AB - Methylphenidate (MPH) is one of the most commonly used and highly effective treatments for attention deficit hyperactivity disorder (ADHD) in children and adults. As the therapeutic use of MPH has increased, so has its abuse and illicit street-use. Yet, the mechanisms associated with development of MPH-associated abuse and dependence are not well understood making it difficult to develop methods to help its mitigation. As a result, many ADHD patients especially children and youth, that could benefit from MPH treatment do not receive it and risk lifelong disabilities associated with untreated ADHD. Therefore, understanding the mechanisms associated with development of MPH addiction and designing methods to prevent it assume high public health significance. Using a mouse model we show that supra-therapeutic doses of MPH produce rewarding effects (surrogate measure for addiction in humans) in a conditioned place preference paradigm and upregulate MU opioid receptor (MOPR) activity in the striatum and nucleus accumbens, brain regions associated with reward circuitry. Co administration of naltrexone, a non-selective opioid receptor antagonist, prevents MPH-induced MOPR activation and the rewarding effects. The MPH-induced MOPR activation and rewarding effect require activation of the dopamine D1 but not the D2-receptor. These findings identify the MOPR as a potential target for attenuating rewarding effects of MPH and suggest that a formulation that combines naltrexone with MPH could be a useful pharmaceutical approach to alleviate abuse potential of MPH and other stimulants. PMID- 21545807 TI - Functional MRI approach to developmental methylmercury and polychlorinated biphenyl neurotoxicity. AB - Prenatal and early childhood exposure to methylmercury (MeHg) or polychlorinated biphenyls (PCBs) are associated with deficits in cognitive, sensory, motor and other functions measured by neurobehavioral tests. The main objective of this pilot study was to determine whether functional magnetic resonance imaging (fMRI) is effective for visualization of brain function alterations related to neurobehavior in subjects with high prenatal exposure to the two neurotoxicants, MeHg and PCBs. Twelve adolescents (all boys) from a Faroese birth cohort assembled in 1986-1987 were recruited based on their prenatal exposures to MeHg and PCB. All underwent fMRI scanning during behavioral tasks at age 15 years. Subjects with high mixed exposure to MeHg and PCBs were compared to those with low mixed exposure on fMRI photic stimulation and a motor task. Boys with low mixed exposures showed patterns of fMRI activation during visual and motor tasks that are typical of normal control subjects. However, those with high exposures showed activation in more areas of the brain and different and wider patterns of activation than the low mixed exposure group. The brain activation patterns observed in association with increased exposures to MeHg and PCBs are meaningful in regard to the known neurotoxicity of these substances. This methodology therefore has potential utility in visualizing structural neural system determinants of exposure-induced neurobehavioral dysfunction. PMID- 21545808 TI - Humoral responses and immune protection in mice immunized with irradiated T. gondii tachyzoites and challenged with three genetically distinct strains of T. gondii. AB - Toxoplasma gondii is an obligate intracellular parasite that infects a variety of mammals and birds. T. gondii also causes human toxoplasmosis; although toxoplasmosis is generally a benign disease, ocular, congenital or reactivated disease is associated with high numbers of disabled people. Infection occurs orally through the ingestion of meat containing cysts or by the intake of food or water contaminated with oocysts. Although the immune system responds to acute infection and mediates the clearance of tachyzoites, parasite cysts persist for the lifetime of the host in tissues such as the eye, muscle, and CNS. However, T. gondii RH strain tachyzoites irradiated with 255Gy do not cause residual infection and induce the same immunity as a natural infection. To assess the humoral response in BALB/c and C57BL/6J mice immunized with irradiated tachyzoites either by oral gavage (p.o.) or intraperitoneal (i.p.) injection, we analyzed total and high-affinity IgG and IgA antibodies in the serum. High levels of antigen-specific IgG were detected in the serum of parenterally immunized mice, with lower levels in mice immunized via the oral route. However, most serum antibodies exhibited low affinity for antigen in both mice strain. We also found antigen specific IgA antibodies in the stools of the mice, especially in orally immunized BALB/c mice. Examination of bone marrow and spleen cells demonstrated that both groups of immunized mice clearly produced specific IgG, at levels comparable to chronic infection, suggesting the generation of IgG specific memory. Next, we challenged i.p. or p.o. immunized mice with cysts from ME49, VEG or P strains of T. gondii. Oral immunization resulted in partial protection as compared to challenged naive mice; these findings were more evident in highly pathogenic ME49 strain challenge. Additionally, we found that while mucosal IgA was important for protection against infection, antigen-specific IgG antibodies were involved with protection against disease and disease pathogenesis. Most antigen responsive cells in culture produced specific high-affinity IgG after immunization, diverse of the findings in serum IgG or from cells after infection, which produced low proportion of high-avidity IgG. PMID- 21545809 TI - Expression of recombinant West Nile virus prM protein fused to an affinity tag for use as a diagnostic antigen. AB - Previous studies have concluded that the Flavivirus prM protein is a suitable viral antigen to distinguish serologically between infections with closely related Flaviviruses (Cardosa et al., 2002). To express the recombinant West Nile virus (WNV) prM antigen fused to a suitable affinity tag for purification, a series of prM-His-tag and prM-V5-tag fusion proteins were generated. Analysis of the prM-His-tag fusion proteins revealed that either prM epitopes were disrupted or the His-tag was not presented properly depending on the location of the His tag and the presence of the prM transmembrane domains in these constructs. This identified domains critical for proper folding of prM, and arrangements that allowed the correct presentation of the His-tag. However, the inclusion of the V5 epitope tag fused to the C terminus of prM allowed formation of the authentic antigenic structure of prM and the proper presentation of the V5 epitope. Capture of tagged recombinant WNV(NY99) prM antigen to the solid phase with anti-V5 antibody in ELISA enabled the detection of prM-specific antibodies in WNV(NY99) immune horse serum, confirming its potential as a useful diagnostic reagent. PMID- 21545810 TI - Development of loop-mediated isothermal amplification assay for detection of human coronavirus-NL63. AB - Human coronavirus NL63 was identified in 2004 in the Netherlands. Due to the high prevalence and world-wide distribution of this pathogen, it is essential to develop a sensitive and specific detection assay suitable for use in a routine diagnostic laboratory. Techniques based on PCR or real-time PCR are laborious and expensive. Detailed analysis of the HCoV-NL63 genome permitted the identification of a conserved nucleic acid sequential motif, which was sufficient for the design of a loop-mediated isothermal amplification (LAMP) assay. Evaluation of the method showed that the test is specific to HCoV-NL63 and that it does not cross react with other respiratory viruses. The detection limit was found to be 1 copy of RNA template per reaction in cell culture supernatants and clinical specimens. PMID- 21545811 TI - Multiplex high resolution melting assay for estimation of Porcine Endogenous Retrovirus (PERV) relative gene dosage in pigs and detection of PERV infection in xenograft recipients. AB - Porcine Endogenous Retrovirus (PERV) poses an infectious risk in the field of xenotransplantation. This risk may be mitigated by breeding selectively animals bearing favorable PERV genetic characteristics including pigs with low levels of PERV integrated in the genome. A real-time quantitative polymerase chain reaction (PCR) assay employing the Roche High Resolution Melting (HRM) Master was used to estimate the relative gene dosage of PERV pol integrated within the pig genome. When assessed across 99 pigs of the Auckland Island breed numerous animals bearing low gene dosage were identified. The assay was adapted further to perform multiplex PCR for the detection of PERV infection within xenograft recipients. Besides PERV, amplification targets for the multiplex PCR include a pig cell marker for the determination of microchimerism and an internal amplification control (IAC) to assess the efficiency of nucleic acid isolation and effects of PCR inhibition. When 12 patients who had received porcine islet transplants were tested no evidence of PERV infection was found. The assay was shown to be specific, highly reproducible with superior performance over conventional nested PCR. This assay can be used as both a screening tool for PERV proviral levels within donor pigs and as a diagnostic tool to examine PERV transmission in human patients treated with porcine xenotransplantation material. PMID- 21545812 TI - Breaking B and T cell tolerance using cationic lipid--DNA complexes (CLDC) as a vaccine adjuvant with hepatitis B virus (HBV) surface antigen in transgenic mice expressing HBV. AB - Cationic lipid DNA complexes (CLDC), referred to here as JVRS-100, were evaluated as an adjuvant for hepatitis B surface antigen (HBsAg) for eliciting B and T cell responses in transgenic mice expressing hepatitis B virus (HBV). To confirm the immunogenicity of HBsAg+JVRS-1000, a study was conducted in C57BL/6 mice, the genetic background of the HBV transgenic mice used in the study. HBsAg+JVRS-100 elicited a T cell response and B cell response as evidenced by interferon-gamma (IFN-gamma) secretion by re-stimulated splenocytes and anti-HBsAg IgG induction, respectively, whereas, HBsAg only elicited a B cell response. In HBV transgenic mice, HBsAg did not elicit either T or B cell responses, unlike the HBsAg+JVRS 100 that elicited both. Energix-B vaccine did perform better than the HBsAg by eliciting a B cell response in the transgenic mice, but it did not perform as HBsAg+JVRS-100 since it did not elicit a T cell response. The response by HBsAg+JVRS-100 was not sufficient to cause destruction of infected liver cells, but it did suppress HBV DNA non-cytolytically. From these results, JVRS-100 might be considered for further development as an adjuvant for HBV therapeutic vaccines. PMID- 21545813 TI - Zinc transporter ZnT3 is involved in memory dependent on the hippocampus and perirhinal cortex. AB - Since zinc transporter ZnT3 is localized to the hippocampus and perirhinal cortex, we used ZnT3 knockout mice (KO) to analyze the role of ZnT3 in memory and behavior dependent on these brain regions. ZnT3KO mice were normal in initial learning in the standard water maze but had difficulty finding a second platform location. The mutants showed increased social interaction but were deficient in social and object recognition memory. These data suggest that ZnT3 is involved in certain types of spatial memory and behavior dependent on the hippocampus and perirhinal cortex. PMID- 21545814 TI - The relationship between adiponectin, ageing and renal function in a bi-ethnic sample. AB - Ageing is associated with elevated adiponectin levels. Our aim was to assess whether age-related increase in adiponectin is associated with a decrease in renal function. The study comprised African (N=277) and Caucasian (N=326) men and women. Adiponectin levels, estimated creatinine clearance rate and obesity indices were determined. African men revealed significantly higher adiponectin levels compared to Caucasian men (p<0.01), reflecting the lower adiposity levels of the African men. No difference in obesity measures (p=0.92) and adiponectin levels (p=0.27) was observed between African and Caucasian women. A significant increase in adiponectin levels with ageing was observed in both African men and women (p<0.01). To the contrary, progressive ageing seems not to be significantly related to elevated adiponectin levels within Caucasians. Renal impairment decreased significantly within all of the groups (p<0.01). Single regression analyses performed in all specified groups revealed significant associations between adiponectin and estimated creatinine clearance, however a multiple regression model revealed that insulin resistance had the strongest association with adiponectin within all the groups. In conclusion, age-related rise in adiponectin levels observed in Africans may not be due to renal impairment. PMID- 21545815 TI - Blockade of angiotensin II improves hyperthyroid induced abnormal atrial electrophysiological properties. AB - BACKGROUND: Previous studies reported that RAS inhibitors prevented atrial fibrillation by improving atrial electrical and structural remodeling. However, the effect of RAS inhibitors on the substrates of atrial fibrillation (AF) underlying hyperthyroid is unclear. METHODS: Forty rabbits were assigned to four groups: sham group, thyroxine group, benazepril group and irbesartan group (10 per group). The atrial effective refractory period (AERP) was measured. The physiologic rate adaptation and the AF vulnerability were evaluated. The real time PCR, Western blot or fluorescent immunohistochemistry was performed to detect the expression of AF related Ca+, K+ channel and gap junction. RESULTS: No significant difference was found in AERP among the thyroxine group, benazepril group and irbesartan group (75.13+/-5.41ms vs. 76.63+/-4.44ms, 79+/-4.95ms, P=0.28). However, benazepril or irbesartan could reduce AF vulnerability underlying hyperthyroid (75% vs. 37%, 44%, for thyroxine group, benazepril group and irbesartan group, respectively), and significantly improved physiologic rate adaptation of the AERP. Furthermore, both drugs significantly reduced L-Ca(2+) channel related subunits (alpha1C or alpha1D) and interstitial fibrosis (17.1+/ 2.2% vs. 12.3+/-1.8, 11.7+/-1.2%, P<0.01, for thyroxine group, benazepril group and irbesartan group, respectively), increased lateral/polar connection of Cx43 (1.04+/-0.16 vs. 1.33+/-0.29,1.28+/-0.25, P<0.01, for thyroxine group, benazepril group and irbesartan group, respectively) and improved the abnormal distribution of gap junctions (Cx40, Cx43) underlying hyperthyroid. CONCLUSION: Blockade of angiotensin II could improve abnormal atrial electrophysiological properties and further reduce AF vulnerability by extenuating ion channel, gap junction and structural remodeling in experimental thyrotoxic rabbits. PMID- 21545816 TI - Aldosterone induction of hepatic stellate cell contraction through activation of RhoA/ROCK-2 signaling pathway. AB - The RhoA/ROCK-2 signaling pathway is necessary for activated hepatic stellate cell (HSC) contraction. HSC contraction plays an important role in the pathogenesis of cirrhosis and portal hypertension. This study investigated whether aldosterone contributes to HSC contraction by activation of the RhoA/ROCK 2 signaling pathway. Primary HSCs were isolated from Sprague-Dawley rats via in situ pronase/collagenase perfusion. We found that aldosterone enhanced the contraction of a collagen lattice seeded with HSCs. This induced contraction was suppressed by the mineralcorticoid receptor (MR) inhibitor spironolactone, the ROCK-2 inhibitor Y27632, and the angiotensin II type 1 receptor (AT(1)R) inhibitor irbesartan. Moreover, actin fiber staining showed that aldosterone significantly increased actin fiber formation in HSCs. Pre-incubating with spironolactone, Y27632, or irbesartan inhibited the aldosterone-induced actin fiber reorganization. Molecularly, the effect of aldosterone on activation of HSC contraction was mediated by phosphorylated myosin light chain (P-MLC) through the RhoA/ROCK-2 signaling pathway. All these inhibitors had the ability to block aldosterone-induced protein expressions in the RhoA/ROCK-2/P-MLC cascade in HSCs. Taken together, our current study suggests that aldosterone induces contraction of activated HSCs through the activation of the RhoA/ROCK-2 signaling pathway. This finding may provide a potential therapeutic target for control of cirrhosis and portal hypertension. PMID- 21545817 TI - Oxytocin in the periaqueductal grey regulates nociception in the rat. AB - Studies have demonstrated that oxytocin (OXT) plays important roles in pain modulation in the central nervous system, and there are OXT receptors in the periaqueductal grey (PAG). The experiment was designed to investigate the effect of OXT in the PAG on antinociception. The results showed that (1) intra-PAG injection of OXT increased the pain threshold, whereas the local administration of the high specific OXT receptor antagonist, desGly-NH(2), d(CH(2))(5)[D-Tyr(2), Thr-sup-4]OVT decreased the pain threshold in a dose-dependent manner; (2) Pain stimulation could elevate OXT concentration in the PAG perfusion liquid. The data suggested that OXT in the PAG was involved in the antinociceptive process through the OXT receptor. PMID- 21545818 TI - A novel flow cytometry-based assay for the quantification of Staphylococcus aureus adhesion to and invasion of eukaryotic cells. AB - Flow cytometry is a powerful tool for analyzing the adhesion to and invasion of Staphylococcus aureus (S. aureus) to eukaryotic cells. Established techniques have used bacteria that have been genetically modified to express fluorescent proteins or directly labeled with fluorochromes prior to infection. Such approaches are appropriate in most cases; however, the use of genetically or chemically altered bacteria could introduce a bias when measuring fine differences in adhesion and invasiveness. Here, we describe a combined flow cytometry-based invasion and adhesion assay that does not require the processing of bacteria prior to internalization. This method was performed on osteoblastic MG-63 cells infected with S. aureus reference strain 8325-4 and its invasion deficient isogenic mutant, which carries deletions in the genes encoding fibronectin-binding proteins A and B. The data from this assay were compared to those obtained using the standard gentamicin protection assay. The results obtained by the two methods were consistent. Moreover, quantification of internalized bacteria was more reproducible using the flow cytometry-based assay than the gentamicin protection assay, which allowed for the simultaneous quantification of host cell adhesion and invasion. PMID- 21545819 TI - Circulating vascular endothelial growth factor is independently and negatively associated with trait anxiety and depressive mood in healthy Japanese university students. AB - OBJECTIVE: Anxiety and depressive mood are sometimes accompanied by modulation of neuroendocrine and immune functions. The aim of this study was to identify circulating immune mediators reflecting anxiety and depressive mood in healthy young adults. METHODS: Anxiety and depressive mood in 209 healthy medical students (125 males and 84 females, aged 20.7+/-2.7years (mean+/-SD)) were assessed by the Spielberger state-trait anxiety inventory (STAI) and the Zung self-rating depression scale (Zung-SDS), respectively. Cortisol and chromogranin A (CgA) levels in saliva were measured using enzyme immunoassay kits, and 50 different mediators in sera were measured by a multiplex-suspension array system. The level of statistical significance was set at alpha=0.05. RESULTS: Forty-four mediators were measurable in sera, and each mediator showed substantial individual variations. After determining Pearson correlation coefficients, we selected candidate cytokines whose levels were associated with STAI-state (2 cytokines), STAI-trait (8 cytokines), or SDS scores (8 cytokines). The candidate cytokines plus interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and macrophage migration inhibitory factor were then subjected to multiple regression analysis adjusted for gender, BMI, and salivary concentrations of cortisol and CgA. Vascular endothelial growth factor (VEGF) was independently and negatively associated with both trait anxiety (p<0.05) and depressive mood (p<0.01). IL 1beta showed independently positive association with depressive mood (p<0.05). Interactions between these two cytokines and gender or BMI were not observed. CONCLUSION: Besides IL-1beta, circulating VEGF may be a potential biomarker for negative mood states in healthy young adults. PMID- 21545820 TI - Human leukocyte antigen class II and type 1 diabetes in Latin America: a combined meta-analysis of association and family-based studies. AB - Conclusions from association studies could be spurious because of population stratification; therefore we combined association with family studies seeking to confirm which human leukocyte antigen (HLA) class II alleles/haplotypes were associated with type 1 diabetes (T1D) in the admixed Latin America. By calculating the effect summary odds ratios (OR) and their 95% confidence intervals (95% CI), data up to June 2010 showed that risk associations were observed with DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [OR]: 7.51; 95% confidence interval [CI]: 3.69-15.25) and DQB1*0302 in presence of DRB1*0405 (OR: 11.64; 95% CI: 3.15-43.01) or DRB1*0401 (OR: 5.85; 95% CI: 3.07-11.14). In contrast, DRB1*0404-DQB1*0302 had a nonsignificant TID risk (OR: 2.23; 95% CI: 0.91-5.43). T1D protective associations were observed with DRB1*11-DQA1*0501 DQB1*0301 (OR: 0.24; 95% CI: 0.1-0.56) and DRB1*15-DQA1*0102-DQB1*0602 (OR: 0.35; 95% CI: 0.17-0.73). These results were similar to those observed in Caucasian and other populations, thus highlighting the primary role of class II HLA in T1D regardless of ethnicity. A DRB1*04 risk hierarchy was confirmed with the DRB1*0405 being in the top. A binding prediction analysis disclosed possible receptor-ligand interactions in the HLA-antigenic peptide complex. PMID- 21545821 TI - Characterization of the murine Th2 response to immunization with liposomal M2e influenza vaccine. AB - While the current influenza vaccine strategy is dependent on eliciting neutralizing antibodies to the hemagglutinin (H or HA) surface glycoprotein, antigenic drifts and occasional antigenic shifts necessitate constant surveillance and annual updates to the vaccine components. The ectodomain of the matrix 2 (M2e) channel protein has been proposed as a universal vaccine candidate, although it has not yet been shown to elicit neutralizing antibodies. Utilizing a liposome-based vaccine technology, an M2e vaccine (L-M2e-HD/MPL) was tested and shown to stimulate the production of anti-M2e antibodies which precipitated with whole virus and inhibited viral cell lysis by multiple type A strains of influenza virus using a novel in vitro assay. The anti-M2e antibodies also conferred complete protection following passive transfer from L-M2e-HD/MPL vaccinated mice to naive mice challenged with H1N1 virus. Significantly higher levels of IL-4 compared to IFN-gamma were secreted by the splenocytes of L-M2e HD/MPL vaccinated mice incubated with M2e. In addition, depletion of CD4 cells or CD4 cells plus CD8 cells from L-M2e-HD/MPL vaccinated mice using monoclonal antibodies markedly decreased the level of protection of the vaccine when compared to just CD8 depletion of L-M2e-HD/MPL vaccinated mice. These results suggest that the protective immune response elicited by this vaccine is mediated primarily by a Th2 mechanism. PMID- 21545822 TI - Seasonal influenza vaccine uptake in Germany 2007/2008 and 2008/2009: results from a national health update survey. AB - In 2008/2009 a nationwide cross-sectional telephone survey was conducted to assess, among other health-relevant parameters, seasonal influenza vaccination coverage. Data from 21,262 household-interviews representative of the adult population in Germany were collected and analyzed. In seasons 2007/2008 and 2008/2009, vaccine uptake in individuals aged >=60 years was 57% and 55% and in individuals with underlying chronic diseases 44% and 42%. Living in the eastern part of Germany, higher age, and medium household income level were independently associated with higher vaccine uptake in both target groups. Healthcare workers were significantly less frequently (21.9% in 2007/2008; 20.4% in 2008/2009) vaccinated than the general population (30.8% and 28.1%). Special effort must be undertaken to develop immunization strategies for improved vaccine uptake in target groups, especially in healthcare workers. PMID- 21545823 TI - Risk assessment of local dermal effects and skin sensitisation under the EU Chemicals Regulation REACH: a proposal for a qualitative, exposure scenario specific, approach. AB - Within the framework of REACH, an assessment regarding local dermal effects and skin sensitisation should be performed for substances. Quantitative hazard information for these effects is often not available. Furthermore, it is difficult to relate the way in which animals are exposed in dermal toxicity studies directly to dermal exposure in practice. In the absence of quantitative information, a qualitative assessment for dermal effects is the most reasonable option. The qualitative approach as proposed in the REACH guidance recommends only general risk management measures (RMM) for three categories with a low, moderate and high identified hazard, without specifying which RMM are needed for a specific exposure scenario. We propose to differentiate frequency of exposure based on differences in activities and to compare measured and estimated local skin exposure levels with rules of thumb for evaluation of control of risks per hazard category. For workers, specific RMM regimes are assigned to each combination of hazard category and process category (PROC). For consumers, a strategy in which RMM are arranged from product-integrated measures to the use of personal protective equipment (PPE) is presented. Our approach may be transferred into automated assessment tools like Chesar and CEFIC GES. PMID- 21545826 TI - Elevation of brain serotonin during dying. AB - Death and dying are central events in the live of an organism, but neurobiological changes during this process are still rarely understood. Extracellular levels of serotonin, one of the phylogenetically oldest neurotransmitters, were measured continuously during dying. Serotonin levels increased threefold, while the EEG recorded simultaneously went down to a zero line of no activity. This could be caused by the neuroprotective activity of brain serotonergic system, which subjectively makes dying easier due to the mood enhancing function of this neurotransmitter. PMID- 21545825 TI - Bioluminescence imaging of the brain response to acute inflammation in living C/EBP reporter mice. AB - The transcription factor CCAAT enhancer binding protein (C/EBP) is a key regulator of inflammation and immune responses, and recent studies suggest it is involved in inflammatory processes in the nervous system. We generated a transgenic reporter mouse model, carrying the luciferase (luc) gene under the transcriptional control of C/EBP, for visualising C/EBP activity in vivo. Real time bioluminescence imaging reflecting C/EBP activity was performed in an acute inflammation model, after systemic administration of lipopolysaccharides (LPS), in C/EBP-luc mice. A striking activity of C/EBP was imaged predominantly in the brain of living C/EBP-luc mice in response to LPS, showing for the first time in vivo that C/EBP mediates the brain response to inflammation. Furthermore, dexamethasone, a potent anti-inflammatory agent, diminished the LPS-induced C/EBP activity demonstrating the physiological regulation of bioluminescence intensity in the brain of C/EBP-luc mice. Our results implicate that C/EBP reporter mice have the potential to be a valuable tool for studies on the mechanisms of brain inflammation in vivo and for the noninvasive preclinical evaluation of therapeutic agents targeting neuroinflammatory diseases. PMID- 21545824 TI - Berberine acutely activates the glucose transport activity of GLUT1. AB - Berberine, which has a long history of use in Chinese medicine, has recently been shown to have efficacy in the treatment of diabetes. While the hypoglycemic effect of berberine has been clearly documented in animal and cell line models, such as 3T3-L1 adipocytes and L6 myotube cells, the mechanism of action appears complex with data implicating activation of the insulin signaling pathway as well as activation of the exercise or AMP kinase-mediated pathway. There have been no reports of the acute affects of berberine on the transport activity of the insulin-insensitive glucose transporter, GLUT1. Therefore, we examined the acute effects of berberine on glucose uptake in L929 fibroblast cells, a cell line that express only GLUT1. Berberine- activated glucose uptake reaching maximum stimulation of five-fold at >40 MUM. Significant activation (P < 0.05) was measured within 5 min reaching a maximum by 30 min. The berberine effect was not additive to the maximal stimulation by other known stimulants, azide, methylene blue or glucose deprivation, suggesting shared steps between berberine and these stimulants. Berberine significantly reduced the K(m) of glucose uptake from 6.7 +/- 1.9 mM to 0.55 +/- 0.08 mM, but had no effect on the V(max) of uptake. Compound C, an inhibitor of AMP kinase, did not affect berberine-stimulated glucose uptake, but inhibitors of downstream kinases partially blocked berberine stimulation. SB203580 (inhibitor of p38 MAP kinase) did not affect submaximal berberine activation, but did lower maximal berberine stimulation by 26%, while PD98059 (inhibitor of ERK kinase) completely blocked submaximal berberine activation and decreased the maximal stimulation by 55%. It appears from this study that a portion of the hypoglycemic effects of berberine can be attributed to its acute activation of the transport activity of GLUT1. PMID- 21545827 TI - Olanzapine plus fluoxetine treatment increases Nt-3 protein levels in the rat prefrontal cortex. AB - Evidence is emerging for a role for neurotrophins in the treatment of mood disorders. In this study, we evaluated the effects of chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on the brain derived-neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in the rat brain. Wistar rats received daily injections of olanzapine (3 or 6 mg/kg) and/or fluoxetine (12.5 or 25mg/kg) for 28 days, and we evaluated for BDNF, NGF and NT-3 protein levels in the prefrontal cortex, hippocampus and amygdala. Our results showed that treatment with fluoxetine and olanzapine alone or in combination did not alter BDNF in the prefrontal cortex (p=0.37), hippocampus (p=0.98) and amygdala (p=0.57) or NGF protein levels in the prefrontal cortex (p=0.72), hippocampus (p=0.23) and amygdala (p=0.64), but NT-3 protein levels were increased by olanzapine 6 mg/kg/fluoxetine 25mg/kg combination in the prefrontal cortex (p=0.03), in the hippocampus (p=0.83) and amygdala (p=0.88) NT-3 protein levels did not alter. Finally, these findings further support the hypothesis that NT-3 could be involved in the effect of treatment with antipsychotic and antidepressant combination in mood disorders. PMID- 21545828 TI - Hepatoprotective effect of curcumin in lipopolysaccharide/-galactosamine model of liver injury in rats: relationship to HO-1/CO antioxidant system. AB - This work studied a relationship between HO-1/CO system and lipid peroxidation with consequent effects on liver functions and NOS-2. We focused on curcumin pretreatment in rat toxic model of d-galactosamine and lipopolysaccharide. Hepatocyte viability, lipid peroxidation, antioxidant status, ALT and AST were evaluated. HO-1 and NOS-2 expressions and respective enzyme activity were determined. Curcumin caused decreases in ALT and AST levels as well as in lipid peroxidation. Furthermore, curcumin pretreatment increased liver HO-1 (2.4-fold, p=0.001), but reduced NOS-2 (4.1-fold, p=0.01) expressions. In conclusion, the tuning of CO/NO pathways is important in shedding light on curcumin's cytoprotective effects in this model. PMID- 21545829 TI - Mechanisms of intake induction of a low-nutritious food in sheep (Ovis aries). AB - Intake induction refers to the phenomenon by which animals increase consumption of a less-valued meal when followed by a highly-preferred food relative to when followed by no food or by the same less-preferred food. In the Training phase of the present experiment, we assessed the induction effect in sheep using a within subject design where learning could be tested while controlling for digestive state. Results showed that, once intake reached stability, subjects ate more low nutritious food (oat hay) when followed than when preceded by a preferred food (soybean meal), supporting the learning hypothesis of induction. The objective of the second, Revaluation, phase of the experiment was to explore the associative mechanism of induction, for which we paired gastrointestinal malaise caused by lithium chloride intoxication with consumption of soybean meal or a control food (wheat bran). Despite subjects partially rejecting soybean meal relative to controls after the aversive conditioning protocol, oat hay consumption seemed unaffected by soybean meal devaluation. We conclude that intake induction in sheep may rely on changes in hedonic properties of the low-nutritious food based on its association with post-ingestive feedback from the preferred food (hedonic hypothesis), but not on an explicit anticipation of the latter (signalling hypothesis). PMID- 21545830 TI - Acute stress disrupts performance of zebrafish in the cued and spatial memory tests: the utility of fish models to study stress-memory interplay. AB - The zebrafish (Danio rerio) has emerged as a promising model organism for affective or cognitive neuroscience research, and may be useful to study the interplay between memory and anxiety-related states. To assess the effects of acute psychological stress on spatial and cued memory, adult zebrafish were trained in an aquatic plus-maze for 14 days using food bait as a reward. Two ecologically relevant stressors (alarm pheromone or Indian leaf fish exposure) were applied to acutely stress zebrafish immediately prior to the final (testing) trial. Overall, acute single inescapable stress markedly impaired spatial and cued memory in zebrafish plus-maze test, reducing the number of correct arm entries and time spent in the target arm. This observation parallels rodent and clinical literature on memory-impairing effects of acute stress, strongly supporting the utility of zebrafish in neurobehavioral research. PMID- 21545831 TI - Biological monitoring for exposure to deltamethrin: a human oral dosing study and background levels in the UK general population. AB - An oral dose of the pyrethroid insecticide deltamethrin was administered to five volunteers at the acceptable daily intake (ADI, 0.01 mg/kg). Total urine was collected from the volunteers at timed intervals for 60h post-exposure. The metabolites 3-(2,2-dibromovinyl)-2,2-dimethyl-(1-cyclopropane)carboxylic acid (DBVA) and 3-phenoxybenzoic acid (3-PBA) were quantified in hydrolysed urine using GC-MS analysis. Both metabolites exhibited rapid elimination half-lives of 3.6 and 7.1h, respectively. Levels of DBVA quantified in urine were approximately 5 times greater than 3-PBA. Mean metabolite levels found in 24h total urine collections, normalised for a 70 kg individual, were 42.8 MUmol DBVA/mol creatinine (range 34.6-63.2; CV=28%) and 8.7 MUmol 3-PBA/mol creatinine (range 6.6-12.7; CV=31%). We calculate that a 70 kg person receiving a dose of deltamethrin at the ADI would be expected to have a 24-h total urine collection level of 32-53 MUmol DBVA/mol creatinine (95% confidence interval). Analysis of 336 samples from adult UK residents with no known exposure to deltamethrin derives an upper reference value (95th percentile) of 0.5 MUmol DBVA/mol creatinine (maximum 4.2 MUmol DBVA/mol creatinine), demonstrating that general population exposure to deltamethrin in the UK is very low and well within levels expected at the ADI. PMID- 21545832 TI - A novel tumor-targeted delivery system with hydrophobized hyaluronic acid spermine conjugates (HHSCs) for efficient receptor-mediated siRNA delivery. AB - A novel target specific small interfering RNA (siRNA) delivery system was successfully developed using hydrophobized hyaluronic acid-spermine conjugates (HHSCs), which were previously synthesized and their properties were also characterized in our published papers. Fluorescein isothiocyanate (FITC) labeled specific Silencer Select siRNAs were used as a model system suppressing the cyclooxygenase-2 (COX-2) gene expression. The polymers were able to effectively bind siRNA, self-assemble into micelles, protect siRNA from degradation by nuclease and release complexed siRNA efficiently in the presence of low concentrations of polyanionic heparin. The cytotoxicity of siRNA/HHSCs complex to SGC-7901 cells was lower than that of siRNA/PEI 25k and Lipofectamine 2000 complex according to the MTT assay. When SGC-7901 and GES-1 cells were treated with FITC labeled siRNA/HHSCs complexes, SGC-7901 cells, with a cluster determinant 44 receptor (CD(44)), showed higher green fluorescent intensity than GES-1 cells because of the HA receptor mediated endocytosis of the complex. In addition, the inhibitory effect on the uptake in the presence of free HA in the transfection medium revealed that siRNA/HHSC-1 complex was selectively taken up to SGC-7901 cells via HA-receptor mediated endocytosis. Based on flow cytometry and microscopy, observation revealed that siRNA/HHSC complex was taken up preferentially through caveolae-mediated endocytosis, which may be a desirable pathway for avoiding the lysosomal degradation of delivered genes. All these results demonstrated that the intracellular delivery of siRNA/HHSC complex could be facilitated by the HA-receptor mediated endocytosis. PMID- 21545833 TI - Effect of short term and chronic administration of Sutherlandia frutescens on pharmacokinetics of nevirapine in rats. AB - Sutherlandia frutescens (sutherlandia), an African herbal supplement was recommended by the South African Ministry of Health for the treatment of AIDS patients. However, no reports yet exist delineating the effect of sutherlandia on pharmacokinetics of antiretroviral agents. Therefore, this investigation aimed at screening the effects of short term and chronic exposure of sutherlandia on oral bioavailability and pharmacokinetics of nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, in Sprague Dawley rats. NVP (6 mg/kg) was administered orally alone (control) and with co-administration of sutherlandia; short term (12 mg/kg single dose) and long term (12 mg/kg, once a day for 5 days). No significant difference in the pharmacokinetic parameters of NVP was found upon short-term co-administration of Sutherlandia. However, there was a 50% decrease (p<0.05) in the AUC and C(max) values of NVP after 5 days of chronic exposure with Sutherlandia. In addition, quantitative RT-PCR studies demonstrated a 2-3-fold increase in the hepatic and intestinal mRNA expression of CYP3A2, relative to vehicle control. To further confirm, if this could translate into a clinically relevant pharmacokinetic interaction in patients, we tested this hypothesis employing LS-180 cells as an in vitro induction model for human CYP3A4. Ninety-six hours post treatment, similar to positive control rifampicin (25 MUM), sutherlandia extract (300 MUg/mL) resulted in elevated m-RNA expression levels and functional activity of CYP3A4 (human homologue of rodent CYP3A2) in LS 180 cells. Taken together, these results suggest that a potential drug-herb interaction is possible when NVP is co-administered with S. frutescens, although this hypothesis still remains to be investigated in a clinical setting. PMID- 21545834 TI - Cardiac triglyceride accumulation following acute lipid excess occurs through activation of a FoxO1-iNOS-CD36 pathway. AB - Obesity due to nutrient excess leads to chronic pathologies including type 2 diabetes and cardiovascular disease. Related to nutrient excess, FoxO1 has a role in regulating fatty acid uptake and oxidation and triglyceride (TG) storage by mechanisms that are largely unresolved. We examined the mechanism behind palmitate (PA)-induced TG accumulation in cardiomyocytes. To mimic lipid excess, rat ventricular myocytes were incubated with albumin-bound PA (1 mM) or rats were administered Intralipid (20%). PA-treated cardiomyocytes showed a substantial increase in TG accumulation, accompanied by amplification of nuclear migration of phospho-p38 and FoxO1, iNOS induction, and translocation of CD36 to the plasma membrane. PA also increased Cdc42 protein and its tyrosine nitration, thereby rearranging the cytoskeleton and facilitating CD36 translocation. These effects were duplicated by TNF-alpha and reversed by the iNOS inhibitor 1400 W. PA increased the nuclear interaction between FoxO1 and NF-kappaB, reduced the nuclear presence of PGC-1alpha, and downregulated expression of oxidative phosphorylation proteins. In vivo a robust increase in cardiac TGs after Intralipid administration was also associated with augmentation of nuclear FoxO1 and iNOS expression. Impeding this FoxO1-iNOS-CD36 pathway could decrease cardiac lipid accumulation and oxidative/nitrosative stress and help ameliorate the cardiovascular complications associated with obesity and diabetes. PMID- 21545835 TI - Removal of H2O2 and generation of superoxide radical: role of cytochrome c and NADH. AB - In cells, mitochondria, endoplasmic reticulum, and peroxisomes are the major sources of reactive oxygen species (ROS) under physiological and pathophysiological conditions. Cytochrome c (cyt c) is known to participate in mitochondrial electron transport and has antioxidant and peroxidase activities. Under oxidative or nitrative stress, the peroxidase activity of Fe3+cyt c is increased. The level of NADH is also increased under pathophysiological conditions such as ischemia and diabetes and a concurrent increase in hydrogen peroxide (H2O2) production occurs. Studies were performed to understand the related mechanisms of radical generation and NADH oxidation by Fe3+cyt c in the presence of H2O2. Electron paramagnetic resonance (EPR) spin trapping studies using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) were performed with NADH, Fe3+cyt c, and H2O2 in the presence of methyl-beta-cyclodextrin. An EPR spectrum corresponding to the superoxide radical adduct of DMPO encapsulated in methyl beta-cyclodextrin was obtained. This EPR signal was quenched by the addition of the superoxide scavenging enzyme Cu,Zn-superoxide dismutase (SOD1). The amount of superoxide radical adduct formed from the oxidation of NADH by the peroxidase activity of Fe3+cyt c increased with NADH and H2O2 concentration. From these results, we propose a mechanism in which the peroxidase activity of Fe3+cyt c oxidizes NADH to NAD(*), which in turn donates an electron to O2, resulting in superoxide radical formation. A UV-visible spectroscopic study shows that Fe3+cyt c is reduced in the presence of both NADH and H2O2. Our results suggest that Fe3+cyt c could have a novel role in the deleterious effects of ischemia/reperfusion and diabetes due to increased production of superoxide radical. In addition, Fe3+cyt c may play a key role in the mitochondrial "ROS induced ROS-release" signaling and in mitochondrial and cellular injury/death. The increased oxidation of NADH and generation of superoxide radical by this mechanism may have implications for the regulation of apoptotic cell death, endothelial dysfunction, and neurological diseases. We also propose an alternative electron transfer pathway, which may protect mitochondria and mitochondrial proteins from oxidative damage. PMID- 21545836 TI - Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury. AB - Retinal ischemia-reperfusion (I/R) involves an extensive increase in reactive oxygen species as well as proinflammatory changes that result in significant histopathologic damage, including neuronal and vascular degeneration. Nrf2 has a well-known cytoprotective role in many tissues, but its protective function in the retina is unclear. We investigated the possible role of Nrf2 as a protective mechanism in retinal ischemia-reperfusion injury using Nrf2(-/-) mice. I/R resulted in an increase in retinal levels of superoxide and proinflammatory mediators, as well as leukocyte infiltration of the retina and vitreous, in Nrf2(+/+) mice. These effects were greatly accentuated in Nrf2(-/-) mice. With regard to histopathologic damage, Nrf2(-/-) mice exhibited loss of cells in the ganglion cell layer and markedly accentuated retinal capillary degeneration, as compared to wild-type. Treatment with the Nrf2 activator CDDO-Me increased antioxidant gene expression and normalized I/R-induced superoxide in the retina in wild-type but not Nrf2(-/-) mice. CDDO-Me treatment abrogated retinal capillary degeneration induced by I/R in wild-type but not Nrf2(-/-) mice. These studies indicate that Nrf2 is an important cytoprotective mechanism in the retina in response to ischemia-reperfusion injury and suggest that pharmacologic induction of Nrf2 could be a new therapeutic strategy for retinal ischemia reperfusion and other retinal diseases. PMID- 21545837 TI - Insulin-like growth factor-I mediates neuroprotection in proteasome inhibition induced cytotoxicity in SH-SY5Y cells. AB - The proteasome is an enzyme complex responsible for targeted intracellular proteolysis. Alterations in proteasome-mediated protein clearance have been implicated in the pathogenesis of aging, Alzheimer's disease (AD) and Parkinson's disease (PD). In such diseases, proteasome inhibition may contribute to formation of abnormal protein aggregates, which in turn activate intracellular unfolded protein responses that cause oxidative stress and apoptosis. In this study, we investigated the protective effect of Insulin-like Growth Factor-I (IGF-1) for neural SH-SY5Y cells treated with the proteasomal inhibitor, Epoxomicin. In SH SY5Y cells, Epoxomicin treatment results in accumulation of intracellular ubiquitinated proteins and cytochrome c release from damaged mitochondria, leading to cell death, in Epoxomicin time- and dose-dependent manner. In cells treated with small amounts of IGF-1, the same dosages of Epoxomicin reduced both mitochondrial damage (cytochrome c release) and reduced caspase-3 activation and PARP cleavage, both of which are markers of apoptosis. Notably, however, IGF-1 treated SH-SY5Y cells still contained ubiquitinated protein aggregates. This result indicates that IGF-1 blocks the downstream apoptotic consequences of Epoxomicin treatment leading to decreased proteasome function. Clues as to the mechanism for this protective effect come from (a) increased AKT phosphorylation observed in IGF-1-protected cells, vs. cells exposed to Epoxomicin without IGF-1, and (b) reduction of IGF-1 protection by pretreatment of the cells with LY294002 (an inhibitor of PI3-kinase). Together these findings suggest that activation of PI3/AKT pathways by IGF-1 is involved in IGF-1 neuroprotection against apoptosis following proteasome inhibition. PMID- 21545838 TI - Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia. AB - Truncating mutations in the SPG11 and SPG15 genes cause complicated spastic paraplegia, severe neurological conditions due to loss of the functions of spatacsin and spastizin, respectively. We developed specific polyclonal anti spatacsin (SPG11) and anti-spastizin (SPG15) antisera, which we then used to explore the intracellular and tissue localizations of these proteins. We observed expression of both proteins in human and rat central nervous system, which was particularly strong in cortical and spinal motor neurons as well as in retina. Both proteins were also expressed ubiquitously and strongly in embryos. In cultured cells, these two proteins had similar diffuse punctate, cytoplasmic and sometimes nuclear (spastizin) distributions. They partially co-localized with multiple organelles, particularly with protein-trafficking vesicles, endoplasmic reticulum and microtubules. Spastizin was also found at the mitochondria surface. This first study of the endogenous expression of spatacsin and spastizin shows similarities in their expression patterns that could account for their overlapping clinical phenotypes and involvement in a common protein complex. PMID- 21545839 TI - Chloroplast phylogeography of Terminalia franchetii (Combretaceae) from the eastern Sino-Himalayan region and its correlation with historical river capture events. AB - The reorganization of major river drainages in the Sino-Himalayan region of Southwest China was caused primarily by river separation and capture events following the most recent uplift of the Tibetan Plateau (<= 3.4 Ma). Terminalia franchetii is a shrub or small tree species endemic to the river valleys of this region. Based on a range-wide sampling comprising 28 populations and 258 individuals, we investigated the relationship between the modern phylogeographic structure of T. franchetii and geological changes in drainage patterns, using chloroplast DNA sequences (trnL-F, petL-psbE). T. franchetii was found to harbor high haplotype diversity (h(T)=0.784) but low average within-population diversity (h(S)=0.124). Mismatch distribution and neutrality tests provided no evidence of recent demographic population growth. Two (out of five) population groups identified exhibited a disjunctive distribution of dominant haplotypes between northern and southern valleys, corresponding to the geography of past drainage systems. We conclude that the modern disjunctive distribution of T. franchetii, and associated patterns of cpDNA haplotype variation, result from vicariance caused by several historical river separation and capture events. Overall, our inferred timings of these events (mostly mid-to-late Pleistocene) agree with previous time estimates of drainage re-arrangements in the Sino-Himalayan region. PMID- 21545840 TI - Discrepancies between subgeneric classification and molecular phylogeny of Ceratitis (Diptera: Tephritidae), can the evolution of host use provide some clues? AB - Using molecular data from three protein encoding genes and 49 taxa (98 specimens from 20 African countries), we provide an extended phylogeny of Ceratitis and investigate the evolution of stenophagy across clades. Bayesian tree reconstructions support previously proposed monophyletic lineages (Pardalaspis, Pterandrus section A, Pterandrus section B+Ceratitis sensu stricto) and reveal the occurrence of two new monophyletic groups including Ceratalaspis/Hoplolophomyia (viz. Cl(A), and Cl(B)+H). The reconstruction of ancestral character states shows that stenophagy evolved repeatedly and independently in five different clades (Podocarpus, Solanum, Strychnos, Tabernaemontana and Vepris feeders). The evolution of feeding preferences is closely related to the phylogenetic patterns of Ceratalaspis/Hoplolophomyia whose sections include either polyphagous species (Cl(A)) or stenophagous taxa (Cl(B)+H) that are further subdivided in Vepris and Solanum feeders. The evolution of stenophagy in the genus Ceratits appears as the result of a process leading to the exploitation of "unconventional" fruits (viz. toxic and/or not fleshy) and involving either metabolic adaptation to toxic plant compounds and/or the capability of penetrating fruits with thick cuticles. PMID- 21545842 TI - Occurrence of microorganisms of public health and spoilage significance in fruit juices sold in retail markets in Greece. AB - Fruit juices are an important part of the modern diet in many countries. However, few data are available concerning the microbiological quality of the fruit juices sold in Greece. Using standard microbiological procedures, we conducted a bacteriological survey of commercially sold, pasteurized, shelf-stable fruit juices from retail markets. A total of 120 samples of fruit juices sold in various retail markets were examined for their bacteriological quality. The pH of the tested juices was 2.4-4.8. Bacteria were isolated from 51 samples (42.5%) and fungi from 78 samples (65%). Escherichia coli O157:H7 was detected in four of the analyzed samples (3.34%), and Staphylococcus aureus was detected in four different samples (3.34%). In 11 samples (9.1%), the total number of microorganisms detected was as high as 125 colony-forming units (CFU). Acidophilic microorganisms were isolated from 26 samples (21.7%) and Blastomyces was detected in 46 samples (38.3%). All samples were negative for Lactobacillus, Clostridium perfrigens, Salmonella spp., Bacillus cereus, total coliforms, E. coli, and Listeria monocytogenes. Many of the microorganisms detected may cause disease in humans; thus, a number of the tested samples did not meet the Greek guidelines for the microbiological quality of juices. Use of a Hazard Analysis Critical Control Point (HACCP) system should be generally introduced into the juice industry sector to improve the quality of fruit juices, as well as other manufactured foods. PMID- 21545841 TI - Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity. AB - Advancing our understanding of neuroplasticity and the development of novel therapeutics based upon this knowledge is critical in order to improve the treatment and prevention of a myriad of nervous system disorders. Epigenetic mechanisms of neuroplasticity involve the post-translational modification of chromatin and the recruitment or loss of macromolecular complexes that control neuronal activity-dependent gene expression. While over a century after Ramon y Cajal first described nuclear subcompartments and foci that we now know correspond to sites of active transcription with acetylated histones that are under epigenetic control, the rate and extent to which epigenetic processes act in a dynamic and combinatorial fashion to shape experience-dependent phenotypic and behavioral plasticity in response to various types of neuronal stimuli over a range of time scales is only now coming into focus. With growing recognition that a subset of human diseases involving cognitive dysfunction can be classified as 'chromatinopathies', in which aberrant chromatin-mediated neuroplasticity plays a causal role in the underlying disease pathophysiology, understanding the molecular nature of epigenetic mechanisms in the nervous system may provide important new avenues for the development of novel therapeutics. In this review, we discuss the chemistry and neurobiology of the histone deacetylase (HDAC) family of chromatin-modifying enzymes, outline the role of HDACs in the epigenetic control of neuronal function, and discuss the potential relevance of these epigenetic mechanisms to the development of therapeutics aiming to enhance memory and neuroplasticity. Finally, open questions, challenges, and critical needs for the field of 'neuroepigenetics' in the years to come will be summarized. PMID- 21545844 TI - Class proximity measures--dissimilarity-based classification and display of high dimensional data. AB - For two-class problems, we introduce and construct mappings of high-dimensional instances into dissimilarity (distance)-based Class-Proximity Planes. The Class Proximity Projections are extensions of our earlier relative distance plane mapping, and thus provide a more general and unified approach to the simultaneous classification and visualization of many-feature datasets. The mappings display all L-dimensional instances in two-dimensional coordinate systems, whose two axes represent the two distances of the instances to various pre-defined proximity measures of the two classes. The Class Proximity mappings provide a variety of different perspectives of the dataset to be classified and visualized. We report and compare the classification and visualization results obtained with various Class Proximity Projections and their combinations on four datasets from the UCI data base, as well as on a particular high-dimensional biomedical dataset. PMID- 21545843 TI - Nampt/visfatin/PBEF affects expression of myogenic regulatory factors and is regulated by interleukin-6 in chicken skeletal muscle cells. AB - Nicotinamide phosphoribosyltransferase (Nampt/visfatin/PBEF) has been identified as a rate-limiting NAD(+) biosynthetic enzyme and an adipokine found in the circulation. Human and chicken skeletal muscles are reported to have the highest level of Nampt expression among various tissues whose functional significance remains undetermined. Expression of Nampt is regulated by interleukin-6 (IL-6), an essential cytokine for postnatal muscle growth in mammals. The objective of the current study was to characterize expression of Nampt in chicken (Gallus gallus) myogenic cells and to determine the effect of Nampt on expression of IL 6, myogenic transcription factors, and glucose uptake. We also sought to determine the effect of IL-6 on Nampt expression in chicken myogenic cells. Nampt mRNA and protein were identified in both myoblasts and myocytes, although expression did not differ between the two cell types. Treatment with recombinant human Nampt was found to decrease myoD and mrf4 expression but to increase myf5 expression in myocytes, while glucose uptake was unaffected. In response to treatment with recombinant Nampt, IL-6 expression in myocytes was increased at 24h but decreased when treated for 48 or 72 h. Forced over-expression of chicken Nampt cDNA significantly decreased myf5 expression in myoblasts. Treatment of myogenic cells with lower levels (1 ng.mL(-1)) of recombinant IL-6 increased Nampt expression, whereas a higher IL-6 concentration (100 ng.mL(-1)) decreased Nampt mRNA abundance. Collectively, these results demonstrate that Nampt, regulated in part by IL-6, alters the expression of key myogenic transcription factors and thereby may influence postnatal myogenesis. PMID- 21545845 TI - Using a shallow linguistic kernel for drug-drug interaction extraction. AB - A drug-drug interaction (DDI) occurs when one drug influences the level or activity of another drug. Information Extraction (IE) techniques can provide health care professionals with an interesting way to reduce time spent reviewing the literature for potential drug-drug interactions. Nevertheless, no approach has been proposed to the problem of extracting DDIs in biomedical texts. In this article, we study whether a machine learning-based method is appropriate for DDI extraction in biomedical texts and whether the results provided are superior to those obtained from our previously proposed pattern-based approach. The method proposed here for DDI extraction is based on a supervised machine learning technique, more specifically, the shallow linguistic kernel proposed in Giuliano et al. (2006). Since no benchmark corpus was available to evaluate our approach to DDI extraction, we created the first such corpus, DrugDDI, annotated with 3169 DDIs. We performed several experiments varying the configuration parameters of the shallow linguistic kernel. The model that maximizes the F-measure was evaluated on the test data of the DrugDDI corpus, achieving a precision of 51.03%, a recall of 72.82% and an F-measure of 60.01%. To the best of our knowledge, this work has proposed the first full solution for the automatic extraction of DDIs from biomedical texts. Our study confirms that the shallow linguistic kernel outperforms our previous pattern-based approach. Additionally, it is our hope that the DrugDDI corpus will allow researchers to explore new solutions to the DDI extraction problem. PMID- 21545846 TI - Critical illness-related corticosteroid insufficiency in patients with cirrhosis and variceal bleeding. AB - BACKGROUND & AIMS: Relative adrenal insufficiency (AI) occurs in patients with cirrhosis with sepsis, but not with variceal bleeding. We evaluated adrenal function in cirrhotic patients with and without bleeding. METHODS: Twenty cirrhotic patients with variceal bleeding were evaluated using the short synacthen test (SST) and 10 using the low-dose synacthen test (LDSST) followed by SST. The control group included 60 stable cirrhotic patients, assessed by LDSST (n = 50) or SST (n = 10), and 14 healthy volunteers. AI was diagnosed using SST, based on peak cortisol levels <= 18 MUg/dL in nonstressed patients or Deltamax <9 MUg/dL or a total cortisol level <10 MUg/dL in stressed patients with variceal bleeding-the current criteria for critical illness-related corticosteroid insufficiency. Using LDSST, diagnosis was based on peak concentrations of cortisol <= 18 MUg/dL in nonstressed patients and <25 MUg/dL (or Deltamax <9 MUg/dL) in patients with variceal bleeding. We evaluated patients with levels of serum albumin >2.5 g/dL, to indirectly assess cortisol binding. RESULTS: All healthy volunteers had normal results from LDSSTs and SSTs. Patients with variceal bleeding had higher median baseline concentrations of cortisol (15.4 MUg/dL) than stable cirrhotic patients (8.7 MUg/dL, P = .001) or healthy volunteers (10.1 MUg/dL, P = .01). Patients with variceal bleeding had higher median peak concentrations of cortisol than stable cirrhotic patients (SST results of 32.7 vs 21 MUg/dL, P = .001; LDSST results of 9.3 vs 8.1 MUg/dL; nonsignificant), with no differences in Deltamax in either test. These differences were greater with variceal bleeding than in stable cirrhotic patients with AI. Subanalysis of patients with albumin levels >2.5 g/dL did not change these differences. CONCLUSIONS: Cirrhotic patients with variceal bleeding have AI. Despite higher baseline concentrations of serum cortisol and subnormal Deltamax values, they did not have adequate responses to stress, and therefore had critical illness-related corticosteroid insufficiency. PMID- 21545847 TI - An overview on the genetic of rheumatoid arthritis: a never-ending story. AB - Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, multi-factorial disease sustained by environmental and genetic factors. These seem to be necessary but not sufficient in the disease development, nonetheless they can be responsible of different clinical pictures and response to therapy, and they can represent potential therapeutic targets. Several genes have been indicated so far in the pathogenesis of RA. The most important region is the Human Leukocyte Antigen (HLA) that contributes to approximately half of the genetic susceptibility for RA. The association seems to be stronger or specific for anti citrullinated protein antibodies positive disease. Several alleles in the epitope recognition part of the HLA molecule that show the highest association with RA susceptibility, also share a common string of amminoacid residues (the so-called shared-epitope hypothesis). Other variants in potentially pathogenic genes located in non-MHC regions have been implicated by recently performed genome wide analysis studies. These genes include PTPN22, TRAF1-C5, PADI4, STAT4. Other polymorphisms seem to be responsible for more aggressive disease phenotype such as those located at TNF, IL-1, IL-6, IL-4, IL-5, OPN, PRF1. However, still nowadays, the genetic background of RA remains to be clearly depicted, and the efforts in the post-genomic era can bring to an estimation of the real likelihood of the genetic effect on RA. Finally, the discovery of new genes associated with the disease can be relevant in finding potential biomarkers, potentially useful in disease diagnosis and treatment. PMID- 21545848 TI - Novel opportunities in automated classification of antinuclear antibodies on HEp 2 cells. AB - The recommended method for antinuclear antibodies (ANA) detection is IIF but it is influenced by many different factors. In order to pursue a high image quality without artefacts and to reduce inter-observer variability, this study aims to evaluate the reliability of using automatically acquired digital images for diagnostic purposes. In this paper we present SLIM-system a comprehensive system that supports the two sides of IIF tests classification. It is based on two systems: the first labels the fluorescence intensity, whereas the second recognizes the staining pattern of positive wells. We populated a dataset of 600 images obtained from sera screened for ANA by IIF on Hep-2 cells. The error rate has been evaluated according to eight-fold cross validation method; the rates reported in the following are the mean of the tests. Performance of the system in positive/negative recognition ranges from 87% up to more than 94%. Staining pattern classification accuracy of main classes ranges from 71% to 74%. The system provides high and reliable identification of negative samples and a flexibility that permits to use this application for different purposes. The analysis of its perspective performance shows the system potential in lowering the method variability, in increasing the level of standardization and in reducing the specialist workload of more than 80%. Our data represent a first step to validate the use of Computer Aided Diagnosis (CAD), thus offering an opportunity for standardizing and automatizing the detection of ANA by IIF. PMID- 21545849 TI - New autoantigens in the antiphospholipid syndrome. AB - The antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis, recurrent miscarriages or fetal loss, and circulating antiphospholipid antibodies (aPL). Enzyme-linked immunosorbent assays for anticardiolipin and anti-beta2-glycoprotein I antibodies and clotting assays for the lupus anticoagulant are the tests recommended for detecting aPL. However, the aPL are a heterogeneous group of antibodies directed against anionic phospholipids but also toward phospholipid-binding plasma proteins or phospholipid-protein complexes. beta2-glycoprotein I (beta2GPI) is the playmaker antigen of APS, however during apoptosis, lysophospholipids can become exposed on the cell surface, and mainly through their interaction with beta2GPI, they can become targets of aPL. Some CL metabolites are likely to escape from the remodeling cycle. This would account for the progressive loss of mitochondrial CL during apoptosis, as well as for the presence of CL and lyso-CL at the cell surface, where they can interact with beta2GPI and become targets of aPL. Other recognized targets of aPL are represented by phosphatidylserine, lyso(bis)phosphatidic acid, Phosphatidylethanolamine, vimentin, and annexin A5. These molecules may allow improving the knowledge on the pathogenesis, and the early identification of APS. Although several studies have shown the presence of antibodies directed against other antigens in APS, their clinical relevance is still a matter of debate, and it needs to be confirmed with experimental data and longitudinal studies. PMID- 21545850 TI - B cells in systemic sclerosis: a possible target for therapy. AB - Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive extracellular matrix (ECM) deposition in the skin and other visceral organs and it is associated with immune activation characterized by autoantibody production, release of various cytokines and T-lymphocyte activation. Several recent lines of evidence in animal models and in SSc patients indicate a potential role for B cells in the SSc. B cells have arisen as a possible player in tissue fibrosis in some experimental models and, since IL-6 produced by B cells, along with TGF beta, may induce matrix synthesis and less collagen degradation, targeting B cells could be one way to reduce ECM deposition and reduce the inflammatory background. Both SSc patients and tight-skin mice, a genetic model of SSc, have intrinsic B-cell abnormalities characterized by chronic B-cell activation. SSc patients present an increased number of naive B cells and an activation of memory B cells, despite a reduction in their number. B cells from SSc patients exhibit increased expression of CD19. Remarkably, CD19 loss or B-cell depletion using antimouse CD20 antibody suppresses the development of skin hyperplasia and autoimmunity in tight-skin mice. Additionally, recent studies revealed a possible beneficial effect of anti-human CD20 antibody (Rituximab) therapy on skin fibrosis and lung involvement in SSc patients. These studies reported also the safety of Rituximab in SSc patients. All these findings suggest a possible role of antiCD20 treatment in SSc patients. PMID- 21545851 TI - Angiogenesis in rheumatoid arthritis: a disease specific process or a common response to chronic inflammation? AB - Angiogenesis is the formation of new blood vessels from existing vessels. During RA new blood vessels can maintain the chronic inflammatory state by transporting inflammatory cells to the site of inflammation and supplying nutrients and oxygen to the proliferating inflamed tissue. The increased endothelial surface area also creates an enormous capacity for the production of cytokines, adhesion molecules, and other inflammatory stimuli, simultaneously the propagation of new vessels in the synovial membrane allows the invasion of this tissue supporting the active infiltration of synovial membrane into cartilage and resulting in erosions and destruction of the cartilage. This angiogenic phenotype is promoted by several pro-angiogenic molecules, the most potent of which is vascular endothelial growth factor (VEGF). Although angiogenesis is recognized as a key event in the formation and maintenance the infiltration of synovial membrane during RA, it is unclear whether angiogenesis should be considered a specific feature of the disease or a common inflammation driven process. However the emergence of biological therapies, such as anti TNF blockade, has suggested that there are features of the inflammatory response that are not general but contextual to the specificity of the tissue where inflammation occurs, and point out the relevant role of tissue-resident stromal cells in determining the site at which inflammation occurs and the specific features of chronic inflammation such as that occurs in RA. PMID- 21545852 TI - Influence of bronchial blood flow and conductance on pulmonary function in stable systolic heart failure. AB - BACKGROUND: The aim of this study was to determine the relationship between airway blood flow (Q(aw)), airway conductance (G(f-aw)) and pulmonary function in patients with stable HF. METHODS: 12 controls (CTRL: age=63+/-9 years, FVC=98+/ 15%pred, LVEF=61+/-6%) (all data presented as mean+/-SD), 16 patients with mild HF (HF-A, NYHA I-II: age=64+/-9 years, FVC=90+/-17%pred, LVEF=28+/-6%), and 14 patients with moderate/severe HF (HF-B, NYHA III-IV: age=65+/-6 years, FVC=84+/ 12%pred, LVEF=26+/-6%) were studied. Q(aw) was assessed using soluble gas measurements; perfusion pressure across airway bed (DeltaP(aw)) was estimated from systemic and pulmonary pressure measurements; G(f-aw) was calculated as Q(aw)/DeltaP(aw); PF was assessed by spirometry. RESULTS: While Q(aw) was not significantly different between CTRL (61.3+/-17.9 MUL min(-1)mL(-1)), HF-A (70.1+/-26.9 MUL min(-1)mL(-1)) and HF-B (56.2+/-14.9 MUL min(-1)mL(-1)) groups, G(f-aw), was elevated in HF-A (1.1+/-0.4 MUL min(-1)mL(-1)mm Hg(-1), p<0.03) and tended to be elevated in HF-B (1.2+/-0.6 MUL min(-1)mL(-1)mm Hg(-1), p=0.07) when compared to CTRL (0.8+/-0.3 MUL min(-1)mL(-1)mm Hg(-1)). Significant positive correlations were found between G(f-aw) and RV/TLC for HF-A (r=0.63, p<0.02) and HF-B (r=0.58, p<0.05). CONCLUSIONS: These results support the hypothesis that increased bronchial conductance and bronchial congestion may be related to greater small airway obstruction and as such may play a role in the PF abnormalities and symptoms of congestion commonly observed in HF patients. PMID- 21545853 TI - Characterization of a novel posttranslational modification in neuronal nitric oxide synthase by small ubiquitin-related modifier-1. AB - The multifaceted functions of nitric oxide (NO) in the CNS are defined by the activity of neuronal NO synathase (nNOS). The activities of nNOS are modulated by posttranslational modifications, such as phosphorylation and ubiquitination, but whether it is modified by small ubiquitin-related modifier (SUMO) remains unknown. The aim of this study was to elucidate whether nNOS is posttranslationally modified by SUMO proteins. Bioinformatic analyses using SUMOplot and SUMOFI predicted that nNOS had potential SUMO modification sites. When HEK293T cells were transiently co-expressed with nNOS and SUMO-1, two bands corresponding to nNOS-SUMO-1 conjugates were detected. In addition, two nNOS-SUMO 1 conjugates were confirmed by an in vitro sumoylation assay using recombinant proteins. Furthermore, nNOS-SUMO-1 conjugates were identified by MALDI-QIT/TOF mass spectrometry. These findings indicate that nNOS is clearly defined as a SUMO 1 target protein both in vitro and at the cellular level. We next characterized specific enzymes in the nNOS-SUMO-1 conjugation cycle at the cellular level. SUMO 1 conjugation of nNOS depended on Ubc9 (E2). The interaction between nNOS and Ubc9 was facilitated by PIASxbeta (E3). On the other hand, SUMO-1 was deconjugated from nNOS by SENP1 and SENP2. Overall, this study has newly identified that nNOS is posttranslationally modified by SUMO-1. PMID- 21545854 TI - Facial transplantation revisited: findings from the very first public engagement exercise. AB - OBJECTIVES: Facial transplantation has emerged as a treatment option in facial reconstruction. In this pilot study, we investigate initial attitudes to this concept in relevant patient and health professional groups. METHOD: Attitudes towards facial transplantation as a procedure were examined among 200 participants, including 30 nurses, 30 doctors, 30 plastic surgeons, 30 renal transplant patients, 30 medical students, 30 members of the lay public and 20 patients with facial disfigurements through the use of a questionnaire. RESULTS: Identity was important for all participating groups with 83.5% positive about receiving a facial transplant provided no resemblance to donor. There was an inverse relationship between the side effects of the immunosuppressant regimen and organ rejection and the willingness to undergo facial transplantation when compared to other forms of organ transplantation. A relationship to the recipient and familiarity with a transplant programme were positively related to potential donation. CONCLUSION: This study identifies the key issues of altered identity and the understanding of immunosuppression and surgical risk as the focus for research and patient selection. The ethical aspects of facial transplantation are not addressed in this study, and have been addressed elsewhere. PMID- 21545856 TI - Prevalence of teen driver errors leading to serious motor vehicle crashes. AB - OBJECTIVES: Motor vehicle crashes are the leading cause of adolescent deaths. Programs and policies should target the most common and modifiable reasons for crashes. We estimated the frequency of critical reasons for crashes involving teen drivers, and examined in more depth specific teen driver errors. METHODS: The National Highway Traffic Safety Administration's (NHTSA) National Motor Vehicle Crash Causation Survey collected data at the scene of a nationally representative sample of 5470 serious crashes between 7/05 and 12/07. NHTSA researchers assigned a single driver, vehicle, or environmental factor as the critical reason for the event immediately leading to each crash. We analyzed crashes involving 15-18 year old drivers. RESULTS: 822 teen drivers were involved in 795 serious crashes, representing 335,667 teens in 325,291 crashes. Driver error was by far the most common reason for crashes (95.6%), as opposed to vehicle or environmental factors. Among crashes with a driver error, a teen made the error 79.3% of the time (75.8% of all teen-involved crashes). Recognition errors (e.g., inadequate surveillance, distraction) accounted for 46.3% of all teen errors, followed by decision errors (e.g., following too closely, too fast for conditions) (40.1%) and performance errors (e.g., loss of control) (8.0%). Inadequate surveillance, driving too fast for conditions, and distracted driving together accounted for almost half of all crashes. Aggressive driving behavior, drowsy driving, and physical impairments were less commonly cited as critical reasons. Males and females had similar proportions of broadly classified errors, although females were specifically more likely to make inadequate surveillance errors. CONCLUSIONS: Our findings support prioritization of interventions targeting driver distraction and surveillance and hazard awareness training. PMID- 21545855 TI - Roles and regulation of microRNAs in cytomegalovirus infection. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post transcriptionally via binding to complementary sites typically located in the 3' untranslated regions (UTRs) of their target mRNAs. This ancient regulatory system has been conserved in eukaryotes throughout evolution, and it is therefore unsurprising that certain viruses have evolved to express their own miRNAs. Since the initial discovery of Epstein-Barr virus (EBV) derived miRNAs in 2004, over 230 viral miRNAs have been identified, the majority arising from herpesviruses. Although the functions of most viral miRNAs remain to be elucidated, an increasing number of their cellular and viral targets have been experimentally validated. Due to their non-immunogenic nature, viral miRNAs represent an elegant tool for the virus to evade the host immune system, and likely play a key role in the latent/lytic switch during the viral lifecycle. In this review, we will focus on the interactions of cytomegaloviruses with cellular and viral miRNAs during infection. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation. PMID- 21545857 TI - Evaluation of rear-end crash risk at work zone using work zone traffic data. AB - This paper aims to evaluate the rear-end crash risk at work zone activity area and merging area, as well as analyze the impacts of contributing factors by using work zone traffic data. Here, the rear-end crash risk is referred to as the probability that a vehicle is involved in a rear-end crash accident. The deceleration rate to avoid the crash (DRAC) is used in measuring rear-end crash risk. Based on work zone traffic data in Singapore, three rear-end crash risk models are developed to examine the relationship between rear-end crash risk at activity area and its contributing factors. The fourth rear-end crash risk model is developed to examine the effects of merging behavior on crash risk at merging area. The ANOVA results show that the rear-end crash risk at work zone activity area is statistically different from lane positions. Model results indicate that rear-end crash risk at work zone activity area increases with heavy vehicle percentage and lane traffic flow rate. An interesting finding is that the lane closer to work zone is strongly associated with higher rear-end crash risk. A truck has much higher probability involving in a rear-end accident than a car. Further, the expressway work zone activity area is found to have much larger crash risk than arterial work zone activity area. The merging choice has the dominated effect on risk reduction, suggesting that encouraging vehicles to merge early may be the most effective method to reduce rear-end crash risk at work zone merging area. PMID- 21545858 TI - The impact of changes to the graduated driver licensing program in Queensland, Australia on the experiences of Learner drivers. AB - PURPOSE: Graduated driver licensing (GDL) has been introduced in numerous jurisdictions in Australia and internationally in an attempt to ameliorate the significantly greater risk of death and injury for young novice drivers arising from road crashes. The GDL program in Queensland, Australia, was extensively modified in July 2007. This paper reports the driving and licensing experiences of Learner drivers progressing through the current-GDL program, and compares them to the experiences of Learners who progressed through the former-GDL program. METHOD: Young drivers (n=1032, 609 females, 423 males) aged 17-19 years (M=17.43, SD=0.67) were recruited as they progressed from a Learner to a Provisional driver's licence. They completed a survey exploring their sociodemographic characteristics, driving and licensing experiences as a Learner. Key measures for a subsample (n=183) of the current-GDL drivers were compared with the former-GDL drivers (n=149) via t-tests and chi-square analyses. RESULTS: As expected, Learner drivers progressing through the current-GDL program gained significantly more driving practice than those in the former program, which was more likely to be provided by mothers than in the past. Female Learners in the current-GDL program reported less difficulty obtaining supervision than those in the former program. The number of attempts needed to pass the practical driving assessment did not change, nor did the amount of professional supervision. The current-GDL Learners held their licence for a significantly longer duration than those in the former program, with the majority reporting that their Logbook entries were accurate on the whole. Compared to those in the former program, a significantly smaller proportion of male current-GDL Learners reported being detected for a driving offence whilst the females reported significantly lower crash involvement. Most current-GDL drivers reported undertaking their supervised practice at the end of the Learner period. CONCLUSIONS: The enhancements to the GDL program in Queensland appear to have achieved many of their intended results. The current-GDL Learners participating in the study reported obtaining a significantly greater amount of supervised driving experience compared to former GDL Learners. Encouragingly, the current-GDL Learners did not report any greater difficulty in obtaining supervised driving practice, and there was a decline in the proportion of current-GDL Learners engaging in unsupervised driving. In addition, the majority of Learners do not appear to be attempting to subvert logbook recording requirements, as evidenced by high rates of self-reported logbook accuracy. The results have implications for the development and the evaluation of GDL programs in Australia and around the world. PMID- 21545859 TI - Young drivers' optimism bias for accident risk and driving skill: Accountability and insight experience manipulations. AB - This study aimed to determine whether two brief, low cost interventions would reduce young drivers' optimism bias for their driving skills and accident risk perceptions. This tendency for such drivers to perceive themselves as more skillful and less prone to driving accidents than their peers may lead to less engagement in precautionary driving behaviours and a greater engagement in more dangerous driving behaviour. 243 young drivers (aged 17-25 years) were randomly allocated to one of three groups: accountability, insight or control. All participants provided both overall and specific situation ratings of their driving skills and accident risk relative to a typical young driver. Prior to completing the questionnaire, those in the accountability condition were first advised that their driving skills and accident risk would be later assessed via a driving simulator. Those in the insight condition first underwent a difficult computer-based hazard perception task designed to provide participants with insight into their potential limitations when responding to hazards in difficult and unpredictable driving situations. Participants in the control condition completed only the questionnaire. Results showed that the accountability manipulation was effective in reducing optimism bias in terms of participants' comparative ratings of their accident risk in specific situations, though only for less experienced drivers. In contrast, among more experienced males, participants in the insight condition showed greater optimism bias for overall accident risk than their counterparts in the accountability or control groups. There were no effects of the manipulations on drivers' skills ratings. The differential effects of the two types of manipulations on optimism bias relating to one's accident risk in different subgroups of the young driver sample highlight the importance of targeting interventions for different levels of experience. Accountability interventions may be beneficial for less experienced young drivers but the results suggest exercising caution with the use of insight type interventions, particularly hazard perception style tasks, for more experienced young drivers typically still in the provisional stage of graduated licensing systems. PMID- 21545860 TI - Preschoolers' perceptions of their mothers' and fathers' reactions to injury-risk behavior. AB - Seventy-eight 3 year-old children participated in structured interviews. Boys reported wanting to engage in higher levels of risk than did girls. Children viewed mothers as allowing boys and girls to engage in similar levels of risk. Conversely, they viewed fathers as permitting higher levels of risk by boys than by girls. These findings are discussed in terms of family socialization. PMID- 21545861 TI - Risky and aggressive driving in young adults: Personality matters. AB - Young, novice drivers constitute a disproportionate percentage of fatalities and injuries in road traffic accidents around the world. This study, attempts to identify motivational factors behind risky driving behavior, and examines the role of personality, especially sensation seeking, impulsivity and sensitivity to punishment/reward in predicting negative driving outcomes (accident involvement and traffic offences) among young drivers. Gender and driver's age are additional factors examined in relation to driving outcomes and personality. Adopting the contextual mediated model of traffic accident involvement (Sumer, 2003), the study is based on the theory that personality, age and gender represent distal factors that predict accident involvement indirectly through their relationship with stable tendencies towards aberrant driving behavior. Results from correlations and Structural Equation Modeling using AMOS 6 indicated that direct personality effects on driving outcomes were few, whereas personality had significant correlations with aberrant driving behavior, showing that personality is a distal but important predictor of negative driving outcomes. These high risk traits appear to be at a peak among young male drivers. Thus, personality is important in understanding aggressive and risky driving by young adults and needs to be taken into consideration in designing targeted accident prevention policies. PMID- 21545862 TI - The relative impact of work-related stress, life stress and driving environment stress on driving outcomes. AB - Previous research has shown the association between stress and crash involvement. The impact of stress on road safety may also be mediated by behaviours including cognitive lapses, errors, and intentional traffic violations. This study aimed to provide a further understanding of the impact that stress from different sources may have upon driving behaviour and road safety. It is asserted that both stress extraneous to the driving environment and stress directly elicited by driving must be considered part of a dynamic system that may have a negative impact on driving behaviours. Two hundred and forty-seven public sector employees from Queensland, Australia, completed self-report measures examining demographics, subjective work-related stress, daily hassles, and aspects of general mental health. Additionally, the Driver Behaviour Questionnaire (DBQ) and the Driver Stress Inventory (DSI) were administered. All participants drove for work purposes regularly, however the study did not specifically focus on full-time professional drivers. Confirmatory factor analysis of the predictor variables revealed three factors: DSI negative affect; DSI risk taking; and extraneous influences (daily hassles, work-related stress, and general mental health). Moderate intercorrelations were found between each of these factors confirming the 'spillover' effect. That is, driver stress is reciprocally related to stress in other domains including work and domestic life. Structural equation modelling (SEM) showed that the DSI negative affect factor influenced both lapses and errors, whereas the DSI risk-taking factor was the strongest influence on violations. The SEMs also confirmed that daily hassles extraneous to the driving environment may influence DBQ lapses and violations independently. Accordingly, interventions may be developed to increase driver awareness of the dangers of excessive emotional responses to both driving events and daily hassles (e.g. driving fast to 'blow off steam' after an argument). They may also train more effective strategies for self-regulation of emotion and coping when encountering stressful situations on the road. PMID- 21545863 TI - Understanding risk compensation in children: Experience with the activity and level of sensation seeking play a role. AB - The aims of this study were to determine if children 7-12 years show risk compensation when engaging in ecologically valid recreational sports tasks, and to explore how experience with the activity and extent of sensation seeking influence this. Children were positioned up on a platform, on a bike or wearing rollerblades, and they were presented varying heights and inclines from which they selected the greatest one they go down when wearing and not wearing safety gear appropriate to the activity; when making their ratings they anticipated actually doing the task. Results revealed that children engaged in significantly more risk taking when wearing safety gear, thereby demonstrating risk compensation, and this was significantly greater for the activity with which they had greater experience. However, children high in sensation seeking demonstrated significantly more risk compensation in both the high and low experience activities, although the injury risk appraisals that predicted risk compensation varied with experience level. Implications for the design of injury prevention programs and directions for future research are discussed. PMID- 21545864 TI - Older drivers: On-road and off-road test results. AB - Eighty-five volunteer drivers, 65-85 years old, without cognitive impairments impacting on their driving were examined, in order to investigate driving errors characteristic for older drivers. In addition, any relationships between cognitive off-road and on-road tests results, the latter being the gold standard, were identified. Performance measurements included Trail Making Test (TMT), Nordic Stroke Driver Screening Assessment (NorSDSA), Useful Field of View (UFOV), self-rating driving performance and the two on-road protocols P-Drive and ROA. Some of the older drivers displayed questionable driving behaviour. In total, 21% of the participants failed the on-road assessment. Some of the specific errors were more serious than others. The most common driving errors embraced speed; exceeding the speed limit or not controlling the speed. Correlations with the P Drive protocol were established for NorSDSA total score (weak), UFOV subtest 2 (weak), and UFOV subtest 3 (moderate). Correlations with the ROA protocol were established for UFOV subtest 2 (weak) and UFOV subtest 3 (weak). P-Drive and self ratings correlated weakly, whereas no correlation between self ratings and the ROA protocol was found. The results suggest that specific problems or errors seen in an older person's driving can actually be "normal driving behaviours". PMID- 21545865 TI - Effectiveness of speed indicator devices: An observational study in South London. AB - Speed indicator devices (SIDs) are vehicle activated signs displaying the real time speeds of passing vehicles. They are part of the array of road safety measures for managing speeds on local authority roads in the United Kingdom. This paper documents an evaluation of the effectiveness of SIDs that was carried out in South London in 2008. SIDs were installed at 10 sites in South London for periods of between one and three weeks. The overall effect of the SIDs being installed was a reduction in vehicle speeds of 1.4mph and a significant reduction in the proportion of vehicles exceeding the speed limit. The research also investigated the distance over which the SIDs are effective and the effect on vehicle speeds once the SID is removed. The results showed that a speed reduction occurred over a distance of up to 400m and that once the SID is removed then, in general, the mean vehicle speeds returned to pre-SID levels by the end of the first week. PMID- 21545866 TI - Jerky driving--An indicator of accident proneness? AB - This study uses continuously logged driving data from 166 private cars to derive the level of jerks caused by the drivers during everyday driving. The number of critical jerks found in the data is analysed and compared with the self-reported accident involvement of the drivers. The results show that the expected number of accidents for a driver increases with the number of critical jerks caused by the driver. Jerk analyses make it possible to identify safety critical driving behaviour or "accident prone" drivers. They also facilitate the development of safety measures such as active safety systems or advanced driver assistance systems, ADAS, which could be adapted for specific groups of drivers or specific risky driving behaviour. PMID- 21545867 TI - Indexing crash worthiness and crash aggressivity by vehicle type. AB - Crash aggressivity (CA), along with conventional crash worthiness (CW), has been recently studied to deal with the crash incompatibility between vehicles on roads. Clearly, injury severity depends on the attacking ability of striking vehicle as well as the protective ability of struck vehicle. This study proposes a systematic crash-based approach to index CA and CW of various vehicles. The approach deviates from existing methods in three aspects: (a) an explicit definition and specification in the model for CW and CA; (b) Bayesian hierarchical analysis to account for the crash-vehicle two-level data structure; (c) a five-level ordinal model to explicitly consider all levels of crash severity. The case study on major vehicle types illustrated the method and confirmed the consistency of results with previous studies. Both crash worthiness and crash aggressivity significantly vary by vehicle types, in which we identified the dominating effect of vehicle mass, and also highlighted the extraordinary aggressivity of Light Trucks and Vans (LTVs). While it was not surprising to identify least CA and CW of motorcycles, buses were unconventionally found to be less aggressive than other motor vehicles. The method proposed in this research is applicable to detailed crash-based vehicle inspection and evaluation. PMID- 21545869 TI - Predicting intentions not to "drink and drive" using an extended version of the theory of planned behaviour. AB - The aim of this study was to determine to what extent the theory of planned behaviour (TPB) extended with moral norm and descriptive norm is able to predict intentions not to drink and drive. We also wanted to examine whether different processes guide intentions among young drivers (35 years and below) versus drivers aged above 35 years, and women's versus men's intentions. Questionnaires were sent to a sample of 4000 people in Norway aged between 18 and 70 years, and were completed by 1025 respondents. Analyses were conducted among those who had a driver's licence and who reported drinking at least 1-2 times per year, resulting in a sample of 879 individuals (46.6% were men, 30.3% were 35 years and younger, M=43.9 years). The results showed that the TPB variables explained 10% of the variance in intentions in the sample as a whole, and that the extension variables added 2% to the explained variance after controlling for the impact of the TPB components. Perceived behavioural control was the strongest predictor of intentions (beta=0.24, p<0.001), followed by descriptive norm (beta=-0.12, p<0.001), attitude (beta=0.09, p<0.01) and moral norm (beta=0.08, p<0.05). Several group differences were found. The extended TPB model explained 16% and 5% of men's and women's intentions, respectively, and 26% and 9% of the variance in intentions among young and older drivers, respectively. The practical implications of these results for the development of interventions to encourage drivers not to drink and drive will be outlined. PMID- 21545868 TI - Identifying factors that increase the likelihood of driving after drinking among college students. AB - Driving after drinking (DAD) is a serious public health concern found to be more common among college students than those of other age groups or same-aged non college peers. The current study examined potential predictors of DAD among a dual-site sample of 3753 (65% female, 58% Caucasian) college students. Results showed that 19.1% of respondents had driven after 3 or more drinks and 8.6% had driven after 5 or more drinks in the past 3 months. A logistic regression model showed that male status, fraternity or sorority affiliation, family history of alcohol abuse, medium or heavy drinking (as compared to light drinking), more approving self-attitudes toward DAD, and alcohol expectancies for sexual enhancement and risk/aggression were independently associated with driving after drinking over and above covariates. These results extend the current understanding of this high risk drinking behavior in collegiate populations and provide implications for preventive strategies. Findings indicate that in addition to targeting at-risk subgroups, valuable directions for DAD-related interventions may include focusing on lowering both self-approval of DAD and alcohol-related expectancies, particularly those associated with risk/aggression and sexuality. PMID- 21545870 TI - Driving behaviors and accident risk under lifetime license revocation. AB - This study explored the driving behaviors and crash risk of 768 drivers who were under administrative lifetime driver's license revocation (ALLR). It was found that most of the ALLR offenders (83.2%) were still driving and only a few (16.8%) of them gave up driving completely. Of the offenders still driving, 67.6% experienced encountering a police roadside check, but were not detained or ticketed by the police. Within this group, 50.6% continued driving while encountering a police check, 18.0% of them made an immediate U-turn and 9.5% of them parked and exited their car. As to crash risk, 15.2% of the ALLR offenders had at least one crash experience after the ALLR had been imposed. The results of the logistic regression models showed that the offenders' crash risk while under the ALLR was significantly correlated with their personal characteristics (personal income), penalty status (incarceration, civil compensation and the time elapsed since license revocation), annual distance driven, and needs for driving (working, commuting and driving kids). Low-income offenders were more inclined to have a crash while driving under the ALLR. Offenders penalized by being incarcerated or by paying a high civil compensation drove more carefully and were less of a crash risk under the ALLR. The results also showed there were no differences in crash risk under the ALLR between hit-and-run offences and drunk driving offences or for offenders with a professional license or an ordinary license. Generally, ALLR offenders drove somewhat more carefully and were less of a crash risk (4.3 crashes per million km driven) than legal licensed drivers (23.1 crashes per million km driven). Moreover, they seemed to drive more carefully than drivers who were under short-term license suspension/revocation which previous studies have found. PMID- 21545871 TI - Understanding whiplash injury and prevention mechanisms using a human model of the neck. AB - OBJECTIVES: Various models for rear crash simulation exist and each has unique advantages and limitations. Our goals were to: determine the neck load and motion responses of a human model of the neck (HUMON) during simulated rear crashes; evaluate HUMON's biofidelity via comparisons with in vivo data; and investigate mechanisms of whiplash injury and prevention. METHODS: HUMON, consisting of a neck specimen (n=6) mounted to the torso of BioRID II and carrying a surrogate head and stabilized with muscle force replication, was subjected to simulated rear crashes in an energy-absorbing seat with fixed head restraint (HR) at peak sled accelerations of 9.9g (DeltaV 9.2kph), 12.0g (DeltaV 11.4kph), and 13.3g (DeltaV 13.4kph). Physiologic spinal rotation ranges were determined from intact flexibility tests. Average time-history response corridors (+/-1 standard deviation) were computed for spinal motions, loads, and injury criteria. RESULTS: Neck loads generally increased caudally and consisted of shear, compression, and flexion moment caused by straightening of the kyphotic thoracic and lordotic lumbar curvatures, upward torso ramping, and head inertial and head/HR contact loads. Nonphysiologic rotation occurred in flexion at C7/T1 prior to head/HR contact and in extension at C6/7 and C7/T1 during head/HR contact. CONCLUSIONS: HUMON's neck load and motion responses compared favorably with in vivo data. Lower cervical spine flexion-compression injuries prior to head/HR contact and extension-compression injuries during head/HR contact may be reduced by refinement of existing seatback, lapbelt, and HR designs and/or development of new injury prevention systems. PMID- 21545872 TI - On the training and testing of entry-level commercial motor vehicle drivers. AB - This study examined the effectiveness of 3 different training types on commercial motor vehicle (CMV) drivers' skill levels. The training types included a conventional 8-week certified course, a conventional 8-week certified course with approximately 60% of driving time spent in a CMV driving simulator, and a Commercial Driver's License (CDL) test focused short course. Participants' scores on the Division of Motor Vehicles (DMV) road and range tests were assessed. In addition to their DMV scores, participants replicated DMV road and range driving tests in an instrumented vehicle and the CMV driving simulator. Results indicated no training group differences in DMV road tests. There were differences between training groups on DMV range tests and real truck and simulator versions of the DMV road and range tests; on these tests conventional- and simulator-trained participants generally scored higher than CDL-focused participants. However, all groups performed higher in the real truck than in the simulator for both road and range tests. These findings indicate the need for a minimum standard of entry level CMV driver training as well as support of the use of a driving simulator for training entry-level drivers; however, testing using a simulator does not appear to be feasible with current technology. PMID- 21545873 TI - Factors associated with alcohol and drug use among traffic crash victims in southern Brazil. AB - OBJECTIVE: To investigate the prevalence of and factors associated with alcohol- or drug-related traffic crashes (TC) in a sample of TC victims who were admitted to the two emergency rooms of Porto Alegre in southern Brazil. METHODS: A cross sectional study with consecutive samples was used. Victims of non-fatal TCs (as drivers, passengers or pedestrians) who had presented at emergency rooms during the 45 days of data collection were selected. Subjects participated in a structured interview, were breathalyzed and underwent salivary drug testing. A multinomial logistic regression model was used to verify factors associated with alcohol or drug use. RESULTS: Of the 609 victims who participated in the interview, 72% were male, and the median age was 29 years (interquartile range 23.0-40.0 years). The drivers were mostly men (p<0.001), with a higher binge drinking rate (p=0.003) and marijuana use (p=0.005) than seen in pedestrian and passengers. The prevalence of a positive blood alcohol concentration (BAC) ranged from 7.8% among the drivers to 9.2% among the pedestrians (p=0.861), and the cannabis prevalence was 13.3% among the drivers. The variables associated with an alcohol-related accident were binge drinking in the prior 12 months (OR 2.4; CI 95% 1.1-5.1) and coming from a party/bar (OR 8.7; CI 95% 2.8-26.7). Alcohol abuse or dependence increased by 5.2-fold the chance of another substance-related TC. CONCLUSION: The large number of individuals found in TC-related emergency room visits in a short time frame is evidence of the Brazilian epidemic of TC. The data showed that alcohol abuse or dependence also increases the risk of intoxication by other drugs, and they point to alcohol and drug use as a major problem requiring specific TC-related public policies and law enforcement. PMID- 21545874 TI - An evaluation of the narrowing gender gap in DUI arrests. AB - Although males account for the vast majority of those convicted of driving under the influence of alcohol and/or other drugs (DUI), female DUI convictions have increased over the past two decades. In this study, we examined the ratio of males-to-females who were court-mandated between the years 1992 and 2008 to attend the Mississippi Alcohol Safety Education Program (MASEP), a DUI intervention program in Mississippi. The data for this study came from MASEP records; the Behavioral Risk Factor Surveillance System (BRFSS); the Uniform Crime Reports (UCR); the Treatment Episode Data Set (TEDS); the National Household Travel Survey (NHTS); and National Highway Traffic Safety Administration (NHTSA), an agency within the US Department of Transportation. Augmented Dickey-Fuller (ADF) tests were used to assess the nature (i.e., convergence, divergence, or stability) of this trend and to identify predictors. The results showed that, over the 17-year period, the gender gap in DUI convictions, self-reported history of prior arrest, official drug arrests, and substance abuse treatment admissions has narrowed considerably. Results from the autoregressive integrated moving average (ARIMA) models show that three factors account for increases in the proportion of women mandated to attend MASEP: self reported arrest prior to the DUI conviction, female admissions to substance abuse treatment, and annual miles driven. Changes in both women's behavior and law enforcement practices have increased female exposure to DUI arrests and narrowed the gender gap in DUI convictions. PMID- 21545875 TI - Accident prevention on ski slopes - Perceptions of safety and knowledge of existing rules. AB - Increases in the numbers of people participating in snow sports raise safety concerns. Despite declining numbers of skiing injuries among recreational skiers, collisions resulting in severe injuries appear to be on the rise. Skiers' risk of injury depends on a considerable number of different factors but only a few studies have investigated risk-taking behaviour and knowledge of proper skiing behaviour. To promote safe skiing the International Ski Federation (FIS) introduced regulations in 1967. We investigated participants' familiarity with the FIS regulations on the ski slopes in relation to age, skiing ability and country of origin. Random interviews were conducted with 1450 recreational skiers at 17 ski resorts in Tyrol, an Austrian province. A questionnaire assessing skiers' knowledge of existing rules, their intuitive behaviour in given situations and perceptions of safety was developed. The study revealed that beginners, young skiers and those who were not local residents displayed insufficient knowledge. Risk-inducing situations that could result in collisions, such as moving upwards during carving, were largely assessed incorrectly. Appropriate intuitive behaviour increases with experience, and beginners are less able to implement FIS regulations than more experienced skiers. Ski resorts, the media and schools should direct educational efforts toward these high-risk groups. More research is needed to determine the causal connection between skiing injuries and disregard of the FIS Rules. PMID- 21545876 TI - Modeling occupant-level injury severity: An application to large-truck crashes. AB - Most of the injury-severity analyses to date have focused primarily on modeling the most-severe injury of any crash, although a substantial fraction of crashes involve multiple vehicles and multiple persons. In this study, we present an extensive exploratory analysis that highlights that the highest injury severity is not necessarily the comprehensive indicator of the overall severity of any crash. Subsequently, we present a panel, hetroskedastic ordered-probit model to simultaneously analyze the injury severities of all persons involved in a crash. The models are estimated in the context of large-truck crashes. The results indicate strong effects of person-, driver-, vehicle-, and crash-characteristics on the injury severities of persons involved in large-truck crashes. For example, several driver behavior characteristics (such as use of illegal drugs, DUI, and inattention) were found to be statistically significant predictors of injury severity. The availability of airbags and the use of seat-belts are also found to be associated with less-severe injuries to car-drivers and car-passengers in the event of crashes with large trucks. Car drivers' familiarity with the vehicle and the roadway are also important for both the car drivers and passengers. Finally, the models also indicate the strong presence of intra-vehicle correlations (effect of common vehicle-specific unobserved factors) among the injury propensities of all persons within a vehicle. PMID- 21545877 TI - A numerical investigation into the effect of CRS misuse on the injury potential of children in frontal and side impact crashes. AB - This research focuses on an investigation into the head and neck injuries sustained by toddlers due to CRS misuse under frontal and side impact crashes. A fully deformable FE model incorporating a Hybrid III 3-year-old dummy was developed which has been previously validated for frontal impacts under CMVSS 208 and FMVSS 213 testing conditions. Furthermore, this model has also been validated under near-side impact conditions in accordance to crash tests carried out by NHTSA. In addition, numerical models incorporating a Q3/Q3s prototype child crash test dummies were developed. The objective of this research was to study the effect of seatbelt slack and the absence of the top tether strap on the head and neck injuries sustained by toddlers in a vehicle crash. Numerical simulations were conducted under full frontal and near side impact crash testing conditions in accordance with FMVSS 213 for the Hybrid III 3-year-old dummy and Q3/Q3s dummies in the absence and presence of slack in the seatbelt webbing, and in the absence and presence of the top tether strap. In addition, the effect of using a cross-shaped rigid ISOFIX system was also investigated. An analysis of the head and chest accelerations, neck loads and moments was completed to investigate the potential of injury due to CRS misuse. An increase in HIC(15) by approximately 30 40% for the frontal impact and 10-20% for the near-side impact respectively was observed for the Q3 child dummy due to both forms of CRS misuse. In the absence of the top tether strap the forward head excursions were observed to be increased by approximately 70% for the Hybrid III 3-year-old dummy and 40% for the Q3 dummy, respectively. Use of the cross-shaped rigid ISOFIX system illustrated a reduction in head and neck injury parameters, for both frontal and side impact conditions, in the absence and presence of CRS misuse. CRS misuse results in a significant increase in injury parameters and potential for contact related head injuries. Use of a rigid ISOFIX system to restrain a CRS provides better CRS and dummy confinement and reduced injury potential than a flexible ISOFIX system. PMID- 21545878 TI - Identifying crash contributory factors at urban roundabouts and using association rules to explore their relationships to different crash types. AB - The use of roundabouts improves intersection safety by eliminating or altering conflict types, reducing crash severity, and causing drivers to reduce speeds. However, roundabout performances can degrade if precautions are not taken during either the design or the operation phase. Therefore, additional information on the safety of the roundabouts is extremely helpful for planners and designers in identifying existing deficiencies and in refining the design criteria currently being used. The aim of the paper was to investigate the crash contributory factors in 15 urban roundabouts located in Italy and to study the interdependences between these factors. The crash data refer to the period 2003 2008. The identification of the crash contributory factors was based on site inspections and rigorous analyses performed by a team of specialists with a relevant road safety engineering background. Each roundabout was inspected once every year from 2004 to 2009, both in daytime and in nighttime. Overall, 62 different contributory factors and 2156 total contributory factors were identified. In 51 crashes, a single contributory factor was found, whereas in the other 223 crashes, a combination of contributory factors was identified. Given the large amount of data, the interdependences between the contributory factors and between the contributory factors and the different crash types were explored by an association discovery. Association discovery is the identification of sets of items (i.e., crash contributory factors and crash types in our study) that occur together in a given event (i.e., a crash in our study). The rules were filtered by support, confidence, and lift. As a result, 112 association rules were discovered. Overall, numerous contributory factors related to the road and environment deficiencies but not related to the road user or to the vehicle were identified. The most important factors related to geometric design were the radius of deflection and the deviation angle. In existing roundabouts, the improvement of these factors might be quite expensive, but the crucial role of a moderate radius of deflection and a large deviation angle in the design of new roundabouts was stressed. Many of the contributory factors were related to markings and signs, and these factors could be easily removed with low-cost safety measures. Furthermore, because of the association between the markings, signs, and geometric design contributory factors, the study results suggest that the improvement in markings and signs might also have a significant effect in the sites where geometric design deficiencies were identified as contributory factors. PMID- 21545879 TI - A comparison of the hazard perception ability of accident-involved and accident free motorcycle riders. AB - Hazard perception is the ability to read the road and is closely related to involvement in traffic accidents. It consists of both cognitive and behavioral components. Within the cognitive component, visual attention is an important function of driving whereas driving behavior, which represents the behavioral component, can affect the hazard perception of the driver. Motorcycle riders are the most vulnerable types of road user. The primary purpose of this study was to deepen our understanding of the correlation of different subtypes of visual attention and driving violation behaviors and their effect on hazard perception between accident-free and accident-involved motorcycle riders. Sixty-three accident-free and 46 accident-involved motorcycle riders undertook four neuropsychological tests of attention (Digit Vigilance Test, Color Trails Test-1, Color Trails Test-2, and Symbol Digit Modalities Test), filled out the Chinese Motorcycle Rider Driving Violation (CMRDV) Questionnaire, and viewed a road-user based hazard situation with an eye-tracking system to record the response latencies to potentially dangerous traffic situations. The results showed that both the divided and selective attention of accident-involved motorcycle riders were significantly inferior to those of accident-free motorcycle riders, and that accident-involved riders exhibited significantly higher driving violation behaviors and took longer to identify hazardous situations compared to their accident-free counterparts. However, the results of the regression analysis showed that aggressive driving violation CMRDV score significantly predicted hazard perception and accident involvement of motorcycle riders. Given that all participants were mature and experienced motorcycle riders, the most plausible explanation for the differences between them is their driving style (influenced by an undesirable driving attitude), rather than skill deficits per se. The present study points to the importance of conceptualizing the influence of different driving behaviors so as to enrich our understanding of the role of human factors in road accidents and consequently develop effective countermeasures to prevent traffic accidents involving motorcycles. PMID- 21545880 TI - Naturalistic assessment of novice teenage crash experience. AB - BACKGROUND: Crash risk is highest during the first months after licensure. Current knowledge about teenagers' driving exposure and the factors increasing their crash risk is based on self-reported data and crash database analyses. While these research tools are useful, new developments in naturalistic technologies have allowed researchers to examine newly-licensed teenagers' exposure and crash risk factors in greater detail. The Naturalistic Teenage Driving Study (NTDS) described in this paper is the first study to follow a group of newly-licensed teenagers continuously for 18 months after licensure. The goals of this paper are to compare the crash and near-crash experience of drivers in the NTDS to national trends, to describe the methods and lessons learned in the NTDS, and to provide initial data on driving exposure for these drivers. METHODS: A data acquisition system was installed in the vehicles of 42 newly-licensed teenage drivers 16 years of age during their first 18 months of independent driving. It consisted of cameras, sensors (accelerometers, GPS, yaw, front radar, lane position, and various sensors obtained via the vehicle network), and a computer with removable hard drive. Data on the driving of participating parents was also collected when they drove the instrumented vehicle. FINDINGS: The primary findings after 18 months included the following: (1) crash and near-crash rates among teenage participants were significantly higher during the first six months of the study than the final 12 months, mirroring the national trends; (2) crash and near-crash rates were significantly higher for teenage than adult (parent) participants, also reflecting national trends; (3) teenaged driving exposure averaged between 507 and 710km (315-441miles) per month over the study period, but varied substantially between participants with standard errors representing 8-14 percent of the mean; and (4) crash and near-crash types were very similar for male and female teenage drivers. DISCUSSION: The findings are the first comparing crash and near-crash rates among novice teenage drivers with those of adults using the same vehicle over the same period of time. The finding of highly elevated crash rates of novice teenagers during the first six months of licensure are consistent with and confirm the archival crash data showing high crash risk for novice teenagers. The NTDS convenience sample of teenage drivers was similar to the US teenage driver population in terms of exposure and crash experience. The dataset is expected be a valuable resource for future in-depth analyses of crash risk, exposure to risky driving conditions, and comparisons of teenage and adult driving performance in various driving situations. PMID- 21545881 TI - The influence of novel compliant floors on balance control in elderly women--A biomechanical study. AB - Novel compliant floors aim to decrease the risk for fall-related injury by providing substantial force attenuation during the impact phase of falls. Certain models of compliant flooring have been shown to have limited influence on postural sway and successful completion of dynamic balance tasks. However, the effects of these products on balance recovery mechanisms following an externally induced perturbation have yet to be quantified. We used a floor translation paradigm to induce a balance perturbation to thirteen elderly community-dwelling women. Outcome measures included the displacement rates and margins of safety for both the underfoot centre-of-pressure and whole-body centre-of-mass across two novel compliant floors (SmartCell, SofTile), two basic foam surfaces (Firm-Foam, Soft-Foam) and a standard 'Rigid' floor as a control condition. The centre-of mass and centre-of-pressure margins of safety, and all centre-of-mass displacement rates, were not significantly lower for the two novel compliant flooring systems compared to the control floor. The centre-of-pressure displacement rates were similar to the control floor for the SmartCell floor condition. The majority of the margin of safety and displacement rate variables for the foam floors were significantly lower than the control condition. This study illustrates that the SmartCell and SofTile novel compliant floors have minimal influences on balance and balance control responses following externally induced perturbations in older community-dwelling women, and supports pilot installations of these floors to inform decisions regarding the development of clinical trials. PMID- 21545882 TI - Development of student drivers' self-assessment accuracy during French driver training: Self-assessments compared to instructors' assessments in three risky driving situations. AB - Promoting self-assessment accuracy among student drivers could help improve road safety for young novice drivers (Minimum Requirement for Driving Instructor Training, 2005). It is crucial to investigate the development of this ability in student drivers, although few studies have been conducted on this issue to our knowledge. The present study was aimed at examining the development of accuracy in student drivers' self-assessments. Students' self-ratings of their skills were compared to instructors' ratings based on the students' progression through the four steps of the French driver training course. The ratings were collected from two versions of an ad hoc questionnaire about students' ability to turn right, overtake another vehicle, and turn left in driving situations. The questionnaire included a three-part assessment scale (six driving subtasks required to perform the maneuver, the number of driving subtasks managed simultaneously, and the student's autonomy), demographic data, and the students' progress in the training program. The participants were 149 student drivers (58 men and 91 women) with a mean age of 22.2 years, and 38 professional driving instructors (36 men and 2 women) from 13 driving schools in Paris. The psychometric quality of the scale was satisfactory (alpha(s)>.9) concerning the self-ratings as well as the instructors' ratings in the three parts of the scale. As a whole and as expected, the self-ratings and the instructors' ratings became increasingly positive as the training progressed, on each part of the assessment scale. The students' and the instructors' ratings did not differ significantly between the three driving situations tested, nor between male and female students in each training step. Furthermore, students' overestimation of their driving skills was mainly observed on step 1, less on steps 2 and 3, but never on step 4. Thus, the students became rather aware of their current driving skills as the driver training course progressed. The results on the development of the self-assessment accuracy in driver training are discussed. PMID- 21545883 TI - Speed maintenance under cognitive load - Implications for theories of driver behaviour. AB - No theory of driver behaviour has yet managed to achieve widespread acceptance and use in the field of Traffic Psychology, partly due to the difficulty in testing many of the theories. However, one class of theories, the motivational theories, can be usefully split into two groups and the differences between them can then be examined. One group posits the constant monitoring and targeting of a certain subjective variable, often risk, as the controlling factor in driving. The other group however states that subjective variables such as risk are only relevant once a certain threshold has been passed. In this study we aimed to examine this difference by manipulating both speed of travel and the amount of cognitive load participants were under. Participants were asked to initially drive at their preferred speed for 1min in a driving simulator. Participant's speed was then automatically increased or decreased by 10, 20 30km/h or left unchanged. Participants were then required to maintain the new speed for 1min. After this 1min the speed was again automatically changed and had to be maintained for one more minute, but this time participants also carried out a secondary mental arithmetic task. Finally participants were asked to again drive for another 1min at their preferred speed. This procedure was repeated seven times, once for each speed manipulation; -30, -20, -10, +0, +10, +20 and +30km/h. After each 1min interval verbal ratings of task difficulty, effort, feeling of risk and the typicality of the speed were collected. The results show a threshold effect in ratings of task difficulty, effort and feeling of risk, with no significant difference given between the ratings during the baseline period and the experimentally decreased speed periods until after participant's preferred speed of travel had been exceeded. Furthermore, even when under cognitive load the threshold relationship was still apparent, if diminished. Finally it appears that when under cognitive load drivers have difficulty maintaining a travelling speed which is lower than the speed at which they would prefer to drive. However, driving at a speed in excess of their preferred speed appears to be easier to maintain, at least in the short term. PMID- 21545884 TI - Making minor rural road networks safer: The effects of 60 km/h-zones. AB - For safety reasons a maximum speed limit of 60km/h has been applied to minor rural roads in the Netherlands since 1998. To support this structurally, a part of these roads have also received additional physical measures in a so-called "low cost design" that is expected to reduce the number of traffic casualties by 10-20%. This measure has been implemented as much as possible in an area oriented way. To measure the design's effectivity, road safety in 20 specific rural areas was studied for 5 years before changes were implemented and, on average, 3.5 years thereafter. The study examined 851km of roads, and a control study was done on 2105km of comparable roads with a speed limit of 80km/h. Both the study and the control roads are managed by water boards. Results show that the measures implemented on the roads in the 60km/h-zones had statistically significant effects (p<0.05) on casualty accidents (-24% overall), especially at intersections (-44%). This high reduction is probably caused by the concentration of technical interventions at intersections. Both outcomes are somewhat higher than previously expected and are comparable with the outcome of a meta-analysis of safety effects on area-wide urban traffic calming schemes. However, the cost effectiveness ratio of the 60km/h zones measures (?33,000 per prevented KSI casualty) is much more favourable than the ratio in urban 30km/h-zones (?86,000 per prevented KSI-casualty). PMID- 21545885 TI - College students' prevalence and perceptions of text messaging while driving. AB - By analyzing self-reports from sample of 91 college students from the United States who are frequent drivers, the present study examined the prevalence of text messaging (or "texting") while driving and the incidence of recklessness and consequences that accompany this behavior. Analyses revealed that 91% of participants reported having used text messaging while driving, with many reporting doing so with passengers, including children, riding in their vehicles. Further, a substantial number of participants reported driving dangerously above the speed limit and drifting into other traffic lanes while texting, and many reported "sexting" and arguing via text messages while driving. However, these young drivers agreed that texting while driving is dangerous and should be illegal. These results and the limitations to the present study are discussed. PMID- 21545886 TI - Gender differences in injury severity risks in crashes at signalized intersections. AB - This paper analyzes gender differences in crash risk severities using data for signalized intersections. It estimates gender models for injury severity risks and finds that driver condition, type of crash, type of vehicle driven and vehicle safety features have different effects on females' and males' injury severity risks. Also, it finds some variables which are significantly related to females' injury severity risks but not males' and others which affect males' injury severity risks but not females'. It concludes that better and more in depth information about gender differences in injury severity risks is gained by estimating separate models for females and males. PMID- 21545887 TI - Estimated incident cost savings in shipping due to inspections. AB - The effectiveness of safety inspections of ships has been analysed from various angles, but until now, relatively little attention has been given to translate risk reduction into incident cost savings. This paper provides a monetary quantification of the cost savings that can be attributed to port state control inspections and industry vetting inspections. The dataset consists of more than half a million ship arrivals between 2002 and 2007 and contains inspections of port state authorities in the USA and Australia and of three industry vetting regimes. The effect of inspections in reducing the risk of total loss accidents is estimated by means of duration models, in terms of the gained probability of survival. The monetary benefit of port state control inspections is estimated to range, on average, from about 70 to 190 thousand dollars, with median values ranging from about 20 to 45 thousand dollars. Industry inspections have even higher benefits, especially for tankers. The savings are in general higher for older and larger vessels, and also for vessels with undefined flag and unknown classification society. As inspection costs are relatively low in comparison to potential cost savings, the results underline the importance of determining ships with relatively high risk of total loss. PMID- 21545888 TI - A model of Beijing drivers' scrambling behaviors. AB - A major, but unstudied, cause of crashes in China is drivers that "scramble" to gain the right of way in violation of traffic regulations. The motivation of this study is to explore the features of drivers' scrambling behaviors and the attitudes and driving skills that influence them. In this study, we established a scrambling behavior scale, and developed a driving attitude scale and a driving skill scale using factor analysis of an Internet survey of 486 drivers in Beijing. A structural equation model of scrambling behavior toward cars and pedestrians/cyclists was developed with attitudes and skills as predictors of behavior. Skills and attitudes of approval toward violations of traffic rules did not predict scrambling behaviors, while the motivation for safety and attitudes against violating traffic rules led to reduced scrambling behaviors. The current work highlights this peculiar aspect of Chinese roads and suggests methods to reduce the behavior. PMID- 21545889 TI - The road safety implications of illegal street racing and associated risky driving behaviours: An analysis of offences and offenders. AB - The purpose of this study was to explore the road safety implications of illegal street racing and associated risky driving behaviours. This issue was considered in two ways: Phase 1 examined the descriptions of 848 illegal street racing and associated risky driving offences that occurred in Queensland, Australia, in order to estimate the risk associated with these behaviours; and Phase 2 examined the traffic and crash histories of the 802 male offenders involved in these offences, and compared them to those of an age-matched comparison group, in order to examine the risk associated with the driver. It was found in Phase 1 that only 3.7% of these offences resulted in a crash (none of which were fatal), and that these crashes tended to be single-vehicle crashes where the driver lost control of the vehicle and collided with a fixed object. Phase 2 found that the offender sample had significantly more traffic infringements, licence sanctions and crashes in the previous three years than the comparison group. It was concluded that while only a small proportion of racing and associated offences result in a crash, these offenders appear to be generally risky drivers that warrant special attention. PMID- 21545890 TI - Comparison of two methods to assess the effect of age and sex on the risk of car crashes. AB - BACKGROUND: This study was designed to compare two methods (direct measurement of exposure and quasi-induced exposure) for assessing the effect of age and sex on the risk of being involved in a car crash in Spain. METHODS: Spanish crash rates (per 10,000,000 driver-km) for age and sex groups of drivers aged 18-64 years old were obtained for 2004-2007, using information from the Spanish General Traffic Office (census of reported car crashes) and the Spanish Household Survey on Alcohol and Drugs (estimate of the mean km driven for each car driver). The rate ratios estimated by direct exposure estimates were compared to those obtained with the quasi-induced exposure method, which compares the age and sex of responsible and non-responsible drivers involved in the same clean collision (in which only one of the drivers committed a driving infraction). RESULTS: Both methods detected an increased risk of involvement in a crash for the youngest (18 20 years) and the oldest drivers (60-64 years), compared to middle-aged drivers (45-49 years). However, the rate ratios obtained with the quasi-induced method for the youngest group (2.0 for men, 1.6 for women) were much lower than those obtained with crash rates (13.4 for men, 5.7 for women). Both methods detected a similar increase in the risk of involvement of male drivers compared to women in the youngest age group. This excess risk for men was maintained with increasing age up to 45-49 years when the quasi-induced method was used. However, direct comparisons of crash rates revealed an increased risk of involvement in women compared to men of the same age from 25-29 years onward. CONCLUSIONS: Both direct measurement of driving exposure and the quasi-induced exposure method detected some well-known patterns of risk associated with driver's age and sex. However, factors that could explain important differences between the two methods deserve attention, especially those related with the excess risk for the youngest drivers as well as sex-related risk. PMID- 21545891 TI - The frequency and predictors of helmet use among Iranian motorcyclists: A quantitative and qualitative study. AB - OBJECTIVE: This study examines the rate of helmet use and identifies barriers and facilitators of wearing helmets among Iranian motorcyclists. A mixed-method approach was used, including a structured seasonal survey with specific observations of a random sample of 6010 riders and qualitative methods that included 29 in-depth interviews and seven focus groups (n=31). RESULTS: Only 10% of motorcyclists wear a standard helmet while riding. However, another 23% of motorcyclists used non-standard or partial helmets that covered only part of the head and do not prevent head trauma injuries effectively. We observed only 2 of 264 child passengers and 22 of 1951 adult passengers wearing helmets. Almost no one used protective pants or clothing made to be more visible in traffic. Themes emerged from qualitative interviews and were grouped into three main categories: (1) helmet characteristics; (2) social and cultural factors; and (3) personal and psychological factors. CONCLUSION: Overall, the motorcyclists in our study believed that wearing a safety helmet protects them against serious injuries or death during a crash; however, only a small percentage of the motorcyclists used safety helmets. National intervention programs addressing motorcycle safety should aim to overcome barriers to and promote facilitators of helmet use, including providing inexpensive standard helmets, banning manufacturing/using unsafe partial or dummy helmets, as well as enforcing helmet use on a consistent basis. PMID- 21545892 TI - Requirements of a system to reduce car-to-vulnerable road user crashes in urban intersections. AB - Intersection crashes between cars and vulnerable road users (VRUs), such as pedestrians and bicyclists, often result in injuries and fatalities. Advanced driver assistance systems (ADASs) can prevent, or mitigate, these crashes. To derive functional requirements for such systems, an understanding of the underlying contributing factors and the context in which the crashes occur is essential. The aim of this study is to use microscopic and macroscopic crash data to explore the potential of information and warning providing ADASs, and then to derive functional sensor, collision detection, and human-machine interface (HMI) requirements. The microscopic data were obtained from the European project SafetyNet. Causation charts describing contributing factors for 60 car-to-VRU crashes had been compiled and were then also aggregated using the SafetyNet Accident Causation System (SNACS). The macroscopic data were obtained from the Swedish national crash database, STRADA. A total of 9702 crashes were analyzed. The results show that the most frequent contributing factor to the crashes was the drivers' failure to observe VRUs due to reduced visibility, reduced awareness, and/or insufficient comprehension. An ADAS should therefore help drivers to observe the VRUs in time and to enhance their ability to interpret the development of events in the near future. The system should include a combination of imminent and cautionary collision warnings, with additional support in the form of information about intersection geometry and traffic regulations. The warnings should be deployed via an in-vehicle HMI and according to the likelihood of crash risk. The system should be able to operate under a variety of weather and light conditions. It should have the capacity to support drivers when their view is obstructed by physical objects. To address problems that vehicle-based sensors may face in this regard, the use of cooperative systems is recommended. PMID- 21545893 TI - Exploring a Bayesian hierarchical approach for developing safety performance functions for a mountainous freeway. AB - While rural freeways generally have lower crash rates, interactions between driver behavior, traffic and geometric characteristics, and adverse weather conditions may increase the crash risk along some freeway sections. This paper examines the safety effects of roadway geometrics on crash occurrence along a freeway section that features mountainous terrain and adverse weather. Starting from preliminary exploration using Poisson models, Bayesian hierarchical models with spatial and random effects were developed to efficiently model the crash frequencies on road segments on the 20-mile freeway section of study. Crash data for 6 years (2000-2005), roadway geometry, traffic characteristics and weather information in addition to the effect of steep slopes and adverse weather of snow and dry seasons, were used in the investigation. Estimation of the model coefficients indicates that roadway geometry is significantly associated with crash risk; segments with steep downgrades were found to drastically increase the crash risk. Moreover, this crash risk could be significantly increased during snow season compared to dry season as a confounding effect between grades and pavement condition. Moreover, sites with higher degree of curvature, wider medians and an increase of the number of lanes appear to be associated with lower crash rate. Finally, a Bayesian ranking technique was implemented to rank the hazard levels of the roadway segments; the results confirmed that segments with steep downgrades are more crash prone along the study section. PMID- 21545894 TI - A grounded theory model for analysis of marine accidents. AB - The purpose of this paper was to design a conceptual model for analysis of marine accidents. The model is grounded on large amounts of empirical data, i.e. the Swedish Maritime Administration database, which was thoroughly studied. This database contains marine accidents organized by ship and variable. The majority of variables are non-metric and some have never been analyzed because of the large number of values. Summary statistics were employed in the data analysis. In order to develop a conceptual model, the database variables were clustered into eleven main categories or constructs, which were organized according to their properties and connected with the path diagram of relationships. For demonstration purposes, one non-metric and five metric variables were selected, namely fatality, ship's properties (i.e. age, gross register tonnage, and length), number of people on board, and marine accidents. These were analyzed using the structural equation modeling (SEM) approach. The combined prediction power of the 'ship's properties' and 'number of people on board' independent variables accounted for 65% of the variance of the fatality. The model development was largely based on the data contained in the Swedish database. However, as this database shares a number of variables in common with other databases in the region and the world, the model presented in this paper could be applied to other datasets. The model has both theoretical and practical values. Recommendations for improvements in the database are also suggested. PMID- 21545895 TI - Twisted cystic artery disclosed by 3-dimensional computed tomography angiography for torsion of the gallbladder. AB - Torsion of the gallbladder is a rare condition that most commonly affects elderly women. The symptoms of torsion mimic acute cholecystitis, but several clinical features and imaging findings can be useful for distinguishing it from typical acute cholecystitis. However, preoperative identification remains difficult. Three-dimensional angiography reconstructed by preoperative multidetector row computed tomography is useful for definitive diagnosis of torsion of the gallbladder. Demonstration of a twisted cystic artery by 3-dimensional computed tomography angiography represents specific and direct evidence of this condition, which allows immediate diagnosis and treatment. PMID- 21545896 TI - Distal gastrectomy for advanced gastric cancer with vascular anomaly after coronary bypass grafting using the right gastroepiploic artery. AB - A 77-year-old woman with a history of coronary artery bypass grafting 5 years earlier presented with anemia and was diagnosed with advanced gastric cancer involving the pylorus. Preoperative angiography revealed that the right gastroepiploic artery (RGEA) graft was patent. Multidetector-row computed tomography showed the running pattern of the RGEA graft and also revealed a vascular anomaly belonging to type V of Adachi's classification. Adachi's type V is a rare vascular anomaly in which the common hepatic artery originates from the superior mesenteric artery. The patient was treated successfully with a distal gastrectomy and removal of the D2 lymph node with preservation of the RGEA graft. Because of the difficulty in confirming the running pattern of the artery during the surgery, it is important to define the arterial running pattern preoperatively by using multidetector-row computed tomography, including 3 dimensional angiographic imaging. PMID- 21545897 TI - Retroperitoneal liposarcoma extending into the thigh. AB - The authors describe a case of a giant retroperitoneal liposarcoma that extended into the thigh along the course of the iliopsoas muscle. The tumor was successfully excised en bloc through an abdominal and a proximal thigh incision. Histopathologic examination revealed a well-differentiated, lipoma-like liposarcoma with clear surgical margins. The patient remains well without any evidence of tumor recurrence 18 months after surgery. PMID- 21545898 TI - The moral imperative of surgery. PMID- 21545899 TI - Remembering Dr. Jim Gillespie as a world adventurer, master surgeon, and invaluable mentor. PMID- 21545900 TI - Outpatient thyroidectomy: is it a safe and reasonable option? AB - BACKGROUND: Outpatient surgery is cost effective and convenient. The aim of this study was to determine the safety and feasibility of outpatient thyroidectomy. METHODS: Retrospective review was performed of all thyroidectomy patients from a tertiary care center between January 2004 and March 2010. RESULTS: One hundred forty-eight patients met the inclusion criteria. Subtotal and hemithyroidectomies (n = 79) were compared against completion and total thyroidectomies (n = 72). Nine total thyroidectomy patients (12.5%) required unplanned overnight admission, compared with 4 hemithyroidectomy patients (5.1%) (P = .15). The majority were admitted for pain and nausea control. Overnight admissions were highest among men (32% vs 5%, P = .002) and patients with Graves' disease (36% vs 6%, P = .003). Postoperative complications occurred in 6 total thyroidectomy patients (8.3%) and 3 hemithyroidectomy patients (3.8%) (P = .31). Only 4 patients (2.6%) required readmission for complications. There were no deaths. CONCLUSIONS: Outpatient thyroidectomy performed by an experienced surgeon is safe and feasible. Men and patients with Graves' disease have a higher probability of requiring postoperative admission. PMID- 21545901 TI - Utilization of thyroidectomy for benign disease in the United States: a 15-year population-based study. AB - BACKGROUND: Recent recommendations suggest that total thyroidectomy (TT) is the preferred treatment for benign thyroid disease. This approach remains controversial because of the increased risk of morbidity compared with a partial thyroidectomy (PT). The aim of this study was to determine the use of thyroidectomy for benign disease over a 15-year period. METHODS: One hundred nineteen thousand eight hundred eighty-five patients from the Nationwide Inpatient Sample database (1993-2007) underwent surgery for benign thyroid disease. Logistic regression was used to assess the relation between extent of thyroidectomy and the year of admission, hospital volume, and surgical outcomes. RESULTS: The use of TT increased from 17.6% (1993-1997) to 39.6% (2003-2007) compared with 82.4% and 60.4% for PT over the same periods (P < .0001). A greater proportion of TTs was performed in high-volume centers in which the rates of postoperative complications were lower than low-volume centers. CONCLUSIONS: The use of TT for benign thyroid disease has increased over the last 15 years in the United States. This pattern of practice is in keeping with the trends reported in recent literature. PMID- 21545902 TI - Predicting malignant intraductal papillary mucinous neoplasm: a single-center review. AB - BACKGROUND: The purpose of this study was to examine the characteristics of pancreatic intraductal papillary mucinous neoplasm (IPMN) in our institution and the selection for resection. Recent publications, including those from the International Consensus Guidelines and the Mayo Clinic, set forth criteria for resection. However, these criteria differ in the definition of main duct IPMN, which is an indication to resect. METHODS: Sixty patients from a single institution were retrospectively reviewed between 2000 and 2009. RESULTS: Thirteen percent of patients had high-grade dysplasia, and 22% had invasive cancer. In multivariate analysis, factors associated with a lower risk of carcinoma were female sex (P = .039) and size <3 cm (P = .024). Patients were retrospectively evaluated with Mayo and International Consensus Guidelines. Eight patients had a diagnosis that would have changed from main duct to branch duct if the International Consensus Guidelines were used. Of these 8, there were 2 cancers. If the International Consensus Guidelines were applied instead of the Mayo, both cancers would have been resected, but 2 patients without cancer would have been spared an operation. CONCLUSIONS: Twenty-two percent of resected patients had invasive cancer, and they had significantly worse survival (37 vs 85 months, P = .032). In our patient group, application of the International Consensus Guidelines identified all malignant IPMN and would have prevented 2 nontherapeutic resections when compared with the Mayo criteria. PMID- 21545903 TI - Immunophenotyping of thyroid tumors identifies molecular markers altered during transformation of differentiated into anaplastic carcinoma. AB - BACKGROUND: The objective of this study was to evaluate the change in the tumor expression profile that occurs during the transformation of differentiated thyroid cancer (DTC) into anaplastic thyroid cancer (ATC) and to evaluate an 8 marker transformation panel previously identified through evaluation of ATCs and their adjacent associated DTCs. METHODS: Tissue microarrays were constructed from 19 ATCs and 96 DTCs (90 papillary carcinomas and 6 follicular carcinomas), and immunohistochemistry was used to evaluate the expression of 54 molecular markers. Significant associations between marker staining and cancer pathology (DTC vs ATC) were determined using contingency table and marginal homogeneity tests. A Random Forests classifier algorithm was also used to identify useful or important molecular classifiers. RESULTS: Overall, there were 25 significantly differentially expressed markers when comparing ATCs with DTCs. These included 5 of the 8 markers that were previously identified as being altered during anaplastic transformation and 3 additional markers were also found to be highly significantly differentially expressed by ATCs and DTCs. Clustering and classification analysis based on the previously identified 8-marker transformation panel, or the 5 of these markers that were found to be most important in the current study, readily separated DTC and ATC with a high degree of accuracy. CONCLUSIONS: The markers observed to change during thyroid cancer progression validate prior observations and represent promising molecular diagnostic or prognostic tools and identify targets for therapy of ATC. PMID- 21545904 TI - Trauma induces a hypercoagulable state that is resistant to hypothermia as measured by thrombelastogram. AB - BACKGROUND: The aim of this study was to test the hypothesis that severely injured trauma patients would be hypercoagulable compared with controls measured by thromboelastography and that this hypercoagulability would persist over a broad range of temperatures. METHODS: A prospective study evaluating the effects of temperature on coagulation in trauma patients with Injury Severity Scores >= 15 and controls was completed. Thromboelastography was performed 24 hours after admission at 4 temperatures ranging from 32 degrees C to 38 degrees C. RESULTS: Ninety-two subjects (46 patients) were analyzed. Patients had a median Injury Severity Score of 20 (interquartile range, 16-26). Time to clot formation increased (P < .001) and fibrin cross-linking decreased (P < .01) in both groups as temperature decreased. Between groups, time to clot formation, fibrin cross linking, and clot strength were significantly different at each temperature (P < .01), with patients being more hypercoagulable. Time to clot formation and fibrin cross-linking were more affected by temperature in controls compared with patients (P < .02). CONCLUSIONS: Severely injured patients are more hypercoagulable than controls throughout a broad range of temperature. Decreasing temperature has a greater effect on coagulation in controls compared with patients. PMID- 21545905 TI - Validation of noninvasive hemoglobin measurements using the Masimo Radical-7 SpHb Station. AB - BACKGROUND: Hemoglobin levels must be obtained through blood draws, which are invasive, time-consuming, and provide only 1 data point at a time rather than continuous measurements. The Masimo Radical-7 SpHb Station (Masimo Corporation, Irvine, CA) has been shown by its manufacturers to provide accurate noninvasive hemoglobin measurements in physiologically normal patients. The objective of this study was to validate noninvasive hemoglobin measurements using the Masimo Radical-7 device. METHODS: Data were prospectively collected in 2 cohorts of patients: major operations requiring hemodynamic monitoring (operating room [OR]) and critically ill patients (intensive care unit [ICU]). Noninvasive hemoglobin measurements (SpHb) were recorded and were then compared with laboratory hemoglobin measurements. RESULTS: Data were collected on 60 patients (OR = 25 and ICU = 45). The overall correlation of the Masimo SpHb and the laboratory Hb was .77 (P < .001) in the OR group with a mean difference of .29 g/dL (95% confidence interval [CI], .08-.49). The overall correlation in the ICU group was .67 (P < .001) with a mean difference of .05 g/dL (95% CI, -.22 to -.31). CONCLUSIONS: Noninvasive hemoglobin monitoring is a new technology that correlated with laboratory values and supports the continued study of noninvasive hemoglobin monitoring. PMID- 21545906 TI - The Hill antireflux repair at 5 institutions over 25 years. AB - BACKGROUND: Long-term (> 5 years) studies of antireflux operations are needed. This study evaluates long-term results of the open Hill repair at multiple institutions. METHODS: This is a retrospective cohort study of open Hill repairs from 1972 to 1997 at 5 North American medical centers with a mean follow-up of 10 years. Objective data and standardized clinical outcomes were collected at a central site. Subjective results, medication use, and satisfaction scales were obtained through scripted phone interview. Results between 2 Hill-trained centers and 3 independent centers were compared. RESULTS: One thousand one hundred eighty one patients met the inclusion criteria. Symptomatic improvement was found in 97% and good to excellent results in 93%. Medication use was markedly reduced. Hiatal hernia recurrence was found in 77 (6.9%); the reoperation rate was 1.9%. Differences in outcomes between Hill centers and independent centers were minor. CONCLUSIONS: Excellent results with the open Hill repair are durable beyond 10 years and are reproducible. Anatomic recurrence and reoperative rates are low. PMID- 21545907 TI - Irradiation effect after mastectomy on breast cancer recurrence in patients presenting with locally advanced disease. AB - BACKGROUND: Current guidelines recommend postmastectomy irradiation (PMI) for patients with tumors >5 cm and/or >=4 positive lymph nodes. This study evaluates the effect of PMI on recurrence and survival within tumor size and node status groups. METHODS: Locoregional and distant recurrences and survival for different tumor and treatment characteristics were analyzed in 2,797 patients with invasive breast cancer treated with mastectomy. RESULTS: Tumor size, positive nodes, extranodal extension, lymphatic/vascular invasion, estrogen receptor/progesterone negative, HER-2 positive, and high grade were associated with significantly increased recurrence. In patients with >=4 positive nodes and patients with tumors >5 cm and positive nodes, PMI decreased local and distant recurrence (overall 53% vs 24%, P < .001) and increased disease-free survival (P < .001) but not overall survival. In patients with less disease, a benefit from PMI irradiation could not be identified. CONCLUSIONS: PMI is indicated for patients with >=4 positive nodes or patients with tumors >5 cm and positive nodes. PMID- 21545908 TI - Incidence of abnormal mammograms after reduction mammoplasty: implications for oncoplastic closure. AB - BACKGROUND: Reduction mammoplasty requires significant tissue dissection, which may impact the interpretation of future mammograms used in breast cancer surveillance. The aim of this study was to define the incidence of abnormal mammography after reduction mammoplasty and to assess the impact of substantial tissue remodeling on interpreting mammography. METHODS: We conducted a single center retrospective case-control study examining results of postoperative mammography after reduction mammoplasty over a 5-year period. RESULTS: Between 2001 and 2005, 87 patients underwent breast reduction and had available postoperative mammography. A control group of 30 patients were identified who underwent consultation for breast reduction but did not have surgery. The median time to postoperative mammography was 52 weeks. The incidence of abnormal first postoperative mammogram (Breast Imaging-Reporting and Data System [BIRADS] 0, 3 6) was not significantly different between reduction mammoplasty patients and controls (n = 23, 26% vs 8, 27%, respectively, P = 1.00). Age, postoperative complications, tissue pathology, history of previous breast biopsy, and abnormal preoperative mammography did not significantly predict abnormal postoperative mammogram. Postoperative mammography led to additional imaging in 20 patients (23%) and breast biopsy in 1 patient (1.1%). CONCLUSIONS: Despite the substantial tissue mobilization performed during reduction mammoplasty, postoperative screening mammography does not lead to significantly more imaging or diagnostic interventions when compared with nonoperative controls. This small case-control study suggests that oncoplastic closure techniques should not adversely impact subsequent mammography. PMID- 21545909 TI - Increasing incidence of bilateral mastectomies: the patient perspective. AB - BACKGROUND: Numerous studies have reported increasing rates of contralateral prophylactic mastectomies (CPMs). Understanding patient rationale for the surgical choice may provide insight into this trend. METHODS: A questionnaire was mailed to 350 mastectomy patients identified from a community health system tumor registry. RESULTS: Two hundred fifty questionnaires were received; of these, 237 had undergone mastectomy. Fifty-two percent had unilateral mastectomy (UM), and 43% had bilateral mastectomies (BMs) (6% for bilateral disease). Women younger than 60 years of age were more likely to choose BM (P = .0046). Those who had CPM were significantly more likely to make the same surgical decision (P < .0001). Reconstruction was performed in 52%, with BM patients more likely to undergo reconstruction (P = .009). Twenty-three (19%) needed unanticipated reoperation for reconstruction complications. CPM had equivalent rates of unanticipated surgery versus UM (P = .64). CONCLUSIONS: Patients choosing BMs are younger, have equivalent rates of reoperation because of reconstruction complications, and are significantly more satisfied with their decision than those who chose UM. PMID- 21545910 TI - Comparison of pulmonary nodule detection rates between preoperative CT imaging and intraoperative lung palpation. AB - BACKGROUND: Recent advances in computed tomographic (CT) imaging have improved the detection rate of pulmonary metastasis. The aim of this study was to test the hypothesis that the pulmonary nodule detection rate for preoperative CT imaging and intraoperative palpation are now equivalent. METHODS: A retrospective review of 108 pulmonary metastasectomies in 84 patients was performed. The number of nodules detected on preoperative CT imaging by radiologist report was compared with the number of malignant nodules identified on pathology. Secondary outcome measures were operative approach and primary malignancy. RESULTS: Sarcoma metastases were the most common indication for resection (n = 54 [50%]). Thirty three percent of metastasectomies were performed using a thoracoscopic approach. When thoracotomy was used, significantly more nodules were palpated and resected than were identified on preoperative CT imaging (3.24 vs 2.12, P < .001). Significantly more of these nodules were confirmed malignant on final pathology (2.40 vs 1.60, P = .01). This difference was not seen for thoracoscopic resections. CONCLUSIONS: Although the sensitivity of CT imaging has improved, a significant number of malignant pulmonary nodules are detected intraoperatively that are not identified on preoperative imaging. Patients undergoing pulmonary metastasectomy require careful intraoperative palpation of lung parenchyma, and therefore open thoracotomy remains the standard of care. PMID- 21545911 TI - Does sacrifice of the inferior mesenteric artery or superior rectal artery affect anastomotic leak following sigmoidectomy for diverticulitis? a retrospective review. AB - BACKGROUND: Anastomotic leak after sigmoidectomy for diverticular disease can have devastating consequences. Preservation or sacrifice of the descending colon or rectal arterial supply may affect the anastomosis. The aim of this study was to evaluate whether preservation of the inferior mesenteric artery (IMA) or superior rectal artery (SRA) was associated with a decreased anastomotic leak rate. METHODS: A retrospective review of adult patients undergoing sigmoidectomies from 2 military tertiary care centers was performed, evaluating patient demographic and operative variables for their effects on anastomotic leak rate. RESULTS: A total of 130 patients were identified. The overall anastomotic leak rate was 5.4%. Laparoscopy was used in 41%, and stapled anastomoses were used in 91%. The IMA was sacrificed in 29% and the SRA in 37%. There were no significant differences in leak rates when the IMA or SRA was sacrificed (0% and 3.7% with the IMA and SRA sacrificed, 9.3% and 6.5% with the vessels preserved; P = .140 and P = .610, respectively). Laparoscopic technique (P = .843), emergency surgery (P = .29), and operative time (P = .78) did not affect leak rate. Hand sewn anastomoses were associated with a higher leak rate (33% vs 2%; odds ratio, 3.44; 95% confidence interval, 1.514-7.817; P < .001). CONCLUSIONS: IMA or SRA preservation or sacrifice was not associated with an increased leak rate from colorectal anastomoses after sigmoidectomy for diverticular disease. Stapled anastomoses were associated with a lower leak rate than hand-sewn anastomoses. PMID- 21545912 TI - Outcomes of salvage surgery for epidermoid carcinoma of the anus following failed combined modality treatment. AB - BACKGROUND: Chemoradiation is first-line therapy for epidermoid carcinoma of the anus (ECA). Surgery is reserved for treatment failures. The authors report outcomes after salvage procedures for ECA. METHODS: All treatment failures managed with radical surgery between 1998 and 2006 in our institution were reviewed. The Kaplan-Meier method was used for survival analysis. Log-rank and Cox regression were used for univariate and multivariate analysis, respectively. RESULTS: Fifty-one patients underwent salvage abdominoperineal resection for locoregional failure. Five-year overall survival after abdominoperineal resection was 29% (median, 22 months). Age, gender, human immunodeficiency virus status, tumor-node-metastasis stage, node status, and failure type did not predict survival. Negative resection margin was most strongly associated with improved overall and disease-free survival (P = .03 and P < .0001, respectively). Median survival for patients undergoing inguinal lymph node dissection for regional recurrence (n = 6) was 11 months, with freedom from cancer achieved in 2 of 6 patients. CONCLUSIONS: Recurrent anal carcinoma after primary chemoradiotherapy carries a poor prognosis. Salvage abdominoperineal resection offers a potential for long-term survival. PMID- 21545913 TI - Laparoscopic converted to open colectomy: predictors and outcomes from the Nationwide Inpatient Sample. AB - BACKGROUND: Early in their learning curve, surgeons need to appropriately select patients to avoid conversion from laparoscopic to an open colectomy. METHODS: Using the Nationwide Inpatient Sample, laparoscopic and laparoscopic converted to open colectomies performed between 2002 and 2007 were compared. We evaluated patient and institutional characteristics to find significant predictors and outcomes of conversion. RESULTS: Between 2002 and 2007, the rate of conversion was high, ranging from 35.7% to 38.0%. Multivariate predictors of conversion included obesity, diverticulitis, inflammatory bowel disease, constipation, metastatic disease, nonelective admission, left or transverse colectomy, intraoperative complication, lower socioeconomic status, uninsured status, and rural hospital location. A colectomy for benign colon polyps was less likely to be converted. Conversion to an open colectomy did not increase inpatient mortality. CONCLUSIONS: Predictors of conversion from open to laparoscopic colectomy were found from a national database reflecting all US laparoscopic colectomies. Conversion did not increase inpatient mortality. PMID- 21545914 TI - Effect of systematic education courses on rectal cancer treatments in a population. AB - PURPOSE: In a strategy aimed to improve perioperative and operative management of rectal cancer in British Columbia (BC), a series of educational events were provided for BC surgeons, radiation oncologists, and pathologists including teaching on the use of preoperative radiation, surgical technique with total mesorectal excision (TME), and pathology reporting. Seminars were offered during 2002 and 2003 each over 2 days with documented attendance from 30 hospitals in the province. We wished to determine whether frequency of preoperative radiation and TME surgery changed on a population level after the rectal cancer education courses in 2002 and 2003. METHODS: All patients were referred to the BC Cancer Agency, the only center for radiation in BC. Treatments and data were abstracted from the Colorectal Cancer Outcomes Unit database. Patients with resected stage I to III rectal cancer were included who were diagnosed before (2000-2001) and after (2004) the education courses. We used changes from 2000 to 2001 to reflect effects of sporadic continued medical education (CME) compared with effects of formal systematic provincial education courses (changes from 2001 to 2004). RESULTS: A total of 778 eligible patients were included from 2000 (n = 264), 2001 (n = 202), and 2004 (n = 312). The percentage of stage III patients was similar in the 3 time periods. The use of preoperative radiation therapy increased significantly over time, 43% (114/264), 56% (113/202), and 86% (268/312) (P < .0001). TME use also increased significantly, 35%, 44%, and 71% (P < .0001). CONCLUSIONS: The implementation of guidelines for the use of preoperative radiation and TME by formal systematic provincial education courses for surgeons, radiation oncologists, and pathologists resulted in significant improvements in rectal cancer management on a provincial level. Such programs may be more effective than "sporadic" CME, particularly in multidisciplinary and complex care settings like adjuvant rectal cancer therapy. PMID- 21545915 TI - Utilization of cancer registry data for monitoring quality of care. AB - BACKGROUND: Cancer Program Practice Profile Reports (CP(3)R), established by the Commission on Cancer, are based on 6 guidelines for breast and colorectal cancer care using cancer registry data. The long-term goal is the use of cancer registry data for real-time interventions to optimize the process of individual patient multidisciplinary care. METHODS: CP(3)R results using 593 analytic breast cancer cases in 2008 were compared in 3 databases: an institutional breast cancer research database, an institutional cancer registry, and a regional Cancer Surveillance System. RESULTS: Compliance with the CP(3)R guidelines calculated using the 3 databases was 80% to 98% for radiation therapy following breast conserving surgery, 78% to 88% for combination chemotherapy of hormone receptor negative stage T1c, II, or III disease, and 53% to 85% for hormone therapy of hormone receptor-positive stage T1c, II, or III disease. There was a high rate of discrepancy of tumor characteristics, treatment, and CP(3)R resulting from inaccurate and incomplete data. CONCLUSIONS: Using national cancer databases prospectively to monitor and ensure optimal multidisciplinary cancer care will require dramatic changes in cancer registry processes. PMID- 21545916 TI - Long-term follow-up in the treatment of peritoneal carcinomatosis. AB - BACKGROUND: The objective of this study was to report a long-term survival analysis of a phase II protocol of cytoreductive surgery (CS) and heated intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinomatosis (PCs). METHODS: Between 2000 and 2008, 101 consecutive patients were treated with CS, HIPEC and early postoperative intraperitoneal chemotherapy using a standardized protocol. Disease recurrence and mortality data were collected prospectively. Primary outcomes were median, 3-year, and 5-year disease free survival (DFS) and overall survival (OS). RESULTS: The median age was 49 years (range, 18-77 years), and the majority (82%) had complete CS with no gross residual cancer. Tumor types included appendiceal (n = 58), colorectal (n = 31), and other (n = 12). Median follow-up was 28 months (range, 0-119 months), with minimum of 24 months among survivors. For appendiceal tumors, median DFS was 34 months (range, 0-119 months) and OS has not yet been defined. Three-year and 5 year DFS was 48% and 42%, respectively, and 3-year and 5-year OS was 76% and 62%, respectively. For colorectal carcinomatosis, median disease-free and OS was 9 months (range, 0-87 months) and 27 months (range, 0-87 months), respectively. Three-year and 5-year DFS was 34% and 26%, respectively, and 3-year and 5-year OS was 38% and 34%, respectively. CONCLUSIONS: Long-term survival with regional treatment of PC from appendiceal or colorectal primary tumors with CS and HIPEC is achievable. PMID- 21545917 TI - Assessment of medical student laparoscopic camera skills and the impact of formal camera training. AB - BACKGROUND: In laparoscopic surgery, the role of camera holder often falls to untrained medical students. Laparoscopic-naive students can easily acquire laparoscopic camera navigation (LCN) skills, yet it is unclear whether this translates into improved LCN performance in the operating room and whether students retain these skills over time. The purpose of this study was to evaluate whether preclinical laparoscopic camera simulator training would result in improved LCN skills, efficiency, and comfort level over the course of a 6-week surgery clerkship. METHODS: A randomized, controlled study was designed to compare students' preclerkship and postclerkship LCN skills on a previously validated box trainer model. The students (n = 70) were randomized via a computer generated table of random numbers into study and control groups. The study group (n = 36) received a brief laparoscope training session before the clerkship, while the control group (n = 36) did not. All students also completed a preclerkship and postclerkship questionnaire detailing their experience and comfort level. RESULTS: Statistical analysis using Wilcoxon's signed-rank test demonstrated that all students improved in skill level (total score, 4 vs 7; P < .0001), efficiency (time, 76 vs 33 seconds; P < .0001), and comfort level (Likert scale score, 2 vs 4; P < .0001), with no statistically significant difference between the control and study groups. CONCLUSIONS: This study demonstrates that novice medical students are able to gain laparoscopic camera skills from "hands on" experience, with no added benefit or retention of skills learned in a preclinical camera simulator training session. PMID- 21545918 TI - Implementation of a standardized procedural checklist in a children's hospital. AB - BACKGROUND: The aim of this study was to examine the implementation and sustainability of checklist use among procedural-based specialties in a pediatric hospital and to survey perceptions of checklist efficacy among staff members and physicians. METHODS: A modified World Health Organization procedural checklist was implemented. Percentage daily compliance was collected for all procedures over a 12-month period. Clinical staff members participated in a survey regarding the checklist. Associations among gender, clinical role, and years of experience were evaluated. RESULTS: Compliance at 12 months was significantly higher than at inception (94% vs 88%, P < .001) with average monthly compliance of 92%. Compliance deteriorated on weekends and holidays. Surgeons had more positive perceptions of using the checklist compared with nurses and anesthesiologists, independent of experience and gender (P = .001). CONCLUSIONS: The implementation of a procedural checklist can be sustained across specialties with high compliance. Off-hours utilization remains problematic. Perceptions of checklist efficacy are disparate among roles in the operating room. PMID- 21545919 TI - Perceived effects of deployments on surgeon and physician skills in the US Army Medical Department. AB - BACKGROUND: The military health care system is unique in that almost every physician deploys for >=6 months to a combat or far-forward setting. The aim of this study was to determine the perceived changes in clinical skills in this deployed population. METHODS: A survey was sent out to all specialty consultants to the Army Surgeon General to query active duty staff physicians in their specialty areas who have deployment experience in August 2007. Questions concerning specialty, length of deployment, perceived changes in skills, skill use while deployed, and time to get back to baseline clinically after deployment were asked. RESULTS: Surveys were sent to approximately 1,500 physicians, of which 673 were usable, for a 45% response rate. More than 70% of respondents were deployed for >6 months. Fifty-nine percent reported that they were used in their specialties <40% of the time deployed. Surgeons rated surgical skills before and after deployment as 6.0 +/- 1.0 and 4.0 +/- 1.5, respectively (on a 7-point, Likert-type scale ranging from 1 = worst to 7 = best; P = .001). Most felt that the time needed to get back to predeployment skill levels was 1 to 6 months. CONCLUSIONS: There was significant perceived degradation in both the surgical and clinical skills of those deploying for >6 months, and the degradation was correlated with the length of time deployed. Most surgical specialists felt that it took them 3 to 6 months to return to their clinical and surgical performance baseline upon returning from a deployment and that 6 months was the most amount of time they could be deployed without a significant decrement in skills. PMID- 21545920 TI - Surgeon's vigilance in the operating room. AB - OBJECTIVE: Surgeons' vigilance regarding patient condition was assessed using eye tracking techniques during a simulated laparoscopic procedure. METHODS: Surgeons were required to perform a partial cholecystectomy in a virtual reality trainer (SurgicalSim; METI Inc, Sarasota, FL) while wearing a lightweight head-mounted eye-tracker (Locarna systems Inc, Victoria, British Columbia, Canada). Half of the patients were preprogrammed to present a mildly unstable cardiac condition during the procedure. Surgical performance (evaluated by task time, instrument trajectory, and errors), mental workload (by the National Aeronautics and Space Administration Task Load Index), and eye movement were recorded and compared between 13 experienced and 10 novice surgeons. RESULTS: Experienced surgeons took longer to complete the task and also made more errors. The overall workload reported by surgeons was similar, but expert surgeons reported a higher level of frustration and a lower level of physical demands. Surgeon workload was greater when operating on the unstable patient than on the stable patient. Novices performed faster but focused more of their attention on the surgical task. In contrast, experts glanced more frequently at the anesthetic monitor. CONCLUSIONS: This study shows the usefulness of using eye-tracking technology to measure a surgeon's vigilance during an operation. Eye-tracking observations can lead to inferences about a surgeon's behavior for patient safety. The unsatisfactory performance of expert surgeons on the VR simulator suggests that the fidelity of the virtual simulator needs to improve to enable surgeons to transfer their clinical skills. This, in turn, suggests using caution when having clinical experts as instructors to teach skills with virtual simulators. PMID- 21545921 TI - Early results after introduction of biliopancreatic diversion/duodenal switch at a military bariatric center. AB - BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD/DS) is one of the most effective procedures in terms of weight loss and durability. It is also one of the most complex and highest risk bariatric procedures. The authors report their initial experience with BPD/DS. METHODS: A retrospective review of all patients undergoing BPD/DS was performed, including a descriptive analysis of demographics, operative data, complications, and outcomes. Results were also compared with those among a group of 100 patients undergoing laparoscopic gastric bypass (LGB). RESULTS: Forty-three patients were identified. Mean preoperative body mass index was 52 kg/m(2), and 56% of patients had body mass indexes > 50 kg/m(2). Twenty (47%) were attempted laparoscopically, with 5 (25%) requiring conversion to open approach. Overall mean operative time was 269 minutes, with no significant difference between laparoscopic (256 minutes) and open (280 minutes). No major intraoperative complications occurred. Major postoperative complications included 4 gastric sleeve leaks, 2 small bowel obstructions, 1 intra-abdominal hemorrhage, and 1 duodenal stump leak. There was 1 death. Mean percentage excess body weight loss was 85% at 1 year. No patients developed severe malabsorptive symptoms or evidence of protein malnutrition. BPD/DS was associated with longer operative times and higher complication rates (P < .05 for both) compared with LGB but had significantly greater weight loss at 1 year (P < .05). CONCLUSION: BPD/DS is a complex procedure associated with increased operative times, increased risk for conversion from laparoscopic to open approach, and higher postoperative complication rates. However, it results in significantly greater weight loss than LGB without major adverse nutritional impact. PMID- 21545922 TI - Determinants of postoperative hypocalcemia in vitamin D-deficient Graves' patients after total thyroidectomy. AB - BACKGROUND: The etiology of postoperative hypocalcemia after total thyroidectomy appears to be multifactorial, that is, postoperative transient hypoparathyroidism, low 25-hydroxy vitamin D (25-OHD) concentrations, aging, and hyperthyroidism with increased bone turnover. Our aim was to evaluate the factors responsible for postoperative hypocalcemia in euthyroid vitamin D deficient/insufficient Graves patients who underwent total thyroidectomy at our institution. METHODS: Thirty-five consecutive patients with Graves disease treated by total thyroidectomy were included in the present study. All patients were vitamin D deficient/insufficient (ie, 25-OHD concentrations of <20/<30 ng/mL, respectively). Patients were divided into 2 groups according to postoperative serum albumin corrected calcium concentrations: group 1 (n = 13) patients had postoperative serum calcium concentrations of 8 mg/dL or less; group 2 (n = 22) patients had serum calcium concentrations greater than 8 mg/dL. Bone turnover markers (deoxypiridinoline, bone-specific alkaline phosphatase) and 25 OHD were determined the day before surgery. RESULTS: In group 1 patients, disease duration was significantly longer, 25-OHD and postoperative parathyroid hormone concentrations were significantly lower, and bone turnover markers were significantly higher. Logistic regression analysis revealed that a postoperative parathyroid hormone concentration less than 10 pg/mL was the most powerful parameter to predict postoperative hypocalcemia (odds ratio, 23; 95% confidence interval, 3.3-156). CONCLUSIONS: In Graves patients with vitamin D deficiency/insufficiency, postoperative (transient) hypoparathyroidism is the most significant parameter to determine the development of postoperative hypocalcemia. PMID- 21545923 TI - Exercise and cardiovascular diseases--a matter of life or death. PMID- 21545924 TI - Physical activity and the prevention of cardiovascular disease: from evolution to epidemiology. AB - For most of human history, the environmental demands of survival necessitated prodigious amounts of physical exertion. The avoidance of predators, hunting, gathering, and the literal "chopping wood and carrying water" of daily existence provided a wholesome dose of physical activity that obviated the need for deliberate exercise. Nevertheless, 21st century humans are now immersed within an environment explicitly designed to eliminate physical labor. Over the past century and especially the past 50 years, an accrual of epidemiological evidence has established that the unintended consequence of humankind's predilection for labor-saving contrivances is an epidemic of hypokinetically induced cardiovascular disease, morbidity, and mortality. This review surveys data from observational studies supporting the premise that physical activity, exercise training, and improvements in cardiorespiratory fitness are essential elements in the prevention and treatment of the cardiovascular diseases induced by an environment in which survival no longer obligates physical exertion. PMID- 21545925 TI - Cardiac rehabilitation and exercise training in secondary coronary heart disease prevention. AB - Substantial evidence indicates that increased levels of physical activity, exercise training, and overall cardiorespiratory fitness provide protection in primary and secondary coronary heart disease (CHD) prevention. Clearly, cardiac rehabilitation and exercise training (CRET) programs have been greatly underused in patients with CHD. We review the benefits of formal CRET programs on CHD risk factors including exercise capacity, obesity indices, plasma lipids, inflammation, and psychosocial stress as well as overall morbidity and mortality. These data support the fact that patients with CHD, especially after major CHD events, need routine referral to CRET programs; and patients should be vigorously encouraged to attend these valuable programs. PMID- 21545926 TI - Exercise therapy in hypertensive cardiovascular disease. AB - Hypertension is rare in the young, but its prevalence increases with age. Exercise contributes to the prevention of hypertension in normotensive subjects and to the control of blood pressure in hypertensive patients. The overall cardiovascular risk of the hypertensive patient does depend not only on blood pressure but also on the presence of other risk factors, target organ damage, and associated clinical conditions. The recommendations for preparticipation screening, sports participation, and follow-up depend on the overall risk profile of the individual patient. When antihypertensive treatment is required in addition to nonpharmacologic measures, calcium-channel blockers and blockers of the renin-angiotensin system are currently the drugs of choice for the patient who exercises. PMID- 21545927 TI - Exercise in obesity, metabolic syndrome, and diabetes. AB - The risk of developing both metabolic syndrome and type 2 diabetes mellitus (T2DM) is inversely associated with regular exercise training (ET). Excess weight is also strongly associated with increased risk of both metabolic syndrome and T2DM. There is strong evidence that even a moderate amount of weight loss achieved through changes in diet and ET can greatly reduce the risk of developing T2DM. For the purpose of general health, exercise programs should have both aerobic and resistance training components. The 2008 federal physical activity (PA) guidelines recommend obtaining at least 150 minutes per week of moderate intensity PA, 75 minutes per week of vigorous-intensity PA, or a combination of the 2. In addition, all individuals should strive for at least 2 days per week of resistance training activity. For the purpose of weight loss, the combination of ET and reduced energy intake has been found to be more effective than either alone. PMID- 21545928 TI - Exercise training in congestive heart failure: risks and benefits. AB - After decades of concern about the safety and effectiveness of exercise training in patients with heart failure (HF) due to reduced ejection fraction, initial research demonstrated the feasibility and physiologic benefits associated with such an intervention. Subsequent controlled studies confirmed these results and suggested improved clinical outcomes as well. This review summarizes the findings from single-site and multisite trials and meta-analyses that addressed the effects of exercise training on exercise capacity and clinical outcomes. Conclusions from these studies indicate that exercise is safe, improves health status and exercise capacity, attenuates much of the abnormal physiology that develops with HF, and yields a modest reduction in clinical events. Future research needs to identify which patient subgroups might benefit the most, the optimal exercise dose needed to lessen disease-related symptoms and maximize clinical benefit, and the effects of exercise training in patients with HF and preserved ejection fraction. PMID- 21545929 TI - Exercise therapy for cardiac transplant recipients. AB - Heart transplantation (HT) is an attractive treatment for patients with terminal heart failure from a variety of causes. Survival at 1- and 5 years after HT averages 90% and 70%, respectively. The physiologic response to exercise is abnormal after HT presumably because the transplanted heart is surgically denervated, although a minority of patients demonstrate signs of partial cardiac reinnervation several months after surgery. The heart rate response to exercise is typically blunted, and exercise capacity is below average for most HT recipients. Multiple studies have demonstrated the benefits of exercise training (ET) after HT. Peak exercise oxygen uptake improves by an average of 24% after 2 to 3 months of ET. Resistance training results in increased skeletal muscle mass and strength. Early mobilization and low-level ET may begin in the hospital after extubation. Outpatient ET, ideally in a supervised environment for at least several weeks, should begin immediately after hospital dismissal. Exercise prescription for HT patients is similar to that for other patients who have undergone cardiothoracic surgery, with the exception of a target heart rate. Ratings of perceived exertion are useful for prescribing exercise intensity. Exercise training does not affect the frequency or severity of episodes of acute rejection. There are no data regarding the effect of ET on survival after HT. PMID- 21545930 TI - Exercise in valvular heart disease: risks and benefits. AB - Valvular heart disease (VHD) carries documented risks for active individuals. At the same time, many individuals with intermediate degrees of valve disease can safely exercise and even participate in competitive athletics. Unfortunately for clinicians caring for these patients, data are scarce. Understanding the pathophysiology and natural history of VHD is key to applying consensus guidelines and making recommendations to individual patients. Careful physical examination and appropriate imaging studies will identify patients at risk; most will require serial evaluation but can exercise and participate in sports as desired. When symptoms develop, prompt treatment of severe, symptomatic disease and intensive cardiac rehabilitation as well as continued surveillance after surgical treatment will maximize the functional ability of active individuals with VHD. PMID- 21545931 TI - Benefits of exercise therapy in peripheral arterial disease. AB - Peripheral arterial disease (PAD) is a common disorder caused largely by atherosclerosis. Although it is associated with increased morbidity and cardiovascular mortality, PAD remains underdiagnosed. Traditional PAD care has involved cardiovascular risk factor modification, use of antiplatelet agents, and revascularization. For those individuals who are eligible and willing to perform exercise therapy (ET), a significant benefit may be recognized. Despite this, ET faces several challenges to implementation. Notably, the lack of reimbursement by third party payers remains the major challenge to routine use of ET. PMID- 21545932 TI - Exercise testing and training in chronic lung disease and pulmonary arterial hypertension. AB - Research examining the clinical value of exercise testing and training in patients with chronic lung disease and pulmonary arterial hypertension (PAH) is less robust compared with cardiac populations but nevertheless highly supportive. Functional limitations are common in these patients, and exercise testing provides important information pertaining to the degree of this limitation, disease severity, and prognosis. Moreover, exercise testing, particularly in conjunction with ventilatory expired gas analysis, serves as a valuable diagnostic tool when the mechanism of the functional limitation and abnormal exertional symptoms is uncertain. Most work with respect to the benefits of exercise training has been performed in chronic obstructive lung disease cohorts and is used to support pulmonary rehabilitation. Emerging data indicate that exercise training is likewise beneficial in patients with interstitial lung disease and PAH. This review summarizes the evidence supporting the value of exercise testing and training and provides recommendations for clinical practice. PMID- 21545933 TI - Impact of exercise training on psychological risk factors. AB - Although the role of psychological risk factors has been underemphasized, considerable evidence indicates the adverse effects of various psychosocial stressors in the pathogenesis and recovery from cardiovascular diseases. Substantial data, especially from cardiac rehabilitation and exercise training programs, have demonstrated the role of physical activity, exercise training, and cardiorespiratory fitness, to improve psychological risk factors, including depression, anxiety, hostility, and total psychological stress, as well as stress related mortality. PMID- 21545934 TI - Exercise like a hunter-gatherer: a prescription for organic physical fitness. AB - A large proportion of the health woes beleaguering modern cultures are because of daily physical activity patterns that are profoundly different from those for which we are genetically adapted. The ancestral natural environment in which our current genome was forged via natural selection called for a large amount of daily energy expenditure on a variety of physical movements. Our genes that were selected for in this arduous and demanding natural milieu enabled our ancestors to survive and thrive, leading to a very vigorous lifestyle. This abrupt (by evolutionary time frames) change from a very physically demanding lifestyle in natural outdoor settings to an inactive indoor lifestyle is at the origin of many of the widespread chronic diseases that are endemic in our modern society. The logical answer is to replicate the native human activity pattern to the extent that this is achievable and practical. Recommendations for exercise mode, duration, intensity, and frequency are outlined with a focus on simulating the routine physical activities of our ancient hunter-gatherer ancestors whose genome we still largely share today. In a typical inactive person, this type of daily physical activity will optimize gene expression and help to confer the robust health that was enjoyed by hunter-gatherers in the wild. PMID- 21545935 TI - Primary cardiac angiosarcoma treated by complete tumor resection with cardiac reconstruction. AB - Primary cardiac sarcoma is a rare malignant neoplasm, with an incidence of .0001% in collected autopsy series. Angiosarcoma is the most common cardiac sarcoma and is present in up to 33% of the cases that are associated with a poor prognosis. Because angiosarcoma is essentially not responsive to current regimens of chemotherapy and irradiation, early complete resection is recommended as the treatment choice. However, complete resection is difficult because of the limited amount of myocardium and expansion of the tumor at the time of diagnosis. We report a case of right atrial angiosarcoma treated by complete tumor resection with cardiac reconstruction with a bovine pericardium patch. PMID- 21545936 TI - Swine influenza (H1N1) pneumonia in hospitalized adults: chest film findings. AB - In patients with swine influenza (H1N1) pneumonia, the admission chest film is critical to rapidly detect simultaneous bacterial pneumonia due to Staphylococcus aureus or subsequent bacterial pneumonia due to Streptococcus pneumoniae or Haemophilus influenzae by the presence of focal infiltrates. Our objective was to characterize the chest film findings in 25 adults hospitalized with H1N1 pneumonia during the pandemic and detect focal infiltrates indicative of bacterial coinfection, that is, bacterial pneumonia. Chest films were obtained on admission, after 48 hours, and thereafter as indicated throughout hospitalization. Chest film findings were classified as no infiltrates, clear with accentuated bibasilar lung markings, or focal segmental/lobar infiltrates. The presence or absence of pleural effusion and cavitation was also noted. Admitted adults with H1N1 pneumonia had negative chest films or accentuated basilar lung markings. After 48 hours, 13% of patients developed patchy bilateral interstitial infiltrates. No patients had or subsequently developed focal segmental/lobar infiltrates indicative of bacterial community-acquired pneumonia during hospitalization. The most common chest film finding was no infiltrates or an accentuation of bibasilar lung markings in hospitalized adults with H1N1 pneumonia. No patients had focal segmental/lobar infiltrates indicative of superimposed bacterial community-acquired pneumonia. PMID- 21545937 TI - Severe swine influenza A (H1N1) versus severe human seasonal influenza A (H3N2): clinical comparisons. AB - At the beginning of the swine influenza (H1N1) pandemic in the spring of 2009, there were still stories of human seasonal influenza A circulating in the New York area. Adult patients admitted with influenza-like illnesses (ILIs) (fever > 102 degrees F, dry cough, and myalgias) presented diagnostic problems. First, clinicians had to differentiate ILIs from influenza, and then differentiate human seasonal influenza A from H1N1 in hospitalized adults with ILIs and negative chest films (no focal segmental/lobar infiltrates). Human seasonal influenza A was diagnosed by rapid influenza diagnostic tests (RIDTs), but H1N1 was often RIDT negative. Reverse transcriptase-polymerase chain reaction for H1N1 was restricted or not available. The Winthrop-University Hospital Infectious Disease Division developed clinical diagnostic criteria (a diagnostic weighted point score system) to rapidly and clinically diagnose H1N1 in patients with negative RIDTs. The point score system was modified and shortened for ease of use, that is, the diagnostic H1N1 triad (any 3 of 4) (ILI, see above) plus thrombocytopenia, relative lymphopenia, elevated serum transaminases, or an elevated creatine phosphokinase. Our clinical experience during the pandemic allowed us to develop the swine diagnostic H1N1 triad. In the process, similarities and differences between human seasonal influenza A and H1N1 were noted. We present 2 illustrative cases of severe influenza, one due to human seasonal influenza A and one due to H1N1, for clinical consideration reflective of our experiences early in the H1N1 pandemic in 2009. PMID- 21545938 TI - Manual hyperinflation: positive end-expiratory pressure to recruit or rapid release for clearance of airway secretions? PMID- 21545939 TI - Vanishing asymmetric septal hypertrophy in a patient with hypertrophic obstructive cardiomyopathy. PMID- 21545941 TI - The year in epidemiology, health services research, and outcomes research. PMID- 21545940 TI - 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. PMID- 21545942 TI - Intraluminal thrombus in facilitated versus primary percutaneous coronary intervention: an angiographic substudy of the ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention) trial. AB - OBJECTIVES: This study investigated the occurrence of intraluminal thrombus and its potential implications with facilitated percutaneous coronary interventions (fPCIs). BACKGROUND: The effect of fPCI on the presence and consequences of intraluminal thrombus is unknown. METHODS: Thrombolysis In Myocardial Infarction (TIMI) flow grade, frame count, and thrombus grade; distal embolization; and slow flow in the infarct-related artery were assessed in a blinded fashion on coronary angiograms in 1,342 patients from the ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy With Percutaneous Coronary Intervention) trial. Residual TIMI thrombus grade >=2 and/or distal embolization and/or slow flow, reflecting thrombus burden (TB), following PCI were correlated with ST segment resolution, epicardial blood flow, and clinical outcome. The clinical composite endpoint was death, congestive heart failure, or shock. RESULTS: In the fPCI group, more TIMI flow grade 2/3 in the infarct-related artery at the first angiogram (73.7% vs. 33.4%, p < 0.001) and a higher TB following PCI (19.7% vs. 13.4%, p = 0.002) were found in comparison with the primary PCI group. Post-PCI TIMI thrombus grade was significantly associated with ST-segment resolution (p < 0.001) and TIMI frame count (p < 0.0001) in both groups. In the fPCI group, the presence of post-PCI thrombus was associated with a significantly worse outcome at 90 days (clinical composite endpoint: 32.1% vs. 18.6%, p = 0.023). Multivariable logistic regression showed that facilitation with tenecteplase (p = 0.005) and TB (odds ratio: 2.43, 95% confidence interval: 1.30 to 4.51, p = 0.0052) were independent predictors of 90-day mortality. CONCLUSIONS: In ASSENT-4 PCI, despite more patency, residual TB was significantly higher in fPCI patients and was associated with less efficient tissue reperfusion and worse clinical outcomes. (A Trial Evaluating the Efficacy and Safety of Tenecteplase Together With Unfractionated Heparin Prior to Early Percutaneous Coronary Intervention [PCI] as Compared to Standard Primary PCI in Patients With Acute Myocardial Infarction [ASSENT-4 PCI]; NCT00168792). PMID- 21545943 TI - Optimal therapy for ST-segment elevation myocardial infarction: the role of residual thrombus. PMID- 21545944 TI - Central obesity and survival in subjects with coronary artery disease: a systematic review of the literature and collaborative analysis with individual subject data. AB - OBJECTIVES: The aim of this study was to examine the association of central (waist circumference [WC] and waist-hip ratio [WHR]) and total obesity (body mass index [BMI]) measures with mortality in coronary artery disease (CAD) patients. BACKGROUND: The question of which measure of obesity better predicts survival in patients with CAD is controversial. METHODS: We searched OVID/Medline, EMBASE, CENTRAL, and Web of Science from 1980 to 2008 and asked experts in the field for unpublished data meeting inclusion criteria, in which all subjects had: 1) CAD at baseline; 2) measures of WC or WHR; 3) mortality data; and 4) a minimum follow-up of 6 months. RESULTS: From 2,188 studies found, 6 met inclusion criteria. We obtained individual subject data from 4, adding unpublished data from a cardiac rehabilitation cohort. A variable called "central obesity" was created on the basis of tertiles of WHR or WC. Cox-proportional hazards were adjusted for age, sex, and confounders. The final sample consisted of 15,923 subjects. There were 5,696 deaths after a median follow-up of 2.3 (interquartile range 0.5 to 7.4) years. Central obesity was associated with mortality (hazard ratio [HR]: 1.70, 95% confidence interval [CI]: 1.58 to 1.83), whereas BMI was inversely associated with mortality (HR: 0.64, 95% CI: 0.59 to 0.69). Central obesity was also associated with higher mortality in the subset of subjects with normal BMI (HR: 1.70, 95% CI: 1.52 to 1.89) and BMI >=30 kg/m(2) (HR: 1.93, 95% CI: 1.61 to 2.32). CONCLUSIONS: In subjects with CAD, including those with normal and high BMI, central obesity but not BMI is directly associated with mortality. PMID- 21545945 TI - Excess visceral adipose tissue/ectopic fat the missing link in the obesity paradox? PMID- 21545946 TI - Results of the post-U.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). AB - OBJECTIVES: The aim of this study was to determine whether results with the HeartMate (HM) II left ventricular assist device (LVAD) (Thoratec Corporation, Pleasanton, California) in a commercial setting are comparable to other available devices for the same indication. BACKGROUND: After a multicenter pivotal clinical trial conducted from 2005 to 2008, the U.S. Food and Drug Administration approved the HM II LVAD for bridge to transplantation (BTT). A post-approval study was required by the U.S. Food and Drug Administration to determine whether results with the device in a commercial setting are comparable to other available devices for the same indication. METHODS: The study was a prospective evaluation of the first 169 consecutive HM II patients enrolled in the national INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) who were listed for transplant or likely to be listed. Patients were enrolled from April through August 2008 at 77 U.S. centers and followed for at least 1 year after implant. A comparison group (COMP) included all patients (n = 169 at 27 centers) enrolled in the INTERMACS registry with other types of LVADs (79% HeartMate XVE, 21% Implantable Ventricular Assist Device [Thoratec Corporation]) for the same BTT indication in the same time period. Survival rates, adverse events, and quality of life with the EuroQol EQ-5D visual analog scale were obtained in the INTERMACS registry. RESULTS: Baseline characteristics were similar, but creatinine and blood urea nitrogen were lower in the HM II versus COMP groups, and there were fewer patients in the highest-risk INTERMACS patient profile Number 1 (24% for HM II vs. 39% for COMP). Adverse event rates were similar or lower for HM II versus COMP for all events. Bleeding was the most frequent adverse event for both groups (1.44 vs. 1.79 events/patient-year). Operative 30 day mortality for HM II was 4% versus 11% for COMP. The percentage of patients reaching transplant, cardiac recovery, or ongoing LVAD support by 6 months was 91% for HM II and 80% for COMP, and the Kaplan-Meier survival for patients remaining on support at 1 year was 85% for HM II versus 70% for COMP. Quality of life was significantly improved at 3 months of support and sustained through 12 months in both groups compared with baseline. CONCLUSIONS: The results in a post market approval, actual patient care setting BTT population support the original findings from the pivotal clinical trial regarding the efficacy and risk profile of the HM II LVAD. These data suggest that dissemination of this technology after approval has been associated with continued excellent results. PMID- 21545948 TI - The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiographic assessment substudy. AB - OBJECTIVES: The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical bradycardic events in patients presenting with acute coronary syndromes. BACKGROUND: Ticagrelor, an oral reversibly binding P2Y(12) inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes. METHODS: Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days). RESULTS: A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses >=3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 [5.8%] vs. 51 [3.6%]; relative risk: 1.61; p = 0.006). At 1 month, pauses >=3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest. CONCLUSIONS: In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872). PMID- 21545947 TI - Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). AB - OBJECTIVES: This study sought to assess the effects of rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). BACKGROUND: Small studies have indicated that adenosine A(1) receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF. METHODS: A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine >=0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7. RESULTS: At baseline, mean +/- SD estimated creatinine clearance was 51.0 +/- 20.5 ml/min in the placebo group and 50.4 +/- 20.0 ml/min in the rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo- and rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44). CONCLUSIONS: In this large, phase III clinical trial, the adenosine A(1) receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458). PMID- 21545949 TI - The prosthetic mitral valve leaflet adhesion. PMID- 21545950 TI - Left atrial hypertension after repeated catheter ablations for atrial fibrillation. PMID- 21545951 TI - Continuous deep sedation until death in Belgium: a survey among nurses. AB - CONTEXT: Continuous deep sedation (CDS) is a subject of important debate, but until now nurses have rarely been questioned about their involvement and perceptions. OBJECTIVES: To study the communication process between nurses and patients, relatives, or physicians before starting CDS, and how nurses perceive this end-of-life practice. METHODS: In 2007, we surveyed 1678 nurses in Flanders, Belgium, who, in an earlier survey, had reported caring for one or more patients who received an end-of-life decision within the previous year. Nurses were surveyed about their most recent case. RESULTS: The response rate was 75.8%: 250 nurses reported a case of CDS (64.4% hospital, 18.4% home, and 17.2% nursing home). In, respectively, 25.8% and 75.4%, the patient and relatives had communicated with the nurse about the CDS. In 17.6%, there was no communication between the nurse and the physician about the CDS; in 29.1%, the physician and nurse only exchanged information; and in 23.4%, they made the decision jointly. Making the decision jointly was associated with a more positive evaluation of the cooperation with the physician (adjusted odds ratio 10.9 and 95% confidence interval 3.0, 39.2). Nurses perceived CDS as partly intended to hasten death partially in 48.4% and explicitly in 28.4% of cases, estimating possible or certain life shortening in 95.6%. CONCLUSION: Nurses in different health care settings are often involved in communication about CDS. They see it mainly as a practice intended to hasten death, with a life-shortening effect; guidelines should recommend clear discussions between caregivers in which the physician states the purpose and estimated effect of the decision. PMID- 21545953 TI - From air insufflation to robotic endoscopic surgery: a rocky road. PMID- 21545954 TI - Pelvic inflammatory reactions to Floseal. PMID- 21545955 TI - Essure perforation and chronic pelvic pain. PMID- 21545956 TI - Laparoscopic treatment of benign multicystic mesothelioma. PMID- 21545958 TI - Gonadotropin-releasing hormone agonist in laparoscopic myomectomy: systematic review and meta-analysis of randomized controlled trials. AB - A systematic review and meta-analysis of randomized controlled trials was performed to estimate the effects on surgical outcomes of pretreatment with gonadotropin-releasing hormone (GnRH) agonist before laparoscopic myomectomy. The electronic bibliographic databases MEDLINE, EMBASE, Web of Knowledge, Scopus, and Cochrane Library, and reference lists from relevant articles were searched for English-language publications describing randomized controlled trials of GnRH agonist pretreatment vs placebo or no treatment before laparoscopic myomectomy. Three studies including 168 participants were identified. Pretreatment with GnRH agonist did not reduce operative time; however, intraoperative blood loss was statistically lowered (mean difference, 60 mL; 95% confidence interval [CI], 39 82). Statistical difference was also observed in postoperative hemoglobin concentration (mean difference, 1.15 g/dL; 95% CI, 0.46-1.83]) and red blood cell count (mean difference, 0.65 * 10(6) cells/mL; 95% CI, 0.16-1.14]) but not serum iron concentration. None of the patients in the studies experienced any major intraoperative or postoperative complications, and only 1 patient in each group required blood transfusion. This study does not show a difference in operative time with GnRH agonist pretreatment, which clarifies the previous conflicting reports on the effect of GnRH agonist therapy on the duration of laparoscopic myomectomy. Furthermore, despite previously reported decreased bleeding conferred by the laparoscopic approach compared with laparotomy, this meta-analysis demonstrates a further reduction in intraoperative blood loss with GnRH agonist pretreatment in patients undergoing laparoscopic myomectomy. Additional high quality studies with appropriate power and follow-up are needed to corroborate these findings and to evaluate the treatment effects on short- and long-term outcomes such as perioperative complications and fertility. PMID- 21545957 TI - Hysterectomy improves sexual response? Addressing a crucial omission in the literature. AB - The prevailing view in the literature is that hysterectomy improves the quality of life. This is based on claims that hysterectomy alleviates pain (dyspareunia and abnormal bleeding) and improves sexual response. Because hysterectomy requires cutting the sensory nerves that supply the cervix and uterus, it is surprising that the reports of deleterious effects on sexual response are so limited. However, almost all articles that we encountered report that some of the women in the studies claim that hysterectomy is detrimental to their sexual response. It is likely that the degree to which a woman's sexual response and pleasure are affected by hysterectomy depends not only on which nerves were severed by the surgery, but also the genital regions whose stimulation the woman enjoys for eliciting sexual response. Because clitoral sensation (via pudendal and genitofemoral nerves) should not be affected by hysterectomy, this surgery would not diminish sexual response in women who prefer clitoral stimulation. However, women whose preferred source of stimulation is vaginal or cervical would be more likely to experience a decrement in sensation and consequently sexual response after hysterectomy because the nerves that innervate those organs, that is, the pelvic, hypogastric, and vagus nerves, are more likely to be damaged or severed in the course of hysterectomy. However, all published reports of the effects of hysterectomy on sexual response that we encountered fail to specify the women's preferred sources of genital stimulation. As discussed in the present review, we believe that the critical lack of information as to women's preferred sources of genital stimulation is key to accounting for the discrepancies in the literature as to whether hysterectomy improves or attenuates sexual pleasure. PMID- 21545959 TI - Laparoscopic management of juvenile cystic adenomyoma: four cases. AB - STUDY OBJECTIVE: To highlight a recently identified rare cause of severe dysmenorrhea in young patients with poor response to medical management. DESIGN: Evidence obtained from several timed series with or without intervention (Canadian Task Force classification II-3). SETTING: Tertiary care referral hospital. PATIENTS: Four young (age, 16-24 years) nulliparous patients with juvenile cystic adenoma with severe secondary dysmenorrhea with poor response to medical management. INTERVENTION: Laparoscopic resection of the cystic adenomyoma. MEASUREMENTS AND MAIN RESULTS: Complete resection of the cystic adenomyoma was performed laparoscopically in all patients. The lesion was uncapsulated (unlike myoma) and locally defined to the uterine myometrium (unlike diffuse adenomyosis), and there was chocolate-colored blood in the cavity. No other mullerian anomaly was observed in any patient. Histopathologic analysis revealed features suggestive of adenomyosis in all cases. After surgery, dysmenorrhea resolved completely in all patients. Compared with preoperative visual analog scores, significant improvement was observed at the first menstrual cycle after surgery. Patients are being followed up every 3 months for a minimum of 12 months to detect development of dysmenorrhea or any other menstrual disorder. CONCLUSION: Juvenile cystic adenomyosis is a rare cause of severe dysmenorrhea. However, it should be included in the differential diagnosis in patients with dysmenorrhea with poor response to medical treatment. All patients reported in the literature and in our series were younger than 30 years, which can be considered as an arbitrary cutoff point to differentiate juvenile from adult cystic adenomyosis. It can be considered a new type of mullerian anomaly that manifests as a noncommunicating accessory uterine cavity lined with endometrium and with an otherwise normal uterus. Surgery is the only therapeutic option for these patients. Minimally invasive surgery in expert hands is advisable to preserve fertility. PMID- 21545960 TI - Laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation of symptomatic uterine leiomyomas: feasibility study using the Halt 2000 Ablation System. AB - Thirty-one women aged 28 to 51 years with symptomatic uterine leiomyomas who desired uterine preservation underwent outpatient laparoscopic, ultrasound guided, radiofrequency volumetric thermal ablation using the Halt 2000 System. Postoperative follow-up occurred at 3, 6, and 12 months. The primary outcome measures were patient safety, frequency of adverse events, repeat intervention rate because of symptoms of myoma, symptom severity, and health-related quality of-life scores from the validated Uterine Fibroid Symptom and Quality-of-Life Questionnaire. Secondary outcome measures were uterine volume changes over time. At 3, 6, and 12 months, respectively, mean symptom severity scores improved significantly compared with baseline, by 59.7% (95% confidence interval [CI], 44.8-74.7], 71.7% [95% CI, 55.7%-87.7%], and 82.0% (95% CI, 70.9%-93.1%). The increase in mean health-related quality-of-life scores over time reached statistical significance (p <.001): 60.15 (95% CI, 51.6%-68.7%) at baseline, 87.9 (95% CI, 82.1%-93.7%) at 3 months, 90.8 (95% CI, 82.1%-99.5%) at 6 months, and 97.8 (95% CI, 96.2-99.4) at 12 months. Mean (SD) uterine volume decreased from 194.4 (105.9 cm(3)) at baseline to 159.5 (66.8) at 3 months, 147.2 (73.0 cm(3)) at 6 months, and 113.2 (53.5 cm(3)) at 12 months (p = .006). There were no procedure-related repeat hospitalizations, repeat treatments, or any procedures related to symptoms of myoma after radiofrequency ablation. An anterior abdominal wall vascular injury was discovered in the early postoperative period and resolved after vessel ligation. Volumetric thermal ablation using the Halt 2000 System produced significant reduction in symptoms and improvement in quality of life at 1 year after treatment, with an excellent safety profile. Additional larger multicenter studies are needed to confirm these results. PMID- 21545961 TI - Laparoscopic adnexectomy of suspect ovarian masses: surgical technique used to avert spillage. AB - Herein is described and evaluated a safe laparoscopic adnexectomy technique for retroperitoneal dissection of suspect ovarian masses including the underlying peritoneum fixed to the ovary. Adopting this technique in cases of suspect adnexal masses enables the reduction of spilling and ensures an intact specimen. Twenty-two consecutive patients with suspect adnexal masses 10 cm or smaller underwent laparoscopic adnexectomy. Patients with bilateral suspect ovarian masses that required bilateral adnexectomy were enrolled only if they were no longer of childbearing age. Laparoscopy was feasible in all patients. No tumor spillage occurred. In 5 patients (23.6%), minilaparotomy was required to extract the specimen. Mean (SD) operating time was 80 (35-160) minutes, and estimated blood loss was 50 (10-100) mL. No major intraoperative complications occurred. Median (range) postoperative stay was 1 (1-3) day. Definitive pathologic analysis revealed benign pathologic conditions in 18 patients (81.8%), an ovarian tumor with low malignant potential in 3 patients (13.7%), and ovarian cancer in 1 patient (4.5%) in whom findings at frozen-section analysis were inconclusive. Median (range) follow-up of malignant ovarian tumors and of tumors with low malignant potential was 27 (21-29) months. No recurrence or port-site metastasis developed during follow-up. The data are encouraging for adoption of this technique to avert spillage during laparoscopic management of suspect adnexal masses, especially those firmly adherent to the peritoneum. However, the procedure must be validated in a larger series of patients to standardize the technique. PMID- 21545962 TI - Simultaneous labia minora and majora reduction: a case report. AB - Labia minora enlargement may constitute a cosmetic or functional problem for a woman, potentially leading to surgery. However, more rarely, the labia majora may also be problematic for women. This case describes the rare situation of a woman presenting with enlargement of both the labia minora and majora and her subsequent simultaneous surgical treatment. PMID- 21545963 TI - Laparoscopic management of pregnancy in a patient with uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis. AB - Pregnancy in a rudimentary uterine horn is a rare and potentially lethal condition. The highest risk of rupture is reported to be during the late first and second trimester. The risk of rupture correlates with the thickness of the myometrium surrounding the fetal pole. In 2005, a 20-year-old woman was incompletely diagnosed by imaging studies and laparoscopy to have an absent right kidney, a bicornate uterus with a right rudimentary uterine horn and a single cervix, a transverse vaginal septum with hematocolpos, and endometriosis caused by reflux menstruation. The transverse vaginal septum was excised, and the surgeon observed a single cervix. Oral contraceptives were prescribed as complementary treatment for the endometriosis and associated dysmenorrhea. In 2009, magnetic resonance imaging confirmed resolution of hematocolpos and revealed a right cervix connected to the right horn of a uterus didelphys and covered by a partial longitudinal vaginal septum. The patient had a contraception failure and presented in 2010 at 9(6/7) weeks' gestation. By ultrasonography and subsequent magnetic resonance imaging, the pregnancy was in the right uterus and the corpus luteum was on the left ovary. The myometrium was thinned to 2 to 3 mm atop the gestational sac. Using the Harmonic ACE, laparoscopic excision of the right fallopian tube and a supracervical right hysterectomy with an intact pregnancy was performed. This case supports the Acien hypothesis that the vagina forms from both Mullerian and Wolffian duct elements, and it illustrates the risk for uterine rupture when pregnancy forms in a rudimentary structure; presumed transperitoneal migration of an ovum that was captured by the opposite fallopian tube; and surgical management of the in situ pregnancy by laparoscopic supracervical excision of the rudimentary uterine body. PMID- 21545964 TI - Disseminated peritoneal leiomyosarcomas after laparoscopic "myomectomy" and morcellation. AB - Herein is reported a case of disseminated peritoneal leiomyosarcoma arising shortly after laparoscopic myomectomy and specimen retrieval with an electromechanical morcellator. The topography of the sarcomas suggests morcellation as a contributing factor. This case shows that caution should be exercised when selecting patients for laparoscopic myomectomy and stresses the need for a thorough pathologic examination of the specimen retrieved. PMID- 21545965 TI - Laparoscopic management of fallopian tube torsion at 35 weeks of gestation: case report. AB - Isolated fallopian tube torsion requiring surgical intervention in pregnancy is rare. Herein is reported a case of fallopian tube torsion that was managed laparoscopically at 35 weeks of gestation. PMID- 21545966 TI - Endometrial cancer after endometrial ablation: systematic review of medical literature. AB - Data are limited regarding the occurrence of endometrial cancer after endometrial ablation (EA). A systematic review of the English-language medical literature was performed of cases of endometrial cancer after EA. This review included the present case report involving a 47-year-old woman with a diagnosis of stage IA, grade 1 endometrial adenocarcinoma 5 years after radiofrequency EA. The systematic literature review identified 22 endometrial cancer cases occurring after EA. Most (76.5%) were stage I at diagnosis. Time to endometrial cancer diagnosis ranged from 2 weeks to 10 years following EA. All but 3 cases involved patients with known endometrial cancer risk factors. To our knowledge, the present case is the first reported occurrence of endometrial cancer after radiofrequency EA. Endometrial cancer has been detected after EA at variable intervals. Occurrence of endometrial cancer after EA is low, yet it continues to be difficult to quantify through retrospective analyses. PMID- 21545967 TI - Transsacral S2-S4 nerve block for vaginal pain due to pudendal neuralgia. AB - Pudendal neuralgia is a type of neuropathic pain experienced predominantly while sitting, and causes a substantial decrease in quality of life in affected patients. Pudendal nerve block is a diagnostic and therapeutic option for pudendal neuralgia. Transsacral block at S2 through S4 results in pudendal nerve block, which is an option for successful relief of pain due to pudendal nerve injury. Herein is reported blockade of S2 through S4 using lidocaine and methylprednisolone for successful treatment of pudendal neuralgia in 2 patients with severe chronic vaginal pain. The patients, aged 44 and 58 years, respectively, were referred from the Gynecology Department to the pain clinic because of burning, stabbing, electric shock-like, unilateral pain localized to the left portion of the vagina and extending to the perineum. Their initial pain scores were 9 and 10, respectively, on a numeric rating scale. Both patients refused pudendal nerve block using classical techniques. Therefore, diagnostic transsacral S2-S4 nerve block was performed using lidocaine 1%, and was repeated using lidocaine 1% and methylprednisolone 80 mg after confirming block efficiency as demonstrated by an immediate decrease in pain scores. After 1 month, pain scores were 1 and 0, respectively, and both patients were free of pain at 6-month follow up. It is suggested that blockade of S2 through S4 using lidocaine and methylprednisolone is an effective treatment option in patients with chronic pudendal neuralgia when traditional pudendal nerve block is not applicable. PMID- 21545968 TI - Fundamental concepts in statistics and study design. PMID- 21545970 TI - Delayed pain after global endometrial ablation (GEA) is usually caused by hematometra. PMID- 21545972 TI - Laparoendoscopic single-site surgery (LESS) in gynecology. PMID- 21545974 TI - Incorrect presentation of our article in an opinion paper. PMID- 21545975 TI - Uterine artery pseudoaneurysm after cesarean section: case report and literature review. PMID- 21545977 TI - Current surgical practice has rationales that are ignored by medical guidelines. PMID- 21545978 TI - The effects of interletter spacing in visual-word recognition. AB - Despite the importance of determining the effects of interletter spacing on visual-word recognition, this issue has often been neglected in the literature. The goal of the present study is to shed some light on this topic. The rationale is that a thin increase in interletter spacing, as in casino, may reduce lateral interference among internal letters without destroying a word's integrity and/or allow a more precise encoding of a word's letter positions. Here we examined whether identification times for word stimuli in a lexical decision task were faster when the target word had a slightly wider than default interletter spacing value relative to the default settings (e.g., casino vs. casino). In Experiment 1, we examined whether interletter spacing interacted with word-frequency, whereas in Experiment 2, we examined whether interletter spacing interacted with word length. Results showed that responses to words using a thin increase in interletter spacing were faster than the responses to words using the default settings-regardless of word-frequency and word length. Thus, interletter spacing plays an important role at modulating the identification of visually presented words. PMID- 21545980 TI - The first step in layer-by-layer deposition: electrostatics and/or non electrostatics? AB - A critical discussion is presented on the properties and prerequisites of adsorbed polyelectrolytes that have to function as substrates for further layer by-layer deposition. The central theme is discriminating between the roles of electrostatic and non-electrostatic interactions. In order to emphasize this feature we refrain from discussing practical problems sometimes incurred in polyelectrolyte adsorption like freezing-in of non-equilibrium situations, patchwise attachment, unclear chemistry and only consider solid substrates. Although it is in principle ambiguous to discriminate between coulombic and non coulombic or "chemical" interactions, it will be shown that, as a rule, non coulombic contributions to the interactions cannot be neglected. They are responsible for the familiar overcharging. For obtaining more insight, it is recommended to consider electrometric techniques such as electrokinetics, conductometry and potentiometry, in combination with other analytical techniques applied to well-defined systems, for which various parameters can be modulated in a systematic way. PMID- 21545979 TI - [Skin reactions on exposure to the pine processionary caterpillar (Thaumetopoea pityocampa)]. AB - The pine processionary caterpillar is the larval form of the Thaumetopoea pityocampa moth. Mediterranean forests regularly suffer plagues of this insect, which has been moving north as a result of global warming. When the small urticating hairs that develop during the last 3 larval stages are shed and can become airborne. If they come in contact with skin, they can cause a variety of reactions, notably contact urticaria and papular rashes. Irritation can also occur if the hairs lodge in the mucosa of the conjunctiva or in the respiratory tract. Several cases of anaphylactic reactions have been reported in recent years. Mechanical (irritative) mechanisms may be involved in the pathogenesis of lesions, or immunoglobulin E-mediated allergic hypersensitivity reactions may be implicated when the process is rapid, recurrent, and progressively more severe. PMID- 21545981 TI - Impact of hypertriglyceridemia on endothelial dysfunction during statin +/- ezetimibe therapy in patients with coronary heart disease. AB - Despite the use of statin therapy and achieving the target for low-density lipoprotein cholesterol, a substantial number of coronary events are not prevented, and residual risk factors remain unsettled. Recently, ezetimibe has been shown to reduce not only low-density lipoprotein cholesterol but also triglyceride (TG) levels. The aim of this study was to investigate the associations of residual risk factors, mainly hypertriglyceridemia, with endothelial function during statin therapy in patients with coronary heart disease and examine the effect of ezetimibe add-on therapy. A total of 109 consecutive patients with coronary heart disease during statin therapy were enrolled. Lipid profile was measured and endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery in a fasting state. Next, 32 patients with high TG levels (>=150 mg/dl) were prospectively assigned to the ezetimibe add-on group or the no-ezetimibe group, and endothelial function was assessed after 3 months. Multivariate linear regression analysis demonstrated that serum TG and high-density lipoprotein cholesterol levels were independent determinants of percentage FMD (beta = -0.210 and 0.208, respectively, p <0.05). In patients with high TG levels, ezetimibe add-on therapy significantly improved percentage FMD (from 3.3 +/- 1.1% to 4.0 +/- 1.1%, p <0.005), whereas no significant change was observed in the no-ezetimibe group. Moreover, the improvement in percentage FMD was significantly associated with reduction in serum TG levels (beta = -0.387, p <0.05) independent of the change in serum low density lipoprotein cholesterol levels. In conclusion, hypertriglyceridemia is independently associated with endothelial dysfunction in patients with coronary heart disease during statin therapy. Ezetimibe add-on therapy improves endothelial function in these high-risk populations. PMID- 21545982 TI - Effect of lipid-lowering treatment on natural history of heterozygous familial hypercholesterolemia in past three decades. AB - Long-term data on the effects of cholesterol-lowering regimens on low-density lipoprotein cholesterol levels and cardiovascular events in patients with familial hypercholesterolemia (FH) are lacking. The present study evaluated the effectiveness of long-term intensive lipid-lowering therapy on the natural history of FH. Of approximately 1,000 adult patients with heterozygous FH treated from 1974 to 2008, the charts of 327 were randomly selected for review. FH was defined according to the Simon Broome Registry Group criteria. The recorded data included age; gender; lipid levels with diet only, with each lipid-lowering regimen, and at the most recent visit during treatment; the length of follow-up; cardiovascular events; and revascularization procedures. The lipid assay calibrations and standardization were unchanged throughout the study period. Of the 327 patients, 60% were men, the mean age at diagnosis was 38 +/- 14 years, and the mean follow-up was 15 +/- 8 years. The baseline and most recent low density lipoprotein cholesterol levels during treatment were 256 +/- 60 mg/dl and 116 +/- 46 mg/dl, respectively, for a mean reduction of 55% from baseline (p <0.0001). At their most recent visit, 24% of all subjects were treated with statin monotherapy, 55% with a statin plus another agent, and 21% with triple therapy; 44% received a statin-ezetimibe combination. The interval between recurrent cardiovascular events tended to increase from 5.3 +/- 4.8 years before treatment to 7.4 +/- 6.7 years after referral (p = 0.1303). In conclusion, advances in drug therapy during the past 3 decades has led to substantial reductions in low-density lipoprotein cholesterol levels and appears to diminish the cardiovascular risk in patients with FH. PMID- 21545983 TI - Effect of early statin therapy on risk of atrial fibrillation after coronary artery bypass grafting with or without concomitant valve surgery. AB - Statins decrease postoperative atrial fibrillation (AF) if given before cardiac surgery. However, whether early administration of statins after surgery decreases the risk of postoperative AF is unknown. The association of early reinstitution of postoperative statin therapy within 48 hours to the occurrence of postoperative AF was studied in propensity-adjusted analyses of 200 consecutive patients in sinus rhythm who had undergone coronary artery bypass grafting with or without valve surgery. Postoperative AF occurred in 36 patients (18%). Of 52 patients who received a statin early after surgery, 4 (7.7%) developed AF compared to 32 (28%) of 148 patients who did not (p = 0.043). In the propensity adjusted analyses, early postoperative statin treatment was associated with a significantly lower occurrence of AF (odds ratio 0.39, 95% confidence interval 0.15 to 0.99), irrespective of concomitant beta-blocker therapy. The length of stay was shorter for the patients who received early postoperative statins (median 6.1 days, interquartile range 4 to 7, vs 7.8 days, interquartile range 5 to 8; p = 0.0031). In conclusion, of preoperative statin users undergoing coronary artery bypass grafting with or without valve surgery, early postoperative reinstitution of statins was associated with a lower occurrence of postoperative AF and a shorter length of stay. Early postoperative statin therapy might be a feasible and safe method of reducing postoperative AF. PMID- 21545984 TI - Usefulness of mild therapeutic hypothermia for hospitalized comatose patients having out-of-hospital cardiac arrest. AB - Mild therapeutic hypothermia has proved beneficial after out-of-hospital cardiac arrest in the adult population, when the initial rhythm is ventricular fibrillation (VF). In this study, data from 110 consecutive patients with out-of hospital cardiac arrest due to VF (n = 86) or to non-VF rhythm (n = 24), admitted to an intensive cardiac care unit with restoration of spontaneous circulation and who remained unconscious on admission, were analyzed. Patients were cooled using an external cooling system. Of the patients with VF, 66% had favorable outcomes (Glasgow-Pittsburgh Cerebral Performance Category 1 or 2), and 30% died. Of the patients with non-VF, 8% had favorable outcomes (p <0.001 vs VF), and 63% died (p = 0.004 vs VF). In patients with VF, those with poor outcomes were older than those with favorable outcomes (odds ratio [OR] 1.61, 95% confidence interval [CI] 1.03 to 2.7, p = 0.001) and had previous ejection fractions <35% (OR 7.72, 95% CI 1.8 to 33, p = 0.002). Outcomes were also worse when patients presented to the emergency room with seizures (OR 20.96, 95% CI 2.48 to 177.42, p = 0.003) or hemodynamic instability (OR 14.4, 95% CI 3.47 to 60, p <0.0001). In the non-VF group, the 2 patients with good outcomes were younger than those with unfavorable outcomes (39 +/- 16 vs 65 +/- 12 years, respectively, p = 0.04), with good left ventricular function on presentation (100% vs 4.5%, p = 0.0001) and with short asystole and/or short time from collapse to restoration of spontaneous circulation. In conclusion, mild therapeutic hypothermia in the adult population is more effective in patients with VF compared to those with non-VF. Good prognostic factors for patients with non-VF could be young age, good left ventricular function, and short anoxic time. PMID- 21545985 TI - Outcomes of hospitalization in adults in the United States with atrial septal defect, ventricular septal defect, and atrioventricular septal defect. AB - Atrial septal defect, ventricular septal defect (VSD), and atrioventricular septal defect (AVSD) are among the most common congenital heart lesions, with most children surviving to adulthood. However, the clinical course of these patients is largely unknown, particularly pertaining to inpatient care. The purpose of this study was to assess hospitalizations for septal defects in adults with congenital heart disease (CHD) and risk factors associated with significant morbidity and mortality. The 2007 Nationwide Inpatient Sample was used to assess national prevalence of hospitalizations in adults with CHD with septal defects. Co-morbidities and risk factors for mortality were also determined. There were 84,308 adult CHD admissions in the United States in 2007. Fifty-four percent of adult CHD admissions had diagnoses of septal defects, with 48% having atrial septal defect, 7% having VSD, and 0.4% having AVSD. Overall in-hospital mortality was 2.1%. Common co-morbidities included arrhythmias (31%), heart failure (20%), and diabetes mellitus (18%). On multivariable analysis, independent risk factors for mortality included presence of VSD (odds ratio 3.1, 95% confidence interval [CI] 1.5 to 6.5), trisomy 21 (odds ratio 2.9, 95% CI 1.1 to 7.5), and pulmonary hypertension (odds ratio 1.5, 95% CI 1.0 to 2.4). In conclusion, this study of hospitalizations in adults with septal defects found that admissions are common and associated with significant co-morbidities. Overall mortality is low but is increased in patients with VSD. Cardiac and noncardiac co-morbidities are commonly encountered. Many noncardiac conditions, including trisomy 21 and the youngest and oldest groups, are associated with an increased risk of death. PMID- 21545986 TI - Non-pharmacologic management of atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice today. Contemporary medical treatment options include atrioventricular nodal blocking agents to control heart rates during AF, antiarrhythmic drugs aimed at maintaining normal sinus rhythm, and anticoagulation therapies to reduce stroke risk. Invasive treatment of AF has emerged because of the toxicities and lack of long-term efficacy of available antiarrhythmic medications along with the lack of improvement in symptoms for rate-controlled patients. The investigators review the evolution of the current catheter-delivered AF procedures, starting with surgical maze up to and including left atrial appendage occlusion devices. Individual catheter ablation targets, anatomic and electrophysiologic, are discussed, with a particular focus on the use of an incremental ablation target strategy dependent on the type of AF being treated. In conclusion, the history of invasive AF therapy provides a basic understanding of contemporary ablation strategies and a backdrop for the cutting-edge rhythm and stroke prevention therapies of today. PMID- 21545987 TI - "Repaired" tetralogy of fallot mimicking arrhythmogenic right ventricular cardiomyopathy (another phenocopy). AB - Described is a 41-year-old man who at age 6 had partial resection of an obstructed right ventricular outflow tract with insertion of a patch and closure of a ventricular septal defect (tetralogy of Fallot). At age 41, cardiac transplantation was performed because of right ventricular outflow patch aneurysm, numerous episodes of ventricular tachycardia, and chronic heart failure, all features of the familial form of arrhythmogenic right ventricular cardiomyopathy (ARVC). Additionally, the patient had bundle branch block and epsilon waves on electrocardiogram, other features of ARVC. The case is described to introduce the concept of acquired ARVC, because the patient had many of the clinically recognized features of familial ARVC. PMID- 21545988 TI - Exercise capacity in patients with severe symptomatic aortic stenosis before and six months after transcatheter aortic valve implantation. AB - Few data exist on the use of the 6-minute walk test (6MWT) to measure the exercise capacity of patients with severe symptomatic aortic stenosis considered at very high surgical risk. The objectives of the present prospective study were (1) to determine the feasibility and safety of the 6MWT as a measure of exercise capacity before and after transcatheter aortic valve implantation (TAVI), and (2) to determine the clinical and hemodynamic parameters associated with the exercise capacity changes in such patients. A total of 64 patients (age 80 +/- 8 years, logistic European System for Cardiac Operative Risk Evaluation score 21 +/- 15%, Society of Thoracic Surgeons' score 7.5 +/- 3.9%) who had undergone successful TAVI were included. The 6MWT was performed within the month before TAVI and at the 6-month follow-up visit. The mean distance walked increased from 165.3 +/- 79.7 to 231.7 +/- 88.9 m (p <0.0001); however, up to 25% of the patients did not improve or even decreased their exercise capacity. After adjustment for the baseline distance walked, multilinear regression analysis showed that a greater degree of renal dysfunction, as evaluated by the serum creatinine levels (r(2) = 0.05, p = 0.03), lower postprocedural hemoglobin values (r(2) = 0.13, p = 0.0012), and a longer hospitalization length (r(2) = 0.08, p = 0.007) were associated with lower improvement in exercise capacity. In conclusion, exercise capacity, as evaluated by the 6MWT, was very poor in patients with severe symptomatic aortic stenosis considered at very high surgical risk. TAVI was associated with a significant increase in exercise capacity, although no improvement was observed in 1/4 of the patients. A greater degree in renal dysfunction, lower postprocedural hemoglobin values, and longer hospitalization stay were predictors of lower improvement in exercise capacity after TAVI. These results suggest that the 6MWT might become an important tool as a part of the evaluation process for TAVI candidates. PMID- 21545989 TI - Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension. AB - The long-term effects of endothelin receptor antagonists on pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) are not well studied. This post hoc analysis examined changes in pulmonary hemodynamics in a cohort of patients with PAH who underwent follow-up right heart catheterization (RHC) in a long-term ambrisentan study (ARIES-E). A retrospective review was conducted of patients who underwent RHC after >3 months of ambrisentan therapy. Changes from baseline in mean PAP, mean right atrial pressure, cardiac index, and PVR were assessed and correlations between these hemodynamic changes and exercise capacity were examined. Sixty eight patients who received ambrisentan in the ARIES studies had >=1 follow-up RHC while receiving ambrisentan. Fifty-eight patients were on ambrisentan alone at the time of the first RHC. Median time from initiation of ambrisentan therapy to follow-up RHC was 60 weeks (range 14 to 158). Significant improvements compared to baseline were observed for mean PAP (-7.6 mm Hg, 95% confidence interval [CI] -10.0 to -5.1), PVR (-266 dyne * s/cm(5), 95% CI -350 to -180), and cardiac index (0.4 L/min/m(2), 95% CI 0.2 to 0.6 L/min/m(2)); for patients on ambrisentan alone, changes in mean PAP and PVR were inversely correlated with change from baseline 6-minute walking distance (r = -0.41 and -0.43, respectively, p <0.001 for the 2 comparisons) at time of follow-up RHC. In conclusion, ambrisentan may provide sustained improvements in pulmonary hemodynamics in patients with PAH who receive long-term treatment and these changes correlate with improvements in exercise capacity. PMID- 21545991 TI - Comparison of contrast-induced nephrotoxicity of iodixanol and iopromide in patients with renal insufficiency undergoing coronary angiography. AB - This prospective, randomized, double-blind study was performed to compare the incidence of contrast-induced nephropathy (CIN) after the administration of the iso-osmolar contrast medium iodixanol to the low-osmolar contrast medium iopromide during coronary angiography in patients with impaired renal function. Patients with creatinine clearance (CrCl) <60 ml/min who underwent coronary angiography and/or percutaneous coronary intervention were randomized to receive either iodixanol (n = 215) or iopromide (n = 205). The primary study end point was the incidence of CIN, which was defined as an absolute increase in serum creatinine (SCr) >=0.5 mg/dl (44.2 mol/L) or a relative increase >=25% compared to baseline SCr. The secondary end points were the proportion of patients with increases in SCr >=0.5 mg/dl, the proportion with SCr increases >=1.0 mg/dl (88.4 mol/L), and the peak increase in SCr. Age, the presence of diabetes mellitus, mean baseline SCr, CrCl, the use of N-acetylcysteine, contrast volume, and the predicted risk score for CIN were similar in the 2 groups. CIN developed in 39 patients (9.3%); there was no significant difference between the iodixanol and iopromide groups (10.7% and 7.8%, respectively; absolute difference 2.9%, 95% confidence interval -3.1% to 8.9%, p = 0.394). The proportions of patients with SCr increases >=0.5 mg/dl (6.5% vs 6.3%) and >=1.0 mg/dl (2.8% vs 2.9%) were similar in the 2 groups. There was a tendency for more patients with relative increases >=25% (10.2% vs 6.8%) and greater peak increases in SCr (0.037 +/- 0.375 vs 0.029 +/- 0.351 mg/dl) to be in the iodixanol group, but these differences were not statistically significant. In conclusion, the incidences of CIN after coronary angiography did not significantly differ between the iodixanol and iopromide groups in patients with impaired renal function. PMID- 21545990 TI - Characterization of the proportion of untreated and antiplatelet therapy treated patients with atrial fibrillation. AB - Despite the efficacy of oral anticoagulants for stroke prevention in atrial fibrillation (AF), evidence suggests that many patients with AF who should be treated with vitamin K antagonists (VKAs) are treated with antiplatelet therapy or remain untreated. The aims of this study were to determine the proportion of patients with AF in each treatment category in clinical practice and to ascertain whether treatment is appropriate for stroke risk. An extensive search of the biomedical research published since 1994 was performed. Studies delineating the treatment of patients with AF were captured. Seventy-eight studies pertaining to the treatment of patients with AF were identified; 56 studies, containing data from 1980 to 2007, met the inclusion criteria. Over time, the use of VKA therapy for stroke prevention increased, while the proportion of untreated patients decreased; antiplatelet use remained static. Looking at the more recent data, (collected from 2000 onward), the proportion of patients receiving no therapy ranged from 4% to 48% (median 18%), antiplatelet therapy from 10% to 56% (median 30%), and VKA therapy from 9% to 86% (median 52%). Although most studies showed a decrease in the proportion of antiplatelet-treated and untreated patients with increasing stroke risk (12 of 14 studies), many patients at moderate or high risk for stroke were not treated according to guidelines. In conclusion, this review shows that up to 56% of patients with AF are treated with antiplatelet therapy, and up to 48% receive no therapy regardless of stroke risk level. This may reflect the inconvenience associated with VKA use, inadequate assessment of stroke risk, or poor adherence to treatment guidelines. PMID- 21545992 TI - Comparison of one-year outcomes of percutaneous coronary intervention versus coronary artery bypass grafting in patients with unprotected left main coronary artery disease and acute coronary syndromes (from the CUSTOMIZE Registry). AB - Uncertainty surrounds the optimal revascularization strategy for patients with left main coronary artery disease presenting with acute coronary syndromes (ACSs), and adequately sized specific comparisons of percutaneous and surgical revascularization in this scenario are lacking. The aim of this study was to evaluate the incidence of 1-year major adverse cardiac events (MACEs) in patients with left main coronary artery disease and ACS treated with percutaneous coronary intervention (PCI) and drug-eluting stent implantation or coronary artery bypass grafting (CABG). A total of 583 patients were included. At 1 year, MACEs were significantly higher in patients treated with PCI (n = 222) compared to those treated with CABG (n = 361, 14.4% vs 5.3%, p <0.001), driven by a higher rate of target lesion revascularization (8.1% vs 1.7%, p = 0.001). This finding was consistent after statistical adjustment for MACEs (adjusted hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.2 to 5.9, p = 0.01) and target lesion revascularization (adjusted HR 8.0, 95% CI 2.2 to 28.7, p = 0.001). No statistically significant differences between PCI and CABG were noted for death (adjusted HR 1.1, 95% CI 0.4 to 3.0, p = 0.81) and myocardial infarction (adjusted HR 4.8, 95% CI 0.3 to 68.6, p = 0.25). No interaction between clinical presentation (ST-segment elevation myocardial infarction or unstable angina/non ST-segment elevation myocardial infarction) and treatment (PCI or CABG) was observed (p for interaction = 0.68). In conclusion, in patients with left main coronary artery disease and ACS, PCI is associated with similar safety compared to CABG but higher risk of MACEs driven by increased risk of repeat revascularization. PMID- 21545995 TI - Bariatric surgery. PMID- 21545993 TI - Prognostic value of plasma renin activity in heart failure. AB - The prognostic role of specific biomarkers of the renin-angiotensin-aldosterone system and sympathetic activation pathways in heart failure has never been investigated in populations with current evidence-weighted treatment. To establish whether the plasma renin activity (PRA), among several neurohormonal biomarkers, is able to predict cardiac events in a population of patients with heart failure on up-to-date treatment, we selected 996 consecutive patients with systolic left ventricular dysfunction (ejection fraction <50%, mean age 65 +/- 13 years), who underwent a complete clinical and humoral characterization and were then followed up (median 36 months, range 0 to 72) for cardiac death and appropriate implantable cardioverter device shock. We recorded 170 cardiac deaths and 27 shocks. On Cox multivariate analysis, only ejection fraction (hazard ratio 0.962, 95% confidence interval 0.938 to 0.986), N-terminal pro-brain natriuretic peptide (NT-proBNP; hazard ratio 1.729, 95% confidence interval 1.383 to 2.161) and PRA (hazard ratio 1.201, 95% confidence interval 1.024 to 1.408) were independent predictors of cardiac death. Receiver operating characteristic curve analysis identified a cutoff value for PRA of 2.30 ng/ml/hour that best predicted cardiac mortality. Independent predictors of PRA were ejection fraction, functional class, sodium, potassium, NT-proBNP, norepinephrine, aldosterone, C reactive protein, and medical therapy. The association of high NT-proBNP and high PRA identified a subgroup (22% of the study population) with the greatest risk of cardiac death. In conclusion, PRA resulted an independent prognostic marker in patients with systolic heart failure additive to NT-proBNP level and ejection fraction. PRA might help to select those patients needing an enhanced therapeutic effort, possibly targeting incomplete renin-angiotensin-aldosterone system blockade. PMID- 21545996 TI - Reanalysis of a randomized trial of 3 techniques of anterior colporrhaphy using clinically relevant definitions of success. AB - OBJECTIVE: The purpose of this study was to reanalyze the results of a previously published trial that compared 3 methods of anterior colporrhaphy according to the clinically relevant definitions of success. STUDY DESIGN: A secondary analysis of a trial of 114 subjects who underwent surgery for anterior pelvic organ prolapse who were assigned randomly to standard anterior colporrhaphy, ultralateral colporrhaphy, or anterior colporrhaphy plus polyglactin 910 mesh from 1996-1999. For the current analysis, success was defined as (1) no prolapse beyond the hymen, (2) the absence of prolapse symptoms (visual analog scale <= 2), and (3) the absence of retreatment. RESULTS: Eighty-eight percent of the women met our definition of success at 1 year. One subject (1%) underwent surgery for recurrence 29 months after surgery. No differences among the 3 groups were noted for any outcomes. CONCLUSION: Reanalysis of a trial of 3 methods of anterior colporrhaphy revealed considerably better success with the use of clinically relevant outcome criteria compared with strict anatomic criteria. PMID- 21545998 TI - Pyloric valve transposition as substitute for a colostomy in humans: a preliminary report. AB - BACKGROUND: The purpose of this article was to show that a transposed pyloric valve (PV) can be mobilized to the perianal region and can function as a replacement for an excised rectal sphincter. Surgical research on animals has shown that a vascularized PV can be taken out of gastroduodenal continuity, transposed to the pelvic region with maintenance of fecal control when positioned in the anal area. METHODS: The surgical procedure has recently proved successful in humans in which the distal end of the left colon was anastomosed to the proximal end of the transposed PV with the distal end of the PV sutured to the skin in the perianal area as the replacement for an excised rectal sphincter. Fecal control was established after the operation. RESULTS: The PV healed in an anal position in humans with no apparent anatomic or physiological reasons to suggest that the operation might not be successful in the future as a substitute for a surgically excised or a severely damaged rectal sphincter. CONCLUSIONS: A vascularized PV supplied by the gastroepiploic artery within an omental pedicle can serve as a replacement for an excised rectal sphincter, thus eliminating the need for a permanent colostomy. PMID- 21545997 TI - Local variations in the epidemiology, microbiology, and outcome of necrotizing soft-tissue infections: a multicenter study. AB - BACKGROUND: Necrotizing soft-tissue infections (NSTIs) are rare and highly lethal. METHODS: A retrospective chart review of patients with NSTIs treated at 6 academic hospitals in Texas between January 1, 2004 and December 31, 2007. Patient demographics, presentation, microbiology, treatment, and outcome were recorded. Analysis of variance, chi-square test, and logistic regression analysis were performed. RESULTS: Mortality rates varied between hospitals from 9% to 25% (n = 296). There was significant interhospital variation in patient characteristics, microbiology, and etiology of NSTIs. Despite hospital differences in treatment, primarily in critical care interventions, patient age and severity of disease (reflected by shock requiring vasopressors and renal failure postoperatively) were the main predictors of mortality. CONCLUSIONS: Significant center differences occur in patient populations, etiology, and microbiology of NSTIs, even within a concentrated region. Management should be based on these characteristics given that adjunctive treatments are unproven and variations in outcome are likely because of patient disease at presentation. PMID- 21546000 TI - Atypical prefrontal connectivity in attention-deficit/hyperactivity disorder: pathway to disease or pathological end point? AB - Functional neuroimaging studies have identified multiple nodes of dysfunction in frontostriatal and mesocorticolimbic networks in attention-deficit/hyperactivity disorder (ADHD). Yet relatively few studies have examined how structural and functional connectivity between nodes in these networks might relate to the behavioral symptoms of ADHD. Moreover, it is unknown whether abnormalities in connectivity are a primary cause of symptoms or arise secondary to common etiologic mechanisms. We review the most recent diffusion tensor imaging and functional magnetic resonance imaging studies of connectivity in ADHD to characterize associations between frontostriatal connectivity abnormalities and the behavioral symptoms of inattention and impulsivity in ADHD. Furthermore, we examine how structural and functional connectivity measures relate to environmental and genetic pathways to ADHD. Diffusion tensor imaging studies indicate that ADHD is associated with significant irregularities in white matter microstructure, especially in frontostriatal and select corticocortical tracts. Resting state functional magnetic resonance imaging studies implicate altered connectivity within a default mode network of structures active during introspective, task-free processes and disrupted interactions between this network and frontostriatal attentional systems. Deficits in functional connectivity within frontostriatal and mesocorticolimbic networks might give rise, in part, to ADHD symptoms. Conversely, structural connectivity deficits and ADHD symptoms might arise incidentally from a common etiologic mechanism, involving altered modulation of synaptic potentiation and pruning by dopamine and other factors during development. Collectively, these studies suggest that the core symptoms of ADHD might derive from dysregulated modulation of cortical plasticity in the developing brain, resulting in altered patterns of corticocortical connectivity that might persist into adulthood. PMID- 21545999 TI - Outcomes after heart transplantation in children under six years of age. AB - BACKGROUND: Survival after heart transplant has improved and more attention is focused on developmental outcomes. We aimed to determine the survival, morbidity, and developmental outcomes of young children after heart transplant. METHODS: All children under 6 years of age having a heart transplant in Edmonton between 1999 and 2006 were included in this inception cohort study. Demographics, pretransplant, transplant, and posttransplant variables were collected. The association of potentially predictive variables with neurodevelopmental outcomes at least 12 months posttransplant were determined by univariate and multiple regression analyses. RESULTS: Thirty-three children had a heart transplant; 18 with congenital heart disease (CHD) and 15 with cardiomyopathy-myocarditis (non CHD). Mortality during 19 (8) months of follow-up was 12% (95% confidence interval [CI] 3% to 28%). Survivors had frequent low weight (28%) and height (31%), and delay in language (41%), motor (52%), mental (34%), and general adaptive composite (48%) scores. Only CHD was associated with death-disability mental delay on multiple regression (odds ratio 7.94; 95% CI 1.6 to 39.4, p=0.011). The CHD was also associated with mental and language delay on multiple regressions. Mental delay occurred in 8 (53%) with CHD and 2 (14%) with non-CHD (p=0.05). Mental score of 85 or greater was found in 13.4% of patients with CHD compared with 50% with non-CHD (p=0.05). CONCLUSIONS: In this single-center inception cohort study, adverse neurodevelopmental outcomes in survivors of heart transplant before the age 6 years were common, particularly in those with CHD. Careful pretransplant and posttransplant counseling are needed, and close follow up with early intervention for these high-risk children is imperative. PMID- 21546001 TI - Bimodal distribution of polyunsaturated fatty acids in schizophrenia suggests two endophenotypes of the disorder. AB - BACKGROUND: There is conflicting evidence of whether polyunsaturated fatty acids (PUFA) in red blood cells are bimodally distributed in schizophrenia. The purpose of this study was to examine the distribution of PUFA, as well as its links to plausible causal factors. METHODS: A 16-week cohort study and a case-control study as part of a randomized controlled trial. Ninety-nine patients with DSM-IV schizophrenia, schizoaffective disorder, or schizophreniform disorder, aged 18 to 39, were consecutively included at admission to psychiatric departments of nine Norwegian hospitals. Fatty acids were measured in 97 of these patients and in 20 healthy control subjects. The primary outcome measure was the bimodality test statistic T, assessed by a chi(2) test of the likelihood of one or two normal distributions of PUFA. RESULTS: At baseline, levels of polyunsaturated fatty acids were highly significantly bimodally distributed among patients. One third of patients constituted a group (low PUFA) who had PUFA levels at one fifth (p < .001) of those in high PUFA patients and healthy control subjects, which did not differ. Bimodality was mainly accounted for by docosahexaenoic acid and arachidonic acid. Bimodality was confirmed after 16 weeks. alpha-tocopherol was a robust predictor of PUFA at both occasions. Desaturase and elongase indexes differed between PUFA groups. Smoking, gender, antipsychotic medication, and dietary factors did not explain the bimodal distribution. CONCLUSIONS: Red blood cell PUFA were bimodally distributed among acutely ill patients with schizophrenia and schizoaffective disorder. Endogenous deficiencies of redox regulation or synthesis of long-chain PUFA in the low PUFA group may explain our findings. PMID- 21546002 TI - Cortical responses to a graded working memory challenge predict functional decline in mild cognitive impairment. AB - BACKGROUND: Early detection of progressive cognitive decline offers an opportunity for preventative interventions with enormous public health implications. Functional neuroimaging during cognitive activity in individuals at risk of dementia has the potential to advance this objective. In a prior study, we evaluated the utility of a novel functional magnetic resonance imaging paradigm that incorporated a graded working memory (WM) task to detect changes associated with mild cognitive impairment (MCI). We observed greater deactivation of posteromedial cortex (PMC) under conditions of increased WM load in MCI compared with control subjects. Our objective here is to test whether this paradigm can predict ensuing functional decline. METHODS: Thirty individuals with MCI who underwent baseline functional magnetic resonance image scanning were followed clinically for 2 years. Multiple linear regression analyses were used to determine whether deactivation in PMC under increased load at baseline independently predicted decline in instrumental activities of daily living (IADL). RESULTS: Greater deactivation in PMC to increased load predicted greater decline in IADL after controlling for baseline clinical severity, MCI subtype, apolipoprotein epsilon4 carrier status, gray matter, PMC and hippocampal volumes, and task performance. CONCLUSIONS: Increased deactivation observed at baseline was a harbinger of subsequent functional decline as measured by IADL in a cohort with MCI. This graded WM challenge may operate like a memory stress test by producing a threshold effect beyond which abnormal deactivation is elicited in MCI subjects who are at greatest risk of functional decline. PMID- 21546003 TI - Regulation of S100B gene in rat hippocampal CA1 area during long term potentiation. AB - In the present study we investigated the regulation of S100B expression during tetanization-induced hippocampal long term potentiation, one of the best characterized forms of synaptic plasticity. Tetanization resulted in time dependent change in S100B gene expression and protein content in hippocampal CA1 area. We analyzed the promoter region of the rat S100B gene and identified response elements for the tumor suppressor p53. ChIP assay revealed that p53 could bind to putative p53-binding sites of the S100B promoter. The time dependent recruitment of p53 to its putative binding sites in the S100B gene promoter paralleled the time-course change of S100B mRNA and protein levels. Thus, these results strongly support the view that S100B gene may be a target of p53. Moreover, we demonstrated that the increase of S100B protein content was accompanied with the decrease of p53 protein content, and it seems that the decrease is regulated on post-translational level. Thus, our results may help to understand the physiological function of the p53-S100B-p53 loop in the process of synaptic plasticity. PMID- 21546004 TI - Probing beta-(1->3)-D-glucans interactions with recombinant human receptors using high-resolution NMR studies. AB - A full characterization of the high-resolution NMR spectrum of the laminarihexaose is described and used for the determination of the binding epitope of the more complex but structurally related laminarin. These biophysical data extend the current knowledge of beta-glucans/Dectin-1 interactions and suggest different biological mechanisms in close relation with the size of the saccharidic chain. PMID- 21546005 TI - [In vitro study of the antimicrobial properties of a silver ion-releasing polyurethane foam]. AB - INTRODUCTION: The antimicrobial properties of a silver ion (Ag+)-releasing polyurethane foam were evaluated using different microorganisms. The diffusion of Ag+ from the medium, as well as any possible cytotoxicity on human cells, was also studied. MATERIAL AND METHODS: Silver release from V.A.C. GranuFoam Silver((r)) was assessed by using inductively coupled plasma mass spectrometry (ICP-MS). An in vitro experimental study was designed to evaluate the bactericide capacity using lethal dose curves on A. baumannii, P. aeruginosa, S. maltophilia, K. pneumoniae, E. coli, P. mirabilis, methicillin resistant S. aureus, E. faecium, S. pyogenes and C. minutissimum. A cytotoxicity study was also performed on human fibroblasts. RESULTS: The silver release showed an exponential curve with a stable meseta phase after 3 hours, with levels of 0.22-0.24 mg/l. A reduction of 99.9% of all the gram-negatives was achieved at 3 hours. The reduction was greater than 99% at 2 hours in S. pyogenes and C. minutissimum, at 6h in S. aureus and at 14 h in E. faecium. In an in vivo simulation model, these reductions were achieved in 6 hours in the gram negatives and 24h in the gram positives. The silver concentrations were no cytotoxic to human fibroblasts, with no differences being observed between the cells exposed to Ag+ and the controls (p=.7) CONCLUSION: V.A.C. Granufoam Silver((r)) releases bactericide concentrations of Ag+ that did not damage human fibroblasts. It appears to be a good alternative for the control and prevention of local infections. PMID- 21546006 TI - [Superior mesenteric artery syndrome]. PMID- 21546007 TI - SNOLL. Sentinel node and occult (impalpable) lesion localization in breast cancer. AB - AIM: To evaluate the efficacy and safety for use of dual radioisotopes for localization of occult (impalpable) breast lesions and sentinel node biopsy as a combined technique (SNOLL) using a lower dose than previous studies. MATERIALS AND METHODS: One hundred and twenty-seven SNOLL procedures were performed. The impalpable breast lesions were localized with an intra-lesion injection of 0.2 ml of (99m)Tc MAA (1 MBq) with a particle size of 10-90 MUm (radio-guided occult lesion localization, or ROLL) 1 to 4 h before surgery. Sentinel node localization was performed using 0.2 mls of (99)Tc nanocolloid (20 MBq) particle size no greater than 80 nm injected subdermally in the periareolar region within the index quadrant, the night before or the morning of surgery. RESULTS: Lesion localization was consistently achieved with a lower dose than that described in other studies without the need to use scintigraphy or additional imaging with radioopaque contrast medium. One hundred percent lesion localization with a negative clearance margin of 94.8% and 100% sentinel node localization was achieved. The use of dual radioisotopes with the lower dose used for ROLL did not compromise the localization of the impalpable lesion or the sentinel nodes. CONCLUSION: The combined use of radioisotopes for lesion and sentinel node removal is feasible and reliable with the lower radioisotope dose suggested compared with previously published studies. This method should be recommended as a standard procedure for SNOLL. PMID- 21546008 TI - Idiopathic orbital pseudotumour. AB - Idiopathic orbital pseudotumour (IOP) is a benign inflammatory condition usually confined to the orbit. This may involve single or multiple intraorbital structures. Extraorbital extension can also occur. The imaging appearances often mimic other orbital diseases. Both computed tomography (CT) and magnetic resonance imaging (MRI) are frequently used to investigate orbital diseases, and it is important for radiologists to be aware of the variety of imaging appearances that occur in IOP. We present the imaging appearances in histopathologically confirmed cases of IOP and discuss the clinical features, natural history, and differential diagnosis of this condition. PMID- 21546009 TI - The importance of low-lying axillary sentinel nodes in breast cancer patients. PMID- 21546010 TI - Doctors' knowledge of radiation -- a two-centre study and historical comparison. AB - AIM: To investigate knowledge of the use of ionizing radiation in 2010 and whether there has been any change in this knowledge since the study was first undertaken over 7 years ago. MATERIALS AND METHODS: In both studies a single chest x-ray was classed as one unit of radiation. Doctors from all grades were asked to evaluate the average radiation dose incurred with 13 commonly undertaken radiological procedures, including magnetic resonance imaging (MRI), computed tomography (CT), etc. Answers within 20% of the actual dose were marked as correct. RESULTS: Two hundred and forty-two questionnaires were completed (130 in 2003; 112 in 2010). Equal numbers of juniors, middle grades, and consultants were questioned, and scores were comparable (23.3% in 2003; 29.4% in 2010). The majority of doctors (92% in 2003; 86% in 2010) correctly noted that ultrasound and MRI involve no radiation. Doctors underestimated the radiation doses of all investigations by a smaller margin in 2010 compared to 2003 (i.e., more accurately), with only one exception: CT of the abdomen. CONCLUSION: Despite evidence of some improvement, doctors of all grades still have a very poor knowledge of radiation exposure even with the most common investigations. The worsening appreciation of the radiation involved in CT scanning is especially worrying considering its increasing use in practice today. PMID- 21546011 TI - The imaging features of MACROLANETM in breast augmentation. AB - MacrolaneTM is an injectable, biocompatible, soft-tissue filler that has been available in the UK since 2008 and is promoted for use in breast augmentation. There are few data available on the long-term effects of this relatively new product and concerns have been raised about the implications for breast imaging, in particular breast screening. In this context we present a spectrum of imaging appearances and complications encountered to date. PMID- 21546012 TI - Evaluation of spinal dural arteriovenous fistulae with gadofosveset trisodium at 3 T (TRICKS and LAVA). PMID- 21546013 TI - Religion and action control: Faith-specific modulation of the Simon effect but not Stop-Signal performance. AB - Previous findings suggest that religion has a specific impact on attentional processes. Here we show that religion also affects action control. Experiment 1 compared Dutch Calvinists and Dutch atheists, matched for age, sex, intelligence, education, and cultural and socio-economic background, and Experiment 2 compared Italian Catholics with matched Italian seculars. As expected, Calvinists showed a smaller and Catholics a larger Simon effect than nonbelievers, while performance of the groups was comparable in the Stop-Signal task. This pattern suggests that religions emphasizing individualism or collectivism affects action control in specific ways, presumably by inducing chronic biases towards a more "exclusive" or "inclusive" style of decision-making. Interestingly, there was no evidence that religious practice affects inhibitory skills. PMID- 21546014 TI - Dysexecutive behaviour following deep brain lesions--a different type of disconnection syndrome? AB - The suppression of automatic prepotent behaviour in favour of more successful, more 'appropriate' behaviour is the primary function of the frontal lobe. Five frontal-subcortical circuits connect the frontal lobe to the basal ganglia and the thalamus. We report 17 patients with small lesions in the downstream structures of the frontal-subcortical circuits displaying severe dysexecutive behaviour. Positron emission tomography (PET) demonstrated hypometabolism of the frontal lobe in some of these patients. The literature on frontal lobe dysfunction after lesions in the basal ganglia and thalamus is discussed and the semiology of frontal lobe dysfunction in relation to the frontal-subcortical circuits is highlighted. Derived from our findings we suggest a disconnection syndrome of the frontal lobe caused by lesions in the downstream structures of the frontal-subcortical circuits. PMID- 21546015 TI - Another piece in the jigsaw: a case report of prosopagnosia with symptomatological, imaging and post mortem anatomical evidence. PMID- 21546016 TI - [Epidemiology, presentation forms, radiological stage and diagnostic methods of sarcoidosis in the area of Leon (2001-2008)]. AB - BACKGROUNDS: The epidemiological studies of sarcoidosis in Spain and other countries are from more than one decade ago. OBJECTIVES: To know the current incidence in the health care area of Leon, the reasons for consultation, the thoracic radiologyl involvement, delay and diagnostic methods. PATIENTS AND METHODS: We reviewed the cases of sarcoidosis seen in our hospital between the years 2001-2008. The study is retrospective. RESULTS: 118 patients fulfilled the criteria for sarcoidosis with an incidence of 4.51/100,000 inhab./year. Of these, 53 (44.9%) were male with a mean age of 36.4 +/- 12.2 and 65 (55.1%) women, with a mean age of 42.6 +/- 17.2 years (P = 0.029). The most frequent presentation form was Lofgren Syndrome with 45.8%, followed by respiratory symptoms 20.3%, radiological findings 12.7%, general syndrome 10.2% and miscellaneous 11%. Thoracic radiological affectations at the time of diagnosis were: stage I: 59.3%, stage II: 19.8%, stage III: 10%, fibrosis 3.4% and stage 0: 8.5%. Transbronchial biopsy was the most frequent diagnosis. Time to diagnosis was very variable with a median of 24.5 days, when it debuted as erythema nodosum, 80 in the less frequent forms. CONCLUSIONS: The incidence of sarcoidosis was superior to that previously demonstrated. It affected young adults, but with an increase in the number of cases in those over 50 years with clear female predominance. Lofgren syndrome was the most frequent presentation form, with a higher incidence in spring. Diagnostic delay varied according to the different presentation forms. Transbronchial biopsy was the main diagnostic tool. PMID- 21546017 TI - [Thyroid dysfunction in patients with chronic hepatitis C treated with pegylated interferon alpha]. PMID- 21546018 TI - [Endocrinological disorders in a patient with thalassemia major]. PMID- 21546019 TI - [Malformations of the vena cava inferior as a cause of deep venous thrombosis: based on two cases]. PMID- 21546020 TI - [Syncope as the first systemic manifestation of mastocytosis]. PMID- 21546021 TI - [Praising of a cell: Passionate digressions on the vascular endothelium]. PMID- 21546023 TI - [Acute hepatitis due to Chlamydophila pneumoniae]. PMID- 21546024 TI - [Education in leadership: a need and a challenge of the modern internist]. AB - Leadership is the ability to guide a team adequately, to ensure that it will be able to completely develop a given project. Being a leader means having the capacity of active listening and exercising a wide variety of communicational aptitudes. Leading means working together, and facilitating that work. A leader needs to have in-depth self-knowledge as well as a good share of humility and internal coherence. The development of many of these features is essential to ameliorate both patient-doctor relationships and professional relationships in the modern day-to-day medical practice. Even though not all of us are destined to lead work teams, there is a common obligation to exercise many of the skills that a leader should have. PMID- 21546025 TI - The turnover of mineralized growth plate cartilage into bone may be regulated by osteocytes. AB - During endochondral ossification, growth plate cartilage is replaced with bone. Mineralized cartilage matrix is resorbed by osteoclasts, and new bone tissue is formed by osteoblasts. As mineralized cartilage does not contain any cells, it is unclear how this process is regulated. We hypothesize that, in analogy with bone remodeling, osteoclast and osteoblast activity are regulated by osteocytes, in response to mechanical loading. Since the cartilage does not contain osteocytes, this means that cartilage turnover during endochondral ossification would be regulated by the adjacent bone tissue. We investigated this hypothesis with an established computational bone adaptation model. In this model, osteocytes stimulate osteoblastic bone formation in response to the mechanical bone tissue loading. Osteoclasts resorb bone near randomly occurring microcracks that are assumed to block osteocyte signals. We used finite element modeling to evaluate our hypothesis in a 2D-domain representing part of the growth plate and adjacent bone. Cartilage was added at a constant physiological rate to simulate growth. Simulations showed that osteocyte signals from neighboring bone were sufficient for successful cartilage turnover, since equilibrium between cartilage remodeling and growth was obtained. Furthermore, there was good agreement between simulated bone structures and rat tibia histology, and the development of the trabecular architecture resembled that of infant long bones. Additionally, prohibiting osteoclast invasion resulted in thickened mineralized cartilage, similar to observations in a knock-out mouse model. We therefore conclude that it is well possible that osteocytes regulate the turnover of mineralized growth plate cartilage. PMID- 21546026 TI - Analysis of pelvic movement in the elderly during walking using a posture monitoring system equipped with a triaxial accelerometer and a gyroscope. AB - The incidence of falls in the elderly is increasing with the aging of society and is becoming a major public health issue. From the viewpoint of prevention of falls, it is important to evaluate the stability of the gait in the elderly people. The pelvic movement, which is a critical factor for walking stability, was analyzed using a posture monitoring system equipped with a triaxial accelerometer and a gyroscope. The subjects were 95 elderly people over 60 years of age. The criteria for instability were open-eye standing on one leg for 15s or less, and 11s or more on 3m timed up and go test. Forty subjects who did not meet both of these criteria comprised the stable group, and the remaining 55 subjects comprised the unstable group. Pelvic movement during walking was compared between the two groups. The angle, angular velocity, and acceleration were analyzed based on the wave shape derived from the device worn around the second sacral. The results indicated that pelvic movement was lower in all three directions in the unstable group compared to the stable group, and the changes in the pelvic movement during walking in unstable elderly people were also reduced. This report is the first to evaluate pelvic movement by both a triaxial accelerometer and a triaxial gyroscope simultaneously. The characteristics of pelvic movement during walking can be applied in screening to identify elderly people with instability, which is the main risk factor associated with falls. PMID- 21546027 TI - The effect of hydrothermal treatment on column performance for monolithic silica capillary columns. AB - Monolithic silica capillary columns with i.d. 100 MUm and monolithic silica rods were prepared with tetramethoxysilane (TMOS) or a mixture of TMOS and metyltrimethoxysilane (MTMS) using different hydrothermal treatments at T=80 degrees C or 120 degrees C. Nitrogen physisorption was applied for the pore characterization of the rods and inverse size exclusion chromatography (ISEC) for that of the capillary columns. Using nitrogen physisorption, it was shown change of pore size and surface area corresponds to that of hydrothermal treatment and silica precursor. The results from ISEC agreed well with those from nitrogen physisorption regarding the pore size distribution (PSD). In addition, the retention factors for hexylbenzene with the ODS-modified capillary columns in methanol/water=80/20 at T=30 degrees C could also support the results from nitrogen physisorption. Furthermore, column efficiency for the columns was evaluated with alkylbenzenes and three kinds of peptides, leucine-enkephalin, angiotensin II, and insulin. Column efficiency for alkylbenzenes was similar independently of the hydrothermal treatment at T=120 degrees C. Even for TMOS columns, there was no significant difference in column efficiency for the peptides despite the difference in hydrothermal treatment. In contrast, for hybrid columns, it was possible to confirm the effect on hydrothermal treatment at T=120 degrees C resulting in a different column efficiency, especially for insulin. This difference supports the results from both nitrogen physisorption and ISEC, showing the presence of more small pores of ca. 3-6 nm for a hybrid silica without hydrothermal treatment at T=120 degrees C. Consequently, the results suggest that hydrothermal treatment for a hybrid column with higher temperature or longer time is necessary, compared to that for a TMOS column, to provide higher column efficiency with increase in molecular size of solute. PMID- 21546028 TI - Profiling allergic asthma volatile metabolic patterns using a headspace-solid phase microextraction/gas chromatography based methodology. AB - Allergic asthma represents an important public health issue with significant growth over the years, especially in the paediatric population. Exhaled breath is a non-invasive, easily performed and rapid method for obtaining samples from the lower respiratory tract. In the present manuscript, the metabolic volatile profiles of allergic asthma and control children were evaluated by headspace solid-phase microextraction combined with gas chromatography-quadrupole mass spectrometry (HS-SPME/GC-qMS). The lack of studies in breath of allergic asthmatic children by HS-SPME led to the development of an experimental design to optimize SPME parameters. To fulfil this objective, three important HS-SPME experimental parameters that influence the extraction efficiency, namely fibre coating, temperature and time extractions were considered. The selected conditions that promoted higher extraction efficiency corresponding to the higher GC peak areas and number of compounds were: DVB/CAR/PDMS coating fibre, 22 degrees C and 60 min as the extraction temperature and time, respectively. The suitability of two containers, 1L Tedlar(r) bags and BIOVOC(r), for breath collection and intra-individual variability were also investigated. The developed methodology was then applied to the analysis of children exhaled breath with allergic asthma (35), from which 13 had also allergic rhinitis, and healthy control children (15), allowing to identify 44 volatiles distributed over the chemical families of alkanes (linear and ramified) ketones, aromatic hydrocarbons, aldehydes, acids, among others. Multivariate studies were performed by Partial Least Squares-Discriminant Analysis (PLS-DA) using a set of 28 selected metabolites and discrimination between allergic asthma and control children was attained with a classification rate of 88%. The allergic asthma paediatric population was characterized mainly by the compounds linked to oxidative stress, such as alkanes and aldehydes. Furthermore, more detailed information was achieved combining the volatile metabolic data, suggested by PLS DA model, and clinical data. PMID- 21546029 TI - Streaming current and wall dissolution over 48 h in silica nanochannels. AB - We present theoretical and experimental studies of the streaming current induced by a pressure-driven flow in long, straight, electrolyte-filled nanochannels. The theoretical work builds on our recent one-dimensional model of electro-osmotic and capillary flow, which self-consistently treats both the ion concentration profiles, via the nonlinear Poisson-Boltzmann equation, and the chemical reactions in the bulk electrolyte and at the solid-liquid interface. We extend this model to two dimensions and validate it against experimental data for electro-osmosis and pressure-driven flows, using eight 1-MUm-wide nanochannels of heights varying from 40 nm to 2000 nm. We furthermore vary the electrolyte composition using KCl and borate salts, and the wall coating using 3 cyanopropyldimethylchlorosilane. We find good agreement between prediction and experiment using literature values for all parameters of the model, i.e., chemical reaction constants and Stern-layer capacitances. Finally, by combining model predictions with measurements over 48 h of the streaming currents, we develop a method to estimate the dissolution rate of the silica walls, typically around 0.01 mg/m(2)/h, equal to 45 pm/h or 40 nm/yr, under controlled experimental conditions. PMID- 21546030 TI - Assembly of nanoparticles at the contact line of a drying droplet under the influence of a dipped tip. AB - The manipulation of colloidal nanoparticles (NPs) in a drying droplet has critical importance not only for several industrial applications but also their assembly into patterns on surfaces. The influence of a tip with hydrophilic or hydrophobic surfaces dipped into a drying droplet on hydrophilic or hydrophobic surfaces on the behavior of 98 nm latex NPs was investigated. The formation of concentric rings on hydrophilic glass surfaces regardless of the surface chemistry of the dipped tip was observed. On the other hand, no pattern formation on hydrophobic surfaces was observed with the insertion of the tip. With a hydrophilic tip, the concentric rings were formed due to stick-slip motion of the solvent contact line resulting from competition between pinning and capillary forces while the capillary effect was not effective until the surface of the tip was changed by adherent NPs making the tip surface available for water adherence with a hydrophobic tip, which results in the pulling of droplet towards the tip. It is also found that the tip thickness and suspension concentration significantly influences the formation of concentric rings on surfaces. This simple procedure can be used to influence the distribution or assembly of NPs in the droplet area. PMID- 21546031 TI - Nanostructured Ag surface fabricated by femtosecond laser for surface-enhanced Raman scattering. AB - Femtosecond laser was employed to fabricate nanostructured Ag surface for surface enhanced Raman scattering (SERS) application. The prepared nanostructured Ag surface was characterized by field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The FESEM images demonstrate the formation of nanostructure covered femtosecond laser-induced periodic surface structure, also termed as ripples, on the Ag surface. The AFM images indicate that the surface roughness of the produced nanostructured Ag substrate is larger than the untreated Ag substrate. The XRD and XPS of the nanostructured Ag surface fabricated by femtosecond laser show a face centered cubic phase of metallic Ag and no impurities of Ag oxide species. The application of the produced nanostructured Ag surface in SERS was investigated by using rhodamine 6G (R6G) as a reference chemical. The SERS intensity of R6G in aqueous solution at the prepared nanostructured Ag surface is 15 times greater than that of an untreated Ag substrate. The Raman intensities vary linearly with the concentrations of R6G in the range of 10(-8)-10(-4)M. The present methodology demonstrates that the nanostructured Ag surface fabricated by femtosecond laser is potential for qualification and quantification of low concentration molecules. PMID- 21546032 TI - Vesicle formation with amphiphilic chitosan derivatives and a conventional cationic surfactant in mixed systems. AB - The self-assembly behavior of mixed systems consisting of amphiphilic chitosan derivatives C(n)-OCMCS (n=4, 6, 8) and the conventional cationic surfactant cetyltrimethylammonium bromide (CTAB) is investigated. Transmission electron microscopy (TEM), dynamic light scattering (DLS), small-angle X-ray diffraction (XRD), UV-vis spectra, and zeta potential measurements have been utilized to characterize the microstructures of C(n)-OCMCS/CTAB mixtures in aqueous solutions. Spherical vesicles are formed spontaneously in the C(n)-OCMCS (n=4, 6, 8)/CTAB mixed systems, and the increased hydrophobic chain length of C(n)-OCMCS enhances the ability to form vesicles. The addition of NaBr with higher concentrations to the vesicle system transforms vesicles into micelles, and an increase in temperature decreases the vesicle size. The results indicate that the main driving forces controlling vesicle formation may be attributed to the strong electrostatic interactions as well as the hydrophobic interactions, and also the hydrogen bonding between C(n)-OCMCS molecules. PMID- 21546033 TI - Magnetically separable polyoxometalate catalyst for the oxidation of dibenzothiophene with H2O2. AB - Two types of polyoxometalate-functionalized magnetic nanoparticles catalysts consisting of H(3)PW(12)O(40) supported on surface-modified Fe(3)O(4) magnetite nanoparticles were prepared using an easy synthetic route and successfully applied for the oxidation of dibenzothiophene. The magnetic catalysts showed a catalytic performance in the oxidation of dibenzothiophene in acetonitrile with hydrogen peroxide, and high conversions were obtained. The catalysts could be easily separated from the reaction solution by applying an external magnetic field and recycled several times. PMID- 21546034 TI - NMR investigations of self-aggregation characteristics of SDS in a model assembled tri-block copolymer solution. AB - The present work was undertaken with a view to understand the influence of a model non-ionic tri-block copolymer PEO-PPO-PEO (poly(ethylene oxide) poly(propylene oxide)-poly(ethylene oxide)) with molecular weight 5800 i.e., P123 [(EO)(20)-(PO)(70)-(EO)(20)] on the self-aggregation characteristics of the anionic surfactant sodium dodecylsulfate (SDS) in aqueous solution (D(2)O) using NMR chemical shift, self-diffusion and nuclear spin-relaxation as suitable experimental probes. In addition, polymer diffusion has been monitored as a function of SDS concentration. The concentration-dependent chemical shift, diffusion data and relaxation data indicated the significant interaction of polymeric micelles with SDS monomers and micelles at lower and intermediate concentrations of SDS, whereas the weak interaction of the polymer with SDS micelles at higher concentrations of SDS. It has been observed that SDS starts aggregating on the polymer at a lower concentration i.e., critical aggregation concentration (cac=1.94 mM) compared to polymer-free situation, and the onset of secondary micelle concentration (C(2)=27.16 mM) points out the saturation of the 0.2 wt% polymer or free SDS monomers/micelles at higher concentrations of SDS. It has also been observed that the parameter cac is almost independent in the polymer concentrations of study. The TMS (tetramethylsilane) has been used as a solubilizate to measure the bound diffusion coefficient of SDS-polymer mixed system. The self-diffusion data were analyzed using two-site exchange model and the obtained information on aggregation dynamics was commensurate with that inferred from chemical shift and relaxation data. The information on slow motions of polymer-SDS system was also extracted using spin-spin and spin-lattice relaxation rate measurements. The relaxation data points out the disintegration of polymer network at higher concentrations of SDS. The present NMR investigations have been well corroborated by surface tension and conductivity measurements. PMID- 21546035 TI - Semi-empirical description of the constant beta in the equation of state for interfacial tension. AB - A semi-empirical expression for the constant, beta, in the Equation of State (EOS) for interfacial tension is proposed that exhibits a dependence on the surface area, heat capacity and thermal expansion coefficient of each of the materials involved in the three phase equilibrium (at constant temperature and pressure). The "wetting function", which yields values between zero and unity as the contact angle, theta, varies from 0 degrees to 180 degrees , is also employed in the description of beta. Empirical data is used to support that equation as well as the initially proposed relationship leading to its derivation that is based entirely on Classical Nucleation theory (CNT) outcomes and a "difference of the squares" correction term for the liquid-vapor and solid-vapor interfacial tensions. PMID- 21546036 TI - Interaction via in situ binding of CdS nanorods onto gelatin. AB - In situ interaction of CdS nanorods (CdSNRs) with gelatin was investigated at pH 12.0. UV-Visible, FT-IR, scanning electron microscopy, dynamic light scattering, synchronous fluorescence, and three-dimensional fluorescence spectroscopy methods were used. It was found that negatively charged CdSNRs quenched the synchronous fluorescence of gelatin by forming a CdS/gelatin complex. The synchronous fluorescence quenching data were analyzed according to Scatchard equation, and the binding constants and corresponding thermodynamic parameters DeltaH, DeltaG, and DeltaS at three different temperatures were calculated. Small positive enthalpy (DeltaH) and entropy (DeltaS) values indicate that both electrostatic and hydrophobic forces played the major roles in the binding reaction of CdSNRs with gelatin. The effect of CdSNRs on the conformation of gelatin was also analyzed from both synchronous fluorescence and three-dimensional fluorescence spectra. The results provide useful information for exploring the chemical mechanism of interaction between nanomaterials and fibrous protein. PMID- 21546037 TI - Specific vapor sorption properties of phosphorus-containing dendrimers. AB - Specific combination of guest sorption properties was observed for phosphorus containing dendrimers, which distinguish them from ordinary polymers and clathrate-forming hosts. The sorption capacity for 30 volatile guests, binding reversibility, guest desorption kinetics and guest exchange, glass transition behavior and ability to be plasticized with guest were studied for phosphorus dendrimers of different generations (G(1)-G(4) and G(9)) using quartz crystal microbalance sensor, FTIR microspectroscopy, atomic force microscopy, simultaneous thermogravimetry and differential scanning calorimetry combined with mass-spectrometry of evolved vapors. The dendrimers were found to have a different selectivity for different homological series of guests, high glass transition points without plasticization with guest even at high temperatures and saturation levels, moderate guest-binding irreversibility and ability both for effective guest exchange and independent guest sorption. These properties constitute an advantage of the studied dendrimers as receptor materials in various applications. PMID- 21546038 TI - Effects of semantic elaboration and typicality on picture naming in Alzheimer disease. AB - PURPOSE: Individuals with probable Alzheimer disease (pAD) are frequently impaired at picture naming. This study examined whether a semantic elaboration task would facilitate naming in pAD, and whether training either semantically typical or atypical stimulus items facilitated generalized improvement in picture naming and category generation tasks. METHODS: Twelve adults with mild-moderate pAD participated in the study. Participants performed an experimental semantic elaboration training task using a subset of typical items from one category and atypical items from another category. The third category, acted as a control (i.e., no items were trained). The study assessed change in category generation and a picture naming within the three target categories. RESULTS: Individuals showed significantly improved category generation and naming, but changes were not limited to trained categories. Naming of trained atypical items improved significantly. Participants showed significantly improved naming of untrained typical items from categories trained with typical items. CONCLUSIONS: Semantic elaboration of typical items within a semantic category can lead to generalized improvement in other typical items in the category in mild-moderate pAD. This is consistent with theories postulating that typical category items share overlapping distributed representations. Further exploration of the effects of semantic elaboration on word-finding in pAD is warranted, especially the possibility of within-category generalization. PMID- 21546040 TI - Diminished emotional sweating in patients with limbic encephalitis. AB - OBJECTIVE: Sweating on the palms of the hands and soles of the feet, so-called emotional sweating, is considered to be mediated by the limbic system, including the amygdala and anterior cingulate cortex. To reveal involvement of the limbic system in emotional sweating, we evaluated emotional sweating on the palms in patients with limbic encephalitis. METHODS: Sweat and skin vasoconstriction responses to arousal stimuli were recorded on the palms of 7 patients with limbic encephalitis caused by viral infection (n=3) or immune-mediated encephalitis (n=4). All patients had amnesia, and magnetic resonance imaging revealed mesial temporal lobe lesions, including those on the amygdala, in 6 of these patients. RESULTS: Sweat responses were absent or markedly reduced in patients with limbic encephalitis compared to normal controls following deep inspiration (p<0.05), mental arithmetic (p<0.01), exercise (p<0.05), and tactile stimulation (p<0.01). Skin vasoconstriction responses in these patients were also impaired, but the extent of such impairment was mild compared to that of the sweating reductions. CONCLUSION: Sweating on the palm was significantly impaired in patients with mesial temporal lesions. Sweating on the palm could be a useful index of limbic function. PMID- 21546039 TI - Assessment of auditory brainstem function in lead-exposed children using stapedius muscle reflexes. AB - The purpose of this study was to investigate the neurological integrity and physiological status of the auditory brainstem tracts and nuclei in children with chronic lead (Pb) exposure using non-invasive acoustic stapedius reflex (ASR) measurements of afferent and efferent-neuromuscular auditory function. Following audiological examinations, uncrossed (ipsilateral) and crossed (contralateral) brainstem ASR responses were evoked by pure tone (500, 1000, and 2000 Hz), and broadband noise (bandwidth: 125-4000 Hz) stimulus activators. The ASR threshold (ASRT), amplitude growth, and decay/fatigue were measured by conventional clinical middle ear immittance methods in a group of Andean children (age range: 2-18 years) with a history of chronic environmental Pb exposure from occupational Pb glazing. Blood lead (PbB) levels of the study group (n=117) ranged from 4.0 to 83.7 MUg/dL with a mean PbB level of 33.5 MUg/dL (SD: 23.6; median: 33.0: CDC III Classification). The PbB distribution data indicated that 77.8% (n=91) of the children had PbB levels greater than the CDC action line of 10 MUg/dL. Repeatable, normal ASRTs were elicited for ipsilateral (mean: <=90 dB HL) and contralateral (mean: <=97 dB HL) stimulation for each acoustic activator. Spearman Rho correlation analysis indicated no significant association between PbB level and ipsilateral or contralateral ASRT for any of the stimulus activators. The ASR amplitude growth results showed typical growth functions with no Pb-associated aberrations. No statistical association was found between ASR decay/adaptation (ASRD) and PbB level for any of the stimulus activators. The results of stapedius muscle reflex testing using several stimulus activators showed no significant relationship between PbB level and the physiological integrity of the auditory brainstem mediated ASR responses in children with chronic Pb exposure and elevated PbB levels. PMID- 21546041 TI - Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males. AB - BACKGROUND: Hereditary spastic paraplegia (HSP) is characterised in its pure form by slowly progressive spastic paraparesis. Around 40% of autosomal dominant (AD) cases are caused by mutations in SPAST, encoding spastin. PATIENTS AND METHODS: The clinical and investigation details of all patients with a SPAST mutation identified through our centre were reviewed. All published reports of SPAST mutations where the sex of patients was given were subsequently analysed in order to determine whether there is evidence of one sex being preferentially affected. RESULTS: In total 22 probable pathogenic changes were detected, including 11 novel ones. One patient carried two adjacent missense mutations. The pathogenicity of a further novel missense mutation is uncertain. Most patients had a pure phenotype, although mild peripheral neuropathy was sometimes present. The total number of patients with SPAST mutations was 27, as three of the previously known mutations were present in more than one person. The excess of males over females in our population (17:10) prompted us to review all published studies where the sex of the patients was given (n=31). A significant excess of males was identified (ratio 1.29, p=0.0007). CONCLUSIONS: Our results are consistent with data suggesting that SPAST mutations mostly cause a pure HSP phenotype. The excess of males in our sample and in published reports suggests that penetrance or severity may be sex-dependent, and merits further investigation as it may have important implications for counselling. PMID- 21546042 TI - [Outpatient parenteral antimicrobial therapy for Staphylococcus aureus bacteremia]. PMID- 21546043 TI - Odd-chain polyunsaturated fatty acids in thraustochytrids. AB - A series of unusual odd-chain fatty acids (OC-FA) were identified in two thraustochytrid strains, TC 01 and TC 04, isolated from waters off the south east coast of Tasmania, Australia. FA compositions were determined by capillary GC and GC-MS, with confirmation of polyunsaturated fatty acids (PUFA) structure performed by analysis of 4,4-dimethyloxazoline derivatives. PUFA constituted 68 74% of the total FA, with the essential PUFA; eicosapentaenoic acid (20:5omega3, EPA), arachidonic acid (20:4omega6, AA) and docosahexaenoic acid (22:6omega3, DHA), accounting for 42-44% of the total FA. High proportions of the saturated OC FA 15:0 (7.1% in TC 01) and 17:0 (6.2% in TC 04) were detected. The OC-FA 17:1omega8 was present at 2.8% in TC 01. Of particular interest, the C21 PUFA 21:5omega5 and 21:4omega7 were detected at 3.5% and 4.1%, respectively, in TC 04. A proposed biosynthesis pathway for these OC-PUFA is presented. It is possible that the unsaturated OC-PUFA found previously in a number of marine animals were derived from dietary thraustochytrids and they could be useful biomarkers in environmental and food web studies. PMID- 21546044 TI - Demonstration of the absence of intervening sequences (IVSs) within 16S rRNA genes of Taylorella equigenitalis and Taylorella asinigenitalis isolates. AB - A total of 57 Taylorella equigenitalis (n=22) and Taylorella asinigenitalis (n=35) isolates was shown not to carry any intervening sequences (IVSs) within 16S rRNA gene sequences. By contrast, we have already shown the genus Taylorella group to carry several kinds of IVSs within the 23S rRNA gene sequences. PMID- 21546045 TI - Detection of herpesvirus DNA in Arctic foxes (Vulpes lagopus; syn. Alopex lagopus) with fatal encephalitis. AB - A captive breeding programme for the Fennoscandian Arctic fox (Vulpes lagopus; syn. Alopex lagopus) failed due to fatal encephalitis. The aim of this study was to identify the causative agent. Viral nucleic acid was detected by PCR and in situ hybridization in the brain of affected foxes. The results suggest that a herpesvirus might be the causative agent. Whether this infection also occurs in free-living Arctic foxes is unknown. PMID- 21546046 TI - [Management of brain metastases from non-small cell lung carcinoma]. AB - INTRODUCTION: In France, approximately 30,000 new patients per year develop brain metastases (BM), most of them resulting from a lung cancer. STATE OF THE ART: Surgery and radiosurgery of all the BM must be considered when possible. In other cases, whole brain radiotherapy remains the standard of care. PERSPECTIVES: The role of chemotherapy, poorly investigated so far, should be revisited. CONCLUSION: This review focused on BM secondary to a non-small cell lung carcinoma. PMID- 21546047 TI - Autosomal dominant cerebellar ataxias. AB - Cerebellar ataxias with autosomal dominant transmission (ADCA) are far rarer than sporadic cases of cerebellar ataxia. The identification of genes involved in dominant forms has confirmed the genetic heterogeneity of these conditions and of the underlying mechanisms and pathways. To date, at least 28 genetic loci and, among them, 20 genes have been identified. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes more complex multisystemic neurological deficits. Seven ADCA (SCA1, 2, 3, 6, 7, 17, and dentatorubro-pallido luysian atrophy) are caused by repeat expansions in the corresponding proteins; phenotype-genotype correlations have shown that repeat size influences the progression of the disease, its severity and clinical differences among patients, including the phenomenon of anticipation between generations. All other ADCA are caused either by non-coding repeat expansions, conventional mutations or large rearrangements in genes with different functions. This review will focus on the genetic features of ADCA and on the clinical differences among the different forms. PMID- 21546048 TI - Possible role of angiotensin-converting enzyme polymorphism on progression of hepatic fibrosis in chronic hepatitis C virus infection. AB - Many functional polymorphisms in the rennin-angiotensin system (RAS) have been described; these polymorphisms have been postulated to contribute to fibrosis in several diseases. Our aim was to study the frequency of ACE I/D polymorphism in chronic hepatitis C virus (HCV) infection and its association with liver fibrosis and response to treatment. This study included 90 patients with chronic hepatitis C. All patients received antiviral therapy in the form of pegylated interferon and ribavirin. Patients were grouped according to the stage of liver fibrosis by biopsy into: group 1 (fibrosis: 0 or 1); group 2 (fibrosis: 2 or 3) and group 3 (fibrosis: 4 or 5). The study included also 170 healthy subjects, as a control group. Polymerase chain reaction was carried out to detect the different ACE genotypes. The D/D genotype was significantly more prevalent among HCV patients compared to controls (65.6% vs 48.2%, P=0.006). Degree of necroinflammation was significantly higher among patients with I/I genotype when compared to patients with D/D genotype (P=0.04). No significant difference in the distribution of the ACE I/D genotypes between the fibrosis groups and between responders and non responders to interferon therapy. The D/D genotype may increase the susceptibility to infection with hepatitis C. PMID- 21546049 TI - An approach to improve the separation of solid-liquid suspensions in inclined plate settlers: CFD simulation and experimental validation. AB - The most important requirements for achieving effective separation conditions in inclined plate settler (IPS) are its hydraulic performance and the equal distribution of suspensions between settler channels, both of which depend on the inlet configuration. In this study, three different inlet structures were used to explore the effect of feeding a bench scale IPS via a nozzle distributor on its hydraulic performance and separation efficiency. Experimental and Computational Fluid Dynamic (CFD) analyses were carried out to evaluate the hydraulic characteristics of the IPS. Comparing the experimental results with the predicted results by CFD simulation implies that the CFD software can play a useful role in studying the hydraulic performance of the IPS by employing residence time distribution (RTD) curves. The results also show that the use of a nozzle distributor can significantly enhance the hydraulic performance of the IPS, which contributes to the improvement of its separation efficiency. PMID- 21546050 TI - Endocrine disrupting activities in sewage effluent and river water determined by chemical analysis and in vitro assay in the context of granular activated carbon upgrade. AB - As part of endocrine disruption in catchments (EDCAT) programme, this work aims to assess the temporal and spatial variations of endocrine disrupting chemicals (EDCs) in River Ray, before and after the commissioning of a full-scale granular activated carbon (GAC) plant at a sewage treatment works (STW). Through spot and passive sampling from effluent and river sites, estrogenic and anti-androgenic activities were determined by chemical analysis and in vitro bio-assay. A correlation was found between chemical analyses of the most potent estrogens (estrone (E1), 17beta-estradiol (E2), 17alpha-ethinylestradiol (EE2)) and yeast estrogen screen (YES) measurement, both showing clearly a reduction in estrogenic activity after the commissioning of the GAC plant at the STW. During the study period, the annual average concentrations of E1, E2 and EE2 had decreased from 3.5 ng L(-1), 3.1 ng L(-1) and 0.5 ng L(-1) to below their limit of detection (LOD), respectively, with a concentration reduction of at least 91%, 81% and 60%. Annual mean estrogenic activity measured by YES of spot samples varied from 1.9 ng L(-1) to 0.4 ng L(-1) E2 equivalent between 2006 and 2008 representing a 79% reduction. Similarly, anti-androgenic activity measured by yeast anti-androgen screen (anti-YAS) of spot samples was reduced from 148.8 to 22.4 MUg flutamide L( 1), or by 85%. YES and anti-YAS values were related to each other, suggesting co existence of both types of activities from chemical mixtures in environmental samples. The findings confirm the effectiveness of a full-scale GAC in removing both estrogenic and anti-androgenic activities from sewage effluent. PMID- 21546051 TI - The water-soluble fraction of potentially toxic elements in contaminated soils: relationships between ecotoxicity, solubility and geochemical reactivity. AB - To better understand the impacts posed by soil contamination to aquatic ecosystems it is crucial to characterise the links between ecotoxicity, chemical availability and geochemical reactivity of potentially toxic elements (PTE's) in soils. We evaluated the adverse effects of water extracts obtained from soils contaminated by chemical industry and mining, using a test battery including organisms from different trophic levels (bacteria, algae and daphnids). These tests provided a quick assessment of the ecotoxicity of soils with respect to possible adverse effects on aquatic organisms although the ecotoxicological responses could be related to the solubility of PTE's only to a limited extent. The analysis of results of bioassays together with the chemical characterisation of water extracts provided additional relevant insight into the role of conductivity, pH, Al, Fe, and Mn of soil extracts on toxicity to organisms. Furthermore, an important conclusion of this study was that the toxicity of extracts to the aquatic organisms could also be related to the soil properties (pH, Org C and Fe(ox)) and to the reactivity of PTE's in soils which in fact control the soluble fraction of the contaminants. The combined assessment of ecotoxicity in water fractions, solubility and geochemical reactivity of PTE's in soils provided a more comprehensive understanding of the bioavailability of inorganic contaminants than ecotoxicological or chemical studies alone and can therefore be most useful for environmental risks assessment of contaminated soils. PMID- 21546052 TI - Estimation of contribution from non-point sources to perfluorinated surfactants in a river by using boron as a wastewater tracer. AB - The contribution of non-point sources to perfluorinated surfactants (PFSs) in a river was evaluated by estimating their fluxes and by using boron (B) as a tracer. The utility of PFSs/B as an indicator for evaluating the impact of non point sources was demonstrated. River water samples were collected from the Iruma River, upstream of the intake of drinking water treatment plants in Tokyo, during dry weather and wet weather, and 13 PFSs, dissolved organic carbon (DOC), total nitrogen (TN), and B were analyzed. Perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluoroheptanoate (PFHpA), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUA), and perfluorododecanoate (PFDoDA) were detected on all sampling dates. The concentrations and fluxes of perfluorocarboxylates (PFCAs, e.g. PFOA and PFNA) were higher during wet weather, but those of perfluoroalkyl sulfonates (PFASs, e.g. PFHxS and PFOS) were not. The wet/dry ratios of PFSs/B (ratios of PFSs/B during wet weather to those during dry weather) agreed well with those of PFS fluxes (ratios of PFS fluxes during wet weather to those during dry weather), indicating that PFSs/B is useful for evaluating the contribution from non-point sources to PFSs in rivers. The wet/dry ratios of PFOA and PFNA were higher than those of other PFSs, DOC, and TN, showing that non-point sources contributed greatly to PFOA and PFNA in the water. This is the first study to use B as a wastewater tracer to estimate the contribution of non-point sources to PFSs in a river. PMID- 21546053 TI - Evaluation of ABC efflux transporters genes expression in kidney of rainbow trout (Oncorhynchus mykiss) fed with melamine and cyanuric acid diets. AB - Gene expression experiments were targeted in order to monitor the ABC efflux transporters, which is potentially involved in cellular detoxification/defense. Changes in expression levels of different ABC genes in kidney of Oncorhynchus mykiss fed with melamine and melamine+cyanuric acid enriched diets were recorded in both treated groups by mRNA DeltaDelta(CT) relative quantification method. Expression profiles of eight different ABC genes basically showed low alterations in melamine group and more consistent changes in melamine+cyanuric acid treated fish, compared with own control. In the last group ABCC2 gene over expression was the more evident alteration. These results suggest that ABC efflux system could be involved in mobilization of hydrophilic molecules in the forcing condition of chronic exposure. PMID- 21546054 TI - Polycyclic aromatic hydrocarbons and hydroxylated metabolites in the muscle tissue of Eurasian perch (Perca fluviatilis) through dietary exposure during a 56 day period. AB - Eurasian perch (Perca fluviatilis) was exposed trophically to phenanthrene, pyrene and benzo[a]pyrene. Accumulation kinetics in the muscle tissue of parent PAHs and hydroxylated metabolites were established for 56 days at 3 levels of exposure (0, 100 and 500 MUg/kg BW). Benzo[a]pyrene and 3-hydroxy-benzo[a]pyrene were not detected in the muscles. During exposure, there was an increase in phenanthrene, pyrene and their hydroxylated metabolites in the muscle tissue. Low transfer to muscle tissue was observed at equilibrium for phenanthrene (4.4+/ 0.6% and 2.7+/-0.8%) and pyrene (1.0+/-0.2% and 0.33+/-0.09%), depending on the concentrations in the spiked feed. PMID- 21546055 TI - A protocol for the evaluation of genotoxicity in bile of carp (Cyprinus carpio) exposed to lake water treated with different disinfectants. AB - A sensitive and rapid method to evaluate toxic and genotoxic properties of drinking water supplied from Lake Trasimeno (Umbria, Central Italy) was worked out analysing bile in Cyprinus carpio exposed for 20 d to lake water treated with 3 different disinfectants, sodium hypochlorite (NaClO), chlorine dioxide (ClO(2)) and peracetic acid (PAA). Fish were sacrificed at 0, 10 and 20 d in order to investigate the time course of these endpoints. An aliquot of bile samples was fractionated by adsorption on C(18) silica cartridges and the genotoxic potential of whole bile and of bile fractions was evaluated by the single-cell microgel electrophoresis (comet) assay on human colonic adenocarcinoma cells (Caco-2). Bile (both whole and fractionated) from specimens exposed to the three disinfectants always showed a genotoxic activity as compared to the control group. The results of this study provide evidence that all three disinfectants cause an increase in bile genotoxicity of chronically exposed fish. PMID- 21546056 TI - The behavior of PCDD and PCDF during thermal treatment of waste incineration ash. AB - The polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) content of three fly ash samples with different elemental compositions from different municipal waste incinerators were analyzed before and after thermal treatment at 300 degrees C or 500 degrees C. Gas phase emissions during the treatments were also collected and analyzed. Substantial reductions in the total PCCD/F content of the ashes were observed after treatment at 500 degrees C, seemingly due to degradation rather than dechlorination. Treatment at 300 degrees C resulted in an increase in the PCDD/F content of the three ashes. Initial concentration of PCDD/F in the untreated ashes did not reflect the outcome of the treatment at the different temperatures. In addition, the composition of the ash was found to influence the rate of decomposition and formation of PCDD and PCDF during thermal treatment; the results showed that Cu, Fe, Ca and S play important roles in these processes. PMID- 21546057 TI - Bromination of 2-methoxydiphenyl ether to an average of tetrabrominated 2 methoxydiphenyl ethers. AB - Brominated 2-phenoxyanisoles (2-methoxydiphenyl ethers, 2-MeO-BDEs) are a class of halogenated natural products, produced by algae and sponges. Especially two tetrabrominated isomers, i.e. 2'-MeO-BDE 68 (BC-2) and 6-MeO-BDE 47 (BC-3), have also been frequently determined in environmental and food samples. In addition, 2 MeO-BDEs are under discussion as metabolites of polybrominated diphenyl ethers (PBDEs). In this study, we synthesized the backbone 2-methoxydiphenyl ether and brominated it to an average degree of four bromine substituents. The reaction mixture only contained one major product (~90%) along with three further MeO-BDEs and ~5% hydroxylated BDEs. In all likelihood, the HO-BDEs were formed in a side reaction by cleavage of the methoxy group. The major MeO-BDE was identified as 6' methoxy-2,3',4,4'-tetrabromodiphenyl ether (6'-MeO-BDE-66). The HO-BDEs were separated by KOH/n-hexane partitioning, and the resulting 2-MeO-BDEs were fractionated by means of high-speed counter-current chromatography (HSCCC). Due to the excellent enrichment facilities of HSCCC, some 15 MeO-BDEs, mainly present at traces only, could be detected in 26 fractions, and eight of them could be characterized by nuclear magnetic resonance spectroscopy (NMR). Only two of the compounds--2'-MeO-BDE 68 and 6-MeO-BDE 123--had been characterized as natural products while the prominent halogenated natural product 6-MeO-BDE 47 was not detected at all in the reaction product. The "non-natural" 2-MeO-BDEs may be useful internal standards in trace analysis. PMID- 21546058 TI - The freshwater planarian Polycelis felina as a sensitive species to assess the long-term toxicity of ammonia. AB - Behavioural endpoints are a good link between physiological and ecological effects. However long-term behavioural endpoints are not uniformly studied over all different organism groups. For example behaviour has been scarcely studied in planarians. Unionized ammonia (NH(3)) is one of the most widespread pollutants in developed countries, and is known to alter animal behaviour. In this study a long term (30 d) bioassay was conducted to assess the effect of this pollutant on survival and behavioural activity (e.g. locomotion activity) of the freshwater planarian Polycelis felina. One control and three environmentally-realistic concentrations of unionized ammonia (treatments of 0.02, 0.05, and 0.09 mg N NH(3) L(-1)) were used in quintuplicate. The behaviour of planarians was measured after 0, 10, 20 and 30 d of ammonia exposure. Mortality was recorded every 2 d. Unionized ammonia increased mortality in the two highest NH(3) concentrations and the locomotory activity was depressed in all treatments after 20 d of exposure. Behavioural effect was observed at concentrations 20 times lower than the short term LC50 for this species. Previous studies proposed safe concentrations of unionized ammonia of 0.01-0.10 mg N-NH(3) L(-1) to aquatic ecosystems, but our study has shown that these concentrations will affect planarians. Because planarians play a key role in streams (as predator/scavenger), safe concentrations should be below 0.02 mg N-NH(3) L(-1) to protect this species in the freshwater community. Our results can contribute to improve the knowledge about ammonia toxicity to freshwater ecosystems, we recommend that safe concentrations of unionized ammonia should be based on very sensitive species. PMID- 21546059 TI - Levels of polybrominated diphenyl ethers and hexabromocyclododecane in the atmosphere and tree bark from Beijing, China. AB - Air samples in four seasons at one site and tree bark samples from four districts were determined to investigate seasonal variation and regional distribution of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) in Beijing, China. The total concentrations of PBDEs (?PBDE) and HBCD (?HBCD) were in the range of 57-470 and 20-1800 pg m(-3) in the atmosphere, respectively. The ?PBDE and ?HBCD concentrations were significantly influenced by the total suspended particulate matter in atmosphere. The total concentrations of PBDEs and HBCD in tree bark samples were in the range of 99-3700 and 26-3400 ng g(-1) lipid weight. It was found that regional distribution of PBDEs and HBCD was related to the function of each district. In addition, the study found that weeping willow bark was an ideal atmospheric PBDEs and HBCD passive sampler. Finally, atmospheric levels of BDE-209 and HBCD at tree bark sampling districts were estimated via applying an established bark/air partitioning model, which had been verified by the measured concentrations in tree bark and atmosphere in Beijing. PMID- 21546060 TI - Vertical profiles of aerosol absorption coefficient from micro-Aethalometer data and Mie calculation over Milan. AB - Vertical profiles of aerosol number-size distribution and black carbon (BC) concentration were measured between ground-level and 500m AGL over Milan. A tethered balloon was fitted with an instrumentation package consisting of the newly-developed micro-Aethalometer (microAeth(r) Model AE51, Magee Scientific, USA), an optical particle counter, and a portable meteorological station. At the same time, PM(2.5) samples were collected both at ground-level and at a high altitude sampling site, enabling particle chemical composition to be determined. Vertical profiles and PM(2.5) data were collected both within and above the mixing layer. Absorption coefficient (b(abs)) profiles were calculated from the Aethalometer data: in order to do so, an optical enhancement factor (C), accounting for multiple light-scattering within the filter of the new microAeth(r) Model AE51, was determined for the first time. The value of this parameter C (2.05+/-0.03 at lambda=880nm) was calculated by comparing the Aethalometer attenuation coefficient and aerosol optical properties determined from OPC data along vertical profiles. Mie calculations were applied to the OPC number-size distribution data, and the aerosol refractive index was calculated using the effective medium approximation applied to aerosol chemical composition. The results compare well with AERONET data. The BC and b(abs) profiles showed a sharp decrease at the mixing height (MH), and fairly constant values of b(abs) and BC were found above the MH, representing 17+/-2% of those values measured within the mixing layer. The BC fraction of aerosol volume was found to be lower above the MH: 48+/-8% of the corresponding ground-level values. A statistical mean profile was calculated, both for BC and b(abs), to better describe their behaviour; the model enabled us to compute their average behaviour as a function of height, thus laying the foundations for valid parametrizations of vertical profile data which can be useful in both remote sensing and climatic studies. PMID- 21546061 TI - Synthesis and toxicity of some metabolites of the microbial degradation of synthetic naphthenic acids. AB - Some ill-defined carboxylic acids, termed 'naphthenic acids' (NA), are best known as important constituents of the >720billionlitres of process-affected water associated with the expanding oil sands industries. Other NA are components of some immature and biodegraded crude oils and these may enter the environment via produced water discharges from oil production platforms. Yet others are used as biocides and in the manufacture of steel radial tyres and these may also enter the environment through disposal and/or weathering. The environmental fate of NA, including the mechanisms of biodegradation, therefore needs to be better understood. In order to better elucidate such mechanisms, previously we studied the biodegradation in the laboratory of some alkylcyclohexylbutanoic synthetic NA. However, we could only tentatively identify the metabolites produced. In the present study we report the synthesis and characterisation of six alkylcyclohexylethanoic NA. Each was characterised by gas chromatography-mass spectrometry (GC-MS; trimethylsilyl esters) and we show by co-chromatography that these were indeed the metabolites. Also, a preferential degradation of the trans- isomers was revealed. Assessment of the toxicity of the synthetic NA (Microtox assay), revealed that the relative toxicity of the alkylcyclohexylbutanoic acids was reduced by biotransformation to the alkylcyclohexylethanoic acids, as observed recently for the corresponding aromatic acids. Very recent studies have shown that at least one commercial NA mixture contains cyclohexylbutanoic and alkylcyclohexylethanoic acids, suggesting that the biotransformation of the acids studied herein may be quite relevant to the environmental fate of such acids. A similar study of the acid extractables of one oil sands process-affected water sample suggests that the synthetic acids may be less good 'models' for oil sands NA. The consortia of microbes present in oil sands process-affected water may also be different to those used herein. However, the heterogeneity of oil sands process water is well-known and further detailed studies will need to be made in order to establish whether degradation of oil sands NA proceeds by beta oxidation as observed for the acids herein, or whether the oil sands acids are more resistant to bioremediation. PMID- 21546062 TI - Wavelet and ANN combination model for prediction of daily suspended sediment load in rivers. AB - In this research, a new wavelet artificial neural network (WANN) model was proposed for daily suspended sediment load (SSL) prediction in rivers. In the developed model, wavelet analysis was linked to an artificial neural network (ANN). For this purpose, daily observed time series of river discharge (Q) and SSL in Yadkin River at Yadkin College, NC station in the USA were decomposed to some sub-time series at different levels by wavelet analysis. Then, these sub time series were imposed to the ANN technique for SSL time series modeling. To evaluate the model accuracy, the proposed model was compared with ANN, multi linear regression (MLR), and conventional sediment rating curve (SRC) models. The comparison of prediction accuracy of the models illustrated that the WANN was the most accurate model in SSL prediction. Results presented that the WANN model could satisfactorily simulate hysteresis phenomenon, acceptably estimate cumulative SSL, and reasonably predict high SSL values. PMID- 21546063 TI - Population-based normative values for the Australian/Canadian (AUSCAN) Hand Osteoarthritis Index: part 2. AB - OBJECTIVES: To develop population-based age- and gender-specific normative values for the pain, stiffness, and physical function subscales of the AUSCAN Index for benchmarking applications. METHODS: A scannable survey questionnaire capable of capturing AUSCAN Index data and demographic information was developed, pretested, and distributed to a stratified random sample of 36,000 members of the Australian general public generated by the Australian Electoral Commission. RESULTS: Age- and gender-specific AUSCAN normative values were estimated based on approximately 7300 subjects. Age-related differences were noted in all 3 AUSCAN subscales. In general, pain, stiffness, and difficulty with physical function percentiles increased with age. CONCLUSIONS: AUSCAN normative values provide opportunity for benchmarking the health status of individuals with hand osteoarthritis against their age- and gender-matched peers in the general population. These normative values provide unique opportunities for using the AUSCAN Index in benchmarking applications, in both clinical practice and research. PMID- 21546064 TI - Resolution of Behcet's syndrome associated pulmonary arterial aneurysms with infliximab. AB - INTRODUCTION: We describe the successful treatment of pulmonary arterial aneurysms in Behcet's syndrome using a tumor necrosis factor (TNF) inhibitor. METHODS: A case is reported of Behcet's syndrome complicated by pulmonary arterial aneurysms that responded to anti-TNF therapy. This is accompanied by a literature review of previously published cases. We searched the English language medical literature using the PubMed and Medline search terms: "Behcet's," "Pulmonary aneurysms," and "infliximab," "etanercept," or "adalimumab." RESULTS: A 43-year-old man with a 6-month history of oral and genital ulcers, weight loss, and fatigue developed arterial aneurysms in the common carotid and common iliac arteries and thromboses in a femoral vein and pulmonary arteries. Treatment with high-dose oral corticosteroids and pulsed intravenous cyclophosphamide was initiated but while on treatment he developed pulmonary arterial aneurysms with hemoptysis. His treatment was changed to intravenous infliximab with methotrexate to which he showed a good response with marked clinical improvement, reduction in his inflammatory markers, and regression of the pulmonary arterial aneurysms. The review of the literature identified 3 reported cases of treatment of pulmonary arterial aneurysms in Behcet's syndrome with anti-TNF therapy, with good outcomes in each case. CONCLUSIONS: Pulmonary artery aneurysms are important complications of Behcet's syndrome. Anti-TNF inhibitors should be considered in patients who do not respond to treatment with corticosteroids and cyclophosphamide. PMID- 21546065 TI - Population-based normative values for the Western Ontario and McMaster (WOMAC) Osteoarthritis Index: part I. AB - OBJECTIVES: To develop population-based age- and gender-specific normative values for the pain, stiffness, and physical function subscales of the WOMAC Index for benchmarking applications. METHODS: A scannable survey questionnaire capable of capturing WOMAC Index data and demographic information was developed, pretested, and distributed to a stratified random sample of 36,000 members of the Australian general public generated by the Australian Electoral Commission. RESULTS: Age- and gender-specific WOMAC normative values were estimated based on approximately 7300 subjects. Age-related differences were noted in all 3 WOMAC subscales. In general, pain, stiffness, and difficulty with physical function percentiles increased with age. CONCLUSIONS: WOMAC normative values provide opportunity for benchmarking the health status of individuals with hip and knee osteoarthritis against their age- and gender-matched peers in the general population. These normative values provide unique opportunities for using the WOMAC Index in benchmarking applications in both clinical practice and research. PMID- 21546066 TI - Correlation between CA-125 serum level and response by RECIST in a phase III recurrent ovarian cancer study. AB - OBJECTIVES: To evaluate in a large phase III recurrent ovarian cancer trial (OVA 301): 1) the concordance between CA-125 level vs. best overall response (OR) and progression-free survival (PFS) determined by radiological assessment 2) the impact of early CA-125 changes over the subsequent radiological response, and 3) the prognostic value of CA-125 response and CA-125 PFS to predict radiological response and PFS. METHODS: Assessment of response in the entire randomized population was performed by the Response Evaluation Criteria in Solid Tumors 1.0 (RECIST) and modified Rustin criteria for CA-125 determination. RESULTS: Most CA 125 decreases were observed in RECIST responders (82% of patients treated with the combination and 74% in the PLD alone). CA-125 progression preceded RECIST progression in 35% of patients with a median lead time of 8.4 weeks. A high concordance rate between CA-125 PFS status at 4 months (PFS4) and CA-125 response as a predictor of PFS4 (87%) and radiological response (79%) was found in the combination, with high positive predictive value for radiological PFS4 (92%) and high negative predictive value for OR (90%). An early CA-125 decrease was predictive for the ultimate response since it was found in a high rate of RECIST responders. CONCLUSION: Radiological response was preceded by a favorable predictive CA-125 decrease in a high proportion of patients, suggesting that CA 125 evaluation may be an appropriate tool for tumor assessment in patients with ovarian cancer. PMID- 21546067 TI - Summary of the 2011 Annual Meeting on Women's Cancers. PMID- 21546068 TI - Longitudinal decline in lung function in patients with primary immunoglobulin deficiencies. PMID- 21546069 TI - Asthma-associated polymorphisms in 17q21 influence cord blood ORMDL3 and GSDMA gene expression and IL-17 secretion. AB - BACKGROUND: In a genome-wide association study, genetic variants on chromosome 17q21 were strongly associated with childhood asthma and orosomucoid 1-like 3 (ORMDL3) gene expression. Regulation of the 17q21 locus and its immunologic relevance early in life have not been well characterized. OBJECTIVE: We investigated the relation between polymorphisms and mRNA expression of 17q21 locus genes and their influence on T-cell subsets in cord blood. METHODS: In 200 children of our cord blood study, 17q21 polymorphisms were genotyped by matrix assisted laser desorption ionization time-of-flight mass spectrometry. Gene expression was assessed for ORMDL3; gasdermin A (GSDMA, alias GSDM1); gasdermin B (GSDMB, alias GSDML); Ikaros family zinc finger 3 (ZNFN1A3), zona pellucida binding protein 2 (ZPBP2); and proteasome (prosome, macropain) 26S subunit, non ATPase, 3 (PSMD3), in cord blood mononuclear cells (CBMCs) and for ORMDL3 in peripheral blood (real-time RT-PCR). Mononuclear cells were assessed before and after microbial (lipid A/peptidoglycan), phytohemagglutinin, or allergen (Der p 1) stimulation. Regulatory T-associated markers (forkhead box protein 3, glucocorticoid-induced TNF receptor, lymphocyte activation gene 3 mRNA expression) and T(h)2/T(h)1/T(h)17 cytokines were examined. RESULTS: In CBMCs, single genetic risk variants within 17q21 were associated with increased ORMDL3 (Der p 1 stimulation; P <= .01) and GSDMA expression (phytohemagglutinin/Der p 1 stimulation; P <= .05). Children homozygous for all 4 risk alleles for 17q21 tagging single nucleotide polymorphisms showed increased expression for ORMDL3 (Der p 1; P = .002) and GSDMA (phytohemagglutinin; P = .0009/Der p 1; P = .004). CBMC ORMDL3 expression was lower compared with PBMCs (P <= .0003) and increased in both CBMC and PBMC after stimulation (phytohemagglutinin/lipid A/peptidoglycan/Der p 1; P <= .006 and phytohemagglutinin/peptidoglycan; P < .05, respectively). No correlation between 17q21 polymorphisms and regulatory T/T(h)2/T(h)1 lineages was detectable. However, 17q21 risk allele carriers showed significantly increased IL-17 secretion (unstimulated, phytohemagglutinin stimulated). CONCLUSION: Our results suggest an association of 17q21 polymorphisms with ORMDL3, GSDMA expression, and IL-17 secretion early in life. These observations may imply a functional role of the 17q21 locus affecting T cell development during immune maturation. PMID- 21546070 TI - Successful allogeneic hematopoietic stem cell transplantation for DOCK8 deficiency. PMID- 21546071 TI - Rapid oral desensitization in combination with omalizumab therapy in patients with cow's milk allergy. PMID- 21546072 TI - Usefulness of simultaneous EEG-NIRS recording in language studies. AB - One of the most challenging tasks in neuroscience in language studies, is investigation of the brain's ability to integrate and process information. This task can only be successfully addressed by applying various assessment techniques integrated into a multimodal approach. Each of these techniques has its advantages and disadvantages, but help to elucidate certain aspects of the capacity of neural networks to process information. These methods provide information about changes in electrical, hemodynamic and metabolic activities. Ideally, they should be noninvasive in order to facilitate their use particularly in children. In the present review, we describe the advantages of simultaneous electroencephalographic (EEG) acquisition with near infrared spectroscopy (NIRS) to provide a better understanding of the mechanisms involved in cerebral activation. This coregistration is also useful to avoid misleading interpretation of NIRS, notably during the various phases of sleep. Development and implementation of the various tools required and assessment strategies are also discussed. PMID- 21546073 TI - The role of the ventral and dorsal pathways in reading Chinese characters and English words. AB - Previous literature in alphabetic languages suggests that the occipital-temporal region (the ventral pathway) is specialized for automatic parallel word recognition, whereas the parietal region (the dorsal pathway) is specialized for serial letter-by-letter reading (Cohen et al., 2008; Ho et al., 2002). However, few studies have directly examined the role of the ventral and dorsal pathways in Chinese reading compared to English reading. To investigate this issue, we adopted the degraded word processing paradigm used by Cohen et al. (2008) and compared brain regions involved in the processing of degraded Chinese characters and English words during lexical decision, using functional magnetic resonance imaging (fMRI). The degraded characters/words were created by inserting blank spaces between radicals of Chinese characters or syllables of English polysyllabic words. Generally, the current study replicated the effects of Cohen et al. (2008), showing that in Chinese - like in alphabetic languages - character spacing modulates both ventral (bilateral cuneus, left middle occipital gyrus) and dorsal (left superior parietal lobule and middle frontal gyrus) pathways. In addition, the current study showed greater activation in bilateral cuneus and right lingual gyrus for Chinese versus English when comparing spaced to normal stimuli, suggesting that Chinese character recognition relies more on ventral visual-spatial processing than English word recognition. Interestingly, bilateral cuneus showed monotonic patterns in response to increasing spacing, while the rest of the regions of interest showed non-monotonic patterns, indicating different profiles for these regions in visual-spatial processing. PMID- 21546074 TI - Shedding light on words and sentences: near-infrared spectroscopy in language research. AB - Investigating the neuronal network underlying language processing may contribute to a better understanding of how the brain masters this complex cognitive function with surprising ease and how language is acquired at a fast pace in infancy. Modern neuroimaging methods permit to visualize the evolvement and the function of the language network. The present paper focuses on a specific methodology, functional near-infrared spectroscopy (fNIRS), providing an overview over studies on auditory language processing and acquisition. The methodology detects oxygenation changes elicited by functional activation of the cerebral cortex. The main advantages for research on auditory language processing and its development during infancy are an undemanding application, the lack of instrumental noise, and its potential to simultaneously register electrophysiological responses. Also it constitutes an innovative approach for studying developmental issues in infants and children. The review will focus on studies on word and sentence processing including research in infants and adults. PMID- 21546075 TI - The cost of dengue control. PMID- 21546076 TI - Dengue vector control strategies in an urban setting: an economic modelling assessment. AB - BACKGROUND: An estimated 2.5 billion people are at risk of dengue. Incidence of dengue is especially high in resource-constrained countries, where control relies mainly on insecticides targeted at larval or adult mosquitoes. We did epidemiological and economic assessments of different vector control strategies. METHODS: We developed a dynamic model of dengue transmission that assesses the evolution of insecticide resistance and immunity in the human population, thus allowing for long-term evolutionary and immunological effects of decreased dengue transmission. We measured the dengue health burden in terms of disability adjusted life-years (DALYs) lost. We did a cost-effectiveness analysis of 43 insecticide-based vector control strategies, including strategies targeted at adult and larval stages, at varying efficacies (high-efficacy [90% mortality], medium-efficacy [60% mortality], and low-efficacy [30% mortality]) and yearly application frequencies (one to six applications). To assess the effect of parameter uncertainty on the results, we did a probabilistic sensitivity analysis and a threshold analysis. FINDINGS: All interventions caused the emergence of insecticide resistance, which, with the loss of herd immunity, will increase the magnitude of future dengue epidemics. In our model, one or more applications of high-efficacy larval control reduced dengue burden for up to 2 years, whereas three or more applications of adult vector control reduced dengue burden for up to 4 years. The incremental cost-effectiveness ratios of the strategies for two high-efficacy adult vector control applications per year was US$615 per DALY saved and for six high-efficacy adult vector control applications per year was $1267 per DALY saved. Sensitivity analysis showed that if the cost of adult control was more than 8.2 times the cost of larval control then all strategies based on adult control became dominated. INTERPRETATION: Six high-efficacy adult vector control applications per year has a cost-effectiveness ratio that will probably meet WHO's standard for a cost-effective or very cost-effective intervention. Year-round larval control can be counterproductive, exacerbating epidemics in later years because of evolution of insecticide resistance and loss of herd immunity. We suggest the reassessment of vector control policies that are based on larval control only. FUNDING: The Fulbright Programme, CAPES (Brazilian federal agency for post-graduate education), the Miriam Burnett trust, and the Notsew Orm Sands Foundation. PMID- 21546077 TI - Effects of temperature on cellular and biochemical parameters in the crab Carcinus aestuarii (Crustacea, Decapoda). AB - The effects of temperature on cellular and biochemical parameters of the crab Carcinus aestuarii were evaluated. Crabs were kept for 7 days at 4, 17 (reference value) and 30 degrees C (salinity of 35 psu), and total haemocyte count (THC), haemocyte volume, haemocyte proliferation, phenoloxidase (PO) activity in both haemocyte lysate (HL) and cell-free haemolymph (CFH), CFH total protein and glucose levels, superoxide dismutase (SOD) and catalase (CAT) activities in both gills and digestive gland were evaluated. The lowest and the highest temperature significantly decreased THC, whereas haemocyte volume and haemolymph glucose concentration did not differ significantly among experimental conditions. Haemolymph protein concentration significantly reduced in crabs maintained at 30 degrees C, when compared with that of animals kept at 4 and 17 degrees C. Haemocyte proliferation increased significantly in crabs kept at 4 and 30 degrees C, when compared with that of crabs held at 17 degrees C. Likewise, a significantly higher PO activity was recorded in CFH from crabs kept at 4 and 30 degrees C, than in control crabs. Conversely, PO activity did not vary significantly in HL. With regard to antioxidant enzyme activities, a significant decrease in CAT activity was observed in gills from crabs kept at 4 degrees C, when compared to that of crabs kept at 17 degrees C and 30 degrees C. Results obtained demonstrated that the highest and lowest temperature tested influenced crab biological responses, and indicated that C. aestuarii modulated its cellular and biochemical parameters (mainly haemocyte proliferation, CFH protein concentrations and CFH PO activity) in order to cope with temperature. PMID- 21546078 TI - A phosphorylcholine-modified chitosan polymer as an endothelial progenitor cell supporting matrix. AB - The aim of the present study was to develop a new biopolymer to increase endothelial progenitor cells (EPC) survival and amplification. As a cell culture platform, bone marrow-derived cells (BMDC) were used to investigate the biocompatibility of chitosan-phosphorylcholine (CH-PC). On CH-PC, BMDC were found in colonies with a mortality rate similar to that of fibronectin (FN), the control matrix. Adhesion/proliferation assays demonstrated a greater number of BMDC on CH-PC after 7 days with an amplification phase occurring during the second week. Difference in adhesion mechanisms between (CH-PC) and the control FN matrix suggest distinctive cell retention ability. Confocal microscopy analyses confirmed that (CH-PC) supported the survival/differentiation of endothelial cells. Moreover, flow cytometry analyses demonstrated that, (CH-PC) increased the percentage of progenitor cells (CD117(+)CD34(+)) (7.1 +/- 0.8%, FN: 4.1 +/- 0.8%) and EPC (CD117(+)CD34(+)VEGFR-2(+)CD31(+)) (2.33 +/- 0.6%, FN: 0.25 +/- 0.1%), while the mesenchymal stem cell fraction (CD44(+)CD106(+)CD90(+)) was decreased (0.07 +/- 0.01%, FN: 0.55 +/- 0.22%). Polymeric substrate CH-PC might provide a suitable surface to promote the amplification of EPC for future vascular therapeutic applications. PMID- 21546079 TI - One-to-one quantum dot-labeled single long DNA probes. AB - Quantum dots (QDs) have been received most attention due to their unique properties. Constructing QDs conjugated with certain number of biomolecules is considered as one of the most important research goals in nanobiotechnology. In this study, we report polymerase chain reaction (PCR) amplification of primer oligonucleotides bound to QDs, termed as QD-based PCR. Characterization of QD based PCR products by gel electrophoresis and atomic force microscopy showed that QD-labeled long DNA strands were synthesized and only a single long DNA strand was conjugated with a QD. The QD-based PCR products still kept fluorescence properties. Moreover, the one-to-one QD-labeled long DNA conjugates as probes could detect a single-copy gene on maize chromosomes by fluorescence in situ hybridization. Labeling a single QD to a single long DNA will make detection of small single-copy DNA fragments, quantitative detection and single molecule imaging come true by nanotechnology, and it will promote medical diagnosis and basic biological research as well as nano-material fabrication. PMID- 21546080 TI - Multi-membrane chitosan hydrogels as chondrocytic cell bioreactors. AB - We investigated the bioactivity of new chitosan-based multi-membrane hydrogel (MMH) architectures towards chondrocyte-like cells. The microstructure of the hydrogels constituting the membranes precludes any living cell penetration, whereas their lower scale architecture allows the protein diffusion. The biological behavior of chondrocytes implanted within the MMH inter-membrane spaces was studied for 45 days in culture. Chondrocytes formed cell aggregates and proliferated without loosing their chondrogenic phenotype as illustrated by collagen II and aggrecan expressions at the mRNA and protein levels. Cells produced neo-formed alcyan blue matrix proteins filling MMH interspaces. The HiF 2alpha/SOX9 pattern of expression suggested that the elevated chondrocytic phenotype in MMH could be related to a better hypoxic local environment than in classical culture conditions. Pro-inflammatory markers were not expressed during the period of culture. The low level of nitric oxide accumulation within the inter-membrane spaces and in the incubation medium implied that chitosan consumed nitrites produced by entrapped chondrocytes, in relation with the decrease of its molecular weight of 50%. Our data suggest that MMH structures may be considered as complex chondrocytic cell bioreactors; "active decoys of biological media", potentially promising for various biomedical applications like the inter vertebral disk replacement. PMID- 21546081 TI - Fine tuning of receptor-selectivity for tumor necrosis factor-alpha using a phage display system with one-step competitive panning. AB - Tumor necrosis factor-alpha (TNF) is one of the attractive targets for the development of anti-inflammatory and anti-tumor drugs, because it is an important mediator in the pathogenesis of several inflammatory diseases and tumor progression. Thus, there is an increasing need to understand the TNF receptor (TNFR1 and TNFR2) biology for the development of TNFR-selective drugs. Nonetheless, the role of TNFRs, especially that of TNFR2, remains poorly understood. Here, using a unique competitive panning, we optimized our phage display-based screening technique for isolating receptor-selective TNF mutants, and identified several TNFR2-specific TNF mutants with high TNFR2 affinity and full bioactivity via TNFR2. Among these mutants, the R2-7 clone revealed very high TNFR2-selectivity (1.8 * 10(5) fold higher than that for the wild-type TNF), which is so far highest among the reported TNFR2-selective TNF mutants. Because of its high TNFR2-selectivity and full bioactivity, the TNF mutant R2-7 would not only help in elucidating the functional role of TNFR2 but would also help in understanding the structure-function relationship of TNF/TNFR2. In summary, our one-step competitive panning system is a simple, useful and effective technology for isolating receptor-selective mutant proteins. PMID- 21546082 TI - Multifunctional nanoassemblies for vincristine sulfate delivery to overcome multidrug resistance by escaping P-glycoprotein mediated efflux. AB - Multifunctional nanoassemblies (MNAs) were successfully developed for controlled delivery of water-soluble cationic vincristine sulfate (VCR) to overcome multidrug resistance (MDR). The incorporation of anionic small molecule of phosphatidylserine (PS) significantly enhanced the encapsulation efficiency of VCR in MNAs up to 94.4% by electrostatic interaction. Obvious sustained-release characteristics were found in VCR-loaded MNAs (VCR-MNAs) as the cumulative release of VCR was 83.2% at 96 h, and burst-release was effectively diminished. In vivo pharmacokinetics in rats following intravenous administration demonstrated that VCR-MNAs had higher AUC and longer t(1/2) than VCR solution (VCR-Sol). To investigate the MDR reversal effect and clarify the possible mechanism induced by MNAs, the cytotoxicity, cellular uptake and uptake mechanism experiments were performed in MCF-7 and P-glycoprotein over-expressing MCF-7/Adr cells, respectively. Compared with VCR-Sol, VCR-MNAs efficiently enhanced the cytotoxicity to 36.5-fold by increasing the cellular accumulation of VCR (12.6 fold higher) in MCF-7/Adr cells. The results of endocytosis inhibition experiment proved that VCR-MNAs were uptaken into the resistant cancer cells by clathrin- and caveolae-mediated endocytosis pathways, which escaped the efflux induced by P gp transporter and thereby overcame the MDR of VCR. PMID- 21546084 TI - mRNA induces RANTES production in trophoblast cells via TLR3 only when delivered intracellularly using lipid membrane encapsulation. AB - BACKGROUND: Trophoblasts express Toll-like receptor 3 (TLR3). The artificial TLR3 ligand, PolyI:C, induces an inflammatory response in trophoblasts but an endogenous ligand has not been identified. Notably, inflammatory disorders of pregnancy are associated with increased circulating placenta-derived mRNA. Endogenous degraded, uncapped mRNA is recognized by TLR3 in other cell lines. OBJECTIVE: We tested the hypothesis that plasma-derived mRNA induces an inflammatory response in a trophoblast cell line via TLR3. METHODS: Experiments were performed in the human first trimester extravillous trophoblast cell line HTR-8/SV neo. Plasma-derived mRNA was amplified using modified template switching and final in vitro transcription. We compared free mRNA (which favors cell surface interaction) to liposomally encapsulated mRNA (which favors intracellular mRNA delivery). We tested for the specific requirement of TLR3 signaling using siRNA. We tested for involvement of the canonical signaling pathway downstream of TLR3 by measuring NF-kappaB and IFN regulatory factor transcriptional activity using firefly-luciferase constructs. RESULTS: Free mRNA did not induce RANTES production. In contrast, liposomal mRNA resulted in marked induction of RANTES production (non-stimulated control 3.4 +/- 0.6 pg/mL, liposomal mRNA 169.7 +/- 26.2 pg/mL, p < 0.001), and this RANTES production was abolished by siRNA for TLR3. Downstream of TLR3, liposomal mRNA-induced dose-response NF-kappaB and IFN regulatory factor transcriptional activity, and IFN beta production. CONCLUSION: Plasma-derived 5' uncapped mRNA delivered intracellularly signals to induce NF kappaB activation and increase RANTES production via TLR3. PMID- 21546083 TI - Role of cellular uptake in the reversal of multidrug resistance by PEG-b-PLA polymeric micelles. AB - Understanding the processes involved in the cellular uptake of nanoparticles is critical for developing effective nano drug delivery systems. In this paper we found that PEG-b-PLA polymeric micelles firstly interacted with cell membrane using atomic force microscopy (AFM) and then released their core-loaded agents into the cell membrane by fluorescence resonance energy transfer (FRET). The released agents were internalized into the cells via lipid raft/caveolae-mediated endocytosis using total internal reflection fluorescence microscopy (TIRFM) and endocytic inhibitors. Further studies revealed that paclitaxel (PTX)-loaded PEG-b PLA micelles (M-PTX) increased the cellular accumulation of PTX in PTX-resistant human ovarian cell line A2780/T which resulted in more apoptosis as measured by flow cytometry and the cleavage of poly (ADP-ribose) polymerase (PARP) compared with free PTX. PEG-b-PLA micelles inhibited P-glycoprotein (Pgp) function and Pgp ATPase activity but had no effect on Pgp protein expression. The membrane microenvironment studies showed that PEG-b-PLA micelles induced cell membrane depolarization and enhanced membrane microviscosity. These results suggested that PEG-b-PLA micelles might inhibit Pgp function to reverse multidrug resistance (MDR) via interaction with cell membrane to affect the membrane microenvironment. This study provides a foundation for understanding the mechanism of reversing MDR by nanoparticles better and designing more effective nano drug carriers. PMID- 21546085 TI - Pregnancy-associated progenitor cells: an under-recognized potential source of stem cells in maternal lung. AB - Novel therapies are needed for the treatment of acute and chronic lung diseases, many of which are incurable. The use of exogenous stem cells has shown promise in both animal models and clinical trials. However, to date, the stem cell literature has under-recognized naturally acquired pregnancy-associated progenitor cells (PAPCs). These cells are found at sites of injury or disease in female tissues. They persist for decades after parturition in maternal blood and organs, with the largest number being found in the maternal lungs. Their presence there may be one explanation for the sex differences observed in the prevalence and prognosis of some lung diseases. Although the clinical significance of these cells is as yet unknown, the literature suggests that some of the PAPCs are stem cells or have stem cell-like properties. PAPCs harvested from the blood or organs of parous women could potentially be used as an alternate source of cells with regenerative properties for the woman herself or her children. Because PAPCs preferentially traffic to the maternal lung they may play a significant role in recovery or protection from lung disease. In this review article, we discuss ongoing research investigating the administration of both adult and placenta derived stem cells to treat lung disease, and how PAPCs may also play an important future therapeutic role. PMID- 21546086 TI - No association between the TP53 codon 72 polymorphism and risk or prognosis of Hodgkin and non-Hodgkin lymphoma. AB - The role of the TP53 gene's R72P polymorphism in non-Hodgkin lymphoma (NHL) has been analyzed in several studies but it has not been studied in Hodgkin lymphoma (HL). We have evaluated the role of R72P in 340 NHL and 298 HL patients. There was no difference in the R72P frequency between analyzed lymphoma cases and 749 controls. We found no association of R72P with the risk of NHL and HL development [OR(ArgPro/ProPro)=0.9 (95% CI 0.7-1.2) and 1.2 (95% CI 0.9-1.5), respectively] or with survival. Our results support the evidence that R72P is not a prognostic factor in Caucasian NHL patients, and they indicate its irrelevance for HL development or prognosis. PMID- 21546087 TI - Forensic child sexual abuse evaluations: assessing subjectivity and bias in professional judgements. AB - OBJECTIVES: Evaluators examining the same evidence often arrive at substantially different conclusions in forensic assessments of child sexual abuse (CSA). This study attempts to identify and quantify subjective factors that contribute to such disagreements so that interventions can be devised to improve the reliability of case decisions. METHODS: Participants included 1106 professionals in the field of child maltreatment representing a range of professional positions or job titles and years of experience. Each completed the Child Forensic Attitude Scale (CFAS), a 28-item survey assessing 3 forensic attitudes believed to influence professional judgments about CSA allegations: emphasis-on-sensitivity (i.e., a focus on minimizing false negatives or errors of undercalling abuse); emphasis-on-specificity (i.e., a focus on minimizing false positives or errors of overcalling abuse); and skepticism toward child and adolescent reports of CSA. A subset of 605 professionals also participated in 1 of 3 diverse decision exercises to assess the influence of the 3 forensic attitudes on ratings of case credibility. RESULTS: Exploratory factor analysis identified 4 factors or attitude subscales that corresponded closely with the original CFAS scales: 2 subscales for emphasis-on-sensitivity and 1 each for emphasis-on-specificity and skepticism. Attitude subscale scores differed significantly by sample source (in state trainings vs. national conferences), gender, years of experience, and professional position, with Child Protective Service workers unexpectedly more concerned about overcalling abuse and more skeptical of child disclosures than other professionals-a pattern of scores associated with an increased probability of disbelieving CSA allegations. The 3 decision exercises offered validation of the attitude subscales as predictors of professional ratings of case credibility, with adjusted R(2)s for the three exercises ranging from .06 to .24, suggesting highly variable effect sizes. CONCLUSIONS: Evaluator disagreements about CSA allegations can be explained, in part, by individual differences in 3 attitudes related to forensic decision-making: emphasis-on-sensitivity, emphasis-on specificity, and skepticism toward child reports of abuse. These attitudes operate as predispositions or biases toward viewing CSA allegations as likely true or likely false. Several strategies for curbing the influence of subjective factors are highlighted including self-awareness of personal biases and team approaches to assessment. PMID- 21546089 TI - The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. AB - PURPOSE: To determine whether different doses and dosing regimens of intravitreal vascular endothelial growth factor (VEGF) Trap-Eye are superior to focal/grid photocoagulation in eyes with diabetic macular edema (DME). DESIGN: Multicenter, randomized, double-masked, phase 2 clinical trial. PARTICIPANTS: A total of 221 diabetic patients with clinically significant macular edema involving the central macula. METHODS: Patients were assigned to 1 of 5 treatment regimens: 0.5 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then every 8 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then on an as-needed (PRN) basis; or macular laser photocoagulation. Assessments were completed at baseline and every 4 weeks thereafter. MAIN OUTCOME MEASURES: Mean change in visual acuity and central retinal thickness (CRT) at 24 weeks. RESULTS: Patients in the 4 VEGF Trap-Eye groups experienced mean visual acuity benefits ranging from +8.5 to +11.4 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters versus only +2.5 letters in the laser group (P <= 0.0085 for each VEGF Trap-Eye group vs. laser). Gains from baseline of 0+, 10+, and 15+ letters were seen in up to 93%, 64%, and 34% of VEGF Trap-Eye groups versus up to 68%, 32%, and 21% in the laser group, respectively. Mean reductions in CRT in the 4 VEGF Trap-Eye groups ranged from 127.3 to -194.5 MUm compared with only -67.9 MUm in the laser group (P = 0.0066 for each VEGF Trap-Eye group vs. laser). VEGF Trap-Eye was generally well tolerated. Ocular adverse events in patients treated with VEGF Trap-Eye were generally consistent with those seen with other intravitreal anti-VEGF agents. CONCLUSIONS: Intravitreal VEGF Trap-Eye produced a statistically significant and clinically relevant improvement in visual acuity when compared with macular laser photocoagulation in patients with DME. PMID- 21546090 TI - Rate and influence of respiratory virus co-infection on pandemic (H1N1) influenza disease. AB - OBJECTIVES: Many patients with influenza have more than one viral agent with co infection frequencies reported as high as 20%. The impact of respiratory virus copathogens on influenza disease is unclear. We sought to determine if respiratory virus co-infection with pandemic H1N1 altered clinical disease. METHODS: Respiratory samples from 229 and 267 patients identified with and without H1N1 influenza respectively were screened for the presence of 13 seasonal respiratory viruses by multiplex RT-PCR. Disease severity between coinfected and monoinfected H1N1 patients were quantified using a standardized clinical severity scale. Influenza viral load was calculated by quantitative RT-PCR. RESULTS: Thirty (13.1%) influenza samples screened positive for the presence of 31 viral copathogens. The most prominent copathogens included rhinovirus (61.3%), and coronaviruses (16.1%). Median clinical severity of both monoinfected and coinfected groups were 1. Patients coinfected with rhinovirus tended to have lower clinical severity (median 0), whereas non-rhinovirus co-infections had substantially higher clinical severity (median 2). No difference in H1N1 viral load was observed between coinfected and monoinfected groups. CONCLUSIONS: Respiratory viruses co-infect patients with influenza disease. Patients coinfected with rhinovirus had less severe disease while non-rhinovirus co infections were associated with substantially higher severity without changes in influenza viral titer. PMID- 21546088 TI - Complement in the brain. AB - The brain is considered to be an immune privileged site, because the blood-brain barrier limits entry of blood borne cells and proteins into the central nervous system (CNS). As a result, the detection and clearance of invading microorganisms and senescent cells as well as surplus neurotransmitters, aged and glycated proteins, in order to maintain a healthy environment for neuronal and glial cells, is largely confined to the innate immune system. In recent years it has become clear that many factors of innate immunity are expressed throughout the brain. Neuronal and glial cells express Toll like receptors as well as complement receptors, and virtually all complement components can be locally produced in the brain, often in response to injury or developmental cues. However, as inflammatory reactions could interfere with proper functioning of the brain, tight and fine tuned regulatory mechanisms are warranted. In age related diseases, such as Alzheimer's disease (AD), accumulating amyloid proteins elicit complement activation and a local, chronic inflammatory response that leads to attraction and activation of glial cells that, under such activation conditions, can produce neurotoxic substances, including pro-inflammatory cytokines and oxygen radicals. This process may be exacerbated by a disturbed balance between complement activators and complement regulatory proteins such as occurs in AD, as the local synthesis of these proteins is differentially regulated by pro inflammatory cytokines. Much knowledge about the role of complement in neurodegenerative diseases has been derived from animal studies with transgenic overexpressing or knockout mice for specific complement factors or receptors. These studies have provided insight into the potential therapeutic use of complement regulators and complement receptor antagonists in chronic neurodegenerative diseases as well as in acute conditions, such as stroke. Interestingly, recent animal studies have also indicated that complement activation products are involved in brain development and synapse formation. Not only are these findings important for the understanding of how brain development and neural network formation is organized, it may also give insights into the role of complement in processes of neurodegeneration and neuroprotection in the injured or aged and diseased adult central nervous system, and thus aid in identifying novel and specific targets for therapeutic intervention. PMID- 21546091 TI - Preliminary evidence for increased frontosubcortical activation on a motor impulsivity task in mixed episode bipolar disorder. AB - BACKGROUND: Of all mood states, patients in mixed episodes of bipolar disorder are at the greatest risk for impulsive behaviors including attempted suicide. The aim of this study was to examine whether the neural correlates of motor impulsivity are distinct in patients with mixed mania. METHODS: Ten patients with bipolar disorder in a mixed episode (BP-M), 10 bipolar comparison participants in a depressed episode (BP-D), and 10 healthy comparison (HC) participants underwent functional MRI while performing a Go/No-Go task of motor impulsivity. RESULTS: Both patient groups had elevated, self-rated motor impulsiveness scores. The BP-M group also had a trend-level increase in commission errors relative to the HC group on the Go/No-Go task. While the full sample strongly activated a ventrolateral prefrontal-subcortical brain network, the BP-M group activated the amygdala and frontal cortex more strongly than the HC group, and the thalamus, cerebellum, and frontal cortex more strongly than the BP-D group. LIMITATIONS: This study is primarily limited by a relatively small sample size. CONCLUSIONS: Higher commission error rates on the Go/No-Go task suggest increased vulnerability to impulsive responding during mixed episodes of bipolar disorder. Moreover, the distinct pattern of increased brain activation during mixed mania may indicate a connection between behavioral impulsivity and a failure of neurophysiological "inhibition", especially in the amygdala. PMID- 21546092 TI - Short self-reported sleep duration and suicidal behavior: a cross-sectional study. AB - BACKGROUND: Prior studies on the association between sleep disturbances and suicidal behavior did not explore whether or not short sleep is a marker of suicide intent, lethality or risk. METHODS: DESIGN: Cross-sectional. PARTICIPANTS: Suicide attempters (SAs) (n=434). Controls included 83 psychiatric inpatients who have never been SAs, and 509 healthy controls. MEASUREMENTS: Short sleep was defined by self-assessment as <= 5 h per day. The MINI and the DSM-IV version of the International Personality Disorder Examination Screening Questionnaire were used to diagnose Axis I and Axis II diagnoses, respectively. Suicide intent and lethality were evaluated through the Beck's Suicidal Intent Scale (SIS) and the Risk-Rescue Rating Scale (RRRS), respectively. Beck's Medical Lethality Scale (BMLS) was administered to assess the degree of medical injury, and the SAD PERSONS mnemonic scale was used to evaluate suicide risk. STATISTICAL ANALYSES: Chi-square tests and logistic regression analyses explored frequencies of short sleep in 3 samples. Chi-square tests explored whether or not suicide intent, lethality and risk were greater in SAs with short-sleep versus those without short-sleep. RESULTS: Short sleep was more prevalent in SAs than in psychiatric controls only in males. In female SAs, short sleep was significantly associated with several SIS items and high scores in the SAD PERSONS. LIMITATIONS: Sleep duration was assessed only by self-report. CONCLUSIONS: The association between short sleep and suicidal behavior may be partly explained by confounders. Short sleep may be a marker of severity of suicidal behavior among female SAs. PMID- 21546093 TI - Age at onset in Canadian OCD patients: mixture analysis and systematic comparison with other studies. AB - OBJECTIVE: This study aimed to determine the distributions of the age at onset (AAO) using mixture analysis and better develop the understanding of AAO as a clinical feature of obsessive-compulsive disorder. METHOD: Mixture analysis was used to identify sub-groups characterized by differences in AAO. Clinical features were analyzed for differences in AAO sub-groups using mixture analysis. Comparisons were made with AAO cut-offs used in previous studies using the 2 Sample Kolmogorov-Smirnov Test. RESULTS: Mixture analysis of our sample (n=196) yielded a combination of 2 normal theoretical distributions with means (SD) of 9.66 (3.12) for the early-onset sub-group and 21.1 (8.36) years for the late onset sub-group. The sub-groups were divided by a cut-off of 15 years. As expected, a negative correlation was found between AAO and duration of illness. The early-onset subjects had significantly lower age at the time of the assessment and they tended to have more often panic attacks but were treated less often with benzodiazepines and other anti-anxiety medications. The comparison analysis showed significant difference in the AAO distribution between our sample and four other study samples. CONCLUSIONS: Our findings support the notion that different AAO sub-groups correspond with differences in clinical presentations of obsessive-compulsive disorder. PMID- 21546094 TI - Demonstration of decreased gray matter concentration in the midbrain encompassing the dorsal raphe nucleus and the limbic subcortical regions in major depressive disorder: an optimized voxel-based morphometry study. AB - BACKGROUND: Previous neuroimaging studies in patients with major depressive disorder (MDD) have reported changes in several brain areas, such as the medial and dorsolateral orbital cortex, amygdala, hippocampus, and basal ganglia. However, the results of these studies are inconsistent, and relatively few studies have been conducted using voxel-based morphometry (VBM) to detect gray matter concentration (GMC) abnormalities in patients with MDD. METHODS: We examined 47 MDD patients and 51 healthy controls to investigate structural abnormalities using a 1.5 T magnetic resonance imaging system, which was normalized to a customized T1 template and segmented with optimized VBM. Analysis of covariance with age and gender as covariates was adopted for the VBM statistics; the level of statistical significance was set at P<0.05 for the corrected false discovery rate. RESULTS: Decreased GMC was found in MDD patients in the bilateral amygdalae, hippocampi, fusiform gyri, lingual gyri, insular gyri, middle-superior temporal gyri, thalami, cingulate gyri, the central lobule of the cerebellum, and the midbrain encompassing the dorsal raphe nuclei (DRN). LIMITATIONS: Half of our study subjects were taking antidepressants. This may have been a potential confounding factor if any of the medications affected cortical volume. CONCLUSIONS: The results suggest that the GMC of several regions associated with emotion regulation was lower in MDD patients. In particular, we found decreased GMC in the DRN. These findings may provide a better understanding of the anatomical properties of the neural mechanisms underlying the etiology of MDD. PMID- 21546095 TI - Finding social phobia patients from the Internet. AB - Patients with social phobia commonly resist face-to-face assessments, and a number of alternative assessment methods based on the Internet are being developed. The aim of this study was to identify patients with social phobia on the Internet and characterize their condition, using the Social Phobia Inventory (SPIN). In Stage I, this study recruited 1307 participants from the Internet, most of whom were well-educated young females, who had remained unmarried and unemployed. The Internet-based SPIN demonstrated excellent internal consistency (Cronbach's alpha=0.937) and good test-retest reliability (intraclass correlation coefficient=0.942). In Stage II, we examined the discriminant validity of the SPIN via structured telephone interviews. The area under the receiver operating characteristic curve used to discriminate social phobia was 0.871 with an optimal cut-off point of 24 on the total score for the SPIN. According to the SPIN scores, 919 of Stage I participants (70.3%) reached the threshold of social phobia, 531 of which (57.8%) had never sought professional help. These results suggest that the Internet is a potential avenue through which to find untreated patients with social phobia. PMID- 21546096 TI - Impulse control disorders in psychiatric inpatients. AB - The aim of this study was to examine the prevalence of impulse control disorders (ICDs) in a European psychiatric inpatient sample. Two hundred thirty four consecutive psychiatric inpatients (62% female) were examined using a module of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) that has been developed for ICDs (SCID-ICD). In addition to intermittent explosive disorder, pyromania, kleptomania, pathological gambling, and trichotillomania, the proposed ICDs not otherwise specified were assessed, including compulsive buying, nonparaphilic compulsive sexual behavior, pathological internet use, and pathological skin picking. Based on the SCID-ICD, a lifetime ICD rate of 23.5% and a current ICD rate of 18.8% were found. The most frequent ICDs were pathological skin picking (lifetime 7.3%, current 6.8%), compulsive buying (lifetime 6.8%, current 6.0%), and intermittent explosive disorder (lifetime 5.6%, current 3.4%). In contrast, referring to admission diagnoses taken from patients' charts only 3.8% of the inpatients were diagnosed with any current ICD. Individuals with comorbid ICD were significantly younger and had more admission diagnoses other than ICD. The results suggest high rates of ICDs among psychiatric inpatients that remain to be under-diagnosed in clinical routine. PMID- 21546097 TI - Is nasal saline just a placebo! PMID- 21546098 TI - Prevalence of gender disparities and predictors affecting the occurrence of mild cognitive impairment (MCI). AB - The aims were to investigate the prevalence of mild cognitive impairment (MCI) within gender disparities in Malaysian older adults, and to determine the predictors of MCI according to gender disparities. A community-based sample of urban, multiethnic dwelling elderly aged 60 years of age and above from Cheras, Kuala Lumpur was recruited. Prevalence of all-type MCI, amnestic-type MCI (am MCI) and non-amnestic-type MCI (nam-MCI) was assessed using comprehensive neuropsychological batteries. The association between demography, socioeconomic status, lifestyle practices, and nutritional status and health risk factors with MCI were examined. Predictors of MCI occurrence between gender disparities were determined. The prevalence of all-type MCI, am-MCI and nam-MCI was 21.1%, 15.4% and 5.7%, respectively. Binary logistic regression indicated that hypercholesterolemia is the significant predictor for MCI in men after adjustment for age, ethnicity and total years of education. While, in women, MCI was best predicted by married status, without exercise practice, overweight and obesity. These results suggest that approximately one-fifth of the studied elderly people had MCI. Predictors for MCI are totally different between men and women. It is critical to identify those at higher risk for MCI in order to implement preventative measures to delay or reverse this abnormal condition. PMID- 21546099 TI - A spontaneous, double-blind, double-dummy cross-over study on the effects of daily vardenafil on arterial stiffness in patients with vasculogenic erectile dysfunction. AB - BACKGROUND: It is known that the incidence of endothelial dysfunction in patients with vascular erectile dysfunction (ED) is increased. The effects of daily vardenafil on endothelial function and arterial stiffness in patients with erectile dysfunction (ED) have never been investigated. METHODS: 20 men complaining vascular ED (mean IIEF5=12 +/- 6 and peak systolic velocity-PSV=24 +/ 2 cm/s) were enrolled in a 4-week, randomized, double-blind, double-dummy, crossover study (mean age 59 +/- 11) and received either vardenafil 10mg daily or 20mg on-demand with a two-week washout interval. Primary endpoints were variation from baseline of reactive hyperemia (RH) and augmentation index (AI) calculated by fingertip peripheral arterial tonometry (PAT) device. Secondary endpoints were variations of IIEF-5 and SEP3 scores from baseline and plasma surrogate markers of endothelial function, i.e. endothelin-1 (ET-1) and adrenomedullin (ADM). RESULTS: Patients who took daily vardenafil (vs. on-demand) reported significant (P<0.01) improvements in arterial stiffness as evaluated by AI and reduction of plasma ADM levels (p<0.05) but no improvement in average RH. When corrected for heart rate, ADM showed a strong direct relationship with AI (r(2)=0.22; p<0.005). The proportion of patients with an IIEF5 score of >= 22 or in SEP3 percentage of success rates were similar. Each treatment resulted in significantly greater IIEF5 scores (p<0.001) and better SEP3 response rates (p<0.0001) compared with baseline. CONCLUSIONS: We demonstrated that daily vardenafil improves arterial stiffness and erectile function measurements in men with severe vasculogenic ED. This effect may be mediated, at least in part, by a reduction in ADM circulating levels. PMID- 21546100 TI - Comparison of the safety between first- and second-generation drug eluting stents: meta-analysis from 19 randomized trials and 16,924 patients. AB - BACKGROUND/OBJECTIVE: Despite the effectiveness of first generation drug eluting stent, DES-1 (Taxus and Cypher) in avoiding restenosis and the need for new revascularizations, a slightly increase in stent thrombosis, ST have been published. Second generation drug eluting stent, DES-2 has been developed to optimize the results of percutaneous coronary intervention in terms of efficacy and safety, for avoiding early and late ST. Our objective was to compare the risk of ST between DES-1 and DES-2. METHODS: We performed a meta-analysis of 19 randomized trials. Overall 16,924 patients; 7294 were allocated to DES-1 and 9630 were allocated to DES-2. The primary endpoint was to compare the risk of overall ST during the first year. Other clinical outcomes of interest were to compare the incidence of early (<1 month) and late ST (>1 month-<1 year). RESULTS: The incidence of overall ST was not increased in patients receiving DES-1 (1.13% DES 1 vs 0.75% DES-2, OR 0.79, 95% CI:0.45-1.40, p 0.43). There were no significant differences in the incidence of; early ST (0.85% DES-1 vs 0.53% DES-2, OR 0.68, 95% CI:0.31-1.51, p 0.35) and late ST (0.40% DES-1 vs 0.25% DES-2, OR 0.69, 95% CI:0.39-1.24, p 0.22). CONCLUSIONS: During the first year after stent implantation, we didn't found differences in ST between DES-1 and DES-2. Most of ST was produced under appropriate anti-platelet therapy so it is possible that many other factors such as; clopidogrel resistance, procedural complications or stent malapposition were implicated. Safety after longer follow-up (>1 year) remains unclear. PMID- 21546101 TI - Comparison of image characteristics of plaques in culprit coronary arteries by 64 slice CT and intravascular ultrasound in acute coronary syndromes. AB - PURPOSE: To evaluate plaque image characteristics in coronary artery culprit lesions in subjects with acute coronary syndromes (ACS), we retrospectively compared coronary arterial images by 64-slice CT before conventional-coronary angiogram with those by intravascular ultrasound (IVUS). MATERIALS-AND-METHODS: Retrospective analysis of coronary arterial images from thirty-one subjects (26 males, mean age 59.3 +/- 12.0 years) exhibiting acute symptoms with suspicion of ACS, where either (1) ECG was un-interpretable or (2) ECG was non diagnostic/cardiac biomarkers was equivocal; with significant stenosis on emergent 64 slice CT and subjects were finally diagnosed as having ACS confirmed by conventional-coronary-angiogram, followed by IVUS before coronary intervention. After principal culprit-lesion components were classified into 1) thrombus, 2) soft plaques, and 3) fibrotic plaques by IVUS, corresponding culprit lesion CT values were measured (two-observers). RESULTS: Nineteen and 12 of 31 subjects were finally diagnosed as unstable angina pectoris and non-ST elevation acute myocardial infarction respectively. Main culprit-lesion components of ACS were identified on MSCT in all subjects. Culprit-lesion CT values diagnosed as soft plaques by IVUS (n=6, 32.9 +/- 8.7 HU) were not lower than those of thrombi (n=18, 43.2 +/- 10.7 HU, p=0.268); both values were significantly lower than those of fibrotic plaques (n=7, 82.5 +/- 22.6 HU) (both p<0.01). Calcification, spotty calcification, and positive arterial remodeling were observed in 67.7%, 61.3%, 58.1% (IVUS) and 58.1%, 51.6%, 74.2% (MSCT), respectively (all p=NS). CT value reproducibilities and culprit-lesion areas, were 0.87 and 0.86, respectively (two analyzers). CONCLUSIONS: 64-slice CT can non-invasively evaluate image characteristics in coronary artery culprit-lesions in ACS subjects accurately; this may help to differentiate soft plaques or thrombi generated by plaque rupture from fibrotic plaques. PMID- 21546102 TI - A high maintenance dose increases the inhibitory response to clopidogrel in patients with high on-treatment residual platelet reactivity. AB - BACKGROUND: Patients with high on-treatment residual adenosine diphosphate inducible platelet reactivity (HRPR) despite clopidogrel therapy are at an increased risk for adverse events after coronary stenting. A higher maintenance dose of clopidogrel may increase the inhibitory response in these patients. METHODS: We randomly assigned 46 patients with HRPR in at least one of three platelet reactivity tests to 75 mg vs. 150 mg clopidogrel for 3 months after angioplasty and stenting for cardiovascular disease. Platelet reactivity was assessed by the VerifyNow P2Y12 assay, the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, and multiple electrode aggregometry (MEA) 24h and 3 months after the intervention. RESULTS: Baseline platelet reactivity data did not differ significantly between treatment groups (all p > 0.2). At 3 months, platelet reactivities by the VerifyNow P2Y12 assay, the VASP assay, and MEA were 262 +/- 74 P2Y12 reaction units (PRU), 59.5 +/- 21.3%, and 46 +/- 19 aggregation units (AU) in the standard dose group vs. 190 +/- 78 PRU, 36.1 +/- 16.8%, and 26 +/- 16 AU in the high maintenance dose group (all p <= 0.003). Further, HRPR was significantly less frequent in patients assigned to 150 mg clopidogrel compared to patients receiving 75 mg clopidogrel per day (33% vs. 87%; p < 0.001). CONCLUSION: A high maintenance dose increases the antiplatelet effects of clopidogrel in patients with HRPR after angioplasty and stenting for cardiovascular disease. However, it needs to be shown that the higher dosage is associated with a beneficial clinical outcome in these patients. PMID- 21546103 TI - Up-regulation of calcitonin gene-related peptide protects streptozotocin-induced diabetic hearts from ischemia/reperfusion injury. AB - BACKGROUND: Diabetic hearts are vulnerable to ischemia/reperfusion (I/R) injury. Pretreatment with exogenous calcitonin gene-related peptide (CGRP) exerts a cardioprotective effect against myocardial I/R injury. Our previous study found that the CGRP level was decreased in diabetic hearts. This study aimed to investigate whether up-regulation of CGRP could reduce I/R injury in diabetic hearts. METHODS AND RESULTS: Adenovirus encoding the CGRP gene (Ad-CGRP) was injected intramyocardially in mice with or without streptozotocin (STZ) treatment. Three days after injection, the hearts were subjected to in vivo and in vitro I/R. Myocardial infarct size, cardiac function, lactate dehydrogenase (LDH) level in plasma and effluents, and cell mitochondrial function were measured. After ischemia (30 min) and reperfusion (24h) in vivo, diabetes mellitus (DM) mice had greater myocardial infarct size than their nondiabetic counterparts, and released more LDH in plasma. However, CGRP gene transfer reduced myocardial infarct size and plasma LDH level in both non-DM and DM hearts. After 30 min global ischemia and 40 min reperfusion in vitro, the DM hearts demonstrated increased left ventricular end-diastolic pressure (LVEDP) and effluent LDH level, and decreased left ventricular developed pressure (LVDP), coronary flow (CF), as well as cell mitochondrial function, when compared with the non-DM hearts. Again, CGRP gene transfer could protect against I/R injury in both non-DM and DM hearts. CONCLUSIONS: Adenovirus-mediated up-regulation of CGRP gene expression protects diabetic hearts against I/R injury. PMID- 21546104 TI - Assessment of in vivo and in vitro tuberculosis diagnostic tests in Mycobacterium caprae naturally infected caprine flocks. AB - Caprine tuberculosis in Spain is mainly caused by Mycobacterium caprae although the progression of the disease and lesion severity is similar to that caused by Mycobacterium bovis. In this study, the sensitivity of the gamma-interferon (IFN gamma) assay using an antigen cocktail containing early secretory antigenic target-6kDa (ESAT-6) and culture filtrate protein 10 (CFP-10) peptides for stimulation was determined and compared with those obtained in single intradermal tuberculin (SIT) and single intradermal cervical comparative tuberculin (SICCT) tests and IFN-gamma assay using purified protein derivative (PPD) in three different flocks infected with M. caprae under different epidemiological conditions. Correlation between specific IFN-gamma production and severity of lesions was also evaluated. Sensitivities of the diagnostic tests varied greatly in the three flocks studied, with higher values in those where higher lesion scores were observed. The results show that IFN-gamma assay applied in goats using PPD or the ESAT-6/CFP-10 peptides cocktail for stimulation yielded similar sensitivity values. A significant yet weak positive correlation between specific IFN-gamma production and lesion scores was detected after the stimulation with PPDs (p=0.004) whereas when the blood samples were stimulated with ESAT-6/CFP-10 peptides, the correlation was not significant (p>0.05). Therefore, specific-IFN gamma production after the stimulation with PPDs or ESAT-6/CFP-10 was not an accurate indicator of lesion severity in naturally tuberculosis infected goats with M. caprae. PMID- 21546105 TI - Evaluation of post-farm-gate passive surveillance in swine for the detection of foot and mouth disease in Australia. AB - Pigs are considered high risk for the introduction and spread of foot and mouth disease (FMD) in Australia. One of the most likely pathways of introduction of FMD into Australia would be through the illegal importation of FMD-contaminated meat, which is then fed to feral or domestic pigs. Locations where animals from different origins are commingled, such as livestock markets and abattoirs, pose a risk for disease spread. Early detection of exotic diseases at these locations is crucial in limiting the spread of an outbreak. The aims of this study were to evaluate the likelihood of exotic disease detection with current passive disease surveillance activities for pigs at saleyards and abattoirs in eastern Australia, and make recommendations for improving surveillance. Sensitivity (Se) of the current post-farm-gate passive surveillance for detection of exotic diseases was estimated using the scenario tree modelling methodology (Martin et al., 2007a). Four surveillance system components were identified: (i) domestic saleyard, (ii) export saleyard, (iii) domestic abattoir, and (iv) export abattoir. Pig farms were classified according to herd size (Small vs. Large) and subsequently into two risk categories depending on the probability of swill feeding (Swill feeding vs. Not swill feeding). A scenario tree representing the pathways by which infected animals could be detected was developed and the Se of detection in each surveillance system component was estimated. Industry statistics, information on previous exotic disease outbreaks, and interviews with pig producers were used to estimate herd category proportions and the relative risk of swill feeding. Quantitative estimates for probabilities of detection were sourced from State legislation and policies, stakeholder consultation and observational studies at saleyards and abattoirs. Results of a FMD case study showed a Se of detection at a representative location for each surveillance system component during a 2-week period of 0.19 at domestic saleyards, 0.40 at export saleyards, 0.32 at domestic abattoirs and, 0.53 at export abattoirs. This output assumed the country was infected with herd and unit design prevalences of 1% and 30%, respectively. Improving disease awareness of saleyard and abattoir stockmen, increasing the presence of inspectors at these venues and identifying those herds posing a higher risk for FMD introduction, could improve the capacity of the country for early detection of emerging animal diseases. PMID- 21546106 TI - SVEPM 2010--the role of veterinary epidemiology in animal health in the world today. PMID- 21546107 TI - Effects of prenatal and early life malnutrition: evidence from the Greek famine. AB - This paper examines the long run education and labor market effects from early life exposure to the Greek 1941-1942 famine. Given the short duration of the famine, we can separately identify the famine effects for cohorts exposed in utero, during infancy and at 1 year of age. We find that adverse outcomes due to the famine are largest for infants. Further, in our regression analysis we exploit the fact that the famine was more severe in urban than in rural areas. Consistent with our prediction, we find that urban-born cohorts show larger negative impacts on educational outcomes than rural-born cohorts. PMID- 21546108 TI - Biotransformations in microstructured reactors: more than flowing with the stream? AB - The state of the art in the application of microstructured flow reactors for biocatalytic process research is reviewed. A microstructured reactor that is fully automated and analytically equipped presents a powerful screening tool with which to perform biocatalyst selection and optimization of process conditions at intermediary stages of process development. Enhanced mass transfer provided by the microstructured reactor can be exploited for process intensification, particularly during multiphase biocatalytic processing where mass transfer across phase boundaries is often limiting. Reversible immobilization of enzymes in microchannels remains a challenge for flexible realization of biotransformations in microstructured reactors. Compartmentalization in microstructured reactors could be useful in performing multistep chemoenzymatic conversions. PMID- 21546109 TI - The interaction of respiration and visual feedback on the control of force and neural activation of the agonist muscle. AB - The purpose of this study was to compare force variability and the neural activation of the agonist muscle during constant isometric contractions at different force levels when the amplitude of respiration and visual feedback were varied. Twenty young adults (20-32 years, 10 men and 10 women) were instructed to accurately match a target force at 15% and 50% of their maximal voluntary contraction (MVC) with abduction of the index finger while controlling their respiration at different amplitudes (85%, 100% and 125% normal) in the presence and absence of visual feedback. Each trial lasted 22s and visual feedback was removed from 8-12 and 16-20s. Each subject performed three trials with each respiratory condition at each force level. Force variability was quantified as the standard deviation of the detrended force data. The neural activation of the first dorsal interosseus (FDI) was measured with bipolar surface electrodes placed distal to the innervation zone. Relative to normal respiration, force variability increased significantly only during high-amplitude respiration (~63%). The increase in force variability from normal- to high-amplitude respiration was strongly associated with amplified force oscillations from 0 to 3 Hz (R(2) ranged from .68 to .84, p< .001). Furthermore, the increase in force variability was exacerbated in the presence of visual feedback at 50% MVC (vision vs. no-vision: .97 vs. .87N) and was strongly associated with amplified force oscillations from 0 to 1 Hz (R(2)= .82) and weakly associated with greater power from 12 to 30 Hz (R(2)= .24) in the EMG of the agonist muscle. Our findings demonstrate that high-amplitude respiration and visual feedback of force interact and amplify force variability in young adults during moderate levels of effort. PMID- 21546110 TI - Yeast biocontrol of fungal spoilage of pears stored at low temperature. AB - To reduce the use of fungicides, biological control with yeasts has been proposed in postharvest pears. Most studies of antagonists selection have been carried out at room temperature. However, in regions like North Patagonia where fruits are stored at -1/0 degrees C during 5-7 months the selection of potential antagonist agents must be carried out at low temperature. In this study, 75 yeast cultures were isolated from healthy pears from two Patagonian cold-storage packinghouses. Aureobasidium pullulans, Cryptococcus albidus, Cryptococcus difluens, Pichia membranifaciens, Pichia philogaea, Rhodotorula mucilaginosa and Saccharomyces cerevisiae yeast species were identified. Additionally, 13 indigenous isolates of Penicillium expansum and 10 isolates of Botrytis cinerea were obtained from diseased pears, characterized by aggressiveness and tested for sensitivity to postharvest fungicides. The yeasts were pre-selected for their ability to grow at low temperature. In a first biocontrol assay using the most aggressive and the most sensitive isolate of each pathogen, two epiphytic isolates of A. pullulans and R. mucilaginosa were the most promising isolates to be used as biocontrol agents. They reduced the decay incidence by P. expansum to 33% and the lesion diameter in 88% after 60 days of incubation in cold. Foreign commercial yeast used as a reference in assays, only reduced 30% of lesion diameter in the same conditions. Yeasts were not able to reduce the incidence of B. cinerea decay. The control activity of the best two yeasts was compared with the control caused by the fungicides in a second bioassay, obtaining higher levels of protection against P. expansum by the yeasts. These two regional yeasts isolates could be promising tools for the future development of commercial products for biological control. PMID- 21546111 TI - A simple method to recover Norovirus from fresh produce with large sample size by using histo-blood group antigen-conjugated to magnetic beads in a recirculating affinity magnetic separation system (RCAMS). AB - Human norovirus (NoV) outbreaks are major food safety concerns. The virus has to be concentrated from food samples in order to be detected. PEG precipitation is the most common method to recover the virus. Recently, histo-blood group antigens (HBGA) have been recognized as receptors for human NoV, and have been utilized as an alternative method to concentrate human NoV for samples up to 40 mL in volume. However, to wash off the virus from contaminated fresh food samples, at least 250 mL of wash volume is required. Recirculating affinity magnetic separation system (RCAMS) has been tried by others to concentrate human NoV from large-volume samples and failed to yield consistent results with the standard procedure of 30 min of recirculation at the default flow rate. Our work here demonstrates that proper recirculation time and flow rate are key factors for success in using the RCAMS. The bead recovery rate was increased from 28% to 47%, 67% and 90% when recirculation times were extended from 30 min to 60 min, 120 min and 180 min, respectively. The kinetics study suggests that at least 120 min recirculation is required to obtain a good recovery of NoV. In addition, different binding and elution conditions were compared for releasing NoV from inoculated lettuce. Phosphate-buffered saline (PBS) and water results in similar efficacy for virus release, but the released virus does not bind to RCAMS effectively unless pH was adjusted to acidic. Either citrate-buffered saline (CBS) wash, or water wash followed by CBS adjustment, resulted in an enhanced recovery of virus. We also demonstrated that the standard curve generated from viral RNA extracted from serially-diluted virus samples is more accurate for quantitative analysis than standard curves generated from serially-diluted plasmid DNA or transcribed-RNA templates, both of which tend to overestimate the concentration power. The efficacy of recovery of NoV from produce using RCAMS was directly compared with that of the PEG method in NoV inoculated lettuce. 40, 4, 0.4, and 0.04 RTU can be detected by both methods. At 0.004 RTU, NoV was detectable in all three samples concentrated by the RCAMS method, while none could be detected by the PEG precipitation method. RCAMS is a simple and rapid method that is more sensitive than conventional methods for recovery of NoV from food samples with a large sample size. In addition, the RTU value detected through RCAMS-processed samples is more biologically relevant. PMID- 21546112 TI - The use of plasma rich in growth factors (PRGF-Endoret) in the treatment of a severe mal perforant ulcer in the foot of a person with diabetes. AB - A 71 year old person with diabetes with a severe mal perforant ulcer in the right foot was treated twice with autologous plasma-rich in growth factors (PRGF) obtained from her own blood. After PRGF treatment the severe mal perforant ulcer completely healed in 10 weeks. PMID- 21546113 TI - Prevention for elderly people: demand-oriented or problem-oriented? AB - OBJECTIVE: To examine the association between self-expressed information needs and corresponding observed health and lifestyle issues in elderly people. METHODS: Data were used from the 2006 community health survey in Utrecht, a medium-sized city in the Netherlands. Data of 1634 people aged 55 years and older were available for analyses (response 64%). Multivariate logistic regression analyses were used to examine possible associations between expressed information needs and variables on demographics, lifestyle risk behaviours, physical and psychosocial health. RESULTS: Several significant associations were found between information needs and corresponding health and lifestyle problems. However, the explanatory power of the observed problems was generally low, explaining only 7% of the informational needs on lifestyle, and 17% and 28% of the informational needs on physical and psychosocial health, respectively. CONCLUSIONS: The findings suggest that prevention amongst the elderly should not be solely based on information needs, but also on observed lifestyle and health. Implications for the use of different approaches of prevention and behavioural models underlying interventions are discussed. PMID- 21546114 TI - L-selectin--a dynamic regulator of leukocyte migration. AB - The leukocytic cell adhesion receptor L-selectin mediates the initial step of the adhesion cascade, the capture and rolling of leukocytes on endothelial cells. This event enables leukocytes to migrate out of the vasculature into surrounding tissues during inflammation and immune surveillance. Distinct domains of L selectin contribute to proper leukocyte migration. In this review, we discuss the contributions of these domains with respect to L-selectin function: the regulation by serine phosphorylation of the cytoplasmic tail, the role of the transmembrane domain in receptor positioning on the cell surface as well as the N glycosylation of the extracellular part and the identification of novel binding partners. PMID- 21546115 TI - Circadian rhythms in electrical circuits of Clivia miniata. AB - The biological clock regulates a wide range of physiological processes in plants. Here we show circadian variation of the Clivia miniata responses to electrical stimulation. The biologically closed electrochemical circuits in the leaves of C. miniata (Kaffir lily), which regulate its physiology, were analyzed in vivo using the charge stimulation method. The electrostimulation was provided with different voltages and electrical charges. Resistance between Ag/AgCl electrodes in the leaf of C. miniata was higher at night than during the day or the following day in the darkness. The biologically closed electrical circuits with voltage gated ion channels in C. miniata are activated the next day, even in the darkness. C. miniata memorizes daytime and nighttime. At continuous light, C. miniata recognizes nighttime and increases the input resistance to the nighttime value even under light. These results show that the circadian clock can be maintained endogenously and has electrochemical oscillators, which can activate voltage gated ion channels in biologically closed electrochemical circuits. The activation of voltage gated channels depends on the applied voltage, electrical charge and speed of transmission of electrical energy from the electrostimulator to the C. miniata leaves. We present the equivalent electrical circuits in C. miniata and its circadian variation to explain the experimental data. PMID- 21546117 TI - Evidence-based emergency medicine. Can a negative D-dimer result rule out acute aortic dissection? PMID- 21546116 TI - [Fungal keratitis]. AB - Fungal keratitis (keratomycosis) is a rare but severe cause of infectious keratitis. Its incidence is constant, due to steroids or immunosuppressive treatments and contact lenses. Pathogens often invade corneas with chronic diseases of the ocular surface but fungal keratitis is also observed following injuries with plant foreign objects. The poor prognosis of these infections is related both to fungal virulence, decreased host defense, as well as delays in diagnosis. However, new antimycotic treatments allow better management and prognosis. PMID- 21546118 TI - On easy solutions. PMID- 21546119 TI - Methylene blue in the treatment of refractory shock from an amlodipine overdose. AB - Amlodipine is a potent vasodilator with a long half-life and delayed onset of action that is particularly concerning after an overdose. Vasodilation occurs through stimulation of nitric oxide release with increased cyclic guanosine monophosphate (cGMP) production. Methylene blue inhibits guanylate cyclase. This enzyme is responsible for the production of cGMP. Methylene blue also has the ability to scavenge nitric oxide, as well as inhibit nitric oxide synthase. We report the use of methylene blue for refractory shock in a patient with amlodipine toxicity. PMID- 21546120 TI - Electronic control device exposure: a review of morbidity and mortality. AB - The use of electronic control devices has expanded worldwide during the last few years, the most widely used model being the Taser. However, the scientific knowledge about electronic control devices remains limited. We reviewed the medical literature to examine the potential implications of electronic devices in terms of morbidity and mortality, and to identify and evaluate all the existing experimental human studies. A single exposure of an electronic control device on healthy individuals can be assumed to be generally safe, according to 23 prospective human experimental studies and numerous volunteer exposures. In case series, however, electronic control devices could have deleterious effects when used in the field, in particular if persons receive multiple exposures, are intoxicated, show signs of "excited delirium," or present with medical comorbidities. As the use of electronic control devices continues to increase, the controversy about its safety, notably in potentially high-risk individuals, is still a matter of debate. The complications of electronic control device exposure are numerous but often recognizable, usually resulting from barbed dart injuries or from falls. Persons exposed to electronic control devices should therefore be fully examined, and traumatic lesions must be ruled out. PMID- 21546121 TI - Evidence-based emergency medicine. What is the role of antiemetics in the treatment of children with acute gastroenteritis? PMID- 21546122 TI - Human papillomavirus, smoking, and head and neck cancer. AB - AIMS: Smoking and human papillomavirus (HPV) are both distinct risk factors for head and neck cancer, but the nature of interaction between these 2 risk factors in the development of head and neck cancer remains unclear. The purpose of this review is to determine the potential effect of smoking in causation of HPV related head and neck carcinoma. METHOD: A literature search was carried out using the keywords human papillomavirus, head and neck cancer, smoking, tobacco, and cervical cancer. The English-language articles, references, and other relevant studies evaluating the association of smoking, HPV, and risk of head and neck cancer were collected and analyzed. CONCLUSION: Overall, our review points to smoking tobacco posing an additional risk for development of head and neck cancer in the presence of HPV infection. This is consistent with available laboratory data that show evidence of biological plausibility for interaction between smoking and progression of HPV infection to carcinogenesis. It is therefore important that cessation of smoking is promoted in smokers with HPV infection. PMID- 21546123 TI - Effectiveness of a novel ozone-based system for the rapid high-level disinfection of health care spaces and surfaces. AB - BACKGROUND: Vapor-based fumigant systems for disinfection of health care surfaces and spaces is an evolving technology. A new system (AsepticSure) uses an ozone based process to create a highly reactive oxidative vapor with broad and high level antimicrobial properties. METHODS: Ozone gas at 50-500 ppm was combined with 3% hydrogen peroxide vapor in a test chamber and upscaled in rooms measuring 82 m3 and 90 m3 in area. Test organisms included methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, Escherichia coli, Pseudomonas aeruginosa, Clostridium difficile, and Bacillus subtilis spores dried onto steel discs or cotton gauze pads. RESULTS: The combination of 80-ppm ozone with 1% hydrogen peroxide vapor achieved a very high level of disinfection, with a >=6 log10 reduction in the bacteria and spores tested on steel discs and MRSA tested on cotton gauze during a 30- to 90-minute exposure. The entire system was scalable such that it achieved the same high level of disinfection in both the 81 m3 and 90-m3 rooms in 60-90 minutes. CONCLUSION: The ozone hydrogen peroxide vapor system provides a very high level of disinfection of steel and gauze surfaces against health care-associated bacterial pathogens. The system is an advanced oxidative process providing a rapid and effective means of disinfecting health care surfaces and spaces. PMID- 21546124 TI - Hypocretin (orexin) loss in Alzheimer's disease. AB - Sleep disturbances in Alzheimer's disease (AD) patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. AD is a neurodegenerative disorder targeting different brain areas and types of neurons. In this study, we assessed whether the neurodegenerative process of AD also affects hypothalamic hypocretin/orexin neurons. The total number of hypocretin-1 immunoreactive neurons was quantified in postmortem hypothalami of AD patients (n = 10) and matched controls (n = 10). In addition, the hypocretin-1 concentration was measured in postmortem ventricular cerebrospinal fluid of 24 AD patients and 25 controls (including the patients and controls in which the hypothalamic cell counts were performed). The number of hypocretin-1 immunoreactive neurons was significantly decreased by 40% in AD patients (median [25th-75th percentiles]); AD 12,935 neurons (9972-19,051); controls 21,002 neurons (16,439-25,765); p = 0.049). Lower cerebrospinal fluid (CSF) hypocretin-1 levels were found in AD patients compared with controls (AD: 275 pg/mL [197-317]; controls: 320 pg/mL [262-363]; p = 0.038). Two AD patients with documented excessive daytime sleepiness showed the lowest CSF hypocretin-1 concentrations (55 pg/mL and 76 pg/mL). We conclude that the hypocretin system is affected in advanced AD. This is reflected in a 40% decreased cell number, and 14% lower CSF hypocretin-1 levels. PMID- 21546125 TI - Sildenafil ameliorates cognitive deficits and tau pathology in a senescence accelerated mouse model. AB - Aging is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. In the present study we tested whether the specific phosphodiesterase 5 inhibitor sildenafil could ameliorate the age-dependent cognitive impairments shown by the senescence-accelerated mouse prone-8 (SAMP8). Sildenafil administration (7.5 mg/kg for 4 weeks) to 5-month-old SAMP8 mice attenuated spatial learning and memory impairments shown by these mice in the Morris Water Maze. Tau hyperphosphorylation (AT8 but not PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of sildenafil-treated mice, an effect probably related to a decrease in cyclin dependent kinase 5 protein expression and activity (p25/p35 ratio). Interestingly, sildenafil also phosphorylated Akt, which was associated with an increase of glycogen synthase kinase-3beta phosphorylation, providing a plausible explanation for the reductions in tau hyperphosphorylation (AT8 and PHF-1 epitopes) and attenuation of cognitive deficits shown by 9-month-old SAMP8 mice. Overall, sildenafil might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases. PMID- 21546127 TI - [Tracheostomy cannula as a cause of false positive result on the whole-body scan with (131)I in the follow-up of differentiated thyroid cancer]. PMID- 21546126 TI - An amyloid beta42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer's disease. AB - The endocannabinoids and their attending cannabinoid (CB)(1) receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear. In the present study, we used liquid chromatography/mass spectrometry to conduct an endocannabinoid-targeted lipidomic analysis of postmortem brain samples from 38 Alzheimer's disease (AD) patients and 17 control subjects, matched for age and postmortem interval. The analysis revealed that midfrontal and temporal cortex tissue from AD patients contains, relative to control subjects, significantly lower levels of the endocannabinoid anandamide and its precursor 1-stearoyl, 2-docosahexaenoyl-sn-glycero-phosphoethanolamine-N arachidonoyl (NArPE). No such difference was observed with the endocannabinoid 2 arachidonoyl-sn-glycerol or 15 additional lipid species. In AD patients, but not in control subjects, statistically detectable positive correlations were found between (1) anandamide content in midfrontal cortex and scores of the Kendrick's Digit Copy test (p = 0.004, r = 0.81; n = 10), which measures speed of information processing; and (2) anandamide content in temporal cortex and scores of the Boston Naming test (p = 0.027, r = 0.52; n = 18), which assesses language facility. Furthermore, anandamide and NArPE levels in midfrontal cortex of the study subjects inversely correlated with levels of the neurotoxic amyloid peptide, amyloid beta-protein (Abeta)(42), while showing no association with Abeta(40) levels, amyloid plaque load or tau protein phosphorylation. Finally, high endogenous levels of Abeta(42) in Swedish mutant form of amyloid precursor protein (APP(SWE))/Neuro-2a cells directly reduced anandamide and NArPE concentrations in cells lysates. The results suggest that an Abeta(42)-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD. PMID- 21546128 TI - [201Thalium SPECT in the detection of recurrent laryngeal carcinoma]. AB - OBJECTIVE: To evaluate the diagnostic yield of (201)Thallium SPECT in the detection of local and/or regional lymph node dissemination of pharyngolaryngeal carcinoma. MATERIAL AND METHODS: 29 patients who had been diagnosed with pharyngolaryngeal carcinoma were studied (mean age: 60.9 years). These patients had been treated by surgery, chemotherapy and radiotherapy. At between 3 to 6 month after finishing the treatment, all of them underwent a planar and SPECT study at one hour after the administration of 148 MBq of (201)Thallium. Uptake was scored on four grades: from 0 (no uptake) to 3 (very intense uptake). The presence or non-presence of lymph nodes with uptake was also evaluated. All the results on the scintigraphy were correlated with long term clinical and radiological follow-up (mean: 2.5 years). The studies were classified as positive for recurrence when the uptake was 2-3 and/or with presence of lymph nodes with uptake. RESULTS: We obtained 9 true positive, 14 true negative, 3 false positive and 3 false negative results. Sensitivity was 75%, specificity was 82.4%, positive predictive value was 75% and negative predictive value was 82.4%. Two out of three false positives corresponded to the surgical bed uptake and one was attributed to the laterocervical lymph nodes. The three false negatives had grade 1 uptakes, two of them corresponding to pulmonary metastasis without evidence of local recurrence. CONCLUSIONS: The use of (201)Thallium SPECT in the prognostic evaluation in patients with a treated laryngeal carcinoma shows very acceptable results in the detection of local recurrence and/or regional lymph node dissemination. PMID- 21546129 TI - [Evaluation of the cobas 4800 CT/NG test for detecting Chlamydia trachomatis]. AB - INTRODUCTION: To evaluate the new automated system cobas 4800 CT/NG test for detection of Chlamydia trachomatis in urogenital specimens. MATERIAL AND METHODS: We analyzed 696 specimens (488 swabs from urethral or cervical specimens, and 208 urines) to detect C. trachomatis. The results of the cobas 4800 CT/NG test (c4800) were compared to those obtained with Cobas AMPLICOR CT/NG test (CAM). Discordant results were analyzed with a conventional PCR assay and microchip electrophoresis system in agarose gel, MultiNA. RESULTS: We made two simultaneous analyses. In the first one, we compared the results obtained with swab specimens using the c4800 system and CAM. In this case, the sensitivity, the specificity, the positive and negative predictive values (PPV and NPV) were: 77.9%, 100%, 100% and 96% respectively. In the second one, we compared the results obtained for urine and its corresponding swab specimens on the c4800. The values obtained were: 100%, 98.9%, 92.9% and 100% respectively. The kappa values of these comparisons were: 0.857 for swab specimens on the c4800 and CAM, and 0.957 for urine versus swab specimens on the c4800. CONCLUSIONS: The results obtained with c4800 system were completely comparable with those obtained with CAM. We also noted an excellent correlation with these results when we compared swab specimens with their urine samples in the c4800 system. Therefore this sample type could be used routinely to diagnose infections in men and women. PMID- 21546130 TI - Neurology and literature 2. AB - INTRODUCTION: Good literary fiction has the potential to move us, extend our sense of life, transform our prospective views and help us in the face of adversity. A neurological disorder is likely to be the most challenging experience a human being may have to confront in a lifetime. As such, literary recreations of illnesses have a doubly powerful effect. OBJECTIVES: Study the synergies between neurology and fictional literature with particular reference to narrative based medicine (NBM). DEVELOPMENT: Doctors establish boundaries between the normal and the abnormal. Taking a clinical history is an act of interpretation in which the doctor integrates the science of objective signs and measurable quantities with the art of subjective clinical judgment. The more discrepancy there is between the patient's experience with the illness and the doctor's interpretation of that disease, the less likely the doctor-patient interaction is to succeed. NBM contributes to a better discernment of the meanings, thus considering disease as a biographical event rather than just a natural fact. Drawing from their own experience with disease, writers of fiction provide universal insights through their narratives, whilst neuroscientists, like Cajal, have occasionally devoted their scientific knowledge to literary narratives. Furthermore, neurologists from Alzheimer to Oliver Sacks remind us of the essential value of NBM in the clinic. CONCLUSIONS: Integrating NBM (the narrative of patients) and the classic holistic approach to patients with our current paradigm of evidence based medicine represents a challenge as relevant to neurologists as keeping up with technological and scientific advances. PMID- 21546131 TI - [Spatial pattern of legionellosis in Spain, 2003-2007]. AB - OBJECTIVES: To analyze the spatial pattern of legionellosis in Spain for men and women during the period 2003-2007 and to identify spatial clustering of risk. METHODS: We identified the spatial pattern of the distribution of legionellosis rates based on calculation of rates by municipality through the direct method. Smoothing of these rates was performed by the Empirical Bayes method for studying the spatial pattern of disease for both sexes. We used Morans index to analyze spatial autocorrelation rates globally. To calculate local rates, the Local Moran's Index [known as local indicators of spatial association (LISA)], was used to analyze the clusters of municipalities with the highest risk. RESULTS: After smoothing the risk, the highest rates (over 50 per 100,000 inhabitants) were grouped in the eastern Mediterranean coastal areas and the north of the mainland, as well as in the Mediterranean islands. Moran's index smoothed rates were 0.15 for men and 0.23 for women. The spatial clusters of statistically significant higher rates calculated by the LISA index were distributed in the north and east for both sexes. CONCLUSIONS: These methods of spatial analysis allow patterns of disease distribution to be identified. All the methods used yielded similar results. These techniques are a complementary tool for epidemiological surveillance of infectious diseases. PMID- 21546132 TI - Adherence to highly active antiretroviral therapy in Spain. A meta-analysis. AB - OBJECTIVES: To estimate the percentage of adherence to highly-active antiretroviral therapy (HAART) in Spanish observational studies and to identify the variables associated with adherence. METHODS: Seven electronic databases were used to locate the studies. Six inclusion criteria were established. Two coders codified the variables independently. Intercoder reliability was calculated. Publication bias was analyzed through the Begg, Egger and Trim and Fill tests. Homogeneity was evaluated using the Q test and the l2 index. A random effects model was assumed to estimate both the overall percentage of adherence and to explain heterogeneity. RESULTS: This meta-analysis included 23 observational studies, yielding a total of 34 adherence estimates. The sample was composed of 9,931 HIV-positive individuals (72% men) older than 18 years under treatment with HAART. The percentage of patients adhering to an intake of >90% of the prescribed antiretroviral drugs was 55%. Wide heterogeneity was detected (I2 =91.20; 95%CI: 88.75-93.13). Adherence was mainly measured using a single strategy (47.8%), the most widely used being self-report (48.7%). In the univariate analysis, the following factors were significant: infection stages A (beta=0.68, p <0.001) and B (beta=-0.56, p <0.01), viral loads >200 copies/ml (beta=-0.41, p <0.05) and <200 (beta=0.39, p <0.05), and university education (beta=-0.66, p<0.05). CONCLUSIONS: The overall percentage of adherence was 55%, although this value may be an overestimate. Adherence was associated with infection stage A and with a viral load of <200 copies/ml. PMID- 21546133 TI - Novel pentamidine derivatives: synthesis, anti-tumor properties and polynucleotide-binding activities. AB - Novel amidino-substituted conformationally restricted derivatives of pentamidine were synthesized and their antiproliferative activity against several human cancer cell lines determined. It was found that introduction of furandicarboxamide core moiety (9, 10) increases antiproliferative activity as well as selectivity against certain tumor cell lines in comparison with amidino substituted furan-mono-carboxamide (5, 6). Unlike the furan series where iso propyl substituted amidine (10) exhibits more potent overall antiproliferative activity and selectivity toward certain cell lines, the same was found for unsubstituted amidines in pyridine series. Amongst all tested compounds the compound 10 is the only one that possesses antiproliferative activity against SW 620 cell line (4 MUM). Spectroscopic studies of the interactions of prepared diamidines with double-stranded DNA and RNA polynucleotides show that all compounds preferentially bind into the minor groove of DNA, while most of them intercalate into RNA. The structure-dependant biological activity and the lack of DNA/RNA selective binding suggest that the mechanism of action of the here presented compounds is controlled not only by the interactions with cellular nucleic acids, but also with other more specific protein targets. PMID- 21546134 TI - Synthesis, nucleic acid binding and cytotoxicity of polyethyleneimine-copper(II) complexes containing 1,10-phenanthroline and l-valine. AB - The polymer-copper(II) complex samples, [Cu(phen)(l-Val) BPEI]Cl.H(2)O, with varying degrees of coordination in the polymer chain, were prepared and characterized by elemental analysis and spectroscopic methods. The binding of these complex samples with both DNA and RNA has been investigated. The experimental results indicate that the polyethyleneimine-copper(II) complex samples bind with DNA and RNA mostly through surface binding; but hydrogen bonding and van der Waals interactions are also present. Evaluation of cytotoxic activity of a sample of polymer-copper(II) complex with higher degree of coordination against different cancer cell lines proved that the complex exhibited cytotoxic specificity and significant cancer cell inhibition rate. PMID- 21546135 TI - Mycobacterium tuberculosis and cholinesterase inhibitors from Voacanga globosa. AB - Globospiramine (1), a new spirobisindole alkaloid possessing an Aspidosperma Aspidosperma skeleton, together with deoxyvobtusine (2), deoxyvobtusine lactone (3), vobtusine lactone (4) and lupeol (5), were isolated and identified from Voacanga globosa through a bioassay-guided purification. The gross structure and absolute stereochemistry of 1 were established by circular dichroism spectroscopy, HR-MS and unambiguous NMR spectroscopic experiments. In addition, a new biogenetic pathway for the formation of the spiro-Aspidosperma-Aspidosperma skeleton is proposed. Alkaloid 1 showed potent antituberculosis activity against Mycobacterium tuberculosis H(37)Rv as evidenced in microplate Alamar blue assay (MIC = 4 MUg/mL) and low-oxygen recovery assay (LORA (MIC = 5.2 MUg/mL). The bisindole alkaloids also exhibited promising activity against acetylcholinesterase and, especially butyrylcholinesterase, with deoxyvobtusine (2) (IC(50) = 6.2 MUM) as the most strongly inhibiting compound. This study extends the variety of alkaloid structural platforms which exhibit antimycobacterial and anticholinesterase activity. PMID- 21546136 TI - [Risk of immunosuppressive drugs given throughout the pregnancy]. PMID- 21546137 TI - Web-based video and feedback in the teaching of cardiopulmonary resuscitation. AB - Knowledge and skills relating to cardiopulmonary resuscitation tend to be lost over time. The combination of simulation sessions with online video records and online feedback allows for an enduring record of skills sessions to assist students in retaining and revising their learning. This paper reports a qualitative evaluation of such a combination used in inter-disciplinary sessions for volunteer nursing and medical students. Methods included focus groups and free text questionnaires; data were gathered from fourteen students and three teachers. Students had used the online material in a variety of personal ways, and found that the addition to their learning was significant. Their memories of the simulation sessions and of the feedback received immediately afterwards were incomplete, and repeated viewing enabled them to identify good and poor practice with more confidence, and to reflect more carefully on their own and others' practice. Teachers found it easier to give more detailed feedback when given the chance to watch the video than immediately after the session. All felt that the sessions would ideally be embedded in the curriculum. PMID- 21546138 TI - One Day in the life of Ivan Denisovich (1962): Alexander Solzhenitsyn. PMID- 21546139 TI - The professional socialization of recently graduated nurses--experiences of an introduction program. AB - Nursing education entails a three-year program leading up to a Bachelor's degree. Recently graduated nurses lack theoretical as well as clinical skills, thus experiencing difficulties in taking on the professional role. Health care institutions have previously expressed great concern about the increase of theoretical focus at the cost of decreased clinical training and consequently employers presently offer introduction programs after the completion of the nursing education. The present study is part two of a larger study. The aim of the present study was to describe and analyze how recently graduated nurses are socialized into the profession. The research was conducted using an ethnographic approach and the empirical data was acquired by means of participant observations, interviews and field notes. The findings revealed that the staff questions the novices' nursing knowledge and strongly doubts their professional skills. In order for novices to attain member status at the clinical facility, they must constantly prove their professional ability. The findings showed furthermore that deviation by the novices from the norms and expectations associated with the professional role results in their becoming outsiders. Within nursing education the ideology of nursing is prominent, but within the profession the emphasis is on good occupational skills. PMID- 21546140 TI - Internal distribution of uranium and associated genotoxic damages in the chronically exposed bivalve Corbicula fluminea. AB - Uranium (U) internal distribution and involved effects in the bivalve Corbicula fluminea have been studied after direct chronic exposure (90 d, 10 MUg.L-1). U distribution was assessed at the subcellular level (Metal Rich Granules -MRG-, pellets and cytosol fractions) in two main organs of the bivalve (gills and visceral mass). Micro-localisation was investigated by TEM-EDX analysis in the gills epithelium. DNA damage in gill and hemolymph samples was measured by the Comet assay. The 90-d exposure period led to a significant increase of U concentration in gills over time (* 5) and a large U quantity in subcellular granules in gills. Finally, a significant increase (* 2) in DNA damage was noted in exposed gills and haemocytes. This study shows that the accumulation levels and consequently the potential toxicity cannot be successfully predicted only on the basis of concentration in water or in tissues and subcellular fractions after chronic exposure. PMID- 21546141 TI - Lymphoma presenting in the neck: current concepts in diagnosis. AB - Lymphoma commonly presents as a painless enlarging lump in the neck. With the establishment of the neck lump one-stop clinic, patients can be assessed promptly. Historically an open node biopsy specimen was required for definitive diagnosis, but in the last few years, many clinicians have advocated use of image guided core biopsies, and some specialist centres monitor patients with fine needle aspiration cytology (FNAC) combined with other diagnostic techniques such as flow cytometry. In this article, we present current published papers on the management of suspected lymphoma in a patient who presents with a neck mass. We discuss the role of FNAC, core biopsy, open node biopsy, and imaging in the diagnosis of lymphoma before the patient is referred to the oncologist. PMID- 21546142 TI - Development and psychometric testing of the scales for measuring maternal satisfaction in normal and caesarean birth. AB - OBJECTIVE: to develop a scale to measure maternal satisfaction with birth to evaluate women's experiences in labour and the early postpartum period. DESIGN: development and psychometric assessment of a multidimensional maternal satisfaction questionnaire. SETTING: maternity unit of a university hospital in Istanbul. PARTICIPANTS: 500 healthy postpartum women. METHODS: five steps were taken in development of the scale: literature review, generating item pool, content validity testing, administration of draft scale and psychometric testing. Two versions of the scale were developed: the Scale for Measuring Maternal Satisfaction-normal birth and the Scale for Measuring Maternal Satisfaction caesarean birth. Content validity was evaluated by experts. The appropriate draft scale and the Newcastle Satisfaction with Nursing Scale were administered to postpartum women before hospital discharge. FINDINGS: content validity index scores for the vaginal and caesarean birth scales were 0.91 and 0.89, respectively. Item-total and subscale-total scores correlated significantly for each scale. Evaluation of construct validity through factor analysis yielded 10 subscales: 'perception of health professionals', 'nursing/midwifery care in labour (in caesarean version: preparation for caesarean)', 'comforting', 'information and involvement in decision making', 'meeting baby', 'postpartum care', 'hospital room', 'hospital facilities', 'respect for privacy' and 'meeting expectations'. Both scales had good internal reliability, with Cronbach's alpha coefficients of 0.91. The scales established their convergent validity with significant correlations with the Newcastle Satisfaction with Nursing Scale. CONCLUSION: the scales are valid and reliable tools for evaluating Turkish women's experiences in labour and the early postpartum period. IMPLICATIONS FOR PRACTICE: the scales can contribute to the assessment of women's satisfaction with different aspects of care, the quality of care and developments in maternity services. PMID- 21546143 TI - Influence of post-cam design of posterior stabilized knee prosthesis on tibiofemoral motion during high knee flexion. AB - BACKGROUNDS: The post-cam design of contemporary posterior stabilized knee prosthesis can be categorized into flat-on-flat or curve-on-curve contact surfaces. The curve-on-curve design has been demonstrated its advantage of reducing stress concentration when the knee sustained an anteroposterior force with tibial rotation. How the post-cam design affects knee kinematics is still unknown, particularly, to compare the difference between the two design features. Analyzing knee kinematics of posterior stabilized knee prosthesis with various post-cam designs should provide certain instructions to the modification of prosthesis design. METHODS: A dynamic knee model was utilized to investigate tibiofemoral motion of various post-cam designs during high knee flexion. Two posterior stabilized knee models were constructed with flat-on-flat and curve-on curve contact surfaces of post-cam. Dynamic data of axial tibial rotation and femoral translation were measured from full-extension to 135 degrees . FINDINGS: Internal tibial rotation increased with knee flexion in both designs. Before post cam engagement, the magnitude of internal tibial rotation was close in the two designs. However, tibial rotation angle decreased beyond femoral cam engaged with tibial post. The rate of reduction of tibial rotation was relatively lower in the curve-on-curve design. From post-cam engagement to extreme flexion, the curve-on curve design had greater internal tibial rotation. INTERPRETATION: Motion constraint was generated by medial impingement of femoral cam on tibial post. It would interfere with the axial motion of the femur relative to the tibia, resulting in decrease of internal tibial rotation. Elimination of rotational constraint should be necessary for achieving better tibial rotation during high knee flexion. PMID- 21546144 TI - Quantifying normal 3D hip ROM in healthy young adult males with clinical and laboratory tools: hip mobility restrictions appear to be plane-specific. AB - BACKGROUND: Hip mobility is known to affect lumbar spine motion, yet the literature is unclear as to what constitutes normal, limited or excessive motion, given differences in methods, postures, age, etc. The purpose of this study was to establish normative and percentile data for hip rotation and extension, in a young adult male population, using varying methods of quantification. METHODS: 77 males (age 18-35) were recruited. Position data was captured using the Vicon Motion capture system, as participants were passively positioned in hip extension (using the Modified Thomas test) and prone hip rotation. 22 of these participants also had measurements obtained with a goniometer. 3D hip extension angles were calculated using Euler angles, and compared to those calculated in 2D. Goniometric results were compared to 2D measurements. FINDINGS: Normal distribution of hip extension and rotation range of motion was established, as were average values for the 5th through 95th percentiles. No significant differences existed between hip extension angles measured with the 2D and 3D approaches. Goniometric measurements of hip extension averaged 3.9 degrees less than 2D, less than 1 degrees different for external rotation, and not different for internal rotation. INTERPRETATION: The normative and percentile data documented here for hip rotation and extension appear to be validly quantified with goniometric techniques when compared to more objective techniques. Further, hip restriction in one plane may not predict restrictions in other planes. PMID- 21546145 TI - Is demand-side financing equity enhancing? Lessons from a maternal health voucher scheme in Bangladesh. AB - Demand-side financing (DSF) is used in the less-developed countries of the world to improve access to healthcare and to encourage market supply. Under DSF, households receive vouchers that can be used to pay for healthcare services. This study evaluated the effects of a universal DSF on maternal healthcare service utilization in Bangladesh. A household survey was conducted in and around the voucher scheme area one year after the initiation of the project. Women who gave birth within a year prior to the survey were interviewed. The utilization rates of maternal health services were found to be higher for all socioeconomic groups in the project area than in the comparison areas. Voucher recipients in the project area were 3.6 times more likely to be assisted by skilled health personnel during delivery, 2.5 times more likely to deliver the baby in a health facility, 2.8 times more likely to receive postnatal care (PNC), 2.0 times more likely to get antenatal care (ANC) services and 1.5 times more likely to seek treatment for obstetric complications than pregnant women not in the program. The degree of socioeconomic inequality in maternal health service utilization was also lower in the project area than in the comparison area. The use of vouchers evidenced much stronger demand-increasing effects on the poor. Poor voucher recipients were 4.3 times more likely to deliver in a health facility and two times more likely to use skilled health personnel at delivery than the non-poor recipients. Contrary to the inverse equity hypothesis, the voucher scheme reduced inequality even in the short run. Despite these improvements, socioeconomic disparity in the use of maternal health services has remained pro-rich, implying that demand-side financing alone will be insufficient to achieve the Millennium Development Goal for maternal health. A comprehensive system-wide approach, including supply-side strengthening, will be needed to adequately address maternal health concerns in poor developing countries. PMID- 21546147 TI - A model of survival from out-of-hospital cardiac arrest using the Boston EMS arrest registry. AB - OBJECTIVES: To characterize the survival rate for out-of-hospital arrests of cardiac aetiology and predictor variables associated with survival in Boston, MA, and to develop a composite multivariate logistic regression model for projecting survival rates. METHODS: This is a retrospective analysis of all arrests of presumed cardiac aetiology (from January 1, 2004 to December 31, 2007) where resuscitation was attempted (n=1156) by 911 emergency responders. RESULTS: The survival-at-hospital discharge rate was 11% (vs. 1-10% often reported). The coefficients and odds ratios in the first equation of the model show that joint presence of presenting rhythm of ventricular fibrillation/tachycardia (VF/VT) and return of spontaneous circulation in the pre-hospital setting (ROSC) is a substantial direct predictor of survival (e.g., 54% of such cases survive). Response time, public location, witnessed, and age are significant but less sizable direct predictors of survival. A second equation shows that these four variables make an additional indirect contribution to survival by affecting the probability of joint presence of VF/VT and ROSC; bystander CPR also makes such an indirect contribution but no significant direct one as shown in the first equation. The projected survival rate if cases had always experienced bystander CPR and rapid response time of less than four minutes is 21%. CONCLUSIONS: The unique model describes the major contribution of VF/VT and ROSC, and key relationships among predictors of survival. These connections may have otherwise gone underreported using standard approaches and should be considered when allocating scarce resources to impact cardiac arrest survival. PMID- 21546146 TI - Regional differences in brain volume predict the acquisition of skill in a complex real-time strategy videogame. AB - Previous studies have found that differences in brain volume among older adults predict performance in laboratory tasks of executive control, memory, and motor learning. In the present study we asked whether regional differences in brain volume as assessed by the application of a voxel-based morphometry technique on high resolution MRI would also be useful in predicting the acquisition of skill in complex tasks, such as strategy-based video games. Twenty older adults were trained for over 20 h to play Rise of Nations, a complex real-time strategy game. These adults showed substantial improvements over the training period in game performance. MRI scans obtained prior to training revealed that the volume of a number of brain regions, which have been previously associated with subsets of the trained skills, predicted a substantial amount of variance in learning on the complex game. Thus, regional differences in brain volume can predict learning in complex tasks that entail the use of a variety of perceptual, cognitive and motor processes. PMID- 21546148 TI - The influence of satellite populations of emerald ash borer on projected economic costs in U.S. communities, 2010-2020. AB - The invasion spread of the emerald ash borer (Agrilus planipennis Fairmaire) (Coleoptera: Buprestidae) is characterized by the formation of satellite populations that expand and coalesce with the continuously invading population front. As of January 2010, satellite infestations have been detected in 13 states and two Canadian provinces. Understanding how newly established satellite populations may affect economic costs can help program managers to justify and design prevention and control strategies. We estimate the economic costs caused by EAB for the 10-yr period from 2010 to 2020 for scenarios of fewer EAB satellite populations than those found from 2005 to 2010 and slower expansion of satellite populations found in 2009. We measure the projected discounted cost of treatment, removal, and replacement of ash trees (Fraxinus spp.) growing in managed landscapes in U.S. communities. Estimated costs for the base scenario with the full complement of satellites in 2005-2010 and no program to mitigate spread is $12.5 billion. Fewer EAB satellites from 2005 to 2010 delay economic costs of $1.0 to 7.4 billion. Slower expansion of 2009 satellite populations delays economic costs of $0.1 to 0.7 billion. Satellite populations that are both distant from the core EAB infestation and close to large urban areas caused more economic costs in our simulations than did other satellites. Our estimates of delayed economic costs suggest that spending on activities that prevent establishment of new satellite EAB populations or slow expansion of existing populations can be cost-effective and that continued research on the cost and effectiveness of prevention and control activities is warranted. PMID- 21546149 TI - River environmental decision support system development for Suzhou Creek in Shanghai. AB - The Suzhou Creek Rehabilitation Project (SCRP) is one of the largest water related environmental rehabilitation schemes ever undertaken in the vicinity of Shanghai, China. This paper details the development and application of a River Environmental Decision Support System (REDSS) for scientific planning and decision-making on the Suzhou Creek project, and illustrates the flexibility of the REDSS framework. We developed the following components: (1) a GIS-based analysis employing Component technology; (2) a "data mart" for multi-dimensional, multi-level, integrated, dynamic, and flexible data querying; and (3) a set of hydrodynamic and water quality models which can simulate complex tidal river networks. In addition, we detail how a water quality assessment model is embedded into the REDSS by employing an Identification Index Method. With the REDSS, all GIS and non-GIS components are integrated seamlessly and data from different sources can be queried simultaneously. This allows for various scenarios to be simulated and analyzed in advance to predict and assess the effects of proposed engineering and management measures. Generated information can thus support effective decisions. All operations of the REDSS can be implemented conveniently through user-friendly interfaces. The function of the REDSS framework is demonstrated through an application to Suzhou Creek. Because the REDSS characteristics are quite general, it may be applied in different geographic regions. PMID- 21546150 TI - Heavy metal content in sediments along the Calore river: relationships with physical-chemical characteristics. AB - In the present study, trace metals contents (V, Cr, Mn, Fe, Ni, Cu, Zn, Cd and Pb) and physico-chemical parameters (nitrogen, organic and inorganic carbon, pH and particle size) in sediments samples along the Calore river were analyzed in two seasons. Sediment samples were collected in ten sites upstream and downstream of the city of Benevento and its industrial area, the confluence of Sabato and Tammaro tributaries, and the confluence of Calore and Volturno rivers. The highest contents of trace metals were found, generally, in the sites immediately downstream of industrial area and of Benevento city. The sites on the Tammaro and Sabato also showed relatively high contents of Ni and, only for Sabato sites, of Cr, and Fe. With the exception of Cd, the heavy metal contents were highest in the last site of Calore river, which therefore is a source of pollution to the Volturno river. Besides the sites downstream of Benevento city showed the higher pH values and also the highest contents of fine particles size and organic matter. Positive correlations among trace metals, organic substance, particle size sediments were found. The data obtained in this study were analyzed with reference to Interim Sediment Quality Guidelines and indicated moderate-to-high pollution by some trace metals (V, Cr, Mn, Fe, Ni, Cu). PMID- 21546151 TI - A comparative evaluation of sonomyography, electromyography, force, and wrist angle in a discrete tracking task. AB - We have previously used the real-time change of muscle thickness detected using ultrasound, namely sonomyography (SMG), for prosthesis motor control purposes. In the present study, we further compared subjects' performance using SMG and surface electromyography (EMG) in a series of discrete tracking tasks, both with and without a concurrent auditory attention task. Sixteen healthy subjects used different signals in a random order to control the cursor on a personal computer screen to cancel the letter "E" in a sequence of vertically arranged letters. Subjects' performance was evaluated under isometric contraction and wrist extension using the extensor carpi radiali muscle. The percentage of successfully cancelled Es using SMG decreased by 21 +/- 16% and 17 +/- 11% in isometric contraction and wrist extension tests, respectively, compared with the corresponding performances using force and angle signals. The corresponding reduction recorded by using EMG was 40 +/- 29% and 41 +/- 25%. In addition, there was a significant decrease by using EMG compared with that by SMG (p < 0.001). The results also demonstrated that there was no significant difference of performances of canceling E between the single and dual tasks by using any of the control signals (p > 0.99). Furthermore, the SMG control provided more consistent performances under the single and dual tasks compared with EMG control. PMID- 21546152 TI - A simple method for quantifying ultrasound-triggered microbubble destruction. AB - Ultrasound-triggered microbubble destruction (UTMD) is essential for targeted drug delivery but currently there is no agreed gold standard for its real-time monitoring. This study used a clinical diagnostic ultrasound scanner to quantify the destruction effects of different values of mechanical index (MI) on microbubble. This was achieved by measuring the signal intensity of peripheral vessels, which is representative of systemic microbubble concentration. Twenty four male Sprague-Dawley rats and SonoVue contrast agent were used for this study, six for the determination of signal saturation and 18 for the study of microbubble destruction. In the first part of the experiment, four different SonoVue doses (200, 400, 600 and 800 MUL/kg) were injected into each of six rats and the signal intensity in their right femoral arteries were recorded using a diagnostic ultrasound scanner. This data was used to plot time-intensity curves (TIC) to determine at which concentration the signal reaches saturation. Then UTMD studies were performed using the 400 MUL/kg dose as its peak signal intensity (PSI) was safely within the linear portion of the intensity concentration curve. The remaining 18 rats were divided into three MI groups (0.2, 0.6 and 1.0) and for each rat, the following was performed: TIC recording of a sham exposure without sonication was performed first using the same scanner from signal saturation study. Simultaneously, another ultrasound scanner was applied to the adductor muscles of left hind limb for sonication later. Then, a sonication TIC recording was performed, with both ultrasound scanners activated. A TIC recording of second sonication was also obtained for comparison. The TICs showed that the area under the curve and the enhancement duration were reduced after sonication in the groups MI = 0.6 and MI = 1.0 but not for the group MI = 0.2. The PSI in the groups with MI of 0.6 and 1.0 were slightly lowered after sonication, although it is not statistically significant. No significant difference of TIC exists between the first and the second sonication for each group. Pharmacokinetic analysis was performed with estimated concentration-time curve derived from TIC curve and found that SonoVue had faster clearance and decreased half-life in the groups MI = 0.6 and MI = 1.0. In conclusion, this study shows that sonographic signal measured from peripheral vessels is a feasible indicator of systemic microbubble concentration and may be used to quantify ultrasound-triggered microbubble destruction at target site. PMID- 21546153 TI - Characterization and diagnostic confidence of contrast-enhanced ultrasound for solid renal tumors. AB - The objective was to determine whether contrast-enhanced ultrasound (CEUS) could improve the diagnostic confidence of solid renal masses. CEUS examinations were performed on 51 patients with renal tumors. Histologic findings from surgical specimens (n = 24) or magnetic resonance imaging follow-up (n = 27) were used as reference procedures for definitive diagnosis. Diffuse heterogeneous/homogeneous enhancement and quick peripheralnodularenhancement were found to be characteristic patterns in renal cell carcinoma (RCC). Dotlike or diffuse heterogeneous/homogeneous enhancement and slow peripheral nodular enhancement were observed as typical enhancement patterns in angiomyolipoma. The results show that CEUS combined with conventional ultrasound significantly improves diagnostic confidence. The sensitivity for RCC diagnosis with this imaging approach was 86% and the specificity was 93%. Both positive and negative predictive values of detection were 90% and the overall accuracy was 90%. PMID- 21546154 TI - Computerized detection and quantification of microcalcifications in thyroid nodules. AB - To improve the ultrasonographic detection rates of thyroid cancers with microcalcifications, we propose to enhance the sensitivity of sonographic calcifications detection and to avoid interobserver variation by a computerized quantification method in a prospective setting. A total of 227 participants with 258 nodules were evaluated. Among them, two nodules were excluded for suspicious aspiration cytology results without pathologic proof. Among the remaining 256 nodules, the diagnosis of 181 nodules was verified by surgical pathology and the diagnosis of 75 was based on fine needle aspiration (FNA) biopsy results. There were 173 benign thyroid nodules and 83 malignant thyroid nodules, which included 74 papillary carcinomas. Patient clinical data were collected and the presence of calcifications on conventional gray-scale ultrasound images was retrospectively reviewed by a thyroid specialist. Quantification of cystic components and calcifications was automatically performed by a proprietary program (AmCAD-UT) implemented with methods proposed in this article. The calcification index (CI) was calculated after the cystic component was excluded. The CI between benign and malignant nodules diagnosed by combined FNA biopsy and surgical pathology results (total number, 256) showed a significant difference (p < 0.0001, AUC = 0.746). Furthermore, we excluded patients without surgical pathology results for further validation and the CI between benign and malignant nodules confirmed by pathology results (total number, 181) showed a significant difference (p < 0.0001, AUC = 0.763). To learn whether our computer program increased our diagnostic capabilities, we analyzed human investigators and their abilities to detect and evaluate. In this study, calcifications were noted in 48.19% (40 of 83) of malignant thyroid nodules and in 10.98% (19 of 173) of benign nodules. This new computer-aided diagnosis method to evaluate the sonographic calcifications of thyroid nodules is a more sensitive and more objective method. It can provide better sensitivity than conventional methods in the diagnosis of thyroid malignancies containing microcalcifications. PMID- 21546156 TI - Epstein Barr virus in relation to apoptosis markers and patients' outcome in pediatric B-cell non-Hodgkin lymphoma. AB - In this study, we investigated Epstein Barr virus (EBV) presence, associated to proliferation and apoptosis proteins in pediatric B-cell Non-Hodgkin lymphoma (B NHL). EBERs, Ki67, active caspase 3, Bax and Bcl2 were analyzed on B-NHL tissue from 40 patients. Forty percent showed EBV expression, significantly higher among patients ?10years (P=0.027), and associated with immunosuppression (P=0.020), but not associated apotosis markers. However, EBV was associated with a worse event free survival (P=0.016), particularly under immunosuppression. Even though EBV did not seem to alter apoptotic pathways, it exhibited survival disadvantage and could be an important cofactor in B-cell lymphomagenesis in younger children. PMID- 21546155 TI - Imaging of wall motion coupled with blood flow velocity in the heart and vessels in vivo: a feasibility study. AB - The mechanical property and geometry changes as a result of cardiovascular disease affect both the wall motion and blood flow in the heart and vessels, whereas the latter two are also coupled and therefore continuously influence one another. Simultaneous and registered imaging of both cardiovascular wall motion and blood velocity may thus contribute to more complete computational models of cardiovascular mechanical and fluid dynamics as well as provide additional diagnostic information. The objective of this paper was to determine the feasibility of imaging cardiovascular wall motion coupled with blood flow in vivo. Normal (n = 6) and infarcted (n = 5) murine left ventricles, and normal (n = 5) and aneurysmal (n = 4) murine abdominal aortas, were imaged in longitudinal views with a 30-MHz ultrasound probe. Using electrocardiogram (ECG) gating, 2-D radio-frequency (RF) data were acquired at a frame rate of 8 kHz. The axial wall velocity and blood velocity were estimated using a speckle-tracking technique. Spatially and temporally registered imaging of both cardiovascular wall motion and blood flow was shown to be feasible. Reduced wall motion was detected in the infarcted region, whereas vortex flow patterns were imaged in diastolic phases of both normal and infarcted left ventricles. The myocardial wall motion and blood flow were found to be more synchronous in the normal heart, where the blood moves toward the anteroseptal wall after the mitral valve opens (i.e., rapid filling phase), and the anteroseptal wall simultaneously undergoes outward motion. In the infarcted heart, however, in the rapid filling phase, the basal anteroseptal wall starts moving about 20 ms before the mitral valve opens and the blood enters the left ventricle. In the normal aorta, the wall motion and blood velocity were uniform and synchronous. In the aneurysmal aorta, reduced and spatially varied wall motion and vortex flow patterns in the aneurysmal sac were found. The wall motion and blood velocity were thus less synchronous in the aneurysmal aorta. Cardiovascular wall motion and blood flow were both imaged in mice in vivo. This dual information may provide important insights for the diagnosis of cardiovascular disease as well as essential parameters for its biomechanical modeling. PMID- 21546157 TI - Annexin V-targeted enzyme prodrug therapy using cytosine deaminase in combination with 5-fluorocytosine. AB - A fusion protein, consisting of cytosine deaminase (CD) linked to human annexin V, was created for use in an enzyme prodrug therapy targeted to the tumor vasculature and associated cancer cells in the primary tumor and distant metastases. The major finding of this study is that the CD-annexin V fusion protein in combination with the prodrug 5-fluorocytosine has significant cytotoxic activity against endothelial cells and two breast cancer cells lines in vitro that expose phosphatidylserine on their surface. The cytotoxicity experiments verified this novel enzyme prodrug system has the ability to produce therapeutic levels of 5-fluorouracil and thus appears promising. PMID- 21546158 TI - Perturbation of an arctic soil microbial community by metal nanoparticles. AB - Technological advances allowing routine nanoparticle (NP) manufacture have enabled their use in electronic equipment, foods, clothing and medical devices. Although some NPs have antibacterial activity, little is known about their environmental impact and there is no information on the influence of NPs on soil in the possibly vulnerable ecosystems of polar regions. The potential toxicity of 0.066% silver, copper or silica NPs on a high latitude (>78 degrees N) soil was determined using community level physiological profiles (CLPP), fatty acid methyl ester (FAME) assays and DNA analysis, including sequencing and denaturing gradient gel electrophoresis (DGGE). The results of these different investigations were amalgamated in order to develop a community toxicity indicator, which revealed that of the three NPs examined, silver NPs could be classified as highly toxic to these arctic consortia. Subsequent culture-based studies confirmed that one of the community-identified plant-associating bacteria, Bradyrhizobium canariense, appeared to have a marked sensitivity to silver NPs. Thus, NP contamination of arctic soils particularly by silver NPs is a concern and procedures for mitigation and remediation of such pollution should be a priority for investigation. PMID- 21546159 TI - Photocatalytic degradation of 3,4-dichlorophenylurea in aqueous gold nanoparticles-modified titanium dioxide suspension under simulated solar light. AB - The TiO(2) modified with nanosized gold particles was prepared by deposition precipitation at pH 7 and calcination in air at various temperatures up to 973 K. The materials were characterized by transmission electron microscope, X-ray diffraction spectrometry, and atomic absorption spectroscopy. The highest photocatalytic efficiency was obtained at the calcination temperature of 873 K. The decrease in 3,4-dichlorophenylurea concentration follows first order kinetics with a half life of 36.6 +/- 2.0 min in 100 mg L(-1) of 0.83 wt% Au/TiO(2). Fifteen degradation products were identified using LC/MS/MS and IC. Degradation pathway was proposed on the basis of the observed transformation products. PMID- 21546160 TI - Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. AB - Studies on the efficacy of ketamine in the treatment of chronic pain indicate that prolonged or repetitive infusions are required to ensure prolonged pain relief. Few studies address ketamine-induced toxicity. Here we present data on the occurrence of ketamine-induced liver injury during repeated administrations of S(+)-ketamine for treatment of chronic pain in patients with complex regional pain syndrome type 1 as part of a larger study exploring possible time frames for ketamine re-administration. Six patients were scheduled to receive 2 continuous intravenous 100-hour S(+)-ketamine infusions (infusion rate 10-20mg/h) separated by 16 days. Three of these patients developed hepatotoxicity. Patient A, a 65 year-old woman, developed an itching rash and fever during her second exposure. Blood tests revealed elevated liver enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, and gamma-glutamyl transferase, all >= 3 times the upper limit of normal) and modestly increased eosinophilic leukocytes. Patient E, a 48-year-old woman, developed elevated liver enzymes of similar pattern as Patient A during her second ketamine administration and a weakly positive response to antinuclear antibodies. In a third patient, Patient F, a 46 year-old man, elevated liver enzymes (alanine transaminase and gamma-glutamyl transferase) were detected on the first day of his second exposure. In all patients, the ketamine infusion was promptly terminated and the liver enzymes slowly returned to reference values within 2 months. Our data suggest an increased risk for development of ketamine-induced liver injury when the infusion is prolonged and/or repeated within a short time frame. Regular measurements of liver function are therefore required during such treatments. PMID- 21546161 TI - NGF enhances electrically induced pain, but not axon reflex sweating. AB - High-affinity receptors for nerve growth factor (NGF) are found on nociceptors and sympathetic efferents. NGF is known to sensitize nociceptors, increase innervation density, and fire frequency of sympathetic fibers. We explored axonal sensitization of afferent and efferent fibers following intracutaneous injection of NGF in human and pig skin. In humans, frequency-dependent (5, 20, 100 Hz) electrically induced pain was assessed 1, 3, 7, 21, and 49 days post injection. Sweat output was recorded in parallel using the quantitative sudomotor axon reflex test (QSART). Electrically induced pain ratings (7.5 mA for 30 s) significantly increased at the NGF sites for 5 Hz (numeric rating scale [NRS] 6+/ 0.5 vs 3.7+/-0.4), 20 Hz (NRS 7.2+/-0.4 vs 5+/-0.5), and 100 Hz stimulation (NRS 6.9+/-0.4 vs 5.4+/-0.3) at day 21, and also for 5 Hz at day 49 (NRS 5.4+/-0.4 vs 3.8+/-0.3). Electrically evoked QSART increased frequency dependent, but was not altered by NGF throughout the entire observation period (average QSART at 5 Hz: 3 mL/h/m(2), 20 Hz: 9 mL/h/m(2), 100 Hz: 10 mL/h/m(2)). Similarly, NGF did not change the activity-dependent slowing of conduction of sympathetic efferents (6+/ 2% vs 5.1+/-1.5%, for 3 minutes, 2 Hz) in pig single-fiber recordings. In parallel to the increased pain ratings recorded in humans, activity-dependent slowing of mechano-insensitive nociceptors was reduced by NGF (18.1+/-2% vs 29+/ 1.4%). In summary, axonal sensitization of nociceptors by NGF could underlie the hyperalgesia to electrical stimulation. Enhanced responses were limited to nociceptors, as no sensitization was found in sympathetic efferent neurons. PMID- 21546162 TI - The epidemiology of civilian inpatients' burns in Chinese military hospitals, 2001-2007. AB - BACKGROUND: In China, large sample research directed at the epidemiology of burns is still scarce. Given the leading position of Chinese military hospitals in domestic clinical practice pertaining to burns, a look into their cases would help shed light on the incidence and hospital care of burns in China today. METHODS: Data were collected from information systems of all the Chinese military hospitals, for the years 2001-2007 inclusive. Retrospective analyses on the epidemiology characteristics of burns from those in patients admitted to all the Chinese military hospitals within this period were conducted. RESULTS: A total of 172,256 cases were studied, with a total number of 1384 fatalities, and the median length of hospital stay (LOS) 11.00 days (interquartile range 6.00-19.00 days). Rate of burn incidence remained high in May, June, July and August. Children of preschool aged and adults in the labor force were at the highest risk of injury. Scalds constituted the majority of injuries (80.5%). Multiple body site burns are the most commonly seen category (31.98%) in terms of injured body region distribution. In fire-related burns, major burns (TBSA>30%) represented a significant proportion. Males with TBSA>30%, fire-related burns resulted in the greatest number of fatalities. Gender, age, site of injury, burn size and outcome are all correlated with the length of hospitalization. CONCLUSION: Although this paper cannot provide information on population estimates of burns due to the absence of data on burns attending civilian hospitals, it finds that the epidemiology of burns in China shows distinct characteristics compared with previous studies of other country and regions, including that of other developing or low and middle-income countries (LMICs), irrespective of China's inclusion in that group. PMID- 21546163 TI - Current state of knowledge regarding the use of antiangiogenic agents with radiation therapy. AB - Angiogenesis has been a central theme of oncologic research for several years. Recently, improved understanding of its mechanisms has led to the development of several antiangiogenic agents. Some have demonstrated their effectiveness in large randomized studies; however, no antiangiogenic agent has yet been approved for treatment in combination with radiotherapy. Numerous preclinical studies and a few small clinical trials have recently reported encouraging results. The objective of this article is to review the concept of targeted antiangiogenic agents and the early clinical results of their use in combination with radiation therapy. PMID- 21546164 TI - Oxytocin administration attenuates stress reactivity in borderline personality disorder: a pilot study. AB - Oxytocin has known stress-reducing and attachment-enhancing effects. We thus hypothesized that oxytocin would attenuate emotional and hormonal responses to stress in borderline personality disorder (BPD). Fourteen BPD and 13 healthy control (HC) adults received 40 IU intranasal oxytocin or placebo in double-blind randomized order followed by the Trier Social Stress Test. Subjective dysphoria (Profile of Mood Changes) and plasma cortisol levels were measured. Childhood trauma history, attachment style, and self-esteem were also rated. A significant "Group * Drug * Time" interaction effect for dysphoria (p=.04) reflected a proportionately greater attenuation of stress-induced dysphoria in the BPD group after oxytocin administration. Additionally, a marginally significant "Group * Drug" interaction effect for cortisol (p=.10) reflected a tendency toward greater attenuation of the stress-induced cortisol surge in the BPD group after oxytocin administration. In the combined sample, the oxytocin-placebo difference in the emotional stress reactivity was significantly predicted by childhood trauma alone (p=.037) and combined with self-esteem (p=.030), whereas the oxytocin-placebo difference in cortisol stress reactivity was predicted only by insecure attachment (p=.013). Results suggest that oxytocin may have a beneficial impact on emotional regulation in BPD, which merits further investigation and could have important treatment implications. PMID- 21546165 TI - Relation between duration of incubation period of prion infections and prion protein conformation. AB - In this paper, we propose the hypothesis that the long incubation period of prion infections is dependent upon a low rate of pathological prion formation and accumulation. Reduced pathological prion formation might be caused by the high content of beta-sheets in the molecule. beta-Sheet folding appears to proceed more slowly than folding of alpha-helices; the former are a major component of the prion secondary structure. This hypothesis strongly agrees with the data about folding of the artificial protein l-polylysine. This protein exists in two subforms: a rapidly folding alpha-helix-enriched form and a beta-sheet-rich form having a very slow speed of secondary and tertiary structure formation. According to our hypothesis, the limiting factor for prion infection propagation is the speed of beta-sheet folding in molecules of pathological prion but not the speed of migration of this protein through the host organism. PMID- 21546166 TI - Cocaine mediated apoptosis of vascular cells as a mechanism for carotid artery dissection leading to ischemic stroke. AB - In arterial dissection, blood may enter the arterial wall through an intimal tear, splitting the arterial wall and activating the coagulation cascade at the site of endothelial damage. Dissection of extracranial and intracranial vessels may lead to ischemic stroke through thromboembolic or hemodynamic mechanisms. Major blunt trauma or rapid acceleration-deceleration may cause dissection, but in patients with inherent arterial wall weakness, dissection can occur spontaneously or as a result of minor neck movement. Cocaine use has been associated with dissection of the aortic arch and coronary and renal arteries through cocaine-mediated hypertension. Recent preclinical studies have suggested, however, that cocaine may cause apoptosis of cells in the vascular wall. In this article, we postulate that cocaine may cause apoptosis of vascular endothelial and/or smooth muscle cells, thus weakening the vascular wall and resulting in a dissection-prone state. We review the literature and propose a biological basis for vasculopathy, vascular dissection, and ischemic stroke in the setting of cocaine use. Further research studies on vascular cells, as well as focused analysis of human pathological material, will be important in providing evidence for or against our hypotheses. PMID- 21546167 TI - Occurrence of recurrent aphthous stomatitis only on lining mucosa and its relationship to smoking--a possible hypothesis. AB - Recurrent aphthous stomatitis (RAS) is one of the most common ulcers affecting the oral cavity. Though it is known that RAS affects only the lining (non keratinized) mucosa sparing the masticatory (keratinized) mucosa and is unlikely to be seen in smokers, no concrete explanations have been put forward. A hypothesis is proposed that the keratin layer blocks the ingress of antigens and prevents the occurrence of RAS on masticatory mucosa. Similarly, combustible products of smoking are known to cause keratinization and therefore have a similar effect on the lining mucosa and inhibit its occurrence. In addition, nicotine or its metabolites can result in decrease of pro-inflammatory cytokines like tumor necrosis factor-alpha, interleukins 1 and 6, and increase of anti inflammatory cytokine interleukin-10. Consequently, there is reduced susceptibility to RAS due to immunosuppression and/or reduction in inflammatory response. PMID- 21546168 TI - How is the instrumental color of meat measured? AB - Peer-reviewed journal articles (n=1068) were used to gather instrumental color measurement information in meat science research. The majority of articles, published in 10 peer-reviewed journals, originated from European countries (44.8%) and North America (38.5%). The predominant species was pork (44.2%), and most researchers used Minolta (60.0%) over Hunter (31.6%) colorimeters. Much of the research was done using illuminant D65 (32.3%); nevertheless, almost half (48.9%) of the articles did not report the illuminant. Moreover, a majority of the articles did not report aperture size (73.6%) or the number of readings per sample (52.4%). Many factors influence meat color, and a considerable proportion of the peer-reviewed, published research articles failed to include information necessary to replicate and/or interpret instrumental color results; therefore, a standardized set of minimum reportable parameters for meat color evaluation should be identified. PMID- 21546169 TI - Genetic parameters of carcass and meat quality traits of double muscled Piemontese cattle. AB - Genetic parameters of meat quality (MQ) were estimated on Longissimus thoracis muscle of 1208 Piemontese young bulls, progeny of 109 AI sires. Carcass weight (CW), conformation (EUS) and pH (pH24h) were recorded at 24h and lightness (L*), redness (a*), yellowness (b*), pH (pH8d), drip loss (DL), cooking loss (CL) and shear force (SF) were assessed. The heritability (h(2)) of pH24h was very low (0.06), but h2 of pH8d was markedly higher (0.42). Heritability was 0.32, 0.33, and, 0.14, for L*, a* and b*, respectively, whereas was 0.24, 0.07 and 0.14, for DL, CL, and SF, respectively. The two pH measures showed opposite genetic relationships with color measures. Genetic correlations of DL and CL were positive with L* and b* and negative with a*. Genetic correlations between carcass traits and MQ suggest that animals with superior growth potential tend to exhibit reduced EUS scores and pale meat with lower tenderness and water holding capacity. Conversely, improvement of EUS score through selection would lead to light, bright, and tender meat with enhanced water holding capacity. PMID- 21546170 TI - Working chute behavior of feedlot cattle can be an indication of cattle temperament and beef carcass composition and quality. AB - The relationship between working chute temperament and beef carcass quality traits were measured on 183 crossbred feedlot steers. Steers were weighed and sorted into 16 pens and weighed every 28 days. Temperament was evaluated as exit velocity (EV), chute score (CS), and catch score (CAPS). Tissue samples were collected for DNA profile including docility (IGENITY(r), Merial Limited, Duluth, GA, U.S.A). Steers were harvested at 14 to 16 months of age (606 +/- 52 kg). Exit velocity increased and CS and CAPS values declined over time. Steers receiving a lower CAPS score had more marbling (P = 0.02). Ribeye steaks from steers with a slow first recorded EV were more tender (P = 0.02) than steaks from faster EV steers. IGENITY(r) docility index had a positive (P = 0.09) correlation (r = 0.15) with Warner-Bratzler shear force (WBS) indicating a higher docility index was loosely associated with tougher meat. PMID- 21546171 TI - Perfusion estimated with rapid dynamic contrast-enhanced magnetic resonance imaging correlates inversely with vascular endothelial growth factor expression and pimonidazole staining in head-and-neck cancer: a pilot study. AB - PURPOSE: To analyze, in a pilot study, rapidly acquired dynamic contrast-enhanced (DCE)-MRI data with a general two-compartment exchange tracer kinetic model and correlate parameters obtained with measurements of hypoxia and vascular endothelial growth factor (VEGF) expression in patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Eight patients were scanned before surgery. The DCE-MRI data were acquired with 1.5-s temporal resolution and analyzed using the two-compartment exchange tracer kinetic model to obtain estimates of parameters including perfusion and permeability surface area. Twelve to 16 h before surgery, patients received an intravenous injection of pimonidazole. Samples taken during surgery were used to determine the level of pimonidazole staining using immunohistochemistry and VEGF expression using quantitative real-time polymerase chain reaction. Correlations between the biological and imaging data were examined. RESULTS: Of the seven tumors fully analyzed, those that were poorly perfused tended to have high levels of pimonidazole staining (r = -0.79, p = 0.03) and VEGF expression (r = -0.82, p = 0.02). Tumors with low permeability surface area also tended to have high levels of hypoxia (r = -0.75, p = 0.05). Hypoxic tumors also expressed higher levels of VEGF (r = 0.82, p = 0.02). CONCLUSIONS: Estimates of perfusion obtained with rapid DCE-MRI data in patients with head-and-neck cancer correlate inversely with pimonidazole staining and VEGF expression. PMID- 21546172 TI - Application of the conditioned taste aversion paradigm to assess discriminative stimulus properties of psychostimulants in rats. AB - BACKGROUND: The conditioned taste aversion (CTA) paradigm is one of the reliable methods to evaluate the discriminative stimulus properties of drugs and is characterized by a short conditioning period and no need for special equipment. This method, however, has not yet been fully investigated for psychostimulants such as cocaine and methamphetamine. METHODS: In the present study, rats were trained to discriminate between cocaine and a vehicle using CTA and substitution tests with various psychostimulants were conducted to evaluate the usefulness of the method for assessing the discriminative stimulus properties of this pharmacological class. Male rats received an intraperitoneal (i.p.) injection of cocaine (10mg/kg) 10 min prior to access saccharin for 20-min, and immediately after the saccharin access they received an i.p. dose of LiCl (1.8 mEq; n=8, Group CL) or the vehicle (n=8, Group CW) on the day of conditioning; on the other days (2 or 3 days between the cocaine conditioning days), they were injected with saline prior to access to saccharin without the LiCl or vehicle injection after the access. RESULTS: By the fifteenth cocaine conditioning trial, all animals acquired discrimination. In the substitution test, cocaine dose dependently decreased saccharin consumption. The psychostimulants, methamphetamine, methylphenidate, bupropion and sibutramine, substituted for cocaine, whereas the opioid MU agonist morphine and the cannabinoid agonist, Delta9 tetrahydrocannabinol, did not substitute for cocaine. Mazindol did not substitute for cocaine although it has CNS stimulant activities. CONCLUSION: These results suggest that discriminative stimulus properties of psychostimulants can be evaluated using the CTA paradigm. PMID- 21546173 TI - Health related quality of life trajectories of patients in opioid substitution treatment. AB - BACKGROUND: While opioid substitution treatment (OST) provides the opportunity for substantial improvements in health related quality of life (HRQoL), this relationship is seldom documented and poorly understood. Our objectives were to identify differences in trajectories of HRQoL among chronic opioid-dependent patients and factors associated with improvement and deterioration in HRQoL following enrolment in opioid substitution treatment. METHODS: In the North American Opiate Medication Initiative (NAOMI) randomized controlled trial, the Euroqol (EQ-5D) and other measures of demographic, health and drug use characteristics were collected at baseline and quarterly follow-up. Latent class growth analysis was applied to identify classes of HRQoL trajectories during treatment, while baseline correlates of class membership and factors associated with changes in HRQoL were identified in multivariate analyses. RESULTS: Three classes of individual HRQoL growth trajectories were identified: class 1: low and constant (19.5%), class 2: moderate and improved (61.2%), and class 3: high and constant (19.3%). Class 1 members were younger and more likely to be female, while class 3 members were less likely to have chronic conditions and had lower illicit drug use severity at baseline. Changes in HRQoL were associated with improvements in housing status (positive), medical events (negative) and decreases in illicit drug use (positive). CONCLUSIONS: Insight into the extent of HRQoL response and characteristics of patients responding to treatment can be used to design interventions that maximize HRQoL improvement. Given its role in economic evaluation and subsequent resource allocation decisions, HRQoL should be considered an endpoint in treatment evaluations for opioid dependence. PMID- 21546174 TI - Occurrence and virulence patterns of E. coli O26, O103, O111 and O145 in slaughter cattle. AB - The study attempted to investigate the occurrence of non-O157 E. coli serogroups O26, O103, O111 and O145 in cattle at slaughter and to determine the virulence potential of these isolates. A total of 399 fecal samples were analyzed by selective plating and E. coli isolates were characterized by polymerase chain reaction (PCR) for the genes vtx1, vtx2, eae and EHEC hlyA. Immunomagnetic separation (IMS) is required to increase the efficiency of the isolation procedure. E. coli O26, O103, O111 and O145 were recovered from 24 (6%) fecal samples. E. coli O26 and O103 seemed to be more abundant in slaughter cattle than E. coli O111 and O145. Sixteen out of the 24 isolates harbored vtx genes. All vtx positive isolates harbored one or more additional virulence factors. Six out of the 8 vtx-negative isolates harbored eae and/or EHEC hlyA, whereas 2 strains harbored none of the tested virulence genes. PMID- 21546175 TI - Identification of 1-butyl-3-(1-(4-methyl)naphthoyl)indole in a herbal mixture. AB - Besides the cannabinoid mimetic JWH-073, a novel 4 methylnaphthoyl homologue of JWH-073 was detected in a herbal mixture. The structure of the compound was elucidated after thin layer chromatographic enrichment from the herbal mixture by nuclear magnetic resonance (NMR) and gas chromatographic mass spectrometric (GC MS) analysis. The paper outlines data after GC-MS, liquid chromatography mass spectrometry (LC-MS) and NMR spectroscopy, and describes the structure elucidation. PMID- 21546176 TI - [Severe cryoglobulinemia secondary to Parvovirus B19 infection]. PMID- 21546177 TI - Prognostic value of preoperative FDG-PET in stage IA lung adenocarcinoma. AB - BACKGROUND: Maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been found to have prognostic value. We previously reported the correlation between SUVmax and pathological invasive area, and determined an SUVmax cut-off value of 2.15 for predicting the recurrence potential of an invasive area of diameter 5mm. Here, we evaluate the validity of FDG-PET for prediction of recurrence in pathological stage IA lung adenocarcinoma. METHODS: From February 2006 to May 2008, 100 patients with pathological stage IA lung adenocarcinoma underwent complete resection at our hospital. Tumors were classified as air-type or solid-type based on thin-section computed tomography (TS-CT) findings and the influence of TS-CT classification, SUVmax, and clinicopathologic features were evaluated in terms of the incidence of recurrence. RESULTS: Unlike air-type adenocarcinomas, recurrent disease was detected in 8 of 62 solid-type adenocarcinomas. SUVmax and diameter of invasive area were significantly correlated with recurrence and a shorter time to recurrence. All 8 recurrent cases had pathological invasive area >5mm. All except one case of recurrence were solid-type adenocarcinomas with SUVmax>=2.15. Three year disease-free survival rates were 100% in air-type adenocarcinomas, 97.1% in solid-type adenocarcinomas with SUVmax<2.15, and 74.1% in solid-type adenocarcinoma with SUVmax>=2.15. CONCLUSION: Combined evaluation of TS-CT classification and SUVmax had significant value in predicting recurrence in stage IA lung adenocarcinoma, reflecting the aggressiveness of primary lung adenocarcinoma. Prediction of tumor aggressiveness could contribute to decision making regarding the choice of surgical procedure and treatment after surgery. PMID- 21546178 TI - Age-related incidence of pulmonary embolism and additional pathologic findings detected by computed tomography pulmonary angiography. AB - OBJECTIVE: To compare the incidence of pulmonary embolism (PE) and additional pathologic findings (APF) detected by computed tomography pulmonary angiography (CTPA) according to different age-groups. MATERIALS AND METHODS: 1353 consecutive CTPA cases for suspected PE were retrospectively reviewed. Patients were divided into seven age groups: <=29, 30-39, 40-49, 50-59, 60-69, 70-79 and >=80 years. Differences between the groups were tested using Fisher's exact or chi-square test. A p-value<0.0024 indicated statistical significance when Bonferroni correction was used. RESULTS: Incidence rates of PE ranged from 11.4% to 25.4% in different age groups. The three main APF were pleural effusion, pneumonia and pulmonary nodules. No significant difference was found between the incidences of PE in different age groups. Furthermore, APF in different age groups revealed no significant differences (all p-values>0.0024). CONCLUSION: The incidences of PE and APF detected by CTPA reveal no significant differences between various age groups. PMID- 21546179 TI - Results of endovascular treatment for intracranial wide-necked saccular and dissecting aneurysms using the Enterprise stent: a single center experience. AB - OBJECTIVE: The aim of the present retrospective study is to compare outcome of the endovascular treatment using the Enterprise stent in intracranial wide-necked saccular and dissecting aneurysms. METHODS: Forty-six patients with 50 complex intracranial aneurysms admitted between June 2009 and November 2010 were treated using Enterprise stents. Thirty-one aneurysms were wide-necked saccular, 19 aneurysms dissecting. In 48 cases, aneurysms were occluded by stent-assisted coiling; in 2 cases, by stent alone. RESULTS: Among the aneurysms treated with the Enterprise stent, patient sex, aneurysm location, hypertension history and the immediate angiographic results differed significantly between the saccular and dissecting aneurysm groups. However, recurrence rate, clinical follow-up outcomes did not differ significantly between the saccular and dissecting groups. There was 1 (2%) procedure-related complication, which caused death in the saccular group. At mean 9.1-month follow-up, the result was good in all dissecting cases and good in 30 saccular cases. There was 1 recurrence in each group. CONCLUSIONS: Enterprise stent is very useful for endovascular embolization of intracranial wide-necked saccular and dissecting aneurysms because it is easy to navigate and place precisely. The overall morbidity and mortality rates were low. PMID- 21546180 TI - Mapping the brain in type II diabetes: Voxel-based morphometry using DARTEL. AB - PURPOSE: To investigate the pattern of brain volume changes of the brain in patients with type II diabetes mellitus using voxel-based morphometry. MATERIAL AND METHODS: Institutional ethics approval and informed consent were obtained. VBM based on the high resolution three-dimensional T1-weighted fast spoiled gradient recalled echo MRI images was obtained from 16 type II diabetes patients (mean age 61.2 years) and 16 normal controls (mean age 59.6 years). All images were spatially preprocessed using Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL) algorithm, and the DARTEL templates were made from 100 normal subjects. Statistical parametric mapping was generated using analysis of covariance (ANCOVA). RESULTS: An atrophy pattern of gray matter was seen in type II diabetes patients compared with controls that involved the right superior, middle, and inferior temporal gyri, right precentral gyrus, and left rolandic operculum region. The loss of white matter volume in type II diabetes mellitus was observed in right temporal lobe and left inferior frontal triangle region. ROI analysis revealed that the gray and white matter volume of right temporal lobe were significant lower in type II diabetes mellitus than that in controls (P<0.05). CONCLUSION: This work demonstrated that type II diabetes mellitus patients mainly exhibited gray and white matter atrophy in right temporal lobe, and this finding supported that type II diabetes mellitus could lead to subtle diabetic brain structural changes in patients without dementia or macrovascular complications. PMID- 21546181 TI - Ultrasonographic differentiation between Kikuchi's disease and lymphoma in patients with cervical lymphadenopathy. AB - PURPOSE: Kikuchi's disease, or histiocytic necrotizing lymphadenitis, is a self limited necrotizing lymphadenitis. Clinically, it resembles lymphoma. We want to compare the sonographic features between Kikuchi's disease and lymphoma in patients with cervical lymphadenopathy. MATERIALS AND METHODS: The study protocol was approved by the institutional review board. Two hundred and twenty six cervical lymph nodes (137 nodes from 21 Kikuchi's disease patients and 89 nodes from 20 malignant lymphoma patients) were examined. The demographic and ultrasonographic characteristics of lymph nodes were collected and analyzed. RESULTS: The Kikuchi's disease patients (mean age, 24.2 years; range, 8-57 years) were younger than those with lymphoma (mean age, 54 years; range, 13-81 years). There was no difference in laterality of nodes (p=0.19). The nodal distribution demonstrated most enlarged neck lymph nodes located at level II, III and V. The ranges of short-axis and long-axis length were 6.5+/-2.3mm (mean+/-SD) versus 13.4+/-5.1mm and 13.4+/-5.0mm versus 21.2+/-9.2mm for Kikuchi's disease versus lymphoma (p<0.01), respectively. The S/R ratio of Kikuchi's disease nodes was 0.5+/-0.2 compared to 0.7+/-0.2 in lymphoma nodes (p<0.01). Eighty-seven of 137 nodes (63.5%) of Kikuchi's disease, and eight of 89 nodes (9%) of malignant lymphoma had signs of cortical widening (p<0.01). Seventy-six nodes (55.5%) of Kikuchi's disease and twenty-eight nodes (31.5%) of malignant lymphoma were matted (p<0.01). Forty-five of 89 nodes among lymphoma and twenty-four among 137 of Kikuchi's disease had features of micronodular reticular echotexture (p<0.01). All nodes exhibited hypoechogenicity except one lymphomatous node demonstrated isoechogenicity, and there was no difference in sharpness of border and presence of echogenic hilum between the two diseases (p>0.05). CONCLUSION: Analysis of basic ultrasonographic characteristics (size, shape, rims, matting and echotexture) helps differentiate cervical lymph nodes in patients with Kikuchi's disease and lymphoma. Cervical lymphadenopathies in patients with Kikuchi's disease have smaller size, less round, less micronodular reticular echotexture, and more signs of matting and cortical widening than those with lymphoma examined under ultrasound. PMID- 21546182 TI - CT angiography of various superficial femoral artery stents: an in vitro phantom study. AB - PURPOSE: To evaluate CT reconstruction parameters to improve stent lumen visualization in vitro. MATERIAL AND METHODS: 12 latest superficial femoral artery (SFA) stents were placed in a vessel phantom (diameter 4.7 mm, intravascular attenuation 250 HU, extravascular density 50 HU). Stents were imaged with a 128-slice scanner (SOMATOM Definition Flash, Siemens, Germany) with standard parameters: 120 kV, 200 mAs, collimation 128mm * 0.6mm. Different reconstruction parameters were evaluated: B26f, B30f, B45f, B46f and B60f kernel; slice thickness of 0.6, 2.0 and 5.0mm. To measure visualization characteristics, stent lumen diameter and intraluminal attenuation were assessed. RESULTS: Best stent lumen visualization could be obtained using the B46f kernel (p<0.001). The visible stent lumen ranged from 66.4% to 83.3% with a mean diameter of 77.7 +/- 4.6%. Nitinol stents showed a significant improved lumen visibility compared to the cobalt-chromium stent (p = 0.02). The most realistic lumen attenuation was achieved using the B46f kernel with a mean attenuation of 259.3 +/- 8.9 HU. The visible lumen diameter in protocols with 5mm slice thickness was significantly lower (70.0 +/- 4.9%) compared to thinner slices (p<0.001). CONCLUSION: CTA of SFA stents should be reconstructed with a slice thickness of 2.0mm and a B46f kernel to achieve best image quality and to become more sensitive to exclude instent restenosis. PMID- 21546183 TI - Imaging of the peripheral nervous system. Editorial. PMID- 21546184 TI - The nerves around the shoulder. AB - Neuropathies of the shoulder are considered to be entrapment syndromes. They are relatively common, accounting for about 2% of cases of sport-related shoulder pain. Many instances involve suprascapular neuropathy, but the clinical diagnosis is often delayed because of nonspecific symptoms. Classically, EMG is the gold standard investigation but MRI currently reveals muscular abnormality in 50% of cases. Muscle edema, the most characteristic symptom, is nonspecific. In general, the topography of edema, the presence of a lesion compressing the nerve and clinical history contribute to the diagnosis. Although atrophy and fatty degeneration may persist after the disappearance of edema, they are rarely symptomatic. The main differential diagnosis is Parsonage-Turner syndrome. Evidence of a cyst pressing on a nerve may prompt puncture-infiltration guided by ultrasonography or CT-scan. PMID- 21546185 TI - The reversed halo sign. Another CT finding useful for distinguish invasive pulmonary aspergillosis and pulmonary lymphoma. PMID- 21546186 TI - Prospective image registration for automated scan prescription of follow-up knee images in quantitative studies. AB - Consistent scan prescription for MRI of the knee is very important for accurate comparison of images in a longitudinal study. However, consistent scan region selection is difficult due to the complexity of the knee joint. We propose a novel method for registering knee images using a mutual information registration algorithm to align images in a baseline and follow-up exam. The output of the registration algorithm, three translations and three Euler angles, is then used to redefine the region to be imaged and acquire an identical oblique imaging volume in the follow-up exam as in the baseline. This algorithm is robust to articulation of the knee and anatomical abnormalities due to disease (e.g., osteophytes). The registration method is performed only on the distal femur and is not affected by the proximal tibia or soft tissues. We have incorporated this approach in a clinical MR system and have demonstrated its utility in automatically obtaining consistent scan regions between baseline and follow-up examinations, thus improving the precision of quantitative evaluation of cartilage. Results show an improvement with prospective registration in the coefficient of variation for cartilage thickness, cartilage volume and T2 relaxation measurements. PMID- 21546187 TI - Improving background suppression in diffusion-weighted imaging of the abdomen and pelvis using STIR with single-axis diffusion encoding. AB - Bowel contents and peripheral nerves often show high signal intensity at diffusion-weighted imaging (DWI) of the abdomen and pelvis, obscuring or mimicking pathology. This study introduced and compared short tau inversion recovery (STIR) with single-axis DWI to the usual combination of spectral fat suppression (SFS) with trace DWI in the suppression of bowel contents and peripheral nerves. Five volunteers underwent both STIR with single-axis DWI and SFS with trace DWI of the abdomen and pelvis. Images were evaluated by two observers with respect to the suppression of signal of bowel contents and peripheral nerves using four-point grading scales (4=poor suppression; 3=moderate suppression; 2=good suppression; 1=excellent suppression). Mean scores (+/-S.D.) regarding the suppression of bowel contents were 1.60+/-0.55 and 1.40+/-0.89 for STIR with single-axis DWI and 3.40+/-0.55 and 3.00+/-1.00 for SFS with trace DWI for observers 1 and 2, respectively. Mean scores regarding the suppression of peripheral nerves were 1.20+/-0.45 and 1.20+/-0.45 for STIR with single-axis DWI and 2.40+/-0.89 and 2.80+/-0.84 for SFS with trace DWI for observers 1 and 2, respectively. In conclusion, STIR with single-axis DWI is superior to SFS with trace DWI in the suppression of bowel signal and peripheral nerves. PMID- 21546188 TI - Deconvolution with simple extrapolation for improved cerebral blood flow measurement in dynamic susceptibility contrast magnetic resonance imaging during acute ischemic stroke. AB - Magnetic resonance (MR) perfusion imaging is a clinical technique for measuring brain blood flow parameters during stroke and other ischemic events. Ischemia in brain tissue can be difficult to accurately measure or visualize when using MR derived cerebral blood flow (CBF) maps. The deconvolution techniques used to estimate flow can introduce a mean transit time-dependent bias following application of noise stabilization techniques. The underestimation of the CBF values, greatest in normal tissues, causes a decrease in the image contrast observed in CBF maps between normally perfused and ischemic tissues; resulting in ischemic areas becoming less conspicuous. Through application of the proposed simple extrapolation technique, CBF biases are reduced when missing high frequency signal components in the MR data removed during deconvolution noise stabilization are restored. The extrapolation approach was compared with other methods and showed a statistically significant increase in image contrast in CBF maps between normal and ischemic tissues for white matter (P<.05) and performed better than most other methods for gray matter. Receiver operator characteristic curve analysis demonstrated that extrapolated CBF maps better-detected penumbral regions. Extrapolated CBF maps provided more accurate CBF estimates in simulations, suggesting that the approach may provide a better prediction of outcome in the absence of treatment. PMID- 21546189 TI - Post-processing central k-space subtraction for high-resolution arterial peripheral MR angiography. AB - Peripheral MR angiography requires high resolution and arterial contrast. Neither can be obtained simultaneously due to the short arterial phase of the contrast agent. To improve temporal resolution, keyhole imaging was developed, which combines high resolution and arterial k-spaces at the time of image acquisition. Here, a related approach is introduced for image post-processing in the Fourier domain. It is demonstrated that simple substitution of the central k-space with low-resolution data leads to severe distortion. Hence, a dedicated calculation scheme is necessary for composite k-space post-processing. A solution is presented for high-resolution arterial peripheral MR angiography that uses subtraction of venous intensities from the central high-resolution k-space. The calculations in the Fourier domain do not require interpolations between the different resolutions. High-resolution steady-state MR angiography, which exhibits contrast-enhanced arteries and veins at an isotropic resolution of 0.65 mm, and standard resolution arterial first-pass MR angiography were combined to obtain images with the resolution of the steady-state images and arterial contrast. Numerical simulations on software phantoms are presented. The operation of the method is demonstrated in five patients. PMID- 21546190 TI - Pulsed arterial spin labeling perfusion imaging at 3 T: estimating the number of subjects required in common designs of clinical trials. AB - Pulsed arterial spin labeling (PASL) is an increasingly common technique for noninvasively measuring cerebral blood flow (CBF) and has previously been shown to have good repeatability. It is likely to find a place in clinical trials and in particular the investigation of pharmaceutical agents active in the central nervous system. We aimed to estimate the sample sizes necessary to detect regional changes in CBF in common types of clinical trial design including (a) between groups, (b) a two-period crossover and (3) within-session single dosing. Whole brain CBF data were acquired at 3 T in two independent groups of healthy volunteers at rest; one of the groups underwent a repeat scan. Using these data, we were able to estimate between-groups, between-session and within-session variability along with regional mean estimates of CBF. We assessed the number of PASL tag-control image pairs that was needed to provide stable regional estimates of CBF and variability of regional CBF across groups. Forty tag-control image pairs, which take approximately 3 min to acquire using a single inversion label delay time, were adequate for providing stable CBF estimates at the group level. Power calculations based on the variance estimates of regional CBF measurements suggest that comparatively small cohorts are adequate. For example, detecting a 15% change in CBF, depending on the region of interest, requires from 7-15 subjects per group in a crossover design, 6-10 subjects in a within-session design and 20-41 subjects in a between-groups design. Such sample sizes make feasible the use of such CBF measurements in clinical trials of drugs. PMID- 21546191 TI - Accuracy of image registration between MRI and light microscopy in the ex vivo brain. AB - A multistep procedure was developed to register magnetic resonance imaging (MRI) and histological data from the same sample in the light microscopy image space, with the ultimate goal of allowing quantitative comparisons of the two datasets. The fixed brain of an owl monkey was used to develop and test the procedure. In addition to the MRI and histological data, photographic images of the brain tissue block acquired during sectioning were assembled into a blockface volume to provide an intermediate step for the overall registration process. The MR volume was first registered to the blockface volume using a combination of linear and nonlinear registration, and two dimensional (2D) blockface sections were registered to corresponding myelin-stained sections using a combination of linear and nonlinear registration. Before this 2D registration, two major types of tissue distortions were corrected: tissue tearing and independent movement of different parts of the brain, both introduced during histological processing of the sections. The correction procedure utilized a 2D method to close tissue tears and a multiple iterative closest point (ICP) algorithm to reposition separate pieces of tissue in the image. The accuracy of the overall MR to micrograph registration procedure was assessed by measuring the distance between registered landmarks chosen in the MR image space and the corresponding landmarks chosen in the micrograph space. The average error distance of the MR data registered to micrograph data was 0.324+/-0.277 mm, only 8% larger than the width of the MRI voxel (0.3 mm). PMID- 21546192 TI - Quantification of myocardial viability distribution with Gd(DTPA) bolus-enhanced, signal intensity-based percent infarct mapping. AB - INTRODUCTION: A substantial, common shortcoming of the currently used semiautomated techniques for the quantification of myocardial infarct with delayed enhancement magnetic resonance imaging is the assumption that the whole myocardial slab that corresponds to the hyperenhanced tomographic area is 100% nonviable. This assumption is, however, incorrect. To resolve this conflict, we have recently proposed the signal intensity percent-infarct mapping method and validated it in an ex vivo, canine experiment. The purpose of the current study has been the validation of the signal intensity percent-infarct mapping method in vivo, using a porcine model of reperfused myocardial infarct. METHODS: In swines (n=6), reperfused myocardial infarct was generated occluding for 90 min by an angioplasty balloon either the left anterior descending or the left circumflex coronary artery. To obtain DE images, Gd(DTPA) enhanced inversion-recovery fast gradient-echo acquisitions were carried out on day 28 after myocardial infarction. Scanning started 15 min after intravenous injection of 0.2 mmol/kg Gd(DTPA). At the end of the MRI session, the animal was sacrificed and 2,3,5 triphenyltetrazolium chloride staining was used to validate the existence and to determine the accurate size of the myocardial infarct. Tissue samples were taken and stained with hematoxylin-eosin and Masson's trichrome for histological assessment of the infarct and the periinfarct zone. The signal intensity percent infarct mapping data were compared with corresponding data from the delayed enhancement images analyzed with SI(remote+2S.D.) thresholding, and with corresponding triphenyltetrazolium-chloride staining data using Friedman's repeated measure analysis of variance on ranks. RESULTS: The infarct volume determined by the triphenyltetrazolium chloride, SI(remote+2S.D.) and signal intensity percent-infarct mapping methods was 3.04 ml [2.74, 3.45], 13.62 ml [9.06, 18.45] and 4.27 ml [3.45, 6.33], respectively. Median infarct volume determined by SI(remote+2S.D.) significantly differed from that determined by triphenyltetrazolium chloride (P<.05). The Bland-Altman overall bias was 12.49% of the volume of the left ventricle. Median infarct volume determined by signal intensity percent-infarct mapping, however, did not differ significantly (NS) from that obtained by triphenyltetrazolium chloride. Signal intensity percent infarct mapping yielded only a 1.99% Bland-Altman overall bias of the left ventricular volume. CONCLUSIONS: This in vivo study in the porcine reperfused myocardial infarct model demonstrates that signal intensity percent-infarct mapping is a highly accurate method for the determination of the extent of myocardial infarct. MRI images for signal intensity percent-infarct mapping are obtained with the pulse sequence of conventional delayed enhancement imaging and are acquired within clinically acceptable scanning time. This makes signal intensity percent-infarct mapping a practical method for clinical implementation. PMID- 21546193 TI - Limitations of the permeability-limited compartment model in estimating vascular permeability and interstitial volume fraction in DCE-MRI. AB - Dynamic contrast-enhanced magnetic resonance imaging commonly uses compartment models to estimate tissue parameters in general and perfusion parameters in particular. Compartment models assume a homogeneous distribution of the injected tracer throughout the compartment volume. Since tracer distribution within a compartment cannot be assessed, the parameters obtained by means of a compartment model might differ from the actual physical values. This work systematically examines the widely used permeability-surface-limited one-compartment model to determine the reliability of the parameters obtained by comparing them with their actual values. A computer simulation was used to model spatial tracer distribution within the interstitial volume using diffusion of contrast agent in tissue. Vascular parameters were varied as well as tissue parameters. The vascular parameters used were capillary radius (4 and 12 MUm), capillary permeability (from 0.03 to 3.3 MUm/s) and intercapillary distances from 30 to 300 MUm. The tissue parameters used were tortuosity (lambda), porosity (alpha) and interstitial volume fraction (v(e)). Our results suggest that the permeability surface-limited compartment model generally underestimates capillary permeability for capillaries with a radius of 4 MUm by factors from ~0.03 for alpha=0.04, to ~ 0.1 for alpha=0.2, to ~ 0.5 for alpha=1.0. An overestimation of actual capillary permeability for capillaries with a radius of 12 MUm by a factor of >=1.3 was found for alpha=1.0, while alpha=0.2 yielded an underestimation by a factor of ~0.3 and alpha=0.04 by a factor of ~ 0.03. The interstitial volume fraction, v(e), obtained by the compartment model differed with increasing intercapillary distances and for low vessel permeability, whereas v(e) was found to be estimated approximately accurately for P=0.3 MUm/s and P=3.3 MUm/s for vessel distances <100 MUm. PMID- 21546195 TI - Detection of pyrogenicity on medical grade polymer materials using rabbit pyrogen, LAL and ELISA method. AB - The objective of the study is to detect the pyrogenicity of five medical grade gelatinous polymer materials, intended for the manufacturing of capsule for pharmaceutical applications, by an indigenously developed ELISA, LAL and rabbit pyrogen assays. The ELISA methodology includes the incubation of the sample extract with blood from a healthy donor at 37 degrees C. Any pyrogen present in the extract induces the IL-1beta which can be determined by ELISA. The rabbit pyrogen and LAL assays were performed as per standards. The result of the ELISA method indicated that all the materials extract induced high level of IL-1beta as a marker for pyrogenicity. The rise in temperature of rabbit pyrogen was above 0.5 degrees C in all materials extract. LAL assay induced an endotoxin level above 0.5EU. All the five polymer materials were found pyrogenic in all the assays. The ELISA method is very sensitive because the lowest limit of detection was 10pg/ml endotoxin. Hence it can be concluded that the ELISA method will be an added advantage for the quality control release of a batch of medical products and improving the existing methodologies in the context of reduction and replacement in the use of animal models. PMID- 21546194 TI - Buspirone, fexofenadine, and omeprazole: quantification of probe drugs and their metabolites in human plasma. AB - Probe drugs are critical tools for the measurement of drug metabolism and transport activities in human subjects. Often several probe drugs are administered simultaneously in a "cocktail". This cocktail approach requires efficient analytical methods for the simultaneous quantitation of multiple analytes. We have developed and validated a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of three probe drugs and their metabolites in human plasma. The analytes include omeprazole and its metabolites omeprazole sulfone and 5'-hydroxyomeprazole; buspirone and its metabolite 1-[2-pyrimidyl]-piperazine (1PP); and fexofenadine. These analytes and the internal standard lansoprazole were extracted from plasma using protein precipitation with acetonitrile. Gradient reverse-phase chromatography was performed with 7.5mM ammonium bicarbonate and acetonitrile, and the analytes were quantified in positive ion electrospray mode with multiple reaction monitoring. The method was validated to quantify the concentration ranges of 1.0-1000ng/ml for omeprazole, omeprazole sulfone, 5'-hydroxyomeprazole, and fexofenadine; 0.1 100ng/ml for buspirone, and 1.0-100ng/ml for 1PP. These linear ranges span the plasma concentrations for all of the analytes from probe drug studies. The intra day precision was between 2.1 and 16.1%, and the accuracy ranged from 86 to 115% for all analytes. Inter-day precision and accuracy ranged from 0.3 to 14% and from 90 to 110%, respectively. The lower limits of quantification were 0.1ng/ml for buspirone and 1ng/ml for all other analytes. This method provides a fast, sensitive, and selective analytical tool for quantification of the six analytes in plasma necessary to support the use of this probe drug cocktail in clinical studies. PMID- 21546196 TI - Identification of lethal Aspergillus at early growth stages based on matrix assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Delayed and incorrect diagnoses are potential risk factors leading to high mortality of invasive aspergillosis (IA). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to acquire a wide mass spectral range and characterize the early process of asexual sporulation of lethal IA pathogens recovered on agar plates. Proteins were extracted using trifluoroacetic acid and soft ionized using an ultraviolet laser with the assistance of ferulic acid. At the second stage of sporulation with various differentiated structures, there are more specific peaks that can be used to discriminate different Aspergillus species than at the first stage, which features vegetative hyphae. Certain specific peaks are found in different strains of the same species, Aspergillus fumigatus. In addition, the relative standard deviations of the m/z ratios are much smaller than those of the relative intensities in these peaks. Therefore, common lethal Aspergillus species can be identified after short-term cultivation by matching species-specific m/z values. PMID- 21546197 TI - Osteomyelitis associated to CTX-M-15-producing Aeromonas hydrophila: first description in the literature. PMID- 21546198 TI - Type distribution of serogroup 6 Streptococcus pneumoniae and molecular epidemiology of newly identified serotypes 6C and 6D in China. AB - The recently determined serotypes 6C and 6D Streptococcus pneumoniae, as well as subtypes 6B-I and 6B-II, were not reported in China. Among the 171 invasive isolates, 19 were identified as serogroup 6. There were equal distribution (42.1%) of 6B-I and 6B-II, 15.8% of 6A and lack of 6C and 6D. Among 1662 noninvasive isolates, 210 were identified as serogroup 6. The rates of types 6A, 6B-I, 6B-II, 6C, and 6D were 42.4%, 21.0%, 29.1%, 4.8%, and 2.9%, respectively. Subtype 6B-II was more resistant to antibiotics than others. The main sequence types (STs) of serotype 6C and 6D isolates were ST2912 and ST982, respectively. These results suggested that all recognized types of serogroup 6 can be found in China and that subtype 6B-II was more drug resistant. The epidemic STs of serotype 6C and 6D did not show genetic association with the STs spreading in other countries. PMID- 21546199 TI - Clinical breakpoints for voriconazole and Candida spp. revisited: review of microbiologic, molecular, pharmacodynamic, and clinical data as they pertain to the development of species-specific interpretive criteria. AB - We reassessed the Clinical and Laboratory Standards Institute (CLSI) clinical breakpoints (CBPs) for voriconazole. We examined i) the essential (EA: +/-2 dilutions) and categorical agreement between 24-h CLSI and EUCAST methods for voriconazole testing of Candida, ii) wild-type (WT) MICs and epidemiologic cutoff values (ECVs) for voriconazole by both CLSI and EUCAST methods, and iii) correlation of MICs with outcomes from previously published data using CLSI methods. We applied these findings to propose new 24-h species-specific CLSI CBPs. Adjusted 24-h CBPs for voriconazole and C. albicans, C. tropicalis, and C. parapsilosis (susceptible, <= 0.125 MUg/mL; intermediate, 0.25-0.5 MUg/mL; resistant, >= 1 MUg/mL) should be more sensitive for detecting emerging resistance among common Candida species and provide consistency with EUCAST CBPs. In the absence of CBPs for voriconazole and C. glabrata (and less common species), we recommend that their respective ECVs be used to detect the emergence of non-WT strains. PMID- 21546200 TI - Risk factors for false-negative results of QuantiFERON-TB Gold In-Tube assay in non-HIV-infected patients with culture-confirmed tuberculosis. AB - Limited information is available on the risk factors for false-negative results with the new generation of QuantiFERON-TB Gold In-Tube (QFT-GIT) tests in non-HIV infected patients with tuberculosis (TB). We sought to identify risk factors for false-negative QFT-GIT results in culture-confirmed TB patients. We reviewed the microbiological, laboratory, radiographic, and clinical data of 362 patients with positive M. tuberculosis cultures who received QFT-GIT tests at a Korean tertiary hospital between September 2006 and March 2010. Of these, 311 (85.9%) had true positive and 51 (14.1%) had false-negative results. The false-negative group was more likely to have immunosuppressant diseases and lower platelet, protein, and albumin levels than the true-positive group. An immunosuppressive condition was an independent risk factor for false-negative QFT-GIT results in non-HIV-infected patients with active TB (odds ratio, 2.98; 95% confidence interval, 1.38-6.47; P = .006). Careful interpretation of negative QFT-GIT results is thus necessary in immunocompromised patients suspected of having active TB. PMID- 21546201 TI - Comparative evaluation of automated and manual commercial DNA extraction methods for detection of Francisella tularensis DNA from suspensions and spiked swabs by real-time polymerase chain reaction. AB - This study evaluated commercial automated and manual DNA extraction methods for the isolation of Francisella tularensis DNA suitable for real-time polymerase chain reaction (PCR) analysis from cell suspensions and spiked cotton, foam, and polyester swabs. Two automated methods, the MagNA Pure Compact and the QIAcube, were compared to 4 manual methods, the IT 1-2-3 DNA sample purification kit, the MasterPure Complete DNA and RNA purification kit, the QIAamp DNA blood mini kit, and the UltraClean Microbial DNA isolation kit. The methods were compared using 6 F. tularensis strains representing the 2 subspecies which cause the majority of reported cases of tularemia in humans. Cell viability testing of the DNA extracts showed that all 6 extraction methods efficiently inactivated F. tularensis at concentrations of <=106 CFU/mL. Real-time PCR analysis using a multitarget 5' nuclease assay for F. tularensis revealed that the PCR sensitivity was equivalent using DNA extracted by the 2 automated methods and the manual MasterPure and QIAamp methods. These 4 methods resulted in significantly better levels of detection from bacterial suspensions and performed equivalently for spiked swab samples than the remaining 2. This study identifies optimal DNA extraction methods for processing swab specimens for the subsequent detection of F. tularensis DNA using real-time PCR assays. Furthermore, the results provide diagnostic laboratories with the option to select from 2 automated DNA extraction methods as suitable alternatives to manual methods for the isolation of DNA from F. tularensis. PMID- 21546202 TI - Antimicrobial susceptibility of daptomycin and comparator agents tested against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: trend analysis of a 6-year period in US medical centers (2005-2010). AB - We evaluated daptomycin activity trends against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE; MIC, >=8 MUg/mL) in a 6-year period (2005-2010) following US regulatory release for clinical use. Consecutive, unique patient strains of clinical significance were collected in 32 US medical centers and susceptibility tested in a central laboratory against daptomycin and various comparator agents by reference broth microdilution methods. A total of 22 858 S. aureus (12 181 [53.3%] MRSA), 4312 Enterococcus faecalis (195 [4.5%] VRE), and 2462 Enterococcus faecium (1867 [75.8%] VRE) were evaluated. Daptomycin susceptibility rates were 99.94%, 99.98%, and 99.68% for S. aureus, E. faecalis, and E. faecium, respectively. Among MRSA (daptomycin MIC50/90, 0.25/0.5 MUg/mL), only 13 (0.11%) daptomycin-non susceptible (MIC, >= 2 MUg/mL) isolates were observed with no MIC creep over the study interval. Daptomycin was very active against vancomycin-resistant E. faecalis (MIC50/90, 1/2 MUg/mL) and E. faecium (MIC50/90, 2/2 MUg/mL). Among VRE, only 4 daptomycin-non-susceptible isolates (all E. faecium) were detected. In conclusion, daptomycin demonstrated sustained activity against an extensive collection of clinical isolates of MRSA and VRE from numerous US medical centers over the last 6 monitored years. PMID- 21546203 TI - Innovative program to increase physical activity following an acute coronary syndrome: randomized controlled trial. AB - OBJECTIVE: To evaluate the impact of a socio-cognitive intervention associated with a pedometer-based program on physical activity, cardiovascular risk factors and self-efficacy expectation during one year following an acute coronary syndrome. METHODS: Sixty-five subjects were randomized during hospitalization in an experimental or a usual care group. Average steps/day was measured every 3 months until one year following discharge. Other dependent variables were measured at baseline, 6 and 12 months follow-up. RESULTS: There were 32 patients in the experimental group and 33 patients in the usual care group. Group characteristics were comparable. At baseline, averages steps/day were similar between groups (5845+/-3246 vs. 6097+/-3055 steps/day; p=0.812). At 3-month follow-up, both groups increased their averages steps/day (p<0.05). This increase was higher in the experimental group (3388+/-844 vs. 1934+/-889 steps/day; p<0.001). At 12-month, interaction effects (group*time) in physical activity and waist circumference were different between groups (p<0.05), whereas self-efficacy expectation increased in both groups similarly (p<0.05). CONCLUSION: The intervention is useful to improve average steps/day and waist circumference during the first year following an acute coronary syndrome. PRACTICE IMPLICATIONS: This study supports development of the home-based cardiac rehabilitation program using socio-cognitive intervention associated with a pedometer after an acute coronary syndrome. PMID- 21546204 TI - Depressive symptoms as a predictor of alcohol relapse after residential treatment programs for alcohol use disorder. AB - Alcohol use disorder (AUD) and depressive disorders often co-occur. Findings on the effects of major depressive disorder (MDD) or depressive symptoms on posttreatment alcohol relapse are controversial. The study's aim is to examine the association of MDD and depressive symptoms with treatment outcomes after residential AUD programs. In a naturalistic-prospective, multisite study with 12 residential AUD treatment programs in the German-speaking part of Switzerland, 64 patients with AUD with MDD, 283 patients with AUD with clinically significant depressive symptoms at admission, and 81 patients with AUD with such problems at discharge were compared with patients with AUD only on alcohol use, depressive symptoms, and treatment service utilization. MDD was provisionally identified at admission and definitively defined at discharge. Whereas patients with MDD did not differ from patients with AUD only at 1-year follow-up, patients with AUD with clinically significant depressive symptoms had significantly shorter time-to first-drink and a lower abstinence rate. These patients also had elevated AUD indices and treatment service utilization for psychiatric disorders. Our results suggest that clinically significant depressive symptoms are a substantial risk factor for relapse so that it may be important to treat them during and after residential AUD treatment programs. PMID- 21546205 TI - Baseline functioning among individuals with posttraumatic stress disorder and alcohol dependence. AB - Comorbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD) may lead to a complicated and potentially severe treatment profile. Our study examined 167 individuals with both PTSD and AD compared with 105 individuals with PTSD without an alcohol use disorder (AUD) and 240 individuals with AD without PTSD on baseline psychosocial functioning. We hypothesized that individuals with PTSD/AD would be more socially and functionally impaired than individuals with only one disorder. Results indicated that participants with PTSD/AD were more likely to be unemployed, have less education, and report less income and were less likely to live with a partner than the participants with only a single disorder. However, they did not differ on symptom severity within these disorders (drinking frequency/quantity, PTSD, and anxiety symptoms) with the exception of depression and alcohol craving. This contradicts clinical lore that comorbid patients are more impaired at treatment initiation and adds support for concurrent treatment as not only feasible but also possibly ideal for these patients. PMID- 21546206 TI - MicroRNA-21 and PDCD4 expression in colorectal cancer. AB - INTRODUCTION: MiRNAs regulate gene expression by binding to target sites and initiating translational repression and/or mRNA degradation. Studies have shown that miR-21 exerts its oncogenic activity by targeting the PDCD4 tumour suppressor 3'-UTR. However, the mechanism of this regulation is poorly understood. In colorectal cancer, loss of PDCD4 has been reported in association with increased tumour aggressiveness and poor prognosis. The purpose of this study was to delineate the interaction between PDCD4 and its oncogenic modulator miR-21 in colorectal cancer. METHODS: A cohort of 48 colorectal tumours, 61 normal tissues and 7 polyps were profiled for miR-21 and PDCD4 gene expression. A subset of 48 specimens (31 tumours and 17 normal tissues) were analysed for PDCD4 protein expression by immunohistochemistry. RESULTS: A significant inverse relationship between miR-21 and PDCD4 gene expression (p < 0.001) was identified by RT-qPCR. In addition, significant reduction of PDCD4 (p < 0.001) expression and reciprocal upregulation of miR-21 (p = 0.005) in a progressive manner from tumour-polyp-normal mucosae was identified. Analysis of protein expression by IHC revealed loss of PDCD4 staining in tumour tissue. Patients with disease recurrence had higher levels of miR-21. CONCLUSION: This study demonstrates the inverse relationship between miR-21 and PDCD4, thus suggesting that miR-21 post transcriptionally modulates PDCD4 via mRNA degradation. Pharmacological manipulation of the miR-21/PDCD4 axis could represent a novel therapeutic strategy in the treatment of colorectal cancer. PMID- 21546207 TI - [Check-lists: the letter and spirit]. PMID- 21546208 TI - [Safety of care: what place for proceduralization?]. PMID- 21546209 TI - Percutaneous coronary intervention with vs without on-site cardiac surgery backup: a systematic review and meta-analysis. AB - Although the popularity of performing percutaneous coronary intervention (PCI) in centres without on-site cardiac surgery backup is increasing, the safety of this practice is unknown. Our goal was to perform a systematic review and meta analysis of PCI with and without on-site cardiac surgery backup. We identified studies using computerized literature searches through July 2009. Main outcomes of interest included in-hospital mortality and early coronary artery bypass grafting (CABG). Analyses were stratified by procedure indication (primary PCI and nonprimary PCI). Pooled estimates were obtained using random-effects models. We identified 9 primary PCI studies (106,089 patients) and 7 nonprimary studies (910,422 patients) comparing centres with and without on-site cardiac surgery. For primary PCI, centres without on-site surgery had no significantly increased risk of in-hospital mortality (odds ratio [OR] 0.93; 95% confidence interval [CI], 0.83-1.05) or early CABG (OR 0.87; 95% CI, 0.68-1.11) compared with centres with on-site surgery. For nonprimary PCI, no increased risk of in-hospital mortality (OR 1.03; 95% CI, 0.64-1.66) and early CABG (OR 1.38; 95% CI, 0.65 2.95) was observed in centres without backup. However, significant heterogeneity existed in estimates of nonprimary PCI studies, suggesting substantial variation in outcomes of nonprimary PCI across centres without on-site cardiac surgery. We demonstrated that rates of in-hospital mortality and early CABG were similar at PCI centres with and without on-site cardiac surgery backup. However, variations in outcomes suggest that assurance of optimal outcomes at each PCI centre without on-site surgery is needed. PMID- 21546210 TI - In-hospital management of atrial fibrillation: the CHADS2 score predicts increased cost. AB - BACKGROUND: Hospitalizations for atrial fibrillation (AF) impose a substantial burden on our health care system, and AF management strategies are increasingly focused on hospitalization reduction. The objectives of this study were to determine the cost of hospitalization for AF and to identify the main determinants of this cost in a Canadian setting. METHODS: Our study population consisted of patients hospitalized for AF and/or atrial flutter at a tertiary care hospital in Canada between April 1, 2001, and March 31, 2007. Patient-level demographics and data on clinical resource use and cost of treatment were collected from a computerized resource use and cost accounting system. The main determinants of in-hospital costs were identified through Bayesian model averaging. RESULTS: Data were collected on 325 consecutive hospitalizations for AF. The median length of stay was 5 days (interquartile range [IQR], 3-9). The mean cost of an AF admission was CAD$4740 (SD = CAD$4457), and the median was CAD$3532 (IQR, CAD$2013-CAD$5944). Multivariate analysis identified 2 independent predictors of increased cost: CHADS2 score (relative increase in cost: 1.24; 95% CI, 1.16-1.33) and warfarin use (relative increase in cost: 1.41; 95% CI, 1.20 1.67). These 2 variables were also independent predictors of increased length of stay. CONCLUSIONS: The main clinical determinants of increased cost and increased length of stay were CHADS2 score and warfarin use. Strategies for reducing AF related costs should focus on preventing hospitalization or decreasing its length in patients with high CHADS2 scores and on finding alternatives to the use of warfarin or using outpatient bridging anticoagulation to facilitate earlier hospital discharge. PMID- 21546211 TI - A case of angioleiomyoma presenting as a pulsatile tumor in the left ring finger. AB - Angioleiomyomas in the finger are rare and their preoperative diagnosis is difficult. Most of them are not associated with arteries and their chief complaint does not reveal pulsation tumor. We report a case of the angioleiomyoma in the finger which was misdiagnosed as arteriovenous fistula of tumor, based on the presence of pulsating tumor and angiography finding. PMID- 21546212 TI - Missed dissection as a result of the ascending pharyngeal artery arising from the internal carotid artery. AB - Unlike high-grade stenosis, dissections of craniocervical arteries are a rare cause of cerebrovascular infarction. If the internal carotid artery (ICA) dissection is verified by duplex scanning or computed tomography angiography (CTA), the therapies of choice are antiplatelet and anticoagulation drugs, and surgical treatment is rarely performed. However, despite distinct clinical and radiological manifestation, carotid dissections are still under-recognized. In this study, we demonstrate the case of a 66-year-old man with dissection of ICA verified by duplex scanning and computed tomography angiography. The cause of missed diagnosis was an ascending pharyngeal artery originating from the ICA that runs parallel to it. Other than being a rare variation, this case may be interesting as a cause of misdiagnosis. PMID- 21546213 TI - A clinical and genetic study of 33 new cases with early-onset absence epilepsy. AB - PURPOSE: To investigate the electroclinical features and the outcome of patients with typical absences starting before the 3 years of life. METHODS: We reviewed the clinical data of patients with absences started before 3 years observed over a 15-year period. Mutation analysis of SLC2A1 (GLUT-1) gene was performed when possible. Their clinical features were compared with those of subjects with a diagnosis of childhood absence epilepsy (CAE). RESULTS: Among 33 children with absence epilepsy starting before 3 years of life, there were 20 boys and 13 girls. Mean seizure onset was at 28.0 +/- 8.3 (range: 8-36) months of life. Two children displayed borderline intellectual functioning at long-term follow-up. Twenty-eight (85%) patients showed excellent response to therapy. Three subjects evolved into a different form of idiopathic generalized epilepsy (IGE). No SLC2A1 mutation was identified in 20 (60.6%) patients tested. The main clinical features of patients with early-onset absences did not differ from those of CAE except for increased prevalence of males (p=0.002) and longer treatment duration (p=0.001) in the former. CONCLUSIONS: Strong similarities in the electroclinical features and outcome between children with early-onset absences and those with CAE support the view that these conditions are part of the wide spectrum of IGE. PMID- 21546214 TI - Increased prevalence of Chlamydophila DNA in post-mortem brain frontal cortex from patients with schizophrenia. AB - Infection can initiate symptoms of mental illness. It has been shown previously that Chlamydophila DNA is present six times more often in the blood of patients with schizophrenia than in the blood of control individuals. Monocytes, the main targets of Chlamydiaceae infection, are microglia precursors. We identified Chlamydiaceae infection using blinded brain DNA samples derived from the frontal cortex. Using PCR and sequence analysis, we found Chlamydophila DNA to be four times greater in patients with schizophrenia than in controls (schizophrenia: N=34, microbial DNA frequency 23.5%; controls: N=35, microbial DNA frequency 5.7%; P=0.045, OR=5.08). Persistent Chlamydophila-infected microglia or neuronal cells may impair neuronal circuits and thus be a mechanism for causing psychiatric illness in these patients. PMID- 21546215 TI - "Just the facts" of schizophrenia in the context of human evolution: commentary on Keshavan et al. (2011). PMID- 21546216 TI - Artemisinin reduces the level of antibodies to gliadin in schizophrenia. AB - OBJECTIVE: To investigate if adjunctive artemisinin, an anti-malarial compound with in vivo activity against Toxoplasma gondii, reduces symptoms or antibodies in schizophrenia. METHOD: N=66 outpatients with schizophrenia were randomized to receive 100mg of artemisinin twice a day or placebo for 10 weeks after a 2 week placebo run-in in addition to their usual psychiatric medications. Symptoms were assessed biweekly. Antibodies to toxoplasma and to gliadin, a food antigen, were assessed at the beginning and end of the trial. RESULTS: A total of 57 participants (26 in the artemisinin arm and 31 in the placebo arm) completed the 12 weeks of the trial. The medication was well tolerated and there were no significant side effects associated with the treatment regimen. There was no significant difference in the change of positive, negative, general, or total PANSS symptoms between groups for all of the randomized patients or for just the completers. However, individuals in the artemisinin arm but not in the placebo arm had significant decreases in the levels of antibodies to gliadin (p<.0005, p>.2, respectively by paired t-test). Neither group had significant changes in antibodies to T. gondii. CONCLUSIONS: The study did not demonstrate clinical benefit of adjunctive artemisinin for schizophrenia symptoms. The finding of reduced levels of antibodies to gliadin in the artemisinin group merits further study. PMID- 21546217 TI - Initial dosing of vancomycin in critically ill patients. PMID- 21546218 TI - Hippocampal size in women but not men with schizophrenia relates to disorder duration. AB - Longitudinal studies have failed to find progressive hippocampal size reduction in schizophrenia. However, negative results may have been due to follow-up intervals at disease stages where no significant progressive brain changes occur. Furthermore, only male or mixed gender samples have been studied. Forty-six patients with schizophrenia (23 females) and 46 healthy controls (23 females) underwent three-dimensional structural magnetic resonance imaging of the hippocampus and a clinical investigation. Compared with controls, male but not female participants with schizophrenia displayed hippocampal size reduction. Hippocampal size of female but not male schizophrenia patients was related to disorder duration, indicating smaller hippocampal size in female patients with longer disorder duration. Female schizophrenia patients displayed normal hippocampal size at the onset of disorder, but similarly reduced hippocampal size as male schizophrenia patients after some years of illness had passed. Our results suggest preserved hippocampal size in women with schizophrenia during the first years of illness. PMID- 21546219 TI - In vivo evidence of global and focal brain alterations in anorexia nervosa. AB - Brain alterations are known to be associated with anorexia nervosa (AN) and tend to be distributed across brain structures, with only a few reports describing focal damage. Magnetic resonance images of 21 anorexic patients with different disease duration and 27 control subjects were acquired and compared using voxel based morphometry (VBM). Patients had a significant reduction of total white matter (WM) volume and focal gray matter (GM) atrophy in cerebellum, hypothalamus, caudate nucleus and frontal, parietal and temporal areas. The cerebellum was more affected in patients with longer disease duration, whereas the hypothalamic alterations were more pronounced in patients with shorter food restriction. A correlation with body mass index (BMI) and GM was found in the hypothalamus. Our data demonstrate a diffuse reduction of WM together with focal areas of GM atrophy in AN. The finding of a hypothalamic focal atrophy points to hormonal dysfunction and opens the possibility for a central dysregulation of homeostasis. The involvement of temporoparietal areas could account for body image distortion. Finally, the cerebellar GM atrophy confirms previous findings and seems to be a late consequence of AN that could play a role in the chronic phase of the disease. PMID- 21546220 TI - Association between cerebrospinal fluid tau and brain atrophy is not related to clinical severity in the Alzheimer's disease continuum. AB - We aimed to assess the association between core cerebrospinal fluid (CSF) biomarkers, regional brain atrophy and clinical severity in the Alzheimer's disease (AD) continuum, as well as to investigate how cognitive reserve (CR) may modulate these putative associations. Forty-nine subjects (11 controls, 10 patients with subjective memory complaints, 19 with mild cognitive impairment and 9 mild AD) underwent lumbar puncture and high-resolution magnetic resonance imaging (MRI). CSF amyloid-beta(1-42) (Abeta(1-42)), total tau (t-tau) and phosphorylated tau (p-tau(181)) were determined. Voxel-based morphometry (VBM) was applied and multiple regression analyses for the whole sample were carried out. Clinical severity was adjusted using the Clinical Dementia Rating Sum of Boxes score (CDR-SB). A negative correlation between t-tau levels and grey matter (GM) volume in temporo-parietal regions was found, regardless of CDR-SB score. In contrast, the negative correlation between p-tau(181) and GM volume was largely explained by clinical severity, except in the posterior cingulate cortex. CR did not significantly modify these correlations. Abeta(1-42) levels were not related to GM volume but were related to clinical severity, an association that was attenuated when CR was considered. In conclusion, the present findings reflect that t-tau CSF concentrations are associated with GM atrophy in neuropathologically relevant areas across the AD continuum, whereas the p tau(181) association is largely dependent on the degree of clinical severity. The relationship between CSF Abeta(1-42) and clinical severity seems to be modulated by CR, suggesting that there may be subjects with pathological levels of Abeta(1 42) and high CR estimates who remain clinically asymptomatic. PMID- 21546221 TI - fMRI brain activation during a delay discounting task in HIV-positive adults with and without cocaine dependence. AB - Cocaine use is associated with poorer HIV clinical outcomes and may contribute to neurobiological impairments associated with impulsive decision making. This study examined the effect of cocaine dependence on brain activation during a delay discounting task involving choices between smaller immediate rewards and larger delayed ones. Participants were 39 HIV-positive adults on antiretroviral therapy who had current cocaine dependence ("active," n=15), past cocaine dependence ("recovered," n=13), or no lifetime substance dependence ("naive," n=11). Based on responses on a traditional delay discounting task, three types of choices were individualized for presentation during functional magnetic resonance imaging: hard (similarly valued), easy (disparately valued), and no (single option). Active participants had significantly smaller increases in activation than naive participants during hard versus easy choices bilaterally in the precentral gyrus and anterior cingulate cortex and in the right frontal pole (including dorsolateral, ventrolateral, and orbitofrontal cortex). During hard and easy choices relative to no choices, active participants had smaller increases in activation compared to naive participants in frontoparietal cortical regions. These deficits in the executive network during delay discounting choices may contribute to impulsive decision making among HIV-positive cocaine users, with implications for risk behaviors associated with disease transmission and progression. PMID- 21546223 TI - White matter abnormalities of fronto-striato-thalamic circuitry in obsessive compulsive disorder: A study using diffusion spectrum imaging tractography. AB - Previous studies have reported white matter abnormalities in patients with obsessive-compulsive disorder (OCD). This study aimed to further explore white matter abnormalities in OCD patients through diffusion spectrum imaging (DSI) and tractography of the two white matter tracts which most probably play an important role in OCD neuropathology: the anterior segment of cingulum bundles (ACB) and the anterior thalamic radiations (ATR). Twelve right-handed, medicated adult patients with OCD and 12 matched controls underwent DSI on a 3 tesla magnetic resonance imaging (MRI) system. Tractography based on DSI data was reconstructed to define the ACB and ATR. Mean generalized fractional anisotropy (GFA) was calculated for each targeted tract and was used to analyze local changes in microstructural integrity along individual tracts. There was a significantly lower mean GFA in both the right ATR and left ACB in OCD subjects compared to controls. OCD subjects also demonstrated decreased left-lateralized asymmetry of the ACB when compared to controls. Furthermore, the mean GFA of the left ACB positively correlated with OCD subjects' obsessive subscores on the Yale-Brown Obsessive-Compulsive scale. This study supports the white matter abnormalities in the ACB and ATR of OCD subjects, which corroborates neurobiological models that posit a defect in fronto-striato-thalamic circuitry in OCD. PMID- 21546222 TI - Rostral anterior cingulate cortex activity and early symptom improvement during treatment for major depressive disorder. AB - In treatment trials for major depressive disorder (MDD), early symptom improvement is predictive of eventual clinical response. Clinical response may also be predicted by elevated pretreatment theta (4-7Hz) current density in the rostral anterior cingulate (rACC) and medial orbitofrontal cortex (mOFC). We investigated the relationship between pretreatment EEG and early improvement in predicting clinical outcome in 72 MDD subjects across three placebo-controlled treatment trials. Subjects were randomized to receive fluoxetine, venlafaxine, or placebo. Theta current density in the rACC and mOFC was computed with Low Resolution Brain Electromagnetic Tomography (LORETA). An analysis of covariance examining week-8 Hamilton Depression Rating Scale (HamD) percent change, showed a significant effect of week-2HamD percent change, and a significant three-way interaction of week-2HamD percent change*treatment*rACC. Medication subjects with robust early improvement showed almost no relationship between rACC theta current density and final clinical outcome. However, in subjects with little early improvement, rACC activity showed a strong relationship with clinical outcome. The model examining the mOFC showed a trend in the three-way interaction. A combination of pretreatment rACC activity and early symptom improvement may be useful for predicting treatment response. PMID- 21546224 TI - Temperature calibration for high-temperature MAS NMR to 913 K: 63Cu MAS NMR of CuBr and CuI, and 23Na MAS NMR of NaNbO3. AB - The solid-state phase transitions of CuBr, CuI and NaNbO(3) can be readily observed using (63)Cu and (23)Na high-temperature magic-angle spinning nuclear magnetic resonance spectroscopy. Temperature has large, linear effects on the peak maximum of (63)Cu in each solid phase of CuBr and CuI, and there is large jump in shift across each phase transition. The (23)Na MAS NMR peak intensities and the line widths in NaNbO(3) also clearly show its high-temperature transition to the cubic phase. These data can be used to calibrate high-temperature MAS NMR probes up to 913 K, which is two hundred degrees higher than the commonly-used temperature calibration based on the chemical shift of (207)Pb in Pb(NO(3))(2). PMID- 21546225 TI - Mixed micelles of 7,12-dioxolithocholic acid and selected hydrophobic bile acids: interaction parameter, partition coefficient of nitrazepam and mixed micelles haemolytic potential. AB - The formation of mixed micelles built of 7,12-dioxolithocholic and the following hydrophobic bile acids was examined by conductometric method: cholic (C), deoxycholic (D), chenodeoxycholic (CD), 12-oxolithocholic (12-oxoL), 7 oxolithocholic (7-oxoL), ursodeoxycholic (UD) and hiodeoxycholic (HD). Interaction parameter (beta) in the studied binary mixed micelles had negative value, suggesting synergism between micelle building units. Based on beta value, the hydrophobic bile acids formed two groups: group I (C, D and CD) and group II (12-oxoL, 7-oxoL, UD and HD). Bile acids from group II had more negative beta values than bile acids from group I. Also, bile acids from group II formed intermolecular hydrogen bonds in aggregates with both smaller (2) and higher (4) aggregation numbers, according to the analysis of their stereochemical (conformational) structures and possible structures of mixed micelles built of these bile acids and 7,12-dioxolithocholic acid. Haemolytic potential and partition coefficient of nitrazepam were higher in mixed micelles built of the more hydrophobic bile acids (C, D, CD) and 7,12-dioxolithocholic acid than in micelles built only of 7,12-dioxolithocholic acid. On the other hand, these mixed micelles still had lower values of haemolytic potential than micelles built of C, D or CD. The mixed micelles that included bile acids: 12-oxoL, 7-oxoL, UD or HD did not significantly differ from the micelles of 7,12-dioxolithocholic acid, observing the values of their haemolytic potential. PMID- 21546226 TI - Vascular mechanisms of cyanidin-3-glucoside response in streptozotocin-diabetic rats. AB - BACKGROUND AND OBJECTIVE: Considering the high incidence of cardiovascular disorders in diabetes mellitus and some evidence on the antioxidant and antidiabetic potential of cyanidin-3-glucoside (C3G), this study was conducted to evaluate the possible beneficial effect of C3G administration on vascular reactivity of isolated thoracic aorta in diabetic rats and some of its underlying mechanisms. MATERIALS AND METHODS: Male diabetic rats received C3G (10mg/kg; i.p.) on alternate days for 8 weeks one week after streptozotocin (STZ) diabetes induction. RESULTS: It was found out that treatment of diabetic rats with C3G exerted a hypoglycaemic effect and attenuated the increased malondialdehyde (MDA) content and reduced the activity of superoxide dismutase (SOD) in aortic tissue. Maximum contractile response of endothelium-intact aortic rings to phenylephrine (PE) was significantly lower in C3G-treated diabetic rats relative to untreated diabetics and endothelium removal abolished this difference. Meanwhile, endothelium-dependent relaxation to acetylcholine (ACh) was significantly higher in C3G-treated diabetic rats as compared to diabetic group. CONCLUSION: Chronic treatment with C3G may prevent some diabetes-related changes in vascular reactivity observed in diabetic rats directly and/or indirectly due to its hypoglycaemic effect and attenuation of lipid peroxidation and through endothelial-derived factors. PMID- 21546227 TI - [Presidential letter]. PMID- 21546228 TI - The endothelial plasma membrane transporter bilitranslocase mediates rat aortic vasodilation induced by anthocyanins. AB - BACKGROUND AND AIMS: Anthocyanins, a sub-class of flavonoids, induce endothelium dependent vasorelaxation, by activating endothelial nitric oxide synthase and consequently increasing production of the vasorelaxant agent nitric oxide. It is not yet clear if anthocyanin-induced vasorelaxation starts with their interaction with plasma membrane receptors in the extracellular compartment, or with their membrane transport toward intracellular molecular targets. We therefore investigated the possible role of bilitranslocase (TC 2.A.65.1.1), an endothelial plasma membrane carrier that transports flavonoids, in the vasodilation activity induced by anthocyanins. METHODS AND RESULTS: Vascular reactivity was assessed in thoracic aortic rings obtained from male Wistar rats. Pre-treatment of aortic rings with anti-sequence bilitranslocase antibodies targeting the carrier, decreased vasodilation induced by cyanidin 3-glucoside and bilberry anthocyanins. CONCLUSION: Here we show for the first time that bilitranslocase mediates a critical step in vasodilation induced by anthocyanins. This offers new insights into the molecular mechanism involved in endothelium-dependent vasorelaxation by flavonoids, and the importance of their specific membrane carriers. PMID- 21546229 TI - Nuts, hypertension and endothelial function. AB - BACKGROUND AND AIMS: High blood pressure (BP) is considered a major risk factor for cardiovascular disease. Among lifestyle factors, diet plays a key role in the prevention and control of high BP. Therefore, it is important to elucidate which dietary components can exert beneficial effects on BP through modulation of endothelial function (EF) or by other mechanisms. In this paper we review the role of nutrients, foods, particularly nuts, and dietary patterns on BP control. DATA SYNTHESIS: Because nuts are low in sodium and contain significant amounts of mono- and polyunsaturated fatty acids, fiber, minerals such as magnesium, potassium and calcium, and antioxidants, they have been suggested as potentially protective foods against hypertension. Limited evidence from prospective studies and clinical trials suggests that nut consumption has a beneficial effect on both BP and EF. However, BP changes were a secondary outcome in nut feeding trials and no study used ambulatory BP monitoring as the standard for BP measurements. CONCLUSIONS: Further clinical trials, ideally using ambulatory BP monitoring, are needed to establish the potential protective effect of nut consumption on hypertension and vascular reactivity. PMID- 21546230 TI - Increased appearance rate of 27-hydroxycholesterol in vivo in hypercholesterolemia: a possible compensatory mechanism. AB - BACKGROUND AND AIMS: The first step in the alternative pathway of bile acid biosynthesis is the 27-hydroxylation of cholesterol, which takes place both in liver and extrahepatic tissues. This pathway is believed to play a role in peripheral cholesterol degradation. Aim of this study was to investigate the impact of hyperlipidemia on 27-hydroxycholesterol appearance rate, and to assess the effects induced by treatment with statins. METHODS AND RESULTS: Seven patients with familial hypercholesterolemia and eight patients with familial combined hyperlipidemia underwent determination of 27-hydroxylation rates in vivo by i.v. infusion of deuterated 27-hydroxycholesterol. Isotope enrichment was assayed by gas chromatography-mass spectrometry, allowing to calculate 27 hydroxycholesterol appearance rates. Six normocholesterolemic subjects were regarded as controls. In some hypercholesterolemic patients the infusions were repeated during treatment with atorvastatin or rosuvastatin. Hydroxylation rates were higher in hypercholesterolemic patients (8.7 +/- 2.5 mg/h; controls, 3.4 +/- 2.0 mg/h; combined hyperlipidemia, 4.4 +/- 1.6 mg/h; mean +/- SD, P < 0.01 vs both). After statin treatment, both plasma cholesterol levels and hydroxylation rates dropped by nearly 50%. No difference was detectable between the two statins. A linear correlation was shown between plasma cholesterol and 27 hydroxylation rates. CONCLUSION: Hypercholesterolemia associates with increased 27-hydroxycholesterol appearance rates, which decrease during hypocholesterolemic treatment. The correlation with cholesterol levels supports the view that 27 hydroxylation may act as a compensatory mechanism in a condition of larger plasma cholesterol pool. A regulatory role for hepatic and extrahepatic nuclear receptors seems reasonable. These data prompt novel pharmacological approaches for the management of hypercholesterolemia and the prevention of atherosclerosis. PMID- 21546231 TI - Lipids in critical care medicine. AB - While enteral nutrition is the basis for the critically ill, parenteral nutrition is often used when a sufficient enteral nutrition is not or not fully achievable. Lipids are a mainstay of caloric supply in both cases as they combine the provision of building blocks for the membranes and are precursors for function molecules including lipid mediators bearing the ability to influence immunity. Pro-inflammatory lipid mediators as prostaglandins and leukotrienes are generated from arachidonic acid (AA), a key member of the n-6 polyunsaturated fatty acids (PUFA). In contrast, lipid mediators derived from the n-3 fatty acids eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) may exhibit less inflammatory properties compared to their AA-derived counterparts. Furthermore, intercellular mediators as resolvins and protectins are generated from n-3 fatty acids. They induce the resolution of inflammation, hence the name resolution phase interaction product-resolvin. Modulating the amount of PUFA and the n-6/n-3 ratio were investigated as means to change the inflammatory response and improve the outcome of patients. Experimental data showed that n-3 fatty acids may improve acute lung injury and sepsis in animal models. Studies in patients undergoing major surgery with application of n-3 fatty acids demonstrated beneficial effects in terms of reduction of length of stay and infectious complications. Clinical data hints that this concept may also improve outcome in critically ill patients. Additionally, experimental and clinical data suggest that a reduction in n-6 PUFA may change the immune response. In conclusion, modulating the amount of PUFA, the n-6/n-3 ratio and the composition of lipid emulsions may prove to be a useful means to improve the outcome of critically ill patients. PMID- 21546232 TI - Expiratory flows and airway inflammation in elderly asthmatic patients. AB - Asthma in the elderly is often underrecognized and suboptimally treated, resulting in an increased morbidity and mortality. The characteristics of asthma related bronchitis and its optimal treatment remain to be determined in this population. We aimed to compare lung function and airway inflammation in elderly and younger asthmatic subjects. Data from two induced sputum databases were analyzed in three groups of asthmatic subjects (18-30 y, n = 136; 31-59 y, n = 385; 60-72 y, n = 172) and one group of healthy elderly subjects (60-89 y, n = 16). Expiratory flows and induced sputum cell counts were analyzed. Airway obstruction was more marked in elderly asthmatics compared with healthy elderly or younger asthmatic subjects (p < 0.01). An increase in sputum neutrophils and a decrease in macrophages and lymphocytes were observed in elderly asthmatics (p < 0.0001). Neutrophil percentages significantly increased with asthma severity in the young and the middle-aged groups, while they remained similar in elderly asthmatics regardless of asthma severity (p < 0.05). Neutrophil percentages weakly correlated with the dose of ICS in all asthmatics (r = 0.17, p < 0.0001). Age and dose of ICS were independent predictors of neutrophil percentage in asthmatic subjects in a regression model (R(2) = 0.12). Asthma in the elderly is associated with a more marked airway obstruction and sputum neutrophilia. Both age and the dose of corticosteroids need to be considered in the interpretation of the clinical relevance of sputum neutrophil count. PMID- 21546233 TI - Endosomal signaling and cell migration. AB - Cell migration is a complex biological process that is under the tight control of diverse signaling events. While many of the involved signaling molecules diffuse rapidly within cells, it now seems that certain key regulators of cell migration prefer to travel on endosomes. In this review we will discuss the multiple roles of signaling endosomes in regulation of local migration stimuli, dynamics of focal adhesions, cell contractility and locomotion. PMID- 21546234 TI - Fluorescence excitation-emission spectroscopy with regional integration analysis for assessment of compost maturity. AB - Composting of animal manures is believed as an alternative way for directly recycling them in farms, and therefore assessment of compost maturity is crucial for achieving high quality compost. Fluorescence excitation-emission matrices (EEMs) combined with regional integration analysis is presented to assess compost maturity. The results showed that the EEM contours of water-extract organic matter (WEOM) from immature composts exhibited four peaks at excitation/emission (Ex/Em) of 220/340nm, 280/340nm, 220/410nm, and 330/410nm, whereas EEM contour of WEOM from mature composts had only two peaks at Ex/Em of 230/420nm and 330/420nm. Pearson correlation demonstrated that peaks intensity rather than their ratios had a significantly correlation with the common indices assessing compost maturity, whereas the normalized excitation-emission area volumes (Phi(i,n)s) from regional integration analysis had a stronger correlation with the common indices assessing compost maturity than peaks intensity. It is concluded that the Phi(i,n)s from regional integration analysis are more suitable to assess the maturity of compost than the intensities of peaks. Therefore, the fluorescence spectroscopy combined with regional integration analysis can be used as a valuable industrial and research tool for assessing compost maturity, given its high sensitivity and selectivity. PMID- 21546235 TI - Indicator organisms for assessing sanitization during composting of plant wastes. AB - The potential for using plant pathogens and seeds as indicator organisms for assessing sanitization of plant wastes during composting was tested in bench scale flask and large-scale systems. Plasmodiophora brassicae was unsuitable due to high temperature tolerance in dry to moist composts, and detection of viable inoculum post-composting using bioassay plants not corresponding with that using TaqMan(r) PCR, possibly due to preservation of nucleic acids at elevated temperatures. Several other plant pathogens (Sclerotinia sclerotiorum, Microdochium nivale, Phytophthora cinnamomi and Phytophthora nicotianae) were unsuitable due their low temperature tolerance. Fusarium oxysporum f.sp. cepae and f.sp. radicis-lycopersici chlamydospores and tomato seeds were suitable indicators due to their moderate temperature tolerance and ease of viability testing post-composting. Abutilon seeds were more tolerant than tomato seeds of compost temperatures >=52 degrees C but more prone to degradation at lower temperatures and therefore less suitable as indicators. Relationships between compost temperature during exposures of 2-10 days and subsequent viability of the above chlamydospores or seeds enabled the sanitizing effect of composting processes to be predicted within 2-6 days. Plant waste type (woody or vegetable) had a small but significant effect on the relationship for tomato seeds but not for F. oxysporum chlamydospores. PMID- 21546236 TI - Semi-continuous anaerobic co-digestion of thickened waste activated sludge and fat, oil and grease. AB - Co-digestion of thickened waste activated sludge (TWAS) and fat, oil and grease (FOG) was conducted semi-continuously under mesophilic conditions. The results showed that daily methane yield at the steady state was 598L/kg VS(added) when TWAS and FOG (64% of total VS) were co-digested, which was 137% higher than that obtained from digestion of TWAS alone. The biogas composition was stabilized at a CH(4) and CO(2) content of 66.8% and 29.5%, respectively. Micronutrients added to co-digestion did not improve the biogas production and digestion stabilization. With a higher addition of FOG (74% of total VS), the digester initially failed but was slowly self-recovered; however, the methane yield was only about 50% of a healthy reactor with the same organic loading rate. PMID- 21546237 TI - Colorimetric artificial tongue for protein identification. AB - Artificial tongue systems are multisensory devices which are highly desirable for the analysis and recognition of complicated composition samples. Herein, a low cost and simple colorimetric sensor array for identification and quantification of proteins were reported. Using prophyrin, porphyrin derivatives (mainly metalloporphyrins) and chemically responsive dyes as the sensing elements, the developed sensor array of artificial tongue showed a unique pattern of colorific change upon its exposure to proteins. The composite pattern for each sample was subjected to principal component analysis (PCA), thus providing a clustering map for more practical visualization. All the pure and mixed proteins, as well as denatured proteins, gave distinct patterns, thus resulting in their unambiguous identification. The PCA analysis also suggested that the unique pattern of colorific change may be due to the change of protein conformation and local environmental pH. These results demonstrate that the developed colorimetric artificial tongue system is an excellent sensing platform for identification and quantitative analysis of protein samples. PMID- 21546238 TI - Effect of passivation on the sensitivity and stability of pentacene transistor sensors in aqueous media. AB - Charge-detecting biosensors have recently become the focal point of biosensor research, especially research onto organic thin-film transistors (OTFTs), which combine compactness, a low cost, and fast and label-free detection to realize simple and stable in vivo diagnostic systems. We fabricated organic pentacene based bottom-contact thin-film transistors with an ultra-thin insulating layer of a cyclized perfluoro polymer called CYTOP (Asahi Glass Co., Tokyo, Japan) on SiO(2) for operation in aqueous media. The stability and sensitivity of these transistor sensors were examined in aqueous buffer media with solutions of variable pH levels after the passivation of perfluoro polymers with thicknesses ranging from 50 to 300 nm. These transistor sensors were further modified with an ultra-thin film (5 nm) functional layer for selective BSA/antiBSA detection in aqueous buffer media, demonstrating a detection capability as low as 500 nM of concentrated antiBSA. The dissociation constant from the antiBSA detection results was 2.1*10(-6)M. Thus, this study represents a significant step forward in the development of organic electronics for a disposable and versatile chemical and bio-sensing platform. PMID- 21546239 TI - Covalent enzyme immobilization by poly(ethylene glycol) diglycidyl ether (PEGDE) for microelectrode biosensor preparation. AB - Poly(ethylene glycol) diglycidyl ether (PEGDE) is widely used as an additive for cross-linking polymers bearing amine, hydroxyl, or carboxyl groups. However, the idea of using PEGDE alone for immobilizing proteins on biosensors has never been thoroughly explored. We report the successful fabrication of microelectrode biosensors based on glucose oxidase, d-amino acid oxidase, and glutamate oxidase immobilized using PEGDE. We found that biosensors made with PEGDE exhibited high sensitivity and a response time on the order of seconds, which is sufficient for observing biological processes in vivo. The enzymatic activity on these biosensors was highly stable over several months when they were stored at 4 degrees C, and over at least 3d at 37 degrees C. Glucose microelectrode biosensors implanted in the central nervous system of anesthetized rats reliably monitored changes in brain glucose levels induced by sequential administration of insulin and glucose. PEGDE provides a simple, low cost, non-toxic alternative for the preparation of in vivo microelectrode biosensors. PMID- 21546240 TI - Engineering porous scaffolds using gas-based techniques. AB - Scaffolds are used in tissue engineering as a matrix for the seeding and attachment of human cells. The creation of porosity in three-dimensional (3D) structures of scaffolds plays a critical role in cell proliferation, migration, and differentiation into the specific tissue while secreting extracellular matrix components. These pores are used to transfer nutrients and oxygen and remove wastes produced from the cells. The lack of oxygen and nutrient supply impedes the cell migration more than 500MUm from the surface. The physical properties of scaffolds such as porosity and pore interconnectivity can improve mass transfer and have a great impact on the cell adhesion and penetration into the scaffolds to form a new tissue. Various techniques such as electrospinning, freeze-drying, and solvent casting/salt leaching have been used to create porosity in scaffolds. The major issues in these methods include lack of 3D structure, control on pore size, and pore interconnectivity. In this review, we provide a brief overview of gas-based techniques that have been developed for creating porosity in scaffolds. PMID- 21546241 TI - Environmental biotechnology for sustainability: unleashing the might of the small. PMID- 21546242 TI - Giant cell tumor of distal phalanx of great toe. A case report. AB - Giant cell tumors are locally aggressive benign osseous neoplasms of unknown origin. They mostly occur after skeletal maturity in 3rd or 4th decade and commonly involve long bones although occasional occurrence at other sites has been reported. It is rare to see these tumors involving the phalangeal bone of foot. We report a case of giant cell tumor involving the distal phalanx of great toe in a 27 year old female who presented with swelling of great toe of right foot. Radiography showed an expansile lesion in distal phalanx of great toe. En bloc resection of phalanx was done. Biopsy showed giant cell tumor and regular follow up of this patient for two years showed no recurrence of tumor. Giant cell tumor at such a location is unusually aggressive and needs regular follow up to detect local recurrence. PMID- 21546243 TI - Effect of beam arrangement on oral cavity dose in external beam radiotherapy of nasopharyngeal carcinoma. AB - This study compared the oral cavity dose between the routine 7-beam intensity modulated radiotherapy (IMRT) beam arrangement and 2 other 7-beam IMRT with the conventional radiotherapy beam arrangements in the treatment of nasopharyngeal carcinoma (NPC). Ten NPC patients treated by the 7-beam routine IMRT technique (IMRT-7R) between April 2009 and June 2009 were recruited. Using the same computed tomography data, target information, and dose constraints for all the contoured structures, 2 IMRT plans with alternative beam arrangements (IMRT-7M and IMRT-7P) by avoiding the anterior facial beam and 1 conventional radiotherapy plan (CONRT) were computed using the Pinnacle treatment planning system. Dose volume histograms were generated for the planning target volumes (PTVs) and oral cavity from which the dose parameters and the conformity index of the PTV were recorded for dosimetric comparisons among the plans with different beam arrangements. The dose distributions to the PTVs were similar among the 3 IMRT beam arrangements, whereas the differences were significant between IMRT-7R and CONRT plans. For the oral cavity dose, the 3 IMRT beam arrangements did not show significant difference. Compared with IMRT-7R, CONRT plan showed a significantly lower mean dose, V30 and V-40, whereas the V-60 was significantly higher. The 2 suggested alternative beam arrangements did not significantly reduce the oral cavity dose. The impact of varying the beam angles in IMRT of NPC did not give noticeable effect on the target and oral cavity. Compared with IMRT, the 2-D conventional radiotherapy irradiated a greater high-dose volume in the oral cavity. PMID- 21546244 TI - Hippocampal regulation of aversive memories. AB - For many years, the hippocampal formation has been implicated in the regulation of negative emotion, yet the nature of this link has remained elusive. Recent studies have made important links between the hippocampus and regulation of stress hormones that affect aversive memory. Additional studies have shown that the hippocampus regulates the gating of fear by contextual information. An emerging literature also links the hippocampus to prediction errors during fear learning and extinction. The mechanisms by which the hippocampus regulates negative emotion are clearly complicated, but suggest that interventions aimed at restoring normal hippocampal function may help with disorders of negative affect, such as depression or post-traumatic stress disorder and depression. PMID- 21546245 TI - Performance of down-flow hanging sponge (DHS) reactor coupled with up-flow anaerobic sludge blanket (UASB) reactor for treatment of onion dehydration wastewater. AB - In this study, a promising system consisting of up-flow anaerobic sludge blanket (UASB) reactor followed by down-flow hanging sponge (DHS) reactor was investigated for onion dehydration wastewater treatment. Laboratory experiments were conducted at two different phases, i.e., phase (1) at overall hydraulic retention time (HRT) of 11h (UASB reactor: 6h and DHS reactor: 5h) and phase (2) at overall HRT of 9.4h (UASB reactor: 5.2h and DHS reactor: 4.2h). Long-term operation results of the proposed system showed that its overall TCOD, TBOD, TSS, TKN and NH(4)-N removal efficiencies were 92 +/- 5, 95 +/- 2, 95 +/- 2, 72 +/- 6 and 99 +/- 1.3%, respectively (phase 1). Corresponding values for the 2nd phase were 85.4 +/- 5, 86 +/- 3, 87 +/- 6, 65 +/- 8 and 95 +/- 2.8%. Based on the available results, the proposed system could be more viable option for treatment of wastewater generated from onion dehydration industry in regions with tropical or sub-tropical climates and with stringent discharge standards. PMID- 21546246 TI - Local bioprospecting for high-lipid producing microalgal strains to be grown on concentrated municipal wastewater for biofuel production. AB - Mass cultivation of microalgae for biofuel production depends heavily on the performance of the microalgae strains used. In this study, 60 algae-like microorganisms collected from different sampling sites in Minnesota were examined using multi-step screening and acclimation procedures to select high-lipid producing facultative heterotrophic microalgae strains capable of growing on concentrated municipal wastewater (CMW) for simultaneous energy crop production and wastewater treatment. Twenty-seven facultative heterotrophic microalgae strains were found, among which 17 strains were proved to be tolerant to CMW. These 17 top-performing strains were identified through morphological observation and DNA sequencing as Chlorella sp., Heynigia sp., Hindakia sp., Micractinium sp., and Scenedesmus sp. Five strains were chosen for other studies because of their ability to adapt to CMW, high growth rates (0.455-0.498 d(-1)) and higher lipid productivities (74.5-77.8 mg L(-1)d(-1)). These strains are considered highly promising compared with other strains reported in the literature. PMID- 21546247 TI - Using a starch-rich mutant of Arabidopsis thaliana as feedstock for fermentative hydrogen production. AB - A mutant plant (Arabidopsis thaliana), sex1-1 (starch excess 1-1), accumulating high starch content in leaves was created to serve as better biomass feedstock for a H2-producing strain Clostridium butyricum CGS2, which efficiently utilizes starch for H2 production but cannot assimilate cellulosic materials. The starch content of the mutant plant increased to 10.67 mg/fresh weight, which is four times higher than that of wild type plant. Using sex1-1 mutant plant as feedstock, C. butyricum CGS2 could produce 490.4 ml/l of H2 with a H2 production rate of 32.9 ml/h/l. The H2 production performance appeared to increase with the increase in the concentration of mutant plant from 2.5 to 10 g/l. The highest H2 to plant biomass yield was nearly 49 ml/g for the mutant plant. This study successfully demonstrated the feasibility of using a starch-rich mutant plant for more effective bioH2 production with C. butyricum CGS2. PMID- 21546248 TI - Sludge exchange process on two serial CSTRs anaerobic digestions: process failure and recovery. AB - The sludge exchange process using two anaerobic digesters (CSTRs) in series was investigated under the mesophilic condition (36-38 degrees C). At first, the digesting sludge of the CSTRs in series with different TVFA/alkalinity ratios was tested in the laboratory by mixing the digesting sludge of two CSTRs from 6.5% to 50% based on volume. The sludge exchange test was then performed using the same CSTRs under batch and continuous processes. The change in the TVFA/alkalinity ratio was found to be linear with the digesting sludge exchange volume. The CSTR of TVFA/alkalinity ratio 1.970 recovered completely failed within 11 days for the batch process and the CSTR of TVFA/alkalinity ratio 1.514 within 3 weeks for the continuous feeding process at a sludge exchange volume of 13%. The reactor operation was stable when the TVFA/alkalinity ratio was less than 1.0 and when the TVFA concentration was lower than 10,000 mg L(-1). PMID- 21546250 TI - Monoterpenoids from the aerial parts of Aruncus dioicus var. kamtschaticus and their antioxidant and cytotoxic activities. AB - The aerial parts of Aruncus dioicus var. kamtschaticus afforded five new monoterpenoids (1-5): 4-(erythro-6,7-dihydroxy-9-methylpent-8-enyl)furan-2(5H) one (1, aruncin A), 2-(8-ethoxy-8-methylpropylidene)-5-hydroxy-3,6-dihydro-2H pyran-4-carboxylic acid (2, aruncin B), 4-(hydroxymethyl)-6-(8-methylprop-7-enyl) 5,6-dihydro-2H-pyran-2-one-11-O-beta-D-glucopyranoside (3, aruncide A), (3S,4S,5R,10R)-3-(10-ethoxy-11-hydroxyethyl)-4-(5-hydroxy-7-methylbut-6 enyl)oxetan-2-one-11-O-beta-D-glucopyranoside (4, aruncide B), and (3S,4S,5R,7R) 5-(9-methylprop-8-enyl)-1,6-dioxabicyclo[3,2,0]heptan-2-one-7-(hydroxymethyl)-12 O-beta-D-glucopyranoside (5, aruncide C). Compound 2 showed potent cytotoxicity against Jurkat T cells with an IC(50) value of 17.15 MUg/mL. In addition, compounds 7 and 10 exhibited moderate antioxidant activity with IC(50) values of 46.3 and 11.7 MUM, respectively. PMID- 21546249 TI - Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series. AB - We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4 yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2 yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity. PMID- 21546251 TI - Plastin 3 expression in discordant spinal muscular atrophy (SMA) siblings. AB - Spinal muscular atrophy (SMA) is caused by loss or mutations of the survival motor neuron 1 gene (SMN1). Its highly homologous copy, SMN2, is present in all SMA cases and is a phenotypic modifier. There are cases where asymptomatic siblings of typical SMA patients possess a homozygous deletion of SMN1 just like their symptomatic brothers or sisters. Plastin 3 (PLS3) when over expressed in lymphoblasts from females has been suggested to act as a genetic modifier of SMA. We studied PLS3 expression in four Spanish SMA families with discordant siblings haploidentical for the SMA locus. We excluded PLS3 as a possible modifier in two of our families with female discordant siblings. In the remaining two, we observed small differences in PLS3 expression between male and female discordant siblings. Indeed, we found that values of PLS3 expression in lymphoblasts and peripheral blood ranged from 12 to 200-fold less than those in fibroblasts. These findings warrant further investigation in motor neurons derived from induced pluripotential stem cells of these patients. PMID- 21546252 TI - TAX1BP1, a ubiquitin-binding adaptor protein in innate immunity and beyond. AB - The innate immune system senses and protects against invading microorganisms and endogenous danger signals by triggering inflammatory and antimicrobial responses. However, dysregulation of these pathways, which involve the transcription factors nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor (IRF) 3, can lead to severe inflammatory diseases. Tax1-binding protein 1 (TAX1BP1) plays a key role in the negative regulation of NF-kappaB and IRF3 signaling by acting in concert with the ubiquitin-editing enzyme A20. In addition to regulating A20 function in anti-inflammatory and antiviral signaling pathways, TAX1BP1 also coordinates its antiapoptotic activities. Moreover, TAX1BP1 can also function as a transcriptional coactivator for nuclear receptors and viral transactivators. In this review, we discuss these findings in light of the emerging role of TAX1BP1 as a ubiquitin-binding adaptor protein. PMID- 21546253 TI - Docking and SAR studies of D- and L-isofagomine isomers as human beta glucocerebrosidase inhibitors. AB - We report the structure-activity relationship of a series of D-, and L isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position of d-isofagomines enhanced the potency toward beta-glycosidases, while the epimerization at the C3 OH group drastically reduced their inhibitory potency by over three orders of magnitude. Furthermore, d-3,4-di-epi-isofagomine abolished their inhibition activities against all enzymes. L-Isofagomine was also a fairly potent inhibitor of human beta-glucocerebrosidase, with an IC50 value of 8.7 MUM. A molecular docking study revealed that the positions and orientations of the piperidine ring of D-3-epi isofagomine in the binding site was similar to that of D-isofagomine, while D-3 epi-isofagomine missed the hydrogen bond interactions between Asp127 and the 3-OH group and between Trp179 and the 3-OH group. Furthermore, the top 10 docking models ranked by IFDscore suggested that D-3,4-di-epi-isofagomine can not bind to beta-glucocerebrosidase at a stable interaction mode. These results provide an insight into the structural requirements of isofagomine isomers for developing a new type of pharmacological chaperone for Gaucher disease. PMID- 21546254 TI - Synthesis and antimycobacterial activities of non-purine analogs of 6-aryl-9 benzylpurines: Imidazopyridines, pyrrolopyridines, benzimidazoles, and indoles. AB - 6,9-Disubstituted purines and 7-deazapurines are known to be powerful inhibitors of Mycobacterium tuberculosis (Mtb) in vitro. Analogs modified in the six membered ring (imidazopyridines, pyrrolopyridines, benzimidazoles, and indoles) were synthesized and evaluated as Mtb inhibitors. The targets were prepared by functionalization on the bicyclic heterocycle or from simple pyridines. The results reported herein, indicate that the purine N-1, but not N-3, is important for binding to the unknown target. The 3-deazapurines appears to be slightly more active compared to the parent purines and slightly less active than their 7 deazapurine isomers. Removal of both the purine N-3 and N-7 did not result in further enhanced antimycobacterial activity but the toxicity towards mammalian cells was increased. Both 3-deaza and 3,7-dideazapurines exhibited a modest activity against of the Mtb isolate in the state of non-replicating persistence. PMID- 21546255 TI - Distinguishing the core from the shell in MnO(x)/MnO(y) and FeO(x)/MnO(x) core/shell nanoparticles through quantitative electron energy loss spectroscopy (EELS) analysis. AB - The structural and chemical characterization of inverted bi-magnetic MnO(x)(antiferromagnetic)/MnO(y)(ferrimagnetic) and FeO(x)(soft ferrimagnetic)/MnO(x)(hard-ferrimagnetic) core/shell nanoparticles has been carried out by means of scanning transmission electron microscopy with electron energy loss spectroscopy analysis, (S)TEM-EELS. Quantitative EELS was applied to assess the local composition of the nanoparticles by evaluating the local Mn oxidation state based on the Mn L3/L2 peak intensity ratio and the Mn L3 peak onset. The analysis allows to unambiguously distinguish the core from the shell and to determine the nature of the involved manganese oxides in both cases. The results evidence that the structure of the nanoparticles is, in fact, more complex than the one designed by the synthesis parameters. PMID- 21546256 TI - Monitoring of gross alpha, gross beta and actinides activities in exhaust air released from the waste isolation pilot plant. AB - The simultaneous measurements of gross alpha and beta activities is one of the simplest radioanalytical technique used as a method for screening samples of both high and low activities of alpha and beta emitting radionuclides in environmental and bioassay samples. Such measurements are of great interest from both a radiological, waste disposal viewpoint, and to establish a trend of radioactivity based on long term monitoring. At the WIPP (Waste Isolation Pilot Plant) site, unfiltered exhaust air from the underground repository is the most important effluent. As part of its monitoring program, the particulates from WIPP exhaust air are collected everyday at a location typically called the Fixed Air Sampler (FAS) site or Station A, this site is located at the release point for aerosol effluents from the underground to the environment. The measurements of gross alpha and beta activity on air filter samples were performed using an ultra low level counter, PIC-MPC 9604-alpha/beta, from Protean Instrument Corporation. The high sensitivity of the gross alpha and beta instrument enables detection of low value activity from the air filters. In 2009, the values of gross alpha and beta activity concentrations ranged from = 2+ IMR underwent either a 24-mm planar ring annuloplasty (n = 5) or a 30-mm planar ring annuloplasty with concomitant posterior leaflet augmentation (n = 5). Real-time three-dimensional echocardiography allowed measurement of indices of leaflet curvature and tethering before and after annuloplasty. RESULTS: Comparing pre- and post-repair values in the P1, P2, and P3 leaflet regions, undersized 24-mm ring annuloplasty made no significant difference to mean septolateral curvature (0.23-0.26, 0.33-0.29, and 0.27-0.37 cm(-1), respectively), whereas leaflet augmentation in combination with a 30-mm ring annuloplasty increased septolateral curvature (P1 0.30-1.02, P2 0.31-1.23, and P3 0.35-0.84 cm(-1), p-values<0.05). The mean tethering angle formed between the annular plane and the posterior leaflet increased in all three posterior regions for the 24-mm ring group (P1 12 23 degrees , P2 26-31 degrees , and P3 16-25 degrees ), but decreased in all regions for the group undergoing leaflet augmentation (P1 +5 to -6 degrees , P2 +13 to -13 degrees , P3 +16-15 degrees , all p-values < 0.05). CONCLUSIONS: Undersized annuloplasty exacerbates leaflet tethering. Posterior leaflet augmentation with less severe annular reduction increases leaflet curvature and decreases tethering; this technique more completely addresses the pathogenic mechanism of IMR and may improve repair durability. PMID- 21546261 TI - Explicit declaration of ethical approval for clinical research. PMID- 21546262 TI - Molecular mechanisms underlying the role of microRNAs (miRNAs) in anticancer drug resistance and implications for clinical practice. AB - Drug resistance remains a major problem in the treatment of cancer patients for both conventional chemotherapeutic and novel biological agents. Intrinsic or acquired resistance can be caused by a range of mechanisms, including increased drug elimination, decreased drug uptake, drug inactivation and alterations of drug targets. Recent data showed that other than by genetic (mutation, amplification) and epigenetic (DNA hypermethylation, histone post-translational modification) changes, drug resistance mechanisms might also be regulated by microRNAs (miRNAs). In this review we provide an overview on the role of miRNAs in anticancer drug resistance, reporting the main studies on alterations in cell survival and/or apoptosis pathways, as well as in drug targets and determinants of drug metabolism, mediated by deregulation of miRNA expression. The current status of pharmacogenetic studies on miRNA and their possible role in cancer stem cell drug resistance are also discussed. Finally, we integrated the preclinical data with clinical evidences, in lung and pancreatic cancers, showing how the study of miRNAs could help to predict resistance of individual tumours to different anticancer drugs, and guide the oncologists in the selection of rationally based tailor-made treatments. PMID- 21546263 TI - Immediate effects of a tibiofibular joint manipulation on lower extremity H reflex measurements in individuals with chronic ankle instability. AB - Persistent muscle inhibition of the fibularis longus and soleus muscles and altered joint arthrokinematics may play a role in chronic ankle instability (CAI). Joint mobilization has been shown to improve ankle joint motion, but effects on surrounding musculature is unknown. The purpose of this study was to determine the change in fibularis longus and soleus activation following tibiofibular joint manipulation in individuals with CAI. Forty-three subjects were randomized to one of three groups (proximal tibiofibular manipulation, distal tibiofibular manipulation, or control). A two-way mixed model ANOVA was used to compare changes in the ratio of the maximum H-reflex and maximum M-wave measurements (H/M ratio) of the fibularis longus and soleus between groups over time (pre, post 0, 10, 20, 30 min). The distal tibiofibular joint manipulation group demonstrated a significant increase (P<.05) in soleus H/M ratio at all post intervention time periods except 20 min post-intervention (P=.48). The proximal tibiofibular joint manipulation and control groups did not demonstrate a change in soleus H/M ratios. All groups demonstrated a decrease (P<.05) from baseline values in fibularis longus (10-30 min post-intervention) and soleus (30 min post intervention) H/M ratios. Interventions directed at the distal tibiofibular joint acutely increase soleus muscle activation. PMID- 21546264 TI - Cystic artery localization with a three-dimensional angiography vessel tracking system compared with conventional two-dimensional angiography. AB - PURPOSE: During transcatheter hepatic therapy, the cystic artery feeding the gallbladder may inadvertently be exposed to tumor therapy. Localization of the cystic artery may help prevent exposure. The objective of this study was to compare the application of a vessel tracking system software based on three dimensional (3D) angiography versus standard two-dimensional (2D) angiography for identifying the cystic artery and its origin. MATERIALS AND METHODS: A software system that can rapidly localize the cystic artery from a 3D common hepatic angiogram was applied in 25 patients and was compared with manual localization of the cystic artery with conventional 2D digital subtraction common hepatic angiograms. RESULTS: With the vessel tracking software prototype, 28 cystic arteries were retrogradely tracked in 25 of 25 cases. The origin sites were correctly located by the software in 27 of 28 cystic arteries, with one mistracked as a result of streak artifact. By contrast, on standard 2D hepatic angiography, the cystic artery was deemed visible with certainty in 12 of 25 cases (P < .001). The vessel tracking system revealed a 56% prevalence of extraanatomic distribution by the cystic artery, with the most common supply going to segment 5 liver parenchyma. CONCLUSIONS: The 3D vessel rapid tracking system has advantages over conventional 2D hepatic angiography in revealing the cystic artery and its origin site. It is also an important tool to identify the complete distribution of the cystic artery without superselective angiography. Supply to adjacent hepatic parenchyma or tumor by the cystic artery is not insignificant and should be considered during hepatic therapies. PMID- 21546265 TI - Detection of atrial fibrillation after stroke and the risk of recurrent stroke. AB - Failure to expeditiously diagnose atrial fibrillation (AF) as the cause of ischemic stroke has unclear consequences. We studied the association between detection of AF after discharge and the risk of recurrent stroke. We followed a prospectively assembled cohort of patients hospitalized for stroke for 1 year for new diagnoses of AF and recurrent stroke. We compared rates of recurrent stroke in patients with a new diagnosis of AF and those without a new diagnosis of AF after discharge using Kaplan-Meier survival statistics. We conducted Cox proportional hazards analysis of the diagnosis and timing of AF and recurrent stroke after adjustment for age, sex, race, preexisting AF, hypertension, dyslipidemia, diabetes, previous stroke, and use of antithrombotic and statin medications. Among 5575 patients with stroke, 113 (2.0%) received a new diagnosis of AF after discharge, and 221 (4.0%) had recurrent stroke. At 1 year, the Kaplan Meier rate of recurrent stroke was 18.9% in those with a new diagnosis of AF and 4.5% in others, including those with AF diagnosed before or during the index hospitalization (P = .001). The association between a new diagnosis of AF and stroke recurrence persisted after adjustment for potential confounders (hazard ratio, 5.6; 95% confidence interval, 3.4-9.1). A new diagnosis of AF after discharge for stroke is associated with an increased risk of recurrent stroke, even compared with patients with known AF. These findings identify a subset of patients at high risk for recurrent stroke and highlight the importance of timely detection of AF in patients with stroke. PMID- 21546266 TI - Evaluation of a previously undescribed transesophageal echocardiographic view of the main pulmonary artery. PMID- 21546267 TI - Pulmonary venous diastolic flow reversal in severe aortic regurgitation. PMID- 21546268 TI - Use of venovenous extracorporeal membrane oxygenation under regional anesthesia for a high-risk rigid bronchoscopy. PMID- 21546269 TI - Levosimendan versus intra-aortic balloon pump in high-risk cardiac surgery patients. AB - OBJECTIVE: Patients with severe left ventricular dysfunction receive inotropic and mechanical circulatory support with an intra-aortic balloon pump (IABP) during the perioperative phase of cardiac surgery. The authors performed the first comparison of levosimendan versus an IABP in patients with poor left ventricular function undergoing cardiac surgery. DESIGN: A case-matched study. SETTING: A teaching hospital. PARTICIPANTS: Twenty-two heart failure patients scheduled to undergo elective coronary artery bypass graft surgery with or without concomitant mitral surgery. INTERVENTIONS: Eleven patients received levosimendan at a dose of 0.1 MUg/kg/min for 24 hours without an initial bolus. The control group, also 11 patients, received a preoperative IABP. The intensive care unit stay was the major endpoint of this study. Biochemical, hemodynamic, and echocardiographic data were collected together with the time on mechanical ventilation and 30-day mortality. MEASUREMENTS AND MAIN RESULTS: The length of intensive care unit stay was reduced in patients receiving levosimendan (median, 2.5; range, 1-3 days) compared with those receiving an IABP (median, 5; range, 3 6 days; p = 0.01). No deaths occurred in the levosimendan group; 1 patient died in the intra-aortic balloon pump group. CONCLUSIONS: Patients receiving levosimendan had a shorter duration of intensive care stay than peers who received a preoperative IABP. The findings of this pilot study should be investigated further in a large randomized controlled study. PMID- 21546270 TI - Laparoscopic gastric bypass in a patient with an implanted left ventricular assist device. PMID- 21546271 TI - Scholarly productivity of united states academic cardiothoracic anesthesiologists: influence of fellowship accreditation and transesophageal echocardiographic credentials on h-index and other citation bibliometrics. AB - OBJECTIVE: The h-index allows the evaluation of scholarly output in academics, but this bibliometric statistic has not been applied extensively to measure productivity in anesthesiology. The authors tested the hypothesis that the h index is dependent on academic rank, American College of Graduate Medical Education (ACGME) accreditation of the training program, and National Board of Echocardiography credentials in perioperative transesophageal echocardiography (TEE) in United States academic cardiothoracic anesthesiologists. DESIGN: Observational. SETTING: Internet analysis. PARTICIPANTS: United States academic cardiothoracic anesthesiologists. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Faculty members from 30 randomly selected fellowship programs with or without accreditation were identified using the Society of Cardiovascular Anesthesiologists web site. The status of each faculty member's credentials in perioperative TEE was defined using the "verify certification" function on the National Board of Echocardiography web site. Publications, citations, citations/publication, and the h-index for each faculty member were obtained using Scopus. Two hundred fifty-nine cardiothoracic anesthesiologists (204 men and 55 women) were identified (8 instructors [3%], 123 assistant professors [48%], 56 associate professors [22%], 63 professors [24%], and 9 chairpersons [3%]). The average cardiothoracic anesthesiologist had an h-index of 6 +/- 7 with 28 +/- 46 publications, 499 +/- 988 total citations, and 13 +/- 18 citations per publication. The h-index increased significantly (p < 0.05) among ranks (instructors [1 +/- 1], assistant professors [3 +/- 3], associate professors [7 +/- 5], professors [12 +/- 8], and chairpersons [18 +/- 13]). Significant differences in the number of publications and total citations also were observed among ranks. Differences in the h-index among ranks were observed regardless of program accreditation status or transesophageal echocardiographic credentials. Faculty members working in American College of Graduate Medical Education accredited programs had more publications and citations and higher h-indices than their counterparts in programs that were not accredited. Except for program directors, the scholarly output of academic cardiothoracic anesthesiologists with or without transesophageal echocardiographic credentials was similar within each academic rank. CONCLUSIONS: The results show that the h-index increases progressively with academic rank and is dependent on fellowship program accreditation status but not transesophageal echocardiographic credentials in United States academic cardiothoracic anesthesiologists. PMID- 21546272 TI - Transesophageal echocardiography in the management of right ventricular bullet embolization from the left brachiocephalic vein. PMID- 21546273 TI - Versican and CD44 in in vitro valvular interstitial cell injury and repair. AB - BACKGROUND: Versican is one of the key components of the extracellular matrix (ECM) that is expressed during injury, inflammatory, and repair processes. The current study evaluated the relationship between versican and the membrane receptor CD44 during in vitro valvular interstitial cell (VIC) injury and repair. METHODS: Subconfluent, confluent, and wounded cultures of human VICs were fixed and immunostained to detect versican and the membrane receptor CD44. To examine the relationship between versican and CD44, a blocking antibody to CD44 was added to cultured VICs, and in vitro wound repair along with pericellular versican organization and stress fiber formation were examined. RESULTS: Immunohistochemistry demonstrated that versican is prominent intracellularly, as well as extracellularly, in actively proliferating VICs. In contrast, versican was only localized to fibrils in the extracellular space in between cells in confluent (quiescent) cultures. Following wounding, versican expression was up regulated, and it was secreted as ECM at the trailing edge of migrating cells. The staining for CD44 was similarly localized to the trailing edge of migrating VICs in wounded cultures. Treatment of VICs with a CD44-blocking antibody disrupted the organization of versican in the pericellular matrix and inhibited stress fiber formation in these cells. Functionally, blocking CD44 significantly inhibited VIC-mediated contraction of type I collagen gels (35.7%+/-0.7% vs. 23.3%+/-1.4% of initial gel area, P<.01). CONCLUSIONS: Versican is a key component of the provisional wound repair ECM that is expressed following injury to VICs. The receptor CD44 plays an important role in organizing the provisional ECM. SUMMARY: Our data suggests VICs synthesize and secrete versican following injury. These cells also up-regulate CD44, a receptor that binds versican. Blocking CD44 disrupted the organization of versican and inhibited stress fiber formation. Functionally, blocking CD44 inhibited cell-mediated contraction of a collagen matrix. Collectively, these data suggest versican expression and organization are important to valve cell injury and repair. PMID- 21546274 TI - Altered melusin pathways involved in cardiac remodeling following acute myocardial infarction. AB - BACKGROUND: Melusin, a muscle-specific integrin-linked protein, has been reported to be a biomechanical sensor and to protect the heart from pressure overload. In the present study, we investigated the possible role that melusin plays during cardiac remodeling after myocardial infarction (MI). METHODS: We constructed a heart failure model of rats induced by left anterior descending coronary artery ligation. At different time points (1, 2, 3, 4, 6, and 8 weeks) following the operation, cardiac function was monitored by echocardiography and hemodynamic assessment; cardiac morphology was measured using hematoxylin-eosin-stained sections. Melusin expression, as well as p-Akt, Akt, and one of the Rho small GTPase family members, CDC42, was determined dynamically by Western blotting analysis during the postinfarction cardiac remodeling. RESULTS: Progressive increase in left ventricular (LV) end-systolic dimension and LV end-diastolic dimension and decrease in percent LV fractional shortening (%FS) and LVdp/dt(max) demonstrated gradually deteriorated cardiac function in rats following MI operation. Morphological analysis revealed cardiac remodeling in MI animals, including increased LV diameter and decreased border zone thickness. We also showed a dynamic change in melusin during heart failure progression; it had an initial decline which was evident at 3 weeks and increased subsequently, reaching peak levels at 6 weeks. This dynamic change in melusin was significantly correlated with %FS and LVdp/dt(max.) p-Akt/Akt and CDC42 protein expression was correlated with melusin content. CONCLUSIONS: The altered melusin pathways and CDC42 parallel the cardiac function progression during cardiac remodeling post MI. The dynamic change of them during this procedure may represent an important molecular mechanism underlying postinfarction cardiac remodeling and provide potential therapeutic targets. PMID- 21546275 TI - The historical evolution of the Department of Veterans Affairs National Surgical Quality Improvement Program. PMID- 21546276 TI - Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism. AB - BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) regulates myocardial apoptosis, cellular proliferation, and the immune response after ischemia/reperfusion (I/R). STAT3 is also necessary for the production of vascular endothelial growth factor (VEGF) by mesenchymal stem cells (MSCs), which are known to reduce myocardial injury after I/R. However, it remains unknown whether STAT3 is an important mediator of MSC-based cardioprotection. We hypothesized that knockout of stem cell STAT3 would reduce MSC-derived myocardial functional recovery and increase myocardial inflammatory and apoptotic signaling. STUDY DESIGN: With a Langendorff apparatus, male rat hearts were subjected to 15 minutes of equilibration and 25 minutes of ischemia, followed by 40 minutes of reperfusion. Immediately before ischemia, hearts received intracoronary infusions of vehicle, wild-type MSCs (WT MSCs) or STAT3 knockout MSCs (STAT3KO MSCs). Heart function was measured continuously. Myocardial homogenates were analyzed for production of interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF alpha). Additionally, MSC production of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) were measured in vitro. RESULTS: Hearts treated with WT MSCs exhibited the greatest functional recovery, and those treated with STAT3KO MSCs had equivalent recovery to vehicle. The highest proinflammatory cytokine levels were seen in vehicle-treated hearts, and the lowest in the WT MSC group. STAT3KO MSCs produced less IGF-1, but more HGF than WT MSCs. Finally, hearts treated with STAT3KO MSCs or vehicle had significantly higher caspase-3 levels than those treated with WT MSCs. CONCLUSIONS: Intracoronary infusions of MSCs improve postischemic left ventricular function and reduce proapoptotic and proinflammatory signaling via a STAT3-dependent mechanism. PMID- 21546277 TI - A prospective randomized multicenter study of Turkish Society of Urooncology comparing two different mechanical bowel preparation methods for radical cystectomy. AB - OBJECTIVE: To investigate the outcomes and complication rates of urinary diversion using mechanical bowel preparation (BP) with 3 day conventional and limited BP method through a standard perioperative care plan. MATERIALS AND METHODS: This study was designed as a prospective randomized multicenter trial. All patients were randomized to 2 groups. Patients in standard 3-day BP protocol received diet restriction, oral antibiotics to bowel flora, oral laxatives, and saline enemas over a 3-day period, whereas limited the BP arm received liberal use of liquid diet, sodium phosphate laxative, and self administered enema the day before surgery. All patients received same perioperative treatment protocol. The endpoints for the assessment of outcome were anastomotic leakage, wound infection, wound dehiscence, intraperitoneal abscess, peritonitis, sepsis, ileus, reoperation, and mortality. Bowel function recovery, including time to first bowel movement, time to first oral intake, time to regular oral intake, and length of hospital stay were also assessed. RESULTS: Fifty-six patients in 3-day BP and 56 in limited BP arm were evaluable for the study end points. Postoperatively, 1 patient in limited BP and 2 patients in 3-day BP arm died. There was no statistical difference in any of the variables assessed throughout the study, however, a favorable return of bowel function and time to discharge as well as lower complication rate were observed in limited BP group. CONCLUSIONS: Regarding all endpoints, including septic and nonseptic complications, current clinical research offers no evidence to show any advantage of 3-day BP over limited BP. PMID- 21546278 TI - Surveillance after EVAR based on duplex ultrasound and abdominal radiography. AB - INTRODUCTION: Computed tomography angiography (CTA) is considered the gold standard imaging technique for surveillance following endovascular aneurysm repair (EVAR). Limitations of CTA include cost, risk of contrast nephropathy and radiation exposure. A modified surveillance protocol involving annual duplex ultrasound (DUS) and abdominal radiography (AXR) was introduced, with CTA performed only if abnormalities were identified or DUS was undiagnostic. METHODS: Prospective records were maintained on patients undergoing infra-renal EVAR at a UK, tertiary referral centre. All patients enrolled with at least one-year follow up were reviewed. Primary outcomes identified were aneurysm rupture and aneurysm related complications. Secondary outcomes included number of CTAs avoided and cost. RESULTS: Median follow-up was 36 months (range 12-57) for 194 patients. The total number of sets of surveillance imaging was 412 of which 70 (17%) required CTA. Abnormalities were found in 30 patients, 18 confirmed by CTA. Eleven patients required secondary intervention, three initially identified by AXR, three by DUS, three by both DUS and AXR, and two by CTA following undiagnostic DUS. No patient presented with rupture or aneurysm-related complications not identified by modified surveillance. Mean annual savings were ?223. CONCLUSION: EVAR surveillance based on DUS and AXR is feasible and safe. The complimentary nature of AXR and DUS is demonstrated. PMID- 21546279 TI - Is open surgery for AAA repair a reason for concern in the EVAR era? PMID- 21546280 TI - Cephalometric variables discriminate among magnetic resonance imaging-based structural characteristic groups of the temporomandibular joint. AB - OBJECTIVE: The aim of this study was to assess retrospectively whether, in patients with temporomandibular joint (TMJ) arthralgia, commonly used cephalometric variables of dentofacial morphology can discriminate among magnetic resonanace imaging (MRI)-based TMJ structural characteristic groups of "uni- or bilateral disc displacement without reduction (DDwoR) associated with bilateral osteoarthrosis (OA)" and "uni- or bilateral disc displacement with reduction (DDwR) without OA." STUDY DESIGN: Bilateral MRI of the TMJ was performed in 56 consecutive TMJ arthralgia patients to identify individuals with specific structural characteristic of uni- or bilateral TMJ DDwoR, DDwR, and OA. Application of the criteria resulted in a study group of 31 patients with "uni- or bilateral DDwoR with bilateral OA" and 25 with "uni- or bilateral DDwR without OA." Linear and angular cephalometric measurements were taken from lateral cephalograms to apply selected criteria of dentofacial morphology. One-way analysis of variance was used to assess differences in cephalometric variables by MRI-based TMJ group. Then, discriminant function analysis predicted TMJ group membership. RESULTS: A-B plane to facial plane angle, palatal plane to occlual plane, and interincisal angle produced a significantly discriminant function that predicted TMJ group membership (P < .001). This function correctly classified 85.7% of original grouped cases. CONCLUSIONS: Cephalometric variables may discriminate among MRI-based TMJ structural characteristic groups. Additional diagnostic information related to MRI-based classification groups was generated. PMID- 21546281 TI - Association of human herpesvirus 6 subtypes with symptomatic apical periodontitis. AB - OBJECTIVE: The occurrence of human herpesvirus (HHV) 6 subtypes A and B in apical periodontitis was determined. The relationship of HHV-6 subtypes to other disease associated herpesviruses, i.e., Epstein-Barr virus (EBV) and human cytomegalovirus, was also investigated. STUDY DESIGN: Forty apical periodontitis samples (17 symptomatic and 23 asymptomatic) and 40 healthy pulp control samples were collected. Nested polymerase chain reaction was used to detect HHV-6 DNA. RESULTS: HHV-6 DNA was observed in significantly higher frequencies in apical periodontitis samples than in control samples (20% vs. 2.5%; P = .03). Further classification of apical lesions revealed that subtype B of HHV-6 was significantly associated with large-sized and symptomatic lesions (P < .01). Thirty-one apical lesions (77%) harbored >=1 of the tested herpesviruses: EBV was the most frequent herpesvirus (72.5%) in apical periodontitis, followed by HHV-6 (20%). CONCLUSION: Our findings suggest that EBV and HHV-6B infections can be associated with symptomatic apical periodontitis. PMID- 21546282 TI - MTAD in endodontics: an update review. AB - The major objective in endodontic therapy is to achieve complete chemomechanical debridement of the entire root canal system. This can be accomplished with biomechanical instrumentation and chemical irrigation. Various endodontic irrigants, such as sodium hypochlorite, chlorhexidene, and iodine potassium iodide, are available, each having its own advantages with some limitations. MTAD, a new endodontic irrigant, has been introduced to fulfill these limitations. MTAD is a mixture of doxycycline, citric acid, and a detergent (Tween 80). Since its introduction, it is a material that has been researched extensively for its properties. This article presents a review on the numerous properties of MTAD, such as antimicrobial activity, smear layer- and pulp dissolving capability, effect on dentin and adhesion, and biocompatibility. PMID- 21546283 TI - Myoepithelial cells are functionally deficient in sialadenosis: still an assumption. PMID- 21546284 TI - Climate change in endodontics: is it time to recycle "garbage in-garbage out" systematic reviews? PMID- 21546285 TI - Cytotoxicity evaluation of dentin bonding agents by dentin barrier test on 3 dimensional pulp cells. AB - OBJECTIVE: The aim of this study was to evaluate the effects of 4 dentin-bonding agents on the cell viability of bovine derived cells. STUDY DESIGN: Cytotoxicity of dentin-bonding agents (G-Bond [GB], Adper Prompt Self-Etch [APSE], Clearfil DC Bond System [CDCB], and Quadrant University-1-Bond [UB]) was analyzed with a dentin barrier test device using 3-dimensional (3D) pulp cell cultures. A commercially available cell culture perfusion chamber was separated into 2 compartments using a 500 MUm dentin disk. The 3D cultures were placed on a dentin disk and held in place with a special biocompatible stainless steel holder. Test materials were introduced into the upper compartment in direct contact with the cavity side of the dentin disks according to the manufacturer's instructions. Subsequently, the pulpal part of the perfusion chamber containing the cell cultures was perfused with a medium (2 mL/h). After an exposure period of 24 hours, cell survival was determined by using the MTT assay. Statistical analyses were performed using the Mann-Whitney U test. RESULTS: In the dentin barrier test, cell survival rates of UB and CDCB were similar to the control group (P > .05). However, all other tested materials were cytotoxic for the 3D pulp-derived cell cultures (P < .05). CONCLUSIONS: Dentin-bonding agents include biologically active ingredients and may modify pulp cell metabolism when the materials are used in deep cavities in spite of a dentin barrier. If these adhesive agents are used in deep cavities, a biocompatible cavity liner should be used. PMID- 21546286 TI - Ancestry of African Americans with sickle cell disease. AB - The inheritance of genetic disease depends on ancestry that must be considered when interpreting genetic association studies and can provide insights when comparing traits in a population. We compared the genetic profiles of African Americans with sickle cell disease to those of Black Africans and Caucasian populations of European descent and found that they are less genetically admixed than other African Americans and have an ancestry similar to Yorubans, Mandenkas and Bantu. PMID- 21546287 TI - Chronic kidney disease in cats: an ounce of prevention is worth a pound of cure. PMID- 21546288 TI - Activated platelet-derived growth factor beta receptor and Ras-mitogen-activated protein kinase pathway in natural bovine urinary bladder carcinomas. AB - Bovine papillomavirus types 1 or 2 (BPV-1/2) are involved in the aetiopathogenesis of bovine urinary bladder cancer. BPV-1/2 E5 activates the platelet-derived growth factor beta receptor (PDGFbetaR). The aim of this study was to analyse the Ras/mitogen-activated protein kinase (MAPK) pathway in relation to activation of PDGFbetaR in natural bovine urinary bladder carcinomas. Co-immunoprecipitation and Western blot analysis demonstrated that recruitment of growth factor receptor bound protein 2 (GRB-2) and Sos-1 to the activated PDGFbetaR was increased in carcinomas compared to normal tissues. Higher grade bovine urinary bladder carcinomas were associated with activation of Ras, but not with activation of downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (Mek 1/2) or extracellular signal-regulated kinase (Erk 1/2). PMID- 21546289 TI - Serum insulin-like growth factor type 1 concentrations in healthy dogs and dogs with spontaneous primary hypothyroidism. AB - Circulating insulin-like growth factor type 1 (IGF-1) concentrations in dogs have been correlated with standard breed bodyweight (SBBW or breed size). Thyroid and somatotropic functions, which have common effects and regulatory mechanisms, were investigated in hypothyroid dogs. IGF-1 was measured in 495 adult healthy dogs (N) and in 220 primary hypothyroid dogs (HOT) with clinical and biological signs of primary hypothyroidism. IGF-1 was determined as a function of SBBW (kg): <=15 (group A); 1540 (group D). In HOT dogs, median fT4 and c-TSH values were 9pmol/L and 1.5ng/mL, respectively. A significant correlation between bodyweight (BW) and IGF-1 was observed in both HOT and N dogs. The median IGF-1 value (ng/mL) was significantly higher (P<0.01) in HOT dogs compared to N in groups B, C and D (230 vs. 182; 316 vs. 230; 606 vs. 306 respectively). In conclusion, IGF-1 concentration should be interpreted in the context of SBBW in dogs and increases in spontaneous primary hypothyroidism. However, it remains unclear if this association is directly due to hypothyroidism or is the result of the weight gain accompanying hypothyroidism. PMID- 21546290 TI - Potential risk factors associated with risk for drop-out and relapse during and following withdrawal of opioid prescription medication. AB - BACKGROUND: Withdrawal of opioid medication in patients with chronic pain has a drop-out and relapse problem. AIM: To evaluate if depressive symptoms, anxiety and pain intensity are potential risk factors for drop-out or relapse during the withdrawal process. Further, to assess internal consistency of scales for assessment of these potential risk factors. METHODS: Twenty-nine patients were included. After 2 years 28 of these were followed-up. RESULTS: Those with depressive symptoms at baseline had a significant risk for drop-out from the withdrawal program (odds ratio 1.37) and relapse into use of opioids at follow-up (odds ratio 1.44). Drop-outs rated depressive symptoms significantly higher before detoxification. Those who relapsed rated significantly higher for pain intensity, depressive symptoms and abstinence prior to withdrawal. All scales had high reliability. PERSPECTIVE: To avoid drop-out and relapse clinical practice need to screen for depressive symptoms, pain intensity, and abstinence. This article presents significant reliability of scales useful within dependency centers. They can be used to identify these risk factors for drop-out and relapse, respectively, when initiating the withdrawal process. Taking these risk factors into consideration could improve the outcome of the withdrawal process by preventing drop-out and relapse. PMID- 21546291 TI - Post-processing of individual signals for de-noising. AB - In this work, we examine the fluctuation of the intensity and the phase of an NMR signal during repetition of experiments and investigate possibilities of using these information to judge suspicious peaks, whose true colors may be noises or genuine signals. We firstly analyze the intensity and the phase of an NMR signal separately, and show that for the accumulated spectral profile the contribution of the intensity is less than that of the phase. Secondly we show that we can de noise a noisy spectrum by using the standard deviation of phase at each spectral point. We then compare the de-noising effect of the present approach and that of the phase-covariance method proposed recently, which is an alternative method of appreciating phase distribution. Finally, effects of the dispersion component are discussed. PMID- 21546292 TI - Clinicopathologic and immunohistochemical characteristics of adult primary cardiac angiosarcomas: analysis of 10 cases. AB - Primary cardiac angiosarcoma is a rare but the most common malignant neoplasm of the heart in adults. The objective of this study is to analyze the clinicopathologic characteristics of primary cardiac angiosarcoma. Ten cases of primary cardiac angiosarcoma treated in a single institution were analyzed for their clinical, pathologic, and immunohistochemical features. There were 6 men and 4 women, with a mean age of 40 years (range, 20-61 years). The patients commonly presented with dyspnea and distant metastasis. All tumors were located in the right atrium, with a mean tumor size of 6.8 cm. Tumors were hemorrhagic, with variegated tan-brown solid areas. Histologically, they exhibited high-grade morphology with mixed solid growth and anatomizing channels. Frequent mitoses and tumor necrosis were common. The tumors were strongly positive for CD31, CD34, FLI 1, and WT-1 but negative for AE1/3, D2-40, human herpesvirus 8, and epidermal growth factor receptor. The tumor cells were focally reactive to p53, with a high rate of Ki-67 expression. A complete tumor resection was not possible in any of the patients because of the size or extensive local invasion of the tumor. Overall survival ranged from 1 to 81 months (mean, 26.6 months) after initial histologic diagnosis. Primary cardiac angiosarcomas are rare tumors that commonly arise in the right atrium. The mean age is much younger than that of soft tissue angiosarcoma. Regional tumor extension and distant metastasis are extremely common at the time of diagnosis. Surgical resection with adjuvant chemotherapy is currently the preferred treatment, and survival time appears to be inversely correlated with the tumor size and degree of regional tumor extension at the time of surgery. PMID- 21546293 TI - Pure hibernoma of the breast: insights about its origins. AB - Hibernomas are rare benign tumors composed of cells reminiscent of brown adipose tissue. In the mammary gland, hibernomas are extraordinary rare, with only 4 cases reported previously. We report the fifth case in a 37-year-old woman who presented with a slowly growing mobile mass in her right breast. A 2.2 cm well circumscribed lobulated mass was completely removed. The histopathologic analysis showed the full characteristics of the hibernoma. A review of the clinicopathologic features of hibernomas, its relation to brown adipose tissue in humans, and considerations about its histogenesis are made. PMID- 21546294 TI - Perivascular epithelioid cell tumor of the sigmoid colon with transcription factor E3 expression. AB - We describe here a 62-year-old woman who presented with a perivascular epithelioid cell tumor arising in the sigmoid colon. Computed tomography revealed a 5-cm-sized intraluminal fungating mass. Histologically, the tumor consisted of plump, epithelioid cells with abundant clear-to-lightly eosinophilic cytoplasm and round nuclei, arranged in an alveolar or trabecular pattern. The tumor cells were strongly positive for HMB-45 and TFE3, but negative for vimentin, cytokeratin, smooth muscle actin, S100 protein, CD117, CD34, synaptophysin, chromogranin, CD10, hepatocyte antigen, CD1a, and desmin. The tumor cells had a high Ki-67 labeling index (up to 20%). Fluorescent in situ hybridization showed no evidence of the EWS rearrangement. Based on these histologic and immunohistochemical features, our patient was diagnosed with a perivascular epithelioid cell tumor of the sigmoid colon. PMID- 21546295 TI - Atypical imaging feature of non-secretory multiple myeloma. AB - Non-secretory multiple myeloma (NSMM) is a rare variant of the classic form of multiple myeloma in which no monoclonal gammopathy can be demonstrated in the serum or urine. We describe a rare case of non-secretory multiple myeloma in a 23 year old female presenting with bilateral limb weakness of two years duration. Clinically she was diagnosed to have Pott's spine and was treated with category 1 anti tubercular drugs. Hematological investigations showed plasmacytosis and radiography showed osteolytic lesions. No monoclonal gammopathy was found in the serum or urine. MRI showed multiple compressions with sclerosis within vertebral bodies suggestive of osteomalacia/ diffuse infiltrative disorder. The free light chain (FLC) assay revealed increment in the free kappa light chain and an abnormal kappa/lambda ratio. Free Light Chain assay (FLC) when used in complement with Protein Electrophoresis (PEP) and Immunofixation Electrophoresis (IFE) were pivotal in diagnosis of non secretory multiple myeloma or light chain myelomas. FLC is a useful monitoring tool because it reflects therapy results due to short serum half life. PMID- 21546296 TI - Schistosomiasis and signet ring cell carcinoma of the rectum. AB - A definitive link between Schistosoma hematobium infection and squamous cell carcinoma of the bladder has been identified. A weaker association between S japonicum infection and colorectal neoplasia has been proposed, although reports are limited to case reports, a case series, and epidemiologic studies. Virtually all cases presented in the literature describe intestinal-type adenocarcinoma occurring in association with S japonicum. We here describe a 40-year-old male Filipino patient with signet ring cell carcinoma of the rectum and evidence of infection by S japonicum. PMID- 21546297 TI - Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type arising in the pleura with pleural fibrous plaques in a lathe worker. AB - Our patient was an 86-year-old man who had worked as a lathe operator for 40 years. He had no history of tuberculosis, pyothorax, or autoimmune disease. He had not been exposed to asbestos. He was asymptomatic, but an imaging study showed gradually increasing pleural plaques. A biopsy specimen of a pleural lesion showed sclerosis of the pleura and diffuse infiltration of small- to medium-sized B lymphocytes. Polymerase chain reaction-based analysis detected monoclonal rearrangement of immunoglobulin heavy-chain genes. Histologic diagnosis was extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma). The lymphoma was negative for Epstein-Barr virus. We report a rare case of a metal worker with MALT lymphoma arising in the pleura with pleural fibrous plaques. It is speculated that MALT lymphoma might develop in the background of pneumoconiosis. Inflammatory and/or immunologic reactions to metal particles might contribute to the oncogenesis of this tumor. PMID- 21546298 TI - Epithelial-myoepithelial carcinoma of the lacrimal gland: a rare case. AB - Epithelial-myoepithelial carcinoma is a rare tumor of the salivary gland constituting only 1% of all tumors. It is a low-grade malignancy characterized by a classical biphasic morphology and immunophenotype. In the lacrimal gland, it is extremely rare with only 3 cases reported in the English medical literature. We describe the fourth case of epithelial-myoepithelial carcinoma, the first case in a female patient, and review the available literature. PMID- 21546299 TI - A novel GH-1 gene mutation (GH-P59L) causes partial GH deficiency type II combined with bioinactive GH syndrome. AB - CONTEXT AND OBJECTIVE: Despite the differences in the main characteristics between the autosomal dominant form of GH deficiency (IGHD II) and the bioinactive GH syndrome, a common feature of both is their impact on linear growth leading to short stature in all affected patients. DESIGN: The index patient, a boy, was referred for assessment of his short stature (-2.54 SD score) and a delayed bone age of 5.9 yrs at the chronological age of 7.7 yrs. The GHD was confirmed by standard GH provocation tests, which revealed modestly reduced GH and IGF-I concentrations. Further genetic analysis of GH-1 gene identified heterozygosity for GH-P59L mutation. The secretion of the GH-P59L following stimulation with forskolin was investigated and compared to that of the wt-GH after expression of both GH variants in AtT-20 cells. Based on the position of P59L mutation that lies within a patch of residues composing the GH binding site 1 for GHR, we performed the analysis of GH-P59L binding to GHR by in silico mutagenesis and molecular dynamics simulations, which suggested possible problems in correct binding of GH-P59L to the GHR. Therefore, the functional characterization of this GH mutant was assessed through studies of GHR binding and activation of Jak2/Stat5 signaling pathway. RESULTS: In line with the clinical data of the patient GH deficiency is suggested, underlined by GH secretion studies revealing a moderate difference in secretion between GH-P59L and wt-GH. In addition, further functional characterization of the GH-P59L by studies of GH-receptor binding and activation of Jak2/Stat5 pathway presented with a reduced binding affinity of GH-P59L for GHR and decreased bioactivity compared to the wt-GH. CONCLUSIONS: The clinical data of the patient combined with the laboratory data support the diagnosis of partial IGHD type II. Since the GH deficiency was not total, additional binding and signaling studies were performed, which revealed that the GH-P59L variant displays some of the common features of bioinactive GH syndrome. Taken together, in this study we report a patient suffering from the combination of two growth disorders (alteration of secretion as well as bioactivity) caused by a GH-1 gene alteration highlighting the necessity of functional analysis of any GH variant, despite the presence of obvious clinical features of IGHD type II. PMID- 21546300 TI - Influence of follicle-stimulating hormone receptor (FSHR) Ser680Asn polymorphism on ovarian function and in-vitro fertilization outcome: a meta-analysis. AB - BACKGROUND: A common follicle-stimulating hormone (FSH) receptor (or FSHR) polymorphism Ser680Asn (rs6166) was found to be associated with altered ovarian response in women undergoing in-vitro fertilization. To further investigate such an association, a meta-analysis was conducted. METHODS: A PubMed literature search was conducted to identify all cohort studies investigating such a relationship. The following parameters-basal FSH levels, total FSH doses, oocytes retrieved, and pregnancy rates-were used to evaluate the ovarian function, its response to exogenous FSH and in-vitro fertilization and intracytoplasmic sperm injection outcome. RESULTS: A total of 1421 cases were collected from eight studies. Of them, a significantly lower basal FSH level was observed in patients harboring Asn/Asn (NN) genotype than those carrying the Ser/Ser (SS) genotype both in Asian (WMD: -2.57 mIU/ml, 95% CI: -2.96 to -2.19, P<0.0001) and Caucasian retrospective groups (WMD: -1.86 mIU/ml, 95%CI: -2.07 to -1.66, P<0.0001) with no heterogeneity. Moreover, carriers of the SS tended to require greater FSH doses than NN (WMD: -268.82IU, 95% CI: -561.28 to 23.63, P=0.07). Other parameters, such as oocytes retrieved and pregnancy rate, were not significantly different between the groups. CONCLUSION: Carriers of the SS variant have slightly higher basal FSH levels, tending to require higher doses of exogenous FSH for stimulation. PMID- 21546301 TI - [Thoughts about an Acronym]. PMID- 21546302 TI - [Application of an OPT model in a paediatric nursing clinical case in primary health care]. AB - This article describes the assessment and nursing diagnostic hypothesis generation on a 10 years old child with a parietal contusion who attended the health care centre with his mother. The health centre is located in a rural area in Catalonia, and a paediatric nurse was placed in charge of the child. In the assessment and the subsequent information analysis, the nurse identified an unhealthy situation for the correct development of the child. The situation required the mother's intervention and a change in her habits and behaviours. For the approach of the case study, the OPT model (Outcome Present-state Testing) by Pesut and Herdman was used. The assessment was made by using Marjory Gordon's Functional Health Patterns assessment, and the NANDA-I nursing diagnoses taxonomy, NOC Outcomes taxonomy and NIC Interventions taxonomy was used for the diagnoses and planning. PMID- 21546303 TI - Epidemiological survey of Crimean-Congo hemorrhagic fever virus in Yunnan, China, 2008. AB - OBJECTIVES: We aimed to determine the seroprevalence of Crimean-Congo hemorrhagic fever virus (CCHFV) infection in Yunnan Province, China. MATERIALS AND METHODS: One thousand six hundred and fifty-seven human serum samples and 1280 ticks (Hyalomma asiaticum) were collected from five counties (Menglian, Menghai, Lancang, Mengla, and Ximeng). Serum samples were analyzed independently by indirect immunofluorescence assay and Western blotting to detected CCHFV antibody. The ticks were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) to detect virus RNA. RESULTS: The CCHFV IgG positivity was 3.4% (57/1657). A multivariate analysis was performed, and variables that increased the chance of infection were found to include history of tick bite or contact (odds ratio (OR) 16.6, 95% confidence interval (CI) 7.5-37.0) and age>30 years (OR 6.8, 95% CI 1.6-28.2). The RT-PCR positive rate for ticks was 14.3% (6/42). CONCLUSIONS: The five counties (Menglian, Menghai, Lancang, Mengla, and Ximeng) in Yunnan are areas with the potential for CCHF outbreaks. Residents should protect themselves against tick bites and the surveillance of CCHFV in this region should be improved. PMID- 21546304 TI - The relative importance of temporal envelope information for intelligibility prediction: a study on cochlear-implant vocoded speech. AB - Vocoder simulation has been long applied as an effective tool to assess factors influencing the intelligibility of cochlear implants listeners. Considering that the temporal envelope information contained in contiguous bands of vocoded speech is correlated and redundant, this study examined the hypothesis that the intelligibility measure evaluating the distortions from a small number of selected envelope cues is sufficient to well predict the intelligibility scores. The speech intelligibility data from 80 conditions was collected from vocoder simulation experiments involving 22 normal-hearing listeners. The relative importance of temporal envelope information in cochlear-implant vocoded speech was modeled by correlating its speech-transmission indices (STIs) with the intelligibility scores. The relative importance pattern was subsequently utilized to determine a binary weight vector for STIs of all envelopes to compute the index predicting the speech intelligibility. A high correlation (r=0.95) was obtained when selecting a small number (e.g., 4 out of 20) of temporal envelope cues from disjoint bands to predict the intelligibility of cochlear-implant vocoded speech. PMID- 21546305 TI - Modelling wall shear stress in small arteries using the Lattice Boltzmann method: influence of the endothelial wall profile. AB - In order to address the problem of blood flow over the endothelium in small arteries, the near-endothelial region is here studied in more detail. The method used is a finite-volume discretisation of a Lattice Boltzmann equation over unstructured grids, named unstructured Lattice Boltzmann equation (ULBE). It is a new scheme based on the idea of placing the unknown fields at the nodes of the mesh and evolving them based on the fluxes crossing the surfaces of the corresponding control volumes. The study shows a significant variation and a high sensitivity of wall shear stress to the height of the endothelium corrugation and the presence of erythrocytes. The latter were modelled as deformable, viscous particles within a fluid continuum. PMID- 21546307 TI - Antibiotic resistance gene spread due to manure application on agricultural fields. AB - The usage of antibiotics in animal husbandry has promoted the development and abundance of antibiotic resistance in farm environments. Manure has become a reservoir of resistant bacteria and antibiotic compounds, and its application to agricultural soils is assumed to significantly increase antibiotic resistance genes and selection of resistant bacterial populations in soil. The genome location of resistance genes is likely to shift towards mobile genetic elements such as broad-host-range plasmids, integrons, and transposable elements. Horizontal transfer of these elements to bacteria adapted to soil or other habitats supports their environmental transmission independent of the original host. The human exposure to soil-borne resistance has yet to be determined, but is likely to be severely underestimated. PMID- 21546306 TI - The Thaumarchaeota: an emerging view of their phylogeny and ecophysiology. AB - Thaumarchaeota range among the most abundant archaea on Earth. Initially classified as 'mesophilic Crenarchaeota', comparative genomics has recently revealed that they form a separate and deep-branching phylum within the Archaea. This novel phylum comprises in 16S rRNA gene trees not only all known archaeal ammonia oxidizers but also several clusters of environmental sequences representing microorganisms with unknown energy metabolism. Ecophysiological studies of ammonia-oxidizing Thaumarchaeota suggest adaptation to low ammonia concentrations and an autotrophic or possibly mixotrophic lifestyle. Extrapolating from the wide substrate range of copper-containing membrane-bound monooxygenases, to which the thaumarchaeal ammonia monooxygenases belong, the use of substrates other than ammonia for generating energy by some members of the Thaumarchaeota seems likely. PMID- 21546308 TI - Honeybees Apis mellifera can detect the scent of Mycobacterium tuberculosis. AB - The proboscis extension reflex in honeybees was evaluated for detection of tuberculosis. Restrained bees were tested with methyl phenylacetate, methyl p anisate, and methyl nicotinate, previously identified from Mycobacterium tuberculosis cultures, to determine honeybee capacity for signature volatile detection. Methyl p-anisate and methyl phenylacetate were detectable over eight orders of magnitude, and honeybees showed proboscis extension response down to 0.1 pg loading of methyl p-anisate on filter paper. Potential exists for trained honeybees in non-invasive diagnostic tests for TB. PMID- 21546310 TI - HIV counselling and testing on the move. PMID- 21546311 TI - Follow-up and treatment of an instable patient with heart failure using telemonitoring and a computerised disease management system: a case report. AB - In the last decades, the introduction of information and communication technology (ICT) in healthcare promised an improved quality of care while reducing workload and improving cost-effectiveness. This might be realised by the use of computer guided decision support systems and telemonitoring. This case study describes the process of care of a patient with chronic heart failure, who was treated with a computerised disease management system in combination with telemonitoring. With the help of these appliances, we think we were probably able to prevent at least two readmissions for heart failure in a period of 10 months. We also gained more insight into patient's behaviour with regards to compliance with the heart failure regimen at home. Frequent contact at distance and the online availability of physiological measurements at home facilitated patient tailored education and helped the patient to react adequately to symptoms of deterioration. Additionally, up-titration of heart failure medication was performed without contacting the patient at the outpatient clinic. PMID- 21546309 TI - Community-based intervention to increase HIV testing and case detection in people aged 16-32 years in Tanzania, Zimbabwe, and Thailand (NIMH Project Accept, HPTN 043): a randomised study. AB - BACKGROUND: In developing countries, most people infected with HIV do not know their infection status. We aimed to assess whether HIV testing could be increased by combination of community mobilisation, mobile community-based voluntary counselling and testing (VCT), and support after testing. METHODS: Project Accept is underway in ten communities in Tanzania, eight in Zimbabwe, and 14 in Thailand. Communities at each site were paired according to similar demographic and environmental characteristics, and one community from each pair was randomly assigned to receive standard clinic-based VCT (SVCT), and the other community was assigned to receive community-based VCT (CBVCT) plus access to SVCT. Randomisation and assignment of communities to intervention groups was done by the statistics centre by computer; no one was masked to treatment assignment because the interventions were community based. Intervention was provided for about 3 years (2006-09). The primary endpoint of HIV incidence is pending completion of assessments after the intervention. In this interim analysis, we examined the secondary endpoint of uptake in HIV testing, differences in characteristics of clients receiving their first HIV test, and repeat testing. Analyses were limited to clients aged 16-32 years. This study is registered with ClinicalTrials.gov, number NCT00203749. FINDINGS: The proportion of clients receiving their first HIV test during the study was higher in CBVCT communities than in SVCT communities in Tanzania (2341 [37%] of 6250 vs 579 [9%] of 6733), Zimbabwe (5437 [51%] of 10,700 vs 602 [5%] of 12,150), and Thailand (7802 [69%] of 11,290 vs 2319 [23%] 10,033). The mean difference in the proportion of clients receiving HIV testing between CBVCT and SVCT communities was 40.2% (95% CI 15.8 64.7; p=0.019) across three community pairs (one per country). HIV prevalence was higher in SVCT communities than in CBVCT communities, but CBVCT detected almost four times more HIV cases than did SVCT across the three study sites (952 vs 264; p=0.003). Repeat HIV testing in CBVCT communities increased in all sites to reach 28% of all those testing for HIV by the end of the intervention period. INTERPRETATION: CBVCT should be considered as a viable intervention to increase detection of HIV infection, especially in regions with restricted access to clinic-based VCT and support services after testing. FUNDING: US National Institute of Mental Health, HIV Prevention Trials Network (via US National Institute of Allergy and Infectious Diseases), and US National Institutes of Health. PMID- 21546312 TI - Implications of incidental finding of testicular microlithiasis in paediatric patients. AB - OBJECTIVE: To improve understanding of the implications of testicular microlithiasis (TM) in paediatric patients diagnosed incidentally on scrotal ultrasonography (US). PATIENTS AND METHODS: 31 boys aged 4-14 years diagnosed with TM based on US between February 2000 and September 2007 were retrospectively reviewed. Demographic data, indications for US, associated inguino-scrotal pathologies and follow-up data were collated. RESULTS: A total of 59 testes were evaluated. Fifty-four had TM at US. The most common indication for US was scrotal swelling (n = 17). Twenty patients (65%) had at least one associated inguino scrotal pathology related to patent processus vaginalis, with cryptorchidism being the most frequently observed (39%). On follow up (mean 39.6 months), 6 patients documented decrease or resolution of TM, while 2 showed increase in TM density. No testicular malignancy was observed during follow up. CONCLUSIONS: TM is commonly diagnosed incidentally on US in paediatric patients. A literature review revealed few case reports on its association with testicular malignancy and a prevalence of 4.2% among asymptomatic boys. The spontaneous resolution of TM supports degeneration of seminiferous tubules as the possible cause and further questions its malignant implication. An appropriate surveillance scheme would require involvement of a well-informed patient and parent with good compliance on testicular self-examination. PMID- 21546313 TI - B cells "transduced" with TAT-fusion proteins can induce tolerance and protect mice from diabetes and EAE. AB - Antigen-immunoglobulin fusion protein expressing B cells have been shown as excellent tolerogenic antigen-presenting cells in multiple disease models. Using efficient protein transduction by fusion with a HIV TAT protein transduction domain, we herein tested the TAT-fusion protein transduced B cells for their effects in antigen-specific tolerance induction in two animal models, experimental autoimmune encephalomyelitis (EAE) and type 1 diabetes. We demonstrated that transfer of TAT-MOG35-55 (myelin oligodendrocyte glycoprotein) Ig 'transduced B cells' 10 days after EAE induction significantly protected mice from disease. Similarly, the onset of disease was delayed when NOD mice received insulin specific TAT-B9-23-B cells. Surprisingly, no protection against EAE was observed in a prophylactic protocol when transduced B cells were given before disease induction. Moreover, TAT-ovalbumin transduced cells were tolerogenic in primed but not naive mice. Our results suggest that TAT-fusion protein transduced B cells were tolerogenic in antigen primed recipients, a condition clinically relevant to autoimmune diseases. PMID- 21546315 TI - Code blue: seizures. AB - Eyewitnesses frequently perceive seizures as life threatening. If an event occurs on the hospital premises, a "code blue" can be called which consumes considerable resources. The purpose of this study was to determine the frequency and characteristics of code blue calls for seizures and seizure mimickers. A retrospective review of a code blue log from 2001 through 2008 identified 50 seizure-like events, representing 5.3% of all codes. Twenty-eight (54%) occurred in inpatients; the other 22 (44%) events involved visitors or employees on the hospital premises. Eighty-six percent of the events were epileptic seizures. Seizure mimickers, particularly psychogenic nonepileptic seizures, were more common in the nonhospitalized group. Only five (17.9%) inpatients had a known diagnosis of epilepsy, compared with 17 (77.3%) of the nonhospitalized patients. This retrospective survey provides insights into how code blues are called on hospitalized versus nonhospitalized patients for seizure-like events. PMID- 21546314 TI - Carbohydrate-binding motif in chitinase 3-like 1 (CHI3L1/YKL-40) specifically activates Akt signaling pathway in colonic epithelial cells. AB - Host-microbial interactions play a key role during the development of colitis. We have previously shown that chinase 3-like 1 (CHI3L1) is an inducible molecule overexpressed in colonic epithelial cells (CECs) under inflammatory conditions. In this study, we found that chitin-binding motif (CBM) of CHI3L1 is specifically associated with the CHI3L1-mediated activation of the Akt-signaling in CEC by transfecting the CBM-mutant CHI3L1 vectors in SW480 CECs. Downstream, CHI3L1 enhanced the secretion of IL-8 and TNFalpha in a dose-dependent manner. We previously show that 325 through 339 amino-acids in CBM are crucial for the biological function of CHI3L1. Here we demonstrated that 325th-339th residues of CBM in CHI3L1 is a critical region for the activation of Akt, IL-8 production, and for a specific cellular localization of CHI3L1. In conclusion, CBM region of CHI3L1 is critical in activating Akt signaling in CECs, and the activation may be associated with the development of chronic colitis. PMID- 21546316 TI - Relationship of child IQ to parental IQ and education in children with fetal antiepileptic drug exposure. AB - Clinical trial designs need to control for genetic and environmental influences when examining cognitive outcomes in children for whom clinical considerations preclude randomization. However, the contributions of maternal and paternal IQ and education to pediatric cognitive outcomes are uncertain in disease populations. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom, which enrolled pregnant women with epilepsy to determine if differential long-term neurodevelopmental effects exist across four commonly used antiepileptic drugs. Here, we examined the relationship of IQ and education in both parents to child IQ at age 3 years. IQ and education for both parents were statistically correlated to child IQ. However, paternal IQ and education were not significant after accounting for maternal IQ effects. Because maternal IQ and education are independently related to child cognitive outcome, both should be assessed in studies investigating the effects of fetal drug exposures or other environmental factors that could affect the child's cognitive outcome. PMID- 21546317 TI - Video/EEG recording of myoclonic absences in GLUT1 deficiency syndrome with a hot spot R126C mutation in the SLC2A1 gene. AB - Glucose transporter type 1 deficiency syndrome (GLUT1DS) is an inborn error of brain energy metabolism characterized by impaired glucose transport into the brain. A classic phenotype comprising epilepsy, mental retardation, an often paroxysmal disorder, and several subtypes has been described. Although typical absences are frequent in GLUT1DS, myoclonic absence seizures are rarely reported. Here we describe a novel Turkish patient with a hot-spot mutation (R126C) in the SLC2A1 gene who presented with unusual myoclonic absence epilepsy and paroxysmal shivering. The case is discussed in view of eight other cases carrying the R126C mutation. PMID- 21546318 TI - Novel bariatric technology: laparoscopic adjustable gastric banded plication: technique and preliminary results. AB - BACKGROUND: The laparoscopic adjustable gastric band has been widely accepted as 1 of the safest bariatric procedures to treat morbid obesity. However, because of variations in the results and the complications that tend to arise from port adjustment, alternative procedures are needed. We have demonstrated, in a university hospital setting, the safety and feasibility of a novel technique, laparoscopic adjustable gastric banded plication, designed to improve the weight loss effect and decrease gastric band adjustment frequency. METHODS: We enrolled 26 patients from May 2009 to August 2010. Laparoscopic adjustable gastric banded plication was performed using 5-port surgery. We placed Swedish bands using the pars flaccida method, divided the greater omentum, and performed gastric plication below the band to 3 cm from the pylorus using a single-row continuous suture. The data were collected and analyzed pre- and postoperatively. RESULTS: The mean operative time was 87.3 minutes without any intraoperative complications. The average postoperative hospitalization was 1.33 days. The mean excess weight loss at 1, 3, 6, 9, and 12 months after surgery was 21.9%, 31.9%, 41.3%, 55.2%, and 59.5%, respectively. The mean follow-up time was 8.1 months (range 2-15), and the gastric band adjustment rate was 1.1 times per patient during this period. Two complications developed: gastrogastric intussusception and tube kinking at the subcutaneous layer. Both cases were corrected by reoperation. No mortality was observed. CONCLUSION: Laparoscopic adjustable gastric banded plication provides both restrictive and reductive effects and is reversible. The technique is safe, feasible, and reproducible and can be used as an alternative bariatric procedure. Comparative studies and long-term follow-up are necessary to confirm our findings. PMID- 21546319 TI - Serial changes in inflammatory biomarkers after Roux-en-Y gastric bypass surgery. AB - BACKGROUND: A number of proteins secreted from adipose tissue, known as adipokines, are involved in the inflammatory process. The expression and secretion of adipokines are altered with obesity, leading to a pro-inflammatory state, with an enhanced vascular immune response. Although weight loss reduces inflammation, the time course for these changes during massive weight loss after bariatric surgery is not well described. We examined the changes in the biomarkers of inflammation after laparoscopic Roux-en-Y gastric bypass (RYGB) in morbidly obese individuals in a university hospital. METHODS: The fasting levels of plasma inflammatory adipokines, including leptin, adiponectin, C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha (TNF-alpha), and soluble receptor 1 for TNF-alpha were measured before surgery (baseline) and 3 weeks, 3 months, and 6 months after surgery in 15 morbidly obese patients who underwent Roux-en-Y gastric bypass without a major complication. RESULTS: The mean weight loss at 6 months was 25.7% +/- 4.5% of the total body weight. The body mass index decreased from a mean of 55.1 +/- 6.6 kg/m(2) to 40.5 +/- 5.5 kg/m(2). The concentrations of leptin, CRP, and soluble receptor 1 for TNF-alpha decreased, and the adiponectin levels had increased from the baseline measures by 6 months postoperatively. The baseline and 6-month TNF-alpha and CRP levels correlated with each other. No other significant associations among the biomarkers were seen. CONCLUSION: RYGB reduced the pro-inflammatory biomarkers and increased the anti-inflammatory mediators of obesity, independent of the magnitude of weight loss. The lack of correlations between the changes in biomarkers and weight loss suggests that the driving force behind the changes in the inflammatory markers is multifactorial and needs further investigation to clarify the health changes that occur after RYGB. PMID- 21546320 TI - Intraoperative fetal monitoring an invaluable tool in pregnant patients with internal hernia after gastric bypass and review of literature. PMID- 21546321 TI - Laparoscopic sleeve gastrectomy and laparoscopic gastric bypass are equally effective for reduction of cardiovascular risk in severely obese patients at one year of follow-up. AB - BACKGROUND: Very few studies have compared laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) outcomes or analyzed improvement in cardiovascular risk (CVR) after bariatric surgery. None of the studies considered the Mediterranean population. Our primary objective was to compare the 10-year estimated CVR reduction achieved by LRYGB and LSG in Spanish subjects with severe obesity. The secondary objectives were to compare the techniques in terms of weight loss and co-morbidity improvement. The study was performed at a university hospital in Barcelona, Spain. METHODS: A 12-month prospective cohort study of 140 consecutive patients (95 LRYGB and 45 LSG) compared the 2 surgical intervention groups to study the percentage of excess weight loss, resolution and improvement/resolution of co-morbidities, and effect on CVR using both the Framingham risk score (FRS) and the Registre Gironi del Cor (REGICOR) model. RESULTS: At 12 months, the overall CVR decreased from 6.6% to 3.4% using the FRS and from 3.7% to 1.9% using the REGICOR score. Neither model found a difference between the 2 surgical intervention groups in decreased postoperative CVR risk, with a FRS of 3.4% +/- 2.2% for LRYGB versus 3.3% +/- 2.1% for LSG (P = .872) and a REGICOR score of 1.9% +/- 1.5% versus 1.8% +/- 1.6%, respectively (P = .813). No differences were observed in the percentage of excess weight loss or the resolution of type 2 diabetes mellitus and hypertension. The hypercholesterolemia improvement/resolution rate was lower in the LSG group than in the LRYGB group. CONCLUSION: Bariatric surgery reduces the estimated CVR by one half at 1 year after surgery. Except for the less-improved cholesterol metabolism, LSG, a restrictive technique, proved to be equally as effective at 1 year of follow-up as LRYGB. PMID- 21546322 TI - Alzheimer's disease management guideline: update 2008. AB - BACKGROUND: Frequent review and update of guidelines are necessary for them to remain current and useful for clinical practices. This second revision of the postdiagnostic management of Alzheimer's disease (AD) guideline by the California Workgroup was prompted by significant advances in knowledge about appropriate care management, including pharmacologic and nonpharmacologic approaches to treatment of the disease, accompanying behavioral problems, and functional decline. The focus remains explicitly on primary care, where the majority of it occurs for those with AD and other dementias. METHODS: In all, 40 experts in dementia care were recruited from a variety of disciplines across California. Four workgroups were created that reviewed recent research findings from a total of 569 publications since 2002. The revised Guideline incorporates 305 new references, including 11 state and federal laws, in addition to 78 references from the previous version. RESULTS: The Guideline is divided into four sections that address postdiagnostic management: (1) assessment, (2) treatment, (3) patient and family education and support, and (4) legal considerations associated with AD. Significant revisions and changes in each area and the underlying research to support the recommendations are presented in this article. New topics related to early stage and end-of-life were identified and recommendations were developed for these specific populations. CONCLUSIONS: The Guideline recommendations provide a framework to inform and improve medical care for AD by primary health care providers. PMID- 21546323 TI - A modified host-cell reactivation assay to quantify DNA repair capacity in cryopreserved peripheral lymphocytes. AB - The host-cell reactivation assay (HCRA) is a functional assay that allows the identification of the genes responsible for DNA repair-deficient syndromes, such as Xeroderma pigmentosum, by cross-complementation experiments. It has also been used in molecular epidemiology studies to correlate the low nucleotide excision repair pathway function in peripheral blood lymphocytes with an increased risk of bladder, head and neck, skin and lung cancers. Herein, we present the technical validation of a newly modified HCRA, where nucleofection is used for the transfection of the pmaxGFP plasmid into cryopreserved peripheral blood lymphocytes (PBLs) or lymphoblastoid cell lines. In each sample, 20-24h after transfection, the relative DNA repair capacity (DRC) was quantified by flow cytometry, comparing the transfection efficiency of nucleoporated cells with undamaged plasmid to those transfected with UV-light damaged plasmid in the seven cell lines that were characterized by different DNA repair phenotypes. Dead cells were excluded from the analysis. We observed a high reproducibility of the relative DRC, transfection efficiency and cell viability. The inter-experimental normalization of the flow cytometry resulted in an increased data accuracy and reproducibility. The amount of cells required for each transfection reaction was reduced fourfold, without affecting the final relative DRC. Furthermore, our HCRA demonstrated strong discrimination power in the UV-light dose-response, both in lymphoblastoid cell lines and cryopreserved PBLs. We also observed a strong correlation of the relative DRC data, when samples were measured against two independent batches of both damaged and undamaged plasmid DNA. The relative DRC variable shows a normal distribution when analyzed in the cryopreserved PBLs from a cohort of 35 lung cancer patients and a 5.59-fold variation in the relative DRC is identified among our patients. The mitotic dynamic was discarded as a confounding factor for the relative DRC measurement in this cohort of patients. The results indicate that our method is highly sensitive, reliable and reproducible, and thus, it suitable for population-based studies to quantify in vitro DNA-repair deficiencies. PMID- 21546325 TI - Engineering the substrate specificity of Alcaligenes D-aminoacylase useful for the production of D-amino acids by optical resolution. AB - D-Aminoacylase from Alcaligenes xylosoxydans subsp. xylosoxydans A-6 (AxD-NAase) offers a novel biotechnological application, the production of D-amino acid from the racemic mixture of N-acyl-DL-amino acids. However, its substrate specificity is biased toward certain N-acyl-D-amino acids. To construct mutant AxD-NAases with substrate specificities different from those of wild-type enzyme, the substrate recognition site of the AxD-NAase was rationally manipulated based on computational structural analysis and comparison of its primary structure with other D-aminoacylases with distinct substrate specificities. Mutations of amino acid residues, Phe191, Leu298, Tyr344, and Met346, which interact with the side chain of the substrate, induced marked changes in activities toward each substrate. For example, the catalytic efficiency (k(cat)/K(m)) of mutant F191W toward N-acetyl-D-Trp and N-acetyl-D-Ala was enhanced by 15.6- and 1.5-folds, respectively, compared with that of the wild-type enzyme, and the catalytic efficiency (k(cat)/K(m)) of mutant L298A toward N-acetyl-D-Trp was enhanced by 4.4-folds compared with that of the wild-type enzyme. Other enzymatic properties of both mutants, such as pH and temperature dependence, were the same as those of the wild-type enzyme. The F191W mutant in particular is considered to be useful for the enzymatic production of D-Trp which is an important building block of some therapeutic drugs. PMID- 21546326 TI - Climate change and vector-borne infections: Comment on "Modeling the impact of global warming on vector-borne infections" by Eduardo Massad, Francisco Antonio Bezerra Coutinho, Luiz Fernandes Lopez and Daniel Rodrigues da Silva. PMID- 21546327 TI - Exploring the myth of the valveless internal mammary vein--a cadaveric study. AB - Over the last thirty years the internal mammary system has become the recipient of choice when performing free tissue transfer breast reconstruction. The cranial ends of the internal mammary artery and vein are safely and reliably used for anastomosis following division. Using these cranial vessels maintains their normal antegrade direction of flow. As the complexity of reconstruction has increased, use of the caudal end of the internal mammary vein (IMV) has been cited as a convenient option for additional venous drainage. This requires blood flow in a retrograde fashion. The literature to date suggests that this is possible based on the principle that there are no valves in the internal mammary vein. This will be shown to be incorrect. In this study, the internal mammary veins of 32 formalin-preserved cadavers were dissected to specifically look for and to map valves. 21 valves were discovered in the internal mammary veins of 14 of the 32 cadavers (99 internal mammary veins and major branches). 20 of these were bicuspid in nature, one being tricuspid. Valves were found before or after the branching point of the IMVs, and at multiple sites within some individuals. The significance of valve position relative to rib-space and arborisation of parent IMVs is discussed. Whereas existing data support the use of retrograde IMVs to provide a source of additional venous drainage, we would urge caution in using them exclusively. A proportion of IMVs appear to have valves between the commonly used 2nd or 3rd rib-spaces, and the next draining side-branch. PMID- 21546328 TI - Circadian blood pressure variation in patients with type 2 diabetes--relationship to macro- and microvascular subclinical organ damage. AB - AIMS: To explore the association between nocturnal blood pressure (BP) dipper status and macro- and microvascular organ damage in type 2 diabetes. METHODS: Cross-sectional data from 663 patients with type 2 diabetes, aged 55-66 years, were analysed. Nurses measured office BP and ambulatory BP during 24h. Individuals with >= 10% difference in nocturnal systolic blood pressure (SBP) relative to daytime values were defined as dippers. Non-dippers were defined as <10% nocturnal decrease in SBP. Estimated glomerular filtration rate (GFR) was calculated and microalbuminuria was measured by albumin:creatinine ratio (ACR). Aortic pulse wave velocity (PWV) was measured with applanation tonometry over the carotid and femoral arteries. RESULTS: We identified 433 dippers and 230 subjects with a nocturnal non-dipping pattern. Nocturnal SBP dipping was independently of office SBP associated with decreased PWV (p = 0.008), lower ACR (p = 0.001) and NT-proBNP (p = 0.001) and increased GFR (p<0.001). CONCLUSIONS: We conclude that diurnal BP variation provides further information about early macro- and microvascular subclinical organ damage that goes beyond standardized office BP measurements in patients with type 2 diabetes. PMID- 21546329 TI - DNA transfer within forensic exhibit packaging: potential for DNA loss and relocation. AB - Crime scene samples after their collection are packaged and transported to the laboratory for examination and DNA analysis. The amount and location of DNA containing material retrieved from an exhibit can be critical in acquiring a profile for incrimination or exclusion purposes and for elucidating criminal events. This paper shows that significant quantities of DNA are frequently: (a) transferred from the exhibit to the inside of the packaging and (b) transferred from its area of initial deposit to other areas of the same exhibit and/or to other exhibits within the same package. There is a distinct possibility of failing to generate adequate profiles in instances where the DNA content may otherwise have been adequate, and for the misinterpretation of a result that could impact negatively on the criminal investigation and court outcome. These findings highlight the need for improvements in the collection and packaging of forensic casework exhibits for DNA analysis. PMID- 21546330 TI - Mesenchymal stromal cells up-regulate CD39 and increase adenosine production to suppress activated T-lymphocytes. AB - Mesenchymal stromal cells (MSCs) suppress T cell responses through mechanisms not completely understood. Adenosine is a strong immunosuppressant that acts mainly through its receptor A(2a) (ADORA2A). Extracellular adenosine levels are a net result of its production (mediated by CD39 and CD73), and of its conversion into inosine by Adenosine Deaminase (ADA). Here we investigated the involvement of ADO in the immunomodulation promoted by MSCs. Human T lymphocytes were activated and cultured with or without MSCs. Compared to lymphocytes cultured without MSCs, co cultured lymphocytes were suppressed and expressed higher levels of ADORA2A and lower levels of ADA. In co-cultures, the percentage of MSCs expressing CD39, and of T lymphocytes expressing CD73, increased significantly and adenosine levels were higher. Incubation of MSCs with media conditioned by activated T lymphocytes induced the production of adenosine to levels similar to those observed in co cultures, indicating that adenosine production was mainly derived from MSCs. Finally, blocking ADORA2A signaling raised lymphocyte proliferation significantly. Our results suggest that some of the immunomodulatory properties of MSCs may, in part, be mediated through the modulation of components related to adenosine signaling. These findings may open new avenues for the development of new treatments for GVHD and other inflammatory diseases. PMID- 21546331 TI - Limb lengthening using ankle joint distraction (arthrodiastasis) followed by arthrodesis. Experience with one case. AB - Tibial aplasias are difficult entities to manage and sometimes require significant limb lengthening. Preserving the joint is the preferred option in these cases. However, when function is not ensured, lengthening beginning in the joint can be attempted followed by arthrodesis. This report presents the clinical and radiological results of a patient treated with intra-articular lengthening (or arthrodiastasis) associated with talocrural arthrodesis. Although this original technique provided satisfactory results, this surgical program remains complicated. PMID- 21546332 TI - Percutaneous internal fixation combined with kyphoplasty for neurologically intact thoracolumbar fractures: a prospective cohort study of 24 patients with one year of follow-up. AB - INTRODUCTION AND HYPOTHESIS: Neurologically intact lumbar and thoracolumbar fractures are frequent but their treatment is not codified. The purpose of this study was to evaluate the effectiveness of minimally invasive treatment of such fractures by percutaneous fixation associated with balloon kyphoplasty. PATIENTS AND METHODS: Between November 2008 and July 2010, 24 patients were treated. There were 12 men and 12 women, with a mean age of 53 years (range 20-88 years). Fractures were classified as one Magerl lesion type A1, one type A2, 19 A3 (five A31, 10 A32, four A33), and three type B2. The treatment was kyphoplasty of the fractured vertebra followed by percutaneous fixation of the vertebra above and below the fracture. Patient follow-up included an analysis of pain using the visual analogic score, the Oswestry score, and functional X-ray and CT analysis. RESULTS: Surgery lasted a mean 99 minutes. At the last follow-up, the mean pain was scored at 0.9 and the Oswestry score was 13.2. Reduction of vertebral kyphosis was 8.6 degrees and reduction of the corrected regional angle was 7.1 degrees . The gain in vertebral height was 17%. All pedicle screws were positioned correctly and no neurological, septic, or thromboembolic complications were observed. DISCUSSION AND CONCLUSION: Percutaneous osteosynthesis combined with balloon kyphoplasty is a valuable surgical technique in the treatment of thoracolumbar and lumbar fractures with no neurologic deficit. The clinical results are good and the technique allows the patient to return home earlier without having to wear a corset. The X-ray result scores are very encouraging, with corrections similar to conventional surgery in terms of vertebral height and kyphosis. This technique can be an alternative to conventional open surgery. LEVEL OF EVIDENCE: IV: Prospective observational study. PMID- 21546333 TI - The arthritic wrist. II--the degenerative wrist: indications for different surgical treatments. AB - For the patient (and the surgeon) the ideal wrist is one that has good mobility, however very often the optimal surgical treatment is one that provides effective pain relief. The patient must be informed of the potential complications and limitations of each procedure. The patient's psychological profile and functional requirements will determine how well he/she adapts to the changes. Also, each surgeon has beliefs and personal experiences that influence the treatment decision and final result. Proximal row carpectomy (PRC) and the Watson procedure are two reference operations for osteoarthritis secondary to scapholunate instability and scaphoid non-union (SLAC and SNAC). Beyond the early complications and drawbacks specific to each, they provide good results that are maintained over time. PRC, which can be performed up to Stage II, is mainly indicated in patients with moderate functional demands, while the Watson procedure is more often done on a patient who performs manual labour, as long as the radiolunate joint space is maintained. Complete denervation is effective in three out of four cases and preserves the remaining mobility. Because of its low morbidity, the procedure can be suggested in patients with a mobile wrist and low functional demands or in older patients, independent of their wrist mobility. Total wrist fusion is not only a rescue procedure. For a young patient who performs heavy manual labour with extensive osteoarthritis and progressive forms of Kienbock's disease, this procedure provides the greatest chance of returning to work and not being socially outcast. The role of osteochondral autografts, implants and wrist prostheses in the treatment arsenal need to be better defined. PMID- 21546334 TI - Management of osteoporosis in liver disease. AB - Osteoporosis resulting in a high risk for fracture is a common complication in patients with liver disease, particularly in those with chronic cholestasis and with end-stage cirrhosis. The pathogenesis of bone loss in liver patients is poorly understood but it mainly results from low bone formation as a consequence of cholestasis or the harmful effects of alcohol or iron on osteoblasts. Increased bone resorption has also been described in cholestatic women with advanced disease. The management of bone disease in liver patients is addressed to reduce or avoid the risk factors for osteoporosis and fracture. Bisphosphonates associated with supplements of calcium and vitamin D are safe and effective for increasing bone mass in patients with chronic cholestasis and after liver transplantation, though no clear achievements in descreasing the incidence of fractures have been described, probably because of the low number of patients included in the therapeutic trials. Randomized studies assessing bisphosphonates in larger series of patients, the development of new drugs for osteoporosis and the improvement in the management of liver transplant recipients may change the future. PMID- 21546335 TI - Residents' corner March 2011. PMID- 21546336 TI - Mal de Meleda with hyperpigmented spots. PMID- 21546337 TI - Globalisation and allergy. AB - Globalisation brings patients more and more into contact with products or food from other cultures or countries. Europeans may be confronted with allergens not yet known in Europe - such as dimethylfumarate - responsible for contact allergy epidemics. Moreover, "low cost" goods, not always legally imported into Europe, sometimes may lead to European legislation being circumvented and thus bring our patients into contact with components that have been banned from manufacturing processes or strongly regulated, such as nickel in jewelry or telephones, some colouring agents in clothes or preservatives in cosmetics. Disinfection measures for freight containers arriving from other continents into our harbours lead to fumigants and other toxic products contaminating the air and the transported products or goods. Globalisation can not only elicit contact allergy but also airborne contact dermatitis or food allergy. The aim of this paper is not to make an exhaustive review of cutaneous allergic problems elicited by globalisation, but to illustrate this new worldwide problem with a few meaningful examples. PMID- 21546338 TI - Occupational diseases due to cooling fluids. AB - Contact dermatitis to cutting fluids is a very frequent cause of occupational skin disease, with different mechanisms for those caused by irritation or allergies. The different allergens in question are many and complex. Different batteries of patch tests are available but the interpretation of the relevance of positive tests is not simple. The aim of this work is to make clearer the investigative methods and the interpretation of the relevance of the results of patch tests, for more effective prevention. PMID- 21546339 TI - [Thromboembolism and antithrombotic management in pregnancy]. AB - Venous thromboembolism occurs approximately in 1 of 1000 pregnancies. It is one of the leading causes of maternal mortality. Physiologic changes associated with pregnancy and delivery favor for developing venous thromboembolism, and there are individual risk factors, too, contributing to its manifestation. The most frequent risk factors of venous thromboembolism developing during pregnancy are the previous venous thromboembolism and the thrombophilias, furthermore, some other diseases and some unique complications of pregnancy and delivery. Beyond mechanical prevention only heparin preparations can be used for preventing and treating venous thromboembolism in pregnancy and among them the low-molecular weight heparins are preferred for applying. Dosage of low-molecular-weight heparin preparations is determined by the type and strength of thrombophilia. For treatment of venous thromboembolism presented during pregnancy subcutaneous 100 IU/kg low-molecular-weight heparin is generally used at every 12 hours. Postpartum the oral anticoagulants can be safely applied, too. PMID- 21546340 TI - [Becoming more "goal-oriented" in therapy of dyslipidemias: results of the Hungarian MULTI GAP 2010]. AB - Previous studies have found that many high-risk patients are not achieving their LDL-cholesterol goals, and many patients, despite being treated with lipid lowering therapy, also have elevated triglycerides and/or low levels of HDL cholesterol. AIMS: Authors analyzed the treatment strategies for dyslipidemic subjects following cardiovascular events similarly to their former survey from 2008 and 2009. METHODS: In the MULTI GAP (MULTI Goal Attainment Problem) 2010 trial data from standard and structured questionnaires of 2332 patients were processed. Authors analyzed the proportion of the patients reaching target levels for total cholesterol, LDL-C, HDL-C, A-C (atherogen cholesterol) and triglyceride. RESULTS: 15% (n = 355) of the patients did not receive any lipid lowering treatment. 44% of the patients treated by specialists reached the target LDL-C level of 2.5 mmol/l. In "high risk" group target levels for HDL-C were reached by 61% of the patients, and for triglyceride by 43% of the subjects. 43% of the patients with the best compliance (>90%) reached the target LDL-C level of 2.5 mmol/l. CONCLUSION: There is a need for more effective lipid lowering therapy with more frequent use of higher doses of statins or combinations of lipid lowering drugs. PMID- 21546341 TI - [Attitude of medical students to smoking and to the regulatory measures related to smoking]. AB - In some countries strict tobacco control measures successfully reduced the number of smokers. Although these measures do not have immediate effects, they may serve as investments in the future healthcare. Health care experts should take part actively in the decision making. AIMS: To investigate medical students' relation to smoking and their attitudes about tobacco control measures. METHODS: Authors applied the Hungarian translation of the Global Health Professionals Student Survey. Medical students from the first and fifth year answered its questions anonymously. Statistical analysis was performed with SPSS. RESULTS: Altogether 245 students completed the questionnaire. It was found that the knowledge of students about health damages caused by tobacco smoking was very good. However, a large number of students are exposed to tobacco smoke (68% of them at home and 85% at public places). Their opinion about tobacco control measures reflects recent law, as only 43% of the students would support a smoking ban in bars and discotheques. CONCLUSIONS: Hungarian health care experts have to take part with more effort in the prevention of tobacco smoking. Medical students have to be trained in this field. PMID- 21546342 TI - [Primary pulmonary epitheloid haemangioendothelioma]. AB - A 49-year-old female patient was admitted in July 2009 because of cough, weight loss and effort dyspnoe. Chest X-ray and CT showed multiple bilateral nodules which have been identified earlier and these nodules were unchanged. However, there was a new parenchymal lesion in the right upper lobe, and new right hilar and mediastinal lymphadenomegaly was also found. Sample was taken by bronchoscope and the pathological diagnosis was pulmonary epitheloid haemangioendothelioma. This rare endothelial tumor usually affects middle-aged patients with a female predominance and it presents with chest pain, effort dyspnoe, cough, sputum, or it may remain asymptomatic. Multiple bilateral nodules are usually detected by radiologic examination. The diagnosis of this tumor is often challenging and, because of its rarity, it does not have any standard therapeutic regimen. Treatment can be surgery, chemo-, radio-, hormone- or immunotherapy. In order to find the most effective anticancer treatment, authors performed in vitro studies. On the basis of the results, chemotherapy was initiated which resulted in a partial regression. PMID- 21546343 TI - [Remembering Prof. Nyikolaj Ivanovics Pirogov (1810-1881)]. PMID- 21546344 TI - ["The Regoly Foundation is a very well thought-out support system." Interview with Prof. Dr. Istvan Karadi by Krisztina Regoly-Merei]. PMID- 21546347 TI - Assessment of fetal brain uptake of paraquat in utero using in vivo PET/CT imaging. AB - Prenatal in utero conditions are thought to play a role in the development of adult diseases including Parkinson's disease (PD). Paraquat is a common herbicide with chemical structure similar to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine, a neurotoxin known to induce parkinsonism. In order to assess the role of in utero paraquat exposure in PD, uptake in maternal and fetal brains were measured using positron emission tomography (PET)/computed tomography (CT) imaging. Two anesthetized pregnant rhesus macaques in the late second trimester of pregnancy were given bolus iv injections of 11C-paraquat, and whole-body PET/CT imaging was performed. Using maternal ventricular blood pool as the input function, the unidirectional influx rate constants (K(i)s), a measure of the irreversible transport of paraquat from plasma to brain, were calculated for the maternal and fetal brains using Patlak graphical analysis. Results indicate minimal uptake of paraquat by both maternal and fetal brains with average K(i)s of 0.0009 and 0.0016 per minute, respectively. The highest regional cerebral uptake in the maternal brain (0.0009% injected dose) was seen in the pineal gland, a structure known to lack a blood brain barrier. The finding of minimal paraquat uptake in maternal and fetal brains is similar to previous findings in adult male macaques and extends the contention that a single acute paraquat exposure, prenatally or postnatally, is unlikely to play a role in PD. PMID- 21546348 TI - Accumulation and debromination of decabromodiphenyl ether (BDE-209) in juvenile fathead minnows (Pimephales promelas) induces thyroid disruption and liver alterations. AB - Polybrominated diphenyl ether (PBDE) flame retardants are known to affect thyroid hormone (TH) regulation. The TH-regulating deiodinases have been implicated in these impacts; however, PBDE effects on the fish thyroid system are largely unknown. Moreover, the liver as a potential target of PBDE toxicity has not been explored in young fish. This study measured decabromodiphenyl ether (BDE-209) effects on TH regulation by measuring deiodinase activity in juvenile fathead minnows (Pimephales promelas). Dietary accumulations and debromination of BDE-209 were also measured, and the morphology of thyroid and liver tissues was examined. Juvenile fathead minnows (28 days old) received a 28-day dietary treatment of BDE 209 at 9.8 +/- 0.16 MUg/g of food at 5% of their body weight per day followed by a 14-day depuration period in which they were fed clean food. Chemical analysis revealed that BDE-209 accumulated in tissues and was metabolized to reductive products ranging from penta- to octaBDEs with 2,2',4,4',5,6'-hexabromodiphenyl ether (BDE-154) being the most accumulative metabolite. By day 28 of the exposure, rates of outer and inner ring deiodination (ORD and IRD, respectively) of thyroxine (T4) were each reduced by ~74% among treatments. Effects on T4-ORD and T4-IRD remained significant even after the 14-day depuration period. Histological examination of treated fish showed significantly increased thyroid follicular epithelial cell heights and vacuolated hepatocyte nuclei. Enlarged biliary passageways may be the cause of the distinctive liver phenotype observed, although further testing is needed. Altogether, these results suggest that juvenile fish may be uniquely susceptible to thyroid disruptors like PBDEs. PMID- 21546349 TI - Hepatic cytochrome P450s attenuate the cytotoxicity induced by leflunomide and its active metabolite A77 1726 in primary cultured rat hepatocytes. AB - The Black Box Warning section of the U.S. drug label for leflunomide was recently updated to include stronger warnings about potential hepatotoxicity from this novel anti-arthritis drug. Because metabolic activation is a key mechanism for drug-induced hepatotoxicity, we examined whether leflunomide and its major metabolite, A77 1726, are cytotoxic to primary rat hepatocytes and whether their toxicity is modulated by hepatic cytochrome P450s (CYPs). As measured by lactate dehydrogenase leakage, time-dependent cytotoxicity was observed at 250-500 MUM for leflunomide and 330-500 MUM for A77 1726 within 20 h. Unexpectedly, three nonisoenzyme-specific CYP inhibitors, including SKF-525A, metyrapone, and 1 aminobenzotriazole, did not reduce but remarkably enhanced the cytotoxicity of leflunomide or A77 1726. SKF-525A pretreatment notably rendered hepatocytes susceptible to as low as 15 MUM leflunomide or A77 1726. Three isoenzyme-specific CYP inhibitors including alpha-naphthoflavone, ticlopidine, and ketoconazole that mainly target CYP1A, CYP2B/2C, and CYP3A, respectively, also enhanced the cytotoxicity. A strong synergistic effect, similar to SKF-525A alone, was noted using a combination of all three of the isoenzyme-specific inhibitors. Hepatocytes pretreated with the CYP inducer dexamethasone for 24 h exhibited decreased cytotoxicity to leflunomide and A77 1726. At the concentrations tested, the CYP inhibitors and inducer showed no cytotoxicity. These data demonstrate that the parent forms of leflunomide and A77 1726 are more toxic to hepatocytes than their poorly characterized metabolites, indicating that the metabolic process of leflunomide is a detoxification step rather than an initiating event leading to toxicity. PMID- 21546350 TI - The updated guidelines on the use of rituximab in rheumatoid arthritis. PMID- 21546351 TI - BSR and BHPR guidelines on the use of rituximab in rheumatoid arthritis. PMID- 21546352 TI - Severe systemic sclerosis developing in a patient of membranous nephropathy. PMID- 21546353 TI - MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. AB - Comparative analysis of molecular sequence data is essential for reconstructing the evolutionary histories of species and inferring the nature and extent of selective forces shaping the evolution of genes and species. Here, we announce the release of Molecular Evolutionary Genetics Analysis version 5 (MEGA5), which is a user-friendly software for mining online databases, building sequence alignments and phylogenetic trees, and using methods of evolutionary bioinformatics in basic biology, biomedicine, and evolution. The newest addition in MEGA5 is a collection of maximum likelihood (ML) analyses for inferring evolutionary trees, selecting best-fit substitution models (nucleotide or amino acid), inferring ancestral states and sequences (along with probabilities), and estimating evolutionary rates site-by-site. In computer simulation analyses, ML tree inference algorithms in MEGA5 compared favorably with other software packages in terms of computational efficiency and the accuracy of the estimates of phylogenetic trees, substitution parameters, and rate variation among sites. The MEGA user interface has now been enhanced to be activity driven to make it easier for the use of both beginners and experienced scientists. This version of MEGA is intended for the Windows platform, and it has been configured for effective use on Mac OS X and Linux desktops. It is available free of charge from http://www.megasoftware.net. PMID- 21546354 TI - Revisiting the yeast PPR proteins--application of an Iterative Hidden Markov Model algorithm reveals new members of the rapidly evolving family. AB - Pentatricopeptide repeat (PPR) proteins are the largest known RNA-binding protein family, and are found in all eukaryotes, being particularly abundant in higher plants. PPR proteins localize mostly to mitochondria and chloroplasts, and many were shown to modulate organellar genome expression on the posttranscriptional level. Although the genomes of land plants encode hundreds of PPR proteins, only a few have been identified in Fungi and Metazoa. As the current PPR motif profiles are built mainly on the basis of the predominant plant sequences, they are unlikely to be optimal for detecting fungal and animal members of the family, and many putative PPR proteins in these genomes may remain undetected. In order to verify this hypothesis, we designed a hidden Markov model-based bioinformatic tool called Supervised Clustering-based Iterative Phylogenetic Hidden Markov Model algorithm for the Evaluation of tandem Repeat motif families (SCIPHER) using sequence data from orthologous clusters from available yeast genomes. This approach allowed us to assign 12 new proteins in Saccharomyces cerevisiae to the PPR family. Similarly, in other yeast species, we obtained a 5-fold increase in the detection of PPR motifs, compared with the previous tools. All the newly identified S. cerevisiae PPR proteins localize in the mitochondrion and are a part of the RNA processing interaction network. Furthermore, the yeast PPR proteins seem to undergo an accelerated divergent evolution. Analysis of single and double amino acid substitutions in the Dmr1 protein of S. cerevisiae suggests that cooperative interactions between motifs and pseudoreversion could be the force driving this rapid evolution. PMID- 21546355 TI - Extensive and evolutionarily persistent mitochondrial tRNA editing in Velvet Worms (phylum Onychophora). AB - Mitochondrial genomes of onychophorans (velvet worms) present an interesting problem: Some previous studies reported them lacking several transfer RNA (tRNA) genes, whereas others found that all their tRNA genes were present but severely reduced. To resolve this discrepancy, we determined complete mitochondrial DNA (mtDNA) sequences of the onychophorans Oroperipatus sp. and Peripatoides sympatrica as well as cDNA sequences from 14 and 10 of their tRNAs, respectively. We show that tRNA genes in these genomes are indeed highly reduced and encode truncated molecules, which are restored to more conventional structures by extensive tRNA editing. During this editing process, up to 34 nucleotides are added to the tRNA sequences encoded in Oroperipatus sp. mtDNA, rebuilding the aminoacyl acceptor stem, the TPsiC arm, and in some extreme cases, the variable arm and even a part of the anticodon stem. The editing is less extreme in P. sympatrica in which at least a part of the TPsiC arm is always encoded in mtDNA. When the entire TPsiC arm is added de novo in Oroperipatus sp., the sequence of this arm is either identical or similar among different tRNA species, yet the sequences show substantial variation for each tRNA. These observations suggest that the arm is rebuilt, at least in part, by a template-independent mechanism and argue against the alternative possibility that tRNA genes or their parts are imported from the nucleus. By contrast, the 3' end of the aminoacyl acceptor stem is likely restored by a template-dependent mechanism. The extreme tRNA editing reported here has been preserved for >140 My as it was found in both extant families of onychophorans. Furthermore, a similar type of tRNA editing may be present in several other groups of arthropods, which show a high degree of tRNA gene reduction in their mtDNA. PMID- 21546356 TI - Monitoring the rate and dynamics of concerted evolution in the ribosomal DNA repeats of Saccharomyces cerevisiae using experimental evolution. AB - Concerted evolution describes the unusual evolutionary pattern exhibited by certain repetitive sequences, whereby all the repeats are maintained in the genome with very similar sequences but differ between related species. The pattern of concerted evolution is thought to result from continual turnover of repeats by recombination, a process known as homogenization. Approaches to studying concerted evolution have largely been observational because of difficulties investigating repeat evolution in an experimental setting with large arrays of identical repeats. Here, we establish an experimental evolution approach to look at the rate and dynamics of concerted evolution in the ribosomal DNA (rDNA) repeats. A small targeted mutation was made in the spacer of a single rDNA unit in Saccharomyces cerevisiae so we could monitor the fate of this unit without the need for a selectable marker. The rate of loss of this single unit was determined, and the frequency of duplication was also estimated. The results show that duplication and deletion events occur at similar rates and are very common: An rDNA unit may be gained or lost as frequently as once every cell division. Investigation of the spatial dynamics of rDNA turnover showed that when the tagged repeat unit was duplicated, the copy predominantly, but not exclusively, ended up near to the tagged repeat. This suggests that variants in the rDNA spread in a semiclustered fashion. Surprisingly, large deletions that remove a significant fraction of total rDNA repeats were frequently found. We propose these large deletions are a driving force of concerted evolution, acting to increase homogenization efficiency over-and-above that afforded by turnover of individual rDNA units. Thus, the results presented here enhance our understanding of concerted evolution by offering insights into both the spatial and temporal dynamics of the homogenization process and suggest an important new aspect in our understanding of concerted evolution. PMID- 21546357 TI - Deficiency of X-linked inverted duplicates with male-biased expression and the underlying evolutionary mechanisms in the Drosophila genome. AB - Inverted duplicates (IDs) are pervasive in genomes and have been reported to play functional roles in various biological processes. However, the general underlying evolutionary forces that maintain IDs in genomes remain largely elusive. Through a systematic screening of the Drosophila melanogaster genome, 20,223 IDs were detected in nonrepetitive intergenic regions, far more than expectation under the neutrality model. 3,846 of these IDs were identified to have stable hairpin structure (i.e., the structural IDs). Based on whole-genome transcriptome profiling data, we found 628 unannotated expressed structural IDs, which had significantly different genomic distributions and structural properties from the unexpressed IDs. Among the expressed structural IDs, 130 exhibited higher expression in males than in females (i.e., male-biased expression). Compared with sex-unbiased ones, these male-biased IDs were significantly underrepresented on the X chromosome, similar to previously reported pattern of male-biased protein coding genes. These analyses suggest that a selection-driven process, rather than a purely neutral mutation-driven mechanism, contributes to the maintenance of IDs in the Drosophila genome. PMID- 21546358 TI - Natural selection on gene order in the genome reorganization process after whole genome duplication of yeast. AB - A genome must locate its coding genes on the chromosomes in a meaningful manner with the help of natural selection, but the mechanism of gene order evolution is poorly understood. To explore the role of selection in shaping the current order of coding genes and their cis-regulatory elements, a comparative genomic approach was applied to the baker's yeast Saccharomyces cerevisiae and its close relatives. S. cerevisiae have experienced a whole-genome duplication followed by an extensive reorganization process of gene order, during which a number of new adjacent gene pairs appeared. We found that the proportion of new adjacent gene pairs in divergent orientation is significantly reduced, suggesting that such new divergent gene pairs may be disfavored most likely because their coregulation may be deleterious. It is also found that such new divergent gene pairs have particularly long intergenic regions. These observations suggest that selection specifically worked against deletions in intergenic regions of new divergent gene pairs, perhaps because they should be physically kept away so that they are not coregulated. It is indicated that gene regulation would be one of the major factors to determine the order of coding genes. PMID- 21546359 TI - TparvaDB: a database to support Theileria parva vaccine development. AB - We describe the development of TparvaDB, a comprehensive resource to facilitate research towards development of an East Coast fever vaccine, by providing an integrated user-friendly database of all genome and related data currently available for Theileria parva. TparvaDB is based on the Generic Model Organism Database (GMOD) platform. It contains a complete reference genome sequence, Expressed Sequence Tags (ESTs), Massively Parallel Signature Sequencing (MPSS) expression tag data and related information from both public and private repositories. The Artemis annotation workbench provides online annotation functionality. TparvaDB represents a resource that will underpin and promote ongoing East Coast fever vaccine development and biological research. Database URL: http://tparvadb.ilri.cgiar.org. PMID- 21546360 TI - A screening system for artificial small RNAs that inhibit the growth of Escherichia coli. AB - We have developed a screening system for artificial small RNAs (sRNAs) that inhibit the growth of Escherichia coli. In this system, we used a plasmid library to express artificial sRNAs (approximately 200 bases long) containing 60 bases of random nucleotide sequence. The induced expression of the known rydB sRNA in the system reduced the amount of its possible target mRNA, rpoS, supporting the reliability of the method. To isolate clones of sRNAs that inhibited the growth of E. coli, we used two successive screening steps: (i) colony size selection on plates and (ii) monitoring E. coli growth in a 96-well plate format. As a result, 83 artificial sRNAs were identified that showed a range of inhibitory effects on bacterial growth. We also introduced nucleotide replacements into one of the highly inhibitory sRNA clones, H12, which partially abolished the inhibition of bacterial growth, suggesting that bacterial growth was inhibited in a sequence specific manner. PMID- 21546361 TI - Characterization of beta-lactoglobulin from buffalo (Bubalus bubalis) colostrum and its possible interaction with erythrocyte lipocalin-interacting membrane receptor. AB - Lipocalins form a widespread class of proteins involved in the transport of weakly soluble vitamins, hormones or hydrophobic molecules. beta-lactoglobulin (BLG-col), a major lipocalin present in whey was purified and characterized from buffalo colostrum. The molecular weight of BLG-col as determined by Liquid chromatography -electrospray ionization mass spectrometry (LC-ESI-MS) was 18.257 kDa and the peptide mass fingerprint of the purified protein revealed 67% sequence homology to buffalo milk beta-lg. The N-terminal-IIVTQ and LC-ESI collision-induced dissociation-Electron transfer dissociation mass spectrometry/mass spectrometry analyses of doubly (m/z 1156(+2)) and triply (m/z 546(+3)) charged ion pairs corresponding to VYVEELKPTPEGDLEILLQK (41-60) and TPEVDDEALEKFDK (125-138) sequences confirmed the identity of BLG-col. Using these peptide sequences, the location of a gene encoding for BLG-col was identified on chromosome 11 at 11q28 loci of bovine genome. The unique property of the BLG-col isolated from buffalo colostrum was its strong and specific haemagglutinating activity with 'O' blood of human erythrocytes with 10,309 HAU/mg protein. The cell surface localization of BLG-col on human erythrocytes was confirmed by immunocytochemistry and the specificity of interaction was established by immunoblot analysis of human erythrocyte membrane proteins. Based on these observations, we suggest the presence of lipocalin receptor (70 kDa) on human erythrocyte membrane and the multiple sequence alignment supported structural diversity among lipocalin receptors. PMID- 21546363 TI - Prioritization of diet and cancer manuscripts: a brief primer. PMID- 21546364 TI - What are the consequences if i postpone treatment of my PSA-detected prostate cancer? PMID- 21546365 TI - What if I don't treat my PSA-detected prostate cancer? Answers from three natural history models. AB - BACKGROUND: Making an informed decision about treating a prostate cancer detected after a routine prostate-specific antigen (PSA) test requires knowledge about disease natural history, such as the chances that it would have been clinically diagnosed in the absence of screening and that it would metastasize or lead to death in the absence of treatment. METHODS: We use three independently developed models of prostate cancer natural history to project risks of clinical progression events and disease-specific deaths for PSA-detected cases assuming they receive no primary treatment. RESULTS: The three models project that 20%-33% of men have preclinical onset; of these 38%-50% would be clinically diagnosed and 12%-25% would die of the disease in the absence of screening and primary treatment. The risk that men age less than 60 at PSA detection with Gleason score 2-7 would be clinically diagnosed in the absence of screening is 67%-93% and would die of the disease in the absence of primary treatment is 23%-34%. For Gleason score 8 to 10 these risks are 90%-96% and 63%-83%. CONCLUSIONS: Risks of disease progression among untreated PSA-detected cases can be nontrivial, particularly for younger men and men with high Gleason scores. Model projections can be useful for informing decisions about treatment. IMPACT: This is the first study to project population-based natural history summaries in the absence of screening or primary treatment and risks of clinical progression events following PSA detection in the absence of primary treatment. PMID- 21546367 TI - Racial disparities in breast cancer mortality--letter. PMID- 21546366 TI - Racial and ethnic disparities in colorectal cancer screening persisted despite expansion of Medicare's screening reimbursement. AB - OBJECTIVE: We examined the effect of Medicare's expansion of colorectal cancer (CRC) screening test reimbursement on racial/ethnic disparities in CRC screening. METHODS: CRC screening was ascertained for Medicare beneficiaries (n = 30,893), aged 70 to 89, who had no history of any tumor and resided in 16 Surveillance, Epidemiology and End Results regions of the United States from 1996 to 2005. CRC screening tests were identified in the 5% sample of Medicare claims. Age-gender adjusted percentages and -adjusted odds of receiving any guideline-specific CRC screening [i.e., annual fecal occult blood test (FOBT), sigmoidoscopy every 5 years or colonoscopy every 10 years] by race/ethnicity and Medicare coverage expansion period (i.e., prior to FOBT coverage, FOBT coverage only, and post colonoscopy coverage) were reported. RESULTS: CRC screening increased as Medicare coverage expanded for white and black Medicare beneficiaries. However, blacks were less likely than whites to receive screening prior to FOBT coverage (OR = 0.74, 95% CI: 0.61-0.90), during FOBT coverage only (OR = 0.66, 95% CI: 0.52 0.83) and after colonoscopy coverage (OR = 0.80, 95% CI: 0.68-0.95). Hispanics were less likely to receive screening after colonoscopy coverage (OR = 0.73, 95% CI: 0.54-0.99). CONCLUSIONS: Despite the expansion of Medicare coverage for CRC screening tests, racial/ethnic differences in CRC screening persisted over time in this universally insured population, especially for blacks and Hispanics. Future studies should explore other factors beyond health insurance that may contribute to screening disparities in this and younger populations. IMPACT: Although CRC screening rates increased over time, they were still low according to recommendations. More effort is needed to increase CRC screening among all Medicare beneficiaries. PMID- 21546369 TI - Cold stress effects on PSI photochemistry in Zea mays: differential increase of FQR-dependent cyclic electron flow and functional implications. AB - Cold-induced inhibition of CO(2) assimilation in maize (Zea mays L.) is associated with a persistent depression of the photochemical efficiency of PSII. However, very limited information is available on PSI photochemistry and PSI dependent electron flow in cold-stressed maize. The extent of the absorbance change (DeltaA(820)) used for in vivo quantitative estimation of photooxidizable P700(+) indicated a 32% lower steady-state oxidation level of the PSI reaction center P700 (P700(+)) in cold-stressed compared with control maize leaves. This was accompanied by a 2-fold faster re-reduction rate of P700(+) in the dark, indicating a higher capacity for cyclic electron flow (CEF) around PSI in cold stressed maize leaves. Furthermore, the increased PSI-dependent CEF(s) was associated with a much higher stromal electron pool size and 56% lower capacity for state transitions compared with control plants. To examine NADP(H) dehydrogenase (NDH)- and ferredoxin:plastoquinone oxidoreductase (FQR)-dependent CEF in vivo, the post-illumination transient increase of F(o)' was measured in the presence of electron transport inhibitors. The results indicate that under optimal growth conditions the relatively low CEF in the maize mesophyll cells is mostly due to the NDH-dependent pathway. However, the increased CEF in cold stressed plants appears to originate from the up-regulated FQR pathway. The physiological role of PSI down-regulation, the increased capacity for CEF and the shift of preferred CEF mode in modulating the photosynthetic electron fluxes and distribution of excitation light energy in maize plants under cold stress conditions are discussed. PMID- 21546371 TI - Extended replacement of a calcified ascending aorta in adulthood sporadic, diffuse type, supravalvular aortic stenosis. AB - The diffuse variant of supravalvular aortic stenosis (SVAS) is one of the most rare congenital vascular pathological conditions of adulthood. Due to its rarity, surgical treatment of this clinical entity is still a matter of debate because of the variable degree of aortic narrowing, presence of multilevel obstruction, and age at presentation, all factors that strongly influence the disease prognosis. We report a case of an adult patient with an extremely calcified diffuse SVAS who underwent successful replacement of the ascending aorta through the interposition of a tubular prosthesis. Six months' follow-up showed complete relief of the aortic gradient and an improvement in clinical performance. PMID- 21546372 TI - Retrieval of scrap metal from an abdominal aortic aneurysm during the follow-up. AB - A 75-year-old patient underwent open repair of a rapidly expanded aneurysm after previous multiple endovascular repair (EVAR) attempts by others. Open surgical reconstruction allowed the explants of all metallic components of implanted stent grafts. This is still an uncommon phenomenon due to the still low late reintervention rate. PMID- 21546373 TI - Closure of a bronchopleural fistula using glue. AB - Bronchopleural fistula after pneumonectomy remains a challenge after lung cancer surgery. It is associated with high mortality, morbidity and prolonged hospital stay necessitating further thoracotomy. We describe a technique using intra mucosal injection of glue to close a bronchopleural fistula via bronchoscopy. PMID- 21546374 TI - Three-dimensional imaging of anomalous origin of the right coronary artery in a young athlete. PMID- 21546375 TI - Prediction of the annuloplasty ring size in patients undergoing mitral valve repair using real-time three-dimensional transoesophageal echocardiography. AB - AIMS: We sought to investigate the additional value of real-time three dimensional transoesophageal echocardiography (RT 3D TOE)-guided sizing for predicting annuloplasty ring size during mitral valve repair. METHODS AND RESULTS: In 53 patients undergoing elective mitral valve repair, an RT 3D TOE was performed pre- and post-operatively. The digitally stored loops were imported into a software for mitral valve assessment. The annuloplasty ring size was predicted by superimposing computer-aided design (CAD) models of annuloplasty rings onto Live 3D zoom loops, measurement of the intercommissural distance, or the height of the anterior mitral leaflet. The surgeon implanted the annuloplasty ring according to the usual surgical technique and was blinded to the echocardiographic measurement results. Pre-operative correlation between the selected ring size with mitral valve assessment and the actual implanted annuloplasty ring size was 0.91. The correlation for measurement of the intercommissural distance was 0.55 and for measurement of the height of the anterior mitral leaflet 0.75. The post-operative correlation with the actual implanted ring size was 0.96 for mitral valve assessment, 0.92 for intercommissural distance, and 0.79 for the anterior mitral leaflet height. CONCLUSION: Superimposition of annuloplasty ring CAD models on the Live 3D zoom loops of the mitral valve using mitral valve assessment is superior to two dimensional measurements of the intercommissural distance or the height of the anterior mitral leaflet in predicting correct annuloplasty ring size. PMID- 21546376 TI - Do community characteristics predict alcohol-related crime? AB - AIMS: Alcohol-related crime is a substantial community problem. There is evidence to suggest that certain geographic areas experience higher rates of alcohol related crime and that both individual and community factors are associated with alcohol-related crime. There is limited research at the community level despite communities being the target of interventions designed to reduce alcohol-related harm. This study aims to determine whether there are differences in alcohol related crime at the community level and examines whether certain community characteristics are associated with increased alcohol-related crime. METHODS: Routinely collected police data from 20 rural communities in New South Wales, Australia were analysed. The ratio of alcohol to non-alcohol-related criminal incidents was used as a proxy for alcohol-related crime. Predictor variables were population-adjusted community characteristics, including demographic and resource variables. RESULTS: Regression analyses suggest that there are differences between communities in alcohol-related crime. Less socioeconomic disadvantage and more GPs and licensed premises (pubs and clubs) are associated with greater alcohol-related crime at the community level. CONCLUSIONS: Decreasing the socioeconomic well-being of a community is not appropriate; however, introducing additional taxes to increase the cost of alcohol may decrease consumption and therefore alcohol-related crime. Reducing or capping the number of licensed premises, specifically the number of pubs and clubs, may be an appropriate strategy to reduce alcohol-related crime in rural communities. PMID- 21546377 TI - Assessing reliability of measures using routinely collected data. PMID- 21546378 TI - Microlaparoscopic hernia repair in children: initial experiences. AB - INTRODUCTION: This study reports the authors' experience with the exclusive use of 2-mm instrument sets and small diameter scopes in 100 children undergoing microlaparoscopic herniorrhaphy. METHOD: This prospective study was designed as a pilot feasibility study; all data related to patients and procedures were prospectively collected. A pneumoperitoneum was established, and 1.7 to 2 mm 0 degrees or 30 degrees scopes were introduced for visualization. Exclusively 2 mm instruments were used. RESULTS: This study included 100 children (aged 15 days to 11 years, median age 2.3 years) undergoing microlaparoscopic hernia repair. A total of 140 hernias were treated. The average operative time for the microlaparoscopically experienced surgeon was 16 minutes for bilateral inguinal hernia and 12 minutes for unilateral hernias. All procedures were completed microlaparoscopically. Hernia recurrence was observed in 2 patients. CONCLUSION: Based on the authors' early experience, it is found that microlaparoscopic hernia repair in children seems to be a safe and feasible procedure. PMID- 21546379 TI - Functional relationship between obesity and male reproduction: from humans to animal models. AB - BACKGROUND: The increase in the incidence of obesity has a substantial societal health impact. Contrasting reports have been published on whether overweight and obesity affect male fertility. To clarify this, we have reviewed published data on the relation between overweight/obesity, semen parameters, endocrine status and human male fertility. Subsequently, we have used results obtained in animal models of obesity to explain the human data. METHODS: Pubmed, Scopus, Web of Science and Google Scholar databases were searched between September 2009 and October 2010 for a comprehensive publication record. Available studies on adult human males were examined. The included animal studies examined obesity and fertility, and focused on leptin, leptin receptor signaling, kisspeptins and/or NPY. RESULTS: Most overweight/obese men do not experience significant fertility problems, despite the presence of reduced testosterone alongside normal gonadotrophin levels. Only a subgroup of subjects suffers from hypogonadotropic hypogonadism. Animal models offer several explanations and show that reduced leptin signaling leads to reduced GnRH neuronal activity. This may be due to decreased hypothalamic Kiss1 expression, a potent regulator of GnRH/LH/FSH release. As the Kiss1 neurons express leptin receptors, the Kiss1 system may participate in transmitting metabolic information to the GnRH neurons, thus providing a bridge between metabolic regulation and fertility. CONCLUSIONS: Infertility in overweight/obese males may be explained by leptin insensitivity. This implies a possible role for the KISS1 system in human obesity-related male infertility. If substantiated, it will pave the way for methods to restore fertility in these subjects. PMID- 21546382 TI - Teaching and learning in outpatients and beyond: how ambulatory care teaching can contribute to student learning in child health. PMID- 21546380 TI - Assessing the pathogenic potential of human Nephronophthisis disease-associated NPHP-4 missense mutations in C. elegans. AB - A spectrum of complex oligogenic disorders called the ciliopathies have been connected to dysfunction of cilia. Among the ciliopathies are Nephronophthisis (NPHP), characterized by cystic kidney disease and retinal degeneration, and Meckel-Gruber syndrome (MKS), a gestational lethal condition with skeletal abnormalities, cystic kidneys and CNS malformation. Mutations in multiple genes have been identified in NPHP and MKS patients, and an unexpected finding has been that mutations within the same gene can cause either disorder. Further, there is minimal genotype-phenotype correlation and despite recessive inheritance, numerous patients were identified as having a single heterozygous mutation. This has made it difficult to determine the significance of these mutations on disease pathogenesis and led to the hypothesis that clinical presentation in an individual will be determined by genetic interactions between mutations in multiple cilia-related genes. Here we utilize Caenorhabditis elegans and cilia associated behavioral and morphologic assays to evaluate the pathogenic potential of eight previously reported human NPHP4 missense mutations. We assess the impact of these mutations on C. elegans NPHP-4 function, localization and evaluate potential interactions with mutations in MKS complex genes, mksr-2 and mksr-1. Six out of eight nphp-4 mutations analyzed alter ciliary function, and three of these modify the severity of the phenotypes caused by disruption of mksr-2 and mksr-1. Collectively, our studies demonstrate the utility of C. elegans as a tool to assess the pathogenicity of mutations in ciliopathy genes and provide insights into the complex genetic interactions contributing to the diversity of phenotypes associated with cilia disorders. PMID- 21546383 TI - Developmental assessment in the over 5s. AB - The paediatrician's role in the developmental assessment of children under the age of 5 is well established, and so he/she might also have a role in the assessment of school-age children, particularly as (i) it is increasingly recognised that subtle presentations of developmental disorders may escape professional notice until school age, (ii) these disorders are interweaving and overlapping, necessitating a truly holistic view and (iii) no another professional group is equipped to deliver a single diagnostic assessment encompassing cognitive, communication, social, emotional and physical domains. However, assessment in the over-5s requires a different set of skills to the under-5s. The emphasis in this age group shifts from assessing developmental impairment, for example, a specific delay in walking or talking or a low developmental quotient, to assessing factors affecting the child's social or academic function. The paediatrician's task is to apply their knowledge of risks and vulnerabilities, using their experience in general and developmental paediatrics, paediatric neurology and child and adolescent mental health to identify environmental and/or biological factors affecting the child. The diagnostic focus that is a strength of paediatric practice needs to be tempered by a more flexible approach taking account of the child's strengths and difficulties. Finally, the clinician needs to decide if further assessment and investigations are required and make recommendations to help improve the outcome for the child. In this paper, the author will set out the context for these assessments, and then guide the reader through a clinical approach that the author has found useful. PMID- 21546381 TI - Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways. AB - The risk of developing neurodegenerative diseases increases with age. Although many of the molecular pathways regulating proteotoxic stress and longevity are well characterized, their contribution to disease susceptibility remains unclear. In this study, we describe a new Caenorhabditis elegans model of Machado-Joseph disease pathogenesis. Pan-neuronal expression of mutant ATXN3 leads to a polyQ length dependent, neuron subtype-specific aggregation and neuronal dysfunction. Analysis of different neurons revealed a pattern of dorsal nerve cord and sensory neuron susceptibility to mutant ataxin-3 that was distinct from the aggregation and toxicity profiles of polyQ-alone proteins. This reveals that the sequences flanking the polyQ-stretch in ATXN3 have a dominant influence on cell-intrinsic neuronal factors that modulate polyQ-mediated pathogenesis. Aging influences the ATXN3 phenotypes which can be suppressed by the downregulation of the insulin/insulin growth factor-1-like signaling pathway and activation of heat shock factor-1. PMID- 21546384 TI - Plasmid-mediated quinolone resistance determinants oqxAB and aac(6')-Ib-cr and extended-spectrum beta-lactamase gene blaCTX-M-24 co-located on the same plasmid in one Escherichia coli strain from China. PMID- 21546385 TI - Uptake of the NHS Health Checks programme in a deprived, culturally diverse setting: cross-sectional study. AB - BACKGROUND: The UK is embarking on a national cardiovascular risk assessment programme called NHS Health Checks; in order to be effective, high and equitable uptake is paramount. METHODS: A cross-sectional study, using data extracted from electronic medical records of persons aged 35-74 years estimated to be at a high risk of developing cardiovascular disease, to examine the uptake of the Health Checks using logistic regression and statin prescribing. RESULTS: A total of 44.8% of high risk patients invited for a Health Check attended. Uptake was lower among younger men but higher among patients from south Asian (AOR = 1.71 [1.29 2.27] compared with white) or mixed ethnic backgrounds (AOR = 2.42 [1.50-3.89]), and patients registered with smaller practices (AOR = 2.53 [1.09-5.84] <3000 patients compared with 3000-5999). The percentage of patients confirmed to be at high risk of CVD prescribed a statin increased from 24.7 to 44.8%. CONCLUSIONS: Uptake of cardiovascular risk assessment and prescribing of statins in high risk patients was considerably lower than projected in the first year of NHS Health Checks programme. Targeting efforts to increase uptake and adherence to interventions in high risk populations and reinvesting resources into population wide strategies to reduce obesity, smoking and salt intake may prove more cost effective in reducing the burden of cardiovascular disease in the UK. PMID- 21546386 TI - The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy. AB - Oxidative stress in the male germ line is thought to affect male fertility and impact upon normal embryonic development. Accordingly, fertility specialists are actively exploring the diagnosis of such stress in spermatozoa and evaluating the possible use of antioxidants to ameliorate this condition. In this review, evidence for the presence of oxidative stress in human spermatozoa, the origins of this phenomenon, its clinical significance in the aetiology of male infertility and recent advances in methods for its diagnosis and treatment are re examined. Moreover, an extensive review of the results presented in published clinical studies has been conducted to evaluate the overall impact of oral antioxidants on measures of sperm oxidative stress and DNA damage. Administration of antioxidants to infertile men has been assessed in numerous clinical studies with at least 20 reports highlighting its effect on measures of oxidative stress in human spermatozoa. A qualitative but detailed review of the results revealed that 19 of the 20 studies conclusively showed a significant reduction relating to some measure of oxidative stress in these cells. Strong evidence also supports improved motility, particularly in asthenospermic patients. However, of these studies, only 10 reported pregnancy-related outcomes, with 6 reporting positive associations. Adequately powered, placebo-controlled comprehensive clinical trials are now required to establish a clear role for antioxidants in the prevention of oxidative stress in the male germ line, such that the clinical utility of this form of therapy becomes established once and for all. PMID- 21546387 TI - During IVF treatment patient preference shifts from singletons towards twins but only a few patients show an actual reversal of preference. AB - BACKGROUND: Knowledge of patients' preferences for elective single embryo transfer (eSET) or double embryo transfer (DET) and for singletons or twins is of great importance in counselling for embryo transfer (ET) strategies. In this study, the stability of IVF patients' preferences over time for either a healthy single child or healthy twins was measured and we investigated which factors could explain preference shifts. METHODS: Infertile women (n = 177) who participated in an RCT comparing one cycle eSET with one cycle DET were included. A satisfaction questionnaire was developed to measure patient preferences and attitudes at two moments in time, i.e. at 2 weeks before ET and at 2 weeks following ET, after the results of the pregnancy test. Regression analysis examined the effect of several variables on preference shifts. RESULTS: Before ET, most patients expressed a preference for a singleton, whereas most patients were indifferent 2 weeks after ET, resulting in an overall preference shift towards twins (P = 0.002; n = 145). Overall, 62% of patients showed a preference shift. Preference shifts were explained by patients' global satisfaction of the information given by the fertility clinic staff received by the fertility clinic staff, and an interaction between the occurrence of pregnancy and transfer policy (eSET or DET). CONCLUSIONS: In general, patients' preferences for a singleton or twins are not stable during IVF treatment. Possible explanations of a shift in preference are that pregnant patients attuned their preferences to what they expect their pregnancy to result in, whereas non-pregnant patients shifted towards a preference for twins in order to be able to fulfil their ultimate child wish. PMID- 21546388 TI - TGF-beta1 induces proteinase-activated receptor 2 (PAR2) expression in endometriotic stromal cells and stimulates PAR2 activation-induced secretion of IL-6. AB - BACKGROUND: Proteinase-activated receptor 2 (PAR2) is a G-protein-coupled receptor that is activated by several serine proteases. PAR2 activation in endometriotic stromal cells (ESCs) has been implicated in the development of endometriosis but the regulatory mechanism of PAR2 expression in ESC is unknown. Our objective was to study the mechanism by which PAR2 expression may be regulated in endometriotic lesions. METHODS: Primary cultures of ESCs were treated with transforming growth factor-beta (TGF-beta) 1, tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and the expression of PAR2 was examined by real-time quantitative PCR. ESCs pretreated with or without TGF beta1 were treated with PAR2 agonist peptide (PAR2AP) and the secretion of the pro-endometriotic cytokine, IL-6, was measured using a specific enzyme-linked immunosorbent assay. Effects of TGF-beta type 1 inhibitor, SB431542, and PAR2 small interfering RNA (siRNA) on the TGF-beta1 stimulation of PAR2 gene expression and PAR2AP-induced IL-6 secretion were also evaluated. To study intracellular signaling, effects of inhibitors of mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K) and of Smad4 siRNA on the TGF-beta1-induced PAR2 gene expression were studied. RESULTS: Only TGF-beta1, but neither TNF-alpha nor IL-1beta, increased gene expression of PAR2. Activation of PAR2 with PAR2AP increased the secretion of IL-6 from ESCs. As expected, TGF beta1 pretreatment dose-dependently enhanced the PAR2AP-induced increase in IL-6 secretion from ESCs. Treatment of ESCs with the TGF-beta type 1 inhibitor, SB431542, inhibited both TGF-beta1-stimulation of PAR2 gene expression and PAR2AP induced IL-6 secretion. Transfection of ESCs with PAR2 siRNA produced a similar inhibition of IL-6 secretion. The TGF-beta1-induced increase in PAR2 gene expression was repressed by inhibition of p38 MAPK, p42/44 MAPK or PI3K, but not by knockdown of Smad4 expression. CONCLUSIONS: In view of significant roles of PAR2 and IL-6 in endometriosis, the TGF-beta1-induced increase in PAR2 expression may be an elaborate mechanism that augments the progression of the disease. PMID- 21546389 TI - Medical abortion and the 'golden rule' of statutory interpretation. BPAS v the Secretary of State for Health [2011] EWHC 235. PMID- 21546390 TI - Multiple-rule bias in the comparison of classification rules. AB - MOTIVATION: There is growing discussion in the bioinformatics community concerning overoptimism of reported results. Two approaches contributing to overoptimism in classification are (i) the reporting of results on datasets for which a proposed classification rule performs well and (ii) the comparison of multiple classification rules on a single dataset that purports to show the advantage of a certain rule. RESULTS: This article provides a careful probabilistic analysis of the second issue and the 'multiple-rule bias', resulting from choosing a classification rule having minimum estimated error on the dataset. It quantifies this bias corresponding to estimating the expected true error of the classification rule possessing minimum estimated error and it characterizes the bias from estimating the true comparative advantage of the chosen classification rule relative to the others by the estimated comparative advantage on the dataset. The analysis is applied to both synthetic and real data using a number of classification rules and error estimators. AVAILABILITY: We have implemented in C code the synthetic data distribution model, classification rules, feature selection routines and error estimation methods. The code for multiple-rule analysis is implemented in MATLAB. The source code is available at http://gsp.tamu.edu/Publications/supplementary/yousefi11a/. Supplementary simulation results are also included. PMID- 21546391 TI - Grid computing for improving conformational sampling in NMR structure calculation. AB - MOTIVATION: Methods for automatic nuclear magnetic resonance (NMR) structure determination need to face a high level of ambiguity encountered in NMR spectra recorded by solid-state NMR and by solution NMR of partially unfolded proteins, leading to time-consuming calculations. The software package Ambiguous Restraints for Iterative Assignment (ARIA) allows for straightforward parallelization of the calculation, as the conformers can be generated in parallel on many nodes. RESULTS: Due to its architecture, the adaptation of ARIA to grid computing can be easily achieved by using the middleware glite and JDL (Job Description Language) scripts. This adaptation makes it possible to address highly ambiguous datasets, because of the much larger conformational sampling that can be generated by use of the grid computational power. AVAILABILITY: The version 2.3.1 of ARIA implemented on the grid is freely available from the ARIA web site: aria.pasteur.fr/downloads. PMID- 21546392 TI - Boulder ALignment Editor (ALE): a web-based RNA alignment tool. AB - SUMMARY: The explosion of interest in non-coding RNAs, together with improvements in RNA X-ray crystallography, has led to a rapid increase in RNA structures at atomic resolution from 847 in 2005 to 1900 in 2010. The success of whole-genome sequencing has led to an explosive growth of unaligned homologous sequences. Consequently, there is a compelling and urgent need for user-friendly tools for producing structure-informed RNA alignments. Most alignment software considers the primary sequence alone; some specialized alignment software can also include Watson-Crick base pairs, but none adequately addresses the needs introduced by the rapid influx of both sequence and structural data. Therefore, we have developed the Boulder ALignment Editor (ALE), which is a web-based RNA alignment editor, designed for editing and assessing alignments using structural information. Some features of BoulderALE include the annotation and evaluation of an alignment based on isostericity of Watson-Crick and non-Watson-Crick base pairs, along with the collapsing (horizontally and vertically) of the alignment, while maintaining the ability to edit the alignment. AVAILABILITY: http://www.microbio.me/boulderale. PMID- 21546393 TI - Molecular signatures database (MSigDB) 3.0. AB - MOTIVATION: Well-annotated gene sets representing the universe of the biological processes are critical for meaningful and insightful interpretation of large scale genomic data. The Molecular Signatures Database (MSigDB) is one of the most widely used repositories of such sets. RESULTS: We report the availability of a new version of the database, MSigDB 3.0, with over 6700 gene sets, a complete revision of the collection of canonical pathways and experimental signatures from publications, enhanced annotations and upgrades to the web site. AVAILABILITY AND IMPLEMENTATION: MSigDB is freely available for non-commercial use at http://www.broadinstitute.org/msigdb. PMID- 21546394 TI - ReMark: an automatic program for clustering orthologs flexibly combining a Recursive and a Markov clustering algorithms. AB - SUMMARY: ReMark is a fully automatic tool for clustering orthologs by combining a Recursive and a Markov clustering (MCL) algorithms. The ReMark detects and recursively clusters ortholog pairs through reciprocal BLAST best hits between multiple genomes running software program (RecursiveClustering.java) in the first step. Then, it employs MCL algorithm to compute the clusters (score matrices generated from the previous step) and refines the clusters by adjusting an inflation factor running software program (MarkovClustering.java). This method has two key features. One utilizes, to get more reliable results, the diagonal scores in the matrix of the initial ortholog clusters. Another clusters orthologs flexibly through being controlled naturally by MCL with a selected inflation factor. Users can therefore select the fitting state of orthologous protein clusters by regulating the inflation factor according to their research interests. AVAILABILITY AND IMPLEMENTATION: Source code for the orthologous protein clustering software is freely available for non-commercial use at http://dasan.sejong.ac.kr/~wikim/notice.html, implemented in Java 1.6 and supported on Windows and Linux. PMID- 21546395 TI - FusionHunter: identifying fusion transcripts in cancer using paired-end RNA-seq. AB - MOTIVATION: Fusion transcripts can be created as a result of genome rearrangement in cancer. Some of them play important roles in carcinogenesis, and can serve as diagnostic and therapeutic targets. With more and more cancer genomes being sequenced by next-generation sequencing technologies, we believe an efficient tool for reliably identifying fusion transcripts will be desirable for many groups. RESULTS: We designed and implemented an open-source software tool, called FusionHunter, which reliably identifies fusion transcripts from transcriptional analysis of paired-end RNA-seq. We show that FusionHunter can accurately detect fusions that were previously confirmed by RT-PCR in a publicly available dataset. The purpose of FusionHunter is to identify potential fusions with high sensitivity and specificity and to guide further functional validation in the laboratory. AVAILABILITY: http://bioen-compbio.bioen.illinois.edu/FusionHunter/. PMID- 21546396 TI - famCNV: copy number variant association for quantitative traits in families. AB - A program package to enable genome-wide association of copy number variants (CNVs) with quantitative phenotypes in families of arbitrary size and complexity. Intensity signals that act as proxies for the number of copies are modeled in a variance component framework and association with traits is assessed through formal likelihood testing. AVAILABILITY AND IMPLEMENTATION: The Java package is made available at www.imperial.ac.uk/medicine/people/m.falchi/. CONTACT: m.falchi@imperial.ac.uk. PMID- 21546397 TI - APOLLO: a quality assessment service for single and multiple protein models. AB - SUMMARY: We built a web server named APOLLO, which can evaluate the absolute global and local qualities of a single protein model using machine learning methods or the global and local qualities of a pool of models using a pair-wise comparison approach. Based on our evaluations on 107 CASP9 (Critical Assessment of Techniques for Protein Structure Prediction) targets, the predicted quality scores generated from our machine learning and pair-wise methods have an average per-target correlation of 0.671 and 0.917, respectively, with the true model quality scores. Based on our test on 92 CASP9 targets, our predicted absolute local qualities have an average difference of 2.60 A with the actual distances to native structure. AVAILABILITY: http://sysbio.rnet.missouri.edu/apollo/. Single and pair-wise global quality assessment software is also available at the site. PMID- 21546398 TI - PLIO: an ontology for formal description of protein-ligand interactions. AB - MOTIVATION: Biomedical ontologies have proved to be valuable tools for data analysis and data interoperability. Protein-ligand interactions are key players in drug discovery and development; however, existing public ontologies that describe the knowledge space of biomolecular interactions do not cover all aspects relevant to pharmaceutical modelling and simulation. RESULTS: The protein -ligand interaction ontology (PLIO) was developed around three main concepts, namely target, ligand and interaction, and was enriched by adding synonyms, useful annotations and references. The quality of the ontology was assessed based on structural, functional and usability features. Validation of the lexicalized ontology by means of natural language processing (NLP)-based methods showed a satisfactory performance (F-score = 81%). Through integration into our information retrieval environment we can demonstrate that PLIO supports lexical search in PubMed abstracts. The usefulness of PLIO is demonstrated by two use case scenarios and it is shown that PLIO is able to capture both confirmatory and new knowledge from simulation and empirical studies. AVAILABILITY: The PLIO ontology is made freely available to the public at http://www.scai.fraunhofer.de/bioinformatics/downloads.html. PMID- 21546399 TI - Clonality: an R package for testing clonal relatedness of two tumors from the same patient based on their genomic profiles. AB - SUMMARY: If a cancer patient develops multiple tumors, it is sometimes impossible to determine whether these tumors are independent or clonal based solely on pathological characteristics. Investigators have studied how to improve this diagnostic challenge by comparing the presence of loss of heterozygosity (LOH) at selected genetic locations of tumor samples, or by comparing genomewide copy number array profiles. We have previously developed statistical methodology to compare such genomic profiles for an evidence of clonality. We assembled the software for these tests in a new R package called 'Clonality'. For LOH profiles, the package contains significance tests. The analysis of copy number profiles includes a likelihood ratio statistic and reference distribution, as well as an option to produce various plots that summarize the results. AVAILABILITY: Bioconductor (http://bioconductor.org/packages/release/bioc/html/Clonality.html) and http://www.mskcc.org/mskcc/html/13287.cfm. PMID- 21546400 TI - Mixture models for analysis of the taxonomic composition of metagenomes. AB - MOTIVATION: Inferring the taxonomic profile of a microbial community from a large collection of anonymous DNA sequencing reads is a challenging task in metagenomics. Because existing methods for taxonomic profiling of metagenomes are all based on the assignment of fragmentary sequences to phylogenetic categories, the accuracy of results largely depends on fragment length. This dependence complicates comparative analysis of data originating from different sequencing platforms or resulting from different preprocessing pipelines. RESULTS: We here introduce a new method for taxonomic profiling based on mixture modeling of the overall oligonucleotide distribution of a sample. Our results indicate that the mixture-based profiles compare well with taxonomic profiles obtained with other methods. However, in contrast to the existing methods, our approach shows a nearly constant profiling accuracy across all kinds of read lengths and it operates at an unrivaled speed. AVAILABILITY: A platform-independent implementation of the mixture modeling approach is available in terms of a MATLAB/Octave toolbox at http://gobics.de/peter/taxy. In addition, a prototypical implementation within an easy-to-use interactive tool for Windows can be downloaded. PMID- 21546401 TI - Echocardiographic assessment of ductal significance: retrospective comparison of two methods. AB - BACKGROUND: Patent ductus arteriosus (PDA) in preterm infants is often assessed with echocardiographic parameters, especially colour Doppler ductal diameter and pulsed Doppler flow pattern. Clinical algorithms have been proposed in which PDA treatment is indicated by either large diameter or a particular flow pattern, however it is unknown whether ductal diameter and flow pattern provide equivalent stratification of infants. AIM: Retrospectively assess both parameters in 197 echocardiograms from 104 infants (gestational age <31 weeks). METHODS: Echocardiograms were independently reviewed and the internal colour Doppler diameter of the PDA and the pulsed Doppler flow pattern were characterised for each study (169 records had both parameters recorded). RESULTS: Diameter varied widely within each group but was significantly associated with flow pattern: mean diameter was greatest in the pulmonary hypertension (PH) group (2.6 mm), progressively narrowed across growing and pulsatile groups, and was smallest in the closing group (1.3 mm). When echocardiograms were categorised using previously published diameters, 82.4% of the PH group had diameters >2.0 mm, large diameters predominated in the growing and pulsatile groups but to a progressively smaller extent, and 98.1% of closing group had diameters <2.0 mm. CONCLUSION: Ductal diameter and flow patterns are significantly associated, consistent with a narrowing of the ductus until closure. Overall, the two parameters are in good agreement but will result in different treatment decisions in some cases. Clinicians might consider using both methods as a cross check against each other, to assist in the management of preterm infants with a clinically detectable PDA. PMID- 21546402 TI - An association between infantile haemangiomas and erythropoietin treatment in preterm infants. AB - BACKGROUND: Infantile haemangiomas are benign vascular neoplasms that occur frequently in premature infants. The authors hypothesised that in addition to gestational age and birth weight, erythropoietin therapy may influence the incidence of these soft tissue tumours in preterm infants. METHODS: 2563 infants born prematurely and admitted to the Division of Neonatology, University of Heidelberg Medical School were investigated in a retrospective analysis. Hospital charts for all infants were reviewed for clinical data. The primary endpoint was the percentage of infants who had received erythropoietin treatment and were diagnosed with a haemangioma. RESULTS: Haemangiomas were diagnosed in 4.3% (n=110) of the 2563 preterm infants. These 110 infants had a median gestational age of 29 weeks (IQR 27-33 weeks) and the female:male ratio was 1.8:1. A higher incidence of haemangiomas (12-15%) was detected in premature infants with a lower gestational age (<31 weeks). Erythropoietin therapy was shown to be an independent risk factor after adjusting for all other known factors and oxygen therapy in multivariable analysis (HR 2.82, 95% CI 1.55 to 5.12). Subgroup analysis revealed that the effect was more pronounced in male than female infants (HR 3.61, 95% CI 1.52 to 8.57). CONCLUSIONS: This retrospective study demonstrates that erythropoietin treatment is associated with an increase in the incidence of these benign vascular tumours after adjusting for all other factors. PMID- 21546403 TI - End-of-life care at an academic medical center: are attending physicians, house staff, nurses, and bereaved family members equally satisfied? Implications for palliative care. AB - BACKGROUND: End-of-life care is deemed to be poor in the United States - particularly in large teaching hospitals. Via a brief survey, we examined satisfaction with end-of-life care for those patients who died in our academic medical center from provider and family perspectives. METHODS: To assess the correlation between overall satisfaction between providers (attending, housestaff, and nurses) as well as family members for decedents who died in our hospital, we conducted a satisfaction survey regarding care in the last three days of life. The nine item survey was administered within 1 week of the patient s death to care providers and approximately 8 to 12 weeks to next of kin. RESULTS: There were 166 deaths examined over the four month study period. Overall satisfaction with care was 3.02 out of 4.0, and differed by respondent group (p= 0.035). Correlation between respondents was very low (range 0.02 to 0.51). The least discordance was between residents and interns (0.5), who had the lowest level of satisfaction (2.72). Housestaff and attendings had the lowest overall correlation in mean satisfaction scores (0.05). Most providers knew their patients for 24 hours or less. CONCLUSIONS: Overall satisfaction was high, but there was discordance among different providers. Continuity of care was limited. Age and location of death alone did not significantly affect satisfaction with end-of-life care. Implications of this type of research for improving end of life care at academic centers are discussed. PMID- 21546404 TI - Association of angiotensin I converting enzyme insertion/deletion polymorphism with breast cancer: a meta-analysis. AB - BACKGROUND: Polymorphisms of angiotensin I converting enzyme (ACE) gene have been inconsistently associated with breast cancer risk. We examined these associations by performing a meta-analysis. MATERIALS AND METHODS: Four studies (cases: 1422; controls: 3044) testing the association between ACE insertion/deletion (I/D) polymorphism and breast cancer were examined. The analyses were performed using the Review Manager 5.0.25 software package. RESULTS: The combined results based on the above four studies showed that there was no significant difference in genotype distribution (DD, ID or II) between breast cancer patients and controls, with the odds ratio (OR) (1.00; 0.94; 1.11) and 95% confidence interval (CI) (0.76 to 1.33; 0.83 to 1.07; 0.96 to 1.28) for DD, ID and II genotype respectively. CONCLUSION: The meta-analysis suggests that ACE I/D polymorphism may not be a genetic risk factor for breast cancer. PMID- 21546405 TI - Urinary shedding of spirochaetes in a dog with acute leptospirosis despite treatment. PMID- 21546406 TI - Preliminary investigation of somatosensory evoked potentials in equine headshaking. AB - The aim of this study was to develop a technique for recording electrical activity of the equine cerebral cortex following application of a noxious electrical stimulus to the maxillary branch of the trigeminal nerve in order to investigate trigeminal nerve neurophysiology in control and headshaking horses. Triphasic somatosensory evoked potentials (SEPs) were recorded using subcutaneous needle electrodes in four control and four headshaking horses under general anaesthesia. Dural electroencephalography electrodes were used to record SEPs in one further control and one further headshaking horse. Headshaking horses appeared to have decreased middle latency and inter-peak intervals following stimulation of the trigeminal nerve compared with control horses, supporting abnormal trigeminal nerve physiology in equine headshaking. PMID- 21546407 TI - Energy metabolites in pre- and postpartum dairy cattle as predictors of reproductive disorders. AB - This study aimed to determine values for selected energy metabolites (non esterified fatty acid [NEFA], beta-hydroxybutyrate [BHB], urea or urea:BHB ratio), together with a body condition score, associated with an increased risk of cows developing a reproductive disorder and to investigate temporal relationships between predictors and reproductive outcome. A cohort of 98 cows on one farm was monitored weekly from four weeks before to 10 weeks after calving; 89 cows provided sufficient data to calculate commencement of luteal activity (C LA). Cows with high NEFA * urea (Nu; product of NEFA and urea) values one and three weeks after calving were twice as likely to develop cystic ovarian disease (risk ratio 2). Cows that developed endometritis had high NEFA values one (P=0.02) or four weeks (P=0.04) before calving, or low urea:BHB ratios two weeks before calving, at calving or three weeks after calving (P=0.024, P=0.031 and P=0.001, respectively). Cows that had delayed C-LA had high NEFA values one week after calving (P=0.05) or low urea:BHB ratios three or four weeks after calving (P=0.004 and P=0.003, respectively). PMID- 21546408 TI - Verocytotoxin-producing and attaching and effacing activity of Escherichia coli isolated from diseased farm livestock. AB - Between May 2005 and June 2008, strategically selected isolates of Escherichia coli obtained from clinical submissions to Veterinary Laboratories Agency (VLA) regional laboratories in England and Wales were serogrouped and examined by PCR for verocytotoxin (VT) production and attaching and effacing (eae) genes, both of which are zoonotic determinants. VT-encoding genes were detected in 54 (5.3 per cent) of the 1022 isolates examined. Only one isolate (0.1 per cent) was identified as verocytotoxigenic E coli (VTEC) O157. Non-O157 VTECs were present in 4.7 per cent of isolates from cattle, compared with 7.9 per cent in pigs, 2.3 per cent in sheep and 6.7 per cent in goats. The predominant serogroup identified in cattle was O26 and the predominant serogroup in pigs was O2. Attaching and effacing activity was attributed to 69 (6.8 per cent) of all isolates. PMID- 21546409 TI - Efficacy of halofuginone lactate in the prevention of cryptosporidiosis in dairy calves. AB - To evaluate the efficacy of halofuginone lactate (Halocur; Intervet) when used prophylactically against cryptosporidiosis in dairy calves, 513 Holstein heifer calves were randomly distributed between two experimental groups. Those in the treatment group (n=259) received 0.1 mg halofuginone base per kg bodyweight daily in a 10 ml solution, for the first seven days following birth, while those in the control group (n=254) received an equal volume of a placebo solution. Faecal samples were collected weekly from all calves until three weeks of age to test for Cryptosporidium oocysts and to assess the diarrhoeal status. Growth parameters of the calves were also recorded at approximately four months of age. Calves that received halofuginone were significantly less likely to shed Cryptosporidium oocysts during the course of the study than placebo-treated calves (odds ratio 0.6, 95 per cent confidence interval 0.4 to 0.9, P=0.009). Mean growth measurements of calves in the treated group were consistently higher than those of the control calves (hipometer-derived P=0.052, wither height P=0.097) and mortality was lower in the treated group (P=0.07). However, these differences were not statistically significant (P>0.05). No association was found between the prophylactic use of halofuginone and the incidence of calf diarrhoea. PMID- 21546410 TI - Activation of the signal transducer and activator of transcription 3 pathway up regulates estrogen receptor-beta expression in lung adenocarcinoma cells. AB - Estrogens contribute to the pathogenesis of female lung cancer and function mainly through estrogen receptor-beta (ERbeta). However, the way in which ERbeta expression is regulated in lung cancer cells remains to be explored. We have found that signal transducer and activator of transcription 3 (Stat3) activation up-regulates ERbeta expression in PC14PE6/AS2 lung cancer cells in a preliminary Affymetrix oligonucleotide array study, and we sought to confirm the findings. In this study, we show that IL-6 induced ERbeta mRNA and protein expression in lung cancer cells. The induction of ERbeta in response to IL-6 was abolished by Janus kinase 2 inhibitor-AG490, dominant-negative mutant of Stat3, and Stat3-targeting short interfering RNA. The luciferase reporter assay and chromatin immunoprecipitation assay confirmed that IL-6-activated Stat3 binds to the ERbeta promoter. Besides the Janus kinase 2/Stat3 pathway, the MEK/Erk pathway contributes to ERbeta up-regulation induced by IL-6; however, the phosphoinositide 3'-kinase/Akt pathway does not. We also found that epidermal growth factor (EGF) stimulation or L858R mutation in EGF receptor (EGFR) induced Stat3 activation as well as ERbeta expression in lung cancer cells. Inhibiting Stat3 activity by pharmacological or genetic approaches reduced EGF- and L858R mutant EGFR-induced ERbeta expression, indicating that Stat3 activation is required for EGFR signaling-mediated ERbeta up-regulation. Silencing ERbeta decreased cell proliferation in lung cancer cells that overexpress L858R mutant EGFR. In conclusion, we have identified that Stat3 activation is essential for ERbeta induction by IL-6, EGF, and the presence of EGFR mutation. The findings shed light on new therapeutic targets for female lung cancer, especially for those with EGFR mutations. PMID- 21546413 TI - Pathological stealing in a patient with systemic lupus erythematosus: rare or hidden? PMID- 21546414 TI - Scaphoid fracture with an associated dorsal lip of lunate fracture - a sign of instability? PMID- 21546412 TI - Thrombotic events during long-term follow-up of obstetric antiphospholipid syndrome patients. AB - Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial and/or venous thromboses and/or pregnancy-associated morbidity. Some patients develop only obstetric complications (obstetric APS), but data on the frequency of thrombotic events during the follow-up of these patients are scarce. This study was undertaken to evaluate the rate of thrombotic events after obstetric APS diagnosis according to the 2006 revised criteria. In total, 32 obstetric APS patients were retrospectively studied, with mean follow-up of 50 +/ 37 months. After delivery, aspirin was prescribed to all patients as primary thrombosis prevention. The thrombosis rate was 3.3/100 patient-years and was 4.6, 4.5 and 10/100 patient-years when we considered at least two antiphospholipid antibody positivities (among lupus anticoagulant, anticardiolipin and anti-beta2 glycoprotein-I), antinuclear antibody positivity or systemic lupus erythematosus associated APS patients, respectively. The thrombosis rate was high after obstetric APS diagnosis, even for patients taking aspirin. Larger, prospective studies are needed to confirm this high frequency and determine the associated risk factors. PMID- 21546415 TI - Outcome of axillary nerve injuries treated with nerve grafts. AB - This study evaluates the outcome of axillary nerve injuries treated with nerve grafting. Thirty-six patients were retrospectively reviewed after a mean of 53 months (minimum 12 months). The mean interval from injury to surgery was 6.5 months. Recovery of deltoid function was assessed by the power of both abduction and retropulsion, the deltoid bulk and extension lag. The deltoid bulk was almost symmetrical in nine of 34 cases, good in 22 and wasted in three. Grade M4 or M5* was achieved in 30 of 35 for abduction and in 32 of 35 for retropulsion. There was an extension lag in four patients. Deltoid bulk continued to improve with a longer follow-up following surgery. Nerve grafting to the axillary nerve is a reliable method of regaining deltoid function when the lesion is distal to its origin from the posterior cord. PMID- 21546416 TI - Displaced unstable transverse fractures of the shaft of the proximal phalanx of the fingers in industrial workers: reduction and K-wire fixation leaving the metacarpophalangeal and proximal interphalangeal joints free. AB - A series of 35 adult male industrial workers with displaced unstable transverse fractures of the shaft of the proximal phalanx of the fingers were treated with reduction and K-wire fixation leaving the metacarpophalangeal and interphalangeal joints free to move immediately after surgery. At final follow-up, the total active motion score of the injured finger was graded as excellent, good, fair, or poor if it was greater than 240 degrees , 220-240 degrees , 180-219 degrees , or less than 180 degrees , respectively. Complications were also documented. The results were compared with our previously published series of these fractures treated with two other techniques: percutaneous K-wires immobilizing the metacarpophalangeal joint and open reduction and interosseous loop wire fixation. The final TAM scores in the current study were excellent in 43%, good in 29%, fair in 14% and poor in 14%. Four out of the 35 patients (11%) had minor pin tract infection. These results were significantly better than the results following percutaneous K-wire fixation immobilizing the metacarpophalangeal joint indicating that immediate mobilization of all joints has a significant effect on the outcome. PMID- 21546417 TI - The biomechanical assessment of gap formation after flexor tendon repair using partial interlocking cross-stitch peripheral sutures. AB - The gap formation of five core plus peripheral suture techniques for flexor tendon repair was evaluated by cyclic load testing. Fifty pairs of dental roll tendon models were sutured using six-strand Pennington modified Kessler core suture with 4-0 Polypropylene. One-half or three-fourths circumferential interlocking cross-stitch, or three complete circumferential peripheral suture techniques were performed using 6-0 Polypropylene. An initial cyclic load of 10 N for 500 cycles was applied and increased by 5 N for an additional 500 cycles at each new load until rupture. The complete circumferential interlocking cross stitch had the greatest fatigue strength. The partial circumferential cross stitches resulted in significantly larger gap formations at both the repaired and unrepaired sides than the complete circumferential sutures, and were also associated with early rupture. The full circumference of the cut tendon must be sutured using an interlocking cross-stitch peripheral suture to improve strength and avoid gap formation. PMID- 21546418 TI - Arsenic in drinking water. PMID- 21546420 TI - The decline in heart transplantation in the UK. PMID- 21546411 TI - Minireview: The roles of small RNA pathways in reproductive medicine. AB - The discovery of small noncoding RNA, including P-element-induced wimpy testis interacting RNA, small interfering RNA, and microRNA, has energized research in reproductive medicine. In the two decades since the identification of small RNA, first in Caenorhabditis elegans and then in other animals, scientists in many disciplines have made significant progress in elucidating their biology. A powerful battery of tools, including knockout mice and small RNA mimics and antagonists, has facilitated investigation into the functional roles and therapeutic potential of these small RNA pathways. Current data indicate that small RNA play significant roles in normal development and physiology and pathological conditions of the reproductive tracts of females and males. Biologically plausible mRNA targets for these microRNA are aggressively being discovered. The next phase of research will focus on elucidating the clinical utility of small RNA-selective agonists and antagonists. PMID- 21546421 TI - Bilateral developmental dysplasia of the hips. PMID- 21546419 TI - Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh: prospective cohort study. AB - OBJECTIVE: To evaluate the association between arsenic exposure and mortality from cardiovascular disease and to assess whether cigarette smoking influences the association. DESIGN: Prospective cohort study with arsenic exposure measured in drinking water from wells and urine. SETTING: General population in Araihazar, Bangladesh. PARTICIPANTS: 11,746 men and women who provided urine samples in 2000 and were followed up for an average of 6.6 years. MAIN OUTCOME MEASURE: Death from cardiovascular disease. RESULTS: 198 people died from diseases of circulatory system, accounting for 43% of total mortality in the population. The mortality rate for cardiovascular disease was 214.3 per 100,000 person years in people drinking water containing <12.0 ug/L arsenic, compared with 271.1 per 100,000 person years in people drinking water with >= 12.0 ug/L arsenic. There was a dose-response relation between exposure to arsenic in well water assessed at baseline and mortality from ischaemic heart disease and other heart disease; the hazard ratios in increasing quarters of arsenic concentration in well water (0.1-12.0, 12.1-62.0, 62.1-148.0, and 148.1-864.0 ug/L) were 1.00 (reference), 1.22 (0.65 to 2.32), 1.35 (0.71 to 2.57), and 1.92 (1.07 to 3.43) (P = 0.0019 for trend), respectively, after adjustment for potential confounders including age, sex, smoking status, educational attainment, body mass index (BMI), and changes in urinary arsenic concentration since baseline. Similar associations were observed when baseline total urinary arsenic was used as the exposure variable and for mortality from ischaemic heart disease specifically. The data indicate a significant synergistic interaction between arsenic exposure and cigarette smoking in mortality from ischaemic heart disease and other heart disease. In particular, the hazard ratio for the joint effect of a moderate level of arsenic exposure (middle third of well arsenic concentration 25.3-114.0 ug/L, mean 63.5 ug/L) and cigarette smoking on mortality from heart disease was greater than the sum of the hazard ratios associated with their individual effect (relative excess risk for interaction 1.56, 0.05 to 3.14; P = 0.010). CONCLUSIONS: Exposure to arsenic in drinking water is adversely associated with mortality from heart disease, especially among smokers. PMID- 21546422 TI - Checking placement of nasogastric feeding tubes in adults (interpretation of x ray images): summary of a safety report from the National Patient Safety Agency. PMID- 21546423 TI - Australia's proposals on plain packaging set new global benchmark in anti-smoking efforts. PMID- 21546424 TI - Penalties mean hospitals might need to make 7% of savings each year, warns regulator. PMID- 21546425 TI - Experts deny claims that peer review system is in crisis. PMID- 21546426 TI - Dynamic of oxidative and nitrosative stress markers during the convalescent period of stroke patients undergoing rehabilitation. AB - BACKGROUND: Stroke patients have a redox imbalance, a consequence of both the cerebrovascular event and the associated pathological conditions. Our study was aimed to investigate the dynamic of some oxidative and nitrosative markers during the convalescent phase of postacute stroke patients undergoing rehabilitation. METHODS: We assessed thiol, advanced oxidation protein product, protein carbonyl, 3-nitro-l-tyrosine, ceruloplasmin and oxidized LDL concentrations, as well as gamma-glutamyltranspeptidase (GGT) activity in 20 patients at the beginning of the hospitalization and at the discharge moment, respectively, and 24 apparently healthy controls. RESULTS: We found significantly increased values for GGT (P = 0.04), ceruloplasmin (P = 0.01) and protein carbonyl (P = 0.04) in stroke patients at the hospitalization moment when compared with healthy controls, while total thiols were significantly decreased (P = 0.002). Rehabilitation was associated with a significant decrease of protein carbonyl (P = 0.03) and oxidized LDL particle concentrations (P = 0.03), as well as GGT activity (P = 0.02). At the hospitalization moment, both GGT and ceruloplasmin were significantly negatively correlated with non-proteic thiols (r = -0.44, P = 0.049, and r = -0.53, P = 0.015, respectively) and significantly positively with protein carbonyls (r = +0.80, P < 0.001, and r = +0.69, P < 0.001, respectively) suggesting putative roles of GGT and ceruloplasmin in the redox imbalance. CONCLUSIONS: These results highlight the existence of a redox imbalance in postacute stroke patients, and the possible benefits of an antioxidant-based therapy for the recovery of these patients. PMID- 21546427 TI - Role of certain trace minerals in oxidative stress, inflammation, CD4/CD8 lymphocyte ratios and lung function in asthmatic patients. AB - BACKGROUND: Asthma is associated with increased inflammation, oxidative stress and abnormal immune system function. We determined the distributions of several essential trace minerals and assessed their relationships to factors that are associated with the pathophysiological status of patients with mild/moderate asthma. METHODS: We enrolled 25 asthmatic patients and 25 healthy subjects. We measured: blood trace minerals, zinc (Zn), copper (Cu) and selenium (Se); oxidative stress markers thiobarbituric acid reactive substances (TBARS); antioxidant enzyme activities; percentages of CD4 and CD8 lymphocyte subsets; high-sensitivity C-reactive protein (hs-CRP); and a lung function index (FEV1/FVC%). RESULTS: Compared with healthy subjects, asthmatics had lower concentrations of Zn and Se; higher Cu concentrations, and Cu/Zn and Cu/Se ratios; and lower antioxidant enzyme glutathione peroxidase (GPx), glutathione reductase (GR) and catalase activities. Significantly increased concentrations of hs-CRP, TBARS and CD4/CD8 lymphocyte ratios were also observed. Furthermore, plasma TBARS or hs-CRP concentrations were negatively associated with Se concentrations, but were positively associated with Cu/Se ratios. CD4/CD8 lymphocyte ratios were inversely correlated with Se, while it was positively correlated with Cu/Se ratio. FEV1/FVC% was also significantly correlated with Se concentrations, and Cu/Se and Cu/Zn ratios. CONCLUSIONS: Abnormal distributions of these trace minerals may aggravate oxidative damage and inflammation, increased CD4/CD8 lymphocyte ratios and decreased lung function in asthma. PMID- 21546428 TI - Xylem structure of four grape varieties and 12 alternative hosts to the xylem limited bacterium Xylella fastidious. AB - BACKGROUND AND AIMS: The bacterium Xylella fastidiosa (Xf), responsible for Pierce's disease (PD) of grapevine, colonizes the xylem conduits of vines, ultimately killing the plant. However, Vitis vinifera grapevine varieties differ in their susceptibility to Xf and numerous other plant species tolerate Xf populations without showing symptoms. The aim of this study was to examine the xylem structure of grapevines with different susceptibilities to Xf infection, as well as the xylem structure of non-grape plant species that support or limit movement of Xf to determine if anatomical differences might explain some of the differences in susceptibility to Xf. METHODS: Air and paint were introduced into leaves and stems to examine the connectivity between stem and leaves and the length distribution of their vessels. Leaf petiole and stem anatomies were studied to determine the basis for the free or restricted movement of Xf into the plant. KEY RESULTS: There were no obvious differences in stem or petiole vascular anatomy among the grape varieties examined, nor among the other plant species that would explain differences in resistance to Xf. Among grape varieties, the more tolerant 'Sylvaner' had smaller stem vessel diameters and 20 % more parenchyma rays than the other three varieties. Alternative hosts supporting Xf movement had slightly longer open xylem conduits within leaves, and more connection between stem and leaves, when compared with alternative hosts that limit Xf movement. CONCLUSIONS: Stem--leaf connectivity via open xylem conduits and vessel length is not responsible for differences in PD tolerance among grape varieties, or for limiting bacterial movement in the tolerant plant species. However, it was found that tolerant host plants had narrower vessels and more parenchyma rays, possibly restricting bacterial movement at the level of the vessels. The implications of xylem structure and connectivity for the means and regulation of bacterial movement are discussed. PMID- 21546429 TI - Function and evolution of sterile sex organs in cryptically dioecious Petasites tricholobus (Asteraceae). AB - BACKGROUND AND AIMS: Why are sterile anthers and carpels retained in some flowering plants, given their likely costs? To address this question, a cryptically dioecious species, Petasites tricholobus, in which male and female plants each have two floret types that appear pistillate and hermaphroditic, was studied. The aim was to understand the function of sterile hermaphroditic florets in females. In addition, the first examination of functions of sterile female structures in male plants was conducted in the hermaphroditic florets on males of this species. These female structures are exceptionally large in this species despite being sterile. METHODS: Differences in floret morphology between the sex morphs were documented and the possible functions of sterile sex organs investigated using manipulative experiments. Tests were carried out to find out if sterile female structures in male florets attract pollinators and if they aid in pollen dispersal, also to find out if the presence and quantity of sterile hermaphroditic florets in females increase pollinator attraction and reproductive success. To investigate what floret types provide nectar, all types of florets were examined under a scanning electron microscope to search for nectaries. KEY RESULTS: The sterile female structures in male florets did not increase pollinator visits but were essential to secondary pollen presentation, which significantly enhanced pollen dispersal. Sterile pistillate florets on male plants did not contribute to floral display and disappeared in nearly half of the male plants. The sterile hermaphroditic florets on female plants attracted pollinators by producing nectar and enhanced seed production. CONCLUSIONS: The presence of female structures in male florets and hermaphroditic florets on female plants is adaptive despite being sterile, and may be evolutionarily stable. However, the pistillate florets on male plants appear non-adaptive and are presumably in decline. Differential fates of the sterile sex organs in the species are determined by both the historical constraints and the ecological functions. PMID- 21546430 TI - Identification and characterization of TcCRP1, a pollen tube attractant from Torenia concolor. AB - BACKGROUND AND AIMS: During sexual reproduction in higher angiosperms, the pollen tubes are directed to the ovules in the pistil to deliver sperm cells. This pollen tube attraction is highly species specific, and a group of small secreted proteins, TfCRPs, are necessary for this process in Torenia fournieri. METHODS: A candidate pollen tube attractant protein in Torenia concolor, a related species of T. fournieri, was isolated and the attractant abilities between them were compared. KEY RESULTS: TcCRP1, an orthologous gene of TfCRP1 from T. concolor, is expressed predominantly in the synergid cell. The gene product attracted pollen tubes in a concentration-dependent manner, but attracted fewer pollen tubes from the other species. CONCLUSIONS: The results indicated that this class of CRP proteins is a common pollen tube attractant in Torenia species. The sequence diversity of these proteins is important for species-specific pollen tube attraction. PMID- 21546431 TI - Tests for inbreeding and outbreeding depression and estimation of population differentiation in the bird-pollinated shrub Grevillea mucronulata. AB - BACKGROUND AND AIMS: Plants show patterns of spatial genetic differentiation reflecting gene flow mediated by pollen and seed dispersal and genotype * environment interactions. If patterns of genetic structure are determined largely by gene flow then they may be useful in predicting the likelihood of inbreeding or outbreeding depression but should be less useful if there is strong site specific selection. For many Australian plants little is known about either their population genetics or the effects on mating systems of variation in pollen transfer distances. Experimental pollinations were used to compare the reproductive success of bird-adapted Grevillea mucronulata plants mated with individuals from a range of spatial scales. A hierarchical survey of microsatellite DNA variation was also conducted to describe the scale of population differentiation for neutral markers. METHODS: The effects of four pollen treatments on reproductive performance were compared. These treatments were characterized by transfer of pollen from (a) neighbouring adults; (b) an adjacent cluster of adults (30-50 m distant); (c) a distant cluster (>5 km distant); and (d) open pollination. Sets of 17.9 +/- 3.3 leaves from each of 15 clusters of plants were genotyped and spatial autocorrelation and F statistics were used to describe patterns of genetic structure. KEY RESULTS: Grevillea mucronulata displayed evidence of both inbreeding and outbreeding depression, with 'intermediate' pollen producing consistently superior outcomes for most aspects of fitness including seed set, seed size, germination and seedling growth. Significant genotypic structuring was detected within clusters (spatial autocorrelation) and among adjacent clusters and clusters separated by >5 km distance (F(ST) = 0.07 and 0.10). CONCLUSIONS: The superior outcome of intermediate pollen transfer and genetic differentiation of adjacent clusters suggests that G. mucronulata selection disfavours matings among closely and distantly related neighbours. Moreover, the performance of open-pollinated seedlings was poor, implying that current mating patterns are suboptimal. PMID- 21546432 TI - Linking water stress effects on carbon partitioning by introducing a xylem circuit into L-PEACH. AB - BACKGROUND AND AIMS: Many physiological processes such as photosynthesis, respiration and transpiration can be strongly influenced by the diurnal patterns of within-tree water potential. Despite numerous experiments showing the effect of water potential on fruit-tree development and growth, there are very few models combining carbohydrate allocation with water transport. The aim of this work was to include a xylem circuit into the functional-structural L-PEACH model. METHODS: The xylem modelling was based on an electrical circuit analogy and the Hagen-Poisseuille law for hydraulic conductance. Sub-models for leaf transpiration, soil water potential and the soil-plant interface were also incorporated to provide the driving force and pathway for water flow. The model was assessed by comparing model outputs to field measurements and published knowledge. KEY RESULTS: The model was able to simulate both the water uptake over a season and the effect of different irrigation treatments on tree development, growth and fruit yield. CONCLUSIONS: This work opens the way to a new field of modelling where complex interactions between water transport, carbohydrate allocation and physiological functions can be simulated at the organ level and describe functioning and behaviour at the tree scale. PMID- 21546433 TI - Acquisition of physical dormancy and ontogeny of the micropyle--water-gap complex in developing seeds of Geranium carolinianum (Geraniaceae). AB - BACKGROUND AND AIMS: The 'hinged valve gap' has been previously identified as the initial site of water entry (i.e. water gap) in physically dormant (PY) seeds of Geranium carolinianum (Geraniaceae). However, neither the ontogeny of the hinged valve gap nor acquisition of PY by seeds of Geraniaceae has been studied previously. The aims of the present study were to investigate the physiological events related to acquisition of PY and the ontogeny of the hinged valve gap and seed coat of G. carolinianum. METHODS: Seeds of G. carolinianum were studied from the ovule stage until dispersal. The developmental stages of acquisition of germinability, physiological maturity and PY were determined by seed measurement, germination and imbibition experiments using intact seeds and isolated embryos of both fresh and slow-dried seeds. Ontogeny of the seed coat and water gap was studied using light microscopy. KEY RESULTS: Developing seeds achieved germinability, physiological maturity and PY on days 9, 14 and 20 after pollination (DAP), respectively. The critical moisture content of seeds on acquisition of PY was 11 %. Slow-drying caused the stage of acquisition of PY to shift from 20 to 13 DAP. Greater extent of cell division and differentiation at the micropyle, water gap and chalaza than at the rest of the seed coat resulted in particular anatomical features. Palisade and subpalisade cells of varying forms developed in these sites. A clear demarcation between the water gap and micropyle is not evident due to their close proximity. CONCLUSIONS: Acquisition of PY in seeds of G. carolinianum occurs after physiological maturity and is triggered by maturation drying. The micropyle and water gap cannot be considered as two separate entities, and thus it is more appropriate to consider them together as a 'micropyle--water-gap complex'. PMID- 21546434 TI - Patient preference for autonomy: does it change as risk rises? AB - BACKGROUND: It is unclear how patient preferences for autonomy vary given different severity of a single condition. OBJECTIVE: To assess patient preferences for autonomy in making decisions about taking medication to prevent a heart attack, across a wide range of personal calculated cardiovascular disease (CVD) 5-year risk. METHODS: Consecutive eligible patients in family practice waiting rooms in Auckland, New Zealand self-completed a questionnaire. Questions related to a hypothetical cardiovascular medication, where risks and benefits were framed from their personal predicted 5-year CVD risk. Participant preference for autonomy was measured by ranking their decision-making preference on 5-point scale from 'doctor only' to 'patient only'. RESULTS: There were 934 participants, with personal predicted 5-year cardiovascular risks that ranged from 5% to 30%. Preference for autonomy decreased as CVD risk increased, after adjustment for age, gender, numeracy and ethnicity. Preference for autonomy increased independently among younger participants, women and those who were more numerate. Compared to participants of European ethnicity, those of Pacific, East Asian and Indian Asian ethnicity were more likely to want the doctor to decide. CONCLUSIONS: No combination of predicted risk, demographics or attitudes strongly predicted the preference of an individual patient. Clinicians should therefore seek to understand and confirm each patient's preferences. PMID- 21546435 TI - Comorbid trends in World Trade Center cough syndrome and probable posttraumatic stress disorder in firefighters. AB - BACKGROUND: We describe the relationship between World Trade Center (WTC) cough syndrome symptoms, pulmonary function, and symptoms consistent with probable posttraumatic stress disorder (PTSD) in WTC-exposed firefighters in the first year post-September 11, 2001 (baseline), and 3 to 4 years later (follow-up). METHODS: Five thousand three hundred sixty-three firefighters completed pulmonary function tests (PFTs) and questionnaires at both times. Relationships among WTC cough syndrome, probable PTSD, and PFTs were analyzed using simple and multivariable models. We also examined the effects of cofactors, including WTC exposure. RESULTS: WTC cough syndrome was found in 1,561 firefighters (29.1%) at baseline and 1,186 (22.1%) at follow-up, including 559 with delayed onset (present only at follow-up). Probable PTSD was found in 458 firefighters (8.5%) at baseline and 548 (10.2%) at follow-up, including 343 with delayed onset. Baseline PTSD symptom counts and probable PTSD were associated with WTC cough syndrome at baseline, at follow-up, and in those with delayed-onset WTC cough syndrome. Similarly, WTC cough syndrome symptom counts and WTC cough syndrome at baseline were associated with probable PTSD at baseline, at follow-up, and in those with delayed-onset probable PTSD. WTC arrival time and work duration were cofactors of both outcomes. A small but consistent association existed between pulmonary function and WTC cough syndrome, but none with PTSD. CONCLUSIONS: The study showed a moderate association between WTC cough syndrome and probable PTSD. The presence of one contributed to the likelihood of the other, even after adjustment for shared cofactors such as WTC exposure. PMID- 21546436 TI - Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. AB - BACKGROUND: The long-term safety and tolerability of sildenafil treatment of pulmonary arterial hypertension (PAH) were assessed. METHODS: Two hundred fifty nine of 277 randomized and treated patients completed a 12-week, double-blind, placebo-controlled trial (SUPER-1 [Sildenafil Use in Pulmonary Arterial Hypertension]) of oral sildenafil in treatment-naive patients with PAH (96% functional class II/III) and entered an open-label uncontrolled extension study (SUPER-2) that continued until the last patient completed 3 years of sildenafil treatment. Patients titrated to sildenafil 80 mg tid; one dose reduction for tolerability was allowed during the titration phase. RESULTS: The median duration of sildenafil treatment across SUPER-1 and SUPER-2 was 1,242 days (range, 1-1,523 days); 170 patients (61%) completed both studies, and 89 patients discontinued from SUPER-2. After 3 years, 87% of 183 patients on treatment were receiving sildenafil 80 mg tid. Of patients remaining under follow-up, 3%, 10%, and 18% were receiving a second approved PAH therapy at 1, 2, and 3 years, respectively. At 3 years post-SUPER-1 baseline, 127 patients had an increased 6-min walk distance (6MWD); 81 improved and 86 maintained functional class. Most adverse events were of mild or moderate severity. At 3 years, 53 patients had died (censored, n = 37). Three-year estimated survival rate was 79%; if all censored patients were assumed to have died, 3-year survival rate was 68%. No deaths were considered to be treatment related. CONCLUSIONS: Long-term treatment of PAH initiated as sildenafil monotherapy was generally well tolerated. After 3 years, the majority of patients (60%) who entered the SUPER-1 trial improved or maintained their functional status, and 46% maintained or improved 6MWD. PMID- 21546437 TI - Silicosis in denim sandblasters. AB - BACKGROUND: During the past 2 decades, silica sand has been used widely in sandblasting denim in Turkey, which has resulted in an epidemic of silicosis. This study was conducted to summarize the clinical outcomes of formerly healthy young people who became disabled or died because of working in the textile industry. METHODS: The medical records of patients with silicosis due to denim sandblasting who were seen at our institution between 2001 and 2009 were reviewed. Follow-up data were assessed. Compensation and vital status of patients were determined, and survival analysis was performed. RESULTS: Thirty-two male patients diagnosed with silicosis due to denim sandblasting over an 8-year period were identified. Mean age was 31.5 years. They worked as denim sandblasters for a mean 66.4 h/wk for a median 28.5 months. Their mean cumulative exposure time to silica sand was 12,957 h. The median follow-up period was 29 months (range 3-101 months). The median latency period (time elapsed between initial exposure and diagnosis) was 5.5 years (range 2-14 years). Six of the followed patients (19%) died of progressive massive fibrosis. Nine of the patients (28%) were compensated because of silicosis. Just two patients with silicosis received compensation before they died. The mean survival rate was 78 months. The estimated 5-year survival rate was 69% for denim sandblasters with silicosis. CONCLUSIONS: Silicosis in young individuals after exposure in the textile sector suggests a lack of awareness of the hazards of silica outside of the traditional occupations associated with silicosis. Death from silicosis in young people suggests overexposure and unsafe working conditions as a result of a lack of control. PMID- 21546438 TI - Clinical patterns and outcome in epithelioid hemangioendothelioma with or without pulmonary involvement: insights from an internet registry in the study of a rare cancer. AB - BACKGROUND: Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm of endothelial origin with clinical behavior intermediate between hemangioma and angiosarcoma. The natural history of EHE is highly variable. This study uses an Internet registry to identify clinical patterns with prognostic significance in EHE. METHODS: Cases from the International Hemangioendothioma, Epithelioid Hemangioendothelioma, and Related Vascular Disorders (HEARD) Support Group were evaluated based on demographics, organ involvement, disease progression, presence or absence of pleural effusion, and treatment. Survival among various cohorts was compared using log-rank analysis of Kaplan-Meier plots. RESULTS: Two hundred sixty-four patients were identified from April 2004 to November 2009. Fifty-eight cases were excluded because of inadequate information or wrong diagnosis. EHE was more common in female patients (61%). Male gender and age >= 55 years were associated with decreased survival. The most commonly affected organs were liver, lung, and bone. No specific organ or combination of organ involvement differentially affected survival, and survival was no different between patients with multiple vs single organ involvement. However, pattern B, defined as lesions without distinct borders (eg, pulmonary infiltrates, pleural effusion, ascites), hemoptysis, or involvement of more than two bones adversely affected survival in all cohorts. CONCLUSION: A novel staging system with prognostic value for EHE is proposed. Pleural effusion or other signs of uncontained tumor growth, hemoptysis, and osseous involvement of more than two bones implied worse survival than did localized and discrete tumors, regardless of number of organs involved. A lay registry can provide useful insights into the clinical behavior of a rare cancer. PMID- 21546439 TI - Diagnosis of pneumothorax by radiography and ultrasonography: a meta-analysis. AB - OBJECTIVE: This study compares, by meta-analysis, the use of anterior-posterior chest radiography (CR) with transthoracic ultrasonography for the diagnosis of pneumothorax. METHODS: English-language articles on the performance of CR and ultrasonography in the diagnosis of a pneumothorax were selected. In eligible studies, data were recalculated, and the forest plots and summary receiver operating characteristic (sROC) curves were analyzed. RESULTS: Pooled sensitivity and specificity were 0.88 and 0.99, respectively, for ultrasonography, and 0.52 and 1.00, respectively, for CR. For ultrasonography performed by clinicians other than radiologists, pooled sensitivity and specificity were 0.89 and 0.99, respectively. The sROC areas under the curve were compared, and no significant differences between ultrasonography and CR were found. Meta-regression analysis implied that the operator is strongly associated with accuracy (relative diagnostic OR, 0.21; 95% CI, 0.05-0.96; P = .0455). CONCLUSIONS: The meta analysis indicated that bedside ultrasonography performed by clinicians had higher sensitivity and similar specificity compared with CR in the diagnosis of pneumothorax, but the accuracy of ultrasonography in the diagnosis of pneumothorax depended on the skill of the operators. PMID- 21546440 TI - Factors associated with bronchiectasis in patients with COPD. AB - BACKGROUND: Previous studies have shown a high prevalence of bronchiectasis in patients with moderate to severe COPD. However, the factors associated with bronchiectasis remain unknown in these patients. The objective of this study is to identify the factors associated with bronchiectasis in patients with moderate to severe COPD. METHODS: Consecutive patients with moderate (50% < FEV(1) <= 70%) or severe (FEV(1) <= 50%) COPD were included prospectively. All subjects filled out a clinical questionnaire, including information about exacerbations. Peripheral blood samples were obtained, and lung function tests were performed in all patients. Sputum samples were provided for monthly microbiologic analysis for 6 months. All the tests were performed in a stable phase for at least 6 weeks. High-resolution CT scans of the chest were used to diagnose bronchiectasis. RESULTS: Ninety-two patients, 51 with severe COPD, were included. Bronchiectasis was present in 53 patients (57.6%). The variables independently associated with the presence of bronchiectasis were severe airflow obstruction (OR, 3.87; 95% CI, 1.38-10.5; P = .001), isolation of a potentially pathogenic microorganism (PPM) (OR, 3.59; 95% CI, 1.3-9.9; P = .014), and at least one hospital admission due to COPD exacerbations in the previous year (OR, 3.07; 95% CI, 1.07-8.77; P = .037). CONCLUSION: We found an elevated prevalence of bronchiectasis in patients with moderate to severe COPD, and this was associated with severe airflow obstruction, isolation of a PPM from sputum, and at least one hospital admission for exacerbations in the previous year. PMID- 21546442 TI - Collective dynamics: when one plus one does not make two. AB - A brief introduction into the interdisciplinary field of collective dynamics is given, followed by an overview of 'Mathematical Models of Collective Dynamics in Biology and Evolution'. PMID- 21546441 TI - Racial differences in the relationship between number of cigarettes smoked and nicotine and carcinogen exposure. AB - INTRODUCTION: Black smokers are reported to have higher lung cancer rates and greater tobacco dependence at lower levels of cigarette consumption compared to non-Hispanic White smokers. We studied the relationship between cigarettes per day (CPD) and biomarkers of nicotine and carcinogen exposure in Black and White smokers. METHODS: In 128 Black and White smokers, we measured plasma nicotine and its main proximate metabolite cotinine, urine nicotine equivalents, 4 (methylnitrosamino)-1-(3)pyridyl-1-butanol (NNAL), and polycyclic aromatic hydrocarbon (PAH) metabolites. RESULTS: The dose-response between CPD and nicotine equivalents, and NNAL and PAH was flat for Black but positive for White smokers (Race * CPD interaction, all ps < .05). Regression estimates for the Race * CPD interactions were 0.042 (95% CI 0.013-0.070), 0.054 (0.023-0.086), and 0.028 (0.004-0.052) for urine nicotine equivalents, NNAL, and PAHs, respectively. In contrast there was a strong correlation between nicotine equivalents and NNAL and PAH independent of race. Nicotine and carcinogen exposure per individual cigarette was inversely related to CPD. This inverse correlation was stronger in Black compared to White smokers and stronger in menthol compared to regular cigarette smokers (not mutually adjusted). CONCLUSIONS: Our data indicate that Blacks on average smoke cigarettes differently than White smokers such that CPD predicts smoke intake more poorly in Black than in White smokers. PMID- 21546443 TI - Effect of zinc supplementation on growth in very low birth weight infants. AB - This was a randomized blinded placebo controlled trial undertaken to study the role of zinc supplementation on growth, primarily the linear growth velocity in very low birth weight (VLBW) infants at 3 months corrected age (CA). Out of 134 neonates with birth weight <1500 g, 101 babies were eligible. Due to lack of consent 10 were excluded. The remaining 91 neonates who were comparable for sex, gestational age, birth weight, APGAR and age at enrollment were randomized to receive either 1 ml of zinc sulfate (10 mg elemental zinc) (n = 46) or 1 ml placebo (n = 45) from enrollment to 60 days. The infants in the zinc group had significantly higher linear growth velocity (0.98 +/- 0.12 cm week(-1)) compared to a placebo group (0.67 +/- 0.15 cm week(-1)) (p < 0.001) at 3 months CA. We concluded that zinc supplementation at 10 mg day(-1) for 60 days in VLBW infants improves their linear growth during infancy. PMID- 21546447 TI - Validation in bioinformatics and molecular medicine. Editorial. PMID- 21546445 TI - Regulation of murine cardiac contractility by activation of alpha(1A)-adrenergic receptor-operated Ca(2+) entry. AB - AIMS: Sympathetic regulation of cardiac contractility is mediated in part by alpha(1)-adrenergic receptors (ARs), and the alpha(1A)-subtype has been implicated in the pathogenesis of cardiac hypertrophy. However, little is known about alpha(1A)-AR signalling pathways in ventricular myocardium. The aim of this study was to determine the signalling pathway that mediates alpha(1A)-AR-coupled cardiac contractility. METHODS AND RESULTS: Using a transgenic model of enhanced cardiac alpha(1A)-AR expression and signalling (alpha(1A)-H mice), we identified a receptor-coupled signalling pathway that enhances Ca(2+) entry and increases contractility. This pathway involves alpha(1A)-AR-activated translocation of Snapin and the transient receptor potential canonical 6 (TRPC6) channel to the plasma membrane. In ventricular cardiomyocytes from alpha(1A)-H and their non transgenic littermates (or WTs), stimulation with alpha(1A)-AR-specific agonists resulted in increased [Ca(2+)](i), which was dose-related and proportional to the level of alpha(1A)-AR expression. Blockade of TRPC6 inhibited the alpha(1A)-AR mediated increase in [Ca(2+)](i) and contractility. External Ca(2+) entry, underlying the [Ca(2+)](i) increase, was not due to store-operated Ca(2+) entry but to a receptor-operated mechanism of Ca(2+) entry resulting from alpha(1A)-AR activation. CONCLUSION: These findings indicate that Ca(2+) entry via the alpha(1A)-AR-Snapin-TRPC6-pathway plays an important role in physiological regulation of cardiac contractility and may be an important target for augmenting cardiac performance. PMID- 21546448 TI - Validation in genetic association studies. AB - Validation of genetic associations is understood to be a cornerstone for the scientific credibility of the results. To approach this topic, the general concept of genetic association studies is introduced briefly, followed by how the term 'validation' is used in the context of genetic association studies. As a central issue, reasons for the importance of validation and for failure of validation will be described. PMID- 21546446 TI - Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium. AB - Prokineticin 1 (PROK1) signalling via prokineticin receptor 1 (PROKR1) regulates the expression of several genes with important roles in endometrial receptivity and implantation. This study investigated PROK1 regulation of Dickkopf 1 (DKK1) expression, a negative regulator of canonical Wnt signalling, and its function in the non-pregnant endometrium and first trimester decidua. DKK1 mRNA expression is elevated during the mid-secretory phase of the menstrual cycle and expression increases further in first trimester decidua. DKK1 protein expression is localized to glandular epithelial and stromal cells during the proliferative, early- and mid-secretory phases, whereas expression is confined to the stroma in the late-secretory phase and first trimester decidua. PROK1 induces the expression of DKK1 in endometrial epithelial cells stably expressing PROKR1 and in first trimester decidua explants, via a Gq-calcium-calcineurin-nuclear factor of activated T-cells-mediated pathway. Endometrial epithelial cell proliferation is negatively regulated by PROK1-PROKR1 signalling. We demonstrate that this effect on cell proliferation occurs via DKK1 expression, as siRNA targeted against DKK1 reduces the PROK1-induced decrease in proliferation. Furthermore, decidualization of primary human endometrial stromal cells with progesterone and cyclic adenosine monophosphate is inhibited by miRNA knock down of PROK1 or DKK1. These data demonstrate important roles for PROK1 and DKK1 during endometrial receptivity and early pregnancy, which include regulation of endometrial cell proliferation and decidualization. PMID- 21546449 TI - The meta-analysis of genome-wide association studies. AB - The pressure to publish novel genetic associations has meant that meta-analysis has been applied to genome-wide association studies without the time for a careful consideration of the methods that are used. This review distinguishes between the use of meta-analysis to validate previously reported genetic associations and its use for gene discovery, and advocates viewing gene discovery as an exploratory screen that requires independent replication instead of treating it as the application of hundreds of thousands of statistical tests. The review considers the use of fixed and random effects meta-analyses, the investigation of between-study heterogeneity, adjustment for confounding, assessing the combined evidence and genomic control, and comments on alternative approaches that have been used in the literature. PMID- 21546451 TI - Nodular parenchymal amyloid, an unusual cause of multiple pulmonary nodules with favourable long term prognosis. PMID- 21546450 TI - Inter-scan variability of coronary artery calcium scoring assessed on 64 multidetector computed tomography vs. dual-source computed tomography: a head-to head comparison. AB - AIMS: Coronary artery calcium (CAC) scoring has emerged as a tool for risk stratification and potentially for monitoring response to risk factor modification. Therefore, repeat measurements should provide robust results and low inter-scanner variability for allowing meaningful comparison. The purpose of this study was to investigate inter-scanner variability of CAC for Agatston, volume, and mass scores by head-to-head comparison using two different cardiac computed tomography scanners: 64-detector multislice CT (MSCT) and 64-slice dual source CT (DSCT). METHODS AND RESULTS: Thirty patients underwent CAC measurements on both 64-MSCT (GE LightSpeed XT scanner: 120 kV, 70 mAs, 2.5 mm slices) and 64 DSCT (Siemens Somatom Definition: 120 kV, 80 mAs, 3 mm slices) within <100 days (0-97). Retrospective intra-scan comparison revealed an excellent correlation. The excellent intra-scan (inter-observer) agreement was documented by narrow limits of agreement and a correlation coefficient of variation (COV) of r >= 0.99 (P < 0.001) for all CAC scores with a low COV for both scanners (64-MSCT/64 DSCT), i.e. Agatston (2.0/2.1%), mass (3.0/2.0%), and volume (4.7/3.9%). Inter scanner comparison revealed larger Bland-Altman (BA) limits of agreement, despite high correlation (r >= 0.97) for all scores, with COV at 15.1, 21.6, and 44.9% for Agatston, mass, and volume scores. The largest BA limits were observed for volume scores (-1552.8 to 574.2), which was massively improved (-241.0 to 300.4, COV 11.5%) after reanalysing the 64-DSCT scans (Siemens) with GE software/workstation (while Siemens software/workstation does not allow cross vendor analysis). Phantom measurements confirmed overestimation of volume scores by 'syngo Ca-Scoring' (Siemens) software which should therefore be reviewed (vendor has been notified). CONCLUSION: Intra- and inter-scan agreement of CAC measurement in a given data set is excellent. Inter-scanner variability is reasonable, particularly for Agatston units in the clinically most relevant range <1000. The use of different software solutions has a greater influence particularly on volume scores than the use of different scanner types. PMID- 21546452 TI - Endobronchial ultrasound-transbronchial needle aspiration and its practical application. AB - Endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) has emerged over the past decade as one of the most exciting and innovative developments in the field of respiratory medicine. This procedure allows sampling of mediastinal lymph nodes and masses in both malignant and benign disease and overcomes some of the disadvantages associated with mediastinoscopy and blind transbronchial needle aspiration. We describe the clinical use, indications for and limitations of EBUS TBNA along with several illustrated clinical examples. PMID- 21546453 TI - Lipase activity in insect oral secretions mediates defense responses in Arabidopsis. AB - How plants perceive herbivory is not yet well understood. We investigated early responses of the model plant Arabidopsis (Arabidopsis thaliana) to attack from the generalist grasshopper herbivore, Schistocerca gregaria (Caelifera). When compared with wounding alone, S. gregaria attack and the application of grasshopper oral secretions (GS) to puncture wounds elicited a rapid accumulation of various oxylipins, including 13-hydroperoxy octadecatrienoic acid, 12-oxo phytodienoic acid (OPDA), jasmonic acid, and jasmonic acid-isoleucine. Additionally, GS increased cytosolic calcium levels, mitogen-activated protein kinase (MPK3 and MPK6) activity, and ethylene emission but not the accumulation of hydrogen peroxide. Although GS contain caeliferin A16:0, a putative elicitor of caeliferan herbivores, treatment with pure, synthetic caeliferin A16:0 did not induce any of the observed responses. With mutant plants, we demonstrate that the observed changes in oxylipin levels are independent of MPK3 and MPK6 activity but that MPK6 is important for the GS-induced ethylene release. Biochemical and pharmacological analyses revealed that the lipase activity of GS plays a central role in the GS-induced accumulation of oxylipins, especially OPDA, which could be fully mimicked by treating puncture wounds only with a lipase from Rhizopus arrhizus. GS elicitation increased the levels of OPDA-responsive transcripts. Because the oral secretions of most insects used to study herbivory-induced responses in Arabidopsis rapidly elicit similar accumulations of OPDA, we suggest that lipids containing OPDA (arabidopsides) play an important role in the activation of herbivory-induced responses. PMID- 21546455 TI - Rice ABI5-Like1 regulates abscisic acid and auxin responses by affecting the expression of ABRE-containing genes. AB - Abscisic acid (ABA) regulates plant development and is crucial for plant responses to biotic and abiotic stresses. Studies have identified the key components of ABA signaling in Arabidopsis (Arabidopsis thaliana), some of which regulate ABA responses by the transcriptional regulation of downstream genes. Here, we report the functional identification of rice (Oryza sativa) ABI5-Like1 (ABL1), which is a basic region/leucine zipper motif transcription factor. ABL1 is expressed in various tissues and is induced by the hormones ABA and indole-3 acetic acid and stress conditions including salinity, drought, and osmotic pressure. The ABL1 deficiency mutant, abl1, shows suppressed ABA responses, and ABL1 expression in the Arabidopsis abi5 mutant rescued the ABA sensitivity. The ABL1 protein is localized to the nucleus and can directly bind ABA-responsive elements (ABREs; G-box) in vitro. A gene expression analysis by DNA chip hybridization confirms that a large proportion of down-regulated genes of abl1 are involved in stress responses, consistent with the transcriptional activating effects of ABL1. Further studies indicate that ABL1 regulates the plant stress responses by regulating a series of ABRE-containing WRKY family genes. In addition, the abl1 mutant is hypersensitive to exogenous indole-3-acetic acid, and some ABRE-containing genes related to auxin metabolism or signaling are altered under ABL1 deficiency, suggesting that ABL1 modulates ABA and auxin responses by directly regulating the ABRE-containing genes. PMID- 21546454 TI - Cell wall damage-induced lignin biosynthesis is regulated by a reactive oxygen species- and jasmonic acid-dependent process in Arabidopsis. AB - The plant cell wall is a dynamic and complex structure whose functional integrity is constantly being monitored and maintained during development and interactions with the environment. In response to cell wall damage (CWD), putatively compensatory responses, such as lignin production, are initiated. In this context, lignin deposition could reinforce the cell wall to maintain functional integrity. Lignin is important for the plant's response to environmental stress, for reinforcement during secondary cell wall formation, and for long-distance water transport. Here, we identify two stages and several components of a genetic network that regulate CWD-induced lignin production in Arabidopsis (Arabidopsis thaliana). During the early stage, calcium and diphenyleneiodonium-sensitive reactive oxygen species (ROS) production are required to induce a secondary ROS burst and jasmonic acid (JA) accumulation. During the second stage, ROS derived from the NADPH oxidase RESPIRATORY BURST OXIDASE HOMOLOG D and JA-isoleucine generated by JASMONIC ACID RESISTANT1, form a negative feedback loop that can repress each other's production. This feedback loop in turn seems to influence lignin accumulation. Our results characterize a genetic network enabling plants to regulate lignin biosynthesis in response to CWD through dynamic interactions between JA and ROS. PMID- 21546456 TI - Nonphosphorylating glyceraldehyde-3-phosphate dehydrogenase is phosphorylated in wheat endosperm at serine-404 by an SNF1-related protein kinase allosterically inhibited by ribose-5-phosphate. AB - Nonphosphorylating glyceraldehyde-3-phosphate dehydrogenase (np-Ga3PDHase) is a cytosolic unconventional glycolytic enzyme of plant cells regulated by phosphorylation in heterotrophic tissues. After interaction with 14-3-3 proteins, the phosphorylated enzyme becomes less active and more sensitive to regulation by adenylates and inorganic pyrophosphate. Here, we acknowledge that in wheat (Triticum aestivum), np-Ga3PDHase is specifically phosphorylated by the SnRK (SNF1-related) protein kinase family. Interestingly, only the kinase present in heterotrophic tissues (endosperm and shoots, but not in leaves) was found active. The specific SnRK partially purified from endosperm exhibited a requirement for Mg(2+) or Mn(2+) (being Ca(2+) independent), having a molecular mass of approximately 200 kD. The kinase also phosphorylated standard peptides SAMS, AMARA, and SP46, as well as endogenous sucrose synthase, results suggesting that it could be a member of the SnRK1 subfamily. Concurrently, the partially purified wheat SnRK was recognized by antibodies raised against a peptide conserved between SnRK1s from sorghum (Sorghum bicolor) and maize (Zea mays) developing seeds. The wheat kinase was allosterically inhibited by ribose-5-phosphate and, to a lesser extent, by fructose-1,6-bisphosphate and 3-phosphoglycerate, while glucose-6-phosphate (the main effector of spinach [Spinacia oleracea] leaves, SnRK1) and trehalose-6-phosphate produced little or no effect. Results support a distinctive allosteric regulation of SnRK1 present in photosynthetic or heterotrophic plant tissues. After in silico analysis, we constructed two np Ga3PDHase mutants, S404A and S447A, identifying serine-404 as the target of phosphorylation. Results suggest that both np-Ga3PDHase and the specific kinase could be under control, critically affecting the metabolic scenario involving carbohydrates and reducing power partition and storage in heterotrophic plant cells. PMID- 21546458 TI - Retraction. Elsheikh E, Uzunel M, He Z, Holgersson J, Nowak G, Sumitran Holgersson S. Only a specific subset of human peripheral-blood monocytes has endothelial-like functional capacity. Blood. 2005;106(7):2347-2355. PMID- 21546457 TI - Vacuolar Ca2+/H+ transport activity is required for systemic phosphate homeostasis involving shoot-to-root signaling in Arabidopsis. AB - Calcium ions (Ca(2+)) and Ca(2+)-related proteins mediate a wide array of downstream processes involved in plant responses to abiotic stresses. In Arabidopsis (Arabidopsis thaliana), disruption of the vacuolar Ca(2+)/H(+) transporters CAX1 and CAX3 causes notable alterations in the shoot ionome, including phosphate (P(i)) content. In this study, we showed that the cax1/cax3 double mutant displays an elevated P(i) level in shoots as a result of increased P(i) uptake in a miR399/PHO2-independent signaling pathway. Microarray analysis of the cax1/cax3 mutant suggests the regulatory function of CAX1 and CAX3 in suppressing the expression of a subset of shoot P(i) starvation-responsive genes, including genes encoding the PHT1;4 P(i) transporter and two SPX domain containing proteins, SPX1 and SPX3. Moreover, although the expression of several PHT1 genes and PHT1;1/2/3 proteins is not up-regulated in the root of cax1/cax3, results from reciprocal grafting experiments indicate that the cax1/cax3 scion is responsible for high P(i) accumulation in grafted plants and that the pht1;1 rootstock is sufficient to moderately repress such P(i) accumulation. Based on these findings, we propose that CAX1 and CAX3 mediate a shoot-derived signal that modulates the activity of the root P(i) transporter system, likely in part via posttranslational regulation of PHT1;1 P(i) transporters. PMID- 21546459 TI - Predictors of unfavorable outcome in intracranial angioplasty and stenting in a single-center comparison: results from the Borgess Medical Center-Intracranial Revascularization Registry. AB - BACKGROUND AND PURPOSE: Intracranial angioplasty and stent placement are used to treat intracranial atherosclerotic disease. The 2 interventions have not been directly compared. MATERIALS AND METHODS: This was a single-center, single operator registry of consecutive, symptomatic subjects receiving treatment (angioplasty, BMS, or WS, chosen based on safety as judged by the operator). After November 2005, angioplasty alone was abandoned following the introduction of the WS. The primary end point was stroke rate per intervention at 30 days. The secondary end point was stroke rate per patient beyond 30 days. Success, dissection, restenosis, and occlusion rates were tracked. RESULTS: From April 2002 to January 2009, 140 subjects with 159 lesions (50%-100% stenosis) underwent 209 interventions: 89 angioplasty, 47 BMS, and 73 WS cases. Overall stroke rate at 30 days was 12.9%. The angioplasty arm had the lowest stroke rate (4.5%), whereas the WS arm had the highest (24.7%; P = .0002), leaving the BMS with 10.7%. Stroke rate beyond 30 days was 9%. The success rate was 58.4% for angioplasty, 81.3% for BMS, and 94.4% for WS, whereas the restenosis rates were 28.2%, 5.8%, and 13.3%, respectively. Dissection increased the risk of stroke in the first 30 days (P = .0439) and restenosis (P = .0051). Perforator vessels were more likely than nonperforators to have stroke within 30 days (P = .008). Eccentric lesions were more likely to have stroke than concentric lesions (P = .0726). CONCLUSIONS: In this comparison, angioplasty had a significantly lower stroke rate than WS. Certain lesion locations, morphologic characteristics, and the presence of dissection after treatment were other predictors of unfavorable outcome. PMID- 21546460 TI - Comparative hospital economics and patient presentation: vertebroplasty and kyphoplasty for the treatment of vertebral compression fracture. AB - BACKGROUND AND PURPOSE: Previous studies evaluating vertebral augmentation procedure costs have not made detailed comparisons between vertebroplasty and kyphoplasty. Our study contrasts hospital costs for vertebroplasty versus kyphoplasty for the treatment of vertebral compression fractures in routine clinical practice in the United States. MATERIALS AND METHODS: This retrospective cohort study analyzed 2007-2008 hospital discharge and billing records from the Premier Perspective data base. The primary outcome variable, differences in total hospital cost between vertebroplasty and kyphoplasty, was assessed by using analysis of covariance. RESULTS: Three thousand six hundred seventeen patients received vertebroplasty (64% inpatient, 36% outpatient), and 8118 received kyphoplasty (54% inpatient, 46% outpatient). Approximately 75% were women, and most were white. Mean total unadjusted inpatient costs were $9837 for vertebroplasty versus $13 187 for kyphoplasty (P < .0001). Outpatient vertebroplasty costs were $3319 versus $8100 for kyphoplasty (P < .0001). Lower vertebroplasty costs were largely due to differences in hospital supply and OR. Mean vertebroplasty OR costs were $73.60 (anesthesia), $112.06 (recovery room), and $990.12 (surgery) versus $172.16 (anesthesia), $257.47 (recovery room), and $1,471.49 (surgery) with kyphoplasty. Adjustments for age, sex, admission status, and disease severity accentuated the differences. Mean adjusted inpatient costs were $11 386 for vertebroplasty versus $16 182 for kyphoplasty (P < .0001), and outpatient costs were $2997 for vertebroplasty versus $7010 for kyphoplasty (P < .0001). After adjustments for the same covariates, length-of-stay differences were no longer evident (P = .4945). CONCLUSIONS: Performing vertebroplasty versus kyphoplasty reduces hospital costs by nearly $5000 for inpatient procedures and by more than $4000 for outpatient procedures. PMID- 21546461 TI - Turn-back embolization technique for effective transvenous embolization of dural arteriovenous fistulas. AB - For effective transvenous embolization of DAVFs, it is important to place coils at the shunting venous pouch in the initial step of the procedure. When it was difficult to navigate a microcatheter to the shunting venous pouch due to the anatomic relationship of approach routes with targeted pouches, we navigated the microcatheters by a "turn-back technique" within the involved sinuses into the target pouches. Complete occlusion or regression of the DAVF was obtained in all cases. PMID- 21546462 TI - Immunoglobulin G4-related sclerosing disease mimicking invasive tumor in the nasal cavity and paranasal sinuses. AB - IgG4RSD affecting the nasal cavity and paranasal sinuses is extremely rare. A 71 year-old man presented with an invasive mass in the nasal cavity and paranasal sinuses that was confirmed by immunostaining to be IgG4RSD. The occurrence of this disease in the nasal cavity and paranasal sinuses can resemble a malignant tumor on diagnostic imaging. PMID- 21546463 TI - Cerebral microbleeds on MR imaging: comparison between 1.5 and 7T. AB - BACKGROUND AND PURPOSE: The detection of microbleeds differs strongly between studies, due to differences in scan protocol. This study aims to compare the visualization of microbleeds with 3D T2*-weighted imaging at 1.5T with 3D dual echo T2*-weighted imaging at 7T. MATERIALS AND METHODS: Thirty-four patients (29 male; mean age, 58 +/- 12 years) with atherosclerotic disease from the Second Manifestations of ARTerial Disease study were included. 3D T2*-weighted imaging at 1.5T and dual-echo T2*-weighted imaging at 7T were done in all patients. The presence and number of definite microbleeds were recorded on minimal intensity projections. Inter- and intraobserver reliability was assessed with Cohen kappa test and the ICC. The difference in presence and number of microbleeds was tested with the McNemar test and Wilcoxon signed rank test. RESULTS: The interobserver ICC at 7T was 0.61 and the intraobserver ICC was 0.94, whereas at 1.5T the interobserver ICC was 0.50 and the intraobserver ICC was 0.59. Microbleeds were detected in significantly more patients on 7T (50%) than on 1.5T scans (21%) (P = .001). The number of microbleeds was also higher at 7T (median, 0.5; range, 0-5) than on 1.5T (median, 0.0; range, 0-6) (P = .002). CONCLUSIONS: 3D dual-echo T2* weighted imaging at 7T results in better and more reliable detection of microbleeds compared with 3D T2*-weighted imaging at 1.5T. PMID- 21546464 TI - Stent-assisted coiling in acutely ruptured intracranial aneurysms: a qualitative, systematic review of the literature. AB - BACKGROUND AND PURPOSE: The use of stents for treatment of morphologically unfavorable, acutely ruptured aneurysms is avoided by most operators because of concerns about the risk of using dual antiplatelet therapy in the setting of acute SAH. Our aim was to review the literature regarding stent-assisted coil embolization of acutely ruptured intracranial aneurysms to determine the safety and efficacy of this treatment option. MATERIALS AND METHODS: Articles including >=5 patients with ruptured aneurysms who were treated acutely with stent-assisted coiling or uncovered stent placement alone were identified. Data on clinical presentation, technical success, surgical crossover, intracranial complications, and clinical outcome were evaluated. RESULTS: A total of 17 articles were identified reporting 339 patients who met inclusion criteria. Among 212 patients with available data, technical success was noted in 198 (93%) patients. Three hundred twenty-six (96%) of 339 patients received both heparin during the procedure and dual-antiplatelet therapy during or immediately postprocedure. One hundred thirty (63%) of 207 aneurysms were completely occluded. Six (2%) of 339 patients required surgical crossover, usually for failure in stent placement or for intraprocedural aneurysm rupture. Clinically significant intracranial hemorrhagic complications occurred in 27 (8%) of 339 patients, including 9 (10%) of 90 patients known to have EVDs who had ventricular drain-related hemorrhages. Clinically significant thromboembolic events occurred in 16 (6%) of 288 patients. Sixty-seven percent of patients had favorable clinical outcomes, 14% had poor outcomes, and 19% died. CONCLUSIONS: Stent-assisted coiling in ruptured aneurysms can be performed with high degrees of technical success, but adverse events appear more common and clinical outcomes are likely worse than those achieved without stent assistance. Thromboembolic complications appear reasonably well controlled. Reported EVD-related hemorrhagic complications were uncommon, though the total number of EVDs placed was unknown. PMID- 21546465 TI - Blazing a trail in T-cell recognition. PMID- 21546466 TI - HCL: insights into biology. PMID- 21546467 TI - Knocking out the PCFT. PMID- 21546468 TI - Erythropoiesis: early, not primitive. PMID- 21546469 TI - Platelet activation by heparin. PMID- 21546470 TI - Elevated fibrinogen causes thrombosis. PMID- 21546471 TI - Understanding reasons for delay in seeking acute stroke care in an underserved urban population. AB - BACKGROUND AND PURPOSE: Few patients arrive early enough at hospitals to be eligible for emergent stroke treatment. There may be barriers specific to underserved, urban populations that need to be identified before effective educational interventions to reduce delay times can be developed. METHODS: A survey of respondents' likely action in a hypothetical stroke situation was given to 253 community volunteers in the catchment areas of a large urban community hospital. Concurrently, 100 structured interviews were conducted in the same hospital with patients with acute stroke or a proxy. RESULTS: In this predominantly urban, black population, if faced with a hypothetical stroke, 89% of community volunteers surveyed said they would call 911 first, and few felt any of the suggested potential barriers applied to them. However, only 12% of patients with stroke interviewed actually called 911 first (OR, 63.9; 95% CI, 29.5 to 138.2). Instead, 75% called a relative/friend. Eighty-nine percent of patients with stroke reported significant delay in seeking medical attention, and almost half said the reason for the delay was thinking the symptoms were not serious and/or they would self-resolve. For those arriving by ambulance, only 25% did so because they thought it would be faster, whereas 35% cited having no other transportation options. CONCLUSIONS: In this predominantly black urban population, although 89% of community volunteers report the intent of calling 911 during a stroke, only 12% of actual patients with stroke did so. Further research is needed to determine and conquer the barriers between behavioral intent and actual behavior to call 911 for witnessed stroke. PMID- 21546472 TI - Trigger factors and their attributable risk for rupture of intracranial aneurysms: a case-crossover study. AB - BACKGROUND AND PURPOSE: Little is known about activities that trigger rupture of an intracranial aneurysm. Knowledge on what triggers aneurysmal rupture increases insight into the pathophysiology and facilitates development of prevention strategies. We therefore aimed to identify and quantify trigger factors for aneurysmal rupture and to gain insight into the pathophysiology. METHODS: During a 3-year period, 250 patients with aneurysmal subarachnoid hemorrhage completed a structured questionnaire regarding exposure to 30 potential trigger factors in the period soon before subarachnoid hemorrhage (hazard period) and for usual frequency and intensity of exposure. We assessed relative risks (RR) of rupture after exposure to triggers with the case-crossover design comparing exposure in the hazard period with the usual frequency of exposure. Additionally, we calculated population-attributable risks. RESULTS: Eight triggers increased the risk for subarachnoid hemorrhage: coffee consumption (RR, 1.7; 95% CI, 1.2-2.4), cola consumption (RR, 3.4; 95% CI,1.5-7.9), anger (RR, 6.3; 95% CI, 4.6-25), startling (RR, 23.3; 95% CI, 4.2-128), straining for defecation (RR, 7.3; 95% CI, 2.9-19), sexual intercourse (RR, 11.2; 95% CI, 5.3-24), nose blowing (RR, 2.4; 95% CI, 1.3-4.5), and vigorous physical exercise (RR, 2.4; 95% CI, 1.2-4.2). The highest population-attributable risks were found for coffee consumption (10.6%) and vigorous physical exercise (7.9%). CONCLUSIONS: We identified and quantified 8 trigger factors for aneurysmal rupture. All triggers induce a sudden and short increase in blood pressure, which seems a possible common cause for aneurysmal rupture. Some triggers are modifiable, and further studies should assess whether reduction of exposure to these factors or measures preventing sudden increase in blood pressure decrease the risk of rupture in patients known to have an intracranial aneurysm. PMID- 21546473 TI - Letter by Doehner et al regarding article, "Association between obesity and mortality after acute first-ever stroke: the obesity-stroke paradox". PMID- 21546474 TI - Letter by Borja and Garcia-Rafanell regarding article, "Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association". PMID- 21546475 TI - Dose effect of intraventricular fibrinolysis in ventricular hemorrhage. AB - BACKGROUND AND PURPOSE: The aim of the current study was to investigate the dose dependent efficacy of intraventricular fibrinolysis (IVF) in patients with severe intraventricular hemorrhage (IVH). METHODS: Patients with intracerebral hemorrhage, severe IVH, and obstructive hydrocephalus with the need for external ventricular drainage were treated with IVF through external ventricular drainage. The time course of IVH resolution and the safety profile were compared between patients treated with high-dose IVF (4 mg alteplase every 12 hours, maximum 20 mg; n=32) and low-dose IVF (1 mg alteplase every 8 hours, maximum 12 mg; n=22). CT scans on Days 1 to 4, 7 +/- 1 and 10 +/- 1 after admission, were analyzed volumetrically. Outcome was assessed after 3 months. RESULTS: The overall effect of IVF dosage was not significantly different between the 2 groups (F=1.3, P=0.25). The course of IVH volume in the third and fourth ventricles was similar with high- and low-dose IVF. High-dose IVF resulted in lower total IVH volumes on Days 7 (4.4 +/- 4.2 mL versus 8.8 +/- 8.1 mL; P=0.01) and 10 (1.4 +/- 2.8 mL versus 4.9 +/- 65.8 mL; P=0.005). Total clot half-life was 78 +/- 43 hours in the low-dose and 56 +/- 25 hours in the high-dose group (P=0.02). One asymptomatic ventricular bleeding, 2 cases of ventriculitis, and 1 death due to pulmonary embolism occurred in the high-dose group. There was no difference in outcome at 3 months. CONCLUSIONS: Low-dose IVF (3 mg alteplase/day) has a similar effect on IVH clearance from the third and fourth ventricles and a similar safety profile when compared with high-dose IVF (8 mg alteplase/day). PMID- 21546476 TI - Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study. AB - BACKGROUND AND PURPOSE: Little is known about the acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with the short-term risk of stroke. METHODS: The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days before an incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years before stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by conditional logistic regression. Confirmatory analyses assessed hazard ratios of stroke from Cox regression models, with hospitalization for infection as a time-varying exposure. RESULTS: During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without a baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days before stroke, OR=3.4 (95% CI, 1.8 to 6.5). The point estimates of risks were higher when we examined shorter intervals: for 30 days, OR=7.3 (95% CI, 1.9 to 40.9), and for 14 days, OR=8.0 (95% CI, 1.7 to 77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted hazard ratio=2.4 (95% CI, 1.6 to 3.4). CONCLUSIONS: Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke. PMID- 21546477 TI - Associations of edge-detected and manual-traced common carotid intima-media thickness measurements with Framingham risk factors: the multi-ethnic study of atherosclerosis. AB - BACKGROUND AND PURPOSE: Carotid intima-media thickness (IMT) is a marker of cardiovascular disease derived from ultrasound images of the carotid artery. In most outcome studies, human readers identify and trace the key IMT interfaces. We evaluate an alternate approach using automated edge detection. METHODS: We studied a subset of 5640 participants with an average age 61.7 years (48% men) of the Multi-Ethnic Study of Atherosclerosis composed of whites, Chinese, Hispanic, and blacks that are part of the Multi-Ethnic Study of Atherosclerosis IMT progression study. Manual tracing IMT (mt-IMT) and edge-detected IMT (ed-IMT) measurements of the far wall of the common carotid artery served as outcome variables for multivariable linear regression models using Framingham cardiovascular risk factors and ethnicity as independent predictors. RESULTS: Measurements of mt-IMT were obtainable in 99.9% (5633/5640) and measurements of ed-IMT were obtainable in 98.9% (5579/5640) of individuals. Average ed-IMT was 0.19 mm larger than mt-IMT. Inter-reader systematic differences (bias) in IMT measurements were apparent for mt-IMT but not ed-IMT. Based on complete data for 5538 individuals, associations of IMT with risk factors were stronger (P<0.0001) for mt-IMT (model r2, 19.5%) than for ed-IMT (model r2, 18.5%). CONCLUSIONS: We conclude that this edge-detection process generates IMT values equivalent to manually traced ones because it preserves key associations with cardiovascular risk factors. It also decreases inter-reader bias, potentially making it applicable for use in cardiovascular risk assessment. PMID- 21546478 TI - Anticoagulation in patients with stroke with infective endocarditis is safe. PMID- 21546479 TI - Anticoagulation in patients with stroke with infective endocarditis: the sword of Damocles. PMID- 21546480 TI - Ischemic stroke during sleep: its association with worse early functional outcome. AB - BACKGROUND AND PURPOSE: Approximately one fourth of stroke occur during sleep. Despite the clinical and radiological similarities between wake-up stroke (WUS) and non-WUS, the functional outcomes of WUS are largely unknown. METHODS: This retrospective analysis reviewed 2289 consecutive patients with acute ischemic stroke who were admitted between November 2002 and December 2009. We used 3 end point analytic techniques to evaluate the association between WUS and functional outcomes: dichotomized analysis for "functional dependency" (a discharge modified Rankin Scale [mRS] score >=2 regardless of initial stroke severity), severity adjusted responder analysis for "unfavorable outcome" (a discharge mRS >=1 for an admission National Institutes of Health Stroke Scale score 0 to 7; mRS >=2 for National Institutes of Health Stroke Scale 8 to 14; or mRS >=3 for National Institutes of Health Stroke Scale >=15), and shift analysis for changes in overall distributions of discharge mRS scores. RESULTS: The initial National Institutes of Health Stroke Scale score of patients with WUS was significantly higher than that of their non-WUS counterparts (median [interquartile range]; 4 [2 to 7] versus 3 [1 to 6]; P<0.01). The dichotomized analysis strategy failed to detect a significant association between WUS and functional dependency at discharge (adjusted OR, 0.99; 95% CI, 0.76 to 1.28). However, the responder analysis showed that patients with WUS were more likely to have "unfavorable outcomes" (adjusted OR, 1.33; 95% CI, 1.02 to 1.72), and the shift analysis also detected significant effect of WUS on the mRS score distributions toward increased dependency (adjusted OR, 1.22; 95% CI, 1.01 to 1.48). CONCLUSIONS: From our study, we documented that WUS was associated with worse short-term outcomes after ischemic stroke. Careful selection of appropriate analytic techniques may help to detect modest associations in observational studies. PMID- 21546481 TI - Three-month and long-term outcomes and their predictors in acute basilar artery occlusion treated with intra-arterial thrombolysis. AB - BACKGROUND AND PURPOSE: Intra-arterial thrombolysis can be used for treatment of basilar artery occlusion. Predictors of outcome before initiation of treatment are of special interest. METHODS: From 1992 to 2010, we treated 106 consecutive patients with basilar artery occlusion with intra-arterial thrombolysis. Baseline characteristics, treatment, clinical course, and 3-month and long-term outcomes (>=12 months) were assessed. Outcome parameters were vessel recanalization after treatment, complications, modified Rankin scale (mRS) score, and mortality after 3 months and in the long-term. RESULTS: At 3 months, clinical outcome was good (mRS score, 0-2) in 33.0% of the patients and moderate (mRS score, 3) in 11.3%. Mortality was 40.6%. Partial or complete recanalization was achieved in 69.8% of the patients, and symptomatic intracranial hemorrhage occurred in 1 patient (0.9%). Between 3-month and long-term follow-up, 22 survivors (40.8%) showed clinical improvement of at least 1 point on the mRS score, 29 (53.7%) were functionally unchanged, and 3 (5.7%) showed functional worsening (P<0.0001). Multivariate analysis identified diabetes as a predictor of poor vessel recanalization (P=0.028). Low baseline National Institutes of Health Stroke Scale score was identified as a predictor of good or moderate clinical outcome (P<0.0001) and survival (P=0.001) at 3 months, and younger age was identified as an additional predictor of survival (P=0.012). For prediction of long-term clinical outcome, age was also an independent predictor (P=0.018). CONCLUSIONS: In our series, intra-arterial thrombolysis as treatment of basilar artery occlusion was safe. National Institutes of Health Stroke Scale score at admission and age were identified as predictors of outcome, and these predictors should be considered for treatment allocation in future randomized trials. PMID- 21546482 TI - Beta 2 microglobulin and the risk for cardiovascular events in patients with asymptomatic carotid atherosclerosis. AB - BACKGROUND AND PURPOSE: Atherosclerosis is a chronic inflammatory disease. Ongoing inflammation is associated with elevated levels of beta 2 microglobulin (B2M). We investigated B2M levels in a large cohort of patients with carotid atherosclerosis for the occurrence of major adverse cardiovascular events. METHODS: One thousand five of 1286 consecutive, neurologically asymptomatic patients with carotid atherosclerosis were followed for a median of 3 years (interquartile range, 2.5 to 3.5) for the occurrence of major adverse cardiovascular events, a composite of myocardial infarction, percutaneous coronary intervention, coronary bypass graft, stroke, and death. RESULTS: We recorded 359 major cardiovascular events in 271 (27%) patients. B2M was significantly associated with the occurrence of major adverse cardiovascular events. With increasing quartiles of B2M, the adjusted hazard ratios were 1.19 (95% CI, 0.81 to 1.73), 1.51 (95% CI, 1.05 to 2.18), and 1.88 (95% CI, 1.26 to 2.79) compared with the lowest quartile, respectively (P<0.001). Adjusted hazard ratios for the occurrence of death, myocardial infarction, and stroke for increasing quartiles of B2M were 1.25 (95% CI, 0.92 to 1.70), 1.52 (95% CI, 1.12 to 2.06), and 1.62 (95% CI, 1.16 to 2.67) compared with the lowest quartile, respectively (P<0.001). Through statistical estimation of improvement in risk stratification, addition of B2M to baseline risk factors improved the risk stratification for major cardiovascular events, at least as much as high sensitivity C-reactive protein or even better. CONCLUSIONS: B2M was independently and significantly associated with adverse cardiovascular outcome in patients with prevalent asymptomatic carotid atherosclerosis. PMID- 21546483 TI - Wisdom and determination in the ongoing pursuit of the ever-elusive neuroprotective agent. PMID- 21546484 TI - Letter by Paraskevas et al regarding article, "Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/american Stroke Association". PMID- 21546485 TI - Anticoagulation should not be used in most patients with stroke with infective endocarditis. PMID- 21546486 TI - Resistin, but not adiponectin and leptin, is associated with the risk of ischemic stroke among postmenopausal women: results from the Women's Health Initiative. AB - BACKGROUND AND PURPOSE: Adipose tissue is considered an endocrine organ that secretes adipokines, which possibly mediate the effects of obesity on the risk of cardiovascular disease. However, there are yet limited prospective data on the association between circulating adipokine levels and the risk of ischemic stroke. We aimed to examine the associations of 3 adipokines (adiponectin, leptin, and resistin) with the risk of ischemic stroke. METHODS: We conducted a prospective nested case-control study (972 stroke cases and 972 matched control subjects) within the Women's Health Initiative Observational Study cohort. The control subjects were matched to cases on age, race/ethnicity, date of study enrollment, and follow-up time. RESULTS: Adipokine levels were associated with established stroke risk factors such as obesity and systolic blood pressure. Adjusted for body mass index, the ORs for incident ischemic stroke comparing the highest (Quartile 4) with the lowest quartile (Quartile 1) were 0.81 (95% CI, 0.61 to 1.08; P trend=0.068) for adiponectin, 1.15 (95% CI, 0.83 to 1.59; P trend=0.523) for leptin, and 1.57 (95% CI, 1.18 to 2.08; P trend=0.002) for resistin. The association for resistin remained significant even after accounting for established stroke risk factors (OR, 1.39; 95% CI, 1.01 to 1.90; P trend=0.036). Further adjustment for markers for inflammation, angiogenesis, and endothelial function also did not affect our results. CONCLUSIONS: Circulating levels of resistin, but not those of adiponectin or leptin, are associated with an increased risk of incident ischemic stroke in postmenopausal women, independent of obesity and other cardiovascular disease risk factors. PMID- 21546487 TI - Phosphatidylinositol-3-kinase gamma plays a central role in blood-brain barrier dysfunction in acute experimental stroke. AB - BACKGROUND AND PURPOSE: Phosphoinositide 3-kinase (PI3K)-gamma is linked to inflammation and oxidative stress. This study was conducted to investigate the role of the PI3Kgamma in the blood-brain barrier dysfunction and brain damage induced by focal cerebral ischemia/reperfusion. METHODS: Wild-type and PI3Kgamma knockout mice were subjected to middle cerebral artery occlusion (60 minutes) followed by reperfusion. Evans blue leakage, brain edema, infarct volumes, and neurological deficits were examined. Oxidative stress, neutrophil infiltration, and matrix metallopeptidase-9 were assessed. Activation of nuclear factor-kappaB and expression of proinflammatory and pro-oxidative genes were studied. RESULTS: PI3Kgamma deficiency significantly reduced blood-brain barrier permeability and brain edema formation, which were time-dependently correlated with preventing the degradation of the tight junction protein, claudin-5, and the basal lamina protein, collagen IV, and the phosphorylation of myosin light chain in brain microvessels. PI3Kgamma deficiency suppressed ischemia/reperfusion-induced nuclear factor-kappaB p65 (Ser536) phosphorylation and the expression of the pro oxidant enzyme NADPH oxidase (Nox1, Nox2, and Nox4) and proinflammatory adhesion molecules (E- and P-selectin, intercellular adhesion molecule-1) at different time points. These molecular changes were associated with significant inhibition of oxidative stress (superoxide production and malondialdehyde content), neutrophil infiltration, and matrix metallopeptidase-9 expression/activity in PI3Kgamma knockout mice. Eventually, PI3Kgamma deficiency significantly reduced infarct volumes and neurological scores at 24 hours after ischemia/reperfusion. CONCLUSIONS: Our results provide the first direct demonstration that PI3Kgamma plays a significant role in ischemia/reperfusion-induced blood-brain barrier disruption and brain damage. Future studies need to explore PI3Kgamma as a potential target for stroke therapy. PMID- 21546488 TI - Using administrative databases to calculate Framingham scores within a large health care organization. AB - BACKGROUND AND PURPOSE: Framingham calculators are typically implemented in 1-on 1 settings to determine if a patient is at high risk for development of cardiovascular disease in the next 10 years. Because health care administrative datasets are including more clinical information, we explored how well administrative data-derived Framingham scores could identify persons who would have stroke develop in the next year. METHODS: Using a nested case-control design, we compared all 313 persons who had a first-time stroke at 5 Veterans Administration Medical Centers with a random sample of 25,361 persons who did not have a first-time stroke in 2008. We compared Framingham scores and risk using administrative data available at the end of 2007. RESULTS: Stroke patients had higher risk profile than controls: older age, higher systolic blood pressure and total cholesterol, more likely to have diabetes, cardiovascular disease, left ventricular hypertrophy, and more likely to use treatment for blood pressure (P<0.05). The mean Framingham generalized cardiovascular disease score (18.0 versus 14.5) as well as the mean Framingham stroke-specific score (13.2 versus 10.2) was higher for stroke cases than controls (both P<0.0001). The c-statistic for the generalized cardiovascular disease score was 0.68 (95% CI, 0.65-0.70) and for the stroke score was 0.64 (95% CI, 0.62-0.67). CONCLUSIONS: Persons who had a stroke develop in the next year had a worse Framingham risk profile, as determined by administrative data. Future studies should examine how to improve the stroke predictive tools and to identify the appropriate populations and uses for applying stroke risk predictive tools. PMID- 21546489 TI - Letter by Naylor regarding article, "Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association". PMID- 21546490 TI - CT cerebral blood flow maps optimally correlate with admission diffusion-weighted imaging in acute stroke but thresholds vary by postprocessing platform. AB - BACKGROUND AND PURPOSE: Admission infarct core lesion size is an important determinant of management and outcome in acute (<9 hours) stroke. Our purposes were to: (1) determine the optimal CT perfusion parameter to define infarct core using various postprocessing platforms; and (2) establish the degree of variability in threshold values between these different platforms. METHODS: We evaluated 48 consecutive cases with vessel occlusion and admission CT perfusion and diffusion-weighted imaging within 3 hours of each other. CT perfusion was acquired with a "second-generation" 66-second biphasic cine protocol and postprocessed using "standard" (from 2 vendors, "A-std" and "B-std") and "delay corrected" (from 1 vendor, "A-dc") commercial software. Receiver operating characteristic curve analysis was performed comparing each CT perfusion parameter both absolute and normalized to the contralateral uninvolved hemisphere-between infarcted and noninfarcted regions as defined by coregistered diffusion-weighted imaging. RESULTS: Cerebral blood flow had the highest accuracy (receiver operating characteristic area under the curve) for all 3 platforms (P<0.01). The maximal areas under the curve for each parameter were: absolute cerebral blood flow 0.88, cerebral blood volume 0.81, and mean transit time 0.82 and relative Cerebral blood flow 0.88, cerebral blood volume 0.83, and mean transit time 0.82. Optimal receiver operating characteristic operating point thresholds varied significantly between different platforms (Friedman test, P<0.01). CONCLUSIONS: Admission absolute and normalized "second-generation" cine acquired CT cerebral blood flow lesion volumes correlate more closely with diffusion-weighted imaging defined infarct core than do those of CT cerebral blood volume or mean transit time. Although limited availability of diffusion-weighted imaging for some patients creates impetus to develop alternative methods of estimating core, the marked variability in quantification among different postprocessing software limits generalizability of parameter map thresholds between platforms. PMID- 21546491 TI - The Albumin in Acute Stroke Part 1 Trial: an exploratory efficacy analysis. AB - BACKGROUND AND PURPOSE: The Albumin in Acute Stroke (ALIAS) Part 2 Trial is directly testing whether 2 g/kg of 25% human albumin (ALB) administered intravenously within 5 hours of ischemic stroke onset results in improved clinical outcome. Recruitment into Part 1 of the ALIAS Trial was halted for safety reasons. ALIAS Part 2 is a new, reformulated trial with more-stringent exclusion criteria. Our aim was to explore the efficacy of ALB in the ALIAS Part 1 data and to assess the statistical assumptions underlying the ALIAS Part 2 Trial. METHODS: ALIAS is a multicenter, blinded, randomized controlled trial. Data on 434 subjects, comprising the ALIAS Part 1 subjects, were analyzed. We examined both the thrombolysis and nonthrombolysis cohorts combined and separately in a "target population" by excluding subjects who would not have been eligible for the ALIAS Part 2 Trial; the latter comprised patients >83 years of age, those with elevated baseline troponin values, and those with in-hospital stroke. We examined the differences in the primary composite outcome, defined as a modified Rankin Scale score of 0 to 1 and/or a National Institutes of Health Stroke Scale score of 0 to 1 at 90 days after randomization. RESULTS: In the combined thrombolysis plus nonthrombolysis cohorts of the target population, 44.7% of subjects in the ALB group had a favorable outcome compared with 36.0% in the saline group (absolute effect size=8.7%; 95% CI, -2.2% to 19.5%). Among thrombolyzed subjects of the target population, 46.7% had a favorable outcome in the ALB group compared with 36.6% in the saline group (absolute effect size=10.1%; 95% CI, -2.0% to 20.0%). CONCLUSIONS: Preliminary results from the ALIAS Part 1 suggest a trend toward a favorable primary outcome in subjects treated with ALB and support the validity of the statistical assumptions that underlie the ALIAS Part 2 Trial. The ALIAS Part 2 Trial will confirm or refute these results. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov/ALIAS. Unique identifier: NCT00235495. PMID- 21546492 TI - Phenotypic and functional evaluation of CD3+CD4-CD8- T cells in human CD8 immunodeficiency. AB - BACKGROUND: Human CD8 immunodeficiency is characterized by undetectable CD8(+) lymphocytes and an increased population of CD4(-)CD8(-) (double negative) T lymphocytes. DESIGN AND METHODS: We hypothesized that the double negative subset corresponds to the cellular population that should express CD8 and is committed to the cytotoxic T lymphocyte lineage. To assess this, we determined the phenotype and function of peripheral blood mononuclear cells and/or magnetically isolated double negative T lymphocytes from two CD8-deficient patients. To analyze the expression and co-localization with different organelles, 293T cells were transfected with plasmids bearing wild-type or mutated CD8alpha. RESULTS: CD8alpha mutated protein was retained in the cytoplasm of transfected cells. The percentages of double negative cells in patients were lower than the percentages of CD8(+) T cells in healthy controls. Double negative cells mostly had an effector or effector memory phenotype whereas naive T cells were under represented. A low concentration of T-cell receptor excision circles together with a skewed T-cell receptor-V repertoire were observed in the double negative population. These data suggest that, in the absence of CD8 co-receptor, the thymic positive selection functions suboptimally and a limited number of mature T cell clones would emerge from the thymus. In vitro, the double negative cells showed a mild defect in cytotoxic function and decreased proliferative capacity. CONCLUSIONS: It is possible that the double negative cells are major histocompatibility complex class-I restricted T cells with cytolytic function. These results show for the first time in humans that the presence of the CD8 co receptor is dispensable for cytotoxic ability, but that it affects the generation of thymic precursors committed to the cytotoxic T lymphocyte lineage and the proliferation of mature cytotoxic T cells. PMID- 21546493 TI - The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study. AB - Chronic graft-versus-host disease is the major long-term complication after allogeneic stem cell transplantation with a suboptimal response rate to current treatments. Therefore, clinical efficacy and changes in lymphocyte subsets before and after rituximab treatment were evaluated in a prospective phase II study in patients with steroid-refractory chronic graft-versus-host disease. Overall response rate was 61%. Only responding patients were found to have increased B cell numbers prior to treatment. B cells had a naive-antigen-presenting phenotype and were mainly CD5 negative or had a low CD5 expression. Normal B-cell homeostasis was reestablished in responding patients one year after ritxumab treatment and associated with a significant decline in skin-infiltrating CD8(+) T cells, suggesting that host B cells play a role in maintaining pathological CD8(+) T-cell responses. Imbalances in B-cell homeostasis could be used to identify patients a priori with a higher chance of response to rituximab treatment (Eudra-CT 2008-004125-42). PMID- 21546494 TI - Rapid diagnosis of chronic myeloid leukemia by flow cytometric detection of BCR ABL1 protein. PMID- 21546495 TI - Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients. AB - During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01-1.04; P=0.002) and lymphopenia (OR 2.49; 1.33-4.67; P<0.001). Thirty three patients (11.5%) required mechanical ventilation. Eighteen patients (6.3%) died from A/H1N1 infection or its complications. Neutropenia (P=0.03) and patient age (P=0.04) were significant risk factors for death. The 2009 A/H1N1 influenza pandemic caused severe complications in stem cell transplant recipients. PMID- 21546496 TI - Novel loci involved in platelet function and platelet count identified by a genome-wide study performed in children. AB - BACKGROUND: Genome-wide association studies are currently identifying new loci with potential roles in thrombosis and hemostasis: these loci include novel polymorphisms associated with platelet function traits and count. However, no genome-wide study performed on children has been reported to date, in spite of the potential that these subjects have in genetic studies, when compared to adults, given the minimal degree of confounders, i.e., acquired and environmental factors, such as smoking, physical activity, diet, and drug or hormone intake, which are particularly important in platelet function. DESIGN AND METHODS: To identify new genetic variants involved in platelet reactivity and count, we performed a genome-wide association study on 75 children (8.5+/-1.8 years) using the Illumina Sentrix Human CNV370-Quad BeadChip containing 320,610 single nucleotide polymorphisms. Functional analyses included assessment of platelet aggregation and granule secretion triggered by different agonists (arachidonic acid, collagen, epinephrine, ADP), as well as platelet count. Associations were selected based on statistical significance and physiological relevance for a subsequent replication study in a similar sample of 286 children. RESULTS: We confirmed previously established associations with plasma levels of factors XII, VII and VIII as well as associations with platelet responses to ADP. Additionally, we identified 82 associations with platelet reactivity and count with a P value less than 10(-5). From the associations selected for further replication, we validated two single nucleotide polymorphisms with mildly increased platelet reactivity (rs4366150 and rs1787566) on the LPAR1 and MYO5B genes, encoding lisophosphatidic acid receptor-1 and myosin VB, respectively; and rs1937970, located on the NRG3 gene coding neuroregulin-3, associated with platelet count. CONCLUSIONS: Our genome-wide association study performed in children, followed by a validation analysis, led us to the identification of new genes potentially relevant in platelet function and biogenesis. PMID- 21546497 TI - An overview of the progress on double umbilical cord blood transplantation. AB - Umbilical cord blood transplantation has been increasingly used over the past years for both malignant and non-malignant hematologic and other diseases as an alternative to mismatched-related or matched-unrelated bone marrow or peripheral blood hematopoietic stem cell transplantation. A disadvantage of cord blood is its low cell content which limits cord blood transplantation to generally low weight recipients, such as children. Various alternatives have been used to overcome this limitation, including co-infusion of two partially HLA-matched cord blood units. According to Eurocord Registry data, this strategy has been applied in approximately 993 adult patients with hematologic diseases since the first double umbilical cord blood transplantation in 1999. In fact, since 2005, the number of adult patients receiving double umbilical cord blood transplantation has surpassed the number of adults transplanted with single cord blood units. The engraftment rate is comparable for both single and double umbilical cord blood transplantation, although the latter is accompanied by a higher incidence of grade II acute graft-versus-host disease and lower leukemia relapse for patients in first complete remission. In the majority of patients undergoing double umbilical cord blood transplantation, transient chimerism, due to the presence of cells from both donor units early post transplant, is replaced by sustained dominance of one unit from which long-term hematopoiesis is derived. Although the biology and the factors that determine unit dominance have not been clarified, the implication of immune-mediated mechanisms has been reported. Preliminary data have demonstrated the safety of double umbilical cord blood transplantation. Ongoing clinical trials and prolonged follow up of the patients will clarify the immunology and determine the efficacy of this approach. We present here a brief overview of the clinical experience on double umbilical cord blood transplantation and its underlying biology. PMID- 21546498 TI - Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia. AB - BACKGROUND: High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution. DESIGN AND METHODS: We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years. RESULTS: At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV. CONCLUSIONS: Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations. PMID- 21546499 TI - Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA. AB - BACKGROUND: As rituximab combined with CHOP improves complete remission and overall survival in diffuse large B-cell lymphoma, intensified chemotherapy followed by autologous stem-cell transplantation has also been advocated for high risk patients. The aim of this study was to establish whether or not combining rituximab with high-dose chemotherapy and auto-transplantation also benefits patient survival. DESIGN AND METHODS: The LNH2003-3 study was a phase II trial including diffuse large B-cell lymphoma patients with 2 or 3 International Prognostic Index factors. They received four cycles of intensive biweekly chemotherapy with rituximab, doxorubicine, cyclophosphamide, vindesine, bleomycine, prednisolone (R-ACVBP) followed by auto-transplantation in responding patients. Two hundred and nine patients under 60 years of age were included in the study and 155 responding patients underwent auto-transplantation. In addition, a case-control study was performed by matching (1:1) 181 patients treated with R-ACVBP with ACVBP patients not given rituximab but submitted to auto-transplantation from the previous LNH1998-3 trial. RESULTS: With a median follow up of 45 months, 4-year progression-free survival and overall survival were estimated at 76% (CI: 69-81) and 78% (CI: 72-83), respectively. There was no difference between patients with 2 or 3 International Prognostic Index factors. Four year progression-free survival was significantly higher in R-ACVBP than ACVBP patients (74% vs. 58%; P=0.0005). There was also a significant increase in 4-year overall survival (76% vs. 68%; P=0.0494). CONCLUSIONS: In high-risk diffuse large B-cell lymphoma patients, treatment with R-ACVBP followed by auto transplantation results in a 78% 4-year overall survival which should be compared to other approaches. PMID- 21546500 TI - Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission. AB - BACKGROUND: In trials designed to evaluate new therapies for hematologic malignancies, end points such as leukemia-free survival are often used as surrogates for overall survival in acute leukemia. We aimed to assess whether leukemia-free survival is an acceptable statistical surrogate for overall survival when applied to remission maintenance therapy for acute myeloid leukemia. DESIGN AND METHODS: Data were analyzed from a randomized Phase III trial of remission maintenance immunotherapy with histamine dihydrochloride plus low-dose interleukin-2 versus no treatment in adults with acute myeloid leukemia. A two-stage surrogate validation model was applied in which correlations between Kaplan-Meier estimates of leukemia-free survival and overall survival, and between log hazard ratios reflecting treatment effects were analyzed. Country of patient enrollment was the unit of analysis. RESULTS: Kaplan-Meier estimates of overall survival at 36, 48, and 60 months and leukemia-free survival at 24 months were reasonably correlated (R(2) ranging from 0.44 to 0.84) both for the overall (n=320) and first complete remission (n=261) populations. The effects of histamine dihydrochloride/interleukin-2 on log hazard ratios for leukemia-free survival and overall survival were well correlated (R(2)=0.88-0.93). CONCLUSIONS: The significant correlations between overall survival and the surrogate end point (leukemia-free survival) and between the effect of histamine dihydrochloride/interleukin-2 on leukemia-free survival and overall survival satisfy the two-stage surrogate validation model. PMID- 21546501 TI - Successful generation of primary virus-specific and anti-tumor T-cell responses from the naive donor T-cell repertoire is determined by the balance between antigen-specific precursor T cells and regulatory T cells. AB - BACKGROUND: One of the major challenges in allogeneic stem cell transplantation is to find a balance between the harmful induction of graft-versus-host disease and the beneficial graft-versus-leukemia and pathogen-specific immune responses. Adoptive transfer of in-vitro generated donor T cells with specific anti-leukemic or pathogen-specific activity may be effective. However, in many cases this requires the in-vitro priming and expansion of antigen-specific precursor T cells from the naive donor T-cell repertoire. DESIGN AND METHODS: Antigen-specific CD8 T cells were generated by co-culture of CD45RO-depleted, regulatory T cell depleted donor peripheral blood mononuclear cells with autologous peptide-loaded dendritic cells, followed by two re-stimulations with peptide-loaded autologous monocytes. Responding T cells were isolated based on CD137 expression and further purified using peptide/major histocompatibility complex tetramers. RESULTS: Using this method we were able to reproducibly generate functionally high avidity T cells directed against multiple viral antigens and minor histocompatibility antigens from the naive T-cell repertoire of seronegative, minor histocompatibility antigen-negative donors. Furthermore, we demonstrated that reduction of the regulatory T-cell frequency by depletion of CD45RO(+) responder cells resulted in improved priming and expansion of antigen-specific precursor T cells. CONCLUSIONS: In conclusion, we present a robust method for the in-vitro induction and isolation of antigen-specific T cells from the naive repertoire. We demonstrate that the likelihood of successful generation of primary immune responses is determined by a delicate balance between the numbers of antigen specific precursor T cells and the numbers and activation state of regulatory T cells locally at the site of priming of the immune response. PMID- 21546502 TI - Predictors of osteoclast activity in patients with sickle cell disease. AB - BACKGROUND: Bone changes are common in sickle cell disease, but the pathogenesis is not fully understood. Tartrate-resistant acid phosphatase (TRACP) type 5b is produced by bone-resorbing osteoclasts. In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease. DESIGN AND METHODS: We examined tartrate-resistant acid phosphatase 5b concentrations in patients with sickle cell disease and normal controls of similar age and sex distribution at steady state. Serum tartrate-resistant acid phosphatase 5b concentration was measured using an immunocapture enzyme assay and plasma concentrations of other cytokines were assayed using the Bio-Plex suspension array system. Tricuspid regurgitation velocity, an indirect measure of systolic pulmonary artery pressure, was determined by echocardiography. RESULTS: Tartrate-resistant acid phosphatase 5b concentrations were higher in 58 adults with sickle cell disease than in 22 controls (medians of 4.4 versus 2.4 U/L, respectively; P=0.0001). Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=-0.28, P=0.031) concentrations, but not with serum ferritin concentration. Frequent blood transfusions (>10 units in life time) were not associated with higher tartrate-resistant acid phosphatase 5b levels in multivariate analysis. There were strong correlations among tartrate resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity (r>0.35, P<0.001). CONCLUSIONS: Patients with sickle cell disease have increased osteoclast activity as reflected by serum tartrate-resistant acid phosphatase 5b concentrations. Our results may support a potential role of inflammation rather than increased iron stores in stimulating osteoclast activity in sickle cell disease. The positive relationships among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity raise the possibility of a common pathway in the pulmonary and bone complications of sickle cell disease. PMID- 21546505 TI - Reassessment of small lymphocytic lymphoma in the era of monoclonal B-cell lymphocytosis. AB - BACKGROUND: In the 2008 World Health Organization classification, small lymphocytic lymphoma is defined as a neoplasm with the tissue morphology and immunophenotype of chronic lymphocytic leukemia, but with absence of leukemia. Minimal criteria of tissue involvement to separate small lymphocytic lymphoma from monoclonal B-cell lymphocytosis have not been defined. DESIGN AND METHODS: We reviewed the clinicopathological features of 36 patients with extramedullary tissue biopsies containing chronic lymphocytic leukemia-type cells and less than 5*10(9)/L peripheral blood monoclonal B cells. Pathological features (extent and patterns of involvement, architectural preservation, presence of proliferation centers) as well as cytogenetic and radiological findings were examined in relation to clinical outcome. RESULTS: The biopsies were performed to evaluate lymphadenopathy in 20 patients and for other reasons (most frequently staging of a non-hematologic neoplasm) in 16 patients. At latest follow-up (median 23 months), 21 untreated patients had no or stable lymphadenopathy, 3 had regressed lymphadenopathy, and 12 had developed progressive lymphadenopathy and/or received therapy for chronic lymphocytic leukemia/small lymphocytic lymphoma. Features associated with progression/treatment included lymph nodes 1.5 cm or greater on imaging studies (P=0.01) and presence of proliferation centers in the biopsied tissue (P=0.004). Neither the size nor extent of involvement of the excised lymph node correlated with progression/treatment. CONCLUSIONS: Our findings suggest that biopsies containing chronic lymphocytic leukemia-type cells, but lacking proliferation centers and with non-enlarged or only slightly enlarged lymph nodes on imaging, represent a very indolent disease that may best be considered a tissue equivalent of monoclonal B-cell lymphocytosis rather than overt small lymphocytic lymphoma. We propose that such cases be designated as tissue involvement by chronic lymphocytic leukemia/small lymphocytic lymphoma-like cells of uncertain significance. PMID- 21546504 TI - High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy. AB - BACKGROUND: Diffuse large B-cell lymphoma is a clinically and molecularly heterogeneous disease. Gene expression profiling studies have shown that the tumor microenvironment affects survival and that the angiogenesis-related signature is prognostically unfavorable. The contribution of histopathological microvessel density to survival in diffuse large B-cell lymphomas treated with immunochemotherapy remains unknown. The purpose of this study is to assess the prognostic impact of histopathological microvessel density in two independent series of patients with diffuse large B-cell lymphoma treated with immunochemotherapy. DESIGN AND METHODS: One hundred and forty-seven patients from the Leukemia Lymphoma Molecular Profiling Project (training series) and 118 patients from the Catalan Lymphoma-Study group-GELCAB (validation cohort) were included in the study. Microvessels were immunostained with CD31 and quantified with a computerized image analysis system. The stromal scores previously defined in 110 Leukemia Lymphoma Molecular Profiling Project cases were used to analyze correlations with microvessel density data. RESULTS: Microvessel density significantly correlated with the stromal score (r=0.3209; P<0.001). Patients with high microvessel density showed significantly poorer overall survival than those with low microvessel density both in the training series (4-year OS 54% vs. 78%; P=0.004) and in the validation cohort (57% vs. 81%; P=0.006). In multivariate analysis, in both groups high microvessel density was a statistically significant unfavorable prognostic factor independent of international prognostic index [training series: international prognostic index (relative risk 2.7; P=0.003); microvessel density (relative risk 1.96; P=0.002); validation cohort: international prognostic index (relative risk 4.74; P<0.001); microvessel density (relative risk 2.4; P=0.016)]. CONCLUSIONS: These findings highlight the impact of angiogenesis in the outcome of patients with diffuse large B-cell lymphoma and the interest of evaluating antiangiogenic drugs in clinical trials. PMID- 21546503 TI - White blood cell count, sex and age are major determinants of heterogeneity of platelet indices in an adult general population: results from the MOLI-SANI project. AB - BACKGROUND: The understanding of non-genetic regulation of platelet indices- platelet count, plateletcrit, mean platelet volume, and platelet distribution width--is limited. The association of these platelet indices with a number of biochemical, environmental and clinical variables was studied in a large cohort of the general population. DESIGN AND METHODS: Men and women (n=18,097, 52% women, 56+/-12 years) were randomly recruited from various villages in Molise (Italy) in the framework of the population-based cohort study "Moli-sani". Hemochromocytometric analyses were performed using an automatic analyzer (Beckman Coulter, IL, Milan, Italy). Associations of platelet indices with dependent variables were investigated by multivariable linear regression analysis. RESULTS: Full models including age, sex, body mass index, blood pressure, smoking, menopause, white and red blood cell counts, mean corpuscular volume, D-dimers, C reactive protein, high-density lipoproteins, low-density lipoproteins, triglycerides, glucose, and drug use explained 16%, 21%, 1.9% and 4.7% of platelet count, plateletcrit, mean platelet volume and platelet distribution width variability, respectively; variables that appeared to be most strongly associated were white blood cell count, age, and sex. Platelet count, mean platelet volume and plateletcrit were positively associated with white blood cell count, while platelet distribution width was negatively associated with white blood cell count. Platelet count and plateletcrit were also positively associated with C-reactive protein and D-dimers (P<0.0001). Each of the other variables, although associated with platelet indices in a statistically significant manner, only explained less than 0.5% of their variability. Platelet indices varied across Molise villages, independently of any other platelet count determinant or characteristics of the villages. CONCLUSIONS: The association of platelet indices with white blood cell count, C-reactive protein and D-dimers in a general population underline the relation between platelets and inflammation. PMID- 21546506 TI - Loss of expression of neutrophil proteinase-3: a factor contributing to thrombotic risk in paroxysmal nocturnal hemoglobinuria. AB - BACKGROUND: A deficiency of specific glycosylphosphatidyl inositol-anchored proteins in paroxysmal nocturnal hemoglobinuria may be responsible for most of the clinical features of this disease, but some functional consequences may be indirect. For example, the absence of certain glycosylphosphatidyl inositol anchored proteins in paroxysmal nocturnal hemoglobinuria cells may influence expression of other membrane proteins. Membrane-bound proteinase 3 co-localizes with glycosylphosphatidyl inositol-linked neutrophil antigen 2a, which is absent in patients with paroxysmal nocturnal hemoglobinuria. DESIGN AND METHODS: We compared expression of proteinase 3 and neutrophil antigen 2a by flow cytometry and western blotting in normal and paroxysmal nocturnal hemoglobinuria cells and measured cytoplasmic and soluble levels of proteinase 3 by enzyme-linked immunosorbent assays in controls and patients with paroxysmal nocturnal hemoglobinuria. Finally, we studied the effects of proteinase 3 on platelet activation using an in vitro aggregometry assay and flow cytometry. RESULTS: We showed that membrane-bound proteinase 3 is deficient in patients' cells, but invariantly present in the cytoplasm regardless of disease phenotype. When we isolated lipid rafts from patients, both molecules were detected only in the rafts from normal cells, but not diseased ones. Membrane-bound proteinase 3 was associated with a decrease in plasma proteinase 3 levels, clone size and history of thrombosis. In addition, we found that treating platelets ex vivo with proteinase 3, but not other agonists, decreased the exposure of an epitope on protease activated receptor-1 needed for thrombin activation. Conversely, treatment of whole blood with serine protease inhibitor enhanced expression of this epitope on protease activated receptor-1 located C-terminal to the thrombin cleavage site on platelets. CONCLUSIONS: We demonstrated that deficiency of glycosylphosphatidyl inositol-anchored proteins in paroxysmal nocturnal hemoglobinuria results in decreased membrane-bound and soluble proteinase 3 levels. This phenomenon may constitute another mechanism contributing to a prothrombotic propensity in patients with paroxysmal nocturnal hemoglobinuria. PMID- 21546507 TI - Using information mining of the medical literature to improve drug safety. AB - OBJECTIVE: Prescription drugs can be associated with adverse effects (AEs) that are unrecognized despite evidence in the medical literature, as shown by rofecoxib's late recall in 2004. We assessed whether applying information mining to PubMed could reveal major drug-AE associations if articles testing whether drugs cause AEs are over-represented in the literature. DESIGN: MEDLINE citations published between 1949 and September 2009 were retrieved if they mentioned one of 38 drugs and one of 55 AEs. A statistical document classifier (using MeSH index terms) was constructed to remove irrelevant articles unlikely to test whether a drug caused an AE. The remaining relevant articles were analyzed using a disproportionality analysis that identified drug-AE associations (signals of disproportionate reporting) using step-up procedures developed to control the familywise type I error rate. MEASUREMENTS: Sensitivity and positive predictive value (PPV) for empirical drug-AE associations as judged against drug-AE associations subject to FDA warnings. RESULTS: In testing, the statistical document classifier identified relevant articles with 81% sensitivity and 87% PPV. Using data filtered by the statistical document classifier, base-case models showed 64.9% sensitivity and 42.4% PPV for detecting FDA warnings. Base-case models discovered 54% of all detected FDA warnings using literature published before warnings. For example, the rofecoxib-heart disease association was evident using literature published before 2002. Analyses incorporating literature mentioning AEs common to the drug class of interest yielded 71.4% sensitivity and 40.7% PPV. CONCLUSIONS: Results from large-scale literature retrieval and analysis (literature mining) compared favorably with and could complement current drug safety methods. PMID- 21546508 TI - Racial differences in out-of-hospital cardiac arrest survival and treatment. AB - OBJECTIVES: To determine whether there are prehospital differences between blacks and whites experiencing out-of-hospital cardiac arrest and to ascertain which factors are responsible for any such differences. METHODS: Cohort study of 3869 adult patients (353 blacks and 3516 whites) in the Illinois Prehospital Database with out-of-hospital cardiac arrest as a primary or secondary indication for emergency medical service (EMS) dispatch between 1 January 1996 and 31 December 2004. RESULTS: Return of spontaneous circulation was lower for black patients (19.8%) than for white patients (26.3%) (unadjusted OR 0.69, 95% CI 0.53 to 0.91). After adjusting for age, sex, prior medical history, prehospital event factors, patient zip code characteristics and EMS agency characteristics, the no difference line was suggestive of a trend, with a CI just transposing 1.00 (adjusted OR 0.71, 95% CI 0.50 to 1.01, p=0.053). CONCLUSIONS: Blacks were less likely to experience a return of spontaneous circulation than whites, less likely to receive defibrillation or cardiopulmonary resuscitation from EMS and more likely to receive medications from EMS. Differences in underlying health, care prior to the arrival of EMS, and delays in the notification of EMS personnel may contribute to racial disparities in prehospital survival after out-of-hospital cardiac arrest. PMID- 21546509 TI - Massive pelviureteric junction obstruction: the role of focused ultrasound in the emergency investigation of abdominal masses in children. PMID- 21546510 TI - Acute intoxication patients presenting to an emergency department in The Netherlands: admit or not? Prospective testing of two algorithms. AB - STUDY OBJECTIVE: After acute intoxication, most patients presenting to the emergency department (ED)--76% of them in The Netherlands--are admitted to hospital. Many will not need medical treatment on the ward. The authors tested two algorithms in the ED, based on vital parameters, ECG findings, and ingested substances, to identify patients who will receive treatment in hospital. METHODS: This prospective inception study enrolled patients aged 14 years and older presenting with acute intoxication between January 2006 and April 2008 to a Dutch university hospital. An algorithm was developed based on a previous retrospective study and the medical literature. In a second algorithm the clinical course during the stay in the ED was also taken into account. RESULTS: Of 313 patients presenting with acute intoxication to the ED, 134 (42.8%) were admitted to a ward for somatic care, but only 74 (23.6%) were treated on the ward. Algorithm 1 had 91.9% sensitivity (95% CI 82.6% to 96.7%) and 53.6% specificity (95% CI 47.0% to 60.0%). Algorithm 2 had 90.5% sensitivity (95% CI 80.9% to 95.8%) and 65.3% specificity (95% CI 58.8% to 71.2%). In line with hospital policy, several patients received N-acetylcysteine treatment for subtoxic paracetamol ingestion because they presented outside of office hours, when no measurements of blood paracetamol concentration are performed by the laboratory. When these patients are considered as untreated, both algorithms had 98.5% sensitivity (95% CI 90.6% to 99.9%). CONCLUSION: The algorithms had good sensitivity and better specificity than current clinical practice in most hospitals. It is too early to advocate their implementation, but results indicate that it is possible to use clinical parameters objectively to reduce unnecessary admissions to the ward. PMID- 21546511 TI - Seventy years of retinopathy of prematurity. PMID- 21546512 TI - Two-quadrant high-volume sub-Tenon's anaesthesia for vitrectomy: a randomised controlled trial. AB - BACKGROUND: Total volume using a standard single inferonasal injection for sub Tenon's anaesthesia is limited by an increase in intraocular pressure (IOP) and commonly requires the operating surgeon to top-up the block intraoperatively. This study compares the efficacy and safety of a two-quadrant technique that allows the use of a higher volume of local anaesthetic. METHODS: 54 patients undergoing vitrectomy were randomised into two groups. The control group (n=27) received a standard 5 ml single inferonasal sub-Tenon injection of a 50:50 mixture of 2% lidocaine and 0.5% bupivacaine with 150 IU hyaluronidase. The study group (n=27) received a 5 ml inferonasal and 5 ml superotemporal injection of the same mixture (10 ml total). The primary outcome measure was the number of intraoperative top-ups required. Secondary outcome measures were intraoperative and postoperative pain scores, IOP, block onset time, ocular akinesia, eyelid akinesia and chemosis. RESULTS: 24 patients required a top-up in the control group. No patients required a top-up in the study group (p<0.001). IOP measurements were similar in both groups. Block onset was shorter, eyelid akinesia was improved and pain scores were also reduced in the study group intraoperatively and at 0-2 h, 4-6 h, 10-14 h and 20-24 h postoperatively. CONCLUSIONS: Two-quadrant sub-Tenon's anaesthesia using 10 ml of a 50:50 mixture of 2% lidocaine and 0.5% bupivacaine with 150 IU hyaluronidase seems to be more effective than a single-quadrant technique at reducing intraoperative and postoperative pain during vitrectomy. PMID- 21546513 TI - Intraocular coccidioidomycosis simulating a neoplasm. AB - Coccidioidomycosis can simulate an intraocular neoplasm. We reviewed a case report of a 10-year-old girl who was referred with an intraocular tumour. This tumour consisted of a coccidioidomycosis infection in the eye. The eye was blind and painful so it was removed. PMID- 21546514 TI - Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy. AB - The neovascular form of age-related macular degeneration (AMD), called wet-AMD or choroidal neovascularisation, begins with damage to the outer retinal cells and retinal pigment epithelium (RPE), which elicits a cascade of inflammatory and angiogenic responses leading to neovascularisation under the macula. Studies showed that oxidative damage, chronic inflammation of the RPE and complement misregulation work at different steps of this disease. After established neovascularisation, several pro- and antiangiogenic agents start to play an important role. Vascular endothelial growth factors (VEGFs) are the most specific and potent regulators of angiogenesis, which are inhibited by intravitreal injections of ranibizumab, bevacizumab, VEGF Trap, pegaptanib sodium and other agents under investigation. Pigment epithelium-derived factor, on the other hand, shows neuroprotective and antiangiogenic activities. Hepatocyte growth factor (HGF) has a mitogenic effect on a wide range of epithelial and endothelial cells, and it is inhibited by an anti-HGF monoclonal antibody. Platelet-derived growth factor is a potent chemoattractant and mitogen for both fibroblasts and retinal RPE cells, which has been inhibited experimentally by VEGF Trap and human anti platelet-derived growth factor-D monoclonal antibody. Fibroblast growth factor-2 has pleiotropic effects in different cell and organ systems, and it is blocked by anti-FGF antibodies, with a greater benefit regarding antiangiogenesis when combined treatment with anti-VEGF is performed. Tumour necrosis factor alpha is expressed in the retina and the choroid, and its blockade in choroidal neovascularisation includes the use of monoclonals such as infliximab. This paper reviews the most important cytokines involved in the pathogenesis of wet-AMD, with emphasis on potential combined therapies for disease control. PMID- 21546515 TI - Wholesale data for surveillance of Australian Aboriginal tobacco consumption in the Northern Territory. AB - OBJECTIVES: Effective monitoring of trends in tobacco use is an essential element of tobacco control policy. Monitoring tobacco consumption using tobacco wholesale data has advantages over other methods of surveillance. In the present work, a research project that monitored tobacco consumption in 25 remote Aboriginal communities and its translation to a policy to implement this monitoring routinely in the entire Northern Territory of Australia is described. METHODS: Tobacco consumption and trends were estimated using wholesale (or occasionally sales) data from all retail outlets in 25 remote Aboriginal communities. Self reported consumption was estimated from the National Aboriginal and Torres Strait Islander Social Survey in 2008. Local consumption results were fed back in posters to local organisations and health staff. RESULTS: Estimates of consumption from wholesale data and self-report were similar (6.8 and 6.7 cigarettes/day/person aged 15 and over). Consumption was higher in the tropical Top End than in arid Central Australia, and 24% of tobacco was consumed as loose tobacco. The overall trend in monthly consumption was not significantly different from 0. Local communities could be ranked by their local trends in monthly consumption. CONCLUSIONS: Monitoring tobacco consumption using wholesale tobacco data is a practical and unobtrusive surveillance method that is being introduced as a new condition of tobacco retail licenses in the Northern Territory of Australia. It overcomes some problems with consumption estimates from routine surveys, enables rapid feedback and use of results and is particularly well suited for hard-to-reach discrete populations, such as remote Aboriginal communities in Australia. It has already been used to evaluate the impact of local tobacco control activities. PMID- 21546517 TI - Good parents would not fulfil their obligation to genetically enhance their unborn children. AB - The purpose of this paper is to unveil the incompleteness of John Harris' view that parents have a moral obligation to genetically enhance their unborn children. Specifically, here two main conclusions are proposed: (1) at present there exist insufficient empirical data for determining whether prenatal genetic enhancement (PGE) is a moral obligation on prospective parents. Although the purpose of PGE research would be to determine the extent to which PGE is safe and effective, the task of determining the veracity of Harris' premises is impossible to achieve without begging the question; we would be forced to assume the moral permissibility of PGE in order to generate the data that are required for determining its moral standing. So, given this empirical blindness, consequence based normative frameworks like that of Harris cannot determine the moral standing of PGE, but merely push the question of the moral standing of PGE back a step, without offering any plausible and morally endorsable recourse for how to answer it; (2) even if PGE research were legal, which it is not, parents nevertheless have good reason not to consent to it for their children, especially as participants in the first wave(s) of such research. PMID- 21546516 TI - The 57 kb deletion in cystinosis patients extends into TRPV1 causing dysregulation of transcription in peripheral blood mononuclear cells. AB - BACKGROUND: Cystinosis is an autosomal recessive disease characterised by the abnormal accumulation of lysosomal cystine. Mutations in the cystinosin gene (CTNS) represent known causes for the disease. The major cystinosis mutation is a 57 kb deletion on human chromosome 17p13 that removes the majority of CTNS and the entire adjacent gene, CARKL/SHPK. OBJECTIVES: In order to identify other genes that may influence the cystinosis pathobiological pathway, peripheral blood mononuclear cells (PBMC) were collected from cystinosis family members, and DNA and RNA extracted. RESULTS: Using whole genome transcriptional profiling, transient receptor potential vanilloid 1 (TRPV1) was found to be differentially expressed in association with cystinosis. This was verified using TaqMan qRT-PCR. There was a 72% reduction in PBMC TRPV1 mRNA levels in cystinosis individuals homozygous for the 57 kb deletion (n=6) compared to unaffected individuals without the deletion (n=6) (p=0.002). TRPV1 is a sensory receptor located on chromosome 17p13, adjacent to CARKL/SHPK. It was ascertained that the 57 kb deletion extends from exon 10 of CTNS, upstream through CARKL/SHPK, to intron 2 of TRPV1, thus deleting the first two non-coding exons. CONCLUSION: This is the first study to report that the 57 kb deletion extends into the TRPV1 gene causing dysregulation of transcription in PBMC isolated from cystinosis patients. PMID- 21546518 TI - Language, foreign nationality and ethnicity in an English prison: implications for the quality of health and social research. AB - BACKGROUND: More than one in 10 of all prisoners in England and Wales are Foreign Nationals. This article discusses whether the research applications to one London prison are aimed at understanding a prisoner population characterised by significant multinational and multilingual complexity. METHODS: We studied all accessible documents relating to research undertaken at a women's prison between 2005 and 2009 to assess the involvement of Foreign National prisoners and women with limited English. The source of information was prison research applications and protocols. We also looked at available final research reports and journal articles. RESULTS: Two key findings emerged from this study. First, studies at this prison frequently excluded Foreign National prisoners and women with limited English. Second, Foreign National prisoners were often clustered as a homogeneous category in the research reports reviewed. This is despite their diverse cultural backgrounds, their variable immigration status and their differing competence in English, all of which affect their lives. CONCLUSIONS: The failure to include and/or identify social subgroups of the population can undermine the value of research, including, in the case of the study prison, funded health research. This can compromise associated needs assessments and service delivery, particularly important in already disadvantaged populations; this may encourage and/or perpetuate a range of health inequalities. There is a pressing need to examine cultural exclusion in other health and criminal justice settings, to assess the ways in which-and the extent to which-such exclusion may compromise the merit of proposed and completed health and social research. PMID- 21546519 TI - British transplant research endangered by the Human Tissue Act. PMID- 21546520 TI - The justification of race in biological explanation. AB - In medicine, racial differences are frequently presented as part of the best explanation of differences in the risk of diseases. The problem of using racial classification in biomedical research has become important because of its ethical consequences in society. However, the biological relevance of the concept of race cannot be established by any ethical argument and the epistemological role of racial categorisation requires clarification. In this paper, different issues related to the concept of race are considered. This paper analyses the semantic problem concerning the definition of race, considers the ontological problem of race, drawing attention to the biological evidence for genetic differences among human groups, and presents a promising epistemological approach to the problem of race. The purpose of the paper is to examine whether, or when, racial categories belong in biological explanations. It shows that the concept of race cannot be justified in biology because it does not lead to successful predictions, and that genetic discontinuities are sufficient to explain differences in diseases but not needed in the explanation. The biomedical field should search for genetic patterns related to diseases, and should not assume racial discontinuities among human groups and use racial clusters as proxies for undetected genetic patterns. PMID- 21546521 TI - Managing the public health risk of a 'sex worker' with hepatitis B infection: legal and ethical considerations. AB - This paper examines the ethical issues faced by health workers managing a fictional case of a female sex worker who is hepatitis B positive with a high level of virus but is asymptomatic. According to guidelines she does not require treatment herself, but is potentially highly infectious to others. Recent legal cases in the UK show it can be criminal to pass on HIV or hepatitis B infection sexually if the risk is known and the partner has not been informed. However, there is no statute or case law showing that health workers are required to intervene to prevent such a potential 'crime', particularly when the partners are unknown, as in this case. The health workers could respond in various ways. They could do nothing, thus making further infection probable. They could advise the sex worker to use condoms and to inform her clients. They could treat the sex worker to reduce her level of infectivity, although there is no benefit to her. They could disclose the sex worker's status, although breaking confidentiality is a serious matter ethically and may be of no benefit to the unknown client group. Regulating prostitution might help; but sex workers with infection may work off licence. This paper discusses the clinical, moral and ethical issues associated with such a scenario and concludes that the most beneficial course is to target clients, through health education, to recognise the potential risks of infection from a sex worker and to take suitable precautions including immunisation against hepatitis B. PMID- 21546522 TI - Ethical issues in the development of tele-ICUs. AB - The past two decades have seen a dramatic increase in the use of telemedicine while the information technology revolution has contributed significantly to its popularity. In addition, there has been a recent increase in the use of telemedicine in the intensive care unit (ICU), partially driven by a critical shortage of intensivists. However, the ethical questions raised by the implementation of tele-ICUs have not been adequately considered. In this essay, we will discuss the development of tele-ICUs from the perspective of autonomy, beneficence/non-malificence, justice and professionalism. PMID- 21546523 TI - Decreased hippocampal volume, indirectly measured, is associated with depressive symptoms and consolidation deficits in multiple sclerosis. AB - BACKGROUND: The human hippocampus plays a role in episodic memory and depression. Recently, it has been shown, using manual tracings, that the hippocampus is smaller in volume in MS patients compared with healthy controls, and that, at least for depression, hippocampal atrophy correlates with symptom severity. METHODS: Because manual tracing of the hippocampus is time consuming, we used a semi-automatic procedure for temporal horn volumetry in 72 multiple sclerosis (MS) patients and 16 control subjects as an indirect measure of hippocampal volume. We analysed memory performance with the California Verbal Learning Test (using separate indices for encoding, consolidation and retrieval) and depressive mood with the Beck's Depression Inventory (distinguishing between psychic and somatic aspects). RESULTS: MS patients had significantly larger temporal horn volumes and volume correlated with psychic symptoms of depressive mood. Temporal horn volume was also associated with consolidation, in particular in the most impaired group. CONCLUSIONS: Temporal horn volume can be measured relatively easily and appears to correlate with two major clinical problems in MS patients: memory performance and depressive mood. The link between temporal horn volume, consolidation and depression may be hippocampal atrophy, as suggested by their adjacent neuroanatomical localization, and by the similarity in functional loss following impairment of these two structures. PMID- 21546524 TI - Triangulating case-finding tools for patient safety surveillance: a cross sectional case study of puncture/laceration. AB - OBJECTIVE: To evaluate the need for triangulating case-finding tools in patient safety surveillance. This study applied four case-finding tools to error associated patient safety events to identify and characterise the spectrum of events captured by these tools, using puncture or laceration as an example for in depth analysis. DATA SOURCES/STUDY SETTING: Retrospective hospital discharge data were collected for calendar year 2005 (n=48,418) from a large, urban medical centre in the USA. STUDY DESIGN: The study design was cross-sectional and used data linkage to identify the cases captured by each of four case-finding tools. DATA COLLECTION/EXTRACTION METHODS: Three case-finding tools (International Classification of Diseases external (E) and nature (N) of injury codes, Patient Safety Indicators (PSI)) were applied to the administrative discharge data to identify potential patient safety events. The fourth tool was Patient Safety Net, a web-based voluntary patient safety event reporting system. RESULTS: The degree of mutual exclusion among detection methods was substantial. For example, when linking puncture or laceration on unique identifiers, out of 447 potential events, 118 were identical between PSI and E-codes, 152 were identical between N codes and E-codes and 188 were identical between PSI and N-codes. Only 100 events that were identified by PSI, E-codes and N-codes were identical. Triangulation of multiple tools through data linkage captures potential patient safety events most comprehensively. CONCLUSIONS: Existing detection tools target patient safety domains differently, and consequently capture different occurrences, necessitating the integration of data from a combination of tools to fully estimate the total burden. PMID- 21546525 TI - Thousands of lives could be saved using tranexamic acid for patients with bleeding trauma. PMID- 21546526 TI - Post-deployment injury among new combat veterans enrolled in Veterans Affairs (VA) healthcare. AB - The purpose of this study was to examine prevalence and potential risk factors for post-deployment injury among Iraq and Afghanistan combat veterans enrolled in Veterans Affairs (VA) healthcare. A national, stratified sample of Iraq/Afghanistan combat Veteran VA users was surveyed in 2008. Mental and physical health, including medically-treated injuries sustained since deployment, were self-reported. Injury risk was estimated using survey logistic regression. Stratified ORs and 95% CIs were adjusted for potential confounders and non response bias and weighted to represent the target population. Nearly half the population reported post-deployment injuries. In multivariate models, veterans with probable post-traumatic stress disorder (OR=2.1; 95% CI 1.3 to 3.5), self reported diagnosed depression (OR=3.6; 95% CI 1.8 to 7.0) and anger problems (OR=2.4; 95% CI 1.4 to 4.2) had greater odds of post-deployment injury. Deployment-related injuries were also strongly associated with odds of post deployment injury. Results suggest that mental health disorders increase the odds of post-deployment injury among combat veteran VA users. Longitudinal research examining these associations is warranted. PMID- 21546527 TI - Violence and social capital among young men in Beirut. AB - BACKGROUND: Research on the links between violence and social capital has produced mixed results and is mainly limited to Western countries. AIMS: To assess the relationship of social capital to physical fights among unmarried boys aged 13-19 years living in three disadvantaged neighbourhoods in the outskirts of Beirut, controlling for variables associated with youth violence. Lebanon has a history of civil and cross-border war, which may influence the production of violence at the individual level. METHODS: 674 boys were interviewed. The dependent variable was being involved in a physical fight in the last 3 months. The independent variable was social capital, classified into six categories: civic engagement and community development; locational capital; trust; reciprocity; hypothetical social support; and social network. RESULTS: One fifth (20%) had been in a fight in the last 3 months. Youth who were members of a group, who had been victimised, who could ask for help from a family member/friend/neighbour when they had a problem, and who liked living in their neighbourhood were more likely to be involved in a fight. CONCLUSION: This research supports the literature that indicates that physical fights are positively related to both individual and social capital variables. Social capital had a detrimental effect on physical fights. This may be related to bonding in a gang-like way. While high levels of social capital are good for other health outcomes and thus should not be reduced, interventions that channel youth energy in positive ways are needed. PMID- 21546529 TI - Macular pigment optical density is related to blood glutathione levels in healthy individuals. AB - PURPOSE: To assess the relationship between macular pigment optical density (MPOD) and blood markers for antioxidant defense in otherwise healthy volunteers. METHODS: Forty-seven healthy volunteers were subjected to blood analysis to detect the level of circulating glutathione in its reduced (GSH) and oxidized (GSSG) forms. The level of MPOD was measured using heterochromatic flicker photometry. Systemic blood pressure (BP) parameters, heart rate (HR), body mass index (BMI), and plasma levels of total, HDL, and LDL cholesterol and triglycerides (TGs) were also determined. RESULTS: A simple correlation model revealed that the level of MPOD correlated significantly and positively with both GSH (P < 0.001) and t-GSH (P < 0.001) levels but not with those of GSSG (P > 0.05). Age, sex, systemic BP parameters, HR, BMI, and plasma levels of cholesterol and TGs did not have any influence on either MPOD or glutathione levels (all P > 0.05). In addition, a forward stepwise multiple regression analysis showed MPOD to have a significantly and independent correlation with GSH levels (beta = 0.63; P < 0.001). CONCLUSIONS: In otherwise healthy older individuals, there is a positive correlation between local and systemic antioxidant defense mechanisms. PMID- 21546528 TI - Transforming growth factor-beta induces extracellular matrix protein cross linking lysyl oxidase (LOX) genes in human trabecular meshwork cells. AB - PURPOSE: The profibrotic cytokine TGFbeta is associated with glaucoma and plays an important role in the regulation of extracellular matrix metabolism in the trabecular meshwork (TM). The purpose of this study was to determine whether expression of ECM cross-linking LOX genes is regulated by TGFbeta in TM cells. METHODS: Expression of the five LOX genes (LOX, LOXL1, LOXL2, LOXL3, and LOXL4) was examined in cultured human TM cells by using RT-PCR, quantitative RT-PCR, and Western immunoblot analysis. TM cells were treated with recombinant TGFbeta1, -2, and -3, to determine the effects on LOX and LOXL1 to -4 expression. The TM cells were pretreated with TGFBR inhibitors (LY364947, SB431542), canonical Smad signaling pathway (SIS3 or Smad2, -3, and -4 siRNAs) inhibitors, or inhibitors of the non-Smad signaling pathways (SP600125, SR11302), to identify the signaling pathway(s) involved in TGFbeta induction of LOX and LOXL gene and protein expression. A novel LOX activity assay was used to determine the effects of the LOX inhibitor BAPN on tropoelastin cross-linking. RESULTS: All five LOX genes (LOX, LOXL1 to -4) were expressed in cultured human TM cells and were induced by all three isoforms of TGFbeta. This TGFbeta induction of LOX and LOXL expression was blocked by TGFbeta inhibitors as well as by inhibitors of the canonical Smad2, -3, and -4 signaling and non-Smad JNK/AP-1 signaling pathways (P < 0.05). CONCLUSIONS: Both Smad and non-Smad signaling pathways are involved in TGFbeta mediated LOX induction, suggesting complex regulation of these important extracellular matrix cross-linking enzymes. Increased LOX activity may be at least partially responsible for TGFbeta-mediated IOP elevation and increased aqueous humor outflow resistance. PMID- 21546530 TI - Choroidal involution is a key component of oxygen-induced retinopathy. AB - PURPOSE: Retinopathy of prematurity (ROP) is a major cause of visual handicap in the pediatric population. To date, this disorder is thought to stem from deficient retinal vascularization. Intriguingly, functional electrophysiological studies in patients with mild or moderate ROP and in the oxygen-induced retinopathy (OIR) model in rats reveal central photoreceptor disruption that overlies modest retinal vessel loss; a paucity of retinal vasculature occurs predominantly at the periphery. Given that choroidal circulation is the major source of oxygen and nutrients to the photoreceptors, the authors set out to investigate whether the choroidal vasculature system may be affected in OIR. METHODS: Rat models of OIR treating newborn animals with 80% or 50/10% alternated oxygen level for the first two postnatal weeks were used to mimic ROP in humans. Immunohistology staining and vascular corrosion casts were used to investigate the vessel layout of the eye. To investigate the effect of 15-deoxy-Delta12,14 PGJ(2) (15d-PGJ(2); a nonenzymatic product of prostaglandin D(2)) on endothelial cells, in vitro cell culture and ex vivo choroid explants were employed and intravitreal injections were performed in animals. RESULTS: The authors herein demonstrate that deficient vascularity occurs not only in the retinal plexus but also in the choroid. This sustained, marked choroidal degeneration is specifically confined to central regions of the retina that present persistent photoreceptor loss and corresponding functional deficits. Moreover, the authors show that 15d-PGJ(2) is a prominent contributor to this choroidal decay. CONCLUSIONS: The authors demonstrate for the first time pronounced, sustained choroidal vascular involution during the development of ROP. Findings also suggest that effective therapeutic strategies to counter ROP should consider choroidal preservation. PMID- 21546531 TI - Misexpression of the constitutive Rpgr(ex1-19) variant leads to severe photoreceptor degeneration. AB - PURPOSE: Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene are a frequent cause of X-linked retinitis pigmentosa. The RPGR transcript undergoes complex alternative splicing to express both constitutive (Rpgr(ex1-19)) and Rpgr(ORF15) variants. Both variants localize to photoreceptor connecting cilia and are believed to play roles in ciliary function. This study examined variability in isoform expression and tested whether the constitutive variant could substitute for Rpgr function in photoreceptors. METHODS: Rpgr(ex1-19) and Rpgr(ORF15) expression during retinal development were compared using immunoblot analysis and immunohistochemistry, and ciliary affinity in adult photoreceptors was assessed by protein fractionation. Transgenic mice expressing either the full length Rpgr(ex1-19) or Rpgr(ORF15) variant were studied using light and electron microscopy and immunofluorescence imaging. The results were compared with those of wild-type and Rpgr(-/-) mice. RESULTS: Rpgr expression undergoes dynamic temporal regulation during retinal development, and variants exhibit variability for ciliary localization in adult photoreceptors. Transgenic expression of both variants grossly exceeded endogenous Rpgr expression in photoreceptors. Although both variants exhibited normal ciliary localization, overexpression of the Rpgr(ex1-19) variant resulted in atypical accumulation of Rpgr in photoreceptor outer segments, abnormal photoreceptor morphology, and severe retinal degeneration. CONCLUSIONS: The Rpgr isoform ratio in the adult retina is critical to photoreceptor integrity. The utilization of distinct Rpgr variants at different stages of photoreceptor maturation suggests independent roles in photoreceptor function. Finally, misexpression of Rpgr(ex1-19) causes retinal degeneration that is considerably more severe than that caused by Rpgr knockout but photoreceptors tolerate overexpression of Rpgr(ORF15) without evidence of degeneration. PMID- 21546532 TI - Combination of the Schirmer I and phenol red thread tests as a rescue strategy for diagnosis of ocular dryness associated with Sjogren's syndrome. AB - PURPOSE: To define a combination of the Schirmer I and phenol red thread (PRT) tests that improves the screening of patients with ocular sicca syndrome. METHODS: The PRT test was performed before (PRT1) and after (PRT2) the Schirmer I test, in both eyes of 143 patients complaining of ocular dryness secondary to Sjogren's syndrome or sicca asthenia polyalgia syndrome (SAPS; 72 and 71 patients, respectively), and in 40 control patients. Groups were matched by age and sex. After determining the best cutoff values using the receiver operating characteristic procedure, several combinations of PRT and Schirmer I were assessed to improve the predictive values of the procedure. RESULTS: The best cutoff value for PRT2, estimated at 15 mm, provided a satisfying match between sensitivity and specificity indexes (68% and 90%, respectively), similar to those obtained with the Schirmer I test. If PRT1 alone was ineffective to screen SGS from control patients, the comparison between PRT1 and PRT2 (so-called "DeltaPRT") was found as a good marker to detect patients with persistent tear reflex. Interestingly, the combination of positive Schirmer I, PRT 2, and/or DeltaPRT tests was found to be highly predictive of severe ocular sicca syndrome. CONCLUSIONS: The combination of the Schirmer I and PRT tests strongly improves the screening procedure to detect patients with ocular dryness related to Sjogren's syndrome or SAPS. It could be more widely used in daily clinical practice, aside from the Schirmer I test, to optimize the work-up of patients presenting with dry-eye subjective signs. PMID- 21546533 TI - Reproducibility of measuring lamina cribrosa pore geometry in human and nonhuman primates with in vivo adaptive optics imaging. AB - PURPOSE: The ability to consistently resolve lamina cribrosa pores in vivo has applications in the study of optic nerve head and retinal disease mechanisms. Repeatability was assessed in imaging laminar pores in normal living eyes with a confocal adaptive optics scanning laser ophthalmoscope (AOSLO). METHODS: Reflectance images (840 nm) of the anterior lamina cribrosa were acquired using the AOSLO in four or more different sessions in two normal rhesus monkey eyes and three normal human eyes. Laminar pore areas, elongations (ratio of major to minor axes of the best-fit ellipse) and nearest neighbor distances were calculated for each session. Measurement repeatability was assessed across sessions. RESULTS: Pore areas ranged from 90 to 4365 MUm(2) in monkeys and 154 to 6637 MUm(2) in humans. Mean variabilities in measuring pore area and elongation (i.e., mean of the standard deviation of measurements made across sessions for the same pores) were 50 MUm(2) (6.1%) and 0.13 (6.7%), respectively, in monkeys and 113 MUm(2) (8.3%) and 0.17 (7.7%), respectively, in humans. Mean variabilities in measuring nearest neighbor distances were 1.93 MUm (5.2%) in monkeys and 2.79 MUm (4.1%) in humans. There were no statistically significant differences in any pore parameters across sessions (ANOVA, P > 0.05). CONCLUSIONS: The anterior lamina cribrosa was consistently imaged in vivo in normal monkey and human eyes. The small intersession variability in normal pore geometry suggests that AOSLO imaging could be used to measure and track changes in laminar pores in vivo during glaucomatous progression. PMID- 21546535 TI - Light scattering and wavefront aberrations in in vivo imaging of the rat eye: a comparison study. AB - PURPOSE: In vivo imaging of the retina is becoming an increasingly important research method. General anesthesia rapidly compromises the corneal surface, which increases scattering. In addition, wavefront aberrations limit the maximum imaging resolution. Three common methods of stabilizing the air-cornea interface and reducing scattering are the use of a contact lens, a microscopy slide coverslip, or mineral oil. These methods have not yet been analyzed regarding their impact on scattering and wavefront aberrations. METHODS: Nineteen eyes of 19 rats were analyzed with a custom-made Hartmann-Shack (HS) wavefront sensor. The amount of scattering was determined by analysis of the HS spot width, and the wavefront was reconstructed for the naked eye and each scattering-reducing method. Their effect on optical quality was determined by calculating the modulation transfer function (MTF). RESULTS: The three methods applied significantly reduced scattering but were differentially effective, with the coverslip performing the best and the mineral oil the worst. The root mean square (RMS) of the wavefront aberration, as well as the intereye variability of the RMS, was significantly smaller with the contact lens than with the coverslip. The MTF was best for the contact lens and worst for the coverslip, which was also illustrated by image simulations. CONCLUSIONS: The coverslip, contact lens, and mineral oil, when applied to the cornea, all reduced scattering. The best performing method, the coverslip, increased wavefront aberrations. Overall, the contact lens had the best influence on image quality, and it appears to be the method of choice for high-resolution retinal imaging in rats. PMID- 21546534 TI - Reversal of stathmin-mediated microtubule destabilization sensitizes retinoblastoma cells to a low dose of antimicrotubule agents: a novel synergistic therapeutic intervention. AB - PURPOSE: To explore the possibility of stathmin as an effective therapeutic target and to evaluate the synergistic combination of stathmin RNAi and the antimicrotubule agents paclitaxel and vincristine to retinoblastoma Y79 cells. METHODS: RNAi-mediated specific inhibition of stathmin expression in Y79 cells was shown by real-time quantitative RT-PCR (RT-Q-PCR), its effect on cell proliferation by MTT assay, cell invasion using matrigel, microtubule polymerization by immunohistochemistry, apoptosis, cell cycle analysis by flow cytometry analysis, and the changes in FOXM1 protein expression were studied by Western blot. The effect of combination treatment of stathmin siRNA and paclitaxel/vincristine was studied by assessing cell viability and apoptosis. RESULTS: Short interfering RNA-mediated transient stathmin downregulation resulted in a marked inhibition of retinoblastoma cell proliferation and cell invasion in vitro. Stathmin inhibition promoted Y79 cells to G2/M phase, and ultimately there were increased apoptotic events as evidenced by higher caspase-3 activation and cleaved poly(ADP-ribose) polymerase expression. Cells transfected with stathmin siRNA showed long and bundled microtubule polymers and sensitized the Y79 cells significantly to paclitaxel and vincristine. CONCLUSIONS: Stathmin may be a pivotal determinant for retinoblastoma tumorigenesis and chemosensitivity. Strategies to inhibit stathmin will help to enhance the cytotoxic effect of paclitaxel while reducing toxicity (or side effects) to normal cells caused by high doses. PMID- 21546536 TI - Association of mean ocular perfusion pressure and diabetic retinopathy in type 2 diabetes mellitus: Sankara Nethralaya diabetic retinopathy epidemiology and molecular genetic study (SN-DREAMS, Report 28). AB - PURPOSE: To elucidate the distribution of mean ocular perfusion pressure (MOPP) and to study the relationship between MOPP and diabetic retinopathy (DR) in a south Indian subpopulation with diabetes. METHODS: This study was a population based, cross-sectional evaluation of 1368 subjects, aged >=40 years, with type 2 diabetes. DR was diagnosed on the basis of the modified Klein classification. Systolic and diastolic blood pressure (SBP and DBP) were recorded with a mercury sphygmomanometer. Intraocular pressure (IOP) was assessed by applanation tonometry. MOPP was derived by the formula: MOPP = 2/3;[DBP + 1/3;(SBP - DBP)] - IOP. RESULTS: The mean +/- SD for MOPP was 52.6 +/- 9.0 mm Hg, higher in the women than in the men (P = 0.046). In comparison to subjects without DR, MOPP was higher in the men with sight-threatening DR (STDR) (P = 0.030) and higher in women with any DR (P = 0.008) and non-STDR (P = 0.006). However, on multivariate analysis after adjustment for all factors, MOPP was found not to be associated with DR (OR = 1.02, 95% CI = 0.99-1.03; P = 0.149), non-STDR (OR = 1.02, 95% CI = 0.99-1.03; P = 0.312), or STDR (OR = 1.02, 95% CI = 0.98-1.05; P = 0.358). CONCLUSIONS: Univariate analysis revealed very small differences in the association of MOPP and DR in both sexes which are probably of no clinical significance. Multivariate analysis showed no association between MOPP and DR. There seems to be very little evidence of a link between MOPP and DR. It may be more informative to evaluate the association in longitudinal studies. PMID- 21546537 TI - Combinatorial effect of probucol and cilostazol in focal ischemic mice with hypercholesterolemia. AB - Hypercholesterolemia may increase stroke risk by accelerating atherosclerosis, narrowing the luminal diameter in cerebral vessels, and disrupting both vascular endothelial and smooth muscle function. In the present study, we investigated the beneficial effects of combinatorial therapy with probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. Apolipoprotein E (ApoE) knockout (KO) mice were fed a high-fat diet with or without 0.5% probucol and/or 0.2% cilostazol for 10 weeks. Probucol alone and probucol and cilostazol significantly decreased total, low-density lipoprotein, and high-density lipoprotein cholesterol, whereas cilostazol did not affect the plasma cholesterol levels in ApoE KO mice. Administration of probucol alone and cilostazol alone significantly decreased atherosclerotic lesion area in the aorta, with a significant decrease evident using combinatorial administration. Middle cerebral artery occlusion resulted in significantly larger infarct volumes in ApoE KO mice fed 10 weeks of high-fat diet compared with those in ApoE KO mice fed a regular diet. The infarct volume was reduced significantly using probucol alone or cilostazol alone and even was reduced significantly by their combinatorial administration. Consistent with a larger infarct size, the combinatorial therapy prominently improved neurological function. The combinatorial administration increased cerebral blood flow during ischemia. Expression of endothelial nitric oxide synthase and adiponectin in the cortex were decreased by high-fat diet but were elevated by combinatorial treatment. Adiponectin expression colocalized within the cerebral vascular endothelium. The data suggest that the combination of probucol and cilostazol prevents cerebrovascular damage in focal cerebral ischemic mice with hypercholesterolemia by up-regulation of endothelial nitric oxide synthase and adiponectin. PMID- 21546538 TI - Physiological and molecular characterization of aristolochic acid transport by the kidney. AB - Consumption of herbal medicines derived from Aristolochia plants is associated with a progressive tubulointerstitial disease known as aristolochic acid (AA) nephropathy. The nephrotoxin produced naturally by these plants is AA-I, a nitrophenanthrene carboxylic acid that selectively targets the proximal tubule. This nephron segment is prone to toxic injury because of its role in secretory elimination of drugs and other xenobiotics. Here, we characterize the handling of AA-I by membrane transporters involved in renal organic anion transport. Uptake assays in heterologous expression systems identified murine organic anion transporters (mOat1, mOat2, and mOat3) as capable of mediating transport of AA-I. Kinetic analyses showed that all three transporters have an affinity for AA-I in the submicromolar range and thus are likely to operate at toxicologically relevant concentrations in vivo. Structure-activity relationships revealed that the carboxyl group is critical for high-affinity interaction of AA-I with mOat1, mOat2, and mOat3, whereas the nitro group is required only by mOat1. Furthermore, the 8-methoxy group, although essential for toxicity, was not requisite for transport. Mouse renal cortical slices avidly accumulated AA-I, achieving slice to-medium concentration ratios >10. Uptake by slices was sensitive to known mOat1 and mOat3 substrates and the organic anion transport inhibitor probenecid, which also blocked the production of DNA adducts formed with reactive intracellular metabolites of AA-I. Taken together, these findings indicate that OAT family members mediate high-affinity transport of AA-I and may be involved in the site selective toxicity and renal elimination of this nephrotoxin. PMID- 21546539 TI - Role of E-cadherin in antimigratory and antiinvasive efficacy of silibinin in prostate cancer cells. AB - The epithelial-to-mesenchymal transition (EMT) in prostate cancer (PCA) cells is considered prerequisite for acquiring migratory/invasive phenotype, and subsequent metastasis. We hypothesized that promoting the E-cadherin expression in PCA cells by using nontoxic phytochemicals, like silibinin, would prevent EMT and consequently invasiveness. Our results showed that silibinin treatment (5-90 MUmol/L) significantly inhibits migratory and invasive potential of advance human PCA PC3, PC3MM2, and C4-2B cells in in vitro assays. Importantly, the antimigratory/antiinvasive efficacy of silibinin was not due to its cytotoxicity toward PCA cells. Molecular analyses showed that silibinin increases E-cadherin level that was localized mainly at cellular membrane as evidenced by subcellular fractional and confocal analyses in PC3 cells, which might be responsible for morphologically observed shift toward epithelial character. Silibinin also decreased the levels of Slug, Snail, phospho-Akt(ser(473)), nuclear beta-catenin, phospho-Src(tyr(419)) and Hakai; together they play an important role in regulating E-cadherin expression/function and EMT. Similar silibinin effects on E cadherin, beta-catenin, phospho-Src(tyr(419)), and Hakai levels were also observed in PC3MM2 and C4-2B PCA cells. Selective Src inhibition by dasatinib also showed increased E-cadherin expression in PC3 cells suggesting a possible involvement of Src inhibition in silibinin-caused increase in E-cadherin level. Additional studies in PC3 cells with stable knock-down of E-cadherin expression revealed that antimigratory/antiinvasive efficacy of silibinin is in-part dependent on E-cadherin expression. Together, our results showing antimigratory/antiinvasive effects of silibinin and associated mechanisms suggest that silibinin should be tested further in clinically relevant animal models toward exploiting its potential benefits against metastatic PCA. PMID- 21546541 TI - Inferring epidemiological parameters on the basis of allele frequencies. AB - In this article, I develop a methodology for inferring the transmission rate and reproductive value of an epidemic on the basis of genotype data from a sample of infected hosts. The epidemic is modeled by a birth-death process describing the transmission dynamics in combination with an infinite-allele model describing the evolution of alleles. I provide a recursive formulation for the probability of the allele frequencies in a sample of hosts and a Bayesian framework for estimating transmission rates and reproductive values on the basis of observed allele frequencies. Using the Bayesian method, I reanalyze tuberculosis data from the United States. I estimate a net transmission rate of 0.19/year [0.13, 0.24] and a reproductive value of 1.02 [1.01, 1.04]. I demonstrate that the allele frequency probability under the birth-death model does not follow the well-known Ewens' sampling formula that holds under Kingman's coalescent. PMID- 21546540 TI - Advanced drug delivery systems of curcumin for cancer chemoprevention. AB - Since ancient times, chemopreventive agents have been used to treat/prevent several diseases including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, antioxidant, antiproliferative, anticarcinogenic, and antiangiogenic activity in various cell cultures and some animal studies. Research over the past 4 decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been shown to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician's armamentarium. PMID- 21546542 TI - Genetic variation and the fate of beneficial mutations in asexual populations. AB - The fate of a newly arising beneficial mutation depends on many factors, such as the population size and the availability and fitness effects of other mutations that accumulate in the population. It has proved difficult to understand how these factors influence the trajectories of particular mutations, since experiments have primarily focused on characterizing successful clones emerging from a small number of evolving populations. Here, we present the results of a massively parallel experiment designed to measure the full spectrum of possible fates of new beneficial mutations in hundreds of experimental yeast populations, whether these mutations are ultimately successful or not. Using strains in which a particular class of beneficial mutation is detectable by fluorescence, we followed the trajectories of these beneficial mutations across 592 independent populations for 1000 generations. We find that the fitness advantage provided by individual mutations plays a surprisingly small role. Rather, underlying "background" genetic variation is quickly generated in our initially clonal populations and plays a crucial role in determining the fate of each individual beneficial mutation in the evolving population. PMID- 21546543 TI - Trex2 enables spontaneous sister chromatid exchanges without facilitating DNA double-strand break repair. AB - Trex2 is a 3' -> 5' exonuclease that removes 3'-mismatched sequences in a biochemical assay; however, its biological function remains unclear. To address biology we previously generated trex2(null) mouse embryonic stem (ES) cells and expressed in these cells wild-type human TREX2 cDNA (Trex2(hTX2)) or cDNA with a single-amino-acid change in the catalytic domain (Trex2(H188A)) or in the DNA binding domain (Trex2(R167A)). We found the trex2(null) and Trex2(H188A) cells exhibited spontaneous broken chromosomes and trex2(null) cells exhibited spontaneous chromosomal rearrangements. We also found ectopically expressed human TREX2 was active at the 3' ends of I-SceI-induced chromosomal double-strand breaks (DSBs). Therefore, we hypothesized Trex2 participates in DNA DSB repair by modifying 3' ends. This may be especially important for ends with damaged nucleotides. Here we present data that are unexpected and prompt a new model. We found Trex2-altered cells (null, H188A, and R167A) were not hypersensitive to camptothecin, a type-1 topoisomerase inhibitor that induces DSBs at replication forks. In addition, Trex2-altered cells were not hypersensitive to gamma radiation, an agent that causes DSBs throughout the cell cycle. This observation held true even in cells compromised for one of the two major DSB repair pathways: homology-directed repair (HDR) or nonhomologous end joining (NHEJ). Trex2 deletion also enhanced repair of an I-SceI-induced DSB by both HDR and NHEJ without affecting pathway choice. Interestingly, however, trex2(null) cells exhibited reduced spontaneous sister chromatid exchanges (SCEs) but this was not due to a defect in HDR-mediated crossing over. Therefore, reduced spontaneous SCE could be a manifestation of the same defect that caused spontaneous broken chromosomes and spontaneous chromosomal rearrangements. These unexpected data suggest Trex2 does not enable DSB repair and prompt a new model that posits Trex2 suppresses the formation of broken chromosomes. PMID- 21546546 TI - New experiments for an undivided genetics. AB - There used to be a broad split within the experimental genetics research community between those who did mechanistic research using homozygous laboratory strains and those who studied patterns of genetic variation in wild populations. The former benefited from the advantage of reproducible experiments, but faced difficulties of interpretation given possible genomic and evolutionary complexities. The latter research approach featured readily interpreted evolutionary and genomic contexts, particularly phylogeny, but was poor at determining functional significance. Such burgeoning experimental strategies as genome-wide analysis of quantitative trait loci, genotype-phenotype associations, and the products of experimental evolution are now fostering a unification of experimental genetic research that strengthens its scientific power. PMID- 21546544 TI - A region of the nucleosome required for multiple types of transcriptional silencing in Saccharomyces cerevisiae. AB - Extended heterochromatin domains, which are repressive to transcription and help define centromeres and telomeres, are formed through specific interactions between silencing proteins and nucleosomes. This study reveals that in Saccharomyces cerevisiae, the same nucleosomal surface is critical for the formation of multiple types of heterochromatin, but not for local repression mediated by a related transcriptional repressor. Thus, this region of the nucleosome may be generally important to long-range silencing. In S. cerevisiae, the Sir proteins perform long-range silencing, whereas the Sum1 complex acts locally to repress specific genes. A mutant form of Sum1p, Sum1-1p, achieves silencing in the absence of Sir proteins. A genetic screen identified mutations in histones H3 and H4 that disrupt Sum1-1 silencing and fall in regions of the nucleosome previously known to disrupt Sir silencing and rDNA silencing. In contrast, no mutations were identified that disrupt wild-type Sum1 repression. Mutations that disrupt silencing fall in two regions of the nucleosome, the tip of the H3 tail and a surface of the nucleosomal core (LRS domain) and the adjacent base of the H4 tail. The LRS/H4 tail region interacts with the Sir3p bromo-adjacent homology (BAH) domain to facilitate Sir silencing. By analogy, this study is consistent with the LRS/H4 tail region interacting with Orc1p, a paralog of Sir3p, to facilitate Sum1-1 silencing. Thus, the LRS/H4 tail region of the nucleosome may be relatively accessible and facilitate interactions between silencing proteins and nucleosomes to stabilize long-range silencing. PMID- 21546547 TI - Plant genetics, sustainable agriculture and global food security. AB - The United States and the world face serious societal challenges in the areas of food, environment, energy, and health. Historically, advances in plant genetics have provided new knowledge and technologies needed to address these challenges. Plant genetics remains a key component of global food security, peace, and prosperity for the foreseeable future. Millions of lives depend upon the extent to which crop genetic improvement can keep pace with the growing global population, changing climate, and shrinking environmental resources. While there is still much to be learned about the biology of plant-environment interactions, the fundamental technologies of plant genetic improvement, including crop genetic engineering, are in place, and are expected to play crucial roles in meeting the chronic demands of global food security. However, genetically improved seed is only part of the solution. Such seed must be integrated into ecologically based farming systems and evaluated in light of their environmental, economic, and social impacts-the three pillars of sustainable agriculture. In this review, I describe some lessons learned, over the last decade, of how genetically engineered crops have been integrated into agricultural practices around the world and discuss their current and future contribution to sustainable agricultural systems. PMID- 21546549 TI - SHAPE analysis of the FIV Leader RNA reveals a structural switch potentially controlling viral packaging and genome dimerization. AB - Feline immunodeficiency virus (FIV) infects many species of cat, and is related to HIV, causing a similar pathology. High-throughput selective 2' hydroxyl acylation analysed by primer extension (SHAPE), a technique that allows structural interrogation at each nucleotide, was used to map the secondary structure of the FIV packaging signal RNA. Previous studies of this RNA showed four conserved stem-loops, extensive long-range interactions (LRIs) and a small, palindromic stem-loop (SL5) within the gag open reading frame (ORF) that may act as a dimerization initiation site (DIS), enabling the virus to package two copies of its genome. Our analyses of wild-type (wt) and mutant RNAs suggest that although the four conserved stem-loops are static structures, the 5' and 3' regions previously shown to form LRI also adopt an alternative, yet similarly conserved conformation, in which the putative DIS is occluded, and which may thus favour translational and splicing functions over encapsidation. SHAPE and in vitro dimerization assays were used to examine SL5 mutants. Dimerization contacts appear to be made between palindromic loop sequences in SL5. As this stem-loop is located within the gag ORF, recognition of a dimeric RNA provides a possible mechanism for the specific packaging of genomic over spliced viral RNAs. PMID- 21546548 TI - The adenovirus E4orf4 protein targets PP2A to the ACF chromatin-remodeling factor and induces cell death through regulation of SNF2h-containing complexes. AB - The adenovirus E4 open-reading-frame 4 (E4orf4) protein regulates the progression of viral infection and when expressed individually it induces non-classical apoptosis in transformed cells. Here we show that E4orf4 associates with the ATP dependent chromatin-remodeling factor ACF that consists of a sucrose non fermenting-2h (SNF2h) ATPase and an Acf1 regulatory subunit. Furthermore, E4orf4 targets protein phosphatase 2A (PP2A) to this complex and to chromatin. Obstruction of SNF2h activity inhibits E4orf4-induced cell death, whereas knockdown of Acf1 results in enhanced E4orf4-induced toxicity in both mammalian and yeast cells, and Acf1 overexpression inhibits E4orf4's ability to downregulate early adenovirus gene expression in the context of viral infection. Knockdown of the Acf1 homolog, WSTF, inhibits E4orf4-induced cell death. Based on these results we suggest that the E4orf4-PP2A complex inhibits ACF and facilitates enhanced chromatin-remodeling activities of other SNF2h-containing complexes, such as WSTF-SNF2h. The resulting switch in chromatin remodeling determines life versus death decisions and contributes to E4orf4 functions during adenovirus infection. PMID- 21546550 TI - The DNA-recognition fold of Sso7c4 suggests a new member of SpoVT-AbrB superfamily from archaea. AB - Organisms growing at elevated temperatures face the challenge of maintaining the integrity of their genetic materials. Archaea possess unique chromatin proteins for gene organization and information processing. We present the solution structure of Sso7c4 from Sulfolobus solfataricus, which has a homodimeric DNA binding fold forming a swapped beta-loop-beta 'Tai-Chi' topology. The fold is reminiscent of the N-terminal DNA-binding domain of AbrB and MazE. In addition, several amide resonances in the heteronuclear single quantum coherence spectra of Sso7c4 are shifted and broadened with the addition of small amounts of duplex DNA oligomers. The locations of the corresponding amides in the Sso7c4 structure define its DNA-interacting surface. NMR spectra of DNA titrated with the protein further indicated that Sso7c4 interacts with DNA in the major groove. Taken together, a plausible model for the Sso7c4-DNA complex is presented, in which the DNA double helix is curved around the protein dimer. PMID- 21546551 TI - iPath2.0: interactive pathway explorer. AB - iPath2.0 is a web-based tool (http://pathways.embl.de) for the visualization and analysis of cellular pathways. Its primary map summarizes the metabolism in biological systems as annotated to date. Nodes in the map correspond to various chemical compounds and edges represent series of enzymatic reactions. In two other maps, iPath2.0 provides an overview of secondary metabolite biosynthesis and a hand-picked selection of important regulatory pathways and other functional modules, allowing a more general overview of protein functions in a genome or metagenome. iPath2.0's main interface is an interactive Flash-based viewer, which allows users to easily navigate and explore the complex pathway maps. In addition to the default pre-computed overview maps, iPath offers several data mapping tools. Users can upload various types of data and completely customize all nodes and edges of iPath2.0's maps. These customized maps give users an intuitive overview of their own data, guiding the analysis of various genomics and metagenomics projects. PMID- 21546552 TI - The BioExtract Server: a web-based bioinformatic workflow platform. AB - The BioExtract Server (bioextract.org) is an open, web-based system designed to aid researchers in the analysis of genomic data by providing a platform for the creation of bioinformatic workflows. Scientific workflows are created within the system by recording tasks performed by the user. These tasks may include querying multiple, distributed data sources, saving query results as searchable data extracts, and executing local and web-accessible analytic tools. The series of recorded tasks can then be saved as a reproducible, sharable workflow available for subsequent execution with the original or modified inputs and parameter settings. Integrated data resources include interfaces to the National Center for Biotechnology Information (NCBI) nucleotide and protein databases, the European Molecular Biology Laboratory (EMBL-Bank) non-redundant nucleotide database, the Universal Protein Resource (UniProt), and the UniProt Reference Clusters (UniRef) database. The system offers access to numerous preinstalled, curated analytic tools and also provides researchers with the option of selecting computational tools from a large list of web services including the European Molecular Biology Open Software Suite (EMBOSS), BioMoby, and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The system further allows users to integrate local command line tools residing on their own computers through a client-side Java applet. PMID- 21546553 TI - Widespread expression of piRNA-like molecules in somatic tissues. AB - Piwi-interacting RNA (piRNA) are small RNA abundant in the germline across animal species. In fruit flies and mice, piRNA have been implicated in maintenance of genomic integrity by transposable elements silencing. Outside of the germline, piRNA have only been found in fruit fly ovarian follicle cells. Previous studies have further reported presence of multiple piRNA-like small RNA (pilRNA) in fly heads and a small number of pilRNA have been reported in mouse tissues and in human NK cells. Here, we analyze high-throughput small RNA sequencing data in more than 130 fruit fly, mouse and rhesus macaque samples. The results show widespread presence of pilRNA, displaying all known characteristics of piRNA in multiple somatic tissues of these three species. In mouse pancreas and macaque epididymis, pilRNA abundance was compatible with piRNA abundance in the germline. Using in situ hybridizations, we further demonstrate pilRNA co-localization with mRNA expression of Piwi-family genes in all macaque tissues. Further, using western blot, we have shown the expression of Miwi protein in mouse pancreas. These findings indicate that piRNA-like molecules might play important roles outside of the germline. PMID- 21546554 TI - Informatics in radiology: use of a macro scripting editor to facilitate transfer of dual-energy X-ray absorptiometry reports into an existing departmental voice recognition dictation system. AB - The process of verbally reporting or manually retyping numeric data generated at dual-energy x-ray absorptiometry (DXA) involves numerous pitfalls. With use of a macro scripting editor, a customized macro was created to automate the transfer of data generated by a DXA scanner into a structured voice recognition dictation system without requiring radiologists to type in a medical record number or accession number to identify the study. A preliminary report is generated with use of software for a DXA unit and a customized template that includes numeric and qualitative assessments of osteoporosis as well as data from prior studies if available. A customized macro is then invoked by the macro scripting editor, which selectively transfers the report from the draft document into the voice recognition dictation system, thereby producing a final structured diagnostic report. All of the radiologists surveyed to evaluate this automated method reported ease of software use and greater efficiency in report production. In addition, a random audit of the 800 DXA scans that have been reported with this technique demonstrated no reports generated under an incorrect accession number and no incorrect transfer of data. Automated DXA reporting is now the preferred method of dictation at the authors' institution and represents an inexpensive, accurate, and customizable means of DXA reporting. PMID- 21546555 TI - Informatics in radiology: envisioning the future of e-learning in radiology: an introduction to SCORM. AB - Computer-based learning, or "e-learning," plays an increasingly important role in healthcare education. Modular, standardized approaches to e-learning make learning content portable, reusable, and interoperable. The Shareable Content Object Reference Model (SCORM) is a standard for educational content that builds upon existing standards for e-learning. The "SCORM for Healthcare" model, which is designed to meet the particular needs of learning in health professions, is being developed to improve communication of educational needs, goals, and competencies among healthcare workers, educational providers, and certifying organizations. Radiologists can benefit from SCORM by becoming familiar with its features and the opportunities it affords to improve online learning. PMID- 21546557 TI - Subcellular location and molecular mobility of human cytosolic sulfotransferase 1C1 in living human embryonic kidney 293 cells. AB - Cytosolic sulfotransferases were first isolated from the hepatic cytosol, and they have been localized in the cytoplasm of formaldehyde-fixed human cell samples. The current work was carried out to determine the subcellular localization and molecular mobility of cytosolic sulfotransferases in living human embryonic kidney (HEK) 293 cells. In this work, the subcellular location of human cytosolic sulfotransferase 1C1 (SULT1C1) was studied in cultured HEK293 cells using confocal laser-scanning microscopy. A green fluorescent protein (GFP) tagged SULT1C1 protein was localized in the cytoplasm of living HEK293 cells. This is consistent with results from previous studies on several other cytosolic sulfotransferase isoforms. Fluorescence recovery after photobleaching microscopy was performed to assess the molecular mobility of the expressed GFP-SULT1C1 molecules. The results suggested that the expressed recombinant GFP-SULT1C1 molecules in living HEK293 cells may include both mobile and immobile populations. To obtain additional insights into the subcellular location of SULT1C1, two machine learning algorithms, Sequential Minimal Optimization and Multilayer Perceptron, were used to compute the probability distribution for the localization of SULT1C1 in nine selected cellular compartments. The resulting probability distribution suggested that the most likely subcellular location of SULT1C1 is the cytosol. PMID- 21546556 TI - DNA-dependent protein kinase and ataxia telangiectasia mutated (ATM) promote cell survival in response to NK314, a topoisomerase IIalpha inhibitor. AB - 4-Hydroxy-5-methoxy-2,3-dihydro-1H-[1,3]benzodioxolo[5,6-c]pyrrolo[1,2-f] phenanthridium chloride (NK314) is a benzo[c] phenanthridine alkaloid that inhibits topoisomerase IIalpha, leading to the generation of DNA double-strand breaks (DSBs) and activating the G(2) checkpoint pathway. The purpose of the present studies was to investigate the DNA intercalating properties of NK314, to evaluate the DNA repair mechanisms activated in cells that may lead to resistance to NK314, and to develop mechanism-based combination strategies to maximize the antitumor effect of the compound. A DNA unwinding assay indicated that NK314 intercalates in DNA, a property that likely cooperates with its ability to trap topoisomerase IIalpha in its cleavage complex form. The consequence of this is the formation of DNA DSBs, as demonstrated by pulsed-field gel electrophoresis and H2AX phosphorylation. Clonogenic assays demonstrated a significant sensitization in NK314-treated cells deficient in DNA-dependent protein kinase (DNA-PK) catalytic subunit, Ku80, ataxia telangiectasia mutated (ATM), BRCA2, or XRCC3 compared with wild-type cells, indicating that both nonhomologous end joining and homologous recombination DNA repair pathways contribute to cell survival. Furthermore, both the DNA-PK inhibitor 8-(4-dibenzothienyl)-2-(4 morpholinyl)-4H-1-benzopyran-4-one (NU7441) and the ATM inhibitor 2-(4 morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one (KU55933) significantly sensitized cells to NK314. We conclude that DNA-PK and ATM contribute to cell survival in response to NK314 and could be potential targets for abrogating resistance and maximizing the antitumor effect of NK314. PMID- 21546558 TI - Gastrointestinal basidiobolomycosis in children: an overlooked emerging infection? AB - Basidiobolus ranarum is a known cause of chronic subcutaneous zygomycosis. During the past decade, many cases have been reported with extracutaneous basidiobolomycosis. We aimed to review the medical literature on gastrointestinal basidiobolomycosis (GIB) as an emerging fungal infection causing a serious, and occasionally fatal, paediatric disease. We reviewed all reported cases of visceral basidiobolomycosis with special focus on the gastrointestinal involvement in children. Twenty-six cases of GIB have been reported worldwide, in 14 adults and 12 children. All cases presented with fever, abdominal pain with mass and high blood eosinophilia and were misdiagnosed as other chronic granulomatous diseases or malignancies. A few cases of retroperitoneal, pulmonary, nasal and disseminated basidiobolomycosis have also been reported. Basidiobolomycosis mostly affects young males as a subcutaneous infection. The visceral form of infection is rare. GIB has been scarcely reported in the medical literature, but recently it has been increasingly recognized. GIB poses diagnostic difficulties. Abdominal pain with mass and eosinophilia were present in all cases, highlighting the necessity of considering GIB in the differential diagnosis of this presentation. B. ranarum has been reported to cause disseminated fatal disease in both immune-competent and -compromised individuals. Culture is the gold standard for diagnosis, but the characteristic histopathological picture of chronic granulomas rich in eosinophils and the Splendore-Hoeppli phenomenon are the usual diagnostic tools. Surgery plus long courses of itraconazole treatment, up to 1 year, appear to be the best management options. GIB is an emerging infection that might lead to diagnostic confusion, morbidity and mortality. Diagnosis requires a high index of suspicion in the differential diagnosis of patients with fever, abdominal pain with mass and eosinophilia. PMID- 21546559 TI - Characterization of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates from the community in Morocco. AB - Of 803 community Escherichia coli (n = 767) and Klebsiella pneumoniae (n = 36) isolates collected from patients with urinary tract infections in three Moroccan cities, 10 E. coli (1.3%) and 2 K. pneumoniae (5.6 %) isolates were shown to produce extended-spectrum beta-lactamases (ESBLs). PFGE revealed that the E. coli isolates comprised seven distinct genotypes. The presence of plasmids in the 12 isolates was revealed by conjugation experiments of plasmids from these Enterobacteriaceae strains with E. coli K(12)J(5), with further isolation of the plasmids in the transconjugants. Subsequent nucleotide sequencing indicated that the plasmids encoded the bla(CTX-M), bla(OXA), bla(TEM) and bla(SHV) genes, including genes for CTX-M-15 (n = 11), OXA-1 (n = 11), TEM-1b (n = 4), SHV-5 (n = 1) and SHV-1 (n = 2). Identification of plasmid-mediated quinolone-resistance genes was performed by PCR. The aac(6')Ib-cr variant was detected in all strains, and two strains co-expressed qnrS1, bla(CTX-M-15) and bla(OXA-1) genes. The presence of ESBLs in the Enterobacteriaceae strains studied was probably due to the dissemination of resistance plasmids with the predominant genotype of bla(CTX M-15.). PMID- 21546561 TI - Nosocomial peripancreatic infection associated with Shewanella xiamenensis. AB - Shewanella xiamenensis, a newly established species originally from sea sediments, was repeatedly recovered from peripancreatic drainages in a patient and was the probable pathogen of hospital-acquired peripancreatic infection. A commercially available system misidentified it as Shewanella putrefaciens, suggesting that some previous reported cases with S. putrefaciens infection might have been caused by other Shewanella species. Precise species identification of Shewanella species usually requires gyrB sequencing. PMID- 21546560 TI - Helicobacter marmotae and novel Helicobacter and Campylobacter species isolated from the livers and intestines of prairie dogs. AB - Prairie dogs (Cynomys ludovicianus) are used to study the aetiology and prevention of gallstones because of the similarities of prairie dog and human bile gallstone composition. Epidemiological and experimental studies have suggested a connection between infection with Helicobacter species and cholesterol cholelithiasis, cholecystis and gallbladder cancer. Ten of the 34 prairie dogs in this study had positive Helicobacter species identified by PCR using Helicobacter genus-specific primers. Ten of 34 prairie dogs had positive Campylobacter species identified in the intestine by PCR with Campylobacter genus specific primers. Six Helicobacter sp. isolates and three Campylobacter sp. isolates were identified taxonomically by 16S rRNA gene analysis. The prairie dog helicobacters fell into three clusters adjacent to Helicobacter marmotae. On the basis of 16S rRNA gene sequence analysis, three strains in two adjacent clusters were included in the species H. marmotae. Three strains were only 97.1 % similar to the sequence of H. marmotae and can be considered a novel species with the provisional designation Helicobacter sp. Prairie Dog 3. The prairie dog campylobacters formed a single novel cluster and represent a novel Campylobacter sp. with the provisional designation Campylobacter sp. Prairie Dog. They branched with Campylobacter cuniculorum at 96.3 % similarity and had the greatest sequence similarity to Campylobacter helveticus at 97.1 % similarity. Whether H. marmotae or the novel Helicobacter sp. and Campylobacter sp. identified in prairie dogs play a role in cholesterol gallstones or hepatobiliary disease requires further studies. PMID- 21546562 TI - Severe pneumonia and jaundice in a young man: an atypical presentation of an uncommon disease. AB - We present a patient with an atypical presentation of Fusobacterium infection, the genus responsible for Lemierre's syndrome. This syndrome, which often affects healthy, young people and can be fatal if not recognized and treated early, is defined as a history of recent oropharyngeal infection with clinical or radiological evidence of internal jugular vein thrombosis and isolation of anaerobic pathogens, mainly Fusobacterium necrophorum. The history, presentation, investigations and management of the patient are described and then contrasted with the existing literature surrounding Lemierre's syndrome, once termed the 'forgotten disease'. PMID- 21546563 TI - An echovirus 18-associated outbreak of aseptic meningitis in Taiwan: epidemiology and diagnostic and genetic aspects. AB - In 2006, an outbreak of aseptic meningitis was noted in Taiwan. From January to October 2006, a total of 3283 specimens collected from patients with viral infection, including 173 cerebrospinal fluid (CSF) samples, were examined for virus isolation and identification. Overall, 339 enterovirus (EV)-positive cases were identified by virus culture: echovirus 18 (E18) formed the majority (27.4 %, 93 cases), followed by coxsackievirus B2 (13.8 %, 47 cases) and coxsackievirus A2 (10.8 %, 37 cases). The manifestations of the 93 E18 cases were aseptic meningitis (44.1 %), viral exanthema (23.6 %), acute tonsillitis (15.1 %), acute pharyngitis (14.0 %), acute gastritis (11.8 %), herpangina (7.5 %) and bronchopneumonia (5.3 %). Of 107 E18 isolates identified, 100, 62.5 and 19 % were obtained following culture in RD, MRC-5 and A549 cells, respectively. E18 was identified most frequently from throat swabs (67.2 %) and less frequently from stool samples (15.9 %) and CSF (16.8 %). The detection rate of E18 was 78.2 % from CSF, 50 % from stool samples and 22.9 % from throat swabs. Phylogenetic relationships among the E18 strains were examined. Analysis of the partial VP1 gene showed 3.7-23.8 % variation in sequence compared with sequences from GenBank and, notably, the amino acid change V152S was detected in a protruding loop within the VP1 protein. These results indicate that a genetic variant of E18 was circulating and caused an outbreak of aseptic meningitis in Taiwan in 2006. PMID- 21546564 TI - The chloroplast genome of the green alga Schizomeris leibleinii (Chlorophyceae) provides evidence for bidirectional DNA replication from a single origin in the chaetophorales. AB - In the Chlorophyceae, the chloroplast genome is extraordinarily fluid in architecture and displays unique features relative to other groups of green algae. For the Chaetophorales, 1 of the 5 major lineages of the Chlorophyceae, it has been shown that the distinctive architecture of the 223,902-bp genome of Stigeoclonium helveticum is consistent with bidirectional DNA replication from a single origin. Here, we report the 182,759-bp chloroplast genome sequence of Schizomeris leibleinii, a member of the earliest diverging lineage of the Chaetophorales. Like its Stigeoclonium homolog, the Schizomeris genome lacks a large inverted repeat encoding the rRNA operon and displays a striking bias in coding regions that is associated with a bias in base composition along each strand. Our results support the notion that these two chaetophoralean genomes replicate bidirectionally from a putative origin located in the vicinity of the small subunit ribosomal RNA gene. Their shared structural characteristics were most probably inherited from the common ancestor of all chaetophoralean algae. Short dispersed repeats account for most of the 41-kb size variation between the Schizomeris and Stigeoclonium genomes, and there is no indication that homologous recombination between these repeated elements led to the observed gene rearrangements. A comparison of the extent of variation sustained by the Stigeoclonium and Schizomeris chloroplast DNAs (cpDNAs) with that observed for the cpDNAs of the chlamydomonadalean Chlamydomonas and Volvox suggests that gene rearrangements as well as changes in the abundance of intergenic and intron sequences occurred at a slower pace in the Chaetophorales than in the Chlamydomonadales. PMID- 21546565 TI - Smoking cessation and counseling: knowledge and views of Canadian physical therapists. AB - BACKGROUND: Physical therapists are uniquely positioned in health care to initiate or support smoking cessation (SC). Little is known, however, about their knowledge and views of SC as part of their practices. Objective The purpose of this study was to assess Canadian physical therapists' knowledge about the health effects of smoking, their views about addressing SC in practice, and their self efficacy in enabling patients to quit smoking. Design This study was a cross sectional survey. METHODS: Licensed physical therapists in Canada were surveyed with postal methods. RESULTS: A total of 738 survey questionnaires were returned. The mean age and years of clinical experience of the respondents were 41.9 (SD=10.8) years and 17.4 (SD=11.0), respectively. Most respondents (78.6%) were women. Canadian physical therapists are largely informed about the negative effects of smoking on health. Although 76.9% of the physical therapists agreed or strongly agreed that the profession should be more involved in helping people who smoke quit, only 56.8% of the physical therapists agreed or strongly agreed that they should receive training on SC. More than 70% of the physical therapists reported that they were not prepared to provide counseling and, overall, the level of self-efficacy regarding counseling about SC was low. Lack of resources and time were reported to be key barriers to counseling patients to quit smoking. Limitations The findings of this study are limited to Canadian physical therapists. Response bias and social desirability bias also are potential limiters in this study. CONCLUSIONS: Overall, the majority of physical therapists expressed the view that advising people who smoke to quit is a clinical responsibility and endorsed greater involvement of the profession in helping people who smoke quit. Discordance existed, however, between these views and the physical therapists' interest in receiving training on counseling about SC. This is a benchmark study that has practical implications for targeting training consistent with the profession's mission to improve health by increasing physical therapists' preparedness and self-efficacy regarding counseling about SC. PMID- 21546566 TI - Current perspectives on motor functioning in infants, children, and adults with autism spectrum disorders. AB - Autism spectrum disorders (ASDs) are the most common pediatric diagnoses in the United States. In this perspective article, we propose that a diverse set of motor impairments are present in children and adults with ASDs. Specifically, we will discuss evidence related to gross motor, fine motor, postural control, and imitation/praxis impairments. Moreover, we propose that early motor delays within the first 2 years of life may contribute to the social impairments of children with ASDs; therefore, it is important to address motor impairments through timely assessments and effective interventions. Lastly, we acknowledge the limitations of the evidence currently available and suggest clinical implications for motor assessment and interventions in children with ASDs. In terms of assessment, we believe that comprehensive motor evaluations are warranted for children with ASDs and infants at risk for ASDs. In terms of interventions, there is an urgent need to develop novel embodied interventions grounded in movement and motor learning principles for children with autism. PMID- 21546567 TI - Muscle strengthening in children and adolescents with spastic cerebral palsy: considerations for future resistance training protocols. AB - Resistance training of the lower limbs is now commonly used in clinical practice in children and adolescents with spastic cerebral palsy (CP). However, the effectiveness of this type of training is still disputed. The most recently published systematic review with meta-analysis included interventions such as electrical stimulation and resistance training and found insufficient evidence to support or refute the efficacy of these exercises in children with CP. Thus, the aim of this article is to evaluate the extent to which training protocols from the most recent randomized controlled trials are in keeping with the evidence for effective resistance training in children who are developing typically, as reflected in the training guidelines of the National Strength and Conditioning Association. RECOMMENDATIONS: for resistance training protocols, based on this evidence and appropriate to children with CP, are provided to help guide both future research and clinical practice for resistance training in children with CP. PMID- 21546568 TI - Stromal niche cells protect early leukemic FLT3-ITD+ progenitor cells against first-generation FLT3 tyrosine kinase inhibitors. AB - Targeting constitutively activated FMS-like tyrosine kinase 3 [(FLT3); FLT3-ITD] with tyrosine kinase inhibitor (TKI) in acute myeloid leukemia (AML) leads to clearance of blasts in the periphery but not in the bone marrow, suggesting a protective effect of the marrow niche on leukemic stem cells. In this study, we examined the effect of stromal niche cells on CD34(+) progenitors from patients with FLT3-ITD(+) or wild-type FLT3 (FLT3-WT) AML treated with the TKIs SU5614 or sorafenib. TKIs effectively and specifically inhibited FLT3 and increased the fraction of undivided progenitors in both FLT3-ITD(+) and FLT3-WT samples. Treatment with SU5614 and sorafenib also reduced the number of mature leukemic progenitors, whereas contact with stroma protected against this cell loss. In contrast, primitive long-term progenitors from both FLT3-ITD(+) and FLT3-WT AML were resistant to TKIs. Additional contact with niche cells significantly expanded long-term FLT3-ITD(+) but not FLT3-WT progenitors in the presence of SU5614 but not that of sorafenib. Thus, TKIs with first-generation inhibitors fail to eradicate early leukemic stem/progenitor cells in FLT3-ITD(+) AML. Further, we defined a specific interaction between FLT3-ITD(+) progenitors and niche cells that enables the maintenance of leukemic progenitors in the presence of TKI. Collectively, our findings suggest that molecular therapy may have unpredicted effects on leukemic progenitors, underscoring the necessity of developing strategies to selectively eliminate the malignant stem cell clone. PMID- 21546569 TI - Glycolytic phenotype and AMP kinase modify the pathologic response of tumor xenografts to VEGF neutralization. AB - VEGF antagonists are now widely used cancer therapeutics, but predictive biomarkers of response or toxicity remain unavailable. In this study, we analyzed the effects of anti-VEGF therapy on tumor metabolism and therapeutic response by using an integrated set of imaging techniques, including bioluminescence metabolic imaging, 18-fluorodeoxyglucose positron emission tomography, and MRI imaging and spectroscopy. Our results revealed that anti-VEGF therapy caused a dramatic depletion of glucose and an exhaustion of ATP levels in tumors, although glucose uptake was maintained. These metabolic changes selectively accompanied the presence of large necrotic areas and partial tumor regression in highly glycolytic tumors. In addition, we found that the central metabolic protein kinase AMP-activated protein kinase (AMPK)-a cellular sensor of ATP levels that supports cell viability in response to energy stress-was activated by anti-VEGF therapy in experimental tumors. AMPK-alpha2 attenuation increased glucose consumption, tumor cell sensitivity to glucose starvation, and tumor necrosis following anti-VEGF therapy. Taken together, our findings reveal functional links between the Warburg effect and the AMPK pathway with therapeutic responses to VEGF neutralization in tumor xenograft models. PMID- 21546570 TI - Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL. AB - Combining microtubule-targeting antimitotic drugs with targeted apoptosis potentiators is a promising new chemotherapeutic strategy to treat cancer. In this study, we investigate the cellular mechanism by which navitoclax (previously called ABT-263), a Bcl-2 family inhibitor, potentiates apoptosis triggered by paclitaxel and an inhibitor of kinesin-5 (K5I, also called a KSP inhibitor), across a panel of epithelial cancer lines. By using time-lapse microscopy, we showed that navitoclax has little effect on cell death during interphase, but strongly accelerates apoptosis during mitotic arrest, and greatly increases the fraction of apoptosis-resistant cells that die. By systematically knocking down individual Bcl-2 proteins, we determined that Mcl-1 and Bcl-xL are the primary negative regulators of apoptosis during prolonged mitotic arrest. Mcl-1 levels decrease during mitotic arrest because of an imbalance between synthesis and turnover, and turnover depends in part on the MULE/HUWE1 E3 ligase. The combination of Mcl-1 loss with inhibition of Bcl-xL by navitoclax causes rapid apoptosis in all lines tested. Variation in expression levels of Mcl-1 and Bcl-xL largely determines variation in response to antimitotics alone, and antimitotics combined with navitoclax, across our panel. We concluded that Bcl-xL is a critical target of Bcl-2 family inhibitors for enhancing the lethality of antimitotic drugs in epithelial cancers, and combination treatment with navitoclax and a spindle specific antimitotic, such as a K5I, might be more effective than paclitaxel alone. PMID- 21546571 TI - In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). AB - Human T cells engineered to express a chimeric antigen receptor (CAR) specific for folate receptor-alpha (FRalpha) have shown robust antitumor activity against epithelial cancers in vitro but not in the clinic because of their inability to persist and home to tumor in vivo. In this study, CARs were constructed containing a FRalpha-specific scFv (MOv19) coupled to the T-cell receptor CD3zeta chain signaling module alone (MOv19-zeta) or in combination with the CD137 (4 1BB) costimulatory motif in tandem (MOv19-BBzeta). Primary human T cells transduced to express conventional MOv19-zeta or costimulated MOv19-BBzeta CARs secreted various proinflammatory cytokines, and exerted cytotoxic function when cocultured with FRalpha(+) tumor cells in vitro. However, only transfer of human T cells expressing the costimulated MOv19-BBzeta CAR mediated tumor regression in immunodeficient mice bearing large, established FRalpha(+) human cancer. MOv19 BBzeta CAR T-cell infusion mediated tumor regression in models of metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer. Importantly, tumor response was associated with the selective survival and tumor localization of human T cells in vivo and was only observed in mice receiving costimulated MOv19-BBzeta CAR T cells. T-cell persistence and antitumor activity were primarily antigen-driven; however, antigen-independent CD137 signaling by CAR improved T-cell persistence but not antitumor activity in vivo. Our results show that anti-FRalpha CAR outfitted with CD137 costimulatory signaling in tandem overcome issues of T-cell persistence and tumor localization that limit the conventional FRalpha T-cell targeting strategy to provide potent antitumor activity in vivo. PMID- 21546572 TI - Tumor galectin-1 mediates tumor growth and metastasis through regulation of T cell apoptosis. AB - Galectin-1 (Gal-1), a carbohydrate-binding protein whose secretion is enhanced by hypoxia, promotes tumor aggressiveness by promoting angiogenesis and T-cell apoptosis. However, the importance of tumor versus host Gal-1 in tumor progression is undefined. Here we offer evidence that implicates tumor Gal-1 and its modulation of T-cell immunity in progression. Comparing Gal-1-deficient mice as hosts for Lewis lung carcinoma cells where Gal-1 levels were preserved or knocked down, we found that tumor Gal-1 was more critical than host Gal-1 in promoting tumor growth and spontaneous metastasis. Enhanced growth and metastasis associated with Gal-1 related to its immunomodulatory function, insofar as the benefits of Gal-1 expression to Lewis lung carcinoma growth were abolished in immunodeficient mice. In contrast, angiogenesis, as assessed by microvessel density count, was similar between tumors with divergent Gal-1 levels when examined at a comparable size. Our findings establish that tumor rather than host Gal-1 is responsible for mediating tumor progression through intratumoral immunomodulation, with broad implications in developing novel targeting strategies for Gal-1 in cancer. PMID- 21546573 TI - Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer. AB - Cancer-testis antigens (CTA), such as NY-ESO-1, MAGE-A1, and MAGE-A3, are immunogenic proteins encoded by genes, which are normally expressed only in male germ cells but are activated by ill-defined epigenetic mechanisms in human tumors, including lung cancers. Previously, we reported induction of these CTAs in cancer cells, but not normal cells, by DNA-demethylating agents and histone deacetylase inhibitors using clinically achievable exposure conditions. In the present study, we evaluated chromatin alterations associated with repression/activation of cancer-testis genes in lung cancer cells to further develop gene-induction regimens for cancer immunotherapy. Repression of NY-ESO-1, MAGE-A1, and MAGE-A3 coincided with DNA hypermethylation, recruitment, and binding of polycomb-group proteins, and histone heterochromatin modifications within the promoters of these genes. Derepression coincided with DNA demethylation, dissociation of polycomb proteins, and presence of euchromatin marks within the respective promoters. Short hairpin RNAs were used to inhibit several histone methyltransferases (KMT) and histone demethylases (KDM) that mediate histone methylation and repress gene expression. Knockdown of KMT6, KDM1, or KDM5B markedly enhanced deoxyazacytidine (DAC)-mediated activation of these cancer-testis genes in lung cancer cells. DZNep, a pharmacologic inhibitor of KMT6 expression, recapitulated the effects of KMT6 knockdown. Following DAC-DZNep exposure, lung cancer cells were specifically recognized and lysed by allogeneic lymphocytes expressing recombinant T-cell receptors recognizing NY-ESO-1 and MAGE A3. Combining DNA-demethylating agents with compounds, such as DZNep, that modulate histone lysine methylation may provide a novel epigenetic strategy to augment cancer-testis gene expression as an adjunct to adoptive cancer immunotherapy. PMID- 21546574 TI - Mitochondria-targeted peptide accelerates ATP recovery and reduces ischemic kidney injury. AB - The burst of reactive oxygen species (ROS) during reperfusion of ischemic tissues can trigger the opening of the mitochondrial permeability transition (MPT) pore, resulting in mitochondrial depolarization, decreased ATP synthesis, and increased ROS production. Rapid recovery of ATP upon reperfusion is essential for survival of tubular cells, and inhibition of oxidative damage can limit inflammation. SS 31 is a mitochondria-targeted tetrapeptide that can scavenge mitochondrial ROS and inhibit MPT, suggesting that it may protect against ischemic renal injury. Here, in a rat model of ischemia-reperfusion (IR) injury, treatment with SS-31 protected mitochondrial structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis and necrosis of tubular cells, and abrogated tubular dysfunction. In addition, SS-31 reduced medullary vascular congestion, decreased IR-mediated oxidative stress and the inflammatory response, and accelerated the proliferation of surviving tubular cells as early as 1 day after reperfusion. In summary, these results support MPT as an upstream target for pharmacologic intervention in IR injury and support early protection of mitochondrial function as a therapeutic maneuver to prevent tubular apoptosis and necrosis, reduce oxidative stress, and reduce inflammation. SS-31 holds promise for the prevention and treatment of acute kidney injury. PMID- 21546575 TI - Effect of kidney transplantation on outcomes among patients with hepatitis C. AB - The long-term outcome of kidney transplantation in patients infected with hepatitis C virus (HCV) and end stage renal disease (ESRD) is not well described. We retrospectively identified 230 HCV-infected patients using enzyme immunoassay and nucleic acid testing obtained during the transplant evaluation. Of 207 patients who had a liver biopsy before transplant, 44 underwent 51 follow-up liver biopsies at approximately 5-year intervals either while on the waitlist for a kidney or after kidney transplantation. Advanced fibrosis was present in 10% of patients biopsied, identifying a population that may warrant consideration for combined liver-kidney transplantation. Kidney transplantation does not seem to accelerate liver injury; 77% of kidney recipients who underwent follow-up biopsies showed stable or improved liver histology. There was a higher risk for death during the first 6 months after transplant, but undergoing transplantation conferred a long-term survival advantage over remaining on the waitlist, which was evident by 6 months after transplant (HR, 0.32; 95% CI, 0.17 to 0.62). Furthermore, the risk for death resulting from infection was significantly higher during the first 6 months after transplant (HR, 26.6; 95% CI, 5.01 to 141.3), whereas there was an early (<=6 months) and sustained decrease in the risk for cardiovascular death (HR, 0.20; 95% CI, 0.08 to 0.47). In summary, these data suggest the importance of liver biopsy before transplant and show that kidney transplantation confers a long-term survival benefit among HCV-infected patients with ESRD compared with remaining on the waitlist. Nevertheless, the higher incidence of early infection-related deaths after transplant calls for further study to determine the optimal immunosuppressive protocol. PMID- 21546576 TI - The pro-apoptotic protein Bim is a microRNA target in kidney progenitors. AB - Understanding the mechanisms that regulate nephron progenitors during kidney development should aid development of therapies for renal failure. MicroRNAs, which modulate gene expression through post-transcriptional repression of specific target mRNAs, contribute to the differentiation of stem cells, but their role in nephrogenesis is incompletely understood. Here, we found that the loss of miRNAs in nephron progenitors results in a premature depletion of this population during kidney development. Increased apoptosis and expression of the pro apoptotic protein Bim accompanied this depletion. Profiling of miRNA expression during nephrogenesis identified several highly expressed miRNAs (miR-10a, miR 106b, miR-17-5p) in nephron progenitors that are either known or predicted to target Bim. We propose that modulation of apoptosis by miRNAs may determine congenital nephron endowment. Furthermore, our data implicate the pro-apoptotic protein Bim as a miRNA target in nephron progenitors. PMID- 21546578 TI - Counteracting effect of TRPC1-associated Ca2+ influx on TNF-alpha-induced COX-2 dependent prostaglandin E2 production in human colonic myofibroblasts. AB - TNF-alpha-NF-kappaB signaling plays a central role in inflammation, apoptosis, and neoplasia. One major consequence of this signaling in the gut is increased production of prostaglandin E(2) (PGE(2)) via cyclooxygenase-2 (COX-2) induction in myofibroblasts, which has been reported to be dependent on Ca(2+). In this study, we explored a potential role of canonical transient receptor potential (TRPC) proteins in this Ca(2+)-mediated signaling using a human colonic myofibroblast cell line CCD-18Co. In CCD-18Co cell, treatment with TNF-alpha greatly enhanced Ca(2+) influx induced by store depletion along with increased cell-surface expression of TRPC1 protein (but not of the other TRPC isoforms) and induction of a Gd(3+)-sensitive nonselective cationic conductance. Selective inhibition of TRPC1 expression by small interfering RNA (siRNA) or functionally effective TRPC1 antibody targeting the near-pore region of TRPC1 (T1E3) antagonized the enhancement of store-dependent Ca(2+) influx by TNF-alpha, whereas potentiated TNF-alpha induced PGE(2) production. Overexpression of TRPC1 in CCD-18Co produced opposite consequences. Inhibitors of NF-kappaB (curcumin, SN 50) attenuated TNF-alpha-induced enhancement of TRPC1 expression, store-dependent Ca(2+) influx, and COX-2-dependent PGE(2) production. In contrast, inhibition of calcineurin-nuclear factor of activated T-cell proteins (NFAT) signaling by FK506 or NFAT Activation Inhibitor III enhanced the PGE(2) production without affecting TRPC1 expression and the Ca(2+) influx. Finally, the suppression of store dependent Ca(2+) influx by T1E3 antibody or siRNA knockdown significantly facilitated TNF-alpha-induced NF-kappaB nuclear translocation. In aggregate, these results strongly suggest that, in colonic myofibroblasts, NF-kappaB and NFAT serve as important positive and negative transcriptional regulators of TNF alpha-induced COX-2-dependent PGE(2) production, respectively, at the downstream of TRPC1-associated Ca(2+) influx. PMID- 21546577 TI - Af17 deficiency increases sodium excretion and decreases blood pressure. AB - The putative transcription factor AF17 upregulates the transcription of the epithelial sodium channel (ENaC) genes, but whether AF17 modulates sodium homeostasis and BP is unknown. Here, we generated Af17-deficient mice to determine whether deletion of Af17 leads to sodium wasting and low BP. Compared with wild-type mice, Af17-deficient mice had lower BP (11 mmHg), higher urine volume, and increased sodium excretion despite mildly increased plasma concentrations of aldosterone. Deletion of Af17 led to increased dimethylation of histone H3 K79 and reduced ENaC function. The attenuated function of ENaC resulted from decreased ENaC mRNA and protein expression, fewer active channels, lower open probability, and reduced effective activity. In contrast, inducing high levels of plasma aldosterone by a variety of methods completely compensated for Af17 deficiency with respect to sodium handling and BP. Taken together, these data identify Af17 as a potential locus for the maintenance of sodium and BP homeostasis and suggest that a particular histone modification is directly linked to these processes. Af17-mediated regulation of BP is largely, but not exclusively, the result of modulating ENaC, suggesting it has potential as a therapeutic target for the control of BP. PMID- 21546579 TI - Intestinal SR-BI is upregulated in insulin-resistant states and is associated with overproduction of intestinal apoB48-containing lipoproteins. AB - Intestinal lipid dysregulation is a common feature of insulin-resistant states. The present study investigated alterations in gene expression of key proteins involved in the active absorption of dietary fat and cholesterol in response to development of insulin resistance. Studies were conducted in two diet-induced animal models of insulin resistance: fructose-fed hamster and high-fat-fed mouse. Changes in the mRNA abundance of lipid transporters, adenosine triphosphate cassette (ABC) G5, ABCG8, FA-CoA ligase fatty acid translocase P4, Niemann-Pick C1-Like1 (NPC1L1), fatty acid transport protein 4 (FATP4), and Scavenger Receptor Class B Type I (SR-BI), were assessed in intestinal fragments (duodenum, jejunum, and ileum) using quantitative real-time PCR. Of all the transporters evaluated, SR-B1 showed the most significant changes in both animal models examined. A marked stimulation of SR-B1 expression was observed in all intestinal segments examined in both insulin-resistant animal models. The link between SR-BI expression and intestinal lipoprotein production was then examined in the Caco-2 cell model. SR-B1 overexpression in Caco-2 cells increased apolipoprotein B (apoB) 100 and apoB48 secretion, whereas RNAi knock down of SR-B1 decreased secretion of both apoB100 and apoB48. We also observed changes in subcellular distribution of SR-B1 in response to exogenous lipid and insulin. Confocal microscopy revealed marked changes in SR-BI subcellular distribution in response to both exogenous lipids (oleate) and insulin. In summary, marked stimulation of intestinal SR-BI occurs in vivo in animal models of diet-induced insulin resistance, and modulation of SR-BI in vitro regulates production of apoB containing lipoprotein particles. We postulate that apical and/or basolateral SR BI may play an important role in intestinal chylomicron production and may contribute to chylomicron overproduction normally observed in insulin-resistant states. PMID- 21546581 TI - Drug trials for older people. AB - We are living in an era of unprecedented aging, with over a billion older people expected to be alive within a few decades. Despite this predictable demographic, drug trials have not kept pace with change and we now have significant evidence practice gaps. These have arisen due to inappropriate age limits in randomized controlled trials and the near-universal exclusion of frail older people from studies. Suggested solutions include the abolition of age limits in new randomized controlled trials, and the routine measurement of frailty, with a new generation of randomized controlled trials to establish whether treatments remain effective and safe in old age and increasing frailty. We should all have a personal interest in ensuring that drugs used in our old age are truly effective. PMID- 21546580 TI - cAMP-guanine exchange factor protection from bile acid-induced hepatocyte apoptosis involves glycogen synthase kinase regulation of c-Jun NH2-terminal kinase. AB - Cholestatic liver disorders are accompanied by the hepatic accumulation of cytotoxic bile acids that induce cell death. Increases in cAMP protect hepatocytes from bile acid-induced apoptosis by a cAMP-guanine exchange factor (cAMP-GEF)/phosphoinositide-3-kinase (PI3K)/Akt pathway. The aim of these studies was to identify the downstream substrate in this pathway and to determine at what level in the apoptotic cascade cytoprotection occurs. Since inhibitory phosphorylation of glycogen synthase kinase-3 (GSK) occurs downstream of PI3K/Akt and this phosphorylation has been implicated in cell survival, we conducted studies to determine whether GSK was downstream in cAMP-GEF/PI3K/Akt-mediated cytoprotection. Our results show that treatment of hepatocytes with the cAMP-GEF specific analog, 4-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cAMP, results in PI3K-dependent phosphorylation of GSK. Direct chemical inhibition of GSK in rat hepatocytes or human HUH7-NTCP cells with several structurally and functionally distinct inhibitors including bromoindirubin-3'-oxime (BIO), maleimides (SB216763, SB415286), thiadiazolidine derivatives, and LiCl attenuates apoptosis induced by glycochenodeoxycholate (GCDC). In addition, genetic silencing of the GSK beta isoform with small interfering RNA attenuates GCDC apoptosis in HUH7-NTCP cells. Adenoviral inhibition of the Rap1 blocks both cAMP GEF-mediated cytoprotection against GCDC-induced apoptosis and Akt/GSK3beta phosphorylation. GCDC-induced phosphorylation of the proapoptotic kinase, c-Jun NH(2)-terminal kinase (JNK) is inhibited by GSK inhibition or cAMP-GEF activation. GCDC-induced apoptosis is accompanied by phosphorylation of the endoplasmic reticulum stress markers pIEF2alpha and IRE-1, and pretreatment with the cAMP-GEF analog or GSK inhibitors prevents this phosphorylation. Collectively, our results support the presence of a cAMP/cAMP GEF/Rap1/PI3K/Akt/GSKbeta survival pathway in hepatocytes that inhibits bile acid induced JNK phosphorylation. PMID- 21546582 TI - Absolute strength and loss of strength as predictors of mobility decline in older adults: the InCHIANTI study. AB - BACKGROUND: Theoretical definitions of sarcopenia traditionally emphasize age related loss of muscle strength; however, most analyses of the association between strength and mobility examine strength at a single time point. This study sought to identify sex-specific cutpoints for muscle strength and power (at one time point) and 3-year changes in strength and power that would maximize prediction of 3-year mobility decline. METHODS: Longitudinal analysis of 934 adults aged >=65 years enrolled in the Invecchiare in Chianti study was conducted. Grip strength, knee extension strength, and lower extremity power were measured at baseline and 3 years postenrollment. Mobility function (gait speed and self-reported mobility disability) was measured at 3 and 6 years postenrollment. Classification and regression tree analysis was used to predict mobility decline from Years 3 to 6. RESULTS: Men with knee extension strength <19.2 kg and grip strength <39.0 kg had clinically meaningful declines in gait speed of .24 m/s. Furthermore, men with power <105 W were nearly nine times more likely to develop incident mobility disability (likelihood ratio = 8.68; 95% confidence interval = 3.91, 19.44). Among women, knee extension strength <18.0 kg was associated with a minimal gait speed decline of 0.06 m/s, and women with leg power <64 W were three times more likely to develop incident mobility disability (likelihood ratio = 3.01; 95% confidence interval = 1.79, 5.08). Three-year changes in strength and power did not predict mobility decline in either sex. CONCLUSIONS: Findings suggest that strength and power measured at one time point are more predictive of mobility decline than 3-year changes and that low strength and power are particularly powerful risk factors in men. PMID- 21546583 TI - Carboxypeptidase activity common to viridans group streptococci cleaves angiotensin I to angiotensin II: an activity homologous to angiotensin-converting enzyme (ACE). AB - We have found that Streptococcus gordonii FSS2, an infective endocarditis (IE) isolate, expresses a dipeptidyl-carboxypeptidase with activity homologous to angiotensin-converting enzyme (ACE). The carboxypeptidase activity was purified to homogeneity as a complex/aggregate from a bacterial surface extract and was also active as a 165 kDa monomer. The specific activity for the carboxypeptidase activity was eightfold higher than that for recombinant human ACE. Selected ACE inhibitors, captopril, lisinopril and enalapril, did not inhibit the ACE activity. The carboxypeptidase also hydrolysed the Aalpha and Bbeta-chains of human fibrinogen, which resulted in impaired fibrin formation by thrombin. The gene encoding ACE carboxypeptidase activity was sequenced and the inferred polypeptide product showed 99 % amino acid homology to SGO_0566, sgc, 'challisin' of S. gordonii CL1 Challis, and had no significant amino acid sequence homology to human ACE. Homologues of challisin ACE activity were commonly detected among the viridans group streptococci most often associated with IE. PMID- 21546584 TI - Stenotrophomonas maltophilia strains replicate and persist in the murine lung, but to significantly different degrees. AB - The environmental bacterium Stenotrophomonas maltophilia is increasingly described as a multidrug-resistant pathogen of humans, being associated with pneumonia, among other diseases. But the degree to which S. maltophilia is capable of replicating in a mammalian host has been an issue of controversy. Using a model of intranasal inoculation into adult A/J mice, we now document that S. maltophilia strain K279a, the clinical isolate of S. maltophilia whose complete genome sequence was recently determined, is in fact capable of replicating in lungs, displaying as much as a 10-fold increase in c.f.u. in the first 8 h of infection. Importantly, as few as 10(4) c.f.u. deposited into the A/J lung was sufficient to promote bacterial outgrowth. Bacterial replication in the lungs of the A/J mice was followed by elevations in pro-inflammatory cytokines and also promoted resistance to subsequent challenge. We also found that DBA/2 mice were permissive for S. maltophilia K279a replication, although the level of growth and persistence in these animals was less than it was in the A/J mice. In contrast, the BALB/c and C57BL/6 mouse strains were non-permissive for S. maltophilia K279a growth. Interestingly, when five additional clinical isolates were introduced into the A/J lung, marked differences in survival were observed, with some strains being much less infective than K279a and others being appreciably more infective. These data suggest that the presence of major virulence determinants is variable among clinical isolates. Overall, this study confirms the infectivity of S. maltophilia for the mammalian host, and illustrates how both host and bacterial factors affect the outcome of Stenotrophomonas infection. PMID- 21546585 TI - The flavanone naringenin reduces the production of quorum sensing-controlled virulence factors in Pseudomonas aeruginosa PAO1. AB - Preliminary screening of the Malagasy plant Combretum albiflorum for compounds attenuating the production of quorum sensing (QS)-controlled virulence factors in bacteria led to the identification of active fractions containing flavonoids. In the present study, several flavonoids belonging to the flavone, flavanone, flavonol and chalcone structural groups were screened for their capacity to reduce the production of QS-controlled factors in the opportunistic pathogen Pseudomonas aeruginosa (strain PAO1). Flavanones (i.e. naringenin, eriodictyol and taxifolin) significantly reduced the production of pyocyanin and elastase in P. aeruginosa without affecting bacterial growth. Consistently, naringenin and taxifolin reduced the expression of several QS-controlled genes (i.e. lasI, lasR, rhlI, rhlR, lasA, lasB, phzA1 and rhlA) in P. aeruginosa PAO1. Naringenin also dramatically reduced the production of the acylhomoserine lactones N-(3 oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) and N-butanoyl-L-homoserine lactone (C4-HSL), which is driven by the lasI and rhlI gene products, respectively. In addition, using mutant strains deficient for autoinduction (DeltalasI and DeltarhlI) and LasR- and RhlR-based biosensors, it was shown that QS inhibition by naringenin not only is the consequence of a reduced production of autoinduction compounds but also results from a defect in the proper functioning of the RlhR-C4-HSL complex. Widely distributed in the plant kingdom, flavonoids are known for their numerous and determinant roles in plant physiology, plant development and in the success of plant-rhizobia interactions, but, as shown here, some of them also have a role as inhibitors of the virulence of pathogenic bacteria by interfering with QS mechanisms. PMID- 21546586 TI - Role of Mycoplasma pneumoniae glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in mediating interactions with the human extracellular matrix. AB - In different, phylogenetically unrelated micro-organisms, glycolytic enzymes play a dual role. In the cytosol they are involved in metabolic reactions whereas the surface-localized fraction of the enzymes contributes to adhesion and virulence. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a typical member of this group of multifunctional proteins. In this study, we characterized the GAPDH of Mycoplasma pneumoniae, a common pathogen of the human respiratory mucosa. Full length GAPDH of M. pneumoniae was successfully expressed and used to produce a polyclonal antiserum. By immunofluorescence, colony blot and ELISA experiments with different fractions of the M. pneumoniae proteins, GAPDH was demonstrated to be present in the cytosol and at even higher concentrations at the surface of mycoplasmas. Nevertheless, antibodies against recombinant GAPDH were not detected in sera of immunized animals or of patients with confirmed M. pneumoniae infection. Recombinant GAPDH bound to different human cell lines in a concentration-dependent manner, and binding was inhibited by specific anti-GAPDH serum. In contrast, this antiserum did not significantly influence the adherence of M. pneumoniae to HeLa cells. When different human extracellular matrix proteins were tested in Western blot assays, GAPDH bound to fibrinogen. The results showed that the GAPDH of M. pneumoniae is a member of the family of cytosol-localized glycolytic enzymes, which also occur at the surface of the bacterium, and mediates interactions with the extracellular matrix proteins of the human host. Thus, the surface-exposed fraction of GAPDH may be a factor that contributes to the successful colonization of the human respiratory tract by M. pneumoniae. PMID- 21546587 TI - Application of suppressive subtractive hybridization to the identification of genetic differences between two Lactococcus garvieae strains showing distinct differences in virulence for rainbow trout and mouse. AB - Lactococcus garvieae is the causative microbial agent of lactococcosis, an important and damaging fish disease in aquaculture. This bacterium has also been isolated from vegetables, milk, cheese, meat and sausages, from cow and buffalo as a mastitis agent, and even from humans, as an opportunistic infectious agent. In this work pathogenicity experiments were performed in rainbow trout and mouse models with strains isolated from human (L. garvieae HF) and rainbow trout (L. garvieae UNIUDO74; henceforth referred to as 074). The mean LD(50) value in rainbow trout obtained for strain 074 was 2.1 * 10(2) +/- 84 per fish. High doses of the bacteria caused specific signs of disease as well as histological alterations in mice. In contrast, strain HF did not prove to be pathogenic either for rainbow trout or for mice. Based on these virulence differences, two suppressive subtractive hybridizations were carried out to identify unique genetic sequences present in L. garvieae HF (SSHI) and L. garvieae 074 (SSHII). Differential dot-blot screening of the subtracted libraries allowed the identification of 26 and 13 putative ORFs specific for L. garvieae HF and L. garvieae 074, respectively. Additionally, a PCR-based screening of 12 of the 26 HF-specific putative ORFs and the 13 074-specific ones was conducted to identify their presence/absence in 25 L. garvieae strains isolated from different origins and geographical areas. This study demonstrates the existence of genetic heterogeneity within L. garvieae isolates and provides a more complete picture of the genetic background of this bacterium. PMID- 21546588 TI - Phosphorylation of the epidermal growth factor receptor (EGFR) is essential for interleukin-8 release from intestinal epithelial cells in response to challenge with Escherichia coli O157 : H7 flagellin. AB - Enterohaemorrhagic Escherichia coli O157 : H7 is a major foodborne and environmental pathogen responsible for both sporadic cases and outbreaks of food poisoning, which can lead to serious sequelae, such as haemolytic uraemic syndrome. The structural subunit of E. coli O157 : H7 flagella is flagellin, which is both the antigenic determinant of the H7 serotype, an important factor in colonization, and an immunomodulatory protein that has been determined to be a major pro-inflammatory component through the instigation of host cell signalling pathways. Flagellin has highly conserved N- and C-terminal regions that are recognized by the host cell pattern recognition receptor Toll-like receptor (TLR) 5. Activation of this receptor triggers cell signalling cascades, which are known to activate host cell kinases and transcription factors that respond with the production of inflammatory mediators such as the chemokine interleukin-8 (IL-8), although the exact components of this pathway are not yet fully characterized. We demonstrate that E. coli O157 : H7-derived flagellin induces rapid phosphorylation of the epidermal growth factor receptor (EGFR), as an early event in intestinal epithelial cell signalling, and that this is required for the release of the pro-inflammatory cytokine IL-8. PMID- 21546589 TI - FvbA is required for vibriobactin utilization in Pseudomonas aeruginosa. AB - Bacteria acquire iron through a highly specific mechanism involving iron chelating molecules termed siderophores. The Gram-negative bacterium Pseudomonas aeruginosa can utilize siderophores produced by other micro-organisms to facilitate iron uptake. Here we show that a P. aeruginosa strain deficient in siderophore production can use the Vibrio cholerae siderophore vibriobactin as an iron source. In addition, we identified a P. aeruginosa gene, PA4156 (fvbA), encoding a protein highly homologous to the V. cholerae vibriobactin receptor (ViuA). A P. aeruginosa mutant in the two endogenous siderophores (pyoverdine and pyochelin) and in fvbA was unable to utilize vibriobactin as an iron source. Additionally, preliminary analyses revealed the involvement of vibriobactin, Fur protein and an IclR-type regulator, FvbR (PA4157), in fvbA regulation. PMID- 21546590 TI - Robotic-assisted parathyroidectomy: a feasibility study. AB - OBJECTIVE: Targeted parathyroidectomy is the gold standard for localized parathyroid disease. A robotic-assisted approach has not been investigated. The aim was to assess the feasibility of a robotic technique that avoids a neck scar. STUDY DESIGN: Feasibility study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Eleven patients with primary hyperparathyroidism were prospectively evaluated. Triple modality concordant localization was a prerequisite. All patients underwent robotic-assisted parathyroidectomy (RAP). Outcome variables assessed were operative time, voice change, biochemical cure, and histopathological confirmation. Patient-reported outcome measures (PROMs) included subjective assessment of pain and scar cosmesis, Voice Handicap Index 2, and EQ-5D quality-of-life assessment. Mean follow-up was 6 months (range, 3-12 months). RESULTS: The parathyroid adenoma was successfully excised in all cases with negligible blood loss (<5 mL). There was 1 conversion. There was no voice change in any case. Robot docking time plateaued to 10 minutes after 8 cases. Mean exposure and console times (31 and 51 minutes, respectively) were affected by body habitus. The mean visual analog scale for scar cosmesis was 75% on the first postoperative day, improving to 92% at 6 months and 95% at 1 year. Pain scores decreased to 8% at 2 weeks. All 5 EQ-5D quality-of-life parameters significantly improved following surgery. CONCLUSION: The robotic approach is feasible for performing targeted parathyroidectomy that avoids a neck scar. The clinical efficacy and cost-effectiveness of the robotic approach compared with conventional targeted parathyroidectomy warrant further evaluation to establish if this represents a viable alternative to the existing targeted techniques. PMID- 21546591 TI - Framing the access to dental care issue: an opportunity for the dental education community. PMID- 21546592 TI - Factors for increasing adoption of e-courses among dental and dental hygiene faculty members. AB - The incorporation of web-based learning into the dental curriculum has been consistently recommended in the literature on reform in dental education. There has been growing support for web-based learning in dental and dental hygiene education as demonstrated by deans' identifying this as a planned curricular innovation. The purpose of our study was to explore characteristics of e-courses that may serve to increase adoption among dental and dental hygiene faculty members. Eight ninety-minute focus groups (three dental; five dental hygiene) were conducted with dental (n=27) and dental hygiene (n=23) faculty members from six academic institutions. The resulting data were analyzed to identify two overarching themes and associated subthemes with regard to benefits and barriers influencing adoption of e-courses. A working conceptual framework, based on the Diffusion of Innovations, was developed from these themes to understand the characteristics that may influence the rate of adoption of e-courses among dental and dental hygiene faculty members. Analysis of the data revealed four main adoption barriers: 1) low perceived relative advantage to faculty members; 2) low compatibility with current curriculum; 3) high perceived time commitment; and 4) complexity of e-course development. This exploratory assessment identifies leverage points for facilitating the adoption and sustainability of e-courses in dental and dental hygiene education. PMID- 21546593 TI - Assessment of willingness to provide diabetes education and counseling in a dental school clinic. AB - Diabetes mellitus is a major public health concern for the U.S. population because of its high prevalence and long-term health implications. The purpose of this study was to apply the Theory of Planned Behavior (TPB) to assess dental faculty member and student willingness to provide diabetes education and counseling to patients in a dental school. A survey was administered to dental students (n=101 respondents) and faculty members (n=39 respondents), and summary scores for seven diabetic educational activities and TPB constructs were calculated and analyzed. Participants were most willing to refer a patient to a physician for treatment and provide basic information about diabetes and oral health, and they were least willing to provide basic information about diabetic medications. Importance, self-efficacy, and barriers constructs predicted willingness to perform diabetic educational or counseling activities. Our findings suggest that, when developing innovative approaches to expand diabetic education and counseling in our dental education environment, programs should demonstrate how diabetic counseling can improve patients' health and should include diabetic management skills-building in the curriculum. PMID- 21546594 TI - Evaluating a dental diagnostic terminology in an electronic health record. AB - Standardized treatment procedure codes and terms are routinely used in dentistry. Utilization of a diagnostic terminology is common in medicine, but there is not a satisfactory or commonly standardized dental diagnostic terminology available at this time. Recent advances in dental informatics have provided an opportunity for inclusion of diagnostic codes and terms as part of treatment planning and documentation in the patient treatment history. This article reports the results of the use of a diagnostic coding system in a large dental school's predoctoral clinical practice. A list of diagnostic codes and terms, called Z codes, was developed by dental faculty members. The diagnostic codes and terms were implemented into an electronic health record (EHR) for use in a predoctoral dental clinic. The utilization of diagnostic terms was quantified. The validity of Z code entry was evaluated by comparing the diagnostic term entered to the procedure performed, where valid diagnosis-procedure associations were determined by consensus among three calibrated academically based dentists. A total of 115,004 dental procedures were entered into the EHR during the year sampled. Of those, 43,053 were excluded from this analysis because they represent diagnosis or other procedures unrelated to treatments. Among the 71,951 treatment procedures, 27,973 had diagnoses assigned to them with an overall utilization of 38.9 percent. Of the 147 available Z codes, ninety-three were used (63.3 percent). There were 335 unique procedures provided and 2,127 procedure/diagnosis pairs captured in the EHR. Overall, 76.7 percent of the diagnoses entered were valid. We conclude that dental diagnostic terminology can be incorporated within an electronic health record and utilized in an academic clinical environment. Challenges remain in the development of terms and implementation and ease of use that, if resolved, would improve the utilization. PMID- 21546595 TI - Predoctoral and postdoctoral students' perspectives about pediatric dental behavior guidance. AB - This study compared acceptability scores of pediatric dental behavior guidance between predoctoral senior dental students and postdoctoral pediatric dentistry graduates. The scores were obtained with an anonymous survey that included twenty five items related to behavior guidance techniques or situations, with the degree of acceptability of each being marked on a visual analog scale. Demographic data collected included year of graduation from the postdoctoral program, type of employment, being board-certified or not, gender, marital and parental status, previously receiving dental or medical treatment, and degree of unpleasantness from these treatments. Thirty-nine predoctoral and fifty-one postdoctoral surveys were compared. Analysis of variance (ANOVA) indicated that the predoctoral acceptability scores were statistically significantly higher than the postdoctoral scores for not allowing the child to speak during treatment, voice control, hand over mouth, active immobilization, and providing an exact explanation to the child. The predoctoral scores were lower than the postdoctoral scores for not using local anesthetic when the child does not want it, parent's presence in the operatory during treatment, or talking with the dentist during treatment. ANOVA of the predoctoral and postdoctoral scores combined indicated statistically significant differences between scores from male and females respondents for parent talking with the dentist during treatment; between married and not married respondents for hand over mouth, encouraging the child not to be a coward, the child being allowed to stop the treatment, and the parent being in the operatory during treatment; and between parents and not parents respondents for child not allowed to speak during the treatment, voice control, and hand over mouth. This study found that perspectives about pediatric dental behavior guidance are influenced by pre- and postdoctoral education and postgraduate experience. PMID- 21546596 TI - Socialization of new dental therapists on entering the profession. AB - Dental therapy is relatively new in the United States. This qualitative study examines the experiences and impressions of the inaugural class of the first dental school-based dental therapy program in the United States. A grounded theory design using open-ended interviews and focus groups was carried out with the nine students in the class at the beginning of their program and after the fall and spring semesters of their first year. Student responses were audiotaped, transcribed verbatim, and presented to the students for feedback and clarification. Results show that students started with an idealistic perception of dental therapy that was consistent with the specific provision of the law creating dental therapy. The team learning approach in which dental therapy students learn alongside dental and dental hygiene students provided the social interaction that allowed them to better articulate and distinguish dental therapy from those other dental professions. In the absence of dental therapists who could serve as role models, the program director, who is perceived to be the dental therapy expert, has assumed the role of the primary socializer. Faculty members are challenged to fulfill their role as role models regardless of their perception of the dental therapy model. PMID- 21546597 TI - Transition of a traditional pharmacology course for dental students to an online delivery format: a pilot project. AB - The purpose of this report is to describe the rationale and subsequent transition of a pharmacology course for dental students from a traditional face-to-face lecture format to online delivery using a course management system (CMS). A dental school faculty member with dental and pharmacology degrees and a Ph.D. was asked to serve as course director and to develop and implement a nontraditional course using the Blackboard CMS technology, which houses asynchronous course content materials, study guides, and online resource materials. Respondus software was used to create, manage, and administer weekly online quizzes. A comprehensive midterm and final examination were conducted in a traditional face to-face setting. A survey was used to capture student satisfaction with this self directed introductory pharmacology course. Participants were second-year dental students (Classes of 2011 and 2012). There was a survey response rate of 91 percent (179/197). The Likert-style survey questions produced ordinal data from which the median and interquartile range were calculated. On a scale in which 1=Poor, 5=Excellent, the median evaluation for the instructor was 4 (IQR=1.5). On a global question that asked how students rate the course overall, the median score was 4 (IQR=1.0). Results show that a majority of students were positive about the online delivery of the introductory pharmacology course and for many students this was their first online course experience. Resistance to self directed learning was a theme with those students who rated the course poorly. In a comparison of overall course grades from the previous year, student performance in this course was much stronger. As a result of student feedback seeking more interaction with the course director, it was determined that the next time the course is offered there will be additional opportunities for greater face-to-face time with the instructor. Ongoing evaluation will be important as new teaching technologies emerge and are adopted for teaching and learning. PMID- 21546598 TI - Incoming dental students' expectations and acceptance of an electronic textbook program. AB - Since 2005, the Louisiana State University Health Sciences Center School of Dentistry has required the VitalSource Technologies, Inc. Bookshelf as the textbook program for all dental students. In a 2008 survey, four classes of dental students expressed dissatisfaction with most features of the bookshelf. With the expectation that incoming students would be more accustomed and amenable to digital textbooks and to further determine student attitudes toward electronic textbooks, we developed two surveys for first-year dental students in the class of 2013. The sixty-five first-year students received a survey (S1) one week before they were introduced to the e-textbook program. Questions centered on their undergraduate experience with e-books and their expectations of studying with an electronic textbook collection. In the second survey (S2), sent nine months later, the questions focused on students' opinion of the VitalSource Bookshelf. Forty-five students (69.2 percent) completed the S1 survey. Of those, thirty-six (80 percent) responded that they never used e-textbooks in college. Of the nine students who responded that they used e-books, only two liked them without reservations. The response rate to S2 increased to fifty students (77 percent). After using VitalSource for nine months, thirty-three students (66 percent) indicated a preference for reading print textbooks, compared to forty seven students (57.3 percent) of the four classes surveyed in 2008. Although we expected incoming dental students to have had previous experience with e textbooks, only nine students had used e-books in college courses. Few students indicated preference for e-textbooks, and over half of the group was undecided. After experience with VitalSource for first-year courses, students indicated that they like VitalSource for the ability to search for specific topics across the entire collection of dental books, but not for reading large amounts of text. PMID- 21546599 TI - Relationship of biomedical science content acquisition performance to students' level of PBL group interaction: are students learning during PBL group? AB - This study assessed biomedical science content acquisition from problem-based learning (PBL) and its relationship to students' level of group interaction. We hypothesized that learning in preparation for exams results primarily from individual study of post-case learning objectives and that outcomes would be unrelated to students' group involvement. During dental curricular years 1 and 2, student-generated biomedical learning issues (LIs) were identified from six randomly chosen PBL cases. Knowledge and application of case concepts were assessed with quizzes based on the identified LIs prior to dissemination of the learning objectives. Students and facilitators were surveyed on students' level of group involvement for the assessed LI topics. Year 1 students had significantly higher assessment scores (p=0.0001). For both student classes, means were significantly higher for the recall item (Q1) than for the application item (Q2). Q1 scores increased along with the student's reported role for Year 1 (p=0.04). However, there was no relationship between the student's reported role and Q1 for Year 2 (p=0.20). There was no relationship between the student's reported role and Q2 for Year 1 (p=0.09) or Year 2 (p=0.19). This suggests that students' level of group involvement on the biomedical learning issues did not significantly impact students' assessment performance. PMID- 21546600 TI - Evaluation of a new assessment tool in problem-based learning tutorials in dental education. AB - The Harvard School of Dental Medicine (HSDM) uses a hybrid problem-based learning (PBL) approach to teaching in the D.M.D. curriculum. Each tutorial group at HSDM is made up of eight to ten students. The objective of this study was to examine the performance of the students in the tutorial sessions as assessed by the tutor. A total of ten tutorial blocks led by twenty-four tutorial leaders were completed at HSDM between summer 2008 and fall 2009. All of the tutors were calibrated to a new assessment system that was developed for student assessment in the tutorials. The students were assessed on three major domains: knowledge acquisition, problem-solving and analytical thinking skills, and personal and interpersonal development. The tutors evaluated the students assigned to their group after the end of each block. Students also filled out a self-assessment form. Simple descriptive statistics were used to summarize the evaluations of the tutors. A total of 290 student evaluations from ten tutorial blocks were available for analysis. Tutors reported that 64 percent of the students preferred to communicate verbally without prompting and 68 percent of students submitted written reports to the groups during tutorial sessions. Tutors reported that a majority of students brought new information to each tutorial session (86.5 percent), brought information that facilitated others' learning (88.7 percent), integrated newly acquired knowledge with previous knowledge (92.7 percent), applied knowledge from self-study to explain issues during case discussions (91.7 percent), asked appropriate questions to stimulate discussions (87.3 percent), generated hypotheses to explain problems under discussion (83.8 percent), evaluated the hypotheses in light of available evidence (85.5 percent), defined and took responsibility for learning goals and objectives (89.3 percent), responded well to criticism (91.7 percent), took a leadership role (74.5 percent), and demonstrated sensitivity to psychosocial issues (88.6 percent). Student communication that tended to take over the group process in a non contributory manner was reported in only 2 percent of the evaluations. Overall, students participating in PBL tutorial sessions appear to exhibit problem-solving and analytical thinking skills and personal and interpersonal attributes. PMID- 21546601 TI - Oral health promotion through an online training program for medical students. AB - The objective of this study was to compare the impact on knowledge and counseling skills of face-to-face and Internet-based oral health training programs on medical students. Participants consisted of 148 (82 percent) of the 180 invited students attending their fifth academic year at the Faculty of Medicine, University of Sao Paulo, Brasil, in 2007. The interventions took place during a three-month training period in the clinical Center for Health Promotion, which comprised part of a clerkship in Internal Medicine. The students were divided into four groups: 1) Control Group (Control), with basic intervention; 2) Brochure Group (Br), with basic intervention plus complete brochure with oral health themes; 3) Cybertutor Group (Cy), with basic intervention plus access to an Internet-based training program about oral health themes; and 4) Cybertutor + Contact Group (Cy+C), the same as Cy plus brief proactive contact with a tutor. The impact of these interventions on student knowledge was measured with pre- and post assessments, and student skills in asking and counseling about oral health were assessed with an objective structured clinical examination (OSCE). Multivariate logistic regression models were applied to identify the odds ratios of scoring above Control's medians on the final assessment and the OSCE. In the results, Cy+C performed significantly better than Control on both the final assessment (OR 9.4; 95% CI 2.7-32.8) and the OSCE (OR 5.6; 95% CI 1.9-16.3) and outperformed all the other groups. The Cy+C group showed the most significant increase in knowledge and the best skills in asking and counseling about oral health. PMID- 21546602 TI - Dental student skill retention eight months after simulator-supported training in oral radiology. AB - The purpose of this project was to investigate the long-term effects on skill to interpret spatial information in radiographs after conventional and simulator supported training. The study was a follow-up of a previously reported randomized experimental study. The original study population was comprised of fifty-seven dental students. Forty-five individuals agreed to participate in a follow-up study eight months after completion of the original study. During the time interval between completion of the previous study and the follow-up study, the participants underwent an examination in oral radiology and had theoretical and clinical training in other topics than oral radiology. Skill at interpreting spatial information in radiographs was assessed with a previously used test instrument. The test instrument was identical with the instrument used for baseline assessment in the original study. The results showed that the skill to interpret spatial relations in radiographs eight months after completion of simulator-supported training was significantly better (p=0.01) than before training. The conventional training showed almost the same pattern, but the difference was smaller and not statistically significant (p=0.11). It is concluded that simulator-supported training is a valuable adjunct to conventional educational methods in oral radiology. PMID- 21546603 TI - Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with increased systemic inflammation. AB - OBJECTIVE: The goal of this study was to assess the independent and collective associations of hepatic steatosis, obesity, and the metabolic syndrome with elevated high-sensitivity C-reactive protein (hs-CRP) levels. METHODS AND RESULTS: We evaluated 2388 individuals without clinical cardiovascular disease between December 2004 and December 2006. Hepatic steatosis was diagnosed by ultrasound, and the metabolic syndrome was defined using National Heart, Lung, and Blood Institute criteria. The cut point of >=3 mg/L was used to define high hs-CRP. Multivariate logistic regression was used to assess the independent and collective associations of hepatic steatosis, obesity, and the metabolic syndrome with high hs-CRP. Steatosis was detected in 32% of participants, 23% met criteria for metabolic syndrome, and 17% were obese. After multivariate regression, hepatic steatosis (odds ratio [OR] 2.07; 95% CI 1.68 to 2.56), obesity (OR 3.00; 95% CI 2.39 to 3.80), and the metabolic syndrome (2.39; 95% CI 1.88 to 3.04) were all independently associated with high hs-CRP. Combinations of these factors were associated with an additive increase in the odds of high hs-CRP, with individuals with 1, 2, and 3 factors having ORs for high hs-CRP of 1.92 (1.49 to 2.48), 3.38 (2.50 to 4.57), and 4.53 (3.23 to 6.35), respectively. CONCLUSIONS: Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with increased odds of high hs-CRP levels. PMID- 21546604 TI - A detailed cardiovascular characterization of obesity without the metabolic syndrome. AB - OBJECTIVE: Although obesity without metabolic disturbances has been regarded as harmless, we have recently shown that obese subjects without the metabolic syndrome (MetS) has an increased risk of cardiovascular (CV) disorders and mortality during long-term follow-up. To investigate the basis for that increased risk, we studied the impact of obesity without MetS on multiple markers of subclinical CV disease. METHODS AND RESULTS: At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors study. According to body mass index (BMI)/MetS status, they were categorized as normal weight (BMI <25 kg/m(2)) without MetS (National Cholesterol Education Program criteria, n=319), normal weight with MetS (n=19), overweight (BMI 25 to 29.9 kg/m(2)) without MetS (n=333), overweight with MetS (n=94), obese (BMI >=30 kg/m(2)) without MetS (n=102), and obese with MetS (n=118). Several different measurements of endothelial reactivity, arterial compliance (plethysmography and ultrasound), carotid artery atherosclerosis, and echocardiography were performed, and 7 markers of coagulation/fibrinolysis were measured. Subjects with obesity without MetS showed impaired vasoreactivity, a more echolucent carotid artery wall, increased left ventricular mass and function together with impaired coagulation/fibrinolysis compared with normal-weight subjects without the MetS (P<0.05 to 0.001). The majority of these disturbances were also seen in overweight subjects without the MetS. CONCLUSIONS: In contrast to some previous studies, our data do not support that obesity without MetS is a benign condition, because obesity without MetS was associated with impairments in multiple markers of subclinical CV disease. This was also the case for overweight subjects without the MetS. PMID- 21546605 TI - Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor deficient mice. AB - OBJECTIVE: Sterol regulatory element-binding protein-1 (SREBP-1) is nutritionally regulated and is known to be a key transcription factor regulating lipogenic enzymes. The goal of this study was to evaluate the roles of SREBP-1 in dyslipidemia and atherosclerosis. METHODS AND RESULTS: Transgenic mice that overexpress SREBP-1c in the liver and SREBP-1-deficient mice were crossed with low-density lipoprotein receptor (LDLR)-deficient mice, and the plasma lipids and atherosclerosis were analyzed. Hepatic SREBP-1c overexpression in LDLR-deficient mice caused postprandial hypertriglyceridemia, increased very-low-density lipoprotein (VLDL) cholesterol, and decreased high-density lipoprotein cholesterol in plasma, which resulted in accelerated aortic atheroma formation. Conversely, absence of SREBP-1 suppressed Western diet-induced hyperlipidemia in LDLR-deficient mice and ameliorated atherosclerosis. In contrast, bone marrow specific SREBP-1 deficiency did not alter the development of atherosclerosis. The size of nascent VLDL particles secreted from the liver was increased in SREBP-1c transgenic mice and reduced in SREBP-1-deficient mice, accompanied by upregulation and downregulation of phospholipid transfer protein expression, respectively. CONCLUSIONS: Hepatic SREBP-1c determines plasma triglycerides and remnant cholesterol and contributes to atherosclerosis in hyperlipidemic states. Hepatic SREBP-1c also regulates the size of nascent VLDL particles. PMID- 21546606 TI - Insulin-like growth factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic potential for myocardial regeneration. AB - RATIONALE: Age and coronary artery disease may negatively affect the function of human cardiac stem cells (hCSCs) and their potential therapeutic efficacy for autologous cell transplantation in the failing heart. OBJECTIVE: Insulin-like growth factor (IGF)-1, IGF-2, and angiotensin II (Ang II), as well as their receptors, IGF-1R, IGF-2R, and AT1R, were characterized in c-kit(+) hCSCs to establish whether these systems would allow us to separate hCSC classes with different growth reserve in the aging and diseased myocardium. METHODS AND RESULTS: C-kit(+) hCSCs were collected from myocardial samples obtained from 24 patients, 48 to 86 years of age, undergoing elective cardiac surgery for coronary artery disease. The expression of IGF-1R in hCSCs recognized a young cell phenotype defined by long telomeres, high telomerase activity, enhanced cell proliferation, and attenuated apoptosis. In addition to IGF-1, IGF-1R(+) hCSCs secreted IGF-2 that promoted myocyte differentiation. Conversely, the presence of IGF-2R and AT1R, in the absence of IGF-1R, identified senescent hCSCs with impaired growth reserve and increased susceptibility to apoptosis. The ability of IGF-1R(+) hCSCs to regenerate infarcted myocardium was then compared with that of unselected c-kit(+) hCSCs. IGF-1R(+) hCSCs improved cardiomyogenesis and vasculogenesis. Pretreatment of IGF-1R(+) hCSCs with IGF-2 resulted in the formation of more mature myocytes and superior recovery of ventricular structure. CONCLUSIONS: hCSCs expressing only IGF-1R synthesize both IGF-1 and IGF-2, which are potent modulators of stem cell replication, commitment to the myocyte lineage, and myocyte differentiation, which points to this hCSC subset as the ideal candidate cell for the management of human heart failure. PMID- 21546607 TI - Antiangiogenic activity of rPAI-1(23) promotes vasa vasorum regression in hypercholesterolemic mice through a plasmin-dependent mechanism. AB - RATIONALE: The antiangiogenic activity of rPAI-1(23), a truncated plasminogen activator inhibitor-1 (PAI-1) protein, induces vasa vasorum collapse and significantly reduces plaque area and plaque cholesterol in hypercholesterolemic low-density lipoprotein receptor-deficient/apolipoprotein B48-deficient mice. OBJECTIVE: The objective of this study was to examine rPAI-1(23)-stimulated mechanisms that cause vasa vasorum collapse. METHODS AND RESULTS: The rPAI-1(23) protein opposed PAI-1 antiproteolytic function by stimulating a 1.6-fold increase in plasmin activity compared with the saline-treated counterpart. The increased proteolytic activity corresponded to increased activity of matrix metalloproteinase-3 and degradation of fibrin(ogen), nidogen, and perlecan in the adventitia of descending aortas. PAI-1 activity was reduced by 48% in response to rPAI-1(23); however, PAI-1 protein expression levels were similar in the rPAI 1(23)- and saline-treated hypercholesterolemic mice. Coimmunoprecipitation assays demonstrated a novel PAI-1-plasminogen complex in protein from the descending aorta of rPAI-1(23)- and saline-treated mice, but complexed PAI-1 was 1.6-fold greater in rPAI-1(23)-treated mice. Biochemical analyses demonstrated that rPAI 1(23) and PAI-1 binding interactions with plasminogen increased plasmin activity and reduced PAI-1 antiproteolytic activity. CONCLUSIONS: We conclude that rPAI 1(23) causes regression or collapse of adventitial vasa vasorum in hypercholesterolemic mice by stimulating an increase in plasmin activity. The rPAI-1(23)-enhanced plasmin activity was achieved through a novel mechanism by which rPAI-1(23) and PAI-1 bound plasminogen in a cooperative manner to increase plasmin activity and reduce PAI-1 activity. PMID- 21546608 TI - Pannexin1 regulates alpha1-adrenergic receptor- mediated vasoconstriction. AB - RATIONALE: The coordination of vascular smooth muscle cell constriction plays an important role in vascular function, such as regulation of blood pressure; however, the mechanism responsible for vascular smooth muscle cell communication is not clear in the resistance vasculature. Pannexins (Panx) are purine-releasing channels permeable to the vasoconstrictor ATP and thus may play a role in the coordination of vascular smooth muscle cell constriction. OBJECTIVE: We investigated the role of pannexins in phenylephrine- and KCl-mediated constriction of resistance arteries. METHODS AND RESULTS: Western blot, immunohistochemistry, and immunogold labeling coupled to scanning and transmission electron microscopy revealed the presence of Panx1 but not Panx2 or Panx3 in thoracodorsal resistance arteries. Functionally, the contractile response of pressurized thoracodorsal resistance arteries to phenylephrine was decreased significantly by multiple Panx inhibitors (mefloquine, probenecid, and (10)Panx1), ectonucleotidase (apyrase), and purinergic receptor inhibitors (suramin and reactive blue-2). Electroporation of thoracodorsal resistance arteries with either Panx1-green fluorescent protein or Panx1 small interfering RNA showed enhanced and decreased constriction, respectively, in response to phenylephrine. Lastly, the Panx inhibitors did not alter constriction in response to KCl. This result is consistent with coimmunoprecipitation experiments from thoracodorsal resistance arteries, which suggested an association between Panx1 and alpha1D-adrenergic receptor. CONCLUSIONS: Our data demonstrate for the first time a key role for Panx1 in resistance arteries by contributing to the coordination of vascular smooth muscle cell constriction and possibly to the regulation of blood pressure. PMID- 21546609 TI - Deficient binocular combination reveals mechanisms of anisometropic amblyopia: signal attenuation and interocular inhibition. AB - Amblyopia is a developmental disorder that results in deficits of monocular and binocular vision. It is presently unclear whether these deficits result from attenuation of signals in the amblyopic eye, inhibition by signals in the fellow eye, or both. In this study, we characterize mechanisms underlying anisometropic amblyopia using a binocular phase and contrast combination paradigm and a contrast gain control model. Subjects dichoptically viewed two slightly different images and reported the perceived contrast and phase of the resulting cyclopean percept. We found that the properties of binocular combination were abnormal in many aspects in amblyopic vision. The observed abnormalities can be explained by a combination of (1) attenuated monocular signal in the amblyopic eye, (2) stronger interocular contrast gain control from the fellow eye to the signal in the amblyopic eye (direct interocular inhibition), and (3) stronger interocular contrast gain control from the fellow eye to the contrast gain control signal from the amblyopic eye (indirect interocular inhibition). We conclude that anisometropic amblyopia led to both monocular and interocular deficits. A complete understanding of the mechanisms underlying amblyopia requires studies of both monocular deficits and binocular interactions. PMID- 21546610 TI - A matched comparison of binocular rivalry and depth perception with fMRI. AB - Psychophysical experiments have demonstrated that it is possible to simultaneously perceive binocular depth and rivalry in plaids (A. Buckthought & H. R. Wilson, 2007). Here, we used fMRI at 3T to image activity in the visual cortex while human subjects perceived depth and rivalry from plaids. Six subjects performed either a rivalry or depth task. The spatial frequencies of the near vertical and diagonal components were, respectively: 2.5, 6.4 cpd; 6.4, 2.5 cpd; or 6.4, 6.4 cpd. The network of activated cortical areas was very similar for the depth compared to the rivalry task. Nevertheless, regions of superior and inferior parietal cortices (including intraparietal sulcus) were activated more during the depth than the rivalry task, independent of spatial frequency, whereas a bias toward rivalry was seen in a lateral occipital region, superior temporal sulcus, and retrosplenial and ventral temporal cortices. Several retinotopic areas in the visual cortex showed a preference for the task with the higher (V1, V2, V3) or lower spatial frequency component (MT+), regardless of the depth or rivalry condition. Our results indicate that depth and rivalry are processed in a similar network of cortical areas and are perceived simultaneously by coexisting in different spatial channels. These results place constraints on binocular vision models. PMID- 21546611 TI - Paternal DNA damage resulting from various sperm treatments persists after fertilization and is similar before and after DNA replication. AB - In spite of its highly condensed state, sperm DNA is vulnerable to damage that can originate from oxidative stress, the activity of sperm-specific nucleases, or both. After fertilization, in the oocyte, paternal chromatin undergoes dramatic changes, and during this extensive remodeling, it can be both repaired and degraded, and these processes can be linked to DNA synthesis. Here, we analyzed sperm response to damage-inducing treatments both before and after fertilization and before or after zygotic DNA replication. Epididymal mouse spermatozoa were either frozen without cryoprotection (FT) or treated with detergent Triton X-100 coupled with dithiothreitol (TX+DTT) to induce DNA damage. Fresh, untreated sperm served as control. Immediately after preparation, spermatozoa from 3 groups were taken for comet assay, or for intracytoplasmic sperm injection into prometaphase I oocytes to visualize prematurely condensed single-chromatid chromosomes, or into mature metaphase II oocytes to visualize chromosomes after DNA replication. Comet assay revealed increased DNA fragmentation in treated sperm when compared with control, with FT sperm more severely affected. Chromosome analysis demonstrated paternal DNA damage in oocytes injected with treated, but not with fresh, sperm, with FT and TX+DTT groups now yielding similar damage. There were no differences in the incidence of abnormal paternal karyoplates before and after DNA synthesis in all examined groups. This study provides evidence that subjecting sperm to DNA damage inducing treatments results in degradation of highly condensed sperm chromatin when it is still packed within the sperm head, and that this DNA damage persists after fertilization. The difference in DNA damage in sperm subjected to 2 treatments was ameliorated in the fertilized oocytes, suggesting that some chromatin repair might have occurred. This process, however, was independent of DNA synthesis and took place during oocyte maturation. PMID- 21546613 TI - Diagnosis and treatment of azoospermia resulting from testicular sarcoidosis. AB - Genitourinary sarcoidosis is uncommon, with only rare documented cases of testicular involvement reported. We detail the case of a 37-year-old male who initially presented for azoospermia and secondary infertility. A testicular biopsy revealed nonnecrotizing granulomas and a chest x-ray identified perihilar lymphadenopathy and granulomatous lung nodules. A corticosteroid regimen was administered, and routine semen analyses were conducted. Significant improvements were noted after prednisone treatments. A successful in vivo fertilization was obtained. This is the first known case of testicular sarcoidosis diagnosed during investigations into azoospermia and secondary infertility which, after treatment with corticosteroids, resulted in natural fertilization. PMID- 21546612 TI - Endothelial antioxidant compound prolonged the endothelial antiapoptotic effects registered after tadalafil treatment in patients with arterial erectile dysfunction. AB - This study evaluated the effects of a chronic treatment with tadalafil, a specific phosphodiesterase V inhibitor, on endothelial apoptosis through changes in the serum concentration of endothelial microparticles (EMP). EMPs were arbitrarily chosen as a marker of endothelial apoptosis, and the changes in their concentration were monitored before and after treatment. Additionally, administration of endothelial antioxidant compound (EAC) during the follow-up, after discontinuation of tadalafil, was evaluated to determine whether this treatment improved the potential effects of tadalafil on the endothelium. Seventy-five patients with arterial erectile dysfunction were evaluated at baseline and after administration of tadalafil (5 mg once daily for 90 days). The International Index of Erectile Function questionnaire was administered, and penile dynamic Doppler and flow-cytometric (serum concentrations of EMPs) analyses were performed before (T0) and after treatment. Time points after tadalafil discontinuation: T1, after 1 week; T2, after 3 months; and T3, after 6 months. Three different schemes of follow-up were evaluated: group A, follow-up with EAC administration, after tadalafil discontinuation, for 6 months; group B, follow-up without other treatment; and group C, follow-up with placebo during the follow-up, after tadalafil cessation. The events CD45(neg)/CD144(pos)/annexinV(pos) were defined EMPs. Patients treated with tadalafil showed a significant decrease in serum EMPs 1 week after discontinuing tadalafil (16.4% +/- 3.6% vs 7.1% +/- 3.3%). This effect was maintained for up to 3 months in the group without other treatment during follow-up and was maintained for up to 6 months in the group treated with EAC during follow-up. Chronic treatment with tadalafil reduces endothelial apoptosis in patients with arterial erectile dysfunction. Further, EAC treatment prolongs and stabilizes the duration of antiapoptotic effects on the endothelium that are initially promoted by tadalafil treatment. PMID- 21546614 TI - Identification of potential regulatory elements in the 5' and 3' UTRs of 12 translationally regulated mRNAs in mammalian spermatids by comparative genomics. AB - To facilitate identifying translational control elements by studies of mutations in transgenic mice, a database of orthologous 5' and 3' ends of 12 messenger RNA (mRNA) species from 13 to 23 mammals that undergo delayed translational activation in spermatids was constructed for the Acev2, Akap3, Akap4v2, Gapdhs, Odf1, Prm1, Prm2, Prm3, Smcp, Spata18, Tnp1, and Tnp2 mRNAs. This database, available here, was searched for conserved sequences in conserved positions and known translational control elements. Numerous potential mRNA-specific elements were identified, including upstream open reading frames, conserved sequences upstream and downstream of the poly(A) signal, and noncanonical and multiple poly(A) signals. RNA electrophoresis mobility shift assays demonstrate that Y box proteins bind 30 of the 36 permutations of the degenerate Y-box recognition sequence (YRS), [UAC][CA]CA[UC]C[ACU], and this information was used to identify hundreds of YRSs in the untranslated region (UTR) database. Collectively, these findings suggest that the distal ends of both UTRs are particularly well conserved, implying that translation of each mRNA is regulated by mechanisms involving the poly(A) binding protein and the closed loop. In addition, the 5' flanking regions of all 12 genes have conserved, gene-specific sequences and configurations of elements that resemble the binding site of the testis-specific isoform of cyclic AMP response element modulator, and all 12 genes lack retrogene paralogues, demonstrating the efficacy of mechanisms that limit the proliferation of retroposons in the male germ line. This study illustrates the power of comparative genomics in identifying novel hypothetical regulatory elements for analysis with biochemical and in vivo genetic approaches. PMID- 21546615 TI - Genetic polymorphisms of glutathione S-transferase M1, T1, and P1, and the assessment of oxidative damage in infertile men with varicoceles from northwestern China. AB - Our objective was to investigate the genetic polymorphisms of the glutathione S transferase M1, T1, and P1 genes (GSTM1, GSTT1, and GSTP1) and to assess the oxidative damage in infertile men with varicoceles from northwestern China. A total of 65 infertile men with varicoceles and 30 controls were included in the study. Multiplex polymerase chain reaction and polymerase chain reaction restriction fragment length polymorphism analyses were used to identify the genotypes. Sperm DNA damage was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL). The levels of 8 hydroxy-2'-deoxyguanosine (8-OH-dG) were measured by high-performance liquid chromatography with electrochemical detection. The activities of malondialdehyde (MDA) and nitric oxide (NO), and the total antioxidant capacity (TAC) were detected by spectroscopic analysis, and sperm characteristics were measured using computer-assisted semen analysis. The frequencies of the GSTM1, GSTT1, and GSTP1 genotypes were not significantly different between the control and patient groups (P > .05). The percentage of TUNEL-positive sperm and the levels of 8-OH dG, MDA, and NO were higher but the sperm concentration and motility and the TAC were lower in the patients with the GSTM1, GSTT1, and GSTM1/T1 null genotypes than those in the patients with the GSTM1, GSTT1, and GSTM1/T1 present genotypes (P < .05). However, no significant differences were observed between the GSTP1 A/A and A/G+G/G genotypes (P > .05). Our results suggest that the GSTM1 and GSTT1 null genotypes may predispose sperm to increased oxidative damage in infertile men with varicoceles; however, GSTP1 allelic variation was not significantly different between the patient and control groups in this study. PMID- 21546616 TI - Hormonal imbalances and psychological scars left behind in infertile men. AB - The effect of infertility on the psychological well-being of couples has been the subject of increasing attention in recent years. The frustration of couples of a relatively young age (ie, in their fourth decades) provokes not only anxiety and depression but also negative effects on the relationships. The objective of this study was to evaluate the effect of a diagnosis of male infertility on anxiety and depression in the men themselves and in fertile female spouses. The prospective cross-sectional study consisted of 264 participants, 72 males diagnosed with nonobstructive azoospermia (NOA) and their fertile spouses and 60 fertile couples attending our university between January 1, 2009, and April 30, 2010. The Beck Anxiety Inventory, Beck Depression Inventory (BDI), and hormone levels were measured during initial and follow-up visits. In NOA men, follicle-stimulating hormone and luteinizing hormone were positively associated with anxiety, in contrast to testosterone, which was inversely associated with anxiety. After the diagnosis of NOA, producing no testicular sperm, the panic intensity among men increased significantly, whereas their spouses exhibited less panic. By contrast, fertile female partners of NOA men reported higher BDI scores after the initial diagnosis of azoospermia, whereas their partners recorded higher levels of depression after the absence of testicular sperm was discovered. Insomnia was the most common complaint for both sexes after the diagnosis of azoospermia. Hormonal abnormalities had a negative effect on the quality of life. Physicians and clinicians should acknowledge the immense psychosocial effect of the diagnosis of male infertility on both males and their fertile female partners. PMID- 21546622 TI - Introduction: fusidic acid enters the United States. PMID- 21546623 TI - New rules for clinical trials of patients with acute bacterial skin and skin structure infections: do not let the perfect be the enemy of the good. AB - Over the past decade, the United States has witnessed an epidemic of acute bacterial skin and skin-structure infections (ABSSSIs) caused primarily by community-acquired methicillin-resistant Staphylococcus aureus. To address this medical need as well as the ongoing threat of increasing resistance, new antibiotics are being developed. Clinical trials involving patients with complicated ABSSSI are being implemented to understand the efficacy and safety of these new antibiotic agents. Because antibiotics clearly have an effect on the resolution of the majority of these infections, placebo-controlled trials have been replaced by noninferiority studies. However, to conduct noninferiority trials a noninferiority margin must be determined on the basis of the effect size of the comparator antibiotic. The lack of modern-day placebo-controlled studies of ABSSSI makes determining effect size/noninferiority margin--and as a result, trial design--challenging. The US Food and Drug Administration (FDA) in collaboration with the Foundation for the National Institutes of Health (FNIH) have been working hard to resolve these issues and develop a new guidance to aid investigators in the conduct of these trials. In this article, we first review the 1998 guidance and its shortcomings. Next, we address the ongoing discussion of the new 2010 guidance as we understand it, along with its perceived strengths and weaknesses. Throughout this process, we wish to emphasize that the continued development of antibiotics is essential. Thus, we hope that as the FDA and FNIH move forward they will strike a balance between "The Perfect" statistical solution and "The Good" practical clinical realities. PMID- 21546624 TI - In vitro antimicrobial findings for fusidic acid tested against contemporary (2008-2009) gram-positive organisms collected in the United States. AB - Fusidic acid has a long history of consistent activity against staphylococcal pathogens including methicillin-resistant Staphylococcus aureus (MRSA). Fusidic acid (CEM-102) was susceptibility tested against a surveillance study collection of 12,707 Gram-positive pathogens (2008-2009) from the United States. Reference broth microdilution method results demonstrated the following MIC(50/90) results: S. aureus (.12/.25 MUg/mL), coagulase-negative staphylococci (.12/.25 MUg/mL), enterococci (4/4 MUg/mL), Streptococcus pyogenes (4/8 MUg/mL), and viridans group Streptococcus spp. (>8/>8 MUg/mL). At a proposed susceptible breakpoint (<=1 MUg/mL), fusidic acid inhibited 99.7% of MRSA strains and 99.3% to 99.9% of multidrug-resistant phenotypes of S. aureus. Furthermore, S. aureus strains nonsusceptible to fusidic acid (.35%) generally had detectable resistance mechanisms (fusA, B, C, and E). Reviews of in vitro susceptibility test development confirm the accuracy and intermethod reproducibility of various fusidic acid methods. Fusidic acid is a promising oral therapy for staphylococcal skin and skin structure infections in the United States, where the contemporary S. aureus population remains without significant resistance. PMID- 21546625 TI - Characterization of global patterns and the genetics of fusidic acid resistance. AB - Fusidic acid binds to elongation factor G (EF-G), preventing its release from the ribosome, thus stalling bacterial protein synthesis. In staphylococci, high-level fusidic acid resistance is usually caused by mutations in the gene encoding EF-G, fusA, and low-level resistance is generally caused by the horizontally transferable mechanisms fusB and fusC that have a putative protective role on EF G. In addition, fusD is responsible for intrinsic resistance in Staphylococcus saprophyticus, and alterations in the L6 portion of rplF (fusE) have a role in fusidic acid resistance. Fusidic acid has been used in Europe and Australia for decades. More recently, it has also been used in other countries and regions, but not in the United States. Worldwide fusidic acid resistance has been slow to develop, and the level of resistance and genetic mechanisms responsible generally reflect the time since introduction, indications for treatment, route of administration, and prescribing practices. PMID- 21546626 TI - Activity of fusidic acid against extracellular and intracellular Staphylococcus aureus: influence of pH and comparison with linezolid and clindamycin. AB - BACKGROUND: Emergence of multidrug-resistant Staphylococcus aureus has triggered a reassessment of fusidic acid (CEM-102, sodium fusidate). METHODS: Fusidic acid was examined for (1) activity against recent methicillin-resistant S. aureus (MRSA) isolates; (2) modulation of activity by acidic pH; and (3) accumulation by phagocytic cells and intracellular activity against methicillin-susceptible S. aureus (MSSA) and MRSA. RESULTS: About 96% of strains (N = 94) were susceptible (European Committee on Antimicrobial Susceptibility Testing breakpoint [<= 1 mg/L]). Activity was enhanced at pH 5.5 (6 dilutions decrease for minimum inhibitory concentration) in parallel with an increase of drug bacterial accumulation (opposite effects for clindamycin; linezolid remained unaffected). Fusidic acid accumulated in THP-1 cells (about 5.5 fold), with further accumulation at pH 5.5 vs pH 7.4. The intracellular activity of Fusidic acid was similar to that of clindamycin and linezolid (maximal relative activity, 0.4-0.6 log(10) colony-forming unit decrease). No cross-resistance to vancomycin or daptomycin was observed. CONCLUSIONS: Fusidic acid is active against S. aureus in broth as well as intracellularly, with no cross-resistance to other antibiotics. PMID- 21546627 TI - Pharmacokinetics and safety of single, multiple, and loading doses of fusidic acid in healthy subjects. AB - A phase 1 trial of fusidic acid (CEM-102), an oral fusidane class antibiotic under development for treatment of gram-positive acute bacterial skin and skin structure infections, evaluating pharmacokinetics and safety is described. A randomized, double-blinded, placebo-controlled, dose escalation study was conducted in healthy adult subjects in the fasting state. Plasma exposure after multiple doses was higher than for single doses, indicating accumulation. Loading doses designed to optimize pharmacodynamic effects were well tolerated and achieved near-steady state concentrations of CEM-102 at 24 h. CEM-102 was safe and generally well tolerated at all single, multiple, and loading doses administered. PMID- 21546628 TI - Application of pharmacokinetic-pharmacodynamic modeling and the justification of a novel fusidic acid dosing regimen: raising Lazarus from the dead. AB - Perhaps the most crucial step in the clinical development of an antimicrobial agent is the selection of a dosing regimen. Such decisions impact not only the success of a program but also the well being of individual patients, the emergence of resistance, and society as a whole. For fusidic acid, the selection of a dosing regimen for the treatment of patients with acute bacterial skin and skin-structure infection (ABSSSI) was based on the integration of knowledge gained from human population pharmacokinetic, in vitro infection, and mathematical models. The overarching goal of these studies was to identify a dosing regimen that would maximize the probabilities of positive clinical outcomes and limit the emergence of bacterial resistance during therapy. Novel dosing regimens identified included 1500 mg twice daily on day 1 followed by 600 mg twice daily for 10-14 days, a regimen that was subsequently found to be effective in a phase 2 clinical study of patients with ABSSSI. Herein, we review the data supporting the use of this novel fusidic acid dosing regimen, which will undergo further clinical evaluation in phase 3 clinical trials. PMID- 21546629 TI - A randomized, double-blind phase 2 study comparing the efficacy and safety of an oral fusidic acid loading-dose regimen to oral linezolid for the treatment of acute bacterial skin and skin structure infections. AB - Fusidic acid (CEM-102), an orally bioavailable fusidane antibiotic with a unique mode of action, is under development for treatment of acute gram-positive bacterial skin and skin structure infections, including those caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus and streptococci. A phase 2, adaptive design, randomized, double-blind, multiple center study of 198 adult patients with cellulitis or wound infections was conducted to evaluate an oral CEM-102 loading-dose regimen (1500 mg twice per day on day 1 followed by 600 mg twice per day) compared with oral linezolid (600 mg twice per day) administered for 10-14 days. The CEM-102 loading-dose regimen demonstrated efficacy, safety, and tolerability that was comparable to linezolid for the treatment of acute gram-positive bacterial skin and skin structure infections. Clinical Trials registration. NCT00948142. PMID- 21546630 TI - The safety record of fusidic acid in non-US markets: a focus on skin infections. AB - Fusidic acid has been in clinical use outside the United States (US) since 1962 for skin infections, including methicillin-resistant Staphylococcus aureus (MRSA). Non-US labeling reflects safety concerns related to gastrointestinal, allergic, hematologic, and neurologic adverse events. We sought to survey available safety data on fusidic acid through the review of published global literature between 1962 and 2007 that contained data on oral fusidic acid safety and a centralized database (VigiBase) of spontaneous safety reports. Overall, the data were concordant with current product labeling, and no serious adverse events, such as death, hospitalization, or hepatotoxicity, were convincingly linked to fusidic acid monotherapy in skin infection patients. Other indications for fusidic acid use were also common, including osteomyelitis with similar reporting of labeled safety characteristics. Study quality was highly varied with limited structure to safety data collection methodology. Significant concerns for recall bias are present, yet these data remain informative in providing signals that require attention in the design and conduct of adequate and well-controlled clinical studies of fusidic acid for potential registration in the United States. PMID- 21546631 TI - Case report: treatment of chronic osteomyelitis. AB - Presented is a case of chronic methicillin-resistant Staphylococcus aureus osteomyelitis, which was unsuccessfully treated with multiple courses of debridement and potent antibiotic therapies. Amputation of the patient's lower limb was believed to be the only option remaining. A compassionate access program, with approval from the US Food and Drug Administration and the institutional review board, enabled the patient to undergo a course of treatment with oral fusidic acid (CEM-102). The patient tolerated the drug well, with no significant toxicities noted to date. His infection improved rapidly, his flap healed, he has returned to work part-time, and he continues to take daily suppressive doses of oral CEM-102. PMID- 21546632 TI - Efforts to support the development of fusidic acid in the United States. AB - Fusidic acid (FA), though used widely throughout the world for decades, has never been approved in the United States. There is now a great need for an oral methicillin-resistant Staphylococcus aureus (MRSA) antibiotic with a long track record of safety. Cempra Pharmaceuticals successfully encouraged passage of a congressional amendment to allow for Hatch-Waxman market exclusivity when this antibiotic is approved in the United States. A new dosing regimen has been patented, allowing FA to be used as monotherapy, and decreased resistance selectivity has been shown. With almost no resistance to FA in the United States, the time is right for introduction into this market. PMID- 21546633 TI - Pharmacists in Arkansas to judge individuals' need for pseudoephedrine. PMID- 21546634 TI - FDA approves gabapentin prodrug as restless legs treatment. PMID- 21546635 TI - Special efforts needed for optimal vaccine storage, use. PMID- 21546636 TI - CMS relaxes short-cycle dispensing plan, delays deadline. PMID- 21546637 TI - Pharmacy technician education, training, and certification: call for a single national standard and public accountability. PMID- 21546638 TI - Nebivolol for the treatment of heart failure. AB - PURPOSE. The pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of nebivolol are reviewed. SUMMARY. Nebivolol, a third-generation, highly beta(1)-specific beta-blocker, is labeled for the treatment of hypertension in the United States. In addition to its beta-blocking effects, nebivolol has been shown to increase endothelin-dependent nitric oxide, giving it a unique peripheral vasodilatory action. Nebivolol is extensively metabolized by cytochrome P-450 isoenzyme 2D6. In patients with heart failure, certain beta blockers antagonize excessive adrenergic stimulation and can slow the progression of the disease. Clinical trials have compared nebivolol at target dosages of 5 and 10 mg once daily with placebo and, in small trials, with carvedilol in the treatment of adults with chronic heart failure. Nebivolol appears to have beneficial effects in patients with heart failure, including improvements in left ventricular ejection fraction, left ventricular volumes, and exercise capacity. In addition, the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure showed a reduction in morbidity and mortality after treatment with nebivolol when compared with placebo, though this effect appeared to be less than that of other beta-blockers currently recommended for the treatment of heart failure. Nebivolol was well tolerated in all clinical trials, with the most frequently reported adverse events including bradycardia, hypotension, and dizziness. To date, no large clinical trials have compared nebivolol with currently recommended beta-blockers in patients with heart failure. CONCLUSION. Nebivolol has beneficial effects in heart failure but cannot be considered equivalent to other currently accepted therapies. PMID- 21546639 TI - Severe hepatotoxicity and probable hepatorenal syndrome associated with sulfadiazine. AB - PURPOSE. The case of a patient who developed hepatorenal syndrome during treatment with sulfadiazine for toxoplasmosis retinitis is reported. SUMMARY: A 20-year-old Caucasian woman weighing 59 kg was admitted to the infectious diseases ward of a hospital in May 2009 with nausea, vomiting, and jaundice. In March 2009, she was diagnosed with toxoplasmosis retinitis and received sulfadiazine 3 g daily, pyrimethamine 50 mg daily, leucovorin 15 mg daily, and prednisolone 75 mg daily; she continued these medications for three weeks. After the development of gastrointestinal symptoms, she stopped taking the prescribed medications (five days before hospital admission). One day before hospital admission, her skin appeared jaundiced. At the time of admission, the patient had high transaminase levels, hyperbilirubinemia, abnormal prothrombin time and International Normalized Ratio values, and clinical evidence of acute fulminant hepatitis complicated by hepatorenal syndrome. Autoimmune hepatitis was excluded as a cause of her hepatotoxicity, as was Wilson's disease, herpes simplex virus, cytomegalovirus, hepatitis A virus, hepatitis E virus, and Epstein-Barr virus. She was diagnosed with probable drug-related fulminant hepatitis, presumably caused by sulfadiazine treatment. Lactulose 20 g was started for the prevention of encephalopathy. She received phytonadione 10 mg daily for three consecutive days, ranitidine 50 mg thrice daily, ciprofloxacin 250 mg twice daily, and acetylcysteine 600 mg thrice daily. The patient underwent hemodialysis five times during her hospital stay. Her symptoms gradually improved, and she was discharged on hospital day 20. CONCLUSION: Probable hepatorenal syndrome requiring hemodialysis occurred in a patient receiving sulfadiazine for the treatment of toxoplasmosis retinitis. PMID- 21546640 TI - Substitution of a heparin correlation value for activated partial thromboplastin time in heparin nomograms. AB - PURPOSE. Use of nomograms based on the "heparin correlation value" (HCV)-a value that corresponds to measured activated partial thromboplastin time (aPTT) and that removes the need to revise nomograms in response to a change in the aPTT reagent or coagulometer used-was evaluated as an alternative to traditional aPTT based anticoagulation nomograms. SUMMARY. Data were collected on patients receiving heparin therapy for selected indications (thrombotic disorders, cardiac conditions, and acute coronary syndromes) during four-month periods before (n = 59) and after (n = 60) implementation of the HCV-based nomograms. The primary endpoints were the rate at which coagulation laboratory measurements were obtained at the appropriate time and the rate of appropriate dosage adjustment in response to reported laboratory values; secondary endpoints included the time to attainment of the first target anticoagulation value. After implementation of HCV based nomograms, coagulation laboratory measurements were obtained at the appropriate time in (mean +/- S.D.) 92.9% +/- 12.8% of patients, compared with 80.1% +/- 15.5% of patients who received aPTT-based monitoring (p < 0.0001). After implementation of HCV-based monitoring, the rate of correct heparin dosage adjustments was improved (mean +/- S.D. 94.7% +/- 7.8% versus 89.3% +/- 14.0%, p = 0.01), and the time to attainment of the first target anticoagulation value was shorter (mean +/- S.D. 16.4 +/- 10.6 hours versus 21.5 +/- 14.8 hours, p = 0.03). CONCLUSION. The HCV, which relates measured aPTT values to corresponding antifactor Xa concentrations, was substituted for aPTT in heparin nomograms and appeared to be a viable alternative to the aPTT. PMID- 21546641 TI - Stability of compounded thioguanine oral suspensions. AB - PURPOSE. Updated information on the stability of compounded thioguanine oral suspensions prepared with currently available ingredients, as well as results of testing to determine if the addition of an antioxidant could extend shelf life by inhibiting formation of guanine, are presented. METHODS. Using triturated thioguanine tablets, three compounded suspensions were prepared: (1) a reference formulation containing methylcellulose and simple syrup, (2) an equivalent formulation using Ora-Plus and Ora-Sweet, and (3) an antioxidant-containing formulation prepared by adding ascorbic acid to the equivalent formulation. The compounded batches were stored at room temperature (19-23 degrees C). The chemical stability of the suspensions was evaluated immediately after compounding and at weekly intervals by a validated liquid chromatography-mass spectrometry (LCMS) assay method; physical stability was evaluated by regular visual checks and weekly pH testing. RESULTS. As demonstrated by serial LCMS testing, mean thioguanine levels in sampled batches of all three suspensions remained above accepted standards and mean guanine formation remained within acceptable limits for up to 63 days. The addition of ascorbic acid appeared to slow guanine formation but did not significantly extend the shelf life of the suspension. CONCLUSION. Compounded oral suspensions of thioguanine 20 mg/mL exhibited acceptable chemical and physical stability for up to nine weeks at 19-23 degrees C. The addition of ascorbic acid at a concentration of 0.1% to the suspension was not effective in consistently increasing the shelf life of the thioguanine suspensions. PMID- 21546642 TI - Efficacy of limited cefuroxime prophylaxis in pediatric patients after cardiovascular surgery. AB - PURPOSE. The efficacy of limited cefuroxime prophylaxis in pediatric patients after cardiovascular surgery was evaluated. METHODS. All patients age 18 years or younger who underwent cardiovascular surgery and received postoperative care from the cardiovascular surgery team between February and July 2006 (preintervention group) and between August 2006 and January 2007 (postintervention group) were eligible for study inclusion. Patients were excluded if they did not receive cefuroxime as postoperative prophylaxis, had a preexisting infection, underwent cardiac transplantation or extracorporeal membrane oxygenation, or underwent delayed sternal closure. The preintervention group received prolonged cefuroxime prophylaxis, and the postintervention group received 24 hours of cefuroxime prophylaxis. Data collected included patient demographics and clinical and laboratory markers of infection, as well as microbiological evidence of and treatment courses for documented or presumed infections. RESULTS. A total of 210 patients were enrolled in the study. The number of patients who required additional antibiotics for suspicion of clinical infection did not significantly differ between the preintervention and postintervention groups (18.6% versus 26.9%, respectively), nor did the rate of documented infection (bacteremia, urinary tract infection, endocarditis, sepsis) (42.1% versus 48.3%, respectively). Moreover, indications for the antibiotics initiated were similar between the preintervention and postintervention groups. Clinical and laboratory signs of postoperative infection were similar between groups. There were no differences in postoperative white blood cell counts, peak serum glucose levels, and platelet nadir between groups. CONCLUSION. Limiting postoperative cefuroxime prophylaxis to 24 hours did not increase infectious outcomes in pediatric patients. PMID- 21546643 TI - Effect of a pharmacist-managed culture review process on antimicrobial therapy in an emergency department. AB - PURPOSE. The impact of an emergency department (ED) procedure requiring pharmacist review of all culture results as a way to improve use of antimicrobial therapies was evaluated. METHODS. Rates of antimicrobial regimen modifications before and after implementation of a pharmacist-managed ED culture review procedure at Carolinas Medical Center-Northeast were determined through retrospective evaluation of medical records. To assess the potential impact of pharmacist-initiated antimicrobial regimen modifications on overall patient care, the frequency of ED readmissions within 96 hours of ED discharge and the reasons for those readmissions were evaluated. RESULTS. In the 12 months before implementation of the pharmacist-managed ED culture review process, the medical center's ED physicians reviewed 2278 culture reports and ordered antimicrobial regimen modifications in about 12% of cases; in about 19% of cases, patients were readmitted to the ED within 96 hours of discharge for treatment failure, patient noncompliance, allergy to medication, adverse drug reactions, and other reasons. In the 12 months after program implementation, pharmacists initiated antimicrobial regimen modifications in about 15% of cases; readmission to the ED occurred in about 7% of cases, with comparatively lower rates of readmission for treatment failure, noncompliance, and allergy to medication. CONCLUSION. ED pharmacists at Carolinas Medical Center-Northeast designed and implemented a pharmacist-managed culture review process. During a one-year period, ED pharmacists reviewed 2361 culture reports and modified the antimicrobial regimens of 355 patients. PMID- 21546644 TI - Projecting future drug expenditures: 2011. AB - PURPOSE. Drug expenditure trends in 2009 and 2010, projected drug expenditures for 2011, and factors likely to influence drug expenditures are discussed. SUMMARY. Various factors are likely to influence drug expenditures in 2011, including drugs in development, the diffusion of new drugs, generic drugs, health care reform, and biosimilars. Two distinct patterns of drug expenditures continue to exist. The dominant trend over the past several years is substantial moderation in expenditure growth for widely used drugs, primarily due to the ongoing introduction of generic medications for high-cost, frequently used medications and the influence of the economic downturn. The second pattern is substantial increases in expenditures for specialized medications, particularly in the outpatient setting. The influence of health care reform, the economy, and the emergence of biosimilars will be important trends to follow over the next several years, but they are unlikely to have substantial impact on drug expenditures in 2011. From 2008 to 2009, total U.S. drug expenditures increased by 5.2%, with total spending rising from $284.8 billion to $299.5 billion. Growth in drug expenditures in clinics grew by 5.1% from 2008 to 2009. Hospital drug expenditures increased at the moderate rate of 2.8% from 2008 to 2009; through the first nine months of 2010, hospital drug expenditures increased by only 0.8% compared with the same period in 2009. CONCLUSION. For 2011, we project a 3-5% increase in drug expenditures in outpatient settings, a 4-6% increase in expenditures for clinic-administered drugs, and a 1-3% increase in hospital drug expenditures. PMID- 21546645 TI - Development and implementation of a pharmacist-managed inpatient anticoagulation monitoring program. AB - PURPOSE. A stepwise approach to development and implementation of a program to standardize and increase pharmacists' involvement in anticoagulation therapy at a large academic medical center is described. SUMMARY. In response to the Joint Commission's national goal of improved patient safety in anticoagulation therapy, a work group of pharmacy administrators, educators, clinical specialists, and decentralized pharmacists at the hospital developed the structure for a comprehensive inpatient anticoagulation program (IAP); the work group also developed a list of required competencies, educational materials, assessment methods, and mechanisms for eliciting feedback from IAP pharmacists and other patient care staff. After completion of training that included structured case review sessions, a one-on-one shadowing experience, and competency assessment, IAP pharmacists began reviewing clinical and laboratory data on patients receiving warfarin and low-molecular-weight heparins and providing recommendations to physicians, nurse practitioners, and other health care team members. Feedback from other clinicians was generally positive, with a majority of those surveyed indicating that increased pharmacist involvement in anticoagulation monitoring and dosage adjustment resulted in improved patient care; about 80% indicated that they concurred with pharmacists' recommendations at least 75% of the time. Results of a survey of IAP pharmacists indicated increased satisfaction with their daily duties but also a need for improved pharmacist-to-pharmacist communication. CONCLUSION. Case-based advanced training and implementation of an IAP in a tertiary care hospital increased pharmacists' involvement in the management of inpatients receiving anticoagulants. PMID- 21546646 TI - Critical issues associated with drug-drug interactions: highlights of a multistakeholder conference. PMID- 21546647 TI - The integration of counseling and nursing services into schools: a comparative review. AB - The purpose of this comparative review was to examine the legislative evolution of school guidance and school nursing over the past century, in hopes of identifying reasons why guidance counselors have been more successful in compliance to recommended ratios than school nurses. A literature review was conducted including CINAHL, MEDLINE, ERIC and other EBSCO databases. The results from this review indicate school guidance programs have been included in more federal legislation, mandating funding, education and certification requirements, which gives counselors a uniformly recognizable credential understood by educators. An extensive effort to develop a national model of school guidance has assisted counselors to uniformly show how they impact student academic success. School nurses can learn how to further integrate the school nursing role into education from the example of guidance counselors. PMID- 21546648 TI - Different associations of periventricular and deep white matter lesions with cognition, neuropsychiatric symptoms, and daily activities in dementia. AB - We investigated the associations of periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) with cognition, activities of daily living (ADLs), and neuropsychiatric symptoms in dementia. This was a hospital-based MRI300 study. We recruited patients newly diagnosed with mild-to moderate dementia caused either by Alzheimer's disease or subcortical ischemic vascular dementia from 13 dementia clinics at university or general hospitals in South Korea. We enrolled 289 patients aged over 50 from August 2007 to March 2008. We compared cognition, ADLs, and neuropsychiatric symptoms among 3 groups according to the severities of PWMHs and DWMHs, respectively, by adjusting for age, vascular risk factors, and level of other WMHs. A higher severity of PWMHs was related to lower cognitive function and severer neuropsychiatric symptoms, whereas basic ADLs were associated with DWMH. Both PWMHs and DWMHs exhibited different associations with cognition, neuropsychiatric symptoms, and daily activities. PMID- 21546649 TI - Feasibility and acceptance of a nonpharmacological cognitive remediation intervention for patients with Parkinson disease. AB - Many patients with idiopathic Parkinson disease (PD) experience deficits in executive skills (ES; eg, attentional control, self-monitoring), which are associated with a range of impairing symptoms such as visual hallucinations, decreased motor control, and increased apathy. Pharmacological methods for improving ES in PD have shown to be somewhat unreliable. The goal of this study was to evaluate the feasibility and patient acceptance of a nonpharmacological cognitive remediation program that aimed to improve sustained, selective, alternating, and divided attentional abilities in a sample of 16 nondemented PD patients. Based on ratings of 4 feasibility dimensions (fatigue, effort, progress, enjoyment), patients with PD demonstrated a high degree of acceptance and successfully engaged in the program. As predicted, ratings of progress differed significantly across tasks according to difficulty level and were positively related to posttraining improvement in ES. Fatigue ratings showed negative associations with other indices across task types, suggesting that monitoring fatigue during cognitive remediation is essential. Patients' ratings of enjoyment did not correspond to task difficulty, indicating that tasks could be simultaneously challenging and rewarding. Males reported exerting greater effort during the training than females. It was concluded that the intervention is appropriate for testing in a randomized controlled trial. PMID- 21546650 TI - Diagnostic indicators of anxiety and depression in older dizzy patients in primary care. AB - BACKGROUND: Dizzy patients with both psychological and physical symptoms tend to have high levels of disability and are at risk of remaining symptomatic and disabled. The objective of this study was to develop a prediction model for the presence of anxiety and/or depression in older dizzy patients in primary care. METHODS: We performed a cross-sectional study among 415 older patients consulting their primary care physician for persistent dizziness. Participants underwent a standardized, comprehensive evaluation and completed self-administered questionnaires regarding anxiety and depression (PRIME-MD Patient Health Questionnaire [PHQ]) and dizziness-related disability (Dizziness Handicap Inventory). To determine the diagnostic indicators of anxiety and/or depression, we used multiple logistic regression analysis with ''presence of Panic Disorder, Other Anxiety Disorder, or Major Depressive Disorder'' as dependent variable. Potential diagnostic indicators included dizziness-related disability, patient characteristics (age, sex, history of anxiety, and history of depression), and dizziness characteristics (description of dizziness, provoking circumstances, associated symptoms, onset, frequency, duration, and avoidance of activities because of dizziness). RESULTS: According to the PHQ, an anxiety and/or depressive disorder was present in 90 patients (22%), of whom 35 reported no medical history of anxiety or depression, nor current pharmacological treatment for these disorders. In the final model, dizziness-related disability, a history of depression, and accompanying fear were associated with an increased odd of anxiety and/or depression, whereas tinnitus and rotational dizziness were associated with a decreased odd of anxiety and/or depression. The model showed good calibration (Hosmer-Lemeshow P value of .46) and discrimination (adjusted area under the receiver operating characteristic curve [AUC] after bootstrapping of .82). CONCLUSIONS: Primary care physicians should consider the existence of anxiety and depression in older patients presenting with dizziness. After external validation, our model may contribute to better recognition and hence better management of anxiety and depression in older patients with dizziness in primary care. PMID- 21546651 TI - Quantitative and qualitative analyses of the clock drawing test in mild cognitive impairment and Alzheimer disease: evaluation of a modified scoring system. AB - The clock drawing test (CDT) has been used as a screening tool for identifying cognitive decline in individuals with Alzheimer disease (AD) and other dementias but has not been extensively evaluated for categorizing individuals with mild cognitive impairment (MCI). This study used both an established quantitative scoring system and a revised scoring method based on qualitative error criteria developed by Rouleau et al to demonstrate the sensitivity of the CDT to MCI. Participants were 66 cognitively healthy older adult, 33 individuals with MCI, and 33 individuals with AD. Sensitivity analyses of the 2 clock drawing methods revealed that the Modified Rouleau scoring method was more sensitive to MCI than the original Rouleau scoring system. Conceptual, graphic, and spatial-planning difficulties were the most commonly committed errors on the CDT across all groups, and conceptual errors along with graphic difficulties were committed more often in the MCI group than the cognitively healthy control group. Participants in the AD group exhibited greater deficits in all error categories and significantly lower total CDT scores compared to both the MCI and older adult controls. Findings observed in this study suggest that qualitative observations of clock drawing errors can help increase sensitivity of the CDT to MCI and that use of a more detailed scoring system is necessary to differentiate individuals with MCI from cognitively healthy older adults. PMID- 21546652 TI - Natural perspective projections for head-mounted displays. AB - The display units integrated in today's head-mounted displays (HMDs) provide only a limited field of view (FOV) to the virtual world. In order to present an undistorted view to the virtual environment (VE), the perspective projection used to render the VE has to be adjusted to the limitations caused by the HMD characteristics. In particular, the geometric field of view (GFOV), which defines the virtual aperture angle used for rendering of the 3D scene, is set up according to the display field of view (DFOV). A discrepancy between these two fields of view distorts the geometry of the VE in a way that either minifies or magnifies the imagery displayed to the user. It has been shown that this distortion has the potential to affect a user's perception of the virtual space, sense of presence, and performance on visual search tasks. In this paper, we analyze the user's perception of a VE displayed in a HMD, which is rendered with different GFOVs. We introduce a psychophysical calibration method to determine the HMD's actual field of view, which may vary from the nominal values specified by the manufacturer. Furthermore, we conducted two experiments to identify perspective projections for HMDs, which are identified as natural by subjects- even if these perspectives deviate from the perspectives that are inherently defined by the DFOV. In the first experiment, subjects had to adjust the GFOV for a rendered virtual laboratory such that their perception of the virtual replica matched the perception of the real laboratory, which they saw before the virtual one. In the second experiment, we displayed the same virtual laboratory, but restricted the viewing condition in the real world to simulate the limited viewing condition in a HMD environment. We found that subjects evaluate a GFOV as natural when it is larger than the actual DFOV of the HMD--in some cases up to 50 percent--even when subjects viewed the real space with a limited field of view. PMID- 21546653 TI - Advanced in situ spectroscopic techniques and their applications in environmental biogeochemistry: introduction to the special section. AB - Understanding the molecular-scale complexities and interplay of chemical and biological processes of contaminants at solid, liquid, and gas interfaces is a fundamental and crucial element to enhance our understanding of anthropogenic environmental impacts. The ability to describe the complexity of environmental biogeochemical reaction mechanisms relies on our analytical ability through the application and developmemnt of advanced spectroscopic techniques. Accompanying this introductory article are nine papers that either review advanced in situ spectroscopic methods or present original research utilizing these techniques. This collection of articles summarizes the challenges facing environmental biogeochemistry, highlights the recent advances and scientific gaps, and provides an outlook into future research that may benefit from the use of in situ spectroscopic approaches. The use of synchrotron-based techniques and other methods are discussed in detail, as is the importance to integrate multiple analytical approaches to confirm results of complementary procedures or to fill data gaps. We also argue that future direction in research will be driven, in addition to recent analytical developments, by emerging factors such as the need for risk assessment of new materials (i.e., nanotechnologies) and the realization that biogeochemical processes need to be investigated in situ under environmentally relevant conditions. PMID- 21546654 TI - X-ray microspectroscopy and chemical reactions in soil microsites. AB - Soils provide long-term storage of environmental contaminants, which helps to protect water and air quality and diminishes negative impacts of contaminants on human and ecosystem health. Characterizing solid-phase chemical species in highly complex matrices is essential for developing principles that can be broadly applied to the wide range of notoriously heterogeneous soils occurring at the earth's surface. In the context of historical developments in soil analytical techniques, we describe applications of bulk-sample and spatially resolved synchrotron X-ray absorption spectroscopy (XAS) for characterizing chemical species of contaminants in soils, and for determining the uniqueness of trace element reactivity in different soil microsites. Spatially resolved X-ray techniques provide opportunities for following chemical changes within soil microsites that serve as highly localized chemical micro- (or nano-)reactors of unique composition. An example of this microreactor concept is shown for micro-X ray absorption near edge structure analysis of metal sulfide oxidation in a contaminated soil. One research challenge is to use information and principles developed from microscale soil chemistry for predicting macroscale and field scale behavior of soil contaminants. PMID- 21546655 TI - Cobalt distribution and speciation: effect of aging, intermittent submergence, in situ rice roots. AB - The speciation and distribution of Co in soils is poorly understood. This study was conducted using x-ray absorption spectroscopy (XAS) techniques to examine the influence of soluble cobalt in the +2 oxidation state (Co[II]) aging, submergence dried cycling, and the presence of in vivo rice roots on the speciation and distribution of added Co(II) in soils. In the aging and submerged-dried cycling studies, Co was found to be associated with Mn oxide fraction (23 to 100% of total Co) and Fe oxide fractions (0 to 77% of total Co) of the soils as either Co(II) species or a mixed Co(II), and Co in the +3 oxidation state (Co[III]) species. The surface speciation of Co in the Mn oxide fraction suggests an innersphere complex was present and the speciation of Co in the Fe oxide fraction was an innersphere surface complex. The in vivo root box experiments showed similar Co speciation in the Mn oxide fraction (13 to 76% of total Co) as the aging and submerged-dried cycling studies. However, the Fe oxide fraction of the soil was unimportant in Co retention. A significant amount (24 to 87% of total Co) of the Co in root box treatments was identified as a Co precipitate. The importance of this finding is that in the presence of rice roots, the Co is redistributed to a Co precipitate. This work confirmed earlier macroscopic work that Mn oxides are important in the sequestration of Co in soils and the influence of roots needs to be taken into account when addressing Co speciation. The information gained from this study will be used to improve models to predict the lability and hence the availability of Co in terrestrial environments. PMID- 21546656 TI - Enhanced transformation of lead speciation in rhizosphere soils using phosphorus amendments and phytostabilization: an x-ray absorption fine structure spectroscopy investigation. AB - To formulate successful phytostabilization strategies in a shooting range soil, understanding how heavy metals are immobilized at the molecular level in the rhizosphere soil is critical. Lead (Pb) speciation and solubility in rhizosphere soils of five different plant species were investigated using extended X-ray absorption fine structure (EXAFS) spectroscopy and chemical extraction. The EXAFS analysis indicated that Pb occurred as PbCO (37%), Pb sorbed to organic matter (Pb-org: 15%), and Pb sorbed to pedogenic birnessite and/or ferrihydrite (Pb-ox: 36%) in the bulk soil. Comparison of the EXAFS spectra between bulk and rhizosphere soils demonstrated notable differences in fine structure, indicating that Pb species had been modified by rhizosphere processes. The estimated proportion of PbCO (25%) in the buckwheat soil was smaller than the other rhizosphere soils (35-39%). The addition of P significantly reduced Pb solubility in the bulk and rhizosphere soil except in the rhizosphere of buckwheat, for which the Pb solubility was 10-fold greater than in the other P-amended soils. This larger solubility in the buckwheat rhizosphere could not be explained by the total Pb speciation in the soil but was presumably related to the acidifying effect of buckwheat, resulting in a decrease of the soil pH by 0.4 units. The reduced Pb solubility by P amendment resulted from the transformation of preexisting PbCO (37%) into Pb(PO)Cl (26-32%) in the bulk and rhizosphere soils. In the P-amended rhizosphere soils, Pb-org species were no longer detected, and the Pb-ox pool increased (51-57%). The present study demonstrated that rhizosphere processes modify Pb solubility and speciation in P-amended soils and that some plant species, like buckwheat, may impair the efficiency of Pb immobilization by P amendments. PMID- 21546657 TI - Speciation and long- and short-term molecular-level dynamics of soil organic sulfur studied by X-ray absorption near-edge structure spectroscopy. AB - We investigated speciation, oxidative state changes, and long- and short-term molecular-level dynamics of organic S after 365 d of aerobic incubation with and without the addition of sugarcane residue using XANES spectroscopy. Soil samples were collected from the upper 15 cm of undisturbed grasslands since 1880, from undisturbed grasslands since 1931, and from cultivated fields since 1880 in the western United States. We found three distinct groups of organosulfur compounds in these grassland-derived soils: (i) strongly reduced (S to S) organic S that encompasses thiols, monosulfides, disulfides, polysulfides, and thiophenes; (ii) organic S in intermediate oxidation (S to S) states, which include sulfoxides and sulfonates; and (iii) strongly oxidized (S) organic S, which comprises ester-SO S. The first two groups represent S directly linked to C and accounted for 80% of the total organic S detected by XANES from the undisturbed soils. Aerobic incubation without the addition of sugarcane residue led to a 21% decline in organanosulfur compounds directly linked to C and to up to an 82% increase inorganic S directly bonded to O. Among the C-bonded S compounds, low-valence thiols, sulfides, thiophenic S, and intermediate-valence sulfoxide S seem to be highly susceptible to microbial attack and may represent the most reactive components of organic S pool in these grassland soils. Sulfonate S exhibited a much lower short-term reactivity. The incorporation of sugarcane residue resulted in an increase in organosulfur compounds directly bonded to C at the early stage of incubation. However, similar to soils incubated without residue addition, the proportion of organic S directly linked to C continued to decline with increasing duration of aerobic incubation, whereas the proportion of organic S directly bonded to O showed a steady rise. PMID- 21546658 TI - Infrared monitoring of dinitrotoluenes in sunflower and maize roots. AB - Infrared microspectroscopy (IMS) is emerging as an important analytical tool for the structural analysis of biological tissue. This report describes the use of IMS coupled to a synchrotron source combined with principal components analysis (PCA) to monitor the fate and effect of dinitrotoluenes in the roots of maize and sunflower plants. Infrared imaging revealed that maize roots metabolized 2,4 dinitrotoluene (DNT) and 2,6-DNT. The DNTs and their derivative aromatic amines were predominantly associated with epidermis and xylem. Both isomers of DNT altered the structure and production of pectin and pectic polysaccharides in maize and sunflower plant roots. Infrared peaks diagnostic for aromatic amines were seen at the 5 mg L concentrations for both DNTs in maize and sunflower treated tissue. However, only infrared peaks for nitro groups, not aromatic amines, were present in the maize treated at 10 mg L For sunflower, the 10 mg L level was toxic and also produced very dark root systems making spectra difficult to obtain. Maize and sunflower seem unable to metabolize effectively at concentrations higher than about 5 mg L DNT in hydroponic solution. Based on the results of this study, IMS combined with PCA can be an effective means of determining the fate and metabolism of organic contaminants in plant tissue when isotopically labeled compounds are not available. PMID- 21546659 TI - Applications of time-resolved laser fluorescence spectroscopy to the environmental biogeochemistry of actinides. AB - Time-resolved laser fluorescence spectroscopy (TRLFS) is a useful means of identifying certain actinide species resulting from various biogeochemical processes. In general, TRLFS differentiates chemical species of a fluorescent metal ion through analysis of different excitation and emission spectra and decay lifetimes. Although this spectroscopic technique has largely been applied to the analysis of actinide and lanthanide ions having fluorescence decay lifetimes on the order of microseconds, such as UO , Cm, and Eu, continuing development of ultra-fast and cryogenic TRLFS systems offers the possibility to obtain speciation information on metal ions having room-temperature fluorescence decay lifetimes on the order of nanoseconds to picoseconds. The main advantage of TRLFS over other advanced spectroscopic techniques is the ability to determine in situ metal speciation at environmentally relevant micromolar to picomolar concentrations. In the context of environmental biogeochemistry, TRLFS has principally been applied to studies of (i) metal speciation in aqueous and solid phases and (ii) the coordination environment of metal ions sorbed to mineral and bacterial surfaces. In this review, the principles of TRLFS are described, and the literature reporting the application of this methodology to the speciation of actinides in systems of biogeochemical interest is assessed. Significant developments in TRLFS methodology and advanced data analysis are highlighted, and we outline how these developments have the potential to further our mechanistic understanding of actinide biogeochemistry. PMID- 21546660 TI - Differential Individual Particle Analysis (DIPA): applications in particulate matter characterization. AB - Operator-controlled and computer-controlled scanning electron microscopy (CCSEM) are used extensively to characterize particulate matter in environmental media. Analysis in a scanning electron microscope (SEM) coupled with chemical extraction is a potentially powerful tool that is capable of determining how various sample components are associated at the individual particle level. This involves initial characterization in a SEM, after which the material is exposed to a liquid or gas phase reaction for a specified time, and once exposure is concluded, the particles are reanalyzed in the SEM. This particle analysis by difference, or differential individual particle analysis (DIPA), possesses considerable potential for describing the behavior of environmental particles under changing chemical conditions. Here we describe DIPA applications with illustrative examples drawn from the analysis of particulate matter modified by reactions in a fluid environment. In situ DIPA permits the same particles to be analyzed in the SEM before and after modification. Repeated exposure to the same, or different modifying conditions, provides information on the time dependence of specific reactions. Significant numbers of particles can be analyzed using CCSEM, and the same particles can be analyzed after the reaction by accurate sample relocation in the SEM. Ex situ DIPA, which involves a bulk sample modification, uses CCSEM to characterize significant numbers of particles pre- and postreaction. The CCSEM approach is extremely efficient; recent developments in silicon drift detectors have increased the speed of characteristic X-rays detection, and very large numbers of particles can be analyzed in a short period of time. PMID- 21546661 TI - Spectroscopic approaches for phosphorus speciation in soils and other environmental systems. AB - In the past decades, environmental scientists have become increasingly involved in developing novel approaches for applying emerging spectroscopic techniques to complex environmental matrices. The objective of this review is to convey the most common chemical species of phosphorus reported for soils, sediments, model systems, and waste materials based on analyses by four spectroscopic techniques: X-ray absorption near-edge structure, nuclear magnetic resonance, Fourier transform infrared spectroscopy, and Raman spectroscopy. Unique information is provided by each technique at a level of specificity that depends in part on matrix complexity. The X-ray absorption near-edge structure and nuclear magnetic resonance techniques reveal inorganic and organic P species in intact environmental matrices or in chemical extracts, whereas the Fourier transform infrared and Raman techniques can provide more specific bonding information about mineral or adsorbed P species in model analogs of matrix components. The most common P species in soils and sediments as indicated by spectroscopy are hydroxyapatite and octacalcium phosphate minerals, phosphate adsorbed on Fe- and Al-oxides, pyrophosphates and polyphosphates, phosphate mono- and di-esters, and phosphonates. Continued advancements in spectroscopic methods should improve speciation-based models of P mobilization and transformations in the environment. PMID- 21546662 TI - Combined application of QEM-SEM and hard X-ray microscopy to determine mineralogical associations and chemical speciation of trace metals. AB - We describe the application of quantitative evaluation of mineralogy by scanning electron microscopy in combination with techniques commonly available at hard X ray microprobes to define the mineralogical environment of a bauxite residue core segment with the more specific aim of determining the speciation of trace metals (e.g., Ti, V, Cr, and Mn) within the mineral matrix. Successful trace metal speciation in heterogeneous matrices, such as those encountered in soils or mineral residues, relies on a combination of techniques including spectroscopy, microscopy, diffraction, and wet chemical and physical experiments. Of substantial interest is the ability to define the mineralogy of a sample to infer redox behavior, pH buffering, and mineral-water interfaces that are likely to interact with trace metals through adsorption, coprecipitation, dissolution, or electron transfer reactions. Quantitative evaluation of mineralogy by scanning electron microscopy coupled with micro-focused X-ray diffraction, micro-X-ray fluorescence, and micro-X-ray absorption near edge structure (mXANES) spectroscopy provided detailed insights into the composition of mineral assemblages and their effect on trace metal speciation during this investigation. In the sample investigated, titanium occurs as poorly ordered ilmenite, as rutile, and is substituted in iron oxides. Manganese's spatial correlation to Ti is closely linked to ilmenite, where it appears to substitute for Fe and Ti in the ilmenite structure based on its mXANES signature. Vanadium is associated with ilmenite and goethite but always assumes the +4 oxidation state, whereas chromium is predominantly in the +3 oxidation state and solely associated with iron oxides (goethite and hematite) and appears to substitute for Fe in the goethite structure. PMID- 21546663 TI - Agroforestry systems and environmental quality: introduction. AB - Investments in agroforestry research during the past three decades-albeit modest have yielded significant gains in understanding the role of trees on farmlands, and the ecological and economic advantages of integrated farming systems. While early research focused mostly on farm or local levels, broader-level ecosystem services of agroforestry systems (AFS) have raised high expectations in recent years. The nine papers included in this special collection deal with three of such environmental benefits of AFS: water-quality enhancement, carbon sequestration, and soil improvement. These benefits are based on the perceived ability of (i) vegetative buffer strips (VBS) to reduce surface transport of agrochemical pollutants, (ii) large volumes of aboveground and belowground biomass of trees to store high amounts of C deeper in the soil profile, and (iii) trees to enhance soil productivity through biological nitrogen fixation, efficient nutrient cycling, and deep capture of nutrients. The papers included have, in general, substantiated these premises and provided new insights. For example, the riparian VBS are reported to increase the reservoir life, in addition to reducing transport of agrochemicals; the variations in C storage in different soil-fraction sizes suggest that microaggregate (250-53 MUm) dynamics in the soil could be a good indicator of its C-storage potential; and the use of vector analysis technique is recommended in AFS to avoid consequences of inaccurate and overuse of fertilizers. The papers also identified significant knowledge gaps in these areas. A common theme across all three environmental quality issues covered is that more and varied research datasets across a broad spectrum of conditions need to be generated and integrated with powerful statistical tools to ensure wide applicability of the results. Furthermore, appropriate management practices that are acceptable to the targeted land users and agroforestry practitioners need to be designed to exploit these environmental benefits. The relative newness of research in environmental quality of AFS will pose some additional challenges as well. These include the lack of allometric equations for tree-biomass determination, absence of standardized norms on soil sampling depth, and limitations of fixed-effect models arising from issues such as pseudo-replication and repeated measures that are common in studies on preexisting field plots. Overall, this special collection is a timely effort in highlighting the promise of AFS in addressing some of the environmental quality issues, and the challenges in realizing that potential. PMID- 21546664 TI - Reducing herbicides and veterinary antibiotics losses from agroecosystems using vegetative buffers. AB - Multiple species vegetative buffer strips (VBSs) have been recommended as a cost effective approach to mitigate agrochemical transport in surface runoff derived from agronomic operations, while at the same time offering a broader range of long-term ecological and environmental benefits. However, the effect of VBS designs and species composition on reducing herbicide and veterinary antibiotic transport has not been well documented. An experiment consisting of three VBS designs and one continuous cultivated fallow control replicated in triplicate was conducted to assess effectiveness in reducing herbicide and antibiotic transport for claypan soils. The three VBS designs include (i) tall fescue, (ii) tall fescue with a switchgrass hedge barrier, and (iii) native vegetation (largely eastern gamagrass). Rainfall simulation was used to create uniform antecedent soil moisture content in the plots and to generate runoff. Our results suggested that all VBS significantly reduced the transport of dissolved and sediment-bound atrazine, metolachlor, and glyphosate in surface runoff by 58 to 72%. Four to 8 m of any tested VBS reduced dissolved sulfamethazine transport in the surface runoff by more than 70%. The tall fescue VBS was overall most effective at reducing dissolved tylosin and enrofloxacin transport in the runoff (>75%). The developed exponential regression models can be used to predict expected field scale results and provide design criteria for effective field implementation of grass buffers. Our study has demonstrated that an optimized VBS design may achieve desired agrochemical reductions and minimize acreage removed from crop production. PMID- 21546665 TI - Agroforestry buffers for nonpoint source pollution reductions from agricultural watersheds. AB - Despite increased attention and demand for the adoption of agroforestry practices throughout the world, rigorous long-term scientific studies confirming environmental benefits from the use of agroforestry practices are limited. The objective was to examine nonpoint-source pollution (NPSP) reduction as influenced by agroforestry buffers in watersheds under grazing and row crop management. The grazing study consists of six watersheds in the Central Mississippi Valley wooded slopes and the row crop study site consists of three watersheds in a paired watershed design in Central Claypan areas. Runoff water samples were analyzed for sediment, total nitrogen (TN), and total phosphorus (TP) for the 2004 to 2008 period. Results indicate that agroforestry and grass buffers on grazed and row crop management sites significantly reduce runoff, sediment, TN, and TP losses to streams. Buffers in association with grazing and row crop management reduced runoff by 49 and 19%, respectively, during the study period as compared with respective control treatments. Average sediment loss for grazing and row crop management systems was 13.8 and 17.9 kg ha yr, respectively. On average, grass and agroforestry buffers reduced sediment, TN, and TP losses by 32, 42, and 46% compared with the control treatments. Buffers were more effective in the grazing management practice than row crop management practice. These differences could in part be attributed to the differences in soils, management, and landscape features. Results from this study strongly indicate that agroforestry and grass buffers can be designed to improve water quality while minimizing the amount of land taken out of production. PMID- 21546666 TI - Sediment measurement and transport modeling: impact of riparian and filter strip buffers. AB - Well-calibrated models are cost-effective tools to quantify environmental benefits of conservation practices, but lack of data for parameterization and evaluation remains a weakness to modeling. Research was conducted in southwestern Oklahoma within the Cobb Creek subwatershed (CCSW) to develop cost-effective methods to collect stream channel parameterization and evaluation data for modeling in watersheds with sparse data. Specifically, (i) simple stream channel observations obtained by rapid geomorphic assessment (RGA) were used to parameterize the Soil and Water Assessment Tool (SWAT) model stream channel variables before calibrating SWAT for streamflow and sediment, and (ii) average annual reservoir sedimentation rate, measured at the Crowder Lake using the acoustic profiling system (APS), was used to cross-check Crowder Lake sediment accumulation rate simulated by SWAT. Additionally, the calibrated and cross checked SWAT model was used to simulate impacts of riparian forest buffer (RF) and bermudagrass [ (L.) Pers.] filter strip buffer (BFS) on sediment yield and concentration in the CCSW. The measured average annual sedimentation rate was between 1.7 and 3.5 t ha yr compared with simulated sediment rate of 2.4 t ha yr Application of BFS across cropped fields resulted in a 72% reduction of sediment delivery to the stream, while the RF and the combined RF and BFS reduced the suspended sediment concentration at the CCSW outlet by 68 and 73%, respectively. Effective riparian practices have potential to increase reservoir life. These results indicate promise for using the RGA and APS methods to obtain data to improve water quality simulations in ungauged watersheds. PMID- 21546668 TI - Soil carbon storage in silvopastoral systems and a treeless pasture in northwestern Spain. AB - Soil particle size and land management practices are known to have considerable influence on carbon (C) storage in soils, but such information is lacking for silvopastoral systems in Spain. This study quantified the amounts of soil C stored at various depths to 100 cm under silvopastoral plots of radiata pine ( D. Don) and birch ( Roth) in comparison to treeless pasture in Galicia, Spain. Soils were fractionated into three size classes (<53, 53-250, and 250-2000 MUm), and C stored in them and in the whole (nonfractionated) soil was determined. Overall, the C stock to 1 m ranged from 80.9 to 176.9 Mg ha in these soils. Up to 1 m depth, 78.82% of C was found in the 0- to 25-cm soil depth, with 12.9, 4.92, and 3.36% in the 25- to 50-, 50- to 75-, and 75- to 100-cm depths, respectively. Soils under birch at 0 to 25 cm stored more C in the 250- to 2000-MUm size class as compared with those under radiata pine; at that depth, pasture had more C than pine silvopasture in the smaller soil fractions (<53 and 53-250 MUm). In the 75- to 100-cm depth, there was significantly more storage of C in the 250- to 2000 MUm fraction in both silvopastures as compared with the pasture. The higher storage of soil C in larger fraction size in lower soil depths of silvopasture suggests that planting of trees into traditional agricultural landscapes will promote longer-term storage of C in the soil. PMID- 21546667 TI - Environmental impacts of the shelter forests in Horqin Sandy land, northeast China. AB - Assessing environmental effects of shelter forests is primarily necessary for realizing their greatest protective benefits. The Three-North Shelter Forest Program (TNSFP), the largest ecological afforestation program in the world, has been operated for three decades in China but so far lacks comprehensive assessment of its environmental impacts. Horqin Sandy Land (HSL) in Northeast China is one of the key areas in the TNSFP implementation. To identify the principal contributors to environmental changes in HSL, we evaluated impacts of variations in landscape features, shelter forest areas, climatic factors, and social factors on changes in sandy land areas from 1978 to 2007, by using Gray Relational Analysis. Our analysis showed that during the period 1978 to 2007, the sandy land area decreased by 3.9% in low aeolian dunes, 14.5% in low mountains and hills, and 98.9% in high elevation alluvial flats of HSL. Factors with Gray Correlation Degrees >0.9 were identified as the patch shape index (PSI) and the landscape isolation index (LII) of grasses in low aeolian dunes, PSI of grasses in mountains and hills, and area of broadleaved forests and LII of shrubs in alluvial flats. It is concluded that establishment of the shelter forests has played a significant role in controlling the expansion of sandy land in HSL. To sustain the long-term environmental benefits of the shelter forests in the remaining period for TNSFP construction, suitable tree species should be selected and planted at appropriate densities based on the local precipitation, groundwater and landform conditions, and the system stability of the total landscape. PMID- 21546669 TI - Soil carbon storage in silvopasture and related land-use systems in the brazilian cerrado. AB - Silvopastoral management of fast-growing tree plantations is becoming popular in the Brazilian Cerrado (savanna). To understand the influence of such systems on soil carbon (C) storage, we studied C content in three aggregate size classes in six land-use systems (LUS) on Oxisols in Minas Gerais, Brazil. The systems were a native forest, a treeless pasture, 24- and 4-yr-old eucalyptus ( sp.) plantations, and 15- and 4-yr-old silvopastures of fodder grass plus animals under eucalyptus. From each system, replicated soil samples were collected from four depths (0-10, 10-20, 20-50, and 50-100 cm), fractionated into 2000- to 250-, 250- to 53-, and <53-MUm size classes representing macroaggregates, microaggregates, and silt + clay, respectively, and their C contents determined. Macroaggregate was the predominant size fraction under all LUS, especially in the surface soil layers of tree-based systems. In general, C concentrations (g kg soil) in the different aggregate size fractions did not vary within the same depth. The soil organic carbon (SOC) stock (Mg C ha) to 1-m depth was highest under pasture compared with other LUS owing to its higher soil bulk density. The soils under all LUS had higher C stock compared with other reported values for managed tropical ecosystems: down to 1 m, total SOC stock values ranged from 461 Mg ha under pasture to 393 Mg ha under old eucalyptus. Considering the possibility for formation and retention of microaggregates within macroggregates in low management-intensive systems such as silvopasture, the macroaggregate dynamics in the soil seem to be a good indicator of its C storage potential. PMID- 21546670 TI - A spatial model approach for assessing windbreak growth and carbon stocks. AB - Agroforestry, the deliberate integration of trees into agricultural operations, sequesters carbon (C) while providing valuable services on agricultural lands. However, methods to quantify present and projected C stocks in these open-grown woody systems are limited. As an initial step to address C accounting in agroforestry systems, a spatial Markov random field model for predicting the natural logarithm (log) of the mean aboveground volume of green ash ( Marsh.) within a shelterbelt, referred to as the log of aboveground volume, was developed using data from an earlier study and web-available soil and climate information. Windbreak characteristics, site, and climate variables were used to model the large-scale trend of the log of aboveground volume. The residuals from this initial model were correlated among sites up to 24 km from a point of interest. Therefore, a spatial dependence parameter was used to incorporate information from sites within 24 km into the prediction of the log of the aboveground volume. Age is an important windbreak characteristic in the model. Thus, the log of aboveground volume can be predicted for a given windbreak age and for values of other explanatory variables associated with a site of interest. Such predictions can be exponentiated to obtain predictions of aboveground volume for windbreaks without repeated inventory. With the capability of quantifying uncertainty, the model has the potential for large regional planning efforts and C stock assessments for many deciduous tree species used in windbreaks and riparian buffers once it is calibrated. PMID- 21546671 TI - Trees' role in nitrogen leaching after organic, mineral fertilization: a greenhouse experiment. AB - New sustainable agriculture techniques are arising in response to the environmental problems caused by intensive agriculture, such as nitrate leaching and surface water eutrophication. Organic fertilization (e.g., with sewage sludge) and agroforestry could be used to reduce nutrient leaching. We assessed the efficiency of establishing trees and pasture species in environmentally sensitive, irrigated Mediterranean grassland soils in controlling nitrate leaching. Four vegetation systems-bare soil, pasture species, cherry trees [ (L.) L.], and pasture-tree mixed plantings-and five fertilization treatments-control, two doses of mineral fertilizer, and two doses of organic fertilizer (sewage sludge)-were tested in a greenhouse experiment over 2 yr. In the experiment, the wet and warm climate characteristics of Mediterranean irrigated croplands and the plant-to-plant and soil-to-plant interactions that occur in open-field agroforestry plantations were simulated. Following a factorial design with six replicates, 120 pots (30-cm radius and 120 cm deep) were filled with a sandy, alluvial soil common in the cultivated fluvial plains of the region. The greatest pasture production and tree growth were obtained with sewage sludge application. Both pasture production and tree growth decreased significantly in the pasture tree mixed planting. Nitrate leaching was negligible in this latter treatment, except under the highest dose of sewage sludge application. The rapid mineralization of sludge suggested that this organic fertilizer should be used very cautiously in warm, irrigated Mediterranean soils. Mixed planting of pasture species and trees, such as , could be a useful tool for mitigating nitrate leaching from irrigated Mediterranean pastures on sandy soils. PMID- 21546672 TI - Diagnosis of nutrient imbalances with vector analysis in agroforestry systems. AB - Agricultural intensification has had unintended environmental consequences, including increased nutrient leaching and surface runoff and other agrarian derived pollutants. Improved diagnosis of on-farm nutrient dynamics will have the advantage of increasing yields and will diminish financial and environmental costs. To achieve this, a management support system that allows for site-specific rapid evaluation of nutrient production imbalances and subsequent management prescriptions is needed for agroecological design. Vector diagnosis, a bivariate model to depict changes in yield and nutritional response simultaneously in a single graph, facilitates identification of nutritional status such as growth dilution, deficiency, sufficiency, luxury uptake, and toxicity. Quantitative data from cocoa agroforestry systems and pigeonpea intercropping trials in Ghana and Tanzania, respectively, were re-evaluated with vector analysis. Relative to monoculture, biomass increase in cocoa ( L.) under shade (35-80%) was accompanied by a 17 to 25% decline in P concentration, the most limiting nutrient on this site. Similarly, increasing biomass with declining P concentrations was noted for pigeonpea [ (L). Millsp.] in response to soil moisture availability under intercropping. Although vector analysis depicted nutrient responses, the current vector model does not consider non-nutrient resource effects on growth, such as ameliorated light and soil moisture, which were particularly active in these systems. We revisit and develop vector analysis into a framework for diagnosing nutrient and non-nutrient interactions in agroforestry systems. Such a diagnostic technique advances management decision-making by increasing nutrient precision and reducing environmental issues associated with agrarian-derived soil contamination. PMID- 21546673 TI - Water resources and land use and cover in a humid region: the southeastern United States. AB - It is widely recognized that forest and water resources are intricately linked. Globally, changes in forest cover to accommodate agriculture and urban development introduce additional challenges for water management. The U.S. Southeast typifies this global trend as predictions of land-use change and population growth suggest increased pressure on water resources in coming years. Close attention has long been paid to interactions between people and water in arid regions; however, based on information from regions such as the Southeast, it is evident that much greater focus is required to sustain a high-quality water supply in humid areas as well. To that end, we review hydrological, physicochemical, biological, and human and environmental health responses to conversion of forests to agriculture and urban land uses in the Southeast. Commonly, forest removal leads to increased stream sediment and nutrients, more variable flow, altered habitat and stream and riparian communities, and increased risk of human health effects. Although indicators such as the percentage of impervious cover signify overall watershed alteration, the threshold to disturbance, or the point at which effects can been observed in stream and riparian parameters, can be quite low and often varies with physiographic conditions. In addition to current land use, historical practices can greatly influence current water quality. General inferences of this study may extend to many humid regions concerning climate, environmental thresholds, and the causes and nature of effects. PMID- 21546674 TI - Do lab-derived distribution coefficient values of pesticides match distribution coefficient values determined from column and field-scale experiments? A critical analysis of relevant literature. AB - In this study, we analyzed sorption parameters for pesticides that were derived from batch and column or batch and field experiments. The batch experiments analyzed in this study were run with the same pesticide and soil as in the column and field experiments. We analyzed the relationship between the pore water velocity of the column and field experiments, solute residence times, and sorption parameters, such as the organic carbon normalized distribution coefficient ( ) and the mass exchange coefficient in kinetic models, as well as the predictability of sorption parameters from basic soil properties. The batch/column analysis included 38 studies with a total of 139 observations. The batch/field analysis included five studies, resulting in a dataset of 24 observations. For the batch/column data, power law relationships between pore water velocity, residence time, and sorption constants were derived. The unexplained variability in these equations was reduced, taking into account the saturation status and the packing status (disturbed-undisturbed) of the soil sample. A new regression equation was derived that allows estimating the values derived from column experiments using organic matter and bulk density with an value of 0.56. Regression analysis of the batch/column data showed that the relationship between batch- and column-derived values depends on the saturation status and packing of the soil column. Analysis of the batch/field data showed that as the batch-derived value becomes larger, field-derived values tend to be lower than the corresponding batch-derived values, and vice versa. The present dataset also showed that the variability in the ratio of batch- to column-derived value increases with increasing pore water velocity, with a maximum value approaching 3.5. PMID- 21546675 TI - Greenhouse gas and alcohol emissions from feedlot steers and calves. AB - Livestock's contributions to climate change and smog-forming emissions are a growing public policy concern. This study quantifies greenhouse gas (GHG) and alcohol emissions from calves and feedlot steers. Carbon dioxide (CO) methane (CH), nitrous oxide (NO), ethanol (EtOH), and methanol (MeOH) were measured from a total of 45 Holstein and Angus steers and 9 Holstein calves representative of four different growth stages commonly present on calf ranches and commercial feedlots. Individuals from each animal type were randomly assigned to three equal replicate groups of nine animals per group. Steers were fed a high concentrate diet and calves a milk replacer and grain supplement. Cattle and calves were housed in groups of three animals in an environmental chamber for 24 h. The CO, NO, EtOH, and MeOH concentrations from the air inlet and outlet of the chamber were measured using an INNOVA 1412 monitor and CH using a TEI 55C methane analyzer. Emission rates (g head h) were calculated. The GHGs were mainly produced by enteric fermentation and respiration and differed across life stages of cattle. Compared with dairy cows, feedlot steers produce relatively less GHG. In general, ethanol and methanol, the most important volatile organic compound (VOC) group in the dairy sector, were below the lower limit of detection of the gas analyzer. The present data will be useful to verify models and to enhance GHG emission inventories for enteric fermentation, respiration, and fresh excreta for numerous cattle life stages across the beef industry. PMID- 21546676 TI - Tannin extracts abate ammonia emissions from simulated dairy barn floors. AB - Feeding more tannin and less crude protein (CP) to dairy cows may have synergistic impacts on reducing NH emissions from dairy barns. Three trials using lab-scale ventilated chambers with concrete floors were conducted to determine the impacts on NH emission of tannin and CP feeding, tannin feeding on urease activity in feces, and tannin application directly to the barn floor. For Trial 1, mixtures of feces and urine from lactating Holstein dairy cows () fed four levels (g kg) of dietary tannin extract [a mixture from red quebracho () and chestnut () trees]: 0 tannin (0T), 4.5 (low tannin [LT]), 9.0 (medium tannin [MT]), and 18.0 (high tannin [HT]); each fed at two levels (g kg) of dietary CP: 155 low CP (LCP) and 168 high CP (HCP) were applied to chambers. For Trial 2, urea solution was added to feces obtained from cows fed 0T, MT, and HT at HCP. For Trial 3, tannin amounts equivalent to those fed at 0T, MT, and HT were applied directly to feces-urine mixtures from 0T-HCP. For all trials, NH emissions were measured 1, 3, 6, 12, 24, 36, and 48 h after treatment application. For Trial 1, reductions in NH emission due to tannin feeding were greatest when fed at LCP: The LCP-LT and LCP-HT treatments emitted 30.6% less NH than LCP-0T, and the HCP-LT and HCP-HT treatments emitted 16.3% less NH than HCP 0T. For Trial 2, feeding tannin decreased urease activity in feces, resulting in an 11.5% reduction in cumulative NH loss. For Trial 3, the application of tannin directly to simulated barn floors also apparently decreased urease activity, resulting in an average reduction in cumulative NH emissions of 19.0%. Larger scale trails are required to ascertain the effectiveness of tannin extracts in abating NH loss from dairy barn floors. PMID- 21546677 TI - Anaerobic degradation of vinyl chloride in aquifer microcosms. AB - The anaerobic degradation potential at a chloroethene-contaminated site was investigated by operating two anoxic column aquifer microcosms enriched in iron(III). One column was fed with vinyl chloride (VC) only (column A) and one with VC and acetate (column B). In column A, after about 600 pore volume exchanges (PVEs), VC started to disappear and reached almost zero VC recovery in the effluent after 1000 PVEs. No formation of ethene was observed. In column B, effluent VC was almost always only a fraction of influent VC. Formation of ethene was observed after 800 PVEs and started to become an important degradation product after 1550 PVEs. However, ethene was never observed in stoichiometric amounts compared with disappeared VC. The average stable isotope enrichment factor for VC disappearance in column A was determined to be -4.30/00. In column B, the isotope enrichment factor shifted from -10.7 to -18.50/00 concurrent with an increase in ethene production. Batch microcosms inoculated with column material showed similar isotope enrichment factors as the column microcosms. These results indicated that two degradation processes occurred, one in column A and two in parallel in column B with increasing importance of reductive dechlorination with time. This study suggests that in addition to reductive dechlorination, other degradation processes such as anaerobic oxidation should be taken into account when evaluating natural attenuation of VC and that isotope analysis can help to differentiate between different pathways of VC removal. PMID- 21546678 TI - Denitrification and availability of carbon and nitrogen in a well-drained pasture soil amended with particulate organic carbon. AB - A well-drained soil in N-fertilized dairy pasture was amended with particulate organic carbon (POC), either sawdust or coarse woody mulch, and sampled every 4 wk for a year to test the hypothesis that the addition of POC would increase denitrification activity by increasing the number of microsites where denitrification occurred. Overall mean denitrifying enzyme activity (DEA), on a gravimetric basis, was 100% greater for the woody mulch treatment and 50% greater for the sawdust treatment compared with controls, indicating the denitrifying potential of the soil was enhanced. Despite differences in DEA, no difference in denitrification rate, as measured by the acetylene block technique, was detected among treatments, with an average annual N loss of ~22 kg N ha yr Soil water content overall was driving denitrification in this well-drained soil as regression of the natural log of volumetric soil water content (VWC) against denitrification rate was highly significant ( = 0.74, < 0.001). Addition of the amendments, however, had significant effects on the availability of both C and N. An additional 20 to 40 kg N ha was stored in POC-amended treatments as a result of increases in the microbial biomass. Basal respiration, as a measure of available C, was 400% greater than controls in the sawdust treatment and 250% greater than controls in the mulch. Net N mineralization, however, was significantly lower in the sawdust treatment, resulting in significantly lower nitrate N levels than in the control. We attribute the lack of measured response in denitrification rate to the high temporal variability in denitrification and suggest that diffusion of nitrate may ultimately have limited denitrification in the amended treatments. Our data indicate that manipulation of denitrification by addition of POC may be possible, particularly when nitrate levels are high, but quantifying differences in the rate of denitrification is difficult because of the temporal nature of the process (particularly the complex interaction of N availability and soil water content). PMID- 21546679 TI - A spatial analysis of phosphorus in the Mississippi river basin. AB - Phosphorus (P) in rivers in the Mississippi River basin (MRB) contributes to hypoxia in the Gulf of Mexico and impairs local water quality. We analyzed the spatial pattern of P in the MRB to determine the counties with the greatest January to June P riverine yields and the most critical factors related to this P loss. Using a database of P inputs and landscape characteristics from 1997 through 2006 for each county in the MRB, we created regression models relating riverine total P (TP), dissolved reactive P (DRP), and particulate P (PP) yields for watersheds within the MRB to these factors. Riverine yields of P were estimated from the average concentration of each form of P during January to June for the 10-yr period, multiplied by the average daily flow, and then summed for the 6-mo period. The fraction of land planted in crops, human consumption of P, and precipitation were found to best predict TP yields with a spatial error regression model ( = 0.48, = 101). Dissolved reactive P yields were predicted by fertilizer P inputs, human consumption of P, and precipitation in a multiple regression model ( = 0.42, = 73), whereas PP yields were explained by crop fraction, human consumption of P, and soil bulk density in a spatial error regression model ( = 0.49, = 61). Overall, the Upper Midwest's Cornbelt region and lower Mississippi basin had the counties with the greatest P yields. These results help to point out specific areas where agricultural conservation practices that reduce losses to streams and rivers and point source P removal might limit the intensity or spatial occurrence of Gulf of Mexico hypoxia and improve local water quality. PMID- 21546681 TI - Phosphorus and nitrogen in runoff after phosphorus- or nitrogen-based manure applications. AB - Application of beef cattle () manure based on nitrogen (N) requirements of crops has resulted in elevated concentrations of soil test phosphorus (P) in surface soils, and runoff from this cropland can contribute to eutrophication of surface waters. We conducted a 3-yr field study (2005-2007) on a Lethbridge loam soil cropped to dryland barley () in southern Alberta, Canada to evaluate the effect of annual and triennial P-based and annual N-based feedlot manure on P and N in runoff. The manure was spring applied and incorporated. There was one unamended control plot. A portable rainfall simulator was used to generate runoff in the spring of each year after recent manure incorporation, and the runoff was analyzed for total P, total dissolved P, total particulate P, dissolved reactive P, total N, total dissolved N, total particulate N, NO-N, and NH-N. Annual or triennial P-based application resulted in significantly ( <= 0.05) lower (by 50 to 94%) concentrations or loads of mainly dissolved P fractions in runoff for some years compared with annual N-based application, and this was related to lower rates of annual manure P applied. For example, mean dissolved reactive P concentrations in 2006 and 2007 were significantly lower for the annual P-based (0.12-0.20 mg L) than for the annual N-based application (0.24-0.48 mg L), and mean values were significantly lower for the triennial P-based (0.06-0.13 mg L) than for the annual N-based application. In contrast, other P fractions in runoff were unaffected by annual P-based application. Our findings suggested no environmental benefit of annual P-based application over triennial P-based application with respect to P and N in runoff. Similar concentrations and loads of N fractions in runoff for the P- and N-based applications indicated that shifting to a P-based application would not significantly influence N in runoff. PMID- 21546680 TI - Interactions of carbamazepine in soil: effects of dissolved organic matter. AB - Pharmaceutical compounds (PCs) and dissolved organic matter (DOM) are co introduced into soils by irrigation with reclaimed wastewater. We targeted carbamazepine (CBZ) as a model compound to study the tertiary interactions between relatively polar PCs, DOM, and soil. Sorption-desorption behavior of CBZ was studied with bulk clay soil and the corresponding clay size fraction in the following systems: (i) without DOM, (ii) co-introduced with DOM, and (iii) pre adsorption of DOM before CBZ introduction. Sorption of the DOM to both sorbents was irreversible and exhibited pronounced sorption-desorption hysteresis. Carbamazepine exhibited higher sorption affinity and nonlinearity, and a higher degree of desorption hysteresis with the bulk soil than the corresponding clay size fraction. This was probably due to specific interactions with polar soil organic matter fractions that are more common in the bulk soil. Co-introduction of CBZ and DOM to the soil did not significantly affect the sorption behavior of CBZ; however, following pre-adsorption of DOM by the bulk soil, an increase in sorption affinity and decrease in sorption linearity were observed. In this latter treatment, desorption hysteresis of CBZ was significantly increased for both sorbents. We hypothesize that this was due to either strong chemical interactions of CBZ with the adsorbed DOM or physical encapsulation of CBZ in DOM clay complexes. Based on this study, we suggest that DOM facilitates stronger interactions of polar PCs with the solid surface. This mechanism can reduce PC desorption ability in soils. PMID- 21546682 TI - Microbial and chemical markers: runoff transfer in animal manure-amended soils. AB - Fecal contamination of water resources is evaluated by the enumeration of the fecal coliforms and Enterococci. However, the enumeration of these indicators does not allow us to differentiate between the sources of fecal contamination. Therefore, it is important to use alternative indicators of fecal contamination to identify livestock contamination in surface waters. The concentration of fecal indicators (, enteroccoci, and F-specific bacteriophages), microbiological markers (Rum-2-bac, Pig-2-bac, and ), and chemical fingerprints (sterols and stanols and other chemical compounds analyzed by 3D-fluorescence excitation matrix spectroscopy) were determined in runoff waters generated by an artificial rainfall simulator. Three replicate plot experiments were conducted with swine slurry and cattle manure at agronomic nitrogen application rates. Low amounts of bacterial indicators (1.9-4.7%) are released in runoff water from swine-slurry amended soils, whereas greater amounts (1.1-28.3%) of these indicators are released in runoff water from cattle-manure-amended soils. Microbial and chemical markers from animal manure were transferred to runoff water, allowing discrimination between swine and cattle fecal contamination in the environment via runoff after manure spreading. Host-specific bacterial and chemical markers were quantified for the first time in runoff waters samples after the experimental spreading of swine slurry or cattle manure. PMID- 21546683 TI - Runoff water quality during drought in a zero-order georgia piedmont pasture: nitrogen and total organic carbon. AB - Approximately 11% of the Southern Piedmont (1.8 million ha) is used for pasture and hay production, mostly under low-input management. Few studies have investigated in the region long-term nitrogen and carbon losses in surface runoff, which can be significant. We present 1999 to 2009 hydrologic and water quality data from a rotationally grazed, 7.8-ha, zero-order pasture (W1) near Watkinsville in the Georgia Piedmont. Annual rainfall was 176 to 463 mm below the long-term average (1240 mm) in 7 of the 11 yr. There were 20 runoff events during 86 mo of below-average rainfall (deficit period), compared with 54 events during 46 mo of nondeficit period. Mean event flow-weighted concentration (in mg L) was 0.96 for nitrate-nitrogen (NO-N), 0.97 for ammonium-nitrogen (NH-N), 3.70 for total nitrogen (TN), and 9.12 for total organic carbon (TOC) ( = 43-47; limited due to instrument problem). Nutrient loads (in kg ha per event) averaged 0.04 for NO-N, 0.03 for NH-N, 0.19 for TN, and 0.54 for TOC. Total loads for N and TOC were 6 to 11 times greater from nondeficit than from deficit periods. The observed N concentrations, while well below maximum drinking water standard limits, could pose risk for eutrophication, which can be stimulated at lower concentrations. However, the ability of headwater streams, such as the one downstream of W1, to reduce nutrient concentrations might partially alleviate this concern. The results of this study point to the need to use a long-term dataset that includes measurements made in drought and wet years when evaluating the efficacy of water quality standards. PMID- 21546684 TI - Escherichia coli load reduction from runoff by vegetative filter strips: a laboratory-scale study. AB - Vegetative filter strips (VFS) are commonly used best management practices for removing contaminants from runoff. Additional research is warranted to determine their efficiency and the most appropriate metrics for predicting fecal bacteria reductions. The objective of this research was to determine VFS effectiveness in removing from runoff relative to inflow rate, infiltration capacity, and flow concentration. This research also investigated the presence of in runoff from clean water runon after diluted manure runon events. A laboratory-scale VFS soil box (200 cm long, 100 cm wide, 7.5% slope) was packed with a sandy loam soil. Ten constant-flow VFS experiments were conducted with and without vegetation (8-10 cm ryegrass [ L.]) at low (20-40 cm s), medium (40-60 cm s), and high (85-120 cm s) flow rates and for a full (100 cm) or concentrated (40 cm) VFS flow width to simulate a channelizing flow condition. Two runon events were investigated for each experimental condition: (i) diluted liquid swine manure runon and (ii) clean water runon 48 h afterward. was used as an indicator of fecal contamination and was quantified by the most probable number (MPN) technique. No concentration reductions were observed based on peak outflow concentrations, and only small concentration reductions were observed based on outflow event mean concentrations. The mass reductions ranged from 22 to 71% and were strongly correlated to infiltration or runoff reduction ( = 0.88), which was dependent on the degree of flow concentration. Little to no effect of sedimentation on transport was observed, hypothesized to be due to minimum attachment to sediment particles because the bacteria originated from manure sources. Therefore, the design of VFS for bacteria removal should be based on the infiltration capacity in the VFS and should prevent concentrated flow, which limits total infiltration. The event mean concentrations in clean water runon experiments were between 10 and 100 MPN per 100 mL; therefore, under these conditions, VFS served as a source of residual from previous runon events. PMID- 21546685 TI - Controlling runoff from subtropical pastures has differential effects on nitrogen and phosphorus loads. AB - A 4-yr (2005-2008) study was conducted to evaluate the potential of pasture water management for controlling nutrient losses in surface runoff in the Northern Everglades. Two pasture water management treatments were investigated on Bahia grass ( Flugge) pastures: reduced flow and unobstructed flow. The reduced flow treatment was applied to four of eight 20.23-ha pastures by installing water control structures in pasture drainage ditches with flashboards set at a predetermined height. Four other pastures received the unobstructed-flow treatment, in which surface runoff exited pastures unimpeded. Automated instruments measured runoff volume and collected surface water samples for nutrient analysis. In analyzing data for before-after treatment analysis, the 2005 results were removed because of structural failure in water control structures and the 2007 results were removed because of drought conditions. Pasture water retention significantly reduced annual total nitrogen (TN) loads, which were 11.28 kg ha and 6.28 kg ha, respectively, in pastures with unobstructed and reduced flow. Total phosphorus (TP) loads were 27% lower in pastures with reduced flow than in pastures with unobstructed flow, but this difference was not statistically significant. Concentrations of available soil P were significantly greater in pastures with reduced flow. Pasture water retention appears to be an effective approach for reducing runoff volume and TN loads from cattle pastures in the Northern Everglades, but the potential to reduce TP loads may be diminished if higher water table conditions cause increased P release from soils, which could result in higher P concentration in surface runoff. PMID- 21546686 TI - Effect of tomato packinghouse wastewater properties on phosphorus and cation leaching in a spodosol. AB - Land application of wastewater is a common practice. However, coarse-textured soils and shallow groundwater in Florida present favorable conditions for leaching of wastewater-applied constituents. Our objective in this study was to determine phosphorus (P) and associated cations (Ca, Mg, K, Na) leaching in a Spodosol irrigated with tomato packinghouse wastewater. We packed 12 polyvinyl chloride soil columns (30 cm internal diameter * 50 cm length) with two soil horizons (Ap and A/E) and conducted 30 sequential leaching events by irrigating with wastewater at low (0.84 cm d), medium (1.68 cm d), and high (2.51 cm d) rates. The control treatment received deionized water at 1.68 cm d Leachate pH was lower (6.4-6.5) and electrical conductivity (EC) was higher in the wastewater treated columns (0.85-1.78 dS m) than in the control treatment (pH 6.9; EC, 0.12 dS m) due to the low pH (6.2) and high EC (2.16 dS m) of applied wastewater. Mean leachate P concentrations were greatest in the control treatment (0.70 mg L), followed by the high (0.60 mg L) and low and medium wastewater-treated columns (0.28-0.33 mg L). Leachate concentrations of Na, Ca, Mg, and K were significantly ( < 0.05) greater in wastewater-treated columns than in the control. Concentrations of P, Na, and K in leachate remained lower than the concentrations in the applied wastewater, indicating their retention in the soil profile. In contrast, leachate Ca and Mg concentrations were greater than in applied wastewater during several leaching events, suggesting that additional Ca and Mg were leached from the soil. Our results suggest that tomato packinghouse wastewater can be beneficially land-applied at 1.68 cm d in Florida's Spodosols without significant P and cation leaching. PMID- 21546687 TI - Seasonal greenhouse gas emissions (methane, carbon dioxide, nitrous oxide) from engineered landfills: daily, intermediate, and final California cover soils. AB - Compared with natural ecosystems and managed agricultural systems, engineered landfills represent a highly managed soil system for which there has been no systematic quantification of emissions from coexisting daily, intermediate, and final cover materials. We quantified the seasonal variability of CH, CO, and NO emissions from fresh refuse (no cover) and daily, intermediate, and final cover materials at northern and southern California landfill sites with engineered gas extraction systems. Fresh refuse fluxes (g m d [+/- SD]) averaged CH 0.053 (+/- 0.03), CO 135 (+/- 117), and NO 0.063 (+/- 0.059). Average CH emissions across all cover types and wet/dry seasons ranged over more than four orders of magnitude (<0.01-100 g m d) with most cover types, including both final covers, averaging <0.1 g m d with 10 to 40% of surface areas characterized by negative fluxes (uptake of atmospheric CH). The northern California intermediate cover (50 cm) had the highest CH fluxes. For both the intermediate (50-100 cm) and final (>200 cm) cover materials, below which methanogenesis was well established, the variability in gaseous fluxes was attributable to cover thickness, texture, density, and seasonally variable soil moisture and temperature at suboptimal conditions for CH oxidation. Thin daily covers (30 cm local soil) and fresh refuse generally had the highest CO and NO fluxes, indicating rapid onset of aerobic and semi-aerobic processes in recently buried refuse, with rates similar to soil ecosystems and windrow composting of organic waste. This study has emphasized the need for more systematic field quantification of seasonal emissions from multiple types of engineered covers. PMID- 21546688 TI - A method to quantitatively trap volatilized organoselenides for stable selenium isotope analysis. AB - If volatile organoselenides are to be analyzed for their stable Se isotope composition to elucidate sources and formation processes, organoselenides need to be trapped quantitatively to avoid artificial Se isotope fractionation. We developed an efficient trap of organoselenides to be used in microcosms designed to determine the Se isotope fractionation by microbial transformation of inorganic Se to volatile organoselenides. The recoveries of volatilized dimethyldiselenide (DMDSe) from aqueous standard solutions by activated charcoal and alkaline peroxide solution with subsequent freeze-drying and purification via a cation exchange resin were tested. Microcosm experiments with the Se methylating fungus in a growth medium were conducted, and tightness of the microcosm was assessed by comparing mass balances of total Se of the fungus, medium, and trapped organoselenides with the supplied Se mass. At the end of the experiment, we calculated deltaSe values of the whole microcosm and compared them with the deltaSe value of supplied Se(IV) and Se(VI). Our results demonstrated that activated charcoal cannot be used for quantitative trapping of organoselenides because generally <64% of the outgassed DMDSe were recovered. The mean recovery of Se volatilized from an aqueous DMDSe standard trapped in alkaline peroxide, in contrast, was 96 +/- 11% (SD) after 2 h ( = 4). The mass balances of total Se in microcosm experiments with alkaline peroxide traps run for 11 to 15 d were 96 +/- 15 and 102 +/- 2.4% for Se(IV) and Se(VI) ( = 3), respectively. The mass-weighted mean deltaSe values for the Se(IV) and Se(VI) batch experiments were -0.31 +/- 0.050/00 ( = 3) and -0.76 +/- 0.070/00 ( = 3), compared with -0.20 +/- 0.100/00 and -0.69 +/- 0.100/00 in the supplied Se oxyanions, respectively. We conclude that the alkaline peroxide trap can reliably be used to determine the Se isotope composition of organoselenides. PMID- 21546695 TI - HOX genes in pancreatic development and cancer. AB - The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are subsequently re expressed in many types of cancer. Some recent studies have shown that HOX genes may have key roles both in pancreatic development and in adult diseases of the pancreas, including cancer. In this review we consider recent advances in elucidating the role of HOX genes in these processes, how they may connect early developmental events to subsequent adult disease, and their potential both as diagnostic markers and therapeutic targets. PMID- 21546696 TI - Left posterior approach to the superior mesenteric vascular pedicle in pancreaticoduodenectomy for cancer of the pancreatic head. AB - CONTEXT: Dissection of the superior mesenteric artery is the most important part of a pancreaticoduodenectomy for pancreatic cancer. Since 2005, we have used the left posterior approach for superior mesenteric vascular pedicle dissection, in which the superior mesenteric artery and the superior mesenteric vein are dissected first in a clockwise fashion. OBJECTIVE: This article presents the technique of a left posterior approach and the clinical outcome. PATIENTS: Forty patients underwent a left posterior approach and were compared to 35 patients treated with a conventional dissection. MAIN OUTCOME MEASURES: The differences in surgical technique between the left posterior approach and the conventional method were described, and the short- and long-term surgical results compared patients who underwent the left posterior approach to those who were treated with the conventional method. INTERVENTION: The superior mesenteric vascular pedicle was first dissected from the left lateral border of the superior mesenteric artery. The superior mesenteric vein was also dissected from the left side. Then, the uncinate process and perivascular soft tissue were separated en bloc from the vasculature. RESULTS: No life-threatening complications occurred after the pancreaticoduodenectomies using a left posterior approach. Diarrhea requiring the administration of antidiarrheal agents occurred in 65% of patients; however, planned adjuvant chemotherapy was completed in all patients who did not have an early tumor recurrence. Survival rate was 52.8% at 3 years after surgery. CONCLUSION: After a pancreaticoduodenectomy with a left posterior approach, most patients had various degrees of diarrhea, but the adjuvant chemotherapy was able to be continued with close monitoring. The left posterior approach facilitates understanding of the topographic anatomy in the superior mesenteric vascular pedicle. PMID- 21546697 TI - Groove pancreatitis. A mini-series report and review of the literature. AB - CONTEXT: Groove pancreatitis is a rare condition characterized by fibrotic inflammation affecting the groove anatomical area between the head of the pancreas, the duodenum and the common bile duct. OBJECTIVES: We report a miniseries of five cases treated surgically in our centre over a period of four years. A review of the literature is also discussed. METHODS: Patients undergoing pancreaticoduodenectomy over a four-year period were retrospectively reviewed. Patients with a confirmed histological diagnosis of groove pancreatitis were assessed under the headings; patient demographics, presenting symptoms, radiological and histological findings. RESULTS: One-hundred and 60 pancreaticoduodenectomies were performed. Thirty-nine cases demonstrated benign disease and within this, five cases (3.1% of total series; 12.8% of benign cases) were groove pancreatitis. All patients presented with abdominal pain and weight loss, and the majority consumed excess alcohol and were smokers. Radiological findings (CT/MRCP/EUS) revealed duodenal wall thickening in all cases, abnormalities at the head of pancreas and bile duct dilation in four, and cystic changes in the duodenal wall and pancreatic duct dilation in three cases. Groove fibrosis, Brunner's gland hyperplasia and cystic changes in duodenal wall were present in all cases on histological review. All patients reported significant improvement in quality of life at 12 months after surgery. CONCLUSION: Groove pancreatitis can present in a similar fashion to head of pancreas cancer and chronic pancreatitis. For this reason it is paramount for clinicians to be aware of groove pancreatitis, as this can lead to the correct diagnosis and management of this unique disease. PMID- 21546698 TI - Potential use of left renal vein graft in pancreaticoduodenectomy combined with long segmental resection of the superior mesenteric-splenic-portal vein confluence. AB - CONTEXT: Various techniques for reconstruction after superior mesenteric-splenic portal vein confluence resection during pancreaticoduodenectomy have been introduced. A certain kind of vascular grafting may be necessary especially when long segmental resection of superior mesenteric-splenic-portal vein confluence is required. CASE REPORT: We herein report the cases of two patients who underwent left renal vein grafting in a pancreaticoduodenectomy with combined resection of the long segment of the superior mesenteric-splenic-portal vein confluence for pancreatic head cancer following neoadjuvant concurrent chemoradiation therapy as well as their long-term outcomes with graft patency without deterioration of renal function. CONCLUSION: Our experience with these two cases indicates that an autologous interposition graft using the left renal vein may be considered a safe and convenient conduit in the case of long segmental resection of the superior mesenteric-splenic-portal vein confluence during a pancreaticoduodenectomy following preoperative neoadjuvant chemoradiation therapy. PMID- 21546699 TI - Heterotopic pancreatic neoplasm presenting as an obstructing mass at the fourth portion of the duodenum. AB - CONTEXT: Heterotopic pancreatic adenocarcinoma is a rare finding at laparotomy. Herein we present the case of a patient with malignant transformation of a heterotopic pancreas located in the fourth portion of the duodenum. CASE REPORT: A 79-year-old woman was admitted to the surgery service with complaints of early satiety and abdominal fullness progressively worsening over the previous two years. A computed tomography scan of the abdomen and an upper endoscopy revealed an obstructing mass in the fourth portion of the duodenum, biopsies were negative for carcinoma. A segmentectomy of the third and fourth portions of the duodenum was performed. Post-operative histology revealed malignant transformation of a heterotopic pancreas. The patient had an unremarkable postoperative recovery and was discharged home. CONCLUSION: In evaluation of patients with distal duodenal masses, we report that heterotopic pancreatic neoplasms should be considered in the differential diagnosis. PMID- 21546700 TI - An unusual case of a coexistent serous cystadenoma and intraductal papillary mucinous neoplasm of pancreas. EUS to the rescue! AB - CONTEXT: Synchronous cystic neoplasms of pancreas are a highly rare occurrence. CASE REPORT: We report a very rare case of coexistent serous cystadenoma and multi-side branch intraductal papillary mucinous neoplasm (IPMN). CONCLUSION: To our knowledge, there has been only one previous case report in the literature of a synchronous serous cystadenoma and a solitary IPMN lesion. This case report is intended to increase the awareness of this condition while alluding to the need for diligent examination by endosonographers. It also highlights the clinical impact of endosonography on the diagnosis and management of cystic legions in the pancreas. PMID- 21546701 TI - The role for prudence before describing novel infectious etiologies for acute pancreatitis. The experience of one institution before describing influenza B pancreatitis. AB - CONTEXT: While the majority of acute pancreatitis is secondary to alcohol and gallstones in the developed world, infectious causes are recognized and recent evidence has linked influenza A to acute pancreatitis. CASE REPORT: We report a patient with acute pancreatitis deemed secondary to influenza B virus; however considering this would be the first reported case, retesting showed that the initial PCR was falsely positive and a system-wide contamination discovered that unearthed other false negatives. CONCLUSIONS: While research must continue to describe novel infectious etiologies of acute pancreatitis, caution must be exercised before new associations are described. New tests are leading to increasing incidence and prevalence of disease and while such testing generally has high sensitivity and specificity, the role for false results still exists. PMID- 21546702 TI - Azathioprine induced pancreatitis in a patient with co-existing autoimmune pancreatitis and hepatitis. AB - CONTEXT: Azathioprine induced pancreatitis usually runs a benign self limited course with rapid disappearance of signs and symptoms upon with drawl of the drug. Azathioprine is used in treating relapses in patients with autoimmune pancreatitis and maintenance of remission in autoimmune hepatitis. Acute pancreatitis complicated by symptomatic pseudocysts requiring drainage is not usually associated with drug induced pancreatitis. The risk of azathioprine use in patients with underlying disease of pancreas including autoimmune pancreatitis is unclear. CASE REPORT: We report here a case of an African American patient with co-existing autoimmune pancreatitis and autoimmune hepatitis who developed azathioprine induced acute pancreatitis complicated by a large symptomatic pseudocyst compressing the duodenum requiring a cystoduodenostomy. CONCLUSIONS: Future studies to investigate the risk of azathioprine induced pancreatitis in the presence of underlying disease of the pancreas including autoimmune pancreatitis are required to further understand the safety of azathioprine in this sub group of patients. PMID- 21546704 TI - Paraganglioma mimicking a pancreatic neoplasm. AB - CONTEXT: Paragangliomas are rare tumours of neural crest origin. Extra-adrenal pancreatic paragangliomas are exceptionally rare. CASE REPORT: A 66-year-old man with abdominal pain was noted to have a complex pancreatic head and uncinate process mass on imaging. He underwent complete resection by pancreaticoduodenectomy with final pathology confirming a 6 cm paraganglioma without evidence of metastases. On histology the tumour was arising from the retroperitoneum and abutting the pancreas. The patient was disease free at 14 month follow-up. CONCLUSION: Pancreatic paragangliomas represent in many cases the retroperitoneal extension of a paraganglioma into the pancreas rather than a true pancreatic neoplasm. Although generally benign, the risk of malignant transformation justifies aggressive management. PMID- 21546703 TI - Simultaneous non-functioning neuroendocrine carcinoma of the pancreas and extra hepatic cholangiocarcinoma. A case of early diagnosis and favorable post-surgical outcome. AB - CONTEXT: Thanks to the wide use of diagnostic imaging modalities, multiple primary malignancies are being diagnosed more frequently and different associations of malignancies have been reported in this setting. CASE REPORT: In this paper, we describe the case of a patient with non-functioning well differentiated neuroendocrine carcinoma of the head of the pancreas associated with extra-hepatic cholangiocarcinoma, in which an early diagnosis using magnetic resonance imaging allowed a good outcome. CONCLUSION: The simultaneous association of neuroendocrine pancreatic tumors and cholangiocarcinoma has not yet been described; however, this association should be considered and, due to the high contrast of magnetic resonance imaging, this technique is recommended in such patient in order to reach an accurate diagnosis. PMID- 21546705 TI - Pseudopapillary tumor of the pancreas. An algorithmic approach. AB - CONTEXT: Solid-cystic pseudopapillary tumor of the pancreas is a rare tumor, but has favorable prognosis even in the presence of distant metastases. It is often associated with diagnostic and therapeutic challenges. CASE REPORTS: Described are two cases of solid-cystic pseudopapillary tumor of the pancreas managed in our hospital between January 2000 and January 2010. One female and one male with mean age of 42 years (range: 33 to 51 years). Data collected were: presenting symptoms, signs, imaging and management. Literature review was obtained from computer generated MEDLINE and Google Scholar search for solid-cystic pseudopapillary tumor of the pancreas between 1980 and 2010. Articles relevant to the scope of this paper were selected. The incidence of solid-cystic pseudopapillary tumors of the pancreas in our institution is 2 cases in 10 years; i.e., 0.2 cases/year. Clinical presentation include; palpable abdominal mass, vague abdominal discomfort, increasing abdominal girth, significant weight loss, nausea and vomiting in both patients. The mean diameter of the tumors was 7.0 cm (range: 5.9 to 8.0 cm). Pancreaticoduodenectomy was performed on both patients. None received adjuvant therapy and no cancer recurrence was detected on follow up. CONCLUSION: Solid-cystic pseudopapillary tumor of the pancreas is a rare tumor with a favorable prognosis even with distant metastases; therefore, attempts must be made to differentiate it from other pancreatic neoplasms. Clinical and radiological studies alone are insufficient to establish the diagnosis of a pancreatic mass and tissue biopsy should be sought. Surgery is generally curative and should be pursued independent of size and distant metastases. PMID- 21546707 TI - Successful management of gastrointestinal haemorrhage associated with ischaemic colonic ulceration in acute pancreatitis with video assisted retroperitoneal debridement. AB - CONTEXT: Colonic involvement is an uncommon but potentially lethal complication of severe acute pancreatitis and has received little attention in the surgical literature. Such complications can range from localized colonic pathology to widespread ischaemic pancolitis. Treatment options have historically been limited to resection of the affected segment. CASE REPORT: We describe the successful role of video assisted retroperitoneal pancreatic debridement in the management of two cases presenting with major gastrointestinal haemorrhage due to localised colonic ulceration on the background of acute necrotising pancreatitis. CONCLUSION: Video assisted retroperitoneal debridement should be considered early in the management of local colonic complications associated with severe acute necrotising pancreatitis. PMID- 21546706 TI - An unusual cause of acute abdomen in adults: giant cystic lymphangioma of the pancreatic head. A clinical case and literature review. AB - CONTEXT: Cystic lymphangioma of the pancreas presenting as acute abdomen in adults has not been reported before. CASE REPORT: We report the case of a young man who presented with severe pain in the upper abdomen and abdominal swelling. On imaging, he was found to have a giant multiseptate cystic lesion occupying almost the entire abdomen anterior to the pancreas. On exploration, a cystic mass involving the head of the pancreas and densely adherent to the antrum, and the second and third parts of the duodenum was found and a classic Whipple pancreaticoduodenectomy was done. Histology revealed a diagnosis of cystic lymphangioma. CONCLUSION: Cystic lymphangioma is a rare benign tumor of the pancreas and this is the first reported case in an adult presenting with acute abdomen. Though rarely diagnosed preoperatively, this entity should also be considered in the differential diagnosis of cystic lesions of the pancreas. Complete surgical excision is curative. PMID- 21546708 TI - Recurrent pancreatic pseudocyst diagnosed 9 years after initial surgical drainage. AB - CONTEXT: A pancreatic pseudocyst is defined as a collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue which is not lined by epithelium. Acute pseudocysts occur in acute pancreatitis but can be found after an acute exacerbation of chronic pancreatitis. Chronic pancreatic pseudocysts are typically found in chronic pancreatitis but may develop after an occurrence of acute pancreatitis as well. Most acute fluid collections and pseudocysts will show spontaneous resolution while the remaining may persist with or without symptoms, or progress to produce complications. Treatment is indicated for persistent, symptomatic pseudocysts and, in the case of complications. There is no clear consensus regarding the optimal clinical or radiologic follow-up after treatment. Detection of late recurrence is not common, and the possibility of a cystic neoplasm must be ruled out. CASE REPORT: We report the case of a 67-year old female patient who was referred to our institution as the result of a pancreatic pseudocyst. The patient had presented a pancreatic pseudocyst 9 years earlier which had been surgically treated by a cystogastrostomy. No additional acute pancreatic episodes occurred. The diagnostic and treatment approach of this unusual late recurrent pancreatic pseudocyst is herein described. CONCLUSION: The unusual late presentation of a recurrent pancreatic pseudocyst requires clinical, laboratory and radiological evaluation. In the present case, the clinical background, amylase fluid levels and tomographic findings were highly suggestive of a pancreatic pseudocyst. PMID- 21546709 TI - Epidermoid cyst occurring within an intrapancreatic accessory spleen. A case report and review of the literature. AB - CONTEXT: Epidermoid cysts occurring within intrapancreatic accessory spleens are exceptionally rare entities, with only 21 previously reported cases. Their clinical presentation prior to pathologic assessment can raise concern for possible malignancy; however, they behave in a benign fashion. CASE REPORT: A 62 year-old male presented with complaints of abdominal pain. Imaging revealed left sided retroperitoneal mass and surgical exploration was recommended. Surgery revealed a cystic cavity containing necrotic debris originating from the tail of the pancreas. Microscopy was consistent with an epidermoid cyst arising within an intrapancreatic accessory spleen with positive immunoperoxidase staining for CEA. CONCLUSION: Epidermoid cysts occurring within intrapancreatic accessory spleens can mimic a malignant process both clinically and radiographically. Surgery with pathologic assessment is the only reliable means of diagnosis. While they are a very rare entity, it is an important component of a complete differential diagnosis for a patient presenting with a pancreatic tail mass. PMID- 21546710 TI - Malignant pancreatic extra-gastrointestinal stromal tumor diagnosed by ultrasound guided fine needle aspiration cytology. A case report with a review of the literature. AB - CONTEXT: Pancreatic extra-gastrointestinal stromal tumors are extremely uncommon neoplasm. To the best of our knowledge, only eleven cases have been reported in the literature. All the case reports published mostly involve diagnoses made on surgical pathology. CASE REPORT: A 40-year-old male patient presented with asthenia, mild abdominal pain, severe anemia and weight loss. Contrast-enhanced computed tomography of the abdomen revealed a heterogeneously enhancing mass (6.5x6.0 cm) in the body and head of the pancreas. Ultrasound-guided fine needle aspiration (US-FNA) was performed on the mass of the pancreas before a pancreaticoduodenectomy. A cytological diagnosis of pancreatic malignant mesenchymal neoplasm was made. The final diagnosis of primary pancreatic extra gastrointestinal stromal tumor was confirmed by histopathological examination and immunohistochemical findings (CD117 positivity). This case was diagnosed by percutaneous transabdominal ultrasound, rather than endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) which had been used in three previous cases. CONCLUSION: We report a very unusual case of pancreatic extra-gastrointestinal stromal tumor which was diagnosed by US-FNA cytology. Although this is uncommon in the pancreas, extra-gastrointestinal stromal tumors should be considered in the differential diagnosis of solid and cystic pancreatic masses on cytology. PMID- 21546711 TI - Splenic parenchymal complications in pancreatitis. AB - CONTEXT: The close proximity of splenic hilum to the tail of pancreas makes it vulnerable to complications in both acute and chronic pancreatitis. In this article, we examine the clinical course of these potentially fatal complications. CASE REPORTS: Citing three clinical cases, we present the spectrum of splenic complications in pancreatitis and explore the anatomical causal relationships and pathological basis of such complications. A literature review was carried out to inform on the incidence, morbidity and mortality rates, and clinical course especially diagnostic and management options for these patients. The spectrum of splenic complications in pancreatitis is wide ranging from pseudo cysts to haematomas, haemorrhages, infarctions and life threatening splenic rupture. Although a contrast enhanced helical CT scan is the investigation of choice a high index of clinical suspicion is essential in their early identification. Splenic complications in pancreatitis incur a high morbidity (79%) and a significant mortality (8%). CONCLUSIONS: Splenic parenchymal complications in pancreatitis are an increasingly recognised entity and should be suspected in patients with inflammation and or necrosis involving the tail of pancreas. Conservative management is feasible with close radiological monitoring for most patients in a tertiary referral centre with appropriate expertise and surgery may be reserved for haemodynamically unstable patients. PMID- 21546712 TI - Acinar cell carcinoma of the pancreas associated with subcutaneous panniculitis. AB - CONTEXT: Acinar cell carcinoma is a rare pancreatic malignant tumor, which can be associated with a particular manifestation: pancreatic panniculitis. It presents with erythematous subcutaneous nodules located mainly on the legs. The skin lesions can precede, be concurrent with or follow the pancreatic illness. The pathogenesis is not fully understood, but it is believed to be associated with high levels of serum lipase produced by the neoplasm, causing fat necrosis in tissues. The treatment of pancreatic panniculitis is directed at the underlying pancreatic disease, which may result in regression of the skin lesions. We report a case of pancreatic acinar cell carcinoma associated with subcutaneous panniculitis together with a review of the English literature. CASE REPORT: A 79 year-old woman, with a 13-month history of acute pancreatitis, asthenia, weight loss, and the CT finding of a mass in the pancreatic head, presented complaining of multiple, migrant and painful subcutaneous nodules on her lower extremities. High serum lipase levels were also present. She underwent a pancreaticoduodenectomy, with subsequent regression of the skin lesions and normalization of her serum lipase levels. Histology revealed an acinar cell carcinoma of the pancreas. Liver metastases occurred six months after surgery, and the patient underwent chemotherapy with gemcitabine. She is still alive 14 months after the initial surgery. CONCLUSIONS: Although rare, the association between acinar cell carcinoma and pancreatic panniculitis has been described in the literature. In a patient with subcutaneous nodules, the presence of acinar cell carcinoma should be considered in order to prevent long delays in the diagnosis and treatment of this pancreatic malignancy. PMID- 21546713 TI - Usefulness of PET/CT imaging in systemic IgG4-related sclerosing disease. A report of three cases. AB - Autoimmune pancreatitis is the pancreatic manifestation of a novel clinicopathological disorder called systemic IgG4-related sclerosing disease. Beside the pancreas, this entity affects other sites (salivary glands, orbit, lung, thyroid, gallbladder, biliary tree system, kidney, abdominal aorta, retroperitoneum, prostate, and lymph node) by infiltration with IgG4-positive plasma cells. Several case reports and small case series have demonstrated the utility of integrated positron emission tomography/computed tomography (PET/CT) in monitoring therapy and documenting relapse and flare-up of autoimmune pancreatitis. However, there are no reports on the usefulness of PET/CT in selecting extrapancreatic sites for tissue sampling. We herein demonstrate the clinical utility of integrated PET/CT in 3 cases of systemic IgG4-related sclerosing disease for targeting extrapancreatic biopsy sites. PMID- 21546714 TI - Cutaneous metastasis in a patient with pancreatic cancer. AB - Pancreatic cancer is known to metastasize rapidly. Liver and peritoneum are the most common sites of metastases in pancreatic cancer, followed by lungs, bones and brain. Less common sites of metastases such as muscle, skin, heart, pleura, stomach, umbilicus, kidney, appendix, spermatic cord and prostate have also been reported in pancreatic cancer. Cutaneous metastasis mostly occurs around umbilicus. A site other than umbilicus is rarely reported. The authors report a case of multiple skin metastases in a patient with primary pancreatic cancer and review the literature. PMID- 21546715 TI - The effect of pathological types of intraductal papillary mucinous neoplasms of the pancreas on survival. PMID- 21546716 TI - Serum vascular endothelial growth factor and interleukin-6 in colorectal cancer. PMID- 21546717 TI - Helicobacter pylori infection and its relationship to metabolic syndrome: is it a myth or fact? AB - Metabolic syndrome is one of the most prevalent global health problems that predisposes to Type 2 diabetes. It is strongly linked to insulin resistance, which results in hyperglycemia. Over the past few years, lot of studies have been carried out on Helicobacter pylori infection and found a possible causal relationship through releasing some of the interleukins factors, which result in endothelial dysfunction. However, some studies attributed that due to coincidence were not able to establish any causal relationship. In this review, the literature has been reviewed to check this possible association. PMID- 21546718 TI - Clinical relevance of serum vascular endothelial growth factor and interleukin-6 in patients with colorectal cancer. AB - BACKGROUND/AIM: Some biological factors play a role in stimulation of malignant growth, metastasis and angiogenesis; however, their clinical relevance has not yet been well established for most of them. This work was aimed at studying the clinical relevance of serum vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), in patients with colorectal cancer (CRC). MATERIALS AND METHODS: Preoperative serum levels of VEGF and IL-6 were measured by enzyme linked immuno-assay in 35 CRC patients and in 30 healthy controls. RESULTS: CRC patients with or without metastasis had significantly higher VEGF and IL-6 levels than healthy controls (all P < 0.001). Patients with advanced clinical stage had significantly higher levels of VEGF and IL-6 than those with early clinical stage (all P < 0.001). Also, patients with metastatic disease had significantly higher VEGF and IL-6 levels than those with localized disease (all P < 0.001). The diagnostic accuracy for invasiveness was 83% for VEGF (cut off value = 240 pg/ml) and 66% for IL-6 (cut off value = 6.7 pg/ml), with sensitivity 79% and 74% and specificity 68% and 59%, respectively. CONCLUSION: In CRC patients, preoperative measurement of serum VEGF and Il-6 may prove useful non-invasive diagnostic indicators associated with advanced clinical stage and tumor metastasis that warrants further investigations. PMID- 21546719 TI - Safety and efficacy of vitamin-based antioxidant therapy in patients with severe acute pancreatitis: a randomized controlled trial. AB - BACKGROUND/AIM: Oxidative stress plays a major role in the pathogenesis of pancreatitis. Antioxidant therapy in the form of high-dose vitamin has been used for the treatment of severe acute pancreatitis with equivocal results. We wished to evaluate the efficacy and safety of antioxidant (vitamin A, vitamin C, vitamin E) therapy in patients with severe acute pancreatitis. SETTING AND DESIGN: This was a single-center, prospective, randomized, open-label with blinded endpoint assessment study of antioxidant therapy, conducted in the emergency department attached to our hospital. MATERIALS AND METHODS: Thirty-nine patients with severe acute pancreatitis were randomly assigned to antioxidant treatment group (n=19) or a control group (n=20) within 96 hours of developing symptoms. Patients in the antioxidant group received antioxidants (vitamin A, vitamin E, vitamin C) in addition to the standard treatment provided to both the groups for a period of 14 days. The primary outcome variable was presence of organ dysfunction at day 7. The secondary outcome variables were length of hospital stay, multiorgan dysfunction (MODS) at day 7, recovery at the end of 4 weeks, complications, and mortality. The change in markers of oxidative stress from baseline was also measured. RESULTS: We demonstrated no significant difference in organ dysfunction (P=1.0), MODS (P=0.8), and length of hospital stay (P=0.29) between the two groups. All the patients survived in the antioxidant-treated group, whereas two patients died in the control group. The change in the levels of malondialdehyde, superoxide dismutase, and reduced glutathione were not significantly different in the two groups at day 7. Univariate analysis showed marginal benefit with antioxidant treatment (P=0.034) in patients with severe acute pancreatitis. CONCLUSIONS: This randomized study demonstrates that there is no significant benefit from antioxidant therapy in patients with established severe acute pancreatitis. PMID- 21546720 TI - Sero-prevalence of hepatitis B virus infection in Balochistan Province of Pakistan. AB - BACKGROUND/AIM: The objective was to evaluate the sero-prevalence of hepatitis B surface antigen (HBsAg) and IgM antibodies to hepatitis core antigen in Balochistan Province of Pakistan. DESIGN OF THE STUDY: A cross-sectional, population-based study. Place and time of the study: The study was conducted in Balochistan from 1 st January 2004 to 31 st December, 2008. The screening areas included Barkhan, Eashani, Khuzdar, Kodi Zikriani, Kohlu, Rakhni and Turbat. MATERIALS AND METHODS: A total of 15,260 subjects were enrolled; 11,900 (78%) agreed to undergo screening. Fresh serum samples were tested for the presence of hepatitis B surface antigen and IgM antibodies to hepatitis B core antigen. RESULTS: HBsAg was detected in 1166 (9.8%) while anti-HBc IgM was found in 117 (10.0%). HBsAg positivity was seen in 875 (12.7%) males and 291 (5.8%) females. The prevalence of hepatitis B in Balochistan varies from 3.3% in Khuzdar to 17.0% in Kodi Zikriani. CONCLUSIONS: It is utmost important to educate the public, to take proper measures to control the spread of infection and vaccination in order to interrupt transmission of this threatening public health problem in Balochistan province of Pakistan. PMID- 21546721 TI - Impact of laparoscopic Nissen fundoplication on non-complicated Barrett's esophagus. AB - BACKGROUND/AIM: Laparoscopic fundoplication can alter the natural course of Barrett's esophagus (BE). This study was undertaken to assess this role in patients with non-complicated BE. MATERIALS AND METHODS: From October 2004 to October 2009, 43 patients with BE (32 men and 11 women) underwent laparoscopic Nissen fundoplication surgery in the Department of Surgery at Minia University Hospital. The median age of these patients was 46 years (range: 22-68 years). Patients with high-grade dysplasia, invasive cancer, or previous antireflux surgery were excluded. All 43 patients had gastroesophageal reflux symptoms. Heartburn was present in all patients, regurgitation in 41 (95.3%), dysphagia in 8 (18.6%), retrosternal pain in 30 (69.8%), upper gastrointestinal hemorrhage in 6 (13.9%), and respiratory symptoms in 19 (44.2%). Nissen fundoplication was performed in all patients. Thirty-four patients (79.1%) had concomitant hiatal hernia and nine patients (20.9%) had low-grade dysplasia. RESULTS: The median follow-up period was 25.6 months. There was significant improvement of symptoms after surgery (P<0.05). Eight (18.6%) of those with short-segment BE had total regression and four (9.3%) of those with long-segment BE had a decrease in total length. Among the nine patients with preoperative low-grade dysplasia, dysplasia disappeared in seven, remained unchanged in one, and progressed to in situ adenocarcinoma in one patient. CONCLUSIONS: laparoscopic fundoplication succeeded in controlling symptoms but had unpredictable effect on dysplasia and regression of BE. Laparoscopic fundoplication does not eliminate the risk of developing esophageal adenocarcinoma and therefore, endoscopic follow-up should be continued in these patients. PMID- 21546722 TI - Surgical management of gastric gastrointestinal stromal tumor: a single center experience. AB - BACKGROUND/AIM: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Surgery remains the mainstay of curative treatment. Our objective is to evaluate the outcome of surgical treatment of primary gastric GIST. MATERIALS AND METHODS: Between January 1997 and April 2008, thirty seven consecutive patients underwent resection for GISTs (35 patients with primary gastric GISTs and two patients with intestinal GISTs who were excluded from the study). These patients underwent upper endoscopy +/- biopsy, barium meal and abdominal CT scan. Patients' demographics and clinical presentations were analyzed. Perioperative parameters measured included operative times, estimated blood loss, intraoperative finding, surgical techniques, morbidity and length of hospitalization. Recurrence and survival were also analyzed. RESULTS: Of the 35 patients with gastric GISTs included in the study, 63% were female. The median age was 59 +/- 14 years (range, 23 to 75 years). The primary presenting symptoms were bleeding and dyspepsia; 43% of these tumors were located mainly in the body of the stomach. Tumor size was < 10 cm in 80% of the patients. The average tumor size was 6.3 +/- 3.2 cm (range from 3 to 13 cm). Regarding the surgical management, 20 patients (57%) underwent gastric wedge resection, eight patients (23%) underwent partial gastrectomy and the remaining seven patients (20%) underwent total gastrectomy. Radical resections were found in 32 patients (91.5%) while palliative resections were found in three patients (8.5%). The resected lymph nodes were negative in 32 patients (91.5%). Recurrence was noted in three patients, with a median time to recurrence of 14.3 months (range, 7 to 28 months). The three- and five-years survival in patients who underwent wedge resection was 92% and 81%, respectively, where it was 95% and 87%, respectively, in patients who underwent gastrectomy (either partial or total). There were no major intraoperative complications or mortalities. CONCLUSION: Complete surgical resection either through wedge resection or gastrectomy with negative margins remains the gold standard treatment in the management of patients with primary resectable gastric GISTs. PMID- 21546723 TI - Biological and histological parameters as predictors of relapse in ulcerative colitis: a prospective study. AB - BACKGROUND/AIM: Ulcerative colitis is a chronic inflammatory disease of unknown etiology characterized by periods of remission and relapses. This study has been carried out in a group of North Indian patients, where the disease has shown an increasing prevalence and frequent relapses. Hence, there is a need to predict relapse for better management and to reduce morbidity. To assess the importance of biological and histological parameters in predicting relapse when the disease is in quiescent phase. MATERIALS AND METHODS: A prospective study of twenty-six patients with quiescent ulcerative colitis was carried out in Dayanand Medical College and Hospital,Punjab. Only patients with clinical and endoscopic remission at the time of screening visit were included. Hemoglobin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum Interleukin-6 (IL-6) levels were measured. The baseline colonoscopic mucosal biopsies were retrieved and studied. Follow-up was conducted for one year at monthly interval or earlier if relapse occurred. RESULTS: Fifteen out of twenty-six patients (57.69%) had evidence of clinical relapse during the follow-up. Hemoglobin, ESR, CRP and IL-6 levels were not found to be significant predictors of relapse. Increased number of eosinophils and neutrophils in the lamina propria were observed to be associated with significantly higher relapse rate. CONCLUSION: A higher risk of relapse in patients with quiescent colitis can be predicted by the presence of increased number of eosinophils and neutrophils in the lamina propria. PMID- 21546724 TI - Liver abscess in children: a 10-year single centre experience. AB - BACKGROUND/AIM: Although liver abscess is more prevalent in developing countries than in developed countries, there is scant data about the characteristics of pediatric liver abscess in our region. We aimed to analyze the characteristics of pediatric liver abscess in our region and compare these with those of developed countries. MATERIALS AND METHODS: The clinical features, laboratory, imaging, microbiologic findings, management strategy, and final outcome were extracted from the patients' records retrospectively. RESULTS: There were 18 cases of liver abscess including 16 pyogenic liver abscess, one amebic liver abscess and one candida liver abscess. Fever and abdominal pain were the most common clinical findings and leukocytosis was the most common laboratory finding. The most predisposing factors of liver abscess were immune deficiency, minor thalassemia. Origin of liver abscess was appendicitis in two patients, the rest were considered as cryptogenic. While one patient was treated with antibiotics alone, five cases were taken for open drainage, and 12 cases were treated with percutaneous aspiration. Percutaneous aspiration failed in two patients who were later taken for open drainage, with an overall mortality rate of 5.5%. CONCLUSION: The overall characteristics of liver abscess in children in our society are not so different from developed countries. However, in contradiction to cases reported in developed countries, most cases of liver abscess were seen in healthy patients in our centre. Moreover, liver abscess was reported in our patients at a younger age and was more commonly seen in male children. Mortality rate was similar to that of developed countries. PMID- 21546725 TI - Experience of laparoscopic cholecystectomy under spinal anesthesia with low pressure pneumoperitoneum--prospective study of 300 cases. AB - INTRODUCTION: Having long experience of open upper abdominal surgery under spinal anesthesia and laparoscopic cholecystectomy under general anesthesia, we performed this study of laparoscopic cholecystectomy with low-pressure pneumoperitoneum under spinal anesthesia to assess its safety and feasibility. MATERIALS AND METHODS: In a private rural health set-up, 300 patients were selected prospectively for laparoscopic cholecystectomy under low-pressure (8 mm) pneumoperitoneum under spinal anesthesia in a span of three years. Only 3.5 ml of 0.5% bupivacaine was used for spinal anesthesia. Fourth port positioned at lower than usual at the level of umbilicus, change of position of the table with different stages of operation, massaging of right shoulder in cases of shoulder pain, removal of smoke if formed during dissection to diminish shoulder pain and holding the body of the gallbladder by the fourth port grasper at the level of lower margin of the liver in cases of long gallbladder were some modifications of standard laparoscopic cholecystectomy made in this study. RESULTS: We successfully performed the operations in 291 patients without major complications. Four patients denied operation under spinal anesthesia. Spinal anesthesia was converted to general anesthesia in two patients due to severe shoulder pain. The operation was converted to open cholecystectomy in three patients. Mean age was 34.6 years (range 21-82 years). Mean BMI was -23.1 (range 20.8-28.3). Mean duration of operation was 39.6 min (range 18-78 min). Mean O 2 saturation was 97.6%. Mean peak respiratory rate was 23.4 (range 16-38). 90.08% patients complained of right shoulder pain--most of them managed by shoulder massage alone. All patients were satisfied on follow up. CONCLUSION: Laparoscopic cholecystectomy under spinal anesthesia with low-pressure pneumoperitoneum can be performed safely and satisfactorily without major complications by experienced surgeons. PMID- 21546726 TI - Omental patch technique for the ileal perforation secondary to typhoid fever. AB - BACKGROUND/AIM: Enteric perforation is a grave complication of typhoid fever. Laparotomy with primary closure is the treatment of choice depending upon the bowel condition. Fecal fistula formation is the main concern in primary closure and the incidence of this complication dramatically decreases when omentum is used as a patch over primary closure. MATERIALS AND METHODS: A total of 176 patients underwent laparotomy for enteric perforation and they were divided into two groups randomly; Group I--Primary closure with omental patch and Group II- Only primary closure. The outcomes were measured in relation to hospital stay, wound infection, septicemia, fecal fistula, and mortality. RESULTS: The incidence of complications including fecal fistula and mortality is significantly lower in the group I patients. Fecal fistula occurs in 7.7% in group II, while in only 1.1% in group I. The mortality is also lower 3.3% in group II, while 1.1% in group I. CONCLUSION: Primary closure with omental patch is a better option as compared with only primary closure in enteric perforation patients. It can be recommended as an alternative method to primary closure only in enteric perforation patients. PMID- 21546728 TI - Radioembolization for hepatocellular carcinoma using TheraSphere(r). AB - BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Radioembolization with yttrium-90 (Y90) microspheres is a new concept in radiation therapy for HCC. This review focuses on the indications, efficacy, side effects, and future direction of Y90 therapy, using TheraSphere(r) , in HCC patients. RESULTS: Comprehensive literature reviews have described the clinical and scientific evidence of Y90 therapy. The Radioembolization Brachytherapy Oncology Consortium has concluded that there is sufficient evidence to support the safe and effective use of this locoregional therapy in HCC patients, including those with portal vein thrombosis. CONCLUSIONS: There are currently no randomized clinical trials done on TheraSphere(r) and none of the studies so far have shown a survival benefit. Thus, although it represents a very promising therapy with excellent initial results, it cannot be fully recommended yet, till well-designed, large, randomized clinical studies are conducted showing survival benefits. PMID- 21546727 TI - Partial internal biliary diversion: a solution for intractable pruritus in progressive familial intrahepatic cholestasis type 1. AB - Biliary diversion offers a potential option for intractable pruritus in children with chronic cholestatic disorders. Progressive familial intrahepatic cholestasis (PFIC) is an inherited disorder of impaired bile acid transport and excretion, which presents with jaundice and pruritus in the first few months of life and progresses to cirrhosis by infancy or adolescence. We report a child with PFIC type 1 who underwent internal biliary diversion for intractable pruritus and was relieved of his symptoms. PMID- 21546729 TI - A middle-aged woman with a persistent gastrointestinal bleed. PMID- 21546730 TI - Epigastric pain and fever in a child. PMID- 21546731 TI - Knotting of ileum by Meckel's diverticulum leading to acute small bowel obstruction: an exceptional case. PMID- 21546732 TI - Percutaneous endoscopic colostomy: a new technique for the treatment of recurrent sigmoid volvulus. PMID- 21546733 TI - Distributive justice and public private participation. PMID- 21546734 TI - Imaging in postpneumonectomy complications: a pictorial review. AB - Pneumonectomy is done in patients with operable bronchogenic cancer and intractable end-stage lung diseases such as tuberculosis and bronchiectasis. It is often followed by postoperative complications with an incidence of 20-60%. Factors influencing the incidence and type of complication after lung resection include age, physical status, and procedure. Many of these complications are life threatening and require appropriate immediate management. Therefore, the knowledge of diverse radiologic appearances of these complications and familiarity with the clinical settings in which specific complications are likely to occur are vital for prompt and effective treatment. This pictorial review intends to educate the radiologists and clinicians regarding early detection of these complications. PMID- 21546735 TI - Orbital retinoblastoma: where do we go from here? AB - Diagnosis of orbital retinoblastoma traditionally carries a dismal prognosis. Although its incidence is less in the developed countries, it continues to contribute to an epidemic of extraocular disease at diagnosis in the developing world. Orbital retinoblastoma encompasses a wide range of distinct clinical entities with varying tumor load. There are no standard treatment protocols as of now but the current preferred management is multimodal with a combination of initial high-dose chemotherapy, surgery, external beam radiotherapy and prolonged chemotherapy for 12 cycles. Though orbital retinoblastoma is a catastrophic event, rapid advances on many fronts, especially the genetic, makes the future appear brighter than what it is now. This review looks at all the new frontiers that are in store in the near as well as the distant future. Looking at the ever expanding horizons makes one believe of a definite hope that one day we will conquer this disease as we have conquered many others in the past. PMID- 21546736 TI - A survey of risk factors in carcinoma esophagus in the valley of Kashmir, Northern India. AB - BACKGROUND/OBJECTIVE: Esophageal cancer has a peculiar geographical distribution and shows marked differences in incidence within a particular geographical region. Presently, as there seems little prospect of early detection of this cancer, an understanding of the etiological factors may suggest opportunities for its primary prevention. In this paper, we have tried to determine the role of diet and other life-style related factors in the etiology of cancer of esophagus. MATERIAL AND METHODS: A total of 100 confirmed squamous cell carcinoma of esophagus patients were enrolled for the study (Group A). 100 healthy subjects were included as controls (Group B). A predesigned questionnaire dealing with the basic patient data, dietary and smoking habits etc. was distributed among the cases in both groups. The data was thoroughly analyzed to define an association with the development of cancer of esophagus. RESULTS: Group A patients included 71 males and 29 females in the age range of 40-70 years. Majority 37% were farmers, 29% house wives. Of the 72% smokers, 66% smoked hookah. 29% had positive family history. More than 90% took salt-tea at breakfast. Meat consumption was low, 44% took it weekly and 42% on monthly basis. 69% took fish yearly. Group B included 75 males and 25 females of which 35.7% were hookah smokers. CONCLUSION: Poor socio-economic status resulting in fewer intakes of fresh fruits, vegetables and fish in addition to heavy hookah smoking are suspected to be the major risk factors for the development of esophageal cancer. PMID- 21546737 TI - Steroid receptor status and its clinicopathological correlation in post menopausal breast cancer patients of Kumaon region of Uttarakhand. AB - BACKGROUND: Estrogen receptor (ER) and progesterone receptor (PR) status has been used since the mid-1970s in the management of breast cancer as an indicator of endocrine responsiveness and as a prognostic factor for early recurrence. AIM: To study the steroid receptor profile and its clinico-pathological correlation in post-menopausal breast cancer patients. SETTING AND DESIGN: A retrospective and prospective analysis of 80 and 68 patients, respectively, was undertaken to study the prevalence of ER and PR in post-menopausal breast cancer patients. The result of collective observations was analyzed statistically. MATERIAL AND METHODS: In this study, retrospective data on hormonal receptor status of 80 post-menopausal breast cancer patients and prospective data of 68 patients were collected and analyzed. STATISTICAL ANALYSIS USED: Student "t" test, Chi-square test. RESULTS: Receptor positivity was high in higher age group but unlike earlier studies the receptor positivity was lower in incidence. The study showed an incidence of 37.83% receptor positive tumors in post-menopausal women. ER was positive in 27.03% patients of whom 16.2% were also PR positive, while the remaining patients were ER/PR negative. ER was negative in 72.47% patients of whom PR was positive in 10.8% and negative in the remaining. Out of 148 cases, 128 (86.48%) had palpable axillary lymph nodes. Out of 148 patients, 36 (24.34%) had supraclavicular lymph node involvement (Chi-square = 1.70, P = 0.193). Out of 148 cases, 144 (92.29%) were infiltration ductal carcinomas. Grade I tumors were more common in receptor positive tumors while grade II and III tumors were more common in receptor negative tumors. Receptor negative tumors were more aggressive in terms of peau de' orange, ulceration, fungation and chest wall invasion. Metastases and axillary lymph node involvement was observed more in receptor negative tumors; however, supraclavicular lymph node involvement was equal in both the groups. Infiltrating ductal carcinoma was the most common type of carcinoma in both the groups. CONCLUSION: The receptor positivity of steroid receptors was more in higher age groups, but the incidence of receptor positivity was lower than that reported in earlier studies. No statistically significant association was found between receptor status and clinical presentation of breast cancer, histopathological status of tumor and metastases. PMID- 21546738 TI - Immunohistochemical expression of progesterone receptors in pleomorphic adenoma and adenoid cystic carcinoma. AB - BACKGROUND: The importance of hormone receptor status in diagnosis, prognosis and response to hormone therapy of breast cancer has already been proven. AIM: Morphologic mimicry and similarity between salivary gland tumors and breast tumors led us to undertake an immunohistochemical evaluation on the expression of progesterone receptors (PRs) in pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) of salivary glands. STUDY AND DESIGN: We researched the role of PRs in tumorigenesis and hormone therapy of PA and ACC with immunohistochemistry and their expression in normal salivary glands was studied. Association of progesterone expression with grade 2 and 3 ACC was researched. METHODS: In a descriptive, analytical, cross-sectional study, 29 paraffin blocks (14 samples of PA and 15 samples of ACC) were prepared for immunohistochemical staining with progesterone antibody. t-Test and Mann-Whitney test were used for the statistical analysis of the results. RESULTS: PR staining was negative in 15 ACC and 13 PA cases. Slight to moderate staining was seen around the tumor in 12 normal cases. Little or no PR staining was observed among endothelial cells, fibroblasts and inflammatory cells. No progesterone expression in grade 2 and 3 ACC in the salivary glands was observed. CONCLUSION: Although progesterone seems to be essential for normal function of the salivary glands, it does not have a role in tumorigenesis and hormone therapy in PA and ACC. No association was found between progesterone expression and differentiation grade in ACC. PMID- 21546740 TI - Off-label use of anti-cancer drugs in India: to be or not to be! AB - BACKGROUND: Administering drugs outside the terms of their official labeling is called off-label use. In the West, oncologists often use drugs off-label, which offers several advantages especially while treating patients with multiple comorbidities or advanced cancer. The practice of off-label prescribing of anticancer agents in India is not well documented. MATERIALS AND METHODS: A survey on prescribing practices of 10 important drugs used in cancer was conducted in March 2010. Ten centers representing all parts of India were identified. One oncologist from each center was contacted by phone or email and explained about the survey. The list of drugs was sent to them by email if they agreed to participate and they were requested to fill all the indications for which these drugs were used in their center. Labeling for each drug was obtained from the Food and Drug Administration (FDA) website. Off-label practice was categorized as those recommended by the National Comprehensive Cancer Network (NCCN) and those without. RESULTS: Nine out of 10 centers agreed to participate in the survey. Four centers responded to the questionnaire. Six out of 10 drugs were used for off-label indications, cisplatin being the most commonly used. All drugs were either used as per FDA labeling or according to the recommendations of NCCN, except for gemcitabine which was used in one center for some indications based on phase II data. CONCLUSION: Very limited off-label prescribing was found in oncology practice in India. Since off-label use offers several advantages, judicious use of this practice should be encouraged among the oncologists. PMID- 21546739 TI - Monte Carlo study of dosimetric parameters and dose distribution effect of inhomogeneities and source position of GammaMed Plus source. AB - BACKGROUND: The conventional treatment planning system (TPS) gives analytical calculations with approximately +/- 15-20% dose uncertainty, which may lead to over exposure of critical organs or under dose of target as well as the presence of inhomogeneities, and the position of source affects the exact dose calculation like in breast and intraluminal brachytherapy. AIM: To obtain dose distribution parameters of GammaMed Plus high dose rate (HDR) 192 Ir source using Monte Carlo (MC) EGSnrc and GEANT4 codes as well as to find the effect on dose distribution due to source position, and due to presence of air and cortical bone by using MC GEANT4 code, and to find the similarity of both studies with any past study of any HDR brachytherapy source for either as input to TPS or verification of TPS calculations. SETTINGS AND DESIGN: It is done using different software of the computer, e.g., excel, MS word, etc. MATERIALS AND METHODS: The source, source position for different studies, water phantom, water characteristics, points of measurements, air and cortical bone inhomogeneities, and position of inhomogeneities were simulated. STATISTICAL ANALYSIS USED: For uncertainties calculation, mean and probability are used. RESULTS: The calculated dose rate constant, radial dose function, and 2D anisotropy function of the source show similarity with published data. Calculated dose distribution differences due to presence of air and cortical bone, and position of source in water phantom also show similarity with published data. CONCLUSION: These results can either be implemented in TPS or can be used for verification of TPS calculations. PMID- 21546741 TI - Set-up uncertainties: online correction with X-ray volume imaging. AB - AIM: To determine interfractional three-dimensional set-up errors using X-ray volumetric imaging (XVI). MATERIALS AND METHODS: Between December 2007 and August 2009, 125 patients were taken up for image-guided radiotherapy using online XVI. After matching of reference and acquired volume view images, set-up errors in three translation directions were recorded and corrected online before treatment each day. Mean displacements, population systematic (Sigma), and random (sigma) errors were calculated and analyzed using SPSS (v16) software. Optimum clinical target volume (CTV) to planning target volume (PTV) margin was calculated using Van Herk's (2.5Sigma + 0.7 sigma) and Stroom's (2Sigma + 0.7 sigma) formula. RESULTS: Patients were grouped in 4 cohorts, namely brain, head and neck, thorax, and abdomen-pelvis. The mean vector displacement recorded were 0.18 cm, 0.15 cm, 0.36 cm, and 0.35 cm for brain, head and neck, thorax, and abdomen-pelvis, respectively. Analysis of individual mean set-up errors revealed good agreement with the proposed 0.3 cm isotropic margins for brain and 0.5 cm isotropic margins for head-neck. Similarly, 0.5 cm circumferential and 1 cm craniocaudal proposed margins were in agreement with thorax and abdomen-pelvic cases. CONCLUSION: The calculated mean displacements were well within CTV-PTV margin estimates of Van Herk (90% population coverage to minimum 95% prescribed dose) and Stroom (99% target volume coverage by 95% prescribed dose). Employing these individualized margins in a particular cohort ensure comparable target coverage as described in literature, which is further improved if XVI-aided set-up error detection and correction is used before treatment. PMID- 21546742 TI - Can current prognostic scores reliably guide treatment decisions in patients with brain metastases from malignant melanoma? AB - PURPOSE: We evaluated the performance of the new 4-tiered melanoma-specific graded prognostic assessment (GPA) score and the previously published general GPA score in patients with brain metastases from malignant melanoma managed with different approaches including best supportive care. MATERIALS AND METHODS: Retrospective analysis of 51 patients. Compared with the original analysis of the melanoma-specific GPA score, these patients were more representative of the general population of patients with brain metastases from this disease. RESULTS: The present data confirmed that both scores identify patients with favorable prognosis who might be candidates for focal treatments. However, survival in the 2 unfavorable prognostic subgroups defined by the melanoma-specific GPA was not significantly different. Median survival in the melanoma-specific GPA classes was 3.1, 3.7, 7.5, and 12.7 months. Karnofsky performance status (KPS) and serum lactatdehydrogenase (LDH) level significantly predicted survival. CONCLUSION: In order to select the right patient to the right treatment and avoid overtreatment and suboptimal resource utilization in patients with very limited survival, improved prognostic tools are needed. The melanoma-specific GPA does not include extracranial disease extent or surrogate markers such as LDH. We suggest that a combination of KPS <70 and elevated LDH might better predict short survival than any of the GPA scores. This hypothesis should be confirmed in larger studies. PMID- 21546743 TI - Fractionated stereotactic radiosurgery for the treatment of meningiomas. AB - BACKGROUND: Although the vast majority of meningiomas are not malignant, their location within the cranial vault often leads to the development of symptoms. Traditional therapy has included observation, surgical resection, radiation therapy or a multimodality approach. The objective of this study is to review the outcomes in patients with meningioma treated at our institution using stereotactic radiosurgery. MATERIALS AND METHODS: A total of 73 patients (median age of 59, 15 male and 58 female) with meningioma (median volume of 5.54 cc) underwent Cyber Knife TM stereotactic radiosurgery at our institution. Sixty patients had WHO grade 1 meningioma, eleven patients had WHO grade 2 meningioma, and two patients had WHO grade 3 meningioma. Treatment consisted of a median dose of 17.5 Gy (range, 6 - 27 Gy) delivered over a median of three fractions (range: 1 - 5). The patients were followed by clinical examination as well as serial imaging with magnetic resonance imaging (MRI). RESULTS: The median follow-up was 16.1 months (range, 1.5 - 98.0). Follow-up MRI was available in all 73 patients. Local failure was documented in 11 cases. Actuarial local control at one year was 95, 71, and 0% for WHO grade 1, WHO grade 2, and WHO grade 3, respectively. There was no acute grade 3 or greater toxicity and only one episode of late grade 3 toxicity. A subjective improvement in the existing, tumor-related symptoms was noted in 60% of the patients. CONCLUSION: Stereotactic radiosurgery is a safe and effective treatment for meningioma. Tumor-related symptoms often improve after treatment. PMID- 21546744 TI - Intensity-modulated radiation to spare neural stem cells in brain tumors: a computational platform for evaluation of physical and biological dose metrics. AB - BACKGROUND: Neurocognitive effects following whole-brain and partial-brain irradiation can cause considerable morbidity. Sparing of neural stem cells (NSCs) is proposed as an avenue for reducing the long-term radiation-induced defects in learning, memory, and intelligence. We performed an analytical study to spare the NSC from partial-brain irradiation by intensity-modulated radiotherapy (IMRT). OBJECTIVE: The aim of this study is to achieve maximal sparing of NSC during irradiation of brain tumors using biologically equivalent dose (BED) for all plans. The consequent clinical benefit will possibly be in terms of acute effects on stem cells and delayed neurologic sequelae to brain. A tool to modulate various physical and biological dose metrics has been used to study the optimization of radiation therapy for brain tumors with constraints imposed on total radiation to NSC. MATERIALS AND METHODS: A total of 10 successive patients of grade III and IV gliomas of brain, who underwent total or near total excision of brain tumors, were included in the study. Patients underwent computed tomography and magnetic resonance imaging fusion for contouring. Computational codes used to analyze the efficacy of the plan are quality of coverage, homogeneity index, and conformity index. Wide range of radiosensitivity parameters were evaluated by using equivalent uniform dose and tumor control probability (TCP) to predict tumor control with and without sparing of NSC. RESULTS: The physical and biological dose metrics were modulated by fitting standard deviation of 0.3% for all plans. The maximum NSC sparing was achieved in IMRT plans with constraints applied to local TCP. Similarly, for BED of plans with and without constraints, the estimated mean reduction in acute complications of NSC achieved was 12.23% (range, 4.27-28.33%). The estimated mean reduction in BED for late complications of late-reacting brain tissue is 14.69% (range, 7.39 33.56%). PMID- 21546745 TI - MammoSite multilumen catheter: dosimetry considerations. AB - PURPOSE: To explore the dosimetric advantages of the new MammoSite multilumen (ML) balloon for breast brachytherapy treatment compared to conventional single lumen (SL) device plan. MATERIALS AND METHODS: Patients deemed appropriate for accelerated partial breast irradiation (APBI) were implanted with the MammoSite ML balloon. Two plans were generated in each patient for the same target coverage (PTV_EVAL) and dose to normal structures were plotted. The first plan used only the central single lumen with single-dwell position (SL), and the second plan (ML) was generated using the other lumens of the device. Dose distributions of the SL and ML plans were compared. RESULTS: For the same PTV_EVAL, the ML balloon improved dose coverage at the tip and base of the applicator compared to SL plan. The skin and rib doses were reduced using the ML plan versus SL plan for the same PTV_EVAL in-patient 2, where the skin-balloon distance was 7 mm and the rib balloon distance was <1 cm. For patient 1, the skin and rib distances were greater than 1 cm and the ML plan did not further minimize the dose to normal structures. CONCLUSION: In our initial experience, dosimetric goals can be better achieved using the ML MammoSite balloon when normal structures (skin and ribs) are close to PTV_EVAL with a distance of <7 mm and rib distance of <1 cm. The multiple lumen of ML balloon can optimize dose and reduce excessive dose to rib and skin and therefore minimize the long-term toxicities of rib discomfort, skin fibrosis and fat necrosis. PMID- 21546747 TI - Hypercalcemia with extraosseous MDP uptake in a bone scan as initial presentation in a case of cutaneous T-cell lymphoma. AB - A middle-aged lady presented with headache, vomiting of sudden-onset with intermittent evening rise of temperature. She also had slurring of speech with no loss of consciousness or altered sensorium. The patient was under evaluation for hypercalcemia. A whole body bone scan was done to look for causes of hypercalcemia and the scan showed extraosseous 99m Tc MDP (Technetium Methylene Di Phosphonate) uptake. One of the causes of extraosseous MDP uptake is cutaneous T-cell lymphoma (CTCL). On close interrogation the patient gave a history of hypopigmented dermal patches for more than 2 years duration. The coexisting dermal patches raised suspicion of CTCL. Skin biopsy confirmed CTCL. The patient was referred to oncology and was planned for six cycles of chemotherapy. PMID- 21546746 TI - Localized cavernous hemangioma of the uterus involving adenomyotic foci. AB - Localized cavernous hemangioma of the uterus is an extremely rare lesion that often presents with heavy uterine bleeding and/or pelvic pain. Though more cases exist for pregnant women, some isolated case reports involve non-pregnant women. The diagnosis is difficult and requires a high index of clinical and radiological suspicion. Here we describe a clinically and radiologically unsuspected case of a localized cavernous hemangioma in a 27-year-old woman, with a prior history of an uneventful Cesarean section. Surgical excision of the lesion at the cornu of the uterus was performed. Histopathology revealed a cavernous hemangioma involving the endomyometrium and invading the foci of adenomyosis. A cavernous hemangioma localized to a portion of the uterus may be clinically silent during pregnancy and throughout delivery thus making it difficult to detect. Though rare, it may be an important differential in any female patient who presents with non responsive uterine bleeding and/or unremitting pelvic pain. PMID- 21546748 TI - Adrenalectomy for isolated adrenal metastasis after Gamma Knife Surgery for an intracerebral metastasis of non-small-cell lung carcinoma. AB - Only a limited group of patients with non-small-cell lung cancer (NSCLC) is eligible for treatment with a curative intent. Adrenalectomy for a solitary adrenal metastasis of NSCLC may be curative when combined with resection of the primary tumor. It is unclear whether resection of an isolated adrenal metastasis is justified in patients with a second metastasis. We report a case of successful adrenalectomy with adjuvant chemotherapy in a patient who was previously treated with a right lower lobe resection and subsequent Gamma Knife treatment of an intracranial metastasis. At 20-month follow-up, patient was in a good clinical condition without signs of recurrent disease. In selected cases, adrenalectomy with adjuvant chemotherapy for an adrenal metastasis of NSCLC may be performed successfully, with good short-term results, even after earlier treatment of a cerebral metastasis. PMID- 21546749 TI - "Very Late" isolated para-aortic nodal recurrence of carcinoma cervix mimicking radiation-induced sarcoma. AB - Only a minority of the patients who develop recurrence after definitive treatment for cervical cancer are detected after 5 years (late recurrence); the numbers are lesser still after 10 years (very late recurrence). Among the infrequent cases that do develop "late" and "very late" recurrence, the commonest site is the pelvis. We report an unusually rare recurrence of treated cervical cancer confined to the para-aortic nodal group after a protracted disease-free interval of 13 years. On the basis of the long disease-free interval, location of the mass at the periphery of the radiation field, and aggressive imaging appearance, a diagnosis of radiation-induced sarcoma was considered. However, the final diagnosis of isolated para-aortic nodal recurrence of cervical cancer was rendered based on the histopathological and immunohistochemistry findings, supported by the absence of disease elsewhere on whole-body imaging. PMID- 21546750 TI - Muscle metastasis from hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma is the most common primary tumor of the liver. Disease dissemination occurs through hematogenous routes and frequently involves the lungs, bone, adrenal glands, and pancreas. The patterns of the extrahepatic manifestations are diverse. Soft tissue metastasis is extremely rare and mandates systematic pathological analysis, which may include the use of specific immunohistochemical staining. We report metastasis from a hepatocellular carcinoma, as a discrete subcutaneous mass to the right humerus muscle. MATERIALS AND METHODS: We detail the approach to diagnosis and management of an unusual case of a patient with hepatocellular carcinoma, in whom we found a metastatic lesion as a subcutaneous mass to the right humerus muscle nine years after right hepatectomy. CONCLUSION: This condition poses differential diagnostic problems in the settings of clinical and pathological investigations. Metastasis of hepatocellular carcinoma should be included in the differential diagnosis of rapidly growing lesions. PMID- 21546751 TI - Polymorphous low-grade adenocarcinoma of the parotid gland. AB - Polymorphous low-grade adenocarcinoma (PLGA) has been recently recognized as a distinct entity with a known predilection for minor salivary glands. We present an unusual case of recurrent PLGA arising within the right parotid gland in a 25 year-old lady. The striking histological picture is diverse architecture combined with benign cytological features. Even in the light of multiple recurrences, our tumor displayed a relatively indolent course which is commonly associated with this adenocarcinoma sub-type. Thus, unusual occurrence demonstrates that this tumor should also be considered in differentials of tumors of the major salivary glands. Long-term follow-up is essential to ensure local control. PMID- 21546752 TI - Malignant mixed Mullerian tumor of broad ligament with synchronous ovarian and endometrial carcinoma: a rare association. AB - Extragenital malignant mixed Mullerian tumor (MMMT) is a rare tumor in females, and it is even more rarely encountered among the multiple genital malignancies. There are some reports of extragenital MMMTs associated with synchronous or metachronous gynecologic tumors of Mullerian duct origin. We recently encountered an MMMT of broad ligament which is associated with papillary serous cystadenocarcinoma of the ovary and endometrioid adenocarcinoma arising in atypical polypoid adenomyoma endometrium in a 76-year-old woman. This case is presented for its rarity and unique presentation. To our knowledge, ours is the first reported case of this unique combination of multiple synchronous genital malignancies. PMID- 21546753 TI - Classic Kaposi's sarcoma in Arabs--widening ethnic involvement. AB - Kaposi's sarcoma is a tumor caused by human herpes virus 8 also known as Kaposi sarcoma-associated herpes virus. Originally described by Kaposi in 1872, this tumor is recognized as an AIDS-defining illness. Classic Kaposi's sarcoma (CKS) is a relatively indolent disease affecting elderly men from the Mediterranean region or of eastern European descent, besides Jews in whom it is the most common. It has been also reported in the Arab population living in Israel. Kaposi's sarcoma has been reported in Arabs after kidney transplantation; however, there are no reports of CKS occurring in non-Israeli Arabs. This is first such article reporting two Arab patients who presented with CKS thus widening the ethnic and geographic area of involvement with this condition. PMID- 21546754 TI - Epidemiological and clinical profile of breast cancer patients at a tertiary care hospital in South India. PMID- 21546755 TI - Primary malignant melanoma presenting as FDG avid large necrotic splenic mass with metastatic retroperitoneal adenopathy: FDG-PET and histopathological correlation. PMID- 21546756 TI - Displaced left kidney masquerading as splenic blush in 99mTc-DTPA GFR study in a patient of paravertebral primitive neuroectodermal tumor. PMID- 21546757 TI - In vivo aneuploidization during the expansion of renal adenocarcinoma. AB - BACKGROUND/AIMS: A correlation has been observed between DNA ploidy and other prognostic parameters such as tumor stage and grade. The present study evaluates tumor aneuploidization during renal adenocarcinoma expansion and growth. METHODS: A total of 252 renal tumors were analyzed between 1969 and 2001. Evaluated variables were age, TNM, Fuhrman classification, histology, size and DNA. A tumor was homogeneous when all the samples were diploid or aneuploid, and a heterogeneous tumor was the coexistence of aneuploid and diploid samples, or all aneuploid with different aneuploid clones. RESULTS: A total of 224 tumors were included (coefficient of variation <8). The DNA study classified 129 (57.6%) as diploid and 95 (42.4%) as aneuploid. The percentage of aneuploid tumors increased significantly with the pathological stage. Both aneuploid patterns were also significantly more frequent in advanced pathological stages. Tumors with multiple aneuploid clones (n = 17) were significantly more frequent in tumors measuring '4 cm. Both aneuploid patterns showed no differences in survival (p = 0.83), indicating that the heterogeneous pattern probably represents an intermediate step between diploid and homogeneous aneuploid tumor status. CONCLUSIONS: The aneuploid pattern is more common in more advanced stages of the disease, with no clear correlation to primary tumor size. This suggests gradual aneuploidization with tumor expansion and growth. PMID- 21546758 TI - Activation of the ERK1/2 mitogen-activated protein kinase cascade by dentin matrix protein 1 promotes osteoblast differentiation. AB - DMP1 has been shown to play many roles in osteogenesis. We recently demonstrated that calcium-mediated stress kinase activation by DMP1 leads to osteoblast differentiation. In this study we demonstrate that DMP1 can also activate the extracellular signal-regulated kinase (ERK)-MAPK pathway. This activation was mediated through the RGD integrin-binding domain in DMP1. Further, we demonstrate that Runx2, an essential transcription factor, is stimulated by the ERK-MAPK pathway. PMID- 21546759 TI - Why does enamel in Klk4-null mice break above the dentino-enamel junction? AB - BACKGROUND: The enamel layerof kallikrein 4 (Klk4)-null mice has a normal thickness and a decussating pattern of enamel rods, but it contains residual enamel proteins, is less highly mineralized, and fractures in its deepest part just above the dentino-enamel junction (DEJ). The plane of fracture is puzzling because the deepest enamel is deposited earliest and, through the action of the secretory stage enamel protease (Mmp20), is the most mature part of the enamel layer at the time of the onset of Klk4 expression. OBJECTIVES: To characterize the planes of fracture in Mmp20- and Klk4-null mice and to localize Klk4 expression in developing teeth. METHODS: Klk4- and Mmp20-null mice were sacrificed at 7 weeks and their mandibular incisors were characterized by scanning electron microscopy. Klk4(+/)(lac)(Z) mice were mated with Klk4(+/)(lac)(Z) mice. Offspring were genotyped by polymerase chain reaction. Klk4(+/)(+), Klk4(+/)(lac)(Z), and Klk4(lac)(Z/)(lac)(Z) (null) littermates on postnatal days 5, 8, 11, and 14 were processed for beta-galactosidase histochemistry. RESULTS: The enamel layer fractures at the DEJ in Mmp20-null mice, and fractures occur in enamel above the DEJ in Klk4-null mice. Klk4 is not expressed by secretory-stage ameloblasts, murine odontoblasts beneath the secretory stage, or maturation-stage ameloblasts. Klk4 is specifically expressed by transition and maturation-stage ameloblasts. CONCLUSIONS: The breakage of enamel near the DEJ in Klk4-null mice is not due to a failure of odontoblasts to express Klk4, but it relates to a progressive hypomineralization of enamel with depth. PMID- 21546760 TI - Regulation of bmp4 expression in odontogenic mesenchyme: from simple to complex. AB - For many years the molecular mechanisms governing bone morphogenetic protein 4 (Bmp4) expression in tooth bud mesenchyme could be explained by an uncomplicated model involving the interaction of the homeobox gene Msx1 and the paired domain gene Pax9 and a limited proximal promoter segment of Bmp4. New insights have led to major revisions, but we are still far from understanding the role of Msx1 and Pax9 in the complex processes that result in the expression of Bmp4 in the mesenchymal layer of the developing tooth bud. The objective of these studies was to gain further insight into the molecular relationship between Pax9, Msx1, and Bmp4 in dental mesenchyme and explore its association with nonsyndromic tooth agenesis in humans. PMID- 21546761 TI - Childhood tumors of the brain: demographic pattern over a ten-year period in the Kashmir Valley. AB - Brain tumors in children represent the second most frequent tumors in this age group after hematologic malignancies. We highlight the demographic pattern after retrospective analysis of brain tumors in children from geographically and ethnically distinct Kashmir Valley managed in our center between 2000 and 2009. We had a total of 248 pediatric patients with brain tumors. The parameters analyzed were age, gender, location of tumors and histopathological subtypes as well as WHO grade of tumor. We also did a comparison between the frequencies of common varieties of tumor in the first and second 5-year periods. We found that 111 tumors (44.75%) were supratentorial, and 137 (55.25%) were infratentorial. The male-to-female ratio was 1.4:1. The proportions of low-grade and high-grade tumors were 60 and 40%, respectively. The most common tumor in our series was astrocytoma. The most common tumors in the supratentorial and infratentorial compartments were craniopharyngioma and medulloblastoma, respectively. Our experience reflects a different demographic profile of pediatric brain tumors as compared with other regions of the world. PMID- 21546762 TI - Failure of a vagus nerve stimulator following a nearby lightning strike. AB - We recently reported our experience with implanted vagus nerve stimulators (VNS) in 62 children over a 7-year period. Here, we present a case of a VNS that successfully reduced the number and severity of seizures in a patient with an unusual seizure pattern, and failed to function shortly after a lightning storm. To our knowledge, the failure of VNS or any implantable electrical devices by lightning has not been reported in the literature. This mechanism of electrical interference, while unusual, may require more attention as these devices are expected to be used more frequently. PMID- 21546763 TI - Gestational dermatosis shortly after implantation associated with parental class II HLA compatibility and maternal immune activation: preliminary report of a prospective case series. AB - BACKGROUND: Pregnancy represents a semi-allograft, subject to similar immune responses as allogeneic organ transplants. Tolerance of pregnancy appears best with maximal class II HLA heterogeneity between mother and father, while compatibilities are associated with increased pregnancy loss and maternal autoimmunity. Tolerance abnormalities often involve skin reactions. Abnormalities in tolerance of the fetal graft may do the same. OBJECTIVE: To define the characteristics of a newly described dermatosis in very early pregnancy. METHODS: Prospective case series of 7 couples/12 clinical episodes. RESULTS: The dermatosis was observed in 7 out of 285 women undergoing in vitro fertilization (IVF; 2.5%; 95% CI 0.66-4.26%) and in 12 out of 277 total IVF cycles reaching embryo transfer (4.3%; 95% CI 1.93-6.73%). Prior to IVF all women reported autoimmune clinically significant allergies. All but 1 couple demonstrated class II HLA compatibility. Two of 4 pregnancies miscarried. All rashes erupted within days from embryo implantation. CONCLUSIONS: The 'implantation rash' reported here is uncommon but not rare. It may be the consequence of abnormal maternal immune responses to embryo implantation in women with prior immune activation, associated with class II HLA compatibility between parents. Further prospective studies are required to better define this condition. PMID- 21546764 TI - Clinical features and treatment of pediatric somatotropinoma: case study of an aggressive tumor due to a new AIP mutation and extensive literature review. AB - CONTEXT: Pediatric somatotropinoma is uncommon but usually more aggressive than in adults, creating therapeutic challenges. No treatment guidelines are available. OBJECTIVES: To describe the features of pediatric somatotropinomas and to assess therapeutic strategies based on an extensive literature review. DESIGN: We describe a pediatric case of aggressive somatotropinoma with an AIP mutation. We identified 137 pediatric somatotropinoma cases published between 1981 and 2010, and found 41 cases with AIP mutations in the main review. RESULTS: We found a slight male preponderance (59%). Median age was 9 years at symptom onset and 14 years at diagnosis. Macroadenomas accounted for 90% of the tumors; 2/3 of the children had hyperprolactinemia at diagnosis. The first-line treatment was pharmacotherapy in one third and surgery in 2/3 of the patients. Pegvisomant was used in 7 patients and produced significant improvement in 4. The male preponderance was higher in the subgroup with AIP mutations. Mutations leading to severe protein abnormalities were more common than reported in adults. CONCLUSION: Higher invasiveness and tumor volume in pediatric somatotropinomas require complex treatment combinations, which produce variable results. Pegvisomant is an effective drug whose usefulness in children remains to be determined. Genetic screening, particularly for AIP mutations, should be performed routinely. PMID- 21546765 TI - Attenuated cardiovascular response to sympathetic system activation during exercise in patients with dialysis-induced hypotension. AB - BACKGROUND: We wished to investigate potential causes of dialysis-induced hypotension (DIH), including the attenuated cardiovascular response to sympathetic system activation during exercise and myocardial dysfunction. METHODS: This study included 26 end-stage renal disease (ESRD) patients with DIH, 30 ESRD patients without DIH (Non-DIH), and 30 control subjects. Each patient was evaluated with echocardiography and a symptom-limited treadmill stress test. The chronotropic index (CRI), heart rate recovery (HRR), systolic blood pressure response to exercise (SBP response), and tissue Doppler systolic myocardial velocities were calculated. RESULTS: The HRR and velocities were reduced in dialysis patients compared to controls; however, they were similar in patients with and without DIH. Patients with DIH had the lowest CRI compared to the Non DIH group (0.62 +/- 0.15 vs. 0.73 +/- 0.17, p = 0.020) and controls (0.62 +/- 0.15 vs. 0.86 +/- 0.11, p < 0.001). Similarly, patients with DIH had the lowest SBP response values compared to the Non-DIH (34.88 +/- 15.01 vs. 55.67 +/- 25.42, p = 0.002) and controls (34.88 +/- 15.01 vs. 59.70 +/- 23.04, p < 0.001). CONCLUSION: Patients with DIH have inadequate sympathetic activity of the cardiovascular system during exercise and impaired left ventricular systolic function. Both factors could contribute to the development of hypotension during hemodialysis. PMID- 21546766 TI - The 'G' that never was. PMID- 21546767 TI - Genome-wide association scan for survival on dialysis in African-Americans with type 2 diabetes. AB - BACKGROUND: African-Americans (AAs) with diabetes have high incidence rates of end-stage renal disease (ESRD) with associated high mortality. Genetic factors modulating the risk of mortality on dialysis are poorly understood. METHODS: A genome-wide association study was performed in 610 AAs with type 2 diabetes (T2D) and ESRD on dialysis, using the Affymetrix 6.0 platform (868,155 SNPs). Time to death was assessed using Cox proportional hazards model adjusting for ancestry and other confounding variables. Cases were censored at kidney transplant or (if living) at study conclusion. RESULTS: Mean follow-up was 5.4 +/- 3.5 years; 434 deaths were recorded. Five SNPs were associated with time to death at p < 1.00 * 10(-6): rs2681019 (HR = 2.58, P(REC) = 8.00 * 10(-8)), rs815815 in CALM2 (HR = 1.51, P(ADD) = 6.50 * 10(-7)), rs926392 (HR = 2.37, P(REC) = 4.80 * 10(-7)), and rs926391 (HR = 2.30, P(REC) = 7.30 * 10(-7)) near DHX35, and rs11128347 in PDZRN3 (HR = 0.57, P(ADD) = 6.00 * 10(-7)). Other SNPs had nominal associations with time to death (p < 1.00 * 10(-5)). CONCLUSION: Genetic variation may modify the risk of death on dialysis. SNPs in proximity to genes regulating vascular extracellular matrix, cardiac ventricular repolarization, and smoking cessation are associated with dialysis survival in AAs with T2D. These results warrant replication in other cohorts and races. PMID- 21546768 TI - Haptoglobin polymorphism as a risk factor for chronic kidney disease: a case control study. AB - AIMS: Taiwan has the highest incidence and prevalence of end-stage renal disease worldwide. Haptoglobin (Hp) has a role in renal protection, and there are known differences in the function of different Hp alleles. We aim to study the association between Hp genotype and chronic kidney disease (CKD) in Taiwan. METHODS: We performed one hospital-based, age-matched case-control study of 213 patients with CKD and 213 controls to evaluate the association between Hp polymorphism and CKD. Three major Hp genotypes were determined using polymerase chain reaction and electrophoresis. An unconditional logistic regression model was used to identify the associated risk factors for the development of CKD. RESULTS: The frequency of Hp2-2 genotype and Hp(2) allele was significantly higher in the CKD group than in controls (p = 0.032 and 0.024, respectively). After adjustment for covariates, the Hp2-2 genotype (vs. Hp1-1; OR 3.841) remained significantly associated with the development of CKD, together with diabetes (OR 3.131), hypertension (OR 1.748) and dyslipidemia (OR 1.646). CONCLUSION: This present study shows that Hp2-2 genotype is an independent risk factor for CKD. Determination of the Hp genotype may be of potential value to the prediction of genetic risk for CKD. PMID- 21546769 TI - Testing the terrain hypothesis: Canada geese see their world laterally and obliquely. AB - The distribution of ganglion cells in the retina determines the specific regions of the visual field with high visual acuity, and thus reflects the perception of a species' visual environment. The terrain hypothesis proposes that animals living in open areas should have a horizontal visual streak across the retina with high ganglion cell density to increase visual acuity along the horizon. We tested this hypothesis in Canada geese (Branta canadensis) by assessing retinal topography, visual field configuration, and scanning behavior. We found that geese have an oblique rather than a horizontal visual streak across the retina: from a dorsal-nasal to a ventral-temporal position. Geese showed narrow blind areas, which increased the range of their lateral vision, and a relatively large degree of eye movement. Canada geese have relatively wide binocular fields and can see their bill tips. Goose head movement rates were low compared to species with a single fovea, and head movement rates increased in visually obstructed habitats. Canada geese have high acuity across their retina, which would allow them to simultaneously scan the ground and the sky when the head is up and parallel to the ground, as well as align the visual streak with the horizon when the head is tilted downwards. Their visual streak, along with their large eye size, may reduce the need for large amplitude head movements during vigilance bouts in visually unobstructed habitats. Overall, the visual system of geese combines features related to the detection of predators/conspecifics in open areas (visual streak, large lateral field, reduced head movements) as well as visual specializations that would allow for monitoring both the ground and sky (oblique streak) and for extracting and handling of food items (wide binocular fields, visualization of the bill tip). PMID- 21546770 TI - Characteristic neurobiological patterns differentiate paternal responsiveness in two Peromyscus species. AB - Rodent paternal models provide unique opportunities to investigate the emergence of affiliative social behavior in mammals. Using biparental and uniparental Peromyscus species (californicus and maniculatus, respectively) we assessed paternal responsiveness by exposing males to biological offspring, unrelated conspecific pups, or familiar brothers following a 24-hour separation. The putative paternal circuit we investigated included brain areas involved in fear/anxiety [cingulate cortex (Cg), medial amygdala (MeA), paraventricular nucleus of the hypothalamus (PVN), and lateral septum (LS)], parental motivation [medial preoptic area (MPOA)], learning/behavioral plasticity (hippocampus), olfaction [pyriform cortex (PC)], and social rewards (nucleus accumbens). Paternal experience in californicus males reduced fos immunoreactivity (ir) in several fear/anxiety areas; additionally, all californicus groups exhibited decreased fos-ir in the PC. Enhanced arginine vasopressin (AVP) and oxytocin (OT) ir cell bodies and fibers, as well as increased neuronal restructuring in the hippocampus, were also observed in californicus mice. Multidimensional scaling analyses revealed distinct brain activation profiles differentiating californicus biological fathers, pup-exposed virgins, and pup-naive virgins. Specifically, associations among MPOA fos, CA1 fos, dentate gyrus GFAP, CA2 nestin-, and PVN OT ir characterized biological fathers; LS fos-, Cg fos-, and AVP-ir characterized pup-exposed virgins, and PC-, PVN-, and MeA fos-ir characterized pup-naive virgins. Thus, whereas fear/anxiety areas characterized pup-naive males, neurobiological factors involved in more diverse functions such as learning, motivation, and nurturing responses characterized fatherhood in biparental californicus mice. Less distinct paternal-dependent activation patterns were observed in uniparental maniculatus mice. These data suggest that dual neurobiological circuits, leading to the inhibition of social-dependent anxiety as well as the activation of affiliative responses, characterize the transition from nonpaternal to paternal status in californicus mice. PMID- 21546771 TI - Neuroanatomical projections of the species-specific tyrosine hydroxylase immunoreactive cells of the male prairie vole bed nucleus of the stria terminalis and medial amygdala. AB - The principal nucleus of the bed nucleus of the stria terminalis (BSTpr) and posterodorsal part of the medial amygdalar nucleus (MEApd) are densely interconnected sites transmitting olfactory information to brain areas mediating sociosexual behaviors. In male prairie voles (Microtus ochrogaster), the BSTpr and MEApd contain hundreds of cells densely immunoreactive for tyrosine hydroxylase (TH). Such tremendous numbers of TH-immunoreactive (TH-ir) cells do not exist in other rodents examined, and studies from our laboratory suggest these cells may be part of a unique chemical network necessary for monogamous behaviors in prairie voles. To obtain information about how these TH-ir cells communicate with other sites involved in social behaviors, we first used biotinylated dextran amine (BDA) to determine sites that receive BSTpr efferents and also contain TH-ir fibers. Only in the medial preoptic area (MPO) and MEApd did we find considerable comingling of BDA-containing and TH-ir fibers. To examine if these sites receive input specifically from BSTpr TH-ir cells, the retrograde tracer Fluorogold was infused into the MPO or MEApd. Almost 80% of TH ir projections to the MPO originated from the BSTpr or MEApd, involving about 40% of all TH-ir cells in these sites. In contrast, the MEApd received almost no input from TH-ir cells in the BSTpr, and received it primarily from the ventral tegmental area. Retrograde tracing from the BSTpr itself revealed substantial input from MEApd TH-ir cells. Thus, the male prairie vole brain contains a species-specific TH-ir network involving the BSTpr, MEApd, and MPO. By connecting brain sites involved in olfaction, sociality and motivation, this network may be essential for monogamous behaviors in this species. PMID- 21546772 TI - Neuronal responses to looming objects in the superior colliculus of the cat. AB - The superior colliculus (SC) in the mammalian mesencephalon is involved in avoidance or escape behaviors, but little is known about the response properties of collicular neurons to an object approaching on a collision course towards the animal. The present study identified two classes of looming-sensitive neurons, rho and eta cells, in the SC of the cat, but did not find any tau cell, which has been observed in the pigeon tectofugal pathway. The looming responses were characterized by distinct firing patterns, in which the neuronal discharge steadily increased as the object was approaching, and peaked approximately at the time of collision (rho cell) or some time earlier (eta cell). The response onset time of both rho and eta cells was linearly related to the square root of the diameter/velocity ratio of looming objects; whereas for eta cells, the response peak time was linearly related to the diameter/velocity ratio. The receptive fields of these collicular cells were composed of an excitatory center and a suppressive surround, but the occurrence and development of neuronal responses to looming stimuli were independent of the receptive-field organization. Although the cell number was relatively small in the deep layers of the SC, the proportion of looming-sensitive neurons was close to that in the superficial layers. These results suggest that a population of collicular cells is involved in signaling impending collision of a looming object with the animal and the neural mechanisms underlying the collision avoidance behaviors are to some extent conservative across species from insects to mammals. PMID- 21546773 TI - Nitric oxide delivering devices to prevent saphenous vein graft failure? PMID- 21546774 TI - 1alpha,25-dihydroxyvitamin D3 attenuates platelet activation and the expression of VCAM-1 and MT1-MMP in human endothelial cells. AB - OBJECTIVE: Inflammatory conditions contribute to increased expression of various activity markers in platelets and endothelial cells, leading to atherosclerotic changes in the vascular wall. The objective of this study was to investigate possible protective effects of 1alpha,25-dihydroxyvitamin D3 in an endothelial cell model. METHODS: After a 24-hour incubation with 1alpha,25-dihydroxyvitamin D3, human umbilical vein endothelial cells were stimulated with lipopolysaccharide (LPS) and incubated in direct contact with platelets. The expression of CD40L and CD62P in platelets, the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1), the urokinase receptor uPAR and membrane type 1 matrix metalloproteinase (MT1-MMP) in endothelial cells and endothelial cell reactive oxygen species generation were measured by flow cytometry. Endothelial nitric oxide synthase was analyzed by Western blot. RESULTS: The increased expression of VCAM-1 and MT1-MMP in endothelial cells by proinflammatory stimulation with LPS and by direct contact with activated platelets was significantly reduced through preincubation with 1alpha,25-dihydroxyvitamin D3. Platelets in direct contact with preincubated endothelial cells showed significantly reduced CD62P expression when compared to platelets incubated with untreated endothelial cells. CONCLUSIONS: 1alpha,25 Dihydroxyvitamin D3 attenuates platelet activation and the expression of VCAM-1 and MT1-MMP in human endothelial cells and could have early therapeutic relevance in atherosclerotic diseases. PMID- 21546775 TI - Gene expression following exposure to celecoxib in humans: pathways of inflammation and carcinogenesis are activated in tumors but not normal tissues. AB - BACKGROUND: The Cox-2 inhibitor, celecoxib (Pfizer Inc., N.Y., USA), is a promising chemopreventive agent [Arber et al.: N Engl J Med 2006;355:885-895; Bertagnolli et al.: N Engl J Med 2006;355:873-884]. This study aims to explore its mechanism by defining changes in gene expression between neoplastic and normal tissue samples before and after treatment. METHODS: Patients with documented colorectal neoplasia in screening colonoscopy, destined to undergo surgical colectomy, were randomized for treatment with celecoxib (n = 11; 400 mg/day) or placebo (n = 3) for 30 days. Tissue samples were taken from the tumor and from normal adjacent mucosa during both colonoscopy and surgery. RNA was extracted and analyzed using Affymetrix Genechip(r). RESULTS: 687 genes differentiated tumor samples before and after treatment, among which 310 genes did not show the same differential expression in the placebo group or normal samples. These genes were significantly related to pathways of cell cycle regulation and inflammation, and of note was the TGF-beta pathway, which held a strong association with the list of genes formerly found to be associated with the colorectal cancer expression profile in microarray analyses, as summarized in a meta-analysis by Cardoso et al. [Biochim Biophys Acta 2007;1775:103-137]. CONCLUSIONS: Celecoxib selectively affects genes and pathways involved in inflammation and malignant transformation in tumor but not normal tissues, this may assist in the development of safer and more effective chemopreventive agents. PMID- 21546776 TI - Surgical management of benign and indeterminate hepatic lesions in the era of laparoscopic liver surgery. AB - BACKGROUND/AIMS: The expansion of the laparoscopic approach for the management of benign liver lesions has raised concerns regarding the risk of widening surgical indications and compromising safety. Large single-centre series focusing on laparoscopic management of benign liver lesions are sporadic. METHODS: We reviewed a prospectively collected database of patients undergoing pure laparoscopic liver resection (LLR) for benign liver lesions. All cases were individually discussed at a multidisciplinary team meeting. RESULTS: Forty-six patients underwent 50 LLRs for benign disease. Indications for surgery were: symptomatic lesions, preoperative diagnosis of adenoma or cystadenoma, and lesions with an indeterminate diagnosis. The preoperative diagnosis was uncertain in 11 cases. Of these, histological diagnosis was hepatocellular carcinoma in one (9%) and benign lesion in 10 patients (91%). Thirteen patients (28%) required major hepatectomy. Three patients (7%) developed postoperative complications. Mortality was nil. The median postoperative hospital stay following major and minor hepatectomy was 4 and 3 days, respectively. CONCLUSION: The laparoscopic approach represents a safe option for the management of benign and indeterminate liver lesions, even when major hepatectomy is required. LLR should be only performed in specialized centres to ensure safety and strict adherence to orthodox surgical indication. PMID- 21546777 TI - Mild and severe anal incontinence after lateral internal sphincterotomy: risk factors, postoperative anatomical findings and quality of life. AB - AIM: This study aims to evaluate the risk factors for incontinence after lateral internal sphincterotomy (LIS) and assess quality of life in different levels of incontinence. METHODS: All consecutive patients (n = 253) with chronic anal fissure who underwent LIS between 2003 and 2006 were retrospectively reviewed. All patients were questioned for possible anal incontinence according to the Wexner Incontinence Score (WIS). Demographics, vaginal delivery history, additional procedures and surgeon's experience were evaluated as risk factors. Endoanal ultrasound (EUS) was performed in incontinent patients to assess the thickness of the remaining internal sphincter and to evaluate any injury in the external sphincter. Quality of life was questioned with SF-36. RESULTS: Twenty eight (11.7%) patients suffered from incontinence (mean WIS = 3.6 +/- 2.5). The search for a risk factor was unsuccessful when continent and incontinent groups were compared. In subgroup analyses, patients were found to be suffering from mild (WIS <5, n = 19) or severe (WIS >5, n = 9) incontinence. Vaginal delivery history was found more often in the severely incontinent subgroup than in the continent group (p < 0.05). Also, vaginal delivery history and the additional procedures were more frequently observed in the severely incontinent subgroup than in the mildly incontinent subgroup. EUS did not find any external sphincter injury in these cases. WIS had negative correlations with the physical and mental component scores of SF-36. CONCLUSION: In our opinion, the threat for incontinence is unpredictable; however, vaginal delivery history may increase the risk of severe incontinence. PMID- 21546778 TI - A population-based survey of cognitive performance in a Sicilian elderly community. AB - BACKGROUND: The global burden of neurodegenerative diseases is increasing. Previous studies reported differences related to age, gender and socioeconomic status. We calculated the cognitive performances of a Sicilian population aged 65 years or older, by means of a door-to-door population-based survey in Bagheria city, Sicily. METHODS: A door-to-door survey was carried out in the city of Bagheria, Sicily (prevalence day September 30, 2006). A cohort of 2,200 persons was randomly stratified, obtaining a 25% sample of the whole population. Cognitive function was assessed by Mini Mental State Examination (MMSE). Percentile distributions by age, gender, education and working activity were calculated. Regression models were used to analyze the relationship between the investigated variables and cognitive performance. RESULTS: A total of 1,837 persons agreed to participate (1,062 women and 775 men). Distribution of MMSE showed a highly significant inverse linear trend related to the increasing age (p < 0.0001) and to the degree of education (p < 0.0001), both in men and women. We observed a significant association between higher education and a better cognitive performance (OR 6.91; CI 3.24-14.76) and an inverse association between manual kind of occupation versus not manual and a poorer cognitive status (OR 0.82; CI 0.67-0.997). Height was associated with decreased cognitive performances in women (OR = 1.03; CI = 1.01-1.05) but not in men (OR = 0.997; CI = 0.993 1.002). CONCLUSIONS: These findings provide a feature of cognitive performances in Sicily, measured by MMSE scores in individuals aged 65 years or older. PMID- 21546779 TI - Epidemiology of Charcot-Marie-Tooth disease in the population of Belgrade, Serbia. AB - BACKGROUND: The aim of this study was to determine prevalence and 15-year survival in Charcot-Marie-Tooth disease (CMT). METHODS: The study covers the period from 1 January 1988 to 31 December 2007 in the territory of Belgrade. Data on a number of CMT-affected persons and their basic demographic characteristics as well as data on the disease were collected from medical records. Data on the course and outcome of the disease were obtained through direct contact with patients, their families and their physicians. RESULTS: We registered 161 patients with CMT in the population of Belgrade. The most frequent type was CMT1. The crude prevalence of CMT disease in the Belgrade population on 31 December 2007 was 9.7/100,000 for all subtypes, 7.1/100,000 for CMT1, and 2.3/100,000 for CMT2. Gender-specific prevalence was 11.2/100,000 for males and 8.3/100,000 for females. The highest age-specific prevalence was registered in the oldest age group (75+ years; 19.1/100,000), and the lowest one in patients aged 5-14 years (5.0/100,000). The cumulative probability of 15-year survival for CMT patients in Belgrade was 85.6 +/- 7.8% (44.9 +/- 31.8% for males and 98.2 +/- 1.8% for females). CONCLUSIONS: The prevalence of CMT found in Belgrade is similar to the prevalence registered in Southern European countries. PMID- 21546780 TI - Quadruple therapy leads to a sustained improvement of vision in patients with wet age-related macular degeneration. AB - AIM: To investigate the efficacy of a combined intravitreal therapy with prior photodynamic therapy (PDT) in patients with wet age-related macular degeneration. METHODS: Fifty-two patients (mean age: 72.7 years) with predominantly classic choroidal neovascularization received low-fluence PDT (42 J/cm2 for 72 s), followed 24 h later by a 0.4-ml core pars plana vitrectomy with intravitreal injection of dexamethasone (0.8 mg) and bevacizumab (1.25 mg). The best-corrected visual acuity (BCVA; 6 m Snellen), central macular thickness (optical coherence tomography), intraocular pressure and the need for retreatment were assessed. RESULTS: BCVA changed significantly (vs. baseline) at 3 months (+0.11), 9 months (+0.19) and 14 months (+0.16). At the end of the follow-up period, BCVA had improved by > 0.1 in the majority of the patients (72.9%), and the mean central retinal thickness had decreased by -44.3% (-211 MUm). The retreatment rate was 25%. No increase in intraocular pressure or other adverse event was reported. CONCLUSIONS: The pharmacological effects of the drugs, the low-fluence PDT, and the physiological effects of the therapy may have contributed to the sustainability of the therapeutic benefits. PMID- 21546781 TI - Intracameral injection of bevacizumab for the treatment of neovascular glaucoma. AB - PURPOSE: To assess the duration of the effect of intracameral bevacizumab in patients presenting with rubeosis iridis and neovascular glaucoma (NVG). METHODS: Retrospective analysis of 24 consecutive eyes of 24 patients with decompensated NVG (> 21 mm Hg) treated with a single intracameral injection of bevacizumab over a minimum follow-up of 6 months. The endpoint of the study was the need for retreatment due to recurrence of raised intraocular pressure (IOP). Secondary outcome was the course of visual acuity (VA) and IOP over 6 months. RESULTS: A Kaplan-Meier calculation revealed a mean duration of the treatment effect of 23 +/- 4.4 days. Compared to mean IOP before treatment (26.3 mm Hg), decreases to 17.5 mm Hg at 1 week after treatment (p < 0.002) and to 17.1 mm Hg (p < 0.005) at 6 months following a single injection were seen. At 6 months, additional treatment was performed in 87.5% (n = 21) of eyes. VA remained stable or improved in 75% (n = 18) of all cases. CONCLUSION: The IOP-lowering effect of intracameral bevacizumab can be seen 1 week after the injection, but is limited to a period of approximately 3 weeks. However, the fast and effective response to intracameral bevacizumab injection opens a time window for additional treatments, which are often necessary. PMID- 21546782 TI - Do pharmacotherapy and/or psychotherapy work in depression? It depends! PMID- 21546783 TI - Alexithymia is associated with depression in de novo Parkinson's disease. PMID- 21546784 TI - Cognitive behavioural treatment is as effective in high- as in low-scoring alexithymic patients with substance-related disorders. PMID- 21546785 TI - Psychological well-being, negative affectivity, and functional impairment in fibromyalgia. PMID- 21546786 TI - Emotion dysregulation as a core feature of borderline personality disorder: comparison of the discriminatory ability of two self-rating measures. AB - BACKGROUND/AIMS: There is growing evidence that emotion dysregulation (ED) is a core feature of borderline personality disorder (BPD). The present study examines whether a self-rating measure, the ED Scale, lets us distinguish between individuals with BPD and those diagnosed with other mental disorders in a way similar to that of a borderline-related screening measure, the German version of the McLean Screening Instrument for Borderline Personality Disorders (MSI-BPD). METHOD: Based on the signal detection theory, receiver operating characteristics as well as reliability and validity indicators are determined in a heterogeneous outpatient sample (n = 168). RESULTS: The values of internal consistency and the validity indicators turned out to be in the expected range. The area under the curve (AUC) for the ED Scale was 0.86, and therefore emerged on a par with the AUC = 0.90 of the MSI-BPD. As required, analyses for both measures revealed equal and high values for sensitivity, as well as corresponding low negative predictive values. There was, however, a lower degree of specificity on the ED Scale as compared to the MSI-BPD. CONCLUSION: The results support the assumption that ED is a core feature of BPD, but should also be taken into account in the assessment and treatment of other mental disorders. PMID- 21546787 TI - Does a more specified version of the HoNOS (Health of the Nation Outcome Scales) increase psychometric properties of the inventory? AB - BACKGROUND: The Health of the Nation Outcome Scales (HoNOS) is a clinician-rated instrument for the differentiated measurement of severity in patients with mental disorder. Item 8 of the instrument, assessing 'Other mental and behavioral problems', is particularly relevant for patients with affective disorders, anxiety disorders, and eating and personality disorders. However, some studies have shown that the scale possesses unsatisfactory psychometric properties. The objective of the present study was therefore to validate the psychometric properties of a more specified version of the HoNOS-D item 8. METHODS: The instrument's reliability and validity were tested using a large, representative, clinical sample of patients with mental disorders (study 1: n = 1,918 and n = 1,357). Additional tests of reliability and criterion validity were performed using a further clinical sample of patients with mental disorders (study 2: N = 55). RESULTS: The extended version of the HoNOS provides a differentiated picture of additional problem areas for the patient. Although inter-rater reliability indicates a need for more detailed instructions, the problem areas of item 8 proved on the whole to be suitable for measuring the extent and severity of mental problems that are present in addition to the primary problem. CONCLUSION: In order to make the extended assessment of the HoNOS useful for clinical routine practice, a supplemental glossary is needed. PMID- 21546788 TI - The relationship between insight and uncertainty in obsessive-compulsive disorder. AB - BACKGROUND: The aim of this study was to investigate the relationship between the levels of insight and checking-related uncertainty in patients with obsessive compulsive disorder (OCD). SAMPLING AND METHODS: Twenty OCD patients with checking compulsions and without current comorbidity were recruited. We used an experimental paradigm that gave subjects the opportunity to check during a decision-making task, thereby allowing for the calculation of a response time index (RTI) as the 'uncertainty cost' during decision-making. The level of insight was assessed with the Brown Assessment of Beliefs Scale (BABS). RESULTS: Regression analyses indicated a significant positive correlation between RTI and BABS scores (r = 0.49). CONCLUSIONS: The level of insight is related to cognitive characteristics underlying OCD symptoms, in particular, checking-related uncertainty in checking OCD patients. STUDY LIMITATIONS: The absence of a comparison group and the low number of included patients are the main limitations of the present study. PMID- 21546789 TI - Gamma knife radiosurgery for central neurocytoma: retrospective analysis of fourteen cases with a median follow-up period of sixty-five months. AB - OBJECT: Central neurocytoma (CN) is considered to be a benign neuronal tumor with possible atypical behavior. Microsurgery, radiation therapy (RT) and radiosurgery all have been used in treating this rare disease during the past decade. In this study, the authors present the experience with gamma knife radiosurgery (GKRS) on 14 patients with CN during a median follow-up period of 65 months and document the safety and efficacy of GKRS in the treatment of CN. METHODS: Between November 1997 and December 2009, 14 patients pathologically diagnosed with CN were treated with GKRS. Follow-up magnetic resonance imaging (MRI) was performed at 6-month intervals. Tumor volume and adverse radiation effects (ARE) were documented to evaluate tumor response to GKRS. The Karnofsky Performance Scale (KPS) and neurological status were used to assess clinical outcome. The mean radiation dose prescribed to the tumor margin was 12.1 Gy (ranging from 11 to 13 Gy). The mean tumor volume was 19.6 ml (ranging from 3.5 to 48.9 ml). The mean follow-up period was 70 months (ranging from 30 to 140 months), and the median follow-up period was 65 months. RESULTS: Tumor shrinkage was found in all patients at the final MRI follow-up. The mean volume reduction was 69% (ranging from 47 to 87%). No tumor progression, ARE or radiation-related toxicity developed in any of the cases. The KPS scores of all patients were the same or had increased, and the neurological functions were all stable without deterioration at the final follow up. CONCLUSION: In our observations, GKRS was found to be an effective and safe alternative as adjuvant therapy for pathology-confirmed CN. The tumor volume and functional outcome can be controlled with a favorable result in long-term observation. Compared with RT and microsurgery, GKRS plays an important role in the treatment of CN as a minimally invasive technique with low morbidity. Regular long-term MRI follow-up should be mandatory to document the tumor response and possible recurrence. Multicenter consortia should be considered for further investigation and evaluation of GKRS for such a rare tumor. PMID- 21546790 TI - Violence and self-reported health: does individual socioeconomic position matter? AB - BACKGROUND: Violence is a major public health problem. Both clinical and population based studies shows that violence against men and women has physical and psychological health consequences. However, elsewhere and in Sweden little is known of the effect of individual socioeconomic position (SEP) on the relation between violence and health outcomes. OBJECTIVE: This study aimed to assess the effect of individual SEP on the relation between violence and three health outcomes (general health, pain and anxiety) among women in Stockholm County. METHODS: The study used data from the Stockholm Public Health Survey, a cross sectional survey carried out in 2006 for the Stockholm County Council by Statistic Sweden. 34 704 respondents answered the survey, the response rate was sixth one percent. Analyses were carried out using descriptive statistics and logistic regression analysis in SPSS v.17.0. RESULTS: Individual SEP increased the odds of reporting poor health outcomes among victimized women in Stockholm County. Regarding self-reported health women in low-SEP who reported victimization in the past twelve months had odds of 2,36 (95% CI 1.48-3.77) for the age group 18-29 years and 3.78 (95% CI 2.53-5.64) for the age group 30-44 years compared with women in high-SEP and non-victim. For pain the odds was 2,41 (95% CI 1,56-3,73) for the age group 18-29 years and 2,98 (95% CI 1,99-4,46) for women aged 30-44 years. Regarding anxiety the age group 18-29 years had odds of 2,53 (95% CI 1,58-4,03) and for the age group 30-44 years had odds of 3,87 (95% CI 2,55-5,87). CONCLUSION: Results showed that individual SEP (measured by occupation) matters to the relationship between violence and health outcomes such as general self-reported health, pain and anxiety. Women in lower SEP and experienced victimization in the past twelve months had increased odds of reporting poorer self-rated health, pain and anxiety compared to those in higher SEP with no experience of victimization. However, further exploration of the relationship between poverty, individual SEP is needed using other Swedish population samples. PMID- 21546791 TI - Methanol elicits the biosynthesis of 4-coumaroylserotonin and feruloylserotonin in rice seedlings. AB - Rice (Oryza sativa cv. Dongjin) plants responded to treatment with methanol by inducing the synthesis of secondary metabolites such as serotonin derivatives which include feruloylserotonin and 4-coumaroylserotonin. This response was not only a dose dependence on methanol showing a maximum effect with 1% methanol concentration, but also methanol specific. No other solvents such as ethanol, atetaldehyde, isopropanol, formaldehyde, and formic acid showed the induced synthesis of serotonin derivatives as methanol did. The methanol induced synthesis of serotonin derivatives was completely blocked by the addition of abscisic acid (ABA), and significantly inhibited by the additions of zeatin and indoleacetic acid (IAA). However, gibberellic acid (GA) had little effect on the action of methanol. Finally, the induced synthesis of serotonin derivatives upon methanol treatment was closely associated with the transient increase in the activity of key enzyme of serotonin N-hydroxycinnamoyl transferase (SHT) which catalyzes the condensation of serotonin and phenolic-CoA into serotonin derivatives. PMID- 21546792 TI - Seventh world congress on vaccines, immunisation and immunotherapy. PMID- 21546793 TI - Letter from the editor. PMID- 21546794 TI - Novel therapeutic vaccine: granulysin and new DNA vaccine against Tuberculosis. AB - PURPOSE: Multi-drug resistant (MDR) Mycobacterium Tuberculosis (M.TB) is a big problem in the world. We have developed novel TB therapeutic vaccines. METHODS AND RESULTS: DNA vaccine expressing mycobacterial heat shock protein 65 and IL-12 was delivered by the hemagglutinating virus of Japan (HVJ)-envelope. M. TB, MDR TB or extremenly drug resistant (XDR-TB) was injected i.v. into DBA/1 mice, and treated with the vaccine three times. This HVJ-E/Hsp65DNA+IL-12DNA vaccine provided strong therapeutic efficacy against MDR-TB and XDR-TB (prolongation of survival time and the decrease in the number of TB) in mice. Therapeutic effect of this vaccine on TB infection was also demonstrated in chronic TB infection murine model using aerosol infection intratracheally. On the other hand, granulysin protein produced from CTL has lethal activity against TB. Granulysin protein vaccine also exerted strong therapeutic effect. Furthermore, we extended our studies to monkey model, which is currently the best animal model of human TB. Hsp65DNA+IL-12 DNA vaccine exerted strong therapeutic efficacy (100% survival and augmentation of immune responses) in the TB-infected monkeys. In contrast, the survival of the saline control group was 60% at 16 week post-challenge. HVJ Envelope/HSP65 DNA+IL-12 DNA vaccine increased the body weight of TB-infected monkeys, improved the erythrocyte sedimentation rate, and augmentated the immune responses (proliferation of PBL and IL-2 production). The enhancement of IL-2 production from monkeys treated with this vaccine was correlated with the therapeutic efficacy of the vaccine. CONCLUSION: These data indicate that novel vaccines might be useful against TB including XDR-TB and MDR-TB for human therapeutic clinical trials. PMID- 21546795 TI - Epidemiological changes after PCV7 implementation in Italy: perspective for new vaccines. AB - The emergence of serotypes not included in 7-valent pneumococcal conjugate vaccine (PCV7), so-called "replacement", could erode the great advantage offered by vaccination. The effect of the replacement phenomena is very variable in different Countries and depends on one or more of several factors i.e. serotype before PCV7 implementation, PCV7 coverage, period from PCV implementation, vaccination schedule, antibiotic use, etc. The long-term epidemiological picture in Europe regarding serotype change is limited because of the relatively recent introduction of PCV7 - the majority of European Countries have only experienced PCV implementation since 2006 - and the difficulty in reaching very high vaccination coverage. In May 2003, a large-scale program of vaccination against Streptococcus pneumoniae with PCV7 was started in Liguria achieving coverage higher than 90%. The results of this program anticipate the results likely to be achieved when high coverage has been reached in Europe for a period of several years. The project included the immunogenicity evaluation of the co administration of PCV7 and exavalent vaccine using the 3-5-11 month schedule, effectiveness evaluation and the active and passive surveillance system of invasive pneumococcal disease (IPD) and non-IPD. Since the beginning of PCV7 implementation, the proportion of PCV7 serotype has declined and in 2009-10 it accounted for about 10% of all Streptocuccus pn responsible for IPD and non-IPD. The new 13-valent pneumococcal conjugate vaccine, available since July 2010, will offer a significant added benefit covering about 90%, 100% of IPD and more than 40% and 60% of non-IPD detected in pre-school and school children, respectively, after PCV7 introduction. PMID- 21546797 TI - HBc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state. AB - HBV covalently closed circular DNA (cccDNA) is the template for the transcription of HBV. HBV core protein (HBc) is a main component of the HBV cccDNA minichromosome. However, the function of HBc in cccDNA is not fully understood. In light of recent findings that HBV cccDNA may be regulated epigenetically, we analyzed the binding of HBc to cccDNA and the impact of HBc on cccDNA epigenetic profile in the liver biopsy samples of 22 patients with chronic Hepatitis B (CHB). We found that HBc binding to HBV cccDNA occurred preferentially at CpG island 2, an important region for the regulation of HBV transcription. Furthermore, the relative abundances of HBc binding to CpG island 2 were positively correlated with the ratios of relaxed circular DNA to cccDNA and the levels of serum HBV DNA in those patients. Interestingly, the relative abundances of HBc binding to CpG island 2 were associated with the binding of CREB binding protein (CBP) and with hypomethylation in CpG island 2 of HBV cccDNA minichromosomes. However, relatively higher amounts of HBc binding to CpG island 2 of cccDNA were accompanied by lower amounts of HDAC1 binding. Multivariate analysis revealed that the abundances of HBc binding to CpG island 2 of cccDNA and positive HBeAg were independent factors associated with the replication of HBV (p = 0.001 for both). Apparently, HBc is a positive regulator of HBV transcription and replication, maintaining the permissive epigenetic state in the critical region of the HBV cccDNA minichromosomes. PMID- 21546796 TI - GIV/Girdin is a rheostat that fine-tunes growth factor signals during tumor progression. AB - GIV/Girdin is a multidomain signaling molecule that enhances PI3K-Akt signals downstream of both G protein-coupled and growth factor receptors. We previously reported that GIV triggers cell migration via its C-terminal guanine-nucleotide exchange factor (GEF) motif that activates Galphai. Recently we discovered that GIV's C-terminus directly interacts with the epidermal growth factor receptor (EGFR), and when its GEF function is intact, a Galphai-GIV-EGFR signaling complex assembles. By coupling G proteins to growth factor receptors, GIV is uniquely poised to intercept the incoming receptor-initiated signals and modulate them via G protein intermediates. Subsequent work has revealed that expression of the highly specialized C-terminus of GIV undergoes a bipartite dysregulation during oncogenesis-full length GIV with an intact C-terminus is expressed at levels ~20 50-fold above normal in highly invasive cancer cells and metastatic tumors, but its C-terminus is truncated by alternative splicing in poorly invasive cancer cells and non-invasive tumors. The consequences of such dysregulation on graded signal transduction and cellular phenotypes in the normal epithelium and its implication during tumor progression are discussed herein. Based on the fact that GIV grades incoming signals initiated by ligand-activated receptors by linking them to cyclical activation of G proteins, we propose that GIV is a molecular rheostat for signal transduction. PMID- 21546798 TI - Increased expression of monocyte tissue factor and soluble CD40 ligand at mid term follow-up following percutaneous coronary intervention. PMID- 21546801 TI - Aborted sudden cardiac death in adolescent. AB - Sudden cardiac death is rare in children and adolescents but accounts for 19% to 30% of sudden deaths until 21 years of age. Fatal ventricular arrhythmias are usual common pathways in such tragic events, and underlying etiologies include cardiac ion channelopathies in majority of cases. We present a case of aborted sudden cardiac death in field, resuscitated successfully, and a clinical event in the pediatric emergency department that led to the diagnosis of the underlying rare condition. PMID- 21546802 TI - Tension chylothorax complicating acute malignant airway obstruction. AB - Acute upper airway obstruction represents one of the most challenging emergencies in pediatric practice. In particular, a tension chylothorax complicating a malignant airway obstruction is a rare and life-threatening complication. We report a rapidly progressing tension chylothorax associated with a cervical mass in a 10-month-old male infant. To our knowledge, the extension of a cervical mass to the supraclavear region resulting in a compressive chylothorax represents an exceptional event in pediatrics. Early recognition and prompt treatment resulted to be essential to relieve the compression and to avoid end-stage hemodynamic and respiratory function derangement. PMID- 21546803 TI - Cranial impalement in a child driving an all-terrain vehicle. AB - BACKGROUND: All-terrain vehicle (ATV) injury is a serious problem in children and adolescents. We report an unusual case of a child with cranial impalement in a rollover ATV crash. CASE: An 8-year-old, reportedly helmeted, was driving an ATV uphill when it rolled over causing cranial impalement of the brake handle just above the left ear. The child was awake and alert at the scene and on arrival in the pediatric emergency department. The child was taken to the operating room where he underwent fiber-optic intubation followed by removal of the brake handle. He was discharged home after 3 days with a normal neurological examination. CONCLUSIONS: All-terrain vehicle injury is an increasing problem in children. This case demonstrates that serious injury can occur even while wearing a helmet. The case demonstrates the dangers associated with children driving or riding ATVs. PMID- 21546804 TI - Transverse divergent dislocation of elbow in a child: a case report and review of current literature. AB - We present a case report on transverse divergent dislocation of the elbow, highlighting the spatial relation among the proximal radius, ulna, and distal humerus in this rare pediatric elbow injury and reasons leading to misinterpretation of radiographs. Elbow dislocation is a rare injury in children. It comprises only 6% of pediatric elbow injuries. Most pure dislocations are posterior, but they can occur in any direction. Divergent dislocation of the elbow is a subgroup of posterior dislocation, which is extremely rare. It is important that the pediatric emergency physician is aware, able to identify, and manage this injury. It is defined as a specific elbow dislocation in which the distal humerus is forced between the proximal radius and ulna, resulting in the divergence of the proximal forearm bones. Joint laxity is said to be a predisposing cause in pediatric age group. Atraumatic divergent dislocation of the elbow has been reported in the adults with rheumatoid arthritis. Imaging is challenging because there is no defined specific radiological views, therefore making the diagnosis difficult. This often leads to misdiagnosis or inappropriate treatment. A thorough understanding of mechanism of injury and basis for atypical radiological findings will help in identifying the injury early, and the simple Thompson technique to relocate the elbow will give an excellent functional outcome. PMID- 21546805 TI - Acute appendicitis presenting with a painful inguinal mass: complication related to patent processus vaginalis and testicular maldescent. AB - Appendicitis with or without perforation is a common pediatric emergency department diagnosis, as are the findings of patent processus vaginalis and cryptorchidism. We describe the unique presentation of perforated appendicitis complicated by a tender inguinal mass resulting from the presence of purulence as well as a cryptorchid but viable testis within a patent processus vaginalis. We describe our diagnostic approach and review the literature relevant to inguinoscrotal presentations of appendicitis. PMID- 21546806 TI - Deep vein thrombosis: rare cases of diagnoses in a pediatric emergency department. AB - Deep vein thrombosis (DVT) has an estimated annual incidence of 0.07/10,000 children. Early diagnosis suspicion in the emergency department is important because it is a serious disease that, if untreated, can lead to a postthrombotic disease or a pulmonary thromboembolism. We report 2 cases of DVT whose diagnosis was made in the pediatric emergency department. Case 1 is a 9-year-old boy, evaluated with corticodependent nephrotic syndrome, who presented with pain in the lower left limb and increase in size of 48 hours' evolution suggestive of DVT. The elevation of D-dimer in the blood analysis and images from the Doppler ultrasound confirmed the diagnosis. His clinical evolution was good after beginning treatment with low molecular weight heparin. Case 2 is a 16-year-old adolescent, mother of a 1-year-old infant, who took oral contraceptives and was an occasional smoker, showed increased size and had pain in the lower left limb of a few hours' evolution. Deep vein thrombosis was suspected, and the diagnosis was confirmed by Doppler ultrasound. The evolution was favorable after beginning treatment with low molecular weight heparin. Although DVT is rare in children, early detection is important, requiring a detailed case history in the presence of edematous, painful, and hot limbs that are keys to the diagnostic suspicion. The imaging test and the laboratory tests will confirm the diagnosis, and anticoagulant treatment will prevent complications. PMID- 21546807 TI - Arm pain and fever as an unusual presentation of lobar pneumonia in a 3-year-old girl: case report. AB - Children with pneumonia presenting with extrathoracic pain, such as abdominal pain, have been previously described. In this report, we describe a 3-year-old girl with fever and right arm pain who was found to have an apical lobar pneumonia. PMID- 21546808 TI - Internal carotid artery pseudoaneurysm with life-threatening epistaxis as a complication of deep neck space infection. AB - Pseudoaneurysm of the cervical internal carotid artery is a very rare, potentially fatal complication of a neck space infection in children associated with high mortality and morbidity. A 3-year-old boy presented with spontaneous massive epistaxis 45 days after a deep neck space infection caused by a peritonsillar abscess. During nasopharyngeal packing, he evolved with cardiac arrest. Intra-arterial angiography was then performed that revealed a large pseudoaneurysm. Endovascular treatment using detachable balloons achieved complete exclusion of the pseudoaneurysm. The child made an uneventful recovery and was discharged with mild left hemiparesis and no deficit of sensory or cognitive functions. Pseudoaneurysms of the internal carotid artery after a deep neck space infection can be associated with delayed and potentially fatal massive epistaxis. Furthermore, a regional (ie, extranasal) blood vessel should be promptly investigated when there are signs of hypovolemic shock. A high level of suspicion and definitive treatment are essential for successful management of these patients. PMID- 21546809 TI - Diagnosis of an intraventricular hemorrhage by a pediatric emergency medicine attending using point-of-care ultrasound: a case report. AB - For the past 2 decades, point-of-care ultrasound (POCU) has been increasingly performed in adult emergency medicine for a variety of indications. However, the incorporation of POCU into pediatric emergency medicine has been much slower. Cranial ultrasound is an integral part in neonatology and is routinely used to diagnose intraventricular hemorrhage (IVH). Although cranial ultrasound is not considered a core emergency ultrasound application in the 2008 American College of Emergency Physicians ultrasound guidelines, this novel approach may prove beneficial in the emergency department (ED) setting. We report a case of a 16-day old male that presented to the pediatric ED with fussiness and found to be anemic. An IVH was diagnosed for the first time using POCU by a pediatric ED attending. Sonographic characteristics of an IVH may be helpful in the prompt diagnosis of this condition, thereby reducing morbidity and mortality and improving the final outcome. PMID- 21546810 TI - Elastic bands on the wrist: a not so "silly" complication. AB - The recent popularity of elastic bands on the wrist may put children at risk for acute compartment syndrome. Acute compartment syndrome is a limb-threatening condition characterized by elevated interstitial pressure in a confined fascial compartment. If left untreated, it may result in tissue necrosis, irreversible nerve and muscle injury, and permanent functional impairment. We report a case of a 21/2-year-old girl with history of a rubber band around her wrist, who presented to the emergency department with a swollen, blue hand suggestive of an impending compartment syndrome. Although this patient ultimately was not diagnosed with acute compartment syndrome, we discuss the importance of prevention, early diagnosis, and prompt treatment of compartment syndrome to prevent permanent disability. PMID- 21546811 TI - Peritoneal inclusion cyst. PMID- 21546812 TI - Near-infrared spectroscopy in the critical setting. AB - Near-infrared spectroscopy is a noninvasive means of determining real-time changes in regional oxygen saturation of cerebral and somatic tissues. Hypoxic neurologic injuries not only involve devastating effects on patients and their families but also increase health care costs to the society. At present, monitors of cerebral function such as electroencephalograms, transcranial Doppler, jugular bulb mixed venous oximetry, and brain tissue oxygenation monitoring involve an invasive procedure, are operator-dependent, and/or lack the sensitivity required to identify patients at risk for cerebral hypoxia. Although 20th century advances in the understanding and management of resuscitation of critically ill and injured children have focused on global parameters (ie, pulse oximetry, capnography, base deficit, lactate, etc), a growing body of evidence now points to regional disturbances in microcirculation that will lead us in a new direction of adjunctive tissue monitoring and response to resuscitation. In the coming years, near-infrared spectroscopy will be accepted as a way for clinicians to more quickly and noninvasively identify patients with altered levels of cerebral and/or somatic tissue oxygenation and, in conjunction with global physiologic parameters, guide efficient and effective resuscitation to improve outcomes for critically ill and injured pediatric patients. PMID- 21546814 TI - Survey science in pediatric emergency medicine. AB - Surveys conveniently acquire and summarize valuable information from a target population. The specific aims, design, target sample, mode of distribution, data analysis, and inherent limitations of the survey methodology should be carefully considered to maximize the validity of the results. This review provides guidance on the methods and standards necessary to complete sound survey science. PMID- 21546815 TI - ECGs in the ED. PMID- 21546816 TI - Wire cutters and penis skin entrapped by zipper sliders. PMID- 21546817 TI - Affective disorder and suicide attempt in a child after carbon monoxide poisoning: close follow-up is imperative. PMID- 21546818 TI - Glucose metabolism disturbances in acute pediatric illness. PMID- 21546820 TI - Forearm bones and sexual variation in Turkish population. AB - Forensic anthropologists are aware that there are considerable differences between human populations and therefore develop study models for each skeletal population. The purpose of this study was to analyze forearm bones obtained from forensic settings in Turkey. The sample consists of 42 males and 38 females with an average age of 40 and 36 years, respectively. Numerous measurements were taken from the radius and ulna including lengths (in millimeters), midshaft diameters, and epiphyseal breadths (0.01 mm). Individuals with any anomaly and pathology were not included in the investigation. A stepwise analysis, when applied to individual bones, selected only length and midshaft transverse dimension in the radius and length only in the ulna. When the length was excluded from the statistic, head diameter and distal breadth of the radius and distal minimum head and midshaft anteroposterior diameters of the ulna provided the best predicting functions. Classification results were 92% for the radius and 91% for the ulna. For the incomplete bones, the accuracy rates were about 92% and 83%, respectively. In conclusion, a sex determination was made, in different rates of accuracy, in the human skeleton. Correct assessment can vary among populations. Dimorphism in our region forearm bones is greater than American whites. This supported the hypothesis that human variation is diverse, and population difference should be taken into account when osteometric standards are applied to others. Further studies are needed to understand why the forearm is more dimorphic in Turks. PMID- 21546821 TI - Behavior of expelled glass fragments during projectile penetration and perforation of glass. AB - Bullets striking common forms of flat glass with an orthogonal intercept angle result in a cloud of ejected glass fragments that are in concert with the exiting bullet's flight path. This is not the case with strikes at angles other than orthogonal. In these situations, the expelled glass fragments follow a very different course from that of the exiting projectile. This is both counterintuitive and a potential source of serious error in the evaluation and reconstruction of a shooting victim's position and orientation at the moment the victim was struck by a bullet that has passed through a nearby source of glass such as a vehicle side window or a window in a building. The flight path of the ejected glass fragments is, however, predictable and is dictated by the orientation of the plane of the glass opposite the projectile's impact site.In all cases, these expelled glass particles have considerable velocity and can produce pseudostippling of the skin in individuals located downrange of bullet struck glass and near the projectile's exit site. The distribution and location of such pseudostippling and its relationship to the associated bullet hole in glass have important reconstructive value. A proper and reliable reconstruction of the victim's position in such cases will require the integration of scene information with the autopsy findings. PMID- 21546822 TI - The importance of histological evaluation in death investigation: two cases of fatal proximal airway masses. AB - A recent prospective study published in the American Journal of Forensic Medicine and Pathology concluded that routine histopathologic examination lacked value. We disagreed with this assertion as we have found routine microscopic examination to be fruitful by documenting gross findings and by revealing interesting and unexpected findings.We designed a retrospective study to determine the benefit and cost of routine histopathologic examination at our institution. Forensic autopsy cases from January 2004 through June 2007 with lethal gross findings were reviewed to determine the number of cases in which microscopic examination provided the definitive cause of death. Cost was based on the average number of hematoxylin-eosin-stained slides per autopsy.One case was found in which the microscopic findings determined the correct cause of death despite compelling history and the initial impression from the autopsy findings. The cost of routine histopathologic examination during this period was approximately $39,000.We conclude that routine histopathologic examination has value. Despite having a low yield, the information it provides is nonetheless important, and its cost is not prohibitive. Furthermore, there are benefits gained from routine microscopic examination as exemplified in the 2 case reports presented in this article. PMID- 21546823 TI - Accidental azygos vein extracorporeal membrane oxygenation cannulation in a neonate with premature closure of the ductus arteriosus. AB - Our group describes a rare complication of inadvertent azygos vein cannulation during initiation of extracorporeal membrane oxygenation (ECMO) in a neonate with prenatal closure of the ductus arteriosus in a neonate born at an outlying facility and referred for possible congenital heart disease. Upon initial echocardiogram, no flow in the ductus arteriosus was present despite being maintained on prostaglandins. He necessitated ECMO support and the azygos vein was inadvertently cannulated. Lateral chest radiograph suggested placement of cannula in the azygos vein, and this was confirmed by echocardiography. Replacement of venous ECMO cannula with echocardiographic visualization of guide wire position restored ECMO flow. This report emphasizes the importance of lateral chest radiograph and prompt echocardiographic guidance at the time of ECMO cannulation particularly in clinical scenarios associated with azygos vein dilatation or elevated pressures in the right atrium or superior vena cava. PMID- 21546824 TI - Clinical experience and patient outcomes associated with the TandemHeart percutaneous transseptal assist device among a heterogeneous patient population. AB - There is a paucity of literature describing the outcomes associated with the use of TandemHeart percutaneous ventricular assist device (PVAD). The literature is limited by analyzing only subsets of patients. We present the clinical outcomes and safety associated with the use of TandemHeart among a series of heterogeneous patients requiring PVAD support. We reviewed the clinical experience, hemodynamic variables, survival outcomes, and complications associated with the implantation of TandemHeart support device among 25 patients presenting to our institution. Indications for PVAD implantation were cardiogenic shock (56%), ST-segment elevation myocardial infarction (STEMI) (20%), postpericardiotomy (16%), and high risk percutaneous coronary interventions (PCI) or ventricular tachycardia (VT) ablation (8%). TandemHeart was used for an average of 4.8 +/- 2.1 days and demonstrated significant hemodynamic improvements (pre- and postimplantation left ventricular ejection fractions were 21.5% +/- 15% and 24.5% +/- 10.5%, respectively [p = 0.06]). The cardiac index improved from a mean 2.04 +/- 075 L/min/m2 to 2.45 +/- 073 L/min/m2 (p = 0.09). The mixed venous oxygen saturation (SVO2) increased from 55.14 +/- 13.34 to 66.43 +/- 7.43 (p = 0.008) after implantation. TandemHeart was used as a bridge to left ventricular assist device implantation (44%) or recovery (20%). Thirty-six percent of patients died on support or shortly after PVAD removal. Thirty, 90-day, and long-term (>90 days) survival rates were 56%, 52%, and 36%, respectively. Procedure-related complications were reported in 13 patients (56%), and the majority (90%) was related to vascular access (bleeding or pseudoaneurysm). The TandemHeart device is a safe therapeutic option as a bridge-to-recovery or bridge-to-bridge for patients with hemodynamic compromise regardless of the etiology. The favorable hemodynamic profile, postimplantation survival rates, and manageable complications support its use to assist hemodynamic recovery in patients refractory to conventional therapy. PMID- 21546825 TI - One arm exercise induces significant interarm diastolic blood pressure difference. AB - OBJECTIVES: This study is designed to investigate the inducing effect of one arm exercise on interarm difference (IAD) in the blood pressure (BP). METHODS: Fifty healthy young participants were included in the study. Three-minute exercises of the right arm elbow flexion and extension were performed. The bilateral brachial BP was simultaneously measured with two automatic BP measurement devices before (basic) and immediately 0, 5, 10, 15, 20, and 30 min after exercise. The absolute difference in the systolic BP (SBP) and diastolic BP (DBP) between the left and right BP of at least 10 mmHg was recognized as sIAD and dIAD. RESULTS: The baseline data of the SBP and DBP in left and right arms revealed no significant difference (SBP: 110 +/- 10 vs. 111 +/- 11 mmHg; DBP: 66 +/- 8 vs. 66 +/- 9 mmHg, both not significant). The prevalence of dIAD was 2% at the baseline. However, this prevalence increased to 80% at 0 min, as right arm exercise induced the right DBP decrease and left DBP increase, and then the prevalence decreased gradually within a 30-min recovery period. The prevalence of sIAD was zero at the baseline and the maximal prevalence was 8% during the 20-min postexercise period. CONCLUSION: One arm exercise can lead to a significant IAD in DBP. Any arm exercise should be avoided before BP measurement. PMID- 21546826 TI - Design and implementation of an interdisciplinary pediatric mock code for undergraduate and graduate nursing students. AB - Higher patient acuity and shortage of healthcare professionals have led to an expansion in the role and responsibilities for nurses, and ultimately, nursing students. Nursing faculty are challenged to develop strategies based on core competencies to obtain optimal practice within this complex system. Use of patient simulators is an effective strategy as it allows for deliberate practice of skills and standardized exposure to limited scenarios. The rarity of pediatric codes and opportunities for students to interact in teams led faculty to develop an interdisciplinary pediatric mock code simulation. Senior baccalaureate students function as members of a pediatric code team with emergency nurse practitioner students as code team leaders. Student preparation included Web based information and an interactive class on code skills and team communication during a sentinel event. The scenario incorporated team roles and family-centered care. The debriefing session reinforced the evidence and reviewed quality improvement and safety through error identification and patient consequences. A total of 43 BSN students and 12 emergency nurse practitioner students participated. The simulation was rated very highly for realism, enjoyment, concept clarification in debriefing, increasing knowledge base, ability to function in the clinical setting, and increasing confidence in caring for a critically ill infant. PMID- 21546827 TI - Brachydactyly: a rare complication of sickle cell anaemia. PMID- 21546830 TI - Strengthening health systems through HIV monitoring and evaluation in Sub-Saharan Africa. AB - PURPOSE OF REVIEW: In this review, we describe the challenges faced by using clinical cohorts to perform Monitoring and Evaluation (M&E) and the possible solutions for increasing and strengthening health systems in low-income and middle-income countries. RECENT FINDINGS: HIV scale-up has facilitated the transition from paper-based medical records to electronic medical records at hundreds of sites in most of the countries in sub-Saharan Africa and the implementation of national HIV databases. However, National M&E systems in resource-limited settings tend to be chronically challenged by persistently incomplete reporting and inaccurate data, which undermines their usefulness. In low-income and middle-income countries, new information technologies such as Web based systems and mobile phone networks are expanding rapidly. Their use will improve data quality and, therefore, reduce participant dropout and improve reporting rates. These systems have the potential to allow real time access to summary reports and to integrate data from other settings such as maternal and infant health clinics. SUMMARY: The efforts to address the AIDS pandemic in sub Saharan Africa will require enhanced information systems. Stronger systems are needed to deliver primary healthcare for those with and without HIV, and it is also essential to build and take advantage of synergies across health information systems. PMID- 21546829 TI - The spectrum of large granular lymphocyte leukemia and Felty's syndrome. AB - PURPOSE OF REVIEW: Patients with chronic large granular lymphocyte (LGL) leukemia often have rheumatoid arthritis (RA), neutropenia and splenomegaly, thereby resembling the manifestations observed in patients with Felty's syndrome, which is a rare complication of RA characterized by neutropenia and splenomegaly. Both entities have similar clinical and laboratory presentation, as well as a common genetic determinant, HLA-DR4, indicating they may be part of the same disease spectrum. This review paper seeks to discuss the underlying pathogenesis and therapeutic algorithm of RA, neutropenia and splenomegaly in the spectrum of LGL leukemia and Felty's syndrome. RECENT FINDINGS: We hypothesize that there may be a common pathogenic mechanism between LGL leukemia and typical Felty's syndrome. Phenotypic and functional data have strongly suggested that CD3 LGL leukemia is antigen-activated. Aberrations in the T-cell repertoire with the emergence of oligoclonal/clonal lymphoid populations have been found to play a pivotal role in pathogenesis of RA. The biologic properties of the pivotal T cell involved in RA pathogenesis are remarkably similar to those in leukemic LGL. SUMMARY: RA associated T-cell LGL leukemia and articular manifestations of typical Felty's syndrome are not distinguishable. A common pathogenetic link between LGL leukemia and RA is proposed. PMID- 21546832 TI - What did we learn on host's genetics by studying large cohorts of HIV-1-infected patients in the genome-wide association era? AB - PURPOSE OF REVIEW: Genome-wide association studies (GWASs) performed in large cohorts of HIV-1-infected patients have shown that high throughput genomics can add valuable information in understanding disease progression. We report recent information gathered in the international field during the last few years and revisit the importance of well documented cohorts for genotype-phenotype association studies. RECENT FINDINGS: The majority of GWASs in the HIV-1 field found that viral loads and disease progression are under the control of variants located in the major histocompatibility complex (MHC) in untreated patients. Although these experiments brought a new and more objective vision of genotype phenotype correlations in HIV-1 disease, they also pointed out that less than 15% of the observed phenotypic variability can be explained as common genetic variants. Most of the studies have included mainly white patients and the few studies performed in Africans are underpowered but suggest that MHC is probably not the only genetic determinant influencing disease progression in this population. SUMMARY: Although the first results of the GWASs in HIV disease look as a confirmation of previous findings, high throughput agnostic genomics entered the field of chronic infectious diseases and will probably unveil new genotype phenotype associations in the future. Networks between existing cohorts leading to 'virtual mega-cohorts' will be necessary to increase the probability to discover new genetic pathways important for HIV disease. Finally, predictive models including genetic information for clinical usage is another challenge in HIV disease genetics. PMID- 21546828 TI - The biology of CD44 and HCELL in hematopoiesis: the 'step 2-bypass pathway' and other emerging perspectives. AB - PURPOSE OF REVIEW: The homing and egress of hematopoietic stem and progenitor cells (HSPCs) to and from marrow, respectively, and the proliferation and differentiation of HSPCs within marrow are complex processes critically regulated by the ordered expression and function of adhesion molecules that direct key cell cell and cell-matrix interactions. The integral membrane molecule CD44, known primarily for its role in binding hyaluronic acid, is characteristically expressed on HSPCs. Conspicuously, human HSPCs uniquely display a specialized glycoform of CD44 known as hematopoietic cell E-/L-selectin ligand (HCELL), which is the most potent ligand for both E-selectin and L-selectin expressed on human cells. This review focuses on recent advances in our understanding of the biology of CD44 and HCELL in hematopoiesis. RECENT FINDINGS: New data indicate that CD44 mediated events in hematopoiesis are more complex than previously imagined. Ex vivo glycan engineering has established that HCELL serves as a 'bone marrow homing receptor'. Moreover, biochemical studies now show that CD44 forms bimolecular complexes with a variety of membrane proteins, one of which is VLA-4. Engagement of CD44 or of HCELL directly induces VLA-4 activation via G-protein dependent signaling, triggering a 'step 2-bypass pathway' of cell migration, and extravascular lodgment, in absence of chemokine receptor engagement. SUMMARY: Recent studies have further clarified the roles of CD44 and its glycoform HCELL in hematopoietic processes, providing key insights on how targeting these molecules may be beneficial in promoting hematopoiesis and in treating hematologic malignancies. PMID- 21546833 TI - Neurocognitive impairment and neuroCART. AB - PURPOSE OF REVIEW: To review recent cohort studies that have examined the relationship between combination antiretroviral therapy (cART) regimens with superior central nervous system (CNS) penetration (neuroCART) in the prevention, treatment and subsequent survival of patients with HIV-associated neurocognitive disorders (HAND). RECENT FINDINGS: HAND remains prevalent including within virologically suppressed populations. The CNS-penetrating effectiveness (CPE) scoring system is an important and evolving tool to determine the therapeutic role of neuroCART in HAND patients. NeuroCART was associated with improved survival in children with HIV encephalopathy and also in adults diagnosed with HIV-associated dementia during the pre and early-cART calendar periods. In one cohort study the benefit of neuroCART was best conferred when cART regimens with high CPE scores and containing more than three drugs were used. Recent data suggest also that neuroCART may be associated with CNS toxicity and poorer neurocognitive performance. SUMMARY: The therapeutic importance of neuroCART in the treatment of HAND remains a vitally relevant, unanswered question. Recent cohort studies have demonstrated that neuroCART may improve survival in children and adults with HIV dementia, although adults may require several drugs to receive full therapeutic benefit. NeuroCART/cART may be neurotoxic in some populations. A randomized controlled trial to address the role of neuroCART in HAND is needed. PMID- 21546831 TI - Cardiovascular disease in HIV infection. AB - PURPOSE OF REVIEW: Highly active antiretroviral therapy (HAART) use has markedly reduced AIDS-related mortality and opportunistic illness. With improved survival, cardiovascular disease (CVD) has emerged as an important noninfectious chronic comorbidity among antiretroviral (ARV)-treated HIV-infected persons. RECENT FINDINGS: HIV infection can impact CVD and comorbidities known to increase CVD risk. Untreated HIV can cause proatherogenic elevations in serum lipids. Chronic HIV viremia results in increases in systemic inflammation, hypercoagulation, and reductions in endovascular reactivity, all of which are at least partially reversible with virally suppressive HAART. Chronic T-cell activation can also result in adverse vascular effects. Use of some ARV drugs can impact CVD risk by causing pro-atherogenic serum lipid elevations, induction of insulin resistance, increases in visceral adiposity or subcutaneous fat loss. Abacavir use may increase myocardial infarction risk by reducing vascular reactivity and/or increasing platelet activation. Traditional risk factors such as advancing age, smoking, hyperlipidemia, and hypertension remain important predictors of CVD among HAART-treated HIV-infected persons. SUMMARY: HIV in the HAART era is a chronic manageable condition. CVD is an important cause of morbidity among HIV infected persons. Untreated HIV can increase CVD risk in several ways and these effects are at least partially reversible with successful treatment. Use of specific ARVs can adversely impact CVD risk but the multiple long-term benefits of chronic HIV suppression and immune reconstitution achievable with potent HAART outweigh the adverse impact upon CVD risks that they may have. Standard CVD screening and risk-reducing interventions should be routinely undertaken for HIV infected persons. PMID- 21546834 TI - Long-term immunological outcomes in treated HIV-infected individuals in high income and low-middle income countries. AB - PURPOSE OF REVIEW: To summarize the recent findings on long-term (at least 3-4 years) immunological responses to combination antiretroviral therapy (cART) and to compare and contrast the findings between cohorts from high-income and low middle income countries (LMICs). RECENT FINDINGS: Cohort studies from high-income settings suggest that a majority of treated HIV-infected patients who maintain suppressed HIV viremia experience a gradual increase in CD4 cell counts for several years to normal levels. However, those who start cART at CD4 cell counts less than 200 cells/MUl (as opposed to CD4 cell counts>200 cells/MUl) spend several more years below the safe CD4 cell count threshold of 500 cells/MUl. Cohorts from LMICs also report persistent improvements in CD4+ cell counts over first 4-5 years of follow-up. However, low-CD4 cell counts (<200 cells/MUl) at the start of cART, high early mortality, and loss to follow-up in LMICs settings suggest that the observed optimistic responses may be affected by survivorship bias and should be cautiously interpreted as the optimal, rather than an average, response in LMICs populations. SUMMARY: LMICs cohorts report similar immunological responses to cART as high-income countries in first 4-5 years of follow-up. Sustaining success in these settings is dependent on timely access to first-line and future cART options, efforts to reduce loss to follow-up, and implementation of treatment guidelines. Cohorts from LMICs are encouraged to continue improving treatment programs and to continue reporting outcomes over the next decade, as surveillance for potential future blunting in responses. PMID- 21546835 TI - Genetic manipulations in the rat: progress and prospects. AB - PURPOSE OF REVIEW: Several advances have been made to manipulate the rat genome in the last 2 years. This review aims to describe these advances in rat genetic manipulations, with an emphasis on their current status and their prospects and applications in the postgenomic era. RECENT FINDINGS: Authentic rat embryonic stem cells were derived in 2008 using the 2i/3i culture system. This led to the generation of the first gene knockout rats via embryonic stem cell-based gene targeting. The development of zinc-finger nucleases (ZFNs) provided an alternative approach that avoids the necessity of germline competent embryonic stem cells. Meanwhile, improvements have been made to the well established random mutagenesis mediated by transposons or N-ethyl-N-nitrosourea (ENU). The in-vitro rat spermatogonial stem cell (SSC) system has greatly optimized these phenotype driven approaches for future applications. SUMMARY: The rat has long been a prime model organism in physiological, pharmacological and neurobehavioral studies. The recent advances of rat reverse genetic approaches, together with the classical ENU and transposon mutagenesis system, will contribute tremendously to the deciphering of gene functions and the creation of rat disease models. PMID- 21546836 TI - Calcium supplementation: lessons from the general population for chronic kidney disease and back. AB - PURPOSE OF REVIEW: Concern that calcium use may increase cardiovascular risk was previously the domain of nephrologists. By contrast, calcium supplementation has been promoted within the general community as beneficial to the maintenance of bone mineral density, as an adjunct to osteoporosis therapies and as potentially useful for cardiovascular health. RECENT FINDINGS: Studies of patients with normal serum creatinine levels have reported that combined calcium and vitamin D supplementation reduced fracture risk, and osteoporosis trials have generally included calcium and vitamin D in placebo and active arms. However, an increased risk of myocardial infarction and other cardiovascular events has now been reported in secondary analysis of a fracture study of patients taking calcium or placebo, in subsequent meta-analysis of 15 similar studies, and most recently in re-analysis of the Women's Health Initiative calcium, vitamin D dataset. These reports have been criticized regarding event ascertainment, adjudication and the use of composite outcomes. SUMMARY: Patients with chronic kidney disease (CKD) have impaired renal calcium regulation, abnormal bone turnover and are predisposed to positive calcium balance. If these general population data are proven, they should heighten our unease regarding the use of calcium salts in all stages of CKD, and particularly for patients with prevalent vascular calcification, suspected adynamic bone and high bone turnover. PMID- 21546837 TI - Optimizing mental health services in low-income and middle-income countries. AB - PURPOSE OF REVIEW: Against the backdrop of a large burden and treatment gap for mental disorders in low-income and middle-income countries (LMICs), recently published articles were reviewed to assess strategies and actions for optimizing mental health services in LMICs. RECENT FINDINGS: Key strategies and actions are as follows: (i) the adoption of a decentralized stepped care approach embracing task shifting to nonspecialists for those disorders for which it has been shown to be effective; (ii) ensuring adequate numbers of mental health specialists to provide a supportive supervisory framework and referral pathways; (iii) ensuring adequate infrastructure to support decentralized care; (iv) promoting mental health literacy; (v) adoption of a social inclusion and developmental model of disability in caring for people with chronic mental illness; and (vi) embracing a multisectoral community collaborative approach. SUMMARY: Optimizing mental health services in LMICs requires legislation, policies and plans that are enabling of the above strategies and actions. Studies demonstrating the cost-effectiveness of integrated stepped packages of care embracing a task-shifting approach, and best practices for strengthening mental health literacy and collaborative arrangements with community caregivers and other sectors, can assist this process. Specialist mental health training programmes in LMICs also need to be responsive to the changing demands on service providers, incorporating a public health approach and equipping specialists for diversification of their roles within the task shifting model. PMID- 21546838 TI - Understanding and promoting resilience in children and youth. AB - PURPOSE OF REVIEW: In a context of global concern about the consequences of stress and extreme adversities, advances in theory and methods for studying human resilience have ushered in a new era of integrative, biopsychosocial research. This review highlights recent theory, findings, and implications of resilience research on young people. RECENT FINDINGS: Resilience research has shifted toward dynamic system models with multiple levels of interaction, including research on the neurobiology of stress and adaption, epigenetic processes, and disasters. Growing evidence indicates individual differences in biological sensitivity to negative and positive experiences, including interventions. Early experiences show enduring programming effects on key adaptive systems, underscoring the importance of early intervention. Studies of developmental cascades demonstrate spreading effects of competence and symptoms over time, with important implications for the timing and targeting of interventions. Disaster research suggests guidelines for planning to protect children in the event of large-scale trauma. SUMMARY: Research is integrating the study of resilience across system levels, with implications for promoting positive adaptation of young people faced with extreme adversity. However, studies on neurobiological and epigenetic processes are just beginning, and more research is needed on efficacy, as well as strategic timing and targeting, of interventions. PMID- 21546839 TI - Bipolar disorder and resembling special psychopathological manifestations in multiple sclerosis: a review. AB - PURPOSE OF REVIEW: The higher prevalence of psychiatric disorders in multiple sclerosis (MS) compared with the general population is well documented, with depression being the leading disorder. Apart from depression, other psychiatric disorders and symptoms such as bipolar disorder, pseudobulbar affect, euphoria sclerotica, anxiety and personality changes are also reported to be overpresented in MS patients. Psychiatric disorders in MS lead to significant disruption in patients' family, work and social life, affecting patients' quality of life in general. Moreover, they are reported to be associated with poorer adherence to MS medication. The literature concerning bipolar disorder and affect disorders in MS is rather scarce. The purpose of this article is to provide a critical review on the latter subject. RECENT FINDINGS: This review focuses upon the recent findings with regard to the epidemiology and the comorbidity rates of bipolar and affect disorders in MS, questions raised about the potential underlying mechanisms that could explain such a high comorbidity, diagnostic issues and the recent developments in the treatment of those psychiatric disorders in MS. SUMMARY: Despite the fact that the higher prevalence of psychiatric disorders in MS is well established, such disorders still remain underdiagnosed and undertreated. A shift in the clinical suspicion towards the psychiatric morbidity in MS patients and the optimal treatment of those disorders is fundamental. PMID- 21546840 TI - Transcatheter arterial chemoembolization for hepatocellular carcinoma in cirrhosis: influence on portal hypertension. AB - BACKGROUND: Transcatheter arterial chemoembolization (TACE) is a routine treatment for hepatocellular carcinoma in cirrhotic patients. Whether TACE influences the degree of portal hypertension remains uncertain. AIM AND PATIENTS: We retrospectively analyzed the clinical course of 283 TACE to investigate the incidence of variceal bleeding and ascites after the procedure. We also prospectively evaluated portal pressure by hepatic venous portal gradient (HVPG) before and within 3 days by TACE in a group of 15 patients. RESULTS: Before TACE, esophageal varices were present in 125 patients. Variceal bleeding occurred in three (1.5%) and ascites in two (1%) patients during the follow-up post-TACE. Patients with variceal bleeding were significantly older (P=0.019). In 15 patients who underwent portal pressure measurement before and within 3 days by TACE, HVPG was unchanged (mean 13.1 vs. 12.8 mmHg, P>0.05). CONCLUSION: In our series portal hypertension-related complications after TACE were rare and did not result in higher mortality. As TACE did not influence HVPG, the preventive ligation of esophageal varices before TACE does not seem justified. PMID- 21546841 TI - Genetic counseling following the detection of hemoglobinopathy trait on the newborn screen is well received, improves knowledge, and relieves anxiety. AB - PURPOSE: The primary purpose of newborn screening for hemoglobinopathies is the presymptomatic diagnosis and early treatment of sickle cell disease. Hemoglobinopathy traits detected on the newborn screening provide an opportunity for genetic counseling of families regarding the trait and information that may impact reproductive decisions of the parents. We describe the results of a study to determine the impact of newborn screening and genetic counseling on the lives of families in which an abnormal hemoglobin trait had been identified. METHODS: From June 2003 to December 2009, families of children with trait attending a clinic visit and receiving professional genetic counseling were asked to participate in a semistructured follow-up survey regarding their experience and the impact of genetic counseling on their families. RESULTS: Of the 300 patients seen in clinic during the specified time period, 209 consented to be recontacted and 114 have completed the survey. Eighty-five percent of responders reported knowing that the newborn screen had been performed, but only 55% understood the purpose of newborn screening. When asked about the effect of finding out that trait was present in their baby, 19% reported feeling guilty or upset, whereas 4% believed that their partner blamed them for the child's results. That genetic counseling was found to be beneficial was indicated by the fact that 99% reported that their questions were answered, 82% reported feeling less anxious, and 78% discussed the trait with their partner after the appointment. CONCLUSIONS: Genetic counseling after newborn screening relieves anxiety, provides knowledge, facilitates dialog within families and between partners about hemoglobinopathy trait, and was seen as a positive experience for the majority of responders. PMID- 21546842 TI - Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. AB - Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is a disorder of development of the vasculature characterized by telangiectases and arteriovenous malformations in specific locations. It is one of most common monogenic disorders, but affected individuals are frequently not diagnosed. The most common features of the disorder, nosebleeds, and telangiectases on the lips, hands, and oral mucosa are often quite subtle. Optimal management requires an understanding of the specific presentations of these vascular malformations, especially their locations and timing during life. Telangiectases in the nasal and gastrointestinal mucosa and brain arteriovenous malformations generally present with hemorrhage. However, complications of arteriovenous malformations in the lungs and liver are generally the consequence of blood shunting through these abnormal blood vessels, which lack a capillary bed and thus result in a direct artery-to-vein connection. Mutations in at least five genes are thought to result in hereditary hemorrhagic telangiectasia, but mutations in two genes (ENG and ACVRL1/ALK1) cause approximately 85% of cases. The frequency of arteriovenous malformations in particular organs and the occurrence of certain rare symptoms are dependent on the gene involved. Molecular genetic testing is used to establish the genetic subtype of hereditary hemorrhagic telangiectasia in a clinically affected individual and family, and for early diagnosis to allow for appropriate screening and preventive treatment. PMID- 21546843 TI - The psychosocial impact of Klinefelter syndrome and factors influencing quality of life. AB - PURPOSE: There is considerable information regarding the medical and cognitive aspects of Klinefelter syndrome yet little research regarding its psychosocial impact. This study investigates the personal impact of Klinefelter syndrome and the influence of age at diagnosis, clinical, social, and demographic factors on adult quality of life outcomes. METHODS: Men from across Australia, diagnosed with KS at different ages, were recruited through multiple sources. Participants completed a questionnaire assessing subjective well-being, body image, self esteem, mental health, social support, and general health. RESULTS: Eighty-seven individuals self-completed the questionnaire. All outcomes were much poorer for the study population than for the general male population. Individuals diagnosed later in life reported many of the same symptoms as those diagnosed at younger ages. Employment status, social support, and phenotypic features were the strongest predictors of psychosocial outcomes. Age at diagnosis was not as influential because it did not correlate with phenotypic severity score. CONCLUSION: This is the first quantitative study to show Klinefelter syndrome has a significant personal impact. Men diagnosed with Klinefelter syndrome later in life reported similar difficulties as those at younger ages, suggesting that they would benefit from early detection and intervention. Understanding factors influencing this can assist in providing adequate services to individuals with Klinefelter syndrome, their partners, families, and the health professionals caring for them. PMID- 21546844 TI - Early postseroconversion CD4 cell counts independently predict CD4 cell count recovery in HIV-1-postive subjects receiving antiretroviral therapy. AB - BACKGROUND: The relationship between CD4 T-cell counts determined soon after seroconversion with HIV-1 (baseline CD4), nadir CD4, and CD4 levels attained during highly active antiretroviral therapy (HAART) is unknown. METHODS: Longitudinal, including baseline (at or soon after HIV diagnosis), intermediate (nadir), and distal (post-HAART) CD4 T-cell counts were assessed in 1085 seroconverting subjects who achieved viral load suppression from a large well characterized cohort. The association of baseline with post-HAART CD4 T-cell count was determined after adjustment for other relevant covariates. RESULTS: A higher baseline CD4 T-cell count predicted a greater post-HAART CD4 T-cell count, independent of the nadir and other explanatory variables. Together, baseline and nadir strongly predicted the post-HAART CD4 count such that a high baseline and lower nadir were associated with a maximal immune recovery after HAART. Likelihood of recovery of the baseline count after HAART was significantly higher when the nadir/baseline count ratio was consistently >= 0.6. CONCLUSIONS: Among viral load suppressing seroconverters, the absolute CD4 T-cell count attained post-HAART is highly dependent on both baseline and nadir CD4 T-cell counts. These associations further support the early diagnosis and initiation of HAART among HIV-infected persons. PMID- 21546845 TI - Improving retention in the early infant diagnosis of HIV program in rural Mozambique by better service integration. AB - Low mother/infant retention has impeded early infant diagnosis of HIV in rural Mozambique. We enhanced the referral process for postpartum HIV-infected women by offering direct accompaniment to the location of exposed infant testing before discharge. Retrospective record review for 395 women/infants (September 2009 to June 2010) found enhanced referral was associated with higher odds of follow-up (adjusted odds ratio = 3.18, 95% confidence interval: 1.76 to 5.73, P < 0.001); and among those followed-up, earlier infant testing (median follow-up: 33 days vs. 59 days, P = 0.01) compared with women receiving standard referral. This simple intervention demonstrates benefits gleaned from attention to system improvement through service integration without increasing staff. PMID- 21546846 TI - Public funding of HIV/AIDS prevention, treatment, and support in California. AB - OBJECTIVES: To determine the amount of public financing for HIV/AIDS in California and its distribution among treatment, prevention, and support services. To determine the geographical distribution of public financing for HIV/AIDS within California. DESIGN: Data on HIV/AIDS expenditures were compiled across federal and state agencies supporting HIV/AIDS in fiscal year 2008. METHODS: Federal and state data on programs that finance HIV/AIDS treatment, prevention, and support services, including the Ryan White Program, the Centers for Disease Control and Prevention, and the California General Fund, were compiled. California-specific expenditures for Medicare and Medicaid were calculated from claims data. Other entitlement program spending was estimated from national HIV/AIDS data. Data on AIDS cases by county were obtained from the California State Office of AIDS. Mapping to California counties was accomplished with Arc-GIS software. RESULTS: Public funders accounted for approximately $1.92 billion in HIV/AIDS services in California in fiscal year 2008. Most (90.4%) supported treatment; prevention accounted for 6.4% and support services for 2.6%. The majority of treatment financing came from 2 Federal health entitlement programs, Medicare (36%), and Medicaid (28%). Counties with the highest case loads had lower expenditures per case, suggesting economies of scale. CONCLUSIONS: Treatment expenditures overshadow prevention spending. The dominance of entitlement programs in funding for HIV/AIDS treatment challenges policy makers to monitor the extent and quality of HIV/AIDS care in California. A unified health information system for HIV/AIDS that bridged the fragmented health payment system's data silos would benefit policy makers' efforts to monitor the delivery of HIV/AIDS services. PMID- 21546847 TI - Limited risk of drug resistance after discontinuation of antiretroviral prophylaxis for the prevention of breastfeeding transmission of HIV. AB - We evaluated 70 HIV-infected pregnant women with CD4+ cell count >350 cells per cubic millimeter who received zidovudine, lamivudine, and nevirapine from week 25 of gestation until 6 months after delivery and a 3-week tail of zidovudine and lamivudine at the moment of drug discontinuation. Forty days after the interruption of all drugs resistance mutations were present in 5 of 70 (7.1%) women. Two of them had the same mutation archived in baseline HIV DNA. The other 3 women had, at least once, detectable viral load and presence of mutations during treatment. Overall, the risk of developing resistance mutations in compliant women was low. PMID- 21546848 TI - High susceptibility to repeated, low-dose, vaginal SHIV exposure late in the luteal phase of the menstrual cycle of pigtail macaques. AB - Fluctuations in susceptibility to HIV or SHIV during the menstrual cycle are currently not fully documented. To address this, the time point of infection was determined in 19 adult female pigtail macaques vaginally challenged during their undisturbed menstrual cycles with repeated, low-dose SHIV(SF162P3) exposures. Eighteen macaques (95%) first displayed viremia in the follicular phase, as compared with 1 macaque (5%) in the luteal phase (P < 0.0001). Due to a viral eclipse phase, we estimated a window of most frequent virus transmission between days 24 and 31 of the menstrual cycle, in the late luteal phase. Thus, susceptibility to vaginal SHIV infection is significantly elevated in the second half of the menstrual cycle when progesterone levels are high and when local immunity may be low. Such susceptibility windows have been postulated before but not definitively documented. Our data support the findings of higher susceptibility to HIV in women during progesterone-dominated periods including pregnancy and contraceptive use. PMID- 21546849 TI - Changes in sexual risk behavior before and after HIV seroconversion in Southern African women enrolled in a HIV prevention trial. AB - BACKGROUND: We examine changes in sexual risk behaviors before and after HIV seroconversion in southern African women enrolled in the Methods for Improving Reproductive Health in Africa trial. METHODS: HIV testing and counseling, and assessment of sexual behaviors by audio computer-assisted self-interviewing were performed approximately every 3 months. We compared the following sexual behaviors: being sexually active, coital frequency, consistent male condom use, use of any female condoms, anal sex, and >1 sex partner, at study visits before and after HIV seroconversion. RESULTS: During the trial, 327 women seroconverted to HIV, contributing 718 pre-HIV and 1110 post-HIV study visits. Women were significantly more likely to report consistent condom use at visits after HIV seroconversion compared with visits before HIV infection [adjusted odds ratio, (AOR): 1.36 (95% confidence interval (CI): 1.11 to 1.67)] and were less likely to have >1 male sex partner after serconversion [AOR: 0.66 (95% CI: 0.48 to 0.91)]. Women reported less frequently being sexually active [AOR: 0.63 (95% CI: 0.39 to 1.02)], fewer episodes of sex [>4 sex acts over the past week AOR: 0.74 (95% CI: 0.60 to 0.91)], and a reduction in anal sex [AOR: 0.58 (95% CI: 0.36 to 0.95)] at visits after HIV seroconversion. The observed reductions in sexual risk behaviors persisted over time. CONCLUSIONS: Women significantly decreased their sexual risk behaviors after HIV seroconversion, but these changes were relatively modest, suggesting the need for further secondary prevention. Timely notification of HIV status coupled with prevention messages can contribute to reductions in sexual risk behaviors. PMID- 21546851 TI - Strengthening the capacity and effectiveness of developmental and behavioral services: implications from Australia. PMID- 21546850 TI - The cost of HIV disease in Northern Italy: the payer's perspective. AB - BACKGROUND: Healthcare expenditures incurred by the Health Service for HIV infected patients have not been reported in Italy. OBJECTIVE: To present health care costs for HIV-infected patients in the Lombardy Region, in 2004-2007, to determine the clinical characteristics of HIV infection associated with costs. METHODS: Retrospective, observational, budget impact study, based on information collected for the period 2004-2007, including hospitalizations, outpatient services, highly active antiretroviral therapy (HAART) and non-HAART drug utilization. Inclusion criteria includes: confirmed HIV infection, age >=18 years, resident in Lombardy Region, and followed at the "L. Sacco" Hospital in Milan from 2004 to 2007. RESULTS: The mean total cost per year to provide healthcare to HIV-positive patients was rather stable (? 9658.36 in 2004 and ? 9745.65 in 2007 (+0.90%)); HAART represented more than 60% of the total cost. We found that hepatitis C virus coinfection was related to higher costs (? 11,003.45 vs. ? 8896.06), as well as CD4 cell count <200 cells/mm (? 12,681.36 vs. ? 9594.11 and ? 9450.36 in 200-499 and >=500 cells/mm, respectively). The mean total cost of HIV health care was higher in patients who initiated antiretroviral treatment before 1997 than in those who started after 1996. CONCLUSIONS: The mean total cost per year to provide health care to HIV-positive patients was stable during the period 2004-2007, with an increase of HAART percentage impact on the total cost. Several clinical characteristics of HIV-infected patients were significantly associated with cost variation. PMID- 21546852 TI - Parental knowledge of healthy sleep in young children: results of a primary care clinic survey. AB - OBJECTIVE: The purpose of this study was to examine the associations among parental knowledge and beliefs about healthy sleep, sleep practices, and insufficient sleep in a pediatric primary care clinic sample. METHODS: A convenience sample of caregivers of patients between 3 months and 12 years attending a hospital-based pediatric primary care clinic in an academic center completed a brief survey on (1) child sleep habits, (2) basic sleep knowledge, and (3) beliefs and attitudes regarding sleep as a health behavior. RESULTS: Of the 184 analyzable surveys (response rate 72%; mean age of index child 4.0 +/- 3.2 years), 42% of children did not have a consistent bedtime, 43% had a bedtime later than 9 pm, 76% had a television in the bedroom, 69% frequently fell asleep with an adult present, and 18% had daily caffeine intake. Although 76% of parents underestimated their child's sleep needs compared to recommended amounts, just 8% reported that their child was not getting adequate sleep. More than half of parents believed that inadequate sleep increases the risk of being underweight and endorsed snoring as a sign of healthy sleep. An increased level of sleep knowledge was associated with a number of positive sleep practices and inversely correlated with sleep duration. CONCLUSION: The results of this study document the need for increased targeted caregiver education regarding healthy sleep practices, the importance of adequate sleep, the impact of insufficient sleep on health, and recognition of potential signs of sleep problems in young children, especially in high-risk populations. PMID- 21546853 TI - Predicting language development at age 18 months: data from the Norwegian Mother and Child Cohort Study. AB - OBJECTIVES: This study investigated predictors of delayed language development at 18 months of age in a large population cohort of Norwegian toddlers. METHODS: Data were analyzed on 42,107 toddlers. Language outcome at age 18 months was measured using a standard parent report instrument, the Ages and Stages Questionnaire, communication scale. Confirmatory factor analysis was conducted on the Ages and Stages Questionnaire items. A theoretically derived set of child, family, and environmental risk factors were used to predict delayed language development at age 18 months using Generalized Estimating Equation. RESULTS: A number of child factors, including being a boy, low birth weight or gestational age, or a multiple birth child were all significantly associated with low scores on the language outcome at age 18 months. Maternal distress/depression and low maternal education, having older siblings, or a non-Norwegian language background also predicted low scores on the language outcome at age 18 months. Overall, estimated variance in language outcome explained by the model was 4% to 7%. CONCLUSIONS: A combination of early neurobiological and genetic factors (e.g., male gender, birth weight, and prematurity) and concurrent family variables (e.g., maternal distress/depression) were associated with slower language development at age 18 months. This finding replicated previous research conducted on slightly older language-delayed 2 year olds but also detected the importance of factors related to family resources for the first time in this younger age group. Despite this finding, most of the variability in language performance in this cohort of 18 month olds remained unexplained by the comprehensive set of purported risk factors. PMID- 21546854 TI - Serious cardiac adverse events after decompressive craniectomy for malignant cerebral infarction. AB - BACKGROUND: There is a significant association between cardiac dysfunction and ischemic stroke. The serious cardiac adverse events (SCAEs) after decompressive craniectomy for malignant cerebral infarction from ischemic stroke were studied retrospectively. METHODS: Retrospective data were collected for preexisting cardiac risk factors, baseline clinical measures, and perioperative SCAEs including life-threatening arrhythmias, myocardial ischemia, cardiac failure, and cardiac arrest. The association between perioperative SCAEs and mortality was assessed using the chi(2) test. RESULTS: Data from 42 patients were analyzed. Mortality occurred in 19 (45.2%) patients. Eleven (57.9% of deaths) suffered mortality because of neurological causes, 7 patients (36.8% of mortality) because of cardiac causes, and 1 because of other causes. Mortality in patients who developed SCAEs was significantly higher than in those without SCAEs [75% mortality with SCAEs vs. 18.2% without SCAEs (P<0.0001)]. The odds ratio for mortality with SCAEs was 13.5 (3.1 to 59.5). There was a significant correlation between the number of SCAEs and mortality (Spearmans rho=0.738 (P<0.0001). CONCLUSION: Serious cardiac events are common in the acute period after stroke and decompressive craniectomy, and are important contributors to mortality. PMID- 21546855 TI - The effect of specialist neurosciences care on outcome in adult severe head injury: a cohort study. AB - BACKGROUND: Head injury is the leading cause of death in trauma. UK national guidelines have recommended that all patients with severe head injury (SHI) should be treated in neuroscience centers. The aim of this study was to investigate the effect of specialist neuroscience care on mortality after SHI. METHODS: We conducted a cohort study using prospectively recorded data from the largest European trauma registry, for adult patients presenting with blunt trauma between 2003 and 2009. Mortality and unadjusted odds of death were compared for patients with SHI treated in neuroscience units (NSU) versus nonspecialist centers. To control for confounding, odds of death associated with non-NSU care were calculated using propensity score-adjusted multivariate logistic regression (explanatory covariates: age, Glasgow Coma Score, Injury Severity Score, treatment center). Sensitivity analyses were performed to study possible bias arising from selective enrollment, from loss to follow-up, and from hidden confounders. RESULTS: 5411 patients were identified with SHI between 2003 and 2009, with 1485 (27.4%) receiving treatment entirely in non-NSU centers. SHI management in a non-NSU was associated with a 11% increase in crude mortality (P<0.001) and 1.72-fold (95% confidence interval: 1.52-1.96) increase in odds of death. The case mix adjusted odds of death for patients treated in a non-NSU unit with SHI was 1.85 (95% confidence interval: 1.57-2.19). These results were not significantly changed in sensitivity analyses examining selective enrollment or loss to follow-up, and were robust to potential bias from unmeasured confounders. CONCLUSIONS: Our data support current national guidelines and suggest that increasing transfer rates to NSUs represents an important strategy in improving outcomes in patients with SHI. PMID- 21546858 TI - Placebo effects on analgesia related to testosterone and premotor activation. AB - Using functional magnetic resonance imaging, we tested whether graded placebo conditions could modulate the degree of placebo effect and brain activation patterns in study participants and whether the placebo effect could be influenced by hormones. Each participant was investigated under three conditions: the control (no placebo) condition, the low-placebo condition, and the high-placebo condition (HPC). Activations of the premotor areas, anterior cingulate cortex, and prefrontal cortex were stronger in the HPC compared with those in the control and low placebo conditions. The premotor areas were activated by increased testosterone levels under the HPC. These results suggest that testosterone may affect the brain activation and response to pain during a high-placebo response, with the data supported by brain imaging. PMID- 21546857 TI - Changes of ferritin and CRP levels in melanoma patients treated with adjuvant interferon-alpha (EORTC 18952) and prognostic value on treatment outcome. AB - Adjuvant therapy with interferon-alpha (IFN) only benefits a small subgroup of melanoma patients and a predictive marker selecting responders does not exist. IFN induces increased ferritin and decreased C-reactive protein (CRP) levels; however, an association with treatment effect was not studied. Serum was collected from patients participating in the European Organization for Research and Treatment of Cancer 18 952 trial comparing adjuvant treatment with IFN to observation. Serial ferritin and CRP levels were determined using enzyme-linked immunosorbent assays, before treatment and up to 24 months. Ferritin levels are influenced by sex and age; therefore ratios of serial ferritin and CRP values with corresponding pretreatment values were calculated. Cox regression model and landmark method at end of induction and 6 months were used to evaluate the association between ferritin, CRP and distant metastasis-free survival (DMFS). Baseline ferritin levels were comparable in the two treatment groups (P=0.92). However, ferritin ratios were significantly higher in IFN-treated patients (N=96) compared with untreated patients (N=21) at end of induction (mean: 2.88 vs. 0.75; P=0.0003) and at 6 months (mean: 3.18 vs. 1.02; P=0.009). In the IFN arm, higher ferritin ratios at end of induction and at 6 months were not associated with improved outcome (respectively, P=0.66 and 0.86). Concerning CRP ratios, no differences between the treatment groups, neither an association with DMFS, were observed. Administration of IFN in melanoma patients induced increase in ferritin levels but not in CRP levels. Ferritin and CRP ratios have no prognostic value regarding DMFS. PMID- 21546859 TI - Gout diagnosis and management: what NPs need to know. AB - Gout is the result of hyperuricemia, from either the body's overproduction or underexcretion. It can result in joint deterioration and destruction when improperly managed. Because primary care providers diagnose and treat the vast majority of patients with gout, it is important that they understand current guidelines and evidence-based practice. PMID- 21546860 TI - Giving responsibility to the patient. PMID- 21546856 TI - Circulating microRNA is a biomarker of pediatric Crohn disease. AB - OBJECTIVE: The gold standard for the diagnosis and evaluation of Crohn disease (CD) is endoscopy/colonoscopy, although this is invasive, costly, and associated with risks to the patient. Recently, circulating microRNAs (miRNAs) have emerged as promising noninvasive biomarkers. Here, we examined the utility of serum miRNAs as biomarkers of CD in children. PATIENTS AND METHODS: Studies were conducted using sera samples from patients with pediatric CD, healthy controls, and a comparison group of patients with pediatric celiac disease. Serum miRNA levels were explored initially using a microfluidic quantitative reverse transcription-polymerase chain reaction array platform. Findings were subsequently validated using quantitative reverse transcription-polymerase chain reaction in larger validation sample sets. The diagnostic utility of CD associated serum miRNA was examined using receiver operating characteristic analysis. RESULTS: A survey of miRNA levels in the sera of control and patients with CD detected significant elevation of 24 miRNAs, 11 of which were chosen for further validation. All of the candidate biomarker miRNAs were confirmed in an independent CD sample set (n = 46). To explore the specificity of the CD associated miRNAs, they were measured in the sera of patients with celiac disease (n = 12); none were changed compared with healthy controls. Receiver operating characteristic analyses revealed that serum miRNAs have promising diagnostic utility, with sensitivities for CD above 80%. Significant decreases in serum miRNAs were observed in 24 incident patients with pediatric CD after 6 months of treatment. CONCLUSIONS: The present study identifies 11 CD-associated serum miRNA with encouraging diagnostic potential. Our findings suggest serum miRNAs may prove useful as noninvasive biomarkers in CD. PMID- 21546862 TI - PharmGKB summary: citalopram pharmacokinetics pathway. PMID- 21546863 TI - Transportable enhanced simulation technologies for pre-implementation limited operations testing: neonatal intensive care unit. AB - INTRODUCTION: Transition of a Neonatal Intensive Care Unit (NICU) to a new physical plant incurs many challenges. These are amplified when the culture of care is changing from traditional cohort-based care to the single-family room model. Altered healthcare delivery systems can be tested in situ with TESTPILOT: Transportable Enhanced Simulation Technologies for Pre-Implementation Limited Operations Testing. The aims of the study included promoting translation of existing processes and identifying staff orientation material. We hypothesized that (1) numerous process gaps would be discovered and resolved, and (2) participants would feel better prepared. METHODS: A functional neonatal intensive care unit was modeled before its opening. Scenarios were developed, volunteers recruited, and rooms supplied with equipment. Participants performed usual duties in two 30-minute in situ simulations followed by facilitated debriefings. As latent safety hazards were identified, they were corrected and retested in subsequent simulations. Staff was surveyed for perceived preparedness. RESULTS: Ninety-six multidisciplinary participants identified 164 latent safety hazards in verbal and written communication, facilities, supplies, staffing, and training, 93% of which were resolved at transition. Staff preparedness varied but showed improving communication, workflow patterns, and awareness of equipment and supply locations. The majority stated that this simulation experience changed their practice. CONCLUSIONS: Simulation is very effective for identifying process gaps before major institutional change. TESTPILOT generated iterative workflow enhancements and staff orientation toward improving patient care at transition and beyond. The extensive coordination required to implement such large-scale simulations is well worth the benefit for systems refinement and patient safety. PMID- 21546861 TI - Long-term impact of maternal substance use during pregnancy and extrauterine environmental adversity: stress hormone levels of preadolescent children. AB - Prenatal cocaine exposure (PCE) is associated with blunted stress responsivity within the extrauterine environment. This study investigated the association between PCE and diurnal salivary cortisol levels in preadolescent children characterized by high biological and/or social risk (n = 725). Saliva samples were collected at their home. Analyses revealed no group differences in basal evening or morning cortisol levels; however, children with higher degrees of PCE exhibited blunted overnight increases in cortisol, controlling for additional risk factors. Race and caregiver depression were also associated with diurnal cortisol patterns. Although repeated PCE may contribute to alterations in the normal or expected stress response later in life, sociodemographic and environmental factors are likewise important in understanding hormone physiology, especially as more time elapses from the PCE. Anticipating the potential long term medical, developmental, or behavioral effects of an altered ability to mount a normal protective cortisol stress response is essential in optimizing the outcomes of children with PCE. PMID- 21546864 TI - A retrospective review of TATRC funding for medical modeling and simulation technologies. AB - INTRODUCTION: In February 2000, the U.S. Army's Telemedicine and Advanced Technology Research Center (TATRC) and the U.S. Army's Simulation, Training, and Instrumentation Command cohosted an Integrated Research Team conference in Maryland. The goal of the conference was to enable end users, researchers, materiel developers, and other government agencies to present their conceptions of how modeling and simulation could and should be developed to meet military medical needs. During the past 9 years, TATRC has funded more than 175 projects relating to simulation. METHODS: This study was a retrospective review of TATRC's Modeling and Simulation Training projects (N = 175). RESULTS: Our results show that most (>75%) of the funded projects in this study involved industry. More than 85% of the projects that involved industry focused on technology development. Industry development projects seemed to meet their deliverables in a timely fashion. However, academia projects using industry-developed technologies and prototypes were delayed largely because the technologies did not meet their needs. DISCUSSION: There seems to be a measurable gap between industry's definition of a completed product technology and academia's ability to implement and use the technology in interactive learning environments. Our findings support the need for a standardized strategic design process that involves a strong industry-academia collaboration and early end-user testing to better facilitate the development of sound requirements that guide technology development. PMID- 21546865 TI - Intrarenal IFN-gamma mRNA expression differentiates clinical and subclinical glomerulitis in renal transplant recipients. AB - BACKGROUND: Transplant glomerulitis, characterized by mononuclear cell infiltration of glomeruli, is likely to occur during clinical or subclinical antibody-mediated rejection. METHODS: To determine whether T-cell phenotype influences the clinical presentation of this pathologic condition, we used reverse transcription quantitative polymerase chain reaction to analyze expression of Treg cells (Foxp3), cytotoxic CD8 T cells (Granzyme B), Th1 cells (INF-gamma,T Bet), Th2 cells (GATA3, IL-4), and Th17 pathway (IL-17). Our study included 20 renal transplant recipients exhibiting subclinical glomerulitis (SG) diagnosed after a routine 3-month posttransplant biopsy. Results were compared with those observed in 22 patients with normal routine biopsies at 3 months (N) and 17 patients with clinical glomerulitis occurring during early acute renal dysfunction within the first year after transplantation in a context of acute antibody-mediated rejection. RESULTS: Our results show that expression of IL-4 mRNA was significantly higher in SG patients than in N patients (P = 0.02). Expression of IFN-gamma was significantly higher in patients with clinical glomerulitis than in patients with SG (P<0.001) and was associated with a clinical expression of glomerulitis. CONCLUSION: Our results suggest that the balance of Th1/Th2 is likely to differentiate clinical expression of transplant glomerulopathy. They also indicate that therapeutic approaches in cases of SG should be defined with caution and take into account transcriptional criteria. PMID- 21546866 TI - Cyclosporine A-based immunotherapy in adult living donor liver transplantation: accurate and improved therapeutic drug monitoring by 4-hr intravenous infusion. AB - BACKGROUND: A paucity of data exists for evaluating therapeutic drug monitoring in association with clinical outcomes of cyclosporine A (CYA) treatment in living donor liver transplantation (LDLT). METHODS: A retrospective cohort analysis was conducted on 50 consecutive adult patients who underwent LDLT between 2001 and 2009 to investigate the feasibility and efficacy of 4-hr continuous intravenous infusion of CYA-based immunotherapy (4-hr CYA-IV, n=27) and compare the pharmacokinetic profile and short-term prognoses with an oral microemulsion formulation of CYA (CYA-ME, n=23). RESULTS: All patients in the 4-hr CYA-IV group reached target CYA peak by day 3 compared with only 22% in the CYA-ME group (P<0.001). Adjustability to achieve the target range was easier in the 4-hr CYA IV group compared with the CYA-ME group (P=0.017). Acute cellular rejection rate was lower in the 4-hr CYA-IV group (0%) compared with the CYA-ME group (17%, P=0.038). A subset analysis of the CYA-ME group revealed that CYA exposure was affected by external bile output (P=0.006). Patients in the CYA-ME group showed increased risk of switch to tacrolimus (35%) compared with the 4-hr CYA-IV group (7%, P=0.030). Toxicities and mortality rates were equivalent. The optimal initial dose of oral CYA at conversion from the 4-hr CYA-IV was considered to be 3-fold greater than that of the intravenous dose. CONCLUSIONS: In LDLT, our 4-hr CYA-IV immunosuppression protocol was superior to CYA-ME oral dosing and allowed accurate therapeutic drug monitoring with excellent patient compliance. PMID- 21546867 TI - Single-center experience with kidney transplantation using deceased donors older than 75 years. AB - BACKGROUND: Use of kidneys from donors aged 75 years and older is controversial. The purpose of this study was to evaluate the outcome of kidney transplantation (KT) involving these expanded criteria donors. MATERIALS AND METHODS: From January 2001 to November 2009, 52 patients were transplanted with grafts from deceased donors aged 75 years and older. Donor and recipient data and intra- and postoperative variables were analyzed by univariate and multivariate regression analyses. Graft and patient survival were calculated using the Kaplan-Meier method. RESULTS: Forty-one single and 11 double KTs were performed. Median recipient age was 66 years. After a median follow-up of 30 months, 37 of 52 patients are alive, 30 with functioning grafts (81%). Graft and patient survival rates at 3 and 5 years are 63% and 53%, and 78% and 64%, respectively. Double KT was significant predictor for graft survival by multivariate analysis. Five-year graft survival for single and double KT was 41% and 90%, respectively (P=0.0394). Comorbidity Index, hospital stay, acute rejection reaction, re-KT, and induction immunosuppressive therapy with interleukin-2 were significant predictors for patient survival by univariate analysis. Hospital stay and induction immunosuppression therapy reached multivariate significance. Double KT, cold ischemia time, and Comorbidity Index were found potential predictors of delayed graft function in our series. CONCLUSIONS: Fairly good long-term outcome of KT from donors aged 75 years and older can be achieved in elderly recipients with low comorbidities when dual kidney grafting is used and when re-transplantations and high grade surgical complications are avoided. PMID- 21546869 TI - Current world literature. PMID- 21546870 TI - Estrogen-related receptor alpha expression and function are associated with vascular endothelial growth factor in human cervical cancer. AB - INTRODUCTION: Estrogen-related receptor alpha (ERRalpha), one of orphan nuclear receptors with an unknown ligand, is expressed in various types of cancer. Increased ERRalpha levels are associated with a higher risk of recurrence and poor clinical outcome in breast cancer, suggesting that ERRalpha could be a negative prognostic factor. Recently, it has been suggested that vascular endothelial growth factor (VEGF) could be one of the transcriptional targets of ERRalpha in breast cancer. Here, we examined the expression of ERRalpha and the association of ERRalpha with VEGF in uterine cervical cancer cells and tissues. METHODS: We evaluated the expression of ERRalpha and VEGF by immunohistologic analysis using specimens from 40 patients with invasive cervical cancer. We also evaluated the VEGF promoter activity of ERRalpha in cervical cancer cell lines by transfection and luciferase assay. We overexpressed or knocked down ERRalpha and examined VEGF expression by real-time polymerase chain reaction. Finally, cell proliferation assay was performed to examine whether ERRalpha affects tumor growth in cervical cancer. RESULTS: Immunohistologic analysis demonstrated that ERRalpha expression in cervical cancer tissues was higher than that in noncancerous tissues and that there was a positive association between ERRalpha and VEGF expression in cancer tissues (P < 0.05). We showed that ERRalpha stimulated the VEGF promoter activity in cervical cancer cell lines. We further showed the overexpression and knockdown of ERRalpha-regulated VEGF expression level by real-time polymerase chain reaction. Moreover, we showed that ERRalpha and VEGF knockdown by small interfering RNA or an inverse agonist of ERRalpha, XCT 790, could suppress cell growth compared with control cells in cervical cancer. CONCLUSIONS: We have provided compelling evidence that ERRalpha affects VEGF expression and tumor growth in cervical cancer. These results justify further investigation into the use of ERRalpha as a therapeutic target for patients with uterine cervical cancer. PMID- 21546871 TI - Conservative treatment with medroxyprogesterone acetate plus levonorgestrel intrauterine system for early-stage endometrial cancer in young women: pilot study. AB - OBJECTIVE: To assess the feasibility of using medroxyprogesterone acetate (MPA) and levonorgestrel intrauterine system (LNG-IUS) to treat early-stage endometrial cancer in young women who want to preserve their reproductive potential. METHODS: Prospective observational study of 5 young patients (mean [SD] age, 38.4 [4.8] years; range, 33-41 years) with a grade 1 endometrial cancer that is presumably confined to the endometrium. The subjects were given a daily oral dose of 500 mg of MPA and LNG-IUS placement. They were followed with dilation and curettage every 3 months. RESULTS: Complete remission was shown in 4 of 5 patients, and one patient showed partial remission. Biopsy results were negative in 2 patients at 3 months, in 1 patient at 6 months, and in 1 patient at 12 months. No treatment related complications occurred. No recurrence was found during the follow-up period (mean [SD], 10.2 [3.6] months; range, 6-16 months). CONCLUSIONS: The concomitant use of MPA with LNG-IUS is feasible for conservative treatment of early-stage endometrial cancer in young women who want to preserve their reproductive potential. PMID- 21546872 TI - Metabolic response of pelvic and para-aortic lymph nodes during radiotherapy for carcinoma of the uterine cervix: using positron emission tomography/computed tomography. AB - OBJECTIVES: We evaluated the metabolic response of lymph nodes (LNs) using consecutive F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) and correlated the metabolic response with the volumetric response measured by consecutive CT. METHODS: Twenty-two patients with cervical cancer that had positive LNs underwent preradiotherapy (pre-RT) and inter-RT PET/CT. The metabolic response of the LNs was assessed quantitatively and semiquantitatively by measurement of the maximal standardized uptake value. All patients underwent inter-RT CT simulation after 45 Gy to the whole pelvis and inter-RT PET/CT scans after median 63 Gy to the gross LNs. RESULTS: A total of 48 pelvic and para aortic LNs were found on the pre-RT PET/CT. The mean maximal standardized uptake value of nodal disease decreased from the pre-RT of 5.2 (SD, 3.1; range, 1.8 15.6) to the inter-RT of 1.1 (SD, 2.1; range, 0-11.1). Classifying the metabolic response of all 48 nodal lesions on the inter-RT PET/CT, 38 had a complete metabolic response. The initial volume of LNs had no correlation with the metabolic response (r = 0.194, P = 0.186). The metabolic response between the pre RT PET/CT and inter-RT PET/CT was significantly associated with the volume response between the pre-RT CT and inter-RT CT (r = 0.314, P < 0.05). However, 18 (38%) LNs showed discrepancy between metabolic response and residual LN volume. Six (27%) patients had modified RT during treatment based on inter-RT PET/CT. CONCLUSIONS: We suggest that the PET/CT can be a useful tool for the evaluation of the interim response of the LNs and aid in selecting patients that need further treatment. The results showed a significant correlation between the metabolic and volumetric responses during RT, although the anatomical changes of LNs would not always represent the metabolic status. PMID- 21546873 TI - Thromboembolic event as a prognostic factor for the survival of patients with stage IIIB cervical cancer. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of thromboembolic event (TEE) on the prognosis and survival of women diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) stage IIIB cervical cancer undergoing treatment at the National Cancer Institute (Instituto Nacional de Cancer [INCA], Ministerio da Saude), Brazil. METHODS: A total of 1020 women with FIGO stage IIIB cervical cancer (International Classification of Diseases, C53.9), who had received treatment at this institute between 2000 and 2004, were identified. Data were obtained from the hospital cancer registry at INCA. Patients were followed up from the date of their diagnosis of cervical cancer at INCA until their death or last follow-up visit. The date of TEE diagnosis was defined as the date of one of the following tests diagnosing this condition: Doppler ultrasound scan, computed tomography scan, or in 1 single case echocardiography. The Kaplan-Meyer method was used to perform long-term survival analysis. CONCLUSIONS: The presence of TEE in patients with FIGO stage IIIB cervical cancer seems to be indicative of the severity of the disease and poorer prognosis. The most important finding is that in the patients who developed TEE, this complication occurred around the time of diagnosis of progression of the disease. Disease progression may have been the triggering factor for the development of TEE. PMID- 21546874 TI - Relationship between body mass index and robotic surgery outcomes of women diagnosed with endometrial cancer. AB - OBJECTIVE: This is a prospective evaluation of the outcome of minimal invasive surgery using robotics in function of the body mass index (BMI) of patients. METHODS: This is a prospective cohort study of consecutive women undergoing surgery for endometrial cancer at a tertiary care facility since the initiation of a robotic program in December 2007. Surgical and personal outcome variables as well as quality of life and postoperative recovery were assessed using a combination of objective and subjective/self-report questionnaires. Women were divided into 3 groups based on their BMI. Comparative analyses among nonobese (n = 52), obese (n = 33) and morbidly obese (n = 23) women were performed on the outcome measures after surgery. RESULTS: The mean BMI and the range in each of the BMI categories was 25 kg/m2 (18.7-29.4 kg/m2), 34 kg/m2 (30.1-38.4 kg/m2), and 46 kg/m2 (40.0-58.8 kg/m2). Women with higher BMI tended to be more frequently affected with comorbidities such as diabetes (15.4%, 26.0%, and 27.3%, respectively; P = 0.32) and hypertension (55.8%, 69.6%, and 69.7%, respectively; P = 0.19). Despite these differences, surgical console time (P = 0.20), major postoperative complications (P = 0.52), overall wound complications (P = 0.18), and median length of hospitalization in days (P = 0.17) were not statistically different among the 3 groups. Only 5.6% of women needed a mini laparotomy all of which were performed for the removal of their enlarged uterus, which could not be delivered safely via the vagina, at the end of the surgical procedure. There was no increased conversion to laparotomy due to increased BMI. Women in all 3 groups reported rapid resumption of hygiene regimens and chores, little need for narcotic analgesia, and high satisfaction with the procedure. CONCLUSIONS: Obese and morbidly obese patients with endometrial cancer are also good candidates for robotic surgery. These women benefit considerably from minimal invasive surgery and have little perioperative complications. PMID- 21546875 TI - Bethanechol chloride for the prevention of bladder dysfunction after radical hysterectomy in gynecologic cancer patients: a randomized controlled trial study. AB - BACKGROUND: Bethanechol chloride is considered as a treatment in patients with high postvoid residual urine (PVR). It enhances detrusor muscle contraction, resulting in higher maximum flow rate, higher detrusor pressure at maximum flow, and lower PVR. The efficacy of this agent in patients after radical hysterectomy is unclear. We aim to evaluate the efficacy of bethanechol chloride compared with placebo for the prevention of bladder dysfunction after type III radical hysterectomy. METHODS: Gynecologic cancer patients who underwent type III radical hysterectomy were randomized by computer-generated schedule to assign patients in a 1:1 ratio into 2 groups. The treatment group received bethanechol chloride (Ucholine 20 mg 3 times a day on the third to seventh postoperative day), and the control group received placebo. Patients and physicians were masked to treatment allocation. The primary end point was the rate of urethral catheter removal at 1 week postoperatively. If PVR was more than 30% of voided volume, the urethral catheter was reinserted, and medication would be continued but not for more than 1 month. This study was registered as ISRCTN92687416. FINDINGS: There were 31 patients in each group without significant difference in baseline characteristics. Twenty-one patients (67.7%) in the treatment group and 12 patients (38.7%) in the control group had the urethral catheter removed at 1 week postoperatively (P = 0.04). Median duration of urethral catheterization was shorter in the treatment group (7 and 14 days, P = 0.03). However, the PVR and the incidence of urinary tract infection at 1 month postoperatively were not significantly different. Nine patients (29%) in the treatment group had adverse events such as nausea, abdominal distension, and abdominal cramping, which was higher than the control group (1 patient, 3.2%; P = 0.01). However, no patients required any medical treatments. CONCLUSIONS: Bethanechol chloride decreases the duration of urethral catheterization in patients who underwent type III radical hysterectomy with manageable adverse events. PMID- 21546876 TI - Salt reduction initiatives around the world. AB - OBJECTIVE: To provide an overview of national salt reduction initiatives around the world, describe core characteristics and develop a framework for future strategy development. METHODS: National strategies were identified from existing reviews and from searches of the literature and relevant websites. Standardized information was extracted about governance and strategy development, baseline assessments and monitoring and implementation. RESULTS: Thirty-two country salt reduction initiatives were identified. The majority of activity was in Europe (19 countries). Most countries (27) had maximum population salt intake targets, ranging from 5 to 8 g/person per day. Twenty-six of the 32 strategies were led by government, five by nongovernment organizations and one by industry. Twenty-eight countries had some baseline data on salt consumption and 18 had data on sodium levels in foods. Twenty-eight countries were working with the food industry to reduce salt in foods, 10 had front-of-pack labelling schemes and 28 had consumer awareness or behaviour change programs. Five countries had demonstrated an impact, either on population salt consumption, salt levels in foods or consumer awareness. These strategies were led by government and were multifaceted including food reformulation, consumer awareness initiatives and labelling actions. CONCLUSION: This is the first review to concisely summarize the most important elements of the many existing salt reduction programmes and highlight the characteristics most likely to be important to programme efficacy. For most countries, implementing a national salt reduction programme is likely to be one of simplest and most cost-effective ways of improving public health. PMID- 21546877 TI - Exposure to the Chinese famine in early life and the risk of hypertension in adulthood. AB - OBJECTIVES: Maternal famine exposure has been associated with higher blood pressure in the offspring. The aim of the present study was to examine the associations of early life exposure to the 1959-1961 Chinese famine with the risk of hypertension in later life, and to examine whether a nutritional 'rich' environment in later life modifies this association. METHODS: We used data of 7874 adults born between 1954 and 1964 from the 2002 China National Nutrition and Health Survey. Excess death rate was used to determine the severity of the famine. RESULTS: In severely affected famine areas, as compared to adults who were not exposed to famine, those exposed during fetal life had a significantly higher SBP [SBP difference 2.2 mmHg, 95% confidence interval (CI) 1.3-3.0, P < 0.0001], DBP (DBP difference 0.9 mmHg, 95% CI 0.3-1.5, P = 0.003) and a marginally higher risk of hypertension (odds ratio 1.88, 95% CI 1.00-3.53, P = 0.05), after adjustment of age, sex, socioeconomic status, lifestyle, dietary factors and family history of hypertension, which was not observed in less severely affected famine areas (P for interaction was 0.08 for SBP, 0.03 for DBP and 0.03 for hypertension). These associations were more pronounced in participants who had a western dietary pattern or who were overweight as adult. CONCLUSION: Our results suggest that fetal famine exposure is associated with higher blood pressure and an increased risk of hypertension in adulthood. These associations are stronger in participants who have a western dietary pattern or who are overweight as adults. PMID- 21546879 TI - Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues. AB - OBJECTIVE: Nuclear receptors are involved in a wide variety of functions, including aldosteronogenesis. Nuclear receptor families NR4A [nerve growth factor induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues. METHODS: We collected tissues of artery (n = 9), cardiomyopathy muscle (n = 9), heart muscle (noncardiomyopathy) (n = 6), adrenal gland (n = 9) and aldosterone producing adenoma (APA) (n = 9). 5'-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT PCR) determined use of alternative noncoding exons 1 (ANEs). RESULTS: In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5'-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues. CONCLUSION: NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland. PMID- 21546878 TI - Effect of number of ultrasound examinations on the assessment of carotid intima media thickness changes over time: the example of the METEOR study. AB - OBJECTIVE: To evaluate the effect of the number and positioning during follow-up of ultrasound examinations on the rate of change in carotid intima-media thickness (CIMT) using METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin) as an example. METHODS: METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced progression of 2-year change in CIMT among low-risk patients with subclinical atherosclerosis. In the full METEOR protocol, ultrasound examinations were performed twice before randomization, once each at 6, 12, and 18 months after randomization, and then twice at the end of study at 24 months. For the present study, 17 study designs were retrospectively constructed with varying number and position of ultrasound examinations during the study. Differences in the rate of change in maximum CIMT between these study designs were compared. RESULTS: Variations in frequency of ultrasound visits gave results in the same direction and magnitude for the change in maximum CIMT for both groups (i.e. nonsignificant change for rosuvastatin and significant progression for placebo, and a significant difference between treatments). However, standard errors were larger when the number of exams reduced. This finding was consistent over different lengths of follow-up, sample sizes, and with CIMT measurements made on different locations. CONCLUSION: Protocols with different number and timing of ultrasound examinations minimally affect the direction and magnitude of treatment effects on the rate of change in CIMT. However, reductions in exam frequency increase standard errors of rates of change, suggesting larger sample sizes would be required to have the same level of statistical power. PMID- 21546880 TI - Calcium channel blockers are independently associated with short sleep duration in hypertensive patients with obstructive sleep apnea. AB - OBJECTIVE: Obstructive sleep apnea (OSA) and hypertension (HYP) frequently coexist and have additive harmful effects on the cardiovascular system. There is also growing evidence that short sleep duration may contribute independently to poor cardiovascular outcome. The aim of this study was to evaluate the potential influence of antihypertensive medication on sleep parameters objectively measured by standard polysomnography in hypertensive patients with OSA. METHODS: We evaluated consecutive patients with a recent diagnosis of OSA by full polysomnography (apnea hypopnea index >= 5 events/h) and HYP. Smokers, patients with diabetes mellitus, heart failure, or using hypnotics and benzodiazepines were excluded. RESULTS: We evaluated 186 hypertensive patients with OSA, 64% men. All patients were on at least one antihypertensive medication, including angiotensin-converting enzyme inhibitors (37%), beta-blockers (35%), angiotensin receptor blockers (32%), diuretics (29%) and calcium channel blockers (21%). Backward multiple regression analysis showed that age (P <= 0.001) and the use of calcium channel blockers (P = 0.037) were the only factors inversely associated with lower total sleep time. Sleep efficiency was inversely associated only with age (P <= 0.001), whereas the use of calcium channel blockers had a nonsignificant trend (P = 0.092). Use of calcium channel blockers was associated with significant reduction in total sleep time (-41 min, P = 0.005) and 8% lower sleep efficiency (P = 0.004). No other antihypertensive medication, including diuretics and beta-blockers, was associated with sleep impairment. CONCLUSION: Calcium channel blockers may impact negatively on sleep duration in hypertensive patients with OSA. The mechanisms and significance of this novel finding warrants further investigation. PMID- 21546881 TI - Diversity-oriented synthesis based on the DPPP-catalyzed mixed double-Michael reactions of electron-deficient acetylenes and beta-amino alcohols. AB - In this study, we prepared oxizolidines through 1,3-bis(diphenylphosphino) propane (DPPP)-catalyzed mixed double-Michael reactions of beta-amino alcohols with electron-deficient acetylenes. These reactions are very suitable for the diversity-oriented parallel syntheses of oxizolidines because: (i) they are performed under mild metal-free conditions and (ii) the products are isolated without complicated work-up. To demonstrate the applicability of mixed double Michael reactions for the preparation of five-membered-ring heterocycles, we prepared 60 distinct oxazolidines from five beta-amino alcohols and 12 electron deficient acetylenes. We synthesized 36 of these 60 oxazolidines in enantiomerically pure form from proteinogenic amino acid-derived beta-amino alcohols. PMID- 21546882 TI - Synthesis of homoveratric acid-imprinted polymers and their evaluation as selective separation materials. AB - A bulk polymerization method was used to easily and efficiently prepare homoveratric acid (3,4-dimethoxyphenylacetic acid)-imprinted polymers from eight basic monomers: 2-vinylpyridine, 4-vinylpyridine, 1-vinylimidazole, N allylaniline, N-allylpiperazine, allylurea, allylthiourea, and allylamine, in the presence of homoveratric acid as a template in N,N-dimethylformamide as a porogen. The imprinted polymer prepared from allylamine had the highest affinity to the template, showing an imprinting factor of 3.43, and allylamine polymers MIP8/NIP8 were selected for further studies. Their binding properties were analyzed using the Scatchard method. The results showed that the imprinted polymers have two classes of heterogeneous binding sites characterized by two pairs of K(d), B(max) values: K(d)(1) = 0.060 MUmol/mL, B(max)(1) = 0.093 MUmol/mg for the higher affinity binding sites, and K(d)(2) = 0.455 MUmol/mL, B(max)(2) = 0.248 MUmol/mg for the lower affinity binding sites. Non-imprinted polymer has only one class of binding site, with K(d) = 0.417 MUmol/mL and B(max) = 0.184 MUmol/mg. A computational analysis of the energies of the prepolymerization complexes was in agreement with the experimental results. It showed that the selective binding interactions arose from cooperative three point interactions between the carboxylic acid and the two methoxy groups in the template and amino groups in the polymer cavities. Those results were confirmed by the recognition studies performed with the set of structurally related compounds. Allylamine polymer MIP8 had no affinity towards biogenic amines. The obtained imprinted polymer could be used for selective separation of homoveratric acid. PMID- 21546883 TI - The influence of CYP2C19 polymorphisms on the pharmacokinetics, pharmacodynamics, and clinical effectiveness of P2Y(12) inhibitors. AB - P2Y(12) antagonists, in combination with aspirin, significantly reduce thrombotic and ischemic events in patients presenting with an acute coronary syndrome and in patients undergoing percutaneous coronary intervention. The thienopyridine clopidogrel is a prodrug that requires bioactivation by the cytochrome P450 (CYP) system in order to exert its antiplatelet effect. Common genetic polymorphisms that reduce the catalytic activity of the CYP2C19 isoenzyme decrease circulating levels of active metabolite, reduce levels of platelet inhibition, and increase the risk of ischemic events in clopidogrel-treated patients. Herein, we review the impact of the CYP2C19 genotype on the pharmacokinetics and pharmacodynamics of clopidogrel, the association between CYP2C19 genotype and clinical outcome, and present the rationale for the implementation of CYP2C19 genotyping to individualize antiplatelet therapy in clinical practice. PMID- 21546884 TI - Dialysis-induced myocardial stunning: the other side of the cardiorenal syndrome. AB - Cardiorenal syndrome is an umbrella term describing the range of interactions between the heart and kidneys. Commonly, this focuses on the potential for reduced renal function as a consequence of heart disease and the impact of reduced renal functional reserve on the heart. Importantly, these interactions include both consequences of the disease state and those arising from therapeutic interventions directed at the cardiorenal axis. This article focuses on the potential impact of dialysis treatment, which generates intermittent circulatory stress and results in both acute and chronic adverse cardiovascular effects. This largely unappreciated dimension of the cardiorenal interaction in patients with end-stage renal failure is common, associated with a significant increase in mortality, and may be amenable to a variety of therapeutic approaches in this population characterized by particularly significant clinical management challenges. PMID- 21546885 TI - The role of oxidative stress in the metabolic syndrome. AB - Loss of reduction-oxidation (redox) homeostasis and generation of excess free oxygen radicals play an important role in the pathogenesis of diabetes, hypertension, and consequent cardiovascular disease. Reactive oxygen species are integral in routine in physiologic mechanisms. However, loss of redox homeostasis contributes to proinflammatory and profibrotic pathways that promote impairments in insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. Redox control of metabolic function is a dynamic process with reversible pro- and anti-free radical processes. Labile iron is necessary for the catalysis of superoxide anion, hydrogen peroxide, and the generation of the damaging hydroxyl radical. Acute hypoxia and cellular damage in cardiovascular tissue liberate larger amounts of cytosolic and extracellular iron that is poorly liganded; thus, large increases in the generation of oxygen free radicals are possible, causing tissue damage. The understanding of iron and the imbalance of redox homeostasis within the vasculature is integral in hypertension and progression of metabolic dysregulation that contributes to insulin resistance, endothelial dysfunction, and cardiovascular and kidney disease. PMID- 21546886 TI - Statin therapy in the perioperative period. AB - Statins are frequently used as chronic therapy for reducing cardiovascular mortality and morbidity, but there has been less emphasis on the role of statins in the perioperative period. This review evaluates data regarding statin use in vascular and noncardiac surgery, the use of statins in combination with beta blockers in the perioperative period, perioperative statin use in patients already treated with statins, and the safety of statin therapy in the perioperative period. Current recommendations state that patients who are prescribed statins as chronic therapy should continue treatment in the perioperative period, but data suggest that there may be benefit from the use of perioperative statins in a wider population. PMID- 21546887 TI - Heart house: report from the ACC leadership forum and board of governors meeting. PMID- 21546888 TI - British Cardiovascular Society. PMID- 21546889 TI - Heart failure readmission rates. PMID- 21546890 TI - Insights into endovascular revascularization in limb salvage procedures: "antegrade-retrograde" technique in chronic total occlusion. AB - Significant occlusions of the peripheral arterial circulation, responsible for chronic limb ischemia (CLI), are a serious cause of morbidity, mortality, and poor quality of life. The currently available treatment options for patients with severely symptomatic CLI include bypass surgery and arterial revascularization. Percutaneous transluminal angioplasty for CLI is shown to be as effective as bypass surgery at high-volume centers, and it also offers a less invasive alternative, leading to quicker patient recovery times and lower short-term costs. This case report reviews the current techniques available and discusses an "antegrade-retrograde" angioplasty approach to successfully recanalize such challenging obstructions. PMID- 21546892 TI - Cardiac magnetic resonance imaging. Prognostic value of high-dose dobutamine stress MRI. PMID- 21546891 TI - Left ventricular outflow tract obstruction after bioprosthetic mitral valve replacement with preservation of the anterior leaflet. AB - A 79-year-old woman with a history of bioprosthetic aortic and mitral valve replacement with coronary artery bypass graft surgery presented with pulmonary edema 4 years after surgery. Transthoracic echocardiography and transesophageal echocardiography revealed an obstruction of the left ventricular outflow tract caused by the bioprosthetic mitral valve. We present this case, accompanied by a review of the literature. PMID- 21546893 TI - Compendium of measures to prevent disease associated with animals in public settings, 2011: National Association of State Public Health Veterinarians, Inc. AB - Certain venues encourage or permit the public to be in contact with animals, resulting in millions of human-animal interactions each year. These settings include county or state fairs, petting zoos, animal swap meets, pet stores, feed stores, zoologic institutions, circuses, carnivals, educational farms, livestock birthing exhibits, educational exhibits at schools and child-care facilities, and wildlife photo opportunities. Although human-animal contact has many benefits, human health problems are associated with these settings, including infectious diseases, exposure to rabies, and injuries. Infectious disease outbreaks have been caused by Escherichia coli O157:H7, Salmonella species, Cryptosporidium species, Coxiella burnetii, Mycobacterium tuberculosis, ringworm, and other pathogens. Such outbreaks have substantial medical, public health, legal, and economic effects. This report provides recommendations for public health officials, veterinarians, animal venue staff members, animal exhibitors, visitors to animal venues, physicians, and others concerned with minimizing risks associated with animals in public settings. The recommendation to wash hands is the most important for reducing the risk for disease transmission associated with animals in public settings. Other important recommendations are that venues prohibit food in animal areas and include transition areas between animal areas and nonanimal areas, visitors receive information about disease risk and prevention procedures, and animals be properly cared for and managed. These updated 2011 guidelines provide new information on the risks associated with amphibians and with animals in day camp settings, as well as the protective role of zoonotic disease education. PMID- 21546897 TI - Energy storage: batteries take charge. PMID- 21546898 TI - Nanotoxicology: nanoparticles versus the placenta. PMID- 21546899 TI - Catalysis: acidic ideas for hydrogen storage. PMID- 21546900 TI - Biosensors: magnets tackle kinetic questions. PMID- 21546901 TI - A novel role of the CX3CR1/CX3CL1 system in the cross-talk between chronic lymphocytic leukemia cells and tumor microenvironment. AB - Several chemokines/chemokine receptors such as CCR7, CXCR4 and CXCR5 attract chronic lymphocytic leukemia (CLL) cells to specific microenvironments. Here we have investigated whether the CX(3)CR1/CX(3)CL1 axis is involved in the interaction of CLL with their microenvironment. CLL cells from 52 patients expressed surface CX(3)CR1 and CX(3)CL1 and released constitutively soluble CX(3)CL1. One third of these were attracted in vitro by soluble CX(3)CL1. CX(3)CL1-induced phosphorylation of PI3K, Erk1/2, p38, Akt and Src was involved in induction of CLL chemotaxis. Leukemic B cells upregulated CXCR4 upon incubation with CX(3)CL1 and this was paralleled by increased chemotaxis to CXCL12. Akt phosphorylation was involved in CX(3)CL1-induced upregulation of CXCR4 on CLL. In proliferation centers from CLL lymph node and bone marrow, CX(3)CL1 was expressed by CLL cells whereas CX(3)CR1 was detected in CLL and stromal cells. Nurselike cells (NLCs) generated from CLL patient blood co expressed surface CX(3)CR1 and CX(3)CL1, but did not secrete soluble CX(3)CL1. Only half of NLC cell fractions were attracted in vitro by CX(3)CL1. In conclusion, the CX(3)CR1/CX(3)CL1 system may contribute to interactions between CLL cells and tumor microenvironment by increasing CXCL12-mediated attraction of leukemic cells to NLC and promoting directly adhesion of CLL cells to NLC. PMID- 21546902 TI - Very early/early relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high heterogeneity in response to initial and relapse treatment. AB - Minimal residual disease (MRD) quantified after induction treatment of childhood acute lymphoblastic leukemia (ALL) predicts risk of relapse. It has been assumed that early relapses derive from a residual population of leukemic cells, which is still present after induction and that relapsed disease will consequently be more resistant to treatment. To test these hypotheses, we performed a prospective study on patients treated according to the frontline-trial ALL-BFM 2000, which used MRD response for risk-group stratification. Patients (n=45) showed a median time to relapse of 1.5 years. In 89% of patients at least one T-cell receptor/immunoglobulin gene rearrangement chosen for initial MRD quantification remained stable; however, at least one of the preferred markers for MRD stratification at relapse was different to diagnosis in 50% of patients. A similar proportion of very early, early and late relapses appeared to gain a marker at relapse although backtracking-analysis revealed that in 77% of cases, the gained markers were present as small sub-clones at initial diagnosis. Comparing initial and relapse MRD response to induction, 38% of patients showed a similar, 38% a better and 25% a poorer response after relapse. These data demonstrate an unexpectedly high clonal heterogeneity among very early/early relapses and challenge some current assumptions about relapsed ALL. PMID- 21546903 TI - Pro-apoptotic activity of inhibitory PAS domain protein (IPAS), a negative regulator of HIF-1, through binding to pro-survival Bcl-2 family proteins. AB - Inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS) is a dominant negative transcription factor that represses hypoxia-inducible factor 1 (HIF-1) activity. In this study, we show that IPAS also functions as a pro-apoptotic protein through binding to pro-survival Bcl-2 family members. In a previous paper, we reported that NF-kappaB-dependent IPAS induction by cobalt chloride repressed the hypoxic response in PC12 cells. We found that prolonged incubation under the same conditions caused apoptosis in PC12 cells. Repression of IPAS induction protected cells from apoptosis. Furthermore, knockdown of IPAS recovered cell viability. EGFP-IPAS protein was localized in both the nucleus and the cytoplasm, with a large fraction associated with mitochondria. Mitochondrial IPAS induced mitochondria depolarization and caspase-3 activation. Immunoprecipitation assays revealed that IPAS is associated with Bcl-x(L), Bcl-w and Mcl-1. The association of IPAS with Bcl-x(L) was also observed in living cells by the FLIM-based FRET analysis, indicating direct binding between the two proteins. IPAS contributed to dysfunction of Bcl-x(L) by inhibiting the interaction of Bcl-x(L) with Bax. These results demonstrate that IPAS functions as a dual function protein involved in transcription repression and apoptosis. PMID- 21546904 TI - Polycomb protein EZH2 regulates cancer cell fate decision in response to DNA damage. AB - Polycomb protein histone methyltransferase enhancer of Zeste homologe 2 (EZH2) is frequently overexpressed in human malignancy and is implicated in cancer cell proliferation and invasion. However, it is largely unknown whether EZH2 has a role in modulating DNA damage response. Here, we show that EZH2 is an important determinant of cell fate decision in response to genotoxic stress. EZH2 depletion results in abrogation of both cell cycle G1 and G2/M checkpoints, directing DNA damage response toward predominant apoptosis in both p53-proficient and p53 deficient cancer cells, but not in normal cells. Mechanistically, EZH2 regulates DNA damage response in p53 wild-type cells mainly through transcriptional repression of FBXO32, which binds to and directs p21 for proteasome-mediated degradation, whereas it affects p53-deficient cells through regulating Chk1 activation by a distinct mechanism. Furthermore, pharmacological depletion of EZH2 phenocopies the effects of EZH2 knockdown on cell cycle checkpoints and apoptosis. These data unravel a crucial role of EZH2 in determining the cancer cell outcome following DNA damage and suggest that therapeutic targeting oncogenic EZH2 might serve as a strategy for improving conventional chemotherapy in a given malignancy. PMID- 21546905 TI - Dysregulation of upstream binding factor-1 acetylation at K352 is linked to impaired ribosomal DNA transcription in Huntington's disease. AB - Huntington's disease (HD) is an autosomal-dominant neurological disorder caused by expanded CAG repeats in the Huntingtin (Htt) gene, but it is not known how this mutation causes neurodegeneration. Herein, we found that dysfunction of upstream binding factor-1 (UBF-1) is linked to reduced ribosomal DNA (rDNA) transcription in HD. We identified that UBF1 acetylation at Lys (K) 352 by CREB binding protein (CBP) is crucial for the transcriptional activity of rDNA. UBF1 mutation (K352A, K352Q, and K352R) decreased rDNA transcriptional activity. Moreover, both CBP-dHAT mutant and knockdown of CBP by siRNA reduced acetylation of UBF1 and resulted in the decreased transcription of rDNA into rRNA. ChIP analysis showed a significant reduction of UBF1 occupancy in the promoter of rDNA in STHdh(Q111) cell line model of HD. These results demonstrate that abnormal activity of UBF1 and its acetylation by CBP are linked to impaired rDNA transcription in HD. This novel mechanism suggests that modulation of UBF mediated rDNA synthesis by CBP may be a therapeutic target for improving neuronal rDNA transcription in HD. PMID- 21546906 TI - Zac1 is a histone acetylation-regulated NF-kappaB suppressor that mediates histone deacetylase inhibitor-induced apoptosis. AB - Histone deacetylase (HDAC) inhibitors are a class of promising anticancer reagents. They are able to induce apoptosis in embryonic carcinoma (EC) cells. However, the underlying mechanism remains poorly understood. Here we show that increased expression of zinc-finger protein regulator of apoptosis and cell-cycle arrest (Zac1) is implicated in HDAC inhibitor-induced apoptosis in F9 and P19 EC cells. By chromatin immunoprecipitation analysis we identified that increased Zac1 expression is mediated by histone acetylation of the Zac1 promoter region. Knockdown of Zac1 inhibited HDAC inhibitor-induced cell apoptosis. Moreover, HDAC inhibitors repressed nuclear factor-kappaB (NF-kappaB) activity, and this effect is abrogated by Zac1 knockdown. Consistently, Zac1 overexpression suppressed cellular NF-kappaB activity. Further investigation showed that Zac1 inhibits NF kappaB activity by interacting with the C-terminus of the p65 subunit, which suppresses the phosphorylation of p65 at Ser468 and Ser536 residues. These results indicate that Zac1 is a histone acetylation-regulated suppressor of NF kappaB, which is induced and implicated in HDAC inhibitor-mediated EC cell apoptosis. PMID- 21546907 TI - Abrogation of Wip1 expression by RITA-activated p53 potentiates apoptosis induction via activation of ATM and inhibition of HdmX. AB - Inactivation of the p53 tumour suppressor, either by mutation or by overexpression of its inhibitors Hdm2 and HdmX is the most frequent event in cancer. Reactivation of p53 by targeting Hdm2 and HdmX is therefore a promising strategy for therapy. However, Hdm2 inhibitors do not prevent inhibition of p53 by HdmX, which impedes p53-mediated apoptosis. Here, we show that p53 reactivation by the small molecule RITA leads to efficient HdmX degradation in tumour cell lines of different origin and in xenograft tumours in vivo. Notably, HdmX degradation occurs selectively in cancer cells, but not in non-transformed cells. We identified the inhibition of the wild-type p53-induced phosphatase 1 (Wip1) as the major mechanism important for full engagement of p53 activity accomplished by restoration of the ataxia telangiectasia mutated (ATM) kinase signalling cascade, which leads to HdmX degradation. In contrast to previously reported transactivation of Wip1 by p53, we observed p53-dependent repression of Wip1 expression, which disrupts the negative feedback loop conferred by Wip1. Our study reveals that the depletion of both HdmX and Wip1 potentiates cell death due to sustained activation of p53. Thus, RITA is an example of a p53-reactivating drug that not only blocks Hdm2, but also inhibits two important negative regulators of p53 - HdmX and Wip1, leading to efficient elimination of tumour cells. PMID- 21546908 TI - Integration of CNS survival and differentiation by HIF2alpha. AB - Hypoxia-inducible factor (HIF) 1alpha and HIF2alpha and the inhibitor of apoptosis survivin represent prominent markers of many human cancers. They are also widely expressed in various embryonic tissues, including the central nervous system; however, little is known about their functions in embryos. Here, we show that zebrafish HIF2alpha protects neural progenitor cells and neural differentiation processes by upregulating the survivin orthologues birc5a and birc5b during embryogenesis. Morpholino-mediated knockdown of hif2alpha reduced the transcription of birc5a and birc5b, induced p53-independent apoptosis and abrogated neural cell differentiation. Depletion of birc5a and birc5b recaptured the neural development defects that were observed in the hif2alpha morphants. The phenotypes induced by HIF2alpha depletion were largely rescued by ectopic birc5a and birc5b mRNAs, indicating that Birc5a and Birc5b act downstream of HIF2alpha. Chromatin immunoprecipitation assay revealed that HIF2alpha binds to birc5a and birc5b promoters directly to modulate their transcriptions. Knockdown of hif2alpha, birc5a or birc5b reduced the expression of the cdk inhibitors p27/cdkn1b and p57/cdkn1c and increased ccnd1/cyclin D1 transcription in the surviving neural progenitor cells. The reduction in elavl3/HuC expression and enhanced pcna, nestin, ascl1b and sox3 expression indicate that the surviving neural progenitor cells in hif2alpha morphants maintain a high proliferation rate without terminally differentiating. We propose that a subset of developmental defects attributed to HIF2alpha depletion is due in part to the loss of survivin activity. PMID- 21546909 TI - A plant alternative to animal caspases: subtilisin-like proteases. AB - Activities displaying caspase cleavage specificity have been well documented in various plant programmed cell death (PCD) models. However, plant genome analyses have not revealed clear orthologues of caspase genes, indicating that enzyme(s) structurally unrelated yet possessing caspase specificity have functions in plant PCD. Here, we review recent data showing that some caspase-like activities are attributable to the plant subtilisin-like proteases, saspases and phytaspases. These proteases hydrolyze a range of tetrapeptide caspase substrates following the aspartate residue. Data obtained with saspases implicate them in the proteolytic degradation of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) during biotic and abiotic PCD, whereas phytaspase overproducing and silenced transgenics provide evidence that phytaspase regulates PCD during both abiotic (oxidative and osmotic stresses) and biotic (virus infection) insults. Like caspases, phytaspases and saspases are synthesized as proenzymes, which are autocatalytically processed to generate a mature enzyme. However, unlike caspases, phytaspases and saspases appear to be constitutively processed and secreted from healthy plant cells into the intercellular space. Apoplastic localization presumably prevents enzyme-mediated protein fragmentation in the absence of PCD. In response to death-inducing stimuli, phytaspase has been shown to re-localize to the cell interior. Thus, plant PCD-related proteases display both common (D-specific protein fragmentation during PCD) and distinct (enzyme structure and activity regulation) features with animal PCD-related proteases. PMID- 21546910 TI - Cease and desist: modulating short-range Dpp signalling in the stem-cell niche. AB - Drosophila ovarian germline stem cells (GSCs) are maintained by the extracellular BMP2/4 orthologue Dpp, which is produced from the surrounding somatic niche. The Dpp signal has a short range; it induces a response in GSCs within the niche, but is rapidly extinguished in their progeny only one cell-diameter away. To ensure the correct balance between stem-cell maintenance and differentiation, several regulatory mechanisms that modulate the Dpp signal at many stages of the pathway have been described. Here, we discuss the nature of the ovarian Dpp signal and review the catalogue of mechanisms that regulate it, demonstrating how the exquisite modulation of Dpp signalling in this context can result in precise and robust control of stem-cell fate. This modulation is applicable to other stem cell environments that use BMPs as a niche signal, and the regulatory mechanisms are conceptually relevant to several other stem-cell systems. PMID- 21546912 TI - Role of the import motor in insertion of transmembrane segments by the mitochondrial TIM23 complex. AB - The TIM23 complex mediates translocation of proteins across, and their lateral insertion into, the mitochondrial inner membrane. Translocation of proteins requires both the membrane-embedded core of the complex and its ATP-dependent import motor. Insertion of some proteins, however, occurs in the absence of ATP, questioning the need for the import motor during lateral insertion. We show here that the import motor associates with laterally inserted proteins even when its ATPase activity is not required. Furthermore, our results suggest a role for the import motor in lateral insertion. Thus, the import motor is involved in ATP dependent translocation and ATP-independent lateral insertion. PMID- 21546911 TI - Wolbachia and the biological control of mosquito-borne disease. AB - Mosquito-borne diseases such as malaria, dengue fever and filariasis cause an enormous health burden to people living in tropical and subtropical regions of the world. Despite years of intense effort to control them, many of these diseases are increasing in prevalence, geographical distribution and severity, and options to control them are limited. The transinfection of mosquitos with the maternally inherited, endosymbiotic bacteria Wolbachia is a promising new biocontrol approach. Fruit fly Wolbachia strains can invade and sustain themselves in mosquito populations, reduce adult lifespan, affect mosquito reproduction and interfere with pathogen replication. Wolbachia-infected Aedes aegypti mosquitoes have been released in areas of Australia in which outbreaks of dengue fever occur, as a prelude to the application of this technology in dengue endemic areas of south-east Asia. PMID- 21546913 TI - Life's demons: information and order in biology. What subcellular machines gather and process the information necessary to sustain life? PMID- 21546914 TI - The outs and the ins of sphingosine-1-phosphate in immunity. AB - The potent lipid mediator sphingosine-1-phosphate (S1P) is produced inside cells by two closely related kinases, sphingosine kinase 1 (SPHK1) and SPHK2, and has emerged as a crucial regulator of immunity. Many of the actions of S1P in innate and adaptive immunity are mediated by its binding to five G protein-coupled receptors, designated S1PR1-5, but recent findings have also identified important roles for S1P as a second messenger during inflammation. In this Review, we discuss recent advances in our understanding of the roles of S1P receptors and describe the newly identified intracellular targets of S1P that are crucial for immune responses. Finally, we discuss the therapeutic potential of new drugs that target S1P signalling and functions. PMID- 21546915 TI - Characteristics of fine vascular network pattern associated with recurrence of polypoidal choroidal vasculopathy. AB - OBJECTIVE: To characterize an irregular capillary-like structure in the vascular network of eyes with polypoidal choroidal vasculopathy (PCV), and to determine whether its presence after photodynamic therapy (PDT) can be used to predict the clinical course of PCV. METHODS: We reviewed the clinical records of 29 eyes of 29 patients with PCV, who underwent PDT and confocal retinal angiographic examinations every 3 months. The images obtained before the PDT were compared with those after the PDT. The correlations between angiography findings and recurrences were evaluated. RESULTS: An area of fine, densely packed capillary like vessels, named the fine vascular network, was identified within the polypoidal vascular network in 25 of 29 cases at the initial examination. The fine vascular network regressed in 23 cases (92%) after the first PDT. Thereafter, the fine vascular network remained or enlarged in 19 eyes, and 17 (84.5%) of these eyes had a recurrence of the polypoidal lesions or had exudative changes. In contrast, recurrences were found in only 2 of 10 (20%) eyes, whose fine network had regressed without a subsequent enlargement (P<0.001 compared with the former group). CONCLUSIONS: A fine irregular vascular network is present in the majority of eyes with PCV before PDT. Its presence or expansion after PDT was significantly associated with a recurrence of PCV. Thus, we recommend that this network be monitored after treatment to determine whether a polypoidal vascular network will recur. PMID- 21546916 TI - The burden of disease of retinal vein occlusion: review of the literature. AB - Retinal vein occlusion (RVO) is the second most common cause of vision loss due to retinal vascular disease. A literature review was undertaken to understand the epidemiology, clinical consequence, current practice patterns, and cost of RVO. Pertinent articles were identified by computerized searches of the English language literature in MEDLINE supplemented with electronic and manual searches of society/association proceedings and bibliographies of electronically identified sources. Population-based studies report a prevalence rate of 0.5-2.0% for branch RVO and 0.1-0.2% for central RVO. The 15-year incidence rate is estimated to be 1.8% for branch RVO and 0.2% for central RVO. Patients with RVO report lower vision-related quality of life than those without ocular disease. Available treatment options are limited. Until recently there was no treatment for central RVO. Laser photocoagulation is only recommended for branch RVO in patients who have not experienced severe vision loss. Emerging evidence on the effectiveness of intravitreal anti-vascular endothelial growth factor therapy and dexamethasone intravitreal implant is promising. Information on the treatment patterns and cost of RVO is extremely limited with one retrospective analysis of secondary insurance payment data identified and limited to the United States population only. A better understanding of the economic and societal impact of RVO will help decision makers evaluate emerging medical interventions for this sight-threatening disease. PMID- 21546917 TI - Idiopathic uveal effusion syndrome causing unilateral acute angle closure in a pseudophakic patient. PMID- 21546918 TI - Development of optic disc drusen in familial pseudopapilloedema: a paediatric case series. PMID- 21546919 TI - Cryptococcal-related exudative retinal detachment. PMID- 21546921 TI - Angle closure glaucoma associated with ectopia lentis in a patient with Sturge Weber syndrome. PMID- 21546920 TI - The biomechanical properties of the cornea in patients with systemic lupus erythematosus. AB - PUPOSE: The purpose of this study was to compare the biomechanical properties of the cornea and intraocular pressure (IOP) between patients with systemic lupus erythematosis (SLE) and age-matched controls. PATIENTS AND METHODS: In this prospective study, 30 healthy individuals (control group) and 30 patients with SLE (study group) underwent Reichert ocular response analyzer (ORA) measurements. In the right eye of each participant, the corneal hysteresis (CH), corneal resistance factor (CRF), and Goldman-related IOP (IOPg) were recorded using the ORA. RESULTS: Mean CH, CRF, IOPg were significantly different between groups. Mean CH was 10.2 +/- 0.6 mm Hg in the study group and 11.3 +/- 1.3 in the control group (P=0.02); mean CRF was 9.7 +/- 1.1 mm Hg and 11.9 +/- 1.5 mm Hg, respectively (P=0.001). Mean IOP(g) was 13.9 +/- 2.9 mm Hg in the study group and 16.9 +/- 2.6 mm Hg in the control group (P=0.001). CONCLUSION: The biomechanical properties of the cornea are altered in patients with SLE compared with normal controls. These findings should be taken into account when measuring IOP values in patients with SLE as IOP readings may be underestimated in SLE eyes. PMID- 21546922 TI - The cataract national data set electronic multi-centre audit of 55,567 operations: case-mix adjusted surgeon's outcomes for posterior capsule rupture. AB - AIMS: To develop a methodology for case-mix adjustment of surgical outcomes for individual cataract surgeons using electronically collected multi-centre data conforming to the cataract national data set (CND). METHODS: Routinely collected anonymised data were remotely extracted from electronic patient record (EPR) systems in 12 participating NHS Trusts undertaking cataract surgery. Following data checks and cleaning, analyses were carried out to risk adjust outcomes for posterior capsule rupture rates for individual surgeons, with stratification by surgical grade. RESULTS: A total of 406 surgeons from 12 NHS Trusts submitted data on 55,567 cataract operations between November 2001 and July 2006 (86% from January 2004). In all, 283 surgeons contributed data on >25 cases, providing 54,319 operations suitable for detailed analysis. Case-mix adjusted results of individual surgeons are presented as funnel plots for all surgeons together, and separately for three different grades of surgeon. Plots include 95 and 99.8% confidence limits around the case-mix adjusted outcomes for detection of surgical outliers. CONCLUSIONS: Routinely collected electronic data conforming to the CND provides sufficient detail for case-mix adjustment of cataract surgical outcomes. The validation of these risk indicators should be carried out using fresh data to confirm the validity of the risk model. Once validated this model should provide an equitable approach for peer-to-peer comparisons in the context of revalidation. PMID- 21546923 TI - Association between corneal biomechanical properties and myopia in Chinese subjects. AB - PURPOSE: To examine the relationship between corneal biomechanical properties and the degree of myopia. METHODS: Chinese subjects (n=172, age: 11-65 years) were divided into diagnostic groups with non-myopia (spherical equivalence (SE)>-0.50 D), low (-3.00 <= SE <= -0.50 D), moderate (-6.00 <= SE < -3.00 D), and high myopia (SE<-6.00 D). Only the right eye of each subject was analyzed. Central corneal thickness (CCT) was measured by optical coherence tomography. An ocular response analyzer was used to measure corneal hysteresis (CH), corneal resistance factor (CRF), intraocular pressure (IOP), and corneal compensated IOP (IOPcc). Refraction was measured by both automated and subjective refractometry and expressed as SE. RESULTS: CH was significantly lower in high myopia compared with both low and non-myopia (P <= 0.002). CCT was 1.5 times more correlated to CH variation compared with refraction. Similarly, CRF was four times more dependent on CCT than refraction. CH (P<0.001) or CRF (P=0.005) was positively correlated to refraction. Both IOP and IOPcc were negatively correlated to refraction (P<0.001), respectively. CONCLUSIONS: CH decreases only in high myopia. Refraction is positively correlated to both CH and CRF but negatively correlated to both IOP and IOPcc. These results indicate that the mechanical strength in anterior segment of the eye is compromised in high myopia. In addition, high myopia may increase the risk of glaucoma. PMID- 21546924 TI - Induction of the glucocorticoid-induced leucine zipper gene limits the efficacy of dendritic cell vaccines. AB - Dendritic cell (DC) vaccines have shown great promise in generating antitumor immune responses but have generally fallen short of producing durable cures. Determining mechanisms by which these vaccines fail will provide one strategy toward improving their success. Several manipulations of DCs have improved their migration and longevity, but the immune inhibitory environment surrounding tumors provides a powerful suppressive influence. To determine the mechanisms by which DCs at the site of the tumor convert to a suppressive phenotype, we evaluated pathways in DCs that become expressed at the tumor site. Our results revealed that tumors lead to induction of the glucocorticoid-induced leucine zipper (GILZ) gene in DCs, and that this gene is critical for the development of tumor-induced tolerance of both DCs and T cells. Previous data suggested that GILZ is a pivotal gene in the balance between activation and tolerance of DCs. Our new data show that GILZ is highly upregulated in DCs in the tumor microenvironment in vivo and that blockade of this gene in DC vaccines significantly improves long-term survival. These results suggest that GILZ may be an ideal candidate gene to target for novel immune-based tumor therapies. PMID- 21546925 TI - MDA-7 results in downregulation of AKT concomitant with apoptosis and cell cycle arrest in breast cancer cells. AB - The melanoma differentiation-associated gene-7 (mda-7) is a known mediator of apoptosis in cancer cells but not in normal cells. We hypothesized that MDA-7 interferes with the prosurvival signaling pathways that are commonly altered in cancer cells to induce growth arrest and apoptosis. We also identified the cell signaling pathways that are antagonized by MDA-7 leading to apoptosis. Using an adenoviral expression system, mda-7 was introduced into the breast cancer cell lines SKBr3, MCF-7 and MDA-MB-468, each with a different estrogen receptor (ER) and HER-2 receptor status. Downstream targets of MDA-7 were assessed by reverse phase protein array analysis, western blot analysis and immunofluorescence confocal microscopy. Our results show that MDA-7-induced apoptosis was mediated by caspases in all cell lines tested. However, MDA-7 modulates additional pathways in SKBr3 (HER-2 positive) and MCF-7 (ER positive) cells including downregulation of AKT-GSK3beta and upregulation of cyclin-dependent kinase inhibitors in the nucleus. This leads to cell cycle arrest in addition to apoptosis. In conclusion, MDA-7 abrogates tumor-promoting pathways including the activation of caspase-dependent signaling pathways ultimately leading to apoptosis. In addition, depending on the phenotype of the breast cancer cell, MDA 7 modulates cell cycle regulating pathways to mediate cell cycle arrest. PMID- 21546926 TI - Reducing obesity stigma: the effectiveness of cognitive dissonance and social consensus interventions. AB - Obese individuals experience pervasive stigmatization. Interventions attempting to reduce obesity stigma by targeting its origins have yielded mixed results. This randomized, controlled study examined the effectiveness of two interventions to reduce obesity stigma: cognitive dissonance and social consensus. Participants were college undergraduate students (N = 64, 78% women, mean age = 21.2 years, mean BMI = 23.1 kg/m2) of diverse ethnicities. Obesity stigma (assessed with the Antifat Attitudes Test (AFAT)) was assessed at baseline (Visit 1) and 1 week later, immediately following the intervention (Visit 2). Participants were randomly assigned to one of three intervention groups where they received standardized written feedback on their obesity stigma levels. Cognitive dissonance participants (N = 21) were told that their AFAT scores were discrepant from their values (high core values of kindness and equality and high stigma), social consensus participants (N = 22) were told their scores were discrepant from their peers' scores (stigma much higher than their peers), and control participants (N = 21) were told their scores were consistent with both their peers' scores and their own values. Following the intervention, omnibus analyses revealed significant group differences on the AFAT Physical/Romantic Unattractiveness subscale (PRU; F (2, 59) = 4.43, P < 0.05). Planned contrasts revealed that cognitive dissonance group means were significantly lower than control means for AFAT total, AFAT PRU subscale, and AFAT social/character disparagement subscale (all P < 0.05). No significant differences were found between social consensus and controls. Results from this study suggest that cognitive dissonance interventions may be a successful way to reduce obesity stigma, particularly by changing attitudes about the appearance and attractiveness of obese individuals. PMID- 21546927 TI - Neural responses to visual food stimuli after a normal vs. higher protein breakfast in breakfast-skipping teens: a pilot fMRI study. AB - This functional magnetic resonance imaging (fMRI) pilot study identified whether breakfast consumption would alter the neural activity in brain regions associated with food motivation and reward in overweight "breakfast skipping" (BS) adolescent girls and examined whether increased protein at breakfast would lead to additional alterations. Ten girls (Age: 15 +/- 1 years; BMI percentile 93 +/- 1%; BS 5 +/- 1*/week) completed 3 testing days. Following the BS day, the participants were provided with, in randomized order, normal protein (NP; 18 +/- 1 g protein) or higher protein (HP; 50 +/- 1 g protein) breakfast meals to consume at home for 6 days. On day 7 of each pattern, the participants came to the laboratory to consume their respective breakfast followed by appetite questionnaires and an fMRI brain scan to identify brain activation responses to viewing food vs. nonfood images prior to lunch. Breakfast consumption led to enduring (i.e., 3-h post breakfast) reductions in neural activation in the hippocampus, amygdala, cingulate, and parahippocampus vs. BS. HP led to enduring reductions in insula and middle prefrontal cortex activation vs. NP. Hippocampal, amygdala, cingulate, and insular activations were correlated with appetite and inversely correlated with satiety. In summary, the addition of breakfast led to alterations in brain activation in regions previously associated with food motivation and reward with additional alterations following the higher-protein breakfast. These data suggest that increased dietary protein at breakfast might be a beneficial strategy to reduce reward-driven eating behavior in overweight teen girls. Due to the small sample size, caution is warranted when interpreting these preliminary findings. PMID- 21546928 TI - Body fat and racial genetic admixture are associated with aerobic fitness levels in a multiethnic pediatric population. AB - Aerobic fitness and adiposity are each independently associated with health outcomes among children, although the relationship between these two variables is unclear. Our objectives were to evaluate (i) the association of adiposity with aerobic fitness using objectively measured levels of percent body fat, compared to BMI as a percentile proxy for adiposity while controlling for genetic admixture, and (ii) the congruence of BMI categories with high and low body fat categories of objectively measured percent body fat. Participants were 232 African-American (AA), European-American (EA), and Hispanic-American (HA) children aged 7-12 years (Tanner stage <3). Aerobic fitness was measured via a submaximal indirect calorimetry treadmill test (VO(2-170)), and physical activity levels with accelerometry. Genetic admixture estimates were obtained using 140 genetic ancestry informative markers to estimate European, African, and Amerindian admixture. Fat mass was determined using dual-energy x-ray absorptiometry (DXA). Children were classified into a low body fat group (<25% in males, <30% in females) or a high body fat group based on their percent body fat; children were also categorized according to BMI percentile. Children in the low body fat group had significantly higher aerobic fitness (P < 0.05) regardless of BMI percentile classification. Higher African genetic admixture was associated with lower aerobic fitness (P < 0.05), while physical activity was positively associated with fitness (P < 0.01). In conclusion, aerobic fitness levels differ by percent body fat and genetic admixture irrespective of BMI classification, and such differences should be taken into account when evaluating outcomes of health interventions. PMID- 21546929 TI - Cardiovascular regulation profile predicts developmental trajectory of BMI and pediatric obesity. AB - The present study examined the role of cardiovascular regulation in predicting pediatric obesity. Participants for this study included 268 children (141 girls) obtained from a larger ongoing longitudinal study. To assess cardiac vagal regulation, resting measures of respiratory sinus arrhythmia (RSA) and RSA change (vagal withdrawal) to three cognitively challenging tasks were derived when children were 5.5 years of age. Heart period (HP) and HP change (heart rate (HR) acceleration) were also examined. Height and weight measures were collected when children were 5.5, 7.5, and 10.5 years of age. Results indicated that physiological regulation at age 5.5 was predictive of both normal variations in BMI development and pediatric obesity at age 10.5. Specifically, children with a cardiovascular regulation profile characterized by lower levels of RSA suppression and HP change experienced significantly greater levels of BMI growth and were more likely to be classified as overweight/at-risk for overweight at age 10.5 compared to children with a cardiovascular regulation profile characterized by high levels of RSA suppression and HP change. However, a significant interaction with racial status was found suggesting that the association between cardiovascular regulation profile and BMI growth and pediatric obesity was only significant for African-American children. An autonomic cardiovascular regulation profile consisting of low parasympathetic activity represents a significant individual risk factor for the development of pediatric obesity, but only for African-American children. Mechanisms by which early physiological regulation difficulties may contribute to the development of pediatric obesity are discussed. PMID- 21546930 TI - Peripheral-specific y2 receptor knockdown protects mice from high-fat diet induced obesity. AB - Y2 receptors, particularly those in the brain, have been implicated in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone mass. Recent evidence also indicates a role for Y2 receptors in peripheral tissues in this process by promoting adipose tissue accretion; however their effects on energy balance remain unclear. Here, we show that adult-onset conditional knockdown of Y2 receptors predominantly in peripheral tissues results in protection against diet-induced obesity accompanied by significantly reduced weight gain, marked reduction in adiposity and improvements in glucose tolerance without any adverse effect on lean mass or bone. These changes occur in association with significant increases in energy expenditure, respiratory exchange ratio, and physical activity and despite concurrent hyperphagia. On a chow diet, knockdown of peripheral Y2 receptors results in increased respiratory exchange ratio and physical activity with no effect on lean or bone mass, but decreases energy expenditure without effecting body weight or food intake. These results suggest that peripheral Y2 receptor signaling is critical in the regulation of oxidative fuel selection and physical activity and protects against the diet-induced obesity. The lack of effects on bone mass seen in this model further indicates that bone mass is primarily controlled by non-peripheral Y2 receptors. This study provides evidence that novel drugs that target peripheral rather than central Y2 receptors could provide benefits for the treatment of obesity and glucose intolerance without adverse effects on lean and bone mass, with the additional benefit of avoiding side effects often associated with pharmaceuticals that act on the central nervous system. PMID- 21546931 TI - Psychometric properties and construct validity of the Weight-Related Eating Questionnaire in a diverse population. AB - This study evaluates the 16-item, four-factor Weight-Related Eating Questionnaire (WREQ), which assesses theory-based aspects of eating behavior, across diverse, nonclinical subgroups. A total of 621 men and women aged 18-81 years (34.3 +/- 16.4) with a mean BMI of 25.7 +/- 6.1 kg/m(2) (range 15.5-74.1 kg/m(2)) were recruited from general education classes at the University of Hawai'i, Manoa and an online survey panel of Hawai'i residents to complete a web-based survey. Participants were predominantly white (23%), Asian/Asian-mix (42%), or Native Hawaiian/Pacific Islander (18%). The WREQ's factor structure was successfully replicated by confirmatory factor analysis (CFA) for the entire sample and by weight status, gender, age, and race with strong internal consistency. Four-week test-retest reliability (n = 31) for the subscales was excellent with interclass correlations of 0.849-0.932. Tests of population invariance confirmed the generalizability of the WREQ across all subgroups having provided no evidence that the factor structure, factor loadings, or indicator intercepts varied significantly between the groups. Multivariate regression analyses showed that emotional eating was independently associated with BMI (beta = 0.272, P < 0.001) as well as moderate- and long-term weight change rates (weight gain) in young adults (beta = 0.152, P = 0.042) and adults (beta = 0.217, P = 0.001). Compensatory restraint was negatively associated with weight gain in adults (beta = -0.133, P = 0.039). Routine restraint and emotional eating were highest among dieters. All associations remained significant after accounting for gender, age, and race. The hypothesized WREQ measurement model demonstrated very good construct validity, confirming the unbiased generalizability of the WREQ measure across sex, age, race, and BMI subgroups, and excellent criterion-related validity with respect to current BMI, weight change, and weight control status. PMID- 21546932 TI - Follistatin and follistatin like-3 differentially regulate adiposity and glucose homeostasis. AB - Transforming growth factor-beta superfamily ligands, including activin and myostatin, modulate body composition, islet function, and glucose homeostasis. Their bioactivity is controlled by the antagonists follistatin (FST) and FST like 3 (FSTL3). The hypothesis tested was that FST and FSTL3 have distinct roles in regulating body composition, glucose homeostasis, and islet function through regulation of activin and myostatin bioactivity. Three genetic mutant mouse lines were created. FSTL3 knockout (FSTL3 KO), a mouse line producing only the FST288 isoform (FST288-only) and a double mutant (2xM) in which the lines were crossed. FST288-only males were lighter that wild-type (WT) littermates while FSTL3 KO and 2xM males had reduced perigonadal fat pad weights. However, only 2xM mice had increased whole body fat mass and decreased lean mass by quantitative nuclear magnetic resonance (qNMR). Fasting glucose levels in FSTL3 WT and KO mice were lower than FST mice in younger animals but were higher in older mice. Serum insulin and pancreatic insulin content in 2xM mice was significantly elevated over other genotypes. Nevertheless, 2xM mice were relatively insulin resistant and glucose intolerant compared to FST288-only and WT mice. Fractional islet area and proportion of beta-cells/islet were increased in FSTL3 KO and 2xM, but not FST288-only mice. Despite their larger size, islets from FSTL3 KO and 2xM mice were not functionally enhanced compared to WT mice. These results demonstrate that body composition and glucose homeostasis are differentially regulated by FST and FSTL3 and that their combined loss is associated with increased fat mass and insulin resistance despite elevated insulin production. PMID- 21546934 TI - Cysteine and obesity. PMID- 21546933 TI - Associations of serum 25-hydroxyvitamin D and components of the metabolic syndrome in obese adolescent females. AB - Vitamin D deficiency may increase the risk for metabolic syndrome. We determined the relationship of serum 25-hydroxyvitamin D (25(OH)D) with metabolic syndrome components in obese adolescent females and assessed whether vitamin D treatment corrects metabolic disturbances. Eighty postmenarchal adolescents (53 African American (AA) and 27 Caucasian American (CA)) were evaluated with blood pressures and fasting measurements of serum 25(OH)D, lipid profile, C-reactive protein, alanine transaminases (ALTs) and aspartate transaminases followed by an oral glucose tolerance test. A subgroup (n = 14) of vitamin D deficient subjects were re-evaluated following vitamin D treatment. Among all subjects, 25(OH)D was inversely associated with fasting glucose (r = -0.28, P = 0.02) and positively associated with low-density lipoprotein (LDL) cholesterol (r = 0.31, P = 0.008), independent of race and BMI. In analyses by race, adjusted for BMI, 25(OH)D was inversely associated with fasting insulin in CA (r = -0.42, P = 0.03) but not AA (r = 0.11, P = 0.43) whereas 25(OH)D was positively associated with ALT in AA, but not CA (r = 0.29, P = 0.04 vs. r = -0.21, P = 0.32). Fasting glucose improved in vitamin D treated subgroup (from 89.07 +/- 8.3 mg/dl to 84.34 +/- 8.4 mg/dl, P = 0.05). A trend toward improvement in fasting glucose remained after exclusion of four subjects whose serum 25(OH)D(2) did not improve following treatment (P = 0.12). In conclusion, serum 25(OH)D was inversely associated with fasting glucose, and vitamin D treatment had beneficial effects on fasting glucose. Relationships of 25(OH)D with fasting insulin and ALT were ethnic specific. The positive relationship with LDL and ALT were suggestive of possible adverse influences of vitamin D. PMID- 21546936 TI - Comparison of measures of adiposity in identifying cardiovascular disease risk among Ethiopian adults. AB - We sought to determine which measures of adiposity can predict cardiovascular disease (CVD) risk and to evaluate the extent to which overall and abdominal adiposity are associated with cardiometabolic risk factors among working adults in Ethiopia. This was a cross-sectional study of 1,853 individuals (1,125 men, 728 women) in Addis Ababa, Ethiopia. The World Health Organization STEPwise approach was used to collect sociodemographic data, anthropometric measurements, and blood samples among study subjects. Fasting blood glucose (FBG) and lipid concentrations were measured using standard approaches. Spearman's rank correlation, receiver operating characteristic (ROC) curves, and logistic regression were employed to determine the association and predictive ability (with respect to CVD risk factors) of four measures of adiposity: BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Overall, FBG is best associated with WHtR in men and WC in women. Systolic blood pressure (SBP) is most strongly associated with BMI in men, but with WC in women. Compared to those with low BMI and low WC, the risk of having CVD is the highest for those with high BMI and high WC and those with high WC and low BMI. Review of ROC curves indicated that WC is the best predictor of CVD risk among study subjects. Findings from our study underscore the feasibility and face validity of using simple measures of central and overall adiposity in identifying CVD risk in resource-poor settings. PMID- 21546937 TI - Predictors of accurate maternal perception of their preschool child's weight status among Hispanic WIC participants. AB - Childhood obesity is a growing problem in the United States. Parental perception of their children's weight status is a key factor that needs to be considered when developing prevention programs for preschool children. Using a randomly selected sample of participants of Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in Los Angeles County, we assessed accuracy of maternal perceptions of their children's weight status by comparing children's weight classification to the mothers' response to the question "Do you consider your child to be overweight, underweight or about right weight for (his) (her) height?" Additionally, we identified possible predictors of accurate maternal perception of their children's weight status by conducting a logistic regression model with child's gender, child's birth weight, maternal age, maternal BMI, maternal education, maternal acculturation level, and maternal language preference as potential predictors. Almost all mothers in the study classified their overweight or obese child as being about the right weight (93.6% and 77.5% of mothers, respectively). Maternal BMI and child's birth weight were the only predictors of maternal perception of their child's weight. Both were negatively associated with accuracy, with higher maternal BMI and higher infant birthweight associated with less accurate maternal perception of child weight. Parents need to be educated on the importance of childhood obesity and how to identify if their children are overweight or obese. If parents fail to recognize that their overweight child is overweight, then it is unlikely that they will recognize that interventions targeting obesity are relevant to their families. PMID- 21546935 TI - Gastric bypass surgery reduces plasma ceramide subspecies and improves insulin sensitivity in severely obese patients. AB - Bariatric surgery is associated with near immediate remission of type 2 diabetes and hyperlipidemia. The mechanisms underlying restoration of normal glucose tolerance postoperatively are poorly understood. Herein, we examined the effect of Roux-en-Y gastric bypass surgery (RYGB) on weight loss, insulin sensitivity, plasma ceramides, proinflammatory markers, and cardiovascular risk factors before and at 3 and 6 months after surgery. Thirteen patients (10 female; age 48.5 +/- 2.7 years; BMI, 47.4 +/- 1.5 kg/m(2)) were included in the study, all of whom had undergone laparoscopic RYGB surgery. Insulin sensitivity, inflammatory mediators and fasting lipid profiles were measured at baseline, 3 and 6 months postoperatively, using enzymatic analysis. Plasma ceramide subspecies (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1) were quantified using electrospray ionization tandem mass spectrometry after separation with HPLC. At 3 months postsurgery, body weight was reduced by 25%, fasting total cholesterol, triglycerides, low-density lipoproteins, and free fatty acids were decreased, and insulin sensitivity was increased compared to presurgery values. These changes were all sustained at 6 months. In addition, total plasma ceramide levels decreased significantly postoperatively (9.3 +/- 0.5 nmol/ml at baseline vs. 7.6 +/- 0.4 at 3 months, and 7.3 +/- 0.3 at 6 months, P < 0.05). At 6 months, the improvement in insulin sensitivity correlated with the change in total ceramide levels (r = -0.68, P = 0.02), and with plasma tumor necrosis factor-alpha (TNF alpha) (r = -0.62, P = 0.04). We conclude that there is a potential role for ceramide lipids as mediators of the proinflammatory state and improved insulin sensitivity after gastric bypass surgery. PMID- 21546938 TI - Antibiotic use for presumed neonatally acquired infections far exceeds that for central line-associated blood stream infections: an exploratory critique. AB - OBJECTIVE: To assess antibiotic use as a complementary neonatal intensive care unit (NICU) infection measure to the central line-associated blood stream infection (CLABSI) rate. STUDY DESIGN: Patient days (PDs), line days, antibiotic (AB) use, CLABSI and other proven infections were analyzed in consecutive admissions to two NICUs over 3 and 6 months, respectively, from 1 January 2008 until discharge. An antibiotic course (AC) consisted of one or more uninterrupted antibiotic days (AD), classified as perinatal or neonatal, if started <=3 d or >=4 d post birth and as rule-out sepsis or presumed infection (PI) if treated <=4 d or >=5d, respectively. Events were expressed per 1000 PD and aggregated by conventional treatment categories and by clinical perception of infection certainty: possible, presumed or proven. RESULT: The cohort included 754 patients, 18,345 PD, 6637 line days, 718 AC and 4553 AD. Of total antibiotic use, neonatal use constituted 39.2% of ACs, and 29.0% of ADs, When analyzed per 1000 PD, antibiotic use to treat PIs vs CLABSIs, was either 14 fold (CI 6.6-30) higher for ACs (5.40 vs 0.38/1000 PD, P<0.0001) or 8.8 fold (CI 7.1-11) higher for ADs (48.3 vs 5.5/1000 PD, P<0.0001). CONCLUSION: CLABSI rates, present a lower limit of NICU-acquired infections, whereas antibiotic-use measures, about 10-fold higher, may estimate an upper limit of that burden. Antibiotic-use metrics should be evaluated further for their ability to broaden NICU infection assessment and to guide prevention and antibiotic stewardship efforts. PMID- 21546939 TI - Neuropsychological and behavioral effects of postnatal dexamethasone in extremely low birth weight preterm children at early school age. AB - OBJECTIVE: To study postnatal dexamethasone treatment effects on cognitive, neuropsychological and behavioral functioning at early school age in preterm children. STUDY DESIGN: We recruited 222 children born between 1998 and 2003: 114 extremely low birth weight (<1000 g; 60 dexamethasone-treated; 54 untreated) and 108 term-born. Data were analyzed using multivariate methods. RESULT: Preterm performed below term-born on all measures. Dexamethasone-treated performed below dexamethasone-untreated in immediate visual memory, visual-motor integration, mathematical skill and motor dexterity. However, stepwise regression indicated that medical and sociodemographic factors other than dexamethasone contributed to preterm group differences. CONCLUSION: Dexamethasone alone does not explain neurocognitive impairment in preterm children. Medical and sociodemographic factors (illness severity, male gender and parental education) are influential. Prospective longitudinal neuropsychological and behavioral study from preschool to school age that considers medical and sociodemographic variables will best address effects of dexamethasone exposure. PMID- 21546940 TI - The effect of late preterm birth on mortality of infants with major congenital heart defects. AB - OBJECTIVE: We evaluated the effect of late preterm delivery (34 to 36 weeks) on hospital mortality of infants with congenital heart defects (CHDs). STUDY DESIGN: Retrospective record review of infants with major CHD born at or after to 34 weeks, cared for in a single tertiary perinatal center between 2002 and 2009. Factors associated with death before discharge from the hospital were ascertained using univariate and multivariate analyses. RESULT: Of the 753 infants with CHD, 117 were born at late preterm. Using logistic regression analysis, white race (OR; 95% CI) (0.60; 0.39 to 0.95), late preterm delivery (2.70; 1.69 to 4.33), and need for intubation in the delivery room (3.15; 1.92 to 5.17) were independently associated with hospital death. CONCLUSION: Late preterm birth of infants with major CHDs was independently associated with increased risk of hospital death compared with delivery at more mature gestational ages. PMID- 21546941 TI - Relationship between interpregnancy interval and birth defects in Washington State. AB - OBJECTIVE: Interpregnancy interval (IPI) influences numerous adverse perinatal outcomes. IPI's impact on birth defects is unclear. STUDY DESIGN: We conducted a population-based case-control study, using 1998 to 2008 administrative data from Washington State. A total of 10, 772 cases, women whose second of two births resulted in an infant with a birth defect, were compared with 32 ,310 controls, women whose second of two births did not result in an infant with a birth defect. RESULT: Compared with mothers with an IPI between 18 to 23 months, those with an IPI <6 months or >=60 months had elevated risks of delivering an infant with a birth defect (odds ratio=1.15, 95% confidence interval: 1.03 to 1.28, and odds ratio=1.15, 95% confidence interval: 1.04 to 1.26, respectively). CONCLUSION: We observed a J-shaped relationship between IPI and risk of having an infant with a birth defect. As this is one of the first studies to evaluate this association, confirmatory studies are needed. PMID- 21546942 TI - Probiotics-supplemented feeding in extremely low-birth-weight infants. AB - OBJECTIVE: The objective of this trial was to test whether probiotic-supplemented feeding to extremely low-birth-weight (ELBW) infants will improve growth as determined by decreasing the percentage of infants with weight below the 10th percentile at 34 weeks postmenstrual age (PMA). Other important outcome measures, such as improving feeding tolerance determined by tolerating larger volume of feeding per day and reducing antimicrobial treatment days during the first 28 days from the initiation of feeding supplementation were also evaluated. STUDY DESIGN: We conducted a multicenter randomized controlled double-blinded clinical study. The probiotics-supplementation (PS) group received Lactobacillus rhamnosus GG and Bifidobacterium infantis added to the first enteral feeding and continued once daily with feedings thereafter until discharge or until 34 weeks (PMA). The control (C) group received unsupplemented feedings. Infant weight and feeding volumes were recorded daily during the first 28 days of study period. Weights were also recorded at 34 weeks PMA. RESULT: A total of 101 infants were enrolled (PS 50 versus C 51). There was no difference between the two groups in the percentage of infants with weight below the 10th percentile at 34 weeks PMA (PS group 58% versus C group 60%, (P value 0.83)) or in the average volume of feeding during 28 days after study entry (PS group 59 ml kg(-1) versus C group 71 ml kg(-1), (P value 0.11)). Calculated growth velocity was higher in the PS group compared with the C group (14.9 versus 12.6 g per day, (P value 0.05)). Incidences of necrotizing enterocolitis (NEC), as well as mortality were similar between the two groups. CONCLUSION: Although probiotic-supplemented feedings improve growth velocity in ELBW infants, there was no improvement in the percentage of infants with growth delay at 34 weeks PMA. There were no probiotic related adverse events reported. PMID- 21546943 TI - An interdisciplinary bronchopulmonary dysplasia program is associated with improved neurodevelopmental outcomes and fewer rehospitalizations. AB - OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a pulmonary disease associated with poor neurodevelopmental and medical outcomes. Patients with BPD are medically fragile, at high risk for complications and require interdisciplinary care. We tested the hypothesis that a chronic care approach for BPD would improve neurodevelopmental outcomes relative to the National Institute of Child and Human Development Neonatal Research Network (NICHD NRN) and reduce medical complications. STUDY DESIGN: Infants were followed as inpatients and outpatients. Bayley developmental exams were carried out at 18-24 months of age and compared with the NICHD NRN report. Finally, rates of readmission (a proxy for medical complications) were compared before and after implementation of the Comprehensive Center for BPD (CCBPD). RESULT: Developmental scores obtained in 2007 and 2008 show that 12 and 10% of patients with moderate BPD (n=61) had Bayley Scores <70 for mental and motor indices respectively, whereas corresponding national rates were 35 and 26%. For patients with severe BPD (n=46), 15 and 11% of patients within the CCBPD vs 50 and 42% of national patients scored <70 for mental and motor indices, respectively. Finally, readmission rates dropped from 29% in the year before the implementation of the CCPD (n=269) to 5% thereafter (n=866, P<0.0001). CONCLUSION: The encouraging neurodevelopmental outcomes and readmission rates associated with a chronic care approach to BPD suggest these infants may be best served by a comprehensive interdisciplinary approach to care that focuses on neurodevelopment throughout the hospital stay. PMID- 21546944 TI - March on, not in. PMID- 21546945 TI - Russia pledges $4 billion for Pharma-2020 plan. PMID- 21546946 TI - Jackson Laboratory's foray into Florida faces murky future. PMID- 21546947 TI - Report backs pending legislation to investigate disease clusters. PMID- 21546948 TI - Companies ponder how truly 'personal' medicines can get. PMID- 21546949 TI - Qatar proposes national council to direct research efforts. PMID- 21546950 TI - China's new WHO flu monitoring center seeks to reverse criticism. PMID- 21546951 TI - Experts emphasize need for speed in launch of Australian trials. PMID- 21546952 TI - Gloomy pharma forecast in Japan downgraded after quake. PMID- 21546954 TI - Despite Canadian government woes, neuroscience should win out. PMID- 21546953 TI - NIH faces marching orders on orphan drug shortage. PMID- 21546956 TI - Bangladesh eyes the generic pharma pie. PMID- 21546955 TI - Companies race to develop first Hedgehog inhibitor cancer drug. PMID- 21546957 TI - New technologies promise to improve blood supply safety. PMID- 21546958 TI - Straight talk with...George Radda. Interview by David Cyranoski. PMID- 21546960 TI - Auctioning the cure. PMID- 21546961 TI - Restructurally sound. PMID- 21546962 TI - Intramural conflicts of interest warrant scrutiny, too. PMID- 21546964 TI - Antitumor properties of histamine in vivo. PMID- 21546966 TI - The B-side story in insulin resistance. PMID- 21546967 TI - Modeling hyperactivity: of mice and men. PMID- 21546968 TI - Locking out hepatitis C. PMID- 21546969 TI - PPAR-gamma action: it's all in your head. PMID- 21546970 TI - Window of opportunity for daclizumab. PMID- 21546972 TI - Getting to the bare bones of fertility. PMID- 21546971 TI - Shedding LIGHT on severe asthma. PMID- 21546973 TI - Scraping fibrosis: expressway to the core of fibrosis. PMID- 21546974 TI - Scraping fibrosis: UMODulating renal fibrosis. PMID- 21546976 TI - Clinicopathological and prognostic implications of genetic alterations in oral cancers. AB - This study evaluated the clinicopathological and prognostic implications of genetic alterations characterizing oral squamous cell carcinoma(OSCC). Comparative genomic hybridization(CGH) was used to identify chromosomal alterations present in primary OSCCs obtained from 97 pateints. In this population, tobacco use was a significant risk factor for OSCC. By contrast, all 97 of our samples are negative for human papillomavirus (HPV) DNA integration, which is another known risk factor for OSCC in certain populations. Results of the Fisher's exact test followed by Benjamini-Hochberg correction for multiple testing, showed a correlation of 7p gain and 8p loss with node-positive OSCC (p<=0.04 for both genetic alterations) and association of 11q13 gain with high grade OSCC (p<=0.05). Univariate Cox-proportional hazard models, also corrected for multiple testing, showed significant association of 11q13 gain and 18q loss with decreased survival (p<=0.05). These findings were supported by multivariate analysis which revealed that 11q13 gain and 18q loss together serve as a strong bivariate predictor of poor prognosis. In conclusion, our study has identified genetic alterations that correlate significantly with nodal status, grade, and poor survival status of OSCC. These potential biomarkers may aid the current TNM system for better prediction of clinical outcome. PMID- 21546977 TI - Different Approaches to the Study of Early Perceptual Learning. PMID- 21546979 TI - Lensfree Fluorescent On-Chip Imaging using Compressive Sampling. PMID- 21546980 TI - The Accountant Who Lost Arithmetic: A Case Report of Acalculia With a Left Thalamic Lesion. AB - Acalculia is usually from dysfunction of the dominant parietal cortex. We report a case of acalculia associated with a lesion of the left thalamus. PMID- 21546978 TI - Alphavirus Entry and Membrane Fusion. AB - The study of enveloped animal viruses has greatly advanced our understanding of the general properties of membrane fusion and of the specific pathways that viruses use to infect the host cell. The membrane fusion proteins of the alphaviruses and flaviviruses have many similarities in structure and function. As reviewed here, alphaviruses use receptor-mediated endocytic uptake and low pH triggered membrane fusion to deliver their RNA genomes into the cytoplasm. Recent advances in understanding the biochemistry and structure of the alphavirus membrane fusion protein provide a clearer picture of this fusion reaction, including the protein's conformational changes during fusion and the identification of key domains. These insights into the alphavirus fusion mechanism suggest new areas for experimental investigation and potential inhibitor strategies for anti-viral therapy. PMID- 21546981 TI - Detection of Amide and Aromatic Proton Resonances of Human Brain Metabolites Using Localized Correlated Spectroscopy Combined with Two Different Water Suppression Schemes. AB - The purpose of the study was to demonstrate the J-coupling connectivity network between the amide, aliphatic, and aromatic proton resonances of metabolites in human brain using two-dimensional (2D) localized correlated spectroscopy (L COSY). Two different global water suppression techniques were combined with L COSY, one before and another after localizing the volume of interest (VOI). Phantom solutions containing several cerebral metabolites at physiological concentrations were evaluated initially for sequence optimization. Nine healthy volunteers were scanned using a 3T whole body MRI scanner. The VOI for 2D L-COSY was placed in the right occipital white/gray matter region. The 2D cross and diagonal peak volumes were measured for several metabolites such as N-acetyl aspartate (NAA), creatine (Cr), free choline (Ch), glutamate/glutamine (Glx), aspartate (Asp), myo-inositol (mI), GABA, glutathione (GSH), phosphocholine (PCh), phosphoethanolamine (PE), tyrosine (Tyr), lactate (Lac), macromolecules (MM) and homocarnosine (Car). Using the pre-water suppression technique with L COSY, the above mentioned metabolites were clearly identifiable and the relative ratios of metabolites were calculated. In addition to detecting multitude of aliphatic resonances in the high field region, we have demonstrated that the amide and aromatic resonances can also be detected using 2D L-COSY by pre water suppression more reliably than the post-water suppression. PMID- 21546982 TI - Differential Control of the Sympathetic Nervous System by Leptin: Implications for Obesity. AB - 1. Leptin is a hormone that is secreted by adipocytes and delivered to the brain to regulate appetite and energy expenditure. Other effects of leptin include activation of the sympathetic nervous system and an increase in arterial pressure.2. Mounting evidence suggests that the sympathetic nervous system subserving different tissues is differentially controlled by leptin. For instance, leptin-induced regional increases in sympathetic nerve activity do not respond uniformly to baroreflex activation and hypothermia.3. In several mouse models of obesity, the ability of leptin to increase renal sympathetic nerve activity is preserved, despite resistance to leptin's effect on food intake, body weight and thermogenic sympathetic tone. Furthermore, obese mice also retain the increase in arterial pressure in response to leptin.3. Although they display a lack of metabolic responses to leptin, animal models of obesity preserve renal sympathetic and arterial pressure responses that potentially cause the adverse cardiovascular consequences of obesity. Thus, it is possible that excess leptin contributes to cardiovascular complications, even when a subject shows metabolic resistance to leptin. PMID- 21546983 TI - Improved Contact X-Ray Microradiographic Method to Measure Mineral Density of Hard Dental Tissues. AB - Contact X-ray microradiography is the current gold standard for measuring mineral densities of partially demineralized tooth specimens. The X-ray sensitive film specified in the last J Res NIST publication on the subject is no longer commercially available. OBJECTIVES: Develop a new microradiographic method by identifying a commercially available film with greater than 3000 lines per millimeter resolution, which is sensitive to X rays, and develop correct film processing for X-ray microradiographic application. METHODS: A holographic film was identified as a potential replacement film. Proper exposure was determined utilizing a thick nickel plate to create test-strips. Film development was bracketed around manufacturer suggestions. Film linearity was determined with aluminum step-wedges. Microradiographs of 100 um thick tooth sections, before and after acidic challenges, were a final test for film. Magnified images were captured with a digital microscope camera with 0.305 micrometers per pixel resolution. RESULTS: The appropriate film exposure was 30 minutes at 80 kV(p) and 3 mA with a development time of 2 minutes. Step-wedge experiments show the system to be linear in terms of pixel intensities with respect to x-ray attenuation for normalized pixel intensity values that are 10% to 90% of full scale (r(2) = 0.997) which encompasses the full exposure region of tooth tissue. Enamel sections were analyzed and show distinctive differences between erosion and demineralization. The image capture device resolution of 0.305 micrometers per pixel limits the system resolution. CONCLUSION: Use of the identified holographic film when combined with the described processing modifications has resulted in an improved X-ray microradiographic method for the measurement of mineral density of dental hard tissues. The method described can be further improved by using a higher resolution digitization system. The method is appropriate for quantitatively measuring changes in mineral density and erosion. PMID- 21546984 TI - SYNTHESIS OF NOVEL BITHIOPHENE-SUBSTITUTED HETEROCYCLES BEARING CARBONITRILE GROUPS. AB - Symmetrical and unsymmetrical bithiophene-substituted heterocycles bearing carbonitriles including imidazo[1,2-a]pyridine, benzimidazole, and pyridine derivatives have been synthesized via different synthetic protocols. The bithiophene bis-imidazo[1,2-a]pyridine derivatives 3a,b were achieved in three steps starting from 2-acetyl-5-bromothiophene. Suzuki coupling reaction of 2a with 5-formylthiophen-2-ylboronic acid forms the formyl derivative 5, which by condensation with 3,4-diaminobenzonitrile in the presence of sodium bisulfite furnishes the unsymmetrical bithiophene derivative 6. The bis-benzimidazole derivative 8 was obtained via hexabutylditin-mediated homocoupling of 5 bromothiophene-2-carboxaldehyde, while the benzimidazole derivatives 12a,b were prepared via the formyl derivatives 11a,b, a product of Velsmier formylation reaction of 10a,b. Two synthetic protocols for the aryl/hetaryl-2,2'-bithiophene derivative 14 have also been presented. In addition, the guanyl hydrazones of bithiophenes, 16 and 17, were prepared from bis(tri-n-butylstannyl)-2,2' bithiophene through a Stille coupling reaction followed by a condensation step. PMID- 21546985 TI - Measurement of Body and Liver Fat in Small Animals Using Peripheral Quantitative Computed Tomography. AB - Peripheral quantitative computed tomography (pQCT) was used to determine percent body fat in mice, and relative liver fat in lemmings fasted for 0, 6, 12 or 18 hours to induce a wide range of liver fat content. Accuracy of the pQCT was determined by comparing pQCT-derived fat to that from chemical extraction using 30 male mice (whole body) and 26 female lemmings (liver only). To determine whether pQCT could measure changes in liver fat (%) in live animals, two groups of lemmings were scanned on 4 consecutive days under anesthesia. Controls (n = 3) had ad libitum access to food, whereas the fasted group (n = 5) was deprived of food for 18 hr before being measured on day 2 and then refed. The coefficient of variation (CV) for determining percent body fat in mice using the pQCT was 3.9% (+/-1.8 SD). Percent body fat determined by pQCT significantly overestimated percent fat as measured by chemical extraction (14.5 +/- 3.2 vs 12.3 +/- 2.9% respectively, P < 0.01, mean +/- SD). However, percent body fat by pQCT was highly related to chemical extraction percent fat (r = 0.95, P < 0.001). The liver attenuation values from pQCT were highly related to percent liver fat (r=0.98, P<0.001) in lemmings. The technique showed excellent precision with a CV of 0.3 +/- 0.1%. The two groups (control vs fasted) did not differ in their percent liver fat on day 1 (5.4% vs 5.8%). On day 2 the fasted group had a significantly higher percent liver fat than controls (5.9% vs 17.3%; p<0.05). Following refeeding, there were no significant group differences in percent liver fat on days 3 and 4. Our data indicate that pQCT has good accuracy and precision for determining percent body fat, and liver fat in small animals and can be used to track changes in liver fat over time. PMID- 21546986 TI - Televised sexual content and parental mediation: Influences on adolescent sexuality. AB - Little research has been conducted to examine the influence of exposure to televised sexual content on adolescent sexuality or how parental intervention may reduce negative effects of viewing such content. This study uses self-report data from 1,012 adolescents to investigate the relations among exposure to sexually suggestive programming, parental mediation strategies, and three types of adolescent sexuality outcomes: participation in oral sex and sexual intercourse, future intentions to engage in these behaviors, and sex expectancies. As predicted, exposure to sexual content was associated with an increased likelihood of engaging in sexual behaviors, increased intentions to do so in the future, and more positive sex expectancies. Often, parental mediation strategies were a significant factor in moderating these potential media influences. PMID- 21546987 TI - Low-Income Students and the Socioeconomic Composition of Public High Schools. AB - Increasing constraints placed on race-based school diversification have shifted attention to socioeconomic desegregation. Although past research suggests that socioeconomic desegregation can produce heightened achievement, the "frog pond" perspective points to potential problems with socioeconomic desegregation in nonachievement domains. Such problems are important in their own right, and they may also chip away at the magnitude of potential achievement benefits. In this article, I report conducted propensity score analyses and robustness calculations on a sample of public high schools in the National Longitudinal Study of Adolescent Health. As the proportion of the student body with middle- or high income parents increased, low-income students progressed less far in math and science. Moreover, as the proportion of the student body with middle- or high income or college-educated parents increased, low-income students experienced more psychosocial problems. Such patterns were often more pronounced among African American and Latino students. These findings suggest curricular and social psychological mechanisms of oft-noted frog pond effects in schools and extend the frog pond framework beyond achievement itself to demographic statuses (e.g., race/ethnicity and SES) perceptually linked to achievement. In terms of policy, these findings indicate that socioeconomic desegregation plans should also attend to equity in course enrollments and the social integration of students more generally. PMID- 21546988 TI - Community First Communication: Reversing Information Disparities to Achieve Environmental Justice. AB - We address how information developed and effectively communicated through community based participatory research (CBPR) can reverse long-standing information disparities, empower a community, and be an agent for sustained change. Substantial information and power disparities existed between the polluted community and both the pollution industry and governmental regulators. An environmental justice partnership between a local community organization, physicians, and university performed CBPR and then developed a novel communication strategy to address a series of information disparities around a local water pollution issue. The community established a set of principles to govern the communication of results as soon as they were determined to be scientifically valid, including informing study participants and the community before other interested parties. CBPR results combined with a community-first communication strategy reversed the preexisting information disparities. The novel communication flow reversed the preferential information flow to industry and government associated with the usual scientific publication process. The community was empowered, and industry and government agencies responded positively to study recommendations. The CBPR results together with community first communication led to adoption of both community-wide and individual solutions and provided powerful motivation for behavioral change by industry and residents. PMID- 21546989 TI - Improving a Gold Standard: Treating Human Relevance Judgments of MEDLINE Document Pairs. AB - Given prior human judgments of the condition of an object it is possible to use these judgments to make a maximal likelihood estimate of what future human judgments of the condition of that object will be. However, if one has a reasonably large collection of similar objects and the prior human judgments of a number of judges regarding the condition of each object in the collection, then it is possible to make predictions of future human judgments for the whole collection that are superior to the simple maximal likelihood estimate for each object in isolation. This is possible because the multiple judgments over the collection allow an analysis to determine the relative value of a judge as compared with the other judges in the group and this value can be used to augment or diminish a particular judge's influence in predicting future judgments. Here we study and compare five different methods for making such improved predictions and show that each is superior to simple maximal likelihood estimates. PMID- 21546990 TI - In Vivo Measurement of Glenohumeral Joint Contact Patterns. AB - The objectives of this study were to describe a technique for measuring in-vivo glenohumeral joint contact patterns during dynamic activities and to demonstrate application of this technique. The experimental technique calculated joint contact patterns by combining CT-based 3D bone models with joint motion data that were accurately measured from biplane x-ray images. Joint contact patterns were calculated for the repaired and contralateral shoulders of 20 patients who had undergone rotator cuff repair. Significant differences in joint contact patterns were detected due to abduction angle and shoulder condition (i.e., repaired versus contralateral). Abduction angle had a significant effect on the superior/inferior contact center position, with the average joint contact center of the repaired shoulder 12.1% higher on the glenoid than the contralateral shoulder. This technique provides clinically relevant information by calculating in-vivo joint contact patterns during dynamic conditions and overcomes many limitations associated with conventional techniques for quantifying joint mechanics. PMID- 21546991 TI - Synthesis of Michael Acceptor Ionomers of Poly(4-Sulfonated Styrene-co Poly(Ethylene Glycol) Methyl Ether Acrylate). AB - Ionomers containing sodium 4-styrene sulfonate (4SS) and poly(ethylene glycol) methyl ether acrylate (PEGA) were synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. The polymerization was mediated by 1-phenylethyl dithiobenzoate chain transfer agent in a dimethylformamide/water solvent system. Well-defined copolymers of pPEGA-co-4SS were produced with molecular weights ranging from 10 kDa to 40 kDa and polydispersity indices (PDIs) of 1.06-1.18 by gel permeation chromatography (GPC) against monodisperse poly(methyl methacrylate) (PMMA) standards. Post polymerization, the dithioester was reduced and trapped in situ with divinyl sulfone to produce a well-defined, semitelechelic pPEGA-co-4SS Michael acceptor polymer. UV-vis, infrared, and (1)H NMR spectroscopy confirmed that the integrity of the polymer backbone was maintained and that the vinyl sulfone was successfully incorporated at the chain end. PMID- 21546992 TI - Description of a new octoploid frog species (Anura: Pipidae: Xenopus) from the Democratic Republic of the Congo, with a discussion of the biogeography of African clawed frogs in the Albertine Rift. AB - We describe a new octoploid species of African clawed frog (Xenopus) from the Lendu Plateau in the northern Albertine Rift of eastern Democratic Republic of the Congo. This species is the sister taxon of Xenopus vestitus (another octoploid), but is distinguished by a unique morphology, vocalization and molecular divergence in mitochondrial and autosomal DNA. Using a comprehensive genetic sample, we provide new information on the species ranges and intra specific diversity of African clawed frogs from the Albertine Rift, including the details of a small range extension for the critically endangered Xenopus itombwensis and previously uncharacterized variation in Xenopus laevis. We also detail a new method for generating cytogenetic preparations in the field that can be stored at room temperature for up to 3 weeks. While extending our understanding of the extant diversity in the Albertine Rift, this new species highlights components of species diversity in ancestral African clawed frogs that are not represented by known extant descendants. PMID- 21546993 TI - Direct measurement of oxygen consumption rates from attached and unattached cells in a reversibly sealed, diffusionally isolated sample chamber. AB - Oxygen consumption is a fundamental component of metabolic networks, mitochondrial function, and global carbon cycling. To date there is no method available that allows for replicate measurements on attached and unattached biological samples without compensation for extraneous oxygen leaking into the system. Here we present the Respiratory Detection System, which is compatible with virtually any biological sample. The RDS can be used to measure oxygen uptake in microliter-scale volumes with a reversibly sealed sample chamber, which contains a porphyrin-based oxygen sensor. With the RDS, one can maintain a diffusional seal for up to three hours, allowing for the direct measurement of respiratory function of samples with fast or slow metabolic rates. The ability to easily measure oxygen uptake in small volumes with small populations or dilute samples has implications in cell biology, environmental biology, and clinical diagnostics. PMID- 21546994 TI - SOCR Analyses - an Instructional Java Web-based Statistical Analysis Toolkit. AB - The Statistical Online Computational Resource (SOCR) designs web-based tools for educational use in a variety of undergraduate courses (Dinov 2006). Several studies have demonstrated that these resources significantly improve students' motivation and learning experiences (Dinov et al. 2008). SOCR Analyses is a new component that concentrates on data modeling and analysis using parametric and non-parametric techniques supported with graphical model diagnostics. Currently implemented analyses include commonly used models in undergraduate statistics courses like linear models (Simple Linear Regression, Multiple Linear Regression, One-Way and Two-Way ANOVA). In addition, we implemented tests for sample comparisons, such as t-test in the parametric category; and Wilcoxon rank sum test, Kruskal-Wallis test, Friedman's test, in the non-parametric category. SOCR Analyses also include several hypothesis test models, such as Contingency tables, Friedman's test and Fisher's exact test.The code itself is open source (http://socr.googlecode.com/), hoping to contribute to the efforts of the statistical computing community. The code includes functionality for each specific analysis model and it has general utilities that can be applied in various statistical computing tasks. For example, concrete methods with API (Application Programming Interface) have been implemented in statistical summary, least square solutions of general linear models, rank calculations, etc. HTML interfaces, tutorials, source code, activities, and data are freely available via the web (www.SOCR.ucla.edu). Code examples for developers and demos for educators are provided on the SOCR Wiki website.In this article, the pedagogical utilization of the SOCR Analyses is discussed, as well as the underlying design framework. As the SOCR project is on-going and more functions and tools are being added to it, these resources are constantly improved. The reader is strongly encouraged to check the SOCR site for most updated information and newly added models. PMID- 21546995 TI - Is volcanic air pollution associated with decreased heart-rate variability? AB - OBJECTIVES: To determine the autonomic cardiovascular control among residents of Hawaii who are exposed to varying levels of volcanic air pollution (vog), which consists largely of sulfur dioxide (SO(2)) and acid aerosols. METHODS: In a cross sectional study between April 2006 and June 2008, the authors measured cardiovagal autonomic function by heart-rate variability (HRV) in 72 healthy individuals who lived in four exposure zones on Hawaii Island: vog-free (n=18); episodic exposure to SO(2) >200 ppb and acid aerosol (n=19); chronic exposure to SO(2) >=30 ppb and acid aerosol (n=15); and chronic exposure to acid aerosols (n=20). Individuals with diabetes or heart disease, or who had smoked in the preceding month were excluded. HRV was measured in all subjects during rest, paced breathing and active standing (Ewing manoeuvre). HRV was analysed in time and frequency domains and compared between the four exposure zones. RESULTS: There were no significant differences between exposure zones in HRV, in either time or frequency domains, even after adjustment for age, gender, ethnicity and body mass index. There was no significant HRV change in three individuals in whom HRV was measured before and during an exposure to combined SO(2) 100-250 ppb and concentration of respirable particles of diameter >=2.5 MU (PM(2.5)) >500 MUg/m(3). Age was significantly correlated with time-domain parameters during paced breathing and the Ewing manoeuvre. CONCLUSIONS: This study of healthy individuals found no appreciable effects of vog on the autonomic nervous system. PMID- 21546996 TI - Integrin targeting for tumor optical imaging. AB - Optical imaging has emerged as a powerful modality for studying molecular recognitions and molecular imaging in a noninvasive, sensitive, and real-time way. Some advantages of optical imaging include cost-effectiveness, convenience, and non-ionization safety as well as complementation with other imaging modalities such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). Over the past decade, considerable advances have been made in tumor optical imaging by targeting integrin receptors in preclinical studies. This review has emphasized the construction and evaluation of diverse integrin targeting agents for optical imaging of tumors in mouse models. They mainly include some near-infrared fluorescent dye-RGD peptide conjugates, their multivalent analogs, and nanoparticle conjugates for targeting integrin alphavbeta3. Some compounds targeting other integrin subtypes such as alpha4beta1 and alpha3 for tumor optical imaging have also been included. Both in vitro and in vivo studies have revealed some promising integrin-targeting optical agents which have further enhanced our understanding of integrin expression and targeting in cancer biology as well as related anticancer drug discovery. Especially, some integrin-targeted multifunctional optical agents including nanoparticle-based optical agents can multiplex optical imaging with other imaging modalities and targeted therapy, serving as an attractive type of theranostics for simultaneous imaging and targeted therapy. Continued efforts to discover and develop novel, innovative integrin-based optical agents with improved targeting specificity and imaging sensitivity hold great promises for improving cancer early detection, diagnosis, and targeted therapy in clinic. PMID- 21546997 TI - PET Imaging and Biodistribution of Silicon Quantum Dots in Mice. AB - Investigation of nanomaterial disposition and fate in the body is critical before such material can be translated into clinical application. Herein a new macrocyclic ligand-(64)Cu(2+) complex was synthesized and used to label dextran coated silicon quantum dots (QD), with an average hydrodynamic diameter of 15.1 +/- 7.6 nm. The chelate showed exceptional stability, demonstrated by no loss radiolabel under a ligand competition reaction with EDTA. The QDs' biodistribution in mice was quantitatively evaluated by in vivo positron emission tomography (PET) imaging and ex vivo gamma counting. Results showed that they were excreted via renal filtration shortly postinjection and also accumulated in the liver. PMID- 21546998 TI - The Current Status of Liver Transplantation. AB - More than thirty patients have now undergone liver transplantation in Denver, some more than once, and survivals of up to two and a half years have been achieved. Through this and other experience it has been learned that graft viability is more critical than histocompatibility matching but that the most important factor in the ultimate outcome is prevention of rejection through vigorous immunosuppressive therapy. PMID- 21546999 TI - A Very Fast Switched Attenuator Circuit for Microwave and R.F. Applications. AB - An electronic circuit was designed and constructed that can switch an r.f. signal between two amplitude levels at very fast speed (less than 10 ns). The circuit incorporates a TTL control for convenient interfacing to existing equipment. The attenuation of the more attenuated state can be adjusted to be up to 12 dB more than for the less attenuated state. The initial application was in Pulsed Electron Paramagnetic Resonance (EPR) spectroscopy to produce a pi/2 - pi pulse sequence with pulses of equal time duration and 6 dB difference in amplitude. A new method for measuring electron spin echoes for narrow, homogeneously-broadened lines is described. PMID- 21547000 TI - A new species of Gekko (Squamata: Gekkonidae) from Ta Kou Nature Reserve, Binh Thuan Province, Southern Vietnam. AB - A new species of Gekko Laurenti is described from Ta Kou Mountain, an isolated granitic peak in Ta Kou Nature Reserve, Ham Thuan Nam district, Binh Thuan province, southern Vietnam. The species is distinguished from its congeners by its moderate size, with snout to vent length (SVL) reaching a maximum 107.0 mm; dorsal pattern of 5-8 white vertebral blotches between the nape and sacrum and 6 8 pairs of short white bars on the flanks; 11-14 precloacal pores in males; 14-17 longitudinal rows of smooth dorsal tubercles; and 18-20 broad lamellae beneath the fourth toe. Gekko takouensis sp. nov. is the second endemic gekkonid discovered in the Ta Kou Nature Reserve, Cyrtodactylus takouensis Ngo & Bauer being the first. PMID- 21547001 TI - Global expression profiling reveals gain-of-function oncogenic activity of a mutated thyroid hormone receptor in thyroid carcinogenesis. AB - Thyroid hormone receptors (TRs) are critical in regulating gene expression in normal physiological processes. Decreased expression and/or somatic mutations of TRs have been shown to be associated several types of human cancers including liver, breast, lung, and thyroid. To understand the molecular mechanisms by which mutated TRs promote carcinogenesis, an animal model of follicular thyroid carcinoma (FTC) (Thrb(PV/PV) mice) was used in the present study. The Thrb(PV/PV) mouse harbors a knockin dominant negative PV mutation, identified in a patient with resistance to thyroid hormone. To understand whether oncogenic actions of PV involve not only the loss of normal TR functions but also gain-of-function activities, we compared the gene expression profiles of thyroid lesions in Thrb(PV/PV) mice and Thra1(-/-)Thrb(-/-) mice that also spontaneously develop FTC, but with less severe malignancy. Analysis of the cDNA microarray data derived from microdissected thyroid tumor cells of these two mice showed contrasting global gene expression profiles. With stringent selection using 2.5 fold change (p<0.01) in cDNA microarray analysis, 241 genes with altered gene expression were identified. Nearly half of the genes (n=103: 42.7% of total) with altered gene expression in thyroid tumor cells of Thrb(PV/PV) mice were associated with tumorigenesis and metastasis; some of these genes function as oncogenes in human thyroid cancers. The remaining genes were found to function in transcriptional regulation, RNA processing, cell proliferation, apoptosis, angiogenesis, and cytoskeleton modification. These results indicate that the more aggressive thyroid tumor progression in Thrb(PV/PV) mice was not due simply to the loss of tumor suppressor functions of TR via mutation but also, importantly, to gain-of-function in the oncogenic activities of PV to drive thyroid carcinogenesis. Thus, the present study identifies a novel mechanism by which a mutated TRbeta evolves with an oncogenic advantage to promote thyroid carcinogenesis. PMID- 21547002 TI - Diacylglycerol Kinase Inhibition and Vascular Function. AB - Diacylglycerol kinases (DGKs), a family of lipid kinases, convert diacylglycerol (DG) to phosphatidic acid (PA). Acting as a second messenger, DG activates protein kinase C (PKC). PA, a signaling lipid, regulates diverse functions involved in physiological responses. Since DGK modulates two lipid second messengers, DG and PA, regulation of DGK could induce related cellular responses. Currently, there are 10 mammalian isoforms of DGK that are categorized into five groups based on their structural features. These diverse isoforms of DGK are considered to activate distinct cellular functions according to extracellular stimuli. Each DGK isoform is thought to play various roles inside the cell, depending on its subcellular localization (nuclear, ER, Golgi complex or cytoplasm). In vascular smooth muscle, vasoconstrictors such as angiotensin II, endothelin-1 and norepinephrine stimulate contraction by increasing inositol trisphosphate (IP(3)), calcium, DG and PKC activity. Inhibition of DGK could increase DG availability and decrease PA levels, as well as alter intracellular responses, including calcium-mediated and PKC-mediated vascular contraction. The purpose of this review is to demonstrate a role of DGK in vascular function. Selective inhibition of DGK isoforms may represent a novel therapeutic approach in vascular dysfunction. PMID- 21547003 TI - Egeson's (George's) transtridecadal weather cycling and sunspots. AB - In the late 19th century, Charles Egeson, a map compiler at the Sydney Observatory, carried out some of the earliest research on climatic cycles, linking them to about 33-year cycles in solar activity, and predicted that a devastating drought would strike Australia at the turn of the 20th century. Eduard Bruckner and William J. S. Lockyer, who, like Egeson, found similar cycles, with notable exceptions, are also, like the map compiler, mostly forgotten. But the transtridecadal cycles are important in human physiology, economics and other affairs and are particularly pertinent to ongoing discusions of climate change. Egeson's publication of daily weather reports preceded those officially recorded. Their publication led to clashes with his superiors and his personal life was marked by run-ins with the law and, possibly, an implied, but not proven, confinement in an insane asylum and premature death. We here track what little is known of Egeson's life and of his bucking of the conventional scientific wisdom of his time with tragic results. PMID- 21547005 TI - HIV and the Gastrointestinal Tract. PMID- 21547006 TI - Imaging studies for evaluating impact of position sampling techniques in PET scanners. AB - Previously we have evaluated two crystal calibration techniques that can be applied to pixelated detector designs to improve system spatial resolution without detector motion. The inter-crystal positioning technique utilizes sub sampling in the crystal flood map to better sample the Compton scatter events in the detector. The Compton scatter rejection technique, on the other hand, rejects those events that are located further from individual crystal centers in the flood map. Here we performed imaging studies with a Mini Deluxe hot rod phantom and a hot sphere phantom (sphere diameters of 4.95 and 7.86-mm with 6:1 uptake relative to background) using the standard crystal calibration technique, as well as the inter-crystal and Compton rejection calibration techniques. Our results show improved separation of 1.6-mm diameter hot rods with the two new crystal calibration techniques that is consistent with improved spatial resolution. For the hot sphere phantom the contrast recovery is improved with both the inter crystal and Compton rejection calibration techniques over the standard calibration technique. The only drawback of the inter-crystal calibration technique is the increase in the number of possible lines-of-response (LORs) (factor of 16) that may slow image reconstruction. With the Compton rejection calibration technique, loss of counts leads to increased noise in the images. PMID- 21547007 TI - Fast Analysis of Molecular Dynamics Trajectories with Graphics Processing Units Radial Distribution Function Histogramming. AB - The calculation of radial distribution functions (RDFs) from molecular dynamics trajectory data is a common and computationally expensive analysis task. The rate limiting step in the calculation of the RDF is building a histogram of the distance between atom pairs in each trajectory frame. Here we present an implementation of this histogramming scheme for multiple graphics processing units (GPUs). The algorithm features a tiling scheme to maximize the reuse of data at the fastest levels of the GPU's memory hierarchy and dynamic load balancing to allow high performance on heterogeneous configurations of GPUs. Several versions of the RDF algorithm are presented, utilizing the specific hardware features found on different generations of GPUs. We take advantage of larger shared memory and atomic memory operations available on state-of-the-art GPUs to accelerate the code significantly. The use of atomic memory operations allows the fast, limited-capacity on-chip memory to be used much more efficiently, resulting in a fivefold increase in performance compared to the version of the algorithm without atomic operations. The ultimate version of the algorithm running in parallel on four NVIDIA GeForce GTX 480 (Fermi) GPUs was found to be 92 times faster than a multithreaded implementation running on an Intel Xeon 5550 CPU. On this multi-GPU hardware, the RDF between two selections of 1,000,000 atoms each can be calculated in 26.9 seconds per frame. The multi GPU RDF algorithms described here are implemented in VMD, a widely used and freely available software package for molecular dynamics visualization and analysis. PMID- 21547008 TI - Divergent Shear Thinning and Shear Thickening Behavior of Supramolecular Polymer Networks in Semidilute Entangled Polymer Solutions. AB - The steady shear behavior of metallo-supramolecular polymer networks formed by bis-Pd(II) cross-linkers and semidilute entangled solutions of poly(4 vinylpyridine) (PVP) in dimethyl sulfoxide (DMSO) or N,N-dimethyl formamide (DMF) is reported. The steady shear behavior of the networks depends on the dissociation rate and association rate of the cross-linkers, the concentration of cross-linkers, and the concentration of the polymer solution. The divergent steady shear behavior-shear thinning versus shear thickening-of samples with identical structure but different cross-linker dynamics (J. Phys. Chem. Lett. 2010, 1, 1683-1686) is further explored in this paper. The divergent steady shear behavior for networks with different cross-linkers is connected to a competition between different time scales: the average time that a cross-linker remains open (tau(1)) and the local relaxation time of a segment of polymer chain (tau(segment)). When tau(1) is larger than tau(segment), shear thickening is observed. When tau(1) is smaller than tau(segment), only shear thinning is observed. PMID- 21547009 TI - Order Amidst Change: Work and Family Trajectories in Japan. AB - Substantial family and work macro-level change has been occurring in Japan. Examples include a decline in the availability of jobs that afford lifetime protection against unemployment, an increase in jobs that do not carry benefits such as a pension, an increase in age at marriage and at first birth, and an increase in marital dissolution. Using life history data from the 2000 National Survey on Family and Economic Conditions, young Japanese appear to have responded to these macro-level changes in a fairly orderly manner. Marriage and childbearing have been postponed, but marriage still precedes childbearing. Education is completed prior to starting work. For men, once work commences they continue working. For women, the classic conflict between work and family roles is evident. For men and women in both the family and work spheres Japanese young adults have more orderly life course trajectories than American young adults. PMID- 21547011 TI - Jackson Heart Study: A Perspective at Ten Years. PMID- 21547010 TI - ALDOSE REDUCTASE: New Insights for an Old Enzyme. AB - In the past years aldose reductase (AKR1B1; AR) is thought to be involved in the pathogenesis of secondary diabetic complications such as retinopathy, neuropathy, nephropathy and cataractogenesis. Subsequently, a number of AR inhibitors have been developed and tested for diabetic complications. Although, these inhibitors have found to be safe for human use, they have not been successful at the clinical studies because of limited efficacy. Recently, the potential physiological role of AR has been reassessed from a different point of view. Diverse groups suggested that AR besides reducing glucose, also efficiently reduces oxidative stress-generated lipid peroxidation-derived aldehydes and their glutathione conjugates. Since lipid aldehydes alter cellular signals by regulating the activation of transcription factors such as NF-kB and AP1, inhibition of AR could inhibit such events. Indeed, a wide array of recent experimental evidence indicates that the inhibition of AR prevents oxidative stress-induced activation of NF-kB and AP1 signals that lead to cell death or growth. Further, AR inhibitors have been shown to prevent inflammatory complications such as sepsis, asthma, colon cancer and uveitis in rodent animal models. The new experimental in-vitro and in-vivo data has provided a basis for investigating the clinical efficacy of AR inhibitors in preventing other inflammatory complications than diabetes. This review describes how the recent studies have identified novel plethoric physiological and pathophysiological significance of AR in mediating inflammatory complications, and how the discovery of such new insights for this old enzyme could have considerable importance in envisioning potential new therapeutic strategies for the prevention or treatment of inflammatory diseases. PMID- 21547013 TI - Pre-activation based stereoselective glycosylations: Stereochemical control by additives and solvent. AB - Stereochemical control is an important issue in carbohydrate synthesis. Glycosyl donors with participating acyl protective groups on 2-O have been shown to give 1,2-trans glycosides reliably under the pre-activation based reaction condition. In this work, the effects of additives and reaction solvents on stereoselectivity were examined using donors without participating protective groups on 2-O. While several triflate salt additives did not have major effects, the amount of AgOTf was found to significantly impact the reaction outcome. Excess AgOTf led to lower stereochemical control presumably due to its coordination with the glycosyl triflate intermediate and a more S(N)1 like reaction pathway. In contrast, the stereoselectivity could be directed by reaction solvents, with diethyl ether favoring the formation of alpha glycosides and dichloromethane leading to beta isomers. The trend of stereochemical dependence on reaction solvent was applicable to a variety of building blocks including the selective formation of beta-mannosides. PMID- 21547014 TI - Development of a Brief Motivational Enhancement Intervention for Intimate Partner Violence in Alcohol Treatment Settings. AB - The current studies were a manual development study and a small pilot study of a 90-minute motivational enhancement style intervention to address IPV in alcohol treatment-seeking men. Analyses of feedback provided during manual development suggest participants: (a) liked the intervention, (b) reported behavior change intentions, and (c) found the feedback compelling. Findings from the pilot study suggest the intervention may be superior to referral only in increasing short term help-seeking and lead to marginally significant enhancements in motivation and self-reported intimacy. Help-seeking and motivation findings were associated with medium-large to large effect sizes. At 3- and 6-month follow-up, both groups showed improvements in self-reported alcohol outcomes, anger, and verbal and physical aggression. These findings support further research on this intervention. PMID- 21547012 TI - Is peroxisome proliferator-activated receptor gamma (PPARgamma) a therapeutic target for the treatment of pulmonary hypertension? AB - Pulmonary hypertension (PH), a progressive disorder associated with significant morbidity and mortality, is caused by complex pathways that culminate in structural and functional alterations of the pulmonary circulation and increases in pulmonary vascular resistance and pressure. Diverse genetic, pathological, or environmental triggers stimulate PH pathogenesis culminating in vasoconstriction, cell proliferation, vascular remodeling, and thrombosis. We conducted a thorough literature review by performing MEDLINE searches via PubMed to identify articles pertaining to PPARgamma as a therapeutic target for the treatment of PH. This review examines basic and preclinical studies that explore PPARgamma and its ability to regulate PH pathogenesis. Despite the current therapies that target specific pathways in PH pathogenesis, including prostacyclin derivatives, endothelin-receptor antagonists, and phosphodiesterase type 5 inhibitors, morbidity and mortality related to PH remain unacceptably high, indicating the need for novel therapeutic approaches. Consequently, therapeutic targets that simultaneously regulate multiple pathways involved in PH pathogenesis have gained attention. This review focuses on peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor superfamily of ligand activated transcription factors. While the PPARgamma receptor is best known as a master regulator of lipid and glucose metabolism, a growing body of literature demonstrates that activation of PPARgamma exerts antiproliferative, antithrombotic, and vasodilatory effects on the vasculature, suggesting its potential efficacy as a PH therapeutic target. PMID- 21547015 TI - The Langevin Hull: Constant pressure and temperature dynamics for non-periodic systems. AB - We have developed a new isobaric-isothermal (NPT) algorithm which applies an external pressure to the facets comprising the convex hull surrounding the system. A Langevin thermostat is also applied to the facets to mimic contact with an external heat bath. This new method, the "Langevin Hull", can handle heterogeneous mixtures of materials with different compressibilities. These systems are problematic for traditional affine transform methods. The Langevin Hull does not suffer from the edge effects of boundary potential methods, and allows realistic treatment of both external pressure and thermal conductivity due to the presence of an implicit solvent. We apply this method to several different systems including bare metal nanoparticles, nanoparticles in an explicit solvent, as well as clusters of liquid water. The predicted mechanical properties of these systems are in good agreement with experimental data and previous simulation work. PMID- 21547016 TI - Anti-contamination device for cryogenic soft X-ray diffraction microscopy. AB - Cryogenic microscopy allows one to view frozen hydrated biological and soft matter specimens with good structural preservation and a high degree of stability against radiation damage. We describe a liquid nitrogen-cooled anti-contamination device for cryogenic X-ray diffraction microscopy. The anti-contaminator greatly reduces the buildup of ice layers on the specimen due to condensation of residual water vapor in the experimental vacuum chamber. We show by coherent X-ray diffraction measurements that this leads to fivefold reduction of background scattering, which is important for far-field X-ray diffraction microscopy of biological specimens. PMID- 21547017 TI - Transferrin as a source of iron for Campylobacter rectus. AB - BACKGROUND AND OBJECTIVE: Campylobacter rectus is considered as one of the bacterial species of etiological importance in periodontitis. Iron-containing proteins such as transferrin are found in periodontal sites and may serve as a source of iron for periodontopathogens. The aim of this study was to investigate the capacity of C. rectus to assimilate transferrin-bound iron to support its growth. DESIGN: Growth studies were performed in broth media pretreated with an iron-chelating resin and supplemented with various iron sources. The uptake of iron by C. rectus was monitored using (55)Fe-transferrin. Transferrin-binding activity was assessed using a microplate assay while the degradation of transferrin and iron removal was evaluated by polyacrylamide gel electrophoresis. A colorimetric assay was used to determine ferric reductase activity. RESULTS: Holotransferrin (iron-saturated form) but not apotransferrin (iron-free form) was found to support growth of C. rectus in an iron-restricted culture medium. Incubation of holotransferrin with cells of C. rectus resulted in removal of iron from the protein. A time dependent intracellular uptake of iron by C. rectus cells from (55)Fe-transferrin was demonstrated. This uptake was significantly increased when bacteria were grown under an iron-limiting condition. Cells of C. rectus did not show transferrin-binding activity or proteolytic activity toward transferrin. However, a surface-associated ferric reductase activity was demonstrated. CONCLUSION: To survive and multiply in periodontal sites, periodontopathogens must possess efficient iron-scavenging mechanisms. In this study, we showed the capacity of C. rectus to assimilate iron from transferrin to support its growth. The uptake of iron appears to be dependent on a ferric reductive pathway. PMID- 21547018 TI - Pathogenesis and treatment of oral candidosis. AB - Oral infections caused by yeast of the genus Candida and particularly Candida albicans (oral candidoses) have been recognised throughout recorded history. However, since the 1980s a clear surge of interest and associated research into these infections have occurred. This has largely been due to an increased incidence of oral candidosis over this period, primarily because of the escalation in HIV-infection and the AIDS epidemic. In addition, changes in medical practice leading to a greater use of invasive clinical procedures and a more widespread use of immunosuppressive therapies have also contributed to the problem. Whilst oral candidosis has previously been considered to be a disease mainly of the elderly and very young, its occurrence throughout the general population is now recognised. Candida are true 'opportunistic pathogens' and only instigate oral infection when there is an underlying predisposing condition in the host. Treatment of these infections has continued (and in some regards continues) to be problematic because of the potential toxicity of traditional antifungal agents against host cells. The problem has been compounded by the emergence of Candida species other than C. albicans that have inherent resistance against traditional antifungals. The aim of this review is to give the reader a contemporary overview of oral candidosis, the organisms involved, and the management strategies that are currently employed or could be utilised in the future. PMID- 21547020 TI - Informing Severely III Patients: Needs, Shortcomings and Strategies for Improvement. AB - SUMMARY: The scope of palliative care has expanded gradually over the last decade. Provision of palliative care is not restricted to the last months of life as in some out-dated concepts. It addresses the needs of severely ill patients in all care settings (in- and outpatients, home care, hospices). Particularly in the last years, the value of integrating palliative care early in the disease trajectory of life-threatening and incurable diseases has become increasingly acknowledged. In order for patients to fully benefit from the concept of early integration of palliative care, they need to be provided with information tailored to their disease trajectory. For example, patients and relatives need to know how symptoms such as pain, depression, fatigue, breathlessness, or anxiety can be alleviated. The patients' knowledge and understanding will support the coping process, improve comfort and enhance patient participation and autonomy. Since information needs are highly individual and vary throughout the course of the disease, an interactive approach of assessing the patients' needs and responding to them adequately is mandatory. In this article, the information needs of advanced cancer patients and their families are explained, shortcomings of the present information concepts are discussed, and an integrative approach to responding to patients' information needs throughout the care pathway is advocated. PMID- 21547021 TI - Radiotherapeutic Options for Symptom Control in Breast Cancer. AB - SUMMARY: The majority of breast cancer patients will require radiation therapy at some time during the course of their disease. An estimated 30-50% of all radiation treatments are of palliative nature, either to alleviate symptoms or prophylactic to prevent deterioration of quality of life due to locally progressive disease. Radiotherapy is a locally effective tool, and typically causes no systemic and mostly mild acute side effects. The following article provides an overview of options and decision-making in palliative radiotherapy for symptom control. PMID- 21547019 TI - Review of osteoimmunology and the host response in endodontic and periodontal lesions. AB - Both lesions of endodontic origin and periodontal diseases involve the host response to bacteria and the formation of osteolytic lesions. Important for both is the upregulation of inflammatory cytokines that initiate and sustain the inflammatory response. Also important are chemokines that induce recruitment of leukocyte subsets and bone-resorptive factors that are largely produced by recruited inflammatory cells. However, there are differences also. Lesions of endodontic origin pose a particular challenge since that bacteria persist in a protected reservoir that is not readily accessible to the immune defenses. Thus, experiments in which the host response is inhibited in endodontic lesions tend to aggravate the formation of osteolytic lesions. In contrast, bacteria that invade the periodontium appear to be less problematic so that blocking arms of the host response tend to reduce the disease process. Interestingly, both lesions of endodontic origin and periodontitis exhibit inflammation that appears to inhibit bone formation. In periodontitis, the spatial location of the inflammation is likely to be important so that a host response that is restricted to a subepithelial space is associated with gingivitis, while a host response closer to bone is linked to bone resorption and periodontitis. However, the persistence of inflammation is also thought to be important in periodontitis since inflammation present during coupled bone formation may limit the capacity to repair the resorbed bone. PMID- 21547022 TI - Fungating Wounds - Multidimensional Challenge in Palliative Care. AB - SUMMARY: The management of fungating, malignant wounds is a challenge for the palliative care team. Open, malodorous, poorly healing lesions are obvious signs of underlying disease. In addition, pain and functional impairment remind the patients of their incurable illness. A multidimensional approach is necessary to meet the needs of these patients and to improve quality of life. Although achieving wound closure is rarely a realistic goal, modern techniques of wound management can help to minimize odours and exudates. Specialist knowledge in palliative care is needed to provide adequate pain control. Psychosocial support may help patients to cope with the situation and their limited abilities. PMID- 21547023 TI - Pain Management and Symptom-Oriented Drug Therapy in Palliative Care. AB - SUMMARY: Patients with advanced life-limiting disease often suffer from symptoms that considerably impair their quality of life and that of their families. Palliative care aims to alleviate these symptoms by a multidimensional approach. Pharmacotherapy is an essential component. The objective of this review is to give an overview of symptom-oriented drug therapy for the most important symptoms in palliative care. Leading symptoms that affect quality of life include pain, dyspnea, nausea and emesis, weakness and disorientation. Careful examination and history taking help to understand the individual mechanisms underlying these symptoms. Specific pharmacotherapy provides an efficient way to achieve symptom control in the context of palliative care. PMID- 21547024 TI - Tumor-Specific Systemic Treatment in Advanced Breast Cancer - How Long does it Make Sense? AB - SUMMARY: Metastatic breast cancer (MBC) is a chronic and incurable disease which can be kept steady for a long time with continuous oncologic therapy. There are various treatment options. Disease-free as well as overall survival were prolonged in many pharmaceutical studies. The therapist focuses on these oncologic parameters as well as the patient's quality of life. One central point of the communication between doctor and patient is the prediction by the medical team of how long to continue oncologic therapy and when to start palliative medicine in terms of best palliative care. Treatment options currently available for MBC as well as the importance of this difficult communication between the involved parties are pointed out. The end of tumor-specific oncologic therapy does not necessarily mean the end of therapeutic measures for the individual patient. PMID- 21547025 TI - Adopting Guidelines into Clinical Practice: Implementation of Trastuzumab in the Adjuvant Treatment of Breast Cancer in Lower Saxony, Germany, in 2007. AB - SUMMARY: BACKGROUND: Few studies have assessed the quality of medical care in breast cancer patients outside clinical studies and certified centres in German speaking countries. We used ONkeyLINE, a voluntary tumour registry, to evaluate the rate of adoption into clinical practice of guidelines on the adjuvant use of trastuzumab and to estimate the reliability of ONkeyLINE in assessing quality of care. MATERIAL AND METHODS: Data from ONkeyLINE were analysed to answer questions on the quality of breast cancer care in daily practice in 2007. The influence of age and area (rural/urban) on treatment patterns was also evaluated. RESULTS: Data from approximately 85% of patients diagnosed with breast cancer in Lower Saxony in 2007 were documented in ONkeyLINE. Within 1 year, more than 77% of patients received adjuvant trastuzumab according to the updated guidelines. Variations in chemotherapy and trastuzumab according to age were evident, in part but not fully attributable to comorbidities in the elderly. Access to trastuzumab therapy in rural areas was as high as in urban areas. CONCLUSIONS: Adoption of national guidelines into clinical practice was observed at a reasonable but still unsatisfactory rate in Lower Saxony. Although voluntary, ONkeyLINE covered most breast cancer cases and proved to be a reliable tool for assessing quality of care. PMID- 21547026 TI - A Rare Complication Following Breast Implant Surgery: Capsular Contracture with a Cutaneous Silicone Fistula after Breast Reconstruction with Silicone Gel Implants. AB - SUMMARY: BACKGROUND: We report the case of a 74-year-old female patient who presented at the Breast Care Centre with watery discharge from a fistula in the inframammary fold of the left breast. CASE REPORT: The patient initially presented with watery discharge coming from the fistula, which later took on a more viscous consistency. She reported mild discomfort as well as mild erythema. Clinical examination and diagnostic approaches including magnetic resonance imaging (MRI) revealed a cutaneous silicone fistula as a rare complication following breast implant reconstruction. The condition was treated with excision of the fistula and bilateral implant removal. CONCLUSIONS: This case report documents a rare complication following breast reconstruction with implants, and is to our knowledge the first described MRI-detected cutaneous silicone fistula. PMID- 21547027 TI - Spontaneous Infarction in a Fibroadenoma of the Breast. AB - SUMMARY: BACKGROUND: Fibroadenomas are common neoplasms in young women but occur in a wide age range from adolescent females to octogenians. CASE REPORT: A 21 year-old female patient presented with a 10-week history of a mass in her breast. Ultrasound examination demonstrated a 3.5 * 3 cm, well-circumscribed, semisolid mass. An excisional biopsy but no fine needle aspiration was performed. The patient had no history of pregnancy or lactation, or trauma or infection to the area of the lesion. The histopathological examination showed a spontaneously infarcted fibroadenoma. CONCLUSIONS: Spontaneous infarction is an uncommon complication in fibroadenoma of the breast, and there are very few reported cases in the literature. PMID- 21547028 TI - Quo vadis chimerism? AB - Although immunity in multicellular organisms is efficient in dealing with alien agents, it may fail for allogeneic chimerism. Natural chimerism is widely documented in nature, distributed in at least ten phyla of protists, invertebrates and plants, vertebrates and mammals, including humans; it is an important ecological/evolutionary tool manipulating metazoans' life history portraits. Instead of purging allogeneic nascent selfish cells, a 'double edged sword' chimerism emerges, displaying environmental dictated costs and benefits for the genotypes involved. Benefits include the development of synergistic complementation, the increase of genetic variability, the assurance of mate location, improved size-dependent ecological qualities (growth rates, reproduction, survivorship, competition, environmental tolerance) and more. Costs include the threat of somatic and germ cell parasitism, developmental instability, death, diseases, autoimmunity, sexual sterility and organ malformations, which develop as well in mammalian natural chimerism, including humans. Because of its importance, medical sciences should study and harness natural chimerism properties for clinical purposes. PMID- 21547029 TI - Male microchimerism in peripheral blood leukocytes from women with multiple sclerosis. AB - BACKGROUND: Fetal microchimerism (F-MC), the persistence of fetal cells in the mother, is frequently encountered following pregnancy. The high prevalence of F MC in autoimmune disease prompts consideration of the role for immune tolerance and regulation. This study examines the association between F-MC and multiple sclerosis (MS), an autoimmune disorder, of undetermined etiology. RESULTS: 21 out of 51 MS-positive subjects (41%) were classified as positive for F-MC; 4 of 22 (18%) of MS-negative sibling controls, were also positive for MC (p = 0.066). Unanticipated F-MC in controls lead to re-evaluation using 30 female singleton cord blood units (CBUs) as a biological control. Four CBUs were low-level positive. STUDY DESIGN AND METHODS: Seventy-three female subjects were assigned to three groups according to disease status and pregnancy history: (1) MS positive (+) women with a history of one male pregnancy before symptom onset (n = 27); (2) MS negative (-) female siblings of MS(+) women with a history of one male pregnancy (n = 22); and (3) MS(+) women that reported never having been pregnant (n = 24). Ten micrograms of genomic DNA obtained from peripheral blood leukocytes of each subject were analyzed for F-MC using allele-specific real-time PCR targeting the SR-Y sequence on the Y-chromosome. MC classification was dichotomous (positive vs. negative) based on PCR results. CONCLUSION: The association between F-MC and MS warrants further study to define this relationship. F-MC in women self-reporting as nulligravid, supports previous findings that a significant proportion of pregnancies go undetected. This lead to re-validation of a Y-chromosome based assay for F-MC detection. PMID- 21547030 TI - Parity and HLA alleles in risk of rheumatoid arthritis. AB - Specific HLA II alleles are associated with rheumatoid arthritis (RA) risk and others with protection. Risk-associated alleles encode similar amino acid sequences from 70 through 74 of HLA-DRbeta1 (QKRAA, QRRAA, RRRAA), referred to as the "shared epitope" (SE) and protective alleles encode DERAA at the same location. Fetal-maternal cell exchange results in long-term microchimerism i.e. harboring small numbers of genetically disparate cells. Women with RA who lack the SE were recently found to harbor microchimerism with the SE more often than healthy women. This finding raises the question whether microchimerism with DERAA confers benefit against RA and is underscored by the observation that overall parity reduces RA risk. While there is currently no test for microchimerism with DERAA, we conducted studies to ask whether parity benefits women at risk for RA, either because they have the SE or lack the protective DERAA sequence. HLA genotyping was conducted for 310 RA and 571 healthy women. Parity was associated with reduced RA risk in women aged <45 years (RR 0.53, 95% CI 0.34-0.82) and further analyses examined this group. RA risk reduction with parity was greater among women with the SE than SE-negative women (RR 0.42, 95%CI 0.22-0.79 vs. RR 0.79, 0.38-1.64). Among women without DERAA, RA risk was significantly reduced with parity (RR 0.44, 95% CI 0.26-0.74) but not among DERAA-positive women (RR 0.95 95% CI 0.34-2.65). In summary, results indicate the effect of parity varied according to a woman's HLA-genotype, and women at increased risk of RA benefited most. PMID- 21547032 TI - Recurrent disease or donor cell leukemia?: Brain teaser after allogeneic bone marrow transplantation. AB - Allogeneic bone marrow transplantation (allo-BMT) is the treatment of choice for many patients with poor prognosis or refractory leukemia. Chimerism and residual tumor load after allo-BMT are widely monitored to detect impending graft rejection and the early phase of relapse. In most cases, the malignant cell population during post-transplant relapse contains host-derived cells, but the leukemic clone can rarely be of donor-cell origin. Various genetic tests with different strategies, targets and sensitivities are available for donor-host discrimination. However, changes in the genomic material of the dominant host cell population as a result of clonal evolution and/or clonal selection can hamper the correct identification of the origin of aberrant cells after allo-BMT, thus confounding the assessment of the chimeric state. Consequently, a good knowledge of the techniques applied in clinical practice and careful interpretation of their results are essential. A lack of host-specific markers at the time of clinical relapse is not adequate for verifying the presence of donor cell leukemia, and unequivocal demonstration of donor-specific markers is also required. PMID- 21547031 TI - Fetomaternal microchimerism: Some answers and many new questions. AB - The transfer of fetal cells into mothers during pregnancy and their organ specific integration is a well recognized phenomenon in placental vertebrates. Recently, it has been reported that some fetal cells found in the mothers have progenitor cell-like features such as multilineage differentiation potential and as a consequence they were termed pregnancy associated progenitor cells (PAPC). The multilineage differentiation potential suggested some level of cellular plasticity, which these cells share with other stem or progenitor cells. In this context, we have shown that PAPCs indeed express neural stem cell and markers for developing neurons in the brain and that PAPCs morphologically mature into neurons over time. The stem/progenitor properties of PAPCs raises the hope that they might be valuable for studying the functional integration of foreign cells into preexisting tissues and organs, for example in cellular therapies. The functional integration of transplanted cells and their connectivity to the host circuitry is still a major bottleneck in cellular therapies particularly for the brain. The animal models of fetomaternal microchimerism might provide valuable insights into the mechanism how cells survive, migrate, integrate and differentiate in a foreign environment of a host. This review discusses some of the recent findings in the field of fetomaternal microchimerism. It also tries to identify some major gaps of knowledge and raises some questions resulting from the recent advances. Studying fetomaternal microchimerism and the properties of PAPCs in greater detail might pave the way to advance cell based regenerative medicine as well as transplantation medicine. PMID- 21547033 TI - Split chimerism between nucleated and red blood cells after bone marrow transplantation for haemoglobinopathies. AB - Previous studies have shown that a stable presence of both donor and recipient haematopoietic derived cells after allogeneic haematopoietic stem cell transplantation (HSCT) occurs in approximately ten percent of the patients affected by beta-Thalassemia. Once achieved this condition, defined as persistent mixed chimerism (PMC), the patients do not require additional red blood cells (RBCs) support and, regardless of the presence in some cases of an extremely low percentage of donor-derived nucleated cells, they are clinically cured by an incomplete, but functional graft. Most of the published papers have, however, investigated the impact of donor engraftment in the nucleated cells rather than in the mature erythrocytes. We have recently published a paper showing that in four long-term transplanted patients affected by hemoglobinopathies, characterized by the presence of few donor engrafted nucleated cells-both in the peripheral blood and in the bone marrow-the majority of the erythrocytes were of donor origin. Moreover we showed that the proportion of donor-derived erythroid precursors, determined by analyzing singularly picked-up burst-forming unit erythroid colonies, was equivalent to that observed in the mature nucleated cells rather than in the red blood cells. These results suggest that in patients characterized by the presence of PMC after HSCT a selective advantage of the donor erythroid precursors maturation might successfully contrast the problems bound to the recipient ineffective erythropoiesis. When genetically modified HSCT will be a possible option for treating Thalassemia Major, the co-existence of the repaired cells with those still expressing the genetic defect will be an expected scenario, not in an allogeneic, but in an autologous environment. PMID- 21547034 TI - Major and minor histocompatibility antigens to NIMA: Prediction of a tolerogenic NIMA effect. AB - The immunologic effects of developmental exposure to non-inherited maternal antigens (NIMA) are heterogeneous, either tolerogenic or immunogenic. The role of minor histocompatibility antigens (MiHA) in NIMA effects is unknown. We have recently reported that the NIMA effect can be classified into two distinct reactivities, low and high responder, to NIMA in utero and during nursing depending on the degree of maternal microchimerism (MMc) and Foxp3 expression of peripheral blood CD4(+)CD25(+) cells after graft-versus-host disease (GVHD) induction. These reactivities were predictable before transplantation, using an MLR-ELISPOT (mixed lymphocyte reaction; enzyme-linked immunospot) assay by comparing the number of IFNgamma-producing cells stimulated with NIMA. Moreover, this assay was also applicable in both major and minor NIMA-mismatched setting. These observations are clinically relevant and suggest that it is possible to predict the immunological tolerance to NIMA. PMID- 21547035 TI - DNA chimerism and its consequences after allogeneic hematopoietic cell transplantation. AB - The unphysiological formation of biological chimeras after allogeneic hematopoietic cell transplantation is not free of consequences. Recent findings suggest that in the transplant recipient some epithelial cells reveal, unexpectedly, donor-derived genotype and/or acquire genomic alterations. Since both phenomena are presented in the host epithelium, one could argue that they might be etiologically linked through a common background mechanism. We recently proposed that the incessant charge of the transplant recipient with donor-DNA and its integration in host epithelium by horizontal DNA transference may indeed be operative in the generation of epithelial cells with donor derived genome. On the other hand, the incessant incorporation of the foreign DNA into the host genome may result in genomic alterations. Lymphocyte-epithelial interactions between the two genetically distinct cell populations in the transplant recipient should be investigated more precisely not only in cellular but also in molecular level. PMID- 21547036 TI - Divide and conquer: Blocking graft versus host but not graft versus leukemia T cells with agonist BTLA co-inhibitory signals. AB - One of the main objectives in allogeneic hematopoietic stem cell transplantation (aHSCT) research is the prevention of graft versus host disease (GVHD) while maintaining the graft versus leukemia/lymphoma (GVL) effect. Whether these two responses generated by donor T cells can be sufficiently separated and controlled remains controversial. While various approaches have been tested to achieve this goal, success has been relatively limited. Lymphocyte responses are negatively regulated by a series of receptors that function along with antigen receptors to deliver co-inhibitory signals. B and T lymphocyte associated (BTLA) is a novel co inhibitory molecule expressed by activated T cells, B cells and other immune cells. A study by Albring et al. has now shown in a murine model that a single injection of agonistic anti-BTLA monoclonal antibody can inhibit GVHD long-term while maintaining GVL responses and immunity to infection. These studies suggest that future development of biologics to harness the function of co-inhibitory signals will be an important approach in the prevention of autoimmunity and GVHD and in protocols to achieve transplantation tolerance. PMID- 21547038 TI - Cardiopulmonary manifestations of ankylosing spondylitis. AB - Ankylosing spondylitis is a chronic inflammatory condition that usually affects young men. Cardiac dysfunction and pulmonary disease are well-known and commonly reported extra-articular manifestation, associated with ankylosing spondylitis (AS). AS has also been reported to be specifically associated with aortitis, aortic valve diseases, conduction disturbances, cardiomyopathy and ischemic heart disease. The pulmonary manifestations of the disease include fibrosis of the upper lobes, interstitial lung disease, ventilatory impairment due to chest wall restriction, sleep apnea, and spontaneous pneumothorax. They are many reports detailing pathophysiology, hypothesized mechanisms leading to these derangements, and estimated prevalence of such findings in the AS populations. At this time, there are no clear guidelines regarding a stepwise approach to screen these patients for cardiovascular and pulmonary complications. PMID- 21547039 TI - Surgical management of temporomandibular joint ankylosis in ankylosing spondylitis. AB - Relatively few patients develop such severe degenerative temporomandibular joint (TMJ) disease that they require total joint replacement. Current indications include those conditions involving condylar bone loss such as degenerative (osteoarthritis) or inflammatory joint disease (ankylosing spondylitis, rheumatoid, and psoriatic). Ankylosis of the temporomandibular joint (TMJ) secondary to ankylosing spondylitis remains an under investigated entity. We aim to provide an overview of treatment objectives, surgical procedures, and our experience with total TMJ replacement for this condition. PMID- 21547037 TI - Pathogenicity of Misfolded and Dimeric HLA-B27 Molecules. AB - The association between HLA-B27 and the group of autoimmune inflammatory arthritic diseases, the spondyloarthropathies (SpAs) which include ankylosing spondylitis (AS) and Reactive Arthritis (ReA), has been well established and remains the strongest association between any HLA molecule and autoimmune disease. The mechanism behind this striking association remains elusive; however animal model and biochemical data suggest that HLA-B27 misfolding may be key to understanding its association with the SpAs. Recent investigations have focused on the unusual biochemical structures of HLA-B27 and their potential role in SpA pathogenesis. Here we discuss how these unusual biochemical structures may participate in cellular events leading to chronic inflammation and thus disease progression. PMID- 21547040 TI - Ayurveda, evidence-base and scientific rigor. PMID- 21547041 TI - Validation of Ayurvedic formulations in animal models requires stringent scientific rigor. PMID- 21547042 TI - Authors' reply. PMID- 21547043 TI - Model organisms in Ayurvedic research. PMID- 21547044 TI - How practical are the "teaching reforms" without "curricular reforms"? PMID- 21547045 TI - Seeing with two eyes: How professionals can help patients trying to integrate medical systems. PMID- 21547046 TI - Health traditions of Sikkim Himalaya. AB - Ancient medical systems are still prevalent in Sikkim, popularly nurtured by Buddhist groups using the traditional Tibetan pharmacopoeia overlapping with Ayurvedic medicine. Traditional medical practices and their associated cultural values are based round Sikkim's three major communities, Lepcha, Bhutia and Nepalis. In this study, a semi-structured questionnaire was prepared for folk healers covering age and sex, educational qualification, source of knowledge, types of practices, experience and generation of practice, and transformation of knowledge. These were administered to forty-eight folk healers identified in different parts of Sikkim.490 medicinal plants find their habitats in Sikkim because of its large variations in altitude and climate. For 31 commonly used by these folk healers, we present botanical name, family, local name, distribution, and parts used, together with their therapeutic uses, mostly Rheumatoid arthritis, Gout, Gonorrhea, Fever, Viral flu, asthma, Cough and Cold, indigestion, Jaundice etc. A case treated by a folk healer is also recounted. This study indicates that, in the studied area, Sikkim's health traditions and folk practices are declining due to shifts in socio-economic patterns, and unwillingness of the younger generation to adopt folk healing as a profession. PMID- 21547047 TI - Ayurveda-modern medicine interface: A critical appraisal of studies of Ayurvedic medicines to treat osteoarthritis and rheumatoid arthritis. AB - The potential of Ayurvedic philosophy and medicines needs to be recognized and converted into real life treatment paradigm. This article describes a comprehensive therapeutic approach used in Ayurveda and modern medicine to treat arthritis. We present concise summary of various controlled drug trials carried out by us to validate standardized Ayurvedic drugs using modern medicine protocol to treat Rheumatoid Arthritis and Osteoarthritis knees. Several of the latter are published. The trials consistently demonstrate excellent safety of Ayurvedic medicines but often fail to unequivocally show superior efficacy. Some key findings of a recently unpublished trial in OA knees are also presented to show equivalence between Ayurvedic medicine and celecoxib and glucosamine, and we speculate that equivalence trials may be a way forward. The data from the trials also supports the Ayurvedic 'Rasayana' concept of immune-modulation and healing. We need to interpret logic of Ayurveda when, adopting modern science tools in drug development and validation and much research is required. Validation of Ayurvedic medicines using the latter approach may lead to an evidence based Ayurveda - Modern Medicine interface. Also, in pursuit of finding better treatment solutions, we ought to step beyond the realm of only drugs and attempt validation of comprehensive specific treatment package as per classical Ayurveda. Finally, validation of a combined (Ayurveda and modern medicine) therapeutic approach with superior efficacy and safety is likely to be a major leap in overcoming some of the current frustrations to treat difficult disorders like arthritis using only modern medicines. PMID- 21547048 TI - Antioxidant and antifungal activities of essential oil of Alpinia calcarata Roscoe rhizomes. AB - Antioxidant and antifungal activity were determined for the essential oil of Alpinia calcarata Roscoe (Zingiberaceae) rhizomes. Its antioxidant properties were investigated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay and thiobarbituric acid reactive substances (TBARS) assay. Butylated hydroxy toluene (BHT) and vitamin E served as positive controls. Antifungal activities were investigated against crop pathogens Curvularia spp. and Colletorichum spp. using the agar plate method. Fifty percent effective concentration (EC(50)) and % antioxidant index of the essential oil were 45 +/- 0.4 and 16.1 +/- 0.2 for DPPH and TBARS assays, respectively. The degree of, the essential oil's inhibition of the growth of crop pathogens Curvularia spp. and Colletorichum spp. varied with time period its effects were higher than greater than for the positive control, daconil. In conclusion, the essential oil of A. calcarata rhizomes possess moderate antioxidant property and promising antifungal activity. PMID- 21547049 TI - A study of standardized extracts of Picrorhiza kurroa Royle ex Benth in experimental nonalcoholic fatty liver disease. AB - As a major organ of intermediary metabolism, the liver is exposed to a variety of metabolic insults due to diseases and xenobiotics viz., insulin resistance (IR) drugs, toxins, microbial products, etc. One of the consequences of these metabolic insults including obesity and type 2 diabetes mellitus is the development of non-alcoholic fatty liver disease (NAFLD). The recent alarming increase in the prevalence of NAFLD compels the need to develop an appropriate animal model of the disease so as to evolve effective interventions. In this study, we have developed, in the rat, a new model of NAFLD showing several key features akin to the disease in humans. Male Wistar rats were challenged with 30% high fat diet (HFD) - butter, for 2 weeks to induce NAFLD. A hydroalcoholic extract of Picrorhiza kurroa was administered to study the possible reversal of fatty changes in the liver. The extract was given in two doses viz., 200mg/kg and 400 mg/kg b.i.d., p.o. for a period of 4 weeks. There were three control groups (n = 6/group) - vehicle with a regular diet, vehicle with HFD, and HFD with silymarin - a known hepatoprotective.Histopathology showed that the P. kurroa extract brought about a reversal of the fatty infiltration of the liver (mg/g) and a lowering of the quantity of hepatic lipids (mg/g) compared to that in the HFD control group (38.33 +/- 5.35 for 200mg/kg; 29.44 +/- 8.49 for 400mg/kg of P. kurroa vs.130.07 +/- 6.36mg/g of liver tissue in the HFD control group; P<0.001). Compared to the standard dose of the known hepatoprotective silymarin, P. kurroa reduced the lipid content (mg/g) of the liver more significantly at the dose of 400mg/kg (57.71 +/- 12.45mg/kg vs. 29.44 +/- 8.49 for the silymarin group vs. 400mg/kg of P. kurroa, P<0.001). In view of the increasing prevalence of metabolic syndrome and NAFLD, P. kurroa should be investigated by the reverse pharmacology path as a potential drug for the treatment of NAFLD, and essential safety studies and preformulation research for concentration of the putative actives should be carried out. PMID- 21547050 TI - Ankylosing spondylitis. AB - Ankylosing spondylitis belongs to a group of rheumatic diseases known as the spondyloarthropathies (SpA), which show a strong association with the genetic marker HLA-B27. Inflammatory back pain and stiffness are prominent early in the disease, whereas chronic, aggressive disease may produce pain and marked axial immobility or deformity. Modern medicine has no established treatment for it. From the Ayurvedic perspective, the disease can fall under amavata, which may be effectively managed when intervention is started in its early stages. Niruha basthi with Balaguduchyadi yoga, combined by Shamana treatment with Rasnerandadi kwatha and Simhanada guggulu have been found effective in curbing its progression. This article presents a single case report in which these treatments achieved considerable success. PMID- 21547051 TI - Herbo-mineral ayurvedic treatment in a high risk acute promyelocytic leukemia patient with second relapse: 12 years follow up. AB - A 47 year old diabetic male patient was diagnosed and treated for high risk AML M3 at Tata Memorial Hospital (BJ 17572), Mumbai in September 1995. His bone marrow aspiration cytology indicated 96% promyelocytes with abnormal forms, absence of lymphocytic series and myeloperoxide test 100% positive. Initially treated with ATRA, he achieved hematological remission on day 60, but cytogenetically the disease persisted. The patient received induction and consolidated chemotherapy with Daunorubicin and Cytarabine combination from 12.01.96 to 14.05.96, following which he achieved remission. However, his disease relapsed in February 97. The patient was given two cycles of chemotherapy with Idarubicine and Etoposide, after which he achieved remission. His disease again relapsed in December 97. The patient then refused more chemotherapy and volunteered for a pilot Ayurvedic study conducted by the Central Council for Research in Ayurveda and Siddha, New Delhi. The patient was treated with a proprietary Ayurvedic medicine Navajeevan, Kamadudha Rasa and Keharuba Pisti for one year. For the subsequent 5 years the patient received three months of intermittent Ayurvedic treatment every year. The patient achieved complete disease remission with the alternative treatment without any adverse side effects. The patient has so far completed 13 years of survival after the start of Ayurvedic therapy. PMID- 21547052 TI - Vaidya v. B. Mhaiskar. PMID- 21547053 TI - Balaraj Maharishi and the first clinical trial of Ayurvedic medicines in the West. PMID- 21547054 TI - Ayurveda in Argentina and other Latin American countries. AB - Over the past 20 years the Fundacion Salud de Ayurved Prema Argentina has spread the knowledge of Ayurveda throughout Latin America. The Fundacion is based in Buenos Aires in the Argentine Republic, where it now runs courses in two of the country's major medical schools - at the School of Medicine of the University of Buenos Aires, and the National University of Cordoba's School of Medicine. Based on an MoU with Gujarat Ayurveda University, at Jamnagar, Gujarat, the Fundacion has been accredited as a Collaborating Center for teaching, assistance and research in the field of Ayurvedic Medicine in Argentina. This has led to successful missions to other countries in the region where the Fundacion and its associates have been able to start dialogues with governments, and in places hold sizeable courses. The knowledge of Ayurveda is now spreading throughout South and Central America and hardly a country remains untouched by it. PMID- 21547055 TI - Fishing fish stem cells and nuclear transplants. AB - Fish has been the subject of various research fields, ranging from ecology, evolution, physiology and toxicology to aquaculture. In the past decades fish has attracted considerable attention for functional genomics, cancer biology and developmental genetics, in particular nuclear transfer for understanding of cytoplasmic-nuclear relationship. This special issue reports on recent progress made in fish stem cells and nuclear transfer. PMID- 21547056 TI - Fish stem cell cultures. AB - Stem cells have the potential for self-renewal and differentiation. First stem cell cultures were derived 30 years ago from early developing mouse embryos. These are pluripotent embryonic stem (ES) cells. Efforts towards ES cell derivation have been attempted in other mammalian and non-mammalian species. Work with stem cell culture in fish started 20 years ago. Laboratory fish species, in particular zebrafish and medaka, have been the focus of research towards stem cell cultures. Medaka is the second organism that generated ES cells and the first that gave rise to a spermatogonial stem cell line capable of test-tube sperm production. Most recently, the first haploid stem cells capable of producing whole animals have also been generated from medaka. ES-like cells have been reported also in zebrafish and several marine species. Attempts for germline transmission of ES cell cultures and gene targeting have been reported in zebrafish. Recent years have witnessed the progress in markers and procedures for ES cell characterization. These include the identification of fish homologs/paralogs of mammalian pluripotency genes and parameters for optimal chimera formation. In addition, fish germ cell cultures and transplantation have attracted considerable interest for germline transmission and surrogate production. Haploid ES cell nuclear transfer has proven in medaka the feasibility of semi-cloning as a novel assisted reproductive technology. In this special issue on "Fish Stem Cells and Nuclear Transfer", we will focus our review on medaka to illustrate the current status and perspective of fish stem cells in research and application. We will also mention semi-cloning as a new development to conventional nuclear transfer. PMID- 21547057 TI - Ovarian germline stem cells in the teleost fish, medaka (Oryzias latipes). AB - In the mammalian testis germline stem cells keep producing many sperms, while there is no direct evidence for the presence of germline stem cells in the ovary. It is widely accepted in mammals that the mature oocytes are supplied from a pool of primordial follicles in the adult ovary. In other vertebrates, such as fish, however, there has been no investigation on the mechanism underlying the high egg producing ability. In this review, we introduce the recently identified ovarian germline stem cells and the surrounding unique structure in teleost fish, medaka (Oryzias latipes) [Nakamura S et al. Science. 2010; 328: 1561-1563]. We also discuss about the expression and function of sox9 that characterizes this unique structure. PMID- 21547058 TI - Fishing pluripotency mechanisms in vivo. AB - To understand the molecular mechanisms that regulate the biology of embryonic stem cells (ESCs) it is necessary to study how they behave in vivo in their natural environment. It is particularly important to study the roles and interactions of the different proteins involved in pluripotency and to use this knowledge for therapeutic purposes. The recent description of key pluripotency factors like Oct4 and Nanog in non-mammalian species has introduced other animal models, such as chicken, Xenopus, zebrafish and medaka, to the study of pluripotency in vivo. These animal models complement the mouse model and have provided new insights into the evolution of Oct4 and Nanog and their different functions during embryonic development. Furthermore, other pluripotency factors previously identified in teleost fish such as Klf4, STAT3, Sox2, telomerase and Tcf3 can now be studied in the context of a functional pluripotency network. The many experimental advantages of fish will fuel rapid analysis of the roles of pluripotency factors in fish embryonic development and the identification of new molecules and mechanisms governing pluripotency. PMID- 21547059 TI - Medaka cleavage embryos are capable of generating ES-like cell cultures. AB - Mammalian embryos at the blastocyst stage have three major lineages, which in culture can give rise to embryonic stem (ES) cells from the inner cell mass or epiblast, trophoblast stem cells from the trophectoderm, and primitive endoderm stem cells. None of these stem cells is totipotent, because they show gene expression profiles characteristic of their sources and usually contribute only to the lineages of their origins in chimeric embryos. It is unknown whether embryos prior to the blastocyst stage can be cultivated towards totipotent stem cell cultures. Medaka is an excellent model for stem cell research. This laboratory fish has generated diploid and even haploid ES cells from the midblastula embryo with ~2000 cells. Here we report in medaka that dispersed cells from earlier embryos can survive, proliferate and attach in culture. We show that even 32-cells embryos can be dissociated into individual cells capable of producing continuously growing ES-like cultures. Our data point to the possibility to derive stable cell culture from cleavage embryos in this organism. PMID- 21547060 TI - Medaka tert produces multiple variants with differential expression during differentiation in vitro and in vivo. AB - Embryonic stem (ES) cells have immortality for self-renewal and pluripotency. Differentiated human cells undergo replicative senescence. In human, the telomerase reverse transcriptase (Tert), namely the catalytic subunit of telomerase, exhibits differential expression to regulate telomerase activity governing cellular immortality or senescence, and telomerase activity or tert expression is a routine marker of pluripotent ES cells. Here we have identified the medaka tert gene and determined its expression and telomerase activity in vivo and in vitro. We found that the medaka tert locus produces five variants called terta to terte encoding isoforms TertA to TertE. The longest TertA consists of 1090 amino acid residues and displays a maximum of 34% identity to the human TERT and all the signature motifs of the Tert family. TertB to TertE are novel isoforms and have considerable truncation due to alternative splicing. The terta RNA is ubiquitous in embryos, adult tissues and cell lines, and accompanies ubiquitous telomerase activity in vivo and in vitro as revealed by TRAP assays. The tertb RNA was restricted to the testis, absent in embryos before gastrulation and barely detectable in various cell lines The tertc transcript was absent in undifferentiated ES cells but became evident upon ES cell differentiation, in vivo it was barely detectable in early embryos and became evident when embryogenesis proceeds. Therefore, ubiquitous terta expression correlates with ubiquitous telomerase activity in medaka, and expression of other tert variants appears to delineate cell differentiation in vitro and in vivo. PMID- 21547061 TI - Identification of pluripotency genes in the fish medaka. AB - Stem cell cultures can be derived directly from early developing embryos and indirectly from differentiated cells by forced expression of pluripotency transcription factors. Pluripotency genes are routinely used to characterize mammalian stem cell cultures at the molecular level. However, such genes have remained unknown in lower vertebrates. In this regard, the laboratory fish medaka is uniquely suited because it has embryonic stem (ES) cells and genome sequence data. We identified seven medaka pluripotency genes by homology search and expression in vivo and in vitro. By RT-PCR analysis, the seven genes fall into three groups of expression pattern. Group I includes nanog and oct4 showing gonad specific expression; Group II contains sall4 and zfp281 displaying gonad preferential expression; Group III has klf4, ronin and tcf3 exhibiting expression also in several somatic tissues apart from the gonads. The transcripts of the seven genes are maternally supplied and persist at a high level during early embryogenesis. We made use of early embryos and adult gonads to examine expression in stem cells and differentiated derivatives by in situ hybridization. Strikingly, nanog and oct4 are highly expressed in pluripotent blastomeres of 16 cell embryos. In the adult testis, nanog expression was specific to spermatogonia, the germ stem cells, whereas tcf3 expression occurred in spermatogonia and differentiated cells. Most importantly, all the seven genes are pluripotency markers in vitro, because they have high expression in undifferentiated ES cells but dramatic down-regulation upon differentiation. Therefore, these genes have conserved their pluripotency-specific expression in vitro from mammals to lower vertebrates. PMID- 21547062 TI - Establishment and characterization of a testicular cell line from the half-smooth tongue sole, Cynoglossus semilaevis. AB - Spermatogenesis within the adult testis is an excellent system for studying stem cell renewal and differentiation, which is under the control of testicular somatic cells. In order to understanding spermatogenesis in the half-smooth tongue sole (Cynoglossus semilaevis) as a marine fish model of aquaculture importance, we established a cell line called CSGC from a juvenile gonad of this organism. CSGC is composed of fibroblast-like cells, retains a diploid karyotype of 42 chromosomes, lacks the heterogametic W chromosome, lacks a female specific marker and expresses the dmrt, a marker for testicular somatic cells. Therefore, CSGC appears to consist of testicular somatic cell cells. We show that this cell line is effective for infection by the turbot reddish body iridovirus and flounder lymphocystis disease virus as evidenced by the appearance of cytopathic effect and virus propagation in the virus-infected cells, and most convincingly, the observation of viral particles by electon microscopy, demonstrateing that CSGC is suitable to study interactions between virus and host cells. As a first fish testicular somatic cell line of the ZZ-ZW genetic sex determination system, CSGC will be a useful tool to study sex-related events and interactions between somatic cells and germ cells during spermatogenesis. PMID- 21547063 TI - Nuclear transfer of embryonic cell nuclei to non-enucleated eggs in zebrafish, Danio rerio. AB - We previously established a novel method for nuclear transfer in medaka (Oryzias latipes) using non-enucleated, diploidized eggs as recipients for adult somatic cell nuclei. Here we report the first attempt to apply this method to another fish species. To examine suitability of using non-enucleated eggs as recipients for nuclear transfer in the zebrafish (Danio rerio), we transferred blastula cell nuclei from a wild-type donor strain to non-enucleated, unfertilized eggs from a golden recipient strain. As a result, 31 of 184 (16.8%) operated eggs developed normally and reached the adult stage. Twenty-eight (15.2%) of these transplants showed wild-type phenotype and the remaining three (1.6%) were golden. Except for one individual that exhibited diploid/tetraploid mosaicism, all of the wild-type nuclear transplants were either triploid or diploid. While all of 19 triploid transplants were infertile, a total of six transplants (21.4%) were fertile (five of the eight diploid transplants and one transplant exhibiting ploidy mosaicism). Except for one diploid individual, all of the fertile transplants transferred both the wild-type golden gene allele (slc24a5) as well as the phenotype, the wild-type body color, to their F(1) and F(2) progeny in a typical Mendelian fashion. PCR analysis of slc24a5 suggested that triploidy originated from a fused nucleus in the diploid donor and haploid recipient nuclei, and that the sole origin of diploidy was the diploid donor nucleus. The results of the present study demonstrated the suitability of using non-enucleated eggs as recipients for nuclear transfer experiments in zebrafish. PMID- 21547064 TI - Sperm nuclear transfer and transgenic production in the fish medaka. AB - Sperm nuclear transfer or intracytoplasmic sperm injection (ICSI) is a powerful assisted reproductive technology (ART) for treating human male infertility. Controversial reports of increased birth defects have raised concerns about the ART's safety. The cause for birth defects, however, has remained elusive for analysis in human because of the sample size, male infertility genetics, physiological heterogeneity and associated procedures such as embryo manipulations. Animal models are required to evaluate factors leading to the increased birth defects. Here we report the establishment of medakafish model for ICSI and transgenic production. This small laboratory fish has high fecundity and easy embryology. We show that ICSI produced a 5% high percentage of fertile animals that exhibited both paternal and maternal contribution as evidenced by the pigmentation marker. Furthermore, when sperm were pre-incubated with a plasmid ubiquitously expressing RFP and subjected to ICSI, 50% of sperm nuclear transplants showed germline transmission. We conclude that medaka is an excellent model for ICSI to evaluate birth defects and that sperm nuclear transfer can mediate stable gene transfer at high efficiency. Although more demanding for experimentation, sperm-mediated transgenesis should be particularly applicable for aquaculture species with a lengthy generation time and/or a large adult body size. PMID- 21547065 TI - Critical developmental stages for the efficiency of somatic cell nuclear transfer in zebrafish. AB - Somatic cell nuclear transfer (SCNT) has been performed extensively in fish since the 1960s with a generally low efficiency of approximately 1%. Little is known about somatic nuclear reprogramming in fish. Here, we utilized the zebrafish as a model to study reprogramming events of nuclei from tail, liver and kidney cells by SCNT. We produced a total of 4,796 reconstituted embryos and obtained a high survival rate of 58.9-67.4% initially at the 8-cell stage. The survival rate exhibited two steps of dramatic decrease, leading to 8.7-13.9% at the dome stage and to 1.5-2.96% by the shield stage. Concurrently, we observed that SCNT embryos displayed apparently delayed development also at the two stages, namely the dome stage (1:30 +/- 0:40) and the shield stage (2:50 +/- 0:50), indicating that the dome and shield stage are critical for the SCNT efficiency. Interestingly, we also revealed that an apparent alteration in klf4 and mycb expression occurred at the dome stage in SCNT embryos from all the three donor cell sources. Taken together, these results suggest that the dome stage is critical for the SCNT efficiency, and that alternated gene expression appears to be common to SCNT embryos independently of the donor cell types, suggesting that balanced mycb and klf4 expression at this stage is important for proper reprogramming of somatic nuclei in zebrafish SCNT embryos. Although the significant alteration in klf4 and mycb expression was not identified at the shield stage between ZD and SCNT embryos, the importance of reprogramming processes at the shield stage should not be underestimated in zebrafish SCNT embryos. PMID- 21547066 TI - Massive production of all-female diploids and triploids in the crucian carp. AB - In many species of aquaculture importance, all-female and sterile populations possess superior productivity due to faster growth and a relatively homogenous size of individuals. However, the production of all-female and sterile fish in a large scale for aquaculture is a challenge in practice, because treatments necessary for gynogenesis induction usually cause massive embryonic and larval mortality, and the number of induced gynogens is too small for their direct use in aquaculture. Here we report the massive production of all-female triploid crucian carp by combining artificial gynogenesis, sex reversal and diploid tetraploid hybridization. Previously, we have obtained an allotetraploid carp population (4n = 200) by hybridization between red crucian carp (Carassius auratus red var; ?) and common carp (Cyprinus carpio; ?). We induced all-female diploid gynogens of the Japanese crucian carp (Carassius cuvieri; 2n = 100). We also generated male diploid gynogens of the same species treated gynogenetic fry with 17-alpha-methyltestosterone, leading to the production of sex-revered gynogenetic males. Finally, these males were used to cross with the female diploid Japanese crucian carp gynogens and the allotetraploid females, resulting in the production of fertile all-female diploid Japanese crucian carp (2n=100) and sterile all-female triploid hybrids (3n = 150), respectively. Therefore, diploid crucian carp gynogenetic females and sex-reversed male together with an allotetraploid line provide an opportunity to produce all-female triploid populations in a large scale to meet demands in aquaculture industry. PMID- 21547067 TI - Resurgence of temporal patterns of responding. AB - The resurgence of temporal patterns of key pecking by pigeons was investigated in two experiments. In Experiment 1, positively accelerated and linear patterns of responding were established on one key under a discrete-trial multiple fixed interval variable-interval schedule. Subsequently, only responses on a second key produced reinforcers according to a variable-interval schedule. When reinforcement on the second key was discontinued, positively accelerated and linear response patterns resurged on the first key, in the presence of the stimuli previously correlated with the fixed- and variable-interval schedules, respectively. In Experiment 2, resurgence was assessed after temporal patterns were directly reinforced. Initially, responding was reinforced if it approximated an algorithm-defined temporal pattern during trials. Subsequently, reinforcement depended on pausing during trials and, when it was discontinued, resurgence of previously reinforced patterns occurred for each pigeon and for 2 of 3 pigeons during a replication. The results of both experiments demonstrate the resurgence of temporally organized responding and replicate and extend previous findings on resurgence of discrete responses and spatial response sequences. PMID- 21547068 TI - The effects of session length on demand functions generated using FR schedules. AB - In comparing open and closed economies, researchers often arrange shorter sessions under the former condition than under the latter. Several studies indicate that session length per se can affect performance and there are some data that indicate that this variable can influence demand functions. To provide further data, the present study exposed domestic hens to series of increasing fixed-ratio schedules with the length of the open-economy sessions varied over 10, 40, 60, and 120 min. Session time affected the total-session response rates and pause lengths. The shortest session gave the greatest response rates and shortest pauses and the longest gave the lowest response rates and longest pauses. The total-session demand functions also changed with session length: The shortest session gave steeper initial slopes (i.e., the functions were more elastic at small ratios) and smaller rates of change of elasticity than the longest session. Response rates, pauses, and demand functions were, however, similar for equivalent periods of responding taken from within sessions of different overall lengths (e.g., total-session data for 10-min sessions and the data for the first 10 min of 120-min sessions). These findings suggest that differences in session length can confound the results of studies comparing open and closed economies when those economies are arranged in sessions that differ substantially in length, hence data for equivalent-length periods of responding, rather than total-session data, should be of primary interest under these conditions. PMID- 21547069 TI - Categorization of multidimensional stimuli by pigeons. AB - Six pigeons responded in a visual category learning task in which the stimuli were dimensionally separable Gabor patches that varied in frequency and orientation. We compared performance in two conditions which varied in terms of whether accurate performance required that responding be controlled jointly by frequency and orientation, or selectively by frequency. Results showed that pigeons learned both category tasks, with average overall accuracies of 85.5% and 82% in the joint and selective control conditions, respectively. Although perfect performance was possible, responding for all pigeons fell short of optimality. Model comparison analyses showed that the General Linear Classifier (GLC; Ashby, 1992) provided a better account of responding in the joint control condition than unidimensional models, but a unidimensional model fitted better for the condition that required selective control by frequency. Our results show that pigeons' responding in a visual categorization task can be controlled jointly or selectively by stimulus dimensions, depending on reinforcement contingencies. However, analysis of residuals confirmed that systematic deviations of GLC predictions from the obtained data were present in both conditions, suggesting that an alternative account of responding in multidimensional category learning tasks may be necessary. PMID- 21547070 TI - Emergent stimulus relations depend on stimulus correlation and not on reinforcement contingencies. AB - We aimed to investigate whether novel stimulus relations would emerge from stimulus correlations when those relations explicitly conflicted with reinforced relations. In a symbolic matching-to-sample task using kanji characters as stimuli, we arranged class-specific incorrect comparison stimuli in each of three classes. After presenting either Ax or Cx stimuli as samples, choices of Bx were reinforced and choices of Gx or Hx were not. Tests for symmetry, and combined symmetry and transitivity, showed the emergence of three 3-member (AxBxCx) stimulus classes in 5 of 5 human participants. Subsequent tests for all possible emergent relations between Ax, Bx, Cx and the class-specific incorrect comparisons Gx and Hx showed that these relations emerged for 4 of 5 the participants after extended overtraining of the baseline relations. These emergent relations must have been based on stimulus-stimulus correlations, and were not properties of the trained discriminated operants, because they required control by relations explicitly extinguished during training. This result supports theoretical accounts of emergent relations that emphasize stimulus correlation over operant contingencies. PMID- 21547071 TI - Nodal structure and stimulus relatedness in equivalence classes: post-class formation preference tests. AB - Three experiments used postclass formation within-class preference test performances to evaluate the effects of nodal distance on the relatedness of stimuli in equivalence classes. In Experiment 1, two 2-node four-member equivalence classes were established using the simultaneous protocol in which all of the baseline relations were trained together, after which all emergent relations probes were presented together. All training and testing was done using match-to-sample trials that contained two comparisons. After class formation, the effects of nodal distance were evaluated using within-class preference tests that contained samples and both comparisons from the same class. These tests yielded inconsistent performances for most participants. Experiment 2 replicated Experiment 1, but a third null comparison was used on all trials during class formation. Thereafter, virtually all of the within-class probes, for all participants, evoked performances that were consistent with the predicted effects of nodal distance, that is, the selection of comparisons that were nodally closer to the samples. It appears, then, that the establishment of the equivalence classes with a third null comparison induced control by nodal structure of the classes. Experiment 3 demonstrated the generality of these findings with larger classes that contained more nodal separations, that is, three-node five-member classes. Emergent-relations tests conducted immediately after the within-class tests showed the classes to be intact. Thus, the differential relatedness of stimuli in a class or their interchangeability depended on the content of a test trial: within-class probes occasioned responding indicative of differential strength among the stimuli in the class, while cross-class tests occasioned responding indicative of interchangeability of stimuli in the same class. PMID- 21547072 TI - Cross-domain analogies as relating derived relations among two separate relational networks. AB - Contemporary behavior analytic research is making headway in analyzing analogy as the establishment of a relation of coordination among common types of trained or derived relations. Previous studies have been focused on within-domain analogy. The current study expands previous research by analyzing cross-domain analogy as relating relations among separate relational networks and by correlating participants' performance with a standard measure of analogical reasoning. In two experiments, adult participants first completed general intelligence and analogical reasoning tests. Subsequently, they were exposed to a computerized conditional discrimination training procedure designed to create two relational networks, each consisting of two 3-member equivalence classes. The critical test was a two-part analogical test in which participants had to relate combinatorial relations of coordination and distinction between the two relational networks. In Experiment 1, combinatorial relations for each network were individually tested prior to analogical testing, but in Experiment 2 they were not. Across both experiments, 65% of participants passed the analogical test on the first attempt. Moreover, results from the training procedure were strongly correlated with the standard measure of analogical reasoning. PMID- 21547073 TI - Sample stimulus control shaping and restricted stimulus control in capuchin monkeys: a methodological note. AB - This paper reports use of sample stimulus control shaping procedures to teach arbitrary matching-to-sample to 2 capuchin monkeys (Cebus apella). The procedures started with identity matching-to-sample. During shaping, stimulus features of the sample were altered gradually, rendering samples and comparisons increasingly physically dissimilar. The objective was to transform identity matching into arbitrary matching (i.e., matching not based on common physical features of the sample and comparison stimuli). Experiment 1 used a two-comparison procedure. The shaping procedure was ultimately effective, but occasional high error rates at certain program steps inspired a follow-up study. Experiment 2 used the same basic approach, but with a three-comparison matching task. During shaping, the monkey performed accurately until the final steps of the program. Subsequent experimentation tested the hypothesis that the decrease in accuracy was due to restricted stimulus control by sample stimulus features that had not yet been changed in the shaping program. Results were consistent with this hypothesis, thus suggesting a new approach that may transform the sample stimulus control shaping procedure from a sometimes useful laboratory tool to a more general approach to teaching the first instance of arbitrary matching performances to participants who show protracted difficulties in learning such performances. PMID- 21547074 TI - Findings from a rapid assessment of avoidable blindness (RAAB) in Southern Malawi. AB - BACKGROUND: Data on prevalence and causes of avoidable blindness in Malawi are not readily available. The purpose of this study was to determine the prevalence and causes of blindness in persons aged 50 and above in southern Malawi to plan eye care services for the community. METHODOLOGY: A population-based survey was conducted in 7 districts in southern Malawi. Villages were selected by probability proportionate to size within each district. Clusters were further subdivided into segments. A predetermined number of segments were selected randomly in each cluster. The survey team moved from house to house in each segment until they had examined 50 people over the age of 50. Examination consisted of visual acuity measurement with tumbling "E" chart and ocular examination by an ophthalmologist. Participants were categorized by visual acuity. Those who were visually impaired (VA<6/18 in the better eye with available correction) were assigned a main cause of visual loss. Further information was sought from anyone who had received cataract surgery. RESULTS: A total number of 3,583 persons aged 50 and above were sampled; among these 3,430 (95.7%) were examined. The prevalence of blindness (presenting visual acuity <3/60 in the better eye) among persons aged 50 and above was 3.3% (95% CI 2.5 4.1). Cataract was the most common cause of blindness contributing to 48.2% of all cases, followed by glaucoma (15.8%) and cornea scarring (12.3%). The cataract surgical coverage in blind persons was 44.6%. CONCLUSION: The prevalence of blindness and visual impairment in persons aged 50 and above was lower than the WHO estimate for Malawi. The majority of the causes were avoidable, with cataract accounting for approximately half of all cases of blindness. The data suggests that expansion of eye care programs to address avoidable causes of blindness is necessary in this area of southern Malawi. PMID- 21547075 TI - Dispersal of Group A streptococcal biofilms by the cysteine protease SpeB leads to increased disease severity in a murine model. AB - Group A Streptococcus (GAS) is a Gram-positive human pathogen best known for causing pharyngeal and mild skin infections. However, in the 1980's there was an increase in severe GAS infections including cellulitis and deeper tissue infections like necrotizing fasciitis. Particularly striking about this elevation in the incidence of severe disease was that those most often affected were previously healthy individuals. Several groups have shown that changes in gene content or regulation, as with proteases, may contribute to severe disease; yet strains harboring these proteases continue to cause mild disease as well. We and others have shown that group A streptococci (MGAS5005) reside within biofilms both in vitro and in vivo. That is to say that the organism colonizes a host surface and forms a 3-dimensional community encased in a protective matrix of extracellular protein, DNA and polysaccharide(s). However, the mechanism of assembly or dispersal of these structures is unclear, as is the relationship of these structures to disease outcome. Recently we reported that allelic replacement of the streptococcal regulator srv resulted in constitutive production of the streptococcal cysteine protease SpeB. We further showed that the constitutive production of SpeB significantly decreased MGAS5005Deltasrv biofilm formation in vitro. Here we show that mice infected with MGAS5005Deltasrv had significantly larger lesion development than wild-type infected animals. Histopathology, Gram-staining and immunofluorescence link the increased lesion development with lack of disease containment, lack of biofilm formation, and readily detectable levels of SpeB in the tissue. Treatment of MGAS5005Deltasrv infected lesions with a chemical inhibitor of SpeB significantly reduced lesion formation and disease spread to wild-type levels. Furthermore, inactivation of speB in the MGAS5005Deltasrv background reduced lesion formation to wild-type levels. Taken together, these data suggest a mechanism by which GAS disease may transition from mild to severe through the Srv mediated dispersal of GAS biofilms. PMID- 21547076 TI - The importance of distance to resources in the spatial modelling of bat foraging habitat. AB - Many bats are threatened by habitat loss, but opportunities to manage their habitats are now increasing. Success of management depends greatly on the capacity to determine where and how interventions should take place, so models predicting how animals use landscapes are important to plan them. Bats are quite distinctive in the way they use space for foraging because (i) most are colonial central-place foragers and (ii) exploit scattered and distant resources, although this increases flying costs. To evaluate how important distances to resources are in modelling foraging bat habitat suitability, we radio-tracked two cave-dwelling species of conservation concern (Rhinolophus mehelyi and Miniopterus schreibersii) in a Mediterranean landscape. Habitat and distance variables were evaluated using logistic regression modelling. Distance variables greatly increased the performance of models, and distance to roost and to drinking water could alone explain 86 and 73% of the use of space by M. schreibersii and R. mehelyi, respectively. Land-cover and soil productivity also provided a significant contribution to the final models. Habitat suitability maps generated by models with and without distance variables differed substantially, confirming the shortcomings of maps generated without distance variables. Indeed, areas shown as highly suitable in maps generated without distance variables proved poorly suitable when distance variables were also considered. We concluded that distances to resources are determinant in the way bats forage across the landscape, and that using distance variables substantially improves the accuracy of suitability maps generated with spatially explicit models. Consequently, modelling with these variables is important to guide habitat management in bats and similarly mobile animals, particularly if they are central-place foragers or depend on spatially scarce resources. PMID- 21547077 TI - Decreased bone formation and osteopenia in lamin a/c-deficient mice. AB - Age-related bone loss is associated with changes in bone cellularity with characteristically low levels of osteoblastogenesis. The mechanisms that explain these changes remain unclear. Although recent in vitro evidence has suggested a new role for proteins of the nuclear envelope in osteoblastogenesis, the role of these proteins in bone cells differentiation and bone metabolism in vivo remains unknown. In this study, we used the lamin A/C null (Lmna-/-) mice to identify the role of lamin A/C in bone turnover and bone structure in vivo. At three weeks of age, histological and micro computed tomography measurements of femurs in Lmna-/- mice revealed a significant decrease in bone mass and microarchitecture in Lmna-/ mice as compared with their wild type littermates. Furthermore, quantification of cell numbers after normalization with bone surface revealed a significant reduction in osteoblast and osteocyte numbers in Lmna-/- mice compared with their WT littermates. In addition, Lmna-/- mice have significantly lower osteoclast number, which show aberrant changes in their shape and size. Finally, mechanistic analysis demonstrated that absence of lamin A/C is associated with increase expression of MAN-1 a protein of the nuclear envelope closely regulated by lamin A/C, which also colocalizes with Runx2 thus affecting its capacity as osteogenic transcription factor. In summary, these data clearly indicate that the presence of lamin A/C is necessary for normal bone turnover in vivo and that absence of lamin A/C induces low bone turnover osteopenia resembling the cellular changes of age-related bone loss. PMID- 21547078 TI - Low digit ratio 2D:4D in alcohol dependent patients. AB - The ratio of the lengths of the second and fourth finger (2D?4D) has been described as reflecting the degree of prenatal androgen exposure in humans. 2D?4D is smaller for males than females and is associated with traits such as left handedness, physical aggression, attention-deficit-hyperactivity disorder and a genetic polymorphism of the androgen receptor. All of these traits are known to be correlated to the vulnerability for alcohol dependency. We therefore hypothesized low 2D?4D in patients with alcohol dependency. In the present study on 131 patients suffering from alcohol dependency and 185 healthy volunteers, we found that alcohol dependent patients had smaller 2D?4D ratios compared to controls with preserved sexual dimorphism but with reduced right-left differences. The detection of alcohol dependency based on 2D?4D ratios was most accurate using the right hand of males (ROC-analysis: AUC 0.725, sensitivity 0.667, specificity 0.723). These findings provide novel insights into the role of prenatal androgen exposure in the development of alcohol dependency and for the use of 2D?4D as a possible trait marker in identifying patients with alcohol dependency. PMID- 21547079 TI - Dose-dependent effects of dietary fat on development of obesity in relation to intestinal differential gene expression in C57BL/6J mice. AB - Excessive intake of dietary fat is known to be a contributing factor in the development of obesity. In this study, we determined the dose-dependent effects of dietary fat on the development of this metabolic condition with a focus on changes in gene expression in the small intestine. C57BL/6J mice were fed diets with either 10, 20, 30 or 45 energy% (E%) derived from fat for four weeks (n = 10 mice/diet). We found a significant higher weight gain in mice fed the 30E% and 45E% fat diet compared to mice on the control diet. These data indicate that the main shift towards an obese phenotype lies between a 20E% and 30E% dietary fat intake. Analysis of differential gene expression in the small intestine showed a fat-dose dependent gradient in differentially expressed genes, with the highest numbers in mice fed the 45E% fat diet. The main shift in fat-induced differential gene expression was found between the 30E% and 45E% fat diet. Furthermore, approximately 70% of the differentially expressed genes were changed in a fat dose dependent manner. Many of these genes were involved in lipid metabolism related processes and were already differentially expressed on a 30E% fat diet. Taken together, we conclude that up to 20E% of dietary fat, the small intestine has an effective 'buffer capacity' for fat handling. From 30E% of dietary fat, a switch towards an obese phenotype is triggered. We further speculate that especially fat-dose dependently changed lipid metabolism-related genes are involved in development of obesity. PMID- 21547080 TI - Chronic methamphetamine administration causes differential regulation of transcription factors in the rat midbrain. AB - Methamphetamine (METH) is an addictive and neurotoxic psychostimulant widely abused in the USA and throughout the world. When administered in large doses, METH can cause depletion of striatal dopamine terminals, with preservation of midbrain dopaminergic neurons. Because alterations in the expression of transcription factors that regulate the development of dopaminergic neurons might be involved in protecting these neurons after toxic insults, we tested the possibility that their expression might be affected by toxic doses of METH in the adult brain. Male Sprague-Dawley rats pretreated with saline or increasing doses of METH were challenged with toxic doses of the drug and euthanized two weeks later. Animals that received toxic METH challenges showed decreases in dopamine levels and reductions in tyrosine hydroxylase protein concentration in the striatum. METH pretreatment protected against loss of striatal dopamine and tyrosine hydroxylase. In contrast, METH challenges caused decreases in dopamine transporters in both saline- and METH-pretreated animals. Interestingly, METH challenges elicited increases in dopamine transporter mRNA levels in the midbrain in the presence but not in the absence of METH pretreatment. Moreover, toxic METH doses caused decreases in the expression of the dopamine developmental factors, Shh, Lmx1b, and Nurr1, but not in the levels of Otx2 and Pitx3, in saline pretreated rats. METH pretreatment followed by METH challenges also decreased Nurr1 but increased Otx2 and Pitx3 expression in the midbrain. These findings suggest that, in adult animals, toxic doses of METH can differentially influence the expression of transcription factors involved in the developmental regulation of dopamine neurons. The combined increases in Otx2 and Pitx3 expression after METH preconditioning might represent, in part, some of the mechanisms that served to protect against METH-induced striatal dopamine depletion observed after METH preconditioning. PMID- 21547081 TI - Enhanced collateral growth by double transplantation of gene-nucleofected fibroblasts in ischemic hindlimb of rats. AB - BACKGROUND: Induction of neovascularization by releasing therapeutic growth factors is a promising application of cell-based gene therapy to treat ischemia related problems. In the present study, we have developed a new strategy based on nucleofection with alternative solution and cuvette to promote collateral growth and re-establishment of circulation in ischemic limbs using double transplantation of gene nucleofected primary cultures of fibroblasts, which were isolated from rat receiving such therapy. METHODS AND RESULTS: Rat dermal fibroblasts were nucleofected ex vivo to release bFGF or VEGF165 in a hindlimb ischemia model in vivo. After femoral artery ligation, gene-modified cells were injected intramuscularly. One week post injection, local confined plasmid expression and transient distributions of the plasmids in other organs were detected by quantitative PCR. Quantitative micro-CT analyses showed improvements of vascularization in the ischemic zone (No. of collateral vessels via micro CT: 6.8+/-2.3 vs. 10.1+/-2.6; p<0.05). Moreover, improved collateral proliferation (BrdU incorporation: 0.48+/-0.05 vs. 0.57+/-0.05; p<0.05) and increase in blood perfusion (microspheres ratio: gastrocnemius: 0.41+/-0.10 vs. 0.50+/-0.11; p<0.05; soleus ratio: soleus: 0.42+/-0.08 vs. 0.60+/-0.08; p<0.01) in the lower hindlimb were also observed. CONCLUSIONS: These results demonstrate the feasibility and effectiveness of double transplantation of gene nucleofected primary fibroblasts in producing growth factors and promoting the formation of collateral circulation in ischemic hindlimb, suggesting that isolation and preparation of gene nucleofected cells from individual accepting gene therapy may be an alternative strategy for treating limb ischemia related diseases. PMID- 21547082 TI - Mouse mutants for the nicotinic acetylcholine receptor beta2 subunit display changes in cell adhesion and neurodegeneration response genes. AB - Mice lacking expression of the beta2 subunit of the neuronal nicotinic acetylcholine receptor (CHRNB2) display abnormal retinal waves and a dispersed projection of retinal ganglion cell (RGC) axons to their dorsal lateral geniculate nuclei (dLGNs). Transcriptomes of LGN tissue from two independently generated Chrnb2-/- mutants and from wildtype mice were obtained at postnatal day 4 (P4), during the normal period of segregation of eye-specific afferents to the LGN. Microarray analysis reveals reduced expression of genes located on the cell membrane or in extracellular space, and of genes active in cell adhesion and calcium signaling. In particular, mRNA for cadherin 1 (Cdh1), a known axon growth regulator, is reduced to nearly undetectable levels in the LGN of P4 mutant mice and Lypd2 mRNA is similarly suppressed. Similar analysis of retinal tissue shows increased expression of crumbs 1 (Crb1) and chemokine (C-C motif) ligand 21 (Ccl21) mRNAs in Chrnb2-/- mutant animals. Mutations in these genes are associated with retinal neuronal degeneration. The retinas of Chrnb2-/- mutants are normal in appearance, but the increased expression of these genes may also be involved in the abnormal projection patterns of RGC to the LGN. These data may provide the tools to distinguish the interplay between neural activity and molecular expression. Finally, comparison of the transcriptomes of the two different Chrnb2-/- mutant strains reveals the effects of genetic background upon gene expression. PMID- 21547083 TI - A program of nutritional education in schools reduced the prevalence of iron deficiency in students. AB - The objective was to determine the prevalence of iron, folates and retinol deficiencies in school children and to evaluate the changes after an intervention of nutritional education. The project was developed in 17 schools. The sample included 1,301 children (678 males and 623 females). A subsample of 480 individuals, was randomly selected for drawing blood for biochemical determinations before and after the intervention of nutritional education, which included in each school: written pre and post-intervention tests, 6 workshops, 2 participative talks, 5 game activities, 1 cooking course and 1 recipe contest. Anthropometrical and biochemical determinations included weight, height, body mass index, nutritional status, hematocrit, serum ferritin, retinol and folate concentrations. There was high prevalence of iron (25%), folates (75%) and vitamin A (43%) deficiencies in school children, with a low consumption of fruit and vegetables, high consumption of soft drinks and snacks and almost no physical activity. The nutritional education intervention produced a significant reduction in iron deficiency prevalence (25 to 14%), and showed no effect on vitamin A and folates deficiencies. There was a slight improvement in nutritional status. This study shows, through biochemical determinations, that nutritional education initiatives and programs have an impact improving nutritional health in school children. PMID- 21547084 TI - Inbuilt mechanisms for overcoming functional problems inherent in hepatic microlobular structure. AB - The spherical anatomy of human and rat liver lobules implies that more central cells have less time to carry out their function than more peripherally located cells because blood flows past them more rapidly. This problem could be overcome if more centrilobular cells could operate at higher temperatures than periportal cells. This study presents evidence for such a temperature gradient. Firstly, we use mathematical modelling to demonstrate that temperature increases towards the centre of the lobule. Secondly, we examine the distribution of a heat-generating protein and of a heat-sensitive protein across the rat and human liver lobules. Double-antibody staining of healthy liver from rat and human was used for visual scoring and for automated histomorphometric quantitation of the localisation of uncoupling protein-2 (known to generate heat) and of the transient receptor potential-v4 protein (known as a highly temperature-sensitive membrane protein). Both these proteins were found to be located predominantly in the centrilobular region of liver lobules. These findings support the suggestion that temperature gradients across the liver lobule may have evolved as a solution to the problem of reduced contact time between blood and cells at the centre as compared to the periphery of mammalian liver lobules. PMID- 21547085 TI - Phytochemical Analysis and Antioxidant Property of Leaf Extracts of Vitex doniana and Mucuna pruriens. AB - Oxidative stress and impaired antioxidant system have been implicated in the pathophysiology of diverse disease states. The phytochemical screening and antioxidant property of fresh leaves of Vitex doniana and Mucuna pruriens, used in the management and treatment of various diseases, were studied. The extracts (ethanol and distilled water) were screened for the presence of phytochemicals, and their inhibition of 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical was used to evaluate their free radical scavenging activity. Liver levels of malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) in carbon tetrachloride- (CCl(4)) treated albino rats were also used to assess the antioxidant activity of the extracts. The animals were treated with 250 mg/kg body weight of the extracts for six consecutive days before a single dose (2.5 mL/kg body weight) of CCl(4). Vitamin C was used as the standard antioxidant. Phytochemical screening revealed the presence of saponins, tannins, anthraquinones, terpenoids, and flavonoids in all the extracts, while alkaloids were detected in extracts of Vitex doniana only, and cardiac glycosides occurred in extracts of Mucuna pruriens only. All the extracts inhibited DPPH radical in a concentration-dependent manner, water extract of Vitex doniana producing highest inhibition which was not significantly different (P > .05) from vitamin C. The extracts produced a significant decrease (P < .05) in liver MDA, while the levels of SOD and CAT significantly increased (P < .05) relative to the positive control. These results are an indication of antioxidant potential of the extracts and may be responsible for some of the therapeutic uses of these plants. PMID- 21547087 TI - Assessment of fetal autonomic nervous system activity by fetal magnetocardiography: comparison of normal pregnancy and intrauterine growth restriction. AB - OBJECTIVE: To clarify the developmental activity of the autonomic nervous system (ANS) of the normal fetus and intrauterine growth restriction (IUGR) cases using fetal magnetocardiography (FMCG). SUBJECTS AND METHODS: Normal pregnancy (n = 35) and IUGR (n = 12) cases at 28-39 and 32-37 weeks of gestation, respectively, were included in this study. The R-R interval variability was used to calculate the coefficient of variance (CV(RR)) and low frequency/high frequency (LF/HF) ratio. RESULTS: The value of CV(RR) in the normal pregnancy group displayed a slight increasing trend with gestational age. However, no such trend was observed in the IUGR group. In contrast, the LF/HF ratio in both the normal pregnancy group and the IUGR group clearly increased over the gestational period; the normal group showing statistical significance. CONCLUSION: The development of fetal ANS activity in IUGR cases might differ from that observed in the normal pregnancy group, and this may facilitate early detection of IUGR. PMID- 21547088 TI - Consequences in infants that were intrauterine growth restricted. AB - Intrauterine growth restriction is a condition fetus does not reach its growth potential and associated with perinatal mobility and mortality. Intrauterine growth restriction is caused by placental insufficiency, which determines cardiovascular abnormalities in the fetus. This condition, moreover, should prompt intensive antenatal surveillance of the fetus as well as follow-up of infants that had intrauterine growth restriction as short and long-term sequele should be considered. PMID- 21547086 TI - Maternal preeclampsia and neonatal outcomes. AB - Preeclampsia is a multiorgan, heterogeneous disorder of pregnancy associated with significant maternal and neonatal morbidity and mortality. Optimal strategies in the care of the women with preeclampsia have not been fully elucidated, leaving physicians with incomplete data to guide their clinical decision making. Because preeclampsia is a progressive disorder, in some circumstances, delivery is needed to halt the progression to the benefit of the mother and fetus. However, the need for premature delivery has adverse effects on important neonatal outcomes not limited to the most premature infants. Late-preterm infants account for approximately two thirds of all preterm deliveries and are at significant risk for morbidity and mortality. Reviewed is the current literature in the diagnosis and obstetrical management of preeclampsia, the outcomes of late-preterm infants, and potential strategies to optimize fetal outcomes in pregnancies complicated by preeclampsia. PMID- 21547089 TI - Women's experiences of preeclampsia: Australian action on preeclampsia survey of women and their confidants. AB - INTRODUCTION: The experience of normal pregnancy is often disrupted for women with preeclampsia (PE). MATERIALS AND METHODS: Postal survey of the 112 members of the consumer group, Australian Action on Pre-Eclampsia (AAPEC). RESULTS: Surveys were returned by 68 women (61% response rate) and from 64 (57%) partners, close relatives or friends. Respondents reported experiencing pre-eclampsia (n = 53), eclampsia (n = 5), and/or Hemolysis, Elevated Liver enzymes, and Low Platelets (HELLP syndrome) (n = 26). Many women had no knowledge of PE prior to diagnosis (77%) and, once diagnosed, did not appreciate how serious or life threatening it was (50%). Women wanted access to information about PE. Their experience contributed substantial anxiety towards future pregnancies. Partners/friends/relatives expressed fear for the woman and/or her baby and had no prior understanding of PE. CONCLUSIONS: The PE experience had a substantial effect on women, their confidants, and their babies and affected their approach to future pregnancies. Access to information about PE was viewed as very important. PMID- 21547090 TI - Public health perspectives of preeclampsia in developing countries: implication for health system strengthening. AB - OBJECTIVES: Review of public health perspectives of preeclampsia in developing countries and implications for health system strengthening. METHODS: Literature from Pubmed (MEDLINE), AJOL, Google Scholar, and Cochrane database were reviewed. RESULTS: The prevalence of preeclampsia in developing countries ranges from 1.8% to 16.7%. Many challenges exist in the prediction, prevention, and management of preeclampsia. Promising prophylactic measures like low-dose aspirin and calcium supplementation need further evidence before recommendation for use in developing countries. Treatment remains prenatal care, timely diagnosis, proper management, and timely delivery. Prevailing household, community, and health system factors limiting effective control of preeclampsia in these countries were identified, and strategies to strengthen health systems were highlighted. CONCLUSION: Overcoming the prevailing challenges in the control of preeclampsia in developing countries hinges on the ability of health care systems to identify and manage women at high risk. PMID- 21547091 TI - The role of placental homeobox genes in human fetal growth restriction. AB - Fetal growth restriction (FGR) is an adverse pregnancy outcome associated with significant perinatal and paediatric morbidity and mortality, and an increased risk of chronic disease later in adult life. One of the key causes of adverse pregnancy outcome is fetal growth restriction (FGR). While a number of maternal, fetal, and environmental factors are known causes of FGR, the majority of FGR cases remain idiopathic. These idiopathic FGR pregnancies are frequently associated with placental insufficiency, possibly as a result of placental maldevelopment. Understanding the molecular mechanisms of abnormal placental development in idiopathic FGR is, therefore, of increasing importance. Here, we review our understanding of transcriptional control of normal placental development and abnormal placental development associated with human idiopathic FGR. We also assess the potential for understanding transcriptional control as a means for revealing new molecular targets for the detection, diagnosis, and clinical management of idiopathic FGR. PMID- 21547092 TI - Diagnosis and management of fetal growth restriction. AB - Fetal growth restriction (FGR) remains a leading contributor to perinatal mortality and morbidity and metabolic syndrome in later life. Recent advances in ultrasound and Doppler have elucidated several mechanisms in the evolution of the disease. However, consistent classification and characterization regarding the severity of FGR is lacking. There is no cure, and management is reliant on a structured antenatal surveillance program with timely intervention. Hitherto, the time to deliver is an enigma. In this paper, the challenges in the diagnosis and management of FGR are discussed. The biophysical profile, Doppler, biochemical and molecular technologies that may refine management are reviewed. Finally, a model pathway for the clinical management of pregnancies complicated by FGR is presented. PMID- 21547094 TI - Intra-abdominal hypertension and gastrointestinal symptoms in mechanically ventilated patients. AB - Background. We aimed to describe the incidence of intra-abdominal hypertension (IAH) and gastrointestinal (GI) symptoms and related outcome in mechanically ventilated (MV) patients. Methods. Intra-abdominal pressure (IAP) and gastric residual volumes were measured at least twice daily. IAH was defined as a mean daily value of IAP >= 12 mmHg. Results. 398 patients were monitored for all together 2987 days. GI symptom(s) occurred in 80.2% patients. 152 (38.2%) patients developed IAH. Majority (93.4%) of patients with IAH had GI symptoms. The more severe IAH was associated with the higher number of concomitant GI symptoms (P < .001). 142 (35.7%) patients developed both IAH and at least one GI symptom at any time in ICU, and in 77 patients they occurred simultaneously on the same day. This subgroup had the highest ICU mortality (21.8%). In contrast, the small group of patients presenting only IAH, but not GI symptoms (10 patients), had no lethal outcome. Three patients (4.4%) died without showing either IAH or GI symptoms. Conclusions. GI symptoms and IAH often, but not always, occur together. The patients having IAH solely without developing GI symptoms have rather good outcome. PMID- 21547093 TI - Lights and shadows of cyclophosphamide in the treatment of multiple sclerosis. AB - Cyclophosphamide (cy) is an alkylating agent used to treat malignancies and immune-mediated inflammatory nonmalignant processes. It has been used as a treatment in cases of worsening multiple sclerosis (MS). Cy is currently used for patients whose disease is not controlled by beta-interferon or glatiramer acetate as well as those with rapidly worsening MS. The most commonly used regimens involve outpatient IV pulse therapy given with or without corticosteroids every 4 to 8 weeks. Side effects include nausea, headache, alopecia, pain, male and women infertility, bladder toxicity, and risk of malignancy. Previous studies suggest that cy is effective in patients in the earlier stages of disease, where inflammation predominates over degenerative processes. Given that early inflammatory events appear to correlate with later disability, a major question is whether strong anti-inflammatory drugs, such as cy, will have an impact on later degenerative changes if given early in the disease to halt inflammation. PMID- 21547095 TI - Dermato-Endocrinology remembers Dr. Frank C. Garland: A great scientist who made major contributions to improve our understanding about the importance of vitamin D for human health! PMID- 21547096 TI - Dr. Frank caldwell garland, june 20, 1950-august 17, 2010. AB - Frank Caldwell Garland, Ph.D., died August 17, 2010 after a year-long battle with cancer. He will be remembered for his seminal work with his brother Cedric F. Garland in proposing the ultraviolet-B (UVB)-vitamin D-cancer hypothesis to explain the geographical variation of colon cancer mortality rates in the United States in 1980. This hypothesis has been extended to about 20 types of cancer using the ecological approach, and supported strongly by observational studies of prediagnostic serum 25-hydroxyvitamin D [25(OH) D] for incidence of breast, colorectal and ovarian cancer, and a randomized controlled trial that used sufficient vitamin D (1,150 IU/day) to and found a strongly beneficial effect on cancer incidence. The UVB-vitamin D-cancer hypothesis is also supported by studies that used as the index of solar UVB irradiance the amount of sunlight exposure in childhood or incidence of non-melanoma skin cancer. Survival after diagnosis was increased for individuals with higher serum 25(OH)D levels at the time of cancer diagnosis for six types of cancer: breast, colorectal, lung and prostate cancer; melanoma and non-Hodgkin's lymphoma. The ecological study approach is ideally suited to studying cancer risk-modifying factors since the lag between cancer initiation and detection or death can be 20-40 years or more, making ordinary observational studies difficult. The impact on vitamin D research by both Frank Garland and Cedric Garland has been immense. Health policy leaders will realize this in the near future, providing a rich legacy for humanity. PMID- 21547097 TI - The JUPITER lipid lowering trial and vitamin D: Is there a connection? AB - There is growing evidence that vitamin D deficiency significantly increases the risk of adverse cardiovascular events and that a vitamin D status representing sufficiency or optimum is protective. Unfortunately, in clinical trials that address interventions for reducing risk of adverse cardiovascular events, vitamin D status is not generally measured. Failure to do this has now assumed greater importance with the report of a study that found rosuvastatin at doses at the level used in a recent large randomized lipid lowering trial (JUPITER) had a large and significant impact on vitamin D levels as measured by the metabolite 25 hydroxyvitamin D. The statin alone appears to have increased this marker such that the participants on average went from deficient to sufficient in two months. The difference in cardiovascular risk between those deficient and sufficient in vitamin D in observational studies was similar to the risk reduction found in JUPITER. Thus it appears that this pleiotropic effect of rosuvastatin may be responsible for part of its unusual effectiveness in reducing the risk of various cardiovascular endpoints found in JUPITER and calls into question the interpretation based only on LDL cholesterol and CRP changes. In addition, vitamin D status is a cardiovascular risk factor which up until now has not been considered in adjusting study results or in multivariate analysis, and even statistical analysis using only baseline values may be inadequate. PMID- 21547098 TI - Seasonal variations of cancer incidence and prognosis. AB - The overall death rates are highest in the winter season in many countries at high latitudes. In some but not all countries, this is also true for more specific diseases such as cancer, cardiovascular diseases and influenza. For internal cancers we find no consistent, significant seasonal variation, neither of incidence nor of death rates. On the other hand, we find a significant seasonal variation of cancer prognosis with season of diagnosis in Norway. Best prognosis is found for summer and autumn diagnosis; i.e., for the seasons of the best status of vitamin D in the population. There were no corresponding seasonal variations, neither of the rates of diagnosis, nor of the rates of death which could explain the variations of prognosis. The most likely reason for this variation is that the vitamin D status in Norway is significantly better in summer and autumn than in winter and spring. Earlier, seasonal variations have been explained by circannual variations of certain hormones, but the data are not consistent. PMID- 21547099 TI - Systemic cholesterol embolization syndrome in a patient positive for anti cardiolipin antibody. AB - Cholesterol embolization syndrome (CES) is caused by a cholesterol crystal embolization from atherosclerotic plaques on the walls of arteries. It often occurs after an invasive vascular procedure. CES exhibits several cutaneous manifestations before systemic symptoms take place. Here, we report a case of CES, positive for an anti-cardiolipin antibody, with a history of cerebral infarction. The existence of anti-phospholipid antibody may be a risk factor for CES after an invasive vascular procedure. PMID- 21547100 TI - Methylmalonic aciduria presenting with recurrent multiple molluscum contagiosum lesions. AB - Methylmalonic aciduria is a rare metabolic disorder with autosomal recessive inheritance. Patients with methylmalonic aciduria develop a variety of skin manifestations: superficial scalded skin lesions, alopecia, psoriasiform eruptions, acrodermatitis enteropathica-like lesions, fulminant ecthyma gangrenosum and ichthyosis. We report a Japanese boy, diagnosed with methylmalonic aciduria, who suffered from recurrent multiple molluscum lesions around the eyes. PMID- 21547101 TI - An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. AB - France has unexplained large latitudinal variations in cancer incidence and mortality rates. Studies of cancer rate variations in several other countries, as well as in multicountry studies, have explained such variations primarily in terms of gradients in solar ultraviolet-B (UVB) doses and vitamin D production. To investigate this possibility in France, I obtained data on cancer incidence and mortality rates for 21 continental regions and used this information in regression analyses with respect to latitude. This study also used dietary data. Significant positive correlations with latitude emerged for breast, colorectal, esophageal (males), lung (males), prostate, both uterine cervix and uterine corpus, all and all less lung cancer. Although correlations with latitude were similar for males and females, the regression variance for all and all less lung cancer was about twice as high for males than for females. Lung cancer incidence and mortality rates for females had little latitudinal gradient, indicating that smoking may have also contributed to the latitudinal gradients for males. On the basis of the available dietary factor, micro- and macronutrient data, dietary differences do not significantly affect geographical variation in cancer rates. These results are consistent with solar UVB's reducing the risk of cancer through production of vitamin D. In the context of serum 25-hydroxyvitamin D level-cancer incidence relations, cancer rates could be reduced significantly in France if everyone obtained an additional 1,000 IU/day of vitamin D. Many other benefits of vitamin D exist as well. PMID- 21547102 TI - An ecological study of cancer mortality rates in the United States with respect to solar ultraviolet-B doses, smoking, alcohol consumption and urban/rural residence. AB - The Cohort Consortium Vitamin D Polling Project of Rarer Cancers (VDPP ) study failed to find a beneficial role of prediagnostic serum 25-hydroxyvitamin D [25(OH)D] levels on risk of seven types of rarer cancer: endometrial, esophageal, gastric, kidney, ovarian and pancreatic cancer and non-Hodgkin's lymphoma (NHL). However, ecological studies and studies of oral vitamin D intake have generally found solar ultraviolet B (UVB) and oral vitamin D inversely correlated with incidence and/or mortality rates of these cancers. To explore the discrepancy, I conducted an ecological study of cancer mortality rates for white Americans in the United States for 1950-1994 with data for 503 state economic areas in multiple linear regression analyses with respect to UVB for July, lung cancer, alcohol consumption and urban/rural residence. UVB was significantly inversely correlated with six types of cancer (not pancreatic cancer) in both periods. However, the adjusted R(2) values were much lower for cancers with lower mortality rates than those in an earlier ecological study that used state averaged data. This finding suggests that the VDPP study may have had too few cases. Thus, the VDPP study should not be considered as providing strong evidence against the solar UVB-vitamin D-cancer hypothesis. PMID- 21547104 TI - Therapeutic Apheresis - Many Ways to Go. PMID- 21547103 TI - The role of vitamin D and SLCO1B1*5 gene polymorphism in statin-associated myalgias. AB - Myalgias are the most common side effect of statin use and the commonest cause for discontinuing therapy. Vitamin D has known physiologic functions in muscle and vitamin D deficiency is known to cause myalgias, with its correction leading to disappearance of muscle symptoms. The 521T>C SLCO1B1*5 gene polymorphism decreasing function in the gene coding for a liver anion transporter that is responsible for statin uptake has been found to explain the majority of statin associated muscle symptoms. Patients with statin-associated myalgias have been reported to improve with vitamin D supplementation. We therefore investigated (i) whether repletion of vitamin D in deficient patients with myalgias could lead to tolerance for subsequent statin therapy and (ii) whether vitamin D status modifies the effect of the SLCO1B1*5 genotype on myalgia risk. Using a retrospective cohort of 64 patients in whom 25-hydroxyvitamin D [25(OH)D] had been measured for any reason while on statin therapy, including 46 patients who consented to be genotyped, we found strong evidence showing that repletion of vitamin D in vitamin D deficient patients improved myalgias. Of 21 vitamin D deficient patients with intolerable statin-associated myalgias, 14 of 15 rechallenged with statins were subsequently symptomfree, with one patient experiencing mild and tolerable symptoms, far exceeding expected rates of acquired tolerability with no therapy (p = 0.01). In addition, while the SLCO1B1*5 genotype was associated with a three-fold increased risk of myalgias (p = 0.07), this risk was not found to differ by vitamin D status (p = 0.60). PMID- 21547106 TI - Cytapheresis as a Non-Pharmacological Therapy for Inflammatory Bowel Disease. AB - SUMMARY: Although inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic recurrent disease with unknown etiology. Recent immunological studies suggest close relation to autoimmune status featured by antibodies against colonic epithelial cells. For patients with IBD, 5-aminosalycilates are often used in case of mild disease, and corticosteroids are standard therapy for moderate-to-severe disease. However, we often encounter patients who are resistant to or dependent of conventional therapy, which are likely to lead to future problems in quality of life due to adverse effects of drugs used, especially corticosteroids. Extracorporeal leukocyte removal therapy (cytapheresis) is one of the adjunctive therapies for IBD patients refractory to steroids. By removing circulating activated leukocytes, especially granulocytes and lymphocytes, impaired immune response is suppressed. In the present article recently published studies are reviewed in order to reflect the current state of the art in the use of cytapheresis for treating IBD, especially UC and CD. Although there are only few randomized controlled trials, clinical experience so far suggests that cytapheresis has superior efficiency than conventional therapies in steroid-resistant moderate-to severe UC. Moreover, cytapheresis features its safety characteristic compared with other conventional medications for severe UC, cytapheresis is regarded as safe treatment regimen. PMID- 21547105 TI - Extracorporeal Photochemotherapy as a Challenging Treatment for Cutaneous T-Cell Lymphoma, Acute and Chronic Graft-versus-Host Disease, Organ Rejection and T Lymphocyte-Mediated Autoimmune Diseases. AB - SUMMARY: 20 years ago, in 1987, Edelson and co-workers published their first report on the effectiveness of a new procedure, called extracorporeal photochemotherapy (ECP), in patients with advanced stage cutaneous T-cell lymphoma (CTCL). The positive response (>70% overall) achieved in those patients encouraged several groups to try out this new technology in other T-lymphocyte mediated autoimmune diseases and a number of dermatological diseases, which sometimes gave conflicting results. In the following years, ECP obtained FDA approval as first line treatment in CTCL. In the 1990s ECP was applied to acute and chronic graft-versus-host disease (GvHD) refractory to conventional immunosuppressive therapy and proved to be effective in >60% of cases of this larger patient population. Today, although the effectiveness of ECP in GvHD is generally acknowledged, this is mainly based on retrospective or observational studies, as data from large, randomized multicenter trials, has yet to be published. Moreover, ECP's real mechanism of action and optimal treatment schedule are still under investigation. The aim of this review is to summarize knowledge acquired to date about ECP. PMID- 21547108 TI - Evaluation of Four Bedside Test Systems for Card Performance, Handling and Safety. AB - SUMMARY: OBJECTIVE: Pretransfusion ABO compatibility testing is a simple and required precaution against ABO-incompatible transfusion, which is one of the greatest threats in transfusion medicine. While distinct agglutination is most important for correct test interpretation, protection against infectious diseases and ease of handling are crucial for accurate test performance. Therefore, the aim of this study was to evaluate differences in test card design, handling, and user safety. DESIGN: Four different bedside test cards with pre-applied antibodies were evaluated by 100 medical students using packed red blood cells of different ABO blood groups. Criteria of evaluation were: agglutination, labelling, handling, and safety regarding possible user injuries. Criteria were rated subjectively according to German school notes ranging from 1 = very good to 6 = very bad/insufficient. RESULTS: Overall, all cards received very good/good marks. The ABO blood group was identified correctly in all cases. Three cards (no. 1, no. 3, no. 4) received statistically significant (p < 0.008) prominence (mean values shown) concerning clearness of agglutination (1.7-1.9 vs. 2.4 for no. 2). Systems with dried antibodies (no. 2, no. 4) outmatched the other systems with respect to overall test system performance (2.0 vs. 2.8-2.9), labelling (1.5 vs. 2.2-2.4), handling (1.9-2.0 vs. 2.5), and user safety (2.5 vs. 3.4). Analysis of card self-explanation revealed no remarkable differences. CONCLUSION: Despite good performance of all card systems tested, the best results when including all criteria evaluated were obtained with card no. 4 (particularly concerning clear agglutination), followed by cards no. 2, no. 1, and no. 3. PMID- 21547107 TI - Erythrocytapheresis: Do Not Forget a Useful Therapy! AB - SUMMARY: In patients with pathologically altered erythrocytes, red blood cell exchange is a very efficient therapeutic measure without important side effects. With increasing migration more patients with e.g. severe malaria or sickle cell anemia have to be treated. In minor or bidirectional ABO-mismatched stem cell transplantations after reduced intensity conditioning, hemolysis can be prevented by prophylactic erythrocytapheresis. Other rare indications for red blood cell exchange are advanced erythropoietic protoporphyria and babesiosis. Sickle cell anemia can be treated with hydroxyurea. Transfusions are administered when necessary, but this results in iron overload in the long term. An expensive but safe and very efficient treatment alternative is red blood cell exchange. In cases with stroke, acute chest syndrome and other severe complications, erythrocytapheresis reproducibly breaks the vicious circle of sickling and increasing oxygen deficiency. At the same time one can aim at an exact end hematocrit. In severe malaria, erythrocytapheresis both reduces parasite load to the designated extent and reconstitutes reduced oxygen transport capacity without serious adverse effects. Here we describe our experience of erythrocytapheresis in long-term prophylaxis of complications in sickle cell anemia and sickle cell thalassemia patients. The documentation of improved iron balance was carried out by liver susceptometry. PMID- 21547109 TI - C-Reactive Protein, Detected with a Highly Sensitive Assay, in Non-Infected Newborns and Those with Early Onset Infection. AB - SUMMARY: BACKGOUND: The aim of this study was to investigate C-reactive protein (CRP), measured by a highly sensitive method (hsCRP) in non-infected newborns and in those with suspected early onset bacterial infection (EOBI) as well as to test whether EOBI would be detectable earlier by hsCRP than by a nephelometric CRP (nsCRP) assay (thresholds > 10 mg/l) or IL-8. PATIENTS AND METHODS: 106 neonates with signs of infection comprised the suspected EOBI group. 134 neonates with risk factors but confirmed exclusion of EOBI served as non-infected controls. RESULTS: In the non-infected group, hsCRP in the first 6 h after birth was low (0.7 mg/l; SD 0.16 mg/l) but showed an increase to 4.11 mg/l (SD 3.33 mg/l) at 72 h (p < 0.001 vs. 6 h). The sensitivity of hsCRP (cut-off 0.3 mg/l) vs. nsCRP for EOBI was 0.46 vs. 0.23 at 6 h after clinical suspicion. Of all parameters measured, IL-8 had the highest sensitivity and specificity to detect EOBI at 6 h (0.60 and 0.90), but declined after 12 and 24 h. CONCLUSION: Lowering the CRP detection threshold by a highly sensitive assay did not improve diagnostic accuracy for EOBI. PMID- 21547110 TI - Influenza Virus. PMID- 21547111 TI - Hepatitis E Virus. PMID- 21547112 TI - Basic Biology of Mesenchymal Stem Cells. PMID- 21547113 TI - Characteristics of Mesenchymal Stem Cells - New Stars in Regenerative Medicine or Unrecognized Old Fellows in Autologous Regeneration? AB - SUMMARY: For years mesenchymal stem cells (MSC) have been in the focus of research in the emerging field of regenerative medicine. Due to the heterogeneity of cells with MSC-like properties their comprehensive characterization is necessary. In the following, issues of nomenclature, basic characterization, sources, sternness, and therapeutic potential of MSC are discussed, highlighting some aspects in the rapidly expanding field of MSC research. PMID- 21547114 TI - Mesenchymal Progenitor Cells: Tissue Origin, Isolation and Culture. AB - SUMMARY: Since the pioneering work of Alexander Friedenstein on multipotent mesenchymal stromal cells (MSCs), a tremendous amount of work has been done to isolate, characterize and culture such cells. Assay of colony forming unit fibroblasts (CFU-Fs), the hallmark of MSCs, is used to estimate their frequency in tissue. MSCs are adherent cells, so they are easy to isolate, and they show contact inhibition. Thus, several parameters must be taken into account for culture: cell density, number of passages, culture medium, and growth factors used. The purity of the initial material is not a limiting parameter. Similar but not identical cell populations are found in almost all mammal or human tissues. MSCs seem to be very abundant in adipose tissue but at low frequency in blood from umbilical cord or in adult tissue. The culture conditions are very similar, whatever the source of cells. Because of their favorable properties, MSCs are very promising tools for regenerative medicine. PMID- 21547115 TI - Phenotypic Characterization of Mesenchymal Stem Cells from Various Tissues. AB - SUMMARY: Research on expanded human stem cells has become an increasing field of interest during the last decade. The increasing interest in adult stem cells, especially mesenchymal stem and mesenchymal stromal cells, in hematology and regenerative medicine is also based on the simplicity of isolation and ex vivo expansion of these cells. These processes require an adequate quality control of source and product. In this review, we summarize various different attempts to characterize mesenchymal stem cells based on surface protein expression by flow cytometry and to define multipotent subpopulations of mesenchymal stem cells for prospective isolation. The importance of defining functional assays and a unique marker panel to characterize mesenchymal stem cells for clinical trials as well as the factors that can modulate the marker expression is discussed. PMID- 21547116 TI - The Stromal Activity of Mesenchymal Stromal Cells. AB - SUMMARY: The mechanism that regulates self-renewal and differentiation of hematopoietic stem cells (HSC) is a central question in stem cell biology that might ultimately lead to reliable protocols for in vitro expansion of HSC. Cellular fate is governed by cell-cell interaction with the microenvironment in the bone marrow, the stem cell niche. Mesenchymal stromal cells (MSC) are precursors of the cellular components, and they secrete extracellular matrix proteins of the bone marrow stroma. Therefore, MSC feeder layer might provide a suitable in vitro model system for the stem cell niche. In vitro assays demonstrate that MSC maintain the stem cell function of HSC and that MSC from bone marrow have a higher hematopoiesis supportive activity than MSC from adipose tissue. Co-cultivation with MSC might pave the way for expansion of long-term repopulating HSC, and various clinical trials indicate that co-transplantation of HSC and MSC might enhance engraftment. Thus, MSC are promising tools to elucidate the underlying mechanism of the cellular microenvironment. The large variety of preparative protocols for isolation and cultivation of MSC affects their stromal activity. Standardized isolation methods and molecular characterization of MSC are of utmost importance for reproducible isolation of hematopoiesis supportive stromal cells and for their potential clinical application. PMID- 21547117 TI - Immune Modulation by Mesenchymal Stem Cells. AB - SUMMARY: Mesenchymal stem cells (MSCs) and their stromal progeny may be considered powerful regulatory cells, a sort of dendritic cell counterpart, which influence all the main immune effectors and functional roles in vivo, as well as potential applications in the treatment of a number of human immunological diseases. By choosing MSC tissue origin, cell dose, administration route, and treatment schedule, all the potential side effects related to MSC use, including tumor growth enhancement, have to be well considered to maximize the benefits of MSC-depen-dent immune regulation without significant risks for the patients. PMID- 21547118 TI - Epigenetic Basis for the Differentiation Potential of Mesenchymal and Embryonic Stem Cells. AB - SUMMARY: Stem cells have the ability to self-renew, and give rise to one or more differentiated cell types. Embryonic stem cells can differentiate into all cell types of the body and have unlimited self-renewal capacity. Somatic stem cells are found in many adult tissues. They have an extensive but finite lifespan and can differentiate into a more restricted range of cell types. Increasing evidence indicates that the multilineage differentiation ability of stem cells is defined by the potential for expression of developmentally regulated transcription factors and of lineage specification genes. Gene expression, or as emphasized here, the potential for gene expression, is largely controlled by epigenetic modifications of DNA (DNA methylation) and chromatin (such as post-translational histone modifications) in the regulatory regions of specific genes. Epigenetic modifications can also influence the timing of DNA replication. We highlight here how mechanisms by which genes are poised for transcription in undifferentiated stem cells are being uncovered through the mapping of DNA methylation profiles on differentiation-regulated promoters and at the genome-wide level, histone modifications, and transcription factor binding. Epigenetic marks on developmentally regulated and lineage specification genes in stem cells seem to define a state of pluripotency. PMID- 21547119 TI - Transcriptional control of mesenchymal stem cell differentiation. AB - SUMMARY: In recent years, transcriptomics and proteomics have provided us with a great deal of information about the expression profiles of various cell types and how these change under different conditions. Stem cell research is one area where this has had a major impact by providing an insight into events at the molecular level that control stem cell growth and differentiation. This includes mesenchymal stem cell (MSC) biology where knowledge about the mechanisms governing differentiation is vital for the development of future therapeutic strategies. Although there is still much to learn, we are starting to build up a picture of the main events in these differentiation processes. This review will discuss control of MSC differentiation at the transcriptional level. Not all the factors which have been shown to play a role in lineage-specific mesenchymal differentiation can be covered here. Instead, we will focus specifically on the key factors that contribute to the regulation of osteogenesis, adipogenesis, and chondrogenesis. PMID- 21547121 TI - In vivo Differentiation Potential of Mesenchymal Stem Cells: Prenatal and Postnatal Model Systems. AB - SUMMARY: Most of our knowledge of mesenchymal stem cell (MSC) biology is derived from in vitro systems that are often highly contrived to favor culture expansion or specific differentiation events. However, any conclusions drawn from in vitro studies regarding MSC differentiation capacity, immune properties, or therapeutic potential must be validated by in vivo studies to ultimately be meaningful. At the present time, there are relatively few in vivo studies demonstrating differentiation and functional integration of MSCs into host tissues after transplantation. There is a need for in vivo model systems to assay MSC biology and to move potential therapeutic strategies forward. Here, we review prenatal model systems as potentially advantageous for the in vivo characterization of MSCs, and we critically review the results of in vivo studies of MSC transplantation in prenatal and postnatal model systems with an emphasis on proven engraftment and differentiation. PMID- 21547122 TI - Bone Marrow - Home of Versatile Stem Cells. AB - SUMMARY: Bone marrow (BM) has been for many years primarily envisioned as the 'home organ' of hematopoietic stem cells (HSC). In this review we will discuss current views of the BM stem cell compartment and present data showing that BM in addition to HSC also contains a heterogeneous population of non-hematopoietic stem cells. These cells have been variously described in the literature as i) endothelial progenitor cells (EPC), ii) mes-enchymal stem cells (MSC), iii) multipotent adult progenitor cells (MAPC), iv) marrow-isolated adult multilineage inducible (MIAMI) cells, v) multipotent adult stem cells (MACS) and vi) very small embryonic-like (VSEL) stem cells. It is likely that in many cases similar or overlapping populations of primitive stem cells in the BM were detected using different experimental strategies and hence were assigned different names. PMID- 21547123 TI - Targeting the cell cycle in esophageal adenocarcinoma: an adjunct to anticancer treatment. AB - Esophageal adenocarcinoma is a major cause of cancer death in men in the developed world. Continuing poor outcomes with conventional therapies that predominantly target apoptosis pathways have lead to increasing interest in treatments that target the cell cycle. A large international effort has led to the development of a large number of inhibitors, which target cell cycle kinases, including cyclin-dependent kinases, Aurora kinases and polo-like kinase. Initial phase I/II trials in solid tumors have often demonstrated only modest clinical benefits of monotherapy. This may relate in part to a failure to identify the patient populations that will gain the most clinical benefit. Newer compounds lacking the side effect profile of first-generation compounds may show utility as adjunctive treatments targeted to an individual's predicted response to treatment. PMID- 21547120 TI - In vitro Differentiation Potential of Mesenchymal Stem Cells. AB - SUMMARY: Mesenchymal stem cells (MSCs) represent a class of multipotent progenitor cells that have been isolated from multiple tissue sites. Of these, adipose tissue and bone marrow offer advantages in terms of access, abundance, and the extent of their documentation in the literature. This review focuses on the in vitro differentiation capability of cells derived from adult human tissue. Multiple, independent studies have demonstrated that MSCs can commit to mesodermal (adipocyte, chondrocyte, hematopoietic support, myocyte, osteoblast, tenocyte), ectodermal (epithelial, glial, neural), and endodermal (hepatocyte, islet cell) lineages. The limitations and promises of these studies in the context of tissue engineering are discussed. PMID- 21547124 TI - Optimizing management in autoimmune hepatitis with liver failure at initial presentation. AB - Autoimmune hepatitis (AIH) is a disease of unknown etiology, its hallmark being ongoing hepatic inflammation. By its very nature, it is a chronic condition, although increasingly, we are becoming aware of patients with acute presentations, some of whom may have liver failure. There are very limited published data on patients with AIH with liver failure at initial diagnosis, which consist mostly of small retrospective studies. As a consequence, the clinical features and optimal management of this cohort remain poorly defined. A subset of patients with AIH who present with liver failure do respond to corticosteroids, but for the vast majority, an urgent liver transplantation may offer the only hope of long-term survival. At present, there is uncertainty on how best to stratify such a cohort into responders and non- responders to corticosteroids as soon as possible after hospitalization, thus optimizing their management. This editorial attempts to answer some of the unresolved issues relating to management of patients with AIH with liver failure at initial presentation. However, it must be emphasized that, at present, this editorial is based mostly on small retrospective studies, and it is an understatement that multicenter prospective studies are urgently needed to address this important clinical issue. PMID- 21547125 TI - A practical approach to the diagnosis of autoimmune pancreatitis. AB - Autoimmune pancreatitis is a disease characterized by specific pathological features, different from those of other forms of pancreatitis, that responds dramatically to steroid therapy. The pancreatic parenchyma may be diffusely or focally involved with the possibility of a low-density mass being present at imaging, mimicking pancreatic cancer. Clinically, the most relevant problems lie in the diagnosis of autoimmune pancreatitis and in distinguishing autoimmune pancreatitis from pancreatic cancer. Since in the presence of a pancreatic mass the probability of tumour is much higher than that of pancreatitis, the physician should be aware that in focal autoimmune pancreatitis the first step before using steroids is to exclude pancreatic adenocarcinoma. In this review, we briefly analyse the strategies to be followed for a correct diagnosis of autoimmune pancreatitis. PMID- 21547126 TI - Endoscopic ultrasonography findings in autoimmune pancreatitis. AB - Endoscopic ultrasonography is an established diagnostic tool for pancreatic masses and chronic pancreatitis. In recent years there has been a growing interest in the worldwide medical community in autoimmune pancreatitis (AIP), a form of chronic pancreatitis caused by an autoimmune process. This paper reviews the current available literature about the endoscopic ultrasonographic findings of AIP and the role of this imaging technique in the management of this protean disease. PMID- 21547127 TI - Effects of alpha-mangostin on apoptosis induction of human colon cancer. AB - AIM: To investigate the effect of alpha-mangostin on the growth and apoptosis induction of human colon cancer cells. METHODS: The three colorectal adenocarcinoma cell lines tested (COLO 205, MIP-101 and SW 620) were treated with alpha-mangostin to determine the effect on cell proliferation by MTT assay, cell morphology, chromatin condensation, cell cycle analysis, DNA fragmentation, phosphatidylserine exposure and changing of mitochondrial membrane potential. The molecular mechanisms of alpha-mangostin mediated apoptosis were further investigated by Western blotting analysis including activation of caspase cascade, cytochrome c release, Bax, Bid, p53 and Bcl-2 modifying factor. RESULTS: The highest inhibitory effect of alpha-mangostin on cell proliferation of COLO 205, MIP-101 and SW 620 were 9.74 +/- 0.85 MUg/mL, 11.35 +/- 1.12 MUg/mL and 19.6 +/- 1.53 MUg/mL, respectively. Further study showed that alpha-mangostin induced apoptotic cell death in COLO 205 cells as indicated by membrane blebbing, chromatin condensation, DNA fragmentation, cell cycle analysis, sub-G1 peak (P < 0.05) and phosphatidylserine exposure. The executioner caspase, caspase-3, the initiator caspase, caspase-8, and caspase-9 were expressed upon treatment with alpha-mangostin. Further studies of apoptotic proteins were determined by Western blotting analysis showing increased mitochondrial cytochrome c release, Bax, p53 and Bmf as well as reduced mitochondrial membrane potential (P < 0.05). In addition, up-regulation of tBid and Fas were evident upon treatment with alpha mangostin (P < 0.01). CONCLUSION: alpha-Mangostin may be effective as an anti cancer agent that induced apoptotic cell death in COLO 205 via a link between extrinsic and intrinsic pathways. PMID- 21547128 TI - Chemometrics of differentially expressed proteins from colorectal cancer patients. AB - AIM: To evaluate the usefulness of differentially expressed proteins from colorectal cancer (CRC) tissues for differentiating cancer and normal tissues. METHODS: A Proteomic approach was used to identify the differentially expressed proteins between CRC and normal tissues. The proteins were extracted using Tris buffer and thiourea lysis buffer (TLB) for extraction of aqueous soluble and membrane-associated proteins, respectively. Chemometrics, namely principal component analysis (PCA) and linear discriminant analysis (LDA), were used to assess the usefulness of these proteins for identifying the cancerous state of tissues. RESULTS: Differentially expressed proteins identified were 37 aqueous soluble proteins in Tris extracts and 24 membrane-associated proteins in TLB extracts. Based on the protein spots intensity on 2D-gel images, PCA by applying an eigenvalue > 1 was successfully used to reduce the number of principal components (PCs) into 12 and seven PCs for Tris and TLB extracts, respectively, and subsequently six PCs, respectively from both the extracts were used for LDA. The LDA classification for Tris extract showed 82.7% of original samples were correctly classified, whereas 82.7% were correctly classified for the cross validated samples. The LDA for TLB extract showed that 78.8% of original samples and 71.2% of the cross-validated samples were correctly classified. CONCLUSION: The classification of CRC tissues by PCA and LDA provided a promising distinction between normal and cancer types. These methods can possibly be used for identification of potential biomarkers among the differentially expressed proteins identified. PMID- 21547129 TI - Dietary treatment of colic caused by excess gas in infants: biochemical evidence. AB - AIM: To evaluate the impact of feeding colicky infants with an adapted formula on the hydrogen breath test and clinical symptoms. METHODS: Hydrogen expiration was measured by SC MicroLyzer gas chromatography at inclusion and 15 d after treatment with an adapted low-lactose formula in 20 colicky infants. RESULTS: All babies were symptomatic: 85% with excess gas, 75% with abnormal feeding pattern, and 85% with excessive crying. The hydrogen breath test at inclusion was abnormal: 35 +/- 3.1 ppm. After 15 d feeding with an adapted low-lactose formula, crying and flatulence decreased in 85% of patients (P < 0.001). For infants in whom no decrease of gas was reported, crying was still reduced (P < 0.01). Moreover, the feeding pattern was improved in 50% of infants when it was initially considered as abnormal. Finally, the hydrogen breath test decreased significantly (10 +/- 2.5 ppm, P < 0.01). CONCLUSION: This study showed an association between clinical improvement and evidence of decreased levels of hydrogen when the infants were fed with a specially designed, low-lactose formula. PMID- 21547130 TI - Levels of matrix metalloproteinase-1 and tissue inhibitors of metalloproteinase-1 in gastric cancer. AB - AIM: To evaluate the levels of preoperative serum matrix metalloproteinase-1 (MMP 1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in gastric cancer. METHODS: One hundred gastric cancer patients who underwent gastrectomy were enrolled in this study. The serum concentrations of MMP-1 and TIMP-1 in these patients and in fifty healthy controls were determined using an enzyme-linked immunosorbent assay. RESULTS: Higher serum MMP-1 and TIMP-1 levels were observed in patients than in controls (P < 0.001). Serum MMP-1 and TIMP-1 levels were positively associated with morphological appearance, tumor size, depth of wall invasion, lymph node metastasis, liver metastasis, perineural invasion, and pathological stage. They were not significantly associated with age, gender, tumor location, or histological type. CONCLUSION: Increased MMP-1 and TIMP-1 were associated with gastric cancer. Although these markers are not good markers for diagnosis, these markers show in advanced gastric cancer. PMID- 21547131 TI - Sunitinib for Taiwanese patients with gastrointestinal stromal tumor after imatinib treatment failure or intolerance. AB - AIM: To report preliminary results of the efficacy and safety of sunitinib in the management of Taiwanese gastrointestinal stromal tumors (GIST) patients facing imatinib mesylate (IM) intolerance or failure. METHODS: Between 2001 and May 2010, 199 Taiwanese patients with metastatic GIST were treated at Chang Gung Memorial Hospital. Among them, 23 (11.6%) patients receiving sunitinib were investigated. RESULTS: Sixteen male and 7 female patients with a median age of 59 years (range: 24-83 years) received sunitinib. Twenty-two GIST patients changed to sunitinib because of IM failure and 1 because of intolerance. The median duration of sunitinib administration was 6.0 mo (range: 2-29 mo). The clinical benefit was 65.2% [2 complete response (CR), 4 partial response (PR), and 9 stationary disease (SD); 15/23]. In 12 patients harboring mutations of the kit gene at exon 11, the clinical benefit rate (CR, PR, and SD) was 75.0% and 6 patients with tumors containing kit exon 9 mutations had a clinical benefit of 50.0% (not significant, P = 0.344). The progression free survival (PFS) and overall survival (OS) did not differ between patients whose GISTs had wild type, KIT exon 9, or KIT exon 11 mutations. Hand-foot syndrome was the most common cause of grade III adverse effect (26.1%), followed by anemia (17.4%), and neutropenia (13.0%). During the median 7.5-mo follow-up after sunitinib use, the median PFS and OS of these 23 GIST patients after sunitinib treatment were 8.4 and 14.1 mo, respectively. CONCLUSION: Sunitinib appears to be an effective treatment for Taiwanese with IM-resistant/intolerant GISTs and induced a sustained clinical benefit in more than 50% of Taiwanese advanced GIST patients. PMID- 21547132 TI - MELD score can predict early mortality in patients with rebleeding after band ligation for variceal bleeding. AB - AIM: To investigate the outcomes, as well as risk factors for 6-wk mortality, in patients with early rebleeding after endoscopic variceal band ligation (EVL) for esophageal variceal hemorrhage (EVH). METHODS: Among 817 EVL procedures performed for EVH between January 2007 and December 2008, 128 patients with early rebleeding, defined as rebleeding within 6 wk after EVL, were enrolled for analysis. RESULT: The rate of early rebleeding after EVL for acute EVH was 15.6% (128/817). The 5-d, 6-wk, 3-mo, and 6-mo mortality rates were 7.8%, 38.3%, 55.5%, and 58.6%, respectively, in these early rebleeding patients. The use of beta blockers, occurrence of hypovolemic shock, and higher model for end-stage liver disease (MELD) score at the time of rebleeding were independent predictors for 6 wk mortality. A cut-off value of 21.5 for the MELD score was found with an area under ROC curve of 0.862 (P < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value were 77.6%, 81%, 71.7%, and 85.3%, respectively. As for the 6-mo survival rate, patients with a MELD score >= 21.5 had a significantly lower survival rate than patients with a MELD score < 21.5 (P < 0.001). CONCLUSION: This study demonstrated that the MELD score is an easy and powerful predictor for 6-wk mortality and outcomes of patients with early rebleeding after EVL for EVH. PMID- 21547133 TI - Study on chronic pancreatitis and pancreatic cancer using MRS and pancreatic juice samples. AB - AIM: To investigate the markers of pancreatic diseases and provide basic data and experimental methods for the diagnosis of pancreatic diseases. METHODS: There were 15 patients in the present study, among whom 10 had pancreatic cancer and 5, chronic pancreatitis. In all patients, pancreatic cancer or chronic pancreatitis was located on the head of the pancreas. Pathology data of all patients was confirmed by biopsy and surgery. Among the 10 patients with pancreatic cancer, 3 people had a medical history of long-term alcohol consumption. Of 5 patients with chronic pancreatitis, 4 men suffered from alcoholic chronic pancreatitis. Pancreatic juice samples were obtained from patients by endoscopic retrograde cholangio-pancreatography. Magnetic resonance spectroscopyn was performed on an 11.7-T scanner (Bruker DRX-500) using Call-Purcell-Meiboom-Gill pulse sequences. The parameters were as follows: spectral width, 15 KHz; time domain, 64 K; number of scans, 512; and acquisition time, 2.128 s. RESULTS: The main component of pancreatic juice included leucine, iso-leucine, valine, lactate, alanine, acetate, aspartate, lysine, glycine, threonine, tyrosine, histidine, tryptophan, and phenylalanine. On performing 1D (1)H and 2D total correlation spectroscopy, we found a triplet peak at the chemical shift of 1.19 ppm, which only appeared in the spectra of pancreatic juice obtained from patients with alcoholic chronic pancreatitis. This triplet peak was considered the resonance of the methyl of ethoxy group, which may be associated with the metabolism of alcohol in the pancreas. CONCLUSION: The triplet peak, at the chemical shift of 1.19 ppm is likely to be the characteristic metabolite of alcoholic chronic pancreatitis. PMID- 21547134 TI - Ku80 gene G-1401T promoter polymorphism and risk of gastric cancer. AB - AIM: To evaluate the possible relationship between the Ku80 gene polymorphism and the risk of gastric cancer in China. METHODS: In this hospital-based case-control study of gastric cancer in Jiangsu Province, China, we investigated the association of the Ku80 G-1401T (rs828907) polymorphism with gastric cancer risk. A total of 241 patients with gastric cancer and 273 age- and sex-matched control subjects were genotyped and analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The frequencies of genotypes GG, GT and TT were 65.6%, 22.8% and 11.6% in gastric cancer cases, respectively, and 75.8%, 17.6% and 6.6% in controls, respectively. There were significant differences between gastric cancer and control groups in the distribution of their genotypes (P = 0.03) and allelic frequencies (P = 0.002) in the Ku80 promoter G-1401T polymorphism. CONCLUSION: The T allele of Ku80 G-1401T may be associated with the development of gastric cancer. PMID- 21547135 TI - Effects of penehyclidine hydrochloride on rat intestinal barrier function during cardiopulmonary bypass. AB - AIM: To test the ability of penehyclidine hydrochloride (PHC) to attenuate intestinal injury in a rat cardiopulmonary bypass (CPB) model. METHODS: Male Sprague-Dawley rats were randomly divided into six groups (eight each): sham operated control; sham-operated low-dose PHC control (0.6 mg/kg); sham-operated high-dose PHC control (2.0 mg/kg); CPB vehicle control; CPB low-dose PHC (0.6 mg/kg); and CPB high-dose PHC (2.0 mg/kg). Blood samples were collected from the femoral artery 2 h after CPB for determination of plasma diamine oxidase (DAO), D lactate and endotoxin levels. Spleen, liver, mesenteric lymph nodes and lung were removed for biochemical analyses. Intestinal tissue ultrastructure was examined by electron microscopy. RESULTS: In the sham-operated groups, high- and low-dose PHC had no significant impact on the levels of DAO, D-lactate and endotoxin, or the incidence of intestinal bacterial translocation (BT). Serum levels of DAO, D lactate, endotoxin and the incidence of intestinal BT were significantly increased in the surgical groups, compared with the sham-operated groups (0.543 +/- 0.061, 5.697 +/- 0.272, 14.75 +/- 2.46, and 0/40 vs 1.038 +/- 0.252, 9.377 +/ 0.769, 60.37 +/- 5.63, and 30/40, respectively, all P < 0.05). PHC alleviated the biochemical and histopathological changes in a dose-dependent manner. Serum levels of DAO, D-lactate, and endotoxin and the incidence of intestinal BT in the high-dose PHC group were significantly lower than in the low-dose PHC group (0.637 +/- 0.064, 6.972 +/- 0.349, 29.64 +/- 5.49, and 14/40 vs 0.998 +/- 0.062, 7.835 +/- 0.330, 38.56 +/- 4.28, and 6/40, respectively, all P < 0.05). CONCLUSION: PHC protects the structure and function of the intestinal mucosa from injury after CPB in rats. PMID- 21547136 TI - p53 gene therapy in combination with transcatheter arterial chemoembolization for HCC: one-year follow-up. AB - AIM: To evaluate the efficacy and safety of combination therapy with recombinant adenovirus p53 injection (rAdp53) and transcatheter hepatic arterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC). METHODS: A total of 82 patients with advanced HCC treated only with TACE served as control group. Another 68 patients with HCC treated with TACE in combination with recombinant adenovirus-p53 injection served as p53 treatment group. Patients were followed up for 12 mo. Safety and therapeutic effects were evaluated according to the improvement in clinical symptoms, leukocyte count, Karnofsky and RECIST criteria. Survival rate was calculated with Kaplan-Meier method. RESULTS: The total effective rate was 58.3% for p53 treatment group, and 26.5% for control group (P < 0.05). The incidence of gastrointestinal symptoms was lower in p53 treatment group than in control group (P < 0.05). The 3-, 6- and 12-mo survival rates were significantly higher for p53 treatment group than for control group (P < 0.01). The combination treatment was well tolerated with such adverse events as fever (51.5%, P = 0.006) and pain of muscles and joints (13.2%, P = 0.003), which were significantly higher than the chemotherapy. Except for these minor adverse effects, no severe vector-related complications were identified. With respect to the efficacy, patients in p53 treatment group had less gastrointerestinal symptoms (P = 0.062), better improvement in tumor-related pain (P = 0.003), less downgrade of leukocyte counts (P = 0.003) and more upgrade of Karnofsky performance score (P = 0.029) than those in control group. The total effective rate (CR + PR) for p53 treatment group and control group was 58.3% and 26.5%, respectively, with distributions of different effect in two groups (P = 0.042). The survival rates were 89.71%, 76.13%, and 43.30% for p53 treatment group, and 68.15%, 36.98%, and 24.02% for control group, respectively, 3, 6 and 12 mo after treatment, suggesting that the survival rates are significantly higher for p53 treatment group than for control group (P = 0.0002). CONCLUSION: The rAd-p53 gene therapy in combination with TACE is a safe and effective treatment modality for advanced HCC. PMID- 21547137 TI - Celiac disease and microscopic colitis: a report of 4 cases. AB - Celiac disease (CD) is an autoimmune disorder of the small intestine that occurs in genetically predisposed people at all ages. However, it can be associated also to other immunopathological disorders, and may be associated with abnormal histology in segments of the gut other than the small bowel including colonic inflammation. While guidelines for endoscopic investigation of the jejunum are well defined, no indication is defined for colonic investigation. We describe four cases of concurrent CD and microscopic colitis (MC) diagnosed at our department over a 10-year period and analyzed the main features and outcomes of CD in this setting. The symptoms of these patients were improved initially by a gluten-free diet before the onset of MC symptoms. Two of the patients were siblings and had an atypical form of CD. The other two patients with CD and MC also presented with fibrosing alveolitis and were anti-Saccharomyces cerevisiae antibody positive. The co-existence of immune-mediated small bowel and colonic inflammatory and pulmonary diseases are not well-known, and no systematic approach has been used to identify the lifelong patterns of these immune-based diseases. Patients can develop, or present with CD at any stage in life, which can co-exist with other gastrointestinal diseases of (auto-) immune origin. In addition, the familial co-existence and prevalence of MC in patients with a prior diagnosis of CD are unclear. Clinicians managing celiac disease should be aware of these associations and understand when to consider colon investigation. PMID- 21547138 TI - Pure red cell aplasia caused by pegylated interferon-alpha-2a plus ribavirin in the treatment of chronic hepatitis C. AB - Pure red cell aplasia (PRCA) is a rare hematological disorder which is characterized by severe anemia, reticulocytopenia and almost complete absence of erythroid precursors in bone marrow. The pathophysiology of PRCA may be congenital or acquired. To our knowledge, there is only one case report in the English literature of PRCA after pegylated interferon combination therapy for chronic hepatitis C. We report a second case of PRCA after pegylated interferon combination treatment for chronic hepatitis C. The diagnosis of PRCA was confirmed by the typical findings of bone marrow biopsy. The possible etiologies of our case are also discussed in this paper. PMID- 21547139 TI - Enucleation for gastrointestinal stromal tumors at the esophagogastric junction: is this an adequate solution? AB - The authors discussed the proposal by Coccolini and colleagues to treat gastrointestinal stromal tumors (GISTs) at the esophagogastric junction with enucleation and, if indicated, adjuvant therapy, reducing the risks related to esophageal and gastroesophageal resection. They concluded that, because the prognostic impact of a T1 high-mitotic rate on esophageal GIST is worse than that of a T1 high-mitotic rate on gastric GIST, enucleation may not be an adequate surgery for esophagogastric GISTs with a high mitotic rate in which the guarantee of negative resection margins and adjuvant therapies can be the only chance of survival. PMID- 21547140 TI - Dermato-Endocrinology: A continuously growing field with many fascinating facets! PMID- 21547141 TI - Time trends and latitude dependence of uveal and cutaneous malignant melanoma induced by solar radiation. AB - In order to evaluate the role of solar radiation in uveal melanoma etiology, the time and latitude dependency of the incidence rates of this melanoma type were studied in comparison with those of cutaneous malignant melanoma (CMM). Norway and several other countries with Caucasian populations were included. there is a marked north-south gradient of the incidence rates of CMM in Norway, with three times higher rates in the south than in the north. No such gradient is found for uveal melanoma. Similar findings have been published for CMM in other Caucasian populations, with the exception of Europe as a whole. In most populations the ratios of uveal melanoma incidence rates to those of CMM tend to decrease with increasing CMM rates. This is also true for Europe, in spite of the fact that in this region there is an inverse latitude gradient of CMM, with higher rates in the north than in the south.In Norway the incidence rates of CMM have increased until about 1990 but have been constant or even decreased (for young people) after that time, indicating constant or decreasing sun exposure. The uveal melanoma rates have been increasing after 1990. In most other populations the incidence rates of CMM have been increasing until recently while those of uveal melanoma have been decreasing. These data generally support the assumption that uveal melanomas are not generated by ultraviolet (UV) radiation and that solar UV, via its role in vitamin D photosynthesis, may have a protective effect. PMID- 21547143 TI - Acute onset disseminated superficial porokeratosis associated with exacerbation of diabetes mellitus due to development of anti-insulin antibodies. AB - The development of disseminated superficial porokeratosis is occasionally observed in association with renal transplant, autoimmune diseases and various hematological disorders, suggesting a certain immunosuppression may trigger a widespread abnormal keratinization. Here we report a case of sudden onset disseminated superficial porokeratosis associated with an exacerbation of diabetes mellitus due to an anti-insulin antibody formation. To our knowledge, this is the first report of disseminated superficial porokeratosis in a patient with severe diabetes mellitus. PMID- 21547142 TI - Comorbidities of hidradenitis suppurativa (acne inversa). AB - Comorbidities of hidradenitis suppurativa (acne inversa) were reviewed by extracting original and review publications included in MEDLINE, EMBASE and COCHRANE libraries using the terms "hidradenitis," "Verneuil" and "acne inversa." Follicular occlusion disorders, inflammatory bowel diseases, especially Crohn disease, spondylarthropathy, other hyperergic diseases, genetic keratin disorders associated with follicular occlusion and squamous cell carcinoma were the most common hidradenitis suppurativa comorbid diseases. A first classification of these major comorbidities and their possible genetic background reveals a list of chromosome loci and genes, which could be hidradenitis suppurativa candidates. Most of these diseases belong to the group of autoinflammatory disorders, where th17 cell cytokines seem to play a central role. PMID- 21547144 TI - Fundamental questions to sun protection: A continuous education symposium on vitamin D, immune system and sun protection at the University of Zurich. AB - Since exposure to sunlight is a main factor in the development of non-melanoma skin cancer and there are associations between malignant melanoma and short-term intense ultraviolet (UV) exposure, particularly burning in childhood, strict protection from UV-radiation is recommended. However, up to 90% of all requisite vitamin D has to be formed within the skin through the action of the sun-a serious problem, for a connection between vitamin D deficiency, demonstrated in epidemiological studies, and various types of cancer and other diseases has been confirmed. A UVB-triggered skin autonomous vitamin D(3) synthesis pathway has recently been described, producing the active Vitamin D metabolite calcitriol. This cutaneous vitamin D(3) pathway is unique. Keratinocytes and dendritic cells can convert vitamin D to calcitriol. Cutaneous T cells activated in the presence of calcitriol express the chemokine receptor CCR10 attracting them to the chemokine CCL27 that keratinocytes express selectively in the epidermis, and migrate from dermal layers of the skin to the epidermis under UV radiation. Thus, calcitriol has endocrine roles beyond its calciotropic action, including cell growth and cancer prevention. Therefore, strict sun protection procedures to prevent skin cancer may induce the risk of vitamin D deficiency. As there is evidence that the protective effect of less intense solar radiation can outweigh its mutagenic effect, better balanced approaches to sun protection should be sought. PMID- 21547145 TI - Skin manifestations in tumor necrosis factor receptor-associated periodic syndrome (TRAPS). AB - Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant inherited disease that belongs to the group of hereditary fever syndromes, that are also named hereditary auto-inflammatory syndromes. TRAPS is characterized by a variety of naturally occurring mutations in a TNF receptor (TNFR), that affect the soluble TNFRSF1A gene in the 12p13 region. In some patients, the pathogenesis of TRAPS involves defective TNFRSF1A shedding from cell membranes in response to varying stimuli. TRAPS is characterized by the periodic occurrence of a broad variety of different clinical symptoms that represent an acute-phase response, including fever and pain in the joints, abdomen, muscles, skin or eyes, with broad variations across patients. In many cases, skin involvement is present that may include migratory patches, skin rashes, erysepela-like erythema, edematous plaques, urticaria, periorbital edema and/or conjunctivitis. The histology of skin lesions in TRAPS is nonspecific, in general a perivascular dermal infiltrate of lymphocytes and monocytes can be found. Cutaneous findings are of particular importance in TRAPS: they have been shown to give direction to the diagnosis of TRAPS and in most cases their treatment is challenging. As the incidence of TRAPS is very low, no prospective randomized controlled trials and only a few studies with case numbers up to twenty-five patients have been published. No guidelines for TRAPS treatment have been established so far. This review summarizes our present knowledge about pathogenesis, clinical outcome and treatment options of skin manifestations in TRAPS. PMID- 21547147 TI - The epidemic of nonmelanoma skin cancer and the widespread use of statins: Is there a connection? AB - We hypothesize that some of the mechanisms involved in the "epidemic" of nonmelanoma skin cancer might also be due to widespread use of cholesterol lowering statin drugs. PMID- 21547148 TI - Axillary accessory breast associated with galactorrhea in an adolescent girl. AB - We present herein a case of right axillary accessory breast associated with galactorrhea in an adolescent girl. A 14-year-old Japanese girl presented with an 11-month history of a tender, subcutaneous lesion in the right axillary fossa. Seven months later, she experienced menarche. Subsequently, the patient noticed pressure-induced galactorrhea from both nipples. Physical examination revealed an elastic, firm and well-demarcated subcutaneous tumor 3 * 2 cm in size. A biopsy specimen showed proliferation of mammary gland tissue in the stroma located below the subcutaneous fat tissue. On the basis of these findings the patient was diagnosed with an accessory breast. Interestingly, the galactorrhea ceased after surgical removal of the accessory breast. PMID- 21547146 TI - Are Hill's criteria for causality satisfied for vitamin D and periodontal disease? AB - There is mounting evidence that periodontal disease (PD) is linked to low serum 25-hydroxyvitamin D [25(OH)D] concentrations in addition to recognized risk factors like diet and smoking. This paper reviews this evidence using Hill's criteria for causality in a biological system. Evidence for strength of association, consistency, cohesion and 'dose-effects' [biological 'gradients'] include strong inverse correlations between serum 25(OH) and PD cross-sectionally and that PD is consistently more prevalent in darker vs. lighter skinned people and increases at higher latitudes with analogy for gingivitis and for disorders associated with PD whose risks also increase with hypovitaminosis D. Evidence for plausibility includes that vitamin D increases calcium absorption and protects bone strength; induces formation of cathelicidin and other defensins that combat bacterial infection; reduces tissue production of destructive matrix metalloproteinases actively associated with PD and that prevalence of PD varies with common vitamin D receptor polymorphisms. Experimental evidence from limited supplementation studies [using calcium and vitamin D] shows that supplementation reduces tooth loss. Thus, existing evidence for hypovitaminosis D as a risk factor for PD to date meets Hill's criteria for causality in a biological system. Further experimental evidence for effectiveness and temporality, preferably from randomized controlled trials of vitamin D supplementation [adjusting for other PD risk factors including diet and smoking to reduce confounding] are necessary to confirm causality. If confirmed, dentists and periodontists could perform a valuable service to their patients by discussing the importance of adequate vitamin D status and how to avoid deficiency. PMID- 21547149 TI - Gait and equilibrium in subcortical vascular dementia. AB - Subcortical vascular dementia is a clinical entity, widespread, even challenging to diagnose and correctly treat. Patients with this diagnosis are old, frail, often with concomitant pathologies, and therefore, with many drugs in therapy. We tried to diagnose and follow up for three years more than 600 patients. Study subjects were men and women, not bedridden, aged 68-94 years, outpatients, recruited from June, 1st 2007 to June, 1st 2010. We examined them clinically, neurologically, with specific consideration on drug therapies. Our aim has been to define gait and imbalance problem, if eventually coexistent with the pathology of white matter and/or with the worsening of the deterioration. Drug intake interference has been detected and considered. PMID- 21547150 TI - Introducing Theranostics Journal - From the Editor-in-Chief. AB - Theranostics is a multidisciplinary journal that publishes innovative and original research papers reflecting the field of molecular imaging, molecular therapeutics, multifunctional nanoparticle platforms, image-guided therapy, and translational nanomedicine. A broad spectrum of biomedical research that can be applied to future theranostic applications is encouraged. PMID- 21547151 TI - Tunable plasmonic nanoprobes for theranostics of prostate cancer. AB - Theranostic applications require coupling of diagnosis and therapy, a high degree of specificity and adaptability to delivery methods compatible with clinical practice. The tunable physical and biological effects of selective targeting and activation of plasmonic nanobubbles (PNB) were studied in a heterogeneous biological microenvironment of prostate cancer and stromal cells. All cells were targeted with conjugates of gold nanoparticles (NPs) through an antibody-receptor endocytosis-nanocluster mechanism that produced NP clusters. The simultaneous pulsed optical activation of intracellular NP clusters at several wavelengths resulted in higher optical contrast and therapeutic selectivity of PNBs compared with those of gold NPs alone. The developed mechanism was termed "rainbow plasmonic nanobubbles." The cellular effect of rainbow PNBs was tuned in situ in target cells, thus supporting a theranostic algorithm of prostate cancer cell detection and follow-up guided destruction without damage to collateral cells. The specificity and tunability of PNBs is promising for theranostic applications and we discuss a fiber optic platform that will capitalize on these features to bring theranostic tools to the clinic. PMID- 21547152 TI - PET Imaging of Integrin alphaVbeta3 Expression. AB - PET imaging of integrin alphavbeta3 expression has been studied intensely by the academia and recently also by the industry. Imaging of integrin alphavbeta3 expression is of great potential value, as the integrin alphavbeta3 is a key player in tumor metastasis and angiogenesis. Therefore PET imaging of this target might be a suitable in-vivo biomarker of angiogenesis and metastatic potential of tumors. In this manuscript, the various strategies for PET imaging of the integrin alphavbeta3 will be summarized, including monomeric and multimeric radiolabelled RGD peptides and nanoparticles. While most experiments have been performed using preclinical tumor models, more and more clinical results on PET imaging of alphavbeta3 expression are available and will be discussed in detail. However, while a multitude of radiotracer strategies have been successfully evaluated for PET imaging of alphavbeta3, the ultimate clinical value of this new imaging biomarker still has to be evaluated in large clinical trials. PMID- 21547154 TI - Integrin Targeted MR Imaging. AB - Magnetic resonance imaging (MRI) is a powerful medical diagnostic imaging modality for integrin targeted imaging, which uses the magnetic resonance of tissue water protons to display tissue anatomic structures with high spatial resolution. Contrast agents are often used in MRI to highlight specific regions of the body and make them easier to visualize. There are four main classes of MRI contrast agents based on their different contrast mechanisms, including T(1), T(2), chemical exchange saturation transfer (CEST) agents, and heteronuclear contrast agents. Integrins are an important family of heterodimeric transmembrane glycoproteins that function as mediators of cell-cell and cell-extracellular matrix interactions. The overexpressed integrins can be used as the molecular targets for designing suitable integrin targeted contrast agents for MR molecular imaging. Integrin targeted contrast agent includes a targeting agent specific to a target integrin, a paramagnetic agent and a linker connecting the targeting agent with the paramagnetic agent. Proper selection of targeting agents is critical for targeted MRI contrast agents to effectively bind to integrins for in vivo imaging. An ideal integrin targeted MR contrast agent should be non-toxic, provide strong contrast enhancement at the target sites and can be completely excreted from the body after MR imaging. An overview of integrin targeted MR contrast agents based on small molecular and macromolecular Gd(III) complexes, lipid nanoparticles and superparamagnetic nanoparticles is provided for MR molecular imaging. By using proper delivery systems for loading sufficient Gd(III) chelates or superparamagnetic nanoparticles, effective molecular imaging of integrins with MRI has been demonstrated in animal models. PMID- 21547155 TI - Application of molecular ultrasound for imaging integrin expression. AB - Stabilized microbubbles with a size between 1-5 um are used as ultrasound contrast agents in the clinical routine. They have shown convincing results for the vascular characterization of tissues as well as in echocardiography. Due to their size, microbubbles strictly remain intravascular where they can be detected with high sensitivity and specificity. This qualifies them for intravascular molecular imaging. Many studies have been published reporting on the successful use of microbubbles conjugated to specific ligands for target identification in vivo. Among them, there are several promising examples on how to use molecular ultrasound for the imaging of integrin expression. This review provides an overview on the composition of ultrasound contrast agents that can be used for molecular imaging and their detection by ultrasound using destructive and non destructive methods. Furthermore, concrete examples are given on the use of molecular ultrasound to characterize integrin expression on vessels. These cover oncological applications where integrin targeted microbubbles were used to identify and characterize tumor angiogenesis and to assess tumor response to antiangiogenic drugs as well as to radiotherapy. In addition, increased accumulation of integrin targeted microbubbles was found during vascular reformation in ischemic tissues as well as in vulnerable atherosclerotic plaques. In summary, there is clear evidence from preclinical studies that integrin targeted ultrasound imaging is a valuable tool for the characterization of a broad spectrum of diseases. Thus, more efforts should be put into translating this promising technology into the clinics. PMID- 21547153 TI - Radiolabeled Cyclic RGD Peptides as Radiotracers for Imaging Tumors and Thrombosis by SPECT. AB - The integrin family is a group of transmembrane glycoprotein comprised of 19 alpha- and 8 beta-subunits that are expressed in 25 different alpha/beta heterodimeric combinations on the cell surface. Integrins play critical roles in many physiological processes, including cell attachment, proliferation, bone remodeling, and wound healing. Integrins also contribute to pathological events such as thrombosis, atherosclerosis, tumor invasion, angiogenesis and metastasis, infection by pathogenic microorganisms, and immune dysfunction. Among 25 members of the integrin family, the alpha(v)beta(3) is studied most extensively for its role of tumor growth, progression and angiogenesis. In contrast, the alpha(IIb)beta(3 )is expressed exclusively on platelets, facilitates the intercellular bidirectional signaling ("inside-out" and "outside-in") and allows the aggregation of platelets during vascular injury. The alpha(IIb)beta(3) plays an important role in thrombosis by its activation and binding to fibrinogen especially in arterial thrombosis due to the high blood flow rate. In the resting state, the alpha(IIb)beta(3) on platelets does not bind to fibrinogen; on activation, the conformation of platelet is altered and the binding sites of alpha(IIb)beta(3 )are exposed for fibrinogen to crosslink platelets. Over the last two decades, integrins have been proposed as the molecular targets for diagnosis and therapy of cancer, thrombosis and other diseases. Several excellent review articles have appeared recently to cover a broad range of topics related to the integrin-targeted radiotracers and their nuclear medicine applications in tumor imaging by single photon emission computed tomography (SPECT) or a positron emitting radionuclide for positron emission tomography (PET). This review will focus on recent developments of alpha(v)beta(3)-targeted radiotracers for imaging tumors and the use of alpha(IIb)beta(3)-targeted radiotracers for thrombosis imaging, and discuss different approaches to maximize the targeting capability of cyclic RGD peptides and improve the radiotracer excretion kinetics from non cancerous organs. Improvement of target uptake and target-to-background ratios is critically important for target-specific radiotracers. PMID- 21547156 TI - Multimodality Imaging of Integrin alpha(v)beta(3) Expression. AB - Over the last decade, integrin alpha(v)beta(3) has been studied with every single molecular imaging modality. Since no single modality is perfect and sufficient to obtain all the necessary information for a particular question, combination of certain molecular imaging modalities can offer synergistic advantages over any modality alone. This review will focus on multimodality imaging of integrin alpha(v)beta(3) expression, where the contrast agent used can be detected by two or more imaging modalities, such as combinations of PET and optical, SPECT and fluorescence, PET and MRI, SPECT and MRI, and lastly, MRI and fluorescence. Most of these agents are based on certain type(s) of nanoparticles. Contrast agents that can be detected by more than two imaging modalities are expected to emerge in the future and a PET/MRI/fluorescence agent will likely find the most future biomedical/clinical applications. Big strides have been made over the last decade for imaging integrin alpha(v)beta(3) expression and several PET/SPECT probes have been tested in human studies. For dualmodality and multimodality imaging applications, a number of proof-of-principle studies have been reported which opened up many new avenues for future research. The next decade will likely witness further growth and continued prosperity of molecular imaging studies focusing on integrin alpha(v)beta(3), which can eventually impact patient management. PMID- 21547157 TI - Integrin imaging to evaluate treatment response. AB - Despite the recent development of various radiolabelled RGD peptides for imaging the alphavbeta3 integrin receptor, relatively little attention has been focused on the ability of these radiotracers to monitor changes in tumour vascularity following treatment with anti-tumour therapies. Here we describe the favourable in vivo kinetics and tumour targeting properties of several novel radiolabeled RGD containing peptides that have the ability to monitor tumour vascularity non invasively in a variety of preclinical tumor models. These tracers may reveal important information when assessing the impact of anti-tumour therapies, in particular those that predominantly target tumour blood vessels. Consequently, these radiolabelled RGD targeting agents represent a useful approach to quantify tumor vasculature, and when used alone or in combination with additional functional imaging modalities, should enhance our mechanistic understanding of how novel therapeutic strategies impact upon tumors. PMID- 21547158 TI - Integrin targeted therapeutics. AB - Integrins are heterodimeric, transmembrane receptors that function as mechanosensors, adhesion molecules and signal transduction platforms in a multitude of biological processes. As such, integrins are central to the etiology and pathology of many disease states. Therefore, pharmacological inhibition of integrins is of great interest for the treatment and prevention of disease. In the last two decades several integrin-targeted drugs have made their way into clinical use, many others are in clinical trials and still more are showing promise as they advance through preclinical development. Herein, this review examines and evaluates the various drugs and compounds targeting integrins and the disease states in which they are implicated. PMID- 21547159 TI - Integrin targeted delivery of chemotherapeutics. AB - Targeted delivery of chemotherapeutics is defined in the sense, that is, to maximize the therapeutic index of a chemotherapeutic agent by strictly localizing its pharmacological activity to the site or tissue of action. Integrins are a family of heterodimeric transmembrane glycoproteins involved in a wide range of cell-to-extracellular matrix (ECM) and cell-to-cell interactions. As cell surface receptors, integrins readily interact with extracellular ligands and play a vital role in angiogenesis, leukocytes function and tumor development, which sets up integrins as an excellent target for chemotherapy treatment. The peptide ligands containing the arginine-glycine-aspartic acid (RGD), which displays a strong binding affinity and selectivity to integrins, particularly to integrin alphavbeta3, have been developed to conjugate with various conventional chemotherapeutic agents, such as small molecules, peptides and proteins, and nanoparticle-carried drugs for integtrin targeted therapeutic studies. This review highlights the recent advances in integrin targeted delivery of chemotherapeutic agents with emphasis on target of integrin alphavbeta3, and describes the considerations for the design of the diverse RGD peptide chemotherapeutics conjugates and their major applications. PMID- 21547160 TI - Integrin targeted delivery of radiotherapeutics. AB - Targeted radionuclide therapy, which is based on the selective delivery of a sufficient radiation dose to tumors without significantly affecting normal tissues, is a promising therapeutic approach for the treatment of a wide variety of malignancies. Integrins, a family of cell adhesion molecules, play key roles during tumor angiogenesis and metastasis. Among all the integrins, alphavbeta3 seems to be the most important in the process of tumor angiogenesis. Integrin alphavbeta3 is highly expressed on activated endothelial cells, new-born vessels as well as some tumor cells, but is not present in resting endothelial cells and most normal organ systems, making it a suitable target for anti-tumor therapy. In this review, we summarize the current development and applications of antibody-, peptide-, and other ligand-based integrin targeted radiotherapeutics for tumor radiation therapy. PMID- 21547162 TI - Evidence-based treatment of chronic leg ulcers. AB - BACKGROUND: Chronic leg ulcers are defined as those that show no tendency to heal after 3 months of appropriate treatment or are still not fully healed at 12 months. In this article, we present an approach to the challenging problem of chronic leg ulcers that is based on the principles of evidence-based medicine, i.e., the explicit use of the best available scientific evidence as a guide to treatment. METHODS: Selective review of the relevant literature, including current guidelines and meta-analyses, concerning diagnostic and therapeutic strategies for chronic leg ulcers. RESULTS: The main types of causally directed treatment are: vein surgery to eliminate pathological reflux, interventions to improve the circulation in arterial occlusive disease, and treatment of underlying diseases, such as diabetes mellitus. CONCLUSION: Physicians providing modern evidence-based management of chronic leg ulcers should make use of their own clinical experience in combination with the best current scientific evidence. It seems clear that the many available treatment options should be evaluated critically in an interdisciplinary setting. In particular, causally directed treatment must be provided in addition to symptomatic, stage-based local wound treatment. PMID- 21547161 TI - Integrin targeted delivery of gene therapeutics. AB - Integrins have become key targets for molecular imaging and for selective delivery of anti-cancer agents. Here we review recent work concerning the targeted delivery of antisense and siRNA oligonucleotides via integrins. A variety of approaches have been used to link oligonucleotides to ligands capable of binding integrins with high specificity and affinity. This includes direct chemical conjugation, incorporating oligonucleotides into lipoplexes, and use of various polymeric nanocarriers including dendrimers. The ligand-oligonucleotide conjugate or complex associates selectively with the integrin, followed by internalization into endosomes and trafficking through subcellular compartments. Escape of antisense or siRNA from the endosome to the cytosol and nucleus may come about through endogenous trafficking mechanisms, or because of membrane disrupting capabilities built into the conjugate or complex. Thus a variety of useful strategies are available for using integrins to enhance the pharmacological efficacy of therapeutic oligonucleotides. PMID- 21547163 TI - Carpal tunnel syndrome as an occupational disease. AB - BACKGROUND: Carpal tunnel syndrome (CTS) has been listed since 2003 in the European Union's list of occupational diseases. In 2001, it took sixth place in frequency among all occupational diseases recognized in the European Union. It was not listed as an occupational disease in Germany until July 2009, when the medical expert advisory panel of the German Federal Ministry of Labour and Social Affairs issued an evaluative paper supporting its listing. METHODS: We selectively reviewed the literature on the potential causation of CTS by occupational activities. RESULTS: Repetitive manual work tasks involving flexion and extension at the wrist, forceful grip with the hand, and/or vibrations of the hand and arm, such as are induced (for example) by hand-held vibrating tools, can damage the median nerve and cause CTS. A combination of these exposures has been found to raise the risk of CTS with a more than additive effect. Harmful exposures arise in a wide variety of occupations; in judging whether a particular case of CTS is of occupational origin, the physician has to consider the actual manual tasks performed by the patient, rather than merely the job title. Working at a computer keyboard seems not to raise the risk of CTS. CONCLUSION: The causation of CTS by occupational activities, either alone or in combination with other factors, has been well documented by epidemiological data and is pathophysiologically plausible. In Germany, a physician who diagnoses carpal tunnel syndrome in an employee with a relevant, damaging occupational exposure is required to report the case to the German Social Accident Insurance. PMID- 21547164 TI - Amniotic membrane transplantation in the human eye. AB - BACKGROUND: Amniotic membrane transplantation (AMT) has a long tradition in ophthalmic surgery and has become very popular recently because of newly developed methods of tissue preservation. METHODS: We selectively review the literature on recent developments, mechanisms of action, and established indications of AMT in the treatment of various diseases of the ocular surface. We searched the PubMed database for articles that appeared from 1994 to 2009 with the key words "amniotic membrane," "cornea," and/or "conjunctiva." RESULTS: Amniotic membrane (AM) can function in the eye as a basement membrane substitute or as a temporary graft. It has anti-inflammatory and anti-scarring effects and contains growth factors that promote epithelial wound healing on the surface of the eye. AMT has been found to be a good alternative for corneal and conjunctival reconstruction in many clinical situations, including acute burns, persistent epithelial defects of the cornea, and diseases that cause conjunctival scarring. Nonetheless, there have been no more than a few randomized and controlled trials of AMT to date. Other studies have shown that AM can serve as a culture substrate to expand epithelial progenitor cells for use in ocular surface reconstruction. CONCLUSION: AMT is an established technique in the treatment of various diseases of the external eye. In the last few years, AMT has brought about major advances in the reconstructive surgery of the ocular surface. PMID- 21547165 TI - Medical Tourism and New Delhi Metallo beta - Lactamase 1- A Concern and Threat. PMID- 21547166 TI - Clonidine in adults as a sedative agent in the intensive care unit. PMID- 21547167 TI - An overview of clinical research for anesthesiologists. PMID- 21547168 TI - PLMA vs. I-gel: A Comparative Evaluation of Respiratory Mechanics in Laparoscopic Cholecystectomy. AB - BACKGROUND: Supraglottic airway devices (SADs), such as ProSealTM laryngeal mask airway (PLMA), which produce high oropharyngeal seal pressure (OSP) and have the facility for gastric decompression have been used in laparoscopic procedures. i gel is a new SAD which shares these features with the PLMA. This study was designed to compare the respiratory mechanics of these two devices during positive pressure ventilation in anaesthetised adult patients undergoing laparoscopic cholecystectomy. PATIENTS #ENTITYSTARTX00026; METHODS: The study included 60 ASA I-II adult patients scheduled for laparoscopic cholecystectomy. The patients were randomized to two groups of 30 each, with either PLMA or i-gel as their airway device. Anaesthesia and premedication were standardized for both the groups. In addition to routine monitoring, neuromuscular monitoring with TOF ratio, OSP and respiratory mechanics monitoring (dynamic compliance, resistance, work of breathing, measured minute ventilation and peak airway pressures) were employed. Fibreoptic evaluation of positioning of the devices and adverse events related to them were also compared. RESULTS: The OSP (cm H2O) were higher for PLMA (38.9 vs. 35.6, P=0.007). The respiratory mechanics parameters using the two devices were comparable apart from the dynamic compliance, which was significantly higher with i-gel (P < 0.05). Malrotation was higher with i-gel than with PLMA (15 vs. 5, P = 0.006). CONCLUSION: The PLMA formed a better seal while the dynamic compliance was higher with the i-gel. Both devices provided optimal ventilation and oxygenation and the adverse events were also comparable. PMID- 21547169 TI - Effect of nalbuphine on haemodynamic response to orotracheal intubation. AB - BACKGROUND: Laryngoscopy and intubation are associated with increase in heart rate and mean blood pressure which are deleterious for patients especially with hypertension, ischaemic heart disease, raised intraocular and intracranial pressure. This study was undertaken with an objective to determine the efficacy of nalbuphine in preventing increase in heart rate and mean arterial pressure in response to laryngoscopy and orotracheal intubation. PATIENTS #ENTITYSTARTX00026; METHODS: A randomized controlled, prospective, double blinded study was undertaken on 60 patients ASA grade I and II posted for elective laparoscopy surgery to receive either saline (group I, control group, n=30) or Nalbuphine 0.2mg kg(-1)(group II, study group, n=30 ) as a bolus dose, 5 minutes before laryngoscopy. Heart rate and mean arterial pressure were taken 3 minute after study drug (T-1), just after intubation (T-2), then after every minute till 5 min (T3-7) and after 10 min of intubation (T-8). Twenty percent rise in heart rate and mean arterial pressure was considered as significant. Students 't' test was used for the analysis of data by using statistical software Medcal version 11.1.1.0. and P < 0.05 was considered significant. RESULTS: There was significant rise in heart rate(20.4%) in group I after intubation at T-2 compared with baseline at T-1 as compared to group II (16.66%). Mean arterial pressure showed rise of 12.35% in group I and 4.39% in group II at T-2 but was not significant. Heart rate and mean arterial pressure then gradually decreased from T3-8 but remained slightly higher than group II at 8th minute. CONCLUSION: We thus conclude that Nalbuphine 0.2 mg kg (-1)prevented a marked rise in heart rate and mean arterial pressure associated with laryngoscopy and orotracheal intubation. PMID- 21547171 TI - Prophylactic low dose ketamine and ondansetron for prevention of shivering during spinal anaesthesia. AB - BACKGROUND: Perioperative shivering is a common problem during anaesthesia. Apart from physical warming many drugs have also been used for prevention of shivering. Ketamine has been used for preventing shivering during anaesthesia in doses of 0.5 to 0.75mg kg(-1), but even these doses causes too much sedation and hallucination. Ondansetron (8 mg) has been recently evaluated for its perioperative antishivering effect in patients under anaethesia. Present study was conducted to evaluate the efficacy and safety of low dose Ketamine (0.25mg kg(-1)) and Ondansetron (4 mg) for prevention of shivering during spinal anaesthesia. PATIENTS #ENTITYSTARTX00026; METHODS: Total 120 patients undergoing lower abdominal surgery under spinal anaesthesia were included. 3ml of hyperbaric bupivacaine 0.5% was used for spinal anaesthesia. After intrathecal injection, the patients were randomly divided in 3 groups of 40 each who received Ketamine 0.25mg kg(-1)or Ondansetron 4mg IV or Saline. Vitals, temperature and shivering scores were recorded every 5 minutes. Side effects i.e. hypotension, nausea and vomiting, sedation and hallucinations were also recorded. RESULTS: Fall in temperature was more significant in saline and ondansetron group (gp) than in ketamine group at all time interval. Out of 40 patients, shivering was maximum & seen in 17 patients (42.50%) in saline gp, 4 patients (10%) in ondansetron gp and in only 1patient (2.5%) in ketamine gp. Odd ratio of ketamine, ondansetron and saline are 1, 4.33 and 28.33 respectively which means that shivering in saline gp was 28.83 times higher than ketamine gp and 6.65 times higher than in ondansetron .Shivering rate was 4.33 times higher in ondansetron gp than in ketamine gp. Hypotension was lowest in ketamine gp (10%) in comparison to ondansetron gp (22.5%) and saline gp. (20%). Mild sedation was seen in almost all (95%) patients in ketamine gp, CONCLUSION: Prophylactic low dose ketamine (0.25mg kg(-1)) and Ondansetron (4mg) significantly decreased shivering in patients undergoing spinal anaesthesia without significant side effects. PMID- 21547170 TI - A comparative study of two different doses of epidural neostigmine coadministered with lignocaine for post operative analgesia and sedation. AB - BACKGROUND: Adjuvants have been used to prolong analgesic effects of epidural local anaesthetics. We studied two different doses of neostigmine. PATIENTS #ENTITYSTARTX00026; METHODS: A randomized double blind study was conducted on ninety adult females scheduled for lower intra abdominal surgeries. The study was designed to compare two doses of epidural neostigmine co administered with lignocaine, with regard to its analgesic efficacy and its effect on sedation in postoperative period. Patients were divided into three groups of 30 each. Group I received lignocaine 1% (9ml) with normal saline (1ml), group II lignocaine1% (9ml) with neostigmine 100MUg in saline (1ml) and group III received lignocaine 1% (9ml) with neostigmine 200MUg in NS (1ml). Group I served as a control. In operating room, after putting epidural catheter, general anesthesia was administered with propofol (2mg kg(-1)), succinylcholine (2mg kg(-1)) and maintained with O2, N2O, relaxant technique. At the end of surgery, patients were reversed. Epidural analgesic medication was administered to after proper recovery from anesthesia. Intensity of pain relief on VAS, duration of analgesia, level of sensory block, motor blockade, sedation by sedation score and complications were assessed. RESULTS: The addition of neostigmine resulted in significant longer duration of analgesia (dose independent) and sedation (dose dependent). Sensory and motor blockade were identical in all three groups. There was no incidence of respiratory depression, pruritus, bradycardia or hypotension in any group. Two patients in control group and one, receiving neostigmine (200MUg), developed nausea/vomiting. CONCLUSION: Co administration of epidural neostigmine and lignocaine appears to be a useful technique for postoperative analgesia as it increases the duration of analgesia and provides desirable sedation at the same time. PMID- 21547172 TI - Effect of Supplementing Oxygen with Positive end Expiratory Pressure During Elective Caesarean Section under Spinal Anaesthesia on Foetus. AB - BACKGROUND: It is known fact that pre-oxygenation with positive end-expiratory pressure (PEEP) improves the Partial pressure of oxygen (PO (2)). In this regard not many studies have been done in pregnant women to know its effect on foetus. In this randomised double blind controlled study, we analysed effect of pre oxygenation with PEEP during caesarean section on foetal umbilical venous PO (2). PATIENTS #ENTITYSTARTX00026; METHODS: 40 term pregnant women, ASA I or II, undergoing elective Caesarean section under spinal anaes-thesia were randomly divided into PEEP and Non-PEEP groups of 20 each. PEEP group received oxygen flow of 6 L/minute with PEEP of 5 cmH (2)O using a modified Mapleson A circuit with fixed unidirectional PEEP valve at the expiratory port during pre-oxygenation and Non PEEP group received same fresh gas flow of oxygen using same breathing circuit without PEEP. Maternal arterial blood samples were collected before applying PEEP and at the end of 5 minutes of facemask application for oxygen analysis. Immediately after baby was delivered umbilical venous samples were taken for blood gas analysis. RESULTS: Both groups were comparable in terms of maternal baseline oxygen saturation (Spo (2)) and base line Po (2). After 5 minutes PO (2)was higher in PEEP Group than non PEEP group (491.65 + 49.96 vs. 452.08 + 77.61). Umbilical venous Po (2)in PEEP group was higher than non PEEP group (34.22 + 6.50 vs. 28.29 + 6.10 mm of Hg). CONCLUSION: Application of PEEP during pre-oxygenation for spinal anaesthesia can increase foetal umbilical venous PO(2). PMID- 21547173 TI - Respiratory changes during spinal anaesthesia for gynaecological laparoscopic surgery. AB - BACKGROUND: It is currently presumed that spinal anaesthesia can compromise respiratory muscle function during carbon dioxide (CO2) pneumoperitoneum. This observational study was designed to delineate the respiratory effects of CO2 pneumoperitoneum under spinal anaesthesia. PATIENTS #ENTITYSTARTX00026; METHODS: Forty one patients undergoing elective gynecological laparoscopy were administered spinal anaesthesia with 15 mg heavy bupivacaine and 50 mcg of fentanyl. Heart rare, blood pressure, tidal volume, respiratory rate and end tidal CO2 were serially recorded before, during and after the pneumoperitoneum. Arterial blood gas analysis was done before and 20 min after initiation of pneumoperitoneum. RESULTS: The mean heart rate and blood pressure decreased by less than 20% of the preoperative value. The mean tidal volume decreased from 353 +/- 81(Standard Deviation) to 299+/-95 ml, p = 0.032, over the first 9 min after the pneumoperitoneum with a complete recovery towards the base line, 340 +/- 72 ml, within 30 min during the surgery. The maximal inspiratory capacity declined from 1308+/-324 ml to 1067+/-296 ml at 20 min and recovered to 1187+/-267 ml, 5min after decompression. There was no observed change in the respiratory rate. Similarly, increase in the end tidal CO2 from 31.68+/-4.13 to 37.62+/-4.21 mmHg, p = 0.000, reached a plateau around 15 min and declined after decompression. Arterial carbon dioxide showed a corresponding increase at 20 min without change in arterial to end tidal CO2 difference. All observed changes were within the physiological limits. CONCLUSION: In a conscious patient undergoing laparoscopy with pneumoperitoneum, under spinal anaesthesia, the preserved inspiratory diaphragmatic activity maintains ventilation and, the gas exchange within physiological limits. Hence it is a safe alternative to general anaesthesia. PMID- 21547174 TI - A comparative study between palonosetron and granisetron to prevent postoperative nausea and vomiting after laparoscopic cholecystectomy. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is commonly seen after laparoscopic surgery. In this randomized double blind prospective clinical study, we investigated and compared the efficacy of palonosetron and granisetron to prevent postoperative nausea and vomiting after laparoscopic cholecystectomy. PATIENTS #ENTITYSTARTX00026; METHODS: Sixty female patients (18-65 yrs of age) undergoing elective laparoscopic cholecystectomy were randomly allocated one of the two groups containing 30 patients each. Group P received palonosetron 75 MUg intravenously as a bolus before induction of anaesthesia. Group G received granisetron 2.5 mg intravenously as a bolus before induction. RESULTS: The incidence of a complete response (no PONV, no rescue medication) during 0-3 hour in the postoperative period was 86.6% with granisetron and 90% with palonosetron, the incidence during 3-24 hour postoperatively was 83.3% with granisetron and 90% with palonosetron. During 24-48 hour, the incidence was 66.6% and 90% respectively (p<0.05). The incidence of adverse effects were statistically insignificant between the groups. CONCLUSION: Prophylactic therapy with palonosetron is more effective than granisetron for long term prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. PMID- 21547175 TI - A Comparative Study of Induction, Maintenance and Recovery Characteristics of Sevoflurane and Halothane Anaesthesia in Pediatric Patients (6 months to 6 years). AB - PATIENTS #ENTITYSTARTX00026; METHODS: In a randomized , double blind clinical study, we studied 30 children, aged 6 months to 6 years, to compare halothane and sevoflurane anaesthesia in patients undergoing short surgical procedures under general anaesthesia. All the patients were premedicated with atropine 0.02mg kg( 1)and midazolam 0.1mg kg(-1)body weight intravenously and received inhalation induction using nitrous oxide in oxygen supplemented with either halothane (maximum inspired concentration of 5%) or sevoflurane (maximum inspired concentration of 8%). Induction was by inhalation of increasing concentrations of sevoflurane (1%) or halothane (0.5%) in the vaporizing setting after every three breaths of the patient. RESULTS: Time to loss of eyelash reflex and tracheal intubation was more rapid using sevoflurane. Cardiac arrhythmias were significantly more frequent during halothane than sevoflurane anaesthesia. Psychomotor recovery was more rapid after sevoflurane anaesthesia. Children who received sevoflurane had comparatively less nausea and vomiting and the incidence of clinically important side effects was significantly less with sevoflurane anaesthesia. CONCLUSION: We conclude that induction with sevoflurane in nitrous oxide and oxygen leads to fast loss of consciousness and provides ideal conditions for managing the airway without supplemental opioids or muscle relaxants with haemodynamic stability and is therefore a reasonable alternative to halothane for paediatric patients. PMID- 21547176 TI - Comparative study of intrathecal sufentanil bupivacaine versus intrathecal bupivacaine in patients undergoing elective cesarean section. AB - BACKGROUND: Sufentanil added to intrathecal bupivacaine for cesarean section has shown to improve intraoperative and postoperative analgesia with no adverse effects on the mother and neonate. We compared the effects of intrathecal sufentanil 5 mcg and placebo when administered with hyperbaric bupivacaine 0.5% 11 mg for cesarean section. PATIENTS AND METHODS: Sixty parturients of ASA grading I and II of age between 18 to 45 years scheduled for elective cesarean section under subarachnoid block were randomly allocated into one of the two groups to receive 5MUg sufentanil + 0.2ml sterile, preservative- free normal saline (Group S) and 0.3ml sterile, preservative-free normal saline (Group C) along with 2.2ml 0.5% hyperbaric bupivacaine making total volume to 2.5 ml. RESULTS: The two groups were compared with respect to their sensory and motor block characteristics, duration of analgesia, intraoperative haemodynamic changes, adverse effects and effect on neonatal Apgar score. Postoperative pain was assessed using the visual analog scale (VAS). Duration of analgesia was defined as the time taken for a VAS score of 4 to be achieved. Mean duration of analgesia was significantly prolonged in sufentanil group (184.0 + 51.50 minutes) than the control group (107.0 +/- 46.40 minutes). There is faster onset of sensory and motor block in the sufentanil group. The incidences of bradycardia and hypotensive episodes were similar in the two groups. There was no evidence of respiratory depression in any of the patients in any groups. Pruritus was observed in 6 (20.0%) patients in Group S which was statistically significant. There was no significant effect on Apgar score of the neonate. CONCLUSION: Thus the addition of Sufentanil (5 mcg) intrathecally provides improved postoperative analgesia and haemodynamic stability with minimal side effects. PMID- 21547177 TI - Comparison of intubating conditions of rocuronium bromide and vecuronium bromide with succinylcholine using "timing principle". AB - BACKGROUND: Rapid and safe endotracheal intubation is of paramount importance in general anaesthesia. The aim of this study was to compare the intubating conditions of succinylcholine with rocuronium bromide and vecuronium bromide using "Timing principle". The timing principle entails administration of a single bolus dose of nondepolarizing muscle relaxant, followed by an induction drug at the onset of clinical weakness. PATIENTS #ENTITYSTARTX00026; METHODS: 75 patients were divided into three groups of 25 each. Patients allocated to Groups A and B received rocuronium 0.6 mg kg(-1) and vecuronium 0.12 mg kg(-1) respectively. At the onset of clinical weakness (ptosis), anesthesia was induced with propofol 2.5 mg kg(-1); intubation was accomplished after 60 seconds of induction agent in both groups. Patients in Group C received propofol 2.5mg kg(-1) followed by succinylcholine 2mg kg(-1) and their tracheas were intubated at 60s.Train of four count was assessed at adductor pollicis muscle using nerve stimulator at intubation and time to loss of TOF was observed. in group A and B. Intubating conditions were assessed according to a grading scale and haemodynamic variables were compared at 1,3 and 5 minutes after intubation. RESULTS: Intubating conditions were either excellent(84% in group A,48% in group B and 88% in group C) or good (16% in group A, 48% in group B and 12 %in group C)and only 4% pt had poor intubating conditions in group B. Patients were interviewed postoperatively, and all were satisfied with the technique of induction of anesthesia.Rocuronium and Vecuronium are haemodynamically stable drugs as compared to Succinylcholine. CONCLUSION: Rocuronium 0.6 mg kg(-1) provides good to excellent intubating conditions at 60 s comparable to succinylcholine after the induction of anesthesia using the timing principle. PMID- 21547178 TI - Midline Submental Orotracheal Intubation in Maxillofacial Injuries: A Substitute to Tracheostomy Where Postoperative Mechanical Ventilation is not Required. AB - BACKGROUND: Maxillofacial fractures present unique airway problems to the anaesthesiologist. Nasotracheal intubation is contraindicated due to associated Lefort I, II or III fractures. The requirement for intraoperative maxillomandibular fixation (MMF) to re-establish dental occlusion in such cases precludes orotracheal intubation. Tracheostomy has a high complication rate and in many patients, an alternative to the oral airway is not required beyond the perioperative period. Hernandez1 in 1986 first described "The submental route for endotracheal intubation". Later some workers faced difficult tube passage, bleeding, and sublingual gland involvement with this approach. They modified this to strict midline submental intubation and there were no operative or postoperative complications in their cases.67&8. Therefore we used mid line approach for submental orotracheal intubation in this study to demonstrate its feasibility and reliability and that it can be used as an excellent substitute to short term tracheostomy. PATIENTS #ENTITYSTARTX00026; METHODS: We used midline submental intubation in 25 cases selected out of 310 consecutively treated patients with maxillofacial trauma over a 3 year period. After induction orotracheal intubation was done with spiral re-inforced tube. A 1.5-2.0 cm skin incision was made in the submental region in the midline 2.0 cm behind the symphysis and endotracheal tube was taken out through this incision in all the cases. At the end of the surgery the procedure was reversed, the submental wound was stitched; all the patients could be extubated & none of them required post operative mechanical ventilation. CONCLUSION: There were no significant operative or postoperative complications. Postoperative submental scarring was acceptable([6]). We conclude that midline submental intubation is a simple and useful technique with low morbidity. It can be chosen in selected cases of maxillofacial trauma and is an excellent substitute to tracheostomy where postoperative mechanical ventilation is not required. PMID- 21547179 TI - Effect of midazolam premedication on the dose of propofol for laryngeal mask airway insertion in children. AB - BACKGROUND: The present study was conducted on 120 pediatric patients of ASA Grade I and II of either sex aged 3-12 years scheduled for pediatric surgeries under general anaesthesia. PATIENTS #ENTITYSTARTX00026; METHODS: All patients were randomly divided into Group A and Group B. Group A was further divided into 3 subgroups of unpremedicated patients who received 3, 4 and 5 mg kg (-1) propofol only designated as A1, A2 and A3 respectively. Group B was further divided into subgroups of premedicated patients with midazolam (0.05 mg kg (-1) ) intravenous and received 3, 4 and 5 mg kg (-1) propofol designated as B1, B2 and B3 respectively. RESULTS: Results showed that increasing dose of propofol decreases the adverse events like inadequate jaw relaxation, limb movements, coughing, gagging and laryngospasm. Midazolam when added to propofol further reduces the incidence of adverse events and provides more favorable environment for insertion of LMA. At higher doses of propofol (5 mg kg (-1) ), hypotension is a major problem due to its cardiovascular depressant action. Therefore, 4 mg kg ( 1) propofol along with midazolam is the optimum dose because there is more hemodynamic stability and we get better conditions for LMA insertion. CONCLUSION: Midazolam is an effective premedication in children which is synergistic with propofol and reduces its effective dose, required for LMA insertion. PMID- 21547180 TI - Intrathecal sufentanil versus fentanyl for lower limb surgeries - a randomized controlled trial. AB - BACKGROUND: To compare the efficacy and safety of intrathecal sufentanil or fentanyl as adjuvants to hyperbaric bupivacaine in patients undergoing major orthopaedic lower limb surgeries in terms of onset and duration of sensory block, motor block and post-operative pain relief. PATIENTS #ENTITYSTARTX00026; METHODS: Ninety patients were recruited in this Prospective, randomized double blind study to receive either intrathecal sufentanil 5 MUg (Group S), fentanyl 25 MUg (Group F) or normal saline 0.5 ml (Group C) as adjuvants to 15 mg of 0.5% hyperbaric bupivacaine. The onset and duration of sensory and motor block were assessed intraoperatively. The pain scores were assessed postoperatively. Duration of complete and effective analgesia was recorded. The incidence of side effects such as nausea, vomiting, pruritus, shivering and PDPH was recorded. RESULTS: The Demographic data, hemodynamic and respiratory parameters were comparable in the three groups. There was a significantly earlier onset and prolonged duration of sensory block in the sufentanil and fentanyl groups. The duration of complete and effective analgesia were also significantly prolonged in the fentanyl and sufentanil groups. Pruritus was noticed in the study groups (Groups S&F). CONCLUSIONS: Intrathecal sufentanil (5 MUg) and fentanyl (25 MUg), as adjuvants lead to an earlier onset and prolonged duration of sensory block. The duration of effective analgesia with intrathecal sufentanil and fentanyl as adjuvants to hyperbaric bupivacaine is longer than that of bupivacaine alone. PMID- 21547181 TI - Is fibreoptic percutaneous tracheostomy in ICU a breakthrough. AB - BACKGROUND: In ICUs, bedside percutaneous tracheostomy (pct) is commonly performed, but it is associated with certain drawbacks as paratracheal placement, posterior tracheal wall injury and tracheoesophageal fistula. To address these fibreoptic bronchoscope (FOB) guided PCT was introduced. We aimed to compare both these methods. PATIENTS #ENTITYSTARTX00026; METHODS: We compared 60 age & sex matched patients into two groups of 30 each. In group 1 tracheostomy was performed by the conventional Ciaglia's method. In group 2, a fibreoptic bronchoscope was used in addition with the aid of an assistant. RESULTS: The fiberoptic method took more time than the conventional method. (18+/-3min vs 15+/ 2min (p=0.001)). The average no. of attempts at insertion of needle was 2.4 in group 1 and 1.2 in group 2 (p=0.001). The fall in SpO2 to <90% was seen in 1 patient in group 1 and in 6 patients in group 2, so much so that the procedure had to be abandoned in 2 patients. CONCLUSION: FOB though definitely advantageous over CPCT in terms of lesser complications and being highly useful in the obese, short necked, and those with scar marks, is not without drawbacks such as requirement of additional staff and increased expenditure. The main being inability to be used in patients with low respiratory reserve. Overall it would be complimentary for any ICU to have FOB facility and must be used in select group of patients. PMID- 21547182 TI - Methylene blue: revisited. PMID- 21547183 TI - A clinical study comparing epinephrine 200MUg or clonidine 90MUg as adjuvants to local anaesthetic agent in brachial plexus block via supraclavicular approach. AB - BACKGROUND: A double blind randomized prospective study was undertaken to determine the effect of adjuncts like epinephrine 200MUg or clonidine 90MUg in combination of bupivacaine and lignocaine into the brachial plexus sheath to study the sensory and motor onset, duration of analgesia, hemodynamic changes and adverse effects. PATIENTS #ENTITYSTARTX00026; METHODS: 60 patients aged 18-65 years, with ASA grade I and II were randomly divided into group I and group II to receive 10 ml of lignocaine2% and 20 ml of bupivacaine0.5% with 1ml of 200MUg epinephrine or 90MUg clonidine respectively. Onset of sensory blockade was determined by pinprick method by a three point score and motor blockade by three point scale. Duration of postoperative analgesia, the hemodynamic changes, sedation scores and any adverse effects were observed. Statistical analysis was done by student's "t" test and p<0.05 was considered significant. RESULTS: It was found that there was faster onset of sensory and motor blockade, the postoperative analgesia was prolonged and the amount of sedation was profound in group II as compared to group I. All the above findings were statistically significant. CONCLUSION: We thereby conclude that clonidine 90MUg is a better option as an additive than epinephrine 200MUg for hastening the onset of sensory and motor block with prolonged postoperative analgesia and sedation as the only adverse effect. PMID- 21547184 TI - Palpatory method of measuring diastolic blood pressure. AB - BACKGROUND: Most common method for measuring blood pressure is palpatory but only systolic pressure can be measured with this method. In this study we are describing palpatory method of measuring diastolic blood pressure as well. PATIENTS #ENTITYSTARTX00026; METHODS: We have studied in 200 patients and compared systolic as well as diastolic blood pressures with two methods, auscutatory and palpatory. Systolic and diastolic blood pressure were measured by one of the authors with new palpatory method and noted down. Then an independent observer, who was blinded to the palpatory method's values, measured blood pressure by auscultatory method and noted down. The values were compared in term of range and percentage. RESULTS: The difference were analysed and found that 102 (51%) patients had systolic and diastolic blood pressure measured by palpatory method, within +/- 2 mmHg of auscutatory method, 37 (19%) patients had within +/- 4 mmHg, 52 (25%) patients had same readings as with auscutatory method, and in 9 (0.5%) patients it could not be measured. CONCLUSION: The palpatory method would be very useful where frequent blood pressure measurement are being done manually like in wards, in busy OPD, patient on treadmill and also whenever stethoscope is not available. The blood pressure can be measured in noisy environment too. PMID- 21547185 TI - "Protective premedication": a comparative study of acetaminophen, gabapentin and combination of acetaminophen with gabapentin for post-operative analgesia. AB - BACKGROUND: We carried out a study to evaluate the effects of protective premedication with Acetaminophen, Gabapentin and combination of Acetaminophen with Gabapentin on post-operative analgesia in patients undergoing open cholecys tectomy under general anesthesia. PATIENTS #ENTITYSTARTX00026; METHODS: The study was conducted in a double-blind randomized and controlled manner in 120 consenting patients of either sex belonging to ASA physical status grade I and II, between the age groups of 20 to 50 years, weighing between 40 to 65 kg and undergoing elective surgery (open cholecystectomy) under general anesthesia. The patients were divided into 4 groups: 1: placebo, 2: Acetaminophen 1000 mg, 3: 1200 mg Gabapentin, 4: Acetaminphen 1000 mg plus 1200 mg Gabapentin. The drugs were given two hours before induction. Time, number and total amount of rescue analgesic (tramadol) and VAS score at rest and on movement. Side effects like any episode of nausea/vomiting and level of sedation were noted. RESULTS: Premedication with antihyperalgesic and analgesic agents helps to decrease postoperative pain scores. Gabapentin premedication is effective for providing better postoperative pain relief with lower and delayed requirements of rescue analgesics, but causes more episodes of nausea and vomiting and higher levels of sedation. PMID- 21547186 TI - Tube migration during laparoscopic gynecological surgery. AB - BACKGROUND: The positioning (trendelenburg) and pneumoperitoneum during laparoscopic gynecological surgeries may cause cephalad movement of diaphragm and subsequent endobronchial intubation. PATIENTS #ENTITYSTARTX00026; METHODS: 50 ASA I/II patients posted for laparoscopic ligation were included in the study. Standardized anaesthesia technique was employed in all the patients. The distance of endotracheal tube to carina was measured in supine position, trendelenberg position, 5 min and 25 minutes post pneumoperitoneum and after deflation of pneumo-peritoneum. RESULTS: The mean distance from the tip of the ETT to the carina was 3.41+/- 1.3 cm, 2.96 +/- 1.4, 2.0 +/- 1.5 and 1.7 +/- 1.6 in supine position, trendelenburg position and 5min and 25 min post pneumoperitoneum. (P<0.01) Following deflation the carina moved back to its position to some extent and was 2.5 +/- 1.5 from the tip of endotracheal tube.( P< 0.05) CONCLUSION: We conclude that pneumoperitoneum and trendelenburg position during laparoscopic surgeries may lead to cephalad migration of carina. PMID- 21547187 TI - Non Cardiac Surgery in a Patient with Eisenmenger Syndrome-Anaesthesiologist's Challenge. PMID- 21547188 TI - Anaesthetic management of emergency cesarean section in a patient with holt oram syndrome. PMID- 21547189 TI - Fat embolism syndrome from subtle to full blown presentation. PMID- 21547190 TI - Stiff man syndrome and anaesthetic considerations: successful management using combined spinal epidural anaesthesia. PMID- 21547191 TI - Fat embolism syndrome presenting as sudden loss of consciousness. PMID- 21547192 TI - Tourniquet failure during total knee replacement due to femoral arterial calcification. PMID- 21547193 TI - Anaesthetic considerations in a patient with von recklinghausen neurofibromatosis. PMID- 21547194 TI - Anaesthetic management of a patient with sarcoidosis presenting for mastectomy. PMID- 21547195 TI - Use of glidescope and external manipulation in airway management of an unusual retropharyngeal lipoma. PMID- 21547196 TI - Inadvertent injection of piperacillin - tazobactum into epidural space. PMID- 21547197 TI - General anaesthesia for caeserean section in a patient with moyamoya disease. PMID- 21547198 TI - Imaging for central venous cannulation: A necessity rather than luxury. PMID- 21547199 TI - Use of Ropivacaine intrathecally. PMID- 21547200 TI - Particulate contamination in intravenous drugs: coring from syringe plunger. PMID- 21547201 TI - Unilateral subarachnoid block for ankle arthrodesis in patient on long term amiodarone therapy. PMID- 21547202 TI - Fentanyl induced rigidity in an infant. PMID- 21547203 TI - Airway management of huge cervical teratoma. PMID- 21547204 TI - Intra-operative ventricular bigeminy: can retractor be a cause. PMID- 21547205 TI - Anaesthetic management in a child with frontonasal encephalocele. PMID- 21547206 TI - Mallampati Class Zero Airway in a 5-yr-old Child. PMID- 21547207 TI - Aggravated Spinal Cord Compression following Electroconvulsive Therapy. PMID- 21547208 TI - Mitochondria, Amyloid beta, and Alzheimer's Disease. AB - Hypometabolism is a hallmark of Alzheimer's disease (AD) and implicates a mitochondrial role in the neuropathology associated with AD. Mitochondrial amyloid-beta (Abeta) accumulation precedes extracellular Abeta deposition. In addition to increasing oxidative stress, Abeta has been shown to directly inhibit mitochondrial enzymes. Inhibition of mitochondrial enzymes as a result of oxidative damage or Abeta interaction perpetuates oxidative stress and leads to a hypometabolic state. Additionally, Abeta has also been shown to interact with cyclophilin D, a component of the mitochondrial permeability transition pore, which may promote cell death. Therefore, ample evidence exists indicating that the mitochondrion plays a vital role in the pathophysiology observed in AD. PMID- 21547209 TI - Perspectives on the History of Bovine TB and the Role of Tuberculin in Bovine TB Eradication. AB - Tuberculosis remains a significant disease of animals and humans worldwide. Bovine tuberculosis is caused by Mycobacteria with an extremely wide host range and serious, although currently probably underdiagnosed, zoonotic potential. Where bovine tuberculosis controls are effective, human zoonotic TB, due to Mycobacterium bovis or M. caprae, is uncommon and clinical cases are infrequent in cattle. Therefore, the control and ultimate eradication of bovine tuberculosis is desirable. Tuberculin tests are the primary screening tool used in bovine eradication. The choice of tuberculin test is dependent on the environment in which it is to be used. Tuberculin potency is critical to test performance, and the accurate determination of potency is therefore particularly important. The design of a control or eradication programme should take into consideration the fundamental scientific knowledge, the epidemiological profile of disease, the experience of other eradication programmes, and the presence, in the same ecosystem, of maintenance hosts, in which infection is self-sustaining and which are capable of transmitting infection. A control or eradication programme will necessarily require modification as it progresses and must be under constant review to identify the optimal desirable goals, the efficacy of policy, and constraints to progress. PMID- 21547210 TI - Metastatic malignant melanoma presenting as an appendiceal mucocele. AB - Melanoma metastatic to the appendix is extremely rare. Here we describe a case of a 31-year-old female from Bolivia with a remote history of metastatic malignant melanoma first diagnosed as a cutaneous malignant melanoma ten years prior to this presentation. The patient was being followed for a mucocele which on resection was found to be metastatic melanoma. "Mucocele" is a generic diagnosis that warrants further characterization and treatment. PMID- 21547211 TI - Use of bayesian inference to correlate in vitro embryo production and in vivo fertility in zebu bulls. AB - The objective of this experiment was to test in vitro embryo production (IVP) as a tool to estimate fertility performance in zebu bulls using Bayesian inference statistics. Oocytes were matured and fertilized in vitro using sperm cells from three different Zebu bulls (V, T, and G). The three bulls presented similar results with regard to pronuclear formation and blastocyst formation rates. However, the cleavage rates were different between bulls. The estimated conception rates based on combined data of cleavage and blastocyst formation were very similar to the true conception rates observed for the same bulls after a fixed-time artificial insemination program. Moreover, even when we used cleavage rate data only or blastocyst formation data only, the estimated conception rates were still close to the true conception rates. We conclude that Bayesian inference is an effective statistical procedure to estimate in vivo bull fertility using data from IVP. PMID- 21547212 TI - Unilateral pulmonary artery aplasia in a pregnant patient. AB - Unilateral pulmonary artery aplasia is a rare anomaly. Case reports of this condition in pregnant patients are even more uncommon and the best approach to management of such patients is still unclear. We report a patient who presented with a history of dyspnea, chest pain, and hemoptysis. Imaging established the diagnosis in a newly pregnant female. Management of the pulmonary artery aplasia patient in pregnancy requires prospective evaluation of pulmonary hypertension. PMID- 21547214 TI - Rhizomucor and scedosporium infection post hematopoietic stem-cell transplant. AB - Hematopoietic stem-cell transplant recipients are at increased risk of developing invasive fungal infections. This is a major cause of morbidity and mortality. We report a case of a 17-year-old male patient diagnosed with severe idiopathic acquired aplastic anemia who developed fungal pneumonitis due to Rhizomucor sp. and rhinoencephalitis due to Scedosporium apiospermum 6 and 8 months after undergoing allogeneic hematopoietic stem-cell transplant from an HLA-matched unrelated donor. Discussion highlights risk factors for invasive fungal infections (i.e., mucormycosis and scedosporiosis), its clinical features, and the factors that must be taken into account to successfully treat them (early diagnosis, correction of predisposing factors, aggressive surgical debridement, and antifungal and adjunctive therapies). PMID- 21547213 TI - Impacts of membrane biophysics in Alzheimer's disease: from amyloid precursor protein processing to abeta Peptide-induced membrane changes. AB - An increasing amount of evidence supports the notion that cytotoxic effects of amyloid-beta peptide (Abeta), the main constituent of senile plaques in Alzheimer's disease (AD), are strongly associated with its ability to interact with membranes of neurons and other cerebral cells. Abeta is derived from amyloidogenic cleavage of amyloid precursor protein (AbetaPP) by beta- and gamma secretase. In the nonamyloidogenic pathway, AbetaPP is cleaved by alpha secretases. These two pathways compete with each other, and enhancing the non amyloidogenic pathway has been suggested as a potential pharmacological approach for the treatment of AD. Since AbetaPP, alpha-, beta-, and gamma-secretases are membrane-associated proteins, AbetaPP processing and Abeta production can be affected by the membrane composition and properties. There is evidence that membrane composition and properties, in turn, play a critical role in Abeta cytotoxicity associated with its conformational changes and aggregation into oligomers and fibrils. Understanding the mechanisms leading to changes in a membrane's biophysical properties and how they affect AbetaPP processing and Abeta toxicity should prove to provide new therapeutic strategies for prevention and treatment of AD. PMID- 21547216 TI - Direction of Information Flow in Alzheimer's Disease and MCI Patients. AB - Is directionality of electroencephalographic (EEG) synchronization abnormal in amnesic mild cognitive impairment (MCI) and Alzheimer's disease (AD)? And, do cerebrovascular and AD lesions represent additive factors in the development of MCI as a putative preclinical stage of AD? Here we reported two studies that tested these hypotheses. EEG data were recorded in normal elderly (Nold), amnesic MCI, and mild AD subjects at rest condition (closed eyes). Direction of information flow within EEG electrode pairs was performed by directed transfer function (DTF) at delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-12 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). Parieto-to-frontal direction was stronger in Nold than in MCI and/or AD subjects for alpha and beta rhythms. In contrast, the directional flow within interhemispheric EEG functional coupling did not discriminate among the groups. More interestingly, this coupling was higher at theta, alpha1, alpha2, and beta1 in MCI with higher than in MCI with lower vascular load. These results suggest that directionality of parieto-to frontal EEG synchronization is abnormal not only in AD but also in amnesic MCI, supporting the additive model according to which MCI state would result from the combination of cerebrovascular and neurodegenerative lesions. PMID- 21547215 TI - Oxidative stress in lead and cadmium toxicity and its amelioration. AB - Oxidative stress has been implicated to play a role, at least in part, in pathogenesis of many disease conditions and toxicities in animals. Overproduction of reactive oxygen species and free radicals beyond the cells intrinsic capacity to neutralize following xenobiotics exposure leads to a state of oxidative stress and resultant damages of lipids, protein, and DNA. Lead and cadmium are the common environmental heavy metal pollutants and have widespread distribution. Both natural and anthropogenic sources including mining, smelting, and other industrial processes are responsible for human and animal exposure. These pollutants, many a times, are copollutants leading to concurrent exposure to living beings and resultant synergistic deleterious health effects. Several mechanisms have been explained for the damaging effects on the body system. Of late, oxidative stress has been implicated in the pathogenesis of the lead- and cadmium-induced pathotoxicity. Several ameliorative measures to counteract the oxidative damage to the body system aftermath or during exposure to these toxicants have been assessed with the use of antioxidants. The present review focuses on mechanism of lead- and cadmium-induced oxidate damages and the ameliorative measures to counteract the oxidative damage and pathotoxicity with the use of supplemented antioxidants for their beneficial effects. PMID- 21547217 TI - Combined venlafaxine and olanzapine prescription in women with psychotic major depression: a case series. AB - Patients with psychotic major depression suffer prolonged duration and greater severity of illness, including an increased likelihood of recurrent episodes and resistance to conventional pharmacotherapies. They do not respond to placebo and respond poorly to antidepressant or antipsychotic monotherapy. On the other hand, as has been demonstrated, they do respond well to antidepressant and antipsychotic combination therapies. Different combinations of drugs were studied, but little is known up to now with regard to the combination of venlafaxine and olanzapine. The following paper presents three separate case studies of female patients suffering from psychotic unipolar major depression, all of whom were admitted to a psychiatric ward and successfully treated with a combination of venlafaxine and olanzapine. PMID- 21547218 TI - Usefulness and limitation of ultrasonography in the diagnosis of intestinal intussusception in cows. AB - The present study was conducted on 6 chronically ill Jersey/Red Sindhi cross-bred cows, which were suspected for intestinal obstruction on the basis of history and clinical signs. These cows were ultimately diagnosed with intestinal intussusception based on a combination of clinical, ultrasonographic and surgical examinations. "Bull's eye lesion" was the most prominent ultrasonographic finding, diagnostic for intussusception either trans-abdominally or transrectally. Dilated intestinal loops greater than 3.1 cm (mean +/- SE, 4.41 +/ 0.25) were imaged in the lower flank and the 12th intercostal space on the right side. Ultrasonography proved to be a useful tool in supplementing and substantiating the transrectal findings in cases of the bovine intestinal intussusception. However, ultrasonography was not significantly helpful where transrectal examination of the cows did not reveal any suspected intestinal mass. PMID- 21547219 TI - The Role of GSK3 in Presynaptic Function. AB - The past ten years of research have identified a number of key roles for glycogen synthase kinase 3 (GSK3) at the synapse. In terms of presynaptic physiology, critical roles for GSK3 have been revealed in the growth and maturation of the nerve terminal and more recently a key role in the control of activity-dependent bulk endocytosis of synaptic vesicles. This paper will summarise the major roles assigned to GSK3 in both immature and mature nerve terminals, the substrates GSK3 phosphorylates to exert its action, and how GSK3 activity is regulated by different presynaptic signalling cascades. The number of essential roles for GSK3, coupled with the numerous signalling cascades all converging to regulate its activity, suggests that GSK3 is a key integrator of multiple inputs to modulate the strength of neurotransmission. Modulation of these pathways may point to potential mechanisms to overcome synaptic failure in neurodegenerative disorders such as Alzheimer's disease. PMID- 21547220 TI - Frequency of Detection of Escherichia coli, Salmonella spp., and Campylobacter spp. in the Faeces of Wild Rats (Rattus spp.) in Trinidad and Tobago. AB - The study was conducted to determine the frequency of isolation of Salmonella, Campylobacter and E. coli O157 in the faecal samples of rats trapped across the regional corporations in Trinidad and to assess their resistance to antimicrobial agents. A total of 204 rats were trapped for the detection of selected bacteria. Standard methods were used to isolate Salmonella, Campylobacter and E. coli O157. Characterization of E. coli was done on sorbitol MacConkey agar to determine non sorbitol fermentation, blood agar to determine haemolytic and mucoid colonies and by using E. coli O157 antiserum to determine O157 strain. The disc diffusion method was used to determine resistance to nine antimicrobial agents. Of the 204 rats, 4 (2.0%), 7 (3.4%) and 171 (83.8%) were positive for Salmonella spp., Campylobacter spp. and E. coli, respectively. Of the 171 isolates of E. coli tested 0 (0.0%), 25 (14.6%) and 19 (11.1%) were haemolytic, mucoid and non sorbitol fermenters, respectively. All isolates were negative for the O157 strain. The frequency of resistance to the 9 antimicrobial agents tested was 75% (3 of 4) for Salmonella, 85.7% (6 of 7) of Campylobacter spp. and 36.3% (62 of 171) for E. coli (P < .05; chi(2)). PMID- 21547222 TI - A Study of the Persistence of Mycobacterium bovis in the Environment under Natural Weather Conditions in Michigan, USA. AB - Reisolation of Mycobacterium bovis from inoculated substrates was used to follow the persistence of viable M. bovis bacteria exposed to natural weather conditions over a 12-month period. Environmental factors were recorded continuously, and factors affecting M. bovis persistence (i.e., temperature, season, and substrate) were studied using survival analysis and Cox's proportional hazards regression. Persistence of M. bovis in the environment was significantly shorter in the spring/summer season, characterized by the highest average daily temperatures over the 12-month period. M. bovis persisted up to 88 days in soil, 58 days in water and hay, and 43 days on corn. These studies demonstrate that M. bovis bacteria persist long enough to represent a risk of exposure for cattle and/or wildlife and strengthen evidence that suggests cattle farm biosecurity and efforts to eliminate supplemental feeding of white-tailed deer will decrease the risk of bovine TB transmission among and between cattle and deer populations. PMID- 21547221 TI - Magnetoencephalography as a putative biomarker for Alzheimer's disease. AB - Alzheimer's Disease (AD) is the most common dementia in the elderly and is estimated to affect tens of millions of people worldwide. AD is believed to have a prodromal stage lasting ten or more years. While amyloid deposits, tau filaments, and loss of brain cells are characteristics of the disease, the loss of dendritic spines and of synapses predate such changes. Popular preclinical detection strategies mainly involve cerebrospinal fluid biomarkers, magnetic resonance imaging, metabolic PET scans, and amyloid imaging. One strategy missing from this list involves neurophysiological measures, which might be more sensitive to detect alterations in brain function. The Magnetoencephalography International Consortium of Alzheimer's Disease arose out of the need to advance the use of Magnetoencephalography (MEG), as a tool in AD and pre-AD research. This paper presents a framework for using MEG in dementia research, and for short term research priorities. PMID- 21547223 TI - A therapeutic and diagnostic dilemma: granular cell tumor of the breast. AB - Six to eight percent of granular cell tumors are seen in the breast. Although mostly benign, they rarely have malignant features clinically and radiologically reminding of breast cancer. This may lead to a potential misdiagnosis of breast carcinoma and overtreatment of patients. The final diagnosis is made by immunohistochemical examination. We performed excisional biopsy on a patient who was diagnosed to have a breast mass. The histopathological examination of the mass revealed granular cell tumor. PMID- 21547224 TI - Evaluation of the Efficacy of Acaricides Used to Control the Cattle Tick, Rhipicephalus microplus, in Dairy Herds Raised in the Brazilian Southwestern Amazon. AB - The adult immersion test (AIT) was used to evaluate the efficacy of acaricide molecules used for control of Rhipicephalus microplus on 106 populations collected in five municipalities in the state of Rondonia in the Brazilian South Occidental Amazon region. The analysis of the data showed that the acaricide formulations had different efficacies on the tick populations surveyed. The synthetic pyrethroids (SPs) acaricides were the least effective (48.35-76.84%), followed by SP + organophosphate (OP) associations (68.91-81.47%) and amidine (51.35-100%). For the macrocyclic lactones (MLs), the milbemycin (94.84-100%) was the most effective, followed by spinosad (93.21-100%) and the avermectins (81.34 100%). The phenylpyrazole (PZ) group had similar efficacy (99.90%) to the MLs. Therefore, SP acaricides, including associations with OP, and formulations based on amidine presented low in vitro efficacy to control the R. microplus populations surveyed. PMID- 21547226 TI - Effects of acute normovolemic anemia on hemodynamic parameters and Acid-base balance in dogs. AB - The aim of this study was to evaluate the hemodynamic and acid-base status of dogs subjected to acute normovolemic anemia. The dogs (n = 10) were evaluated 15 minutes and 24 hours after induction of anemia (hematocrit below 18%) with blood withdrawal and simultaneously replacement of same volume of Ringer's lactate solution and hydroxyethyl starch-based solution in a 2 : 1 ratio. The cardiac output was measured by Doppler echocardiography and blood pressure by oscillometric device, and posteriorly hemodynamic parameters were calculated. The anemic groups had increase in cardiac index (P < .05) (3.82 +/- 1.05 to 5.86 +/- 1.49 and 5.81 +/- 1.63 L/min * m(2)) and decreases (P < .05) in the indices of total peripheral resistance (6797.81 +/- 3060.22 to 3220.14 +/- 1275.02 and 3887.74 +/- 1394.89 dina.seg/cm(5) * m(2)) and oxygen delivery (7942.84 +/- 3344.00 to 4021.68 +/- 1627.00 and 4430.82 +/- 1402.61 mL/min * m(2)), respectively. There were no significant changes in pH, but PaO(2) and SaO(2) values were increased, and PaCO(2) reduced in anemic dogs (P < .05). Therefore, acute normovolemic anemia can create significant hemodynamic changes and despite some hemogasometric changes, there were no changes in the acid-base status in dogs. PMID- 21547227 TI - MRI shows more severe hippocampal atrophy and shape deformation in hippocampal sclerosis than in Alzheimer's disease. AB - While hippocampal atrophy is a key feature of both hippocampal sclerosis (HS) and Alzheimer's disease (AD), the pathology underlying this finding differs in these two conditions. In AD, atrophy is due primarily to loss of neurons and neuronal volume as a result of neurofibrillary tangle formation. While the etiology of HS is unknown, neuron loss in the hippocampus is severe to complete. We compared hippocampal volume and deformations from premortem MRI in 43 neuropathologically diagnosed cases of HS, AD, and normal controls (NC) selected from a longitudinal study of subcortical ischemic vascular disease (IVD Program Project). HS cases (n = 11) showed loss of neurons throughout the rostral-caudal extent of the hippocampus in one or both hemispheres. AD cases (n = 24) met NIA-Reagan criteria for high likelihood of AD. Normal control cases (n = 8) were cognitively intact and showed no significant AD or hippocampal pathology. The mean hippocampal volumes were significantly lower in HS versus AD groups (P < .001). Mean shape deformations in the CA1 and subiculum differed significantly between HS versus AD, HS versus NC, and AD versus NC (P < .0001). Additional study is needed to determine whether these differences will be meaningful for clinical diagnosis of individual cases. PMID- 21547225 TI - Membrane Incorporation, Channel Formation, and Disruption of Calcium Homeostasis by Alzheimer's beta-Amyloid Protein. AB - Oligomerization, conformational changes, and the consequent neurodegeneration of Alzheimer's beta-amyloid protein (AbetaP) play crucial roles in the pathogenesis of Alzheimer's disease (AD). Mounting evidence suggests that oligomeric AbetaPs cause the disruption of calcium homeostasis, eventually leading to neuronal death. We have demonstrated that oligomeric AbetaPs directly incorporate into neuronal membranes, form cation-sensitive ion channels ("amyloid channels"), and cause the disruption of calcium homeostasis via the amyloid channels. Other disease-related amyloidogenic proteins, such as prion protein in prion diseases or alpha-synuclein in dementia with Lewy bodies, exhibit similarities in the incorporation into membranes and the formation of calcium-permeable channels. Here, based on our experimental results and those of numerous other studies, we review the current understanding of the direct binding of AbetaP into membrane surfaces and the formation of calcium-permeable channels. The implication of composition of membrane lipids and the possible development of new drugs by influencing membrane properties and attenuating amyloid channels for the treatment and prevention of AD is also discussed. PMID- 21547228 TI - Ultrasonographic examination of the rumen in healthy cows. AB - 10 healthy Indian Jersey/Red Sindhi crossbred nonpregnant cows were subjected to transabdominal ultrasonography to develop baseline topographical data of the rumen. The wall of the rumen could be identified as a thick echogenic line adjacent to the left abdominal wall from left flank to 8th intercostal space. The motility pattern of rumen was characterized by approximately 1 contraction every minute. The mean amplitude of the ruminal contraction was 3.2 cm. Ultrasonography of the rumen in healthy cows is a useful adjunct to the noninvasive diagnostic investigation of the rumen. PMID- 21547230 TI - Serological detection of viral infections in captive wild cats from costa rica. AB - Serum samples from a total of 44 wildcats, 28 margays (Leopardus wiedii), 10 ocelots (Leopardus pardalis), four jaguaroundis (Herpailurus yaguaroundi), one oncilla (Leopardus tigrina), and one jaguar (Panthera onca) were obtained between January 2001 and August 2002 from the Profelis Centre for rehabilitation of wild felids, located in the northwestern region of Costa Rica. Forty three samples were tested for antibodies against feline immunodeficiency virus (FIV) and p27 antigen of feline leukemia virus (FeLV), 42 samples for antibodies against feline parvovirus (FPV), and 30 for antibodies against feline calicivirus (FCV). None of the samples contained detectable antibodies against FIV or p27 antigen of FeLV, all samples contained antibodies against FPV, and one sample contained antibodies against FCV. PMID- 21547231 TI - Surveillance of Aflatoxin and Microbiota Related to Brewer's Grain Destined for Swine Feed in Argentina. AB - Cordoba province in the center of Argentina is an important area of swine production. The use of industry by-product (brewer's grain) as feedstuff for swine is a regular practice and increases animal performance on these animals production. The occurrence of aflatoxin contamination is global, causing severe problems especially in developing countries. No reports on aflatoxin B(1) production, micoflora, and potential aflatoxin B(1) producing microorganism from brewer's grain are available. The aims of this study were (1) to isolate the microbiota species from brewer's grain, (2) to determine aflatoxin B(1) natural contamination levels, and (3) to determine the ability of Aspergillus section Flavi isolates to produce aflatoxins in vitro. Physical properties, total fungal counts, lactic acid bacteria, and fungal genera distribution were determined on this substrate. In 65% of the samples, fungal counts were higher than recommended by GMP, and lactic bacterium counts ranged from 1.9 * 10(5) to 4.4 * 10(9) CFU g( 1). Aspergillus spp. prevailed over other fungal genera. Aspergillus flavus was the prevalent species followed by A. fumigatus. Aflatoxin B(1) levels in the samples were higher than the recommended limits (20 ng g(-1)) for complementary feedstuffs. Several Aspergillus section Flavi strains were able to produce aflatoxin B(1) in vitro. Inadequate storage conditions promote the proliferation of mycotoxin-producing fungal species. Regular monitoring of feeds is required in order to prevent chronic and acute toxic syndromes related to this kind of contamination. PMID- 21547229 TI - Neuroimaging measures as endophenotypes in Alzheimer's disease. AB - Late onset Alzheimer's disease (AD) is moderately to highly heritable. Apolipoprotein E allele epsilon4 (APOE4) has been replicated consistently as an AD risk factor over many studies, and recently confirmed variants in other genes such as CLU, CR1, and PICALM each increase the lifetime risk of AD. However, much of the heritability of AD remains unexplained. AD is a complex disease that is diagnosed largely through neuropsychological testing, though neuroimaging measures may be more sensitive for detecting the incipient disease stages. Difficulties in early diagnosis and variable environmental contributions to the disease can obscure genetic relationships in traditional case-control genetic studies. Neuroimaging measures may be used as endophenotypes for AD, offering a reliable, objective tool to search for possible genetic risk factors. Imaging measures might also clarify the specific mechanisms by which proposed risk factors influence the brain. PMID- 21547232 TI - A review of bovine tuberculosis in the kafue basin ecosystem. AB - The Kafue basin ecosystem is the only remaining natural habitat for the endangered Kafue lechwe antelope (Kobus leche Kafuensis). However, hydroelectricity power production, large-scale sugar plantations, commercial fishing and increasing livestock production are threatening its natural existence and sustainability. Further, increasing human settlements within and around the Kafue basin have resulted in decreased grazing grounds for the Kafue lechwe antelopes despite a corresponding increase in cattle population sharing the same pasture. Baseline epidemiological data have persistently reported findings of bovine tuberculosis (BTB) in both wild and domestic animals, although these have been deficient in terms of describing direct evidence in the role of either lechwe antelopes or cattle in the reported observations. Despite the current literature being deficient in establishing the casual role and transmission patterns of BTB, a bimodal route of infection at the livestock/wildlife interface has been postulated. Likewise, it is not known how much of (BTB) has the potential of causing disease in humans. This paper, seeks to underline those aspects that need further research and update available data on BTB in the Kafue basin with regards to the prevalence, distribution, risk factors, threats on wildlife conservation, livestock production, public health implications, and possible mitigatory measures. PMID- 21547233 TI - Bovine Leukemia Virus Infection in Dairy Cattle: Effect on Serological Response to Immunization against J5 Escherichia coli Bacterin. AB - Thirteen bovine leukemia virus- (BLV-) negative and 22 BLV-positive Holstein cows were immunized with J5 Escherichia coli bacterin at dry off, three weeks before calving, during the second week after calving, and three weeks after the third immunization. Serum was collected before the initial immunization, immediately before the third and fourth immunizations, and 21 days after the fourth immunization. Anti-J5 E. coli IgM, IgG1, and IgG2 titers were determined by ELISA. Anti-J5 E. coli IgM titers did not differ significantly (P = .98) between groups. Increases in anti-J5 E. coli IgG1 titers were higher in the BLV-negative cows (P = .057). Geometric mean anti-J5 E. coli IgG2 titers increased fourfold in the BLV-negative cows, which was significantly higher (P = .007) than the twofold increase in the BLV-positive cows. Cattle infected with BLV may have impaired serologic responses following immunization with J5 bacterin, and response may differ according to antibody isotype. PMID- 21547234 TI - Bovine tuberculosis in a nebraska herd of farmed elk and fallow deer: a failure of the tuberculin skin test and opportunities for serodiagnosis. AB - In 2009, Mycobacterium bovis infection was detected in a herd of 60 elk (Cervus elaphus) and 50 fallow deer (Dama dama) in Nebraska, USA. Upon depopulation of the herd, the prevalence of bovine tuberculosis (TB) was estimated at ~71-75%, based upon histopathology and culture results. Particularly with elk, gross lesions were often severe and extensive. One year ago, the majority of the elk had been tested for TB by single cervical test (SCT), and all were negative. After initial detection of a tuberculous elk in this herd, 42 of the 59 elk were tested by SCT. Of the 42 SCT-tested elk, 28 were TB-infected with only 3/28 reacting upon SCT. After SCT, serum samples were collected from the infected elk and fallow deer from this herd at necropsy and tested by three antibody detection methods including multiantigen print immunoassay, cervidTB STAT-PAK, and dual path platform VetTB (DPP). Serologic test sensitivity ranged from 79 to 97% depending on the test format and host species. Together, these findings demonstrate the opportunities for use of serodiagnosis in the rapid detection of TB in elk and fallow deer. PMID- 21547235 TI - Ultrasonographic application in the diagnosis and prognosis of pericarditis in cows. AB - The present study was conducted on 5 cows diagnosed with late-stage pericarditis based on a combination of clinical, radiographic, ultrasonographic, and postmortem examinations. On clinical examination, all the cows were found to be depressed, dyspnoeic, and moderately to severely tachycardic. The main radiographic findings were poor thoracic details and indistinguishable cardiophrenic silhouette. Ultrasonographically, the pericardial sac contained varying quantities of hypoechogenic exudate and echogenic fibrin shreds, which had caused physical compression of the cardiac chambers. The clinical and radiographic findings did not allow a definitive diagnosis of pericarditis, because all of the characteristic signs were not present in every case. Thoracic and abdominal ultrasonography played an important role in the early diagnosis and prognosis of the disease. PMID- 21547236 TI - Mycobacterium bovis in Swine: Spoligotyping of Isolates from Argentina. AB - A total of 143 Mycobacterium bovis isolates of pigs, from the most productive swine area in Argentina, were typed by spoligotyping. Twenty-two different spoligotypes were identified, and 133 (93%) isolates were grouped into 12 clusters. One of them, designed SB0140, was the most frequent because it held 83 (58%) isolates. This spoligotype also grouped 362 (43%) out of 841 isolates from previously typed cattle and, thus, constitutes the most frequent in our country. In addition, 135 (94%) isolates revealed spoligotypes identical to those of cattle, showing an epidemiological link. On the other hand, there were seven novel spoligotypes, six of which were also unique since they had only one isolate each. This study aimed to identify the spoligotypes of M. bovis isolated from pigs to contribute to a better understanding of the distribution of bovine tuberculosis in the main productive area of Argentina. PMID- 21547237 TI - A New Experimental Infection Model in Ferrets Based on Aerosolised Mycobacterium bovis. AB - There is significant interest in developing vaccines to control bovine tuberculosis, especially in wildlife species where this disease continues to persist in reservoir species such as the European Badger (Meles meles). However, gaining access to populations of badgers (protected under UK law) is problematic and not always possible. In this study, a new infection model has been developed in ferrets (Mustela furo), a species which is closely related to the badger. Groups of ferrets were infected using a Madison infection chamber and were examined postmortem for the presence of tuberculous lesions and to provide tissue samples for confirmation of Mycobacterium bovis by culture. An infectious dose was defined, that establishes infection within the lungs and associated lymph nodes with subsequent spread to the mesentery lymph nodes. This model, which emphasises respiratory tract infection, will be used to evaluate vaccines for the control of bovine tuberculosis in wildlife species. PMID- 21547238 TI - Socioeconomic Status and the Increased Prevalence of Autism in California. AB - The prevalence of autism has increased precipitously-roughly 10-fold in the past 40 years-yet no one knows exactly what caused this dramatic rise. Using a large and representative dataset that spans the California birth cohorts from 1992 through 2000, we examine individual and community resources associated with the likelihood of an autism diagnosis over time. This allows us to identify key social factors that have contributed to increased autism prevalence. While individual-level factors, such as birth weight and parental education, have had a fairly constant effect on likelihood of diagnosis over time, we find that community-level resources drive increased prevalence. This study suggests that neighborhoods dynamically interact with the people living in them in different ways at different times to shape health outcomes. By treating neighborhoods as dynamic, we can better understand the changing socioeconomic gradient of autism and the increase in prevalence. PMID- 21547239 TI - Future Connectivity for Disaster and Emergency Point of Care. AB - OBJECTIVE: The goal of this paper is to identify strategies for connectivity that will optimize point-of-care testing (POCT) organized as small-world networks in disaster settings. METHODS: We evaluated connectivity failures during the 2010 Haiti Earthquake, applied small-world network concepts, and reviewed literature for point-of-care (POC) connectivity systems. RESULTS: Medical teams responding to the Haiti Earthquake faced connectivity failures that affected patient outcomes. Deploying robust wireless connectivity systems can enhance the efficiency of the disaster response by improving health care delivery, medical documentation, logistics, response coordination, communication, and telemedicine. Virtual POC connectivity education and training programs can enhance readiness of disaster responders. CONCLUSIONS: The admirable humanitarian efforts of more than 4000 organizations substantially impacted the lives of earthquake victims in Haiti. However, the lack of connectivity and small-world network strategies, combined with communication failures, during early stages of the relief effort must be addressed for future disaster preparedness. PMID- 21547240 TI - GENDER, SEXUALITY, AND ETHNICITY AS FACTORS OF CLUB DRUG USE AMONG ASIAN AMERICANS. AB - This article examines the relationship between substance use and gender, sexuality, ethnicity, and nativity among 250 Asian American youths involved in the dance club/rave scene. We find distinct patterns of drug use differing by country of origin and ethnicity. However, contrary to some literature we do not find significant differences corresponding to immigration status, or number of years in the U.S. The most significant differences between subgroups are related to gender and sexuality: male respondents consume more drugs, more frequently than female respondents, and non-heterosexual respondents consume more than heterosexual respondents, with differing patterns for men's and women's sexual subgroups. There were also significant gender and sexuality differences with respect to the contexts in which respondents consume drugs, with the most significant differences being between heterosexual and non-heterosexual men. As we discuss, these findings illustrate the need for further investigation of drug use patterns of gender and sexuality within Asian American communities. PMID- 21547241 TI - A Large-scale Dissemination and Implementation Model for Evidence-based Treatment and Continuing Care. AB - Multiple evidence-based treatments for adolescents with substance use disorders are available; however, the diffusion of these treatments in practice remains minimal. A dissemination and implementation model incorporating research-based training components for simultaneous implementation across 33 dispersed sites and over 200 clinical staff is described. Key elements for the diffusion of the Adolescent Community Reinforcement Approach and Assertive Continuing Care were: (a) three years of funding to support local implementation; (b) comprehensive training, including a 3.5 day workshop, bi-weekly coaching calls, and ongoing performance feedback facilitated by a web tool; (c) a clinician certification process; (d) a supervisor certification process to promote long-term sustainability; and (e) random fidelity reviews after certification. Process data are summarized for 167 clinicians and 64 supervisors. PMID- 21547242 TI - Social Care: a new initiative in England to fill evidence gaps. PMID- 21547243 TI - Patient perceptions of vulvar vibration therapy for refractory vulvar pain. AB - The objective of this study was to describe acceptability of vulvar vibration therapy (VVT), a novel treatment approach to vulvodynia. We included women with vulvodynia who attended the Pelvic Pain Clinic and had used VVT for at least two weeks. Participants completed a three-page, 65-item, questionnaire assessing demographics, VVT usage and responses to Likert statements regarding accessibility, comfort and symptom response to VVT. Of 69 qualifying patients, results from 49 (72%) were eligible for analysis. Participants were primarily white, married and well-educated, with a median age of 30 (range 19-68 years). Median duration of vulvar pain and dyspareunia was two years (0-23) and three years (0-30), respectively. Median duration of VVT was five months (1-18) and three days per week (0.5-7). Fully, 83% said that, "vibrator treatment is an acceptable treatment", 83% said that they were "satisfied with vibrator treatment", 76% endorsed vibrator as comfortable to use, 73% indicated that sex is less painful since starting vibration treatment and 88% would recommend VVT to others. We conclude that the therapeutic rationale for VVT is based on the anti nocioceptive properties of vibration and on the favorable response of vulvodynia to physical therapy. Vulvar vibration therapy is safe, inexpensive and, in this survey, acceptable to most patients, many of whom described improvement in symptoms. PMID- 21547244 TI - STOCK MARKET CRASH AND EXPECTATIONS OF AMERICAN HOUSEHOLDS. AB - This paper utilizes data on subjective probabilities to study the impact of the stock market crash of 2008 on households' expectations about the returns on the stock market index. We use data from the Health and Retirement Study that was fielded in February 2008 through February 2009. The effect of the crash is identified from the date of the interview, which is shown to be exogenous to previous stock market expectations. We estimate the effect of the crash on the population average of expected returns, the population average of the uncertainty about returns (subjective standard deviation), and the cross-sectional heterogeneity in expected returns (disagreement). We show estimates from simple reduced-form regressions on probability answers as well as from a more structural model that focuses on the parameters of interest and separates survey noise from relevant heterogeneity. We find a temporary increase in the population average of expectations and uncertainty right after the crash. The effect on cross-sectional heterogeneity is more significant and longer lasting, which implies substantial long-term increase in disagreement. The increase in disagreement is larger among the stockholders, the more informed, and those with higher cognitive capacity, and disagreement co-moves with trading volume and volatility in the market. PMID- 21547246 TI - Psychopathy and Identification of Facial Expressions of Emotion. AB - The authors examined the association between psychopathy and identification of facial expressions of emotion. Previous research in this area is scant and has produced contradictory findings (Blair et. al., 2001, 2004; Glass & Newman, 2006; Kosson et al., 2002). One hundred and forty-five male jail inmates, rated using the Hare Psychopathy Checklist: Screening Version participated in a facial affect recognition task. Participants were shown faces containing one of five emotions (happiness, sadness, fear, anger, or shame) displayed at one of two different levels of intensity of expression (100% or 60%). The authors predicted that psychopathy would be associated with decreased affect recognition, particularly for sad and fearful emotional expressions, and decreased recognition of less intense displays of facial affect. Results were largely consistent with expectations in that psychopathy was negatively correlated with overall facial recognition of affect, sad facial affect, and recognition of less intense displays of affect. An unexpected negative correlation with recognition of happy facial affect was also found. These results suggest that psychopathy may be associated with a general deficit in affect recognition. PMID- 21547245 TI - Fluorescence fluctuation spectroscopy: ushering in a new age of enlightenment for cellular dynamics. AB - Originally developed for applications in physics and physical chemistry, fluorescence fluctuation spectroscopy is becoming widely used in cell biology. This review traces the development of the method and describes some of the more important applications. Specifically, the methods discussed include fluorescence correlation spectroscopy (FCS), scanning FCS, dual color cross-correlation FCS, the photon counting histogram and fluorescence intensity distribution analysis approaches, the raster scanning image correlation spectroscopy method, and the Number and Brightness technique. The physical principles underlying these approaches will be delineated, and each of the methods will be illustrated using examples from the literature. PMID- 21547247 TI - Cultural resistance to fast-food consumption? A study of youth in North Eastern Thailand. AB - Increased intake of saturated fat and refined sugars underlies much of the problem of emerging obesity all over the world. This includes middle-income countries like Thailand, which are subject to successful marketing of Western fast foods especially targeted at adolescents. In this study we explore the socio cultural influences on fast-food intake for non-metropolitan (rural and urban) adolescents in North East Thailand (Isan). Our questionnaire sample included 634 persons aged 15-19 years who are in and out of formal schooling and who are randomly representing upper, central and lower Isan. All were asked about their knowledge of fast-food health risks and their attitudes towards, and consumption of, fast food and traditional food. As well, we used several focus groups to obtain qualitative data to complement the information derived from the questionnaire. Some three quarters of sampled youth were aware that fast food causes obesity and half knew of the link to heart disease. About half consumed fast food regularly, induced by the appeal of 'modern' lifestyles, social events and marketing, as well as by the convenience, speed and taste. Nearly two-thirds thought that local foods should be more popular and these beliefs were more likely to be found among children from educated and urban families. Local foods already constitute a cultural resistance to fast-food uptake. We propose several methods to boost this resistance and protect the youth of Thailand against fast food and its many adverse health consequences. PMID- 21547248 TI - Family history of cancer and tobacco exposure in index cases of pancreatic ductal adenocarcinoma. AB - Aim. To examine interaction between history of cancer in first-degree relatives and tobacco smoking in index patients of pancreatic adenocarcinoma. Methods. We carried out a case-control involving 113 patients with pancreatic adenocarcinoma and 110 controls over a 12-month period at the Freeman Hospital, Newcastle upon Tyne, UK. They were all administered a detailed tobacco exposure questionnaire and a family history questionnaire. We calculated cumulative tobacco exposure and risk for pancreas cancer. Results. Both smokers (OR 3.01 (95% CI: 1.73 to 5.24)) and those with a family history of malignancy (OR 1.98 (95% CI: 1.15-3.38)) were more likely to develop pancreatic cancer. Having more than one first-degree relative with cancer did not significantly further increase the risk of pancreatic cancer. Amongst pancreatic cancer cases, cumulative tobacco exposure was significantly decreased (P = .032) in the group of smokers (current and ex smokers) who had a family history of malignancy [mean (SD): 30.00 (24.77) pack years versus 44.69 (28.47) pack-years with no such history]. Conclusions. Individuals with a family history of malignancy are at an increased risk of pancreatic cancer. Furthermore, individuals with a family history of malignancy and who smoke appear to require a lesser degree of tobacco exposure for the development of pancreatic cancer. PMID- 21547249 TI - Elucidating the Complex Interactions between Stress and Epileptogenic Pathways. AB - Clinical and experimental data suggest that stress contributes to the pathology of epilepsy. We review mechanisms by which stress, primarily via stress hormones, may exacerbate epilepsy, focusing on the intersection between stress-induced pathways and the progression of pathological events that occur before, during, and after the onset of epileptogenesis. In addition to this temporal nuance, we discuss other complexities in stress-epilepsy interactions, including the role of blood-brain barrier dysfunction, neuron-glia interactions, and inflammatory/cytokine pathways that may be protective or damaging depending on context. We advocate the use of global analytical tools, such as microarray, in support of a shift away from a narrow focus on seizures and towards profiling the complex, early process of epileptogenesis, in which multiple pathways may interact to dictate the ultimate onset of chronic, recurring seizures. PMID- 21547250 TI - Effects of neonatal systemic inflammation on blood-brain barrier permeability and behaviour in juvenile and adult rats. AB - Several neurological disorders have been linked to inflammatory insults suffered during development. We investigated the effects of neonatal systemic inflammation, induced by LPS injections, on blood-brain barrier permeability, endothelial tight junctions and behaviour of juvenile (P20) and adult rats. LPS treatment resulted in altered cellular localisation of claudin-5 and changes in ultrastructural morphology of a few cerebral blood vessels. Barrier permeability to sucrose was significantly increased in LPS treated animals when adult but not at P20 or earlier. Behavioural tests showed that LPS treated animals at P20 exhibited altered behaviour using prepulse inhibition (PPI) analysis, whereas adults demonstrated altered behaviour in the dark/light test. These data indicate that an inflammatory insult during brain development can change blood-brain barrier permeability and behaviour in later life. It also suggests that the impact of inflammation can occur in several phases (short- and long-term) and that each phase might lead to different behavioural modifications. PMID- 21547251 TI - Superficial palmar arch aneurysm after carpal tunnel decompression, a rare complication: a case report. AB - False aneurysms of the palmar arteries are rare. They are usually associated with traumatic injuries to the hand vasculature. We present a case of superficial palmar arch aneurysm (SPAA), complicating carpal tunnel decompression which presented as a pulsatile mass at the site of previous surgery. Initial diagnosis was made on clinical examination and confirmed on doppler ultrasound (US) and computed tomographic angiography (CTA). The feeding vessel of the aneurysm was subsequently occluded using coil embolization. PMID- 21547252 TI - Resolution of dialyzer membrane-associated thrombocytopenia with use of cellulose triacetate membrane: a case report. AB - Blood and dialyzer membrane interaction can cause significant thrombocytopenia through the activation of complement system. The extent of this interaction determines the biocompatibility of the membrane. Although the newer synthetic membranes have been shown to have better biocompatibility profile than the cellulose-based membranes, little is known about the difference in biocompatibility between synthetic membrane and modified cellulose membrane. Herein, we report a case of a patient on hemodialysis who developed dialyzer membrane-related thrombocytopenia with use of synthetic membrane (F200NR polysulfone). The diagnosis of dialyzer membrane-associated thrombocytopenia was suspected by the trend of platelet count before and after dialysis, and the absence of other possible causes of thrombocytopenia. We observed significant improvement in platelet count when the membrane was changed to modified cellulose membrane (cellulose triacetate). In patients at high risk for thrombocytopenia, the modified cellulose membrane could be a better alternative to the standard synthetic membranes during hemodialysis. PMID- 21547254 TI - Immunology and cell biology of parasitic diseases. PMID- 21547253 TI - Dual specificity phosphatase 1 regulates human inducible nitric oxide synthase expression by p38 MAP kinase. AB - The role of dual specificity phosphatase 1 (DUSP1) in inducible nitric oxide synthase (iNOS) expression in A549 human pulmonary epithelial cells, J774 mouse macrophages and primary mouse bone marrow-derived macrophages (BMMs) was investigated. iNOS expression was induced by a cytokine mixture (TNF, IFNgamma and IL-1beta) in A549 cells and by LPS in J774 cells, and it was inhibited by p38 MAPK inhibitors SB202190 and BIRB 796. Stimulation with cytokine mixture or LPS enhanced also DUSP1 expression. Down-regulation of DUSP1 by siRNA increased p38 MAPK phosphorylation and iNOS expression in A549 and J774 cells. In addition, LPS induced iNOS expression was enhanced in BMMs from DUSP1((-/-)) mice as compared to that in BMMs from wild-type mice. The results indicate that DUSP1 suppresses iNOS expression by limiting p38 MAPK activity in human and mouse cells. Compounds that enhance DUSP1 expression or modulate its function may be beneficial in diseases complicated with increased iNOS-mediated NO production. PMID- 21547255 TI - Effect of omega-3 fatty acid on gastrointestinal motility after abdominal operation in rats. AB - OBJECTIVE: To investigate whether omega-3 fatty acid could stimulate gastrointestinal motility after abdominal operation. METHOD: Wistar rats were randomly divided into 3 group (normal saline group, intralipid group, and omega-3 fatty acid group, n = 18/group) after partial caecectomy and gastrostomosis, each group was divided into 3 groups (POD1, POD3, and POD6, n = 6/group). Serum gastrin (GAS), motilin (MTL), interleukin-1 (IL-1), interleukin-6 (IL-6), tissue necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), gastric emptying rate, and small bowel propulsion rate were measured. RESULTS: On POD 3, gastric emptying rate and small bowel propulsion rate in omega-3 fatty acid group were higher than those in normal saline group and intralipid group. Serum GAS and MTL levels in omega-3 fatty acid group were higher than those in normal saline group, but serum IL-1, IL-6, TNF-alpha, and COX-2 levels were lower than those in normal saline group and intralipid group. CONCLUSION: omega-3 fatty acid could accelerate the recovery of gastrointestinal mobility after abdominal operation in rats, mainly by relieving postoperative inflammation. PMID- 21547256 TI - IL-6 serum levels and production is related to an altered immune response in polycystic ovary syndrome girls with insulin resistance. AB - Polycystic ovarian syndrome (PCOS) is frequently characterized by obesity and metabolic diseases including hypertension, insulin resistance, and diabetes in adulthood, all leading to an increased risk of atherosclerosis. The present study aimed to evaluate serum and production of inflammatory markers in adolescent Sardinian PCOS. On the basis of HOMA findings, patients were divided into noninsulin resistant (NIR) and insulin resistant (IR), and were weight- and age matched with healthy girls. Inflammatory cytokines (TNF-alpha, IL-6, Il-10, TGF beta) and lipokines (leptin, adiponectin), the reactant hs-CRP, and in vitro inflammatory lympho-monocyte response to microbial stimulus were evaluated. In healthy and PCOS subjects, leptin and hs-CRP were correlated with BMI, whereas adiponectin was significantly reduced in all PCOS groups. Although cytokines were similar in all groups, Interleukin-6 (IL-6) was significantly higher in IR PCOS. Moreover, in the latter group lipopolysaccharide-activated monocytes secreted significantly higher levels of IL-6 compared to NIR and control subjects. To conclude, IR PCOS displayed increased IL-6 serum levels and higher secretion in LPS-activated monocytes, whilst revealing no differences for other inflammatory cytokines. These results suggest that in PCOS patients an altered immune response to inflammatory stimuli is present in IR, likely contributing towards determining onset of a low grade inflammation. PMID- 21547257 TI - CCL5/RANTES gene polymorphisms in Slavonic patients with myocardial infarction. AB - Coronary artery inflammation is a critical process in the pathogenesis of myocardial infarction (MI). The chemokine CCL5/RANTES (regulated upon activation, normal T cells expressed and secreted) is expressed in advanced atherosclerotic lesions. Functional polymorphisms of the RANTES gene can, therefore, be involved in the pathogenesis of coronary artery disease. We examined the association of polymorphisms in the RANTES gene with myocardial infarction in Slavonic populations of Czech and Russian origin. A total of 467 post-MI patients and 337 control subjects were genotyped for RANTES promoter G-403A (rs2107538) and intron 1.1 T/C (rs2280789) variants by PCR-SSP. Both RANTES genotypes and allele frequencies did not differ between case and control groups. Haplotype-based analysis also failed to reveal an association between MI and investigated markers. Strong linkage disequilibrium was detected between particular RANTES alleles. The data do not support an association between RANTES G-403A polymorphism and MI, as reported previously. PMID- 21547258 TI - Pro- and anti-inflammatory cytokines during immune stimulation: modulation of iron status and red blood cell profile. AB - Forty-eight patients were subdivided according to C-reactive protein (CRP) levels, resulting in 19 patients with normal (2.8 +/- 2.8 mg/L) and 29 with elevated (82.2 +/- 76.2 mg/L) CRP levels. The elevated CRP group had iron and red blood cell (RBC) profiles characteristic of chronic immune stimulation (CIS), and the normal CRP group, profiles of true iron deficiency. Normal relationships between storage iron, bioavailable iron, and RBC indices were absent in the elevated CRP group-implying the role of iron as major determinant of the RBC profile to be diminished during CIS. The elevated CRP group had significant increases in proinflammatory cytokines (INF-gamma, TNF-alpha, Il-1beta, Il-6, and Il-8). Anti-inflammatory cytokine levels were normal, except for Il-10, supporting previous indications that Il-10 contributes to reducing bioavailable iron. Regression analysis suggested decreases in transferrin to be related to increases in Il-8 and an increase in ferritin to be related to a decrease in Il 12 levels. TGF-beta levels were positively related to transferrin and negatively to ferritin. PMID- 21547259 TI - Systemically administered ligands of Toll-like receptor 2, -4, and -9 induce distinct inflammatory responses in the murine lung. AB - OBJECTIVE: To determine whether systemically administered TLR ligands differentially modulate pulmonary inflammation. METHODS: Equipotent doses of LPS (20 mg/kg), CpG-ODN (1668-thioat 1 nmol/g), or LTA (15 mg/kg) were determined via TNF activity assay. C57BL/6 mice were challenged intraperitoneally. Pulmonary NFkappaB activation (2 h) and gene expression/activity of key inflammatory mediators (4 h) were monitored. RESULTS: All TLR ligands induced NFkappaB. LPS increased the expression of TLR2, 6, and the cytokines IL-1alphabeta, TNF-alpha, IL-6, and IL-12p35/p40, CpG-ODN raised TLR6, TNF-alpha, and IL12p40. LTA had no effect. Additionally, LPS increased the chemokines MIP-1alpha/beta, MIP-2, TCA-3, eotaxin, and IP-10, while CpG-ODN and LTA did not. Myeloperoxidase activity was highest after LPS stimulation. MMP1, 3, 8, and 9 were upregulated by LPS, MMP2, 8 by CpG-ODN and MMP2 and 9 by LTA. TIMPs were induced only by LPS. MMP-2/-9 induction correlated with their zymographic activities. CONCLUSION: Pulmonary susceptibility to systemic inflammation was highest after LPS, intermediate after CpG-ODN, and lowest after LTA challenge. PMID- 21547260 TI - Gene expression profiling in lungs of chronic asthmatic mice treated with galectin-3: downregulation of inflammatory and regulatory genes. AB - BACKGROUND: Asthma is a disorder characterized by a predominance of Th2 cells and eosinophilic inflammation. Suppressors of cytokine signaling (SOCS) proteins act as negative regulators of cytokine signaling. In particular, SOCS1 and SOCS3 play an important role in immune response by controlling the balance between Th1 and Th2 cells. In a previous study, we demonstrated that treatment of chronic asthmatic mice with gene therapy using plasmid encoding galectin-3 (Gal-3) led to an improvement in Th2 allergic inflammation. METHODS: Using a microarray approach, this study endeavored to evaluate the changes produced by therapeutic Gal-3 delivered by gene therapy in a well-characterized mouse model of chronic airway inflammation. Results were confirmed by real-time RT-PCR, Western blot and immunohistochemical analysis. RESULTS: We identify a set of genes involved in different pathways whose expression is coordinately decreased/increased in mice treated with Gal-3 gene therapy. We report a correlation between Gal-3 treatment and inhibition of SOCS1 and SOCS3 expression in lungs. CONCLUSION: These results suggest that negative regulation of SOCS1 and 3 following Gal-3 treatment could be a valuable therapeutic approach in allergic disease. PMID- 21547261 TI - Apparent Prevalence of Beef Carcasses Contaminated with Mycobacterium avium subsp. paratuberculosis Sampled from Danish Slaughter Cattle. AB - Presence of Mycobacterium avium subsp. paratuberculosis (MAP) in beef has been reported as a public health concern because asymptomatically infected cattle may contain MAP in tissues that are used for human consumption. Associations between MAP carcasses contamination and animal characteristics such as age, breed, production type, and carcass classification were assessed. Cheek muscles from 501 carcasses were sampled cross-sectionally at a Danish abattoir and tested for presence of viable MAP and MAP DNA by bacterial culture and IS900 realtime PCR, respectively. Cheek muscle tissues from carcasses of two dairy cows were positive by culture whereas 4% of the animals were estimated with >=10 CFU/gram muscle based on realtime PCR. Age was found to be associated with carcass contamination with MAP. The observed viable MAP prevalence in beef carcasses was low. However, detection of MAP and MAP DNA in muscle tissues suggested that bacteremia occurred in slaughtered cattle. PMID- 21547262 TI - Oxidative stress in dog with heart failure: the role of dietary Fatty acids and antioxidants. AB - In dogs with heart failure, cell oxygenation and cellular metabolism do not work properly, leading to the production of a large amount of free radicals. In the organism, these free radicals are responsible of major cellular damages: this is oxidative stress. However, a suitable food intake plays an important role in limiting this phenomenon: on the one hand, the presence of essential fatty acids in the composition of membranes decreases sensitivity of cells to free radicals and constitutes a first protection against the oxidative stress; on the other hand, coenzyme Q10, vitamin E, and polyphenols are antioxidant molecules which can help cells to neutralize these free radicals. PMID- 21547263 TI - Comparative Study of Serological Tests for Mycoplasma synoviae Diagnosis in Commercial Poultry Breeders. AB - Avian mycoplasmosis causes great economic losses to the poultry industry, and one of the major agents involved is Mycoplasma synovie (MS). Serum from commercial poultry breeders (n = 2781) was tested for MS by serum plate agglutination (SPA), hemagglutination inhibition (HI), and enzyme-linked immunosorbent assay (ELISA). From 2,781 samples tested, 736 (26.46%) were positive in SPA. From 712 SPA positive sera, 30 samples (4.21%) were positive in HI, and 150 samples (21.06%) were positive in ELISA. Copositivity between ELISA and HI was 90%, and conegativity was 82.0%. Agreement between HI and ELISA was rejected by McNemar's test (P <= .001), and Kappa coefficient showed a weak correlation between the two techniques (k = 0.25; 0.21 <= k < 0.40). Weak statistical correlation was observed between all serological tests (SPA, HI, and ELISA), and they should only be used for initial screening for MS. PMID- 21547264 TI - Survey of Canine Dirofilaria immitis Infection in New Caledonia. AB - Canine dirofilariosis is a frequent parasitic disease in New-Caledonia. A survey of canine heartworm (Dirofilaria immitis) infection among dogs from the cities of Tontouta, Nandai and Noumea, was performed in March 2009 using two antigen test kits; the microwell ELISA test: DiroCHE (Synbiotics Europe) and the Rapid Immuno Migration (RIM) test: WITNESS DIROFILARIA (Synbiotics Europe). Blood samples were collected from 64 dogs: 49 strays and 15 military working dogs. The military dogs received a permanent chemoprophylaxis (moxidectin). In 11 stray dogs, both tests were positive (22.4%). All the military dogs were negative, showing efficiency of chemoprophaxis. Results were discrepant in 6 dogs, negative with one test and doubtful with the other. Antigen heartworm test kits are available and reliable diagnostic tools. They are useful to evaluate the efficiency of chemoprophylaxis and to detect infected animals in order to treat them and to prevent the spreading of the disease. PMID- 21547265 TI - Smoking, alcohol, and betel quid and oral cancer: a prospective cohort study. AB - We aimed to investigate the association between smoking, alcoholic consumption, and betel quid chewing with oral cancer in a prospective manner. All male patients age >=18 years who visited our clinic received an oral mucosa inspection. Basic data including personal habits were also obtained. A multivariate logistic regression model was utilized to determine relevant risk factors for developing oral cavity cancer. A total of 10,657 participants were enrolled in this study. Abnormal findings were found in 514 participants (4.8%). Three hundred forty-four participants received biopsy, and 230 patients were proven to have oral cancer. The results of multivariate logistic regression found that those who smoked, consumed alcohol, and chewed betel quid on a regular basis were most likely to develop cancer (odds ratio: 46.87, 95% confidence interval: 31.84-69.00). Therefore, habitual cigarette smokers, alcohol consumers, and betel quid chewers have a higher risk of contracting oral cancer and should receive oral screening regularly so potential oral cancer can be detected as early as possible. PMID- 21547266 TI - Use of rituximab in autoimmune hemolytic anemia associated with non-hodgkin lymphomas. AB - The association between non-Hodgkin lymphomas and autoimmune disorders is a well known event. Also autoimmune hemolytic anemia (AHA), although much more frequent in patients with chronic lymphocytic leukemia (CLL), has been described in this group of patients. In recent years, among the more traditional therapeutic options, rituximab, an anti-CD20 monoclonal antibody, has shown interesting results in the treatment of primary AHA. Although this drug has been frequently used for AHA in patients with CLL, much less data are available on its use in NHL patients. However, considering that the main pathogenetic mechanism of AHA in course of lymphoproliferative disorders seems to be an antibody production directly or indirectly mediated by the neoplastic clone, this monoclonal antibody represents an ideal therapeutic approach. In this paper we will briefly describe some biological and clinical features of NHL-patients with AHA. We will then analyze some studies focusing on rituximab in primary AHA, finally reviewing the available literature on the use of this drug in NHL related AHA. PMID- 21547267 TI - Episcleritis Related to Drug-Induced Lupus Erythematosus following Infliximab Therapy: A Case Report. AB - Drug-induced lupus erythematosus is defined as a lupus-like syndrome temporally related to continuous drug exposure which resolves after discontinuation of the offending drug. Herein, we describe a patient with distinct clinical manifestations of anti-TNF-associated DILE related to infliximab therapy. The patient exhibited clinical and laboratory findings of lupus-like illnesses as well as ocular disorders, such as episcleritis. The main message is that the symptoms of DILE should not be overlooked, although sometimes other systematic conditions may underlie them. As a result, it is very important for the clinicians to evaluate the symptoms of DILE and manage appropriately these cases. PMID- 21547268 TI - 12-month herbal medicine use for mental health from the national Comorbidity Survey Replication (NCS-R). AB - BACKGROUND: Herbal medicine is widely used by individuals with mental health problems, although research on their health characteristics and health care utilization patterns-including concomitant treatment with conventional mental health care and psychotropic medication-remains limited. METHODS: We gathered data from the National Comorbidity Survey Replication (NCS-R), a representative survey of US adults in which diagnoses of mental disorders were based on a fully structured diagnostic interview. RESULTS: Our analysis found that NCS-R respondents with mental disorders were significantly more likely to have used herbal medicines for mental health problems than respondents who did not meet criteria for a mental disorder. Users of herbal medicines for mental health problems were likely to utilize conventional health care as well, particularly conventional psychiatric medication. Herbal use also was associated with having multiple comorbid medical problems. CONCLUSIONS: A substantial proportion of US adults use herbal medicine to treat mental health problems. Herbal medicine is frequently used concomitantly with conventional health care, including prescription psychotropic medication. Herbal use also is associated with having multiple chronic medical problems. These factors increase the potential for interactions between herbal medicines and psychiatric and nonpsychiatric medications. PMID- 21547269 TI - Performance characteristics of the PTSD Checklist in retired firefighters exposed to the World Trade Center disaster. AB - BACKGROUND: Since the World Trade Center (WTC) attacks on September 11, 2001, the Fire Department, City of New York Monitoring Program has provided physical and mental health screening services to rescue/recovery workers. This study evaluated performance of the self-report PTSD Checklist (PCL) as a screening tool for risk of posttraumatic stress disorder (PTSD) in firefighters who worked at Ground Zero, compared with the interviewer-administered Diagnostic Interview Schedule (DIS). METHODS: From December 2005 to July 2007, all retired firefighter enrollees completed the PCL and DIS on the same day. Sensitivity, specificity, receiver operating characteristic (ROC) curves, and Youden index (J) were used to assess properties of the PCL and to identify an optimum cutoff score. RESULTS: Six percent of 1,915 retired male firefighters were diagnosed with PTSD using the DIS to assess DSM-IV criteria. Depending on the PCL cutoff, the prevalence of elevated risk relative to DSM-IV criteria varied from 16% to 22%. Youden index identified an optimal cutoff score of 39, in contrast with the frequently recommended cutoff of 44. At 39, PCL sensitivity was 0.85, specificity was 0.82, and the area under the ROC curve was 0.91 relative to DIS PTSD diagnosis. CONCLUSIONS: This is the first study to validate the PCL in retired firefighters and determine the optimal cutoff score to maximize opportunities for PTSD diagnosis and treatment. PMID- 21547271 TI - Sleep disturbances in euthymic bipolar patients. AB - BACKGROUND: Sleep disturbance has been implicated in both prodromal and syndromal phases of bipolar illness. METHODS: Charts of bipolar disorder (BD) patients who had been euthymic for at least 2 months were reviewed for mood symptoms, Clinical Global Impression scores, Global Assessment of Functioning scores, and sleep. RESULTS: Among 116 patients, 10 never achieved a euthymic interval of 2 months' duration. Among the remaining 106 euthymic patients, 59 (55.6%) had BD I, 23 (21.7%) had BD II, and 24 (22.8%) had BD not otherwise specified (NOS). The mean age was 43.3+/-SD 14.6, and 35% were male. A total of 25 patients (23.6%) had a clinically significant ongoing sleep disturbance (27.1% of those with BD I, 21.7% of those with BD II, and 16.6% of those with BD NOS). Of 16 patients for whom a sleep description was available, 25% had difficulty falling asleep, 81.25% had middle insomnia (2 patients experienced both), and none had early morning awakening. Eleven patients (10.4%) received sleep aids, and 33 (31.1%) received sedating antipsychotics (3 patients received both). CONCLUSIONS: Sleeping aids and sedating antipsychotics can potentially disguise an underlying sleep disturbance. Thus, it is possible that study patients taking these medications (n = 58; 54.7%) suffer from a sleep disturbance that is being adequately or inadequately treated. PMID- 21547270 TI - Strategic vs nonstrategic gambling: characteristics of pathological gamblers based on gambling preference. AB - BACKGROUND: Although prior studies have examined various clinical characteristics of pathological gambling (PG), limited data exist regarding the clinical correlates of PG based on preferred forms of gambling. METHODS: We grouped patients meeting DSM-IV criteria for pathological gambling into 3 categories of preferred forms of gambling: strategic (eg, cards, dice, sports betting, stock market), nonstrategic (eg, slots, video poker, pull tabs), or both. We then compared the groups' clinical characteristics, gambling severity (using the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling, the Clinical Global Impression-Severity scale, and time and money spent gambling) and psychiatric comorbidity. RESULTS: The 440 patients included in this sample (54.1% females; mean age 47.69+/-11.36 years) comprised the following groups: strategic (n = 56; 12.7%), nonstrategic (n = 200; 45.5%), or both (n = 184; 41.8%). Nonstrategic gamblers were significantly more likely to be older and female. Money spent gambling, frequency of gambling, gambling severity, and comorbid disorders did not differ significantly among groups. CONCLUSIONS: These preliminary results suggest that preferred form of gambling may be associated with certain age groups and sexes but is not associated with any specific clinical differences. PMID- 21547272 TI - Diabetes prevalence estimates in schizophrenia and risk factor assessment. AB - BACKGROUND: Atypical antipsychotics have been indirectly associated with the diagnosis of type 2 diabetes mellitus (T2DM) in patients with schizophrenia. The purpose of this cross-sectional study was to determine the prevalence of T2DM and to examine the risk factors associated with T2DM among outpatients diagnosed with schizophrenia. The study also sought to determine which risk factors are of particular screening importance in monitoring the metabolic status of these patients. METHODS: This study included 202 patients diagnosed with schizophrenia. Data on a number of known and hypothesized risk factors for T2DM were collected. RESULTS: Risk factors for T2DM identified by bivariate analyses in this sample included older age, waist-to-hip ratio >1.0, sedentary lifestyle, number of hours worked per week, hyperlipidemia, previous screening for T2DM, higher random blood glucose, and number of years on atypical antipsychotics risperidone or olanzapine. However, further scrutiny using multiple logistic regression identified only sedentary lifestyle, waist-to-hip ratio >=1.0, and a diagnosis of hyperlipidemia as significant risk factors in these patients. Similar to other studies, there was an 11.5% (22/192) lifetime prevalence rate of diabetes among this population. CONCLUSIONS: Risk factors traditionally associated with T2DM, as well as waist-to-hip ratio, are the factors most strongly associated with increased risk of diabetes in patients with schizophrenia. PMID- 21547275 TI - Role of atypical antipsychotics in rapid cycling bipolar disorder: a review of the literature. AB - BACKGROUND: The role of atypical antipsychotics in the management of bipolar disorder continues to expand. This review summarizes the literature on use of atypicals in rapid cycling bipolar disorder in clinical practice and highlights areas for future study. METHODS: A PubMed search was done using keywords rapid cycling, atypical antipsychotics, refractory bipolar, aripiprazole, clozapine, olanzapine, risperidone, quetiapine, and ziprasidone. Reference lists from original peer-reviewed articles, review articles, and book chapters were reviewed and articles were extracted. RESULTS: Data on the use of atypical antipsychotics in rapid cycling bipolar disorder are sparse. Atypical antipsychotics may be effective as anti-manic agents during acute mania and may reduce depressive symptoms when used for short and intermediate durations. Their efficacy as mood stabilizers in maintenance therapy has not been demonstrated. CONCLUSIONS: The study of atypical antipsychotics in rapid cycling bipolar disorder is in its infancy. Although atypical antipsychotics are useful in acute mania, current data do not support their use as maintenance agents. Future double-blind, randomized studies are needed to establish their efficacy relative to traditional mood stabilizers and their utility as adjuvant agents in this subset of patients. PMID- 21547273 TI - Alexithymia in oncologic disease: association with cancer invasion and hemoglobin levels. AB - BACKGROUND: The literature suggests that alexithymia is the result of individual differences and/or biological mechanisms. Both individual differences and disease mechanisms may play a role among individuals with medical or surgical conditions. The relative weight of clinical and individual differences factors related to alexithymia has not been studied in patients with cancer. The purpose of this study was to examine the extent to which individual differences in perceived stress and biological markers of illness severity are associated with alexithymia among patients with cancer. METHODS: Treated oncologic outpatients (N = 37) were assessed using the 20-item Toronto Alexithymia Scale and Perceived Stress Scale. Alexithymia was examined in relation to perceived stress, tumor staging, and hemoglobin levels. RESULTS: Among the patients studied, 34.2% endorsed the established cutoff score (>=61) for alexithymia. Higher alexithymia scores were found in patients with more advanced stages of cancer invasion. Alexithymia correlated directly with perceived stress and indirectly with hemoglobin levels. Hemoglobin levels and cancer invasion significantly correlated with alexithymia when controlling for perceived stress. CONCLUSIONS: A significant component of alexithymia in cancer patients may be construed as acquired. But awareness of health status influencing perceived stress might partially mediate the role of cancer invasion and hemoglobin on alexithymia. PMID- 21547274 TI - Obesity in adults with serious and persistent mental illness: a review of postulated mechanisms and current interventions. AB - BACKGROUND: An epidemic of overweight and obesity in the United States has had profound effects on the health of the general population, with consequent development of metabolic syndrome and related morbidity and mortality. However, these effects have been more widespread among adults with serious and persistent mental illness. METHODS: A literature search was conducted using the PubMed and Ovid databases. Terms used, in varying combinations, were schizophrenia, schizoaffective disorder, bipolar disorder, obesity, atypical antipsychotic, diabetes mellitus, hyperlipidemia, and metabolic syndrome. Of 103 articles generated, 71 were deemed pertinent to the current study. One reference was decided upon based on personal communication. RESULTS: Both nonpharmacologic and pharmacologic factors contribute to obesity development in adults with serious and persistent mental illness. Consequently, similarly targeted nonpharmacologic and pharmacologic interventions have been used to mitigate against body weight gain. Although the results obtained thus far are promising, effect sizes only in the low to medium range have been realized, with nonpharmacologic interventions demonstrating slight superiority. CONCLUSIONS: Improved therapeutic methods are needed to address the effects of obesity on individuals with serious and persistent mental illness. Factors that will likely contribute to such advancement are a better understanding of the mechanisms involved, earlier intervention, and adequately powered, randomized controlled trials of sufficient duration, with baseline body weight as a covariate. PMID- 21547276 TI - Periodic catatonia. PMID- 21547277 TI - Tamoxifen-SSRIs interaction: clinical manifestations of inhibition and lack of inhibition of CYP2D6. PMID- 21547282 TI - SERS from molecules bridging the gap of particle-in-cavity structures. AB - We demonstrate that by combining silver nanoparticles and structured gold SSV surfaces the SERS for those molecules that bridge the nanoparticle-cavity gap is preferentially enhanced using 4-mercaptoaniline and 4-mercaptobenzoic acid as examples. PMID- 21547283 TI - Tuning ionic liquids for hydrate inhibition. AB - Pyrrolidinium cation-based ionic liquids were synthesized, and their inhibition effects on methane hydrate formation were investigated. It was found that the ionic liquids shifted the hydrate equilibrium line to a lower temperature at a specific pressure, while simultaneously delaying gas hydrate formation. PMID- 21547284 TI - Analysis of the unbinding force between telomestatin derivatives and human telomeric G-quadruplex by atomic force microscopy. AB - The force analysis between a macrocyclic hexazole (6OTD) monomer/dimer and telomeric DNA using atomic force microscopy revealed the difference in their binding modes. The 6OTD dimer bound to the G-quadruplex more strongly than the monomer by sandwiching the G-quadruplex. PMID- 21547285 TI - Harmonic generation in ablation plasmas of wide bandgap semiconductors. AB - Third and fifth harmonic generation of an IR (1.064 MUm) pulsed laser has been produced in ablation plasmas of the wide bandgap semiconductors CdS and ZnS. The study of the temporal behaviour of the harmonic emission has revealed the presence of distinct compositional populations in these complex plasmas. Species ranging from atoms to nanometre-sized particles have been identified as emitters, and their nonlinear optical properties can be studied separately due to strongly differing temporal behaviour. At short distances from the target (<1 mm), atomic species are mostly responsible for harmonic generation at early times (<500 ns), while clusters and nanoaggregates mostly contribute at longer times (>1 MUs). Harmonic generation thus emerges as a powerful and universal technique for ablation plasma diagnosis and as a tool to determine the nonlinear optical susceptibility of ejected clusters or nanoparticles. PMID- 21547286 TI - Facile solution deposition of ZnIn2S4 nanosheet films on FTO substrates for photoelectric application. AB - In this paper, ZnIn(2)S(4) perpendicular nanosheet films have been directly deposited on FTO substrates by a facile hydrothermal method and investigated as the electrode materials for solar cells. The crystal structure, morphology, and optical properties of the obtained ZnIn(2)S(4) films were characterized by measurements such as X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), energy dispersive spectrum (EDS), X-ray photoelectron spectrum (XPS) and UV-vis spectra. The results revealed a uniform perpendicular ZnIn(2)S(4) film with thickness of 4 MUm and with an average nanosheet thickness of about 30 nm on FTO substrate, along with the band gap of 2.35 eV. The reaction conditions influencing the formation of ZnIn(2)S(4) films, such as the substrate treatment and reaction time were investigated. A possible mechanism for the formation of ZnIn(2)S(4) films on FTO substrates under hydrothermal conditions has been proposed. Furthermore, after heat treatment, the ZnIn(2)S(4) film electrode exhibited a photoelectrical conversion efficiency of 0.23% in FTO/ZnIn(2)S(4)/polysulfide/Au liquid-junction solar cell under AM 1.5 (100 mW cm(-2)). PMID- 21547287 TI - D-Glucose as green ligand for selective copper-catalyzed phenol synthesis from aryl halides with an easy catalyst removal. AB - With the growing demand of environmentally friendly reagents for organic reactions, for the first time the utility of D-glucose as a ligand in its direct form has been described using a typical example of copper-catalyzed coupling reaction for phenol synthesis with a high degree of selectivity and easy catalyst removal. PMID- 21547288 TI - Brief, efficient and highly diastereoselective synthesis of (+/-)-pumiliotoxin C based on the generation of an octahydroquinoline precursor via a four-component reaction. AB - A short and highly diastereoselective synthesis of the amphibian alkaloid pumiliotoxin C is described, based on the preparation of an octahydroquinoline derivative through a four-component reaction. The route proceeds in 66% overall yield from 1,3-cyclohexanedione and includes two hydrogenation steps, whose stereochemical outcome was controlled via nitrogen acylation. PMID- 21547289 TI - Synthesis and coordination behavior of Cu(I) bis(phosphaethenyl)pyridine complexes. AB - Cu(I) complexes bearing BPEP as a PNP-pincer type phosphaalkene ligand undergo effective bonding interactions with SbF(6)(-) and PF(6)(-) as non-coordinating anions to give [Cu(SbF(6))(BPEP)] and [Cu(2)(BPEP)(2)(MU-PF(6))](+), respectively [BPEP = 2,6-bis(1-phenyl-2-phosphaethenyl)pyridine]. NMR and theoretical studies indicate a reduced anionic charge of the MU-PF(6) ligand, which is induced by the strong pi-accepting ability of BPEP. PMID- 21547290 TI - Gold(I)-catalyzed rearrangement of aryl alkynylaziridines to spiro[isochroman 4,2'-pyrrolines]. AB - Alkynylaziridines carrying an aryl group could be efficiently converted to spiro[isochroman-4,2'-pyrrolines] with gold salts as catalysts. This new rearrangement involved a Friedel-Crafts type intramolecular reaction followed by cyclization of the aminoallene intermediate, both initiated by the dual sigma and pi Lewis acidities of gold. PMID- 21547291 TI - The Diels-Alder reaction of C60 and cyclopentadiene in mesoporous silica as a reaction medium. AB - As a new organic reaction medium, a periodic mesoporous inorganic material was found to function as a "solid solvent" in a Diels-Alder reaction of C(60) with cyclopentadiene. This finding was supported by a concentration effect and a kinetic study of the reaction. PMID- 21547292 TI - Expanded redox accessibility via ligand substitution in an octahedral Fe6Br6 cluster. AB - Oxidation of the nominally all-ferrous hexanuclear cluster ((H)L)(2)Fe(6) with six equivalents of ferrocenium in the presence of bromide ions results in a six electron oxidation of the Fe(6) core to afford the nominally all-ferric cluster ((H)L)(2)Fe(6)Br(6). The hexabromide cluster is also structurally characterized in a 4+ core oxidation state. A structural comparison of these two clusters provides an insight into the Fe(6) core electronic structure. PMID- 21547293 TI - "Proof-of-principle" concept for ultrasensitive detection of cytokines based on the electrically heated carbon paste electrode. AB - The proof-of-principle of the integration of electrically heated carbon paste electrode with immunoassay as a potential alternative for ultrasensitive detection of cytokines was demonstrated. PMID- 21547294 TI - Triggered activity of a nicking endonuclease for mercuric(II) ion-mediated duplex like DNA cleavage. AB - The cleavage activity of a nicking endonuclease towards metal-ion-mediated duplex like DNA can be triggered by the corresponding metal ions, which was demonstrated with mercuric(II) ion as a model via a simple electrochemical protocol. PMID- 21547295 TI - Constructed wetlands using aluminium-based drinking water treatment sludge as P removing substrate: should aluminium release be a concern? AB - This study investigated an important issue of aluminium (Al) release from a novel reuse of Al-based water treatment sludge (Al-WTS) in constructed wetland system (CWs) as alternative substrate for wastewater treatment. Al-WTS is an inevitable by-product of drinking water treatment plants that use Al-salt as coagulant for raw water purification. It has recently been demonstrated that Al-WTS can be reused as a low-cost phosphorus (P) adsorbent and biofilm carrier in CWs for wastewater treatment. However, to facilitate the large scale application of Al WTS in CWs as wetland substrate, concerns about Al leaching during its reuse in CWs must be addressed as Al is a dominant constituent in Al-WTS. In this study, a desk review of literature on Al release during Al-WTS reuse was conducted. Furthermore, a 42-week Al monitoring was carried out on a pilot field-scale CWs employing Al-WTS as main substrate. Results show that 22 out of the 35 studies reviewed, reported Al release with levels of soluble Al reported ranging from 0.01 to about 20 mg L(-1). Monitoring of Al in the pilot field-scale CWs shows that there was Al leaching. However, except for the first three weeks of operation, effluents concentrations of both total- and soluble-Al were all below the general regulatory guideline limit of 0.2 mg L(-1). Overall, the study addresses a vital concern regarding the successful application of Al-WTS in CWs and shows that Al release during such novel reuse is quite low and should not preclude its use. PMID- 21547296 TI - Multiple kinetic Langmuir modeling to predict the environmental behaviour of As(v) in soils. AB - A soil with a relatively high Fe content (2.82% [w/w]) was loaded for up to one year with As(v) by equilibrating it with a solution containing 1000 mg l(-1) As(v) at a soil mass-to-solution ratio of 0.1 kg l(-1). The incorporation of As(v) into the soil and its distribution over the soil phases were monitored by sampling at strategic time intervals using an operationally defined five-step sequential extraction procedure (Wenzel et al., Anal. Chim. Acta, 2001, 436, 309) and subsequent As measurement. A multiple kinetic Langmuir model was developed to retrieve the dynamic parameters (adsorption and desorption rate constants, capacities and Langmuir equilibrium constants) for each of the soil phases by numerical fitting of the experimental adsorption data to the model. Under the equilibration conditions used the adsorption rate constants for all five operationally defined soil phases were very similar but the desorption rate constants decreased by a factor of ca. 150 from soil phase 1 (non-specifically sorbed As) to 5 (residual phases). This implies that As(v) incorporation "deeper" into the soil leads to stronger binding which is associated with the Langmuir equilibrium constants (adsorption rate constants/desorption rate constants). Equilibration of the soil with As(v) was complete in ca. 10 days with As(v) predominantly bound to soil phase 2 (specifically sorbed As) and soil phase 3 (amorphous and poorly crystalline hydrous oxides). X-Ray absorption spectroscopy techniques revealed that these binding characteristics may be related to adsorption of As(v) on Si- and/or Al-containing structures and natural hydrous iron oxide (HFO) surface sites, respectively. Since the model is independent of the initial As(v) concentration in the solution and the soil mass-to-solution ratio, the behaviour of the thus characterized soil-As(v) system can be predicted for a range of conditions. Simulations showed that in an accidental As(v) spill the soil studied would actively scavenge As(v) by instantaneous adsorption onto all soil phases followed by redistribution of As(v) from weaker binding sites to stronger ones over time. PMID- 21547299 TI - Mesoporous silica nanoparticles for bioadsorption, enzyme immobilisation, and delivery carriers. AB - Mesoporous silica nanoparticles (MSNs) provide a non-invasive and biocompatible delivery platform for a broad range of applications in therapeutics, pharmaceuticals and diagnosis. The creation of smart, stimuli-responsive systems that respond to subtle changes in the local cellular environment are likely to yield long term solutions to many of the current drug/gene/DNA/RNA delivery problems. In addition, MSNs have proven to be promising supports for enzyme immobilisation, enabling the enzymes to retain their activity, affording them greater potential for wide applications in biocatalysis and energy. This review provides a comprehensive summary of the advances made in the last decade and a future outlook on possible applications of MSNs as nanocontainers for storage and delivery of biomolecules. We discuss some of the important factors affecting the adsorption and release of biomolecules in MSNs and review of the cytotoxicity aspects of such nanomaterials. The review also highlights some promising work on enzyme immobilisation using mesoporous silica nanoparticles. PMID- 21547298 TI - Alterations in urinary metabolites due to unilateral ureteral obstruction in a rodent model. AB - Urinary tract obstruction (UTO) results in renal compensatory mechanisms and may progress to irrecoverable functional loss and histologic alterations. The pathophysiology of this progression is poorly understood. We identified urinary metabolite alterations in a rodent model of partial and complete UTO using (1)H nuclear magnetic resonance ((1)H-NMR) spectroscopy. Principal component analysis (PCA) was used for classification and discovery of differentiating metabolites. UTO was associated with elevated urinary levels of alanine, succinate, dimethylglycine (DMG), creatinine, taurine, choline-like compounds, hippurate, and lactate. Decreased urinary levels of 2-oxoglutarate and citrate were noted. The patterns of alteration in partial and complete UTO were similar except that an absence of elevated urinary osmolytes (DMG and hippurate) was noted in complete UTO. This pattern of metabolite alteration indicates impaired oxidative metabolism of the mitochondria in renal proximal tubules and production of renal protective osmolytes by the medulla. Decreased production of osmolytes in complete obstruction better elucidates the pathophysiology of progression from renal compensatory mechanisms to irrecoverable changes. Further confirmation of these potential biomarkers in children with UTO is necessary. PMID- 21547297 TI - Functional diversification of the RING finger and other binuclear treble clef domains in prokaryotes and the early evolution of the ubiquitin system. AB - Recent studies point to a diverse assemblage of prokaryotic cognates of the eukaryotic ubiquitin (Ub) system. These systems span an entire spectrum, ranging from those catalyzing cofactor and amino acid biosynthesis, with only adenylating E1-like enzymes and ubiquitin-like proteins (Ubls), to those that are closer to eukaryotic systems by virtue of possessing E2 enzymes. Until recently E3 enzymes were unknown in such prokaryotic systems. Using contextual information from comparative genomics, we uncover a diverse group of RING finger E3s in prokaryotes that are likely to function with E1s, E2s, JAB domain peptidases and Ubls. These E1s, E2s and RING fingers suggest that features hitherto believed to be unique to eukaryotic versions of these proteins emerged progressively in such prokaryotic systems. These include the specific configuration of residues associated with oxyanion-hole formation in E2s and the C-terminal UFD in the E1 enzyme, which presents the E2 to its active site. Our study suggests for the first time that YukD-like Ubls might be conjugated by some of these systems in a manner similar to eukaryotic Ubls. We also show that prokaryotic RING fingers possess considerable functional diversity and that not all of them are involved in Ub-related functions. In eukaryotes, other than RING fingers, a number of distinct binuclear (chelating two Zn atoms) and mononuclear (chelating one zinc atom) treble clef domains are involved in Ub-related functions. Through detailed structural analysis we delineated the higher order relationships and interaction modes of binuclear treble clef domains. This indicated that the FYVE domain acquired the binuclear state independently of the other binuclear forms and that different treble clef domains have convergently acquired Ub-related functions independently of the RING finger. Among these, we uncover evidence for notable prokaryotic radiations of the ZF-UBP, B-box, AN1 and LIM clades of treble clef domains and present contextual evidence to support their role in functions unrelated to the Ub-system in prokaryotes. In particular, we show that bacterial ZF-UBP domains are part of a novel cyclic nucleotide-dependent redox signaling system, whereas prokaryotic B-box, AN1 and LIM domains have related functions as partners of diverse membrane-associated peptidases in processing proteins. This information, in conjunction with structural analysis, suggests that these treble clef domains might have been independently recruited to the eukaryotic Ub-system due to an ancient conserved mode of interaction with peptides. PMID- 21547300 TI - Convergent strategies in biosynthesis. AB - This review article focuses on how nature sometimes solves the same problem in the biosynthesis of small molecules but using very different approaches. Four examples, involving isopentenyl diphosphate, menaquinone, lysine, and aromatic polyketides, are highlighted that represent different strategies in convergent metabolism. PMID- 21547301 TI - Fast copper-free click DNA ligation by the ring-strain promoted alkyne-azide cycloaddition reaction. AB - Templated DNA strand ligation by the ring-strain promoted alkyne-azide [3+2] cycloaddition reaction is very fast; with dibenzocyclooctyne, the reaction is essentially complete in 1 min. It is inhibited by the presence of a single mismatched base pair suggesting applications in genetic analysis. PMID- 21547302 TI - Ultrasensitive protein detection using an aptamer-functionalized single polyaniline nanowire. AB - A highly sensitive, conductometric and label-free biosensor for the detection of immunoglobulin E (IgE) is developed based on the immobilzation of the IgE aptamer onto a single polyaniline nanowire electrochemically synthesized in a facile and controllable way. PMID- 21547303 TI - Palladium-catalyzed aerobic oxidation of 1-phenylethanol with an ionic liquid additive. AB - The aerobic oxidation of 1-phenylethanol over a carbon nanotube supported palladium catalyst was improved with an ionic liquid additive [emim][NTf(2)], showing an excellent TON of 149,000 which can be maintained for 5 recycle runs. PMID- 21547304 TI - Peroxynitrite generation from a NO-releasing nitrobenzene derivative in response to photoirradiation. AB - Photocontrollable ONOO(-) generation from a nitrobenzene derivative was demonstrated. The designed compound released NO in response to photoirradiation, and the resulting semiquinone reduced molecular oxygen to generate O(2)(-); reaction of the two generated ONOO(-), as confirmed with an ONOO(-) fluorescent probe, HKGreen-3. PMID- 21547306 TI - Importance of dynamic hydrogen bonds and reorientation barriers in proton transport. AB - The dynamic nature of hydrogen bonds in phenolic polymers, where the hydrogen bond donor/acceptor reorientation can occur in a single site, presents lower barriers for proton transport. PMID- 21547305 TI - Metabolic footprinting of the anaerobic bacterium Fusobacterium varium using 1H NMR spectroscopy. AB - Metabolic footprinting of the anaerobic bacterium Fusobacterium varium demonstrated the accumulation of six carboxylic acids as metabolic end-products and revealed specific growth requirements and utilization capabilities towards amino acids. Guided by (1)H NMR determinations of residual amino acids in spent medium, a modified chemically defined minimal medium (CDMM*) was developed by minimizing the amino acid composition while satisfying nutritional requirements to support abundant growth of F. varium. Quantitative determinations of carboxylate salts and residual substrates were readily performed by (1)H NMR analysis of lyophilized residues from CDMM* cultures without interference from initial medium components. Only small concentrations of alanine, arginine, glycine, isoleucine, leucine, methionine, proline and valine were required to support growth of F. varium, whereas larger quantities of aspartate, asparagine, cysteine, glutamine, glutamate, histidine, lysine, serine and threonine were utilized, most likely as energy sources. Both bacterial growth and the distribution of carboxylate end-products depended on the composition of the chemically defined medium. In cultures provided with glucose as the primary energy source, the accumulation of butyrate and lactate correlated with growth, consistent with the regeneration of reduced coenzyme formed by the oxidative steps of glucose catabolism. PMID- 21547307 TI - A highly efficient chemical sensor material for ethanol: Al2O3/Graphene nanocomposites fabricated from graphene oxide. AB - Al(2)O(3)/Graphene nanocomposites are firstly produced from GO solution by a one step, green, facile, low-cost SC CO(2) method. The as-prepared nanocomposite papers display high CL sensitivity and high selectivity to the ethanol gas, which provides a facile, green and low-cost route for the preparation of ethanol nanoscopic sensing devices with wide applications. PMID- 21547308 TI - Variations of periphytic diatom sensitivity to the herbicide diuron and relation to species distribution in a contamination gradient: implications for biomonitoring. AB - Diatoms are commonly used as bioindicators of trophic and saprobic pollution in rivers. However, more knowledge is needed concerning their sensitivity to toxicants such as agricultural herbicides. In this study, seven species of periphytic diatoms were isolated from the Morcille River (Beaujolais area, France) which presents a streamward contamination gradient by pesticides and particularly diuron. The sensitivity of these species to diuron was assessed through ecotoxicological tests based on short-term growth inhibition of monospecific cultures. After application of an appropriate toxicological model, EC50 were determined and the species were ranked according to their tolerance. EC50 values ranged from 4.5 to 19 MUg L(-1). Finally, the results were related to field periphyton samples from an upstream and a downstream site in order to check if variations in specific relative abundance between sites are consistent with differences in tolerance to diuron. Species distribution between sites was only partially in accordance with toxicological results suggesting that other factors (toxic or trophic) have an important influence on diatom communities in the river. Nevertheless, diatoms showed their potential to indicate water contamination by pesticides and toxic indices could be developed in complement to existing trophic indices. PMID- 21547309 TI - BINEPINES: chiral binaphthalene-core monophosphepine ligands for multipurpose asymmetric catalysis. AB - The atropisomeric structure of 4,5-dihydro-3H-dinaphtho[2,1-c;1',2'-e]phosphepine is the common axially chiral scaffold of a library of monophosphine ligands nicknamed BINEPINES that have shown a quite remarkable stereoselection efficiency in a broad variety of enantioselective reactions involving the formation of new C H or C-C or C-X bonds. In this critical review the properties and scope of this type of chiral ligands are illustrated (70 references). PMID- 21547310 TI - "Bioelectronic super-taster" device based on taste receptor-carbon nanotube hybrid structures. AB - We have developed a method to monitor the activities of human taste receptor protein in lipid membrane using carbon nanotube transistors, enabling a "bioelectronic super-taster (BST)", a taste sensor with human-tongue-like selectivity. In this work, human bitter taste receptor protein expressed in E. coli was immobilized on a single-walled carbon nanotube field effect transistor (swCNT-FET) with the lipid membrane. Then, the protein binding activity was monitored using the underlying swCNT-FET, leading to the operation as a BST device. The fabricated BST device could detect bitter tastants at 100 fM concentrations and distinguish between bitter and non-bitter tastants with similar chemical structures just like a human tongue. Furthermore, this strategy was utilized to differentiate the responses of taster or non-taster types of the bitter taste receptor proteins. PMID- 21547311 TI - Synthesis of stereoregular ROMP polymers using molybdenum and tungsten imido alkylidene initiators. AB - Three of the four possible structures for polymers formed from an achiral monomer through a single ROMP polymerization step have been prepared for a small collection of monomers. Trans,syndiotactic structures have been prepared through chain end control, cis,isotactic polymers have been prepared through enantiomorphic site control, and cis,syndiotactic polymers have been prepared through stereogenic metal control. Stereogenic metal control at the metal center as a means of forming syndiotactic polymers is virtually unknown. Synthesis of ROMP polymers with a regular structure that contain alternating enantiomers from a racemic mixture of monomers is a natural consequence of stereogenic metal control. Ruthenium catalysts do not display ROMP specificities analogous to those described here, perhaps since alkylidene isomers have not been observed for Ru catalysts and the barrier to rotation of the carbene in a generic NHC dichloride Ru catalyst has been calculated to be relatively low. PMID- 21547312 TI - Reactions of Zn bis-ferrocenyl-beta-diketiminates with [Ph3C][B(C6F5)4]. AB - The ZnMe complexes of bis-ferrocenyl-beta-diketiminate ligands are prepared and the reactions with [Ph(3)C][B(C(6)F(5))(4)] are found to yield the salts [H(Ph(3)C)C(MeC(N(C(5)H(4))FeCp)(2)ZnMe] [B(C(6)F(5))(4)] and [CH(2)=C(MeC(N(C(5)H(4))FeCp)(2)ZnMe][B(C(6)F(5))(4)], derived from electrophilic substitution and hydride abstraction. PMID- 21547313 TI - Photochemical and photophysical properties of dibenzoylmethane derivatives within protein. AB - In the present work, three dibenzoylmethane derivatives in their beta-diketo form have been selected to investigate their photophysical and photochemical behavior upon interaction with human serum albumin (HSA). In organic solvents, absorption and phosphorescence emission spectra of the alpha-bromo derivative of avobenzone (BrAB) were similar to those of the alpha-methylated and alpha-propyl analogs (MeAB and PrAB). However, laser flash photolysis experiments revealed a different transient species centered at 350 nm, assigned to the radical obtained from a singlet excited state dehalogenation process. Interestingly, the transient absorption spectrum of BrAB within HSA showed the typical features of the beta diketone triplet excited state. In the case of MeAB and PrAB derivatives, binding to HSA was associated with a significant increase of their triplet lifetimes as compared to acetonitrile. Finally, the Norrish type II process has been considered as a model to evaluate the influence of the protein microenvironment on the photoreactivity. In this context, photodegradation of PrAB in aerated solutions, to give avobenzone (AB), has been monitored by UV spectroscopy. Interestingly, the quantum yields of AB formation were markedly dependent on the reaction medium (1.4 * 10(-2) in acetonitrile and 3.9 * 10(-2) within albumin medium); by contrast, chemical yields of ca. 50% were obtained in both cases. PMID- 21547314 TI - Carbon nanotube based separation columns for high electrical field strengths in microchip electrochromatography. AB - Electrically insulated carbon nanotube (CNT) based separation columns have been fabricated that can withstand an electrical field strength of more than 2.0 kV cm(-1) without bubble formation from electrolysis. The carbon nanotubes were grown in a pillar array defined by photolithographic patterning of the catalyst layer used for synthesis of the nanotubes. Multiwall carbon nanotubes are inherently electrically conductive and cannot be used as a continuous layer in the microfluidic channels, without short circuiting the electrical field in the separation column, when the field strength is more than a couple of 100 V cm(-1). Here, the carbon nanotubes are grown in an array of hexagonal pillars, where the nanotubes in the individual pillars are not in direct electrical contact with the nanotubes of the adjacent pillars. This makes it possible to increase the electrical field strength from around 100 V cm(-1) to more than 2.0 kV cm(-1) and thereby to use the CNT columns for electrokinetic separations with the high electrical field strengths that are typically used in this application. An electrochromatographic separation of two Coumarin dyes was demonstrated on the CNT column with an acetonitrile content of 90%. PMID- 21547315 TI - Mixing enhancement for high viscous fluids in a microfluidic chamber. AB - Due to small channel dimensions and laminar flows, mixing in microfluidic systems is always a challenging task, especially for high viscous fluids. Here we report a method of enhancing microfluidic mixing for high viscous fluids using acoustically induced bubbles. The bubbles can be generated in an acoustically profiled microfluidic structure by using a piezoelectric disk activated at a working frequency range between 1.5 kHz and 2 kHz. The mixing enhancement is achieved through interactions between the oscillating bubbles and fluids. Both experimental studies and numerical simulations are conducted. In the experiments, DI water-glycerol mixture solutions with various viscosities were used. The results, based on the mixing efficiency calculated from experimentally acquired fluorescent images, showed that good mixing can occur in the DI water-glycerol solutions with their maximum viscosity up to 44.75 mPa s, which to our best knowledge is the highest viscosity of fluids in microfluidic mixing experiments. To explain the mechanisms of bubble generation, the numerical simulation results show that, corresponding to the actuations at the working frequency range used in the experiment, there exists a low pressure region where the pressure is lower than the water vapor pressure in the DI water-glycerol solutions, resulting in the generation of bubbles. PMID- 21547316 TI - Transient deflection response in microcantilever array integrated with polydimethylsiloxane (PDMS) microfluidics. AB - We report the integration of a nanomechanical sensor consisting of 16 silicon microcantilevers with polydimethylsiloxane (PDMS) microfluidics. For microcantilevers positioned near the bottom of a microfluidic flow channel, a transient differential analyte concentration for the top versus bottom surface of each microcantilever is created when an analyte-bearing fluid is introduced into the flow channel (which is initially filled with a non-analyte containing solution). We use this effect to characterize a bare (nonfunctionalized) microcantilever array in which the microcantilevers are simultaneously read out with our recently developed high sensitivity in-plane photonic transduction method. We first examine the case of non-specific binding of bovine serum albumin (BSA) to silicon. The average maximum transient microcantilever deflection in the array is -1.6 nm, which corresponds to a differential surface stress of only 0.23 mN m(-1). This is in excellent agreement with the maximum differential surface stress calculated based on a modified rate equation in conjunction with finite element simulation. Following BSA adsorption, buffer solutions with different pH are introduced to further study microcantilever array transient response. Deflections of 20-100 nm are observed (2-14 mN m(-1) differential surface stress). At a flow rate of 5 MUL min(-1), the average measured temporal width (FWHM) of the transient response is 5.3 s for BSA non-specific binding and 0.74 s for pH changes. PMID- 21547317 TI - Miniature magnetic resonance system for point-of-care diagnostics. AB - We have developed a next generation, miniaturized platform to diagnose disease at the point-of-care using diagnostic magnetic resonance (DMR-3). Utilizing a rapidly growing library of functionalized magnetic nanoparticles, DMR has previously been demonstrated as a versatile tool to quantitatively and rapidly detect disease biomarkers in unprocessed biological samples. A major hurdle for bringing DMR to the point-of-care has been its sensitivity to temperature variation. As an alternative to costly and bulky mechanisms to control temperature, we have implemented an automated feedback system to track and compensate for the temperature drift, which enables reliable and robust DMR measurements in realistic clinical environments (4-50 degrees C). Furthermore, the new system interfaces with a mobile device to facilitate system control and data sharing over wireless networks. With such features, the DMR-3 platform can function as a self-contained laboratory even in resource-limited, remote settings. The clinical potential of the new system is demonstrated by detecting trace amounts of proteins and as few as 10 bacteria (Staphylococcus aureus) in a short time frame (<30 min). PMID- 21547318 TI - An organic ionic plastic crystal electrolyte based on the triflate anion exhibiting high proton transport. AB - A novel organic ionic plastic crystal (OIPC) electrolyte based on a quaternary ammonium cation and the triflate anion has been synthesized, which shows fast proton transport and high thermal stability in the solid state when doped with triflic acid. PMID- 21547319 TI - Rationalizing current strategies to protect N-heterocyclic carbene-based ruthenium catalysts active in olefin metathesis from C-H (de)activation. AB - Defending second generation Ru-catalysts in olefin metathesis from C-H (de)activation reactions requires precise catalyst design strategies. Computer simulations are used here to rationalize precisely the role of the currently used catalyst structural modifications, and the way these modifications cooperate. PMID- 21547320 TI - Effect of zeolite precursor on the formation of MCM-41 molecular sieve containing zeolite Y building units. AB - The effect of zeolite Y precursor on the formation of MCM-41 containing zeolite Y building units has been investigated by means of UV Raman spectroscopy, X-ray diffraction (XRD), infrared spectroscopy (IR) and electron microscopy (SEM and TEM). Study of the precursor formation shows that 4-membered ring species are formed at the early stages of crystallization. Zeolite Y begins to appear after crystallization for 4 h, and its crystallinity increases with increasing crystallization time. However, lowering the pH value to ~9.3 in the second step not only facilitates the polymerization of silicate species, but also leads to the structural change of the precursors. Pure MCM-41 mesoporous phase containing zeolite Y building units and the mixture of zeolite Y and MCM-41 can be formed combining the effects of the precursor structure and the pH adjustment. PMID- 21547321 TI - Dielectric anisotropy of the single crystal of isopropylviologen copper(I) triiodide. AB - Solvothermal reactions of CuI with isopropanol, 4,4'-bipyridine, I(2) and a small amount of water in MeCN produced one coordination compound [isopropylviologen][CuI(3)] (isopropylviologen = N,N'-diisopropyl-4,4' bipyridinium) (1). The dielectric constants of the single crystal of 1 along the three crystal axes are different with the largest diversity ratio of ~3.3, showing dielctric anisotropic behavior. Under low temperature (<273 K) or medium electric field frequency range (1 KHz-1 MHz), the dielectric constant of the title compound is nearly unchanged, exhibiting a temperature/frequency independent characteristics. The crystalline powder of 1 has a low dielectric constant and low dielectric loss in the medium electric field frequency range, which is comparable to the traditional low-k material SiO(2). PMID- 21547322 TI - Physical assessment of toxicology at nanoscale: nano dose-metrics and toxicity factor. AB - In this work, we propose a systematic and reproducible evaluation of nanoparticles (NPs) toxicology in living systems, based on a physical assessment and quantification of the toxic effects of NPs by the experimental determination of the key parameter affecting the toxicity outcome (i.e., the number of NPs) and of the NPs "toxicity factor". Such a strategy was applied to a well determined scenario, i.e., the ingestion of citrate-capped gold NPs (AuNPs) of different sizes by the model system Drosophila melanogaster. Using these AuNPs as a reference toxicity standard, we were able to define different regions in the multiparametric space of toxicity, enabling the classification of the toxic levels of other nanomaterials, such as quantum dots and pegylated AuNPs. This approach may pave the way to a systematic classification of nanomaterials, leading to important developments in risk assessment and regulatory approval, as well as in a wide range of nanomedicine applications. PMID- 21547323 TI - A europium(III) chelate as an efficient time-gated luminescent probe for nitric oxide. AB - The first Eu(3+) chelate-based luminescent probe specific for nitric oxide (NO) has been designed and synthesized for highly sensitive and selective time-gated luminescence detection of NO. Based on the probe, a time-gated luminescence imaging technique was developed for imaging the endogenous NO production in living plant cells/tissues. PMID- 21547324 TI - Protolytic defluorination of trifluoromethyl-substituted arenes. AB - A series of trifluoromethyl-substituted arenes were studied in their reactions with Bronsted superacids. The products from these reactions suggest the formation of reactive electrophiles, such as carbocations, acylium cations or equivalent electrophilic species. As such, Friedel-Crafts-type reactions occur between these species and arene nucleophiles. NMR studies were done, and the results suggest the formation of an acyl group from the trifluoromethyl groups in the superacid. PMID- 21547325 TI - CO catalytic oxidation by a metal organic framework containing high density of reactive copper sites. AB - A new metal organic framework containing high density of active Cu sites demonstrates 100% oxidative conversion of CO to CO(2). PMID- 21547326 TI - Controlled morphology and photoreduction characteristics of polyoxometalate(POM)/lipid complexes and the effect of hydrogen bonding at molecular interfaces. AB - Supramolecular complexes consisting of anionic polyoxometalate (POM) and chiral, cationic lipids are newly developed. They give nanofibers, helical ribbons, and nanotapes in organic media depending on the chemical structure of lipid molecules. Lipid ammonium groups exert significant influence on their photoreduction characteristics. PMID- 21547327 TI - Structure inducing ionic liquids-enhancement of alpha helicity in the Abeta(1-40) peptide from Alzheimer's disease. AB - We have studied the impact of ionic liquid solvents on the structure of the Abeta(1-40) peptide from Alzheimer's disease and found that ionic liquid solvents were able to induce a conformational change in the structure of the Abeta(1-40) peptide. This conformational change impacts the self-assembly of the peptide into amyloid fibrils. PMID- 21547328 TI - Unprecedented binding and activation of CS2 in a dinuclear copper(I) complex. AB - The first structural characterisation of a copper-carbondisulfide complex revealed a hitherto unknown binding mode for CS(2): it interacts with two metal centres (Cu(I)) simultaneously via both C=S pi bonds. DFT calculations showed that complex formation occurs mainly due to a donation of electron density from the copper centres into the C=S pi* orbitals. PMID- 21547329 TI - Targeted photodynamic therapy--a promising strategy of tumor treatment. AB - Targeted therapy is a new promising therapeutic strategy, created to overcome growing problems of contemporary medicine, such as drug toxicity and drug resistance. An emerging modality of this approach is targeted photodynamic therapy (TPDT) with the main aim of improving delivery of photosensitizer to cancer tissue and at the same time enhancing specificity and efficiency of PDT. Depending on the mechanism of targeting, we can divide the strategies of TPDT into "passive", "active" and "activatable", where in the latter case the photosensitizer is activated only in the target tissue. In this review, contemporary strategies of TPDT are described, including new innovative concepts, such as targeting assisted by peptides and aptamers, multifunctional nanoplatforms with navigation by magnetic field or "photodynamic molecular beacons" activatable by enzymes and nucleic acid. The imperative of introducing a new paradigm of PDT, focused on the concepts of heterogeneity and dynamic state of tumor, is also called for. PMID- 21547330 TI - Ratiometric molecular beacons based on the perylene bisimide as a dimeric internal DNA base substitution. AB - Molecular beacons with an excitonically interacting perylene bisimide base pair show the presence of the complementary olignucleotide sequence by both absorption and fluorescence changes. PMID- 21547331 TI - Capturing protein structural kinetics by mass spectrometry. AB - Precise knowledge of the three-dimensional structure of a protein is critical, if we are to understand its biological role and mode of action. However, today it is becoming increasingly clear that dissecting the protein's structural architecture is not enough: a complete description of biomolecular activity must also include the dimension of time. Protein motion and dynamics are crucial for protein stability and reactivity. A range of techniques have been developed for probing dynamic processes. In this tutorial review, we focus on one of these approaches- structural mass spectrometry (MS). MS has the ability to capture functional conformational transitions in the slow time regime, from a few milliseconds to hours. The power of this approach lies not only in its sensitivity and speed of analysis, but also in the fact that it is a non-ensemble technique. Thus, within a single spectrum, the entire distribution of co-existing states can be resolved. In discussing the challenges, advantages and limitations of the field, as well as future directions, we highlight the applicability of MS for quantitative monitoring of structural kinetics. In particular, we describe the array of MS based strategies that are available for capturing protein folding, enzymatic reactions, ligand interactions, subunit exchange and biogenesis pathways. PMID- 21547332 TI - Post-infectious bronchiolitis obliterans in children. AB - OBJECTIVE: To review publications about the main features of post-infectious bronchiolitis obliterans and its history, etiology, epidemiology, risk factors, pathogenesis, histological findings, clinical presentation, complementary tests, diagnostic criteria, differential diagnosis, treatment and prognosis. SOURCES: Non-systematic review of MEDLINE and LILACS databases and selection of 66 most relevant studies. SUMMARY OF THE FINDINGS: In the post-infectious bronchiolitis obliterans there is an insult to respiratory epithelial cells, and its clinical severity is associated with the degree of lesion and inflammation. Diagnosis is made according to clinical signs and symptoms, by exclusion of main differential diagnoses and with the aid of complementary tests. High resolution CT, particularly images obtained during inspiration and expiration, provide information for the evaluation of the small airways. Pulmonary function tests show fixed airway obstructions and marked decrease of FEF25-75%. Treatment has not been definitely established, and corticoids have been administered as pulse therapy or by inhalation of high doses of steroids. However, data about its efficacy are scarce in the literature. Long-term prognosis is variable, and there might be either clinical improvement or deterioration into respiratory insufficiency and death. CONCLUSION: Post-infectious bronchiolitis obliterans is a disease with a high morbidity rate; it should be treated by a multidisciplinary team, and patients should be followed up for a long period of time. PMID- 21547333 TI - In this issue: glycine substitution mutations in the COL7A1 gene: implications for inheritance of dystrophic epidermolysis bullosa - dominant vs. recessive. PMID- 21547334 TI - Melanotropic peptides: what exactly is meant by "melanotan"? PMID- 21547335 TI - Survival data for 299 patients with primary cutaneous lymphomas: a monocentre study. AB - The aim of this study was retrospectively to assess the validity of the 2005 WHO EORTC classification for primary cutaneous lymphomas (PCL) in a large cohort of patients of a single German skin cancer unit. All patients with PCLs consecutively visiting our hospital between January 1980 and December 2005 were included in a retrospective monocentre study, analysing their histological and clinical data. A total of 312 patients fulfilled the inclusion criteria for PCL. In 299 patients clinical information and paraffin material were sufficient for detailed classification. Of the 299 patients, 63% expressed a T-cell and 37% a B cell phenotype. Mycosis fungoides was the entity with the highest frequency (30.9%), followed by primary cutaneous follicle centre lymphomas (16.9%) and lymphomatoid papulosis (15.9%). The mean follow-up period was 38.4 months. Five year disease-specific survival was 80.5% for mycosis fungoides, 92.5% in primary cutaneous anaplastic large cell lymphoma, 100% in lymphomatoid papulosis, 98.1% in primary cutaneous follicle center lymphoma, 100% in primary cutaneous marginal zone lymphoma and 63.2% in diffuse large B-cell lymphoma, leg type. Our data are in line with the data collected by the WHO-EORTC. This is further evidence for the reliability of the WHO-EORTC classification and staging system. PMID- 21547336 TI - Molecular markers associated with clinical response to bexarotene therapy in cutaneous T-cell lymphoma. AB - Bexarotene (Targretin((r))), was registered for the treatment of cutaneous T-cell lymphoma (CTCL) in 2002, and has been reported to induce a 45% overall response. Responses are mostly partial or generate a stable, skin-restricted disease. This study explored the usefulness of a novel cancer-associated gene, NAV3 and corresponding chromosome 12 copy numbers as possible biomarkers to monitor the therapeutic response to bexarotene in 21 Finnish patients with CTCL. Six patients (29%) reached complete remission (CR) and 3 of these remained in CR for more than 24 months, 12 (57%) reached a partial response (PR, with one stable disease) and 3 were non-responders. Low-level NAV3 deletions were detected using a fluorescence in-situ hybridization (FISH) assay in the lesions of 5 patients, 4 of whom were non-responders or progressed after short PR. This occurrence of NAV3 deletions was statistically significant compared with non-progressors (p = 0.011, Fisher's exact test). Chromosome 12 tetraploidy was found in the lesions of two of the 3 patients with CR who remained in remission. While such tetraploidy is a feature of proliferating normal T cells, this observation may reflect a favourable anti-tumour immune response among the skin-infiltrating lymphocytes. PMID- 21547337 TI - Quality of life, use of topical medications and socio-economic data in hand eczema: a Swedish nationwide survey. AB - Hand eczema is common and has an adverse impact on the lives of patients. There is a need for population-based surveys on the pharmacoepidemiological aspects, quality of life and impact of socioeconomic factors in hand eczema. The aim of this cross-sectional study was to investigate these factors. A questionnaire based nationwide survey of health was performed, including questions on hand eczema, use of pharmaceuticals and socioeconomic factors. Quality of life was estimated with the generic instrument Short Form 36 (SF-36). The questionnaire was sent to 7,985 persons (age range 18-84 years), response rate 61.1% (n = 4,875). The 1-year prevalence of hand eczema in the study population was 7.5%. In this group, quality of life was lower. All dimensions of SF-36 were affected, most markedly general health and those dimensions reporting on mental health. In the group with self-reported hand eczema, 51% reported using topical pharmaceuticals. Hand eczema was more common among women (9.1%, n = 2,630) than among men (5.6%, n = 2,245) and in the age group below 65 years (8.5%, n = 3,274) compared with those aged 65 years and over (4.3%, n = 1,151). This survey clearly demonstrates the impact of hand eczema on several dimensions of life and also highlights age, gender and socioeconomic differences. PMID- 21547338 TI - Treatment of pre-ulcerative necrobiosis lipoidica with infliximab. PMID- 21547339 TI - Tako-tsubo cardiomyopathy after a hymenoptera sting and treatment with catecholamines. PMID- 21547340 TI - Pruritus differences between psoriasis and lichen planus. PMID- 21547341 TI - Stability of the cathelicidin peptide LL-37 in a non-healing wound environment. AB - The endogenous cathelicidin peptide LL-37 is strongly expressed at the wound edge early in the process of acute wound healing, but only weakly expressed in chronic wounds. Excessive proteolysis may limit the therapeutic usefulness of exogenous LL-37, especially in ulcers colonized with Pseudomonas aeruginosa that produce elastase, which degrades LL-37. This study investigated the stability of synthetic LL-37 against two types of proteinases in the presence or absence of wound fluid samples (diluted to 10-20%) from nine non-healing venous leg ulcers. Incubation of LL-37 (10 ug/ml) at 37 degrees C for 6 h resulted in complete degradation by the serine proteinase trypsin (>= 10 ng/ml), while no degradation was observed with matrix metalloproteinase-9. LL-37 susceptibility to trypsin was diminished considerably in the presence of wound fluid, and there was no apparent cleavage of exogenous LL-37 incubated in wound fluid for up to 24 h at 37 degrees C even when using fluids from ulcers with resident P. aeruginosa (n = 2). In conclusion, LL-37 was degraded by trypsin, but not by matrix metalloproteinase-9, and was fairly resistant to proteolytic cleavage ex vivo by incubation with wound fluid from non-healing venous leg ulcers. Thus, the proteolytic environment of chronic wounds does not seem to prevent the therapeutic use of topical LL-37. PMID- 21547342 TI - Patients with psoriasis are more likely to be treated for latent tuberculosis infection prior to biologics than patients with inflammatory bowel disease. AB - Screening for latent tuberculosis infection (LTBI) is recommended before treatment with biologics is initiated in patients with psoriasis or inflammatory bowel disease (IBD). Our objective was to evaluate the effect of underlying disease (psoriasis or IBD) on the risk of LTBI diagnosis prior to anti-tumor necrosis factor-alpha (TNF-alpha) therapy. During a two-year period LTBI diagnosis rate was compared in consecutive patients with psoriasis or IBD (Crohn's disease or ulcerative colitis). IBD patients (n = 33) had significantly smaller tuberculin skin testing compared to psoriasis patients (n = 30) (p = 0.007). Applying LTBI diagnosis guidelines resulted in more psoriasis (50%) than IBD patients (24.2%) receiving treatment for LTBI prior to onset of anti-TNF alpha treatment (p = 0.04). In conclusion, current recommendations for LTBI diagnosis must be re-evaluated to account for the unique tuberculin hyperactive state of the skin of patients with psoriasis. PMID- 21547343 TI - Normal endothelial function in patients with mild-to-moderate psoriasis: a case control study. AB - Evidence is increasing that severe psoriasis is an independent cardiovascular risk factor. Results from case-control studies of endothelial dysfunction, a marker of early atherosclerosis, in patients with moderate-to-severe psoriasis have been conflicting and were conducted with operator-dependent and technically demanding ultrasound measurement of brachial artery flow-mediated vasodilation. Therefore, we decided to measure endothelial function and other cardiovascular risk factors in patients with mild-to-moderate psoriasis (n = 30) and controls (n = 30) using a newer and relatively operator-independent technique. No difference was detected between the groups with regards to endothelial function. However, despite the patients experiencing rather mild psoriasis they did exhibit higher levels of certain cardiovascular risk factors, including waist circumference, resting heart rate, systolic and diastolic blood pressures, and plasma levels of triglycerides, very-low-density lipoprotein cholesterol and glycated glucose, compared with controls. This indicates that even mild-to-moderate psoriasis may be regarded as a systemic inflammatory disease, and that an increased risk of cardiovascular morbidity may be present in these mild-to-moderately affected patients in the long-term. PMID- 21547344 TI - "Bathing trunk" eruption of papules and nodules in a young woman. Eruptive disseminated Spitz naevi. PMID- 21547345 TI - Cold panniculitis in Finnish horse riders. PMID- 21547346 TI - Patch testing with a textile dye mix in a baseline series in two countries. AB - Disperse dyes are the most common contact sensitizers among textile dyes. The main aim of this study was to investigate the outcome of patch testing with a textile dye mix 6.6%. A total of 2,049 patients from Sweden and 497 from Belgium were tested with the mix, consisting of Disperse (D) Blue 35, D Yellow 3, D Orange 1 and 3, D Red 1 and 17, 1.0% each, and D Blue 106 and D Blue 124, 0.3% each. Of the total number, 65 patients, 2.6%, tested positively to the mix, 4.2% of the Belgian patients and 2.1% of the Swedish patients. Patch testing with the mix 6.6% revealed significantly more patients with contact allergy compared with testing with a previous mix 3.2% (p < 0.01). Contact allergy to the mix was significantly more common in the Belgian than in the Swedish patients. PMID- 21547347 TI - No evidence for ErbB4 gene amplification in malignant melanoma. PMID- 21547348 TI - Imiquimod and lymphatic field clearance: a new hypothesis based on a remote immune action on skin cancer. AB - Basal cell carcinoma and actinic keratosis are frequent neoplasms. Topical treatments include the recently approved imiquimod cream. We describe here the case of a 68-year-old man with multiple actinic keratosis on the forehead, upper trunk and on the left cheek. In addition, an exulcerated basal cell carcinoma was observed. The patient was advised only to treat lesions on the forehead with imiquimod cream. This resulted in complete clearance of actinic keratosis within 6 weeks. At follow-up, a planned surgical excision of the basal cell carcinoma and actinic keratosis on the cheek was carried out. Histopathologically, both excision specimens no longer showed features of basal cell carcinoma or actinic keratosis, despite the fact that the imiquimod treatment was not applied to the cheek. Imiquimod cream is a topical immune response modifier, which has shown antiviral and anti-tumorous properties by inducing the production of cytokines as well as by stimulating dendritic cells and lymphocytes. Our observation supports the concept of lymphatic transport of immune cells and factors with subsequent immunological curing of tumours, not only in the treated area, but also those in the area between the imiquimod application site and the regional lymph nodes (the "lymphatic field clearance"). PMID- 21547349 TI - Antifouling bastadin congeners target mussel phenoloxidase and complex copper(II) ions. AB - Synthetically prepared congeners of sponge-derived bastadin derivatives such as 5,5'-dibromohemibastadin-1 (DBHB) that suppress the settling of barnacle larvae were identified in this study as strong inhibitors of blue mussel phenoloxidase that is involved in the firm attachment of mussels to a given substrate. The IC50 value of DBHB as the most active enzyme inhibitor encountered in this study amounts to 0.84 MUM. Inhibition of phenoloxidase by DBHB is likely due to complexation of copper(II) ions from the catalytic centre of the enzyme by the alpha-oxo-oxime moiety of the compound as shown here for the first time by structure activity studies and by X-ray structure determination of a copper(II) complex of DBHB. PMID- 21547351 TI - Over expression of LDOC1 and PARP1, two pro-apoptotic genes, in a patient with cryptorchidism and DiGeorge anomaly. PMID- 21547350 TI - Within-group differences between native-born and foreign-born Black men on prostate cancer risk reduction and early detection practices. AB - To better address prostate cancer disparities, we investigated the differences among US-born, African-born, and Caribbean-born Black men on prostate cancer risk reduction and early detection behaviors. Data were collected from over 3,400 Black men in five cities in Florida. One-way analysis of variance was used to explore the ethnic variations among the three study groups. We found that there were significant differences among the three groups. The US-born Black men had the highest knowledge, were most likely to have health insurance, and consume the most meat compared to African-born, and Caribbean-born Black men. African-born Black men were most likely to use chemoprevention products and discuss prostate cancer risk-reduction and early detection with a physician. Given the significant number of foreign-born Blacks in the US, it is important to disaggregate the data of US-born and foreign-born Blacks to develop effective programs and policies to address the needs of each group. PMID- 21547352 TI - MDM2 SNP309 is associated with endometrial cancer susceptibility: a meta analysis. AB - Epidemiological studies have investigated the association between MDM2 promoter SNP 309 (T/G) and endometrial cancer susceptibility. However, the results are still controversial. To obtain a more precise estimate of the relationship, we conducted a meta-analysis of 1,001 cases and 1,889 controls from 6 published case control studies (one of five articles contains two studies) to estimate the effect of SNP309 on endometrial cancer risk. The strength of association between MDM2 SNP309 and endometrial cancer susceptibility was assessed by calculating pooled odds ratios (ORs) with 95% confidence intervals (CIs). When all the eligible studies were pooled in the meta-analysis, we found that elevated endometrial cancer risk was significantly associated with GG variant genotype, however, heterozygous genotype TG seemed to be only a minor modifier on endometrial cancer risk (for GG vs. TT, OR = 1.54, 95% CI = 1.21-1.95, P = 0.0004; for TG vs. TT, OR = 0.96, 95% CI = 0.81-1.14, P = 0.66; for dominant model, OR = 1.09, 95% CI = 0.93-1.29, P = 0.29; for recessive model, OR = 1.65, 95% CI = 1.33-2.04, P < 0.00001). Overall, the meta-analysis suggested that the GG genotype of MDM2 SNP309 was significantly associated with the increased endometrial cancer risk. PMID- 21547353 TI - Evaluation of postmortem serum and cerebrospinal fluid growth hormone levels in relation to the cause of death in forensic autopsy. AB - Previous studies have shown that postmortem serum levels of adrenocorticotropic hormone (ACTH) were significantly lower in cases of asphyxia and poisoning than in other groups, whereas ACTH levels in cerebrospinal fluid (CSF) were significantly lower for hypothermia and hyperthermia. This study comparatively analyzed growth hormone (GH) levels in serum and CSF in relation to cause of death in routine forensic work. Autopsy cases (n = 116), including cases of blunt injury, sharp instrument injury, fire fatality, asphyxia, drowning, hypothermia, and acute myocardial infarction/ischemia (AMI), were examined. GH concentrations were measured using an immunoradiometric assay technique. GH levels in serum were significantly higher in cases of blunt injury, sharp instrument injury, hypothermia, and AMI than in the other groups. GH levels in CSF were significantly higher in fire fatality cases with a high COHb level than in the other groups. In a previous study ACTH immunopositivity in the adenohypophysis was significantly higher in cases of blunt injury, fire fatality, and AMI whereas GH immunopositivity was not significantly different among the groups, although positivity was higher in cases of fire fatality with a low COHb level. These observations suggest that postmortem serum/CSF GH and ACTH levels in acute deaths change differently, depending on the cause of death, because of varied stress reactions of the hypothalamic-pituitary-adrenal (HPA) axis. PMID- 21547354 TI - Effects of tamoxifen on the endometrium and its mechanism of carcinogenicity. AB - This study was conducted to clarify the clinicopathological characteristics of tamoxifen-associated endometrial carcinomas and its mechanisms of carcinogenesis. Seven patients with tamoxifen-associated endometrial carcinomas (TAM group) and 28 with sporadic endometrioid adenocarcinomas (EMC group) were included in the study. The clinicopathological factors, such as FIGO stage, histological type, grade, lymph node metastases, vascular invasion and the coexistence of hyperplasia, were investigated in both groups. The protein expression of p53, PTEN, hMLH1 and hMSH2 was investigated by immunohistochemistry. Microsatellite instability (MSI), k-ras and p53 mutation were also examined. In the TAM group, the histological types included five endometrioid, one endometrioid combined with serous and one clear cell type. The rates of coexistence with hyperplasia (five of seven cases) and vascular invasion (four cases) were significantly higher in the TAM group. The rates of stage III/IV (four cases) and lymph node metastasis (three cases) tended to be higher in the TAM group. Although there were no significant differences in PTEN, hMLH1 and hMSH2 expression between the two groups, p53 mutation was more frequent in three out of five cases (60%) in the TAM group compared with 2 of 15 cases in the EMC group (13.3%). No significant differences were observed concerning MSI and k-ras mutation in either group. These results suggested that TAM-associated endometrial carcinomas have overlapping biological characteristics of type I and type II endometrial carcinomas. This might explain the somewhat worse prognosis of these tumors than sporadic endometrioid carcinomas. PMID- 21547355 TI - IL-23/IL-23R: potential mediator of intestinal tumor progression from adenomatous polyps to colorectal carcinoma. AB - PURPOSE: Interleukin 23 (IL-23) affects tumor growth by regulating Th cells and plays a vital role in immunosuppression in tumor tissues. However, whether tumor cells are IL-23R positive or whether IL-23 has the potential to influence the growth of cancer cells directly remains unclear. The aim of this study was to clarify the molecular expression patterns of IL-23, IL-23R, and Forkhead box P3 (FOXP3) in normal tissues adjacent to cancer, in intestinal polyps (IP), and in colorectal carcinoma (CRC), and to infer the relationship between the expression patterns of these three molecules and the progress of intestinal tumors from adenomatous polyps to colorectal cancer. METHODS: The levels of IL-23A, IL-23R, and FOXP3 were evaluated in normal tissues adjacent to cancer (NT, n = 13), IP (n = 26), and CRC (n = 13) using real-time PCR, ELISA, western blotting, immunohistochemistry, and immunocytochemistry. RESULTS: The expression of IL-23 and FOXP3 increased progressively from NT through to CRC. Immunohistochemistry staining showed that IL-23R was highly positive in carcinoma cells of the CRC group, whereas it was partially positive in cells of other groups. In addition, the human CRC cell line SW-480 exhibited weak IL-23R immunocytochemical positivity. CONCLUSIONS: We propose that the IL-23/IL-23R pathway is a potential route to facilitate the malignant progression of cancers. The relationship between IL-23 and FOXP3 in the microenvironment of carcinoma led us to deduce that these two molecules may interact with each other. Although the exact mechanism underlying this interaction remains a mystery, we are convinced that these two molecules are relevant in cancer progression and that IL-23 could be a potential target for cancer immunotherapy. PMID- 21547356 TI - Laparoscopic resection for low rectal cancer: evaluation of oncological efficacy. AB - INTRODUCTION: Laparoscopic resection of low rectal cancer poses significant technical difficulties for the surgeon. There is a lack of published follow-up data in relation to the surgical, oncological and survival outcomes in these patients. AIM: The aim of this study is to evaluate the surgical, oncological and survival outcomes in all patients undergoing laparoscopic resection for low rectal cancer. METHODS: Consecutive patients undergoing laparoscopic resection for low rectal cancers were included in the study. Clinical, pathological and follow-up data were recorded over a 4-year period. The mean follow-up was 25 months RESULTS: A total of 53 patients were included in the study, 30 of whom were males. The mean age was 64.14 years (range, 34-86 years). The mean hospital stay was 8.2 days (range, 4-42 days). Fifty were completed laparoscopically and three were converted to an open procedure. Thirty-eight were anterior resections and 15 were abdominoperineal resections. Twenty-four patients received neoadjuvant chemoradiotherapy. The total mesorectal excision was optimal in 51 (98%) cases. There were no anastomotic sequelae and no surgical mortality. There was no local recurrence detected. The overall survival (mean follow-up, 25 months) was 93.5%. CONCLUSION: Laparoscopic resection for low rectal cancers permits optimum oncological control. In our series, this technical approach is associated with excellent 4-year survival and clinical outcomes. PMID- 21547357 TI - Using the knee-specific Hughston Clinic Questionnaire, EQ-5D and SF-6D following arthroscopic partial meniscectomy surgery: a comparison of psychometric properties. AB - PURPOSE: To compare the psychometric properties of the Hughston Clinic Questionnaire (HCQ), EQ-5D and SF-6D in patients following arthroscopic partial meniscectomy surgery. METHODS: A total of 84 participants (86% men; mean age 40) were recruited. The questionnaires were completed on average 5 days, 6 weeks and 6 months after surgery and compared for internal consistency, convergent validity, sensitivity to change and floor and ceiling effects. RESULTS: Internally, the HCQ was the most consistent instrument (alpha = 0.923) followed by the SF-6D and EQ-5D. The EQ-5D and SF-6D were moderately correlated with the HCQ (rho = 0.499 and 0.394, respectively). Six weeks after surgery, the most sensitive measures were the HCQ and EQ-5D (effect size: 2.04 and 0.99, respectively), at 6 months, with a smaller cohort (n = 42), again it was the HCQ and EQ-5D (effect size: 2.03 and 1.04, respectively). The SF-6D demonstrated no ceiling or floor effect during the study; the HCQ demonstrated a ceiling affect for 5% of respondents at 6 months after surgery compared to 26% of respondents for the EQ-5D. CONCLUSION: For this patient population, our findings indicated that the EQ-5D was more consistently responsive to change over time, as a utility index was better at distinguishing differences between groups and reflected the results of the joint-specific HCQ for knee recovery better than the SF-6D. It is therefore recommended that for similar populations, the EQ-5D is preferable to the SF-6D for utilisation alongside the HCQ. PMID- 21547358 TI - Race and gender associations between obesity and nine health-related quality-of life measures. AB - PURPOSE: To assess how health-related quality of life (HRQoL) varies by body mass index (BMI) category among gender and racial subgroups using nine HRQoL measures. METHODS: Among 3,710 US adults, we evaluated self-reported height, weight, and HRQoL that was measured by six indexes (EQ-5D; HUI2; HUI3; SF-6D; QWB-SA; HALex) and three summary measures (theta; PCS; MCS). Mean HRQoL was estimated by weighted regression for normal, overweight, and obese subgroups (BMI: 18.5-24.9 kg/m(2); 25-29.9; and 30-50). RESULTS: HRQoL was significantly lower (P < 0.0001) with increasing BMI category except for MCS. Obese individuals were 5.3 units lower on PCS (1-100 scale) and 0.05-0.11 lower on the HRQoL indexes (0-1 scale) than those with normal weight. MCS scores were significantly lower for obese than normal-weight among women (P = 0.04) but not men (P = 0.11). Overweight blacks had higher HRQoL than blacks in other BMI categories (P = 0.033). CONCLUSIONS: Six commonly used HRQoL indexes and two of three health status summary measures indicated lower HRQoL with obesity and overweight than with normal BMI, but the degree of decrement varied by index. The association appeared driven primarily by physical health, although mental health also played a role among women. Counter to hypotheses, blacks may have highest HRQoL when overweight. PMID- 21547359 TI - A 7-item version of the fatigue severity scale has better psychometric properties among HIV-infected adults: an application of a Rasch model. AB - PURPOSE: To examine the psychometric properties of the 9-item Fatigue Severity Scale (FSS) using a Rasch model application. METHODS: A convenience sample of HIV infected adults was recruited, and a subset of the sample was assessed at 6-month intervals for 2 years. Socio-demographic, clinical, and symptom data were collected by self-report questionnaires. CD4 T-cell count and viral load measures were obtained from medical records. The Rasch analysis included 316 participants with 698 valid questionnaires. RESULTS: FSS item 2 did not advanced monotonically, and items 1 and 2 did not show acceptable goodness-of-fit to the Rasch model. A reduced FSS 7-item version demonstrated acceptable goodness-of-fit and explained 61.2% of the total variance in the scale. In the FSS-7 item version, no uniform Differential Item Functioning was found in relation to time of evaluation or to any of the socio-demographic or clinical variables. CONCLUSION: This study demonstrated that the FSS-7 has better psychometric properties than the FSS-9 in this HIV sample and that responses to the different items are comparable over time and unrelated to socio-demographic and clinical variables. PMID- 21547360 TI - Sulfur- and seleno-containing amino acids. PMID- 21547361 TI - Comparisons of treatment means when factors do not interact in two-factorial studies. AB - Scientists in the fields of nutrition and other biological sciences often design factorial studies to test the hypotheses of interest and importance. In the case of two-factorial studies, it is widely recognized that the analysis of factor effects is generally based on treatment means when the interaction of the factors is statistically significant, and involves multiple comparisons of treatment means. However, when the two factors do not interact, a common understanding among biologists is that comparisons among treatment means cannot or should not be made. Here, we bring this misconception into the attention of researchers. Additionally, we indicate what kind of comparisons among the treatment means can be performed when there is a nonsignificant interaction among two factors. Such information should be useful in analyzing the experimental data and drawing meaningful conclusions. PMID- 21547362 TI - Detecting thermophilic proteins through selecting amino acid and dipeptide composition features. AB - Detecting thermophilic proteins is an important task for designing stable protein engineering in interested temperatures. In this work, we develop a simple but efficient method to classify thermophilic proteins from mesophilic ones using the amino acid and dipeptide compositions. Since most of the amino acid and dipeptide compositions are redundant, we propose a new forward floating selection technique to select only a useful subset of these compositions as features for support vector machine-based classification. We test the proposed method on a benchmark data set of 915 thermophilic and 793 mesophilic proteins. The results show that our method using 28 amino acid and dipeptide compositions achieves an accuracy rate of 93.3% evaluated by the jackknife cross-validation test, which is higher not only than the existing methods but also than using all amino acid and dipeptide compositions. PMID- 21547363 TI - Methionine synthase reductase A66G polymorphism contributes to tumor susceptibility: evidence from 35 case-control studies. AB - Methionine synthase reductase (MTRR) gene is involved in tumorigenesis by regulating DNA methylation through activation of methionine synthase (MTR). MTRR is polymorphic at nucleotide 66 (A-to-G) and the resulting variant enzyme has a lower affinity for MTR. The reported associations of MTRR A66G polymorphism with cancer risk are contradictory. Therefore, we performed a meta-analysis to better assess the associations, including 18,661 cases and 27,678 controls from 35 studies. Crude ORs with 95% CIs were used to assess the strength of association between the MTRR A66G polymorphism and cancer risk. The pooled ORs were performed for homozygote model (GG vs. AA), heterozygote model (GG vs. GA), recessive genetic model (GG vs. GA + AA), and dominant genetic model (GG + GA vs. AA), respectively. Overall, results indicated that the G allele and GG variant genotypes were associated with a significantly increased cancer risk (G vs. A: OR, 1.039; 95% CI, 1.009-1.078; homozygote model: OR, 1.094; 95% CI, 1.006 1.191). In subgroup analysis by ethnicity, significant increased risks were found among Asians with G allele (G vs. A: OR, 1.063; 95% CI, 1.011-1.119; homozygote model: OR, 1.189; 95% CI, 1.055-1.341; recessive model: OR, 1.197; 95% CI, 1.068 1.341). For stratification analysis, the cancer types with fewer than three studies were categorized into "other cancers", and the results indicated that there was a significant elevated cancer risk in "other cancers" in all genetic models, not in colorectal cancer, lymphoid leukemia or breast cancer. In summary, our study suggests that the MTRR A66G polymorphism is a potential biomarker for cancer risk. PMID- 21547364 TI - Novel mutations of endothelin-B receptor gene in Pakistani patients with Waardenburg syndrome. AB - Mutations in EDNRB gene have been reported to cause Waardenburg-Shah syndrome (WS4) in humans. We investigated 17 patients with WS4 for identification of mutations in EDNRB gene using PCR and direct sequencing technique. Four genomic mutations were detected in four patients; a G to C transversion in codon 335 (S335C) in exon 5 and a transition of T to C in codon (S361L) in exon 5, a transition of A to G in codon 277 (L277L) in exon 4, a non coding transversion of T to A at -30 nucleotide position of exon 5. None of these mutations were found in controls. One of the patients harbored two novel mutations (S335C, S361L) in exon 5 and one in Intronic region (-30exon5 A>G). All of the mutations were homozygous and novel except the mutation observed in exon 4. In this study, we have identified 3 novel mutations in EDNRB gene associated with WS4 in Pakistani patients. PMID- 21547365 TI - A novel single nucleotide polymorphism in exon 7 of LPL gene and its association with carcass traits and visceral fat deposition in yak (Bos grunniens) steers. AB - Lipoprotein lipase (LPL) is considered as a key enzyme in the lipid deposition and metabolism in tissues. It is assumed to be a major candidate gene for genetic markers in lipid deposition. Therefore, the polymorphisms of the LPL gene and associations with carcass traits and viscera fat content were examined in 398 individuals from five yak (Bos grunniens) breeds using PCR-SSCP analysis and DNA sequencing. A novel nucleotide polymorphism (SNP)-C->T (nt19913) was identified located in exon 7 in the coding region of the LPL gene, which replacement was responsible for a Phe-to-Ser substitution at amino acid. Two alleles (A and B) and three genotypes designed as AA, AB and BB were detected in the PCR products. The frequencies of allele A were 0.7928, 0.7421, 0.7357, 0.6900 and 0.7083 for Tianzhu white yak (WY), Gannan yak (GY), Qinghai-Plateau yak (PY), Xinjiang yak (XY) and Datong yak (DY), respectively. The SNP loci was in Hardy-Weinberg equilibrium in five yak populations (P>0.05). Polymorphism of LPL gene was shown to be associated with carcass traits and lipid deposition. Least squares analysis revealed that there was a significant effect on live-weight (LW) (P<0.01), average daily weight gain (ADG) and carcass weight (P<0.05). Individuals with genotype BB had lower mean values than those with genotype AA and AB for loin eye area and viscera fat weight (% of LW) in 25-36 months (P<0.05). The results indicated that LPL gene is a strong candidate gene that affects carcass traits and fat deposition in yak. PMID- 21547366 TI - Identification and evaluation of two diagnostic markers linked to Fusarium wilt resistance (race 4) in banana (Musa spp.). AB - Fusarium wilt caused by the fungus Fusarium oxysporum f. sp. cubense race 4 (FOC4) results in vascular tissue damage and ultimately death of banana (Musa spp.) plants. Somaclonal variants of in vitro micropropagated banana can hamper success in propagation of genotypes resistant to FOC4. Early identification of FOC4 resistance in micropropagated banana plantlets is difficult, however. In this study, we identified sequence-characterized amplified region (SCAR) markers of banana associated with resistance to FOC4. Using pooled DNA from resistant or susceptible genotypes and 500 arbitrary 10-mer oligonucleotide primers, 24 random amplified polymorphic DNA (RAPD) products were identified. Two of these RAPD markers were successfully converted to SCAR markers, called ScaU1001 (GenBank accession number HQ613949) and ScaS0901 (GenBank accession number HQ613950). ScaS0901 and ScaU1001 could be amplified in FOC4-resistant banana genotypes ("Williams 8818-1" and Goldfinger), but not in five tested banana cultivars susceptible to FOC4. The two SCAR markers were then used to identify a somaclonal variant of the genotype "Williams 8818-1", which lost resistance to FOC4. Hence, the identified SCAR markers can be applied for a rapid quality control of FOC4 resistant banana plantlets immediately after the in vitro micropropagation stage. Furthermore, ScaU1001 and ScaS0901 will facilitate marker-assisted selection of new banana cultivars resistant to FOC4. PMID- 21547367 TI - The impact of the AIDS pandemic on health services in Africa: evidence from demographic and health surveys. AB - We document the impact of the AIDS crisis on non-AIDS-related health services in 14 sub-Saharan African countries. Using multiple waves of Demographic and Health Surveys (DHS) for each country, we examine antenatal care, birth deliveries, and rates of immunization for children born between 1988 and 2005. We find deterioration in nearly all these dimensions of health care over this period. The most recent DHS survey for each country collected data on HIV prevalence, which allows us to examine the association between HIV burden and health care. We find that erosion of health services is the largest in regions that have developed the highest rates of HIV. Regions of countries that have light AIDS burdens have witnessed small or no declines in health care, using the measures noted above, while those regions shouldering the heaviest burdens have seen the largest erosion in non-HIV-related health services for pregnant women and children. Using semiparametric techniques, we can date the beginning of the divergence in the use of antenatal care and in children's immunizations between high- and low-HIV regions to the mid-1990s. PMID- 21547368 TI - The fate of camptothecin glycoconjugate: report of a clinical hold during a phase II study of BAY 56-3722 (formerly BAY 38-3441), in patients with recurrent or metastatic colorectal cancer resistant/refractory to irinotecan. AB - INTRODUCTION: BAY 56-3722 (formerly BAY 38-3441) is a glycoconjugated campthotecin, which was considered an attractive drug to assess in colorectal cancer (CRC). PATIENT AND METHODS: Phase II study design evaluating the antitumor activity of BAY 56-3722 i.v. 320 mg/m(2) daily for 3 days every 3 weeks in patients with recurrent or metastatic inoperable CRC resistant to irinotecan. RESULTS: Twenty-four patients received the study treatment. Triggered by adverse events in two other studies with this compound the study was put on a clinical hold while the safety data were reviewed for the entire program. After the review Bayer decided to withdraw BAY 56-3722 from all clinical investigations. DISCUSSION: We felt it was our obligation to share this interrupted phase II study for two reasons: to report the fate of camptothecin glycoconjugate and to report the unique situation of a clinical hold during a phase II study. PMID- 21547370 TI - Push-pull fluorophores based on imidazole-4,5-dicarbonitrile: a comparison of spectral properties in solution and polymer matrices. AB - Spectral properties of novel type of fluorophores consist of a pi-conjugated system end-capped with an electron-donating N,N-dimethylaminophenyl group and an electron-withdrawing imidazole-4,5-dicarbonitrile moiety were examined. An additional pi-linker separating these two structural units comprises simple bond (B1P), phenyl (B2B), styryl (B3S) and ethynylphenyl (B4A) moieties. The absorption and fluorescence spectra were taken in cyclohexane, chloroform, acetonitrile, methanol and in polymer matrices such as polystyrene, poly(methyl methacrylate) and poly(vinylchloride). The longest-wavelength absorption band was observed in the range of 300 to 400 nm. Intense fluorescence with quantum yields of 0.2 to 1.0 was observed in cyclohexane, chloroform and in polymer matrices within the range of 380 to 500 nm. The fluorescence was strongly quenched in neat acetonitrile and methanol. The fluorescence lifetimes are in the range of 1-4 ns for all measured fluorophores. The large Stokes shift (4,000 to 8,000 cm(-1)) indicates a large difference in the spatial arrangement of the chromophore in the absorbing and the emitting states. The observed fluorescence of all fluorophores in chloroform was quenched by 1-oxo-2,2,6,6-tetramethyl-4-hydroxy piperidine by the diffusion-controlled bimolecular rate (cca 2 * 10(10) L mol(-1) s(-1)). Polar solvents such as acetonitrile and methanol quenched the fluorescence as well but probably via a different mechanism. PMID- 21547369 TI - The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis. AB - Recent research suggests that altered redox control of melanoma cell survival, proliferation, and invasiveness represents a chemical vulnerability that can be targeted by pharmacological modulation of cellular oxidative stress. The endoperoxide artemisinin and semisynthetic artemisinin-derivatives including dihydroartemisinin (DHA) constitute a major class of antimalarials that kill plasmodium parasites through induction of iron-dependent oxidative stress. Here, we demonstrate that DHA may serve as a redox chemotherapeutic that selectively induces melanoma cell apoptosis without compromising viability of primary human melanocytes. Cultured human metastatic melanoma cells (A375, G361, LOX) were sensitive to DHA-induced apoptosis with upregulation of cellular oxidative stress, phosphatidylserine externalization, and activational cleavage of procaspase 3. Expression array analysis revealed DHA-induced upregulation of oxidative and genotoxic stress response genes (GADD45A, GADD153, CDKN1A, PMAIP1, HMOX1, EGR1) in A375 cells. DHA exposure caused early upregulation of the BH3 only protein NOXA, a proapototic member of the Bcl2 family encoded by PMAIP1, and genetic antagonism (siRNA targeting PMAIP1) rescued melanoma cells from apoptosis indicating a causative role of NOXA-upregulation in DHA-induced melanoma cell death. Comet analysis revealed early DHA-induction of genotoxic stress accompanied by p53 activational phosphorylation (Ser 15). In primary human epidermal melanocytes, viability was not compromised by DHA, and oxidative stress, comet tail moment, and PMAIP1 (NOXA) expression remained unaltered. Taken together, these data demonstrate that metastatic melanoma cells display a specific vulnerability to DHA-induced NOXA-dependent apoptosis and suggest feasibility of future anti-melanoma intervention using artemisinin-derived clinical redox antimalarials. PMID- 21547371 TI - Drawings of very preterm-born children at 5 years of age: a first impression of cognitive and motor development? AB - INTRODUCTION: The aim of this study was to examine differences in drawing skills between very preterm and term children, and to determine whether very preterm children's cognitive and motor development is reflected in the draw-a-person test (DAP) at age 5. Seventy-two very preterm children (birth weight <1,500 g and/or gestational age <32 weeks) and 60 term children at 5 years of age were compared on the DAP. Cognitive and motor skills of the very preterm children had been assessed four times, at 1/2, 1, 2, and 5 years of age. Very preterm children showed a developmental delay in drawing ability. Structural equation modeling revealed a positive relation between both cognitive as well as motor development and the DAP. CONCLUSION: The DAP could be a crude parameter for evaluating cognitive and motor deficits of very preterm children. A worrisome result should be followed by more standardized tests measuring cognitive and motor skills. PMID- 21547372 TI - Cytogenetic damage induced by mouthrinses formulations in vivo and in vitro. AB - The aim of the present study was to comparatively evaluate DNA damage and cellular death in cells exposed to various commercially available mouthrinses: Listerine Cepacol, Plax alcohol free, Periogard, and Plax Whitening. A total of 75 volunteers were included in the search distributed into five groups containing 15 people each for in vivo study. Exfoliated buccal mucosa cells were collected immediately before mouthrinse exposure and after 2 weeks. Furthermore, blood samples were obtained from three healthy donors for in vitro study. The micronucleus test was used to evaluate mutagenicity and cytotoxicity in vivo. The single-cell gel (comet) assay was used to determine DNA damage in vitro. After 2 weeks exposure, Periogard showed 1.8% of micronucleated cells with significant statistical differences (p < 0.05) compared to before exposure (0.27%). Plax Whitening presented high tail moment value (4.5) when compared to negative control (0.6). The addition of all mouthrinses to cells incubated with methyl methanesulfonate did not alter the number of strand breaks in the genetic material. Listerine was able to reduce genetic damage induced by hydrogen peroxide because a decrease of tail moment was noticed. The results of the present study suggest that Periogard and Plax Whitening can induce genetic damage, whereas Listerine is an antioxidant agent. Since DNA damage is considered to be prime mechanism during chemical carcinogenesis, these data may be relevant in risk assessment for protecting human health and preventing carcinogenesis. PMID- 21547373 TI - Sexual dimorphism in teeth? Clinical relevance. AB - Many morphometric studies show a sexual dimorphism in human teeth. We wanted to know whether it is possible to determine the sex of an individual if only the anterior teeth are visible. Fifty intraoral photographs showing the front tooth region of female and male individuals (age: from 7 to 75 years) were randomly arranged in actual size on a questionnaire. The lip region was covered in each case. Besides "female" and "male", one was also able to check "?" if undecided. The questionnaires were distributed to 50 expert test persons (dentists, dental technicians, dental assistants, and students of dental medicine) and to 50 laymen and were all returned for evaluation. Although the correct sex was recognized on single photographs to a maximum of 76%, it was incorrect in 69% on other photographs. Altogether, the statistical evaluation showed that in most cases, the sex was only recognized correctly by one half, and incorrect by the other half. It can be concluded that a sexual dimorphism of human teeth-although measurable morphometrically-could not be recognized visually on the basis of photographs of the front tooth region. Neither experts in the field of dentistry nor laymen were able to properly distinguish between male and female teeth. PMID- 21547374 TI - Enteric methane mitigation technologies for ruminant livestock: a synthesis of current research and future directions. AB - Enteric methane (CH(4)) emission in ruminants, which is produced via fermentation of feeds in the rumen and lower digestive tract by methanogenic archaea, represents a loss of 2% to 12% of gross energy of feeds and contributes to global greenhouse effects. Globally, about 80 million tonnes of CH(4) is produced annually from enteric fermentation mainly from ruminants. Therefore, CH(4) mitigation strategies in ruminants have focused to obtain economic as well as environmental benefits. Some mitigation options such as chemical inhibitors, defaunation, and ionophores inhibit methanogenesis directly or indirectly in the rumen, but they have not confirmed consistent effects for practical use. A variety of nutritional amendments such as increasing the amount of grains, inclusion of some leguminous forages containing condensed tannins and ionophore compounds in diets, supplementation of low-quality roughages with protein and readily fermentable carbohydrates, and addition of fats show promise for CH(4) mitigation. These nutritional amendments also increase the efficiency of feed utilization and, therefore, are most likely to be adopted by farmers. Several new potential technologies such as use of plant secondary metabolites, probiotics and propionate enhancers, stimulation of acetogens, immunization, CH(4) oxidation by methylotrophs, and genetic selection of low CH(4)-producing animals have emerged to decrease CH(4) production, but these require extensive research before they can be recommended to livestock producers. The use of bacteriocins, bacteriophages, and development of recombinant vaccines targeting archaeal specific genes and cell surface proteins may be areas worthy of investigation for CH(4) mitigation as well. A combination of different CH(4) mitigation strategies should be adopted in farm levels to substantially decrease methane emission from ruminants. Evidently, comprehensive research is needed to explore proven and reliable CH(4) mitigation technologies that would be practically feasible and economically viable while improving ruminant production. PMID- 21547375 TI - Probability sampling of stony coral populations in the Florida Keys. AB - Principles of probability survey design were applied to guide large-scale sampling of populations of stony corals and associated benthic taxa in the Florida Keys coral reef ecosystem. The survey employed a two-stage stratified random sampling design that partitioned the 251-km(2) domain by reef habitat types, geographic regions, and management zones. Estimates of the coefficient of variation (ratio of standard error to the mean) for stony coral population density and abundance ranged from 7% to 12% for four of six principal species. These levels of survey precision are among the highest reported for comparable surveys of marine species. Relatively precise estimates were also obtained for octocoral density, sponge frequency of occurrence, and benthic cover of algae and invertebrates. Probabilistic survey design techniques provided a robust framework for estimating population-level metrics and optimizing sampling efficiency. PMID- 21547376 TI - Dentatorubrothalamic tract in human brain: diffusion tensor tractography study. AB - INTRODUCTION: The dentatorubrothalamic tract (DRTT) originates from the dentate nucleus in the cerebellum and terminates in the contralateral ventrolateral nucleus (VL) of the thalamus after decussating to the contralateral red nucleus. Identification of the DRTT is difficult due to the fact that it is a long, multisynaptic, neural tract crossing to the opposite hemisphere. In the current study, we attempted to identify the DRTT in the human brain using a probabilistic tractography technique of diffusion tensor imaging. METHODS: Diffusion tensor imaging was performed at 1.5-T using a synergy-L sensitivity encoding head coil. DRTTs were obtained by selection of fibers passing through three regions of interest (the dentate nucleus, the superior cerebellar peduncle, and the contralateral red nucleus) from 41 healthy volunteers. Probabilistic mapping was obtained from the highest probabilistic location at 2.3 mm above the anterior commissure-posterior commissure level. RESULTS: DRTTs of all subjects, which originated from the dentate nucleus, ascended through the junction of the superior cerebellar peduncle and the contralateral red nucleus and then terminated at the VL nucleus of the thalamus. The highest probabilistic location for the DRTT at the thalamus was compatible with the location of the VL nucleus. CONCLUSIONS: We identified the DRTT in the human brain using probabilistic tractography. Our results could be useful in research on movement control. PMID- 21547377 TI - Incremental value of dual-energy CT to coronary CT angiography for the detection of significant coronary stenosis: comparison with quantitative coronary angiography and single photon emission computed tomography. AB - To determine the value of dual-energy CT (DECT) and combined information of perfusion and angiography in diagnosing coronary artery disease (CAD), with single photon emission computed tomography (SPECT) and quantitative coronary angiography (QCA) as a reference standard. Thirty-four patients were enrolled in this study. DECT was used as a contrast-enhanced retrospectively ECG-gated scan protocol during the rest state and tubes were set at 140/100 kV. DECT angiography (DE-CTA) and DECT perfusion (DE-CTP) were calculated from two kV images. DE-CTP results were compared with SPECT and DE-CTA with QCA, respectively. The combined DE-CTP with DE-CTA data were compared to QCA in diagnosis of obstructive CAD (stenosis >= 50%). DECT showed diagnostic image quality in 31 patients. Using SPECT as a reference, DE-CTP had sensitivity of 68%, specificity of 93%, and sensitivity of 81%, and specificity of 92% for identifying any type of perfusion deficits on the segment- and territory-based analysis, respectively. Using QCA as a reference standard, DE-CTA showed sensitivity of 82%, specificity of 91% and accuracy of 86% for detecting >=50% coronary stenosis on the vessel-based analysis, whereas the combination of DE-CTA and DE-CTP gave sensitivity of 90%, specificity of 86% and accuracy of 88% for detecting >=50% coronary stenosis, respectively. Combination of DE-CTP and DE-CTA may improve diagnostic performance compared to CTA alone for the diagnosis of significant coronary stenosis. PMID- 21547378 TI - Intravenous amantadine is safe and effective for the perioperative management of patients with Parkinson's disease. PMID- 21547379 TI - The role of 123I-FP-CIT-SPECT in the differential diagnosis of Parkinson and tremor syndromes: a critical assessment of 125 cases. AB - (123)I-FP-CIT-SPECT is useful in the differential diagnosis of Parkinson's disease (PD) and tremor syndromes. Recently, there have been reports on normal nigrostriatal uptake of radio ligands in PD patients, referred to as scans without evidence of dopaminergic deficit (SWEDDs). Furthermore, a dopaminergic deficit has been described in some cases of different tremor types. We sought to clarify the occurrence of SWEDDs in PD and a possible association of various tremor types with PD. We performed a retrospective case analysis of 125 patients with diagnostically uncertain Parkinsonian or non-Parkinsonian tremor syndromes with clinical assessments and (123)I-FP-CIT-SPECT. A total of 36/40 (90%) patients with the predominant clinical feature of a postural and/or kinetic tremor showed normal DAT SPECT; 73/85 (86%) with predominant clinical symptoms of PD showed abnormal DAT SPECT with lower overall radio ligand uptake and a significant asymmetry contralateral to the clinically more affected side. In all, 4/40 (10%) of non-Parkinsonian tremor patients had abnormal DAT SPECT, but no corresponding asymmetry of radio ligand uptake. Probable essential tremor was considered clinically in follow-up assessments although final diagnosis of these four tremor cases remains inconclusive. A total of 12/85 (14%) clinically suspected PD patients had normal DAT SPECT (SWEDDs). Clinical reassessment identified two patients with dystonic tremor. Five patients with a positive response to levodopa remained unclear. In four cases of suspected PD with normal DAT SPECT, non-neurologic diseases were identified. One case showed a complete and spontaneous remission of symptoms. DAT SPECT offers an objective method to confirm or exclude a dopaminergic deficit in tremor predominant parkinsonism for clinically inconclusive cases. There was no evidence of a decrease in DAT binding in the majority of patients with postural and/or kinetic tremor. The striatal asymmetry index is a further helpful tool for differentiating PD from non-PD tremor syndromes. PMID- 21547380 TI - Recurrent transient topographical amnesia: a patient with frequent episodes. PMID- 21547381 TI - Central inflammation versus peripheral regulation in multiple sclerosis. AB - Th17 cells are a highly pro-inflammatory T-helper cell subset characterised by the expression of IL17. They have been implicated in a variety of allergic and autoimmune conditions. T-regulatory (Treg) cells, a subset of CD4 cells which express Foxp3, CD25, IL10 and TGFbeta, can suppress the activity of Th17 cells. In this study, we show that the circulating levels of Th17 and Treg cells in peripheral blood are correlated; furthermore, the expression of the pro inflammatory cytokine IL17 and the anti-inflammatory cytokine IL10 by CD4 cells are also correlated. However, we found no clear correlation between cerebrospinal fluid (CSF) IL10 and IL17 cytokine levels in MS, approaching a negative correlation at the time of relapse, and an overall negative correlation between CSF IL17 and TGFbeta levels, suggesting a lack of central regulation of pro:anti inflammatory balance in this demyelinating condition. PMID- 21547382 TI - Nutritional support by "conventional" percutaneous endoscopic gastrostomy feeding may not result in weight gain in Parkinson's disease. PMID- 21547383 TI - Laminotomy in adults: technique and results. AB - The objective of this study was to describe step by step our surgical technique of laminotomy and analyze our series with regard to spinal deformities (risk and predisposing factors), postoperative pain and rate of postoperative contusions. Data regarding patients who underwent our technique of laminotomy (N = 40, mean follow-up: 52 ms) (N = 40) between 2002 and 2006 were retrospectively evaluated. The technique used is illustrated in depth. Chronic pain was present in 30% with a mean score of 3/10 cm (Graphic Rating Scale). Postoperative kyphoses occurred in three patients, all below 35 years of age and with laminotomies which involved C2 and/or C7. None of these deformities required further surgical treatment because they were self-limiting or asymptomatic at a mean follow-up of 52 months. Based on the results, our technique proved to be safe and effective in terms of late deformities, blood loss, early and chronic postoperative pain and protection from postoperative accidents over the surgical site. PMID- 21547384 TI - Coexistence of vasculitides with familial Mediterranean fever. AB - Familial Mediterranean fever (FMF) is the most common autoinflammatory disease characterized by recurrent self-limited attacks of fever accompanied with peritonitis, pleuritis, or arthritis. FMF may coexist with various systemic inflammatory diseases including vasculitides, spondyloarthritis, multiple sclerosis, and inflammatory bowel disease. Among these coexistences, this review concentrates on vasculitic disorders, with the aim of increasing the awareness of FMF-vasculitis association. This association does not merely show a coincidentally increased frequency of vasculitic disorders in FMF; rather, it seems that FMF patients might be at increased risk of developing vasculitis. Indeed, as also suggested by some authors, vasculitis might be an essential feature of FMF. Among the vasculitic disorders reported to be associated with FMF, Henoch-Schonlein purpura, and classical polyarteritis nodosa come the first, possibly followed up by protracted febrile myalgia. There is also an ongoing debate whether Behcet's disease (BD) more frequently seen in FMF than expected by chance alone. In this review, the associations of various vasculitic disorders with FMF and the possible pathogenic mechanisms underlying these associations, as well as the frequencies and clinical significances of FMF-related MEFV mutations in various vasculitides including BD, are discussed in the context of the available data. PMID- 21547385 TI - A potential explanation of the reported low prevalence of hepatitis B virus infection in patients with systemic lupus erythematosus. PMID- 21547386 TI - Biofilm detection in chronic rhinosinusitis by combined application of hematoxylin-eosin and gram staining. AB - The pathomechanism of chronic rhinosinusitis with nasal polyposis (CRS/NP) seems to be unclear. Bacterial-, fungal- and combined biofilms might play a potential role in the pathogenesis of various inflammatory diseases and recently in CRS/NP. A prospective, blinded observational study was performed to confirm that the combination of conventional hematoxylin-eosin (HE) and Gram staining protocols could be used to detect bacterial and fungal biofilms in patients with CRS/NP. A total of 50 patients with CRS/NP undergoing endoscopic sinus surgery (ESS) were analyzed. The negative control group consisted of 12 patients undergoing septoplasty for nasal obstruction without CRS/NP. The nasal polyps and inferior turbinate mucosa specimens applied as negative controls were processed to HE and Gram staining. Biofilm was detected in 44 of 50 patients with CRS/NP and in none of 12 negative controls. In our series, HE method showed an obvious correlation with the results of Gram staining and was allocated to be a good predictor of biofilm existence. It was found that the microscopic structure and thickness of biofilms were strongly associated with the integrity of nasal mucosa and with the characteristics of subepithelial cellular infiltration. This study confirmed the presence of bacterial and fungal biofilms on the surface of NPs obtained from patients with CRS. Since biofilms may affect the severity and recurrence rate of CRS treated by ESS they should be detected histologically. In conclusion, HE staining combined with Gram protocol is a robust and reliable method for the detection of bacterial and fungal biofilms in CRS/NP. PMID- 21547387 TI - Head and neck cancers manifested as deep neck infection. AB - The incidence of head and neck cancers in patients with an initial presentation of deep neck infection is unclear and may be underestimated. Thus, the aim of this study was to assess the incidence of head and neck cancers initially manifested as deep neck infection. Also, the possible risk factors and pathophysiology are discussed. This study was a retrospective medical chart review in a tertiary referral center. A total of 81 consecutive patients admitted with a diagnosis of deep neck infection over a 46-month period were analyzed. The demographic data, physical examinations, laboratory findings, radiographic studies, and pathology report were analyzed. Among the 81 deep neck infection patients, head and neck cancers were histologically demonstrated in four patients (4.9%) with the initial symptom of a painful neck mass. The incidence of head and neck cancer initially manifested as deep neck infection was found to increase in patients aged over 40 years (6.7%; 3/45 vs. 2.8%; 1/36). A detailed history of all patients with deep neck infection should be taken. Furthermore, endoscopic examination, thyroid examination and routine pathological examination should be performed, especially in those aged over 40. Also, careful explanation to the patient and his/her family about the possibility of underlying head and neck cancer (incidence 1-5%) may be needed. If the neck swelling diminishes, but does not disappear completely after full course of antibiotics, repeated fine needle aspiration, endoscopy, or image study should be considered. PMID- 21547388 TI - Analysis of factors influencing voice quality and therapeutic approaches in vocal polyp patients. AB - The task of the present study was to investigate the relationship between parameters and factors predictive of voice quality and to suggest treatment guidelines for patients suffering from vocal polyps. In total, 158 patients diagnosed with vocal polyps and who received voice therapy were enrolled. Clinicomorphological factors such as size, location, color, and type of the polyp were evaluated. Perceptive and acoustic voice evaluation was conducted and the relationship of these voice parameters with clinicomorphological factors was analyzed. Additionally, factors favorable for voice therapy were investigated. GRBAS scale grade was closely related to acoustic parameters, such as jitter and shimmer. Univariate analysis showed the size of the polyp, the color of the vocal fold, a history of voice abuse, associated muscle tension dysphonia (MTD), and opposing reactive scar affected voice quality. In multivariate analysis, only the size of the polyp was associated with voice quality. The patients in whom the voice quality improved with voice therapy initially had smaller polyps and whitish-colored vocal folds. Results of the present study indicate that although the most influential factor on voice quality in vocal polyp patients was the size, several other factors should be considered in evaluating and treating vocal polyps. The size of the polyp and the color of the vocal fold are indicative of success or failure in voice therapy. PMID- 21547389 TI - Evaluation and development of a predictive model for ultrasound-guided investigation of neck metastases. AB - Ultrasound investigations for the correct identification of lymph node metastases depend on the experience and qualifications of the investigator; thus, model that provides better preoperative evaluation is desired. Data from 290 patients with an upcoming neck dissection were analyzed to compare the preoperative ultrasound assessment of neck metastases with the pathologically proven postoperative neck status. In total, 364 data sets with 200 malignant and 164 benign lymph nodes were explored. The minimal and maximal transverse diameters and their ratio were shown to be especially good parameters for sensitivity, whereas the echostructure and the presence of a hilum were good for specificity. A model incorporating the evaluated markers is presented. The model provides better judgement of neck lymph nodes in a more objective manner. Using logistic regression, five parameters were identified to predict metastases. PMID- 21547390 TI - Coblation tonsillectomy: is it inherently bloody? AB - The aim of the study was to compare a single surgeon's post-tonsillectomy haemorrhage rates using cold steel dissection and coblation tonsillectomy techniques. Retrospective study on patients, who underwent tonsillectomy at West Wales General Hospital (WWGH) performed by a single surgeon from 2006 to 2010 employing both cold steel and coblation tonsillectomies. Data were analysed using Mann-Whitney and Chi-squared tests. The nominated surgeon performed 239 tonsillectomies at WWGH from 2006 to 2010. 119 patients underwent cold steel dissection and 120 had coblation tonsillectomy. There was no demographic difference between the two groups. There was no statistically significant difference in the length of hospital stay between the two groups (median 1 day in each group). 6/119 (5.0%) patients in the cold steel group, and 7/120 (5.8%) in the coblation group had post-operative bleeding (p = 1.00). The return to theatre rate for cold steel dissection was 1/119 (0.84%) and for coblation surgery was 1/120 (0.83%) (p = 1.00). Among the first 60 cases of coblation tonsillectomies, 4 patients (6.6%) had post-operative haemorrhage and the latter 60 cases had 3 patients (5%). There was no evidence of a difference in the overall post operative bleeding between those who had cold steel dissection and coblation tonsillectomies. These data suggest that higher post-operative haemorrhage is not inherent to coblation tonsillectomy. PMID- 21547391 TI - Tyrosine 381 in E. coli copper amine oxidase influences substrate specificity. AB - Copper amine oxidases are important for the metabolism of a range of biogenic amines. Here, we focus on substrate specificity in the E. coli copper amine oxidase (ECAO) and specifically the role of Tyr 381. This residue, and its equivalent, in other copper amine oxidases has been referred to as a "gating" residue able to move position depending upon the presence or absence of amine substrate. The position of this residue suggests a role in substrate selectivity. We have compared the properties of two variant forms of ECAO, Y381F and Y381A, with wild-type enzyme by steady-state kinetics of oxidation of a number of amine substrates, modes of inhibitor interactions and X-ray structure determination. Y381F displays a similar catalytic efficiency to wild type against the preferred substrate beta-phenylethylamine. In both cases oxidation of the alternative aromatic amine substrate benzylamine is relatively poor, although Y381F represents an efficient benzylamine oxidase. By contrast, Y381A performed poorly against both aromatic substrates predominantly due to an increased K (M) which we propose is due to the lack of an aromatic residue to orient substrate towards the TPQ and active site base. These results are supported by different behaviour of Y381A to inhibition with 2-hydrazinopyridine. We also report on methylamine turnover by the three enzymes. We propose that Y381, together with another residue Y387, may be considered of critical importance for the substrate selectivity of ECAO, through stacking or hydrophobic interactions with substrate. PMID- 21547392 TI - Rare brain biopsy findings in a first ADEM-like event of pediatric MS: histopathologic, neuroradiologic and clinical features. AB - Pediatric MS tends to present more often with an acute onset and a polysymptomatic form of the disease, possibly with encephalopathy and large tumefactive lesions similar to those observed in some cases of acute disseminated encephalomyelitis (ADEM), which makes it more difficult to differentiate between an explosive and severe onset of MS vs. ADEM. An ADEM-like first demyelinating event can be the first attack of pediatric MS, but international consensus definitions require two or more non-ADEM demyelinating events for diagnosis of MS. In our patient KIDMUS MRI criteria for MS (Mikaeloff et al. J Pediatr 144:246 252, 2004a; Mikaeloff et al. Brain 127:1942-1947, 2004b) were negative at first attack, but Barkhof criteria for lesion dissemination in space in adults (Barkhof et al. 120:2059-2069, 1997), Callen modified MS-criteria and Callen MS-ADEM criteria for children (Callen et al. Neurology 72:961-967, 2009a; Callen et al. Neurology 72:968-973, 2009b) were positive suggesting pediatric MS. As the clinical course was devastating with non-responsiveness upon high-dose immune modulatory therapy and due to the absence of an alternative diagnosis other than demyelinating disease brain biopsy was performed. Brain biopsy studies or autopsy case reports of fulminant pediatric MS patients are extremely rare. Histopathology revealed an inflammatory demyelinating CNS process with confluent demyelination, indicating the likelihood of a relapsing disease course compatible with an acute to subacute demyelinating inflammatory disease. This pattern was corresponding to the early active multiple sclerosis subtype I of Lucchinetti et al. (Ann Neurol 47(6):707-717, 2000). PMID- 21547393 TI - Efficacy of abamectin against the fowl tick, Argas (Persicargas) persicus (Oken, 1818) (Ixodoidea: Argasidae). AB - Abamectin, in aqueous solutions of dose rates 0.0625, 0.125, 0.25, 0.5, and 1 mL/L, was sprayed on different feeding stages of the tick Argas (P.) persicus. The results revealed a marked increase of immobile and dead male or female ticks following a single treatment with the above doses, particularly the higher ones, and during the 5 weeks after treatment. Abamectin seriously decreased the percentage of fed ticks as well as that of oviposition and hatching. A decrease in the amount of emitted coxal fluid was observed also following treatment. Although the amount of ingested blood increased following abamectin treatment, digestion remained similar. The study also revealed that spraying a dose of 0.5 mL/L of abamectin in fowl shelters, i.e., floor, walls, ceiling, etc., is sufficient to eradicate A. persicus population. PMID- 21547394 TI - TNFRSF13B/TACI alterations in Greek patients with antibody deficiencies. AB - TNFRSF13B/TACI defects have recently been associated with common variable immunodeficiency (CVID) pathogenesis. Considering that TNFRSF13B/TACI is very polymorphic and the frequency of its alterations may be different in various ethnic groups, we analyzed their prevalence in 47 Greek patients with antibody deficiencies, including CVID (16 patients), IgAD (16 patients), selective IgG4D (11 patients), and transient hypogammaglobulinemia of infancy (4 patients). A rather high frequency of TNFRSF13B/TACI defects was identified in patients with selective IgG4D (18.18%). Moreover, a patient with CVID was heterozygous in the common C104R mutation (6.25%). Both his children and a further healthy individual carried the same mutation, albeit without recurrent infections and/or hypogammaglobulinemia. The common polymorphisms V220A and P251L were identified in all disease subgroups, in an almost similar frequency with that observed in 259 healthy controls. Our data provide further evidence that TNFRSF13B/TACI alterations are not causative of CVID. Possibly, they predispose to humoral deficiencies and/or contribute to their phenotype when combined with other immune gene alterations. PMID- 21547395 TI - Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas. AB - COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m(2)/day and escalated by 25 mg/m(2)/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m(2)/day in the -EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. -EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m(2)/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas. PMID- 21547396 TI - Clinicopathological features of breast cancers predict the development of leptomeningeal metastases: a case-control study. AB - The incidence of leptomeningeal metastases (LM) in patients with breast cancer (BC) is increasing as a result of increased screening and improved patient survival. However, the median survival time after diagnosis of LM is between 5 weeks (without any treatment) and 5 months (for aggressively treated patients). In an attempt to identify clinicopathological risk factors for LM, we carried out a case-control study of 100 women with BC. Fifty patients with BC and LM were enrolled and an additional 50 patients with BC and no CNS metastases including leptomeningeal spread were selected as controls. Patients who had developed LM were selected between December 2006 and August 2008. The control group was matched for: age at diagnosis, year of diagnosis, and initiation of chemotherapy at BC diagnosis. The ILC type (P = 0.03), ER-negative (P = 0.01) and PR-negative status (P = 0.03), and initial M+ status at BC diagnosis (P = 0.008) tended to be more frequent in LM patients. These characteristics should lead to early appropriate assessments being performed in this targeted population when a neurological complaint appears, in order to detect LM as soon as possible. PMID- 21547397 TI - Glioblastoma-dependent differentiation and angiogenic potential of human mesenchymal stem cells in vitro. AB - Tumor angiogenesis is of central importance in the malignancy of glioblastoma multiforme (GBM). As previously shown, human mesenchymal stem cells (hMSC) migrate towards GBM and are incorporated into tumor microvessels. However, phenotype and function of recruited hMSC remain unclear. We evaluated the differentiation and angiogenic potential of hMSC after stimulation with glioblastoma-conditioned medium in vitro. Immunostaining with endothelial, smooth muscle cell and pericyte markers was used to analyze hMSC differentiation in different concentrations of tumor-conditioned medium (CM), and the angiogenic potential was evaluated by matrigel-based tube-formation assay (TFA). Immunofluorescence staining revealed that tumor-conditioned hMSC (CM-hMSC) expressed CD 151, VE-cadherin, desmin, alpha-smooth muscle actin, nestin, and nerval/glial antigen 2 (NG2) in a CM concentration-dependent manner, whereas no expression of von-Willebrand factor (vWF) and smooth myosin could be detected. These findings are indicative of GBM-dependent differentiation of hMSC into pericyte-like cells, rather than endothelial or smooth muscle cells. Furthermore, TFA of hMSC and CM-hMSC revealed CM-dependent formation of capillary-like networks, which differed substantially from those formed by human endothelial cells (HUVEC), also implying pericyte-like tube formation. These results are indicative of GBM-derived differentiation of hMSC into pericyte-like mural cells, which might contribute to the neovascularization and stabilization of tumor vessels. PMID- 21547398 TI - Influence of cobalt and zinc exposure on mRNA expression profiles of metallothionein and cytocrome P450 in rainbow trout. AB - The present research aims to evaluate the effects of cobalt and zinc exposure of rainbow trout (Oncorhynchus mykiss) on metallothioneins and cytocrome P450. Mature rainbow trouts were exposed to 10 mg/L CoCl(2).6H(2)O and 1 mg/L ZnSO(4).7H(2)O. After 6, 12, 24, and 48 h of treatment, expressions of muscle MT A, MT-B, and CYP P4501A1 mRNAs were measured by means of quantitative real-time polymerase chain reaction. During the exposure experiments, no mortalities occurred. We observed that expression levels of all genes increased with exposure time. Since the organism has not learned how to completely dispose of heavy metals and tends to bioaccumulate them, our results indicate that cobalt and zinc exposure may result in accumulation of the non-eliminated metals which may lead to fish death. PMID- 21547399 TI - Levels of arsenic, cadmium, lead, manganese and zinc in biological samples of paralysed steel mill workers with related to controls. AB - The determination of essential trace and toxic elements in the biological samples of human beings is an important clinical screening procedure. This study aimed to assess the possible effects of environmental exposure on paralysed male workers (n = 75) belonging to the production and quality control departments of a steel mill. In this investigation, the concentrations of arsenic, cadmium, lead, manganese and zinc were determined in biological samples (blood, urine and scalp hair samples) of exposed paralysis and non-paralysed steel mill workers. For comparative purposes, unexposed healthy subjects of same age group were selected as referents. The elements in the biological samples were measured by atomic absorption spectrophotometry prior to microwave-assisted acid digestion. The validity of the methodology was checked by the biological certified reference materials. The results indicate that the level understudy elements in all three biological samples were significantly higher in paralysed workers of both groups (quality control and production) as compared to referents (p < 0.01). The possible connection of these elements with the aetiology of disease is discussed. The results also show the need for immediate improvements of workplace ventilation and industrial hygiene practices. PMID- 21547400 TI - Arsenic, antimony, and bismuth uptake and accumulation by plants in an old antimony mine, China. AB - Arsenic (As), antimony (Sb), and bismuth (Bi) are metalloids that share similar chemical properties, the objective of this study was to characterize the uptake and accumulation of these metalloids by plants colonized on heavy contaminated sites in an old Sb mine. Sixty-five plant samples from seven species as well as the associated soil samples were collected at ten sites of Xikuangshan (XKS), Hunan province, China. Concentrations of As, Sb, and Bi in plants and soils were measured. As, Sb, and Bi were found to be evidently elevated due to the long history and intensive mining and smelting activities; the respective ranges for the levels of As, Sb, and Bi at the sites were 40.02-400.2 mg kg(-1) As, 610 54,221 mg kg(-1) Sb, and n.d. to 1,672 mg kg(-1) Bi. No correlation was found between As and Sb at the sites, while Bi was found to be positively correlated with As whereas negative with Sb at the sites. In general, the contents in the plants in XKS were in the order of As > Sb > Bi, and the contents of As was positively correlated with Sb and Bi in plants. The highest contents of As and Sb recorded was 607.8 mg kg(-1) As in Pteris vittata and 90.98 mg kg(-1) Sb in Hippochcaete ramosissima, while the highest Bi content as 2.877 mg kg(-1) Bi was measured in Buddleja davidii. Bioconcentration factors defined as the ratios of metalloids in shoots of plants to those in soils for various plants were lower than 1. The results showed plants colonized at the heavy contaminated sites in XKS had great tolerance to As, Sb, and Bi, and demonstrated similarities in plant uptake and accumulation of these three elements. PMID- 21547401 TI - Gender difference in accumulation of calcium and phosphorus in the left coronary arteries of Thais. AB - To examine whether there were gender differences in compositional changes of the coronary artery with aging, the authors investigated the gender difference in age related changes of elements in the left coronary arteries of Thais by direct chemical analysis. After ordinary dissections by students at Chiang Mai University were finished, the left coronary arteries were resected from Thai subjects. The Thai subjects consisted of 69 men and 34 women. The ages of the male subjects ranged from 25 to 87 years (average age = 62.6 +/- 11.4 years) and of the female subjects from 24 to 86 years (average age = 59.4 +/- 14.6 years). After incinerating the arteries with nitric acid and perchloric acid, the element content was determined by inductively coupled plasma-atomic emission spectrometry. The Ca and P contents tended to increase in the left coronary arteries of men with age, but the increases were not statistically significant. In the left coronary arteries of women, the Ca and P contents increased significantly and progressively with aging. In addition, the Na content increased significantly in the left coronary arteries of both men and women with aging. The differences in the average contents of Ca and P by age group were observed between the left coronary arteries of men and women. With Student's t test, significant gender differences in the average contents of Ca and P were found in both the 40s and the 70s. The Ca and P contents of the left coronary arteries in the 40s were significantly higher in men than in women. In contrast, the Ca and P contents in the 70s were significantly higher in women than in men. These results indicated that the accumulation of Ca and P in the left coronary arteries of Thais occurred at least 10 years earlier in men than in women, but a higher accumulation of Ca and P in old age occurred in the left coronary arteries of women compared with those of men. The present study revealed that there were significant gender differences in the left coronary arteries with regard to the accumulation of Ca and P with aging. It is reasonable to presume that taking clinical findings into consideration, the gender differences in the left coronary arteries may result from hormonal and/or genetic factors rather than lifestyle factors. PMID- 21547402 TI - Lead and calcium content in the human hip joint. AB - Concentration of lead in bone, unlike in soft tissues, increases during the lifetime and reflects severity of exposure to this element. The main aim of the study was to determine concentrations of lead and calcium and to find possible relationship between calcium and lead in the tissues of the hip joints obtained from inhabitants of the Upper Silesian Industrial Area. We also attempted to identify factors that might affect this relationship. The samples were harvested intraoperatively during total hip replacement procedures; in most cases, the indication for the surgery was hip osteoarthritis. Concentrations of lead and calcium were measured with a Pye Unicam SP-9 acetylene-oxygen flame atomic absorption spectrometer. The highest mean concentration of lead was found in the cancellous bone from the femoral head, followed by articular cartilage, cortical bone and the intertrochanteric cancellous bone (0.75 MUg/g). The smallest concentration was found in the joint capsule (0.19 MUg/g). The highest mean concentration of calcium was found in cancellous bone from the femoral head, followed by cancellous bone from the intertrochanteric area, cortical bone, articular cartilage and joint capsule. The concentration of lead showed no correlation with sex. The bone concentration of calcium decreased with age. In the analysed hips, this finding was true in the cortical bone, as well as in the cancellous bone of the intertrochanteric area. Statistically significant correlation between calcium and lead was found only in the hip articular cartilage. PMID- 21547403 TI - Systematic review of erosion after laparoscopic adjustable gastric banding. AB - Erosion of the laparoscopic adjustable gastric band (LAGB) into the lumen of the stomach is a recognised complication of this procedure. We undertook a systematic literature review of the incidence, clinical features and management of erosions occurring after LAGB. A systematic search of relevant medical databases for full text original articles looking for LAGB patients and reported erosions was conducted. We focussed on incidence, aetiology, clinical presentation, treatment, complications and weight loss. Twenty-five studies of LAGB reported 231 erosions in 15,775 patients (overall incidence of 1.46%). The mean number of patients per study was 631 (+/-486), and the mean follow-up was 3.73 (+/-2.4) years. In four reports involving less than 100 patients, there were 27 erosions in a total of 270 patients (10%) compared with 180 erosions in 12,978 patients (1.386%) in the remaining 21 reports. Multiple regression analysis showed that erosion rate was significantly predicted by number of patients and number of years of surgeon experience (r(2) = 0.186). Treatment was most commonly by removal of the band, repair of the stomach and later, band replacement. Other options were removal alone or conversion to another procedure. Weight loss was retained after treatment of the erosion with a mean weight loss at final follow-up of 50.34 +/- 3.9 percent excess weight loss. Incidence of erosion after gastric banding is relatively low and can be related to surgeon experience. The most common treatment described in the literature is removal of the eroded band with delayed replacement. Replacement of the band is associated with maintenance of weight loss. PMID- 21547404 TI - Is intestinal gluconeogenesis a key factor in the early changes in glucose homeostasis following gastric bypass? AB - BACKGROUND: In 2008, Troy et al. hypothesised that under fasting conditions, intestinal gluconeogenesis generates glucose levels in the portal vein which trigger the portal sensor to change insulin resistance and that this mechanism contributes to the effects of Roux-en-Y gastric bypass (RYGB) surgery on type 2 diabetes mellitus (T2DM). In a recent paper, Kashyap et al. (Int J Obes 34(3):426 471, 2010) cited this hypothesis as a potential explanation for the early changes in insulin sensitivity and beta cell function seen after RYGB. We proposed a study to examine this possibility. METHODS: We simultaneously sampled fasting portal venous blood and central venous blood in 28 patients (eight diabetics and 20 non-diabetics) before and again six days after RYGB surgery in morbidly obese patients, for measurement of glucose levels. RESULTS: We found no significant difference in the glucose levels from the two sites either before or after RYGB in diabetic patients and a small, but significant difference in the post operative glucose levels from non-diabetic patients (4.2 vs 4.0 mM, p < 0.0001). CONCLUSIONS: Direct simultaneous measurement of fasting glucose in portal and central venous blood before and 6 days after RYGB provides no evidence to support the hypothesis that intestinal gluconeogenesis contributes to the resolution of T2DM seen after RYGB. PMID- 21547405 TI - Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, Sao Paulo, Brazil. AB - To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in Sao Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings. PMID- 21547406 TI - A study to determine chest wall vibratory attachment interface locations for a low frequency sonic vibrator in treatment of acute coronary thrombosis. AB - Our institution is developing a non-invasive Diastolic Timed Vibrator (DTV) to enhance emergency clearance of acute coronary thrombosis. Sonic frequency diastolic vibro-percussion (i.e. 50 Hz, 2 mm amplitude) applied upon the rib spaces of the left sternal border has shown to improve left ventricular performance and coronary flow in human volunteers. However, therapeutic acoustic penetrability cannot be assumed depending on varying chest size and lung position which attenuates acoustic transmissions. Furthermore, chest locations enabling a direct lung free pathway overlying the base of the heart (wherein the coronaries arise) should be promoted, while locations overlying the left ventricular apex (site of potential thrombus formation) should be avoided. We therefore set out to determine preferred chest wall placement positions for a vibratory interface suitable for treatment of ST Elevation Myocardial Infarction (STEMI). Inter Costal Space (ICS) positions to the left or right of the sternum were interrogated in 90 adults following routine Echocardiography to ascertain whether the base of the heart could be imaged (hence inferring acoustic transmissibility), and to determine over what part of the heart each transducer position was overlying. The third and fourth ICS proximate the left sternal border provided acoustic transmissibility in 96 and 100% of cases respectively, with only one unwanted occurrence from the fourth ICS where the transducer overlaid the apical third of the left ventricle. Acoustic transmissibility from third and fourth ICS right sternal border was documented in 53 and 85% of cases respectively. A vibration interface in STEMI treatment should allow for contact overlying the left and right third and fourth ICS generally proximate the sternal borders. As vibration transmission to the cardiac apex and/or left atrium cannot be completely avoided, vibration therapy should be contra-indicated in late presenters for antero-septal apical STEMI, and in cases of new onset atrial fibrillation persisting greater than 48 h which have not been adequately anti coagulated. PMID- 21547408 TI - Prognostic value of oncoprotein expressions in thyroid papillary carcinoma. AB - The aim of this study was to evaluate the expressions of oncoproteins and to correlate the results with clinicopathologic parameters in papillary thyroid carcinoma (PTC). Papillary thyroid cancer (PTC) is the most common form and accounts for about 80% of all thyroid cancers. Although PTC generally has a good prognosis, some patients suffer from local recurrence and/or distant metastasis. Oncogenes have reported to be related not only in carcinogenesis but also in tumor prognosis, tumor type, differentiation and site of tumor in epithelial malignant tumors such as thyroid, breast, ovarian, and stomach cancer. This study was planned retrospectively and was performed in 87 patients (47 PTC, 40 benign lesions). The data of clinicopathologic parameters and tissue samples were collected from the archives. Sections stained with H&E were evaluated for each case and after confirming the diagnosis of PTC, oncoprotein expressions were determined by immunohistochemical analysis. The differences of oncoprotein expressions in PTC compared with control group were statistically significant. Cyclin D1 and p53 expressions were significantly increased in PTC. The expressions of bcl-2 and c-erbB-2 in PTC were found as increased, but the correlation between these proteins and poor prognostic parameters were not significant. We suggest that increased expressions of cyclin D1 and p53 could be used as prognostic factors in patients with PTC. PMID- 21547407 TI - Inflammation and cellular stress: a mechanistic link between immune-mediated and metabolically driven pathologies. AB - BACKGROUND: Multiple cellular stress responses have been implicated in chronic diseases such as obesity, diabetes, cardiovascular, and inflammatory bowel diseases. Even though phenotypically different, chronic diseases share cellular stress signaling pathways, in particular endoplasmic reticulum (ER) unfolded protein response (UPR). RESULTS AND METHODS: The purpose of the ER UPR is to restore ER homeostasis after challenges of the ER function. Among the triggers of ER UPR are changes in the redox status, elevated protein synthesis, accumulation of unfolded or misfolded proteins, energy deficiency and glucose deprivation, cholesterol depletion, and microbial signals. Numerous mouse models have been used to characterize the contribution of ER UPR to several pathologies, and ER UPR-associated signaling has also been demonstrated to be relevant in humans. Additionally, recent evidence suggests that the ER UPR is interrelated with metabolic and inflammatory pathways, autophagy, apoptosis, and mitochondrial stress signaling. Furthermore, microbial as well as nutrient sensing is integrated into the ER-associated signaling network. CONCLUSION: The data discussed in the present review highlight the interaction of ER UPR with inflammatory pathways, metabolic processes and mitochondrial function, and their interrelation in the context of chronic diseases. PMID- 21547409 TI - The association between self-efficacy and hypertension self-care activities among African American adults. AB - Chronic disease management requires the individual to perform varying forms of self-care behaviors. Self-efficacy, a widely used psychosocial concept, is associated with the ability to manage chronic disease. In this study, we examine the association between self-efficacy to manage hypertension and six clinically prescribed hypertension self-care behaviors. We interviewed 190 African Americans with hypertension who resided in the greater metropolitan Charlotte area about their self-efficacy and their hypertension self-care activities. Logistic regression for correlated observations was used to model the relationship between self-efficacy and adherence to hypertension self-care behaviors. Since the hypertension self-care behavior outcomes were not rare occurrences, an odds ratio correction method was used to provide a more reliable measure of the prevalence ratio (PR). Over half (59%) of participants reported having good self-efficacy to manage their hypertension. Good self-efficacy was statistically significantly associated with increased prevalence of adherence to medication (PR = 1.23, 95% CI: 1.08, 1.32), eating a low-salt diet (PR = 1.64, 95% CI: 1.07-2.20), engaging in physical activity (PR = 1.27, 95% CI: 1.08-1.39), not smoking (PR = 1.10, 95% CI: 1.01-1.15), and practicing weight management techniques (PR = 1.63, 95% CI: 1.30-1.87). Hypertension self-efficacy is strongly associated with adherence to five of six prescribed self-care activities among African Americans with hypertension. Ensuring that African Americans feel confident that hypertension is a manageable condition and that they are knowledgeable about appropriate self care behaviors are important factors in improving hypertension self-care and blood pressure control. Health practitioners should assess individuals' self-care activities and direct them toward practical techniques to help boost their confidence in managing their blood pressure. PMID- 21547410 TI - Obesity, hope, and health: findings from the HOPE Works community survey. AB - According to hope theory, hope is defined as goal-directed thinking in which people perceive that they can find routes to desired goals and the motivation to use those routes. The purpose of this study was to explore relationships between hope and body mass index and hope and self-rated health among women completing a community survey conducted in four rural counties in eastern North Carolina. The survey was administered as part of Hope Works, a participatory, community-led intervention program to improve weight, health and hope among low-income women in rural North Carolina. Survey data from 434 women were analyzed. In multivariate models adjusting for age, race, education and income, higher hope was positively related to self-reported health (OR:0.92; 95% CI: 0.89-0.95) and negatively related to BMI (P < 0.01). These results indicated that women who reported better self-rated health also had higher hope scores and women who were heavier had lower hope scores. While these findings are exploratory, they suggest directions for further research. State-based hope is considered to be a characteristic that is malleable and open to development. Future interventions should examine the importance of hope as a construct to examine in weight loss studies. For example, programs could be designed to increase hope by focusing on goal setting and providing support, information and resources to help women work toward their goals. PMID- 21547411 TI - Neighborhood deprivation, supermarket availability, and BMI in low-income women: a multilevel analysis. AB - High levels of neighborhood deprivation and lack of access to supermarkets have been associated with increased risk of obesity in women. This multilevel study used a statewide dataset (n = 21,166) of low-income women in the Special Supplemental Nutrition Program for Women, Infants, and Children to determine whether the association between neighborhood deprivation and BMI is mediated by the availability of retail food stores, and whether this relationship varied across the urban rural continuum. Residence in a high deprivation neighborhood was associated with a 0.94 unit increase in BMI among women in metropolitan areas. The relationship between tract deprivation and BMI was not linear among women in micropolitan areas, and no association was observed in rural areas. The presence of supermarkets or other retail food stores did not mediate the association between deprivation and BMI among women residing in any of the study areas. These results suggest that level of urbanity influences the effect of neighborhood condition on BMI among low-income women, and that the availability of supermarkets and other food stores does not directly influence BMI among low income populations. PMID- 21547412 TI - Young children with autism spectrum disorder do not preferentially attend to biological motion. AB - Preferential attention to biological motion can be seen in typically developing infants in the first few days of life and is thought to be an important precursor in the development of social communication. We examined whether children with autism spectrum disorder (ASD) aged 3-7 years preferentially attend to point light displays depicting biological motion. We found that children with ASD did not preferentially attend to biological motion over phase-scrambled motion, but did preferentially attend to a point-light display of a spinning top rather than a human walker. In contrast a neurotypical matched control group preferentially attended to the human, biological motion in both conditions. The results suggest a core deficit in attending to biological motion in ASD. PMID- 21547413 TI - 50 years ago in CORR: Osteomalacia, osteoporosis, and calcium deficiency. B.E.C. Nordin, MD, MRCP, PhD 1960;17:235-258. PMID- 21547414 TI - Smartphone apps for orthopaedic surgeons. AB - BACKGROUND: The use of smartphones and their associated applications (apps) provides new opportunities for physicians, and specifically orthopaedic surgeons, to integrate technology into clinical practice. PURPOSE: The purpose of this study was twofold: to review all apps specifically created for orthopaedic surgeons and to survey orthopaedic residents and surgeons in the United States to characterize the need for novel apps. METHODS: The five most popular smartphone app stores were searched for orthopaedic-related apps: Blackberry, iPhone, Android, Palm, and Windows. An Internet survey was sent to ACGME-accredited orthopaedic surgery departments to assess the level of smartphone use, app use, and desire for orthopaedic-related apps. RESULTS: The database search revealed that iPhone and Android platforms had apps specifically created for orthopaedic surgery with a total of 61 and 13 apps, respectively. Among the apps reviewed, only one had greater than 100 reviews (mean, 27), and the majority of apps had very few reviews, including AAOS Now and AO Surgery Reference, apps published by the American Academy of Orthopaedic Surgeons and AO Foundation, respectively. The national survey revealed that 84% of respondents (n = 476) have a smartphone, the majority (55%) have an iPhone, and that 53% of people with smartphones already use apps in clinical practice. Ninety-six percent of respondents who use apps reported they would like more orthopaedic apps and would pay an average of nearly $30 for useful apps. The four most requested categories of apps were textbook/reference, techniques/guides, OITE/board review, and billing/coding. CONCLUSION: The use of smartphones and apps is prevalent among orthopaedic care providers in academic centers. However, few highly ranked apps specifically related to orthopaedic surgery are available, and the types of apps available do not appear to be the categories most desired by residents and surgeons. PMID- 21547415 TI - Human periosteum is a source of cells for orthopaedic tissue engineering: a pilot study. AB - BACKGROUND: Periosteal cells are important in embryogenesis, fracture healing, and cartilage repair and could provide cells for osteochondral tissue engineering. QUESTIONS/PURPOSE: We determined whether a population of cells isolated from human periosteal tissue contains cells with a mesenchymal stem cell (MSC) phenotype and whether these cells can be expanded in culture and used to form tissue in vitro. METHODS: We obtained periosteal tissue from six patients. Initial expression of cell surface markers was assessed using flow cytometry. Cells were cultured over 10 generations and changes in gene expression evaluated to assess phenotypic stability. Phenotype was confirmed using flow cytometry and colony-forming ability assays. Mineral formation was assessed by culturing Stro 1(-) and unsorted cells with osteogenic supplements. Three cell culture samples were used for a reverse transcription-polymerase chain reaction, four for flow cytometry, three for colony-forming assay, and three for mineralization. RESULTS: Primary cultures, containing large numbers of hematopoietic cells were replaced initially by Stro-1 and ALP-expressing immature osteoblastic cell types and later by ALP-expressing cells, which lacked Stro-1 and which became the predominant cell population during subculture. Approximately 10% of the total cell population continued to express markers for Stro1(+)/ALP(-) cells throughout. CONCLUSIONS: These data suggest periosteum contains a large number of undifferentiated cells that can differentiate into neotissue and persist despite culture in noncell specific media for over 10 passages. CLINICAL RELEVANCE: Cultured periosteal cells may contribute to tissue formation and may be applicable for tissue engineering applications. PMID- 21547417 TI - Idebenone induces apoptotic cell death in the human dopaminergic neuroblastoma SHSY-5Y cells. AB - Idebenone is a coenzyme Q10 analog and an antioxidant that has been used clinically to treat Friedreich Ataxia. Being an antioxidant, idebenone could have potential therapeutic potential to treat other neurodegenerative diseases such as Parkinson's disease in which oxidative stress plays a role in their pathogenesis. But whether idebenone can be used to treat Parkinson's disease has not been evaluated. In this study, we found that exposure of the dopaminergic neuroblastoma SHSY-5Y cells to 1-10 MUM idebenone for 72 h had no effect on the cell viability revealed by trypan blue exclusion assay and MTT assay. However, cells exposed to 25 MUM or higher concentrations of idebenone showed extensive trypan blue-positive staining and significant reduction in cell viability revealed by MTT assay indicating that most of the cells were no longer viable. Idebenone-induced cell death was characterized by genomic DNA fragmentation and accumulation of cytochrome c in the cytosol indicating that the death was apoptotic in nature. In addition, idebenone induced an increase in the total RNA of the pro-apoptosis protein BAX, it also increased the caspase-3 activity in the cell lysates when compared with the untreated control cells or cells exposed to 10 MUM or lower concentrations of idebenone. The detrimental effect of idebenone was attenuated by glutathione, an antioxidant, suggesting that oxidative stress contributed to the idebenone-induced cell death. In conclusion, our results suggest that antioxidant idebenone induced apoptosis when used in high concentrations. PMID- 21547419 TI - Of checklists and iPatients: some suggestions for cancer educators. PMID- 21547418 TI - Unpacking the blockers: understanding perceptions and social constraints of health communication in hereditary breast ovarian cancer (HBOC) susceptibility families. AB - Family communication is essential for accurate cancer risk assessment and counseling; family blockers play a role in this communication process. This qualitative analysis of social exchanges is an extension of earlier work characterizing those who are perceived by study participants as health information gatherers, disseminators, and blockers within families with Hereditary Breast and Ovarian Cancer (HBOC) susceptibility. Eighty-nine women, ages 23-56 years, enrolled in a Breast Imaging Study (BIS) and participated in a sub-study utilizing a social assessment tool known as the Colored Ecological Genetic Relational Map (CEGRM). Purposive sampling ensured that participants varied according to numbers of participating family members e.g., ranging from 1 to 6. Eighty-nine women from 42 families (1-8 relatives/family) participated. They collectively designated 65 blockers, both male and female. Situational factors, beliefs, attitudes and cultural traditions, privacy and protectiveness comprised perceived reasons for blocking intra-family health communications. Longitudinal data collected over 4 years showed families where blocking behavior was universally recognized and stable over time, as well as other families where blocking was less consistent. Self-blocking was observed among a significant minority of participating women. Blocking of health communications among family members with HBOC was variable, complex, and multifaceted. The reasons for blocking were heterogeneous; duration of the blocking appeared to depend on the reasons for blocking. Blocking often seemed to involve bi-directional feedback loops, in keeping with Lepore's Social Constraints and Modulation Theory. Privacy and protectiveness predominated as explanations for long-term blocking. PMID- 21547420 TI - Incidental gallbladder cancer by the AFC-GBC-2009 Study Group. AB - BACKGROUND: Incidental gallbladder cancer (GBC) is frequently discovered on the specimen when cholecystectomy for a benign disease is performed. The objective of the present study was to assess the management of incidental GBC patients in a French registry. METHODS: Data on patients with GBC treated between 1998 and 2008 were retrospectively collated in a French, multicenter database. RESULTS: The registry contained 218 patients with incidental GBC (67 men and 151 women; median age = 64 years; age range = 31-88). One hundred forty-eight (68%) patients underwent re-resection after a median time interval of 48 days (range = 2-245). The most common complete procedure (66% of cases) was 4b + 5 segmentectomy with lymphadenectomy but not bile duct resection. Port-site excision was performed in 54 patients. The mortality and morbidity rates were 3 and 37%, respectively. Resection of the common bile duct (43%) increased postoperative complications (60 vs. 23%, p = 0.0001). Local residual tumor was found in 83 (56%) patients; it was significantly correlated with the T stage and influenced long-term survival. R0 was obtained in 143 (97%) patients and port-site invasion was histologically confirmed in one patient (1.8%). After a median follow-up period of 34 months, the 1-, 3-, and 5-year survival rates for the 148 patients with re-resection were 76, 54, and 41%, respectively. Re-resection significantly increased survival in patients with T2 (p = 0.0001) and T3 (p = 0.04) disease. Resection of the common bile duct increased neither R0 resection nor overall survival (p = 0.06). CONCLUSION: This study validates the concept of re-resection in T2 and T3 GBC. Bile duct resection increases postoperative morbidity but does not improve survival. There is currently a modification in the surgical management of incidental GBC, with minor liver resection and no common bile duct resection. PMID- 21547421 TI - Does prophylactic biologic mesh placement protect against the development of incisional hernia in high-risk patients? AB - BACKGROUND: The purpose of this study was to determine whether the prophylactic use of a biologic prosthesis protects against the development of incisional hernia in a high-risk patient population. METHODS: A prospective, nonrandomized trial was conducted on 134 patients undergoing open Roux-en-Y gastric bypass by a single surgeon, at two institutions, from January 2005 to November 2007. At Hospital A, all patients (n=59) underwent fascial closure of the abdominal midline wound with the prophylactic placement of a biologic mesh (AlloDerm(r)) in an in-lay fashion. Patients at Hospital B (n=75) underwent primary abdominal wall closure using #1 PDS in a running fashion. Data collected included patient demographics, abdominal wall closure technique, postoperative wound complications, follow-up period, and incidence of incisional hernia. RESULTS: During the study period 134 patients (mean age=40.4 years, 80.7% female) underwent open Roux-en-Y gastric bypass (59.7% mesh, 41.5% nonmesh). Twenty-eight patients were excluded from the analysis secondary to a short follow-up period (mesh=13, nonmesh=11) and/or reoperative surgery unrelated to the development of an incisional hernia (mesh=2, nonmesh=2). The mean follow-up period was 17.3+/ 8.5 months. The overall incidence of incisional hernia was 11.3% (95% CI: 5.2 17.45). The incidence of incisional hernia was significantly lower in the mesh group versus the nonmesh group (2.3 vs. 17.7%, P=0.014). In a multivariate logistic regression model that adjusted for age, sex, body mass index, albumin, smoking, diabetes, prior surgery, seroma formation, weight loss, and mesh placement, the development of incisional hernia was found to be associated with smoking (adjusted odds ratio [OR] 8.46, 95% CI: 1.79-40.00, P=0.007) while prophylactic mesh was noted to be protective against hernia development (adjusted OR 0.06, 95% CI: 0.006-0.69, P=0.02). CONCLUSION: The prophylactic use of biologic mesh for abdominal wall closure appears to reduce the incidence of incisional hernia in patients with multiple risk factors for incisional hernia development. PMID- 21547423 TI - Short-term exercise-heat acclimation enhances skin vasodilation but not hyperthermic hyperpnea in humans exercising in a hot environment. AB - We tested the hypothesis that short-term exercise-heat acclimation (EHA) attenuates hyperthermia-induced hyperventilation in humans exercising in a hot environment. Twenty-one male subjects were divided into the two groups: control (C, n = 11) and EHA (n = 10). Subjects in C performed exercise-heat tests [cycle exercise for ~75 min at 58% [Formula: see text] (37 degrees C, 50% relative humidity)] before and after a 6-day interval with no training, while subjects in EHA performed the tests before and after exercise training in a hot environment (37 degrees C). The training entailed four 20-min bouts of exercise at 50% [Formula: see text] separated by 10 min of rest daily for 6 days. In C, comparison of the variables recorded before and after the no-training period revealed no changes. In EHA, the training increased resting plasma volume, while it reduced esophageal temperature (T (es)), heart rate at rest and during exercise, and arterial blood pressure and oxygen uptake ([Formula: see text]) during exercise. The training lowered the T (es) threshold for increasing forearm vascular conductance (FVC), while it increased the slope relating FVC to T (es) and the peak FVC during exercise. It also lowered minute ventilation ([Formula: see text]) during exercise, but this effect disappeared after removing the influence of [Formula: see text] on [Formula: see text]. The training did not change the slope relating ventilatory variables to T (es). We conclude that short term EHA lowers ventilation largely by reducing metabolism, but it does not affect the sensitivity of hyperthermia-induced hyperventilation during submaximal, moderate-intensity exercise in humans. PMID- 21547424 TI - Brain phenotype of carbonic anhydrase IX-deficient mice. AB - Preliminary observations have suggested mild behavioral changes and a morphological disruption of brain histology in 1.5-year-old carbonic anhydrase IX (CA IX)-deficient (Car9 (-/-)) mice. These findings led us to design a 1-year follow-up study in which the behavior and brain histology of Car9 (-/-) and wild type mice were monitored. Morphological analysis revealed vacuolar degenerative changes in the brains of Car9 (-/-) mice. The changes became visible at the age of eight to ten months. Behavioral tests showed that the Car9 (-/-) mice exhibited abnormal locomotor activity and poor performance in a memory test. To further identify the transcriptomic responses to CA IX deficiency in the brain, genome-wide cDNA microarray analyses were performed. Thirty-one and 37 genes were significantly up- or down-regulated, respectively, in the brain of Car9 (-/-) mice compared to the wild-type mice. Functional annotation revealed that the genes with increased expression were involved in several processes, such as RNA metabolism, and the genes with reduced expression were implicated in other important processes, including the regulation of cellular ion homeostasis. Notably, the biological processes "behavior" and "locomotory behavior" were the two prominent terms overrepresented among the down-regulated genes, which is consistent with the behavioral phenotype. These results suggest that CA IX may directly or indirectly play novel functions in brain tissue. Furthermore, the brain phenotype of Car9 (-/-) mice seems to be age-dependent. The results indicate that the functional changes precede the microscopic alterations in the brains of Car9 (-/-) mice. PMID- 21547425 TI - A three-dimensional study of the atlantodental interval in a normal Chinese population using reformatted computed tomography. AB - The atlantodental interval has been usually used for the evaluation of atlantoaxial instability. However, the asymmetry of the lateral atlantodental interval is occasionally found in healthy individuals. Controversy therefore exists as to the clinical significance of this asymmetry in patients after trauma. The purpose of this study was to determine the normal range of atlantodental intervals in normal individuals using reformatted computed tomography. In this study, C1-C2 vertebrae were imaged in 230 adult patients by a Lightspeed Vct CT (General Electric, CT, USA) with a slice thickness of 0.625 mm. After reformatting the original images, the anterior atlantodental interval (AADI) and lateral atlantodental interval (LADI) were measured. The AADI was found to be 1.83 +/- 0.46 mm (0.9-3.4 mm) in males and 1.63 +/- 0.43 mm (0.5-3.2 mm) in females. The AADI was significantly greater in males than in females (p < 0.05). The 95% confidence interval for AADI was 1.75-1.90 mm in males and 1.54 1.72 mm in females. No statistically significant differences were found between males and females in the left and right LADI, and LADI asymmetry. The left LADI was found to be 3.38 +/- 0.87 mm (1.7-6.0 mm), and the right LADI was 3.42 +/- 0.84 mm (1.7-5.9 mm) in males, while the left LADI was 3.30 +/- 0.73 mm (1.5-5.3 mm) and the right LADI was 3.37 +/- 0.92 mm (1.7-5.9 mm) in females. The 95% confidence interval for left LADI was 3.23-3.52 and 2.94-3.25 mm, and for right LADI was 3.27-3.56 and 3.18-3.56 mm in males and females, respectively. The mean asymmetry of LADI was 0.76 +/- 0.66 mm (0.0-3.5 mm) in males and 0.73 +/- 0.70 mm (0.0-3.7 mm) in females. The 95% confidence interval for LADI asymmetry was 0.65 0.87 mm in males and 0.59-0.88 mm in females. Most of the population was found to have an asymmetry ranging between 0.1 and 2.0 mm. The current study shows that LADI asymmetry is common in patients without any cervical spine abnormalities. LADI asymmetry may be a normal anatomic variant and there is no evidence to confirm that LADI asymmetry is a sensitive or specific indicator of traumatic atlantoaxial instability. Radiologists and clinicians should be aware of this normal range of asymmetry when interpreting CT scans of the atlantoaxial region. PMID- 21547426 TI - Neurological development in 21 children on peritoneal dialysis in infancy. AB - Few studies have focused on the neurodevelopment of infants on peritoneal dialysis (PD). Infants are the most demanding patient group on PD and thus are vulnerable to neurological sequelae. We studied 21 patients <2 years of age (mean 0.59 years) at onset of PD. They were evaluated by a neurologist, otologist, physiotherapist, and occupational therapist during PD. Neuropsychological tests were collected from all patients at least 5 years old, and the brain images were reviewed. Eleven patients (52%) had a pre- or neonatal problem or comorbidity as risk factor for their development at onset of PD. All infants tolerated PD well. At the end of the study, 71% had some neurological abnormality, 29% a major impairment (all with predialysis risk factors), and 43% a minor one. Brain infarcts were detected in four patients (19%) and other ischemic lesions in three (14%). Three patients (14%) developed hearing defect. Mortality rate was 5%. PD is a safe treatment modality for end-stage renal failure in infants. Some patients had risk factors for development, but their neurological problems did not progress during PD. Patients without risk factors tolerated PD well without major neurological sequelae. PMID- 21547427 TI - Enantioselective analysis of zopiclone and its metabolites in plasma by liquid chromatography/tandem mass spectrometry. AB - A high-performance liquid chromatographic method with triple-quadrupole mass spectrometry detection (LC-MS-MS) was developed and validated for the first time for the simultaneous quantification of zopiclone and its metabolites in rat plasma samples. The analytes were isolated from rat plasma by liquid-liquid extraction and separated using a chiral stationary phase based on an amylose derivative, Chiralpak ADR-H column, and ethanol-methanol-acetonitrile (50:45:5, v/v/v) plus 0.025% diethylamine as the mobile phase, at a flow-rate of 1.0 mL min(-1). Moclobemide was used as the internal standard. The developed method was linear over the concentration range of 7.5-500 ng mL(-1). The mean absolute recoveries were 74.6 and 75.7; 61.6 and 56.9; 72.5, and 70.7 for zopiclone enantiomers, for N-desmethyl zopiclone enantiomers and for zopiclone-N-oxide enantiomers, respectively, and 75.9 for the internal standard. Precision and accuracy were within acceptable levels of confidence (<15%). The method application in a pilot study of zopiclone kinetic disposition in rats showed that the levels of (+)-(S)-zopiclone were always higher than those of (-)-R-zopiclone. Higher concentrations were also observed for (+)-(S)-N-desmethyl zopiclone and (+)-(S)-N-oxide zopiclone, confirming the stereoselective disposition of zopiclone. PMID- 21547428 TI - Evaluation and evidence of natural gangliosides with two unsaturated bonds in the ceramide structure obtained by a combination of MALDI-MS and NMR spectroscopy. AB - Gangliosides are membrane-associated glycosphingolipids. N-Acetyl GM3 and N glycolyl GM3 are two tumor-associated antigens expressed in cancer tissues such as melanoma and mammalian cancer. In order to use these antigens in GM3-based vaccines for patients with early stage cancer, the synthetic version is recommended to avoid the risk of animal virus transmission from the source. However, the isolation of natural gangliosides is of comparative value for the structural characterization. The structures of N-acetyl and N-glycolyl GM3 extracted from dog and horse erythrocytes were evaluated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and nuclear magnetic resonance techniques; additionally, the natural N-acetyl ganglioside was compared to a synthetic one. In addition to the main compound with C24:0 fatty acid chain, a minor component with an additional unsaturation in the ceramide chain was detected, in both the dog and the horse gangliosides. This paper shows spectroscopic evidence of the aforementioned compounds. PMID- 21547429 TI - Kinetic analyses and performance of a colloidal magnetic nanoparticle based immunoassay dedicated to allergy diagnosis. AB - In this paper, we demonstrate the possibility to use magnetic nanoparticles as immunosupports for allergy diagnosis. Most immunoassays used for immunosupports and clinical diagnosis are based on a heterogeneous solid-phase system and suffer from mass-transfer limitation. The nanoparticles' colloidal behavior and magnetic properties bring the advantages of homogeneous immunoassay, i.e., species diffusion, and of heterogeneous immunoassay, i.e., easy separation of the immunocomplex and free forms, as well as analyte preconcentration. We thus developed a colloidal, non-competitive, indirect immunoassay using magnetic core shell nanoparticles (MCSNP) as immunosupports. The feasibility of such an immunoassay was first demonstrated with a model antibody and described by comparing the immunocapture kinetics using macro (standard microtiter plate), micro (microparticles) and nanosupports (MCSNP). The influence of the nanosupport properties (surface chemistry, antigen density) and of the medium (ionic strength, counter ion nature) on the immunocapture efficiency and specificity was then investigated. The performances of this original MCSNP-based immunoassay were compared with a gold standard enzyme-linked immunosorbent assay (ELISA) using a microtiter plate. The capture rate of target IgG was accelerated 200-fold and a tenfold lower limit of detection was achieved. Finally, the MCSNP-based immunoassay was successfully applied to the detection of specific IgE from milk allergic patient's sera with a lower LOD and a good agreement (CV < 6%) with the microtiter plate, confirming the great potential of this analytical platform in the field of immunodiagnosis. PMID- 21547430 TI - Optical coherence tomography-current technology and applications in clinical and biomedical research. AB - Optical coherence tomography (OCT) is a noninvasive imaging technique that provides real-time two- and three-dimensional images of scattering samples with micrometer resolution. By mapping the local reflectivity, OCT visualizes the morphology of the sample. In addition, functional properties such as birefringence, motion, or the distributions of certain substances can be detected with high spatial resolution. Its main field of application is biomedical imaging and diagnostics. In ophthalmology, OCT is accepted as a clinical standard for diagnosing and monitoring the treatment of a number of retinal diseases, and OCT is becoming an important instrument for clinical cardiology. New applications are emerging in various medical fields, such as early-stage cancer detection, surgical guidance, and the early diagnosis of musculoskeletal diseases. OCT has also proven its value as a tool for developmental biology. The number of companies involved in manufacturing OCT systems has increased substantially during the last few years (especially due to its success in opthalmology), and this technology can be expected to continue to spread into various fields of application. PMID- 21547431 TI - A selective adenosine sensor derived from a triplex DNA aptamer. AB - The aim of this study is to develop a selective adenosine aptamer sensor using a rational approach. Unlike traditional RNA aptamers developed from SELEX, duplex DNA containing an abasic site can function as a general scaffold to rationally design aptamers for small aromatic molecules. We discovered that abasic site containing triplex DNA can also function as an aptamer and provide better affinity than duplex DNA aptamers. A novel adenosine aptamer sensor was designed using such a triplex. The aptamer is modified with furano-dU in the binding site to sense the binding. The sensor bound adenosine has a dissociation constant of 400 nM, more than tenfold stronger than the adenosine aptamer developed from SELEX. The binding quenched furano-dU fluorescence by 40%. It was also demonstrated in this study that this sensor is selective for adenosine over uridine, cytidine, guanosine, ATP, and AMP. The detection limit of this sensor is about 50 nM. The sensor can be used to quantify adenosine concentrations between 50 nM and 2 MUM. PMID- 21547432 TI - Quantitative determination of small selenium species in human serum by HPLC/ICPMS following a protein-removal, pre-concentration procedure. AB - Protein precipitation was incorporated into a sample preparation method for the quantitative determination of small "non-protein" selenium species in human serum by high-performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC/ICPMS). The advantages of cleaner matrix and concomitant concentration of the small compounds result in quantification limits in the native serum at the sub-micrograms Se per litre level. Spiking experiments with methyl 2-acetamido-2-deoxy-1-seleno-beta-D-galactopyranoside (selenosugar 1), trimethylselenonium ion, selenomethionine, methylselenocysteine (MeSeCys) and selenate yielded recoveries from 73% to 103%. Selenite had a low recovery (44%), possibly owing to protein binding. The validated method was applied to serum samples from two volunteers before and after ingestion of a selenium food supplement. HPLC/ICPMS analysis showed, besides ingested selenate, the presence of selenosugar 1 and trace amounts of MeSeCys and methyl 2-amino-2-deoxy-1-seleno beta-D-galactopyranoside, which have not been reported in human serum before. PMID- 21547433 TI - A system method for the assessment of integrated water resources management (IWRM) in mountain watershed areas: the case of the "Giffre" watershed (France). AB - In the last fifty years, many mountain watersheds in temperate countries have known a progressive change from self-standing agro-silvo-pastoral systems to leisure dominated areas characterized by a concentration of tourist accommodations, leading to a drinking water peak during the winter tourist season, when the water level is lowest in rivers and sources. The concentration of water uses increases the pressure on "aquatic habitats" and competition between uses themselves. Consequently, a new concept was developed following the international conferences in Dublin (International Conference on Water and the Environment - ICWE) and Rio de Janeiro (UN Conference on Environment and Development), both in 1992, and was broadly acknowledged through international and European policies. It is the concept of Integrated Water Resource Management (IWRM). It meets the requirements of different uses of water and aquatic zones whilst preserving the natural functions of such areas and ensuring a satisfactory economic and social development. This paper seeks to evaluate a local water resources management system in order to implement it using IWRM in mountain watersheds. The assessment method is based on the systemic approach to take into account all components influencing a water resources management system at the watershed scale. A geographic information system was built to look into interactions between water resources, land uses, and water uses. This paper deals specifically with a spatial comparison between hydrologically sensitive areas and land uses. The method is applied to a French Alps watershed: the Giffre watershed (a tributary of the Arve in Haute-Savoie). The results emphasize both the needs and the gaps in implementing IWRM in vulnerable mountain regions. PMID- 21547434 TI - TMDL implementation in agricultural landscapes: a communicative and systemic approach. AB - Increasingly, total maximum daily load (TMDL) limits are being defined for agricultural watersheds. Reductions in non-point source pollution are often needed to meet TMDL limits, and improvements in management of annual crops appear insufficient to achieve the necessary reductions. Increased adoption of perennial crops and other changes in agricultural land use also appear necessary, but face major barriers. We outline a novel strategy that aims to create new economic opportunities for land-owners and other stakeholders and thereby to attract their voluntary participation in land-use change needed to meet TMDLs. Our strategy has two key elements. First, focused efforts are needed to create new economic enterprises that capitalize on the productive potential of multifunctional agriculture (MFA). MFA seeks to produce a wide range of goods and ecosystem services by well-designed deployment of annual and perennial crops across agricultural landscapes and watersheds; new revenue from MFA may substantially finance land-use change needed to meet TMDLs. Second, efforts to capitalize on MFA should use a novel methodology, the Communicative/Systemic Approach (C/SA). C/SA uses an integrative GIS-based spatial modeling framework for systematically assessing tradeoffs and synergies in design and evaluation of multifunctional agricultural landscapes, closely linked to deliberation and design processes by which multiple stakeholders can collaboratively create appropriate and acceptable MFA landscape designs. We anticipate that application of C/SA will strongly accelerate TMDL implementation, by aligning the interests of multiple stakeholders whose active support is needed to change agricultural land use and thereby meet TMDL goals. PMID- 21547435 TI - Single feature polymorphisms (SFPs) for drought tolerance in pigeonpea (Cajanus spp.). AB - Single feature polymorphisms (SFPs) are microarray-based molecular markers that are detected by hybridization of DNA or cRNA to oligonucleotide probes. With an objective to identify the potential polymorphic markers for drought tolerance in pigeonpea [Cajanus cajan (L.) Millspaugh], an important legume crop for the semi arid tropics but deficient in genomic resources, Affymetrix Genome Arrays of soybean (Glycine max), a closely related species of pigeonpea were used on cRNA of six parental genotypes of three mapping populations of pigeonpea segregating for agronomic traits like drought tolerance and pod borer (Helicoverpa armigiera) resistance. By using robustified projection pursuit method on 15 pair-wise comparisons for the six parental genotypes, 5,692 SFPs were identified. Number of SFPs varied from 780 (ICPL 8755 * ICPL 227) to 854 (ICPL 151 * ICPL 87) per parental combination of the mapping populations. Randomly selected 179 SFPs were used for validation by Sanger sequencing and good quality sequence data were obtained for 99 genes of which 75 genes showed sequence polymorphisms. While associating the sequence polymorphisms with SFPs detected, true positives were observed for 52.6% SFPs detected. In terms of parental combinations of the mapping populations, occurrence of true positives was 34.48% for ICPL 151 * ICPL 87, 41.86% for ICPL 8755 * ICPL 227, and 81.58% for ICP 28 * ICPW 94. In addition, a set of 139 candidate genes that may be associated with drought tolerance has been identified based on gene ontology analysis of the homologous pigeonpea genes to the soybean genes that detected SFPs between the parents of the mapping populations segregating for drought tolerance. PMID- 21547436 TI - Immunity of embryonic stem cell-derived hematopoietic progenitor cells. AB - A number of medical conditions including hematopoietic stem cell malignancies, immunodeficiencies, and autoimmune diseases can be treated using bone marrow cells. However, the major hindrance to the routine use of bone marrow cells is their unparalleled immunogenicity, requiring the use of harsh and toxic preconditioning regimens that can be fatal. Thus, identification of a safer alternative source of hematopoietic stem cells that can be broadly used in such therapies is highly desirable. Despite the current limited number of human ES cell lines, we believe that the newer technology of reprogramming adult somatic cells into pluripotent cells will eventually lead to greater availability of stem cell lines. Even more compelling is the possibility to directly reprogram a somatic cell into another adult cell type of a different tissue without the need for generating pluripotent cells. Here, I will discuss the immunological properties of mouse ES cell-derived hematopoietic progenitor cells. These progenitor cells poorly express MHC class I antigens but are responsive to stimulation by IFN-gamma and other cytokines. However, despite upregulating MHC class I antigens after stimulation, they do not express class II molecules, a consequence of their lack of expression of the critical class II transcription factor CIITA. In this overview, I will discuss some of the published data on antigenicity and immunogenicity of ES cell-derived tissues. As more cells and tissues derived from ES cells become available for transplantation, we will gain more insight and into their abilities to interact with immune cells. PMID- 21547437 TI - Lithium perchlorate-nitromethane-promoted alkylation of anilines with arylmethanols. AB - A new application of lithium perchlorate-nitromethane (LPNM) for the formation of aromatic C-N and C-C bonds is introduced. LPNM-promoted reactions of anilines with diarylmethanols selectively generate N-alkylated anilines or mono and double Friedel-Crafts alkylation products under different conditions by changing the reaction time, reaction temperature, and the ratio of the reactants. This method does not require the use of transition metal catalysts to prepare alkylated aniline derivatives. PMID- 21547438 TI - Bone mineral density and frequency of osteoporosis among Vietnamese women with early rheumatoid arthritis. AB - Generalised bone mineral density (BMD) reduction often occurs in established rheumatoid arthritis (RA); however, in early RA, there is a disagreement with regard to BMD in the femoral neck and lumbar spine, and there is no available information for the whole body. Therefore, the aims of this study were to investigate the BMD, frequency of osteoporosis and the risk factors for BMD reduction in Vietnamese women with early RA. BMD in the femoral neck, lumbar spine L1-4 and whole body was measured in 105 women with early RA (disease duration <=3 years) and 105 age-matched healthy women (26-73 years) using a dual energy X-ray absorptiometry. Femoral neck and whole body BMD in women with RA were lower (p < 0.05) than controls, while lumbar spine BMD was similar between two groups. The frequency of osteoporosis in the femoral neck, lumbar spine and whole body in women with RA aged >=50 were higher (p < 0.05) than controls: 41.8% versus 29.5%, 42.2% versus 37.7% and 37.1% versus 28%, respectively. There were associations between the frequencies of osteoporosis at all sites with postmenopausal status, glucocorticoid use, rheumatoid factor positivity and disease activity with lumbar spine BMD and disease disability with femoral neck and whole body BMD. In conclusion, women with early RA had significantly lower femoral neck and whole body BMD, but had similar lumbar spine BMD compared with controls. The frequency of osteoporosis at all sites was significantly higher in women with RA than controls, suggesting that assessment of BMD should be considered in women with early RA. PMID- 21547439 TI - Inverse correlation of programmed death 1 (PD-1) expression in T cells to the spinal radiologic changes in Taiwanese patients with ankylosing spondylitis. AB - Programmed death 1 (PD-1) has been shown to be involved in the negative regulation of the immune response. However, the role of PD-1 in ankylosing spondylitis (AS) has not been studied. Therefore, we analyzed the expression of PD-1 in peripheral blood mononuclear cells (PBMC) from patients with AS. Twenty three AS patients, 20 rheumatoid arthritis (RA) patients, and 25 normal healthy subjects were recruited. The percentage of the PBMC and PD-1 levels in these subjects were measured by flow cytometry. A higher percentage of CD4+ T cells was noted in AS patients than in healthy controls (37.53+/-1.65% vs. 31.55+/-0.92%, P<0.01), but a similar result was not observed with regard to CD3+ T lymphocytes, CD4+CD25 high+regulatory T cells, CD19+ B cells, and CD14+ and CD16+ monocytes/macrophages. PD-1 levels in PBMC were not significantly higher in AS patients than in RA patients or age- and gender-matched healthy controls and were also not correlated to the erythrocyte sedimentation rate, C-reactive protein, limitation of back flexion, and chest expansion in patients with AS. Of interest, the percentages of PD-1+CD3+ T cells and PD-1+CD4+ T cells were significantly lower in AS patients with higher modified Stokes Ankylosing Spondylitis Spinal Scores (mSASSS >=30) than in those with lower mSASSS (<30; 0.07+/-0.04% vs. 0.42+/-0.14%, P<0.05; 0.06+/-0.03% vs. 0.40+/-0.14%, P<0.05, respectively). These results have suggested that the increased number of T helper cells lacking PD-1 may contribute to the spinal radiologic changes in AS patients. PMID- 21547440 TI - Splenic volume and hematological parameters in extrahepatic portal vein obstruction. PMID- 21547441 TI - The complete genome sequence and genome structure of passion fruit mosaic virus. AB - In this study, we determined the complete sequence of the genomic RNA of a Florida isolate of maracuja mosaic virus (MarMV-FL) and compared it to that of a Peru isolate of the virus (MarMV-P) and those of other known tobamoviruses. Complete sequence analysis revealed that the isolate should be considered a member of a new species and named passion fruit mosaic virus (PafMV). The genomic RNA of PafMV consists of 6,791 nucleotides and encodes four open reading frames (ORFs) coding for proteins of 125 kDa (1,101 aa), 184 kDa (1,612 aa), 34 kDa (311 aa) and 18 kDa (164 aa) in consecutive order from the 5' to the 3' end. The sequence homologies of the four ORFs of PafMV were from 78.8% to 81.6% to those of MarMV-P at the amino acid level. The sequence homologies of the four ORFs of PafMV ranged from 36.0% to 77.9% and from 21.7% to 81.6% to those of other tobamoviruses, at the nucleotide and amino acid level, respectively. Phylogenetic analysis revealed that these PafMV-encoded proteins are closely related to those of MarMV-P. In conclusion, the results indicate that PafMV and MarMV-P belong to different species within the genus Tobamovirus. PMID- 21547443 TI - Spica MRI after closed reduction for developmental dysplasia of the hip. PMID- 21547444 TI - Testicular epidermoid cysts in children: sonographic characteristics with pathological correlation. AB - BACKGROUND: Testicular epidermoid cyst is a rare benign tumor in children. Although this entity is widely described in adults in literature, there are no large series describing the pathological and radiological findings in children. Knowledge of the sonographic features seen in children may alter surgical treatment. OBJECTIVE: To describe the specific US characteristics of testicular epidermoid cyst in children and to correlate these findings with pathology. MATERIALS AND METHODS: All children with pathologically proven epidermoid cyst and preoperative sonograms diagnosed at a single children's hospital between 1978 and 2008 were included. For each child, the medical records, preoperative US and pathological specimens were reviewed and correlated. RESULTS: Eleven patients (ages 1-17 years old) met our criteria. Nine cysts had characteristic target or onion ring appearances, the youngest patient had a simple cyst-like lesion, one cyst had a heterogeneous appearance, and more than 80% of the cysts presented daughter cysts attached along the periphery of the main cyst. CONCLUSION: In addition to the commonly described findings of the epidermoid cyst (the target and onion ring appearances), simple cysts and the presence of daughter lesions are newly described findings that point to the diagnosis of this benign entity in children. PMID- 21547445 TI - Synchrony in the phenology of a culturally iconic spring flower. AB - We examine the flowering phenology of the cultural iconic Spring Snowflake Leucojum vernum, a considerable tourist attraction, recorded from two sites in western Poland. Flowering dates at the two sites were closely correlated but about 6 days later at the more natural area. The end of flowering was associated with the start of canopy leafing. Early flowering was related to a longer flowering season which may benefit ecotourism under future climate warming. PMID- 21547446 TI - Reproducibility of results on chronic pain with MC5-A Calmare(r) device from independent studies. PMID- 21547447 TI - A physician as a cancer of the neck patient: getting irradiated. AB - This manuscript presents my personal experiences as a physician undergoing radiation therapy for throat cancer. I describe the physical and emotional effects of the radiation treatment and how I coped with them. The side effects that emerged during of the radiation treatment included: fatigue, mental cloudiness, pain and dryness in my throat, food aversion, inability to taste, and skin burning around the neck. It is my hope that both patients and health care providers will benefit from reading my personal story. I hope that my perspectives will assist individuals who undergo radiation treatment cope better with them. It is also my hope that health care professionals who care for these patients will gain insight into what their patients experience and feel so that they would be able to better assist them during this difficult time. PMID- 21547448 TI - Relationships between the characteristics of oncohematology services providing palliative care and the sociodemographic characteristics of caregivers using health indicators: social support, perceived stress, coping strategies, and quality of work life. AB - OBJECTIVE: The aim of this study was to analyze the relationships between the characteristics of the management of oncohematology services and the psychosocial determinants of caregivers' health at work including social support, stress, and coping strategies. DESIGN: Investigation using questionnaires was carried out about nurses and nurse aides in hematology and oncology services. SETTING: All hematology and oncology services of Western France were requested. Five questionnaires concerning sociodemographic characteristics, measurements of quality of work life, of social support, of perceived stress, and of coping strategies and quality of work life were delivered among health professionals. PARTICIPANTS: Five hundred seventy-four questionnaires from 53 different services were analyzed. There were 57.4% nurses and 42.6% nurse aides. Some 94.1% were female and 33.5% were older than 40 years. RESULTS: Several characteristics of oncohematology services were significantly linked to health indicators, as the need for time and recognition, the importance of training (in palliative care, pain management, and help relationship), the care of patients and their families, the interdisciplinary efficiency, and external interventions (psychologists and volunteers). We showed that participative management which includes implementation of service projects and of multidisciplinary staff influence the quality of work life of health professionals. We showed also how much the characteristics of services organized around an effective social support (need for recognition) favor a better quality of work life among caregivers, influencing their perceived stress and their coping strategies. CONCLUSION: To our knowledge, it is the first study showing a relationship between participative management (including multidisciplinary staffs, approach with a service project, and internal training) and the quality of work life in the domain of health care. The implementation of this model should be promoted in health care services. PMID- 21547449 TI - Prodigiosin from Vibrio sp. DSM 14379; a new UV-protective pigment. AB - Pigments such as melanin, scytonemin and carotenoids protect microbial cells against the harmful effects of ultraviolet (UV) radiation. The role in UV protection has never been assigned to the prodigiosin pigment. In this work, we demonstrate that prodigiosin provides a significant level of protection against UV stress in Vibrio sp. DSM 14379. In the absence of pigment production, Vibrio sp. was significantly more susceptible to UV stress, and there was no difference in UV survival between the wild-type strain and non-pigmented mutant. The pigment's protective role was more important at higher doses of UV irradiation and correlated with pigment concentration in the cell. Pigmented cells survived high UV exposure (324 J/m(2)) around 1,000-fold more successfully compared to the non-pigmented mutant cells. Resistance to UV stress was conferred to the non pigmented mutant by addition of exogenous pigment extract to the growth medium. A level of UV protection equivalent to that exhibited by the wild-type strain was attained by the non-pigmented mutant once the prodigiosin concentration had reached comparable levels to those found in the wild-type strain. In co-culture experiments, prodigiosin acted as a UV screen, protecting both the wild-type and non-pigmented mutants. Our results suggest a new ecophysiological role for prodigiosin. PMID- 21547450 TI - DORNROSCHEN-LIKE expression marks Arabidopsis floral organ founder cells and precedes auxin response maxima. AB - Live imaging during floral development revealed that expression of the DORNROSCHEN-LIKE (DRNL) gene encoding an AP2-like transcription factor, marks all organ founder cells. Transcription precedes the perception of auxin response maxima as measured by the DR5 reporter and is unaffected in early organogenesis, by mutation of four canonical auxin response elements (AuxREs) in the DRNL promoter. DRNL expression identifies discrete modes of organ initiation in the four floral whorls, from individual or pairs of organ anlagen in the outer whorl of sepals to two morphogenetic fields pre-patterning petals and lateral stamens, or a ring-shaped field giving rise to the medial stamens before carpel primordia are specified. DRNL function only overlaps in the central stem cell zone with that of its paralogue, DORNROSCHEN (DRN). drnl mutants are affected in floral organ outgrowth, which functionally interplays with boundary specification as organ fusions are sensitized by loss of CUP-SHAPED COTYLEDON (CUC) gene activity, and synergistic interactions exist with mutants in local auxin biosynthesis and polar transport. DRNL apparently monitors and contributes to cellular decisions in the SAM and thus provides a novel molecular access to the interplay of founder cell specification, organ anlage and organogenesis in the SAM peripheral zone. PMID- 21547451 TI - Investigation on the absorption of phillyrin and forsythiaside in rat digestive tract. AB - In the present study, an in situ rat model was employed to systemically investigate the absorption of phillyrin and forsythiaisde. Three concentrations of phillyrin (0.2, 0.4 and 1.5 mg) were tested and the results showed that phillyrin cannot be absorbed in the digestive tract. The absorption rates of forsythiaside in stomach were 7.773, 7.228 and 6.751% h(-1) for 0.5, 1 and 2.5 mg, and no significant difference was found in different concentrations. The absorptions of forsythiaside in intestine were investigated in different concentrations and different absorption sites. The mean P% were 6.618, 7.199, 9.210 and 9.747% h(-1) of forsythiaside in intestine for 0.25, 0.5, 1, 2.5 mg dosage, and the statistical analysis showed that the absorption had no relation with concentration. In addition, in different digestive segments, the mean P% were 7.528, 8.382, 8.191, 9.109 and 6.908% h(-1) for the gastric, duodenum, jejunum, ileum and colon, respectively. No statistical differences of absorption were found for forsythiaside among different digestive segments indicated no specific absorption site was found. PMID- 21547452 TI - Delayed cilioretinal artery occlusion after a hemiretinal vein occlusion. AB - The purpose of this study is to report a case of combined hemiretinal vein occlusion and cilioretinal artery occlusion (CLRAO), in which the development of the CLRAO was substantially delayed. This interventional case report illustrates the sequential development of a cilioretinal artery occlusion following a hemiretinal vein occlusion with colour fundus and fluorescein angiogram photographs. Systemic examination revealed previously unrecorded hypertension for which her general practitioner commenced treatment. The patient developed an inferior visual field defect however made a visual recovery to 20/40 at 6-month follow-up. In this report, the risk factors and the likely pathogenesis for such an event are studied. PMID- 21547453 TI - Amelogenin promotes odontoblast-like MDPC-23 cell differentiation via activation of ERK1/2 and p38 MAPK. AB - Amelogenin (AMG) is a highly conserved protein secreted by ameloblasts. Some research indicates that AMG might induce the differentiation and maturation of odontoblasts. The aim of this study was to clarify the function of AMG during the differentiation of odontoblast-like MDPC-23 cells. The results revealed that the alkaline phosphatase activity and the number of mineralized nodules were significantly enhanced in AMG-overexpressing MDPC-23 cells during the mineralization process. Tissue-specific markers such as dentin matrix protein 1 and dentin sialophosphoprotein also elevated significantly, indicating the cell differentiation and maturation process. Furthermore, AMG could upregulate the phosphorylation levels of ERK1/2 and p38 MAPK. However, JNK, another MAPK pathway molecule, didn't change the activity at all. And the differentiation induced by AMG was abrogated when the MDPC-23 cells were treated with U0126 and SB203580, the inhibitors of ERK1/2 and p38, respectively. Taken together, our present results showed that AMG could promote the differentiation of odontoblast-like MDPC-23 cells via ERK1/2 and p38 MAPK pathways. PMID- 21547454 TI - Lipid profiles and oxidative stress parameters in male and female hemodialysis patients. AB - To study atherogenesis markers in patients with stage 5D chronic kidney disease (CKD-5D) on hemodialysis to determine which parameters are modified and whether their behavior differ between male and female patients of similar age. Total cholesterol, triglycerides, glucose, total proteins, HDL-cholesterol, LDL cholesterol, oxidative modification of low-density lipoprotein-cholesterol, autoantibodies against oxidized low-density lipoproteins-cholesterol, homocysteine (Hcy), folate, and vitamin B12 were measured in male and female controls and CKD-5D patients on hemodialysis for >6 months. The CKD-5D patients had significantly lower cholesterol, LDL-c and ox-LDL levels and significantly higher ox-LDL-AB and Hcy levels versus their respective controls. The reduction in ox-LDL in CKD patients does not imply a lower risk of atherosclerosis. In fact, the risk may be higher due to a greater capture of ox-LDL by macrophage scavenger receptors, which are increased in these patients. Elevated Hcy levels may also be a risk factor for atherosclerosis in male and female CKD-5D patients. PMID- 21547455 TI - Root cultures of Hypericum perforatum subsp. angustifolium elicited with chitosan and production of xanthone-rich extracts with antifungal activity. AB - Hypericum perforatum is a well-known medicinal plant which contains a wide variety of metabolites, including xanthones, which have a wide range of biological properties, including antifungal activity. In the present study, we evaluated the capability of roots regenerated from calli of H. perforatum subsp. angustifolium to produce xanthones. Root biomass was positively correlated with the indole-3-butyric acid concentration, whereas a concentration of 1 mg l(-1) was the most suitable for the development of roots. High auxin concentrations also inhibited xanthone accumulation. Xanthones were produced in large amounts, with a very stable trend throughout the culture period. When the roots were treated with chitosan, the xanthone content dramatically increased, peaking after 7 days. Chitosan also induced a release of these metabolites into the culture. The maximum accumulation (14.26 +/- 0.62 mg g(-1) dry weight [DW]) and release (2.64 +/- 0.13 mg g(-1) DW) of xanthones were recorded 7 days after treatment. The most represented xanthones were isolated, purified, and spectroscopically characterized. Antifungal activity of the total root extracts was tested against a broad panel of human fungal pathogen strains (30 Candida species, 12 Cryptococcus neoformans, and 16 dermatophytes); this activity significantly increased when using chitosan. Extracts obtained after 7 days of chitosan treatment showed high antifungal activity (mean minimum inhibitory concentration of 83.4, 39.1, and 114 MUg ml(-1) against Candida spp., C. neoformans, and dermatophytes, respectively). Our results suggest that root cultures can be considered as a potential tool for large-scale production of extracts with stable quantities of xanthones. PMID- 21547456 TI - Identifying genes that impact on aroma profiles produced by Saccharomyces cerevisiae and the production of higher alcohols. AB - During alcoholic fermentation, many volatile aroma compounds are formed by Saccharomyces cerevisiae, including esters, fatty acids, and higher alcohols. While the metabolic network that leads to the formation of these compounds is reasonably well mapped, surprisingly little is known about specific enzymes involved in specific reactions, the regulation of the network, and the physiological roles of individual pathways within the network. Furthermore, different yeast strains tend to produce significantly different aroma profiles. These differences are of tremendous biotechnological interest, since producers of alcoholic beverages such as wine and beer are searching for means to diversify and improve their product range. Various factors such as the redox, energy, and nutritional balance of a cell have previously been suggested to directly or indirectly affect and regulate the network. To gain a better understanding of the regulations and physiological role of this network, we screened a subset of the EUROSCARF strain deletion library for genes that, when deleted, would impact most significantly on the aroma profile produced under fermentative conditions. The 10 genes whose deletion impacted most significantly on higher alcohol production were selected and further characterized to assess their mode of action within or on this metabolic network. This is the first description of a large-scale screening approach using aroma production as the primary selection criteria, and the data suggest that many of the identified genes indeed play central and direct roles within the aroma production network of S. cerevisiae. PMID- 21547457 TI - Production, purification, and characterization of a novel killer toxin from Kluyveromyces siamensis against a pathogenic yeast in crab. AB - The yeast Kluyveromyces siamensis HN12-1 isolated from mangrove ecosystem was found to be able to produce killer toxin against the pathogenic yeast (Metschnikowia bicuspidata WCY) in crab. When the killer yeast was grown in the medium with pH 4.0 and 0.5% NaCl and at 25 degrees C, it could produce the highest amount of killer toxin against the pathogenic yeast M. bicuspidata WCY. The killing activity of the purified killer toxin against the pathogenic yeast M. bicuspidata WCY was the highest when it was incubated at 25 degrees C in the assay medium without added NaCl and pH 4.0. The molecular weight of the purified killer toxin was 66.4 kDa. The killer toxin produced by the yeast strain HN12-1 could kill only the whole cells of M. bicuspidata WCY among all the yeast species tested in this study. This is the first time to report that the killer toxin produced by the yeast K. siamensis HN12-1 isolated from the mangrove ecosystem only killed pathogenic yeast M. bicuspidata WCY. PMID- 21547458 TI - High-flux isobutanol production using engineered Escherichia coli: a bioreactor study with in situ product removal. AB - Promising approaches to produce higher alcohols, e.g., isobutanol, using Escherichia coli have been developed with successful results. Here, we translated the isobutanol process from shake flasks to a 1-L bioreactor in order to characterize three E. coli strains. With in situ isobutanol removal from the bioreactor using gas stripping, the engineered E. coli strain (JCL260) produced more than 50 g/L in 72 h. In addition, the isobutanol production by the parental strain (JCL16) and the high isobutanol-tolerant mutant (SA481) were compared with JCL260. Interestingly, we found that the isobutanol-tolerant strain in fact produced worse than either JCL16 or JCL260. This result suggests that in situ product removal can properly overcome isobutanol toxicity in E. coli cultures. The isobutanol productivity was approximately twofold and the titer was 9% higher than n-butanol produced by Clostridium in a similar integrated system. PMID- 21547459 TI - The history of vaginal birth. AB - Vaginal delivery, as known today, is a still unfinished product that originated hundreds of million years ago, much before mammals evolved on land. In this article, we will discuss the way in which our direct ancestors were born over the eons until the present day, focusing on the factors that presented substantial changes in how birth occurred, in relation to our earlier ancestors. The history begins with the first amniotes around 300 million years ago and ends with the appearance of the first Homo sapiens around 160,000 years ago. PMID- 21547460 TI - Maternal plasma noradrenaline levels at 29 weeks and gestational age at birth. AB - OBJECTIVE: To investigate the relationship between maternal plasma noradrenaline levels at a mean gestational age of 29 weeks and gestational age and weight at birth. DESIGN: Original research. SAMPLE: Seventy-four pregnant women with a mean gestational age of 29 weeks. METHODS: Psychological anxiety levels (Spielberger State and Trait questionnaire) and plasma stress hormone levels (noradrenaline and adrenaline) were measured in pregnant women at a mean gestational age of 29 weeks. Statistical analysis was applied to investigate links between these variables and gestational age and weight at birth. OUTCOME MEASURES: Self-rating anxiety, State and Trait Spielberger questionnaire, maternal noradrenaline and adrenaline levels, gestational age and weight at birth. RESULTS: There was a significant inverse relationship between maternal noradrenaline levels and the infant gestational age at birth (r = 0.09, p = 0.05). There was no relationship between maternal noradrenaline levels and weight at birth. CONCLUSIONS: There was a significant inverse relationship between maternal noradrenaline levels and gestational age at birth, suggesting the possibility of underlying mechanisms linking maternal noradrenaline and timing of delivery. PMID- 21547461 TI - The WRKY transcription factor OsWRKY78 regulates stem elongation and seed development in rice. AB - WRKY proteins are a large super family of transcriptional regulators primarily involved in various plant physiological programs. In present study, the expression profile and putative function of the WRKY transcriptional factor, WRKY78, in rice were identified. Real-time RT-PCR analysis showed that OsWRKY78 transcript was most abundant in elongating stems though its expression was detected in all the tested organs. The expression profiles were further confirmed by using promoter-GUS analysis in transgenic rice. OsWRKY78::GFP fusion gene transient expression analysis demonstrated that OsWRKY78 targeted to the nuclei of onion epidermal cell. Furthermore, OsWRKY78 RNAi and overexpression transgenic rice lines were generated. Transgenic plants with OsWRKY78 overexpression exhibited a phenotype identical to the wild type, whereas inhibition of OsWRKY78 expression resulted in a semi-dwarf and small kernel phenotype due to reduced cell length in transgenic plants. In addition, a T-DNA insertion mutant line oswrky78 was identified and a phenotype similar to that of RNAi plants was also observed. Grain quality analysis data showed no significant differences, with the exception of minor changes in endosperm starch crystal structure in RNAi plants. Taken together, these results suggest that OsWRKY78 may acts as a stem elongation and seed development regulator in rice. PMID- 21547462 TI - Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC). AB - Paragangliomas/pheochromocytomas (PGL/PCC) are tumors of the paraganglia. They can occur sporadically, as one sign in a hereditary (tumor) syndrome or as the only manifestation in hereditary PGL/PCC. To date, five forms of hereditary PGL/PCC have been described. They are inherited as autosomal dominant traits and are caused by mutations in genes required for structure and function of complex II of the respiratory chain (succinate-ubiquinone oxidoreductase, succinate dehydrogenase, SDH). Mutations in genes encoding the small subunits of SDH, i.e., SDHD and SDHC, cause PGL1 and PGL3. Mutations in the large subunit genes SDHB, SDHA (currently only one case), and in SDHAF2 cause PGL4, 5, and 2, respectively. This article gives an overview of PGL/PCC in the context of the anatomy and function of paraganglia. It describes SDH, the genes encoding SDH, and provides information on genetic mechanisms in hereditary PGL/PCC. A model is proposed to explain exclusive paternal inheritance and loss of the maternal (putatively imprinted) allele as a prerequisite for tumor formation in PGLs 1 and 2. PMID- 21547463 TI - The changing picture of substance abuse problems among Finnish prisoners. AB - PURPOSE: Marginalized people are often absent from population surveys of substance use and from research based on care data. Special methods are needed to reach these small but very significant groups. This study analyses how patterns of intoxicant use have changed over time among one of the most marginalized group of people, the prisoners. METHODS: Nationally representative samples of Finnish prisoners were examined: 903 prisoners in 1985, 325 prisoners in 1992, and 410 prisoners in 2006. Comprehensive field studies consisting of interviews and a clinical medical examination were used. RESULTS: In 1985, a diagnosis for alcoholism was given to 41% of the men and 36% of the women prisoners. An increase over time was observed, and in 2006, 52% of men and 51% of women prisoners were alcohol dependent. Dependence on a drug was diagnosed in 6% of men and 3% of women in 1985; this prevalence had increased to 58% of men and 60% of women in 2006. CONCLUSIONS: A dramatic change in prevalence of illegal drug use and drug addiction among prisoners has taken place in the past 20 years. Recognizing this shift from alcohol to other intoxicants is important since drugs are illegal substances and thus tend to lead to involvement with the judicial sector, thus stigmatizing and deepening the spiral of marginalization. PMID- 21547464 TI - Concomitant urethral triplication, bladder, and colon duplication. AB - The concomitant presence of urethral triplication and caudal duplication is extremely rare with no previous reported cases. We report a case of urethral triplication associated with bladder, sigmoid, and rectum duplication. The patient was initially referred with a history of fecaluria and recurrent urinary tract infection. Physical examination revealed 2 meatal opening on the glans penis. Further investigation revealed three distinct urinary streams, two terminating on the glans penis, and one in the rectum in voiding cystourethrography and retrograde urethrography. Computed tomography demonstrated the bladder divided into two compartments by a complete sagittal septum. The patient was managed by the excision of the rectal ending urethra and removal of the bladder sagittal septum during which, two sigmoidal and rectal segments (the right one filled with fecal) were revealed. The right sigmoid and rectum was resected. The two ventral urethras were kept intact. The postoperative course was uneventful. At his 4 month readmission for colostomy closure, the patient reported good urethral voiding with no complication and recurrence of urinary tract infection and the colostomy was closed with no major complication. PMID- 21547465 TI - Fluoroquinolone-resistant acute prostatitis requiring hospitalization after transrectal prostate biopsy: effect of previous fluoroquinolone use as prophylaxis or long-term treatment. AB - OBJECTIVES: This study aims to scrutinize the hospitalized patients with the diagnosis of acute prostatitis after transrectal ultrasound-guided biopsy of the prostate (TRUSBP) focusing their history of previous antibiotic use, clinical pictures, microbiologic features, and resistance patterns of the isolates. PATIENTS AND METHODS: A retrospective evaluation of the records between 2005 and 2010 revealed 13 patients. All patients received ciprofloxacin 500 mg twice a day starting from the day before TRUSBP for 5 days. RESULTS: Positive 13 urine and 7 blood samples (Escherichia coli in 12 patients, Enterococcus species in one) were evaluated for resistance patterns. All were resistant to fluoroquinolones. Extended spectrum beta-lactamase producing E. coli isolated in 4 patients were treated with carbapenems. Empirical ceftriaxone was shifted to carbapenem (4 patients), vancomycin (1 patient). Empirical carbapenem was maintained in 5 patients. Seven patients with elevated PSA received fluoroquinolones for 4 weeks before TRUSBP on the assumption that they had subclinical infectious prostatitis. Previous exposure to fluoroquinolones did not lead to important differences in respect to the studied parameters. CONCLUSIONS: The prompt initiation of effective treatment is essential to decrease morbidity and mortality. Empirical treatment would be a second or third generation cephalosporins, or carbapenems according to clinical severity of patients. PMID- 21547466 TI - Quality of life and mental health in hemodialysis and peritoneal dialysis patients: the role of health beliefs. AB - BACKGROUND AND OBJECTIVE: Patients' beliefs regarding their health are important to understand responses to chronic disease. The present study aimed to determine (i) whether beliefs about health differ between different renal replacement therapies in end-stage renal disease (ESRD) patients and (ii) whether these beliefs are associated with health-related quality of life (HQoL), as well as with mental health. METHODS: A sample of 89 ESRD patients, 41 on hemodialysis (HD) treatment and 48 on peritoneal dialysis (PD) treatment, completed the World Health Organization Quality of Life instrument, the General Health Questionnaire, the State-Trait Anxiety Inventory, the Center for Epidemiologic Studies Depression Scale, and the Multidimensional Health Locus of Control. RESULTS: Regarding differences in health beliefs between the two groups, HD patients focused more on the dimension of internal health locus of control than PD patients. This dimension was associated with better QoL (P = <0.01) and general health (P = 0.03) in the total sample. On the contrary, the dimension of important others in health locus of control was associated with higher depression (P = 0.02). CONCLUSIONS: The beliefs that dialysis patients hold about their illness appear to be related to the type of renal replacement therapy. These cognitions are associated with HQoL and with mental health. PMID- 21547467 TI - Changes in interstitial cell of Cajal-like cells density in congenital ureteropelvic junction obstruction. AB - PURPOSE: The authors examined the number of interstitial cells of Cajal-like cells (ICC-LCs) in obstructed ureteropelvic junction (UPJ) in comparison with normal UPJ specimens and age-related changes. MATERIALS AND METHODS: A total of 20 human formalin fixed, paraffin-embedded specimens of intrinsic UPJO from children at the mean age of 8.1 years (age range: 8 months-16.8 years) and 5 control samples from children at the mean age of 2.3 years (range 2.4 months-7.4 years) were investigated immunohistochemically for the expression of c-kit proto oncogene by light microscopy with computerized image analysis. The results were examined by Fisher's exact test, Yates' chi-square test, and t test for Pearson's correlation coefficient. A P value less than 0.05 was considered statistically significant. RESULTS: The number of ICC-LCs-dense fields was significantly higher in UPJO specimens in comparison with the normal group (P = 0.0004). The number of ICC-LCs-sparse fields was significantly lowered in UPJO specimens in comparison with the normal group (P = 0.0122). There was no significant difference in the number of ICC-LCs-medium fields in obstructed and normal UPJ specimens. The number of ICC-LCs was decreasing significantly with increasing age of the patients with UPJO (P = 0.0038). CONCLUSIONS: The higher density of c-kit positive ICC-LCs in UPJ may manifest the compensation of altered peristalsis in UPJO. The number of ICC-LCs-dense fields decreasing with age may show the failure of compensation and regression of the compensatory changes. PMID- 21547468 TI - It is not polite to ask a dialysis patient his age! PMID- 21547469 TI - Allopurinol, uric acid, and oxidative stress in cardiorenal disease. AB - In humans, the hepatic end product of purine metabolism is uric acid. Serum uric acid levels physiologically and gradually rise during human lifetime. Hyperuricemia also arises from excess dietary purine or ethanol intake, decreased renal excretion of uric acid, tumor lysis in lymphoma, leukemia or solid tumors, and sometimes pharmacotherapy. The definition of hyperuricemia is currently arbitrary. Hyperuricemia is associated with chronic kidney disease, arterial hypertension, coronary artery and heart disease, cerebrovascular disease and diabetes mellitus. Xanthine oxidase, a hepatic enzyme, catalyzes the production of uric acid, nitric oxide, and reactive oxygen species, which potentially damage deoxyribonucleic acid, ribonucleic acid and proteins, inactivate enzymes, oxidize amino acids and convert poly-unsaturated fatty acids to lipids. This is believed to contribute to atherosclerosis, endothelial dysfunction, renovascular hypertension, and cardiovascular disease. Xanthine oxidase inhibition efficiently blocks uric acid generation, and this improves glomerular filtration rates, systemic blood pressure, and cerebro-cardiovascular outcomes. Here, data from animal, in vivo, retro- and prospective, and interventional studies are reported. PMID- 21547470 TI - Comparison of patients undergoing a two-stage sacral nerve stimulation procedure: is there a cost benefit for a single-stage procedure? AB - AIMS: Sacral neurostimulation (SNS) involves a two-stage procedure to assess outcomes prior to permanent implantation. Stage 1 involves placement of a sacral lead that is externalized and tested for 2 weeks. Stage 2 is the implantation of a pulse generator in responders (>= 50% improved). This study's purpose was to determine the overall response rate, costs of a two-staged versus single-stage approach, and explore predictors of a positive response. METHODS: A prospective database of 145 patients undergoing SNS was analyzed. Demographics, history, and operative data were collected from the medical records. Cost data were collected from our institutions' reported average reimbursement for all stages of Interstim implantation and explantation in 2008. Wilcoxon rank test were used for analysis. RESULTS: Of 145 patients, 131 (90.3%) progressed to Stage 2 and 14 (9.7%) had removal. Explanted patients were older (mean 63 years) than implanted patients (56 years); however, this was not statistically significant. Total Medicare and Blue Cross/Blue Shield (BCBS) reimbursement for a two-stage procedure was calculated at $21,428/case and $26,968. Implanting the lead and generator as a single-stage would cost Medicare and BCBS $20,696 and $21,602, respectively. Since 9.7% were explanted, overall cost saving might be significant: a single stage approach would yield savings of $3,655/case (BC/BS) over a two-stage approach (after the cost of explantation is factored in). CONCLUSIONS: The majority of patients tested with SNS would benefit from a single-stage procedure (90.3%). This would reduce operative and anesthesia risks, time lost from work, and burden on patients and providers. PMID- 21547471 TI - Prognostic factors for upper urinary tract urothelial carcinomas: stage, grade, and smoking status. AB - OBJECTIVES: Upper urinary tract urothelial carcinomas are relatively rare malignancies. The aim of this study was to investigate the factors affecting prognosis of patients undergoing nephroureterectomy. METHODS: Data of 140 patients undergoing nephroureterectomy were retrospectively analyzed. Age of patients, gender, focality and localization of tumor, clinical and pathological stage, relationship with bladder cancer (prior, synchronous, after), and history of smoking were retrospectively recorded. The condition of local recurrence, metastases to distant organs, and requirement of adjuvant treatment were evaluated. RESULTS: The disease-specific and recurrence-free 5-year survival rate was determined as 78.9 and 68.4%, respectively. Bladder recurrence was determined in 20 of the patients after a mean of 21 months (7-37 months). Relationship between the duration of recurrence and variables showed that patients with T2 and higher stages (P = 0.014), with high-grade tumors (P = 0.028), with multifocal tumors (P < 0.001), and patients who were cigarette smokers (P = 0.010) had significantly shorter durations of recurrence. The mean survival of the 19 (18.1%) patients who had distant metastases was 19 months. Pathological stage T2 and higher tumors (P = 0.006), nodal involvement (P = 0.04), high-grade urothelial carcinoma (P < 0.001), multifocal tumors (P < 0.001), and tumors localized in the ureter (P < 0.001) were observed to have shorter duration of metastatic development. CONCLUSIONS: Presence of T2 and higher-stage tumors, high grade tumors, and multifocality are combined risk factors for urinary bladder recurrence and distant organ metastasis. Patients with the additional risk factors of cigarette smoking (urinary bladder recurrence) and nodal disease (distant organ metastasis) should be followed up closely after surgery. PMID- 21547472 TI - Renal cell carcinoma of native kidney in Chinese renal transplant recipients: a report of 12 cases and a review of the literature. AB - OBJECTIVES: To present and discuss the epidemiological and clinical aspects, as well as therapeutic options and outcome of de novo renal cell carcinoma (RCC) of the native kidneys in a series of Chinese renal transplant recipients. PATIENTS AND METHODS: A retrospective, cohort study examining all renal transplant recipients with the diagnosis of RCC of native kidney followed up in two major regional hospitals in Hong Kong between January 2000 and December 2009. Clinical data included age, gender, cause of renal failure, symptoms at presentation, duration of transplantation, immunosuppressive therapy, and history of acquired cystic kidney disease (ACKD). Laboratory, radiographic, operative, and pathology reports were used to assess the tumor extent. RESULTS: Among the 1,003 renal transplant recipients recruited, 12 transplant recipients had a nephrectomy for a total of 13 RCC. The prevalence of de novo RCC was 1.3%. The mean age at diagnosis of RCC was 48.4 years, and the median time from transplantation to diagnosis was 6.1 years. ACKD was found in 6 (50%) of the patients. All patients except one were asymptomatic. pT1 disease was found in ten patients with a mean tumor size of 3.2 cm. All patients were treated successfully with radical nephrectomy. After a median follow-up of 38 months, two patients (16.7%) died. One died of sepsis, and the other died of metastatic carcinoma. CONCLUSIONS: With increasing data showing a better prognosis if RCC is detected early by screening, it is time to consider screening all kidney transplant recipients for ACKD and RCC. PMID- 21547473 TI - An experimental study of low-level laser therapy in rat Achilles tendon injury. AB - The aim of this controlled animal study was to investigate the effect of low level laser therapy (LLLT) administered 30 min after injury to the Achilles tendon. The study animals comprised 16 Sprague Dawley male rats divided in two groups. The right Achilles tendons were injured by blunt trauma using a mini guillotine, and were treated with LLLT or placebo LLLT 30 min later. The injury and LLLT procedures were then repeated 15 hours later on the same tendon. One group received active LLLT (lambda = 904 nm, 60 mW mean output power, 0.158 W/cm(2) for 50 s, energy 3 J) and the other group received placebo LLLT 23 hours after LLLT. Ultrasonographic images were taken to measure the thickness of the right and left Achilles tendons. Animals were then killed, and all Achilles tendons were tested for ultimate tensile strength (UTS). All analyses were performed by blinded observers. There was a significant increase in tendon thickness in the active LLLT group when compared with the placebo group (p < 0.05) and there were no significant differences between the placebo and uninjured left tendons. There were no significant differences in UTS between laser-treated, placebo-treated and uninjured tendons. Laser irradiation of the Achilles tendon at 0.158 W/cm(2) for 50 s (3 J) administered within the first 30 min after blunt trauma, and repeated after 15 h, appears to lead to edema of the tendon measured 23 hours after LLLT. The guillotine blunt trauma model seems suitable for inflicting tendon injury and measuring the effects of treatment on edema by ultrasonography and UTS. More studies are needed to further refine this model. PMID- 21547474 TI - Effects of 940 nm light-emitting diode (led) on sciatic nerve regeneration in rats. AB - The objective of the present study was to evaluate the effect of 940 nm wavelength light emitting diode (LED) phototherapy on nerve regeneration in rats. Forty male Wistar rats weighing approximately 300 g each were divided into four groups: control (C); control submitted to LED phototherapy (CLed); Sciatic Nerve Lesion without LED phototherapy (L); Sciatic Nerve Lesion with LED phototherapy (LLed). The lesion was caused by crushing the right sciatic nerve. A dose of 4 J/cm(2) was used for ten consecutive days beginning on the first postoperative day. Groups C and L were submitted to the same procedure as the LLed group, but the equipment was turned off. The LED phototherapy with 940 nm wavelength reduced the areas of edema, the number of mononuclear cells present in the inflammatory infiltration, and increased functional recovery scores at 7, 14 and 21 days. The results suggest that the use of phototherapy at 940 nm after nerve damage improves morphofunctional recovery and nerve regeneration. PMID- 21547475 TI - Clinical usefulness of combinatorial protocol with stress only myocardial perfusion SPECT, CTA and SPECT/CTA 3-dimensional fusion image. AB - BACKGROUND: This study was designed to assess the value of a combinatorial protocol, namely, stress only myocardial perfusion SPECT (MPS), 64-slice coronary computed tomographic angiography (CTA), and SPECT/CTA 3-dimensional (3D) fusion imaging for the evaluation of coronary artery disease. METHODS: A total of 142 patients were retrospectively reviewed. All underwent stress only MPS and 64 slice CTA before invasive coronary angiography (ICA). The SPECT/CTA 3D fusion images were generated. We compared the results of the combinatorial protocol with ICA. RESULTS: Seventy nine (76.0%) subjects were found to have >=50% stenoses, by ICA. The sensitivity of the combinatorial examination was 100% and its specificity 80.8%. Its positive and negative predictive values were 94.0 and 100%, respectively. The number of lesion for abnormal MPS with matching significant stenoses on CTA is 94 [43 in left anterior descending (LAD); 19 in left circumflex (LCX); 32 in right coronary artery (RCA)], the number of lesion for equivocal perfusion defect with matching stenoses on CTA is 24 (14 in LAD; 7 in LCX; 3 in RCA). The number of coronary arterial stenoses without MPS abnormality is 10, 4 stenoses were detected in left main lesion and the other stenoses were comparatively mild lesion in multi-vessel disease. CONCLUSION: Stress only MPS/CTA 3D fusion imaging could provide the potential for improved diagnostic accuracy and additional information of hemodynamically relevant coronary arterial stenoses. PMID- 21547476 TI - The impact of adenosine pharmacologic stress combined with low-level exercise in patients undergoing myocardial perfusion imaging (BIWAKO adenosine-Ex trial). AB - BACKGROUND: The combination of adenosine infusion with low-level exercise has become a common approach for inducing stress during stress myocardial perfusion imaging (MPI). We investigated stress MPI performed by combined low-level exercise and adenosine infusion. This combined protocol can decrease adverse reactions and reduce the effect of scattered rays from the liver. METHODS AND RESULTS: Subjects were clinically referred for a 53-min rest-stress Tc-99m Sestamibi MPI procedure using BIWAKO PROTOCOL. Ninety-eight patients (44.5%) underwent adenosine infusion with ergometer exercise testing and 122 patients (55.5%) underwent adenosine infusion without exercise testing. We evaluated the liver/heart (L/H) uptake ratio, background activity in the upper mediastinum, and adverse reactions. RESULTS: The L/H ratio and background activity were lower in the adenosine-exercise group than in the adenosine-non-exercise group (1.8 +/- 0.54 vs. 2.1 +/- 0.62, P < 0.0056; 43.1 +/- 12.2 vs. 61.5 +/- 15.4, P < 0.0001). The adenosine-exercise group had fewer adverse reactions than the adenosine-non exercise group (11.2 vs. 19.7%). All of the adverse reactions were minor, with the exception of severe back pain in one case. The incidence of adverse reactions in our study was lower than that in previous studies for unknown reason. CONCLUSION: Adenosine infusion in combination with low-level exercise seems to result in higher-quality images and fewer adverse reactions than adenosine infusion without exercise. The combined protocol decreases adverse reactions and improves the quality of myocardial perfusion images by decreasing background activity. PMID- 21547477 TI - Clinical value of FDG-PET for preoperative evaluation of endometrial cancer. AB - OBJECTIVE: Whole body positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) has been widely used in various malignancies, but the clinical value of FDG-PET for endometrial cancer has not been fully investigated. The purpose of this study was to evaluate the usefulness of FDG-PET for preoperative evaluation of endometrial cancer. METHODS: Forty female patients suspected of having endometrial cancer were included in this study. All patients underwent an FDG-PET or PET/CT scan, and images were interpreted visually. The diagnostic performance in detecting the primary tumor, regional nodal status, and distant metastasis was determined. In addition, the usefulness of PET was assessed in terms of additional information and clinical impact for therapeutic management. RESULTS: Of 40 patients, 30 were histologically confirmed to have endometrial cancer. The patient-based sensitivity and specificity of FDG-PET for primary tumors were 83 and 100%, respectively, and 100 and 100%, respectively, for nodal metastases. There were 12 distant metastases in 6 patients and two second primary cancers in two patients, which were all accurately diagnosed by PET on a patient-basis. PET yielded 12 additional findings in 10 patients, and had a bearing on the therapeutic management of four patients, including one patient with recurrent breast cancer. CONCLUSIONS: FDG-PET had a reasonably high diagnostic accuracy in endometrial cancer. Although the number of cases with clinical impact was limited, additional information by PET was obtained in one third of the cases. PMID- 21547478 TI - Radiological features of an ossifying subperiosteal hematoma in a patient with severe motor and intellectual disability. PMID- 21547479 TI - Os odontoideum with cervical mylopathy due to posterior subluxation of C1 presenting sleep apnea. PMID- 21547480 TI - Post-traumatic extra-articular osteoid osteoma of the calcaneus following military training. PMID- 21547481 TI - Incorporating FMRI functional networks in EEG source imaging: a Bayesian model comparison approach. AB - Brain functional networks extracted from fMRI can improve the accuracy of EEG source localization. However, the coupling between EEG and fMRI remains poorly understood, i.e., whether fMRI networks provide information about the magnitude of neural activity, and whether neural sources demonstrate temporal correlations within each network. In this paper, we present an improved version of the NEtwork based SOurce Imaging method (iNESOI) through Bayesian model comparison. Different models correspond to various matching between EEG and fMRI, and the appropriate one is selected by data with the model evidence. Synthetic and real data tests show that iNESOI has potential to select the appropriate fMRI priors to reach a better source reconstruction than some other typical approaches. PMID- 21547482 TI - Practical aspects of running developmental studies in the MEG. AB - Developmental neuroimaging studies offer a unique opportunity to gain insight into the underpinnings of various cognitive functions by examining age-related changes in brain structure and function. There is an increasing body of neuroimaging literature discussing issues related to testing children in developmental studies (Crone et al. Human Brain Mapping 31:835-837, 2010). These deal with fMRI developmental studies and discuss methods (Luna et al. Human Brain Mapp 31:863-871, 2010), data interpretation (Poldrack Human Brain Mapp 31:872 878, 2010), and theoretical approaches (Karmiloff-Smith Human Brain Mapp 31:934 941, 2010). There has not yet been an equivalent discussion for MEG developmental studies. This paper will address issues specific to data acquisition, analysis, and interpretation for MEG developmental studies. PMID- 21547483 TI - Retinal vein occlusions: a review for the internist. AB - Retinal vein occlusion (RVO) is a disease that is often associated with a variety of systemic disorders including arterial hypertension, diabetes mellitus, dyslipidemia and systemic vasculitis. There are various types of RVO, categorized on the basis of the site of occlusion and on the type of consequent vascular damage. Central retinal vein occlusion (CRVO) is the most clinically relevant type of RVO. In addition to well-known classical risk factors, new thrombophilic factors have been investigated in patients with RVO. Data concerning a number of the parameters remain contradictory; yet, hyperhomocysteinemia and vitamins involved in methionine metabolism appear to play a significant role in the pathogenesis of this disease. Alterations in the fibrinolysis pathway (elevated levels of PAI-1 and Lipoprotein (a)), together with haemorheologic modifications have been recently consistently associated with the disease. Medical treatment includes identification and correction of vascular risk factors. In addition, LMWHs appear to be the best therapeutic approach even if based on a limited number of trials, conducted on a limited number of patients. No data are available on the possible role of antithrombotic strategies in the long-term prevention of recurrent RVO or vascular events. PMID- 21547484 TI - A case of chest pain and heart failure. PMID- 21547485 TI - Predictors of resistant hypertension in an unselected sample of an adult male population in Italy. AB - Prevalence, incidence and predictors of resistant hypertension (RH), (defined as blood pressure persistently above goal in spite of the concurrent use of three antihypertensive agents of different classes) in the general population remain largely unknown. A complete database including anthropometric and biochemical data was collected in 1994-1995 (baseline examination) in 1,019 participants (mean age 51.8, range: 25-79 years) and again in 2002-2004 in 794 male participants of the Olivetti Heart Study (OHS) in southern Italy. The incidence of RH over the average follow-up time of 7.9 years was 4.8% (38/794) in the whole study population and 10.1% (31/307) among hypertensive participants. Basal blood pressure (systolic, diastolic or pulse pressure), cholesterol and urinary albumin/creatinine ratio (ACR) significantly predicted the risk of developing RH using a logistic regression model that also included age as covariates. If in the same model we added basal pharmacological treatment, the fractional excretion of sodium (FENa) also became a statistically significant predictor, and this last model explained nearly 25% of the risk of developing RH. In this unselected sample of an adult male population, ACR (an early marker of organ damage), an elevated FENa (a proxy for dietary sodium intake), cholesterol and a higher basal blood pressure level were independent predictors of RH. PMID- 21547486 TI - Best linear unbiased prediction and optimum allocation of test resources in maize breeding with doubled haploids. AB - With best linear unbiased prediction (BLUP), information from genetically related candidates is combined to obtain more precise estimates of genotypic values of test candidates and thereby increase progress from selection. We developed and applied theory and Monte Carlo simulations implementing BLUP in 2 two-stage maize breeding schemes and various selection strategies. Our objectives were to (1) derive analytical solutions of the mixed model equations under two breeding schemes, (2) determine the optimum allocation of test resources with BLUP under different assumptions regarding the variance component ratios for grain yield in maize, (3) compare the progress from selection using BLUP and conventional phenotypic selection based on mean performance solely of the candidates, and (4) analyze the potential of BLUP for further improving the progress from selection. The breeding schemes involved selection for testcross performance either of DH lines at both stages (DHTC) or of S(1) families at the first stage and DH lines at the second stage (S(1)TC-DHTC). Our analytical solutions allowed much faster calculations of the optimum allocations and superseded matrix inversions to solve the mixed model equations. Compared to conventional phenotypic selection, the progress from selection was slightly higher with BLUP for both optimization criteria, namely the selection gain and the probability to select the best genotypes. The optimum allocation of test resources in S(1)TC-DHTC involved >= 10 test locations at both stages, a low number of crosses (<= 6) each with 100-300 S(1) families at the first stage, and 500-1,000 DH lines at the second stage. In breeding scheme DHTC, the optimum number of test candidates at the first stage was 5-10 times larger, whereas the number of test locations at the first stage and the number of test candidates at the second stage were strongly reduced compared to S(1)TC-DHTC. PMID- 21547488 TI - Differential display RT-PCR reveals genes associated with lithium-induced neuritogenesis in SK-N-MC cells. AB - Lithium is shown to be neurotrophic and protective against variety of environmental stresses both in vitro as well as in vivo. In view of the wider clinical applications, it is necessary to examine alterations in levels of expression of genes affected by lithium. Lithium induces neuritogenesis in human neuroblastoma cell line SK-N-MC. Our aim was to elucidate genes involved in lithium-induced neuritogenesis using SK-N-MC cells. The differential display reverse transcriptase polymerase chain reaction (DD-RT-PCR) technique was used to study gene expression profiles in SK-N-MC cells undergoing lithium-induced neuritogenesis. Differential expression of genes in control and lithium (2.5 mM, 24 h)-treated cells was compared by display of cDNAs generated by reverse transcription of mRNA followed by PCR using arbitrary primers. Expression of four genes was altered in lithium-treated cells. Real-time PCR was done to confirm the levels of expression of each of these genes using specific primers. Lithium significantly up-regulated NCAM, a molecule known to stimulate neuritogenesis, occludin, a molecule participating in tight junctions and PKD2, a molecule known to modulate calcium transport. ANP 32c, a gene whose function is not fully known yet, was found to be down-regulated by lithium. This is the first report demonstrating altered levels of expression of these genes in lithium-induced neuritogenesis and contributes four hitherto unreported candidates possibly involved in the process. PMID- 21547489 TI - Akt as a victim, villain and potential hero in Parkinson's disease pathophysiology and treatment. AB - There are two major purposes of this essay. The first is to summarize existing evidence that irrespective of the initiating causes, neuron death and degeneration in Parkinson's disease (PD) are due to the common feature of failure of signaling by Akt, a kinase involved in neuron survival and maintenance of synaptic contacts. The second is to consider possible means by which such a failure of Akt signaling might be benignly prevented or reversed in neurons affected by PD, so as to treat PD symptoms, block disease progression, and potentially, promote recovery. PMID- 21547490 TI - A study of the distribution and density of the VEGFR-2 receptor on glioma microvascular endothelial cell membranes. AB - The purpose of the study was to examine the nanoscale distribution and density of the VEGFR-2 membrane receptor on the endothelial cell surface of glioma microvasculature. Immunofluorescence and atomic force microscopy combined with immunogold labeling techniques were used to characterize and determine the position of the glioma microvasculature endothelial cell surface receptor VEGFR 2. We aimed to indirectly detect the distribution of VEGFR-2 on the cell membrane at the nanoscale level and to analyze VEGFR-2 quantitatively. Immunofluorescence imaging showed a large amount of VEGFR-2 scattered across the endothelial cell surface; atomic force microscopy imaging also showed two globular structures of different sizes scattered across the endothelial cell surface. The difference between the average diameter of the small globular structure outside the cell surface (43.67 +/- 5.02 nm) and that of IgG (44.61 +/- 3.19 nm) was not statistically significant (P > 0.05). The three-dimensional morphologies of the small globular structure outside the cell surface and IgG were similar. The difference between the average diameter of the large globular structure outside the cell surface (74.19 +/- 9.10 nm) and that of IgG-SpA-CG (74.54 +/- 15.93 nm) was also not statistically significant (P > 0.05). The three-dimensional morphologies of this large globular structure outside the cell surface and IgG SpA-CG were similar. The total density of these two globular structures within the unit area was 92 +/- 19 particles MUm(2). No globular structures were seen on the cell surface in the control group. The large globular structure on the surface of glioma microvascular endothelial cells was categorized as a VEGFR-2 IgG-SpA-CG immune complex, whereas the small globular structure was categorized as a VEGFR-2-IgG immune complex. The positions of the globular structures were the same as the positions of the VEGFR-2 molecules. A large amount of VEGFR-2 was scattered across glioma microvascular endothelial cell surfaces; the receptor density was about 92 per square micron. PMID- 21547491 TI - The effect of posterior instrumentation of the spine on canal dimensions and neurological recovery in thoracolumbar and lumbar burst fractures. AB - A prospective study was designed to determine whether posterior instrumentation of the spine in thoracolumbar and lumbar burst fractures produces indirect decompression of the spinal canal leading to better remodeling and neurological recovery. The study was conducted in Kasturba Medical College Manipal, India. Sixty-eight consecutive cases of thoracolumbar and lumbar burst fractures were treated by posterior instrumentation, and approval from the hospital ethical committee was obtained. The degree of initial spinal canal compromise, indirect decompression, and remodeling were assessed from the computed tomography scans. The neurological status at the time of presentation and at final follow-up was assessed by the American Spinal Injury Association's modified Frankel's grading. The median canal compromise in patients with and without neurological deficit was 47.32 and 39.33%, respectively. The overall mean canal compromise at the time of admission, post-operative, and final follow-up were 47.37, 26.58 and 14.85%, respectively (P = <0.001). The median canal compromise in patients who recovered was 44.5% and in those with no neurological recovery was 55.85%. The median percentage of canal decompression achieved in patients who recovered was 22.15%, whereas it was 22% in those who did not recover. The median remodeling in recovered and non-recovered groups was 64.50 and 80%, respectively. None of these differences was statistically significant. This study shows that posterior instrumentation of the spine produces significant indirect decompression of the spinal canal and better remodeling. However, these factors may not improve the neurological recovery. PMID- 21547492 TI - Idiopathic ventricular tachycardia in a newborn: immediate response to lidocaine. PMID- 21547494 TI - Subspecialisation in neurosurgery-does size matter? PMID- 21547493 TI - Mutagenesis and phenotypic selection as a strategy toward domestication of Chlamydomonas reinhardtii strains for improved performance in photobioreactors. AB - Microalgae have a valuable potential for biofuels production. As a matter of fact, algae can produce different molecules with high energy content, including molecular hydrogen (H(2)) by the activity of a chloroplastic hydrogenase fueled by reducing power derived from water and light energy. The efficiency of this reaction, however, is limited and depends from an intricate relationships between oxygenic photosynthesis and mitochondrial respiration. The way toward obtaining algal strains with high productivity in photobioreactors requires engineering of their metabolism at multiple levels in a process comparable to domestication of crops that were derived from their wild ancestors through accumulation of genetic traits providing improved productivity under conditions of intensive cultivation as well as improved nutritional/industrial properties. This holds true for the production of any biofuels from algae: there is the need to isolate multiple traits to be combined and produce organisms with increased performances. Among the different limitations in H(2) productivity, we identified three with a major relevance, namely: (i) the light distribution through the mass culture; (ii) the strong sensitivity of the hydrogenase to even very low oxygen concentrations; and (iii) the presence of alternative pathways, such as the cyclic electron transport, competing for reducing equivalents with hydrogenase and H(2) production. In order to identify potentially favorable mutations, we generated a collection of random mutants in Chlamydomonas reinhardtii which were selected through phenotype analysis for: (i) a reduced photosynthetic antenna size, and thus a lower culture optical density; (ii) an altered photosystem II activity as a tool to manipulate the oxygen concentration within the culture; and (iii) State 1-State 2 transition mutants, for a reduced cyclic electron flow and maximized electrons flow toward the hydrogenase. Such a broad approach has been possible thanks to the high throughput application of absorption/fluorescence optical spectroscopy methods. Strong and weak points of this approach are discussed. PMID- 21547495 TI - The impact of provider surgical volumes on survival in children with primary tumors of the central nervous system--a population-based study. AB - BACKGROUND: Provider volume is often a central topic in debates about centralization of procedures. In Norway, there is considerable variation in provider volumes of the neurosurgical centers treating children. We sought to explore long-term survival after surgery for central nervous system tumors in children in relation to regional provider volumes. METHOD: Based on data from the Norwegian Cancer Registry we analyzed survival in all reported central nervous system tumors in children under the age of 16 treated over two decades, between March 1988 and April 2008; a total of 816 patients with histologically confirmed disease. RESULTS: There was no overall difference in survival between regions. In the subgroup of PNET/medulloblastomas, both living in the high-provider volume health region and receiving treatment in the high-volume region was significantly associated with inferior survival. CONCLUSIONS: In this population-based study of children operated over a period of two decades, we found no evidence of improved long-term survival in the high-provider volume region. Surprisingly, a subgroup analysis indicated that survival in PNET/medulloblastomas was significantly better if living outside the most populated health region with the highest provider volumes. One should, however, be careful of interpreting this directly as a symptom of quality of care, as there may be unseen confounders. Our study demonstrates that provider case volume may serve as an axiom in debates about centralization of cancer surgery while perhaps much more reliable and valid but less quantifiable factors are important for the final results. PMID- 21547496 TI - Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial. AB - AIMS/HYPOTHESIS: Traditional blood glucose lowering agents do not prevent the progressive loss of beta cell function in patients with type 2 diabetes. The dipeptidylpeptidase (DPP)-4 inhibitor vildagliptin improves beta cell function both acutely and chronically (up to 2 years). Whether this effect persists after cessation of treatment remains unknown. Here, we assessed the insulin secretory capacity in drug-naive patients with type 2 diabetes after a 52 week treatment period with vildagliptin or placebo, and again after a 12 week washout period. METHODS: This study was conducted at a single university medical centre, and was a double-blind, randomised clinical trial in 59 drug-naive patients with type 2 diabetes and mild hyperglycaemia to either vildagliptin 100 mg (n = 29) or placebo (n = 30). Randomisation was performed by a validated 1:1 system. Neither patient, nor caregiver, was informed about the assigned treatment. Inclusion criteria were drug-naive patients >=30 years, with HbA(1c) <=7.5% and BMI of 22 45 kg/m(2). The mildly hyperglycaemic patient population was chosen to minimise glucose toxicity as a confounding variable. Beta-cell function was measured during an arginine-stimulated hyperglycaemic clamp at week 0, week 52 and after a 12 week washout period. All patients with at least one post-randomisation measure were analysed (intent-to-treat). RESULTS: Fifty-two week vildagliptin 100 mg (n = 26) treatment increased the primary efficacy variable, combined hyperglycaemia and arginine-stimulated C-peptide secretion (AIR(arg)), by 5.0 +/- 1.8 nmol/l * min, while it decreased by 0.8 +/- 1.8 nmol/l * min with placebo (n = 25) (between-group difference p = 0.030). No significant between-group difference in AIR(arg) was seen after the 12 week washout period. The between-group difference adjusted mean 52 week changes from baseline was -0.19 +/- 0.11, p = 0.098 and 0.22 +/- 0.23%, p = 0.343 for HbA(1c) and fasting plasma glucose, respectively. There were no suspected drug treatment-related serious adverse events. CONCLUSIONS/INTERPRETATION: One year treatment with vildagliptin significantly increased beta cell secretory capacity. This effect was not maintained after the washout, indicating that this increased capacity was not a disease modifying effect on beta cell mass and/or function. TRIAL REGISTRATION: ClinicalTrials.gov NCT00260156. PMID- 21547497 TI - Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat islets. AB - AIMS/HYPOTHESIS: Pro-atherogenic and pro-oxidant, oxidised LDL trigger adverse effects on pancreatic beta cells, possibly contributing to diabetes progression. Because oxidised LDL diminish the expression of genes regulated by the inducible cAMP early repressor (ICER), we investigated the involvement of this transcription factor and of oxidative stress in beta cell failure elicited by oxidised LDL. METHODS: Isolated human and rat islets, and insulin-secreting cells were cultured with human native or oxidised LDL or with hydrogen peroxide. The expression of genes was determined by quantitative real-time PCR and western blotting. Insulin secretion was monitored by EIA kit. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei. RESULTS: Exposure of beta cell lines and islets to oxidised LDL, but not to native LDL raised the abundance of ICER. Induction of this repressor by the modified LDL compromised the expression of important beta cell genes, including insulin and anti-apoptotic islet brain 1, as well as of genes coding for key components of the secretory machinery. This led to hampering of insulin production and secretion, and of cell survival. Silencing of this transcription factor by RNA interference restored the expression of its target genes and alleviated beta cell dysfunction and death triggered by oxidised LDL. Induction of ICER was stimulated by oxidative stress, whereas antioxidant treatment with N-acetylcysteine or HDL prevented the rise of ICER elicited by oxidised LDL and restored beta cell functions. CONCLUSIONS/INTERPRETATION: Induction of ICER links oxidative stress to beta cell failure caused by oxidised LDL and can be effectively abrogated by antioxidant treatment. PMID- 21547499 TI - Effects of tutor-related behaviours on the process of problem-based learning. AB - Tutors in a Problem-Based Learning (PBL) curriculum are thought to play active roles in guiding students to develop frameworks for use in the construction of knowledge. This implies that both subject-matter expertise and the ability of tutors to facilitate the learning process must be important in helping students learn. This study examines the behavioural effects of tutors in terms of subject matter expertise, social congruence and cognitive congruence on students' learning process and on their final achievement. The extent of students' learning at each PBL phase was estimated by tracking the number of relevant concepts recalled at the end of each learning phase, while student achievement was based on students' ability to describe and elaborate upon the relationship between relevant concepts learned. By using Analysis of Covariance, social congruence of the tutor was found to have a significant influence on learning in each PBL phase while all of the tutor-related behaviours had a significant impact on student achievement. The results suggest that the ability of tutors to communicate informally with students and hence create a less threatening learning environment that promotes a free flow exchange of ideas, has a greater impact on learning at each of the PBL phases as compared to tutors' subject-matter expertise and their ability to explain concepts in a way that is easily understood by students. The data presented indicates that these tutor-related behaviours are determinants of learning in a PBL curriculum, with social congruence having a greater influence on learning in the different PBL phases. PMID- 21547498 TI - Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia. AB - AIMS/HYPOTHESIS: Hepatic steatosis is strongly associated with hepatic and whole body insulin resistance. It has proved difficult to determine whether hepatic steatosis itself is a direct cause of insulin resistance. In patients with familial hypobetalipoproteinaemia (FHBL), hepatic steatosis is a direct consequence of impaired hepatic VLDL excretion, independently of metabolic derangements. Thus, patients with FHBL provide a unique opportunity to investigate the relation between increased liver fat and insulin sensitivity. METHODS: We included seven male participants with FHBL and seven healthy matched controls. Intrahepatic triacylglycerol content and intramyocellular lipid content were measured using localised proton magnetic resonance spectroscopy (1H-MRS). A two-step hyperinsulinaemic-euglycaemic clamp, using stable isotopes, was assessed to determine hepatic and peripheral insulin sensitivity. RESULTS: 1H-MRS showed moderate to severe hepatic steatosis in patients with FHBL. Basal endogenous glucose production (EGP) and glucose levels did not differ between the two groups, whereas insulin levels tended to be higher in patients compared with controls. Insulin-mediated suppression of EGP during lower dose insulin infusion and insulin-mediated peripheral glucose uptake during higher dose insulin infusion were comparable between FHBL participants and controls. Baseline fatty acids and lipolysis (glycerol turnover) at baseline and during the clamp did not differ between groups. CONCLUSIONS/INTERPRETATION: In spite of moderate to severe hepatic steatosis, people with FHBL do not display a reduction in hepatic or peripheral insulin sensitivity compared with healthy matched controls. These results indicate that hepatic steatosis per se is not a causal factor leading to insulin resistance. TRIAL REGISTRATION: ISRCTN35161775. PMID- 21547500 TI - Lung immunoreactivity and airway inflammation: their assessment after scorpion envenomation. AB - Release and activation of pro-inflammatory mediators are among the most important induced factors that are involved in the scorpion envenomation pathogenesis. Inflammatory response and lung reactivity were studied in mice following subcutaneous injection with Androctonus australis hector (Aah) venom. Venom immunodetection in lungs and sequestered cell population in the airways were determined. Cytokines, cellular peroxidase activities (eosinophil peroxidase, myeloperoxydase), and IgE antibodies were also assessed. Immunohistochemical study revealed a positive detection of the Aah venom in the alveolar wall, venule lumens, and inside inflammatory cells. Severe lung edema associated with rapid inflammatory response was observed after animal envenomation. Lung neutrophilia and eosinophilia were accompanied with IL-4, IL-5 release, and IgE synthesis. In conclusion, high cytokine levels, recruitment of inflammatory cells (eosinophils and neutrophils), and increased IgE concentration may contribute to the exacerbation and maintenance of the induced inflammatory response in lungs by scorpion venom. These results lead to the better understanding of this induced pathogenesis and could help the physicians to take care of envenomed patients. PMID- 21547501 TI - How tumors might withstand gammadelta T-cell attack. AB - Several clinical trials are currently assessing the therapeutic activity of human TCRVgamma9Vdelta2(+) lymphocytes in cancer. Growing tumors usually follow a triphasic "Elimination, Equilibrium, Escape" evolution in patients. Thus, at diagnostic, most tumors have already developed some means to escape to immune protection. We review here the conventional immunoescape mechanisms which might also protect against cytolytic TCRVgamma9Vdelta2(+) lymphocytes activated by phosphoantigens. Neutralization of these deleterious processes might prove highly valuable to improve the efficacy of ongoing gammadelta cell-based cancer immunotherapies. PMID- 21547503 TI - A telematic tool to predict the risk of colorectal cancer in white men and women: ColoRectal Cancer Alert (CRCA). AB - Colorectal cancer is an important disease because of its severity and also since it affects much of the population. Nothing helps patients and doctors to determine the risk of suffering from colorectal cancer during their lives, except for medical tests such as the colonoscopy. There have been several studies and research to try to estimate the relative risks of colorectal cancer based on various factors and the applications to calculate the risk of this cancer, but these are not within everyone's research. This project offers a multilingual Web tool, called ColoRectal Cancer Alert (CRCA), to calculate the risk of colorectal cancer for life in men and women of white race. With this application, doctors can carry out research in a few minutes to explore this risk when they are seeing a patient. The platform is designed in such a way that anyone can use it. It is easy to use and intuitive. We should keep in mind that this tool does not replace diagnostic tests such as the colonoscopy or the sigmoidoscopy. It is designed so that users with the assistance of their doctor know the risk and act accordingly (for example, having more checkups on the disease in case of high risk). To access the tool a computer with Internet connection will be required. Currently, 250 users of white race under the supervision of a specialist have completed the questionnaire. PMID- 21547504 TI - SVM feature selection based rotation forest ensemble classifiers to improve computer-aided diagnosis of Parkinson disease. AB - Parkinson disease (PD) is an age-related deterioration of certain nerve systems, which affects movement, balance, and muscle control of clients. PD is one of the common diseases which affect 1% of people older than 60 years. A new classification scheme based on support vector machine (SVM) selected features to train rotation forest (RF) ensemble classifiers is presented for improving diagnosis of PD. The dataset contains records of voice measurements from 31 people, 23 with PD and each record in the dataset is defined with 22 features. The diagnosis model first makes use of a linear SVM to select ten most relevant features from 22. As a second step of the classification model, six different classifiers are trained with the subset of features. Subsequently, at the third step, the accuracies of classifiers are improved by the utilization of RF ensemble classification strategy. The results of the experiments are evaluated using three metrics; classification accuracy (ACC), Kappa Error (KE) and Area under the Receiver Operating Characteristic (ROC) Curve (AUC). Performance measures of two base classifiers, i.e. KStar and IBk, demonstrated an apparent increase in PD diagnosis accuracy compared to similar studies in literature. After all, application of RF ensemble classification scheme improved PD diagnosis in 5 of 6 classifiers significantly. We, numerically, obtained about 97% accuracy in RF ensemble of IBk (a K-Nearest Neighbor variant) algorithm, which is a quite high performance for Parkinson disease diagnosis. PMID- 21547502 TI - Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes. AB - Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy. PMID- 21547505 TI - A new phenotypic manifestation of familial adenomatous polyposis. AB - Familial adenomatous polyposis (FAP) is an autosomal dominant disease with hundreds of colorectal adenomas in teenagers and progression to colorectal cancer if colectomy is not performed. We investigated the association of two phenotypic manifestations-oral mucosal vascular density (OMVD) and oral mucosal reflectance (OMR)--with FAP and patients with multiple colorectal adenomas. Thirty-three patients with FAP from 29 unrelated pedigrees with APC gene mutation, 5 with multiple adenomas and no known gene mutations, and 50 population controls were evaluated for the two different manifestations utilizing a photographic/spectrophotometric system capturing images and reflectance at various wavelengths. Statistical analysis was performed with student t test and test performance characteristics were calculated. There were no significant differences in demographic variables between the FAP and control group. A significant difference in OMVD between FAP patients and controls was noted, P < 0.001. The sensitivity and specificity of oral mucosal vascular density for FAP was 91 and 90%, respectively. No association between this phenotypic manifestation and age or gender was found. All 5 patient with multiple polyps were positive for OMVD and the value was significantly higher than controls, P = 0.002. No significant difference was noted in OMR between the two patient groups and controls. OMVD is a new phenotypic manifestation in patients with FAP and also may identify those with multiple adenomas without known gene mutation. PMID- 21547506 TI - A comparison on insulin regimen treatment of elderly (>70 years) and younger (<70 years) type 2 diabetic patients in actual clinical practice. AB - The incidence of type 2 diabetes mellitus increases with age. However, there are few data about the most adequate type of insulin, or the most adequate insulin regimen, for elderly patients with diabetes. The present study compared insulin regimens in patients aged more than 70 years (100 subjects) with those aged less than 70 years (73 subjects) who attended a diabetes outpatient clinic. The weight, body mass index, diabetes-associated chronic complications, other cardiovascular risk factors, type of insulin, insulin regimen, total daily dose of insulin, weight-adjusted total daily dose of insulin, concomitant treatment with oral hypoglycaemic agents (OHA) and glycosylated haemoglobin (HbA1c) were compared between the two groups. Although both groups had the same level of metabolic control (HbA1c: 7.66 +/- 0.91 in the elderly group vs. 7.62 +/- 0.96 in the younger group), we have found that elderly subjects were more likely to be treated with a simple regimen, as shown by a higher use of basal insulin (15% in young patients and 41% in the elderly group; P < 0.001), lower use of fast-acting insulin (32.8% vs. 15%; P = 0.005), and fewer daily injections (45% vs. 22% received at least three injections each day; P = 0.001). There were no differences in the use of OHA; however, the majority of young patients were treated with metformin, whereas repaglinide was most commonly used in the elderly group. In conclusion, in everyday clinical practice, elderly subjects were treated with the simplest regimen and achieved the same level of metabolic control as young diabetic patients. PMID- 21547507 TI - Antioxidant properties of Amaranthus hypochondriacus seeds and their effect on the liver of alcohol-treated rats. AB - Amaranth constitutes a valuable pseudocereal, due to its nutritional quality and its nutraceutical properties, which contribute to improve human health. This work evaluated the effect of a diet based on Amaranthus hypochondriacus (Ah) seed on oxidative stress and antioxidant status in the liver of rats sub-chronically exposed to ethanol. The seed extract was investigated for antioxidant capacity in vitro, showing an adequate content of total phenols and antioxidant activity elevated. For in vivo assays, four groups of six rats each were fed with an AIN 93 M diet for 28 days. In groups III and IV casein was replaced by Ah as the protein source; groups II and IV were received ethanol in the drinking water (20% v/v). When comparing groups IV and II, the following was observed: significant decrease in the activity of aspartate aminotransferase and content of malondialdehyde (p<0.001) in serum; decrease of malondialdehyde and increase in the activity and gene expression of Cu,Zn-superoxide dismutase, also, decrease in the NADPH oxidase transcript levels (p<0.05) in liver. Our data suggest that Ah is a good source of total phenols and exerts a protective effect in serum and in liver of rats intoxicated with ethanol. PMID- 21547508 TI - Value of ultrasound and cytological classification system to predict the malignancy of thyroid nodules with indeterminate cytology. AB - Although fine-needle aspiration cytology is considered the gold standard for evaluating thyroid nodules, in about 10-30% of the cases, cytology is indeterminate. This study aimed to determine the value of cytological classification system and ultrasound (US) to predict malignancy in indeterminate thyroid nodule. This retrospective analysis enrolled 80 patients surgically treated at a single center, 75% (60) with benign vs. 25% (20) with malignant lesions at final histology. The clinical, scintigraphic, sonographic, and cytological classification (Bethesda) variables were analyzed in these selected cases of indeterminate cytology, and a prediction model was designed after the multivariate analysis. There was a 25% prevalence of malignancy (20/80). There were no differences in gender, serum thyroid-stimulating hormone and FT4 levels, thyroid auto-antibodies, thyroid dysfunction, and scintigraphic results between benign and malignant nodule groups. The border irregularity in sonographic study was at increased risk for malignancy. The cytological analysis based on Bethesda System (category IV) was an independent predictor for malignancy in indeterminate thyroid nodules. After the multivariate analysis, the model obtained showed border irregularity and Bethesda System category IV as predictive factors of malignancy in indeterminate thyroid nodules, featuring 76.9% of accuracy. This study confirmed a significant increase of risk for malignancy in thyroid nodules with indeterminate cytology showing Bethesda System category IV and suspicious features at US. These findings enhance our current limited predictive armamentarium and can be used to guide surgical decision making. PMID- 21547511 TI - The prevalence of adrenal incidentaloma in routine clinical practice. AB - The prevalence of adrenal incidentaloma (AI) on computed tomography (CT) in the general population has been reported to be as high as 4.2%. However, many of the previous studies in this field utilised a prospective approach with analysis of CT scans performed by one or more radiologists with a specialist interest in adrenal tumours and a specific focus on identifying the presence of an adrenal mass. A typical radiology department, with a focus on the patient's presenting complaint as opposed to the adrenal gland, may not be expected to diagnose as many adrenal incidentalomas as would be identified in a dedicated research protocol. We hypothesised that the number of AI reported in routine clinical practice is significantly lower than the published figures would suggest. We retrospectively reviewed the reports of all CT thorax and abdomen scans performed in our hospital over a 2 year period. 3,099 patients underwent imaging, with 3,705 scans performed. The median age was 63 years (range 18-98). Thirty-seven true AI were diagnosed during the time period studied. Twenty-two were diagnosed by CT abdomen (22/2,227) and 12 by CT thorax (12/1,478), a prevalence of 0.98 and 0.81% with CT abdomen and thorax, respectively, for AI in routine clinical practice. PMID- 21547512 TI - Endogenously released GLP-1 is not sufficient to alter postprandial glucose regulation in the dog. AB - Glucagon-like peptide-1 (GLP-1) is secreted from the L cell of the gut in response to oral nutrient delivery. To determine if endogenously released GLP-1 contributes to the incretin effect and postprandial glucose regulation, conscious dogs (n = 8) underwent an acclimation period (t = -60 to -20 min), followed by a basal sampling period (t = -20 to 0 min) and an experimental period (t = 0-320 min). At the beginning of the experimental period, t = 0 min, a peripheral infusion of either saline or GLP-1 receptor (GLP-1R) antagonist, exendin (9-39) (Ex-9, 500 pmol/kg/min), was started. At t = 30 min, animals consumed a liquid mixed meal, spiked with acetaminophen. All animals were studied twice (+/- Ex-9) in random fashion, and the experiments were separated by a 1-2-week washout period. Antagonism of the GLP-1R did not have an effect, as indicated by repeated measures MANOVA analysis of the Delta AUC from t = 45-320 min of arterial plasma glucose, GLP-1, insulin, glucagon, and acetaminophen levels. Therefore, endogenous GLP-1 is not sufficient to alter postprandial glucose regulation in the dog. PMID- 21547513 TI - Cardiovascular disease risk characteristics of the main polycystic ovary syndrome phenotypes. AB - The aim of this article was to evaluate the clinical, endocrine, and cardiovascular disease risk profile differences among main polycystic ovary syndrome (PCOS) phenotypes. One hundred and thirty-nine consecutive women were included in the study. Body mass index (BMI), serum follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, estradiol, testosterone, dehydroepiandrosterone sulfate, fasting glucose, low density lipoprotein (LDL-C), total cholesterol, high density lipoprotein (HDL-C) high sensitive CRP, c peptide, insulin, insulin sensitivity and carotid intima thickness were compared among different phenotype groups of PCOS: Group 1-PCO (polycystic ovaries) anovulation (n = 34), Group 2-Hyperandrogenemia (HA)-anovulation (n = 30), Group 3-HA-PCO (n = 32), and Group 4-HA-PCO-anovulation (n = 43). Statistically significant differences among the different phenotype groups in terms of waist hip ratio, total cholesterol, LH, estradiol, fasting glucose, progesterone, free testosterone, and carotid intima media thickness were observed. The lowest mean CIMT was observed in Group 3, and the highest fasting glucose levels were in Group 4, while the lowest mean free testesterone was measured in Group 1. BMI, LDL-C, and total cholesterol showed significant positive correlations with CIMT (r = 0.411, P = 0.001; r = 0.258, P = 0.006; r = 0.199, P = 0.033). The lowest LDL-C, total cholesterol, and BMI were found in Group 3, but differences were not statistically significant. High-sensitive CRP levels were similar among the groups (P = 0.103). Group 3 PCOS with PCO and hyperandrogenemia phenotype has lower cardiovascular disease risk compared to other phenotypes. PMID- 21547514 TI - Development and characterization of a Chinese hamster ovary cell-specific oligonucleotide microarray. AB - The Chinese hamster ovary (CHO) cell line is one of the most widely used mammalian cell lines for biopharmaceutical production. We have developed and characterized a gene expression microarray (WyeHamster2a) specific for CHO cells that has enabled the study of ~3,500 sequences. Analysis of multiple sets of replicate scans showed that data derived from the WyeHamster2a array is highly reproducible confirming it as a robust tool for profiling. Twelve gene sequences were selected for follow-up RT-qPCR to confirm the accuracy and precision of the microarray results. In all but the most subtle gene expression differences, the microarray proved to be a reliable measure of differential gene expression. Finally, we were able to quantify the difference between using a bona fide CHO specific microarray for profiling CHO cells versus an alternate, commercially available, rodent microarray such as a mouse or rat-specific format. PMID- 21547515 TI - HON label and DISCERN as content quality indicators of health-related websites. AB - Content quality indicators are warranted in order to help patients and consumers to judge the content quality of health-related on-line information. The aim of the present study is to evaluate web-based information on health topics and to assess particular content quality indicators like HON (Health on the Net) and DISCERN. The present study is based on the analysis of data issued from six previous studies which assessed with a standardized tool the general and content quality (evidence-based health information) of health-related websites. Keywords related to Social phobia, bipolar disorders, pathological gambling as well as cannabis, alcohol and cocaine addiction were entered into popular World Wide Web search engines. Websites were assessed with a standardized proforma designed to rate sites on the basis of accountability, presentation, interactivity, readability and content quality (evidence-based information). "Health on the Net" (HON) quality label, and DISCERN scale scores were used to verify their efficiency as quality indicators. Of 874 websites identified, 388 were included. Despite an observed association with higher content quality scores, the HON label fails to predict good content quality websites when used in a multiple regression. Sensibility and specificity of a DISCERN score >40 in the detection of good content quality websites were, respectively, 0.45 and 0.96. The DISCERN is a potential quality indicator with a relatively high specificity. Further developments in this domain are warranted in order to facilitate the identification of high-quality information on the web by patients. PMID- 21547516 TI - Assessment of patient doses in CR examinations throughout a large health region. AB - Optimization and standardization of radiographic procedures in a health region minimizes patient exposure while producing diagnostic images. This report highlights the dose variation in common computed radiography (CR) examinations throughout a large health region. The RadChex cassette was used to measure the radiation exposure at the table or wall bucky in 20 CR rooms, in seven hospitals, using CR technology from two vendors. Exposures were made to simulate patient exposure (21 cm polymethyl methacrylate) under standard conditions for each bucky: 81 kVp at 100 cm for anteroposterior abdomen table bucky exposures (180 cm for posteroanterior chest wall bucky exposures), using the left, the right, or the center automatic exposure control (AEC) cells. Protocol settings were recorded. An average of 37% variation was found between AEC chambers, with a range between 4% and 137%. A 60% difference in dose was discovered between manufacturers, which was the result of the manufacture's image processing algorithm and subsequently corrected via software updates. Finally, standardizing AEC cell selection during common chest examinations could reduce patient dose by up to 30%. In a large health region, variation in exam protocols can occur, leading to unnecessary patient dose from the same type of examination. Quality control programs must monitor exam protocols and AEC chamber calibration in CR to ensure consistent, minimal, patient dose, regardless of hospital or CR vendor. Furthermore, this report highlights the need for communication between radiologists, technologists, medical physicist, service engineers, and manufacturers required to optimize CR protocols. PMID- 21547517 TI - False positive marks on unsuspicious screening mammography with computer-aided detection. AB - The contribution of computer-aided detection (CAD) systems as an interpretive aid in screening mammography can be hampered by a high rate of false positive detections. Specificity, false positive rate, and ease of dismissing false positive marks from two CAD systems are retrospectively evaluated. One hundred screening mammographic studies with a BI-RADS assessment code of 1 or 2 and at least 2-year normal mammographic follow-up were retrospectively reviewed using two CAD systems. Breast density, CAD marks, and radiologist's ease of dismissing false positive marks were recorded. Specificities from the two CAD versions considering all marks were 23% and 15% (p value = 0.07); mass marks, 35% and 17% (p value < 0.01); and calcification marks 62% and 75% (p value = 0.01). The two CAD versions did not differ regarding mean and median marks per case for all marks (2.3, 2.0 and 2.3, 2.0, p value = 0.65) or mass marks (1.6, 1.0 and 1.8, 2.0, p value = 0.15), but differed for calcification marks (0.8, 0 and 0.5, 0, p value < 0.01). Slightly higher specificity and fewer marks per case observed in dense breasts did not reach statistical significance. The reviewing radiologist classified most marks from both CAD systems (84% and 88%) as very easy/easy to dismiss. The two CAD versions had small differences in specificity and false positive marks. Differences, although not statistically significant, in specificities and false positive rates between dense and non-dense breasts warrant further research. Most false positive marks are easily dismissed and should not affect clinical performance. PMID- 21547518 TI - A comprehensive descriptor of shape: method and application to content-based retrieval of similar appearing lesions in medical images. AB - We have developed a method to quantify the shape of liver lesions in CT images and to evaluate its performance for retrieval of images with similarly-shaped lesions. We employed a machine learning method to combine several shape descriptors and defined similarity measures for a pair of shapes as a weighted combination of distances calculated based on each feature. We created a dataset of 144 simulated shapes and established several reference standards for similarity and computed the optimal weights so that the retrieval result agrees best with the reference standard. Then we evaluated our method on a clinical database consisting of 79 portal-venous-phase CT liver images, where we derived a reference standard of similarity from radiologists' visual evaluation. Normalized Discounted Cumulative Gain (NDCG) was calculated to compare this ordering with the expected ordering based on the reference standard. For the simulated lesions, the mean NDCG values ranged from 91% to 100%, indicating that our methods for combining features were very accurate in representing true similarity. For the clinical images, the mean NDCG values were still around 90%, suggesting a strong correlation between the computed similarity and the independent similarity reference derived the radiologists. PMID- 21547519 TI - Automated tracing of the adventitial contour of aortoiliac and peripheral arterial walls in CT angiography (CTA) to allow calculation of non-calcified plaque burden. AB - Aortoiliac and lower extremity arterial atherosclerotic plaque burden is a risk factor for the development of visceral and peripheral ischemic and aneurismal vascular disease. While prior research allows automated quantification of calcified plaque in these body regions using CT angiograms, no automated method exists to quantify soft plaque. We developed an automatic algorithm that defines the outer wall contour and wall thickness of vessels to quantify non-calcified plaque in CT angiograms of the chest, abdomen, pelvis, and lower extremities. The algorithm encodes the search space as a constrained graph and calculates the outer wall contour by deriving a minimum cost path through the graph, following the visible outer wall contour while minimizing path tortuosity. Our algorithm was statistically equivalent to a reference standard made by two reviewers. Absolute error was 1.9 +/- 2.3% compared to the inter-observer variability of 3.9 +/- 3.6%. Wall thickness in vessels with atherosclerosis was 3.4 +/- 1.6 mm compared to 1.2 +/- 0.4 mm in normal vessels. The algorithm shows promise as a tool for quantification of non-calcified plaque in CT angiography. When combined with previous research, our method has the potential to quantify both non calcified and calcified plaque in all clinically significant systemic arteries, from the thoracic aorta to the arteries of the calf, over a wide range of diameters. This algorithm has the potential to enable risk stratification of patients and facilitate investigations into the relationships between asymptomatic atherosclerosis and a variety of behavioral, physiologic, pathologic, and genotypic conditions. PMID- 21547520 TI - Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis. AB - Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8 weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin alpha(2C)-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca(2+)/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload. PMID- 21547521 TI - Catching the mind in flight: using behavioral indices to detect mindless reading in real time. AB - Although mind wandering during reading is extremely common, researchers have only recently begun to study how it relates to reading behavior. In the present study, we used a word-by-word reading paradigm to investigate whether it could be possible to predict in real time whether a participant would report mind wandering when probed. By taking advantage of the finding that reaction times to individual words vary based on reports of mind wandering (with participants being less affected by length, number of syllables, and familiarity, and also showing an overall speed-up, during mindless reading), we were able to develop an algorithm that could successfully predict in real time whether a participant would report being on versus off task. In addition, for participants run without thought probes, there was a significant negative correlation between the number of predicted mind-wandering episodes and reading comprehension. Together, these findings offer a key advance toward the development of pedagogical tools for minimizing the negative impact of mindless reading, and they provide a new covert measure that could be used to study mind wandering without requiring participants to report on their mental states. PMID- 21547522 TI - Validating new tuberculosis computational models with public whole cell screening aerobic activity datasets. AB - PURPOSE: The search for small molecules with activity against Mycobacterium tuberculosis (Mtb) increasingly uses high throughput screening and computational methods. Several public datasets from the Collaborative Drug Discovery Tuberculosis (CDD TB) database have been evaluated with cheminformatics approaches to validate their utility and suggest compounds for testing. METHODS: Previously reported Bayesian classification models were used to predict a set of 283 Novartis compounds tested against Mtb (containing aerobic and anaerobic hits) and to search FDA approved drugs. The Novartis compounds were also filtered with computational SMARTS alerts to identify potentially undesirable substructures. RESULTS: Using the Novartis compounds as a test set for the Bayesian models demonstrated a >4.0-fold enrichment over random screening for finding aerobic hits not in the computational models (N = 34). A 10-fold enrichment was observed for finding Mtb active compounds in the FDA drugs database. 85.9% of the Novartis compounds failed the Abbott SMARTS alerts, a value substantially higher than for known TB drugs. Higher levels of failures of SMARTS filters from different groups also correlate with the number of Lipinski violations. CONCLUSIONS: These computational approaches may assist in finding desirable leads for Tuberculosis drug discovery. PMID- 21547523 TI - Editor's note. Plagiarism. PMID- 21547524 TI - Is embolization of the pancreas safe? Pancreatic histological changes after selective transcatheter arterial embolization with N-butyl cyanoacrylate in a swine model. AB - PURPOSE: This study was designed to evaluate the safety of selective transcatheter arterial embolization (TAE) with N-butyl cyanoacrylate (NBCA) in a swine model in terms of histological changes in the pancreas. METHODS: Three groups of two female swine (58-64 kg) per group underwent TAE of the dorsal pancreatic artery, under anesthesia, with 1:1, 1:4, and 1:9 mixtures of NBCA and iodized oil. Blood parameters were evaluated at days 1, 4, and 10 after TAE, after which the animals were sacrificed and pancreatic tissues were examined under light microscopy. RESULTS: All of the animals were asymptomatic and survived for 10 days. Cone beam computed tomographic angiography revealed occlusion of the dorsal pancreatic artery and no enhancement in the embolized area. The white blood cell count and C-reactive protein level were elevated slightly on day 1 after TAE (mean +/- SD: 252.7 +/- 27.8 * 10(2)/MUl and 0.15 +/- 0.07 mg/l, respectively), but they normalized or remained near the upper normal limit thereafter. The serum amylase and lipase levels also were elevated on day 1 (8831.7 +/- 2169.2 U/l and 130 +/- 53.4 U/l, respectively) but normalized thereafter. Histologically, necrosis and fibrosis were noted only in the embolized segment, and necrosis and acute inflammatory reactions were absent in the nonembolized segment. The border between both segments was well defined. Lymphocytic infiltration and foreign body reaction were noted around the embolized vessels. CONCLUSIONS: Selective TAE with NBCA in the pancreas caused localized ischemic necrosis without clinically significant pancreatitis; therefore, this procedure is tolerable in swine. PMID- 21547525 TI - Oedema and fatty degeneration of the soleus and gastrocnemius muscles on MR images in patients with Achilles tendon abnormalities. AB - OBJECTIVE: The purpose of this study was to evaluate the frequency of oedema and fatty degeneration of the soleus and gastrocnemius muscles in patients with Achilles tendon abnormalities. METHODS: Forty-five consecutive patients (mean 51 years; range 14-84 years) with achillodynia were examined with magnetic resonance (MR) images of the calf. The frequency of oedema and fatty degeneration in the soleus and gastrocnemius muscles was determined in patients with normal tendons, tendinopathy and in patients with a partial tear or a complete tear of the Achilles tendon. RESULTS: Oedema was encountered in 35% (7/20) of the patients with tendinopathy (n = 20; range 13-81 years), and in 47% (9/19) of the patients with partial tears or complete tears (n = 19; 28-78 years). Fatty degeneration was encountered in 10% (2/20) of the patients with tendinopathy, and in 32% (6/19) of the patients with tears. The prevalence of fatty degeneration was significantly more common in patients with a partial or complete tear compared with the patients with a normal Achilles tendon (p = 0.032 and p = 0.021, respectively). CONCLUSION: Oedema and fatty degeneration of the soleus and gastrocnemius muscles are common in patients with Achilles tendon abnormalities. PMID- 21547526 TI - Distinguishing benign from malignant parotid gland tumours: low-dose multi-phasic CT protocol with 5-minute delay. AB - OBJECTIVES: To explore the percentage enhancement wash-out ratio (PEW) and relative PEW (RPEW) of low-dose multi-phasic computed tomography (CT) in distinguishing benign from malignant parotid gland tumours. METHODS: This study was approved by the ethics committee, and informed patient consent was obtained. 51 patients with parotid tumours proven by histopathology received CT, including 18 with pleomorphic adenomas, 14 with Warthin's tumours and 19 with malignant tumours. Size and attenuation of parotid tumours were measured. Compared with 5 min attenuation, the 30-s and 90-s PEW (PEW(30,) PEW(90)) and RPEW (RPEW(30), RPEW(90)) were calculated. RESULTS: There was a significant difference in PEW(30), RPEW(30), PEW(90) and RPEW(90) in the parotid neoplasms groups (P < 0.01), and statistical significance existed simultaneously in pleomorphic adenomas vs malignant tumours and Warthin's tumours vs malignant tumours according to SNK-q test. The optimal diagnosis results of malignancy with 100% specificity (32/32) was obtained by using a combination of the following criteria: -70% > PEW(30) < 36%, -30% > PEW(30) < 19%, PEW(90) > 12%, and the sensitivity (74%) for diagnosis of malignancy was yield. CONCLUSIONS: Wash-out ratio may assist in differentiating the benign from malignant parotid gland tumours. Combining the percentage of enhanced wash-out ratios of CT protocols can yield diagnostic results for malignancy. PMID- 21547527 TI - Treatment of chronic migraine headache with onabotulinumtoxinA. AB - Chronic migraine headache remains an exceedingly difficult entity to manage. Treatment of chronic migraine headache with onabotulinumtoxinA has recently been shown to be effective in reducing the severity and frequency of chronic migraine headache, in the PREEMPT trials, a landmark achievement. However, the studies use a primarily fixed dose and site approach to treatment, allowing some individualized injections. However, the authors do not address the issue of myofascial trigger points as potential triggers of migraine that could be inactivated using onabotulinumtoxinA, despite several studies that support the role of myofascial trigger points in initiating some migraine headaches. PMID- 21547528 TI - Statistical learning of action: the role of conditional probability. AB - Identification of distinct units within a continuous flow of human action is fundamental to action processing. Such segmentation may rest in part on statistical learning. In a series of four experiments, we examined what types of statistics people can use to segment a continuous stream involving many brief, goal-directed action elements. The results of Experiment 1 showed no evidence for sensitivity to conditional probability, whereas Experiment 2 displayed learning based on joint probability. In Experiment 3, we demonstrated that additional exposure to the input failed to engender sensitivity to conditional probability. However, the results of Experiment 4 showed that a subset of adults-namely, those more successful at identifying actions that had been seen more frequently than comparison sequences-were also successful at learning conditional-probability statistics. These experiments help to clarify the mechanisms subserving processing of intentional action, and they highlight important differences from, as well as similarities to, prior studies of statistical learning in other domains, including language. PMID- 21547530 TI - Downregulation of GABA(A) beta subunits is transcriptionally controlled by Fmr1p. AB - Fragile X mental retardation syndrome is caused by the transcriptional silence of FMR1. Here, a quantitative PCR technique was used to examine the effect of Fmr1p on the expression of GABA(A) beta subunits in different mouse brain regions. Our results demonstrated the reduction of GABA(A) beta2 mRNA in all brain regions assessed, and the reduction of GABA(A) beta3 mRNA in the cortex, suggesting that the expression of GABA(A) beta subunits is transcriptionally regulated by Fmr1p. This finding may help to establish the link between the transcriptional profile of the GABAergic inhibitory system and the development of fragile X mental retardation syndrome. PMID- 21547529 TI - Male hormonal contraception: potential risks and benefits. AB - An effective, safe, reversible, and acceptable method of contraception is an important component of reproductive health and provides the opportunity of shared responsibility for family planning for both partners. Female hormonal contraceptives have been proven to be safe, reversible, available and widely acceptable by different populations. In contrast, male hormonal contraception, despite significant progress showing contraceptive efficacy comparable to female hormonal methods during last three decades, has not yet led to an approved product. Safety of a pharmaceutical product is an appropriate concern but the majority of male hormonal contraceptive clinical trials have not reported significant short term safety concerns. While the absence of serious adverse effects is encouraging, the studies have been designed for efficacy endpoints not long term safety. In this review we summarize potential risks and benefits of putative male hormonal contraceptives on reproductive and non-reproductive organs. While the review covers what we believe will be the likely class of drugs used for male hormonal contraception a true assessment of long term risks and benefits cannot be achieved without an available product. PMID- 21547531 TI - Polymorphisms in ABLIM1 are associated with personality traits and alcohol dependence. AB - Personality traits like novelty seeking (NS), harm avoidance (HA), and reward dependence (RD) are known to be moderately heritable (30-60%). These personality traits and their comorbidities, such as alcohol dependence (AD), may share genetic components. We examined 11,120 single nucleotide polymorphisms (SNPs) genotyped in 292 nuclear families from the Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). A family-based association analysis was performed using the FBAT program. NS, HA, and RD were treated as quantitative traits and AD as a binary trait. Based on a multivariate association test of three quantitative traits in FBAT, we observed 20 SNPs with p < 10(-3). Interestingly, several genes (TESK2, TIPARP, THEMIS, ABLIM1, RFX4, STON2 and LILRA1) are associated with three personality traits with p < 10(-3) using single trait analysis and AD. Especially, SNP rs727532 within ABLIM1 gene at 10q25 showed the most significant association (p = 6.4 * 10(-5)) in the multivariate test and strong associations with NS, HA, RD, and AD (p = 4.48 * 10( 4), 1.2 * 10(-5), 5.6 * 10(-5), 3.12 * 10(-4), respectively) in the COGA sample. In addition, the association of rs727532 with AD was confirmed in a replication study. This study reports some newly recognized associations between several genetic loci and both AD and three personality traits. PMID- 21547532 TI - Variable restricted feeding disrupts the daily oscillations of Period2 expression in the limbic forebrain and dorsal striatum in rats. AB - Predictable restricted feeding schedules limit food availability to a single meal at the same time each day, lead to the induction and entrainment of circadian rhythms in food-anticipatory activity, and shift daily rhythms of clock gene expression in areas of the brain that are important in the regulation of motivational and emotional state. In contrast, when food is delivered under a variable restricted feeding (VRF) schedule, at a new and unpredictable mealtime each day, circadian rhythms in food-anticipatory activity fail to develop. Here, we study the effects of VRF on the daily rhythm of plasma corticosterone and of clock gene expression in the limbic forebrain and dorsal striatum, of rats provided a 2-h access to a complete meal replacement (Ensure Plus) at an unpredictable time each day. VRF schedules varied the mealtimes within the 12 h of light (daytime VRF), the 12 h of dark (nighttime VRF), or across the 24 h light-dark cycle (anytime VRF). Our results show that contrary to the synchronizing effects of predictable restricted feeding, VRF blunts the daily corticosterone rhythm and disrupts daily rhythms of PER2 expression in a region specific and mealtime-dependent manner. PMID- 21547533 TI - Orexins/hypocretins acting at Gi protein-coupled OX 2 receptors inhibit cyclic AMP synthesis in the primary neuronal cultures. AB - Orexins A and B are newly discovered neuropeptides with pleiotropic activity. They signal through two G protein-coupled receptors: OX(1) and OX(2). In this study, we examined the expression of orexin receptors and effects of the receptors' activation on cyclic AMP formation in the primary neuronal cell cultures from rat cerebral cortex. Both types of orexin receptors were expressed in rat cortical neurons; the level of OX(2)R was markedly higher compared to OX(1)R. Orexin A (an agonist of OX(1)R and OX(2)R) and [Ala(11)-D-Leu(15)]orexin B (a selective agonist of OX(2)R) did not affect basal cyclic AMP formation in the primary neuronal cell cultures. Both peptides (0.001-1 MUM) inhibited, in a concentration-dependent manner and IC(50) values in low nanomolar range, the increase in the nucleotide production evoked by forskolin (1 MUM; a direct activator of adenylyl cyclase), pituitary adenylate cyclase-activating polypeptide (PACAP27; 0.1 MUM), and vasoactive intestinal peptide (VIP; 3 MUM). Effects of orexin A on forskolin-, PACAP27-, and VIP-stimulated cyclic AMP synthesis were blocked by TCS OX2 29 (a selective antagonist of OX(2)R), and unaffected by SB 408124 (a selective antagonist of OX(1)R). Pretreatment of neuronal cell cultures with pertussis toxin (PTX) abolished the inhibitory action of orexin A on forskolin- and PACAP-stimulated cyclic AMP accumulation. It is suggested that in cultured rat cortical neurons orexins, acting at OX(2) receptors coupled to PTX-sensitive G(i) protein, inhibit cyclic AMP synthesis. PMID- 21547534 TI - Polymorphism of GDF9 gene and its association with litter size in goats. AB - Growth differentiation factor 9 (GDF9) was studied as a candidate gene for high prolificacy in goats. The polymorphism of exon 1 and flanking of GDF9 gene was detected by PCR-SSCP in five goat breeds with different prolificacy. Three genotypes (AA, AB and BB) were detected in goat breeds joined and two silent mutations (c.183A>C and c.336C>T) were identified in comparison genotype AA with genotype BB. Heterozygous genotype AB and wild type BB were detected in all five goat breeds and homozygous genotype AA was only detected in Jining Grey goats. The frequencies of genotypes AA, AB and BB were 0.18, 0.42 and 0.40 in Jining Grey goats, respectively. The genotype distribution was different (P < 0.01) between high prolificacy breed (Jining Grey goat) and low prolificacy breeds (Boer, Wendeng Dairy, Liaoning Cashmere and Beijing native goats). The Jining Grey goat does with genotype AA and AB had 0.72 (P < 0.01) and 0.56 (P < 0.01) kids more than those with genotype BB, respectively. The does with genotype AA had 0.16 (P > 0.05) kids more than those with genotype AB. These indicated that the allele A may have certain correlation with prolificacy in Jining Grey goats. PMID- 21547535 TI - Host sex discrimination by an egg parasitoid on Brassica leaves. AB - Egg parasitoids are able to find their hosts by exploiting their chemical footprints as host location cues. In nature, the apolar epicuticular wax layer of plants that consists of several classes of hydrocarbons serves as the substrate that retains these contact kairomones. However, experiments on chemical footprints generally have used filter paper as substrate to study insect behavior. Here, we explored the ability of Trissolcus basalis (Scelionidae) females to discriminate between footprint cues left by male and female Nezara viridula (Pentatomidae) on leaves of their host plant Brassica oleracea (broccoli). Furthermore, we analyzed the chemical composition of the outermost wax layer of broccoli leaves to evaluate the degree of overlap in insect and plant cuticular hydrocarbons that could lead to masking effects in the detection of footprint cues. Our results showed that B. oleracea epicuticular wax retains the chemical footprints of adult bugs and allows T. basalis females to differentiate hosts of different sex. Traces of female bugs elicited more extensive searching behavior in egg parasitoids than traces of males. The application of n-nonadecane, a compound specific to male N. viridula, on the tarsi of female bugs prevented parasitoid females from distinguishing between host male and host female footprints. Analyses of B. oleracea leaves revealed that epicuticular waxes were mainly composed of linear alkanes, ketones, and secondary alcohols. Alkanes were dominated by n-nonacosane (nC29) and n hentriacontane (nC31), while male-specific n-nonadecane (nC19) was absent. The ecological significance of these results for parasitoid host location behavior is discussed. PMID- 21547536 TI - Paradigms in multiple sclerosis: time for a change, time for a unifying concept. AB - It has recently been suggested that, rather than being an autoimmune disease, multiple sclerosis (MS) is an example of a neurocristopathy, a pathological process resulting from a faulty development of the neural crest. Whilst several characteristics of the disease suggest a neurocristopathy, other aetiological factors require consideration, including hygiene-related factors that alter the immune responses to common pathogens resulting in an eclipse of immune reactivity that could protect against MS, the possible role of human endogenous retroviruses (HERVs) in pathogenesis and autoimmune phenomena, HLA polymorphism, vitamin D levels before and after birth and immune repair mechanisms. A postulated aetiological factor in MS, associated with altered vitamin D metabolism and abnormal HERV expression, is a long-lasting disturbed redox regulation in the biosynthesis of a melanoma-like melanin pigment. Although intensive further studies on melanin pigments in nerve tissue in MS are required, the known properties of a pathological form of such pigments in melanoma could explain a number of observations in MS, including the impact of light, UV-light, and vitamin D, and could explain the clinical manifestations of MS on the basis of an oscillating process of oxidative charge and discharge of the pigments and a threshold phenomenon with a change of the quasi-catalytic function of the pigment from destroying reactive oxygen radicals or species to transforming them to more harmful long-persisting highly reactive species. Taken together with the consequences of an adaptive process in partly demyelinated neurons, resulting in an increase in number of mitochondria, and the impact of stressful life events, these conditions are necessary and sufficient to explain the disease process of MS with its spatial (plaques) and temporal (attacks and remissions) characteristics. This suggested unifying concept of the pathogenesis of MS may open perspectives for prevention, diagnosis and therapy. In particular, prevention may be achieved by vaccinating against Epstein-Barr virus in early childhood. PMID- 21547537 TI - Highly sensitive poly[glycidyl methacrylate-co-poly(ethylene glycol) methacrylate] brush-based flow-through microarray immunoassay device. AB - Flow-through immunoassay is an attractive method for fast, inexpensive and high throughput protein analyses. However, its practical application is limited by low sensitivity. In this work, a highly sensitive flow-through microarray immunoassay device is developed, in which a poly[glycidyl methacrylate-co-poly(ethylene glycol) methacrylate] (P(GMA-co-PEGMA)) brush as a flexible matrix is uniformly coated on a glass slide through a purge-free surface-initiated atom transfer radical polymerization (SI-ATRP) to immobilize capture proteins for a larger loading capacity and higher bioactivity while allowing easy target access to the brush-attached probes for efficient antibody-antigen (Ab-Ag) bindings. The integrated device is then constructed by simply laminating the protein-arrayed slide onto a ready-for-bonding double-sided adhesive tape-attached poly(methyl methacrylate) (PMMA) microfluidic structure. As a demonstration, a parallel microarray panel is designed to perform flow-through immunoassays for good detection flexibility and simultaneous analysis of various samples. The limit of detection (LOD) of 1-10 pg/mL for detected target proteins is achieved, which is one to two orders better than those of reported flow-through immunoassays. The device also demonstrates significantly reduced total assay time over the static microarray immunoassay. The rapid and sensitive detection can be mainly ascribed to the P(GMA-co-PEGMA) brushed substrate, of which both the hydrophilicity from its PEG component and the binding capability from its GMA moiety result in higher protein loading capacity, lower nonspecific adsorption, and higher Ab-Ag binding efficiency. The integrated microfluidic device was further used to detect an important cancer biomarker carcinoembryonic antigen (CEA) in serum and achieved a LOD of 10 pg/mL, demonstrating its great potential for clinical applications. PMID- 21547538 TI - The pharmacological effects of the thermostabilising (m23) mutations and intra and extracellular (beta36) deletions essential for crystallisation of the turkey beta-adrenoceptor. AB - The X-ray crystal structure of the turkey beta-adrenoceptor has recently been determined. However, mutations were introduced into the native receptor that was essential for structure determination. These may cause alterations to the receptor pharmacology. It is therefore essential to understand the effects of these mutations on the pharmacological characteristics of the receptor. This study examined the pharmacological effects of both the m23 mutations and the beta36 deletions, both alone and then in combination in the beta36-m23 mutant used in the crystallisation and structure determination of the turkey beta adrenoceptor. Stable CHO-K1 cell lines were made of each of the receptor mutants and the affinity and efficacy of ligands assessed by (3)H-CGP 12177 whole cell ligand binding, (3)H-cAMP accumulation, and CRE-SPAP gene transcription assays. The m23 mutations reduced affinity for agonists, partial agonists and neutral antagonists by about tenfold whilst the beta36 deletions alone had no effect on ligand affinity. Both sets of changes appeared to reduce the agonist activation of the receptor. Both the m23 and the beta36 receptors retained two active agonist-induced receptor conformations similar to that of the original tbetatrunc receptor. The combined beta36-m23 receptor bound ligands with similar affinity to the m23 receptor; however, agonist activation was only observed with a few agonists including the catecholamines. Although the combination of mutations severely reduced the activation ability, the final crystallised receptor (beta36 m23) was still a fully functional receptor capable of binding agonist and antagonist ligands and activating intracellular agonist responses. PMID- 21547539 TI - Orphanin FQ/nociceptin activates nuclear factor kappa B. AB - Endogenous neuropeptide orphanin FQ/nociceptin (OFQ/N) and its receptor, nociceptin orphanin FQ peptide receptor (NOPr), play a modulatory role throughout the body including nociceptive sensitivity, motor function, spatial learning, and the immune system. NOPr is an inhibitory G protein coupled receptor (GPCR) that modulates expression and release of inflammatory mediators from immune cells and in the CNS. Inhibitory GPCRs have been shown to activate the immune and central nervous system regulator, nuclear factor kappa B (NFkappaB), whose family consists of several subunits. When activated, NFkappaB translocates to the nucleus and can modify transcription. To determine if OFQ/N modulates NFkappaB activity, SH-SY5Y human neuroblastoma cells were treated with OFQ/N and assessed for changes in nuclear accumulation, DNA binding, and transcriptional activation. For the first time, we show that OFQ/N increases the nuclear accumulation (1.9 2.8-fold) and the DNA binding of NFkappaB (2.9-fold) by 2 h as determined by immunoblotting and electromobility shift assay, respectively. OFQ/N induction of NFkappaB binding to DNA is protein kinase C-dependent and NOPr-specific. OFQ/N stimulated binding of both NFkappaB p50 and p65 subunits to their consensus binding site on DNA. OFQ/N also induces transcriptional activation of an NFkappaB reporter gene 2.2-fold by 2 h with an EC(50) of 6.3 nM. This activation of NFkappaB by OFQ/N suggests a likely mechanism for its modulation of the central nervous and immune systems. PMID- 21547540 TI - Over-expression of Oct4 in human esophageal squamous cell carcinoma. AB - The Octamer 4 gene (Oct4) is a master pluripotency controller that has been detected in several types of tumors. Here, we examine the expression of Oct4 in human esophageal squamous cell carcinoma (ESCC). We found that punctate Oct4 protein was expressed in most (93.7%) ESCC samples but it was not observed in esophageal mucosa. Some ESCC cells had the capacity to form tumorospheres; those with an Oct4(+)-rich cell phenotype had increased proliferation and Oct4 mRNA levels compared to those of differentiated cells in culture or xenograft tumors. The over-expression of Oct4 in ESCCs suggests that it is a potential target for ESCC therapy. Oct4 could be a useful tumor marker in an immunohistochemical panel designed to differentiate between ESCC and esophageal mucosa. Expression of Oct4 in tumorospheres might indicate the presence of a population of ECSCs and its expression in xenograft tumors suggests that Oct4 is also associated with tumor metastasis. PMID- 21547541 TI - Review and management of side effects associated with antiplatelet therapy for prevention of recurrent cerebrovascular events. AB - The risk of secondary events following noncardioembolic ischemic stroke or transient ischemic attack (TIA) is high and especially pronounced in the first days and weeks following the initial event; to reduce this risk, it is recommended that antiplatelet therapy be initiated immediately. Although the risk and impact of antiplatelet-associated side effects are generally far less substantial than those of secondary events, some (especially bleeding) can be severe and even life-threatening, and others may reduce adherence to antiplatelet regimens. Therefore, clinicians should implement strategies to reduce the risk of side effects and to manage those that occur. Three antiplatelet regimens have demonstrated substantial reductions in secondary event risk and are currently recommended by consensus panels: aspirin monotherapy at 50-325 mg/day; the combination of aspirin plus extended-release dipyridamole (ER-DP); and clopidogrel monotherapy. Bleeding is potentially the most significant antiplatelet-associated side effect. As bleeding risk with aspirin monotherapy is dose dependent, while preventive efficacy appears similar at all doses above 50 mg/day, aspirin doses should be kept as low as possible. Clopidogrel bleeding risk is similar to aspirin, although a reduced incidence of gastrointestinal bleeding events suggests lower gastrotoxicity. Clopidogrel should not be combined with aspirin after stroke or TIA, as the combination increases bleeding risk without improving antiplatelet efficacy. Patients should be assessed for bleeding risk (especially gastrointestinal bleeding) before initiating antiplatelet therapy; those at elevated risk should be made aware of the signs and symptoms of bleeding events to facilitate prompt treatment. The addition of ER-DP to aspirin does not increase bleeding risk, although ER-DP is associated with risk of headache, which may be severe. The prevalence of headache drops rapidly following initiation of ER-DP, suggesting most patients are able to "push through" this side effect; for those who find headache intolerable, short-term use of a reduced dose regimen may be helpful. PMID- 21547542 TI - National Guard service members returning home after deployment: the case for increased community support. AB - National Guard service members and their families face unique circumstances that distinguish them from other branches of the military. In this article, we highlight unique National Guard needs and argue that more can be done by policy makers to help this population. We present the findings from a representative survey of Michigan citizens showing that public support exists for increased assistance for these service members. Using the multiple streams framework, we propose that policy makers currently have the opportunity to facilitate increased support for National Guard members and families. Specifically we suggest policy implications that feature the important role of state and local resources. PMID- 21547543 TI - Friendship as protection from peer victimization for girls with and without ADHD. AB - The goal of this study was to examine the ability of friendship to moderate the association between behavioral risk and peer victimization for girls with attention-deficit/hyperactivity disorder (ADHD; n = 140) and comparison girls (n = 88) in a 5-week naturalistic summer camp setting. Participants were an ethnically and socioeconomically diverse group of girls ages 6-12. Parents and teachers reported on pre-summer internalizing behavior, externalizing behavior, and social competence. Participants reported on friendships and peer victimization through a peer report measure at the summer camps; friendship was scored via mutual nominations. Pre-summer externalizing behavior, internalizing behavior, and low social competence predicted peer victimization at the summer camps. Friendship moderated the association between behavioral risk and victimization for the entire sample, such that the presence of at least one friend reduced the risk of victimization. Additional analyses suggested that girls with ADHD were no more or less protected by the presence of a friendship than were comparison girls. Finally, preliminary analyses suggested that girls having only friends with ADHD were not significantly less protected than girls with at least one comparison friend. Future directions and implications for intervention are discussed. PMID- 21547544 TI - Genus specific unusual carotenoids in purple bacteria, Phaeospirillum and Roseospira: structures and biosyntheses. AB - Phototrophic bacteria necessarily contain carotenoids for photosynthesis, and a few phototrophic purple bacteria accumulate unusual carotenoids. The carotenoids in the genera Phaeospirillum and Roseospira were identified using spectroscopic methods. All species of the genus Phaeospirillum contained characteristic polar carotenoids in addition to lycopene and hydroxylycopene (rhodopin); hydroxylycopene glucoside, dihydroxylycopene, and its mono- and/or diglucosides. From the structures of these carotenoids, their accumulation was suggested to be due to absence of CrtD (acyclic carotenoid C-3,4 desaturase) and to possession of glucosyltransferase. Species of the genus Roseospira have been reported to have unusual absorption spectra in acetone extract, and they were found to accumulate 3,4-didehydrorhodopin as a major carotenoid. This may be due to low activity of CrtF (acyclic 1-hydroxycarotenoid methyltransferase). The study concludes in identifying genus specific unusual carotenoids, which is probably due to characteristic nature of some carotenogenesis enzymes. PMID- 21547545 TI - Update on repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: different targets. AB - Obsessive-compulsive disorder (OCD) is a chronic, disabling disorder. Ten percent of patients remain treatment refractory despite several treatments. For these severe, treatment-refractory patients, repetitive transcranial magnetic stimulation (rTMS) has been suggested as a treatment option. Since 1997, in published trials, a total of 110 OCD patients have been treated with rTMS. This review aims to provide an update on rTMS treatment in patients with OCD. First, the mechanism of action is discussed, followed by the efficacy and side effects of rTMS at various brain targets, and finally implications for the future. Due to the lack of studies with comparable stimulation or treatment parameters and with reliable designs, it is difficult to draw clear conclusions. In general, rTMS appears to be effective in open-label studies; however, this has not yet been replicated in randomized, sham-controlled trials. PMID- 21547546 TI - A DFT study of aminonitroimidazoles. AB - Density functional theory (DFT) calculations at the B3LYP/aug-cc-pVDZ level were performed to explore the geometric and electronic structures, band gaps, thermodynamic properties, densities and performances of aminonitroimidazoles. The calculated performance properties, stabilities and sensitivities of the model compounds appear to be promising compared with those of the known explosives 2,4 dinitro-1H-imidazole (2,4-DNI), 1-methyl-2,4,5-trinitroimidazole (MTNI), hexahydro-1,3,5-trinitro-1,3,5-triazinane (RDX), and octahydro-1,3,5,7-tetranitro 1,3,5,7-tetraazocane (HMX). The position of the NH(2) or the number of NO(2) groups on the diazole presumably determines the structure, heat of formation, stability, sensitivity, density and performance of the compound. PMID- 21547547 TI - An important factor in relation to shock-induced chemistry: resonance energy. AB - With density function theory BLYP/DNP method, together with homodesmotic reactions and isodesmic reactions, we calculated the resonance energies of some explosives, including eight nitro compounds which contains benzene rings, three nitro compounds which contains azaheterocycles (2,4-dinitroimidazole (2,4-DNI), 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105) and 2,4,6-trinitro-1,3,5 triazine) and one nitrogen-rich energetic compound of 3,3'-azobis(6-amino-s tetrazine) (DAAT). The results indicate that their resonance energies are in relation to their shock sensitivity which measuring their threshold pressures of initiation, that is, the lower the resonance energy is, the higher the shock sensitivity of the explosive behaves. And this measuring method according to resonance energy is based on the global property of the molecule instead of the local one, such as one nitro group in the molecule. It is meaningful to calculate resonance energies of these kind of compounds quickly and accurately because resonance structures exist widely in these organic compounds and resonance energies may play a significant role in determining their shock sensitivity, and it is helpful in the rational design or synthesis of high energy and insensitive materials. PMID- 21547548 TI - Interactions between Al12X (X = Al, C, N and P) nanoparticles and DNA nucleobases/base pairs: implications for nanotoxicity. AB - The interactions between neutral Al(12)X(I ( h )) (X = Al, C, N and P) nanoparticles and DNA nucleobases, namely adenine (A), thymine (T), guanine (G) and cytosine (C), as well as the Watson-Crick base pairs (BPs) AT and GC, were investigated by means of density functional theory computations. The Al(12)X clusters can tightly bind to DNA bases and BPs to form stable complexes with negative binding Gibbs free energies at room temperature, and considerable charge transfers occur between the bases/BPs and the Al(12)X clusters. These strong interactions, which are also expected for larger Al nanoparticles, may have potentially adverse impacts on the structure and stability of DNA and thus cause its dysfunction. PMID- 21547549 TI - Molecular dynamics simulations of the growth of poly(chloro-para-xylylene) films. AB - Parylene C, poly(chloro-para-xylylene) is the most widely used member of the parylene family due to its excellent chemical and physical properties. In this work we analyzed the formation of the parylene C film using molecular mechanics and molecular dynamics methods. A five unit chain is necessary to create a stable hydrophobic cluster and to adhere to a covered surface. Two scenarios were deemed to take place. The obtained results are consistent with a polymer film scaling growth mechanism and contribute to the description of the dynamic growth of the parylene C polymer. PMID- 21547551 TI - On the electronic properties of two-dimensional honeycomb GaInN and GaAlN alloys: a molecular analysis. AB - We have performed first principles total energy calculations to investigate the structural and the electronic properties of two-dimensional honeycomb GaAlN and GaInN alloys. Calculations were done using a coronene-like (C(24)H(12)) cluster and for different numbers of Ga, Al, and In atoms. The exchange and correlation potential energies were treated within the generalized gradient approximation (GGA). The bond length, dipole moment, binding energy, and gap between the HOMO and the LUMO are reported as a function of x. The stability of the structures depends on the site of the substituted atom; for example, when three Ga atoms are substituted, the GaInN alloy becomes unstable. The gap in the GaAlN increases from 3.76 eV (GaN) to 4.51 eV (AlN), and in the GaInN decreases to 2.11 eV. The biggest polarity occurs when eight and four Ga atoms are substituted, for GaAlN and GaInN, respectively. PMID- 21547552 TI - The configurations and the materials of the components of commercial coaxial or single-tube breathing circuits. PMID- 21547550 TI - Multiple receptor conformation docking and dock pose clustering as tool for CoMFA and CoMSIA analysis - a case study on HIV-1 protease inhibitors. AB - Multiple receptors conformation docking (MRCD) and clustering of dock poses allows seamless incorporation of receptor binding conformation of the molecules on wide range of ligands with varied structural scaffold. The accuracy of the approach was tested on a set of 120 cyclic urea molecules having HIV-1 protease inhibitory activity using 12 high resolution X-ray crystal structures and one NMR resolved conformation of HIV-1 protease extracted from protein data bank. A cross validation was performed on 25 non-cyclic urea HIV-1 protease inhibitor having varied structures. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were generated using 60 molecules in the training set by applying leave one out cross validation method, r (loo) (2) values of 0.598 and 0.674 for CoMFA and CoMSIA respectively and non-cross validated regression coefficient r(2) values of 0.983 and 0.985 were obtained for CoMFA and CoMSIA respectively. The predictive ability of these models was determined using a test set of 60 cyclic urea molecules that gave predictive correlation (r (pred) (2) ) of 0.684 and 0.64 respectively for CoMFA and CoMSIA indicating good internal predictive ability. Based on this information 25 non-cyclic urea molecules were taken as a test set to check the external predictive ability of these models. This gave remarkable out come with r (pred) (2) of 0.61 and 0.53 for CoMFA and CoMSIA respectively. The results invariably show that this method is useful for performing 3D QSAR analysis on molecules having different structural motifs. PMID- 21547553 TI - The quality of defibrillation performance among students of the University of Medical Sciences. AB - The major objective was to assess the time period from a witnessed ventricular fibrillation (VF) to the first defibrillation (DEF) in a simulated manikin scenario, while the minor objective was to analyze the most common errors that occurred during DEF and the maintenance of 2-min intervals during resuscitation. We examined 210 students (medical faculty students, MF; and paramedic faculty students, PF) who had to treat a patient with VF. In the study we used the Laerdal((r)) Training Manikin and the Zoll M Series((r)) defibrillator. The mean time period from the witnessed VF to the first DEF was 50.1 s (SD 32.5 s) in the MF group and 62.9 s (SD 36.9 s) in the PF group (no statistically significant difference). The delay resulted from the lack of constant ECG monitoring and charging in the option "Monitor" instead of the option "Defibrillation." The PF group shortened the 2-min cycles between defibrillations. The problems observed during the study were technical and educational. We concluded that the option "Monitor" should be removed from the equipment because it seems to be redundant. The teaching problems were a lack of constant ECG monitoring, incorrect handling of the defibrillator, and not keeping to 2-min loops of CPR. PMID- 21547554 TI - Impact of intraoperative hypotension on hospital stay in major abdominal surgery. AB - PURPOSE: Although the relationship between preoperative risk factors and outcomes has been extensively studied, the effect of intraoperative hemodynamic changes in a patient's postoperative course has been less well defined. METHODS: We designed a prospective observational study to assess the impact of several variables, and especially hypotension, on postoperative outcome. Patients considered eligible for the study, all more than 18 years old, were mentally stable patients scheduled for major abdominal surgery with an expected duration of more than 2 h. Total hypotension time (THT), with other variables that possibly influence the outcome, was analyzed using multivariate logistic regression analysis in 100 consecutive patients. RESULTS: Total hypotension time was isolated as a factor significantly associated with morbidity [odds ratio, 5.1 (1.95-13.35)] and significantly prolonged hospital stay [odds ratio, 4.56 (1.85-10.96)]. Patients who had prolonged THT presented more complications (50 vs. 30), especially of the cardiovascular, pulmonary, and gastrointestinal systems. These complications led to delayed hospital discharge in a significant number of patients (36 with THT vs. 17 others). Finally, duration of surgery was associated with postoperative complications [odds ratio, 3.1 (1.2-8.0)]. CONCLUSION: Persistent hypotension during elective major abdominal surgery is a significant risk factor for postoperative complications and may prolong hospitalization and affect patient outcomes. Anesthetic management for the avoidance of hypotension, as much as possible, during major abdominal surgery may positively affect outcomes. PMID- 21547555 TI - Non-polar lipid components of human cerumen. AB - Human cerumen was separated by column chromatography into the following groups of compounds: hydrocarbons, squalene, wax esters and cholesterol esters, triacylglycerols, free fatty acids, free fatty alcohols, monoacylglycerols, free cholesterol, free sterols, and free hydroxy acids. The groups of compounds obtained were examined in detail by gas chromatography and gas chromatography mass spectrometry. In total, about one thousand compounds have been identified. PMID- 21547556 TI - Pelvic floor therapies in chronic pelvic pain syndrome. AB - Chronic pelvic pain syndrome is a poorly understood clinical entity associated with urinary symptoms, pelvic floor dysfunction, and multisystem disorders. Treatment of pelvic floor dysfunction is difficult and often frustrating for the patient as well as for the involved physician. The purpose of this review is to update clinicians on the latest research for the treatment of pelvic floor dysfunction in relation to chronic pelvic pain syndrome. PMID- 21547558 TI - Interpersonal Fitts' law: when two perform as one. AB - Intra- and interpersonal coordination was investigated using a bimanual Fitts' law task. Participants tapped rhythmically between pairs of targets. Tapping was performed with one hand (unimanual), two hands (intrapersonal coordination), and one hand together with another participant (interpersonal coordination). The sizes and distances of targets in a pair were manipulated independently for each hand. When target difficulty was unequal across hands, movement times were similar in the coordination conditions, in violation of Fitts' law. Processing speed (measured by index of performance) increased for more difficult tasks, suggesting increased attention, even for dyads. These findings suggest that similar processes, not captured by centralized control, guide coordination for both individuals and dyads. Measures of coordination, though, still showed stronger coordination tendencies for intrapersonal coordination, indicating a possible role for centralized mechanisms. PMID- 21547559 TI - The effects of task and content on digit placement on a bottle. AB - In addition to hand shaping, previous studies have shown that subjects adapt placement of individual digits to object properties such as its weight and center of mass. However, the extent to which digit placement varies based on task context is unknown. In the present study, we investigated where subjects place their digits on a bottle when the upcoming task (lift versus pour) and object content (i.e., amount of liquid: empty, half, and full) were manipulated. Our results showed that subjects anticipated both the upcoming task and content by varying digit placement when grasping the bottle prior to the onset of manipulation. Specifically, subjects increased the vertical distance between the thumb and index finger for pouring but not for lifting. This larger moment arm might have been established to decrease the amount of force required to tilt the bottle. Content also affected digit placement: the digits were placed higher and were wrapped more around the bottle with increasing content. This strategy may maximize grip surface contact, and hence grasp stability. These findings extend previous research showing that grasp planning not only takes place at a macroscopic level (whole-hand position relative to an object), but also at the level of individual digit placement. This finer level of control appears to be sensitive to the expected mechanical properties of the object and how these may affect grasp stability throughout the upcoming manipulation. PMID- 21547560 TI - [Right heart failure resulting from pacemaker lead-induced tricuspid valve regurgitation]. AB - Pacemaker lead-induced tricuspid valve regurgitation is a severe and often underdiagnosed complication due to the widely variable time interval between implantation and the development of severe tricuspid valve insufficiency with ensuing right heart failure. Complete explantation of inactive pacemaker leads is necessary to avoid permanent damage to right heart structures. If performed in a timely fashion, regression of tricuspid insufficiency can be achieved without additional cardiac procedures. PMID- 21547561 TI - [Syncope: still a chameleon in cardiology?]. PMID- 21547557 TI - GABA(A) receptor and glycine receptor activation by paracrine/autocrine release of endogenous agonists: more than a simple communication pathway. AB - It is a common and widely accepted assumption that glycine and GABA are the main inhibitory transmitters in the central nervous system (CNS). But, in the past 20 years, several studies have clearly demonstrated that these amino acids can also be excitatory in the immature central nervous system. In addition, it is now established that both GABA receptors (GABARs) and glycine receptors (GlyRs) can be located extrasynaptically and can be activated by paracrine release of endogenous agonists, such as GABA, glycine, and taurine. Recently, non-synaptic release of GABA, glycine, and taurine gained further attention with increasing evidence suggesting a developmental role of these neurotransmitters in neuronal network formation before and during synaptogenesis. This review summarizes recent knowledge about the non-synaptic activation of GABA(A)Rs and GlyRs, both in developing and adult CNS. We first present studies that reveal the functional specialization of both non-synaptic GABA(A)Rs and GlyRs and we discuss the neuronal versus non-neuronal origin of the paracrine release of GABA(A)R and GlyR agonists. We then discuss the proposed non-synaptic release mechanisms and/or pathways for GABA, glycine, and taurine. Finally, we summarize recent data about the various roles of non-synaptic GABAergic and glycinergic systems during the development of neuronal networks and in the adult. PMID- 21547562 TI - Animal models of human genetic diseases: do they need to be faithful to be useful? AB - With the advances in molecular genetics, animal models of human diseases are becoming more numerous and more refined every year. Despite this, one must recognize that they generally do not faithfully and comprehensively mimic the homologous human disease. Faced with these imperfections, some geneticists believe that these models are of little value, while for others, on the contrary, they are important tools. We agree with this second statement, and in this review, we examine the reasons that may explain the observed differences and suggest means to circumvent or even exploit them. Our opinion is that animal models should be regarded more as tools capable of answering specific questions rather than mere replicas, at a smaller scale, of a given human disease. Far from disappointing they are probably called for a promising future. PMID- 21547563 TI - The protective Th1 response in mice is induced in the T-cell zone only three weeks after infection with Leishmania major and not during early T-cell activation. AB - The protozoan parasite Leishmania spp. causes clinical pictures ranging in severity from spontaneously healing skin ulcers to systemic disease. The immune response associated with healing involves the differentiation of IFNgamma producing Th1 cells, whereas the non-healing phenotype is associated with IL4 producing Th2 cells. The widespread assumption has been that the T-cell differentiation that leads to a healing or non-healing phenotype is established at the time of T-cell activation early after infection. By selectively analyzing the expression of cytokine genes in the T-cell zones of lymph nodes of resistant (Th1) C57BL/6 mice and susceptible (Th2) BALB/c mice during an infection with Leishmania major in vivo, we show that the early T-cell response does not differ between C57BL/6 mice and BALB/c mice. Instead, Th1/Th2 polarization appears suddenly 3 weeks after infection. At the same time point, the number of parasites increases in lymph nodes of both mouse strains, but about 100-fold more in susceptible BALB/c mice. We conclude that the protective Th1 response in C57BL/6 mice is facilitated by the capacity of their innate effector cells to keep parasite numbers at low levels. PMID- 21547564 TI - Automated reconstruction of neuronal morphology based on local geometrical and global structural models. AB - Digital reconstruction of neurons from microscope images is an important and challenging problem in neuroscience. In this paper, we propose a model-based method to tackle this problem. We first formulate a model structure, then develop an algorithm for computing it by carefully taking into account morphological characteristics of neurons, as well as the image properties under typical imaging protocols. The method has been tested on the data sets used in the DIADEM competition and produced promising results for four out of the five data sets. PMID- 21547567 TI - Editorial: concepts of animal welfare. PMID- 21547568 TI - Hematological, biochemical, and behavioral responses of Oncorhynchus mykiss to dimethoate. AB - The effects of dimethoate on hematological, biochemical parameters, and behavior were investigated in Oncorhynchus mykiss exposed to sublethal concentrations of 0.0735, 0.3675, and 0.7350 mg/l for 5, 15, and 30 days. Significant decrease was determined in erythrocyte and leukocyte counts, hemoglobin, hematocrit, MCV, and MCH, which was pronounced after prolonged exposure indicating the appearance of microcytic hypochromic anemia. There were no prominent changes in thrombocyte and MCHC. The glucose concentration showed an ascending pattern that proved to be positively correlated with duration. The protein concentration declined in higher dimethoate concentrations following 15 and 30 days. Negative and significant correlation was detected between glucose and protein concentrations. The fish showed remarkable behavioral abnormality such as loss of balance, erratic swimming, and convulsion. Present findings revealed that dimethoate exerts its toxic action even in sublethal concentrations and hematological parameters and abnormal behavior may be sensitive indicators to evaluate pesticide intoxication. PMID- 21547565 TI - Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs. AB - The activation of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway is a known causal mechanism of oncogenesis and resistance to cancer treatments. The process of PI3K-Akt pathway activation is complex and includes receptor tyrosine kinase(RTK) activation, PIK3CA mutations, loss of phosphatase and tensin homolog (PTEN), Akt mutations, tuberous sclerosis complex (TSC) mutations, and Ras homologue enriched in brain (RHEB) gene amplifications. The blockage of mammalian target of rapamycin (mTOR), the key downstream pathway protein, has been successful in selected cancer types, with mTOR-targeting agents available for clinical use. Other novel drugs blocking this pathway such as PI3K inhibitors, Akt inhibitors and PDK-1 inhibitors are currently only available for investigational use, but have shown promise as cancer therapies in both preclinical and early phase clinical studies. The newer generations of these inhibitors are more specific and have improved potency and safety. The combinations of targeted treatments against this pathway, blocking multiple different steps, are under preliminary investigation. Further research is needed to identify the biomarkers that predict treatment response and resistance in order to optimize personalized medicine. PMID- 21547569 TI - Prevalence of psychological distress, as measured by the Kessler 6 (K6), and related factors in Japanese employees. AB - The aim of this study was to examine the prevalence of and related factors for psychological distress among employees. The employees in Akita prefecture, Japan, were invited to complete the Kessler 6 (K6). A value of 13 or higher on the K6 scale indicated high psychological distress. Furthermore, we identified the relationships among the prevalence of high psychological distress, socio demographic status, and employment-related variables. The data of 1,709 employees indicated that 10.8% of the employees had high psychological distress; the proportion of psychological distress found in the present study was high compared to that found in previous studies. The identified socio-demographic and occupation-related factors included young age groups associated with a high risk and clerical or administrative tasks associated with a low risk of psychological distress. The data of this study can be used as K6 benchmark values, which enhance the significance of future corporate health risk appraisal surveys. PMID- 21547571 TI - Pulmonary toxicity among cancer patients treated with a combination of docetaxel and gemcitabine: a meta-analysis of clinical trials. AB - PURPOSE: The combination of docetaxel and gemcitabine was tested in several studies in patients with lung, breast, and pancreatic cancers and other tumor entities. Some studies reported cases of severe or even fatal pulmonary toxicity that led to early termination of some trials. We created a meta-analysis model of published studies to identify explanatory factors for docetaxel-gemcitabine dependent pulmonary toxicity. METHODS: We searched MEDLINE/Pubmed, EMBASE, and Cochrane Clinical Trials database for prospective full-text studies that used a schedule of docetaxel and gemcitabine to treat a malignant disease. We performed a meta-analysis for proportions using the arcsine transformation and a meta regression using a generalized linear mixed model based on a binomial distribution and a logit link. RESULTS: We included 103 trials with 113 treatment arms comprising 5,065 patients (major entities included non-small cell lung cancer (n = 2,550), breast cancer (n = 1,119), pancreatic cancer (n = 466), and urothelial cancer (n = 161)). For the incidence of severe lung toxicity (common toxicity criteria [CTC] grades 3-5), we found a combined estimate of 2.70% (95% CI 2.26, 3.14). The estimate for the proportion of fatal cases was 0.35% (95% CI 0.21, 0.58). We found that the sequence of the chemotherapy schedule had no influence on the incidence of severe pulmonary adverse events (F-test F = 0.65, df = 3,113, P = 0.58) nor did the study phase, treatment line or ethnicity of the participants. We found that patients with breast cancer, compared to lung cancer patients, developed severe lung toxicity less frequently (OR = 0.18, 95% CI (0.09, 0.36)). CONCLUSION: We could not demonstrate that a particular chemotherapy sequence of docetaxel-gemcitabine is associated with excess pulmonary toxicity. Patients with lung cancer are at a higher risk for severe pulmonary side effects with docetaxel-gemcitabine than are patients with breast cancer. PMID- 21547570 TI - Attitudes toward help-seeking and duration of untreated mental disorders in a sectorized Athens area of Greece. AB - The purpose of the present study was to investigate the association of opinions towards seeking psychiatric help with the duration of untreated mental disorders in a sectorized Athens area, served by a Community Mental Health Centre. The sample consisted of 134 individuals who had sought help from health or mental health non sectorized services prior to their visit to the Centre (group A) and 156 individuals whose visit to the Center was their first ever contact with a mental health service (group B). Opinions were assessed by the "Attitudes Toward Seeking Professional Psychological Help scale. Both groups were selected from a total of 1,008 individuals who had visited the Centre in four consecutive years. The duration of untreated mental disorders was found to be shorter in group A compared to group B. Males and females of both groups, who had visited the Centre in a time period shorter than 12 months since the onset of their psychopathology, expressed more positive views towards help-seeking, compared to their counterparts with longer duration of untreated mental disorder. The variables of gender (females), age at symptom onset (younger) and education (higher) predicted a shorter duration without psychiatric treatment and more positive views about the necessity of help-seeking. More severe type of diagnoses was associated with shorter durations before accessing care. Our findings underline that mental health awareness programs are clearly required in order to strengthen the early recognition of the need for help- seeking. The development of liaison and outreach activities could also prevent prolonged delays in psychiatric treatment. PMID- 21547572 TI - Tesetaxel, a new oral taxane, in combination with capecitabine: a phase I, dose escalation study in patients with advanced solid tumors. AB - PURPOSE: This phase I study was conducted primarily to determine the maximum tolerated dose (MTD) of tesetaxel, a novel, orally active, semisynthetic microtubule inhibitor of the taxane class, administered with oral capecitabine to patients with advanced solid tumors. METHODS: During each 21-day cycle, patients were to receive tesetaxel on Day 1 and capecitabine twice daily on Days 1 through 14. The starting dose was tesetaxel 18 mg/m(2) and capecitabine 1,250 mg/m(2)/day. These doses were increased based on tolerability during the first cycle according to the protocol-specified dose-escalation scheme. Response was evaluated every other treatment cycle according to RECIST. Serial blood samples were collected during the first and second cycles to explore possible pharmacokinetic drug interactions. RESULTS: Twenty-seven patients were enrolled and treated. The most frequently reported dose-limiting toxicities were neutropenia and febrile neutropenia, with individual patients experiencing dose limiting stomatitis and diarrhea. The MTD for the treatment regimen was defined as tesetaxel 27 mg/m(2) and capecitabine 2,500 mg/m(2)/day. The most common >= Grade 3 treatment-related adverse events included leukopenia (44% of patients) and neutropenia (41%). Of 22 evaluable patients, the best overall response was stable disease in 82% and progressive disease in 18%. No meaningful pharmacokinetic drug interactions were apparent. CONCLUSIONS: The results of this study demonstrate that these two orally active agents can be combined at the individual MTD of each drug with acceptable toxicity. These data further support the continued clinical development of tesetaxel both as a single agent and in combination with other active cancer therapeutics. PMID- 21547573 TI - Thermal dependence of locomotor performance in two cool-temperate lizards. AB - Temperate-zone ectotherms experience varying or very low ambient temperatures and may have difficulty in attaining preferred body temperatures. Thus, adaptations to reduce the thermal dependence of physiological processes may be present. We measured the optimal temperature range for sprint speed and compared it with the selected body temperatures (T (sel)) of two sympatric, cool-temperate lizards: the diurnal skink Oligosoma maccanni and the primarily nocturnal gecko Woodworthia (previously Hoplodactylus) "Otago/Southland". We also investigated whether time-of-day influenced sprint speed. Contrary to results for other reptiles, we found that time-of-day did not influence speed in either species. For each species, the optimal temperature range for sprinting and T (sel) overlapped, supporting the 'thermal coadaptation' hypothesis. However, the optimal range of temperatures for speed is not always attainable during activity by either species, which have limited opportunities to attain T (sel) in the field. The thermal sensitivity of sprint speed in these two species does not appear to have evolved to fully match their current thermal environment. More data on cold-adapted species are needed to fully understand physiological adaptation in ectotherms. PMID- 21547574 TI - Analysis of the activation mechanism of Pseudomonas stutzeri cytochrome c peroxidase through an electron transfer chain. AB - The activation mechanism of Pseudomonas stutzeri cytochrome c peroxidase (CCP) was probed through the mediated electrochemical catalysis by its physiological electron donor, P. stutzeri cytochrome c-551. A comparative study was carried out, by performing assays with the enzyme in the resting oxidized state as well as in the mixed-valence activated form, using cyclic voltammetry and a pyrolytic graphite membrane electrode. In the presence of both the enzyme and hydrogen peroxide, the peak-like signal of cytochrome c-551 is converted into a sigmoidal wave form characteristic of an E(r)C'(i) catalytic mechanism. An intermolecular electron transfer rate constant of (4 +/- 1) * 10(5) M(-1) s(-1) was estimated for both forms of the enzyme, as well as a similar Michaelis-Menten constant. These results show that neither the intermolecular electron transfer nor the catalytic activity is kinetically controlled by the activation mechanism of CCP in the case of the P. stutzeri enzyme. Direct enzyme catalysis using protein film voltammetry was unsuccessful for the analysis of the activation mechanism, since P. stutzeri CCP undergoes an undesirable interaction with the pyrolytic graphite surface. This interaction, previously reported for the Paracoccus pantotrophus CCP, induces the formation of a non-native conformation state of the electron transferring haem, which has a redox potential 200 mV lower than that of the native state and maintains peroxidatic activity. PMID- 21547575 TI - Effect of the charge distribution along the "ferritin-like" pores of the proteins from the Dps family on the iron incorporation process. AB - DNA-binding proteins from starved cells (Dps) differ in the number and position of charged residues along the "ferritin-like" pores that are used by iron to reach the ferroxidase center and the protein cavity. These differences are shown to affect significantly the electrostatic potential at the pores, which determines the extent of cooperativity in the iron uptake kinetics and thereby the mass distribution of the ferric hydroxide micelles inside the protein cavity. These conclusions are of biotechnological value in the preparation of protein enclosed nanomaterials and are expected to apply also to ferritins. They were reached after characterization of the Dps from Listeria innocua, Helicobacter pylori, Thermosynechococcus elongatus, Escherichia coli, and Mycobacterium smegmatis. The characterization comprised the calculation of the electrostatic potential at the pores, determination of the iron uptake kinetics in the presence of molecular oxygen or hydrogen peroxide, and analysis of the proteins by means of the sedimentation velocity after iron incorporation. PMID- 21547576 TI - Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically detected breast cancers. Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown. METHODS: In the current study, we used multiplex ligation dependent probe amplification (MLPA), a multiplex PCR-based test, to compare copy numbers of 21 breast cancer related genes between laser-microdissected DCIS and adjacent IDC lesions in 39 patients. Genes included in this study were ESR1, EGFR, FGFR1, ADAM9, IKBKB, PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD, MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA. RESULTS: There were no significant differences in copy number for the 21 genes between DCIS and adjacent IDC. Low/intermediate-grade DCIS showed on average 6 gains/amplifications versus 8 in high-grade DCIS (p = 0.158). Furthermore, alterations of AURKA and CCNE1 were exclusively found in high-grade DCIS, and HER2, PRDM14 and EMSY amplification was more frequent in high-grade DCIS than in low/intermediate-grade DCIS. In contrast, the average number of alterations in low/intermediate and high grade IDC was similar, and although EGFR alterations were exclusively found in high grade IDC compared to low/intermediate-grade IDC, there were generally fewer differences between low/intermediate-grade and high-grade IDC than between low/intermediate-grade and high-grade DCIS. CONCLUSION: In conclusion, there were no significant differences in copy number for 21 breast cancer related genes between DCIS and adjacent IDC, indicating that DCIS is genetically as advanced as its invasive counterpart. However, high grade DCIS showed more copy number changes than low/intermediate grade DCIS with specifically involved genes, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes that progress to IDC in different routes. These high grade DCIS specific genes may be potential targets for treatment and/or predict progression. PMID- 21547577 TI - Gene copy number variation in male breast cancer by aCGH. AB - BACKGROUND: Male breast cancer (MBC) is a rare disease and little is known about its etiopathogenesis. Array comparative genomic hybridization (aCGH) provides a method to quantitatively measure the changes of DNA copy number and to map them directly onto the complete linear genome sequences. The aim of this study was to investigate DNA imbalances by aCGH and compare them with a female breast cancer dataset. METHODS: We used Agilent Human Genome CGH Microarray Kit 44B and 44 K to compare genomic alterations in 25 male breast cancer tissues studied at NCC of Bari and 16 female breast cancer deposited with the Gene Expression Omnibus (GSE 12659). Data analysis was performed with Nexus Copy Number 5.0 software. RESULTS: All the 25 male and 16 female breast cancer samples displayed some chromosomal instability (110,93 alterations per patient in female, 69 in male). However, male samples presented a lower frequency of genetic alterations both in terms of loss and gains. CONCLUSION: aCGH is an effective tool for analysis of cytogenetic aberrations in MBC, which involves different biological processes than female. Male most significant altered regions contained genes involved in cell communication, cell division and immunological response, while female cell-cell junction maintenance, regulation of transcription and neuron development. PMID- 21547578 TI - High frequency microsatellite instability has a prognostic value in endometrial endometrioid adenocarcinoma, but only in FIGO stage 1 cases. AB - OBJECTIVES: To analyze the prognostic value of microsatellite instability (MSI) in a population-based study of FIGO stage 1-4 endometrial endometrioid adenocarcinomas. STUDY DESIGN: Survival analysis in 273 patients of MSI status and clinico-pathologic features. Using a highly sensitive pentaplex polymerase chain reaction to establish MSI status, cases were divided into microsatellite stable (MSS), MSI-low (MSI-L, 1 marker positive) and MSI-high (MSI-H, 2-5 markers positive). RESULTS: After 61 months median follow-up (1-209), 34 (12.5%) of the patients developed metastases but only 6.4% of the FIGO-1. MSI (especially as MSI H versus MSS/MSI-Lcombined) was prognostic in FIGO-1 but not in FIGO2-4. The 5 and 10 year recurrence-free survival rates were 98% and 95% in the MSS/MSI-L versus 85% and 73% in the MSI-H patients (P = 0.005). CONCLUSIONS: MSI-H status assessed by pentaplex polymerase chain reaction is an indicator of poor prognosis in FIGO 1, but not in FIGO 2-4 endometrial endometrioid adenocarcinomas. PMID- 21547580 TI - [Interventions on the wrist joint]. PMID- 21547579 TI - VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin. AB - BACKGROUND: Von Hippel-Lindau (VHL) tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC) development. The VHL protein (pVHL) has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-alpha (HIF-alpha), carbonic anhydrase (CA)IX, heterogeneous nuclear ribonucleoprotein (hnRNP)A2/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue. METHODS: The VHL gene was sequenced in 23 CCRCC patients and VHL transcript levels were evaluated by Real-Time RT-PCR. Expression of pVHL's protein targets were determined by Western blotting in 17 paired patient samples. RESULTS: VHL genetic alterations were identified in 43.5% (10/23) of CCRCCs. HIF-1alpha, HIF-2alpha and CAIX were up-regulated in 88.2% (15/17), 100% (17/17) and 88.2% (15/17) of tumors respectively and their expression is independent of VHL status. hnRNP A2/B1 and osteopontin expression was variable in CCRCCs and had no association with VHL genetic status. CONCLUSION: As expression of these proposed pVHL targets can be achieved independently of VHL mutation (and possibly by hypoxia alone), this data suggests that other pVHL targets may be more crucial in renal carcinogenesis. PMID- 21547581 TI - Tool choice on the basis of rigidity in capuchin monkeys. AB - Wild capuchin monkeys select stone tools to crack open nuts on the basis of their weight and friability, two non-visual functional properties. Here, we investigated whether they would select new stick-like tools on the basis of their rigidity. In Experiment 1, subjects faced an out-of-reach reward and a choice of three unfamiliar tools differing in color, diameter, material, and rigidity. In order to retrieve the reward, capuchins needed to select the rigid tool exemplar. Capuchins gathered information regarding tools' pliability either by (1) manipulating the tools themselves (manipulation condition), (2) observing a human demonstrator repeatedly bending the tools (observation condition), or (3) seeing the tools placed on a platform without any manipulation taking place (visual static condition). Subjects selected the rigid tool above chance levels in both the manipulation and observation conditions, but not in the visual static condition. In Experiment 2, subjects needed to select and use a flexible tool to access a liquid reward (as opposed to the rigid tool, as in previous experiment). Again, capuchins selected above chance levels the appropriate tool (i.e., flexible), thus demonstrating a good appreciation of the relation between the tool properties and the task requirements. PMID- 21547582 TI - Late proximal coronary artery stenosis complicating percutaneous endovascular catheterisation procedures. AB - BACKGROUND: Late-onset proximal coronary artery stenosis caused by preceding percutaneous catheterisation procedures remains under-surveyed. METHODS: From 1993, all patients undergoing percutaneous coronary procedures and a second session within 3 years were included except those ever treated by coronary bypass surgery or chest radiotherapy during this 3-year period. Emergence of a new lesion or worsening of an initially insignificant lesion to >50% of diameter stenosis at the never-treated ostial/proximal coronary segment on the follow-up angiogram was defined as late coronary stenosis caused by the previous catheterisation procedure and was analysed. RESULTS: From January 1993 to December 2005, 3240 patients who underwent 5025 procedures met the inclusion criteria. Of them, 23 patients experienced an event of late coronary artery stenosis (overall incidence 0.46%), and interventional procedures, specifically shaped catheters (Voda, XB, Amplatz Left) and atherosclerosis vulnerability correlated with risks of adverse events. Most of these events could be managed by contemporary medical, interventional, or surgical strategies, yet hazards of mortality and long-term restenosis still existed from this catheter-induced complication. CONCLUSIONS: Percutaneous catheterisation procedures could be complicated by late proximal coronary artery stenosis. Thus, when conducting these procedures, operators should select and manipulate catheters with caution, especially in patients with susceptible clinical characteristics. PMID- 21547583 TI - Comparative FISH mapping of Daucus species (Apiaceae family). AB - The cytogenetic characterization of the carrot genome (Daucus carota L., 2n = 18) has been limited so far, partly because of its somatic chromosome morphology and scant of chromosome markers. Here, we integrate the carrot linkage groups with pachytene chromosomes by fluorescent in situ hybridization (FISH) mapping genetically anchored bacterial artificial chromosomes (BACs). We isolated a satellite repeat from the centromeric regions of the carrot chromosomes, which facilitated the study of the pachytene-based karyotype and demonstrated that heterochromatic domains were mainly confined to the pericentromeric regions of each chromosome. Chromosome-specific BACs were used to: (1) physically locate genetically unanchored DNA sequences, (2) reveal relationships between genetic and physical distances, and (3) address chromosome evolution in Daucus. Most carrot BACs generated distinct FISH signals in 22-chromosome Daucus species, providing evidence for syntenic chromosome segments and rearrangements among them. These results provide a foundation for further cytogenetic characterization and chromosome evolution studies in Daucus. PMID- 21547584 TI - Effect of long-term irrigation with sewage effluent on the metal content of soils, Berlin, Germany. AB - This study aimed to determine whether >110 years of sewage application has led to recognizable changes in the metal chemistry of soils from former sewage farms, Berlin, Germany. Background concentrations of soils and element enrichment factors were used for the evaluation of possible perturbations of natural element abundances in sewage farm soils. Calculations verify that precious metals (Ag, Au) as well as P, C(org), and heavy metals (Cd, Cu, Ni, Pb, Sn, and Zn) are invariably enriched in sewage farm topsoils (0-0.1 m depth) compared to local and regional background soils. Long-term irrigation of soils with municipal wastewater has caused significant heavy metal contamination as well as a pronounced enrichment in precious metals. Leaching of metals including Ag into underlying aquifers may impact on the quality of drinking water supplies. PMID- 21547585 TI - [Voice classification in professional singers: the influence of vocal fold length, vocal tract length and body measurements]. AB - Professional voice performance is strongly affected by the functional adjustments of the structures involved in voice production. Generally, these functional skills are required by means of intensive training. On the other hand, the individual morphology of the larynx and vocal tract limits this functional variability. Thus, to neglect morphological conditions might result in voice problems. The present paper summarizes investigations on the influence of morphological measurements on the voice classification of professional singers. Vocal fold length, vocal tract length and body height have been found to differ systematically between sopranos, mezzosopranos, altos, tenors, baritones and basses. Although the knowledge of morphological measures does not permit a definite assignment or prediction of the individual voice classification, the data are valuable for counseling by voice teachers and phoniatricians. This might contribute to the prevention of voice disorders. PMID- 21547586 TI - [Large cystic tumor of the right neck]. AB - A 32-year-old patient presented to our department with a large cystic lesion in the right lateral neck (diameter 6 cm). After complete resection, the histopathological examination revealed a lymph node metastasis of a papillary thyroid carcinoma. We performed total thyroidectomy and bilateral selective neck dissection. There was a papillary microcarcinoma in the right lobe of the thyroid. The postoperative course was uneventful. Therapy with radioiodine was conducted. At 30 months after surgery the patient is free of disease. PMID- 21547589 TI - Special issues. PMID- 21547587 TI - [Allergic rhinitis. Immunological and neurogenic mechanisms]. AB - Allergic rhinitis is one of the most common diseases to affect humans. It is important to note that it is an immunological disease which is associated with significant changes in the mucous membrane of the respiratory tract. Clinical symptoms of allergic rhinitis include sneezing, rhinorrhea, nasal itching, and nasal congestion. The mechanism underlying the development of symptoms associated with allergic rhinitis are complex, including activation and infiltration of inflammatory cells, edema, increased and altered gland activity, nerve terminal activation, triggering of neurogenic inflammation and morphologically detectable remodelling processes in the mucous membrane. Finally, a systematic activation of immune processes also takes place. Thus, allergic rhinitis is clearly a serious disease requiring prompt and effective treatment; moreover, it has been unjustly trivialized to date, not least because of its high incidence. PMID- 21547588 TI - Bonding interactions and stability assessment of biopolymer material prepared using type III collagen of avian intestine and anionic polysaccharides. AB - The present study demonstrate bonding interactions between anionic polysaccharides, alginic acid (AA) and type III collagen extracted from avian intestine used for the preparation of thermally stable and biodegradable biopolymer material. Further the study describes, optimum conditions (pH, temperature and NaCl concentration) required for the formation of fibrils in type III collagen, assessment on degree of cross-linking, nature of bonding patterns, biocompatibility and biodegradability of the cross-linked biomaterial. Results revealed, the resultant biopolymer material exhibit high thermal stability with 5 6 fold increase in tensile strength compared to the plain AA and collagen materials. The degree of cross-linking was calculated as 75%. No cytotoxicity was observed for the cross-linked biopolymer material when tested with skin fibroblast cells and the material was biodegradable when treated with enzyme collagenase. With reference to bonding pattern analysis we found, AA cross-linked with type III collagen via (i) formation of covalent amide linkage between -COOH group of AA and epsilon-NH2 group of type-III collagen as well as (ii) intermolecular multiple hydrogen bonding between alginic acid -OH group with various amino acid functional group of type-III collagen. Comparisons were made with other cross-linking agents also. For better understanding of bonding pattern, bioinformatics analysis was carried out and discussed in detail. The results of the study emphasize, AA acts as a suitable natural cross-linker for the preparation of wound dressing biopolymer material using collagen. The tensile strength and the thermal stability further added value to the resultant biopolymer. PMID- 21547590 TI - Cerebrovascular events after bevacizumab treatment: an early and severe complication. AB - BACKGROUND: The indications for bevacizumab (a vascular endothelial growth factor inhibitor) have been expanded recently. Despite concerns for cerebrovascular events from bevacizumab treatment, detailed clinical and radiologic information are lacking. METHODS: Using the Mayo Clinic Rochester database (January 2006 September 2010), we identified bevacizumab-treated patients who developed intracerebral hemorrhage, ischemic stroke or transient ischemic attack within 3 weeks of bevacizumab treatment. Functional recovery was assessed using the modified Rankin scale 3 months following the onset of cerebrovascular events. RESULTS: Ten consecutive patients (median age 58 years, range 37-86) were included in this study. These patients received bevacizumab for a median duration of 3 months (range 2-4 months) for cancer treatment, and developed cerebrovascular events that comprised intratumoral hemorrhage (n = 7), cerebral watershed infarction (n = 1), transient ischemic attack (n = 1), and left vertebral artery occlusion (n = 1). Seven patients had chronic hypertension which was adequately controlled with a single anti-hypertensive agent. Significant increase in blood pressure was observed in nine patients during their acute presentation as compared with their baseline outpatient readings. Six patients died within 3 months of these cerebrovascular events, and the remaining four patients had modest functional recovery. CONCLUSIONS: Cerebrovascular events are early and serious complications that should be considered in bevacizumab-treated patients who present with an acute neurologic deterioration. PMID- 21547593 TI - Author's reply to letter "an alternative surgical technique for caval preservation in liver transplantation". PMID- 21547592 TI - Delayed gastric emptying after pancreaticoduodenectomy: influence of the orthotopic technique of reconstruction and intestinal motilin receptor expression. AB - BACKGROUND: Delayed gastric emptying (DGE) is still a common postoperative complication after pancreaticoduodenectomy (PD). Because different reconstruction techniques after PD and the influence of motilin receptor expression are controversially discussed, the present study analyzed the influence of a total orthotopic reconstruction technique on DGE after PD. METHODS: Data from patients undergoing PD and reconstruction using a total orthotopic technique were reviewed, and correlations between DGE and clinico-pathological variables were analyzed. Motilin receptor expression was measured within the duodenum, jejunum, and terminal ileum. RESULTS: Three hundred seven patients received orthotopic reconstruction using a single jejunal loop. DGE grade B or C could be observed in 16.6% of the patients. DGE was significantly associated with the severity of a postoperative pancreatic fistula, the need for a reoperation, wound infections, and vascular complications. Furthermore, these parameters correlated significantly with the grade of DGE. The density of motilin receptor expression decreased significantly behind the duodenum in aboral direction. CONCLUSIONS: The orthotopic reconstruction after PD is the shortest distance without resection of a jejunal segment, preserves the greatest length of jejunum and thus the highest density of motilin receptors, and should therefore be recommended to reduce the incidence of DGE after PD. PMID- 21547594 TI - The evolving surgeon shortage in the health reform era. AB - The evolving surgeon shortage is occurring at a time of societal change. For one of the first times in history, a scientific revolution is occurring while the organization of health care is also changing. With a demand for a more quality health care and a population that has both aged significantly and grown by ten million citizens each decade, the shortage of health care providers is problematic. For surgery, the shortage is particularly challenging. In 1981, 1047 surgeons were certified by the American Board of Surgery; in 2008, that number had dropped to just 909. PMID- 21547595 TI - Frequent malpositions of peripherally inserted central venous catheters in patients undergoing head and neck surgery. AB - PURPOSE: Peripherally inserted central venous catheters (PICCs) do not interfere with surgical access during neck dissection and are used in patients undergoing head and neck surgery. However, severe complications associated with malpositioning of PICCs have been reported in these patients. We conducted a retrospective study to determine the incidence of aberrant positioning of PICCs in patients undergoing free flap reconstructive (FFR) surgery for head and neck malignancies. METHODS: We analyzed a database of 269 patients undergoing FFR surgery. After induction of general anesthesia, a PICC was inserted successfully in 130 patients (48%) at bedside without image guidance. A PICC was not used in 139 patients (52%). A chest x-ray was performed at admission to the postanesthetic care unit, stored digitally, and reviewed retrospectively by two independent observers. Based on the chest x-ray findings, the PICC position was classified as proper, suboptimal, or aberrant and defined according to the position of the PICC tip, i.e., proper, if situated in the ipsilateral innominate vein or in the superior vena cava; suboptimal, if situated in the subclavian vein; and aberrant, if situated in any other location. RESULTS: Proper, suboptimal, and aberrant PICC positions were found in 68 (52%), 17 (13%), and 45 (35%) patients, respectively. The proper position was confirmed more frequently with a left- than with a right-sided approach: 23/29 (79%) vs 45/101 (44%) patients, respectively (P < 0.001). CONCLUSIONS: There is a high incidence of aberrant positioning when PICCs are inserted without image guidance. The left sided approach might be preferable due to a lower incidence of malpositions. The risk-benefit ratio should be estimated carefully before using a PICC in patients undergoing FFR procedures. PMID- 21547596 TI - Foxp3 expression in melanoma cells as a possible mechanism of resistance to immune destruction. AB - The forkhead transcription factor Foxp3 is the only definitive marker of CD4(+)CD25(+) regulatory T cells (Tregs) and has been identified as a key regulator in the development and function of Tregs. Foxp3 expression has been reported in a variety of solid tumors, including melanoma. In this study, we validated Foxp3 expression in both tumor-infiltrating Tregs and melanoma cells by performing immunohistochemical analysis of human melanoma tissue sections. Further, we assessed Foxp3 expression in melanoma cell lines by performing flow cytometry, confocal microscopic analysis, reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting. Inhibition of Foxp3 expression in melanoma cells using small interfering RNA (siRNA) resulted in downregulation of B7-H1 and transforming growth factor (TGF)-beta expression; in contrast, Foxp3 overexpression resulted in the upregulation of the expression of these proteins. Coculture of Foxp3-expressing melanoma cells with naive CD4(+)CD25(-) T cells resulted in strong inhibition of T-cell proliferation. This antiproliferative effect was partially abrogated by specific inhibition of Foxp3 expression and was effectively enhanced by overexpression of Foxp3. We observed an attenuated antiproliferative effect even when melanoma cells and T cells in the coculture were separated using Transwell inserts. These findings indicated that melanoma cells could have Foxp3-dependent Treg-like suppressive effects on T cells and suggested that the mimicking of Treg function by melanoma cells may represent a possible mechanism of tumor resistance to immune destruction in the melanoma tumor microenvironment. PMID- 21547597 TI - Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study. AB - BACKGROUND AND AIMS: Dendritic cell (DC)-based vaccination can induce antitumor T cell responses in vivo. This clinical pilot study examined feasibility and outcome of DC-based tumor vaccination for patients with advanced pancreatic adenocarcinoma. METHODS: Tumor lysate of patients with pancreatic carcinoma was generated by repeated freeze-thaw cycles of surgically obtained tissue specimens. Patients were eligible for DC vaccination after recurrence of pancreatic carcinoma or in a primarily palliative situation. DC were generated from peripheral blood mononuclear cells (PBMC), loaded with autologous tumor lysate, stimulated with TNF-alpha and PGE(2) and injected intradermally. All patients received concomitant chemotherapy with gemcitabine. Disease response was the primary endpoint. Individual immunological responses to DC vaccination were analyzed by T cell-based immunoassays using pre- and post-vaccination samples of non-adherent PBMC. RESULTS: Twelve patients received DC vaccination and concomitant chemotherapy. One patient developed a partial remission, and two patients remained in stable disease. Median survival was 10.5 months. No severe side effects were observed. Tumor-reactive T cells could be detected prior to vaccination. DC vaccination increased the frequency of tumor-reactive cells in all patients tested; however, the degree of this increase varied. To quantify the presence of tumor-reactive T cells, stimulatory indices (SI) were calculated as the ratio of proliferation-inducing capacity of lysate-loaded versus -unloaded DC. The patient with longest overall survival of 56 months had a high SI of 6.49, indicating that the presence of a pre-vaccination antitumor T cell response might be associated with prolonged survival. Five patients survived 1 year or more. CONCLUSION: DC-based vaccination can stimulate an antitumoral T cell response in patients with advanced or recurrent pancreatic carcinoma receiving concomitant gemcitabine treatment. PMID- 21547598 TI - Cardiac resynchronization therapy and bone marrow cell transplantation in patients with ischemic heart failure and electromechanical dyssynchrony: a randomized pilot study. AB - Most studies have confirmed the beneficial effects of autologous bone marrow mononuclear cell (BMMC) transplantation on angina, myocardial perfusion, regional wall motion, and LV ejection fraction (LVEF). Cardiac resynchronization therapy (CRT) has also shown a beneficial effect in patients with heart failure (HF) and electrical/mechanical dyssynchrony. However, the relative contribution of BMMC and CRT in patients with ischemic HF and electromechanical dyssynchrony has never been investigated. The aim of this study was to evaluate the benefit of combining BMMC transplantation with CRT in patients with severe ischemic HF, left bundle branch block (LBBB), and mechanical dyssynchrony. Patients with ischemic HF, LVEF < 35%, LBBB, and mechanical dyssynchrony underwent intramyocardial transplantation of BMMC and CRTD system implantation. This randomized, single blind, crossover study compared clinical and echocardiographic parameters during two follow-up periods: 6 months of active CRT (BMMC + CRTact) and 6 months of inactive CRT (BMMC + CRTinact). Physical performance was assessed by means of a 6 min walking test. Myocardial perfusion was evaluated by SPECT. Quality of Life (QoL) was assessed through the Minnesota Living with HF Questionnaire (MLwHFQ). Twenty-six patients (64 +/- 7 years) were enrolled in the study. The distance covered by the patients during the 6-min walking test significantly increased in the BMMC + CRTinact phase (BMMC therapy only) in comparison with the baseline (269 +/- 68 vs 206 +/- 51; p = 0.007) and in the BMMC + CRTact phase (BMMC therapy + CRT) in comparison with the BMMC + CRTinact (378 +/- 59 vs 269 +/- 68; p < 0.001). The summed rest and stress score (SPECT) decreased significantly in the BMMC + CRTact and BMMC + CRTinact phases in comparison with the baseline (p <= 0.03). Both phases showed equivalent myocardial perfusion in the segments into which BMMC had been injected. QoL score was significantly lower in the BMMC + CRTinact phase than at the baseline (44.1 +/- 14 vs 64.8 +/- 19; p < 0.001), and in the BMMC + CRTact phase than in the BMMC + CRTinact phase (26.4 +/- 12 vs 44.1 +/- 14; p = 0.004). BMMC and CRT seem to act independently on myocardial perfusion and electromechanical dyssynchrony, respectively. Combining these two complementary therapies can significantly improve LV performance in patients with severe HF and electromechanical dyssynchrony. PMID- 21547599 TI - [Centrifugal plaques with central atrophy and peripheral scale on the scalp]. AB - A 62-year-old man presented with slowly progredient, centrifugal, peripherally hyperkeratotic, centrally atrophic, slightly pruritic lesions on his scalp for at least 9 months. A punch biopsy stained with hematoxylin-eosin (HE) revealed minimal epidermal acanthosis and chimney-like parakeratosis (cornoid lamella) around a follicle. Discrete spongiosis of the epidermis was observed, as well as a lymphocytic cell infiltration in the papillary dermis. Based on the clinical picture and the histopathological examination the diagnosis of porokeratosis of Mibelli was made. Topical treatment was started using an urea and vitamin A acid preparation. PMID- 21547600 TI - 18F-FDG PET/CT detects systemic involvement in sarcoidosis. PMID- 21547601 TI - Individualized quantification of brain beta-amyloid burden: results of a proof of mechanism phase 0 florbetaben PET trial in patients with Alzheimer's disease and healthy controls. AB - PURPOSE: Complementing clinical findings with those generated by biomarkers--such as beta-amyloid-targeted positron emission tomography (PET) imaging--has been proposed as a means of increasing overall accuracy in the diagnosis of Alzheimer's disease (AD). Florbetaben ([(18)F]BAY 94-9172) is a novel beta amyloid PET tracer currently in global clinical development. We present the results of a proof of mechanism study in which the diagnostic efficacy, pharmacokinetics, safety and tolerability of florbetaben were assessed. The value of various quantitative parameters derived from the PET scans as potential surrogate markers of cognitive decline was also investigated. METHODS: Ten patients with mild-moderate probable AD (DSM-IV and NINCDS-ADRDA criteria) and ten age-matched (>= 55 years) healthy controls (HCs) were administered a single dose of 300 MBq florbetaben, which contained a tracer mass dose of < 5 MUg. The 70-90 min post-injection brain PET data were visually analysed by three blinded experts. Quantitative assessment was also performed via MRI-based, anatomical sampling of predefined volumes of interest (VOI) and subsequent calculation of standardized uptake value (SUV) ratios (SUVRs, cerebellar cortex as reference region). Furthermore, single-case, voxelwise analysis was used to calculate individual "whole brain beta-amyloid load". RESULTS: Visual analysis of the PET data revealed nine of the ten AD, but only one of the ten HC brains to be beta amyloid positive (p = 0.001), with high inter-reader agreement (weighted kappa >= 0.88). When compared to HCs, the neocortical SUVRs were significantly higher in the ADs (with descending order of effect size) in frontal cortex, lateral temporal cortex, occipital cortex, anterior and posterior cingulate cortices, and parietal cortex (p = 0.003-0.010). Voxel-based group comparison confirmed these differences. Amongst the PET-derived parameters, the Statistical Parametric Mapping-based whole brain beta-amyloid load yielded the closest correlation with the Mini-Mental State Examination scores (r = -0.736, p < 0.001), following a nonlinear regression curve. No serious adverse events or other safety concerns were seen. CONCLUSION: These results indicate florbetaben to be a safe and efficacious beta-amyloid-targeted tracer with favourable brain kinetics. Subjects with AD could be easily differentiated from HCs by both visual and quantitative assessment of the PET data. The operator-independent, voxel-based analysis yielded whole brain beta-amyloid load which appeared valuable as a surrogate marker of disease severity. PMID- 21547602 TI - Evaluation of matrix-assisted laser desorption/ionisation time-of-flight (MALDI TOF) mass spectrometry for identification of Candida parapsilosis, C. orthopsilosis and C. metapsilosis. AB - We have evaluated matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry for the rapid identification of Candida parapsilosis, C. orthopsilosis and C. metapsilosis. A total of 103 isolates, including reference strains and clinical isolates, were identified by pyrosequencing of the ITS1 region and then assay by MALDI-TOF mass spectrometry. Concordance between the two methods was 100%, showing that MALDI-TOF may be useful as a rapid and reliable method for discrimination of species within the C. parapsilosis group. PMID- 21547603 TI - Postoperative voiding function in patients undergoing tension-free vaginal mesh procedure for pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: We compared pre- and postoperative voiding function in patients with POP and assessed the efficacy of urodynamic studies in these cases. METHODS: Forty-six patients treated with the tension-free vaginal mesh (TVM) procedure between January 2009 and February 2010 underwent pressure flow study pre- and postoperatively. Pre- and postoperative voiding functions were assessed according to Schafer nomograms. RESULTS: The mean postoperative detrusor pressure at maximal flow was decreased significantly compared with that preoperatively. The mean maximum flow rate was also improved significantly and the proportion of normal contractility was increased significantly after the operation, as was the proportion of non-obstructive patients. CONCLUSIONS: The TVM procedure for pelvic organ prolapse improved both detrusor contractility and urethral obstruction. PMID- 21547604 TI - Semantic context effects in the comprehension of reduced pronunciation variants. AB - Listeners require context to understand the highly reduced words that occur in casual speech. The present study reports four auditory lexical decision experiments in which the role of semantic context in the comprehension of reduced versus unreduced speech was investigated. Experiments 1 and 2 showed semantic priming for combinations of unreduced, but not reduced, primes and low-frequency targets. In Experiment 3, we crossed the reduction of the prime with the reduction of the target. Results showed no semantic priming from reduced primes, regardless of the reduction of the targets. Finally, Experiment 4 showed that reduced and unreduced primes facilitate upcoming low-frequency related words equally if the interstimulus interval is extended. These results suggest that semantically related words need more time to be recognized after reduced primes, but once reduced primes have been fully (semantically) processed, these primes can facilitate the recognition of upcoming words as well as do unreduced primes. PMID- 21547605 TI - "If only" counterfactual thoughts about exceptional actions. AB - People create counterfactual alternatives that change an exceptional action to be like a usual one (e.g., "if he had placed his usual small bet he would have lost less"), as shown in Experiment 1. Experiments 2 and 3 eliminated and reversed this well-known effect: An exceptional action is instead changed to an exceptional alternative when it leads to a better outcome. Experiments 4 and 5 show that the reversal occurs whether or not the exceptional alternative is a justified action. The results indicate that the tendency to change an exceptional action to be like a usual one is guided by the optimality of the counterfactual outcome more than the exceptionality or justifiability of the action. The implications for theories of the counterfactual imagination are discussed. PMID- 21547606 TI - Association between psychological complaints and recurrence of vasovagal syncope. AB - PURPOSE: Vasovagal syncope (VVS), the most common cause of transient loss of consciousness (T-LOC), is often accompanied by higher levels of psychological distress. We investigated to what extent psychological complaints interact with the effects of non-pharmacological treatment in patients with frequently recurring VVS. METHODS: Patients with >=3 episodes of VVS in the 2 years prior to the start of the study openly received non-pharmacological treatment. Before treatment initiation, we determined the level of general psychological complaints by the Symptom Checklist 90-R (SCL-90-R) questionnaire. We regularly evaluated syncopal recurrence during follow-up. We compared the SCL-90-R scores of VVS patients in our study with the corresponding scores of healthy Dutch subjects (reference population). We examined whether patients with more recurrences during follow-up had higher SCL-90-R scores at baseline and whether this association changed when adjusting for other factors associated with recurrence using logistic regression. RESULTS: Total SCL-90-R scores were higher in our cohort of patients with frequent episodes of VVS than in the reference population (142 vs. 118; p < 0.001). During the first 6 months of treatment, 42% of patients experienced syncopal recurrence(s). The SCL-90-R scores of these patients were significantly higher compared with patients without syncopal recurrence in this period (160 vs. 130; p = 0.01). After adjusting for other predictors of recurrence, especially the number of episodes before inclusion, the association between SCL-90-R scores and recurrence remained intact. CONCLUSIONS: Levels of general psychological complaints are higher in patients with syncopal recurrence during non-pharmacological treatment of VVS, even after adjusting for previous syncopal episodes. PMID- 21547607 TI - Respiratory vulnerability to vehicle buffeting. AB - OBJECTIVE: Buffeting in a jerky ride in a bus or ambulance normally provokes a sustained tachypnoea driven by vibration and sensory mechanisms including vestibular signals. Tachypnoea reinforces the torso against mechanical shocks but results in overbreathing, causing a mild fall in CO(2). However, normal CO(2) is rapidly restored by a reduction in depth of breathing. We test the hypothesis that vulnerable subjects, exemplified by elderly individuals and patients with vestibular disorders, may fail to adapt to buffeting. METHODS: Respiratory and cardiovascular functions were recorded from five elderly subjects, two patients with bilateral loss of vestibular function and five patients with 'BPPV,' while being exposed to 15-min buffeting in a flight simulator which simulated transport in an ambulance over rough pavement. Results were compared with published norms. RESULTS: Some subjects sustained overbreathing during motion, through either tachypnoea or deep breathing, causing a marked reduction in CO(2) levels (3/5, 2/2 avestibular, 4/5 elderly, 4/5 BPPV). Others failed to raise breathing frequency which would render them susceptible to mechanical shock (4/5 elderly, 1/2 avestibular). Overbreathing was particularly evident in three anxious subjects. INTERPRETATION: Overbreathing during buffeting could be caused by (1) resetting of CO(2) rest levels lower; (2) change in receptor sensitivity; (3) adjustment of central drive to breathing; and (4) stiffening of posture because of motion discomfort reduced the ability to modulate breathing. The buffeting experienced was moderately violent. More profound hypocapnia and mechanical shock are likely to result in vulnerable individuals failing to adapt to severe buffeting in transport on unpaved roads, in war zones or by sea ambulance. PMID- 21547608 TI - Inspiratory muscle weakness and autonomic cardiovascular dysfunction in type 2 diabetes mellitus. PMID- 21547609 TI - Polyomavirus JC reactivation and noncoding control region sequence analysis in pediatric Crohn's disease patients treated with infliximab. AB - The recent introduction of monoclonal antibodies in Crohn's disease (CD) management has been associated with the development of serious complications, such as the progressive multifocal leukoencephalopathy (PML), caused by JC polyomavirus (JCV) reactivation. Therefore, the aims of our study have been the investigation of the possible JCV reactivation in pediatric CD patients treated or not with infliximab, performing quantitative PCR in urine, plasma, and intestinal biopsies at the time of recruitment (t0) and every 4 months in 1 year of follow-up (t1, t2, and t3), and the analysis of the JCV noncoding control region (NCCR) to detect cellular transcription factors binding site mutations. Results obtained showed that, in urine and ileal specimens, JCV load significantly increased in infliximab-treated patients after 1 year of treatment (t3), while viremia was significantly higher at t1. JCV NCCR sequence analysis showed a structure similar to CY archetype in 65/80 analyzed sequences, but the remaining 15/80, obtained exclusively from plasma and biopsies, evidenced a CY NCCR organization with two recurrent nucleotide changes, the 37-T to G transversion in box A Spi-B binding site and the 217-G to A transition in box F, and a box D deletion. These rearrangements were always found at t3 within seven infliximab-treated CD patients, who presented a very severe disease at t0. We can conclude that our rearranged NCCR sequences could be considered a marker of JCV virulence during mAb treatment, although none of our examined patients developed PML, and further studies on a larger cohort of patients should be performed. PMID- 21547610 TI - Patient-reported racial/ethnic healthcare provider discrimination and medication intensification in the Diabetes Study of Northern California (DISTANCE). AB - BACKGROUND: Racial/ethnic minority patients are more likely to report experiences with discrimination in the healthcare setting, potentially leading to reduced access to appropriate care; however, few studies evaluate reports of discrimination with objectively measured quality of care indicators. OBJECTIVE: To evaluate whether patient-reported racial/ethnic discrimination by healthcare providers was associated with evidence of poorer quality care measured by medication intensification. RESEARCH DESIGN AND PARTICIPANTS: Baseline data from the Diabetes Study of Northern California (DISTANCE), a random, race-stratified sample from the Kaiser Permanente Diabetes Registry from 2005-2006, including both survey and medical record data. MAIN MEASURES: Self-reported healthcare provider discrimination (from survey data) and medication intensification (from electronic prescription records) for poorly controlled diabetes patients (A1c >=9.0%; systolic BP >=140 mmHg or diastolic BP >=90 mmHg; low-density lipoprotein (LDL) >=130 mg/dl). KEY RESULTS: Of 10,409 eligible patients, 21% had hyperglycemia, 14% had hyperlipidemia, and 32% had hypertension. Of those with hyperglycemia, 59% had their medications intensified, along with 40% with hyperlipidemia, 33% with hypertension, and 47% in poor control of any risk factor. In adjusted log-binomial GEE models, discrimination was not associated with medication intensification [RR = 0.96 (95% CI: 0.74, 1.24) for hyperglycemia, RR = 1.23 (95% CI: 0.93, 1.63) for hyperlipidemia, RR = 1.06 (95% CI: 0.69, 1.61) for hypertension, and RR = 1.08 (95% CI: 0.88, 1.33) for the composite cohort]. CONCLUSIONS: We found no evidence that patient-reported healthcare discrimination was associated with less medication intensification. While not associated with this technical aspect of care, discrimination could still be associated with other aspects of care (e.g., patient-centeredness, communication). PMID- 21547611 TI - Involvement of energetic metabolism in the effects of ischemic postconditioning on the ischemic-reperfused heart of fed and fasted rats. AB - The effects of ischemic-postconditioning (IPOC) on functional recovery and cell viability of ischemic-reperfused hearts from fed and fasted rats were studied in relation to triacylglycerol and glycogen mobilization, ATP content, glucose-6 phosphate dehydrogenase activity and reduced/oxidized glutathione (GSH/GSSG). Oxidative damage was estimated by measuring thiobarbituric acid reactive substances (TBARS). IPOC improved contractile recovery and cell viability in the fed but attenuated them in the fasted hearts. In both groups ischemia lowered glycogen. IPOC further reduced it. Triacylglycerol remained unchanged during ischemia-reperfusion in both groups, but triacylglycerol mobilization was activated by IPOC in the fasted group. ATP was increased by IPOC in the fed hearts, but lowered in the fasted ones, which appeared to be associated with the rates of ATP synthesis in isolated mitochondria. In the fed hearts IPOC raised glucose-6-phosphate dehydrogenase activity and GSH/GSSG, and lowered TBARS. These results suggest that IPOC effects are associated with changes in the ATP supply, mobilization of energy sources and glutathione antioxidant ratio. PMID- 21547612 TI - Influence of religious factors on attitudes towards suicidal behaviour in Ghana. AB - The objective of this qualitative study was to understand how religion influences lay persons' attitudes towards suicide in Ghana. Twenty-seven adults from both rural and urban settings were interviewed. Interpretative phenomenological analysis was used to analyse the data. Results showed that the participants are committed to core and normative religious beliefs and practices they perceived as life preserving. Such an understanding influenced their view of suicidal behaviour as unacceptable. Nevertheless, religion facilitated their willingness to help people during suicidal crisis. Religious commitment theory is used to explain some of the findings of this study. Implications for suicide prevention are discussed. PMID- 21547613 TI - 3 Tesla MR neurography--technique, interpretation, and pitfalls. AB - MRI has been used for almost two decades for the evaluation of peripheral nerve disorders. This article highlights the relative advantages and disadvantages of 3T MR neurography in the evaluation of peripheral neuropathies. The authors also describe the high-resolution MR neurography technique on 3T MRI, along with the approach to its interpretation that has evolved at one institution. PMID- 21547614 TI - Dental caries experience in relation to salivary findings and molecular identification of S. mutans and S. sobrinus in subjects with Down syndrome. AB - This study investigated the association between clinical and salivary or molecular parameters in Down syndrome subjects. Sixty individuals (1- to 48-year old) were clinically examined using DMFT/DMFS. Stimulated saliva was collected; salivary flow was calculated (mL/min), buffering capacity was measured using a standard pH tape. In addition, 25 MUL of saliva was diluted using 10-fold dilution method and then placed on Mitis-Salivarius-Bacitracin agar to count colony forming units (CFU/mL) of mutans streptococci. Polymerase chain reaction analysis identified species. Caries indexes were 0.65-13.5 (DMFT) and 0.65-26.0 (DMFS) according to groups. Ninety-four percent of subjects had low flow rate (0.7-1.0 mL/min) and 44% had low buffering capacity (pH < 4). Besides, 60% had more than 1 * 10(6) CFU/mL, 60% had S. mutans, and 41.4% had S. sobrinus. Caries indexes did not significantly correlate with flow rate, buffering capacity, CFU/mL by Pearson's correlation (p > 0.05), and showed no significant association with prevalence of species by Chi-square (p > 0.05). There is no association between clinical picture and salivary or molecular parameters in Down syndrome subjects. PMID- 21547616 TI - Control of multistability in ring circuits of oscillators. AB - The essential dynamics of some biological central pattern generators (CPGs) can be captured by a model consisting of N neurons connected in a ring. These circuits, like many oscillatory nonlinear circuits of sufficient complexity, are capable of multistability, that is, of generating different firing patterns distinguished by the phasic relationships between the firing in each circuit element (neuron). Moreover, a shift in firing pattern can be induced by a transient perturbation. A systematic approach, based on phase-response curve (PRC) theory, was used to determine the optimum timing for perturbations that induce a shift in the firing pattern. The first step was to visualize the solution space of the ring circuit, including the attractive basins for each stable firing pattern; this was possible using the relative phase of N-1 oscillators, with respect to an arbitrarily selected reference oscillator, as coordinate axes. The trajectories in this phase space were determined using an iterative mapping based only on the PRCs of the uncoupled component oscillators; this algorithm was called a circuit emulator. For an accurate mapping of the attractive basin of each pattern exhibited by the ring circuit, the emulator had to take into account the effect of a perturbation or input on the timing of two bursts following the onset of the perturbation, rather than just one. The visualization of the attractive basins for rings of two, three, and four oscillators enabled the accurate prediction of the amounts of phase resetting applied to up to N-1 oscillators within a cycle that would induce a transition from any pattern to any another pattern. Finally, the timing and synaptic characterization of an input called the switch signal was adjusted to produce the desired amount of phase resetting. PMID- 21547615 TI - Rituximab for prevention and treatment of graft-versus-host disease. AB - Growing understanding of the important role of B lymphocytes in alloreactivity has paved the way for evaluating anti-B cell therapy with rituximab in patients undergoing allogeneic hematopoietic cell transplantation. Data suggesting a beneficial reduction in incidence and severity of acute graft-versus-host disease (GVHD) are limited to non-randomized studies from single institutions using higher than conventional doses of rituximab. Additionally, rituximab is used as an effective treatment of corticosteroid-refractory chronic GVHD with good responses, particularly in cases of dermatologic and mucosal involvement. Post transplant administration of rituximab appears to reduce the rate of chronic GVHD in preliminary studies. PMID- 21547618 TI - Cover essay. PMID- 21547619 TI - Foreword for inaugural issue of Journal of Neurodevelopmental Disorders. PMID- 21547621 TI - Visuospatial working memory in children and adolescents with 22q11.2 deletion syndrome; an fMRI study. AB - 22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with a microdeletion of chromosome 22q11. In addition to high rates of neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder, children with 22q11DS have a specific neuropsychological profile with particular deficits in visuospatial and working memory. However, the neurobiological substrate underlying these deficits is poorly understood. We investigated brain function during a visuospatial working memory (SWM) task in eight children with 22q11DS and 13 healthy controls, using fMRI. Both groups showed task-related activation in dorsolateral prefrontal cortex (DLPFC) and bilateral parietal association cortices. Controls activated parietal and occipital regions significantly more than those with 22q11DS but there was no significant between group difference in DLPFC. In addition, while controls had a significant age related increase in the activation of posterior brain regions and an age-related decrease in anterior regions, the 22q11DS children showed the opposite pattern. Genetically determined differences in the development of specific brain systems may underpin the cognitive deficits in 22q11DS, and may contribute to the later development of neuropsychiatric disorders. PMID- 21547620 TI - Deficient maternal care resulting from immunological stress during pregnancy is associated with a sex-dependent enhancement of conditioned fear in the offspring. AB - Activation of maternal stress response systems during pregnancy has been associated with altered postpartum maternal care and subsequent abnormalities in the offspring's brain and behavioral development. It remains unknown, however, whether similar effects may be induced by exposure to immunological stress during pregnancy. The present study was designed to address this issue in a mouse model of prenatal immune activation by the viral mimic polyriboinosinic polyribocytidilic acid (PolyI:C). Pregnant mice were exposed to PolyI:C-induced immune challenge or sham treatment, and offspring born to PolyI:C- and sham treated dams were simultaneously cross-fostered to surrogate rearing mothers, which had either experienced inflammatory or vehicle treatment during pregnancy. We evaluated the effects of the maternal immunological manipulation on postpartum maternal behavior, and we assessed the prenatal and postnatal maternal influences on anxiety- and fear-related behavior in the offspring at the peri-adolescent and adult stage of development. We found that PolyI:C treatment during pregnancy led to changes in postpartum maternal behavior in the form of reduced pup licking/grooming and increased nest building activity. Furthermore, the adoption of neonates by surrogate rearing mothers, which had experienced PolyI:C-induced immunological stress during pregnancy, led to enhanced conditioned fear in the peri-adolescent and adult offspring, an effect that was exclusively seen in female but not male subjects. Unconditioned (innate) anxiety-related behavior as assessed in the elevated plus maze and open field explorations tests were not affected by the prenatal and postnatal manipulations. Our results thus highlight that being raised by gestationally immune-challenged surrogate mothers increases the vulnerability for specific forms of fear-related behavioral pathology in later life, and that this association may be mediated by deficits in postpartum maternal care. This may have important implications for the identification and characterization of early-life risk factors involved in the developmental etiology of fear-related neuropsychiatric disorders. PMID- 21547622 TI - Functional magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders. AB - A comprehensive neuropsychological/psychiatric, MR imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified, and distinguish diagnostic subclassifications across the spectrum. The four study groups included: 1. FAS/Partial FAS; 2. Static Encephalopathy/Alcohol Exposed (SE/AE); 3. Neurobehavioral Disorder/Alcohol Exposed (ND/AE); and 4. healthy peers with no prenatal alcohol exposure. fMRI outcomes are reported here. The neuropsychological/psychiatric, MRI, and MRS outcomes are reported separately. fMRI was used to assess activation in seven brain regions during performance of N back working memory tasks. Children across the full spectrum of FASD exhibited significant working memory deficits and altered activation patterns in brain regions that are known to be involved in working memory. These results demonstrate the potential research and diagnostic value of this non-invasive MR tool in the field of FASD. PMID- 21547623 TI - Recent status of gelatin-resorcin-formalin glue for acute type A aortic dissection. PMID- 21547624 TI - Surgical left ventricular reconstruction. AB - Because of the shortage of donors for heart transplantation, surgical ventricular reconstruction (SVR) has been under development to treat end-stage heart failure due to a dilated left ventricle. The operative procedures have been developed and modified based on the clinical results and preoperative findings of several examinations. SVR is performed to reduce the size and volume of the ventricle as well as to reshape it. The procedures, which differ based on the particular left ventricular lesion, are endoventricular patch plasty or septal anterior ventricular restoration for anteroseptal exclusion and partial left ventriculectomy or a posterior restoration procedure for posterolateral exclusion. In the indicated patients, SVR has been emerging as an alternative to heart transplantation. The accumulating surgical knowledge may provide new opportunities for the treatment of ischemic dilated cardiomyopathy. The Surgical Treatment for Ischemic Heart Failure (STICH) trial seems to have arrived at a misguided conclusion. Surgeons have to know not only the operative procedures for SVR; they must also be aware of the systolic and diastolic functioning and the volume and size of the left ventricle before and after SVR. Hence, SVR is reviewed and discussed here. PMID- 21547625 TI - In vitro study of the optimum volume ratio of activator to adhesive in gelatin resorcin-formalin glue. AB - OBJECTIVE: Excessive use of activator (formaldehyde + glutaraldehyde) may cause late complications after use of gelatin-resorcin-formalin (GRF) glue during surgery. The goal of the study was to define the appropriate ratio of activator to adhesive and to establish an approach for accurate control of this ratio. METHODS: The relation between adhesive force and the activator/adhesive ratio was studied by attaching two sheets of equine pericardium using GRF glue, with ratios from 1: 50 to 1: 2. The amount of activator was measured per drip from the needle in the GRF glue kit and other needles (27, 25, 23, 22, and 21 gauge). RESULTS: The adhesive force was about 400 gram-weight (gw) for activator/adhesive ratios from 1: 50 to 1: 20. This force showed a significant increase to 1317 +/- 462 gw for a ratio of 1: 10 compared to the force at a ratio 1: 20 (P = 0.0069) but did not increase significantly for ratios above 1: 10. The activator volume was 12.5 MUl in one drip from the needle in the GRF glue kit and 4.3 MUl in one drip from the 27-gauge needle. Therefore, the 27-gauge needle is suitable for measuring the activator volume. CONCLUSION: In vitro, an activator at a ratio of one-tenth the volume of the adhesive provides approximately maximum force; any more activator is residual and potentially harmful. Measurement of the activator volume using a 27-gauge needle and the adhesive volume using a syringe is recommended to control the ratio accurately. PMID- 21547626 TI - Early entry closure for acute type B aortic dissection by open stent grafting. AB - PURPOSE: We describe the long-term efficacy of early entry closure for acute type B aortic dissection by open stent grafting based on long-term results and changes in the false lumen on enhanced computed tomography (CT). METHODS: We performed open stent grafting for acute type B aortic dissection in 28 28 patients between 1998 a 2008. They included 14 patients with complicated type B aortic dissection (11 patients with limb and/or visceral ischemia and 4 patients with impending rupture). Uncomplicated type B aortic dissection was present in 14 patients, including 4 patients with an ulcer-like projection and 10 patients who had stable dissection with a patent false lumen. RESULTS: Two patients who had the ischemic type died within 30 days. Postoperative complications occurred in two patients, including one case of paraplegia and one of mediastinitis. Two more deaths occurred during a median follow-up period of 45 months (range 6-114 months), with one related to open stent-graft infection and one due to pneumonia. The overall survival rate 5 years after open stent grafting was 77%. According to follow-up by CT, the false lumen was completely thrombosed and obliterated in all 26 patients with stent grafts. CONCLUSION: Early entry closure for both complicated and uncomplicated acute type B aortic dissection with an open stent graft has an acceptable early outcome and provides a high aortic remodeling rate. PMID- 21547627 TI - Increase in preoperative serum reactive oxygen metabolite levels indicates nodal extension in patients with clinical stage I lung adenocarcinoma. AB - PURPOSE: Reactive oxygen species contribute to various features of malignant tumors, including carcinogenesis, aberrant growth, metastasis, and angiogenesis. Investigation of serum oxidative stress levels may predict the tumor's condition, including malignant and metastatic potential. METHODS: We recruited 46 patients (27 men, 19 women; median age 70 years) with clinical stage I lung adenocarcinoma who had undergone pulmonary resection with mediastinal lymph node dissection. Preoperative serum reactive oxygen metabolite (ROM) levels were measured as an indicator of oxidative stress. RESULTS: The serum ROM level was significantly correlated with the increase in tumor size (P = 0.018) and pathological nodal extension (P = 0.005). Multivariate analysis revealed that pathological nodal extension was significantly correlated with the increase in serum ROM level (P = 0.027). The prognostic cutoff value was determined according to receiver operating characteristic curve analysis for patients with and those without nodal extension; the cutoff value was determined to be 318 Carratelli units (U.CARR). CONCLUSION: The findings of our study revealed that patients with clinical stage I lung adenocarcinoma and a serum ROM level above 318 U.CARR were likely to develop nodal extension. The finding of a significant correlation between serum ROM level and nodal extension may help in the development of new treatment strategies. PMID- 21547628 TI - Cardiac surgery for annuloaortic ectasia and mitral regurgitation in an adult patient with dextrocardia. AB - We report a surgical case of dextrocardia complicated with annuloaortic ectasia (AAE) and mitral regurgitation, which induced congestive heart failure. Preoperative electrocardiography-gated multidetector-row computed tomography (MDCT) showed the following complex cardiovascular abnormalities without motion artifacts: dextrocardia, situs inversus, polysplenia, AAE, absence of the inferior vena cava, azygos vein continuation, drainage of the hepatic vein into the right atrium, and bilateral superior venae cavae. On the basis of the MDCT data, we established a cardiopulmonary bypass; and a modified Bentall procedure (Piehler method) and mitral valve replacement were performed without complications. PMID- 21547629 TI - Successful operation for mitral regurgitation in a patient with Gilbert's syndrome. AB - A 72-year-old woman complaining of dyspnea on effort was diagnosed as having mitral regurgitation (MR). Asymptomatic jaundice had initially been noticed during primary school, and an examination had shown hyperbilirubinemia. After the diagnosis of constitutional jaundice, she had remained well without further examination or medical treatment. Laboratory data showed a total serum bilirubin (TB) level of 12.2 mg/dl and a direct bilirubin level of 0.6 mg/dl. Transesophageal echocardiography showed severe MR, and we replaced the mitral valve. Postoperatively, genetic analyses identified constitutional jaundice as Gilbert's syndrome with Y486D mutation. The TB level gradually decreased. Four years after operation she is doing well with moderate hyperbilirubinemia and a TB level of 5 mg/dl. She is free from heart failure. PMID- 21547630 TI - Acute early failure of a bioprosthesis after mitral valve replacement with completely preserved annuloventricular continuity. AB - We report a case of acute early bioprosthetic failure after mitral valve replacement with completely preserved annuloventricular continuity. A 77-year-old man with left ventricular dysfunction underwent double valve replacement with Carpentier-Edwards pericardial bioprostheses. Routine postoperative echocardiography revealed 1.4 cm(2) of estimated mitral valve area, and computed tomography revealed a large thrombus in the left atrium. Transesophageal echocardiography showed a restricted opening of the bioprosthetic leaflets. After a month of strict anticoagulation therapy, cusp mobility improved, with a calculated mitral valve area of 3.5 cm(2); and the left atrial thrombus had almost disappeared 2 months after initiation of therapeutic anticoagulation. Surgeons should be watchful for bioprosthetic thrombosis in patients with left ventricular dysfunction who undergo mitral valve replacement with a preserved mitral subvalvular apparatus. PMID- 21547631 TI - St. Jude prosthetic valve obstruction in the mitral position. AB - We report a surgical case of prosthetic valve obstruction after mitral valve replacement by a St. Jude Medical valve. A 66-year-old woman was admitted because of congestive heart failure. Prosthetic valve obstruction was diagnosed by transthoracic echocardiography and cine-fluoroscopy. Re-do cardiac surgery was indicated after a week of heparinization. Circumferential pannus formation into the orifice beyond the pivot guard of the prosthesis on the atrial side and one piece of the leaflet was covered with a fibrous overgrowth on the atrial side. We concluded that once the diagnosis of valve thrombosis is established, urgent operation is preferred in patients with hemodynamic instability before the development of cardiogenic shock or multiple organ failure. PMID- 21547632 TI - Hypertrophic cardiomyopathy with apical aneurysm: left ventricular reconstruction and cryoablation for ventricular tachycardia. AB - This is a case study of a 58-year-old patient with hypertrophic cardiomyopathy, mid-ventricular obstruction, and apical aneurysm who had an episode of syncope due to ventricular tachycardia. Cardiovascular magnetic resonance imaging revealed asymmetrical left ventricular hypertrophy with mid-ventricular obstruction and an apical aneurysm. His coronary angiography was normal, and his ventricular tachycardia was induced by hypertrophic cardiomyopathy without ischemia. Apical aneurysmectomy, left ventricular reconstruction, and cryoablation at the rim of the aneurysm were performed. Fifteen days after the operation, an automatic implantable cardioverter-defibrillator was implanted. The postoperative course was uneventful, and ventricular tachyarrhythmia did not recur during 18 months of follow-up. PMID- 21547633 TI - Reconstruction of nonconfluent pulmonary artery using the retroaortic innominate vein for a single ventricle. AB - The innominate vein usually courses anterior to the aortic arch, where it joins the right brachiocephalic vein to form the superior caval vein. A retroaortic innominate vein is an uncommon finding in patients with congenital heart disease. We report a patient with a single ventricle, single atrium, pulmonary atresia, nonconfluent pulmonary artery, persistent left superior caval vein, absent inferior caval vein (azygos connection), right aortic arch, and retroaortic innominate vein. His innominate vein took an anomalous course. The right brachiocephalic vein crossed from right to left underneath the aortic arch and formed a left superior caval vein with the left brachiocephalic vein and the azygos vein. We reconstructed the nonconfluent pulmonary artery using the retroaortic innominate vein and then performed a total cavopulmonary shunt when he was 32 months of age. Thereafter, a total cavopulmonary connection was carried out at age 42 months. PMID- 21547634 TI - Parietal pleura lipoma: a rare intrathoracic tumor. AB - Lipoma is a common benign tumor of soft tissues in adults. An intrathoracic location, particularly in the parietal pleura, is rare. We report two cases of pleural parietal lipoma with a review of literature. A preoperative diagnosis was established histologically by fine-needle aspiration in the first case and radiologically by computed tomography scan in the second. Both patients underwent surgical excision via thoracotomy and video-assisted thoracic surgery. Pathology examination confirmed the diagnosis of lipoma. The authors emphasize the necessity of surgical resection because of preoperative diagnostic difficulty of discerning lipoma from well-differentiated liposarcoma. PMID- 21547635 TI - Intrathoracic rupture of an extraskeletal myxoid chondrosarcoma. AB - Extraskeletal myxoid chondrosarcoma (EMC) is typically a slow-growing tumor with a prolonged clinical course. We describe a case of EMC that was complicated by intrathoracic rupture of the tumor and took an aggressive clinical course. A 64 year-old man with a precordial tumor suddenly began suffering from acute chest pain. Radiographic examination revealed a massive pleural effusion. Emergency surgery was performed but resulted in rupture of the pleural side of the tumor. The tumor was resected with the chest wall. The patient died 16 months after surgery owing to abdominal wall recurrence. PMID- 21547636 TI - Pulmonary mucosa-associated lymphoid tissue lymphoma with a pulmonary arteriovenous fistula. AB - We report an extremely rare case of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma with a pulmonary arteriovenous fistula (PAVF). A 60-year-old woman with vulvar carcinoma was admitted to our hospital for further examination of an abnormal shadow on chest computed tomography (CT). She showed hypoxemia in the arterial blood gas analysis. (18)F-Fluorodeoxyglucose positron emission tomography (FDG-PET) showed consolidations in the left lower lobe and soft-tissue density lesions in the anterior mediastinum. Each lesion showed heterogeneous FDG uptake. Although needle biopsy of these lesions was performed, a pathological diagnosis was not obtained. For the evaluation of hypoxemia, chest contrast enhanced CT was performed, and a PAVF in the consolidation of the left lower lobe was revealed. For diagnostic and therapeutic purposes, we performed left lower lobectomy under video-assisted thoracoscopic surgery. In the surgical specimen the PAVF measured 3 cm, and histopathological examination revealed pulmonary MALT lymphoma adjacent to the PAVF. PMID- 21547637 TI - Three-dimensional computed tomography for lung cancer in a patient with three right vein ostia. AB - Some variations in pulmonary vein anatomy can have serious consequences in patients undergoing lung surgery, but clinicians rarely encounter patients with these variations. We report here a thoracoscopic lobectomy for right lung cancer in a patient with three right vein ostia. Preoperative review of three dimensional 64-row multidetector computed tomography (3D-MDCT) of the patient showed a variation that was not confirmed in transverse plane computed tomography films. However, the variant anomaly was confirmed during thoracoscopic right lower lobectomy. The postoperative course was uneventful, and the patient was discharged on postoperative day 10. Preoperative 3D-MDCT of the pulmonary vein produced a precise preoperative simulation for the surgeon and clearly showed the orientation of the patient's vascular variant during surgery. This imaging technology contributes to safer thoracic surgery, especially thoracoscopic surgery. PMID- 21547638 TI - Use of contrast-enhanced computed tomography for management of a late-onset spontaneous massive chest wall hematoma. AB - This is a rare case of a 68-year-old woman who was rehospitalized after uneventful redo double-valve surgery. An 8.3 * 12.9 * 16.4 cm tense right chest wall hematoma was diagnosed. This was precipitated by a single cough. Contrast enhanced computed tomography revealed a bleeding source. Hematoma evacuation and hemostasis following emergency warfarin reversal produced an excellent outcome. PMID- 21547639 TI - Non-small-cell lung cancer: unusual presentation in the gluteal muscle. AB - Lung cancer is one of the most commonly diagnosed cancers in both men and women worldwide. It is also one of the most common forms of cancer in Ireland, accounting for about 20% of all deaths from cancer each year. Early detection of lung cancer is infrequent, and most cases are not diagnosed and treated until they are at an advanced stage. Distant metastases in lung cancer commonly involve the adrenal glands, liver, bones, and central nervous system; they are only rarely seen in the skeletal system. We report a rare case of metastasis to the gluteal muscle as the initial presentation of lung cancer. PMID- 21547640 TI - Rosai-Dorfman disease mimicking mediastinal lymphoma. AB - Rosai-Dorfman disease is rare and typically presents with cervical lymphadenopathy. The disease is generally indolent and self-limited, but it carries a poor or fatal prognosis when it is advanced or when it involves and compresses vital structures. We herein report a rare case of Rosai-Dorfman disease affecting only the mediastinal-hilar region in a 66-year-old woman. PMID- 21547641 TI - [The therapy of obesity in children and adolescents : An insufficiently researched area?]. PMID- 21547642 TI - [Is it possible to treat obesity in children and adolescents?]. AB - The question of whether or not treatment of obesity in children and adolescents is possible, feasible, or effective cannot be answered at the present time. Obesity is the most common chronic disorder in the industrialized societies. Its impact on individual lives as well as on health economics has to be recognized by physicians and the public alike: obesity at a young age is a major burden for the economy. Huge sums of money are thought to be spent on diet foods, products, and programs to lose weight. Treatments aim to reduce weight and as a consequence cardiovascular risks and other comorbidities. By doing so, economic costs could also substantially be reduced. In addition and most importantly, for the individual the impact of a given treatment on quality of life and social participation might be even more important than the medical benefit as such: especially since children and adolescents very often cannot estimate the medical burden of long-term sequelae of their obesity. Apart from individual therapies, interventions on a population base might be more cost effective and more important. However, the effectiveness of such interventions should also be assessed prospectively and continuously. PMID- 21547643 TI - [Dietary interventions and social care for treating obesity in children]. AB - The prevalence of obesity and associated comorbidities among children and adolescents has risen worldwide throughout the past 3 decades. To break this trend, population-based activities in health promotion/prevention and health care are necessary. Studies showed that long-term eating behavior improvement with the cooperation of the patient's family together with child-friendly organization support both individual therapeutic improvements as well as a relevant reduction of obesity prevalence. A significant BMI reduction can be achieved with a normal varied diet, whose energetic value is 300-400 kcal/day below the patient's daily energetic needs, due to the lower consumption of fat and sugar. This requires, however, that the entire family be willing to change their unhealthy eating behaviors (e.g., soft drinks and fast food) and to introduce regular meals into their daily routine. Sensibly, most therapies combine diet therapy with increased physical activity and parental training. Controlled media consumption, active leisure-time behavior, and a structured daily routine are further conditions for successful weight reduction. The high-risk groups for pediatric obesity, i.e., families with migration background and/or low socioeconomic status, have been poorly reached by established programs. PMID- 21547644 TI - [Therapy of juvenile obesity from the sports medicine/science viewpoint]. AB - Overweight and obesity in children and adolescents had reached its highest level worldwide. In the development of overweight and within interdisciplinary training programs, physical activity and the avoidance of sedentary habits play an important role. Not only is there an increase in energy consumption, but potential comorbidities (e.g., cardiovascular risk factors) are improved. In addition, positive psychosocial benefits occur, e.g., increasing self-esteem, personal, and social skills. During realization, possible risks (e.g., exercise induced asthma) and barriers have to be taken into account. In terms of physical activity programs, the child's surroundings have to be integrated, and transfer into daily routine should be promoted. Therefore, in addition to athletic content, daily activities have to be trained and supported, e.g., via pedometers. At least 60, better 90 and more minutes of physical activity per day are recommended; the use of audiovisual media should be reduced to a minimum (max. 120 minutes). PMID- 21547645 TI - [Obesity in children and adolescents. Risks, causes, and therapy from a psychological perspective]. AB - The proportion of overweight and obese children and adolescents in Germany and Europe has increased dramatically since the 1990s. About a third of obese preschool children and half of obese school children will become obese adults; the economic, medical, and psychosocial consequences are substantial. This article presents an overview of psychological risk factors and causes of obesity in children and adolescents, including comorbidity with psychological disorders, stigmatization, and relationships with peers, family, and other environment factors, as well as interactions between genes and behavior. Understanding risk factors and causes for obesity is the basis for adequate psychological interventions. We provide an overview of psychological aspects of obesity, such as motivation and impulsivity, and present components of cognitive behavioral therapy and modalities of intervention. A better understanding of psychological factors is necessary to achieve more effective interventions and long-term success of behavior change. This also holds true for changes in the social, media, and physical environment structures with the goal of promoting healthy eating and physical activity. PMID- 21547646 TI - [Motivational interviewing in adolescent obesity treatment. Ensuring quality and preventing relapse]. AB - Group and individual counseling sessions play a key role in adolescent obesity treatment. The requirements of these training sessions are defined in national guidelines, e.g., the German "Adipositas-Konsensuspapier" (Obesity Consensus Paper). Literature research between 2005 and 2010 showed that the long-term effects of these sessions were low, based on five reviews considering obesity treatment and six reviews dealing with motivational interviewing (MI). The reviews underline high attrition and dropout rates associated with decreasing compliance. Individual requirements for resilient motivation and relapse prevention are described with the help of the transtheoretical model of behavioral change and the self-control model. By integrating MI into group and individual counseling sessions, behavioral change can be encouraged over the long term. The stages of change can be ascertained and coping strategies of three different risk situations can be established. MI seems to be helpful especially at the beginning and end of treatment, during the state of maintenance. PMID- 21547647 TI - [Psychological aspects of obesity. Consquences for content, indication, and success of therapy]. AB - To simply reduce obesity to the medical set of problems falls short due to the complexity of the disorder. The focus of the affected children and adolescents is less on acute and future somatic health impairments but on the psychosocial aspects of obesity. The high degree of stigmatization especially accounts for the psychosocial burdens of the persons concerned. Constraints in the quality of life and a higher prevalence of mental disorders are reported by overweight and obese children and adolescents. In the sense of a vicious psychosocial circle, these variables in turn influence our eating and exercise behavior and hence central influences of weight control actions. Therefore, complex multimodal programs, which take into account these relationships, have long since been established in therapy. Numerous studies have underscored the efficacy of such lifestyle interventions resulting in moderate weight loss effects. Parent involvement and including behavioral strategies is associated with better results. Future studies should focus more on various psychosocial outcomes and addressing the question of psychosocial predictors of short- and long-term treatment success. PMID- 21547648 TI - The development of pharmacological treatment of obesity in children. A European regulatory perspective. AB - Childhood obesity is recognized by the World Health Organization as one of the most serious public health challenges of the 21st century. Current treatment recommendations consider the role of pharmacotherapy in the treatment of childhood obesity, as an adjunct to lifestyle modifications. This article focuses on key requirements for paediatric development of medicines for obesity in Europe with reference to the European Medicines Agency guideline and a review of Paediatric Investigation Plans (PIP) submitted for this condition, under Regulation (EC) No. 1901/2006 on medicines for paediatric use. To date the European Medicines Agency (EMA) received four paediatric investigation plans for childhood obesity. Issues encountered during the assessment of paediatric investigation plans were all related to the characteristics of the patient population, trial design, choice of endpoints, and safety aspects. Although the number of paediatric investigation plans submitted to the European Medicines Agency thus far is limited, current experience highlights the need for clinical trial protocols that are in line with the specific European guideline. Divergent approaches should be discussed with regulatory authorities before paediatric trials are initiated and included in paediatric investigation plans. PMID- 21547649 TI - [Bariatric surgery in extremely obese children and adolescents]. AB - The management of childhood obesity is a clinical dilemma. Validated and evidence based intervention programs are still missing for this age group, and pediatricians increasingly see children with morbid obesity and with obesity related comorbidities. For those extremely obese patients who failed to respond to the classical therapeutic approaches, bariatric surgery is a therapeutic option. Although available data for bariatric surgery in childhood and adolescence is limited to date, significant postoperative reduction in BMI and an evident improvement of preoperatively existing metabolic and cardiovascular comorbidities and psychosocial well-being have been reported. The indication for bariatric surgery in adolescents follows strict criteria and should be proposed within an interdisciplinary team in specialized centers, including a clinical ethics committee. This review discusses the present guidelines for bariatric surgery in childhood and adolescence as well as available follow-up data for both adults and pediatric patients. PMID- 21547650 TI - [Evidence-based therapy guideline of the German Working Group on Obesity in Childhood and Adolescence]. AB - Obesity in childhood and adolescence has increased worldwide in recent years. A consensus guideline (S2) for treating obesity in childhood and adolescence in Germany was first published by the German Working Group on Obesity in Childhood and Adolescence (AGA) in 2000. The intention is to gradually replace this consensus-based (S2) guideline with an evidence-based (S3) guideline. Following a systematic literature search, 21 recommendations were predominantly approved with "strong consensus" (agreement >95%). Body weight and body fat mass can be significantly influenced by conventional behavior-based measures and also by the currently available drug therapies. However, the extent of the achieved weight reduction is small. Surgical measures (unproven, experimental therapy) to reduce body weight, in contrast, are very successful. In addition to the long version of this evidence-based guideline, an abbreviated version exists and a practice guideline is planned. This guideline should be further developed within the competence network on obesity of the German Federal Ministry of Education and Research. The guideline will be published in the scholarly journals of the professional associations concerned, will be available via the Internet, and will also be distributed through periodicals, congress events, and information at facilities. PMID- 21547651 TI - [Practical implementation of treatment guidelines concerning obesity in children and adolescents]. AB - Guidelines recommend a long-term outpatient lifestyle intervention in obese children and adolescents that also addresses the children's parents. However, lifestyle interventions are performed only in 1% of the 1,000,000 obese children and adolescents in Germany, suggesting a large gap between guidelines and medical care in real life. Possible reasons are a lacking awareness of the consequences of overweight, no time resources, and the lack of motivation to change lifestyle habits in some obese children and their families. Furthermore, there is no treatment option throughout Germany. The long-term success rate varies widely between outpatient treatment centers (<50% up to >70%), while the long-term effectiveness of short-term, inpatient intervention (rehabilitation) is unknown. However, many more obese children are treated by short-term rehabilitation compared to long-term outpatient intervention. Older and extreme obese children and adolescents are treated by lifestyle intervention, although this kind of intervention is more effective in younger and not so obese children. Some subgroups (extreme obese adolescents, obese disabled children) have no meaningful and effective treatment options. PMID- 21547652 TI - [Certification of therapy institutions, obesity trainers, and obesity trainer academies by the German Working Group on Obesity in Children and Adolescents (AGA)]. AB - There is a vast choice of behavioral therapy for obesity in children and adolescents, with wide differences in quality. In order to provide orientation for families, physicians, and health insurance companies, the German Working Group on Obesity in Children and Adolescents (AGA), which is affiliated with the German Obesity Society (DAG) and the German Pediatric Society (DGKJ), offers to certify institutions providing patient education programs for obese children and adolescents, obesity trainers, and academies for obesity trainers. Currently, 60 institutions offer obesity care, while 81 obesity trainers and 8 trainer academies are certified. This article summarizes requirements for certification and preliminary experience. PMID- 21547653 TI - [Evaluation of obesity treatment in children and adolescents (EvAKuJ Study). Role of therapeutic concept, certification, and quality indicators]. AB - AIM: Different providers of obesity treatment in children and adolescents in Germany were compared using the following criteria: outpatient/inpatient; with/without AGA certification; good/less good quality. METHODS: A total of 1,916 patients (8-16.9 years) from 48 study centers were examined before (t0), after (t1), and at least 1 year after therapy (t2/3). Body mass index (BMI), blood pressure, blood lipids, and psychosocial data were measured. RESULTS: Patients from inpatient rehabilitation centers were older and more obese. Patients from AGA-certified centers were more obese, and the completeness of comorbidity screening was higher. There were no differences in short- or long-term BMI reduction. "Good" treatment centers (classified after the UKE study 2004) did not differ from those centers not rated as "good" in weight reduction. Patients treated in "good" centers were more obese, and screening for comorbidity was better. No differences in drop out and loss to follow-up were found. CONCLUSION: There were only small differences between the different groups. Pronounced differences were found between the individual treatment centers. In order to improve therapy processes and outcomes, benchmarking and quality management have to be extended. PMID- 21547654 TI - [Economic aspects of prevention and treatment of overweight and obesity in children and adolescents]. AB - This article provides an overview of the costs associated with overweight and obesity in children and adolescents, and of the cost effectiveness of preventive and therapeutic interventions. First, the results of cost-of-illness studies from the international literature are presented. These studies show ambiguous results, but indicate moderate excess costs due to obesity for this age group. Subsequently, this paper describes the methods that can be used to analyze the cost effectiveness of preventive and therapeutic interventions. Problems arise from the necessity to estimate long-term effects on costs and health consequences of multiple, associated diseases. A number of economic evaluations of preventive and therapeutic interventions published in the scientific literature have reported favorable cost effectiveness. In order to increase the efficiency of health care, more cost-effective services for overweight and obesity should be developed and used. PMID- 21547655 TI - [Treatment of extremely obese adolescents and young adults at the Insula Obesity Center in Bischofswiesen]. AB - The Insula Obesity Center has been treating extremely obese adolescents and young adults since 1992. Various programs ranging from 2-9 months' duration are offered. The mean BMI at admission has been increasing continuously and is presently 41.5 kg/m(2) with occasional extremes over 80 kg/m(2). Obesity comorbidities are common. A mean weight reduction of 1.3 kg/week is achieved during a mean duration of treatment of 4.7 months. Follow-up in residential support groups is offered for up to 2 years for selected patients with special challenges such as lack of family support. PMID- 21547656 TI - [The Obeldicks concept. An example for a successful outpatient lifestyle intervention for overweight or obese children and adolescents]. AB - The outpatient lifestyle interventions Obeldicks (for 8- to 16-year-old obese children; 1-year intervention), Obeldicks Light (for 8- to 16-year-old overweight children; 6-month intervention), and Obeldicks Mini (for 4- to 7-year-old obese children; 1-year intervention) are based on nutrition education, physical activity, behavior therapy, and individual psychological care. Only 17% dropped out of the intervention, and 79% of the more than 1,000 participants reduced their degree of overweight. The mean SDS-BMI reduction was 0.4 (~1.5-2 kg/m(2) BMI reduction) and was associated with a significant improvement of hypertension, dyslipidemia, and disturbed glucose metabolism in the participants compared to an untreated control group. This efficiency was also proven by a multicenter randomized controlled trial. Furthermore, the quality of life of the participants improved significantly. Even 4 years after the end of intervention, the achieved weight loss was sustained. Training manuals and training seminars for professionals assist in the implementation of these lifestyle interventions at further locations. PMID- 21547657 TI - [The influence of migration background and parental education on childhood obesity and the metabolic syndrome]. AB - Obesity and metabolic syndrome are important risk factors for cardiovascular diseases. In this study, the influence of migration background and parental education on the degree of obesity and the presence of the metabolic syndrome (MS) in children and adolescents (N=492) requiring sociopediatric care were investigated. Two regression models were computed with the dependent variables BMI-SDS and MS, respectively. Age, gender, migration background, and parental education were used as independent variables. When controlling for age and gender, higher BMI-SDS were found among Turkish patients (beta=0.21; p=0.002) and patients with other migration backgrounds (beta=0.11; p=0.085) compared to German patients. The BMI-SDS values were also higher among patients from families with a low parental education level compared to those with a higher education level (beta=0.31; p<0.001). The key risk factor for MS is the BMI-SDS (OR: 8.9; p=0.011). No influence could be determined for migration background and parental education, when controlling for age, gender, and BMI-SDS. Obesity therapy should be increasingly tailored to the needs of identified risk groups. This will also allow for a targeted prevention of comorbidities. PMID- 21547658 TI - [Key measures for developing palliative care from a public health perspective. Initial results from a three-round Delphi study]. AB - Recently, six key targets for public health initiatives to improve palliative care in Germany were defined. This article reports the initial results of a follow-up study aiming at developing concrete measures to achieve these targets. We carried out a three-round Delphi study with stakeholders acting on the meso- and macro-levels of the German healthcare system (e.g., representatives of patient organizations, health insurance funds, politics, medical and nursing associations). In the first Delphi round, participants proposed measures to achieve the six key targets using free-text answers. The answers were analyzed with a qualitative-descriptive approach. In total, 107 stakeholders responded to the first Delphi round. After data reduction, 37 measures were extracted and grouped into six major categories: family carers, qualification, quality, public relations, services, and coordination. The range of measures on the different levels of policy, health care, and education presents a substantiated basis for the elaboration of targeted public health action plans to improve palliative care. Prioritization of measures in the second and third Delphi rounds will provide empirical support for decision making. PMID- 21547659 TI - [Substance monograph and reference values for monocyclic amino-aromatics in urine. Opinion of the Commission - Office of the Federal Environmental Biomonitoring]. PMID- 21547663 TI - Debate about the single etiognostic study. PMID- 21547664 TI - A promising anti-inflammatory and anti-thrombotic drug for sepsis treatment. PMID- 21547665 TI - Synthesis and biological evaluation of 3-(1H-indol-3-yl)pyrazole-5-carboxylic acid derivatives. AB - A series of novel compounds bearing a 3-(1H-indol-3-yl)pyrazole-5-carboxylic acid nucleus were synthesized. Analytical and spectral data confirmed the structures of the new compounds. The structures of the regioisomers in this series were determined by (1)H-NMR spectra. The title compounds were evaluated for their endothelin-1 antagonist activities. In the in vitro functional assay, compounds 23, 24, 28 and 29 exhibited significant efficacy at the concentration of 1 MUg/mL, and compounds 5b, 5c, 26 and 28 were as potent as the positive control bosentan at high concentration. In the experiment to assess prevention of endothelin-1-induced sudden death in mice, compound 5b showed comparable activity to bosentan, and 30 was more potent than bosentan. The final compounds were also screened for antibacterial activity against four Gram-positive and -negative bacteria. Some of the tested compounds showed weak antibacterial activity. PMID- 21547666 TI - Structural influence of indole C5-N-substitutents on the cytotoxicity of seco duocarmycin analogs. AB - A series of racemic indole C5-substituted seco-cyclopropylindoline compounds (2,3 and 5-7) were prepared by coupling 1-(tert-butyloxycarbonyl)-3 (chlorocarbonyl)indoline (seg-A) with 5,6,7-trimethoxy-, 5,6-dimethoxy-, 5-amino , 5-methylsulfonylamino- and 5-(N,N-dimethylaminosulfonylamino) indole-2 carboxylic acid as seg-B in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. The synthetic compounds (2,3 and 5-7) were tested for cytotoxic activity against human cancer cell lines (COLO 205, SK-MEL-2, A549, and JEG-3) using the MTT assay. PMID- 21547667 TI - Pulsatile multiparticulate drug delivery system for metoprolol succinate. AB - Cardiovascular diseases and their treatment pose a great challenge. Many instances of cardiovascular disease occur in the early morning hours. Hence, the objective of this study was to develop a time-controlled release formulation of metoprolol succinate based on a pulsatile multiparticulate (pellets) drug delivery system. The formulation was intended to be administered in the evening at 22:00 hours to evaluate symptoms of cardiovascular disease that are experienced in the early morning hours (from 04:00 to 06:00). Drug layering followed by a swelling layer and finally by an insoluble coat application was done using a Sanmour fluid bed processor. Metoprolol succinate layered on sugar pellets (74% w/w) layered with 20% (w/w) ion doshion resin P-547 and coated with 15% (w/w) ethocel with the addition of 20% castor oil showed a lag time of 4 h and was then followed a sigmoidal release pattern with more than 95% drug having been released by the 10(th) h. PMID- 21547668 TI - Constituents from Senecio scandens and their antioxidant bioactivity. AB - Forty-one compounds including two new constituents, senecainin A (1) and 3 methoxyisonicotinic acid (2), were characterized from the methanol extracts of the whole plant of Senecio scandens. The structures of the new compounds were comprehensively established with the aid of 1D and 2D NMR spectroscopic and mass spectrometric analyses. The chemical structures of known compounds were identified by comparison of their spectroscopic and physical data with those reported in the literature. In addition, the antioxidant activity of some of the isolates was examined in the DPPH free radical scavenging assay. Among the tested compounds, (-)-monoepoxylignanolide, (-)-pinoresinol and (-)-epi-pinoresinol displayed significant antioxidant bioactivity. PMID- 21547669 TI - Chemical constituents of the leaves of Glochidion obliquum and their bioactivity. AB - A new flavonoid glycoside, globlin A (1), and eleven known compounds were isolated from methanolic extracts of the leaves of Glochidion obliquum. The structure of this new compound was established with a combination of 2D NMR techniques (COSY, NOESY, HMQC and HMBC) and HR-ESI-MS analyses. Chemical structures of the other known compounds were identified by comparison of their spectroscopic and physical data with those reported in the literature. Some of the isolates were examined for their bioactivities. Among the tested compounds, rotundic acid (4) displayed significant cytotoxicity and anti-inflammatory activities. PMID- 21547670 TI - Enhanced solubility and bioavailability of flurbiprofen by cycloamylose. AB - The effect of cycloamylose on the aqueous solubility of flurbiprofen was investigated. To improve the solubility and bioavailability of flurbiprofen (poor water solubility), a solid dispersion was spray dried with a solution of flurbiprofen and cycloamylose at a weight ratio of 1:1. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with a commercial product. Cycloamylose increased solubility of flurbiprofen approximately 12-fold and dissolution of it by 2-fold. Flurbiprofen was present in an unchanged crystalline state, and cycloamylose was a solubilizing agent for flurbiprofen in this solid dispersion. Furthermore, the dispersion gave higher AUC and C(max) values compared with the commercial product, indicating that it improved the oral bioavailability of flurbiprofen in rats. Thus, the solid dispersion may be useful to deliver flurbiprofen with enhanced bioavailability without changes in crystalline structure. PMID- 21547671 TI - Combination immunotherapy of MAb B6.1 with fluconazole augments therapeutic effect to disseminated candidiasis. AB - We recently reported that IgM MAb B6.1, specific for beta-1, 2-mannotriose on the cell wall of Candida albicans, is therapeutic to disseminated candidiasis due to C. albicans. In the current study, we examined if MAbB6.1 enhances therapeutic effect of fluconazole (FLC) to the disseminated disease. To assess the combination effect, determination by the kidneys-colony forming unit and survival times were used. Results showed that the therapeutic effect of FLC on mice with disseminated candidiasis was dose-dependent, but a FLC dose at 0.8 mg/kg body weight of mice was ineffective. To determine combination effect, mice treated intraperitoneally with a combination of FLC plus MAb B6.1 at 1 h post-infection - a condition of developing partial therapeutic activity - enhanced survival times beyond the effect by only antibody (p < 0.05). The resulting MST (mean survival times) value from the combination-received mice was almost the same as MST value from 3.2 mg FLC dose-given animals (p < 0.05). Another combination of 1.6 mg FLC dose and B6.1 reduced severity of the disseminated disease at almost the same rate as combination efficacy of 0.8 mg FLC dose plus B6.1. This data indicates that B6.1 acts in concert with FLC and that this combination therapy augments protection, which suggests a possibility of reducing FLC dose. The augmentation response was specific because an irrelevant IgM MAb S9 was not effective to the disseminated disease. Thus, our present studies demonstrate that this combination immunotherapy may be a way of solving the problem of limited antifungal drug choices caused by drug-resistant C. albicans. PMID- 21547672 TI - Combination of paclitaxel- and retinoic acid-incorporated nanoparticles for the treatment of CT-26 colon carcinoma. AB - The aim of this study was to evaluate the antitumor effect of combinatorial targeted therapy with paclitaxel and all-trans retinoic acid (ATRA) nanoparticles in vitro. Paclitaxel-incorporated pullulan acetate (PA) nanoparticles were prepared by the nanoprecipitation-solvent evaporation method. ATRA-incorporated nanoparticles were prepared by dialysis using a methoxy poly(ethylene glycol) grafted chitosan (ChitoPEG) copolymer. Particle sizes of paclitaxel-incorporated nanoparticles and ATRA-incorporated nanoparticles were about 160 nm and 60 nm, respectively. Nanoparticles were reconstituted in various aqueous media such as deionized water, phosphate-buffered saline, and fetal bovine serum-supplemented cell culture media. The combination of paclitaxel + ATRA (10 + 10 MUg/mL) delivered by nanoparticles showed a synergistic antiproliferative effect against CT26 cells that was not observed with other combinations. Furthermore, the activity of MMP-2, a key enzyme in tumor cell invasion, was significantly decreased in cells treated with the combination of paclitaxel and ATRA while other combinations and single agents did not significantly affect its activity. A matrigel assay supported these results, indicating that paclitaxel/ATRA combination nanoparticles are effective for the inhibition of the invasion of tumor cells. The results of the present study suggest that combination treatment with paclitaxel and ATRA could be an effective treatment for the inhibition of tumor cell proliferation and invasion, and that nanoparticles are promising candidates for antitumor drug delivery. PMID- 21547673 TI - Inhibitory activity of Plantago major L. on angiotensin I-converting enzyme. AB - Eight compounds were isolated from methanol extract of Plantago major L. leaves and investigated for their ability to inhibit angiotensin I-converting enzyme activity. Among them, compound 1 showed the most potent inhibition with rate of 28.06 +/- 0.21% at a concentration of 100 MUM. Compounds 2 and 8 exhibited weak activities. These results suggest that compound 1 might contribute to the ability of P. major to inhibit the activity of angiotensin I- converting enzyme. PMID- 21547674 TI - Anti-metastatic properties of the leaves of Eriobotrya japonica. AB - The leaves of Eriobotrya japonica Lindl. have been widely used as a traditional medicine for the treatment of many diseases including gastroenteric disorders, diabetes mellitus, chronic bronchitis and asthma. In the present study, the anti metastatic action of the EtOAc fraction of the leaves of E. japonica (LEJ) was investigated. LEJ showed potent inhibitory effects on MMP-2 and MMP-9 activities and expressions via down-regulation of NF-kappaB translocation to the nucleus in B16F10 cells. In addition, the cell migration and invasion were down-regulated by LEJ. LEJ also significantly suppressed lung metastasis in vivo. Moreover, we isolated the compounds ursolic acid and 2alpha-hydroxyursolic acid from LEJ and both compounds also significantly suppressed MMP-2 and MMP-9 activities, indicating that they are the active components of LEJ. The present results demonstrate that LEJ may be used as valuable antimetastatic agent for the treatment of cancer metastasis. PMID- 21547675 TI - Chalcones isolated from Angelica keiskei and their inhibition of IL-6 production in TNF-alpha-stimulated MG-63 cell. AB - Six chalcone compounds, 2',4',4-trihydroxy-3'-[2-hydroxy-7-methyl-3-methylene-6 octaenyl]chalcone (1), 2',4',4-trihydroxy-3'-geranylchalcone (2), 2',4',4 trihydroxy-3'-[6-hydroxy-3,7-dimethyl-2,7-octadienyl]chalcone (3), 2',4-dihydroxy 4'-methoxy-3'-[2-hydroperoxy-3-methyl-3-butenyl]chalcone (4), 2',4-dihydroxy-4' methoxy-3'-geranylchalcone (5), and 2',4-dihydroxy-4'-methoxy-3'-[3-methyl-3 butenyl]chalcone (6) were isolated from the leaves of Angelica keiskei K (Umbelliferae). The structure of each isolated compound was determined using spectroscopic methods. Among the isolates, compounds 1-3 appeared to have potent inhibitory activity of IL-6 production in TNF-alpha-stimulated MG-63 cell, while compounds 4-6 did not. The distinct structural difference between compounds 1-3 and 4-6 was the presence of C-4' hydroxyl group in the chalcone moiety. Our results imply that the inhibitory activity of IL-6 production in TNF-alpha stimulated MG-63 cell may be affected by the presence of C-4' hydroxyl group in the chalcone moiety. PMID- 21547676 TI - Therapeutic and cost effectiveness of proton pump inhibitor regimens for idiopathic or drug-induced peptic ulcer complication. AB - Peptic ulcer (PU) disease has a high rate of occurrence and recurrence in Korean and the selection of drug for treatment is diverse. In this study, the therapeutical effectiveness of regimens including proton pump inhibitors (PPI) was compared with the single PPI therapy. The clinical data were collected from 1,658 patients having idiopathic or drug-induced PU complication from a Medical Center in Daegu, Korea, and analyzed retrospectively based on the results of endoscopic examination, the drug history and the therapeutic cost depending on drugs used. The comparison of complete healing rate and recurrence rate showed no significant differences between the single PPI groups and the combination group with antacids, prokinetic agent or mucosa protectants. However, the combination therapy of PPI with mucosa protectants gave a slightly better therapeutic outcome than single PPI treatment in gastric ulcer patients. Comparatively, the combination of PPI with antacids significantly reduced the therapeutic effectiveness in duodenal ulcer patients. The analysis of cost-based therapeutic effectiveness reveals that any economic benefits in PU treatment were not gained by the combination of other class of ulcer drugs. Even though the rapidity of healing rate was not considered, it can be concluded that the PPI combination therapy might be not desirable in PU treatment. Particularly triplet or quartet combination therapy in PPI regimen was absolutely economically ineffective therapy in spite of the increase of medication costs. PMID- 21547677 TI - Comparison of the solubility and pharmacokinetics of sildenafil salts. AB - To develop sildenafil lactate, a salt form of sildenafil with improved solubility and bioavailability of poorly water-soluble sildenafil base, this salt form was prepared using a spray dryer. Its solubility and pharmacokinetics in rabbits were evaluated compared with sildenafil base and sildenafil citrate. Sildenafil lactate improved the solubility of sildenafil in various solvents including distilled water compared with sildenafil citrate. It provided higher AUC and C(max) and, shorter t(1/2) values than did the other materials, indicating that it improved the oral bioavailability of sildenafil in rabbits. Our results suggest that sildenafil lactate would be useful to deliver sildenafil in a pattern that allows fast absorption and late metabolism. Furthermore, the plasma concentration at 0.25 h in sildenafil lactate was similar to the C(max) value at T(max) (0.5 h) in sildenafil citrate. Thus, sildenafil lactate might provide a faster onset of action and immediate erection compared with sildenafil citrate, the conventional drug. PMID- 21547678 TI - Simultaneous determination of bioactive flavonoids in some selected Korean thistles by high-performance liquid chromatography. AB - In order to facilitate the quality control of some selected Korean thistles (Cirsii Herb), Cirsium japonicum var ussuriense, C. japonium var spinosissimum, C. setidens, C. pendulum, C. nipponicum, Carduus crispus, and Breea segetum, a simple, accurate and reliable high performance liguid chromatography method was developed for the simultaneous determination of the six flavonoids: luteolin 5-O glucoside (1), luteolin 7-O-glucoside (2), hispidulin 7-O-neohesperidoside (3), luteolin (4), pectolinarin (5), and apigenin (6), which were selected as the chemical markers of the thistles. Separation was achieved on an Agilent Eclipse XDB-C18 column with a gradient solvent system of 0.1% trifluoroacetic acid aqueous-methanol at a flow-rate of 1.0 mL/min and detected at 254 nm. All six calibration curves showed good linearity (R(2) > 0.991). The method was reproducible with intra- and inter-day variations of less than 6%. The recoveries were in the range of 90.01-100.05%. This analysis method was successfully utilized to quantify the six flavonoids in the 22 batches of the thistles. The results demonstrated that this method is simple, reliable and suitable for the quality control of this medicinal herb. PMID- 21547679 TI - Comparative study of telmisartan tablets prepared via the wet granulation method and pritorTM prepared using the spray-drying method. AB - The wet granulation method was successfully used to manufacture amorphous telmisartan tablets (CNU) for comparison with the spray-drying method, used for PritorTM. Drug crystallinity in the tablet was characterized using differential scanning calorimetry and powder X-ray diffraction, and pharmaceutical properties of the tablets such as hardness, friability, water absorption, and in vitro dissolution in pH 1.2, 4.0, 6.8 and 7.5 were characterized. Especially with regard to the water absorption feature, the CNU tablets showed better performance by maintaining their original structures and by absorbing less water. Since both PritorTM and CNU tablets had similar physical properties of crystallinity, hardness, friability, and > 50 f(2) value in an in vitro dissolution study, the bioequivalence of CNU tablets should be analyzed in a future in vivo study. Therefore, telmisartan tablets can be produced using a more economical and easier method than that used to produce PritorTM tablets. PMID- 21547680 TI - Mangiferin induces apoptosis by suppressing Bcl-xL and XIAP expressions and nuclear entry of NF-kappaB in HL-60 cells. AB - Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-beta-D: -glucoside (C glucosylxanthone), is a xanthone derivative that is widely distributed in higher plants. Recently, mangiferin was found to exhibit potential antitumor effects. However, the molecular mechanisms of this effect have not been elucidated. In the present study, we attempt to clarify the mechanism of mangiferin-induced apoptosis in the human acute myeloid leukemia cell line HL-60; mangiferin was found to induce apoptosis. We also observed a concurrent increase in caspase-3 activity and DNA fragmentation. Furthermore, on examining the survival signals expressed during apoptotic induction, we observed that mangiferin caused a remarkable decrease in the nuclear entry of NF-kappaB p65. However, there were no changes in the expression of other survival signals, such as extracellular signal regulated kinase 1/2, protein kinase B, and p38 mitogenactivated protein kinase. In addition, mangiferin suppressed the expressions of Bcl-xL and XIAP; however, we did not note any changes in the levels of Bcl-2, Bax, and Bim. These results indicate that mangiferin induces apoptosis by suppressing NF-kappaB activation and expressions of Bcl-xL and XAIP. These findings suggest that mangiferin may be useful as an anticancer agent and can be used in combination therapy with other anticancer drugs for the treatment of acute myeloid leukemia. PMID- 21547681 TI - Salvianolic acid B reverses the epithelial-to-mesenchymal transition of HK-2 cells that is induced by transforming growth factor-beta. AB - Salvianolic acid B (Sal B) is the most abundant bioactive molecule from Radix Salviae Miltiorrhizae, and has recently been used for treating renal fibrosis in traditional Chinese medicine. Here we investigated the ability reversal of Sal B to reverse the transdifferentiation of human kidney proximal tubular epithelial cells that was induced by transforming growth factor-beta 1 (TGF-beta1). The effects of Sal B on HK-2 cell morphology were observed by phase contrast microscopy, while alpha smooth muscle actin and E-cadherin were studied by immunocytochemistry and real-time reverse transcription polymerase chain reaction, respectively. Exposure of HK-2 cells to TGF-beta1 for 72 h induced a complete conversion of the epithelial cells to myofibroblasts. When HK-2 cells were co-incubated with Sal B and TGF-beta1 for a further 72 h, the morphology of myofibroblasts returned to that of proximal tubular epithelial cells, whereas the myofibroblast phenotype was maintained after exposure of cells to TGF-beta1 for 144 h. Sal B reduced alpha smooth muscle actin levels and increased E-cadherin levels compared with their epithelial-to-mesenchymal transition controls. The reversal effect of Sal B was dose-dependent. That Sal B reverses the epithelial to-mesenchymal transition in vitro suggests that it could possibly facilitate the repair of tubular epithelial structures and the regression of renal fibrosis in injured kidneys. PMID- 21547682 TI - Effects of the anti-sepsis drug, (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline (CKD-712), on mortality, inflammation, and organ injuries in rodent sepsis models. AB - CKD-712 is a 1-naphthyl analog of higenamine that has been reported to have potent antiinflammatory and thus anti-sepsis effects. The purpose of this study was to investigate the potential of CKD-712 as a medicine for sepsis and to confirm its protective effects on organs in animal sepsis models. Pretreatment with CKD-712 dose-dependently increased survival rate in a lipopolysaccharide induced sepsis model in mice. Body temperature decrease, an important pre-symptom of septic death, was also prevented by CKD-712. CKD-712 still significantly increased survival rate even when administered one and four hours after lipopolysaccharide injection. Therapeutic efficacy of CKD-712 was also confirmed against sepsis following zymosan-induced endotoxemia and in cecal ligation and puncture surgery in mice. In a disseminated intravascular coagulation model in rats, CKD-712 showed organ-protective effect by reducing serum glutamate oxaloacetate transaminase, glutamate-pyruvate transferase, blood urea nitrogen, and creatinine levels. CKD-712 also prevented histological damage to the lung and liver. In this same model, CKD-712 showed anti-inflammatory effects through decreases in tumor necrosis factor-alpha and interleukin-6 in the blood and reduced translocation of nuclear factor-kappaB to the nuclei of lung cells. CKD 712 administration also diminished infiltration of leukocytes into the lung and liver. Taken together, these results show that CKD-712 has excellent potential as an effective medicine for sepsis. PMID- 21547683 TI - Chlorogenic acid inhibits the formation of advanced glycation end products and associated protein cross-linking. AB - Advanced glycation end products (AGEs) play an important role in the development of chronic diabetic complications. Chlorogenic acid (CGA) is a phenolic compound formed by the esterification of caffeic and quinic acids. In this study, we evaluated the inhibitory effects of CGA against the formation of AGEs and AGEs protein cross-linking in vitro. An in vitro assay for glycation of bovine serum albumin by high glucose showed that CGA inhibited AGEs formation with an IC(50) value of 148.32 MUM and was found to be more effective than aminoguanidine, a well-known AGEs inhibitor (IC(50); 807.67 MUM). In an indirect AGE-ELISA assay, the CGA exhibited more potent inhibitory activity on the cross-linking of AGEs to collagen than aminoguanidine. In addition, the inhibitory effects of CGA on AGEs formation and on its cross-linking with collagen might be caused by its interactions with reactive decarbonyl compounds, such as methylglyoxal. These results suggest that CGA could be beneficial in the prevention of AGEs progression in patients with diabetes because CGA can attenuate AGEs deposition in glucose. PMID- 21547685 TI - Hydrogen production with nanostructured and sensitized metal oxides. AB - Recent advances in the field of photoelectrochemical cells (PECs) applied to solar water and H2S splitting and hydrogen production are reviewed with meaningful examples and case studies. At the molecular level, significant recent efforts have been directed towards the development of stable dye sensitizers/water oxidation catalyst assemblies. In the field of photoactive nanostructured materials and interfaces, novel highly ordered semiconductors nanostructures (i.e., anodically grown titania nanotubes) are drawing an increasing interest, under both the fundamental and applicative points of view, due to improved charge transfer kinetics with respect to more conventional sintered nanoparticle substrates. These features, coupled with low cost and ease of fabrication, stand as a good promise for the realization of solar devices capable of solar hydrogen production at a useful rate. PMID- 21547684 TI - The analgesic effects and mechanisms of orally administered eugenol. AB - In the present study, the antinociceptive profiles of eugenol were examined in ICR mice. Eugenol administered orally (from 1 to 10 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid induced writhing test. Duration of antinociceptive action of eugenol maintained at least for 30 min. Moreover, the cumulative response time of nociceptive behaviors induced by an intraplantar formalin injection was reduced by eugenol treatment during the 2(nd) phases. Furthermore, the cumulative nociceptive response time for intrathecal injection of substance P (0.7 MUg) or glutamate (20 MUg) was diminished by eugenol. Intraperitoneal pretreatment with yohimbine (alpha2-adrenergic receptor antagonist) or naloxone (opioid receptor antagonist) attenuated antinociceptive effect induced by eugenol in the writhing test. However, methysergide (5-HT serotonergic receptor antagonist) did not affect antinociception induced by eugenol in the writhing test. Our results suggest that eugenol shows an antinociceptive property in various pain models. Furthermore, this antinociceptive effect of eugenol may be mediated by alpha2-adrenergic and opioidergic receptors, but not serotonergic receptor. PMID- 21547686 TI - Artificial photosynthesis challenges: water oxidation at nanostructured interfaces. AB - Innovative oxygen evolving catalysts, taken from the pool of nanosized, water soluble, molecular metal oxides, the so-called polyoxometalates (POMs), represent an extraordinary opportunity in the field of artificial photosynthesis. These catalysts possess a highly robust, totally inorganic structure, and can provide a unique mimicry of the oxygen evolving center in photosynthetic II enzymes. As a result POMs can effect H2O oxidation to O2 with unprecedented efficiency. In particular, the tetra-ruthenium based POM [Ru(IV) 4(MU-OH)2(MU-O)4(H2O)4(gamma SiW(10)O(36))2](10-), Ru4(POM), displays fast kinetics, electrocatalytic activity powered by carbon nanotubes and exceptionally light-driven performance. A broad perspective is presented herein by addressing the recent progress in the field of metal-oxide nano-clusters as water oxidation catalysts, including colloidal species. Moreover, the shaping of the catalyst environment plays a fundamental role by alleviating the catalyst fatigue and stabilizing competent intermediates, thus responding to what are the formidable thermodynamic and kinetic challenges of water splitting. The design of nano-interfaces with specifically tailored carbon nanostructures and/or polymeric scaffolds opens a vast scenario for tuning electron/proton transfer mechanisms. Therefore innovation is envisaged based on the molecular modification of the hybrid photocatalytic center and of its environment. PMID- 21547687 TI - Synthesis of morphine alkaloids and derivatives. AB - This review summarizes recent developments in the total synthesis of morphine alkaloids and some of the semisynthetic derivatives. The literature is covered for the period of 5 years after the publication of the last review in 2005. The syntheses that appeared in this period are covered in detail and are placed in the context of all syntheses of opiate alkaloids since the original one published by Gates in 1952. The introduction covers the historical aspects of total synthesis of these alkaloids. The synthesis of some of the medicinally useful derivatives is reviewed in the last section along with some of the methodology required for their preparation. PMID- 21547688 TI - Toward the enrichment of human Cell. PMID- 21547689 TI - Use of BAC array CGH for evaluation of chromosomal stability of clinically used human mesenchymal stem cells and of cancer cell lines. AB - Array-based comparative genomic hybridization (aCGH) using bacterial artificial chromosomes (BAC) is a powerful method to analyze DNA copy number aberrations of the entire human genome. In fact, CGH and aCGH have revealed various DNA copy number aberrations in numerous cancer cells and cancer cell lines examined so far. In this report, BAC aCGH was applied to evaluate the stability or instability of cell lines. Established cell lines have greatly contributed to advancements in not only biology but also medical science. However, cell lines have serious problems, such as alteration of biological properties during long term cultivation. Firstly, we investigated two cancer cell lines, HeLa and Caco 2. HeLa cells, established from a cervical cancer, showed significantly increased DNA copy number alterations with passage time. Caco-2 cells, established from a colon cancer, showed no remarkable differences under various culture conditions. These results indicate that BAC aCGH can be used for the evaluation and validation of genomic stability of cultured cells. Secondly, BAC aCGH was applied to evaluate and validate the genomic stabilities of three patient's mesenchymal stem cells (MSCs), which were already used for their treatments. These three MSCs showed no significant differences in DNA copy number aberrations over their entire chromosomal regions. Therefore, BAC aCGH is highly recommended for use for a quality check of various cells before using them for any kind of biological investigation or clinical application. PMID- 21547690 TI - Clinical significance of side population in ovarian cancer cells. AB - Recently, accumulating evidence has suggested that tumors, including ovarian cancer, are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. The emergence of drug resistance is one of the most difficult problems in the treatment of ovarian cancer, which has been explained recently by the potential of CSCs to have superior resistance against anti-cancer drugs than conventional cancer cells. In this study, we expanded this line of study to examine whether this phenomenon is also observed in clinical specimens of ovarian cancer cells. In total we could analyze 28 samples out of 60 obtained from ovarian cancer patients. The clinical samples were subjected to testing of the expression of side population (SP) as a CSC marker, and according to the presence of SP (SP+) or absence of SP (SP-), clinicopathological significances were analyzed. Although there was no statistical significance, there were more SP+s in recurrent cases as well as in ascitic and peritoneal dissemination than in primary tumor of the ovary. There was no correlation between SP status and FIGO staging. In 19 cases of those who could be followed more than 6 months from initial therapy, there were 8 cases of recurrence or death from disease, and all of these were SP+. On the other hand, in 11 cases of disease-free survivors, 6 were SP+. There was a significant difference in prognosis between SP+ and SP- (p = 0.017). Although this study was limited, it revealed that SP could be contained more in recurrent or metastatic tumors than in primary tumors, and also that the presence of SP could be a risk factor of recurrence in ovarian cancer. Therefore, a novel therapeutic strategy targeting SP could improve the prognosis of ovarian cancer. PMID- 21547691 TI - Hexaploid H1 (ES) cells established from octaploid H1 cells are as DNA stable as pentaploid H1 cells. AB - Hexaploid H1 (ES) cells (6H1 cells) were established from octaploid H1 cells (8H1 cells), as were pentaploid H1 cells (5H1 cells). 6H1 cells were compared with 5H1 cells. The number of chromosomes of 6H1 cells was 115, 20 more than the 95 of 5H1 cells. The durations of G(1), S, and G(2)/M phases of 6H1 cells were 3, 7, and 6 h, respectively, almost the same as those of 5H1 cells. The cell volume of 6H1 cells was equivalent that of 5H1 cells. The morphology of 6H1 cells was flattened circular cluster, different from the spherical cluster of 5H1 cells. 6H1 cells exhibited alkaline phosphatase activity as well as 5H1 cells. The DNA content of 6H1 cells was stable and maintained for 300 days of culturing, the same as that of 5H1 cells. The DNA stability of 6H1 cells was explained using a hypothesis concerning the DNA structure of polyploid cells because the asymmetric configuration of homologous chromosomes in 6H1 cells inhibited chromosome loss. PMID- 21547692 TI - Heterogeneity of anticancer drug sensitivity in squamous cell carcinoma of the tongue. AB - Heterogeneity is known to be present to varying degrees in cancer cell groups. There have been no reports, however, of studies in which a single cell clone was prepared from a cancer cell group to examine heterogeneity with respect to anticancer drug sensitivity. Thus, the authors herein report an investigation into the heterogeneity of cancer cells within the same tumor with respect to anticancer drug sensitivity. Anticancer drug sensitivity was investigated in primary tumors, metastatic lymph node tumors, recurrent tumors and established cell lines obtained from four cases of tongue cancer using an oxygen electrode apparatus. As differences were observed in anticancer drug sensitivity from one case to another, even though all four were of the same pathological tissue type, the individual differences were apparently significant. Moreover, primary tumors and recurrent tumors demonstrated different sensitivities to the anticancer drugs even in the same patient. When single cell clones were prepared from primary tumors and anticancer drug sensitivity testing was carried out, sensitivity to anticancer drugs that was not seen in the primary tumors was observed. We performed RT-PCR on cell groups derived from this single cell using MDR1, MRP1, MRP2 and ERCC1, which are primary genes that are resistant to anticancer drugs. Expression of MDR and ERCC1 was not observed in single cell clones nos. 1-10. MRP1 and MRP2, on the other hand, were expressed in all of these single cell clones. Because cells with different sensitivity levels were initially present in the cancer cell groups, even when large numbers of cancer cells died in response to anticancer drug therapy, the results suggest the possibility that recurrence and metastasis occur based on cells with differing sensitivities. After examining anticancer drug sensitivity at the single cell level, we believe that anticancer drug-resistant genes may be involved in the heterogeneity of anticancer drug sensitivity with respect to cancer cell groups. PMID- 21547693 TI - Fibroblasts have plasticity and potential utility for cell therapy. AB - Fibroblasts exist in the interstices of various organs as a component of connective tissue and are one of several types of somatic cells that have been well established in culture. They have been reported to undergo myogenic conversion and to induce the expression of genes associated with pluripotency. However, their own plasticity with regard to direct differentiation has scarcely been described. Here, we show that human fibroblasts are able to differentiate directly to all three germ layer derivatives. The results indicate that human dermal fibroblasts have more plasticity than has been generally thought and that fibroblasts have potential utility as a source for cell therapy. PMID- 21547694 TI - Cardiomyocyte marker expression in a human lymphocyte cell line using mouse cardiomyocyte extract. AB - Cell transplantation shows potential for the treatment of cardiac diseases. Embryonic stem cells, cord blood and mesenchymal stem cells have been suggested as sources for transplantation therapy. Because of some technical limitations with the use of stem cells, transdifferentiation of fully differentiated cells is a potentially useful alternative. We investigated whether human peripheral blood cells could transdifferentiate into cardiomyocyte. Transdifferentiation was induced in a human B lymphocyte cell line (Raji). Cardiomyocyte extract was prepared from adult mouse cardiomyocytes. The cells were treated with 5-aza-2 deoxycytidine and trichostatin A, permeabilized with streptolysin O, and exposed to the mouse cardiomyocyte extract. They were cultured for 10 days, 3 weeks and 4 weeks. Cardiomyocyte markers were detected with immunohistochemistry and flow cytometry. Immunocytochemistry revealed that some cells expressed myosin heavy chain, alpha-actinin and cardiac troponin T after 3 and 4 weeks. Flow cytometry confirmed these data. In cells exposed to trichostatin A and 5-aza-2 deoxycytidine and permeabilized in the presence of the cardiomyocyte extract, troponin T expression was seen in 3.53% of the cells and 3.11% of them expressed alpha-actinin. After exposure to the cardiomyocyte extract, some permeabilized cells adhered to the plate loosely; however, the morphology did not change significantly, and they continued to show a rounded shape after 4 weeks. Our treated lymphocytes expressed cardiomyocyte markers. Our results suggest that lymphocytes may be useful in future research as a source of cells for reprogramming procedures. PMID- 21547695 TI - Dentinogenic potential of human adult dental pulp cells during the extended primary culture. AB - Despite the frequent use of primary dental pulp cells in dental regenerative research, few systematic studies of stemness for osteogenic and dentinogenic differentiation of human adult pulp cells have been reported. To investigate the stemness of human adult dental pulp cells, pulp tissues were obtained from extracted third molars and used as a source of pulp cells. In FACS analysis and immunophenotyping, the general mesenchymal stem cell markers CD44, CD90, and CD146 were highly expressed in early passages of the pulp cell culture. The stem cell population was dramatically decreased in an expansion culture of human dental pulp cells. When pulp cells were treated with additives such as beta glycerophosphate, ascorbic acid, and dexamethasone, nodule formation was facilitated and mineralization occurred within 2 weeks. Expression of osteogenic markers such as alkaline phosphatase, osteocalcin, and osteonectin was relatively low in undifferentiated cells, but increased significantly under differentiation conditions in whole passages. Dentinogenic markers such as dentin sialophosphoprotein and dentin matrix protein-1 appeared to decrease in their expression with increasing passage number; however, peak levels of expression occurred at around passage 5. These data suggested that stem cells with differentiation potential might exist in the dental pulp primary culture, and that their phenotypes were changed during expansion culture over 8-9 passages. Under these conditions, a dentinogenic population of pulp cells occurred in limited early passages, whereas osteogenic cells occurred throughout the whole passage range. PMID- 21547696 TI - Isolation of Oct4+, Nanog+ and SOX2- mesenchymal cells from peripheral blood of a diabetes mellitus patient. AB - Diabetes mellitus is a chronic metabolic disorder that affects millions of people worldwide. The most common form is type 2 diabetes mellitus, which results in impaired beta cell function combined with insulin resistance in peripheral organs. One recently proposed treatment approach is the use of adult stem cells derived from bone marrow in autologous stem cell transplantation. Alternatively, peripheral blood can be obtained in a more non-invasive manner. In this study, we isolated and cultured mesenchymal cells (MCs) from the peripheral blood of a diabetes mellitus patient. The cultured cells were large and elongated and had an in vitro migratory capacity in the culture dish. They expressed embryonic stem cell pluripotency markers Nanog and Oct 4 as well as mesenchymal markers CD105 and CD13, and they lacked expression of hematopoietic marker CD45. These characteristics suggest that these cells have a mesenchymal phenotype similar to that obtained from bone marrow cells. The SOX2 gene was downregulated in both the peripheral blood cells and the isolated mesenchymal cell line, indicating a defective mechanism of SOX2 in diabetes mellitus. The overall results of study demonstrate that peripheral blood can be used as a source of MCs from diabetes mellitus patients for use in future regenerative stem cell therapy and that this particular model system may be useful to study the mechanism of diabetes mellitus involving downregulation of the SOX2 cascade. PMID- 21547697 TI - Instrumented transforaminal lumbar interbody fusion with single cage for the treatment of degenerative lumbar disease. AB - INTRODUCTION: There are several practical problems encountered in the TLIF procedure with implantation of two titanium cages, such as difficulty in achieving symmetric positioning with two cages, loosening of the first cage following insertion of the second cage and higher direct costs to the patient. METHOD: From January 2005 to December 2007, a total of 76 consecutive patients treated with instrumented TLIF with single cage and excised local bone were enrolled in the current study. There were 45 males and 31 females aged between 31 and 75 years (mean 50.9 years). Forty-five patients had degenerative disc diseases alone, 23 had associated isthmic or degenerative spondylolisthesis and 8 had recurrent disc herniations. Clinical outcomes were evaluated using the Oswestry Disability Index and a visual analog scale. Intervertebral height and fusion status were assessed on X-ray and two-dimensional computed tomography reconstruction. RESULTS: All the patients followed up. The mean follow-up period was 21.8 months (range from 12 to 48 months). No nerve injuries occurred during operation. Postoperative ODI and VAS scores in all the patients were more than the preoperative ones with significant differences. All the patients had complete interbody fusion and, at the final follow-up, none had instrumentation failure. Postoperative intervertebral height in all the patients was better than the preoperative ones with statistical significances. CONCLUSIONS: Instrumented TLIF with single cage is a safe and effective method for the treatment of degenerative lumbar diseases. PMID- 21547698 TI - Effect of Zn(II) on the reduction and accumulation of Cr(VI) by Arthrobacter species. AB - Natural habitats are often characterized by the coexistence of Zn and Cr. This study assessed the potential of two Gram-positive, Cr(VI)-reducing, aerobic bacterial strains belonging to Arthrobacter genera, which were isolated from basalt samples taken from the most polluted region of the Republic of Georgia, to remediate Cr(VI) in environments in the presence of Zn(II). Our batch experiments revealed that the addition of Zn(II) to the tested bacterial cells significantly enhanced the accumulation of Cr. According to electron spin resonance (ESR) measurements, the presence of Zn(II) ions did not change the nature of Cr(V) and Cr(III) complexes generated during the microbial reduction of Cr(VI). The efficiency of Cr(VI) reduction also remained unchanged after the addition of 50 mg/l of Zn(II) to the bacterial cells. However, at high concentrations of Zn(II) (higher than 200 mg/l), the transformation of Cr(VI) to Cr(V) and Cr(III) complexes decreases significantly. In addition, it was shown that the accumulation pattern of Zn in the tested bacterial species in the presence of 100 mg/l of Cr(VI) fits the Langmuir-Freundlich model well. The two tested bacterial strains exhibited different characteristics of Zn accumulation. PMID- 21547699 TI - Maternal plasma and amniotic fluid coenzyme Q10 levels in preterm and term gestations: a pilot study. AB - OBJECTIVE: To measure maternal plasma and amniotic fluid coenzyme Q10 (CoQ10) levels in preterm and term gestations. STUDY DESIGN: This pilot study comprised a convenience sample of 72 women admitted for labor with singleton live gestations and intact membranes (preterm n = 27 and term n = 45). RESULTS: Median [interquartile range] maternal plasma CoQ10 levels did not differ among the studied women (preterm, 0.47 [0.12] vs. term, 0.47 [0.23] mmol/L, p = 0.90). Overall CoQ10 amniotic fluid levels were nearly tenfold lower than those found in maternal plasma, with a significant lower level observed among those delivering preterm (0.050 [0.05] vs. 0.062 [0.04] mmol/L, p = 0.007). Multiple linear regression analysis controlling for several covariates determined a significant correlation between amniotic fluid CoQ10 levels and neonatal gestational age. CONCLUSION: This is the first study to assess CoQ10 levels in amniotic fluid during pregnancy in which levels were significantly lower among those delivering preterm. More research is warranted in this regard. PMID- 21547700 TI - A case of relapsing polychondritis associated with auricular cartilage infiltration of immunoglobulin G4-positive plasma cells and lung cancer. AB - A 79-year-old man was diagnosed with relapsing polychondritis, from symptoms of bilateral auricular deformity and pigmentation, polyarthralgia, and audiovestibular damage, and from histological examination of the left auricular cartilage. The left auricular cartilage biopsy specimen revealed cartilage destruction with infiltration of plasmacytes expressing IgG4. This case suggests that IgG4 may be involved in the pathogenesis and etiology of relapsing polychondritis. PMID- 21547701 TI - Significant attenuation of macrovascular involvement by bosentan in a patient with diffuse cutaneous systemic sclerosis with multiple digital ulcers and gangrene. AB - Systemic sclerosis (SSc) is characterized by vascular injuries, and bosentan has recently been proved to be efficacious for the prevention of new digital ulcers in SSc. We herein report a case of SSc in a patient with refractory digital ulcers and gangrene treated with bosentan. Stenosis of the ulnar artery, evaluated by magnetic resonance angiography, was attenuated by the bosentan treatment, suggesting that bosentan exerts a reverse remodeling effect against the pathological organic changes of arteries in SSc. PMID- 21547702 TI - Elevated preoperative neutrophil:lymphocyte ratio as a predictor of postoperative disease recurrence in esophageal cancer. AB - BACKGROUND: The prognosis for patients with esophageal cancer is poor, even among those who undergo potentially curative esophagectomy. The neutrophil:lymphocyte ratio (NLR) is hypothesized to reflect the systemic inflammatory response created by a tumor and is possibly predictive of tumor aggressiveness and propensity for metastasis. METHODS: We performed a single-center retrospective analysis of esophageal cancer patients who underwent attempted curative esophagectomy at Weill Cornell Medical Center between 1996 and 2009. We collected data on patient demographics, clinical characteristics, and receipt of neoadjuvant treatment. Preoperative blood tests were used to calculate NLR. Elevated NLR was defined a priori as >=5.0. Logistic regression modeling was performed to analyze characteristics associated with elevated NLR. We conducted Kaplan-Meier analyses and Cox regression modeling to determine estimates and predictors of disease-free and overall survival. RESULTS: We identified a total of 295 patients who underwent esophagectomy. The median duration of follow-up was 31 months (interquartile range [IQR] 13-61). There were 56 patients (18.9%) who had elevated NLR preoperatively. Receipt of neoadjuvant therapy was independently associated with high NLR (odds ratio [OR] 2.14, 95% confidence interval [95% CI] 1.02-4.51). In multivariable analyses, elevated NLR was associated with significantly worse disease-free (hazard ratio [HR] 2.26, 95% CI 1.43-3.55) and overall survival (HR 2.31, 95% CI 1.53-3.50). CONCLUSIONS: Preoperative NLR is a potential prognostic marker for recurrence and death after esophagectomy. It is unclear whether NLR reflects the degree of inflammatory response to the primary tumor or other patient-specific or tumor characteristics that predispose to recurrence. Further investigation is warranted to clarify the mechanisms explaining the observed associations between elevated NLR and poor outcomes in esophageal cancer. PMID- 21547703 TI - Value of EUS in Determining Curative Resectability in Reference to CT and FDG PET: The Optimal Sequence in Preoperative Staging of Esophageal Cancer? AB - BACKGROUND: The separate value of endoscopic ultrasonography (EUS), multidetector computed tomography (CT), and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the optimal sequence in staging esophageal cancer has not been investigated adequately. METHODS: The staging records of 216 consecutive operable patients with esophageal cancer were reviewed blindly. Different staging strategies were analyzed, and the likelihood ratio (LR) of each module was calculated conditionally on individual patient characteristics. A logistic regression approach was used to determine the most favorable staging strategy. RESULTS: Initial EUS results were not significantly related to the LRs of initial CT and FDG-PET results. The positive LR (LR+) of EUS-fine-needle aspiration (FNA) was 4, irrespective of CT and FDG-PET outcomes. The LR+ of FDG-PET varied from 13 (negative CT) to 6 (positive CT). The LR+ of CT ranged from 3-4 (negative FDG PET) to 2-3 (positive FDG-PET). Age, histology, and tumor length had no significant impact on the LRs of the three diagnostic tests. CONCLUSIONS: This study argues in favor of PET/CT rather than EUS as a predictor of curative resectability in esophageal cancer. EUS does not correspond with either CT or FDG PET. LRs of FDG-PET were substantially different between subgroups of negative and positive CT results and vice versa. PMID- 21547704 TI - Detection and management of hypothyroidism following thyroid lobectomy: evaluation of a clinical algorithm. AB - BACKGROUND: The objectives of this study were to determine: (1) the incidence permanent hypothyroidism after thyroid lobectomy (TL), (2) whether asymptomatic patients with mildly elevated thyrotropin (TSH) levels can be managed without thyroid hormone replacement, and (3) if the degree of lymphocytic infiltration (LI) and germinal center (GC) formation in the resected thyroid lobe correlates with the development of post-TL hypothyroidism. METHODS: Subjects undergoing TL between January 2006 and January 2008 at 2 centers were enrolled in the study and thyroid function was followed prospectively based on a previously published algorithm. The histology of each resected thyroid lobe was examined, and the degree of LI and GC was quantified. RESULTS: The study cohort consisted of 117 patients. Early postoperative TSH levels were significantly increased over preoperative levels (P < .001). TSH measured at 6 months to 1 year postoperatively, while still significantly increased over preoperative levels (P < .001), was also significantly reduced (P = .006) compared with early postoperative levels. Of the patients who presented with early postoperative hypothyroidism, 69.2% recovered to normal levels without intervention. The overall incidence of early postoperative hypothyroidism was 21.6%, and permanent hypothyroidism was 7.8%. A high degree of LI and GC correlated with a significantly higher mean TSH level (P = .003). CONCLUSIONS: The incidence of hypothyroidism following TL is low, and a significant proportion of individuals who become biochemically hypothyroid will demonstrate only a transient elevation in their TSH levels. As well, individuals with LI, or GC formation, within their resected thyroid lobe may be at increased risk for post-TL hypothyroidism. PMID- 21547705 TI - Mechanisms of mTOR inhibitor resistance in cancer therapy. AB - Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that regulates cell cycle progression, protein translation, metabolism, and cellular proliferation. The mTOR pathway promotes cell proliferation under energy or nutrient-rich conditions by increasing ribosomal biogenesis and protein synthesis. Since enhanced activity of the mTOR pathway is frequently observed in malignant cells, inhibition of this kinase has become an attractive strategy to treat cancer. Rapamycin and its analogs temsirolimus, everolimus, and ridaforolimus referred to as "rapalogs" have demonstrated promising efficacy against renal cell carcinoma and are under investigation for the treatment of other malignancies. However, the emergence of drug resistance may ultimately limit the utility of rapalog therapy. Here we summarize the known mechanisms of resistance to mTOR-inhibitor therapy and describe potential strategies to overcome these for the current agents that target this pathway. PMID- 21547708 TI - Management strategies for internal hernia after gastric bypass. AB - BACKGROUND: Internal hernia after gastric bypass is common, occurring with an incidence approaching 10% in some series. Operative management of internal hernia after gastric bypass presents significant conceptual and technical challenges. METHODS: This manuscript reviews management of internal hernia after gastric bypass with a focus on operative strategy. PMID- 21547706 TI - Super-selection of a subgroup of hepatocellular carcinoma patients at minimal risk of recurrence for liver transplantation. AB - BACKGROUND: A majority of patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT) meet the Milan criteria, but these are still regarded as the narrowest criteria for transplantation. Prognostic analysis of incidentally detected HCC after LT suggests that a subgroup of HCC patients is at very low risk of recurrence. To determine the criteria defining this super selection group, we retrospectively analyzed survival data of 593 adult living donor LT recipients with HCC in the explanted liver DISCUSSION: Tumor features of incidental HCC in 38 patients not showing recurrence were analyzed. Of these patients, 34 (89.5%) each had <=2 tumors and tumors <=2.0 cm in size. Applying these criteria to 555 patients with pretransplant known HCC (pkHCC) allowed us to identify 79 patients with untreated pkHCCs <=2.0 cm in size. To date, only two of these patients have shown recurrence, making the conditions for super-selection the presence of tumors <=2.0 cm in size, <=2 tumors, alpha-fetoprotein <=200 ng/mL, and no pretransplant treatment. In 87 patients satisfying these criteria, the 10-year recurrence and survival rates were 1.3% and 92.1%, respectively. After excluding patients meeting these criteria, the 5-year recurrence rates in patients satisfying the Milan, University of California at San Francisco, and Asan criteria were increased by 2.9-4.0%. In conclusion, this super-selection or super-Milan category may be used for validation assessment of various indication criteria and for the development of cost-effective post-transplantation HCC surveillance protocols. Further studies should be followed for deceased-donor LT and patients who have undergone pretransplant treatment. PMID- 21547707 TI - Prognostic factors of patients with advanced gallbladder carcinoma following aggressive surgical resection. AB - BACKGROUND: The prognosis for patients with advanced gallbladder carcinoma is dismal despite aggressive surgical resection. The aim of this study is to determine useful prognostic factors for patients with gallbladder carcinoma following aggressive surgical resection. METHODS: Medical records of 62 patients with gallbladder carcinoma who underwent surgical resection were retrospectively reviewed. Univariate and multivariate models were used to analyze the effect of clinicopathological factors on long-term survival. RESULTS: According to the UICC staging system, ten (16%), 11 (18%), eight (13%), 16 (25%), nine (15%), and eight patients (13%) were diagnosed with stages I, II, IIIA, IIIB, IVA, and IVB disease, respectively. Partial hepatectomy and pancreatoduodenectomy were performed for 43 (69%) and 11 (18%) patients, respectively. Overall survival rates of all 62 and 41 patients with UICC stages III and IV disease were 71% and 56% at 1 year, 48% and 23% at 3 years, and 48% and 23% at 5 years, respectively (median survival time, 15.8 and 12.7 months, respectively). Multivariate analysis revealed that independent prognostic factors included tumor differentiation (p = 0.006), hepatic invasion (p = 0.002), lymph node metastasis (p = 0.009), and surgical margin status (p = 0.002) for all patients, and adjuvant chemotherapy (p = 0.005), tumor differentiation (p = 0.008), hepatic invasion (p = 0.001), and surgical margin status (p = 0.022) for patients with UICC stages III and IV disease. CONCLUSIONS: R0 resection and adjuvant chemotherapy are significant prognostic factors in advanced gallbladder carcinoma and should be performed to improve survival. PMID- 21547709 TI - Cover essay. PMID- 21547710 TI - Medical conditions in autism spectrum disorders. AB - Autism spectrum disorder (ASD) is a behaviourally defined syndrome where the etiology and pathophysiology is only partially understood. In a small proportion of children with the condition, a specific medical disorder is identified, but the causal significance in many instances is unclear. Currently, the medical conditions that are best established as probable causes of ASD include Fragile X syndrome, Tuberous Sclerosis and abnormalities of chromosome 15 involving the 15q11-13 region. Various other single gene mutations, genetic syndromes, chromosomal abnormalities and rare de novo copy number variants have been reported as being possibly implicated in etiology, as have several ante and post natal exposures and complications. However, in most instances the evidence base for an association with ASD is very limited and largely derives from case reports or findings from small, highly selected and uncontrolled case series. Not only therefore, is there uncertainty over whether the condition is associated, but the potential basis for the association is very poorly understood. In some cases the medical condition may be a consequence of autism or simply represent an associated feature deriving from an underlying shared etiology. Nevertheless, it is clear that in a growing proportion of individuals potentially causal medical conditions are being identified and clarification of their role in etio pathogenesis is necessary. Indeed, investigations into the causal mechanisms underlying the association between conditions such as tuberous sclerosis, Fragile X and chromosome 15 abnormalities are beginning to cast light on the molecular and neurobiological pathways involved in the pathophysiology of ASD. It is evident therefore, that much can be learnt from the study of probably causal medical disorders as they represent simpler and more tractable model systems in which to investigate causal mechanisms. Recent advances in genetics, molecular and systems biology and neuroscience now mean that there are unparalleled opportunities to test causal hypotheses and gain fundamental insights into the nature of autism and its development. PMID- 21547714 TI - Cover essay. PMID- 21547712 TI - Fragile x syndrome and autism: from disease model to therapeutic targets. AB - Autism is an umbrella diagnosis with several different etiologies. Fragile X syndrome (FXS), one of the first identified and leading causes of autism, has been modeled in mice using molecular genetic manipulation. These Fmr1 knockout mice have recently been used to identify a new putative therapeutic target, the metabotropic glutamate receptor 5 (mGluR5), for the treatment of FXS. Moreover, mGluR5 signaling cascades interact with a number of synaptic proteins, many of which have been implicated in autism, raising the possibility that therapeutic targets identified for FXS may have efficacy in treating multiple other causes of autism. PMID- 21547713 TI - Tuberous sclerosis complex: everything old is new again. AB - Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease caused by loss of function of either the TSC1 (encodes hamartin) or TSC2 (encodes tuberin) genes. Patients with TSC have benign tumors (hamartomas) in multiple organs though brain involvement is typically the most disabling aspect of the disease as very high rates of neurodevelopmental disorders are seen. While first described well over 120 years ago, recent advances have transformed TSC into a prototypical disorder that exemplifies the methods and potential of molecular medicine. This review will detail historical aspects of TSC and its strong associations with neurodevelopmental disorders focusing on epilepsy and autism. Finally, promising new approaches for the treatment of epilepsy and autism in patients with TSC as well as those in the general population will be discussed. PMID- 21547715 TI - Prevalence of treated autism spectrum disorders in Aruba. AB - To study autism outside of a narrow range of settings previously studied, and in a particularly distinctive setting in the Caribbean. The aim of the Aruba Autism Project was to determine the prevalence of autism spectrum disorders (ASDs) in birth years 1990-1999 in Aruba. A record review study was conducted; cases were ascertained from children treated at the Child & Adolescent Psychiatry Clinic of Aruba, the first and only child psychiatry service on the island. In these 10 birth years we found a prevalence for autistic disorder (AD) of 1.9 per 1,000 (95% CI 1.2-2.8) and for autism spectrum disorders of 5.3 per 1,000 (95% CI 4.1 6.7). Comparison analysis with a cumulative incidence report from the UK, showed a similar cumulative incidence to age five in Aruba. Prevalence of ASDs in birth years 1990-1999 and cumulative incidence to age five in Aruba are similar to recent reports from the United Kingdom and the United States. PMID- 21547711 TI - The pathophysiology of restricted repetitive behavior. AB - Restricted, repetitive behaviors (RRBs) are heterogeneous ranging from stereotypic body movements to rituals to restricted interests. RRBs are most strongly associated with autism but occur in a number of other clinical disorders as well as in typical development. There does not seem to be a category of RRB that is unique or specific to autism and RRB does not seem to be robustly correlated with specific cognitive, sensory or motor abnormalities in autism. Despite its clinical significance, little is known about the pathophysiology of RRB. Both clinical and animal models studies link repetitive behaviors to genetic mutations and a number of specific genetic syndromes have RRBs as part of the clinical phenotype. Genetic risk factors may interact with experiential factors resulting in the extremes in repetitive behavior phenotypic expression that characterize autism. Few studies of individuals with autism have correlated MRI findings and RRBs and no attempt has been made to associate RRB and post-mortem tissue findings. Available clinical and animal models data indicate functional and structural alterations in cortical-basal ganglia circuitry in the expression of RRB, however. Our own studies point to reduced activity of the indirect basal ganglia pathway being associated with high levels of repetitive behavior in an animal model. These findings, if generalizable, suggest specific therapeutic targets. These, and perhaps other, perturbations to cortical basal ganglia circuitry are mediated by specific molecular mechanisms (e.g., altered gene expression) that result in long-term, experience-dependent neuroadaptations that initiate and maintain repetitive behavior. A great deal more research is needed to uncover such mechanisms. Work in areas such as substance abuse, OCD, Tourette syndrome, Parkinson's disease, and dementias promise to provide findings critical for identifying neurobiological mechanisms relevant to RRB in autism. Moreover, basic research in areas such as birdsong, habit formation, and procedural learning may provide additional, much needed clues. Understanding the pathophysioloy of repetitive behavior will be critical to identifying novel therapeutic targets and strategies for individuals with autism. PMID- 21547716 TI - A functional polymorphism of the brain derived neurotrophic factor gene and cortical anatomy in autism spectrum disorder. AB - Autism Spectrum Disorder (ASD) is associated with both (i) post-mortem and neuroimaging evidence of abnormal cortical development, and (ii) altered signalling in Brain Derived Neurotrophic Factor (BDNF) pathways - which regulate neuroproliferative and neuroplastic processes. In healthy controls genotype at a single nucleotide polymorphism that alters BDNF signalling (Val66met) has been related to regional cortical volume. It is not known however if this influence on brain development is intact in ASD. Therefore we compared the relationship between genotype and cortical anatomy (as measured using in vivo Magnetic Resonance Imaging) in 41 people with ASD and 30 healthy controls. We measured cortical volume, and its two sole determinants - cortical thickness and surface area - which reflect differing neurodevelopmental processes. We found "Group-by Genotype" interactions for cortical volume in medial (caudal anterior cingulate, posterior cingulate) and lateral (rostral middle, lateral orbitofrontal, pars orbitalis and pars triangularis) frontal cortices. Furthermore, within (only) these regions "Group-by-Genotype" interactions were also found for surface area. No effects were found for cortical thickness in any region. Our preliminary findings suggest that people with ASD have differences from controls in the relationship between BDNF val66met genotype and regional (especially frontal) cortical volume and surface area, but not cortical thickness. Therefore alterations in the relationship between BDNF val66met genotype and surface area in ASD may drive the findings for volume. If correct, this suggests ASD is associated with a distorted relationship between BDNF val66met genotype and the determinants of regional cortical surface area - gyrification and/or sulcal positioning. PMID- 21547718 TI - Cover essay. PMID- 21547717 TI - Developmental learning impairments in a rodent model of nodular heterotopia. AB - Developmental malformations of neocortex-including microgyria, ectopias, and periventricular nodular heterotopia (PNH)-have been associated with language learning impairments in humans. Studies also show that developmental language impairments are frequently associated with deficits in processing rapid acoustic stimuli, and rodent models have linked cortical developmental disruption (microgyria, ectopia) with rapid auditory processing deficits. We sought to extend this neurodevelopmental model to evaluate the effects of embryonic (E) day 15 exposure to the anti-mitotic teratogen methylazoxymethanol acetate (MAM) on auditory processing and maze learning in rats. Extensive cortical anomalies were confirmed in MAM-treated rats post mortem. These included evidence of laminar disruption, PNH, and hippocampal dysplasia. Juvenile auditory testing (P21-42) revealed comparable silent gap detection performance for MAM-treated and control subjects, indicating normal hearing and basic auditory temporal processing in MAM subjects. Juvenile testing on a more complex two-tone oddball task, however, revealed a significant impairment in MAM-treated as compared to control subjects. Post hoc analysis also revealed a significant effect of PNH severity for MAM subjects, with more severe disruption associated with greater processing impairments. In adulthood (P60-100), only MAM subjects with the most severe PNH condition showed deficits in oddball two-tone processing as compared to controls. However, when presented with a more complex and novel FM sweep detection task, all MAM subjects showed significant processing deficits as compared to controls. Moreover, post hoc analysis revealed a significant effect of PNH severity on FM sweep processing. Water Maze testing results also showed a significant impairment for spatial but not non-spatial learning in MAM rats as compared to controls. Results lend further support to the notions that: (1) generalized cortical developmental disruption (stemming from injury, genetic or teratogenic insults) leads to auditory processing deficits, which in turn have been suggested to play a causal role in language impairment; (2) severity of cortical disruption is related to the severity of processing impairments; (3) juvenile auditory processing deficits appear to ameliorate with maturation, but can still be elicited in adulthood using increasingly complex acoustic stimuli; and (4) malformations induced with MAM are also associated with generalized spatial learning deficits. These cumulative findings contribute to our understanding of the behavioral consequences of cortical developmental pathology, which may in turn elucidate mechanisms contributing to developmental language learning impairment in humans. PMID- 21547719 TI - Choline transporter gene variation is associated with attention-deficit hyperactivity disorder. AB - The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer's Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Disorder (ADHD). The presynaptic choline transporter (CHT, SLC5A7) is the major, rate-limiting determinant of ACh production in the brain and periphery and is consequently upregulated during tasks that require sustained attention. Given the contribution of central cholinergic circuits to the control of movement and attention, we hypothesized that functional CHT gene variants might impact risk for ADHD. We performed a case-control study, followed by family-based association tests on a separate cohort, of two purportedly functional CHT polymorphisms (coding variant Ile89Val (rs1013940) and a genomic SNP 3' of the CHT gene (rs333229), affording both a replication sample and opportunities to reduce potential population stratification biases. Initial genotyping of pediatric ADHD subjects for two purportedly functional CHT alleles revealed a 2-3 fold elevation of the Val89 allele (n = 100; P = 0.02) relative to healthy controls, as well as a significant decrease of the 3'SNP minor allele in Caucasian male subjects (n = 60; P = 0.004). In family based association tests, we found significant overtransmission of the Val89 variant to children with a Combined subtype diagnosis (OR = 3.16; P = 0.01), with an increased Odds Ratio for a haplotype comprising both minor alleles. These studies show evidence of cholinergic deficits in ADHD, particularly for subjects with the Combined subtype, and, if replicated, may encourage further consideration of cholinergic agonist therapy in the disorder. PMID- 21547720 TI - Autistic behavior in boys with fragile X syndrome: social approach and HPA-axis dysfunction. AB - The primary goal of this study was to examine environmental and neuroendocrine factors that convey increased risk for elevated autistic behavior in boys with Fragile X syndrome (FXS). This study involves three related analyses: (1) examination of multiple dimensions of social approach behaviors and how they vary over time, (2) investigation of mean levels and modulation of salivary cortisol levels in response to social interaction, and (3) examination of the relationship of social approach and autistic behaviors to salivary cortisol. Poor social approach and elevated baseline and regulation cortisol are discernible traits that distinguish boys with FXS and ASD from boys with FXS only and from typically developing boys. In addition, blunted cortisol change is associated with increased severity of autistic behaviors only within the FXS and ASD group. Boys with FXS and ASD have distinct behavioral and neuroendocrine profiles that differentiate them from those with FXS alone and typically developing boys. PMID- 21547721 TI - Novel copy number variants in children with autism and additional developmental anomalies. AB - Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip(r) (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone. PMID- 21547722 TI - Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia. AB - Growth factor Neuregulin 1 (NRG1) plays an essential role in development and organization of the cerebral cortex. NRG1 and its receptors, ERBB3 and ERBB4, have been implicated in genetic susceptibility for schizophrenia. Disease symptoms include asociality and altered social interaction. To investigate the role of NRG1-ERBB signaling in social behavior, mice heterozygous for an Nrg1 null allele (Nrg1+/-), and mice with conditional ablation of Erbb3 or Erbb4 in the central nervous system, were evaluated for sociability and social novelty preference in a three-chambered choice task. Results showed that deficiencies in NRG1 or ERBB3 significantly enhanced sociability. All of the mutant groups demonstrated a lack of social novelty preference, in contrast to their respective wild-type controls. Effects of NRG1, ERBB3, or ERBB4 deficiency on social behavior could not be attributed to general changes in anxiety-like behavior, activity, or loss of olfactory ability. Nrg1+/- pups did not exhibit changes in isolation-induced ultrasonic vocalizations, a measure of emotional reactivity. Overall, these findings provide evidence that social behavior is mediated by NRG1 ERBB signaling. PMID- 21547723 TI - Introduction to section I: overview of approaches to study cystic fibrosis pathophysiology. AB - Mutation of the CFTR chloride channel was identified as the genetic basis of cystic fibrosis over 20 years ago; however, correlation of the pathophysiological changes occurring in CF lung disease with the mutation of a chloride channel is ongoing. The failure of innate lung defense in CF, and the subsequent cyclical microbial colonization of airways, explains the gross anatomical changes that occur in CF pathophysiology. However, ongoing research is focused on how the lack of the CFTR channel explains the failure of innate lung defense. Hydration status of the mucus blanket is key to understanding this link, and this series of chapters details the recent progress that has been made in understanding the interplay between ion transport activity and innate lung defense, and the initiation of CF lung pathophysiology. PMID- 21547724 TI - Imaging CFTR protein localization in cultured cells and tissues. AB - CFTR functions as a chloride channel at the apical membrane of airway, gastrointestinal, and other epithelial cells. Immunofluorescence microscopy is commonly used to assess the subcellular localization and relative abundance of CFTR. Visualization of heterologously overexpressed CFTR is typically unproblematic and straightforward, whereas detection of small quantities of endogenous CFTR in tissues can be challenging and requires highly specific antibodies and optimized staining protocols. CFTR tagged by green fluorescent protein can be employed to study trafficking in live cells. Tagging of CFTR with an extracellular epitope permits detection exclusively at the cell surface and subsequent chasing allows visualization of endocytic trafficking. PMID- 21547725 TI - CFTR regulation of epithelial sodium channel. AB - Cystic fibrosis (CF) is a lethal genetic disorder, characterized by both clinical and genetic complexities, and arises as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The gene encodes a Cl( ) channel belonging to the ABC (ATP Binding Cassette) superfamily of transporters. The members of this superfamily use ATP hydrolysis to fulfill their function as active transporters. So far, CFTR is the only member of this family to function as a cAMP-activated Cl(-) channel. Intense research following the cloning of the CFTR gene has extended the role of the CFTR beyond that of a Cl(-) channel. One of the best recognized, yet still controversial, functions of the CFTR is its ability to modulate the functioning of other transporters. The modulation of epithelial Na(+) channel (ENaC) function serves as a prime example of regulatory function of the CFTR. In this chapter, we will briefly describe an integrated protocol consisting of biochemical and electrophysiological approaches to study the regulation of ENaC by CFTR. PMID- 21547726 TI - Methods for evaluating inflammation in cystic fibrosis. AB - Cystic fibrosis is characterized by excessive pulmonary inflammation, which presents early in life and becomes self-sustaining, eventually leading to the destruction of the lung. Treating inflammation is one of the most pressing needs in CF therapy and has been shown to slow lung function deterioration. However, it remains unclear whether excessive inflammation is a direct result of CFTR dysfunction, and thus innate, or develops in response to early stimulation of inflammatory pathways. Here, we will discuss clinically relevant studies and the methods employed by them. We will focus on investigations in cell and animal models as well as patients. Our discussion will describe the character of pulmonary inflammation in CF and present potential therapeutic approaches that can ameliorate excessive responses and improve disease prognosis. PMID- 21547727 TI - Methods for ASL measurements and mucus transport rates in cell cultures. AB - The healthy human respiratory tract is lined with a pseudostratified epithelia composed of ~80% ciliated cells and ~20% goblet cells. These cells produce and are bathed by a layer of airway surface liquid (ASL), which plays a critical role in lung defense by helping to maintain the sterility of the lung. This layer is composed of two phases: the mucus layer which functions to trap particulates, bacteria, and viruses, and the underlying periciliary liquid layer (PCL), which provides hydration, enabling mucus transport and clearance. This chapter describes the methods used to measure the structure and height of the ASL by XZ confocal microscopy and mucus transport rates using epifluorescent microscopy in live airway cultures. Furthermore, we also demonstrate that these methods are also applicable in novel ways to probe the ultrastructure of the airways including the establishment of pH gradients and the ability of the apical membrane glycocalyx in excluding larger molecules from the cell surface. PMID- 21547728 TI - Measurement of fluid secretion from intact airway submucosal glands. AB - Human airways are kept sterile by a mucosal innate defense system that includes mucus secretion. Mucus is secreted in healthy upper airways primarily by submucosal glands and consists of defense molecules mixed with mucins, electrolytes, and water and is also a major component of sputum. Mucus traps pathogens and mechanically removes them via mucociliary clearance while inhibiting their growth via molecular (e.g., lysozyme) and cellular (e.g., neutrophils, macrophages) defenses. Fluid secretion rates of single glands in response to various mediators can be measured by trapping the primary gland mucus secretions in an oil layer, where they form spherical bubbles that can be optically measured at any desired interval to provide detailed temporal analysis of secretion rates. The composition and properties of the mucus (e.g., solids, viscosity, pH) can also be determined. These methods have now been applied to mice, ferrets, cats, pigs, sheep, and humans, with a main goal of comparing gland secretion in control and CFTR-deficient humans and animals. PMID- 21547729 TI - Measurements of intracellular calcium signals in polarized primary cultures of normal and cystic fibrosis human airway epithelia. AB - The airways are continuously challenged by a variety of stimuli including bacteria, viruses, allergens, and inflammatory factors that act as agonists for G protein-coupled receptors (GPCR). Intracellular calcium (Ca(2+) (i)) mobilization in airway epithelia in response to extracellular stimuli regulates key airway innate defense functions, e.g., Ca(2+)-activated Cl(-) secretion, ciliary beating, mucin secretion, and inflammatory responses. Because Ca(2+) (i) mobilization in response to luminal stimuli is larger in CF vs. normal human airway epithelia, alterations in Ca(2+) (i) signals have been associated with the pathogenesis of CF airway disease. Hence, assessment of Ca(2+) (i) signaling has become an important area of CF research. This chapter will focus on measurements of cytoplasmic and mitochondrial Ca(2+) signals resulting from GPCR activation in polarized primary cultures of normal and CF human bronchial epithelia (HBE). PMID- 21547730 TI - Identification and quantification of mucin expression. AB - The major phenotype of CF is the accumulation of mucus, a phenomenon whose relation to the dysfunctional CFTR is still not fully understood. This means that studies of mucus and its main component, the mucins, are important. Due to the large size and high glycosylation level, such questions need special considerations and methodology. We describe methods for the general quantification of heavily glycosylated proteins as the mucins using dot/slot blot. We also describe the separation of the mucins by gel electrophoresis and the identification with specific antibodies on Western blot and by proteomics. PMID- 21547731 TI - Methods to classify bacterial pathogens in cystic fibrosis. AB - Many bacteria can be detected in CF sputum, pathogenic and commensal. Modified Koch's criteria for identification of established and emerging CF pathogens are therefore described. Methods are described to isolate bacteria and to detect bacterial biofilms in sputum or lung tissue from CF patients by means of conventional culturing and staining techniques and by the PNA FISH technique. Additionally, the confocal scanning laser microscopy technique is described for studying biofilms in vitro in a flow cell system. The recA-gene PCR and the RFLP based identification methods are described for identification of isolates from the Burkholderia complex to the species level. DNA typing by PFGE, which can be used for any bacterial pathogen, is described as it is employed for Pseudomonas aeruginosa. A commercially available ELISA method is described for measuring IgG antibodies against P. aeruginosa in CF patients. PMID- 21547732 TI - Approaches to study differentiation and repair of human airway epithelial cells. AB - One of the main functions of the airway mucosa is to maintain a mechanical barrier at the air-surface interface and to protect the respiratory tract from external injuries. Differentiation of human airway epithelial cells (hAECs) to polarized airway mucosa can be reproduced in vitro by culturing the cells on microporous membrane at the air-liquid interface. Here, we describe approaches to study differentiation as well as repair of the hAECs by using a commercially available airway cell culture model called MucilAirTM. PMID- 21547733 TI - Introduction to section II: omics in the biology of cystic fibrosis. AB - Cystic fibrosis (CF) is a disease that manifests itself in the context of cell, tissue, and organismal (patho)physiology. While a strong focus on the cystic fibrosis transmembrane conductance regulator (CFTR) since its discovery in 1989 has dominated the field with a wealth of experiments that have provided substantial insight into protein function and structure, a largely untapped area of high relevance to both our basic understanding of CFTR function and its role in clinical disease is the realization that CFTR operates in the context of a cellular network. This is a composite of protein-protein interactions and specific cellular and subcellular environments that balance ion conductance at the cell surface with trafficking through the exocytic and endocytic pathways to promote tissue hydration. To address challenges critical for understanding the system responsible for CFTR physiology and CF pathophysiology, a new era of technologies and methodologies focused on systems-level approaches to analysis of cell and tissue function has emerged. These technologies focus our understanding on the environment supporting protein function (referred to genomics) and the protein composition of the cell (referred to as proteomics) that dictates function. In this section, four chapters focus on emerging "omic" approaches to understanding the cellular environment imposed by message levels in the cell (genomics), the protein composition of the cell and network of interactions dictating cell and CFTR function (proteomics), and the lipid environment (metabolomics) that dictates the functionality of numerous membrane environments in the cell that are integral to CFTR function. PMID- 21547734 TI - Microarray mRNA expression profiling to study cystic fibrosis. AB - To understand the links between CFTR mutations and the development of cystic fibrosis (CF) phenotypes, it is imperative to study the transcriptome in affected cell types. Microarray expression profiling provides a platform to study global gene expression in detail. This approach may provide the necessary information to segregate phenotypic characteristics of CF, differentiate between genetic or environmental factors, and assess the advent and progression of disease phenotypes. Moreover, if a "CF signature" of genes with altered expression is defined, this can be used to monitor effectiveness of treatment. We provide here detailed protocols and tips for collecting and preserving tissues and cells, and preparing total RNA. We also outline novel strategies for experimental design and data analysis, and describe some powerful gene and pathway discovery tools. PMID- 21547735 TI - Quantitative differential proteomics of cystic fibrosis cell models by SILAC (stable isotope labelling in cell culture). AB - Differential proteomics represents an enticing strategy to unmask the proteins involved in CF pathogenesis and to discover potential therapeutic targets and/or markers of disease progression. Quantitative proteomics is possible nowadays owing to the recent progress in protein labelling and/or in label-free approaches, combined to sensitive detection by mass spectrometry (MS). In this chapter, we present one strategy to perform differential quantitative proteomic studies on different cellular compartments of proliferating cell lines expressing wild-type (WT) CFTR and F508del-CFTR using stable isotope labelling in cell culture (SILAC). PMID- 21547736 TI - Application of mass spectrometry to study proteomics and interactomics in cystic fibrosis. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) does not function in isolation, but rather in a complex network of protein-protein interactions that dictate the physiology of a healthy cell and tissue and, when defective, the pathophysiology characteristic of cystic fibrosis (CF) disease. To begin to address the organization and operation of the extensive cystic fibrosis protein network dictated by simultaneous and sequential interactions, it will be necessary to understand the global protein environment (the proteome) in which CFTR functions in the cell and the local network that dictates CFTR folding, trafficking, and function at the cell surface. Emerging mass spectrometry (MS) technologies and methodologies offer an unprecedented opportunity to fully characterize both the proteome and the protein interactions directing normal CFTR function and to define what goes wrong in disease. Below we provide the CF investigator with a general introduction to the capabilities of modern mass spectrometry technologies and methodologies with the goal of inspiring further application of these technologies for development of a basic understanding of the disease and for the identification of novel pathways that may be amenable to therapeutic intervention in the clinic. PMID- 21547737 TI - Functional genomics assays to study CFTR traffic and ENaC function. AB - As several genomes have been sequenced, post-genomic approaches like transcriptomics and proteomics, identifying gene products differentially expressed in association with a given pathology, have held promise both of understanding the pathways associated with the respective disease and as a fast track to therapy. Notwithstanding, these approaches cannot distinguish genes and proteins with mere secondary pathological association from those primarily involved in the basic defect(s). New global strategies and tools identifying gene products responsible for the basic cellular defect(s) in CF pathophysiology currently being performed are presented here. These include high-content screens to determine proteins affecting function and trafficking of CFTR and ENaC. PMID- 21547738 TI - New lipidomic approaches in cystic fibrosis. AB - Lipid analysis has been a crucial source of information in cystic fibrosis (CF). New methodologies for qualitative and quantitative lipidomics allow evaluation of a large number of samples, of special interest in patient screening for diagnostic and prognostic biological markers, as well as in cell physiology. In this chapter, two new complementary approaches are described: matrix-assisted laser desorption coupled to time of flight (MALDI-TOF-ClinProToolsTM) and liquid chromatography coupled to ion trap mass spectrometry (LC-MS( n )). MALDI-TOF ClinProToolsTM offers a large unbiased screening for the discovery of potential lipid alterations in diseased patients. LC-MS( n ) represents a state-of-the-art lipidomic tool for the identification and quantification of such alterations. The combination of both may open new perspectives in the quest for lipids participating in CF pathogenesis, therapy targets, and biomarkers. PMID- 21547739 TI - Introduction to section III: resources for CFTR research. AB - This section of Cystic Fibrosis Protocols and Diagnosis focuses on resources available to facilitate the activities of the research community in the field of cystic fibrosis (CF). An overview of the protocols and resources described in subsequent chapters of this book section is provided, as well as how they can accelerate research in this area. PMID- 21547740 TI - Primary epithelial cell models for cystic fibrosis research. AB - When primary human airway epithelial (hAE) cells are grown in vitro on porous supports at an air-liquid interface (ALI), they recapitulate in vivo morphology and key physiologic processes. These cultures are useful for studying respiratory tract biology and diseases and for testing new cystic fibrosis (CF) therapies. This chapter gives protocols enabling creation of well-differentiated primary CF and non-CF airway epithelial cell cultures with non-proprietary reagents. We also discuss the production of retroviral and lentiviral vectors, the derivation of hAE cell lines, reporter gene assays, and the evolving science of gene overexpression and knockdown in ALI hAE cultures. PMID- 21547741 TI - Comparative biology of cystic fibrosis animal models. AB - Animal models of human diseases are critical for dissecting mechanisms of pathophysiology and developing therapies. In the context of cystic fibrosis (CF), mouse models have been the dominant species by which to study CF disease processes in vivo for the past two decades. Although much has been learned through these CF mouse models, limitations in the ability of this species to recapitulate spontaneous lung disease and several other organ abnormalities seen in CF humans have created a need for additional species on which to study CF. To this end, pig and ferret CF models have been generated by somatic cell nuclear transfer and are currently being characterized. These new larger animal models have phenotypes that appear to closely resemble human CF disease seen in newborns, and efforts to characterize their adult phenotypes are ongoing. This chapter will review current knowledge about comparative lung cell biology and cystic fibrosis transmembrane conductance regulator (CFTR) biology among mice, pigs, and ferrets that has implications for CF disease modeling in these species. We will focus on methods used to compare the biology and function of CFTR between these species and their relevance to phenotypes seen in the animal models. These cross-species comparisons and the development of both the pig and the ferret CF models may help elucidate pathophysiologic mechanisms of CF lung disease and lead to new therapeutic approaches. PMID- 21547742 TI - CFTR Folding Consortium: methods available for studies of CFTR folding and correction. AB - The CFTR Folding Consortium (CFC) was formed in 2004 under the auspices of the Cystic Fibrosis Foundation and its drug discovery and development affiliate, CFF Therapeutics. A primary goal of the CFC is the development and distribution of reagents and assay methods designed to better understand the mechanistic basis of mutant CFTR misfolding and to identify targets whose manipulation may correct CFTR folding defects. As such, reagents available from the CFC primarily target wild-type CFTR NBD1 and its common variant, F508del, and they include antibodies, cell lines, constructs, and proteins. These reagents are summarized here, and two protocols are described for the detection of cell surface CFTR: (a) an assay of the density of expressed HA-tagged CFTR by ELISA and (b) the generation and use of an antibody to CFTR's first extracellular loop for the detection of endogenous CFTR. Finally, we highlight a systematic collection of assays, the CFC Roadmap, which is being used to assess the cellular locus and mechanism of mutant CFTR correction. The Roadmap queries CFTR structure-function relations at levels ranging from purified protein to well-differentiated human airway primary cultures. PMID- 21547743 TI - Evaluation of the disease liability of CFTR variants. AB - Over 1600 novel sequence variants in the CFTR gene have been reported to the CF Mutation Database (http://www.genet.sickkids.on.ca/cftr/Home.html). While about 25 mutations are well characterized by clinical studies and functional assays, the disease liability of most of the remaining mutations is either unclear or unknown. This gap in knowledge has implications for diagnosis, therapy selection, and counseling for patients and families carrying an uncharacterized CFTR mutation. This chapter will describe a critical approach to assessing the disease implications of CFTR mutations utilizing clinical data, literature review, functional testing, and bioinformatic in silico methods. PMID- 21547744 TI - Age-group differences in facets of positive and negative affect. AB - OBJECTIVES: The higher order structure of Positive Affect (PA) and Negative Affect (NA) is comparable in self-report affect data from younger and older adults. The current study advances this work by comparing the factor structure of facets of PA and NA in older and younger adults using exploratory and confirmatory factor analyses. METHOD: Older (N = 203; M age = 73.5 years, range 65-92) and younger (N = 349; M age = 19.1 years, range 18-30) adults completed the Positive and Negative Affect Schedule-Expanded Form (PANAS-X) (Watson, D., & Clark, L.A. (1999). Manual for the Positive and Negative Affect Schedule -- Expanded Form. Iowa City, IA: The University of Iowa), which measures General PA and NA as well as three facets of PA (Joviality, Self-Assurance, and Attentiveness) and four facets of NA (Fear, Sadness, Guilt, and Hostility). RESULTS: Item-level exploratory factor analyses of the facet scales revealed structures that were similar in older and younger adults; however, older adult solutions were more diffuse and diverged more from the PANAS-X scale structure. The facet of Sadness exhibited the largest age-group difference, relating more to guilt and anxiety in older than younger adults. CONCLUSION: Older adults may discriminate less amongst specific affect terms or may experience greater affective heterogeneity. Further, Sadness may manifest in age-specific ways. The construct variance of Sadness, and how this issue might be related to the assessment of depression in older adults, is discussed. PMID- 21547745 TI - Self-efficacy for managing dementia may protect against burden and depression in Alzheimer's caregivers. AB - BACKGROUND: Self-efficacy is the belief that one can perform a specific task or behaviour and is a modifiable attribute which has been shown to influence health behaviours. Few studies have examined the relationship between self-efficacy for dementia-related tasks and symptoms of burden and depression in caregivers. METHODS: Eighty four patient/caregiver dyads with Alzheimer's disease were recruited through a memory clinic. Patient function, cognition and neuropsychiatric symptoms were assessed together with caregiver burden, personality, depressive symptoms, coping strategies and self-efficacy for completing tasks related to dementia care. RESULTS: 33% (28) of caregivers reported significant depressive symptoms (CES-D >= 10). In multivariate analyses, caregiver burden was predicted by self-efficacy for symptom management, neuroticism, patient function and neuropsychiatric symptoms while caregiver depression was predicted by self-efficacy for symptom management, caregiver educational level, neuroticism, emotion-focused coping, dysfunctional coping and patient function. In patients with moderate to severe impairment (MMSE <= 20), self-efficacy for symptom management behaved as a mediator between patient neuropsychiatric symptoms and symptoms of burden and depression in caregivers. CONCLUSIONS: Further longitudinal investigation is warranted to determine if self efficacy might be usefully considered a target in future interventional studies to alleviate symptoms of burden and depression in Alzheimer's caregivers. PMID- 21547746 TI - The impact of comorbidity and other clinical and sociodemographic factors on health-related quality of life in Greek patients with Parkinson's disease. AB - OBJECTIVES: This study was designed to evaluate the impact of other common self reported comorbid disorders (hypertension, dyslipidemia, ischemic heart disease, diabetes mellitus, minor stroke, arthritis, low back pain or osteoporosis and depression) on health-related Quality of Life (HRQoL) of Parkinson's disease (PD) patients and to explore the association of their HRQoL with various sociodemographic and clinical factors. METHODS: Data about age, gender, education, occupation, income, marital and residential status, social relations, disease duration, functional status, treatment and concomitant diseases were collected of 139 Greek patients (68 men and 71 women) with PD. Patients were consecutively recruited from the outpatient clinic of the first Neurology Department of Athens National University at Aeginition Hospital. Disease severity was assessed using the unified Parkinson's disease rating scale including Hoehn and Yahr and Schwab and England (S&E) scales. HRQoL was measured by the specific Parkinson's disease questionnaire (PDQ-39). A multivariate multiple regression model with normal errors was used for the statistical analysis. RESULTS: The main determinants of HRQoL were low degree of independence measured by the S&E scale (F = 35.942, p < 0.001), social isolation (F = 20.508, p < 0.001), disease duration (F = 14.983, p < 0.001), sleep (F = 6.507, p = 0.013) and gastrointestinal disturbances (F = 4.643, p = 0.035) and the presence of depression (F = 6.022, p = 0.017). CONCLUSION: Among the other chronic comorbidities only depression was associated with a poor HRQoL in PD patients. Functional dependence and social isolation contributed most to worse HRQoL. Our findings suggest that adequate social support and management of depression, sleep and gastrointestinal disturbances could reduce the distress and improve HRQoL in patients with PD. PMID- 21547747 TI - Use of the Distress Thermometer for the Elderly in the identification of distress and need in nursing and care homes. AB - BACKGROUND: Previous studies have found high levels of undetected psychological distress and unaddressed need among care home residents. The aim of this study was to investigate the usability and usefulness of the Distress Thermometer for the Elderly (DTE; modified from a measure used in cancer care) in the identification of distress and need with older people in care homes. METHOD: This was a single group, cross-sectional study. Staff in 12 nursing homes and one care home in England completed the DTE and a measure of depression with their older residents (n = 66). Quantitative methods were employed to investigate the relationship between the Distress Thermometer rating, depression scores and problems or needs selected on the DTE. RESULTS: The DTE was found to be feasible for completion by residents with assistance from staff. The level of distress on the DTE was significantly related to depression, number of problems and practical physical problems. Each of 50 problems in the checklist was checked by at least one of the respondents. More problem items and physical-practical problems were selected by individuals who reached clinical levels of depression. CONCLUSIONS: In this preliminary study, results indicate promising potential for the use of the DTE as a simple screening tool for distress, as well as to enable residents to record their perceived needs as part of care-planning and a broader person centred approach. PMID- 21547748 TI - The relationship between exercise participation and well-being of the retired elderly. AB - The objective of this study is to identify the relationship between physical exercise and the feelings of well-being of the retired elderly. Face-to-face questionnaire survey was adopted, and quota sampling was chosen to select the respondents. A total of 352 valid questionnaires were collected in selected parks in Taipei. The survey found that the Taiwanese retired elderly participated in a wide range of sports, from light exercise such as walking to vigorous exercise such as tennis and aerobics, and their participation frequency was very high. Most of the respondents (87.2%) were defined as having positive well-being. The results showed that exercise frequency and well-being were positively correlated, but a negative correlation was found between exercise intensity and well-being. The survey found that the intensity of exercise was self-evaluated by as being low to moderate, but most of the activities were in the categories of moderate or vigorous intensity according to the metabolic equivalents suggested by American College of Sports Medicine. The study suggest that the elderly felt more comfortable and gained more pleasure psychologically while participating in exercises less intensive. As a result, the retired elderly are recommended to take exercise as frequently as possible. As to exercise intensity, self-evaluated low-to-moderate intensity exercise might be better for the psychological well being of the elderly. PMID- 21547749 TI - Self-esteem in carers of frail older people: resentment predicts anxiety and depression. AB - OBJECTIVES: Anxiety and depression are major health problems for carers of frail older people. Positive reactions to caregiving have been shown to protect people against anxiety and depression. The aims of this study are to explore specific aspects of self-esteem, termed positive caregiving reactions, and examine its relationship with caregiving anxiety and depressive symptoms. METHOD: A cross sectional study of a cohort of carers (n = 119) of community-living people (70 years) identified empirically as frail completed postal questionnaires. Positive caregiver reactions were evaluated using the self-esteem subscale (seven items) of the Caregiver Reaction Assessment (CRA). Anxiety and depressive symptoms were measured using the Hospital Anxiety and Depression Scale. RESULTS: Anxiety and depressive symptoms were related significantly (p < 0.05) to six of the seven CRA self-esteem items. Caregiving resentment scores were relatively low, mean score (SD) 1.79 (0.91) on a 1-5 scale with higher scores indicating more resentment: yet regression analysis revealed that this factor was the only independent predictor of anxiety and depressive symptoms (r2 = 0.093, p = 0.044 for anxiety, and r2 = 0.121, p = 0.041 for depression). CONCLUSION: The results of this study indicate that those carers who resent having to care for their frail older relative are susceptible to anxiety and depressive symptoms. This study supports the notion that there is a need for assessment of caregiving reactions in carers of frail older people. PMID- 21547750 TI - Impact of dementia on caring for patients' diabetes. AB - OBJECTIVE: To explore caregivers' challenges and quality-of-life issues managing diabetes in patients with dementia. METHOD: We conducted six focus groups with 21 caregivers of patients with dementia and type 2 diabetes. Focus groups were digitally recorded, transcribed, and translated using a software coding system. Emergent themes were identified and confirmed. RESULTS: Three themes emerged. (1) Memory loss was the first identified cause of self-care neglect leading to caregiver intervention. (2) Behavioral and psychological symptoms of dementia (BPSD) disrupted the daily diabetes care routine, with 'denial' of having diabetes or memory loss (anosognosia) being the most disruptive. (3) Caregivers reported that caring for both diabetes and dementia was highly burdensome, felt overwhelmed with BPSD, and wanted more support from family and patients' healthcare providers. CONCLUSION: Caregivers of patients with dementia and diabetes face extraordinary challenges managing both conditions and the accompanying BPSD. Their identified need for a greater response from the healthcare system should be tested in quality improvement programs for this overlooked yet rapidly growing population. PMID- 21547751 TI - Psychometric properties of the Spanish QoL-AD with institutionalized dementia patients and their family caregivers in Spain. AB - OBJECTIVES: To evaluate the psychometric attributes of the Spanish version of the Quality of Life-Alzheimer's Disease Scale (QoL-AD) in institutionalized patients and family caregivers in Spain. METHOD: 101 patients (88.1% women; mean age, 83.2 +/- 6.3) with Alzheimer's disease (AD) (n = 82) and mixed dementia (n = 19) and their closest family caregivers. Patient-related variables included severity of dementia, cognitive status, perceived general health, quality of life, behavior, apathy, depression, and functional status. QoL-AD acceptability, reliability, and construct validity were analyzed. RESULTS: The mean Mini-Mental State Examination (MMSE) score was 7.2 +/- 6.1 and Global Deterioration Scale was: stage four (4%); five (21.2%); six (34.3%); and seven (40.4%). Both, QoL-AD patient version (QoL-ADp) (n = 40; MMSE = 12.0 +/- 4.5) and QoL-AD caregiver version (QoL-ADc) (n = 101) lacked significant floor and ceiling effects and the Cronbach alpha index was 0.90 and 0.86, respectively. The corrected item-total correlation was 0.11-0.68 (QoL-ADc) and 0.28-0.84 (QoL-ADp). Stability was satisfactory for QoL ADp (intraclass correlation coefficient [ICC]=0.83) but low for QoL-ADc (ICC = 0.51); the standard error of measurement was 2.72 and 4.69. Construct validity was moderate/high for QoL-ADc (QUALID=-0.43; EQ-5D = 0.65), but lower for QoL ADp. No significant correlations were observed between QoL-ADp and patient variables or QoL-ADc. A low to high association (r = 0.18-0.55) was obtained between QoL-ADc and patient-related measures of neuropsychiatric, function, and cognitive status. CONCLUSION: Differences in their psychometric attributes, and discrepancy between them, were found for QoL-ADp and QoL-ADc. In patients with AD and advanced dementia, the QoL perceived by the patient could be based on a construct that is different from the traditional QoL construct. PMID- 21547752 TI - Caring and coping: the dementia caregivers. AB - OBJECTIVES: Caring for a family member with Alzheimer's disease is associated with increased burden and depression. Effective coping with the hardships and demands of caring may help to sustain the caregiver and lessen the effect of the stressors. The objective of this study was to examine caregivers' coping styles and the relationship with reported levels of burden and depression. METHOD: A cross-sectional correlation study was employed. One hundred and seventy-two caregivers of patients suffering from Alzheimer's type dementia participated in the study. All patients were recruited from neurology clinics. The Greek versions of four measuring instruments used were: the Memory and Behaviour Problem Checklist, the Burden Interview, the Centre for Epidemiological studies Depression scale and the Ways of Coping Questionnaire. RESULTS: Positive coping is negatively correlated with burden (r = -0.20) and wishful thinking strategies were related positively (r = 0.16). The relation between depression and positive coping strategies is highly significant (p < 0.01), whereas for burden the relation is significant (p < 0.05). Regression analyses showed that positive coping strategies are the most powerful, both in terms of predicting depression levels, and also in terms of moderating the effect of burden on depression. CONCLUSION: Positive coping approaches need to be developed by caregivers so as to continue their caring role. PMID- 21547753 TI - Psychosocial correlates of aspects of sleep quality in community-dwelling Irish older adults. AB - OBJECTIVES: While it is known that psychosocial factors affect overall sleep quality, there is little consensus on the factors that affect different aspects of sleep. The Pittsburgh Sleep Quality Index (PSQI) provides a means of examining these separate aspects of sleep. METHOD: This study investigated whether the different components of the PSQI are affected by different psychosocial factors, or whether all aspects of sleep are associated with the same factors. 505 community-dwelling older adults took part in this study. Psychosocial status, comprising of measures of depression, anxiety, perceived stress, social and emotional loneliness and personality, was assessed for each participant. Health related factors (pain, comorbidities, polypharmacy) as well as age and gender were also measured. RESULTS: Neuroticism, depression, anxiety and age accounted for overall sleep quality. Further analyses revealed that different psychosocial and health-related factors such as pain, loneliness and personality accounted for scores in the different components. CONCLUSION: Interventions for poor sleep quality may depend on the aspect of sleep affected in the individual, and treatment may be contingent on a number of different psychosocial variables. Future research could focus on developing personalised treatment programs for older adults with sleep complaints. PMID- 21547754 TI - Willingness to undergo HIV testing among factory workers in Surabaya, Indonesia. AB - The objective of this study is to investigate workers' perceptions of HIV testing in the workplace in Indonesia. In a cross-sectional study, we used a self administered questionnaire in Surabaya, Indonesia. A convenient sample of 536 workers was chosen from two factories with similar sample characteristics from March through June 2008. Of these workers, 433 (response rate: 80.8%) answered questions about their willingness to undergo HIV testing. More than 40% of workers were willing to undergo HIV testing. Not knowing where to get tested (adjusted odds ratio [AOR] = 0.40, confidence interval [CI] = 0.18-0.89) and not feeling the need to be tested for HIV (AOR = 0.02, CI = 0.01-0.04) were negatively associated with willingness to undergo HIV testing. HIV prevention in the workplace needs to reach out to individuals who are not willing to undergo HIV testing - workers unaware of where to get tested for HIV and not feeling the need to get tested - through education, information, and communication in the workplace in light of the stigma and discrimination associated with HIV. High impact voluntary counseling and testing (VCT) strategies need to be quickly developed to improve HIV prevention and access to care in the workplace. PMID- 21547755 TI - Disinfection of bacterial biofilms in pilot-scale cooling tower systems. AB - The impact of continuous chlorination and periodic glutaraldehyde treatment on planktonic and biofilm microbial communities was evaluated in pilot-scale cooling towers operated continuously for 3 months. The system was operated at a flow rate of 10,080 l day(-1). Experiments were performed with a well-defined microbial consortium containing three heterotrophic bacteria: Pseudomonas aeruginosa, Klebsiella pneumoniae and Flavobacterium sp. The persistence of each species was monitored in the recirculating cooling water loop and in biofilms on steel and PVC coupons in the cooling tower basin. The observed bacterial colonization in cooling towers did not follow trends in growth rates observed under batch conditions and, instead, reflected differences in the ability of each organism to remain attached and form biofilms under the high-through flow conditions in cooling towers. Flavobacterium was the dominant organism in the community, while P. aeruginosa and K. pneumoniae did not attach well to either PVC or steel coupons in cooling towers and were not able to persist in biofilms. As a result, the much greater ability of Flavobacterium to adhere to surfaces protected it from disinfection, whereas P. aeruginosa and K. pneumoniae were subject to rapid disinfection in the planktonic state. PMID- 21547756 TI - Persister cells in a biofilm treated with a biocide. AB - This study investigated the physiology and behaviour following treatment with ortho-phthalaldehyde (OPA), of Pseudomonas fluorescens in both the planktonic and sessile states. Steady-state biofilms and planktonic cells were collected from a bioreactor and their extracellular polymeric substances (EPS) were extracted using a method that did not destroy the cells. Cell structure and physiology after EPS extraction were compared in terms of respiratory activity, morphology, cell protein and polysaccharide content, and expression of the outer membrane proteins (OMP). Significant differences were found between the physiological parameters analysed. Planktonic cells were more metabolically active, and contained greater amounts of proteins and polysaccharides than biofilm cells. Moreover, biofilm formation promoted the expression of distinct OMP. Additional experiments were performed with cells after EPS extraction in order to compare the susceptibility of planktonic and biofilm cells to OPA. Cells were completely inactivated after exposure to the biocide (minimum bactericidal concentration, MBC = 0.55 +/- 0.20 mM for planktonic cells; MBC = 1.7 +/- 0.30 mM for biofilm cells). After treatment, the potential of inactivated cells to recover from antimicrobial exposure was evaluated over time. Planktonic cells remained inactive over 48 h while cells from biofilms recovered 24 h after exposure to OPA, and the number of viable and culturable cells increased over time. The MBC of the recovered biofilm cells after a second exposure to OPA was 0.58 +/- 0.40 mM, a concentration similar to the MBC of planktonic cells. This study demonstrates that persister cells may survive in biocide-treated biofilms, even in the absence of EPS. PMID- 21547757 TI - Surface exploration of Amphibalanus amphitrite cyprids on microtextured surfaces. AB - Microtopography is one of several strategies used by marine organisms to inhibit colonization by fouling organisms. While replicates of natural microtextures discourage settlement, details of larval interactions with the structured surfaces remain scarce. Close-range microscopy was used to quantify the exploration of cyprids of Amphibalanus amphitrite on cylindrical micropillars with heights of 5 and 30 MUm and diameters ranging from 5 to 100 MUm. While 5 MUm high structures had little impact, 30 MUm-high pillars significantly influenced cyprid exploration. An observed step length decrease and step duration increase on 5 MUm diameter pillars is attributed to the small dimensions of the voids excluding the cyprid's attachment disc and consequently reducing the area of adhesive contact. When exploring larger diameter pillars, cyprids preferred using the voids to form temporary attachment points. This may enhance their resistance to flow. No-choice assay settlement patterns mirrored this exploration behaviour, albeit in a pattern counter to what was predicted. PMID- 21547758 TI - Surface-associated fucoxanthin mediates settlement of bacterial epiphytes on the rockweed Fucus vesiculosus. AB - The chemical defence against microfouling in the brown seaweed Fucus vesiculosus was investigated and an inhibitor of bacterial settlement was isolated by bioassay-guided fractionation of non-polar surface extracts. UV-vis and mass spectrometry were used to identify the compound as the carotenoid fucoxanthin. The metabolite was tested at the natural concentration (in a surface volume based assay) against the settlement of four bacterial strains isolated from F. vesiculosus and 11 strains isolated from co-occurring algae and marine sediment. Surface concentrations between 1.4 and 6 MUg cm(-2) resulted in 50% inhibition of four of these isolates, which were studied in more detail using a surface area based assay, while a fifth isolate proved to be less sensitive. The presence of fucoxanthin on the surface of F. vesiculosus was demonstrated with two different surface extraction methods. Fucoxanthin was detected at concentrations between 0.7 and 9 MUg cm(-2) on the algal surface. Fucoxanthin was still present at the algal surface after removal of associated diatoms through mechanical cleaning and germanium dioxide treatment and was thus mainly produced by F. vesiculosus rather than by diatoms. Thus, the photosynthetic pigment fucoxanthin appears to be ecologically relevant as a surface-associated antimicrobial agent, acting against the settlement of bacteria on the surface of the macroalga F. vesiculosus. PMID- 21547759 TI - Proust revisited: odours as triggers of aversive memories. AB - According to the Proust phenomenon, olfactory memory triggers are more evocative than other-modality triggers resulting in more emotional and detailed memories. An experimental paradigm was used to investigate this in aversive memories, similar to those experienced by patients with posttraumatic stress disorder. Seventy healthy participants watched an aversive film, while simultaneously being exposed to olfactory, auditory and visual triggers, which were matched on intensity, valence, arousal and salience. During a second session one week later, participants were randomly exposed to one of the three triggers, and asked to think back about the film and to rate the resulting memory. Results revealed that odour-evoked memories of aversive events were more detailed, unpleasant and arousing than memories evoked by auditory, but not visual, triggers. PMID- 21547760 TI - Age differences in affective forecasting and experienced emotion surrounding the 2008 US presidential election. AB - In everyday life, people frequently make decisions based on tacit or explicit forecasts about the emotional consequences associated with the possible choices. We investigated age differences in such forecasts and their accuracy by surveying voters about their expected and, subsequently, their actual emotional responses to the 2008 US presidential election. A sample of 762 Democratic and Republican voters aged 20 to 80 years participated in a web-based study; 346 could be re contacted two days after the election. Older adults forecasted lower increases in high-arousal emotions (e.g., excitement after winning; anger after losing) and larger increases in low-arousal emotions (e.g., sluggishness after losing) than younger adults. Age differences in actual responses to the election were consistent with forecasts, albeit less pervasive. Additionally, among supporters of the winning candidate, but not among supporters of the losing candidate, forecasting accuracy was enhanced with age, suggesting a positivity effect in affective forecasting. These results add to emerging findings about the role of valence and arousal in emotional ageing and demonstrate age differences in affective forecasting about a real-world event with an emotionally charged outcome. PMID- 21547761 TI - Visual search for schematic emotional faces risks perceptual confound. AB - Several studies have used a visual search task to demonstrate that schematic negative-face targets are found faster and/or more efficiently than positive ones, with these findings taken as evidence that negative emotional expression is capable of guiding attentional allocation in visual search. A common hypothesis is that these effects should be disrupted by face inversion; however, this has not been consistently demonstrated, and raises the possibility of a perceptual confound. One candidate confound is the feature of "closure" (see Wolfe & Horowitz, 2004) caused by the down-turned mouth adjacent to edge of the face. This was investigated in the present series of experiments. In Experiment 1, the speed advantage for upright negative faces was replicated. In Experiment 2, the effect was not disrupted with inversion, and an efficiency advantage emerged, suggesting that perceptual features could be causing the advantage. In Experiment 3, speed and efficiency effects were seen when this perceptual characteristic remained but face features were scrambled. Taken together, these findings suggest that visual search using schematic faces containing a curved-line mouth feature cannot provide a valid test of guided search by negative facial emotion unless this confound is controlled. PMID- 21547762 TI - Emotion recognition in music changes across the adult life span. AB - In comparison with other modalities, the recognition of emotion in music has received little attention. An unexplored question is whether and how emotion recognition in music changes as a function of ageing. In the present study, healthy adults aged between 17 and 84 years (N=114) judged the magnitude to which a set of musical excerpts (Vieillard et al., 2008) expressed happiness, peacefulness, sadness and fear/threat. The results revealed emotion-specific age related changes: advancing age was associated with a gradual decrease in responsiveness to sad and scary music from middle age onwards, whereas the recognition of happiness and peacefulness, both positive emotional qualities, remained stable from young adulthood to older age. Additionally, the number of years of music training was associated with more accurate categorisation of the musical emotions examined here. We argue that these findings are consistent with two accounts on how ageing might influence the recognition of emotions: motivational changes towards positivity and, to a lesser extent, selective neuropsychological decline. PMID- 21547763 TI - Acoustic correlates of emotional dimensions in laughter: arousal, dominance, and valence. AB - Although laughter plays an essential part in emotional vocal communication, little is known about the acoustical correlates that encode different emotional dimensions. In this study we examined the acoustical structure of laughter sounds differing along four emotional dimensions: arousal, dominance, sender's valence, and receiver-directed valence. Correlation of 43 acoustic parameters with individual emotional dimensions revealed that each emotional dimension was associated with a number of vocal cues. Common patterns of cues were found with emotional expression in speech, supporting the hypothesis of a common underlying mechanism for the vocal expression of emotions. PMID- 21547764 TI - Adult attachment and attentional inhibition of interpersonal stimuli. AB - In two studies, we used a negative affective priming task with pictures of angry (Study 1), sad (Study 2), and happy faces (Studies 1 and 2) to measure attentional inhibition of emotional stimuli as a function of attachment style. Results showed that attachment avoidance was associated with a stronger inhibition of both angry and sad faces. This indicates that the regulatory strategies of avoidant individuals involve inhibition of different types of negative, but not positive, stimuli. Attachment anxiety, on the other hand, showed no association with inhibitory responding to negative stimuli, although we did find indications of impaired inhibitory processing of happy faces in Study 1. The results are discussed in relation to current evidence on avoidant affect regulation strategies. PMID- 21547765 TI - Effects of 7.5% CO(2) inhalation on allocation of spatial attention to facial cues of emotional expression. AB - Increased vigilance to threat-related stimuli is thought to be a core cognitive feature of anxiety. We sought to investigate the cognitive impact of experimentally induced anxiety, by means of a 7.5% CO(2) challenge, which acts as an unconditioned anxiogenic stimulus, on attentional bias for positive and negative facial cues of emotional expression in the dot-probe task. In two experiments we found robust physiological and subjective effects of the CO(2) inhalation consistent with the claim that the procedure reliably induces anxiety. Data from the dot-probe task demonstrated an attentional bias to emotional facial expressions compared with neutral faces regardless of valence (happy, angry, and fearful). These attentional effects, however, were entirely inconsistent in terms of their relationship with induced anxiety. We conclude that the previously reported poor reliability of this task is the most parsimonious explanation for our conflicting findings and that future research should develop a more reliable paradigm for measuring attentional bias in this field. PMID- 21547766 TI - Evaluative conditioning depends on higher order encoding processes. AB - Evaluative conditioning (EC) is commonly conceived as stimulus-driven associative learning. Here, we show that internally generated encoding activities mediate EC effects: Neutral conditioned stimuli (CS) faces were paired with positive and negative unconditioned stimuli (US) faces. Depending on the encoding task (Is CS a friend vs. enemy of US?), Experiment 1 yielded either normal EC effects (CS adopting US valence) or a reversal. This pattern was conditional on the degree to which encoding judgements affirmed friend or enemy encoding schemes. Experiments 2a and 2b replicated these findings with more clearly valenced US faces and controlling for demand effects. Experiment 3 demonstrated unconditional encoding effects when participants generated friend or enemy relations between CS and US faces. Explicitly stated friend or enemy relations in Experiment 4 left EC effects unaffected. Together, these findings testify to the importance of higher order cognitive processes in conditioning, much in line with recent evidence on the crucial role of conditioning awareness. PMID- 21547767 TI - Joint presentation reduces the effect of emotion on evaluation of public actions. AB - In four experiments conducted on the world wide web, subjects evaluated the priority of policies presented separately or presented jointly in pairs, and/or reported their emotional responses to the problem that each policy addressed. Strength of emotional responses was more strongly related to priority when policies were presented separately than when they were presented jointly. We found evidence for one mechanism that could produce these results: joint presentation increases the evaluability of the policies, thus increasing the influence of cognitive evaluations of importance on priority judgements, and reducing the relative influence of emotional responses. We also found evidence that importance can affect emotional responses. We found no evidence for other mechanisms in which the emotions evoked by one item spread to the other item in joint presentation. The role of evaluability points to the applied value of evaluating policies in the context of alternatives. PMID- 21547768 TI - An inkblot for sexual preference: a semantic variant of the Affect Misattribution Procedure. AB - A newly developed Semantic Misattribution Procedure (SMP), a semantic variant of the Affect Misattribution Procedure (AMP), was used in three studies as an indirect measure of sexual interest. Using a known-group approach, homosexual men (Studies 1 and 2), heterosexual men (Studies 1 to 3) and heterosexual women (Study 3) were asked to guess the meaning of briefly presented Chinese ideographs as "sexual" or "not sexual". The ideographs were preceded by briefly presented primes depicting male and female individuals of varying sexual maturity. As hypothesised, the frequency of "sexual" responses increased after priming with pictures of individuals of the preferred sex and increasing sexual maturation. The SMP showed satisfactory reliability and convergent validity as indicated by correlations with direct and two indirect measures of sexual interest. In two further studies, the hypothesised pattern was replicated whereas a standard AMP with the identical prime stimuli did not produce this result. The potential usefulness of semantic variants of the AMP is discussed. PMID- 21547769 TI - Hemispheric asymmetry in the processing of negative and positive words: a divided field study. AB - Research on the lateralisation of brain functions for emotion has yielded different results as a function of whether it is the experience, expression, or perceptual processing of emotion that is examined. Further, for the perception of emotion there appear to be differences between the processing of verbal and nonverbal stimuli. The present research examined the hemispheric asymmetry in the processing of verbal stimuli varying in emotional valence. Participants performed a lexical decision task for words varying in affective valence (but equated in terms of arousal) that were presented briefly to the right or left visual field. Participants were significantly faster at recognising positive words presented to the right visual field/left hemisphere. This pattern did not occur for negative words (and was reversed for high arousal negative words). These results suggest that the processing of verbal stimuli varying in emotional valence tends to parallel hemispheric asymmetry in the experience of emotion. PMID- 21547770 TI - Attentional biases using the body in the crowd task: are angry body postures detected more rapidly? AB - Research using schematic faces has consistently demonstrated attentional biases towards threatening information (angry faces), which are accentuated for individuals with higher levels of anxiety. However, research has yet to reveal whether this is the case for other nonverbal channels of communication. In the research reported here, ninety-five undergraduates completed a body in the crowd task analogous to the face in the crowd task, to examine whether attentional biases for threat existed for schematic body postures. Participants demonstrated faster detection of threat. A discrepant angry posture in a neutral crowd was identified quicker than a discrepant happy posture in a neutral crowd. This effect was pronounced for individuals with higher self-reported levels of trait anxiety. Results also demonstrated evidence of delayed disengagement from threat. Individuals were slower (i.e., more distracted) by identical crowds of angry postures rather than happy or neutral crowds and were slower to detect a discrepant neutral posture among an angry crowd than neutral among a happy crowd. These findings are the first to establish threat biases using body postures in a visual search paradigm. The results are in accordance with previous research using schematic face stimuli. Theoretical and practical implications are discussed. PMID- 21547771 TI - An exploratory mindset reduces preference for prototypes and increases preference for novel exemplars. AB - Previous research has shown that prototypes of familiar categories are preferred over novel exemplars of familiar and unfamiliar categories. The present research demonstrates a reversal of this effect by simply inducing an exploratory mindset. Specifically, participants were asked to judge the attractiveness of dot patterns that represented prototypes of familiar categories, exemplars of familiar categories, or exemplars of novel categories. An exploratory mindset was manipulated by asking participants to imagine the stimuli as stars (versus as peas). Results show that participants in the exploration condition preferred exemplars of novel categories (thereby reversing the classical prototypicality effect), whereas participants in the control condition preferred prototypes. The role of mindsets and familiarity in attractiveness ratings is discussed. PMID- 21547772 TI - A feel for disgust: tactile cues to pathogen presence. AB - One function of disgust is to act as a pathogen-avoidance system preventing contact with substances harbouring disease-causing organisms. Avoiding pathogens, however, requires systems for their detection. Whereas previous research on disgust has focused on visual and olfactory detection cues, one largely overlooked modality is touch. Here we examine whether tactile cues play a role in pathogen detection and activate the disgust response. Participants briefly touched and then rated stimuli varying along dimensions predicted to correlate with pathogen presence: moisture, temperature, and consistency. Results show that participants rated wet stimuli and stimuli resembling biological consistencies as more disgusting than dry stimuli and stimuli resembling inanimate consistencies, respectively. No main effect for temperature was found. We report on predicted interactions, the relationship between disgust ratings and perceived infection risk, and individual differences. Taken together, these data suggest that touch is an important modality providing information for disgust-related processes. PMID- 21547773 TI - Subliminal mere exposure and explicit and implicit positive affective responses. AB - Research suggests that repeated subliminal exposure to environmental stimuli enhances positive affective responses. To date, this research has primarily concentrated on the effects of repeated exposure on explicit measures of positive affect (PA). However, recent research suggests that repeated subliminal presentations may increase implicit PA as well. The present study tested this hypothesis. Participants were either subliminally primed with repeated presentations of the same stimuli or only exposed to each stimulus one time. Results confirmed predictions showing that repeated exposure to the same stimuli increased both explicit and implicit PA. Implications for the role of explicit and implicit PA in attitudinal judgements are discussed. PMID- 21547774 TI - Implicit memory and depression: preserved conceptual priming in subclinical depression. AB - Depression impairs explicit memory but research on implicit memory is equivocal. Initial studies indicated preserved implicit memory, implying a depressive deficit in intentional but not unintentional forms of memory. Subsequent research indicated that conceptual priming is reduced in depression, implying a deficit in conceptual memory processes be they implicit or explicit. However, the findings with conceptual priming may be compromised by explicit contamination. The present study compared subclinically depressed and non-depressed participants on matched conceptual tests of explicit memory (category-cued recall) and implicit memory (category production). The implicit test was followed by a post-test questionnaire used to categorise participants as test-aware or test-unaware. On the explicit test, the subclinically depressed participants recalled less than the non-depressed participants. The results on the implicit test depended on test awareness. Among test-unaware participants, conceptual priming was equivalent across the two groups, whereas for the test-aware, non-depressed participants produced significantly more priming than the subclinically depressed. This indicates that when explicit contamination is controlled, depression does not impair conceptual priming. The depressive dissociation between implicit and explicit memory is better accounted for by the difference between intentional and unintentional forms of memory rather than by the difference between conceptual and perceptual memory processes. PMID- 21547775 TI - Valence, arousal and word associations. AB - This study aimed at testing the relative effects of valence and arousal on the generation of unusual first associates in response to non-emotional inducers. To examine this question, four specific moods varying along both the valence and the arousal dimensions were induced: happiness (positive mood, high arousal), serenity (positive mood, low arousal), anger (negative mood, high arousal) and sadness (negative mood, low arousal). The results indicate that the uniqueness of word-associations is influenced by arousal levels rather than by the valence of mood. No matter what the valence, high-arousing moods enhanced the production of unusual associates in contrast to low-arousing moods. PMID- 21547776 TI - Individual differences at high perceptual load: the relation between trait anxiety and selective attention. AB - Attentional control theory (Eysenck et al., 2007) posits that taxing attentional resources impairs performance efficiency in anxious individuals. This theory, however, does not explicitly address if or how the relation between anxiety and attentional control depends upon the perceptual demands of the task at hand. Consequently, the present study examined the relation between trait anxiety and task performance using a perceptual load task (Maylor & Lavie, 1998). Sixty-eight male college students completed a visual search task that indexed processing of irrelevant distractors systematically across four levels of perceptual load. Results indicated that anxiety was related to difficulty suppressing the behavioural effects of irrelevant distractors (i.e., decreased reaction time efficiency) under high, but not low, perceptual loads. In contrast, anxiety was not associated with error rates on the task. These findings are consistent with the prediction that anxiety is associated with impairments in performance efficiency under conditions that tax attentional resources. PMID- 21547777 TI - Who is looking at me? The cone of gaze widens in social phobia. AB - Gaze direction is an important cue that regulates social interactions and facilitates joint attention. Although humans are very accurate in determining gaze directions in general, they have a surprisingly liberal criterion for the presence of mutual gaze. Using an established psychophysical task that required observers to adjust the eyes of a virtual head to the margins of the area of mutual gaze, we examined whether the resulting cone of gaze is altered in people with social phobia. It turned out that during presence of a second virtual person, the gaze cone's width was specifically enlarged in patients with social phobia as compared to healthy controls. The size of this effect was correlated with the severity of social anxiety. As this effect was found for merely virtual lookers, it seems to be a fundamental mechanism rather than a specific effect related to the fear of being observed and evaluated by others. PMID- 21547778 TI - Efficacy of telehealth treatments for posttraumatic stress-related symptoms: a meta-analysis. AB - This meta-analysis summarizes the findings of outcome research on the degree to which telehealth treatments reduce posttraumatic stress disorder (PTSD)-related symptoms. In a search of the literature, 13 studies were identified for inclusion in the meta-analysis and were coded for relevant variables. A total of 725 participants were included. Results indicate that telehealth treatments are associated with significant pre- to postreduction in PTSD symptoms (d = 0.99, 95% confidence interval [CI]: 0.87-1.11, p < .001), and result in superior treatment effects relative to a wait-list comparison condition (d = 1.01, 95% CI: 0.76 1.26, p < .001). However, no significant findings were obtained for telehealth intervention relative to a supportive counseling telehealth comparison condition (d = 0.11, 95% CI: - 0.38 to 0.60, p = .67), and telehealth intervention produced an inferior outcome relative to a face-to-face intervention (d = - 0.68, 95% CI: 0.39 to - 0.98, p < .001). Findings for depression symptom severity outcome were generally consistent with those for PTSD outcome. Telehealth interventions produced a significant within-group effect size (d = 0.98, 95% CI: 0.86 to 1.10, p < .001) and superior effect relative to wait-list comparison condition (d = 0.80, 95% CI: 0.56-1.05, p < .001). Relative to face-to-face interventions, telehealth treatments produced comparable depression outcome effects (d = 0.13, 95% CI: - 0.55 to 0.28, p = .53). Taken together, these findings support the use of telehealth treatments for individuals with PTSD-related symptoms. PMID- 21547779 TI - Pulse transit time reveals drug kinetics on vascular changes affected by propofol. AB - Pulse transit time (PTT) is the duration in which a pulse wave travels between two arterial sites within the same cardiac cycle. The aim of our study is to use PTT to examine propofol's effects on the vascular system. Methods. We collected data from 50 healthy women, between 28 and 51 years old, who underwent gynaecological surgery under general anaesthesia. The general anaesthesia was induced with propofol injection (2 mg/kg). PTT measurements were obtained from the R-wave of electrocardiogram and the pulse wave of photoplethysmograph. Two PTT values were obtained; one before (the control) and the other after propofol injection. The results were analysed by Student's t-test. Results. After propofol injection, the PTT was prolonged. The change in the PTT value from that of baseline was significant statistically (P < 0.05, by Student's t-test). The PTT change over time correlated with the degree of vasodilatation over time. Monitoring of PTT not only revealed the magnitude of vascular changes but also demonstrated the onset of vascular dilation, its peak and duration. We conclude that PTT is a useful guide in monitoring the drug kinetics of propofol. PMID- 21547780 TI - Growing multiblock structures: a semi-automated approach to block placement for multiblock hexahedral meshing. AB - Finite element (FE) analysis is a cornerstone of orthopaedic biomechanics research. Three-dimensional medical imaging provides sufficient resolution for the subject-specific FE models to be generated from these data-sets. FE model development requires discretisation of a three-dimensional domain, which can be the most time-consuming component of a FE study. Hexahedral meshing tools based on the multiblock method currently rely on the manual placement of building blocks for mesh generation. We hypothesise that angular analysis of the geometric centreline for a three-dimensional surface could be used to automatically generate building block structures for the multiblock hexahedral mesh generation. Our algorithm uses a set of user-defined points and parameters to automatically generate a multiblock structure based on a surface's geometric centreline. This significantly reduces the time required for model development. We have applied this algorithm to 47 bones of varying geometries and successfully generated a FE mesh in all cases. This work represents significant advancement in automatically generating multiblock structures for a wide range of geometries. PMID- 21547781 TI - The muscle line of action in current models of the human cervical spine: a comparison with in vivo MRI data. AB - Cervical muscles are commonly represented by line-of-action models. This investigation evaluates the performance of three types of model implementations, based on their ability to mimic geometric in-vivo aspects of muscles. Five prominent pairs of neck muscles were reconstructed in three head positions using magnetic resonance imaging. Based on the reconstructions, muscle approximations were created that represent the muscles with piecewise straight lines. Measured and modelled muscle approximations were compared with respect to their pulling directions at the attachment sites and the overall distance between the muscle paths. Muscle lengths were evaluated in two ways. First, length discrepancies were determined between measured and modelled muscles depending on the head position. Second, the difference of muscle lengths in neutral and deflected head positions for measurement and models were calculated. The results indicate considerable differences between models and measurements. Pulling directions, for instance, differed by up to 40 degrees , depending on the chosen muscle and the type of muscle implementation. PMID- 21547782 TI - Postural sway parameters using a triaxial accelerometer: comparing elderly and young healthy adults. AB - The purpose of this study was to evaluate the sensitivity of 16 parameters derived from acceleration to detect changes caused by age and visual conditions during quiet standing and detect and minimise possible sources of unwanted variability that could affect accelerometer measures on the trunk. Twenty-seven healthy subjects, including 16 elderly (age, 69.3 +/- 3.6 years) and 11 young (age, 23.6 +/- 2.2 years) subjects, were evaluated. The parameters evaluated include root-mean-square values, fractal dimensions, path length, range, frequency dispersion and power spectrum among others derived from these values. These 16 parameters evaluated for each axis of movement and/or derivations resulted in 59 sub-parameters. These 59 sub-parameters were analysed in the elderly and young groups and under the open-eye and closed-eye conditions. The results showed that 30 sub-parameters detected differences for an age effect with open eyes, 18 detected differences with closed eyes, 25 detected differences for the young group standing with closed-open eyes and 37 detected differences for the elderly with closed and open eyes (p < 0.01). We used simple signal processing for the accelerometry signals to minimise the effects of unwanted variability that could affect the results. The results showed better performance compared with those results published previously using force platforms to evaluate postural sway. The results presented here should be useful for researchers who want to use accelerometry to evaluate steady postural balance. PMID- 21547783 TI - Left ventricular wall stress compendium. AB - Left ventricular (LV) wall stress has intrigued scientists and cardiologists since the time of Lame and Laplace in 1800s. The left ventricle is an intriguing organ structure, whose intrinsic design enables it to fill and contract. The development of wall stress is intriguing to cardiologists and biomedical engineers. The role of left ventricle wall stress in cardiac perfusion and pumping as well as in cardiac pathophysiology is a relatively unexplored phenomenon. But even for us to assess this role, we first need accurate determination of in vivo wall stress. However, at this point, 150 years after Lame estimated left ventricle wall stress using the elasticity theory, we are still in the exploratory stage of (i) developing left ventricle models that properly represent left ventricle anatomy and physiology and (ii) obtaining data on left ventricle dynamics. In this paper, we are responding to the need for a comprehensive survey of left ventricle wall stress models, their mechanics, stress computation and results. We have provided herein a compendium of major type of wall stress models: thin-wall models based on the Laplace law, thick-wall shell models, elasticity theory model, thick-wall large deformation models and finite element models. We have compared the mean stress values of these models as well as the variation of stress across the wall. All of the thin-wall and thick wall shell models are based on idealised ellipsoidal and spherical geometries. However, the elasticity model's shape can vary through the cycle, to simulate the more ellipsoidal shape of the left ventricle in the systolic phase. The finite element models have more representative geometries, but are generally based on animal data, which limits their medical relevance. This paper can enable readers to obtain a comprehensive perspective of left ventricle wall stress models, of how to employ them to determine wall stresses, and be cognizant of the assumptions involved in the use of specific models. PMID- 21547784 TI - Prediction of shape and internal structure of the proximal femur using a modified level set method for structural topology optimisation. AB - A computational framework was developed to simulate the bone remodelling process as a structural topology optimisation problem. The mathematical formulation of the Level Set technique was extended and then implemented into a coronal plane model of the proximal femur to simulate the remodelling of internal structure and external geometry of bone into the optimal state. Results indicated that the proposed approach could reasonably mimic the major geometrical and material features of the natural bone. Simulation of the internal bone remodelling on the typical gross shape of the proximal femur, resulted in a density distribution pattern with good consistency with that of the natural bone. When both external and internal bone remodelling were simulated simultaneously, the initial rectangular design domain with a regularly distributed mass reduced gradually to an optimal state with external shape and internal structure similar to those of the natural proximal femur. PMID- 21547785 TI - Using topological equivalence to discover stable control parameters in biodynamic systems. AB - In order to better understand the mechanisms that contribute to low back pain, researchers have developed mathematical models and simulations. A mathematical model including neuromuscular feedback control is developed for a person balancing on an unstable sitting apparatus, the wobble chair. When the application of a direct method fails to discover appropriate controller gain parameters for the wobble chair, we show how topological equivalence can be used to indirectly identify appropriate parameter values. The solution is found by first transforming the wobble chair into the Acrobot, another member of the same family of topologically equivalent dynamical systems. After finding appropriate gain parameters for the Acrobot, a continuous transformation is performed to convert the Acrobot back to the wobble chair, during which the gain parameters are adjusted to maintain stability. Thus, we demonstrate how topological equivalence can be used to indirectly solve a problem that was difficult to solve directly. PMID- 21547786 TI - Implant-bone interface healing and adaptation in resurfacing hip replacement. AB - Hip resurfacing demonstrates good survivorship as a treatment for young patients with osteoarthritis, but occasional implant loosening failures occur. On the femoral side there is radiographic evidence suggesting that the implant stem bears load, which is thought to lead to proximal stress shielding and adaptive bone remodelling. Previous attempts aimed at reproducing clinically observed bone adaptations in response to the implant have not recreated the full set of common radiographic changes, so a modified bone adaptation algorithm was developed in an attempt to replicate more closely the effects of the prosthesis on the host bone. The algorithm features combined implant-bone interface healing and continuum bone remodelling. It was observed that remodelling simulations that accounted for progressive gap filling at the implant-bone interface predicted the closest periprosthetic bone density changes to clinical X-rays and DEXA data. This model may contribute to improved understanding of clinical failure mechanisms with traditional hip resurfacing designs and enable more detailed pre-clinical analysis of new designs. PMID- 21547787 TI - The research-practice relationship in ergonomics and human factors--surveying and bridging the gap. AB - Significant discord has been aired regarding the widening research-practice gap in several disciplines (e.g. psychology, healthcare), especially with reference to research published in academic journals. The research-practice gap has profound and wide-ranging implications for the adequacy of ergonomics and human factors (E/HF) research and the implementation of research findings into practice. However, no substantive research on this issue has been identified in E/HF. Using an online questionnaire, practitioners were asked about their application of scientific research findings published in peer-reviewed journals and to suggest ways to improve research application in practice. A total of 587 usable responses were collected, spanning 46 countries. This article describes some of the key differences and correlations concerning reading, usefulness and barriers to application among respondents, who varied in terms of organisational type, percentage of work time devoted to application vs. research, society membership and experience. Various solutions proposed by the survey respondents on ways to bridge the research-practice gap are discussed. STATEMENT OF RELEVANCE: The relationship between research and practice in E/HF has long been a subject of discussion, with commentators pointing to tension and possible implications for the adequacy of the discipline. Findings from a cross-sectional survey provide ergonomics practitioners' views on research, leading to discussion of strategies for achieving better integration. PMID- 21547788 TI - Long-term impact of role stress and cognitive rumination upon morning and evening saliva cortisol secretion. AB - The long-term impact of role stress (conflict and ambiguity), cognitive rumination and their interaction were analysed upon morning and evening saliva cortisol secretion. The sample consisted of 52 male and 24 female British white collars who had participated in a survey study on psychosocial working conditions 3.5 years earlier. Saliva cortisol secretion was measured over seven consecutive days with two measures: in the morning on awakening and at 22.00 hours. Stepwise linear multiple regression analyses was used for the statistical analyses. Role ambiguity at baseline and the interaction between role ambiguity and trait rumination contributed to explaining elevations in morning saliva cortisol secretion 3.5 years later (R(2) = 0.045; F = 4.57; p < 0.05), while role conflict at baseline significantly predicted increases in long-term evening saliva cortisol (R(2) = 0.057; F = 8.99; p < 0.01). The findings support a long-term relationship between chronic stress exposure and saliva cortisol secretion and some support for the assumption of cognitive rumination moderating the stressor strain relationship. STATEMENT OF RElevance: The study is of interest for ergonomics practice because it demonstrates that work role ambiguity and role conflict, typically associated with organisational downsizing and restructuring, may contribute to long-term psycho-physiological reactivity. This could expose workers to increased health risks. Therefore, stress management programmes should include the concept of role stress, especially at a time where many work organisations are undergoing significant change. Management should also be made aware of the importance of communicating clear goals, objectives and lines of authority as well as providing sufficient training for those in new job roles. PMID- 21547789 TI - Integrating human factors and operational research in a multidisciplinary investigation of road maintenance. AB - There has been limited collaboration between researchers in human factors and operational research disciplines, particularly in relation to work in complex, distributed systems. This study aimed to investigate work at the interface between human factors and operational research in the case example of road resurfacing work. Descriptive material on the factors affecting performance in road maintenance work was collected with support from a range of human factors based methods and was used to inform operational research analyses. Investigation of the case example from a different perspective, for the supply of asphalt from a distribution centre to multiple work locations, gave a broader picture of the complexity and challenges for the improvement of road maintenance processes. Factors affecting performance in the road maintenance context have been assessed for their potential for further investigation using an integrated human factors and operational research approach. Relative strengths of the disciplines and a rationale for ongoing, collaborative work are described. STATEMENT OF RELEVANCE: The paper provides evidence of the potential benefits of greater collaboration across human factors and operational research disciplines, using investigation of a case example in the complex, distributed system of road resurfacing. PMID- 21547790 TI - The effects of age, viewing distance, display type, font type, colour contrast and number of syllables on the legibility of Korean characters. AB - This study evaluated the effects of age (20s and 60s), viewing distance (50 cm, 200 cm), display type (paper, monitor), font type (Gothic, Ming), colour contrast (black letters on white background, white letters on black background) and number of syllables (one, two) on the legibility of Korean characters by using the four legibility measures (minimum letter size for 100% correctness, maximum letter size for 0% correctness, minimum letter size for the least discomfort and maximum letter size for the most discomfort). Ten subjects in each age group read the four letters presented on a slide (letter size varied from 80 pt to 2 pt). Subjects also subjectively rated the reading discomfort of the letters on a 4 point scale (1 = no discomfort, 4 = most discomfort). According to the ANOVA procedure, age, viewing distance and font type significantly affected the four dependent variables (p < 0.05), while the main effect of colour contrast was not statistically significant for any measures. Two-syllable letters had smaller letters than one-syllable letters in the two correctness measures. The younger group could see letter sizes two times smaller than the old group could and the viewing distance of 50 cm showed letters about three times smaller than those at a 200 cm viewing distance. The Gothic fonts were smaller than the Ming fonts. Monitors were smaller than paper for correctness and maximum letter size for the most discomfort. From a comparison of the results for correctness and discomfort, people generally preferred larger letter sizes to those that they could read. The findings of this study may provide basic information for setting a global standard of letter size or font type to improve the legibility of characters written in Korean. STATEMENT OF RELEVANCE: Results obtained in this study will provide basic information and guidelines for setting standards of letter size and font type to improve the legibility of characters written in Korean. Also, the results might offer useful information for people who are working on design of visual displays. PMID- 21547791 TI - Effects of target location, stature and hand grip type on in-vehicle reach discomfort. AB - In order to improve car interior design, data of perceived discomfort and reach posture were collected for 75 different target locations. Altogether, 24 males and females of different statures participated in the experiment. In addition to three-finger grip, index fingertip reach and five finger grip were also compared. The effects of target location, stature and hand grip on reach discomfort were analysed. Predictive regression equations were provided. In addition to the confirmation of target location effects, the results showed that seat back and steering wheel affected discomfort. Their effects differed according to the subject's anthropometry. A detailed analysis of possible interference between the car interior and reach movement showed that short females were more likely impeded by the seat back when a target was close to the body. A significant difference between three hand grip types could be explained by the change of hand reach distance when changing hand grip type. STATEMENT OF RELEVANCE: The present study analysed the effects of target location, stature and hand grip type on reach discomfort, based on the statistical analysis of subjective ratings when reaching a target in a vehicle. The results would help to optimise the location of automotive controls for improving car interior design. PMID- 21547792 TI - Technique, muscle activity and kinematic differences in young adults texting on mobile phones. AB - The aim of this study was to investigate whether there are differences in technique between young adults with and without musculoskeletal symptoms when using a mobile phone for texting and whether there are differences in muscle activity and kinematics between different texting techniques. A total of 56 young adults performed a standardised texting task on a mobile phone. Their texting techniques were registered using an observation protocol. The muscular activity in six muscles in the right forearm/hand and both shoulders were registered by surface electromyography and the thumb abduction/adduction and flexion/extension were registered using a biaxial electrogoniometer. Differences in texting techniques were found between the symptomatic and the asymptomatic group, with a higher proportion of sitting with back support and forearm support and with a neutral head position in the asymptomatic group. Differences in muscle activity and kinematics were also found between different texting techniques. The differences in texting technique between symptomatic and asymptomatic subjects cannot be explained by them having symptoms but may be a possible contribution to their symptoms. STATEMENT OF RELEVANCE: There has been a dramatically increased use of mobile phones for texting especially among young people during the last years. A better understanding of the physical exposure associated with the intensive use is important in order to prevent the development of musculoskeletal disorders and decreased work ability related to this use. PMID- 21547793 TI - The transmission of vibration through gloves: effects of push force, vibration magnitude and inter-subject variability. AB - The extent to which a glove modifies the risks from hand-transmitted vibration is quantified in ISO 10819:1996 by a measure of glove transmissibility determined with one vibration magnitude, one contact force with a handle and only three subjects. This study was designed to investigate systematically the vibration transmissibility of four 'anti-vibration' gloves over the frequency range 16-1600 Hz with 12 subjects, at six magnitudes of vibration (0.25-8.0 ms(-2) r.m.s.) and with six push forces (5 N to 80 N). The four gloves showed different transmissibility characteristics that were not greatly affected by vibration magnitude but highly dependent on push force. In all conditions, the variability in transmissibility between subjects was as great as the variability between gloves. It is concluded that a standardised test of glove dynamic performance should include a wide range of hands and a range of forces representative of those occurring in work with vibratory tools. STATEMENT OF RELEVANCE: The transmission of vibration through anti-vibration gloves is highly dependent on the push force between the hand and a handle and also highly dependent on the hand that is inside the glove. The influence of neither factor is well reflected in ISO 10819:1996, the current standard for anti-vibration gloves. PMID- 21547794 TI - Heat stress in chemical protective clothing: porosity and vapour resistance. AB - Heat strain in chemical protective clothing is an important factor in industrial and military practice. Various improvements to the clothing to alleviate strain while maintaining protection have been attempted. More recently, selectively permeable membranes have been introduced to improve protection, but questions are raised regarding their effect on heat strain. In this paper the use of selectively permeable membranes with low vapour resistance was compared to textile-based outer layers with similar ensemble vapour resistance. For textile based outer layers, the effect of increasing air permeability was investigated. When comparing ensembles with a textile vs. a membrane outer layer that have similar heat and vapour resistances measured for the sum of fabric samples, a higher heat strain is observed in the membrane ensemble, as in actual wear, and the air permeability of the textile version improves ventilation and allows better cooling by sweat evaporation. For garments with identical thickness and static dry heat resistance, but differing levels of air permeability, a strong correlation of microclimate ventilation due to wind and movement with air permeability was observed. This was reflected in lower values of core and skin temperatures and heart rate for garments with higher air permeability. For heart rate and core temperature the two lowest and the two highest air permeabilities formed two distinct groups, but they did not differ within these groups. Based on protection requirements, it is concluded that air permeability increases can reduce heat strain levels allowing optimisation of chemical protective clothing. STATEMENT OF RELEVANCE: In this study on chemical, biological, radiological and nuclear (CBRN) protective clothing, heat strain is shown to be significantly higher with selectively permeable membranes compared to air permeable ensembles. Optimisation of CBRN personal protective equipment needs to balance sufficient protection with reduced heat strain. Using selectively permeable membranes may optimise protection but requires thorough consideration of the wearer's heat strain. PMID- 21547795 TI - Toward a criterion for suspect thiouracil administration in animal husbandry. AB - Thyreostats are growth-promoters banned in Europe since 1981. The identification of thiouracil (TU) in animal biological matrices can, however, no longer be systematically interpreted as a consequence of illegal administration. Indeed, some experimental results have indicated a causal link between cruciferous-based diet and the presence of TU in urine of bovines. The present study aims at investigating, on a large scale (n > 1300), the natural occurrence of thiouracil in urine samples collected from different animal species. TU was identified in main breeding animal species: bovine, porcine and ovine. The natural distribution of TU allowed proposing threshold values to differentiate compliant from suspect urine samples. Suggested values are 5.7 and 9.1 ug l(-1) in male adult bovines (6 24 months), 3.1 and 8.1 ug l(-1) in female adult bovines (6-24 months), 7.3 and 17.7 ug l(-1) in calves (<6 months), 3.9 and 8.8 ug l(-1) in female bovines (>24 months), and 2.9 and 4.1 ug l(-1) in porcines at a 95 and 99% confidence level, respectively. PMID- 21547796 TI - Influence of fertilisation with foliar urea on the content of amines in wine. AB - Amines are substances that could cause toxic effects in the consumer. The concentration of amines in wine depends on different factors such as grape variety, vinification conditions and nitrogen fertilisation of the vines. The aim of this work was to study the influence of the application of foliar urea on the concentration of amines in wine. To carry out the study, grapevines of Tempranillo variety were used. These grapevines were treated with foliar urea at two different concentrations: 2 and 4 kg N ha(-1). Treatment with foliar urea significantly increased (p < 0.05) the concentration of histamine in the wines compared with the control sample (65% in the treatment with 2 kg N ha(-1) and 93% in the treatment with 4 kg N ha(-1)), reaching higher concentrations than the threshold level where it could provoke toxic effects in the consumer (8-20 mg l( 1)). On the other hand, treatment with foliar urea did not increase the concentrations of other amines which could be toxic such as tyramine or phenylethylamine, nor amines such as putrescine which could enhance the toxic effect of histamine. In the case of the volatile amines containing secondary amine groups, the concentration of pirrolidine increased by 37% after treatment with 2 kg N ha(-1) and 61% after treatment with 4 kg N ha(-1). PMID- 21547797 TI - Comparison of PCDD/F and dl-PCB levels in Turkish foodstuffs: industrial versus rural, local versus supermarket products, and assessment of dietary intake. AB - Polychlorinated dibenzo-p-dioxin and dibenzofurans (PCDD/Fs) and dioxin-like and non-dioxin-like (indicator) polychlorinated biphenyls (PCBs) were monitored in various foodstuffs of animal origin and edible oil samples obtained from two different cities in Turkey both rural and industrial. Total dioxin+dioxin-like PCBs and indicator PCB concentrations of pooled samples ranged 0.20-4.19 pg World Health Organization-Toxic Equivalency (WHO-TEQ)(1998)/g fat and 57.2-1710 pg/g fat, respectively. The dominant congeners were 2,3,4,7,8-PeCDF, 1,2,3,7,8-PeCDD, 2,3,7,8-TCDD and PCB126. Dietary intake of dioxin+dioxin-like PCBs and indicator PCBs from fish, dairy products, edible oil, egg and meat was 0.509 pg WHO TEQ1998/kg bw (body weight)/day and 839 pg/kg bw/day in Afyon and 0.588 pg WHO TEQ1998/ kg bw/day and 1070 pg/kg bw/day in Kocaeli, respectively. The major contributors to total exposure were dairy products and fish. Despite the unexplained high contamination level in an individual egg sample from Kocaeli, average concentration levels in Turkey, even in industrialized regions, were low compared to reported concentrations in Western Europe. Exposure levels were well below the tolerable daily intake (TDI) of 2 pg WHO-TEQ1998/kg body weight. PMID- 21547798 TI - Production of Fusarium verticillioides biocontrol agents, Bacillus amyloliquefaciens and Microbacterium oleovorans, using different growth media: evaluation of biomass and viability after freeze-drying. AB - The aims of this study were to compare the viability and biomass production of B. amyloliquefaciens and M. oleovorans in different growth media, and the efficiency of a freeze-drying method as a possible formulation process. B. amyloliquefaciens and M. oleovorans were grown in 100 ml of four different media. Media water activity was modified at 0.99, 0.98, 0.97 and 0.96. Nutrient yeast dextrose broth (NYDB) and molasses soy powder (MSB) media were selected and survival levels of cells were determined before and after the freeze-drying process. B. amyloliquefaciens showed the highest survival after freeze-drying when grown in NYDB medium at 0.99 a(w), whereas, at 0.98, 0.97 and 0.96 a(w), the highest survival was obtained in MSB medium. M. oleovorans showed the highest survival in MSB medium at 0.99 a(w). MSB medium was select for biomass production due to high growth and survival after freeze-drying. PMID- 21547799 TI - Determination of zearalenone in traditional Chinese medicinal plants and related products by HPLC-FLD. AB - A HPLC-FLD method has been developed and validated for zearalenone (ZON) in 107 widely consumed Chinese medicinal herbs and related products collected from different regions of China. Samples were extracted with methanol/water (80 : 20, v/v), and the extracts were cleaned-up through immunoaffinity columns (IAC). ZON was quantified by HPLC with fluorescence detection. Recoveries from three different medicinal herbs spiked with ZON at levels ranging from 30 to 600 ug kg( 1) were from 80.8 to 98.3%. The limit of detection was 9.5 ug kg(-1), based on a signal-to-noise ratio of 3 : 1. Naturally occurring ZON was only found in coix seed medicinal herb (all nine samples), with levels ranging from 18.7 to 211.4 ug kg(-1). Positive results were confirmed by UV spectrum and LC-ESI-MS/MS. This is the first report of ZON contamination of a Chinese medicinal herb. PMID- 21547800 TI - Maternal/child health. Editorial. PMID- 21547801 TI - Cultural childbirth practices, beliefs, and traditions in postconflict Liberia. AB - In this qualitative study we used an interpretive, critical ethnographic approach to provide an understanding of childbirth and maternal illness and death in Liberia through the lens of women, families, and communities. We identified three major themes from the data: (a) secrecy surrounding pregnancy and childbirth; (b) power and authority; and (c) distrust of the health care system. The interpretive theory, Behind the House, generated from data analysis provides an understanding of the larger social and cultural context of childbirth in Liberia. Our findings provide a more complete understanding of the contextual factors that impact on the intractable problem of maternal mortality. PMID- 21547802 TI - Infants delivered in maternity homes run by traditional birth attendants in urban Nigeria: a community-based study. AB - We explored factors associated with traditional maternity/herbal homes (TMHs) run by traditional birth attendants (TBAs) compared with hospital or home delivery in Lagos, Nigeria, and found that infants delivered at TMHs were less likely to have severe hyperbilirubinemia compared with infants delivered in hospitals or residential homes. These infants were also less likely to be preterm compared with those delivered in hospitals or undernourished compared with infants delivered in residential homes. We concluded that infants delivered at TMHs who survive are unlikely to be at greater risks of some adverse perinatal outcomes than those delivered in hospitals or family homes. PMID- 21547803 TI - Maternal birth outcomes: processes and challenges in Anambra State, Nigeria. AB - The views of nurse experts and policymakers on maternal birth outcomes in Anambra State, Nigeria, were explored using qualitative content analysis. The findings indicate that although there are different levels of birth attendants in Anambra State, nurses attend to most deliveries; are highly favored; and are the most trusted obstetric providers among skilled personnel. Obstetric complications are extensive, leading to high mortality and morbidity. Poverty, gender inequity, and weak health systems-encompassing insufficiency of trained nursing workforce among other issues-intensify poor maternal birth outcomes. PMID- 21547804 TI - "A planned baby is a rarity:" monitoring and planning pregnancy in Russia. AB - Russia provides an interesting case for comparative research of maternity care due to the rapid social change and steep fertility decline since the collapse of the Soviet Union. I analyze out-patient maternity care in public sector women's clinics in St. Petersburg on the basis of qualitative observation and interview data. Gynecologists' role in monitoring pregnancy is central, resulting in an emphasis on medical expertise and risk management. Ideally, gynecologists see themselves as medical experts and maternal caretakers, but the latter role seldom materializes in practice. Gynecologists' ideas of pregnancy planning demonstrate a wish for further medicalization of maternity care. PMID- 21547805 TI - Cautionary tales about extended breastfeeding and weaning. AB - Extended breastfeeding is uncommon and accorded limited research attention in the United States. In this article I analyze in-depth interviews with 66 breastfeeding mothers in Northern California. Mothers reveal their understanding of extended breastfeeding through descriptions of the surveillance of breastfeeding and cautionary tales. I examine the form and content of cautionary tales, emphasizing the pervasive culture of surveillance that underpins their relevance to nursing mothers. I interpret the cautionary tales in light of the dyadic encounter of breastfeeding, maternal identity, and norms about older breastfeeding children. The analysis is relevant to future explorations of early weaning in other regions. PMID- 21547807 TI - Micro-environmental characteristics related to body weight, diet, and physical activity of children and adolescents: a systematic umbrella review. AB - This umbrella review analyzed the relationships between social and physical micro environmental (neighborhood, school) characteristics as predictors of child and adolescent diet, physical activity, and body weight. Eight systematic reviews, discussing 132 original studies (97% correlational, 3% experimental) yielded 98 social, physical, and socio-economic characteristics, as categorized in the original reviews. Among micro-environmental predictors stronger support (i.e., replicated results) was obtained for 12 out of 98 original micro-environmental variables, with physical activity as the outcome in 10 out of 12 cases. In particular, replicated significant relationships were found for several physical activity-specific neighborhood and school characteristics (e.g., community opportunities to exercise, lower costs of physical activity facilities, physical activity build environment) and adolescent physical activity. Among more general (i.e., not behavior-specific) micro-environmental characteristics, stronger support was found for low crime level, school type, and child/adolescent physical activity. PMID- 21547808 TI - Risk of Giardia infection for drinking water and bathing in a peri-urban area in Sao Paulo, Brazil. AB - A high incidence of waterborne diseases is observed worldwide and in order to address contamination problems prior to an outbreak, quantitative microbial risk assessment is a useful tool for estimating the risk of infection. The objective of this paper was to assess the probability of Giardia infection from consuming water from shallow wells in a peri-urban area. Giardia has been described as an important waterborne pathogen and reported in several water sources, including ground waters. Sixteen water samples were collected and examined according to the US EPA (1623, 2005). A Monte Carlo method was used to address the potential risk as described by the exponential dose response model. Giardia cysts occurred in 62.5% of the samples (<0.1-36.1 cysts/l). A median risk of 10-1 for the population was estimated and the adult ingestion was the highest risk driver. This study illustrates the vulnerability of shallow well water supply systems in peri-urban areas. PMID- 21547809 TI - Particulate air pollution and short-term mortality due to specific causes among the elderly in Madrid (Spain): seasonal differences. AB - A time-series study was conducted to ascertain the short-term effects of different-sized airborne particulate matter (PM) on daily respiratory and cardiovascular cause-specific mortality in winter and summer, among subjects aged over 75 years in Madrid. Poisson regression was used to analyse the time-series, in which the dependent variable was daily mortality due to different specific respiratory and circulatory causes, and the principal independent variables were daily mean PM10, PM2.5 and PM10-2.5 concentrations; other variables: other air pollutants (chemicals, biotic and acoustic), influenza, trend, seasonality and autocorrelation of the series. The results indicated an association between coarser PM fractions (PM10 and PM10-2.5) and respiratory-specific mortality on the one hand, and between PM2.5 and cardiovascular-specific mortality on the other. While the risk of mortality due to exposure to particulate matter was greater in summer than in winter, this difference was statistically significant solely for total organic-cause mortality. PMID- 21547810 TI - Zootechnical wastewater reuse: constructed wetland as a challenge for protozoan parasite removal. AB - Samples of soil, well water, and wastewater from a zootechnical farm, water after phytodepuration and maize plants (Zea mays) grown on soils irrigated with these different kinds of water were analysed for indicator bacteria and the protozoa Giardia and Cryptosporidium. Protozoa and bacterial indicators, except coliforms, were not recovered from well water samples. In the effluent from the zootechnical farm, high parasitological concentrations were observed, whilst water after the phytodepuration process showed a concentration reduction of two orders of magnitude. The high numbers of Giardia and Cryptosporidium in the zootechnical effluent could represent a potential risk for the spread of the pathogens. Nevertheless the environmental spread is minimized when data on soils and plants are observed. From the study, it emerges that this water treatment system could represent an alternative option to other conventional wastewater treatments and an economic and environmental advantage. PMID- 21547811 TI - Exposure sources and reasons for testing among women with low blood lead levels. AB - Previous research has focused on highly elevated blood lead (PbB). This study examined reasons for testing and potential sources of exposure among women with PbBs less than 0.72 MUmol/l (15 MUg/dl). A questionnaire was mailed to 18- to 49 year-old women in upstate New York, USA, who were PbB tested in 2007. The most common testing reason was pregnancy among 125 women who returned the questionnaire. Among women tested for PbB during pregnancy, doctors ordered approximately 80% of tests regardless of lead level. Few women with PbBs less than 0.24 MUmol/l (5 MUg/dl) reported a potential source of lead exposure. However, among women with PbBs of 0.24-0.71 MUmol/L (5-14.9 MUg/dl), 29.2% had a job and 21.2% had a hobby with potential lead exposure. There are systematic differences in reasons for testing and exposure sources among women with PbBs less than 0.72 MUmol/l and these differences have implications for screening. PMID- 21547812 TI - Follicle-stimulating hormone levels in female workers exposed to urban pollutants. AB - The aim of this study was to evaluate if there were alterations in FSH plasma levels in female outdoor workers (traffic policewomen and drivers) exposed to chemical urban stressors vs. control group. After excluding subjects with main confounding factors, traffic policewomen, drivers and indoor workers were matched by age, working life, socioeconomic status, marital status, menstrual cycle day, age of menarche, habitual consumption of Italian coffee and soy. A total of 129 female subjects were included in the study: some 63 workers studied during proliferative phase and 66 during secretory phase of menstrual cycle. Proliferative phase of menstrual cycle: FSH mean values were significantly higher in traffic policewomen compared to controls (p < 0.05). Results suggest that in outdoor workers exposed to urban chemical stressors there are alterations in FSH levels; therefore FSH may be used as an early biological marker, valuable for the group, used in occupational set. PMID- 21547813 TI - Gender-specific differences in effects of prenatal and postnatal environmental tobacco smoke exposure on respiratory symptoms in 23,474 children with and without allergic predisposition: results from 25 districts of northeast China. AB - To assess the interaction of environmental tobacco smoke (ETS) exposure and allergic predisposition regarding respiratory health among Chinese children, a sample of 23,474 children (6-13 years old) was studied from 25 districts in Liaoning province, China. The results showed that children without allergic predisposition were more susceptible to ETS than children with allergic predisposition. Among children without allergic predisposition, ETS exposure was associated with more respiratory symptoms and diseases in boys than in girls; In utero ETS exposure was associated with history of asthma (OR, 1.86; 95% CI, 1.44 2.40) and current asthma (OR, 2.25; 95% CI, 1.48-3.44) only among boys without allergic predisposition. Among children with allergic predisposition, more associations between ETS exposure and respiratory symptoms and diseases were detected in girls. In conclusion, ETS exposure was more evident in boys without family atopy history and more associations were detected in girls with family atopy history. PMID- 21547814 TI - Mapping under-five mortality in the Wenchuan earthquake using hierarchical Bayesian modeling. AB - More than two years after the 2008 earthquake in Wenchuan, China, the total number of lives lost remains unclear, particularly for children under five years old. Mortality for this age group can be estimated using a variety of techniques, but sample proportion estimates may be unreliable in areas with low populations of children under five. To address this problem, we propose a hierarchical Bayesian model to map the distribution of under-five mortality in Wenchuan at the township scale. This model is based on conditional distributions for data conditioned on a spatial process and parameters to capture uncertainties usually identified as either spatially-correlated effects or heterogeneity effects. The method was adapted to obtain reliable estimates of the under-five mortality rate in townships with low under-five populations. The approach was compared to other models and, despite some limitations, was found to outperform other methods in its smoothing effect as well as in exploration of other aspects of spatial patterns. PMID- 21547815 TI - Association between ozone and emergency department visits: an ecological study. AB - The objective of this study was to examine the association between the levels of ozone concentration and emergency department (ED) visits for respiratory and cardiovascular conditions in Maryland in the United States by considering temporal and spatial characteristics, including socioeconomic status (SES), as a covariate. This study used multiple large datasets derived from government agencies for data of ozone, weather, census, and ED visits to represent Maryland in the summer of 2002. Block kriging was used to estimate the daily ozone and weather factors by ZIP code-day level. Results from a negative binomial regression showed that a 10-ppb increment of the 8-hr ozone level as a three-day average was associated with increased respiratory ED visits by 2.4%, after adjusting for weather factors, SES, and day of the week. For cardiovascular ED visits, an increment of 10 ppb of the 8-hr ozone level as a five-day average increased by 3.5%. PMID- 21547816 TI - Complicated head trauma from machete wounds: the experience from a tertiary referral hospital in Jamaica. AB - There have been limited reports on machete wounds to the cranium. This study was carried out to document the injury profile in a series of patients who have sustained cranial injuries from machete wounds in this setting. Between 1 January 1998 and 1 January 2008, demographic and clinical data were retrospectively collected from all patients treated with complicated head injuries from machete wounds with at least one of the following clinical or radiological features: a recorded Glasgow Coma Score < 8 at any point during admission; compound skull fractures; protruding brain matter; cerebrospinal fluid (CSF) leaks; intra cranial bleeding; parenchymal contusions; lacerations and/or oedema. The data were analysed using the SPSS version 12.0. Of the 40 patients with complex injuries to the cranium, there was a 6:1 male preponderance with a mean age of 32.5 +/- 13.7 years (Mean +/- SD). The injuries included open skull fractures in all the 40 (100%) patients, depressed skull fractures in 20 (50%) patients, CSF leaks in 4 (10%) patients, protruding brain matter in 4 (10%) patients, cerebral contusions in 3 (7.5%) patients and extra cranial injuries in 16 (40%) patients. Tetanus prophylaxis and intravenous antibiotics were administered to all patients, and phenytoin was required in 16 (40%) cases. There were 37 (92%) patients requiring operative intervention at a mean of 10.4 h after presentation (SD +/- 18.1; Median 6). The operative procedures included elevation of depressed fractures in 20 (54.1%) patients, dural repair in 10 (27.0%) patients and intra cranial debridement in 7 (18.9%) patients. There were three deaths (7.5%), and seizures were recorded in 5 (12.5%) cases with no reports of infectious morbidity. Eighty percent of patients had a normal Glasgow outcome score on discharge. Complicated machete head trauma is uncommon at this health care facility in Jamaica. We achieved a satisfactory outcome with aggressive management consisting of prompt assessment of the extent of injury, appropriate antibiotics, anticonvulsants for those with seizures or cortical injury and early operation to decrease the risk of complications. PMID- 21547818 TI - Characterization and treatment of water used for human consumption from six sources located in the Cameron/Tuba City abandoned uranium mining area. AB - The purpose of this research was the characterization and improvement of the quality of water used for human consumption of unregulated/regulated water sources located in the Cameron/Tuba City abandoned uranium mining area (NE Arizona, western edge of the Navajo Nation). Samples were collected at six water sources which included regulated sources: Wind Mill (Tank 3T-538), Badger Springs and Paddock Well as well as unregulated sources: Willy Spring, Water Wall and Water Hole. Samples taken from Wind Mill, Water Wall and Water Hole were characterized with high turbidity and color as well as high level of manganese, iron and nickel and elevated value of molybdenum. High level of iron was also found in Badger Spring, Willy Spring, and Paddock Well. These three water sources were also characterized with elevated values of fluoride and vanadium. Significant amounts of zinc were found in Water Wall and Water Hole samples. Water Wall sample was also characterized with high level of Cr(VI). Compared to primary or secondary Navajo Nation Environmental Protection Agency (NNEPA) water quality standard the highest enrichment was found for turbidity (50.000 times), color (up to 1.796 times) and manganese (71 times), Cr(VI) (17.5 times), iron (7.4 times) and arsenic (5.2 times). Activities of (226)Ra and (238)U in water samples were still in agreement with the maximum contaminant levels. In order to comply with NNEPA water quality standard water samples were subjected to electrochemical treatment. This method was selected due to its high removal efficiency for heavy metals and uranium, lower settlement time, production of smaller volume of waste mud and higher stability of waste mud compared to physico chemical treatment. Following the treatment, concentrations of heavy metals and activities of radionuclides in all samples were significantly lower compared to NNEPA or WHO regulated values. The maximum removal efficiencies for color, turbidity, arsenic, manganese, molybdenum and nickel were 100.0%. Maximum removal percentage of Cu, F(-), V, Zn, (137)Cs, (226)Ra, (232)Th, (238)U were as follows: 98.0%; 82.7%; 99.9%; 95.6%; 75.0%; 76.9%; 80.0% and 99.2%. From the results presented it could be concluded that electrochemical treatment is a suitable approach for the purification of drinking water with complex mixture of contaminants, especially those with high turbidity and color. PMID- 21547817 TI - Demographically corrected norms for African Americans and Caucasians on the Hopkins Verbal Learning Test-Revised, Brief Visuospatial Memory Test-Revised, Stroop Color and Word Test, and Wisconsin Card Sorting Test 64-Card Version. AB - Memory and executive functioning are two important components of clinical neuropsychological (NP) practice and research. Multiple demographic factors are known to affect performance differentially on most NP tests, but adequate normative corrections, inclusive of race/ethnicity, are not available for many widely used instruments. This study compared demographic contributions for widely used tests of verbal and visual learning and memory (Brief Visual Memory Test Revised, Hopkins Verbal Memory Test-Revised) and executive functioning (Stroop Color and Word Test, Wisconsin Card Sorting Test-64) in groups of healthy Caucasians (n = 143) and African Americans (n = 103). Demographic factors of age, education, gender, and race/ethnicity were found to be significant factors on some indices of all four tests. The magnitude of demographic contributions (especially age) was greater for African Americans than for Caucasians on most measures. New, demographically corrected T-score formulas were calculated for each race/ethnicity. The rates of NP impairment using previously published normative standards significantly overestimated NP impairment in African Americans. Utilizing the new demographic corrections developed and presented herein, NP impairment rates were comparable between the two race/ethnicities and were unrelated to the other demographic characteristics (age, education, gender) in either race/ethnicity group. Findings support the need to consider extended demographic contributions to neuropsychological test performance in clinical and research settings. PMID- 21547819 TI - Octanol-water distribution of engineered nanomaterials. AB - The goal of this study was to examine the effects of pH and ionic strength on octanol-water distribution of five model engineered nanomaterials. Distribution experiments resulted in a spectrum of three broadly classified scenarios: distribution in the aqueous phase, distribution in the octanol, and distribution into the octanol-water interface. Two distribution coefficients were derived to describe the distribution of nanoparticles among octanol, water and their interface. The results show that particle surface charge, surface functionalization, and composition, as well as the solvent ionic strength and presence of natural organic matter, dramatically impact this distribution. Distributions of nanoparticles into the interface were significant for nanomaterials that exhibit low surface charge in natural pH ranges. Increased ionic strengths also contributed to increased distributions of nanoparticle into the interface. Similarly to the octanol-water distribution coefficients, which represent a starting point in predicting the environmental fate, bioavailability and transport of organic pollutants, distribution coefficients such as the ones described in this study could help to easily predict the fate, bioavailability, and transport of engineered nanomaterials in the environment. PMID- 21547820 TI - Development of a bench-scale immersed ultrafiltration apparatus for coagulation pretreatment experiments. AB - The purpose of this paper is to present results of a project that focused on developing a standardized bench-scale apparatus and operating procedures for immersed ultrafiltration (UF) membrane systems to assess integrated process designs (e.g., coagulation-UF) under controlled laboratory conditions. The integrated test apparatus, termed Immersed Ultrafiltration Enhanced Coagulation (IUEC), was designed using a hollow-fiber, outside-in UF module immersed in a single compartment water preparation and filtration tank equipped with aeration mixing capabilities for coagulation and flocculation process evaluations. Bench scale experiments were conducted with alum on a low turbidity surface water source to evaluate system performance of the integrated IUEC apparatus compared to a standard jar test unit. The experiments were evaluated by measuring the removal of natural organic matter and zeta-potential analysis from water collected from a conventional mechanically-mixed process with a manual transfer to a UF membrane system and comparing these results to the IUEC system. The results of this study demonstrated that using the single-compartment IUEC apparatus can provide water quality data that is congruent with those obtained through conventional methods that rely on use of standard jar tests. PMID- 21547821 TI - Sterols and fatty acid biomarkers as indicators of changes in soil microbial communities in a uranium mine area. AB - Included in the 2nd tier of a site specific risk assessment that is being carried out in an abandoned uranium mine (Cunha Baixa uranium mine, Central Portugal), fatty acids biomarkers and sterols were analyzed to assess the impact of soil contamination with metals and radionuclides in the structure of the microbial community in seven sampling sites located at different distances from the mine. Surface soil samples were collected in those sampling sites in the four different seasons of the year. Principal component analysis (PCA) was performed on fatty acid biomarkers and sterols. Subsequently PCA scores obtained for both components were used to test the effect of sites and seasons, on soil samples collected in the Cunha Baixa uranium mine, through bi-factorial ANOVAs. Through PCA analysis, two distinct groups were set apart along the first two components. One group included sites at a great distance from the mine which were negatively correlated with higher contents of iC15:0 and iC17:0, both indicators of Gram-positive bacteria, as well as with ergosterol, cholestanol and cholesterol. The second group, in turn, was composed of the sampling sites most impacted by ore exploration, in situ leaching of poor ore, and spread of sludge from the effluent treatment pond. These sites were positively correlated with higher levels of iC16:0 (Gram-positive bacteria indicator), cyC17:0 (generally common in gram negative bacteria) and C18:0 and C17:0 biomarkers of non-specific bacteria. The profile of fatty acids obtained in the sampling sites revealed variable predominance of groups of bacteria which are a clear indication of differences in the soil microbial communities that are directly related to the environmental conditions prevailing in the uranium mine area. PMID- 21547822 TI - Increased levels of lead in the blood and frequencies of lymphocytic micronucleated binucleated cells among workers from an electronic-waste recycling site. AB - In recent years, adverse health effects of chemicals from electronic waste (e waste) have been reported. However, little is known about the genotoxic effects of chemicals in e-waste. In the present study, air concentrations of the toxic metals at e-waste and control sites were analyzed using inductively-coupled plasma mass spectrometry. Levels of toxic metals (lead, copper and cadmium) in blood and urine were detected using atomic absorption spectrophotometry in 48 exposed individuals and 56 age- and sex-matched controls. The frequencies of lymphocytic micronucleated binucleated cells (MNBNCs) were determined using a cytokinesis-block micronucleus assay. Results indicated that blood lead levels were significantly higher in the exposed group (median: 11.449 MUg/dL, 1st/3rd quartiles: 9.351-14.410 MUg/dL) than in the control group (median: 9.104 MUg/dL, 1st/3rd quartiles: 7.275-11.389 MUg/dL). The exposed group had higher MNBNCs frequencies (median: 4.0 per thousand, 1st/3rd quartiles: 2.0-7.0 per thousand) compared with the controls (median: 1.0 per thousand, 1st/3rd quartiles: 0.0-2.0 per thousand). Additionally, MNBNCs frequencies and blood lead levels were positively correlated (r = 0.254, p<0.01). Further analysis suggested that a history of working with e-waste was a predictor for increased blood lead levels and MNBNCs frequencies in the subjects. The results suggest that both the living and occupational environments at the e-waste site may be risk factors for increased MNBNCs frequencies among those who are exposed. PMID- 21547823 TI - Carbofuran degradation by the application of MW-assisted H2O2 process. AB - Carbofuran removal performance of a microwave (MW)-assisted H2O2 system under different MW-power levels (300-900 W) was investigated. Batch experiments were conducted at 100 mg/L carbofuran concentration using a modified-MW reactor with 2450 MHz of fixed frequency. As a precursor, control experiments were carried out with H2O2 alone, MW alone and conventional heating (CH). A maximum carbofuran removal of 14 % was observed in both H2O2 alone and CH systems. On the other hand, only 2 % removal was observed in the MW alone system irrespective of the operation-mode, i.e. continuous or pulsed. The combination of MW and H2O2 produced 100 % carbofuran removal in all the MW-assisted experiments. The MW assisted system operated under continuous-mode and at 750 W has showed rapid carbofuran degradation, i.e. 30 sec, with the highest first-order removal rate constant of 25.82/min. However, 97 % carbon oxygen demand (COD) removal was observed in the same system only after 30 min. On the other hand, 100 % carbofuran removal and 49 % COD removal were observed in the pulsed-mode MW assisted H2O2 system after 10 and 30 min, respectively. Carbofuran mineralization in the system was evidenced by the formation of ammonium and nitrate, and carbofuran intermediates. PMID- 21547824 TI - Effects of feed-supplementation and hide-spray application of two sources of tannins on enteric and hide bacteria of feedlot cattle. AB - Pathogenic bacteria attached to the hide or shed in the feces of cattle at slaughter can contaminate carcasses intended to be processed for human consumption. Therefore, new pre-harvest interventions are needed to prevent the carriage and excretion of foodborne pathogens in cattle presented to the processing plant. The objectives of this study were to examine the antimicrobial effects of hydrolysable tannin-rich chestnut and condensed tannin-rich mimosa extracts on bacterial indicators of foodborne pathogens when applied as a hide intervention and as a feed additive to feedlot cattle. Water (control) or solutions (3 % wt/vol) of chestnut- and mimosa-extract treatments were sprayed (25 mL) at the left costal side of each animal to a 1000 cm2 area, divided in four equal quadrants. Hide-swabs samples obtained at pre-, 2-min, 8-h, and 24-h post-spray application were cultured to enumerate Escherichia coli/total coliforms and total aerobic plate counts. In a second experiment, diets supplemented without (controls) or with (1.5 % of diet dry matter) chestnut- or mimosa-extracts were fed during a 42-day experimental feeding period. Weekly fecal samples starting on day 0, and rumen fluid obtained on days 0, 7, 21 or 42 were cultured to enumerate E.coli/total coliforms and Campylobacter. Tannin spray application showed no effect of treatment or post-application-time (P > 0.05) on measured bacterial populations, averaging 1.7/1.8, 1.5/1.6 and 1.5/1.7 (log10CFU/cm2) for E. coli/total coliforms, and 4.0, 3.4 and 4.2 (log10CFU/cm2) in total aerobes for control, chestnut and mimosa treatments, respectively. Mean (+/- SEM) ruminal E. coli and total coliform concentrations (log(10) CFU/mL) were reduced (P < 0.01) in steers fed chestnut-tannins (3.6 and 3.8 +/- 0.1) in comparison with the controls (4.1 and 4.2 +/- 0.1). Fecal E. coli concentrations were affected by treatment (P< 0.01), showing the highest values (log10 CFU/g) in fecal contents from mimosa-fed steers compared to controls (5.9 versus 5.6 +/- 0.1 SEM, respectively). Total coliforms (log CFU/g) showed the highest values (P < 0.01) in feces from chestnut- and mimosa-fed steers (6.0 and 6.1 +/- 0.1 respectively) in comparison with controls (5.7 +/- 0.1). Fecal Campylobacter concentrations (log10CFU/g) were affected by treatment (P < 0.05), day (P < 0.001) and their interaction (P < 0.01) with the controls having lower concentrations than chestnut- and mimosa-fed steers (0.4, 1.0, and 0.8 +/- 0.3, respectively). It was concluded that under our research conditions, tannins were not effective in decreasing measured bacterial populations on beef cattle hides. Additionally, chestnut tannin reduced E. coli and total coliforms within the rumen but the antimicrobial effect was not maintained in the lower gastrointestinal tract. Further research is necessary to elucidate the possible antimicrobial effects of tannins at site-specific locations of the gastrointestinal tract in beef cattle fed high-grain and high-forage diets. PMID- 21547825 TI - Ecological impacts of the N-viro biosolids land-application for wild blueberry (Vaccinium angustifolium. Ait) production in Nova Scotia. AB - Land application of biosolids from processed sewage sludge may deteriorate soil, water, and plants. We investigated the impact of the N-Viro biosolids land application on the quality of the soil water that moved through Orthic Humo Ferric Podzols soil of Nova Scotia (NS) at the Wild Blueberry Research Institute, Debert, NS Canada. In addition, the response of major soilproperties and crop yield was also studied. Wild blueberry (Vaccinium angustifolium. Ait) was grown under irrigated and rainfed conditions in 2008 and 2009. Four experimental treatments including (i) NI: N-Viro irrigated, (ii) NR: N-Viro rainfed, (iii) FI: inorganic fertilizer irrigated, and (iv) FR: inorganic fertilizer rainfed (control) were replicated 4 times under randomized complete block design. Soil samples were collected at the end of each year and analyzed for changes in cation exchange capacity (CEC), soil organic matter (SOM), and pH.Soil water samples were collected four times during the study period from the suction cup lysimeters installed within and below crop root zone at 20 and 40 cm depths, respectively. The samples were analyzed for a range of water quality parameters including conductance, hardness, pH, macro- and micronutrients, and the infectious pathogens Escherichia coli (E. coli) and salmonella. Berries were harvested for fruit yield estimates. Irrigation significantly increased CEC during 2008 and the soil pH decreased from 4.93 (2008) to 4.79 (2009). There were significant influences of irrigation, fertilizer, and their interaction, in some cases, on most of the soil water quality parameters except on the infectious bacteria. No presence of E. coli or salmonella were observed in soil and water samples, reflecting the absence of these bacteria in biosolids used in this experiment. Nutrient concentration in the soil water samples collected from the four treatments were higher in the sequence NI > NR > FI > FR. The irrigation treatment had significant effect on the unripe fruit yield. We conclude that the comparable performance of N-Viro biosolids and the increasing prices of inorganic fertilizers would compel farmers to use economically available N-Viro biosolids that, coupled with the supplemental irrigation, did not deteriorate the studied soil properties, soil water quality, and the wild blueberry yield during this experiment. PMID- 21547826 TI - Disaster, vulnerability, and older adults: toward a social work response. PMID- 21547827 TI - The third-age African American seniors: benefits of participating in senior multipurpose facilities. AB - This article examines the contexts and benefits of African American seniors' participation in multipurpose facilities. Using qualitative data from 15 in-depth participant interviews and 6-month on-site participant observations as well as a survey result, research revealed the physical, emotional, and social benefits that African American seniors reported as a result of their participation in various activities offered in a multipurpose senior center in Atlanta Georgia. The study presents a social context in which African American seniors constructed their new third age identities that is different from the wide-spread negative images depicted by the mainstream about this minority group. Findings from this study increase the knowledge about African American seniors' participation in multipurpose facilities and provide a better understanding for the diverse socio economic backgrounds of African American seniors. Study results will have policy implications for a better development of senior centers for minority population in the United States for the promotion of productive and successful aging. PMID- 21547828 TI - A comparison of attitudes about cremation among Black and White middle-aged and older adults. AB - Social workers must be instrumental in educating elders and their families to make informed decisions about death and dying. As part of a larger qualitative study, we explored attitudes about cremation of 25 older and 25 middle-aged adults, evenly split between Black and White respondents. Major themes emerged about disposition of the body after death. Costs and land conservation influenced support for cremation; reasons against cremation include religious beliefs, lack of closure, and sense of place. Additionally, some respondents were against cremation primarily because of lack of exposure, as it was not their family tradition, suggesting a role for education. PMID- 21547829 TI - Trauma and stress among older adults in the criminal justice system: a review of the literature with implications for social work. AB - The purpose of this article was to review the empirical literature that investigated trauma and stress among older adults in the criminal justice system. Nineteen journal articles published between 1988 and 2010 were identified and extracted via research databases and included mixed age samples of adjudicated older and younger adults (n = 11) or older adult only samples (n = 8). Findings revealed past and current trauma and stress, consequences and/or correlates, and internal and external coping resources among aging offenders. The implications and future directions for gerontological social work, research, and policy with older adults in the criminal justice system are advanced. PMID- 21547830 TI - The impact of acculturation on depression among older Muslim immigrants in the United States. AB - Using a cross-sectional design, this study utilized a self-administered survey to examine the relationship between acculturation, physical and emotional health, health locus of control (LOC), life events and depression among a convenient sample of 70 immigrant Muslim elderly in United States of America. In addition to demographic variables, 5 standardized measures including the Vancouver Index of Acculturation, Center for Epidemiologic Studies Depression Scale (CESD), Iowa Self-Assessment Inventory, Multidimensional Health Locus of Control Scale, and the Geriatric Scale of Recent Life Events were utilized in this study. The results showed that about 50% of participants reported a score of 16 and above on the CESD scale, indicating a presence of depressive symptoms. In addition, most participants identified with their heritage culture compared to the American culture. The results of multiple regression analysis revealed 4 significant predictors of depression: cognitive status (beta = -.34, p < .01), heritage culture (beta = .35, p < .01), physical health (beta = -.27, p < .05), and internal health locus of control (beta = -.25, p < .05). These factors explain about 37% of the total variance in levels depression (R = .61). PMID- 21547832 TI - The effects of different initial restrictive pressures used to reduce blood flow and thigh composition on tissue oxygenation of the quadriceps. AB - Blood flow restriction training technique can be affected by several factors resulting in changes in responses to training; therefore it is necessary to investigate and reveal detailed information about this novel training technique. Participants had their thigh size, thickness of subcutaneous fat, and regional bone free muscle mass measured prior to testing. A Near-Infrared Spectrometer was used to measure tissue oxygenation and a cardiovascular profiling system was utilised to measure stroke volume and heart rate. Initial restrictive pressure of 30, 50, and 70 mmHg were set in random order on three separate days, and then six target pressures were sequentially applied. Tissue oxygenation decreased significantly as both initial restrictive pressure and target pressures increased, but the magnitude of decreases was stronger with higher initial restrictive pressure. There were significant negative correlations between tissue oxygenation and leg lean body mass, total lean body mass, and thigh circumference when initial restrictive pressure was set at 30 mmHg. The findings indicated that changes in initial restrictive pressure affected the amount of venous return verified by the decreases in tissue oxygenation and stroke volume. In addition, thigh composition and size had a significant impact on the effects of initial restrictive pressure. PMID- 21547833 TI - Effects of optimal pacing strategies for 400-, 800-, and 1500-m races on the VO2 response. AB - The aim of this study was to compare the evolution of oxygen uptake (VO2) in specifically trained runners during running tests based on the 400-, 800-, and 1500-m pacing strategies adopted by elite runners to optimize performance. Final velocity decreased significantly for all three distances, with the slowest velocity in the last 100 m expressed relative to the peak velocity observed in the 400 m (77%), 800 m (88%), and 1500 m (96%). Relative to the previously determined VO2max values, the respective VO 2peak corresponded to 94% (400 m) and 100% (800 and 1500 m). In the last 100 m, a decrease in VO2 was observed in all participants for the 400-m (15.6 +/- 6.5%) and 800-m races (9.9 +/- 6.3%), whereas a non-systematic decrease (3.6 +/- 7.6%) was noted for the 1500 m. The amplitude of this decrease was correlated with the reduction in tidal volume recorded during the last 100 m of each distance (r = 0.85, P < 0.0001) and with maximal blood lactate concentrations after the three races (r = 0.55, P < 0.005). The present data demonstrate that the 800 m is similar to the 400 m in terms of decreases in velocity and VO2. PMID- 21547834 TI - Effects of cigarette smoking on cardiac autonomic function during dynamic exercise. AB - The purpose of this study was to investigate the acute effect of cigarette smoking on cardiac autonomic function in young adult smokers during dynamic exercise. Fourteen healthy young smokers (21.4 +/- 3.4 years) performed peak and submaximal exercise protocols under control and smoking conditions. Resting and submaximal beat-to-beat R-R series were recorded and spectrally decomposed using the fast Fourier transformation. Smoking resulted in a significant decrease in work time, VO(2peak) and peak O(2) pulse (P < 0.05). Heart rate increased at rest and during submaximal exercise after smoking (P < 0.05). The raw high frequency and low frequency power were significantly reduced by smoking, both at rest and during exercise (P < 0.05). The low to high frequency ratio was higher after smoking (P < 0.05). The normalised low frequency power was also significantly increased by smoking, but only at rest (P < 0.05). These data demonstrate that the tachycardic effect elicited by smoking is accompanied by acute changes in heart rate spectral components both at rest and during exercise. Therefore, the cardiac autonomic control is altered by smoking not only at rest, but also during exercise, resulting in reduced vagal modulation and increased sympathetic dominance. PMID- 21547835 TI - The rating of perceived exertion predicts intermittent vertical jump demand and performance. AB - The aims of this study were (a) to assess the ability of the rating of perceived exertion (RPE) to predict performance (i.e. number of vertical jumps performed to a fixed jump height) of an intermittent vertical jump exercise, and (b) to determine the ability of RPE to describe the physiological demand of such exercise. Eight healthy men performed intermittent vertical jumps with rest periods of 4, 5, and 6 s until fatigue. Heart rate and RPE were recorded every five jumps throughout the sessions. The number of vertical jumps performed was also recorded. Random coefficient growth curve analysis identified relationships between the number of vertical jumps and both RPE and heart rate for which there were similar slopes. In addition, there were no differences between individual slopes and the mean slope for either RPE or heart rate. Moreover, RPE and number of jumps were highly correlated throughout all sessions (r = 0.97-0.99; P < 0.001), as were RPE and heart rate (r = 0.93-0.97; P < 0.001). The findings suggest that RPE can both predict the performance of intermittent vertical jump exercise and describe the physiological demands of such exercise. PMID- 21547836 TI - A systematic review of strength and conditioning programmes designed to improve fitness characteristics in golfers. AB - It has been suggested that conditioning programmes have the potential to improve golf performance through fitness adaptations. The primary aim of this systematic review was to evaluate the effectiveness of conditioning programmes on measures of golf-related fitness and golf performance. Four electronic library databases were searched and the quality of the studies was assessed using criteria adapted from the Consolidated Standard of Reporting Trials statement. Thirteen studies satisfied our criteria for inclusion. Nine studies involved middle-aged to older male recreational golfers and four studies used younger more skilled golfers. Conditioning programmes involved the use of machine weights, free weights, medicine balls, and elastic bands, and most studies included a flexibility component. Most studies assessed changes in fitness characteristics and generally resulted in improvements. All but two of the studies assessed changes in club head speed and reported increases. The findings from this review suggest that strength and conditioning programmes can have a positive effect on the golf swing and fitness characteristics of golfers. The majority of studies in this review evaluated the effects of generic conditioning programmes on fitness characteristics and club head speed. Future studies should investigate the effects of more golf-specific strength and conditioning programmes to improve fitness and overall golf performance. PMID- 21547837 TI - Autonomic nervous system modulation during an archery competition in novice and experienced adolescent archers. AB - We assessed autonomic nervous system modulation through changes in heart rate variability during an archery competition as well as archery performance by comparing novice and experienced adolescent archers. Seven novice (age 14.0 +/- 8.5 years, body mass index 22.9 +/- 4.3 kg . m(-2), training experience 0.4 +/- 0.3 years) and ten experienced archers (age 16.5 +/- 10.3 years, body mass index 22.4 +/- 3.1 kg . m(-2), training experience 4.1 +/- 0.9 years) volunteered. Using beat-by-beat heart rate monitoring, heart rate variability was measured for 20 s before each arrow shot during two rounds of competition. We found that, compared with novices, experienced adolescent archers: (i) take more time per shot; (ii) have a higher low frequency band, square root of the mean of squared differences between successive R-R intervals (i.e. the time elapsing between two consecutive R waves in the electrocardiogram), and percentage of successive normal-to-normal intervals greater than 50 ms; and (iii) demonstrate an increase in parasympathetic nervous system activity compared with pre-competition values. We propose that these characteristics of experienced archers are appropriate for optimal performance during competition. PMID- 21547838 TI - Optimisation and characterisation of various extraction conditions of phenolic compounds and antioxidant activity in olive seeds. AB - This study was conducted to optimise the extraction conditions of phenolic compounds to evaluate antioxidant extraction parameters and to identify the major free and bound phenolic compounds in olive seeds. The results obtained using methanol as an extraction solvent for olive seeds indicated that the optimised total phenolic content and antioxidant activity were obtained at an extraction time of 12 h, an extraction temperature of 70 degrees C and an extraction cycle of three stages. The correlation coefficient between total phenolic compounds and antioxidant activities was positive (R2 = 0.83). The major finding is that the predominant phenolic compounds in olive seeds were present in free form. However, a small percentage of the bound phenolic compounds was found in olive seeds compared to that of the free phenolic compounds. This study recommends that olive seeds with optimised extraction conditions (i.e. optimised correlation between phenolic compound contents and antioxidant activities) can be used as potential food additive candidates in functional, nutraceutical and pharmaceutical industries. PMID- 21547839 TI - Antibacterial compounds from Siraitia grosvenorii leaves. AB - Luo Han Guo (LHG) fruits (Siraitia grosvenorii Swingle) have been used as traditional medicine in China for centuries to treat sore throats and coughs. However, LHG leaves are seldom used and minimal scientific information is available on them. In our recent study on the leaves of S. grosvenorii, the bioactive compounds beta-amyrin (2), aloe emodin (5), aloe-emodin acetate (6), 5alpha,8alpha-epidioxy-24(R)-methylcholesta-6,22-dien-3beta-ol (7) and p-hydroxyl benzyl acid (8), accompanied by n-hexadecaoic acid (1), 12-methyltetradecanoic acid (3), beta-sitosterol (4) and daucosterol (9) were first obtained. Their structures have been identified on the basis of spectroscopic studies. The activities of these compounds were evaluated in vitro against the growth of oral bacterial species Streptococcus mutans, Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum and the yeast Candida albicans, and their minimum inhibition concentrations were determined. Furthermore, the activity against S. mutans is likely to be due to the inhibition of glucosyltransferase. The experimental data provide important information on bioactive phytochemicals in the leaf of S. grosvenorii, which shows that the leaf can be a new resource as an antibacterial agent. PMID- 21547840 TI - A new compound, jolynamine, from marine brown alga Jolyna laminarioides. AB - A new compound, jolynamine (1), was isolated from the marine brown alga Jolyna laminarioides collected from the coast of Karachi, Pakistan. In addition, four known compounds, namely saringosterol (2), loliolide (3), methyl-4 hydroxybenzoate (4) and propyl-4-hydroxybenzoate (5), were isolated for the first time from the marine brown alga Iyengaria stellata, and two known compounds, namely 3,4,5-trimethylaniline (6) and harmine (7), were isolated for the first time from the marine brown alga Melanothamnus afaqhusainii. Compound 6 is synthetically known but was isolated for the first time from a natural source. The structures of these compounds were elucidated with the help of powerful spectroscopic techniques. Furthermore, the methanolic extracts of both algae showed anti-microbial activities against various bacteria and fungi. PMID- 21547841 TI - A novel prenylated xanthone from the stems and leaves of Calophyllum inophyllum. AB - A novel prenylated xanthone, caloxanthone Q, was isolated from the stems and leaves of Calophyllum inophyllum. The structure elucidation was carried out by detailed spectroscopic analysis. PMID- 21547842 TI - Volatile oils from the plant and hairy root cultures of Ageratum conyzoides L. AB - Two lines of hairy root culture of Ageratum conyzoides L. induced by Agrobacterium rhizogenes ATCC 15834 were established under either complete darkness or 16 h light/8 h dark photoperiod conditions. The volatile oil yields from aerial parts and roots of the parent plant, the hairy root culture photoperiod line and the hairy root culture dark line were 0.2%, 0.08%, 0.03% and 0.02%, (w/w), respectively. The compositions of the volatiles from the hairy roots, plant roots and aerial parts were analysed by GC and GC-MS. The main components of the volatiles from the hairy root cultures were beta-farnesene, precocene I and beta-caryophyllene, in different amounts, depending on light conditions and also on the age of cultures. Precocene I, beta-farnesene, precocene II and beta-caryophyllene were the main constituents of the volatile oils from the parent plant roots, whereas precocene I, germacrene D, beta caryophyllene and precocene II were the main constituents of the aerial parts of the parent plant. Growth and time-course studies of volatile constituents of the two hairy root lines were compared. Qualitative and quantitative differences were found between the volatile oils from the roots of the parent plant and those from the hairy roots. PMID- 21547843 TI - Identification of the antioxidant principles of Polyalthia longifolia var. pendula using TEAC assay. AB - Activity-guided fractionation of the ethanolic extract of the leaves of the Polyalthia longifolia var. pendula led to the identification of quercetin (1), quercetin-3-O-beta-glucopyranoside (2), kaempferol-3-O-alpha-rhamnopyranosyl-(1 > 6)-beta-galactopyranoside (3), kaempferol-3-O-alpha-rhamnopyranosyl-(1 -> 6) beta-glucopyranoside (4), rutin (5) and allantoin (6) as the active constituents from the butanol fraction. Compounds 2-4 are reported for the first time from this natural source. Structures of the compounds were confirmed on the basis of their 1D and 2D NMR coupled with other spectroscopic methods. All the isolated compounds and the fractions were evaluated for their antioxidant potential using the TEAC assays and it was found that the activity of the active fraction was due to quercetin (1) and its glycosides (2 and 5), with TEAC values of 4.10, 1.91 and 2.38 mM, respectively, while the kaempferol glycosides were found to be inactive. This is the first study on the antioxidant activity of this plant species. PMID- 21547844 TI - Essential oils of Retama raetam from Libya: chemical composition and antimicrobial activity. AB - Retama raetam (Forssk) Webb & Berthel is well known in the folk medicine of North and East Mediterranean regions for the treatment of microbial infections. The powdered leaves are used to heal circumcision wounds and used as an antiseptic for wounds, skin rash and pruritus. In this study, to validate this antiseptic property, the chemical composition and antimicrobial activity of the essential oil from the flowers of R. raetam was evaluated. The oil was obtained using hydrodistillation and was analysed by gas chromatography-mass spectrometry. The antibacterial activity was achieved using disc diffusion and broth dilution assay against six bacteria species. Analysis of the essential oil revealed the presence of beta-linalool (51%), 2-decen-1-ol (6.6%) and limonene (7.4%) as the major components. The results showed significant activity against microorganisms, especially Staphylococcus aureus, with inhibition zones and minimal inhibitory concentration values in the range of 5.0 mm and 3.0 mg mL-1, respectively. The results on the antibacterial activity provide scientific support for the use of these plants in traditional herbal preparations. PMID- 21547845 TI - A rare head-head binding pattern in bisbenzylisoquinoline alkaloids. AB - Bioassay-guided fractionation of Berberis tabiensis against Culex quinquefasciatus third instar larvae afforded a new bisbenzyltetrahydroisoquinoline alkaloid having an unusual head-head binding pattern. This new alkaloid (tabienine B) is the first member of this family found to possess a diphenyl ether bridge in C-6 and C-7'. PMID- 21547846 TI - The neural architecture of expert calendar calculation: a matter of strategy? AB - Savants and prodigies are individuals with exceptional skills in particular mental domains. In the present study we used functional magnetic resonance imaging to examine neural correlates of calendar calculation in two individuals, a savant with Asperger's disorder and a self-taught mathematical prodigy. If there is a modular neural organization of exceptional performance in a specific mental domain, calendar calculation should be reflected in a considerable overlap in the recruitment of brain circuits across expert individuals. However, considerable individual differences in activation patterns during calendar calculation were noted. The present results indicate that activation patterns produced by complex mental processing, such as calendar calculation, seem to be influenced strongly by learning history and idiosyncratic strategy usage rather than a modular neural organization. Thus, well-known individual differences in complex cognition play a major role even in experts with exceptional abilities in a particular mental domain and should in particular be considered when examining the neural architecture of complex mental processes and skills. PMID- 21547847 TI - Anthropometric, dietary, and hormonal correlates of serum adiponectin in Asian American women. AB - There is increasing evidence that adiponectin has a critical role in the development of breast cancer, but factors that influence adiponectin concentrations have not been well studied. We conducted a cross-sectional study among Asian-American controls who participated in a population-based case-control study of breast cancer. Participants were interviewed in-person and donated a blood specimen. Using multivariate models, we investigated the relationships between serum adiponectin concentrations and lifestyle factors (including adiposity and dietary factors) and serum sex-hormones and growth factors among postmenopausal women who were nonhormone-users at blood draw (n = 196). Adiponectin concentrations were significantly positively associated with green tea intake (P trend = 0.03); levels were 31% higher among those who drank green tea 4 or more times per wk (14.5 +/- 1.10 MUg/mL) compared with nongreen-tea drinkers (11.0 +/- 1.09 MUg/mL); this association remained after adjustment for body mass index (BMI) and waist/hip ratio (WHR), both of which were significantly and inversely associated with adiponectin. Adiponectin concentrations were positively associated with sex-hormone-binding globulin (P trend < 0.0001) and the ratios of total testosterone (T)/total estradiol (E2) (P trend <0.004) after adjustment for BMI and WHR. Confirmation of our findings on green tea and adiponectin is needed. PMID- 21547848 TI - Polymorphisms in WNT6 and WNT10A and colorectal adenoma risk. AB - The WNT/beta-catenin signaling pathway upregulates transcription of genes involved in cell proliferation and cancer progression; it has been implicated in colorectal adenoma formation. To date, no studies have examined polymorphisms in WNT genes or WNT gene-environment interactions in relation to adenoma risk. Within a colonoscopy-based case-control study of 628 adenoma cases and 516 polyp free controls, we analyzed two tagSNPs in WNT6 (rs6747776 G > C, rs6754599 G > C) and WNT10A (rs7349332 G > A, rs10177996 A > G). The WNT6 rs6747776 homozygous minor allele (CC) was associated with increased risk of colorectal adenoma (OR = 2.75, 95% CI: 1.03-7.31). We observed a statistically significant interaction between WNT6 rs6747776 and the proportion of calories from total fat (P-int = 0.02), where the highest risk was observed among those with minor alleles and lowest fat intake. We also detected a marginally significant (0.05 < P <= 0.10) interaction with fish intake (P-int = 0.09). Additionally, a marginally significant interaction was observed between proportion of calories from saturated fat and the WNT10A rs7349332 polymorphism. Our results suggest that genetic variability in the WNT pathway may play a role in colorectal adenoma formation or may partly mediate the increased risk of colorectal cancer associated with fat intake. PMID- 21547849 TI - Inflammation-related signaling pathways implicating TGFbeta are revealed in the expression profiling of MCF7 cell treated with fermented soybean, chungkookjang. AB - Chungkookjang is a Korean fermented soybean containing microorganisms, proteinase, and diverse bioactive compounds, including a high concentration of isoflavones and peptides. Growth of breast cancer MCF7 cells decreased dependent on the concentration of fermented soybean extracts. The effect of fermented soybean on cellular gene expression was determined in a systematic manner comprehensively. DNA microarray analysis was performed using 25,804 probes. Ninety one genes whose expression levels were significantly changed were selected. TGFbetaI and Smad3 were upregulated. Downregulation of inflammation related CSF2, CSF2RA, and CSF3 was found. Differential expression of chemokines CCL2, CCL3, CCL3L3, CXCL1, and CXCL2 were observed. Network analysis identified ERbeta in the network. Based on the experimental results, taking fermented soybean might be helpful for preventing breast cancer by a mechanism activating TGFbeta pathway and depressing inflammation. PMID- 21547850 TI - Foods and food groups associated with the incidence of colorectal polyps: the Adventist Health Study. AB - Colorectal cancer (CRC) is a leading cause of cancer death in the United States. The majority of CRC arise in adenomatous polyps and 25-35% of colon adenoma risk could be avoidable by modifying diet and lifestyle habits. We assessed the association between diet and the risk of self-reported physician-diagnosed colorectal polyps among 2,818 subjects who had undergone colonoscopy. Subjects participated in 2 cohort studies: the AHS-1 in 1976 and the AHS-2 from 2002-2005. Multivariate logistic regression analysis was used to estimate the period risk of incident cases of polyps; 441 cases of colorectal polyps were identified. Multivariate analysis adjusted by age, sex, body mass index, and education showed a protective association with higher frequency of consumption of cooked green vegetables (OR 1 time/d vs. <5/wk = 0.76, 95% CI = 0.59-0.97) and dried fruit (OR 3+ times/wk vs. <1 time/wk = 0.76, 95%CI = 0.58-0.99). Consumption of legumes at least 3 times/wk reduced the risk by 33% after adjusting for meat intake. Consumption of brown rice at least 1 time/wk reduced the risk by 40%. These associations showed a dose-response effect. High frequency of consumption of cooked green vegetables, dried fruit, legumes, and brown rice was associated with a decreased risk of colorectal polyps. PMID- 21547856 TI - What about inhibition in the Wisconsin Card Sorting Test? AB - The commercially available Wisconsin Card Sorting Test (WCST) is one of the most commonly used tests for assessing executive functions within clinical settings. Importantly, however, it remains relatively unclear exactly what processes are assessed by the test. Conceptually, increased perseverative errors in sorting cards are usually related to deficient inhibition processes. Empirically, evidence supporting this conclusion is limited. In a sample of 38 healthy adults we addressed the question to what extent inhibition mechanisms assessed by the go/no-go and the stop-signal paradigm are related to WCST performances. Inhibition-related scores were found to predict non-perseverative errors better than perseverative errors. Consequently we conclude that the non-perseverative errors score reflects processes that are partly dependent on inhibition functions. PMID- 21547857 TI - Social environmental and individual factors associated with smoking among a panel of adolescent girls. AB - This study assessed changes in the influence of social environmental and individual factors-and the interaction of these factors with time-on smoking prevalence for girls. Longitudinal panel surveys of adolescent girls (N = 921 in both 2000 and 2004) from schools in Louisiana were completed in the ninth grade (2000) and then again in the twelfth grade (2004). A fixed effects hierarchical multiple regression model assessed the relation of changes in social environmental and individual factors to smoking prevalence. Increases in smoking prevalence over time among adolescent girls were associated with their perceptions of themselves as overweight and perceiving low risk associated with smoking. Increases in smoking prevalence over time were also associated with having friends who smoked, perceptions of friends' approval of smoking, having family members who smoked, and having monetary discretionary spending. Having friends who smoked was more strongly associated with smoking in the twelfth grade than in the ninth grade. While more black adolescent girls smoked than did white girls in the ninth grade, by the twelfth grade, more white adolescents girls smoked than did black girls. Interventions that target adolescent girls should consider the temporal variability of individual and social environmental factors. PMID- 21547858 TI - Breast cancer risk perception, benefits of and barriers to mammography adherence among a group of Iranian women. AB - The study aimed to assess associations between Health Belief Model variables, stages of change, and participation in mammography for early detection of breast cancer in a sample of Iranian women. A total of 414 women, aged 40 to 73 years, were recruited by random sampling. The study took place in the winter of 2007, using a self-report questionnaire and structured interviews, designed to measure the five Health Belief Model constructs and stages of adoption for mammography. The study indicated that 45.8% of the women were in the pre-contemplation and contemplation stages of a mammogram, and 29% of participants reported having had at least one mammogram. Screening behavior was associated with older age, familial history of breast cancer, history of breast disease, health insurance coverage, and living in an urban area. Furthermore, the perceived susceptibility to breast cancer, perceived benefits and barriers for mammography, and cues to action variables defined by the Health Belief Model were four factors related to having a mammogram. The study concludes that health care professionals must provide women with more fear appeals that outline vulnerability to developing breast cancer, remove cognitive barriers to seeking mammography, and apply effective guidance on the participation of women in breast cancer screening programs. PMID- 21547852 TI - Know thyself: real-world behavioral correlates of self-appraisal accuracy. AB - Accurate appraisal of one's own abilities is one metacognitive skill considered to be an important factor affecting learning and behavior in childhood. The present study measured self-appraisal accuracy in children using tasks of executive function, and investigated relations between self-appraisal and informant ratings of real-world behaviors measured by the BRIEF. We examined self appraisal accuracy on fluency tasks in 91 children ages 10-17. More accurate self appraisal was correlated with fewer informant ratings of real-world behavior problems in inhibition and shifting, independent of actual performance. Findings suggest that self-appraisal represents cognitive processes that are at least partially independent of other functions putatively dependent on the frontal lobes, and these self-appraisal-specific processes have unique implications for optimal daily function. PMID- 21547859 TI - Pregnant women's fear of childbirth in midwife- and obstetrician-led care in Belgium and the Netherlands: test of the medicalization hypothesis. AB - Fear of childbirth has gained importance in the context of increasing medicalization of childbirth. Belgian and Dutch societies are very similar but differ with regard to the organization of maternity care. The Dutch have a high percentage of home births and low medical intervention rates. In contrast, home births in Belgium are rarer, and the medical model is more widely used. By comparing the Belgian and Dutch maternity care models, the association between fear of childbirth and medicalization can be explored. For this study an antenatal questionnaire was completed by 833 women at 30 weeks of pregnancy. Fear of childbirth was measured by a shortened Dutch version of the Childbirth Attitudes Questionnaire. A four-dimensional model with baby-related, pain and injuries-related, general and personal control-related, and medical interventions and hospital care-related fear, fitted well in both countries. Multiple regression analysis showed no country differences, except that Belgian women in midwife-led care were more fearful of medical interventions and hospital care than the Dutch. For the other dimensions, both Belgian and Dutch women receiving midwifery care reported less fear compared to those in obstetric antenatal care. Hence, irrespective of the maternity care model, antenatal care providers are crucial in preventing fear of childbirth. PMID- 21547860 TI - Effects of Pilates-based exercise on life satisfaction, physical self-concept and health status in adult women. AB - The objective of this study was to determine the effect of Pilates-based mat exercises on life satisfaction, perception of appreciation by other people, perception of physical appearance, perception of functionality, total physical self-concept, and perception of health status in healthy women. A randomized controlled trial was conducted in Evora, Portugal, in 2008, in which 62 healthy adult women were randomized to a Pilates-based mat (experimental group) (n = 38, mean age +/- SD, 41.08 +/- 6.64 years) or a control group (n = 24, mean age +/- SD, 40.25 +/- 7.70 years). Experimental group participants performed the Initial Mat of Body Control Pilates twice per week, 60-minutes per session. Repeated measurements were performed at baseline, 3 months and 6 months. No significant differences between the two groups were observed in life satisfaction, perception of appreciation by other people, perception of physical appearance, perception of functionality, total physical self-concept, and perception of health status at three time point measures (baseline, after 3 months, and after 6 months). No significant differences were observed in the control group over time. The experimental group showed significant improvements between baseline and six months in life satisfaction (p = .04), perception of appreciation by other people (p = .002), perception of physical appearance (p = .001), perception of functionality (p = .01), total physical self-concept (p = .001), perception of health status (p = .013) and between three and six months in life satisfaction (p = .002), perception of appreciation by other people (p = .05), perception of physical appearance (p = .001), perception of functionality (p = .02), and total physical self-concept (p = .001). Life satisfaction, perception of appreciation by other people, perception of physical appearance, perception of functionality, total physical self-concept and perception of health status may improve after 6 months of Pilates-based mat exercise. PMID- 21547861 TI - "If we can endure, we continue": understanding differences between users, discontinuers, and non-users of hormonal contraceptive methods in Pursat Province, Cambodia. AB - In Cambodia, 79% of married women ages 15 to 49 years wish to limit or delay births', yet only 27% are using a modern method of contraception. This paper reports on the results of a qualitative study to understand the different characteristics of and barriers to the use of contraceptives (particularly hormonal contraceptives) among current users, women who have discontinued contraceptive use, and women who have never used a modern method. Over several weeks in December 2006, the researchers conducted 14 in-depth interviews and 10 focus group discussions with different contraceptive user types in Pursat Province, Cambodia. A total of 84 women were included in the study. Findings showed that rumors of myths and misconceptions about side effects of hormonal contraceptives were the main barriers to the use and were wide-spread among all women. Differences between the three user types showed that positive husband support, access to health providers, and a high degree of self-efficacy for contraceptive use may have contributed to successful initiation and continuation of modern methods. This research has practical implications for programmatic applications. Results may be used to design efforts aimed at reducing misconceptions about contraceptive methods and increasing partner and provider support for women's use of hormonal contraceptives. PMID- 21547862 TI - Effects of psychosocial characteristics of work on pregnancy outcomes: a critical review. AB - Birth outcomes may influence subsequent susceptibility to chronic diseases. With the increased number of women who continue to work during pregnancy, occupational stress has been hypothesized to be a potential contributor to adverse reproductive health outcomes. The Job Demand and Control model has been primarily used in investigating associations between work-related stress and outcomes such as preterm delivery, low birth weight, and spontaneous abortion. A literature review of occupational factors that have been associated with adverse reproductive outcomes was conducted. In studies assessing preterm delivery and low birth weight, some evidence has suggested a modest association with work related stress but has not been conclusive. In the literature on psychosocial characteristics of work and spontaneous abortion, job strain alone was often not associated with adverse outcomes. However the presence of other risk factors resulted in a synergistic effect which strengthened the odds of an adverse outcome. Future studies should use a prospective design with a large study sample, in which work-related stress exposure data are collected before or in the early stages of the pregnancy. In addition, future research should measure psychosocial characteristics of work both objectively and subjectively. PMID- 21547863 TI - Training, leptin receptors and SOCS3 in human muscle. AB - Endurance exercise induces SUPPRESSOR of CYTOKINE SIGNALING 3 (SOCS3) mRNA expression in rodent skeletal muscle and endurance training overimposed on strength training blunts the hypertrophic response to strength training by an unknown mechanism. The aim of this study was to determine the effects of a concurrent strength and endurance training on fat mass, serum leptin concentration, muscle morphology, and muscle vastus lateralis leptin receptors (OB-Rb) and SOCS3 protein expression. 16 healthy young men were assigned to a control (C; n=7), and to a 12-week weightlifting (3 sessions/week)+endurance training program (T; n=9) group. Training enhanced maximal dynamic strength in lower and upper body exercises (18-54%), reduced fat mass by 1.8 kg and serum leptin concentration per kg of fat mass, and elicited muscle hypertrophy of type 2 (+18.5%, P<0.05) but not of type 1 muscle fibres (+4.6%, P=NS). No significant changes were observed in either OB-Rb or SOCS3 protein expression with training. In conclusion, concurrent strength and endurance training reduces fat mass and serum leptin and the ratio leptin/fat mass without significant effects on vastus lateralis OB-Rb protein expression. Training does not increase the basal expression of SOCS3 protein in humans. PMID- 21547864 TI - Cardiac biomarker response to intermittent exercise bouts. AB - The impact of intermittent exercise on cardiac biomarker release has not been clearly established. In experienced athletes, we examined the acute effect of a heavy resistance training session (n=18 males) and an indoor soccer match (n=21, 11 males, 10 females) on the release of cTnI, cTnT, and NT-proBNP. Biomarkers were assayed from blood samples collected at rest, immediately post- and at 1, 3, 6, 12, and 24 h post-exercise. The heavy resistance training session resulted in an increase in NT-proBNP (pre: 15 +/- 17, peak post: 41 +/- 56 ng L (-1); p=0.001) but not in cTnI (pre: 0.024 +/- 0.009, peak post: 0.025 +/- 0.011 MUg L (-1), p=0.809) or cTnT (undetectable in all samples). The indoor soccer match led to an increase in the release of NT-proBNP (pre: 28 +/- 32, peak post: 66 +/- 56 ng L (-1); p=0.000) and cTnI (pre: 0.026 +/- 0.047, peak post: 0.033 +/- 0.051 MUg L (-1); p=0.008) in both males and females but not cTnT (detectable in only one subject). The current data suggest that intermittent bouts of exercise result in only modest perturbations of cardiac biomarkers with very limited evidence of myocyte injury/insult. PMID- 21547865 TI - Refractory focal epilepsy in a patient with methylmalonic aciduria: case report on positive and long-lasting effect of rufinamide. AB - We report on a 5-year-old boy with methylmalonic aciduria, an autosomal recessive inborn error of metabolism leading to accumulation of methylmalonic-CoA and thereby causing intoxication with leading symptoms of hyperammonaemia and metabolic acidosis. Hyperammonemia itself causes brain oedema. In our patient, this led to a vast metabolic stroke of the left hemisphere and subsequent pharmacoresistant epilepsy. Guided by his main seizures--drop attacks--the orphan drug rufinamide (RUF) was introduced as "off-label use" and led to freedom of drop attacks and tonic-clonic seizures over a period of 14 months as well as normalisation of the electroencephalogramm. Only once during an episode of fever and diarrhoea with reduced level of RUF did some provoked seizures with focal complex semiology for the time period of infection occur. In the 16 months follow up, the patient also improved in his development, showing a more stable gait with the hemiparesis and understanding more complex sentences. PMID- 21547866 TI - [Diagnosis and therapy of fibromyalgia syndrome]. PMID- 21547867 TI - [Uncommon differential diagnosis of persistent otorrhea]. PMID- 21547868 TI - [Mechanically disturbed phonation - a case report]. PMID- 21547869 TI - [Bilateral mastoiditis as the first manifestation of a Langerhans' cell histiocytosis]. PMID- 21547870 TI - A systems approach to the biology of mood disorders through network analysis of candidate genes. AB - Meta analysis of association data of mood disorders has shown evidence for the role of particular genes in genetic risk. Integration of association data from meta analysis with differential expression data in brains of mood disorder patients could heighten the level of support for specific genes. To identify molecular mechanisms that may be disrupted in disease, a systems approach that involves analysis of biological networks created by these selected genes was employed.Interaction networks of hierarchical groupings of selected genes were generated using the Michigan Molecular Interactions (MiMI) software. Large networks were deconvoluted into subclusters of core complexes by using a community clustering program, GLay. Network nodes were functionally annotated in DAVID Bioinformatics Resource to identify enriched pathways and functional clusters. MAPK and beta adrenergic receptor signaling pathways were significantly enriched in the ANK3 and CACNA1C network. The PBRM1 network bolstered the enrichment of chromatin remodeling and transcription regulation functional clusters. Lowering the stringency for inclusion of other genes in network seeds increased network complexity and expanded the recruitment of enriched pathways to include signaling by neurotransmitter and hormone receptors, neurotrophin, ErbB and the cell cycle. We present a strategy to interrogate mechanisms in the cellular system that might be perturbed in disease. Network analysis of meta analysis- generated candidate genes that exhibited differential expression in mood disorder brains identified signaling pathways and functional clusters that may be involved in genetic risk for mood disorders. PMID- 21547871 TI - Bursts and the efficacy of selective serotonin reuptake inhibitors. AB - We present a new hypothesis for the efficacy of selective serotonin reuptake inhibitors (SSRIs). We propose that SSRIs bring the response to the phasic firing of raphe nucleus cells back to normal, even though the average extracellular 5HT concentration remains low. We discuss burst firing in the raphe nuclei and use mathematical models to argue that tonic firing and phasic firing may be decoupled and may come from different mechanisms. We use a mathematical model for serotonin synthesis, release, and reuptake in terminals to illustrate the responses in terminal regions to bursts in a normal individual and in an individual with low vesicular serotonin. We then show that acute doses of SSRIs do not bring the response to bursts back to normal, but that chronic doses do return the response to normal. These model results need to be confirmed by new electrophysiological and pharmacological experiments. PMID- 21547872 TI - [Do the New German OPS codes map the relevant therapeutic activities in psychiatric clinics?]. AB - OBJECTIVE: Actual codes for operations and procedures (OPS) in psychiatry and psychosomatics should map cost separating therapeutic activities so far defined in Germany by the normative specifications of the psychiatry staff enactment (PsychPV). OPS codes should also allow re-estimating underlying therapy times. METHOD: Therapeutic activities of the PsychPV fulfilling the minimal criteria of the OPS definition were classified as multiples of a therapeutic 25 minute unit. RESULTS: Therapeutic activities of the PsychPV are mapped to OPS complex codes in a variable degree (psychiatrists 35 %, psychologists 42 %, nurses 43 %, special therapists 59 %). CONCLUSION: Actual OPS codes are inappropriate for identifying relevant cost-separating factors in the therapy of psychiatric in-patients. They cannot assure in their actual form the standards given by the PsychPV and need substantial revision. PMID- 21547873 TI - [The "subjective aspects" of restraint and violence in psychiatry]. PMID- 21547874 TI - [Memory clinics in community mental health care]. PMID- 21547875 TI - [Evaluation of the German version of the STAR scale]. AB - OBJECTIVE: The assessment of the therapeutic relationship has become increasingly important due to evidence suggesting that it has a direct therapeutic effect and may improve outcome indirectly. In Great Britain and Sweden the STAR (Scale To Assess Therapeutic Relationship) was developed for pan-theoretical assessment of therapeutic relationships from both clinicians' and patients' points of view. We translated the English version of the instrument into German and made an analysis of its feasibility and reliability. METHODS: The German translation (STAR-D) was generated in a consensus procedure. The STAR-D was then administered to 100 patients admitted to the Psychiatric University Hospital Zurich (STAR-P) and their clinicians in charge (STAR-C). The psychometric qualities of feasibility and reliability were assessed. RESULTS: The overall results for the scales in terms of feasibility and reliability were satisfactory. We did, however, find shortcomings concerning the subscales. They could not be extracted in the principal component analysis and showed high inter-correlation coefficients. CONCLUSIONS: STAR can serve as an important tool in research concerning the therapeutic relationship. We suggest conducting further analyses concerning the validity of the subscales in the German version. PMID- 21547876 TI - [The development of legal guardianship and involuntary treatment in a Bavarian catchment area in comparison to trends at the federal state and the federal level between 1999 and 2009]. AB - OBJECTIVE: In this study trends in legal guardianship and involuntary treatment in a Bavarian catchment area in comparison to trends at federal state and federal level between 1999 and 2009 will be examined. METHODS: Data from the federal department of justice, from the federal health monitoring system and data from a district court were used to compute rates, quotas and quotients. Regression analyses were conducted to analyse associations between time series. RESULTS: In comparison to the federal state and the federal level the target region shows a significantly higher rate of new guardianships but a lower rate of judicial ordered mobility restrictions and at least in comparison to the federal state level a significantly lower rate of involuntary admissions according to guardianship law. CONCLUSIONS: The obtained differences indicate significant differences in the legal guardianship and involuntary admission practise which cannot be explained by epidemiological developments. Therefore it is necessary to investigate potential socio-cultural and socioeconomic sources for these varieties. PMID- 21547877 TI - [The risk for myocarditis of clozapine and other atypical antipsychotics: case report and study of the literature]. AB - OBJECTIVE: Clozapine is considered as a strong psychopharmaceutic agent in symptom control of psychotic disturbances. However, possible side effects to hematologic, metabolic and cardiologic systems are still entailing a defensive application in psychiatric praxis. METHODS: A patient suffering from schizoaffective disorder clinically developed symptoms of cardial disturbances under the psychopharmacotherapy of Clozapine. Specific laboratory analysis and technical procedures were applied, clarifying the background of this serious event. RESULTS: ECG and specific myocardial enzymes (CK, Troponine-I) requesting an acute myocardial infarction were negative. Specific laboratory analysis revealed positive inflammation markers with elevated C-reactive protein and interleukin-6. Additionally, there was increasing of TNF-alpha and C3 as well as an eosinophilia at differential blood cell count. Echocardiography found an unspecific dyskinesia of the left ventricle, but contrast-enhanced cardial MRI showed structural intramyocardial inhomogeneities suggesting a myocarditis. CONCLUSIONS: In spite of the striking psycho-pharmacotherapeutic benefit, Clozapine may be associated with serious cardial events. We discuss these cardiological problems in association to a Clozapine therapy in regard to its clinical relevance in treatment of psychotic disturbances. PMID- 21547878 TI - Propofol sedation during endoscopy in patients with cirrhosis, and utility of psychometric tests and critical flicker frequency in assessment of recovery from sedation. AB - BACKGROUND AND STUDY AIMS: Patients with cirrhosis who undergo endoscopy under sedation could be at increased risk of complications. We assessed the utility of the critical flicker frequency (CFF) in the recovery of cognitive function. PATIENTS AND METHODS: This was a prospective study in patients with cirrhosis who underwent endoscopy under sedation with propofol in a tertiary care center. The main outcome was deterioration in cognitive function as measured by the number connection test A and B (NCT-A, -B), digit symbol test (DST), serial dotting test (SDT), and line tracing test (LTT) before and 2 h after endoscopy. CFF was recorded before and then every 30 min after endoscopy for the next 2 h. RESULTS: In the 108 patients there was no deterioration in results of the psychometric tests after the endoscopy (NCT-A 65.2 +/- 44.4 vs. 62.4 +/- 43.6 s, P = 0.01; NCT B 110.4 +/- 34.7 vs. 109.6 +/- 44.6 s, P = 0.45; DST 26.2 +/-1 0.0 vs. 26.7 +/- 9.9, P = 0.25; SDT 88.6 +/- 47.5 vs. 84.3 +/- 44.1 s, P = 0.02; LTT 116.6 +/- 55.2 vs. 115.4 +/- 51.3 s, P = 0.47.) Patients with minimal hepatic encephalopathy (MHE; n = 64) did not show any deterioration in cognitive function at 2 h (NCT-A 87.7 +/- 45.4 vs. 84.3 +/- 44.9 s, P = 0.06; NCT-B 134.8 +/- 65.4 vs. 132.7 +/- 58.8 s, P = 0.46; DST 21.4 +/- 8.9 vs. 22.2 +/- 8.8, P = 0.09; SDT 107.1 +/- 53.0 vs. 102.7 +/- 48.5 s, P = 0.03; and LTT 131.5 +/- 62.2 vs. 129.6 +/- 57.2 s, P = 0.46). There was a significant difference between CFF at baseline and at 30 min and 1 h but no difference thereafter in non-MHE patients, MHE patients, and in controls. A total of 30 patients (28 %) had CFF < 38 Hz. In these patients, CFF at 2 h did not significantly differ from baseline CFF (35.9 +/- 1.5 vs. 36.1 +/- 2.0 Hz; P = 0.19). A total of 10 patients (9 %) had transient hypoxemia and 18 (17 %) had hypotension during the procedure. The endoscopy was completed in all patients. CONCLUSIONS: Propofol is safe in patients with cirrhosis and the CFF is a useful tool for the assessment of recovery from sedation in these patients. PMID- 21547879 TI - Bowel cleansing for colonoscopy: prospective randomized assessment of efficacy and of induced mucosal abnormality with three preparation agents. AB - BACKGROUND AND STUDY AIMS: Bowel-cleansing studies are frequently underpowered, poorly designed, and use subjective bowel cleansing assessments. Consensus on efficacy, tolerability, and preparation-induced mucosal abnormalities is lacking. This study aimed to clarify the differences in efficacy and preparation-induced mucosal inflammation of sodium phosphate (NaP), colonLYTLEY (PEG), and Picoprep (Pico). PATIENTS AND METHODS: This was a prospective randomized single-blinded trial of ambulatory patients to assess the efficacy of bowel preparation and preparation-induced mucosal inflammation. Proceduralists who were blinded to the preparation taken, assessed both bowel cleansing by using the Ottawa bowel preparation assessment tool and preparation-induced mucosal inflammation. RESULTS: Of the 634 patients, 98 % ingested more than 75 % of the bowel preparation and data were complete for colonic preparation scoring in 99 %. The preparation used, time of procedure, and patient sex all independently impacted on bowel cleansing. NaP was less efficacious than PEG ( P < 0.001) and Pico ( P < 0.001) for morning procedures whereas all bowel preparations were equally efficacious for afternoon procedures. Preparation-induced mucosal inflammation was 10-fold greater with NaP ( P = 0.03) and Pico ( P = 0.03) compared with PEG. CONCLUSIONS: This is the largest published prospective randomized blinded study on this topic and the first to evaluate the three major classes of preparation with a validated tool. The bowel preparation used, time of procedure, and patient sex all independently impacted on bowel cleansing. NaP gave the worst preparation for morning procedures whereas all preparations were equally effective for afternoon procedures. NaP and Pico induced mucosal inflammation 10-fold more frequently than PEG, a finding that requires further investigation. PMID- 21547880 TI - Endoscopy and antiplatelet agents. European Society of Gastrointestinal Endoscopy (ESGE) Guideline. AB - With the increasing use of antiplatelet agents (APA), their management during the periendoscopic period has become a more common and more difficult problem. The increase in use is due to the availability of new drugs and the widespread use of drug-eluting coronary stents. Acute coronary syndromes can occur when APA therapy is withheld for noncardiovascular interventions. Guidelines about APA management during the periendoscopic period are traditionally based on assessments of the procedure-related risk of bleeding and the risk of thrombosis if APA are stopped. New data allow better assessment of these risks, of the necessary duration of APA discontinuation before endoscopy, of the use of alternative procedures (mostly for endoscopic retrograde cholangiopancreatography [ERCP]), and of endoscopic methods that can be used to prevent bleeding (following colonic polypectomy). This guideline makes graded, evidence-based, recommendations for the management of APA for all currently performed endoscopic procedures. A short summary and two tables are included for quick reference. PMID- 21547882 TI - Comment to the article: Magnetic resonance spectroscopic imaging for visualization of the infiltration zone of glioma. PMID- 21547883 TI - Cubital tunnel syndrome - a review and management guidelines. AB - Cubital tunnel syndrome (CuTS) is the second most common peripheral nerve compression syndrome. In German-speaking countries, cubital tunnel syndrome is often referred to as sulcus ulnaris syndrome (retrocondylar groove syndrome). This term is anatomically incorrect, since the site of compression comprises not only the retrocondylar groove but the cubital tunnel, which consists of 3 parts: the retrocondylar groove, partially covered by the cubital tunnel retinaculum (lig. arcuatum or Osborne ligament), the humeroulnar arcade, and the deep flexor/pronator aponeurosis. According to Sunderland , cubital tunnel syndrome can be differentiated into a primary form (including anterior subluxation of the ulnar nerve and compression secondary to the presence of an anconeus epitrochlearis muscle) and a secondary form caused by deformation or other processes of the elbow joint. The clinical diagnosis is usually confirmed by nerve conduction studies. Recently, the use of ultrasound and MRI have become useful diagnostic tools by showing morphological changes in the nerve within the cubital tunnel. A differential diagnosis is essential in atypical cases, and should include such conditions as C8 radiculopathy, Pancoast tumor, and pressure palsy. Conservative treatment (avoiding exposure to external noxes and applying of night splints) may be considered in the early stages of cubital tunnel syndrome. When nonoperative treatment fails, or in patients who present with more advanced clinical findings, such as motor weakness, muscle atrophy, or fixed sensory changes, surgical treatment should be recommended. According to actual randomized controlled studies, the treatment of choice in primary cubital tunnel syndrome is simple in situ decompression, which has to be extended at least 5-6 cm distal to the medial epicondyle and can be performed by an open or endoscopic technique, both under local anesthesia. Simple decompression is also the therapy of choice in uncomplicated ulnar luxation and in most post-traumatic cases and other secondary forms. When the luxation is painful, or when the ulnar nerve actually "snaps" back and forth over the medial epicondyle of the humerus, subcutaneous anterior transposition may be performed. In cases of severe bone or tissue changes of the elbow (especially with cubitus valgus), the anterior transposition of the ulnar nerve may again be indicated. In cases of scarring, submuscular transposition may be preferred as it provides a healthy vascular bed for the nerve as well as soft tissue protection. Risks resulting from transposition include compromise in blood flow to the nerve as well as kinking of the nerve caused by insufficient proximal or distal mobilization. In these cases, revision surgery is necessary. Epicondylectomy is not common, at least in Germany. Recurrence of compression on the ulnar nerve at the elbow may occur. This review is based on the German Guideline "Diagnose und Therapie des Kubitaltunnelsyndroms" ( www.leitlinien.net ). PMID- 21547884 TI - Minimal inspiratory flow from dry powder inhalers according to a biphasic model of pressure vs. flow relationship. AB - Inhalation therapy using the dry powder inhaler (DPI) is now the first choice for obstructive pulmonary diseases. We previously measured relationships between inspiratory pressure (PI) and flow rate of almost all of the DPIs available in Japan, and described an importance of inspiratory efforts. In the present study, we further analyzed the data obtained in the previous study. Although there were linear relationships between PI and flow2, the slope became steeper when PI was less than a certain value (critical PI, existed between 15-20 cmH2O). When PI was less than critical PI, linear rather than parabolic regression between PI and flow yielded better fits (r > 0.90, p < 0.001). Inspiratory flows at the critical PI were 53.9 (Diskus), 65.8 (Diskhaler), 45.9 (Turbuhaler for Pulmincort), 48.6 (Turbuhaler for Symbicort) and 38.0 l/min (Twisthaler). These findings suggested that flow through the DPI becomes laminar rather than turbulent flow in the range below critical PIs. We suggest that patients should inhale from the DPIs with inspiratory pressure higher than critical PI. PMID- 21547885 TI - Intramucosal carbon dioxide partial pressure measurement rescued the reconstructed gastric tube. AB - A 60-year-old male patient with esophageal carcinoma underwent esophagectomy and gastric tube construction with cervical esophagogastrostomy. A tonometer catheter (TonometricsTM Catheter, TONO-16 F, Datex-Ohmeda, Finland) was placed transnasally into the lumen of the gastric tube just after the gastric tube formation. The catheter was connected to a TONOCAP (Datex Ohmeda) monitor. The intramucosal partial pressure of carbon dioxide (PiCO2) was then measured intermittently. A PiCO2 of 105 mmHg just after the gastric tube formation indicated the possibility of an impaired blood flow in the gastric tube. Reanastomosis of the artery and vein to the gastric tube was performed immediately to improve perfusion. This procedure salvaged the gastric tube and PiCO2 decreased to 43 mmHg at the end of the operation. Subsequently, PiCO2 returned to the normal range. PiCO2 is regularly measured to assess the state of the reconstructed gastric tube during the postoperative period in the intensive care unit (ICU). The clinical course of the patient suggests that measuring PiCO2 using a tonometer catheter is useful to detect any abnormal blood supply to the reconstructed gastric tube not only in the postoperative period in the ICU but also in the intraoperative period. PMID- 21547886 TI - Good response chemotherapy for late-recurring gastric cancer in the gluteals, with peritoneal and retroperitoneal dissemination. AB - A 64-year-old woman presented with advanced gastric cancer (signet ring cell carcinoma) and underwent total gastrectomy in 1996. Postoperative recovery was good, and she was monitored regularly on an outpatient basis. Abdominal computed tomography in 1999 revealed a soft tissue shadow ventral to the origin of the celiac artery. Careful monitoring was continued on an outpatient basis. The patient began to experience gluteal swelling and pain in April 2008. Symptoms rapidly exacerbated and the patient was hospitalized for further examination. Gluteal muscle biopsy revealed signet ring cell carcinoma and bilateral hydronephrosis. Gluteal recurrence of the original gastric cancer was suggested, and systemic chemotherapy consisting of S-1 at 100 mg/day (3 weeks on, 1 week off) and CDDP (day 8) was started. Following the 6th cycle of chemotherapy, gluteal symptoms disappeared and the patient was judged to have achieved clinical complete response (CR). No adverse events or image findings suggesting new recurrence have since been identified. The patient received a total CDDP dose of 585 mg and clinical CR has been maintained as of 14 years after total gastrectomy and 18 months after recurrence. PMID- 21547887 TI - Single incision laparoscopic surgery for a life-threatening, cyst of liver. AB - Most liver cysts are asymptomatic and tend to have a benign clinical course. However, symptomatic or complicated liver cysts sometimes require surgical intervention. The laparoscopic approach is crucial and provides definitive treatment for such cysts. Recently, a trend of laparoscopic procedure has been toward minimizing the number of incisions. We performed single incision laparoscopic surgery (SILS) for a huge liver cyst with chronic heart failure and thrombosis of the inferior vena cava. An 83 year-old female presented with a month-long history of general fatigue and loss of appetite. She had a history of a huge liver cyst with chronic heart failure and this had been treated in another hospital eight months previously. Physical examination revealed a huge mass in the right upper abdomen without local tenderness or any peritoneal signs. A CT scan demonstrated simple liver cysts and compression of the IVC and right ventricule, with IVC thrombosis. After heparinization, we performed needle aspiration for cytology of the largest cyst and improvement of cardiac function. Six days later, we performed wide unroofing by Single Incision Laparoscopic Surgery (SILS). She was moved to a rehabilitation ward two weeks after surgery. No recurrence of the liver cyst was detected two months later. PMID- 21547888 TI - Surgical management of vulvar lymphangioma circumscriptum: two case reports. AB - OBJECTIVE: To evaluate the efficacy of major labiaectomy as a surgical management of vulvar lymphangioma circumscriptum, we report two cases of this rare clinical entity. CASE REPORTS: Two female patients, aged 56 and 68 years, presented with persistent edema of the lower limbs, papule-like condyloma of the labia majora, and lymph oozing from these papules of the vulva, which had developed 24 and 10 years, respectively, after radical hysterectomy with adjuvant pelvic radiation therapy for cervical cancer. After major labiaectomy was performed, symptoms in the first case, of extensive resected skin margin, improved clearly, in the second case, vulvar lymphangioma circumscriptum was more severe than in the first case, and a small amount of lymph oozing occurred from residual papules of the labia majora. In both cases, histology revealed lymphangioma circumscriptum of the vulva. CONCLUSION: Major labiaectomy is an effective therapy for vulvar lymphangioma circumscriptum. Particularly, in the case which was extensive and deep resected skin margin, symptoms such as papules of the labia majora and lymph oozing from these papules of the vulva associated with lymphangioma seemed to be clearly improved. PMID- 21547889 TI - Clinical images: Peripheral ulcerative keratitis associated with rheumatoid arthritis. PMID- 21547890 TI - Zinc-finger protein 145, acting as an upstream regulator of SOX9, improves the differentiation potential of human mesenchymal stem cells for cartilage regeneration and repair. AB - OBJECTIVE: Human mesenchymal stem cells (hMSCs) represent one of the most promising stem cell therapies for traumatic injury and age-related degenerative diseases involving cartilage. However, few genetic factors regulating chondrogenesis of MSCs have been identified. One study showed that zinc-finger protein 145 (ZNF145), a transcription factor, was up-regulated during 3-lineage differentiation of hMSCs. The present study was undertaken to validate whether this novel transcription factor is useful for the repair and regeneration of cartilage. METHODS: Human MSCs were transfected with lentiviral short hairpin RNA (for small interfering RNA knockdown of ZNF145) and a lentiviral vector for overexpression of ZNF145, and the effects of ZNF145 on chondrogenesis were studied using quantitative polymerase chain reaction and immunostaining. Microarray and transient expression analyses were used to determine whether ZNF145 is a factor operating upstream of SOX9. Allogeneic transplantation of hMSCs into osteochondral defects in rats was performed to determine the effects of ZNF145 on repair of cartilage in vivo. RESULTS: Small interfering RNA-mediated gene silencing of ZNF145 slowed down chondrogenesis, whereas overexpression of ZNF145 enhanced chondrogenesis. Global gene expression profiling showed up regulated gene expression in ZNF145-overexpressing MSCs, and transient overexpression of ZNF145 enhanced the expression of SOX9, suggesting that ZNF145 acts as a factor upstream of SOX9, the master regulator of chondrogenesis. Moreover, allogeneic transplantation of hMSCs into osteochondral defects of rat knees showed that ZNF145-overexpressing MSCs repaired cartilage defects better and earlier than empty control MSCs. CONCLUSION: These findings suggest that ZNF145 gene therapy may be a very useful strategy for improving the quality of cartilage regeneration and repair. PMID- 21547891 TI - Treatment of severe progressive systemic sclerosis with transplantation of mesenchymal stromal cells from allogeneic related donors: report of five cases. PMID- 21547892 TI - Prediction of pulmonary hypertension related to systemic sclerosis by an index based on simple clinical observations. AB - OBJECTIVE: To develop a score to estimate the risk of developing pulmonary hypertension (PH) in patients with systemic sclerosis (SSc). METHODS: We first examined the prevalence and characteristics of precapillary PH confirmed by right heart catheterization in a cross-sectional (derivation) sample of 1,165 SSc patients, and we developed a risk prediction score (RPS) based on simple clinical observations associated with PH. We next prospectively tested the 3-year predictive power of the "Cochin RPS" in a separate (validation) sample of 443 patients presenting with PH-free SSc at baseline. RESULTS: In the derivation sample, age, forced vital capacity, and diffusing capacity for carbon monoxide/alveolar volume were independently associated with the presence of PH and were used to create the Cochin RPS. PH developed during followup in 20 patients in the validation sample. The area under the receiver operating characteristic curve of the Cochin RPS was 0.87 (95% confidence interval 0.79 0.95). With a cutoff value of 2.73, patients at risk of PH during followup could be identified with 89.5% sensitivity and 74.1% specificity. PH occurred in 0.6% of patients in the lowest 2 quintiles of the Cochin RPS, in 1.7% of patients in the third and fourth quintiles, and in 17.1% of patients in the highest quintile (P<0.0001 by log rank test). Patients in the highest quintile incurred a >35-fold higher risk of developing PH compared with patients in the 2 lowest quintiles (P=0.001). CONCLUSION: Using routine clinical observations, we developed a simple score that accurately predicted the risk of PH in SSc. PMID- 21547893 TI - Synovial fibroblast hyperplasia in rheumatoid arthritis: clinicopathologic correlations and partial reversal by anti-tumor necrosis factor therapy. AB - OBJECTIVE: Synovial fibroblast (SF) hyperplasia contributes to the pathogenesis of rheumatoid arthritis (RA), but quantitative information on this process is scarce. This study was undertaken to evaluate the fibroblast-specific marker Hsp47 as a quantitative marker for SFs and to analyze its clinicopathologic correlates and evolution after anti-tumor necrosis factor alpha (anti-TNFalpha) therapy. METHODS: Synovial biopsy samples were obtained from 48 patients with RA and 20 controls who were healthy or had osteoarthritis (OA). Twenty-five RA patients who had active disease at the time of biopsy underwent a second biopsy after anti-TNFalpha therapy. Immunolabeling for Hsp47, inflammatory cells, and vascular cell markers was performed. Hsp47-positive lining and sublining fractional areas were quantified, and their correlation with clinicopathologic variables was analyzed. RESULTS: In normal and diseased synovial tissue, Hsp47 was specifically and uniformly expressed by lining, sublining, and perivascular fibroblasts. Lining SF area was significantly increased in both RA and late OA tissue compared to normal tissue. Sublining SF area was increased in RA tissue but not in late OA tissue compared to normal tissue. Lining SF area was positively correlated with macrophage density, Disease Activity Score in 28 joints, and RA disease duration. In contrast, sublining SF area was negatively correlated with RA disease duration and activity. A significant reduction in lining SF area but not sublining SF area was observed after anti-TNFalpha therapy. CONCLUSION: Our findings indicate that Hsp47 is a reliable marker for quantifying SFs in human synovial tissue. Our data suggest that lining and sublining SFs undergo different dynamics during the course of the disease. Lining SF expansion parallels the activity and temporal progression of RA and can be partially reversed by anti-TNFalpha therapy. PMID- 21547894 TI - Epidemiology of generalized joint laxity (hypermobility) in fourteen-year-old children from the UK: a population-based evaluation. AB - OBJECTIVE: Although diagnostic criteria for generalized ligamentous laxity (hypermobility) in children are widely used, their validity may be limited, due to the lack of robust descriptive epidemiologic data on this condition. The present study was undertaken to describe the point prevalence and pattern of hypermobility in 14-year-old children from a population-based cohort. METHODS: We performed a cross-sectional analysis using the Avon Longitudinal Study of Parents and Children, a large population-based birth cohort. Hypermobility among children in the cohort (mean age 13.8 years) was measured using the Beighton scoring system. Objective measures of physical activity were ascertained by accelerometry. Data on other variables, including puberty and socioeconomic status, were collected. Simple prevalence rates were calculated. Chi-square tests and logistic regression analyses were used to assess associations of specific variables with hypermobility. RESULTS: Among the 6,022 children evaluated, the prevalence of hypermobility (defined as a Beighton score of >=4 [i.e., >=4 joints affected]) in girls and boys age 13.8 years was 27.5% and 10.6%, respectively. Forty-five percent of girls and 29% of boys had hypermobile fingers. There was a suggestion of a positive association between hypermobility in girls and variables including physical activity, body mass index, and maternal education. No associations were seen in boys. CONCLUSION: We have shown that the prevalence of hypermobility in UK children is high, possibly suggesting that the Beighton score cutoff of >=4 is too low or that this scoring is not appropriate for use in subjects whose musculoskeletal system is still developing. These results provide a platform to evaluate the relationships between the Beighton criteria and key clinical features (including pain), thereby testing the clinical validity of this scoring system in the pediatric population. PMID- 21547896 TI - Anti-N-methyl-D-aspartate receptor encephalitis: a newly recognized inflammatory brain disease in children. AB - OBJECTIVE: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a newly recognized antineuronal antibody-mediated inflammatory brain disease that causes severe psychiatric and neurologic deficits in previously healthy children. The present study was undertaken to describe characteristic clinical features and outcomes in children diagnosed as having anti-NMDAR encephalitis. METHODS: Consecutive children presenting over a 12-month period with newly acquired psychiatric and/or neurologic deficits consistent with anti-NMDAR encephalitis and evidence of central nervous system (CNS) inflammation were screened. Children were included in the study if they had confirmatory evidence of anti-NMDAR antibodies in the serum and/or cerebrospinal fluid. Features at clinical presentation and results of investigations were recorded. Type and duration of treatment and outcomes at last followup were documented. RESULTS: Seven children were screened, and 3 children with anti-NMDAR encephalitis were identified. All patients presented with neurologic and/or psychiatric abnormalities, seizures, speech disorder, sleep disturbance, and fluctuating level of consciousness. The 2 older patients had more prominent psychiatric features, while the younger child had significant autonomic instability and prominent involuntary movement disorder. None had an underlying tumor. Immunosuppressive therapy resulted in near or complete recovery; however, 2 of the patients had early relapse necessitating re-treatment. CONCLUSION: Anti-NMDAR encephalitis is an important cause of neuropsychiatric deficits in children, which must be included in the differential diagnosis of CNS vasculitis and other inflammatory brain diseases. Early diagnosis and treatment are essential for neurologic recovery. PMID- 21547895 TI - Does knee osteoarthritis differentially modulate proprioceptive acuity in the frontal and sagittal planes of the knee? AB - OBJECTIVE: Impaired proprioception may alter joint loading and contribute to the progression of knee osteoarthritis (OA). Although frontal plane loading at the knee contributes to OA, proprioception and its modulation with OA in this direction have not been examined. The aim of this study was to assess knee proprioceptive acuity in the frontal and sagittal planes in patients with knee OA and healthy subjects. We hypothesized that proprioceptive acuity in both planes of movement will be decreased in patients with OA. METHODS: The study group comprised 13 patients with knee OA and 14 healthy age-matched subjects. Proprioceptive acuity was assessed in varus, valgus, flexion, and extension using threshold to detection of passive movement (TDPM) tests. Repeated-measures analysis of variance was used to assess differences in TDPM values between the 2 groups and across movement directions. Linear regression analyses were performed to assess the correlation of the TDPM between and within planes of movement. RESULTS: The TDPM was significantly higher (P<0.05) in the group with knee OA compared with the control group for all directions tested, indicating reduced proprioceptive acuity. Differences in the TDPM between groups were consistent across all movement directions, with mean differences as follows: for valgus, 0.94 degrees (95% confidence interval [95% CI] 0.20-1.65 degrees ); for varus, 0.92 degrees (95% CI 0.18-1.68 degrees ); for extension, 0.93 degrees (95% CI 0.19-1.66 degrees ); for flexion, 1.11 degrees (95% CI 0.38-1.85 degrees ). The TDPM measures across planes of movement were only weakly correlated, especially in the group with knee OA. CONCLUSION: Consistent differences in the TDPM between the group of patients with knee OA and the control group across all movement directions suggest a global, not direction-specific, reduction in sensation in patients with knee OA. PMID- 21547898 TI - Reduction of in vitro invasion and in vivo cartilage degradation in a SCID mouse model by loss of function of the fibrinolytic system of rheumatoid arthritis synovial fibroblasts. AB - OBJECTIVE: Urokinase plasminogen activator (uPA), uPA receptor (uPAR), and PA inhibitor 1 (PAI-1) have pivotal roles in the proliferation and invasion of several cell types, including synovial fibroblasts (SFs). The aim of this study was to investigate the possibility of controlling the invasion of rheumatoid arthritis (RA) SFs in vitro and in vivo by inhibiting uPA and uPAR. METHODS: Normal SFs, SFs from patients with RA, and SFs from patients with psoriatic arthritis (PsA) were used. The levels of uPA, uPAR, and PAI-1 were measured by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction analysis of messenger RNA. The activity of uPA was studied by zymography. Proliferation was measured by cell counting, and cell invasion was measured with a Boyden chamber assembled with Matrigel-coated porous filters. Human cartilage and RA SF implantation in the SCID mouse model of RA were used to study cartilage invasion in vivo. RESULTS: RA SFs and PsA SFs overexpressed uPAR and as a result were more active than their normal counterparts in terms of both Matrigel invasion and proliferation. This effect was counteracted by a specific inhibitor of uPA enzymatic activity (WX-340) and by uPAR antisense treatment. The use of both WX-340 and uPAR antisense treatment in vitro showed cooperative effects in RA SFs that were more intense than the effects of either treatment alone. Significant inhibition of cartilage invasion was obtained in vivo with uPAR antisense treatment, while uPA inhibition was inefficient, either alone or in combination with antisense treatment. CONCLUSION: The decrease in uPAR expression in RA SFs reduced invasion of human cartilage in vitro and in the SCID mouse model. PMID- 21547897 TI - Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease. AB - OBJECTIVE: To identify baseline characteristics of patients with scleroderma related interstitial lung disease (SSc-ILD) that could serve as predictors of the most favorable response to 12-month treatment with oral cyclophosphamide (CYC). METHODS: Regression analyses were retrospectively applied to the Scleroderma Lung Study data in order to identify baseline characteristics that correlated with the absolute change in forced vital capacity (FVC) (% predicted values) and the placebo-adjusted change in % predicted FVC over time (the CYC treatment effect). RESULTS: Completion of the CYC arm of the Scleroderma Lung Study was associated with a placebo-adjusted improvement in the % predicted FVC of 2.11% at 12 months, which increased to 4.16% when patients were followed up for another 6 months (P=0.014). Multivariate regression analyses identified the maximal severity of reticular infiltrates (assessed as maximum fibrosis scores) on high-resolution computed tomography (HRCT) at baseline, the modified Rodnan skin thickness score (MRSS) at baseline, and the Mahler baseline dyspnea index as independent correlates of treatment response. When patients were stratified on the basis of whether 50% or more of any lung zone was involved by reticular infiltrates on HRCT and/or whether patients exhibited an MRSS of at least 23, a subgroup of patients emerged in whom there was an average CYC treatment effect of 9.81% at 18 months (P<0.001). Conversely, there was no treatment effect (a -0.58% difference) in patients with less severe HRCT findings and a lower MRSS at baseline. CONCLUSION: A retrospective analysis of the Scleroderma Lung Study data identified the severity of reticular infiltrates on baseline HRCT and the baseline MRSS as patient features that might be predictive of responsiveness to CYC therapy. PMID- 21547899 TI - Maternal depression and anxiety are associated with altered gene expression in the human placenta without modification by antidepressant use: implications for fetal programming. AB - We sought to determine if maternal depression, anxiety, and/or treatment with selective serotonin reuptake inhibitors (SSRIs) affect placental human serotonin transporter (SLC6A4), norepinephrine transporter (SLC6A2), and 11beta hydroxysteroid dehydrogenase type 2 (11beta-HSD2) gene expression. Relative mRNA expression was compared among placental samples (n = 164) from healthy women, women with untreated depression and/or anxiety symptoms during pregnancy, and women who used SSRIs. SLC6A4 expression was significantly increased in placentas from women with untreated mood disorders and from women treated with SSRIs, compared to controls. SLC6A2 and 11beta-HSD2 expression was increased in noncontrol groups, though the differences were not significant. SLC6A4, SLC6A2, and 11beta-HSD2 expression levels were positively correlated. The finding that maternal depression/anxiety affects gene expression of placental SLC6A4 suggests a possible mechanism for the effect(s) of maternal mood on fetal neurodevelopmental programming. SSRI treatment does not further alter the elevated SLC6A4 expression levels observed with exposure to maternal depression or anxiety. PMID- 21547900 TI - Autonomic regulation in fragile X syndrome. AB - Autonomic reactivity was studied in individuals with fragile X syndrome (FXS), a genetic disorder partially characterized by abnormal social behavior. Relative to age-matched controls, the FXS group had faster baseline heart rate and lower amplitude respiratory sinus arrhythmia (RSA). In contrast to the typically developing controls, there was a decrease in RSA with age within the FXS group. Moreover, within the FXS group heart rate did not slow with age. The FXS group also responded with an atypical increase in RSA to the social challenge, while the control group reduced RSA. In a subset of the FXS group, the autonomic profile did not change following 2 months and 1 year of lithium treatment. The observed indices of atypical autonomic regulation, consistent with the Polyvagal Theory, may contribute to the deficits in social behavior and social communication observed in FXS. PMID- 21547901 TI - Predator and restraint stress during gestation facilitates pilocarpine-induced seizures in prepubertal rats. AB - Stress during gestation can result in early and long-term developmental aberrations. This study aimed to assess the impact of prenatal restraint or predator stress on pilocarpine-induced epileptic behavior. Pregnant rats were exposed to stressors on gestational days 15, 16, and 17. Restraint stress consisted of daily restraint of the dam. During predator stress, caged rats were exposed to a cat in a cage. On postnatal day 25, male pups were injected with pilocarpine and the behavior of each rat was observed. Prenatal stress led to low birth weight and increased blood corticosterone levels. Both stressors significantly potentiated pilocarpine-induced seizures. Predator-stressed pups exhibited significantly severe tonic-clonic seizures compared with restraint stressed animals. These data emphasize the impact of prenatal stress on fetal growth, and neural and endocrine function. The results also suggest that psychosocial stressors have a greater impact on neural and endocrine function than physical stressors do. PMID- 21547902 TI - Colon cancer associated transcript-1: a novel RNA expressed in malignant and pre malignant human tissues. AB - Early detection of colorectal cancer (CRC) is currently based on fecal occult blood testing (FOBT) and colonoscopy, both which can significantly reduce CRC related mortality. However, FOBT has low-sensitivity and specificity, whereas colonoscopy is labor- and cost-intensive. Therefore, the discovery of novel biomarkers that can be used for improved CRC screening, diagnosis, staging and as targets for novel therapies is of utmost importance. To identify novel CRC biomarkers we utilized representational difference analysis (RDA) and characterized a colon cancer associated transcript (CCAT1), demonstrating consistently strong expression in adenocarcinoma of the colon, while being largely undetectable in normal human tissues (p < 000.1). CCAT1 levels in CRC are on average 235-fold higher than those found in normal mucosa. Importantly, CCAT1 is strongly expressed in tissues representing the early phase of tumorigenesis: in adenomatous polyps and in tumor-proximal colonic epithelium, as well as in later stages of the disease (liver metastasis, for example). In CRC-associated lymph nodes, CCAT1 overexpression is detectable in all H&E positive, and 40.0% of H&E and immunohistochemistry negative lymph nodes, suggesting very high sensitivity. CCAT1 is also overexpressed in 40.0% of peripheral blood samples of patients with CRC but not in healthy controls. CCAT1 is therefore a highly specific and readily detectable marker for CRC and tumor-associated tissues. PMID- 21547903 TI - CpG island methylation status of miRNAs in esophageal squamous cell carcinoma. AB - Previous studies on esophageal squamous cell carcinoma (ESCC) indicated that it contains much dysregulation of microRNAs (miRNAs). DNA hypermethylation in the miRNA 5' regulatory region is a mechanism that can account for the downregulation of miRNA in tumors (Esteller, N Engl J Med 2008;358:1148-59). Among those dysregulated miRNAs, miR-203, miR-34b/c, miR-424 and miR-129-2 are embedded in CpG islands, as is the promoter of miR-34a. We investigated their methylation status in ESCC by bisulfite sequencing PCR (BSP) and methylation specific PCR (MSP). The methylation frequency of miR-203 and miR-424 is the same in carcinoma and in the corresponding non-tumor tissues. The methylation ratio of miR-34a, miR 34b/c and miR-129-2 is 66.7% (36/54), 40.7% (22/54) and 96.3% (52/54), respectively in ESCC, which are significantly higher than that in the corresponding non-tumor tissues(p < 0.01). Quantitative RT-PCR analysis in clinical samples suggested that CpG island methylation is significantly correlated with their low expression in ESCC, 5-aza-2'-deoxycytidine (DAC) treatment partly recovered their expression in EC9706 cell line. We conclude that CpG island methylation of miR-34a, miR-34b/c and miR-129-2 are frequent events and important mechanism for their low expression in ESCC. DNA methylation changes have been reported to occur early in carcinogenesis and are potentially good early indicators of carcinoma (Laird, Nat Rev Cancer 2003;3:253-66). The high methylation ratio of miR-129-2 indicated its potential as a methylation biomarker in early diagnosis of ESCC. PMID- 21547904 TI - Low serum pepsinogen I and pepsinogen I/II ratio and Helicobacter pylori infection are associated with increased risk of gastric cancer: 14-year follow up result in a rural Chinese community. AB - The correlation between low serum PG level and H. pylori infection with the development of gastric cancer has caused considerable concerns all over the world. Some authors exclaimed that gastric cancer developed only in patients infected with H. pylori, whereas the other had different findings. In this study, 1,501 adult local residents with determined serum PG levels and anti H. pylori IgG status were followed for 14 years for the development of gastric cancer in a rural community with high risk of gastric cancer in Hebei Province, China. The results showed the accumulated gastric cancer incidence in the subjects with abnormal PG level and those with H. pylori infection were all significantly higher than that in the corresponding normal controls (53.90/00 vs. 12.70/00, p < 0.05 and 23.10/00 vs. 5.930/00, p < 0.05). The highest gastric cancer incidence was seen in the subjects with both abnormal serum PG and positive H. pylori (56.00/00), and followed by the subjects with abnormal PG and negative H. pylori (47.60/00) and those with normal serum PG and positive H. pylori (18.40/00). The abnormal serum PG level (OR 3.029) and H. pylori infection (OR 4.345) were all risk factors for the development of gastric cancer. The results suggested that the subjects with abnormal serum PG level and/or positive H. pylori infection in the rural area of China were all high risk population for gastric carcinoma and the subjects with both abnormal serum PG and positive H. pylori infection were at especially high risk for the development of gastric carcinoma. PMID- 21547905 TI - Talin-1 overexpression defines high risk for aggressive oral squamous cell carcinoma and promotes cancer metastasis. AB - Oral squamous cell carcinoma (OSCC) is highly invasive and is associated with frequent tumour recurrences and lymph node metastases. Identification of genes involved in the aggressiveness of OSCC may provide new targets for clinical intervention. A genome-wide study based on the Sty1 250K SNP array indicated the involvement of the Talin-1 (TLN1) gene in the 9p13.3 amplicon, which was further validated by dual colour fluorescence in situ hybridization (FISH). Comparative analyses revealed that TLN1 was the most highly expressed integrin-cytoskeleton cross-linker that can trigger integrin activation. IHC analyses and mouse study also revealed an association between TLN1 overexpression and advanced OSCC with invasion to adjacent tissues. Survival analyses indicated a significant association between TLN1 genetic gain/overexpression and a reduced overall survival in patients. Functional knockdown by a dominant negative TLN1 fragment reduced cell growth and invasiveness in TLN1-overexpressing cells via inactivation of downstream oncogenic signalling. The present study suggests an important role for TLN1 in oral cancer development. TLN1 overexpression could serve as a diagnostic marker for aggressive phenotypes and a potential target for treating OSCC. PMID- 21547906 TI - Ewing sarcoma cells express RANKL and support osteoclastogenesis. AB - Ewing sarcoma (ES) is a primary malignant round cell tumour of bone characterized by rapid and extensive osteolysis. Cellular mechanisms underlying the rapid bone resorption in ES have not been characterized. Osteoclasts are marrow-derived multinucleated cells that effect tumour osteolysis. The role of ES tumour cells in influencing osteoclast formation and/or directly contributing to the osteolysis in ES has not been determined. Using a tissue culture bioassay, we found that lacunar resorption is not carried out by (CD99(+) ) ES tumour cells, but by (CD68(+) ) macrophage/osteoclast-like cells; this resorption occurred in the absence of the osteoclastogenic factor, receptor activator of nuclear factor kappaB ligand (RANKL). ES cell lines cultured directly on dentine slices did not resorb the mineral or organic components of the bone matrix. Immunohistochemistry of ES tissue microarrays, western blotting, and RT-PCR studies showed that ES cells strongly expressed both RANKL and macrophage-colony stimulating factor (M CSF), two major osteoclastogenic factors. When co-cultured with human monocytes, ES cells induced the formation of TRAP(+) osteoclastic cells. Conditioned medium from cultured ES cells did not result in osteoclast formation, indicating that cell-cell contact is required for ES-induced osteoclastogenesis. Our findings indicate that ES cells do not resorb bone directly but that they may support osteoclast formation by a RANKL-dependent mechanism. PMID- 21547907 TI - Molecular characteristics and biological behaviours of the oncocytic and pancreatobiliary subtypes of intraductal papillary mucinous neoplasms. AB - Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes. Of those, pancreatobiliary and oncocytic types are recently recognized and relatively uncommon, and usually exhibit high-grade dysplasia. The biological properties and molecular characteristics of these two types have not been well documented. The few molecular studies of the oncocytic type showed absence of KRAS mutations commonly seen in the other subtypes, raising the possibility that the oncocytic type is distinct from the other subtypes. Thus, we examined clinicopathological features and molecular alterations of the two subtypes. The study cohort consisted of 12 pancreatobiliary and 18 oncocytic IPMN cases. KRAS, BRAF, and PIK3CA mutations and TP53, SMAD4, and beta-catenin expression were analysed, and the results of molecular and clinicopathological profiles were compared between the two subtypes. KRAS mutations were identified in the oncocytic type, but less frequently than the pancreatobiliary type (17% versus 58%, p = 0.048). BRAF mutation was found in a single oncocytic tumour, and no PIK3CA mutations were seen in any of the study cohort. TP53 overexpression was less frequent in the oncocytic type than in the pancreatobiliary type (11% versus 58%, p = 0.013). Invasive components were present in 50% of the oncocytic and 92% of the pancreatobiliary types, with lymph node metastasis more frequently seen in the latter, corresponding to better outcomes in the former (5-year survival rates: 93% versus 32%, p = 0.014). Our demonstration of KRAS and BRAF mutations in the oncocytic-type IPMN supports a role for the activation of the RAS-MAPK pathway in this tumour type. However, the less frequent TP53 overexpression associated with the significantly lower rates of invasion and nodal disease in the oncocytic type correlates with better outcomes compared to the pancreatobiliary type. PMID- 21547908 TI - Rapid lamina propria retraction and zipper-like constriction of the epithelium preserves the epithelial lining in human small intestine exposed to ischaemia reperfusion. AB - To ensure a sufficient barrier between a host and noxious luminal content, the intestinal epithelium must be equipped with efficient mechanisms to limit damage to the epithelial lining. Using a human model, we were able to investigate these mechanisms in the human gut exposed to ischaemia-reperfusion (IR) over the time course of 150 min. In 10 patients a part of jejunum, to be removed for surgical reasons, was selectively exposed to IR. Control tissue was collected, as well as tissue exposed to 30 min of ischaemia with 0, 30 or 120 min of reperfusion. Haematoxylin/eosin staining demonstrated the appearance of subepithelial spaces following 30 min of ischaemia, while the epithelial lining remained intact at this stage. Western blot for myosin light chain kinase (MLCK) revealed a significant increase in protein levels after ischaemia (p < 0.01), and selective staining of MLCK and phosphorylated MLC (pMLC) in lamina propria muscle fibres indicated that appearance of subepithelial spaces was a consequence of active villus contraction. Early during reperfusion, accumulation of pMLC was observed exclusively at the basal side of enterocytes that had lost contact with the collagen-IV-positive basement membrane. These epithelial sheets were pulled together like a zipper, even before these cells were shed. This constriction, verified by increased F-actin and pMLC double staining, accounted for a 45% reduction in virtual wound surface (p < 0.001) at 30 min of reperfusion. In addition, these mechanisms were involved in resealing remaining small epithelial defects, resulting in a fully restored epithelial lining within 120 min of reperfusion. In conclusion, we show in a human in vivo model that the human jejunum has the ability to preserve the epithelial lining during intestinal IR by rapid lamina propria contraction and zipper-like constriction of epithelial cells that are to be shed into the lumen. These newly described phenomena limit exposure to noxious luminal content. PMID- 21547909 TI - Increased production of sonic hedgehog by ballooned hepatocytes. AB - Ballooned hepatocytes distinguish non-alcoholic steatohepatitis (NASH) from steatosis. Such cells contain dilated endoplasmic reticulum and ubiquitin aggregates, characteristics of endoplasmic reticulum stress. Hepatocyte ballooning increases the risk for fibrosis in NASH, suggesting that ballooned hepatocytes release pro-fibrogenic factors. Hedgehog ligands function as pro fibrogenic factors in liver diseases, but mechanisms for hedgehog ligand production remain poorly understood. We evaluated the hypothesis that endoplasmic reticulum stress induces hepatocyte production of hedgehog ligands that provide paracrine pro-fibrogenic signals to neighbouring cells. In livers from NASH patients, keratin 8/18 and ubiquitin staining demonstrated enlarged, keratin 8/18 negative/ubiquitin-positive hepatocytes (ballooned hepatocytes) that were positive for Sonic hedgehog. In order to model endoplasmic reticulum stress in vitro, primary mouse hepatocytes were treated with tunicamycin. Compared to vehicle, tunicamycin significantly increased Sonic hedgehog and Indian hedgehog expression. Furthermore, conditioned medium from tunicamycin-treated hepatocytes increased Gli-luciferase reporter activity 14-fold more than conditioned medium from vehicle-treated hepatocytes. Cyclopamine (hedgehog signalling inhibitor) abrogated the effect of conditioned medium from tunicamycin-treated hepatocytes, verifying that soluble hepatocyte-derived factors activate hedgehog signalling. Ballooned hepatocytes in NASH patients did not express the hedgehog target gene, Gli2, alpha-smooth muscle actin or vimentin, but were surrounded by Gli2-positive stromal cells expressing these myofibroblast markers. Trichrome staining demonstrated the accumulation of ballooned hepatocytes in areas of matrix deposition, and numbers of Sonic hedgehog-positive hepatocytes correlated with the degree of ballooning and fibrosis stage. Hepatocytes undergoing endoplasmic reticiulum stress generate hedgehog ligands which act as paracrine pro-fibrogenic factors for hedgehog-responsive stromal cells. These results help to explain why fibrosis stage correlates with hepatocyte ballooning in NASH. PMID- 21547910 TI - Somatic mutation of fibroblast growth factor receptor-3 (FGFR3) defines a distinct morphological subtype of high-grade urothelial carcinoma. AB - FGFR3 mutations are common in low-grade urothelial carcinoma and represent a potential therapeutic target in this disease. Their incidence and functional role in high-grade urothelial carcinoma (HGUC), which displays an increased propensity for recurrence and muscularis propria invasion, is less well defined. We developed a mass spectrometry-based genotyping assay to define the incidence of FGFR3 mutations in a large clinically annotated set of urothelial carcinomas. FGFR3 mutations were found in 17% of HGUC versus 84% of low-grade lesions. Retrospective pathological review of the class of FGFR3 mutant HGUC revealed unique histological features, characterized by a bulky, exophytic component with branching papillary architecture as well as irregular nuclei with a koilocytoid appearance. The predictive value of this histological appearance was confirmed using a prospective set of 49 additional HGUCs. Prospective histological review was able to correctly predict for the presence of an FGFR3 mutation in 13/24 HGUC specimens that exhibited the distinct morphology (54%). All 25 specimens lacking the defined histological features were FGFR3 wild-type for a negative predictive value of 100%. Macrodissection of individual tumours confirmed the presence of the FGFR3 mutant allele in non-invasive and invasive, low and high-grade regions of individual tumours and in the lymph node metastases of patients whose tumours possessed the characteristic morphological signature, suggesting that FGFR3 mutations are not restricted to the more clinically indolent regions of HGUCs. These data suggest that histological screening of HGUCs followed by confirmatory genotyping can be used to enrich for the population of HGUCs most likely to harbour activating mutations in the FGFR-3 receptor tyrosine kinase. Histological review could thus aid in the development of targeted inhibitors of FGFR-3 by facilitating the identification of the subset of patients most likely to harbour activating mutations in the FGFR3 gene. PMID- 21547912 TI - Formation of amide- and imide-linked degradation products between the peptide drug oxytocin and citrate in citrate-buffered formulations. AB - Citric acid is widely used to buffer pharmaceutical formulations including protein pharmaceuticals. In accelerated stability studies of the small cyclic peptide oxytocin, we have noted that additional degradation products form when oxytocin is formulated in citrate that do not form in other common buffers such as acetate and phosphate. Using high-pressure liquid chromatography combined with high-resolution and tandem mass spectrometry, we identified these degradation products as amide- and imide-linked adducts of oxytocin and citrate. The site of reaction was shown to be the N-terminal amine of cysteine. The adducts have been found to form for oxytocin formulated in citrate buffer over the pH range of 3-6; the extent of formation is greatest at a pH of 4-4.5. We have additionally identified these same adducts in samples of oxytocin formulated in citrate buffer that had been stored in the dark for 3 months at room temperature. Altogether, these results demonstrate that reaction between citrate and oxytocin leads to the formation of covalent amide- and imide-linked adducts. PMID- 21547911 TI - Highly loaded, sustained-release microparticles of curcumin for chemoprevention. AB - Curcumin, a dietary polyphenol, has preventive and therapeutic potential against several diseases. Because of the chronic nature of many of these diseases, sustained-release dosage forms of curcumin could be of significant clinical value. However, extreme lipophilicity and instability of curcumin are significant challenges in its formulation development. The objectives of this study were to fabricate an injectable microparticle formulation that can sustain curcumin release over a 1-month period and to determine its chemopreventive activity in a mouse model. Microparticles were fabricated using poly(D, L-lactide-co-glycolide) polymer. Conventional emulsion solvent evaporation method of preparing microparticles resulted in crystallization of curcumin outside of microparticles and poor entrapment (~1%, w/w loading). Rapid solvent removal using vacuum dramatically increased drug entrapment (~38%, w/w loading; 76% encapsulation efficiency). Microparticles sustained curcumin release over 4 weeks in vitro, and drug release rate could be modulated by varying the polymer molecular weight and/or composition. A single subcutaneous dose of microparticles sustained curcumin liver concentration for nearly a month in mice. Hepatic glutathione-s transferase and cyclooxygenase-2 activities, biomarkers for chemoprevention, were altered following treatment with curcumin microparticles. The results of these studies suggest that sustained-release microparticles of curcumin could be a novel and effective approach for cancer chemoprevention. PMID- 21547913 TI - Reversion of sulfenamide prodrugs in the presence of free thiol-containing proteins. AB - The purpose of this work was to study the reaction kinetics between two model sulfenamide prodrugs of linezolid, N-(phenylthio)linezolid and N-[(2 ethoxycarbonyl)ethylthio]linezolid, with free thiol-containing proteins; commercial human serum albumin (HSA); a constitutively active mutant of the protein tyrosine phosphatase PRL-1 (PRL-1-C170S-C171S), a model protein; and diluted fresh human plasma. The reaction was followed by high-performance liquid chromatography, both for the loss of prodrug and appearance of linezolid, and at different pH values with molar excess of the proteins relative to the prodrugs. Pseudo first-order kinetics was observed. Consistent with earlier findings for the reaction between similar sulfenamides and small-molecule thiols, the reaction kinetics appeared to be consistent with thiolate attack at the sulfenamide bond to release the parent drug. The proteins reacted significantly slower on a molar basis than their small-molecule counterparts. It appears that proteins such as HSA may play a role in the in vivo conversion of sulfenamide prodrugs to their parent drug. PMID- 21547914 TI - Estimated pKa values for specific amino acid residues in daptomycin. AB - Daptomycin is a cyclic lipopeptide antibiotic. The ionization constants of daptomycin have not been individually elucidated. The objective of this research is to determine the sequence-specific ionization constants of daptomycin in the monomeric state. The pH titrations of daptomycin were performed by nuclear magnetic resonance (NMR) spectroscopy. The sequence-specific pKa values for the four acidic residues and one aromatic amine (Kyn-13) in daptomycin were determined by two-dimensional total correlation spectroscopy (1) H NMR. From the NMR pH titration, the estimated pKa values for Asp-3, Asp-9, and methylglutamic acid (mGlu-12) were determined to be 4.2, 3.8, and 4.6 in the absence of salt, and 4.1, 3.8, and 4.4 in the presence of 150 mM NaCl, respectively. The pKa value for Asp-7 is estimated to be approximately 1.0 in the absence of salt and 1.3 in the presence of salt. The estimated Hill coefficients for Asp-7 were 0.72 and 1.31 in the absence and presence of salt, respectively. The increase in Hill coefficients from 0.72 to 1.31 with increasing salt concentration is consistent with the estimated lower pKa in the absence of salt, and suggests that a salt bridge is formed in solution possibly between Asp-7 acidic group and the neighboring Orn-6 basic group. PMID- 21547915 TI - Peritoneal carcinomatosis of colon cancer origin: highest incidence in women and in patients with right-sided tumors. AB - BACKGROUND AND OBJECTIVES: The aim of the study was to evaluate the incidence of peritoneal carcinomatosis (PC) in a prospectively recorded series of colon cancer patients from a defined cohort and to compare clinicopathological characteristics, survival, and TP53 mutation status in primary tumors from patients with and without PC. METHODS: Clinical data from all colon cancer patients admitted in 1993-2006 were registered prospectively (n = 1,124). In a subset of PC patients, DNA was retrieved from tumor tissue and TP53 mutations analyzed and compared to the mutation status in a historical series. RESULTS: In the prospective series 10% of female and 7% of male patients had PC (P = 0.05). The PC patients were younger than those without PC (median 4 years, P = 0.002). The incidence of PC was 10.3% and 6.2% (P = 0.03) in patients with primary tumors in the right and left colon, respectively. TP53 was mutated in 57% of the PC patients as compared to 41% in the series of patients without PC (P = 0.05). CONCLUSIONS: The incidence of PC was higher in right-sided colon cancer and among women. PC patients were younger than non-PC patients, and PC was independently associated with TP53 mutation in the primary tumor. PMID- 21547916 TI - Effect of harvest time on seed oil and protein contents and compositions in the oleaginous gourd Lagenaria siceraria (Molina) Standl. AB - BACKGROUND: The stage of fruit ripeness at the time of harvest determines the final quality of ripe fruit. In this study, changes in the chemical composition of seed kernels from the oleaginous gourd Lagenaria siceraria (Molina) Standl. during maturation were evaluated to determine the best time to harvest the berries. Two cultivars (round and oval berry) were studied at three maturation stages (30 and 50 days after fruit set (DAFS) and complete plant whiteness (CPW)). RESULTS: Seed kernels were rich in oil (527.2-544.6 g kg(-1)), protein (402.8-403.3 g kg(-1)), minerals and energy. Maturation influenced the chemical compounds of the two cultivars differently. Best quantities of these components were reached at 50 DAFS. However, protein bioavailability was better at 30 DAFS and CPW in the round and oval berry cultivars respectively. Lagenaria siceraria oils were of good quality, containing an abundance of essential fatty acids (647.2-667.0 g kg(-1)). CONCLUSION: Both cultivars of L. siceraria should be harvested at 50 DAFS owing to the good nutritional properties of their seeds and oils. However, to obtain best-quality proteins, round and oval berry cultivars should be harvested at 30 DAFS and CPW respectively. The results of this study will be useful in reducing the production time of fruits and improving the nutritional quality of their seeds. PMID- 21547917 TI - Exploration of Islamic medicine plant extracts as powerful antifungals for the prevention of mycotoxigenic Aspergilli growth in organic silage. AB - BACKGROUND: Feed contamination with mycotoxins is a major risk factor for animals and humans as several toxins can exist as residues in meat and milk products, giving rise to carry-over to consumers via ingestion of foods of animal origin. The starting point for prevention, in this chain, is to eliminate the growth of mycotoxigenic fungi in the animal forage. Ten plant extracts, recommended in Islamic medicine, were evaluated as antifungal agents against mycotoxigenic Aspergilli, i.e. Aspergillus flavus and A. ochraceus, growth in organic maize silage. RESULTS: Most extracts had remarkable antifungal activities using both qualitative and quantitative evaluation methods. Cress (Lepidium sativum) seed extract was proven to be the most powerful among the plants examined. Blending of the most effective extracts (garden cress seed, pomegranate peel and olive leaf extracts), individually at their minimal fungicidal concentrations, with maize silage resulted in the reduction of inoculated A. flavus colony counts by 99.9, 99.6 and 98.7%, respectively, whereas silage blending with the combined extracts completely prohibited fungal growth for up to 30 days of incubation under aerobic conditions. CONCLUSION: Besides the health promoting effects, silage blending with the bioactive plant extracts examined could lead to the required protection from pathogenic and mycotoxigenic fungi. PMID- 21547918 TI - Individual and interactive effects of cultivar maturation time, nitrogen regime and temperature level on accumulation of wheat grain proteins. AB - BACKGROUND: Background and reasons for differences in wheat grain protein accumulation and polymerization are not fully understood. This study investigated individual and interactive effects of genetic and environmental factors on wheat grain protein accumulation and amount and size distribution of polymeric proteins (ASPP). RESULTS: Individual factors, e.g. maturation time of a cultivar, nitrogen regime and temperature level, influenced grain protein accumulation and ASPP, although interaction of these factors had a greater influence. Early maturation time and long grain maturation period (GMP) in a cultivar resulted in high amounts of sodium dodecyl sulphate (SDS)-extractable proteins (TOTE) and low percentage of SDS-unextractable polymeric proteins in total polymeric proteins (%UPP). Cultivars with late maturation time and short GMP resulted in low TOTE and high %UPP. Late versus early nitrogen application regime resulted in low %UPP versus low TOTE and high %UPP, respectively. High versus low temperature resulted in high %UPP and low %UPP, respectively. Differences in ASPP at maturity started as changes in protein accumulation from 12 days after anthesis. CONCLUSION: Length of GMP, especially in relation to length until maturity, governs gluten strength (%UPP) and grain protein concentration (TOTE). Length of GMP is determined by cultivar, temperature during GMP and late nitrogen availability. PMID- 21547919 TI - Optimized extraction of polysaccharides from corn silk by pulsed electric field and response surface quadratic design. AB - BACKGROUND: Corn silk is a traditional Chinese herbal medicine, which has been widely used for treatment of some diseases. In this study the effects of pulsed electric field on the extraction of polysaccharides from corn silk were investigated. RESULTS: Polysaccharides in corn silk were extracted by pulsed electric field and optimized by response surface methodology (RSM), based on a Box-Behnken design (BBD). Three independent variables, including electric field intensity (kV cm(-1) ), ratio of liquid to raw material and pulse duration (us), were investigated. The experimental data were fitted to a second-order polynomial equation and also profiled into the corresponding 3-D contour plots. Optimal extraction conditions were as follows: electric field intensity 30 kV cm(-1) , ratio of liquid to raw material 50, and pulse duration 6 us. Under these condition, the experimental yield of extracted polysaccharides was 7.31% +/- 0.15%, matching well with the predicted value. CONCLUSION: The results showed that a pulsed electric field could be applied to extract value-added products from foods and/or agricultural matrix. PMID- 21547920 TI - Genotype and environment effects on nitrate accumulation in a diversity set of lettuce accessions at commercial maturity: the influence of nitrate uptake and assimilation, osmotic interactions and shoot weight and development. AB - BACKGROUND: The causes of the natural variation in nitrate accumulation and associated traits are studied using a diverse population of 48 mature lettuce accessions grown hydroponically in winter and summer seasons. Information on the effects of genotype, environment and their interactions will inform future selection strategies for the production of low-nitrate varieties more suited to meeting EU requirements for harvested produce. RESULTS: The effects of genotype (G), environment (E) and G * E interactions were all significant, with nitrate concentrations lower but covering a wider range in summer. Concentrations of nitrate-N were positively correlated with those of water and total-N and negatively with assimilated-C in the shoot in both seasons, with all relationships partitioned according to morphotype and/or seasonal type. Corresponding relationships between nitrate-N and assimilated-N or with shoot fresh or dry weight were generally weak or inconsistent. Nitrate concentrations at an early growth stage were strongly related to those at maturity in winter, but not in summer when light levels were less variable. CONCLUSION: The effects of genotype and environment on nitrate accumulation in lettuce are strongly influenced by morphotype, with most G * E interactions between accessions within the same morphotype predominantly of the non-crossover type. All low-nitrate accumulating genotypes have increased concentrations of organic solutes (concentration regulation) and reduced water (volume regulation) to help stabilise osmotic potential within the shoots. Variability in nitrate accumulation arises more from differences in uptake than in efficiency of its chemical reduction. Genotypic differences in nitrate accumulation can be masked by changes in head morphology during maturation, provided that they are not confounded by substantial changes in intercepted light. Recent selection strategies do not appear to have produced lower-nitrate-accumulating cultivars. PMID- 21547921 TI - Recycling coffee grounds and tea leaf wastes to improve the yield and mineral content of grains of paddy rice. AB - BACKGROUND: Coffee grounds and tea leaf wastes exhibit strong affinity for metals such as Fe and Zn. The objective of this experiment was to evaluate the effect of top-dressing application of Fe- and Zn-enriched coffee grounds and tea leaf wastes at the panicle initiation stage on the mineral content of rice grains and the yield of paddy rice. RESULTS: The Fe and Zn contents of brown rice grains increased significantly on application of both coffee and tea waste materials. The concentration of Mn was increased by top-dressing application of coffee waste material only. For Cu, no significant (P < 0.05) differences were found between the control and ferrous sulfate/zinc sulfate treatment. The application of coffee and tea waste materials led to a significant (P < 0.05) increase in the number of grains per panicle, which was reflected in increases in the total number of grains per hill and in grain yield. CONCLUSION: The top-dressing application of these materials is an excellent method to recycle coffee grounds and tea wastes from coffee shops. Use of these novel materials would not only reduce the waste going to landfill but would also benefit the mineral nutrition of rice consumers at low cost by increasing Fe and Zn levels of rice grains as well as grain yield. PMID- 21547922 TI - Influence of N doses and form on 15N natural abundance of pepper plants: considerations for using delta15N values as indicator of N source. AB - BACKGROUND: The aim of this study was to ascertain the effect of the N form (NO(3) (-) , NH(4) (+) and organic N) and N concentration on plant isotopic fractionation and on the contribution of the different N sources to the plant N budget, in order to evaluate the feasibility of using plant delta(15) N values for discriminating between conventional and organic crops. To this end, different N concentrations (applied as NO(3) (-) ), N forms (NO(3) (-) versus NH(4) (+) ), and increasing NO(3) (-) applications to an organic N-based fertilization regime were studied. RESULTS: When using NO(3) (-) as N source, intra-plant fractionation was significant and tended to increase when NO(3) (-) concentration increased in the root medium. However, negligible net isotopic fractionation was observed when comparing theoretical and measured plant delta(15) N values. On the other hand, when plants are fertilized with a mixture of NO(3) (-) and NH(4) (+) , differences in uptake patterns for both salts could result in variation in plant delta(15) N regarding to the expected value. Finally, the application of NO(3) (-) to plants was detected when it was combined with high levels of organic N sources, from 99:1 organic:inorganic N ratio. CONCLUSION: Under certain conditions and following some considerations concerning sampling, delta(15) N values can be considered to be a potential tool to guarantee the authenticity of organic products. PMID- 21547923 TI - Antioxidant/anti-inflammatory activities and total phenolic content of extracts obtained from plants grown in Vietnam. AB - BACKGROUND: Medicinal plants have been used to treat various diseases since ancient times. Their specific activities, such as antioxidant, anti-inflammatory and anti-cancer, have been studied intensively. In particular, plants grown in Vietnam have attracted considerable attention among food chemists as ideal sources of natural medicinal chemicals. RESULTS: The methanol extracts from three edible Vietnamese-grown plants, Tram, Voi and Gac, tested with the DPPH assay showed antioxidant activities of 91.7 +/- 0.4, 63.4 +/- 0.7 and 3.7 +/- 0.1% respectively. The malonaldehyde/gas chromatography assay also revealed strong antioxidant activity in Tram and Voi at a level of 25 ug mL(-1) (95.5 +/- 0.3 and 78.5 +/- 1.4% respectively). These results were confirmed by the thiobarbituric acid assay. The antioxidant activities correlated positively with the level of total phenolics in all plants. Tram exhibited dose response-related lipoxygenase inhibitory activity, with values of 74.2 +/- 3.1% at 5 ug mL(-1) , 62.0 +/- 0% at 0.5 ug mL(-1) and 3.0 +/- 1.5% at 0.05 ug mL(-1) . Conversely, Voi and Gac showed negative anti-lipoxygenase activity. CONCLUSION: The antioxidant/anti inflammatory activities and total phenolic contents of the three edible plants grown in Vietnam revealed that they are good sources of supplements for human health. PMID- 21547924 TI - Effects of harvest date, wilting and inoculation on yield and forage quality of ensiling safflower (Carthamus tinctorius L.) biomass. AB - BACKGROUND: Safflower (Carthamus tinctorius L.), usually grown as a source of oil crop, can be used as fodder either for hay or ensiling purposes, particularly in semi-arid regions. RESULTS: A 2-year trial was conducted in southern Italy to evaluate the production and forage quality of safflower biomass cv. Centennial, harvested at three different stages: 1, at complete appearance of primary buds (PB); 2, at complete appearance of secondary and tertiary buds (STB); and 3, at 25% of flowering stage (FS). For each stage of growth, 50% of the biomass was ensiled in 4 L glass jars without and with inoculation (Lactobacillus plantarum, LAB), and the other 50% was field wilted for 24 h before ensiling. Dry matter (DM) content and yield (DMY), pH, buffering capacity (BC) and water soluble carbohydrates (WSC) were determined on fresh forage. On safflower silages were also evaluated ammonia-N, crude protein (CP), fibre fractions, fat, lactic and acetic acids, Ca and P, and gas losses. DMY ranged from 4.5 t ha(-1) (PB harvesting) to 11.6 t ha(-1) (FS harvesting). DM content varied from 129 g kg(-1) (PB not wilted) to 630 g kg(-1) (FS wilted). The WSC in forage before ensiling with not wilting ranged from 128 (PB stage) to 105 and 100 g kg(-1) DM at STB and FS stages, respectively. The wilted safflower forage showed a lower WSC compared to wilted forage. The high sugar substrate allowed lactic acid fermentation and a good conservation quality in all the harvesting stages. Silages quality was strongly influenced by the treatment performed. Wilting practice increased DM, pH and NDF contents but reduced lactic acid, acetic acid and NH(3) -N values. Inoculation reduced DM, pH and NDF contents, but increased lactic and acetic acids, CP and ash. CONCLUSION: As result, wilting the forage for 1 day was very effective in the early harvesting stage because this practice significantly increased DM, reducing on the same time the intensive fermentation and proteolysis processes of silage. When harvesting is performed at the beginning of the flowering stage wilting is not necessary. PMID- 21547925 TI - Efficacy of essential oils of Lippia alba (Mill.) N.E. Brown and Callistemon lanceolatus (Sm.) Sweet and their major constituents on mortality, oviposition and feeding behaviour of pulse beetle, Callosobruchus chinensis L. AB - BACKGROUND: Pulse beetle, Callosobruchus chinensis L., is the most destructive insect pest of pulses under storage in Asia and Africa. Keeping in view the negative impacts of synthetic insecticides and the demands of botanical pesticides, the present investigation explores the repellents, antifeedants, ovicidal, larvicidal and pupaecidal activity of two plant essential oils (EOs) and their major components, geranial and 1,8-cineole, when applied as fumigants for the management of the pulse beetle. RESULTS: EO of Callistemon lanceolatus (Sm.) Sweet caused 100% repellency of pulse beetle in a Y-shaped olfactometer at a dose of 150 uL, while Lippia alba (Mill.) N.E. Brown EO and 1,8-cineole showed 76 and 74.7% repellency at the same dose. At 0.1 uL mL(-1) , both the oils and 1,8-cineole provided 100% insect mortality. The EO of C. lanceolatus was recorded as the most effective fumigant, showing 96.03% oviposition deterrency and 100% antifeedant activity at 0.1 uL mL(-1) . The LD(50) of L. alba (11049.2 uL kg(-1) ) and C. lanceolatus (14 626.3 uL kg(-1) ) exhibited their favourable safety profiles when recorded on mice. CONCLUSION: EOs of L. alba and C. lanceolatus exhibited significant biological activity on the mortality and reproductive behaviour of pulse beetle. Based on their high LD(50) values, the oils could be safely recommended as non-mammalian toxic fumigants in management strategies for pulse beetle. PMID- 21547926 TI - Impacts of phosphorus and zinc levels on phosphorus and zinc nutrition and phytic acid concentration in wheat (Triticum aestivum L.). AB - BACKGROUND: Zinc (Zn) and phytic acid content in grain crops are directly related to their nutritional quality and therefore human health. To investigate the nutritional influences of phosphorus (P) and Zn levels on wheat (Triticum aestivum L.), plants were grown hydroponically to maturity in chelator-buffered solutions. RESULTS: Appropriate amounts of P, coupled with sufficient Zn, increased P and Zn concentrations in wheat grain. The Zn supply decreased both phytic acid and the molar ratios of phytic acid to Zn in wheat grain with respect to the Zn(0) treatment. Furthermore, proportions of Zn and P content in the grain relative to that of the whole plant were improved. With increasing P, the proportion of Zn and P content in the grain relative to the whole plant decreased. P and Zn acted antagonistically in roots. Excess P inhibited Zn uptake in roots, while Zn decreased the transfer of P from roots to shoots. For P that had been transported to the shoots, supplemental Zn facilitated its transfer to the grain. CONCLUSION: Excess P decreased the distribution of Zn in grain, while Zn enhanced the uptake of Zn and P in grain, The combined application of Zn fertilizer with the extensive use of P fertilizer can effectively increase the P and Zn concentration and Zn bioavailability of wheat grain, and hence Zn nutritional quality. PMID- 21547928 TI - "Hugging sisters": thoracoomphalopagus with anencephaly confirmed by three dimensional ultrasonography at 9 weeks of gestation. AB - We describe a rare conjoined twinning at 9 weeks of gestation. We compared the results of two- and three-dimensional sonography with autopsy findings after the termination of pregnancy. These results showed a thoracoomphalopagus with a shared heart and visceral organs. Three-dimensional sonography showed anencephaly in one of the embryos. Early and accurate prenatal diagnosis of this type of conjoined twins using three-dimensional sonography is critical for both parental counseling and minimizing maternal morbidity. PMID- 21547927 TI - Transrectal ultrasound guided multi-core prostate biopsy: pain control: results of 106 patients. AB - PURPOSE: To determine the efficacy of periprostatic nerve block (PPNB) for control of transrectal ultrasound (TRUS)-guided multicore prostate biopsy-related pain. METHODS: A total of 106 cases with suspicion of prostate cancer underwent TRUS-guided multicore prostate biopsy under local anesthesia using a total of 10 ml of 1% lidocaine for each patient. Lidocaine was injected around the neurovascular bundle at the base of the prostate just lateral to the seminal vesicle-prostate junction. The pain score was assessed using visual analog pain score from 0 to 10. All patients were questioned for whether they would accept repeat biopsy or not, if necessary. RESULTS: Pain score ranged from 0 to 5 (mean: 1.4). Thirty-five percent (37/106) of patients reported a score of 0, whereas 17% (18/106), 32% (34/106), 8.4% (9/106), 6.7% (7/106), 0.9% (1/106) reported pain scores of 1, 2, 3, 4, and 5, respectively. There were no pain scores of 6-10. Answers for the question "would you accept repeat biopsy or not, if necessary?" was "yes" for 82% (87/106) of the patients. CONCLUSIONS: PPNB prior to multi-core TRUS-guided prostate biopsy is an easy, safe, and effective technique for the control of procedure-related pain. PMID- 21547929 TI - Sonographic and magnetic resonance imaging findings of pelvic abscess following uterine perforation sustained during office endometrial sampling. AB - Pipelle endometrial sampling, an outpatient, office-based procedure, provides comparative successful endometrial sampling in comparison with other techniques including conventional dilatation and curettage. We present an unusual occurrence in which office Pipelle endometrial sampling in a perimenopausal patient was complicated 10 days later by lower abdominal pain and intermittent fever. Sonography depicted findings consistent with a large pelvic abscess overriding the uterine fundus. Sonography and magnetic resonance imaging confirmed the presence of the unusual pelvic abscess and, in addition, noted findings consistent with perforation of the uterus during endometrial sampling. PMID- 21547930 TI - Deep vein thrombosis associated with protein C and protein S deficiency: an unusual cause of acute abdomen. AB - Deep venous thrombosis is an extremely rare cause of acute abdomen and is often difficult to diagnose. Protein C and protein S deficiencies are rare genetic abnormalities that predispose the patient to thrombophilia and lead to thrombosis. We report the case of a previously healthy 7-year-old boy with iliofemoral thrombosis due to protein C and protein S deficiencies mimicking acute abdomen. PMID- 21547931 TI - Infective endocarditis complicated by fatal cerebral hemorrhage revealing an unrepaired univentricular heart in a 19-year-old woman. AB - Univentricular heart is a complex and rare cyanotic congenital heart disease. When not operated, affected patients exceptionally reach adulthood. We report the unprecedented case of a 19 year-old young woman, admitted to the hospital for a severe deterioration of general status and ultimately diagnosed to have an infective endocarditis with multiple vegetations in a previously undiagnosed univentricular heart of left ventricular morphology, subsequently rapidly complicated by fatal cerebral hemorrhage. PMID- 21547932 TI - Role of Doppler sonography in the diagnosis of pulmonary sequestration in an elderly patient: a case report. AB - An 83-year-old man presented with an asymptomatic mass-like lesion in left lower lobe on chest radiograph and CT, with no change over the past 7 years. Because of discrepancy between clinical and radiological manifestations, chest color Doppler sonography was done and identified a large tortuous pulsating vessel with systemic arterial waveform flowing toward the probe and entering the lesion at its apex. Subsequent contrast-enhanced reconstructed CT scans of the chest with angiography confirmed the diagnosis of intralobar pulmonary sequestration. PMID- 21547933 TI - Sonographic features of intravascular papillary endothelial hyperplasia (Masson's tumor) in the forearm. AB - Intravascular papillary endothelial hyperplasia, also known as Masson's tumor, is a benign, vascular lesion in which there is papillary proliferation of endothelial cells. The lesion presents as a palpable soft-tissue mass, often located within normal or dilated vascular spaces, and may be mistaken for a sarcomatous tumor on imaging. We present the case of an intravascular papillary endothelial hyperplasia in the forearm, with a remarkable appearance on color Doppler sonography, and suggest that this entity will be encountered more frequently by sonologists in the future. PMID- 21547934 TI - Determination of N-acetylaspartic acid concentration in the mouse brain using HPLC with fluorescence detection. AB - The concentration of brain N-acetylaspartic acid (NAA) in mice was determined by high-performance liquid chromatography (HPLC) using fluorescence detection after pre-column derivatization with 4-N,N-dimethylaminosulfonyl-7-N-(2 aminoethyl)amino-2,1,3-benzoxadiazole (DBD-ED). Six different brain parts, namely, the prefrontal cortex, olfactory bulb, nucleus accumbens, striatum, cerebellum and hippocampus, of male C57BL6/J mice, were investigated. The NAA concentration (nmol/mg protein) was highest in the olfactory bulb (58.2 +/- 4.0, n = 8) and lowest in the hippocampus (42.8 +/- 1.6, n = 8). The proposed HPLC method with fluorescence detection was successfully used to determine the NAA concentration in each investigated brain area. PMID- 21547935 TI - Noninvasive assessment of liver fibrosis. PMID- 21547936 TI - Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis. AB - Human patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with increased liver fat content and liver injury. Here, we show that nutritional status regulates PNPLA3 gene expression in the mouse liver. Sterol response element binding protein-1 (SREBP-1) activated PNPLA3 gene transcription via sterol regulatory elements (SREs) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that SREBP-1 proteins bound to the identified SREs. Furthermore, SREBP-1c mediated the insulin and liver X receptor agonist TO901317-dependent induction of PNPLA3 gene expression in hepatocytes. Adenovirus-mediated overexpression of mouse PNPLA3 increased intracellular triglyceride content in primary hepatocytes, and knockdown of PNPLA3 suppressed the ability of SREBP-1c to stimulate lipid accumulation in hepatocytes. Finally, the overexpression of PNPLA3 in mouse liver increased the serum triglyceride level and impaired glucose tolerance; in contrast, the knockdown of PNPLA3 in db/db mouse liver improved glucose tolerance. CONCLUSION: Our data suggest that mouse PNPLA3, which is a lipogenic gene directly targeted by SREBP-1, promotes lipogenesis in primary hepatocytes and influences systemic lipid and glucose metabolism. PMID- 21547937 TI - The morphology of the squirrel spermatozoon: a highly complex male gamete with a massive acrosome. AB - This study describes the morphology of the spermatozoon from the cauda epididymidis of representative members of two squirrel subfamilies, the Sciurinae and Callosciurinae, as determined by fluorescent, scanning, and transmission electron microscopy. All species examined possess a massive apical segment of the sperm acrosome. It varied markedly in the extent of its caudal flexion but was always much larger, and more complex, than that of the spermatozoon of most other rodents so far documented, although somewhat similar to that of some hystricomorph species. Because this sperm form appears to be present within at least two of the three major living clades of Rodentia, it is possible that it is the ancestral condition within this mammalian order. PMID- 21547938 TI - Near real-time, on-site, quantitative analysis of PAHs in the aqueous environment using an antibody-based biosensor. AB - Rapid, on-site, quantitative assessments of dissolved polycyclic aromatic hydrocarbons (PAHs) were demonstrated for two field applications. The platform, a KinExA Inline Sensor (Sapidyne Instruments), employed the monoclonal anti-PAH antibody, 7B2.3, which has specificity for 3- to 5-ring PAHs. A spatial study was conducted near a dredging site where contaminated sediments were being removed, and a temporal study was performed during a rainfall event. Most importantly, the generation of near real-time data guided management decisions in the field and determined proper sampling protocols for conventional analyses. The method was able to determine PAH concentrations as low as 0.3 ug/L, within 10 min of sample acquisition, and to assess 80+ samples (not including standards and blanks) in less than 3 d. These results were compared with a laboratory-based gas chromatography-mass spectrometry method in which a wide array of PAHs, including alkylated homologs, were examined. This system shows great promise as a field instrument for the rapid monitoring of PAH pollution. PMID- 21547939 TI - Dynamic plantar pressure analysis and midterm outcomes in percutaneous correction for mild hallux valgus. AB - Mild hallux valgus (HV), which can lead to alteration of the plantar pressure pattern with an overpressure under the hallux, can be repaired percutaneously. Our goals were to determine whether the percutaneous distal soft tissue release (DSTR)-Akin procedure restores the loading pattern and to evaluate which are the determinants of the measures of post-operative outcome. Seventy-nine percutaneous DSTR-Akin procedures were performed in the same number of patients. The plantar pressure patterns were evaluated using the BioFoot/IBV(r) in-shoe system and compared with measurements from 98 controls. The clinical and radiological outcome parameters measured were the pre- and post-operative AOFAS scores, and the first intermetatarsal, hallux abductus, and first metatarsal-hallux declination angles (FIMA, HAA, FMHDA) in weight-bearing radiographs. The mean follow-up was 28.1 (range 24-33) months. The plantar pressure analysis showed a significant decrease (328-152 kPa, p = 0.001) in the mean pressure under the hallux. Significant improvements occurred in the AOFAS scores, and angular deviations were reduced. The post-operative HAA correlated with the mean pressure under the 1st toe (r(2) = 0.132, p < 0.001). The DSTR-Akin percutaneous technique in mild HV restores physiological patterns of pressure on the hallux and achieves significant correction of radiographic angles and commensurate improvement in clinical status. PMID- 21547940 TI - Effects of alpha-tocopherol on the early phase of osteoporotic fracture healing. AB - Fracture healing is a complex process, which is more complicated if the bone is osteoporotic. One of the vitamin E isomers, alpha-tocopherol, has been found to prevent osteoporosis and improve bone fracture healing but its role in the healing of osteoporotic fractures is still unclear. We carried out a study on the effects of alpha-tocopherol supplementation on osteoporotic fracture healing using an ovariectomized rat model, whereby we focused on the early phase of fracture healing, that is, the phase with excessive production of free radicals. Twenty-four female Sprague-Dawley rats were divided into three groups: sham operated (SO), ovariectomized-control (OVC), and ovariectomized + alpha tocopherol supplementation (ATF) groups. The right femora of all the rats were fractured at mid-diaphysis and K-wires were inserted for internal fixation. After 2 weeks of treatment, the rats were euthanized and the femora were dissected out for measurement of callous volume by CT-scan and radiological staging of callous formation and fracture healing. The oxidative parameters of the fractured femora were also measured. The results showed that the callous volume and callous staging were not different between the groups. However, the fracture healing stage of the OVC group was lower than the SO group, while alpha-tocopherol supplementation in the ATF group had improved the healing until it was comparable to the SO group. The activities of the anti-oxidatant enzymes, superoxide dismutase, and glutathione peroxidase in the ATF group were found to be significantly higher than in the OVC group. In conclusion, alpha-tocopherol improved fracture healing but had no effect on the callous volume and staging. The improvement in fracture healing may be due to the increased activities of the anti-oxidatant enzymes in the bone during the early phase of fracture healing of osteoporotic bone. PMID- 21547941 TI - Biomechanical effect of increasing or decreasing degrees of freedom for surgery of trapeziometacarpal joint arthritis: a simulation study. AB - Osteoarthritis of the trapeziometacarpal (TMC) joint can be treated by arthrodesis and arthroplasty, which potentially decreases or increases the degrees of freedom (DoF) of the joint, respectively. The aim of our study was to bring novel biomechanical insights into these joint surgery procedures by investigating the influence of DoF at the TMC joint on muscle and joint forces in the thumb. A musculoskeletal model of the thumb was developed to equilibrate a 1 N external force in various directions while the thumb assumed key and pulp pinch postures. Muscle and joint forces were computed with an optimization method. In comparison to that of the 2-DoF (intact joint) condition, muscle forces slightly decreased in the 0-DoF (arthrodesis) condition, but drastically increased in the 3-DoF (arthroplasty) condition. TMC joint forces in the 3-DoF condition were 12 times larger than the 2-DoF joint. This study contributes to a further understanding of the biomechanics of the intact and surgically repaired TMC joint and addresses the biomechanical consequences of changing a joint's DoF by surgery. PMID- 21547942 TI - Time efficient design of multi dimensional RF pulses: application of a multi shift CGLS algorithm. AB - Designing multi dimensional ratio frequency excitation pulses in the small flip angle regime commonly reduces to the solution of a least squares problem, which requires regularization to be solved numerically. Usually, regularization is carried out by the introduction of a penalty, lambda, on the solution norm. In most cases, the optimal regularization parameter is not known a priori and the problem needs to be solved for several values of lambda. The optimal value can be selected, typically by plotting the L-curve. In this article, a conjugate gradients-based algorithm is applied to design ratio frequency pulses in a time efficient way without a priori knowledge of the optimal regularization parameter. The computation time is reduced considerably (by a factor 10 in a typical set up) with respect to the standard conjugate gradients for least square since just one run of the algorithm is required. Simulations are shown and the performance is compared to that of conjugate gradients for least square. PMID- 21547944 TI - 2D-NMR studies of a model for Krytox(r) fluoropolymers. AB - Multiple two-dimensional nuclear magnetic resonance (2D-NMR) techniques have been used to study the structures of Krytox((r)) perfluoro(polyalkyl ether) and its mechanism of polymerization. Model compound K(4), containing four Krytox((r)) fluoropolymer repeat units, was analyzed to interpret the multiplet patterns in the NMR spectra from the polymer model. (19)F {(13)C}-Heteronuclear single quantum correlation experiments, performed with delays optimized for (1)J(CF) and (2)J(CF), provided spectra that permitted identification of resonances from individual monomer units. Selective, (19)F-(19)F COSY 2D-NMR experiments were performed with different excitation regions; these experiments were combined with selective inversion pulses to remove (19)F-(19)F J couplings in the f(1) dimension. The resulting COSY spectra were greatly simplified compared with standard (19)F-(19)F COSY spectra, which are too complicated to interpret. They give information regarding the attachments of monomer units and also provide insights into the nature of the stereoisomers that might be present in the polymer. Both infrared and NMR spectra show peaks identifying chain end structures. With the help of these studies, resonances can be assigned, and the average number of repeat units in the polymer chain can be calculated based on the assignments obtained. PMID- 21547943 TI - Precision studies in supramolecular chemistry: a 1H NMR study of hydroxymethoxyacetophenone/beta-cyclodextrin complexes. AB - The association constants for the interactions of 2-hydroxy-4 methoxyacetophenone, 2-hydroxy-5-methoxyacetophenone, 2-hydroxy-6 methoxyacetophenone, 3-hydroxy-4-methoxyacetophenone and 4-hydroxy-3 methoxyacetophenone with beta-cyclodextrin in water were measured by (1)H NMR and by isothermal titration calorimetry. Very good agreement was obtained between the different methods. The errors associated with the NMR method for measuring mM binding affinities were estimated to be 10-30%, and by isothermal titration calorimetry, 10-20%. Rotating frame nuclear Overhauser effect spectroscopy studies show that the solution phase host-guest complexes formed by beta cyclodextrin with these hydroxymethoxyacetophenone derivatives are not structurally well defined but that the hydroxymethoxyacetophenone derivatives are mostly associated with the narrow primary hydroxyl rim. PMID- 21547945 TI - 1-Oxo-1,3-dithiolanes--synthesis and stereochemistry. AB - 1-Oxo-1,3-dithiolane (4) and its cis- and trans-2-methyl (5,6), -4-methyl (7,8) and -5-methyl (9,10) derivatives were prepared by oxidizing the corresponding 1,3 dithiolanes (1-3) with NaIO(4) in water. The oxides were purified and their isomers separated using thin layer chromatography. The structural characterization was carried out with (1)H and (13)C NMR spectroscopy and molecular modelling. The sulfoxides 4-6 and 8-10 attain two S(1) type envelopes (sometimes slightly distorted) the S=O(ax) envelope greatly dominating. Cis-4 methyl-1-oxo-1,3-dithiolane is a special case exhibiting both two closely related S=O(ax) (30 and 27%) as well as S=O(eq) (21 and 22%) forms [S(1) and C(4) envelopes, respectively]. The relative energies of these conformations, the values of (1)H-(1)H coupling constants and (1)H and (13)C chemical shifts were estimated by computational methods and they support well the conclusions based on the experimental data. PMID- 21547946 TI - Structure elucidation of the dye Acid Red 131: complete (1)H, (13)C and (15)N NMR data assignment. AB - The chemistry of dyes and pigments is relevant to the textile industry, because of the importance to establish the best conditions for the finishing process and to understand the interactions among various compounds to yield the correct hue and nuances. For this reason, the molecular structure of a monoazo acid dye, C.I. Acid Red 131, was elucidated and characterized by homo- and hetero-nuclear NMR, MS, IR and UV spectroscopy techniques. PMID- 21547947 TI - The effect of red pigment on the amyloidization of yeast proteins. AB - The intensity of amyloid-bound thioflavine T fluorescence was studied in crude lysates of yeast strains carrying mutations in the ADE1 or ADE2 genes and accumulating the red pigment (a result of polymerization of aminoimidazoleribotide), and in white isogenic strains--either adenine prototrophs or carrying mutations at the first stages of purine biosynthesis. We found that the red pigment leads to a drop of amyloid content. This result, along with the data on separation of protein polymers of white and red strains in PAGE, suggests that the red pigment inhibits amyloid fibril formation. The differences in transmission of the thioflavine T fluorescence pattern by cytoduction and in blot-hybridization of pellet proteins of red and white [PSI(+) ] strains with Sup35p antibodies confirmed this conclusion. Purified red pigment treatment also led to a decrease of fluorescence intensity of thioflavine T bound to insulin fibrils and to yeast pellet protein aggregates from [PSI(+) ] strains. This suggests red pigment interaction with amyloid fibrils. Comparison of pellet proteins from red and white isogenic strains separated by 2D-electrophoresis followed by MALDI analysis has allowed us to identify 48 pigment-dependent proteins. These proteins mostly belong to functional classes of chaperones and proteins involved in glucose metabolism, closely corresponding to prion-dependent proteins that we characterized previously. Also present were some proteins involved in stress response and proteolysis. We suppose that the red pigment acts by blocking certain sites on amyloid fibrils that, in some cases, can lead in vivo to interfere with their contacts with chaperones and the generation of prion seeds. PMID- 21547948 TI - A fast and inexpensive method for random spore analysis in Schizosaccharomyces pombe. AB - Random spore analysis is a fundamental tool of yeast genetics for determining gene linkage and the generation of recombinant progeny by genetic crosses. Experimentally it involves treatment of a mating mix with enzymes, such as zymolyase or lyticase, that selectively lyse the cell wall of vegetative cells rather than the spores. Here, we describe a method whereby the relative refractory nature of the spores to treatment with elevated temperature and repeated freeze-thawing facilitates random spore analysis at low cost in fission yeast Schizosaccharomyces pombe. Because of similar properties of spores in budding yeast, this method should prove to be useful for random spore analysis in both budding and fission yeasts. PMID- 21547949 TI - Bradykinesia: why do Parkinson's patients have it and what trouble does it cause? PMID- 21547950 TI - Deep brain stimulation effects in dystonia: time course of electrophysiological changes in early treatment. AB - Deep brain stimulation to the internal globus pallidus is an effective treatment for primary dystonia. The optimal clinical effect often occurs only weeks to months after starting stimulation. To better understand the underlying electrophysiological changes in this period, we assessed longitudinally 2 pathophysiological markers of dystonia in patients prior to and in the early treatment period (1, 3, 6 months) after deep brain stimulation surgery. Transcranial magnetic stimulation was used to track changes in short-latency intracortical inhibition, a measure of excitability of GABA(A) -ergic corticocortical connections and long-term potentiation-like synaptic plasticity (as a response to paired associative stimulation). Deep brain stimulation remained on for the duration of the study. Prior to surgery, inhibition was reduced and plasticity increased in patients compared with healthy controls. Following surgery and commencement of deep brain stimulation, short-latency intracortical inhibition increased toward normal levels over the following months with the same monotonic time course as the patients' clinical benefit. In contrast, synaptic plasticity changed rapidly, following a nonmonotonic time course: it was absent early (1 month) after surgery, and then over the following months increased toward levels observed in healthy individuals. We postulate that before surgery preexisting high levels of plasticity form strong memories of dystonic movement patterns. When deep brain stimulation is turned on, it disrupts abnormal basal ganglia signals, resulting in the absent response to paired associative stimulation at 1 month. Clinical benefit is delayed because engrams of abnormal movement persist and take time to normalize. Our observations suggest that plasticity may be a driver of long-term therapeutic effects of deep brain stimulation in dystonia. PMID- 21547951 TI - The Movement Disorders task force review of dysautonomia rating scales in Parkinson's disease with regard to symptoms of orthostatic hypotension. AB - Orthostatic hypotension is defined as a blood pressure fall of > 20 mm Hg systolic and/or 10 mm Hg diastolic within 3 minutes of an upright position. The Movement Disorders Society commissioned a task force to assess existing clinical rating scales addressing symptoms of orthostatic hypotension in Parkinson's disease. Seven neurologists and a clinimetrician assessed each scale's previous use and critiqued its clinimetric properties. A scale was "recommended" if it had been applied to populations of patients with Parkinson's disease, with data on its use in studies beyond the group that developed the scale, and was found to be clinimetrically valid. A scale was considered "suggested" if it had been applied to Parkinson's disease, but only 1 of the other criteria was applied. A scale was "listed" if it met only 1 criterion. Symptoms of orthostatic hypotension are generally assessed in scales on wider autonomic or nonmotor symptoms. Some scales designed to detect orthostatic hypotension-related symptoms provide information on their severity: the AUTonomic SCale for Outcomes in PArkinson's Disease and the COMPosite Autonomic Symptom Scale met criteria for recommended with some limitations; the Novel Non-Motor Symptoms Scale and the Orthostatic Grading Scale were classified as suggested. The Self-completed Non-Motor Symptoms Questionnaire for Parkinson's Disease was classified as suggested as a tool for screening orthostatic symptoms. However, these and the listed scales need further validation and application before they can be recommended for clinical use in patients with Parkinson's disease. PMID- 21547952 TI - Action observation treatment improves autonomy in daily activities in Parkinson's disease patients: results from a pilot study. PMID- 21547953 TI - Role of Muller cells in cone mosaic rearrangement in a rat model of retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is a type of inherited retinal degenerative disease, which leads to blindness. The primary pathological event of this disease is the death of rods because of genetic mutations. The S334ter-line-3 rat is a transgenic model developed to express a rhodopsin mutation similar to that found in RP. In this study, the rod's death triggered are organization of the cone mosaic into an orderly array of rings. Four observations were relevant to understand this reorganization. First, rods died in hot spots, which progressively increased as circular waves, leaving rod-less zones behind. Second, rings of cones formed around these zones. Third, remodeled Muller glia processes enveloped cones and filled the center of their rings. Zonula occludens-1 located between the photoreceptor inner segments and the apical processes of Muller cells showed in the rings. Fourth, these rings were formed before the onset of cone cell deaths and were maintained until late stages of RP. From these observations,we hypothesize that cone-Muller-cell interactions mediate and maintain the rings. A test of this hypothesis can be performed by injecting DL-a aminoadipic acid (AAA), which is known to disrupt Muller cell metabolism. A single intravitreal injection of AAA at P50 disrupted the rings of cones 3 days after the injection. These findings indicate that the rearrangement of cones in rings is modulated by Muller cells in RP. Thus, if the relationship between photoreceptors and Muller glia is better understood, the latter could potentially be manipulated for effective neuroprotection or the restoration of normal cone arrays. PMID- 21547955 TI - The role of intimate relationships, appraisals of military service, and gender on the development of posttraumatic stress symptoms following Iraq deployment. AB - A retrospective cohort study was conducted to examine risk and protective factors for combat-related posttraumatic stress disorder (PTSD) symptoms reported by soldiers (n = 2,583) at postdeployment. Positive appraisals of military service related negatively, OR = 0.86, 95% CI [0.83, 0.89], to screening positive for presumed PTSD at postdeployment. Decreases in perceived intimate relationship strength from predeployment to postdeployment were positively associated with presumed PTSD at higher, but not lower, levels of combat exposure; this effect, OR = 1.91, 95% CI [1.08, 3.39], was found only for female soldiers. Overall risk for postdeployment presumed PTSD was found to be nearly 2.5 times greater for women, as compared to men. In addition, positive screening rates of anxiety, depression, hazardous alcohol use, and PTSD increased from predeployment to postdeployment, with the most prominent increase found for PTSD. PMID- 21547954 TI - Cancer stem cells in gliomas: identifying and understanding the apex cell in cancer's hierarchy. AB - Neuro-oncology research has rediscovered a complexity of nervous system cancers through the incorporation of cellular heterogeneity into tumor models with cellular subsets displaying stem-cell characteristics. Self-renewing cancer stem cells (CSCs) can propagate tumors and yield nontumorigenic tumor bulk cells that display a more differentiated phenotype. The ability to prospectively isolate and interrogate CSCs is defining molecular mechanisms responsible for the tumor maintenance and growth. The clinical relevance of CSCs has been supported by their resistance to cytotoxic therapies and their promotion of tumor angiogenesis. Although the field of CSC biology is relatively young, continued elucidation of the features of these cells holds promise for the development of novel patient therapies. (c) 2011 Wiley-Liss, Inc. PMID- 21547956 TI - PTSD criterion A1 events: a literature-based categorization. AB - Thirty years after creation of the posttraumatic stress disorder (PTSD) diagnosis, its literature could still benefit from standardization of traumatic events. The authors report the type and frequency of traumatic events found in the mainstream PTSD literature using a bibliometric approach, and propose a categorization based on the terms used for their description. Articles containing [ptsd OR "stress disorder*"] in the title field found in the ISI/Thompson Reuters (Philadelphia, PA) 1991-2006 database were classified according to the event studied. The authors describe each event's absolute and proportional figures, and construct a categorization of the events. The bibliometric analysis of PTSD literature is helpful in planning research, and the proposed categorization may represent an advance toward the standardization of traumatic events. PMID- 21547957 TI - Evaluation of the safe zone for percutaneous Kirschner-wire placement in the distal radius: Cadaveric study. AB - Distal radius fractures are a common injury that is often reduced with percutaneous K-wires. The sensory nerves in this area are at risk of injuring from pin placement. Cadaveric studies of the nerve distribution patterns have elucidated certain safe zones for pin placement that limits the risk of sensory nerve injury. These studies have advocated a limited open technique that involves a shallow incision followed by blunt dissection to the bone before a k-wire is drilled into the radius. A previously identified safe zone in the anatomical snuffbox was evaluated in 40 cadaver wrists for k-wire placement via a percutaneous technique that involves putting the pin directly through the skin without an incision or blunt dissection. After k-wire placement each wrist was dissected and sensory nerve distribution relative to the pin placement was evaluated. The variability of the distribution of the sensory nerves, namely the lateral antebracheal cutaneous nerve and the superficial branch of the radial nerve, is such that no truly safe zone exists for pin placement with the percutaneous technique in this area. PMID- 21547958 TI - Osseous microarchitecture of the scaphoid: Cadaveric study of regional variations and clinical implications. AB - Bone strength and structure are closely associated with fracture and screw fixation, however osseous micro architecture on scaphoid has not been clearly addressed. We conducted histomorphometric study of the scaphoid using micro CT to find regional variations and differences in the scaphoid to provide better understanding of fracture mechanism and suggest optimal screw position. We divided scaphoid into eight regions and collected regional data from eleven different cadaveric scaphoids. A computer program was used to measure parameters, which includes mean subchondral bone thickness, bone mineral density for bone density parameters, and tissue mineral density, trabecular thickness, trabecular spacing, trabecular number and bone volume fraction for bone quality parameters. All bone strength parameters were measured the maximum value in the regions where scaphoid articulates with radius. Articular regions presented higher bone strength parameters and thicker subchondral bone. The minimum value of trabecular number was in midcarpal side of waist portion. There was trend of higher subchondral bone thickness in the scaphoid which articulates with capitate and radius. This histomorphometric study showed regional variation of the scaphoid in terms of bone density and quality parameters. Waist portion presented thick subchondral and trabecular bone for high cross section moment of inertia against bending. Three point bending for scaphoid fracture and vertical screw placement are suggested based on these variations. PMID- 21547959 TI - Selective modification of the acid-base properties of ceria by supported Au. AB - Au supported on CeO(2) prepared by deposition-precipitation with urea leads to a basic catalyst. Au acts in two ways as surface modifier. First, Au selectively interacts with Ce(4+) cations by either blocking access to or reducing Ce(4+) to Ce(3+). Second, the resulting Au atoms (presumably as Au(+) ions) act as soft, weak Lewis acid sites stabilizing carbanion intermediates and enhancing hydride abstraction in the dehydrogenation of alcohols. In consequence, the thus synthesized basic catalyst catalyzes the dehydrogenation of propan-2-ol to acetone with high efficiency and without notable deactivation. Additionally, the dehydration pathway of propan-2-ol is eliminated, as Au also quantitatively blocks access to strongly acidic Ce(4+) ions or reduces them to Ce(3+). PMID- 21547960 TI - Layered structure of room-temperature ionic liquids in microemulsions by multinuclear NMR spectroscopic studies. AB - Microemulsions form in mixtures of polar, nonpolar, and amphiphilic molecules. Typical microemulsions employ water as the polar phase. However, microemulsions can form with a polar phase other than water, which hold promise to diversify the range of properties, and hence utility, of microemulsions. Here microemulsions formed by using a room-temperature ionic liquid (RTIL) as the polar phase were created and characterized by using multinuclear NMR spectroscopy. (1)H, (11)B, and (19)F NMR spectroscopy was applied to explore differences between microemulsions formed by using 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]) as the polar phase with a cationic surfactant, benzylhexadecyldimethylammonium chloride (BHDC), and a nonionic surfactant, Triton X-100 (TX-100). NMR spectroscopy showed distinct differences in the behavior of the RTIL as the charge of the surfactant head group varies in the different microemulsion environments. Minor changes in the chemical shifts were observed for [bmim](+) and [BF(4)](-) in the presence of TX-100 suggesting that the surfactant and the ionic liquid are separated in the microemulsion. The large changes in spectroscopic parameters observed are consistent with microstructure formation with layering of [bmim](+) and [BF(4)](-) and migration of Cl(-) within the BHDC microemulsions. Comparisons with NMR results for related ionic compounds in organic and aqueous environments as well as literature studies assisted the development of a simple organizational model for these microstructures. PMID- 21547961 TI - Controllable synthesis of Y2O3 microstructures for application in cataluminescence gas sensing. AB - Y(2)O(3) dumbbells, microspheres, and nanosheets were synthesized by a facile hydrothermal procedure followed by calcination. Electron microscopy, X-ray diffraction, and N(2) adsorption measurements were used to characterize the yttrium oxide microstructures. On the basis of a time-dependent study of nanostructure evolution and the effect of other processing parameters, a kinetic "homogeneous nucleation-self assembly-anisotropic growth" mechanism is proposed to explain the growth of these microstructures under hydrothermal conditions. The sensitivity of as-prepared Y(2)O(3) structures to a series of gaseous chemicals was examined by using a homemade cataluminescence sensing system. The designed cataluminescence sensor based on the yttrium oxide dumbbells shows good sensing performance for 16 common volatile organic compounds. PMID- 21547962 TI - Modulated synthesis of Zr-based metal-organic frameworks: from nano to single crystals. AB - We present an investigation on the influence of benzoic acid, acetic acid, and water on the syntheses of the Zr-based metal-organic frameworks Zr-bdc (UiO-66), Zr-bdc-NH(2) (UiO-66-NH(2)), Zr-bpdc (UiO-67), and Zr-tpdc-NH(2) (UiO-68-NH(2)) (H(2) bdc: terephthalic acid, H(2) bpdc: biphenyl-4,4'-dicarboxylic acid, H(2) tpdc: terphenyl-4,4''-dicarboxylic acid). By varying the amount of benzoic or acetic acid, the synthesis of Zr-bdc can be modulated. With increasing concentration of the modulator, the products change from intergrown to individual crystals, the size of which can be tuned. Addition of benzoic acid also affects the size and morphology of Zr-bpdc and, additionally, makes the synthesis of Zr bpdc highly reproducible. The control of crystal and particle size is proven by powder XRD, SEM and dynamic light scattering (DLS) measurements. Thermogravimetric analysis (TGA) and Ar sorption experiments show that the materials from modulated syntheses can be activated and that they exhibit high specific surface areas. Water proved to be essential for the formation of well ordered Zr-bdc-NH(2) . Zr-tpdc-NH(2), a material with a structure analogous to that of Zr-bdc and Zr-bpdc, but with the longer, functionalized linker 2'-amino 1,1':4',1''-terphenyl-4,4''-dicarboxylic acid, was obtained as single crystals. This allowed the first single-crystal structural analysis of a Zr-based metal organic framework. PMID- 21547963 TI - Rodlike macromolecules through spatial overlapping of thiophene dendrons. AB - Two novel dendritic macromonomers 7 and 8 functionalized with electroactive conjugated thiophene oligomers were synthesized by stepwise cross-coupling reactions and the introduction of a vinyl group at the focal point. Both macromonomers were polymerized into dendronized polymers 9 and 10 by using a radical polymerization method. The photophysical and redox behaviors of dendronized polymers 9 and 10 are significantly different from those of the corresponding macromonomers. This difference may result from the spatial overlapping of thiophene dendrons through pi-pi interactions when the dendrons are connected to a polymer backbone. The dendronized polymers can organize into large-area two-dimensional sheets with a thickness of 4.8 nm. Polymer 9, which has all-dendritic thiophene side chains, exhibited enhanced conductivity by partial doping with iodine or nitrosonium tetrafluoroborate (NOBF(4)). The novel amphiphilic dendronized polymer 15 was synthesized by the atom-transfer radical polymerization of macromonomer 7 from a poly(ethylene glycol) (PEG) macroinitiator and was found to have a self-organized structure in water. PMID- 21547964 TI - New 8-amino-BODIPY derivatives: surpassing laser dyes at blue-edge wavelengths. AB - The development of highly efficient and stable blue-emitting dyes to overcome some of the most important shortcomings of available chromophores is of great technological importance for modern optical, analytical, electronic, and biological applications. Here, we report the design, synthesis and characterization of new tailor-made BODIPY dyes with efficient absorption and emission in the blue spectral region. The major challenge is the effective management of the electron-donor strength of the substitution pattern, in order to modulate the emission of these novel dyes over a wide spectral range (430-500 nm). A direct relationship between the electron-donor character of the substituent and the extension of the spectral hypsochromic shift is seen through the energy increase of the LUMO state. However, when the electron-donor character of the substituent is high enough, an intramolecular charge-transfer process appears to decrease the fluorescence ability of these dyes, especially in polar media. Some of the reported novel BODIPY dyes provide very high fluorescence quantum yields, close to unity, and large Stokes shifts, leading to highly efficient tunable dye lasers in the blue part of the spectrum; this so far remains an unexploited region with BODIPYs. In fact, under demanding transversal pumping conditions, the new dyes lase with unexpectedly high lasing efficiencies of up to 63 %, and also show high photostabilities, outperforming the laser action of other dyes considered as benchmarks in the same spectral region. Considering the easy synthetic protocol and the wide variety of possible substituents, we are confident that this strategy could be successfully extended for the development of efficient blue-edge emitting materials and devices, impelling biophotonic and optoelectronic applications. PMID- 21547965 TI - Synthesis and photoswitching studies of difurylperfluorocyclopentenes with extended pi-systems. AB - In an attempt to design molecular optoelectronic switches functioning in molecular junctions between two metal tips, we synthesized a set of photochromic compounds by extending the pi-system of 1,2-bis-(2-methyl-5-formylfuran-3 yl)perfluorocyclopentene through suitable coupling reactions involving the formyl functions, thereby also introducing terminal groups with a binding capacity to gold. Avoiding the presence of gold-binding sulphur atoms in the photoreactive centre, as they are present in the frequently used analogous thienyl compounds, the newly synthesized compounds should be more suitable for the purpose indicated. The kinetics of reversible photoswitching of the new compounds by UV and visible light was quantitatively investigated in solution. The role of conformational flexibility of the pi-system for the width of the UV/Vis spectra was clarified by using quantum chemical calculations with time-dependent (TD) DFT. As a preliminary test of the potential of the new compounds to serve as optoelectronic molecular switches, monolayer formation and photochemical switching on gold surfaces was observed by using surface plasmon resonance. PMID- 21547966 TI - Amino acids with hydrogen-bonding side chains have an intrinsic tendency to sample various turn conformations in aqueous solution. AB - Local structure in unfolded proteins, especially turn segments, has been suggested to initiate the hierarchical protein-folding process. To determine the intrinsic propensity to form such turn structures, amide I' band profiles of the Raman, IR, and vibrational circular dichroism (VCD) spectra, and several structure-sensitive NMR J-coupling constants, have been measured for a series of GxG (x=D, N, T, C) peptides, in which the central x residues are abundant in various turn motifs in folded proteins. In addition, we revisited earlier measured GSG experimental data. To check whether this relatively high propensity for these residues to sample turns reflects an intrinsic propensity, the experimental data were analyzed in terms of conformational distributions that can be described as a superposition of two-dimensional Gaussian distributions associated with different so-called mesostates. The analysis reveals that the investigated residues sample dihedral angles similar to those found in the corner residues of various turns, namely, type I/I', II/II', and IV beta-turns. Aspartic acid (D) was found to predominantly sample regions attributed to turns, including distributions at the upper border of the upper-right quadrant of the Ramachandran plot, which bear some resemblance to asx-turns observed in proteins. This conformation enables hydrogen bonding between the side-chain carboxylate and the C-terminal amide group. Altogether, the study shows that the high propensity for T, S, C, N, and D to be located in turn motifs reflects, to a substantial degree, an intrinsic property and supports the role of these residues as initiation sites for hierarchical folding processes that can lead to compact structures in the unfolded state of peptides and proteins. PMID- 21547967 TI - Thermodynamics, structure and properties of polynuclear lanthanide complexes with a tripodal ligand: insight into their self-assembly. AB - Self-assembly processes between a tripodal ligand and Ln(III) cations have been investigated by means of supramolecular analytical methods. At an equimolar ratio of components, tetranuclear tetrahedral complexes are readily formed in acetonitrile. The structural analysis of the crystallographic data shows a helical wrapping of binding strands around metallic cations. The properties of this series of highly charged 3D compounds were examined by using NMR spectroscopy and optical methods in solution and in the solid state. In the presence of excess metal, a new trinuclear complex was identified. The X-ray crystal structure elucidated the coordination of metallic cations with two ligands of different conformations. By varying the metal/ligand ratio, a global speciation of this supramolecular system has been evidenced with different spectroscopic methods. In addition, these rather complicated equilibria were successfully characterised with the thermodynamic stability constants. A rational analysis of the self-assembly processes was attempted by using the thermodynamic free energy model and the impact of the ligand structure on the effective concentration is discussed. PMID- 21547968 TI - Chemical and thermal stability of isotypic metal-organic frameworks: effect of metal ions. AB - Chemical and thermal stabilities of isotypic metal-organic frameworks (MOFs) like Al-BDC (Al-benzenedicarboxylate called MIL-53-Al), Cr-BDC (MIL-53-Cr) and V-BDC (MIL-47-V), after purification to remove uncoordinated organic linkers, have been compared to understand the effect of the central metal ions on the stabilities of the porous MOF-type materials. Chemical stability to acids, bases, and water decreases in the order of Cr-BDC>Al-BDC>V-BDC, suggesting stability increases with increasing inertness of the central metal ions. However, thermal stability decreases in the order of Al-BDC>Cr-BDC> V-BDC, and this tendency may be explained by the strength of the metal-oxygen bond in common oxides like Al(2)O(3), Cr(2)O(3), and V(2)O(5). In order to evaluate precisely the stability of a MOF, it is necessary to remove uncoordinated organic linkers that are located in the pores of the MOF, because a filled MOF may be more stable than the same MOF after purification. PMID- 21547969 TI - Palladium-catalyzed borylation of aryl mesylates and tosylates and their applications in one-pot sequential Suzuki-Miyaura biaryl synthesis. PMID- 21547970 TI - On the role of intermolecular interactions on structural and spin-crossover properties of 2D coordination networks [Fe(bbtr)3]A2 (bbtr=1,4-bis(1,2,3-triazol 1-yl)butane; A=ClO4(-), BF4(-)). AB - A series of complexes [M(bbtr)(3)]A(2) (M=Fe(II), Zn(II); bbtr=1,4-bis(1,2,3 triazol-1-yl)butane; A=ClO(4)(-), BF(4)(-)) and [Fe(x)Zn(1 x)(bbtr)(3)](ClO(4))(2) (0= 50%. Multiple global vessels were more often seen in tumors of Stage IB or greater than in Stage IA tumors (P = 0.02), in Grade 3 tumors than in Grade 1 and 2 tumors (P = 0.02) and in tumors with a tumor/uterine AP ratio of >= 50% (P < 0.001). A moderate/high color score was significantly more common in tumors of higher stage (P = 0.03) and larger size (P = 0.001). CONCLUSION: The sonographic appearance of endometrial cancer is significantly associated with tumor stage, grade and size. More advanced tumors often have a mixed/hypoechoic echogenicity, a higher color score and multiple globally entering vessels, whereas less advanced tumors are more often hyperechoic and have no or a low color score. PMID- 21547975 TI - Impact of Doppler sonography on intrauterine management and neonatal outcome in preterm fetuses with intrauterine growth restriction. AB - OBJECTIVES: To test the hypothesis that earlier delivery may be warranted to improve neonatal outcome of fetuses with intrauterine growth restriction (IUGR) with abnormal Doppler parameters. METHODS: This was a retrospective cohort study of 110 fetuses with an antenatal diagnosis of IUGR due to placental insufficiency which had a very low birth weight (< 1500 g), delivered at the Department of Fetomaternal Medicine of the Medical University of Vienna, Austria, between January 1999 and July 2009. Doppler results before delivery were classified as follows: Group 1: abnormal umbilical artery (UA) pulsatility index (PI) more than 2 SD above the mean for normal reference data, or absent UA end-diastolic flow, both with normal middle cerebral artery (MCA) PI (mean +/- 2 SD); Group 2: abnormal UA-PI > mean + 2 SD, or absent or reversed UA end-diastolic flow, with abnormal MCA-PI (< mean - 2 SD) and normal ductus venosus (DV) PI (mean +/- 2 SD); Group 3: absent or reversed UA end-diastolic flow, with abnormal MCA-PI (< mean - 2 SD) and abnormal DV-PI (> mean + 2 SD) and/or absent or reversed end diastolic DV flow. Pregnancy outcome was analyzed according to Doppler results. RESULTS: Due to very poor prognosis, 19 fetuses underwent expectant management and died in utero. These were excluded from further analyses. Of the remaining 91 cases, 17 were in Doppler Group 1, 44 in Group 2 and 30 in Group 3. Within 4 weeks after delivery, 0/17 (0%) infants in Group 1 died, 2/44 (4.5%) infants in Group 2 died and 7/30 (23.3%) infants in Group 3 died (P = 0.019). None of the 42 Group 2 cases that delivered at or after 28 completed gestational weeks died within 4 weeks after delivery, in contrast to 4/20 (20.0%) Group 3 cases (P = 0.009). In comparison, among infants delivered before 27 completed gestational weeks, 2/2 (100%) Group 2 cases died and 3/10 (30.0%) Group 3 cases died; P = 0.152). CONCLUSIONS: Doppler examinations are highly predictive in assessing the outcome of IUGR fetuses. From 28 completed gestational weeks, early delivery before the onset of fetal cardiac decompensation might be beneficial. PMID- 21547976 TI - Fetal aortic valvuloplasty as a means to survival. PMID- 21547977 TI - Well-aligned nano-fiberous membranes based on three-pole electrospinning with channel electrode. AB - Three-pole electrospinning devices integrated with a blade-cage collector were developed to fabricate well-aligned nano-fiberous membranes. The proposed three pole configuration with a channel electrode can be a powerful tool in aligning nano-fibers with regular diameter because the generated electric field can be accurately controlled without severe fluctuation in comparison with other methods. The three-pole electrospinning method is also valid for industrial mass production and accurate diameter control of the aligned nano-fibers. PMID- 21547978 TI - Spousal violence and paternal disinvestment among Tsimane' forager horticulturalists. AB - OBJECTIVES: We develop and test a conceptual model of factors influencing the likelihood of physical wife abuse. The paternal disinvestment model emphasizes that spousal conflict over resource use results from men's attempts to increase individual fitness at a cost to the family (e.g., through pursuit of extramarital affairs). We propose that men use violence to control women's responses to the diversion of resources away from the family: to quell women's objections to male disinvestment, maintain women's parental investment, and to dissuade women from pursuing relationships with other men. METHODS: Interviews were conducted among men and women to determine rates of violence and demographic and behavioral covariates. Structural equation modeling and generalized estimating equations analyses were used to test predictions derived from the model. We also collected data on frequent complaints in marriage and women's perceptions of arguments precipitating violence. RESULTS: Over 85% of women experienced physical wife abuse (n = 49). Indicators of paternal disinvestment positively covary with indicators of marital strife and with rates of wife abuse. The wife's age, matrilocal residence, and presence of joint dependent offspring decrease the likelihood of violence through direct and indirect routes. CONCLUSIONS: Wife abuse is linked to the importance of paternal investment in human families, and is a means by which men control women's responses to a dual reproductive strategy of familial investment and pursuit of extramarital sexual relationships. This framework is more general than traditional sociological and evolutionary perspectives emphasizing patriarchy and men's sexual jealousy, respectively. PMID- 21547979 TI - Variability of the BCHE gene in Amerindians from Parana, Brazil. AB - OBJECTIVE: This study aims to better understand the variability of the BCHE gene, and regions adjacent to it, in different populations. More specifically, it also aims to analyze the diversity of this DNA segment among two Amerindian populations, whose distinct characteristics provide us an extremely interesting material for genetic, evolutionary and anthropological studies, since they diverge genetically and culturally in spite of a very close living relationship in space and time. METHODS: The two Amerindian populations analysed were from Guarani-Mbya and Kaingang ethnic groups, both from the Rio das Cobras indian reservation area (Parana, Brazil). The other populations data were obtained from the HapMap Project data, NCBI data and previously studies. The variability of seven SNPs was analyzed: two downstream, three within and two upstream of the BCHE gene. RESULTS: The number of different BCHE variants in Amerindians is lower than in other populations. The present data are in accordance with the genetic distance between Guarani and Kaingang, and from them to other populations. Some SNPs (rs3495, rs7624915 and rs4387996) presented an interesting frequency pattern, with a higher frequency of the ancestral allele in the region of the modern human origin and its frequency decreasing gradually, from Africa toward the Americas. CONCLUSIONS: Despite the geographical coexistence throughout their dispersion, each of these two Amerindian groups retains a high degree of genetic identity, probably maintained by cultural and social isolation. PMID- 21547980 TI - Is low digit ratio linked with late menarche? Evidence from the BBC internet study. AB - OBJECTIVES: Age at menarche (AAM) in the general population may be influenced by prenatal sex steroids. The ratio of the second and fourth digits (2D:4D) is a putative correlate of prenatal sex steroids, but the relationship of 2D:4D to AAM is controversial. Matchock ([2008]: Am J Hum Biol 20:487-489) has reported that right 2D:4D (but not left) was negatively related to AAM, but Helle ([2010a]: Am J Hum Biol 22:418-420) found no relationship. Here the association between 2D:4D, AAM, and self-reported rate of pubertal development (RPD) is considered. METHODS: The sample consisted of self-measured finger lengths and AAM and RPD reported by women in the BBC internet study. RESULTS: There were 70,658 white women who reported a mean (+/- SD) AAM of 12.54 (1.48) years. Right 2D:4D was negatively related to AAM and positively related to RPD. These relationships were independent of left 2D:4D, age and height. Between-country variation in right 2D:4D was also significantly related to AAM such that in countries with low 2D:4D women mean AAM was higher. CONCLUSIONS: In support of the findings of Matchock, right 2D:4D was found to be negatively related to AAM. In addition, right 2D:4D was positively related to RPD. In a sample of 19 countries, mean right 2D:4D was negatively correlated with mean national AAM. These findings suggest that women with high prenatal testosterone and low prenatal estrogen tend to show late menarche and slow pubertal development. PMID- 21547981 TI - Chromosome remodeling and differentiation of tetraploid embryos during preimplantation development. AB - Although it is known that the tetraploid embryo contributes only to the placenta, the question of why tetraploid embryos differentiate into placenta remains unclear. To study the effect of electrofusion on the development of mouse tetraploid oocytes, mouse two-cell embryos were fused and cultured in vitro in Chatot-Ziomek-Bavister medium. After electrofusion, two chromosome sets from the tetraploid blastomere were individually duplicated before nuclear fusion. At 8-10 hr after electrofusion, each chromosome set was condensing and the nuclear membrane was breaking down. Around 12-14 hr after electrofusion, the two chromosome sets had combined together and had reached the second mitotic metaphase, at this point with 8n sets of chromosomes. Interestingly, we discovered that expression of OCT4, an inner cell mass cells biomarker, is lost by the tetraploid expanded blastocysts, but that CDX2, a trophectoderm cells biomarker, is strongly expressed at this stage. This observation provides evidence clarifying why tetraploid embryos contribute only to trophectoderm. PMID- 21547982 TI - Top-down-directed synchrony from medial frontal cortex to nucleus accumbens during reward anticipation. AB - The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using noninvasive techniques. We recorded electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deep-brain-stimulation treatment for obsessive-compulsive disorder. Patients performed a simple reward motivation task previously shown to activate the ventral striatum. Spectral Granger causality analyses were applied to dissociate "top-down" (cortex -> nucleus accumbens)- from "bottom-up" (nucleus accumbens -> cortex)-directed synchronization (functional connectivity). "Top-down"-directed synchrony from cortex to nucleus accumbens was maximal over medial frontal sites and was significantly stronger when rewards were anticipated. These findings provide direct electrophysiological evidence for a role of the MFC in modulating nucleus accumbens reward-related processing and may be relevant to understanding the mechanisms of deep-brain stimulation and its beneficial effects on psychiatric conditions. PMID- 21547984 TI - A five-coordinate iron center in the active site of [Fe]-hydrogenase: hints from a model study. PMID- 21547986 TI - Crystal structure prediction--dawn of a new era. PMID- 21547985 TI - Pan-Src family kinase inhibitors replace Sox2 during the direct reprogramming of somatic cells. PMID- 21547987 TI - Mixing an aqueous suspension of Pd or Au nanocrystals with a less polar solvent can cause changes to size, morphology, or both. PMID- 21547989 TI - Static and dynamic stereochemistry of chiral Ln DOTA analogues. AB - Ln DOTA derivatives (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) are known to undergo relevant stereoisomeric equilibria in solution, which greatly modulate their chemical as well as their magnetic and optical properties. The subject is reviewed in terms of classical stereochemical description, with reference to conformational enthalpies. Yb is taken as the reference element because of its unique spectroscopic properties, namely, a small contact contribution to the paramagnetic shift and an intense near-infrared electronic circular dichroism, endowed with an easily recognizable fine structure. PMID- 21547992 TI - The induction of anhydrobiosis in the sleeping chironomid: current status of our knowledge. AB - An African chironomid, Polypedilum vanderplanki, is the only insect known to be capable of extreme desiccation tolerance, or anhydrobiosis. In the 1950s and 1960s, Hinton strenuously studied anhydrobiosis in this insect from a physiological standpoint; however, nobody has afterward investigated the phenomenon. In 2000, research on mechanisms underlying anhydrobiosis was resumed due to successful establishment of a rearing system for P. vanderplanki. This review is focused on the latest findings on the physiological and molecular mechanisms underlying the induction of anhydrobiosis in P. vanderplanki. Early experiments demonstrated that the induction of anhydrobiosis was possible in isolated tissues and independent from the control of central nervous system. However, to achieve successful anhydrobiosis, larvae need a slow regime of desiccation, allowing them to synthesize molecules, which will protect cells and tissues against the deleterious effects of dehydration. Trehalose, a nonreducing disaccharide, which accumulates in P. vanderplanki larvae up to 20% of the dry body mass, is thought to replace the water in its tissues. Similarly, highly hydrophilic proteins called the late embryogenesis abundant (LEA) proteins are expressed in huge quantities and act as a molecular shield to protect biological molecules against aggregation and denaturation. This function is shared by heat shock proteins, which are also upregulated during the desiccation process. At the same time, desiccating larvae express various antioxidant molecules and enzymes, to cope with the massive oxidative stress, which is responsible for general damage to membranes, proteins, and DNA in dehydrating cells. Finally, specific water channels, called aquaporins, accelerate dehydration, and trehalose together with LEA proteins forms a glassy matrix, which protects the biological molecules and the structural integrity of larvae in the anhydrobiotic state. PMID- 21547993 TI - A unique case of renal artery fibromuscular dysplasia. AB - Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic disorder resulting in arterial stenosis. Here, a unique case of renal artery FMD (RA FMD) is presented. With the use of angiograpic and intravascular ultrasound (IVUS) imaging modalities, a patient was diagnosed with two distinct types of FMD. Until now, the prevalence of FMD has been underestimated due to limitations in diagnostic modalities. Clinically, the correct identification of RA FMD is essential because these patients have been shown to respond to revascularization therapy with significant improvement in blood pressure whereas renal artery lesions secondary to other etiologies such as atherosclerosis have yet to show the same consistent response. Further, the presence of two subtypes of FMD in a single patient may suggest the possibility of genetic factors that predispose certain vessels to certain subtypes of FMD. PMID- 21547994 TI - Validating the EXCEL hypothesis: a propensity score matched 3-year comparison of percutaneous coronary intervention versus coronary artery bypass graft in left main patients with SYNTAX score <=32. AB - OBJECTIVES: The aim of this study is to verify the study hypothesis of the EXCEL trial by comparing percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) in an EXCEL-like population of patients. BACKGROUND: The upcoming EXCEL trial will test the hypothesis that left main patients with SYNTAX score <= 32 experience similar rates of 3-year death, myocardial infarction (MI), or cerebrovascular accidents (CVA) following revascularization by PCI or CABG. METHODS: We compared the 3-year rates of death/MI/CVA and death/MI/CVA/target vessel revascularization (MACCE) in 556 patients with left main disease and SYNTAX score <= 32 undergoing PCI (n = 285) or CABG (n = 271). To account for confounders, outcome parameters underwent extensive statistical adjustment. RESULTS: The unadjusted incidence of death/MI/CVA was similar between PCI and CABG (12.7% vs. 8.4%, P = 0.892), while MACCE were higher in the PCI group compared to the CABG group (27.0% vs. 11.8%, P < 0.001). After propensity score matching, PCI was not associated with a significant increase in the rate of death/MI/CVA (11.8% vs. 10.7%, P = 0.948), while MACCE were more frequently noted among patients treated with PCI (28.8% vs. 14.1%, P = 0.002). Adjustment by means of SYNTAX score and EUROSCORE, covariates with and without propensity score, and propensity score alone did not change significantly these findings. CONCLUSIONS: In an EXCEL-like cohort of patients with left main disease, there seems to be a clinical equipoise between PCI and CABG in terms of death/MI/CVA. However, even in patients with SYNTAX score <= 32, CABG is superior to PCI when target vessel revascularization is included in the combined endpoint. PMID- 21547995 TI - Successful retrieval of an entrapped Rotablator burr using 5 Fr guiding catheter. AB - BACKGROUND: Although burr entrapment is a rare complication of the Rotablator, it is extremely difficult to retrieve a fixedly entrapped burr without surgical procedure. CASE REPORT: An 84-year-old male with effort angina had heavily calcified coronary trees as well as severe stenosis in the mid LCx, and moderate stenosis in the proximal LCx, and in the LMT. We planned to perform rotational atherectomy in the LCx lesions. Using 7 Fr Q-curve guiding catheter and Rotawire floppy, we began to ablate using 1.5-mm burr at 200,000 rpm. Because the burr could not pass the proximal stenosis, we exchanged the wire for Rotawire extrasupport and the burr for 1.25-mm burr, and restarted the ablation at 220,000 rpm. Although the burr could manage to pass the proximal stenosis, it had become trapped in the mid LCx lesion. Simple pull on the Rotablator, rotation of the burr, and crossing the Conquest (Confianza) wire could not retrieve it. Thus, we cut off the drive shaft and sheath of the Rotablator, inserted 5 Fr 120-cm straight guiding catheter (Heartrail ST01; Terumo) through the remaining Rotablator system, pushed the catheter tip to the lesion around the burr as well as simultaneously pulled the Rotablator, and finally could retrieve it. Then we implanted stents in the LCx and in the LMT without difficulty. CONCLUSIONS: The 5 Fr straight guiding catheter might be useful for retrieving an entrapped burr (1.25-mm burr). PMID- 21547996 TI - The ability to achieve complete revascularization is associated with improved in hospital survival in cardiogenic shock due to myocardial infarction: Manitoba cardiogenic SHOCK Registry investigators. AB - OBJECTIVES: To identify predictors of survival in a retrospective multicentre cohort of patients with cardiogenic shock undergoing coronary angiography and to address whether complete revascularization is associated with improved survival in this cohort. BACKGROUND: Early revascularization is the standard of care for cardiogenic shock. Coronary bypass grafting and percutaneous intervention have complimentary roles in achieving this revascularization. METHODS: A total of 210 consecutive patients (mean age 66 +/- 12 years) at two tertiary centres from 2002 to 2006 inclusive with a diagnosis of cardiogenic shock were evaluated. Univariate and multivariate predictors of in-hospital survival were identified utilizing logistic regression. RESULTS: ST elevation infarction occurred in 67% of patients. Thrombolysis was administered in 34%, PCI was attempted in 62% (88% stented, 76% TIMI 3 flow), CABG was performed in 22% (2.7 grafts, 14 valve procedures), and medical therapy alone was administered to the remainder. The overall survival to discharge was 59% (CABG 68%, PCI 57%, medical 48%). Independent predictors of mortality included complete revascularization (P = 0.013, OR = 0.26 (95% CI: 0.09-0.76), hyperlactatemia (P = 0.046, OR = 1.14 (95% CI: 1.002-1.3) per mmol increase), baseline renal insufficiency (P = 0.043, OR = 3.45, (95% CI: 1.04-11.4), and the presence of anoxic brain injury (P = 0.008, OR = 8.22 (95% CI: 1.73-39.1). Within the STEMI with concomitant multivessel coronary disease subgroup of this population (N = 101), independent predictors of survival to discharge included complete revascularization (P = 0.03, OR = 2.5 (95% CI: 1.1-6.2)) and peak lactate (P = 0.02). CONCLUSIONS: The ability to achieve complete revascularization may be strongly associated with improved in hospital survival in patients with cardiogenic shock. PMID- 21547997 TI - Fungal endocarditis after transfemoral aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) was introduced in 2006 as an alternative for surgical aortic valve replacement (SAVR) as treatment for patients with aortic stenosis. Endocarditis after TAVI has been anecdotally reported, but concerns aroused because SAVR is often needed to explant the endocarditic valve in a high risk patient previously deemed not to be a surgical candidate. We report a case of a patient who underwent TAVI because he was too high risk to undergo SAVR. Several months later, he developed an intermittent self-limiting fever of unknown origin which eventually was diagnosed as endocarditis. The valve was surgically removed, and pathology showed an infection caused by Histoplasma capsulatum. The patient recovered fully and remains in good condition. PMID- 21547998 TI - Quality assessment and improvement in interventional cardiology: a Position Statement of the Society of Cardiovascular Angiography and Interventions, Part II: public reporting and risk adjustment. PMID- 21547999 TI - Determination of puerarin in biological samples and its application to a pharmacokinetic study by flow-injection chemiluminescence. AB - A simple and sensitive flow injection-chemiluminescence (FI-CL) method has been developed for the determination of puerarin, based on the fact that puerarin can greatly inhibit CL of the luminol-H2O2-haemoglobin system. The inhibition of CL intensity was linear to the logarithm of the concentration of puerarin in the range 0.08-10.0 MUg/mL (r2 = 0.9912). The limit of detection was 0.05 MUg/mL (3sigma) and the relative standard deviation (RSD) for 1.0 MUg/mL (n = 11) of puerarin solution was 1.4%. Coupled with solid-phase extraction (SPE) as the sample pretreatment, the determination of puerarin in biological samples and a preliminary pharmocokinetic study of puerarin in rats were performed. The recoveries for plasma and urine at three different concentrations were 89.2 110.0% and 91.4-104.8%, respectively. The pharmacokinetics of puerarin in plasma of rat coincides with the two-compartment open model. The T(1/2alpha) , T(1/2beta) , CL/F, V(Z/F), AUC(0-t), MRT0-infinity, T(max) and C(max) were 0.77 +/- 0.21 h, 7.55 +/- 2.64 h, 2.43 +/- 1.02 L/kg/h, 11.40 +/- 3.45 L/kg, 56.67 +/- 10.65 mg/h/L, 5.04 +/- 2.78 h, 1.00 +/- 0.35 h and 19.70 +/- 4.67 MUg/mL, respectively. PMID- 21548000 TI - Determination of clomipramine by flow-injection analysis with acidic potassium permanganate-formic acid chemiluminescence detection. AB - A sensitive and simple chemiluminescent (CL) method for the determination of clomipramine has been developed by combining the flow-injection analysis (FIA) technique, which is based on the CL intensity generated from the redox reaction of potassium permanganate (KMnO(4))-formic acid in sulphuric acid (H(2)SO(4)) medium. Under the optimum conditions, the linear range for the determination of clomipramine was 0.04-4 ug/mL, with a correlation coefficient of 0.9988 (n = 10) and a detection limit of 0.008 ug/mL (3sigma), and the relative standard deviation (RSD) for 2.0 ug/mL clomipramine (n = 11) is 1.26%. The proposed method has been successfully applied to the determination of the studied clomipramine in pharmaceutical preparations. The possible reaction mechanism is discussed. PMID- 21548001 TI - Benchmark study on glyphosate-resistant cropping systems in the United States. Part 6: Timeliness of economic decision-making in implementing weed resistance management strategies. AB - BACKGROUND: The introduction of glyphosate-resistant (GR) crops in the late 1990s made weed control in maize, cotton and soybean simple. With the rapid adoption of GR crops, many growers began to rely solely on glyphosate for weed control. This eventually led to the evolution of GR weeds. Growers are often reluctant to adopt a weed resistance best management practice (BMP) because of the added cost of additional herbicides to weed control programs which would reduce short-term revenue. This study was designed to evaluate when a grower that is risk neutral (profit maximizing) or risk averse should adopt a weed resistance BMP. RESULTS: Whether a grower is risk neutral or risk averse, the optimal decision would be to adopt a weed resistance BMP when the expected loss in revenue is greater than 30% and the probability of resistance evolution is 0.1 or greater. However, if the probability of developing resistance increases to 0.3, then the best decision would be to adopt a weed resistance BMP when the expected loss is 10% or greater. CONCLUSION: Given the scenarios analyzed, risk-neutral or risk-averse growers should implement a weed resistance BMP with confidence that they have made the right decision economically and avoided the risk of lost revenue from resistance. If the grower wants to continue to see the same level of return, adoption of BMP is required. PMID- 21548002 TI - An exposure study to assess the potential impact of fipronil in treated sunflower seeds on honey bee colony losses in Spain. AB - BACKGROUND: There is great concern about the high losses and strong depopulation of honey bee colonies in some areas of Spain. Some beekeepers have suggested that sunflower seeds treated with the insecticide fipronil could be an important factor in causing those losses. Therefore, an in-depth field study has been carried out in two regions of Spain where sunflower production is intense (Cuenca and Andalucia) and where, for some crops and varieties, fipronil has been used as seed insecticide. RESULTS: Samples of adult bees and pollen were analysed for bee pathogens and pesticide residues respectively. Neither fipronil residues nor its metabolites were detected in any of the samples analysed, indicating that short term or chronic exposure of bees to fipronil and/or its metabolites can be ruled out in the apiaries surveyed. Varroa destructor and Nosema ceranae were found to be very prevalent. CONCLUSION: The combination of the two pathogens could augment the risk of colony death in infected colonies, without fipronil residues exerting a significant effect in the given field conditions. Indeed, in this study the losses observed in apiaries located close to sunflower crops were similar to those in apiaries situated in forested areas with wild vegetation. PMID- 21548003 TI - Acaricide resistance and resistance mechanisms in Tetranychus urticae populations from rose greenhouses in the Netherlands. AB - BACKGROUND: Spider mites are important crop pests that rapidly develop resistance to acaricides. To investigate whether acaricide resistance is a threat to greenhouse rose culture in the Netherlands, the susceptibility of 15 strains of Tetranychus urticae was tested to several currently used acaricides, and resistance mechanisms were investigated. RESULTS: Although the observed levels of susceptibility differed between strains and acaricides, resistance was detected in most strains. The activity of detoxifying enzymes was significantly increased in most field-collected strains, and a number of amino acid substitutions known to be involved in resistance were detected. CONCLUSIONS: Resistance levels to traditional acaricides such as bifenthrin and abamectin were prominent, and might result in control failure under field conditions. Resistance to more recently registered compounds was detected in several populations. Resistance levels were generally unstable in the laboratory without selection pressure. The toxicological, biochemical and genetic data in this study will be essential in devising an efficient resistant management for Dutch rose culture. PMID- 21548004 TI - Herbicide-resistant weed management: focus on glyphosate. AB - This review focuses on proactive and reactive management of glyphosate-resistant (GR) weeds. Glyphosate resistance in weeds has evolved under recurrent glyphosate usage, with little or no diversity in weed management practices. The main herbicide strategy for proactively or reactively managing GR weeds is to supplement glyphosate with herbicides of alternative modes of action and with soil-residual activity. These herbicides can be applied in sequences or mixtures. Proactive or reactive GR weed management can be aided by crop cultivars with alternative single or stacked herbicide-resistance traits, which will become increasingly available to growers in the future. Many growers with GR weeds continue to use glyphosate because of its economical broad-spectrum weed control. Government farm policies, pesticide regulatory policies and industry actions should encourage growers to adopt a more proactive approach to GR weed management by providing the best information and training on management practices, information on the benefits of proactive management and voluntary incentives, as appropriate. Results from recent surveys in the United States indicate that such a change in grower attitudes may be occurring because of enhanced awareness of the benefits of proactive management and the relative cost of the reactive management of GR weeds. PMID- 21548005 TI - Teratology Society 51st Annual Meeting, June 25-29, 2011, Coronado, California, USA. Abstracts. PMID- 21548007 TI - Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program. AB - BACKGROUND: Genz-644282 is a novel non-camptothecin topoisomerase I poison that is in clinical development. PROCEDURES: Genz-644282 was tested against the PPTP in vitro panel (0.1 nM to 1 uM), and in vivo using three times per week * 2 schedule repeated at day 21 at its maximum tolerated dose (MTD) of 4 mg/kg. Subsequently Genz-644282 was tested at 4, 3, 2, and 1 mg/kg in 3 models to assess the dose-response relationship. mRNA gene signatures predictive for Genz-644282 response in vitro were applied to select 15 tumor models that were evaluated prospectively. RESULTS: In vitro, Genz-644282 demonstrated potent cytotoxic activity with a median IC(50) of 1.2 nM (range 0.2-21.9 nM). In vivo, Genz-644282 at its MTD (4 mg/kg) induced maintained complete responses (MCR) in 6/6 evaluable solid tumor models. At 2 mg/kg Genz-644282 induced CR or MCR in 3/3 tumor models relatively insensitive to topotecan, but there were no objective responses at 1 mg/kg. Further testing at 2 mg/kg showed that Genz-644282 induced objective regressions in 7 of 17 (41%) models. There was a significant correlation between predictive response scores based on Affymetrix U133Plus2 baseline tumor expression profiles and the observed in vivo responses to Genz-644282. CONCLUSIONS: Genz-644282 was highly active within a narrow dose range (2-4 mg/kg), typical of other topoisomerase I poisons. As with other topoisomerase I poisons, how accurately these data will translate to clinical activity will depend upon the drug exposures that can be achieved in children treated with this agent. PMID- 21548008 TI - Late sequelae of symptomatic epidural compression in children with localized neuroblastoma. AB - BACKGROUND: To describe late sequelae and their correlation with presenting clinical features and tumor treatment in children with symptomatic epidural compression (EC) secondary to localized neuroblastoma. PROCEDURES: A total of 98 evaluable children diagnosed with neuroblastoma and EC, who survived a minimum of 2 years were identified in two Italian and French neuroblastoma series. RESULTS: Symptoms of EC at diagnosis included motor deficit in 94 cases and sphincter deficits in 33. Initial treatment was chemotherapy in 66 cases, neurosurgical decompression in 29 and radiotherapy in 3. Chemotherapy was chosen more frequently for younger children and for those with stage 3 disease. Overall treatment consisted of chemotherapy alone in 44 cases, neurosurgery and chemotherapy in 38, radiotherapy and chemotherapy, with or without neurosurgery, in 16. After a median follow-up of 7.3 years, 57 children (58.2%) had one or more sequelae. Motor sequelae involved 50/57 of these children and correlated with age and severity of motor deficit at diagnosis and neurosurgical treatment. Spine deformities involved 27/57 children and were more frequent in those with severe motor deficit at diagnosis, or who were treated by neurosurgery or radiotherapy. Sphincter dysfunctions involved 31/57 children and were more frequent among children who presented with sphincter symptoms and severe motor deficit. CONCLUSIONS: Fifty-eight percent of the children with localized neuroblastoma and symptomatic EC registered in this study developed late sequelae. The severity of motor deficit at diagnosis was the main risk factor. PMID- 21548009 TI - Memory deficits in patients with pediatric CNS germ cell tumors. AB - BACKGROUND: Germ cell tumors (GCT) of the central nervous system including germinomas and nongerminomatous germ cell tumors are rare neoplasms most commonly affecting children and adolescents. Many GCT patients seen at The Children's Hospital Denver complain of memory difficulties at the time of presentation, or demonstrate memory difficulties when assessed. Although case studies suggest that memory deficits may be associated with GCT, this is the first study to investigate memory function across a series of pediatric intracranial GCT patients. PROCEDURE: A total of 26 GCT patients were retrospectively examined for diagnosis, imaging results, intelligence quotient, treatment variables, evidence of increased intracranial pressure at diagnosis, and memory function. Patient Full Scale IQ was measured using the Wechsler intelligence scales. Memory was evaluated with the California Verbal Learning Test. RESULTS: The incidence of amnesia in GCT patients was 42%. GCT patients with amnesia were significantly older at diagnosis than those who did not develop amnesia. There was no association between hydrocephalus at presentation or having received radiation and the presence of memory deficits. Several cases of amnesia were not associated with involvement of classic memory structures. CONCLUSION: The high incidence of measurable memory deficits in GCT patients suggests that amnesia may be a significant risk in this patient population. Memory assessment at diagnosis and appropriate follow-up services may prove beneficial for GCT patients. PMID- 21548010 TI - Career burnout among pediatric oncologists. AB - BACKGROUND: Burnout is a work-related syndrome consisting of emotional exhaustion, depersonalization, and diminished feelings of personal accomplishment. Physicians who care for patients with life-threatening illnesses are at high risk for developing burnout. This survey evaluates the prevalence of burnout among pediatric oncologists, and assesses risk factors associated with the development of burnout. PROCEDURE: A questionnaire was sent via email to 1,047 practicing pediatric oncologists. The survey included the 22 question Maslach Burnout Inventory (MBI), as well as questions regarding work-related and lifestyle-related factors associated with developing burnout. RESULTS: Four hundred ten pediatric oncologists (40%) responded to the survey. Thirty-eight percent of pediatric oncologists had high levels of burnout on the MBI, while 72% had at least moderate levels of burnout. Women (47% vs. 32%, P < 0.004) and physicians practicing for <10 years (50% vs. 33%, P < 0.004) had significantly higher rates of burnout. Physicians who reported satisfaction with their lives outside of work were less likely to have burnout (odds ratio 0.238, 0.143-0.396, P < 0.001). The availability of a forum for debriefing, and services for physicians affected by burnout were both associated with lower rates of burnout (24% vs. 46%, P < 0.001 and 23% vs. 46%, P < 0.001). Thirty-six percent of respondents reported their institution has a forum for debriefing and 40% of respondents reported their institution has services available for physicians experiencing symptoms of burnout. CONCLUSIONS: Approximately three quarters of pediatric oncologists experience burnout. Further research is needed on the effectiveness of interventions aimed at preventing and treating work-related burnout. PMID- 21548012 TI - Sinonasal adenocarcinoma: a rare second malignancy in long term retinoblastoma survivors. AB - Retinoblastoma is the most common primary cancer of the eye in children. The incidence of second tumors in survivors of bilateral retinoblastoma and in survivors of unilateral retinoblastoma who presumably carry a germline RB1 mutation is documented. This article describes the previously unrecognized association of sinonasal adenocarcinoma as a second malignancy in retinoblastoma survivors. We present three cases who received radiation therapy as a part of their treatment and developed sinonasal adenocarcinoma as a second malignancy. Sinonasal adenocarcinoma should be considered as a second malignancy in retinoblastoma survivors who present with vague sinus symptoms. PMID- 21548011 TI - Congenital pancytopenia and absence of B lymphocytes in a neonate with a mutation in the Ikaros gene. AB - BACKGROUND: Congenital pancytopenia is a rare and often lethal condition. Current knowledge of lymphoid and hematopoietic development in mice, as well as understanding regulators of human hematopoiesis, have led to the recent discovery of genetic causes of bone marrow failure disorders. However, in the absence of mutations of specific genes or a distinct clinical phenotype, many cases of aplastic anemia are labeled as idiopathic, while congenital immune deficiencies are described as combined immune deficiency. PROCEDURE: We describe the case of a 33-week gestation age male with severe polyhydramnios, hydrops, and ascites who was noted to be pancytopenic at birth. Bone marrow examination revealed a hypocellular marrow with absent myelopoiesis. An immune workup demonstrated profound B lymphopenia, near absent NK cells, and normal T cell number. Due to the similarity of the patient's phenotype with the IKAROS knockout mouse, studies were performed on bone marrow and peripheral blood to assess a potential pathogenic role of Ikaros. RESULTS: DNA studies revealed a point mutation in one allele of the IKAROS gene, resulting in an amino acid substitution in the DNA binding zinc finger domain. Functional studies demonstrated that the observed mutation decreased Ikaros DNA-binding affinity, and immunofluorescence microscopy revealed aberrant Ikaros pericentromeric localization. CONCLUSIONS: Our report describes a novel case of congenital pancytopenia associated with mutation of the IKAROS gene. Furthermore, these data suggest a critical role of IKAROS in human hematopoiesis and immune development. PMID- 21548013 TI - Reduced bone mineral density in adult patients with Langerhans cell histiocytosis. AB - This retrospective study evaluated bone mineral density (BMD) and bone turnover in adults with LCH. Twenty-five adult patients and 25 matched controls were evaluated with BMD measurement and indices of bone metabolism. A BMD value below the expected range for age (Z-score <= - 2.0) was found in 20% of patients; in particular, all postmenopausal women and men over 50-years had either osteoporosis or osteopenia. Patients with active disease had significantly lower Z-scores compared to patients with inactive disease and controls. Reduced bone turnover was found in all 14 patients treated with chemotherapy. No fractures due to osteoporosis were identified during 305.15 patient-years of follow-up. PMID- 21548014 TI - The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations. AB - Fanconi anemia (FA) is characterized by progressive marrow failure, congenital anomalies, and predisposition to malignancy. Biallelic FANCD1/BRCA2 mutations are the genetic basis of disease in a small proportion of children with FA with earlier onset and increased incidence of leukemia and solid tumors. Patients with FA have increased sensitivity to chemotherapy and radiation, and upon development of a solid tumor, require modification of these therapies. We report clinical and molecular features of three patients with FA associated with FANCD1/BRCA2 mutations, including two novel mutations, and discuss treatment of malignancy and associated side effects in this particularly vulnerable group. PMID- 21548015 TI - Methodological and ethical aspects of randomized controlled clinical trials in minors with malignant diseases. AB - BACKGROUND: Due to the new European regulations for pediatric medications, future clinical trials will include an increasing number of minors. It is therefore important to reconsider and evaluate recent methodological and ethical aspects of clinical trials in minors. PROCEDURE: The following questions were investigated: How are randomized controlled clinical trials (RCTs) performed in practice? Do investigators take into consideration biomedical ethical principles, explicated for example by Beauchamp and Childress, when planning and conducting a trial? The study was conducted in a descriptive manner. A systematic, algorithm-guided search focusing on RCTs in minors with malignant diseases was carried out in PubMed. One-thousand-nine-hundred-sixty-two publications from 2001 to 2005 were randomized in sequence. The first 1,000 publications were screened according to a priori defined inclusion criteria. One hundred seventy-five publications met the criteria and were reviewed using the SIGN methodological checklist (2004), the CONSORT Statement (2001, section Methods, items 3-12) and indicators for ethical aspects. Seventeen publications were checked by two raters. RESULTS: Information on randomization and blinding was often equivocal. The publications were mainly rated positive for the criteria of the SIGN checklist, and mostly rated negative for the additional items of the CONSORT Statement. Regarding the ethical principles, only few contributions were found in the publications. Inter-rater reliability was good. CONCLUSIONS: In the publications analyzed, we found only limited information concerning methods and reflections on ethical principles of the trials. Improvements are thus necessary and possible. We suggest how such trials and their respective publications can be optimized for these aspects. PMID- 21548016 TI - Cord blood iron profile and breast milk micronutrients in maternal iron deficiency anemia. AB - BACKGROUND: Micronutrient deficiencies among pregnant women are widespread in low income countries, including Egypt. Iron deficiency anemia (IDA) is the most frequent nutritional deficiency during pregnancy, with an impact on maternal and fetal morbidity and mortality. We aimed to evaluate the effect of maternal IDA and nutritional status on birth anthropometry, cord blood iron profile and breast milk micronutrients in 50 anemic (hemoglobin <11 g/dl) and 30 healthy pregnant women. PROCEDURE: Maternal and neonatal anthropometric measures were recorded. Hemoglobin, red blood cell (RBC) indices, and indices of iron nutriture were measured in maternal and cord blood. Breast milk minerals; iron, copper, zinc, calcium, and magnesium were assessed. RESULTS: Hemoglobin, RBC indices, and iron profile showed significant differences in the neonates born to anemic mothers compared to controls, particularly in moderate to severe anemia and linear correlations with maternal hemoglobin, iron, and ferritin levels were found (P < 0.01). Anthropometric measurements of anemic mothers and their neonates were positively correlated (P < 0.05). Breast milk micronutrients were significantly reduced in all anemic mothers showing significant relations with maternal serum iron (P < 0.01). CONCLUSIONS: Maternal IDA wields a significant influence on maternal and fetal nutritional status. IDA during pregnancy adversely affects both cord blood iron and breast milk mineral status, particularly in moderate to severe anemia and concurrent micronutrient deficiencies occur in maternal IDA. Further investigations including larger population of pregnant women with severe anemia are needed to verify the nutritional interrelation between maternal anemia and breast milk mineral status. PMID- 21548017 TI - Simultaneous biochemical and topographical patterning on curved surfaces using biocompatible sacrificial molds. AB - A method for the simultaneous (bio)chemical and topographical patterning of enclosed structures in poly(dimethyl siloxane) (PDMS) is presented. The simultaneous chemical and topography transference uses a water-soluble chitosan sacrificial mold to impart a predefined pattern with micrometric accuracy to a PDMS replica. The method is compared to conventional soft-lithography techniques on planar surfaces. Its functionality is demonstrated by the transference of streptavidin directly to the surface of the three-dimensional PDMS structures as well as indirectly using streptavidin-loaded latex nanoparticles. The streptavidin immobilized on the PDMS is tested for bioactivity by coupling with fluorescently labeled biotin. This proves that the streptavidin is immobilized on the PDMS surface, not in the bulk of the polymer, and is therefore accessible for use as signaling/binding element in micro and bioengineering. The use of a biocompatible polymer and processes enables the technique to be used for the chemical patterning of tissue constructions. PMID- 21548018 TI - Aligned 3D human aortic smooth muscle tissue via layer by layer technique inside microchannels with novel combination of collagen and oxidized alginate hydrogel. AB - Tissue engineering of the small diameter blood vessel medial layer has been challenging. Recreation of the circumferentially aligned multilayer smooth muscle tissue has been one of the major technical difficulties. Some research has utilized cyclic stress to align smooth muscle cells (SMCs) but due to the long time conditioning needed, it was not possible to use primary human cells because of expeditious senescence occurred . We demonstrate rapid buildup of a homogeneous relatively thick (30-40 MUm) aligned smooth muscle tissue via layer by layer (LBL) technique within microchannels and a soft cell-adhesive hydrogel. Using a microchannelled scaffold with gapped microwalls, two layers of primary human SMCs separated by an interlayer hydrogel were cultured to confluence within the microchannels. The SMCs aligned along the microchannels because of the physically constraining microwalls. A novel double layered gel consisting of a mixture of pristine and oxidized alginate hydrogel coated with collagen was designed to place between each layer of cells, leading to a thicker tissue in a shorter time. The SMCs penetrated the soft thin interlayer hydrogel within 6 days of seeding of the 2nd cell layer so that the entire construct became more or less homogeneously populated by the SMCs. The unique LBL technique applied within the micropatterned scaffold using a soft cell-adhesive gel interlayer allows rapid growth and confluence of SMCs on 2D surface but at the same time aligns the cells and builds up multiple layers into a 3D tissue. This pseudo-3D buildup method avoids the typical steric resistance of hydrogel embedding. PMID- 21548019 TI - Maternal vitamin D receptor genetic variation contributes to infant birthweight among black mothers. AB - Racial disparity in pregnancy outcomes is one of the most striking and poorly understood inequalities in American health. Genetic variability may be an important host factor influencing disparate birth outcomes between non-Hispanic black (NHB) and non-Hispanic white (NHW) women. Race-specific allelic frequencies in the vitamin D receptor (VDR) gene suggest its potential as a gene involved in health disparities. The Healthy Pregnancy, Healthy Baby Study is a prospective cohort of pregnant women aimed at identifying genetic, social, and environmental contributors to disparities in pregnancy outcomes in Durham, NC. VDR haplotype tagging single nucleotide polymorphisms (SNPs) were genotyped via Taqman assays for 615 women. Analysis of variance was used to examine the association between maternal genotype and infant birthweight. Eight of 38 SNPs examined showed nominal significance among NHB women, with one VDR SNP (rs7975232) surpassing the multiple testing significance threshold. rs7975232, an anonymous polymorphism, is part of a VDR gene haplotype associated with variation in mRNA stability. mRNA stability can affect the amount of protein produced, thus directly affecting vitamin D levels and calcium homeostasis. In contrast to NHBs, there was no association between any VDR SNP and birthweight for NHWs. Genetic factors contributing to disparities in birth outcomes are not expected to be explained entirely by variation in a single gene. Nevertheless, our results suggest that maternal VDR gene polymorphisms do influence birthweight with differential effects accruing across racial groups. Further research identifying the functionality of VDR gene polymorphisms in pregnant women will improve our understanding of the underlying mechanisms influencing birthweight. PMID- 21548020 TI - Cancer predisposition in children with Kabuki syndrome. PMID- 21548021 TI - Identification of SPRED1 deletions using RT-PCR, multiplex ligation-dependent probe amplification and quantitative PCR. AB - Legius syndrome, is a recently identified autosomal dominant disorder caused by loss of function mutations in the SPRED1 gene, with individuals mainly presenting with multiple cafe-au-lait macules (CALM), freckling and macrocephaly. So far, only SPRED1 point mutations have been identified as the cause of this syndrome. To determine if copy number changes (CNCs) are a cause of Legius syndrome, we have used a Multiplex Ligation-dependent Probe Amplification (MLPA) assay covering all SPRED1 exons in a cohort of 510 NF1-negative patients presenting with multiple CALMs with or without freckling, but no other NF1 diagnostic signs. Four different deletions were identified by MLPA and confirmed by quantitative PCR, reverse transcriptase PCR and/or array CGH: a deletion of exon 1 and the SPRED1 promoter region in a proband and two first-degree relatives; a deletion of the entire SPRED1 gene in a sporadic patient; a deletion of exon 2-6 in a proband and her father; and an ~6.6 Mb deletion on chromosome 15 that spans SPRED1 in a sporadic patient. Deletions account for ~10% of the 40 detected SPRED1 mutations in this cohort of 510 individuals. These results indicate the need for dosage analysis to complement sequencing-based SPRED1 mutation analyses. PMID- 21548022 TI - Significant liver disease in a patient with Y116H mutation in the MVK gene. PMID- 21548060 TI - Knowledge, attitude, and practices regarding whole body donation among medical professionals in a hospital in India. AB - Voluntary body donation has become an important source of cadavers for anatomical study and education. The objective of this study was to assess knowledge, attitude, and practice (KAP) regarding whole body donation among medical professionals in a medical institute in India. A cross sectional study was conducted at Kasturba Hospital, Manipal, India, among medical doctors. Data was collected from consenting individuals in the age group of 25-65 years by convenience sampling method. A semi-structured, pretested, questionnaire designed to assess KAP regarding whole body donation was provided to the study population (n = 106); 97 individuals returned the completed questionnaire. Results showed that 8% of the medical professionals were unaware of the term body donation and 85% believed that donated bodies were misused. A large proportion of the respondents did not know about the authority that oversaw body donation, or its criteria for accepting donated bodies and diseases for which bodies were screened before acceptance. Only 22% of polled physicians were willing to donate their bodies for medical education, but 68% expected the public to do the same. While only 7% had already registered their own names for body donation, 64% were not aware of any known person having registered and 72% indicated that their decision would not be influenced even if they knew of friends who had registered. These results suggest that educating medical students and professionals regarding the altruistic act of body donation is as important as educating the general public. PMID- 21548061 TI - Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. AB - Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS-MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan-like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co-occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A > G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c.1226G > C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, cafe-au-lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p.Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co-occurrence of RAS-MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis-NS phenotypes. Taken together, the results suggest that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway may contribute to the clinical variability observed among NS patients. PMID- 21548062 TI - Grafting of dermatan sulfate on polyethylene terephtalate to enhance biointegration. AB - The aim of the present study was to achieve the immobilization of dermatan sulfate (DS) on polyethylene terephthalate (PET) surfaces and to evaluate its biocompatibility. DS obtained from the skin of Scyliorhinus canicula shark was immobilized via carbodiimide on knitted PET fabrics, modified with carboxyl groups. PET-DS characterization was performed by SEM, ATR-FTIR and contact angle measurements. Biocompatibility was evaluated by investigating plasma protein adsorption and endothelial cell proliferation, as well as by subcutaneous implantations in rats. The results indicated that DS immobilization on PET was achieved at ~8 MUg/cm2. ATR-FTIR evidenced the presence of sulfate groups on the PET surface. In turn, contact angle measurements indicated an increase in the surface wettability. DS immobilization increased albumin adsorption on the PET surface, whereas it decreased that of fibrinogen. In vitro cell culture revealed that endothelial cell proliferation was also enhanced on PET-DS. Histological results after 15 days of subcutaneous implantation showed a better integration of PET-DS samples in comparison to those of nonmodified PET. In summary, DS was successfully grafted onto the surface of PET, providing it new physicochemical characteristics and biological properties for PET, thus enhancing its biointegration. PMID- 21548063 TI - Intraperitoneal adhesions--an ongoing challenge between biomedical engineering and the life sciences. AB - Peritoneal adhesions remain a relevant clinical problem despite the currently available prophylactic barrier materials. So far, the physical separation of traumatized serosa areas using barriers represents the most important clinical strategy for adhesion prevention. However, the optimal material has not yet been found. Further optimization or pharmacological functionalization of these barriers could give an innovative input for peritoneal adhesion prevention. Therefore, a more complete understanding of pathogenesis is required. On the basis of the pathophysiology of adhesion formation the main barriers currently in clinical practice as well as new innovations are discussed in the present review. Physiologically, mesothelial cells play a decisive role in providing a frictionless gliding surface on the serosa. Adhesion formation results from a cascade of events and is regulated by a variety of cellular and humoral factors. The main clinically applied strategy for adhesion prevention is based on the use of liquid or solid adhesion barriers to separate physically any denuded tissue. Both animal and human trials have not yet been able to identify the optimal barrier to prevent adhesion formation in a sustainable way. Therefore, further developments are required for effective prevention of postoperative adhesion formation. To reach this goal the combination of structural modification and pharmacological functionalization of barrier materials should be addressed. Achieving this aim requires the interaction between basic research, materials science and clinical expertise. PMID- 21548064 TI - CaSiO3 microstructure modulating the in vitro and in vivo bioactivity of poly(lactide-co-glycolide) microspheres. AB - Poly(lactide-co-glycolide) (PLGA) microspheres have been used for regenerative medicine due to their ability for drug delivery and generally good biocompatibility, but they lack adequate bioactivity for bone repair application. CaSiO3 (CS) has been proposed as a new class of material suitable for bone tissue repair due to its excellent bioactivity. In this study, we set out to incorporate CS into PLGA microspheres to investigate how the phase structure (amorphous and crystal) of CS influences the in vitro and in vivo bioactivity of the composite microspheres, with a view to the application for bone regeneration. X-ray diffraction (XRD), N2 adsorption-desorption analysis, and scanning electron microscopy (SEM) were used to analyze the phase structure, surface area/pore volume, and microstructure of amorphous CS (aCS) and crystal CS (cCS), as well as their composite microspheres. The in vitro bioactivity of aCS and cCS-PLGA microspheres was evaluated by investigating their apatite-mineralization ability in simulated body fluids (SBF) and the viability of human bone mesenchymal stem cells (BMSCs). The in vivo bioactivity was investigated by measuring their de novo bone-formation ability. The results showed that the incorporation of both aCS and cCS enhanced the in vitro and in vivo bioactivity of PLGA microspheres. cCS/PLGA microspheres improved better in vitro BMSC viability and de novo bone formation ability in vivo, compared to aCS/PLGA microspheres. Our study indicates that controlling the phase structure of CS is a promising method to modulate the bioactivity of polymer microsphere system for potential bone tissue regeneration. PMID- 21548065 TI - Degradation, cytotoxicity, and biocompatibility of NIPAAm-based thermosensitive, injectable, and bioresorbable polymer hydrogels. AB - A thermosensitive, injectable, and bioresorbable polymer hydrogel, poly(N isopropylacrylamide-co-dimethyl-gamma-butyrolactone acrylate-co-acrylic acid) [poly(NDBA)], was synthesized by radical copolymerization with 7.00 mol % dimethyl-gamma-butyrolactone acrylate in tetrahydrofuran. The chemical composition was determined by acid titration in conjunction with (1) H NMR quantification. The molecular weight and polydispersity were determined by gel permeation chromatography in conjunction with static light scattering. The degradation properties of the polymer hydrogel were characterized using differential scanning calorimetry, percentage mass loss, cloud point test, and swelling ratio over time. It was found that the initial lower critical solution temperature (LCST) of the polymer is between room temperature and body temperature and that it takes about 2 weeks for the LCST to surpass body temperature under physiological conditions. An indirect cytotoxicity test indicated that this copolymer has relatively low cytotoxicity as seen with 3T3 fibroblast cells. The in vivo-gelation and degradation study showed good agreement with in vitro-degradation findings, and no detrimental effects to adjacent tissues were observed after the complete dissolution of the polymer. (c) 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2011. PMID- 21548066 TI - Development of bioactive photocrosslinkable fibrous hydrogels. AB - Three-dimensional (3D) fibrous hydrogels were fabricated by blending two photoactive polymers, poly(ethylene glycol) diacrylate (PEGDA) and poly(vinyl alcohol) (PVA), and the resulting solution was electrospun. PEGDA is a commonly used hydrogel material for tissue engineering applications since its interaction with cells can be tuned by crosslinking in a variety of bioactive molecules including peptides and proteins. The PVA in these materials aids in fiber formation and stabilizes the fibrous network when hydrated. The average dry fiber diameter in the hydrogels was 1.02 MUm and upon swelling, the fiber diameter increased approximately six-fold. Fibers were stable under cell culture conditions for up to 5 days. The adhesive ligand, RGDS, was readily incorporated into the fibrous network via the conjugation of RGDS to PEG-monoacrylate which was then crosslinked with the fibers. The bioactivity of the fibrous hydrogels was compared with peptide-modified PEGDA-based hydrogels. The two hydrogel materials had similar cell adhesion and viability. Cell morphology on the fibrous hydrogels was dendritic showing a more in vivo like representation, as compared to spread cell morphology on the PEGDA gels. The ability to generate 3D fibrous architectures in hydrogel systems opens up new areas of investigation in cell material interactions and tissue formation. PMID- 21548067 TI - Preparation and characterization of antibacterial P2O5-CaO-Na2O-Ag2O glasses. AB - 60P2O5-20CaO-(20-x) Na2O-xAg2O and 60P2O5-30CaO-(10-x) Na2O-xAg2O glasses, x = 0, 0.5,1, and 2 mol % were prepared using normal glass melting technique. The antibacterial activity of pressed disks of powdered glass (undoped and silver doped glass) was investigated against S.aureus, P.aeruginosa, and E.coli micro organisms using agar disk-diffusion assays at 37 degrees C for 24 h. The antibacterial activity was deduced from the inhibition zone diameter (IZD), zone of no bacterial growth, measured under the stated experimental conditions. The antibacterial activity increases with the increase in IZD and vice versa. Dissolution of glass in water at 37 degrees C, pH changes of water during glass dissolution, and concentrations of silver ions released from silver-doped glasses into water during their dissolution were determined. An increase in the concentration of silver ions released from silver-doped glasses into water was observed with increasing time of glass dissolution and with increasing Ag2O content. The tested silver-free and silver-doped glasses demonstrated different antibacterial activity against the tested micro-organisms. For silver-free glasses, an increase in IZD was observed with the increase in the glass dissolution rate and with the decrease in pH of water. Also, the IZD showed an increase with increasing Ag2O content of silver-doped glasses. PMID- 21548068 TI - The ionic products of bioactive glass particle dissolution enhance periodontal ligament fibroblast osteocalcin expression and enhance early mineralized tissue development. AB - This study resulted in enhanced collagen type 1 and osteocalcin expression in human periodontal ligament fibroblasts (hPDLF) when exposed to bioactive glass conditioned media that subsequently may promote early mineralized tissue development. Commercial BioglassTM (45S5) and experimental bioactive coating glass (6P53-b), were used to make a glass conditioned media (GCM) for comparison to control medium. ICP-MS analysis showed increased concentrations of Ca(2+), PO(4) (3-), Si(4+), and Na(+), for 45S5 GCM and Mg(2+), K(+), Ca(2+), PO(4)(3-), Si(4+), and Na(+) for 6P53-b GCM (relative to control medium). Differentiating hPDLF cultures exposed to 45S5 and 6P53-b GCM showed enhanced expression of collagen type 1 (Col1alpha1, Col1alpha2), osteocalcin, and alkaline phosphatase gene expression. These GCM also enhanced osteocalcin protein expression. After 16 d of culture, 45S5 and 6P53-b GCM treated cells showed regions of deep red Alizarin staining, indicating increased Ca within their respective extracellular matrices (ECM), while control-treated cells did not exhibit these features. SEM analysis showed more developed ECM in GCM treated cultures, indicated by multiple tissue layering and abundant collagen fiber bundle formation, while control treated cells did not exhibit these features. SEM analysis showed polygonal structures suggestive of CaP in 45S5 GCM treated cultures. These results indicate the osteogenic potential of bioactive coating glass in periodontal bone defect filling applications. PMID- 21548069 TI - Synthesis of GTMAC modified chitin-PAA gel and evaluation of its biological properties. AB - The dressing prepared from GTMAC modified chitin-PAA was introduced with the aim of facilitating wound healing, particularly those effectively absorbing exudates, maintaining a moist wound environment and controlling bacterial proliferation. Chitin was chemically modified with acrylic acid to encourage a moist wound healing environment. The highly water-absorbable resulting product (chitin-PAA) was further reacted with glycidyltrimethylammonium chloride (GTMAC) to impart antibacterial activities. The final product, chitin-PAA-GTMAC was characterized by the techniques of Fourier Transform Infrared (FTIR), solid state (15) N NMR, and elemental analysis. Their cytotoxicity and antibacterial activities against S. epidermidis and E. coli were evaluated which found increasing effects in those properties with increasing degree substitution of GTMAC. All materials also showed good blood-clotting ability. The collagen gel contraction assay was used to analyze the behavior of fibroblasts after contact with the gels. The extent of the gel contraction as well as the examination of the secreted interleukin-8 (IL 8) and transforming growth factor-beta1 (TGF-beta1) were investigated. The results showed that chitin-PAA modified with GTMAC could stimulate the production of IL-8, but TGF-beta1. Fibroblasts presented normal spreading and formation of cellular processes in the collagen gels with all of the modifications. Furthermore, all modified gels except for the highest GTMAC content gel [chitin PAA-GTMAC (1:20)] were found a greater extent in gel contraction than the unmodified chitin-PAA. It suggested the promoting effect of GTMAC on cell proliferation if the GTMAC content in the gel was not too high, that is, the mole ratio of glucosamine to GTMAC of the gel should not greater than 1:10. PMID- 21548070 TI - Molecular plasma deposited peptides on anodized nanotubular titanium: an osteoblast density study. AB - A large amount of work is currently being conducted to design, fabricate, and characterize materials coated or immobilized with bioactive molecules for tissue engineering applications. Here, a novel method, molecular plasma deposition (MPD), is introduced with can efficiently coat materials with numerous bioactive peptides. Specifically, here, RGDS (arginine-glycine-aspartic acid-serine), KRSR (lysine-arginine-serine-arginine), and IKVAV (isoleucine-lysine-valine-alanine valine) were coated on anodized nanotubular titanium using MPD. The anodized nanotubular titanium surfaces were characterized using scanning electron microscopy (SEM), atomic force microscopy (AFM), and water contact angle measurements. Peptide coatings were examined by X-ray photoelectron spectroscopy (XPS) and an amine reactive fluorescence molecule, 3-(4 carboxybenzoyl)quinoline 2-carboxaldehyde (CBQCA). Electrospray ionization (ESI) was used to confirm peptide integrity. Osteoblast (bone-forming cell) density was determined on the materials of interest. Results confirmed peptide coatings and showed that the MPD RGDS and KRSR coatings on anodized nanotubular titanium increased osteoblast density compared with uncoated substrates and those coated with IKVAV and a control peptide (RGES) after 4 h and 7 days. SEM confirmed differences in the morphology of the attached cells. These results, to the best of our knowledge, are the first reports using MPD to efficiently create peptide coatings to increase osteoblast density on metals commonly used in orthopedics. Since MPD represents a quick, inexpensive, and versatile technique to coat implants with peptides, it should be further studied for numerous implant applications. PMID- 21548071 TI - In situ forming poly(ethylene glycol)-based hydrogels via thiol-maleimide Michael type addition. AB - The incorporation of cells and sensitive compounds can be better facilitated without the presence of UV or other energy sources that are common in the formation of biomedical hydrogels such as poly(ethylene glycol) hydrogels. The formation of hydrogels by the step-growth polymerization of maleimide- and thiol terminated poly(ethylene glycol) macromers via Michael-type addition is described. The effects of macromer concentration, pH, temperature, and the presence of biomolecule gelatin on gel formation were investigated. Reaction kinetics between maleimide and thiol functional groups were found to be rapid. Molecular weight increase over time was characterized via gel permeation chromatography during step-growth polymerization. Swelling and degradation results showed incorporating gelatin enhanced swelling and accelerated degradation. Increasing gelatin content resulted in the decreased storage modulus (G'). The in vitro release kinetics of fluorescein isothiocyanate (FITC)-labeled dextran from the resulting matrices demonstrated the potential in the development of novel in situ gel-forming drug delivery systems. Moreover, the resulting networks were minimally adhesive to primary human monocytes, fibroblasts, and keratinocytes thus providing an ideal platform for further biofunctionalizations to direct specific biological response. PMID- 21548072 TI - Light microscopic description of the effects of laser phototherapy on bone defects grafted with mineral trioxide aggregate, bone morphogenetic proteins, and guided bone regeneration in a rodent model. AB - We carried out a histological analysis on bone defects grafted with mineral trioxide aggregate (MTA) treated or not with laser, bone morphogenetic protein (BMP), and guided bone regeneration (GBR). Benefits of the use of MTA, laser, BMPs, and GBR on bone repair are well known, but there is no report on their association with laser light. Ninety rats were divided into 10 groups each subdivided into 3. Defects on G II and I were filled with the blood clot. G II was further irradiated with LED. G III and IV were filled with MTA; G IV was further irradiated with laser. G V and VI, the defects filled with MTA and covered with a membrane (GBR). G VI was further irradiated with laser. G VII and VIII, BMPs were added to the MTA and group VIII further irradiated with laser. G IX and X, the MTA + BMP graft was covered with a membrane (GBR). G X was further irradiated with laser. Laser light (lambda = 850 nm, 150 mW, 4 J/cm(2) ) was applied over the defect at 48-h intervals and repeated for 15 days. Specimens were processed, cut and stained with H&E and Sirius red and underwent histological analysis. Subjects on group X were irradiated. The results showed different tissue response on all groups during the experimental time. Major changes were seen on irradiated subjects and included marked deposition of new bone in advanced maturation. It is concluded that near infrared laser phototherapy improved the results of the use of the MTA on bone defects. PMID- 21548073 TI - The cytotoxicity assessment of the novel latex urinary catheter with prolonged antimicrobial activity. AB - The purpose of this study was to evaluate the in vitro biocompatibility of the novel Sparfoxacin (SPA)-treated latex catheter with previously performed prolonged antimicrobial activity. Rectangular-shaped test samples of silicone latex catheter were fabricated according to patented procedure permitting the immobilization of SPA on heparin (HP)-coated catheter by means of mixed, covalent and non-covalent bonds. Samples subjected to cytotoxicity assay were divided into four groups: (1) the untreated catheter, (2) HP-coated catheter, (3) HP-coated catheter with SPA immobilized in low SPA concentration solution (SPA-L treated sample), and (4) high SPA concentration solution (SPA-H treated sample). Then the samples were placed directly into green monkey kidney (GMK) cell monolayer for 24 h. After the incubation period, cytotoxicity was determined by 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The degree of cytotoxicity of each sample was evaluated according to the reference value represented by the control cells cultured without catheter sample. Statistical significance was determined by repeated t-test (P < 0.05). The cytotoxic effect of treated and untreated catheters was also estimated by microscopic observations of GMK cells morphological changes. SPA-treated catheters demonstrated high survival rates in MTT assay (>93%) on the contrary to the untreated catheters (6.13%) and HP-coated catheters (80.90%). Moreover, microscopic observation of GMK cells exposed to SPA-treated samples revealed no morphological changes and no cell growth reduction. We suggest that SPA-treated latex catheters are biofilm formation resistant (as we revealed in our previous work), considerably less toxic than untreated ones, and can be undoubtedly used in urological practice. PMID- 21548076 TI - Modular phenotypic plasticity: divergent responses of barnacle penis and feeding leg form to variation in density and wave-exposure. AB - Traits can evolve both in response to direct selection and in response to indirect selection on other linked traits. Although the evolutionary significance of coupled traits (e.g., through shared components of developmental pathways, or through competition for shared developmental resources) is now well accepted, we know comparatively little about how developmental coupling may restrict the independent responses of two or more phenotypically plastic traits in response to conflicting environmental cues. Such studies are important because coupled development, if present, could act as an important limit to the evolution of functionally independent plasticity in multiple traits. I tested whether developmental coupling can restrict the direction of plastic responses by studying how penis form and leg form--both highly plastic traits of barnacles- varied in response to differences in conspecific density and water velocity. Penis length and leg length in Balanus glandula varied in parallel with variation in wave-exposure but varied in opposite directions with variation in conspecific density. This study represents one of the rare tests of developmental coupling between multiple (demonstrably adaptive) plastic traits: Barnacle legs and penises appear to exhibit modular development that can respond concurrently--yet in independent directions--to conflicting environmental cues. PMID- 21548077 TI - Telomerase deficiency in a colonial ascidian after prolonged asexual propagation. AB - In organisms that propagate by agametic cloning, the parental body is the reproductive unit and fitness increases with clonal size, so that colonial metazoans, despite lack of experimental data, have been considered potentially immortal. Using asexual propagation rate as a measure of somatic performance, and telomerase activity and relative telomere length as molecular markers of senescence, old (7-12 years) asexual strains of a colonial ascidian, Diplosoma listerianum, were compared with their recent sexually produced progeny. We report for the first time evidence for long-term molecular senescence in asexual lineages of a metazoan, and that only passage between sexual generations provides total rejuvenation permitting indefinite propagation and growth. Thus, this colonial ascidian has not fully escaped ageing. The possibility of somatic replicative senescence also potentially helps to explain why metazoans, with the capacity for asexual propagation through agametic cloning, commonly undergo cycles of sexual reproduction in the wild. PMID- 21548078 TI - Wormometry-on-a-chip: Innovative technologies for in situ analysis of small multicellular organisms. AB - Small multicellular organisms such as nematodes, fruit flies, clawed frogs, and zebrafish are emerging models for an increasing number of biomedical and environmental studies. They offer substantial advantages over cell lines and isolated tissues, providing analysis under normal physiological milieu of the whole organism. Many bioassays performed on these alternative animal models mirror with a high level of accuracy those performed on inherently low throughput, costly, and ethically controversial mammalian models of human disease. Analysis of small model organisms in a high-throughput and high-content manner is, however, still a challenging task not easily susceptible to laboratory automation. In this context, recent advances in photonics, electronics, as well as material sciences have facilitated the emergence of miniaturized bioanalytical systems collectively known as Lab-on-a-Chip (LOC). These technologies combine micro- and nanoscale sciences, allowing the application of laminar fluid flow at ultralow volumes in spatially confined chip-based circuitry. LOC technologies are particularly advantageous for the development of a wide array of automated functionalities. The present work outlines the development of innovative miniaturized chip-based devices for the in situ analysis of small model organisms. We also introduce a new term "wormometry" to collectively distinguish these up-and-coming chip-based technologies that go far beyond the conventional meaning of the term "cytometry." PMID- 21548079 TI - Optimal reprogramming factor stoichiometry increases colony numbers and affects molecular characteristics of murine induced pluripotent stem cells. AB - Somatic cells can be reprogrammed toward pluripotency by overexpression of a set of transcription factors, yielding induced pluripotent stem cells (iPSCs) with features similar to embryonic stem cells. Little is known to date about stoichiometric requirements of the individual reprogramming factors (RFs) for efficient reprogramming and especially about whether stoichiometry also influences the quality of derived iPSCs. To address this important issue, we chose bicistronic lentiviral vectors coexpressing fluorescent reporters (eGFP, dTomato, Cerulean, or Venus) along with the canonical RFs to transduce a bulk of murine embryonic fibroblasts (MEFs). Using a flow cytometric approach, we were able to independently and proportionally quantify all fluorophores in multiple infected MEFs and more importantly could sort these cells into all 16 stoichiometric combinations of high or moderate expression of the four factors. On average, we obtained about 600 alkaline phosphatase-expressing colonies from 20,000 seeded cells. Interestingly, only seven different stoichiometric ratios gave rise to any colonies at all. The by far most colonies were obtained from those fractions, where Oct4 was in excess over the other three factors (2,386 colonies/20,000 cells), or where both Oct4 and c-Myc were in excess over Sox2 and Klf4 (1,593 colonies/20,000 cells). Our findings suggest that increased Oct4 levels opposite to modest ones for Sox2 and Klf4 are required for satisfying reprogramming efficiencies and that these stoichiometries are also highly beneficial for achieving a stable pluripotent state independent of ectopic RF expression. Finally, the eligible Oct4(high) , Sox2(low) , and Klf4(low) subpopulation only resembles a small fraction of cells targeted by equal vector amounts, suggesting the necessity to address stoichiometry also in alternative approaches for iPSC generation or between different experimental systems. PMID- 21548080 TI - Polarized light-scattering profile-advanced characterization of nonspherical particles with scanning flow cytometry. AB - We instrumentally, theoretically, and experimentally demonstrate a new approach for characterization of nonspherical individual particles from light scattering. Unlike the original optical scheme of the scanning flow cytometer that measures an angle-resolved scattering corresponding in general to S11 element of the light scattering matrix, the modernized instrument allows us to measure the polarized light-scattering profile of individual particles simultaneously. Theoretically, the polarized profile is expressed by the combination of a few light-scattering matrix elements. This approach supports us with additional independent data to characterize a particle with a complex shape and an internal structure. Applicability of the new method was demonstrated from analysis of polymer bispheres. The bisphere characteristics, sizes, and refractive indices of each sphere composing the bisphere were successfully retrieved from the solution of the inverse light-scattering problem. The solution provides determination of the Eulerian angles, which describe the orientation of the bispheres relative to the direction of the incident laser beam and detecting polarizer of the optical system. Both the ordinary and polarized profiles show a perfect agreement with T matrix simulation resulting to 50-nm precision for sizing of bispheres. PMID- 21548083 TI - Electronic interactions between "pea" and "pod": the case of oligothiophenes encapsulated in carbon nanotubes. AB - One of the most challenging strategies to achieve tunable nanophotonic devices is to build robust nanohybrids with variable emission in the visible spectral range, while keeping the merits of pristine single-walled carbon nanotubes (SWNTs). This goal is realized by filling SWNTs ("pods") with a series of oligothiophene molecules ("peas"). The physical properties of these peapods are depicted by using aberration-corrected high-resolution transmission electron microscopy, Raman spectroscopy, and other optical methods including steady-state and time resolved measurements. Visible photoluminescence with quantum yields up to 30% is observed for all the hybrids. The underlying electronic structure is investigated by density functional theory calculations for a series of peapods with different molecular lengths and tube diameters, which demonstrate that van der Waals interactions are the bonding mechanism between the encapsulated molecule and the tube. PMID- 21548084 TI - Ultrasensitive determination of cysteine based on the photocurrent of nafion functionalized CdS-MV quantum dots on an ITO electrode. PMID- 21548085 TI - Magnetic mixed hemimicelles solid-phase extraction of xanthohumol in beer coupled with high-performance liquid chromatography determination. AB - In this study, silica-coated magnetic nanoparticles (Fe(3)O(4)/SiO(2) NPs) modified by cetyltrimethylammonium bromide (CTAB) were synthesized. They were successfully applied for extraction of xanthohumol in beer based on magnetic mixed hemimicelles solid-phase extraction (MMHSPE) coupled with high-performance liquid chromatography-ultraviolet determination. The main factors influencing the extraction efficiency including the surfactant amount, the beer pH, the extraction time, the desorption condition and the maximum extraction beer volume were optimized. Under the optimized conditions, a concentration factor of 60 was achieved by extracting 120 mL beer sample using MMHSPE and the detection limit of xanthohumol is 0.0006 mg/L. The proposed method was successfully applied for determination of xanthohumol in various beer samples with the xanthohumol contents in the range of 0.031-0.567 mg/L. The satisfactory recoveries (90-103%) were obtained in analyzing spiked beer samples. PMID- 21548086 TI - Development of a new stir bar sorptive extraction coating and its application for the determination of six pesticides in sugarcane juice. AB - In this article, a novel polydimethylsiloxane/activated carbon (PDMS-ACB) material is proposed as a new polymeric phase for stir bar sorptive extraction (SBSE). The PDMS-ACB stir bar, assembled using a simple Teflon((r))/glass capillary mold, demonstrated remarkable stability and resistance to organic solvents for more than 150 extractions. The SBSE bar has a diameter of 2.36 mm and a length of 2.2 cm and is prepared to contain 92 MUL of polymer coating. This new PDMS-ACB bar was evaluated for its ability to determine the quantity of pesticides in sugarcane juice samples by performing liquid desorption (LD) in 200 MUL of ethyl acetate and analyzing the solvent through gas chromatography coupled with mass spectrometry (GC-MS). A fractional factorial design was used to evaluate the main parameters involved in the extraction procedure. Then, a central composite design with a star configuration was used to optimize the significant extraction parameters. The method used demonstrated a limit of quantification (LOQ) of 0.5-40 MUg/L, depending on the analyte detected; the amount of recovery varied from 0.18 to 49.50%, and the intraday precision ranged from 0.072 to 8.40%. The method was used in the analysis of real sugarcane juice samples commercially available in local markets. PMID- 21548087 TI - Preparation and characterization of silica monolith modified with bovine serum albumin-gold nanoparticles conjugates and its use as chiral stationary phases for capillary electrochromatography. AB - This paper describes the development of silica monolith modified with bovine serum albumin-gold nanoparticles (BSA-GNPs) conjugates as chiral stationary phases for capillary electrochromatography (CEC). The bare monolithic silica column was prepared by a sol-gel process and has been modified chemically with 3 mercaptopropyltrimethoxysilane to provide thiol groups, followed by immobilization of gold nanoparticles via the formation of an Au-S bond and modification with BSA as the chiral selector via the nitrogen lone pair of electrons. It has been demonstrated that the monolithic chiral stationary phases can be used for the enantioseparation of a number of phenylthiocarbamyl amino acids (PTC-D/L-AAs) by CEC. Ten pairs of tested amino acids enantiomers were successfully resolved within 18 min under optimized conditions, and the resolution values were in the range of 1.486-2.083. With PTC-D/L-tryptophan used as the probe solute, the influences of applied voltage, organic modifier and buffer pH in mobile phase on apparent retention factor, enantioselectivity and resolution factor were also investigated. PMID- 21548088 TI - Liquid chromatographic method for enantiopurity control of alaptide using polysaccharide stationary phases. AB - Separation of veterinary drug alaptide ((S)-8-methyl-6,9-diazaspiro(4,5)decane 7,10-dione) from a chiral impurity (R-enantiomer) was developed. Five chiral columns (three amylose and two cellulose type) were evaluated in a reversed-phase system. Three of them offered satisfactory enantiomeric resolution. Finally, three methods were validated and proved to be applicable for the determination of a chiral impurity content below 0.1% (method A: 3-AmyCoat column, tris-[3,5 dimethylphenyl]carbamoyl amylose; mobile phase: water/methanol/propan-2-ol/butan 2-ol=75:20:3.5:1.5 v/v, flow rate: 0.40 mL/min; column temperature: 30 degrees C; method B: Chiralpak AS-3R, tris-[1-phenylethyl]carbamoyl amylose; water/acetonitrile=80:20 v/v, 0.40 mL/min; 40 degrees C; method C: Chiralcel OZ 3R, tris-[3-chloro-4-methylphenyl] carbamoyl cellulose; water/acetonitrile=80:20 v/v, 0.40 mL/min; 40 degrees C). Some decrease in efficiency with repeated sample injections was observed for the 3-AmyCoat column. The resistance to mass transfer in the stationary phase increased probably due to the change in chiral selector conformation. This effect was considerably suppressed by propan-2-ol or to a greater extent by butan-2-ol added to a mobile phase. Simple regeneration was also suggested to recover efficiency of the column. PMID- 21548089 TI - Biomarker discovery and proteomic evaluation of cadmium toxicity on a collembolan species, Paronychiurus kimi (Lee). AB - The goal of this study was to identify promising new biomarkers of cadmium by identifying differentially expressed proteins in Paronychiurus kimi after exposure to cadmium. Through proteomic analysis of P. kimi using 1-D PAGE and nano-LC-MS/MS, 36 downregulated proteins and 40 upregulated proteins were found. Some of the downregulated and upregulated proteins were verified by LC-MS/MS analysis after 2-D PAGE. Downregulated proteins in response to cadmium exposure were involved in glycolysis and energy metabolism, chaperones, transcription, reproduction, and neuron growth. In contrast, proteins involved in glycolysis and energy production, neurogenesis, defense systems response to bacteria, and protein biosynthesis were upregulated in cadmium-treated collembolans. Cubulin may be a potential biomarker for the detection of cadmium in P. kimi since this biomarker was able to low levels (3.5 mg/kg) of cadmium. The 14-3-3 zeta was also found to be a potential biomarker for the detection of medium levels (14 mg/kg) of cadmium. Collembolans may be an alternative tool to humans because many collembolans proteins show a high homology to human proteins. PMID- 21548090 TI - Proteomic technologies for the identification of disease biomarkers in serum: advances and challenges ahead. AB - Serum is an ideal biological sample that contains an archive of information due to the presence of a variety of proteins released by diseased tissue, and serum proteomics has gained considerable interest for the disease biomarker discovery. Easy accessibility and rapid protein changes in response to disease pathogenesis makes serum an attractive sample for clinical research. Despite these advantages, the analysis of serum proteome is very challenging due to the wide dynamic range of proteins, difficulty in finding low-abundance target analytes due to the presence of high-abundance serum proteins, high levels of salts and other interfering compounds, variations among individuals and paucity of reproducibility. Sample preparation introduces pre-analytical variations and poses major challenges to analyze the serum proteome. The label-free detection techniques such as surface plasmon resonance, microcantilever, few nanotechniques and different resonators are rapidly emerging for the analysis of serum proteome and they have exhibited potential to overcome few limitations of the conventional techniques. In this article, we will discuss the current status of serum proteome analysis for the biomarker discovery and address key technological advancements, with a focus on challenges and amenable solutions. PMID- 21548091 TI - Proteomic characterization of a selenium-metabolizing probiotic Lactobacillus reuteri Lb2 BM for nutraceutical applications. AB - Selenium (Se), Se-cysteines and selenoproteins have received growing interest in the nutritional field as redox-balance modulating agents. The aim of this study was to establish the Se-concentrating and Se-metabolizing capabilities of the probiotic Lactobacillus reuteri Lb2 BM, for nutraceutical applications. A comparative proteomic approach was employed to study the bacteria grown in a control condition (MRS modified medium) and in a stimulated condition (4.38 mg/L of sodium selenite). The total protein extract was separated into two pI ranges: 4-7 and 6-11; the 25 identified proteins were divided into five functional classes: (i) Se metabolism; (ii) energy metabolism; (iii) stress/adhesion; (iv) cell shape and transport; (v) proteins involved in other functions. All the experimental results indicate that L. reuteri Lb2 BM is able to metabolize Se(IV), incorporating it into selenoproteins, through the action of a selenocysteine lyase, thus enhancing organic Se bioavailability. This involves endo-ergonic reactions balanced by an increase of substrate-level phosphorylation, chiefly through lactic fermentation. Nevertheless, when L. reuteri was grown on Se a certain degree of stress was observed, and this has to be taken into account for future applicative purposes. The proteomic approach has proven to be a powerful tool for the metabolic characterization of potential Se concentrating probiotics. PMID- 21548092 TI - Minimising iTRAQ ratio compression through understanding LC-MS elution dependence and high-resolution HILIC fractionation. AB - Application of iTRAQ-based workflows for protein profiling has become widespread. Concomitantly, the idiosyncratic limitations of iTRAQ, such as its tendency to underestimate quantifications, have been studied and recognised. This report shows that the influence of ratio compression and limiting transmission in iTRAQ MS/MS in high-complexity mixtures (iTRAQ-labelled lysates) can be partly alleviated using high-resolution sample fractionation. Here, we also investigate in greater detail the dependency of iTRAQ quantification on the dynamics of online chromatography in low-complexity mixtures (iTRAQ-labelled standards). These findings will allow more efficient strategies to be designed for iTRAQ proteomics, alleviating iTRAQ underestimation and thus facilitating the detection of subtle abundance changes. PMID- 21548093 TI - How microbial proteomics got started. AB - Publication in 1975 by Patrick O'Farrell of a procedure to separate the proteins of Escherichia coli in a two-dimensional array on polyacrylamide gels marked the birth of the field now called proteomics. Although O'Farrell's contribution was soon to have wide ranging effects on research in many fields, the initial impact was greatest in the arena of whole cell physiology. Refinements and amplification of the original procedure, including improved standardization and reproducibility of gel patterns, introduction of techniques to measure the quantity of protein in individual spots, and biochemical identification of the protein spots, afforded investigators the ability to explore for the first time the integrated working of control circuits in the living cell. From O'Farrell's contribution has grown the rich array of techniques currently employed and still being developed in the diverse field of microbial proteomics. PMID- 21548094 TI - Mining quorum sensing regulated proteins - Role of bacterial cell-to-cell communication in global gene regulation as assessed by proteomics. AB - Many bacteria utilize cell-to-cell communication systems that rely on small diffusible signal molecules to monitor the size of their population in a process known as quorum sensing (QS). QS plays a central role in coordinating genes that are generally mediating prokaryotic interactions with its eukaryotic host. In pathogens, this form of gene regulation is, for instance, believed to ensure that the cells remain invisible to the immune system until the pathogen has reached a critical population density sufficient to overwhelm host defenses and to establish an infection. This review summarizes proteome analyses to identify QS regulated proteins focussing on Gram-negative bacteria interacting with their eukaryotic hosts either as symbionts or as pathogens. In most studies, the power of comparative 2-D PAGE coupled to MS analysis has been employed to recognize and identify QS-controlled proteins. The high number of QS-regulated proteins in the majority of the investigated species strongly supports the importance of QS as global regulatory system and suggests that it also operates via post transcriptional mechanisms. As QS has been proven to be a central regulator for the expression of pathogenic traits and biofilm formation in various opportunistic pathogens, it represents a highly attractive target for the development of novel antibacterial drugs. Proteomics has also been exploited to validate the target specificity of natural and synthetic QS inhibitors that have a great potential as alternative therapeutics for the treatment of bacterial infections. PMID- 21548095 TI - Bacterial adaptation to life in association with plants - A proteomic perspective from culture to in situ conditions. AB - Diverse bacterial taxa that live in association with plants affect plant health and development. This is most evident for those bacteria that undergo a symbiotic association with plants or infect the plants as pathogens. Proteome analyses have contributed significantly toward a deeper understanding of the molecular mechanisms underlying the development of these associations. They were applied to obtain a general overview of the protein composition of these bacteria, but more so to study effects of plant signaling molecules on the cytosolic proteome composition or metabolic adaptations upon plant colonization. Proteomic analyses are particularly useful for the identification of secreted proteins, which are indispensable to manipulate a host plant. Recent advances in the field of proteome analyses have initiated a new research area, the analysis of more complex microbial communities. Such studies are just at their beginning but hold great potential for the future to elucidate not only the interactions between bacteria and their host plants, but also of bacteria-bacteria interactions between different bacterial taxa when living in association with plants. These include not only the symbiotic and pathogenic bacteria, but also the commensal bacteria that are consistently found in association with plants and whose functions remain currently largely uncovered. PMID- 21548096 TI - A systematic analysis of the effects of increasing degrees of serum immunodepletion in terms of depth of coverage and other key aspects in top-down and bottom-up proteomic analyses. AB - Immunodepletion of clinical fluids to overcome the dominance by a few very abundant proteins has been explored but studies are few, commonly examining only limited aspects with one analytical platform. We have systematically compared immunodepletion of 6, 14, or 20 proteins using serum from renal transplant patients, analysing reproducibility, depth of coverage, efficiency, and specificity using 2-D DIGE ('top-down') and LC-MS/MS ('bottom-up'). A progressive increase in protein number (>=2 unique peptides) was found from 159 in unfractionated serum to 301 following 20 protein depletion using a relatively high-throughput 1-D-LC-MS/MS approach, including known biomarkers and moderate lower abundance proteins such as NGAL and cytokine/growth factor receptors. On the contrary, readout by 2-D DIGE demonstrated good reproducibility of immunodepletion, but additional proteins seen tended to be isoforms of existing proteins. Depletion of 14 or 20 proteins followed by LC-MS/MS showed excellent reproducibility of proteins detected and a significant overlap between columns. Using label-free analysis, greater run-to-run variability was seen with the Prot20 column compared with the MARS14 column (median %CVs of 30.9 versus 18.2%, respectively) and a corresponding wider precision profile for the Prot20. These results illustrate the potential of immunodepletion followed by 1-D nano-LC-LTQ Orbitrap Velos analysis in a moderate through-put biomarker discovery process. PMID- 21548097 TI - Identification of a novel protein isoform derived from cancer-related splicing variants using combined analysis of transcriptome and proteome. AB - Splicing variation enhances proteome diversity and modulates cancer-associated proteins. Thus, the identification of alternative splice forms is significant for discovery of new cancer-related biomarkers. However, relatively few screening approaches of alternative splicing via proteomics have been reported. In the present study, we describe a combined analysis with proteome and transcriptome to simultaneously identify cancer-related splicing variants and splicing variant derived protein fragments that are differentially expressed in a highly metastatic gastric cancer cell line MKN45P versus its parental cell line MKN45. We found three potential alternative-spliced genes using MS-based shotgun method and two different microarray platforms. Among them, aldolase C, fructose bisphosphate (ALDOC) was predicted to have novel alternative splice forms. We successfully identified and validated novel splice forms of ALDOC gene by RT-PCR and DNA sequencing analyses, the expression level of which were higher in MKN45P than in MKN45. Furthermore, the protein fragment derived from the validated splicing variant was identified using custom-built data set including sequences of ALDOC variants in MS/MS analysis. Our combined analysis will be a promising technique for screening of cancer-related splicing variants and their protein isoforms. PMID- 21548098 TI - Fully automatable two-dimensional reversed-phase capillary liquid chromatography with online tandem mass spectrometry for shotgun proteomics. AB - Herein, we describe the development of a fully automatable technology that features online coupling of high-pH RP separation with conventional low-pH RP separation in a two-dimensional capillary liquid chromatography (2-D LC) system for shotgun proteomics analyses. The complete analysis comprises 13 separation cycles, each involving transfer of the eluate from the first-dimension, high-pH RP separation onto the second RP dimension for further separation. The solvent strength increases across the 13 fractions (cycles) to elute all peptides for further resolution on the second-dimension, low-pH RP separation, each under identical gradient-elution conditions. The total run time per analysis is 52 h. In triplicate analyses of a lysate of mouse embryonic fibroblasts, we used this technology to identify 2431 non-redundant proteins, of which 50% were observed in all three replicates. A comparison of RP-RP 2-D LC and strong cation exchange-RP 2-D LC analyses reveals that the two technologies identify primarily different peptides, thereby underscoring the differences in their separation chemistries. PMID- 21548099 TI - Structure-activity studies of RFamide peptides reveal subtype-selective activation of neuropeptide FF1 and FF2 receptors. AB - Selectivity is a major issue in closely related multiligand/multireceptor systems. In this study we investigated the RFamide systems of hNPFF1R and hNPFF2R that bind the endogenous peptide hormones NPFF, NPAF, NPVF, and NPSF. By use of a systematic approach, we characterized the role of the C-terminal dipeptide with respect to agonistic properties using synthesized [Xaa 7]NPFF and [Xaa 8]NPFF analogues. We were able to identify only slight differences in potency upon changing the position of Arg 7, as all modifications resulted in identical behavior at the NPFF1R and NPFF2R. However, the C-terminal Phe 8 was able to be replaced by Trp or His with only a minor loss in potency at the NPFF2R relative to the NPFF1R. Analogues with shorter side chains, such as alpha-amino-4 guanidino butyric acid ([Agb 7]NPFF) or phenylglycine ([Phg 8]NPFF), decreased efficacy for the NPFF1 R to 25-31 % of the maximal response, suggesting that these agonist-receptor complexes are more susceptible to structural modifications. In contrast, mutations to the conserved Asp 6.59 residue in the third extracellular loop of both receptors revealed a higher sensitivity toward the hNPFF2R receptor than toward hNPFF1R. These data provide new insight into the subtype-specific agonistic activation of the NPFF1 and NPFF(2) receptors that are necessary for the development of selective agonists. PMID- 21548100 TI - Enzyme-responsive multifunctional magnetic nanoparticles for tumor intracellular drug delivery and imaging. AB - Enzyme-responsive, hybrid, magnetic silica nanoparticles have been employed for multifunctional applications in selective drug delivery and intracellular tumor imaging. In this study, doxorubicin (Dox)-conjugated, enzyme-cleavable peptide precursors were covalently tethered onto the surface of uniform silica-coated magnetic nanoparticles through click chemistry. This enzyme-responsive nanoparticle conjugate demonstrated highly efficient Dox release upon specific enzyme interactions in vitro. It also exhibits multiple functions in selective tumor intracellular drug delivery and imaging in the tumor cells with high cathepsin B expression, whereas it exhibited lower cytotoxicity towards other cells without enzyme expression. PMID- 21548101 TI - Biphenomycin B and derivatives: total synthesis and translation inhibition. AB - A full account on the synthesis of the antibiotic natural product biphenomycin B and several derivatives is reported, which employs a Suzuki coupling reaction of a free carboxylic acid and macrolactam formation as key transformations. Liberal exchange of the central amino acid was demonstrated. This procedure gave derivatives to study the influence of the polar side chain of the central amino acids on translation inhibition. PMID- 21548102 TI - Physical chemistry of biological interfaces: generic and specific roles of soft interlayers. AB - Nature defines the spatial boundaries between different phases using membranes, and the interfacial interactions are mediated by soft biopolymer interlayers that contain various carbohydrates. This Review provides a comprehensive overview on the interplay of generic and specific interactions at cell-cell and cell-tissue interfaces. A focus will be put on the combination of defined model systems, experimental techniques in real- and reciprocal space, and theoretical simulations. PMID- 21548103 TI - Platinum-catalyzed synthesis of beta-keto tetrahydropyrans and cyclic dienolethers. PMID- 21548104 TI - Optical diagnostic test of stress conditions of aquatic organisms. AB - Global climate change has become a dire reality and its impact is expected to rise dramatically in the near future. Combined with the day-to-day human activities the climatic changes heavily affect the environment. In particular, a global temperature increase accompanied by a number of anthropogenic chemicals falling within the freshwater ecosystem results in a dramatic enhancement of the overall stress for most aquatic organisms. This leads to a significant shift in the species inventory and potential breakdown of the water ecosystem with severe consequences for local economies and water supply. In order to understand and predict the influence of climatic changes on the physiological and biochemical processes that take place in living aquatic organisms we explore the application of optical spectroscopy for monitoring and quantitative assessment of antioxidant enzymes activity in benthic amphipods of Lake Baikal. We demonstrate that the changes of the enzymes activity in Baikal amphipods undergoing thermal and/or hypoxia stress can be observed and documented by UV and optical spectroscopy both in vivo and in vitro. PMID- 21548105 TI - Amine-tethered solid adsorbents coupling high adsorption capacity and regenerability for CO2 capture from ambient air. AB - Silica supported poly(ethyleneimine) (PEI) materials are prepared via impregnation and demonstrated to be promising adsorbents for CO(2) capture from ultra-dilute gas streams such as ambient air. A prototypical class 1 adsorbent, containing 45 wt% PEI (PEI/silica), and two new modified PEI-based aminosilica adsorbents, derived from PEI modified with 3-aminopropyltrimethoxysilane (A PEI/silica) or tetraethyl orthotitanate (T-PEI/silica), are prepared and characterized by using thermogravimetric analysis and FTIR spectroscopy. The modifiers are shown to enhance the thermal stability of the polymer-oxide composites, leading to higher PEI decomposition temperatures. The modified adsorbents present extremely high CO(2) adsorption capacities under conditions simulating ambient air (400 ppm CO(2) in inert gas), exceeding 2 mol(CO (2)) kg(sorbent)(-1), as well as enhanced adsorption kinetics compared to conventional class 1 sorbents. The new adsorbents show excellent stability in cyclic adsorption-desorption operations, even under dry conditions in which aminosilica adsorbents are known to lose capacity due to urea formation. Thus, the adsorbents of this type can be considered promising materials for the direct capture of CO(2) from ultra-dilute gas streams such as ambient air. PMID- 21548106 TI - Product distribution from the fast pyrolysis of hemicellulose. AB - Hemicellulose is one of the major constituents of biomass. Surprisingly, only very limited information regarding its product distribution under fast pyrolysis conditions is available in the literature. In the present study, a combination of several analytical techniques, including micro-pyrolyzer-GC-MS/FID, gas analysis, and capillary electrophoresis, were used to study the primary pyrolysis product distribution of hemicelluloses extracted and purified from switchgrass. A total of 16 products were identified and quantified, which accounted for 85% of the overall mass balance. The pyrolysis behavior of hemicellulose was found to be considerably different than cellulose and was explained on the basis of a proposed mechanism for glycosidic bond cleavage. Further, the effect of minerals and temperature was investigated. The study provides insight into the fast pyrolysis behavior of hemicellulose and provides a basis for developing models that can predict bio-oil composition resulting from overall biomass fast pyrolysis. PMID- 21548107 TI - Isohexide derivatives from renewable resources as chiral building blocks. PMID- 21548110 TI - Reordering histology to enhance engagement. PMID- 21548109 TI - Identification of serum protein markers for breast cancer relapse with SELDI-TOF MS. AB - Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to screen serum samples to identify protein markers for early breast cancer relapse. We collected 67 serum samples from patients with breast cancer (24 preoperative; 23 postoperative without breast cancer relapse; 20 postoperative with breast cancer relapse). Eight protein peaks varied between the presurgical group and the postsurgical group without breast cancer relapse; 4 protein peaks were differentially expressed between the postsurgical patients without relapse and patients with relapse. The peak at 3964 m/z dropped after surgery and rebounded after relapse (P < 0.01). These results indicate that there are differences in serum protein expression among the three different groups of patients. SELDI-TOF MS could be used to screen blood samples for the early detection of relapse in primary breast cancer patients. Specifically, protein peak at 3964 m/z is a potential biomarker for the detection of early breast cancer relapse. PMID- 21548111 TI - Simultaneous determination of iridoid glycosides and flavanoids in Lamionphlomis rotate and its herbal preparation by a simple and rapid capillary zone electrophoresis method. AB - Iridoid glycosides and flavanoids are two main effective components of Lamiophlomis rotata (Benth.) kudo. However, there is no method for simultaneous analysis of iridoid glycosides and flavanoids in L. rotata and its pharmaceutical preparations. A simple and rapid capillary zone electrophoresis (CZE) method was developed and validated for simultaneous determination of two iridoid glycosides (8-O-acetylshanzhiside methylester and 8-deoxyshanzhiside) and three flavanoids (apigenin, quercetin and luteolin) in L. rotata. Operational variables, such as the voltage, buffer concentration and pH were optimized, the final optimum separation condition was 10 mM sodium tetraborate-20 mM NaH(2) PO(4) (pH 8.5)-15% (v/v) methanol, 238 nm UV detection, 18 kV applied voltage. The linearity and the recovery of the proposed method were very satisfactory (correlation coefficients were 0.9994-0.9998 and the recoveries were 94.5-108.8% for the analytes) and the method allowed analytes in real samples to be determined within 9 min. The proposed CZE method can be used for quality control of iridoid glycosides and flavanoids in L. rotata and its herbal preparation. PMID- 21548112 TI - Robust polarity specification operates above a threshold of microtubule dynamicity. AB - Microtubule arrays effect cell polarisation by directing cellular cues for cortical remodelling and growth. Their function depends crucially on the intrinsic dynamic properties of constituent microtubules. Microtubule dynamicity is restricted to a certain range within the confines of a cellular geometry. Thus it is of great interest to determine whether rescaling of dynamic properties of microtubules has consequences for cell polarity. We constructed fission yeast strains exhibiting depressed microtubule dynamics by mutating the beta-tubulin gene, nda3. This interfered with efficient accumulation of a polarity factor Tea1 at cell tips. Interestingly, the polarity machinery in the mutant cells was highly susceptible to perturbations. Simulations of growth zone formation followed by imaging of actin distribution showed a significantly delayed onset of bipolar growth. We propose that there exists a threshold of microtubule dynamicity that allows robust cellular polarisation. PMID- 21548113 TI - Different positions of tropomyosin isoforms on actin filament are determined by specific sequences of end-to-end overlaps. AB - Tropomyosins are dimeric rod-like proteins which polymerize along actin filaments and regulate interactions with other actin-binding proteins. Homologous sequences responsible for the binding of tropomyosin to consecutive actin monomers repeat along tropomyosin and are called actin-binding periods. In this work, the localization of tropomyosin isoforms on actin alone and on actin-myosin complex was evaluated by measuring Forster resonance energy transfer (FRET) distances between a donor (AEDANS) attached to either the N-terminal actin-binding period 1 or to the central actin-binding period 5 and an acceptor (DABMI) bound to actin's Cys374. The recombinant -tropomyosin isoforms-TM2, TM5a, and TM1b9a, used in this study, had various amino acid sequences of the N- and C-termini forming the end to-end overlap. Although the sequences of actin-binding period 5 of the three isoforms were identical, the donor-acceptor distances calculated for each isoform varied between 38.6 and 41.5 A. Differences in FRET distances between the three tropomyosin isoforms labeled in actin-binding period 1 varied between 34.8 and 40.2 A. Rigor binding of myosin heads to actin increased all measured distances. The degree and cooperativity of myosin-induced shift was different for each of the isoforms and actin-binding periods. The structural differences correlate with cooperative regulation of actin-activated S1 ATPase by the three tropomyosins. The results indicate that amino acid sequences of the end-to-end overlap determine specific orientation of tropomyosin isoform on actin. This can be important for steric and cooperative regulation of the actin filament and determine functional specificity of multiple tropomyosin isoforms present in eucaryotic cells. PMID- 21548114 TI - Negative images of crystalline immunoglobulin in crystal storing histiocytosis: A potential cytologic mimic of mycobacteria in smears. AB - Two cases are described of crystal storing histiocytosis (CSH) associated with extranodal marginal zone lymphoma, presenting as lung and subcutaneous masses respectively. Fine-needle aspiration of subcutis and smears prepared from the resected lung masses showed negative images. Cytology slides of both cases were reviewed to identify cytomorphological features for the differential diagnosis between immunoglobulin crystals and mycobacteria. The crystals in CSH consist of straight and needle shaped rods with pointed or angular edges and are more variable in thickness than the uniformly thin mycobacteria. Mycobacteria show a haphazard distribution, whereas crystals are frequently present in parallel arrays. Small lymphoid or plasma cells are identified in the background of CSH, whereas a necrotic and inflammatory background is seen in mycobacteriosis. Additional samples for culture in the case of mycobacteriosis, or flow cytometry and molecular clonality testing in the case of CSH can provide critical data for a definitive diagnosis. PMID- 21548116 TI - Morphometric image analysis of pancreatic disease by ThinPrep liquid-based cytology. AB - Liquid-based cytology preparations are being increasingly used in nongynecologic specimens. The aim of this study is to objectively evaluate pancreatic disease by ThinPrep (TP) liquid-based cytology using morphometric image analysis. In all, 30 patients undergoing preoperative evaluation of pancreatic disease by TP were investigated from January to April 2009. We analyzed cytological features, such as cluster area, cluster circularity, and nucleus area, using morphometric image analysis software and further investigated the cytological findings of TP to determine which are useful for detecting malignancy. Pancreatic cytological findings of TP showed small clusters and loss of cluster irregularity in malignant cells. The patients were diagnostically categorized as inadequate, normal or benign, indeterminate, suspected malignancy, and malignant in 6.6% (2), 46.7% (14), 13.3% (4), 13.3% (4), and 20.0% (6) of the cases, respectively. Morphometric image analysis of 28 patients by TP,excluding two inadequate patients, showed no statistical difference in cluster area or cluster circularity among these cytological categories. In contrast, nucleus area in the normal or benign, indeterminate, suspected malignancy, and malignant categories was 17.6, 57.2, 67.4, and 68.0 MUm(2) , respectively, and was associated with diagnostic category (P < 0.05). Pancreatic cytological findings of TP preparations generally show small, round cluster shapes in pancreatic disease; however, nucleus size is a more important criteria for detecting malignancy by TP in pancreatic disease. PMID- 21548115 TI - Fine-needle aspiration diagnosis of an intraosseous amyloidoma. AB - Fine-needle aspiration (FNA) is frequently used as the initial diagnostic procedure for the investigation of bone and soft tissue masses. The majority of the lesions detected will represent metastatic carcinoma. Amyloid is a rare cause of a bone mass, with less than 15 published reports describing amyloid deposition within bone. The majority of reported cases involve the vertebral column. We report the finding of a massive amyloidoma of the iliac wing in a 46-year-old man. FNA smears and cell block preparations demonstrated fragments of waxy acellular material misinterpreted as necrotic debris. Subsequent open biopsy established the diagnosis of amyloid with congo red staining demonstrating apple green birefringence. Subsequent workup disclosed the patient to have anemia, hypogammaglobulinemia and trace monoclonal light chain gammopathy. Bone marrow examination revealed CD138a positive lambda restricted plasma cells consistent with plasma cell dyscrasia. Careful attention to the staining characteristics of amyloid in FNA derived material should allow the diagnosis of amyloidoma. PMID- 21548117 TI - Fine-needle aspiration biopsy of breast adenomyoepithelioma: a potential false positive pitfall and presence of intranuclear cytoplasmic inclusions. AB - Cytologic diagnosis of adenomyoepithelioma can be very challenging. We report fine needle aspiration cytology (FNAC) findings of a benign adenomyoepithelioma. The cytologic features are characterized by hypercellularity and the presence of numerous atypical dispersed cells with epithelioid morphology and intact cytoplasm. The nuclei showed stippled chromatin, irregular nuclear membrane, and prominent eosinophilic nucleoli. No necrosis or mitoses were seen. The presence of naked nuclei, and extensive intranuclear cytoplasmic inclusions were identified and raised the possibility of adenomyoepithelioma. Immunohistochemically, the atypical cells showed strong positivity for myosin heavy chain, p63, and CK5/6, while the epithelial cells reacted with estrogen receptors. This immunophenotypic pattern supports the myoepithelial origin of the atypical cell proliferation and favors the diagnosis of benign adenomyoepithelioma. However, biopsy was recommended to exclude malignancy. Histologically, the tumor showed prominent myoepithelial cells with significant atypia, intranuclear cytoplasmic inclusions, and dense cytoplasm. No evidence of malignancy was identified. In conclusion, we report a case of adenomyoepithelioma with a significant cytological atypia that may result in confusion with malignant breast tumors. The presence of intranuclear cytoplasmic inclusions, naked nuclei, and expression of myoepithelial markers should provide clues to the right diagnosis and benign nature of this lesion. Cytopathologists should be familiarized with this entity to avoid a misdiagnosis of carcinoma. PMID- 21548118 TI - Cytomorphologic findings of Schneiderian papilloma: a case report. AB - Schneiderian papilloma or inverted papilloma (IP) is the most common sinonasal papilloma yet a rare tumor with the greatest potential for recurrence and local destruction and association with malignant transformation. Tissue biopsy is routinely performed to examine these lesions. However, Fine needle aspiration may provide an immediate diagnosis. Herein, we report cytomorphologic findings of IP in a 46-year-old man with histopathologic correlation and review of the literature. PMID- 21548119 TI - Paget's disease of the breast masquerading as squamous cell carcinoma on cytology: a case report. AB - Paget's disease is an uncommon manifestation of breast carcinoma occurring in 1 2% of female patients with breast cancer. Here, we present a case of Paget's disease of the breast, which was initially interpreted as squamous cell carcinoma on cytology. This case report raises two issues. First, histological and cytological specimens of Paget's disease show a mixed population of epithelial cells including squamous cells with reactive changes and malignant glandular cells. In the current case, a mixed population of atypical keratinizing and nonkeratinizing epithelial cells was initially interpreted as squamous cell carcinoma of cutaneous origin. The marked reactive changes in the squamous epithelium involved by Paget's disease should be recognized. Second, this case is an unusual clinical presentation for Paget's disease of the breast as the nipple areolar complex and underlying breast tissue were surgically absent at the time of diagnosis. Clinical suspicion, along with an awareness of the cytologic features and clinical presentation of Paget's disease, can help in reaching the correct diagnosis in a timely fashion. PMID- 21548120 TI - Intranuclear peudoinclusions: morphology, pathogenesis, and significance. AB - Intranuclear pseudoinclusions represent invaginations of the cytoplasm into the nucleus. The nuclear pseudoinclusions are generally easier to appreciate in cytological preparations than frozen sections or histopathology thus forming an important cytological feature. In the present article we have reviewed the morphology, pathogenesis, differential diagnosis, and clinical significance of intranuclear cytoplasmic pseudoinclusion. PMID- 21548121 TI - The diagnostic reliability of urinary cytology: a retrospective study. AB - The aim of this study was twofold. The first aim was to estimate the diagnostic reliability of urinary cytology for detection and management of urothelial neoplasms by using a specific preserving fluid for sample collection, and the liquid-based thin layer method for specimen preparation, the estimate was based on the correlation between the cytological findings of 10,000 non-hospitalized patients, and their histological diagnoses. A second aim was to compare the reliability of two instruments for thin-layer preparation, i.e., TP2000, TP3000, capable of processing the specimens at very different rates. The preservation of cell structure is ameliorated by the procedure of sample collection and treatment here described. This allows a more accurate reading of LBC slides as shown by: (a) the significant concordance between cytological and histological diagnosis (92%); (b) the significant number of low-grade urothelial carcinomas (20.5%) revealed by urinary cytology and validated by histologic diagnosis; (c) the low rate (8%) of misjudgement of cytological diagnosis reached in this study. The quality of performances of the two instruments tested for thin-layer preparation, i.e., TP2000 and TP3000, is statistically comparable. We recommend the procedure that makes use of preserving fluid for sample collection (cytolytTM) and treatment (preservcyt TM) as here described. We also recommend the use of thin layer method for specimen preparation since it allows a more uniform distribution of the cells on the support with reduction of overlapping phenomena. Finally, economic considerations suggest the preferential use of Thin Prep 3000. PMID- 21548122 TI - Primary Ewing's sarcoma/primitive neuroectodermal tumor of the kidney: Report of a case diagnosed by fine needle aspiration cytology and confirmed by immunocytochemistry and RT-PCR along with review of literature. AB - Primary Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) of the kidney is a distinct entity that can be mistaken for variety of round cell tumors. We report a rare case of ES/PNET of the kidney in a 35-year-old female patient diagnosed by fine needle aspiration cytology (FNAC) and confirmed by immunohistochemistry (IHC) and reverse-transcriptase polymerase chain reaction (RT-PCR). Ultrasound guided FNAC smears from the kidney mass showed a population of malignant small round cells with perivascular arrangement and focal rosette formation. IHC performed on the cell block, showed strong immunopositivity for CD99 (MIC2) and vimentin. Molecular analysis of the aspirate by RT-PCR confirmed the EWS-FLI type1 transcript. The application of RT-PCR on FNAC material for establishing a diagnosis of renal ES/PNET is being reported for the first time. FNAC also confirmed metastases in the right level I cervical lymph node. The utility of IHC and molecular techniques in diagnosis of such a rare case is stressed and relevant literature is discussed. PMID- 21548123 TI - Cytological diagnostic clues in fine needle aspiration of breast myofibroblastoma: a case report. AB - Myofibroblastoma of the breast is a rare, benign mesenchymal tumor derived from the stroma and tends to occur mainly in middle-aged to elderly men. There are a few cases reported in the literature describing its cytological features. We report the cytological and histological findings of a breast myofibroblastoma in a 68-year-old man. He presented with a palpable nodule of 2-months duration in his left breast. The cytological smears obtained by fine needle aspiration showed less cohesive cellularity in a fascicular arrangement consisting of spindle cells with elongated cytoplasm, occasional nuclear grooves, and intranuclear cytoplasmic inclusions associated to fragments of stromal collagen. The cytological diagnosis was a mesenchymal proliferation suggesting the possibility of myofibroblastoma which was confirmed on histopathological examination. The breast myofibroblastoma has distinctive cytological features that in conjunction with the clinical and radiological data allow a specific diagnosis. PMID- 21548124 TI - Acral myxoinflammatory fibroblastic sarcoma fine needle aspiration: a case report. AB - Cytological diagnosis of low grade sarcomas can be a daunting task, owing to the varied cytomorphological appearances possible. We report a case of acral myxoinflammatory fibroblastic sarcoma (AMIFS) in a woman who presented with a longstanding mass on the dorsum of her left foot. The diagnosis was suggested by fine needle aspiration cytology and established by wide excision. Microscopic examination showed that fine needle aspirate smears of this lesion contained the characteristic features seen in the surgical excision of this AMIFS: myxoid material, spindled to epithelioid cells with variably prominent nucleoli, nuclear pseudoinclusions, bipolar cytoplasmic extensions, globules of extracellular material, and bizarre virocyte or ganglion-like giant cells. PMID- 21548125 TI - Fine-needle aspiration features of paraduodenal pancreatitis (groove pancreatitis): a report of three cases. AB - Chronic pancreatitis is notorious for mimicking both the clinical and radiologic presentation of pancreatic carcinoma. Paraduodenal pancreatitis is believed to result from focal chronic pancreatitis which affects the minor papilla of the duodenum. Currently, there is limited information available regarding the cytologic features of paraduodenal pancreatitis. In this study, we report the cytologic features of three patients with paraduodenal pancreatitis who had EUS guided FNAs of the pancreas. The cytologic features were highly variable between cases, likely due to sampling of the various components of paraduodenal pancreatitis. The most common findings were spindled stromal cells, foamy cells, and granular debris. Although most often interpreted as negative for malignancy, the sampling of an area with abundant spindle cells or Brunner gland hyperplasia can mimic neoplasia. Careful attention to the clinical history and radiologic description can help to prevent over-diagnosis on FNA. PMID- 21548126 TI - Is autosomal recessive Silver-Russel syndrome a separate entity or is it part of the 3-M syndrome spectrum? AB - Intrauterine growth retardation (IUGR) is a nonspecific finding that occurs in approximately 0.17% of all live-births. However, IUGR can also be a significant feature of many recognized genetic syndromes including Silver-Russel syndrome (SRS), Three M syndrome (3-M), Dubowitz syndrome, and Mulibrey nanism. Differentiation of 3-M syndrome from autosomal recessive SRS has been difficult because of the phenotypic variability of the latter. Limb length asymmetry is seen in over half of those with autosomal recessive SRS, but not in individuals with 3-M syndrome. Characteristic radiologic findings of 3-M syndrome are not present in SRS. We used single nucleotide polymorphism (SNP) microarrays to investigate the cause of phenotypic features of SRS that shows autosomal recessive inheritance in three consanguineous families, two from United Arab Emirates (UAE), and one from Jordan. The mapped regions contained CUL7 and OBSL1, the genes that have recently been shown to cause 3-M syndrome. Subsequently, direct DNA sequencing of CUL7 and OBSL1 genes revealed novel mutations in both genes including two mutations in OBSL1 [c.1119G>C (p.W373C) and c.681_682delinsTT (p.Q228X)], and a nonsense mutation in CUL7 [c.203G>A (p.W68X)]. In addition, a six nucleotide deletion in CUL7 [c.649_654delAGCCGC (p.217_218delSR)] was found in a consanguineous family from UAE that had the typical features of 3-M. As a result of these findings, we question the identity of the autosomal recessive SRS and suggest that all apparently recessive SRS families should be tested for mutations in CUL7 and OBSL1. PMID- 21548127 TI - Balanced information about Down syndrome: what is essential? AB - The purpose of this study was to explore the perspectives of genetic counselors and parents of children with Down syndrome to define essential information for the initial discussion of a new diagnosis. We compared information given in both prenatal and postnatal settings, and also aimed to distinguish differences between the informational needs of parents and the information genetic counselors provide. Online surveys were distributed to members of the National Down Syndrome Congress, National Down Syndrome Society, and National Society of Genetic Counselors. Participants included 993 parents of children with Down syndrome and 389 genetic counselors. Participants rated 100 informational features about Down syndrome as Essential, Important, or Not Too Important for inclusion in the first discussion of the diagnosis. Responses identified 34 essential informational items for the initial discussion of Down syndrome, including clinical features, developmental abilities, a range of prognostications, and informational resources. Healthcare providers should consider incorporating these items in their initial discussion of a diagnosis in both prenatal and postnatal settings. Statistically significant differences between parent and genetic counselor responses illustrate that information is valued differently and that parents appreciate information about the abilities and potential of people with Down syndrome, as opposed to clinical details. Balancing clinical information with other aspects of the condition, as well as a better understanding of the information parents consider most important, may enable healthcare professionals to more effectively satisfy families' informational needs following a new diagnosis of Down syndrome. PMID- 21548128 TI - Multiple capillary skin malformations, epilepsy, microcephaly, mental retardation, hypoplasia of the distal phalanges: report of a new case and further delineation of a new syndrome. PMID- 21548130 TI - Preparative purification of gentamicin components using high-speed counter current chromatography coupled with electrospray mass spectrometry. AB - We developed a useful and preparative method based on high-speed counter-current chromatography with mass spectrometry (HSCCC/MS) to purify gentamicin C1a, C2/2a and C1 from standard powder. The analytes were purified on the HSCCC model CCC 1000 (multi-layer coil planet centrifuge) with a volatile two-phase solvent system composed of n-butanol/10% aqueous ammonia solution (50:50, v/v) and detected on an LCMS-2020EV quadrupole mass spectrometer fitted with an electrospray ionization (ESI) source system in positive ionization following scan mode (m/z 100-500). The HSCCC/ESI-MS peaks indicated that gentamicin C1a (m/z 450: [M+H](+)), C2/2a (m/z 464: [M+H](+)) and C1 (m/z 478: [M+H](+)) have the peak resolution values of 1.3 and 1.7 from 30 mg of loaded gentamicin powder. The HSCCC yielded 3.9 mg of gentamicin C1a, 12.6 mg of gentamicin C2/2a and 12.0 mg of gentamicin C1. These purified substances were analyzed by LC/MS with scan positive-mode. Based on the LC/MS chromatograms and spectra of the fractions, analytes were estimated to be over 95% pure. These gentamicin isomers of C1a, C2/2a and C1 were evaluated for their antibacterial activities. The overall results indicate that this approach of HSCCC/MS is a powerful technique for the purification of gentamicin components. PMID- 21548129 TI - Distinctive phenotype in 9 patients with deletion of chromosome 1q24-q25. AB - Reports of individuals with deletions of 1q24->q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome. PMID- 21548131 TI - Simultaneous chemical fingerprinting and quantitative analysis of crude and processed Radix Scrophulariae from different locations in China by HPLC. AB - A validated liquid chromatography method was first developed to evaluate the quality of crude and processed Radix Scrophulariae extracts through establishing chromatographic fingerprint and simultaneous determination of five bioactive compounds, namely 5-hydroxymethylfurfural (5-HMF), acteoside, angroside C, harpagoside and cinnamic acid. The chromatographic were separated on an Agilent Zorbax Extend C(18) column (250 mm * 4.6 mm, 5 MUm) and detected by diode array detector (DAD). Mobile phase was composed of (A) aqueous phosphoric acid (0.03%, v/v) and (B) acetonitrile using a gradient elution. Analytes were performed at 30 degrees C with a flow rate of 1.0 mL/min and UV detection at 280 nm. All calibration curves showed good linear regression (r(2) >=0.9996) within the tested ranges, and the recovery of the method was in the range of 98.12-103.38%, with RSD values ranging from 0.6 to 2.8%. In addition, the contents of those five bioactive compounds in crude and processed Radix Scrophulariae prepared by different locations of China were determined to establish the effectiveness of the method. The results demonstrate that the developed method is accurate and reproducible and could be readily utilized as a suitable quality control method for the quantification of Radix Scrophulariae. PMID- 21548132 TI - Control of 6-exo and 7-endo cyclizations of alkynylamides using platinum and bismuth catalysts. PMID- 21548133 TI - Tenogenic differentiation of stem cells for tendon repair-what is the current evidence? AB - Tendon/ligament injuries are very common in sports and other rigorous activities. Tendons regenerate and repair slowly and inefficiently in vivo after injury. The limited ability of tendon to self-repair and the general inefficiencies of current treatment regimes have hastened the motivation to develop tissue engineering strategies for tissue repair. Of particular interest in recent years has been the use of adult mesenchymal stem cells (MSCs) to regenerate functional tendons and ligaments. Different sources of MSCs have been studied for their effects on tendon repair. However, ectopic bone and tumour formation has been reported in some special circumstances after transplantation of MSCs. The induction of MSCs to differentiate into tendon-forming cells in vitro prior to transplantation is a possible approach to avoid ectopic bone and tumour formation while promoting tendon repair. While there are reports about the factors that might promote tenogenic differentiation, the study of tenogenic differentiation is hampered by the lack of definitive biomarkers for tendons. This review aims to summarize the cell sources currently used for tendon repair as well as their advantages and limitations. Factors affecting tenogenic differentiation were summarized. Molecular markers currently used for assessing tenogenic differentiation or neotendon formation are summarized and their advantages and limitations are commented upon. Finally, further directions for promoting and assessing tenogenic differentiation of stem cells for tendon repair are discussed. PMID- 21548134 TI - In vitro study of chondrocyte redifferentiation with lentiviral vector-mediated transgenic TGF-beta3 and shRNA suppressing type I collagen in three-dimensional culture. AB - Chondrocytes are the primary candidate therapeutic cells to cure cartilaginous lesions. Ideally, for transplantation, autologous chondrocytes are isolated from the patient, amplified in vitro, seeded in a scaffold and implanted back. However, significant concerns arise with chondrocyte dedifferentiation during monolayer amplification, whereby cells lose their chondrocytic phenotype by rapidly downregulating the expression of cartilage markers such as type II collagen (Col II) and aggrecan. The accompanying upregulation in type I collagen (Col I) is also problematic, as it leads to unexpected fibrosis and causes such engineered cartilage to lack the desired mechanical strength to make up joint lesions. Transforming growth factor-beta3 (TGF-beta3) has been proved effective in maintaining chondrocytic morphology and promoting total collagen production. In this study, we aimed to deliver the TGF-beta3 gene into dedifferentiated chondrocytes with recombinant lentiviral vectors; by transgenic expression of TGF beta3, chondrocytic redifferentiation is catalysed. Simultaneously, shRNA targeting Col I was also incorporated into the vector to suppress Col I production. The results indicated that chondrocytes underwent dedifferentiation in monolayer culture in the presence or absence of transgenic TGF-beta3. In three dimensional culture, effective redifferentiation was managed in the dedifferentiated chondrocytes that were transduced with transgenic TGF-beta3. The incorporation and expression of Col I-targeting shRNA were also effective in reducing Col I production in a post-transcriptional manner. PMID- 21548135 TI - Influence of the mesenchymal cell source on oral epithelial development. AB - The extent of the influence of mesenchymal tissue on epithelial development is still debated, and elucidation of epithelial-mesenchymal interactions should be of relevance for controlling normal as well as pathological growth and development. The aim of the present study was to elucidate the influence of the mesenchymal cell type on oral mucosa epithelial development in vitro, using tissue-engineering principles, by including three different sources for mesenchymal cell type, viz. oral mucosa, skin and cornea, each of them presenting a distinct type of epithelium in situ. We investigated epithelial-mesenchymal interactions, considering both morphological criteria and protein expression (filaggrin, keratin 10, keratin 12, keratin 13 and laminin 5). The results of the histology, immunohistochemistry and transmission electron microscopy of the three types of tissue-engineered constructs composed of mesenchymal cells of different sources (oral, dermal and corneal fibroblasts) and of the same oral epithelial cells showed that the mesenchymal cell source had a significant influence on the thickness and ultrastructure of the epithelium, but not on the differentiation of oral epithelial cells, which might be an intrinsic property of these cells due to their genetic programming. PMID- 21548136 TI - Bone morphogenetic protein-2 in biodegradable gelatin and beta-tricalcium phosphate sponges enhances the in vivo bone-forming capability of bone marrow mesenchymal stem cells. AB - Bone marrow mesenchymal stem cells (MSCs) have been used for bone tissue engineering due to their osteogenic differentiation capability, but their application is controversial. To enhance their capability, we prepared biodegradable gelatin sponges incorporating beta-tricalcium phosphate ceramics (GT sponge), which has been shown to possess excellent controlled drug-release properties. The GT sponge was used as a carrier for both rat MSCs and bone morphogenetic protein-2 (BMP-2) and osteogenic differentiation was assessed by subcutaneous implantation of four different kinds of implants, i.e. GT-alone, MSC GT composites, BMP-GT composites and BMP-GT composites supplemented with MSCs (BMP-MSC-GT) in rats. Two weeks after implantation, histological sections showed new bone formation in the peripheral parts of the BMP-GT and in almost the total volume of the BMP-MSC-GT implants. After 4 weeks, histology as well as microCT analyses demonstrated extensive bone formation in BMP-MSC-GT implants. Gene expression and biochemical analyses of both alkaline phosphatase and bone specific osteocalcin confirmed the histological findings. These results indicate that the combination of MSCs, GT and BMP synergistically enhances osteogenic capability and provides a rational basis for their clinical application in bone reconstruction. PMID- 21548137 TI - Evaluation of the potential of novel PCL-PPDX biodegradable scaffolds as support materials for cartilage tissue engineering. AB - Cartilage is a specialized tissue represented by a group of particular cells (the chondrocytes) and an abundant extracellular matrix. Because of the reduced regenerative capacity of this tissue, cartilage injuries are often difficult to handle. Nowadays tissue engineering has emerged as a very promising discipline, and biodegradable polymeric scaffolds are widely used as tissue supports. In cartilage injuries, the use of autologous chondrocyte implantation from non affected cartilage zones has emerged as a very interesting technique, where chondrocytes are expanded in order to obtain a greater number of cells. Nevertheless, it has been reported that chondrocytes in bidimensional cultures suffer a dedifferentiation process. The present study sought, in the first place, to standardize a novel protocol in order to obtain primary cultures of chondrocytes from newborn rabbit hyaline cartilage from the xiphoid process. Second, the potential of porous three-dimensional (3D) biodegradable polymeric matrices as support materials for chondrocytes was evaluated: a novel poly(epsilon-caprolactone)-poly(p-dioxanone) (PCL-PPDX) blend in a 90:10 w:w ratio and poly(epsilon-caprolactone) (PCL). After achieving the standardization, a typical round-shaped chondrocyte morphology and the expression of collagen type II and aggrecan, evaluated by RT-PCR, were observed. Second-passage chondrocytes adhered effectively to these scaffolds, although cell growth at 7 days in culture was significantly less in the PCL-PPDX blend. After 3 weeks of culture on PCL PPDX or PCL, the cells expressed collagen type II. The present study demonstrates the potential, unknown until now, of PCL-PPDX blend scaffolds in the field of cartilage tissue engineering. PMID- 21548138 TI - Indirect fibre-optic colorimetric determination of ascorbic acid using 2-(5-bromo 2-pyridylazo)-5-diethylaminophenol and cloud point extraction. AB - A new method has been developed for the indirect determination of ascorbic acid (AA) in commercial syrup preparations based on cloud point extraction (CPE) separation and preconcentration, and determination by molecular absorption spectrometry. The colorimetric method was based on the reduction of Fe(III) to Fe(II) and complexation of Fe(II) with 2-(5-bromo-2-pyridylazo)-5 diethylaminophenol (Br-PADAP), followed by its extraction into Triton X-114. Selectivity of the method was increased with the use of EDTA as a masking agent. The absorbance was measured at 742 nm. Various influencing factors on the separation and preconcentration of AA have been investigated systematically, and the optimized operation conditions were established. The proposed method allows the determination of AA in the range 5-200 ug L(-1) with a relative standard deviation of 3.0%. The detection limit was found to be 0.9 ug L(-1) for AA. This method has been applied to the determination of ascorbic acid in commercial pharmaceutical preparations. PMID- 21548139 TI - Determination of urinary concentrations of pseudoephedrine and cathine after therapeutic administration of pseudoephedrine-containing medications to healthy subjects: implications for doping control analysis of these stimulants banned in sport. AB - Due to its stimulatory effects on the central nervous system, and its structural similarity to banned stimulants such as ephedrine and methamphetamine, pseudoephedrine (PSE) at high doses is considered as an ergogenic aid for boosting athletic performance. However, the status of PSE in the International Standard of the Prohibited List as established under the World Anti-Doping Code has changed over the years, being prohibited until 2003 at a urinary cut-off value of 25 ug/ml, and then subsequently removed from the Prohibited List during the period 2004-2009. The re-consideration of this position by the World Anti Doping Agency (WADA) List Expert Group has led to the reintroduction of PSE in the Prohibited List in 2010. In this manuscript, we present the results of two WADA-sponsored clinical studies on the urinary excretion of PSE and its metabolite cathine (CATH) following the oral administration of different PSE formulations to healthy individuals at therapeutic regimes. On this basis, the current analytical urinary threshold for the detection of PSE as a doping agent in sport has been conservatively established at 150 ug/ml PMID- 21548140 TI - Acute toxicity and withdrawal syndromes related to gamma-hydroxybutyrate (GHB) and its analogues gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD). AB - Gamma-hydroxybutyrate (GHB) has been used as a recreational drug since the 1990s and over the last few years there has been increasing use of its analogues gamma butyrolactone (GBL) and to a lesser extent 1,4-butanediol (1,4BD). This review will summarize the literature on the pharmacology of these compounds; the patterns and management of acute toxicity associated with their use; and the clinical patterns of presentation and management of chronic dependency associated with GHB and its analogues. PMID- 21548141 TI - Purification of pharmaceutical preparations using thin-layer chromatography to obtain mass spectra with Direct Analysis in Real Time and accurate mass spectrometry. AB - Forensic analysis of pharmaceutical preparations requires a comparative analysis with a standard of the suspected drug in order to identify the active ingredient. Purchasing analytical standards can be expensive or unattainable from the drug manufacturers. Direct Analysis in Real Time (DARTTM) is a novel, ambient ionization technique, typically coupled with a JEOL AccuTOFTM (accurate mass) mass spectrometer. While a fast and easy technique to perform, a drawback of using DARTTM is the lack of component separation of mixtures prior to ionization. Various in-house pharmaceutical preparations were purified using thin-layer chromatography (TLC) and mass spectra were subsequently obtained using the AccuTOFTM- DARTTM technique. Utilizing TLC prior to sample introduction provides a simple, low-cost solution to acquiring mass spectra of the purified preparation. Each spectrum was compared against an in-house molecular formula list to confirm the accurate mass elemental compositions. Spectra of purified ingredients of known pharmaceuticals were added to an in-house library for use as comparators for casework samples. Resolving isomers from one another can be accomplished using collision-induced dissociation after ionization. Challenges arose when the pharmaceutical preparation required an optimized TLC solvent to achieve proper separation and purity of the standard. Purified spectra were obtained for 91 preparations and included in an in-house drug standard library. Primary standards would only need to be purchased when pharmaceutical preparations not previously encountered are submitted for comparative analysis. TLC prior to DARTTM analysis demonstrates a time efficient and cost saving technique for the forensic drug analysis community. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21548142 TI - Overproduction of human M3 muscarinic acetylcholine receptor: an approach toward structural studies. AB - Human M(3) muscarinic acetylcholine receptor (M3R), present in both the central and the peripheral nervous system, is involved in several neurodegenerative and autoimmune diseases. Recently, M3R overexpression has been suggested to play a role in certain forms of cancer, showing promise as a new potential pharmacological target. However, the lack of structural information hampered to develop a new potent selective and potent antagonist. We describe here different strategies for overexpressing functional M3R on the perspective of future biophysical studies. To achieve this goal, four tagged M3R genes were engineered and codon optimized. Different heterologous expression systems, including mammalian cells and viral transfection, were employed to overexpress M3R. Although codon optimization resulted in only twofold to threefold increase of M3R expression, we found that epitope tagging of the synthetic M3R, especially with hemagglutinin and Flag epitope tags, could improve M3R expression levels. On the other hand, viral transfection led to a yield of 27 pmol/mg protein that is the highest level reported so far for this receptor subtype in mammalian cells. Taking together several of the strategies used can help increasing M3R expression, not only to start purification efforts but also for secondary structural analysis trial and functional analyses. PMID- 21548143 TI - Functional and morphological effects of indirect gradual elongation of peripheral nerve: electrophysiological and morphological changes at different elongation rates. AB - We investigated the neuropathy induced by leg lengthening histological evaluation using teased nerve fiber specimens and electrophysiological evaluation. Indirect elongation of the sciatic nerve associated with leg lengthening was performed at 1 and 3 mm/day over 30 mm in rats. Electrophysiological evaluation was performed immediately and 60 days after the end of elongation, teased nerve fiber specimens were prepared, and the mean axonal diameter was calculated. The electrophysiological results were more wrong, and the recovery was poorer, in the 3-mm than in the 1-mm group. In the 1-mm group, the nerve conduction velocity (NCV) and the duration of the compound nerve action potential (C-NAP) recovered to a level close to the intact side, but the decrease in the amplitude of the C NAP persisted. In the teased fiber study, while paranodal demyelination was observed in both groups immediately after elongation, demyelination was decreased in the 1-mm group indicationg recovery compared to the 3-mm group. Paranodal demyelination caused by indirect nerve elongation is considered to have induced electrophysiological disorders. Electrophysiological and morphological damages appeared to be more severe according to elongation speed. The nerve disorder were remained even at 1 mm per day in 60 days. PMID- 21548144 TI - Reoperation for metalwork complications following the use of volar locking plates for distal radius fractures: a United Kingdom experience. AB - Volar locking plates are increasingly used in the management of distal radius fractures. As with any new implant, understanding the rate and type of potential metalwork related complications is important. In this study, we reviewed 114 distal radius fractures treated with volar locking plating. Our aim was to determine the type and rate of metalwork complications requiring reoperation. In our series, 12 cases (10%) underwent further surgery for metalwork related complications mainly for screw protrusion into the radiocarpal joint following fracture collapse. Our results suggest that volar locking plates are associated with a high rate of metal work related complications requiring further surgery. Technical aspects to reduce such complications are discussed. PMID- 21548145 TI - Long term results of matched hemiresection interposition arthroplasty for DRUJ arthritis in rheumatoid patients. AB - INTRODUCTION: The distal radioulnar joint (DRUJ) is commonly affected in rheumatoid arthritis and is associated with significant functional morbidity. The aim of our study is to review our results with matched hemi-resection interposition arthroplasty in patients with DRUJ arthritis. METHODS: This was a retrospective study of 39 patients with 51 wrists that were treated at Queen Mary Hospital in Hong Kong from 1989 to 2007. All patients underwent matched hemi resection interposition arthroplasty and dorsal wrist synovectomy. Long arm hinged elbow brace was used for three weeks followed by intensive rehabilitation up to twelve weeks. The indicators of outcome included range of motion assessment, pain, wrist stiffness, grip of strength and need for revision assessed during follow-up. Statistical analysis was performed with student t test. RESULTS: The average age of patients was 50.5 years (25 to 77 years) and there was a 35:4 female to male ratio. The average follow up was 4.5 years ranging from 1 to 18 years. Associated extensor tendon ruptures were found in 31.4% patients. The average increase in supination was from 73 degrees preoperatively to 81 degrees at long term follow up (p = 0.10 at 1 year and 0.13 at long term follow-up). The average increase in pronation was from 68 degrees preoperatively to 74 degrees on long term follow up (p = 0.57 at 1 year and 0.02 at long term follow-up). There was evidence of painless, relatively stiff but functional wrist in 37.25% of patients. There was an increase in grip strength from an average of 6.1 kilogram force preoperatively to an average of 11.5 kilogram force at follow-up (p = 0.004 at 1 year and 0.15 at long term follow up). Complete relief of ulnar sided pain was seen in 43 wrists (84%), partial relief was seen in 7 wrists (13.7%) and no relief was found in one wrist (1.9%). CONCLUSIONS: DRUJ arthroplasty is a rewarding procedure and most of the patients obtain pain free movement. PMID- 21548146 TI - Arthroscopic assisted bone grafting for early stages of Kienbock's disease. AB - Kienbock's disease is known for its difficulty in being diagnosed and treated at early stages; option treatments are few and most of them quite aggressive. The author describes his experience with arthroscopic assisted lunate bone grafting. Three patients with diagnosis of stage I avascular necrosis of the lunate (average age: 45 years), were treated. Before surgical procedure, the patients underwent to a conservative treatment. After harvesting the bone graft from the volar surface of the radius, arthroscopic bone grafting was performed. At an average follow-up of 13.5 months (9-15), all the patients show a normal density of the lunate and no arthritic changes in radiographs. The MRI confirmed the lunate vascularity. The number of patients is definitely small, due also to the rarity of the disease and the difficulty in diagnosis, but, despite the very high learning curve, could be the proper first choice of treatment. PMID- 21548147 TI - An inverting circumferential suture for flexor tenorraphy. AB - Zone two flexor tendon repair remains challenging with significant outcome variation using recognised techniques. Tendon adhesion formation results in poor outcomes and rehabilitation regimes aim to limit this. Some repairs augment strength, but increasing bulk mitigates against movement. This novel epitendinous technique causes tendon inversion with potential gliding benefits and improved outcomes. 60 porcine tendons were randomised to a 2-stranded modified Kessler or a 4-stranded Adelaide repair, then sudivided into three different circumferential technique groups: locked running, Silfverskiold, or a new inverting repair. Tendon load to failure (LTF), 2 mm gap formation, bulking effect and method of failure were analysed during digital tensiometry. Four-stranded repairs demonstrated better LTF than 2-stranded techniques. The inverting epitendinous and Silfverskiold repairs showed higher LTF characteristics than the locked running suture, and better tissue holding capacity. The inverting repair has similar properties to commonly used suturing methods and the conformation creates a smooth inverted repair. PMID- 21548148 TI - Intramedullary fixation of proximal phalangeal fractures through a volar extra tendon sheath approach. AB - We present an operative technique and the results of intramedullary fixation of proximal phalangeal shaft fractures through a volar extra-tendon sheath approach. A J-shaped nail, which is a curved Kirschner wire sharply bent at the proximal end, was inserted from the palmar aspect of the proximal phalangeal base. Six fingers of the six patients (all male) were treated with this method. The mean age of the patients was 51 years (range, 20-69 years). There were four open and two closed fractures. All fingers attained successful fracture union and one of them had correction loss. No patient complained of pain at the final follow-up, and the average of total active motion was 223 degrees (190 degrees - 255 degrees ). This method may be an alternative for treatments of the proximal phalangeal shaft fractures because of its less invasive nature, although it does not offer anatomical reduction. PMID- 21548149 TI - Giant cell tumours of tendon sheath of hand: causes and strategies to prevent recurrence. AB - Giant cell tumours of tendon sheath of hand present a surgical dilemma due to their high incidence of local recurrence. We present a case series of 46 patients with 47 histologically confirmed giant cell tumours of tendon sheath over a ten year period from 1998 to 2008. The mean follow-up was 47 months (range 25-124 months). We identified tumours with bony erosions and piecemeal resections as predictors of recurrence. Our recurrence rate of 9% was at the lower end of spectrum of previously published reports (range 7%-44%). We recommend "en-masse" excision of these tumours. All the patients with suspicion of these tumours should have preoperative radiographs to identify erosions. A thorough curettage of the bone should be done in cases with osseous erosion to prevent recurrence. Patients with these risk factors should be followed up annually for five years and be warned about recurrence. PMID- 21548150 TI - Early combined neurosurgery and orthopaedic surgery in Neonatal Brachial Plexus Palsy. AB - Three cases are presented in which neurosurgical reconstruction of a Neonatal Brachial Plexus Palsy was combined with orthopaedic reconstruction of a posterior glenohumeral dislocation. The authors believe that a combined procedure is indicated if the neurological deficit meets the criteria for neural reconstruction and the complication of a posterior glenohumeral dislocation has occurred prior to nerve surgery. Two children with C5-6 lesions and a third child with a pan-plexus lesion obtained good shoulder function following the combined reconstruction. PMID- 21548151 TI - Surgical treatment of neurogenic thoracic outlet syndrome secondary to the clavicle haematogenic subacute osteomyelitis. AB - A rare case of neurogenic thoracic outlet syndrome secondary to subacute osteomyelitis (SOM) of clavicle is presented. It was treated successfully with scalenectomy combined with clavicle and first rib resection and reconstruction of the clavicle using vascularised seventh rib transfer. Various issues involved in the diagnosis and management of such a case are discussed. PMID- 21548152 TI - Permanent ulnar nerve palsy after embolotherapy of arteriovenous malformation around the elbow. AB - Permanent nerve palsy is an extremely rare but critical complication after embolotherapy of arteriovenous malformations of the extremities. The authors present a case of permanent ulnar nerve palsy after embolotherapy of an arteriovenous malformation around the elbow, and caution that transcatheter embolotherapy of arteriovenous malformations located close to major neurovascular structures must be carefully planned and individualized. PMID- 21548153 TI - Spontaneous partial posterior interosseous nerve palsy not caused by an adjacent ganglion. AB - We report a case of spontaneous partial posterior interosseous nerve palsy where the ganglion adjacent to the nerve was not the main cause of the compression. Instead, a thick fascial band deep to the distal edge of the supinator was found responsible. This case illustrates the importance of completing the nerve exploration to fit with the clinical picture. PMID- 21548154 TI - Volar radiocarpal dislocation: case report and review of literature. AB - We describe here an unusual case of volar dislocation of the radiocarpal joint due to a complete tear of the dorsal radiocarpal ligament. Plain radiographs taken at initial presentation did not reveal any obvious abnormality. There was no associated bony lesion or intrinsic wrist ligament injury. Radiocarpal dislocations should be considered in the diagnosis of high-energy wrist injuries, even when initial radiographs look normal. The importance of a high index of suspicion in high velocity wrist injuries and need for further evaluation and imaging is highlighted. PMID- 21548155 TI - Ulnar-sided wrist pain due to isolated disk tear of triangular fibrocartilage complex within the distal radioulnar joint: two case reports. AB - Wrist arthroscopy has been successfully used with many modifications and improvements. However, distal radioulnar joint (DRUJ) arthroscopy is still uncommon. We experienced 2 cases of ulnar-sided wrist pain due to isolated triangular fibrocartilage complex (TFCC) disk tear within the DRUJ. DRUJ arthroscopy in these cases showed horizontal tear and fibrillation of TFCC disk without TFCC tear at the radiocarpal joint. Foveal attachment was intact in both cases. These were treated with debridement, which relieved pain after surgery and achieved good functional recovery. Although DRUJ arthroscopy is technically difficult, it is mandatory for making a diagnosis and treating ulnar-sided wrist pain. PMID- 21548156 TI - Osteochondroma of the lunate with extensor tendons rupture of the index finger: a case report. AB - Osteochondroma rarely develops from the carpal bones. We report a first case in which a dorsal osteochondroma of the lunate caused attritional rupture of the tendon of the extensor indicis proprius and a tendon of the extensor digitorum communis of index finger. PMID- 21548157 TI - Severe isolated trapezoid fracture: a case report. AB - Isolated trapezoid fractures are rare. We present a case of severe isolated trapezoid fracture associated with bone loss and proximal migration of the second metacarpal, which was treated successfully by open reduction and internal fixation with bone grafting and joint fusion. PMID- 21548158 TI - Post-traumatic combined flexion of the thumb, index and middle finger after intrinsic muscles reconstruction of the hand: a case report. AB - We report a case in which simultaneous flexion of the thumb, index and middle finger occurred 6 months after the surgical reconstruction of the adductor (AM) and first dorsal interosseous (IO) muscles. An anomalous connection in the form of tendon slip associated to fibrous adhesions between the flexor pollicis longus (FPL) tendon, flexor digitorum profundus indicis (FDPI) and middle finger (FDPM) tendons were found. Either ultrasound (US) examination or magnetic resonance imaging (MRI) were unable to detect the site of adhesion. Excision of the slip and radical tenosynoviectomy led to early functional recovery. PMID- 21548159 TI - Spontaneous ulnar dislocation of the index, long, ring and small finger extensor tendons at the metacarpophalangeal joints: a case report. AB - Finger extensor tendon dislocation at the metacarpophalangeal joint is caused by various etiologies, such as trauma, congenital anomaly, or rheumatoid arthritis. When the dislocation occurs with no etiology, this is called spontaneous dislocation. Although spontaneous extensor tendon dislocation in one, two or three fingers has been described, to our knowledge, simultaneous dislocation in four fingers has not been reported. In this paper, we report a spontaneous ulnar dislocation of all the extensor tendons in the index, long, ring, and small fingers. Repair of the radial sagittal bands of the extensor digitorum communis of the middle and ring fingers reduced dislocation of all the extensor tendons in four fingers. PMID- 21548160 TI - Locked metacarpophalangeal joint of the little finger due to hyperextension injury: a case report. AB - We treated a rare case of locked metacarpophalangeal joint of the little finger due to a hyperextension injury. The mechanism of the occurrence was considered to be closely similar to those that happened in the thumb, and the locking was successfully released by a manual reduction without complication. PMID- 21548161 TI - Malignant transformation of an enchondroma of the hand: a case report. AB - Secondary chondrosarcomas according to malignant transformations of the solitary enchondromas were extremely rare in the hand. The aim of this study is to present a case of a 43-year-old male having rare malignant transformation of the solitary enchondroma treated with total excision and replacement with iliac bone graft. PMID- 21548162 TI - Avulsion of flexor digitorum profundus secondary to recurrent enchondroma. AB - We report a case of avulsion of the flexor digitorum profundus secondary to recurrent enchondroma. The tumor was curetted with bone grafting of cancellous bone from the distal radius, and the fragment avulsed by the flexor digitorum profundus tendon was fixed to its original site using a pullout suture through the distal phalanx to the nail. The lesion healed and function recovered 6 years after surgery. PMID- 21548163 TI - Outcome of reconstruction for duplication of the thumb in adults aged over 40. AB - Congenital duplication of the thumb is usually reconstructed by 18 months of age. This paper reports satisfactory outcome following reconstruction of two Wassel Type IV duplicate thumbs in adults aged over 40. Both achieved a good outcome based on Tada's criteria and a subjective Visual analogue score 8. PMID- 21548164 TI - Bipartite distal phalanx--watch out for this condition! AB - We present a hitherto unreported condition of a bipartite distal phalanx in a child. The condition mimics a fracture and may even lead one to suspect a non union. Potential pitfalls of such a mistaken diagnosis can include unnecessary splinting or even surgery. This could potentially cause injury to the growth plate with resultant growth arrest. Careful clinical and radiographic examination of both hands combined with an awareness of this condition can help avoid such problems. PMID- 21548165 TI - Osteocutaneous radial forearm free flaps: prophylactic fixation of donor site using locking plate augmented with mineral cement. AB - Prophylactic plating of donor site in osteocutaneous radial forearm free flaps have demonstrated improvement in fracture rates. Previous series used conventional plating systems which rely on plate-bone friction forces to generate stability and can result in iatrogenic fractures if not accurately contoured. Locking plates have superior stability and do not require contouring. This retrospective series reports our experience using locking plate fixation augmented with calcium phosphate mineral cement. Twenty patients' records were reviewed; 13 were alive and reviewed clinically. Mean radiological follow-up was 28.2 months. Two deceased patients had donor site fractures diagnosed on the first postoperative radiograph. These fractures were related to technical fixation errors and failure to apply correct locking fixation principles. None of the other patients with proper locking fixation had fractures or metalwork related complications. We believe that locking fixation augmented with mineral cement can provide more biological stability and enhance restoration of bone structural strength. PMID- 21548166 TI - Fixation of comminuted distal radius fractures with a mixture of calcium phosphate and calcium sulfate cement. AB - Distal radius fracture alignment and stabilization can be a surgical challenge in the face of severe comminution and bone loss. We describe a technique using a calcium phosphate/sulfate bone cement, as an adjunct to internal fixation. This bone cement is biocompatible, osteoconductive, and sets quickly with an isothermic reaction. The use of bone cement eliminates the need for primary autologous bone grafting and allows for easier reduction and retention of reduction at the time of surgery. Bone cement is employed for the following purposes in comminuted fractures: (1) to fill a void due to lost or crushed cancellous bone, (2) to hold larger unstable fragments while hardware is placed, and (3) to retain fragments too small to take hardware. Available bone cements, studies involving the use of bone cement for distal radius fractures, indications, and surgical technique will be reviewed. PMID- 21548167 TI - Use of a hand drill to remove particulate contamination within a traumatic bone tunnel. AB - We report a novel method of debridement for penetrating trauma to the hand involving bone using a sterile hand drill. This provides a means for adequate clearance of debris which may otherwise be left in-situ due to poor access to the contaminants when conventional techniques of debridement are used. PMID- 21548168 TI - Headaches in older adults. Sorting out the cause. PMID- 21548169 TI - Jury still out on low-dose aspirin and cancer. PMID- 21548170 TI - Small-bowel obstruction. A gut-pain emergency. PMID- 21548171 TI - What causes a collapsed vertebra in the spine? PMID- 21548172 TI - [Fitness for employment]. PMID- 21548173 TI - Ask the doctor. I recently developed a craving to chew on several ice cubes a day. What causes this? Is it unhealthy? PMID- 21548174 TI - Diabetes: criteria for the diagnosis and treatment of gestational diabetes mellitus--time for a change. PMID- 21548175 TI - Cancer: screening for thyroid cancer in patients with FAP is worthwhile. PMID- 21548176 TI - Diabetes: retinopathy: a surrogate measure of T2DM duration. PMID- 21548177 TI - Lipids: HDL cholesterol--new insights. PMID- 21548178 TI - Probiotics and obesity: a link? PMID- 21548179 TI - Abstracts of IFCC (International Federation of Clinical Chemistry and Laboratory Medicine) WorldLab Berlin 2011. May 15-19, 2011. Berlin, Germany. PMID- 21548180 TI - Evaluating diagnostics: dengue. PMID- 21548181 TI - Venous thromboembolism after total hip arthroplasty and total knee arthroplasty: current and future perspectives. Epilogue. PMID- 21548182 TI - A guide for diagnostic evaluations. AB - Accurate diagnostic tests have a key role in patient management and the control of most infectious diseases. Unfortunately, in many developing countries, clinical care is often critically compromised by the lack of regulatory controls on the quality of these tests. The information available on the performance of a diagnostic test can be biased or flawed because of failings in the design of the studies which assessed the performance characteristics of the test. As a result, diagnostic tests are sold and used in much of the developing world without evidence of effectiveness. Misdiagnosis leading to failure to treat a serious infection or wasting expensive treatment on people who are not infected remains a serious obstacle to health. PMID- 21548183 TI - Venous thromboembolism after total hip arthroplasty and total knee arthroplasty: current and future perspectives. PMID- 21548184 TI - Evaluation of diagnostic tests for infectious diseases: general principles. PMID- 21548185 TI - Evaluation of diagnostic tests: dengue. PMID- 21548186 TI - Changing needs of community-acquired bacterial pneumonia: experience with ceftaroline fosamil. Preface. PMID- 21548187 TI - Abstracts of the 56th Annual Meeting of the Plastic Surgery Research Council. April 27-30, 2011. Louisville, Kentucky, USA. PMID- 21548188 TI - US stem-cell funding ban overturned. PMID- 21548189 TI - Proceedings of the First International PlantPower Symposium. February 10, 2011. Ghent, Belgium. PMID- 21548191 TI - Engaging communities to create active living environments. Proceedings of the Active Living Research Annual Conference. February 9-11, 2010. San Diego, California, USA. PMID- 21548190 TI - US farm-science head quits. PMID- 21548192 TI - Systems immunology: complexity captured. PMID- 21548193 TI - [Is Romanian pneumology in crisis?]. PMID- 21548194 TI - [Update regarding the role of biomarkers in early diagnosis of non-small cell bronchopulmonary cancer]. AB - Early diagnosis of lung cancer by non-invasive methods has a low sensibility: 60% of peripheral cancers could be diagnosed by computed tomography, 60% of the central ones by sputum cytology. More specific for detecting central microinvasive lesions could be bronchoscopy with autofluorescence, but this is a method with a low number of patients to be performed on, because of the specific technique. For all these reasons there are some other methods to be tried in this respect--one of them is to find one or more molecules--tumoral markers--which have to be specific in establishing the risk of developing lung cancer, to make an early diagnosis of cancer and to predict the evolution under treatment. The detecting tumoral markers in sputum, blood, bronchoalveolar lavage was not so largely explored related to the final goal--the possibility of identifying and quantifying the most specific ones for the screening of lung cancer. The present paper has as purpose to make an review of tumoral markers--"classical" markers as: CEA, NSE, TPA, beta2 microglobulina, CA 125, CA 15-3--considered not such a high sensibility and specificity for lung cancer screening versus new molecules, studied intensively as: SCC-Ag, CYFRA 21-1, ferritin, sIL-2R, CCK-BB, glycosyltransferases. Those new molecules have a higher sensibility, but also could have a higher specificity for each type of lung cancer. PMID- 21548195 TI - [What is new in the interpretation of polysomnography according to the revised manual for sleep staging in adults? A comparative analysis]. AB - Aim of this paper is to compare the new polysomnography staging manual according to American Academy of Sleep Medicine with Rechtschaffen & Kales rules, underlying the newly introduced aspects and illustrated with polysomnographic images. The new rules simplify the staging but increase the time of electrodes application. They were established on the base of low levels of evidence, without being included in the multicenter statistical validation. For the first time in literature are given details about the criteria for the interpretation of sleep in children, but there are problems still remain unanswered, such as those regarding the scoring of hypopnea. In Romania, the main problem is primarily limited access to investigation and the deficit of health professionals. PMID- 21548196 TI - [Indacaterol--a new hope for maximising bronchodilation?]. AB - Development new treatments for chronic obstructive respiratory disease is still a far away dream. Naturally, researchers focused on improving efficiency of existent molecules. A new beta-2 adrenergic class was born recently: the ultra LABA's. First player that was already adopted in current practice is indacaterol. Indacaterol is a beta-2 adrenergic rapidly acting, with an onset of action in 5 minutes, like salbutamol and formoterol but with a sustained bronchodilator effect, that last for 24 hours, like tiotropium. Indacaterol clinical study program, INERGIZE, followed three main directions: prove superiority over placebo, evaluate indacaterol among others established bronchodilators routinely used in COPD management and establish long-term safety profile. In patients with moderate-severe COPD, indacaterol, both 150 and 300 microg showed a rapidly and sustained improvement in pulmonary function, increasing FEV1 with 130-180 ml (p < 0.001) versus placebo (INLIGHT 1). Comparing to salmeterol, there was a superior improvement in FEV1, that starts from day 1 and last unchanged till the end of study (p < 0.01 vs salmeterol; INLIGHT 2). Over 12 mcg formoterol twice daily, 300 microg indacaterolul, once daily showed superiority in improving pulmonary (p < 0.001 vs formoterol; Involve), that is present form day 2, with no ceiling effects over one year, unlike formoterol. As an outcome for secondary objectives, indacaterol proved superior improvement in breathlessness at 12 weeks, (TDI score, p < 0.01 vs formoterol). Regarding exacerbations, indacaterol was at least as effective in reducing exacerbations, as formoterol. Open-label study over tiotropium, INHANCE, compared indacaterol, 150 and 300 microg, with tiotropium, 18 microg, both once daily, for 6 month. At 12 weeks, primary objective for all indacaterol studies, both indacaterol doses showed FEV1 improvement of 180 ml versus 140 ml for tiotropium (p < or = 0.01). % of patients with improvement in TDI score > 1 unit at the end of the study was in favour of indacaterol 300 microg (p < or = 0.01). Authors conclusion was that once daily indacaterol is at least as effective as tiotropium, in its symptoms and health status. The availability of a new once daily bronchodilator, that maximize efficiency of beta 2 adrenergics may provide clinicians with more flexibility in treating COPD, and may increase adherence to treatments for patients. PMID- 21548197 TI - [Pathophysiology and treatment of bronchectasis]. AB - Bronchiectasis is a complex pathology which consists of some important morphopathological changes in the lumen of the bronchi that consecutively determines recurrent pulmonary infections with a diversity of germs. The repeated episodes of infection are associated with chronic colonization of the respiratory system with certain pathogen microorganisms and play an important role in the maintenance of the chronic inflammatory syndrome, as well as the decline of the pulmonary function. This chronic inflammation is represented by a series of fisiopathological changes (the raised number of neutrophiles, macrophages, alteration in the expression of pro-inflammatory cytokine and adhesion molecules). The first hand treatment of patients with infected bronchiectas is the antibiotic treatment, followed by anti-inflammatory treatment and adjuvant therapy. The use of macrolides in the long-term treatment schemes has confirmed their role in the reduction of the chronic inflammatory syndrome associated with this disease, moreover its association with the anti-inflammatory medication has significantly improve the patient's health status. PMID- 21548198 TI - [Antibiotic resistance of S. pneumoniae and H. influenzae strains isolated from patients with community acquired respiratory tract infections. BACTRO multicenter, multidisciplinary study]. AB - Community respiratory tract infections are common in clinical practice. Antimicrobial treatment should be promptly administered and guided by a probabilistic approach according to the clinical presentation and local patterns of bacterial resistance. Bacterial resistance is widespread, with large geographical variations related to behaviors in antibiotics prescription. S. pneumoniae and H. influenzae are the most frequent pathogens responsible for respiratory tract infections etiology. METHODS: We assessed the antibiotics susceptibility of S. pneumoniae and H. influenzae strains isolated from patients with community respiratory tract infections, prospectively enrolled over a period of 3 consecutive years, by determining the MIC. Analysis was performed using both cutoffs provided by European Committee on Antimicrobial Susceptibility testing (EUCAST) and CLSI. Consequently we evaluated the influence of different factors associated with the development of bacterial resistance. RESULTS: We analyzed 293 S. pneumoniae strains and 265 H. influenzae strains isolated during 1999-2001, mainly from sputum (68.3% and 74.9% respectively of total isolates). We observed a high proportion of S. pneumoniae resistant to penicillin (6.1% resistant and 48.5% with intermediate susceptibility) and to erythromycin (39% resistant strains). H. influenzae strains were resistant to amoxicillin in 26% of cases and the presence of betalactamase was certified in 13% of tested isolates; 18.3% of H. influenzae strains were resistant to amoxicillin through specific mechanisms other than by producing betalactamase. Other antibiotic resistances were assessed. CONCLUSIONS: In Romania clinician must consider the high prevalence of antibiotic resistance, particulary of S. pneumoniae to macrolides and beta lactams (thus requiring the use of high doses of betalactams) and the high proportion of beta-lactamase producing H. influenzae. PMID- 21548199 TI - [Radiation induced lung injuries secondary to radiotherapy for breast cancer]. AB - Modern radiotherapy decreased the number and severity of the effects of irradiation on the lung. Yet, the increased cancer incidence makes the related radiation injuries to remain actual, radiotherapy being frequently used in cancer treatment. Aim of the study consists in analysis of the radiological pattern of radiation induced lung disease due to radiotherapy for breast cancer. MATERIAL AND METHOD: Sixty-eight female patients were evaluated for clinical and radiological suspicion of radiation pneumonitis after radiotherapy for breast cancer between 2001 and 2009 in "Marius Nasta" Institute of Pneumophtiziology, Bucharest. The following procedures were performed: medical history, physical examination, chest radiography and CT-scan (in a subgroup of 27 patients). Radiotherapy toxicity was evaluated based on the RTOG/EORTC (Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer) classification and radiological lesions based on Arriagada classification. RESULTS: Fifty patients (73.5%) were symptomatic (fever, dry cough, dyspnea, chest pain, fatigability), the other 18 were asymptomatic. Symptoms were mild to moderate corresponding to grade 1 (27 patients, 39.7%) or grade 2 (23 patients, 33.8%) according to RTOG/EORTC scale. All patients had radiological lesions: 25 patients (36.7%) had grade 2 lesions (linear opacities), 25 patients (36.7%) had grade 3 lesions (patchy opacities) and 18 patients (26.5%) had grade 4 lesions (dense opacities), according to Arriagada classification. Symptoms were more frequent in patients with extensive lesions on chest radiography. CT-scan, performed in 27 patients, showed more accurate images. CONCLUSIONS: Chest radiography remains the simplest method in screening for radiation pneumonitis and monitoring its outcome. Adverse effects secondary to radiotherapy are usually mild and self-limited, and the most difficult task remains the differential diagnosis with infections and cancer relapse. PMID- 21548200 TI - [Influence of cheeks support on the results of respiratory resistance measured by the interrupter technique in children]. AB - INTRODUCTION: Interrupter technique (TIF) determines the respiratory resistance (Rocc) and can be used successfully in children, even at low ages as it requires only minimal cooperation. Efforts to standardize this technique are focused on limiting the contribution of upper airway resistance during the measurement. OBJECTIVE: Assessing the influence of cheeks support during the examination on the results of Rocc determined by TIF, both when used as basal examination or for measurement of bronchodilator response. MATERIAL AND METHODS: Sixty-one children diagnosed with asthma were included. Rocc was determined in all patients with both cheeks supported, and without support. Forty-three children subsequently performed spirometry in order to assess the correlation between spirometry and Rocc in the two situations described. To assess bronchodilator response two groups of children were studied, one with the basal and postsalbutamol measurements made with the cheeks supported and the other group with the same tests made without support. RESULTS: Rocc mean values were higher when the cheeks are supported during the examination, the difference being statistically significant. Regarding the correlation with spirometry, there is a good correlation between FEV1, PEF, MEF50 and Rocc in both cases (P < 0.001). deltaFEV1 correlated better with deltaRocc when cheeks were supported. CONCLUSIONS: Rocc measurements using interrupter technique with the cheeks supported registered higher values than those obtained in the absence of cheek support. Assessment of bronchodilator response using the interrupter technique is more accurate when performed with the cheeks supported. PMID- 21548201 TI - [Pulmonary hydatic cyst--a case report]. AB - We present the case of a patient diagnosed in our clinic with pulmonary hydatid cyst, the discovery being incidental, during the investigations for a febrile syndrome accompanied by cough and thoracic pain. Pulmonary Hydatidosis is a disease caused by the location and growing inside the lungs of larval form of Taenia echinococcus granulosus, the way of infection is digestive. Hydatid cyst is a rare pathology, the incidence is higher in some populations related to professions such as sheep or goat raising. Pulmonary cyst diagnosis is made by imagistic methods (chest x-ray, CT, MRI) and bio-umoral methods (white cell count, specific serology), anamnesis and clinical exam can be inconclusive. The treatment of the hydatid cyst is surgical, medical treatment (antibiotic, parasiticid) has some specific indication. We administer antibiotics when we have bacterial suprainfection and parasiticid postoperatively for preventing recurrences or when we suspect rupture of the cyst. From the surgical methods cystectomy followed by capitonnage of the residual cavity (Dor procedure) is to be chosen, so that this fulfills the objectives of removing the cyst and treating the residual cavity with preserving as much as possible from the lung tissue. PMID- 21548202 TI - [P70S6K is involved in the inhibition of testosterone production in TM3 mouse Leydig cells overexpressing Cox7a2]. AB - OBJECTIVE: To investigate the effects of Cox7a2 on the LH-induced testosterone production and the involved autophagy regulating signals in TM3 mouse Leydig cells. METHODS: The Cox7a2-pEYFP-N1 fluorescent protein vector was constructed and transfected into TM3 mouse Leydig cells. The level of testosterone was determined by ELISA, and the effects of Cox7a2 on the expression of the steroidogenic acute regulatory protein (StAR) and the phosphorylation of the autophagy regulatory factor P70S6K were detected by Western blot. RESULTS: LH stimulation increased the StAR protein expression and testosterone production, while Cox7a2 decreased P70S6K phosphorylation, reduced StAR expression and consequently inhibited LH-induced testosterone biosynthesis in the TM3 Leydig cells. CONCLUSION: Cox7a2 inhibits testosterone production by decreasing the StAR protein expression, which might be at least in part related with the activation of autophagy in TM3 mouse Leydig cells. PMID- 21548203 TI - [Semen quality of the men from six districts in Chongqing]. AB - OBJECTIVE: To investigate the quality and spatial distribution features of semen and to evaluate the reproductive health of the males in the Chongqing section of the Three-Gorge Reservoir area. METHODS: We collected semen samples by masturbation after 2 -7 days of abstinence from the men in Nan'an, Shapingba, Zhongxian, Wanzhou, Yunyang and Wushan of Chongqing, which are geographically and demographically representative of the Three-Gorge Reservoir area. We analyzed the semen quality of all the samples and evaluated the reproductive health of the men. RESULTS: The mean value of the five semen parameters of the male subjects from the six districts was within the normal range, including semen volume, sperm concentration, total sperm count, rapid progressive motile sperm, and total motile sperm. Those from Shapingba, Yunyang and Zhongxian exhibited abnormal sperm motility. According to the WHO criteria, normal value of all the semen parameters was found in less than 50% of the semen samples from the six districts, in 47% of those from Yunyang, and only 16% of those from Wanzhou. Spatial distribution maps of the semen parameters revealed significant spatial differences in seminal quality among the six districts, the highest in Yunyang, and the lowest in Wanzhou and Wushan that are located in the middle and lower reaches of the Three-Gorge Reservoir area. CONCLUSION: The mean value of semen parameters was low in a large proportion of men in the Chongqing section of the Three-Gorge Reservoir area, with spatial differences along the Changjiang river. PMID- 21548204 TI - [Effects of a microfluidic sperm sorter on sperm routine parameters and DNA integrity]. AB - OBJECTIVE: To investigate the effects of a microfluidic sperm sorter on the routine parameters and DNA integrity of human sperm. METHODS: We divided 40 semen samples into two aliquots and performed sperm sorting using a self-made polydimethylsiloxane microfluidic sperm sorter and the swim-up method, respectively. Then we evaluated and compared the effects of these two methods on the sperm routine parameters and DNA integrity by computer-assisted sperm analysis and sperm chromatin dispersion test. RESULTS: After processing, sperm motility, normal morphology and tail hypoosmotic swelling rate were significantly improved, while sperm DNA damage remarkably decreased (P < 0.01). The microfluidic sperm sorter achieved a significantly lower rate of sperm DNA damage than the swim-up method ([ 8.4 +/- 5.8 ]% vs [16.4 +/- 9.2] %, P < 0.01), but no statistically significant differences were found in all other parameters between the two methods. CONCLUSION: High-quality sperm with less DNA integrity damage could be obtained in sperm sorting with the microfluidic sperm sorter. PMID- 21548205 TI - [Stromal cells inhibit Kallikrein 7 expression in the epithelial cells of benign prostate hyperplasia]. AB - OBJECTIVE: To investigate the influence of stromal cells on the Kallikrein 7 (KLK7) expression of epithelial cells in benign prostate hyperplasia (BPH). METHODS: We constructed a stromal-epithelial co-culture model after separating the two types of cells from BPH tissues and identifying them by cell morphology and chemiluminescent microparticle immunoassay (CMIA). The expression of KLK7 mRNA was detected by RT-PCR in the epithelial cells with or without the stromal cells, and that of the KLK7 protein (hK7) determined by Western blot. RESULTS: Stromal and epithelial cells were successfully separated and identified, and a stromal-epithelial co-culture model successfully established. RT-PCR showed that the mRNA expression of the KLK7 gene was higher in the epithelial cells co cultured with stromal cells than in the epithelial cells alone, and the gray value of KLK7 to GAPDH was 1.41 +/- 0.041 in the former and 1.78 +/- 0.10 in the latter (P < 0.01). The results of Western blot were consistent with those of RT PCR. CONCLUSION: Stromal cells can suppress the expression of the KLK7 gene in the epithelial cells in BPH. KLK7 may be involved in the change of epithelial cells stimulated by stromal cells. PMID- 21548206 TI - [Pentosan polysulfide sodium for chronic non-bacterial prostatitis in the rat model]. AB - OBJECTIVE: To investigate the therapeutic effect of pentosan polysulfide sodium (PPS) on chronic non-bacterial prostatitis (CNP) in rats. METHODS: Based on Robinette's method, we established a CNP model in 80 male SD rats, aged 6 months and weighing 315 - 450 g, by castration followed by subcutaneous injection of estradiol at 0.25 mg / (kg x d) for 30 consecutive days. Then we randomly allocated the model rats into a placebo group (n = 40) and a PPS group (n = 40) to receive intragastric administration of normal saline and PPS, respectively. After 8 weeks of treatment, the pathological changes in the rat prostatic tissue were observed by HE staining. RESULTS: Varied degrees of chronic inflammation and inflammatory cell infiltration were seen in the prostatic tissues of both groups of rats before the treatment. The inflammation was significantly improved after the treatment in the PPS group but not in the placebo group. CONCLUSION: PPS has some therapeutic effect on CNP in the rat, and its mechanism may be associated with the abilities of PPS to repair the damaged glycosaminoglycan layer and inhibit inflammation in the prostate. PMID- 21548207 TI - [Characterization of prostate cancer cell lines and their epithelial-mesenchymal transition in subcutaneous tumors]. AB - OBJECTIVE: To identify the differences in the expression of epithelial or mesenchymal standard proteins between prostate cancer cell lines and tumors, and to investigate the relationship between the process of the prostate cancer cell line forming subcutaneous tumors and epithelial-mesenchymal transition (EMT) by comparing the characteristics of different prostate cell lines forming subcutaneous tumors in SCID mice. METHODS: We constructed prostate cancer models in male SCID mice by subcutaneous injection of 4 human prostate cancer cell lines DU145, Tsu, PC3 and LNCaP, and compared the characteristics of tumor formation. We used Western blot to detect the expressions of E-cadherin and Vimentin in the cancer cell lines and subcutaneous tumors, observed their differences before and after tumor formation, and explore the relationship between EMT and tumor formation. RESULTS: The EMT positive cells DU145 and Tsu showed a higher rate and speed of tumor formation than the EMT negative ones PC3 and LNCaP. The expression of E-cadherin was down-regulated in DU145, up-regulated in Tsu, and absent in PC3 and LNCaP. CONCLUSION: EMT positive cells have a stronger ability of forming tumors than EMT negative cells, and mesenchymal-epithelial transition does exist in subcutaneous tumor formation. PMID- 21548208 TI - [Effects of nonylphenol and cadmium on sperm acrosome reaction in vitro in mice]. AB - OBJECTIVE: To study the effects of nonylphenol and cadmium on acrosome reaction in vitro in mouse spermatozoa. METHODS: Sperm were collected from the vas deferens of mice, capacitated in vitro and stimulated with A23187 at 30 micromol/L to induce acrosome reaction. Then the sperm suspension was treated with nonylphenol at 10, 20, 30, 60 and 100 micromol/L or cadmium at 500, 2500 and 5 000 micromol/L, and the control group treated with the carrier solvent. Acrosome reaction of the sperm was analyzed by FITC-PSA staining. RESULTS: Compared with the control group, nonylphenol significantly inhibited acrosome reaction at the concentration of > 60 micromol/L (P < 0.01), but not at < 30 micromol/L (P > 0.05), and the sperm survival rate was reduced with increased concentration of nonylphenol. However, cadmium exhibited no significant influence on either acrosome reaction (P > 0.05) or sperm survival rate at 500 - 5 000 micromol/L. CONCLUSION: Nonylphenol and cadmium affect the spermatogenesis of mice in different ways; the former directly inhibits sperm acrosome reaction, while the latter has no direct effect on it. PMID- 21548209 TI - [Small-dose vardenafil restores erectile function after penile surgery]. AB - OBJECTIVE: To investigate the impact of penile surgery on the erectile function of the patient and to evaluate the role of small-dose vardenafil in restoring the impaired penile erection. METHODS: Sixty cases of penile cavernosum surgery were equally and randomly divided into a vardenafil and a control group, the former treated 5 - 7 days after surgery with 10 mg vardenafil every other day, while the latter given vitamin E at 100 mg once a day, both for 12 weeks. The penile erectile function of the patients was evaluated with the IIEF-5 questionnaire before surgery and at 3 and 6 months after vardenafil medication. RESULTS: The mean IIEF-5 scores of the vardenafil group were 18.83 +/- 2.98 and 20.13 +/- 2.98 at 3 and 6 months after vardenafil medication, significantly higher than 14.21 +/ 3.62 before surgery (P > 0.05), while that of the control group was significantly decreased at 3 months as compared with the preoperative score (13.38 +/- 2.82 versus 15.80 +/- 3.02, P < 0.05). The vardenafil group showed the highest IIEF-5 score after surgery (P < 0.05). CONCLUSION: Long-term administration of small-dose vardenafil after penile surgery helps to restore and maintain penile erectile function. PMID- 21548210 TI - [Expression of RhoGDI alpha in human testes and sperm and its correlation with the success rate of IVF]. AB - OBJECTIVE: To investigate the expression of RhoGDIalpha in human testes and spermatozoa, and compare the expression of RhoGDIalpha in the ejaculated spermatozoa from normozoospermic me and infertile patients men receiving in vitro fertilization (IVF). METHODS: The localization of RhoGDIalpha in the human testis was determined by immunohistochemistry, and that in the pre-capacitated, capacitated and acrosome-reacted sperm by immunofluorescence. Western blot was used to detect the expression of RhoGDIalpha in the semen samples obtained from normozoospermic males (n = 10), IVF patients with high fertilization rates (> or = 60%, n = 12) and those with low fertilization rates (< 60%, n = 13). RESULTS: Immunohistochemistry showed that the RhoGDIalpha protein was located in all spermatogenic cells and highly expressed in the elongated spermatids. Immunofluorescence exhibited a high expression of RhoGDIalpha in the acrosome and flagellum of human sperm, which decreased in the acrosome after capacitation and disappeared after acrosome reaction. Western blot revealed an obviously decreased expression of RhoGDIalpha in the spermatozoa of the IVF patients with low fertilization rates (0.66 +/- 0.18), with statistically significant difference from those with high fertilization rates (0.97 +/- 0.17) and the normozoospermic men (1.13 +/- 0.21). CONCLUSION: The RhoGDIalpha protein is located in the acrosome and flagellum of human sperm, and might be involved in sperm movement, capacitation and acrosome reaction. The significantly reduced expression of RhoGDIalpha in the sperm of low-fertilization patients suggests that it may be a new diagnostic biomarker for male infertility, and has a potential application value in sperm selection for IVF. PMID- 21548211 TI - [Binding characteristics of interleukin 11 analogue-cyclic nonapeptide c(CGRRAGGSC) to human prostate cancer PC-3 cells: an in vitro study]. AB - OBJECTIVE: To investigate the binding characteristics of interleukin 11 (IL-11) analogue-cyclic nonapeptide c(Cys-Gly-Arg-Arg-Ala-Gly-Gly-Ser-Cys) NH2 C30H54N16O10S2, c(CGRRAGGSC), and human prostate cancer PC-3 cells. METHODS: c(CGRRAGGSC) was labeled with fluorescent dye LSS670, and the location of LSS670 cyclic nonapeptide in the PC-3 cells was investigated by fluorescent microscopy. Flow cytometry was used to detect the fluorescence intensity of the in vitro binding of LSS670-c (CGRRAGGSC) to PC-3 cells and calculate its IC50 and Ki in competitive inhibition experiments. 99Tcm-DTPA-c(CGRRAGGSC) was synthesized by the reaction of 99mTcO4- with c(CGRRAGGSC). The binding characteristics of 99mTc DTPA-c(CGRRAGGSC) and IL11R in the PC-3 cells were analyzed by radioreceptor assay. Bmax and Kd were calculated in saturability and reversibility experiments. RESULTS: The binding of LSS670-c(CGRRAGGSC) to the PC-3 cells showed the characteristics of saturability and concentration-time dependence. Unlabeled c(CGRRAGGSC) and LSS670-c(CGRRAGGSC) exhibited a competitive inhibition on the PC 3 cells (IC50 = [6.31 +/- 0.12] nmol/L, Ki = [2.11 +/- 0.14] nmol/L). Fluorescence was mainly distributed in the cell membrane (Kd = [0.32 +/- 0.02] nmol/L, Bmax = [754 +/- 34] fmol/mg pro). CONCLUSION: c (CGRRAGGSC) could bind PC 3 cells through a receptor-mediated pathway. PMID- 21548212 TI - [Clinicopathological analysis of testicular mixed germ cell tumor]. AB - OBJECTIVE: To investigate the clinicopathological characteristics of primary testicular mixed germ cell tumor (MGCT). METHODS: We retrospectively analyzed the clinicopathological data of 13 cases of primary testicular MGCT and reviewed other relevant literature. RESULTS: MGCT accounted for 24.1% (13/54) of all the testicular germ cell tumors diagnosed in our hospital. The patients ranged in age from 2 to 53 years, averaging at 28.3 years. All were unilateral cases, 6 in the left and 7 in the right testis, with a left/right ratio of 0.86:1. Morphologically, testicular MGCT displayed a variety of subtypes, embryonal carcinoma in 11 cases (84.6%), seminoma in 8 (61.5%), teratoma in 6 (46.2%), choriocarcinoma in 4 (30.8%) and yolk sac tumor in 4 (30.8%). Nine of the cases (69.2%) were composed of two different germ cell histological elements, 3 (23.1%) composed of three, and 1 (7.7%) composed of five. CONCLUSION: Testicular MGCT is rather rare and most commonly occurs in young men. Its biological behavior, clinical management and prognosis vary with its different histological elements. Therefore accurate pathological diagnosis is essential and immunohistochemistry plays an important role in the diagnosis and differential diagnosis of testicular MGCT. PMID- 21548213 TI - [Diet-induced obesity increases the apoptosis of testicular spermatogenic cells in pubertal male rats]. AB - OBJECTIVE: To investigate the effect of diet-induced obesity on the apoptosis of testicular spermatogenic cells in pubertal male rats. METHODS: Forty healthy male rats were equally and randomly divided into a control and a high-fat group, the former fed on normal diet, while the latter high-fat and high-calorie diet. The testes of the rats were harvested at the end of 10 weeks for detection of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) in the peripheral blood with the automatic biochemical analyzer. Pathological changes of the testis were observed under the light microscope, the apoptosis of the testicular cells detected by TUNEL, the expressions of Bcl-2 and Bax proteins determined by immunohistochemistry, and those of Bcl-2 mRNA and Bax mRNA measured by RT-PCR. RESULTS: The levels of TC, TG, LDL-C and HDL-C were significantly higher in the high-fat group (5.17 +/- 0.17, 1.18 +/- 0.09, 1.76 +/- 0.11 and 5.08 +/- 0.18) than in the control (1.38 +/- 0.12, 0.39 +/- 0.05, 0.97 +/- 0.07 and 0.75 +/- 0.06) (P < 0.05), so was the apoptotic index of spermatogenic cells (37.17 +/- 2.74 versus 5.16 +/- 0.81, P < 0.01), and the apoptotic spermatogenic cells were mainly spermatogonia and spermatocytes. The expressions of Bax protein and Bax mRNA were markedly higher in the high-fat group (153.26 +/- 8.74 and 1.08 +/- 0.12) than in the control (101.81 +/- 6.14 and 0.37 +/- 0.04) (P < 0.01), while those of Bcl-2 protein and Bcl-2 mRNA remarkably lower in the former (139.26 +/- 7.21 and 0.46 +/- 0.05) than in the latter (159.37 +/- 8.96 and 1.05 +/- 0.11) (P < 0.01). CONCLUSION: Diet-induced obesity can increase the apoptosis of spermatogenic cells in the rat testis, which may be associated with the reduced expression of Bcl-2 and elevated expression of Bax. PMID- 21548214 TI - [Tolterodine tartrate combined with alpha-receptor blocker for benign prostatic hyperplasia with detrusor overactivity]. AB - OBJECTIVE: To evaluate the efficacy and safety of Tolterodine Tartrate combined with the alpha-receptor blocker in the treatment of benign prostatic hyperplasia with detrusor overactivity (BPH-DO). METHODS: A total of 113 patients with BPH-DO were randomly assigned to receive Tolterodine Tartrate combined with Cardura (Group A) and Cardura alone (Group B), both for 12 weeks. Then we recorded and compared their average 24 h urinary frequency, IPSS and QOL score, maximum urinary flow rate, residual urine volume and urinary retention times before and after the treatment. RESULTS: After the treatment, Group A showed significantly better improvement in the average 24 h urinary frequency and scores on IPSS and QOL than Group B. No significant differences were found between the two groups in the maximum urinary flow rate and residual urine volume. No acute urinary retention occurred in either group. CONCLUSION: The combined use of Tolterodine Tartrate and the alpha-receptor blocker can effectively relieve the symptoms of dysuria, urinary frequency and urinary urgency in patients with BPH-DO, with neither significant adverse effects on the maximum flow rate and residual urine volume nor increase in the incidence of acute urinary retention. PMID- 21548215 TI - [Cigarette smoke extract reduces NOS activity and CX43 expression in the corporal cavernosum]. AB - OBJECTIVE: To study the effects of different doses of cigarette smoke extract (CSE) on the erectile function of male rats and the mechanism of smoking-induced erectile dysfunction (ED). METHODS: A total of 75 healthy male SD rats were randomly divided into Groups A (control), B (dimethyl sulphoxide [DMSO]), C (low dose CSE), D (medium-dose CSE) and E (high-dose CSE). CSE models were established in male SD rats by hypodermic injection, and 60 days later observed for penile erection following subcutaneous injection of apomorphine. Then the rats were killed and the penile cavernous body obtained for the examination of NOS activity by chromatometry and the determination of Cx43 expression by laser scanning confocal fluorescence microscopy (LCSM). RESULTS: Compared with the control and DMSO groups, penile erection frequency, NOS activity and Cx43 expression in the penile cavernous tissue were significantly decreased in the CSE groups (P < 0.05), and the decrease was proportional to the increase of the doses of CSE. No statistically significant differences were observed between the control and DMSO groups (P > 0.05). CONCLUSION: Cigarette smoke obviously reduces NOS activity and Cx43 expression in the penile cavernous tissue and seriously affects penile erection. The higher the dose, the more serious the influence. The decreases of NOS activity and Cx43 expression may be an important mechanism of ED. PMID- 21548216 TI - [Advances in the study of the differentiation of stem cells into male gametes]. AB - male gametes play a critical role in transmitting hereditary information to the offspring. Gametogenesis, especially spermatogenesis, is a complicated differentiation process including mitosis and meiosis. However, for lack of an efficient and reproducible model, the mechanism of male germ development is not yet clear. Researches on stem cells'differentiation into male gametes in vitro will promote the study of germ cell development and even reproductive biology. This article updates the researches on the culture of primordial germ cells and stem cells' differentiation into male gametes. PMID- 21548217 TI - [Molecular genetics of Kallmann syndrome: an update]. AB - Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder that occurs in either an inherited or a sporadic manner. KS results from failed embryonic migration of GnRH-1 neurons from the nasal placode to the hypothalamus, due to the abnormal development of olfactory nerves and bulbs. Hypogonadotropic hypogonadism is related to GnRH deficiency, and anosmia is associated with the absence or hypoplasia of olfactory bulbs and tracts. KS patients can also present some non-reproductive or non-olfactory anomalies in addition to the above typical symptoms. For the high complexity of the molecular genetic mechanism of KS, to date, only 6 KS-related genes have been identified. The KAL1 gene is responsible for the X chromosome-linked recessive form of KS, while the fibroblast growth factor receptor 1 (FGFR1/KAL2) and fibroblast growth factor 8 (FGF8/KAL6) genes are related to the autosomal dominant form of the disease. However, the mutations in these 6 genes account for only about 25 - 30% of all KS cases, which suggests that other pathogenic genes involved in KS remain to be discovered. This article presents an overview on the studies of the pathogenic genes, clinical diagnosis and treatment of KS. PMID- 21548218 TI - [Patient drug information?]. PMID- 21548219 TI - [Intracerebral calcifications]. PMID- 21548220 TI - [Vascular Ehlers-Danlos syndrome]. PMID- 21548221 TI - [Hyperventilation syndrome]. AB - Hyperventilation syndrome is a disorder affecting children and adults, mostly women. It is frequently associated with anxiety disorders, and greatly affects quality of life. Diagnosis, which unfortunately is most often established late, is a diagnosis of elimination. It rests on a wide range of non-specific signs, on Nijmegen's clinical scale as well as on a hyperventilation provocative test. In most cases, specialized therapeutic interventions allow for an adequate control of ventilation and symptom relief. PMID- 21548222 TI - [Sweet's syndrome]. PMID- 21548223 TI - [Nontuberculous mycobacterial infections]. AB - The nontuberculous mycobacteria (NTM) denomination includes a large number of species with highly variable pathogenicity for humans. NTM infections are increasingly recognized. Several reasons explain their emergence as a human disease: increasing number of patients at risk, improved microbiological techniques, perhaps a more frequent exposure. Therefore, clinicians must know the clinical spectrum of NTM disease. This article summarizes the classification of NTM. It describes the clinical features of NTM infections and their treatment. PMID- 21548224 TI - [Observation of the child from 3 to 12 years. An uninterrupted maturation period associated with many vulnerabilities]. PMID- 21548225 TI - [Clinical exam of children from 3 to 12 years]. AB - The specific aims of clinical exams of children from 3 to 12 years of age are to assess: growth including weight and height, and body mass index (BMI) to prevent obesity, neurodevelopment both motor and intellectual including sensorial impairment to detect early learning disabilities, immunization adequacy by assessing routine schedule of vaccination and booster. The GP or paediatrician should cooperate with specialised services and nursery or primary schools to match the system of education to the needs of a given child, particularly in case of learning disabilities (normally, entry into kindergarden at 6 years of age). PMID- 21548226 TI - [Specific impairments and neurodevelopmental disorders in 3- to 12-year olds]. AB - Difficulties in scholarship in children are very frequent reasons for consultation in general practice. General practitioners' role is primordial in screening, diagnosis and management in these complex and long-lasting disorders. Learning difficulties often stem from developmental disorders, which are frequently co-occurring and may be associated with emotional and behavioural disorders. They often persist in adulthood, but may benefit from active management associating training interventions and school accommodations. PMID- 21548227 TI - [Hearing disorders in 3- to 12-year-olds]. AB - The hearing disorders of the child between 3 and 12 years are dominated by the conductive hearing loss. The questioning, looking for risk factors, as well as the otoscopy are essential to detect and diagnose a hearing disorder. Screening tests help to identify the children with risk of hearing loss. Then, the child is sent for diagnosis towards an ENT specialist or a specialized structure. In spite of the frequency of the conductive hearing loss, in case of the slightest doubt, a sensorineural hearing loss must be always looked for by a puretone audiometry examination via the headphones. PMID- 21548228 TI - [Vision in 3- to 12-year-olds]. PMID- 21548229 TI - [Early signs of mental disorders in children aged 3-12 years]. AB - Neurodevelopmental disorders, affective/emotional disorders and exposure to adverse life circumstances are the main sources of psychological impairment in school age children. They should be distinguished from transient psychological symptoms occurring in normal development that do not significantly affect children's emotional and social functioning. An early recognition and assessment is the first step towards adequate treatment of conditions associated with psychological impairment. Any severe or persistant behavioral or emotional symptom occurring in children should be considered a possible early sign of a neurodevelopmental disorder warranting further investigation. Neurodevelopmental disorders are generally associated with delays early in development affecting several domains (language, social functioning, emotional and behavorial regulation) and are predominant in boys. These disorders are highly comorbid and require multidisciplinary assessments and treatment plans. Emotional and behavioral conditions arising from early deprivation or maltreatment also affect various developmental domains and may have lasting consequences. Finally, many of the disorders showing rising prevalences in adolescence or early adulthood also have some developmental precursors before puberty. Progress in identification, appropriate assessment and treatment of early manifesting symptoms and conditions interfering with adaptive functioning is a major mental health issue requiring multidisciplinary competencies. PMID- 21548230 TI - [Sleep disorders in children from 3 to 12 years]. PMID- 21548231 TI - [Nutritional problems in children from 3 to 12 years]. AB - Assessing the nutritional status is like the bottom line of children's health. The first step is to measure height and weight in proper conditions and to calculate the body mass index (BMI). BMI for sex and age allows identifying overweight and obese as well as underweight children. Both situations lead to a clinical exam in order to find causative disease (obesity of endocrine or genetic origin, malnutrition from somatic or behavioral disease). Routine lab study might help whenever referral to specialist is necessary. Nutritional anemia and vitamin D deficiency are two common situations in children that have to be screened and treated. The general practitioner has a central role in nutritional problems in children since he can manage the care within the whole family. This is particularly the case for obesity but also for dyslipidemia, that has to be screened around 8 years, both being major familial risk factor for cardiovascular diseases. PMID- 21548232 TI - [Follow-up vaccination of children from 3 to 12 years]. AB - From the age of 3 to the age of 12, each consultation should be viewed as an opportunity to review the child's immunization schedule and update his vaccination, if necessary, so that each child receives: two doses of the trivalent measles-mumps-rubella vaccine, one dose of conjugate C meningococcal vaccine, a full immunization against the hepatitis B, on a three-dose schedule until the age of 11, and a two-dose schedule between 11 and 15 years. At-risk populations should be identified so that they can receive additional vaccines (influenza and hepatitis A at any age, pneumococcal invasive infections until the age of 5). PMID- 21548233 TI - [Preteen visit]. AB - Preadolescence, which is considered as an uneventful period since a long time, deserves to be rediscovered. It offers the clinician the opportunity to locate the emergence of diseases hitherto ignored (masked childhood disorders, early beginnings of adolescent pathologies), and to start the care before the pubertal transformations... The challenge is important at a time when the therapeutic alliance is simpler to establish, promotes the accompaniment of anxiety disorders in all their forms (separation anxiety, OCD), mood disorders or ADHD for example. We will touch the specificities of consultations proposed to a population more and more "sucked" by adolescence, and whose profile evolves singularly. PMID- 21548234 TI - [Medical genetics consultation]. AB - Medical genetics have three components: clinical, chromosomal and molecular The role of this clinical-biological discipline is to diagnose genetic diseases, participate in the management of patients, offer genetic counselling to family members concerning the probability of occurrence or reoccurrence of genetic diseases, and suggest preventive measures to couples at risk. A specific aspect of genetic counselling is that it is aimed at healthy or affected individuals taking into account all the members of their family. PMID- 21548235 TI - [Genetic counselor: a new career]. PMID- 21548236 TI - [Genetic tools]. PMID- 21548237 TI - [Role of the geneticist in prenatal diagnosis]. AB - Medical geneticists, assisted by genetic counselors, are one of the main actors of prenatal diagnostic centers. They are involved at all stages of pregnancy: when there is an upstream project and a specific parental history, during pregnancy in case of accidental discovery of anomalies in fetal ultrasound, but also after a medical termination of pregnancy to clarify the subsequent genetic counseling. If possible, genetic counseling should be done before conception, as a first step in accurate diagnosis is often necessary. The results of some sophisticated tests will be known only after several months. PMID- 21548238 TI - [Genetic counseling for children with abnormal embryonic development of genetic origin]. AB - Until recently, clinical dysmorphology was poorly considered in medicine and human genetics. However, the studies of children affected with multiple congenital anomalies syndromes lead to syndrome identification, prognosis and care for the affected children, and genetic counselling for the families. The identification of developmental genes involved in normal and abnormal morphogenesis leads to a better understanding of genetic causes and embryological development. PMID- 21548239 TI - [Genetic counseling for adults: the risk of late-onset inherited diseases]. AB - Genetic counselling for adults is not classical since it deals with prospective assessment of risk in developing disease. 1% of adults have a monogenic disease, or are carriers of a genotype predisposing to a disease. Situations that need genetic counselling are: confirmation of a diagnosis of an inherited disease already known in the family; discovery of a new genetic disease in an adult with no family history of the disease (reduced penetrance); and presymptomatic and prenatal diagnosis for late onset diseases. The prescription of presymptomatic testing is limited to the intervention of multidisciplinary teams, bringing together medical expertise and notified to needed. This is a special situation because it is not always followed by a preventive action or treatment. PMID- 21548241 TI - [Continuing education in the health professions]. PMID- 21548240 TI - [Genetic consultation: hereditary cancer risk?]. AB - Cancer is a genetic disease of cells linked to the accumulation of mutations in genes mainly involved in cell cycle, apoptosis, and in DNA damage repair. In most patients, these mutations are acquired (somatic) during life; in some others, some mutations may be germline, inherited from one parent and transmissible to the offspring. The latter are more prone to cancer. Family cancer genetic clinics, developed since the early nineties, aim to understand the origin of a family history through the first analysis of an index case and to provide adapted counselling regarding the management of index cases and his relatives (genetic test targeted on a mutation identified in the index case). The two most frequent cancer predispositions are presented: breast-ovary syndrome linked to BRCA1 and BRCA2 mutations and Lynch syndrome linked to mutations in the DNA mismatch repair genes and associated with high risks of colorectal and endometrial cancers. PMID- 21548242 TI - [Drug prescriptions: anticipating interactions]. PMID- 21548243 TI - [Anxiety disorders: diagnostic difficulties]. PMID- 21548244 TI - [Travel in tropical countries]. PMID- 21548245 TI - [Genital infections in men]. PMID- 21548246 TI - [Genital infections in women]. PMID- 21548247 TI - [Gastroesophageal reflux, hiatal hernia in infants and children]. PMID- 21548248 TI - [Gait and balance disorders. Falls in the elderly]. PMID- 21548249 TI - [Two centuries of cholera: from India to Haiti]. PMID- 21548250 TI - [Science in simple words]. PMID- 21548251 TI - [Infection prevention during the perioperative period of primary hip and knee arthroplasty]. AB - All surgical wounds are at risk of contamination by pathogens that may get in through the incision. The pre-surgical bath with a skin antiseptic agent 24 hours prior to the surgery, the timing of administration of prophylactic antibiotics, the choice and postoperative duration of the latter, the number of individuals within the OR and the movement inside it, the choice of chlorhexidine gluconate for its long duration against gram-positive and gram-negative organisms, and the use of a hair remover or an electric razor, all of the former concepts, some new and others not so new, led to performing an extensive bibliographic review with the idea of starting a standardization process that could change the way in which institutions operate when performing primary joint replacement, trying to reduce the annual infection rate and upgrade the quality of life of patients. PMID- 21548252 TI - [Steroid infiltrations in orthopedics]. AB - For the past 60 years intraarticular infiltrations have been performed with variable results. However, they have improved with time as a result of the innovations seen in the techniques and the glucocorticoids used, according to reports by several authors. We report the experience and results obtained in 10 years in 793 patients applying 5 mg of betamethasone dipropionate and 2 mg of betamethasone sodium phosphate (Diprospan). This was a retrospective, therapeutic and cross-sectional study. Betamethasone was combined with 1 ml of 2% plain lidocaine and 1 ml of bupivacaine or ropivacaine. Infiltrations were used to treat intraarticular conditions, post-traumatic acute inflammatory conditions and degenerative intraarticular conditions of the knee and shoulder. In the soft tissues they were used to treat bursitis, entrapment syndromes, epicondylitis, plantar fasciitis and sprains. Ninety-two percent had an improved clinical picture; it was possible to avoid surgery for several conditions. The conclusion is that infiltrations with betamethasone, both intraarticular and in periarticular structures, are fully justified in orthopedics. If applied properly, they are safe and effective. PMID- 21548253 TI - [Total knee arthroplasty with ultracongruent tibial insert. Two-year follow-up]. AB - INTRODUCTION: There is no single criterion to select a posterior stabilization system for an arthroplasty; the ultracongruent system may avoid the complications observed with the drawer and the post. OBJECTIVE: To assess the clinical and functional status of total knee arthroplasty with the ultracongruent system and compare the results with those published in the international literature. MATERIAL AND METHODS: A retrospective study was carried out with a descriptive and comparative analysis of the total knee arthroplasties in which the Consensus system was used, to determine the operative time, the range of motion, pain, the Western Ontario and McMaster Universities Osteoarthritis Scale (WOMAC), and the level of satisfaction. RESULTS: Sixty-six arthroplasties were performed; mean age was 70.58 years; 45.5% were right and 54.5% left; the operative time was 76.84 minutes, the VAS pain score was 2.02, the WOMAC score was 17.11, and the range of motion was 96.5 +/- 14.04. Ninety-two percent of the patients are satisfied with the surgical procedure. CONCLUSIONS: The prosthesis with the ultracongruent insert is an effective option to relieve pain in patients with knee pathology. The clinical and functional results were similar to those reported with other stabilization systems. The system is well accepted by the patients. It is recommended as an alternative to prevent the possible complications that occur with the drawer and post system. PMID- 21548254 TI - [The Ludloff-Ferguson approach for congenital hip dislocation in children ages 2 4 years]. AB - OBJECTIVE: The objective of this study is to show that the Ludloff-Ferguson approach is feasible in patients aged 2-4 years and as an outpatient procedure. MATERIAL AND METHODS: Prospective, longitudinal, clinical-trial type of study, conducted from January 2008 to December 2009. Patients aged 2-4 years with a diagnosis of congenital hip dislocation were included. All of them underwent open reduction using the Ludloff-Ferguson approach as an outpatient procedure and they wore a Callot type of cast for 6 weeks. Bilateral hips were treated in a single stage. The study variables included the age, sex, operative time, bleeding, anesthetic time, infections and avascular necrosis of the femoral head. A nonrandomized, non-probabilistic sampling was performed; the statistical analysis included the central trend and scatter measurements, the relative risk, the Spearman correlation and chi2. RESULTS: Fifteen patients were included, 8 females and 7 males, for a total of 21 hips. The latter included 4 left and 3 right hips, and 7 cases were bilateral. Median age was 3 years (range 2-4 years). The mean bleeding was 20 cc with a SD of 5 cc (range: 15-30 cc). The mean operative time was 25 minutes, SD = 7 minutes (range: 17-30 minutes). The chi2 test rejected the Ho for sex and necrosis, and age and avascular necrosis, with a P = 0.005. The results of the Spearman test for sex and necrosis were r = 0.23, P = 0.002, for age and necrosis r = 0.25, and a P = 0.003, for the operative time and avascular hip necrosis r = 0.28, P = 001. There were no infections. DISCUSSION: The open reduction technique with the Ludloff-Ferguson approach is feasible in patients aged 2-4 years as an outpatient procedure, and the risk of avascular necrosis was minimum. PMID- 21548255 TI - [Application of the ubiquicidin 29-41 scan in the diagnosis of pyogenic vertebral osteomyelitis]. AB - BACKGROUND: The non-invasive diagnosis of vertebral osteomyelitis is a difficult one. Studies confirm MRI as the gold standard with 92% sensitivity and 94% specificity. Scintigraphy combined with Tc99-Ga67 used to be the procedure of choice before the advent of PET with labeled glucose, which has a high sensitivity and specificity, but cannot distinguish a focus of infection from inflammation. Scintigraphy with UBI29-41 is an infection-specific study that was recently described in the literature. There are no studies showing its value in the diagnosis of vertebral osteomyelitis. OBJECTIVE: The purpose of the study is to show that the Tc99-UBI29-41 scan has 99% sensitivity for vertebral osteomyelitis. METHODS: This is a study of a diagnostic test. The case series was composed of the records of UBI scans performed at the Nuclear Medicine Department, HcHMAE. The scans were interpreted in a blind and independent fashion by 2 experienced observers. The final diagnosis was obtained with the histopathologic study or a microbiologic culture or with the clinical findings after a follow-up of at least 6 months. The sensitivity, specificity, positive and negative predictive values, and the positive and negative probability ratio were determined, always using a 95% confidence interval (CI). The sample size necessary to show 99% sensitivity with a 95% CI and a statistical power of 80% was 15 patients. The concordance with the kappa index was determined. RESULTS: Twenty-seven patients with suspected vertebral osteomyelitis were included; 15 males and 12 females, with a mean age of 50 years (SD = 16). Fourteen patients had a history of surgery and 12 had metallic implants. Nine patients had a history if spinal infiltrations. The number of patients with a positive scan was 20. The sensitivity for detecting pyogenic vertebral osteomyelitis was 100% (CI: 0.901-1) and the specificity was 87.5% (CI: 0.647-0.875). The positive predictive value was 0.95 (CI: 0.859-0.950), and the negative predictive value was 1 (CI: 0.739-1). The intra- and interobserver kappa value was 1. CONCLUSIONS: The UBI scan showed 100% sensitivity and 88% specificity for vertebral osteomyelitis. Although the role of this method in the diagnostic protocol of the patient with suspected vertebral osteomyelitis has not yet been defined, the scan was useful in this group of patients to arrive at a certain diagnosis. PMID- 21548257 TI - [Comparison between arthrodesis and non-arthrodesis in thoracic and lumbar spine fractures: two-year follow-up]. AB - INTRODUCTION: The currently accepted treatment of thoracolumbar fractures is reduction, decompression, fixation and arthrodesis. However, it is not the perfect solution due to the medium- and long-term consequences of arthrodesis, which include the wear of the adjacent segments above and below. Some previous studies have proposed the treatment with fixation without arthrodesis. However, there are no reports on the medium- and long-term clinical and radiographic follow-up. MATERIAL AND METHODS: Two 20-patient groups treated with transpedicular fixation and decompression, one with and one without posterolateral arthrodesis, were compared. RESULTS: CONTROL GROUP: The mean hospital stay was 5 days. The postoperative visual analog scale pain score was 2 3 in 4 patients; the rest were asymptomatic. The functional Oswestry disability index was 8.3%. The functional economic rehabilitation scale was 4.55. Case group: The mean hospital stay was 5 days. The postoperative visual analog scale pain score was 1-2 in 2 patients; the rest were asymptomatic. The functional Oswestry disability index was 6.3%. The functional economic rehabilitation scale was 6.4. CONCLUSIONS: Both groups had very similar results. The group without arthrodesis had better results in the Oswestry functional disability scale and the functional economic rehabilitation scale. PMID- 21548256 TI - [CT scan evaluation of the syndesmotic diastasis in AO/OTA B and C ankle fractures]. AB - BACKGROUND: There are anatomical variants of the tibiofibular syndesmosis that lead to changes in the radiographic criteria applied to its injury. OBJECTIVE: To determine the syndesmotic diastasis using CAT scan in B and C (AO/OTA) ankle fractures and relate the anatomical variants of the tibial incisure with the separation from the fibula. MATERIAL AND METHODS: Comparative, cross-sectional and prolective screening that included all patients with B and C (AO/OTA) ankle fractures who completed their X-ray and CAT scan assessment. The radiographic parameters included the tibiofibular clearance, tibiofibular overlapping and the internal clearance. The length, depth and shape of the tibial incisure were measured with CAT scan. The statistical method used was the chi2. RESULTS: The total number of patients was 17:8 females (47%) and 9 males (53%), with a mean age of 41 years. Fourteen (82%) had a syndesmotic fracture and 3 had suprasyndesmotic fractures. The CAT scan found 10 concave incisures, 4 irregular and 3 flat ones. The mean depth of the incisure was 2.82 +/- 0.89 mm, and the mean width was 22.18 +/- 3.04. No syndesmotic diastasis was detected radiographically in 6 cases (35.2%); the CAT scan only detected 3 of them (17.7%). The diagnosis of syndesmotic diastasis was made with plain X-rays in 11 cases (64.8%) and with CAT scan in 14 (82.3%) (p = 0.043). CONCLUSION: The X-rays are questionable to define the syndesmotic diastasis, so the CAT scan should be considered in cases of a doubtful diagnosis. PMID- 21548258 TI - [Use of an external fixator in open tibial shaft fractures as definitive treatment]. AB - BACKGROUND: We conducted a study evaluating the clinical and radiologic results of the open tibial shaft fractures using an external fixator as definitive treatment. METHODS: Clinical, observational, descriptive, prospective and longitudinal study. Forty-six patients were included, 40 males (87%) and 6 females (13%), whose age was 31.02 +/- 14.62 years; the time elapsed from the accident to admission in the Emergency Room was 1-16 hours, with a mean of 5.1 +/ 3.35 hours. Ten patients (21.74%) had a Gustilo grade I open fracture, and 36 patients (78.26%) a Gustilo grade II fracture. They were also classified according to the AO classification, with the following resulting groups: 13 (28.9%) patients were A3, 12 (26.1%) were B3, 8 (17.4%) B1, 8 (17.4%) were B2, and 5 (10.9%) were A2. The dynamization of the fixator was done at a mean of 11.56 +/- 1.10 weeks. RESULTS: Forty-three patients had healing at 23.51 +/- 3.62 weeks; Gustilo I fractures healed at 22.8 +/- 3.5 weeks; Gustilo II fractures at 23.7 +/- 3.7 weeks, with a P value of 0.48. In 3 patients (6.53%), due to absence of healing, the external fixator was exchanged for an intramedullary nail with a bone graft, with healing occurring at 18 weeks. Six infections (13%) were reported at the nail insertion site; angulations ranged from 0 degrees to 8 degrees, which is tolerable. CONCLUSIONS: This fixator is safe in properly selected patients, since the few complications that occurred are similar to other reports using different internal fixation methods. PMID- 21548259 TI - [Massive allograft and wrist arthrodesis for a giant cell tumor of the distal radius. Report of two cases and literature review]. AB - INTRODUCTION: The giant cell tumor represents 5% of all the primary bone tumors and 20% of the benign bone neoplasias. The most common locations are the distal femur and the proximal tibia (50%) as well as the distal radius (10%). Treatment methods include the intralesional resection of the latent and active tumors, and broad resection for the aggressive lesions. The wrist reconstruction after broad resection of the distal radius represents a challenge for the orthopedic surgeon. OBJECTIVE: To present 2 clinical cases of patients diagnosed with giant cell tumor of the distal radius who were treated with broad resection and placement of a massive allograft with wrist arthrodesis. To perform a bibliographic review and the analysis of the different treatment methods described. MATERIAL AND METHODS: Description of the treatment and course of each case, as well as a bibliographic review and the analysis of the treatments found. RESULTS: Radiologic data of the allograft integration at 11 months and a functionality which was compatible with all the activities of daily living. DISCUSSION: The massive allograft of the distal radius with wrist arthrodesis represents a very safe and appropriate option for the reconstruction of this anatomic segment after broad resection. PMID- 21548260 TI - [Treatment of unrecent patellar tendon tear with semitendinous and gracilis tendons]. AB - The patellar tendon lesion is very important due to the role of this tendon on the conformation of the extensor mechanism of the quadriceps. When the terminal end of this mechanism is injured, the extensor function of the knee is completely lost and thus the functional capability of the involved limb is completely disrupted. PMID- 21548261 TI - [Anterolateral ankle pain: differential diagnosis and approach. A case report]. AB - The ankle soft tissue pathology represents a very painful disorder for patients who, often times, are not precisely diagnosed. Anterolateral ankle impingement is a condition that occurs in young people and athletes due to a plantar flexion inversion mechanism. We report a case of anterolateral ankle impingement describing the arthroscopic technique and making the differential diagnosis considering other conditions. PMID- 21548262 TI - [Professor Hans-Wilhelm Buchholz]. PMID- 21548263 TI - [Whiplash injury]. PMID- 21548265 TI - [The analysis of language competence and students' needs in teaching English for medical purposes to students of medicine, dentistry and health care]. AB - INTRODUCTION: The paper deals with the analysis of the language competence of the students of Medicine, Dentistry and Health Care at the Medical School of Novi Sad University at the level of their basic language skills of general English and English for Medical Purposes. It also presents the analysis of students' needs of these skills within the field of teaching English for Medical Purposes. OBJECTIVES: The aim of the study was to determine the level of students' language skills, knowledge of general and medical vocabulary and of academic writing in English and to determine which of the skills have the greatest priority in teaching English for Medical Purposes. MATERIALS AND METHODS: The students were given a questionnaire and were asked to grade their language skills and knowledge of general and medical vocabulary and of academic writing on the scale from one to five. For the same skills, the students had to determine the level of priority in teaching English for Medical Purposes. RESULTS: The results were given for each of the groups of students evaluated, and the average grade was calculated for all the skills. The students' needs in terms of the priority of the evaluated skills were also presented in the same manner. Analysis Students' skills were analyzed according to the average grade acquired through the students' self evaluation. The distinction was made between the general language skills and the knowledge of medical vocabulary and academic writing. The analysis of needs was conducted with the same distinction in mind. The study groups were analyzed separately and the general common conclusions for all the groups were made. CONCLUSION: For a successful program of English for Medical Purposes, it is necessary to conduct "the level of general language competence" test and to test the students' needs beforehand. The difference in the level of knowledge between different study groups points to a need of a student oriented teaching program. The analysis of needs shows the importance of all language skills which have to be included in the course Of teaching English for Medical Purposes. PMID- 21548264 TI - [One-year clinical evaluation of tooth-coloured materials in non-carious cervical lesions]. AB - INTRODUCTION: The restoration of non-carious cervical lesions is specific, mostly because of the location of their margins, especially the cervical margin, which is determined in cement and/or dentine. This feature makes the cervical margin more susceptible to micro-leakage, causing marginal discoloration, postoperative sensitivity, development of the secondary caries and loss of the restoration. MATERIAL AND METHODS: One of the criteria for inclusion of a patient in this study was the presence of at least two non-carious cervical lesions to be restored with the minimum depth of 1 mm, independently of their location in the dental arch. A total of 60 restorations were placed in 30 patients. and every patient received both tested materials (composite resins and compomer) on their non-carious cervical lesions. The clinical evaluation of the therapeutic success was performed six months and then one year after the day of the placement of restorations using the modified-United States Public Health Service criteria. The following was evaluated retention, marginal integrity, marginal discoloration, wear, postoperative sensitivity and secondary caries. RESULTS: A statistically significant high percent of restorations/teeth with postoperative sensitivity was found in the group of resin composite restorations after six months. At the end of the evaluation period, that is after one year, there were no statistically significant differences between materials for all evaluated criteria. CONCLUSION: The results of this study show the identical quality of both examined materials one year after the readjustment of non-carious cervical lesions. PMID- 21548266 TI - [Fear of having the antiepileptic drug withdrawn]. AB - INTRODUCTION: The decision to withdraw antiepileptic drugs is based mostly on a balanced view of the overall risk of seizure relapse and factors most likely to affect that risk. The aim of this study was to find out the patient and family's attitudes towards the fear of having antiepileptic drug withdrawn, after three years of seizure control. MATERIAL AND METHODS: This research was carried out at the Institute for Child and Youth Health care of Vojvodina in Novi Sad. During the study, which lasted from 2003 to 2008, a face-to-face interview about fear of having the antiepileptic therapy withdrawn was done within the adolescent patient examination. The study population included 150 adolescent patients and 265 of their parents. RESULTS: In general, the adolescent patients were ready to accept a significantly higher risk of having recurrences after the antiepileptic drug withdrawal (p < 0.05) than their parents. None of their parents was ready to accept the risk 50% higher than the one in the general population. CONCLUSION: It is important to take into consideration the fear of both adolescent patients and their parents of having recurrences of epileptic seizures before opting for the antiepileptic drug withdrawal. PMID- 21548267 TI - [Complications after placement of peritoneal catheter]. AB - INTRODUCTION: Peritoneal dialysis is one of the modalities used for treatment of end-stage chronic kidney failure. Nowadays, this method is complementary to haemodialysis and renal transplantation. Owing to the rich vascularization of the peritoneum, it is used in the processes of osmosis and diffusion, enabling the removal of uremic material from the body. The procedure includes introduction of peritoneal fluid via the peritoneal catheter. COMPLICATIONS: The catheter is placed through the anterior abdominal wall with its tip positioned in the small pelvis. There are several techniques for catheter placement considered minimally invasive, which, however, may be associated with various complications. These complications can be divided into mechanical (catheter dysfunction, cuff protrusion, hernia, dialysate leaks, visceral perforation) and infectious (early peritonitis, exit site or tunnel infection, surgical wounds). In most cases, such complications are rare and can be successfully managed using conservative therapy; however, in some situations severe complications can endanger the life of the patient. On-time recognition of complications, particularly in patients at risk, is of paramount importance for an effective treatment. The development of complications can increase the morbidity and the chance of treatment failure, and therefore transfer to haemodialysis. CONCLUSION: The preoperative evaluation and determination of the risk factors as well as the early recognition and adequate management of complications are essential in their prevention. PMID- 21548268 TI - [Working disability evaluation of mentally ill persons in times of socioeconomic crisis]. AB - INTRODUCTION: Mental disorders reduce social functioning of ill persons in general and often cause permanent work disability. Psychiatric services try to solve individual professional or financial status in economic crisis conditions. The possible causes of disability in psychiatric patients, besides illness, are psychosocial factors. The aim of this research was to determine the number of mentally ill persons as well as morbidity structure changes in work disability evaluation in the last five years. MATERIAL AND METHODS: The research included 617 psychiatric patients referred for work disability evaluation in this five year period (2004-2008). The data contained gender, age, psychiatric diagnosis and the suggested level of disability. RESULTS AND CONCLUSION: In the morbidity structure, a significant increase was found in the group of patients with psychoactive substance abuse, in whom the likelihood of permanent work disability was frequent. A significant decrease was observed in the group of patients with mental retardation. The number of patients with schizophrenia was similar in the study period. The patients with mood disorders, neurotic, stress-related and somatoform disorders were present in a relatively high number. The evaluation and suggestion for permanent work disability increased statistically significantly, while the number of patients in need for material security decreased in the period of socioeconomic crisis. Disability trend in the population of mentally ill patients is still not favourable, and therefore, their work disability monitoring is an adequate parameter which identifies work inefficacy and unemployment as an important factor of a poor life quality in psychiatric patients. PMID- 21548269 TI - [Conformal radiotherapy of prostate carcinoma--procedure description]. AB - INTRODUCTION: Today, three-dimensional conformal radiotherapy is a standard way in the radical treatment of localized prostate cancer, and it is an alternative to the radical prostatectomy. This method of radiotherapy treatment is widely accepted in the treatment of prostate cancer patients, and provides irradiation of targeted volume (prostate, seminal vesicles) with dose escalation sparing the surrounding healthy tissues (rectum, bladder) at the same time. That is not possible with the conventional two dimension technique. PROCEDURE DESCRIPTION: Three-dimensional conformal radiotherapy is a volumetric, visual simulation according to the computed tomography slices; it defines the tumour and organ at risk individually in each patient. Results of several studies have shown that there is a significant decrease in the development of acute toxicity when prostate cancer patients are treated with conformal radiotherapy. High dose irradiation gives excellent results in treatment of localized prostate carcinoma and improves treatment results in the patients with locally advanced carcinoma of prostate. DISCUSSION: Prostate carcinoma irradiation techniques have been changed dramatically during recent years. Data obtained by computed tomography are important since the size and shapes of the prostate as well as its anatomic relations towards the rectum and bladder are considerably different in individual patients. The three-dimension plan of irradiation can be designed for each patient individually by performing computed tomography technique when planning radiotherapy. CONCLUSION: The advanced planning systems for conformal radiotherapy can reconstruct the anatomic structures of pelvis in three-dimension technique on the basis of computed tomography scans, which provides better conformality between the irradiation beam and geometrical shape of the tumour with minimal irradiation of the surrounding healthy tissue. PMID- 21548270 TI - [Use of beta blockers in various clinical states]. AB - INTRODUCTION: According to the convincing evidence, a decline in mortality rate has been achieved with beta-blockers in patients with an acute myocardial infarction and in post-infarction follow-up. In fact, there has been a clear reduction of sudden coronary death. The necessary condition for the efficiency of beta-blockers is an early use. They are also a medication of choice for angina after an infarction. The objective of this work was to evaluate the use of beta blockers after a myocardial infarction in various clinical states and to eliminate doubts concerning their prescription. BETA BLOCKERS: Even in conditions considered contraindications for administration of beta blockers such as old age, diabetes, non-Q-wave myocardial infarction, peripheral vascular disease, arterial disease, heart insufficiency; ventricular arrhythmias, renal disease, chronic obstructive pulmonary disease, asthma and depression, patients benefit from beta blockers when they are given along with a right choice of the medication and a regular followup of the patient. Preference is given to cardioselective beta blockers in patients with diabetes or lung disease. Beta-blockers do not cause long-term lipid alterations. Therefore, the matter of clinically significant alterations of lipids or blood glucose levels should not need further consideration as a problem of the treatment of diabetics. DISCUSSION AND CONCLUSION: Investigations have proved that the use of beta-blockers reduces the development of cerebrovascular accidents, heart insufficiency and hypertension. Despite strong arguments and numerous recommendations, beta-blockers have not been accepted to a sufficient extent as an integral part of treatment of acute coronary syndrome and related diseases, to the detriment of many lost lives and in spite of favourable pharmaco-economic aspect. PMID- 21548271 TI - [Psychomotor re-education--movement as therapeutic method]. AB - INTRODUCTION: Psychomotor re-education represents a multidimensional therapeutic approach in dealing with children and adults with psychomotor disorders. Therapeutic programs should be based on individual differences, abilities and capabilities, relationships, feelings and individual developmental needs as well as emotional condition of a child. BODY AND MOVEMENT AS THE Bases OF THE TREATMENT: A movement, glance, touch, voice and word, all being an integral part of a process of psychomotor re-education, are used with a purpose of helping children to discover their own body, their feelings, needs, behaviour. When moving, children discover the space of their own bodily nature, and, subsequently, gestural space and objective space. The body represents a source of pleasure and the freedom of movement, as well as one's own existence, are soon to be discovered. PRACTICAL APPLICATION: An adequate assessment is a precondition to design a work plan, select the best exercises for each child individually and direct the course of therapy. This is the most suitable method for treating children with slow or disharmonious development, mentally challenged children, children with speech and behaviour disorders. It is also used in the treatment of children with dyspraxic difficulties, difficulties in practognostic and gnostic development, pervasive developmental disorder and children with lateral dominance problems. CONCLUSION: Therefore, a systematic observation seems to be necessary as well as an increased number of research projects aimed at assessing results obtained by exercises in order to get a more precise insight into the process of re-education, selection of exercises, duration period and possible outcomes. PMID- 21548272 TI - [Out-of-hospital treatment in case of drowning]. AB - INTRODUCTION: Drowning is a leading preventable cause of unintentional morbidity and mortality. The dominant pathophysiological mechanism of drowning includes the development of acute hypoxia. FIRST AID: The rescue procedure of a drowning person includes careful pulling the victim out of the water, examination, maintenance of the airways passable and urgent transfer to hospital. BASIC LIFE SUPPORT: The first and most important treatment option of a drowning victim is the provision of ventilation which increases the chances of survival. As soon as the unresponsive victim is removed from the water, the lay rescuer should immediately begin chest compressions and provide cycles of ventilations and compressions. Some recent investigations have revealed that exterior compression of the chest is a necessary measure even in a situation when bystanders cannot provide airway. It is recommended to train bystanders to provide basic life support and apply automated external defibrillator in a drowning person whenever indicated and as early as possible. ADVANCED LIFE SUPPORT: In drowning, the victim with cardiac arrest requires advanced life support, including an early intubation. Extended medical measures, which are primarily provided by medical professionals, include cervical spine immobilization in case a spinal injury is suspected, or, establishment of the ventilation with oxygen, emergency transport, application of reanimation and advanced vital support measures. PMID- 21548273 TI - [Diagnostics of dry eye]. AB - INTRODUCTION: Dry eye is a multi-factorial disease of tears and ocular surface resulting in symptoms of discomforts, vision disabilities, unstable tear film and possible damage to the ocular surface. The final diagnosis of dry eye results from collecting various data obtained in the course of several diagnostic procedures. DRY EYE - DIAGNOSTIC METHODS: Diagnosis of dry eye involves performing a series of clinical methods and laboratory tests. This paper presents some of the procedures used in the diagnosis of dry eye. Biomicroscopy of the eye with objective tests to check the tear film (Schirmer I, rose bengal, time break up precorneal tear film), verification of corneal sensitivity and impression cytology of the conjunctiva, are the optimum dry eye diagnostic routine procedures. CONCLUSION: The combination of clinical and histopathological methods of examination of the anterior ocular surface is the basis for a quality and precise diagnosis of dry eye. PMID- 21548274 TI - [A prospective evaluation of laparoscopic cholecystectomy in the treatment of chronic cholelithiasis--a five-year experience]. AB - INTRODUCTION: Laparoscopic cholecystectomy is a method of choice in the treatment of symptomatic cholecystolithiasis because of less postoperative pain, shorter hospitalization and lower cost of treatment. The study was aimed at analysing the outcome of laparoscopic cholecystectomy in patients surgically treated for chronic calculous cholecystitis (symptomatic cholelithiasis). MATERIAL AND METHODS: The research was done in the period from December 2003 to December 2008. In the prospective study of 386 patients, we analyzed operative and postoperative complications, the reasons for conversion to open cholecystectomy, duration of hospitalization and mortality. RESULTS: The average duration of laparoscopic cholecystectomy was 31.9 +/- 14.5 min: dissection of adhesions 3.2 +/- 0.7 min., elements of Calot's triangle 9.8 +/- 3.2 min., gallbladder releasing from its bed 12.8 +/- 2.8 min., the abdominal cavity lavage and removal of gallbladder from the abdomen 6.8 +/- 0.9 min. Some operative difficulties emerged in 22 (5.7%) patients--4 (1%) during releasing of gallbladder adhesions from the surrounding structures, 9 (2.3%) during dissection of elements of the Calot's triangle, 6 (1.5%) during gallbladder releasing from its bed, 3 (0.7%) during gallbladder removal from the abdomen. Some post-operative complications, single or associated, occurred in 36 (9.3%) patients: perforation of gallbladder 21 (5.4%), bleeding from gallbladder bed 18 (4.6%)/ injury of extra hepatic bile ducts 1 (0.20%), 9 (2.3%) spillage of stones; 3 (0.7%) conversions were made. The average duration of preoperative and postoperative hospitalization was 1.1 +/- 0.3 and 1.4 +/- 0.5 days, respectively. The pathohistological examination revealed 2 (0.5%) adenocarcinoma of gallbladder. There were no lethal outcomes. CONCLUSION: Laparoscopic cholecystectomy is a safe procedure and rational choice in the treatment of biliary dyskinesia and symptomatic biliary calculosis with an acceptable rate of conversion. PMID- 21548275 TI - [Level of knowledge about sexually transmitted infections in the population of female students at the University of Novi Sad]. AB - INTRODUCTION: The reason for extremely high incidence of sexually transmitted inflections is the lack of necessary knowledge about the mode of transmission and protection measures. The aim of this study was to determine the level of knowledge about sexually transmitted infections in the population of female students of the University of Novi Sad. MATERIAL AND METHODS: The study included 397 female students at the University of Novi Sad from different faculties. A questionnaire was designed for the purpose of this research. RESULTS AND DISCUSSION: Students from all faculties (55.7-66.7%), with the exception of the medical students, believe that the use of condoms is the safest way of protection from sexually transmitted infections. The medical students showed a different attitude and opinion on the use of condoms and avoidance of multiple sexual partners, which are important measures in the prevention of these diseases (38.8%). The fact that some sexually transmitted infections caused by viruses are associated with the malignancy of the cervix was recognized by 74.81% of students. The fact that the main therapeutic approach for treatment of sexually transmitted diseases is the simultaneous treatment of both partners was known by 81.86% of female students. As it is known, sexually transmitted infections may not always be symptomatic, which is an opinion held by 73.55% of students. CONCLUSION: Results obtained in this study indicate the need for implementation of educational activities about sexually transmitted infections, which would enable the preservation and promotion of reproductive health of young people. PMID- 21548276 TI - [Thoracoabdominal teratoma--rare location]. AB - INTRODUCTION: Teratomas are tumours derived from pluripotent germ cells. They appear most frequently on ovaries. However, other locations are also possible: testicles, retroperitoneum, stomach, neck, and bottom of the mouth cavity. It is not very common to find teratomas in two different body cavities. CASE REPORT: A 51-year-old patient visited her doctor complaining of an intensive pain which suddenly appeared in her low back. The computed tomography scan of the abdomen was performed, which revealed cystic formation, 12.5 x 18 cm in size, with remarkable capsule visualization. It had paraaortic, subdiaphragmatic, retropancreatic and suprarenal left localisation with signs of compression and pancreatic dislocation. The cystic formation had a septated appearance filled with clear fluid in all its parts except at the bottom, where it was dense. The intra-operative finding was left retroperitoneal mass placed above the left kidney, dislocating surrounding structures and their infiltration could not be excluded for sure. A tumour mass passed through the diaphragmatic hiatus and continued in the left thoracic space. The cyst was only drained and the fenestration was performed. Three months later, the second operation was performed--splenectomy, left suprarenaladenectomy, left nephrectomy, aortic deliberalisation, the left diaphragmatic crus was opened and tumour mass was completely removed from the thoracic space. The histological examination showed mature teratoma with morphological characterisations of the skin, so the definite diagnosis was dermoid cyst. CONCLUSION: The patient presented with thoracoabdominal teratoma. Although without malignant transformation, the teratoma required splenectomy, supraadrenalectomy and nefrectomy due to its position and size. PMID- 21548277 TI - [Mixed malignant germ cell tumor of ovary]. AB - INTRODUCTION: Malignant tumours of ovary germ epithelium are very rare and account for about 2-5% of all ovarian tumours of germ origin. In adolescent patients under 20 years of age diagnosed to have ovarian tumour, these tumours originate from germ cells in about 70% of cases. Depending on the stage of the disease, medical treatment and age, the death rate ranges from 25% to 84%. A special group of germ tumours are mixed germ cells tumours built of two or more different types of germ tumours. CASE REPORT: This paper gives a diagnostic therapeutic procedure and the clinical picture with the course and outcome of the decease in a nineteen-year old patient with a mixed malignant germ tumour (dysgerminoma, choriocarcinoma, immature teratoma) found in one of the ovaries. It also deals with the appearance and development, some characteristics and histological build of the tumours diagnosed in this case. CONCLUSION: Malignant tumours of ovary germ epithelium are very rare and develop in female population under 30 years of age. They are characterized by a high degree of malignity. They are resistant to cytostatic treatment, they spread very quickly with the lethal outcome. The course of the disease is not characteristic and is usually masked under some other acute gynaecological disease. The definitive diagnosis is made after laparotomy and pathohistological analysis of the tumour tissue. PMID- 21548278 TI - [Forgotten great men of medicine--Baron Dominique Jean Larrey (1766-1842)]. AB - BIOGRAPHY: Baron Dominique Jean Larrev was a French army surgeon who rose to become a surgeon-in-chief of Napoleon's Grande Armee. Many advances in the field of surgery have been attributed to him: he was one of the first to amputate at the hip-joint (1812); he pioneered the use of maggots to prevent infection in wounds; he gave the first description of a trench foot, and originated the first aid to combatants by getting stretcher-bearers to take wounded men immediately from the battlefield. EDUCATION AND CAREER: Larrey studied medicine in Paris and spent a short time in the navy before resuming his studies at the Parisian College de Chirurgie. He joined the army in 1792 and spent the rest of his active life there, taking part in 60 battles and 400 other engagements, having been wounded three times. During this time, he initiated the modern method of army surgery, field hospitals and the system of army ambulance corps. After seeing the speed with which the carriages of the French flying artillery manoeuvred across the battlefields. Larrey adapted them as Flying Ambulances for rapid transport of the wounded and staffed them with trained crews of drivers, corpsmen and litter bearers. Larrey also increased the mobility and improved the organization of field hospitals, effectively creating a forerunner of the modern MASH (Mobile Army Surgical Hospital) units. He was made a baron in 1809. He remained loyal to Napoleon even after his abdication in 1814, and followed him on his final campaign (the hundred days). At Waterloo, he was captured and sentenced to death; however, he was saved by the personal intervention of the Prussian commander Blucher. Many historians put him in the line with chemist Antoine Lavoisier and doctors Joseph Guillotin and Jean Paul Marat. PMID- 21548279 TI - [Interpretation of dark neurons in experimental model of ischemia, neurointoxication and brain infection]. AB - INTRODUCTION: Findings of dark neurons is still a big controversy. Do they represent a simple artifact or neuropatological findings? The aim is to explain the appearance of "dark" neurons in different experimental animal models. MATERIAL AND METHODS: The experiments included three experimental models. Neuroischemia: where in postmortal fixed rat brain after 10', 30', 45', 1.5h, 3h, 6h, 12h, 24h histologically was examined the appearance of dark neurons; intoxication: after 28 days of oral administratio AlCl3 in rats analyse changes in the brain; neuroinfection: where hamsters perorally given culture larvae T. canis and after 5 weeks analyse neuropatological findings in the brain. All brains were processed by standard histological techniques and stained with H&E, Walton and Cresil violet methods. RESULTS: Neuroishemia--in the group fixed brain specimens after 10 and 30' found only insignificant number of dark neurons increases until the time of fixation, their number was increasing, and after 12 and 24 hours dark shape assumed virtually all neurons. Neuroinfection: laminar flow is characterized by deterioration of nerve cells and the concentration of dark neurons in V lamina of cerebral cortex. Neuroinfection--in the area granulomatous pathohistological lesions and other changes observed increased concentration of irreversible stages of dark neurons. DISCUSSION AND CONCLUSION: The same histopathology characteristics of dark neurons in all experimental models can be attributed to postmortem artificial ischemia, to which to every tissue is exposed during histological processing. The abundance of appearance of dark neurons depend on the length of exposure to ischemia and the previous patophysiological state of tissue especially if the pretreatment included a harmful substances. Any harmful substances leading to pathophysiological changes in vivo cause increased sensitivity of cells to arteficial ischemia and the development of dark neurons. PMID- 21548280 TI - [CO2 flux characteristics and their influence on the carbon budget of a larch plantation in Maoershan region of Northeast China]. AB - From January to December 2008, the CO2 flux in a larch plantation (Larix gmeilinii) in Maoershan region of Shangzhi County, Heilongliang Province was measured by eddy covanance method, and the diurnal changes of leaf photosynthetic rate were measured in growth season (from May to October). There existed differences in the net ecosystem exchange (NEE) of the plantation in different time periods under the effects of environmental factors. In the afternoon (12:00 24:00), the NEE changed more slowly with the variation of vapor pressure deficit (VPD) than in the morning (0:00-12:00); and in the morning, tbe light use efficiency was 0.6284 mol x mol(-1), 14% more than that in afternoon. The NEE increased with increasing temperature, and the increment in the morning was 50% higher than that in the afternoon (air temperature > 15 degrees C). These differences in responding to environmental changes led to 88% NEE implemented in the morning, and only 12% NEE implemented in the afternoon. The annual gross ecosystem productivity (GEP) in the morning took a percentage of 60%, and that in afternoon took 40%. These findings were supported by the observation at leaf level, i.e., on average of whole growth season, the leaf photosynthetic capacity in the morning was over 2-fold higher than that in afternoon. Generally, the annual NEE, ecosystem respiration (Re), and GEP of the plantation in 2008 were 263-264 g C x m(-2), 718-725 g C x m(-2), and 981-989 g C x m(-2), respectively. PMID- 21548281 TI - [Distribution patterns of Picea schrenkiana var. tianschanica population in Tianshan Mountains]. AB - A vertical transect investigation on Picea schrenkiana var. tianschanica forests was conducted at five different longitudinal sites (Zhaosu, Gongliu, Wusu, Urumqi, and Hami) in Tianshan Mountains, and the distribution pattern of P. schrenkiana var. tianschanica population at each site was analyzed based on theoretical distribution model and aggregation intensity index. On the whole, the P. schrenkiana var. tianschanica population in Tianshan Mountains presented a clumped distribution, and the distribution pattern and clustering intensity were affected by the developmental stages of stem and the ranges of altitude to some degree. The clustering intensity increased with the increasing size (DBH) or developmental stage of stem, and had the highest values at high altitudes. PMID- 21548282 TI - [Effects of thinning intensity on community stability of Quercus liaotungensis forest on Loess Plateau]. AB - A sampling plot investigation was conducted on the Quercus liaotungensis forests on Loess Plateau, China under close-to-natural management thinning 13.4% (light thinning) and 30.0% (heavy thinning). Taking the un-thinned forest as the control, the population regeneration, woodland productivity, soil fertility, and species diversity of the forests after 5 years of thinning were studied, with the community stability evaluated by calculating the subordinate function values based on fuzzy comprehensive evaluation. Comparing with the control, the regeneration potential of the forests after light and heavy thinning promoted by 14.2% and 20.2%, arbor volume reduced by 9.0% and 23.8%, shrub biomass increased by 7.3% and 12.2%, and herb biomass increased by 10.5% and 31.6%, respectively. In addition, the soil fertility and species diversity indices were higher in thinning forests than in the control. The community stability showed the order of heavy thinning forest > light thinning forest > un-thinned forest, suggesting that the close-to-natural management thinning 30.0% was more suitable to the management of secondary Q. liaotungensis forest on Loess Plateau. PMID- 21548283 TI - [Simulation of soil water dynamics in triploid Populus tomentosa root zone under subsurface drip irrigation]. AB - Based on the observed data of triploid Populus tomentosa root distribution, a one dimensional root water uptake model was proposed. Taking the root water uptake into account, the soil water dynamics in triploid P. tomentosa root zone under subsurface drip irrigation was simulated by using HYDRUS model, and the results were validated with field experiment. Besides, the HYDRUS model was used to study the effects of various irrigation technique parameters on soil wetting patterns. The RMAE for the simulated soil water content by the end of irrigation and approximately 24 h later was 7.8% and 6.0%, and the RMSE was 0.036 and 0.026 cm3 x cm(-3), respectively, illustrating that the HYDRUS model performed well in simulating the short-term soil water dynamics in triploid P. tomentosa root zone under drip irrigation, and the root water uptake model was reasonable. Comparing with 2 and 4 L x h(-1) of drip discharge and continuous irrigation, both the 1 L x h(-1) of drip discharge and the pulsed irrigation with water applied intermittently in 30 min periods could increase the volume of wetted soil and reduce deep percolation. It was concluded that the combination of 1 L x h(-1) of drip discharge and pulsed irrigation should be the first choice when applying drip irrigation to triploid P. tomentosa root zone at the experiment site. PMID- 21548284 TI - [Spatiotemporal variation of Populus euphratica's radial increment at lower reaches of Tarim River after ecological water transfer]. AB - Taking the Populus euphratica at lower reaches of Tarim River as test object, and by the methods of tree dendrohydrology, this paper studied the spatiotemporal variation of P. euphratic' s branch radial increment after ecological water transfer. There was a significant difference in the mean radial increment before and after ecological water transfer. The radial increment after the eco-water transfer was increased by 125%, compared with that before the water transfer. During the period of ecological water transfer, the radial increment was increased with increasing water transfer quantity, and there was a positive correlation between the annual radial increment and the total water transfer quantity (R2 = 0.394), suggesting that the radial increment of P. euphratica could be taken as the performance indicator of ecological water transfer. After the ecological water transfer, the radial increment changed greatly with the distance to the River, i.e. , decreased significantly along with the increasing distance to the River (P = 0.007). The P. euphratic' s branch radial increment also differed with stream segment (P = 0.017 ), i.e. , the closer to the head water point (Daxihaizi Reservoir), the greater the branch radial increment. It was considered that the limited effect of the current ecological water transfer could scarcely change the continually deteriorating situation of the lower reaches of Tarim River. PMID- 21548285 TI - [Distribution responses of Lespedeza davurica community on Loess Plateau to climate change]. AB - Field survey and position monitoring were conducted from 2000 to 2009 to study the effects of climate change on the distribution and growth of Lespedeza davurica community on Loess Plateau. As affected by air temperature, the appropriate growth region of L. davurica community on the Plateau had an obvious zonal distribution from northwest to southeast. For the distribution of L. davurica community, the suitable air temperature was 7.4 degrees C-10 degrees C, average population density was 13.9 plants x m(-2), and reproductive branch was averagely 11.4 per cluster. As affected by precipitation gradient, the horizontal distribution of L. davurica community changed from a constructive or predominant species in typical grassland region into a companion species in forest steppe region, and then, the community gradually became dominant species. The L. davurica community appeared as an occasional species on the half sunny slope of gullies and valleys and the sand dunes in desert steppe region, and extended gradually from its optimal region with yearly precipitation 300 -500 mm to the region with yearly precipitation 270-600 mm. Also, the L. davurica community extended from its optimal altitude 1100-1700 m to 600-1950 m. Under the background of global climate change, the eco-breadth of L. davurica community expanded gradually. PMID- 21548286 TI - [Spatiotemporal dynamics of forest carbon storage in Taihe County of Jiangxi Province in 1985-2030]. AB - Based on the sixth forest inventory data of Taihe County, Jiangxi Province, this paper analyzed the curve relations between the carbon densities and ages of major forest types by using Logistic equation, and estimated the total amounts and change trends of the biomass and carbon storage of forest vegetation from 1985 to 2003 by the method of biomass expansion factor. The carbon storage in 2020 and 2030 was estimated by setting 2003 as the baseline year and assuming that the area of forest vegetation remained stable and without consideration of forest rotation. In 2003, the total forest area of Taihe County was 15.74 x 10(4) hm2, the total biomass was 6.71 Tg, the vegetation carbon storage was 4.14 Tg C, and the average carbon density was 26.31 t C x hm(-2). In 1985, 1994, 2003, 2020, and 2030, the forest carbon storage was 1.06, 2.83, 4.14, 5.65, and 6.35 Tg C, respectively. The carbon density of the forest vegetation in Taihe County decreased from the eastern and western regions to the central. Artificial afforestation contributed significantly to the increase of forest stand area, and consequently, to the improvement of forest carbon sequestration capacity. PMID- 21548287 TI - [Quantitative driving analysis of forest biomass changes in Changbai Mountain forest region]. AB - Based on the forest inventory data and single tree biomass model, the forest biomass in the sampling plots in Changbai Mountain forest region was calculated, and, by using the estimated forest biomass from four periods' remote sensing data and based on high accuracy remote sensing models, the changes of regional forest biomass were analyzed. In the meanwhile, the driving factors such as meteorological factors, management factors, and socio-economic factors that caused forest biomass change were selected by bootstrap method, and the driving model of forest biomass change in different time period was set up by using partial least-squares method. The Variable Importance in Projection (VIP) values representing the importance of each of the factors affecting the forest biomass change in study region were calculated. The results showed that the influence of human activity factors (VIP values) on Changhai Mountain forest biomass changes was less than that of natural factors, suggesting that the national forest protection policy for forest regions had played an obvious role. Our research broadened the content of forest biomass change driving analysis, and the introduction of calculating VIP value, which can quantitatively represent the influence of driving factors to forest biomass change, provided a new way for the quantitative analysis on forest biomass change. PMID- 21548288 TI - [Effects of strong solar UV-B radiation on photosynthesis and photosynthetic pigment contents of Saussurea superba on Qinghai-Tibet Plateau]. AB - Taking the main companion species Saussurea superba in an alpine Kobresia humilis meadow on Qinghai-Tibet Plateau as test material, a UV-B exclusion experiment with UV-B excluding and UV-B transmitting filters was performed to study the effects of strong solar UV-B on the photosynthesis, photosynthetic pigments, and UV-B-absorbing compounds of S. superba, aimed to examine the adaptation capability of alpine plants to strong solar UV-B radiation. The removal of UV-B components from natural sunlight increased the net photosynthetic rate (P < 0.05) and PS II photochemistry efficiency of S. superba. The relatively increased leaf thickness under ambient UV-B could compensate the photo-oxidation of photosynthetic pigments, an inherent characteristic of alpine plants growing in intense UV-B. Short-term removal of UV-B radiation had no obvious effects on the UV-B-absorbing compounds, suggesting that these compounds in epidermal layer of S. superba could hardly be affected by the environment. It was concluded that the increase of photosynthetic pigment contents due to the enhancement of leaf thickness was a specious phenomenon, but the strong solar UV-B radiation on Qinghai-Tibet Plateau still had a potential negative impact on the photo physiological processes in alpine plant S. superba. PMID- 21548289 TI - [Effects of litters and tannin on forest soil inorganic nitrogen]. AB - A laboratory incubation test was conducted to study the effects of litters and tannin on forest soil nitrate- and ammonium N. The addition of litters and tannic acid made the soil nitrate- and ammonium N decreased. With the addition of fir litter, the nitrate- and ammonium N contents in red soil decreased by 6.1%-25. 9% and 19.7%-68.6%, respectively, and the decrements in yellow-red soil were higher than those with the addition of bamboo litter, being significant for ammonium N. Compared with the control, the addition of tannin decreased the ammonium N content in yellow-red soil significantly, and there was a positive correlation between the concentration of added tannin and the decrement of soil ammonium N content. When the concentration of added tannin was high, the decrement of the ammonium N reached 31.9%-57.8%. With the addition of low concentration tannin, the soil nitrate N content decreased with time, and the decrement on the 84th day reached 4.5%. However, the addition of high concentration tannin increased the soil nitrate N content by 10.3%-18.5% in the first 7-28 days, but decreased it by 23.9% and 42.3% on the 56th and 85th day, respectively. PMID- 21548290 TI - [Effects of low temperature stress during flowering period on pollen characters and flag leaf physiological and biochemical characteristics of rice]. AB - Taking cold-tolerant rice cultivar 996 and cold-sensitive rice cultivar 4628 as test materials, a growth chamber experiment was conducted to investigate their pollen characters and flag leaf physiological and biochemical characteristics under the effects of low temperature stress. The plants were respectively treated with low temperature [ 19 degrees C (06:00-8:00; 19:00-23:00 )/21 degrees C (08:00-10:00; 16:00-19:00)/23 degrees C (10:00-16:00)/17 degrees C (23:00-06:00)] and optimal temperature [24 degrees C (06:00-8:00; 19:00-23:00)/26 degrees C (08:00-10:00; 16:00-19:00)/30 degrees C (10:00-16:00)/22 degrees C (23:00-06:00)] for seven days after heading. Low temperature stress decreased the anther dehiscence coefficient and pollen germination rate, as well as the sterile pollen rate of spikelets on middle and lower parts of panicles, with the anther dehiscence coefficient and pollen germination rate of cultivar 996 being significantly higher than those of cultivar 4628, indicating that cold-tolerant cultivar 996 had the capability to keep better pollination and pollen germination. Under low temperature stress, the flag leaf soluble protein and free proline contents and their increments of cultivar 996 were significantly higher than those of cultivar 4628, while the MDA content and relative conductivity and their increment were in adverse, indicating that cold-tolerant cultivar 996 had more quick and strong protective responses, and was able to keep stable membrane structure and function. PMID- 21548291 TI - [Effects of different application rates of water-retaining agent on root physiological characteristics of winter wheat at its different growth stages]. AB - A field experiment was conducted at the Yuzhou Experimental Base of Henan Province to study the effects of different application rates (0, 30, 60, and 90 kg x hm(-2)) of water-retaining agent (WRA) on the root physiological characteristics, biomass, and grain yield of two winter wheat cultivars Zhengmai 9694 and Aikang-58, aimed to probe into the action mechanisms of WRA on the root system of winter wheat at its different growth stages. The application of WRA decreased the root membrane permeability and soluble sugar content, and increased the root vigor. After the application of WRA, the Zhengmai-9694 at its different growth stages had a greater decrement of root membrane permeability, compared with Aikang-58. In all treatments except 90 kg x hm(-2) of WRA, the root vigor of Aikang-58 was obviously higher than that of Zhengmai-9694. At booting and grain filling stages, the root soluble sugar content of Zhengmai-9694 decreased much more than that of Aikang-58. In the whole growth period of the two cultivars, their root membrane permeability and soluble sugar content were the lowest in treatment 60 kg x hm(-2) of WRA, and no significant differences were observed between treatments 60 and 90 kg x hm(-2) of WRA. The root vigor of Zhengmai-9694 increased remarkably with the increasing rate of WRA application, while that of Aikang-58 was the highest in treatment 60 kg x hm(-2) of WRA. The application of WRA also increased root biomass, and at jointing and booting stages, the root biomass of Aikang-58 was much higher than that of Zhengmai-9694. However, at grain-filling stage, the biomass of Aikang-58 in treatments 60 and 90 kg x hm(-2) of WRA was lower than that of Zhengmai-9694. Treatment 60 kg x hm(-2) of WRA had the highest grain yield of the two cultivars. It was concluded that WRA had more significant effects on Zhengmai-9694 than on Aikang-58, and applying 60 kg x hm( 2) of WRA could obtain the best effect. PMID- 21548292 TI - [Responses of winter wheat photosynthetic characteristics and chlorophyll content to water-retaining agent and N fertilizer]. AB - The effects of water-retaining agent (60 kg x hm(-2)) and nitrogen fertilizer (0, 225, and 450 kg x hm(-2)) on the leaf photosynthetic characteristics, chlorophyll content, and water utilization of winter wheat at jointing and grain-filling stages were studied under field conditions. In all treatments, the net photosynthetic rate, stomata conductance, intercellular CO2 concentration, water use efficiency, and chlorophyll content were greater at grain-filling stage than at jointing stage. Under nitrogen fertilization but without water-retaining agent application, the water use efficiency (WUE) of single leaf at jointing stage increased with increasing nitrogen fertilization rate, while the net photosynthetic rate, stomata conductance, intercellular CO2 concentration, and transpiration rate decreased after an initial increase. The chlorophyll content was the highest under 225 kg x hm(-2) nitrogen fertilization. In the treatments of water-retaining agent application, the intercellular CO2 con- centration decreased with increasing nitrogen application rate, but the net photosynthetic rate, transpiration rate, and WUE increased. The application of water-retaining agent or its combination with nitrogen fertilization increased the chlorophyll content, but excessive nitrogen fertilization had lesser effects. At grain filling stage, applying nitrogen fertilizer alone significantly increased the net photosynthetic rate and WUE, but decreased the stomata conductance, intercellular CO2 concentration, and transpiration rate. The chlorophyll content increased with increasing nitrogen application rate. After applying water-retaining agent and with the increase of nitrogen fertilization rate, the photosynthetic rate and WUE decreased after an initial increase, while the intercellular CO2 concentration and transpiration rate were in adverse but still lower than those without water retaining agent application. The stomata conductance increased with increasing nitrogen fertilization rate. The chlorophyll content increased significantly under the application of water-retaining agent, but somewhat decreased under the combined application of water-retaining agent and nitrogen fertilizer. The application of both water-retaining agent and nitrogen fertilizer increased the 1000 grain mass, grain yield, and water production efficiency of winter wheat significantly, with the best effect in the treatment of water-retaining agent with 225 kg x hm(-2) nitrogen fertilization. PMID- 21548293 TI - [Effects of ground cover and water-retaining agent on winter wheat growth and precipitation utilization]. AB - An investigation was made at a hilly upland in western Henan Province to understand the effects of water-retaining agent (0, 45, and 60 kg x hm(-2)), straw mulching (3000 and 6000 kg x hm(-2)), and plastic mulching (thickness < 0.005 mm) on winter wheat growth, soil moisture and nutrition conditions, and precipitation use. All the three measures promoted winter wheat growth, enhanced grain yield and precipitation use efficiency, and improved soil moisture and nutritional regimes. These positive effects were more obvious when the straw- or plastic mulching was combined with the use of water-retaining agent. Comparing with the control, all the measures increased the soil moisture content at different growth stages by 0.1%-6.5%. Plastic film mulching had the best water retention effect before jointing stage, whereas water-retaining agent showed its best effect after jointing stage. Soil moisture content was the lowest at flowering and grain-filling stages. Land cover increased the grain yield by 2.6% 20.1%. The yield increment was the greatest (14.2%-20.1%) by the combined use of straw mulching and water-retaining agent, followed by plastic mulching combined with water-retaining agent (11.9% on average). Land cover also improved the precipitation use efficiency (0.4-3.2 kg x mm(-1) x hm(-2)) in a similar trend as the grain yield. This study showed that land cover and water-retaining agent improved soil moisture and nutrition conditions and precipitation utilization, which in turn, promoted the tillering of winter wheat, and increased the grain number per ear and the 1000-grain mass. PMID- 21548294 TI - [Effects of long-term application of organic fertilizer and superphosphate on accumulation and leaching of Olsen-P in Fluvo-aquic soil]. AB - Based on a 20-year experiment of fertilization with organic and chemical fertilizers on a Fluvo-aquic soil under wheat-corn cropping system, this paper studied the relationships between Olsen-P concentration in plough layer and crop yields as well as the accumulation and vertical translocation of Olsen-P in soil profile. The results showed that when the Olsen-P concentration in plough layer maintained at 10-40 mg x kg(-1), the grain yields of wheat and corn were higher, whereas when the concentration of Olsen-P in plough layer was higher than 40 mg x kg(-1), it started to leach, which meant that in light loam Fluvo-aquic soil, the threshold value for P leaching might be 40 mg x kg(-1). In the treatments of chemical fertilization (NPK) and corn straw returning (SNPK) with the P application rate of 77-90 kg x hm(-2), the Olsen-P concentration in plough layer was increased by 0.63-0.72 mg x kg(-1) per 100 kg x hm(-2) of applied P, with an annual increment of 0.49-0.65 mg x kg(-1) and needed 45-60 years for reaching the threshold value for P leaching. In the treatments of chemical fertilization combined with manure application (MNPK, MNPK2, and 1.5MNPK), the formula of Olsen P accumulation in 0-20 cm soil layer were Y(MNPK) = 3.1097x + 6.9615 (R2 = 0.8562), Y(MNPK2) = 2.4765x + 13.563 (R2 = 0.9307), and Y1.5MNPK = 4.506x + 6.4464 (R2 = 0.8862). It might take 8 years to reach the threshold value for Olsen-P leaching when the P application rate in treatment 1.5MNPK was 210 kg x hm(-2), 11 years when the P application rate in treatments MNPK2 and MNPK was 125 and 140 kg x hm(-2). Organic fertilization combined with chemical fertilization increased the Olsen-P accumulation rate being 2.5 times higher than chemical fertilization. Excessive application of organic fertilizer could increase the accumulation and leaching of Olsen-P in soil profile. PMID- 21548295 TI - [Effects of no-tillage on soil water content and physical properties of spring corn fields in semiarid region of northern China]. AB - Field experiments were conducted in 2006-2008 to study the effects of no-tillage on the spatiotemporal dynamics of soil water content and related soil physical properties in spring corn fields in Beijing region during growth season. In study period, the water storage in 0-100 cm soil layer in tillage and no-tillage treatments had the same variation trend with time and precipitation, but the water storage at different time periods and under different precipitations was 2.7%-30.3% higher in no-tillage treatment than in tillage treatment. When the precipitation was relatively abundant, the increment of soil water storage was somewhat increased, but no-tillage was still worth to be popularized in the regions relatively deficit in precipitation. Under no-tillage, the average water storage in 0-100 cm soil layer during the three growth seasons in 2006-2008 was 3.4%-12.8% higher than that under conventional tillage, and the increment of the water storage in 0-20 cm and 80-100 cm soil layers under no-tillage was higher than that in intermediate layer, with the highest increment reached 22.2%. No tillage improved soil water-holding capacity and water use efficiency via decreasing soil bulk density, increasing soil porosity, and promoting the formation of soil water-stable aggregates, and thereby, promoted crop yielding. After 3 years no-tillage, the soil water use efficiency and spring corn yield were increased by 13.3% and 16.4%, respectively, compared with those under conventional tillage. PMID- 21548296 TI - [Simulation on the restoration effect of soil moisture in alfalfa (Medicago sativa)-grain rotation system in semi-arid and drought-prone regions of Loess Plateau]. AB - With the combination of field survey and EPIC modeling, this paper simulated the restoration effect of soil moisture in different alfalfa (Medicago sativa)-grain rotation systems in semi-arid and drought-prone regions of Loess Plateau. In perennial alfalfa field and in grain crop field after alfalfa, the correlation coefficients between the simulated and observed values of soil moisture content in 0-10 m layer were larger than 0.9 (P < 0.01), and their relative root mean square errors were between 0.05 and 0.16, with the relative errors less than 10%. The dynamic changes of the simulated soil moisture contents in different soil layers were consistent with those of the observed values. In the study regions, it was difficult for the restoration of soil moisture in the deep soil layers of alfalfa field. During the cultivation of alfalfa, the soil moisture content in the layers at 8-10 m depth should not be less than 5.7%. Considering the sustainable development of agricultural production, the appropriate cultivation duration of alfalfa should be 4-6 years and no more than 8 years. For the restoration of soil moisture after alfalfa cultivation in the study regions, the rotation system potato (Solanum tuberosum) --> potato --> spring wheat (Triticum aestivum) could be adopted, and alfalfa could be cultivated again after 32-33 years. PMID- 21548297 TI - [Effect of plantation of transgenic Bt cotton on the amount of rhizospheric soil microorganism and bacterial diversity in the cotton region of Yellow River basin]. AB - Traditional culture-dependent method and PCR-DGGE were adopted to investigate the amount of microorganism and bacterial diversity in rhizospheric soil of transgenic Bt cotton in four provinces of Yellow River basin at four growth stages, i.e., 30, 60, 90, and 120 days after sowing. In the same province and at the same growth stage, no significant difference was observed in the amount of microorganism in rhizospheric soils of transgenic and non-transgenic Bt cottons. Within the same province the amount of microorganism was mainly affected by growth stage; while in different provinces, it was greatly affected by regional conditions. In the four provinces, the bacterial diversity in rhizospheric soil of transgenic Bt cotton was abundant; and in the same province and at the same growth stage, there were no significant differences in the Shannon index, evenness, and richness of bacteria in rhizospheric soils of transgenic and non transgenic Bt cottons. In different provinces, the bacterial diversity in rhizospheric soils was dependent on regional conditions, but the difference was rather small. PMID- 21548298 TI - [Spatial variation of soil properties and quality evaluation for arable Ustic Cambosols in central Henan Province]. AB - A GIS-based 500 m x 500 m soil sampling point arrangement was set on 248 points at Wenshu Town of Yuzhou County in central Henan Province, where the typical Ustic Cambosols locates. By using soil digital data, the spatial database was established, from which, all the needed latitude and longitude data of the sampling points were produced for the field GPS guide. Soil samples (0-20 cm) were collected from 202 points, of which, bulk density measurement were conducted for randomly selected 34 points, and the ten soil property items used as the factors for soil quality assessment, including organic matter, available K, available P, pH, total N, total P, soil texture, cation exchange capacity (CEC), slowly available K, and bulk density, were analyzed for the other points. The soil property items were checked by statistic tools, and then, classified with standard criteria at home and abroad. The factor weight was given by analytic hierarchy process (AHP) method, and the spatial variation of the major 10 soil properties as well as the soil quality classes and their occupied areas were worked out by Kriging interpolation maps. The results showed that the arable Ustic Cambosols in study area was of good quality soil, over 95% of which ranked in good and medium classes and only less than 5% were in poor class. PMID- 21548299 TI - [GIS-based evaluation of farmland soil fertility and its relationships with soil profile configuration pattern]. AB - Taking the mid and low yielding fields in Yanjin County, Henan Province as a case, and selecting soil organic matter, total N, total P, total K, available N, available P, available K, pH value, and cation exchange capacity as indicators, a comprehensive evaluation on soil fertility was conducted by the method of fuzzy mathematics and using software ArcGIS 9.2. Based on this evaluation, the differences in the soil fertility level under different soil profile configuration pattern were analyzed. In the study region, soils were slightly alkaline, poorer in total N, total P, available N, cation exchange capacity, organic matter, and available K, and medium in available P and total K. The integrated fertility index was 0.14-0.63, indicating that the soil fertility in the region was on the whole at a lower level. There existed significant differences in all indicators except available P and total K under different soil profile configuration patterns (P < 0.05), suggesting the close relationship between soil fertility and soil profile configuration. The soil profile loamy in surface soil and clayey in subsurface soil had a higher level of soil fertility, followed by that loamy in surface soil and sandy in subsurface soil, and sandy in both surface and surface soil. Overall, the soils in the region were bad in profile configuration, poor in water and nutrient conservation, and needed to be ameliorated aiming at these features. PMID- 21548300 TI - [Three-dimensional morphological modeling and visualization of wheat root system]. AB - Crop three-dimensional (3D) morphological modeling and visualization is an important part of digital plant study. This paper aimed to develop a 3D morphological model of wheat root system based on the parameters of wheat root morphological features, and to realize the visualization of wheat root growth. According to the framework of visualization technology for wheat root growth, a 3D visualization model of wheat root axis, including root axis growth model, branch geometric model, and root axis curve model, was developed firstly. Then, by integrating root topology, the corresponding pixel was determined, and the whole wheat root system was three-dimensionally re-constructed by using the morphological feature parameters in the root morphological model. Finally, based on the platform of OpenGL, and by integrating the technologies of texture mapping, lighting rendering, and collision detection, the 3D visualization of wheat root growth was realized. The 3D output of wheat root system from the model was vivid, which could realize the 3D root system visualization of different wheat cultivars under different water regimes and nitrogen application rates. This study could lay a technical foundation for further development of an integral visualization system of wheat plant. PMID- 21548301 TI - [Effects of canal-lining project on groundwater and ecological environment in Hetao Irrigation District of Inner Mongolia]. AB - The canal-lining project in Hetao Irrigation District (HID) for water-saving irrigation has been implemented for many years. By using statistical method, ordinary Kriging, and software ArcGIS 9.0, this paper analyzed the spatiotemporal variation of groundwater table depth and salinity in HID in September, 2001 and 2009. In the meantime, the vegetation distribution on the both shores of the lining part and non-lining part of Yangjiahe channel was also investigated. After the many years implementation of the project, the water diversion amount in HID in 2009 was reduced to 44.5 x 10(8) m3. The region area of groundwater table with a depth of 2.5-3.0 m was increased from 1.2 x 10(4) hm2 in 2001 to 9.11 x 10(4) hm2 in 2009. The region area of groundwater table with a depth of 2.0-2.5 m in 2009 took 80% of the total area of HID. In the northwestern region of HID, the groundwater salinity had reduced from 5000-10000 mg x L(-1) to 3000-5000 mg x L( 1). In Wulate irrigation region, the areas of salt water belt and half-salt water belt were increasing. After the canal-lining of Yangjiahe channel, the plant species and diversity index on both shores reduced, and some herbaceous plants with shallow roots showed degradation signs. The implementation of the project and the reduction of water diversion for irrigation did not exert negative effects on the maintenance of water surface area of Wuliangsuhai Lake. PMID- 21548302 TI - [Spatiotemporal distribution characteristics of rainfall erosivity in Three Gorges Reservoir Area]. AB - Based on the 1976-2005 daily rainfall records from 25 weather stations in the Three Gorges Reservoir Area and its surrounding regions, this paper studied the spatiotemporal distribution characteristics of rainfall erosivity in the Area, with the focus on the annual and inter-annual trends of the rainfall erosivity around seven main weather stations. In 1976-2005, the average annual rainfall erosivity (R) in the Area was from 4389.0 to 8021.0 MJ x mm x hm(-2) x h(-1) x a( 1), being increased first from the northeast to the southwest, reached the peak in the central, and then decreased. The annual rainfall erosivity around the seven main weather stations mostly concentrated in the period from April to October, with the R value increased first from April, reached the highest in June or July, and then decreased. The maximum rainfall erosivity in consecutive three months around each of the seven weather stations accounted for 54.2%-60.7% of the total annual rainfall erosivity. In the study period, the coefficients of variation of the annual rainfall erosivity around the seven main weather stations varied moderately from 0.278 to 0.387, and the tendency rate ranged from -431.1 to 263.5 MJ x mm x hm(-2) x h(-1) x (10 a)(-1). However, the coefficients of tendency did not pass the confidence test with 5% level of significance, and the changes of annual rainfall erosivity showed random fluctuation. The variation degree of monthly rainfall erosivity was larger than the variation of annual rainfall erosivity, but only showed an obvious climate trend in a few months around parts of the weather stations. PMID- 21548303 TI - [Fractal characteristics of daily discharge in different scales watersheds]. AB - Based on the fractal theory and the long-term daily discharge records, this paper analyzed the fractal characteristics of daily discharge in mid-scale watershed (Wushui watershed) and small-scale watersheds (Zhenfu and Shuangxi watersheds). Under the same time scales and different threshold values of daily runoff, the fractal characteristics of daily discharge in the watersheds of different spatial scales and of same spatial scales were evident, and existed self-similarity. With the increase of the threshold values of daily runoff, the fractal dimensions of the daily discharge of different space-scale watersheds decreased gradually. The set of fractal dimensions of the daily discharge in different space-scale watersheds tended to be saturated when the time scale was 120-150 days, and the critical threshold values of daily runoff might appear when the time scale exceeded this number of days. PMID- 21548304 TI - [Spatiotemporal variation of urban heat island in Zhengzhou City based on RS]. AB - By using two Landsat remote sensing images (May 14, 1988 by TM sensor and May 10, 2001 by ETM+ sensor) and local meteorological data, this paper analyzed the causes and harms of urban heat island (UHI) in Zhengzhou City. The brightness temperatures of the images were calculated by mono-window algorithm, and related thematic maps were figured out. The results showed that with the expanding urban area of Zhengzhou City, the UHI effect was growing. Comparing with that in 1988, the high-temperature region of the City in 2001 had a clear shift and expansion towards northeast and southwest, being similar to the change trends of the low vegetation coverage area and urban land area. In order to alleviate the growing UHI effect, attentions should be paid on the urban greening work and the choice of reasonable greening patterns in the process of urbanization. PMID- 21548305 TI - [Landscape pattern gradient dynamics and desakota features in rapid urbanization area: a case study in Panyu of Guangzhou]. AB - In order to understand the landscape pattern gradient dynamics and desakota features in rapid urbanization area, this paper took the rapidly urbanizing Panyu District of Guangzhou City as a case, and analyzed its land use and land cover data, based on four Landsat TM images from 1990 to 2008. With the combination of gradient analysis and landscape pattern analysis, and by using the landscape indices in both class and landscape scales, the spatial dynamics and desakota feature of this rapidly urbanizing district were quantified. In the study district, there was a significant change in the landscape pattern, and a typical desakota feature presented along buffer gradient zones. Urban landscape increased and expanded annually, accompanied with serious fragmentation of agricultural landscape. The indices patch density, contagion, and landscape diversity, etc., changed regularly in the urbanization gradient, and the peak of landscape indices appeared in the gradient zone of 4-6 km away from the urban center. The landscape patterns at time series also reflected the differences among the dynamics in different gradient zones. The landscape pattern in desakota region was characterized by complex patch shape, high landscape diversity and fragmentation, and remarkable landscape dynamics. The peaks of landscape indices spread from the urban center to border areas, and desakota region was expanding gradually. The general trend of spatiotemporal dynamics in desakota region and its driving forces were discussed, which could be benefit to the regional land use policy making and sustainable development planning. PMID- 21548306 TI - [Health assessment on aquatic ecosystem in Liaohe River of Liaoning Province]. AB - Based on the investigation of the hydrology, water quality, periphytic algae, and habitat conditions of 20 hydrologic sections in the Tieling, Shenyang, and Panjin reaches of Liaohe River from June to August 2009, the indicators and their weights for the health assessment of aquatic ecosystem in the River were screened and determined by the method of principal component analysis, and the River's health assessment indicator system and health assessment standard system were constructed. The modified gray correlative degree method was also used to evaluate the aquatic ecosystem health condition at six sections of the River. Among the sections evaluated, three of them had a fair health level, two were worse or worst, and only one reached sub-health degree, suggesting that the aquatic ecosystem in the River was seriously degraded. Special attention should be paid to the ecological recovery of the river system, and comprehensive measures should be taken to control the River' s water pollution. PMID- 21548307 TI - [Ecological security assessment of Baishan City in Jilin Province based on DPSIR]. AB - This paper explored the main driving forces and stresses contributing to the eco environmental changes of Baishan City in Jilin Province, through the analysis of the ecological security problems in the City. The framework of DPSIR was applied to establish an ecological security assessment index system, and further, to create an ecological security assessment model suitable for mountain areas. By using the 1989, 1999, and 2006 TM images, and in combining with the DEM data and field survey data, the interpretation of the land cover in Baishan City was conducted, and the landscape classification was carried out. With the support of Fragstats, the important ecological indicators were extracted. Then, the situations of ecological security in various districts and counties of Baishan City were assessed. The results indicated that there was an obvious regional difference in the ecological security of Baishan City, with a deteriorating trend of the overall ecological security situation. Human activities had deeper influence on the land cover pattern and species habitat distribution, and even, became the main driving force of the pattern changes in ecological security. PMID- 21548308 TI - [Effects of organic fertilization on arsenic absorption of pakchoi (Brassica chinensis) on arsenic-contaminated red soil]. AB - A pot experiment with arsenic-contaminated red soil was conducted to study the effects of applying pig dung and chicken manure on the growth and arsenic absorption of pakchoi (Brassica chinensis), and on soil available arsenic. Applying pig dung and chicken manure to the arsenic-contaminated red soil increased the biomass of pakchoi to some extent. Comparing with the control, applying pig dung increased the pakchoi biomass significantly (P < 0.05). The soil available arsenic content after applying pig dung increased by 394.9% 1033.6% (P < 0.05), and that after applying chicken manure increased by 30.4% 94.1%. Organic fertilization promoted the arsenic absorption of pakchoi, with the arsenic uptake after applying pig dung increased by 20.7%-53.9%. The application of pig dung and chicken manure to arsenic-contaminated red soil could somewhat increase the soil available arsenic content and the arsenic uptake by crops, and thus, increase the risks of agricultural product quality and environment. PMID- 21548309 TI - [Concentration and speciation of arsenic in greenhouse vegetable soil in Shouguang County of Shandong Province]. AB - A sampling survey was conducted in the typical areas in Shouguang County of Shandong Province to study the characteristics of arsenic (As) concentration and speciation in greenhouse vegetable soil. The total As concentration in the surface (0-20 cm) and subsurface (20-40 cm) soil was averagely 8.27 and 7.93 mg x kg(-1), being 19% and 23% higher than that of the control (open field soil), and the soluble As (AE-As) concentration was 0.13 and 0.06 mg x kg(-1), 63% and 200% higher than that of the control, respectively. The ratio of residual As (O-As) to total arsenic reached more than 63.0%, and the concentrations of different As speciation decreased in the order of O-As > iron-bound As (Fe-As) > calcium bound As (Ca-As) > aluminum bound As (AlAs) > AE-As. With the increasing planting years, the AE-As concentration enhanced significantly, and the Al-As concentration also increased to some degree. After 15 years planting, the AE-As concentration in surface and subsurface soil increased by 75.0% and 150.0%, and Al-As concentration increased by 51.6% and 190.4%, respectively, while the concentrations of Fe-As and Ca-As all decreased to some degree. PMID- 21548310 TI - [Minimum amounts of suitable habitat for wheat aphid, parasitoid, and hyperparasitoid in facility-based agricultural landscapes]. AB - Minimum amount of suitable habitat (MASH) is the minimum habitat area that a population requires to persist in a given environmental setting for a long time, being an important aspect of population viability analysis (PVA). In this paper, we estimated the MASH for wheat aphids, parasitoids, and hyperparasitoids in facility-based agricultural landscapes in Yinchuan Plain of Northwest China, based on the relationships between population density and habitat area, and by using regression analysis. It was found that the population density and growth rate were consistently inversely related to area, but the exact mathematical functions varied with different species, especially those at different trophic levels. The MASH values for Macrosiphum avenae, Schizaphis graminum, Aphidius avenae, Aphidius gifuensis, and Pachyneuron aphidis were estimated with a polynormal regression model of density-area relationship, and the results were similar to those estimated from an inverse relationship between population and area. The differences of MASH between trophic levels were significant. It was concluded that these species had different values of MASH, which reflected their different habitat requirements and their differences in body size, migration, trophic position, and habitat quality. For parasitoids, the highest parasitic rates always took place at a spatial scale of 800-1000 m2, which could be considered as the base of aphids control with parasitoids, while the difference of MASH among trophic levels could be used to suppress the pest population. PMID- 21548311 TI - [Effects of perfluorooctane sulfonate on acute lethality and avoidance behavior of earthworm]. AB - As a new kind of persistent organic pollutants, perfluorooctane sulfonate (PFOS) has become a research spot of environmental science and toxicology. Its impacts on ecological environment should be deeply studied. In this paper, standard contact filter paper test of OECD, artificial soil test, and natural soil test were adopted to study the effects of PFOS on the acute lethality and avoidance behavior of earthworm. The results showed that the acute toxicity of PFOS on earthworm was related to the toxicant exposure time and concentration. The LC50, 48 h in filter paper test, LC50,14 d in artificial soil test, and LC50, 14 d in natural soil test were 13.64 microg x cm(-2), 955.28 mg x kg(-1), and 542.08 mg x kg(-1), respectively. At the maximum test concentration of 160 mg x kg(-1), the earthworm in artificial soil and natural soil showed significant avoidance behavior, which proved that earthworm could perceive and avoid the soil contaminated by a higher concentration of PFOS. To assess PFOS-contaminated soils, the avoidance endpoint was more sensitive than the mortality endpoint. PFOS had higher acute toxicity on earthworm in natural soil than in artificial soil. Meanwhile, more significant avoidance reaction was observed in natural soil than in artificial soil at the same concentrations of PFOS. PMID- 21548312 TI - [Longevity and emergence rhythm of adult parasitoids of Coccobius asumai Tachikawa (Hymenoptera:Aphelinidae) introduced from Japan]. AB - A series of feeding experiment and regular observation were conducted in laboratory to explore the effects of diet and temperature on the longevity of Coccobius azumai adults and their temporal rhythm of emergence. Diet had significant effects on the longevity of the adults. Without any diet supply, the mean longevity of the females and males was 1.5 d; but with the supplement of 20% honey water and of 20% honey water + fresh pine needles, the mean longevity reached 14.8 d and 11.3 d, and 17.3 d and 12.3 d, respectively. Temperature also played an important role on the longevity of the adults fed with 20% honey water. At 23 degrees C and 26 degrees C, the longevity of the females and males was obviously longer; while at 32 degrees C, the longevity was the shortest. At same temperatures, the mean longevity of the females was significantly longer than that of the males. In their circadian cycle, most of the females emerged from 11:00 to 15:00, but most males emerged from 9:00 to 12:00. Few females emerged after 18:00, and few males after 17:00. Most of the adult parasitoids enclosed from July to September. The amount of emerged adults peaked in July, and showed a fluctuant and descending trend in the subsequent August and September. Over 80% of the emerged adults were female in most days, and the males were always fluctuating in a low level in this period. A separate experiment showed that in the collection of the adult parasitoids, cloth shed was more superior to paper box. This study showed that limited energy was conserved in the parasitoids before adult emergence, and thus, supplementing suitable diet to newly emerged adults before release was necessary for prolonging their longevity and improving the efficiency of biological control. In Fujian and Guandong of China, there would be some potential disadvantage factors against the continuation of the parasitoid population, e.g., high temperature in summer, lack of temporal synchronization between the adult parasitoid females and their hosts (adult females of pine armored scale), and greatly high proportion of parasitoid females. Cloth shed benefited the collection of large amount of the parasitoids, being available in the biological control activities. PMID- 21548313 TI - [Monopolization of honeydew sources by Crematogaster macaoensis and its effects on lac production]. AB - From October 2008 to May 2010, an investigation was made in a lac plantation in Yayi region of Mojiang County, Yunnan Province, China, aimed to understand the behavior of the monopolization of honeydew sources by ant Crematogaster macaoensis, and its effects on the sex ratio, mortality, fecundity, and lac production of Yunnan lac insect Kerria yunnanensis. The results showed that C. macaoensis fed and monopolized the honeydews around the clock during the whole life cycle of K. yunnanensis on the stick-lac, and the average number of visiting C. macaoensis ranged from 16.8 +/- 2.3 to 39.3 +/- 10.0 per 10 cm length of the stick-lac. C. macaoensis constructed shelters to prevent other animals from visiting the lac insect. C. macaoensis monopolization reduced the lac production of individual K. yunnanensi significantly, but had no significant effects on the lac production of whole lac insect colony. In addition, C. macaoensis monopolization reduced the mortality of K. yunnanensis significantly, and increased the percentage of K. yunnanensis females and the adult female fecundity. It was concluded that ant monopolization of the lac insect honeydew seemed to be beneficial to the lac production by the Yunnan lac insect. PMID- 21548314 TI - [Phytoplankton in Yangtze River estuary and its adjacent waters in spring in 2009: species composition and size-fractionated chlorophyll a]. AB - Based on the multidisciplinary cruise investigation in the Yangtze River estuary and its adjacent waters in April 2009, the phytoplankton species and their abundance were analyzed by the Utermohl method, and the size-fractionated chlorophyll a concentrations were determined. In the meantime, the relationships between the dominant phytoplankton species and environmental physicochemical factors were explored by Canonical Correspondence Analysis (CCA). A total of 3 phyla, 46 genera, and 64 species (not including uncertain species) were found, mostly diatoms and dinoflagellates, with diatoms dominant. Most of these species were temperate and coastal, but a few brackish and oceanic species also presented. There were 33 diatom genera including 45 species. The dominant species were Skeletonema dohrnii, Paralia sulcata, Thalassionema nitzschioides, Pseudo nitzschia pungens, Melosira granulata var. angustissima, Pseudo-nitzschia delicatissima, and Guinardia delicatula. The phytoplankton cell abundance ranged from 0.3 to 13447.7 cells x ml(-1), with an average of 1142.385 cells x ml(-1). Concerning the horizontal distribution, cell abundance was the highest in the middle-northern part of the survey area, with S. dohrnii dominant. The phytoplankton cell abundance was high in the surface layer water, and decreased with increasing depth. The Shannon diversity index and Pielou evenness index were consistently low in the middle-northern part of the survey area, in contrast to the trend of phytoplankton cell abundance. The chlorophyll a concentrations ranged from 0.34 to 29 g x L(-1), with an average of 3.3 g x L(-1), consistent with the cell abundance distribution. Size-fractionated chlorophyll a results showed that the biomass in the middle-northern part of the survey area was mainly composed of microphytoplankton (> 20 microm), while that in offshore waters was mainly composed of nanophytoplankton (2-20 microm) and picophytoplankton (< 2 microm). The CCA showed that the distribution of predominant species S. dohrnii was mainly affected by the water nitrate content, pH value, and microzooplankton grazing. On the contrary, the distribution of other common species including dinoflagellates was mainly associated with water salinity, and phosphate and silicate contents. The paper also compared the differences in the methods of phytoplankton quantification used by the present study and by the previous studies based on net samples. It was suggested that in future work, the autecological study of genus Skeletonema in the Yangtze River estuary and its adjacent waters should be strengthened. PMID- 21548315 TI - [Precipitation pulses and ecosystem responses in arid and semiarid regions: a review]. AB - Precipitation events in arid/semi-arid environment are usually occurred in "pulses", with highly variable arrival time, duration, and intensity. These discrete and largely unpredictable features may lead to the pulsed availability of soil water and nutrients in space and time. Resources pulses can affect the life history traits and behaviors at individual level, numerous responses at population level, and indirect effects at community level. This paper reviewed the most recent research advances in the related fields from the aspects of the effects of resources pulses and the responses of ecosystems. It was emphasized that the following issues are still open, e.g., the effects of the pulsed features of resources availability on ecosystems, the discrepancy among the effects of resources pulses in different ecosystems, the eco-hydrological mechanisms that determine the persistence of pulsed resources effects, and the effects of the pulsed resources availability on ecosystem processes. Given the potential global climate and precipitation pattern change, an important research direction in the future is to determine how the resources pulses affect the ecosystem responses at different scales under different climate scenarios. PMID- 21548316 TI - [Affecting factors of plant stomatal traits variability and relevant investigation methods]. AB - Stoma is the main routeway for water and gas exchange in terrestrial plants, playing an important role on the global water and carbon cycles. Stomatal traits, including stomatal density, stomatal shape, stomatal size, and stomatal index, are the long term adaptation result of plants to environmental factors during evolution, and sensitive to the changes of environmental factors. This paper reviewed the last 30 years research advances in the relationships between stomatal traits and environmental factors (e.g., air CO2 concentration, temperature, water, and light, etc. ) and the main relevant investigation methods, and proposed the main directions of future research in stomatal traits in context of climate change. PMID- 21548317 TI - [Methods and applications of population viability analysis (PVA): a review]. AB - With the accelerating human consumption of natural resources, the problems associated with endangered species caused by habitat loss and fragmentation have become greater and more urgent than ever. Conceptually associated with the theories of island biogeography, population viability analysis (PVA) has been one of the most important approaches in studying and protecting endangered species, and this methodology has occupied a central place in conservation biology and ecology in the past several decades. PVA has been widely used and proven effective in many cases, but its predictive ability and accuracy are still in question. Also, its application needs expand. To overcome some of the problems, we believe that PVA needs to incorporate some principles and methods from other fields, particularly landscape ecology and sustainability science. Integrating landscape pattern and socioeconomic factors into PVA will make the approach theoretically more comprehensive and practically more useful. Here, we reviewed the history, basic conception, research methods, and modeling applications and their accuracies of PVA, and proposed the perspective in this field. PMID- 21548318 TI - [Effects of climate factors on the epidemic of apple Marssonina blotch in Shaanxi Province and related prediction models]. AB - Based on the long term (1999-2008) monitoring of air temperature and relative humidity and of the occurrence and epidemiological trend of Marssonina blotch in the main apple-production area of Shaanxi Province, this paper analyzed the occurrence time, pathogenesis regularity, and epidemiological level of Marssonina blotch, with the 1- and 3-dimensional models for predicting Marssonina blotch under effects of ten-day mean air temperature (T) and relative humidity (Hm) constructed. In study area, the development of Marssonina blotch was mainly affected by environment factors. This disease spread rapidly in field in July and August, causing orchard defoliation, and the harm persisted until September. After the first frost, new disease spots no longer developed. The data of T and Hm in the models showed a good fitting with field condition. The 3-dimensional dynamic prediction model of Marssonina blotch was f(T, Hm) = -0.0172 T3 + 0.9497T2--16.2209T + 88.9923-0.00001Hm3 + 0.00354Hm2--0.15554Hm + 2.36578, where f(T, Hm) was disease index. The modeling results showed that the T for the occurrence of Marssonina blotch in field was 15 degrees C, and the disease would have an epidemic peak when the T and Hm in July and August reached 23 degrees C and > or = 90%, respectively. PMID- 21548320 TI - [Surgical treatment of cardial achalasia]. AB - There was analyzed a 35-years experience of surgical treatment of 683 patients, suffering achalasia of cardia. Comparative analysis of different methods of operative interventions efficacy, including those, using laparoscopic access, was conducted. There was established, that esophagocardiomyotomy together with partial widening fundoplication guarantees good late results achievement in 96.6% of patients. Application of laparoscopic esophagocardiomyotomy and anterior widening fundoplication permits to secure all advantages of miniinvasive access and efficacy, comparable with such of the open access. PMID- 21548319 TI - [Subgingival air-polishing: new perspectives for periodontal maintenance?]. AB - After completion of comprehensive periodontal therapy, the main objective is to maintain gingival tissues in a clinically healthy state. Traditional methods like curettes and ultrasonic devices used during maintenance are responsible of irreversible hard tissue damages ensuing from repeated mechanical scraping of tooth surfaces. A new approach to clean root surfaces without inducing these damages may be the air-polishing technology. Original air-polishing systems are highly abrasive to root cementum and dentin and cannot be used safely in the subgingival area (risk of inducing hard and soft tissue lesions and emphysema). New low abrasive powders and nozzles were designed in order to allow access to root surfaces and to permit the use of the air-polishing devices safely. Recent clinical studies have shown the short-term clinical efficacy of such devices in residual pockets and their safety when used on root surfaces. The new subgingival air-polishing devices are perceived more acceptable by the patients and are more time efficient than scaling and root planning during maintenance. Long-term studies are still lacking to prove their clinical and microbiological efficacy. PMID- 21548321 TI - [Symptomatic laser endoscopic recanalization in inoperable esophageal cancer]. AB - The results of clinical usage of conventional and original methods of laser endoscopic recanalization in patients with inoperable esophageal cancer were analyzed. It was established, that application of modifications, elaborated in the clinic--combined laser endoscopic recanalization with bougienage and without it have permitted to raise essentially a rate of the complete esophageal recanalization achievement, to reduce a quantity of the procedures needed to restore the tumoral stenotic region passability and to reduce a recanalization course duration. PMID- 21548322 TI - [Residual choledocholithiasis: modern realities]. AB - In 748 patients, ageing 28-80 yrs, residual calculi of common biliary duct were removed, using various methods. Transfistular removing of biliary calculi was the method of choice in presence of external drain and endoscopic papillosphincterotomy (EPST) - in its absence. Efficacy of the first variant have had constituted 95.2% and of the second--88%. In 9.5% patients the reoperations were performed--open or laparoscopic. Late results in majority of patients were studied in terms not less than 3 years. Good late results of transdrainage nonoperative elimination of calculi in the first 3 years have had constituted 90% and in the next 6-10 years--99%; while in EPST--accordingly, 85 and 88%. In spite of constantly widening possibilities of the residual choledocholithiasis elimination the main task for modern biliary surgery--the prophylaxis of this not rare complication of cholelithic disease--persist. PMID- 21548323 TI - [Surgical treatment of an acute non-biliary aseptic necrotizing pancreatitis]. AB - The results of treatment of 345 patients, operated on for an acute nonbiliary aseptic necrotic pancreatitis, are adduced. There was established, that rejection to perform an early open access operations with simultaneous application of modern miniinvasive procedures for peritonitis of the enzyme origin (laparoscopy, laparocentesis), an acute aseptic accumulations of liquid in bursa omentalis and cellular tissue of retroperitoneal space, pancreatic pseudocysts (puncture drainage interventions under ultrasonographic guidance) and as well as direct operative interventions on pancreatic gland and cellular tissue of retroperitoneal space, using extraperitoneal miniaccesses in presence of sequesters, have permitted to lower postoperative lethality from 15.2 to 4.1%, and to secure a purulent-septic complications prophylaxis in 93.2% of patients. Application of the puncture-drainage interventions under ultrasonographic control, as well as lumbotomy and sequestrectomy, in the environment of aseptic inflammation, have permitted to escape purulent complications occurrence while an acute aseptic accumulations of liquid are present in bursa omentalis in 96.1% of patients and in cellular tissue of retroperitoneal space--in 69.6%. PMID- 21548324 TI - [Study of changes in the system of the blood neutrophils in acute pancreatitis]. AB - The changes in a system of the blood neutrophils in 65 patients, suffering different forms of an acute pancreatitis, were studied. The trustworthy differences in a neutrophils system structure were determined in patients while their effective conservative treatment, effective surgical treatment, complicated course of postoperative period and exitus lethalis. This data permit to adjust a base for algorithm creation on prognostication, diagnosis and monitoring in patients, suffering an acute pancreatitis. PMID- 21548325 TI - [Anti-inflammatory effect of anesthesiological support of intervention for infected pancreonecrosis]. AB - The protocols of conventional (total intravenous narcosis) and innovation antinociceptive anesthesiological support of interventions, made for an acute destructive pancreatitis and infected pancreonecrosis, are adduced. There was estimated the antiinflammatory capacity of the anesthesiological method proposed and of perioperative intensive therapy. PMID- 21548326 TI - [The immune system status in patients with thrombohemorrhagic syndrome caused by peritonitis]. AB - The changes of immune system were studied in patients, suffering thrombohemorrhagic syndrome (THS), occurred in environment of peritonitis of various severity. A Mannheim's Peritonitis Index (MPI), based on calculation of a point's sum, providing the patient's state characterization, was used for the peritonitis severity estimation. In MPI lesser than 20 points a first degree peritonitis was diagnosed, in a range of 20-30 points--a second degree and more than 30 points--a third degree. The immunogram indices were analyzed in 120 patients, suffering THC with peritonitis. Disorders of cellular and humoral parts of immunity are mostly expressed in patients with THS and peritonitis of II-III degrees (according to MPI). The immunogram changes revealed have served as a background for incorporation of immunomodulating therapy to the complex program of treatment in such patients. PMID- 21548327 TI - [Efficacy of preparation metrogil in abdominal surgery]. AB - There was summarized the experience of Metrogil (metronidazol, produced by company "Unique Pharmaceutical Laboratories", India) application for the treatment of anaerobic infection in diseases of hepatobiliary zone organs as well as for prophylaxis of purulent-septic complications in abdominal surgery. PMID- 21548328 TI - [Efficacy of fibrooptic laryngoscope Flaplight for tracheal intubation in surgical intervention on the thyroid gland]. AB - There were examined 400 patients, operated on for the thyroid gland pathology. A comparative characteristic of various laryngoscopes was conducted. It was established, that laryngoscope Flaplight is mostly effective for the tracheal intubation. PMID- 21548329 TI - [Mini-invasive interventions for cystic formations of the spleen]. AB - The data of complex clinical examination and surgical treatment of 89 patients, having splenic cysts (SC), are analyzed. Indications and contraindications for miniinvasive methods of treatment (laparoscopic and puncture-draining procedures under ultrasonographic control) application are substantiated, taking into account their size, localization, pathogenesis and presence of SC complications. Diagnostic efficacy of abdominal ultrasonography, computer tomography for SC was estimated, the significance of these methods, while choosing a rational tactics of treatment, was determined. There were elaborated and introduced into clinical practice the stages of endosurgical procedures, including performance of organpreserving operations for SC. Introduction of the elaborated diagnostic algorithm and tactics of treatment of SC have permitted to reduce postoperative complications rate and the patients stay in hospital, improving their quality of life as well. PMID- 21548330 TI - [Clinico-endoscopic peculiarities of gastric ulcer of type I and II]. AB - A detailed analysis of clinico-endoscopic peculiarities of gastric ulcer type I and II was presented. The peculiarities of a clinical course and the complications character of differently localized gastric ulcers were determined. There was shown the connection between concomitant disorders of esophagogastroduodenal motor-evacuation function and gastric ulcer localization and type. While tactics of treatment and operative procedure choosing it is mandatory to take into account the clinical course peculiarities and the results of endoscopic investigation. PMID- 21548331 TI - [Venous forms of the inborn vascular malformations of the lower extremities. Diagnosis and surgical treatment]. AB - Pathogenetically substantiated approach, using surgical, laser and echosclerosing methods, was applied for improvement of the treatment results in patients, suffering venous forms of the inborn vascular malformations of the lower extremities. The results of examination and treatment in 2006-2009 period were analyzed in 98 patients. The stem malformations with superficial venous system affection was diagnosed in 59 (60.2%) patients, the same with a deep venous system affection--in 27 (27.6%), the extrastem affections--in 7 (7.1%) and the combined malformations--in 5 (5.1%). There was differential tactics of the surgical treatment used together with combination of original surgical procedures, newest laser methods and sclerotherapy, which have permitted to achieve satisfactory late results in 73 (74.5%) patients. Poor results in 25 (25.5%) patients were caused by the pathological process spread and proliferative activity of malformation, what was confirmed by immunohistochemical and morphological investigations data. PMID- 21548332 TI - [Application of mini-invasive methods of elimination of horizontal reflux in patients with varicose disease of the lower extremities complicated by active trophic ulcers]. AB - The results of surgical treatment of 153 patients for varicose disease of the lower extremities, complicated by trophic ulcers of the feet, were summarized. Miniinvasive methods were applied in patients of the main group for elimination of horizontal reflux, causing the increase of the favorable (excellent and good) results of treatment rate by 36.22% and the reduction of unfavorable results rate -by 15.29%. Introduction of the individualized methods of surgical treatment, using modern technologies of diagnosis and treatment, the choice of optimal variant of operation, applying miniinvasive methods, have permitted to reduce an early postoperative complications rate, a recurrence rate of trophic ulcer of the lower extremities, duration of the patients stationary treatment, as well as to achieve good and satisfactory results in 94.4% of patients during three years after performance of the operation. PMID- 21548333 TI - [Application of tivortin in complex treatment of diabetic foot syndrome]. AB - Theoretical pre-conditions and practical possibilities of preparation Tivortin application in a complex of surgical treatment of diabetic foot syndrome were studied up. Basing on the result of the investigation performed it was established, that while this preparation application a postoperative period course improves, the carbohydrates metabolism normalizes, the pain syndrome intensity reduces. PMID- 21548334 TI - [Modern possibilities of hepacef combi (cefoperazon/sulbactam) application for the treatment of surgical infection]. PMID- 21548335 TI - [Criteria of efficacy of skin-fat flap transplantation in the treatment of large wound defects of foot in patients with diabetes mellitus]. PMID- 21548336 TI - [Dorsal adipofascial flap--alternative plasty of the fingers defects]. PMID- 21548337 TI - [Nursing Council, toward the termination of payments?]. PMID- 21548338 TI - [Advanced practice nurses in France and internationally]. PMID- 21548339 TI - [Advanced practice nursing in the United Kingdom]. PMID- 21548340 TI - [A course designed step by step for advanced practice nursing]. PMID- 21548341 TI - [Outcome of an experimental study of collaboration between health care professionals]. PMID- 21548342 TI - [Toward advanced practice nursing within a health care team]. PMID- 21548343 TI - [Advanced practice nursing in France, a political choice above all]. PMID- 21548344 TI - [Anne Ribes, when the spirit of the garden combines with nursing care]. PMID- 21548345 TI - [Access modalities to the nursing record]. PMID- 21548346 TI - [Sensual pleasure and conviviality around meals in palliative care]. PMID- 21548347 TI - [Blood glucose ruler, a tool for diabetic patients]. PMID- 21548348 TI - ["If I were to have a stroke..."]. PMID- 21548349 TI - [Dietary education and insecurity: how to involve caregivers?]. PMID- 21548350 TI - [Prevention team, monitoring and analysis in aging]. PMID- 21548351 TI - [Managing acute coronary syndrome]. PMID- 21548352 TI - [Injection ports or implanted catheter device]. PMID- 21548353 TI - [Anxiety disorders]. PMID- 21548354 TI - [Allelopathy of Andrographis paniculata vegetative]. AB - OBJECTIVE: Andrographis paniculata at vegetative stage were analyzed for the allelopathic effect on cabbage (Brassica chinensis), Radis (Raphanus sativus), and Desmodium styracifolium, and provided the theory reference for their application of compounding planting pattern in practice. METHODS: Water extracts of Andrographis paniculata root, stem and leaf were used to dispose Brassica chinensis, Raphanus sativus and Desmodium styracifolium seeds, young seedlings. RESULTS: There were allelopathic effect of water extracts of Andrographis paniculata on seed germination of Brassica chinensis, Raphanus sativus and Desmodium styracifolium, but there were difference on allelopathic effect. The suppression effects of roots on seed germination rates of Brassica chinensis showed more significantly, the stems and leaves of Andrographis paniculata on the allelopathic effects on Brassica chinensis seed germination rate index was also significantly higher than the other two receptors plants. Under the treating condition of root, stem and leaf aqueous extracts of Andrographis paniculata, the root growth of receptors seeding mostly showed inhibition effect. Under low concentrations treated. The effects on the seedlings height of Raphanus sativus and Desmodium styracifolium showed the results in which low concentration promoted and high concentration inhibited, and with increasing concentration increased the promotion or inhibition effects. But in the measured concentration range, the effects on the seedlings height of Brassica chinensis were showed promote effect. CONCLUSION: Within the testing concentration range, water extracts of Andrographis paniculata on allelopathic effects of cabbage (Brassica chinensis), Radis (Raphanus sativus) and Desmodium styracifolium showed allelopathic effect, and roughly showed inhibiti effect. However, showed different effect in which high concentration inhibitied and low concentration promoted to different receptor. PMID- 21548355 TI - [Tissue culture and rapid propogation of seeds of Uyghur traditional herbal Capparis spinosa]. AB - OBJECTIVE: To optimize the tissue culture and rapid proliferation techniques of seeds of Capparis spinosa for producing large scale seedlings. METHODS: The seeds of Capparis spinosa were collected as explants and cultivated in different MS media, which were from Turpan in Xinjiang. The optimum media were selected by adjusting the combinations of different hormone and concentration. RESULTS: The best on institution of asepsis explants was rinsing for 8 hours and 0.1% HgCl2 for 12 minutes. The medium MS + 6-BA 0.6 mg/L + NAA 0.1 mg/L was suitable for primary and second culture. The medium MS + 6-BA 0.6 mg/L + 2,4-D 1.0 mg/L was suitable for proliferation, and the optimum medium of rooting was MS + IBA 0.8 mg / L + 300 mg/L activated carbon. CONCLUSION: The rapid proliferation technique of seeds of Capparis spinosa can be used for producing large scale seedlings. PMID- 21548356 TI - [Identification of medical Dendrobium herbs by ISSR marker]. AB - OBJECTIVE: A molecular biology method was studied to identify medical Dendrobium and to provide a method for quality control of these plants. METHOD: ISSR primer was screened through ISSR-PCR reaction according to its gene resolving power, and digital barcodes were established for identification. RESULTS: Screening 2 primers which Rp value above 8, This primers can identify medical Dendrobium from 6 kinds 8 groups. CONCLUSION: ISSR molecular maker technology is useful for identifying species and habitats of medical Dendrobium plants. PMID- 21548357 TI - [Comparative analysis on the configuration of vegetative organs of medicinal Chrysanthemum from different original locations and species]. AB - OBJECTIVE: Compared the difference of the configuration of vegetative organs of medicinal Chrysanthemum in the same habitats but from various original locations and species, in order to provide scientific basis for the study of introduction, differentiation within the species, breeding and genetic diversity. METHODS: The experimental plot were divided into some groups randomly in design and the configuration of vegetative organs were observed, measureed and analysed. RESULTS: The differences of the type and shape of the leaves were obvious. All the Chrysanthemum morifolium cv. 'Gongju' had deep notch long-leaves; Chrysanthemum morifolium cv. 'Boju', Chrysanthemum morifolium cv. 'Chuju', Chrysanthemum morifolium cv. 'Hang bai ju' and Chrysanthemum morifolium cv. 'Hang huang ju' had deep notch correctitude-leaves; Chrysanthemum nakingense and Chrysanthemum indicum had long-leaves; Chrysanthemum indicum had clump-leaves. All the 12 medicinal Dendranthema material had auricle except Chrysanthemum morifolium cv. 'Boju' and Chrysanthemum morifolium cv. 'Chuju'. The young leaves of Chrysanthemum morifolium cv. 'Gongju', Chrysanthemum morifolium cv. 'Gongju' and Chrysanthemum morifolium cv. 'Hang bai ju' did not split and the rest were all splitting. CONCLUSION: The differences of the configuration of vegetative organs were obvious and the Key of Vegetative organs was built. PMID- 21548358 TI - [Studies of burnt folium nelumbinis in anastalsis and processing]. AB - OBJECTIVE: To research the hemostatic components of burnt Folium Nelumbinis and select a better method of processing. METHOD: The anastalsis of medicinal materials between various collection period and the main astrictive parts of burnt Folium Nelumbinis were reviewed by slide method. The powder was observed by microscopic identification. The content of alkaloid was assayed by HPLC. The new method of processing was selected by the orthogonal experiment. RESULT: The lotus leaf in terminal growth can significantly shorten the clotting time and its carbon is more significant which is consistent with other analysis results. The n butanol part from burnt Folium Nelumbinis can significantly shorten the clotting time. The optimum processing of the new method is 140 degrees C, 20 min and its product meets relevant regulations. CONCLUSION: In preliminary view, n-butanol part from burnt Folium Nelumbinis is the main astrictive site. It is reasonable to make the lotus leaf in terminal growth into carbon. It is feasible to carbonize by muffle furnace. PMID- 21548359 TI - [Determination of rosmarinic acid in seeds and its processed products of Perilla frutescens var. typica and Perilla frutescens var. acuta]. AB - OBJECTIVE: To determine the content of rosmarinic acid in seeds and its processed products of Perilla frutescens var. typica (PFT), Perilla frutescens var. acuta (PFA) and Perilla frutescens var. acuta form. discolor (PFAD). METHODS: The content of rosmarinic acid was determined by RP-HPLC with Welch C18 (250 mm x 4.6 mm, 5 microm) column, using methanol-phosphonic acid solution (39:61) as mobile phase at flow rate of 1.0 mL/min. UV detection wavelength was set at 330 nm and column temperature was set at 28 degrees C. RESULTS: The content of rosmarinic acid in roasted seeds of PFT is higher than in its seeds, but that of PFA and PFAD are lower; The content of rosmarinic acid in seeds of PFT, PFA and PFAD decline after the seeds are honey-pocessed and made into frost-like powder, and that of honey-processed one decline by a larger margin. CONCLUSION: The content of rosmarinic acid in seeds of PFT, PFA and PFAD are prone to decline by heat processing. PMID- 21548360 TI - [Identification of the different cultivated Magnolia biondii]. AB - OBJECTIVE: To distinguish Magnolia biondii of ten different cultivated. METHODS: The original species can be identified by the morphological characteristics and microscopic characteristics. The volatile oil is determinated by the method of Chinese pharmacopoeia. RESULTS: The ten cultivated Mangolia biondii have obviously differents in morphological characteristics, microscopic characteristics and volatile oil. CONCLUSION: It is important for development application of Magnolia biondii and variety improvement. PMID- 21548361 TI - [Fingerprints of Curcuma wenyujin by RP-HPLC]. AB - OBJECTIVE: To establish a mutual mode fingerprint of Curcuma wenyujin for quality control of C. wenyujin. METHODS: Waters Symmetry C18 column was used; the mobile phase was methanol-water in a linear gradient elution with the flow rate of 1.0 mL/ min, the temperature of column was 30 degrees C; the detection wavelength was set at 215 nm. 10 batches of C. wenyujin from different places and different time were determined, 3 batches of C. phaeocaulis and 3 batches of C. kwangsiensis were determined in the same chromatographic conditions. RESULTS: 11 mutual peaks in the fingerprint of the 10 groups of C. wenyujin, and the S peak among them represented germacrone. CONCLUSION: Curcuma wenyujin's fingerprints have strong feature and specificity, which can be combined with assaying in the quality control of C. wenyujin. PMID- 21548362 TI - [Chemical constituents of rhizoma imperatae and their anti-complementary activity]. AB - OBJECTIVE: To study the chemical constituents of Rhizoma Imperatae and their anti complementary activity. METHODS: By the hemolysis test, the petroleum extraction, ethyl acetate extraction, n-butanol extraction and the water extraction was tested for anti-complementary activity. Compounds were isolated and purified by silica gel column chromatography, Sephadex LH-20 and reversed-phase column chromatography. The structures were identified by the various spectroscopic data of ESI-MS, 1H-NMR, 13C-NMR. The compounds were evaluated for anti-complementary activity in vitro. RESULTS: The petroleum extraction, ethyl acetate extraction showed significant anti-complementary activity. Ten compounds were isolated from the petroleum and EtOAc soluble fractions and identified as cylindrin (1), arundoin (2), friedelin (3), beta-sitosterol (4), siderin (5), ethyl p hydroxybenzoate (6), 5-methoxyflavone (7), vanillic acid (8), trans-p-coumaric acid (9), 5-hydroxymethylfurfural (10). CONCLUSION: Compounds 6, 7, 8, and 10 are isolated from the genus for the first time, and compounds 3, 8 and 9 inhibited the complement system towards the classical pathway. PMID- 21548363 TI - [The secondary metabolites of the HS-3 Alternaria sp. fungus associated with holothurians]. AB - OBJECTIVE: The metabolites of HS-3 associated with holothurians were studied, which was identified by molecular biology as Alternaria sp.. METHODS: The holothurians were gathered from the Sea of Zhifu Islet, Shandong Province. HS-3 Alternaria sp. was culternitived in potato medium, and four compound was got by TLC, chromatography and HPLC, and 1-hydroxyl-3-methylanthracene-9,10-dione (1), chrysophanol (2), sterigmatocystin (3) and cerebroside (4) were elucated by modern spectrum. CONCLUSION: All of this provides scientific data for further study of holothurians, and the four coumpouns are isolated from the microbe associated with holothurians for the first time. PMID- 21548364 TI - [Study on the chemical constitutes of submerged cultivation mycelium of Cordyceps jiangxiensis]. AB - OBJECTIVE: In an effort to investigate the chemical constitutes of submerged cultivation mycelium of Cordyceps jiangxiensis anamorph. METHODS: The mycelia of C. jiangxiensis anamorph produced by submerged cultivation technique were separated and purified using various chromatographic techniques such as repeated liquid column chromatography, preparative thin layer chromatography etc. , and then the chemical structures of compounds obtained were elucidated on the basis of physicochemical analysis and spectroscopic techniques such as 1H-NMR, 13C-NMR and MS. RESULTS: Nine compounds were obtained from the petroleum ether and ethyl acetate extractive fractions of mycelial methanol extract, and were identified as follows: uracil (I), adenine (II), adenosine (III), uridine (IV), 3' methoxyuridine (V), succinic acid (VI), nicotinic acid (VII), 1-monostearin (VIII), tetracosanoic acid (IX). CONCLUSION: Chemical constitutes of C. jiangxiensis anamorph are systematically separated for the first time, and compounds V, VII, VIII, and IX obtained are separated from Cordyceps species firstly. PMID- 21548365 TI - [Study on the alkaloids in Stephania hernandifolia]. AB - OBJECTIVE: To study the alkaloids in Stephania hernandifolia. METHODS: The dried herbs of S. hernandifolia were extracted with 95% ethanol. After removal of the solvent, the residue was first partitioned between acid water and petroleum ether, then the aqueous layer was basified and extracted with chloroform to obtain crude alkaloids. Column chromatography on silica gel, Rp-18, MCI CHP 20P, Sephadex LH-20 were applied for the isolation and purification of the crude alkaloids fraction. The structures were elucidated by their physicochemical properties and spectral data. RESULTS: Six alkaloids were obtained and identified as Cepharamine (I), l-tetrahadropalmatine (II), Plmatine (III), Stephamiersine (IV), Telitoxine (V), Daurioxoisoporphine D (VI). CONCLUSIONS: Compounds I - VI are isolated from this plant for the first time, and compounds V, VI are isolated from the plants of Stephania for the first time. PMID- 21548366 TI - [Study on the chemical constituents of Phlomis younghusbandii]. AB - OBJECTIVE: To study the chemical constituents of Phlomis younghusbandii. METHODS: Column chromatography was used in the isolation procedure. The structures of isolated compounds were elucidated by spectral data RESULTS: Eight compounds were isolated and their structures were identified as barlerin (1), sesamoside (2), phloyoside II (3), salidroside (4), shanzhiside methyl ester (5), acteoside (6), luteolin-7-O-glucoside (7), daucosterol (8). CONCLUSION: Compound 4 is firstly isolated from Phlomis genus. Compound 4 and 6 are obtained from this plant for the first time. PMID- 21548367 TI - [The volatile components of three radix et rhizoma asari]. AB - OBJECTIVE: To analyze and compare the volatile components of Asarum sieboldii Miq, Asarum himalaicum Hook. F. et Thoms and Asarum. debile Franch in the same area. METHODS: The volatile components were extracted from three Radix et Rhizoma Asari by solid-phrase microextraction and their contents were analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: 59, 99 and 85 volatile components were identified from Asarum sieboldii Miq, Asarum himalaicum Hook. F. et Thoms and Asarum debile Franch, representing the ralative content of 82.75% - 99.43% of the volatile oil. 16 of same components were identified in the three Radix et Rhizoma Asari, and the contents of the same components were different among them. In addition, some unique components were identified in them respectively. CONCLUSION: There were differences among the chemical components and the contents of the volatile oil of the three Radix et Rhizoma Asari. The results could give certain reference value for the medicine whether Asarum himalaicum Hook. F. et Thoms and Asarum debile Franch can replace Asarum sieboldii Miq. PMID- 21548368 TI - [Comparative study on the osteogenic differentiation of rat bone marrow stromal cells effected by icariin and icariside II]. AB - OBJECTIVE: To investigate the effects of icariin and it's main metabolites icariside II on the osteogenic differentiation of rat bone marrow stromal cells (rBMSCs). METHODS: rBMSCs were cultured by adherence screening method, icariin and icariside II were supplemented into the culture at 5 x 10(-5) mol/L respectively. The osteogenic differentiation markers including alkaline phosphatase (ALP) activity, CFU-F(ALp), osteocalcin secretion, calcium deposition and mineralized bone modulus were compared among the icariin-supplemented group, icariside II and the control. The gene expressions of bFGF, IGF-1, Osterix and Runx-2 were examined by RT-Real Time PCR. RESULTS: Both icariside II and icariin significantly improved ALP activity, CFU-F(ALP) amount, osteocalcin secretion, calcium deposition and mineralized modulus. Besides, they enhanced the gene expressions of bFGF, IGF-1, Osterix and Runx-2. Icariside II was obviously stronger than icariin at the above activities. CONCLUSION: Icariside II is stronger than icariin at enhancing the osteogenic differentiation of rBMSCs, suggesting that icariin can be administered via oral and it's metabolites are the effective constitutes for antiosteoporosis activity. PMID- 21548369 TI - [Molecular mechanism of protective effect of puerarin solid lipid nanoparticle on cerebral ischemia-reperfusion injury in gerbils]. AB - OBJECTIVE: To investigate the effects of puerarin solid lipid nanoparticle on fore brain ischemic-reperfusion injury in gerbils and it's mechanisms. METHODS: Gerbils were randomly divided into 4 groups: sham group, cerebral ischemia reperfusion injury group, puerarin solid lipid nanoparticle group and puerarin injection control group. The gerbils' cerebral ischemia-reperfusion injury model was constructed with ligating bilater carotids method. The histomorphology and Bcl-2, Caspase-3 and HSP70 expressions were detected by HE dyeing and immunohistochemical method. RESULTS: After 24 h ischemia and reperfusion in gerbils, the level of Bcl-2 and HSP70 expressions in puerarin solid lipid nanoparticle group increased (P < 0.01) compared with the ischemic-reperfusion model group, and the level of Caspase-3 expression decreased (P < 0.01). The same results was consistent in puerarin injection control group. CONCLUSIONS: Puerarin solid lipid nanoparticle group can protect the cerebral ischemia-reperfusion injury in gerbils, which may be related to the upregulation of Bcl-2 and HSP70 expression and downregulation of Caspase-3 expression. PMID- 21548370 TI - [Study on the best concentration of combination of the effects of the four original constituents of liu-wei di-huang pill on the proliferation and differentiation of rat preadipocyte]. AB - OBJECTIVE: To investigate the effects of four original constituents (Loganin, Morroniside, Peoniflorin, Paeonol) of Liu-wei Di-huang pills on the proliferation and differentiation of rat preadipocyte, and optimize the best concentration by the orthogonal test. METHODS: The rat preadipocytes were cultured, then above four original constituents according to 4 factors and 3 levels to make L9 (3(4)) orthogonal test, and the control was performed at the same time. The proliferation of preadipocytes was determined by MTT method, and the accumulation of cellular lipid was determined by Oil Red O staining, the differences between factors and variances were compared by the value of absorbance. RESULTS: The combination of four original constituents of Liu-wei Di-huang pills could stimulate rat preadipocyte proliferation and inhibited its lipid accumulation. Both the effects were highly significant (P < 0.01) with the combination of A3 B1 C3 D2; Compared with the monosomic group, the effects of the A3 B1 C3 D2 was highly significant (P < 0.01). CONCLUSION: Compared with the monosomic group, the effects of the combination of the four original constituents of Liu-wei Di-huang pills on the proliferation and differentiation of rat preadipocyte were highly significant. This combination consists of Loganin, morroniside with high doses, Paeonol, Peoniflorin with mid-dose and low-dose, respectively. Regnesent the overall regulatory role of synergy and officiencg. PMID- 21548371 TI - [Effect and mechanism of Aconitum vaginatum on the proliferation, invasion and metastasis in human A549 lung carcinoma cells]. AB - OBJECTIVE: To study the effects and mechanism of Aconitum vaginatum on proliferation, invasion and metastasis of human lung adenocarcinoma A549 cell lines. METHODS: A549 cells were treated with Aconitum vaginatum at different concentrations, and divided into 4 groups: Aconitum vaginatum 0.01, 0.1, 1 mg/mL groups and control group, respectively. MTT assay was used to evaluate cell proliferation; migration and invasion (with matrigel) assay was conducted in the transwell chamber; gelatin zymography was performed to evaluated the impacts of Aconitum vaginatum on matrix metalloproteinase (MMP)-2, MMP-9. RESULTS: Aconitum vaginatum exhibited a concentration-dependent inhibitory on proliferation and invasion of A549 cells. Aconitum vaginatum was also found to decrease the activity of MMP-2, MMP-9 in a concentration-dependent manner (P < 0.05). CONCLUSION: Aconitum vaginatum can inhibit the proliferation, invasion and metastasis of human adenocarcinoma A549 cell lines, the mechanism maybe deceasing MMP-2, MMP-9 activity. PMID- 21548372 TI - [Effects of Astragalus polysaccharide on nephritis induced by cationic bovine serum albumin in rats]. AB - OBJECTIVE: To study the effects of Astragalus polysaccharide on nephritis induced by cationic bovine serum albumin in rats. METHODS: C-BSA induced nephritis model was utilized in rats. The effects of Astragalus polysaccharide on this model were investigated. RESULTS: Proteinuria of the Astragalus polysaccharide group was alleviated. The pathological damages of the Astragalus polysaccharide group were less severe in comparison with the model group. The Astragalus polysaccharide group could improve erythrocyte immune function and increase the CD35 and CD44s contents of red blood cells. CONCLUSION: Astragalus polysaccharide exerts a good effect in alleviating glomerular immune inflammation and improving erythrocyte immune function in the treatment of C-BSA induced nephritis. PMID- 21548373 TI - [Study on preparation and characterization of resveratrol solid lipid nanoparticles and its anticancer effects in vitro]. AB - OBJECTIVE: To prepare resveratrol solid lipid nanoparticles (Res-SLN) and investigate its physical and chemical speciality and anticancer effects in vitro. METHODS: Res-SLN was prepared by the solvent emulsification-evaporation method. Its morphology, particle size and zata potential were examined by transmission electron microscope and laser granularity equipment. Its entrapment efficiency, drug loading, release concentration were determined by HPLC. Its anticancer effect of Res-SLN in vitro were studied by MTT. RESULTS: Res-SLN assumed spherical shape. Its distribution of diameter was even with average particle size of 96. 7 nm, zata potential was--16.3mV, drug loading was (7.95 +/- 0.21)%, entrapment efficiency was (91.34 +/- 0.18)%; Res-SLN could retard drug release in vitro and its cytotoxicity was significantly higher than that of oridonin solution against HepG2 cells. CONCLUSION: Res-SLN has high entrapment efficiency and drug loading, uniform particle size, and can retard drug release in vitro and enhance anticancer effect. PMID- 21548374 TI - [Design, optimization and quality evaluation of curcumin self-emulsifying drug delivery system (SEDDS)]. AB - OBJECTIVE: To develop the self-emulsifying drug delivery system (SEDDS) of curcumin, and evaluate its quality in vitro. METHODS: The excipients of curcumin SEDDS were selected via its solubility study in various oils, surfactants and co surfactants and the formulation was optimized using ternary phase diagram study and central composite design-response surface methodology (oil, surfactant and co surfactant percentages as factors; solubility, droplet size, polydispersity index and emulsifying time as responses). The appearance, droplet size and polydispersity index after emulsifying and the emulsifying time of optimized curcumin SEDDS were studied. The solubility of curcumin in the solution of SEDDS was determined. RESULTS: Castor oil-(tween-80) -ethanol = 28: 55: 20 (w/ w/w) was selected for optimum curcumin SEDDS. The droplet size was 222. 2 nm, polydispersity index was 0. 171. The time of self-emulsifying was 10 s and the solubility of curcumin in SEDDS was 1.93 mg/mL. CONCLUSION: Curcumin SEDDS formulation is selected and optimized successfully, and the preparation of curcumin SEDDS is simple, the quality is stable. PMID- 21548375 TI - [Study on purification of polysaccharides in root of Salvia miltiorrhiza by macroporous adsorption resin and ion-exchange resin methods]. AB - OBJECTIVE: To study the purification and isolation of polysaccharides from Salvia miltiorrhiza. METHODS: The root was extracted by water purified preliminarily by alcohol precipitation, and then four different types macroporous adsorption resin and one ion-exchange resin were comparatively investigated in the purification and isolation of Salvia polysaccharides. RESULTS: The total polysaccharides of crude extracts was 40.35%, and protein content amounted to 8.96%. Compared with the traditional methods, AB-8, DB-301 type of resin used in purification of polysaccharides could simplify the working process and obtain better effect. Then the obtained crude polysaccharides through AB-8 resin were purified by ion exchange resin DEAE-52. Three portions of powder were obtained through lyophilization and named as SMP1, SMP2, SMP3. CONCLUSION: Purification of Salvia polysaccharides can be conducted by adoping AB-8, DB-301 type of resin and DEAE 52 ion-exchange resin. PMID- 21548376 TI - [Studies on the extraction of volatile oil from Thymus marschallianus and preparation of its beta-CD inclusion compounds]. AB - OBJECTIVE: To study the optimum conditions for the extraction of volatile oil from Thymus marschallianus and the preparation of its beta-CD inclusion compounds. METHODS: The study was carried out with single factor and orthogonal design. With the percentages of extracted volatile oil of Thymus marschallianus as the target marker we selected the optimum conditions for extracting the volatile oil. The ration of inclusion and the oiling-bearing from the inclusion as the target marker was to optimize the conditions for including the oils with beta-CD. RESULTS: The optimized extraction conditions were as follows: the water was 12 times of the herbs in weight, Thymus marschallianus should be extracted for 4 hours after soaked 0.5 hours with water. The optimized inclusion conditions were as follows: applying the saturated aqueous solution method, the proportion of oil and beta-CD was 1 mL: 8 g, the temperature and time were 60 degrees C and 60 minutes, respectively. CONCLUSION: The established process can be used for the extraction and the inclusion of volatile oil from Thymus marschallianus with its high ration of oil and the economic cost. PMID- 21548377 TI - [Application of tunica vaginalis flap for multi-fistulas after urethroplasty in hypospadias]. AB - OBJECTIVE: To discussed a new technique for multi-fistulas after urethroplasty in hypospadias. METHODS: 8 cases with postoperative multi-fistulas, which were not successfully repaired by previous treatment, were reoperated with tunica vaginalis flap combined with urethral stent and elastic dressing. The multi fistulas were located between glan and scrotum. The number of fistulas was 3-7 (median, 5). RESULTS: Primary healing was achieved in all the 8 cases. The micturition and esthetic result were satisfied. 5 cases were followed up for 8-10 months with no recurrence of fistula. There was also no dysuria and penile curvature. CONCLUSIONS: Tunica vaginalis flap combined with urethral stent and elastic dressing is an effective technique for multi-fistulas after urethroplasty. It is easily performed with reliable result. PMID- 21548378 TI - [Tubed oral mucosa for staged treatment of congenital hypospadias in infancy]. AB - OBJECTIVE: To discuss the treatment of congenital hypospadias in infancy. METHODS: After correction of chordee, the tubed oral mucosa was used to prefabricate urethra in penis as free graft. The urethral anastomosis was performed at the second stage. The scrotum fascia flap, pedicled with scrotal artery, was transferred to cover the penile defect. RESULTS: From Jan. 2007 to May 2010, 42 cases were treated. The tubed oral mucosa was 3.0-4.0 cm in length, and 0.6-0.8 cm in diameter. The maximum size of scrotum flap was 1.5 cm x 3.0 cm. Urethral fistula happened in two cases due to necrosis at the distal end of scrotal flap, which was healed spontaneously after dressing for 1-2 weeks. Primary healing was achieved in all the other cases. After operation, the 26 cases have been visited for 6 months to 3 years, no urethra fistula , narrow and the penis curved. There is an universal urinate for oneself and a good form. CONCLUSIONS: The tubed oral mucosa can be used to prefabricate urethra, which is anastomosed at the second stage. The tubed oral mucosa combined with scrotal fascial flap which has a reliable blood supply, is very suitable for hypospadias in infancy. PMID- 21548379 TI - [Application of anterolateral thigh myocutaneous flap in the reconstruction of tongue and mouth floor defect after tongue carcinoma]. AB - OBJECTIVE: To investigate the application of free anterolateral thigh myocutaneous flap in the reconstruction of tongue and mouth floor defect after radical resection of tongue carcinoma. METHODS: From June 2006 to April 2009, 14 cases with tongue carcinoma underwent radical resection, leaving tongue and mouth floor defects which were reconstructed by anterolateral thigh myocutaneous flaps at the same stage. These 14 cases included tongue carcinoma at lingual margin (n=9), at ventral tongue (n=3) and at mouth floor (n=2). The flap size ranged from 7 cm x 9 cm to 5 cm x 7 cm. RESULTS: All the 14 flaps survived completely with primary healing. There was no functional morbidity in the lower extremities. The patients were followed up for 12-26 months with satisfied esthetic and functional results in reconstructed tongue. Only one case (T4 N1 M0) died of metastasis carcinoma 14 months after operation. No local recurrence happened. CONCLUSIONS: The anterolateral thigh myocutaneous flap has abundant tissue volume to reconstruct the tongue and mouth floor defect, while leaving less morbidity at donor site. Both satisfied esthetic and functional results can be achieved. PMID- 21548380 TI - [Application of internal mammary artery perforator flap for tracheostoma and anterior cervical defect]. AB - OBJECTIVE To investigate the application of pedicled internal mammary artery perforator (IMAP) flap for tracheostoma and anterior cervical defect. METHODS: From April to December 2009, 4 IMAP flaps, based on the second internal mammary artery perforator, were used for two cases of tracheostoma and two cases of anterior cervical skin defect. The flap size was (4-7) cm x (10-13) cm. RESULTS: 3 of 4 flaps survived completely. Partial necrosis happened in one flap. The defects at donor sites were closed directly. CONCLUSIONS: The IMAP flap is a new method for head and neck defect. It is very suitable for tracheostoma and cervical skin defect, with less morbidity at donor site. PMID- 21548381 TI - [Narrowing and sliding genioplasty procedure combined with mandibular outer cortex ostectomy technique to correct square jaw in short face]. AB - OBJECTIVE: To evaluate the the feasibility and effectiveness of narrowing and sliding genioplasty combined with mandibular outer cortex ostectomy technique to reshape a square jaw in short face. METHODS: From July 2005 to October 2009, a total of 57 patients received narrowing and sliding genioplasty combined with mandibular outer cortex ostectomy procedure to correct square jaw in short face. All the patients had standard frontal and lateral cephalometric radiographs, panoramic radiographs, and were photographed preoperatively and postoperatively to assess their face contour. The alteration of mandibular angle, mental contour and width of lower face was observed for 6 to 24 months postoperatively. Questionnaires were used to assess the patients' satisfactory. RESULTS: It showed that the postoperative lower face had narrowed and become softer, slender and oval, with a slick mental region. The final aesthetic outcomes were quite satisfactory in all cases from both the view of surgeons and patients. CONCLUSIONS: Narrowing and sliding genioplasty combined with mandibular outer cortex ostectomy procedure could efficiently adjust the shape and position of chin to obtain a good proportion of the lower face, and to change square and short face to slender oval one by single operation in accordance with the fashionable aesthetics in orientals. PMID- 21548382 TI - [Application of bi-pedicled frontal expanded flap for cervical cicatricial contracture]. AB - OBJECTIVE: To investigate the therapeutic effect of bi-pedicled frontal expanded flap for cervical cicatricial contracture. METHODS: Tissue expanders were implanted under frontal muscle. After expansion, the frontal flaps were designed based on bilateral superficial temporal vessels and were transferred to the neck wound. The cervical spine movement and the mento-cervical angle was measured and analyzed by SPSS16.0 and t test. RESULTS: From September 2006 to May 2010, 7 patients were treated by this method. The range of active cervical movement was improved in all direction. The mento-cervical angle decreased from (152.7 +/- 1.9) to (90.7 +/- 2.2) degrees after operation. The patients were followed up for 5 months to 3 years with satisfactory result and no contracture recurrence. CONCLUSIONS: The bi-pedicled expanded frontal flap has a reliable blood supply and is very suitable for cervical cicatricial contracture with good functional and esthetic results, leaving less morbidity at donor site. PMID- 21548383 TI - [Repair of soft tissue defects in the upper limbs using multiple types of posterior interosseous artery flaps]. AB - OBJECTIVE: To summarize the therapeutic effect of multiple types of posterior interosseous artery flaps for repair of soft tissue defects in the upper extremities. METHODS: From March 2003 to June 2010, 42 cases with soft tissue defects in the upper limbs resulting from burn and traumatic injuries were treated using multiple types of posterior interosseous artery flaps, including retrograde flaps and composite flaps, antegrade flaps ,and free flaps. Flap size ranged from 2.5 cm x 2.0 cm-14.0 cm x 9.0 cm. The defects in the donor sites were closed directly or covered by skin graft. RESULTS: The conventional retrograde posterior interosseous artery flaps were used in 11 cases, the modified retrograde posterior interosseous artery flaps were used in 13 cases, the retrograde posterior interosseous artery composite flaps incorporating partial extensors were used in 2 cases, the antegrade posterior interosseous artery flaps were used in 3 cases, the free posterior interosseous artery flaps were used in 7 cases, and the free perforator flap based on the radiodorsal septocutaneous perforator of the posterior interosseous artery were used in 6 cases. Partial necrosis happened in one case at the distal portion of the flap. Muscular branch of the posterior interosseous nerve was injured in one case with conventional reverse posterior interosseous artery flaps. All the other flaps survived uneventually with no complication. All wounds were primarily healed. 32 cases were followed up for 1 to 48 months with satisfactory aesthetic and functional results both in the donor sites and in the recipient areas. The color,texture and thickness of the flaps were satisfied as well. CONCLUSIONS: The posterior interosseous artery flap has a constant vascular anatomy and a great flexibility, which is practical and suitable for repair of Soft tissue defect in the upper extremities arising from burn and traumatic injury. PMID- 21548384 TI - [Application of electrochemical therapy in high-flow vascular malformation in maxillofacial region]. AB - OBJECTIVE: To explore the therapeutic effect of electrochemical therapy(ECT) for high-flow vascular malformation in maxillofacial region. METHODS: 38 patients with high-flow vascular malformation in maxillofacial region were treated with ECT. The voltage was 6-8 V, and the electric current was 80-100 mA. The electric quantity was 10-20 C/cm2. RESULTS: Among the 38 cases, 32 cases received only one treatment, 5 cases received two treatments and one case received three treatments. The patients were followed up for 2 months to 3 years. The total effective rate was 100% with 55.26% of cure rate and 44.74% of partial cure rate. No hemolysis happened during follow-up period. CONCLUSIONS: ECT is a simple and effective method for high-flow vascular malformation with less morbidity. PMID- 21548385 TI - [Effect of the botulinum toxin type A on myocutaneous flap expansion in minipigs model]. AB - OBJECTIVE: To investigate the histologic effect of botulinum toxin type A (Botox A) injection on myocutaneous flap expansion in minipigs model. METHODS: Seven minipigs were included in this study. Two symmetric tattoo area, 10 cm x 6 cm in size, were selected on the bilateral flank of the pigs. The Botox A was injected into one tattoo area randomly, 4 U every point, 2 cm apart, with a total dose of 96 U. The same dose of sterile normal saline (0.9%) was injected in the same fashion on the opposite side as control. 3 days after injection , two 200 ml expanders were inserted beneath the cutaneous muscle at the tattoo area. After complete expansion of 200 ml, the specimens were drawn from both groups symmetrically and were stained by means of HE and Masson. The histologic changes of myocutaneous flap were compared. Thickness of each layer in myocutaneous flap was measured in histological section. RESULTS: The thickness of cutaneous muscle, capsule, dermis were (275.74 +/- 28.93) microm, (468.03 +/- 34.28) microm, (1990.79 +/- 102.10) microm in Botox group, and (409.13 +/- 44.63) microm, (626.55 +/- 44.05) microm, (2508.44 +/- 70.71) microm in saline group, respectively, show a significant difference between the two groups (P < 0.01). The Masson stained slice showed that collagen average gray of capsule in Botox group was 185.38 +/- 9.56, which was significantly higher than that in the saline group (120.77 +/- 10.31, P < 0.01). Light microscope (HE stained sections ) showed that muscle in Botox group was significantly atrophy and cross-section of muscle fiber decreased. The muscle fiber in saline group was generally normal. It was observed through transmission electron microscope that the light and dark band of muscle cell became fuzzy and the Z line bending in Botox group. The light and dark band in saline group arranged neatly, the Z line was clear. CONCLUSIONS: Application of Botox A in myocutaneous flap expansion can make the muscle atrophy and reduce the content of collagen in capsule layer, making the myocutaneous flap thinner which is suitable for reconstruction in face and neck. PMID- 21548386 TI - [Effect of hirudin on random skin flap survival in rats]. AB - OBJECTIVE: To investigate the effect of Hirudin on random skin flap survival in rats. METHODS: 24 SD rats were randomly divided into control group and experimental group. The "McFarlane flap (3 cm x 9 cm)" rat models were established on the rat dorsum. 3 ml Hirudin (30 ATU) was injected into the flap in the experimental group, while 3 ml saline in the control group. The injection was performed for 7 days. The flap survival area in the two groups was measured. The tissue samples were taken from proximal (I), middle (II) and distal (III) portions of flaps for histologic study. The VEGF and bFGF expression was also detected with immunohistochemistry method. RESULTS: 7 days after operation, the flap survival rate was (69.52 +/- 3.23)% in the experimental group, while (50.36 +/- 2.37)% in control group, showing a significant difference between the two groups (P < 0. 01). In the middle portion, tissue edema and infiltration of neutrophils in experimental group was markedly slighter than that in control group. The VEGF and bFGF expression and neovascularization was enhanced markedly in experimental group. CONCLUSIONS: Hirudin can increase the survival of random pattern skin flaps. It may increase the VEGF, bFGF expression through a series of complex regulatory pathway. Then flap neovascularization is promoted and the flap blood supply is increased. PMID- 21548387 TI - [Experimental study on the relationship between the ratio of length to width of slender narrow pedicle and random flap survival area in pig]. AB - OBJECTIVE: To explore the relationship between the ratio of length to width of slender narrow pedicle and random flap survival area, and to provide a theoretical basis for the clinical application of slender narrow pedicle flaps. METHODS: 25 pigs were randomly divided into 5 groups, 5 pigs in each group. The ratio of length to width of slender narrow pedicle in 5 groups respectively was: 0:2, 1:2, 2:2, 3:2, 4:2. Every ratio' s slender narrow pedicle was carrying five different size of random flaps, which were 2 cm x 2 cm(A), 3 cm x 3 cm(B),4 cm x 4 cm(C), 5 cm x 5 cm(D), 6 cm x 6 cm(E), respectively. Flap A was control flap. In each group, flap A, B, C, D and E were created in each pigs' bilateral back. The order in both sides back is contrary. The flaps were evaluated with the general observation, fluorescence examination, blood flow ECT test, pathological expression and computerized analysis of survival area. RESULTS: (1) The living process and pathologic process of traditional flap and slender narrow pedicle flap were consistent. It could not postpone the flap living process when the flap pedicle became long and narrow. (2) When the ratio of the length to width of the slender narrow pedicle was constant, along with the flap area increased, the flap survival area also increased, but when the flap reached a certain area , the distal flap would necrosis,the flap survival area would not reduce. (3) When the flap size remained unchanged, along with the ratio of the length to width of the slender narrow pedicle increased, the flap survival area was not affected, but when the ratio of the length to width of the slender narrow pedicle increased to a certain limit, distal flap would necrosis, the flap survival area would reduce. CONCLUSIONS: (1) Pedicle width of random flap can be much smaller than flap width. The ratio of pedicle width to flap length is far less than traditional ratio. (2) The pedicle of random flap can be designed as slender shape, so that the whole flap looks like "pingpang bat", which makes the narrow pedicle flap rotate easily. (3) A certain ratio of the length to width of a slender narrow pedicle has a maximum flap survival area, and increasing the flap size or ratio of the length to width of a slender narrow pedicle in a certain extent will not lead to flap necrosis. PMID- 21548389 TI - [Expression of estrogen sulfotransferase in the mammary gland of hypertrophic breast and its significance]. AB - OBJECTIVE: To investigate the expression of estrogen sulfotransferase (EST) in the mammary gland of hypertrophic breast and its significance. METHODS: EST expression in the mammary gland was detected by EnVision two step method of immunohistochemistry in 15 cases with normal breasts and 32 cases with hypertrophic breasts, including 19 gland-associated cases and 13 fat-associated cases. RESULTS: The positive expression rate of EST in mammary gland was 34.4% (11/32) in hypertrophic group and 93.3% (14/15) in normal group, showing a significant difference between the two groups (P < 0.01). The positive expression rate of EST was 10.5% (2/19) in gland-associated group and 69.2% (9/ 13) in fat associated group, showing a significant difference between the two groups (P < 0.01). CONCLUSIONS: Decrease or deletion of EST in the mammary gland may be related to the development of hypertrophic breast, especially gland-associated hypertrophic breast. PMID- 21548388 TI - [The cellular and molecular mechanism of inhibitory effect of asiaticoside on capsular contracture following breast augmentation]. AB - OBJECTIVE: To explore the cellular and molecular mechanism of the inhibitory effect of asiaticoside on capsular contracture following breast augmentation. METHODS: Contracture capsule derived fibroblasts were cultured in medium with different concentration of asiaticoside. The cell proliferation, collage synthesis and alpha-SMA expression were detected by means of 3H-thymidine incorporation, 3H-proline incorporation, and Western-blot. The results were analyzed by SPSS 11.0 with t test. RESULTS: DNA and collagen synthesis of fibroblasts were dramatically inhibited when the asiaticoside reached the concentration of 50 mg/L. The inhibitory rate was 34.7% and 30.1% respectively, showing a significant difference from that in control group (P < 0.05). The inhibitory effect increased with the rise of the asiaticoside concentration in a dose-dependent manner. When the concentration of asiaticoside reached 25 mg/L, the expression of alpha-SMA was down-regulated with an activation index of 1.673, showing a significant difference when compared with that in control group (P < 0.05). CONCLUSIONS: asiaticoside can effectively inhibit the DNA and collagen synthesis of capsule-derived fibroblasts. The trans-differentiation of fibroblast to myo-fibroblasts is also prevented by it. PMID- 21548390 TI - [The cellular plasticity of human adipocytes]. AB - OBJECTIVE: To explore the dedifferentiation phenomenon of human mature adipocytes cultured in vitro and to discuss the possibility of using dedifferentiation adipocytes (DA) as seed cells. METHODS: Mature adipocytes and ASCs were harvested from human fat aspirates. Mature adipocytes were cultured and induced to DA by ceiling adherent culture method. Cell morphology were observed during the whole process. Viabilities of DA and ASCs were compared by MTT chromatometry and cell growth curves were drawn based on it. Cell surface markers of DA and ASCs were detected by flow cytometry. The adipogenic, osteogenic and chondrogenic ability of DA and ASCs were assessed by oil red O staining, alizarin bordeaux staining and alcian blue staining, respectively. RESULTS: Human mature adipocytes can dedifferentiate into fibroblast-shaped DA. MTT chromatometry assay demonstrated that DA and ASCs both had strong reproductive activity, with no significant difference between them. Flow cytometry assay demonstrated that both DA and ASCs expressed HLA-ABC, CD29 and CD44, while didn't express CD45, CD34 and CD106. After two weeks of adipogenic differentiation, lipid droplets could be displayed by oil red O staining in both DA and ASCs. After two weeks of osteogenic differentiation, calcium salts mineralization in DA and ASCs could be detected by alizarin bordeaux staining. After two weeks of chondrogenic differentiation, matrix of cartilage cells in DA and ASCs could be detected by alcian blue staining. CONCLUSIONS: Mature adipocytes can be dedifferentiated into DA in vitro. DA has strong reproductive activity, as well as osteogenic, chondrogenic ability and strong adipogenic ability. It expresses some of the stem cell-related cell surface proteins and is a promising seed cell for adipose tissue engineering. PMID- 21548391 TI - [Directional differentiation of human adipose-derived stem cells into endothelial cells]. AB - OBJECTIVE: To investigate the possibility of directional differentiation of human adipose stem cells (hADSCs) into endothelial cells (EC), so as to provide seed cells for tissue engineered vessels. METHODS: hADSCs were isolated from human adipose tissue by collagenase digestion, cultured and amplified by adherence to flasks. Then hADSCs were directionally induced to differentiate into EC by a combination of fibronectin (FN), endothelial cells support liquid (EGM2-MV) containing various growth factors and high concentration of VEGF165 (50 ng/ml). Then, the cells morphology, phenotype and function were identified. RESULTS: Highly homologous hADSCs were obtained, and then hADSCs were directionally differentiated into EC. CD31 and CD34, the specific markers for EC, and vascular endothelial growth factor receptor (KDR) were positive by immunohistochemical staining and RT-PCR. In addition, unique Weibel-Palade bodies in EC were observed under transmission electron microscope. Functionally, hADSCs could swallow Dil-Ac LDL and form tube-like structures in matrigel after endothelial differentiation. CONCLUSIONS: hADSCs can be successfully induced to differentiate into endothelial cells in vitro. PMID- 21548392 TI - [Gingival hyperplasia as side effect of the calcium channel blocker amlodipine]. AB - Medically induced gingival overgrowth is one of the major side effects of phenytoine, cyclosporine A and the channel blocker Nifedipine and it is well documented in various studies and case series. Recently an alternative channel blocker, Amlodipine, has been implemented into the clinical treatment of cardiovascular diseases. By means of a clinical case presentation it was shown that Amlodipine is able to induce gingival overgrowth in the oral cavity as well. Additionally, the causes of Amlodipine-induced gingival hyperplasia are critically discussed and several options of therapy modalities presented. PMID- 21548393 TI - Pediatric sedation and distraction. PMID- 21548394 TI - Therapy: trimming the excess. PMID- 21548395 TI - Tumour microenvironment: the same, but different. PMID- 21548396 TI - DNA damage: Wrap-around care. PMID- 21548397 TI - Chromosome instability: Chaos from within. PMID- 21548398 TI - Tumorigenesis: Wound-up tumours. PMID- 21548399 TI - Medicare program; inpatient psychiatric facilities prospective payment system- update for rate year beginning July 1, 2011 (RY 2012). Final rule. AB - This final rule updates the prospective payment rates for Medicare inpatient hospital services provided by inpatient psychiatric facilities (IPFs) for discharges occurring during the rate year (RY) beginning July 1, 2011 through September 30, 2012. The final rule also changes the IPF prospective payment system (PPS) payment rate update period to a RY that coincides with a fiscal year (FY). In addition, the rule implements policy changes affecting the IPF PPS teaching adjustment. It also rebases and revises the Rehabilitation, Psychiatric, and Long-Term Care (RPL) market basket, and makes some clarifications and corrections to terminology and regulations text. PMID- 21548400 TI - Of cancer and cave fish. AB - We propose that the drivers of carcinogenesis lie more in the adaptive changes that are enabled by local or systemic alterations of tissue architecture than in the genetic changes observed in cancer cells. A full understanding of cancer biology and therapy through a cataloguing of the cancer genome is unlikely unless it is integrated into an evolutionary and ecological context. PMID- 21548401 TI - Medicare program; hospital inpatient value-based purchasing program. Final rule. AB - This final rule implements a Hospital Inpatient Value-Based Purchasing program (Hospital VBP program or the program) under section 1886(o) of the Social Security Act (the Act), under which value-based incentive payments will be made in a fiscal year to hospitals that meet performance standards with respect to a performance period for the fiscal year involved. The program will apply to payments for discharges occurring on or after October 1, 2012, in accordance with section 1886(o) (as added by section 3001(a) of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (collectively known as the Affordable Care Act)). Scoring in the Hospital VBP program will be based on whether a hospital meets or exceeds the performance standards established with respect to the measures. By adopting this program, we will reward hospitals based on actual quality performance on measures, rather than simply reporting data for those measures. PMID- 21548402 TI - The health of aging lesbian, gay and bisexual adults in California. AB - Research on the health of lesbian, gay and bisexual (LGB) adults generally overlooks the chronic conditions that are the most common health concerns of older adults. This brief presents unique population-level data on aging LGB adults (ages 50-70) documenting that they have higher rates of several serious chronic physical and mental health conditions compared to similar heterosexual adults. Although access to care appears similar for aging LGB and heterosexual adults, aging LGB adults generally have higher levels of mental health services use and lesbian/bisexual women report greater delays in getting needed care. These data indicate a need for general health care and aging services to develop programs targeted to the specific needs of aging LGB adults, and for LGB-specific programs to increase attention to the chronic conditions that are common among all older adults. PMID- 21548403 TI - One-fifth of nonelderly Californians do not have access to job-based health insurance coverage. AB - Lack of job-based health insurance does not affect just workers, but entire families who depend on job-based coverage for their health care. This policy brief shows that in 2007 one-fifth of all Californians ages 0-64 who lived in households where at least one family member was employed did not have access to job-based coverage. Among adults with no access to job-based coverage through their own or a spouse's job, nearly two-thirds remained uninsured. In contrast, the majority of children with no access to health insurance through a parent obtained public health insurance, highlighting the importance of such programs. Low-income, Latino and small business employees were more likely to have no access to job-based insurance. Provisions enacted under national health care reform (the Patient Protection and Affordable Care Act of 2010) will aid some of these populations in accessing health insurance coverage. PMID- 21548404 TI - [Sepsis and thrombocytopenia in diabetic with chronic renal insufficiency ]. PMID- 21548405 TI - Too much transparency? Clinical data become weapon in union negotiations, hospital acquisitions. PMID- 21548406 TI - Community(-specific) benefit. Tax-exemption rules must allow hospitals the flexibility to meet local needs. PMID- 21548407 TI - Forging a path for ACOs. Panelists discuss how ACOs will work and how providers can get ready. PMID- 21548408 TI - Halifax health improves Medicaid eligibility screening. PMID- 21548409 TI - University of Pennsylvania Health System. PMID- 21548410 TI - Preparing for ICD-10. PMID- 21548411 TI - Self-auditing is smart business. PMID- 21548412 TI - Risk factors for cerebrovascular events: end-diastolic flow velocity. AB - INTRODUCTION: There are very few studies analysing blood flow velocity parameters of common carotid arteries (CCA), obtained with color Doppler examination as a predictor in cerebrovascular events (CVE). In everyday clinical practice there are number of patients (pts) without carotid stenosis or occlusion but with decreased blood flow velocities. AIM: We performed this study to compare data of velocity parameters with type of cerebrovascular events (CVE) and multiple risk factors in patients without stenotic or occlusive extracranial disease. METHODS: We included total of 127 consecutive patients who experienced various subtypes of cerebrovascular events, 68 females, 59 males, mean age 70.2 +/- SD 12.4 years, out of them 48 pts. had transients ischemic attacs (TIAs), 31 pts. had recurrent TIAs (recTIAs), 32 pts. developed ischemic stroke (IS), and 16 recurrent IS (recIS). All patients were without hemodynamically significant carotid stenosis or occlusion. As a control group we took 50 patients with comparable mean age and gender distribution, all without cerebrovascular events, but with at least 1 multiple risk factor. We included the following clinical variables: age, gender, hypertension, tobacco smoking, hyperlipidemia, obesity, diabetes mellitus. Velocity parameters were: peak-systolic velocity (PSV), end-diastolic velocity (EDV), pulsatility index (PI), resistive index (RI). Examination was performed on distal portion of CCA, and we took the mean of both CCA. RESULTS: Hemodynamic parameters in CVE pts were: PSV 83.5 cm/sec, EDV 19.5 cm/sec, PI 1.54, and RI 0.77, and in Controls values were: PSV 87.5 cm/sec, EDV 28.5 cm/sec, PI 1.42, RI 0.67, respectively. No sign. diff. in PSV and PI were found between CVE (n=127) and Controls (n=50), p = 0.2, while difference in EDV was significant, p < 0.01. We found significance for the following variables: age, tobacco smoking, hypertension, hyperlipidemia and obesity. The best single predictors for CVE were: age (70.1%, p < 0.01), tobacco smoking (63%, p < 0.01, hypertension (52.8%, p < 0.01) and obesity (51.2%, p < 0.01). and among hemodynamic parameters, end diastolic velocity less than 18 cm/sec (p < 0.05). Decreased EDV (below 18 cm/sec) revealed a significant association with CVE. CONCLUSIONS: (a) we found significantly lower EDV in pts with IS and recIS, (b) EDV below 18 cm/sec was the best single predictor of IS, and recIS, (c) in our CVE pts--age, tobacco smoking, hypertension, obesity, were the best single predictors for CVE. PMID- 21548413 TI - Left bundle branch block (LBBB) in patients with heart failure (HF) in Mostar region of Bosnia and Herzegovina. AB - WORK GOAL: to determine the influence of Left branch block Hissa (LBBB) on: (a) the degree of heart weakness according to NYHA classification; (b) structural remodelling based on echocardiographic, and (c) functional remodelling based on EFLV i FS (echo), comparing patients with heart failure (HF) and the left branch block Hissa (LBBB) on EKG with heart failure with heart failure (HF) without the left branch block Hissa (LBBB). METHODS AND WORK: We selected group of So hospital patients with heart weakness of NYHA class II-IV with and 50 without the left branch block Hissa on EKG (LBBB). RESULTS: There was a clinical and echocardiographic evaluation of all patients and we determined their correlation related to the sex, NYHA class, structural and functional remodelling of heart cavities, EFLV, FS and survival and the number of hospitalisation in the last three years. The results where shown in a form of a table SAS 9.13 was used for statistic analysis. DISCUSSION AND CONCLUSION: LBBB is an important component of electric heart remodeling in patients with heart failure and represent an important clinic data in evaluation of patients and therapeutic approach. Because all our variables were expressed as a frequencies, chi square and Fisher exact test were used to test for potential differences. It particularly stressed the correlation of LBBB with echocardiographic movability parameters of i.v. septum and left atrium dimension (p < 0.001) while septum fibrosis (p < 0.001), paradoxal septum movability (p = 0.193) and EFLV (p < 0.001) point to a close correlation with LBBB. Other analysed parameters showed no correlation with LBBB. PMID- 21548414 TI - SCD in the world, Europe, Bosnia and Herzegovina and Mostar. AB - Sudden cardiac death (SCD) is "a natural death due to cardiac causes, heralded by abrupt loss of consciousness within 1 hour of the onset of acute symptoms". Annual incidence is 0.36-1.28/1000 inhabitants. More than 1000 sudden deaths occur each day is in USA, and 100,000 people annually dead in the United Kingdom. Epidemiology differs greatly in 100-fold between young and old, and between developing and developed worlds. SCD is one of the leading causes of death and accounts for over 50% of the cardiac deaths. New data show that SCD is not nearly as sudden in most cases as the term may suggest. Warning symptoms that precede the sudden cardiac death are present for a surprisingly long time in many patients. Coronary artery disease (CAD) is the most common cause of death in the developed world. The major causes are inherited arrythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), anomalous coronary arteries and hereditary channelopathies (e.g., Long QT syndrome, LQTS). Prevalence is 3-4 fold higher in men, reflecting that of CAD. In adults, the incidence of CAD-related SCD varies with geography and age. The incidence of SCD increases with congestive heart failure (CHF), stroke, cancer and metabolic syndrome, particularly in the developed world. Coronary thrombi and plaque rupture or erosion are found in two thirds of SCD. In women over 50, rupture accounted for 80% of coronary thrombi. In Europe SCD accounts for 200,000 dead in 1 year. In FBiH rate of SCD fluctuates around 0.62/1000 inhabitants, in HNK it is 0.78/1000 and in Mostar 0.54/1000. A wide range of cardiac etiology and development of various management procedures in the primary and secondary preventive pharmacotherapy, device therapy, lifestyle changes and genetic profiling have had a major impact on the prediction and prevention of SCD. Improved resuscitation and defibrillation techniques together with advances in implantable pacemaker and defibrillator technology (AED) have all improved treatment outcome. Education of the Red Cross, Police, Army, Civic Protection members, public, patients and relatives to recognize and respond to symptoms of heart disease holds promise for reducing mortality attributed to sudden death. Developing a better understanding of the circumstances of sudden cardiac death and preventive measures and proper reactions to the impending events. Training in cardio-pulmonary resuscitation with public access defibrillation programs is necessary in fighting sudden death. Systematic screening of young athletes and implantation of implantable cardioverter defibrillators should prevent SCD. CONCLUSION: SCD remains one of the major public health problems in the world and is most commonly caused by CAD. Risk stratification is effective for groups, but difficult in case of individuals. There is a need for major improvements in prevention, risk protection, resuscitation and therapy. PMID- 21548415 TI - The evolution of percutaneous coronary intervention: from balloons to drug eluting stents. AB - Percutaneous coronary balloon angioplasty was pioneered by Andreas Gruentzig who designed and assembled balloon dilatation catheters in his own kitchen. In 1976, he reported the successful application in canine coronary experiments. He performed the first successful coronary angioplasty in a patient in September 1977 in Zurich. The dilation catheter consisted of a balloon attached to a long shaft and a short wire attached to its tip. Since then, remarkable refinement in the technology paved the way for the emergence of new percutaneous coronary devices that include coronary atherectomy catheters, laser and stents. The 1980's and early 1990's was primarily a balloon angioplasty era. PMID- 21548416 TI - Lessons learned from large cardiovascular trials. AB - Controlled clinical trial methodology includes unbiased data gathering, subject to statistical analysis, eliminating subjective and environmental influences on the results. These studies compare treatments in patients minimizing or equalizing all variables except the intervention (mostly a drug) under evaluation. The scope of this short review is to present how much recent clinical trials have improved our understanding and treatment of cardiovascular diseases. PMID- 21548417 TI - Building predictive medical models on incomplete data. AB - While working on the National Cardiovascular Network (NCN) Outcomes Management Report our group was confronted with a high percentage of missing data, despite the large size of our registry. One of our goals was to find a way to compare the results achieved at different sites. Excluding cases with missing data significantly decreased the number of cases and, in some instances, all the data from a particular center was eliminated, thereby removing them from comparison. To avoid such a scenario, we utilized multiple imputation. The obtained results and methods used are subject of this article. PMID- 21548418 TI - Effective managers say the same thing twice (or more). PMID- 21548419 TI - The wise leader. AB - In an era of increasing discontinuity, wise leadership has nearly vanished. Many leaders find it difficult to reinvent their corporations rapidly enough to cope with new technologies, demographic shifts, and consumption trends. They can't develop truly global organizations that operate effortlessly across borders. And they find it tough to ensure that their people adhere to values and ethics. The authors assert that leaders must acquire practical wisdom, or what Aristotle called phronesis: experiential knowledge that enables people to make ethically sound judgments. Wise leaders demonstrate six abilities: (i) They make decisions on the basis of what is good for the organization and for society. (2) They quickly grasp the essence of a situation and fathom the nature and meaning of people, things, and events. (3) They provide contexts in which executives and employees can interact to create new meaning. (4) They employ metaphors and stories to convert their experience into tacit knowledge that others can use. (5) They exert political power to bring people together and spur them to act. (6) They use apprenticeship and mentoring to cultivate practical wisdom in orders. PMID- 21548421 TI - The hocus-pocus behind Paul Ryan's Medicare 'reform'. PMID- 21548420 TI - Forced shut down. PMID- 21548422 TI - Varicocele in adolescents. AB - Varicocele is the condition of abnormal venous dilatation of the pampiniform venous system presented at the upper pole of the testicle, sometimes associated with intratesticular varices. Dominantly presented on the left testicle, it is rarely noted on the right one or bilaterally. According to one interpretation, higher incidence in puberty can be accounted for by testicular blood flow increase in the testicular veins. Whatever the primary etiological factor may be, venous hypertension in the venous cord due to renospermatic venous reflux is a constant feature and is responsible for different pathological changes which occur in both the cord veins and the testicle. Vein congestion and heat exchange disturb and increase scrotal temperature having a negative effect on spermatogenesis and also induce irregular apoptosis in germ cells. Recently, reactive oxygen species production in association with decreased antioxidant capacity have been put under suspicion of deteriorating spermatogenesis. Varicoceles in adolescents are usually asymptomatic and the diagnosis is most frequently made according to the typical appearance by the routine annual school physical examination. Ultrasonography and Doppler mode are the most practical and non- invasive examinations. Semen analysis is possible three years after the onset of puberty when semen parameters reach adult values. Deterioration of spermatogenesis and infertility in adults could be accepted as a distant complication of adolescent varicocele. Many agree that indications for surgical intervention in adolescent are: pain, large varicoceles, hypotrophy of the involved testicle, bilateral varicocele, intratesticular varicocele and patients with abnormal semen parameters on serial evaluation. The ideal method for treating adolescent varicocele still remains controversial, but the main task is to decrease the number of recurrences and complications, while retaining optimum testicular function. Because of that, many surgeons respect the attitude "catch up growth". PMID- 21548423 TI - Peritoneal dialysis--experiences. AB - Peritoneal dialysis is the method of treatment of terminal-stage chronic kidney failure. Nowadays, this method is complementary to haemodialysis. It is based on the principles of the diffusion of solutes and ultrafiltration of fluids across the peritoneal membrane, which acts as a filter. The dialysate is introduced into the peritoneum via the previously positioned peritoneal catheter. The peritoneal dialysis is carried out on daily basis, at home by the patient, and the "exchange" is repeated 4-5 times during the 24 hours. The first steps in peritoneal dialysis at the Department for Haemodialysis of the Clinical Centre of Vojvodina date back to 1973. Until 1992, the patients were subjected to this program only sporadically. Since 1998 the peritoneal dialysis method has been performed at the Clinic for Nephrology and Clinical Immunology. In the period 1998-2008 ninety nine peritoneal catheters were placed. Chronic glomerulonephritis, nephroangiosclerosis and diabetes were identified as the most common causes of chronic renal failure. Two methods of catheter placement were applied: the standard open surgery method (majority of patients) and laparoscopy. Most of the patients were subjected to continuous ambulatory peritoneal dialysis, whereas four patients received automatic dialysis. Transplantation was performed in 10 patients, i.e. cadaveric transplantation and living-related donor transplantation, each in 5 patients. Peritoneal dialysis was available as a service outside our institution as well. A ten-year experience in peritoneal dialysis gained at our Centre has proved the advantages and qualities of this method, strongly supporting its wider application in the treatment of terminal stage chronic kidney failure. PMID- 21548424 TI - Tuberculosis in the 21st century--challenges, endeavours and recommendations to doctors. AB - The magnitude of problem with tuberculosis lies in the fact that one third of the world population is infected by Mycobacterium tuberculosis. Even in the 21st century, tuberculosis kills more people than any other infective agent. Definition of case of resistance--the case of resistant tuberculosis is precisely defined by the recommendations of the World Health Organization as primary, initial, acquired multidrug resistant and extensively drug resistant tuberculosis. The development of resistance tuberculosis may result from the administration of mono-therapy or inadequate combinations of anti-tuberculosis drugs. A possible role of doctors in the development of multi drug-resistant tuberculosis is very important. Actually, multi drug-resistant tuberculosis is a direct consequence of mistakes in prescribing chemotherapy, provision of anti tuberculosis drugs, surveillance of the patient and decision-making regarding further treatment as well as in a wrong way of administration of anti tuberculosis drugs. The problem of extensively drug-resistant tuberculosis in the world has become very alarming. In South Africa, extensively drug resistant tuberculosis accounts for 24% of all tuberculosis case. It can be concluded that only adequate treatment according to directly supervised short regiment for correctly categorized cases of tuberculosis can stop the escalation of multidrug or extensively drug resistant tuberculosis, which is actually an incurable illness in the 21st century. PMID- 21548425 TI - Henry J. Franey: mergers should create economic value. PMID- 21548426 TI - VBP in the works: perspectives on CMS's proposed rule. PMID- 21548427 TI - Payment reform: complexities to consider. AB - Providers and payers should take the following actions to prepare for imminent payment reforms from CMS and commercial payers: Adopt industry standard value based pricing principles. Identify variations in costs, reimbursement rates, and payment terms within your managed care contracts and day-to-day operations. Establish core, evidence-based costs and payments to cover those core, evidence based costs. Adopt new delivery tactics to manage a sustainable margin on lower unit reimbursement increases. PMID- 21548428 TI - Hospital-physician alignment: the 1990s versus now. AB - Although the employment model was a bust in the 1990s, it can be successful today if hospitals: Allow physicians to shape health system strategy. Engage physicians and offer opportunities for leadership. Develop best practices to share across physician practices. Use management services organizations to add efficiency and profitability. Use technology wisely. PMID- 21548429 TI - Capital planning for clinical integration. AB - When assessing the financial implications of a physician alignment and clinical integration initiative, a hospital should measure the initiative's potential ROI, perhaps best using a combination of net present value and payback period. The hospital should compare its own historical and projected performance with rating agency median benchmarks for key financial indicators of profitability, debt service, capital and cash flow, and liquidity. The hospital should also consider potential indirect benefits, such as retained outpatient/ancillary revenue, increased inpatient revenue, improved cost control, and improved quality and reporting transparency. PMID- 21548430 TI - Maureen Bisognano: finance is key to achieving quality and cost goals. PMID- 21548431 TI - 8 strategies for hospital borrowers in 2011. AB - Given the likelihood that volatility and unexpected events will continue to challenge the capital markets, healthcare borrowers should implement the following strategic responses: Protect the organization's credit rating. Identify and address organizationwide risk. Establish a global capital strategy for the hospital. Diversify debt and investments. Anticipate challenges in the banking market. Anticipate challenges in the municipal bond market. Fully integrate leasing into the organization's capital structure strategy. Ensure the solidity of the organization's financial plan and future strategies. PMID- 21548432 TI - Medical real estate in an age of reform. AB - The following are four ways healthcare organizations are fulfilling their medical real estate needs in an era of change: Real estate monetization. Renovation of existing facilities. A careful focus on containing materials costs. Joint ventures with real estate organizations. PMID- 21548433 TI - Healthcare capital projects: how to avoid common problems. AB - Hospital management teams should be aware of and prepared to avoid eight key problems for healthcare capital projects: Inadequate resources from the start. Over-reliance on equipment planners. Limited coordination between construction and acquisition teams. Insufficient budget management process. Failure to engage proper outside assistance. Limited management experience with large capital projects. Lack of predefined internal process management. Inefficient organizational feedback channels. PMID- 21548434 TI - How to optimize an equipment leasing program. AB - To enable their organizations to get the most value from an equipment leasing contract, healthcare finance executives should: Be aware of "yield enhancers" that could result in unnecessary expenses for the organization (including advance fee requests, restocking fees, and conditions related to contract renewals) Know how to incorporate value-added services as part of contracts (such as asset tracking, memory scrubbing, and equipment disposal) Thoroughly understand the master lease agreements and schedules and be prepared to negotiate, if possible, cross-default language that links to other indebtedness or material contracts PMID- 21548435 TI - Energy management: opportunities and challenges for the healthcare industry. AB - Managing energy efficiently can reduce long-term costs for healthcare organizations. The two top improvement areas in energy management are lighting and heating and cooling. Financing investments in energy efficiency is a challenge, but several financing options are available. PMID- 21548436 TI - 4 decisions that can affect your anesthesia subsidy. AB - Four key considerations can affect the size of an anesthesia subsidy: Staffing models. The fair market value compensation for clinicians. The type of provider the organization needs. The payment approach for management of anesthesia services. PMID- 21548437 TI - Managing bundled payments. AB - Results of Medicare's ACE demonstration project and Geisinger Health System's ProvenCare initiative provide insight into the challenges hospitals will face as bundled payment proliferates. An early analysis of these results suggests that hospitals would benefit from bringing full automation using clinical IT tools to bear in their efforts to meet these challenges. Other important factors contributing to success include board and physician leadership, organizational structure, pricing methodology for bidding, evidence-based medical practice guidelines, supply cost management, process efficiency management, proactive and aggressive case management, business development and marketing strategy, and the financial management system. PMID- 21548438 TI - Tips for choosing back-office technologies that reduce costs. PMID- 21548439 TI - What would you do? Should we develop a children's hospital? PMID- 21548440 TI - Rural hospital profitability. PMID- 21548441 TI - Teenagers in the United States: sexual activity, contraceptive use, and childbearing, national survey of family growth 2006-2008. AB - OBJECTIVE: This report presents national estimates of sexual activity, contraceptive use, and births among males and females 15-19 years of age in the United States in 2006-2008 from the National Survey of Family Growth (NSFG). Selected data are also presented from the 1988, 1995, and 2002 NSFGs, and from the 1988 and 1995 National Survey of Adolescent Males (NSAM), conducted by the Urban Institute. METHODS: Descriptive tables of numbers and percents are presented and discussed. Data were collected through in-person interviews of the household population in the United States, conducted between July 2006 and December 2008. Interviews were conducted with 7,356 females-1,381 of whom were teenagers--and 6,140 males--1,386 of whom were teenagers-for a total of 2,767 teenagers. The overall response rate for the 2006-2008 NSFG was 75%. The response rate for female teenagers was 77% and for male teenagers 75%. RESULTS: In 2006 2008, about 42% of never-married female teenagers (4.3 million), and about 43% of never-married male teenagers (4.5 million) had had sexual intercourse at least once. These levels of sexual experience have not changed significantly from 2002, the last time the NSFG collected these data. Among never-married teenagers, 79% of females and 87% of males used a method of contraception at first sex. With a few exceptions, teenagers' use of contraceptives has changed little since 2002, and the condom remained the most commonly used method. One exception was an increase in the use of condoms and the use of a condom combined with a hormonal contraceptive (dual method use) among males. Another exception was a significant increase in the percent of female teenagers who had ever used periodic abstinence, or the "calendar rhythm" method. This method had been used by 17% of female teenagers in 2006-2008. PMID- 21548442 TI - Design and operation of the Survey of Adult Transition and Health, 2007. AB - OBJECTIVES: This report documents the survey design and operating procedures for the 2007 Survey of Adult Transition and Health (SATH). Sponsored by the Maternal and Child Health Bureau of the Health Resources and Services Administration, SATH was conducted by the Centers for Disease Control and Prevention's National Center for Health Statistics as a module of the State and Local Area Integrated Telephone Survey program. A follow-back survey design was used to attempt to locate and contact 10,933 eligible cases originally identified in the 2001 National Survey of Children with Special Health Care Needs (NS-CSHCN). These data examine the transition experience of adolescents as they switched from pediatric health care providers to those that treat adults only. Eligible persons were aged 14-17 years as of 2001, had at least one special health care need, and lived in English-speaking households. In 2007, these cases involved young adults aged 19 23. State estimates cannot be obtained from SATH. METHODS: Telephone numbers sampled in 2001 were dialed to locate the 2001 NS-CSHCN respondent. This person was asked for current contact information for the eligible SATH young adult to be contacted directly. Data were collected from June 12 through August 26, 2007. RESULTS: Although we were unable to contact 7409 (68%) of the 2001 parent/guardian respondents, almost all of the young adults we were able to contact participated (98%). The SATH public-use microdata file contains interview data collected in 2007 from 1,865 young adults, along with variables from the 2001 NS-CSHCN public-use file. The unweighted interview completion rate was 17.5%. PMID- 21548443 TI - Cross-reactivity syndromes in food allergy. AB - The immunological phenomenon of cross-reactivity has consequences for the diagnosis and treatment of certain food allergies. Once allergy to a particular food has been confirmed, positive test results are often obtained against other foods and, although less frequently, true clinical cross-reactivity is determined. This article reviews the relevant clinical aspects of food allergies in which the underlying mechanism is cross-reactivity between foods that are both related and unrelated taxonomically. PMID- 21548444 TI - Hypersensitivity reactions to blood components: document issued by the allergy committee of the French medicines and healthcare products regulatory agency. AB - These guidelines represent a consensus among experts on hypersensitivity reactions occurring after transfusion of blood components. They cover recognition, investigation, treatment, and prevention of such reactions. Implemented in France under the auspices of the French Medicines and Healthcare Products Regulatory Agency (AFSSAPS) and based on current knowledge, research, and experience, they aim to provide effective and easily teachable means of further improving the quality of hemovigilance databases, promote interest in this field, and help identify possible mechanisms and at-risk patient groups. PMID- 21548445 TI - Human basophils: a unique biological instrument to detect the allergenicity of food. AB - BACKGROUND: Labeling of major food allergens is mandatory for the safety of allergic consumers. Although enzyme-linked immunosorbent assay, polymerase chain reaction, and mass spectrometry are sensitive and specific instruments to detect trace amounts of food proteins, they cannot measure the ability of food constituents to trigger activation of mast cells or basophils. AIM: We evaluated the basophil activation test as an instrument to determine the allergenic potential of trace amounts of food allergens in complex matrices. Peanut (Arachis hypogaea) allergy was selected as a proof-of-concept model. METHODS: The study population comprised 5 severely peanut-allergic patients (3 males/2 females; median age, 12 years) all sensitized to 3 major peanut allergens (Ara h 1, Ara h 2, and Ara h 3) and 5 peanut-tolerant individuals (2 males/3 females; median age, 8 years). Basophils from patients and controls were stimulated with pure peanut extract and blank and peanut-spiked (0.1, 0.01, and 0.001 ppm) biscuits (baking time 11, 16, 21, 26 minutes) and chocolate extracts. RESULTS: Blank biscuits and chocolate did not induce cell activation in patients or controls. A comparison between patients and controls showed significantly higher activation of basophils after stimulation with 0.1 and 0.01 ppm of peanut-spiked biscuit at all baking times and peanut-spiked chocolate (P < .05). CONCLUSIONS: The basophil activation test is a highly sensitive and specific tool to detect traces of functionally active food allergens. For biscuits, its accuracy seems independent of baking time. Furthermore, it allows even the most sensitive patients to be included in study protocols. PMID- 21548446 TI - Immature dendritic cells expressing indoleamine 2,3-dioxygenase suppress ovalbumin-induced allergic airway inflammation in mice. AB - BACKGROUND: Proliferation of activated CD4+ T lymphocytes is inhibited by indoleamine 2,3-dioxygenase (IDO). OBJECTIVE: We undertook the present study to test the hypothesis that IDO-expressing immature DCs (imDCs) can restore immune tolerance in mice suffering from allergic airway inflammation. METHODS: imDCs were generated from murine bone marrow cells using granulocyte-macrophage colony stimulating factor.The imDCs were subsequently transfected with an IDO expression vector (pEGFP-N1-IDO). Surface marker expression, including CD11c, MHCII, CD80, and CD86, was analyzed using flow cytometry. IDO-expressing imDCs were injected into the trachea of ovalbumin (OVA)-sensitized mice, and lung histopathology and cytokine expression in bronchoalveolar lavage fluid were assessed. The splenic CD4+ T cells of OVA-sensitized mice were isolated and co-cultured with pEGFP-N1 IDO-expressing imDCs, and apoptosis of CD4+ T cells was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. RESULTS: Expression of IDO in imDCs did not alter cell surface molecule expression. We observed marked lung inflammation, elevated total cell and eosinophil count, and altered cytokine levels in OVA-sensitized mice. These parameters improved upon inoculation with IDO-expressing imDCs. Co-culture with IDO-expressing imDCs also induced apoptosis, inhibited IL-4 and IL-5 expression, and upregulated IFN-gamma expression in CD4+ T cells. CONCLUSIONS: IDO-expressing imDCs induced T(H)2 cell apoptosis and reduced T(H)2 cell activation and allergic airway inflammation in OVA-sensitized mice. Thus, upregulation of IDO expression may provide a novel immunointervention strategy for asthma treatment. PMID- 21548447 TI - Gender gap in psychogenic factors may affect perception of asthma symptoms. AB - BACKGROUND AND OBJECTIVE: Clinical practice suggests that asthma coping strategies might be different in women and men. The aim of this study was to compare the relationship between psychological variables and the perception of asthma symptoms in women and men. PATIENTS AND METHODS: A total of 165 adult asthma patients with mild to severe persistent asthma were studied. We performed spirometric tests, measured dyspnea on the Borg scale, assessed psychological health using the Goldberg 28-item General Health Questionnaire (GHQ-28), and measured the tendency towards social desirability using the lie scale from the Eysenck Personality Questionnaire. RESULTS: Women had significantly worse results than men on the GHQ somatic symptoms and anxiety/insomnia subscales and on the overall scale that measures the general index of perceived health. Sex was a statistically significant moderator on the correlation between dyspnea and both the tendency to lie and the GHQ-28 functional disorders/social dysfunction subscale. The correlation between dyspnea and the tendency to lie was positive in women and negative in men. CONCLUSIONS: Perceived dyspnea is correlated with psychological health and the tendency to lie and the correlation between perceived dyspnea and certain psychological variables is different in women and men. PMID- 21548448 TI - Regulatory T cells in elderly patients with asthma. AB - BACKGROUND: Airway walls in asthma present an accumulation of activated cells that determine bronchial structural changes and disease progression and severity. During the aging process, the immunoinflammatory response changes as a consequence of chronic antigenic stress. OBJECTIVE: To evaluate T-cell subsets with regulatory functions associated with asthma in elderly patients METHODS: A group of 153 individuals (95 with controlled asthma and 58 healthy controls) aged over 65 years was studied. Blood samples were collected for flow cytometry analyses of CD3, CD4, CD8, CD56, CD56CD8, CD3CD4CD25, CD3CD4CD25CD127, CD4HLA-DR and TCRgamma delta. RESULTS: Asthmatic patients showed a statistically significant increase in CD4+ T cells. CD3CD4CD25high and CD3CD4CD25highCD127high cells were also significantly increased in asthmatic patients, while CD3CD4CD25highCD127low cells had similar values in asthmatics and in the control group. CD4HLA-DR cells were within the normal range in both groups. A positive correlation between CD3CD4CD25highCD127low and CD4HLA-DR was observed and gamma delta T cells were significantly decreased in the asthmatic patients compared to the controls. CONCLUSIONS: Since T cells with regulatory functions were within normal ranges or reduced in asthmatic patients compared to healthy controls, at least in basal conditions, it can be speculated that they probably play a limited role in chronic asthma in elderly patients.These data suggest an absence of a modulatory effect on the inflammatory response that characterizes asthma and allergy, which in turn would facilitate the persistence of disease in this population. Underlying inflammatory processes that are involved in chronic diseases associated with aging could provide an additional explanation for the attenuated differences observed between asthmatic and nonasthmatic individuals. PMID- 21548449 TI - Quantitative and functional evaluation of innate immune responses in patients with common variable immunodeficiency. AB - OBJECTIVES: We evaluate the frequency and functional response of innate immune cells in peripheral blood (PB) from patients with common variable immunodeficiency (CVID) and healthy controls upon activation with agonists of the Toll-like receptors (TLR) TLR2, TLR4, and TLR9. In addition, several nonsynonymous single nucleotide polymorphisms (SNPs) within these TLR genes were examined. METHODS: Flow cytometry was used to perform immunophenotyping and evaluate the expression of cell surface markers. Levels of cytokines in the culture supernatants were evaluated using cytometric bead array technology. SNPs in the TLR genes were evaluated from genomic DNA using different sequencing techniques. RESULTS: Our results demonstrate that the frequency of CD1d restricted TCR invariant natural killer T cells in PB was significantly reduced in the patients with CVID. A marked, though not significant, reduction in absolute numbers of plasmacytoid dendritic cells and natural killer cells was also observed in these patients. Interestingly, CD80 and CD86 expression on innate cells upon stimulation with TLR ligands was not altered in the patients although 3 of them exhibited low baseline levels of these surface molecules on monocytes compared to healthy controls. We also observed a significant increase in TNF-alpha levels in supernatants of PB mononuclear cells from CVID patients after stimulation with lipopolysaccharide. Finally, no association was found between the presence of nonsynonymous SNPs within the TLR genes and the clinical presentation of CVID. CONCLUSIONS: Taken together, our study demonstrates than innate immune responses are disturbed in some CVID patients and prompts the evaluation of innate immunity genes as candidates to explain the CVID clinical phenotype. PMID- 21548450 TI - Induced sputum in children: success determinants, safety, and cell profiles. AB - BACKGROUND: Sputum induction is a noninvasive method for the assessment of airway inflammation. OBJECTIVES: To evaluate the safety of the procedure and the clinical predictors of successful induction, and to analyze the relationship between sputum cell counts and clinical features in asthmatic and nonasthmatic children. METHODS: We reviewed sputum inductions performed in our department between 2006 and 2008 in individuals under 18 years; 34 asthmatic and 24 nonasthmatic children were included. Sputum induction was performed with 4.5% saline for 5-minute periods with salbutamol pretreatment. The most viscid portions were selected for processing. Inductions which were tolerated for less than 4 minutes or which produced a sample volume of less than 1 mL or a sample with a squamous cell percentage of over 80% were considered unsuccessful. RESULTS: Sputum induction was successful in 43 (74%) of the 58 children studied.The total median induction time was 15 minutes (interquartile range, 10 15 minutes). Only 7 individuals (12%) experienced mild symptoms, which were easily reversed with salbutamol inhalation in all cases. The mean (SD) overall PEF variation with induction was -2.5% (7%), with no significant differences between asthmatics and nonasthmatics. Asthmatics had significantly higher total cell counts (P = .007), macrophages (P = .033), and relatively fewer neutrophils (P = .003) than nonasthmatics; metachromatic cells were rare and seen only in asthmatics (P = .026). We found a positive correlation between exhaled nitric oxide and sputum eosinophil count (r = 0.363, P = .017). CONCLUSIONS: Sputum induction is a safe, noninvasive, and feasible procedure that allows the direct assessment of airway inflammation in most children. PMID- 21548451 TI - Relationship between airborne pollen counts and the results obtained using 2 diagnostic methods: allergen-specific immunoglobulin E concentrations and skin prick tests. AB - BACKGROUND: Patients with pollinosis show allergic symptoms related to airborne pollen levels, although this association is not always close. The use of new diagnostic techniques could improve our knowledge of this relationship. OBJECTIVE: To evaluate the relationship between pollen counts and the results obtained using 2 diagnostic techniques: the skin prick test and allergen-specific immunoglobulin E (slgE) concentrations in serum. METHODS: Sixty-eight pollen allergic patients were diagnosed using a combination of the high-capacity screening approach ADVIA Centaur with a panel of 13 purified allergens and a skin prick test (SPT) with conventional extracts. Pollen levels were obtained by means of a volumetric sampler. RESULTS: The highest percentages of sensitization were detected for grass mixture allergens and major recombinant grass allergens (Phl p 1 and Phi p 5), followed by olive tree extracts and olive allergens (Ole e 1 and Ole e 9), in SPT and using recombinant allergens, respectively. The main pollen types registered in the atmosphere during 2006 and 2007 were Quercus, Poaceae, and Cupressaceae. A statistically significant correlation was observed between total pollen levels and median values of slgE, especially in 2007. CONCLUSION: A strong and significant positive correlation was found between pollen counts and slgE levels. This correlation was weaker in the case of SPT and airborne pollen. PMID- 21548452 TI - Rupatadine improves nasal symptoms, quality of life (ESPRINT-15) and severity in a subanalysis of a cohort of Spanish allergic rhinitis patients. AB - BACKGROUND: According to current guidelines, new second-generation oral Hi antihistamines, as well as intranasal corticosteroids (ICSs), are recommended for the treatment of allergic rhinitis (AR) in adults and children. OBJECTIVE: To assess changes in AR severity, in addition to nasal symptoms and health-related quality of life (HRQoL), after 4 weeks of treatment with rupatadine in a cohort of AR patients. METHODS: A subanalysis of a longitudinal, observational, prospective, multicenter Spanish study was carried out in spring-summer 2007. Enrolled patients had a clinical diagnosis of AR of at least 2 years' evolution, a total nasal symptom score (TNSS) of at least 5, and had not received antihistamines in the previous week or ICSs in the previous 2 weeks. HRQoL (ESPRINT-15 questionnaire), disease severity (using both the original and modified Allergic Rhinitis and its Impact on Asthma [ARIA] classifications), and nasal symptoms (TNSS) were measured at baseline and after 4 weeks of rupatadine treatment. RESULTS: Data from a cohort of 360 patients treated with rupatadine were analyzed (57.2% women, 42.5% with intermittent AR, 36.4% with asthma, and 61.7% with conjunctivitis). After 4 weeks of treatment, the patients showed a significantly lower mean (SD) TNSS (8.2 [1.9] vs 3.1 [2.1], P < .001), a significant improvement in HRQoL (3.0 [1.2] vs 1.0 [0.9], P < .001) and significantly reduced AR severity (P < .0001). CONCLUSIONS: In addition to an improvement in nasal symptoms and HRQoL, rupatadine reduced AR severity after 4 weeks of treatment. PMID- 21548453 TI - Cucumber anaphylaxis in a latex-sensitized patient. AB - We report the case of a 76-year-old woman who experienced dizziness, vomiting, dyspnea, thoracic erythema, and vaginal itching within 5 minutes of eating cucumber. She had been diagnosed 3 months earlier with papaya urticaria and latex sensitization. The results of skin prick tests were positive for cucumber, watermelon, papaya, and latex and negative for melon and profilin extracts. ImmunoCAP for latex-specific serum immunoglobulin (Ig) E was positive. Cucumber specific serum IgE was negative. Immunoblot analysis using patient serum revealed a 30- to 32-kDa protein band in the cucumber (peel) and papaya extracts. Immunoblot inhibition with latex extract demonstrated inhibition of the band in both extracts. Immunoblot inhibition with cucumber-papaya and papaya-cucumber revealed inhibition of the same band in the cucumber and papaya extracts, respectively. We present a case of IgE-mediated allergy to cucumber and papaya. Our results strongly suggest that the allergen(s) implicated are associated with latex sensitization. To our knowledge, this is the first report of cucumber-latex and cucumber-papaya cross-reactivity. PMID- 21548454 TI - Swimming pool-induced asthma. AB - A 13-year-old elite swimmer presented with wheezing after indoor swimming training. On the basis of her clinical history and the tests performed, exercise induced asthma and mold-induced asthma were ruled out and a diagnosis of chlorine induced asthma was made. PMID- 21548455 TI - Selective immunoglobulin A deficiency and celiac disease: let's give serology a chance. AB - Patients with selective immunoglobulin (Ig) A deficiency have a 10- to 20-fold increased risk of celiac disease. In these patients, serological diagnosis of celiac disease can be difficult, since specific IgA-based assays are usually negative and IgG-specific antibody tests are insufficiently reliable. We describe a girl with selective IgA deficiency who had a troublesome diagnosis of celiac disease that was established only after an unexpected positive test result for antitransglutaminase IgA and antiendomysium IgA. Our observation indicates that IgA-based serology should not be forgotten in patients with selective IgA deficiency, since positive results for antitransglutaminase IgA, antiendomysium IgA, or both can be observed at any time during diagnostic investigations. PMID- 21548456 TI - Hypersensitivity to repaglinide. AB - Meglitinides (repaglinide and nateglinide) are insulin secretagogues used to treat diabetes mellitus. We present a case of hypersensitivity reaction to repaglinide in a 61-year-old man who developed a maculopapular rash 5 days after treatment. Skin prick tests including repaglinide (0.5 g/mL) and patch tests (0.05% in pet and saline) were performed, and the results were negative. A blind oral challenge test with repaglinide was performed and the therapeutic dose was subsequently taken at home every 24 hours for 7 days. The result was positive with a delayed reaction at day 3. A punch biopsy of the skin lesions revealed drug-induced exanthema. The clinical manifestations, the latency period, the reappearance of cutaneous lesions after rechallenge, and the histopathology report of the skin biopsy suggest a type IV mechanism. PMID- 21548457 TI - Subacute prurigo and eosinophilia in a patient with rheumatoid arthritis receiving infliximab and etanercept. PMID- 21548458 TI - Inflammatory phenotypes in nonsmoking asthmatic patients. PMID- 21548460 TI - Occupational asthma induced by Mucor species contaminating esparto fibers. PMID- 21548459 TI - Drug fever caused by piperacillin-tazobactam. PMID- 21548461 TI - Significance of the ECDC (European Center for Disease Control) initiative to mark the European Antimicrobial Resistance Awareness Day. Key messages of the 2009 information campaign for primary care physicians. PMID- 21548462 TI - Participation of Romania in the ECDC (European Center for Disease Control) initiative of the Antimicrobial Resistance Awareness Day 2009. PMID- 21548463 TI - Does evidence-based medicine really reduce costs? AB - The high cost of oncology is gaining a lot of attention these days. With cancer care accounting for ten percent of healthcare costs, payers are hungry to find ways to be more frugal. As oncologists, it is in our best interest, as well as the best interest of our patients, to take a proactive, leadership role in finding solutions that sustain our ability to deliver high-quality care. PMID- 21548464 TI - Epigenetics in cancer: what's the future? AB - Epigenetics is a rapidly expanding field that focuses on stable changes in gene expression that are not accompanied by changes in DNA sequence and that are mediated primarily by DNA methylation and histone modifications. Disruption of the epigenome is a fundamental mechanism in cancer, and several epigenetic drugs that have proved to prolong survival and to be less toxic than conventional chemotherapy were recently approved by the FDA for cancer treatment. These include azacitidine (Vidaza), decitabine (Dacogen), vorinostat (Zolinza), and romidepsin (Istodax). Promising results of combination clinical trials with DNA methylation inhibitors and histone deacetylase inhibitors have recently been reported, and data are emerging that describe molecular determinants of clinical responses. Despite significant advances, challenges remain, including a lack of predictive markers, unclear mechanisms of response and resistance, and rare responses in solid tumors. Preclinical studies are ongoing with novel classes of agents that target various components of the epigenetic machinery. In this review, we focus on recent clinical and translational data in the epigenetics field that have potential in cancer therapy. PMID- 21548465 TI - Cancer epigenetics and targeted therapies. PMID- 21548466 TI - Epigenetic targeted anti-cancer drugs: an unfolding story. PMID- 21548467 TI - Immunotherapy in castration-resistant prostate cancer: integrating sipuleucel-T into our current treatment paradigm. AB - The availability of several novel antibodies, coupled with viral, DNA, and dendritic-cell vaccines, has renewed interest in immunotherapeutic approaches to the treatment of advanced prostate cancer. Although promising, none of these approaches have led to major clinical activity, and in the case of cell-based immunotherapy with GVAX, new concerns about safety arose when this therapy was used in the castration-resistant setting. A more attractive yet toxic approach has also utilized a check-point blockade with CTLA-4 antibodies. Although initial clinical efficacy has been observed, toxicity appears to be the major limitation of its use in prostate cancer. Sipuleucel-T (Provenge) is an autologous active cellular immunotherapy product that includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphataase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite the lack of objective anti-tumor activity seen with sipuleucel-T, a recently reported phase III trial demonstrated a significant improvement in the overall survival of men with asymptomatic, minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). This agent is the first FDA-approved novel immunotherapeutic compound for the treatment of a solid malignancy. A better understanding of how clinicians should incorporate this novel agent into the current management of CRPC is needed. PMID- 21548468 TI - Putting Provenge in perspective. PMID- 21548469 TI - Prostate cancer immunotherapy: the role for sipuleucel-T and other immunologic approaches. PMID- 21548470 TI - Inflammatory breast cancer: what progress have we made? AB - Inflammatory breast cancer (IBC) is a rare and aggressive subtype of locally advanced breast cancer (LABC). Its diagnosis is primarily clinical; however, a pathological confirmation of invasive cancer is required. Historically, IBC was a uniformly fatal disease. A major advance in the last three decades has been the introduction of a multidisciplinary approach to the management of this aggressive disease, incorporating pre-operative chemotherapy, surgery, and radiation therapy; this approach has significantly improved survival. Our review focuses on the progress made in the field of IBC research over the last decade, with particular attention to advances in the areas of epidemiology, molecular biology, arid clinical management. PMID- 21548471 TI - Have we made progress in inflammatory breast cancer? Not so fast. PMID- 21548472 TI - Inflammatory breast cancer: the road to progress. PMID- 21548474 TI - Candidacy for sorafenib in HCC patients: is there a slippery slope beyond a SHARP edge? PMID- 21548473 TI - What is the indication for sorafenib in hepatocellular carcinoma? A clinical challenge. AB - The incidence of hepatocellular carcinoma is rising in many countries, including the United States. Approval of sorafenib (Nexavar) as the first targeted therapy for treatment of advanced hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. The approval was based on two large randomized phase III trials from the Western and Eastern hemispheres that showed an overall survival benefit compared with placebo in patients with well-preserved liver function. The exact indication for sorafenib is unclear, however. The U.S. Food and Drug Administration (FDA) authorized use of sorafenib for "unresectable HCC", an indication which is very broad, vague, and confusing. Less is known about the effects of sorafenib in patients with decompensated liver disease, or of sorafenib in combination with local therapy or in a transplant setting. Prospective trials are lacking in these areas. We will review current data on use of sorafenib in HCC. PMID- 21548475 TI - Sorafenib for HCC: a pragmatic perspective. PMID- 21548476 TI - 'The way forward'. New collaborative HHS initiative garners praise. PMID- 21548477 TI - Keys to success. Effective ACOs depend on management: studies. PMID- 21548478 TI - Anesthesia allegations. California joins billing suit against Sutter Health. PMID- 21548479 TI - Is this utopia? Providers likely to pay up, regardless of budget-deficit compromise. PMID- 21548481 TI - Who'll be first? Medical-mart projects making progress in Cleveland and Nashville. PMID- 21548480 TI - An unquestionable role. AARP can fend off congressional critics by leading healthy-living campaign. PMID- 21548482 TI - Drug theft goes big. PMID- 21548483 TI - Expression profiling of genes involved in Taxuyunnanine C biosynthesis in cell suspension cultures of Taxus chinensis by repeated elicitation with a newly synthesized jasmonate and sucrose feeding. AB - Taxus suspension cell culture has the potential to provide a sustainable source of anticancer drug paclitaxel (Taxol) and other taxoids. In the cell culture of Taxus chinensis, Taxuyunnanine C (Tc) is the primary taxoid. To design a rational strategy for redirecting the precursor fluxes from other taxoids into paclitaxel production, we employed Real-time Quantitative PCR (RQ-PCR) to understand the dynamic profiling of key biosynthetic pathway genes of palcitaxel and taxoids during the culture process. Six genes (TASY, TDAT, T5alphaH, TalphaH, T10betaH and T14betaH) were quantified under the process condition of double elicitation by 2,3-dihydroxylpropanyl jasmonate (DHPJA) (100 micromol/L on day 7 and day 12), and sucrose feeding (20 g/L) on day 7. This process treatment led to a high accumulation of Tc at (554.46 +/- 21.28) mg/L 8 days after the first elicitation. Then 9 days after the second elicitation, Tc production was as high as (997.72 +/ 1.51) mg/L. The early pathway genes TASY and TDAT were significantly up regulated by 182-fold and 98-fold, respectively for the first DHPJA elicitation and by 208-fold and 131-fold, respectively for the second elicitation. The induction occurred after each elicitation lasted for about 24 h before their abundances decreased. Things are somewhat different in the case of the other four genes T5alphaH, TalphaH, T10betaH and T14betaH. For gene TalphaH, it was highly up-regulated by 3061-fold for the first DHPJA elicitation and by 1016-fold for the second elicitation. For the other three genes T5alphaH, T10betaH, T14betaH, they were up-regulated by 13-fold, 38-fold and 20-fold, respectively for the first DHPJA elicitation and by 7-fold, 16-fold and 6-fold, respectively for the second elicitation. The RQ-PCR results showed that there is tight correlation between gene expression and Tc accumulation. Gene expression was in accordance with Tc yield. Elicitation could improve expression of six genes. While along with culture course, high expression of the genes weakened. Elicitation for the second time would promote high expression of the genes again. PMID- 21548484 TI - Well-oiled workflows. How to get your efficiency in gear. PMID- 21548485 TI - Innovation, creativity fuel practice growth. PMID- 21548486 TI - Embracing the age of the tech-savvy patients. PMID- 21548487 TI - Going live. PMID- 21548488 TI - Financial lessons from the trenches. PMID- 21548489 TI - In death, we don't part. PMID- 21548490 TI - Getting 'schooled' by patients. PMID- 21548491 TI - An effective mantra. PMID- 21548492 TI - The convergence of medical imaging practices in the United States and Europe. PMID- 21548493 TI - Being the best manager you can be. PMID- 21548494 TI - Revisit, revamp and revitalize your business plan: part 1. AB - The diagnostic imaging department has a pivotal role within the hospital and its pillar services. Understanding this role and also understanding the population served helps to further define and justify the "what" and "why" of the business plan. Understand the market capacity and how market needs can be satisfied. Develop a "go-to-market" strategy, which is the part of the business plan where it is decided how to share that message with the market. In the aftermath of healthcare reform and the economic recession, investing in new imaging technology has never been under greater scrutiny. A three step process for developing support is provided. PMID- 21548496 TI - ICD-10: physician documentation. PMID- 21548495 TI - Accuracy in NIPS. AB - The impact of the coding revisions for the noninvasive studies will vary by facility but it is important to review your organization's protocols and practices to ensure that you have successfully implemented any needed changes for 2011. Failure to do so could result in insufficient documentation and/or potential refund obligations. PMID- 21548497 TI - Medical malpractice tort reform. AB - A tort is generally defined as a civil wrong which causes an injury, for which a victim may seek damages, typically in the form of money damages, against the alleged wrongdoer. An overview of the tort system is detailed, specifically in the context of a medical malpractice lawsuit, in order to provide a better understanding of the practical evolution of medical malpractice litigation and its proposed reforms. Rising premiums and defensive medicine are also discussed as part of the tort reform dialogue. Because medical malpractice litigation will never disappear entirely, implementing sound risk management and compliance programs are critical to every radiology department in order to improve the safety and quality of the care that its radiologists and technologists provide. PMID- 21548498 TI - CT dose reduction in pediatric patients. AB - CT is an incredibly valuable imaging tool, but there are unique concerns with pediatric patients, including the increase of sensitivity to radiation, increase risk of cancer formation with the longer life expectancy, and larger radiation doses received when adult CT settings are used. With a grant from the AHRA and Toshiba Putting Patients First program, Memorial Hermann Healthcare System was able to better educate technologists and physicians which helped in reducing radiation dose to pediatric patients by as much as 60%. Standardizing CT protocols and properly training staff are very important. But to make improvements on a larger scale, strategies for tracking compliance and providing feedback must be used. PMID- 21548499 TI - Radiology management goes to the C-suite. PMID- 21548500 TI - Delayed growth in the development of the radiologist assistant's role. AB - The physician extender model has been established for many years (e.g., NP, PA) and radiology departments would benefit by fully adopting this model, as well, through the hiring of radiologist assistants (RAs). Potential benefits of this role are facility cost reductions and increased customer satisfaction. An RA is an advanced level radiologic technologist who works under the supervision of a radiologist to promote high standards of patient care by assisting radiologists in the diagnostic imaging environment. Agreements by stakeholders such as the ASRT, ARRT, and the ACR have to convene and regulatory hurdles involving the CMS have to be resolved in order for this physician extender position to thrive. PMID- 21548501 TI - A new era of competitiveness. AB - Many of my family, friends, and colleagues would describe me as competitive and that at times I overuse this skill with a win-at-all-costs attitude. I would tend to agree. I love to win. Yet for me winning is not about me, it is as our coaches suggest, about others. I was recently asked by a new clinical leader if I missed taking care of patients. Without thinking, my response was that I take part in the care (add value) of every patient as a leader. Every decision we make as leaders (coaches) impacts many others regardless of the magnitude of our decision and, at times, our direct involvement. Operational excellence, in any field, is about winning. We all have different definitions of winning, defined by the strategic vision for our organizations. An organization's managers, supervisors, and employees all play an important role in the team to achieve the vision of the organization. As some elite coaches have suggested, winning starts with each of us being our best. Today's environment requires consistent change. Yet many in the radiology field change the wrong things for the wrong reasons. Many organizations and individuals look for instant gratification, specifically in this new era of competitiveness. Many evaluate what their competitors are doing in the market, what cars their neighbors are buying, or become jealous over a friend's success. Focusing on others and not improving yourself takes your focus away from what is important-you and the team you lead. Keeping your focus on your operations and what you can control may very well help you coach a winning team. PMID- 21548502 TI - A culture of extraordinary care: part 1. PMID- 21548503 TI - A new level of accountability. PMID- 21548504 TI - Leveraging quality improvement to achieve equity in health care. AB - INEQUALITY IN QUALITY: Disparities in health care and quality for racial, ethnic, linguistic, and other disadvantaged groups are widespread and persistent. Health care organizations are engaged in efforts to improve quality in general but often make little attempt to address disparities. STANDARD VERSUS CULTURALLY COMPETENT QUALITY IMPROVEMENT (QI): Most QI interventions are broadly targeted to the general population-a "one-size-fits-all" approach. These standard QI efforts may preferentially improve quality for more advantaged patients and maintain or even worsen existing disparities. Culturally competent QI interventions place specific emphasis on addressing the unique needs of minority groups and the root causes of disparities. HOW QI CAN REDUCE DISPARITIES: QI interventions can reduce disparities in at least three ways: (1) In some cases, standard QI interventions can improve quality more for those with the lowest quality, but this is unreliable; (2) group-targeted QI interventions can reduce disparities by preferentially targeting disparity groups; and (3) culturally competent QI interventions, by tailoring care to cultural and linguistic barriers that cause disparities, can improve care for everyone but especially for disparity groups. GUIDELINES FOR CULTURALLY COMPETENT QI: A culturally competent approach to QI should (1) identify disparities and use disparities data to guide and monitor interventions, (2) address barriers unique to specific disparity groups, and (3) address barriers common to many disparity group. CONCLUSIONS: To achieve equity in health care, hospitals and other health care organizations should move toward culturally competent QI and disparities-targeted QI interventions to achieve equity in health care, a key pillar of quality. PMID- 21548505 TI - Mobile in situ obstetric emergency simulation and teamwork training to improve maternal-fetal safety in hospitals. AB - BACKGROUND: Evidence from other high-risk industries has demonstrated that teamwork skills can be taught and effective teamwork may improve safety. Increasingly, health care providers, hospital administrators, and quality and safety professionals are considering simulation as a strategy to improve quality and patient safety. MOBILE OBSTETRIC SIMULATION AND TEAM TRAINING PROGRAM: A mobile obstetric emergency simulation and team training program was created to bring simulation technology and teamwork training used routinely in other high reliability fields directly to health care institutions. A mobile unit constituted a practical approach, given the expense of simulation equipment, the time required for staff to develop educational materials and simulation scenarios, and the need to have a standardized program to promote consistent evaluation across sites. Between 2007 and 2009, in situ simulation of obstetric emergencies and teamwork training was tested with more than 150 health care professionals in labor and delivery units across four rural and two community hospitals in Oregon. HOW DO ORGANIZATIONS DETERMINE WHICH TYPE OF SIMULATION IS BEST FOR THEM? Because simulation technologies are relatively costly to start and maintain, it can be challenging for hospitals and health care professionals to determine which format (send staff to a simulation center, develop in-house simulation program, develop a consortium of hospitals that run a simulation program, or use a mobile simulation program) is best for them. CONCLUSIONS: In situ simulation is an effective way to develop new skills, to maintain infrequently used clinical skills even among experienced clinical teams, and to uncover and address latent safety threats in the clinical setting. PMID- 21548506 TI - Teaching quality improvement in a primary care residency. AB - BACKGROUND: Several organizations emphasize that medical education should include how to improve patient outcomes effectively using quality improvement (QI) methods. In spite of the importance of teaching QI principles, limited literature exists on the implementation and evaluation of these in residency programs. METHODS: The Clinical Scholars Program was established in 1996 to provide residents an opportunity to participate in a scholarly activity. The program, fully integrated into a community-based, university-affiliated family medicine residency program, is currently structured as a longitudinal educational experience, with specific time lines in which all second- and third-year residents are required to participate in and successfully complete a project before graduation. Factors influencing project success are also presented. RESULTS: During the five-year period evaluated, 61 residents completed 53 Scholars projects, 39.6% of which were QI projects. Residents have delivered 86 local presentations, 50 state presentations, 11 national presentations, and 8 international presentations. Nine resident projects have been published in peer reviewed journals. Factors associated with successful interventions include focus on a topic relevant and common in primary care practice, change in the system of patient care (for example, use of group visits, providing patient education directly to the patient prior to his or her visit), use of the electronic medical record to provide relevant clinical information during office visits, and interdisciplinary team participation in the project. CONCLUSION: This program is an example of the successful integration of scholarly activity and QI education into a residency program. It serves as a potential model for other residency programs to meet the needs of residency training and to promote QI and research in primary care practices. PMID- 21548507 TI - A proactive risk avoidance system using failure mode and effects analysis for "same-name" physician orders. AB - BACKGROUND: Of the nearly one million physicians in the United States, only 24% have unique last names. More than 875,000 medical licensees share an exact last name with another colleague. It is rational to conclude that orders written by "same-name" (including similarly named) physicians have the potential to delay or impede the correct medical order implementation or the interpretation of diagnostic results. However, no guidelines are available for addressing same-name physicians within a health care system. RISK IDENTIFICATION AND PROACTIVE RISK ASSESSMENT: Proactive identification of this potential risk occurred at a midwest community hospital through the use of patient safety leadership walk-arounds. A team chartered to address the issue proactively used a Failure Mode and Effects Analysis process. The risk of identifying the wrong physician was quantified using risk priority numbers (RPNs) on the basis of the team's assessment of the occurrence, detectibility, and severity of the potential problem. The team developed multiple innovations to reduce the risk. For example, a feature of forced entry within the EMR was implemented--staff entering an order written by a same-name physician were forced to delineate between physicians by using additional identifiers to proceed any further in the EMR. Individualized methods of communicating with all employees and physicians were developed to ensure accurate implementation of innovations. POSTIMPLEMENTATION RESULTS: Development of a structured, objective method for identifying same-name physicians in orders has reduced the potential risks to patient safety, as measured by the change in the RPN from 573 to 275, in less than one year. CONCLUSIONS: Accurate identification of same-name physicians averted a safety risk that has widespread implications across health care settings. PMID- 21548508 TI - Improving the quality of quality improvement projects. AB - As the stakes grow for evaluating the quality of health care delivery, so too should greater attention be paid to the integrity of the design, conduct, and inferences made from QI projects. QI projects that seek to make inferences, especially public inferences, about the impact of an intervention to improve quality of care should be rigorously designed and evaluated, and limitations and potential biases transparently reported to understand how they may affect the conclusions suggested by the project. Our patients deserve nothing less. PMID- 21548509 TI - An interview with Mark Chassin. Interview by Steven Berman. PMID- 21548510 TI - Clinical trials in perspective. PMID- 21548511 TI - Alopecia: the case for medical necessity. AB - Although alopecia is one of the most prevalent dermatologic conditions in the United States, it is typically viewed as a benign process with only cosmetic consequences. Androgenic alopecia has an especially strong perception as a cosmetic management issue. This contribution reviews literature gathered through MEDLINE from PubMed to emphasize the value of hair as a part of the system and to illustrate that androgenic alopecia, like psoriasis, can have severe consequences and serve as a risk factor for the development of life-threatening diseases. Individuals with alopecia experience psychosocial and psychiatric illness and may be at risk for cardiovascular disease, prostatic cancer, and squamous cell carcinoma of the scalp. All persons with alopecia should be evaluated and treated by a physician to minimize its psychological effects and reduce the risk of developing other medical conditions and be further assessed for the presence of commonly associated comorbid conditions. PMID- 21548512 TI - Pulsed azithromycin treatment is as effective and safe as 2-week-longer daily doxycycline treatment of acne vulgaris: a randomized, double-blind, noninferiority study. AB - Efficacy and safety of azithromycin and doxycycline for the treatment of moderate acne vulgaris were evaluated (240 patients) in both intention-to-treat and per protocol populations. The evaluation of clinical efficacy was based on the change in the number of facial inflammatory lesions from baseline to the end of treatment, and noninferiority was defined by the upper 95% confidence limit of the difference between two treatments being less than 9. Reduction in the number of lesions was similar with both azithromycin and doxycycline treatments (27 +/- 12 and 30 +/- 12, respectively) in both groups. Also, the upper 95% confidence limit of 5 inflammatory lesions has satisfied the noninferiority criterion. The incidence of adverse events did not differ between the two treatment groups. The shorter and simpler treatment schedule of azithromycin had similar efficacy and safety as doxycycline in the treatment of moderate acne vulgaris, confirming noninferiority of azithromycin as compared with doxycycline. PMID- 21548513 TI - Cutaneous amyloidosis. AB - Amyloidosis is generally classified as either systemic or cutaneous, with both primary and secondary forms. There are also heredofamilial and hemodialysis associated varieties of amyloidosis, all with specific amyloid fibril derivatives. Nodular cutaneous amyloidosis is the most rare form of primary cutaneous amyloidosis. Lesions typically present as a crusted nodule on the face, extremities, or acral sites. The amyloid fibrils are immunoglobulin-derived and either kappa or lambda light chains. Systemic involvement is dependent on plasma cell amyloid protein deposition. Lesions may otherwise be classified as a local plasma cell clone or cutaneous plasmacytoma. Recent reports state that there is <10% risk of systemic progression. Workup should include at least a full history and physical examination; serum protein electrophoresis and urine protein electrophoresis; and gingival, rectal, or abdominal fat pad biopsies to rule out the presence of extracutaneous amyloid deposition. Management of nodular cutaneous amyloidosis is challenging, as there is no consistently effective treatment and local recurrence is common. PMID- 21548514 TI - Nail biology, morphologic changes, and clinical ramifications: part II. AB - Nail changes in children have been reviewed in the backdrop of nail biology. The authors review nail changes caused by a variety of cosmetics and ingestion of drugs. Nail biopsy and its significance in the diagnosis is emphasized. PMID- 21548515 TI - Nanotechnology in cosmetic products. AB - Nanotechnology is a subject of extensive global interest. The ability to control matter at the nanoscale level presents a revolutionary opportunity to benefit society in numerous disciplines. Nanotechnology is currently found in cosmetic products, particularly sunscreen products containing titanium dioxide and zinc oxide. Published information in scientific journals suggests that nano-sized ingredients used in cosmetic products pose no more risk to human health than larger sized counterparts. The issue remains under investigation. PMID- 21548517 TI - Historical diagnosis & treatment: psoriasis. 1910. PMID- 21548516 TI - Mastocytosis: the disappearing dermatosis. PMID- 21548518 TI - Treatment of decubitus ulcers. PMID- 21548519 TI - Genodermatoses among the ancients: basal cell nevus syndrome in Egyptian dynastic brothers. PMID- 21548520 TI - Pseudoxanthoma elasticum: clinical, histologic, and genetic studies--a report of two sisters. AB - CASE 1: A 24-year-old black woman was referred to our clinic in September 1999 by the department of dermatology. She was referred to confirm the diagnosis of pseudoxanthoma elasticum (PXE). Her medical history was normal. Dermatologic examination revealed confluent papules that gave the skin a "plucked chicken" appearance on the flexural surfaces in the neck, axillae, clavicle, thigh, and periumbilical area (Figure 1). The patient stated that the changes in her skin had begun in the periumbilical region at about 5 years of age and had since been slowly progressive. Physical examination showed brownish black pigmentation on the left side of the face, left eyelid, and left sclera, which was diagnosed as Nevus of Ota (Figure 2). Her visual acuity was 20/10 in both eyes, with no afferent pupillary defect. Intraocular pressure in both eyes was normal. Slit lamp examination showed no abnormalities. Findings from fundus examination revealed angioid streaks that formed an incomplete ring around the optic disc and anteriorly radiated toward the equator of the globe, multiple calcified drusen like structures, and "peau d'orange" changes. Skin biopsy (skin tissue from the neck) was taken and the diagnosis of PXE was confirmed. Histopathologic findings revealed calcification of the elastic fibers and abnormalities of the collagen (Figure 3). The patient was not known to have sickle cell anemia or sickle cell trait, and her blood pressure levels had never elevated. Other systemic causes of angioid streaks were excluded by findings from extensive laboratory examination. Her relatives were asked to come in for examination but lived far away. One of the patient's sisters lived in Kinshasa, Africa, however, and is presented in case 2. CASE 2: The 27-year-old sister of the previous patient was examined on April 19, 2000. At examination, she was found to have PXE. Her medical history was significant for systemic hypertension since 1998 and genital hemorrhage. She underwent an ablation of a cyst of her left ovary in 1988. Her ocular history was unremarkable. On physical examination, raised (yellow) papillary lesions, typical of pseudoxanthoma, were found on the neck, axillae, clavicle, thigh, and periumbilical regions. External and anterior segment examinations (of her eyes) were unremarkable. She was found to have a best-corrected visual acuity of 20/10 in both eyes. Intraocular pressure was normal. Funduscopy revealed bilateral angioid streaks, crystalline bodies, and "peau d'orange," but to a lesser extent than in her sister. In both cases, after informed consent, peripheral blood cells were taken and sent for extraction of DNA. Analysis was performed but could not demonstrate the known gene defects of PXE. PMID- 21548521 TI - Lymphangioma circumscriptum and Whimster's hypothesis revisited. AB - An 11-year-old boy was referred to our department for vesicular lesions of the buttocks of 7 years' duration (Figure 1). He also complained of intermittent oozing of serosanguineous fluid, which caused social impairment. On clinical examination, clusters of flesh-colored to translucent papules were present over the buttocks, perianal area, and left calf. The lesions were excised 4 years ago, after confirming the diagnosis of lymphangioma circumscriptum on histopathology. They started recurring on and around the surgical site within 6 months of surgery. Magnetic resonance imaging (MRI) was performed to evaluate the deeper extension of the lesion. The lymphangioma previously identified by cutaneous examination manifested as an altered T2 signal, spreading to subcutaneous tissues and major and minor muscles and infiltrating the sacral vertebrae and presacral area (Figure 2). Although the muscles were infiltrated, the boy was asymptomatic. He did not have pain, tenderness, or difficulty in the movement of the back and hip muscles. Renal function was also normal. Options of surgical resection and sclerotherapy were rejected by the parents because of the extensive spread of lymphangioma and fear of disfigurement. Carbon dioxide laser ablation was performed, and the parents were asked to follow up regularly for control of any symptoms, if they appear in the future. PMID- 21548522 TI - Disseminated lupus vulgaris. AB - A 28-year-old woman presented with reddish raised, shiny lesions over the face and ears present for the past 3 years. Four years ago, she developed in her left axilla a nodule that became fluctuant and tender, which ruptured to discharge seropurulent material. It subsided after the patient had received antibiotics for 6 months, leaving puckered scarring. There was no history of antituberculous treatment. After 1 year, she developed papulonodular lesions on her face, nose, and ears. There was now a history of malaise, fever, dry cough, and anorexia and weight loss for the past 2 months. The patient was fully vaccinated in childhood, including against varicella infection. The general physical examination revealed lymphadenopathy involving cervical, axillary, and inguinal lymph nodes 0.5 x 0.5 cm to 1 x 1.5 cm, firm in consistency, and nontender. They were discrete except in the left axilla where multiple matted lymph nodes were present with overlying scarring and a papule. Her systemic examination was normal. Cutaneous examination showed a shiny erythematous plaque 3x2 cm with central atrophy and scarring on the face (Figure). It was comprised of multiple shiny nontender soft papules arranged in annular configuration. Similar discrete papules and nodules with adherent fine scaling were seen bilaterally on the alar prominence of the nose, lower lip, and post-auricular area. On diascopy, apple jelly nodules were seen. The hemogram, liver function tests, and renal function tests were normal, except for an elevated erythrocyte sedimentation rate. The Mantoux test showed erythema and an induration of 20 x 20 cm. A posteroanterior view on the chest x-ray showed fibrotic changes suggestive of pulmonary tuberculosis. Ultrasonography of the abdomen and pelvis showed no tubercular foci. Human immunodeficiency virus serology by enzyme-linked immunosorbent assay with 3 different kits was nonreactive. Histopathology from a nodule showed a focally thinned-out epidermis with follicular plugging and multiple epithelioid cell granulomas, rimmed by lymphocytes in the deeper portion of the dermis, mainly peri-appendageal. Stain for acid-fast bacteria was negative. Cultures from the skin lesions were negative. The patient was diagnosed as having lupus vulgaris with multiple lesions of varying morphology at different sites with pulmonary tuberculosis and healed lymph node involvement. PMID- 21548523 TI - Facial self-induced paraffinoma in an elderly woman. AB - A 72-year-old Caucasian woman without remarkable medical history presented with an asymptomatic bilateral periocular swelling, which had been present for 2 months. Physical examination showed symmetric indurated periocular erythematous plaques (Figure 1). Biopsy of a skin lesion revealed aggregates of vacuoles of different sizes (Figure 2) surrounded by a prominent inflammatory infiltrate constituted by macrophages, lymphocytes, neutrophils, and granulomatous foreign body reaction throughout the reticular dermis and hypodermis. These histological findings were consistent with the injection of an oily foreign substance. The patient denied the self-induced nature of the lesions, so she was referred for psychiatric evaluation and admitted having self-injected mineral oil as an impulsive attempt to get attention from her family. She was diagnosed with borderline personality disorder (BPD) and started treatment with oral fluoxetine, showing a rapid decrease of impulsive behavior and anxiety from the second week with a mean dose of 80 mg/d. PMID- 21548524 TI - Pruritus as an unusual symptom in multiple piloleiomyoma. AB - A 30-year-old woman presented with multiple pruritic raised skin lesions at the proximal part of her left arm for the past 15 years. At the age of 15, the patient noticed red nodules accompanied with severe pruritus over the arm, which started to spread and involved the dorsal aspect of her scapula (Figure 1). They had been increasing in number during the past 15 years. There was no history of pain either spontaneously or in response to cold, tactile, or emotional stress, with no bleeding or oozing. There was no family history of similar skin lesions; however, she had a history of gynecologic problems for 10 years, and examination of her uterus showed uterine leiomyomas. The patient complained about severe pruritus. This symptom was exaggerated with sun exposure, cold, emotional stress, and rough cloths. It was so severe that it caused sleep disturbances. Clinical examination showed multiple pink and red nodules ranging from 5 mm to 20 mm over the above-described sites. The lesions were firm, smooth, not mobile, and nontender, with no pain on touch. Routine hematologic and biochemical investigations were normal. Kidney and pelvic ultrasonography showed myomatous uterus and normal kidneys. Microscopic examination of one of the nodules in hematoxylin and eosin-stained sections showed proliferation of smooth muscle cells with fascicular aspect in dermis. These cells had thin, elongated eel-like nuclei with blunt edges (Figure 2 and Figure 3). The diagnosis of leiomyoma was made and the patient was referred for surgical excision. Due to the extension and site of the lesions, the plastic surgeon did not recommend surgical procedure and the patient was treated with an antihistamine (loratadine 10 mg/d). PMID- 21548525 TI - Coexistence of generalized morphea and lichen sclerosus et atrophicus mimicking systemic disease. AB - A 70-year-old white housewife presented with a rare presentation of coexistent generalized morphea and lichen sclerosus et atrophicus with unusual clinical aspects. The patient had disseminated erythematous lesions that evolved into indurated large plaques. Hypopigmentation and hyperpigmentation developed later, in addition to ivory, white, and shiny plaques on the trunk (Figure 1). The skin of the arms and legs showed a wavy contour (Figure 2). Various areas were markedly sclerotic and some had edematous papules (Figure 3). Multiple indurated, ivory, white, shiny, large, and hypochromic plaques were seen on the trunk Laboratory examinations showed increased immunoglobulin A and antinuclear antibodies 1:200 speckled. Scl-70, anti-centromere, anti-ribonucleoprotein, and anti-DNA tests were negative. Esophageal manometry and abdominal and pelvic ultrasound findings were all normal. Complete blood cell count, blood profile, and urinalysis were also within normal limits. Skin biopsy of an arm lesion showed an atrophic epidermis with orthokeratotic hyperkeratosis and follicular plugging. A broad area of homogenization and edema was seen in the papillary dermis with dilated capillaries and a perivascular lymphocytic infiltration. There was also collagen sclerosis throughout the reticular dermis, and thickened, homogenized collagen bundles replaced the subcutaneous fat. Vessel walls showed proliferated intima with mucin deposition and sclerosis, as well as multiplied elastic layers. There was edema of the papillary dermis in some areas and incipient deposition of calcium (Figures 4-7). PMID- 21548526 TI - Topical griseofulvin in dermatophytoses. PMID- 21548527 TI - The price of oil. PMID- 21548528 TI - Electron spin resonance. Part one: a diagnostic method in the biomedical sciences. AB - A review is presented of some of the ways in which electron spin resonance (ESR) spectroscopy may be useful to investigate systems of relevance to the biomedical sciences. Specifically considered are: spin-trapping in biological media; the determination of antioxidant efficiencies; lipid-peroxidation; the use of nitroxides as probes of metabolic activity in cells and as structumral probes of cell-membranes; ESR coupled with materials for radiation-dosimetry; food- and drug-irradiation; studies of enzyme systems and ofcyclodextrins; diagnosis of cancer and rheumatoid arthritis; measurement of oxidative stress in synovial tissue in preparation for joint replacement; determination of oxidative species during kidney dialysis; measurement of biological oxygen concentrations (oximetry); trapping in living cells of the endothelium-derived relaxing factor nitric oxide (NO); measurement of hydrogen peroxide; determination of drugs of abuse (opiates); ESR measurements of whole blood and as a means to determine the age of bloodstains for forensic analysis are surveyed, and also a determination of the aqueous volume of human sperm cells is described, among other topics. PMID- 21548530 TI - We're all in this together. PMID- 21548529 TI - Nanoparticles and modulation of immune responses. AB - The exact role of engineered nanomaterials in immune system modulation remains unclear. The aim of this concise review is to give a comprehensive insight into recent published scientific data concerning the modulation of innate and adaptive immune responses by engineered nanoparticles, and to provide a basis for future experimental work related to designing safer, and more efficient biomaterials. PMID- 21548531 TI - Embrace disruption now. PMID- 21548532 TI - Workforce. Advanced paramedics deliver on the front line. PMID- 21548533 TI - Nursing workforce. A special case for development. PMID- 21548534 TI - Hospital landscape. Building bridges to improvement. PMID- 21548535 TI - 'Brave new world'. Updated health IT strategy called 'ambitious'. PMID- 21548536 TI - Keep your game face on. Big Impact Tournament a tipoff to magazine's 35th anniversary celebration. PMID- 21548538 TI - Fight and flight. Some physician investors getting out of hospital ownership while others stay their course. PMID- 21548537 TI - Growing more important. Building a philanthropy campaign requires leadership buy in, right staff. PMID- 21548539 TI - Unintended consequences. Providers fear unfair penalties if Medicaid adopts Medicare no-pay rules. PMID- 21548540 TI - Intermittent jaw pain, part II: case study. PMID- 21548541 TI - Nanotechnology: The science of small. PMID- 21548542 TI - Effect of single dose intravenous zoledronic acid on bone mineral density in post menopausal osteoporosis of Bangladeshi women. AB - The osteoporosis is a major health threat that affects every third post menopausal women. Postmenopausal osteoporosis is complicated with vertebral, femoral or radius fracture. This prospective study on post-menopausal osteoporosis was carried out in the Pain Centre, Department of Anaesthesia, Analgesia and Intensive Care Medicine of BSMMU, Dhaka during the period of January 2008 to January 2010. The post-menopausal women with back pain were screened by spinal radiographs and dual-energy X-ray absorptiometry (DXA) of lumbar spine to determine the bone mineral density (BMD). The woman after menopause with a BMD T-score of -2.5 or less with or without evidence of vertebral fracture is considered as post-menopausal osteoporosis. A total of 55 post-menopausal osteoporotic patients were assigned to receive a single dose of IV infusion of zoledronic acid (5 mg) along with dietary calcium and vitamin-D. The spinal radiographs and dual-energy X-ray absorptiometry (DXA) were repeated in all the 55 patients at 12 months following zoledronic acid infusion. The mean BMD of lumbar spine increased significantly from pre-infusion value of 0.75695 g/cm2 to post-infusion of 0.80216 g/cm2. The T-score also increased from pre infusion value of -3.567 +/- 0.77 to -3.158 +/- 0.08 in 12 months following the infusion (P < 0.01). The increase is 5.026% higher than pre infusion values. The spinal radiographs taken before infusion of zoledronic acid, showed 14 fractures. There was no new fracture in any case during the 12 months study period. So, it can be concluded that once yearly IV infusion of zoledronic acid is associated with a significant increase in BMD and decrease in the risk of vertebral fracture. PMID- 21548543 TI - Feeding practice in acute stroke patients in a tertiary care hospital. AB - BACKGROUND: Feeding is a basic component of care and it is the most common and difficult management issue for stroke patients. Objective of this study was to know the practice of feeding (oral & nasogastric tube feeding), different types of food used and their caloric value in stroke patients. MATERIALS & METHODS: This direct observational study was done from June 2010 to November 2010, in different medicine wards of Dhaka Medical College Hospital, and included 100 acute stroke patients confirmed by CT scan or MRI of brain and duration of hospital stay for at least 24 hours. RESULTS: Out of 100 cases, 22% took their feeding orally and 78% cases through nasogastric tube. Artificial milk powder 66% cases (NG tube vs. Orally, 58% vs. 8%), juice 18% (NG tube 13% vs. orally 5%), horlicks & juice & soup 10% (NG tube vs. Orally, 7% vs. 3%), khichury 2% orally, bread & egg & shuji 4% cases orally. In 100 cases studied, none of them fulfilled the calorie requirement up to the standard level according to the guideline of Nutrition & Food Science Institute, of Dhaka University, Bangladesh. CONCLUSION: Though this study was small scale but the magnitude of under nutrition among stroke patients revealed is alarming and needs urgent attention. PMID- 21548544 TI - Protective effects of the dietary supplementation of turmeric (Curcuma longa L.) on sodium arsenite-induced biochemical perturbation in mice. AB - The present study was undertaken to evaluate the protective effect of turmeric powder on arsenic toxicity through mice model. Swiss albino male mice were divided into four groups. The first group was used as control, while groups 2, 3, and 4 were treated with turmeric powder (T, 50 mg/kg body weight/day), sodium arsenite (Sa, 10 mg/kg body weight/day) and turmeric plus Sa (T+Sa), respectively. Results showed that oral administration of Sa reduced the weight gain of the mice compared to the control group and food supplementation of turmeric prevented the reduction of weight gain. Turmeric abrogated the Sa induced elevation of serum urea, glucose, triglyceride (TG) level and alanine aminotransferase (ALT) activity except the activity of alkaline phosphatase (ALP). Turmeric also prevented the Sa-induced perturbation of serum butyryl cholinesterase activity (BChE). Therefore, ameliorating effect of turmeric on Sa treated mice suggested the future application of turmeric to reduce or to prevent arsenic toxicity in human. PMID- 21548545 TI - Role of computed tomography in the evaluation of pediatric brain tumor. AB - A total of forty two clinically diagnosed pediatric brain tumors were studied over a period of two years. The study was aimed to evaluate the efficacy of computed tomography (CT) in pre-operative diagnosis of pediatric brain tumors by correlating the imaging findings with postoperative histopathological findings. Site, density, mass effect and contrast enhancement of the lesion were studied as primary efficacy variables of CT scan. In the present study, the common pediatric brain tumors were astrocytoma, medulloblastoma, craniopharyngioma and ependymoma. In 18(42.9%) cases the tumors were supratentorial and in 24 (57.1%), they were infratentorial in location. The findings of CT scan in different intracranial neoplasm strongly correlated with those of histopathology. The validity tests for CT scan were found to be 88.9% sensitive, 100% specific and about 95% accurate in diagnosing astrocytoma. Similarly the sensitivity, specificity, and accuracy for medulloblastoma were 100%, 96.9% and 97.7% respectively. For craniopharyngioma the values were 85.7%, 100% and 97.7% respectively. The study concludes that CT is an invaluable imaging modality in preoperative diagnosis of pediatric brain tumor due to its excellent characterization of tumors. PMID- 21548546 TI - Evaluation of myocardial protection in off-pump vs. on-pump coronary bypass surgery by troponin I estimation. AB - BACKGROUND: This prospective non-randomized clinical study was done to compare Off-pump and On-pump myocardial revascularization by Troponin I release in patients undergoing first elective coronary artery bypass graft used to evaluate myocardial injury. METHODS: One hundred an twenty patients were non-randomly assigned to a Off-pump or On-pump myocardial revascularization group. Cardiac Troponin I (CTnI) were measured in serial venous blood samples drawn preoperatively in both groups. In On-pump group after aortic unclamping at 12 and 24 hours and in Off-pump group after the last distal anastomosis at 12 and 24 hours. RESULTS: The total amount of CTnI release were significantly higher in On pump group than in Off-pump group. In On-pump group it was 2.1 +/- 1.9 (mean +/- SD) ng/ml vs in Off-pump group it was 1.0 +/- 1.7 (mean +/- SD) ng/ml at 12 hours and in On-pump group it was 1.6 +/- 1.6 (mean +/- SD) ng/ml vs. in Off-pump group it was .9 +/- 1.6 (mean +/- SD) ng/ml at 24 hours (P < 0.0001 for the pattern). CONCLUSION: The lower release of CTnI in the Off-pump myocardial revascularization group indicates that the arrested heart coronary revascularization group causes more damage to the heart due to cardiopulmonary bypass than Off-pump myocardial revascularization group. PMID- 21548547 TI - Lipoprotein (a) level in pre-eclampsia patients. AB - This study was carried in BSMMU from July 2001 to June 2003. During the study period, 60 pregnant women were studied. Thirty patients were preeclamptic and thirty were normal healthy pregnant women served as control. Serum lipoprotein(a) was found significantly higher in preeclamptic women 56.63 +/- 22.6 mg/dl and found within limit in normal healthy pregnant women, 12.89 +/- 4.59 mg/dl. Result is statistically highly significant (P < 0.001). Mean systolic blood pressure was 163.33 +/- 29.63 mmHg and 117.00 +/- 11.19 mmHg in case and control and Diastolic Blood Pressure was 108.53 +/- 14.54 mmHg and 76.00 +/- 6.87 mmHg respectively in case and control group. Result was highly significant as P < 0.001. The mean (+/- SD) serum lipoprotein(a) concentration in normal pregnancies and preeclampsia were found to be 12.91 +/- 4.94 and 56.65 +/- 22.62. Moderate proteinuria was found in 77.5% and severe proteinuria in 22.2% cases of preeclampsia respectively. Regardless of mechanism and pathophysiology of preeclampsia, we found high serum level of lipoprotein (a) in preeclampsia patients. These high levels of lipoprotein (a) significantly correlated with blood pressure and proteinuria. PMID- 21548548 TI - Obesity in the north of Iran (south east of Caspian Sea). PMID- 21548549 TI - Surgical management of ventricular septal defect with pulmonary stenosis with idiopathic thrombocytopenic purpura. PMID- 21548550 TI - Combined genomic-metabolomic approach for the differentiation of geographical origins of natural products: deer antlers as an example. AB - The correct identification of the geographical origin of deer antlers is essential to quality control, as its positive physiological effects correlate with chemical components. In this study, we applied both genomics and metabolomics to the origin-identification of 101 samples from Canada, New Zealand, and Korea. The genomics identified deer species in each country but failed to categorize all the samples, due to the presence of identical species in different countries. For identical species, NMR-based metabolomics gave clean separations, compounds specific to each country were identified, and the validity was confirmed by prediction analysis. As the genomics provided unambiguous read outs for different species, and the metabolomics cleanly distinguished among identical species from different countries, their combined use could be a robust method for origin-identification even in difficult cases. We believe the method to be generally applicable to many herbal medicinal products for which various species are grown internationally. PMID- 21548551 TI - Top-gated chemical vapor deposition grown graphene transistors with current saturation. AB - Graphene transistors are of considerable interest for radio frequency (rf) applications. In general, transistors with large transconductance and drain current saturation are desirable for rf performance, which is however nontrivial to achieve in graphene transistors. Here we report high-performance top-gated graphene transistors based on chemical vapor deposition (CVD) grown graphene with large transconductance and drain current saturation. The graphene transistors were fabricated with evaporated high dielectric constant material (HfO(2)) as the top-gate dielectrics. Length scaling studies of the transistors with channel length from 5.6 MUm to 100 nm show that complete current saturation can be achieved in 5.6 MUm devices and the saturation characteristics degrade as the channel length shrinks down to the 100-300 nm regime. The drain current saturation was primarily attributed to drain bias induced shift of the Dirac points. With the selective deposition of HfO(2) gate dielectrics, we have further demonstrated a simple scheme to realize a 300 nm channel length graphene transistors with self-aligned source-drain electrodes to achieve the highest transconductance of 250 MUS/MUm reported in CVD graphene to date. PMID- 21548552 TI - Chemical wiring and soldering toward all-molecule electronic circuitry. AB - Key to single-molecule electronics is connecting functional molecules to each other using conductive nanowires. This involves two issues: how to create conductive nanowires at designated positions, and how to ensure chemical bonding between the nanowires and functional molecules. Here, we present a novel method that solves both issues. Relevant functional molecules are placed on a self assembled monolayer of diacetylene compound. A probe tip of a scanning tunneling microscope is then positioned on the molecular row of the diacetylene compound to which the functional molecule is adsorbed, and a conductive polydiacetylene nanowire is fabricated by initiating chain polymerization by stimulation with the tip. Since the front edge of chain polymerization necessarily has a reactive chemical species, the created polymer nanowire forms chemical bonding with an encountered molecular element. We name this spontaneous reaction "chemical soldering". First-principles theoretical calculations are used to investigate the structures and electronic properties of the connection. We demonstrate that two conductive polymer nanowires are connected to a single phthalocyanine molecule. A resonant tunneling diode formed by this method is discussed. PMID- 21548553 TI - s-Allyl cysteine, s-ethyl cysteine, and s-propyl cysteine alleviate beta-amyloid, glycative, and oxidative injury in brain of mice treated by D-galactose. AB - The neuroprotective effects of s-allyl cysteine, s-ethyl cysteine, and s-propyl cysteine in D-galactose (DG)-treated mice were examined. DG treatment increased the formation of Abeta(1-40) and Abeta(1-42), enhanced mRNA expression of beta amyloid precursor protein (APP) and beta-site APP cleavage enzyme 1 (BACE1), and reduced neprilysin expression in brain (P < 0.05); however, the intake of three test compounds significantly decreased the production of Abeta(1-40) and Abeta(1 42) and suppressed the expression of APP and BACE1 (P < 0.05). DG treatments declined brain protein kinase C (PKC) activity and mRNA expression (P < 0.05). Intake of test compounds significantly retained PKC activity, and the expression of PKC-alpha and PKC-gamma (P < 0.05). DG treatments elevated brain activity and mRNA expression of aldose reductase (AR) and sorbitol dehydrogenase as well as increased brain levels of carboxymethyllysine (CML), pentosidine, sorbitol, and fructose (P < 0.05). Test compounds significantly lowered AR activity, AR expression, and CML and pentosidine levels (P < 0.05). DG treatments also significantly increased the formation of reactive oxygen species (ROS) and protein carbonyl and decreased the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (P < 0.05); however, the intake of test compounds in DG-treated mice significantly decreased ROS and protein carbonyl levels and restored brain GPX, SOD, and catalase activities (P < 0.05). These findings support that these compounds via their anti-Abeta, antiglycative, and antioxidative effects were potent agents against the progression of neurodegenerative disorders such as Alzheimer's disease. PMID- 21548554 TI - Exploiting bioorthogonal chemistry to elucidate protein-lipid binding interactions and other biological roles of phospholipids. AB - Lipids play critical roles in a litany of physiological and pathophysiological events, often through the regulation of protein function. These activities are generally difficult to characterize, however, because the membrane environment in which lipids operate is very complex. Moreover, lipids have a diverse range of biological functions, including the recruitment of proteins to membrane surfaces, actions as small-molecule ligands, and covalent protein modification through lipidation. Advancements in the development of bioorthogonal reactions have facilitated the study of lipid activities by providing the ability to selectively label probes bearing bioorthogonal tags within complex biological samples. In this Account, we discuss recent efforts to harness the beneficial properties of bioorthogonal labeling strategies in elucidating lipid function. Initially, we summarize strategies for the design and synthesis of lipid probes bearing bioorthogonal tags. This discussion includes issues to be considered when deciding where to incorporate the tag, particularly the presentation within a membrane environment. We then present examples of the application of these probes to the study of lipid activities, with a particular emphasis on the elucidation of protein-lipid binding interactions. One such application involves the development of lipid and membrane microarray analysis as a high-throughput platform for characterizing protein-binding interactions. Here we discuss separate strategies for binding analysis involving the immobilization of either whole liposomes or simplified isolated lipid structures. In addition, we present the different strategies that have been used to derivatize membrane surfaces via bioorthogonal reactions, either by using this chemistry to produce functionalized lipid scaffolds that can be incorporated into membranes or through direct modification of intact membrane surfaces. We then provide an overview of the development of lipid activity probes to label and identify proteins that bind to a particular lipid from complex biological samples. This process involves the strategy of activity-based proteomics, in which proteins are collectively labeled on the basis of function (in this case, ligand binding) rather than abundance. We summarize strategies for designing and applying lipid activity probes that allow for the selective labeling and characterization of protein targets. Additionally, we briefly comment on applications other than studying protein-lipid binding. These include the generation of new lipid structures with beneficial properties, labeling of tagged lipids in live cells for studies involving fluorescence imaging, elucidation of covalent protein lipidation, and identification of biosynthetic lipid intermediates. These applications illustrate the early phase of the promising field of applying bioorthogonal chemistry to the study of lipid function. PMID- 21548555 TI - NCO quantitative measurement in premixed low pressure flames by combining LIF and CRDS techniques. AB - NCO is a short-lived species involved in NO(x) formation. It has never been quantitatively measured in flame conditions. In the present study, laser-induced fluorescence (LIF) and cavity ring-down spectroscopy (CRDS) were combined to measure NCO radical concentrations in premixed low-pressure flames (p = 5.3 kPa). NCO LIF excitation spectrum and absorption spectrum (using CRDS) measured in a stoichiometric CH(4)/O(2)/N(2)O/N(2) flame were found in good agreement with a simulated spectrum using PGOPHER program that was used to calculate the high temperature absorption cross section of NCO in the A(2)Sigma(+)-X(2)Pi transition around 440.479 nm. The relative NCO-LIF profiles were measured in stoichiometric CH(4)/O(2)/N(2)O/N(2) flames where the ratio N(2)O/O(2) was progressively decreased from 0.50 to 0.01 and in rich CH(4)/O(2)/N(2) premixed flames. Then, the LIF profiles were converted into NCO mole fraction profiles from the absorption measurements using CRDS in a N(2)O-doped flame. PMID- 21548556 TI - Effects of river flooding on polybrominated diphenyl ether (PBDE) levels in cows' milk, soil, and grass. AB - The first investigation into PBDE levels in food produced from flood-prone land on industrial river catchments was conducted. In August 2008 samples of cows' milk, along with grass and soil were taken from 5 pairs of flood-prone and control farms on the River Trent (Central UK). The sum of 7 BDE congeners (28, 47, 99, 100, 153, 154, and 183) was calculated. Higher PBDE levels occurred in soil on flood-prone compared to control farms (median 770 vs 280 ng/kg dry weight). These higher levels were not reflected in the grass samples indicating that PBDE contamination on soils is not transferred efficiently to grass. This observation alongside the fact that cows on flood-prone farms spend time on non flood-prone land and are fed substantial quantities of commercial feed are reasons why higher PBDE levels were not found in milk from flood-prone farms (median 300 vs 250 ng/kg fat weight). Similar BDE47/BDE99 ratios were observed in soil and grass samples compared to the PBDE product commonly used in the UK, indicating few differences in source-pathway transfer efficiencies between congeners. The BDE47/BDE99 ratio in the milk samples was greater than those in the grass and feed indicating differential food to milk transfer efficiencies between congeners. PMID- 21548557 TI - Effect of substituents on the strength of N-X (X = H, F, and Cl) bond dissociation energies: a high-level quantum chemical study. AB - The effect of substituents on the strength of N-X (X = H, F, and Cl) bonds has been investigated using the high-level W2w thermochemical protocol. The substituents have been selected to be representative of the key functional groups that are likely to be of biological, synthetic, or industrial importance for these systems. We interpreted the effects through the calculation of relative N-X bond dissociation energies (BDE) or radical stabilization energies (RSE(NX)). The BDE and RSE(NX) values depend on stabilizing/destabilizing effects in both the reactant molecule and the product radical of the dissociation reactions. To assist us in the analysis of the substituent effects, a number of additional thermochemical quantities have been introduced, including molecule stabilization energies (MSE(NX)). We find that the RSE(NH) values are (a) increased by electron donating alkyl substituents or the vinyl substituent, (b) increased in imines, and (c) decreased by electron-withdrawing substituents such as CF(3) and carbonyl moieties or through protonation. A different picture emerges when considering the RSE(NF) and RSE(NCl) values because of the electronegativities of the halogen atoms. The RSE(NX)s differ from the RSE(NH) values by an amount related to the stabilization of the N-halogenated molecules and given by MSE(NX). We find that substituents that stabilize/destabilize the radicals also tend to stabilize/destabilize the N-halogenated molecules. As a result, N-F- and N-Cl containing molecules that include alkyl substituents or correspond to imines are generally associated with RSE(NF) and RSE(NCl) values that are less positive or more negative than the corresponding RSE(NH). In contrast, N-F- and N-Cl containing molecules that include electron-withdrawing substituents or are protonated are generally associated with RSE(NF) and RSE(NCl) values that are more positive or less negative than the corresponding RSE(NH). PMID- 21548558 TI - Quantitative evaluation of the sensitivity of library-based Raman spectral correlation methods. AB - Library-based Raman spectral correlation methods are widely used in surveillance applications in multiple areas including the pharmaceutical industry, where Raman spectroscopy is commonly used in verification screening of incoming raw materials. While these spectral correlation methods are rapid and require little or no sample preparation, their sensitivity to the presence of contaminants has not been adequately evaluated. This is particularly important when dealing with pharmaceutical excipients, which are susceptible to economically motivated adulteration by substances having similar physical/chemical/spectroscopic properties. We report a novel approach to evaluating the sensitivity of library based Raman spectral correlation methods to contaminants in binary systems using a hit-quality index model. We examine three excipient/contaminant systems, glycerin/diethylene glycol, propylene glycol/diethylene glycol, and lactose/melamine and find that the sensitivity to contaminant for each system is 18%, 32%, and 4%, respectively. These levels are well-correlated to the minimum contaminant composition that can be detected by both verification and identification methods. Our studies indicate that the most important factor that determines the sensitivity of a spectral correlation measurement to the presence of contaminant is the relative Raman scattering cross section of the contaminant. PMID- 21548559 TI - En route to white-light generation utilizing nanocomposites composed of ultrasmall CdSe nanodots and excited-state intramolecular proton transfer dyes. AB - One single material that emits white light is of paramount interest for the development of white light-emitting diodes (WLEDs). Here we report a novel nanocomposite, in which a new type of excited-sate intramolecular proton transfer (ESIPT) molecule, namely 5-(1,2-dithiolan-3-yl)-N-(2-{[4-(3-hydroxy-4-oxo-4H chromen-2-yl)phenyl](methyl)amino}ethyl)pentanamide (HF-N-LA), is anchored onto the surface of ultrasmall CdSe quantum dots through dithiol functionality. Authentic white light with a CIE coordinate of (0.33, 0.33) could then be generated by confluence of 440 nm emission from CdSe and 570 nm proton-transfer tautomer emission from HF-N-LA. Moreover, linear color tunability could be achieved simply by altering relative amount of the two species, i.e., number of HF-N-LA onto CdSe, in one single nanocomposite, thus opening an innovative route toward applying nanocrystals in the field of WLEDs. PMID- 21548560 TI - Self-assembly of an optically active conjugated oligoelectrolyte. AB - Conjugated oligoelectrolytes are of emerging technological interest due to their recent function in the fabrication of optoelectronic devices, application in biosensors, and as species that facilitate transmembrane charge migration. Solubility in aqueous, or highly polar, solvents is important for many of these applications; however, there are few studies on how the self-assembly of conjugated oligoelectrolytes into multichromophore species influences linear and nonlinear optical properties. Here, we examine 1,4-bis(4'-(N,N-bis(6''-(N,N,N trimethylammonium)hexyl)amino)-styryl)benzene tetraiodide (DSBNI) in water, a conjugated oligoelectrolyte based on the distyrylbenzene framework. We find that DSBNI aggregation leads to increased fluorescence lifetimes, coupled with hypsochromic shifts, and larger two-photon absorption cross sections. Liquid atomic force microscopy (AFM) and cryogenic transmission electron microscopy (cryo-TEM) were used to image DSBNI aggregates and to confirm that the planar molecules stack to form nanocylinders above a critical aggregation concentration. Finally, small-angle neutron scattering (SANS) was used to quantify the aggregate dimensions in situ. Comparison of the results highlights that the hydrophilic mica surface used to image via liquid AFM and the high concentrations required for cryo-TEM facilitate the propagation of the cylinders into long fibers. SANS experiments are consistent with equivalent molecular packing geometry but lower aspect ratios. It is therefore possible to understand the evolution of optical properties as a function of concentration and aggregation and the general geometric features of the resulting supramolecular structures. PMID- 21548561 TI - Trialkylphosphine-stabilized copper(I) phenylchalcogenolate complexes--crystal structures and copper-chalcogenolate bonding. AB - A series of trialkylphosphine-stabilized copper(I) phenylchalcogenolate complexes [(R(3)P)(m)(CuEPh)(n)] (R = Me, Et, (i)Pr, (t)Bu; E = S, Se, Te) has been prepared and structurally characterized by X-ray diffraction. Structures were found to be mono-, di-, tri-, tetra-, hexa-, hepta-, or decanuclear, depending mainly on size and amount of phosphine ligand. Several structural details were observed, including unusually long Cu-E bonds or secondary Cu-E connections, MU(4)-bridging, and planar bridging chalcogenolate ligands. Relatively rigid Cu-E C angles were found to be of significant influence on the flexible molecular structures, especially for bridging chalcogenolate ligands, since in these cases a correlation results between the Cu-E-Cu angles and the inclination of the E-C bonds to their Cu-E-Cu planes. We further address some of these phenomena by means of density functional computations. PMID- 21548562 TI - Solution, solid state, and film properties of a structurally characterized highly luminescent molecular europium plastic material excitable with visible light. AB - The synthesis and X-ray crystal structure of the ligand L (4,7-dicarbazol-9-yl [1,10]-phenanthroline) are reported, as well as those of the molecular complex, [Eu(tta)(3)(L)] (1), (tta = 2-thenoyl trifluoroacetylacetonate). Their photophysical properties have been investigated both in solution and in the solid state. It was shown that the ligands used for designing 1 are well-suited for sensitizing the Eu(III) ion emission, thanks to a favorable position of the triplet state as investigated in the Gd(III) complex [Gd(tta)(3)(L)], (2). The low local symmetry of the Eu(III) ion shown by the X-ray crystal structure of 1 is also revealed by luminescence spectroscopy. Because of interesting volatility and solubility properties, 1 is shown to behave as a real molecular material that can be processed both by thermal evaporation and from solution. When doped in poly(methylmethacrylate) (PMMA), 1 forms air-stable and highly red-emitting plastic materials that can be excited in a wide range of wavelengths from the UV to the visible part of the electromagnetic spectrum (250-560 nm). Absolute quantum yields of 80% have been obtained for films comprising 1-3% of 1. Ellipsometry measurements have been introduced to gain information on physical data of 1. They have been performed on thin films of 1 deposited by thermal evaporation and gave access to the refractive index, n, and the absorption coefficient, k, as a function of the wavelength. A value of 1.70 has been found for n at 633 nm. These thin films also show interesting air-stability. PMID- 21548564 TI - Preparation, characterization, and theoretical analysis of group 14 element(I) dimers: a case study of magnesium(I) compounds as reducing agents in inorganic synthesis. AB - A synthetic route to the new amidine (DipNH)(DipN)C(C(6)H(4)Bu(t)-4) (ButisoH; Dip = C(6)H(3)Pr(i)(2)-2,6) has been developed. Its deprotonation with either LiBu(n) or KN(SiMe(3))(2) yields the amidinate complexes [M(Butiso)] (M = Li or K). Their reactions with group 14 element halides/pseudohalides afford the heteroleptic group 14 complexes [(Butiso)SiCl(3)], [(Butiso)ECl] (E = Ge or Sn), and [{(Butiso)Pb(MU-O(3)SCF(3))(THF)}(infinity)], all of which have been crystallographically characterized. In addition, the synthesis and spectroscopic characterization of the homoleptic complex [Pb(Butiso)(2)] is reported. Reductions of the heteroleptic complexes with a soluble magnesium(I) dimer, [{((Mes)Nacnac)Mg}(2)] ((Mes)Nacnac = [(MesNCMe)(2)CH](-); Mes = mesityl), have given moderate-to-high yields of the group 14 element(I) dimers [{(Butiso)E}(2)] (E = Si, Ge, or Sn), the X-ray crystallographic studies of which reveal trans bent structures. The corresponding lead(I) complex could not be prepared. Comprehensive spectroscopic and theoretical analyses of [{(Butiso)E}(2)] have allowed their properties to be compared. All complexes possess E-E single bonds and can be considered as intramolecularly base-stabilized examples of ditetrelynes, REER. Taken as a whole, this study highlights the synthetic utility of soluble and easy to prepare magnesium(I) dimers as valuable alternatives to the harsh, and often insoluble, alkali-metal reducing agents that are currently widely employed in the synthesis of low-oxidation-state organometallic/inorganic complexes. PMID- 21548563 TI - Eu(III) complexes as anion-responsive luminescent sensors and paramagnetic chemical exchange saturation transfer agents. AB - The Eu(III) complex of (1S,4S,7S,10S)-1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10 tetraazacyclododecane (S-THP) is studied as a sensor for biologically relevant anions. Anion interactions produce changes in the luminescence emission spectrum of the Eu(III) complex, in the (1)H NMR spectrum, and correspondingly, in the PARACEST spectrum of the complex (PARACEST = paramagnetic chemical exchange saturation transfer). Direct excitation spectroscopy and luminescence lifetime studies of Eu(S-THP) give information about the speciation and nature of anion interactions including carbonate, acetate, lactate, citrate, phosphate, and methylphosphate at pH 7.2. Data is consistent with the formation of both innersphere and outersphere complexes of Eu(S-THP) with acetate, lactate, and carbonate. These anions have weak dissociation constants that range from 19 to 38 mM. Citrate binding to Eu(S-THP) is predominantly innersphere with a dissociation constant of 17 MUM. Luminescence emission peak changes upon addition of anion to Eu(S-THP) show that there are two distinct binding events for phosphate and methylphosphate with dissociation constants of 0.3 mM and 3.0 mM for phosphate and 0.6 mM and 9.8 mM for methyl phosphate. Eu(THPC) contains an appended carbostyril derivative as an antenna to sensitize Eu(III) luminescence. Eu(THPC) binds phosphate and citrate with dissociation constants that are 10-fold less than that of the Eu(S-THP) parent, suggesting that functionalization through a pendent group disrupts the anion binding site. Eu(S-THP) functions as an anion responsive PARACEST agent through exchange of the alcohol protons with bulk water. The alcohol proton resonances of Eu(S-THP) shift downfield in the presence of acetate, lactate, citrate, and methylphosphate, giving rise to distinct PARACEST peaks. In contrast, phosphate binds to Eu(S-THP) to suppress the PARACEST alcohol OH peak and carbonate does not markedly change the alcohol peak at 5 mM Eu(S-THP), 15 mM carbonate at pH 6.5 or 7.2. This work shows that the Eu(S-THP) complex has unique selectivity toward binding of biologically relevant anions and that anion binding results in changes in both the luminescence and the PARACEST spectra of the complex. PMID- 21548565 TI - Structure and binding of specifically mutated neurotensin fragments on a silver substrate: vibrational studies. AB - Here, we report a systematic study showing an analogy between the activities of peptide structural component interactions with both a metal substrate and a G protein-coupled seven-transmembrane receptor. In the present work, N-terminal fragments of human neurotensin (NT), NT(1-6), NT(1-8), and NT(1-11), and C terminal fragments of human neurotensin, NT(8-13) and NT(9-13), as well as six specifically mutated analogues with the following modifications, Acetyl-NT(8-13), [Dab(9)]NT(8-13), [Lys(8),Lys(9)]NT(8-13), [Lys(8)-((r))-Lys(9)]NT(8-13), [Lys(9),Trp(11),Glu(12)]NT(8-13), and Boc[Lys(9),Leu(13)OMe]NT(9-13), were immobilized onto an electrochemically roughened silver electrode surface in an aqueous solution. The orientation of the adsorbed molecules and the adsorption mechanism were determined from surface-enhanced Raman scattering (SERS) spectra. A comparison was made between the structures of the mutated fragments to determine how changes in the mutation of the structure influenced the adsorption properties. The contribution of the structural components to the peptides' ability to interact with the NTR1 receptor was correlated with the SERS patterns. The SERS spectra revealed that the substitution of native amino acids in the investigated peptides slightly influenced their adsorption state on an electrochemically roughened silver surface. Thus, all of the investigated peptides, excluding [Lys(9),Trp(11),Glu(12)]NT(8-13), tended to adsorb to the surface mainly via the oxygen atom of the deprotonated phenol group, and the phenyl ring became rearranged in a slightly different edge-on manner (NT(1-8), NT(1-11), NT(8-13), Acetyl-NT(8-13), [Dab(9)]NT(8-13), [Lys(8),Lys(9)]NT(8-13), [Lys(8)-((r))-Lys(9)]NT(8-13), NT(9-13), and Boc[Lys(9), Leu(13)OMe]NT(9-13)) or in an almost horizontal manner (N(1-6)) of the tyrosine residue. Meanwhile, [Lys(9),Trp(11),Glu(12)]NT(8-13) bound to this substrate through the tilted phenyl coring of the tryptophan residue. Small changes in the enhancement of the CCNH(2), COO(-), and -CONH- group modes upon adsorption, which were consistent with the adsorption of these peptides, also occurred (with slightly different strengths) through the nitrogen and oxygen lone pair of electrons in these groups. However, for NT(1-8), a greater preferential interaction between the guanidine group of Arg(8) and the roughened silver substrate was observed in comparison to that between the guanidine moiety of the other investigated peptides and the substrate. Vibrational spectroscopy was also used to produce an extensive table of Raman and absorption infrared spectra to allow for a rapid and accurate structural determination of these biomolecules and to allow the reader to easily follow the proposed SERS assignments. PMID- 21548566 TI - Anion effects on interfacial absorption of gases in ionic liquids. A molecular dynamics study. AB - Molecular dynamics simulations with many-body interactions were carried out to systematically study the effect of anion type, tetrafluoroborate [BF(4)] or hexafluorophosphate [PF(6)], paired with the cation 1-butyl-3-methylimidazolium [bmim], on the interfacial absorption of gases in room temperature ionic liquids (RTILs). The potentials of mean force (PMF) of CO(2) and H(2)O at 350 K were calculated across the air-liquid interfaces of [bmim][BF(4)] and [bmim][PF(6)]. We found that the PMFs for H(2)O exhibited no interfacial minima at both interfaces, while the corresponding PMFs for CO(2) had significant free energy minima there. However, the PMFs for H(2)O showed a much higher interfacial free energy than in the bulk for [bmim][BF(4)], but only a slightly higher interfacial free energy for [bmim][PF(6)] than in bulk. The reason for this was due to the more hydrophilic nature of the [BF(4)] anion, and the fact that [BF(4)] was found to have little propensity for the interface. Our results show that H(2)O is much more likely to be found at the air-[bmim][PF(6)] interface than at the air [bmim][BF(4)] interface. The free energies of solvation were found to be more negative for [bmim][BF(4)] than [bmim][PF(6)] for water and similar for CO(2). This observation is consistent with experimental Henry's law coefficients. Our results show that anion type, in addition to affecting the free energy of solvation into RTILs, should also significantly influence the uptake mechanism. PMID- 21548567 TI - Controlled lateral spreading and pinning of oil droplets based on topography and chemical patterning. AB - Geometric pinning sites can be used to control the lateral spreading and pinning of oils on surfaces. The geometric pinning effect combined with lithographic surface chemistry patterning allows controlling the shapes of oil droplets. We study the confinement effect on test structures of various protruding and intruding geometries, and employ scanning electron microscopy analysis to study the shape of the meniscus at the edges of the chemical patterns. Nanopillar and micropillar topographies are compared, revealing that it is a necessity for accurate oil patterns that the length scale of the roughness is smaller than the resolution of the surface chemistry pattern. We also find that there exists a critical, geometry-dependent threshold contact angle, below which the geometric confinement does not work, as olive oil with a static advancing contact angle of 57 degrees accurately replicated the chemical pattern on top of nanopillar topography, but hexadecane with a static advancing contact angle of 50 degrees penetrated the pinning sites and wetted the whole surface. PMID- 21548568 TI - Electrospray as a tool for drug micro- and nanoparticle patterning. AB - Carbamazepine (CBZ) microparticles of different sizes and shapes, including spheres, q-tips, elongated spheres, and tear-shaped particles, were formed by electrospraying solutions of different CBZ concentrations. The particle characteristics were determined by the interplay between jet formation, droplet breakup, solvent evaporation, and eventual particle solidification. The average particle size increased with increasing CBZ concentration, with particles of different shapes being observed for different CBZ concentrations. The cascade of sizes and shapes observed was interpreted in terms of Rayleigh instability theory as applied to charged jets and droplets, with the final sizes depending upon the time needed to evaporate the solvent sufficiently for CBZ to solidify; the lower the initial concentration of CBZ, the smaller the final droplets/particles that are formed. PMID- 21548569 TI - Heteroatom-substituted analogues of orphan nuclear receptor small heterodimer partner ligand and apoptosis inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3 chlorocinnamic acid. AB - (E)-4-[3'-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell cycle arrest and apoptosis of cancer cells. Because its pharmacologic properties-solubility, bioavailability, and toxicity-required improvement for translation, structural modifications were made by introducing nitrogen atoms into the cinnamyl ring and replacing its E-double bond with XCH(2) (X = O, N, and S) with the objective of enhancing these properties without impacting apoptosis-inducing activity. Analogues having nitrogen atoms in heterocyclic rings corresponding to the cinnamyl phenyl ring displayed equal or higher biological activities. The pyrimidine and pyridine analogues were more soluble in both phosphate-buffered saline and water. While the 2,5-disubstituted pyridine analogue was the most potent inducer of KG-1 acute myeloid leukemia cell apoptosis, on the basis of apoptotic activity in KG-1 cells and solubility, the 2,5-disubstituted pyrimidine proved to be the more promising candidate for treatment of acute myeloid leukemia. PMID- 21548570 TI - Dynamics of ion transfer potentials at liquid-liquid interfaces. AB - The Nernst-Planck-Poisson finite difference method is used to simulate the dynamic evolution of a water-nitrobenzene system with initially equimolar concentrations of a monovalent salt present in both liquids. The effect of single ion partition coefficients on the evolution of the liquid junction is investigated. The results from simulations reveal two separable components of the potential difference, similar to the behavior observed in recent works on the dynamic theory of membrane potentials [Ward, K. R.; et al. J. Phys. Chem. B2010, 114, 10763-10773]: a localized static component purely dependent on the ratio of single ion partition coefficients and a dynamically expanding diffuse component dependent on the mean salt partition coefficient and the diffusion coefficients of the constituent ions. PMID- 21548571 TI - Studying the electromagnetic-induced changes of the secondary structure of bovine serum albumin and the bioprotective effectiveness of trehalose by Fourier transform infrared spectroscopy. AB - Samples of bovine serum albumin in H(2)O and D(2)O solutions, in the absence or presence of trehalose, were exposed separately to a static magnetic field at 200 mT and to a 50 Hz electromagnetic field at 1.8 mT, studying the relative effects on the secondary structure of the protein by means of Fourier transform infrared spectroscopy. The spectra acquired in the mid-infrared region after 2 and 4 h of exposures to the static magnetic field showed a decrease in amide A and amide I band intensities for the protein in bidistilled aqueous solutions that was also evidenced after exposures to a 50 Hz electromagnetic field. These results led us to conclude that electromagnetic fields of low intensities can affect the C?O and C-N stretching vibrations and N-H plane bending of peptide linkages. Furthermore, mid-infrared spectra of bovine serum albumin in trehalose aqueous solutions were not significantly modified after the exposures, confirming the hypothesis of the possible bioprotective effectiveness of trehalose against electromagnetic fields. PMID- 21548572 TI - Spectroscopic and microscopic investigation of gold nanoparticle formation: ligand and temperature effects on rate and particle size. AB - We report a spectroscopic and microscopic investigation of the synthesis of gold nanoparticles (AuNPs) with average sizes of less than 5 nm. The slow reduction and AuNP formation processes that occur by using 9-borabicyclo[3.3.1]nonane (9 BBN) as a reducing agent enabled a time-dependent investigation based on standard UV-vis spectroscopy and transmission electron microscopy (TEM) analyses. This is in contrast to other borohydride-based syntheses of thiolate monolayer protected AuNPs which form particles very rapidly. We investigated the formation of 1 octadecanethiol (ODT) protected AuNPs with average diameters of 1.5-4.3 nm. By studying the progression of nanoparticle formation over time, we find that the nucleation rate and the growth time, which are interlinked with the amount of ODT and the temperature, influence the size and the size dispersion of the AuNPs. High-resolution TEM (HRTEM) analyses also suggest that the nanoparticles are highly single crystalline throughout the synthesis and appear to be formed by a diffusion-controlled Ostwald-ripening growth mechanism. PMID- 21548573 TI - Mobility of molecules and ions solubilized in protein gels: diffusion in the thick fraction of hen egg white. AB - The thick fraction of hen egg white is a protein hydrogel with an immeasurably high viscosity composed of ~90% water that can serve as a model system for mammalian mucous membrane. Measurements of the rate constants of diffusion controlled reactions occurring within the gel (and corresponding activation energies) and electric conductivity revealed that the thick fraction of egg white can be envisioned as a 3D network comprising hydrated protein molecules (held by intermolecular S-S bridges) surrounded by water pools and channels (of nonuniform diameters) that have a microviscosity that is very similar to that of bulk water. This was corroborated by differential scanning calorimetry measurements that revealed that 16% of water is bound to proteins. The melting kinetics of ice crystallites (produced from the freezable water) indicates nonhomogeneous water pool size. PMID- 21548574 TI - Contributions of the D-Ring to the activity of etoposide against human topoisomerase IIalpha: potential interactions with DNA in the ternary enzyme- drug--DNA complex. AB - Etoposide is a widely prescribed anticancer drug that stabilizes covalent topoisomerase II-cleaved DNA complexes. The drug contains a polycyclic ring system (rings A-D), a glycosidic moiety at C4, and a pendant ring (E-ring) at C1. Interactions between human topoisomerase IIalpha and etoposide in the binary enzyme--drug complex appear to be mediated by substituents on the A-, B-, and E rings of etoposide. These protein--drug contacts in the binary complex have predictive value for the actions of etoposide within the ternary topoisomerase IIalpha--drug--DNA complex. Although the D-ring of etoposide does not appear to contact topoisomerase IIalpha in the binary complex, etoposide derivatives with modified D-rings display reduced cytotoxicity against murine leukemia cells [Meresse, P., et al. (2003) Bioorg. Med. Chem. Lett. 13, 4107]. This finding suggests that alterations in the D-ring may affect etoposide activity toward topoisomerase IIalpha in the ternary enzyme--drug--DNA complex. Therefore, to address the potential contributions of the D-ring to the activity of etoposide, we characterized drug derivatives in which the C13 carbonyl was moved to the C11 position (retroetoposide and retroDEPT) or the D-ring was opened (D-ring diol). All of the D-ring alterations decreased the ability of etoposide to enhance DNA cleavage mediated by human topoisomerase IIalpha in vitro and in cultured cells. They also weakened etoposide binding in the ternary enzyme--drug--DNA complex and altered sites of enzyme-mediated DNA cleavage. On the basis of these findings, we propose that the D-ring of etoposide has important interactions with DNA in the ternary topoisomerase II cleavage complex. PMID- 21548575 TI - Effects of noncovalent platinum drug-protein interactions on drug efficacy: use of fluorescent conjugates as probes for drug metabolism. AB - The overall efficacy of platinum based drugs is limited by metabolic deactivation through covalent drug-protein binding. In this study the factors affecting cytotoxicity in the presence of glutathione, human serum albumin (HSA) and whole serum binding with cisplatin, BBR3464, and TriplatinNC, a "noncovalent" derivative of BBR3464, were investigated. Upon treatment with buthionine sulfoximine (BSO), to reduce cellular glutathione levels, cisplatin and BBR3464 induced apoptosis was augmented whereas TriplatinNC-induced cytotoxicity was unaltered. Treatment of A2780 ovarian carcinoma cells with HSA-bound cisplatin (cisplatin/HSA) and cisplatin preincubated with whole serum showed dramatic decreases in cytotoxicity, cellular accumulation, and DNA adduct formation compared to treatment with cisplatin alone. Similar effects are seen with BBR3464. In contrast, TriplatinNC, the HSA-bound derivative (TriplatinNC/HSA), and TriplatinNC pretreated with whole serum retained identical cytotoxic profiles and equal levels of cellular accumulation at all time points. Confocal microscopy of both TriplatinNC-NBD, a fluorescent derivative of TriplatinNC, and TriplatinNC NBD/HSA showed nuclear/nucleolar localization patterns, distinctly different from the lysosomal localization pattern seen with HSA. Cisplatin-NBD, a fluorescent derivative of cisplatin, was shown to accumulate in the nucleus and throughout the cytoplasm while the localization of cisplatin-NBD/HSA was limited to lysosomal regions of the cytoplasm. The results suggest that TriplatinNC can avoid high levels of metabolic deactivation currently seen with clinical platinum chemotherapeutics, and therefore retain a unique cytotoxic profile after cellular administration. PMID- 21548576 TI - Role of the heat capacity change in understanding and modeling melting thermodynamics of complementary duplexes containing standard and nucleobase modified LNA. AB - Melting thermodynamic data obtained by differential scanning calorimetry (DSC) are reported for 43 duplexed oligonucleotides containing one or more locked nucleic acid (LNA) substitutions. The measured heat capacity change (DeltaC(p)) for the helix-to-coil transition is used to compute the changes in enthalpy and entropy for melting of an LNA-bearing duplex at the T(m) of its corresponding isosequential unmodified DNA duplex to allow rigorous thermodynamic analysis of the stability enhancements provided by LNA substitutions. Contrary to previous studies, our analysis shows that the origin of the improved stability is almost exclusively a net reduction (DeltaDeltaS degrees < 0) in the entropy gain accompanying the helix-to-coil transition, with the magnitude of the reduction dependent on the type of nucleobase and its base pairing properties. This knowledge and our average measured value for DeltaC(p) of 42 +/- 11 cal mol(-1) K(-1) bp(-1) are then used to derive a new model that accurately predicts melting thermodynamics and the increased melting temperature (DeltaT(m)) of heteroduplexes formed between an unmodified DNA strand and a complementary strand containing any number and configuration of standard LNA nucleotides A, T, C, and G. This single-base thermodynamic (SBT) model requires only four entropy-related parameters in addition to DeltaC(p). Finally, DSC data for 20 duplexes containing the nucleobase-modified LNAs 2-aminoadenine (D) and 2-thiothymine (H) are reported and used to determine SBT model parameters for D and H. The data and model suggest that along with the greater stability enhancement provided by D and H bases relative to their corresponding A and T analogues, the unique pseudocomplementary properties of D-H base pairs may make their use appealing for in vitro and in vivo applications. PMID- 21548577 TI - Multifrequency electron paramagnetic resonance characterization of PpoA, a CYP450 fusion protein that catalyzes fatty acid dioxygenation. AB - PpoA is a fungal dioxygenase that produces hydroxylated fatty acids involved in the regulation of the life cycle and secondary metabolism of Aspergillus nidulans . It was recently proposed that this novel enzyme employs two different heme domains to catalyze two separate reactions: within a heme peroxidase domain, linoleic acid is oxidized to (8R)-hydroperoxyoctadecadienoic acid [(8R)-HPODE]; in the second reaction step (8R)-HPODE is isomerized within a P450 heme thiolate domain to 5,8-dihydroxyoctadecadienoic acid. In the present study, pulsed EPR methods were applied to find spectroscopic evidence for the reaction mechanism, thought to involve paramagnetic intermediates. We observe EPR resonances of two distinct heme centers with g-values typical for Fe(III) S = (5)/(2) high-spin (HS) and Fe(III) S = (1)/(2) low-spin (LS) hemes. (14)N ENDOR spectroscopy on the S = (5)/(2) signal reveals resonances consistent with an axial histidine ligation. Reaction of PpoA with the substrate leads to the formation of an amino acid radical on the early millisecond time scale concomitant to a substantial reduction of the S = (5)/(2) heme signal. High-frequency EPR (95- and 180-GHz) unambiguously identifies the new radical as a tyrosyl, based on g-values and hyperfine couplings from spectral simulations. The radical displays enhanced T(1) spin-lattice relaxation due to the proximity of the heme centers. Further, EPR distance measurements revealed that the radical is distributed among the monomeric subunits of the tetrameric enzyme at a distance of approximately 5 nm. The identification of three active paramagnetic centers involved in the reaction of PpoA supports the previously proposed reaction mechanism based on radical chemistry. PMID- 21548578 TI - Azaphilones from the endophyte Chaetomium globosum. AB - Six new azaphilones, 5'-epichaetoviridin A (7), 4'-epichaetoviridin F (9), 12beta hydroxychaetoviridin C (10), and chaetoviridins G-I (11-13), and six known azaphilones, chaetoviridins A-E (1-5) and 4'-epichaetoviridin A (8), were isolated from the endophytic fungus Chaetomium globosum cultivated in PDB medium for 21 days. The structure elucidation and the assignment of the relative configurations of the new natural products were based on detailed NMR and MS spectroscopic analyses. The structure of compound 1 was confirmed by single crystal X-ray diffraction analysis. The absolute configurations of compounds 4, 7, 8, and 12 were determined using Mosher's method. The antibiotic activity of the compounds was evaluated using an in vivo Caenorhabditis elegans infection model. PMID- 21548579 TI - Hippolides A-H, acyclic manoalide derivatives from the marine sponge Hippospongia lachne. AB - Eight new acyclic manoalide-related sesterterpenes, hippolides A-H (1-8), together with two known manoalide derivatives, (6E)-neomanoalide (9) and (6Z) neomanoalide (10), were isolated from the South China Sea sponge Hippospongia lachne. The absolute configurations of 1-8 were established by the modified Mosher's method and CD data. Compound 1 exhibited cytotoxicity against A549, HeLa, and HCT-116 cell lines with IC50 values of 5.22*10(-2), 4.80*10(-2), and 9.78 MUM, respectively. Compound 1 also showed moderate PTP1B inhibitory activitiy with an IC50 value of 23.81 MUM, and compound 2 showed moderate cytotoxicity against the HCT-116 cell line and PTP1B inhibitory activity with IC50 values of 35.13 and 39.67 MUM, respectively. In addition, compounds 1 and 5 showed weak anti-inflammatory activity, with IC50 values of 61.97 and 40.35 MUM for PKCgamma and PKCalpha, respectively. PMID- 21548580 TI - Bioactive terpenes from Spongia officinalis. AB - The terpene metabolite pattern of Mediterranean Spongia officinalis was chemically investigated. This study resulted in the isolation of a series of sesterterpenes and C21 furanoterpenes, according to the literature data on this sponge. Four new oxidized minor metabolites (compounds 1, 2, 3, and 4) were isolated along with six known compounds of the furospongin series (compounds 5-8, 9, and 10) and three scalarane sesterterpenes (compounds 11-13). Interestingly, tetrahydrofurospongin-2 (6) and dihydrofurospongin-2 (7), which were among the main metabolites, induced biofilm formation by Escherichia coli. All compounds isolated were also assayed for antibacterial and antifungal properties. PMID- 21548581 TI - 1H-Detected 13C photo-CIDNP as a sensitivity enhancement tool in solution NMR. AB - NMR is a powerful yet intrinsically insensitive technique. The applicability of NMR to chemical and biological systems would be substantially extended by new approaches going beyond current signal-to-noise capabilities. Here, we exploit the large enhancements arising from (13)C photochemically induced dynamic nuclear polarization ((13)C photo-CIDNP) in solution to improve biomolecular NMR sensitivity in the context of heteronuclear correlation spectroscopy. The (13)C PRINT pulse sequence presented here involves an initial (13)C nuclear spin polarization via photo-CIDNP followed by conversion to anti-phase coherence and transfer to (1)H for detection. We observe substantial enhancements, up to ?200 fold, relative to the dark (laser off) experiment. Resonances of both side-chain and backbone CH pairs are enhanced for the three aromatic residues Trp, His, and Tyr, the sigma(32) peptide, and the drkN SH3 protein. The sensitivity of this experiment, defined as signal-to-noise per square root of unit time (S/N)(t), is unprecedented in the NMR polarization enhancement literature dealing with polypeptides in solution. Up to a 16-fold larger (S/N)(t) than for the (1)H-(13)C SE-HSQC reference sequence is achieved, for the sigma(32) peptide. Data collection time is reduced up to 256-fold, highlighting the advantages of (1)H detected (13)C photo-CIDNP in solution NMR. PMID- 21548582 TI - Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole- and pyrazole-based histone deacetylase probes. AB - The design, synthesis, docking, and biological evaluation of novel potent HDAC3 and HDAC8 isoxazole- and pyrazole-based diazide probes suitable for binding ensemble profiling with photoaffinity labeling (BEProFL) experiments in cells is described. Both the isoxazole- and pyrazole-based probes exhibit low nanomolar inhibitory activity against HDAC3 and HDAC8, respectively. The pyrazole-based probe 3f appears to be one of the most active HDAC8 inhibitors reported in the literature with an IC(50) of 17 nM. Our docking studies suggest that unlike the isoxazole-based ligands the pyrazole-based ligands are flexible enough to occupy the second binding site of HDAC8. Probes/inhibitors 2b, 3a, 3c, and 3f exerted the antiproliferative and neuroprotective activities at micromolar concentrations through inhibition of nuclear HDACs, indicating that they are cell permeable and the presence of an azide or a diazide group does not interfere with the neuroprotection properties, or enhance cellular cytotoxicity, or affect cell permeability. PMID- 21548583 TI - Ratiometric temperature sensing with semiconducting polymer dots. AB - This communication describes ultrabright single-nanoparticle ratiometric temperature sensors based on semiconducting polymer dots (Pdots). We attached the temperature sensitive dye-Rhodamine B (RhB), whose emission intensity decreases with increasing temperature-within the matrix of Pdots. The as-prepared Pdot-RhB nanoparticle showed excellent temperature sensitivity and high brightness because it took advantage of the light harvesting and amplified energy transfer capability of Pdots. More importantly, the Pdot-RhB nanoparticle showed ratiometric temperature sensing under a single wavelength excitation and has a linear temperature sensing range that matches well with the physiologically relevant temperatures. We employed Pdot-RhB for measuring intracellular temperatures in a live-cell imaging mode. The exceptional brightness of Pdot-RhB allows this nanoscale temperature sensor to be used also as a fluorescent probe for cellular imaging. PMID- 21548584 TI - Analysis of gating transitions among the three major open states of the OpdK channel. AB - OpdK is an outer membrane protein of the pathogenic bacterium Pseudomonas aeruginosa. The recent crystal structure of this protein revealed a monomeric, 18 stranded beta-barrel with a kidney-shaped pore, whose constriction features a diameter of 8 A. Using systematic single-channel electrical recordings of this protein pore reconstituted into planar lipid bilayers under a broad range of ion concentrations, we were able to probe its discrete gating kinetics involving three major and functionally distinct conformations, in which a dominant open substate O(2) is accompanied by less thermodynamically stable substates O(1) and O(3). Single-channel electrical data enabled us to determine the alterations in the energetics and kinetics of the OpdK protein when experimental conditions were changed. In the future, such a semiquantitative analysis might provide a better understanding on the dynamics of current fluctuations of other beta-barrel membrane protein channels. PMID- 21548585 TI - Delivery of soluble VEGF receptor 1 (sFlt1) by gene electrotransfer as a new antiangiogenic cancer therapy. AB - Since tumor growth is highly dependent on the formation of new blood vessels, angiogenesis inhibitors have become important players in anticancer treatments. Although less cytotoxic than conventional chemotherapy, most of the available antiangiogenic agents may provoke severe adverse effects which can limit their use. The design of new antiangiogenic strategies therefore requires integrating an early evaluation of possible interference with quiescent endothelial cells and nontumor angiogenesis. Here, we describe such a novel antiangiogenic approach based on the in vivo delivery by gene electrotransfer of a negative regulator of angiogenesis, namely, sFlt1. We found that this soluble variant of the vascular endothelial growth factor receptor 1 (Flt1, also known as VEGFR1), which acts as a VEGF trap, differentially influences tumor and postischemic hind limb angiogenesis in mice. sFlt1 gene electrotransfer in tibial cranial muscle leads to high sFlt1 protein expression and secretion, leading to a significant delay in the growth of syngeneic tumors but not altering the revascularization of ischemic peripheral tissue. The higher sensitivity of tumor-bearing animals toward sFlt1 trapping effects (vs ischemia-recovering animals) might be explained by a distinct pattern of VEGF release, as shown by VEGF measurements in plasma and tissue. In conclusion, our data support sFlt1 gene electrotransfer as a novel and safe modality to target VEGF-driven tumor angiogenesis and to maintain unaltered the recovery potential of ischemic tissues. PMID- 21548586 TI - Role of induced fit in limiting discrimination against AZT by HIV reverse transcriptase. AB - Single turnover kinetic studies were conducted using fluorescently labeled HIV reverse transcriptase (RT) to evaluate the role of nucleotide-induced changes in enzyme structure in the selectivity against AZT in order to explore why AZT resistant forms of the enzyme fail to significantly discriminate against AZT. Fluorescent labeling of HIV RT provided a signal to monitor the isomerization from "open" to "closed" states following nucleotide binding. We measured the rate constants governing nucleotide binding and enzyme isomerization for TTP and AZT triphosphate by the wild-type and AZT-resistant forms of the enzyme containing the thymidine analogue mutations (TAMs). We show that the TAMs alter the kinetics of AZT incorporation by weakening ground-state nucleotide binding and decreasing the rate of chemistry relative to the wild-type enzyme. However, the slower rate of incorporation of AZT by the TAMs HIV RT is counterbalanced a lower K(m), resulting from the equilibration of the conformational change step. In contrast, the K(m) for the wild-type enzyme reflects the balance between rates of binding and incorporation so the conformational change step does not come to equilibrium. These data once again demonstrate that the rate of substrate release, limited by the reverse of the substrate-induced conformational change, is the key determinant of the role of induced fit in enzyme specificity. Mutations leading to slower rates of incorporation have the unfortunate consequence of lowering the K(m) value by allowing the conformational change step to come to equilibrium. PMID- 21548587 TI - Frustrated Lewis pairs beyond the main group: cationic zirconocene phosphinoaryloxide complexes and their application in catalytic dehydrogenation of amine boranes. AB - The cationic zirconocene-phosphinoaryloxide complexes [Cp(2)ZrOC(6)H(4)P(t Bu)(2)][B(C(6)F(5))(4)] (3) and [Cp*(2)ZrOC(6)H(4)P(t-Bu)(2)][B(C(6)F(5))(4)] (4) were synthesized by the reaction of Cp(2)ZrMe(2) or Cp*(2)ZrMe(2) with 2 (diphenylphosphino)phenol followed by protonation with [2,6-di-tert butylpyridinium][B(C(6)F(5))(4)]. Compound 3 exhibits a Zr-P bond, whereas the bulkier Cp* derivative 4 was isolated as a chlorobenzene adduct without this Zr-P interaction. These compounds can be described as transition-metal-containing versions of linked frustrated Lewis pairs (FLPs), and treatment of 4 with H(2) under mild conditions cleaved H(2) in a fashion analogous to that for main-group FLPs. Their reactivity in amine borane dehydrogenation also mimics that of main group FLPs, and they dehydrogenate a range of amine borane adducts. However, in contrast to main-group FLPs, 3 and 4 achieve this transformation in a catalytic rather than stoichiometric sense, with rates superior to those for previous high valent catalysts. PMID- 21548589 TI - Eu3+:Y2O3 microspheres and microcubes: a supercritical synthesis and characterization. AB - A new approach that uses mixed supercritical solvents of water/1-propanol and water/methanol (400 degrees C, 40 MPa) to prepare morphology-controlled precursor materials in a very short reaction time, such as 10 min, followed by calcinations has been developed to form Eu(3+):Y(2)O(3) microspheres of 2-3 MUm in diameter or microcubes of 2-3 MUm in side length, respectively. Eu(3+):Y(2)O(3) microspheres and microcubes exhibited strong red emission at 610 nm corresponding to (5)D(0) -> (7)F(2) transition. The highest photoluminescence emission was obtained for the microspheres after calcination at 1000 degrees C for 1 h in air. PMID- 21548588 TI - Human mitochondrial RNA polymerase: evaluation of the single-nucleotide-addition cycle on synthetic RNA/DNA scaffolds. AB - The human mitochondrial RNA polymerase (h-mtRNAP) serves as both the transcriptase for expression and the primase for replication of mitochondrial DNA. As such, the enzyme is of fundamental importance to cellular energy metabolism, and defects in its function may be related to human disease states. Here we describe in vitro analysis of the h-mtRNAP kinetic mechanism for single, correct nucleotide incorporation. This was made possible by the development of efficient methods for expression and purification of h-mtRNAP using a bacterial system and by utilization of assays that rely on simple, synthetic RNA/DNA scaffolds without the need for mitochondrial transcription accessory proteins. We find that h-mtRNAP accomplishes single-nucleotide incorporation by using the same core steps, including conformational change steps before and after chemistry, that are prototypical for most types of nucleic acid polymerases. The polymerase binds to scaffolds via a two-step mechanism consisting of a fast initial encounter step followed by a much slower isomerization that leads to catalytic competence. A substantial solvent deuterium kinetic isotope effect was observed for the forward reaction, but none was detectable for the reverse reaction, suggesting that chemistry is at least partially rate-limiting in the forward direction but not in the reverse. h-mtRNAP appears to exercise much more stringent surveillance over base than over sugar in determining the correctness of a nucleotide. The utility of developing the robust in vitro assays described here and of establishing a baseline of kinetic performance for the wild-type enzyme is that biological questions concerning h-mtRNAP may now begin to be addressed. PMID- 21548591 TI - Charge transfer and intraligand excited state interactions in platinum-sensitized dithienylethenes. AB - The photophysical behavior for two photochromic Pt-terpyridine acetylide complexes containing pendant dithienylethenes (DTEs) bound to the metal through the alkynyl linkage is presented. Selective excitation of the Pt complex with visible light resulted in the metal-sensitized ring closing of the DTE unit. The central purpose of this study was to understand how excited state interactions govern the photophysics by correlating differences in the linkage of the two components with differences in the intramolecular energy transfer processes that occur between the Pt complex and the DTE. A series of model complexes without photochromic ligands were prepared and studied to elucidate the contributions of the triplet metal-to-ligand charge transfer and triplet intraligand states. It is demonstrated that reducing the orbital overlap of the metal-based and intraligand states by lengthening the linkage and eliminating a conjugated pathway is effective at dramatically decreasing the efficiency of intramolecular energy transfer. This is evidenced by the appearance of Pt-terpyridine based phosphorescence and a significant decrease in the observed rate of metal sensitized ring closing of the DTE. PMID- 21548590 TI - Nafion-coating of the electrodes improves the flow-stability of the Ag/SiO2/Ag2O electroosmotic pump. AB - When a current or a voltage is applied across the ceramic membrane of the nongassing Ag/Ag(2)O-SiO(2)-Ag/Ag(2)O pump, protons produced in the anodic reaction 2Ag(s) + H(2)O -> Ag(2)O(s) + 2H(+) + 2e(-) are driven to the cathode, where they are consumed by the reaction Ag(2)O(s) + H(2)O + 2e(-) -> 2Ag(s) + 2 OH(-). The flow of water is induced by momentum transfer from the electric field driven proton-sheet at the surface of the ceramic membrane. About 10(4) water molecules flowed per reacted electron. Because dissolved ions decrease the field at the membrane surface, the flow decreases upon increasing the ionic strength. For this reason Ag(+) ions introduced through the anodic reaction and by dissolution of Ag(2)O decrease the flow. Their accumulation is reduced by applying Nafion-films to the electrodes. The 20 MUL min(-1) flow rate of 6 mm i.d. pumps with Nafion coated electrodes operate daily for 5 min at 1 V for 1 month, for 70 h when the pump is pulsed for 30 s every 30 min, and for 2 h when operating continuously. PMID- 21548592 TI - Syntheses and crystal structures of two new bismuth hydroxyl borates containing [Bi2O2]2+ layers: Bi2O2[B3O5(OH)] and Bi2O2[BO2(OH)]. AB - Two new bismuth hydroxyl borates, Bi(2)O(2)[B(3)O(5)(OH)] (I) and Bi(2)O(2)[BO(2)(OH)] (II), have been synthesized under hydrothermal conditions. Their structures were determined by single-crystal and powder X-ray diffraction data, respectively. Compound I crystallizes in the orthorhombic space group Pbca with the lattice constants of a = 6.0268(3) A, b = 11.3635(6) A, and c = 19.348(1) A. Compound II crystallizes in the monoclinic space group Cm with the lattice constants of a = 5.4676(6) A, b = 14.6643(5) A, c = 3.9058(1) A, and beta = 135.587(6) degrees . The borate fundamental building block (FBB) in I is a three-ring unit [B(3)O(6)(OH)](4-), which connects one by one via sharing corners, forming an infinite zigzag chain along the a direction. The borate chains are further linked by hydrogen bonds, showing as a borate layer within the ab plane. The FBB in II is an isolated [BO(2)(OH)](2-) triangle, which links to two neighboring FBBs by strong hydrogen bonds, resulting in a borate chain along the a direction. Both compounds contain [Bi(2)O(2)](2+) layers, and the [Bi(2)O(2)](2+) layers combine with the corresponding borate layers alternatively, forming the whole structures. These two new bismuth borates are the first ones containing [Bi(2)O(2)](2+) layers in borates. The appearance of Bi(2)O(2)[BO(2)(OH)] (II) completes the series of compounds Bi(2)O(2)[BO(2)(OH)], Bi(2)O(2)CO(3), and Bi(2)O(2)[NO(3)(OH)] and the formation of Bi(2)O(2)[B(3)O(5)(OH)] provides another example in demonstrating the polymerization tendency of borate groups. PMID- 21548593 TI - Interaction of beta-lactam carbenes with 3,6-diphenyltetrazines: a five-step cascade reaction for the direct construction of indeno[2,1-b]pyrrol-2-ones. AB - A study of the nucleophilic addition of beta-lactam carbenes to 3,6 diphenyltetrazines is reported. Instead of the formation of pyrazole derivatives like most reactions between nucleophilic or ambiphilic carbenes and 3,6 disubstituted tetrazines, beta-lactam carbenes reacted with 3,6 diphenyltetrazines to produce indeno[2,1-b]pyrrol-2-ones in good yields. The reaction proceeds most probably through a five-step cascade process. This work has not only provided a one-pot operation for the efficient construction of mutisubstituted indeno[2,1-b]pyrrol-2-ones but also revealed the nucleophilicity of beta-lactam carbenes. PMID- 21548594 TI - Crystal orbital Hamilton population (COHP) analysis as projected from plane-wave basis sets. AB - Simple, yet predictive bonding models are essential achievements of chemistry. In the solid state, in particular, they often appear in the form of visual bonding indicators. Because the latter require the crystal orbitals to be constructed from local basis sets, the application of the most popular density-functional theory codes (namely, those based on plane waves and pseudopotentials) appears as being ill-fitted to retrieve the chemical bonding information. In this paper, we describe a way to re-extract Hamilton-weighted populations from plane-wave electronic-structure calculations to develop a tool analogous to the familiar crystal orbital Hamilton population (COHP) method. We derive the new technique, dubbed "projected COHP" (pCOHP), and demonstrate its viability using examples of covalent, ionic, and metallic crystals (diamond, GaAs, CsCl, and Na). For the first time, this chemical bonding information is directly extracted from the results of plane-wave calculations. PMID- 21548595 TI - Total synthesis of epicoccin G. AB - An expedient enantioselective total synthesis of epicoccin G and related dithiodiketopiperazines through a strategy featuring direct two-directional sulfenylation, photooxygenation, and Kornblum-DeLaMare rearrangement is described. PMID- 21548596 TI - Effects of 1-butyl-3-methyl imidazolium tetrafluoroborate ionic liquid on Triton X-100 aqueous micelles: solvent and rotational relaxation studies. AB - The effect of added room-temperature ionic liquids on the nature of water molecules in the palisade layer of a Triton X-100 (TX-100) micelle has been investigated using solvation and rotational relaxation studies of coumarin 153 in the presence of different wt % of [bmim][BF(4)] and thus to understand the changes in micellar palisade layer, especially the entrapped water structures in the palisade layer. It has been observed that in the presence of added [bmim][BF(4)] the solvation dynamics becomes faster. It has previously been demonstrated (Behera et al. J. Chem. Phys.2007, 127, 184501) that in the present micellar systems, in the presence of [bmim][BF(4)] micellar size and aggregation number (N(agg)) decreases giving rise to more water molecules penetrating in to the micellar phase which results in increased microfluidity. In accordance with solvation dynamics results, fluorescence anisotropy studies also indicate an increased microfluidity for the palisade layer of the TX-100 micelle with the added [bmim][BF(4)]. Wobbling-in-cone analysis of the anisotropy data also supports this finding. PMID- 21548597 TI - Unambiguous one-molecule conductance measurements under ambient conditions. AB - One of the challenging goals of molecular electronics is to wire exactly one molecule between two electrodes. This is generally nontrivial under ambient conditions. We describe a new and straightforward protocol for unambiguously isolating a single organic molecule on a metal surface and wiring it inside a nanojunction under ambient conditions. Our strategy employs C(60) terminal groups which act as molecular beacons allowing molecules to be visualized and individually targeted on a gold surface using an scanning tunneling microscope. After isolating one molecule, we then use the C(60) groups as alligator clips to wire it between the tip and surface. Once wired, we can monitor how the conductance of a purely one molecule junction evolves with time, stretch the molecule in the junction, observing characteristic current plateaus upon elongation, and also perform direct I-V spectroscopy. By characterizing and controlling the junction, we can draw stronger conclusions about the observed variation in molecular conductance than was previously possible. PMID- 21548598 TI - Notable structural property of 2,4,6-tri-tert-butylanilide enolates: interconversion between the rotamers and their reactivity. AB - Interconversion between the separable 2,4,6-tri-tert-butylanilide rotamers was found to easily occur through formation of the lithium enolate. Protonation of the anilide enolate gave the anilide rotamer mixture of E-major. On the other hand, reactions of lithium enolate prepared from 2,4,6-tri-tert butylpropionanilide with alkyl bromides preferentially afforded a Z-rotamer of alkylated products. PMID- 21548599 TI - Copper-catalyzed direct amination of electron-deficient arenes with hydroxylamines. AB - The C-H amination of electron-deficient arenes such as polyfluoroarenes and azole compounds with O-acylated hydroxylamines effectively proceeds in the presence of a copper catalyst even at room temperature to provide the corresponding anilines and aminoazoles in good yields. PMID- 21548600 TI - Imaging drug delivery to skin with stimulated Raman scattering microscopy. AB - Efficient drug delivery to the skin is essential for the treatment of major dermatologic diseases, such as eczema, psoriasis and acne. However, many compounds penetrate the skin barrier poorly and require optimized formulations to ensure their bioavailability. Here, stimulated Raman scattering (SRS) microscopy, a recently developed, label-free chemical imaging tool, is used to acquire high resolution images of multiple chemical components of a topical formulation as it penetrates into mammalian skin. This technique uniquely provides label-free, nondestructive, three-dimensional images with high spatiotemporal resolution. It reveals novel features of (trans)dermal drug delivery in the tissue environment: different rates of drug penetration via hair follicles as compared to the intercellular pathway across the stratum corneum are directly observed, and the precipitation of drug crystals on the skin surface is visualized after the percutaneous penetration of the cosolvent excipient in the formulation. The high speed three-dimensional imaging capability of SRS thus reveals features that cannot be seen with other techniques, providing both kinetic information and mechanistic insight into the (trans)dermal drug delivery process. PMID- 21548601 TI - Influence of cultivar, harvest time, storage conditions, and peeling on the antioxidant capacity and phenolic and ascorbic acid contents of apples and pears. AB - Apple and pear fruits are important sources of secondary plant metabolites and one of the major sources of dietary phenolics consumed all year round. The aim of this work was to identify the main variables influencing phenolic content and antioxidant capacity in apples. Higher phenolic and antioxidant contents were observed in some varieties (such as the Delbar Estival apple and Durondeau pear). Storage conditions were important. Our results also showed that fruits should be consumed rapidly after purchase and with their peel. After one week of domestic storage, the ascorbic acid content was found to decrease by 75%. Peeling led to a more than 25% decrease in total phenolics and ascorbic acid. The harvest time (at normal ripeness) had only a limited impact, but significant year-to-year variations were observed. In conclusion, well-chosen and well-stored apples and pears may contribute to an antioxidant-rich diet if consumed rapidly and with their peel. PMID- 21548603 TI - Synthesis and morphogenesis of organic polymer materials with hierarchical structures in biominerals. AB - Synthesis and morphogenesis of polypyrrole (PPy) with hierarchical structures from nanoscopic to macroscopic scales have been achieved by using hierarchically organized architectures of biominerals. We adopted biominerals, such as a sea urchin spine and nacreous layer, having hierarchical architectures based on mesocrystals as model materials used for synthesis of an organic polymer. A sea urchin spine led to the formation of PPy macroscopic sponge structures consisting of nanosheets less than 100 nm in thickness with the mosaic interior of the nanoparticles. The morphologies of the resultant PPy hierarchical architectures can be tuned by the structural modification of the original biomineral with chemical and thermal treatments. In another case, a nacreous layer provided PPy porous nanosheets consisting of the nanoparticles. Conductive pathways were formed in these PPy hierarchical architectures. The nanoscale interspaces in the mesocrystal structures of biominerals are used for introduction and polymerization of the monomers, leading to the formation of hierarchically organized polymer architectures. These results show that functional organic materials with complex and nanoscale morphologies can be synthesized by using hierarchically organized architectures as observed in biominerals. PMID- 21548602 TI - Elucidation of the Hsp90 C-terminal inhibitor binding site. AB - The Hsp90 chaperone machine is required for the folding, activation, and/or stabilization of more than 50 proteins directly related to malignant progression. Hsp90 contains small molecule binding sites at both its N- and C-terminal domains; however, limited structural and biochemical data regarding the C terminal binding site is available. In this report, the small molecule binding site in the Hsp90 C-terminal domain was revealed by protease fingerprinting and photoaffinity labeling utilizing LC-MS/MS. The identified site was characterized by generation of a homology model for hHsp90alpha using the SAXS open structure of HtpG and docking the bioactive conformation of NB into the generated model. The resulting model for the bioactive conformation of NB bound to Hsp90alpha is presented herein. PMID- 21548604 TI - Understanding and controlling organic-inorganic interfaces in mesostructured hybrid photovoltaic materials. AB - The chemical compositions and structures of organic-inorganic interfaces in mesostructurally ordered conjugated polymer-titania nanocomposites are shown to have a predominant influence on their photovoltaic properties. Such interfaces can be controlled by using surfactant structure-directing agents (SDAs) with different architectures and molecular weights to promote contact between the highly hydrophobic electron-donating conjugated polymer species and hydrophilic electron-accepting titania frameworks. A combination of small-angle X-ray scattering (SAXS), scanning and transmission electron microscopy (SEM, TEM), and solid-state NMR spectroscopy yields insights on the compositions, structures, and distributions of inorganic and organic species within the materials over multiple length scales. Two-dimensional NMR analyses establish the molecular-level interactions between the different SDA blocks, the conjugated polymer, and the titania framework, which are correlated with steady-state and time-resolved photoluminescence measurements of the photoexcitation dynamics of the conjugated polymer and macroscopic photocurrent generation in photovoltaic devices. Molecular understanding of the compositions and chemical interactions at organic inorganic interfaces are shown to enable the design, synthesis, and control of the photovoltaic properties of hybrid functional materials. PMID- 21548605 TI - Confined diffusion in periodic porous nanostructures. AB - We performed fluorescence correlation spectroscopy measurements to assess the long-time self-diffusion of a variety of spherical tracer particles in periodic porous nanostructures. Inverse opal structures with variable cavity sizes and openings in the nanometer domain were employed as the model system. We obtained both the exponent of the scaling relation between mean-square displacement and time and the slow-down factors due to the periodic confinement for a number of particle sizes and confining characteristics. In addition, we carried out Brownian dynamics simulations to model the experimental conditions. Good agreement between experimental and simulation results has been obtained regarding the slow-down factor. Fickian diffusion is predicted and seen in almost all experimental systems, while apparent non-Fickian exponents that show up for two strongly confined systems are attributed to polydispersity of the cavity openings. The utility of confining periodic porous nanostructures holds promise toward understanding of constrained diffusion with a wide range of applications ranging from water purification and drug delivery to tissue engineering. PMID- 21548606 TI - Synthesis of tetrachloro-azapentacene as an ambipolar organic semiconductor with high and balanced carrier mobilities. AB - Two new azapentacene derivatives 9,10-dibromo-6,13-bis(triisopropylsilylethynyl) 1-azapentacene (a) and 8,9,10,11-tetrachloro-6,13-bis(triisopropylsilylethynyl)-1 azapentacene (b) were synthesized, and their FET properties were investigated. Compound b exhibits high and balanced ambipolar transport properties, with the hole and electron mobilities reaching up to 0.12 and 0.14 cm(2) V(-1) s(-1), respectively. This work suggests that chlorination to the N-heteropentacene framework is an efficient way for producing high performance ambipolar organic semiconductors. PMID- 21548607 TI - Controlled molecular self-assembly behaviors between cucurbituril and bispyridinium derivatives. AB - Two stable supramolecular loops (1 and 2) were successfully constructed by the molecular recognition of cucurbit[8]uril (CB[8]) and the homoditopic bispyridinium derivatives (3 and 4). Interestingly, the interconversion of molecular loops and [2]pseudorotaxanes could be reversibly switched under neutral and acidic condition, exhibiting the controlled electrochemical and spectroscopic behaviors. PMID- 21548608 TI - Ratiometric fluorescence imaging of cellular glutathione. AB - A fluorescent probe (1) with a hydrogen bond was designed for the detection of GSH. The probe exhibited a rapid and ratiometric fluorescence response to GSH through a Michael reaction and allowed us to obtain clear cellular images for GSH. PMID- 21548609 TI - An isofagomine analogue with an amidine at the pseudoanomeric position. AB - (3R,4R,5R)-2-Imino-3,4-dihydroxy-5-hydroxymethylpiperidine hydrocloride or isofagomidine was synthesized from D-arabinose in 12 steps and an overall yield of 9.9%. The synthesis proceeded by introduction of an aminomethyl group in the 4 position of D-arabinose and conversion of C-1 into a nitrile. The key step in the synthesis was a copper-catalyzed cyclization of aminonitrile to amidine. Isofagomidine was a potent alpha-mannosidase inhibitor (K(i) = 0.75 MUM). PMID- 21548610 TI - Treponema denticola PurE Is a bacterial AIR carboxylase. AB - De novo purine biosynthesis proceeds by two divergent paths. In bacteria, yeasts, and plants, 5-aminoimidazole ribonucleotide (AIR) is converted to 4-carboxy-AIR (CAIR) by two enzymes: N(5)-carboxy-AIR (N(5)-CAIR) synthetase (PurK) and N(5) CAIR mutase (class I PurE). In animals, the conversion of AIR to CAIR requires a single enzyme, AIR carboxylase (class II PurE). The CAIR carboxylate derives from bicarbonate or CO(2), respectively. Class I PurE is a promising antimicrobial target. Class I and class II PurEs are mechanistically related but bind different substrates. The spirochete dental pathogen Treponema denticola lacks a purK gene and contains a class II purE gene, the hallmarks of CO(2)-dependent CAIR synthesis. We demonstrate that T. denticola PurE (TdPurE) is AIR carboxylase, the first example of a prokaryotic class II PurE. Steady-state and pre-steady-state experiments show that TdPurE binds AIR and CO(2) but not N(5)-CAIR. Crystal structures of TdPurE alone and in complex with AIR show a conformational change in the key active site His40 residue that is not observed for class I PurEs. A contact between the AIR phosphate and a differentially conserved residue (TdPurE Lys41) enforces different AIR conformations in each PurE class. As a consequence, the TdPurE.AIR complex contains a portal that appears to allow the CO(2) substrate to enter the active site. In the human pathogen T. denticola, purine biosynthesis should depend on available CO(2) levels. Because spirochetes lack carbonic anhydrase, the corresponding reduction in bicarbonate demand may confer a selective advantage. PMID- 21548611 TI - Comparative triplex tandem mass spectrometry assays of lysosomal enzyme activities in dried blood spots using fast liquid chromatography: application to newborn screening of Pompe, Fabry, and Hurler diseases. AB - We report a comparative study of triplex tandem mass spectrometry (MS/MS) based assays of lysosomal enzymes in dried blood spots for the early detection of Pompe, Fabry, and Hurler diseases in newborns. Four methods have been evaluated that differed in sample handling and the equipment used. A newly developed method uses assay quenching with acetonitrile to precipitate blood proteins followed by analysis on an LC-electrospray/MS/MS system capable of multiple consecutive sample injections on two parallel chromatographic columns. This method requires 1.5 min per a triplex analysis of enzyme products and internal standards, which matches the throughput of the previously reported flow injection method. LC separation reduces matrix effects and allows for more facile sample workup. The new LC-based method showed figures of merit that were superior to those of the currently used method based on liquid-liquid extraction into ethyl acetate and flow injection into the mass spectrometer. The other methods we investigated for comprehensive comparison involved liquid-liquid extraction into ethyl acetate followed by LC-ESI-MS/MS and acetonitrile quenching followed by direct flow injection. Both methods using acetonitrile quenching were found to be robust and provide good quality data while requiring fewer liquid transfer steps and less disposable material and labor than did the extraction methods. The individual merits of the new methods are discussed to present an evaluated alternative approach to high-throughput analysis in newborn screening laboratories. PMID- 21548613 TI - Probing the interaction of hydrogen chloride with low-temperature water ice surfaces using thermal and electron-stimulated desorption. AB - The interaction and autoionization of HCl on low-temperature (80-140 K) water ice surfaces has been studied using low-energy (5-250 eV) electron-stimulated desorption (ESD) and temperature programmed desorption (TPD). There is a reduction of H(+) and H(2)(+) and a concomitant increase in H(+)(H(2)O)(n=1-7) ESD yields due to the presence of submonolayer quantities of HCl. These changes are consistent with HCl induced reduction of dangling bonds required for H(+) and H(2)(+) ESD and increased hole localization necessary for H(+)(H(2)O)(n=1-7) ESD. For low coverages, this can involve nonactivated autoionization of HCl, even at temperatures as low as 80 K; well below those typical of polar stratospheric cloud particles. The uptake and autoionization of HCl is supported by TPD studies which show that for HCl doses <=0.5 +/- 0.2 ML (ML = monolayer) at 110 K, desorption of HCl begins at 115 K and peaks at 180 K. The former is associated with adsorption of a small amount of molecular HCl and is strongly dependent on the annealing history of the ice. The latter peak at 180 K is commensurate with desorption of HCl via recombinative desorption of solvated separated ion pairs. The activation energy for second-order desorption of HCl initially in the ionized state is 43 +/- 2 kJ/mol. This is close to the zero-order activation energy for ice desorption. PMID- 21548614 TI - Photoinduced electron transfer and persistent spectral hole-burning in natural emerald. AB - Wavelength-selective excited-state lifetime measurements and absorption, luminescence, and hole-burning spectra of a natural African emerald crystal are reported. The (2)E excited-state lifetime displays an extreme wavelength dependence, varying from 190 to 37 MUs within 1.8 nm of the R(1)-line. Overall, the excited state is strongly quenched, in comparison to laboratory-created emerald (tau=1.3 ms), with an average quenching rate of ~6 * 10(3) s(-1) at 2.5 K. This quenching is attributed to photoinduced electron transfer caused by a relatively high concentration of Fe(2+) ions. The forward electron-transfer rate, k(f), from the nearest possible Fe(2+) sites at around 5 A is estimated to be ~20 * 10(3) s(-1) at 2.5 K. The photoreductive quenching of the excited Cr(3+) ions by Fe(2+) is followed by rapid electron back-transfer in the ground state upon deactivation. The exchange interaction based quenching can be modeled by assuming a random quencher distribution within the possible Fe(2+) sites with the forward electron-transfer rate, k(f), given as a function of acceptor-donor separation R by exp[(R(f)-R)/a(f)]; R(f) and a(f) values of 13.5 and 2.7 A are obtained at 2.5 K. The electron transfer/back-transfer reorganizes the local crystal lattice, occasionally leading to a minor variation of the short-range structure around the Cr(3+) ions. This provides a mechanism for spectral hole-burning for which a moderately high quantum efficiency of about ~0.005% is observed. Spectral holes are subject to spontaneous hole-filling and spectral diffusion, and both effects can be quantified within the standard two-level systems for non-photochemical hole-burning. Importantly, the absorbance increases on both sides of broad spectral holes, and isosbestic points are observed, in accord with the expected distribution of the "photoproduct" in a non-photochemical hole-burning process. PMID- 21548612 TI - Brominated tyrosine and polyelectrolyte multilayer analysis by laser desorption vacuum ultraviolet postionization and secondary ion mass spectrometry. AB - The small molecular analyte 3,5-dibromotyrosine (Br(2)Y) and chitosan-alginate polyelectrolyte multilayers (PEM) with and without adsorbed Br(2)Y were analyzed by laser desorption postionization-mass spectrometry (LDPI-MS). LDPI-MS using a 7.87 eV laser and tunable 8-12.5 eV synchrotron vacuum ultraviolet (VUV) radiation found that desorption of clusters from Br(2)Y films allowed detection by <=8 eV single photon ionization. Thermal desorption and electronic structure calculations determined the ionization energy of Br(2)Y to be ~8.3 +/- 0.1 eV and further indicated that the lower ionization energies of clusters permitted their detection at <=8 eV photon energies. However, single photon ionization could only detect Br(2)Y adsorbed within PEMs when using either higher photon energies or matrix addition to the sample. All samples were also analyzed by 25 keV Bi(3)(+) secondary ion mass spectrometry (SIMS), with the negative ion spectra showing strong parent ion signal which complemented that observed by LDPI-MS. However, the negative ion SIMS appeared strongly dependent on the high electron affinity of this specific analyte and the analyte's condensed phase environment. PMID- 21548615 TI - Absolute photoionization cross section of the ethyl radical in the range 8-11.5 eV: synchrotron and vacuum ultraviolet laser measurements. AB - The absolute photoionization cross section of C(2)H(5) has been measured at 10.54 eV using vacuum ultraviolet (VUV) laser photoionization. The C(2)H(5) radical was produced in situ using the rapid C(2)H(6) + F -> C(2)H(5) + HF reaction. Its absolute photoionization cross section has been determined in two different ways: first using the C(2)H(5) + NO(2) -> C(2)H(5)O + NO reaction in a fast flow reactor, and the known absolute photoionization cross section of NO. In a second experiment, it has been measured relative to the known absolute photoionization cross section of CH(3) as a reference by using the CH(4) + F -> CH(3) + HF and C(2)H(6) + F -> C(2)H(5) + HF reactions successively. Both methods gave similar results, the second one being more precise and yielding the value: sigma(C(2)H(5))(ion) = (5.6 +/- 1.4) Mb at 10.54 eV. This value is used to calibrate on an absolute scale the photoionization curve of C(2)H(5) produced in a pyrolytic source from the C(2)H(5)NO(2) precursor, and ionized by the VUV beam of the DESIRS beamline at SOLEIL synchrotron facility. In this latter experiment, a recently developed ion imaging technique is used to discriminate the direct photoionization process from dissociative ionization contributions to the C(2)H(5)(+) signal. The imaging technique applied on the photoelectron signal also allows a slow photoelectron spectrum with a 40 meV resolution to be extracted, indicating that photoionization around the adiabatic ionization threshold involves a complex vibrational overlap between the neutral and cationic ground states, as was previously observed in the literature. Comparison with earlier photoionization studies, in particular with the photoionization yield recorded by Ruscic et al. is also discussed. PMID- 21548616 TI - On the influence of density functional approximations on some local Bader's atoms in-molecules properties. AB - In this article, we assess the ability of various density functionals to predict accurate values for some basic properties of the bond critical points of about 50 small molecules, including the recently proposed reduced gradient variation rates and involving typical ionic and covalent bonds, agostic interactions, and van der Waals complexes. The relation between the computed deviations and the geometric variations are discussed, as well as the topology variations. The possible correlation of these descriptors to atomization energies is considered, and the relevance of an accurate QTAIM analysis for correct descriptions of potential energy surfaces is addressed. Finally, we provide typical margins of error for the evaluation of these quantities and discuss their consequences for computational applications. PMID- 21548617 TI - Diffusion and filtration properties of self-assembled gold nanocrystal membranes. AB - Close-packed nanoparticle monolayers have recently been shown to form mechanically robust, free-standing membranes. We report the first measurements of molecular transport through such ultrathin sheets, self-assembled from dodecanethiol-ligated gold nanocrystals. For aqueous solutions we find filtration coefficients 2 orders of magnitude larger than those observed in polymer-based filters, sieving of large solutes, and for smaller solutes a pronounced dependence of rejection on being charged. These results open up new possibilities for controlled delivery and separation of nano-objects. PMID- 21548618 TI - Surface-engineered magnetic nanoparticle platforms for cancer imaging and therapy. AB - Enormous efforts have been made toward the translation of nanotechnology into medical practice, including cancer management. Generally the applications have fallen into two categories: diagnosis and therapy. Because the targets are often the same, the development of separate approaches can miss opportunities to improve efficiency and effectiveness. The unique physical properties of nanomaterials enable them to serve as the basis for superior imaging probes to locate and report cancerous lesions and as vehicles to deliver therapeutics preferentially to those lesions. These technologies for probes and vehicles have converged in the current efforts to develop nanotheranostics, nanoplatforms with both imaging and therapeutic functionalities. These new multimodal platforms are highly versatile and valuable components of the emerging trend toward personalized medicine, which emphasizes tailoring treatments to the biology of individual patients to optimize outcomes. The close coupling of imaging and treatment within a theranostic agent and the data about the evolving course of an illness that these agents provide can facilitate informed decisions about modifications to treatment. Magnetic nanoparticles, especially superparamagnetic iron oxide nanoparticles (IONPs), have long been studied as contrast agents for magnetic resonance imaging (MRI). Owing to recent progress in synthesis and surface modification, many new avenues have opened for this class of biomaterials. Such nanoparticles are not merely tiny magnetic crystals, but potential platforms with large surface-to-volume ratios. By taking advantage of the well-developed surface chemistry of these materials, researchers can load a wide range of functionalities, such as targeting, imaging and therapeutic features, onto their surfaces. This versatility makes magnetic nanoparticles excellent scaffolds for the construction of theranostic agents, and many efforts have been launched toward this goal. In this Account, we introduce the surface engineering techniques that we and others have developed, with an emphasis on how these techniques affect the role of nanoparticles as imaging or therapeutic agents. We and others have developed a set of chemical methods to prepare magnetic nanoparticles that possess accurate sizes, shapes, compositions, magnetizations, relaxivities, and surface charges. These features, in turn, can be harnessed to adjust the toxicity and stability of the nanoparticles and, further, to load functionalities, via various mechanisms, onto the nanoparticle surfaces. PMID- 21548619 TI - Mild redox complementation enables H2 activation by [FeFe]-hydrogenase models. AB - Mild oxidants such as [Fe(C(5)Me(5))(2)](+) accelerate the activation of H(2) by [Fe(2)[(SCH(2))(2)NBn](CO)(3)(dppv)(PMe(3))](+) ([1](+)), despite the fact that the ferrocenium cation is incapable of oxidizing [1](+). The reaction is first order in [1](+) and [H(2)] but independent of the E(1/2) and concentration of the oxidant. The analogous reaction occurs with D(2) and proceeds with an inverse kinetic isotope effect of 0.75(8). The activation of H(2) is further enhanced with the tetracarbonyl [Fe(2)[(SCH(2))(2)NBn](CO)(4)(dppn)](+) ([2](+)), the first crystallographically characterized model for the H(ox) state of the active site containing an amine cofactor. These studies point to rate-determining binding of H(2) followed by proton-coupled electron transfer. Relative to that by [1](+), the rate of H(2) activation by [2](+)/Fc(+) is enhanced by a factor of 10(4) at 25 degrees C. PMID- 21548620 TI - The need for enzymatic steering in abietic acid biosynthesis: gas-phase chemical dynamics simulations of carbocation rearrangements on a bifurcating potential energy surface. AB - Abietic acid, a constituent of pine resin, is naturally derived from abietadiene -a process that requires four enzymes: one (abietadiene synthase) for conversion of the acyclic, achiral geranylgeranyl diphosphate to the polycyclic, chiral abietadiene (a complex process involving the copalyl diphosphate intermediate) and then three to oxidize a single methyl group of abietadiene to the corresponding carboxylic acid. In previous work (Nature Chem.2009, 1, 384), electronic structure calculations on carbocation rearrangements leading to abietadienyl cation revealed an interesting potential energy surface with a bifurcating reaction pathway (two transition-state structures connected directly with no intervening minimum), which links two products--one natural and one not yet isolated from Nature. Herein we describe direct dynamics simulations of the key step in the formation of abietadiene (in the gas phase and in the absence of the enzyme). The simulations reveal that abietadiene synthase must intervene in order to produce abietadiene selectively, in essence steering this reaction to avoid the generation of byproducts with different molecular architectures. PMID- 21548621 TI - Development of an immunochromatographic strip test for rapid detection of melamine in raw milk, milk products and animal feed. AB - A simple, rapid and sensitive immunogold chromatographic strip test based on a monoclonal antibody was developed for the detection of melamine (MEL) residues in raw milk, milk products and animal feed. The limit of detection was estimated to be 0.05 MUg/mL in raw milk, since the detection test line on the strip test completely disappeared at this concentration. The limit of detection was 2 MUg/mL (or 2 MUg/g) for milk drinks, yogurt, condensed milk, cheese, and animal feed and 1 MUg/g for milk powder. Sample pretreatment was simple and rapid, and the results can be obtained within 3-10 min. A parallel analysis of MEL in 52 blind raw milk samples conducted by gas chromatography-mass spectrometry showed comparable results to those obtained from the strip test. The results demonstrate that the developed method is suitable for the onsite determination of MEL residues in a large number of samples. PMID- 21548622 TI - The role played by salts in the formation of SBA-15, an in situ small-angle X-ray scattering/diffraction study. AB - The influence of salts (NaCl, NaBr, and NaI) on the formation of mesoporous silica SBA-15 was studied in situ by small-angle X-ray scattering and diffraction. Pluronic P104 was used as structure director. The micellar properties and the dynamics of formation were clearly dependent on the presence of salt. It was also shown that the kinetics of mesophase formation, the initial value of the cell parameters, and the extent of long-range order were all influenced by salt additions. The observations are explained to primarily originate from the influence of the anions on the ethylene oxide part of the polymer, i.e., the corona region of the Pluronic micelles. Two effects are identified: a general ion effect causing dehydration of the ethylene oxide part and consequently inducing micellar growth, and a specific ion effect that counterbalances this. The study provides the basis for understanding the means by which addition of simple Na-salts influence the formation of mesoscopically ordered silicas synthesized using nonionic surfactants as structure directors, hence advancing the knowledge base toward a more rational design of mesoporous materials. PMID- 21548623 TI - Responsive organometallic polymer grafts: electrochemical switching of surface properties and current mediation behavior. AB - Quantitative adherence and friction measurements between atomic force microscopy (AFM) tips and reversibly oxidized and reduced poly(ferrocenyl dimethylsilane) (PFDMS) molecular layers grafted to Au are reported. Poly(ferrocenylsilanes) (PFSs) such as PFDMS owe their redox responsiveness to the presence of ferrocene units, bridged by substituted silicon units, in the main chain. Polymers were obtained by anionic polymerization, which allowed us to copolymerize sulfur containing end groups that facilitated grafting to Au surfaces. Electrochemical atomic force microscopy (ECAFM) was used to study adherence and friction as a function of the oxidation state of the polymer. Measurements of interfacial friction as a function of applied load on the nanoscale using Si(3)N(4) AFM tips revealed a reversible increase of the friction coefficient and adherence strength of the PFDMS layers with increasing oxidation state in NaClO(4) electrolytes. The variation of the electrolyte salts (NaClO(4) or NaNO(3)) allowed an assessment of surface counterion adsorption effects. Issues related to the interpretation of observed friction and adherence changes such as electrolyte anion-ferrocenium ion pair effects, and electrostatic forces due to tip surface charges are discussed. Unidirectional current flow was detected in cyclic voltammograms of the PFDMS layers in NaClO(4). This electrode rectification behavior could in principle be utilized for applications in thin film devices based on PFS films. PMID- 21548624 TI - Luminescent charge-transfer complexes: tuning emission in binary fluorophore mixtures. AB - Charge-transfer (CT) complexes composed of a pi-electron-poor naphthalene diimide (NDI) derivative combined with a series of pi-electron-rich donors were investigated. Solutions of the CT complexes are nonemissive; however, solid-state complexes and aqueous suspensions display emission that is dependent on the energy of the HOMO of the electron donor. Crystallographic analysis of a pyrene NDI complex reveals columnar packing and a high degree of frontier molecular orbital (FMO) overlap that likely contributes to the observed optical properties. The fluorescent CT particles are utilized as imaging agents; additional luminescent CT complexes may be realized by considering FMO energies and topologies. PMID- 21548625 TI - Noncovalent antibody immobilization on porous silicon combined with miniaturized solid-phase extraction (SPE) for array based immunoMALDI assays. AB - This paper presents a new strategy to combine the power of antibody based capturing of target species in complex samples with the benefits of microfluidic reverse phase sample preparation on an integrated sample enrichment target (RP ISET) and the analysis speed of MALDI MS. The immunoaffinity step is performed on an in-house developed 3D-structured high surface area porous silicon (PSi) matrix, which allows efficient antibody immobilization by surface adsorption without any coupling agents in 30-60 min. The hydrophilic nature of the porous silicon surface at the molecular level displays a low adsorption of background peptides when exposed to complex digests or plasma samples, improving the conditions for the antigen specific extraction and subsequent readout. At the same time, the hydrophobic behavior, due to the nanostructured surface, of the PSi material facilitates liquid confinement during the assay. Using a footprint conforming to the standard for 384 well microplates, direct adaption of the protocol into standard sample handling robots is possible. The performance of the proposed immunoaffinity PSi-ISET immunoMALDI (iMALDI) assay was evaluated by specific detection of angiotensin I at a 10 femtomol level in diluted plasma samples (10 MUL, 1 nM). PMID- 21548626 TI - Nonadiabatic dynamics of uracil: population split among different decay mechanisms. AB - Nonadiabatic dynamics simulations performed at the state-averaged CASSCF method are reported for uracil. Supporting calculations on stationary points and minima on the crossing seams have been performed at the MR-CISD and CASPT2 levels. The dominant mechanism is characterized by relaxation into the S(2) minimum of pipi* character followed by the relaxation to the S(1) minimum of npi* character. This mechanism contributes to the slower relaxation with a decay constant larger than 1.5 ps, in good agreement with the long time constants experimentally observed. A minor fraction of trajectories decay to the ground state with a time constant of about 0.7 ps, which should be compared to the experimentally observed short constant. The major part of trajectories decaying with this time constant follows the pipi* channel and hops to the ground state via an ethylenic conical intersection. A contribution of the relaxation proceeding via a ring-opening conical intersection was also observed. The existence of these two latter channels together with a reduced long time constant is responsible for a significantly shorter lifetime of uracil compared to that of thymine. PMID- 21548627 TI - Molecular simulation study of water mobility in aerosol-OT reverse micelles. AB - In this work, we present results from molecular dynamics simulations on the single-molecule relaxation of water within reverse micelles (RMs) of different sizes formed by the surfactant aerosol-OT (AOT, sodium bis(2 ethylhexyl)sulfosuccinate) in isooctane. Results are presented for RM water content w(0) = [H(2)O]/[AOT] in the range from 2.0 to 7.5. We show that translational diffusion of water within the RM can, to a good approximation, be decoupled from the translation of the RM through the isooctane solvent. Water translational mobility within the RM is restricted by the water pool dimensions, and thus, the water mean-squared displacements (MSDs) level off in time. Comparison with models of diffusion in confined geometries shows that a version of the Gaussian confinement model with a biexponential decay of correlations provides a good fit to the MSDs, while a model of free diffusion within a sphere agrees less well with simulation results. We find that the local diffusivity is considerably reduced in the interfacial region, especially as w(0) decreases. Molecular orientational relaxation is monitored by examining the behavior of OH and dipole vectors. For both vectors, orientational relaxation slows down close to the interface and as w(0) decreases. For the OH vector, reorientation is strongly affected by the presence of charged species at the RM interface and these effects are especially pronounced for water molecules hydrogen-bonded to surfactant sites that serve as hydrogen-bond acceptors. For the dipole vector, orientational relaxation near the interface slows down more than that for the OH vector due mainly to the influence of ion-dipole interactions with the sodium counterions. We investigate water OH and dipole reorientation mechanisms by studying the w(0) and interfacial shell dependence of orientational time correlations for different Legendre polynomial orders. PMID- 21548628 TI - Development of a terbium complex-based luminescent probe for imaging endogenous hydrogen peroxide generation in plant tissues. AB - A highly sensitive Tb(3+) complex-based luminescent probe, N,N,N(1),N(1)-[2,6-(3' aminomethyl-1'-pyrazolyl)-4-(3'',4''-diaminophenoxy)methylene-pyridine] tetrakis(acetate)-Tb(3+) (BMTA-Tb(3+)), has been designed and synthesized for the recognition and detection of hydrogen peroxide (H(2)O(2)) in aqueous solutions. This probe is almost nonluminescent because the Tb(3+) luminescence is effectively quenched by the electron-rich moiety, diaminophenyl, on the basis of the photoinduced electron transfer (PET) mechanism. In the presence of peroxidase, the probe can react with H(2)O(2) to cause the cleavage of the diaminophenyl ether, which affords a highly luminescent Tb(3+) complex, N,N,N(1),N(1)-[2,6-bis(3'-aminomethyl-1'-pyrazolyl)-4-hydroxymethyl-pyridine] tetrakis(acetate)-Tb(3+) (BHTA-Tb(3+)), accompanied by a 39-fold increase in luminescence quantum yield with the increase of luminescence lifetime from 1.95 to 2.76 ms. The dose-dependent luminescence enhancement of the probe shows a good linearity with a detection limit of 3.7 nM for H(2)O(2), which is approximately 14-fold lower than those of the commonly used fluorescent probes. The probe was used for the time-resolved luminescence imaging detection of the oligosaccharide induced H(2)O(2) generation in tobacco leaf epidermal tissues. On the basis of the probe, a background-free time-resolved luminescence imaging method for detecting H(2)O(2) in complicated biological systems was successfully established. PMID- 21548629 TI - Comparative changes in color features and pigment composition of red wines aged in oak and cherry wood casks. AB - The color features and the evolution of both the monomeric and the derived pigments of red wines aged in oak and cherry 225 L barriques have been investigated during a four months period. For cherry wood, the utilization of 1000 L casks was tested as well. The use of cherry casks resulted in a faster evolution of pigments with a rapid decline of monomeric anthocyanins and a quick augmentation formation of derived and polymeric compounds. At the end of the aging, wines stored in oak and cherry barriques lost, respectively, about 20% and 80% of the initial pigment amount, while in the 1000 L cherry casks, the same compounds diminished by about 60%. Ethyl-bridged adducts and vitisins were the main class of derivatives formed, representing up to 25% of the total pigment amount in the cherry aged samples. Color density augmented in both the oak and cherry wood aged samples, but the latter had the highest values of this parameter. Because of the highly oxidative behavior of the cherry barriques, the use of larger casks (e.g., 1000 L) is proposed in the case of prolonged aging times. PMID- 21548630 TI - Anthocyanin accumulation and expression of anthocyanin biosynthetic genes in radish (Raphanus sativus). AB - Radish [Raphanus sativus (Rs)] is an important dietary vegetable in Asian countries, especially China, Japan, and Korea. To elucidate the molecular mechanisms of anthocyanin accumulation in radish, the gene expression of enzymes directly involved in anthocyanin biosynthesis was analyzed. These genes include phenylalanine ammonia lyase (PAL), cinnamate 4-hydroxylase (C4H), 4-coumarate-CoA ligase (4CL), chalcone synthase (CHS), chalcone isomerase (CHI), flavanone 3 hydroxylase (F3H), dihydroflavonol reductase (DFR), and anthocyanidin synthase (ANS). RsDFR and RsANS were found to accumulate in the flesh or skin of two radish cultivars (Man Tang Hong and Hong Feng No.1). Radish skin contained higher CHS, CHI, and F3H transcript levels than radish flesh in all three cultivars. In the red radish, 16 anthocyanins were separated and identified by high-performance liquid chromatography (HPLC) and elctrospray ionization-tandem mass spectrometry (ESI-MS/MS). Some of them were acylated with coumaroyl, malonoyl, feruoyl, and caffeoyl moieties. Furthermore (-)-epicatechin and ferulic acid were also identified in the three cultivars. PMID- 21548631 TI - Characteristic phenolic composition of single-cultivar red wines of the Canary Islands (Spain). AB - The detailed phenolic composition of five single-cultivar (Baboso Negro, Listan Negro, Negramoll, Tintilla, and Vijariego Negro) young and aged (vintages 2005 2009) red wines of the Canary Islands has been determined by HPLC-DAD-ESI-MS(n). Despite the total monomeric anthocyanin content decreasing for older wines in each set of single-cultivar wines, the corresponding anthocyanin profiles remained almost unchanged. Although all wine anthocyanin profiles were dominated by malvidin 3-glucoside, their differentiation by grape cultivar was possible, with the exception of Listan Negro. In contrast, the total content of non anthocyanin phenolics did not appreciably change within vintages but polymerization, hydrolysis, and isomerization reactions greatly modified the phenolic profiles. Aglycone-type flavonol profiles offered the best results for differentiation of the wines according to grape cultivar (Listan Negro and Negramoll; Baboso Negro and Vijariego Negro; and Tintilla). Within flavan-3-ols, the B-ring trihydroxylated monomers ((-)-epigallocatechin and (-)-gallocatechin) and also (-)-epicatechin provided additional cultivar differentiation. Hydroxycinnamic acid derivatives and stilbene profiles were very heterogeneous with regard to both grape cultivar and vintage and did not significantly contribute to wine differentiation, even when structure-type profiles were obtained, with the exception of Tintilla, which always appeared as the most different single-cultivar wines. Finally, most Canary Islands wines showed characteristic high contents of stilbenes, especially trans-resveratrol. PMID- 21548632 TI - Interfacial reactivity of Au, Pd, and Pt on BiI3 (001): implications for electrode selection. AB - Understanding the contact-semiconductor interface is important in determining the performance of a semiconductor device. This study investigated the contact chemistry of BiI(3) single crystal with Au, Pd, and Pt electrodes using X-ray photoelectron spectroscopy (XPS), a technique widely used to probe the interfacial chemistry of many materials. Chemical reactions were identified on the BiI(3) surface for the case of Pd and Pt contacts, while Au showed no reactivity with BiI(3). The difference in reactivities correlated with different surface morphologies of the contact on the BiI(3) surface, which was evidenced by atomic force microscopy (AFM) characterization. The dark resistivity of the BiI(3) crystal with above contact materials was measured by I-V characterization. The highest resistivity was obtained when Au was employed as the contact. These results suggest that Au is better than Pd and Pt as the contact material for BiI(3) single crystal. PMID- 21548633 TI - Mild and efficient functionalization of hydrogen-terminated Si(111) via sonochemical activated hydrosilylation. AB - Efficient chemical functionalization of hydrogen-terminated Si(111) with simple and bifunctional 1-alkenes was achieved via novel sonochemical activated hydrosilylation, utilizing just a simple ultrasonic bath. It is an extremely mild method that allows the specific attachment of unprotected bifunctional alkenes such as undecenol, undecylenic acid, and even a heat/UV-sensitive alkene, bearing an activated leaving group (N-succinimidyl undecylenate), without suffering any degradation. PMID- 21548635 TI - ADME evaluation in drug discovery. 9. Prediction of oral bioavailability in humans based on molecular properties and structural fingerprints. AB - Oral bioavailability is an essential parameter in drug screening cascades and a good indicator of the capability of the delivery of a given compound to the systemic circulation by oral administration. In the present work, we report a database of oral bioavailability of 1014 molecules determined in humans. A systematic examination of the relationships between various physicochemical properties and oral bioavailability were carried out to investigate the influence of these properties on oral bioavailability. A number of property-based rules for bioavailability classification were generated and evaluated. We found that no rule was an effective predictor for oral bioavailability because these simple rules cannot characterize the influence of important metabolic processes on bioavailability. Finally, the genetic function approximation (GFA) technique was employed to construct the multiple linear regression models for oral bioavailability using structural fingerprints as the basic parameters, together with several important molecular properties. The best model is able to predict human oral bioavailability with an r of 0.79, a q of 0.72, and a RMSE (root-mean square error) of 22.30% of the compounds from the training set. The analysis of the descriptors chosen by GFA shows that the important structural fingerprints are primarily related to important intestinal absorption and well-known metabolic processes. The predictive power of the models was further evaluated using a separate test set of 80 compounds, and the consensus model can predict the oral bioavailability with r(test) = 0.71 and RMSE = 23.55% for the tested compounds. Since the necessary molecular properties and structural fingerprints can be calculated easily and quickly, the models we proposed here may help speed up the process of finding or designing compounds with improved oral bioavailability. PMID- 21548634 TI - Apple peel polyphenols protect against gastrointestinal mucosa alterations induced by indomethacin in rats. AB - The stability of an apple peel polyphenol extract (APPE) with powerful antioxidant activity was evaluated under acidic conditions in vitro, and its protective effect against gastrointestinal damage was investigated in rats treated with indomethacin. The antioxidant activity of APPE remained stable at pH 2.0 for 4 h. In rats treated with indomethacin (40 mg/kg ig), the previous administration of APPE protected the gastric, intestinal, and colonic mucosa from oxidative stress by preventing increased malondialdehyde concentrations and decreasing the GSH/GSSG ratio. APPE also displayed anti-inflammatory effects by preventing neutrophil infiltration in the mucosa, as evidenced by the lower myeloperoxidase activity. These protective effects of APPE resulted in the prevention of macro- and microscopic damage and of barrier dysfunction along the gastrointestinal tract of the indomethacin-treated animals. This study supports the concept that apple peel polyphenols may be useful in the prevention and/or treatment of nonsteroidal anti-inflammatory drug-associated side effects. PMID- 21548636 TI - Unintended water mediated cocrystal formation in carbamazepine and aspirin tablets. AB - The water of crystallization released during dehydration of dibasic calcium phosphate dihydrate (DCPD) mediated the cocrystal formation between carbamazepine (CBZ) and nicotinamide (NMA) in intact tablets. The dehydration of DCPD, the disappearance of the reactants (CBZ and NMA) and the appearance of the product (CBZ-NMA cocrystal) were simultaneously monitored by quantitative powder X-ray diffractometry. In a second model system, the water of crystallization released by the dehydration of DCPD caused the chemical decomposition of aspirin. Salicylic acid, one of the decomposition products, reacted with CBZ to form CBZ salicylic acid cocrystal in tablets. This is the first report of cocrystal formation in intact tablets, demonstrating water mediated noncovalent synthesis in a multicomponent matrix. While the potential implications of such transformations, on both the mechanical and biopharmaceutical properties, can be profound, their characterization, using conventional solution based analytical techniques, can be challenging. PMID- 21548637 TI - Organocatalytic asymmetric halogenation/semipinacol rearrangement: highly efficient synthesis of chiral alpha-oxa-quaternary beta-haloketones. AB - A novel asymmetric halogenation/semipinacol rearrangement reaction catalyzed by cinchona alkaloid derivatives was developed. Two types of beta-haloketones (X = Br, Cl) were obtained with up to 95% yield and 99% enantiomeric excess. The desired (+) and (-) enantiomers of the beta-haloketones were readily obtained. PMID- 21548638 TI - Fast and slow components in the crystallization of a model multicomponent system, NaKCa(NO3): the role of composition fluctuations. AB - We use calorimetrically detected crystal nucleation and growth studies to broaden the discussion of fluctuation-induced nucleation processes to include composition fluctuations in ionic complex-forming systems. We use the model system Ca(NO(3))(2)-KNO(3) with NaNO(3) introduced as a third component, so that crystallization kinetics can be controlled by change of alkali cation at constant mole fraction of Ca(NO(3))(2). At fixed NaNO(3) content, we find separate and thermodynamically anomalous kinetics for the crystallization of NaNO(3) and Ca(NO(3))(2),which we attribute to the importance of slow concentration fluctuations in the latter case. The "nose" of the time-temperature transformation TTT curve for crystallization of the Ca(NO(3))(2) occurs at much higher temperatures and longer times than that for NaNO(3) and the shape of the curve is different. Above the metastable liquidus surface of NaNO(3), supercooled ternary melts can persist for long times. Suppression of the fast NaNO(3) crystallization, by replacement of Na(+) by K(+), is a prerequisite for easy vitrification in this system. PMID- 21548640 TI - Vibrational characteristics of outer-sphere surface complexes: example of sulfate ions adsorbed onto metal (hydr)oxides. AB - The vibrational characteristics of outer-sphere complexes of sulfate at several mineral oxide-water interfaces were investigated by in situ attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy. In the IR spectra obtained from surface outer-sphere complexes, only one peak of the asymmetric stretching vibrational mode upsilon(3) similar to that of free sulfate ion SO(4)(2-) in aqueous solution is observed. However, on the investigated (hydr)oxide surfaces of Al(3+), Ti(4+), Fe(2+/3+), Cr(3+), Ce(4+), Cu(2+), Y(3+), Zn(2+), and Nd(3+), a shift of up to 14 cm(-1) was found, which was correlated to the polarizing power of the metal cations. A high polarizing power was found to result in a stronger shift of upsilon(3) compared to that of the aqueous SO(4)(2 ) ion. Furthermore, the impact of the metal oxide structure on the characteristics of the formed outer-sphere complex was negligible because different Al and Fe (hydr)oxides did not show any changes in the respective IR spectra. Finally, the ionic strength (1-10(-4) M) and pH (6.8-3.1) have been modified to change the surface potential, showing no direct influence on the spectra (i.e., on the geometry of the outer-sphere complex). PMID- 21548642 TI - Cyclopropenium cation promoted dehydrative glycosylations using 2-deoxy- and 2,6 dideoxy-sugar donors. AB - Dehydrative glycosylation reactions using 2-deoxy- and 2,6-dideoxy-sugar donors promoted by a combination of 3,3-dichloro-1,2-diphenylcyclopropene and tetrabutylammonium iodide (TBAI) are described. The reactions are alpha-selective and proceed under mild conditions at room temperature without the need for special dehydrating agents. The reaction is shown to be effective with a number of glycosyl acceptors, including those possessing acid and base sensitive functionality. PMID- 21548641 TI - Identification and characterization of 2'-deoxyadenosine adducts formed by isoprene monoepoxides in vitro. AB - Isoprene, the 2-methyl analogue of 1,3-butadiene, is ubiquitous in the environment, with major contributions to total isoprene emissions stemming from natural processes despite the compound being a bulk industrial chemical. Additionally, isoprene is a combustion product and a major component in cigarette smoke. Isoprene has been classified as possibly carcinogenic to humans (group 2B) by IARC and as reasonably anticipated to be a human carcinogen by the National Toxicology Program. Isoprene, like butadiene, requires metabolic activation to reactive epoxides to exhibit its carcinogenic properties. The mode of action has been postulated to be that of a genotoxic carcinogen, with the formation of promutagenic DNA adducts being essential for mutagenesis and carcinogenesis. In rodents, isoprene-induced tumors show unique point mutations (A->T transversions) in the K-ras protooncogene at codon 61. Therefore, we investigated adducts formed after the reaction of 2'-deoxyadenosine (dAdo ) with the two monoepoxides of isoprene, 2-ethenyl-2-methyloxirane (IP-1,2-O) and propen-2-yloxirane (IP-3,4-O), under physiological conditions. The formation of N1-2'-deoxyinosine (N1-dIno) due to the deamination of N1-dAdo adducts was of particular interest, since N1-dIno adducts are suspected to have high mutagenic potential based on in vitro experiments. Major stable adducts were identified by HPLC, UV-spectroscopy, and LC-MS/MS and characterized by (1)H NMR and (1)H,(13)C HSQC and HMBC NMR experiments. Adducts of IP-1,2-O that were fully identified are R,S-C1-N(6)-dAdo, R-C2-N(6)-dAdo, and S-C2-N(6)-dAdo; adducts of IP-3,4-O are S-C3-N(6)-dAdo, R-C3 N(6)-dAdo, R,S-C4-N(6)-dAdo, S-C4-N1-dIno, R-C4-N1-dIno, R-C3-N1-dIno, S-C3-N1 dIno, and C3-N7-Ade. Both monoepoxides formed adducts on the terminal and internal oxirane carbons. This is the first study to describe adducts of isoprene monoepoxides with dAdo. Characterization of adducts formed by isoprene monoepoxides with deoxynucleosides and subsequently with DNA represent the first step toward evaluating their potential for being converted into a mutation or as biomarkers of isoprene metabolism and exposure. PMID- 21548643 TI - A simple copper-catalyzed synthesis of tertiary acyclic amides. AB - The N-arylation of aromatic and aliphatic secondary acyclic amides, known to be poor nucleophiles, has been accomplished using a simple and cheap copper catalytic system. The corresponding tertiary acyclic amides, which can be found in numerous biologically active compounds, have been obtained in good to excellent yields. PMID- 21548644 TI - Asymmetric total synthesis of (-)-scabronine G via intramolecular double Michael reaction and Prins cyclization. AB - The enantioselective total synthesis of (-)-scabronine G is described. The key features of the present synthesis include the construction of a 5-6 ring system containing two quaternary carbon centers via a diastereoselective intramolecular double Michael reaction and the formation of a seven-membered ring using a Prins cyclization. PMID- 21548645 TI - Cell-permeable iminocoumarine-based fluorescent dyes for mitochondria. AB - A class of small molecule fluorophores, 2-iminocoumarin-3-carboxamide derivatives, has been developed by a rapid microwave-assisted process. These fluorescent probes are cell membrane permeable with low cytotoxicity and able to selectively stain organelles in living cells. PMID- 21548646 TI - Calcium binding and transport by coenzyme Q. AB - Coenzyme Q10 (CoQ10) is one of the essential components of the mitochondrial electron-transport chain (ETC) with the primary function to transfer electrons along and protons across the inner mitochondrial membrane (IMM). The concomitant proton gradient across the IMM is essential for the process of oxidative phosphorylation and consequently ATP production. Cytochrome P450 (CYP450) monoxygenase enzymes are known to induce structural changes in a variety of compounds and are expressed in the IMM. However, it is unknown if CYP450 interacts with CoQ10 and how such an interaction would affect mitochondrial function. Using voltammetry, UV-vis spectrometry, electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), fluorescence microscopy and high performance liquid chromatography-mass spectrometry (HPLC-MS), we show that both CoQ10 and its analogue CoQ1, when exposed to CYP450 or alkaline media, undergo structural changes through a complex reaction pathway and form quinone structures with distinct properties. Hereby, one or both methoxy groups at positions 2 and 3 on the quinone ring are replaced by hydroxyl groups in a time-dependent manner. In comparison with the native forms, the electrochemically reduced forms of the new hydroxylated CoQs have higher antioxidative potential and are also now able to bind and transport Ca(2+) across artificial biomimetic membranes. Our results open new perspectives on the physiological importance of CoQ10 and its analogues, not only as electron and proton transporters, but also as potential regulators of mitochondrial Ca(2+) and redox homeostasis. PMID- 21548647 TI - Gd2@C79N: isolation, characterization, and monoadduct formation of a very stable heterofullerene with a magnetic spin state of S = 15/2. AB - The dimetallic endohedral heterofullerene (EHF), Gd(2)@C(79)N, was prepared and isolated in a relatively high yield when compared with the earlier reported heterofullerene, Y(2)@C(79)N. Computational (DFT), chemical reactivity, Raman, and electrochemical studies all suggest that the purified Gd(2)@C(79)N, with the heterofullerene cage, (C(79)N)(5-) has comparable stability with other better known isoelectronic metallofullerene (C(80))(6-) cage species (e.g., Gd(3)N@C(80)). These results describe an exceptionally stable paramagnetic molecule with low chemical reactivity with the unpaired electron spin density localized on the internal diatomic gadolinium cluster and not on the heterofullerene cage. EPR studies confirm that the spin state of Gd(2)@C(79)N is characterized by a half-integer spin quantum number of S = 15/2. The spin (S = 1/2) on the N atom of the fullerene cage and two octet spins (S = 7/2) of two encapsulated gadoliniums are coupled with each other in a ferromagnetic manner with a small zero-field splitting parameter D. Because the central line of Gd(2)@C(79)N is due to the Kramer's doublet with a half-integer spin quantum number of S = 15/2, this relatively sharp line is prominent and the anisotropic nature of the line is weak. Interestingly, in contrast with most Gd(3+) ion environments, the central EPR line (g = 1.978) is observable even at room temperature in a toluene solution. Finally, we report the first EHF derivative, a diethyl bromomalonate monoadduct of Gd(2)@C(79)N, which was prepared and isolated via a modified Bingel-Hirsch reaction. PMID- 21548648 TI - A new and facile method to prepare uniform hollow MnO/functionalized mSiO2 core/shell nanocomposites. AB - Trifunctional uniform nanoparticles comprising a manganese nanocrystal core and a functionalized mesoporous silica shell (MnO@mSiO(2)(Ir)@PEG, where Ir is an emissive iridium complex and PEG is polyethylene glycol) have been strategically designed and synthesized. The T(1) signal can be optimized by forming hollow core (H-MnO@mSiO(2)(Ir)@PEG) via a novel and facile etching process, for which the mechanism has been discussed in detail. Systematic investigation on correlation for longitudinal relaxation (T(1)) versus core shapes and shell silica porosity of the nanocomposites (MnO, H-MnO, MnO@SiO(2), MnO@mSiO(2), H-MnO@mSiO(2)) has been carried out. The results show that the worm-like nanochannels in the mesoporous silica shell not only increase water permeability to the interior hollow manganese oxide core for T(1) signal but also enhance photodynamic therapy (PDT) efficacy by enabling the free diffusion of oxygen. Notably, the H MnO@mSiO(2)(Ir)@PEG nanocomposite with promising r(1) relaxivity demonstrates its versatility, in which the magnetic core provides the capability for magnetic resonance imaging, while the simultaneous red phosphorescence and singlet oxygen generation from the Ir complex are capable of providing optical imaging and inducing apoptosis, respectively. PMID- 21548650 TI - Identification of the medicinal off-flavor compound formed from ascorbic acid and (E)-hex-2-enal. AB - A test apple beverage made up of apple juice (20%), high-fructose corn syrup (11.5%), citric acid (0.43%), trisodium citrate (0.02%), apple-odor flavor (0.1%), and ascorbic acid (0.02%) was stored at 40 degrees C and then analyzed for the change of odor in the beverage. Although no thermoacidophilic bacteria (TAB) were detected, a medicinal off-flavor was perceived after the 8 weeks of storage. Model experiments on the ingredients of the test apple beverage revealed that the off-flavor compound had been formed by ascorbic acid and (E)-hex-2-enal. Synthesis and NMR (1H, 13C, HMQC, and HMBC) analyses identified the compound as 6 propylbenzofuran-7-ol. The odor quality, retention index (RI), and mass spectrum of synthetic 6-propylbenzofuran-7-ol were identical with those of the medicinal odor compound from the test apple beverage. Sensory evaluation revealed the recognition thresholds for medicinal odor were 31.4 ppb in water and 24.0 ppb in apple beverage, and the detection thresholds were 19.6 ppb in water and 8.6 ppb in apple beverage, respectively. The quantified concentration of 6 propylbenzofuran-7-ol formed in test apple beverage was 90 ppb, approximately. This concentration was well above the odor threshold, so it was concluded that the compound was the source of the medicinal off-flavor. PMID- 21548649 TI - Asymmetric Rh(II)-catalyzed cyclopropanation of alkenes with diacceptor diazo compounds: p-methoxyphenyl ketone as a general stereoselectivity controlling group. AB - Different diacceptor diazo compounds bearing an alpha-PMP-ketone group were found to be effective carbene precursors for the highly stereoselective Rh(2)(S TCPTTL)(4)-catalyzed cyclopropanation of alkenes (EWG = NO(2), CN, CO(2)Me). The resulting products were readily transformed into a variety of biologically relevant enantiopure molecules, such as cyclopropane alpha- and beta-amino acid derivatives. Different mechanistic studies carried out led to a rationale for the high diastereo- and enantioselectivity obtained, where the PMP-ketone moiety was found to play a critical role in the stereoinduction process. Additionally, the use of catalytic amounts of achiral Lewis bases to influence the enantioinduction of the reactions developed is documented. PMID- 21548651 TI - Phenolic composition and antioxidant activity in seed coats of 60 Chinese black soybean (Glycine max L. Merr.) varieties. AB - Phenolics in black soybean seed coat (BSSC) are considered to be responsible for the health benefits of black soybean. BSSCs of 60 Chinese varieties were examined for phenolic contents, anthocyanin profiles, and antioxidant activity. Total phenolic and condensed tannin contents ranged from 512.2 to 6057.9 mg gallic acid equivalents/100 g and from 137.2 to 1741.1 mg (+)-catechin equivalents/100 g, respectively. Six anthocyanins (delphinidin-3-glucoside, cyanidin-3-galactoside, cyanidin-3-glucoside, petunidin-3-glucoside, peonidin-3-glucoside, and malvidin-3 glucoside) were detected by HPLC. Total anthocyanin contents (TAC) were from 98.8 to 2132.5 mg/100 g, and cyanidin-3-glucoside was the most abundant anthocyanin in all varieties, with a distribution of 48.8-94.1% of TAC. Antioxidant properties detected by DPPH, FRAP, and ORAC methods all showed wide variations ranging from 4.8 to 65.3 MUg/100 mL (expressed as EC(50)), from 17.5 to 105.8 units/g, and from 42.5 to 1834.6 MUmol Trolox equivalent/g, respectively. Sixty varieties were classified into four groups by hierarchical clustering analysis, and group 4 consisting of nine varieties had the highest phytochemicals content and antioxidant activity. PMID- 21548652 TI - Differential recovery of lupin proteins from the gluten matrix in lupin-wheat bread as revealed by mass spectrometry and two-dimensional electrophoresis. AB - Bread made from a mixture of wheat and lupin flour possesses a number of health benefits. The addition of lupin flour to wheat flour during breadmaking has major effects on bread properties. The present study investigated the lupin and wheat flour protein interactions during the breadmaking process including dough formation and baking by using proteomics research technologies including MS/MS to identify the proteins. Results revealed that qualitatively most proteins from both lupin and wheat flour remained unchanged after baking as per electrophoretic behavior, whereas some were incorporated into the bread gluten matrix and became unextractable. Most of the lupin alpha-conglutins could be readily extracted from the lupin-wheat bread even at low salt and nonreducing/nondenaturing extraction conditions. In contrast, most of the beta-conglutins lost extractability, suggesting that they were trapped in the bread gluten matrix. The higher thermal stability of alpha-conglutins compared to beta-conglutins is speculated to account for this difference. PMID- 21548653 TI - Structure of human telomeric DNA in crowded solution. AB - G-quadruplex structures formed by DNA at the human telomeres are attractive anticancer targets. Human telomeric sequences can adopt a diverse range of intramolecular G-quadruplex conformations: a parallel-stranded conformation was observed in the crystalline state, while at least four other forms were seen in K(+) solution, raising the question of which conformation is favored in crowded cellular environment. Here, we report the first NMR structure of a human telomeric G-quadruplex in crowded solution. We show that four different G quadruplex conformations are converted to a propeller-type parallel-stranded G quadruplex in K(+)-containing crowded solution due to water depletion. This study also reveals the formation of a new higher-order G-quadruplex structure under molecular crowding conditions. Our molecular dynamics simulations of solvent distribution provide insights at molecular level on the formation of parallel stranded G-quadruplex in environment depleted of water. These results regarding human telomeric DNA can be extended to oncogenic promoters and other genomic G rich sequences. PMID- 21548655 TI - Molecular mechanism-based network-like similarity graphs reveal relationships between different types of receptor ligands and structural changes that determine agonistic, inverse-agonistic, and antagonistic effects. AB - Receptor ligands might act as agonists, partial agonists, inverse agonists, or antagonists and it is often difficult to understand structural modifications that alter the mechanism of action. In order to compare ligands that are active against a given receptor but have different mechanisms of action, we have designed molecular networks that mirror similarity relationships and incorporate both mechanism of action information and mechanism-specific SAR features. These network representations make it possible to systematically evaluate relationships between different types of receptor ligands and identify communities of structurally very similar ligands with different mechanisms. From a series of such ligands, structural modifications can often be deduced that lead to "mechanism hops". PMID- 21548654 TI - Superacid-promoted additions involving vinyl-substituted pyrimidines, quinoxalines, and quinazolines: mechanisms correlated to charge distributions. AB - The superacid-promoted reactions of vinyl-substituted N-heterocycles have been studied. Diprotonated pyrimidines, quinoxalines, and quinazolines exhibit an unusual regioelectronic effect that controls the type of addition reaction observed. Depending on the ring position of the vinyl substituent, either conjugate addition or Markovnikov addition occurs. The mode of addition has been shown to correlate well to NBO calculated charges. PMID- 21548656 TI - Investigation of the discoloration of smalt pigment in historic paintings by micro-X-ray absorption spectroscopy at the Co K-edge. AB - Smalt was commonly used as a pigment by artists between the 16th and 18th centuries. It is a powdered blue potash glass colored by cobalt ions and often degrades causing dramatic changes in the appearance of paintings. The aim of the work presented in this paper was to investigate the changes in the structure and environment around the cobalt ion on deterioration, to further our understanding of the basis of the loss of color. Particles of well-preserved and altered smalt in microsamples from paintings in the National Gallery, London, and the Louvre, Paris, were analyzed using synchrotron micro-X-ray absorption spectroscopy at the Co K-edge. X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine structure (EXAFS) measurements showed that in intense blue particles the cobalt is predominantly present as Co(2+) in tetrahedral coordination, whereas in colorless altered smalt the Co(2+) coordination number in the glass structure is increased and there is a shift from tetrahedral toward octahedral coordination. The extent of this shift correlates clearly with the alkali content, indicating that it is caused by leaching of potassium cations, which act as charge compensators and stabilize the tetrahedral coordination of the cobalt ions that is responsible for the blue color. PMID- 21548657 TI - Photochemistry of 2-naphthoyl azide. An ultrafast time-resolved UV-vis and IR spectroscopic and computational study. AB - The photochemistry of 2-naphthoyl azide was studied in various solvents by femtosecond time-resolved transient absorption spectroscopy with IR and UV-vis detection. The experimental findings were interpreted with the aid of computational studies. Using polar and nonpolar solvents, the formation and decay of the first singlet excited state (S(1)) was observed by both time-resolved techniques. Three processes are involved in the decay of the S(1) excited state of 2-naphthoyl azide: intersystem crossing, singlet nitrene formation, and isocyanate formation. The lifetime of the S(1) state decreases significantly as the solvent polarity increases. In all solvents studied, isocyanate formation correlates with the decay of the azide S(1) state. Nitrene formation correlates with the decay of the relaxed S(1) state only upon 350 nm excitation (S(0) -> S(1) excitation). When S(n) (n >= 2) states are populated upon excitation (lambda(ex) = 270 nm), most nitrene formation takes place within a few picoseconds through the hot S(1) and higher singlet excited states (S(n)) of 2 naphthoyl azide. The data correlate with the results of electron density difference calculations that predict nitrene formation from the higher-energy singlet excited states, in addition to the S(1) state. For all of these experiments, no recovery of the ground state was observed up to 3 ns after photolysis, which indicates that both internal conversion and fluorescence have very low efficiencies. PMID- 21548659 TI - Pediatric psychocutaneous disorders: a review of primary psychiatric disorders with dermatologic manifestations. AB - Psychocutaneous disorders (PCDs) are conditions that are characterized by psychiatric and skin manifestations. Classifications of PCDs and their nomenclature are matters of debate. For the purpose of this review, we adopted the classification that distinguishes primary dermatologic disorders with psychiatric co-morbidity (PDDPC) from primary psychiatric disorders with dermatologic manifestations (PPDDM). PDDPC includes the psychophysiologic disorders such as atopic eczema, psoriasis, vitiligo, and alopecia areata. PPDDM includes impulse control disorders, obsessive-compulsive disorders, factitious disorder, factitious disorder by proxy, self-mutilation, delusions of parasitosis, psychogenic purpura/Gardner-Diamond syndrome, and cutaneous sensory disorders. Diagnosis and treatment of PCDs are challenging and require that the underlying psychopathology be addressed. A specific PCD may have different underlying psychopathologies and, at times, multiple overlapping psychopathologies may coexist. Most often, both non-pharmacologic management and psychopharmacologic treatment are necessary. The choice of psychopharmacologic agent depends on the nature of the underlying psychopathology (e.g. anxiety, depression, obsessive-compulsive disorder, psychosis). This article reviews the spectrum of PPDDM in children. PMID- 21548658 TI - TPGS-750-M: a second-generation amphiphile for metal-catalyzed cross-couplings in water at room temperature. AB - An environmentally benign surfactant (TPGS-750-M), a diester composed of racemic alpha-tocopherol, MPEG-750, and succinic acid, has been designed and readily prepared as an effective nanomicelle-forming species for general use in metal catalyzed cross-coupling reactions in water. Several "name" reactions, including Heck, Suzuki-Miyaura, Sonogashira, and Negishi-like couplings, have been studied using this technology, as have aminations, C-H activations, and olefin metathesis reactions. Physical data in the form of DLS and cryo-TEM measurements suggest that particle size and shape are key elements in achieving high levels of conversion and, hence, good isolated yields of products. This new amphiphile will soon be commercially available. PMID- 21548661 TI - Communication: The electrostatic polarization is essential to differentiate the helical propensity in polyalanine mutants. AB - The folding processes of three polyalanine peptides with composition of Ac (AAXAA)(2)-GY-NH(2) (where X is chosen to be Q, K, and D) are studied by molecular dynamics simulation in solvent of 40% trifluoroethanol using both polarized and unpolarized force fields. The simulations reveal the critical role of polarization effect for quantitative description of helix formation. When polarized force field is used, peptides with distinctive helical propensity are correctly differentiated and the calculated helical contents are in close agreement with experimental measurement, indicating that consideration of polarization effect can correctly predict the effect of sequence variation on helix formation. PMID- 21548660 TI - Effect of food on the pharmacokinetic profile of etamicastat (BIA 5-453). AB - BACKGROUND: Etamicastat is a novel, potent, and reversible peripheral dopamine beta-hydroxylase inhibitor that has been administered orally at doses up to 600 mg once daily for 10 days to male healthy volunteers and appears to be well tolerated. OBJECTIVE: The aim of this study was to investigate the effect of food on the pharmacokinetics of etamicastat. MATERIAL AND METHODS: A single-center, open-label, randomized, two-way crossover study in 12 healthy male subjects was performed. Subjects were administered a single dose of etamicastat 200 mg following either a standard high-fat and high-calorie content meal (test) or 10 hours of fasting (reference). The statistical method for testing the effect of food on the pharmacokinetic parameters of interest was based upon the 90% confidence interval (CI) for the test/reference geometric mean ratio (GMR). The parameters of interest were maximum plasma concentration (C(max)), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUC(last)), and AUC from time zero to infinity (AUC(infinity)). Bioequivalence was assumed when the 90% CI fell within the recommended acceptance interval (80, 125). RESULTS: Etamicastat C(max), AUC(last), and AUC(infinity) were 229 ng/mL, 1856 ng . h/mL, and 2238 ng . h/mL, respectively, following etamicastat in the fasting, and 166 ng/mL, 1737 ng . h/mL, and 2119 ng . h/mL, respectively, following etamicastat in the fed condition. Etamicastat test/reference GMR was 72.27% (90% CI 64.98, 80.38) for C(max), 93.59% (90% CI 89.28, 98.11) for AUC(last), and 96.47% (90% CI 91.67, 101.53) for AUC(infinity). Time to C(max) was prolonged by the presence of food (p < 0.001). The C(max), AUC(last), and AUC(infinity) values of the inactive metabolite BIA 5-961 were 275 ng/mL, 1827 ng . h/mL, and 2009 ng . h/mL, respectively, in the fasting, and 172 ng/mL, 1450 ng . h/mL, and 1677 ng . h/mL, respectively, in the fed condition. BIA 5-961 test/reference GMR was 62.42% (90% CI 56.77, 68.63) for C(max), 79.41% (90% CI 56.77, 68.63) for AUC(last), and 83.47% (90% CI 76.62, 90.93) for AUC(infinity). A total of six mild to moderate unspecific adverse events were reported by four subjects. There was no clinically significant abnormality in laboratory assessments. CONCLUSION: Etamicastat was well tolerated. The C(max) of etamicastat decreased 28% following oral administration of etamicastat in the presence of food, while AUC remained within the pre-defined acceptance interval. The delay in absorption and decrease in peak exposure of etamicastat is not clinically significant, and therefore etamicastat could be administered without regard to meals. TRIAL REGISTRATION: EudraCT No. 2007-006530-33. PMID- 21548662 TI - Communication: Bubbles, crystals, and laser-induced nucleation. AB - Short intense laser pulses of visible and infrared light can dramatically accelerate crystal nucleation from transparent solutions; previous studies invoke mechanisms that are only applicable for nucleation of ordered phases or high dielectric phases. However, we show that similar laser pulses induce CO(2) bubble nucleation in carbonated water. Additionally, in water that is cosupersaturated with argon and glycine, argon bubbles escaping from the water can induce crystal nucleation without a laser. Our findings suggest a possible link between laser induced nucleation of bubbles and crystals. PMID- 21548663 TI - Communication: Avoiding unbound anions in density functional calculations. AB - Converged approximate density functional calculations usually do not bind anions due to large self-interaction error. But Hartree-Fock (HF) calculations have no such problem, producing negative HOMO energies. Thus, electron affinities can be calculated from density functional total energy differences using approximations such as PBE and B3LYP, evaluated on HF densities (for both anion and neutral). This recently proposed scheme is shown to work very well for molecules, better than the common practice of restricting the basis set except for cases such as CN, where the HF density is too inaccurate due to spin contamination. PMID- 21548664 TI - Communication: A simple method for simulation of freezing transitions. AB - Despite recent advances, precise simulation of freezing transitions continues to be a challenging task. In this work, a simulation method for fluid-solid transitions is developed. The method is based on a modification of the constrained cell model which was proposed by Hoover and Ree [J. Chem. Phys. 47, 4873 (1967)]. In the constrained cell model, each particle is confined in a single Wigner-Seitz cell. Hoover and Ree pointed out that the fluid and solid phases can be linked together by adding an external field of variable strength. High values of the external field favor single occupancy configurations and thus stabilize the solid phase. In the present work, the modified cell model is simulated in the constant-pressure ensemble using tempering and histogram reweighting techniques. Simulation results on a system of hard spheres indicate that as the strength of the external field is reduced, the transition from solid to fluid is continuous at low and intermediate pressures and discontinuous at high pressures. Fluid-solid coexistence for the hard-sphere model is established by analyzing the phase transition of the modified model in the limit in which the external field vanishes. The coexistence pressure and densities are in excellent agreement with current state-of-the-art techniques. PMID- 21548665 TI - Communication: Stable carbon nanoarches in the initial stages of epitaxial growth of graphene on Cu(111). AB - To fully exploit the device potential of graphene, reliable production of large area, high-quality samples is required. Epitaxial growth on metal substrates have shown promise in this regard, but further improvement would be facilitated by a more complete understanding of the atomistic processes involved in the early growth stages. Using first-principles calculations within density functional theory, we have investigated the energetics and kinetics of graphene nucleation and growth on a Cu(111) surface. Our calculations have revealed an energetic preference for the formation of stable one-dimensional carbon nanoarches consisting of 3-13 atoms when compared to two-dimensional compact islands of equal sizes. We also estimate the critical cluster size that marks the transition from nanoarch dominance to island dominance in the growth sequence. Our findings may provide the structural link between nucleated carbon dimers and larger carbon nanodomes, and are expected to stimulate future experimental efforts. PMID- 21548666 TI - Communication: New insight into the barrier governing CO2 formation from OH + CO. AB - Despite its relative simplicity, the role of tunneling in the reaction OH + CO -> H + CO(2) has eluded the quantitative predictive powers of theoretical reaction dynamics. In this study a one-dimensional effective barrier to the formation of H + CO(2) from the HOCO intermediate is directly extracted from dissociative photodetachment experiments on HOCO and DOCO. Comparison of this barrier to a computed minimum-energy barrier shows that tunneling deviates significantly from the calculated minimum-energy pathway, predicting product internal energy distributions that match those found in the experiment and tunneling lifetimes short enough to contribute significantly to the overall reaction. This barrier can be of direct use in kinetic and statistical models and aid in the further refinement of the potential energy surface and reaction dynamics calculations for this system. PMID- 21548667 TI - Correlation effects in molecular conductors. AB - The source-sink potential (SSP) model introduced previously [F. Goyer, M. Ernzerhof, and M. Zhuang, J. Chem. Phys. 126, 144104 (2007)] enables one to eliminate the semi-infinite contacts in molecular electronic devices (MEDs) in favor of complex potentials. SSP has originally been derived for independent electrons and extended to interacting two-electron systems subsequently [A. Goker, F. Goyer, and M. Ernzerhof, J. Chem. Phys. 129, 194901 (2008)]. Here we generalize SSP to N-electron systems and consider the impact of electron correlation on the transmission probability. In our correlated method for molecular conductors, the molecular part of the Huckel Hamiltonian of the original SSP is replaced by the Hubbard Hamiltonian. For the contacts, however, the single-electron picture is retained and they are assumed to be spin polarized. Using our method, we study electron transmission in molecular wires, cross-conjugated chains, as well as aromatic systems. We find that, for realistic values of the electron-electron repulsion parameter, correlation effects modify the transmission probability quantitatively, the qualitative features remain. However, we find subtle new effects in correlated MEDs, such as Coulomb drag, that are absent in uncorrelated systems. PMID- 21548668 TI - Testing the parametric two-electron reduced-density-matrix method with improved functionals: application to the conversion of hydrogen peroxide to oxywater. AB - Parametrization of the two-electron reduced density matrix (2-RDM) has recently enabled the direct calculation of electronic energies and 2-RDMs at the computational cost of configuration interaction with single and double excitations. While the original Kollmar energy functional yields energies slightly better than those from coupled cluster with single-double excitations, a general family of energy functionals has recently been developed whose energies approach those from coupled cluster with triple excitations [D. A. Mazziotti, Phys. Rev. Lett. 101, 253002 (2008)]. In this paper we test the parametric 2-RDM method with one of these improved functionals through its application to the conversion of hydrogen peroxide to oxywater. Previous work has predicted the barrier from oxywater to hydrogen peroxide with zero-point energy correction to be 3.3-to-3.9 kcal/mol from coupled cluster with perturbative triple excitations [CCSD(T)] and -2.3 kcal/mol from complete active-space second-order perturbation theory (CASPT2) in augmented polarized triple-zeta basis sets. Using a larger basis set than previously employed for this reaction-an augmented polarized quadruple-zeta basis set (aug-cc-pVQZ)-with extrapolation to the complete basis set limit, we examined the barrier with two parametric 2-RDM methods and three coupled cluster methods. In the basis-set limit the M parametric 2-RDM method predicts an activation energy of 2.1 kcal/mol while the CCSD(T) barrier becomes 4.2 kcal/mol. The dissociation energy of hydrogen peroxide to hydroxyl radicals is also compared to the activation energy for oxywater formation. We report energies, optimal geometries, dipole moments, and natural occupation numbers. Computed 2-RDMs nearly satisfy necessary N-representability conditions. PMID- 21548669 TI - Reactivity indicators for degenerate states in the density-functional theoretic chemical reactivity theory. AB - Density-functional-theory-based chemical reactivity indicators are formulated for degenerate and near-degenerate ground states. For degenerate states, the functional derivatives of the energy with respect to the external potential do not exist, and must be replaced by the weaker concept of functional variation. The resultant reactivity indicators depend on the specific perturbation. Because it is sometimes impractical to compute reactivity indicators for a specific perturbation, we consider two special cases: point-charge perturbations and Dirac delta function perturbations. The Dirac delta function perturbations provide upper bounds on the chemical reactivity. Reactivity indicators using the common used "average of degenerate states approximation" for degenerate states provide a lower bound on the chemical reactivity. Unfortunately, this lower bound is often extremely weak. Approximate formulas for the reactivity indicators within the frontier-molecular-orbital approximation and special cases (two or three degenerate spatial orbitals) are presented in the supplementary material. One remarkable feature that arises in the frontier molecular orbital approximation, and presumably also in the exact theory, is that removing electrons sometimes causes the electron density to increase at the location of a negative (attractive) Dirac delta function perturbation. That is, the energetic response to a reduction in the external potential can increase even when the number of electrons decreases. PMID- 21548670 TI - Determining partial differential cross sections for low-energy electron photodetachment involving conical intersections using the solution of a Lippmann Schwinger equation constructed with standard electronic structure techniques. AB - A method for obtaining partial differential cross sections for low energy electron photodetachment in which the electronic states of the residual molecule are strongly coupled by conical intersections is reported. The method is based on the iterative solution to a Lippmann-Schwinger equation, using a zeroth order Hamiltonian consisting of the bound nonadiabatically coupled residual molecule and a free electron. The solution to the Lippmann-Schwinger equation involves only standard electronic structure techniques and a standard three-dimensional free particle Green's function quadrature for which fast techniques exist. The transition dipole moment for electron photodetachment, is a sum of matrix elements each involving one nonorthogonal orbital obtained from the solution to the Lippmann-Schwinger equation. An expression for the electron photodetachment transition dipole matrix element in terms of Dyson orbitals, which does not make the usual orthogonality assumptions, is derived. PMID- 21548671 TI - Markov models of molecular kinetics: generation and validation. AB - Markov state models of molecular kinetics (MSMs), in which the long-time statistical dynamics of a molecule is approximated by a Markov chain on a discrete partition of configuration space, have seen widespread use in recent years. This approach has many appealing characteristics compared to straightforward molecular dynamics simulation and analysis, including the potential to mitigate the sampling problem by extracting long-time kinetic information from short trajectories and the ability to straightforwardly calculate expectation values and statistical uncertainties of various stationary and dynamical molecular observables. In this paper, we summarize the current state of the art in generation and validation of MSMs and give some important new results. We describe an upper bound for the approximation error made by modeling molecular dynamics with a MSM and we show that this error can be made arbitrarily small with surprisingly little effort. In contrast to previous practice, it becomes clear that the best MSM is not obtained by the most metastable discretization, but the MSM can be much improved if non-metastable states are introduced near the transition states. Moreover, we show that it is not necessary to resolve all slow processes by the state space partitioning, but individual dynamical processes of interest can be resolved separately. We also present an efficient estimator for reversible transition matrices and a robust test to validate that a MSM reproduces the kinetics of the molecular dynamics data. PMID- 21548672 TI - Intrinsic stability and hydrogen affinity of pure and bimetallic nanowires. AB - A density functional theory study of the intrinsic stability of pure and bimetallic wires is presented. Several bimetallic combinations forming one-atom thick wires are studied. An explanation for the experimental instability of Cu wires in contrast to the stability of Au and Ag wires is given, which relies on the higher surface energy of the former. All the possible intercalations between Ni, Pd, Pt, Cu, Ag, and Au are studied. The bimetallic wires AuCu and AuAg were found to be the most stable ones. The reactivity of the latter two systems is also examined using hydrogen adsorption as a microscopic probe. It was found that at the inter-metal interface, up to second neighbors, Cu and Ag become more reactive and Au becomes more inert than the corresponding pure wires. These results are explained within the d-band model. PMID- 21548673 TI - Accelerating chemical reactions: exploring reactive free-energy surfaces using accelerated ab initio molecular dynamics. AB - A biased potential molecular dynamics simulation approach, accelerated molecular dynamics (AMD), has been implemented in the framework of ab initio molecular dynamics for the study of chemical reactions. Using two examples, the double proton transfer reaction in formic acid dimer and the hypothetical adiabatic ring opening and subsequent rearrangement reactions in methylenecyclopropane, it is demonstrated that ab initio AMD can be readily employed to efficiently explore the reactive potential energy surface, allowing the prediction of chemical reactions and the identification of metastable states. An adaptive variant of the AMD method is developed, which additionally affords an accurate representation of both the free-energy surface and the mechanism associated with the chemical reaction of interest and can also provide an estimate of the reaction rate. PMID- 21548674 TI - Theoretical study of the photodissociation of Li(2)+ in one-color intense laser fields. AB - A theoretical treatment of the photodissociation of the molecular ion Li(2) (+) in one-color intense laser fields, using the time-dependent wave packet approach in a Floquet Born-Oppenheimer representation, is presented. Six electronic states 1,2 (2)Sigma(g)(+), 1,2 (2)Sigma(u)(+), 1 (2)Pi(g), and 1 (2)Pi(u) are of relevance in this simulation and have been included. The dependences of the fragmental dissociation probabilities and kinetic energy release (KER) spectra on pulse width, peak intensity, polarization angle, wavelength, and initial vibrational level are analyzed to interpret the influence of control parameters of the external field. Three main dissociation channels, 1 (2)Sigma(g)(+) (m = 1), 2 (2)Sigma(g)(+) (m = -2), and 2 (2)Sigma(u)(+) (m = -3), are seen to dominate the dissociation processes under a wide variety of laser conditions and give rise to well separated groups of KER features. Different dissociation mechanisms for the involved Floquet channels are discussed. PMID- 21548675 TI - Thermal Gaussian molecular dynamics for quantum dynamics simulations of many-body systems: application to liquid para-hydrogen. AB - A new method, here called thermal Gaussian molecular dynamics (TGMD), for simulating the dynamics of quantum many-body systems has recently been introduced [I. Georgescu and V. A. Mandelshtam, Phys. Rev. B 82, 094305 (2010)]. As in the centroid molecular dynamics (CMD), in TGMD the N-body quantum system is mapped to an N-body classical system. The associated both effective Hamiltonian and effective force are computed within the variational Gaussian wave-packet approximation. The TGMD is exact for the high-temperature limit, accurate for short times, and preserves the quantum canonical distribution. For a harmonic potential and any form of operator A, it provides exact time correlation functions C(AB)(t) at least for the case of B, a linear combination of the position, x, and momentum, p, operators. While conceptually similar to CMD and other quantum molecular dynamics approaches, the great advantage of TGMD is its computational efficiency. We introduce the many-body implementation and demonstrate it on the benchmark problem of calculating the velocity time auto correlation function for liquid para-hydrogen, using a system of up to N = 2592 particles. PMID- 21548676 TI - Balancing single- and multi-reference correlation in the chemiluminescent reaction of dioxetanone using the anti-Hermitian contracted Schrodinger equation. AB - Direct computation of energies and two-electron reduced density matrices (2-RDMs) from the anti-Hermitian contracted Schrodinger equation (ACSE) [D. A. Mazziotti, Phys. Rev. Lett. 97, 143002 (2006)], it is shown, recovers both single- and multi reference electron correlation in the chemiluminescent reaction of dioxetanone especially in the vicinity of the conical intersection where strong correlation is important. Dioxetanone, the light-producing moiety of firefly luciferin, efficiently converts chemical energy into light by accessing its excited-state surface via a conical intersection. Our previous active-space 2-RDM study of dioxetanone [L. Greenman and D. A. Mazziotti, J. Chem. Phys. 133, 164110 (2010)] concluded that correlating 16 electrons in 13 (active) orbitals is required for realistic surfaces without correlating the remaining (inactive) orbitals. In this paper we pursue two complementary goals: (i) to correlate the inactive orbitals in 2-RDMs along dioxetanone's reaction coordinate and compare these results with those from multireference second-order perturbation theory (MRPT2) and (ii) to assess the size of the active space-the number of correlated electrons and orbitals-required by both MRPT2 and ACSE for accurate energies and surfaces. While MRPT2 recovers very different amounts of correlation with (4,4) and (16,13) active spaces, the ACSE obtains a similar amount of correlation energy with either active space. Nevertheless, subtle differences in excitation energies near the conical intersection suggest that the (16,13) active space is necessary to determine both energetic details and properties. Strong electron correlation is further assessed through several RDM-based metrics including (i) total and relative energies, (ii) the von Neumann entropy based on the 1-electron RDM, as well as the (iii) infinity and (iv) squared Frobenius norms based on the cumulant 2-RDM. PMID- 21548677 TI - Laser control of molecular excitations in stochastic dissipative media. AB - In the present work, ideas for controlling photochemical reactions in dissipative environments using shaped laser pulses are presented. New time-local control algorithms for the stochastic Schrodinger equation are introduced and compared to their reduced density matrix analog. The numerical schemes rely on time-dependent targets for guiding the reaction along a preferred path. The methods are tested on the vibrational control of adsorbates at metallic surfaces and on the ultrafast electron dynamics in a strong dissipative medium. The selective excitation of the specific states is achieved with improved yield when using the new algorithms. Both methods exhibit similar convergence behavior and results compare well with those obtained using local optimal control for the reduced density matrix. The favorable scaling of the methods allows to tackle larger systems and to control photochemical reactions in dissipative media of molecules with many more degrees of freedom. PMID- 21548678 TI - Cutoff radius effect of the isotropic periodic sum and Wolf method in liquid vapor interfaces of water. AB - As a more economical but similarly accurate computation method than the Ewald sum, the isotropic periodic sum (IPS) method for nonpolar molecules (IPSn) and polar molecules (IPSp), along with the Wolf method are of interest, but the cutoff radius dependence is an important issue. To evaluate the cutoff radius effect of the three methods, a water-vapor interfacial system has been studied by molecular dynamics. The Wolf method can produce adequate results for surface tension compared to that of the Ewald sum (within 2.9%) at a long enough cutoff radius, r(c). However, the estimation of the electrostatic potential profile and dipole orientational function is poor. The Wolf method cannot estimate electrostatic configuration at r(c) <= L(z)/2 (L(z) is the longest lattice of the system). We have found that the convergence of the surface tension and the electrostatic configuration of the IPSn method is faster than that of the IPSp method. Moreover, the IPSn method is most accurate among the three methods for the same cutoff radius. Furthermore, the behavior of the surface tension against the cutoff radius shows a greater difference for the IPSn and IPSp method. The surface tension of the IPSp method fluctuates and presents a similar result to that of the Ewald sum, but the surface tension for the IPSn method greatly deviates near r(c) = L(z)/3. The cause of this deviation is the difference between the interfacial configuration of the water surface and the cutoff treatment of the IPS method. The deviation becomes insignificant far from r(c) = L(z)/3. In spite of this shortcoming, the IPSn method gives the most accurate result in estimating the surface tension at r(c) = L(z)/2. From all the results in this work, the IPSn and IPSp method have been found to be more accurate than the Wolf method. In conclusion, the surface tension and structure of water-vapor interface can be calculated by the IPSn method when r(c) is greater than or equal to the longest lattice of the system. The IPSp method and the Wolf method require a longer cutoff radius than the longest lattice of the system to estimate interfacial properties. PMID- 21548679 TI - Sensitivity analysis of state-specific multireference perturbation theory. AB - State-specific multireference perturbation theory (SS-MRPT) developed by Mukherjee et al. [Int. J. Mol. Sci. 3, 733 (2002)] is examined focusing on the dependence of the perturbed energy on the initial model space coefficients. It has been observed earlier, that non-physical kinks may appear on the potential energy surface obtained by SS-MRPT while related coupled-cluster methods may face convergence difficulties. Though exclusion or damping of the division by small coefficients may alleviate the problem, it is demonstrated here that the effect does not originate in an ill-defined division. It is shown that non-negligible model space coefficients may also be linked with the problem. Sensitivity analysis is suggested as a tool for detecting the coefficient responsible. By monitoring the singular values of sensitivity matrices, orders of magnitude increase is found in the largest value, in the vicinity of the problematic geometry point on the potential energy surface. The drastic increase of coefficient sensitivities is found to be linked with a degeneracy of the target root of the effective Hamiltonian. The nature of the one-electron orbitals has a profound influence on the picture: a rotation among active orbitals may screen or worsen the effect. PMID- 21548680 TI - Generating transition paths by Langevin bridges. AB - We propose a novel stochastic method to generate paths conditioned to start in an initial state and end in a given final state during a certain time t(f). These paths are weighted with a probability given by the overdamped Langevin dynamics. We show that these paths can be exactly generated by a non-local stochastic differential equation. In the limit of short times, we show that this complicated non-solvable equation can be simplified into an approximate local stochastic differential equation. For longer times, the paths generated by this approximate equation do not satisfy the correct statistics, but this can be corrected by an adequate reweighting of the trajectories. In all cases, the paths are statistically independent and provide a representative sample of transition paths. The method is illustrated on the one-dimensional quartic oscillator. PMID- 21548681 TI - Collisional transfer of population and orientation in NaK. AB - Collisional satellite lines with |DeltaJ| <= 58 have been identified in recent polarization spectroscopy V-type optical-optical double resonance (OODR) excitation spectra of the Rb(2) molecule [H. Salami et al., Phys. Rev. A 80, 022515 (2009)]. Observation of these satellite lines clearly requires a transfer of population from the rotational level directly excited by the pump laser to a neighboring level in a collision of the molecule with an atomic perturber. However to be observed in polarization spectroscopy, the collision must also partially preserve the angular momentum orientation, which is at least somewhat surprising given the extremely large values of DeltaJ that were observed. In the present work, we used the two-step OODR fluorescence and polarization spectroscopy techniques to obtain quantitative information on the transfer of population and orientation in rotationally inelastic collisions of the NaK molecules prepared in the 2(A)(1)Sigma(+)(v' = 16, J' = 30) rovibrational level with argon and potassium perturbers. A rate equation model was used to study the intensities of these satellite lines as a function of argon pressure and heat pipe oven temperature, in order to separate the collisional effects of argon and potassium atoms. Using a fit of this rate equation model to the data, we found that collisions of NaK molecules with potassium atoms are more likely to transfer population and destroy orientation than collisions with argon atoms. Collisions with argon atoms show a strong propensity for population transfer with DeltaJ = even. Conversely, collisions with potassium atoms do not show this DeltaJ = even propensity, but do show a propensity for DeltaJ = positive compared to DeltaJ = negative, for this particular initial state. The density matrix equations of motion have also been solved numerically in order to test the approximations used in the rate equation model and to calculate fluorescence and polarization spectroscopy line shapes. In addition, we have measured rate coefficients for broadening of NaK 3(1)Pi <- 2(A)(1)Sigma(+)spectral lines due to collisions with argon and potassium atoms. Additional broadening, due to velocity changes occurring in rotationally inelastic collisions, has also been observed. PMID- 21548682 TI - Calculation of the structure, potential energy surface, vibrational dynamics, and electric dipole properties for the Xe:HI van der Waals complex. AB - We report the structure and spectroscopic characteristics for the Xe:HI van der Waals binary isomers determined from variational solutions of two-dimensional and three-dimensional (3D) vibrational Schrodinger equations. The solutions are based on a potential energy surface computed at the coupled-cluster level of theory including single and double excitations and a non-iterative perturbation treatment of triple excitations [CCSD(T)]. The dipole moment surface was calculated using quadratic configuration interaction (QCISD). The global potential minimum is shown to be located at the anti-hydrogen-bonded Xe-IH isomer, 21 cm(-1) below the secondary local minimum associated with the hydrogen bonded Xe-HI isomeric form. The dissociation energy from the global minimum is 245.9 cm(-1). 3D Schrodinger equations are solved for the rotational quantum numbers J = k = 0, 1, and 2, without invoking an adiabatic separation of high- and low-frequency degrees of freedom. The vibrational ground state resides in the Xe-HI potential well, while the first excited state, 8.59 cm(-1) above the ground, occupies the Xe-IH well. We find that intra-complex dynamics exhibits a sudden transformation upon increase of the r(HI) bond length, accompanied by abrupt changes in the geometric and dipole parameters. A similar chaotic behavior is predicted to occur for Xe:DI at a shorter r(DI) bond length, which implies stronger coupling between low- and high-frequency motions in the heavier complex. Our calculations confirm a strong enhancement for the r(HI) stretch fundamental and a significant weakening for the first overtone vibrational transitions in Xe:HI, as compared to those in the free HI molecule. A qualitative explanation of this, earlier experimentally detected effect is suggested. PMID- 21548683 TI - Observation of the pure rotational spectra of trans- and cis-HOCO. AB - Pure rotational spectra of trans- and cis-HOCO have been observed by Fourier transform microwave spectroscopy and the millimeter-wave double resonance technique, where gas phase spectra of the cis-conformer were observed for the first time. These radicals were produced in a supersonic jet by discharging a mixture gas of CO and H(2)O diluted in Ar. The molecular constants including the fine and hyperfine constants have been precisely determined for both conformers. Deuterated analogs have also been observed. The determined r(0) structures agree with these of ab initio calculations. The Fermi contact constants show a difference of the unpaired electron densities on the protons between the two conformers. Intensity of the spectrum for cis-HOCO was compared with that of trans-HOCO, leading to a conclusion that both conformers were produced nearly equally in abundance under the present experimental conditions. PMID- 21548684 TI - Low energy (e,2e) studies from CH4: results from symmetric coplanar experiments and molecular three-body distorted wave theory. AB - Low energy experimental and theoretical triply differential cross sections are presented for electron impact ionization of methane (CH(4)) for both the highest occupied molecular orbital (HOMO) and next highest occupied molecular orbital (NHOMO). The HOMO is a predominantly p-type orbital which is labeled 1t(2) and the NHOMO is predominantly s-type labeled 2a(1). Coplanar symmetric (symmetric both in final state electron energies and observation angles) are presented for final state electron energies ranging from 2.5 to 20 eV. The theoretical M3DW (molecular three-body distorted wave) results are in surprisingly good agreement with experiment for the HOMO state and less satisfactory agreement for the NHOMO state. The molecular NHOMO results are also compared with the ionization of the 2s shell of neon which is the isoelectronic atom. PMID- 21548685 TI - Electric-field-induced dissociation of heavy Rydberg ion-pair states. AB - A classical trajectory Monte Carlo approach is used to simulate the dissociation of H(+)???F(-) and K(+)???Cl(-) heavy Rydberg ion pairs induced by a ramped electric field, a technique used experimentally to detect and probe ion-pair states. Simulations that include the effects of the strong short-range repulsive interaction associated with ion-pair scattering are in good agreement with experimental results for Stark wavepackets probed by a ramped field, demonstrating that many of the characteristics of field-induced dissociation can be well described using a quasi-classical model. The data also show that states with a given value of principal quantum number (i.e., binding energy) can dissociate over a broad range of applied fields, the exact field being governed by the initial orbital angular momentum and orientation of the state. PMID- 21548686 TI - Dissociative photoionization of 1,3-butadiene: experimental and theoretical insights. AB - The vacuum-ultraviolet photoionization and dissociative photoionization of 1,3 butadiene in a region ~8.5-17 eV have been investigated with time-of-flight photoionization mass spectrometry using tunable synchrotron radiation. The adiabatic ionization energy of 1,3-butadiene and appearance energies for its fragment ions, C(4)H(5)(+), C(4)H(4)(+), C(4)H(3)(+), C(3)H(3)(+), C(2)H(4)(+), C(2)H(3)(+), and C(2)H(2)(+), are determined to be 9.09, 11.72, 13.11, 15.20, 11.50, 12.44, 15.15, and 15.14 eV, respectively, by measurements of photoionization efficiency spectra. Ab initio molecular orbital calculations have been performed to investigate the reaction mechanism of dissociative photoionization of 1,3-butadiene. On the basis of experimental and theoretical results, seven dissociative photoionization channels are proposed: C(4)H(5)(+) + H, C(4)H(4)(+) + H(2), C(4)H(3)(+) + H(2) + H, C(3)H(3)(+) + CH(3), C(2)H(4)(+) + C(2)H(2), C(2)H(3)(+) + C(2)H(2) + H, and C(2)H(2)(+) + C(2)H(2) + H(2). Channel C(3)H(3)(+) + CH(3) is found to be the dominant one, followed by C(4)H(5)(+) + H and C(2)H(4)(+) + C(2)H(2). The majority of these channels occur via isomerization prior to dissociation. Transition structures and intermediates for those isomerization processes were also determined. PMID- 21548687 TI - Inelastic collisions in molecular oxygen at low temperature (4 <= T <= 34 K). Close-coupling calculations versus experiment. AB - Close-coupling calculations and experiment are combined in this work, which is aimed at establishing a set of state-to-state rate coefficients for elementary processes ij -> lm in O(2):O(2) collisions at low temperature involving the rotational states i, j, l, m of the vibrational ground state of (16)O(2)((3)Sigma(g)(-)). First, a set of cross sections for inelastic collisions is calculated as a function of the collision energy at the converged close coupled level via the MOLSCAT code, using a recent ab-initio potential energy surface for O(2)-O(2) [M. Bartolomei et al., J. Chem. Phys. 133, 124311 (2010)]. Then, the corresponding rates for the temperature range 4 <= T <= 34 K are derived from the cross sections. The link between theory and experiment is a Master Equation which accounts for the time evolution of rotational populations in a reference volume of gas in terms of the collision rates. This Master Equation provides a linear function of the rates for each rotational state and temperature. In the experiment, the evolution of rotational populations is measured by Raman spectroscopy in a tiny reference volume (~2 * 10(-4) mm(3)) of O(2) travelling along the axis of a supersonic jet at a velocity of ~700 m/s. The accuracy of the calculated rates is assessed experimentally for 10 <= T <= 34 K by means of the Master Equation. The rates, jointly with their confidence interval estimated by Monte Carlo simulation, account to within the experimental uncertainty for the evolution of the populations of the N = 1, 3, 5, 7 rotational triads along the supersonic jet. Confidence intervals range from ~6% for the dominant rates at 34 K, up to ~17% at 10 K. These results provide an experimental validation of state-to-state rates for O(2):O(2) inelastic collisions calculated in the close-coupling approach and, indirectly, of the anisotropy of the O(2) O(2) intermolecular potential employed in the calculation for energies up to 300 cm(-1). PMID- 21548688 TI - Collisional stabilization of van der Waals states of ozone. AB - The mixed quantum-classical theory developed earlier [M. Ivanov and D. Babikov, J. Chem. Phys. 134, 144107 (2011)] is employed to treat the collisional energy transfer and the ro-vibrational energy flow in a recombination reaction that forms ozone. Assumption is that the van der Waals states of ozone are formed in the O + O(2) collisions, and then stabilized into the states of covalent well by collisions with bath gas. Cross sections for collision induced dissociation of van der Waals states of ozone, for their stabilization into the covalent well, and for their survival in the van der Waals well are computed. The role these states may play in the kinetics of ozone formation is discussed. PMID- 21548689 TI - Hyperfine effects on collisional line shape. I. A self-consistent set of equations. AB - We show that the treatment available in the literature for calculating hyperfine effects on collisional line shape is affected by an error making the theory not self-consistent. By correcting such an error we show that the two hyperfine effects on the line shape, modification of the resolved components and collisional coupling between them, cancel each other when hyperfine structure collapses into a single line. PMID- 21548690 TI - Hyperfine effects on spectral line shape. II. The case DCO+-He. AB - We discuss the hyperfine effect on the shape of rotational spectral lines of DCO(+) broadened by collisions with helium. Hyperfine scattering matrix is calculated by the recoupling technique from the spin-free scattering matrix which is obtained by close-coupling calculations and by a previously tested potential. Line shape is calculated for different rotational transitions, perturber density values, and collisional energies. As forecast by a semiclassical treatment and contrary to what may happen for a symmetric top absorber, hyperfine effects are small for a linear absorber. In our case they are of about 2%. We could also verify that the two hyperfine effects on the line shape, modification of resolved components and collisional coupling between them, cancel each other at high values of helium density when hyperfine structure collapses into a single line. PMID- 21548691 TI - Photoabsorption and S 2p photoionization of the SF6 molecule: resonances in the excitation energy range of 200-280 eV. AB - Photoabsorption and S 2p photoionization of the SF(6) molecule have been studied experimentally and theoretically in the excitation energy range up to 100 eV above the S 2p ionization potentials. In addition to the well-known 2t(2g) and 4e(g) shape resonances, the spin-orbit-resolved S 2p photoionization cross sections display two weak resonances between 200 and 210 eV, a wide resonance around 217 eV, a Fano-type resonance around 240 eV, and a second wide resonance around 260 eV. Calculations based on time-dependent density functional theory allow us to assign the 217-eV and 260-eV features to the shape resonances in S 2p photoionization. The Fano resonance is caused by the interference between the direct S 2p photoionization channel and the resonant channel that results from the participator decay of the S 2s(-1)6t(1u) excited state. The weak resonances below 210-eV photon energy, not predicted by theory, are tentatively suggested to originate from the coupling between S 2p shake-up photoionization and S 2p single hole photoionization. The experimental and calculated angular anisotropy parameters for S 2p photoionization are in good agreement. PMID- 21548692 TI - Spectroscopic investigation of fluoroiodomethane, CH2FI: Fourier-transform microwave and millimeter-/submillimeter-wave spectroscopy and quantum-chemical calculations. AB - Guided by theoretical predictions, the rotational spectrum of fluoroiodomethane, CH(2)FI, has been recorded and assigned. Accurate values are reported for the ground-state rotational constants, all quartic, sextic, and two octic centrifugal distortion constants. The hyperfine structure of the rotational spectrum was thoroughly investigated using a Fourier-transform microwave spectrometer and the Lamb-dip technique in the millimeter-/submillimeter-wave region, thus allowing the accurate determination of the complete iodine quadrupole-coupling tensor and of the diagonal elements of the iodine spin-rotation tensor. Relativistic effects turned out to be essential for the accurate theoretical prediction of the dipole moment and quadrupole-coupling constants and were accounted for by direct perturbation theory and a spin-free four-component treatment based on the Dirac Coulomb Hamiltonian. The relativistic corrections to the dipole moment amount to up to 34% and to the iodine quadrupole-coupling tensor to about 15-16% of the total values. PMID- 21548693 TI - Vibron frequencies of solid H2 and D2 to 200 GPa and implications for the P-T phase diagram. AB - Vibrational spectroscopy of the intramolecular stretching mode (vibron) of the hydrogen isotopes has been used for the past 20 years in different laboratories using various techniques to probe phase diagrams of this system under extreme conditions. Available vibrational spectroscopy data in hydrogen and deuterium to 200 GPa at 10-300 K are analyzed and reassessed to identify the existence of an additional molecular phase (I') to phases I, II, and III previously identified at megabar pressures. The results do not support the existence of phase I' in the pressure-temperature range studied. Previously proposed boundaries between phases I, II, and III are re-examined and updated phase diagrams of hydrogen and deuterium are proposed. PMID- 21548694 TI - Crystallization of tetrahedral patchy particles in silico. AB - We investigate the competition between glass formation and crystallization of open tetrahedral structures for particles with tetrahedral patchy interactions. We analyze the outcome of such competition as a function of the potential parameters. Specifically, we focus on the separate roles played by the interaction range and the angular width of the patches, and show that open crystal structures (cubic and hexagonal diamond and their stacking hybrids) spontaneously form when the angular width is smaller than about 30 degrees . Evaluating the temperature and density dependence of the chemical potential of the fluid and of the crystal phases, we find that adjusting the patch width affects the fluid and crystal in different ways. As a result of the different scaling, the driving force for spontaneous self-assembly rapidly grows as the fluid is undercooled for small-width patches, while it only grows slowly for large-width patches, in which case crystallization is pre-empted by dynamic arrest into a network glass. PMID- 21548695 TI - Solvation dynamics through Raman spectroscopy: hydration of Br2 and Br3(-), and solvation of Br2 in liquid bromine. AB - Raman spectroscopy of bromine in the liquid phase and in water illustrates uncommon principles and yields insights regarding hydration. In liquid Br(2), resonant excitation over the B((3)Pi(0u)(+)) <- X((1)Sigma(g)(+)) valence transition at 532 nm produces a weak resonant Raman (RR) progression accompanied by a five-fold stronger non-resonant (NR) scattering. The latter is assigned to pre-resonance with the C-state, which in turn must be strongly mixed with inter molecular charge transfer states. Despite the electronic resonance, RR of Br(2) in water is quenched. At 532 nm, the homogeneously broadened fundamental is observed, as in the NR case at 785 nm. The implications of the quenching of RR scattering are analyzed in a simple, semi-quantitative model, to conclude that the inertial evolution of the Raman packet in aqueous Br(2) occurs along multiple equivalent water-Br(2) coordinates. In distinct contrast with hydrophilic hydration in small clusters and hydrophobic hydration in clathrates, it is concluded that the hydration shell of bromine in water consists of dynamically equivalent fluxional water molecules. At 405 nm, the RR progression of Br(3)(-) is observed, accompanied by difference transitions between the breathing of the hydration shell and the symmetric stretch of the ion. The RR scattering process in this case can be regarded as the coherent photo-induced electron transfer to the solvent and its radiative back-transfer. PMID- 21548696 TI - Exciton dynamics in chromophore aggregates with correlated environment fluctuations. AB - We study the effects of correlated molecular transition energy fluctuations in molecular aggregates on the density matrix dynamics, and their signatures in the optical response. Correlated fluctuations do not affect single-exciton dynamics and can be described as a nonlocal contribution to the spectral broadening, which appears as a multiplicative factor in the time-domain response function. Intraband coherences are damped only by uncorrelated transition energy fluctuations. The signal can then be expressed as a spectral convolution of a local contribution of the uncorrelated fluctuations and the nonlocal contribution of the correlated fluctuations. PMID- 21548697 TI - Fingerprints of the hydrogen bond in the photoemission spectra of croconic acid condensed phase: an x-ray photoelectron spectroscopy and ab-initio study. AB - The electronic structure of Croconic Acid in the condensed phase has been studied by comparing core level and valence band x-ray photoelectron spectroscopy experiments and first principles density functional theory calculations using the Heyd-Scuseria-Ernzerhof screened hybrid functional and the GW approximation. By exploring the photoemission spectra for different deposition thicknesses, we show how the formation of the hydrogen bond network modifies the O 1s core level lineshape. Moreover, the valence band can be explained only if the intermolecular interactions are taken into account in the theoretical approach. PMID- 21548698 TI - The intermolecular structure of phosphoric acid-N,N-dimethylformamide mixtures as studied by computer simulation. AB - The computer simulation of H(3)PO(4)-N,N-dimethylformamide (DMF) mixtures over the whole concentration range using molecular dynamic (MD) methods has been carried out. The preferential orientations of the nearest neighbors of H(3)PO(4) and DMF molecules were obtained using the ranked radial distribution functions technique. On the basis of MD results, the parameters of hydrogen bonds between molecules in mixture were calculated. The changes of the intermolecular structure of mixture as a function of acid composition over the whole concentration range were analyzed and reported. Analysis of O...H distance distributions and angles between O-H (H(3)PO(4)) and C=O (DMF) or P=O (H(3)PO(4)) vector distributions showed that O(DMF) and O(H(3)PO(4)) may each have two hydrogen bonds. PMID- 21548699 TI - Slow magnetic relaxation and electron delocalization in an S = 9/2 iron(II/III) complex with two crystallographically inequivalent iron sites. AB - The magnetic, electronic, and Mossbauer spectral properties of [Fe(2)L(MU OAc)(2)]ClO(4), 1, where L is the dianion of the tetraimino-diphenolate macrocyclic ligand, H(2)L, indicate that 1 is a class III mixed valence iron(II/III) complex with an electron that is fully delocalized between two crystallographically inequivalent iron sites to yield a [Fe(2)](V) cationic configuration with a S(t) = 9/2 ground state. Fits of the dc magnetic susceptibility between 2 and 300 K and of the isofield variable-temperature magnetization of 1 yield an isotropic magnetic exchange parameter, J, of -32(2) cm(-1) for an electron transfer parameter, B, of 950 cm(-1), a zero-field uniaxial D(9/2) parameter of -0.9(1) cm(-1), and g = 1.95(5). In agreement with the presence of uniaxial magnetic anisotropy, ac susceptibility measurements reveal that 1 is a single-molecule magnet at low temperature with a single molecule magnetic effective relaxation barrier, U(eff), of 9.8 cm(-1). At 5.25 K the Mossbauer spectra of 1 exhibit two spectral components, assigned to the two crystallographically inequivalent iron sites with a static effective hyperfine field; as the temperature increases from 7 to 310 K, the spectra exhibit increasingly rapid relaxation of the hyperfine field on the iron-57 Larmor precession time of 5 * 10(-8) s. A fit of the temperature dependence of the average effective hyperfine field yields |D(9/2)| = 0.9 cm(-1). An Arrhenius plot of the logarithm of the relaxation frequency between 5 and 85 K yields a relaxation barrier of 17 cm(-1). PMID- 21548700 TI - Electronic structures and bonding of graphyne sheet and its BN analog. AB - Using density functional theory and generalized gradient approximation for exchange and correlation, we present theoretical analysis of the electronic structure of recently synthesized graphyne and its boron nitride analog (labeled as BN-yne). The former is composed of hexagonal carbon rings joined by C-chains, while the latter is composed of hexagonal BN rings joined by C-chains. We have explored the nature of bonding and energy band structure of these unique systems characterized by sp and sp(2) bonding. Both graphyne and BN-yne are found to be direct bandgap semiconductors. The bandgap can be modulated by changing the size of hexagonal ring and the length of carbon chain, providing more flexibilities of energy band engineering for device applications. The present study sheds theoretical insight on better understanding of the properties of the novel carbon based 2D structures beyond the graphene sheet. PMID- 21548701 TI - A perturbative density functional theory for square-well fluids. AB - We report a perturbative density functional theory for quantitative description of the structural and thermodynamic properties of square-well fluids in the bulk or at inhomogeneous conditions. The free-energy functional combines a modified fundamental measure theory to account for the short-range repulsion and a quadratic density expansion for the long-range attraction. The long-correlation effects are taken into account by using analytical expressions of the direct correlation functions of bulk fluids recently obtained from the first-order mean spherical approximation. The density functional theory has been calibrated by extensive comparison with simulation data from this work and from the literature. The theory yields good agreement with simulation results for the radial distribution function of bulk systems and for the density profiles of square-well fluids near the surfaces of spherical cavities or in slit pores over a broad range of the parameter space and thermodynamic conditions. PMID- 21548702 TI - Imaging sequential dehydrogenation of methanol on Cu(110) with a scanning tunneling microscope. AB - Adsorption of methanol and its dehydrogenation on Cu(110) were studied by using a scanning tunneling microscope (STM). Upon adsorption at 12 K, methanol preferentially forms clusters on the surface. The STM could induce dehydrogenation of methanol sequentially to methoxy and formaldehyde. This enabled us to study the binding structures of these products in a single-molecule limit. Methoxy was imaged as a pair of protrusion and depression along the [001] direction. This feature is fully consistent with the previous result that it adsorbs on the short-bridge site with the C-O axis tilted along the [001] direction. The axis was induced to flip back and forth by vibrational excitations with the STM. Two configurations were observed for formaldehyde, whose structures were proposed based on their characteristic images and motions. PMID- 21548703 TI - Two- and three-body interactions among nanoparticles in a polymer melt. AB - We perform direct three-dimensional density functional theory (DFT) calculations of two- and three-body interactions in polymer nanocomposites. The nanoparticles are modeled as hard spheres, immersed in a hard-sphere homopolymer melt of freely jointed chains. The two-particle potential of mean force obtained from the DFT is in near quantitative agreement with the potential of mean force obtained from self-consistent polymer reference interaction site model theory. Three-body interactions among three nanoparticles are found to be significant, such that it is not possible to describe these systems with a polymer-mediated two-body interaction calculated from the potential of mean force. PMID- 21548704 TI - Gelation in semiflexible polymers. AB - Molecular dynamics simulations have been employed to study the formation of a physical gel by semiflexible polymer chains. The formation of a geometrically connected network of these chains is investigated as a function of temperature and rate of cooling. The stiffness of the molecules is controlled via a potential between beads separated by two bonds. As the temperature is lowered, a percolated homogeneous solution phase separates to form a high-density, non-percolated nematic fluid and a low-density gas phase. On further decreasing the temperature, the chains are dynamically arrested preventing the completion of the vapor-liquid (VL) phase separation. As a result, the chains are stuck in a three-dimensional network of nematic bundles forming a percolated gel. Apart from temperature, the rate of cooling also plays an important role in the formation of the gel. Cooling the system at a faster rate yields gel while slower rates result in complete VL phase separation. PMID- 21548705 TI - Microviscoelasticity of soft repulsive sphere dispersions: tracer particle microrheology of triblock copolymer micellar liquids and soft crystals. AB - Tracer particle microrheology using diffusing wave spectroscopy-based microrheology is demonstrated to be a useful method to study the dynamics of aqueous PluronicTM F108 solutions, which are viewed as solutions of repulsive soft spheres. The measured zero-shear microviscosity of noncrystallizing micellar dispersions indicates micelle corona dehydration upon increasing temperature. Colloidal sphere thermal motion is shown to be exquisitely sensitive to the onset of crystallization in these micellar dispersions. High temperature dynamics are dominated by an apparent soft repulsive micelle-micelle interaction potential indicating the important role played by lubrication forces and ultimately micelle corona interpenetration and compression at sufficiently high concentrations. The measured microscopic viscoelastic storage and loss moduli are qualitatively similar to those experimentally observed in mechanical measurements on colloidal dispersions and crystals, and calculated from mode coupling theory of colloidal suspensions. The observation of subdiffusive colloidal sphere thermal motion at short time-scales is strong evidence that the observed microscopic viscoelastic properties reflect the dynamics of individual micelles rather than a dispersion of micellar crystallites. PMID- 21548706 TI - Anhydrous crystals of DNA bases are wide gap semiconductors. AB - We present the structural, electronic, and optical properties of anhydrous crystals of DNA nucleobases (guanine, adenine, cytosine, and thymine) found after DFT (Density Functional Theory) calculations within the local density approximation, as well as experimental measurements of optical absorption for powders of these crystals. Guanine and cytosine (adenine and thymine) anhydrous crystals are predicted from the DFT simulations to be direct (indirect) band gap semiconductors, with values 2.68 eV and 3.30 eV (2.83 eV and 3.22 eV), respectively, while the experimentally estimated band gaps we have measured are 3.83 eV and 3.84 eV (3.89 eV and 4.07 eV), in the same order. The electronic effective masses we have obtained at band extremes show that, at low temperatures, these crystals behave like wide gap semiconductors for electrons moving along the nucleobases stacking direction, while the hole transport are somewhat limited. Lastly, the calculated electronic dielectric functions of DNA nucleobases crystals in the parallel and perpendicular directions to the stacking planes exhibit a high degree of anisotropy (except cytosine), in agreement with published experimental results. PMID- 21548707 TI - Studies on mechanism of reaction and density behavior during anhydrous D-fructose mutarotation in the supercooled liquid state. AB - Recently, we have studied the mutarotation kinetics in D-fructose by means of dielectric spectroscopy. In the present work we investigate density behavior of D fructose during mutarotation process. By performing volume measurements at temperature T = 303 K and pressure p = 10 MPa we are able to monitor kinetics of this process. As a result we found nearly the same value of the rate constant as previously determined from dielectric measurements. However, these two experimental methods monitor different molecular aspects of mutarotation phenomenon in D-fructose. Dielectric spectroscopy is sensitive to the decay of former ring as well as to the forming of another, while specific volume measurements are sensitive to the forming of new tautomers only. Calculations of activation energy of mutarotation in D-fructose led us to the conclusion, that mechanism of this reaction in amorphous phase could be based on internal proton transfer. Moreover it was found that the main mutarotation path in quenched D fructose melt is transformation of alpha,beta-furanose to beta-pyranose. PMID- 21548709 TI - Rural healthcare delivery using a phone patch service in the teleconsultation program of the Ateneo de Zamboanga University School of Medicine in Western Mindanao, Philippines. PMID- 21548711 TI - Evaluation of thermal-oxidative stability and antiglioma activity of Zanthoxylum tingoassuiba essential oil entrapped into multi- and unilamellar liposomes. AB - Zanthoxylum tinguassuiba essential oil (ZtEO) contains alpha-bisabolol, a known antiglioma sesquiterpene, among other potentially active substances. Medical applications of this essential oil require advances in the design of distinctive carriers due to its low water solubility and easy degradation by heat, light, and oxygen. The aim of this work was to evaluate enhancement in oxidative stability and the ability to reduce glioblastoma cell viability of ZtEO loaded into liposomes. Multi- and unilamellar vesicles were prepared to carry ZtEO. By using thermal analysis, it was observed that thermal-oxidative stability of the liposomal ZtEO was enhanced, when compared to its free form. Liposomal ZtEO also presented significant apoptotic-inducing activity for glioma cells. These results show that liposomal systems carrying ZtEO may be a potential alternative for gliobastoma treatment. PMID- 21548710 TI - A tissue-engineered muscle repair construct for functional restoration of an irrecoverable muscle injury in a murine model. AB - There are no effective clinical treatments for volumetric muscle loss (VML) resulting from traumatic injury, tumor excision, or other degenerative diseases of skeletal muscle. The goal of this study was to develop and characterize a more clinically relevant tissue-engineered muscle repair (TE-MR) construct for functional restoration of a VML injury in the mouse lattissimus dorsi (LD) muscle. To this end, TE-MR constructs developed by seeding rat myoblasts on porcine bladder acellular matrix were preconditioned in a bioreactor for 1 week and implanted in nude mice at the site of a VML injury created by excising 50% of the native LD. Two months postinjury and implantation of TE-MR, maximal tetanic force was ~72% of that observed in native LD muscle. In contrast, injured LD muscles that were not repaired, or were repaired with scaffold alone, produced only ~50% of native LD muscle force after 2 months. Histological analyses of LD tissue retrieved 2 months after implantation demonstrated remodeling of the TE-MR construct as well as the presence of desmin-positive myofibers, blood vessels, and neurovascular bundles within the TE-MR construct. Overall, these encouraging initial observations document significant functional recovery within 2 months of implantation of TE-MR constructs and provide clear proof of concept for the applicability of this technology in a murine VML injury model. PMID- 21548712 TI - ReGeneraTing agents matrix therapy regenerates a functional root attachment in hamsters with periodontitis. AB - Matrix-based therapy restoring the cell microenvironment is a new approach in regenerative medicine successfully treating human chronic pathologies by using a heparan sulfate mimetic (ReGeneraTing agents [RGTA]). Periodontitis are inflammatory diseases destroying the tooth-supporting tissues with no satisfactory therapy. We studied in vivo RGTA ability to fully restore the tooth supporting tissues. After periodontitis induction, hamsters were treated with RGTA (1.5 mg kg(-1) w(-1)) or saline. Bone loss was evaluated and immunohistochemical labeling of molecules expressed during cementum development was performed. RGTA treatment restored alveolar bone and the attachment apparatus where fibers were inserted in acellular decorin-negative cementum. RGTA treatment increased the epithelial rests of Malassez, previously depleted by periodontitis. Bone morphogenetic protein (BMP) expressions were compartmentalized: BMP-3 was strongly expressed by epithelial rests of Malassez; BMP-7 was expressed by cells lying on the cementum and BMP-2 by osteoprogenitors around bone formation sites but not at the root-bone interface. Cells near the cementum and bone expressed the ALK2 receptor. This is the first evidence that reconstructing the extracellular matrix scaffold with a heparan sulfate mimetic regenerated the root interface despite the persistence of the bacteria responsible for the disease The improved cellular microenvironment led to the sequential recruitment of cell populations involved in attachment apparatus regeneration. PMID- 21548713 TI - Stents as a platform for drug delivery. AB - INTRODUCTION: Drug delivery stents have proved their efficacy at preventing coronary restenosis and their potential in treating the occlusion or stricture of other body passageways, such as peripheral vessels and alimentary canals. The drug delivery systems on such stent platforms contribute to this improved therapeutic efficacy by providing improved drug delivery performance, along with reduced concerns encountered by current stents (e.g., in-stent restenosis, late thrombosis and delayed healing). AREAS COVERED: A wide variety of drug delivery stents (metallic drug-eluting stents, absorbable drug-eluting stents, and polymer free drug-eluting stents for coronary and other applications) that are commercially available or under investigation are collected and summarized in this review, with emphasis on their drug delivery aspects. This review also gives insights into the progression of stent-based drug delivery strategies for the prevention of stent-related problems, or the treatment of local diseases. In addition, a critical analysis of the advantages and challenges of such strategies is provided. EXPERT OPINION: With an in-depth understanding of drug properties, tissue/organ biology and disease conditions, stent drug delivery systems can be improved further, to endow the stents with better efficacy and safety, along with lower toxicity. There is also a great need for stents that can simultaneously deliver multiple drugs, to treat complex diseases from multiple aspects, or to treat several diseases at the same time. Drug release kinetics greatly determines the stent performance, thus effective strategies should also be developed to achieve customized kinetics. PMID- 21548714 TI - Dynamic behavior and spontaneous differentiation of mouse embryoid bodies on hydrogel substrates of different surface charge and chemical structures. AB - Differentiation of embryoid bodies (EBs) into particular cell lineages has been extensively studied. There is an increasing interest in the effect of soft hydrogel scaffolds on the behavior of EBs, such as the initial adhesion, dynamic morphology change, and differentiation. In this study, without adding any other bioactive factors in the serum-containing medium, dynamic behaviors of mouse EBs loaded on the surface of hydrogels with different surface charge and chemical structures are investigated. EBs adhered quickly to negatively charged poly(sodium p-styrene sulfonate) (PNaSS) hydrogels, which facilitates EBs spreading, migration, and differentiation into three germ layers with high efficiency of cardiomyocytes differentiation, similar to that on gelatin coated polystyrene (PS) culture plate. While on neutral poly(acrylamide) (PAAm) hydrogels, EBs maintained the initial spherical morphology with high expression of pluripotency-related markers in the short culture periods, and then showed the significantly greater levels of selected endoderm markers after long-time culture. EBs cultured on negatively charged poly(2-acrylamido-2-methyl-propane sulfonic acid sodium salt) (PNaAMPS) gels demonstrated the analogous behaviors with that of neutral PAAm gels at early differentiation phase (day 4+1). Then, their adhesion, spreading and differentiation were quite similar to that on negatively charged PNaSS gels. The correlation between surface properties of hydrogels and EBs differentiation was discussed. PMID- 21548715 TI - AMP-activated protein kinase modulators: a patent review (2006 - 2010). AB - INTRODUCTION: AMPK is a key player in the regulation of energy balance at both the cellular and whole-body levels, placing it at the center stage in studies of metabolic disorders. Recently, AMPK has also been identified as a potential target for either therapy or prevention of some types of cancer. Thus, identification of AMPK modulators for possible use as novel therapeutic drugs, both for treatment of metabolic disorders and cancer, will have a high commercial potential. AREAS COVERED: This review covers the structures and activities of AMPK modulators described in the patent literature since 2006. The patents reviewed include those for direct and/or indirect activators of AMPK, and novel pharmaceutical compounds with potential for use in the prevention and/or treatment of metabolic disorders, and cancer targeting AMPK. EXPERT OPINION: Targeting of AMPK appears to be an attractive strategy in the treatment of metabolic disorders. However, some detrimental effects of AMPK have also been reported, including a possible tumor-promoting effect in some settings and a heart disease-causing effect. Moreover, activation of AMPK in the hypothalamus may cause undesired consequences, such as an increase in feeding and body weight gain. These effects, therefore, must be carefully assessed for the development of therapeutic drugs targeting AMPK. PMID- 21548716 TI - Pharmacokinetic evaluation of eltoprazine. AB - INTRODUCTION: Approvals and availability of drugs and delivery systems to treat attention-deficit/hyperactivity disorder (ADHD) have increased steadily in the last decade. The development of new pharmacological agents to treat ADHD symptoms in adults allows for both single and combination therapy for optimal efficacy. Eltoprazine hydrochloride, a serotonergic agent currently under development, is the focus of the current paper. AREAS COVERED: This paper provides an overview of the pharmacokinetics (PK) of the non-stimulant medication eltoprazine. The PK profile of eltoprazine, based on standard PK sampling accompanied by safety monitoring, is described. A literature search and review of the studies published on eltoprazine were carried out using the PubMed database up to November 2010. EXPERT OPINION: Although clinical studies of eltoprazine did not conclusively demonstrate its efficacy in treating pathological aggression in humans, eltoprazine has shown to be a well-tolerated drug in both healthy volunteers and patients across several indications studied thus far. More recently, the role of eltoprazine in reducing symptoms of ADHD in adults has been explored in a clinical trial. Future research may provide endophenotypical characteristics to help identify specific subgroups of patients with ADHD, who can benefit from the development of eltoprazine, to maximize efficacy while minimizing adverse reactions. PMID- 21548717 TI - Molecular targets for selective killing of TRAIL-resistant leukemic cells. AB - INTRODUCTION: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, and shows promising therapeutic activity against solid tumors and lymphomas, in a variety of Phase I and II clinical trials. In contrast, primary leukemias have shown poor susceptibility to TRAIL-mediated cytotoxicity, suggesting the need for sensitizing TRAIL-resistant leukemic cells, by combining soluble recombinant TRAIL either with chemotherapeutic drugs, or with targeted small molecules. AREAS COVERED: This review discusses potential therapeutic applications of combinations able to restore the sensitivity of leukemic cells to either recombinant TRAIL or anti-TRAIL-receptor agonistic antibodies for the treatment of hematological malignancies. EXPERT OPINION: Up-to date knowledge of the most innovative anti-leukemic therapies including functional screening of specific-sensitizers, enhancing TRAIL-mediated cytotoxicity. Strategies aimed to enhance TRAIL-mediated apoptosis, include the combination of novel sensitizers, functionally identified from libraries of pharmaceutically active, synthetic or naturally derived compounds. Other approaches aim to employ the administration of stem cells engineered to express TRAIL, in the leukemic stem cell niche, and promise to be a successful treatment with reduced specific toxicity. PMID- 21548718 TI - Preparation of stable micron-sized crystalline irbesartan particles for the enhancement of dissolution rate. AB - PURPOSE: In this study, micron-sized crystalline drug particles of irbesartan (IBS) were prepared to improve its stability and dissolution rate. METHOD: The approach to crystalline particles was based on the liquid precipitation process by which the amorphous particles were prepared. Pharmaceutical acceptable additives were used as the crystallization agent to convert the amorphous drug into crystalline particles. High pressure homogenization (HPH) process has been employed to reduce the size of the crystalline particles, and the micron-sized particles were obtained by the freeze-drying process. RESULTS: Different additives show different influences on the polymorphic form of IBS. Polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) were effective in stabilizing amorphous particles instead of converting amorphous drug into crystalline particles, while poloxamer407 (F127) and tween80 (T80) could convert the amorphous drug into crystalline particles. T80 was also effective in controlling the particle size than that of F127. After HPH, crystalline particles with an average of 0.8 MUm were obtained. The freeze-dried micron-sized crystalline particles exhibited significantly enhanced in vitro dissolution rate when compared to the raw drug. SEM, FT-IR, XRD, DSC and dissolution rate studies indicated that the micron-sized particles were stable during 6 months storage. CONCLUSION: The preparation of micron-sized crystalline drug particles is an effective way to improve the stability and dissolution rate of irbesartan. PMID- 21548719 TI - Pegaptanib octasodium for the treatment of diabetic macular edema. PMID- 21548720 TI - Exenatide once weekly in type 2 diabetes mellitus. PMID- 21548721 TI - Prevention of atrial fibrillation complications with antiarrhythmic drugs: still an unmet need in clinical practice. PMID- 21548722 TI - Cilostazol in patients with ischemic stroke. PMID- 21548723 TI - Carmustine-impregnated wafers and their impact in the management of high-grade glioma. PMID- 21548724 TI - Duloxetine use in painful conditions. PMID- 21548725 TI - A state of art review on vardenafil in men with erectile dysfunction and associated underlying diseases. PMID- 21548726 TI - The quest for an optimized protocol for whole-heart decellularization: a comparison of three popular and a novel decellularization technique and their diverse effects on crucial extracellular matrix qualities. AB - Decellularized cardiac extracellular matrix (ECM) has been introduced as a template for cardiac tissue engineering, providing the advantages of a prevascularized scaffold that mimics native micro- and macroarchitecture to a degree difficult to achieve with synthetic materials. Nonetheless, the decellularization protocols used to create acellular myocardial scaffolds vary widely throughout the literature. In this study we performed a direct comparison of three previously described protocols while introducing and evaluating a novel, specifically developed fourth protocol, by decellularizing whole rat hearts through software-controlled automatic coronary perfusion. Although all protocols preserved the macroarchitecture of the hearts and all resulting scaffolds could successfully be reseeded with C2C12 myoblasts, assessing their biocompatibility for three-dimensional in vitro studies, we found striking differences concerning the microcomposition of the ECM scaffolds on a histological and biochemical level. While laminin could still be detected in all groups, other crucial ECM components, like elastin and collagen IV, were completely removed by at least one of the protocols. Further, only three protocols maintained a glycosaminoglycan content comparable to native tissue, whereas the remaining DNA content within the ECM varied highly throughout all four tested protocols. This study showed that the degree of acellularity and resulting ECM composition of decellularized myocardial scaffolds strongly differs depending on the decellularization protocol. PMID- 21548728 TI - Cell therapy industry: billion dollar global business with unlimited potential. PMID- 21548727 TI - Preparation and evaluation of poly(lactic-co-glycolic acid) microparticles as a carrier for pulmonary delivery of recombinant human interleukin-2: II. In vitro studies on aerodynamic properties of dry powder inhaler formulations. AB - OBJECTIVE: The aim of this study was the preparation and evaluation of dry powder formulations of recombinant human interleukin-2 (rhIL-2)-loaded microparticles to be administered to the lung by inhalation. METHODS: As indicated in our previous study, the microparticles were prepared by modified water-in-oil-in-water (w(1)/o/w(3)) double emulsion solvent extraction method using poly(lactic-co glycolic acid) (PLGA) polymers. The dry powder formulations were prepared with blending of microparticles and mannitol as a coarse carrier. The actual aerodynamic characteristics of the microparticles alone and prepared mixtures with mannitol are evaluated by using the eight-stage Andersen cascade impactor. RESULTS: Due to the low tapped density of microparticles (<0.4 g/cm(3)), the theoretical aerodynamic diameter (MMADt) values were calculated (<5 MUm) on the basis of the geometrical particle diameter and tapped density values. The lowest tapped density value (0.17 g/cm(3)) belongs to the cyclodextrin-containing formulation. According to the results obtained using the cascade impactor, the emitted doses for all microparticle formulations were found to be rather high and during the aerosolization for all the formulations except F3 and F5, >90% of the capsule content was determined to be released. However, the actual aerodynamic diameter (MMADa) values were seen to be higher than the MMADt values. The blending of the microparticles with mannitol allowed their aerodynamic diameters to decrease and their fine particle fraction values to increase. CONCLUSION: The obtained results have shown that the mixing of rhIL-2-loaded microparticles with mannitol possess suitable aerodynamic characteristics to be administered to the lungs by inhalation. PMID- 21548729 TI - An ethical framework for expanded access to cell-based therapies. PMID- 21548736 TI - Modification of human embryonic stem cell-derived dendritic cells with mRNA for efficient antigen presentation and enhanced potency. AB - AIM: Dendritic cell (DC)-based vaccines are designed to exploit the intrinsic capacity of these highly effective antigen presenting cells to prime and boost antigen-specific T-cell immune responses. Successful development of DC-based vaccines will be dependent on the ability to utilize and harness the full potential of these potent immune stimulatory cells. Recent advances to generate DCs derived from human embryonic stem cells (hESCs) that are suitable for clinical use represent an alternative strategy from conventional approaches of using patient-specific DCs. Although the differentiation of hESC-derived DCs in serum-free defined conditions has been established, the stimulatory potential of these hESC-derived DCs have not been fully evaluated. METHODS: hESC-derived DCs were differentiated in serum-free defined culture conditions. The delivery of antigen into hESC-derived DCs was investigated using mRNA transfection and replication-deficient adenoviral vector transduction. hESC-derived DCs modified with antigen were evaluated for their capacity to stimulate antigen-specific T cell responses with known HLA matching. Since IL-12 is a key cytokine that drives T-cell function, further enhancement of DC potency was evaluated by transfecting mRNA encoding the IL-12p70 protein into hESC-derived DCs. RESULTS: The transfection of mRNA into hESC-derived DCs was effective for heterologous protein expression. The efficiency of adenoviral vector transduction into hESC-derived DCs was poor. These mRNA-transfected DCs were capable of stimulating human telomerase reverse transcriptase antigen-specific T cells composed of varying degrees of HLA matching. In addition, we observed the transfection of mRNA encoding IL-12p70 enhanced the T-cell stimulation potency of hESC-derived DCs. CONCLUSION: These data provide support for the development and modification of hESC-derived DCs with mRNA as a potential strategy for the induction of T-cell mediated immunity. PMID- 21548737 TI - Restoration of motor control and dopaminergic activity in rats with unilateral 6 hydroxy-dopamine lesions. AB - AIM: To restore motor function and dopaminergic activity in the nigrostriatum of rats with unilateral 6-hydroxy-dopamine lesions using implants of encapsulated porcine choroid plexus cells. MATERIALS & METHODS: Neonatal porcine choroid plexus cells were prepared and maintained in culture, then encapsulated within alginate-polyornithine capsules (600-660 um). Rats were unilaterally injected with 6-hydroxy-dopamine into the striatum. Those with lesions verified after 2 and 4 weeks were selected for experiments. Rats were implanted adjacent to the lesion with ten capsules 2-4 days later with (treated, n = 12) or without (control, n = 10) choroid plexus cells. RESULTS: The choroid plexus cells were shown to produce a wide range of neurorestorative proteins. The treated group had a 60% improvement in motor behavior compared with the control group (p < 0.01). The treated group also had a significant improvement in nigrostriatal dopaminergic activity (31%, p < 0.02). CONCLUSION: Capsules containing porcine choroid plexus cells release therapeutic molecules that stimulate regeneration of the lesioned nigrostriatum in rats. PMID- 21548738 TI - Self-renewal and scalability of human embryonic stem cells for human therapy. AB - Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and retain the pluripotency to differentiate into all cell types in the body. Therefore, as a renewable source of various cell types, hESCs hold great promise for human cell replacement therapy. While significant progress has been made in establishing the culture conditions for the long-term self-renewal of hESCs, several challenges remain to be overcome for the clinical application of hESCs. One such challenge is to develop strategies to scale-up the production of clinic-grade hESCs in xeno free and chemically defined medium without inducing genomic instability. To achieve this goal, it is critical to elucidate the molecular pathways required to maintain the self-renewal, survival and genomic stability of hESCs. This article describes recent progress in addressing this challenge and discusses the strategies to improve the scalability of the production of hESCs by inhibiting their apoptosis. PMID- 21548740 TI - Prospects of stem cell therapy in osteoarthritis. AB - Osteoarthritis is a common disorder in which there is not only extensive degeneration but also an aberrant attempt at repair in joints. Stem cell therapy could provide a permanent, biological solution, with all sources of stem cells (embryonic, fetal and adult) showing some degree of potential. Mesenchymal stromal/stem cells, however, appear to be the leading candidates because of their ability to be sourced from many or all joint tissues. They may also modulate the immune response of individuals, in a manner influenced by local factors. This biological behavior of stem cells renders the application of regulatory standardizations challenging in comparison to pharmaceutical therapies. However, this would not be an issue if endogenous stem cells were activated to effect repair of an arthritic joint. PMID- 21548739 TI - Advances in bone marrow-derived cell therapy: CD31-expressing cells as next generation cardiovascular cell therapy. AB - In the past few years, bone marrow (BM)-derived cells have been used to regenerate damaged cardiovascular tissues post-myocardial infarction. Recent clinical trials have shown controversial results in recovering damaged cardiac tissue. New progress has shown that the underlying mechanisms of cell-based therapy relies more heavily on humoral and paracrine effects rather than on new tissue generation. However, studies have also reported the potential of new endothelial cell generation from BM cells. Thus, efforts have been made to identify cells having higher humoral or therapeutic effects as well as their surface markers. Specifically, BM-derived CD31+ cells were isolated by a surface marker and demonstrated high angio-vasculogenic effects. This article will describe recent advances in the therapeutic use of BM-derived cells and the usefulness of CD31+ cells. PMID- 21548743 TI - Low Karnofsky Performance Scale score and glioblastoma multiforme. PMID- 21548744 TI - Comprehensive analysis of risk factors for seizures after deep brain stimulation surgery. Clinical article. AB - OBJECT: The aim of this study was to assess risk factors for postoperative seizures after deep brain stimulation (DBS) lead implantation surgery and the impact of such seizures on length of stay and discharge disposition. METHODS: The authors reviewed a consecutive series of 161 cases involving patients who underwent implantation of 288 electrodes for treatment of movement disorders at a single institution to determine the absolute risk of postoperative seizures, to describe the timing and type of seizures, to identify statistically significant risk factors for seizures, and to determine whether there are possible indications for seizure prophylaxis after DBS lead implantation. The electronic medical records were reviewed to identify demographic details, medical history, operative course, and postoperative outcomes and complications. To evaluate significant associations between potential risk factors and postoperative seizures, both univariate and multivariate analyses were performed. RESULTS: Seven (4.3%) of 161 patients experienced postoperative seizures, all of which were documented to have been generalized tonic-clonic seizures. In 5 (71%) of 7 cases, patients only experienced a single seizure. Similarly, in 5 of 7 cases, patients experienced seizures within 24 hours of surgery. In 6 (86%) of the 7 cases, seizures occurred within 48 hours of surgery. Univariate analysis identified 3 significant associations (or risk factors) for postoperative seizures: abnormal findings on postoperative imaging (hemorrhage, edema, and or ischemia; p < 0.001), age greater than 60 years (p = 0.021), and transventricular electrode trajectories (p = 0.023). The only significant factor identified on multivariate analysis was abnormal findings on postoperative imaging (p < 0.0001, OR 50.4, 95% CI 5.7-444.3). Patients who experienced postoperative seizures had a significantly longer length of stay than those who were seizure free (mean +/- SD 5.29 +/- 3.77 days vs 2.38 +/- 2.38 days; p = 0.002, Student 2-tailed t-test). Likewise, final discharge to home was significantly less likely in patients who experienced seizures after implantation (43%) compared with those patients who did not (92%; p = 0.00194, Fisher exact test). CONCLUSIONS: These results affirm that seizures are an uncommon complication of DBS surgery and generally occur within 48 hours of surgery. The results also indicate that hemorrhage, edema, or ischemia on postoperative images ("abnormal" imaging findings) increases the relative risk of postoperative seizures by 30- to 50-fold, providing statistical credence to the long-held assumption that seizures are associated with intracranial vascular events. Even in the setting of a postimplantation imaging abnormality, long-term anticonvulsant therapy will not likely be required because none of our patients developed chronic epilepsy. PMID- 21548745 TI - Treatment outcomes for patients with glioblastoma multiforme and a low Karnofsky Performance Scale score on presentation to a tertiary care institution. Clinical article. AB - OBJECT: The object of this study was to determine the benefit of surgery, radiation, and chemotherapy for patients with glioblastoma multiforme (GBM) and a low Karnofsky Performance Scale (KPS) score. METHODS: The authors retrospectively evaluated the records of patients who underwent primary treatment for pathologically confirmed GBM and with a KPS score <= 50 on initial evaluation for radiation therapy at a tertiary care institution between 1977 and 2006. Seventy four patients with a median age of 69 years (range 19-88 years) and a median KPS score of 50 (range 20-50) were retrospectively grouped into the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) Classes IV (11 patients), V (15 patients), and VI (48 patients). Patients underwent biopsy (38 patients) or tumor resection (36 patients). Forty-seven patients received radiation. Nineteen patients also received chemotherapy (53% temozolomide), initiated concurrently (47%) or after radiotherapy. RESULTS: The median survival overall was 2.3 months (range 0.2-48 months). Median survival stratified by RPA Classes IV, V, and VI was 6.6, 6.6, and 1.8 months, respectively (p < 0.001, log rank test). Median survival for patients receiving radiation (5.2 months) was greater than that for patients who declined radiation (1.6 months, p < 0.001). Patients in RPA Class VI appeared to benefit from radiotherapy only when tumor resection was also performed. The median survival from treatment initiation was greater for patients receiving chemotherapy concomitantly with radiotherapy (9.8 months) as compared with radiotherapy alone (1.7 months, p = 0.002). Of 20 patients seen for follow-up in the clinic at a median of 48 days (range 24-196 days) following radiotherapy, 70% were noted to have an improvement in the KPS score of between 10 and 30 points from the baseline score. On multivariate analysis, only RPA class (p = 0.01), resection (HR = 0.37, p = 0.001), and radiation therapy (HR = 0.39, p = 0.02) were significant predictors of a decreased mortality rate. CONCLUSIONS: Patients with a KPS score <= 50 appear to have increased survival and functional status following tumor resection and radiation. The extent of benefit from concomitant chemotherapy is unclear. Future studies may benefit from reporting that utilizes a prognostic classification system such as the RTOG RPA class, which has been shown to be effective at separating outcomes even in patients with low performance status. Patients with GBMs and low KPS scores need to be evaluated in prospective studies to identify the extent to which different therapies improve outcomes. PMID- 21548741 TI - Achieving stable human stem cell engraftment and survival in the CNS: is the future of regenerative medicine immunodeficient? AB - There is potential for a variety of stem cell populations to mediate repair in the diseased or injured CNS; in some cases, this theoretical possibility has already transitioned to clinical safety testing. However, careful consideration of preclinical animal models is essential to provide an appropriate assessment of stem cell safety and efficacy, as well as the basic biological mechanisms of stem cell action. This article examines the lessons learned from early tissue, organ and hematopoietic grafting, the early assumptions of the stem cell and CNS fields with regard to immunoprivilege, and the history of success in stem cell transplantation into the CNS. Finally, we discuss strategies in the selection of animal models to maximize the predictive validity of preclinical safety and efficacy studies. PMID- 21548746 TI - A 10-year experience of radiosurgical treatment for cerebral arteriovenous malformations: a perspective from a series with large malformations. Clinical article. AB - OBJECT: The purpose of this study was to describe a 10-year experience in the use of radiosurgery (RS) for patients with arteriovenous malformations (AVMs) in Puerto Rico. METHODS: This retrospective analysis was performed for all patients with AVMs treated with RS by the senior author (R.H.B.) in Puerto Rico. Between February 1999 and December 2009, a total of 83 patients underwent the procedure. All charts were reviewed for recollection of demographic data, and AVM and treatment characteristics. Clinical and radiographic follow-up information was collected retrospectively. RESULTS: Eighty-three patients were treated and 86 RS procedures for AVMs were performed during a 10-year period. Eight patients were lost to follow-up. The remaining 75 patients included 36 males and 39 females, whose median age was 34.5 years. Hemorrhage was the initial presentation in 40% of patients. Fifty-seven AVMs (73%) were treated previously with endovascular neurosurgery, without success. The median volume of the malformation was 17.7 ml. Nearly 65% of the malformations were considered large (>= 10 ml) in volume. Forty patients had AVMs with largest diameter >= 3.5 cm. The overall obliteration rate was 56.4%, and the median time for obliteration was 29 months. The AVMs >= 3.5 cm in diameter had a greater latency period than those < 3.5 cm (31 months vs 46 months, respectively; p = 0.01). In addition, AVM obliteration was inversely associated with its volume, especially in large lesions (p = 0.037). In bivariate analysis, patients achieving obliteration had lower Spetzler-Martin scores compared with patients in whom obliteration was not achieved (p = 0.009). Postradiosurgery hemorrhages were seen in 9 cases. Eleven patients underwent surgery after RS. Major neurological deficits developed in 9 patients, whereas 17 had only minor deficits. The occurrence of neurological deficits was significantly associated with lesions with volume >= 10 ml. CONCLUSIONS: Radiosurgery is a reasonable treatment option for AVMs in the majority of cases, in spite of the large, difficult-to-treat malformations. PMID- 21548747 TI - Perineural extension of cutaneous desmoplastic melanoma mimicking an intracranial malignant peripheral nerve sheath tumor. Case report. AB - The authors present a case illustrating the importance of obtaining a biopsy of any facial skin lesions in a patient presenting with an intracranial tumor involving the facial or trigeminal nerve. Conventional malignant melanoma metastasizes to the brain frequently and does not usually pose diagnostic difficulties. Direct intracranial spread of cutaneous melanoma is rare. In our patient, desmoplastic melanoma with perineural spread to the Meckel cave mimicked a malignant peripheral nerve sheath tumor clinically, radiographically, and histologically. PMID- 21548748 TI - Segmental anatomy of cerebellar arteries: a proposed nomenclature. Laboratory investigation. AB - OBJECT: The conceptual division of intracranial arteries into segments provides a better understanding of their courses and a useful working vocabulary. Segmental anatomy of cerebral arteries is commonly cited by a numerical nomenclature, but an analogous nomenclature for cerebellar arteries has not been described. In this report, the microsurgical anatomy of the cerebellar arteries is reviewed, and a numbering system for cerebellar arteries is proposed. METHODS: Cerebellar arteries were designated by the first letter of the artery's name in lowercase letters, distinguishing them from cerebral arteries with the same first letter of the artery's name. Segmental anatomy was numbered in ascending order from proximal to distal segments. RESULTS: The superior cerebellar artery was divided into 4 segments: s(1), anterior pontomesencephalic segment; s(2), lateral pontomesencephalic segment; s(3), cerebellomesencephalic segment; and s(4), cortical segment. The anterior inferior cerebellar artery was divided into 4 segments: a(1), anterior pontine segment; a(2), lateral pontine segment; a(3), flocculopeduncular segment; and a(4), cortical segment. The posterior inferior cerebellar artery was divided into 5 segments: p(1), anterior medullary segment; p(2), lateral medullary segment; p(3), tonsillomedullary segment; p(4), telovelotonsillar segment; and p(5), cortical segment. CONCLUSIONS: The proposed nomenclature for segmental anatomy of cerebellar artery complements established nomenclature for segmental anatomy of cerebral arteries. This nomenclature is simple, easy to learn, and practical. The nomenclature localizes distal cerebellar artery aneurysms and also localizes an anastomosis or describes a graft's connections to donor and recipient arteries. These applications of the proposed nomenclature with cerebellar arteries mimic the applications of the established nomenclature with cerebral arteries. PMID- 21548749 TI - Histopathological features with angiographic correlates of internal carotid artery pseudo-occlusion: impact of plaque compositions. Clinical article. AB - OBJECT: This study describes clinicopathological characteristics of pseudo occlusion of the internal carotid artery with regard to its possible mechanisms. METHODS: The authors retrospectively reviewed 17 patients with pseudo-occlusion and 23 with high-grade stenosis (North American Symptomatic Carotid Endarterectomy Trial criteria >= 90%, but no collapsed distal internal carotid artery) who underwent carotid endarterectomy. Atherosclerotic risk factors, clinical presentation, angiographic findings, and histological features of plaque obtained from the carotid endarterectomy were investigated and comparisons were made between groups. RESULTS: Plaques obtained in the pseudo-occlusion group were significantly more fibrous and less atheromatous than those in the high-grade stenosis group. Old, organized thrombi were more frequently found in pseudo occlusion group plaques than in high-grade stenosis group plaques. Plaques acquired in the pseudo-occlusion group had 2 different histological features: the presence or absence of the original lumen. The pseudo-occlusion plaques with total occlusion and recanalization (8 patients) were composed of thrombotic total occlusion with lumen recanalization by large neovascular channels, whereas those with severe stenosis (9 patients) were fibrous or fibroatheromatous and had severe stenosis of the original lumen. In patients with pseudo-occlusion and total occlusion and recanalization, the authors observed a significantly higher incidence of transient ischemic attack and anterior communicating artery posterior communicating artery collateral flow than those with high-grade stenosis and pseudo-occlusion with severe stenosis. CONCLUSIONS: Plaques of the pseudo-occlusion group were more fibrous than those of the high-grade stenosis group and had 2 different histological features: pseudo-occlusion with total occlusion and recanalization or pseudoocclusion with severe stenosis. This difference in plaque histology may be related to the clinical features of pseudoocclusion, such as symptoms and collateral flow patterns. PMID- 21548750 TI - Awake surgery for WHO Grade II gliomas within "noneloquent" areas in the left dominant hemisphere: toward a "supratotal" resection. Clinical article. AB - OBJECT: It has been demonstrated that an extensive resection (total or subtotal) may significantly increase the overall survival in patients with WHO Grade II gliomas (low-grade gliomas [LGGs]). Yet, recent data have shown that conventional MR imaging underestimates the spatial extent of LGG, since tumor cells were found up to 20 mm around MR imaging abnormalities. Thus, it was hypothesized that an extended resection with a margin beyond MR imaging-defined abnormalities-a "supratotal" resection-might improve the outcome of LGG. However, because of the frequent location of LGG within "eloquent" brain areas, it is often difficult to achieve such a supratotal resection. This could nevertheless be possible when LGGs involve "noneloquent" areas, even in the left dominant hemisphere. The authors report on their use of awake electrical mapping to tailor the resection according to functional boundaries, that is, to pursue the resection beyond MR imaging-defined abnormalities, until corticosubcortical eloquent structures are encountered. Their aim was to apply this reliable surgical technique to LGGs located not within eloquent areas but distant from eloquent areas, to take a margin around the LGG visible on MR imaging while preserving brain function. METHODS: Fifteen right-handed patients with a total of 17 tumors underwent resection of WHO Grade II gliomas involving nonfunctional areas within the left dominant hemisphere. In all patients, seizures were the initial manifestation of the tumors. Awake surgery with intraoperative electrostimulation was performed in all cases. The resection was continued until the surgeon reached cortical and subcortical areas crucial for brain function, especially language, as defined by the intrasurgical electrical mapping. The extent of resection was evaluated on postoperative FLAIR-weighted MR images. RESULTS: Despite transient neurological worsening in 60% of cases, all patients recovered and returned to a normal life. Seizure control was obtained in all patients with a decrease of antiepileptic drug therapy. Postoperative MR imaging showed that total resection was achieved in all 17 tumors and supratotal resection in 15. The average volume of the postoperative cavity (36.8 cm(3)) was significantly larger than the mean preoperative tumor volume (26.6 cm(3)) (p = 0.009). Neuropathological examination confirmed the diagnosis of WHO Grade II glioma in all cases. The mean duration of postoperative follow-up was 35.7 months (range 6-135 months). Only 4 of 15 patients experienced recurrence (without anaplastic transformation); the average time to recurrence in these cases was 38 months; radiotherapy was performed 6 years after the relapse in 1 case; no other patients received any adjuvant treatment. This series was compared with a control group of 29 patients who had "only" complete resection: anaplastic transformation was observed in 7 cases in the control group but not in any case in the series of patients who underwent supracomplete resection (p = 0.037). Furthermore, adjuvant treatment was administered in 10 patients in the control group compared with 1 patient who underwent supracomplete resection (p = 0.043). CONCLUSIONS: These findings support the usefulness of awake surgery with intraoperative functional (language) mapping with the attempt to perform supratotal resection of LGGs involving noneloquent areas in the left hemisphere. Indeed, the extent of resection was significantly increased in all cases but 2, with no additional permanent deficit and with control of seizures in all patients. The goal of supracomplete resection is currently to delay the anaplastic transformation, even if it does not (yet) enable a cure. PMID- 21548751 TI - Use of 5-aminolevulinic acid for the confirmation of deep-seated brain tumors during stereotactic biopsy. Report of 2 cases. AB - 5-Aminolevulinic acid (ALA) has been successfully used to confirm the target tumor tissues obtained during stereotactic biopsy. The authors report their experience with 2 patients who underwent stereotactic biopsies of thalamic malignant lymphoma and pontine glioma utilizing 5-ALA. Intraoperatively, the tumor specimens fluoresced, allowing for confirmation that the obtained target specimen contained tumor tissues. No serious side effects or complications occurred. PMID- 21548753 TI - Interhemispheric hygroma. PMID- 21548754 TI - Low-grade gliomas. PMID- 21548755 TI - Crystalline silica and lung cancer: a critical review of the occupational epidemiology literature of exposure-response studies testing this hypothesis. AB - IARC (2009; Metals, Particles and Fibres. IARC Monographs on the Evaluaton of Carcinogenic Risks to Humans. Volume 100C. Lyon, France: IARC) concluded that crystalline silica in occupational settings is a lung carcinogen. This conclusion is based primarily on studies with exposure-response (E-R) analyses and a pooled analysis of 10 major studies with about 1000 lung cancer cases. The purpose of this review is to critically assess this cancer classification based on E-R analyses in 18 studies from eight countries with about 2000 lung cancer cases and the same database used by IARC (2009) . The most appropriate exposure-response analysis is selected from latest study with least effect from bias, confounding, and presented graphically to assist individual assessment of the weight of evidence. Strength of association is consistently weak in the majority of studies. At the highest exposure level the mean relative risk (RR) is 1.5; four studies have strong associations (RRs > 2), three have moderate strong associations (RRs 1.5-2.0), six have weak-negligible associations (RRs 1-1.5), and five have no associations (RRs <=1.0). Biological gradients were an inconsistent finding. Three studies had clear positive E-R trends; 3 had suggestive trends; and 12 had no E-R trends, 9 of which were flat or negative. There was a negative ER slope using RRs at the highest exposure of each study. Consistent findings of weak associations and lack of E-R trends does not support a causal association. Weight of evidence from occupational epidemiology does not support a causal association of lung cancer and silica exposure, which is contrary to the IARC conclusion using essentially the same data. PMID- 21548756 TI - Low co-morbidity, low levels of malnutrition, and low risk of falls in a community-dwelling sample of 85-year-olds are associated with successful aging: the Octabaix study. AB - The population is aging throughout the world. Preserving physical and cognitive functions is crucial to successful aging. The aim of this study was to determine the proportion of 85-year-old community-dwelling subjects aging successfully, applying a quantitative approach, and assessing the association of successful aging with sociodemographic data, global geriatric assessment, and co-morbidity. This was a community-based survey of inhabitants aged 85 years, with 328 out of 487 subjects born in 1924 assigned to seven primary health-care teams, representing a participation rate of 67.5%. Sociodemographic variables, Barthel index (BI), the Spanish version of the Mini-Mental State Examination (MEC), Mini Nutritional Assessment (MNA), Charlson Index, Gait Rating Scale, social risk, quality of life (QoL), and prevalent chronic diseases were assessed. Subjects scoring higher than 90 on the BI and higher than 24 on the MEC were compared with the rest. Multiple regression analysis was performed. Using these criteria, successful aging status was defined in 162 (49.3%) subjects. Using multiple logistic regression analysis, successful agers had significantly lower co morbidity scores (p < 0.02, odds ratio [OR] = 0.791, 95% confidence interval [CI] 0.657-0.952), higher scores on the Gait Rating Scale identifying lower risk of falls (p < 0.0001, OR = 1.753, 95% CI 1.501-2.046), and higher scores on the MNA, indicating lower risk of malnutrition (p < 0.0001, OR = 1.190, 95% CI 1.090 01.299). Regarding QoL, successful agers had significantly higher values than their unsuccessful aging counterparts (p > 0.0001). Almost half of the individuals presented successful aging. Successful agers had less co-morbidity and a lower risk of falls or malnutrition, and they had higher scores on the QoL scale. PMID- 21548757 TI - Proton MR spectroscopy of neural stem cells: does the proton-NMR peak at 1.28 ppm function as a biomarker for cell type or state? AB - Recently, a peak at 1.28 ppm in proton magnetic resonance spectroscopy ((1)H-MRS) of neural stem cells (NSCs) was introduced as a noninterventional biomarker for neurogenesis in vivo. This would be an urgently needed requisite for translational studies in humans regarding the beneficial role of adult neurogenesis for the structural and functional integrity of the brain. However, many concerns have risen about the validity of the proposed signal as a specific marker for NSCs. The peak has also been related to cell-type-independent phenomena such as apoptosis or necrosis. Thus, we compared the 1.28-ppm peak in various immature stem cell populations, including embryonic stem cells, mouse embryonic fibroblasts, embryonic stem cell- and induced pluripotent stem cell derived NSCs, ex vivo isolated embryonic NSCs, as well as mature and tumor cell types from different germ layers. To correlate the integral peak intensity with cell death, we induced both apoptosis with camptothecin and necrosis with sodium azide. A peak at 1.28 ppm was found in most cell types, and in most, but not all, NSCH cultures, demonstrating no specificity for NSCs. The intensities of the 1.28 ppm resonance significantly correlated with the rate of apoptosis, but not with the rate of necrosis, cell cycle phase distribution, cell size, or type. Multiple regression analysis displayed a significant predictive value of the peak intensity for apoptosis only. In this context, its specificity for apoptosis as a major selection process during neurogenesis may suggest this resonance as an indirect marker for neurogenesis in vivo. PMID- 21548758 TI - Role of hnRNP-A1 and miR-590-3p in neuronal death: genetics and expression analysis in patients with Alzheimer disease and frontotemporal lobar degeneration. AB - An association study of heterogeneous nuclear ribonucleoprotein (hnRNP)-A1 was carried out in a population of 274 patients with frontotemporal lobar degeneration (FTLD) and 287 with Alzheimer disease (AD) as compared with 344 age- and gender-matched controls. In addition, we evaluated expression levels of hnRNP A1 and its regulatory microRNA (miR)-590-3p in blood cells from patients and controls. A statistically significant increased frequency of the hnRNP-A1 rs7967622 C/C genotype was observed in FTLD, but not in AD, in patients as compared to controls (23.0 versus 15.4%; p = 0.022, odds ratio [OR] 1.64, confidence interval [CI] 1.09-2.46). Stratifying according to gender, a statistically significant increased frequency of the hnRNP-A1 rs7967622 C/C genotype was observed in male patients as compared to male controls (23.1 versus 11.3%; p = 0.015, OR 2.36, CI 1.22-4.58 but not in females. Considering the rs4016671 single-nucleotide polymorphism (SNP), all patients and controls were wild type. Significantly increased hnRNP-A1 relative expression levels in peripheral blood mononuclear cells (PBMCs) was observed in patients with AD, but not with FTLD, as compared to controls (2.724 +/- 0.570 versus 1.076 +/- 0.187, p = 0.021). Decreased relative expression levels of hsa-miR-590-3p was observed in patients with AD versus controls (0.685 +/- 0.080 versus 0.931 +/- 0.111, p = 0.079), and correlated negatively with hnRNP-A1 mRNA levels (r = -0.615, p = 0.0237). According to these findings, hnRNP-A1 and its transcription regulatory factor miR-590-3p are disregulated in patients with AD, and the hnRNP-A1 rs7967622 C/C genotype is likely a risk factor for FTLD in male populations. PMID- 21548759 TI - Increased susceptibility to liver fibrosis with age is correlated with an altered inflammatory response. AB - It has been suggested that increasing age is correlated with an acceleration of the progression of liver fibrosis induced by various agents, such as hepatitis C virus or chronic alcohol consumption. However, the cellular and molecular changes underlying this predisposition are not entirely understood. In the context of an aging population, it becomes challenging to decipher the mechanisms responsible for this higher susceptibility of older individuals to this acquired liver disorder. To address this issue, we induced liver fibrosis by carbon tetrachloride (CCl(4)) chronic administration to 8-week- and 15-month-old mice. We confirmed that susceptibility to fibrosis development increased with age and showed that aging did not affect fibrosis resolution capacity. We then focused on the impairment of hepatocyte proliferation, oxidative stress, and inflammation as potential mechanisms accelerating the development of fibrosis in the elderly. We detected no inhibition of hepatocyte proliferation after CCl(4) injury in 15 month-old mice, whereas it was inhibited after a partial hepatectomy. Finally, we observed that, in a context in which liver oxidative stress was not differentially increased in both experimental groups, there was a higher recruitment of inflammatory cells, including mostly macrophages and lymphocytes, oriented toward a T helper 2 (T(H)2) response in older mice. Our data show that in conditions of equivalent levels of oxidative stress and maintained hepatocyte proliferative capacity, an increased inflammatory reaction mainly composed of CD4(+) lymphocytes and macrophages expressing T(H)2 cytokines is the main factor involved in the higher susceptibility to fibrosis with increasing age. PMID- 21548760 TI - The delicate pygmy rice rat (Oligoryzomys delicatus) is the principal host of Maporal virus (family Bunyaviridae, genus Hantavirus). AB - Choclo virus (CHOV) and Maporal virus (MAPV) are enzootic in Panama and western Venezuela, respectively. The results of previous studies suggested that the fulvous pygmy rice rat (Oligoryzomys fulvescens) is the principal host of both viruses. The results of an analysis of nucleotide sequence data in this study indicated that the rodent associated with CHOV is the Costa Rican pygmy rice rat (Oligoryzomys costaricensis) and that the rodent associated with MAPV is the delicate pygmy rice rat (Oligoryzomys delicatus). As such, MAPV is ecologically distinct from CHOV and should be considered a species separate from CHOV. PMID- 21548761 TI - Escherichia coli concentrations in feces of geese, coots, and gulls residing on recreational water in The Netherlands. AB - Contamination of recreational water by bird feces is a main concern of water managers. It is important to understand the sources of Escherichia coli contamination since the organism is frequently used as a water hygiene parameter. Here, we address presence and levels of E. coli in fecal shedding from several waterfowl (25 geese, 20 coots, and 40 gulls) and demonstrate that there is a bird species variation. Results indicate that gull feces contain a greater average concentration of E. coli per gram than do geese or coot feces. However, contamination risks also depends on bird abundance. These are important aspects for effective water bird management. PMID- 21548762 TI - International travel increase and malaria importation in Romania, 2008-2009. AB - OBJECTIVES: This report aims to assess the epidemiological characteristics of imported malaria in Romania in the context of international travel increase, and to compare them with the data reported by other European countries. METHODS: Data on malaria cases were provided by the National Centre for Surveillance and Control of the Communicable Disease, whereas the data regarding international travels to and from Romania were retrieved from the Romanian Statistical Yearbook. RESULTS: The number of Romanian citizens who traveled to Africa in 2007 increased by over 600% as compared to the previous year. During the years 2008 2009, 25 cases of imported malaria were registered in Romania, with no fatalities. All patients were male and most of them (84%) acquired the infection in Africa. Plasmodium falciparum was involved in 68% of cases. The majority of the affected patients (41%) were aged 31 to 40 years. Labor was the main reason for traveling (72%), and 92% of cases took either partial or no chemoprophylaxis. CONCLUSION: The continuous growth of professional and leisure voyages to malaria endemic regions may lead to a dramatic increase of imported cases, especially if prophylactic measures are not strictly followed. PMID- 21548763 TI - Rift Valley fever epidemiology, surveillance, and control: what have models contributed? AB - BACKGROUND: Rift Valley fever (RVF) is an emerging vector-borne zoonotic disease that represents a threat to human health, animal health, and livestock production, particularly in Africa. The epidemiology of RVF is not well understood, so that forecasting RVF outbreaks and carrying out efficient and timely control measures remains a challenge. Various epidemiological modeling tools have been used to increase knowledge on RVF epidemiology and to inform disease management policies. AIM: This narrative review gives an overview of modeling tools used to date to measure or model RVF risk in animals, and presents how they have contributed to increasing our understanding of RVF occurrence or informed RVF surveillance and control strategies. METHODOLOGY: Systematic literature searches were performed in PubMed and ISI Web of Knowledge. Additional research work was identified from other sources. RESULTS: Literature was scarce. Research work was highly heterogeneous in methodology, level of complexity, geographic scale of approach, and geographical area of study. Gaps in knowledge and data were frequent, and uncertainty was not always explored. Spatial approaches were the most commonly utilized techniques and have been used at both local and continental scales, the latter leading to the implementation of an early warning system. Three articles using dynamic transmission models explored the potential of RVF endemicity. Risk factor studies identified water-related environmental risk factors associated with RVF occurrence in domestic livestock. Risk assessments identified importation of infected animals, contaminated products, or infected vectors as key risk pathways for the introduction of RVF virus into disease-free areas. CONCLUSIONS: Enhanced outbreak prediction and control and increased knowledge on RVF epidemiology would benefit from additional field data, continued development, and refinement of modeling techniques for exploring plausible disease transmission mechanisms and the impact of intervention strategies. PMID- 21548764 TI - Skin lesion by methicillin-resistant Staphylococcus aureus ST398-t1451 in a Spanish pig farmer: possible transmission from animals to humans. AB - Skin lesions by methicillin-resistant Staphylococcus aureus (MRSA) of the lineage ST398-t1451 were detected in a pig-farmer in Spain in 2010. Similar MRSA ST398 t1451 strains were also detected in nasal samples from the patient, his brother, and nine pigs from his farm. All human and animal strains were ascribed to the SCCmec type V and the agr type I, showed tetracycline-erythromycin-clindamycin resistances, and harbored the tetK, tetM, and ermC resistance genes. They were negative for all tested toxin genes (lukS/lukF, tst, eta, etb, and etd). All human and animal strains showed closely related pulsed-field gel electrophoresis ApaI patterns. Possible MRSA transmission from animals to humans is suggested. PMID- 21548765 TI - West Nile virus in Europe: a comparison of surveillance system designs in a changing epidemiological context. AB - Current knowledge suggests that there is a low-level and recurrent circulation of West Nile virus (WNV) in Europe, with sporadic human and/or equines cases. However, recent events indicate that this picture is changing, raising the possibility that Europe could experience a modification in the virus' circulation patterns. We used an existing model of WNV circulation between Southern Europe and West Africa to estimate the sample size of equivalent West Nile surveillance systems, either passive (based upon horse populations and sentinel veterinarians) or active (sentinel horses, sentinel chickens, or WNV genome detection in trapped mosquito pools). The costs and calendar day of first detection of these different surveillance systems were compared under three different epidemiological scenarios: very low level circulation, low level recurrent circulation, and epidemic situation. The passive surveillance of 1000 horses by specialized veterinarian clinics appeared to be the most cost-effective system in the current European context, and estimated median dates of first detection appeared consistent with recent field observations. Our results can be used to optimize surveillance designs for different epidemiological requirements. PMID- 21548766 TI - Rodents as sentinels for the prevalence of tick-borne encephalitis virus. AB - INTRODUCTION: Tick-borne encephalitis virus (TBEV) causes one of the most important flavivirus infections of the central nervous system, affecting humans in Europe and Asia. It is mainly transmitted by the bite of an infected tick and circulates among them and their vertebrate hosts. Until now, TBE risk analysis in Germany has been based on the incidence of human cases. Because of an increasing vaccination rate, this approach might be misleading, especially in regions of low virus circulation. METHOD: To test the suitability of rodents as a surrogate marker for virus spread, laboratory-bred Microtus arvalis voles were experimentally infected with TBEV and analyzed over a period of 100 days by real time (RT)-quantitative polymerase chain reaction. Further, the prevalence of TBEV in rodents trapped in Brandenburg, a rural federal state in northeastern Germany with autochthonous TBE cases, was determined and compared with that in rodents from German TBE risk areas as well as TBE nonrisk areas. RESULTS: In experimentally infected M. arvalis voles, TBEV was detectable in different organs for at least 3 months and in blood for 1 month. Ten percent of all rodents investigated were positive for TBEV. However, in TBE risk areas, the infection rate was higher compared with that of areas with only single human cases or of nonrisk areas. TBEV was detected in six rodent species: Apodemus agrarius, Apodemus flavicollis, Apodemus sylvaticus, Microtus agrestis, Microtus arvalis, and Myodes glareolus. M. glareolus showed a high infection rate in all areas investigated. DISCUSSION AND CONCLUSION: The infection experiments proved that TBEV can be reliably detected in infected M. arvalis voles. These voles developed a persistent TBE infection without clinical symptoms. Further, the study showed that rodents, especially M. glareolus, are promising sentinels particularly in areas of low TBEV circulation. PMID- 21548767 TI - Isolation of enterotoxigenic Staphylococcus aureus from pet dogs and cats: a public health implication. AB - Staphylococcus aureus is a globally distributed bacterium causing wide variety of illnesses in humans, which attributed to its ability to produce wide array of virulence factors, including enterotoxins that are responsible for staphylococcal food poisoning outbreaks. The current study was carried out to investigate the prevalence of enterotoxigenic S. aureus among pet dogs and cats and its public health implication. For this purpose, nasal, oral, and wound swabs were collected from 70 dogs and 47 cats, whereas nasal swabs were collected from 26 human contacts. All samples were examined for the presence of enterotoxigenic S. aureus by isolation of S. aureus in culture media and then tested by specific ELISA kits to detect the produced toxins in bacterial cultures. The prevalence of enterotoxigenic S. aureus was 10% and 2.1% for pet dogs and cats, respectively, whereas the nasal carriage rate in human contacts was 7.7%. The majority of animal isolates were obtained from mouth of the apparently healthy animals. All types of staphylococcal enterotoxins were detected in both animal and human isolates. High prevalence of enterotoxigenic S. aureus among pet dogs highlights the possibility of zoonotic transmission to human contacts leading to nasal and/or hand carriage of such strains; thus, pet animals may be incriminated in the epidemiology of household staphylococcal food poisoning outbreaks. PMID- 21548768 TI - Detection of Shiga toxin-producing Escherichia coli O26, O45, O103, O111, O113, O121, O145, and O157 serogroups by multiplex polymerase chain reaction of the wzx gene of the O-antigen gene cluster. AB - O-antigens on the surface of Escherichia coli are important virulence factors that are targets of both the innate and adaptive immune system and play a major role in pathogenicity. O-antigens that are responsible for antigenic specificity of the strain determine the O-serogroup. E. coli O26, O45, O103, O111, O113, O121, O145, and O157 have been the most commonly identified O-serogroups associated with Shiga toxin-producing E. coli (STEC) implicated in outbreaks of human illness all over the world. A multiplex polymerase chain reaction assay was developed to simultaneously detect the eight STEC O-serogroups targeting the wzx (O-antigen-flippase) genes of all O-antigen gene clusters. The sensitivity of the multiplex polymerase chain reaction was found to be 10 colony forming units for each O-group when enriched in broth and 100 colony forming units when enriched in artificially inoculated apple juice diluted with tryptic soy broth for 16 h at 37 degrees C. The method can be used for detecting STEC O-groups simultaneously and may be exploited for improving the safety of food products. PMID- 21548769 TI - Genetic markers of pandemic Vibrio parahaemolyticus: are they truly unique? PMID- 21548770 TI - Motivations of orthodontic residents in Canada and the United States to treat patients with craniofacial anomalies, cleft lip/palate, and special needs. AB - OBJECTIVES: To determine the motivation of orthodontic residents in Canada and the United States to treat patients with cleft lip/palate (CLP), craniofacial anomalies (CFA), and special needs (SN). METHODS: In March 2009, an e-mail with a link to a 41-item survey was sent to all orthodontic residents in Canada and the United States (n = 944). RESULTS: Of 944 residents contacted, 339 viewed and 208 completed the survey (22.03%). Using a seven-point Likert scale, residents recognized the importance of treating patients with CLP/CFA/SN. When asked if they plan to treat patients with CLP/CFA/SN, 54.48% responded yes, 13.46% no, and 36.06% were unsure. A total of 38.05% said they would charge the same fee as a typical multiarch case, while 58.05% would charge more, and 60% of fourth-year residents would charge twice the fee. Of the respondents, 43.00% were aware of the established fellowship programs in CLP/CFA/SN. Canadian residents (67.9%) were more enthusiastic about completing a fellowship than Americans were. Of the respondents, 29.33% would complete a 1-year fellowship, while 70.67% would not. A total of 78.4% of male respondents and 77.4% of American residents indicated they would not pursue a fellowship. CONCLUSIONS: Residents supported the importance of treating patients with CLP/CFA/SN, and more than 54% indicated they plan to treat these patients. Residents who indicated that they would not treat these patients sited limited experience and inadequate expertise as the reasons. Less than 30% indicated a willingness to pursue a fellowship program. PMID- 21548771 TI - Application of high-throughput DNA sequencing in phytopathology. AB - The new sequencing technologies are already making a big impact in academic research on medically important microbes and may soon revolutionize diagnostics, epidemiology, and infection control. Plant pathology also stands to gain from exploiting these opportunities. This manuscript reviews some applications of these high-throughput sequencing methods that are relevant to phytopathology, with emphasis on the associated computational and bioinformatics challenges and their solutions. Second-generation sequencing technologies have recently been exploited in genomics of both prokaryotic and eukaryotic plant pathogens. They are also proving to be useful in diagnostics, especially with respect to viruses. PMID- 21548772 TI - Zinc in neurotransmission. AB - A subset of glutamatergic synapses in the central nervous system contains zinc; it is sequestered into the lumen of synaptic vesicles, where it colocalizes with glutamate. Extracellularly applied zinc is known to interact with various postsynaptic receptors and channels; however, the role of endogenous vesicular zinc is still an enigma. The aim of this review is to present the physiology of tonic and phasic zinc modulation of excitatory and inhibitory signals and to discuss the potential role of zinc in synaptic plasticity. Zinc homeostasis is known to be altered under pathological conditions. The importance of the careful investigation of the potential sources of zinc involved in physiological and pathological processes is highlighted. PMID- 21548773 TI - Energy intake and response to infection with influenza. AB - Influenza is a worldwide public health concern, particularly with emerging new strains of influenza to which vaccines are ineffective, limited, or unavailable. In addition, the relationship between adequate nutrition and immune function has been repeatedly demonstrated. Mouse models provide strong evidence that energy extremes, including energy restriction (ER) and diet-induced obesity (DIO), have deleterious effects on the immune response to influenza infection. Both ER and DIO mice demonstrate increased susceptibility and mortality to influenza infection. The effects of ER are more pronounced during innate responses to influenza infection, whereas the effects of DIO are evidenced during innate and adaptive responses to both primary and secondary infection. There are striking similarities between ER and DIO during influenza infection, including impaired natural killer cell function and altered inflammation. Future studies must develop effective nutritional paradigms to offset the effects of these energy extremes on the immune response to an acute infection. PMID- 21548775 TI - Potential mechanisms by which polyphenol-rich grapes prevent obesity-mediated inflammation and metabolic diseases. AB - Obesity and metabolic disease-related health problems (e.g., type 2 diabetes, atherosclerosis, and hypertension) are the most prevalent nutrition-related issues in the United States. An emerging feature of obesity and type 2 diabetes is their linkage with chronic inflammation that begins in white adipose tissue and eventually becomes systemic. One potential strategy to reduce inflammation and insulin resistance is consumption of polyphenol-rich foods like grapes or their by-products, which have anti-inflammatory properties. Polyphenols commonly found in grape products have been reported to reduce inflammation by (a) acting as an antioxidant or increasing antioxidant gene or protein expression, (b) attenuating endoplasmic reticulum stress signaling, (c) blocking proinflammatory cytokines or endotoxin-mediated kinases and transcription factors involved in metabolic disease, (d) suppressing inflammatory- or inducing metabolic-gene expression via increasing histone deacetylase activity, or (e) activating transcription factors that antagonize chronic inflammation. Thus, polyphenol-rich grape products may reduce obesity-mediated chronic inflammation by multiple mechanisms, thereby preventing metabolic diseases. PMID- 21548774 TI - The implication of brown adipose tissue for humans. AB - We here discuss the role of brown adipose tissue on energy homeostasis and assess its potential as a target for body weight management. Because of their high number of mitochondria and the presence of uncoupling protein 1, brown fat adipocytes can be termed as energy inefficient for adenosine-5'-triphosphate (ATP) production but energy efficient for heat production. Thus, the energy inefficiency of ATP production, despite high energy substrate oxidation, allows brown adipose tissue to generate heat for body temperature regulation. Whether such thermogenic property also plays a role in body weight regulation is still debated. The recent (re)discovery of brown adipose tissue in human adults and a better understanding of brown adipose tissue development have encouraged the quest for new alternatives to treat obesity since obese individuals seem to have less brown adipose tissue mass/activity than do their lean counterparts. In this review, we discuss the physiological relevance of brown adipose tissue on thermogenesis and its potential usefulness on body weight control in humans. PMID- 21548776 TI - Knockout mouse models of iron homeostasis. AB - Murine models have made valuable contributions to our understanding of iron metabolism. Investigation of mice with inherited forms of anemia has led to the discovery of novel proteins involved in iron homeostasis. A growing number of murine models are being developed to investigate mitochondrial iron metabolism. Mouse strains are available for the major forms of hereditary hemochromatosis. Findings in murine models support the concept that the pathogenesis of nearly all forms of hereditary hemochromatosis involves inappropriately low expression of hepcidin. The availability of mice with floxed iron-related genes allows the study of the in vivo consequences of cell-selective deletion of these genes. PMID- 21548777 TI - How is maternal nutrition related to preterm birth? AB - The incidence of preterm birth in developed countries is increasing, and in some countries, including the United States, it is almost as high as in developing countries. Demographic changes in women becoming pregnant can account for only a relatively small proportion of the increase. A significant proportion of spontaneous preterm birth continues to be of unknown cause. Experimental data from animal studies suggesting that maternal undernutrition may play a role in spontaneous, noninfectious, preterm birth are supported by observational data in human populations, which support a role for maternal prepregnancy nutritional status in determining gestation length. In addition, intakes or lack of specific nutrients during pregnancy may influence gestation length and thus the risk of preterm birth. As yet, the role of paternal nutrition in contributing to gestation length is unexplored. PMID- 21548778 TI - The role of microRNAs in cholesterol efflux and hepatic lipid metabolism. AB - MicroRNAs (miRNAs) represent an elegant mechanism of posttranscriptional control of gene expression that serves to fine-tune biological processes. These tiny noncoding RNAs (20-22 nucleotide) bind to the 3' untranslated region of mRNAs, thereby repressing gene expression. Recent advances in the understanding of lipid metabolism have revealed that miRNAs, particularly miR-122 and miR-33, play major roles in regulating cholesterol and fatty acid homeostasis. miR-122, the most abundant miRNA in the liver, appears to maintain the hepatic cell phenotype, and its inhibition decreases total serum cholesterol. miR-33, an intronic miRNA located with the sterol response element-binding protein (SREBP)-2 gene, regulates cholesterol efflux, fatty acid beta oxidation, and high-density lipoprotein metabolism. These findings have highlighted the complexity of lipid homeostasis and the important role that miRNAs play in these processes, potentially opening new avenues for the treatment of dyslipidemias. PMID- 21548780 TI - Structural biology of the Toll-like receptor family. AB - Innate immune receptors respond to common structural patterns in microbial molecules and are called pattern recognition receptors. Toll-like receptors (TLRs) play critical roles in the innate immune system by recognizing microbial lipids, carbohydrates, nucleic acids, and proteins. Precise definition of the ligand "pattern" of TLRs has been difficult to determine primarily owing to a lack of high-resolution structures. Recently, the structures of several TLR ligand complexes and the intracellular signaling domains have been determined by X-ray crystallography. This new structural information, combined with extensive biochemical and immunological data accumulated over decades, sheds new light on ligand-recognition and -activation mechanisms. In this review, we summarize the TLR structures and discuss proposed ligand-recognition and -activation mechanisms. PMID- 21548779 TI - STIM proteins and the endoplasmic reticulum-plasma membrane junctions. AB - Eukaryotic organelles can interact with each other through stable junctions where the two membranes are kept in close apposition. The junction that connects the endoplasmic reticulum to the plasma membrane (ER-PM junction) is unique in providing a direct communication link between the ER and the PM. In a recently discovered signaling process, STIM (stromal-interacting molecule) proteins sense a drop in ER Ca(2+) levels and directly activate Orai PM Ca(2+) channels across the junction space. In an inverse process, a voltage-gated PM Ca(2+) channel can directly open ER ryanodine-receptor Ca(2+) channels in striated-muscle cells. Although ER-PM junctions were first described 50 years ago, their broad importance in Ca(2+) signaling, as well as in the regulation of cholesterol and phosphatidylinositol lipid transfer, has only recently been realized. Here, we discuss research from different fields to provide a broad perspective on the structures and unique roles of ER-PM junctions in controlling signaling and metabolic processes. PMID- 21548781 TI - Quantitative, high-resolution proteomics for data-driven systems biology. AB - Systems biology requires comprehensive data at all molecular levels. Mass spectrometry (MS)-based proteomics has emerged as a powerful and universal method for the global measurement of proteins. In the most widespread format, it uses liquid chromatography (LC) coupled to high-resolution tandem mass spectrometry (MS/MS) to identify and quantify peptides at a large scale. This peptide intensity information is the basic quantitative proteomic data type. It is used to quantify proteins between different proteome states, including the temporal variation of the proteome, to determine the complete primary structure of proteins including posttranslational modifications, to localize proteins to organelles, and to determine protein interactions. Here, we describe the principles of analysis and the areas of biology where proteomics can make unique contributions. The large-scale nature of proteomics data and its high accuracy pose special opportunities as well as challenges in systems biology that have been largely untapped so far. PMID- 21548784 TI - Biogenesis and cargo selectivity of autophagosomes. AB - Autophagy is a major catabolic pathway in eukaryotes, which is required for the lysosomal/vacuolar degradation of cytoplasmic proteins and organelles. Interest in the autophagy pathway has recently gained momentum largely owing to identification of multiple autophagy-related genes and recognition of its involvement in various physiological conditions. Here we review current knowledge of the molecular mechanisms regulating autophagy in mammals and yeast, specifically the biogenesis of autophagosomes and the selectivity of their cargo recruitment. We discuss the different steps of autophagy, from the signal transduction events that regulate it to the completion of this pathway by fusion with the lysosome/vacuole. We also review research on the origin of the autophagic membrane, the molecular mechanism of autophagosome formation, and the roles of two ubiquitin-like protein families and other structural elements that are essential for this process. Finally, we discuss the various modes of autophagy and highlight their functional relevance for selective degradation of specific cargos. PMID- 21548782 TI - Genomic and biochemical insights into the specificity of ETS transcription factors. AB - ETS proteins are a group of evolutionarily related, DNA-binding transcriptional factors. These proteins direct gene expression in diverse normal and disease states by binding to specific promoters and enhancers and facilitating assembly of other components of the transcriptional machinery. The highly conserved DNA binding ETS domain defines the family and is responsible for specific recognition of a common sequence motif, 5'-GGA(A/T)-3'. Attaining specificity for biological regulation in such a family is thus a conundrum. We present the current knowledge of routes to functional diversity and DNA binding specificity, including divergent properties of the conserved ETS and PNT domains, the involvement of flanking structured and unstructured regions appended to these dynamic domains, posttranslational modifications, and protein partnerships with other DNA-binding proteins and coregulators. The review emphasizes recent advances from biochemical and biophysical approaches, as well as insights from genomic studies that detect ETS-factor occupancy in living cells. PMID- 21548785 TI - Advances in the mass spectrometry of membrane proteins: from individual proteins to intact complexes. AB - Rapid advances in structural genomics and in large-scale proteomic projects have yielded vast amounts of data on soluble proteins and their complexes. Despite these advances, progress in studying membrane proteins using mass spectrometry (MS) has been slow. This is due in part to the inherent solubility and dynamic properties of these proteins, but also to their low abundance and the absence of polar side chains in amino acid residues. Considerable progress in overcoming these challenges is, however, now being made for all levels of structural characterization. This progress includes MS studies of the primary structure of membrane proteins, wherein sophisticated enrichment and trapping procedures are allowing multiple posttranslational modifications to be defined through to the secondary structure level in which proteins and peptides have been probed using hydrogen exchange, covalent, or radiolytic labeling methods. Exciting possibilities now exist to go beyond primary and secondary structure to reveal the tertiary and quaternary interactions of soluble and membrane subunits within intact assemblies of more than 700 kDa. PMID- 21548783 TI - Transmembrane communication: general principles and lessons from the structure and function of the M2 proton channel, K+ channels, and integrin receptors. AB - Signal transduction across biological membranes is central to life. This process generally happens through communication between different domains and hierarchical coupling of information. Here, we review structural and thermodynamic principles behind transmembrane (TM) signal transduction and discuss common themes. Communication between signaling domains can be understood in terms of thermodynamic and kinetic principles, and complex signaling patterns can arise from simple wiring of thermodynamically coupled domains. We relate this to functions of several signal transduction systems: the M2 proton channel from influenza A virus, potassium channels, integrin receptors, and bacterial kinases. We also discuss key features in the structural rearrangements responsible for signal transduction in these systems. PMID- 21548786 TI - The mechanism of peptidyl transfer catalysis by the ribosome. AB - The ribosome catalyzes two fundamental biological reactions: peptidyl transfer, the formation of a peptide bond during protein synthesis, and peptidyl hydrolysis, the release of the complete protein from the peptidyl tRNA upon completion of translation. The ribosome is able to utilize and distinguish the two different nucleophiles for each reaction, the alpha-amine of the incoming aminoacyl tRNA versus the water molecule. The correct binding of substrates induces structural rearrangements of ribosomal active-site residues and the substrates themselves, resulting in an orientation suitable for catalysis. In addition, active-site residues appear to provide further assistance by ordering active-site water molecules and providing an electrostatic environment via a hydrogen network that stabilizes the reaction intermediates and possibly shuttles protons. Major questions remain concerning the timing, components, and mechanism of the proton transfer steps. This review summarizes the recent progress in structural, biochemical, and computational advances and presents the current mechanistic models for these two reactions. PMID- 21548787 TI - Amino acid signaling in TOR activation. AB - The target of rapamycin (TOR) is a central cell growth regulator conserved from yeast to mammals. Uncontrolled TOR activation is commonly observed in human cancers. TOR forms two distinct structural and functional complexes, TORC1 and TORC2. TORC1 promotes cell growth and cell size by stimulating protein synthesis. A wide range of signals, including nutrients, energy levels, and growth factors, are known to control TORC1 activity. Among them, amino acids (AA) not only potently activate TORC1 but are also required for TORC1 activation by other stimuli, such as growth factors. The mechanisms of growth factors and cellular energy status in activating TORC1 have been well elucidated, whereas the molecular basis of AA signaling is just emerging. Recent advances in the role of AA signaling on TORC1 activation have revealed key components, including the Rag GTPases, protein kinases, nutrient transporters, and the intracellular trafficking machinery, in relaying AA signals to TORC1 activation. PMID- 21548788 TI - The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. AB - Kinases are highly regulated enzymes with diverse mechanisms controlling their catalytic output. Over time, chemical discovery efforts for kinases have produced ATP-competitive compounds, allosteric regulators, irreversible binders, and highly specific inhibitors. These distinct classes of small molecules have revealed many novel aspects about kinase-mediated signaling, and some have progressed from simple tool compounds into clinically validated therapeutics. This review explores several small-molecule inhibitors for kinases highlighting elaborate mechanisms by which kinase function is modulated. A complete surprise of targeted kinase drug discovery has been the finding of ATP-competitive inhibitors that behave as agonists, rather than antagonists, of their direct kinase target. These studies hint at a connection between ATP-binding site occupancy and networks of communication that are independent of kinase catalysis. Indeed, kinase inhibitors that induce changes in protein localization, protein protein interactions, and even enhancement of catalytic activity of the target kinase have been found. The relevance of these findings to the therapeutic efficacy of kinase inhibitors and to the future identification of new classes of drug targets is discussed. PMID- 21548789 TI - Intensity of acute care services at the end of life: nonclinical determinants of treatment variation in an older adult population. AB - Technological advances in medicine have led to increasing complexity in health care decision making, and subsequently, greater opportunity for variation in the delivery of end-of-life care. Factors such as age, race/ethnicity, physician and hospital system characteristics, and geographic location have been found to be strong predictors of variation in acute interventions before death, even when controlling for medical acuity. The study presented here explores factors affecting health care utilization at end of life for a hospitalized older adult population in a major metropolitan area of Arizona. The study results reveal that effects of age, minority status, health plan, and hospital characteristics all affect hospital utilization and intensity of care above and beyond clinical factors. PMID- 21548791 TI - Survey on the prevalence of pain in Dutch district nursing care. AB - According to the international literature the prevalence of chronic pain is high. In the general population prevalence rates of chronic pain vary widely, from 2% to 40%. In nursing homes and homes for the elderly, higher prevalence rates of 45% to 80% have been reported. Prevalence rates in district nursing care in general, however, are lacking. This article is a report of a one-day survey to assess the prevalence and intensity of acute and chronic pain in Dutch district nursing care. We found that the prevalence of pain in patients with district nursing care is high and similar to reported prevalence rates in nursing homes and homes for elderly. PMID- 21548790 TI - Palliative care symptom assessment for patients with cancer in the emergency department: validation of the Screen for Palliative and End-of-life care needs in the Emergency Department instrument. AB - OBJECTIVE: We sought to develop and validate a novel palliative medicine needs assessment tool for patients with cancer in the emergency department. METHODS: An expert panel trained in palliative medicine and emergency medicine reviewed and adapted a general palliative medicine symptom assessment tool, the Needs at the End-of-Life Screening Tool. From this adaptation a new 13-question instrument was derived, collectively referred to as the Screen for Palliative and End-of-life care needs in the Emergency Department (SPEED). A database of 86 validated symptom assessment tools available from the palliative medicine literature, totaling 3011 questions, were then reviewed to identify validated test items most similar to the 13 items of SPEED; a total of 107 related questions from the database were identified. Minor adaptations of questions were made for standardization to a uniform 10-point Likert scale. The 107 items, along with the 13 SPEED items were randomly ordered to create a single survey of 120 items. The 120-item survey was administered by trained staff to all patients with cancer who met inclusion criteria (age over 21 years, English-speaking, capacity to provide informed consent) who presented to a large urban academic emergency department between 8:00 am and 11:00 pm over a 10-week period. Data were analyzed to determine the degree of correlation between SPEED items and the related 107 selected items from previously validated tools. RESULTS: A total of 53 subjects were enrolled, of which 49 (92%) completed the survey in its entirety. Fifty three percent of subjects were male, age range was 24-88 years, and the most common cancer diagnoses were breast, colon, and lung. Cronbach coefficient alpha for the SPEED items ranged from 0.716 to 0.991, indicating their high scale reliability. Correlations between the SPEED scales and related assessment tools previously validated in other settings were high and statistically significant. CONCLUSION: The SPEED instrument demonstrates reliability and validity for screening for palliative care needs of patients with cancer presenting to the emergency department. PMID- 21548792 TI - Aspirin-triggered lipoxin A4 (15-epi-LXA4) increases the endothelial viability of human corneas storage in Optisol-GS. AB - PURPOSE: The human corneal endothelium has a very low mitotic rate, and with aging there is a decrease in the number of cells. 15-epi-LXA4 is an anti inflammatory, bioactive lipid formed when aspirin acetylates cyclooxygenease-2 and redirects cyclooxygenease-2 catalytic activity away from prostaglandins. The purpose of the current study was to evaluate the action of 15-epi-LXA4 in the endothelium viability of human corneas stored in Optisol-GS. METHODS: Human corneal endothelial (HCE) cells along with the Descemet's membrane were isolated from fresh human eyes obtained from National Disease Research Interchange. Cell phenotype was identified by using the tight junctions cell marker ZO-1. LXA4 receptor (FPR2/ALX) was detected by immunostaining of HCE cells and human corneal tissue using a polyclonal antibody. Cell proliferation was evaluated with Ki-67 antibody. To measure cell migration, confluent HCE cells were wounded by a linear scraping with a sterile pipette tip in the center of the well and incubated for 24 h with or without 15-epi-LXA4. To evaluate the reparative capacity of 15-epi LXA4, 7 pairs of human corneas were incubated in Dulbecco's modified Eagle's medium/F12 media at 37 degrees C with or without 100 nM 15-epi-LXA4 for 24 h and then stored at 4 degrees C in Optisol-GS for 12 days. Endothelial viability was assessed by 2 staining techniques: a viability/cytotoxicity kit and trypan blue combined with alizarin red S. RESULTS: HCE cells and the endothelium of human corneal sections strongly expressed the LXA4 receptor. There was a 3-fold increase in cell proliferation when HCE cells were incubated with 100 nM 15-epi LXA4 for 24 h. No significant migration was observed after 24 h incubation with 15-epi-LXA4. Corneas incubated for 24 h in Dulbecco's modified Eagle's medium/F12 media in the presence of 15-epi-LXA4 and then stored for 12 days in Optisol-GS had a 36% to 56% increase in viability compared with controls without 15-epi LXA4. CONCLUSIONS: 15-epi-LXA4 is an important mediator that protects the integrity of the human endothelium during corneal preservation in Optisol-GS. PMID- 21548793 TI - Efficient penetration into aqueous humor by administration of oral and topical levofloxacin. AB - PURPOSE: We investigated whether an optimized combination of oral and topical levofloxacin would lead to higher levofloxacin concentrations in aqueous humor. METHODS: Fifteen patients with cataracts in both eyes began topical treatment at 1 week before the first surgery and oral treatment at 1 day before the first surgery. On the day of surgery, they received oral and topical levofloxacin at 4 h and 1 h before surgery, respectively. Two days after the first operation, we performed cataract surgery on the second eye with the same drug administration protocol. RESULTS: Postsurgery concentrations of levofloxacin in the aqueous humor of the first and second eyes were 2.87+/-0.89 MUg/mL (mean+/-standard deviation, n=15) and 3.76+/-1.32 MUg/mL, respectively; the levofloxacin level in the second eye was significantly higher than that in the first eye (P=0.0085). CONCLUSIONS: Our protocol to achieve high aqueous humor concentrations of levofloxacin may be favorable in preventing endophthalmitis after eye surgery. PMID- 21548794 TI - Making hay. PMID- 21548795 TI - Flexor tendon tissue engineering: acellularization of human flexor tendons with preservation of biomechanical properties and biocompatibility. AB - OBJECTIVE: Acellular human tendons are a candidate scaffold for tissue engineering flexor tendons of the hand. This study compared acellularization methods and their compatibility with allogeneic human cells. METHOD: Human flexor tendons were pretreated with 0.1% ethylenediaminetetracetic acid (EDTA) for 4 h followed by 24 h treatments of 1% Triton X-100, 1% tri(n-butyl)phosphate, or 0.1% or 1% sodium dodecyl sulfate (SDS) in 0.1% EDTA. Outcomes were assessed histologically by hematoxylin and eosin and SYTO green fluorescent nucleic acid stains and biochemically by a QIAGEN DNeasy kit, Sircol collagen assay, and 1,9 dimethylmethylene blue glycosaminoglycan assay. Mechanical data were collected using a Materials Testing System to pull to failure tendons acellularized with 0.1% SDS. Acellularized tendons were re-seeded in a suspension of human dermal fibroblasts. Attachment of viable cells to acellularized tendon was assessed biochemically by a cell viability assay and histologically by a live/dead stain. Data are reported as mean+/-standard deviation. RESULT: Compared with the DNA content of fresh tendons (551+/-212 ng DNA/mg tendon), only SDS treatments significantly decreased DNA content (1% SDS [202.8+/-37.4 ng DNA/mg dry weight tendon]; 0.1% SDS [189+/-104 ng DNA/mg tendon]). These findings were confirmed by histology. There was no decrease in glycosaminoglycans or collagen following acellularization with SDS. There was no difference in the ultimate tensile stress (55.3+/-19.2 [fresh] vs. 51.5+/-6.9 [0.1% SDS] MPa). Re-seeded tendons demonstrated attachment of viable cells to the tendon surface using a viability assay and histology. CONCLUSION: Human flexor tendons were acellularized with 0.1% SDS in 0.1% EDTA for 24 h with preservation of mechanical properties. Preservation of collagen and glycoaminoglycans and re-seeding with human cells suggest that this scaffold is biocompatible. This will provide a promising scaffold for future human flexor tendon tissue engineering studies to further assess biocompatibility through cell proliferation and in vivo studies. PMID- 21548796 TI - Accuracy of marker analysis, quantitative real-time polymerase chain reaction, and multiple ligation-dependent probe amplification to determine SMN2 copy number in patients with spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by absence of or mutations in the survival motor neuron1 gene (SMN1). All SMA patients have a highly homologous copy of SMN1, the SMN2 gene. Severe (type I) SMA patients present one or two SMN2 copies, whereas milder chronic forms (type II-III) usually have three or four SMN2 copies. SMN2 dosage is important to stratify patients for motor function tests and clinical trials. Our aim was to compare three methods, marker analysis, real-time quantitative polymerase chain reaction using the LightCycler instrument, and multiple ligation-dependent probe amplification (MLPA), to characterize their accuracy in quantifying SMN2 genes. We studied a group of 62 genetically confirmed SMA patients, 54 with homozygous absence of exons 7 and 8 of SMN1 and 8 with SMN2-SMN1 hybrid genes. A complete correlation using the three methods was observed in 32 patients (51.6%). In the remaining 30 patients, discordances between the three methods were found, including under or overestimation of SMN2 copies by marker analysis with respect to the quantitative methods (LightCycler and MLPA) because of lack of informativeness of markers, 3' deletions of SMN genes, and breakpoints in SMN2 SMN1 hybrid genes. The technical limitations and advantages and disadvantages of these methods are discussed. We conclude that the three methods complement each other in estimating the SMN2 copy number in most cases. However, MLPA offers additional information to characterize SMA cases with particular rearrangements such as partial deletions and hybrid genes. PMID- 21548797 TI - The role of health anxiety in online health information search. AB - This article is one of the first to empirically explore the relationship between health anxiety and online health information search. Two studies investigate how health anxiety influences the use of the Internet for health information and how health anxious individuals respond to online health information. An exploratory survey study with 104 Dutch participants indicates that health anxiety is related to an increase in online health information search. Moreover, results suggest that health anxious individuals experience more negative consequences from online health information search. Findings from an experimental study (n=120) indicate that online health information results in greater worries among health anxious individuals compared to nonhealth anxious individuals only if the information stems from a trustworthy governmental Web site. Information from a less trustworthy online forum does not lead to greater worries among health anxious individuals. In sum, the Internet appears to play a pivotal role in the lives of health anxious individuals. PMID- 21548798 TI - Time to face it! Facebook intrusion and the implications for romantic jealousy and relationship satisfaction. AB - Young people's exposure to social network sites such as Facebook is increasing, along with the potential for such use to complicate romantic relationships. Yet, little is known about the overlaps between the online and offline worlds. We extended previous research by investigating the links between Facebook intrusion, jealousy in romantic relationships, and relationship outcomes in a sample of undergraduates currently in a romantic relationship. A Facebook Intrusion Questionnaire was developed based on key features of technological (behavioral) addictions. An eight-item Facebook Intrusion Questionnaire with a single-factor structure was supported; internal consistency was high. Facebook intrusion was linked to relationship dissatisfaction, via jealous cognitions and surveillance behaviors. The results highlight the possibility of high levels of Facebook intrusion spilling over into romantic relationships, resulting in problems such as jealousy and dissatisfaction. The results have implications for romantic relationships and for Facebook users in general. PMID- 21548799 TI - Comparative effect of Lactobacillus casei and a commercial mangosteen dietary supplement on body weight gain and antibody response to Newcastle disease virus vaccine in fighting roosters. AB - The aim of the present study was to compare the effect of Lactobacillus casei and a commercial mixed combination of fruit juice that included Garcinia mangostana fruit extract on body weight gain from 7 to 90 days of age, on the antibody response 23 days after vaccination against Newcastle disease virus (NDV), and on the mortality in fighting roosters. Fifty-four 7-day-old birds were randomly distributed into three groups (treated with L. casei, G. mangostana, and saline solution [LC, GM, and SS groups, respectively]) of 18 animals each; all birds were orally treated daily. At 60 and 90 days, the LC group showed the highest body weight gain compared with the other two groups (P<.01). The mean levels of antibody to NDV were significantly higher in the GM group compared with the LC and SS groups (P<.05). Throughout the study the percentages of mortality were 5.55%, 0%, and 22.22% for the LC, GM, and SS groups, respectively. The results indicate that L. casei and the commercial mangosteen dietary supplement intake, compared with the control group, induce beneficial effects in fighting roosters- L. casei on weight gain and the commercial mixed combination of fruit juice with G. mangostana fruit extract on humoral immune response--and both showed none or very low mortality. PMID- 21548800 TI - Garlic allicin as a potential agent for controlling oral pathogens. AB - Garlic has been used medicinally throughout human history. Allicin is considered the most therapeutic constituent of garlic. This study tested the antimicrobial activity of garlic allicin on oral pathogens associated with dental caries and periodontitis. Allicin was found effective against all the tested bacteria. The broth dilution method revealed that planktonic growth of the cariogenic, gram positive species Streptococcus mutans, S. sobrinus, and Actinomyces oris was inhibited by an allicin concentration of 600 MUg/mL or higher. Planktonic growth of the tested gram-negative periopathogenic species Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum was inhibited by a minimum allicin concentration of 300 MUg/mL. Porphyromonas gingivalis, an anaerobic, gram negative pathogen and the bacterium most associated with chronic periodontitis, demonstrated the lowest sensitivity to allicin (2,400 MUg/mL). Gel zymography and the synthetic chromogenic substrate N(alpha)-benzoyl-L-arginine 4-nitroanilide hydrochloride demonstrated that allicin inhibits the proteases of P. gingivalis, including the arginine and lysine gingipains known as major virulence factors of this organism. A gingipain-inactivated mutant demonstrated high sensitivity to allicin (<300 MUg/mL), revealing that gingipains confer resistance to allicin. Live/dead staining followed by analysis with confocal laser scanning microscopy revealed that allicin was bactericidal to S. mutans grown in mature biofilms. However, this bactericidal effect was reduced as biofilm depth increased. In conclusion, these results support the traditional medicinal use of garlic and suggest the use of allicin for alleviating dental diseases. PMID- 21548801 TI - Unrefined and refined black raspberry seed oils significantly lower triglycerides and moderately affect cholesterol metabolism in male Syrian hamsters. AB - Unrefined and refined black raspberry seed oils (RSOs) were examined for their lipid-modulating effects in male Syrian hamsters fed high-cholesterol (0.12% g/g), high-fat (9% g/g) diets. Hamsters fed the refined and the unrefined RSO diets had equivalently lower plasma total cholesterol and high-density lipoprotein (HDL) cholesterol in comparison with the atherogenic coconut oil diet. The unrefined RSO treatment group did not differ in liver total and esterified cholesterol from the coconut oil-fed control animals, but the refined RSO resulted in significantly elevated liver total and esterified cholesterol concentrations. The unrefined RSO diets significantly lowered plasma triglycerides (46%; P=.0126) in comparison with the coconut oil diet, whereas the refined RSO only tended to lower plasma triglyceride (29%; P=.1630). Liver triglyceride concentrations were lower in the unrefined (46%; P=.0002) and refined (36%; P=.0005) RSO-fed animals than the coconut oil group, with the unrefined RSO diet eliciting a lower concentration than the soybean oil diet. Both RSOs demonstrated a null or moderate effect on cholesterol metabolism despite enrichment in linoleic acid, significantly lowering HDL cholesterol but not non-HDL cholesterol. Dramatically, both RSOs significantly reduced hypertriglyceridemia, most likely due to enrichment in alpha-linolenic acid. As a terrestrial source of alpha-linolenic acid, black RSOs, both refined and unrefined, provide a promising alternative to fish oil supplementation in management of hypertriglyceridemia, as demonstrated in hamsters fed high levels of dietary triglyceride and cholesterol. PMID- 21548802 TI - Determination of antimicrobial activity of sorrel (Hibiscus sabdariffa) on Escherichia coli O157:H7 isolated from food, veterinary, and clinical samples. AB - The use of medicinal plants as natural antimicrobial agents is gaining popularity. Sorrel (Hibiscus sabdariffa) is widely used for the treatment of diseases. The objective of this study was to investigate the antimicrobial activity of sorrel on Escherichia coli O157:H7 isolates from food, veterinary, and clinical samples. Phenolics of the calyces were extracted from 10 g of ground, freeze-dried samples using 100 mL of 80% aqueous methanol. Concentrations of 10%, 5%, and 2.5% methanol extract of sorrel were investigated for its antimicrobial activity. Inhibition zones were indicated by a lack of microbial growth due to inhibitory concentrations of sorrel diffused into semisolid culture medium beneath the sorrel-impregnated disk. The results of this experiment showed that the most potent sorrel concentration was 10%, then 5%, and finally 2.5%. The overall mean zone of inhibition for the sorrel extract was 12.66 mm for 10%, 10.75 mm for 5%, and 8.9 mm for 2.5%. The highest inhibition zones (11.16 mm) were observed in veterinary samples, and the lowest (10.57 mm) in the food samples. There were significant (P<.05) differences among mean zones of inhibition found in the food, veterinary, and clinical sources. Based on the source of samples and concentration of sorrel extract, the lowest mean inhibition was 7.00+/-0.04 mm from clinical samples, and the highest was 15.37+/-0.61 mm from a food source. These findings indicated that sorrel was effective at all levels in inhibiting E. coli O157:H7; thus it possesses antimicrobial activity and hold great promise as an antimicrobial agent. PMID- 21548803 TI - Evaluation of the effects of the flavonoid apigenin on apoptotic pathway gene expression on the colon cancer cell line (HT29). AB - Apigenin (4',5,7-trihydroxyflavone) is one of the leading components supporting targeted treatment options. We explored the cytotoxic and apoptotic effects of various doses of apigenin administered alone and together with 5-fluorouracil (5 FU)-a chemotherapeutic agent with high cytotoxicity-for different incubation periods, on morphologic, DNA, RNA (messenger RNA [mRNA]), and protein levels on the p53 mutant HT29 human colon adenocarcinoma cell line. Treatment with apigenin alone for a 72-hour incubation at 90-MUM dose resulted in an apoptotic percentage of 24.92% (P=.001). A higher percentage (29.13%) was observed after treatment with the same dose of apigenin plus 5-FU for the same incubation period (P=.001). These results were confirmed as mRNA and protein expression levels of caspase-3 increased 2.567-fold and mRNA expression levels of caspase-8 increased 3.689-fold compared with the control group. On the other hand, mRNA expression levels of mammalian target of rapamycin (mTOR) and cyclin D1 (CCND1) decreased by 0.423 fold and 0.231-fold, respectively. To our knowledge this is the first study showing that treatment with apigenin alone results in cell cycle arrest through activation of caspase cascade and stimulation of apoptosis in HT29 cells. It also shows that use of apigenin plus 5-FU further increases this effect. This study draws attention to the probable clinical effectiveness of apigenin plus a chemotherapeutic agent with high cytotoxicity. It also highlights the induction of desirable apoptotic effects by targeting the caspase cascade pathway through administration of reduced doses for shorter incubation periods. PMID- 21548805 TI - Morinda citrifolia Linn leaf extract possesses antioxidant activities and reduces nociceptive behavior and leukocyte migration. AB - Herbal drugs have been used since ancient times to treat a wide range of diseases. Morinda citrifolia Linn (popularly known as "Noni") has been used in folk medicine by Polynesians for over 2,000 years. It is reported to have a broad range of therapeutic effects, including effects against headache, fever, arthritis, gingivitis, respiratory disorders, infections, tuberculosis, and diabetes. The aim of this study was to investigate the antioxidant, anti inflammatory, antinociceptive, and antibacterial properties of the aqueous extract from M. citrifolia leaves (AEMC). Antioxidant activity was observed against lipid peroxidation, nitric oxide, and hydroxyl radicals. The antinociceptive effect of AEMC was observed in the acetic acid-induced writhing test at the higher dose. Moreover, AEMC significantly reduced the leukocyte migration in doses of 200 and 400 mg/kg and showed mild antibacterial activity. Together, the results suggest that properties of M. citrifolia leaf extract should be explored further in order to achieve newer tools for managing painful and inflammation conditions, including those related to oxidant states. PMID- 21548804 TI - Effect of gamma-irradiation on some chemical characteristics and volatile content of linseed. AB - The effect of irradiation (2.5, 4.0, 5.5, and 7.0 kGy) on chemical properties and volatile contents of linseed was investigated. Consistent decreases were observed in both protein and oil content of the irradiated linseed samples with increasing irradiation doses. The ash content of the irradiated linseed samples increased significantly (P<.05) with increasing irradiation doses except for 5.5 kGy. Irradiation treatment caused irregular changes in palmitic and stearic acid content. Although styrene and p-xylene content decreased as a result of irradiation, 1-hexanol content only decreased at 7.0 kGy. Benzaldehyde, p-cymene, and nonanol were not determined at irradiation doses above 4.0 kGy. PMID- 21548806 TI - Volatile compounds and bioactivity of Eremurus spectabilis (Ciris), a Turkish wild edible vegetable. AB - Eremurus spectabilis grows in the spring as a wild vegetable and for many years has been used both as a food or food additive and for therapeutic purposes. This study investigated the total phenolic content and the antimicrobial, antioxidant, and antiradical activities of methanol, ethanol, and aqueous extracts of E. spectabilis (obtained from the Antalya region of Turkey). In addition, volatile compounds of E. spectabilis were characterized by using gas chromatography/mass spectrometry. Major components of E. spectabilis volatile compounds were carvone (44.64%), carvacrol (14.45%), pentane, 2-methyl- (7.34%), (E)-caryophyllene (5.57%), valencene (5.11%), cis-calamenene (2.01%), cadalene (1.10%), and acetic acid (1.12%). The highest total phenolic content was seen with methanol extract (mean+/-standard deviation, 31.92 +/- 0.48 mg gallic acid equivalents/g dry extract). The ethanol extract showed the highest antiradical activity, with a 50% inhibitory concentration of 35.14 MUg/L in the 1,1-diphenyl-2- picrylhydrazyl assay. The strongest antioxidant activity was detected in methanol extract (81.72 +/- 0.62 mg ascorbic acid equivalents/g). Twelve bacteria species were used to analyze the antimicrobial activity of extracts. The 1% concentrations of all extracts showed no inhibitive effect on any bacterium. The most resistant bacterium was Yersinia enterocolitica, and the most sensitive bacterium was Pseudomonas aeruginosa. A positive correlation was seen between concentrations and inhibition zones, and some differences occurred between antimicrobial activity of other concentrations. PMID- 21548807 TI - Pomegranate seed extract attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity in rats. AB - Cisplatin (CDDP), one of the most active cytotoxic agents against cancer, has adverse side effects, such as nephrotoxicity and hepatotoxicity. The present study was designed to investigate the potential protective effect of pomegranate seed extract (PSE) against oxidative stress caused by CDDP injury of the kidneys and liver by measuring tissue biochemical and antioxidant variables and immunohistochemically testing caspase-3-positive cells. Twenty-four Sprague Dawley rats were divided into 4 groups: control; CDDP: injected intraperitoneally with CDDP (7 mg/kg body weight, single dose); PSE: treated for 15 consecutive days by gavage with PSE (300 mg/kg per day); and PSE+CDDP: treated by gavage with PSE 15 days after a single injection of CDDP. The degree of protection against CDDP injury afforded by PSE was evaluated by determining the levels of malondialdehyde as a measure of lipid peroxidation. The levels of glutathione and activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase were estimated from liver and kidney homogenates; the liver and kidney were also histologically examined. PSE elicited a significant protective effect toward liver and kidney by decreasing the level of lipid peroxidation; elevating the levels of glutathione S-transferase; and increasing the activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase. These biochemical observations were supported by immunohistochemical findings and suggested that PSE significantly attenuated nephrotoxicity and hepatotoxicity by the way of its antioxidant, radical-scavenging, and antiapoptotic effects. This PSE extract could be used as a dietary supplement in patients receiving chemotherapy medications. PMID- 21548808 TI - Counting RNA pseudoknotted structures. AB - In 2004, Condon and coauthors gave a hierarchical classification of exact RNA structure prediction algorithms according to the generality of structure classes that they handle. We complete this classification by adding two recent prediction algorithms. More importantly, we precisely quantify the hierarchy by giving closed or asymptotic formulas for the theoretical number of structures of given size n in all the classes but one. This allows us to assess the tradeoff between the expressiveness and the computational complexity of RNA structure prediction algorithms. PMID- 21548809 TI - Exploiting genome structure in association analysis. AB - A genome-wide association study involves examining a large number of single nucleotide polymorphisms (SNPs) to identify SNPs that are significantly associated with the given phenotype, while trying to reduce the false positive rate. Although haplotype-based association methods have been proposed to accommodate correlation information across nearby SNPs that are in linkage disequilibrium, none of these methods directly incorporated the structural information such as recombination events along chromosome. In this paper, we propose a new approach called stochastic block lasso for association mapping that exploits prior knowledge on linkage disequilibrium structure in the genome such as recombination rates and distances between adjacent SNPs in order to increase the power of detecting true associations while reducing false positives. Following a typical linear regression framework with the genotypes as inputs and the phenotype as output, our proposed method employs a sparsity-enforcing Laplacian prior for the regression coefficients, augmented by a first-order Markov process along the sequence of SNPs that incorporates the prior information on the linkage disequilibrium structure. The Markov-chain prior models the structural dependencies between a pair of adjacent SNPs, and allows us to look for association SNPs in a coupled manner, combining strength from multiple nearby SNPs. Our results on HapMap-simulated datasets and mouse datasets show that there is a significant advantage in incorporating the prior knowledge on linkage disequilibrium structure for marker identification under whole-genome association. PMID- 21548810 TI - Gene expression complex networks: synthesis, identification, and analysis. AB - Thanks to recent advances in molecular biology, allied to an ever increasing amount of experimental data, the functional state of thousands of genes can now be extracted simultaneously by using methods such as cDNA microarrays and RNA Seq. Particularly important related investigations are the modeling and identification of gene regulatory networks from expression data sets. Such a knowledge is fundamental for many applications, such as disease treatment, therapeutic intervention strategies and drugs design, as well as for planning high-throughput new experiments. Methods have been developed for gene networks modeling and identification from expression profiles. However, an important open problem regards how to validate such approaches and its results. This work presents an objective approach for validation of gene network modeling and identification which comprises the following three main aspects: (1) Artificial Gene Networks (AGNs) model generation through theoretical models of complex networks, which is used to simulate temporal expression data; (2) a computational method for gene network identification from the simulated data, which is founded on a feature selection approach where a target gene is fixed and the expression profile is observed for all other genes in order to identify a relevant subset of predictors; and (3) validation of the identified AGN-based network through comparison with the original network. The proposed framework allows several types of AGNs to be generated and used in order to simulate temporal expression data. The results of the network identification method can then be compared to the original network in order to estimate its properties and accuracy. Some of the most important theoretical models of complex networks have been assessed: the uniformly-random Erdos-Renyi (ER), the small-world Watts-Strogatz (WS), the scale free Barabasi-Albert (BA), and geographical networks (GG). The experimental results indicate that the inference method was sensitive to average degree variation, decreasing its network recovery rate with the increase of . The signal size was important for the inference method to get better accuracy in the network identification rate, presenting very good results with small expression profiles. However, the adopted inference method was not sensible to recognize distinct structures of interaction among genes, presenting a similar behavior when applied to different network topologies. In summary, the proposed framework, though simple, was adequate for the validation of the inferred networks by identifying some properties of the evaluated method, which can be extended to other inference methods. PMID- 21548811 TI - The irredundant class method for remote homology detection of protein sequences. AB - The automatic classification of protein sequences into families is of great help for the functional prediction and annotation of new proteins. In this article, we present a method called Irredundant Class that address the remote homology detection problem. The best performing methods that solve this problem are string kernels, that compute a similarity function between pairs of proteins based on their subsequence composition. We provide evidence that almost all string kernels are based on patterns that are not independent, and therefore the associated similarity scores are obtained using a set of redundant features, overestimating the similarity between the proteins. To specifically address this issue, we introduce the class of irredundant common patterns. Loosely speaking, the set of irredundant common patterns is the smallest class of independent patterns that can describe all common patterns in a pair of sequences. We present a classification method based on the statistics of these patterns, named Irredundant Class. Results on benchmark data show that the Irredundant Class outperforms most of the string kernels previously proposed, and it achieves results as good as the current state-of-the-art method Local Alignment, but using the same pairwise information only once. PMID- 21548812 TI - Adjustable chain trees for proteins. AB - A chain tree is a data structure for changing protein conformations. It enables very fast detection of clashes and free energy potential calculations. A modified version of chain trees that adjust themselves to the changing conformations of folding proteins is introduced. This results in much tighter bounding volume hierarchies and therefore fewer intersection checks. Computational results indicate that the efficiency of the adjustable chain trees is significantly improved compared to the traditional chain trees. PMID- 21548813 TI - The effect of comorbidity burden on health care utilization for patients with cancer using hospice. AB - BACKGROUND: The treatment of patients with advanced cancer with multiple comorbid illnesses is complex. Although an increasing number of such patients are being referred to hospice, the comorbidity burden of this patient population is largely unknown but has implications for the complexity of care provided by hospices. This study reports the comorbidity burden in a national sample of hospice users with cancer and estimates the effect of higher comorbidity on health care use and site of death. METHODS: Cross-sectional study using Surveillance, Epidemiology and End Results-Medicare data for hospice users who died of cancer in 2002 (N = 27,166). We measured comorbidity burden using the Charlson comorbidity index and used multivariable generalized estimating equations to estimate the association between comorbidity burden and the following outcomes: emergency department and intensive care unit (ICU) admission, hospitalization, hospice disenrollment, and hospital death. RESULTS: Patients with cancer who used hospice had an average Charlson comorbidity index value of 1.24, including 18.8% who suffered from comorbid dementia. In analyses adjusted for patient demographics, site of primary cancer, and number of days with hospice, higher comorbidity burden was associated with higher likelihood of emergency department admission (odds ratio [OR] = 1.69, 95% confidence interval [CI] 1.52, 1.87), ICU admission (OR = 3.28, 95% CI 2.45, 4.38), inpatient hospitalization (OR = 2.14, 95% CI 1.90, 2.42), hospice disenrollment (OR = 1.41, 95% CI 1.29, 1.56) and hospital death (OR = 2.51, 95% CI 2.08, 3.02). CONCLUSION: These findings underscore the complexity of the hospice patient population and highlight a potential need to risk adjust the per diem hospice reimbursement rates to account for increased resource requirements for hospices serving patients with higher comorbidity burden. PMID- 21548814 TI - Opposing systematic reviews: the effects of two quality rating instruments on evidence regarding t'ai chi and bone mineral density in postmenopausal women. AB - PURPOSE: This article compares and contrasts two systematic reviews of t'ai chi (TC) interventions on bone mineral density in postmenopausal women. The aim is to examine how chosen quality rating instruments can impact systematic reviews of TC literature. METHODS: The rating instruments in the reviews, the three-item scale of Jadad et al. and the ad hoc checklist of Wayne et al., were analyzed using Oxman's evaluation criteria for systematic reviews regarding inclusion of articles, interpretation of results, and overall implications for the efficacy of TC on bone mineral density. RESULTS: According to Oxman's criteria, the Jadad scale did not address advances in statistical methods and was not comprehensive enough to adapt to the clinical context or topic. In contrast, the checklist by Wayne et al. was comprehensive, adaptable to clinical context and topical relevance, and compatible with recent developments in statistics and experimental design. These quality rating instruments were critical in the inclusion of studies, analyses, and overall conclusions summarizing the TC literature. The conclusions from the two systematic reviews were starkly opposing; Lee et al. found no convincing evidence, dismissing TC studies as low quality, while Wayne et al. stated that TC may be an effective, safe, and practical intervention. CONCLUSIONS: Readers must exercise caution concerning high or low ratings from systematic reviews of TC studies because the choice of quality rating tool can dramatically influence the summary and conclusions of the reviews. There is no consensus on quality rating standards at this time. Of the two, the Jadad scale was not only inadequate but also inappropriate for reviewing TC studies, potentially misleading researchers, clinicians and policymakers. Future systematic reviews of TC should utilize instruments that are updated to current scientific standards, comprehensive, adaptable to clinical context, and relevant to the research topic. PMID- 21548815 TI - Variability of angular measurements of head posture within a session, within a day, and over a 7-day period in healthy participants. AB - Head posture (HP) is used as part of the clinical examination of patients with neck pain to inform diagnosis, plan treatment, and monitor progress. For related information to be interpreted correctly, clinicians need to know how much of the variation in HP between measurements can be attributed to a change in the patient condition and how much is due to measurement error and/or biological variation. The aim of this study was to investigate the variability of angular measurements indicative of forward HP, head extension, and side flexion within a session, within a day, and over a 7-day period. Angles were calculated from 27 participants in three sessions over a period of 7 days through digitization of video images. Intraclass correlation coefficients (ICC) and standard error of measurement (SEM) showed that forward HP (ICC between 0.82 and 0.91; SEM between 1.42 degrees and 1.70 degrees ) and side flexion (ICC between 0.63 and 0.85; SEM between 0.83 degrees and 1.27 degrees ) were stable within a session, within a day, and over a 7-day period. Head extension was found to be less stable (ICC between 0.71 and 0.83; SEM between 2.69 degrees and 3.72 degrees ). Time of day did not appear to influence forward HP, side flexion, or head extension. PMID- 21548816 TI - Nonsteroidal antiinflammatory drugs (NSAIDs) and paracetamol for acute musculoskeletal injuries: physiotherapists' understanding of which is safer, more effective, and when to initiate treatment. AB - Physiotherapists are primary care practitioners, and are often the first health professional to consult with patients presenting with acute sprains or strains, and such patients may ask for advice regarding medications. Paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) are readily available without a prescription and are commonly used by patients. The aim of this study was to investigate New Zealand physiotherapists' knowledge regarding the comparative safety, effectiveness, and appropriate timing of paracetamol and NSAIDs for acute musculoskeletal sprains and strains. A questionnaire was mailed to all members of the New Zealand Society of Physiotherapists currently practicing in the field of musculoskeletal physiotherapy (n = 948). Of 278 respondents (29.3%), just over half (52%) thought that NSAIDs were more effective than paracetamol in the treatment of sprains and strains. Almost half (45%) believed that NSAIDs should be withheld because of the potential for interrupting the beneficial role of inflammation in healing and that NSAIDs could increase bleeding into the injured tissue. In contrast, the majority of respondents (81%) recognised that there was no need to withhold paracetamol in the initial postinjury period. Knowledge regarding safety, effectiveness, and risks of paracetamol and NSAIDs may assist physiotherapists to recommend appropriate management of acute musculoskeletal injuries, within regulatory boundaries. PMID- 21548818 TI - Traditional Chinese medicine for Parkinson's disease in China and beyond. PMID- 21548817 TI - Development of an instrument to assess the quality of acupuncture: results from a Delphi process. AB - BACKGROUND: Quality acupuncture influences the outcomes of clinical research, and issues associated with effective administration of acupuncture in randomized controlled trials need to be addressed when appraising studies. OBJECTIVE: The study objective was to achieve consensus on domains and items for inclusion in a rating scale to assess quality acupuncture administered in clinical research. STUDY DESIGN AND SUBJECTS: An active group of Australian acupuncture researchers initially identified a pool of items assessing quality. The Delphi consensus process was then used to select and reduce the number of items, and an additional expert panel of 42 researchers were invited to participate. Participants initially ranked items along a five-point scale for the first Delphi round, and indicated an agree or disagree response during the second round. For an item to be retained into the second round, an item had to attain greater than 80% agreement that the item described a dimension of quality acupuncture and related study design. RESULTS: Thirty-two (32) experts agreed to participate in the study. After two rounds of the Delphi process, consensus was reached on 14 domains and 26 items relating to quality acupuncture. Domains, items, and minimum standards related to study design; rationale of the intervention; criteria relating to needling stimulation either manual or electrostimulation; duration and frequency of treatment; and practitioner training. CONCLUSIONS: Items for inclusion in an instrument to assess quality acupuncture in clinical research were identified. Further development of the instrument including relative weighting of items and reliability testing is under way. PMID- 21548819 TI - Scapular dyskinesis in trapezius myalgia and intraexaminer reproducibility of clinical tests. AB - The aims were to test the intraexaminer reproducibility and report the presence of specific clinical variables of scapular dyskinesis in cases with trapezius myalgia and healthy controls, along with general health and work ability. A total of 38 cases and 23 controls were tested for scapular dyskinesis, general health, and work ability, and 19 cases and 14 controls participated in the reproducibility study. Intraexaminer reproducibility was good to excellent for 6 of 10 clinical variables (Intraclass Correlation Coefficient [ICC] 0.76-0.91; kappa 0.84-1.00), and fair to good for four variables (ICC 0.42-0.74), test for muscular weakness having the lowest ICC (0.42). Cases showed significantly larger medial border misalignment, larger lower horizontal distance of the inferior scapular angle and larger passive shoulder internal rotation, by 110% (1.02 cm), 15% (1.38 cm), and 8% (5.5 degrees ), respectively. Cases with the highest degree of scapular dyskinesis showed reduced work ability and general health. The present specific clinical variables on scapular dyskinesis showed satisfactory intraexaminer reproducibility. An increased standardization must be implemented to increase reproducibility of tests for muscular weakness, and the interexaminer reproducibility must be tested for all variables. Finally, scapular dyskinesis in cases with trapezius myalgia must be followed longitudinally for clinical importance. PMID- 21548820 TI - Inclusion of disability within national strategic responses to HIV and AIDS in Eastern and Southern Africa. AB - PURPOSE: National strategic plans (NSPs) provide a framework for a comprehensive response to human immunodeficiency virus (HIV) including strategies such as prevention, treatment, care and support for all affected. Research indicates limited recognition of the interrelationship between disability and HIV in the Eastern and Southern Africa (ESA). This paper analyses the extent to which NSPs in ESA address disability, and identify good practice. METHOD: Using a tool based on relevant rights in the UN Convention on the Rights of Persons with Disabilities and the UNAIDS International Guidelines on HIV and Human Rights, a review of 18 NSPs in ESA was conducted to determine the extent to which they included disability. RESULTS: Although many NSPs fail to integrate disability issues, there are examples of good practice from which much can be learned, particularly with respect to disability and HIV-prevention efforts. There is limited provision for treatment, care and support for disability in the context of HIV and AIDS. CONCLUSIONS: Many NSPs in ESA are due for review, providing ample opportunities for the development of disability-inclusive responses. Future NSPs need to integrate the needs of people with disabilities within structures, programmes and monitoring and evaluation, and make provision for increased rehabilitation needs caused by HIV. A rights-based approach and specific financial allocation of resources are crucial for this process. PMID- 21548821 TI - Perceptions of persons with Parkinson's disease, family and professionals on quality of life: an international focus group study. AB - PURPOSE: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Motor and non-motor symptoms have an impact on persons' lives. To what extent this is effecting persons' quality of life (QOL) is not clear. Therefore, the aim of this qualitative study was to identify factors that persons perceive as eminently important for QOL. METHOD: Focus groups were employed with persons with PD, caregivers and health professionals. RESULTS: The results, obtained through thematic and conceptual qualitative analysis, largely support the framework of domains and facets of the World Health Organization Quality of Life (WHOQOL) assessment instrument. Three new themes were identified, reflecting (i) practical adaptations to PD, (ii) personal adaptations to PD and (iii) the ability to communicate and the availability of communication supports. CONCLUSION: This study demonstrated that focus groups are a valid and reliable way of eliciting views on QOL from persons with PD, caregivers and professionals. The focus group method confirmed the original WHOQOL parameters and also provided some new QOL themes. In addition, the results of this study pointed out that the impact of PD on QOL goes beyond the physical, social and emotional domains of health-related QOL (HRQOL). PMID- 21548822 TI - ABM clinical protocol #8: human milk storage information for home use for full term infants (original protocol March 2004; revision #1 March 2010). AB - A central goal of The Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. PMID- 21548823 TI - Dignity therapy implementation in a community-based hospice setting. AB - BACKGROUND: Dignity Therapy is a brief, empirically supported, individualized psychotherapy designed to address legacy needs among patients at the end of life. To date, this psychotherapy has not been implemented in a "real-world" community based hospice setting. This study was designed to offer information about the pragmatic aspects of implementing Dignity Therapy for patients receiving hospice care. METHOD: Twenty-seven patients completed Dignity Therapy as part of a clinical service newly offered at a community-based hospice. Referral and enrollment procedures, as well as the logistics of therapy implementation were monitored. Patients' legacy transcripts were also qualitatively analyzed to measure emergent themes. RESULTS: Patients were most commonly referred by social workers, and on average produced Dignity Therapy legacy transcripts approximately 3000 words/8 pages in length. The mean number of sessions spent with patients was 4, equating to an average of 380 minutes of clinician time per patient. Qualitative analyses revealed the most commonly discussed topics among patients were (in rank order): autobiographical information, love, lessons learned in life, defining roles in vocations or hobbies, accomplishments, character traits, unfinished business, hopes and dreams, catalysts, overcoming challenges, and guidance for others. DISCUSSION: This was the first study to implement Dignity Therapy in a community sample, with results highlighting the practical aspects of treatment as well as the most common themes discussed by clinical patients in a hospice setting. These findings provide useful data for clinicians or organizational leaders who may consider offering Dignity Therapy in their setting, and offer general insight regarding the legacy topics most frequently discussed by patients near the end of life. PMID- 21548824 TI - Measuring impact of environmental factors on human functioning and disability: a review of various scientific approaches. AB - PURPOSE: The objective of this paper is to present a framework for systematically describing different approaches to measure environmental factors (EF) and to discuss some strengths and weaknesses of these approaches. METHODS: Identification of suitable criteria for ordering measurements of EF was based on an analysis of existing reviews, a qualitative literature review and feedback from experts. Items of selected EF measures were linked to the International Classification of Functioning, Disability and Health. RESULTS: Experimental and observational designs for the study of EF are distinguished and illustrated with examples. Approaches to study EF are differentiated into those directly measuring an environmental interaction with function and those relying on an independent assessment of environmental features. By applying these criteria, a three dimensional matrix framework for measurement of EF in observational studies is developed. CONCLUSION: The acknowledgement of different measurement approaches to the scientific study of EF is one pathway towards an increased understanding of the connection between environments and functioning. Many different measures may be used to approximate the realities of disabling or enabling environments. This review provides an initial framework for improving our fundamental comprehension of the complexity of the measurement of EF in the context of human health and disability. PMID- 21548825 TI - The potential role for lixivaptan in heart failure and in hyponatremia. AB - INTRODUCTION: Hypervolemia and hyponatremia are common features in heart failure and have been associated with increased morbidity and mortality. Stimulation of arginine vasopressin (AVP) plays an important role in the development of both hypervolemia and hyponatremia. Lixivaptan is a selective vasopressin type 2 (V(2)) receptor antagonist that has been demonstrated to have the ability to induce aquaresis, the electrolyte sparing excretion of water, resulting in fluid removal as well as correction of hyponatremia. AREAS COVERED: This article describes the prevalence, pathophysiology and current treatment limitations of hyponatremia, highlights the importance of arginine vasopressin and the potential role of arginine vasopressin antagonists and reviews all available literature on lixivaptan, a selective V(2) receptor antagonist. EXPERT OPINION: The available experience of lixivaptan in heart failure, although limited, is encouraging. Its aquaretic effect provides the basis for its use to correct hypervolemia and hyponatremia in patients with heart failure, and the absence of neurhormonal stimulation provides positive signal for the exploration of its potential in improving outcomes. PMID- 21548826 TI - Production of cloned and transgenic embryos using buffalo (Bubalus bubalis) embryonic stem cell-like cells isolated from in vitro fertilized and cloned blastocysts. AB - Here, we report the isolation and characterization of embryonic stem (ES) cell like cells from cloned blastocysts, generated using fibroblasts derived from an adult buffalo (BAF). These nuclear transfer embryonic stem cell-like cells (NT ES) grew in well-defined and dome-shaped colonies. The expression pattern of pluripotency marker genes was similar in both NT-ES and in vitro fertilization (IVF) embryo-derived embryonic stem cell-like cells (F-ES). Upon spontaneous differentiation via embryoid body formation, cells of different morphology were observed, among which predominant were endodermal-like and epithelial-like cell types. The ES cell-like cells could be passaged only mechanically and did not form colonies when plated as single cell suspension at different concentrations. When F-ES cell-like, NT-ES cell-like, and BAF cells of same genotype were used for hand-made cloning (HMC), no significant difference (p > 0.05) was observed in cleavage and blastocyst rate. Following transfer of HMC embryos to synchronized recipients, pregnancies were established only with F-ES cell-like and BAF cell derived embryos, and one live calf was born from F-ES cell-like cells. Further, when transfected NT-ES cell-like cells and BAF were used for HMC, no significant difference (p > 0.05) was observed between cleavage and blastocyst rate. In conclusion, here we report for the first time the derivation of ES cell-like cells from an adult buffalo, and its genetic modification. We also report the birth of a live cloned calf from buffalo ES cell-like cells. PMID- 21548827 TI - Scriptaid corrects gene expression of a few aberrantly reprogrammed transcripts in nuclear transfer pig blastocyst stage embryos. AB - Nuclear transfer efficiency in the pig is low and is thought to be caused by inadequate nuclear reprogramming. The objective of this study was to identify differentially represented transcripts in pig in vivo derived (BLIVV), in vitro fertilized (BLIVF), or nuclear transfer derived (NT, three different activation methods) blastocyst stage embryos and the donor cell line by microarray analysis, and to determine if treatment of reconstructed embryos with the histone deacetylase inhibitor, Scriptaid (NTS), for 14 h postactivation would correct gene expression in a subset of the identified aberrantly reprogrammed transcripts. There were 1481 differentially expressed transcripts when comparing all six treatment groups (p < 0.05). Transcripts that were different between BLIVV and NT (p < 0.20) and significantly different from donor cells (p < 0.05) were classified as being aberrantly reprogrammed (179 transcripts). Fourteen transcripts were chosen to determine the effect of Scriptaid treatment. After real-time PCR relative gene expression was compared among BLIVV, NT pool, cells, and NTS by the comparative Ct method, statistical analysis was performed in SAS 9.1 (p < 0.05). NTS embryos had three transcripts returning to the same level as BLIVV (H3F3A, CAPG, and SEPT7). Half of the transcripts (7/14) were not affected by NTS treatment, for example, SIRT1 and H1F0. Scriptaid treatment resulted high expression of COX5A and very low expression of GPD1L, EIF3E, and GSTA3. Scriptaid also reduced the number of 5-Methylcytidine-positive nuclei in blastocyst stage embryos (p < 0.0003). Scriptaid treatment significantly affected gene expression in 7 of the 14 transcripts evaluated and returned 3 genes to BLIVV levels. PMID- 21548828 TI - Isolation and in vitro characterization of putative porcine embryonic stem cells from cloned embryos treated with trichostatin A. AB - We report here the establishment and characterization of putative porcine embryonic stem cell (ESC) lines derived from somatic cell nuclear transfer embryos (NT-ESCs). These cells had a similar morphology to that described previously by us for ESCs derived from in vitro produced embryos, namely, a polygonal shape, a relatively small (10-15 MUm) diameter, a small cytoplasmic/nuclear ratio, a single nucleus with multiple nucleoli and multiple lipid inclusions in the cytoplasm. NT-ESCs could be passaged at least 15 times and vitrified repeatedly without changes in their morphology, karyotype, or Oct-4 and Nanog expression. These cells formed embryoid bodies and could be directed to differentiate in vitro to cell types representative of all three germ layers. Following their injection into blastocysts, these cells preferentially localized in the inner cell mass. In conclusion, we have isolated putative porcine ESCs from cloned embryos that have the potential to be used for a variety of applications including as a model for human therapeutic cloning. PMID- 21548829 TI - LIF and FGF cooperatively support stemness of rabbit embryonic stem cells derived from parthenogenetically activated embryos. AB - We investigated the individual and combined effects of leukemia inhibitory factor (LIF) and basic fibroblast growth factor 2 (bFGF2) on the derivation and maintenance of rabbit embryonic stem cell lines isolated from parthenogenetic activated embryos (p-rES). First, we demonstrated that p-rES cell lines can be prevented from differentiation via LIF (STAT3) and bFGF2 (MEK-ERK1/2 and PI3K AKT) signaling on MEF feeders. High levels of ERK1/2 and AKT activities were crucial for maintaining p-rES cells in an undifferentiated state. Although the p rES cells under the influence of LIF (500, 1000, and 2000 U/mL) or bFGF2 (5, 10, and 20 ng/mL) alone showed enhanced expression in the pluripotency markers, the highest levels of marker expressions coincided with the simultaneous presence of LIF (1000 U/mL) and bFGF2 (10 ng/mL). The phosphorylation status of LIF and bFGF2 downstream signaling molecules including STAT3, ERK, and AKT was also intensively involved in the maintenance of p-rES cell proliferation and self-renewal. Induced dephosphorylation of STAT3, ERK1/2, and AKT by specific inhibitors caused remarkable losses of self-renewal capacity of p-rES cells. We conclude that bFGF2 and LIF by itself are self-sufficient in maintaining the state of undifferentiation and self-renewal of rabbit p-ES cells, yet are most effective when acting concomitantly. PMID- 21548830 TI - VTX-1463, a novel TLR8 agonist for the treatment of allergic rhinitis. AB - INTRODUCTION: Allergic rhinitis significantly impacts quality of life and current treatments are frequently unsatisfying. VTX-1463 is a potent, selective, Toll like receptor (TLR) 8 agonist administered weekly via the intranasal route without concomitant administration of allergen for the treatment of allergic rhinitis. AREAS COVERED: The rationale for TLR8 as a therapeutic target in allergic disease is summarized. The potency of VTX-1463 for TLR8 is outlined, and preclinical efficacy data from a ragweed-sensitized beagle dog model of allergic rhinitis are reviewed. Results of three randomized, double-blind, placebo controlled trials with VTX-1463 are also reviewed: (i) a first-in-man study in healthy volunteers, (ii) an allergen challenge study in atopic individuals out of pollen seasons and (iii) an allergen challenge study in atopic individuals during season. EXPERT OPINION: Two or four weekly pretreatments with VTX-1463 in subjects with grass pollen allergies provided statistically significant improvement in nasal symptoms, as measured by total nasal symptom score (TNSS) and active anterior rhinomanometry (AAR), while subjects were exposed to grass pollen in the Vienna Challenge Chamber (VCC). Improvement in nasal secretion weights and ocular symptom scores was also observed. VTX-1463 is a promising new agent for the treatment of seasonal, and potentially perennial, allergic rhinitis. PMID- 21548831 TI - Environmental risk factors in the first year of life and childhood asthma in the Central South of Chile. AB - BACKGROUND: Childhood asthma has a high prevalence in South America--a region of the world currently undergoing a thorough modernization and transition process. Asthma in South America is mainly associated with poor urban environment, which actually may challenge the role of the hygiene hypothesis. We systematically assessed the impact of environmental factors in the first year of life on asthma. METHODS: A case-control study including 188 asthmatics and 294 hospital-based controls aged 6-15 years was carried out in the Central South of Chile. Parents of study participants completed a computer-assisted interview on environmental factors (such as birth order, day-care attendance, pneumonia infection, regular animal and furry pet contact, and environmental tobacco smoke exposure) in the first year of life and potential confounders. Atopy was assessed using skin prick tests. Multivariate logistic regression models were calculated to assess the association between exposures and asthma, adjusting for potential confounders. RESULTS: Day-care attendance (OR = 0.31; 95% CI: 0.10, 0.94) and regular farm animal contact (OR = 0.38; 95% CI: 0.17, 0.85) were inversely related to childhood asthma in the logistic regression models. Pneumonia infection (OR = 2.24; 95% CI: 1.21, 4.16) and mold or dampness in the home (OR = 1.87; 95% CI: 1.18, 2.97) in the first year of life were positively associated with asthma. CONCLUSION: Our results suggest that the hygiene hypothesis is also applicable in the Chilean setting, a South American country in epidemiological transition. PMID- 21548832 TI - Tumor treating fields: concept, evidence and future. AB - INTRODUCTION: Local control is fundamental, both for the curative as well as the palliative treatment of cancer. Tumor treating fields (TTFields) are low intensity (1 ? 2 V/cm), intermediate frequency (100 ? 200 kHz) alternating electric fields administered using insulated electrodes placed on the skin surrounding the region of a malignant tumor. TTFields were shown to destroy cells within the process of mitosis via apoptosis, thereby inhibiting tumor growth. TTFields have no effect on non-dividing cells. AREAS COVERED: This article reviews in vitro and in vivo preclinical studies, demonstrating the activity of TTFields both as a monotherapy as well as in combination with several cytotoxic agents. Furthermore, it summarizes the clinical experience with TTFields, mainly in two indications: one in recurrent glioblastoma multiforme: in a large prospective randomized Phase III trial TTFields was compared with best standard care (including chemotherapy): TTFields significantly improved median overall survival (OS) compared with standard therapy (7.8 vs 6.1 months) for the patients treated per protocol. Importantly, quality of life was also better in the TTFields group. The second indication was a Phase II study in second-line non small cell lung cancer, where TTFields was administered concomitantly with pemetrexed. This combination resulted in an excellent median OS of 13.8 months. Interestingly, the progression-free survival (PFS) within the area of the TTFields was 28, however, outside the TTFields the PFS was only 22 weeks. EXPERT OPINION: The proof of concept of TTFields has been well demonstrated in the preclinical setting, and the clinical data seem promising in various tumor types. The side effects of TTFields were minimal and in general consisted of skin reaction to the electrodes. There are a number of ways in which TTFields could be further evaluated, for example, in combination with chemotherapy, as a maintenance treatment, or as a salvage therapy if radiotherapy or surgery is not possible. While more clinical data are clearly needed, TTFields is an emerging and promising novel treatment concept. PMID- 21548833 TI - Association between prenatal and postnatal tobacco smoke exposure and allergies in young children. AB - BACKGROUND: Many studies have shown a positive association between environmental tobacco smoke (ETS) exposure and allergic disorders, whereas epidemiological evidence of the effect of maternal smoking during pregnancy on allergic diseases is inconsistent. We investigated the independent and joint effects of in utero exposure to maternal smoking and postnatal ETS exposure at home on allergic disorders among Japanese children. METHODS: Study subjects were 1951 children aged 3 years. Data on maternal smoking during pregnancy and postnatal exposure to ETS at home, allergic symptoms, and potential confounders were collected through the use of a questionnaire. Outcomes were defined according to the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC). RESULTS: The prevalence values of symptoms of wheeze, asthma, and eczema in the previous 12 months were 22.0%, 8.8%, and 17.2%, respectively. We found that postnatal ETS exposure at home in the absence of in utero exposure to maternal smoking was associated with a higher prevalence of wheeze (adjusted odds ratio (OR) = 1.30, 95% confidence interval (CI): 1.01-1.67). In contrast, in utero exposure without subsequent postnatal ETS exposure at home or exposure to postnatal ETS at home in addition to in utero exposure to maternal smoking was not associated with the prevalence of wheeze. No measurable associations were observed between fetal, postnatal, or joint exposure and the prevalence of asthma or eczema. CONCLUSIONS: Data from this study indicate that ETS at home may be associated with a higher prevalence of wheeze among young Japanese children. PMID- 21548834 TI - Tasimelteon for insomnia. AB - INTRODUCTION: Insomnia is a prevalent disorder with nearly 50% of the US adult population reporting insomnia symptoms during the past year and 10 - 15% reporting chronic insomnia. In addition, insomnia is a frequent comorbidity with depression, anxiety and pain, as well as other medical and psychiatric disorders. Tasimelteon is a melatonin receptor agonist developed by Bristol-Myers Squibb Co. and later licensed to Vanda Pharmaceuticals in 2004. It is being developed for the treatment of sleep disorders, including insomnia and mood disorders. AREAS COVERED: The nature and prevalence of insomnia are described in this review, along with the current pharmacological treatments for the disorder. Summaries of the available pharmacological and clinical data for tasimelteon are also provided. A Medline search using the terms tasimelteon, melatonin and insomnia was undertaken to assess the current literature on these topics. EXPERT OPINION: While the few clinical trials of the medication have been promising, much more extensive testing, along with more detailed reporting of the drug's pharmacokinetics and pharmacodynamics, is needed before tasimelteon can be considered a worthwhile addition to the available treatments for insomnia. In particular, testing of the drug's effectiveness in treating maintenance insomnia, as well as tests of its long-term effectiveness and safety, is much needed. PMID- 21548835 TI - Enhanced differentiation of adult bone marrow-derived stem cells to liver lineage in aggregate culture. AB - Hepatocyte-like cells derived from stem cells hold great potential for clinical and pharmaceutical applications, including high-throughput drug toxicity screening. We report a three-dimensional aggregate culture system for the directed differentiation of adult rat bone marrow-derived stem cells, rat multipotent adult progenitor cells, to hepatocyte-like cells. Compared to adherent monolayer cultures, differentiation in the aggregate culture system resulted in significantly higher expression level of liver-specific transcripts, including an increased albumin mRNA level, and higher levels of albumin and urea secretion. This coincides with the presence of significantly more cells that express intracellular albumin at levels found in primary hepatocytes. The differentiated cell aggregates exhibited cytochrome P450-mediated ethoxyresorufin O-dealkylation and pentoxyresorufin-O-dealkylation activity. Consistent with these increased mature functions, cells within the aggregates were shown to have many ultrastructural features of mature hepatocytes by transmission electron microscopy. With the scalability of the aggregate culture system and the enhanced differentiation capability, this system may facilitate translation of generating hepatocytes from stem cells to technology. PMID- 21548836 TI - Prevalence rate of exercise-induced bronchoconstriction in Annaba (Algeria) schoolchildren. AB - BACKGROUND: We studied the prevalence rate of exercise-induced bronchoconstriction (EIB) in Annaba schoolchildren. No previous assessment of this syndrome had ever been done in Algeria. METHODS: EIB was evaluated using the 6 min free running test (6MFRT) on 286 children, 87.4% of whom were 10-12 years old. They performed the test in the morning, during the autumn-winter season. Peak expiratory flow rate (PEFR) was measured before, and then 5 and 10 min after the 6MFRT, a 15% or more decrease in post-exercise PEFR being defined as significant. RESULTS: EIB was much more frequent in asthmatic than in nonasthmatic children (47.0% vs. 13.9%, p < .001) and the drop in PEFR was more marked among the former. EIB was observed more often in a cool temperature (<8 degrees C). There were relatively more children who were either eutrophic or overweight among those presenting an EIB. Past histories of nocturnal wheezing and rhinoconjunctivitis presented respectively the best specificity (96.7%) and sensitivity (84.8%). Children of unemployed workers presented the highest occurrence of EIB. Passive smoking appeared as the only factor being related to EIB among the indoor pollutants. The prevalence rate of asthma (6.7%) was higher than in a previous cross-sectional epidemiological survey study performed in the Maghreb. The prevalence rate of EIB (13.9%) was situated in the upper range of the results given worldwide. CONCLUSIONS: These features of a fairly high bronchial hyperresponsiveness could be facilitated by the polluted environment of the city. PMID- 21548837 TI - Clinical impact and drivers of non-adherence to maintenance medication for inflammatory bowel disease. AB - INTRODUCTION: Inflammatory bowel diseases (IBDs) require maintenance medication to sustain remission and as a prophylaxis against the development of colorectal dysplasia. Non-adherence can compromise the effectiveness of treatment plans. AREAS COVERED: Depending on study cohort and country, 7 - 72% of IBD patients do not adhere to maintenance medication plans. Non-adherence is associated with an increased number of flares and increased healthcare utilization costs. Several factors, such as experiencing side effects and demographic, socioeconomic, disease-specific and psychological variables have been associated with non adherence in IBD. Data on demographic, socioeconomic and disease-specific variables are inconsistent, while data on psychological distress, patients' beliefs about medication and discordant doctor-patient relationships are more consistently associated with non-adherence. There has been a change towards investigation of modifiable factors for non-adherence in the recent literature. EXPERT OPINION: Currently, there is no simple and effective intervention to improve adherence to IBD maintenance medication. Anxiety, beliefs about medicines and the doctor-patient relationship are promising targets for interventions, but require further study. PMID- 21548838 TI - Adverse drug reactions in newborns, infants and toddlers: pediatric pharmacovigilance between present and future. AB - INTRODUCTION: The detection, assessment, understanding and prevention of adverse drug reactions (ADRs) are the primary aims of pharmacovigilance activities. Pediatric patients, especially all newborns and infants, are particularly at risk for experiencing drug-related adverse events. AREAS COVERED: This review briefly analyzes the physiological peculiarities of pharmacodynamic and pharmacokinetic aspects of drugs in newborns, infants and toddlers and children. It also deals with specific pediatric pharmacovigilance aspects, such as the frequent use of unlicensed and/or off-label drugs in neonatal intensive care units in European countries and in Australia. This review reports on European, American and Canadian data about the incidence and type of pediatric ADRs, particularly focusing on neonates, infants and toddlers. EXPERT OPINION: The awareness of pediatricians about the importance of reporting ADRs should be stimulated, new reporting systems should be encouraged and pediatric pharmacovigilance activities should be improved, first, by intensifying active post-marketing surveillance methods. PMID- 21548839 TI - Curcumin attenuates hyperglycaemia-mediated AMPK activation and oxidative stress in cerebrum of streptozotocin-induced diabetic rat. AB - Oxidative stress has been strongly implicated in the pathogenesis of diabetic encephalopathy (DE). Numerous studies have demonstrated a close relationship between oxidative stress and AMPK activation in various disorders, including diabetes-related brain disorders. Since curcumin has powerful antioxidant properties, this study investigated its effects on hyperglycaemia-mediated oxidative stress and AMPK activation in rats with DE. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ-55 mg/kg BW). The diabetic rats were then orally administered curcumin (100 mg/kg BW) or vehicle for 8 weeks. The cerebra of the diabetic rats displayed upregulated protein expression of AdipoR1, p-AMPKalpha1, Tak1, GLUT4, NADPH oxidase sub-units, caspase-12 and 3-NT and increased lipid peroxidation in comparison with the controls and all of these effects were significantly attenuated with curcumin treatment, except for the increase in AdipoR1 expressions. These results provide a new insight into the beneficial effects of curcumin on hyperglycaemia-mediated DE, which are produced through the down-regulation of AMPK-mediated gluconeogenesis associated with its anti-oxidant property. PMID- 21548840 TI - Profound changes in drug metabolism enzymes and possible effects on drug therapy in neonates and children. AB - INTRODUCTION: There are profound changes that take place in drug metabolism enzymes during fetal and postnatal development. These changes may significantly impact drug therapy in children. AREAS COVERED: A combination of focused and comprehensive literature searches using PubMed and reference lists (from inception to 7 November 2009) is undertaken to identify reports on in vitro and in vivo development of drug metabolism enzymes as well disposition of selected drugs and their effect in children. The article provides an update on development of drug metabolism enzymes and their impact on drug substrate disposition and disease, which may aid to improve clinical practice and optimally design clinical trials in children. EXPERT OPINION: Drug metabolism enzyme activity changes profoundly throughout the continuum of postnatal development and often results in different disposition pathways than in adults. Genetics and co-morbidity interact significantly with these developmental changes. Translation of existing knowledge into age-adjusted dosing guidelines and clinical trial design is highly needed for there to be an improvement in drug therapy in children. PMID- 21548841 TI - Heparin-chitosan-coated acellular bone matrix enhances perfusion of blood and vascularization in bone tissue engineering scaffolds. AB - Currently, the main hurdle in the tissue engineering field is how to provide sufficient blood supply to grafted tissue substitutes in the early post transplanted period. For three-dimensional, cell-dense, thick tissues to survive after transplantation, treatments are required for hypoxia, nutrient insufficiency, and the accumulation of waste products. In this study, a biomacromolecular layer-by-layer coating process of chitosan/heparin onto a decellularized extracellular bone matrix was designed to accelerate the blood perfusion and re-endothelialization process. The results of in vitro measurements of the activated partial thromboplastin time supported the theory that the combination of chitosan and heparin could bring both anticoagulation and hemocompatibility to the scaffold. A rabbit bone defect model was established for further evaluation of the application of this kind of surface-modified scaffold in vivo. The final results of computed tomography (CT) perfusion imaging and histological examination proved that this facile coating approach could significantly promote blood perfusion and re-endothelialization in the early post transplanted period compared with an acellular bone matrix due to its much improved anticoagulation property. PMID- 21548842 TI - Therapeutic compounds: patent evaluation of WO2011011652A1. AB - A series of sulfonamide derivatives, incorporating azabicyclo[3.2.1]octane and phenyl-propyl scaffolds, were prepared by a succession of original steps. The compounds are claimed to act as antagonists of the C-C chemokine receptor 5 (CCR5) involved in the entry of HIV-1 to cells, but only semi-quantitative antiviral data are provided. HIV entry inhibitors, including CCR5 antagonists, are clinically used for the treatment of this viral infection; the compounds claimed in the patent, possessing a new and original scaffold, seem to be of interest for developing novel antiviral agents belonging to this class. PMID- 21548843 TI - The redesigned follitropin alpha pen injector for infertility treatment. AB - INTRODUCTION: Treatment for infertility may require multiple drugs and complex dosing schedules. Available injection devices for patients who require regular injections during treatment are reviewed in this article, focusing on pen injectors used to self-administer recombinant human follicle-stimulating hormone (follitropin alpha). Following the introduction of the first and second follitropin alpha pen injectors in the last decade, a third pen injector with improved design for the administration of follitropin alpha has been developed for use in fertility treatment cycles. AREAS COVERED: This paper presents the results of the dose accuracy testing with this pen injector that was performed in accordance with international standards (EN ISO 11608-1:2000). This overview also provides an understanding of the key features of the redesigned pen injector that are of interest to healthcare professionals. EXPERT OPINION: The availability of an improved injection device for the delivery of follitropin alpha used during infertility treatment cycles of ovulation induction and assisted reproductive technology offers patients and healthcare professionals new treatment administration options. As fertility treatment cycles involve the use of several injectable gonadotropins, a standard device that could be used for all such treatments would simplify both the administration and the teaching of administration considerably. PMID- 21548844 TI - The effect of mesenchymal stem cell osteoblastic differentiation on the mechanical properties of engineered bone-like tissue. AB - Mesenchymal stem cells (MSCs) can give rise to osteoblasts and have therefore been suggested as a cell source for bone engineering. Here we hypothesized that MSC osteoblastic differentiation and maturation can be supported by three dimensional cultures in collagen hydrogels (hydrogel culture) to ultimately give rise to mechanically robust bone-like tissue. We first compared the osteoblastic differentiation efficiency of MSCs using osteoinductive supplements (beta glycerophosphate, vitamin C, and dexamethasone) in a hydrogel culture and in a two-dimensional culture (2D culture) by assessing surrogate parameters for osteoblastic differentiation, including osteocalcin (OC) secretion and calcium (Ca) deposition. We next constructed ring-shaped bone-like tissues using MSCs in the hydrogel cultures, and assessed their mechanical (strain-strain analysis), biochemical/molecular (OC secretion, Ca deposition, and Runx2/osterix mRNA levels), and morphological (von Kossa staining) properties. OC secretions and Ca depositions were significantly higher in the hydrogel cultures than those in the 2D cultures, suggesting better osteoblastic differentiation and maturation in the hydrogel cultures. Collagen hydrogel-based ring-shaped bone-like tissues conditioned with osteoinductive supplements developed enhanced biomechanical properties, including high tissue stiffness and ultimate burst strength, superior molecular/biochemical properties, and morphological signs typically found in mineralized bone. These results may be exploited not only to generate bioartificial bone, but also to elucidate the basic mechanisms of bone physiology. PMID- 21548845 TI - Gene therapy for lysosomal storage disorders. AB - INTRODUCTION: Lysosomal storage disorders (LSDs) encompass more than 50 distinct diseases, caused by defects in various aspects of lysosomal function. Neurodegeneration and/or dysmyelination are the hallmark of roughly 70% of LSDs. Gene therapy represents a promising approach for the treatment of CNS manifestations in LSDs, as it has the potential to provide a permanent source of the deficient enzyme, either by direct injection of vectors or by transplantation of gene-corrected cells. In this latter approach, the biology of neural stem/progenitor cells and hematopoietic cells might be exploited. AREAS COVERED: Based on an extensive literature search up until March 2011, the author reviews and discusses the progress, the crucial aspects and the major challenges towards the development of novel gene therapy strategies aimed to target the CNS, with particular attention to direct intracerebral gene delivery and transplantation of neural stem/progenitor cells. EXPERT OPINION: The implementation of viral vector delivery systems with specific tropism, regulated transgene expression, low immunogenicity and low genotoxic risk and the improvement in isolation and manipulation of relevant cell types to be transplanted, are fundamental challenges to the field. Also, combinatorial strategies might be required to achieve full correction in LSDs with neurological involvement. PMID- 21548846 TI - Modulation of GDP-fucose level for generating proteins with reduced rate of fucosylation (WO2010141855). AB - BACKGROUND: The application (WO2010141855) is in the field of glycobiology, and involves the control of the rate of fucosylation of proteins by exogenous factors. OBJECTIVE: It aims at controlling the rate of protein fucosylation with inhibitors (drugs or nucleic acid antagonists) of enzymes involved in the synthesis of GDP-fucose. METHODS: Mammalian cell lines were cultured in the presence of inhibitors, for example, siRNA. The rates of GDP-fucose in cells and during protein fucosylation were characterized. RESULTS: The level of protein fucosylation decreases rapidly in response to a decrease in GDP-fucose level. CONCLUSION: The relationship between the rate of fucosylation of proteins and the level of GDP-fucose in a cell is non-linear. Reduction in the rate of protein fucosylation can be achieved with a minimal reduction of the level of GDP-fucose in cells. The paradigm may be used to synthesize proteins and antibodies, with a reduced rate of fucosylation. The application claims that the use of drugs or nucleic acid antagonists that inhibit the enzymes involved in GDP-fucose biosynthesis optimizes the level of GDP-fucose present in cells, and reduces the rate of fucosylation of glycoproteins. PMID- 21548847 TI - Seminal molecular markers as a non-invasive diagnostic tool for the evaluation of spermatogenesis in non-obstructive azoospermia. AB - Non-obstructive azoospermia (NOA) is currently evaluated by the use of conventional histopathological methods. In some cases, focal spermatogenesis is present in the testes of patients with NOA which may be almost undetectable by routine histopathological examinations. Application of molecular markers in semen to predict the spermatogenesis status in the testis will emphasize the probability of finding sperm in NOA testis through further search using TESE or mTESE. Detection of germ cell-specific transcripts in semen is a signal of germ cells present in the testis. In this study, we used molecular methods to evaluate spermatogenesis status in azoospermic men. Semen samples were collected from 203 men with azoospermia. Total RNA was extracted from the semen precipitates. First strand complementary deoxyribonucleic acid (cDNA) was synthesized by reverse transcriptase then, (RT)-PCRs were carried out using primers for testis stage specific genes (DAZ, AKAP4, PRM1, and PRM2). Testicular tissue biopsies were used for evaluating spermatogenesis status in testis. Histopathological examination and LH, FSH, and testosterone level measurements (chemiluminescence assay) were performed. The presence of DAZ and PRM2 transcripts in semen significantly indicated the presence of spermatogonia and spermatids in the testicular tissues. Absence of all four markers in semen confirmed the histopathological results corresponding to sertoli cell only syndrome (SCO). Although TESE should not be excluded solely on this criteria, using PRM1, PRM2, AKAP4, and DAZ transcripts in semen would provide a non-invasive molecular diagnostic tool to better counsel patients before undergoing TESE. PMID- 21548848 TI - Non-viral episomal modification of cells using S/MAR elements. AB - INTRODUCTION: The early potential of gene therapy is slowly becoming realized following the recent treatment of patients with severe combined immunodeficiency and ocular diseases. However at present the field of gene therapy is tempered by the toxicity issues, mainly that of the integrated retroviral vector used in most trials which led to oncogenesis in several of the treated patients. The development of safer, alternative vectors is therefore vital for further progress in this field, in particular vectors which remain episomal and are therefore less genotoxic. One such unique class of vectors are those based on scaffold matrix attachment regions (S/MARs) elements, which are maintained extra-chromosomally and replicate in vitro and in vivo. AREAS COVERED: The overview here describes the most relevant studies utilizing the S/MAR element to episomally modify mammalian cells and tissues with a particular focus on liver tissue, as well as the brain, the muscle, the eye, cancer cells, embryonic cells and neonatal mice. For this purpose, recently published data in these areas (mainly articles published between 2000 and 2010) are reviewed. EXPERT OPINION: The utilisation of vectors harbouring an S/MAR element is an efficient, safe and cost-effective way to episomally modify mammalian cells. PMID- 21548849 TI - MEK inhibitors: a patent review 2008 - 2010. AB - INTRODUCTION: MAPK/extracellular signal-regulated kinase (MEK) inhibitors target the Ras/Raf/MEK/ERK signaling pathway, which is important in cell growth, differentiation and development. The pathway has been implicated in the progression of a variety of diseases, in particular cancer, as well as in immune and inflammatory diseases such as rheumatoid arthritis, organ transplant rejection, septic shock, asthma and viral infection. AREAS COVERED: A comprehensive review of the patent literature (2008 - 2010) covering MEK inhibitors and combinations thereof is provided in this paper. EXPERT OPINION: The first MEK inhibitor was described in the literature in 1995, and several companies are still active in the research and development of MEK inhibitors for various disease states. The emerging role of MEK inhibitors in disease has prompted further investigations of this important target. The combination of MEK inhibitors with other agents/therapies in the treatment of diseases, particularly cancer, is a key development in the field. PMID- 21548850 TI - Parthenogenetically activated human oocytes and parthenogenetic embryonic stem cells: US20100233143. AB - BACKGROUND: The application (US20100233143) is in the field of embryonic stems cells (ESCs) and the generation of ESCs from parthenogenetically activated human oocytes. OBJECTIVE: It aims at determining optimal conditions for parthenogenetically activating human oocytes. METHODS: Oocytes isolated from female donors were activated in vitro in the presence of an ionophore at high oxygen (O(2)) tension and by a serine-threonine kinase inhibitor under low O(2) tension. The blastocysts were transferred to a feeder layer, and the inner cell masses (ICMs) were mechanically isolated. RESULTS: Human ESCs were derived from the ICMs of the parthenogenetically activated oocytes. CONCLUSION: Parthenogenetic ESCs (pESCs) provide a model for cellular therapy and regenerative medicine. The paradigm may be used for generating isogenic cells lines relative to the donors. The application claims the method for parthenogenetically activating human oocytes, including cryopreserved oocytes or parthenotes, and for generating pESC lines for therapy and drug discovery. The application further claims the establishment of a cell bank of human pESCs. PMID- 21548851 TI - The Val34Leu genetic variation in the A subunit of coagulation factor XIII in recurrent spontaneous abortion. AB - The present study was carried out to assess the frequencies of factor XIII (FXIII) Val34Leu genetic variation in the patients with recurrent spontaneous abortion and healthy fertile women of Azeri Turkish origin. A total of 54 patients with recurrent spontaneous abortion and 46 healthy fertile women as controls were studied for the FXIII Val34Leu genetic variation by a RFLP-PCR method. Statistical analysis showed that patients (chi2 = 2.4, p value = 0.292) and controls (chi2 = 1.035, p value = 0.596) were in agreement with Hardy Weinberg equilibrium. The Leu allele frequency was 0.18 and 0.13 in patients and controls, respectively. FXIII Leu34Leu (homozygous for 34Leu) genotype was not found in patients and controls. FXIII Val/Leu and Val/Val genotype frequencies were 19 (35.19%) and 31 (64.81%) in patients and 12 (26.09%) and 34 (73.91%) in controls, respectively. FXIII 34Leu allele and Val34Leu genotypes were more common in the case group containing individuals with unexplained RSA but the differences of FXIII Val34Leu (G/T genotype) (odds ratio = 0.65 (0.25 < OR < 1.67) corresponding to 95% CI, chi2 = 0.96, p value = 0.32) and FXIII 34Leu (T allele) (odds ratio = 0.70 (0.30 < OR < 1.64) corresponding to 95% CI, chi2 = 0.78, p value = 0.37) was not statistically significant. These results suggest that factor XIII Val34Leu genetic variation is not associated with recurrent spontaneous abortion. PMID- 21548852 TI - Boehringer Ingleheim's selective glucocorticoid receptor agonist development candidate: evaluation of WO2010141331, WO2010141332 and WO2010141333. AB - Three applications from Boehringer Ingelheim all relate to the preparation of non steroidal glucocorticoid receptor agonists useful in the treatment of inflammatory respiratory diseases. The first two applications claim chiral processes for the preparation of these compounds or intermediates useful therein. These provide two alternative routes, respectively, using achiral and chiral reagents. The third application relates to the preparation of a crystalline salt of the preferred compound on a multi-kilogram scale in micronised form. PMID- 21548853 TI - Effects of symptoms of co-morbid psychopathology on challenging behaviours among infants and toddlers with Autistic Disorder and PDD-NOS as assessed with the Baby and Infant Screen for Children with aUtIsm Traits (BISCUIT). AB - PURPOSE: To examine whether level of symptoms of co-morbid psychopathology exacerbated challenging behaviours in young children with autism spectrum disorders (ASD). METHOD: Using the Baby and Infant Screen for Children with aUtIsm Traits (BISCUIT)-Part 2 which measures co-morbid symptoms and the BISCUIT- Part 3 which examines challenging behaviours, 362 infants and toddlers with ASD were evaluated. RESULTS: Findings showed that participants scoring high on symptoms of Avoidance and Tantrum/Conduct problems had greater rates of aggressive/destructive behaviours, self-injurious behaviours (SIB) and stereotypies compared to those with low scores. Participants with high levels of Inattention/Impulsivity or Eat/Sleep concerns, compared to those with low levels, demonstrated greater aggressive/destructive behaviour and stereotypies. For symptoms of Anxiety/Repetitive Behaviours, participants with high scores displayed greater levels of stereotypies. CONCLUSIONS: Symptoms of co-morbid psychopathology are present at a very early age for children with ASD and elevated levels of these symptoms may exacerbate challenging behaviours. PMID- 21548854 TI - Measuring changes in functional mobility in children with mild cerebral palsy. AB - OBJECTIVE: To support the use of TUG and TUDS to detect changes in functional mobility in children with mild cerebral palsy. METHODS: Six children with spastic cerebral palsy and classified by GMFCS as level I or II were enrolled in the study. The gross motor function was measured by the GMFM and functional mobility by the TUG and TUDS. The participants were assessed before and after an 8-week follow-up. RESULTS: After this period, increased GMFM scores were found at dimensions D (standing) and E (walking, running and jumping). The time to complete TUG and TUDS was shorter after the follow-up period. Negative correlations were found between GMFM dimension E and the TUG and TUDS tests. CONCLUSION: Changes in the gross motor skills measured by the GMFM may be accompanied by changes in the movement speed measured by TUG and TUDS. These tests may complement information provided by GMFM. PMID- 21548855 TI - Activity participation of children with complex communication needs, physical disabilities and typically-developing peers. AB - OBJECTIVE: To describe and compare the context of participation of children with physical disabilities and complex communication needs (Group CCN) in out-of school activities with children with physical disabilities only (Group PD) and typically-developing peers (Group TD). METHOD: A cross-sectional, matched, multi group design was used. Thirty-nine participants between 10-15 years of age were administered the Children's Assessment of Participation and Enjoyment. RESULTS: Kruskall-Wallis analyses revealed that there were significant differences among the three groups for overall location, enjoyment of the activities and with whom they did the social and self-improvement activities with. Mean trends showed that Group CCN participated in activities closer to home rather than in the community, were restricted in social participation and reported higher levels of enjoyment in activity participation than the other two groups. CONCLUSIONS: Group CCN appeared to experience differences in participation when compared to peers with and without disability. PMID- 21548856 TI - Linguistic development in Alzheimer's disease: 12 months language training including use of a personal computer system: a pilot study. AB - OBJECTIVE: To assess linguistic development in patients with mild and moderate Alzheimer's disease (AD) who underwent treatment with a drug and regularly performed language activities. METHODS: For 12 months, five patients with mild-to moderate AD participated in a Stimulation-Activation-Training programme (SAT) including pragmatic, semantic, writing, conversation and counting sessions. A computer with exercise programs and a keyboard with a printer were used as complements to ordinary stationery. The linguistic competence was assessed using a standardized assessment tool. RESULTS: The assessment indicated preservation or slight changes of the patients' linguistic competence over the period and greater confidence in the management of the language. The personal computer system was a well accepted novelty. CONCLUSION: The documented approach, SAT training interlaced with everyday life tasks, may be helpful in maintaining and improving remaining language functions in patients with mild or moderate AD. PMID- 21548857 TI - Effects of strength training on neuromuscular facial rehabilitation. AB - OBJECTIVE: Physical trauma is the third leading cause of facial nerve damage, which can disrupt communication, social interaction and emotional expression. The objective of this report was to investigate the effects of facial muscle exercise as a stand-alone treatment in a young adult with unilateral facial nerve damage 13-years post-onset. METHOD: This single case study examines the long-term results of a 7-week intensive facial exercise programme followed by a 16-week moderate facial exercise programme. RESULTS: Intensive exercise increased facial strength and upper lip elevation on the affected side and upper and lower lip strength on the affected and non-affected sides. With subsequent moderate exercise followed by 24 weeks of rest, strength was maintained but not increased. CONCLUSION: With intensive facial exercise, muscle weakness resulting from facial nerve damage sustained during childhood can be improved years after injury. PMID- 21548858 TI - The effects of hearing impairment on symptoms of autism in toddlers. AB - OBJECTIVE: Individuals diagnosed with certain medical conditions, such as those with hearing loss or impairment, may present with symptoms that mimic those of Autism Spectrum Disorders (ASD). Therefore, the aim of this study was to investigate how hearing-compromised toddlers would score relative to toddlers diagnosed with an ASD on a measure of autism symptomatology. METHODS: The Baby and Infant Screen for Children with aUtIsm Traits (BISCUIT) was utilized to compare toddlers diagnosed with an ASD or who had hearing problems. RESULTS: The BISCUIT was effective in differentiating between children with ASD and those with hearing problems. However, atypically developing toddlers scored significantly lower than those with compromised hearing within the communication domain. CONCLUSION: Communication impairment, albeit lower than in toddlers with ASD, is present in toddlers with compromised hearing. As such, this factor should be taken into account when assessing for ASD in toddlers with hearing loss or impairment. PMID- 21548859 TI - Facilitating clinical decision-making about the use of virtual reality within paediatric motor rehabilitation: application of a classification framework. AB - AIM: Multiple virtual reality (VR) systems are used to improve motor function in children and youth with neurological impairments. Galvin and Levac developed a classification framework to facilitate clinical decision-making about VR system use. This paper applies the classification framework to identify its strengths and limitations. METHOD: The classification framework is applied to three case studies where therapists may consider using VR with children involved in paediatric rehabilitation programmes. RESULTS: The classification framework identified VR systems that met each child's individual needs. The relevance of each category to clinical decision-making varied depending on each child's goals. Categories requiring further development and suggestions for additional categories are discussed. CONCLUSIONS: The classification framework facilitates child-centred decision-making about the use of VR as a therapeutic intervention. It has shown initial utility but requires further validation with clinicians working in a variety of clinical settings and with a range of client populations. PMID- 21548860 TI - Promoting mouth drying to reduce the effects of drooling in a woman with multiple disabilities: a new evaluation of microswitch-programme conditions. AB - OBJECTIVE: Extending the use of microswitch-based programmes to (a) establish mouth-drying responses and reduce the effects of drooling, (b) assess the possibility of widening inter-response intervals and (c) determine whether different microswitch solutions would impact the accuracy/effectiveness of mouth drying. METHOD: During the intervention phases of the study, the participant (woman) performed mouth-drying responses via a special napkin. Such napkin contained two pressure sensors/microswitches, a microprocessor and an MP3 serving to monitor responses and ensure stimulation contingent on them. RESULTS: The participant (a) learned to dry her mouth and reduce her chin wetness, (b) stabilized her responding at lower frequencies (i.e. when the stimulation period was extended) and (c) produced more accurate/effective responses when she was required to trigger both sensors of the napkin. CONCLUSION: Microswitch-based programmes may promote practically sustainable and effective mouth drying to reduce drooling effects in persons with multiple disabilities. PMID- 21548861 TI - Nitrous oxide induced manic relapse. PMID- 21548862 TI - Emerging drugs in gastrointestinal tract. PMID- 21548863 TI - New cell therapy using bone marrow-derived stem cells/endothelial progenitor cells to accelerate neovascularization in healing of experimental ulcerative colitis. AB - Inflammatory bowel disease (IBD): ulcerative colitis (UC) and Crohn disease (CD) are characterized by recurrent inflammation and ulceration of intestinal and/or colonic mucosa and an inappropriate and delayed healing. Current therapies with, e.g., anti-TNFalpha antibody (infliximab) and other anti-inflammatory drugs (e.g., mesalamine) do not induce sustained remission, complete healing or prevent recurrence of UC. Although the pathogenesis of UC is not fully understood, pathologic angiogenesis has been postulated as a critical pathogenic component in UC. Recent studies demonstrated that the poor healing, chronic inflammation in colon of UC could be the result of microvascular dysfunction and endothelial barrier defect, resulting in sustained tissue hypoperfusion and ischemia in the colon. Previously, regeneration of injured endothelium and neovascularization were believed to rely solely on the migration and proliferation of neighboring endothelial cells from existing blood vessels. However, accumulating evidence shows that additional mechanisms may exist, and may be mediated by the circulating pool of bone marrow-derived endothelial progenitor cells (BMD-EPC). Furthermore, stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 have been demonstrated to play an important role in the "homing" of BMD-EPC to injured sites and neovascularization in tissue repair. Recent studies by others and us showed reduced BMD-EPC levels in the circulation of IBD patients and rats with experimental UC. However, the potential therapeutic effect of BMD-EPC on neovascularization and colonic mucosal repair in UC has not been elucidated. In this review, we discussed the possibility that impaired contribution of BMD-EPC (i.e., decreased release of BMD-EPC from bone marrow to circulation and/or blocked/impaired homing of BMD-EPC to colonic lesions) may be a critical component of mechanisms in the incomplete/delayed healing of UC, and may offer a novel form of cell therapy for IBD. PMID- 21548864 TI - Ghrelin: new insight to mechanisms and treatment of postoperative gastric ileus. AB - Postoperative gastric ileus develops after abdominal surgery and if prolonged leads to longer hospitalization times. Besides discomfort for the patient such as abdominal bloating and pain, this condition is associated with a great increase in healthcare costs. In order to develop new and effective treatment strategies to alleviate the ileus, a good understanding of the pathophysiogical underlying mechanisms is necessary. Postoperative gastric ileus consists of two phases, a first neural/humoral phase and a second inflammatory phase. The present review will focus on the role of the orexigenic and prokinetic hormone ghrelin in the development of postoperative ileus. Although ghrelin and ghrelin mimetics have been used during the recent years in pre-clinical and a first clinical trial to alleviate symptoms of postoperative ileus, the regulation of this hormone under conditions of abdominal surgery has just recently begun to be explored. Growing evidence indicates that postoperative restoration of ghrelin signaling leads to an orexigenic effect whereas the gastroprokinetic actions seem to require supraphysiological doses. Since the expression of ghrelin-O-acyltransferase (GOAT), the only ghrelin acylating enzyme, is reduced after abdominal surgery, the stimulation of GOAT signaling may also be a new promising approach to restore levels of acyl ghrelin under these conditions and a potential useful addition to ghrelin mimetics. PMID- 21548865 TI - Lipoxins, the novel mediators of gastroprotection and gastric adaptation to ulcerogenic action of aspirin. AB - Previous studies revealed that prostaglandins contribute to the mechanism of maintenance of gastrointestinal integrity and mediate various physiological aspects of mucosal defense. The suppression of prostaglandin synthesis in the stomach is a critical event in terms of the development of mucosal injury after administration of various NSAID including aspirin (ASA). A worldwide use of ASA is now accepted due to its remarkable analgesic, antipyretic and anti-thrombotic prophylactics against myocardial infarct and coronary disorders despite the fact that the use of NSAIDs is associated with the risk of gastrointestinal bleedings, haemorrhagic lesions and ulcerations. It has become clear that other mediators besides prostaglandins can similarly act to protect the gastrointestinal mucosa of experimental animals and humans from injury induced by ASA. For instance, nitric oxide (NO) released from vascular epithelium, epithelial cells of gastrointestinal tract and sensory nerves can influence many of the same components of mucosal defense as do prostaglandins. This review was designed to provide an updated overview based on the experimental and clinical evidence on the involvement COX-2 derived products, lipoxins in the mechanism of gastric defense, gastroprotection and gastric adaptation to ASA. Lipoxins were recently considered as another group of lipid mediators that can protect the stomach similarly as NO-donors known to exert protective influence on the stomach from the injury under condition where the mucosal prostaglandin levels are suppressed. The new class of NO-releasing NSAIDs, including NO-aspirin or NO-naproxen, represent a very promising approach to reducing the toxicity of their parent NSAIDs. Aspirin-triggered lipoxin (ATL) synthesis, via COX-2, acts to reduce the severity of damage induced by this NSAID. Lipoxin analogues may prove to be useful for preventing mucosal injury and for modulating mucosal inflammation. Evidence presented in this review documents that ATL also play in important role in gastric adaptation during chronic ASA administration. Suppression of COX-2 activity by selective COX-2 inhibitors such as rofecoxib or celecoxib was shown to abolish the production of ATL and to diminish the gastric tolerability of ASA and gastric adaptation developed in response to repetitive administration of this NSAID. Synthetic analogues of lipoxins as well as newer class of NSAIDs releasing NO may be used in the future as the therapeutic approach to counteract adverse effects in the stomach associated with NSAIDs ingestion. PMID- 21548866 TI - Angiogenic and anti-angiogenic therapy for gastrointestinal ulcers: new challenges for rational therapeutic predictions and drug design. AB - Gastrointestinal (GI) ulcers are essentially internal wounds that resist normal healing processes. Since their pathogenesis is poorly understood, and the etiologic (e.g., gastric acid, aspirin-like drugs, stress) and aggravating factors (e.g., H. pylori) are not well characterized, the remaining therapeutic option is to accelerate healing. Superficial mucosal lesions, i.e., erosions usually heal by epithelial regeneration and restitution, but when ulcers involve the muscularis propria, smooth muscle cells do not divide/regenerate. These deep lesions are filled by granulation tissue, i.e., angiogenesis followed by proliferation of connective tissue fibroblasts that deposit collagen over which adjacent surviving and dividing epithelial cells migrate to complete the healing. Our laboratory was the first to postulate that stimulation of angiogenesis alone might be sufficient to accelerate ulcer healing in the GI tract. Indeed, daily treatment of rats with bFGF, PDGF or VEGF markedly improved the healing of cysteamine-induced chronic duodenal ulcers, without any reduction in gastric acid secretion. These results were reproduced by a single dose of gene therapy by adenoviral vectors encoding PDGF or VEGF genes. The molar potency of angiogenic growth factors was 2-7 million times better than the antiulcerogenic effect of antisecretory H2 antagonists. Since histologically & pathologically gastroduodenal ulcers look similar to ulcers in the lower GI tract, we also predicted that the healing of experimental ulcerative colitis might be also improved by these angiogenic growth factors. Rectal enemas containing bFGF or PDGF indeed accelerated the healing of chemically induced ulcerative colitis in rats. VEGF, also known as VPF (vascular permeability factor), however, had no effect or slightly aggravated the colonic lesions. Injection of anti-VEGF neutralizing antibodies, however, counteracted the increased vascular permeability in the early stages of experimental ulcerative colitis and subsequently decreased the number of inflammatory cells in colonic ulcers in rats, resulting in significantly improved healing in the lower GI tract lesions. Thus, the three angiogenic growth factors tested exerted beneficial effect on gastroduodenal ulcers, and rectal enemas with bFGF or PDGF also accelerated the healing of experimental ulcerative colitis. Surprisingly, we achieved the latter effect with anti-VEGF antibodies, most likely because of the pro-inflammatory actions of VEGF in the pathogenesis of ulcerative colitis. PMID- 21548867 TI - Stable gastric pentadecapeptide BPC 157: novel therapy in gastrointestinal tract. AB - Stable gastric pentadecapeptide BPC 157 is an anti-ulcer peptidergic agent, safe in inflammatory bowel disease clinical trials (GEPPPGKPADDAGLV, M.W. 1419, PL 14736) and wound healing, stable in human gastric juice and has no reported toxicity. We focused on BPC 157 as a therapy in peridontitis, esophagus, stomach, duodenum, intestine, liver and pancreas lesions. Particularly, it has a prominent effect on alcohol-lesions (i.e., acute, chronic) and NSAIDs-lesions (interestingly, BPC 157 both prevents and reverses adjuvant arthritis). In rat esophagitis and failed function of both lower esophageal sphincter (LES) and pyloric sphincters (PS), BPC 157 increased pressure in both sphincters till normal and reduced esophagitis. However, in healthy rats, it may decrease (PS) or increase (LES) the pressure in sphincters. It has strong angiogenic potential, it acts protectively on endothelium, prevents and reverses thrombus formation after abdominal aorta anastomosis, affects many central disturbances (i.e., dopamine and 5-HT system), the NO-system (either L-arginine and L-NAME effects), endothelin, acts as a free radical scavenger (counteracting CCl4-, paracetamol-, diclofenac-injuries) and exhibits neuroprotective properties. BPC 157 successfully heals the intestinal anastomosis, gastrocutaneous, duodenocutaneous and colocutaneous fistulas in rats, as well as interacting with the NO-system. Interestingly, the fistula closure was achieved even when the BPC 157 therapy was postponed for one month. In short-bowel syndrome escalating throughout 4 weeks, the constant weight gain above preoperative values started immediately with peroral and parental BPC 157 therapy and the villus height, crypth depth and muscle thickness (inner (circular) muscular layer) additionally increased. Thus, BPC 157 may improve gastrointestinal tract therapy. PMID- 21548868 TI - Gastric ulcerogenic and healing impairment actions of alendronate, a nitrogen containing bisphosphonate - prophylactic effects of rebamipide. AB - Alendronate, a nitrogen containing bisphosphonate (BPP), when given p.o., decreases the transmucosal potential difference by direct irritating action, resulting in non-hemorrhagic lesions in both the corpus and antrum of fasted rats, and after re-feeding produces large ulcers in the antrum with increased vascular permeability and submucosal edema. The pathogenesis of these ulcers may be explained by the impairment of the mucosal anti-oxidative system and does not involve acid digestion as well as a deficiency of prostaglandins (PGs). Alendronate, although does not affect cyclooxygenase/ PGE(2) production in the ulcerated mucosa, but impairs the healing of gastric ulcers in rats, and this effect may be related to the down-regulation of vascular endothelial growth factor and basic fibroblast growth factor (bFGF), the important growth factors for the vascularization/granulation as well as the suppression of the stimulatory action of epidermal growth factor on the epithelial proliferation/migration. Rebamipide, a mucosal protective and antiulcer drug, does not affect the direct irritating action of alendronate in the gastric mucosa but prevents the alendronate-induced antral ulceration, probably due to anti-oxidative and anti inflammatory actions. In addition, this agent also antagonizes the healing impairment action of alendronate by counteracting the down-regulation of bFGF expression in the ulcerated mucosa. It is assumed that rebamipide is a promising drug that can be used as a prophylactic against the adverse effects of BPPs in the stomach. PMID- 21548869 TI - Visceral pain: spinal afferents, enteric mast cells, enteric nervous system and stress. AB - This review aims to examine current basic and clinical concepts, the results of which are expanding our understanding of visceral hypersensitivity and functional abdominal pain of intestinal origin in relation to the enteric nervous system (ENS), spinal sensory neurons and enteric mast cells. Advances in this sphere are translating to improved insight into chronic functional abdominal and pelvic pain syndromes in general. PMID- 21548870 TI - Approaches to gastrointestinal cytoprotection: from isolated cells, via animal experiments to healthy human subjects and patients with different gastrointestinal disorders. AB - Our clinical observations proved that the the duodenal ulcer in patients healed without any inhibition of gastric acid secretion (1965), and the healing rates of atropine vs cimetidine vs Carbenoxolone were equal and superior to that of placebo in randomized, prospective and multiclinical study of DU patients (1978). The phenomenon of gastric cytoprotection was defined by Andre Robert in rats (1979). The essential point of this phenomenon is that the prostaglandins prevent the chemical-induced gastric mucosal damage without affecting gastric acid secretion, this being originally suggested as a reaction specific to prostaglandins. Since then gastrointestinal cytoprotection has been shown with various agents (anticholinergic agents, H(2)RA, growth factors, body protecting compound, BPC) and retinoids in animals; the latter differing from the actions of vitamin A. In examining the various components of gastrointestinal cytoprotection , different studies have performed in isolated cells, stable cell lines, animal experiments, healthy human subjects, in patients chronic gastric and duodenal ulcers, and with different gastrointestinal disorders. Our attention has focused on the effects of cytoprotective agents on cellular viability, mitochondrial and DNA damage, oxygen free radicals, natural antioxidant systems, mucosal biochemistry, vascular events, gastrointestinal mucosal protection as well as in their prevention of different human diseases. This paper gives an overview on the different approaches for the exploring gastrointestinal cytoprotection (at the level of isolated cells, animal experiments, healthy human beings and patients with different gastrointestinal disorders). It has been indicated that the gastric cytoprotection exists in animals, human healthy subjects, patients with different gastrointestinal disorders. The our human observation in patients with duodenal ulcer healed without any changes of gastric acid secretion, there were no significant differences between the cimetidine vs. atropine (as antisecterory agents) or vs. Carbenoxolone vs. retinoid (as cytoprotective compounds) treatment. Also we indicated the presence of intact vagal nerve basically necessary for development of gastrointestinal cytoprotection and for capsaicin sensitive vagal nerve induced mucosal protection (1982). PMID- 21548871 TI - The possible existence of a gut-bone axis suggested by studies of genetically manipulated mouse models? AB - Recently, reports published in Nature Medicine and Cell have suggested the existence of a gut-bone axis based on studies of gene knockout mice. First, impaired gastric acid secretion was claimed to negatively affect calcium homeostasis and bone mass; which was based on the bone phenotype of cholecystokinin-B (or 2) receptor knockout mice. However, also histidine decarboxylase knockout mice suffered from impaired gastric acid secretion, while exhibiting a very different bone phenotype. This argues against the view that lack of gastric acid causes bone loss. Second, circulating serotonin was claimed to inhibit bone formation. This claim was based on the observation that mice deficient in low-density lipoprotein receptor-related protein 5 (Lrp5) exhibited bone loss coupled with accelerated serotonin synthesis. Lrp5 was claimed to control bone formation by a link involving duodenal serotonin synthesis. However, the accelerated serotonin synthesis in Lrp5 knockouts occurred after the onset of bone loss, a sequence of events that does not suggest a causal relationship between elevated serotonin in blood and bone loss. Moreover, pharmacological inhibition of serotonin synthesis prevented bone loss following ovariectomy in wild-type mice and rats, an observation that does not support the existence of Lrp5 pathway in the serotonin-bone axis. PMID- 21548872 TI - Antibacterial peptides and gastrointestinal diseases. AB - Defensins and cathelicidins are small cationic peptides produced by neutrophils and epithelial cells. They are highly expressed during infection. The role of constitutive and inducible antibacterial peptides has been extensively studied over the recent years; especially in the gastrointestinal (GI) tract, where the balance between the luminal bacteria and antibacterial peptides is crucial in the maintenance of a healthy GI tract. There are reports showing that the expressions of defensins and cathelicidins in the gut are dysregulated in various disease states. They could participate in the development of different disorders ranging from inflammation to cancer. Experimental findings showed that supplementation with animal cathelicidin promoted gastric ulcer healing in rats and suppressed tumorigenesis of gastric cancer in mice. Mouse cathelicidin could alleviate murine colitis by preserving mucus content and suppression of apoptosis. Other clinical applications for these antibacterial peptides are awaiting for further studies. PMID- 21548873 TI - Somatostatin and octreotide on the treatment of acute pancreatitis - basic and clinical studies for three decades. AB - The finding that somatostatin (SST) or its analogue, octreotide caused a dose dependent reduction in exocrine pancreatic secretions triggered their research as therapeutic options for acute pancreatitis (AP), a life-threatening illness. However, the accumulative clinical trials of SST or octreotide in AP treatment present the controversial results. The insufficient secretory capacity of acinar cells in AP patients also queries the validity of traditional assumption on the effects of SST and octreotide. This reviewer updates the current pharmacological concepts of SST and octreotide in treatment of AP and the clinical strategies of their application. The impressive inhibitive effects on the massive inflammatory injury via the several signal pathways make SST as an important anti-inflammatory peptide. Furthermore, endocrine SST may decrease the sphincter tone of Oddi (SO) by its potential role on the neurocrine of SST in SO. Therefore, it should be rational that exogenous supplement of SST or octreotide for AP patients due to the plasma level of SST during AP is usually lower than that of normal. In accordance with these findings, the optimal stage of SST or octreotide administration, application in high risk population, the cost-effective dosage or duration as well as the design of suitable clinical outcomes would be the interesting topics of translational medical research for both basic scientists and clinicians. PMID- 21548874 TI - Neuropeptide - adipose tissue communication and intestinal pathophysiology. AB - Until recently, fat was considered a relatively inactive tissue serving only as a depot for the storage of excess lipid around the body. Over the last decade, however, several studies have established fat as a metabolically active endocrine organ able to affect human pathophysiology at multiple levels. During this time adipose tissue has been shown to produce a number of hormones and inflammatory mediators collectively termed as adipokines. These molecules have been shown to be involved in the etiology of a number of inflammation-associated pathological conditions ranging from atherosclerosis and hypertension to diabetes and cancer. Despite the close physical association of abdominal fat and the intestine in the visceral cavity and the significant paracrine functions now attributed to adipose tissue, very little is known on the potential interactions between these tissues as they may relate to intestinal homeostasis. Considering the dramatic alterations in mesenteric fat depot size and placement during at least one intestinal disease, Crohn's disease, the potential involvement of fat tissue in the development as well as the progression of this and other pathological conditions should be considered. In this review we discuss the latest knowledge on neuropeptide-adipose tissue communication and the potential changes such interaction may induce in intra-abdominal fat tissue physiology. Finally we will discuss evidence on the potential pathways by which such changes in fat physiology may affect the development and progress of intestinal pathological conditions such as inflammatory bowel disease. PMID- 21548875 TI - Sulforaphane enhances protection and repair of gastric mucosa against oxidative stress in vitro, and demonstrates anti-inflammatory effects on Helicobacter pylori-infected gastric mucosae in mice and human subjects. AB - Helicobacter pylori infection induces oxidative stress on gastric mucosa, thereby causing mucosal damage, retarding mucosal repair, and eventually inducing gastric cancer. Cells can survive against chronic oxidative stress by enhancing activities of antioxidant enzymes, thereby protecting cells from DNA damage. Recent studies have clearly shown that the genes encoding nrf2 (NF-E2 p45-related factor-2) and keap1 (Kelch-like ECH-associated protein 1) play an important role in the induction of antioxidant enzymes against oxidative stress. In this paper, we will first describe the cellular mechanisms by which the nrf2-keap1 system contributes to induction of a variety of antioxidant enzymes during exposure to oxidative stress. Secondly, we will also mention beneficial effects of a natural compound sulforaphane, an isothiocyanate family, rich in broccoli sprouts, on gastric mucosa. Sulforaphane stimulates nrf2 gene-dependent antioxidant enzyme activities, thereby protecting cells from oxidative injury. Finally, we will show our data on the effect of sulforaphane, a natural chemical compound rich in broccoli sprouts, on protection and repair of gastric mucosa against oxidative stress, and anti-inflammatory effects on gastric mucosa during H. pylori infection, which appears to be closely related to chemoprotection against gastric cancer induced by .H. pylori-infection. PMID- 21548876 TI - Effective therapy with the neuroleptic thioridazine as an adjunct to second line of defence drugs, and the potential that thioridazine offers for new patents that cover a variety of "new uses". AB - New and active infections of tuberculosis continue to increase globally. Although antibiotic susceptible infections can be readily cured with isoniazide and rifampicin, infections resistant to these two antibiotics, named Multi-Drug Resistant TB (MDR TB), are problematic for therapy, extol high costs in terms of human suffering and finances, and when these MDR infections progress to Extensive Drug Resistant TB (XDR TB) status, they are not only difficult to treat, they produce high levels of mortality regardless of therapeutic modality employed. The neuroleptic thioridazine (TZ) has been shown to have wide spectrum in vitro and ex vivo activities against antibiotic susceptible, MDR and XDR strains, and has been successfully used for curing mice of active tuberculosis produced by antibiotic susceptible and MDR strains, and has cured 10 out of 12 XDR TB patients when used in combination with three antibiotics to which the XDR TB patients were non-responsive. Mycobacterium tuberculosis TZ has been recommended for "Compassionate Therapy" of MDR/XDR TB infections whose prognoses are significantly serious and anticipated to result in mortality. This review of TZ activity and its potential to cure MDR/XDR TB supports the contention that this neuroleptic offers patenting opportunities for "New Use". The motivation for patents therefore is expected to rapidly bring TZ to the forefront for therapy of MDR/XDR TB and therefore, the striving for new patents is expected to contribute to the prevention of new infections of antibiotic resistant tuberculosis. PMID- 21548877 TI - Thioridazine: the good and the bad. AB - Thioridazine is a phenothiazine drug which has previously been extensively used for its antipsychotic properties as it is associated with a low risk of extra pyramidal side-effects. There is good evidence to suggest that, in common with other phenothiazine drugs, thioridazine has important anti-microbial activity and is a potential candidate for development as an anti-microbial drug against multi resistant organisms, including drug-resistant strains of M. tuberculosis. The clinical pharmacology and toxicity profile of thioridazine are reviewed in this article and the implications for future drug development along with the patent are discussed. PMID- 21548878 TI - Latent tuberculosis: is there a role for thioridazine? AB - Approximately 1/3 of the world's population is infected with Mycobacterium tuberculosis. In the vast majority of cases this results in latent not active disease. Latent disease is defined as a positive reaction to tuberculin antigens but without any further clinical symptoms. Models have been developed to study latent tuberculosis with the two most prominent being the in vivo murine model and the in vitro Wayne model. In both cases M. tuberculosis undergoes a change in its respiratory profile as it shifts down to a nonreplicating state. However in both the mouse and the Wayne model, dormant M. tuberculosis is sensitive to the phenothiazine thioridazine. This antibiotic has several targets, and the main one is respiration. There is a growing burden of multidrug resistant and extensively drug resistant tuberculosis. Treatment of these cases is expensive with high mortality. We propose that thioridazine alone, or with other antibiotics, be used to treat drug resistant latent tuberculosis. The advantages are that thioridazine is inexpensive, effective against drug resistant tuberculosis, well characterized and unlikely to induce drug resistance. The disadvantages include possible side effects, although these should be rare at the doses and length of time of treatment. Recent patents involving analogs of thioridazine suggest this class of drugs may hold great promise for the future treatment of the most drug resistant strains. PMID- 21548879 TI - Global clinical trials for the treatment of TB with thioridazine. AB - Current evidence shows that thioridazine (THZ) is ready for global clinical evaluation, while some of its derivatives and other efflux pump inhibitors reach the end stage of preclinical evaluation. In this paper, a clinical trial plan is described that investigates the antituberculosis potency, the safety profile and the role of THZ and/or its derivatives in the treatment of TB in humans, both in patients infected with drug sensitive strains as in patients infected with multi or extensive drug resistant strains of Mycobacterium tuberculosis and some of the patents related to thioridazine are also discussed. PMID- 21548880 TI - TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia causing mutations on expression, activity, localization and development. AB - Mutations that truncate the C-terminal non-catalytic moiety of TTBK2 (tau tubulin kinase 2) cause the inherited, autosomal dominant, SCA11 (spinocerebellar ataxia type 11) movement disorder. In the present study we first assess the substrate specificity of TTBK2 and demonstrate that it has an unusual preference for a phosphotyrosine residue at the +2 position relative to the phosphorylation site. We elaborate a peptide substrate (TTBKtide, RRKDLHDDEEDEAMSIYpA) that can be employed to quantify TTBK2 kinase activity. Through modelling and mutagenesis we identify a putative phosphate-priming groove within the TTBK2 kinase domain. We demonstrate that SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. We generate an SCA11-mutation-carrying knockin mouse and show that this leads to inhibition of endogenous TTBK2 protein kinase activity. Finally, we find that, in homozygosity, the SCA11 mutation causes embryonic lethality at embryonic day 10. These findings provide the first insights into some of the intrinsic properties of TTBK2 and reveal how SCA11-causing mutations affect protein expression, catalytic activity, localization and development. We hope that these findings will be helpful for future investigation of the regulation and function of TTBK2 and its role in SCA11. PMID- 21548881 TI - Structure and activity of the Saccharomyces cerevisiae dUTP pyrophosphatase DUT1, an essential housekeeping enzyme. AB - Genomes of all free-living organisms encode the enzyme dUTPase (dUTP pyrophosphatase), which plays a key role in preventing uracil incorporation into DNA. In the present paper, we describe the biochemical and structural characterization of DUT1 (Saccharomyces cerevisiae dUTPase). The hydrolysis of dUTP by DUT1 was strictly dependent on a bivalent metal cation with significant activity observed in the presence of Mg2+, Co2+, Mn2+, Ni2+ or Zn2+. In addition, DUT1 showed a significant activity against another potentially mutagenic nucleotide: dITP. With both substrates, DUT1 demonstrated a sigmoidal saturation curve, suggesting a positive co-operativity between the subunits. The crystal structure of DUT1 was solved at 2 A resolution (1 A=0.1 nm) in an apo state and in complex with the non-hydrolysable substrate alpha,beta-imido dUTP or dUMP product. Alanine-replacement mutagenesis of the active-site residues revealed seven residues important for activity including the conserved triad Asp87/Arg137/Asp85. The Y88A mutant protein was equally active against both dUTP and UTP, indicating that this conserved tyrosine residue is responsible for discrimination against ribonucleotides. The structure of DUT1 and site-directed mutagenesis support a role of the conserved Phe142 in the interaction with the uracil base. Our work provides further insight into the molecular mechanisms of substrate selectivity and catalysis of dUTPases. PMID- 21548882 TI - Metabolic oxidative stress elicited by the copper(II) complex [Cu(isaepy)2] triggers apoptosis in SH-SY5Y cells through the induction of the AMP-activated protein kinase/p38MAPK/p53 signalling axis: evidence for a combined use with 3 bromopyruvate in neuroblastoma treatment. AB - We have demonstrated previously that the complex bis[(2-oxindol-3-ylimino)-2-(2 aminoethyl)pyridine-N,N']copper(II), named [Cu(isaepy)(2)], induces AMPK (AMP activated protein kinase)-dependent/p53-mediated apoptosis in tumour cells by targeting mitochondria. In the present study, we found that p38(MAPK) (p38 mitogen-activated protein kinase) is the molecular link in the phosphorylation cascade connecting AMPK to p53. Transfection of SH-SY5Y cells with a dominant negative mutant of AMPK resulted in a decrease in apoptosis and a significant reduction in phospho-active p38(MAPK) and p53. Similarly, reverse genetics of p38(MAPK) yielded a reduction in p53 and a decrease in the extent of apoptosis, confirming an exclusive hierarchy of activation that proceeds via AMPK/p38(MAPK)/p53. Fuel supplies counteracted [Cu(isaepy)(2)]-induced apoptosis and AMPK/p38(MAPK)/p53 activation, with glucose being the most effective, suggesting a role for energetic imbalance in [Cu(isaepy)(2)] toxicity. Co administration of 3BrPA (3-bromopyruvate), a well-known inhibitor of glycolysis, and succinate dehydrogenase, enhanced apoptosis and AMPK/p38(MAPK)/p53 signalling pathway activation. Under these conditions, no toxic effect was observed in SOD (superoxide dismutase)-overexpressing SH-SY5Y cells or in PCNs (primary cortical neurons), which are, conversely, sensitized to the combined treatment with [Cu(isaepy)(2)] and 3BrPA only if grown in low-glucose medium or incubated with the glucose-6-phosphate dehydrogenase inhibitor dehydroepiandrosterone. Overall, the results suggest that NADPH deriving from the pentose phosphate pathway contributes to PCN resistance to [Cu(isaepy)(2)] toxicity and propose its employment in combination with 3BrPA as possible tool for cancer treatment. PMID- 21548884 TI - When will you adopt a method? PMID- 21548885 TI - BioSpotlight. PMID- 21548886 TI - Citations. PMID- 21548883 TI - Cleavage of Notch1 by granzyme B disables its transcriptional activity. AB - Granzyme-mediated cell death is the main pathway for cytotoxic lymphocytes to kill virus-infected and tumour cells. A major player in this process is GrB (granzyme B), which triggers apoptosis in both caspase-dependent and caspase independent pathways. A caspase-independent substrate of GrB is the highly conserved transmembrane receptor Notch1. The GrB cleavage sites in Notch1 and functional consequences of Notch1 cleavage by GrB were unknown. In the present study, we confirmed that Notch1 is a direct and caspase-independent substrate of GrB. We demonstrate that GrB cleaved the intracellular Notch1 domain at least twice at two distinct aspartic acids, Asp1860 and Asp1961. GrB cleavage of Notch1 can occur in all subcellular compartments, during maturation of the receptor, at the membrane, and in the nucleus. GrB also displayed perforin-independent functions by cleaving the extracellular domain of Notch1. Overall, cleavage of Notch1 by GrB resulted in a loss of transcriptional activity, independent of Notch1 activation. We conclude that GrB disables Notch1 function, probably resulting in anti-cellular proliferation and cell death signals. PMID- 21548887 TI - Profile of Gabriela G. Cezar. Interview by Kristie Nybo. PMID- 21548889 TI - Metabolomics: where seeing is believing. PMID- 21548891 TI - The selenium content of cell culture serum influences redox-regulated gene expression. PMID- 21548892 TI - Use of a negative selectable marker for rapid selection of recombinant vaccinia virus. AB - Vaccinia virus has been a powerful tool in molecular biology and vaccine development. The relative ease of inserting and expressing foreign genes combined with its broad host range has made it an attractive antigen delivery system against many heterologous diseases. Many different approaches have been developed to isolate recombinant vaccinia virus generated from homologous recombination; however, most are time-consuming, often requiring a series of passages or specific cell lines. Herein we introduce a rapid method for isolating recombinants using the antibiotic coumermycin and the interferon-associated PKR pathway to select for vaccinia virus recombinants. This method uses a negative selection marker in the form of a fusion protein, GyrB-PKR, consisting of the coumermycin dimerization domain of Escherichia coli gyrase subunit B fused to the catalytic domain of human PKR. Coumermycin-dependent dimerization of this protein results in activation of PKR and the phosphorylation of translation initiation factor, eIF2alpha. Phosphorylation of this factor leads to an inhibition of protein synthesis, and an inhibition of virus replication. In the presence of coumermycin, recombinants are isolated due to the loss of this coumermycin sensitive gene by homologous recombination. We demonstrate that this method of selection is highly efficient and requires limited rounds of enrichment to isolate recombinant virus. PMID- 21548893 TI - Automated feature detection and imaging for high-resolution screening of zebrafish embryos. AB - The development of automated microscopy platforms has enabled large-scale observation of biological processes, thereby complementing genome scale biochemical techniques. However, commercially available systems are restricted either by fixed-field-of-views, leading to potential omission of features of interest, or by low-resolution data of whole objects lacking cellular detail. This limits the efficiency of high-content screening assays, especially when large complex objects are used as in whole-organism screening. Here we demonstrate a toolset for automated intelligent high-content screening of whole zebrafish embryos at cellular resolution on a standard wide-field screening microscope. Using custom-developed algorithms, predefined regions of interest such as the brain-are automatically detected. The regions of interest are subsequently imaged automatically at high magnification, enabling rapid capture of cellular resolution data. We utilize this approach for acquiring 3-D datasets of embryonic brains of transgenic zebrafish. Moreover, we report the development of a mold design for accurate orientation of zebrafish embryos for dorsal imaging, thereby facilitating standardized imaging of internal organs and cellular structures. The toolset is flexible and can be readily applied for the imaging of different specimens in various applications. PMID- 21548894 TI - Extraction of genomic DNA from yeasts for PCR-based applications. AB - We have developed a quick and low-cost genomic DNA extraction protocol from yeast cells for PCR-based applications. This method does not require any enzymes, hazardous chemicals, or extreme temperatures, and is especially powerful for simultaneous analysis of a large number of samples. DNA can be efficiently extracted from different yeast species (Kluyveromyces lactis, Hansenula polymorpha, Schizosaccharomyces pombe, Candida albicans, Pichia pastoris, and Saccharomyces cerevisiae). The protocol involves lysis of yeast colonies or cells from liquid culture in a lithium acetate (LiOAc)-SDS solution and subsequent precipitation of DNA with ethanol. Approximately 100 nanograms of total genomic DNA can be extracted from 1 * 10(7) cells. DNA extracted by this method is suitable for a variety of PCR-based applications (including colony PCR, real-time qPCR, and DNA sequencing) for amplification of DNA fragments of <= 3500 bp. PMID- 21548895 TI - Endo-Porter-mediated delivery of phosphorodiamidate morpholino oligos (PMOs) in erythrocyte suspension cultures from Cope's gray treefrog Hyla chrysoscelis. AB - Cope's gray treefrog, Hyla chrysoscelis, is a freeze-tolerant anuran that accumulates cryoprotective glycerol during cold acclimation. H. chrysoscelis erythrocytes express the aquaglyceroporin HC-3, which facilitates transmembrane glycerol and water movement. Aquaglyceroporins have no pharmacological inhibitors, and no genetic knockout tools currently exist for H. chrysoscelis. A phosphorodiamidate morpholino oligo (PMO)-mediated expression knockdown approach was therefore pursued to provide a model for testing the role of HC-3. We describe a novel procedure optimized for specific, efficient knockdown of HC-3 expression in amphibian erythrocyte suspensions cultured at nonmammalian physiological temperatures using Endo-Porter. Our protocol includes three critical components: pre-incubation at 37 degrees C, two rounds of Endo-Porter and HC-3 PMO administration at ~23 degrees C, and continuous shaking at 190 rpm. This combination of steps resulted in 94% reduction in HC-3 protein expression (Western blot), substantial decrease in HC-3 expression in >65% of erythrocytes, and no detectable expression in an additional 30% of cells (immunocytochemistry). PMID- 21548897 TI - Making the conference scene virtual. PMID- 21548900 TI - Focused serendipity. Interview by Kristie Nybo. AB - Aaron Wheeler's development of new microfluidic tools to solve biological problems caught our attention. Curious to know more, BioTechniques contacted him to find out about the ambitions, character, and motivations that led to his success. PMID- 21548905 TI - What lies beneath: in vivo stem cell imaging. AB - No other branch of science is quite so laden with expectation. But while corralling stem cells for viable therapies, researchers have found themselves asking an entirely separate question: How do we track them? PMID- 21548903 TI - Application of linear polyacrylamide coprecipitation of denatured templates for PCR amplification of ultra-rapidly reannealing DNA. PMID- 21548906 TI - Rapid quantification of inflammation in tissue samples using perfluorocarbon emulsion and fluorine-19 nuclear magnetic resonance. AB - Quantification of inflammation in tissue samples can be a time-intensive bottleneck in therapeutic discovery and preclinical endeavors. We describe a versatile and rapid approach to quantitatively assay macrophage burden in intact tissue samples. Perfluorocarbon (PFC) emulsion is injected intravenously, and the emulsion droplets are effectively taken up by monocytes and macrophages. These 'in situ' labeled cells participate in inflammatory events in vivo resulting in PFC accumulation at inflammatory loci. Necropsied tissues or intact organs are subjected to conventional fluorine-19 ((19)F) NMR spectroscopy to quantify the total fluorine content per sample, proportional to the macrophage burden. We applied these methods to a rat model of experimental allergic encephalomyelitis (EAE) exhibiting extensive inflammation and demyelination in the central nervous system (CNS), particularly in the spinal cord. In a cohort of EAE rats, we used (19)F NMR to derive an inflammation index (IFI) in intact CNS tissues. Immunohistochemistry was used to confirm intracellular colocalization of the PFC droplets within CNS CD68+ cells having macrophage morphology. The IFI linearly correlated to mRNA levels of CD68 via real-time PCR analysis. This (19)F NMR approach can accelerate tissue analysis by at least an order of magnitude compared with histological approaches. PMID- 21548907 TI - Recombinase-mediated cassette exchange (RMCE) and BAC engineering via VCre/VloxP and SCre/SloxP systems. AB - Site-specific recombination is a powerful biotechnological tool for genome engineering. We previously reported two novel site-specific recombination systems, VCre/VloxP and SCre/SloxP, that do not cross-react with Cre/loxP and Flp/FRT in culture cells and mouse embryonic stem (ES) cells. In this study, a site-specific recombination assay in Escherichia coli was used to examine the activity of mutant VCre (H314L and Y349F) and mutant SCre (H317L and Y352F), in which both mutated residues lie within the active center of Cre recombination. The site-specific recombination activity of both mutants was significantly decreased. Recombinase-mediated cassette exchange (RMCE) using VloxP and the Vlox2272 mutant site was performed in E. coli by introducing a cassette bearing VloxP and Vlox2272 into a recipient plasmid bearing the same sites. RMCE using SloxP and Slox2272 was also performed by SCre recombinase. Moreover, BAC engineering via Red recombination and VCre/VloxP were demonstrated. First, the DNA cassette for modification was introduced into a BAC clone via Red recombination; second, the antibiotics resistance gene flanked by VloxP was removed from the BAC clone by induction of VCre recombinase. Such site-specific recombination systems may effectively be used in combination with other site specific recombination systems or engineering tools (e.g., Red recombination). PMID- 21548908 TI - Adaptation of the AFLP technique as a new tool to detect genetic instability and transposition in interspecific hybrids. AB - An adapted amplified fragment length polymorphism (AFLP) protocol is presented for detection of hybrid instability in the genome of interspecific hybrids between Drosophila buzzatii and D. koepferae species. Analyses of 15 AFLP instability markers (new bands detected in hybrids) show that up to 81% are the result of transposable element (TE) activity. Twenty TEs associated with AFLP instability markers have been detected by this method in backcross hybrids and segmental hybrids, demonstrating its validity in detecting transposition events occurring during the hybridization process. New insertions of Helena TE have been observed in the hybrid genome after hybridization of the TGTCG22 instability marker by FISH. The AFLP marker technique proved to be an efficient method that improves upon traditional and bioinformatic tools previously used to detect TE mobilization. This newly adapted AFLP protocol may also be applied to a large number of organisms outside the Drosophila genus, making it of interest to evolutionary and population genetic researchers working with species where the knowledge of the genome is scarce. PMID- 21548909 TI - A modular perfused chamber for low- and normal-temperature microscopy of living cells. AB - An inexpensive modular perfused chamber (MPC) designed for low- and normal temperature live-cell imaging is presented. The device consists of four lathed pieces of stainless steel assembled as a cylindrical open chamber that can hold either round or square glass coverslips. The chamber is connected to a thermal bath operating with recirculation. For image acquisition at 4 degrees C, cooled air is blown toward the coverslip surface to prevent condensation. Principal advantages of this device are thermal stability in the sample environment, rapid response to changes in temperature set point, and easy sample insertion. The device enables the study of dynamic processes in cells governed by large temperature differences such as those imposed by hypothermic preservation of cells (0-4 degrees C) followed by rewarming to normothermia (37 degrees C). The capabilities of the MPC were demonstrated by monitoring the internalization of fluorescent quantum dots (QDs) in rat hepatocytes after hypothermic storage and during rewarming with an inverted microscope. PMID- 21548910 TI - Cold-adapted protease enables quantitation of surface proteins in the absence of membrane trafficking. AB - We report here an improved method for analyzing protein surface expression utilizing a cold-adapted trypsin. Preservation of activity of the enzyme at 0-4 degrees C permits modification of the protease method of surface analysis to temperatures at which trafficking of mammalian plasmalemmal proteins is blocked. This is an important advantage over established trypsin-cleavage protocols. Moreover, the method is less time-consuming than surface biotinylation. PMID- 21548911 TI - dsDNA-coated quantum dots. AB - Because of their unique spectral properties, quantum dots (QDs) have recently proved useful as fluorescent labels for biosensing probes. We developed a versatile QD label by modifying dsDNA with biotin and thiol groups at opposite ends and attaching it to quantum dots via a metal-thiol bond. These dsDNA-coated QDs fluorescently label their targets through biotin-streptavidin binding and show excellent histological results when used to detect biotin-labeled chromosome probes. The dsDNA coating also circumvented the common problems of aggregation and steric hindrance that occur with other QD probes. PMID- 21548912 TI - Role of the repartition of wetland breeding sites on the spatial distribution of Anopheles and Culex, human disease vectors in southern France. AB - BACKGROUND: In this study, carried out in the Camargue region (France), we combined entomological data with geomatic and modelling tools to assess whether the location of breeding sites may explain the spatial distribution of adult mosquitoes. The species studied are important and competent disease vectors in Europe: Culex modestus Ficalbi and Cx. pipiens Linnaeus (West Nile virus), Anopheles atroparvus Van Thiel, a former Plasmodium vector, and An. melanoon Hackett, competent to transmit Plasmodium.Using a logistic regression model, we first evaluated which land cover variables determined the presence of Culex and Anopheles larva. The resulting probability map of larval presence then was used to project the average probability of finding adults in a buffer area. This was compared to the actual number of adults collected, providing a quantitative assessment of adult dispersal ability for each species. RESULTS: The distribution of Cx. modestus and An. melanoon is mainly driven by the repartition of irrigated farm fields and reed beds, their specific breeding habitats. The presence of breeding sites explained the distribution of adults of both species. The buffer size, reflecting the adult dispersal ability, was 700 m for Cx. modestus and 1000 m for An. melanoon. The comparatively stronger correlation observed for Cx. modestus suggested that other factors may affect the distribution of adult An. melanoon. We did not find any association between Cx. pipiens larval presence and the biotope due to the species' ubiquist character. CONCLUSION: By applying the same method to different species, we highlighted different strengths of association between land cover (irrigated farm fields and reed beds), larval presence and adult population distribution.This paper demonstrates the power of geomatic tools to quantify the spatial organization of mosquito populations, and allows a better understanding of links between landcover, breeding habitats, presence of immature mosquito populations and adult distributions for different species. PMID- 21548913 TI - Peer victimization as reported by children, teachers, and parents in relation to children's health symptoms. AB - BACKGROUND: Victims of bullying in school may experience health problems later in life. We have assessed the prevalence of children's health symptoms according to whether peer victimization was reported by the children, by their teachers, or by their parents. METHODS: In a cross-sectional study of 419 children in grades 1-10 the frequency of peer victimization was reported by children, teachers and parents. Emotional and somatic symptoms (sadness, anxiety, stomach ache, and headache) were reported by the children.Frequencies of victimization reported by different informants were compared by the marginal homogeneity test for paired ordinal data, concordance between informants by cross-tables and Spearman's rho, and associations of victimization with health symptoms were estimated by logistic regression. RESULTS: The concordance of peer victimization reported by children, teachers, and parents varied from complete agreement to complete discordance also for the highest frequency (weekly/daily) of victimization. Children's self reported frequency of victimization was strongly and positively associated with their reports of emotional and somatic symptoms. Frequency of victimization reported by teachers or parents showed similar but weaker associations with the children's health symptoms. CONCLUSION: The agreement between children and significant adults in reporting peer victimization was low to moderate, and the associations of reported victimization with the children's self-reported health symptoms varied substantially between informants. It may be useful to assess prospectively the effects of employing different sources of information related to peer victimization. PMID- 21548914 TI - Vibrio parahemolyticus septicaemia in a liver transplant patient: a case report. AB - INTRODUCTION: Vibrio parahemolyticus is the leading cause of vibrio-associated gastroenteritis in the United States of America, usually related to poor food handling; only rarely has it been reported to cause serious infections including sepsis and soft tissue infections. In contrast, Vibrio vulnificus is a well-known cause of septicaemia, especially in patients with cirrhosis. We present a patient with V. parahemolyticus sepsis who had an orthotic liver transplant in 2007 and was on immunosuppression for chronic rejection. Clinical suspicion driven by patient presentation, travel to Gulf of Mexico and soft tissue infection resulted in early diagnosis and institution of appropriate antibiotic therapy. CASE PRESENTATION: A 48 year old Latin American man with a history of chronic kidney disease, orthotic liver transplant in 2007 secondary to alcoholic end stage liver disease on immunosuppressants, and chronic rejection presented to the emergency department with fever, vomiting, abdominal pain, left lower extremity swelling and fluid filled blisters after a fishing trip in the Gulf of Mexico. Samples from the blister and blood grew V. parahemolyticus. The patient was successfully treated with ceftriaxone and ciprofloxacin. CONCLUSION: Febrile patients with underlying liver disease and/or immunosuppression should be interviewed regarding recent travel to a coastal area and seafood ingestion. If this history is obtained, appropriate empiric antibiotics must be chosen. Patients with liver disease and/or immunosuppresion should be counselled to avoid eating raw or undercooked molluscan shellfish. People can prevent Vibrio sepsis and wound infections by proper cooking of seafood and avoiding exposure of open wounds to seawater or raw shellfish products. PMID- 21548915 TI - Prolonged venous bleeding due to traditional treatment with leech bite: a case report. AB - INTRODUCTION: The medicinal leech, Hirudo medicinalis, has been used in the treatment of many diseases for thousands of years. In Turkey, it is used most commonly in the management of venous diseases of lower extremities. CASE PRESENTATION: A 25-year-old Turkish woman presented to our emergency room with bleeding from her left leg. She had been treated for varicose veins in her lower extremities with leeches about 24 hours before admission to the emergency room. The bleeding was controlled by applying pressure with sterile gauze upon the wound, and she was discharged. She returned after four hours having started bleeding again. Hemostasis was achieved by vein ligation under local anesthesia. CONCLUSIONS: Leech bite should be evaluated as a special injury. Prolonged bleeding can be seen after leech bites. In such cases, hemostasis either with local pressure or ligation of the bleeding vessel is mandatory. PMID- 21548917 TI - Low levels of vitamin C in dialysis patients is associated with decreased prealbumin and increased C-reactive protein. AB - BACKGROUND: Subclinical inflammation is a common phenomenon in patients on either continuous ambulatory peritoneal dialysis (CAPD) or maintenance hemodialysis (MHD). We hypothesized that vitamin C had anti-inflammation effect because of its electron offering ability. The current study was designed to test the relationship of plasma vitamin C level and some inflammatory markers. METHODS: In this cross-sectional study, 284 dialysis patients were recruited, including 117 MHD and 167 CAPD patients. The demographics were recorded. Plasma vitamin C was measured by high-performance liquid chromatography. And we also measured body mass index (BMI, calculated as weight/height(2)), Kt/V, serum albumin, serum prealbumin, high-sensitivity C-reactive protein (hsCRP), ferritin, hemoglobin. The relationships between vitamin C and albumin, pre-albumin and hsCRP levels were tested by Spearman correlation analysis and multiple regression analysis. Patients were classified into three subgroups by vitamin C level according to previous recommendation 12 in MHD and CAPD patients respectively: group A: < 2 ug/ml (< 11.4 umol/l, deficiency), group B: 2-4 ug/ml (11.4-22.8 umol/l, insufficiency) and group C: > 4 ug/ml (> 22.8 umol/l, normal and above). RESULTS: Patients showed a widely distribution of plasma vitamin C levels in the total 284 dialysis patients. Vitamin C deficiency (< 2 ug/ml) was present in 95(33.45%) and insufficiency (2-4 ug/ml) in 88(30.99%). 73(25.70%) patients had plasma vitamin C levels within normal range (4-14 ug/ml) and 28(9.86%) at higher than normal levels (> 14 ug/ml). The similar proportion of different vitamin C levels was found in both MHD and CAPD groups. Plasma vitamin C level was inversely associated with hsCRP concentration (Spearman r = -0.201, P = 0.001) and positively associated with prealbumin (Spearman r = 0.268, P < 0.001), albumin levels (Spearman r = 0.161, P = 0.007). In multiple linear regression analysis, plasma vitamin C level was inversely associated with log(10)hsCRP (P = 0.048) and positively with prealbumin levels (P = 0.002) adjusted for gender, age, diabetes, modality of dialysis and some other confounding effects. CONCLUSIONS: The investigation indicates that vitamin C deficiency is common in both MHD patients and CAPD patients. Plasma vitamin C level is positively associated with serum prealbumin level and negatively associated with hsCRP level in both groups. Vitamin C deficiency may play an important role in the increased inflammatory status in dialysis patients. Further studies are needed to determine whether inflammatory status in dialysis patients can be improved by using vitamin C supplements. PMID- 21548918 TI - Subclavian thrombosis in a patient with advanced lung cancer: a case report. AB - INTRODUCTION: Lung cancer is now considered the most common cause of death among cancer patients. Although target biological regimens have emerged in recent years for non-small cell lung carcinoma, the survival and quality of life of patients with this condition still remain low. The five-year survival rate for all stages of lung cancer is 17% or less. CASE PRESENTATION: We describe the case of a 53 year-old Caucasian woman who was diagnosed with advanced stage IIIa (T2aN2M0) non small cell lung carcinoma (adenocarcinoma) and underwent a complete left upper lobectomy three years ago. After two and a half years of follow-up, she suddenly presented with facial edema and venous distension and was immediately treated for superior vena cava syndrome. Because of a diagnostic check, a major clot was detected in the right subclavian vein. Our patient was informed about treatment options, and she was taken to the catheterization laboratory for percutaneous stenting of the superior vena cava to restore superior vena cava patency. CONCLUSION: Lung cancer has a vast number of complications. Superior vena cava syndrome and thrombosis should be considered upon the presentation of a patient with obstructive symptoms. In this case report, even though we expected the clot to be on the side of the former lesion, it was present on the opposite side. Treatment should also start immediately in these patients with clinical suspicion of thrombosis to avoid further complications, even in cases with a differential diagnosis problem. Finally, although patients with non-small cell lung carcinoma have a high incidence of thromboembolic events, anticoagulant treatment is given only as maintenance therapy after a first event occurs. PMID- 21548916 TI - Aciculatin inhibits lipopolysaccharide-mediated inducible nitric oxide synthase and cyclooxygenase-2 expression via suppressing NF-kappaB and JNK/p38 MAPK activation pathways. AB - OBJECTIVES: Natural products have played a significant role in drug discovery and development. Inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been suggested to connect with various inflammatory diseases. In this study, we explored the anti-inflammatory potential of aciculatin (8-((2R,4S,5S,6R)-tetrahydro-4,5-dihydroxy-6-methyl-2H-pyran-2-yl) 5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one), one of main components of Chrysopogon aciculatis, by examining its effects on the expression and activity of iNOS and COX-2 in lipopolysaccharide (LPS)-activated macrophages. METHODS: We used nitrate and prostaglandin E2 (PGE2) assays to examine inhibitory effect of aciculatin on nitric oxide (NO) and PGE2 levels in LPS-activated mouse RAW264.7 macrophages and further investigated the mechanisms of aciculatin suppressed LPS-mediated iNOS/COX-2 expression by western blot, RT-PCR, reporter gene assay and confocal microscope analysis. RESULTS: Aciculatin remarkably decreased the LPS (1 MUg/mL)-induced mRNA and protein expression of iNOS and COX 2 as well as their downstream products, NO and PGE2 respectively, in a concentration-dependent manner (1-10 MUM). Such inhibition was found, via immunoblot analyses, reporter gene assays, and confocal microscope observations that aciculatin not only acts through significant suppression of LPS-induced NF kappaB activation, an effect highly correlated with its inhibitory effect on LPS induced IkappaB kinase (IKK) activation, IkappaB degradation, NF-kappaB phosphorylation, nuclear translocation and binding of NF-kappaB to the kappaB motif of the iNOS and COX-2 promoters, but also suppressed phosphorylation of JNK/p38 mitogen-activated protein kinases (MAPKs). CONCLUSION: Our results demonstrated that aciculatin exerts potent anti-inflammatory activity through its dual inhibitory effects on iNOS and COX-2 by regulating NF-kappaB and JNK/p38 MAPK pathways. PMID- 21548920 TI - Breaking evolutionary and pleiotropic constraints in mammals: On sloths, manatees and homeotic mutations. AB - BACKGROUND: Mammals as a rule have seven cervical vertebrae, except for sloths and manatees. Bateson proposed that the change in the number of cervical vertebrae in sloths is due to homeotic transformations. A recent hypothesis proposes that the number of cervical vertebrae in sloths is unchanged and that instead the derived pattern is due to abnormal primaxial/abaxial patterning. RESULTS: We test the detailed predictions derived from both hypotheses for the skeletal patterns in sloths and manatees for both hypotheses. We find strong support for Bateson's homeosis hypothesis. The observed vertebral and rib patterns cannot be explained by changes in primaxial/abaxial patterning. Vertebral patterns in sloths and manatees are similar to those in mice and humans with abnormal numbers of cervical vertebrae: incomplete and asymmetric homeotic transformations are common and associated with skeletal abnormalities. In sloths the homeotic vertebral shift involves a large part of the vertebral column. As such, similarity is greatest with mice mutant for genes upstream of Hox. CONCLUSIONS: We found no skeletal abnormalities in specimens of sister taxa with a normal number of cervical vertebrae. However, we always found such abnormalities in conspecifics with an abnormal number, as in many of the investigated dugongs. These findings strongly support the hypothesis that the evolutionary constraints on changes of the number of cervical vertebrae in mammals is due to deleterious pleitropic effects. We hypothesize that in sloths and manatees low metabolic and activity rates severely reduce the usual stabilizing selection, allowing the breaking of the pleiotropic constraints. This probably also applies to dugongs, although to a lesser extent. PMID- 21548919 TI - The effect of family-based multidisciplinary cognitive behavioral treatment in children with obesity: study protocol for a randomized controlled trial. AB - BACKGROUND: The prevalence of childhood obesity has increased rapidly during the last three decades in the Netherlands. It is assumed that mainly environmental factors have contributed to this trend. Parental overweight and low social economic status are risk factors for childhood obesity. Childhood obesity affects self-esteem and has negative consequences on cognitive and social development. Obese children tend to become obese adults, which increases the risk for developing cardiovascular complications, type 2 diabetes mellitus, and psychosocial problems. Additionally, the secretion of several gastrointestinal hormones, responsible for appetite and food intake, is impaired in obese subjects. Weight reduction through lifestyle changes in order to change health risks is, until now, suggested as the preferred treatment for childhood obesity.The objective of this study is the effect evaluation of a family-based cognitive behavioral multidisciplinary lifestyle treatment. The intervention aims to establish long-term weight reduction and stabilization, reduction of obesity related health consequences and improvement of self-image by change of lifestyle and learning cognitive behavioral techniques. STUDY DESIGN/METHODS: In this randomized clinical trial newly presented children with obesity (8-17 years old) are divided, by randomization, in an intervention and control group, both consisting of 40 obese children. The intervention is carried out in groups of 8 11 children, and consists of respectively 7 and 5 separate group meetings for the children and their parents and 1 joint group meeting of 2 1/2 hours. Main topics are education on nutrition, self-control techniques, social skills, physical activity and improvement of self-esteem. The control group is given advice on physical activity and nutrition. For normal data comparison, data were collected of 40 normal-weight children, 8-17 years old. DISCUSSION: Because of the increasing prevalence of childhood obesity and the impact on the individual as well as on society, prevention and treatment of obesity in children is of great importance. For evaluation of short- and long-term effects of the treatment, measurements are taken before and after 3 months of treatment, and after 12 and 24 months follow-up. During these visits clinical and biochemical data are determined, cardiovascular fitness tests are performed and quality of life questionnaires are completed. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register ISRCTN36146436 PMID- 21548921 TI - Mitochondrial targeting of human NADH dehydrogenase (ubiquinone) flavoprotein 2 (NDUFV2) and its association with early-onset hypertrophic cardiomyopathy and encephalopathy. AB - BACKGROUND: NADH dehydrogenase (ubiquinone) flavoprotein 2 (NDUFV2), containing one iron sulfur cluster ([2Fe-2S] binuclear cluster N1a), is one of the core nuclear-encoded subunits existing in human mitochondrial complex I. Defects in this subunit have been associated with Parkinson's disease, Alzheimer's disease, Bipolar disorder, and Schizophrenia. The aim of this study is to examine the mitochondrial targeting of NDUFV2 and dissect the pathogenetic mechanism of one human deletion mutation present in patients with early-onset hypertrophic cardiomyopathy and encephalopathy. METHODS: A series of deletion and point mutated constructs with the c-myc epitope tag were generated to identify the location and sequence features of mitochondrial targeting sequence for NDUFV2 in human cells using the confocal microscopy. In addition, various lengths of the NDUFV2 N-terminal and C-terminal fragments were fused with enhanced green fluorescent protein to investigate the minimal region required for correct mitochondrial import. Finally, a deletion construct that mimicked the IVS2+5_+8delGTAA mutation in NDUFV2 gene and would eventually produce a shortened NDUFV2 lacking 19-40 residues was generated to explore the connection between human gene mutation and disease. RESULTS: We identified that the cleavage site of NDUFV2 was located around amino acid 32 of the precursor protein, and the first 22 residues of NDUFV2 were enough to function as an efficient mitochondrial targeting sequence to carry the passenger protein into mitochondria. A site directed mutagenesis study showed that none of the single-point mutations derived from basic, hydroxylated and hydrophobic residues in the NDUFV2 presequence had a significant effect on mitochondrial targeting, while increasing number of mutations in basic and hydrophobic residues gradually decreased the mitochondrial import efficacy of the protein. The deletion mutant mimicking the human early onset hypertrophic cardiomyopathy and encephalopathy lacked 19-40 residues in NDUFV2 and exhibited a significant reduction in its mitochondrial targeting ability. CONCLUSIONS: The mitochondrial targeting sequence of NDUFV2 is located at the N-terminus of the precursor protein. Maintaining a net positive charge and an amphiphilic structure with the overall balance and distribution of basic and hydrophobic amino acids in the N-terminus of NDUFV2 is important for mitochondrial targeting. The results of human disease cell model established that the impairment of mitochondrial localization of NDUFV2 as a mechanistic basis for early-onset hypertrophic cardiomyopathy and encephalopathy. PMID- 21548922 TI - Enhanced transfection of cell lines from Atlantic salmon through nucoleofection and antibiotic selection. AB - BACKGROUND: Cell lines from Atlantic salmon kidney have made it possible to culture and study infectious salmon anemia virus (ISAV), an aquatic orthomyxovirus affecting farmed Atlantic salmon. However, transfection of these cells using calcium phosphate precipitation or lipid-based reagents shows very low transfection efficiency. The Amaxa Nucleofector technologyTM is an electroporation technique that has been shown to be efficient for gene transfer into primary cells and hard to transfect cell lines. FINDINGS: Here we demonstrate, enhanced transfection of the head kidney cell line, TO, from Atlantic salmon using nucleofection and subsequent flow cytometry. Depending on the plasmid promoter, TO cells could be transfected transiently with an efficiency ranging from 11.6% to 90.8% with good viability, using Amaxa's cell line nucleofector solution T and program T-20. A kill curve was performed to investigate the most potent antibiotic for selection of transformed cells, and we found that blasticidin and puromycin were the most efficient for selection of TO cells. CONCLUSIONS: The results show that nucleofection is an efficient way of gene transfer into Atlantic salmon cells and that stably transfected cells can be selected with blasticidin or puromycin. PMID- 21548923 TI - Efficient production of human acidic fibroblast growth factor in pea (Pisum sativum L.) plants by agroinfection of germinated seeds. AB - BACKGROUND: For efficient and large scale production of recombinant proteins in plants transient expression by agroinfection has a number of advantages over stable transformation. Simple manipulation, rapid analysis and high expression efficiency are possible. In pea, Pisum sativum, a Virus Induced Gene Silencing System using the pea early browning virus has been converted into an efficient agroinfection system by converting the two RNA genomes of the virus into binary expression vectors for Agrobacterium transformation. RESULTS: By vacuum infiltration (0.08 Mpa, 1 min) of germinating pea seeds with 2-3 cm roots with Agrobacteria carrying the binary vectors, expression of the gene for Green Fluorescent Protein as marker and the gene for the human acidic fibroblast growth factor (aFGF) was obtained in 80% of the infiltrated developing seedlings. Maximal production of the recombinant proteins was achieved 12-15 days after infiltration. CONCLUSIONS: Compared to the leaf injection method vacuum infiltration of germinated seeds is highly efficient allowing large scale production of plants transiently expressing recombinant proteins. The production cycle of plants for harvesting the recombinant protein was shortened from 30 days for leaf injection to 15 days by applying vacuum infiltration. The synthesized aFGF was purified by heparin-affinity chromatography and its mitogenic activity on NIH 3T3 cells confirmed to be similar to a commercial product. PMID- 21548924 TI - High mobility group box 1 (HMGB1) and anti-HMGB1 antibodies and their relation to disease characteristics in systemic lupus erythematosus. AB - INTRODUCTION: High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein. HMGB1, which is secreted by inflammatory cells and passively released from apoptotic and necrotic cells, may act as a pro-inflammatory mediator. As apoptotic cells accumulate in systemic lupus erythematosus (SLE), HMGB1 levels might be increased in SLE. HMGB1 may also serve as an autoantigen, leading to the production of anti-HMGB1 antibodies. In this study we determined levels of HMGB1 and anti-HMGB1 in SLE patients in comparison to healthy controls (HC) and analysed their relation with disease activity. METHODS: The study population consisted of 70 SLE patients and 35 age- and sex-matched HC. Thirty-three SLE patients had quiescent disease, the other 37 patients were selected for having active disease. Nineteen of these had lupus nephritis. HMGB1 levels were measured with both Western blot and ELISA. Anti-HMGB1 levels were measured by ELISA. Clinical and serological parameters were assessed according to routine procedures. RESULTS: HMGB1 levels in SLE patients could be measured reliably by Western blotting only, and were significantly increased compared to HC. During active disease HMGB1 levels increased, in particular in patients with renal involvement. Serum HMGB1 levels correlated with SLEDAI, proteinuria, and anti dsDNA levels, and showed a negative correlation with complement C3. Anti-HMGB1 levels were significantly increased in SLE patients compared to HC, and positively correlated with HMGB1 levels. CONCLUSIONS: Levels of HMGB1 in the sera of SLE patients, in particular in those with active renal disease, are increased. Serum HMGB1 levels are related to SLEDAI scores and proteinuria, as well as to levels of anti-HMGB1 antibodies. These findings suggest that besides HMGB1, HMGB1 anti-HMGB1 immune complexes play a role in the pathogenesis of SLE, in particular in patients with renal involvement. PMID- 21548925 TI - Maintenance therapy in NSCLC: why? To whom? Which agent? AB - Maintenance therapy is emerging as a treatment strategy in the management of advanced non small cell lung cancer (NSCLC). Initial trials addressing the question of duration of combination chemotherapy failed to show any overall survival benefit for the prolonged administration over a fixed number of cycles with an increased risk for cumulative toxicity. Nowadays several agents with different ways of administration and a different pattern of toxicity have been formally investigated in the maintenance setting. Maintenance strategies include continuing with an agent already present in the induction regimen or switching to a different one. Taking into consideration that no comparative trials of maintenance with different chemotherapy drugs or targeted agents have been conducted, the choice and the duration of maintenance agents is largely empirical. Furthermore, it is still unknown and it remains an open question if this approach needs to be proposed to every patient in the case of partial/complete response or stable disease after the induction therapy. Here, we critically review available data on maintenance treatment, discussing the possibility to tailor the right treatment to the right patient, in an attempt to optimize costs and benefits of an ever-growing panel of different treatment options. PMID- 21548926 TI - Tyrosine phosphorylation of Munc18c on residue 521 abrogates binding to Syntaxin 4. AB - BACKGROUND: Insulin stimulates exocytosis of GLUT4 from an intracellular store to the cell surface of fat and muscle cells. Fusion of GLUT4-containing vesicles with the plasma membrane requires the SNARE proteins Syntaxin 4, VAMP2 and the regulatory Sec1/Munc18 protein, Munc18c. Syntaxin 4 and Munc18c form a complex that is disrupted upon insulin treatment of adipocytes. Munc18c is tyrosine phosphorylated in response to insulin in these cells. Here, we directly test the hypothesis that tyrosine phosphorylation of Munc18c is responsible for the observed insulin-dependent abrogation of binding between Munc18c and Syntaxin 4. RESULTS: We show that Munc18c is directly phosphorylated by recombinant insulin receptor tyrosine kinase in vitro. Using pull-down assays, we show that phosphorylation abrogates binding of Munc18c to both Syntaxin 4 and the v-SNARE VAMP2, as does the introduction of a phosphomimetic mutation into Munc18c (Y521E). CONCLUSION: Our data indicate that insulin-stimulated tyrosine phosphorylation of Munc18c impairs the ability of Munc18c to bind its cognate SNARE proteins, and may therefore represent a regulatory step in GLUT4 traffic. PMID- 21548927 TI - Rationale and study design of PROVHILO - a worldwide multicenter randomized controlled trial on protective ventilation during general anesthesia for open abdominal surgery. AB - BACKGROUND: Post-operative pulmonary complications add to the morbidity and mortality of surgical patients, in particular after general anesthesia >2 hours for abdominal surgery. Whether a protective mechanical ventilation strategy with higher levels of positive end-expiratory pressure (PEEP) and repeated recruitment maneuvers; the "open lung strategy", protects against post-operative pulmonary complications is uncertain. The present study aims at comparing a protective mechanical ventilation strategy with a conventional mechanical ventilation strategy during general anesthesia for abdominal non-laparoscopic surgery. METHODS: The PROtective Ventilation using HIgh versus LOw positive end-expiratory pressure ("PROVHILO") trial is a worldwide investigator-initiated multicenter randomized controlled two-arm study. Nine hundred patients scheduled for non laparoscopic abdominal surgery at high or intermediate risk for post-operative pulmonary complications are randomized to mechanical ventilation with the level of PEEP at 12 cmH(2)O with recruitment maneuvers (the lung-protective strategy) or mechanical ventilation with the level of PEEP at maximum 2 cmH(2)O without recruitment maneuvers (the conventional strategy). The primary endpoint is any post-operative pulmonary complication. DISCUSSION: The PROVHILO trial is the first randomized controlled trial powered to investigate whether an open lung mechanical ventilation strategy in short-term mechanical ventilation prevents against postoperative pulmonary complications. TRIAL REGISTRATION: ISRCTN: ISRCTN70332574. PMID- 21548928 TI - Pediatric functional magnetic resonance neuroimaging: tactics for encouraging task compliance. AB - BACKGROUND: Neuroimaging technology has afforded advances in our understanding of normal and pathological brain function and development in children and adolescents. However, noncompliance involving the inability to remain in the magnetic resonance imaging (MRI) scanner to complete tasks is one common and significant problem. Task noncompliance is an especially significant problem in pediatric functional magnetic resonance imaging (fMRI) research because increases in noncompliance produces a greater risk that a study sample will not be representative of the study population. METHOD: In this preliminary investigation, we describe the development and application of an approach for increasing the number of fMRI tasks children complete during neuroimaging. Twenty eight healthy children ages 9-13 years participated. Generalization of the approach was examined in additional fMRI and event-related potential investigations with children at risk for depression, children with anxiety and children with depression (N=120). Essential features of the approach include a preference assessment for identifying multiple individualized rewards, increasing reinforcement rates during imaging by pairing tasks with chosen rewards and presenting a visual 'road map' listing tasks, rewards and current progress. RESULTS: Our results showing a higher percentage of fMRI task completion by healthy children provides proof of concept data for the recommended tactics. Additional support was provided by results showing our approach generalized to several additional fMRI and event-related potential investigations and clinical populations. DISCUSSION: We proposed that some forms of task noncompliance may emerge from less than optimal reward protocols. While our findings may not directly support the effectiveness of the multiple reward compliance protocol, increased attention to how rewards are selected and delivered may aid cooperation with completing fMRI tasks. CONCLUSION: The proposed approach contributes to the pediatric neuroimaging literature by providing a useful way to conceptualize and measure task noncompliance and by providing simple cost effective tactics for improving the effectiveness of common reward-based protocols. PMID- 21548929 TI - MicroRNA-196a regulates bovine newborn ovary homeobox gene (NOBOX) expression during early embryogenesis. AB - BACKGROUND: Oocyte-derived maternal RNAs drive early embryogenesis when the newly formed embryo is transcriptionally inactive. Recent studies in zebrafish have identified the role of microRNAs during the maternal-to-embryonic transition (MET). MicroRNAs are short RNAs that bind to the 3' UTR of target mRNAs to repress their translation and accelerate their decay. Newborn ovary homeobox gene (NOBOX) is a transcription factor that is preferentially expressed in oocytes and essential for folliculogenesis in mice. NOBOX knockout mice are infertile and lack of NOBOX disrupts expression of many germ-cell specific genes and microRNAs. We recently reported the cloning and expression of bovine NOBOX during early embryonic development and our gene knockdown studies indicate that NOBOX is a maternal effect gene essential for early embryonic development. As NOBOX is a maternal transcript critical for development and NOBOX is depleted during early embryogenesis, we hypothesized that NOBOX is targeted by microRNAs for silencing and/or degradation. RESULTS: Using an algorithm "MicroInspector", a potential microRNA recognition element (MRE) for miR-196a was identified in the 3' UTR of the bovine NOBOX mRNA. Expression analysis of miR-196a in bovine oocytes and during early embryonic development indicated that it is expressed both in oocytes and embryos and tends to increase at the four-cell and eight-cell stages. Ectopic expression of NOBOX and miR-196a in HeLa cells inhibited the expression of NOBOX protein compared to the control cells without miR-196a. Similarly, the activity of a luciferase construct containing the entire 3' UTR of bovine NOBOX was suppressed, and the regulation was abolished by mutations in the miR-196a binding site indicating that the predicted MRE is critical for the direct and specific binding of miR-196a to the NOBOX mRNA. Furthermore, ectopic expression of miR 196a mimic in bovine early embryos significantly reduced the NOBOX expression at the both mRNA and protein levels. CONCLUSION: Collectively, our results demonstrate that miR-196a is a bona fide negative regulator of NOBOX during bovine early embryogenesis. PMID- 21548930 TI - Loss of aquaporin-4 expression and putative function in non-small cell lung cancer. AB - BACKGROUND: Aquaporins (AQPs) have been recognized to promote tumor progression, invasion, and metastasis and are therefore recognized as promising targets for novel anti-cancer therapies. Potentially relevant AQPs in distinct cancer entities can be determined by a comprehensive expression analysis of the 13 human AQPs. METHODS: We analyzed the presence of all AQP transcripts in 576 different normal lung and non-small cell lung cancer (NSCLC) samples using microarray data and validated our findings by qRT-PCR and immunohistochemistry. RESULTS: Variable expression of several AQPs (AQP1, -3, -4, and -5) was found in NSCLC and normal lung tissues. Furthermore, we identified remarkable differences between NSCLC subtypes in regard to AQP1, -3 and -4 expression. Higher transcript and protein levels of AQP4 in well-differentiated lung adenocarcinomas suggested an association with a more favourable prognosis. Beyond water transport, data mining of co-expressed genes indicated an involvement of AQP4 in cell-cell signalling, cellular movement and lipid metabolism, and underlined the association of AQP4 to important physiological functions in benign lung tissue. CONCLUSIONS: Our findings accentuate the need to identify functional differences and redundancies of active AQPs in normal and tumor cells in order to assess their value as promising drug targets. PMID- 21548932 TI - Clinical Trials: Minimising source data queries to streamline endpoint adjudication in a large multi-national trial. AB - BACKGROUND: The UK Clinical Trial Regulations and Good Clinical Practice guidelines specify that the study sponsor must ensure clinical trial data are accurately reported, recorded and verified to ensure patient safety and scientific integrity. The methods that are utilised to assess data quality and the results of any reviews undertaken are rarely reported in the literature. We have recently undertaken a quality review of trial data submitted to a Clinical Endpoint Committee for adjudication. The purpose of the review was to identify areas that could be improved for future clinical trials. The results are reported in this paper. METHODS: Throughout the course of the study, all data queries were logged. Following study close out, queries were coded and categorised. A descriptive and comparative analysis was conducted to determine the frequency of occurrence for each category by country of origin. RESULTS: From 1595 endpoint packages reviewed, 782 queries were generated. No source data queries were generated for countries with <= 25 recruited subjects, but both low recruiting and high recruiting countries had a high number of queries relating to subject identifiers. CONCLUSIONS: The implementation of some simple measures could help improve data quality and lead to significant savings. PMID- 21548931 TI - Pathogenesis of Lassa fever in cynomolgus macaques. AB - BACKGROUND: Lassa virus (LASV) infection causes an acute and sometimes fatal hemorrhagic disease in humans and nonhuman primates; however, little is known about the development of Lassa fever. Here, we performed a pilot study to begin to understand the progression of LASV infection in nonhuman primates. METHODS: Six cynomolgus monkeys were experimentally infected with LASV. Tissues from three animals were examined at an early- to mid-stage of disease and compared with tissues from three animals collected at terminal stages of disease. RESULTS: Dendritic cells were identified as a prominent target of LASV infection in a variety of tissues in all animals at day 7 while Kupffer cells, hepatocytes, adrenal cortical cells, and endothelial cells were more frequently infected with LASV in tissues of terminal animals (days 13.5-17). Meningoencephalitis and neuronal necrosis were noteworthy findings in terminal animals. Evidence of coagulopathy was noted; however, the degree of fibrin deposition in tissues was less prominent than has been reported in other viral hemorrhagic fevers. CONCLUSION: The sequence of pathogenic events identified in this study begins to shed light on the development of disease processes during Lassa fever and also may provide new targets for rational prophylactic and chemotherapeutic interventions. PMID- 21548933 TI - In vitro antiproliferative activity of partially purified Trigona laeviceps propolis from Thailand on human cancer cell lines. AB - BACKGROUND: Cancers are some of the leading causes of human deaths worldwide and their relative importance continues to increase. Since an increasing proportion of cancer patients are acquiring resistance to traditional chemotherapeutic agents, it is necessary to search for new compounds that provide suitable specific antiproliferative affects that can be developed as anticancer agents. Propolis from the stingless bee, Trigona laeviceps, is one potential interesting source that is widely available and cultivatable (as bee hives) in Thailand. METHODS: Propolis (90 g) was initially extracted by 95% (v/v) ethanol and then solvent partitioned by sequential extractions of the crude ethanolic extract with 40% (v/v) MeOH, CH2Cl2 and hexane. After solvent removal by evaporation, each extract was solvated in DMSO and assayed for antiproliferative activity against five cancer (Chago, KATO-III, SW620, BT474 and Hep-G2) and two normal (HS27 fibroblast and CH-liver) cell lines using the MTT assay. The cell viability (%) and IC50 values were calculated. RESULTS: The hexane extract provided the highest in vitro antiproliferative activity against the five tested cancer cell lines and the lowest cytotoxicity against the two normal cell lines. Further fractionation of the hexane fraction by quick column chromatography using eight solvents of increasing polarity for elution revealed the two fractions eluted with 30% and 100% (v/v) CH2Cl2 in hexane (30DCM and 100DCM, respectively) had a higher anti proliferative activity. Further fractionation by size exclusion chromatography lead to four fractions for each of 30DCM and 100DCM, with the highest antiproliferative activity on cancer but not normal cell lines being observed in fraction# 3 of 30DCM (IC50 value of 4.09 - 14.7 MUg/ml). CONCLUSIONS: T. laeviceps propolis was found to contain compound(s) with antiproliferative activity in vitro on cancer but not normal cell lines in tissue culture. The more enriched propolis fractions typically revealed a higher antiproliferative activity (lower IC50 value). Overall, propolis from Thailand may have the potential to serve as a template for future anticancer-drug development. PMID- 21548934 TI - Enhancement of bacteriolysis of shuffled phage PhiX174 gene E. AB - Bacterial ghosts that are generated using the regulated PhiX174 lysis gene E offer a new avenue for the study of inactivated vaccines. Here, we constructed a library of mutant gene E using a gene-shuffling technique. After screening and recombination with the prokaryotic non-fusion expression vector pBV220, two lysis plasmids were selected. Among which, a novel mutant E gene (named mE), consisting of a 74-bp non-encoding sequence at 5'-end and a 201-bp gene DeltaE, significantly increased the lysis effect on prokaryotic Escherichia coli and Salmonella enteritidis. Moreover, lysis efficiency, as measured by the OD600 value, reached 1.0 (109 CFU), avoiding the bottleneck problem observed with other bacterial lysis procedures, which results in a low concentration of bacteria in suspension, and consequent low production of bacterial ghosts. Our results may provide a promising avenue for the development of bacterial ghost vaccines. PMID- 21548935 TI - Effects of early life trauma are dependent on genetic predisposition: a rat study. AB - BACKGROUND: Trauma experienced early in life increases the risk of developing a number of psychological and/or behavioural disorders. It is unclear, however, how genetic predisposition to a behavioural disorder, such as attention deficit/hyperactivity disorder (ADHD), modifies the long-term effects of early life trauma. There is substantial evidence from family and twin studies for susceptibility to ADHD being inherited, implying a strong genetic component to the disorder. In the present study we used an inbred animal model of ADHD, the spontaneously hypertensive rat (SHR), to investigate the long-term consequences of early life trauma on emotional behaviour in individuals predisposed to developing ADHD-like behaviour. METHODS: We applied a rodent model of early life trauma, maternal separation, to SHR and Wistar-Kyoto rats (WKY), the normotensive control strain from which SHR were originally derived. The effects of maternal separation (removal of pups from dam for 3 h/day during the first 2 weeks of life) on anxiety-like behaviour (elevated-plus maze) and depressive-like behaviour (forced swim test) were assessed in prepubescent rats (postnatal day 28 and 31). Basal levels of plasma corticosterone were measured using radioimmunoassay. RESULTS: The effect of maternal separation on SHR and WKY differed in a number of behavioural measures. Similar to its reported effect in other rat strains, maternal separation increased the anxiety-like behaviour of WKY (decreased open arm entries) but not SHR. Maternal separation increased the activity of SHR in the novel environment of the elevated plus-maze, while it decreased that of WKY. Overall, SHR showed a more active response in the elevated plus-maze and forced swim test than WKY, regardless of treatment, and were also found to have higher basal plasma corticosterone compared to WKY. Maternal separation increased basal levels of plasma corticosterone in SHR females only, possibly through adaptive mechanisms involved in maintaining their active response in behavioural tests. Basal plasma corticosterone was found to correlate positively with an active response to a novel environment and inescapable stress across all rats. CONCLUSION: SHR are resilient to the anxiogenic effects of maternal separation, and develop a non-anxious, active response to a novel environment following chronic mild stress during the early stages of development. Our findings highlight the importance of genetic predisposition in determining the outcome of early life adversity. SHR may provide a model of early life trauma leading to the development of hyperactivity rather than anxiety and depression. Basal levels of corticosterone correlate with the behavioural response to early life trauma, and may therefore provide a useful marker for susceptibility to a certain behavioural temperament. PMID- 21548936 TI - An association study on contrasting cystic fibrosis endophenotypes recognizes KRT8 but not KRT18 as a modifier of cystic fibrosis disease severity and CFTR mediated residual chloride secretion. AB - BACKGROUND: F508del-CFTR, the most frequent disease-causing mutation among Caucasian cystic fibrosis (CF) patients, has been characterised as a mutant defective in protein folding, processing and trafficking. We have investigated the two neighbouring cytokeratin genes KRT8 and KRT18 in a candidate gene approach to ask whether variants in KRT8 and/or KRT18 modify the impaired ion conductance known as the CF basic defect, and whether they are associated with correct trafficking of mutant CFTR and disease severity of CF. METHODS: We have selected contrasting F508del-CFTR homozygous patient subpopulations stratified for disease severity, comparing 13 concordant mildly affected sib pairs vs. 12 concordant severely affected sib pairs, or manifestation of the CF basic defect in intestinal epithelium, comparing 22 individuals who exhibit CFTR-mediated residual chloride secretion vs. 14 individuals who do not express any chloride secretion, for an association. The KRT8/KRT18 locus was initially interrogated with one informative microsatellite marker. Subsequently, a low density SNP map with four SNPs in KRT8 and two SNPs in KRT18, each selected for high polymorphism content, was used to localize the association signal. RESULTS: KRT8, but not KRT18, showed an association with CF disease severity (Pbest=0.00131; Pcorr=0.0185) and CFTR mediated residual chloride secretion (Pbest=0.0004; Pcorr=0.0069). Two major four-marker-haplotypes spanning 13 kb including the entire KRT8 gene accounted for 90% of chromosomes, demonstrating strong linkage disequilibrium at that locus. Absence of chloride secretion was associated with the recessive haplotype 1122 at rs1907671, rs4300473, rs2035878 and rs2035875. The contrasting haplotype 2211 was dominant for the presence of CFTR mediated residual chloride secretion. In consistency, the KRT8 haplotype 2211 was associated with mild CF disease while 1122 was observed as risk haplotype. Analysis of microsatellite allele distributions on the SNP background suggests that the mild KRT8 haplotype 2211 is phylogenetically older than its severe counterpart. CONCLUSIONS: The two opposing KRT8 alleles which have been identified as a benign and as a risk allele in this work are likely effective in the context of epithelial cell differentiation. As the mild KRT8 allele is associated with CFTR mediated residual chloride secretion among F508del-CFTR homozygotes, the KRT8/KRT18 heterodimeric intermediary filaments of the cytoskeleton apparently are an essential component for the proper targeting of CFTR to the apical membrane in epithelial cells. PMID- 21548937 TI - A comprehensive platform for highly multiplexed mammalian functional genetic screens. AB - BACKGROUND: Genome-wide screening in human and mouse cells using RNA interference and open reading frame over-expression libraries is rapidly becoming a viable experimental approach for many research labs. There are a variety of gene expression modulation libraries commercially available, however, detailed and validated protocols as well as the reagents necessary for deconvolving genome scale gene screens using these libraries are lacking. As a solution, we designed a comprehensive platform for highly multiplexed functional genetic screens in human, mouse and yeast cells using popular, commercially available gene modulation libraries. The Gene Modulation Array Platform (GMAP) is a single microarray-based detection solution for deconvolution of loss and gain-of function pooled screens. RESULTS: Experiments with specially constructed lentiviral-based plasmid pools containing ~78,000 shRNAs demonstrated that the GMAP is capable of deconvolving genome-wide shRNA "dropout" screens. Further experiments with a larger, ~90,000 shRNA pool demonstrate that equivalent results are obtained from plasmid pools and from genomic DNA derived from lentivirus infected cells. Parallel testing of large shRNA pools using GMAP and next generation sequencing methods revealed that the two methods provide valid and complementary approaches to deconvolution of genome-wide shRNA screens. Additional experiments demonstrated that GMAP is equivalent to similar microarray based products when used for deconvolution of open reading frame over-expression screens. CONCLUSION: Herein, we demonstrate four major applications for the GMAP resource, including deconvolution of pooled RNAi screens in cells with at least 90,000 distinct shRNAs. We also provide detailed methodologies for pooled shRNA screen readout using GMAP and compare next-generation sequencing to GMAP (i.e. microarray) based deconvolution methods. PMID- 21548938 TI - ArrayInitiative - a tool that simplifies creating custom Affymetrix CDFs. AB - BACKGROUND: Probes on a microarray represent a frozen view of a genome and are quickly outdated when new sequencing studies extend our knowledge, resulting in significant measurement error when analyzing any microarray experiment. There are several bioinformatics approaches to improve probe assignments, but without in house programming expertise, standardizing these custom array specifications as a usable file (e.g. as Affymetrix CDFs) is difficult, owing mostly to the complexity of the specification file format. However, without correctly standardized files there is a significant barrier for testing competing analysis approaches since this file is one of the required inputs for many commonly used algorithms. The need to test combinations of probe assignments and analysis algorithms led us to develop ArrayInitiative, a tool for creating and managing custom array specifications. RESULTS: ArrayInitiative is a standalone, cross platform, rich client desktop application for creating correctly formatted, custom versions of manufacturer-provided (default) array specifications, requiring only minimal knowledge of the array specification rules and file formats. Users can import default array specifications, import probe sequences for a default array specification, design and import a custom array specification, export any array specification to multiple output formats, export the probe sequences for any array specification and browse high-level information about the microarray, such as version and number of probes. The initial release of ArrayInitiative supports the Affymetrix 3' IVT expression arrays we currently analyze, but as an open source application, we hope that others will contribute modules for other platforms. CONCLUSIONS: ArrayInitiative allows researchers to create new array specifications, in a standard format, based upon their own requirements. This makes it easier to test competing design and analysis strategies that depend on probe definitions. Since the custom array specifications are easily exported to the manufacturer's standard format, researchers can analyze these customized microarray experiments using established software tools, such as those available in Bioconductor. PMID- 21548939 TI - Development and validation of a paediatric long-bone fracture classification. A prospective multicentre study in 13 European paediatric trauma centres. AB - BACKGROUND: The aim of this study was to develop a child-specific classification system for long bone fractures and to examine its reliability and validity on the basis of a prospective multicentre study. METHODS: Using the sequentially developed classification system, three samples of between 30 and 185 paediatric limb fractures from a pool of 2308 fractures documented in two multicenter studies were analysed in a blinded fashion by eight orthopaedic surgeons, on a total of 5 occasions. Intra- and interobserver reliability and accuracy were calculated. RESULTS: The reliability improved with successive simplification of the classification. The final version resulted in an overall interobserver agreement of kappa = 0.71 with no significant difference between experienced and less experienced raters. CONCLUSIONS: In conclusion, the evaluation of the newly proposed classification system resulted in a reliable and routinely applicable system, for which training in its proper use may further improve the reliability. It can be recommended as a useful tool for clinical practice and offers the option for developing treatment recommendations and outcome predictions in the future. PMID- 21548940 TI - Regulation of PBX3 expression by androgen and Let-7d in prostate cancer. AB - BACKGROUND: The pre-leukemia transcription factor 3 (PBX) is part of the PBX family of transcription factors, which is known to regulate genes involved in differentiation of urogenital organs and steroidogenesis. This is of interest with regard to prostate cancer progression as regulation of steroidogenesis is one of the mechanisms involved in the development of castration-resistant prostate cancer. In light of this we wanted to investigate the possible involvement of androgen regulation of PBX3 expression in prostate cancer. RESULTS: In this study, we show that PBX3 is post-transcriptionally regulated by androgen in prostate cancer cells and that the effect might be independent of the androgen receptor. Furthermore, PBX3 was identified as a target of Let-7d, an androgen regulated microRNA. Let-7d was down-regulated in malignant compared to benign prostate tissue, whereas up-regulation of PBX3 expression was observed. CONCLUSIONS: We demonstrate that PBX3 is up-regulated in prostate cancer and post transcriptionally regulated by androgen through Let-7d. PMID- 21548941 TI - Network meta-analysis of survival data with fractional polynomials. AB - BACKGROUND: Pairwise meta-analysis, indirect treatment comparisons and network meta-analysis for aggregate level survival data are often based on the reported hazard ratio, which relies on the proportional hazards assumption. This assumption is implausible when hazard functions intersect, and can have a huge impact on decisions based on comparisons of expected survival, such as cost effectiveness analysis. METHODS: As an alternative to network meta-analysis of survival data in which the treatment effect is represented by the constant hazard ratio, a multi-dimensional treatment effect approach is presented. With fractional polynomials the hazard functions of interventions compared in a randomized controlled trial are modeled, and the difference between the parameters of these fractional polynomials within a trial are synthesized (and indirectly compared) across studies. RESULTS: The proposed models are illustrated with an analysis of survival data in non-small-cell lung cancer. Fixed and random effects first and second order fractional polynomials were evaluated. CONCLUSION: (Network) meta-analysis of survival data with models where the treatment effect is represented with several parameters using fractional polynomials can be more closely fitted to the available data than meta-analysis based on the constant hazard ratio. PMID- 21548942 TI - A large scale survey reveals that chromosomal copy-number alterations significantly affect gene modules involved in cancer initiation and progression. AB - BACKGROUND: Recent observations point towards the existence of a large number of neighborhoods composed of functionally-related gene modules that lie together in the genome. This local component in the distribution of the functionality across chromosomes is probably affecting the own chromosomal architecture by limiting the possibilities in which genes can be arranged and distributed across the genome. As a direct consequence of this fact it is therefore presumable that diseases such as cancer, harboring DNA copy number alterations (CNAs), will have a symptomatology strongly dependent on modules of functionally-related genes rather than on a unique "important" gene. METHODS: We carried out a systematic analysis of more than 140,000 observations of CNAs in cancers and searched by enrichments in gene functional modules associated to high frequencies of loss or gains. RESULTS: The analysis of CNAs in cancers clearly demonstrates the existence of a significant pattern of loss of gene modules functionally related to cancer initiation and progression along with the amplification of modules of genes related to unspecific defense against xenobiotics (probably chemotherapeutical agents). With the extension of this analysis to an Array-CGH dataset (glioblastomas) from The Cancer Genome Atlas we demonstrate the validity of this approach to investigate the functional impact of CNAs. CONCLUSIONS: The presented results indicate promising clinical and therapeutic implications. Our findings also directly point out to the necessity of adopting a function-centric, rather a gene-centric, view in the understanding of phenotypes or diseases harboring CNAs. PMID- 21548943 TI - Provider perceptions of barriers to the emergency use of tPA for acute ischemic stroke: a qualitative study. AB - BACKGROUND: Only 1-3% of ischemic stroke patients receive thrombolytic therapy. Provider barriers to adhering with guidelines recommending tPA delivery in acute stroke are not well known. The main objective of this study was to describe barriers to thrombolytic use in acute stroke care. METHODS: Twenty-four hospitals were randomly selected and matched into 12 pairs. Barrier assessment occurred at intervention sites only, and utilized focus groups and structured interviews. A pre-specified taxonomy was employed to characterize barriers. Two investigators independently assigned themes to transcribed responses. Seven facilitators (three emergency physicians, two nurses, and two study coordinators) conducted focus groups and interviews of emergency physicians (65), nurses (62), neurologists (15), radiologists (12), hospital administrators (12), and three others (hospitalists and pharmacist). RESULTS: The following themes represented the most important external barriers: environmental and patient factors. Important barriers internal to the clinician included familiarity with and motivation to adhere to the guidelines, lack of self-efficacy and outcome expectancy. The following themes were not substantial barriers: lack of awareness of the existence of acute stroke guidelines, presence of conflicting guidelines, and lack of agreement with the guidelines. CONCLUSIONS: Healthcare providers perceive environmental and patient-related factors as the primary barriers to adherence with acute stroke treatment guidelines. Interventions focused on increasing physician familiarity with and motivation to follow guidelines may be of highest yield in improving adherence. Improving self-efficacy in performing guideline concordant care may also be useful. PMID- 21548944 TI - Expression and distribution of PPP2R5C gene in leukemia. AB - BACKGROUND: Recently, we clarified at the molecular level novel chromosomal translocation t(14;14)(q11;q32) in a case of Sezary syndrome, which caused a rearrangement from TRAJ7 to the PPP2R5C gene. PPP2R5C is one of the regulatory B subunits of protein phosphatase 2A (PP2A). It plays a crucial role in cell proliferation, differentiation, and transformation. To characterize the expression and distribution of five different transcript variants of the PPP2R5C gene in leukemia, we analyzed the expression level of PPP2R5C in peripheral blood mononuclear cells from 77 patients with de novo leukemia, 26 patients with leukemia in complete remission (CR), and 20 healthy individuals by real-time PCR and identified the different variants of PPP2R5C by RT-PCR. FINDINGS: Significantly higher expression of PPP2R5C was found in AML, CML, T-ALL, and B CLL groups in comparison with healthy controls. High expression of PPP2R5C was detected in the B-ALL group; however, no significant difference was found compared with the healthy group. The expression level of PPP2R5C in the CML-CR group decreased significantly compared with that in the de novo CML group and was not significantly different from the level in the healthy group. By using different primer pairs that covered different exons, five transcript variants of PPP2R5C could be identified. All variants could be detected in healthy samples as well as in all the leukemia samples, and similar frequencies and distributions of PPP2R5C were indicated. CONCLUSIONS: Overexpression of PPP2R5C in T-cell malignancy as well as in myeloid leukemia cells might relate to its proliferation and differentiation. Investigation of the effect of target inhibition of this gene might be beneficial to further characterization of molecular mechanisms and targeted therapy in leukemia. PMID- 21548945 TI - Genome-scale computational analysis of DNA curvature and repeats in Arabidopsis and rice uncovers plant-specific genomic properties. AB - BACKGROUND: Due to its overarching role in genome function, sequence-dependent DNA curvature continues to attract great attention. The DNA double helix is not a rigid cylinder, but presents both curvature and flexibility in different regions, depending on the sequence. More in depth knowledge of the various orders of complexity of genomic DNA structure has allowed the design of sophisticated bioinformatics tools for its analysis and manipulation, which, in turn, have yielded a better understanding of the genome itself. Curved DNA is involved in many biologically important processes, such as transcription initiation and termination, recombination, DNA replication, and nucleosome positioning. CpG islands and tandem repeats also play significant roles in the dynamics and evolution of genomes. RESULTS: In this study, we analyzed the relationship between these three structural features within rice (Oryza sativa) and Arabidopsis (Arabidopsis thaliana) genomes. A genome-scale prediction of curvature distribution in rice and Arabidopsis indicated that most of the chromosomes of both genomes have maximal chromosomal DNA curvature adjacent to the centromeric region. By analyzing tandem repeats across the genome, we found that frequencies of repeats are higher in regions adjacent to those with high curvature value. Further analysis of CpG islands shows a clear interdependence between curvature value, repeat frequencies and CpG islands. Each CpG island appears in a local minimal curvature region, and CpG islands usually do not appear in the centromere or regions with high repeat frequency. A statistical evaluation demonstrates the significance and non-randomness of these features. CONCLUSIONS: This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants. PMID- 21548947 TI - Effect of questionnaire length, personalisation and reminder type on response rate to a complex postal survey: randomised controlled trial. AB - BACKGROUND: Minimising participant non-response in postal surveys helps to maximise the generalisability of the inferences made from the data collected. The aim of this study was to examine the effect of questionnaire length, personalisation and reminder type on postal survey response rate and quality and to compare the cost-effectiveness of the alternative survey strategies. METHODS: In a pilot study for a population study of travel behaviour, physical activity and the environment, 1000 participants sampled from the UK edited electoral register were randomly allocated using a 2*2 factorial design to receive one of four survey packs: a personally addressed long (24 page) questionnaire pack, a personally addressed short (15 page) questionnaire pack, a non-personally addressed long questionnaire pack or a non-personally addressed short questionnaire pack. Those who did not return a questionnaire were stratified by initial randomisation group and further randomised to receive either a full reminder pack or a reminder postcard. The effects of the survey design factors on response were examined using multivariate logistic regression. RESULTS: An overall response rate of 17% was achieved. Participants who received the short version of the questionnaire were more likely to respond (OR=1.48, 95% CI 1.06 to 2.07). In those participants who received a reminder, personalisation of the survey pack and reminder also increased the odds of response (OR=1.44, 95% CI 1.01 to 1.95). Item non-response was relatively low, but was significantly higher in the long questionnaire than the short (9.8% vs 5.8%; p=.04). The cost per additional usable questionnaire returned of issuing the reminder packs was L23.1 compared with L11.3 for the reminder postcards. CONCLUSIONS: In contrast to some previous studies of shorter questionnaires, this trial found that shortening a relatively lengthy questionnaire significantly increased the response. Researchers should consider the trade off between the value of additional questions and a larger sample. If low response rates are expected, personalisation may be an important strategy to apply. Sending a full reminder pack to non-respondents appears a worthwhile, albeit more costly, strategy. PMID- 21548946 TI - GDF-15 is abundantly expressed in plexiform lesions in patients with pulmonary arterial hypertension and affects proliferation and apoptosis of pulmonary endothelial cells. AB - BACKGROUND: Growth-differentiation factor-15 (GDF-15) is a stress-responsive, transforming growth factor-beta-related cytokine, which has recently been reported to be elevated in serum of patients with idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to examine the expression and biological roles of GDF-15 in the lung of patients with pulmonary arterial hypertension (PAH). METHODS: GDF-15 expression in normal lungs and lung specimens of PAH patients were studied by real-time RT-PCR and immunohistochemistry. Using laser-assisted micro-dissection, GDF-15 expression was further analyzed within vascular compartments of PAH lungs. To elucidate the role of GDF-15 on endothelial cells, human pulmonary microvascular endothelial cells (HPMEC) were exposed to hypoxia and laminar shear stress. The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein. RESULTS: GDF-15 expression was found to be increased in lung specimens from PAH patients, compared to normal lungs. GDF-15 was abundantly expressed in pulmonary vascular endothelial cells with a strong signal in the core of plexiform lesions. HPMEC responded with marked upregulation of GDF-15 to hypoxia and laminar shear stress. Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein. CONCLUSIONS: GDF-15 expression is increased in PAH lungs and appears predominantly located in vascular endothelial cells. The expression pattern as well as the observed effects on proliferation and apoptosis of pulmonary endothelial cells suggest a role of GDF-15 in the homeostasis of endothelial cells in PAH patients. PMID- 21548948 TI - Thermodynamically consistent model calibration in chemical kinetics. AB - BACKGROUND: The dynamics of biochemical reaction systems are constrained by the fundamental laws of thermodynamics, which impose well-defined relationships among the reaction rate constants characterizing these systems. Constructing biochemical reaction systems from experimental observations often leads to parameter values that do not satisfy the necessary thermodynamic constraints. This can result in models that are not physically realizable and may lead to inaccurate, or even erroneous, descriptions of cellular function. RESULTS: We introduce a thermodynamically consistent model calibration (TCMC) method that can be effectively used to provide thermodynamically feasible values for the parameters of an open biochemical reaction system. The proposed method formulates the model calibration problem as a constrained optimization problem that takes thermodynamic constraints (and, if desired, additional non-thermodynamic constraints) into account. By calculating thermodynamically feasible values for the kinetic parameters of a well-known model of the EGF/ERK signaling cascade, we demonstrate the qualitative and quantitative significance of imposing thermodynamic constraints on these parameters and the effectiveness of our method for accomplishing this important task. MATLAB software, using the Systems Biology Toolbox 2.1, can be accessed from http://www.cis.jhu.edu/~goutsias/CSS lab/software.html. An SBML file containing the thermodynamically feasible EGF/ERK signaling cascade model can be found in the BioModels database. CONCLUSIONS: TCMC is a simple and flexible method for obtaining physically plausible values for the kinetic parameters of open biochemical reaction systems. It can be effectively used to recalculate a thermodynamically consistent set of parameter values for existing thermodynamically infeasible biochemical reaction models of cellular function as well as to estimate thermodynamically feasible values for the parameters of new models. Furthermore, TCMC can provide dimensionality reduction, better estimation performance, and lower computational complexity, and can help to alleviate the problem of data overfitting. PMID- 21548949 TI - Perceived discrimination is associated with severity of positive and depression/anxiety symptoms in immigrants with psychosis: a cross-sectional study. AB - BACKGROUND: Immigration status is a significant risk factor for psychotic disorders, and a number of studies have reported more severe positive and affective symptoms among immigrant and ethnic minority groups. We investigated if perceived discrimination was associated with the severity of these symptoms among immigrants in Norway with psychotic disorders. METHODS: Cross-sectional analyses of 90 immigrant patients (66% first-generation, 68% from Asia/Africa) in treatment for psychotic disorders were assessed for DSM-IV diagnoses with the Structured Clinical Interview for DSM Disorders (SCID-I, sections A-E) and for present symptom severity by The Structured Positive and Negative Syndrome Scale (SCI-PANSS). Perceived discrimination was assessed by a self-report questionnaire developed for the Immigrant Youth in Cultural Transition Study. RESULTS: Perceived discrimination correlated with positive psychotic (r=0.264, p<0.05) and depression/anxiety symptoms (r=0.282, p<0.01), but not negative, cognitive, or excitement symptoms. Perceived discrimination also functioned as a partial mediator for symptom severity in African immigrants. Multiple linear regression analyses controlling for possible confounders revealed that perceived discrimination explained approximately 10% of the variance in positive and depression/anxiety symptoms in the statistical model. CONCLUSIONS: Among immigrants with psychotic disorders, visible minority status was associated with perceived discrimination and with more severe positive and depression/anxiety symptoms. These results suggest that context-specific stressful environmental factors influence specific symptom patterns and severity. This has important implications for preventive strategies and treatment of this vulnerable patient group. PMID- 21548950 TI - Evaluation of 22 genetic variants with Crohn's disease risk in the Ashkenazi Jewish population: a case-control study. AB - BACKGROUND: Crohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population. METHODS: We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, NOD2, IL23R, IRGM, ATG16L1, PTGER4, NKX2-3, IL12B, PTPN2, TNFSF15 and STAT3, and assessed their association with CD status. We generated genetic scores based on the risk allele count alone and the risk allele count weighed by the effect size, and evaluated their predictive value. RESULTS: Three NOD2 SNPs, two IL23R SNPs, and one SNP each at IRGM and PTGER4 were independently associated with CD risk. Carriage of 7 or more copies of these risk alleles or the weighted genetic risk score of 7 or greater correctly classified 92% (allelic count score) and 83% (weighted score) of the controls; however, only 29% and 47% of the cases were identified as having the disease, respectively. This cutoff was associated with a >4-fold increased disease risk (p < 10e-16). CONCLUSIONS: CD-associated genetic risks were similar to those reported in NJ population and are unlikely to explain the excess prevalence of the disease in AJ individuals. These results support the existence of novel, yet unidentified, genetic variants unique to this population. Understanding of ethnic and racial differences in disease susceptibility may help unravel the pathogenesis of CD leading to new personalized diagnostic and therapeutic approaches. PMID- 21548951 TI - Pulsed Electromagnetic Fields in the treatment of fresh scaphoid fractures. A multicenter, prospective, double blind, placebo controlled, randomized trial. AB - BACKGROUND: The scaphoid bone is the most commonly fractured of the carpal bones. In the Netherlands 90% of all carpal fractures is a fracture of the scaphoid bone. The scaphoid has an essential role in functionality of the wrist, acting as a pivot. Complications in healing can result in poor functional outcome. The scaphoid fracture is a troublesome fracture and failure of treatment can result in avascular necrosis (up to 40%), non-union (5-21%) and early osteo-arthritis (up to 32%) which may seriously impair wrist function. Impaired consolidation of scaphoid fractures results in longer immobilization and more days lost at work with significant psychosocial and financial consequences.Initially Pulsed Electromagnetic Fields was used in the treatment of tibial pseudoarthrosis and non-union. More recently there is evidence that physical forces can also be used in the treatment of fresh fractures, showing accelerated healing by 30% and 71% reduction in nonunion within 12 weeks after initiation of therapy. Until now no double blind randomized, placebo controlled trial has been conducted to investigate the effect of this treatment on the healing of fresh fractures of the scaphoid. METHODS/DESIGN: This is a multi center, prospective, double blind, placebo controlled, randomized trial. Study population consists of all patients with unilateral acute scaphoid fracture. Pregnant women, patients having a life supporting implanted electronic device, patients with additional fractures of wrist, carpal or metacarpal bones and pre-existing impairment in wrist function are excluded. The scaphoid fracture is diagnosed by a combination of physical and radiographic examination (CT-scanning).Proven scaphoid fractures are treated with cast immobilization and a small Pulsed Electromagnetic Fields bone growth stimulating device placed on the cast. Half of the devices will be disabled at random in the factory.Study parameters are clinical consolidation, radiological consolidation evaluated by CT-scanning, functional status of the wrist, including assessment by means of the patient rated wrist evaluation (PRWE) questionnaire and quality of life using SF-36 health survey questionnaire.Primary endpoint is number of scaphoid unions at six weeks, secondary endpoints are time interval to clinical and radiological consolidation, number of non-unions, functional status at 52 weeks and non-adherence to the treatment protocol. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2064. PMID- 21548952 TI - CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes. AB - INTRODUCTION: Interleukin (IL)-6-type cytokines exert their effects through activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade. The JAK/STAT pathways play an important role in rheumatoid arthritis, since JAK inhibitors have exhibited dramatic effects on rheumatoid arthritis (RA) in clinical trials. In this study, we investigated the molecular effects of a small molecule JAK inhibitor, CP690,550 on the JAK/STAT signaling pathways and examined the role of JAK kinases in rheumatoid synovitis. METHODS: Fibroblast-like synoviocytes (FLS) were isolated from RA patients and stimulated with recombinant oncostatin M (OSM). The cellular supernatants were analyzed using cytokine protein chips. IL-6 mRNA and protein expression were analyzed by real-time PCR method and ELISA, respectively. Protein phosphorylation of rheumatoid synoviocytes was assessed by Western blot using phospho-specific antibodies. RESULTS: OSM was found to be a potent inducer of IL-6 in FLS. OSM stimulation elicited rapid phosphorylation of STATs suggesting activation of the JAK/STAT pathway in FLS. CP690,550 pretreatment completely abrogated the OSM induced production of IL-6, as well as OSM-induced JAK/STAT, and activation of mitogen-activated kinases (MAPKs) in FLS. CONCLUSIONS: These findings suggest that IL-6-type cytokines contribute to rheumatoid synovitis through activation of the JAK/STAT pathway in rheumatoid synoviocytes. Inhibition of these pro inflammatory signaling pathways by CP690,550 could be important in the treatment of RA. PMID- 21548953 TI - A protein network-guided screen for cell cycle regulators in Drosophila. AB - BACKGROUND: Large-scale RNAi-based screens are playing a critical role in defining sets of genes that regulate specific cellular processes. Numerous screens have been completed and in some cases more than one screen has examined the same cellular process, enabling a direct comparison of the genes identified in separate screens. Surprisingly, the overlap observed between the results of similar screens is low, suggesting that RNAi screens have relatively high levels of false positives, false negatives, or both. RESULTS: We re-examined genes that were identified in two previous RNAi-based cell cycle screens to identify potential false positives and false negatives. We were able to confirm many of the originally observed phenotypes and to reveal many likely false positives. To identify potential false negatives from the previous screens, we used protein interaction networks to select genes for re-screening. We demonstrate cell cycle phenotypes for a significant number of these genes and show that the protein interaction network is an efficient predictor of new cell cycle regulators. Combining our results with the results of the previous screens identified a group of validated, high-confidence cell cycle/cell survival regulators. Examination of the subset of genes from this group that regulate the G1/S cell cycle transition revealed the presence of multiple members of three structurally related protein complexes: the eukaryotic translation initiation factor 3 (eIF3) complex, the COP9 signalosome, and the proteasome lid. Using a combinatorial RNAi approach, we show that while all three of these complexes are required for Cdk2/Cyclin E activity, the eIF3 complex is specifically required for some other step that limits the G1/S cell cycle transition. CONCLUSIONS: Our results show that false positives and false negatives each play a significant role in the lack of overlap that is observed between similar large-scale RNAi-based screens. Our results also show that protein network data can be used to minimize false negatives and false positives and to more efficiently identify comprehensive sets of regulators for a process. Finally, our data provides a high confidence set of genes that are likely to play key roles in regulating the cell cycle or cell survival. PMID- 21548954 TI - Mitochondrial dysfunction in Trypanosoma cruzi: the role of Serratia marcescens prodigiosin in the alternative treatment of Chagas disease. AB - BACKGROUND: Chagas disease is a health threat for many people, mostly those living in Latin America. One of the most important problems in treatment is the limitation of existing drugs. Prodigiosin, produced by Serratia marcescens (Rhodnius prolixus endosymbiont), belongs to the red-pigmented bacterial prodiginine family, which displays numerous biological activities, including antibacterial, antifungal, antiprotozoal, antimalarial, immunosuppressive, and anticancer properties. Here we describe its effects on Trypanosoma cruzi mitochondria belonging to Tc I and Tc II. RESULTS: Parasites exposed to prodigiosin altered the mitochondrial function and oxidative phosphorylation could not have a normal course, probably by inhibition of complex III. Prodigiosin did not produce cytotoxic effects in lymphocytes and Vero cells and has better effects than benznidazole. Our data suggest that the action of prodigiosin on the parasites is mediated by mitochondrial structural and functional disruptions that could lead the parasites to an apoptotic-like cell death process. CONCLUSIONS: Here, we propose a potentially useful trypanocidal agent derived from knowledge of an important aspect of the natural life cycle of the parasite: the vector-parasite interaction. Our results indicate that prodigiosin could be a good candidate for the treatment of Chagas disease. PMID- 21548955 TI - Menarche delay and menstrual irregularities persist in adolescents with type 1 diabetes. AB - BACKGROUND: Menarche delay has been reported in adolescent females with type 1 diabetes (T1DM), perhaps due to poor glycemic control. We sought to compare age at menarche between adolescent females with T1DM and national data, and to identify factors associated with delayed menarche and menstrual irregularity in T1DM. METHODS: This was a cross-sectional study and females ages 12- 24 years (n = 228) with at least one menstrual period were recruited during their outpatient diabetes clinic appointment. The National Health and Nutrition Examination Survey (NHANES) 2001-2006 data (n = 3690) for females 12-24 years were used as a control group. RESULTS: Age at menarche was later in adolescent females with T1DM diagnosed prior to menarche (12.81 +/- 0.09 years) (mean+/- SE) (n = 185) than for adolescent females diagnosed after menarche (12.17 0.19 years, p = 0.0015) (n = 43). Average age of menarche in NHANES was 12.27 +/- 0.038 years, which was significantly earlier than adolescent females with T1DM prior to menarche (p < 0.0001) and similar to adolescent females diagnosed after menarche (p = 0.77). Older age at menarche was negatively correlated with BMI z-score (r = -0.23 p = 0.0029) but not hemoglobin A1c (A1c) at menarche (r = 0.01, p = 0.91). Among 181 adolescent females who were at least 2 years post menarche, 63 (35%) reported usually or always irregular cycles. CONCLUSION: Adolescent females with T1DM had a later onset of menarche than both adolescent females who developed T1DM after menarche and NHANES data. Menarche age was negatively associated with BMI z score, but not A1c. Despite improved treatment in recent decades, menarche delay and high prevalence of menstrual irregularity is still observed among adolescent females with T1DM. PMID- 21548956 TI - Nursing education and beliefs towards tobacco cessation and control: a cross- sectional national survey (GHPSS) among nursing students in Greece. AB - BACKGROUND: Within the healthcare system, nurses have the ability to influence their patients' smoking habits through counselling. Therefore, it is of great importance to appropriately train health professionals on smoking cessation strategies with the aim to help them provide advice to their patients. In light of the above, the objective of this study was to assess the association between Greek nursing students' beliefs towards tobacco control/smoking cessation and the professional training received. METHODS: During February 2009, we conducted a cross sectional national survey among all 3rd year nursing students of the two university based nursing departments in Greece (University of Athens, University of the Peloponnese). The Global Health Professional Student Survey (GHPSS) questionnaire was applied and following written informed consent 73% provided a completed questionnaire (n = 192/263 enrolled students). RESULTS: Overall, 33% were current active smokers, while 74% reported ever to experiment smoking. In regards to their beliefs towards tobacco control policies, non smokers were more positive in regards to banning smoking in restaurants (94% vs. 61%, p < 0.001), in bars and cafes (82% vs. 34%, p < 0.001), and all public places (93% vs. 51%, p < 0.001) when compared to current smokers. In comparison with students who had not received training on the importance of asking patients about their smoking habits, those that did were more likely to believe that nurses should have a role in smoking cessation and should act as role models for their patients. CONCLUSIONS: Resources should be invested in improving the quality of undergraduate education in nursing departments in Greece with respect to tobacco control and smoking cessation. PMID- 21548957 TI - A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes. AB - BACKGROUND: The individual character of pharmacokinetics is of great importance in the risk assessment of new drug leads in pharmacological research. Amongst others, it is severely influenced by the properties and inter-individual variability of the enzymes and transporters of the drug detoxification system of the liver. Predicting individual drug biotransformation capacity requires quantitative and detailed models. RESULTS: In this contribution we present the de novo deterministic modeling of atorvastatin biotransformation based on comprehensive published knowledge on involved metabolic and transport pathways as well as physicochemical properties. The model was evaluated on primary human hepatocytes and parameter identifiability analysis was performed under multiple experimental constraints. Dynamic simulations of atorvastatin biotransformation considering the inter-individual variability of the two major involved enzymes CYP3A4 and UGT1A3 based on quantitative protein expression data in a large human liver bank (n = 150) highlighted the variability in the individual biotransformation profiles and therefore also points to the individuality of pharmacokinetics. CONCLUSIONS: A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology. PMID- 21548958 TI - The location of olfactory receptors within olfactory epithelium is independent of odorant volatility and solubility. AB - BACKGROUND: Our objective was to study the pattern of olfactory receptor expression within the dorsal and ventral regions of the mouse olfactory epithelium. We hypothesized that olfactory receptors were distributed based on the chemical properties of their ligands: e.g. receptors for polar, hydrophilic and weakly volatile odorants would be present in the dorsal region of olfactory epithelium; while receptors for non-polar, more volatile odorants would be distributed to the ventral region. To test our hypothesis, we used micro transplantation of cilia-enriched plasma membranes derived from dorsal or ventral regions of the olfactory epithelium into Xenopus oocytes for electrophysiological characterization against a panel of 100 odorants. FINDINGS: Odorants detected by ORs from the dorsal and ventral regions showed overlap in volatility and water solubility. We did not find evidence for a correlation between the solubility and volatility of odorants and the functional expression of olfactory receptors in the dorsal or ventral region of the olfactory epithelia. CONCLUSIONS: No simple clustering or relationship between chemical properties of odorants could be associated with the different regions of the olfactory epithelium. These results suggest that the location of ORs within the epithelium is not organized based on the physico-chemical properties of their ligands. PMID- 21548959 TI - A combination of l-arabinose and chromium lowers circulating glucose and insulin levels after an acute oral sucrose challenge. AB - BACKGROUND: A growing body of research suggests that elevated circulating levels of glucose and insulin accelerate risk factors for a wide range of disorders. Low risk interventions that could suppress glucose without raising insulin levels could offer significant long-term health benefits. METHODS: To address this issue, we conducted two sequential studies, the first with two phases. In the first phase of Study 1, baseline fasting blood glucose was measured in 20 subjects who consumed 70 grams of sucrose in water and subsequently completed capillary glucose measurements at 30, 45, 60 and 90 minutes (Control). On day-2 the same procedure was followed, but with subjects simultaneously consuming a novel formula containing l-arabinose and a trivalent patented food source of chromium (LA-Cr) (Treatment). The presence or absence of the LA-Cr was blinded to the subjects and testing technician. Comparisons of changes from baseline were made between Control and Treatment periods. In the second phase of Study 1, 10 subjects selected from the original 20 competed baseline measures of body composition (DXA), a 43-blood chemistry panel and a Quality of Life Inventory. These subjects subsequently took LA-Cr daily for 4 weeks completing daily tracking forms and repeating the baseline capillary tests at the end of each of the four weeks. In Study 2, the same procedures used in the first phase were repeated for 50 subjects, but with added circulating insulin measurements at 30 and 60 minutes from baseline. RESULTS: In both studies, as compared to Control, the Treatment group had significantly lower glucose responses for all four testing times (AUC=P<0.0001). Additionally, the Treatment was significantly more effective in lowering circulating insulin after 60 minutes from baseline (AUC=P=<0.01). No adverse effects were found after acute sucrose challenge or in those who consumed LA-Cr daily for four weeks. CONCLUSIONS: As compared to a placebo control, consumption of a LA-Cr formula after a 70-gram sucrose challenge was significantly more effective in safely lowering both circulating glucose and insulin levels. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01107431. PMID- 21548960 TI - Dysregulation of fragile * mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of individuals with autism: a postmortem brain study. AB - BACKGROUND: Fragile * syndrome is caused by loss of function of the fragile * mental retardation 1 (FMR1) gene and shares multiple phenotypes with autism. We have previously found reduced expression of the protein product of FMR1 (FMRP) in vermis of adults with autism. METHODS: In the current study, we have investigated levels of FMRP in the superior frontal cortex of people with autism and matched controls using Western blot analysis. Because FMRP regulates the translation of multiple genes, we also measured protein levels for downstream molecules metabotropic glutamate receptor 5 (mGluR5) and gamma-aminobutyric acid (GABA) A receptor beta3 (GABRbeta3), as well as glial fibrillary acidic protein (GFAP). RESULTS: We observed significantly reduced levels of protein for FMRP in adults with autism, significantly increased levels of protein for mGluR5 in children with autism and significantly increased levels of GFAP in adults and children with autism. We found no change in expression of GABRbeta3. Our results for FMRP, mGluR5 and GFAP confirm our previous work in the cerebellar vermis of people with autism. CONCLUSION: These changes may be responsible for cognitive deficits and seizure disorder in people with autism. PMID- 21548961 TI - The four Zn fingers of MBNL1 provide a flexible platform for recognition of its RNA binding elements. AB - BACKGROUND: Muscleblind-like 1 (MBNL1) is an alternative splicing factor containing four CCCH Zinc fingers (ZnFs). The sequestration of MBNL1 by expanded CUG and CCUG repeats is a major component in causing myotonic dystrophy. In addition to binding the structured expanded CUG and CCUG repeats; previous results suggested that MBNL1 binds single-stranded RNAs containing GC dinucleotides. RESULTS: We performed a systematic analysis of MBNL1 binding to single-stranded RNAs. These studies revealed that a single GC dinucleotide in poly-uridine is sufficient for MBNL1 binding and that a second GC dinucleotide confers higher affinity MBNL1 binding. However additional GC dinucleotides do not enhance RNA binding. We also showed that the RNA sequences adjacent to the GC dinucleotides play an important role in MBNL1 binding with the following preference: uridines >cytidines >adenosines >guanosines. For high affinity binding by MBNL1, the distance between the two GC dinucleotides can vary from 1 to 17 nucleotides. CONCLUSIONS: These results suggest that MBNL1 is highly flexible and able to adopt different conformations to recognize RNAs with varying sequence configurations. Although MBNL1 contains four ZnFs, only two ZnF - GC dinucleotide interactions are necessary for high affinity binding. PMID- 21548962 TI - A quantitative real-time RT-PCR assay for mature C. albicans biofilms. AB - BACKGROUND: Fungal biofilms are more resistant to anti-fungal drugs than organisms in planktonic form. Traditionally, susceptibility of biofilms to anti fungal agents has been measured using the 2,3-bis(2-methoxy-4-nitro-5 sulfophenyl)-2H-tetrazolium-5-carboxyanilide (XTT) assay, which measures the ability of metabolically active cells to convert tetrazolium dyes into colored formazan derivatives. However, this assay has limitations when applied to high C. albicans cell densities because substrate concentration and solubility are limiting factors in the reaction. Because mature biofilms are composed of high cell density populations we sought to develop a quantitative real-time RT-PCR assay (qRT-PCR) that could accurately assess mature biofilm changes in response to a wide variety of anti-fungal agents, including host immune cells. RESULTS: The XTT and qRT-PCR assays were in good agreement when biofilm changes were measured in planktonic cultures or in early biofilms which contain lower cell densities. However, the real-time qRT-PCR assay could also accurately quantify small-medium size changes in mature biofilms caused by mechanical biomass reduction, antifungal drugs or immune effector cells, that were not accurately quantifiable with the XTT assay. CONCLUSIONS: We conclude that the qRT-PCR assay is more accurate than the XTT assay when measuring small-medium size effects of anti-fungal agents against mature biofilms. This assay is also more appropriate when mature biofilm susceptibility to anti-fungal agents is tested on complex biological surfaces, such as organotypic cultures. PMID- 21548964 TI - Applying neutral drift to the directed molecular evolution of a beta glucuronidase into a beta-galactosidase: Two different evolutionary pathways lead to the same variant. AB - BACKGROUND: Directed protein evolution has been used to modify protein activity and research has been carried out to enhance the production of high quality mutant libraries. Many theoretical approaches suggest that allowing a population to undergo neutral selection may be valuable in directed evolution experiments. FINDINGS: Here we report on an investigation into the value of neutral selection in a classical model system for directed evolution, the conversion of the E. coli beta-glucuronidase to a beta-galactosidase activity. We find that neutral selection, i.e. selection for retaining glucuronidase activity, can efficiently identify the majority of sites of mutation that have been identified as beneficial for galactosidase activity in previous experiments. Each variant demonstrating increased galactosidase activity identified by our neutral drift experiments contained a mutation at one of four sites, T509, S557, N566 or W529. All of these sites have previously been identified using direct selection for beta galactosidase activity. CONCLUSIONS: Our results are consistent with others that show that a neutral selection approach can be effective in selecting improved variants. However, we interpret our results to show that neutral selection is, in this case, not a more efficient approach than conventional directed evolution approaches. However, the neutral approach is likely to be beneficial when the resulting library can be screened for a range of related activities. More detailed statistical studies to resolve the apparent differences between this system and others are likely to be a fruitful avenue for future research. PMID- 21548963 TI - Eukaryotic protein kinases (ePKs) of the helminth parasite Schistosoma mansoni. AB - BACKGROUND: Schistosomiasis remains an important parasitic disease and a major economic problem in many countries. The Schistosoma mansoni genome and predicted proteome sequences were recently published providing the opportunity to identify new drug candidates. Eukaryotic protein kinases (ePKs) play a central role in mediating signal transduction through complex networks and are considered druggable targets from the medical and chemical viewpoints. Our work aimed at analyzing the S. mansoni predicted proteome in order to identify and classify all ePKs of this parasite through combined computational approaches. Functional annotation was performed mainly to yield insights into the parasite signaling processes relevant to its complex lifestyle and to select some ePKs as potential drug targets. RESULTS: We have identified 252 ePKs, which corresponds to 1.9% of the S. mansoni predicted proteome, through sequence similarity searches using HMMs (Hidden Markov Models). Amino acid sequences corresponding to the conserved catalytic domain of ePKs were aligned by MAFFT and further used in distance-based phylogenetic analysis as implemented in PHYLIP. Our analysis also included the ePK homologs from six other eukaryotes. The results show that S. mansoni has proteins in all ePK groups. Most of them are clearly clustered with known ePKs in other eukaryotes according to the phylogenetic analysis. None of the ePKs are exclusively found in S. mansoni or belong to an expanded family in this parasite. Only 16 S. mansoni ePKs were experimentally studied, 12 proteins are predicted to be catalytically inactive and approximately 2% of the parasite ePKs remain unclassified. Some proteins were mentioned as good target for drug development since they have a predicted essential function for the parasite. CONCLUSIONS: Our approach has improved the functional annotation of 40% of S. mansoni ePKs through combined similarity and phylogenetic-based approaches. As we continue this work, we will highlight the biochemical and physiological adaptations of S. mansoni in response to diverse environments during the parasite development, vector interaction, and host infection. PMID- 21548966 TI - Physiological properties of enkephalin-containing neurons in the spinal dorsal horn visualized by expression of green fluorescent protein in BAC transgenic mice. AB - BACKGROUND: Enkephalins are endogenous opiates that are assumed to modulate nociceptive information by mediating synaptic transmission in the central nervous system, including the spinal dorsal horn. RESULTS: To develop a new tool for the identification of in vitro enkephalinergic neurons and to analyze enkephalin promoter activity, we generated transgenic mice for a bacterial artificial chromosome (BAC). Enkephalinergic neurons from these mice expressed enhanced green fluorescent protein (eGFP) under the control of the preproenkephalin (PPE) gene (penk1) promoter. eGFP-positive neurons were distributed throughout the gray matter of the spinal cord, and were primarily observed in laminae I-II and V-VII, in a pattern similar to the distribution pattern of enkephalin-containing neurons. Double immunostaining analysis using anti-enkephalin and anti-eGFP antibodies showed that all eGFP-expressing neurons contained enkephalin. Incubation in the presence of forskolin, an activator of adenylate cyclase, increased the number of eGFP-positive neurons. These results indicate that eGFP expression is controlled by the penk1 promoter, which contains cyclic AMP responsive elements. Sections obtained from sciatic nerve-ligated mice exhibited increased eGFP-positive neurons on the ipsilateral (nerve-ligated side) compared with the contralateral (non-ligated side). These data indicate that PPE expression is affected by peripheral nerve injury. Additionally, single-neuron RT PCR analysis showed that several eGFP positive-neurons in laminae I-II expressed glutamate decarboxylase 67 mRNA and that some expressed serotonin type 3 receptors. CONCLUSIONS: These results suggest that eGFP-positive neurons in laminae I-II coexpress enkephalin and gamma-aminobutyric acid (GABA), and are activated by forskolin and in conditions of nerve injury. The penk1-eGFP BAC transgenic mouse contributes to the further characterization of enkephalinergic neurons in the transmission and modulation of nociceptive information. PMID- 21548965 TI - Comparison of hemodynamic, biochemical and hematological parameters of healthy pregnant women in the third trimester of pregnancy and the active labor phase. AB - BACKGROUND: Pregnancy is accompanied by several hemodynamic, biochemical and hematological changes which revert to normal values after labor. The mean values of these parameters have been reported for developed countries, but not for Mexican women. Furthermore, labor constitutes a stress situation, in which these factors may be altered. It is known that serologic increase of heat shock protein (Hsp) 70 is associated with abnormal pregnancies, presenting very low level in normal pregnant women. Nevertheless, there are no studies where these measurements are compared in healthy pregnant women at their third trimester of pregnancy (3TP) and the active labor phase (ActLP). METHODS: Seventy five healthy Mexican pregnant women were included. Hemodynamic, biochemical and hematological parameters were obtained in all cases, and serum Hsp70 levels were measured in a sample of 15 women at 3TP and at ActLP. RESULTS: Significant differences were found in most analysis performed and in Hsp70 concentration at 3TP as compared to ActLP, however all were within normal range in both conditions, supporting that only in pathological pregnancies Hsp70 is drastically increased. CONCLUSION: Results obtained indicate that 3TP and ActLP have clinical similarities in normal pregnancies, therefore if abnormalities are found during 3TP, precautions should be taken before ActLP. PMID- 21548967 TI - Correction: Multiple sequence-directed possibilities provide a pool of nucleosome position choices in different states of activity of a gene. PMID- 21548968 TI - Evaluation of a school-based HIV prevention intervention among Yemeni adolescents. AB - BACKGROUND: This article describes an evaluation of a school-based peer education intervention for HIV prevention among students in twenty seven high schools in Aden, Yemen. The intervention was developed after a survey among the same population in 2005, which revealed a high level of stigma towards people living with HIV (PLWH) and a low level of HIV knowledge. METHODS: In a quasi experimental design students who received the peer education intervention (78.6%) were compared with students who did not receive the intervention (21.4%). No systematic procedure was applied in selecting students for the intervention condition. Data were collected using a self-administered questionnaire from a sample of 2510 students from all 27 high-schools in Aden governorate. To increase internal validity, students were also compared with a cohort control sample surveyed in 2005, which was a random sample of 2274 students from the same schools. RESULTS: Sixty eight percent of students targeted by peer education had good knowledge scores, compared with 43.3% of students not targeted by peer education (chi(2) = (df = 1) = 111.15, p < .01). Multi-level regression analysis revealed that, although there was a significant difference among schools, the intervention effect of peer education at the individual level was significant; students who received peer education had a statistically higher knowledge score(9.24 out of 12.0) compared with those not targeted (7.89 out of 12.0), OR = 2.11, 95% CI = 1.04-4.27, p < .05). Compared with the 2005 cohort control sample, students targeted by peer education had better knowledge on the modes of transmission and prevention and fewer misconceptions; and knowledge on the use of condoms increased from 49.4% to 67.8%. In addition, students who received the peer education interventions suggested significantly more actions to provide care and support for PLWH. Also, the levels of stigma and discrimination were much higher among the 2005 cohort control group, compared with those who received the peer education intervention. CONCLUSION: The school-based peer education intervention has succeeded in improving levels of knowledge on modes of transmission and prevention, and in decreasing levels of stigma and discrimination in a culturally conservative setting. PMID- 21548969 TI - Effect of chemokine receptors CCR7 on disseminated behavior of human T cell lymphoma: clinical and experimental study. AB - BACKGROUND: The expression of chemokine receptors CCR7 has been studied in relation to tumor dissemination and poor prognosis in a limited number of cancers. No such studies have been done on CCR7 expression in non-Hodgkin's lymphoma (T-NHL). Our aim in this paper is to investigate the association between CCR7 expression and progression and prognosis of T-NHL. METHODS: 1) Analysis of clinical data: The specimens were obtained from 41 patients with T-NHL and 19 patients with lymphoid hyperplasia. Their corresponding clinicopathologic data were also collected. The expression levels of CCR7, MMP-2, and MMP-9 were examined by immunohistochemical staining. 2) Human T-NHL cell lines Hut 78 (cutaneous T-cell lymphoma) and Jurkat (adult T-cell leukemia/lymphoma) were cultured. The invasiveness of the two cell lines were measured with a Transwell invasion assay, and then used to study the effects of chemokine receptors on T NHL invasion and the underlying molecular mechanism. The transcript and expression of CCR7 were evaluated using RT-PCR and western blotting. RESULTS: 1) The higher CCR7 and MMP-9 expression ratios were significantly associated with multiple lesions and higher stage III/IV. Moreover, a positive correlation was observed between CCR7 and MMP-9 expression. 2) The Hut 78 cell line was more invasive than the Jurkat cells in the Transwell invasion assay. The transcript and expression levels of CCR7 were significantly higher in Hut78 than that of Jurkat cell line. The T-NHL cell lines were co-cultured with chemokine CCL21 which increased the invasiveness of T-NHL cell. The positive association between CCL21 concentration and invasiveness was found. 3) The stronger transcript and expression of PI(3)K, Akt and p- Akt were also observed in Hut78 than in Jurkat cell line. CONCLUSIONS: High CCR7 expression in T-NHL cells is significantly associated with lymphatic and distant dissemination as well as with tumor cell migration and invasion in vitro. Its underlying mechanism probably involves the PI(3)K/Akt signal pathway. PMID- 21548970 TI - Differential pathogenicity of two different recombinant PVY(NTN) isolates in Physalis floridana is likely determined by the coat protein gene. AB - A previous study has identified two types of recombinant variants of Potato virus Y strain NTN (PVY(NTN)) in China and sequenced the complete genome of the variant PVY(NTN)-HN2. In this study, the complete genome of isolate PVY(NTN)-HN1 was fully sequenced and analyzed. The most striking difference between the two variants was the location of recombinant joint three (RJ3). In PVY(NTN)-HN1, like other typical European-PVY(NTN) isolates such as PVY(NTN)-Hun, the RJ3 was located at nucleotide (nt) 9183, namely the 3' proximal end of the CP gene (nt. 8571-9371), thus leading to most (the first 613 nucleotides from the 5' proximal end) of the CP gene (801 bp) with a PVYN origin and PVYN-serotype; whereas in contrast, the RJ3 in PVY(NTN)-HN2 was located at nt 8572, consequently leading to a CP gene of PVYO origin and PVYO-serotype. The varied genome composition among PVY(O), PVY(N), PVY(N:O), PVY(NTN_-HN1 and PVY(NTN)-HN2 made them useful for the investigation of possible roles of gene segment(s) in symptom formation on host plants. When Physalis floridana plants were infected with different PVY isolates, two types of symptoms were induced. PVY(N) and PVY(NTN)-HN1 induced mild symptoms (mainly mild mottling) whereas PVY(O), PVY(N:O) and PVY(NTN)-HN2 induced serve symptoms including leaf and stem necrosis, leaf-drop and stunting. These results, together with a previous study using artificial PVY chimeras, demonstrate that the CP gene, especially the 5' proximal segment (nt 8572-9183), and/or CP likely determine the pathogenicity of PVY in P. floridana. PMID- 21548971 TI - Radiological findings in patients undergoing revision endoscopic sinus surgery: a retrospective case series study. AB - BACKGROUND: Functional endoscopic sinus surgery (FESS) is now a well-established strategy for the treatment of chronic rhinosinusitis which has not responded to medical treatment. There is a wide variation in the practice of FESS by various surgeons within the UK and in other countries. OBJECTIVES: To identify anatomic factors that may predispose to persistent or recurrent disease in patients undergoing revision FESS. METHODS: Retrospective review of axial and coronal CT scans of patients undergoing revision FESS between January 2005 and November 2008 in a tertiary referral centre in South West of England. RESULTS: The CT scans of 63 patients undergoing revision FESS were reviewed. Among the patients studied, 15.9% had significant deviation of the nasal septum. Lateralised middle turbinates were present in 11.1% of the studied sides, and residual uncinate processes were identified in 57.1% of the studied sides. There were residual cells in the frontal recess in 96% of the studied sides. There were persistent other anterior and posterior ethmoidal cells in 92.1% and 96% of the studied sides respectively. CONCLUSIONS: Analysis of CT scans of patients undergoing revision FESS shows persistent structures and non-dissected cells that may be responsible for persistence or recurrence of rhinosinusitis symptoms. Trials comparing the outcome of conservative FESS techniques with more radical sinus dissections are required. PMID- 21548972 TI - Ifugao males, learning and teaching for the improvement of maternal and child health status in the Philippines: an evaluation of a program. AB - BACKGROUND: Improving Maternal and Child Health (MCH) is a prioritized global agenda in achieving the United Nations Millennium Development Goal 5. In this challenge, involving males has been an important agenda, and a program with such intent was conducted in Alfonso Lista, Ifugao, of the Philippines. The objectives of this study were: (1) to evaluate the effectiveness in knowledge, attitude, and practice before and after a MCH session; (2) to evaluate the session's effectiveness in relation to socio-demographic characteristics; and (3) to examine if males who have learned about MCH topics can teach another group of males. METHODS: A male community representative who received a lecture from the health office staff was assigned to teach a group of community males [Group 1, N = 140] in 5 sessions, using educational materials. 10 male volunteers from Group 1 then taught a different group of males [Group 2, N = 105] in their own barangays (villages). To evaluate its effectiveness, a self-administered questionnaire survey pertaining knowledge, attitude and practice regarding MCH was conducted at three different time points: before the session (Time 1, T1), after the session (Time 2, T2), and 3 months following the session (Time 3, T3). A repeated measures analysis of variance was conducted to test for changes over time and its interaction effect between specific socio-demographic variables. RESULTS: In Group 1, there was a significant positive increase in knowledge score over time at T1-T2 and T1-T3 (p < 0.001). For attitude, the score increased only at T1-T2 (p = 0.027). The effectiveness in knowledge and attitude did not vary by socio-demographic characteristics. As for practice, majority of the participants reported that they had talked about MCH topics in their community and assisted a pregnant woman in some ways. A comparison between Group 1 and Group 2 revealed that Group 2 had similar effectiveness as Group 1 in knowledge improvement immediately after the session (p < 0.001), but no such improvement in the attitude score. CONCLUSION: Although the change in attitude needs further assessment, this strategy of continuous learning and teaching of MCH topics within community males is shown to improve knowledge and has a potential to uplift the MCH status, including the reduction of maternal deaths, in Alfonso Lista, Ifugao, Philippines. PMID- 21548973 TI - Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of gastric cancer with peritoneal carcinomatosis: evidence from an experimental study. AB - BACKGROUND: Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been considered as a promising treatment modality for gastric cancer with peritoneal carcinomatosis (PC). However, there have also been many debates regarding the efficacy and safety of this new approach. Results from experimental animal model study could help provide reliable information. This study was to investigate the safety and efficacy of CRS + HIPEC to treat gastric cancer with PC in a rabbit model. METHODS: VX2 tumor cells were injected into the gastric submucosa of 42 male New Zealand rabbits using a laparotomic implantation technique, to construct rabbit model of gastric cancer with PC. The rabbits were randomized into control group (n = 14), CRS alone group (n = 14) and CRS + HIPEC group (n = 14). The control group was observed for natural course of disease progression. Treatments were started on day 9 after tumor cells inoculation, including maximal removal of tumor nodules in CRS alone group, and maximal CRS plus heperthermic intraperitoneal chemoperfusion with docetaxel (10 mg/rabbit) and carboplatin (40 mg/rabbit) at 42.0 +/- 0.5 degrees C for 30 min in CRS + HIPEC group. The primary endpoint was overall survival (OS). The secondary endpoints were body weight, biochemistry, major organ functions and serious adverse events (SAE). RESULTS: Rabbit model of gastric cancer with PC was successfully established in all animals. The clinicopathological features of the model were similar to human gastric PC. The median OS was 24.0 d (95% confidence interval 21.8 - 26.2 d ) in the control group, 25.0 d (95% CI 21.3 - 28.7 d ) in CRS group, and 40.0 d (95% CI 34.6 - 45.4 d ) in CRS + HIPEC group (P = 0.00, log rank test). Compared with CRS only or control group, CRS + HIPEC could extend the OS by at least 15 d (60%). At the baseline, on the day of surgery and on day 8 after surgery, the peripheral blood cells counts, liver and kidney functions, and biochemistry parameters were all comparable. SAE occurred in 0 animal in control group, 2 animals in CRS alone group including 1 animal death due to anesthesia overdose and another death due to postoperative hemorrhage, and 3 animals in CRS + HIPEC group including 1 animal death due to anesthesia overdose, and 2 animal deaths due to diarrhea 23 and 27 d after operation. CONCLUSIONS: In this rabbit model of gastric cancer with PC, CRS alone could not bring benefit while CRS + HIPEC with docetaxel and carboplatin could significantly prolong the survival with acceptable safety. PMID- 21548974 TI - Assessing affymetrix GeneChip microarray quality. AB - BACKGROUND: Microarray technology has become a widely used tool in the biological sciences. Over the past decade, the number of users has grown exponentially, and with the number of applications and secondary data analyses rapidly increasing, we expect this rate to continue. Various initiatives such as the External RNA Control Consortium (ERCC) and the MicroArray Quality Control (MAQC) project have explored ways to provide standards for the technology. For microarrays to become generally accepted as a reliable technology, statistical methods for assessing quality will be an indispensable component; however, there remains a lack of consensus in both defining and measuring microarray quality. RESULTS: We begin by providing a precise definition of microarray quality and reviewing existing Affymetrix GeneChip quality metrics in light of this definition. We show that the best-performing metrics require multiple arrays to be assessed simultaneously. While such multi-array quality metrics are adequate for bench science, as microarrays begin to be used in clinical settings, single-array quality metrics will be indispensable. To this end, we define a single-array version of one of the best multi-array quality metrics and show that this metric performs as well as the best multi-array metrics. We then use this new quality metric to assess the quality of microarry data available via the Gene Expression Omnibus (GEO) using more than 22,000 Affymetrix HGU133a and HGU133plus2 arrays from 809 studies. CONCLUSIONS: We find that approximately 10 percent of these publicly available arrays are of poor quality. Moreover, the quality of microarray measurements varies greatly from hybridization to hybridization, study to study, and lab to lab, with some experiments producing unusable data. Many of the concepts described here are applicable to other high-throughput technologies. PMID- 21548975 TI - The best practice for preparation of samples from FTA(r)cards for diagnosis of blood borne infections using African trypanosomes as a model system. AB - BACKGROUND: Diagnosis of blood borne infectious diseases relies primarily on the detection of the causative agent in the blood sample. Molecular techniques offer sensitive and specific tools for this although considerable difficulties exist when using these approaches in the field environment. In large scale epidemiological studies, FTA(r)cards are becoming increasingly popular for the rapid collection and archiving of a large number of samples. However, there are some difficulties in the downstream processing of these cards which is essential for the accurate diagnosis of infection. Here we describe recommendations for the best practice approach for sample processing from FTA(r)cards for the molecular diagnosis of trypanosomiasis using PCR. RESULTS: A comparison of five techniques was made. Detection from directly applied whole blood was less sensitive (35.6%) than whole blood which was subsequently eluted from the cards using Chelex(r)100 (56.4%). Better apparent sensitivity was achieved when blood was lysed prior to application on the FTA cards (73.3%) although this was not significant. This did not improve with subsequent elution using Chelex(r)100 (73.3%) and was not significantly different from direct DNA extraction from blood in the field (68.3%). CONCLUSIONS: Based on these results, the degree of effort required for each of these techniques and the difficulty of DNA extraction under field conditions, we recommend that blood is transferred onto FTA cards whole followed by elution in Chelex(r)100 as the best approach. PMID- 21548976 TI - Male involvement in birth preparedness and complication readiness for emergency obstetric referrals in rural Uganda. AB - BACKGROUND: Every pregnant woman faces risk of life-threatening obstetric complications. A birth-preparedness package promotes active preparation and assists in decision-making for healthcare seeking in case of such complications. The aim was to assess factors associated with birth preparedness and complication readiness as well as the level of male participation in the birth plan among emergency obstetric referrals in rural Uganda. METHODS: This was a cross sectional study conducted at Kabale regional hospital maternity ward among 140 women admitted as emergency obstetric referrals in antenatal, labor or the postpartum period. Data was collected on socio-demographics and birth preparedness and what roles spouses were involved in during developing the birth plan. Any woman who attended antenatal care at least 4 times, received health education on pregnancy and childbirth danger signs, saved money for emergencies, made a plan of where to deliver from and made preparations for a birth companion, was deemed as having made a birth plan. Multivariate logistic regression analysis was conducted to analyze factors that were independently associated with having a birth plan. RESULTS: The mean age was 26.8 +/- 6.6 years, while mean age of the spouse was 32.8 +/- 8.3 years. Over 100 (73.8%) women and 75 (55.2%) of their spouses had no formal education or only primary level of education respectively. On multivariable analysis, Primigravidae compared to multigravidae, OR 1.8 95%CI (1.0-3.0), education level of spouse of secondary or higher versus primary level or none, OR 3.8 95%CI (1.2-11.0), formal occupation versus informal occupation of spouse, OR 1.6 95%CI (1.1-2.5), presence of pregnancy complications OR 1.4 95%CI (1.1-2.0) and the anticipated mode of delivery of caesarean section versus vaginal delivery, OR 1.6 95%CI (1.0-2.4) were associated with having a birth plan. CONCLUSION: Individual women, families and communities need to be empowered to contribute positively to making pregnancy safer by making a birth plan. PMID- 21548977 TI - Cu, Zn-superoxide dismutase 1 (SOD1) is a novel target of Puromycin-sensitive aminopeptidase (PSA/NPEPPS): PSA/NPEPPS is a possible modifier of amyotrophic lateral sclerosis. AB - Accumulation of misfolded neurotoxic Cu, Zn-superoxide dismutase-1 (SOD1) protein found in both familial and sporadic amyotrophic lateral sclerosis (ALS) is recognized as an important contributing factor of neuronal cell death. However, little is known about the mechanisms controlling the accumulation and turnover of SOD1 protein. Puromycin-sensitive aminopeptidase (PSA/NPEPPS) was recently identified as a major peptidase acting on neurotoxic TAU protein and protecting against TAU-induced neurodegeneration. In addition, recent report implicated PSA/NPEPPS in the direct removal of neurotoxic polyglutamine repeats. These combined data suggest that PSA/NPEPPS might represent a novel degradation pathway targeting pathologically aggregating neurotoxic protein substrates including SOD1. Here, we report that PSA/NPEPPS directly regulates SOD1 protein abundance and clearance via proteolysis. In addition, PSA/NPEPPS expression is significantly decreased in motor neurons of both SODG93A transgenic mice and sporadic ALS patients, suggesting its possible contribution to the disease pathogenesis. These results implicate SOD1 as a new target protein of PSA/NPEPPS and point to the possible neuroprotective role of PSA/NPEPPS in ALS. PMID- 21548978 TI - Use of gel caps to aid endoscopic insertion of nasogastric feeding tubes: a comparative audit. AB - INTRODUCTION: Nutrition is crucial to successful outcomes in peri-operative head and neck cancer patients. Nasogastric feeding tubes are an accepted and safe method of providing enteral nutrition in the short-term. Many methods have been advocated for successfully inserting and securing nasogastric tubes and each practitioner will have his or her preferred technique. OBJECTIVES: To confirm the effectiveness of using gel caps combined with the flexible nasendoscope for the insertion of nasogastric feeding tubes in head and neck cancer patients following failure of traditional methods. PARTICIPANTS: Thirty-five consecutive patients requiring nasogastric feeding tubes were included in this comparative audit. All had failed traditional insertion methods after 2 attempts and were therefore eligible for inclusion. Patients were randomised to undergo attempted insertion with the flexible nasendoscope with or without the use of a gel cap (both methods have been previously described). AUDIT OUTCOME: Primary outcome measures showed no significant difference between the two techniques. DISCUSSION: We found the methodology to be of no greater benefit to our patients when compared to our alternative current practice for failed blind nasogastric tube insertion. We retain this methodology in our armamentarium for difficult circumstances but have continued with our standard practice for most patients needing nasogastric tube placement. PMID- 21548979 TI - Differential regulation of diacylglycerol kinase isoform in human failing hearts. AB - Evidence from several studies indicates the importance of Galphaq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG), and protein kinase C, in the development of heart failure. DAG kinase (DGK) acts as an endogenous regulator of GPCR signaling pathway by catalyzing and regulating DAG. Expressions of DGK isoforms alpha, epsilon, and zeta in rodent hearts have been detected; however, the expression and alteration of DGK isoforms in a failing human heart has not yet been examined. In this study, we detected mRNA expressions of DGK isoforms gamma, eta, epsilon, and zeta in failing human heart samples obtained from patients undergoing cardiovascular surgery with cardiopulmonary bypass. Furthermore, we investigated modulation of DGK isoform expression in these hearts. We found that expressions of DGKeta and DGKzeta were increased and decreased, respectively, whereas those of DGKgamma and DGKepsilon remained unchanged. This is the first report that describes the differential regulation of DGK isoforms in normal and failing human hearts. PMID- 21548980 TI - Pneumatosis intestinalis leading to perioperative hypovolemic shock: Case report. AB - Pneumatosis intestinalis (PI) is an uncommon disorder defined as multiple foci of gas within the intestinal wall. Despite recognition of an increasing number of cases of PI, the optimal management strategy, whether through surgical or other means, remains controversial. The present report describes the case of a patient with PI who underwent exploratory laparotomy without specific findings and who ultimately died due to extensive intestinal hemorrhage that was possibly triggered by surgery. PMID- 21548982 TI - Effects of furosemide on the hearing loss induced by impulse noise. AB - BACKGROUND: The permanent hearing loss following exposure to intense noise can be due either to mechanical structural damage (tearing) caused directly by the noise or to metabolic (biochemical) damage resulting from the elevated levels of free radicals released during transduction of the sound overstimulation. Drugs which depress active cochlear mechanics (e.g. furosemide and salicylic acid) or anti oxidants (which counteract the free radicals) are effective in reducing the threshold shift (TS) following broadband continuous noise. This study was designed to determine whether furosemide can reduce the TS following exposure to impulse noise, similar to its action with continuous broadband noise. METHODS: Shortly after furosemide injection, mice were exposed to simulated M16 rifle impulse noise produced by different loudspeakers and amplifiers in different exposure settings and, in other experiments, also to actual M16 rifle shots. RESULTS: Depending on the paradigm, the simulated noises either did not produce a TS, or the TS was reduced by furosemide. The drug was not effective in reducing TS resulting from actual impulse noise. CONCLUSION: Simulated M16 rifle impulse noise may not truly replicate the rapid rise time and very high intensity of actual rifle shots so that the TS following exposure to such noise can be reduced by these drugs. On the other hand, actual M16 impulse noise probably causes direct (frank) mechanical damage, which is not reduced by these drugs. PMID- 21548981 TI - Serine 204 phosphorylation and O-beta-GlcNAC interplay of IGFBP-6 as therapeutic indicator to regulate IGF-II functions in viral mediated hepatocellular carcinoma. AB - Hepatocellular carcinoma is mainly associated with viral hepatitis B and C. Activation of cell growth stimulator IGF-II gene is observed in tumor formation especially in viral associated hepatocellular carcinoma. Elevated IGF-II levels are indicator of increased risk for cholangiocellular and hepatocellular carcinomas through over saturation of IGF-II binding capacities with IGF receptors leading to cellular dedifferentiation. In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form. IGFBP-6 is a specific inhibitor of IGF-II actions. Affinity of IGFBPs with IGFs is controlled by post-translational modifications. Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II. O-glycosylation and phosphorylation operate the functional expression of cellular proteins, this switching on and off the protein expression is difficult to monitor in vivo. By using neural network based prediction methods, we propose that alternate O-beta-GlcNAc modification and phosphorylation on Ser 204 control the binding of IGFBP-6 with IGF-II. This information may be used for developing new therapies by regulating IGFBP-6 assembly with IGF-II to minimize the risk of viral associated hepatocellular carcinoma. We can conclude that during HCV/HBV infection, O-beta-GlcNAc of IGFBP 6 at Ser 204 diminish their binding with IGF-II, increase IGF-II cellular expression and promote cancer progression which can lead to hepatocellular carcinoma. Furthermore, this site can be used for developing new therapies to control the IGF-II actions during viral infection to minimize the risk of hepatocellular carcinoma. PMID- 21548983 TI - Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria. AB - BACKGROUND: The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC. METHODS: Data were obtained from 26 pregnant women in the second (22-26 weeks) or the third (32 36 weeks) trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling. RESULTS: A simultaneous parent metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788 1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 72.3%). CONCLUSIONS: In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls. PMID- 21548984 TI - Occurrence and characteristics of group 1 introns found at three different positions within the 28S ribosomal RNA gene of the dematiaceous Phialophora verrucosa: phylogenetic and secondary structural implications. AB - BACKGROUND: Group 1 introns (ribozymes) are among the most ancient and have the broadest phylogenetic distribution among the known self-splicing ribozymes. Fungi are known to be rich in rDNA group 1 introns. In the present study, five sequences of the 28S ribosomal RNA gene (rDNA) regions of pathogenic dematiaceous Phialophora verrucosa were analyzed using PCR by site-specific primers and were found to have three insertions, termed intron-F, G and H, at three positions of the gene. We investigated the distribution of group 1 introns in this fungus by surveying 34 strains of P. verrucosa and seven strains of Phialophora americana as the allied species. RESULTS: Intron-F's (inserted at L798 position) were found in 88% of P. verrucosa strains, while intron-G's (inserted at L1921) at 12% and intron-H's (inserted at L2563) at 18%. There was some correlation between intron distribution and geographic location. In addition, we confirmed that the three kinds of introns are group 1 introns from results of BLAST search, alignment analysis and Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Prediction of secondary structures and phylogenetic analysis of intron sequences identified introns-F and G as belonging to subgroup IC1. In addition, intron-H was identified as IE. CONCLUSION: The three intron insertions and their insertion position in the 28S rDNA allowed the characterization of the clinical and environmental isolates of P. verrucosa and P. americana into five genotypes. All subgroups of introns-F and G and intron-H were characterized and observed for the first time in both species. PMID- 21548985 TI - Relationship of APOA5, PPARgamma and HL gene variants with serial changes in childhood body mass index and coronary artery disease risk factors in young adulthood. AB - BACKGROUND: Triglycerides is an independent risk factor for coronary artery disease (CAD) and is especially important in Indians because of high prevalence of hypertriglyceridemia in this population. Both genetic and environmental factors determine triglyceride levels. In a birth cohort from India, hypertriglyceridemia was found in 41% of men and 11% of women. Subjects who had high triglycerides had more rapid body mass index (BMI) or weight gain than rest of the cohort throughout infancy, childhood and adolescence. We analysed polymorphisms in APOA5, hepatic lipase and PPARgamma genes and investigated their association with birth weight and serial changes in BMI. RESULTS: Polymorphisms in APOA5 (-1131T > C, S19W), PPARgamma (Pro12Ala) and hepatic lipase (-514C > T) were studied by polymerase chain reaction (PCR) followed by restriction digestion in 1492 subjects from the New Delhi Birth Cohort (NDBC). We assessed whether these polymorphisms influence lipid and other variables and serial changes in BMI, both individually and together.The risk allele of APOA5 (-1131C) resulted in 23.6 mg/dl higher triglycerides as compared to normal allele (P < 0.001). Risk allele of HL (-514T) was associated with significantly higher HDL2 levels (P = 0.002). Except for the marginal association of PPARgamma Pro12Ala variation with a lower conditional weight at 6 months, (P = 0.020) and APOA5 S19W with a higher conditional BMI at 11 yrs of age (P = 0.030), none of the other associations between the gene polymorphisms and serial changes in body mass index from birth to young adulthood were significant. CONCLUSION: The promoter polymorphism in APOA5 was associated with raised serum triglycerides and that of HL with raised HDL2 levels. None of the polymorphisms had any significant relationship with birth weight or serial changes in anthropometry from birth to adulthood in this cohort. PMID- 21548986 TI - Economic modeling of the combined effects of HIV-disease, cholesterol and lipoatrophy based on ACTG 5142 trial data. AB - BACKGROUND: This study examines the cost and consequences of initiating an ARV regimen including Lopinavir/ritonavir (LPV/r) or Efavirenz (EFV), using data from a recent clinical trial in a previously published model of HIV-disease. METHODS: We populated the Markov model of HIV-disease with data from ACTG 5142 study to estimate the economic outcomes of starting ARV therapy with a PI-containing regimen as compared to an NNRTI-containing regimen, given their virologic and immunologic efficacy and effects on cholesterol and lipoatrophy. CNS toxicities and GI tolerability were not included in the model because of their transient nature or low cost remedies, and therefore lack of economic impact. CD4+ T-cell counts and the HIV-1 RNA (viral load) values from the study were used to assign a specific health state (HS) to each patient for each quarter year. The resulting frequencies used as "raw" data directly into the model obviate the reliance on statistical tests, and allow the model to reflect actual patient behavior in the clinical trial. An HS just below the last observed HS was used to replace a missing value. RESULTS: The modeled estimates (undiscounted) for the LPV/r-based regimen resulted in 1.41 quality-adjusted life months (QALMs) gained over a lifetime compared to the EFV-based regimen. The LPV/r-based regimen incurred $7,458 (1.8%) greater cost over a lifetime due to differences in drug costs and survival. The incremental cost effectiveness ratio using the discounted cost and QALYs was $88,829/QALY. Most of the higher costs accrue before the 7th year of treatment and were offset by subsequent savings. The estimates are highly sensitive to the effect of lipoatrophy on Health-related Quality of Life (HRQOL), but not to the effect of cholesterol levels. CONCLUSIONS: The cost effectiveness of ARV regimens may be strongly affected by enduring AEs, such as lipoatrophy. It is important to consider specific AE effects from all drugs in a regimen when ARVs are compared. TRIAL REGISTRATION: (ClinicalTrials.gov number, NCT00050895http://[ClinicalTrials.gov]). PMID- 21548987 TI - Structural and histological characterization of oviductal magnum and lectin binding patterns in Gallus domesticus. AB - BACKGROUND: Although chicken oviduct is a useful model and target tissue for reproductive biology and transgenesis, little is known because of the highly specific hormonal regulation and the lack of fundamental researches, including lectin-binding activities and glycobiology. Because lectin is attached to secreted glycoproteins, we hypothesized that lectin could be bound to secretory egg-white proteins, and played a crucial role in the generation of egg-white protein in the oviduct. Hence, the purpose of this study was to investigate the structural, histological and lectin-binding characteristics of the chicken oviductal magnum from juvenile and adult hens. METHODS: The oviductal magnums from juvenile and adult hens were prepared for ultrastructural analysis, qRT-PCR and immunostaining. Immunohistochemistry of anti-ovalbumin, anti-ESR1 and anti PGR, and mRNA expression of egg-white genes and steroid hormone receptor genes were evaluated. Lectin histochemical staining was also conducted in juvenile and adult oviductal magnum tissues. RESULTS: The ultrastructural analysis showed that ciliated cells were rarely developed on luminal surface in juvenile magnum, but not tubular gland cells. In adult magnum, two types of epithelium and three types of tubular gland cells were observed. qRT-PCR analysis showed that egg-white genes were highly expressed in adult oviduct compared with the juvenile. However, mRNA expressions of ESR1 and PGR were considerably higher in juvenile oviduct than adult (P < 0.05). The immunohistochemical analysis showed that anti ovalbumin antibody was detected in adult oviduct not in juvenile, unlikely anti ESR1 and anti-PGR antibodies that were stained in both oviducts. In histological analysis, Toluidine blue was stained in juvenile and adult oviductal epithelia, and adult tubular glands located in the outer layer of oviductal magnum. In contrast, PAS was positive only in adult oviductal tubular gland. Lectins were selectively bound to oviductal epithelium, stroma, and tubular gland cells. Particularly, lectin-ConA and WGA were bound to electron-dense secretory granules in tubular gland. CONCLUSIONS: The observation of ultrastructural analysis, mRNA expression, immunohistochemistry and lectin staining showed structural and physiological characterization of juvenile and adult oviductal magnum. Consequently, oviduct study could be helped to in vitro culture of chicken oviductal cells, to develop epithelial or tubular gland cell-specific markers, and to understand female reproductive biology and endocrinology. PMID- 21548988 TI - Hepatitis C in HIV-infected individuals: cure and control, right now. AB - For persons living with HIV, hepatitis C is a major public health problem that must be controlled and could be eliminated. The challenge arises because the hepatitis C virus (HCV) is prevalent among HIV-infected persons in most parts of the world, because HIV worsens all HCV outcomes, and because HCV may add additional individual economic and psychosocial complications to HIV disease. Despite the major benefits of antiretroviral therapy on HIV outcomes, antiretroviral therapy is not sufficient to halt the complications of HCV. Nonetheless, HCV can be controlled at all stages, including prevention of infection and cure. Thus, HCV is an eradicable disease. There are significant inequalities worldwide in HCV control that could markedly constrain the impact of these measures. PMID- 21548989 TI - A comparative immunofluorescence analysis of three clinical-stage antibodies in head and neck cancer. AB - BACKGROUND: The antibody-based targeted delivery of bioactive molecules to tumour vasculature is an attractive avenue to concentrate therapeutic agents at cancer sites, while sparing normal organs. L19, F8 and F16 are three fully human monoclonal antibodies, specific to splice isoforms of fibronectin and tenascin-C, which bind to sites of active tissue remodeling and which are currently in Phase I and II clinical trials as radio-immunoconjugates and immunocytokines in patients with cancer and arthritis.In this article, we report the first comparative analysis of expression patterns for the extra domains EDB and EDA of fibronectin and A1 of tenascin-C in both primary and metastatic head and neck cancer lesions. METHODS: We performed a comparative immunofluorescence analysis with the L19, F8 and F16 antibodies in 40 freshly frozen human head and neck cancer specimens. RESULTS: On average, F8 and F16 exhibited similar staining intensities, which were typically stronger than L19. Interestingly, some specimens exhibited striking differences in staining by the three antibodies. CONCLUSIONS: These results suggests that an individualized treatment procedure (e.g., choice of L19, F8 or F16 based on immuno-PET or immunofluorescence procedure) may represent the most logical avenue for offering the best possible antibody to any given patient. PMID- 21548990 TI - The CTGF -945GC polymorphism is not associated with plasma CTGF and does not predict nephropathy or outcome in type 1 diabetes. AB - The -945GC polymorphism (rs6918698) in the connective tissue growth factor gene promoter (CTGF/CCN-2) has been associated with end organ damage in systemic sclerosis. Because CTGF is important in progression of diabetic kidney disease, we investigated whether the -945GC polymorphism is associated with plasma CTGF level and outcome in type 1 diabetes. The study cohort consisted of 448 diabetic nephropathy patients and 419 normoalbuminuric diabetic patients with complete data concerning renal function and cardiovascular characteristics. Genomic DNA was genotyped by a QPCR-based SNP assay. We observed no relation between the 945GC polymorphism and plasma CTGF level, and the genotype frequencies were not different in nephropathy patients vs. normoalbuminuric controls. General and cardiovascular mortality, and renal function decline was similar in patients with CC, CG or GG genotypes. In conclusion, the -945GC SNP does not affect plasma CTGF levels, incidence and prognosis of diabetic nephropathy, and cardiovascular outcome. PMID- 21548991 TI - Development and validation of a complementary map to enhance the existing 1998 to 2008 Abbreviated Injury Scale map. AB - INTRODUCTION: Many trauma registries have used the Abbreviated Injury Scale 1990 Revision Update 98 (AIS98) to classify injuries. In the current AIS version (Abbreviated Injury Scale 2005 Update 2008 - AIS08), injury classification and specificity differ substantially from AIS98, and the mapping tools provided in the AIS08 dictionary are incomplete. As a result, data from different AIS versions cannot currently be compared. The aim of this study was to develop an additional AIS98 to AIS08 mapping tool to complement the current AIS dictionary map, and then to evaluate the completed map (produced by combining these two maps) using double-coded data. The value of additional information provided by free text descriptions accompanying assigned codes was also assessed. METHODS: Using a modified Delphi process, a panel of expert AIS coders established plausible AIS08 equivalents for the 153 AIS98 codes which currently have no AIS08 map. A series of major trauma patients whose injuries had been double-coded in AIS98 and AIS08 was used to assess the maps; both of the AIS datasets had already been mapped to another AIS version using the AIS dictionary maps. Following application of the completed (enhanced) map with or without free text evaluation, up to six AIS codes were available for each injury. Datasets were assessed for agreement in injury severity measures, and the relative performances of the maps in accurately describing the trauma population were evaluated. RESULTS: The double-coded injuries sustained by 109 patients were used to assess the maps. For data conversion from AIS98, both the enhanced map and the enhanced map with free text description resulted in higher levels of accuracy and agreement with directly coded AIS08 data than the currently available dictionary map. Paired comparisons demonstrated significant differences between direct coding and the dictionary maps, but not with either of the enhanced maps. CONCLUSIONS: The newly developed AIS98 to AIS08 complementary map enabled transformation of the trauma population description given by AIS98 into an AIS08 estimate which was statistically indistinguishable from directly coded AIS08 data. It is recommended that the enhanced map should be adopted for dataset conversion, using free text descriptions if available. PMID- 21548992 TI - An NIH intramural percubator as a model of academic-industry partnerships: from the beginning of life through the valley of death. AB - In 2009 the NIH publicly announced five strategic goals for the institutes that included the critical need to translate research discoveries into public benefit at an accelerated pace, with a commitment to find novel ways to engage academic investigators in the process. The emphasis on moving scientific advancements from the laboratory to the clinic is an opportune time to discuss how the NIH intramural program in Bethesda, the largest biomedical research center in the world, can participate in this endeavor. Proposed here for consideration is a percolator-incubator program, a 'percubator' designed to enable NIH intramural investigators to develop new medical interventions as quickly and efficiently as possible. PMID- 21548993 TI - Circulating osteopontin: a dual marker of bone destruction and angiogenesis in patients with multiple myeloma. AB - The matrix protein osteopontin has been shown to be a marker of osteoclastic activity in multiple myeloma patients, as well as a regulator of angiogenesis. We measured serum levels of osteopontin in 50 untreated multiple myeloma patients (in 25, also after treatment) and examined the relation to markers of osteolytic and angiogenic activity. The median (range) of serum osteopontin was 85 (5-232) in the patient group vs. 36 (2-190) ng/ml in the control group. Serum osteopontin levels were significantly higher in patients with advanced stage or grade of myeloma disease. All patients with serum osteopontin levels >100 ng/ml had advanced stage (II or III) or high grade bone disease, whereas stage I or low grade patients had serum osteopontin levels <100ng/ml. Serum osteopontin levels significantly decreased after treatment. There was a positive correlation of osteopontin with the bone turnover marker N-terminal propeptide of procollagen type I (NTx) and the angiogenic markers vascular endothelial growth factor (VEGF) and bone marrow microvessel density (r: 0.35, 0.47 and 0.30 respectively, p < 0.05). These results support osteopontin as a dual marker of bone destruction and angiogenic activity in myeloma patients. Osteopontin represents a useful biomarker for monitoring myeloma disease activity. PMID- 21548994 TI - Gene expression profile analysis of tobacco leaf trichomes. AB - BACKGROUND: Leaf trichomes of Nicotiana tabacum are distinguished by their large size, high density, and superior secretion ability. They contribute to plant defense response against biotic and abiotic stress, and also influence leaf aroma and smoke flavor. However, there is limited genomic information about trichomes of this non-model plant species. RESULTS: We have characterized Nicotiana tabacum leaf trichome gene expression using two approaches. In the first, a trichome cDNA library was randomly sequenced, and 2831 unique genes were obtained. The most highly abundant transcript was ribulose bisphosphate carboxylase (RuBisCO). Among the related sequences, most encoded enzymes involved in primary metabolism. Secondary metabolism related genes, such as isoprenoid and flavonoid biosynthesis related, were also identified. In the second approach, a cDNA microarray prepared from these 2831 clones was used to compare gene expression levels in trichome and leaf. There were 438 differentially expressed genes between trichome and leaves minus-trichomes. Of these, 207 highly expressed genes in tobacco trichomes were enriched in second metabolic processes, defense responses, and the metabolism regulation categories. The expression of selected unigenes was confirmed by semi quantitative RT-PCR analysis, some of which were specifically expressed in trichomes. CONCLUSION: The expression feature of leaf trichomes in Nicotiana tabacum indicates their metabolic activity and potential importance in stress resistance. Sequences predominantly expressed in trichomes will facilitate gene mining and metabolism control of plant trichome. PMID- 21548995 TI - Parental willingness to pay for child safety seats in Mashad, Iran. AB - BACKGROUND: Iran has one of the highest rates of road traffic crash death rates throughout the world and road traffic injuries are the leading cause of years of life lost in the country. Using child car safety seats is not mandatory by law in Iran. The purpose of this research was to determine the parental willingness to pay (WTP) for child restraints in Mashad, the second most populated city in Iran with one of the highest rates of road traffic-related deaths. METHODS: We surveyed 590 car-owner parents of kindergarten children who were willing to participate in the study in the year 2009. We asked them about the maximum amount of money they were willing to pay for car safety seats using contingent valuation method. RESULTS: The mean age of children was 33.5 months. The median parental WTP for CSS was about $15. Considering the real price of CSSs in Iran, only 12 percent of responders could be categorized as being willing to pay for it. Family income level was the main predictor of being willing to pay. CONCLUSIONS: The median parental WTP was much lower than the actual price of the safety seats, and those who were of lower socio-economic class were less willing to pay. Interventions to increase low-income families' access to child safety seats such as providing free of charge or subsidized seats, renting or health insurance coverage should be considered. PMID- 21548996 TI - Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety. AB - BACKGROUND: Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. METHODS: Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days. RESULTS: We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. CONCLUSIONS: Intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh HGF at an increased dose. PMID- 21548998 TI - PLAYgrounds: effect of a PE playground program in primary schools on PA levels during recess in 6 to 12 year old children. Design of a prospective controlled trial. AB - BACKGROUND: The relative number of children meeting the minimal required dose of daily physical activity remains execrably low. It has been estimated that in 2015 one out of five children will be overweight. Therefore, low levels of physical activity during early childhood may compromise the current and future health and well-being of the population, and promoting physical activity in younger children is a major public health priority. This study is to gain insight into effects of a Physical Education based playground program on the PA levels during recess in primary school children aged 6-12. METHODS/DESIGN: The effectiveness of the intervention program will be evaluated using a prospective controlled trial design in which schools will be matched, with a follow-up of one school year. The research population will consist of 6-12 year old primary school children. The intervention program will be aimed at improving physical activity levels and will consist of a multi-component alteration of the schools' playground. In addition, playground usage will be increased through altered time management of recess times, as well as a modification of the Physical Education content. DISCUSSION: The effects of the intervention on physical activity levels during recess (primary outcome measure), overall daily physical activity and changes in physical fitness (secondary outcome measures) will be assessed. Results of this study could possibly lead to changes in the current playground system of primary schools and provide structured health promotion for future public health. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2386. PMID- 21548997 TI - A case of native valve endocarditis caused by Burkholderia cepacia without predisposing factors. AB - BACKGROUND: Infective endocarditis is rarely caused by Burkholderia cepacia. This infection is known to occur particularly in immunocompromised hosts, intravenous heroin users, and in patients with prosthetic valve replacement. Most patients with Burkholderia cepacia endocarditis usually need surgical treatment in addition to antimicrobial treatment. CASE PRESENTATION: Here, we report the case of a patient who developed Burkholderia cepacia-induced native valve endocarditis with consequent cerebral involvement without any predisposing factors; she was successfully treated by antimicrobial agents only. CONCLUSION: In this report, we also present literature review of relevant cases. PMID- 21548999 TI - Frozen Elephant Trunk: a technique which can be offered in complex pathology to fix the whole aorta in one setting. AB - We report a case of treating complex aortic pathology with the use of the Frozen Elephant Trunk technique in a patient with chronic type B aortic dissecting aneurysm associated with arch and ascending aorta dilatation, proximal aortic disease and coronary disease. The case was further complicated due to the involvement of the abdominal vessels and preexisting femoral to femoral crossover bypass. In addition the patient had a tracheostomy for laryngeal cancer.We emphasize the role of the Frozen Elephant Trunk to fix the whole aorta in one setting with special attention given to the changes taking place in vascular perfusion following correction and reconstitution of the true lumen. PMID- 21549000 TI - Barriers and facilitators affecting vasectomy acceptability (a multi stages study in a sample from north eastern of Iran), 2005-2007. AB - BACKGROUND: In this study we aimed to find factors affecting vasectomy acceptability in Shahroud (north eastern Iran). METHODS: This study was carried out in three stages. The first stage was a survey of couples that had the vasectomy procedure during 2004-2007 in the Shahroud area. In the second stage of the study we compared characteristics of the cases (the couples who had the vasectomy procedure during the study period) and controls (including couples with at least one child that choose other contraceptive methods excluding a vasectomy) using chi2 and T student tests. In the third stage of the study we aimed to assess the knowledge and attitudes of those who did not choose to have a vasectomy as there contraception method by filling out questionnaires in personal interviews. RESULTS: An increasing trend toward the vasectomy procedure was observed during 2005 to 2007. We found positive associations between male and female educational levels and choosing to have a vasectomy (p < 0.05). Majority of women (88.44%) thought that their husbands would prefer to have a tubectomy to a vasectomy. CONCLUSION: The study results show a necessity for both couples to participate in educational programs about the vasectomy procedure. PMID- 21549001 TI - Management of spontaneous isolated dissection of the superior mesenteric artery: Case report and literature review. AB - BACKGROUND AND METHOD: The aim of this study was to assess retrospectively the clinical presentation, management and outcome of three patients with isolated SMA dissection encountered at Okinawa Prefectural Chubu Hospital, Japan from 2005 to 2006, along with a review of the literature. We follow up the patient's clinical symptoms and the image by using enhanced dynamic CT at 1 week, 1 or 2 months, 6 months, and yearly after onset. CASE PRESENTATION: We present three patients with acute abdominal pain due to spontaneous dissection of the superior mesenteric artery (SMA), who were treated by surgical revascularization or conservative management. Two patients underwent surgery because of signs or symptoms of intestinal ischemia and one patient elected conservative management. The SMA was repaired by bypass graft in two cases, and in one of these, the graft was occluded because of prominent native flow from the SMA. All patients were symptom free and there was no evidence of disease recurrence after a median follow-up of 4.3 years. CONCLUSION: Although the indications for surgery are still controversial, we should proceed with exploratory laparotomy if the patient has acute symptoms with suspicion of mesenteric ischemia. A non-operative approach for SMA dissection requires close follow-up abdominal CT, with a focus on the clinical signs of mesenteric ischemia and the vascular supply of the SMA, including collateral flow from the celiac artery and inferior mesenteric artery. PMID- 21549002 TI - Physiological synaptic signals initiate sequential spikes at soma of cortical pyramidal neurons. AB - The neurons in the brain produce sequential spikes as the digital codes whose various patterns manage well-organized cognitions and behaviors. A source for the physiologically integrated synaptic signals to initiate digital spikes remains unknown, which we studied at pyramidal neurons of cortical slices. In dual recordings from the soma vs. axon, the signals recorded in vivo induce somatic spikes with higher capacity, which is associated with lower somatic thresholds and shorter refractory periods mediated by voltage-gated sodium channels. The introduction of these parameters from the soma and axon into NEURON model simulates sequential spikes being somatic in origin. Physiological signals integrated from synaptic inputs primarily trigger the soma to encode neuronal digital spikes. PMID- 21549003 TI - Nutritional status of pre-school children from low income families. AB - BACKGROUND: We evaluated growth and nutritional status of preschool children between 2 and 6 years old from low income families from 14 daycare centers. METHODS: Cross-sectional study with 1544 children from daycare centers of Santo Andre, Brazil. Body weight (W), height (H) and body mass index (BMI) were classified according to the 2000 National Center for Health Statistics (CDC/NCHS). Cutoff points for nutritional disorders: -2 z scores and 2.5 and 10 percentiles for malnutrition risk, 85 to 95 percentile for overweight and above BMI 95 percentile for obesity. Stepwise Forward Regression method was used including age, gender, birth weight, breastfeeding duration, age of mother at birth and period of time they attended the daycare center. RESULTS: Children presented mean z scores of H, W and BMI above the median of the CDC/NCHS reference. Girls were taller and heavier than boys, while we observed similar BMI between both genders. The z scores tended to rise with age. A Pearson Coefficient of Correlation of 0.89 for W, 0.93 for H and 0.95 for BMI was documented indicating positive association of age with weight, height and BMI. The frequency of children below -2 z scores was lower than expected: 1.5% for W, 1.75% for H and 0% for BMI, which suggests that there were no malnourished children. The other extremity of the distribution evidenced prevalence of overweight and obesity of 16.8% and 10.8%, respectively. CONCLUSION: Low income preschool children are in an advanced stage of nutritional transition with a high prevalence of overweight. PMID- 21549004 TI - Mammalian Sirt1: insights on its biological functions. AB - Sirt1 (member of the sirtuin family) is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase that removes acetyl groups from various proteins. Sirt1 performs a wide variety of functions in biological systems. The current review focuses on the biological functions of Sirt1 in obesity-associated metabolic diseases, cancer, adipose tissue, aging, cellular senescence, cardiac aging and stress, prion-mediated neurodegeneration, inflammatory signaling in response to environmental stress, development and placental cell survival. PMID- 21549005 TI - Biochemical properties of pancreatic colipase from the common stingray Dasyatis pastinaca. AB - BACKGROUND: Pancreatic colipase is a required co-factor for pancreatic lipase, being necessary for its activity during hydrolysis of dietary triglycerides in the presence of bile salts. In the intestine, colipase is cleaved from a precursor molecule, procolipase, through the action of trypsin. This cleavage yields a peptide called enterostatin knoswn, being produced in equimolar proportions to colipase. RESULTS: In this study, colipase from the common stingray Dasyatis pastinaca (CoSPL) was purified to homogeneity. The purified colipase is not glycosylated and has an apparent molecular mass of around 10 kDa. The NH2-terminal sequencing of purified CoSPL exhibits more than 55% identity with those of mammalian, bird or marine colipases. CoSPL was found to be less effective activator of bird and mammal pancreatic lipases than for the lipase from the same specie. The apparent dissociation constant (Kd) of the colipase/lipase complex and the apparent Vmax of the colipase-activated lipase values were deduced from the linear curves of the Scatchard plots. We concluded that Stingray Pancreatic Lipase (SPL) has higher ability to interact with colipase from the same species than with the mammal or bird ones. CONCLUSION: The fact that colipase is a universal lipase cofactor might thus be explained by a conservation of the colipase-lipase interaction site. The results obtained in the study may improve our knowledge of marine lipase/colipase. PMID- 21549006 TI - Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone. AB - BACKGROUND: Traumatic brain injury (TBI) causes acute inflammatory responses that result in an enduring cascade of secondary neuronal loss and behavioral impairments. It has been reported that progesterone (PROG) can inhibit the increase of some inflammatory cytokines and inflammation-related factors induced by TBI. Toll-like receptors (TLRs) play a critical role in the induction and regulation of immune/inflammatory responses. Therefore, in the present study, we examined the genomic profiles of TLR-mediated pathways in traumatically injured brain and PROG's effects on these genes. METHODS: Bilateral cortical impact injury to the medial frontal cortex was induced in C57BL/6J mice. PROG was injected (i.p., 16 mg/kg body weight) at 1 and 6 h after surgery. Twenty-four hours post-surgery, mice were killed and peri-contusional brain tissue was harvested for genomic detection and protein measurement. RT-PCR arrays were used to measure the mRNA of 84 genes in TLR-mediated pathways. Western blot, ELISA and immunohistochemistry were used to confirm the protein expression of genes of interest. RESULTS: We found that 2 TLRs (TLR1 and 2), 5 adaptor/interacting proteins (CD14, MD-1, HSPA1a, PGRP and Ticam2) and 13 target genes (Ccl2, Csf3, IL1a, IL1b, IL1r1, IL6, IL-10, TNFa, Tnfrsf1a, Cebpb, Clec4e, Ptgs2 and Cxcl10) were significantly up-regulated after injury. Administration of PROG significantly down-regulated three of the 13 increased target genes after TBI (Ccl-2, IL-1b and Cxcl-10), but did not inhibit the expression of any of the detected TLRs and adaptor/interacting proteins. Rather, PROG up-regulated the expression of one TLR (TLR9), 5 adaptor/interacting proteins, 5 effectors and 10 downstream target genes. We confirmed that Ccl-2, Cxcl-10, TLR2 and TLR9 proteins were expressed in brain tissue, a finding consistent with our observations of mRNA expression. CONCLUSION: The results demonstrate that TBI can increase gene expression in TLR-mediated pathways. PROG does not down-regulate the increased TLRs or their adaptor proteins in traumatically injured brain. Reduction of the observed inflammatory cytokines by PROG does not appear to be the result of inhibiting TLRs or their adaptors in the acute stage of TBI. PMID- 21549008 TI - A comparison of ultrasound and clinical examination in the detection of flexor tenosynovitis in early arthritis. AB - BACKGROUND: Tenosynovitis is widely accepted to be common in rheumatoid arthritis (RA) and postulated to be the first manifestation of RA, but its true prevalence in early disease and in particular the hand has not been firmly established. The aims of this study were first to investigate the frequency and distribution of finger flexor tenosynovitis using ultrasound in early arthritis, second to compare clinical examination with ultrasound (US) using the latter as the gold standard. METHODS: 33 consecutive patients who had who were initially diagnosed with polyarthritis and suspected of polyarthritis and clinical suspicion of inflammatory arthritis of the hands and wrists were assessed during consecutive, routine presentations to the rheumatology outpatient clinic. We scanned a total of 165 finger tendons and subsequent comparisons were made using clinical examination. RESULTS: Flexor tenosynovitis was found in 17 patients (51.5%) on ultrasound compared with 16 (48.4%) of all patients on clinical examination. Most commonly damaged joint involved on US was the second finger followed by the third, fifth, and fourth. Both modalities demonstrated more pathology on the second and third metacarpophalangeal (MCP) compared with the fourth and fifth MCP. A joint-by-joint comparison of US and clinical examination demonstrated that although the sensitivity, specificities and positive predictive values of clinical examination were relatively high, negative predictive value of clinical examination was low (0.23). CONCLUSIONS: Our study suggest that clinical examination can be a valuable tool for detecting flexor disease in view of its high specificity and positive predictive values, but a negative clinical examination does not exclude inflammation and an US should be considered. Further work is recommended to standardize definitions and image acquisition for peritendinous inflammation for ultrasound. PMID- 21549007 TI - CD248 facilitates tumor growth via its cytoplasmic domain. AB - BACKGROUND: Stromal fibroblasts participate in the development of a permissive environment for tumor growth, yet molecular pathways to therapeutically target fibroblasts are poorly defined. CD248, also known as endosialin or tumor endothelial marker 1 (TEM1), is a transmembrane glycoprotein expressed on activated fibroblasts. We recently showed that the cytoplasmic domain of CD248 is important in facilitating an inflammatory response in a mouse model of arthritis. Others have reported that CD248 gene inactivation in mice results in dampened tumor growth. We hypothesized that the conserved cytoplasmic domain of CD248 is important in regulating tumor growth. METHODS: Mice lacking the cytoplasmic domain of CD248 (CD248CyD/CyD) were generated and evaluated in tumor models, comparing the findings with wild-type mice (CD248WT/WT). RESULTS: As compared to the response in CD248WT/WT mice, growth of T241 fibrosarcomas and Lewis lung carcinomas was significantly reduced in CD248CyD/CyD mice. Tumor size was similar to that seen with CD248-deficient mice. Conditioned media from CD248CyD/CyD fibroblasts were less effective at supporting T241 fibrosarcoma cell survival. In addition to our previous observation of reduced release of activated matrix metalloproteinase (MMP)-9, CD248CyD/CyD fibroblasts also had impaired PDGF-BB induced migration and expressed higher transcripts of tumor suppressor factors, transgelin (SM22alpha), Hes and Hey1. CONCLUSIONS: The multiple pathways regulated by the cytoplasmic domain of CD248 highlight its potential as a therapeutic target to treat cancer. PMID- 21549010 TI - A systematic review of different models of home and community care services for older persons. AB - BACKGROUND: Costs and consumer preference have led to a shift from the long-term institutional care of aged older people to home and community based care. The aim of this review is to evaluate the outcomes of case managed, integrated or consumer directed home and community care services for older persons, including those with dementia. METHODS: A systematic review was conducted of non-medical home and community care services for frail older persons. MEDLINE, PsycINFO, CINAHL, AgeLine, Scopus and PubMed were searched from 1994 to May 2009. Two researchers independently reviewed search results. RESULTS: Thirty five papers were included in this review. Evidence from randomized controlled trials showed that case management improves function and appropriate use of medications, increases use of community services and reduces nursing home admission. Evidence, mostly from non-randomized trials, showed that integrated care increases service use; randomized trials reported that integrated care does not improve clinical outcomes. The lowest quality evidence was for consumer directed care which appears to increase satisfaction with care and community service use but has little effect on clinical outcomes. Studies were heterogeneous in methodology and results were not consistent. CONCLUSIONS: The outcomes of each model of care differ and correspond to the model's focus. Combining key elements of all three models may maximize outcomes. PMID- 21549009 TI - From planning to practice: building the national network for the Surveillance of Severe Maternal Morbidity. AB - BACKGROUND: Improving maternal health is one of the Millennium Development Goals for 2015. Recently some progress has been achieved in reducing mortality. On the other hand, in developed regions, maternal death is a relatively rare event compared to the number of cases of morbidity; hence studying maternal morbidity has become more relevant. Electronic surveillance systems may improve research by facilitating complete data reporting and reducing the time required for data collection and analysis. Therefore the purpose of this study was to describe the methods used in elaborating and implementing the National Network for the Surveillance of Severe Maternal Morbidity in Brazil. METHODS: The project consisted of a multicenter, cross-sectional study for the surveillance of severe maternal morbidity including near-miss, in Brazil. RESULTS: Following the development of a conceptual framework, centers were selected for inclusion in the network, consensus meetings were held among the centers, an electronic data collection system was identified, specific software and hardware tools were developed, research material was prepared, and the implementation process was initiated and analyzed. CONCLUSION: The conceptual framework developed for this network was based on the experience acquired in various studies carried out in the area over recent years and encompasses maternal and perinatal health. It is innovative especially in the context of a developing country. The implementation of the project represents the first step towards this planned management. The system online elaborated for this surveillance network may be used in further studies in reproductive and perinatal health. PMID- 21549011 TI - Characterization of nonstructural protein 3 of a neurovirulent Japanese encephalitis virus strain isolated from a pig. AB - BACKGROUND: Japanese encephalitis virus (JEV), as a re-emerging virus that causes 10,000-15,000 human deaths from encephalitis in the world each year, has had a significant impact on public health. Pigs are the natural reservoirs of JEV and play an important role in the amplification, dispersal and epidemiology of JEV. The nonstructural protein 3 (NS3) of JEV possesses enzymatic activities of serine protease, helicase and nucleoside 5'-triphosphatase, and plays important roles in viral replication and pathogenesis. RESULTS: We characterized the NS3 protein of a neurovirulent strain of JEV (SH-JEV01) isolated from a field-infected pig. The NS3 gene of the JEV SH-JEV01 strain is 1857 bp in length and encodes protein of approximately 72 kDa with 99% amino acid sequence identity to that of the representative immunotype strain JaGAr 01. The NS3 protein was detectable 12 h post-infection in a mouse neuroblastoma cell line, Neuro-2a, and was distributed in the cytoplasm of cells infected with the SH-JEV01 strain of JEV. In the brain of mice infected with the SH-JEV01 strain of JEV, NS3 was detected in the cytoplasm of neuronal cells, including pyramidal neurons of the cerebrum, granule cells, small cells and Purkinje cells of the cerebellum. CONCLUSIONS: The NS3 protein of a neurovirulent strain of JEV isolated from a pig was characterized. It is an approximately 72 kDa protein and distributed in the cytoplasm of infected cells. The Purkinje cell of the cerebellum is one of the target cells of JEV infection. Our data should provide some basic information for the study of the role of NS3 in the pathogenesis of JEV and the immune response. PMID- 21549012 TI - mRNA transcript quantification in archival samples using multiplexed, color-coded probes. AB - BACKGROUND: A recently developed probe-based technology, the NanoString nCounterTM gene expression system, has been shown to allow accurate mRNA transcript quantification using low amounts of total RNA. We assessed the ability of this technology for mRNA expression quantification in archived formalin-fixed, paraffin-embedded (FFPE) oral carcinoma samples. RESULTS: We measured the mRNA transcript abundance of 20 genes (COL3A1, COL4A1, COL5A1, COL5A2, CTHRC1, CXCL1, CXCL13, MMP1, P4HA2, PDPN, PLOD2, POSTN, SDHA, SERPINE1, SERPINE2, SERPINH1, THBS2, TNC, GAPDH, RPS18) in 38 samples (19 paired fresh-frozen and FFPE oral carcinoma tissues, archived from 1997-2008) by both NanoString and SYBR Green I fluorescent dye-based quantitative real-time PCR (RQ-PCR). We compared gene expression data obtained by NanoString vs. RQ-PCR in both fresh-frozen and FFPE samples. Fresh-frozen samples showed a good overall Pearson correlation of 0.78, and FFPE samples showed a lower overall correlation coefficient of 0.59, which is likely due to sample quality. We found a higher correlation coefficient between fresh-frozen and FFPE samples analyzed by NanoString (r = 0.90) compared to fresh frozen and FFPE samples analyzed by RQ-PCR (r = 0.50). In addition, NanoString data showed a higher mean correlation (r = 0.94) between individual fresh-frozen and FFPE sample pairs compared to RQ-PCR (r = 0.53). CONCLUSIONS: Based on our results, we conclude that both technologies are useful for gene expression quantification in fresh-frozen or FFPE tissues; however, the probe-based NanoString method achieved superior gene expression quantification results when compared to RQ-PCR in archived FFPE samples. We believe that this newly developed technique is optimal for large-scale validation studies using total RNA isolated from archived, FFPE samples. PMID- 21549013 TI - Prevalence of human herpesvirus 8 infection in systemic lupus erythematosus. AB - BACKGROUND: For decades, scientists have tried to understand the environmental factors involved in the development of systemic lupus erythematosus (SLE), in which viral infections was included. Previous studies have identified Epstein Barr virus (EBV) to incite SLE. Human herpesvirus 8 (HHV-8), another member of the gammaherpesvirus family, shares a lot in common with EBV. The characteristics of HHV-8 make it a well-suited candidate to trigger SLE. RESULTS: In the present study, serum samples from patients (n = 108) with diagnosed SLE and matched controls (n = 122) were collected, and the prevalence of HHV-8 was compared by a virus-specific nested PCR and a whole virus enzyme-linked immunoassay (EIA). There was significant difference in the prevalence of HHV-8 DNA between SLE patients and healthy controls (11 of 107 vs 1 of 122, p = 0.001); significant difference was also found in the detection of HHV-8 antibodies (19 of 107 vs 2 of 122, p < 0.001).We also detected the antibodies to Epstein-Barr virus viral capsid antigen (EBV-VCA) and Epstein-Barr nuclear antigen-1 (EBNA-1). Both patients and controls showed high seroprevalence with no significant difference (106 of 107 vs 119 of 122, p = 0.625). CONCLUSION: Our finding indicated that there might be an association between HHV-8 and the development of SLE. PMID- 21549014 TI - Clinical implementation of whole-genome array CGH as a first-tier test in 5080 pre and postnatal cases. AB - BACKGROUND: Array comparative genomic hybridization (CGH) is currently the most powerful method for detecting chromosomal alterations in pre and postnatal clinical cases. In this study, we developed a BAC based array CGH analysis platform for detecting whole genome DNA copy number changes including specific micro deletion and duplication chromosomal disorders. Additionally, we report our experience with the clinical implementation of our array CGH analysis platform. Array CGH was performed on 5080 pre and postnatal clinical samples from patients referred with a variety of clinical phenotypes. RESULTS: A total of 4073 prenatal cases (4033 amniotic fluid and 40 chorionic villi specimens) and 1007 postnatal cases (407 peripheral blood and 600 cord blood) were studied with complete concordance between array CGH, karyotype and fluorescence in situ hybridization results. Among 75 positive prenatal cases with DNA copy number variations, 60 had an aneuploidy, seven had a deletion, and eight had a duplication. Among 39 positive postnatal cases samples, five had an aneuploidy, 23 had a deletion, and 11 had a duplication. CONCLUSIONS: This study demonstrates the utility of using our newly developed whole-genome array CGH as first-tier test in 5080 pre and postnatal cases. Array CGH has increased the ability to detect segmental deletion and duplication in patients with variable clinical features and is becoming a more powerful tool in pre and postnatal diagnostics. PMID- 21549015 TI - A functional mutation at position -155 in porcine APOE promoter affects gene expression. AB - BACKGROUND: Apolipoprotein E, a component of the plasma lipoproteins, plays an important role in the transport and metabolism of cholesterol and other lipids. Three single nucleotide polymorphisms (SNPs) -491A>T, -219T>G and +113G>C in the regulatory region of human apolipoprotein E gene (APOE) change the promoter activity and are associated with a wide variety of disorders including Alzheimer disease (AD). Functional SNPs in porcine APOE gene 5' regulatory region have not been explored. RESULTS: We examined SNPs within this region (from -831 to +855), and the analysis revealed that the T>A SNP at position -155 among these three polymorphism sites (-440, -155, +501) was found to exert a marked influence on the transcription of the porcine APOE gene. Electrophoretic mobility shift assays showed that the binding affinity of oligonucletides containing the -155A to transcription factor(s) was stronger than that of the -155T. Transient transfection assays and quantitative real-time PCR results revealed that the 155T>A variant enhanced the activity of the APOE promoter and was associated with increased APOE mRNA levels in vivo. CONCLUSIONS: These data suggest that the 155T>A mutation in the promoter region of the porcine APOE gene is an important functional variant. The results provided new insights into aspects of pig genetics and might also facilitate the application of pigs in biomedical studies addressing important human diseases. PMID- 21549016 TI - Role of Potash Alum in hepatitis C virus transmission at barber's shop. AB - Hepatitis C virus (HCV) is the main cause of severe liver disease, including hepatocellular carcinoma, cirrhosis and end stage liver disease. In Pakistan most of HCV positive patients have history of facial/armpit shaving from barbers. 79% of barbers are rubbing Potash Alum stone on facial shaving cuts. Dark blood spots are analyzed on Potash Alum stones being used at different barber shops. The aim of the study was to check the viability of hepatitis C virus on potash alum stone being used at barber shops. Blood samples from HCV positive patients were taken and treated with 0.1, 0.2, 0.3, 0.4 and 0.5 molar concentrations of Potash Alum for different periods of time. Blood was centrifuged to isolate the serum; HCV RNA was extracted from serum and subjected to first strand synthesis and PCR. PCR fragments were confirmed by sequencing. PCR amplification was observed in all the samples, treated with different concentrations of Potash Alum, indicated that the virus remains alive on Potash Alum stone for a long period of time. Potash Alum being used by barbers on facial shaving cuts has definite role in HCV transmission in Pakistani population. Therefore use of Potash Alum stone should be banned on facial shaving cuts at barber shops. PMID- 21549017 TI - Becoming a general practitioner--which factors have most impact on career choice of medical students? AB - BACKGROUND: In Germany, there is a shortage of young physicians in several specialties, the situation of general practitioners (GP) being especially precarious. The factors influencing the career choice of German medical students are poorly understood. This study aims to identify factors influencing medical students' specialty choice laying a special focus on general practice. METHODS: The study was designed as a cross-sectional survey. In 2010, students at the five medical schools in the federal state of Baden-Wuerttemberg (Germany) filled out an online-questionnaire. On 27 items with 5-point Likert scales, the students rated the importance of specified individual and occupational aspects. Furthermore, students were asked to assign their intended medical specialty. RESULTS: 1,299 students participated in the survey. Thereof, 1,114 students stated a current choice for a specialty, with 708 students choosing a career in one of the following 6 specialties: internal medicine, surgery, gynaecology and obstetrics, paediatrics, anaesthetics and general practice. Overall, individual aspects ('Personal ambition', 'Future perspective', 'Work-life balance') were rated as more important than occupational aspects (i.e. 'Variety in job', 'Job related ambition') for career choice. For students favouring a career as a GP individual aspects and the factor 'Patient orientation' among the occupational aspects were significantly more important and 'Job-related ambition' less important compared to students with other specialty choices. CONCLUSIONS: This study confirms that future GPs differ from students intending to choose other specialties particularly in terms of patient-orientation and individual aspects such as personal ambition, future perspective and work-life balance. Improving job-conditions in terms of family compatibility and work-life balance could help to increase the attractiveness of general practice. Due to the shortage of GPs those factors should be made explicit at an early stage at medical school to increase the number of aspirants for general practice. PMID- 21549018 TI - Process evaluation of a community-based adolescent obesity prevention project in Tonga. AB - BACKGROUND: The rising burden of obesity in Tonga is alarming. The promotion of healthy behaviours and environments requires immediate urgent action and a multi sectoral approach. A three-year community based study titled the Ma'alahi Youth Project (MYP) conducted in Tonga from 2005-2008 aimed to increase the capacity of the whole community (schools, churches, parents and adolescents) to promote healthy eating and regular physical activity and to reduce the prevalence of overweight and obesity amongst youth and their families. This paper reflects on the process evaluation for MYP, against a set of Best Practice Principles for community-based obesity prevention. METHODS: MYP was managed by the Fiji School of Medicine. A team of five staff in Tonga were committed to planning, implementation and evaluation of a strategic plan, the key planks of which were developed during a two day community workshop. Intervention activities were delivered in villages, churches and schools, on the main island of Tongatapu. Process evaluation data covering the resource utilisation associated with all intervention activities were collected, and analysed by dose, frequency and reach for specific strategies. The action plan included three standard objectives around capacity building, social marketing and evaluation; four nutrition; two physical activity objectives; and one around championing key people as role models. RESULTS: While the interventions included a wide mix of activities straddling across all of these objectives and in both school and village settings, there was a major focus on the social marketing and physical activity objectives. The intervention reach, frequency and dose varied widely across all activities, and showed no consistent patterns. CONCLUSIONS: The adolescent obesity interventions implemented as part of the MYP program comprised a wide range of activities conducted in multiple settings, touched a broad spectrum of the population (wider than the target group), but the dose and frequency of activities were generally insufficient and not sustained. Also the project confirmed that, while the MYP resulted in increased community awareness of healthy behaviours, Tonga is still in its infancy in terms of conducting public health research and lacks research infrastructure and capacity. PMID- 21549020 TI - Carework and caring: A path to gender equitable practices among men in South Africa? AB - BACKGROUND: The purpose of this study was to examine the relationship between men who engage in carework and commitment to gender equity. The context of the study was that gender inequitable masculinities create vulnerability for men and women to HIV and other health concerns. Interventions are being developed to work with masculinity and to 'change men'. Researchers now face a challenge of identifying change in men, especially in domains of their lives beyond relations with women. Engagement in carework is one suggested indicator of more gender equitable practice. METHODS: A qualitative approach was used. 20 men in three South African locations (Durban, Pretoria/Johannesburg, Mthatha) who were identified as engaging in carework were interviewed. The men came from different backgrounds and varied in terms of age, race and socio-economic status. A semi-structured approach was used in the interviews. RESULTS: Men were engaged in different forms of carework and their motivations to be involved differed. Some men did carework out of necessity. Poverty, associated with illness in the family and a lack of resources propelled some men into carework. Other men saw carework as part of a commitment to making a better world. 'Care' interpreted as a functional activity was not enough to either create or signify support for gender equity. Only when care had an emotional resonance did it relate to gender equity commitment. CONCLUSIONS: Engagement in carework precipitated a process of identity and value transformation in some men suggesting that support for carework still deserves to be a goal of interventions to 'change men'. Changing the gender of carework contributes to a more equitable gender division of labour and challenges gender stereotypes. Interventions that promote caring also advance gender equity. PMID- 21549019 TI - Defective interfering virus protects elderly mice from influenza. AB - BACKGROUND: We have identified and characterised a defective-interfering (DI) influenza A virus particles containing a highly deleted segment 1 RNA that has broad-spectrum antiviral activity. In young adult mice it exerts protection against several different subtypes of influenza A virus (defined here as homologous or genetically compatible protection) and against a paramyxovirus and an influenza B virus (heterologous or genetically unrelated protection). Homologous protection is mediated by replication competition between the deleted and full-length genomes, and heterologous protection occurs through stimulation of innate immunity, especially interferon type I. METHODS: A single dose of the protective DI virus was administered intranasally to elderly mice at -7, -1 and +1 days relative to intranasal challenge with influenza A virus. RESULTS: A single dose of the DI virus given 1 or 7 days protected elderly mice, reducing a severe, sometimes fatal disease to a subclinical or mild infection. In contrast, all members of control groups treated with inactivated DI virus before challenge became extremely ill and most died. Despite the subclinical/mild nature of their infection, protected mice developed solid immunity to a second infectious challenge. CONCLUSIONS: The defective interfering virus is effective in preventing severe influenza A in elderly mice and may offer a new approach to protection of the human population. PMID- 21549021 TI - Epilepsy (partial). AB - INTRODUCTION: About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of starting antiepileptic drug treatment following a single seizure? What are the effects of drug monotherapy in people with partial epilepsy? What are the effects of additional drug treatments in people with drug-resistant partial epilepsy? What is the risk of relapse in people in remission when withdrawing antiepileptic drugs? What are the effects of behavioural and psychological treatments for people with epilepsy? What are the effects of surgery in people with drug-resistant temporal lobe epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiepileptic drugs after a single seizure; monotherapy for partial epilepsy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second line drugs for drug-resistant partial epilepsy (allopurinol, eslicarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, losigamone, oxcarbazepine, retigabine, tiagabine, topiramate, vigabatrin, or zonisamide); antiepileptic drug withdrawal for people with partial or generalised epilepsy who are in remission; behavioural and psychological treatments for partial or generalised epilepsy (biofeedback, cognitive behavioural therapy (CBT), educational programmes, family counselling, relaxation therapy (alone or plus behavioural modification therapy, yoga); and surgery for drug-resistant temporal lobe epilepsy ( lesionectomy, temporal lobectomy, vagus nerve stimulation as adjunctive therapy). PMID- 21549022 TI - Diabetes: glycaemic control in type 1. AB - INTRODUCTION: Type 1 diabetes occurs when destruction of the pancreatic islet beta cells, usually attributable to an autoimmune process, causes the pancreas to produce too little insulin or none at all. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of intensive treatment programmes, psychological interventions, and educational interventions in adults and adolescents with type 1 diabetes? What are the effects of different insulin regimens or frequency of blood glucose monitoring in adults and adolescents with type 1 diabetes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 42 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: different frequencies of insulin administration (continuous subcutaneous insulin infusion compared with multiple daily subcutaneous insulin injections), different frequencies of blood glucose self-monitoring (including continuous blood glucose monitoring compared with intermittent/conventional monitoring), educational interventions, intensive treatment programmes, and psychological interventions. PMID- 21549023 TI - Low back pain (acute). AB - INTRODUCTION: Low back pain affects about 70% of people in resource-rich countries at some point in their lives. Acute low back pain can be self-limiting; however, 1 year after an initial episode, as many as 33% of people still have moderate-intensity pain and 15% have severe pain. Acute low back pain has a high recurrence rate; 75% of those with a first episode have a recurrence. Although acute episodes may resolve completely, they may increase in severity and duration over time. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments for acute low back pain? What are the effects of local injections for acute low back pain? What are the effects of non-drug treatments for acute low back pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 49 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics (paracetamol, opioids), back exercises, back schools, bed rest, behavioural therapy, electromyographic biofeedback, epidural corticosteroid injections, lumbar supports, massage, multidisciplinary treatment programmes, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), spinal manipulation, temperature treatments (short-wave diathermy, ultrasound, ice, heat), traction, and transcutaneous electrical nerve stimulation (TENS). PMID- 21549024 TI - GC-MS and GC-IRD studies on the ring isomers of N-methyl-2-methoxyphenyl-3 butanamines (MPBA) related to 3,4-MDMA. AB - The mass spectra of the controlled substance 3,4-MDMA and its regioisomer 2,3 MDMA are characterized by an imine fragment base peak at m/z 58 and additional fragments at m/z 135/136 for the methylenedioxybenzyl cation and radical cation, respectively. Three positional ring methoxy isomers of N-methyl-2-(methoxyphenyl) 3-butanamine (MPBA) have an isobaric relationship to 2,3- and 3,4-MDMA. All five compounds have the same molecular weight and produce similar EI mass spectra. This lack of mass spectral specificity for the isomers in addition to the possibility of chromatographic co-elution could result in misidentification. The lack of reference materials for the potential imposter molecules constitutes a significant analytical challenge. Perfluoroacylation of the amine group reduced the nitrogen basicity and provided individual fragmentation pathways for discrimination among these compounds based on unique fragment ions and the relative abundance of common ions. Studies using gas chromatography with infrared detection provided additional structure-IR spectra relationships. The underivatized amines and the perfluoroacylated derivatives (PFPA and HFBA) were resolved by capillary gas chromatography on a 100% dimethylpolysiloxane stationary phase. The perfluoroacylated derivatives showed better resolution on a cyclodextrin modified stationary phase. PMID- 21549025 TI - Using fast gas chromatography-mass spectrometry with auto-headspace solid-phase microextraction to determine ultra trace residues of organophosphorus pesticides in fruits. AB - Organophosphorus pesticides (OPs) in apple and tomato were determined by using fast gas chromatography-mass spectrometry (FGC-MS) coupled with auto-headspace solid-phase microextraction (SPME). The experimental conditions of FGC were investigated and developed. Three different fibers were studied and compared and it was found that the polydimethysiloxane (PDMS) was the best. Factors affecting the extract efficiency, such as extraction time, temperature, ion strength, agitator speed, and content of organic solvents, were investigated and optimized. The limits of detection (LOD) of OPs were achieved between 0.002 ng/g and 0.955 ng/g; the RSD was less than 20.9%, and the recoveries were from 79% to 117%. For most commercial fruit samples, ultra trace residues of OPs were found, mainly on the surface, and their concentrations were generally lower than LOD of conventional methods. PMID- 21549026 TI - Determination of nitrogen mustard hydrolysis products in rat urine samples using GC-MS. AB - A gas chromatographic-mass spectrometric method was developed, validated and demonstrated by measuring the levels of nitrogen mustard hydrolysis products in the urine collected from dosed rats. The recovery values for trimethylsilyl derivatives of EDEA and MDEA are between 82-95% and 88-112%, respectively. In vivo studies performed by using three different doses (0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg) of HN2 base of nitrogen mustard. MDEA concentrations were between 43.1 232.2 ng/mL. The limit of detection (S/N = 3) values are 2.5 ng/mL and 1.6 ng/mL for EDEA and MDEA, respectively, and the precision of the method in terms of RSD is between 5-8%. PMID- 21549027 TI - Determination of atenolol in human urine by gas chromatography-mass spectrometry method. AB - A sensitive and efficient method was developed for the determination of atenolol in human urine by gas chromatography-mass spectrometry (GC-MS). Atenolol and metoprolol (internal standard, IS) were extracted from human urine with a mixture of chloroform and butanol at basic pH with liquid-liquid extraction. The extracts were derivatized with N-Methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) and analyzed by GC-MS using a capillary column. The standard curve was linear (r = 0.99) over the concentration range of 50-750 ng/mL. Intra- and inter-day precision, expressed as the relative standard deviation were less than 5.0%, and accuracy (relative error) was better than 7.0%. The analytical recovery of atenolol from human urine has averaged 91%. The limit of quantification was 50 ng/mL. Also, the method was successfully applied to a patient with hypertension who had been given an oral tablet of 50 mg atenolol. PMID- 21549028 TI - Fast gas chromatographic separation of biodiesel. AB - A high-speed gas chromatographic method has been developed to determine the FAME distribution of B100 biodiesel. The capillary column used in this work has dimensions of 20 m * 0.100 mm and is coated with a polyethylene glycol film. Analysis times are typically on the order of 4-5 min depending upon the composition of the B100. The application of this method to a variety of vegetable and animal derived B100 is demonstrated. Quantitative results obtained with this method were in close agreement with those obtained by a more conventional approach on a 100 m column. The method, coupled with solid-phase extraction, was also found suitable to determine the B100 content of biodiesel-diesel blends. PMID- 21549029 TI - Determination of dihydroxyacetone and glycerol in fermentation process by GC after n-methylimidazole catalyzed acetylation. AB - A gas chromatographic method that accurately measures glycerol and dihydroxyacetone from a fermentation broth is described in this paper. The method incorporates a sample derivatization reaction using n-methylimidazole as catalyst in the presence of acetic anhydride. Resulting derivatives are separated on a DB 5 capillary column and flame ionization detector. Results show that 10 MUL n methylimidazole and 75 MUL acetic anhydride are sufficient to complete the acetylation for glycerol and dihydroxyacetone at room temperature for 5 min. The present method exhibits good linearity at a concentration range of 1-100 g/L with excellent regression (R(2) > 0.9997). The limits of detection are 0.025 and 0.013 g/L for dihydroxyacetone and glycerol, respectively. The method has been successfully applied to the monitoring and control of the fermentation process, and recoveries are in the range of 95.5-98.8% with relative standard deviations below 1%. PMID- 21549030 TI - Improved HRGC separation of cis, trans CLA isomers as Diels-Alder adducts of alkyl esters. AB - This paper reports the separation of four isomers of conjugated linoleic acid (CLA), c,t/t,c-8,10; c,t/t,c-9,11; c,t/t,c-10,12; c,t/t,c-11,13, after reaction of esterification with aliphatic alcohols of different chain length and adduct formation with 4-methyl-1,2,4-triazoline-3,5-dione (MTAD). The high resolution gas chromatographic analyses were carried out using a simple 50-m cyanopropyl polysiloxane capillary column both with a flame ionization detector and a mass spectrometer. The resolution between the two pair of isomers: c,t/t,c-9,11 and c,t/t,c-10,12 and between c,t/t,c-10,12 and c,t/t,c-11,13 isomers were good for all the investigated alkyl esters and increased with the chain length of alcohol esterified to carboxylic moiety of CLA isomers. The most interesting result was relative to the c,t/t,c-8,10 and c,t/t,c-9,11 isomers, critical pair of isomers also when analyzed with a 120-m cyanopropyl polysiloxane capillary column; their resolution also increased from methyl to hexyl esters of CLA isomers and reached an acceptable value (0.8) in the case of hexyl esters. The best resolutions of the four considered CLA isomers were obtained with the hexyl esters of MTAD adducts of the isomers, without excessive analysis time. This method was useful and simple to evaluate the profile of the four main c,t isomers in commercial CLA samples. PMID- 21549031 TI - A review of chromatographic characterization techniques for biodiesel and biodiesel blends. AB - This review surveys chromatographic technology that has been applied to the characterization of biodiesel and its blends. Typically, biodiesel consists of fatty acid methyl esters produced by transesterification of plant or animal derived triacylglycerols. Primary attention is given to the determination of trace impurities in biodiesel, such as methanol, glycerol, mono-, di-, and triacylglycerols, and sterol glucosides. The determination of the fatty acid methyl esters, trace impurities in biodiesel, and the determination of the biodiesel content of commercial blends of biodiesel in conventional diesel are also addressed. PMID- 21549032 TI - Development of an HPLC method for the determination of anidulafungin in human plasma and saline. AB - An ultraviolet high-performance liquid chromatography (HPLC) method was developed to analyze anidulafungin in human plasma and saline. A reversed-phase column was used with a UV detector set at 310 nm. The mobile phase consisted of methanol and ammonium phosphate buffer at a flow rate of 1 mL/min. Micafungin was used as the internal standard. Both standard curves were linear over a range of 1 to 10 MUg/mL. The intra-assay relative standard deviations (RSD) for plasma and saline matrices were 1.60-1.81% and 1.96-3.70%, respectively. The inter-assay RSD for plasma and saline matrices were 2.41-7.25% and 1.31-3.16%, respectively. This method successfully recapitulated anidulafungin plasma concentrations previously analyzed by HPLC-tandem mass spectrometry with precision and accuracy of 6.9% and 1.59%, respectively. PMID- 21549033 TI - A new total antioxidant potential measurements using RP-HPLC assay with fluorescence detection. AB - In this paper, an improved total antioxidant potential (TAP) estimation using high-performance liquid chromatographic (HPLC) assay with fluorometric detection has been described. The principle of this method is based on the hydroxyl radicals generated in the Fenton-like reaction and subsequently detected using hydroxyterephthalic acid (HTPA), which is a reaction product of hydroxyl radicals and terephthalic acid (TPA), working as a sensing compound. HTPA quantity in the samples was measured by fluorescence detector working at excitation and emission wavelengths equal to 312 and 428 nm, respectively. A number of key experimental conditions including the influence of the reaction (incubation) time on the surface areas of HTPA peaks, concentration of Fe(II) ions as well as the influence of concentration of TPA on the surface area of the chromatographic peak of HTPA were optimized to the characteristic feature of TAP measurements. The elaborated assay has been used to evaluate TAP values of selected low-molecular mass compounds like pyrogallol, tryptamine, and n-alcohols (methanol, ethanol, and n-propanol) as well as chlorogenic and ascorbic acids and benzoic acid derivatives, which are commonly present in the food samples. PMID- 21549034 TI - Development and validation of a single RP-HPLC assay method for analysis of bulk raw material batches of four parabens that are widely used as preservatives in pharmaceutical and cosmetic products. AB - A stability-indicating, robust, fast, and user friendly reversed-phase high performance liquid chromatographic (RP-HPLC) assay method has been developed and validated for the analysis of commercial raw material batches of methylparaben, ethylparaben, propylparaben, and butylparaben. These four parabens are widely used as preservatives in pharmaceutical and cosmetic products. Accurate assay value of each of the parabens in their respective commercial lots is critical to determine the correct weight of the paraben that is needed to obtain the target concentration of the paraben in a specific lot of pharmaceutical or cosmetic products. Currently, there are no single HPLC assay methods (validated as per ICH requirements) available in the literature that can be used to analyze the commercial lots of each of the four parabens. The analytical method reported herein analyzes all four parabens in less than 10 min. The method presented in this report was successfully validated as per ICH guidelines. Therefore, this method can be implemented in QC laboratories to analyze and assay the commercial bulk lots of the four parabens. PMID- 21549035 TI - Quantitative determination of imatinib in human plasma with high-performance liquid chromatography and ultraviolet detection. AB - A simple and sensitive high-performance liquid chromatography (HPLC) method was developed to quantitate imatinib in human plasma. Imatinib and the internal standard dasatinib were separated using a mobile phase of 0.5% KH(2)PO(4) (pH3.5) acetonitrile-methanol (55:25:20, v/v/v) on a CAPCELL PAK C18 MG II column (250 mm * 4.6 mm) at a flow rate of 0.5 mL/min and measurement at UV 265 nm. Analysis required 100 MUL of plasma and involved a solid phase extraction with an Oasis HLB cartridge, which gave recoveries of imatinib from 73% to 76%. The lower limit of quantification for imatinib was 10 ng/mL. The linear range of this assay was between 10 and 5000 ng/mL (regression line r(2) > 0.9992). Inter- and intra-day coefficients of variation were less than 11.9% and accuracies were within 8.3% over the linear range. The plasma concentrations of imatinib obtained by our present method were almost the same as those assayed by an LC-MS-MS method at the Toray Research Center, Inc. This method can be applied effectively to measure imatinib concentrations in clinical samples. PMID- 21549036 TI - Descriptive epidemiology of hereditary angioedema hospitalizations in the United States, 2004-2007. AB - Hereditary angioedema (HAE) is a rare inherited disorder of complement factor C1 inhibitor. There are ~6000 HAE cases in the United States, nearly one-half of whom suffer a monthly exacerbation. Little is known about hospital use patterns by patients with HAE attacks in the United States. This study was designed to examine burden, epidemiology, and outcomes of hospitalizations among HAE patients. We evaluated epidemiology, resource use, and discharge destinations of HAE (ICD-9-CM code 277.6) hospitalizations within the NIS, part of Agency's for Healthcare Research and Quality Healthcare Costs and Utilization Project in 2004 through 2007. There were 10,125 hospitalizations with HAE, of which 3216 (31.8%) had HAE as the principal diagnosis (HAE-PD). Two-thirds of all HAE hospitalizations were among women, and 60% were white. Hypertension was the most common comorbidity (26.9%, all HAE, and 28.0%, HAE-PD). Mortality was 1.4% in HAE and 0.3% in the HAE-PD group. Mean hospital length of stay (3.7, 95% CI 3.0-4.4 days vs. 5.0, 95% CI 4.6-5.4 days) and costs ($4,760, 95% CI $3,612-$5,907 vs. $8,383, 95% CI $7,432-$9,334) were lower in HAE-PD than in the HAE cohort. Although >80% in each group were discharged home routinely, 15.9% of HAE and 4.9% of HAE-PD required either home health care or a transfer to another short-term hospital or a skilled nursing facility. HAE hospitalization volume is substantial. Because diagnostic uncertainty is likely, HAE and its related resource use may be underestimated. HAE prevention strategies need to be examined in the context of these outcomes. PMID- 21549037 TI - Studies on a novel gelatin sponge: preparation and characterization of cross linked gelatin scaffolds using 2-chloro-1-methylpyridinium iodide as a zero length cross-linker. AB - We prepared a novel porous gelatin (GEL) sponge which was cross-linked (CL) with a zero-length crosslinker of 2-chloro-1-methylpyridinium iodide (CMPI), and compared CPMI with 1-ethyl-3,3-dimethylaminoproplycarbodiimide (EDC). The ninhydrin assay indicated that the CMPI-CL-GEL sponge had a higher degree of cross-linking than the EDC-CL-GEL sponge at cross-linking saturation. In contrast, the EDC-CL-GEL sponge demonstrated poor water uptake and a much slower enzymatic degradation rate than the CMPI-CL-GEL sponge. Scanning electron microscopy (SEM) images of the gelatin sponge fabricated using a gradient frozen lyophilization method showed uniformly distributed and interconnected pores. Human 3T3 fibroblasts were successfully seeded onto the scaffolds, and cell proliferation was sustained on all CL-GEL sponges. CMPI-CL-GEL sponges demonstrated significantly increased cell numbers after day 1, and cell numbers steadily rose from day 1 to 12. Meanwhile, the CMPI-CL-GEL sponge had a higher cell number than the EDC-CL-GEL sponge (P < 0.05) by day 4. In vitro studies with 3T3 fibroblasts demonstrated an increased cell viability for those cells grown on sponges cross-linked with CMPI compared to those cross-linked with EDC. SEM images revealed attachment and spreading of cells, the CMPI-CL-GEL sponges had more cells that had elongated, migrated, and formed interconnected networks with neighboring cells. PMID- 21549039 TI - Quantitative assessment of the microbial risk of leafy greens from farm to consumption: preliminary framework, data, and risk estimates. AB - This project was undertaken to relate what is known about the behavior of Escherichia coli O157:H7 under laboratory conditions and integrate this information to what is known regarding the 2006 E. coli O157:H7 spinach outbreak in the context of a quantitative microbial risk assessment. The risk model explicitly assumes that all contamination arises from exposure in the field. Extracted data, models, and user inputs were entered into an Excel spreadsheet, and the modeling software @RISK was used to perform Monte Carlo simulations. The model predicts that cut leafy greens that are temperature abused will support the growth of E. coli O157:H7, and populations of the organism may increase by as much a 1 log CFU/day under optimal temperature conditions. When the risk model used a starting level of -1 log CFU/g, with 0.1% of incoming servings contaminated, the predicted numbers of cells per serving were within the range of best available estimates of pathogen levels during the outbreak. The model predicts that levels in the field of -1 log CFU/g and 0.1% prevalence could have resulted in an outbreak approximately the size of the 2006 E. coli O157:H7 outbreak. This quantitative microbial risk assessment model represents a preliminary framework that identifies available data and provides initial risk estimates for pathogenic E. coli in leafy greens. Data gaps include retail storage times, correlations between storage time and temperature, determining the importance of E. coli O157:H7 in leafy greens lag time models, and validation of the importance of cross-contamination during the washing process. PMID- 21549040 TI - Effect of repeated irrigation with water containing varying levels of total organic carbon on the persistence of Escherichia coli O157:H7 on baby spinach. AB - The California lettuce and leafy greens industry has adopted the Leafy Greens Marketing Agreement (LGMA), which allows for 126 most-probable-number (MPN) Escherichia coli per 100 ml in irrigation water. Repeat irrigation of baby spinach plants with water containing E. coli O157:H7 and different levels of total organic carbon (TOC) was used to determine the epiphytic survival of E. coli O157:H7. Three irrigation treatments (0 ppm of TOC, 12 or 15 ppm of TOC, and 120 or 150 ppm of TOC) were prepared with bovine manure containing E. coli O157:H7 at either low (0 to 1 log CFU/100 ml) or high (5 to 6 log CFU/100 ml) populations, and sprayed onto baby spinach plants in growth chambers by using a fine-mist airbrush. MPN and direct plating techniques were used to determine the E. coli O157:H7 populations on the aerial plant tissue. Plants irrigated with high E. coli O157:H7 populations, regardless of TOC levels, showed a 3-log reduction within the first 24 h. Low levels of E. coli O157:H7 were observed for up to 16 days on all TOC treatments, ranging from 76.4 MPN per plant (day 1) to 0.40 MPN per plant (day 16). No viable cells were detected on spinach tissue 24 h after irrigation with water containing fewer than 126 CFU/100 ml E. coli O157:H7. Under growth chamber conditions in this study, E. coli O157:H7 populations in irrigation water that complies with the LGMA standards will not persist for more than 24 h when applied onto foliar surfaces of spinach plants. PMID- 21549041 TI - Effect of modified atmosphere packaging on the persistence and expression of virulence factors of Escherichia coli O157:H7 on shredded iceberg lettuce. AB - Fresh-cut leafy greens contaminated with Escherichia coli O157:H7 have caused foodborne outbreaks. Packaging conditions, coupled with abusive storage temperatures of contaminated lettuce, were evaluated for their effect on the potential virulence of E. coli O157:H7. Shredded lettuce was inoculated with 5.58 and 3.98 log CFU E. coli O157:H7 per g and stored at 4 and 15 degrees C, respectively, for up to 10 days. Lettuce was packaged under treatment A (modified atmosphere packaging conditions used for commercial fresh-cut produce, in gas permeable film with N(2)), treatment B (near-ambient air atmospheric conditions in a gas-permeable film with microperforations), and treatment C (high-CO(2) and low-O(2) conditions in a gas-impermeable film). E. coli O157:H7 populations from each treatment were determined by enumeration of numbers on MacConkey agar containing nalidixic acid. RNA was extracted from packaged lettuce for analysis of expression of virulence factor genes stx(2), eae, ehxA, iha, and rfbE. E. coli O157:H7 populations on lettuce at 4 degrees C under all treatments decreased, but most considerably so under treatment B over 10 days. At 15 degrees C, E. coli O157:H7 populations increased by at least 2.76 log CFU/g under all treatments. At 15 degrees C, expression of eae and iha was significantly greater under treatment B than it was under treatments A and C on day 3. Similarly, treatment B promoted significantly higher expression of stx(2), eae, ehxA, and rfbE genes on day 10, compared with treatments A and C at 15 degrees C. Results indicate that storage under near-ambient air atmospheric conditions can promote higher expression levels of O157 virulence factors on lettuce, and could affect the severity of E. coli O157:H7 infections associated with leafy greens. PMID- 21549042 TI - Effect of vaccinating breeder chickens with a killed Salmonella vaccine on Salmonella prevalences and loads in breeder and broiler chicken flocks. AB - The objective of this study was to evaluate the effect of vaccination of breeder chickens on Salmonella prevalences and loads in breeder and broiler chicken flocks. Chickens housed on six commercial breeder farms were vaccinated with a killed Salmonella vaccine containing Salmonella Typhimurium, Salmonella Enteritidis, and Salmonella Kentucky. Unvaccinated breeders placed on six additional farms served as controls. Eggs from vaccinated and unvaccinated breeder flocks were kept separately in the hatchery, and the resulting chicks were used to populate 58 commercial broiler flock houses by using a pair-matched design. Vaccinated breeder flocks had significantly higher Salmonella-specific antibody titers than did the unvaccinated breeder flocks, although they did not differ significantly with respect to environmental Salmonella prevalences or loads. Broiler flocks that were the progeny of vaccinated breeders had significantly lower Salmonella prevalences and loads than broiler flocks that were the progeny of unvaccinated breeders. After adjusting for sample type and clustering at the farm level, the odds of detecting Salmonella in samples collected from broiler flocks originating from vaccinated breeders were 62% lower (odds ratio [95% confidence interval] = 0.38 [0.21, 0.68]) than in flocks from unvaccinated breeders. In addition, the mean load of culture-positive samples was lower in broilers from vaccinated breeders by 0.30 log most probable number per sample (95% confidence interval of -0.51, -0.09; P = 0.004), corresponding to a 50% decrease in Salmonella loads. In summary, vaccination of broiler breeder pullets increased humoral immunity in the breeders and reduced Salmonella prevalences and loads in their broiler progeny, but did not significantly decrease Salmonella in the breeder farm environment. PMID- 21549043 TI - Effect of native microflora on the growth kinetics of salmonella enteritidis strain 04-137 in raw ground chicken. AB - Effects of native microflora (NM) on growth kinetics of Salmonella Enteritidis strain 04-137 were studied in raw ground chicken. First, samples of ground chicken with high and low levels of NM (10(7.1) and 10(4.9) CFU/g, respectively) were spiked with Salmonella at doses ranging from 10(1) to 10(4) CFU/g. The growth kinetics, including the rate constant of growth, r, and the lag period, were similar, but the maximum cell level, N(max), was higher at higher initial Salmonella doses for both NM levels. Second, samples of ground chicken with high and low NM levels (10(6.8) and 10(4.7) CFU/g, respectively) were spiked with Salmonella and then stored at various constant temperatures ranging from 8 to 32 degrees C. Both N(max) and r for Salmonella were higher at higher temperatures for both NM levels. Although r for total bacteria, which consisted of NM and Salmonella, was also higher at higher temperatures, N(max) was constant at all temperatures for both NM levels. Further, Salmonella growth was compared among samples of ground chicken with high and low NM levels and samples of sterilized chicken. Salmonella growth, characterized by both N(max) and r, was highest in sterilized chicken, followed by chicken with the low NM level. Our growth model successfully described and analyzed the growth of Salmonella and total bacteria in chicken at constant temperatures; using the data obtained, the model also successfully predicted the growth of Salmonella and total bacteria in chicken stored at dynamic temperatures. Our study clarified the effects that different doses of NM in ground chicken had on the growth kinetics of the Salmonella strain and demonstrated the usability of the growth model for foods with NM. PMID- 21549044 TI - Efficacy of epsilon-polylysine, lauric arginate, or acidic calcium sulfate applied sequentially for Salmonella reduction on membrane filters and chicken carcasses. AB - Salmonella contamination continues to be one of the major concerns for the microbiological safety of raw poultry products. Application of more than one decontamination agent as a multihurdle intervention to carcasses in a processing line might produce greater reductions than one treatment alone due to different modes of action of individual antimicrobials. In this study, all possible two-way combinations and individual applications of epsilon-polylysine (EPL), lauric arginate (LAE), and acidic calcium sulfate (ACS) solutions were evaluated for their effects against Salmonella enterica serovars, including Enteritidis and Typhimurium, using a sterile membrane filter model system. The combinations that provided higher Salmonella reductions were further evaluated on inoculated chicken carcasses in various concentrations applied in a sequential manner. Sequential spray applications of 300 mg of EPL per liter followed by 30% ACS and of 200 mg of LAE per liter followed by 30% ACS produced the highest Salmonella reductions on inoculated chicken carcasses, by 2.1 and 2.2 log CFU/ml, respectively. Our results indicated that these sequential spray applications of decontamination agents are effective for decreasing Salmonella contamination on poultry carcasses, but further studies are needed to determine the effectiveness of these combinations over a storage period. PMID- 21549045 TI - Influence of growth conditions on pressure resistance of Vibrio parahaemolyticus in oysters and the optimization of postpressure treatment recovery conditions. AB - Vibrio parahaemolyticus ATCC 43996 was grown at 15 degrees C for 53 h, 20 degrees C for 24 h, 25 degrees C for 12 h, 30 degrees C for 9 h, 35 degrees C for 9 h, or 40 degrees C for 6 h to early stationary phase. Oyster meats were blended, autoclaved at 121 degrees C for 15 min, inoculated with V. parahaemolyticus, and pressure treated at 250 MPa for 2 and 3 min and at 300 MPa for 1 and 2 min at 21 degrees C. Overall, growth temperatures of 20 and 40 degrees C yielded the greatest pressure resistance in V. parahaemolyticus. The effects of salt concentration and H(2)O(2)-degrading compounds on the recovery of V. parahaemolyticus also were investigated. Sterile oyster meats were inoculated with V. parahaemolyticus and treated at 250 MPa for 1, 2, or 3 min at 21 degrees C. These meats were then blended with 0.1% peptone water supplemented with 0.5 to 1.5% NaCl and plated on tryptic soy agar (TSA) supplemented with 0 to 3.5% NaCl. For recovery of pressure-injured cells, peptone water with 1% NaCl and TSA with 0.5% NaCl were the best diluent and plating medium, respectively. Addition of sodium pyruvate (0.05 to 0.2%) or catalase (8 to 32 U/ml) did not increase the recovery of V. parahaemolyticus after pressure treatment. The effect of incubation temperature and gas atmosphere on the recovery of V. parahaemolyticus after pressure treatment also was determined. Aerobic incubation at 30 degrees C resulted in the highest recovery of V. parahaemolyticus in sterile oyster meats. The 30 degrees C incubation temperature was also the optimum temperature for recovery of V. parahaemolyticus in pressure-treated live oysters. The results of this study indicate that the growth conditions for V. parahaemolyticus before and after high hydrostatic pressure treatment should be taken into consideration when assessing the efficacy of pressure inactivation. PMID- 21549046 TI - Prevalence of Salmonella enterica, Listeria monocytogenes, and Escherichia coli virulence factors in bulk tank milk and in-line filters from U.S. dairies. AB - The zoonotic bacteria Salmonella enterica, Listeria monocytogenes, and Escherichia coli are known to infect dairy cows while not always causing clinical signs of disease. These pathogens are sometimes found in raw milk, and human disease outbreaks due to these organisms have been associated with the consumption of raw milk or raw milk products. Bulk tank milk (BTM) samples (536) and in-line milk filters (519) collected from dairy farms across the United States during the National Animal Health Monitoring System's Dairy 2007 study were analyzed by real-time PCR for the presence of S. enterica and pathogenic forms of E. coli and by culture techniques for the presence of L. monocytogenes. S. enterica was detected in samples from 28.1% of the dairy operations, primarily in milk filters. Salmonella was isolated from 36 of 75 PCR-positive BTM samples and 105 of 174 PCR-positive filter samples, and the isolates were serotyped. Cerro, Kentucky, Muenster, Anatum, and Newport were the most common serotypes. L. monocytogenes was isolated from 7.1% of the dairy operations, and the 1/2a complex was the most common serotype, followed by 1/2b and 4b (lineage 1). Shiga toxin genes were detected in enrichments from 15.2% of the BTM samples and from 51.0% of the filters by real-time PCR. In most cases, the cycle threshold values for the PCR indicated that toxigenic strains were not a major part of the enrichment populations. These data confirm those from earlier studies showing significant contamination of BTM by zoonotic bacterial pathogens and that the consumption of raw milk and raw milk products presents a health risk. PMID- 21549047 TI - Inactivation of pathogens on pork by steam-ultrasound treatment. AB - The objective of the study was to evaluate a new pathogen inactivation concept that combines application of pressurized steam simultaneously with high-power ultrasound through a series of nozzles. On skin and meat surfaces of pork jowl samples, counts of total viable bacteria were reduced by 1.1 log CFU/cm(2) after treatment for 1 s and by 3.3 log CFU/cm(2) after treatment for 4 s. The mean reduction of 1.7 to 3.3 log CFU/cm(2) on the skin surface was significantly higher than the reduction of 1.1 to 2.5 log CFU/cm(2) on the meat surface. The inactivation of Salmonella Typhimurium, Salmonella Derby, Salmonella Infantis, Yersinia enterocolitica, and a nonpathogenic Escherichia coli was studied on inoculated samples that were treated for 0.5 to 2.0 s. With one exception, no significant differences in reduction were observed among the bacterial types. After treatment for 0.5 s, the 0.9-to 1.5-log reductions of E. coli were significantly higher than the 0.4- to 1.1-log reductions for Salmonella and Y. enterocolitica. Overall, reductions increased by increasing treatment time; reductions were 0.4 to 1.5 log CFU/cm(2) after treatment for 0.5 s and 2.0 to 3.6 log CFU/cm(2) after treatment for 2 s. Reductions on the skin (1 to 3.6 log CFU/cm(2)) were significantly higher than reductions on the meat surface (1 to 2.5 log CFU/cm(2)). The reduced effect on the meat surface may be explained by greater protection of bacteria in deep structures at the muscle surface. No significant difference in reduction was observed between samples inoculated with 10(4) CFU/cm(2) and those inoculated with 10(7) CFU/cm(2), and cold storage of samples for 24 h at 5 degrees C after steam-ultrasound treatment did not lead to changes in recovery of bacteria. PMID- 21549048 TI - Analysis of total aerobic viable counts in raw fish by high-throughput optical oxygen respirometry. AB - A simple, miniaturized, and automated screening assay for the determination of total aerobic viable counts in fish samples is presented here. Fish tissue homogenates were prepared in peptone buffered water medium, according to standard method, and aliquots were dispensed into wells of a 96-well plate with the phosphorescent, oxygen-sensing probe GreenLight. Sample wells were covered with mineral oil (barrier for ambient oxygen), and the plate was monitored on a standard fluorescent reader at 30 degrees C. The samples produced characteristic profiles, with a sharp increase in fluorescence above the baseline level at a certain threshold time, which could be correlated with initial microbial load. Five different fish species were analyzed: salmon, cod, plaice, mackerel, and whiting. Using a conventional agar plating method, the relationship between the threshold time and total aerobic viable counts load (in CFU per gram) was established, calibration curve generated, and the test was validated with 169 unknown fish samples. It showed a dynamic range of 10(4) to 10(7) CFU/g, accuracy of +/- 1 log(CFU/g), assay time of 2 to 12 h (depending on the level of contamination), ruggedness with respect to the key assay parameters, simplicity (three pipetting steps, no serial dilutions), real-time data output, high sample throughput, and automation. With this test, quality of fish samples, CFU-per-gram levels, and their respective time profiles were determined. PMID- 21549049 TI - Effects of oligochitosan on postharvest Alternaria rot, storage quality, and defense responses in Chinese jujube (Zizyphus jujuba Mill. cv. Dongzao) fruit. AB - Effects of oligochitosan (OCH) on postharvest rot caused by Alternaria alternata in Chinese jujube (Zizyphus jujuba Mill. cv. Dongzao) fruit were investigated. An in vitro test indicated that mycelial growth of A. alternata was strongly suppressed by OCH at 0.5, 1, 2, 5, 10, 15, or 20 g/liter. The half-inhibition concentration of OCH against this fungus was 0.76 and 1.69 g/liter on days 4 and 6 of incubation, respectively. Lesion area and disease incidence in the jujube fruit inoculated with A. alternata were remarkably reduced by the OCH treatments at concentrations higher than 1 g/liter, but 5 g/liter OCH was considered the optimal treatment for inhibiting disease development. OCH also significantly reduced postharvest natural decay, promoted fruit firmness, delayed decline in soluble solids and loss of ascorbic acid, and increased total phenolic compounds during storage at 0 degrees C and 85 to 95% relative humidity. Biochemical evaluations revealed that the activities of the main defense-related enzymes in the jujube fruit, including phenylalanine ammonia-lyase, peroxidase, chitinase, and beta-1,3-glucanase, were significantly enhanced (P < 0.05) by OCH treatment. OCH increased superoxide dismutase activity but decreased catalase activity and, consequently, elevated hydrogen peroxide levels in the fruit. These results suggest that OCH might trigger several defense mechanisms in the jujube fruit for disease control in addition to its direct antifungal activity. OCH could be a viable alternative to conventional control of postharvest diseases of horticultural products. PMID- 21549050 TI - Liquid chromatography-tandem mass spectrometry determination of the toxicity and identification of fish species in a suspected tetrodotoxin fish poisoning. AB - Suspected tetrodotoxin (TTX) poisoning was associated with eating unknown fish in April 2009 in Taiwan. After ingestion of the fish, symptoms of the victim included perioral paresthesia, nausea, vomiting, ataxia, weakness of all limbs, respiration failure, and death within several hours. The toxicity in the remaining fish was determined, with the mice exhibiting symptoms of neurotoxin poisoning. The implicated fish and deceased victim tissues were analyzed for TTX by liquid chromatography-tandem mass spectrometry. The urine, bile, cerebrospinal fluid (spinal cord), pleural effusion, and pericardial effusion of the victim contained TTX. In addition, the partial cytochrome b gene of the implicated fish was determined by PCR. The DNA sequence in the partial 465-bp cytochrome b gene identified the implicated fish as Chelonodon patoca (puffer fish). These results indicate that people should avoid eating unknown fish species from fish markets where harvested fish may include toxic species. PMID- 21549051 TI - Occurrence of heavy metals (Hg, Cd, and Pb) and polychlorinated biphenyls in salted anchovies. AB - The most popular brands of salted anchovies (Engraulis encrasicolus) from the Mediterranean Sea and Atlantic Ocean were purchased from several Italian supermarkets and grocery stores. Heavy metal (Hg, Cd, and Pb) and polychlorinated biphenyl (PCB) levels were determined and assessed by comparing the concentrations in these samples with the maximum permissible limits set by the European Union (Reg EC 629/2008 and Reg EC 1881/2006 [Off. J. Eur. Union L 173:3 9 and 364:5-24, respectively]). The Hg and Cd levels were higher than those of Pb in all samples examined. For Hg and Pb, the concentrations recorded in this study were below the authorized limits, while an appreciable percentage of samples from both locations (Mediterranean Sea, 35%, and Atlantic Ocean, 25%) showed Cd levels exceeding the threshold recommended for human consumption. Concerning PCBs, the results of principal component analysis showed that samples from the two different marine areas appeared to be discriminate, with Mediterranean anchovies more contaminated than the others, in spite of their lower lipid content. However, anchovy samples from both locations had dioxinlike-PCB levels (Mediterranean Sea, 0.011 pg World Health Organization toxic equivalency [WHO TEQ] g(-1), wet weight, and Atlantic Ocean, 0.007 pg WHO-TEQ g(-1), wet weight) that were below the WHO-TEQ maximum concentration set by European regulation. The results of this study will help in generating data needed for the assessment of heavy metal and PCB intake from this food. PMID- 21549052 TI - Yoghurt consumption regulates the immune cells implicated in acute intestinal inflammation and prevents the recurrence of the inflammatory process in a mouse model. AB - Crohn's disease and ulcerative colitis, two forms of inflammatory bowel disease, are important problems in industrialized countries. The complete etiology of these two diseases is still unknown but likely involves genetic, environmental, and immunological factors. The aim of the present work was to determine whether the anti-inflammatory effects reported for yoghurt in acute trinitrobenzene sulfonic acid-induced intestinal inflammation in mice also could prevent or attenuate the recurrent intestinal inflammation, thus maintaining remission. The innate response also was evaluated through participation of Toll-like receptors (TLRs) and the analysis of T-cell populations to determine the effects of yoghurt in an acute inflammatory bowel disease model. Yoghurt exerted a beneficial effect on acute intestinal inflammation by regulating T-cell expansion and modulating the expression of TLRs, with decrease of TLR4(+) and increase of TLR9(+) cells. The anti-inflammatory effect of yoghurt also was demonstrated in a recurrent inflammation model. Yoghurt administration during the remission phase prevented the recurrence of inflammation without producing undesirable side effects. The yoghurt effect may be mediated by increased interleukin 10 production and changes in intestinal microbiota. PMID- 21549053 TI - Prevalence of Salmonella spp. and Listeria monocytogenes at small-scale spanish factories producing traditional fermented sausages. AB - The manufacturing of fermented sausages is subject to natural contamination processes that can potentially carry foodborne pathogens along the process chain and result in contamination of the final product. The aim of this study was to evaluate the occurrence of Salmonella spp. and Listeria monocytogenes at different sampling points during the manufacturing process of fuet, a type of traditional fermented sausage, at 10 small-scale Spanish factories. The presence of both pathogens was studied in the raw materials (19 casings and 19 meat batters), the final products (19 fermented sausages), and the factory equipment (12 mincing, 12 mixing, and 19 stuffing machines, 19 cutting tables, 11 knives, and 12 cold rooms) by using classical microbiological techniques and real-time PCR. Salmonella was not detected in the equipment analyzed or in the final products, but it was detected in the raw materials (23.7% of samples). L. monocytogenes showed higher incidence than Salmonella and was detected in the equipment (11.8% of samples), the raw materials (28.9%), and the final products (15.8%), confirming its ubiquity throughout the manufacturing process of fermented sausages. Five factories were further investigated to study the changes in the distribution of pathogens in the fuet production process over a period of either 2 or 3 years. There was considerable variation in the incidence of both pathogens at different sampling periods, and there was no relation between seasonal variations or geographic location of the factories. PMID- 21549054 TI - Incidence of Listeria monocytogenes in cheese manufacturing plants from the northeast region of Sao Paulo, Brazil. AB - The incidence of Listeria monocytogenes in three cheese manufacturing plants from the northeastern region of Sao Paulo, Brazil, was evaluated from October 2008 to September 2009. L. monocytogenes was found in samples from two plants, at percentages of 13.3% (n = 128) and 9.6% (n = 114). Samples of raw and pasteurized milk, water, and Minas Frescal cheese were negative for L. monocytogenes, although the pathogen was isolated from the surface of Prato cheese and in brine from one of the plants evaluated. L. monocytogenes was also isolated from different sites of the facilities, mainly in non-food contact surfaces such as drains, floors, and platforms. Serotype 4b was the most predominant in the plants studied. The results of this study indicate the need for control strategies to prevent the dispersion of L. monocytogenes in the environment of cheese manufacturing plants. PMID- 21549055 TI - Mitigating the antimicrobial activities of selected organic acids and commercial sanitizers with various neutralizing agents. AB - This study was conducted to evaluate the abilities of five neutralizing agents, Dey-Engley (DE) neutralizing broth (single or double strength), morpholinepropanesulfonic acid (MOPS) buffer, phosphate-buffered saline (PBS), and sodium thiosulfate buffer, in mitigating the activities of acetic or lactic acid (2%) and an alkaline or acidic sanitizer (a manufacturer-recommended concentration) againt the cells of Shiga toxin-producing Escherichia coli (STEC; n = 9). To evaluate the possible toxicity of the neutralizing agents to the STEC cells, each STEC strain was exposed to each of the neutralizing agents at room temperature for 10 min. Neutralizing efficacy was evaluated by placing each STEC strain in a mixture of sanitizer and neutralizer under the same conditions. The neutralizing agents had no detectable toxic effect on the STEC strains. PBS was least effective for neutralizing the activity of selected organic acids and sanitizers. Single-strength DE and sodium thiosulfate neutralized the activity of both acetic and lactic acids. MOPS buffer neutralized the activity of acetic acid and lactic acid against six and five STEC strains, respectively. All neutralizing agents, except double-strength DE broth, had a limited neutralizing effect on the activity of the commercial sanitizers used in the study. The double-strength DE broth effectively neutralized the activity of the two commercial sanitizers with no detectable toxic effects on STEC cells. PMID- 21549056 TI - Proteolytic activity of lactic acid bacteria strains and fungal biota for potential use as starter cultures in dry-cured ham. AB - During the processing of dry-cured meat products, sarcoplasmic and myofibrillar proteins undergo proteolysis, which has a marked effect on product flavor. Microbial proteolytic activity is due to the action of mostly lactic acid bacteria (LAB) and to a lesser extent micrococci. The proteolytic capacity of molds in various meat products is of interest to meat processors in the Mediterranean area. Eleven LAB and mold strains from different commercial origins were tested for proteolytic activity against pork myosin, with a view to possible use of these strains as starter cultures for Iberian dry-cured ham. Proteolytic activity was tested by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The LAB strains with the highest proteolytic activity were Lactobacillus plantarum (L115), Pediococcus pentosaceus (Saga P TM), and Lactobacillus acidophilus (FARGO 606 TM). The best fungal candidate was Penicillium nalgiovense LEM 50I followed by Penicillium digitatum, Debaryomyces hansenii, and Penicillium chrysogenum. PMID- 21549057 TI - Assessment of hot peppers for aflatoxin and mold proliferation during storage. AB - Aflatoxin contamination and mold proliferation in three hot pepper hybrids (Sky Red, Maha, and Wonder King) were studied during 5 months of storage at three temperatures (20, 25, and 30 degrees C) and under different packaging conditions (low-density polyethylene bags and jute bags). The presence of aflatoxins in hot pepper samples was determined by high-performance liquid chromatography with a UV Vis detector. Sampling for analysis of aflatoxins, total mold counts, and Aspergillus counts was carried out at 0, 50, 100, and 150 days of storage. Hot peppers packed in jute bags were more susceptible to aflatoxin contamination than those packed in polyethylene bags; aflatoxin concentrations were 75% higher in peppers stored in jute bags. The effect of storage temperature resulted in aflatoxin concentrations that were 61% higher in hot peppers stored at 25 and 30 degrees C than in those stored at 20 degrees C. Of the three pepper hybrids, Wonder King was more susceptible to aflatoxin contamination, with a maximum of 1.50 MUg/kg when packed in jute bags and stored at 25 degrees C for 150 days. However, no sample exceeded the maximum permitted level for total aflatoxins in spices established by European Union regulations (10 MUg/kg). Total mold counts and Aspergillus counts increased with storage duration, but all counts were significantly lower in peppers stored in polyethylene bags. A gradual increase in temperature during prolonged storage of hot peppers in combination with aeration may be the main reasons for increases in fungal biomass and Aspergillus proliferation with the subsequent aflatoxin production. PMID- 21549058 TI - Ozone inactivation of norovirus surrogates on fresh produce. AB - Preharvest contamination of produce by foodborne viruses can occur through a variety of agents, including animal feces/manures, soil, irrigation water, animals, and human handling. Problems of contamination are magnified by potential countrywide distribution. Postharvest processing of produce can involve spraying, washing, or immersion into water with disinfectants; however, disinfectants, including chlorine, have varying effects on viruses and harmful by-products pose a concern. The use of ozone as a disinfectant in produce washes has shown great promise for bacterial pathogens, but limited research exists on its efficacy on viruses. This study compares ozone inactivation of human norovirus surrogates (feline calicivirus [FCV] and murine norovirus [MNV]) on produce (green onions and lettuce) and in sterile water. Green onions and lettuce inoculated with FCV or MNV were treated with ozone (6.25 ppm) for 0.5- to 10-min time intervals. Infectivity was determined by 50% tissue culture infectious dose (TCID(50)) and plaque assay for FCV and MNV, respectively. After 5 min of ozone treatment, >6 log TCID(50)/ml of FCV was inactivated in water and ~2-log TCID(50)/ml on lettuce and green onions. MNV inoculated onto green onions and lettuce showed a >2-log reduction after 1 min of ozone treatment. The food matrix played the largest role in protection against ozone inactivation. These results indicate that ozone is an alternative method to reduce viral contamination on the surface of fresh produce. PMID- 21549059 TI - Investigations on the frequency of norovirus contamination of ready-to-eat food items in Istanbul, Turkey, by using real-time reverse transcription PCR. AB - Investigation of norovirus (NoV) contamination of food items is important because many outbreaks occur after consumption of contaminated shellfish, vegetables, fruits, and water. The frequency of NoV contamination in food items has not previously been investigated in Turkey. The aim of this study was to investigate the frequency of human NoV genogroups (G) I and II in ready-to-eat tomatoes, parsley, green onion, lettuce, mixed salads, and cracked wheat balls. RNA was extracted with the RNeasy Mini Kit, and a real-time reverse transcription (RT) PCR assay was performed using primers specific for NoV GI and GII. Among the 525 samples analyzed, NoV GII was detected in 1 green onion sample and 1 tomato sample by both SYBR Green and TaqMan real-time RT-PCR assays; no GI virus was detected. The Enterobactericaeae and Escherichia coli levels in the NoV-positive green onion were 6.56 and 1.28 log CFU/g, and those in the tomato were 5.55 and 1.30 log CFU/g, respectively. No significant difference in the bacterial levels was found between the NoV-positive and NoV-negative samples. This study is the first in which NoV GII was found in ready-to-eat food collected from Istanbul, Turkey; thus, these foods may be considered a risk to human health. Epidemiological studies and measures to prevent NoV infection should be considered. PMID- 21549060 TI - Effect of some physical factors on the viability of third-stage Gnathostoma binucleatum larvae. AB - To diminish the risk of transmission to humans of advanced third-stage larvae (A3L) of Gnathostoma binucleatum in fish foods, we evaluated the effects of some physical factors on larval viability. A3L protected within fish meatballs were subjected to freezing, refrigeration, boiling, dry heat, and immersion in lemon juice. By freezing, larvae were killed in 48 h, by refrigeration after 30 days, by boiling in 4 min, and by broiling for 60 min. By lemon juice immersion (pH 2.5), encysted larvae were killed after 5 days and nonencysted larvae in 7 h. Results show that freezing fish at -10 to -20 degrees C for 48 h, or cooking fish by frying, boiling, or broiling, will prevent transmission of G. binucleatum. Furthermore, results dispel the popular myth that lemon juice kills encysted larvae in fish. PMID- 21549061 TI - An overview of molecular stress response mechanisms in Escherichia coli contributing to survival of Shiga toxin-producing Escherichia coli during raw milk cheese production. AB - The ability of foodborne pathogens to survive in certain foods mainly depends on stress response mechanisms. Insight into molecular properties enabling pathogenic bacteria to survive in food is valuable for improvement of the control of pathogens during food processing. Raw milk cheeses are a potential source for human infections with Shiga toxin-producing Escherichia coli (STEC). In this review, we focused on the stress response mechanisms important for allowing STEC to survive raw milk cheese production processes. The major components and regulation pathways for general, acid, osmotic, and heat shock stress responses in E. coli and the implications of these responses for the survival of STEC in raw milk cheeses are discussed. PMID- 21549062 TI - [Study on the nuclear translocation mechanism in the inhibition of nuclear factor KappaB activation in bacterial lipoprotein-tolerant THP-1 cells]. AB - OBJECTIVE: To approach the nuclear factor-KappaB (NF-KappaB) nuclear translocation mechanism in bacterial lipoprotein (BLP) tolerance. METHODS: Human monocytic THP-1 cells were first pretreated with 10, 100, 1 000 ng/ml BLP for 20 hours to induce BLP tolerance. Then THP-1 cells without BLP pretreatment (control group) or with BLP pretreatment (tolerance group) were stimulated with 0, 10, 100, 1 000 ng/ml BLP again for 6 hours. The tumor necrosis factor-alpha (TNF alpha) content in culture medium was measured by enzyme linked immunosorbent assay (ELISA) in order to determine the most suitable BLP pretreatment and stimulation concentration. Western blotting was used to detect the protein level, nuclear translocation and phosphorylation of NF-KappaB p50 and p65 in the cells of control and tolerance groups treated with respective conditions for 0, 0.5, 1, 2 and 6 hours. RESULTS: In control group BLP stimulation (10, 100, 1 000 ng/ml) could induce THP-1 activation and TNF-alpha production (pg/ml: 184.86+/-32.51, 3 215.88+/-167.09, 6 042.96+/-245.37) in a dose-dependent manner. In tolerance group, 100 ng/ml BLP pretreatment resulted in almost complete inhibition of TNF alpha production as induced by 101 000 ng/ml BLP stimulation. Therefore, 100 ng/ml BLP pretreatment and 1 000 ng/ml stimulation were selected for following cell treatment. Western blotting analysis showed that there was an increase of p50 protein level in BLP-tolerant cells comparing with control group (0 hour: 542.9+/-15.6 vs. 272.8+/-13.2, 0.5 hour: 558.0+/-16.9 vs. 236.4+/-11.8, 1 hour: 524.7+/-17.5 vs. 211.6+/-9.8, 2 hours: 584.9+/-15.6 vs. 222.4+/-12.3, all P<0.01), whereas the p65 protein level was similar between the two groups. BLP stimulation also induced the nuclear translocation of p50 and p65 in control group (1-hour p50: 344.2+/-13.6 vs. 79.0+/-5.2, p65: 78.4+/-4.5 vs. 0, both P<0.05), but not in tolerance group. In addition, the phosphorylation of p65 at serine 536 was induced after BLP stimulation in control THP-1 cells (0.5 hour: 0.67+/-0.08 vs. 0.04+/-0.01, 1 hour: 0.71+/-0.11 vs. 0.04+/-0.01, both P<0.05), but this change was not detected in BLP-tolerant cells. CONCLUSION: It was found that in BLP-tolerant cells, the expression of inhibitory subunit p50 was increased and the nuclear translocation and phosphorylation of p65 with trans activation ability was inhibited. These changes are likely responsible for the reduced gene expression of NF-KappaB dependent genes in BLP-tolerant cells. PMID- 21549063 TI - [Relation of mesenteric lymph node and innate immune function in septic rats]. AB - OBJECTIVE: To investigate the changes in T helper cells (Th1 and Th2) of mesenteric lymph node (MLN) and blood Th1 and Th2 cells in septic rats. METHODS: Ninety-six male Wistar rats were randomly divided into two groups according to random number table method: sham operation group and model group. Intra-abdominal infection with sepsis was induced by cecal ligation and puncture (CLP). Eight rats in each group were sacrificed after collection of blood samples and MLN samples at 0, 6, 12, 24, 48 and 72 hours after CLP. The ratio of Th1/Th2 and the percentage of regulatory T cell (Treg) in CD4+ T cells in blood and MLN were respectively determined by flow cytometry. RESULTS: In model group, the ratio of Th1/Th2 in abdominal aorta blood increased significantly at 6 hours and reached summit at 12 hours, then it decreased persistently, and when compared with sham group, the ratio of Th1/Th2 was significantly higher at 6, 12, 24 hours (0.82+/ 0.15 vs. 0.60+/-0.22, 1.23+/-0.44 vs. 0.76+/-0.31, 0.85+/-0.25 vs. 0.66+/-0.32) and lower at 72 hours (0.41+/-0.16 vs. 0.59+/-0.13, P<0.05 or P<0.01). The ratio of Th1/Th2 in MLN of model group reached summit at 6 hours, then decreased significantly, and when compared with sham group, the ratio of Th1/Th2 was significantly higher at 6 hours (1.01+/-0.16 vs. 0.52+/-0.13) and lower at 12, 24, 48 and 72 hours (0.34+/-0.11 vs. 0.53+/-0.09, 0.23+/-0.08 vs. 0.51+/-0.09, 0.17+/-0.07 vs. 0.47+/-0.15, 0.16+/-0.06 vs. 0.53+/-0.11, P<0.05 or P<0.01). Compared with sham group, the percentage of Treg in MLN of model group was increased at 12, 24, 48 and 72 hours after CLP (9.62+/-0.69 vs. 7.65+/-0.67, 9.84+/-0.74 vs. 8.08+/-1.06, 10.95+/-2.09 vs. 7.83+/-1.15, 10.81+/-1.34 vs. 8.35+/-1.12, P<0.05 or P<0.01). There was a negative correlation between the ratio of Th1/Th2 and the percentage of Treg in MLN (r=-0.882, P<0.05). CONCLUSION: Cellular immune function of MLN is suppressed during severe intra abdominal infection, which induces translocation of gut-derived endotoxin to mesenteric lymphatics, resulting in corporal immuno-suppression, with manifestation of Th1/Th2 cell shift. Immuno-suppression of MLN is related to a higher percentage of Treg due to the effect of endotoxin. PMID- 21549064 TI - [Alterations in reactive oxygen species and dimethylarginine dimethylaminohydrolase-asymmetric dimethyl-arginine system in the process of endothelial cell senescence induced by high glucose]. AB - OBJECTIVE: To investigate the changes in reactive oxygen species (ROS) and dimethyl- arginine dimethylaminohydrolase-asymmetric dimethylarginine (DDAH-ADMA) system in the process of endothelial cell senescence after exposure to high glucose. METHODS: The human umbilical vein endothelial cells (HUVECs) were cultured with different concentrations of glucose, e.g. 5.5 mmol/L (normal level), and high levels as 11.0, 22.0 and 33.0 mmol/L, for 48 hours, respectively. Subsequently, SA-beta-gal staining was used to evaluate senescence of cells. Telomerase activity was detected by polymerase chain reaction-enzyme linked immunosorbent assay (PCR-ELISA). The intracellular ROS level was measured by flow cytometry. The ADMA concentration and DDAH activity were determined with high-performance liquid chromatography. RESULTS: Compared with normal glucose concentration group, after the endothelial cells were treated with high glucose concentration (11.0-33.0 mmol/L) for 48 hours, the number of SA-beta-gal positive cells was increased significantly [(7.00+/-1.73)%, (12.67+/-2.03)%, (16.00+/ 2.26)% vs. (4.00+/-1.33)%, P>0.05, P<0.05, P<0.05] and the telomerase activity was inhibited dramatically [(91.32+/-4.01)%, (78.44+/-3.78)%, (56.04+/-3.35)% vs. 100%, all P<0.05]. The ROS level (mfi) was increased in all high glucose groups (159.84+/-27.52, 188.99+/-18.77, 244.56+/-20.96 vs.117.11+/-18.76, P<0.05 or P<0.01). At the same time, the ADMA (MUmol/L) production was increas ed (0.78+/ 0.14, 0.88+/-0.18, 1.08+/-0.15 vs. 0.70+/-0.12, P>0.05, P<0.05, P<0.05), and DDAH activity was decreased [(91.32+/-4.01)%, (78.44+/-3.78)%, (56.04+/-3.35)% vs.100%, all P<0.05]. CONCLUSION: High glucose can accelerate endothelial cells senescence in dose-dependent manner and the underlying mechanism may be related to an increased oxidative stress and change in DDAH-ADMA system. PMID- 21549065 TI - [Clinical study on plasma soluble triggering receptor expressed on myeloid cells 1 in patients with sepsis]. AB - OBJECTIVE: To observe the dynamic changes in plasma soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), and to approach the effect on predicting outcome of the patient with sepsis combined with sepsis-related organ failure assessment (SOFA) score. METHODS: Using prospective, randomly control study design, 32 patients admitted to intensive care unit (ICU) of the Second Hospital of Tianjin Medical University suffering from sepsis between May 2009 and June 2010 were collected.They were divided into survival group (n=21) and non-survival group (n=11) according to 28-day survival. Platelet count (PLT) was determined on the 1st, 3rd, 7th day and SOFA score was assessed. Levels of sTREM-1 in plasma were measured by enzyme linked immunosorbant assay (ELISA). Twenty-five health volunteers served as controls. RESULTS: The PLT was (248.88+/-48.62)*10(9)/L and the level of sTREM-1 was 25.7 (21.5, 53.3) ng/L in the control group. In non survivors, the level of PLT (*10(9)/L) was significantly lower on 1st day with a tendency of degression (the level on 1st, 3rd, 7th day was 95.77+/-47.42, 91.92+/ 35.78, 82.31+/-31.04, respectively), SOFA score decreased gradually (the score on 1st, 3rd, 7th day was 12.36+/-4.30, 10.90+/-5.32, 7.87+/-4.60, respectively). On the contrary, the level of sTREM-1 (ng/L) was significantly higher on 1st day with a tendency of elevation [the level on 1st, 3rd, 7th day was 360.5 (262.2, 434.5), 373.5 (263.1, 495.6), 496.6 (380.0, 571.8), respectively]. In survivors, PLT (*10(9)/L) began to decrease on the 3rd day, and then it increased (the level on 1st, 3rd, 7th day was 152.94+/-85.59, 136.18+/-75.30, 165.41+/-61.36, respectively), SOFA score lowered gradually (the score on 1st, 3rd, 7th day was 6.76+/-2.71, 4.29+/-2.31, 2.52+/-1.03, respectively), the peak level of sTREM-1 (ng/L) appeared on the 1st day, then it decreased gradually [the level on 1st, 3rd, 7th day was 204.1 (175.0, 269.6), 164.0 (145.9, 194.2), 81.5 (62.1, 109.0), respectively]. PLT was significantly lower, and SOFA score and sTREM-1 were significantly higher in non-survivors than those of survivors at different time points (P<0.05 or P<0.01). The level of sTREM-1 showed obvious negative correlation with PLT (r=-0.257, P=0.042), positive correlation with SOFA score (r=0.736, P=0.002). CONCLUSION: The plasma sTREM-1 concentration was elevated at the early stage in patients with sepsis. Dynamic changes in sTREM-1 level combined with SOFA score may be helpful in predicting outcome of the patient with sepsis. PMID- 21549066 TI - [The relationship of ultrastructure and function of hypothalamus-pituitary adrenal axis in early stage of sepsis in rats]. AB - OBJECTIVE: To observe the changes in ultrastructure and function of hypothalamic pituitary-adrenal axis (HPAA), and to approach the relationship between them in early stage of sepsis in rats. METHODS: Thirty male Sprague-Dawley (SD) rats were randomly divided into normal control group, sham group, sepsis group. The sepsis model was reproduced by cecal ligation and puncture (CLP). The rats were sacrificed after collection of blood at 6 hours after CLP, and the levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in the plasma, and the corticotropin release hormone (CRH) in the tissue of hypothalamus were detected. The histopathological changes in HPAA were observed with transmission electron microscopy. RESULTS: The levels of ACTH and CORT in plasma, and the CRH in hypothalamus tissue of sepsis group were increased in the early stage of sepsis compared with the normal control group or sham group [ACTH (pmol/L): 5.78+/-0.36 vs. 1.94+/-0.31, 2.51+/-0.10; CORT (nmol/L): 88.48+/-4.47 vs. 22.02+/ 1.62, 34.20+/-2.51; CRH (MUg/L): 101.92+/-6.61 vs. 61.65+/-6.05, 66.65+/-4.03, P<0.05 or P<0.01]. The changes in ultrastructure of the hypothalamus, pituitary and adrenal were also found. In sepsis group, the ultrastructure of hypothalamus was as follows. Rough endoplasmic reticulum expansion and degranulation of rough endoplasmic reticulum, and swelling of Golgi complex were found. A large number of endocrine granules could be seen in ATCH cells in the pituitary with depletion of adrenal lipid droplets. CONCLUSION: In septic rats, the HPAA was excessively activated, and ACTH and CORT in plasma, and CRH in hypothalamus were significantly increased in early stage of sepsis. The changes in ultrastructure of HPAA were obvious, and the change in function was closely related to the ultrastructural changes. PMID- 21549067 TI - [The protective effect of chronic schistosoma japonica infestation against sepsis in mice]. AB - OBJECTIVE: To preliminarily study the protective effect of chronic schistosoma japonica (SJ) infestation against sepsis in mice and its mechanism. METHODS: BALB/c male mice were used, and the experiment was divided into three parts. Experiment 1: chronic SJ infestation model was reproduced by SJ cercaria inoculation through abdominal skin for 8 weeks. Twenty mice were randomly grouped into normal group (n=10) and SJ group (n=10). The levels of interleukins (IL-4, IL-10),tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in serum were detected by enzyme linked immunosorbent assay (ELISA). Real-time polymerase chain reaction (PCR) was employed to detect the levels of IL-10 mRNA and TNF-alphamRNA in abdominal macrophages. This experiment was meant to evaluate immune state in mice with chronic SJ infestation. Experiment 2: lipopolysaccharide (LPS) was intraperitoneally injected to reproduce sepsis model. Thirty mice were randomly grouped into LPS group (n=15) and SJ-LPS group (n=15). The levels of cytokines were determined by ELISA at 0, 24, 48 and 72 hours after LPS injection. This experiment was meant to detect the effect of chronic SJ infestation in mice during the septic process. Experiment 3: two types of sepsis model were reproduced by cecal ligation and puncture (CLP) and LPS injection, respectively. The survival rate of mice with chronic SJ infestation in 72 hours in either type of sepsis was evaluated. RESULTS: Experiment 1: compared with normal group [IL-4 (56.32+/-8.66) ng/L, IL-10 (48.17+/-7.23) ng/L], chronic SJ infestation showed an increase in serum IL-4 [(151.35+/-12.24) ng/L] and IL-10 [(133.22+/-11.09) ng/L, both P<0.05]. Chronic SJ infestation also resulted in an increase in IL-10 mRNA expression (SJ group 4.46+/-1.82, normal group 1.52+/ 0.60) and inhibited TNF-alpha mRNA expression (SJ group 1.61+/-0.93, normal group 2.32+/-1.03) in abdominal macrophages (both P<0.05), indicating that macrophages could be differentiated into alternative activated macrophages. Experiments 2 and 3 showed that the levels of serum IL-4 and IL-10 were increased at 0 hour after LPS injection, and then gradually decreased in SJ-LPS group, but the levels were still higher than those in LPS group at 72 hours [IL-4 (ng/L): 92.2+/-7.6 vs. 41.5+/-4.5; IL-10 (ng/L): 92.1+/-7.8 vs. 35.6+/-4.0, both P<0.05]; the levels of TNF-alpha and IFN-gamma were increased at 24 hours, and then decreased in SJ-LPS group, and the levels were lower than those in LPS group at 72 hours [TNF-alpha (ng/L): 82.9+/-5.6 vs. 91.5+/-5.2; IFN-gamma (ng/L): 44.1+/-4.8 vs. 52.6+/-4.0, both P<0.05]. Therefore, chronic SJ infestation could improve the survival rate of mice with sepsis induced by CLP or LPS (CLP: 80% vs. 20%, LPS: 70% vs. 30%, both P<0.05). CONCLUSION: Chronic SJ infestation could elevate anti-inflammatory factors in septic mice, thus ameliorating the survival rate, so it has protective effect on mice with sepsis. PMID- 21549068 TI - [Granulocyte-monocyte colony-stimulating factor for the treatment of sepsis: a meta analysis]. AB - OBJECTIVE: To systematically assess the effects and safety of granulocyte monocyte colony-stimulating factor (GM-CSF) in the treatment of sepsis. METHODS: All randomized controlled trials (RCTs) of GM-CSF for the treatment of sepsis were retrieved from the databases, including PubMed (1966-2009.10), EMbase (1974 2009.10), Cochrane Clinical Trials Library (Issue 4, 2009), China Biomedicine Literature Database (CBM, 1978-2009.10), Weipu (VIP, 1989-2009.10), China National Knowledge Internet (CNKI, 1994-2009.10) and Wanfang Database (1997 2009.10). The quality of the included RCTs was assessed with the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0. The Cochrane Collaboration's software RevMan 5.0 was used for Meta-analysis. RESULTS: Four RCTs (154 patients) were included. Meta-analysis showed that there was no significant difference between the GM-CSF treatment and traditional therapy regarding 28-day mortality rate [relative risk (RR)=0.63, 95% confidence interval (95%CI) 0.27-1.45, P=0.28]. Meta-analysis also showed that there was no significant difference in the rate of adverse events (RR=0.89, 95%CI 0.342.33, P=0.82). Descriptive analysis showed that GM-CSF could improve immuno suppression, reduce the complications of infection and shorten the duration of mechanical ventilation, but there was no difference in length of stay in hospital or intensive care unit (ICU) and sepsis-related organ failure assessment (SOFA) score. CONCLUSION: The current evidence shows that, compare with the conventional therapy the GM-CSF has the benefit of improving immune function, reducing the complications of infection, and shortening the duration of mechanical ventilation. However, there is no difference in reducing mortality and adverse event, or shortening the length of stay in hospital or ICU and SOFA score with the use of GM-CSF. PMID- 21549069 TI - [The value of serum interleukin-18 and 10 in the evaluation of severity and prognosis in the early stage of sepsis]. AB - OBJECTIVE: To observe the dynamic changes in levels of serum interleukins (IL-18, IL-10) in the early stage of sepsis, and to appraise their values in the evaluation of severity and prognosis of sepsis. METHODS: Prospective randomized controlled study was conducted. Thirty-eight patients with sepsis who stayed longer than 72 hours in intensive care unit (ICU) from December 2009 to August 2010 were enrolled as sepsis group. At the same time, 20 patients without sepsis served as control group. The patients were classified as survival (n=12) or death group (n=26) according to 28-day survival. The clinical laboratory examination data were recorded at 24, 48, 72 hours after admission to the ICU, and venous blood was obtained at the same time. The IL-18, IL-10 levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The vital signs, blood routine, liver function, renal function, coagulation function, arterial blood gas, and electrolyte showed no significant difference between sepsis group and control group 24, 48, 72 hours after admission, the levels of IL-18 were lowered, IL-10 elevated, the IL-18/IL-10 ratio was lowered in the sepsis group, and all of them were higher than control group at each time point. The levels of IL-18, IL 10 in death group of patients with sepsis were all higher than those of survival group at 24, 48, and 72 hours [ IL-18 (ng/L): 108.36+/-18.54 vs. 91.66+/-21.49, 92.13+/-28.92 vs. 54.16+/-31.76, 91.78+/-17.33 vs. 76.04+/-22.09; IL-10 (ng/L): 99.42+/-12.10 vs. 77.20+/-9.47, 103.39+/-17.24 vs. 67.88+/-18.90, 118.99+/-11.20 vs. 99.20+/-12.46, P<0.05 or P<0.01]. IL-18/IL-10 ratios were all lowered in both non-survivors and survivors with sepsis at 24, 48, 72 hours, while the differences were not statistically significant (1.09+/-0.19 vs. 1.20+/-0.32, 0.92+/-0.18 vs. 0.98+/-0.29, 0.78+/-0.15 vs. 0.77+/-0.23, all P>0.05). CONCLUSION: The levels of serum IL-18, IL-10 were all elevated in the early stage of patients with sepsis, and in non-survivors they were higher than those of survivors. With the progress of the illness, IL-18 showed a lowering tendency, while IL-10 showed an elevation. The levels of serum IL-18 and IL-10 may be valuable in evaluating the severity of sepsis and prognosis of patients with sepsis. PMID- 21549070 TI - [The relationship of peroxisome proliferator activated receptor gamma ligands activity in nucleated cell and interleukin-6 level in septic rats]. AB - OBJECTIVE: To observe the relationship between activity of peroxisome proliferator activated receptor gamma (PPARgamma) in nucleated cell and level of pro-inflammatory mediator interleukin-6 (IL-6) in plasma of rats with sepsis. METHODS: According to the random number table, 90 male Sprague-Dawley (SD) rats were randomly divided into three groups, namely control group, sham operation group and sepsis group. Each group was further divided into three subgroups according to postoperative time points, i.e. 12, 24 and 48-hour subgroups. Each subgroup consisted of 10 rats. Sepsis was reproduced by cecal ligation and puncture (CLP). The PPARgamma activity in nucleated cells and IL-6 level in plasma were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The PPARgamma activity in nucleated cells was significantly decreased at 12, 24 and 48 hours in sepsis group (A value: 0.279+/-0.004, 0.264+/-0.009, 0.245+/-0.012) compared with control group (0.292+/-0.007, 0.293+/-0.004, 0.293+/-0.005) and sham operation group (0.295+/-0.008, 0.295+/-0.006, 0.294+/-0.007), while the IL 6 level was significantly increased in sepsis group (ng/L: 365.25+/-15.53, 507.16+/-20.86, 437.89+/-25.09) compared with control group (43.54+/-11.10, 48.82+/-10.62, 42.96+/-9.52) and sham operation group (42.43+/-6.77, 40.32+/ 6.48, 44.10+/-9.36, all P<0.05). When septic condition became worse, the PPARgamma activity in nucleated cells of sepsis group lowered, and IL-6 level was gradually elevated after operation, reaching the peak at 24 hours, and then gradually lowered, and the difference of the value between any two time points was all statistically significant (all P<0.05). There was a negative correlation between the PPARgamma activity in nucleated cells and IL-6 level in 12-hour subgroup of sepsis group (r=-0.703, P=0.023). CONCLUSION: In septic rats, the PPARgamma activity in nucleated cells was lowered while the pro-inflammatory mediator IL-6 level in plasma elevated, and there was a negative correlation between PPARgamma activity and IL-6 level. PMID- 21549071 TI - [Expression of soluble triggering receptor expressed on myeloid cells-1 in septic patients and its relation with prognosis]. AB - OBJECTIVE: To approach the relationship between the contents of soluble form of triggering receptor expressed on myeloid cells-1 (sTREM-1) and prognosis in patients with sepsis. METHODS: Using prospective, control study design, a total of 50 patients with sepsis who were admitted in intensive care unit (ICU) of the Second Hospital of Tianjin Medical University from March to December in the year of 2009 were enrolled. Firstly, the patients were divided into sepsis (n=28) and severe sepsis (n=22) groups according to the patients' condition. Then the patients were divided into survival group (n=34) and death group (n=16) according to the clinical outcome at 28 days after onset of sepsis. Clinical and laboratory data including blood routine tests, blood chemistry, blood gas analysis, C reactive protein (CRP) and procalcitonin (PCT) were collected on the 1st, 3rd and 7th day after onset. Acute physiology and chronic health evaluation II (APACHEII) score was determined. sTREM-1 levels were determined using enzyme linked immunosorbent assay (ELISA) method. Correlation analysis of the sTREM-1, APACHEII score, white blood cell count (WBC) and CRP, using Logistic regression analysis. A total of 30 healthy persons were enrolled into the control group. RESULTS: The sTREM-1 levels (ng/L) in 50 septic patients on the 1st day were higher than those of the healthy persons (52.80+/-9.30 vs. 23.29+/-6.22, P<0.01). The sTREM-1 levels (ng/L) in severe sepsis group on the 1st, 3rd and 7th day (58.25+/-10.59, 65.75+/-13.57, 50.18+/-21.73) were higher than those of the sepsis group (48.55+/ 5.20, 42.85+/-8.54, 34.02+/-12.86, P<0.05 or P<0.01). The sTREM-1 levels (ng/L) of the survival group on the 1st, 3rd and 7th day (53.07+/-10.47, 45.04+/-9.89, 32.84+/-8.42) were decreased with the progression of the ailment. The sTREM-1 levels did not differ significantly between the control group and survival group on the 7th day (P>0.05). The sTREM-1 levels (ng/L) in the death group on the 1st, 3rd and 7th day were increased with the progression of the ailment (52.27+/-6.42, 69.67+/-12.83, 75.70+/-10.55), and the level was significantly higher than that in survival group on the 3rd and 7th day (both P<0.01). The contents of sTREM-1 were positive correlated with APACHEII score (r=0.657, P<0.01), but not correlated with WBC (r=0.023, P>0.05), while somewhat correlated with CRP (r=0.150, P<0.10). Logistic regression analysis showed that sTREM-1 [odds ratio (OR)=0.893,P=0.000] and APACHEII score (OR=0.771, P=0.000) might be potential prognostic factors for septic patients. The area under the receiver operator characteristic curve was 0.868 and 0.930. The sensitivity of prognostic evaluation was 81.1% and specificity was 74.5% with sTREM-1 50 ng/L, and the sensitivity was 83.8% and specificity was 86.3% with APACHEII score 20 to estimate the outcome. CONCLUSION: The serum sTREM-1 are elevated at early stage in sepsis patients. It can reflect the severity of the condition. The sTREM-1 level, which might be considered as a potential prognostic factor for septic patients, is significantly correlated with APACHEII score. PMID- 21549072 TI - [Analysis of the occurrence of pulmonary embolism in 20 years in single medical center]. AB - OBJECTIVE: To evaluate the correlation of pulmonary embolism (PE) and original diseases by retrospectively analysis of the patients for 20 years in single medical center. METHODS: Five hundred and five patients with PE were admitted and treated in General Hospital of Chinese PLA from January 1989 to January 2009, and their clinical data were retrospectively reviewed to analyze the risk factors of PE and the correlations of PE with the original diseases. RESULTS: Of the 505 patients with PE in the past 20 years, the incidence of PE was increased year by year, especially it increased spectacularly after the year of 2004 [61.2% (309) vs. 38.8% (196)]. It was found to be most prevalent in patients of 4160 years old. Its incidence in males was 1.52 folds higher than that of the females [60.4% (305) vs. 39.6% (200)]. Dyspnea, chest pain and hemoptysis were the initial symptoms in the PE patients. Among the 505 patients, 40.0% of them complained dyspnea with chest pain and hemoptysis. Among them, dyspnea occurred in 100.0% of patients, hemoptysis in 52.1%, and chest pain in 40.0%. In 31.1% of the patients if was complicated with deep venous thrombosis (DVT), 19.8% of them suffering from varicosity, 9.5% of them had the history of surgery less than 30 days before, 22.0% of them suffering from neoplasm, 3.6% of them were accompanied with cerebrovascular disease within 4 days, 17.4% of them were accompanied with infection, 10.1% of them were accompanied with primary pulmonary hypertension, and 16.8% of them were accompanied with heart diseases. Multivariate analysis showed that the history of surgery, DVT and neoplasm had significant correlation with the occurrence of PE [odds ratio (95% confidence interval), OR (95%CI) was 4.540 (2.186-9.443), 0.325 (0.155-0.682), 2.610 (1.020-6.708), P<0.05 or P<0.01], while oral contraception, primary pulmonary hypertension and cerebrovascular disease showed a less significant correlation with the occurrence of PE [OR (95%CI) was 0.297 (0.078-1.126), 3.210 (0.855-12.110), 2.939 (0.862-10.020), all P>0.05]. The age and infection did not show significant correlation with the occurrence of PE [OR (95%CI) was 1.041 (0.674-1.607) and 0.820 (0.410-1.665), both P>0.05]. CONCLUSION: The PE is difficult in diagnosis, but with increasing cognizance, the diagnostic rate of PE has been increased. Patients with history of surgical operation, DVT or neoplasm, who complain dyspnea without known cause, chest pain or hemoptysis, should be subjected to further examinations, as to confirm the diagnosis of PE, then the survival rate of the patients with PE may be elevated. PMID- 21549073 TI - [The application of perioperative clinical pathway for severe preeclampsia patients in intensive care unit]. AB - OBJECTIVE: To evaluate the effect of implementation of perioperative clinical pathway (CP) for severe preeclampsia patients in intensive care unit (ICU), and to discuss variation factors in order to improve clinical quality. METHODS: Thirty-six patients treated in ICU in the Second Clinical Hospital of Fujian Medical University were divided into two groups according to time of 1 year before implementation of CP (from January to December in 2009, n=14) and 1 year after implementation of CP (from January to December in 2010, n=22). The length of stay in ICU, cost of hospitalization, occurrence of major complications and mortality, as well as the total effective rate of control of blood pressure in the first 3 days after operation were compared. RESULTS: Compared with the group of patients of 1 year before implementation of CP, in the group of patients of 1 year after implementation of CP, the length of stay in ICU (hours) was significantly shorter (65.5+/-24.9 vs. 86.3+/-28.2, t=2.321, P<0.05), the cost of hospitalization (yuan) was significantly lower (6 463.6+/-1 838.2 vs. 8 136.5+/-2 142.8, t=2.496, P<0.05), the occurrence rate of major complications was lower (36.4% vs. 42.8%, chi2=0.100, P>0.05), the total effective control rate of blood pressure was significant improved on the 1st and the 2nd postoperative day (1 day: 59.1% vs. 14.3%, 2 days: 86.4% vs. 50.0%, both P<0.05), but there was no significant change on the 3rd postoperative day (95.4% vs. 85.7%, P>0.05). One patient died before the application of CP, and none after its application. CONCLUSION: These results suggested that it was beneficial to implement the program in preeclampsia patients to improve medical quality. PMID- 21549074 TI - [The use of nested chain reaction to rapidly identify Gram stain property of micro-organism in patients with sepsis]. PMID- 21549075 TI - [Advances in the study of the effects of enteric-defensins on the pathogenesis of inflammatory bowel diseases]. PMID- 21549076 TI - Vascular Ehlers-Danlos syndrome: a case with fatal outcome. AB - A 13-year-old boy, born prematurely and hypotonic, from non-consanguineous healthy parents, was referred to our department because of easy bruising. A slightly extensible, thin and translucent skin, associated with dysmorphic facies, acrogeria, multiple ecchymoses, hypermobility of the small joints, dorsal kyphosis, genu valgum, flat feet, elongated upper limbs, and low muscle tone were all evident. A history of learning disability and bilateral inguinal hernia was present. Blood and imaging studies were unremarkable. A skin biopsy disclosed an unremarkable dermis; electron microscopy showed abnormalities in the diameter, contour, and shape of collagen fibrils/fibers. Genetic analysis revealed heterozygosity for a novel mutation in COL3A1 gene (c.3527G>A), confirming the diagnosis of vascular Ehlers-Danlos syndrome (VEDS). The patient died at 15 years of age because of aortic dissection. Vascular Ehlers-Danlos syndrome is a rare, life-threatening, autosomal dominant variant of EDS, resulting from mutations in COL3A1 gene. Affected individuals are prone to serious and potentially fatal complications, especially vascular, intestinal, and uterine ruptures. Delay in diagnosis is common, even when the clinical presentation is typical. Therefore, dermatologists should be familiar with VEDS features because the skin findings may be the first signs. Early diagnosis will improve management of visceral complications and allow early genetic counseling. PMID- 21549077 TI - Cellular neurothekeoma with neuroendocrine differentiation. AB - We report a case of cellular neurothekeoma with unusual clinicopathological features in which neuroendocrine markers, determined by immunohistochemistry were observed. Histologically, the tumor showed a micronodular architecture with hypercellular lobules composed of slightly spindled to epithelioid cells, with nuclear atypia or pleomorphism and extension into fat, skeletal muscle. Neoplastic cells were immunoreactive for NKI/C3, CD68, CD10, and smooth-muscle actin, whereas S100 and HMB-45 staining was negative. An intriguing feature was the strong expression by tumor cells of different neuroendocrine markers. Clinical follow up showed no local recurrences after five months despite the presence of positive margins. The presence of atypical histopathological features may cause diagnostic problems with malignant mesenchymal tumors, nevo-melanocytic lesions, and fibrohistiocytic tumors. The immunohistochemical profile including the positive staining for neuroendocrine markers may suggest divergent differentiation or an origin from myofibroblast and neuroendocrine cells. PMID- 21549078 TI - D-penicillamine elastosis perforans serpiginosa: description of two cases and review of the literature. AB - Long term D-penicillamine (DPA) therapy to treat Wilson disease can induce elastosis perforans serpiginosa (EPS), a very rare degenerative skin disease characterized by a transepidermal elimination of elastic fiber aggregates. The iatrogenous disease depends on DPA capacity to chelate copper and cause its depletion. Lysyl-oxidase is a copper dependent enzyme crucial to the dermal elastic fiber cross-linking, which is strongly affected by DPA copper depletion. Direct binding of the drug to collagen precursors also affects elastic fiber assemblage and maturation. The abnormal elastin accumulates into the middle dermis and produces a characteristic bramble brush or "lumpy-bumpy" appearance. In this way it acts as a foreign body and is progressively extruded through the epidermis. Clinically, the disease presents with multiple firm keratotic papules and nodules arranged in annular plaques over the neck, axillae, antecubital fossae, and forearms. The rarity of the disease frequently causes misdiagnoses and the process continues unabated causing concerns about systemic elastopathy. PMID- 21549079 TI - Neurofibromatosis-Noonan syndrome: case report and clinicopathogenic review of the Neurofibromatosis-Noonan syndrome and RAS-MAPK pathway. AB - Neurofibromatosis-Noonan syndrome is an entity that combines both features of Noonan syndrome and Neurofibromatosis type 1. This phenotypic overlap can be explained by the involvement of the RAS-MAPK pathway (mitogen-activated protein kinase) in both disorders. We report the case of a 17-year-old boy with Neurofibromatosis 1 with Noonan-like features, who complained of the progressive appearance of blue-gray lesions on his back. PMID- 21549080 TI - A family with Fabry disease diagnosed by a single angiokeratoma. AB - This case presents a 39-year-old gentleman with a single angiokeratoma on the abdomen. Because of a family history of early onset cardiac disease, testing for Fabry disease was performed and a mis-sense mutation (A143T) in the Fabry gene confirmed the diagnosis. The unusual aspect of this case is that the patient otherwise had normal health. His only detectable abnormality was a high serum creatinine at 116 mmol/L. Two further affected males and four carrier females were detected on family screening. We tested a further five patients with a single angiokeratoma for Fabry disease. In the five tested though, no suggestive personal or family history was given for any of the patients and no further cases were detected. This case highlights the need for vigilance within dermatology clinics to consider Fabry disease even if a solitary angiokeratoma is the only presenting feature. Some patients do display a milder phenotype and thus a detailed family history should always be taken. As in this case, a solitary angiokeratoma and a suspicious family history may be the only clue. Because enzyme replacement therapy is now available, the potential benefits for the patient and their family are high. PMID- 21549081 TI - Granuloma faciale of the scalp. AB - Granuloma faciale (GF) is an uncommon dermatosis with characteristic clinicopathological features. Extrafacial isolated GF is extremely rare. Pulsed dye laser (PDL) is a treatment option for GF to minimize the risk of scarring. We report a case of a 78-year-old male with an extensive GF of the scalp successfully treated with pulsed dye laser (PDL). PMID- 21549082 TI - Dorfman-Chanarin syndrome in two female siblings: a case report and discussion on approach and management. AB - Dorfman-Chanarin syndrome (DCS) is a very rare disorder of lipid metabolism that exhibits an autosomal recessive pattern of inheritance. Besides ichthyosis, systemic manifestations may be present. We report two female siblings with DCS who presented with non-bullous ichthyosiform erythroderma (NBIE). A peripheral blood smear demonstrated Jordan anomaly. This case emphasizes the need for peripheral blood smear screening in patients with congenital ichthyosis. CASE REPORT: A 21/2-year-old female child and her 1-month-old sibling presented with generalized erythema and scaling, which was suggestive of NBIE. Hepatomegaly and ectropion were seen in the older sibling. A peripheral blood smear of both the patients revealed Jordan anomaly. Serum biochemistry revealed abnormal liver function tests, abnormal lipid profile, and elevated muscle-derived enzymes. A diagnosis of Dorfman-Chanarin syndrome was made in both the siblings. Screening for Jordan anomaly in the family members including the parents and maternal and paternal grandmothers was negative. CONCLUSION: The peculiarities in our case include the presence of this disorder in both female siblings along with alopecia in the younger sibling. Hyperlipidemia, noted in one of our cases, is also not a common association. Diagnosing DCS is fairly simple and a high index of suspicion may lead to higher rates of detection of this rare disorder. PMID- 21549083 TI - Unknown: A woman with nodular lesion in a patient with diabetes mellitus. PMID- 21549084 TI - Orf parapoxvirus infection from a cat scratch. AB - A 53-year-old woman presented with an enlarging, tender, ulcerated nodule on her dorsal hand after being scratched by a stray kitten. Histology was consistent with orf parapoxvirus infection. The lesion resolved without scarring after several weeks of treatment with imiquimod 5 percent cream. Orf is a zoonosis transmitted to humans from sheep and goats by direct contact or by fomites. Transmission by cat scratch has not been previously described in the literature. PMID- 21549085 TI - Malignant melanoma arising in a nevus spilus. AB - Malignant melanoma arising within a nevus spilus is rare. Nevus spilus is characterized by darkly pigmented macules and papules with background hyperpigmention. We report a 65-year-old woman who presented with a melanoma arising in a nevus spilus that had been present since birth. PMID- 21549086 TI - Utility of myeloperoxidase stain in the differential diagnosis of leukemia cutis vs. hystiocitoid Sweet syndrome. AB - Leukemia cutis is defined as a skin infiltration by leukemic cells. The diagnosis of myeloid leukemia cutis (MLC) can represent a challenge, especially in those cases without symptoms of systemic disease. The clinical appearance, histopathological analysis and immunohistochemical profile can be indistinguishable from those observed in cases of hystiocitoid Sweet syndrome (HSS). We present a case of MLC in which the cutaneous affectation was the first sign of the systemic leukemia. In this setting, the myeloperoxidase stain was the clue to rule out the possibility of HSS. We discuss the role and the utility of the myeloperoxidase stain in the differentiation of these two entities. PMID- 21549087 TI - Retiform purpura in a patient with a history of cocaine use. AB - There have been rare published cases of retiform purpura related to cocaine use. Levamisole, a common adulterant, has been implicated as the etiologic agent. We describe a female patient, aged 48 years, with cocaine-related retiform purpura involving her face, abdomen, and legs and alert physicians to the dangers of levamisole-contaminated cocaine. PMID- 21549088 TI - Pseudoxantoma elasticum-like dermal elastolysis: a case report. AB - Elastic fibers are components of dermal connective tissue that can be affected in several acquired disorders. Recently, a new entity known as pseudoxanthoma-like papillary dermal elastolysis has been described. We present a case in a 61-year old woman. PMID- 21549089 TI - Ustekinumab treats psoriasis refractory to seven conventional and biologic therapies. PMID- 21549090 TI - Two cases of refractory discoid lupus erythematosus successfully treated with topical tocoretinate. AB - Discoid lupus erythematosus (DLE), the most common lupus erythematosus (LE) specific chronic manifestation of the skin, is often resistant to therapy. Atrophy, scarring, and pigmentation are often observed. In this study, we report two cases of DLE that were successfully treated with tocoretinate, a compound containing a mixture of retinoic acid and tocopherol. Atrophy and pigmentation improved in both cases. The mechanism of action of tocoretinate is discussed. PMID- 21549091 TI - Salt-inducible kinase 1 is present in lung alveolar epithelial cells and regulates active sodium transport. AB - Salt-inducible kinase 1 (SIK1) in epithelial cells mediates the increases in active sodium transport (Na(+), K(+)-ATPase-mediated) in response to elevations in the intracellular concentration of sodium. In lung alveolar epithelial cells increases in active sodium transport in response to beta-adrenergic stimulation increases pulmonary edema clearance. Therefore, we sought to determine whether SIK1 is present in lung epithelial cells and to examine whether isoproterenol dependent stimulation of Na(+), K(+)-ATPase is mediated via SIK1 activity. All three SIK isoforms were present in airway epithelial cells, and in alveolar epithelial cells type 1 and type 2 from rat and mouse lungs, as well as from human and mouse cell lines representative of lung alveolar epithelium. In mouse lung epithelial cells, SIK1 associated with the Na(+), K(+)-ATPase alpha-subunit, and isoproterenol increased SIK1 activity. Isoproterenol increased Na(+), K(+) ATPase activity and the incorporation of Na(+), K(+)-ATPase molecules at the plasma membrane. Furthermore, those effects were abolished in cells depleted of SIK1 using shRNA, or in cells overexpressing a SIK1 kinase-deficient mutant. These results provide evidence that SIK1 is present in lung epithelial cells and that its function is relevant for the action of isoproterenol during regulation of active sodium transport. As such, SIK1 may constitute an important target for drug discovery aimed at improving the clearance of pulmonary edema. PMID- 21549092 TI - Combined effect of sodium selenite and docetaxel on PC3 metastatic prostate cancer cell line. AB - Docetaxel and sodium selenite are well known for their anticancer properties. While resistance to docetaxel remains an obstacle in prostate cancer chemotherapy, sodium selenite, has been exploited as a new therapeutic approach. Currently, development of therapies affecting a multitude of cell targets, have been proposed as a strategy to overcome drug resistance. This association may reduce systemic toxicity counteracting a wide range of side effects. Here we report the effect of docetaxel and sodium selenite combination on the PC3 prostate cancer cell line, derived from bone metastasis. Therefore we evaluate cell growth, cell cycle progression, viability, mitochondria membrane potential, cytochrome C, Bax/Bcl2 ratio, caspase-3 expression and reactive oxygen species production. Our results suggest that sodium selenite and docetaxel combination have a synergistic effect on cell growth inhibition (67%) compared with docetaxel (22%) and sodium selenite (24%) alone. This combination also significantly induced cell death, mainly by late apoptosis vs necrosis, which is correlated with mitochondria membrane potential depletion. On the other hand, cytochrome C, Bax/Bcl2 ratio and caspase-3, known as proapoptotic factors, significantly increased in the presence of sodium selenite alone, but not in the presence of docetaxel in monotherapy or in combination with sodium selenite. These findings suggest that docetaxel and sodium selenite combination may be more effective on prostate cancer treatment than docetaxel alone warranting further evaluation of this combination in prostate cancer therapeutic approach. PMID- 21549093 TI - A novel mouse PKCdelta splice variant, PKCdeltaIX, inhibits etoposide-induced apoptosis. AB - Protein kinase C (PKC) delta plays an important role in cellular proliferation and apoptosis. The catalytic fragment of PKCdelta generated by caspase-dependent cleavage is essential for the initiation of etoposide-induced apoptosis. In this study, we identified a novel mouse PKCdelta isoform named PKCdeltaIX (Genebank Accession No. HQ840432). PKCdeltaIX is generated by alternative splicing and is ubiquitously expressed, as seen in its full-length PKCdelta. PKCdeltaIX lacks the C1 domain, the caspase 3 cleavage site, and the ATP binding site but preserves an almost intact c-terminal catalytic domain and a nuclear localization signal (NLS). The structural characteristics of PKCdeltaIX provided a possibility that this PKCdelta isozyme functions as a novel dominant-negative form for PKCdelta due to its lack of the ATP-binding domain that is required for the kinase activity of PKCdelta. Indeed, overexpression of PKCdeltaIX significantly inhibited etoposide-induced apoptosis in NIH3T3 cells. In addition, an in vitro kinase assay showed that recombinant PKCdeltaIX protein could competitively inhibit the kinase activity of PKCdelta. We conclude that PKCdeltaIX can function as a natural dominant-negative inhibitor of PKCdeltain vivo. PMID- 21549094 TI - Regulation of cancer stem cell properties by CD9 in human B-acute lymphoblastic leukemia. AB - Although the prognosis of acute lymphoblastic leukemia (ALL) has improved considerably in recent years, some of the cases still exhibit therapy-resistant. We have previously reported that CD9 was expressed heterogeneously in B-ALL cell lines and CD9(+) cells exhibited an asymmetric cell division with greater tumorigenic potential than CD9(-) cells. CD9(+) cells were also serially transplantable in immunodeficient mice, indicating that CD9(+) cell possess self renewal capacity. In the current study, we performed more detailed analysis of CD9 function for the cancer stem cell (CSC) properties. In patient sample, CD9 was expressed in the most cases of B-ALL cells with significant correlation of CD34-expression. Gene expression analysis revealed that leukemogenic fusion proteins and Src family proteins were significantly regulated in the CD9(+) population. Moreover, CD9(+) cells exhibited drug-resistance, but proliferation of bulk cells was inhibited by anti-CD9 monoclonal antibody. Knockdown of CD9 remarkably reduced the leukemogenic potential. Furthermore, gene ablation of CD9 affected the expression and tyrosine-phosphorylation of Src family proteins and reduced the expression of histone-deubiquitinase USP22. Taken together, our results suggest that CD9 links to several signaling pathways and epigenetic modification for regulating the CSC properties of B-ALL. PMID- 21549095 TI - Induction of apoptosis in colon cancer cells by a novel topoisomerase I inhibitor TopIn. AB - The tumor suppressor p53 plays an important role in cellular emergency mechanisms through regulating the genes involved in cell cycle arrest and apoptosis. To identify small molecules that can activate p53-responsive transcription, we performed chemical screening using genetically engineered HCT116 reporter cells. We found that TopIn (7-phenyl-6H-[1,2,5]oxadiazolo[3,4-e]indole 3-oxide) efficiently activated p53-mediated transcriptional activity and induced phosphorylation of p53 at Ser15, thereby stabilizing the p53 protein. Furthermore, TopIn upregulated the expression of p21(WAF1/CIP1), a downstream target of p53, and suppressed cellular proliferation in various colon cancer cells. Additionally, TopIn induced DNA fragmentation, caspase-3/7 activation and poly ADP ribose polymerase cleavage, typical biochemical markers of apoptosis, in p53 wild-type and mutated colon cancer cells. Finally, we found that TopIn inhibited topoisomerase I activity, but not topoisomerase II, in vitro and induced the formation of the topoisomerase I-DNA complex in HCT116 colon cancer cells. Unlike camptothecin (CPT) and its derivative SN38, TopIn did not affect the activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP) or multidrug-resistant protein-1 (MDR-1). These results suggest that TopIn may present a promising new topoisomerase I-targeting anti-tumor therapeutics. PMID- 21549096 TI - Alternative splicing of PDLIM3/ALP, for alpha-actinin-associated LIM protein 3, is aberrant in persons with myotonic dystrophy. AB - Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder of muscular dystrophy characterized by muscle weakness and wasting. DM1 is caused by expansion of CTG repeats in the 3'-untranslated region (3'-UTR) of DM protein kinase (DMPK) gene. Since CUG-repeat RNA transcribed from the expansion of CTG repeats traps RNA-binding proteins that regulate alternative splicing, several abnormalities of alternative splicing are detected in DM1, and the abnormal splicing of important genes results in the appearance of symptoms. In this study, we identify two abnormal splicing events for actinin-associated LIM protein 3 (PDLIM3/ALP) and fibronectin 1 (FN1) in the skeletal muscles of DM1 patients. From the analysis of the abnormal PDLIM3 splicing, we propose that ZASP-like motif-deficient PDLIM3 causes the muscular symptoms in DM. PDLIM3 binds alpha actinin 2 in the Z-discs of muscle, and the ZASP-like motif is needed for this interaction. Moreover, in adult humans, PDLIM3 expression is highest in skeletal muscles, and PDLIM3 splicing in skeletal muscles is regulated during human development. PMID- 21549097 TI - Cu/Zn superoxide dismutase is differentially regulated in period gene-mutant mice. AB - The circadian clock in the brain coordinates the phase of peripheral oscillators that regulate tissue-specific physiological outputs. Here we report that circadian variations in the expression and activity of Cu/Zn superoxide dismutase (SOD1; EC 1.15.1.1) are present in liver homogenates from mice. The SOD1 mRNA expression from wild-type (WT) mice peaked at Zeitgeber Time 9 (ZT9; 9h after lights-on time). While there was no rhythmicity in that from period2 (per2) gene knockout (P2K) mice, the level of SOD1 from per1/per2 double knockout (DKO) mice was significantly elevated at ZT5. The enzyme activity of SOD1 was also rhythmic in the mouse liver. Moreover, the total amount of the SOD1 exhibited a rhythmic oscillation with a peak at ZT9 in the liver from WT mice. We also found that tert butylhydroperoxide (t-BHP)-induced oxidative damage in both WT and P2K mouse embryonic fibroblast (MEF) cells resulted in the up-regulation of SOD1 levels. Our data suggest that the expression of an important antioxidant enzyme, SOD1, is under circadian clock control and that mice are more susceptible to oxidative stress depending on the time of day. PMID- 21549098 TI - The influence of natural mineral water on aquaporin water permeability and human natural killer cell activity. AB - Aquaporins are the intrinsic membrane proteins functioning as water channel to transport water and/or mineral nutrients across the biological membrane systems. In this research, we aimed to clarify if the selected mineral water can affect aquaporin functions in vitro and the assumption of the mineral water can modify aquaporin expression and activate natural killer cell activity in human body. First, we expressed six human and eight plant aquaporin genes in oocytes and compared the effect of different kinds of natural mineral water on aquaporin activity. The oocyte assay data show that Hita tenryosui water could promote water permeability of almost all human and plant aquaporins in varying degrees, and freeze-dry and organic solvent extraction could reduce AQP2 activity but pH change and boiling could not. Second, each volunteer in two groups (10 in one group) received an oral Hita tenryosui or tap water load of 1000 ml/day for total four weeks. We found that these two kinds of water did not directly affect the relative expression levels of AQP1 and AQP9 in the blood cells, but intriguingly, the natural killer cell activities of the volunteers drinking Hita tenryosui water were significantly improved, suggesting that Hita tenryosui water has obvious health function, which opens a new and interesting field of investigation related to the link between mineral water consumption and human health and the therapies for some chronic diseases. PMID- 21549099 TI - Analysis of apolipoprotein A-I as a substrate for matrix metalloproteinase-14. AB - Substrates for matrix metalloproteinase (MMP)-14 were previously identified in human plasma using proteomic techniques. One putative MMP-14 substrate was apolipoprotein A-I (apoA-I), a major component of high-density lipoprotein (HDL). In vitro cleavage assays showed that lipid-free apoA-I is a more accessible substrate for MMP-14 compared to lipid-bound apoA-I, and that MMP-14 is more prone to digest apoA-I than MMP-3. The 28-kDa apoA-I was cleaved into smaller fragments of 27, 26, 25, 22, and 14-kDa by MMP-14. ApoA-I sites cleaved by MMP-14 were determined by isotope labeling of C-termini derived from the cleavage and analysis of the labeled peptides by mass spectrometry, along with N-terminal sequencing of the fragments. Cleavage of apoA-I by MMP-14 resulted in a loss of ability to form HDL. Our results suggest that cleavage of lipid-free apoA-I by MMP-14 may contribute to reduced HDL formation, and this may be occurring during the development of various vascular diseases as lipid metabolism is disrupted. PMID- 21549100 TI - The ECS(SPSB) E3 ubiquitin ligase is the master regulator of the lifetime of inducible nitric-oxide synthase. AB - The ubiquitin-proteasome pathway is an important regulatory system for the lifetime of inducible nitric-oxide synthase (iNOS), a high-output isoform compared to neuronal NOS (nNOS) and endothelial NOS (eNOS), to prevent overproduction of NO that could trigger detrimental effects such as cytotoxicity. Two E3 ubiquitin ligases, Elongin B/C-Cullin-5-SPRY domain- and SOCS box containing protein [ECS(SPSB)] and the C-terminus of Hsp70-interacting protein (CHIP), recently have been reported to target iNOS for proteasomal degradation. However, the significance of each E3 ubiquitin ligase for the proteasomal degradation of iNOS remains to be determined. Here, we show that ECS(SPSB) specifically interacted with iNOS, but not nNOS and eNOS, and induced the subcellular redistribution of iNOS from dense regions to diffused expression as well as the ubiquitination and proteasomal degradation of iNOS, whereas CHIP neither interacted with iNOS nor had any effects on the subcellular localization, ubiquitination, and proteasomal degradation of iNOS. These results differ from previous reports. Furthermore, the lifetime of the iNOS(N27A) mutant, a form of iNOS that does not bind to ECS(SPSB), was substantially extended in macrophages. These results demonstrate that ECS(SPSB), but not CHIP, is the master regulator of the iNOS lifetime. PMID- 21549101 TI - Angptl4 deficiency decreases serum triglyceride levels in low-density lipoprotein receptor knockout mice and streptozotocin-induced diabetic mice. AB - Angiopoietin-like protein family 4 (Angptl4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). In familial hypercholesterolemia (FH), individuals lacking low-density lipoprotein receptor (LDLR) present not only hypercholesterolemia, but also increased plasma triglyceride (TG)-rich lipoprotein remnants, and develop atherosclerosis. In addition, the most common type of dyslipidemia in individuals with diabetes is increased TG levels. We first generated LDLR(-/-)Angptl4(-/-) mice to study the effect of Angptl4 deficiency on the lipid metabolism. Fasting total cholesterol, VLDL-C, LDL-C, HDL-C and TG levels were decreased in LDLR(-/-)Angptl4(-/-) mice compared with LDLR(-/-)Angptl4(+/+) mice. In particular, post olive oil-loaded TG excursion were largely attenuated in LDLR(-/-)Angptl4(-/-) mice compared with LDLR(-/-)Angptl4(+/+) mice. We next introduced diabetes by streptozotocin (STZ) treatment in Angptl4(-/-) mice and examined the impacts of Angptl4 deficiency. Compared with diabetic Angptl4(+/+) mice, diabetic Angptl4(-/-) mice showed the improvement of fasting and postprandial hypertriglyceridemia as well. Thus, targeted silencing of Angptl4 offers a potential therapeutic strategy for the treatment of dyslipidemia in individuals with FH and insulin deficient diabetes. PMID- 21549102 TI - Rad GTPase induces cardiomyocyte apoptosis through the activation of p38 mitogen activated protein kinase. AB - Rad is a member of a subclass of small GTP-binding proteins, the RGK family. In the present study we investigated the role of Rad protein in regulating cardiomyocyte viability. DNA fragmentation and TUNEL assays demonstrated that Rad promoted rat neonatal cardiomyocyte apoptosis. Rad silencing fully blocked serum deprivation induced apoptosis, indicating Rad is necessary for trigger cardiomyocyte apoptosis. Rad overexpression caused a dramatic decrease of the anti-apoptotic molecule Bcl-x(L), whereas Bcl-x(L) overexpression protected cardiomyocytes against Rad-induced apoptosis. Rad-triggered apoptosis was mediated by the activation of p38 MAPK. The p38 blocker SB203580 effectively protected cardiomyocytes against Rad-evoked apoptosis. PMID- 21549103 TI - Monoubiquitination of Tob/BTG family proteins competes with degradation-targeting polyubiquitination. AB - Tob belongs to the anti-proliferative Tob/BTG protein family. The expression level of Tob family proteins is strictly regulated both transcriptionally and through post-translational modification. Ubiquitin (Ub)/proteosome-dependent degradation of Tob family proteins is critical in controlling cell cycle progression and DNA damage responses. Various Ub ligases (E3s) are responsible for degradation of Tob protein. Here, we show that Tob family proteins undergo monoubiquitination even in the absence of E3s in vitro. Determination of the ubiquitination site(s) in Tob by mass spectrometric analysis revealed that two lysine residues (Lys48 and Lys63) located in Tob/BTG homology domain are ubiquitinated. A mutant Tob, in which both Lys48 and Lys63 are substituted with alanine, is more strongly polyubiquitinated than wild-type Tob in vivo. These data suggest that monoubiquitination of Tob family proteins confers resistance against polyubiquitination, which targets proteins for degradation. The strategy for regulating the stability of Tob family proteins suggests a novel role for monoubiquitination. PMID- 21549104 TI - Mouse gamma-butyrobetaine dioxygenase is regulated by peroxisome proliferator activated receptor alpha through a PPRE located in the proximal promoter. AB - Convincing evidence from studies with peroxisome proliferator-activated receptor (PPAR)alpha-deficient mice suggested that the carnitine biosynthetic enzyme gamma butyrobetaine dioxygenase (BBD) is regulated by PPARalpha. However, the identification of BBD as a direct PPARalpha target gene as well as its exact regulation remained to be demonstrated. In silico-analysis of the mouse BBD promoter revealed seven putative peroxisome proliferator response elements (PPRE) with high similarity to the consensus PPRE. Luciferase reporter gene assays using mutated and non-mutated serial 5'-truncation BBD promoter reporter constructs revealed that one PPRE located at -75 to -87 relative to the transcription start site in the proximal BBD promoter is probably functional. Using gel shift assays we observed in vitro-binding of PPARalpha/RXRalpha heterodimer to this PPRE confirming that it is functional. In conclusion, the present study clearly shows that mouse BBD is a direct PPARalpha target gene and that transcriptional up regulation of mouse BBD by PPARalpha is likely mediated by binding of the PPARalpha/RXR heterodimer to one PPRE located in its proximal promoter region. The results confirm emerging evidence from recent studies that PPARalpha plays a key role in the regulation of carnitine homeostasis by controlling genes involved in both, carnitine synthesis and carnitine uptake. PMID- 21549105 TI - Mucolipidosis in a Chinese family with compound heterozygous mutations at the GNPTAB gene. AB - BACKGROUND: Mucopolysaccharidoses (MPS) are caused by the deficiency in the metabolism of one or more types of mucopolysaccharides or glycosaminoglycans (GAGs). Mucolipidoses (ML) are a group of genetic disorders in which both glycosaminoglycans (GAGs) and sphingolipids build up in the body. Both of MPS and ML belong to lysosomal storage diseases and show similar clinical manifestations. Distinction of these two types of diseases has not been always possible using conventional clinical diagnoses. Genetic test provides a definitive diagnosis for ML and MPS diseases. METHODS: The initial clinical diagnosis had suspected the proband as either MPS or ML. To verify the clinical diagnosis, linkage analysis was performed with a panel of microsatellite markers flanking 10 candidate genetic loci for mucopolysaccharidosis and 2 loci for mucolipidosis. Two-point logarithm of odds (lod) scores was calculated using Linkage Package 5.2 program. Direct DNA sequence analyses of GNPTAB in the family members were performed. RESULTS: By using linkage and mutational analyses, we have identified that the family members contain compound heterozygous mutations of p.R364X and c.2715+1G>A in the GNPTAB gene. We determine the family as MLIII based on the DNA-test and clinical diagnoses. CONCLUSION: Our study confirms the pathological relationship between the patients' genotype and phenotype in the clinical ML manifestation, and suggests that DNA-based diagnosis serves as a better way to define ML and MPS. PMID- 21549106 TI - Enzymatic assay of phosphatidylethanolamine in serum using amine oxidase from Arthrobacter sp. AB - BACKGROUND: In human serum, as for phospholipids not containing choline, phosphatidylethanolamine (PE) exists approximately 5% in a whole phospholipid. PE is well known as one of the main components of biological membranes, and also plays important roles that contribute to apoptosis and cell signaling. However, it could not measure PE with other phospholipids due to a lack of choline in them. METHODS: Using an amine oxidase (EC 1.4.3.6), from Arthrobacter species, a simple and rapid enzymatic assay for measurements of PE in serum was established. That assay used the Hitachi 7170 analyzer to evaluate the analytical performance. RESULTS: The average within-run CVs were 0.38-1.27% (n=20) at 69-160 MUmol/l. The correlation between values obtained with the present method (y) and the high performance liquid chromatography (HPLC) method (x) was: y=0.944x+9.441 (r=0.977, S(y|x)=5.82, n=34). In addition, the reference interval of healthy subjects was 115+/-45 MUmol/l. CONCLUSIONS: This new enzymatic method shows a high specificity for serum PE and can be easily applied to an automated analyzer. The present method is available as a novel marker of changes in the clinical condition of serum phospholipids. PMID- 21549107 TI - Diagnostic performances of HE4 and CA125 for the detection of ovarian cancer from patients with various gynecologic and non-gynecologic diseases. AB - OBJECTIVES: We compared diagnostic performance of CA125 and HE4 in various gynecologic and non-gynecologic diseases. DESIGN AND METHODS: Sera from 176 patients with various diseases were collected, and CA125 and HE4 levels were compared. ROC curves were constructed to estimate the diagnostic performance. RESULTS: Levels of both markers were elevated in ovarian cancer. CA125 was also high in benign gynecologic diseases, but HE4 was not. CA125 levels of pregnant women were higher than those of control group, and HE4 was increased in chronic renal diseases. The sensitivity for discriminating ovarian cancer from healthy or benign conditions was 44.8% for HE4 and 55.2% for CA125 at 95% specificity. The ROC-AUC values for HE4 and CA125 were 0.85 and 0.87 respectively. CONCLUSIONS: HE4 demonstrated comparable diagnostic performances to CA125, though each marker had its own strengths and weaknesses. Combining CA125 and HE4 might be more advantageous than either one alone. PMID- 21549108 TI - Cryopreservation of sperm from Atlantic halibut (Hippoglossus hippoglossus, L.) for commercial application. AB - Development of Atlantic halibut (Hippoglossus hippoglossus) aquaculture will be enhanced with cryopreservation of halibut sperm by ensuring a reliable supply of sperm of desired quality and quantity. To assist in its commercial application, the cryopreservation of large volumes of halibut sperm was investigated. Three cryoprotectants were compared: dimethyl sulfoxide (DMSO), polyethylene glycol (PG) and glycerol (GLY) at two concentrations (10% or 15%). Two salt solutions, Hanks' balanced salt solution (HBSS) and 0.1M KHCO(3) with 0.125 M sucrose solution (KS) were tested as diluents. Both factors were examined in 1.6 mL volumes. A cryopreservation volume of 4 mL and a low dilution ratio (1:1) were examined separately. Based on motility and fertilization rate, 10% and 15% DMSO diluted with HBSS or KS solution proved to be effective extenders with mean fertilization rates ranging from 52.2 +/- 27.2% to 65.8 +/- 26.1%; none of which were significantly different from that of the control. Four other extenders, 10% PG or 10% GLY with HBSS or KS, resulted in significantly lower fertilization rates. Use of a 4 mL cryopreservation volume did not exhibit a significant effect on fertilization rate or motility of post-thawed sperm compared to a 1.6 mL volume (P>0.05); while the use of a dilution ratio of one part sperm with three parts cryopreservation solution (1:3 v/v with sperm concentration of 0.51+/- 0.11*10(10)cells/ml) had a significantly better preservation effect than using a ratio of 1:1 with sperm concentration of 1.02 +/- 0.21*10(10)cells/ml (P<0.05). From these results, an optimized protocol for the cryopreservation of Atlantic halibut sperm using a volume as large as 4mL has been established. PMID- 21549109 TI - The unfolded protein response in human corneal endothelial cells following hypothermic storage: implications of a novel stress pathway. AB - Human corneal endothelial cells (HCEC) have become increasingly important for a range of eye disease treatment therapies. Accordingly, a more detailed understanding of the processing and preservation associated stresses experienced by corneal cells might contribute to improved therapeutic outcomes. To this end, the unfolded protein response (UPR) pathway was investigated as a potential mediator of corneal cell death in response to hypothermic storage. Once preservation-induced failure had begun in HCECs stored at 4 degrees C, it was noted that necrosis accounted for the majority of cell death but with significant apoptotic involvement, peaking at several hours post-storage (4-8h). Western blot analysis demonstrated changes associated with apoptotic activation (caspase 9, caspase 3, and PARP cleavage). Further, the activation of the UPR pathway was observed through increased and sustained levels of ER folding and chaperone proteins (Bip, PDI, and ERO1-Lalpha) in samples experiencing significant cell death. Modulation of the UPR pathway using the specific inhibitor, salubrinal, resulted in a 2-fold increase in cell survival in samples experiencing profound cold-induced failure. Furthermore, this increased cell survival was associated with increased membrane integrity, cell attachment, and decreased necrotic cell death populations. Conversely, addition of the UPR inducer, tunicamycin, during cold exposure resulted in a significant decrease in HCEC survival during the recovery period. These data implicate for the first time that this novel cell stress pathway may be activated in HCEC as a result of the complex stresses associated with hypothermic exposure. The data suggest that the targeted control of the UPR pathway during both processing and preservation protocols may improve cell survival and function of HCEC thus improving the clinical utility of these cells as well as whole human corneas. PMID- 21549110 TI - Lineage specific trimethylation of H3 on lysine 4 during C. elegans early embryogenesis. AB - In many organisms early embryogenesis is characterised by a period refractory to transcription. In Caenorhabditis elegans, the one-cell embryo is transcriptionally inactive, but at around eight-cell stage transcription is activated in the somatic lineage. This model suggests that histone tail modifications associated with activation of transcription, such as di- or trimethylation of histone 3 on lysine 4 (H3K4me2/me3) should be enriched in the somatic lineage. Here, we have investigated the deposition of H3K4me3 during embryogenesis and found that it is more dynamic than anticipated. In the eight cell stage embryo, H3K4me3 deposition is poor in the germline blastomere, as expected, but surprisingly three somatic blastomeres also remain poor in H3K4me3. All the other somatic blastomeres show robust deposition of H3K4me3. Interestingly, the three somatic blastomeres poor in H3K4me3 are descendants of the first germline blastomere, implying an activity that impedes on H3K4me3 deposition in these cells. In contrast, the deposition of H3K4me2 and H3K27me2/3 is not lineage restricted. Taken together, our data reveal that H3K4me3 deposition is highly regulated according to the cell lineage involved. PMID- 21549111 TI - The molecular and cellular basis of variable craniofacial phenotypes and their genetic rescue in Twisted gastrulation mutant mice. AB - The severity of numerous developmental abnormalities can vary widely despite shared genetic causes. Mice deficient in Twisted gastrulation (Twsg1(-/-)) display such phenotypic variation, developing a wide range of craniofacial malformations on an isogenic C57BL/6 strain background. To examine the molecular basis for this reduced penetrance and variable expressivity, we used exon microarrays to analyze gene expression in mandibular arches from several distinct, morphologically defined classes of Twsg1(-/-) and wild type (WT) embryos. Hierarchical clustering analysis of transcript levels identified numerous differentially expressed genes, clearly distinguishing severely affected and unaffected Twsg1(-/-) mutants from WT embryos. Several genes that play well known roles in craniofacial development were upregulated in unaffected Twsg1(-/-) mutant embryos, suggesting that they may compensate for the loss of TWSG1. Imprinted genes were overrepresented among genes that were differentially expressed particularly between affected and unaffected mutants. The most severely affected embryos demonstrated increased p53 signaling and increased expression of its target, Trp53inp1. The frequency of craniofacial defects significantly decreased with a reduction of p53 gene dosage from 44% in Twsg1(-/-)p53(+/+) pups (N=675) to 30% in Twsg1(-/-)p53(+/-) (N=47, p=0.04) and 15% in Twsg1(-/-)p53(-/-) littermates (N=39, p=0.001). In summary, these results demonstrate that phenotypic variability in Twsg1(-/-) mice is associated with differential expression of certain developmentally regulated genes, and that craniofacial defects can be partially rescued by reduced p53 levels. We postulate that variable responses to stress may contribute to variable craniofacial phenotypes by triggering differential expression of genes and variable cellular apoptosis. PMID- 21549112 TI - Effect of compound IMMLG5521, a novel coumarin derivative, on carrageenan-induced pleurisy in rats. AB - Accumulative evidences have showed that some coumarin derivatives have significantly anti-inflammatory effects. To investigate the potential anti inflammatory effect of compound IMMLG5521, a novel coumarin derivative, carrageenan-induced pleurisy model in rats was employed. The results showed that IMMLG5521 (5, 10 and 20 mg/kg) exhibited anti-inflammatory effects, reducing pleural exudate formation, decreasing total number of inflammation cells and polymorphonuclear leukocytes infiltration, attenuating histological injury and reducing TNF-alpha, IL-1beta, MIP-2 and IL-8 release. Further investigation revealed that the compound may exert its anti-inflammatory effect via inhibiting nuclear translocation of NF-kB in inflammatory cells collected from pleural exudates. Taken together, the present results suggested that IMMLG5521 inhibited acute inflammation in carrageenan-induced pleurisy model that could be, in part, related to a reduction of release of inflammatory factors, another part may be related to an inhibition of NF-kB activation. PMID- 21549113 TI - Pentoxifylline and melatonin in combination with pioglitazone ameliorate experimental non-alcoholic fatty liver disease. AB - Insulin resistance, oxidative stress and cytokine imbalance are key pathophysiological mechanisms in non-alcoholic fatty liver disease (NAFLD). This study aimed at evaluating the effect of treatment with the insulin sensitizer, pioglitazone, the tumor necrosis factor-alpha inhibitor, pentoxifylline, and the antioxidant, melatonin and their combinations in rats with NAFLD. Rats were fed a high-fat diet (HFD) for eight weeks to induce NAFLD. For an additional eight weeks, rats were fed the HFD along with pioglitazone, pentoxifylline, melatonin alone or in combination. Liver index and insulin resistance index were calculated. Serum liver enzyme activities, total cholesterol, triglycerides and tumor necrosis factor-alpha (TNF-alpha) were determined. Tissue triglycerides, malondialdehyde and reduced glutathione were measured and liver injury was evaluated by histopathological examination. HFD induced severe hepatic steatosis, inflammation and fibrosis. In addition, liver index, insulin resistance index, activities of liver enzymes and serum level of total cholesterol, triglycerides and TNF-alpha were elevated. This was coupled with an increase in tissue triglycerides, malondialdehyde and depletion of reduced glutathione. Pioglitazone, pentoxifylline and melatonin, alone or in combination; reduced the insulin resistance index, activities of liver enzymes, hepatic malondialdehyde and increased hepatic reduced glutathione level. Pentoxifylline led to a decrease in serum TNF-alpha level, however, pioglitazone and melatonin reduced serum total cholesterol and triglycerides. In conclusion, data in this study indicate that pentoxifylline and melatonin can be used as promising adjuvant therapies to pioglitazone in the clinical management of NAFLD. PMID- 21549114 TI - Hepatoprotective activity of a vinylic telluride against acute exposure to acetaminophen. AB - Acetaminophen (APAP) hepatotoxicity has been related with several cases of cirrhosis, hepatitis and suicides attempts. Notably, oxidative stress plays a central role in the hepatic damage caused by APAP and antioxidants have been tested as alternative treatment against APAP toxicity. In the present study, we observed the hepatoprotector activity of the diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP), an organotellurium compound with low toxicity and high antioxidant potential. When the dose of 200 mg/kg of APAP was used, we observed that all used doses of DPTVP were able to restore the -SH levels that were depleted by APAP. Furthermore, the increase in thiobarbituric acid reactive substances levels and in the seric alanine aminotransferase (ALT) activity and the histopathological alterations caused by APAP were restored to control levels by DPTVP (30, 50 and 100 MUmol/kg). On the other hand, when the 300 mg/kg dose of APAP was used, DPTVP restored the non-proteic -SH levels and repaired the normal liver morphology of the intoxicated mice only at 50 MUmol/kg. Our in vitro results point out to a scavenging activity of DPTVP against several reactive species, action that is attributed to its chemical structure. Taken together, our results demonstrate that the pharmacological action of DPTVP as a hepatoprotector is probably due to its scavenging activity related to its chemical structure. PMID- 21549115 TI - Effects of baicalein and wogonin isolated from Scutellaria baicalensis roots on skin damage in acute UVB-irradiated hairless mice. AB - Solar ultraviolet (UV) radiation causes skin damage including increases in skin thickness, edema, and flush. In this study, we examined the effects of two main flavonoids (wogonin and baicalein) isolated from the roots of Scutellaria baicalensis, a traditional remedy for allergic inflammatory diseases long used in China and Japan, on acute UVB irradiation-induced skin damage in hairless mice. Baicalein and wogonin (10 or 50 mg/kg) were administered orally twice daily for 14 consecutive days. The UVB irradiation was performed at a dose of 200 mJ/cm(2) on days 7 and 8 of the treatment with the two main flavonoids. Baicalein, and wogonin prevented the increases in skin thickness and the levels of matrix metalloproteinase (MMP)-9, and vascular endothelial growth factor (VEGF) induced by the irradiation. Wogonin reduced the levels of cyclooxygenase (COX)-2 and hypoxia inducible factor (HIF)-1alpha in UVB-treated HaCaT cells. These findings suggest that wogonin inhibits irradiation-induced skin damage by suppressing increases in the levels of MMP-9, and VEGF through the inhibition of COX-2 and HIF-1alpha expression. Baicalein inhibited COX-2 and NF-kappaB/p65 expression, but stimulated HIF-1alpha expression. Therefore, its inhibitory action is likely due to the expression of MMP-9 and VEGF through the suppression of COX-2 and NF kappaB/p65 expression. Furthermore, the inhibitory effects of baicalein on UVB irradiated hyperplasia of skin epidermis may be due to the stimulation of HIF 1alpha expression. PMID- 21549117 TI - Force measurements of the disruption of the nascent polypeptide chain from the ribosome by optical tweezers. AB - We show that optical tweezers are a valuable tool to study the co-translational folding of a nascent polypeptide chain at the ribosome in real-time. The aim of this study was to demonstrate that a stable and intact population of ribosomes can be tethered to polystyrene beads and that specific hook-ups to the nascent polypeptide chain by dsDNA handles, immobilized on a second bead, can be detected. A rupture force of the nascent chain in the range of 10-50 pN was measured, which demonstrates that the system is anchored to the surface in a stable and specific way. This will allow in numerous future applications to follow protein folding using much lower forces. PMID- 21549116 TI - Behavioral sensitization and cross-sensitization between methylphenidate amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in female SD rats. AB - The psychostimulants amphetamine and methylphenidate (MPD/Ritalin) are the drugs most often used to treat attention deficit hyperactivity disorder (ADHD). In addition, students of all ages take these drugs to improve academic performance but also abuse them for pleasurable enhancement. In addition, other psychostimulants such as 3,4-methylenedioxymethamphetamine (MDMA/ecstasy) are used/abused for similar objectives. One of the experimental markers for the potential of a drug to produce dependence is its ability to induce behavioral sensitization and cross sensitization with other drugs of abuse. The objective of this study is to use identical experimental protocols and behavioral assays to compare in female rats the effects of amphetamine, MPD and MDMA on locomotor activity and to determine if they induce behavioral sensitization and/or cross sensitization with each other. The main findings of this study are as follows: (1) acute amphetamine, MPD and MDMA all elicited increases in locomotor activity; (2) chronic administration of an intermediate dose of amphetamine or MPD elicited behavioral sensitization; (3) chronic administration of MDMA elicited behavioral sensitization in some animals and behavioral tolerance in others; (4) cross sensitization between MPD and amphetamine was observed; and (5) MDMA did not show either cross sensitization or cross tolerance with amphetamine. In conclusion, these results suggest that MDMA acts by different mechanisms compared to MPD and amphetamine. PMID- 21549118 TI - Tissue-specific thyroid hormone regulation of gene transcripts encoding iodothyronine deiodinases and thyroid hormone receptors in striped parrotfish (Scarus iseri). AB - In fish as in other vertebrates, the diverse functions of thyroid hormones are mediated at the peripheral tissue level through iodothyronine deiodinase (dio) enzymes and thyroid hormone receptor (tr) proteins. In this study, we examined thyroid hormone regulation of mRNAs encoding the three deiodinases dio1, dio2 and dio3 - as well as three thyroid hormone receptors tralphaA, tralphaB and trbeta - in initial phase striped parrotfish (Scarus iseri). Parrotfish were treated with dissolved phase T(3) (20 nM) or methimazole (3 mM) for 3 days. Treatment with exogenous T(3) elevated circulating T(3), while the methimazole treatment depressed plasma T(4). Experimentally-induced hyperthyroidism increased the relative abundance of transcripts encoding tralphaA and trbeta in the liver and brain, but did not affect tralphaB mRNA levels in either tissue. In both sexes, methimazole-treated fish exhibited elevated dio2 transcripts in the liver and brain, suggesting enhanced outer-ring deiodination activity in these tissues. Accordingly, systemic hyperthyroidism elevated relative dio3 transcript levels in these same tissues. In the gonad, however, patterns of transcript regulation were distinctly different with elevated T(3) increasing mRNAs encoding dio2 in testicular and ovarian tissues and dio3, tralphaA and tralphaB in the testes only. Thyroid hormone status did not affect dio1 transcript abundance in the liver, brain or gonads. Taken as a whole, these results demonstrate that thyroidal status influences relative transcript abundance for dio2 and dio3 in the liver, provide new evidence for similar patterns of dio2 and dio3 mRNA regulation in the brain, and make evident that fish exhibit tr subtype-specific transcript abundance changes to altered thyroid status. PMID- 21549119 TI - Testosterone modulation of cardiac beta-adrenergic signals in a rat model of heart failure. AB - In this study, we examined the effects of castration and testosterone replacement on beta-adrenoceptor and G protein expression in rats subjected to doxorubicin induced heart failure. Five groups were included in this report: control, sham castration with heart failure, castration with heart failure, castration+testosterone replacement with heart failure and castration+testosterone replacement and flutamide with heart failure. At 4 weeks post-treatment, echocardiography, hemodynamics and histopathology were assessed. Castration led to a further deterioration in myocardial performance, apoptosis and fibrosis, while testosterone replacement ameliorated these effects. Data obtained from Western blots revealed that testosterone upregulated the expression of beta(2)-adrenoceptor, Gs, Gi(2) and bcl2 levels, downregulated the expression of beta(3)-adrenoceptor, Gi(3) and GRK2 levels, and did not modify the expression of beta(1)-adrenoceptor levels in the hearts of castrated rats subjected to doxorubicin-induced heart failure. Analyses of serum 17beta-estradiol concentrations test confirmed that these effects of testosterone were exerted through the androgen pathway. Thus our findings suggest that testosterone may have beneficial effects for male heart failure patients with androgen deficiency and this protection involves modulation of the cardiac beta-adrenergic system. PMID- 21549120 TI - Effect of cortisol on permeability and tight junction protein transcript abundance in primary cultured gill epithelia from stenohaline goldfish and euryhaline trout. AB - Primary cultured gill epithelia from goldfish and rainbow trout were used to investigate a role for cortisol in the regulation of paracellular permeability and tight junction (TJ) protein transcript abundance in representative stenohaline versus euryhaline freshwater (FW) fish gills. Glucocorticoid and mineralocorticoid receptors are expressed in cultured goldfish gill preparations and cortisol treatment (100, 500 and 1000 ng/mL) dose-dependently elevated transepithelial resistance (TER) and reduced paracellular [(3)H]PEG-4000 flux across cultured goldfish gill epithelia. Despite these dose-dependent 'tightening' effects of cortisol, the response of goldfish TJ protein transcripts (i.e. occludin, claudin b, c, d, e, h, 7, 8d and 12, and ZO-1) were surprisingly small, with only claudin c and h, and ZO-1 transcript levels significantly decreasing at a dose of 1000 ng/mL. Extending the duration of cortisol exposure from 24 to 48 or 96 h (at 500 ng/mL) did little to alter this phenomenon. By comparison, exposing primary cultured trout gill epithelia (i.e. a euryhaline fish gill model) to 500 ng/mL cortisol resulted in a qualitatively similar, but quantitatively stronger epithelial 'tightening' response. Furthermore, transcript abundance of orthologous trout TJ proteins (i.e. occludin, and claudin 30, 28b, 3a, 7, 8d and 12) significantly elevated as would be expected in a 'tighter' epithelium. Taken together, data suggest a conservative role for cortisol in the endocrine regulation of paracellular permeability across the goldfish gill that may relate to stenohalinity. PMID- 21549121 TI - Environmental enrichment affects adrenocortical stress responses in the endangered black-footed ferret. AB - Potential stressors of wildlife living in captivity, such as artificial living conditions and frequent human contact, may lead to a higher occurrence of disease and reduced reproductive function. One successful method used by wildlife managers to improve general well-being is the provision of environmental enrichment, which is the practice of providing animals under managed care with environmental stimuli. The black-footed ferret (Mustela nigripes) is a highly endangered carnivore species that was rescued from extinction by removal of the last remaining individuals from the wild to begin an ex situ breeding program. Our goal was to examine the effect of environmental enrichment on adrenocortical activity in ferrets by monitoring fecal glucocorticoid metabolites (FGM). Results demonstrated that enrichment lowered FGM in juvenile male ferrets, while increasing it in adult females; enrichment had no effect on FGM in juvenile females and adult males. These results correspond with our findings that juvenile males interacted more with the enrichment items than did adult females. However, we did not detect an impact of FGM on the incidence of disease or on the ability of ferrets to become reproductive during the following breeding season. We conclude that an environmental enrichment program could benefit captive juvenile male ferrets by reducing adrenocortical activity. PMID- 21549122 TI - Invader danger: lizards faced with novel predators exhibit an altered behavioral response to stress. AB - Animals respond to stressors by producing glucocorticoid stress hormones, such as corticosterone (CORT). CORT acts too slowly to trigger immediate behavioral responses to a threat, but can change longer-term behavior, facilitating an individual's survival to subsequent threats. To be adaptive, the nature of an animal's behavior following elevated CORT levels should be matched to the predominant threats that they face. Seeking refuge following a stressful encounter could be beneficial if the predominant predator is a visual hunter, but may prove detrimental when the predominant predator is able to enter these refuge sites. As a result, an individual's behavior when their CORT levels are high may differ among populations of a single species. Invasive species impose novel pressures on native populations, which may select for a shift in their behavior when CORT levels are high. We tested whether the presence of predatory invasive fire ants (Solenopsis invicta) at a site affects the behavioral response of native eastern fence lizards (Sceloporus undulatus) to elevated CORT levels. Lizards from an uninvaded site were more likely to hide when their CORT levels were experimentally elevated; a response that likely provides a survival advantage for lizards faced with native predatory threats (e.g. birds and snakes). Lizards from a fire ant invaded site showed the opposite response; spending more time moving and up on the basking log when their CORT levels were elevated. Use of the basking log likely reflects a refuge-seeking behavior, rather than thermoregulatory activity, as selected body temperatures were not affected by CORT. Fleeing off the ground may prove more effective than hiding for lizards that regularly encounter small, terrestrially-foraging fire ant predators. This study suggests that invasive species may alter the relationship between the physiological and behavioral stress response of native species. PMID- 21549123 TI - Molecular characterization of an ecdysteroid inducible carboxylesterase with GQSCG motif in the corn borer, Sesamia nonagrioides. AB - We obtained a full-length cDNA encoding a carboxylesterase in Sesamia nonagrioides. The complete cDNA sequence is comprised of 1838 bp with an open reading frame encoding 576 amino acid residues with predicted molecular mass of 64.24 kDa. The deduced amino acid sequence showed high identity to JHE-Related of Trichoplusia ni (65% amino acid identity) and 49-46% amino acid identity to JHEs of other lepidopterans and contained all five functional motifs of insect JHEs. The gene has been termed as SnJHE-Related (SnJHER) to denote its similarity to other insect JHE genes and the occurrence of an unusual cysteine residue immediately adjacent to the catalytic serine, instead of the conventional alanine residue. Phylogenetic analyses localised SnJHER together with TnJHER in a branch of the lepidopteran's JHEs group, with other carboxylesterases (COEs) occuring in separated groups. The JH analog methoprene did not affect the expression of SnJHER in contrast to other insect JHEs. Additionally, ecdysteroid analogs induced SnJHER gene expression. The SnJHER mRNA levels were higher in long-day non-diapausing larvae than in short-day diapausing ones. In the fifth instar of non-diapausing and ninth instar of diapausing larvae, the SnJHER mRNAs reached higher expression levels on the days close to each larval molt. In the last (sixth) non-diapausing larval instar, SnJHER mRNA levels peaked in the intermolt period but were lower than during the fifth instar. PMID- 21549124 TI - Novel targets for the treatment of heart failure: perspectives from a heart failure clinician and trialist. PMID- 21549125 TI - Preclinical studies of human disease: time to take methodological quality seriously. PMID- 21549126 TI - Mapping of DNA binding sites in the Tetrahymena telomerase holoenzyme proteins by UV cross-linking and mass spectrometry. AB - The Tetrahymena telomerase holoenzyme consists of a major catalytic protein [telomerase reverse transcriptase (TERT)], an RNA subunit, and accessory proteins. We used site-specific UV cross-linking and mass spectrometry to map interactions between the holoenzyme and the telomeric DNA. In one series of experiments, an oligodeoxyribonucleotide containing a 5-iododeoxyuridine residue or 4-thio-deoxythymidine residue was cross-linked to the telomerase by irradiation with UV light-emitting diodes. The DNA was extended by the cross linked enzyme with a radioactively labeled or unlabeled nucleotide. The complexes were subsequently resolved by SDS-PAGE. Proteins were isolated from strips in the unlabeled gels corresponding to bands observed in the radioactive gels. Mass spectrometric analysis of these proteins revealed a major cross-linking site in TERT. Serendipitous cleavage of TERT near amino acid 254 indicated that this site maps within the N-terminal cleavage product, which includes primarily the telomerase essential N-terminal (TEN) domain. Moreover, the absence of this N terminal segment in TERT was found to cause a reduction in DNA binding by the telomerase and/or its activity to undetectable levels. In other experiments, similar unresolved cross-linked complexes were digested with trypsin, two exonucleases, and alkaline phosphatase. Tandem mass spectrometry was then used to search for peptides linked to the residual deoxyribonucleoside. Using this approach, we identified the phenylalanine residue F351 in the accessory protein p45 as a minor DNA cross-linking site. Our study constitutes the first direct mapping of DNA interaction sites in telomerase holoenzyme complexes. This mapping represents a significant contribution to the understanding of the mechanism of telomere extension by telomerase. PMID- 21549127 TI - ICF syndrome mutations cause a broad spectrum of biochemical defects in DNMT3B mediated de novo DNA methylation. AB - The DNMT3B de novo DNA methyltransferase (DNMT) plays a major role in establishing DNA methylation patterns in early mammalian development, but its catalytic mechanism remains poorly characterized. Here, we provide a comprehensive biochemical analysis of human DNMT3B function through the characterization of a series of site-directed DNMT3B variants associated with immunodeficiency, centromere instability, and facial anomalies (ICF) syndrome. Our data reveal several novel and important aspects of DNMT3B function. First, DNMT3B, unlike DNMT3A, requires a DNA cofactor in order to stably bind to S adenosyl-l-methionine (SAM), suggesting that it proceeds according to an ordered catalytic scheme. Second, ICF mutations cause a broad spectrum of biochemical defects in DNMT3B function, including defects in homo-oligomerization, SAM binding, SAM utilization, and DNA binding. Third, all tested ICF mutations, including the A766P and R840Q variants, result in altered catalytic properties without interfering with DNMT3L-mediated stimulation; this indicates that DNMT3L is not involved in the pathogenesis of ICF syndrome. Finally, our study reveals a novel level of coupling between substrate binding, oligomerization, and catalysis that is likely conserved within the DNMT3 family of enzymes. PMID- 21549128 TI - ALS-causing SOD1 mutations promote production of copper-deficient misfolded species. AB - Point mutations scattered throughout the sequence of Cu,Zn superoxide dismutase (SOD1) cause a subset of amyotrophic lateral sclerosis (ALS) cases. SOD1 is a homodimer in which each subunit binds one copper atom and one zinc atom. Inclusions containing misfolded SOD1 are seen in motor neurons of SOD1-associated ALS cases. The mechanism by which these diverse mutations cause misfolding and converge on the same disease is still not well understood. Previously, we developed several time-resolved techniques to monitor structural changes in SOD1 as it unfolds in guanidine hydrochloride. By measuring the rates of Cu and Zn release using an absorbance-based assay, dimer dissociation through chemical cross-linking, and beta-barrel conformation changes by tryptophan fluorescence, we established that wild-type SOD1 unfolds by a branched pathway involving a Zn deficient monomer as the dominant intermediate of the major pathway, and with various metal-loaded and Cu-deficient dimers populated along the minor pathway. We have now compared the unfolding pathway of wild-type SOD1 with those of A4V, G37R, G85R, G93A, and I113T ALS-associated mutant SOD1. The kinetics of unfolding of the mutants were generally much faster than those of wild type. However, all of the mutants utilize the minority pathway to a greater extent than the wild type protein, leading to greater populations of Cu-deficient intermediates and decreases in Zn-deficient intermediates relative to the wild-type protein. The greater propensity of the mutants to populate Cu-deficient states potentially implicates these species as a pathogenic form of SOD1 in SOD1-associated ALS and provides a novel target for therapeutic intervention. PMID- 21549129 TI - Unexpected active-site flexibility in the structure of human neutrophil elastase in complex with a new dihydropyrimidone inhibitor. AB - Human neutrophil elastase (HNE), a trypsin-type serine protease, is of pivotal importance in the onset and progression of chronic obstructive pulmonary disease (COPD). COPD encompasses a group of slowly progressive respiratory disorders and is a major medical problem and the fifth leading cause of death worldwide. HNE is a major target for the development of compounds that inhibit the progression of long-term lung function decline in COPD patients. Here, we present the three dimensional structure of a potent dihydropyrimidone inhibitor (DHPI) non covalently bound to HNE at a resolution of 2.0 A. The inhibitor binds to the active site in a unique orientation addressing S1 and S2 subsites of the protease. To facilitate further analysis of this binding mode, we determined the structure of the uncomplexed enzyme at a resolution of 1.86 A. Detailed comparisons of the HNE:DHPI complex with the uncomplexed HNE structure and published structures of other elastase:inhibitor complexes revealed that binding of DHPI leads to large conformational changes in residues located in the S2 subsite. The rearrangement of residues Asp95-Leu99B creates a deep, well-defined cavity, which is filled by the P2 moiety of the inhibitor molecule to almost perfect shape complementarity. The shape of the S2 subsite in complex with DHPI clearly differs from all other observed HNE structures. The observed structural flexibility of the S2 subsite is a key feature for the understanding of the binding mode of DHPIs in general and the development of new HNE selective inhibitors. PMID- 21549130 TI - Dark matters: exploitation as cooperation. AB - The empirical literature on human cooperation contains studies of communitarian institutions that govern the provision of public goods and management of common property resources in poor countries. Scholars studying those institutions have frequently used the Prisoners' Dilemma game as their theoretical tool-kit. But neither the provision of local public goods nor the management of local common property resources involves the Prisoners' Dilemma. That has implications for our reading of communitarian institutions. By applying a fundamental result in the theory of repeated games to a model of local common property resources, it is shown that communitarian institutions can harbour exploitation of fellow members, something that would not be possible in societies where cooperation amounts to overcoming the Prisoners' Dilemma. The conclusion we should draw is that exploitation can masquerade as cooperation. PMID- 21549131 TI - Heterogeneity in predator micro-habitat use and the maintenance of Mullerian mimetic diversity. AB - Mullerian mimicry, where groups of chemically defended species display a common warning color pattern and thereby share the cost of educating predators, is one of the most striking examples of ecological adaptation. Classic models of Mullerian mimicry predict that all unpalatable species of a similar size and form within a community should converge on a single mimetic pattern, but instead communities of unpalatable species often display a remarkable diversity of mimetic patterns (e.g. neotropical ithomiine butterflies). It has been suggested that this apparent paradox may be explained if different suites of predators and species belonging to different mimicry groups utilize different micro-habitats within the community. We developed a stochastic individual-based model for a community of unpalatable mimetic prey species and their predators to evaluate this hypothesis and to examine the effect of predator heterogeneity on prey micro habitat use. We found that community-level mimetic diversity was higher in simulations with heterogeneous predator micro-habitat use than in simulations with homogeneous predator micro-habitat use. Regardless of the form of predation, mimicry pattern-based assortative mating caused community-level mimetic diversity to persist. Heterogeneity in predator micro-habitat use led to an increased association between mimicry pattern and prey micro-habitat use relative to homogeneous predator micro-habitat use. This increased association was driven, at least in part, by evolutionary convergence of prey micro-habitat use when predators displayed heterogeneous micro-habitat use. These findings provide a theoretical explanation for an important question in evolutionary biology: how is community-level Mullerian mimetic diversity maintained in the face of selection against rare phenotypes? PMID- 21549133 TI - MiRNAs as regulators of the response to inhaled environmental toxins and airway carcinogenesis. AB - miRNAs are a class of small, noncoding RNAs averaging 22 nucleotides in length that down-regulate gene expression by complimentary binding to the 3' UTR of target genes. A growing body of research suggests that these small RNA species play significant roles in modulating the cellular response to a variety of types of stress. In this review, we summarize the available literature regarding the general response of miRNA to cellular stress, and then specifically focus on the miRNA response to inhaled toxins. These miRNA responses to inhaled toxins appear to be recapitulated in lung carcinogenesis, opening the possibility that modulation of the miRNA response could be a novel strategy for chemoprevention. PMID- 21549134 TI - Accelerated long-term forgetting in temporal lobe but not idiopathic generalised epilepsy. AB - Temporal lobe epilepsy (TLE) has been associated with the phenomenon of accelerated long-term forgetting (ALF), in which memories are retained normally over short delays but are then lost at an accelerated rate over days or weeks. The causes of ALF, and whether it represents a consolidation deficit distinct from the one associated with forgetting over short delays, remain unclear. In addition, methodological issues have made results of some previous studies difficult to interpret. This study used improved methodology to investigate the role of seizure activity in ALF. Forgetting was assessed in participants with TLE (who have involvement of temporal lobe structures) and idiopathic generalised epilepsy (IGE; in which seizures occur in the absence of identified structural pathology in the temporal lobes). Learning of novel stimuli was matched between patients with TLE, patients with IGE and healthy controls matched for age and IQ. Results indicated that the TLE group showed accelerated forgetting between 30-min and three-weeks, but not between 40-s and 30-min. In contrast, rates of forgetting did not differ between patients with IGE and controls. We conclude that (1) ALF can be demonstrated in TLE in the absence of methodological confounds; (2) ALF is unlikely to be related to the experience of epilepsy that does not involve the temporal lobes; (3) neither seizures during the three-week delay nor polytherapy was associated with ALF. PMID- 21549132 TI - Interplay between FAK, PKCdelta, and p190RhoGAP in the regulation of endothelial barrier function. AB - Disruption of either intercellular or extracellular junctions involved in maintaining endothelial barrier function can result in increased endothelial permeability. Increased endothelial permeability, in turn, allows for the unregulated movement of fluid and solutes out of the vasculature and into the surrounding connective tissue, contributing to a number of disease states, including stroke and pulmonary edema (Ermert et al., 1995; Lee and Slutsky, 2010; van Hinsbergh, 1997; Waller et al., 1996; Warboys et al., 2010). Thus, a better understanding of the molecular mechanisms by which endothelial cell junction integrity is controlled is necessary for development of therapies aimed at treating such conditions. In this review, we will discuss the functions of three signaling molecules known to be involved in regulation of endothelial permeability: focal adhesion kinase (FAK), protein kinase C delta (PKCdelta), and p190RhoGAP (p190). We will discuss the independent functions of each protein, as well as the interplay that exists between them and the effects of such interactions on endothelial function. PMID- 21549135 TI - Bulimia nervosa and evidence for striatal dopamine dysregulation: a conceptual review. AB - OBJECTIVE: This article reviews concepts and evidence, based in particular on the work of Bartley G. Hoebel and colleagues, which suggest that a better understanding of the role of striatal dopamine (DA) in the initiation and/or maintenance of bulimia nervosa (BN) may result in a clearer characterization of mechanisms underlying BN. METHODS: Literature review, using PubMed search. RESULTS: Several lines of evidence, including the work of Bartley G. Hoebel, implicate the importance of striatal DA in feeding behavior, as well as in the disordered eating behaviors relevant to BN. Preclinical models of 'BN-like' eating behaviors have been associated with changes in striatal DA and DA receptor measures. Emerging clinical research also suggests that striatal DA abnormalities exist in individuals with BN. CONCLUSION: Alterations in striatal DA may exist in patients with BN. While the precise relationship between these findings and the etiology and maintenance of bulimic symptomatology remains unclear, further investigation of brain DA systems is a fruitful avenue of future research in BN. PMID- 21549138 TI - Psychoactive effects of tasting chocolate and desire for more chocolate. AB - The purpose of this study was to characterize the psychoactive effects of tasting chocolate and to evaluate the contribution of the main chocolate components to the desire to consume more of it. A total of 280 participants, (F-155; M=125) ranging in age from 18-65, completed the study. Participants were randomly assigned to taste 12.5 g of either white chocolate ("control") or one of four chocolate ("cocoa") samples varying in sugar, fat and percent cocoa content, then answered the question: "Do you want more of this chocolate?" and "If yes, how many more pieces of this chocolate would you like to eat?" They completed pre- and post-consumption surveys, consisting of 30 questions derived from the Addiction Research Center Inventory (ARCI) subscales, Morphine-Benzedrine Group (MBG), Morphine (M) and Excitement (E). Significant decreases in post-pre consumption changes in MBG subscale were observed between the control sample and the 70% cocoa (p=0.046) or the 85% cocoa sample (p=0.0194). Proportionally more men than women wanted more of the tasted chocolate (p=0.035). Participants were more likely to want more of the tasted chocolate if they displayed a greater change in the MBG scale, and if their chocolate sample had high sugar and cocoa content, as assessed by multiple logistic regression. Our results suggest that multiple characteristics of chocolate, including sugar, cocoa and the drug-like effects experienced, play a role in the desire to consume chocolate. PMID- 21549136 TI - Feeding and reward: perspectives from three rat models of binge eating. AB - Research has focused on understanding how overeating can affect brain reward mechanisms and subsequent behaviors, both preclinically and in clinical research settings. This work is partly driven by the need to uncover the etiology and possible treatments for the ongoing obesity epidemic. However, overeating, or non homeostatic feeding behavior, can occur independent of obesity. Isolating the variable of overeating from the consequence of increased body weight is of great utility, as it is well known that increased body weight or obesity can impart its own deleterious effects on physiology, neural processes, and behavior. In this review, we present data from three selected animal models of normal-weight non homeostatic feeding behavior that have been significantly influenced by Bart Hoebel's 40+-yr career studying motivation, feeding, reinforcement, and the neural mechanisms that participate in the regulation of these processes. First, a model of sugar bingeing is described (Avena/Hoebel), in which animals with repeated, intermittent access to a sugar solution develop behaviors and brain changes that are similar to the effects of some drugs of abuse, serving as the first animal model of food addiction. Second, another model is described (Boggiano) in which a history of dieting and stress can perpetuate further binge eating of palatable and non-palatable food. In addition, a model (Boggiano) is described that allows animals to be classified as having a binge-prone vs. binge resistant behavioral profile. Lastly, a limited access model is described (Corwin) in which non-food deprived rats with sporadic limited access to a high fat food develop binge-type behaviors. These models are considered within the context of their effects on brain reward systems, including dopamine, the opioids, cholinergic systems, serotonin, and GABA. Collectively, the data derived from the use of these models clearly show that behavioral and neuronal consequences of bingeing on a palatable food, even when at a normal body weight, are different from those that result from simply consuming the palatable food in a non-binge manner. These findings may be important in understanding how overeating can influence behavior and brain chemistry. PMID- 21549137 TI - Neurobiology of aversive states. AB - Hoebel and colleagues are often known as students of reward and how it is coded in the CNS. This article, however, attempts to focus on the significant advances by Hoebel and others in dissecting out behavioral components of distinct aversive states and in understanding the neurobiology of aversion and the link between aversive states and addictive behaviors. Reward and aversion are not necessarily dichotomous and may reflect an affective continuum contingent upon environmental conditions. Descriptive and mechanistic studies pioneered by Bart Hoebel have demonstrated that the shift in the reward-aversion spectrum may be, in part, a result of changes in central dopamine/acetylcholine ratio, particularly in the nucleus accumbens. The path to aversion appears to include a specific neurochemical signature: reduced dopamine release and increased acetylcholine release in "reward centers" of the brain. Opioid receptors may have a neuromodulatory role on both of these neurotransmitters. PMID- 21549140 TI - The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: ensuing energetic and oxidative stress implications. AB - Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 MUM) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca2+ efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP+ transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. PMID- 21549139 TI - The reinforcement-enhancing effects of nicotine: implications for the relationship between smoking, eating and weight. AB - Concerns about body weight represent an important barrier to public health efforts aimed at reducing smoking. Epidemiological studies have found that current smokers weigh less than non-smokers, smoking cessation results in weight gain, and weight restriction is commonly cited as a reason for smoking. The mechanisms underlying the relationship between smoking and weight are complex and may involve a number of factors including changes in caloric intake, physical activity, metabolic rate, and lipogenesis. Amongst these possible mechanisms, nicotine-induced enhancement of food reinforcement may be particularly important. In this paper, we first review data from our laboratory that highlight two distinct ways in which nicotine impacts reinforced behavior: 1) by acting as a primary reinforcer; and 2) by directly (non-associatively) enhancing the reinforcing effects of other stimuli. We then elaborate on the reinforcement enhancing effects of nicotine as they pertain to behaviors and stimuli related to food. Data from both laboratory animals and humans support the assertion that nicotine enhances the reinforcing efficacy of food and suggest that the influence of these effects on eating may be most important after nicotine cessation when nicotine's effects on satiety subside. Finally, we discuss the theoretical and clinical implications of this perspective for understanding and addressing the apparent tradeoff between smoking and weight gain. Better understanding of the mechanisms underlying the reinforcement-enhancing effects of nicotine broadly, and the effects on food reinforcement per se, may aid in the development of new treatments with better long term outcomes. PMID- 21549141 TI - Toluene effects on oxidative stress in brain regions of young-adult, middle-age, and senescent Brown Norway rats. AB - The influence of aging on susceptibility to environmental contaminants is not well understood. To extend knowledge in this area, we examined effects in rat brain of the volatile organic compound, toluene. The objective was to test whether oxidative stress (OS) plays a role in the adverse effects caused by toluene exposure, and if so, if effects are age-dependent. OS parameters were selected to measure the production of reactive oxygen species (NADPH Quinone oxidoreductase 1 (NQO1), NADH Ubiquinone reductase (UBIQ-RD)), antioxidant homeostasis (total antioxidant substances (TAS), superoxide dismutase (SOD), gamma-glutamylcysteine synthetase (gamma-GCS), glutathione transferase (GST), glutathione peroxidase (GPX), glutathione reductase (GRD)), and oxidative damage (total aconitase and protein carbonyls). In this study, Brown Norway rats (4, 12, and 24 months) were dosed orally with toluene (0, 0.65 or 1g/kg) in corn oil. Four hours later, frontal cortex, cerebellum, striatum, and hippocampus were dissected, quick frozen on dry ice, and stored at -80 degrees C until analysis. Some parameters of OS were found to increase with age in select brain regions. Toluene exposure also resulted in increased OS in select brain regions. For example, an increase in NQO1 activity was seen in frontal cortex and cerebellum of 4 and 12 month old rats following toluene exposure, but only in the hippocampus of 24 month old rats. Similarly, age and toluene effects on glutathione enzymes were varied and brain-region specific. Markers of oxidative damage reflected changes in oxidative stress. Total aconitase activity was increased by toluene in frontal cortex and cerebellum at 12 and 24 months, respectively. Protein carbonyls in both brain regions and in all age groups were increased by toluene, but step-down analyses indicated toluene effects were statistically significant only in 12month old rats. These results indicate changes in OS parameters with age and toluene exposure resulted in oxidative damage in frontal cortex and cerebellum of 12 month old rats. Although increases in oxidative damage are associated with increases in horizontal motor activity in older rats, further research is warranted to determine if these changes in OS parameters are related to neurobehavioral and neurophysiological effects of toluene in animal models of aging. PMID- 21549142 TI - Adapted response of the antioxidant defense system to oxidative stress induced by deoxynivalenol in Hek-293 cells. AB - The mycotoxin deoxynivalenol (DON), a contaminant of certain foods and feeds, is cytotoxic and genotoxic to mammalians cells. Exposure of human embryonic kidney (Hek-293) cells to DON led to a dose- and time-dependent decrease in cell viability, with an IC(50) about 7.6 MUM. The DON effects on Hek-293 morphology, reactive oxygen species, lipid peroxidation and antioxidative system and caspase 3 and bcl-2 expression were studied. Cells became round and in some are progressive loss of cell attachment appeared. These biochemical parameters were assessed after 6, 12 and 24 h of treatment with 2.5 and 5 MUM DON. An increase in superoxide dismutase activity within the interval 6-12 h and almost complete recovery by the end of experiment for both concentrations was observed, whereas the profile of catalase activity was the same with the superoxide dismutase one for 2.5 MUM and decreased in a time-dependent manner for 5 MUM. A temporary activation of glutathione peroxidase and glutathione reductase was recorded at 12 h post-exposure, while the glutathione-S-transferase activity was unchanged for both concentrations. The NADP(+)-dependent isocitrate dehydrogenase activity showed a transient increase at the 12 h post-exposure. The caspase 3 expression remained unchanged and the bcl-2 one decreased after 24 h of exposure for the two concentrations. Our results showed the dose- and time specific changes in the antioxidants system of Hek-293 cells, which could not counteract efficiently the effects DON exposure. The different types of cell death which could be activated by this DON induced changes are mentioned. PMID- 21549143 TI - Neutralization of Bothrops alternatus regional venom pools and individual venoms by antivenom: a systematic comparison. AB - In this study we report that variation in lethality, hemorrhagic potency and procoagulation between individual samples of Bothrops alternatus venom from a single region, and variation between regional pools at the national level are comparable in range. Furthermore, the range of relative neutralization potencies of individual venoms within a region overlaps, and sometimes exceeds, the range of neutralization of regional venom pools throughout the country. Thus, the potency of neutralization of a national venom pool is poorly predictive of the potencies of neutralization of its constituent regional venom pools and, furthermore, the potency of neutralization of a regional venom pool is poorly predictive of the potencies of neutralization of its individual venom constituents. The efficiencies of neutralization of each of these effects (lethality, hemorrhage and procoagulation) were not significantly related to each other and did not correlate to the corresponding toxic potency of each venom or venom pool. Some implications of these findings are discussed in the context of the distinction between experimental quantitation of antivenom potency and the amount of antivenom that might be actually required to successfully treat two apparently comparable B. alternatus envenomations. PMID- 21549144 TI - ERP evidence for the speed of face categorization in the human brain: Disentangling the contribution of low-level visual cues from face perception. AB - How fast are visual stimuli categorized as faces by the human brain? Because of their high temporal resolution and the possibility to record simultaneously from the whole brain, electromagnetic scalp measurements should be the ideal method to clarify this issue. However, this question remains debated, with studies reporting face-sensitive responses varying from 50 ms to 200 ms following stimulus onset. Here we disentangle the contribution of the information associated with the phenomenological experience of a face (phase) from low-level visual cues (amplitude spectrum, color) in accounting for early face-sensitivity in the human brain. Pictures of faces and of a category of familiar objects (cars), as well as their phase-scrambled versions, were presented to fifteen human participants tested with high-density (128 channels) EEG. We replicated an early face-sensitivity - larger response to pictures of faces than cars - at the level of the occipital event-related potential (ERP) P1 (80- ). However, a similar larger P1 to phase-scrambled faces than phase-scrambled cars was also found. In contrast, the occipito-temporal N170 was much larger in amplitude for pictures of intact faces than cars, especially in the right hemisphere, while the small N170 elicited by phase-scrambled stimuli did not differ for faces and cars. These findings show that sensitivity to faces on the visual evoked potentials P1 and N1 (N170) is functionally dissociated: the P1 face-sensitivity is driven by low-level visual cues while the N1 (or N170) face-sensitivity reflects the perception of a face. Altogether, these observations indicate that the earliest access to a high-level face representation, that is, a face percept, does not precede the N170 onset in the human brain. Furthermore, they allow resolving apparent discrepancies between the timing of rapid human saccades towards faces and the early activation of high-level facial representations as shown by electrophysiological studies in the primate brain. More generally, they put strong constraints on the interpretation of early (before 100 ms) face-sensitive effects in the human brain. PMID- 21549145 TI - On the origin of cancer: can we ignore coherence? AB - A growing number of inconsistencies have accumulated within the genetically deterministic paradigm of the origin of cancer. Among them the most important are the nonspecific nature of cancer mutations and the non-cell-autonomous factors of cancer initiation and progression. Epigenetic aspects of cancer and cancer systems biology represent novel approaches to cancer aetiology and converge in the notion that cancer is characterized by a nonspecific progressive destabilization of multiple molecular pathways. The coherent behaviour of certain cellular subsystems has been theoretically predicted for a long time to have a general role in coordinating biological processes. However, it has only recently gained major scientific interest when it was measured on photosynthetic complexes at physiological temperatures and confirmed to have a direct effect over the dynamics of the energy transfer. Several theoretical and experimental considerations suggest that cancer might be associated with the absence or impairment of the proper coherent dynamics in certain biological structures, most notably in the microtubules. We review those models and suggest that impaired coherence might largely contribute to the progressive destabilization of the molecular and gene regulatory networks, thus connecting different non-genetic aspects of cancer. PMID- 21549147 TI - MRI-based age prediction using hidden Markov models. AB - Cortical thinning and intracortical gray matter volume losses are widely observed in normal ageing, while the decreasing rate of the volume loss in subjects with neurodegenerative disorders such as Alzheimer's disease is reported to be faster than the average speed. Therefore, neurodegenerative disease is considered as accelerated ageing. Accurate detection of accelerated ageing based on the magnetic resonance imaging (MRI) of the brain is a relatively new direction of research in computational neuroscience as it has the potential to offer positive clinical outcome through early intervention. In order to capture the faster structural alterations in the brain with ageing, we propose in this paper a computational approach for modelling the MRI-based structure of the brain using the framework of hidden Markov models, which can be utilized for age prediction. Experiments were carried out on healthy subjects to validate its accuracy and its robustness. The results have shown its ability of predicting the brain age with an average normalized age-gap error of two to three years, which is superior to several recently developed methods for brain age prediction. PMID- 21549146 TI - Powerful behavioral interactions between methamphetamine and morphine. AB - Use of drugs of abuse in combination is common among recreational users and addicts. The combination of a psychomotor stimulant with an opiate, known as a 'speedball,' reportedly produces greater effects than either drug alone and has been responsible for numerous deaths. Historically, the most popular speedball combination is that of cocaine and heroin. However, with the growing popularity of methamphetamine in recent years, there has been increased use of this drug in combination with other drugs of abuse, including opiates. Despite this, relatively little research has examined interactions between methamphetamine and opiates. In the current research, behavioral interactions between methamphetamine and the prototypical opiate, morphine, were examined across a variety of dose combinations in Sprague-Dawley rats. The combination of methamphetamine and morphine produced stimulation of behavior that was dramatically higher than either drug alone; however, the magnitude of the interaction was dependent on the dose of the drugs and the specific behaviors examined. The results demonstrate complex behavioral interactions between these drugs, but are consistent with the idea that this combination is used because it produces a greater effect than either drug alone. PMID- 21549148 TI - Generation and characterisation of monoclonal antibodies against influenza virus A, subtype H5N1. AB - The emergence of highly pathogenic avian influenza A virus (HPAIV) subtype H5N1 in 1997 has since resulted in large outbreaks in poultry and in transmission from poultry to humans, mostly in southeast Asia, but also in several European countries. Effective diagnosis and control measures are essential for the management of HPAIV infections. To develop a rapid diagnostic test, a panel of murine monoclonal antibodies (mAbs) against influenza virus A subtype H5 was generated. Eleven mAbs were produced and characterised according to their reactivity by indirect and sandwich ELISA and western blotting against different H5 subtypes representing past and viruses currently circulating. Ten out of 11 mAbs reacted strongly with the haemagglutinin (HA) protein of H5 viruses, whereas one mAb reacted with the M1 protein. Targeted HA protein epitopes seemed to be conformational. One hybridoma clone binds to a linear epitope of the M1 protein. One specific mAb reacts with HPAIV H5 in the immunofluorescence test, and two antibodies neutralised H5 viruses. On the basis of the results, the set of seven mAbs is appropriate for developing diagnostic tests. With the generated mAbs, a sandwich ELISA was developed recognising all H5N1 strains tested but no other influenza viruses. With this ELISA, as little as 0.005 HA units or 0.1 ng/ml H5N1 was detected, surpassing other ELISA tests. The novel reagents have the potential to improve significantly available rapid antigen detection systems. PMID- 21549149 TI - HIV-1 nucleotide mixture detection in the virco((r))TYPE HIV-1 genotyping assay: a comparison between Sanger sequencing and 454 pyrosequencing. AB - HIV-1 Protease (PR) and Reverse Transcriptase (RT) genotyping is well established for the management of antiretroviral (ARV) drug therapy, as it is able to detect gene mutations encoding resistance to ARV compounds or drug classes, that are associated with reduced drug susceptibility (i.e. phenotype). A correct phenotypic interpretation from the derived PR-RT genotype (i.e. virtual phenotype), requires a well characterized geno-phenotype correlative database and appropriate statistical predictive models. The applicability of the virtual phenotype for the patient, will, however, not only depend on the accuracy of the statistical models and the database they rely on, but also depend largely on the sequence information that is provided. Since HIV-1 evolves as a complex of closely related but non-identical viral genomes (i.e. quasispecies) it is crucial that the sequencing method used, is able to characterize most of the genetic mixtures that make up the different quasispecies within a single patient. US regulatory agencies require that developers of HIV-1 genotyping assays, determine and report the HIV-1 mixture detection level of their assay. Hence, the mixture scoring sensitivity of the population-based Sanger sequencing method, along with the defined mixture scoring rules, used to drive the virco((r))TYPE HIV-1 virtual phenotype, was investigated by comparing it to the 454 pyrosequencing technique, which is able to generate the complete viral population sequence. To this end the PR-RT coding sequence of 20 clinical isolates was determined by both sequencing methodologies. The genotyping assay which feeds the virco((r))TYPE HIV-1 virtual phenotype was able to call automatically 97.5% (i.e. 268 mixtures) and 95.3% (i.e. 326 mixtures) of the mixtures that were present between 25 and 75% and between 20 and 80% in the viral population, as detected by 454. From the not called mixtures, all but one did present a mixture sequence in the Sanger DNA chromatograms, however, with a peak surface area for the second peak that was below the threshold setting for automatic mixture calling in the basecaller software (i.e. 25%). Viral loads ranged from 470 to 629,000 copies/mL and exerted no effect on the mixture calling relationship between both sequencing methodologies (R(2)=0.92). In some occasions (i.e. 55 mixtures) the genotyping assay would detect automatically mixtures that were present below 20% in the viral population, when measured by 454. Hence, the mixture scoring sensitivity of the automated high throughput virco((r))TYPE HIV-1 genotyping assay is currently set at 97.5% and 95.3%, for mixtures present at 25 and 20% in the viral population and may identify occasionally mutations that are present at lower frequencies. These findings were not influenced by the viral load of the examined samples. PMID- 21549150 TI - Real-time polymerase chain reaction assay based on high-resolution melting analysis for the determination of the rs12979860 polymorphism involved in hepatitis C treatment response. AB - Treatment of chronic hepatitis C is associated with varying success rates, substantial medical costs and serious side effects. Several host polymorphisms have been identified near the IL28B gene, of which the homozygous rs12979860 CC was found to be associated with significantly favourable treatment outcome. To determine accurately the presence of this variant, a real-time PCR assay with detection based on post-PCR high-resolution melting analysis (HRM) was developed. The assay, performed on a Roche LightCycler 480, was able to differentiate among all three rs12979860 variants (CC, TT, CT) across a dynamic range of four orders of magnitude (10(3)-10(7)). The sensitivity of the assay was determined at a 95% detection level to be 44.6 copies/reaction for the CC variant, 57.1 copies/reaction for the TT variant and 47.4 copies/reaction for the CT variant. Input DNA amount above 10(3) copies/reaction is recommended for clinical samples to ensure optimal performance. Clinical performance was assessed on 60 clinical samples by comparative testing using the assay and Sanger sequencing. Concordant results were obtained for all 60 samples, showing high specificity of the assay. The novel assay can be easily added to the testing repertoire of virological laboratories, providing additional information for physicians treating chronic hepatitis C patients. PMID- 21549152 TI - Effect of telbivudine therapy on the cellular immune response in chronic hepatitis B. AB - Weak T-cell reactivity to the hepatitis B virus (HBV) is believed to be the dominant cause of chronic HBV infection. Several lines of experimental evidence suggest that treatment with telbivudine increases the rate of HBV e antigen (HBeAg) loss, undetectable HBV DNA, and normalization of serum alanine aminotransferase (ALT) in chronic hepatitis B patients (CHB). However, it is still unclear how early antiviral therapy affects cellular immune responses during sustained telbivudine treatment. In order to investigate this issue, we measured detailed prospective clinical, virological, and biochemical parameters, and we examined the frequency of T cell subgroups as well as the ability of peripheral blood mononuclear cells (PBMC) to respond to stimuli at five protocol time points for 51 CHB patients who received telbivudine therapy for one year. The preliminary data from this study revealed that effective-treated patients showed an increased frequency of peripheral blood CD4(+)T lymphocytes, an augmented proliferative response of HBV-specific T-cells to the hepatitis B core antigen (HBcAg), and the induction of cytokines, such as interferon gamma (IFN gamma), tumour necrosis factor alpha (TNF-alpha) release at the site of infection compared to non-responsive patients. Enhanced HBV-specific T-cell reactivity to telbivudine therapy, which peaked at treatment week 12, was confined to a subgroup of effective-treated patients who achieved greater viral suppression. PMID- 21549151 TI - Characterization of in vivo anti-rotavirus activities of saponin extracts from Quillaja saponaria Molina. AB - Rotavirus is the leading cause of severe diarrhea disease in newborns and young children worldwide with approximately 300,000 pre-adolescent deaths each year. Quillaja saponins are a natural aqueous extract obtained from the Chilean soapbark tree. The extract is approved for use in humans by the FDA for use in beverages as a food addictive. We have demonstrated that Quillaja extracts have strong antiviral activities in vitro against six different viruses. In this study, we evaluated the in vivo antiviral activity of these extracts against rhesus rotavirus (RRV) using a mouse model. We established that at a dosage of 0.015 mg/mouse of saponin extract, RRV induced diarrhea can be significantly reduced from 79% to 11% when mice are exposed to 500 plaque-forming-units (PFU) for each of five consecutive days. Additionally, while a reduction of RRV induced diarrhea depended both on the concentration of virus introduced and on the amount of Quillaja extract given to each mouse, the severity and interval of diarrhea under a variety of conditions tested, in all the treated mice were greatly reduced when compared to those that did not receive the Quillaja extracts. Mechanistically, there is strong evidence that the Quillaja extracts are able to "block" rotavirus infection by inhibiting virus-host attachment through disruption of cellular membrane proteins and/or virus receptors. We believe that Quillaja extracts have promise as antivirals to reduce rotavirus infection and the severity of the disease in humans. PMID- 21549153 TI - Immune responses of chickens inoculated with a recombinant fowlpox vaccine coexpressing HA of H9N2 avain influenza virus and chicken IL-18. AB - Control of the circulation of H9N2 avian influenza virus (AIV) is a major concern for both animal and public health, and H9N2 AIV poses a major threat to the chicken industry worldwide. Here, we developed a recombinant fowlpox virus (rFPV HA) expressing the haemagglutinin (HA) gene of the A/CH/JY/1/05 (H9N2) influenza virus and a recombinant fowlpox virus (rFPV-HA/IL18) expressing the HA gene and chicken interleukin-18 (IL-18) gene. Recombinant plasmid pSY-HA/IL18 was constructed by cloning chicken IL-18 expression cassette into recombinant plasmid pSY-HA containing the HA gene. Two rFPVs were generated by transfecting two recombinant plasmids into the chicken embryo fibroblast cells pre-infected with S FPV-017, and assessed for their immunological efficacy on one-day-old White Leghorn specific-pathogen-free chickens challenged with the A/CH/JY/1/05 (H9N2) strain. There was a significant difference in HI antibody levels (P<0.05) elicited by either rFPV-HA or rFPV-HA/IL18. The level of splenocyte proliferation response in the rFPV-HA/IL18-vaccinated group was significantly higher (P<0.05) than that in the rFPV-HA group. After challenge with 10(6.5)ELD(50) H9N2 AIV 43days after immunization, rFPVs vaccinated groups could prevent virus shedding and replication in multiple organs in response to H9N2 AIV infection, and rFPV HA/IL18 vaccinated group had better inhibition of viruses than rFPV-HA vaccinated group. Our results show that the protective efficacy of the rFPV-HA vaccine could be enhanced significantly by simultaneous expression of IL-18. PMID- 21549155 TI - Persistent behavioral impairments and alterations of brain dopamine system after early postnatal administration of thimerosal in rats. AB - The neurotoxic organomercurial thimerosal (THIM), used for decades as vaccine preservative, is a suspected factor in the pathogenesis of some neurodevelopmental disorders. Previously we showed that neonatal administration of THIM at doses equivalent to those used in infant vaccines or higher, causes lasting alterations in the brain opioid system in rats. Here we investigated neonatal treatment with THIM (at doses 12, 240, 1440 and 3000 MUg Hg/kg) on behaviors, which are characteristically altered in autism, such as locomotor activity, anxiety, social interactions, spatial learning, and on the brain dopaminergic system in Wistar rats of both sexes. Adult male and female rats, which were exposed to the entire range of THIM doses during the early postnatal life, manifested impairments of locomotor activity and increased anxiety/neophobia in the open field test. In animals of both sexes treated with the highest THIM dose, the frequency of prosocial interactions was reduced, while the frequency of asocial/antisocial interactions was increased in males, but decreased in females. Neonatal THIM treatment did not significantly affect spatial learning and memory. THIM-exposed rats also manifested reduced haloperidol-induced catalepsy, accompanied by a marked decline in the density of striatal D2 receptors, measured by immunohistochemical staining, suggesting alterations to the brain dopaminergic system. Males were more sensitive than females to some neurodisruptive/neurotoxic actions of THIM. These data document that early postnatal THIM administration causes lasting neurobehavioral impairments and neurochemical alterations in the brain, dependent on dose and sex. If similar changes occur in THIM/mercurial-exposed children, they could contribute do neurodevelopmental disorders. PMID- 21549154 TI - Interference of ribosomal frameshifting by antisense peptide nucleic acids suppresses SARS coronavirus replication. AB - The programmed -1 ribosomal frameshifting (-1 PRF) utilized by eukaryotic RNA viruses plays a crucial role for the controlled, limited synthesis of viral RNA replicase polyproteins required for genome replication. The viral RNA replicase polyproteins of severe acute respiratory syndrome coronavirus (SARS-CoV) are encoded by the two overlapping open reading frames 1a and 1b, which are connected by a -1 PRF signal. We evaluated the antiviral effects of antisense peptide nucleic acids (PNAs) targeting a highly conserved RNA sequence on the - PRF signal. The ribosomal frameshifting was inhibited by the PNA, which bound sequence-specifically a pseudoknot structure in the -1 PRF signal, in cell lines as assessed using a dual luciferase-based reporter plasmid containing the -1 PRF signal. Treatment of cells, which were transfected with a SARS-CoV-replicon expressing firefly luciferase, with the PNA fused to a cell-penetrating peptide (CPP) resulted in suppression of the replication of the SARS-CoV replicon, with a 50% inhibitory concentration of 4.4MUM. There was no induction of type I interferon responses by PNA treatment, suggesting that the effect of PNA is not due to innate immune responses. Our results demonstrate that -1 PRF, critical for SARS-CoV viral replication, can be inhibited by CPP-PNA, providing an effective antisense strategy for blocking -1 PRF signals. PMID- 21549157 TI - Running in laboratory and wild rodents: differences in context sensitivity and plasticity of hippocampal neurogenesis. AB - Adult hippocampal neurogenesis, i.e. the formation of new neurons within the existing neuronal network of the dentate gyrus, is subject to modulation by internal and external factors. Among them, voluntary physical exercise is one of the best investigated positive stimulators of neurogenesis in laboratory rodents. Straightforward translation of the observed running-increased neurogenesis has nourished the commonsensical idea that physical challenges would keep our brains healthy and young. However, several lines of evidence indicate that the tempting assumption that, through physical exercise neurogenesis increases and hence cognition improves, might fall short of more complex effects and interactions. In the present work we argue that motivation may be a key factor in determining whether exercise will positively affect neurogenesis in the hippocampus of laboratory animals. In addition, it has been shown that in genetically heterogeneous wild mouse species hippocampal neurogenesis can be exercise- and context-independent. It appears that in wild rodents adult hippocampal neurogenesis is stabilized to the sum of transient pleasant and aversive stimuli characterizing a natural environment. Variability in the regulation of adult neurogenesis questions if the concept of an improved cognition mediated by a running-increased neurogenesis can be easily transferred to the human condition. The present review surveys the research on exercise and hippocampal neurogenesis in the context of motivation, genetic background and species differences. PMID- 21549156 TI - The effects of a high-fat sucrose diet on functional outcome following cortical contusion injury in the rat. AB - Traumatic brain injury (TBI) is a major public health issue affecting 1.7 million Americans each year, of which approximately 50,000 are fatal. High-fat sucrose (HFS) diets are another public health issue which can lead to obesity, hypertension, and many other debilitating disorders. These two disorders combined can lead to more complicated issues. It has recently been shown that HFS diets can reduce levels of brain-derived neurotrophic factor (BDNF) leading to reductions in neuronal and behavioral plasticity. This reduction in BDNF is suspected of increasing the susceptibility of the brain to injury. To test the effects of a HFS diet on recovery of function post-TBI, male Sprague-Dawley rats were used in this study. Eight weeks prior to TBI, rats were placed on a special HFS diet (n=14) or a standard rodent diet (n=14). Following this eight-week period, rats were prepared with bilateral frontal cortical contusion injuries (CCI) or sham procedures. Beginning two days post-TBI, animals were tested on a battery of behavioral tests to assess somatosensory dysfunction and spatial memory in the Morris water maze, with a reference memory and a working memory task. Following testing, animals were sacrificed and their brains processed for lesion analysis. The HFS diet worsened performance on the bilateral tactile adhesive removal test in sham animals. Injured animals on the Standard diet had a greater improvement in somatosensory performance in the adhesive removal test and had better performance on the working memory task compared to animals on the HFS diet. The HFS diet also resulted in significantly greater loss of cortical tissue post-CCI than in the Standard diet group. This study may aid in determining how nutritional characteristics or habits interact with damage to the brain. PMID- 21549158 TI - Ghrelin- and growth hormone secretagogue receptor-immunoreactive cells in Xenopus pancreas. AB - Ghrelin and its receptor, growth hormone secretagogue receptor (GHS-R), are produced by various cell types and affect feeding behavior, metabolic regulation, and energy balance. In the mammalian pancreas, the types of endocrine cells immunoreactive for ghrelin vary. Further, no study has clarified the type of endocrine cells producing ghrelin and GHS-R in the non-mammalian pancreas. We immunohistochemically investigated ghrelin-like and GHS-R-like immunoreactivities in the Xenopus pancreas. Ghrelin-immunoreactive cells were observed both in islets and extrainsular regions, and they corresponded to insulin-containing cells. GHS-R-immunoreactive cells were observed in the islets, and these immunoreactive cells corresponded to insulin- and somatostatin-containing cells. These observations suggest that ghrelin is co-secreted with insulin and that ghrelin may act in an autocrine fashion for insulin-containing cells and in a paracrine fashion for somatostatin-containing cells in this species. PMID- 21549159 TI - Neonatal endotoxin exposure changes neuroendocrine, cardiovascular function and mortality during polymicrobial sepsis in adult rats. AB - Our aim was to investigate whether neonatal LPS challenge may improve hormonal, cardiovascular response and mortality, this being a beneficial adaptation when adult rats are submitted to polymicrobial sepsis by cecal ligation and puncture (CLP). Fourteen days after birth, pups received an intraperitoneal injection of lipopolysaccharide (LPS; 100MUg/kg) or saline. After 8-12 weeks, they were submitted to CLP, decapitated 4, 6 or 24h after surgery and blood was collected for vasopressin (AVP), corticosterone and nitrate measurement, while AVP contents were measured in neurohypophysis, supra-optic (SON) and paraventricular (PVN) nuclei. Moreover, rats had their mean arterial pressure (MAP) and heart rate (HR) evaluated, and mortality and bacteremia were determined at 24h. Septic animals with neonatal LPS exposure had higher plasma AVP and corticosterone levels, and higher c-Fos expression in SON and PVN at 24h after surgery when compared to saline treated rats. The LPS pretreated group showed increased AVP content in SON and PVN at 6h, while we did not observe any change in neurohypophyseal AVP content. The nitrate levels were significantly reduced in plasma at 6 and 24h after surgery, and in both hypothalamic nuclei only at 6h. Septic animals with neonatal LPS exposure showed increase in MAP during the initial phase of sepsis, but HR was not different from the neonatal saline group. Furthermore, neonatally LPS exposed rats showed a significant decrease in mortality rate as well as in bacteremia. These data suggest that neonatal LPS challenge is able to promote beneficial effects on neuroendocrine and cardiovascular responses to polymicrobial sepsis in adulthood. PMID- 21549160 TI - GLP-1-derived nonapeptide GLP-1(28-36)amide inhibits weight gain and attenuates diabetes and hepatic steatosis in diet-induced obese mice. AB - BACKGROUND: The metabolic syndrome is an obesity-associated disease manifested as severe insulin resistance, hyperlipidemia, hepatic steatosis, and diabetes. Previously we proposed that a nonapeptide, FIAWLVKGRamide, GLP-1(28-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might have insulin-like actions. Recently, we reported that the nonapeptide appears to enter hepatocytes, target to mitochondria, and suppress glucose production and reactive oxygen species. Therefore, the effects of GLP-1(28-36)amide were examined in diet-induced obese, insulin-resistant mice as a model for the development of human metabolic syndrome. METHODS AND RESULTS: Three- to 11-week infusions of GLP-1(28-36)amide were administered via osmopumps to mice fed a very high fat diet (VHFD) and to control mice on a normal low fat diet (LFD). Body weight, DXA, energy intake, plasma insulin and glucose, and liver triglyceride levels were assessed. GLP-1(28-36)amide inhibited weight gain, accumulation of liver triglycerides, and improved insulin sensitivity by attenuating the development of fasting hyperglycemia and hyperinsulinemia in mice fed VHFD. GLP 1(28-36)amide had no observable effects in control LFD mice. Surprisingly, the energy intake of peptide-infused obese mice is 25-70% greater than in obese mice receiving vehicle alone, yet did not gain excess weight. CONCLUSIONS: GLP-1(28 36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28-36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome. PMID- 21549161 TI - Contribution of neurotensin in the immune and neuroendocrine modulation of normal and abnormal enteric function. AB - Among various hormones, which are synthesized by intestinal cells and influence enteric function, neurotensin (NT) has gained scientific attention the last three decades. This neuropeptide, mainly located in neuronal synaptic vesicles of hypothalamus and in neuroendocrine cells of the small bowel, participates in enteric digestive processes, gut motility and intestinal inflammatory mechanisms by cooperating with other regulators such as histamine, substance P and somatostatin. NT plays an important role mainly in intestinal lipid metabolism by cooperating with cholecystokinin and establishes a hormonal brain-gut-adipose tissue connection, which could adjust appetite, weight status and generally eating behavior with the amount and the content (particularly fat) of food intake. Moreover, NT achieves a multi-level control of intestinal motility by cooperating with the enteric- and central nervous system, and other enteric hormones (such as somatostatin). NT regulates motility patterns related to the efficiency of the digestive process, stool emptying, transition from the fasted to the postprandial state and reestablishment of the fasted status. In addition, NT possesses a long-term enteroprotective role towards the intestinal tract, despite the fact that under certain circumstances NT may participate in short term subcellular pathways promoting an acute inflammatory response. The aim of this review is two-fold. First, is to provide an up-to-date synopsis of the available knowledge regarding the involvement of neurotensin in enteric functional status, and highlight its significance in physiological and pathological conditions. Second, is to propose new research directions concerning the role of neurotensin and other intestinal regulatory peptides in the establishment of the brain-gut axis and in the development of functional disorders of the abdominal tract. Conclusively, to clarify the areas, in which an experimental therapeutic intervention, based on NT analogs, may lead to encouraging results. PMID- 21549162 TI - Difference of EGCg adhesion on cell surface between Staphylococcus aureus and Escherichia coli visualized by electron microscopy after novel indirect staining with cerium chloride. AB - We developed a novel method using indirect staining with cerium chloride for visualization of the catechin derivative epigallocatechin gallate (EGCg) on the surface of particles, i.e., polystyrene beads and bacterial cells, by electron microscopy. The staining method is based on the fact that in an alkaline environment, EGCg produces hydrogen peroxide, and then hydrogen peroxide reacts with cerium, resulting in a cerium hydroperoxide precipitate. This precipitate subsequently reacts with EGCg to produce larger deposits. The amount of precipitate is proportional to the amount of EGCg. Highly EGCg-sensitive Staphylococcus aureus and EGCg-resistant Escherichia coli were treated with EGCg under various pH conditions. Transmission electron microscopy observation showed that the amount of deposits on S. aureus increased with an increase in EGCg concentration. After treating bacterial cells with 0.5mg/mL EGCg (pH 6.0), attachment of EGCg was significantly lower to E. coli than to S. aureus. This is the first report that shows differences in affinity of EGCg to the cell surfaces of Gram-positive and -negative bacteria by electron microscopy. PMID- 21549163 TI - Miniaturized enzyme production and development of micro-assays for cellulolytic and xylanolytic enzymes. AB - Miniaturized fungal cultivation and enzyme assays were developed. Cultivation for enzyme production was performed in 50mL conical tubes. In addition, the miniaturized enzyme assays reduced the amount of enzymes and reagents necessary. These procedures can be adopted in screening fungi to determine if they produce cellulolytic and xylanolytic enzymes. PMID- 21549164 TI - Real-time PCR methods for quantitative monitoring of streptomycin and tetracycline resistance genes in agricultural ecosystems. AB - Antibiotic application in plant agriculture is primarily used to control fire blight caused by Erwinia amylovora in pome fruit orchards. In order to facilitate environmental impact assessment for antibiotic applications, we developed and validated culture-independent quantitative real-time PCR multiplex assays for streptomycin (strA, strB, aadA and insertion sequence IS1133) and tetracycline (tetB, tetM and tetW) resistance elements in plant and soil samples. The qPCR were reproducible and consistent whether the DNA was extracted directly from bacteria, plant and soil samples inoculated with bacteria or soil samples prior to and after manure slurry treatment. The genes most frequently identified in soils pre- and post-slurry treatment were strB, aadA, tetB and tetM. All genes tested were detected in soils pre-slurry treatment, and a decrease in relative concentrations of tetB and the streptomycin resistance genes was observed in samples taken post-slurry treatment. These multiplex qPCR assays offer a cost effective, reliable method for simultaneous quantification of antibiotic resistance genes in complex, environmental sample matrices. PMID- 21549165 TI - Generation of an infectious clone of duck enteritis virus (DEV) and of a vectored DEV expressing hemagglutinin of H5N1 avian influenza virus. AB - We report on the generation of an infectious bacterial artificial chromosome (BAC) clone of duck enteritis virus (DEV) and a vectored DEV vaccine expressing hemagglutinin (H5) of high pathogenicity H5N1 avian influenza virus (AIV). For generation of the DEV BAC, we inserted mini-F vector sequences by homologous recombination in lieu of the UL44 (gC) gene of DEV isolate 2085. DNA of the resulting in recombinant virus v2085-GFPDeltagC was electroporated into Escherichia coli and a full-length DEV BAC clone (p2085) was recovered. Transfection of p2085 into chicken embryo cells resulted in DEV-specific plaques exhibiting green autofluorescence. A gC-negative mutant, v2085DeltagC, was generated by deleting mini-F vector sequences by using Cre-Lox recombination, and a revertant virus v2085DeltagC-R was constructed by co-transfection of p2085 with UL44 sequences. Finally, AIV H5 was inserted into p2085, and high-level H5 expression of the v2085_H5 virus was detected by indirect immunofluorescence and western blotting. Plaque area measurements showed that v2085DeltagC plaques were significantly increased (12%) over those of parental 2085 virus or the v2085DeltagC-R revertant virus (ANOVA, P<0.05), while plaque areas of the H5- or GFP-expressing DEV mutants were significantly smaller. There was no significant difference between DEV with respect to virus titers determined after trypsinization titration of infected cells, while virus titers of infected-cell supernatants revealed significant reductions in case of the gC-negative viruses of more than 700-fold when compared to parental 2085 or v2085DeltagC-R. Cell associated virus titers of gC-negative DEV also showed significant reduction of 50-500-fold (ANOVA, P<0.05). We conclude that (i) absence of DEV gC results in increased plaque sizes in vitro, (ii) gC plays a role in DEV egress, and (iii) generation of an infectious DEV clone allows rapid generation of vectored vaccines. PMID- 21549166 TI - Biophysical characterization of hyper-branched polyethylenimine-graft polycaprolactone-block-mono-methoxyl-poly(ethylene glycol) copolymers (hy-PEI-PCL mPEG) for siRNA delivery. AB - A library of mono-methoxyl-poly(ethylene glycol)-block-poly(epsilon-caprolactone) (mPEG-PCL) modified hyperbranched PEI copolymers (hy-PEI-PCL-mPEG) was synthesized to establish structure function relationships for siRNA delivery. These amphiphilic block-copolymers were thought to provide improved colloidal stability and endosomal escape of polyplexes containing siRNA. The influence of the mPEG chain length, PCL segment length, hy-PEI molecular weight and the graft density on their biophysical properties was investigated. In particular, buffer capacity, complex formation constants, gene condensation, polyplex stability, polyplex size and zeta-potential were measured. It was found that longer mPEG chains, longer PCL segments and higher graft density beneficially affected the stability and formation of polyplexes and reduced the zeta-potential of siRNA polyplexes. Significant siRNA mediated knockdown was observed for hy-PEI25k (PCL900-mPEG2k)(1) at N/P 20 and 30, implying that the PCL hydrophobic segment played a very important role in siRNA transfection. These gene delivery systems merit further investigation under in vivo conditions. PMID- 21549167 TI - A method for enhancing the ocular penetration of eye drops using nanoparticles of hydrolyzable dye. AB - This report describes a method for enhancing the ocular penetration of eye drops using nanoparticles of hydrolyzable dye, which is similar to a prodrug approach. The entry of eye drops into the ocular globe is restricted predominantly by corneal barrier functions. The barrier functions are epithelial tight junctions as well as a physicochemical property consisting of the opposite characteristics of a lipophilic epithelium and a hydrophilic stroma. We found that using a formulation of nanoparticles of hydrolyzable dye (with particles of 200 nm in diameter on average) attained a greater than tenfold higher (about 50-fold) ocular penetration than that of micron-sized particles. The nanoparticles were prepared by a carrier-free technique; i.e., the reprecipitation method. Confocal laser fluorescence microscopy showed that dyes originating from the nanoparticles surmounted the corneal epithelium barrier, which has tight junctions, and achieved deeper penetration into the cornea. The high penetration rate of the dyes into the cornea was attributed to the size of particles (i.e., nanoparticles) and a transformation of dye polarity from lipophilic to hydrophilic in in vivo hydrolysis reactions. We concluded that utilizing in vivo hydrolysis reactions to alter the physicochemical nature of nanoparticles consisting of hydrolyzable compounds was an effective approach for enhancing the ocular penetration of eye drops. PMID- 21549168 TI - Coeliac disease. Following the diet and eating habits of participating individuals in the Federal District, Brazil. AB - The western diet includes several food items based on wheat. Adherence and obedience to a gluten-free diet requires self-determination on the part of the person with Coeliac disease, as well as their family members. The objective of this research is to identify the main difficulties noted by people with Coeliac disease in their eating habits, the frequency of consumption and their satisfaction with gluten-free products. We employed an adapted already validated questionnaire, with open, closed, and multiple choice questions. Of the 105 participants with Coeliac disease, 90.38% of them followed, where possible, a gluten-free diet; 67.12% consumed food with gluten inadvertently or because of a lack of alternatives and/or information in food found in public places. Seventy percent affirmed that their diet provided all the energy and nutrients they need; 77.67% of the Coeliac participants prepared their meals by themselves or this task was assumed by their caregivers; 77.14% read the manufacturers labels on products, and, 74.49% expressed dissatisfaction regarding the price and availability of gluten-free products. The data show an association only between the energy and nutrients needed for good health and gluten-free dietary tracking (p=0.0315). That is, people with Coeliac disease who avoided gluten consumed more calories and were more likely to have adequate nutrients in their diet. PMID- 21549169 TI - Influence of substrate oxidation on the reward system, no role of dietary fibre. AB - It has been suggested that a high intake of dietary fibre helps regulate energy intake and satiety. The present study aimed to examine whether dietary fibre influenced the liking and wanting components of the food reward system, the metabolic state or subsequent intake. Five sessions involving 32 normal-weight subjects (16 men and 16 women, 30.6 +/- 7.6 year) were held. The sessions differed in the composition of the bread eaten during breakfasts (dietary fibre content varied from 2.4 to 12.8 g/100 g). Several factors such as the palatability, weight, volume, energy content and macronutrient composition of the breakfasts were adjusted. Energy expenditure, the respiratory quotient (R), olfactory liking for four foods, wanting for six other foods, and hunger sensations were evaluated before and after the breakfast, as well as before a morning snack. The results showed no significant differences after ingestion of the various breads. Interestingly, R correlated with olfactory liking and with wanting, which highlights in an original manner the influence of the metabolic state on hedonic sensations for food. In conclusion, dietary fibre was found to have no effect on olfactory liking and wanting, and had no detectable effect on satiety sensations or on subsequent energy intake. PMID- 21549170 TI - The impact of glycogen synthase kinase 3beta gene on psychotic mania in bipolar disorder patients. AB - OBJECTIVE: The aim of this study was to examine the relationships between glycogen synthase 3beta gene polymorphisms and bipolar I disorder, manic in a Korean sample. METHODS: Patients with bipolar disorder (n=118) and a control group (n=158) were assessed by genotyping for GSK3beta single nucleotide polymorphisms (SNPs) -1727A/T and -50C/T. The patients were divided into two groups according to the presence of psychotic symptoms (psychotic mania, n=92; non-psychotic mania, n=26) and also divided based on gender and age of onset. The severity of symptoms was measured using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). RESULTS: There were no significant differences in the genotype distributions or allelic frequencies of GSK3beta polymorphisms and gender between patients with bipolar disorder and a normal control group. According to haplotype analysis, there was no association between these two groups. However, analysis of the age of onset of bipolar disorder revealed significant differences in genotype and allele distributions among the patients. Patients who were homozygous for the wild-type variant (TT) had an older age of onset than carriers of the mutant allele (A/A: 27.4+/-9.1; A/T: 30.1+/-11.8; T/T: 42.3+/-19.9; p=0.034). We detected differences in allele frequencies of the GSK3beta -1727A/T polymorphism between the psychotic mania group and the non-psychotic mania group. CONCLUSION: This study suggests that GSK3beta polymorphisms are not associated with bipolar disorder. However, the GSK3beta SNP -1727A/T is associated with age of onset and presence of psychotic symptoms in bipolar disorder. PMID- 21549171 TI - The SIGMAR1 gene is associated with a risk of schizophrenia and activation of the prefrontal cortex. AB - Several studies have identified the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathogenesis of schizophrenia. The Gln2Pro polymorphism in the SIGMAR1 gene has been extensively examined for an association with schizophrenia. However, findings across multiple studies have been inconsistent. We performed a meta-analysis of the association between the functional Gln2Pro polymorphism and schizophrenia using combined samples (1254 patients with schizophrenia and 1574 healthy controls) from previously published studies and our own additional samples (478 patients and 631 controls). We then used near-infrared spectroscopy to analyze the effects of the Gln2Pro genotype, a schizophrenia diagnosis and the interaction between genotype and diagnosis on activation of the prefrontal cortex (PFC) during a verbal fluency task (127 patients and 216 controls). The meta-analysis provided evidence of an association between Gln2Pro and schizophrenia without heterogeneity across studies (odds ratio=1.12, p=0.047). Consistent with previous studies, patients with schizophrenia showed lower bilateral activation of the PFC when compared to controls (p<0.05). We provide evidence that Pro carriers, who are more common among patients with schizophrenia, have significantly lower activation of the right PFC compared to subjects with the Gln/Gln genotype (p=0.013). These data suggest that the SIGMAR1 polymorphism is associated with an increased risk of schizophrenia and differential activation of the PFC. PMID- 21549172 TI - Association study of RELN polymorphisms with schizophrenia in Han Chinese population. AB - Schizophrenia (SZ) is a common and complex psychiatric disorder with a strong genetic component. Previous research suggests that mutations altering genes in neurodevelopmental pathways contribute to SZ. Reelin gene (RELN) maps to chromosome 7q22.1, the encoded protein plays a pivotal role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports had indicated that reduced RELN expression is associated with human mental illnesses such as SZ, mood disorders and autism. In this study, case control association analyses were performed in the Han Chinese population to determine if the RELN gene is a susceptibility gene for SZ. Thirty-seven single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was found between rs12705169 and SZ (p=0.001). Moreover, the haplotypes constructed from five SNPs showed significant differences between cases and controls (p=0.041). When subjects were divided by gender, rs12705169 remained significant difference only in females (OR=0.24, 95%CI=0.14-0.40 for CC and OR=0.40, 95%CI=0.27-0.58 for AC), both in the allele and genotype (p=0.0001 for both). This study describes a positive association between RELN and SZ in the Han Chinese population, and provides genetic evidence to support the gender difference of SZ. PMID- 21549173 TI - Placental docosahexaenoic and arachidonic acids correlate weakly with placental polychlorinated dibenzofurans (PCDF) and are uncorrelated with polychlorinated dibenzo-p-dioxins (PCDD) or polychlorinated biphenyls (PCB) at delivery: a pilot study. AB - Long chain polyunsaturated fatty acids (LC-PUFA), ARA (arachidonic acid, 20:4n-6) and DHA (docosahexaenoic acid, 22:6n-3) have positive effects and environment pollutants, polychlorinated dibenzo-p-dioxins/dibenzofurans(PCDD/F) and polychlorinated biphenyls (PCB) have negative effects on neural development during early life. Placental dioxin/PCB serves as markers for cumulative exposure to fetus. Fatty acid composition of placenta depends on nutrient supply during pregnancy, serving as indicators for fetal ARA and DHA accretion. This study investigated correlation between placental PCDD/F and PCB toxic equivalent (TEQ) and LC-PUFA in 34 pregnant women from Taiwan. Placental PCDF TEQ were inversely correlated with placental ARA (p=0.020), C20:3n-6 (p=0.01), C22:4n-6 (p=0.04), C22:5n-6 (p<0.01) and with DHA (p=0.03), but ARA and DHA did not vary with PCDD, dioxin-like and indicator PCB. After adjustment for age and body mass index, a one-unit PCDF TEQ increase was associated with 1.021%w/w and 0.312%w/w decreases in ARA (beta=-1.021, p=0.03) and DHA (beta=-0.312, p=0.03). Since ARA and DHA were unrelated to three classes of toxins, and a weak negative association was found with PCDF, these data provide no basis for discouraging marine fish consumption during pregnancy for Taiwan women on the basis of these organics. Pregnant women should consume fish for its unique package of nutrients while avoiding few species with high organic pollutant or mercury contamination. PMID- 21549174 TI - The evolving world of protein-G-quadruplex recognition: a medicinal chemist's perspective. AB - The physiological and pharmacological role of nucleic acids structures folded into the non canonical G-quadruplex conformation have recently emerged. Their activities are targeted at vital cellular processes including telomere maintenance, regulation of transcription and processing of the pre-messenger or telomeric RNA. In addition, severe conditions like cancer, fragile X syndrome, Bloom syndrome, Werner syndrome and Fanconi anemia J are related to genomic defects that involve G-quadruplex forming sequences. In this connection G quadruplex recognition and processing by nucleic acid directed proteins and enzymes represents a key event to activate or deactivate physiological or pathological pathways. In this review we examine protein-G-quadruplex recognition in physiologically significant conditions and discuss how to possibly exploit the interactions' selectivity for targeted therapeutic intervention. PMID- 21549175 TI - Accelerated lymphocyte reconstitution and long-term recovery after transplantation of lentiviral-transduced rhesus CD34+ cells mobilized by G-CSF and plerixafor. AB - OBJECTIVE: Granulocyte colony-stimulating factor (G-CSF) in combination with plerixafor produces significant mobilization of CD34(+) cells in rhesus macaques. We sought to evaluate whether these CD34(+) cells can stably reconstitute blood cells with lentiviral gene marking. MATERIALS AND METHODS: We performed hematopoietic stem cell transplantation using G-CSF and plerixafor-mobilized rhesus CD34(+) cells transduced with a lentiviral vector, and these data were compared with those of G-CSF and stem cell factor mobilization. RESULTS: G-CSF and plerixafor mobilization resulted in CD34(+) cell yields that were twofold higher than yields with G-CSF and stem cell factor. CD123 (interleukin-3 receptor) expression was greater in G-CSF and plerixafor-mobilized CD34(+) cells when compared to G-CSF alone. Animals transplanted with G-CSF and plerixafor mobilized cells showed engraftment of all lineages, similar to animals who received G-CSF and stem cell factor-mobilized grafts. Lymphocyte engraftment was accelerated in animals receiving the G-CSF and plerixafor-mobilized CD34(+) cells. One animal in the G-CSF and plerixafor group developed cold agglutinin associated skin rash during the first 3 months of rapid lymphocyte recovery. One year after transplantation, all animals had 2% to 10% transgene expression in all blood cell lineages. CONCLUSIONS: G-CSF and plerixafor-mobilized CD34(+) cells accelerate lymphocyte engraftment and contain hematopoietic stem cell capable of reconstituting multilineage blood cells. These findings indicate important differences to consider in plerixafor-based hematopoietic stem cell mobilization protocols in rhesus macaques. PMID- 21549176 TI - Paracrine regulation of megakaryo/thrombopoiesis by macrophages. AB - OBJECTIVE: Megakaryo/thrombopoiesis is a complex process regulated by multiple signals provided by the bone marrow microenvironment. Because macrophages are relevant components of the bone marrow stroma and their activation induces an upregulation of molecules that can regulate hematopoiesis, we analyzed the impact of these cells on the control of megakaryocyte development and platelet biogenesis. MATERIALS AND METHODS: The different stages of megakaryo/thrombopoiesis were analyzed by flow cytometry using an in vitro model of human cord blood CD34(+) cells stimulated with thrombopoietin in either a transwell system or conditioned media from monocyte-derived macrophages isolated from peripheral blood. Cytokines secreted from macrophages were characterized by protein array and enzyme-linked immunosorbent assay. RESULTS: Resting macrophages released soluble factors that promoted megakaryocyte growth, cell ploidy, a size increase, proplatelet production, and platelet release. Lipopolysaccharide stimulation triggered the secretion of cytokines that exerted opposite effects together with a dramatic switch of CD34(+) commitment to the megakaryocytic lineage toward the myeloid lineage. Neutralization of interleukin-8 released by stimulated macrophages partially reversed the inhibition of megakaryocyte growth. Activation of nuclear factor kappaB had a major role in the synthesis of molecules involved in the megakaryocyte inhibition mediated by lipopolysaccharide stimulated macrophages. CONCLUSIONS: Our study extends our understanding about the role of the bone marrow microenvironment in the regulation of megakaryo/thrombopoiesis by showing that soluble factors derived from macrophages positively or negatively control megakaryocyte growth, differentiation, maturation, and their ability to produce platelets. PMID- 21549177 TI - Redox regulation in respiring Saccharomyces cerevisiae. AB - BACKGROUND: In biological systems, redox reactions are central to most cellular processes and the redox potential of the intracellular compartment dictates whether a particular reaction can or cannot occur. Indeed the widespread use of redox reactions in biological systems makes their detailed description outside the scope of one review. SCOPE OF THE REVIEW: Here we will focus on how system wide redox changes can alter the reaction and transcriptional landscape of Saccharomyces cerevisiae. To understand this we explore the major determinants of cellular redox potential, how these are sensed by the cell and the dynamic responses elicited. MAJOR CONCLUSIONS: Redox regulation is a large and complex system that has the potential to rapidly and globally alter both the reaction and transcription landscapes. Although we have a basic understanding of many of the sub-systems and a partial understanding of the transcriptional control, we are far from understanding how these systems integrate to produce coherent responses. We argue that this non-linear system self-organises, and that the output in many cases is temperature-compensated oscillations that may temporally partition incompatible reactions in vivo. GENERAL SIGNIFICANCE: Redox biochemistry impinges on most of cellular processes and has been shown to underpin ageing and many human diseases. Integrating the complexity of redox signalling and regulation is perhaps one of the most challenging areas of biology. This article is part of a Special Issue entitled Systems Biology of Microorganisms. PMID- 21549178 TI - A miR-centric view of head and neck cancers. AB - Head and Neck Squamous Cell Carcinomas (HNSCCs) constitute the sixth most common cancer worldwide with an average 5-year survival rate of around 50%. Several microRNAs, small non-coding RNAs involved in post-transcriptional gene regulation, have been linked to HNSCC based on their differential expression in tumors. Here, we present a compilation of multiple types of information on each HNSCC linked miRNA including their expression status in tumors, their molecular targets relevant to cancer, results of gene manipulation studies and association with clinical outcome. Further, we use this information to devise a new scheme for classifying them into causal and non-causal miRNAs in HNSCC. We also discuss the possibility of using miRNAs as prognostic and diagnostic biomarkers for HNSCC, based on existing literature. Finally, we present available evidence that shows how altered expression of specific miRNAs can contribute to various "hallmarks of cancer" phenotypes such as limitless replicative potential owing to abnormal cell cycle regulation, evasion of apoptosis, reduced response to anti growth signals, and Epithelial-Mesechymal transition (EMT). PMID- 21549180 TI - The effects of acoustic trauma that can cause tinnitus on spatial performance in rats. AB - Previous studies have shown that acoustic trauma can disrupt the firing of place cells in the hippocampus and also inhibit hippocampal neurogenesis, suggesting that such trauma might impair spatial memory. In this study, we investigated performance in the alternating T maze and Morris water maze of rats exposed to acoustic trauma (16 kHz, 110 dB SPL pure tone for 1 h), who had elevated auditory brainstem response thresholds and the psychophysical attributes of tinnitus (using a conditioned lick suppression task). To our surprise, we found that rats with tinnitus did not perform significantly differently from sham control animals in either the alternating T maze task or any aspect of the reference or working memory versions of the Morris water maze task except for a faster acquisition in T maze alternation. These results suggest that acoustic trauma and tinnitus may not impair spatial memory in rats. PMID- 21549179 TI - Up-regulation of low-threshold tetrodotoxin-resistant Na+ current via activation of a cyclic AMP/protein kinase A pathway in nociceptor-like rat dorsal root ganglion cells. AB - The effects of forskolin on low-threshold tetrodotoxin-resistant (TTX-r) Na(+) currents was studied in small diameter (average ~ 25 MUm) dorsal root ganglion (DRG) cells. All DRG cells included in the study were categorized as type-2 or non-type-2 based on the expression of a low-threshold A-current. In all type-2 and some non-type-2 DRG cells held at -80 mV, the adenylyl cyclase (AC) activator forskolin (10 MUM) up-regulated TTX-r Na(+) currents evoked with steps to -55 mV through -35 mV (low-threshold current). Up-regulation of low-threshold current by forskolin was mimicked by the protein kinase A (PKA) agonist Sp-cAMPs and the inflammatory mediator serotonin, and blocked by the PKA antagonist Rp-cAMPs. Forskolin-induced up-regulation of low-threshold current evoked from a holding potential of -60 mV was blocked by 40 ms steps to 0 mV, which presumably induced a long lasting inactivation of the low-threshold channels. Reducing to 3 ms the duration of steps to 0 mV, significantly increased the number of DRG cells where low-threshold current was up-regulated by forskolin, presumably by reducing the long-lasting inactivation of the low-threshold channels. In the same cells, high threshold current, evoked by 40 ms or 3 ms steps to 0 mV, was consistently up regulated by forskolin. The selective Na(V)1.8 channel blocker A-803467 markedly blocked high-threshold current but not low-threshold current. The different voltage protocols observed to activate and inactivate the low- and high-threshold currents, and the observation that A-803467 blocked high- but not low-threshold current suggests that the two currents were mediated by different channels, possibly Na(V)1.8 and Na(V)1.9, respectively. Inflammatory mediators may simultaneously up-regulate Na(V)1.8 and Na(V)1.9 channels in the same nociceptor via a AC/PKA signaling pathway, increasing nociceptor signaling strength, and lowering nociceptor threshold, respectively. PMID- 21549181 TI - Minocycline promotes remyelination in aggregating rat brain cell cultures after interferon-gamma plus lipopolysaccharide-induced demyelination. AB - Minocycline has been shown to inhibit microglia reactivity, and to decrease the severity and progression of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. It remained to be examined whether minocycline was also able to promote remyelination. In the present study, myelinating aggregating brain cell cultures were used as a model to study the effects of minocycline on microglial reactivity, demyelination, and remyelination. Cultures were treated simultaneously with two inflammatory agents, interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS), which caused an inflammatory response accompanied by demyelination. The inflammatory response was characterized by microglial reactivity, upregulation of inflammatory cytokines and iNOS, and increased phophorylation of P38 and P44/42 mitogen activated protein (MAP) kinases. Minocycline inhibited microglial reactivity, and attenuated the increased phophorylation of P38 and P44/42 MAP kinases. Demyelination, determined by a decrease in myelin basic protein (MBP) content and immunoreactivity 48 h after the treatment with the inflammatory agents, was not prevented by minocycline. However, 1 week after demyelination was assessed, the MBP content was restored in presence of minocycline, indicating that remyelination was promoted. Concomitantly, in cultures treated with minocycline, the markers of oligodendrocyte precursors cells (OPCs) and immature oligodendrocytes NG2 and O4, respectively, were decreased compared to cultures treated with the inflammatory agents only. These results suggest that minocycline attenuates microglial reactivity and favors remyelination by enhancing the differentiation of OPCs and immature oligodendrocytes. PMID- 21549182 TI - The clinical and therapeutic potentials of dehydroepiandrosterone and pregnenolone in schizophrenia. AB - Neurosteroids such as dehydroepiandrosterone (DHEA), pregnenolone (PREG), and their sulfates (DHEAS and PREGS) display multiple effects on the central nervous system. Specifically, neurosteroids have various functions associated with neuroprotection, response to stress, mood regulation, and cognitive performance. In addition, neurosteroid levels are altered in stress-related neuropsychiatric disorders. This review focuses on the alterations of these neurosteroids in schizophrenia and on their association with clinical and neurocognitive manifestations. As described henceforth, findings from clinical studies have revealed that PREG, DHEA, and their sulfates might be involved in the pathophysiology of schizophrenia, and in some of its manifestations. Clinical trials for the evaluation of these neurosteroids face challenges in terms of experimental design, dosing strategy, data analysis, and interpretation. The review concludes with a list of suggested topics for future research. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. PMID- 21549183 TI - Two cDNAs coding for the porcine CD51 (alphav) integrin subunit: cloning, expression analysis, adhesion assays and chromosomal localization. AB - CD51 (alpha(v)) is an integrin chain that associates with multiple beta integrin chains to form different receptor complexes that mediate important human processes. Pigs show substantial physiological, immunological and anatomical similarities to humans, and are therefore a good model system to study immunological and pathological processes. Here we report the cloning and characterization of two cDNAs produced by alternative splicing that encode two different porcine CD51 proteins that differ in five amino acid residues. Pig CD51 cDNAs encode polypeptides of 1046 or 1041 amino acid residues, respectively, that share with other mammalian homologous proteins a high percentage amino acid identity and the functional domains. Expression analysis of CD51 was carried out at two different levels. RT-PCR analysis revealed that both CD51 transcripts were expressed ubiquitously but heterogeneously, with the exception of some platelets in which only the smallest CD51 transcript was detected. A specific monoclonal antibody against a pig CD51 recombinant protein was made and used in the immunohistochemical localization of CD51 proteins. It showed that CD51 was mainly expressed in hematopoietic cells of myeloid linage, epithelial and endothelial cells, osteoclasts, nervous fibers and smooth muscle. Adhesion assays showed that in the presence of Mn(++) pig alpha(v)-CHO-B2 transfected cells increased their attachment to fibronectin and vitonectin, but not to fibrinogen. Finally, we localized the CD51 gene on the porcine chromosome 15 (SSC15), q23-q26. PMID- 21549184 TI - Gene dosage imbalance of human chromosome 21 in mouse embryonic stem cells differentiating to neurons. AB - Gene dosage imbalance is the central working hypothesis in understanding cognitive impairment and learning difficulty in Down syndrome. A mouse embryonic stem cell line containing single human chromosome 21 was used to study genomic and transcriptomic implications of autosomal imbalance during early neurogenesis. In this study bioinformatic analysis in the differentiating aneuploid neurons showed 53.6% primary dosage, 25% dosage compensation, and 21.4% reverse dosage effects on trisomic genes, revealing locus-specific secondary dosage effects on disomic genes and its specific trans-acting networks for neural attenuation, degeneration and apoptosis. The obtained results supported the significant gene dosage effects of autosomal imbalance on early neural development, suggesting novel molecular regulations for neurodevelopmental abnormalities in Down syndrome. PMID- 21549185 TI - Human sphingomyelin synthase 1 gene (SMS1): organization, multiple mRNA splice variants and expression in adult tissues. AB - We have previously characterized the structure of the human MOB gene (TMEM23), which encodes a hypothetical transmembrane protein (Vladychenskaya et al., 2002, 2004). The primary structure of the peptide that we predicted coincided completely with the amino acid sequence of the later identified sphingomyelin synthase 1 protein (SMS1), which catalyses the transfer of a phosphorylcholine moiety from phosphatidylcholine to ceramide, producing sphingomyelin and diacylglycerol (Huitema et al., 2004; Yamaoka et al., 2004). The gene we found was the SMS1 gene. The combination of in silico and RT-PCR data helped us identify and characterize numerous new transcripts of the human SMS1 gene. We identified mRNA isoforms that vary in the 5'-untranslated region (UTR) and encode the full-length protein, and transcripts resulting from alternative combinations of the exons in the coding region of the gene and the 3'-UTR. Comparison of the discovered transcripts' structures with the sequence of human chromosome 10 showed that the human SMS1 gene comprises at least 24 exons. RT-PCR and real-time PCR data showed that the expression patterns of the alternative SMS1 transcripts are tissue specific. Our results indicate that the regulation of SMS1 expression is complex and occurs at the transcriptional, post-transcriptional and translational levels. PMID- 21549186 TI - Evaluation of the physicochemical characteristics of crospovidone that influence solid dispersion preparation. AB - A solid dispersion (SD) powder of indomethacin (IM) with crospovidone (CrosPVP) shows useful characteristics for manufacturing dosage forms. Four types of commercial CroPVP, Polyplasdone XL (XL) used as the initial carrier, Polyplasdone XL10 and INF-10 manufactured by milling XL, and Kollidon CL (CL) marketed by another company, were compared. The limit of the IM-CrosPVP weight ratio with which an SD can be prepared (maximum IM content) was calculated on the basis of the heat of fusion of physical mixtures of IM and CrosPVP with various weight ratios. When Polyplasdones were used, the maximum IM content increased with the specific surface area of the CrosPVP. When CL was used, however, it was about half of that obtained with XL, even though the difference between XL and CL was not observed in the physicochemical characteristics (particle size, specific surface area, flowability, glass transition temperature, IR spectra, and solid state NMR spectra). As determined by pore size distribution measurement, the volume of pore of which size is larger than the particle size of IM was less in CL than in XL. Therefore, the effective surface area of CrosPVP that comes in contact with IM is important for the preparation of the SD. PMID- 21549187 TI - Oil based nanocarrier for improved oral delivery of silymarin: In vitro and in vivo studies. AB - Silymarin, obtained from Silybum marianum is used for hepatoprotection and having poor aqueous solubility and low bioavailability. Therefore, it was thought to incorporate the drug into oil-in-water (o/w) based nanocarrier to increase its oral bioavailability. In the present study, o/w nanocarrier was prepared by titration method and was characterized for droplet size, viscosity, etc. In vitro drug release was carried out by dialysis membrane method. A pharmacokinetic study was performed to determine maximum plasma concentration (C(max)), area under the curve (AUC), etc. and hepatoprotective activity was evaluated in terms of serum enzyme estimation. The optimized nanoemulsion formulation consisted of sefsol-218 as oil, tween 80 as a surfactant and ethanol as a co-surfactant having nano droplet size and low viscosity. In vitro dissolution studies showed higher drug release from nanoemulsion as compared to bulk drug suspension. The AUC and C(max) of nanoemulsion after oral administration were 4-fold and 6-fold higher than those of drug suspension of silymarin. The results of pharmacokinetic studies showed better effects of developed nanoemulsion than drug suspension and marketed formulation. The present study showed that the nanoemulsion being a versatile technology has the potential to improve the biopharmaceutics properties of silymarin. PMID- 21549188 TI - Lack of metabolic ageing in the long-lived flatworm Schmidtea polychroa. AB - Freshwater planarians have a large totipotent stem cell population allowing high rates of cell renewal and morphological plasticity. It is often suggested that they are able to rejuvenate during fission, regeneration and starvation. These features, together with the rapidly expanding molecular toolset, make planarians such as Schmidtea polychroa and S. mediterranea interesting for ageing research. Yet, the basic demographic and physiological data are lacking or still based on fragmentary observations of one century ago. Here, we present the first longitudinal physiological study of the species S. polychroa. Survival, size and metabolic rate, measured by microcalorimetry, of a cohort of 28 individuals were followed over a period of three years. Sexual maturity was reached during the second month after which the worms continued growing up to 5 months. This initial growth phase was followed by alternating periods of synchronised growth and degrowth. Although mass-specific metabolic rates declined during the initial growth phase, no changes were found later in life. The absence of metabolic ageing may be explained by the very high rate of cell renewal during homeostasis and alternating phases of degrowth and growth during which tissues are renewed. Surprisingly, all deaths occurred in pairs of worms that were housed in the same culture recipient, suggesting that worms did not die from ageing. Taking into account the metabolic and demographic data, we suggest that S. polychroa shows negligible ageing. Detailed analyses of size and metabolic rate revealed a remarkable biphasic allometric scaling relation. During the initial growth phase (months 1-5) the allometric scaling exponent b was 0.86 while later in life, it increased to an unusually large value of 1.17, indicating that mass-specific metabolic rate increases with size in adult S. polychroa. PMID- 21549189 TI - Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome. AB - Hypocortisolism is a frequent finding in individuals with chronic fatigue syndrome (CFS) with other research findings implying potential dysregulation of glucocorticoid signaling. Glucocorticoid signaling is under the influence of several pathways, several of which are of interest in the study of CFS. Oxidative stress and decreased antioxidant capacity are known to disrupt the hypothalamic pituitary-adrenal (HPA) axis (Epel et al., 2004) and the presence of histone deacetylases (HDAC) could also impact glucocorticoid signaling. The intent of this pilot study was to investigate the relationship among oxidative stress elements, select HDAC's (2/3) and glucocorticoid receptor signaling in an elderly sample with CFS. Findings suggest increased histone deacetylase activity, lower total antioxidant power, in the context of decreased plasma cortisol and increased plasma dehydroepiandrosterone concomitant with decreased expression of the encoding gene for the glucocorticoid receptor. These findings support the presence of HPA axis dysregulation in elderly individuals with CFS. PMID- 21549190 TI - Nitric oxide signaling: classical, less classical, and nonclassical mechanisms. AB - Although nitric oxide (NO) was identified more than 150 years ago and its effects were clinically tested in the form of nitroglycerine, it was not until the decades of 1970-1990 that it was described as a gaseous signal transducer. Since then, a canonical pathway linked to cyclic GMP (cGMP) as its quintessential effector has been established, but other modes of action have emerged and are now part of the common body of knowledge within the field. Classical (or canonical) signaling involves the selective activation of soluble guanylate cyclase, the generation of cGMP, and the activation of specific kinases (cGMP-dependent protein kinases) by this cyclic nucleotide. Nonclassical signaling alludes to the formation of NO-induced posttranslational modifications (PTMs), especially S nitrosylation, S-glutathionylation, and tyrosine nitration. These PTMs are governed by specific biochemical mechanisms as well as by enzymatic systems. In addition, a less classical but equally important pathway is related to the interaction between NO and mitochondrial cytochrome c oxidase, which might have important implications for cell respiration and intermediary metabolism. Cross talk trespassing these necessarily artificial conceptual boundaries is progressively being identified and hence an integrated systems biology approach to the comprehension of NO function will probably emerge in the near future. PMID- 21549191 TI - Diffusion tensor imaging and cognition in cerebral small vessel disease: the RUN DMC study. AB - BACKGROUND: Cerebral small vessel disease (SVD) is very common in elderly and related to cognition, although this relation is weak. This might be because the underlying pathology of white matter lesions (WML) is diverse and cannot be properly appreciated with conventional FLAIR MRI. In addition, conventional MRI is not sensitive to early loss of microstructural integrity of the normal appearing white matter (NAWM), which might be an important factor. Diffusion tensor imaging (DTI) provides alternative information on microstructural white matter integrity and we have used this to investigate the relation between white matter integrity, in both WML and NAWM, and cognition among elderly with cerebral SVD. METHODS: The RUN DMC study is a prospective cohort study among 503 independently living, non-demented elderly with cerebral SVD aged between 50 and 85 years. All subjects underwent MRI and DTI scanning. WML were segmented manually. We measured mean diffusivity (MD) and fractional anisotropy (FA), as assessed by DTI in both WML and NAWM. RESULTS: Inverse relations were found between MD in the WML and NAWM and global cognitive function (beta=-.11, p<0.05; beta=-.18, p<0.001), psychomotor speed (beta=-.15, p<0.01; beta=-.18, p<0.001), concept shifting (beta=-.11, p<0.05; beta=-.10, p<0.05) and attention (beta=-.12, p<0.05; beta=-.15, p<0.001). The relation between DTI parameters in both WML and NAWM and cognitive performance was most pronounced in subjects with severe WML. CONCLUSION: DTI parameters in both WML and NAWM correlate with cognitive performance, independent of SVD. DTI may be a promising tool in exploring the mechanisms of cognitive decline and could function as a surrogate marker for disease progression in therapeutic trials. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease. PMID- 21549192 TI - GSK-3beta/CREB axis mediates IGF-1-induced ECM/adhesion molecule expression, cell cycle progression and monolayer permeability in retinal capillary endothelial cells: Implications for diabetic retinopathy. AB - Various growth factors and cytokines are implicated in endothelial dysfunction and blood-retinal barrier (BRB) breakdown in early diabetic retinopathy (DR). However, cellular and molecular mechanisms that may underlie the pathology of DR are not fully understood yet. We therefore examined the effect of insulin-like growth factor (IGF)-1 on ECM/adhesion molecule expression, cell cycle regulation and monolayer permeability in an endothelial cell line (TR-iBRB2). We investigate whether the action of IGF-1 (1) involves glycogen synthase kinase 3beta (GSK 3beta) and cAMP responsive transcription factor (CREB) and (2) alters ECM/adhesion molecule gene expression. Treatment of TR-iBRB2 cell with IGF-1 (100ng/ml for 0-24h) increases phosphorylation of (i) Akt Thr308, and its substrates including GSK-3beta at Ser9, which inactivates its kinase function, and (ii) CREB at Ser133 (activation). These phosphorylations correlate positively with enhanced expression of CREB targets such as ECM protein fibronectin and cell cycle progression factor cyclin D1. However, stable transfection of a mutant GSK3beta(S9A) or a dominant negative K-CREB in TR-iBRB2 prevents IGF-1-induced fibronectin and cyclin D1 expression. Furthermore, IGF-1 reduces the level of intercellular adherence molecule VE-cadherin and increases monolayer permeability in TR-iBRB2 cells when measured by FITC-dextran leakage. The effect of IGF-1 on VE-cadherin and membrane permeability is absent in TR-iBRB2 cells expressing the GSK-3beta(S9A). Similarly, K-CREB reverses IGF-1 down-regulation of VE-cadherin and up-regulation of fibronectin. These results indicate that GSK-3beta/CREB axis alters ECM/adhesion molecule expression and cell cycle progression in retinal endothelial cells, and may potentially contribute to endothelial dysfunction and BRB leakage in DR. PMID- 21549193 TI - The mode of action of a nitroconjugated neonicotinoid and the effects of target site mutation Y151S on its potency. AB - Neonicotinoid insecticides, such as imidacloprid, are selective agonists of the insect nicotinic acetylcholine receptors (nAChRs) with -NO(2) or -CN group in trans-configuration. Previously we reported the excellent insecticidal activity of a series of nitroconjugated neonicotinoids with -NO(2) or -CN group in cis configuration by replacing nitromethylene pharmacophore with a nitroconjugated system. To understand the action mode of these nitroconjugated neonicotinoids, a representative member IPPA152201 was chosen to perform toxicity and pharmacology studies. IPPA152201 showed a comparable toxicity with imidacloprid against Nilaparvata lugens in a susceptible strain and had no significant cross resistance in an imidacloprid resistant strain. IPPA152201 showed good efficacies on the isolated cockroach neurons (pEC(50) = 5.91 +/- 0.14) and the evoked responses by IPPA152201 could be blocked by the typical nAChRs antagonists methyllycaconitine citrate (MLA) and dihydro-beta-erythroidine (DHbetaE), with pIC(50) of 6.56 +/- 0.07 and 6.89 +/- 0.12. The efficacy of IPPA152201 on hybrid receptors Nlalpha1/beta2 in Xenopus oocytes and response inhibition by MLA and DHbetaE were also observed. These data demonstrate that IPPA152201 acts on insect nAChRs as an agonist. In addition, the influence of a Nlalpha1 mutation (Y151S), which has been linked to the lab-generated neonicotinoid resistance in N. lugens, has been examined. Compared to the wildtype Nlalpha1/beta2, this mutation reduced I(max) for IPPA152201 to 63.2% and caused a 1.5-fold increase in EC(50), which is much smaller than the effects on imidacloprid. The high insecticidal activity and little influence by Y151S mutation make IPPA152201 to be a potential insecticide to manage N. lugens. PMID- 21549194 TI - The structural, compositional and mechanical features of the calcite shell of the barnacle Tetraclita rufotincta. AB - The microstructure and chemical composition of the calcite shell of the sea barnacle Tetraclita rufotincta (Pilsbry, 1916) were investigated using microscopic and analytical methods. The barnacle shell was separated mechanically into its three substructural units: outer, interior, and inner layers. The organic matrices of these structural parts were further separated into soluble and insoluble constituents and their characteristic functional groups were studied by FTIR. Investigation of the mechanical properties of the interior mass of the shell reveals remarkable viscoelastic behavior. In general, the mechanical behavior of the shell is a function of its geometry as well as of the material, of which it is constructed. In the case of T. rufotincta, as calcite is a brittle material, the elastic behavior of the shell is apparently related to its micro- and macroarchitecture. The latter enables the shell to fulfill its primary function which is to protect the organism from a hostile environment and enables its survival. Our detailed identification of the similarities and differences between the various structural components of the shell in regard to the composition and properties of the organic component will hopefully throw light on the role of organic matrices in biomineralization processes. PMID- 21549195 TI - 17Beta-estradiol affects the response of complement components and survival of rainbow trout (Oncorhynchus mykiss) challenged by bacterial infection. AB - Research on the endocrine role of estrogens has focused on the reproductive system, while other potential target systems have been less studied. Here, we investigated the possible immunomodulating role of 17beta-estradiol (E2) using rainbow trout (Oncorhynchus mykiss) as a model. The aims of the study were to examine a) whether estrogens can modulate immune gene transcription levels, and b) whether this has functional implications for the resistance of trout towards pathogens. Trout were reared from fertilization until 6 months of age under (1) control conditions, (2) short-term E2-treatment (6-month-old juveniles were fed a diet containing 20 mg E2/kg for 2 weeks), or c) long-term E2-treatment (twice a 2 h-bath-exposure of trout embryos to 400 MUg 17beta-estradiol (E2)/L, followed by rearing on the E2-spiked diet from start-feeding until 6 months of age). Analysis of plasma estrogen levels indicated that the internal estrogen concentrations of E2-exposed fish were within the physiological range and analysis of hepatic vitellogenin mRNA levels indicated that the E2 administration was effective in activating the endogenous estrogen receptor pathway. However, expression levels of the hepatic complement components C3-1, C3-3, and Factor H were not affected by E2-treatment. In a next step, 6-month-old juveniles were challenged with pathogenic bacteria (Yersinia ruckeri). In control fish, this bacterial infection resulted in significant up-regulation of the mRNA levels of hepatic complement genes (C3-1, C3-3, Factor B, Factor H), while E2-treated fish showed no or significantly lower up-regulation of the complement gene transcription levels. Apparently, the E2-treated trout had a lower capacity to activate their immune system to defend against the bacterial infection. This interpretation is corroborated by the finding that survival of E2-treated fish under bacterial challenge was significantly lower than in the control group. In conclusion, the results from this study suggest that estrogens are able to modulate immune parameters of trout with functional consequences on their ability to cope with pathogens. PMID- 21549196 TI - A novel type III crustin (CrusEs2) identified from Chinese mitten crab Eriocheir sinensis. AB - Antimicrobial peptides are important effectors in the host innate immune response against microbial invasion. In the present study, the cDNA encoding a crustin (designated CrusEs2) was cloned from Chinese mitten crab Eriocheir sinensis by using EST analysis and rapid amplification of cDNA ends (RACE) approach. The full length cDNA of CrusEs2 was of 1237 bp, containing a 5' untranslated region (UTR) of 12 bp, a 3' UTR of 886 bp with a poly (A) tail, and an open reading frame (ORF) of 339 bp encoding a polypeptide of 112 amino acids with a signal peptide of 19 amino acids. The CrusEs2 contained a typical WAP domain, but lacked the Gly rich domain of the type II crustin and the Cys-rich region present in both type I and type II crustin, suggesting that CrusEs2 should be classified as a type III crustin. The mRNA transcripts of CrusEs2 could be detected in haemocytes and gill, and its expression level in haemocytes was up-regulated after Listonella anguillarum challenge, while decreased after Micrococcus luteus challenge. The mature peptide coding region of CrusEs2 was cloned into pET-21a+ and expressed in Escherichia coli. The purified recombinant CrusEs2 inhibited the growth of Gram positive bacteria at MIC of 0.093-0.37 MUM. The results indicated that CrusEs2 was involved in immune response of E. sinensis against bacterial challenge. PMID- 21549197 TI - Characterization of Toll-like receptor 3 gene in large yellow croaker, Pseudosciaena crocea. AB - Toll-like receptor 3 (TLR3) plays an important role in innate immune responses. In this report, the full-length cDNA sequence and genomic structure of Pseudosciaena crocea TLR3 (PcTLR3) were identified and characterized. The full length cDNA of PcTLR3 was of 3384 bp, including a 5'-terminal untranslated region (UTR) of 65 bp, a 3'-terminal UTR of 589 bp and an open reading frame (ORF) of 2730 bp encoding a polypeptide of 909 amino acid residues. The full-length genome sequence of PcTLR3 was composed of 5721 nucleotides, including five exons and four introns. The putative PcTLR3 protein contained a signal peptide sequence, 16 leucine-rich repeat (LRR) motifs, a transmembrane region and a Toll/interleukin-1 receptor (TIR) domain. Quantitative real-time reverse transcription PCR analysis revealed a broad expression of PcTLR3 in most tissues, with the predominant expression in liver, then intestine, and the weakest expression in blood cells. The expression of PcTLR3 after injection with poly inosinic:cytidylic (I:C) and Vibrio parahemolyticus was tested in spleen, blood cells and liver. The results indicated that PcTLR3 transcripts could be induced in the three tissues by injection with poly I:C. The highest expression was in the blood cells with 43.5 times (at 6h) greater expression than in the control (p<0.05). In addition, after V. parahemolyticus challenge, a moderate up-regulation and down-regulation of PcTLR3 was found in blood cells and liver, respectively. Our results suggested that PcTLR3 might play an important role in fish's defense against both viral and bacterial infection. PMID- 21549198 TI - Gene profiling and characterization of arginine kinase-1 (MrAK-1) from freshwater giant prawn (Macrobrachium rosenbergii). AB - Arginine kinase-1 (MrAK-1) was sequenced from the freshwater prawn Macrobrachium rosenbergii using Illumina Solexa Genome Analyzer Technique. MrAK-1 consisted of 1068 bp nucleotide encoded 355 polypeptide with an estimated molecular mass of 40 kDa. MrAK-1 sequence contains a potential ATP:guanido phosphotransferases active domain site. The deduced amino acid sequence of MrAK-1 was compared with other 7 homologous arginine kinase (AK) and showed the highest identity (96%) with AK-1 from cherry shrimp Neocaridina denticulate. The qRT-PCR analysis revealed a broad expression of MrAK-1 with the highest expression in the muscle and the lowest in the eyestalk. The expression of MrAK-1 after challenge with the infectious hypodermal and hematopoietic necrosis virus (IHHNV) was tested in muscle. In addition, MrAK-1 was expressed in Escherichia coli by prokaryotic expression plasmid pMAL-c2x. The optimum temperature (30 degrees C) and pH (8.5) was determined for the enzyme activity assay. MrAK-1 showed significant (P < 0.05) activity towards 10-50 mM ATP concentration. The enzyme activity was inhibited by alpha-ketoglutarate, glucose and ATP at the concentration of 10, 50 and 100 mM respectively. Conclusively, the findings of this study indicated that MrAK-1 might play an important role in the coupling of energy production and utilization and the immune response in shrimps. PMID- 21549199 TI - Effects of atrazine and chlorpyrifos on the mRNA levels of IL-1 and IFN-gamma2b in immune organs of common carp. AB - Atrazine (ATR) and chlorpyrifos (CPF) are widely used in agriculture has resulted in a series of toxicological and environmental problems. The aim of this study was to investigate the effects of ATR, CPF and their mixture on the mRNA levels of interleukin-1beta (IL-1beta), interleukin receptor I (IL-1RI) and interferon gamma (IFN-gamma2b) in both spleen and head kidney of Common carp. In this study, juvenile common carp were exposed to ATR (at concentrations of 4.28, 42.8 and 428 MUg/L), CPF (at concentrations of 1.16, 11.6 and 116 MUg/L), and their mixture (at concentrations of 1.16, 11.6 and 116 MUg/L). The mRNA levels of IL-1beta, IL 1R1 and IFN-gamma2b in spleen and head kidney were detected by using RT-PCR. Our results indicated that IL-1beta, IL-1R1 expression significantly increased after exposure in high concentration ATR, CPF and their mixture, but IFN-gamma2b mRNA shown different expression trends. Our results suggested that ATR, CPF and their mixture probably induced damages on spleen and head kidney may be association with increasing IL-1beta, IL-1R1 mRNA synthesis. After 20-day recovery test, IL 1beta, IL-1R1 and IFN-gamma2b mRNA expression remain at high level in majority of the treated groups, we concluded that the restoration of tissue and immune system damage probably needs longer time. PMID- 21549200 TI - Transcriptional analysis of disk abalone (Haliotis discus discus) antioxidant enzymes against marine bacteria and virus challenge. AB - Diverse antioxidant enzymes are essential for marine organisms to overcome oxidative stress as well as for the fine-tuning of immune reactions through activating different signal transduction pathways. This study describes the transcriptional analysis of antioxidant enzymes of disk abalone by challenging with bacteria (Vibrio alginolyticus, Vibrio parahemolyticus, and Listeria monocytogenes) and viral hemorrhagic septicemia virus (VHSV). Upon bacteria and VHSV challenge, Manganese superoxide dismutase (MnSOD), Copper, Zinc superoxide dismutase (CuZnSOD), catalase, thioredoxin peroxidase (TPx), Selenium-dependent glutathione peroxidase (SeGPx), and thioredoxin-2 (TRx-2) expression levels were altered in gills, and hemocytes at different magnitudes. In gills, only MnSOD, catalase, and SeGPx genes were completely upregulated by post-challenge of bacterial and VHSV. Among them, SeGPx demonstrated strong upregulation by 16-fold (bacteria) and 2-fold (VHSV) in gills, and 5-fold (bacteria) and 3.0-fold (VHSV) in hemocytes. None of the genes examined were downregulated (in gills and hemocytes) by bacteria challenge even though CuZnSOD and TPx showed downregulation (completely) in hemocytes by VHSV. In general, abalone hemocytes had lower potential to induce antioxidant enzyme transcripts upon bacteria and VHSV challenge than gills. Based upon these results, we suggest that abalones induce oxidative stress in tissues during the bacteria and VHSV challenge, and the identified response of antioxidant enzymes could be supported for maintaining a low-level of reactive oxygen species (ROS) that may serve as a signal for activating immune reactions against pathogenic conditions. PMID- 21549201 TI - Cultural influences on neural basis of intergroup empathy. AB - Cultures vary in the extent to which people prefer social hierarchical or egalitarian relations between individuals and groups. Here we examined the effect of cultural variation in preference for social hierarchy on the neural basis of intergroup empathy. Using cross-cultural neuroimaging, we measured neural responses while Korean and American participants observed scenes of racial ingroup and outgroup members in emotional pain. Compared to Caucasian-American participants, Korean participants reported experiencing greater empathy and elicited stronger activity in the left temporo-parietal junction (L-TPJ), a region previously associated with mental state inference, for ingroup compared to outgroup members. Furthermore, preferential reactivity within this region to the pain of ingroup relative to outgroup members was associated with greater preference for social hierarchy and ingroup biases in empathy. Together, these results suggest that cultural variation in preference for social hierarchy leads to cultural variation in ingroup-preferences in empathy, due to increased engagement of brain regions associated with representing and inferring the mental states of others. PMID- 21549202 TI - Relationship of dopamine D1 receptor binding in striatal and extrastriatal regions to cognitive functioning in healthy humans. AB - Dopamine (DA) availability in both striatal and extrastriatal brain regions has been implicated in cognitive performance. Given that different brain regions are neuroanatomically and functionally different, DA receptor binding in different brain regions may be selectively important to specific cognitive functions. Using PET and the radioligand SCH23390, we measured D1 receptor binding potential (BP(ND)) in dorsolateral prefrontal cortex (DLPFC), hippocampus (HC), as well as in sensorimotor (SMST), associative (AST), and limbic (LST) striatum in 20 healthy younger persons. Subjects completed tasks assessing executive functioning, episodic memory, speed, and general knowledge. Unlike previous reports, we found no linear or curvilinear relationships between D1 receptor binding in DLPFC and performance in any cognitive task. However, BP(ND) in HC was positively linked to executive performance as well as to speed and knowledge. With regard to the striatal subregions, D1 BP(ND) in SMST was more strongly related to speed compared to the other striatal subregions, whereas D1 BP(ND) in AST was more strongly linked to general knowledge. These findings provide support for the notion that D1 receptors in separate brain regions are differentially related to performance in tasks tapping various cognitive domains. PMID- 21549203 TI - T2*-based fiber orientation mapping. AB - Recent MRI studies at high field have observed that, in certain white matter fiber bundles, the signal in T(2)*-weighted MRI (i.e. MRI sensitized to apparent transverse relaxivity) is dependent on fiber orientation theta relative to B(0). In this study, the characteristics of this dependency are quantitatively investigated at 7 T using ex-vivo brain specimens, which allowed a large range of rotation angles to be measured. The data confirm the previously suggested variation of R(2)* (=1/T(2)*) with theta and also indicate that this dependency takes the shape of a combination of sin2theta and sin4theta functions, with modulation amplitudes (=DeltaR(2)*) reaching 6.44+/-0.15 Hz (or DeltaT(2)*=2.91+/ 0.33 ms) in the major fiber bundles of the corpus callosum. This particular dependency can be explained by a model of local, sub-voxel scale magnetic field changes resulting from magnetic susceptibility sources that are anisotropic. As an illustration of a potential use of the orientation dependence of R(2)*, the feasibility of generating fiber orientation maps from R(2)* data is investigated. PMID- 21549204 TI - A topographic latent source model for fMRI data. AB - We describe and evaluate a new statistical generative model of functional magnetic resonance imaging (fMRI) data. The model, topographic latent source analysis (TLSA), assumes that fMRI images are generated by a covariate-dependent superposition of latent sources. These sources are defined in terms of basis functions over space. The number of parameters in the model does not depend on the number of voxels, enabling a parsimonious description of activity patterns that avoids many of the pitfalls of traditional voxel-based approaches. We develop a multi-subject extension where latent sources at the subject-level are perturbations of a group-level template. We evaluate TLSA according to prediction, reconstruction and reproducibility. We show that it compares favorably to a Naive Bayes model while using fewer parameters. We also describe a hypothesis testing framework that can be used to identify significant latent sources. PMID- 21549205 TI - Longitudinal studies of ischemic penumbra by using 18F-FDG PET and MRI techniques in permanent and transient focal cerebral ischemia in rats. AB - At present, the goal of stroke research is the identification of a potential recoverable tissue surrounding the ischemic core, suggested as ischemic penumbra, with the aim of applying a treatment that attenuates the growth of this area. Our purpose was to determine whether a combination of imaging techniques, including (18)F-FDG PET and MRI could identify the penumbra area. Longitudinal studies of (18)F-FDG PET and MRI were performed in rats 3 h, 24 h and 48 h after the onset of ischemia. A transient and a permanent model of focal cerebral ischemia were performed. Regions of interest were located, covering the ischemic core, the border that progresses to infarction (recruited tissue), and the border that recovers (recoverable tissue) with early reperfusion. Analyses show that permanent ischemia produces severe damage, whereas the transient ischemia model does not produce clear damage in ADC maps at the earliest time studied. The only significant differences between values for recoverable tissue, (18)F-FDG (84+/ 2%), ADC (108+/-5%) and PWI (70+/-8%), and recruited tissue, (18)F-FDG (77+/-3%), ADC (109+/-4%) and PWI (77+/-4%), are shown in (18)F-FDG ratios. We also show that recoverable tissue values are different from those in non-infarcted tissue. The combination of (18)F-FDG PET, ADC and PWI MRI is useful for identification of ischemic penumbra, with (18)F-FDG PET being the most sensitive approach to its study at early times after stroke, when a clear DWI deficit is not observed. PMID- 21549206 TI - Contrast agent electrostatic attraction rather than repulsion to glycosaminoglycans affords a greater contrast uptake ratio and improved quantitative CT imaging in cartilage. AB - PURPOSE: The purpose of this study is to evaluate the effect of contrast agent charge on the contrast agent uptake ratio (CUR) in cartilage and to image the naturally occurring variations in glycosaminoglycan (GAG) content present in bovine articular cartilage. METHODS: In an ex vivo bovine osteochondral plug model, we utilized three charged contrast agents (Gadopentetate/Magnevist [-2], Ioxaglate/Hexabrix [-1], and CA4+ [+4]) and MUCT to image cartilage. The X-ray attenuation of the cartilage tissue after equilibration in each contrast agent was also related to the initial X-ray attenuation of each contrast agent in solution to compute the uptake of the respective contrast agent (i.e., the CUR). RESULTS: Use of the cationic contrast agent resulted in significantly higher equilibrium X-ray attenuations in cartilage ECM than either of the anionic contrast agents (Gadopentetate [-2] and Ioxaglate [-1]). The CUR (Mean+/-SD) as computed in this study was 2.38 (+/-0.26) for the cationic contrast agent indicating a 2.38 fold increase in computed tomography (CT) attenuation of the cartilage. For the anionic contrast agents, the CUR was 0.62 (+/-0.26) for Ioxaglate [-1] and 0.52 (+/-0.17) for Gadopentetate [-2], indicating exclusion of 38% Ioxaglate and 48% Gadopentetate from the cartilage extracellular matrix. The cationic contrast agent exhibited significant correlations between CT attenuation and GAG content whereas Ioxaglate and Gadopentetate did not (R(2)=0.83 for CA4+, R(2)=0.20 for Ioxaglate, and R(2)=0.22 for Gadopentetate). CONCLUSION: Electrostatic attraction of CA4+ allowed effective imaging of the GAG components of articular cartilage at 50% lower molar concentration than Ioxaglate and 20 fold lower molar concentration than Gadopentetate. The CA4+ contrast agent exhibited a significant correlation between CT attenuation and GAG content in ex vivo bovine osteochondral plugs. PMID- 21549207 TI - The involvement of epigenetic defects in mental retardation. AB - Mental retardation is a group of cognitive disorders with a significant worldwide prevalence rate. This high rate, together with the considerable familial and societal burden resulting from these disorders, makes it an important focus for prevention and intervention. While the diseases associated with mental retardation are diverse, a significant number are linked with disruptions in epigenetic mechanisms, mainly due to loss-of-function mutations in genes that are key components of the epigenetic machinery. Additionally, several disorders classed as imprinting syndromes are associated with mental retardation. This review will discuss the epigenetic abnormalities associated with mental retardation, and will highlight their importance for diagnosis, treatment, and prevention of these disorders. PMID- 21549208 TI - Intestinal lactoflora in Estonian and Norwegian patients with antibiotic associated diarrhea. AB - The disruption of intestinal microbiota is an important risk factor for the development of Clostridium difficile caused antibiotic associated diarrhea (AAD). The role of intestinal lactoflora in protection against C. difficile is unclear. Fecal samples (n = 74) from AAD patients were investigated for C. difficile and lactobacilli by culture and real-time PCR. Lactobacilli were identified by enterobacterial repetitive intergenic consensus PCR (ERIC-PCR) and sequencing of 16S rRNA. In C. difficile negative cases we found somewhat higher counts of intestinal Lactobacilli (5.02 vs. 2.15 CFU log(10)/g; p = 0.053) by culture and more frequently Lactobacillus plantarum (33.3% vs. 9.4%; p = 0.03) as compared with positive ones. Results of total counts of lactobacilli comparing Estonian and Norwegian samples were conflicting by culture and PCR. We found higher colonization of Norwegian AAD patients with L. plantarum (21% vs. 5%, p = 0.053) and Estonians with Lactobacillus gasseri (19% vs. 2%, p = 0.023). Particular lactobacilli (e.g. L. plantarum) may have a role in protection against C. difficile, whereas the meaning of total counts of lactobacilli remains questionable. In different persons and nations, different lactobacilli species may have a protective role against C. difficile. PMID- 21549209 TI - Probiotics from an industrial perspective. AB - Probiotic products have gained popularity with consumers that expect that the products they consume are healthy and help them maintain health. Hence, the need and preferences of the consumers are translated into a product format concept. Probiotics have been used for a long time as natural components in supplements and functional foods, mainly in fermented dairy products. Most of the strains used as probiotics belong to the genera Lactobacillus and Bifidobacterium. By definition, a strain has to have documented health benefits, in order to be called a probiotic. Although each bacterial strain is unique, there are some points that are essential when selecting a probiotic regarding the genetic stability, survival, and technical properties of a strain. Proper components, food matrices and production processes need to be selected since the matrices may affect the viability of the strain in the product and the intestine. Survival in the product is considered a requirement for the beneficial effects of probiotics. PMID- 21549210 TI - Influence of sexual intercourse on genital tract microbiota in infertile couples. AB - Several studies have suggested the association of disturbed genital tract microbiota with infertility. Our aim was to clarify the influence of sexual intercourse on partner's genital tract microbiota in infertile couples. Seventeen couples were studied, and in 5 men inflammatory prostatitis (IP) was diagnosed. Semen samples were collected during menstruation of the female counterpart, two self-collected vaginal samples were taken 3-5 days later - before intercourse and 8-12 h after intercourse. Ureaplasma parvum was found in 59% of women, its prevalence was higher in women whose partner had IP, as well as in half of their male partners. Sexual intercourse caused significant shifts in vaginal microbiota - increase of Nugent score and shifts in cultured microbiota (emergence and disappearance of several species). These changes were less expressed in the presence of normal vaginal microbiota but more prominent in the partners of IP men. These changes may interfere with fertilization. PMID- 21549211 TI - Microbial and sensory quality of "Lollo verde" lettuce and rocket salad stored under active atmosphere packaging. AB - Samples of fresh rocket "Eruca Sativa" were stored either alone or with the addition of lettuce "Lollo verde" leaves under two different atmosphere modifications (5% O(2) and 10% CO(2) for MAP A and 2% O(2) and 5% CO(2) for MAP B). Throughout the storage period of 10 days the microbial (mesophilic, psychrotrophic bacteria and Enterobacteriacae) populations, firmness, color and organoleptic parameters were monitored. Elevated CO(2) levels created by both atmosphere modifications inhibited mesophile and psychrophile growth (p < 0.05). Color was better maintained in MAP samples. Shelf life of rocket leaves was extended by 4 days under MAP A while mixed salads shelf life was limited to 9 days. PMID- 21549213 TI - Study of the effect of atmosphere modification in conjunction with honey on the extent of shelf life of Greek bakery delicacy "touloumpaki". AB - The aim of the present work was to evaluate the effect of atmosphere modification on microbial (mesophiles, yeast and molds) qualities, color, pH, texture and water activity of the Greek bakery product "touloumpaki". Samples were stored under MAP (60% CO(2)) either alone or with the addition of honey syrup for 16 days at room temperature (22-24 degrees C). Texture was better maintained under MAP and the addition of honey prevented the increase of shear force needed (1.498 and 3.20 for samples with and without honey). Honey inhibited the growth of yeasts on samples stored under MAP (1.6 and 2.02 log CFU/g for samples under MAP with and without honey respectively) while multivariant analysis showed that MAP and honey acted synergistically in confining yeasts. Presence of honey restrained the mesophilic growth until the end of storage period (5.21 and 4.29 log CFU/g for MAP and control samples respectively) while MAP did not have any beneficial effect. Water activity (a(W) < 0.754) was strongly associated with reduced mesophile growth. Lightness values showed a significant decrease during time with no significant changes among treatments in both internal layers and external surface of the product. PMID- 21549212 TI - Prevalence and susceptibility of Saccharomyces cerevisiae causing vaginitis in Greek women. AB - Saccharomyces cerevisiae is an ascomycetous yeast, that is traditionally used in wine bread and beer production. Vaginitis caused by S. cerevisiae is rare. The aim of this study was to evaluate the frequency of S. cerevisiae isolation from the vagina in two groups of women and determined the in vitro susceptibility of this fungus. SUBJECTS AND METHODS: Vaginal samples were collected from a total of 262 (asymptomatic and symptomatic) women with vaginitis attending the centre of family planning of General hospital of Piraeus. All blastomycetes that isolated from the vaginal samples were examined for microscopic morphological tests and identified by conventional methods: By API 20 C AUX and ID 32 C (Biomerieux). Antifungal susceptibility testing for amphotericin B,fluconazole itraconazole,voriconazole, posaconazole and caspofungin was performed by E -test (Ab BIODIKS SWEDEN) against S. cerevisiae. RESULTS: A total of 16 isolates of S. cerevisiae derived from vaginal sample of the referred women, average 6.10%. Susceptibility of 16 isolates of S. cerevisiae to a variety of antimycotic agents were obtained. So all isolates of S. cerevisiae were resistant to fluconazole, posaconazole and intraconazole, but they were sensitive to voriconazole caspofungin and Amphotericin B which were found sensitive (except 1/16 strains). None of the 16 patients had a history of occupational domestic use of baker's yeast. CONCLUSIONS: Vaginitis caused by S. cerevisiae occur, is rising and cannot be ignored. Treatment of Saccharomyces vaginitis constitutes a major challenge and may require selected and often prolonged therapy. PMID- 21549214 TI - Effect of three MAP compositions on the physical and microbiological properties of a low fat Greek cheese known as "Anthotyros". AB - Anthotyros is a type of low fat cheese produced from a mixture of sheep and goat milk. Anthotyros cheese in Crete is produced from the whey of hard cheese such as kefalotyri and graviera. Anthotyros is a cheese which comes from the myzithra cheese (whey) dehydration. The dehydrated anthotyros' physicochemical properties are moisture content of 35%, fat content in dry matter of 55% and low concentration of salt. The purpose of this study was to identify which of the three gas compositions applied; MAP(1):40% CO(2), 55% N(2), 5% O(2), MAP(2): 60% CO(2), 40% N(2) and MAP(3): 50% CO(2), 50% N(2) can lead to greater shelf life prolongation of anthotyros. The control samples were packaged in air. All cheese samples were kept under refrigeration (4 +/- 0.5 degrees C) for 55 days. The statistical analysis of organoleptic characteristics was carried out by using the Principal Component Analysis (PCA) by means of JMP5.0.1. PMID- 21549215 TI - Study of changes in physicochemical and microbiological characteristics of shrimps (Melicertus kerathurus) stored under modified atmosphere packaging. AB - Fresh minimally processed shrimps were stored under modified atmosphere packaging (60% CO(2):40% N(2) for MAP A and 92.9% N(2):5.1% CO(2):2% O(2) for MAP B) for 5 days at 3 degrees C. Total mesophiles, H(2)S forming bacteria, Pseudomonas spp., Brochothrix thermosphacta, firmness, color and sensory parameters were investigated throughout the whole time of the experiment. During storage period samples stored under MAP B managed to retain firmness values close to the initial values. All microbial populations growth was suppressed by the presence of MAP A. Samples stored under MAP B managed to maintain their firmness values close to the initial ones while MAP A samples were significantly less firm (p < 0.05). PMID- 21549216 TI - Do leafy green vegetables and their ready-to-eat [RTE] salads carry a risk of foodborne pathogens? AB - Over the past 10 years, there is an increasing demand for leafy green vegetables and their ready-to-eat (RTE) salads since people changed their eating habits because of healthier lifestyle interest. Nevertheless fresh leafy green vegetables and their RTE salads are recognized as a source of food poisoning outbreaks in many parts of the world. However, this increased proportion of outbreaks cannot be completely explained by increased consumption and enhanced surveillance of them. Both in Europe and in the USA, recent foodborne illness outbreaks have revealed links between some pathogens and some leafy green vegetables such as mostly lettuces and spinaches and their RTE salads since fresh leafy green vegetables carry the potential risk of microbiological contamination due to the usage of untreated irrigation water, inappropriate organic fertilizers, wildlife or other sources that can occur anywhere from the farm to the fork such as failure during harvesting, handling, processing and packaging. Among a wide range of pathogens causing foodborne illnesses, Escherichia coli O157:H7, Salmonella spp., and Listeria monocytogenes are the most common pathogens that contaminate leafy green vegetables. Children, the elderly, pregnant women and immunocompromised people are the most at risk for developing complications from foodborne illness as a result of eating contaminated leafy greens or their RTE salads. These outbreaks are mostly restaurant associated or they sometimes spread across several countries by international trade routes. This review summarizes current observations concerning the contaminated leafy green vegetables and their RTE salads as important vehicles for the transmission of some foodborne pathogens to humans. PMID- 21549217 TI - Intravenous busulfan-cyclophosphamide as a preparative regimen before allogeneic hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia. AB - The use of i.v. busulfan (BU) instead of the oral formulation can improve outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) by reducing toxicity and transplantation-related mortality (TRM). There are limited reports of i.v. BU used to treat patients with acute lymphoblastic leukemia (ALL). The present study was performed to evaluate the efficacy and toxicity of i.v. BU/cyclophosphamide (CY) conditioning in adult ALL. We retrospectively analyzed 42 consecutive patients who underwent allo-HSCT with BU/CY conditioning between January 2007 and October 2010 with an HLA-matched donor (sibling, n = 18; unrelated, n = 24). Thirty-three patients were in first complete remission (CR1), 2 were in second complete remission (CR2), and 7 were in a more advanced stage. Median patient age was 28 years (range, 17~55 years). The median follow-up was 15 months (range, 1~48 months). Overall, 13 patients died, for a 30-month overall survival of 56.5% +/- 10.6% (65.7% +/- 12.5% for patients in CR1 vs 25.4% +/- 15.5% for those in CR2 or beyond; P < .001). Eleven patients experienced relapse between 2 and 26 months after allo-HSCT, with a 30 month relapse rate (RR) of 40% +/- 10.9% (32.0% +/- 12.7% for patients in CR1 vs 71.4% +/- 17.1% for those in CR2 or beyond; P = .001). The incidence of grade II IV acute graft-versus-host disease (GVHD) was 39.2% +/- 8.8%, and that of grade III-IV acute GVHD was 7.4% +/- 4.1%. The incidence of chronic GVHD was 63.9% +/- 11.7%, and that of extensive chronic GVHD was 19.3% +/- 7.9%. Only 2 cases of clinically diagnosed veno-occlusive disease (VOD) were documented (4.7%), and 1 of these patients died of severe VOD. Other BU/CY conditioning-associated toxicities were diffuse alveolar hemorrhage in 1 patient and hemorrhagic cystitis in 8 patients. Four patients died due to TRM, for a 30-month TRM of 9.7% +/- 4.6%. This study demonstrates that i.v. BU/CY can be considered a feasible conditioning regimen for adult ALL, with low incidences of VOD and TRM. PMID- 21549218 TI - Effects of tributyltin and benzo[a]pyrene on the immune-associated activities of hemocytes and recovery responses in the gastropod abalone, Haliotis diversicolor. AB - Our previous study reports that short-term exposure to sublethal concentrations of benzo[a]pyrene (BaP) induces immunomodulation in the gastropod abalone, Haliotis diversicolor. In the present study, it was further observed that long term chronic exposure to sublethal concentrations of BaP modulated the immunocompetence of abalones in terms of the change in activity of the antioxidant and immune associated parameters tested. In addition, the effect of tributyltin (TBT), another important genotoxicant in the aquatic environment, was investigated. Exposure of abalones to sublethal concentrations of TBT and BaP for 21 days resulted in significant decrease of total hemocyte count, phagocytosis, membrane stability and lysozyme activity. Conversely induction of extra and intra cellular superoxide generation, nitric oxide, nitric oxide synthase and myeloperoxidase activity was present when the abalones were exposed to TBT and BaP. Most of the immune associated parameters tested showed clear time dependent response to both toxicants. Within 14 days after the 21 day exposure to BaP, recovery was observed as evidenced by most of the parameters returning to their normal level. However, no recovery was observed within 14 days after the 21 day exposure to TBT as evidenced by continued elevation of intra cellular superoxide and nitrite production and decrease in THC, membrane stability and lysozyme activity. This suggested a prolonged TBT-induced impact on the immune reaction and possibly more damage than that caused by BaP. Overall the results suggest that chronic exposure to sublethal concentrations of TBT or BaP causes modulations in the immunocompetence of abalones with most of the immune associated parameters tested being stimulated, and this might be harmful to the host. PMID- 21549219 TI - G6PD A-variant influences the antibody responses to Plasmodium falciparum MSP2. AB - High antibody levels directed to Plasmodium falciparum merozoite surface proteins (MSP), including MSP2, as well as genetically related red blood cell defects, have previously been found to be associated with protection against malaria. Here, our main objective was to study the changes in MSP2-specific total IgG, IgG1 and IgG3 responses during a malaria transmission season in order to assess the impact of sickle-cell, alpha(+)-thalassemia and G6PD variants on antibody kinetics. Repeated parasitological assessments of a cohort of children were conducted during an 8-month period. Antibody responses to recombinant MSP2/3D7 and MSP2/FC27 proteins were measured at the beginning and at the end of transmission season. We found that (i) the period of last Plasmodium falciparum infection during the transmission season was associated with IgG3 anti-MSP2 change. Compared to the IgG3 levels of children infected in January 2003 (end of transmission season), the IgG3 level of children decreased with the length of the period without infection, (ii) G6PD A- carriers had a lower increase of IgG3 levels to MSP2/FC27 and MSP2/3D7 during the transmission season than the noncarriers. This latter finding is suggestive of qualitative and/or quantitative reduction of exposure to malarial antigens related to this genetic variant, leading to weaker stimulation of specific antibody responses. We speculate that cell-mediated immune activity may explain the clinical protection afforded by this genetic trait. PMID- 21549220 TI - Cellular players in angiogenesis during the course of systemic sclerosis. AB - Vascular endothelial injury in Systemic Sclerosis (SSc) leads to pathological changes in the blood vessels that adversely impact the physiology of many organs, resulting in chronic tissue ischemia. The response to hypoxia induces complex cellular and molecular mechanisms in the attempt to recover endothelial cell function and tissue perfusion. The progressive losses of capillaries on one hand, and the vascular remodeling of arteriolar vessels on the other, result in insufficient blood flow, causing severe and chronic hypoxia. Hypoxia is a major stimulus of angiogenesis, leading to the expression of pro-angiogenic molecules, mainly of Vascular Endothelial Growth Factor (VEGF), which triggers the angiogenic process. Nevertheless, in SSc patients there is no evidence of adaptive angiogenesis. Failure of the angiogenic process in SSc largely depends on alteration in the balance between pro- and anti-angiogenic factors, as well as on functional alterations of the cellular players involved in the angiogenic and vasculogenic program. A decreased urokinase plasminogen activator (uPA) dependent invasion, proliferation, and capillary morphogenesis, was showed in SSc endothelial cells (EC). Although hematopoietic endothelial progenitor cells (EPC) count in the peripheral blood of SSc patients is still a matter of controversy, alterations in mobilization process, an excessive immune-mediated EPC destruction in the peripheral circulation or in the bone marrow, a progressive depletion of EPCs following homing to ischemic tissues under persistent peripheral vascular injury, an intrinsic functional impairment could lead to poor vasculogenesis. Human mesenchymal stem cells represent an alternative source of endothelial progenitor cells and it has been observed that their angiogenic potential is reduced in SSc. Targeting autologous stem and progenitor cells could be an ideal tool to counteract and repair dysfunctional angiogenesis. PMID- 21549221 TI - Role of the complement system in rheumatoid arthritis and psoriatic arthritis: relationship with anti-TNF inhibitors. AB - The complement system is an essential component of innate immunity and also plays an important role in modulating adaptive immunity. It comprises more than 30 plasma and membrane-bound proteins and can be activated through three pathways: the classical, the alternative and the lectin pathways. Its activation contributes to the pathogenesis of several autoimmune and inflammatory conditions. The evidence of complement activation in synovial fluid of Rheumatoid Arthritis (RA) patients is abundant, while few data exist in Psoriatic Arthritis (PsA) patients. Levels of complement proteins are generally depressed in the synovial fluid of patients with RA, reflecting consumption of complement. On the other hand, elevated levels of several complement cleavage products have been observed in synovial fluid. Involvement of complement in the pathogenesis of RA was also confirmed in animal models of arthritis: mice deficient for complement proteins are protected against the development of collagen-induced arthritis and administration of the anti-C5 monoclonal antibody prevents the onset of this arthritis. In the last decade anti-tumor necrosis factor agents have shown to be effective for the treatment of both RA and PsA and some studies suggest that the interaction between TNFalpha and complement system may contribute to the pathogenesis of these diseases. Reduction of the complement activation could be one of the mechanism by which TNFalpha-inhibitors exert their effectiveness in inflammatory arthritides. Because of these findings, complement could be an attractive therapeutic target both in RA and in PsA. PMID- 21549222 TI - The multifaceted pyridoxal 5'-phosphate-dependent O-acetylserine sulfhydrylase. AB - Cysteine is the final product of the reductive sulfate assimilation pathway in bacteria and plants and serves as the precursor for all sulfur-containing biological compounds, such as methionine, S-adenosyl methionine, iron-sulfur clusters and glutathione. Moreover, in several microorganisms cysteine plays a role as a reducing agent, eventually counteracting host oxidative defense strategies. Cysteine is synthesized by the PLP-dependent O-acetylserine sulfhydrylase, a dimeric enzyme belonging to the fold type II, catalyzing a beta replacement reaction. In this review, the spectroscopic properties, catalytic mechanism, three-dimensional structure, conformational changes accompanying catalysis, determinants of enzyme stability, role of selected amino acids in catalysis, and the regulation of enzyme activity by ligands and interaction with serine acetyltransferase, the preceding enzyme in the biosynthetic pathway, are described. Given the key biological role played by O-acetylserine sulfhydrylase in bacteria, inhibitors with potential antibiotic activity have been developed. This article is part of a Special Issue entitled: Pyridoxal Phospate Enzymology. PMID- 21549223 TI - Preparation of stem cell aggregates with gelatin microspheres to enhance biological functions. AB - The objective of this study is to improve the viability and osteogenic differentiation of cultured rat bone marrow-derived mesenchymal stem cells (MSC) by the use of gelatin hydrogel microspheres. Gelatin was dehydrothermally crosslinked at 140 degrees C for 48 h in a water in oil emulsion state. When cultured with the gelatin hydrogel microspheres in round, U-bottomed wells of 96 well plates coated with poly(vinyl alcohol) MSC formed aggregates homogeneously incorporating the microspheres. The viability of the cell aggregates was significantly higher compared with that of aggregates formed without microspheres. MSC proliferation in the aggregates depended on the number and diameter of the incorporated microspheres. Higher MSC proliferation was observed for aggregates incorporating a greater number of larger gelatin microspheres. When evaluated as a measure of aerobic glycolysis the ratio of l-lactic acid production/glucose consumption in MSC was significantly lower for MSC cultured with gelatin microspheres than those without microspheres. MSC production of alkaline phosphatase (ALP) and sulfated glycosaminaglycan (sGAG) was examined to evaluate their potential osteogenic and chondrogenic differentiation. The amount of ALP produced was significantly higher for MSC aggregates cultured with gelatin microspheres than that of MSC cultured without microspheres. On the other hand, the amount of sGAG produced was significantly lower for MSC aggregates containing microspheres. It is concluded that the incorporation of gelatin hydrogel microspheres prevents the aggregated MSC suffering from a lack of oxygen, resulting in enhanced MSC aggregation and cell proliferation and osteogenic differentiation. PMID- 21549224 TI - An atypical HLH protein OsLF in rice regulates flowering time and interacts with OsPIL13 and OsPIL15. AB - In plants, flowering as a crucial developmental event is highly regulated by both genetic programs and environmental signals. Genetic analysis of flowering time mutants is instrumental in dissecting the regulatory pathways of flowering induction. In this study, we isolated the OsLF gene by its association with the T DNA insertion in the rice late flowering mutant named A654. The OsLF gene encodes an atypical HLH protein composed of 419 amino acids (aa). Overexpression of the OsLF gene in wild type rice recapitulated the late flowering phenotype of A654, indicating that the OsLF gene negatively regulates flowering. Flowering genes downstream of OsPRR1 such as OsGI and Hd1 were down regulated in the A654 mutant. Yeast two hybrid and colocalization assays revealed that OsLF interacts strongly with OsPIL13 and OsPIL15 that are potentially involved in light signaling. In addition, OsPIL13 and OsPIL15 colocalize with OsPRR1, an ortholog of the Arabidopsis APRR1 gene that controls photoperiodic flowering response through clock function. Together, these results suggest that overexpression of OsLF might repress expression of OsGI and Hd1 by competing with OsPRR1 in interacting with OsPIL13 and OsPIL15 and thus induce late flowering. PMID- 21549225 TI - Production and properties of two collagenases from bacteria and their application for collagen extraction. AB - Two collagenolytic protease (collagenase) producing bacteria, a Gram positive Bacillus cereus CNA1 and a Gram negative Klebsiella pneumoniae CNL3, were isolated under alkaline and acidic conditions, respectively. The production of collagenase by these two bacteria was optimized. Glycerol was the suitable carbon source for collagenase production by both strains. The optimal initial pH values for collagenase production by CNA1 and CNL3 were 7.5 and 6.0, respectively, and the optimal temperature was 37 degrees C for both strains. The maximum activity of the partially purified collagenase from CNA1 was at pH 7.0 and 45 degrees C. Its pH and thermal stability were in the range of 6-8 and below 40 degrees C, respectively. The maximum activity of the partially purified collagenase from CNL3 was at pH 6.0 and 40 degrees C. Its pH and thermal stability were in the range of 5-7 and below 37 degrees C, respectively. The collagenase from CNL3 was more stable at a low pH compared with that from CNA1. Collagenases from both strains were used to extract collagen from salmon fish skin. The use of collagenases from CNA1 and CNL3 combined with acid treatment yielded a high collagen extraction of 54.6% and 53.0%, of the fish skin dry weight, respectively. PMID- 21549226 TI - Lipase from marine Aspergillus awamori BTMFW032: production, partial purification and application in oil effluent treatment. AB - Marine fungus BTMFW032, isolated from seawater and identified as Aspergillus awamori, was observed to produce an extracellular lipase, which could reduce 92% fat and oil content in the effluent laden with oil. In this study, medium for lipase production under submerged fermentation was optimized statistically employing response surface method toward maximal enzyme production. Medium with soyabean meal-0.77% (w/v); (NH(4))(2)SO(4)-0.1m; KH(2)PO(4)-0.05 m; rice bran oil 2% (v/v); CaCl(2)-0.05 m; PEG 6000-0.05% (w/v); NaCl-1% (w/v); inoculum-1% (v/v); pH 3.0; incubation temperature 35 degrees C and incubation period-five days were identified as optimal conditions for maximal lipase production. The time course experiment under optimized condition, after statistical modeling, indicated that enzyme production commenced after 36 hours of incubation and reached a maximum after 96 hours (495.0 U/ml), whereas maximal specific activity of enzyme was recorded at 108 hours (1164.63 U/mg protein). After optimization an overall 4.6 fold increase in lipase production was achieved. Partial purification by (NH(4))(2)SO(4) precipitation and ion exchange chromatography resulted in 33.7% final yield. The lipase was noted to have a molecular mass of 90 kDa and optimal activity at pH 7 and 40 degrees C. Results indicated the scope for potential application of this marine fungal lipase in bioremediation. PMID- 21549227 TI - lux-Marking and application of carbofuran degrader Burkholderia cepacia PCL3. AB - A luxAB-mutant of the carbofuran degrading bacterium Burkholderia cepacia PCL3 was successfully constructed with the capability to emit a luminescence signal of 1.6*10(-3)RLUcfu(-1). The mutant has a growth pattern and carbofuran degradation ability similar to PCL3 wild-type. The luminescent emission by PCL3:luxAB1 directly correlated with the metabolic activity of the cells. The optimal pH, temperature and n-decanal concentration for luminescence emission are 7.0, 35 degrees C and 0.01%, respectively. PCL3:luxAB1 was used to assess the toxicity of carbofuran and carbofuran phenol in basal salt medium (BSM) in which the different sensitivity of the cells is dependent on the biomass concentration. With the luciferase system, the degradative fraction of the augmented PCL3:luxAB1 and the difference between the active augmented PCL3:luxAB1 and indigenous microorganisms at the contaminated site could be indicated. PMID- 21549228 TI - Protein signatures for survival and recurrence in metastatic melanoma. AB - Patients with melanoma metastatic to regional lymph nodes exhibit a range in tumor progression, survival, and treatment. Current approaches to stratify patients with this stage of disease predominantly involve clinical and histological methods. Molecular classification thus far has focused almost exclusively on genetic mutations. In this study, proteomic data from 69 melanoma lymph node metastases and 17 disease free lymph nodes acquired by histology directed MALDI imaging mass spectrometry were used to classify tumor from control lymph node and to molecularly sub-classify patients with stage III disease. From these data, 12 survival associated protein signals and 3 recurrence associated signals in the acquired mass spectra were combined to generate a multiplex molecular signature to group patients into either poor or favorable groups for recurrence and survival. Proteins represented in the signature include cytochrome c, s100 A6, histone H4, and cleaved forms of thymosin beta-4, thymosin beta-10, and ubiquitin. In total over 40 protein signals from the tissue were identified. PMID- 21549229 TI - Epigenetic mechanisms in the endosperm and their consequences for the evolution of flowering plants. AB - The sudden rise of angiosperms to ecological dominance was an "abominable mystery" to Charles Darwin, and understanding the underlying evolutionary driving force has remained a scientific challenge since then. The recognition of polyploidization as an important factor for plant speciation is likely to hold a key to this mystery and we will discuss possible mechanisms underlying this phenomenon. Polyploidization raises an immediate reproductive barrier in the endosperm, pointing towards an important but greatly underestimated role of the endosperm in preventing interploidy hybridizations. Parent-of-origin-specific gene expression is largely restricted to the endosperm, providing an explanation for the dosage sensitivity of the endosperm. Here, we review epigenetic mechanisms causing endosperm dosage sensitivity, their possible consequences for raising interploidy and interspecies hybridization barriers and their impact on flowering plant evolution. This article is part of a Special Issue entitled: Epigenetic Control. PMID- 21549230 TI - DNA methylation in higher plants: past, present and future. AB - A relatively high degree of nuclear DNA (nDNA) methylation is a specific feature of plant genomes. Targets for cytosine DNA methylation in plant genomes are CG, CHG and CHH (H is A, T, C) sequences. More than 30% total m(5)C in plant DNA is located in non-CG sites. DNA methylation in plants is species-, tissue-, organelle- and age-specific; it is involved in the control of all genetic functions including transcription, replication, DNA repair, gene transposition and cell differentiation. DNA methylation is engaged in gene silencing and parental imprinting, it controls expression of transgenes and foreign DNA in cell. Plants have much more complicated and sophisticated system of the multicomponent genome methylations compared to animals; DNA methylation in plant mitochondria is performed in other fashion as compared to that in nuclei. The nDNA methylation is carried out by cytosine DNA methyltransferases of, at least, three families. In contrast to animals the plants with the major maintenance methyltransferase MET1 (similar to animal Dnmt1) inactivated do survive. One and the same plant gene may be methylated at both adenine and cytosine residues; specific plant adenine DNA methyltransferase was described. Thus, two different systems of the genome modification based on methylation of cytosines and adenines seem to coexist in higher plants. This article is part of a Special Issue entitled: Epigenetic control of cellular and developmental processes in plants. PMID- 21549231 TI - Estrogen and peptide YY are associated with bone mineral density in premenopausal exercising women. AB - BACKGROUND: In women with anorexia nervosa, elevated fasting peptide YY (PYY) is associated with decreased bone mineral density (BMD). Prior research from our lab has demonstrated that fasting total PYY concentrations are elevated in exercising women with amenorrhea compared to ovulatory exercising women. PURPOSE: The purpose of this study was to assess the association between fasting total PYY, average monthly estrogen exposure and BMD in non-obese premenopausal exercising women. METHODS: Daily urine samples were collected and assessed for metabolites of estrone 1-glucuronide (E1G) and pregnandiol glucuronide (PdG) for at least one menstrual cycle if ovulatory or a 28-day monitoring period if amenorrheic. Fasting serum samples were pooled over the measurement period and analyzed for total PYY and leptin. BMD and body composition were assessed by dual-energy X-ray absorptiometry. Multiple regression analyses were performed to determine whether measures of body composition, estrogen status, exercise minutes, leptin and PYY explained a significant amount of the variance in BMD at multiple sites. RESULTS: Premenopausal exercising women aged 23.8+/-0.9years with a mean BMI of 21.2+/ 0.4kg/m(2) exercised 346+/-48min/week and had a peak oxygen uptake of 49.1+/ 1.8mL/kg/min. Thirty-nine percent (17/44) of the women had amenorrhea. Fasting total PYY concentrations were negatively associated with total body BMD (p=0.033) and total hip BMD (p=0.043). Mean E1G concentrations were positively associated with total body BMD (p=0.033) and lumbar spine (L2-L4) BMD (p=0.047). The proportion of variance in lumbar spine (L2-L4) BMD explained by body weight and E1G cycle mean was 16.4% (R(2)=0.204, p=0.012). The proportion of variance in hip BMD explained by PYY cycle mean was 8.6% (R(2)=0.109, p=0.033). The proportion of variance in total body BMD explained by body weight and E1G cycle mean was 21.9% (R(2)=0.257, p=0.003). CONCLUSION: PYY, mean E1G and body weight are associated with BMD in premenopausal exercising women. Thus, elevated PYY and suppressed estrogen concentrations are associated with, and could be directly contributing to, low BMD in exercising women with amenorrhea, despite regular physical activity. PMID- 21549232 TI - Titanium surface topography affects collagen biosynthesis of adherent cells. AB - Collagen-dependent microstructure and physicochemical properties of newly formed bone around implant surfaces represent key determinants of implant biomechanics. This study investigated the effects of implant surface topography on collagen biosynthesis of adherent human mesenchymal stem cells (hMSCs). hMSCs were grown for 0 to 42 days on titanium disks (20.0 * 1.0 mm) with smooth or rough surfaces. Cell attachment and spreading were evaluated by incubating cells with Texas-Red conjugated phalloidin antibody. Quantitative real-time PCR was used to measure the mRNA levels of Col1alpha1 and collagen modifying genes including prolyl hydroxylases (PHs), lysyl oxidases (LOXs) and lysyl hydroxylases (LHs). Osteogenesis was assessed at the level of osteoblast specific gene expression and alizarin red staining for mineralization. Cell layer-associated matrix and collagen content were determined by amino acid analysis. At 4h, 100% cells were flattened on both surfaces, however the cells on smooth surface had a fibroblast like shape, while cells on rough surface lacked any defined long axis. PH, LH, and most LOX mRNA levels were greater in hMSCs grown on rough surfaces for 3 days. The mineralized area was greater for rough surface at 28 and 42 days. The collagen content (percent total protein) was also greater at rough surface compared to smooth surface at 28 (36% versus 26%) and 42 days (46% versus 29%), respectively (p<.05). In a cell culture model, rough surface topography positively modulates collagen biosynthesis and accumulation and the expression of genes associated with collagen cross-linking in adherent hMSC. The altered biosynthesis of the collagen-rich ECM adjacent to endosseous implants may influence the biomechanical properties of osseointegrated endosseous implants. PMID- 21549235 TI - Isolated limb perfusion and isolated limb infusion for malignant lesions of the extremities. PMID- 21549236 TI - Dermatopathology. Preface. PMID- 21549237 TI - Nevi of special sites. AB - Melanocytic nevi can have a wide range of histologic appearances. Within the spectrum of nevi, there exists a group that presents in certain anatomic locations with histologically worrisome features but nonetheless benign behavior. This group of nevi has been broadly categorized as nevi of special sites. The anatomic locations affected by this group include the embryonic milkline (breast, axillae, umbilicus, genitalia), flexural areas, acral surfaces, ear, and scalp. Nevi in these locations may be mistaken for melanomas because of their histologic appearance, resulting in inappropriate overtreatment of patients. In this article, the authors review the histologic features of these special site nevi and discuss the criteria that help distinguish them from melanoma. PMID- 21549238 TI - Nevoid melanoma. AB - This article discusses the key features of nevoid melanoma. Gross features, microscopic features, immunohistochemistry, differential diagnosis, diagnosis, prognosis, and treatment are also discussed. PMID- 21549239 TI - Dysplastic nevi. AB - Patients with multiple dysplastic nevi have an increased risk for malignant melanoma, and dysplastic nevi themselves have at least some potential for malignant transformation. Development of malignant melanoma is uncommon within dysplastic nevi, however. Since this transformation occurs in other types of nevi, their role as a marker of increased risk for melanoma in the patients who bear them seems to be of greater significance. This article discusses the gross, clinical and microscopic features; diagnosis; and prognosis of dysplastic nevi. The key features and pitfalls of diagnosing malignant melanoma, congenital nevus, and recurrent nevus are given. PMID- 21549240 TI - Congenital melanocytic nevi. AB - This article reviews congenital melanocytic nevi (CMN), which are present at birth or appear shortly thereafter, and their main histologic features. Several histologic variants and histopathologic criteria that differentiate CMN from other nevi, such as atypical or dysplastic nevi, and from nevoid malignant melanoma, are discussed. Histologic pitfalls in the correct identification of lentiginous melanocytic hyperplasia, pagetoid scatter, and proliferative nodules in the context of CMN are discussed. The risk for development of malignant melanoma in association with a congenital melanocytic nevus and variable causes for changing mole are discussed. PMID- 21549241 TI - Acral lentiginous melanoma. AB - Acral lentiginous melanoma is an uncommon skin malignancy that occurs with equal frequency in all races and has a worse prognosis than other types of melanoma; it presents as dark, irregular macules, papules, or nodules on the feet and, less commonly, the hands. The histologic findings of acral lentiginous melanoma are characterized by an asymmetric, poorly circumscribed proliferation of continuous single melanocytes at the dermoepidermal junction. Single melanocytes predominate over nests. The tumor must be distinguished from benign acral lentiginous nevi, which can display site-related atypia. PMID- 21549242 TI - Melanoma margin assessment. AB - Primary cutaneous melanoma is treated by excisional surgery and careful histologic assessment of the specimen margins is a crucial component of pathology reporting. Surgical margins may be assessed by conventional transverse (bread loaf) vertical sections, by en face vertical sections, or by en face oblique sections. Transverse techniques only sample a small percentage of the surgical margin. En face techniques are technically challenging but allow assessment of close to 100% of the margin. Margin assessment for melanoma removed from chronically sun-damaged skin is difficult. Melanoma in situ shows contiguous melanocyte growth, nesting, or intraepidermal pagetoid spread. Pitfalls include solar melanocytic hyperplasia, solar lentigines, melanocytic hyperplasia secondary to previous biopsy, lichenoid reactions, and invasive melanoma mimicking scar or benign nevus. En face sections can be used to assess margins for melanoma on sun-damaged skin, and evidence suggests that frozen sections may also be employed by experienced clinicians. Immunohistochemistry is a useful ancillary technique, enabling more accurate identification of in situ melanoma within a surgical margin. PMID- 21549243 TI - Sentinel lymph nodes in cutaneous melanoma. AB - Examination of sentinel lymph nodes (SLN) has probably become the most popular method of early staging of patients who have cutaneous melanoma because SLN are considered to be the lymph nodes most likely to contain metastatic deposits; they can be examined in a more intense manner than in standard lymphadenectomy. There are several protocols to examine SLN but most of them use formalin-fixed, paraffin-embedded sections stained with hematoxylin and eosin with the addition of immunohistochemistry. By using these protocols, approximately 20% of patients who have cutaneous melanoma have melanoma cells in the SLN. Current studies are evaluating the possible therapeutic value of removal of positive SLN, but it is accepted by most authors that detection of positive SLN conveys an impaired prognosis for patients who have cutaneous melanoma. PMID- 21549244 TI - Spitz nevi, atypical spitzoid neoplasms, and spitzoid melanoma. AB - Spitz nevi and melanoma represent benign and malignant counterparts commonly coupled in the same differential diagnosis. The precise distinction between the two entities remains an ongoing challenge in dermatopathology and surgical pathology. In past years, considerable work has been devoted to the assembly of criteria to permit exact diagnosis. Although diagnostic accuracy has improved, many lesions remain challenging to classify based solely upon conventional microscopic criteria. In this article, the clinical and histopathological attributes of Spitz nevi and spitzoid melanoma are reviewed. Lesions that cannot be definitively classified based solely upon conventional microscopic criteria are referred to as atypical spitzoid neoplasms, which the authors view as a provisional diagnostic category rather than as a formal disease entity. Molecular assessment by way of comparative genomic hybridization or fluorescence in situ hybridization is increasingly used to facilitate assessment of this challenging differential and is especially germane to the evaluation of ambiguous lesions. PMID- 21549245 TI - Desmoplastic melanoma. AB - Desmoplastic melanoma (DM) is a variant of spindle cell melanoma characterized by the presence of abundant fibrous matrix. It is typically found in the head and neck region on chronically sun-damaged skin of older individuals. Early detection is uncommon, because its clinical features are not distinctive. DM is prone to misdiagnosis not only clinically but also histologically. It may simulate a sclerosing melanocytic nevus and various benign and malignant nonmelanocytic lesions. Among melanomas said to be desmoplastic by various pathologists there is significant variation with regard to the extent of intratumoral fibrosis. It may be prominent throughout the entire tumor (pure DM) or represent a portion of an otherwise nondesmoplastic melanoma (combined DM). Immunophenotypically, DM are usually strongly and homogeneously positive for S-100 protein, but are often negative or only focally positive for melanocyte differentiation antigens. DM differs from conventional melanoma in its clinical course. It is associated with a higher tendency for local recurrence, but metastases to regional lymph nodes are less common. PMID- 21549246 TI - Molecular aspects of melanoma. AB - Melanoma is the most serious type of skin cancer. Unfortunately, treatment has progressed little and advanced melanoma has appalling survival rates. A goal of molecular analysis is to fully describe the alterations that underpin melanoma's clinical phenotype so that diagnosis can be more accurate, outcome can be predicted with greater confidence, and treatment that is tailored to the patient can be given. This article describes the handful of "signature" changes that are known to occur, describes how some recent studies have shed light on changes beyond this signature, and finally discusses the impact of molecular pathology for practicing histopathologists. PMID- 21549247 TI - Blue nevi and related tumors. AB - Blue nevi and related lesions are characterized by the proliferation of dermal dendritic melanocytes. Although they share certain common clinical and histologic features, they encompass a spectrum of lesions ranging from benign melanocytic hamartomas and common blue nevi to borderline malignant pigmented epithelioid melanocytoma and aggressive malignant blue nevi. This article succinctly describes the common dermal dendritic proliferations and updates readers on newly classified entities and variants. The differential diagnosis of the main entities and strategies to distinguish them from their melanocytic and nonmelanocytic mimics is also presented. PMID- 21549248 TI - The Holman Research Pathway in radiation oncology. PMID- 21549249 TI - Effect of breast volume on treatment reproducibility on a tomotherapy unit in the treatment of breast cancer. AB - PURPOSE: To determine whether the volume of a patient's breast is correlated with reliable daily setup in treatment of breast cancer with a helical tomotherapy treatment unit. METHODS AND MATERIALS: Thirty-six consecutive patients with breast cancer were treated on a helical tomotherapy unit. During simulation, kilovoltage CT images were obtained for treatment planning. These were fused with daily megavoltage CT scans, and after setup based on skin marks and laser alignment the necessary shifts were carried out. The magnitude of daily shifts (in millimeters) was retrospectively obtained from the daily image fusions, and the breast volume was obtained from the treatment plan. A total of 873 fusion scans were reviewed. Random error for absolute and directional daily shifts was evaluated for correlation to volume. Variation over time was also evaluated. RESULTS: Mean (SD) random shift for all patients in the lateral, longitudinal, and vertical directions was 2.7 (2.0), 3.1 (1.5), and 3.2 (2.6) mm, respectively. Mean (SD) absolute distance shifted was 6.0 (3.5) mm. There was no significant correlation between mean absolute or mean directional daily shift and breast volume (0.08, 0.08, 0.22, and 0.07, respectively). There was no correlation between setup variation and time. CONCLUSIONS: In this cohort, there was no correlation between breast volume and degree of daily shift. There was no correlation between time course and setup variation. Therefore, setup variation does not improve or degrade with repeated treatment setups. PMID- 21549250 TI - Long-term effects of 56Fe irradiation on spatial memory of mice: role of sex and apolipoprotein E isoform. AB - PURPOSE: To assess whether the effects of cranial (56)Fe irradiation on the spatial memory of mice in the water maze are sex and apolipoprotein E (apoE) isoform dependent and whether radiation-induced changes in spatial memory are associated with changes in the dendritic marker microtubule-associated protein 2 (MAP-2) and the presynaptic marker synaptophysin. METHODS AND MATERIALS: Two month-old male and female mice expressing human apoE3 or apoE4 received either a 3-Gy dose of cranial (56)Fe irradiation (600 MeV/amu) or sham irradiation. Mice were tested in a water maze task 13 months later to assess effects of irradiation on spatial memory retention. After behavioral testing, the brain tissues of these mice were analyzed for synaptophysin and MAP-2 immunoreactivity. RESULTS: After irradiation, spatial memory retention of apoE3 female, but not male, mice was impaired. A general genotype deficit in spatial memory was observed in sham irradiated apoE4 mice. Strikingly, irradiation prevented this genotype deficit in apoE4 male mice. A similar but nonsignificant trend was observed in apoE4 female mice. Although there was no change in MAP-2 immunoreactivity after irradiation, synaptophysin immunoreactivity was increased in irradiated female mice, independent of genotype. CONCLUSIONS: The effects of (56)Fe irradiation on the spatial memory retention of mice are critically influenced by sex, and the direction of these effects is influenced by apoE isoform. Although in female mice synaptophysin immunoreactivity provides a sensitive marker for effects of irradiation, it cannot explain the apoE genotype-dependent effects of irradiation on the spatial memory retention of the mice. PMID- 21549251 TI - A new method for synthesizing radiation dose-response data from multiple trials applied to prostate cancer: in regard to Diez P, et al. (Int J Radiat Oncol Biol Phys 2010;77:1066-1071). PMID- 21549253 TI - Marginal misses after postoperative intensity-modulated radiotherapy for head and neck cancer: in regard to Chen et al. (Int J Radiat Oncol Biol Phys. 2010 Jul 23). PMID- 21549255 TI - Reply to Dr. Kang's letter entitled "Effect of omega-3 fatty acids on lifespan". PMID- 21549257 TI - The prevalence and characteristics of young and mid-age women who use yoga and meditation: results of a nationally representative survey of 19,209 Australian women. AB - OBJECTIVE: To determine the characteristics of yoga and meditation users and non users amongst young and mid-aged Australian women. DESIGN AND SETTING: The research was conducted as part of the Australian Longitudinal Study on Women's Health (ALSWH) which was designed to investigate multiple factors affecting the health and well being of women over a 20-year period. PARTICIPANTS: The younger (28-33 years) (n=8885) and mid-aged (56-61 years) (n=10,324) cohorts of the ALSWH who completed Survey 5 in 2006 and 2007 respectively. MAIN OUTCOME MEASURE: Use of yoga. RESULTS: This study estimates that 35% of Australian women aged 28-33 and 27% of Australian women aged 56-61 use yoga or meditation. Younger women with back pain (OR=1.28; 95% CI: 1.08, 1.52) and allergies (OR=1.25; 95% CI: 1.06, 1.49) were more likely to use yoga or meditation, while younger women with migraines or headaches (OR=0.73; 95% CI: 0.62, 0.87) were less likely to use yoga or meditation. Mid-age women with low iron (OR=1.68; 95% CI: 1.29, 2.19) and bowel problems (OR=1.37; 95% CI: 1.13, 1.65) were more likely to use yoga or meditation, while mid age women with hypertension (OR=0.62; 95% CI: 0.52, 0.76) were less likely to use yoga or meditation. CONCLUSION: A large percentage of the female population are using yoga or meditation. Given that women who regularly use yoga or meditation positively associated with measures of mental and physical health, there is a need for further research to examine the experiences and potential benefits of these mind-body practices for women's health. PMID- 21549256 TI - Prevalence and sociodemographic correlates of spiritual healer use: findings from the National Survey of American Life. AB - OBJECTIVES: This study investigates sociodemographic and health-related correlates of use of a spiritual healer for medical help. A large national, multiracial-multiethnic data source permits a more comprehensive investigation than was possible in previous studies. It also enables a closer focus on socioeconomic disadvantage and health need as determinants of utilization. DESIGN AND SETTING: Respondents are from the National Survey of American Life: Coping with Stress in the 21st Century (NSAL), a nationally representative multi-stage area-probability survey of U.S. adult African Americans, Caribbean Blacks, and non-Hispanic Whites conducted from 2001 to 2003. The sample contains 6082 adults aged 18 and over. MAIN OUTCOME MEASURES: NSAL respondents were surveyed about lifetime use of alternative providers for medical care or advice. Response categories included two types of spiritual healers: faith healers and psychics. These outcomes were logistically regressed, separately, onto 10 sociodemographic or health-related indicators: race/ethnicity, age, gender, marital status, education, household income, region, medical care use, insurance coverage, and self-rated health. RESULTS: Lifetime utilization of a faith healer is more prevalent among respondents in good health and less prevalent among Caribbean Blacks and never married persons. Users of a psychic healer are more likely to be educated, residents of the Northeast or West, and previously married, and less likely to report excellent health. CONCLUSIONS: Use a spiritual healer is not due, on average, to poor education, marginal racial/ethnic or socioeconomic status, dire health straits, or lack of other healthcare options. To some extent, the opposite appears to be true. Use of a spiritual healer is not associated with fewer social and personal resources or limitations in health or healthcare. PMID- 21549258 TI - Cupping - is it reproducible? Experiments about factors determining the vacuum. AB - OBJECTIVES: Cupping is a traditional method for treating pain which is investigated nowadays in clinical studies. Because the methods for producing the vacuum vary considerably we tested their reproducibility. METHODS: In a first set of experiments (study 1) four methods for producing the vacuum (lighter flame 2 cm (LF1), lighter flame 4 cm (LF2), alcohol flame (AF) and mechanical suction with a balloon (BA)) have been compared in 50 trials each. The cupping glass was prepared with an outlet and stop-cock, the vacuum was measured with a pressure gauge after the cup was set to a soft rubber pad. In a second series of experiments (study 2) we investigated the stability of pressures in 20 consecutive trials in two experienced cupping practitioners and ten beginners using method AF. RESULTS: In study 1 all four methods yielded consistent pressures. Large differences in magnitude were, however, observed between methods (mean pressures -200+/-30 hPa with LF1, -310+/-30 hPa with LF2, -560+/-30 hPa with AF, and -270+/-16 hPa with BA). With method BA the standard deviation was reduced by a factor 2 compared to the flame methods. In study 2 beginners had considerably more difficulty obtaining a stable pressure yield than advanced cupping practitioners, showing a distinct learning curve before reaching expertise levels after about 10-20 trials. CONCLUSIONS: Cupping is reproducible if the exact method is described in detail. Mechanical suction with a balloon has the best reproducibility. Beginners need at least 10-20 trials to produce stable pressures. PMID- 21549259 TI - Integrative medicine models in contemporary primary health care. AB - OBJECTIVE: To determine what models of integrative medicine (IM) are being employed in contemporary health care settings, and how and which factors affect and facilitate the success of IM in terms of the integration of complementary and alternative medicine (CAM) and conventional medicine in primary health care (PHC). DESIGN: Literature review. SETTING: Australian and international PHC settings, and hospitals. MEASURES: Australian and international peer-reviewed literature identified from database searches, reference lists, desktop searches, texts, and relevant website searches (e.g., government and health-related departments and agencies). Focus was literature with the keywords 'integrative' or 'integrated' in conjunction with 'medicine' or 'health care'. Articles were analysed for descriptions of continuous and integrative services involving contemporary IM practices, their background, characteristics, and implementation. FINDINGS AND DISCUSSION: Classifications of IM in the literature present various ways that IM can be implemented, and it appears that strategies have been successfully developed to facilitate integration. Although few of the barriers to the integration of CAM and conventional medicine have been resolved, concerns over the legitimacy of CAM in health care (e.g., safety, biomedical evidence, and efficacy) are being overcome by the use of evidence-based practice in IM delivery. There are two dominant models of IM that have been developed. One is the selective combination of both biomedical evidence and experience-based evidence of both CAM and conventional medicine. The other is the selective incorporation of exclusively evidence-based CAMs into conventional medicine. The two model types signify different levels of equity between CAM and conventional medicine in regard to the power, autonomy, and control held by each. However, the factors common to all IM models, whether describing CAM as supplementary (and subordinate) or complementary (and partnered) to conventional medicine, is the concept of a health care model that aspires to be client-centred and holistic, with focus on health rather than disease as well as mutual respect among peer practitioners. CONCLUSIONS: The growth and viability of IM will depend on evidence-based practices, non-hierarchal IM practices, and identifying the successful influences on the integration of CAM and conventional medicine for recognition of its inherent value in PHC. PMID- 21549260 TI - Upright water-based exercise to improve cardiovascular and metabolic health: a qualitative review. AB - Research regarding the benefits of exercise for cardiovascular and metabolic health is extensive and well-documented. However, weight-bearing exercise may not be suitable for individuals with orthopaedic or musculoskeletal limitations, excess adiposity or other medical conditions. Water-based exercise may provide an attractive alternative to land-based exercise for achieving improved health and fitness in these populations. Although swimming is a popular form of water-based exercise it requires specific skills and is often undertaken at intensities that may not be safely prescribed in patient populations. Therefore upright, water based exercise has been suggested as a viable water-based alternative. However, surprisingly little is known about the effects of upright water-based exercise on improvements in cardiovascular and metabolic health. Limited evidence from water based studies indicate that regular deep or shallow water exercise can exert beneficial effects on cardiorespiratory fitness, strength, and body fat distribution. However, the impacts of water-based exercise on lipid profile, bodyweight, and carbohydrate metabolism are still unclear. Further studies are warranted to establish the effects of non-swimming, water-based exercise on cardiometabolic risks in humans. PMID- 21549261 TI - Psychotherapy and professional identity development: the relevance of CAM. PMID- 21549262 TI - Randomized blinding in basic research of homeopathy: some comments. PMID- 21549263 TI - Safety in the operating room: team approach saves lives. AB - Improvements in technology, classic peer review, and even relentless determination of the individual practitioner have proven insufficient to eliminate adverse events in surgical patients. Preventing avoidable harm must focus on changing the operating room culture from one of separate--and well meaning individuals--to a cohesive approach by surgeons, anesthesiologists, nurses, and associated or health staff. Neily and colleagues report the results of a comprehensive team training program implemented across 74 Veterans Health or facilities, which was associated with an 18% reduction in annual mortality (rate ratio = 0.82; P = 0.01). PMID- 21549264 TI - MicroRNAs and prognosis of lung cancer. AB - MicroRNAs have recently emerged as important regulatory molecules of normal and abnormal cellular behavior. They are small (18-22 nucleotides) noncoding RNA that control translation by sequence complementarity of their "seed" sequence to the 3' untranslated regions (UTR) of their target mRNAs, which are RNA species that code for proteins. Apart from their biological importance, these small molecules have received attention as biomarkers because of their remarkable stability in tissues and body fluids and the ease of their measurement. A recent article in Cancer Research by Voortman et al has failed to validate the hypothesis that tumor microRNA expression is associated with prognosis. In light of this significant finding, this article summarizes the current state of the art of microRNA biomarkers for the prognostication of lung cancer. PMID- 21549265 TI - Comparing apples to apples: a call for unification of complication reporting across health systems. AB - The formalization of assessment of surgical outcomes across health care systems for complex procedures is a significant problem in the surgical literature. Low and colleagues present support for the use of the Accordion Severity Grading System as a tool to provide simple and comprehensive assessment of postoperative complications. PMID- 21549266 TI - The National Lung Cancer Screening Trial: the ripple effect begins? AB - Preliminary results of the National Lung Screening Trial were recently announced. The significant implications of this trial for thoracic surgical practice are reviewed. PMID- 21549267 TI - Calcific aortic valve disease: new concepts. AB - Our understanding of calcific aortic stenosis has changed dramatically during the past 3 decades, with the concept of a "mechanical" disease of aging now replaced by the concept of an active disease process at the tissue level that may be amenable to medical therapy. The ability of echocardiography to provide early diagnosis and an accurate measurement of disease severity has increased our knowledge of the natural history of this disease process and allows us to follow individual patients over time, long before valve replacement is needed. We now recognize that even mild symptoms are an indication for valve replacement when severe obstruction is present. This review discusses the optimal approach to measurement of disease severity, the presymptomatic disease course, and the underlying causes of calcific valve disease, followed by a summary of clinical trials of medical therapy and the current indications and choices for valve replacement. PMID- 21549268 TI - Understanding risk assessment in cardiac surgery patients. AB - Understanding the risk of surgery in valvular disease is of interest because aging of the population renders decision making more difficult and the magnitude of risk will influence not only the decision to intervene but also the choice of intervention and its timing. To assist clinicians in assessing the risk of cardiac surgery, multivariate risk scores are increasingly used to estimate operative mortality. Overall, the currently available scores, mostly U.S. Society of Thoracic Surgeons score and European System for Cardiac operative Risk Evaluation, achieve acceptable discrimination but suboptimal calibration in estimating the operative mortality of heart valve surgery. The intrinsic limitations of scoring systems highlight the fact that risk scores should be integrated into clinical judgment but should not be a substitute for it. A multidisciplinary approach involving cardiologists, cardiac surgeons, and anesthesiologists is required for this purpose, especially in high-risk patients. PMID- 21549269 TI - Does straight deep hypothermic circulatory arrest suffice for brain preservation in aortic surgery? PMID- 21549270 TI - Natural orifice trans-luminal endoscopic surgery (NOTES) in thoracic surgery. AB - Natural orifice transluminal endoscopic surgery (NOTES) proposes the possibility of less-invasive, incisionless surgery. Initially conceived to replace abdominal procedures, more recently interest has focused on mediastinal and thoracic procedures as possible logical applications of transluminal approaches. A survey of the literature as well as the author's own experience is performed, examining experimental and increasingly human use of mediastinal and thoracoscopic flexible endoscopy. Issues regarding instrumentation, orientation, and best access are discussed. The literature describes both direct transesophageal access to the mediastinum and pleural cavities and submucosal flap access. Other techniques include transgastric, transvesicular, and percutaneous access via a neck incision. Overall, the early results of transesophageal Heller myotomy show the most promise for early clinical adoption. NOTES has an interesting role in thoracic and mediastinal surgery. Although initially thought of as a highly improbable application, the "home run" of per-oral endoscopic myotomy is indicating that the thorax may be one of the most useful places for NOTES. PMID- 21549271 TI - Prophylaxis of atrial fibrillation after noncardiac thoracic surgery. AB - Atrial fibrillation (AF) occurs commonly after noncardiac thoracic surgery, including lobectomy, pneumonectomy and esophagectomy. While not as extensively investigated as AF following cardiac surgery, some strategies for prophylaxis of AF after noncardiac thoracic surgery have been studied. Evidence from prospective, randomized controlled studies supports the use of beta-blockers, diltiazem, amiodarone or magnesium for prevention of AF after pulmonary resection. Limited evidence supports the efficacy of intravenous amiodarone for prevention of AF after esophagectomy. Further study is necessary to determine the safest and most effective methods of prophylaxis of AF after noncardiac thoracic surgery, and to identify patients most likely to benefit from AF prophylaxis. PMID- 21549272 TI - Barrett's: evolving techniques for dysplasia detection and endoscopic resection. AB - Advanced endoscopic imaging techniques have made the early diagnosis of neoplastic lesions in Barrett's esophagus easier. A new chapter in minimal invasive cancer therapy has been opened. Endoscopic treatment of early neoplasia in Barrett's esophagus (high-grade intraepithelial neoplasia and mucosal adenocarcinoma) has become the method of choice in most countries. Long-term results for endoscopic treatment in a large group of patients are now available. These emerging data suggest that endoscopic therapy is safe and highly effective with long-term complete remission rates of more than 94%. All visible lesions should be treated by endoscopic resection for histologic confirmation of the neoplastic lesion rather than by ablative techniques. After successful endoscopic resection of all visible and localizable high-grade intraepithelial neoplasia and mucosal cancer, ablative treatment of the remaining Barrett's epithelium at risk should be performed to reduce the rate of recurrent or metachronous neoplasia. PMID- 21549273 TI - Bronchoscopic lung volume reduction. AB - Lung volume-reduction surgery is a proven palliative procedure for emphysema, and in patients with heterogeneous upper-lobe disease as well as low baseline exercise capacity, even mortality benefits can be realized. However, its application is limited by high postoperative morbidity and stringent selection criteria that effectively exclude many patients. This has been the impetus for the development of less-invasive approaches to lung volume reduction. A range of different bronchoscopic techniques, such as endobronchial blockers, airway bypass, endobronchial valves, thermal vapor ablation, biological sealants, and airway implants have been investigated. The underlying physiological mechanisms of the various endoscopic modalities differ and both homogeneous, as well as heterogeneous, emphysema have been targeted. The currently available data on efficacy of bronchoscopic lung volume reduction are not conclusive, although subjective benefit in dyspnea scores and quality of life is a frequent finding. Improvements in objective outcomes, such as spirometry or exercise tolerance, have been only modest. Refining patient selection and dose of treatment are subjects of ongoing research to improve the efficacy data. Safety profiles are more promising, with rare procedure-related mortality and fewer complications experienced than with surgical lung volume reduction. The field of bronchoscopic lung volume reduction continues to evolve, with the aim of making symptom palliation more available to a wider range of patients at lower risks. PMID- 21549274 TI - Minimally invasive pyloroplasty. PMID- 21549275 TI - Circular stapled pyloroplasty during esophagectomy with gastric pull-up. PMID- 21549276 TI - Diagnostic approach to pulmonary nodules in the postpneumonectomy patient. PMID- 21549277 TI - The epidemiology of hospitalized postpartum depression in New York State, 1995 2004. AB - PURPOSE: The purpose of this study is to describe the patterns of hospitalization for depression in the year after delivery in relation to social, demographic, and behavioral characteristics. METHODS: Data on births were linked to hospitalizations for depression over the subsequent year to describe the frequency and patterns of hospitalized postpartum depression among 2,355,886 deliveries in New York State from 1995 to 2004. We identified "definite postpartum depression" based on International Classification of Diseases (ICD) codes indicative of "mental disorders specific to pregnancy," and "possible postpartum depression" by ICD codes for hospitalization with any depressive disorders. RESULTS: In New York State, we identified 1363 women (5.8 per 10,000) who were hospitalized with definite postpartum depression, and 6041 women (25.6 per 10,000) with possible postpartum depression, with lower risks in the New York City area. Postpartum depression was more common in later years and among mothers who were older, Black, smokers, lacking private insurance, and with multiple gestations, and was rarer among Asians. For possible postpartum depression, socioeconomic gradients were enhanced. CONCLUSIONS: Risk of hospitalized postpartum depression is strongly associated with socioeconomic deprivation and varies markedly by ethnicity, with direct implications for screening and health services, also providing suggestions for etiologic studies. PMID- 21549280 TI - Carbon monoxide poisoning in a 55-year-old man after a suicide attempt. AB - A flight team was activated for a scene call in rural Vermont for a patient with apparent carbon monoxide (CO) poisoning. Per ground emergency medical services (EMS) personnel, this 55-year-old man with a history of coronary artery disease (CAD) was found unresponsive in his parked vehicle in his garage. "Dryer hose" tubing ran from the tailpipe into the rear window of his sedan. EMS providers also stated that a variety of unidentified pills were found on the floormat. There were no pill bottles in the vehicle or in the home to identify the medications. Whether the pills had been consumed was unclear. Ground EMS removed the patient from the vehicle and immediately placed the patient on high-flow oxygen. The duration of the exposure was unknown. PMID- 21549281 TI - Delay in treatment. PMID- 21549278 TI - A prospective study of diabetes, lifestyle factors, and glaucoma among African American women. AB - PURPOSE: To evaluate the association of self-reported type 2 diabetes, anthropometric factors, alcohol consumption, and cigarette smoking with risk of primary open-angle glaucoma (POAG) in a prospective cohort study of African American women. METHODS: From 1995 through 2007, 32,570 Black Women's Health Study participants aged 21 to 69 years at baseline were followed for incident POAG. Questionnaires were mailed biennially to update exposures and identify incident cases of POAG. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were derived from Cox regression models. RESULTS: During 416,171 person years of follow-up, 366 incident POAG cases were confirmed by physician report. After adjustment for potential confounders, the IRR comparing women with and without type 2 diabetes was 1.58 (95% CI, 1.17-2.13), and the IRR comparing current with never alcohol consumers was 1.35 (95% CI, 1.05-1.73). Among women younger than 50, associations with diabetes and alcohol consumption were stronger, and POAG was significantly associated with body mass index, waist circumference, waist-to-hip ratio, and both long-duration and high-intensity current smoking. CONCLUSIONS: These results suggest that type 2 diabetes and current alcohol consumption are independent risk factors for POAG among African American women, and that in addition to those factors, overall and central adiposity and smoking may be associated with increased risk of early-onset POAG. PMID- 21549283 TI - The silent majority. PMID- 21549284 TI - Hospital Wing: 25 years of critical care in the air. PMID- 21549285 TI - Physical stressors during neonatal transport: helicopter compared with ground ambulance. AB - OBJECTIVES: This study was undertaken to assess concurrent mechanical stresses from shock, vibration, and noise to which a critically ill neonate is exposed during emergency transfer. METHODS: For neonates transported by a French specialized emergency medical service, we measured and analyzed 27 physical parameters recorded during typical transport by ambulance and by helicopter. The noninvasive sensors were placed to allow better representation of the exposure of the newborn to the physical constraints. RESULTS: Based on 10 hours of transport by ambulance and 2 hours by helicopter, noise, whole body vibration, rate of turn, acceleration, and pitch were extracted as the five most representative dynamic harshness indicators. A helicopter produces a higher-level but more stable (lower relative dispersion) whole body dynamic exposure than an ambulance, with a mean noise level of 86 +/- 1 dBA versus 67 +/- 3 dBA, mean whole body vibration of 1 +/- 0.1 meter per second squared (m/s(2)) versus 0.4 6 0.2 m/s(2), and acceleration of 1 6 0.05 m/s(2) versus 0.4 6 0.1 m/s(2). A ground ambulance has many more dynamic effects in terms of braking, shock, and impulsive noise than a helicopter (1 impulsive event per 2 minutes vs. 1 per 11 minutes). CONCLUSIONS: Our results show significant exposure of the sick neonate to both stationary and impulsive dynamic physical stressors during transportation, particularly in a ground ambulance. The study suggests opportunities to reduce physical stressors during neonatal transport. PMID- 21549286 TI - Airway management in the air medical setting. AB - BACKGROUND: Airway management is a key component of air medical care for seriously ill and injured patients. This meta-analysis of the prehospital airway management literature explored the pooled air-medical placement success rates for oral endotracheal intubation (OETI), including rapid sequence intubation (RSI) and drug-facilitated intubation (DFI), nasotracheal intubation (NTI), blind insertion airway devices (BIAD), and surgical cricothyrotomy (SCRIC). METHODS: We performed a systematic literature search for all English language articles reporting success rates for airway procedures performed in the prehospital setting. After identifying articles specific to the air-medical environment, pooled estimates of success rates for each airway technique were calculated using a random effects meta-analysis model. RESULTS: Thirty-six unique studies, encompassing 4,574 procedures, reported airway management success rates in the air medical environment. The pooled estimates (95% CI) for intervention success across all clinicians and patients were: OETI (without RSI/DFI): 86.4% (81.2% 90.3%); DFI: 95.1% (84.1%-98.6%); RSI: 96.7% (94.8%-97.9%); NTI: 76.1% (71.9% 79.9%); BIAD: 94.0% (85.8%-97.6%); and SCRIC: 90.8% (80.6%-95.9%). CONCLUSION: We provide pooled estimates for airway management procedural success rates in the air medical setting. These data can be used by program managers and medical directors in determining the most appropriate airway management procedures to incorporate into their services and for benchmarking in quality improvement activities. PMID- 21549287 TI - Fixed-wing medical transport crashes: characteristics associated with fatal outcomes. AB - INTRODUCTION: Previous studies within the aeromedical literature have looked at factors associated with fatal outcomes in helicopter medical transport, but no analysis has been conducted on fixed-wing aeromedical flights. The purpose of this study was to look at fatality rates in fixed-wing aeromedical transport and compare them with general aviation and helicopter aeromedical flights. METHODS: This study looked at factors associated with fatal outcomes in fixed-wing aeromedical flights, using the National Transportation Safety Board Aviation Accident Incident Database from 1984 to 2009. RESULTS: Fatal outcomes were significantly higher in medical flights (35.6 vs. 19.7%), with more aircraft fires (20.3 vs. 10.5%) and on-ground collisions (5.1 vs. 2.0%) compared with commercial flights. Aircraft fires occurred in 12 of the 21 fatal crashes (57.1%), compared with only 2 of the 38 nonfatal crashes (5.3%) (P < .001). In the multiple logistic regression model, the only factor with increased odds of a fatal outcome was the presence of a fire (56.89; 95% CI, 4.28-808.23). CONCLUSIONS: Similar to published studies in helicopter medical transport, postcrash fires are the primary factor associated with fatal outcomes in fixed wing aeromedical flights. PMID- 21549288 TI - Major incident patient evacuation: full-scale field exercise feasibility study. AB - INTRODUCTION: Major incident management relies on efficient patient transportation. In the absence of a standardized, field-friendly approach to multiple casualty management, the Norwegian Air Ambulance Foundation developed Optimal Patient Evacuation Norway (OPEN). OPEN aims to save time, improve patient handling, prevent hypothermia, and simplify scene management. We evaluated the feasibility of the OPEN concept in full-scale major incident field exercises. METHODS: Emergency service personnel participated in two standardized bus crash field exercises, without and with access to OPEN. The instructors timed completion of patient evacuation, and the students participated in a self-report before and after study. Each question was scored on a 7-point Likert scale, with points labeled "Did not work" (1) through "Worked excellently" (7). RESULTS: Among the 93 study participants, 31% confirmed that stretchers could be available at the scene within 30 minutes in their catchment area. The students reported improved interdisciplinary cooperation for patient evacuation after the course (mean, 5.8, with 95% CI 5.7-6.0 after vs. 5.4 with 95% CI 5.2-5.6 before, P < .001). CONCLUSION: OPEN is a feasible and time-efficient way to standardize patient transport and may serve as a candidate for a future national standard for major incident patient evacuation. PMID- 21549289 TI - Auscultation in flight: comparison of conventional and electronic stethoscopes. AB - OBJECTIVES: The ability to auscultate during air medical transport is compromised by high ambient-noise levels. The aim of this study was to assess the capabilities of a traditional and an electronic stethoscope (which is expected to amplify sounds and reduce ambient noise) to assess heart and breath sounds during medical transport in a Boeing C135. METHODS: We tested one model of a traditional stethoscope (3MTM Littmann Cardiology IIITM) and one model of an electronic stethoscope (3MTM Littmann Stethoscope Model 3000). We studied heart and lung auscultation during real medical evacuations aboard a medically configured C135. For each device, the quality of auscultation was described using a visual rating scale (ranging from 0 to 100 mm, 0 corresponding to "I hear nothing," 100 to "I hear perfectly"). Comparisons were accomplished using a t-test for paired values. RESULTS: A total of 36 comparative evaluations were performed. For cardiac auscultation, the value of the visual rating scale was 53 +/- 24 and 85 +/- 11 mm, respectively, for the traditional and electronic stethoscope (paired t-test: P = .0024). For lung sounds, quality of auscultation was estimated at 27 +/- 17 mm for traditional stethoscope and 68 +/- 13 for electronic stethoscope (paired t test: P = .0003). The electronic stethoscope was considered to be better than the standard model for hearing heart and lung sounds. CONCLUSION: Flight practitioners involved in air medical evacuation in the C135 aircraft are better able to practice auscultation with this electronic stethoscope than with a traditional one. PMID- 21549290 TI - ACCF/AHA/HFSA 2011 survey results: current staffing profile of heart failure programs, including programs that perform heart transplant and mechanical circulatory support device implantation. AB - OBJECTIVES: There have been no published recommendations about staffing needs for a heart failure (HF) clinic or an office setting focused on heart transplant. The goal of this survey was to understand the current staffing environment of HF, transplant, and mechanical circulatory support device (MCSD) programs in the United States and abroad. This report identifies current staffing patterns but does not endorse a particular staffing model. METHODS: An online survey, jointly sponsored by the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and the Heart Failure Society of America (HFSA), was sent to the members of all 3 organizations who had identified themselves as interested in HF, heart transplant, or both, between March 12, 2009, and May 12, 2009. RESULTS: The overall response rate to the 1,823 e-mail surveys was 23%. There were 257 unique practices in the United States (81% of total sites) and 58 international sites (19%); approximately 30% of centers were in a cardiovascular group practice and 30% in a medical school hospital setting. The large majority of practices delivered HF care in both an inpatient and outpatient environment, and slightly more centers were implanting MCSDs (47%) than performing cardiac transplantation (39%). Most practices (43%) were small, with <4 staff members, or small- to medium-sized (34%), with 4 to 10 staff members, with only 23% being medium (11-20 staff) or large programs (>20 staff). On average, a U.S. HF practice cared for 1,641 outpatients annually. An average HF program with transplant performed 10 transplants. Although larger programs were able to perform more transplants and see more outpatient HF visits, their clinician staffing volume tended to double for approximately every 500 to 700 additional HF visits annually. The average staffing utilization was 2.65 physician full-time equivalents (FTEs), 2.21 nonphysician practitioner (nurse practitioner or physician assistant) FTEs, and 2.61 nurse coordinator FTEs annually. CONCLUSIONS: The HF patient population is growing in number in the United States and internationally, and the clinicians who provide the highly skilled and time-consuming care to this population are under intense scrutiny as a result of focused quality improvement initiatives and reduced financial resources. Staffing guidelines should be developed to ensure that an adequate number of qualified professionals are hired for a given practice volume. These survey results are an initial step in developing such standards. PMID- 21549291 TI - Antiinflammatory autoimmune cellular responses to cardiac troponin I in idiopathic dilated cardiomyopathy. AB - BACKGROUND: Autoimmune mechanisms, particularly through generation of autoantibodies, may contribute to the pathophysiology of idiopathic dilated cardiomyopathy (iDCM). The precise role of cellular autoimmune responses to cardiac-specific antigens has not been well described in humans. The purpose of this study was to characterize the cellular autoimmune response to cardiac troponin I (cTnI), specifically, the release of cytokines by peripheral blood mononuclear cells (PBMCs), in subjects with iDCM and healthy control subjects. METHODS AND RESULTS: We performed enzyme-linked immunospot assays on PBMCs isolated from subjects with iDCM and healthy control subjects to examine the ex vivo interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) production in response to cTnI exposure. Thirty-five consecutive subjects with iDCM (mean age 53 +/- 11 years, 60% male, left ventricular ejection fraction 23 +/- 7%) and 26 control subjects (mean age 46 +/- 13 years, 46% male) were prospectively enrolled. IFN-gamma production in response to cTnI did not differ between the groups (number of secreting cells 26 +/- 49 vs 38 +/- 53, respectively; P = .1). In contrast, subjects with iDCM showed significantly higher IL-10 responses to cTnI compared with control subjects (number of secreting cells 386 +/- 428 vs 152 +/- 162, respectively; P < .05). Among iDCM subjects, heightened IL-10 response to cTnI was associated with reduced systemic inflammation and lower prevalence of advanced diastolic dysfunction compared with those with normal IL-10 response to cTnI. CONCLUSIONS: Our preliminary findings suggest that a heightened cellular autoimmune IL-10 response to cTnI is detectable in a subset of patients with iDCM, which may be associated with reduced systemic levels of high-sensitivity C reactive protein and lower prevalence of advanced diastolic dysfunction. PMID- 21549292 TI - Hemodynamic factors associated with acute decompensated heart failure: part 2- use in automated detection. AB - BACKGROUND: The purpose of this study was to develop an automated surveillance system, using pressure-based hemodynamic factors that would detect which patients were making the transition from compensated to decompensated heart failure before they developed worsening symptoms and required acute medical care. METHODS AND RESULTS: Intracardiac pressures in 274 patients with heart failure were measured using an implantable hemodynamic monitor (IHM) and were analyzed in a retrospective manner. An automated pressure change detection (PCD) algorithm was developed using the cumulative sum method. The performance characteristics of the PCD algorithm were defined in all patients who developed a heart failure-related event (HFRE); patients without HFRE served as controls. Optimal PCD threshold values were chosen using a receiver operator curve analysis. Each of the pressures measured with the IHM were evaluated using the PCD analysis. All had sensitivities >=80% and false-positive rates <4.7/patient-year; however, estimated pulmonary artery diastolic pressure (ePAD) had the best performance. An ePAD based on the optimized PCD threshold of 6.0 yielded a sensitivity of 83% and a false-positive rate of 4.1/patient-year for detecting patients making the transition from compensated to decompensated heart failure. These performance characteristics were not significantly different for patients with an ejection fraction > vs. <50%, estimated glomerular filtration rate > vs. <60 mL/min/1.73 m(2), or age > vs. <60 years. CONCLUSIONS: The automated PCD algorithm had high sensitivity and acceptable false-positive rates in detecting the development of decompensated heart failure before the patient developed worsening symptoms and required acute medical care. These data support the development of a prospective study to examine the utility of adding an automated PCD algorithm to IHM-based management strategies to prevent decompensated heart failure. PMID- 21549293 TI - Waist circumference, body mass index, and survival in systolic heart failure: the obesity paradox revisited. AB - BACKGROUND: Higher body mass index (BMI) is associated with improved heart failure (HF) survival, but the role of waist circumference (WC) in HF outcomes has not been studied. METHODS AND RESULTS: A total of 344 patients with advanced systolic HF had WC and BMI measured at presentation. High WC was defined as >=88 cm in women and >=102 cm in men, and high BMI as >=25 kg/m(2). Two-year urgent heart transplant (UT)-free survival in high vs normal WC groups was 77.9% vs 64.3% (P = .025) and in high vs normal BMI was 89.8% vs 58.2% (P < .001). After multivariable adjustment, normal WC compared with high WC was associated with higher all-cause mortality (risk ratio [RR] 2.76, 95% confidence interval [CI] 1.34-5.71) and higher risk of death/UT (RR 2.14, 95% CI 1.25-3.68). The best outcomes were seen in those with both high WC and high BMI. CONCLUSIONS: High WC, an alternative anthropometric index of obesity more specific to abdominal adiposity, high BMI, and the combination of high WC/high BMI were each associated with improved outcomes in this advanced HF cohort, lending further support for an obesity paradox in HF. The role of body composition in HF survival should be a focus of future investigation. PMID- 21549294 TI - Weighing in on obesity and the obesity paradox in heart failure. PMID- 21549295 TI - Myocardial blood flow and fibrosis in hypertrophic cardiomyopathy. AB - BACKGROUND: We investigated the relationship between myocardial blood flow (MBF), fibrosis, risk factors for sudden death, and clinical manifestations in hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Sixty-two patients with HCM (45 men, overall mean age 47 +/- 16 years), 15 acromegalic patients with left ventricular hypertrophy (9 man, overall mean age 47 +/- 12 years), and 20 healthy subjects underwent cardiac magnetic resonance. Resting MBF was measured as the ratio between coronary sinus flow measured by phase-contrast technique and left ventricular mass. Myocardial fibrosis was evaluated by late gadolinium enhancement (LGE) technique. In HCM patients, MBF was significantly lower than in control subjects and acromegalic patients. Patients with LGE had lower MBF than those without it (0.46 +/- 0.2 vs 0.66 +/- 0.29 mL.min(-1).g(-1); P < .005). Patients with ventricular tachycardia at Holter monitoring had lower MBF (0.4 +/- 0.14 vs 0.6 +/- 0.29 mL.min(-1).g(-1); P < .04). Among patients with preserved systolic function, those in New York Heart Association (NYHA) functional class >=II had lower MBF than those in NYHA functional class I (0.46 +/- 0.2 vs 0.69 +/ 0.3 mL.min(-1).g(-1); P < .003). MBF was the only independent predictor of worse clinical status (NYHA >=II; P = .01). CONCLUSIONS: In HCM patients low resting MBF is associated with the presence of fibrosis. MBF is a predictor of worse clinical status. PMID- 21549296 TI - Additive value of right ventricular dyssynchrony indexes in predicting the success of cardiac resynchronization therapy: a speckle-tracking imaging study. AB - BACKGROUND: The purpose of our study was to analyze the evolution of left and right ventricular (LV, RV) parameters before and after cardiac resynchronization therapy (CRT) using speckle-tracking imaging (STI). METHODS AND RESULTS: Eighty one patients with dilated cardiomyopathy (New York Heart Association functional class III or IV), left bundle branch block (QRS >=120 ms), and LV ejection fraction <=35% were studied with STI echocardiography before and after CRT. LV longitudinal (LV-SD12-l), radial (LV-SD6-r), and circumferential (LV-SD6-c) intraventricular dyssynchrony and LV twist (LV-t) were determined. RV dyssynchrony (RV-SD6) was defined as the standard deviation of the 6 time to peak systolic strain values. At 6 months' follow-up after CRT, the degree of dyssynchrony correlated significantly with LV ejection fraction improvement and end-systolic volume reduction. In receiver operating characteristic curve analysis, the following variables predictive of successful CRT were obtained: LV SD12-l (area under the curve [AUC] 0.69), LV-SD6-c (AUC 0.66), LV-SD6-r (AUC 0.79), LV-t (AUC 0.81), and RV-SD6+LV-SD6-r (AUC 0.83). By combining LV and RV intraventricular dyssynchrony (LV-SD12-l + LV-SD6-r + RV-SD6), the AUC was significantly improved to 0.89 (P < .005 compared with RV-SD6+LV-SD6-r; P < .001 compared with LV-t). CONCLUSIONS: Our data show that assessment of RV dyssynchrony parameters has an incremental value in the evaluation of candidates for CRT and may supplement LV dyssynchrony information. PMID- 21549297 TI - Prediction of the response to cardiac resynchronization therapy: is it worthwhile doing an echocardiography and looking for mechanical dyssynchrony? PMID- 21549298 TI - Accuracy of Doppler echocardiography to estimate key hemodynamic variables in subjects with normal left ventricular ejection fraction. AB - BACKGROUND: The accuracy of Doppler echocardiography to estimate key hemodynamic parameters in subjects with normal left ventricular ejection fraction (LVEF) has not been fully investigated. METHODS AND RESULTS: Thirty-six subjects with LVEF >50% (median age 62 years), with a broad clinical profile, underwent Doppler echocardiography immediately followed by right heart catheterization. Correlation coefficients between invasive and noninvasive right atrial pressure (RAP), systolic (sPAP) and mean (mPAP) pulmonary artery pressure, cardiac output (CO), and pulmonary vascular resistance (PVR) were 0.39, 0.70, 0.72, 0.57, and 0.60 (P < .001 for all). There was no significant correlation between invasive and noninvasive (based on the peak early transmitral to peak early septal mitral annular velocity ratio) pulmonary capillary wedge pressure (PCWP; r = 0.23; P = .18). Bland-Altman plots revealed variable bias but with consistently large limits of agreement for all noninvasive parameters, particularly PCWP. Areas under the receiver operating characteristic curve for noninvasive sPAP, CO, PVR, and PCWP to predict an invasively assessed mPAP >=25 mm Hg, cardiac index <2.5 L min(-1) m(-2), PVR >3 Wood units, and PCWP <=15 mm Hg, respectively, were 0.92, 0.83, 0.70, and 0.58. CONCLUSIONS: Single Doppler echocardiography parameters are not accurate enough to reliably estimate key hemodynamic parameters, particularly PCWP, in subjects with normal LVEF. PMID- 21549299 TI - A qualitative meta-analysis of heart failure self-care practices among individuals with multiple comorbid conditions. AB - BACKGROUND: Most heart failure (HF) patients have other comorbid conditions. HF self-care requires medication and diet adherence, daily weight monitoring, and a thoughtful response to symptoms when they occur. Self-care is complicated when other chronic conditions have additional self-care requirements. The purpose of this study is to explore how comorbidity influences HF self-care. METHODS: Using qualitative descriptive meta-analysis techniques, transcripts from 3 mixed methods studies (n = 99) were reexamined to yield themes about perceptions about HF and self-care and to explore the influence on HF self-care. The Charlson Comorbidity Index identified comorbid conditions. RESULTS: The sample was 74% Caucasian, 66% male (mean age of 59.6 years +/- 15 years). Fifty-three percent of the sample was New York Heart Association Class III. All had at least 1 other chronic condition. Narrative accounts revealed that adherence to diet, symptom monitoring, and differentiating symptoms from multiple conditions were the most challenging self-care skills. Emerging themes included 1) attitudes drive self care prioritization and 2) fragmented self-care instruction leads to poor self care integration and self-care skill deficits. CONCLUSIONS: Individuals with multiple chronic conditions are vulnerable to poor self-care. Research testing coaching interventions that integrate self-care requirements and focus on developing skill in self-care across multiple chronic conditions is needed. PMID- 21549300 TI - High prevalence of sleep apnea in heart failure outpatients: even in patients with preserved systolic function. AB - BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with reduced ejection fraction (EF). However, little is known about the prevalence of SDB in a general heart failure population including patients with preserved EF (HFPEF). METHODS: We prospectively enrolled stable heart failure outpatients from our heart failure clinic to assess the prevalence of SDB independent of systolic left ventricular function. RESULTS: Among 115 patients (62% with reduced EF, 38% with preserved EF, New York Heart Association Class II-IV) SDB was present in 81% (27% central sleep apnea, 54% obstructive sleep apnea [OSA]). HFPEF patients had SDB in 80% of the cases, 62% had OSA. This group had significantly more hypertension. CONCLUSIONS: This study shows a high prevalence of SDB in a general heart failure population, also in patients with HFPEF. These patients have predominantly OSA. Especially in patients with HFPEF SDB should be kept in mind and referral to a sleep specialist should be considered. PMID- 21549301 TI - Evaluation of the clinical relevance of baseline left ventricular ejection fraction as a predictor of recovery or persistence of severe dysfunction in women in the United States with peripartum cardiomyopathy. AB - BACKGROUND: Baseline left ventricular ejection fraction (LVEF) has been shown to be associated with likelihood of recovery in patients with peripartum cardiomyopathy (PPCM). The clinical relevance of this association for individual patients is unclear. METHODS AND RESULTS: We analyzed baseline parameters of LVEF in 187 PPCM patients with >=6 months follow-up data in an attempt to detect the value of baseline LVEF as a predictor of early recovery or persistence of severe LV dysfunction. Recovery of LV function (LVEF >=50%) at 6 months after diagnosis was found in 115 patients (61%). Multivariate analysis identified baseline LVEF >30% as a significant predictor for recovery (odds ratio 5.2, 95% confidence interval 1.96-7.70; P > .0001). Recovery of LV function was 6.4-fold higher in women with baseline LVEF >= 30% (group III) and 3.9-fold higher in women with LVEF 20%-29% (group II) compared with those with LVEF 10%-19% (group I). Failure to achieve full recovery was seen in 63% of group I patients, 32% of group II (P = .03), and 21% of group III (P = .02 vs group I). Failure to achieve LVEF >=30% was seen in 30% of group I patients and 13% of group II (P = .09). CONCLUSIONS: Early recovery in patients with PPCM is significantly related to the degree of myocardial insult at time of diagnosis. Baseline LVEF however, has a limited sensitivity for prediction of failure to improve in individual patients and can not be used as an indication for premature use of aggressive therapy including devices or cardiac transplantation. PMID- 21549302 TI - Use and predictors of heart failure disease management referral in patients hospitalized with heart failure: insights from the Get With the Guidelines Program. AB - BACKGROUND: Heart failure disease management (HFDM) may be beneficial in heart failure (HF) patients at risk for readmission or post-discharge mortality. However, characteristics of hospitalized HF patients referred to HFDM are not known. METHODS AND RESULTS: Get With the Guidelines (GWTG) program data was used to analyze 57,969 patients hospitalized with HF from January 2005 through January 2010 from 235 sites. Factors associated with referral to HFDM and rates of HF quality measures by referral status were studied. Mean age of patients was 69.7 +/- 14.5 years, 52% were men, and 65% were white. HFDM referral occurred in 11,150 (19.2%) patients. The median rate of HFDM referral among all hospitals was 3.5% (25th-75th percentiles 0%-16.7%) and 8.7% (2.8%-27.7%) among hospitals with at least one previous HFDM referral. Quality and performance measures were higher in patients referred to HFDM. HFDM referral was associated with atrial fibrillation, implanted cardiac device, depression, and treatment at larger hospitals. Patients at higher 90-day mortality risk were paradoxically less likely to receive HFDM referral. CONCLUSIONS: HFDM referral occurred in less than one-fifth of hospitalized HF patients and was more frequently recommended to lower-risk patients. Increasing use and optimizing selection of patients for HFDM referral is a potential target for quality improvement. PMID- 21549303 TI - Broken silence restored--remodeling primes for deacetylation at replication forks. AB - Faithful propagation of chromatin structures requires assimilation of new histones to the modification profile of individual loci. In this issue of Molecular Cell, Rowbotham and colleagues identify a remodeler, SMARCAD1, acting at replication sites to facilitate histone deacetylation and restoration of silencing. PMID- 21549304 TI - A web of interactions at the ends. AB - The synthesis of telomeric DNA by telomerase entails repeated cycles of reverse transcription on a short RNA template. In this issue of Molecular Cell, Robart and Collins (2011) describe a set of interactions between human telomerase RNA, protein domains, and the substrate DNA that drives the intricate reaction cycle. PMID- 21549305 TI - The search for nonconventional mitochondrial determinants of aging. AB - Mitochondria are conventionally believed to modulate aging by affecting free radical production and the energy supply. In this issue of Molecular Cell, Caballero et al. (2011) reveal that altering protein complexes involved in mitochondrial translation control extends life span independent of redox homeostasis and oxidative phosphorylation. PMID- 21549306 TI - When signaling kinases meet histones and histone modifiers in the nucleus. AB - Signaling pathways involve cascades of protein phosphorylation and ultimately affect regulation of transcription in the nucleus. However, most of the kinases in these pathways have not been generally considered to directly modulate transcription thus far. Here, recent significant progress in the field elucidating direct modifications of histones and histone modifiers by upstream kinases is summarized, and future directions are discussed. PMID- 21549307 TI - Maintenance of silent chromatin through replication requires SWI/SNF-like chromatin remodeler SMARCAD1. AB - Epigenetic marks such as posttranslational histone modifications specify the functional states of underlying DNA sequences, though how they are maintained after their disruption during DNA replication remains a critical question. We identify the mammalian SWI/SNF-like protein SMARCAD1 as a key factor required for the re-establishment of repressive chromatin. The ATPase activity of SMARCAD1 is necessary for global deacetylation of histones H3/H4. In this way, SMARCAD1 promotes methylation of H3K9, the establishment of heterochromatin, and faithful chromosome segregation. SMARCAD1 associates with transcriptional repressors including KAP1, histone deacetylases HDAC1/2 and the histone methyltransferase G9a/GLP and modulates the interaction of HDAC1 and KAP1 with heterochromatin. SMARCAD1 directly interacts with PCNA, a central component of the replication machinery, and is recruited to sites of DNA replication. Our findings suggest that chromatin remodeling by SMARCAD1 ensures that silenced loci, such as pericentric heterochromatin, are correctly perpetuated. PMID- 21549308 TI - Processive and distributive extension of human telomeres by telomerase under homeostatic and nonequilibrium conditions. AB - Specific information about how telomerase acts in vivo is necessary for understanding telomere dynamics in human tumor cells. Our results imply that, under homeostatic telomere length-maintenance conditions, only one molecule of telomerase acts at each telomere during every cell division and processively adds ~60 nt to each end. In contrast, multiple molecules of telomerase act at each telomere when telomeres are elongating (nonequilibrium conditions). Telomerase extension is less processive during the first few weeks following the reversal of long-term treatment with the telomerase inhibitor Imetelstat (GRN163L), a time when Cajal bodies fail to deliver telomerase RNA to telomeres. This result implies that processing of telomerase by Cajal bodies may affect its processivity. Overexpressed telomerase is also less processive than the endogenously expressed telomerase. These findings reveal two major distinct extension modes adopted by telomerase in vivo. PMID- 21549309 TI - Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1. AB - 53BP1 is a DNA damage protein that forms phosphorylated H2AX (gamma-H2AX) dependent foci in a 1 Mb region surrounding DNA double-strand breaks (DSBs). In addition, 53BP1 promotes genomic stability by regulating the metabolism of DNA ends. We have compared the joining rates of paired DSBs separated by 1.2 kb to 27 Mb on chromosome 12 in the presence or absence of 53BP1. 53BP1 facilitates joining of intrachromosomal DSBs but only at distances corresponding to gamma H2AX spreading. In contrast, DNA end protection by 53BP1 is distance independent. Furthermore, analysis of 53BP1 mutants shows that chromatin association, oligomerization, and N-terminal ATM phosphorylation are all required for DNA end protection and joining as measured by immunoglobulin class switch recombination. These data elucidate the molecular events that are required for 53BP1 to maintain genomic stability and point to a model wherein 53BP1 and H2AX cooperate to repress resection of DSBs. PMID- 21549310 TI - Histone methylation by PRC2 is inhibited by active chromatin marks. AB - The Polycomb repressive complex 2 (PRC2) confers transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3). Here, we examined how PRC2 is modulated by histone modifications associated with transcriptionally active chromatin. We provide the molecular basis of histone H3 N terminus recognition by the PRC2 Nurf55-Su(z)12 submodule. Binding of H3 is lost if lysine 4 in H3 is trimethylated. We find that H3K4me3 inhibits PRC2 activity in an allosteric fashion assisted by the Su(z)12 C terminus. In addition to H3K4me3, PRC2 is inhibited by H3K36me2/3 (i.e., both H3K36me2 and H3K36me3). Direct PRC2 inhibition by H3K4me3 and H3K36me2/3 active marks is conserved in humans, mouse, and fly, rendering transcriptionally active chromatin refractory to PRC2 H3K27 trimethylation. While inhibition is present in plant PRC2, it can be modulated through exchange of the Su(z)12 subunit. Inhibition by active chromatin marks, coupled to stimulation by transcriptionally repressive H3K27me3, enables PRC2 to autonomously template repressive H3K27me3 without overwriting active chromatin domains. PMID- 21549311 TI - Direct interactions of OCA-B and TFII-I regulate immunoglobulin heavy-chain gene transcription by facilitating enhancer-promoter communication. AB - B cell-specific coactivator OCA-B, together with Oct-1/2, binds to octamer sites in promoters and enhancers to activate transcription of immunoglobulin (Ig) genes, although the mechanisms underlying their roles in enhancer-promoter communication are unknown. Here, we demonstrate a direct interaction of OCA-B with transcription factor TFII-I, which binds to DICE elements in Igh promoters, that affects transcription at two levels. First, OCA-B relieves HDAC3-mediated Igh promoter repression by competing with HDAC3 for binding to promoter-bound TFII-I. Second, and most importantly, Igh 3' enhancer-bound OCA-B and promoter bound TFII-I mediate promoter-enhancer interactions, in both cis and trans, that are important for Igh transcription. These and other results reveal an important function for OCA-B in Igh 3' enhancer function in vivo and strongly favor an enhancer mechanism involving looping and facilitated factor recruitment rather than a tracking mechanism. PMID- 21549312 TI - Arabidopsis Argonaute 2 regulates innate immunity via miRNA393(*)-mediated silencing of a Golgi-localized SNARE gene, MEMB12. AB - Argonaute (AGO) proteins are critical components of RNA silencing pathways that bind small RNAs and mediate gene silencing at their target sites. We found that Arabidopsis AGO2 is highly induced by the bacterial pathogen Pseudomonas syringae pv. tomato (Pst). Further genetic analysis demonstrated that AGO2 functions in antibacterial immunity. One abundant species of AGO2-bound small RNA is miR393b(*), which targets a Golgi-localized SNARE gene, MEMB12. Pst infection downregulates MEMB12 in a miR393b(*)-dependent manner. Loss of function of MEMB12, but not SYP61, another intracellular SNARE, leads to increased exocytosis of an antimicrobial pathogenesis-related protein, PR1. Overexpression of miR393b(*) resembles memb12 mutant in resistance responses. Thus, AGO2 functions in antibacterial immunity by binding miR393b(*) to modulate exocytosis of antimicrobial PR proteins via MEMB12. Since miR393 also contributes to antibacterial responses, miR393(*)/miR393 represent an example of a miRNA(*)/miRNA pair that functions in immunity through two distinct AGOs: miR393(*) through AGO2 and miR393 through AGO1. PMID- 21549313 TI - Single-molecule fluorescence measurements of ribosomal translocation dynamics. AB - We employ single-molecule fluorescence resonance energy transfer (smFRET) to study structural dynamics over the first two elongation cycles of protein synthesis, using ribosomes containing either Cy3-labeled ribosomal protein L11 and A- or P-site Cy5-labeled tRNA or Cy3- and Cy5-labeled tRNAs. Pretranslocation (PRE) complexes demonstrate fluctuations between classical and hybrid forms, with concerted motions of tRNAs away from L11 and from each other when classical complex converts to hybrid complex. EF-G?GTP binding to both hybrid and classical PRE complexes halts these fluctuations prior to catalyzing translocation to form the posttranslocation (POST) complex. EF-G dependent translocation from the classical PRE complex proceeds via transient formation of a short-lived hybrid intermediate. A-site binding of either EF-G to the PRE complex or of aminoacyl tRNA?EF-Tu ternary complex to the POST complex markedly suppresses ribosome conformational lability. PMID- 21549314 TI - Cdk1-dependent destruction of Eco1 prevents cohesion establishment after S phase. AB - Accurate genome segregation depends on cohesion mechanisms that link duplicated sister chromatids, thereby allowing their tension-dependent biorientation in metaphase. In Saccharomyces cerevisiae, cohesion is established during DNA replication when Eco1 acetylates the cohesin subunit Smc3. Cohesion establishment is restricted to S phase of the cell cycle, but the molecular basis of this regulation is unknown. Here, we show that Eco1 is negatively regulated by the protein kinase Cdk1. Phosphorylation of Eco1 after S phase targets it to SCF(Cdc4) for ubiquitination and subsequent degradation. A nonphosphorylatable mutant of Eco1 establishes cohesion after DNA replication, suggesting that Cdk1 dependent phosphorylation of Eco1 is a key factor limiting establishment to S phase. We also show that deregulation of Eco1 results in chromosome separation defects in anaphase. We conclude that this regulatory mechanism helps optimize the level of sister chromatid cohesion, ensuring a robust and efficient anaphase. PMID- 21549316 TI - Prevalence and characteristics of pain in patients with chronic obstructive pulmonary disease compared to the Norwegian general population. AB - The purpose of this study was to evaluate the prevalence and characteristics of pain in patients with chronic obstructive pulmonary disease (COPD) compared to a sample from the Norwegian general population. This cross-sectional study evaluated 100 COPD patients with and without pain and 333 individuals from the Norwegian population with pain. After controlling for age and sex, a significantly higher percentage of patients with COPD (45%) reported pain than the general population (34%; P = .02). No differences were found in pain intensity scores, pain interference score, or number of pain locations between COPD patients and the general population. COPD patients reported moderate-to severe pain located primarily in the chest, shoulders, neck, and thorax. For both groups, the most common pain treatment was analgesic use. Acupuncture/transcutaneous electrical nerve stimulation was used more frequently by COPD patients (P < .001) while physiotherapy was used more frequently by the general population (P = .007) to treat their pain. Pain is a significant problem for COPD patients. Additional research is warranted to replicate these findings and to provide a more detailed characterization of how pain changes over time and influences COPD patients' ability to function and their quality of life. PERSPECTIVE: Compared to the general population, pain is more common in patients with COPD and ranges from moderate to severe in its intensity. PMID- 21549315 TI - Absence of mitochondrial translation control proteins extends life span by activating sirtuin-dependent silencing. AB - Altered mitochondrial functionality can extend organism life span, but the underlying mechanisms are obscure. Here we report that inactivating SOV1, a member of the yeast mitochondrial translation control (MTC) module, causes a robust Sir2-dependent extension of replicative life span in the absence of respiration and without affecting oxidative damage. We found that SOV1 interacts genetically with the cAMP-PKA pathway and the chromatin remodeling apparatus. Consistently, Sov1p-deficient cells displayed reduced cAMP-PKA signaling and an elevated, Sir2p-dependent, genomic silencing. Both increased silencing and life span extension in sov1Delta cells require the PKA/Msn2/4p target Pnc1p, which scavenges nicotinamide, a Sir2p inhibitor. Inactivating other members of the MTC module also resulted in Sir2p-dependent life span extension. The data demonstrate that the nuclear silencing apparatus senses and responds to the absence of MTC proteins and that this response converges with a pathway for life span extension elicited by reducing TOR signaling. PMID- 21549317 TI - A nervous hedgehog rolls into the hair follicle stem cell scene. PMID- 21549318 TI - Human induced pluripotent stem cells: a new model for schizophrenia? PMID- 21549319 TI - An epigenetic mark that protects the epithelial phenotype in health and disease. PMID- 21549320 TI - Neural stem cells: disposable, end-state glia? PMID- 21549321 TI - Target populations for first-in-human embryonic stem cell research in spinal cord injury. AB - Geron recently announced that it had begun enrolling patients in the world's first-in-human clinical trial involving cells derived from human embryonic stem cells (hESCs). This trial raises important questions regarding the future of hESC based therapies, especially in spinal cord injury (SCI) patients. We address some safety and efficacy concerns with this research, as well as the ethics of fair subject selection. We consider other populations that might be better for this research: chronic complete SCI patients for a safety trial, subacute incomplete SCI patients for an efficacy trial, and perhaps primary progressive multiple sclerosis (MS) patients for a combined safety and efficacy trial. PMID- 21549322 TI - Response to Frederic Bretzner et al. "Target populations for first-in-human embryonic stem cell research in spinal cord injury". AB - We address concerns raised in this issue by Bretzner et al. (2011) by explaining the rationale for including subjects with subacute, neurologically complete spinal cord injuries in the Phase 1 trial of GRNOPC1. We also present elements of the informed consent process that minimize the likelihood of therapeutic misconception. PMID- 21549323 TI - The tragedy of translation: the case of "first use" in human embryonic stem cell research. AB - Who should go first in phase-I human trials when neither risks nor benefits can be estimated? By assessing concerns raised by Bretzner et al. (2011), we highlight a tragic dimension underlying all such trials. We discuss strategies to avoid the pitfalls of ethical hubris by promoting fidelity and trust. PMID- 21549324 TI - Deadly teamwork: neural cancer stem cells and the tumor microenvironment. AB - Neural cancers display cellular hierarchies with self-renewing tumorigenic cancer stem cells (CSCs) at the apex. Instructive cues to maintain CSCs are generated by both intrinsic networks and the niche microenvironment. The CSC-microenvironment relationship is complex, as CSCs can modify their environment and extrinsic forces induce plasticity in the cellular hierarchy. PMID- 21549325 TI - Eyes wide open: a critical review of sphere-formation as an assay for stem cells. AB - Sphere-forming assays have been widely used to retrospectively identify stem cells based on their reported capacity to evaluate self-renewal and differentiation at the single-cell level in vitro. The discovery of markers that allow the prospective isolation of stem cells and their progeny from their in vivo niche allows the functional properties of purified populations to be defined. We provide a historical perspective of the evolution of the neurosphere assay and highlight limitations in the use of sphere-forming assays in the context of neurospheres. We discuss theoretical and technical considerations of experimental design and interpretation that surround the use of this assay with any tissue. PMID- 21549326 TI - Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. AB - Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging. PMID- 21549327 TI - MAP3K4/CBP-regulated H2B acetylation controls epithelial-mesenchymal transition in trophoblast stem cells. AB - Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histones H2A and H2B by CBP is required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4-deficient TS cells defines an H2B acetylation regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveals previously unrecognized genes potentially contributing to breast cancer. PMID- 21549328 TI - Human ESC-derived neural crest model reveals a key role for SOX2 in sensory neurogenesis. AB - The transcription factor SOX2 is widely known to play a critical role in the central nervous system; however, its role in peripheral neurogenesis remains poorly understood. We recently developed an hESC-based model in which migratory cells undergo epithelial to mesenchymal transition (EMT) to acquire properties of neural crest (NC) cells. In this model, we found that migratory NC progenitors downregulate SOX2, but then start re-expressing SOX2 as they differentiate to form neurogenic dorsal root ganglion (DRG)-like clusters. SOX2 downregulation was sufficient to induce EMT and resulted in massive apoptosis when neuronal differentiation was induced. In vivo, downregulation of SOX2 in chick and mouse NC cells significantly reduced the numbers of neurons within DRG. We found that SOX2 binds directly to NGN1 and MASH1 promoters and is required for their expression. Our data suggest that SOX2 plays a key role for NGN1-dependent acquisition of neuronal fates in sensory ganglia. PMID- 21549329 TI - Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. AB - In adult skin, stem cells in the hair follicle bulge cyclically regenerate the follicle, whereas a distinct stem cell population maintains the epidermis. The degree to which all bulge cells have equal regenerative potential is not known. We found that Sonic hedgehog (Shh) from neurons signals to a population of cells in the telogen bulge marked by the Hedgehog response gene Gli1. Gli1-expressing bulge cells function as multipotent stem cells in their native environment and repeatedly regenerate the anagen follicle. Shh-responding perineural bulge cells incorporate into healing skin wounds where, notably, they can change their lineage into epidermal stem cells. The perineural niche (including Shh) is dispensable for follicle contributions to acute wound healing and skin homeostasis, but is necessary to maintain bulge cells capable of becoming epidermal stem cells. Thus, nerves cultivate a microenvironment where Shh creates a molecularly and phenotypically distinct population of hair follicle stem cells. PMID- 21549330 TI - Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. AB - Production of new neurons in the adult hippocampus decreases with age; this decline may underlie age-related cognitive impairment. Here we show that continuous depletion of the neural stem cell pool, as a consequence of their division, may contribute to the age-related decrease in hippocampal neurogenesis. Our results indicate that adult hippocampal stem cells, upon exiting their quiescent state, rapidly undergo a series of asymmetric divisions to produce dividing progeny destined to become neurons and subsequently convert into mature astrocytes. Thus, the decrease in the number of neural stem cells is a division coupled process and is directly related to their production of new neurons. We present a scheme of the neurogenesis cascade in the adult hippocampus that includes a proposed "disposable stem cell" model and accounts for the disappearance of hippocampal neural stem cells, the appearance of new astrocytes, and the age-related decline in the production of new neurons. PMID- 21549332 TI - [Thirteen years' experience with partial superficial parotidectomy as treatment for benign parotid tumours]. PMID- 21549331 TI - Genome-wide analysis of self-renewal in Drosophila neural stem cells by transgenic RNAi. AB - The balance between stem cell self-renewal and differentiation is precisely controlled to ensure tissue homeostasis and prevent tumorigenesis. Here we use genome-wide transgenic RNAi to identify 620 genes potentially involved in controlling this balance in Drosophila neuroblasts. We quantify all phenotypes and derive measurements for proliferation, lineage, cell size, and cell shape. We identify a set of transcriptional regulators essential for self-renewal and use hierarchical clustering and integration with interaction data to create functional networks for the control of neuroblast self-renewal and differentiation. Our data identify key roles for the chromatin remodeling Brm complex, the spliceosome, and the TRiC/CCT-complex and show that the alternatively spliced transcription factor Lola and the transcriptional elongation factors Ssrp and Barc control self-renewal in neuroblast lineages. As our data are strongly enriched for genes highly expressed in murine neural stem cells, they are likely to provide valuable insights into mammalian stem cell biology as well. PMID- 21549333 TI - Attention and gaze shifting in dual-task and go/no-go performance with vocal responding. AB - Evidence from go/no-go performance on the Eriksen flanker task with manual responding suggests that individuals gaze at stimuli just as long as needed to identify them (e.g., Sanders, 1998). In contrast, evidence from dual-task performance with vocal responding suggests that gaze shifts occur after response selection (e.g., Roelofs, 2008a). This difference in results may be due to the nature of the task situation (go/no-go vs. dual task) or the response modality (manual vs. vocal). We examined this by having participants vocally respond to congruent and incongruent flanker stimuli and shift gaze to left- or right pointing arrows. The arrows required a manual response (dual task) or determined whether the vocal response to the flanker stimuli had to be given or not (go/no go). Vocal response and gaze shift latencies were longer on incongruent than congruent trials in both dual-task and go/no-go performance. The flanker effect was also present in the manual response latencies in dual-task performance. Ex Gaussian analyses revealed that the flanker effect on the gaze shifts consisted of a shift of the entire latency distribution. These results suggest that gaze shifts occur after response selection in both dual-task and go/no-go performance with vocal responding. PMID- 21549334 TI - Inhibition and shifting capacities mediate adults' age-related differences in strategy selection and repertoire. AB - Young and older adults differ in how many strategies they use to accomplish cognitive tasks. They also differ in how often they select the best strategy on each problem. Two experiments were run to determine whether two executive functions-inhibition and shifting capacities-mediate age-related differences in strategy repertoire and in strategy selection. Both experiments were run in arithmetic problem solving. In Experiment 1, young and older adults' strategy repertoire was assessed on a problem-by-problem basis while participants solved two-digit addition problems (e.g., 42+76). In Experiment 2, young and older participants had to select the best strategy on each problem to find estimates of two-digit multiplication problems (e.g., 43*72). In both experiments, individuals' inhibition and shifting capacities were assessed with the Trail Making Test and the Stroop Test. The main results showed that (a) older adults used a smaller strategy repertoire (Expt. 1) and selected the best strategy on each problem less frequently (Expt. 2) than young adults, (b) inhibition and shifting capacities mediated age-related differences in strategy repertoire and strategy selection, and unique age effects were no longer significant in strategy repertoire but were still significant in strategy selection after statistical control of inhibition and shifting capacities. We discuss important implications of these findings to further our understanding of strategic variations during cognitive aging. PMID- 21549335 TI - Symmetry brings an impression of familiarity but does not improve recognition memory. AB - Studies have shown that symmetric stimuli are recognized better than asymmetric stimuli but evidence suggests that this advantage may result from a familiarity bias induced by symmetry. We used a classic episodic memory paradigm to test this bias and see if it truly accounts for the symmetry advantage. Subjects first encoded symmetric and asymmetric figures. During a subsequent recognition phase, they discriminated the encoded (old) figures from new intermixed figures. The recognition rate of old figures was higher with symmetric figures than asymmetric figures. However, the tendency to falsely recognize new figures was also higher when they were symmetric, meaning that the higher recognition rate for symmetric figures was artificially inflated by a response bias. Three other experiments further tested this finding and examined the influence of some variables (rotation in virtual 3D space, stimulus meaningfulness, and redundancy of information) on the bias. A fifth experiment with photo stimuli confirmed that the response bias also applies to objects that we regularly encounter in everyday life. In conclusion, our results show that symmetry does not enhance mnemonic processes but instead induces a response bias leading individuals to judge such stimuli as having been seen. PMID- 21549336 TI - Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X-chromosomal hearing loss. AB - The fact that hereditary hearing loss is the most common sensory disorder in humans is reflected by, among other things, an extraordinary allelic and nonallelic genetic heterogeneity. X-chromosomal hearing impairment represents only a minor fraction of all cases. In a study of a Spanish family the locus for one of the X-chromosomal forms was assigned to Xp22 (DFNX4). We mapped the disease locus in the same chromosomal region in a large German pedigree with X chromosomal nonsyndromic hearing impairment by using genome-wide linkage analysis. Males presented with postlingual hearing loss and onset at ages 3-7, whereas onset in female carriers was in the second to third decades. Targeted DNA capture with high-throughput sequencing detected a nonsense mutation in the small muscle protein, X-linked (SMPX) of affected individuals. We identified another nonsense mutation in SMPX in patients from the Spanish family who were previously analyzed to map DFNX4. SMPX encodes an 88 amino acid, cytoskeleton-associated protein that is responsive to mechanical stress. The presence of Smpx in hair cells and supporting cells of the murine cochlea indicates its role in the inner ear. The nonsense mutations detected in the two families suggest a loss-of function mechanism underlying this form of hearing impairment. Results obtained after heterologous overexpression of SMPX proteins were compatible with this assumption. Because responsivity to physical force is a characteristic feature of the protein, we propose that long-term maintenance of mechanically stressed inner ear cells critically depends on SMPX function. PMID- 21549337 TI - Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. AB - Accelerated aging syndromes represent a valuable source of information about the molecular mechanisms involved in normal aging. Here, we describe a progeroid syndrome that partially phenocopies Hutchinson-Gilford progeria syndrome (HGPS) but also exhibits distinctive features, including the absence of cardiovascular deficiencies characteristic of HGPS, the lack of mutations in LMNA and ZMPSTE24, and a relatively long lifespan of affected individuals. Exome sequencing and molecular analysis in two unrelated families allowed us to identify a homozygous mutation in BANF1 (c.34G>A [p.Ala12Thr]), encoding barrier-to-autointegration factor 1 (BAF), as the molecular abnormality responsible for this Mendelian disorder. Functional analysis showed that fibroblasts from both patients have a dramatic reduction in BAF protein levels, indicating that the p.Ala12Thr mutation impairs protein stability. Furthermore, progeroid fibroblasts display profound abnormalities in the nuclear lamina, including blebs and abnormal distribution of emerin, an interaction partner of BAF. These nuclear abnormalities are rescued by ectopic expression of wild-type BANF1, providing evidence for the causal role of this mutation. These data demonstrate the utility of exome sequencing for identifying the cause of rare Mendelian disorders and underscore the importance of nuclear envelope alterations in human aging. PMID- 21549338 TI - A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal dominant retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is an inherited form of retinal degeneration that leads to progressive visual-field constriction and blindness. Although the disease manifests only in the retina, mutations in ubiquitously expressed genes associated with the tri-snRNP complex of the spliceosome have been identified in patients with dominantly inherited RP. We screened for mutations in PRPF6 (NM_012469.3), a gene on chromosome 20q13.33 encoding an essential protein for tri-snRNP assembly and stability, in 188 unrelated patients with autosomal dominant RP and identified a missense mutation, c.2185C>T (p.Arg729Trp). This change affected a residue that is conserved from humans to yeast and cosegregated with the disease in the family in which it was identified. Lymphoblasts derived from patients with this mutation showed abnormal localization of endogenous PRPF6 within the nucleus. Specifically, this protein accumulated in the Cajal bodies, indicating a possible impairment in the tri-snRNP assembly or recycling. Expression of GFP-tagged PRPF6 in HeLa cells showed that this phenomenon depended exclusively on the mutated form of the protein. Furthermore, analysis of endogenous transcripts in cells from patients revealed intron retention for pre mRNA bearing specific splicing signals, according to the same pattern displayed by lymphoblasts with mutations in other PRPF genes. Our results identify PRPF6 as the sixth gene involved in pre-mRNA splicing and dominant RP, corroborating the hypothesis that deficiencies in the spliceosome play an important role in the molecular pathology of this disease. PMID- 21549339 TI - A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia. AB - The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi. PMID- 21549340 TI - Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP. AB - We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints. PMID- 21549341 TI - Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6. AB - The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy. PMID- 21549342 TI - Next-generation sequencing identifies mutations of SMPX, which encodes the small muscle protein, X-linked, as a cause of progressive hearing impairment. AB - In a Dutch family with an X-linked postlingual progressive hearing impairment, a critical linkage interval was determined to span a region of 12.9 Mb flanked by the markers DXS7108 and DXS7110. This interval overlaps with the previously described DFNX4 locus and contains 75 annotated genes. Subsequent next-generation sequencing (NGS) detected one variant within the linkage interval, a nonsense mutation in SMPX. SMPX encodes the small muscle protein, X-linked (SMPX). Further screening was performed on 26 index patients from small families for which X linked inheritance of nonsyndromic hearing impairment (NSHI) was not excluded. We detected a frameshift mutation in SMPX in one of the patients. Segregation analysis of both mutations in the families in whom they were found revealed that the mutations cosegregated with hearing impairment. Although we show that SMPX is expressed in many different organs, including the human inner ear, no obvious symptoms other than hearing impairment were observed in the patients. SMPX had previously been demonstrated to be specifically expressed in striated muscle and, therefore, seemed an unlikely candidate gene for hearing impairment. We hypothesize that SMPX functions in inner ear development and/or maintenance in the IGF-1 pathway, the integrin pathway through Rac1, or both. PMID- 21549343 TI - Whole-Exome sequencing identifies FAM20A mutations as a cause of amelogenesis imperfecta and gingival hyperplasia syndrome. AB - Amelogenesis imperfecta (AI) describes a clinically and genetically heterogeneous group of disorders of biomineralization resulting from failure of normal enamel formation. AI is found as an isolated entity or as part of a syndrome, and an autosomal-recessive syndrome associating AI and gingival hyperplasia was recently reported. Using whole-exome sequencing, we identified a homozygous nonsense mutation in exon 2 of FAM20A that was not present in the Single Nucleotide Polymorphism database (dbSNP), the 1000 Genomes database, or the Centre d'Etude du Polymorphisme Humain (CEPH) Diversity Panel. Expression analyses indicated that Fam20a is expressed in ameloblasts and gingivae, providing biological plausibility for mutations in FAM20A underlying the pathogenesis of this syndrome. PMID- 21549344 TI - Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. AB - Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure. PMID- 21549345 TI - Peptide-directed highly selective targeting of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a disorder of the pulmonary vasculature associated with elevated pulmonary vascular resistance. Despite recent advances in the treatment of PAH, with eight approved clinical therapies and additional therapies undergoing clinical trials, PAH remains a serious life-threatening condition. The lack of pulmonary vascular selectivity and associated systemic adverse effects of these therapies remain the main obstacles to successful treatment. Peptide-mediated drug delivery that specifically targets the vasculature of PAH lungs may offer a solution to the lack of drug selectivity. Herein, we show highly selective targeting of rat PAH lesions by a novel cyclic peptide, CARSKNKDC (CAR). Intravenous administration of CAR peptide resulted in intense accumulation of the peptide in monocrotaline-induced and SU5416/hypoxia induced hypertensive lungs but not in healthy lungs or other organs of PAH rats. CAR homed to all layers of remodeled pulmonary arteries, ie, endothelium, neointima, medial smooth muscle, and adventitia, in the hypertensive lungs. CAR also homed to capillary vessels and accumulated in the interstitial space of the PAH lungs, manifesting its extravasation activity. These results demonstrated the remarkable ability of CAR to selectively target PAH lung vasculature and effectively penetrate and spread throughout the diseased lung tissue. These results suggest the clinical utility of CAR in the targeted delivery of therapeutic compounds and imaging probes to PAH lungs. PMID- 21549346 TI - Aberrant overexpression of the cell polarity module scribble in human cancer. AB - Human Scribble (Scrib) is an evolutionary-conserved cell polarity protein, but its potential role in human cancer is controversial. Herein, we show that Scrib is nearly universally overexpressed in cultured tumor cell lines and genetically disparate cancer patient series compared with matched normal tissues in vivo. Instead of a membrane association seen in normal epithelia, tumor-associated Scrib is mislocalized and found predominantly in the cytosol. Small-interfering RNA silencing of Scrib in model lung adenocarcinoma A549 cells inhibited cell migration in wound-healing assays, suppressed tumor cell invasion across Matrigel coated inserts, and down-regulated the expression of cell motility markers and mediators of epithelial-mesenchymal transition. These data uncover a previously unrecognized exploitation of Scrib for aberrant tumor cell motility and invasion, thus potentially contributing to disease progression in humans. PMID- 21549347 TI - Image characteristics as predictors for thoracoscopic anatomic lung resection in patients with pulmonary tuberculosis. AB - BACKGROUND: A variety of complications occur in patients with pulmonary tuberculosis. The feasibility of a thoracoscopic approach to anatomic lung resection for the complications of mycobacterial infection has not been well evaluated. METHODS: We retrospectively analyzed chest computed tomography (CT) scans of patients who underwent anatomic lung resections without additional procedures for tuberculosis between January 2007 and September 2009. Image characteristics on chest CT scans were classified as bullae, pleural thickening, peribronchial lymph node calcification, tuberculoma, cavity, aspergilloma, atelectasis, and bronchiectasis, and graded according to the number of the lesions and degree of lobar involvement. Patients were divided into two groups, video-assisted thoracoscopic surgery (VATS) and thoracotomy for anatomic lung surgery, according to the eventual operative procedure. The variables between these two groups were compared using the Student t test; the image characteristics were compared using a chi2 test. RESULTS: Fifty patients were enrolled; 21 given VATS and 29 given a thoracotomy. The VATS group had significantly lower gradings in pleural thickening, peribronchial lymph node calcification, tuberculoma, cavity, and aspergilloma than did the thoracotomy group (p=0.000, 0.015, 0.001, 0.023, and 0.022, respectively). Mean operative time, blood loss, and complication rate were not significantly different, but the mean hospital stay was significantly shorter (10.00 days versus 14.96 days, p=0.048) in the VATS group. CONCLUSIONS: Multiple cavities, multiple aspergillomas, multilobar tuberculoma, extensive pleural thickening, and peribronchial lymph node calcification preclude VATS. It is reasonable to attempt a thoracoscopic approach in patients without these preoperative image characteristics. PMID- 21549349 TI - Esophageal stent placement for the treatment of acute intrathoracic anastomotic leak after esophagectomy. AB - BACKGROUND: Anastomotic leak after intrathoracic esophagogastrostomy remains a dreaded complication of esophagectomy. Traditional therapy has most often consisted of reoperative repair or observation and drainage, each prolonging hospitalization and the initiation of oral nutrition. This investigation summarizes our experiences treating these patients using an occlusive, removable esophageal stent. METHODS: Over a 4-year period, patients found to have an acute, significant intrathoracic anastomotic leak after esophagectomy for benign or malignant disease undergoing surgery at or transferred to a single institution were offered endoluminal esophageal stent placement as initial therapy. Stents were placed endoscopically utilizing general anesthesia and fluoroscopy. Leak occlusion was confirmed by esophagram. Patients were followed until their stent was removed and their anastomotic leak had resolved. RESULTS: Seventeen patients had an esophageal stent placed for an anastomotic leak during the study period. Leak occlusion occurred in all 17 patients. One patient was found to also have a perforation of the gastric conduit and underwent operative repair. Fourteen patients (82%) were able to initiate oral nutrition within 72 hours of stent placement. Stent migration occurred in 3 patients (18%), requiring repositioning in 2 and replacement in 1. All stents were removed at a mean of 17+/-9 days after placement. CONCLUSIONS: Endoluminal esophageal stent placement is a safe and effective method for the treatment of an intrathoracic anastomotic leak after esophagectomy. This treatment resulted in rapid leak occlusion, provided the opportunity for earlier oral nutrition, and avoided the potential morbidity of reoperative repair or esophageal diversion. PMID- 21549348 TI - A bovine jugular vein conduit: a ten-year bi-institutional experience. AB - BACKGROUND: We retrospectively reviewed the 12-year (1999 to 2010) clinical and echocardiographic performance of 232 bovine jugular vein conduits for extracardiac right ventricular outflow tract reconstruction in non-Ross patients. METHODS: The bovine jugular vein conduit cohorts, group 1 (12 to 14 mm), group 2 (16 to 18 mm), and group 3 (20 to 22 mm), had mean follow-up of 48 +/- 30 months. Graft dysfunction is defined as right ventricular outflow tract obstruction with peak echo Doppler gradient greater than 40 mm Hg or grade 3/4 valve regurgitation. Graft failure is the need for conduit replacement or transcatheter or surgical reintervention. RESULTS: Early mortality (4 of 232; 2%) and late mortality (8 of 228; 3.5%) were not conduit related. Twenty-four conduits (10%) were explanted. Mean implant Z score was significantly lower for group 1 (1.7+/ 0.08 versus group 2, 2.7+/-0.6, or group 3, 2.5+/-1.5; p=0.001). Ten-year actuarial survival (group 1, 84% versus 2, 100%, and 3, 99%; p=0.001) and freedom from conduit dysfunction (group 1, 64%; group 2, 92%; and group 3, 90%) and failure (group 1, 75%; 2, 82%; and 3, 91%; p=0.002) were significantly better for groups 2 and 3. CONCLUSIONS: Bovine jugular vein is an excellent immediate substitute for right ventricular outflow tract reconstruction, with early durability superior to that of pulmonary homografts reported at similar follow up. Conduits larger than 14 mm have improved performance. Longer follow-up will define the structural integrity and efficacy of this prosthesis. PMID- 21549350 TI - Bioactivity and cellular structure of Candida albicans and Candida glabrata biofilms grown in the presence of fluconazole. AB - OBJECTIVE: The aim of this study was to evaluate whether fluconazole (FLZ) could affect the bioactivity and cellular structure of Candida albicans or Candida glabrata biofilms grown in the presence of FLZ. MATERIALS AND METHODS: Tokens were fabricated using poly(methylmethacrylate) resin (PMMA) in a hot water bath. Salivary pellicles were formed on the PMMA surface, and biofilms of a reference strain and two clinical isolates of C. albicans (ATCC 90028, P01 and P34) and C. glabrata (ATCC 2001, P11 and P31) were developed for a period of 48 h. Control and experimental groups were formed. FLZ at the bioavailable concentration in saliva (2.56 MUg/mL) was added to the medium of the experimental group. The culture mediums of the control and experimental groups were changed after 24h. The bioactivities of the biofilms were evaluated using an XTT reduction colorimetric assay. The cellular structure was analysed by confocal scanning laser microscopy and by transmission electron microscopy. The data were analysed by the independent sample Student's t-test, with the significance level set at 5%. RESULTS: The presence of FLZ decreased the bioactivity of all C. albicans biofilms (p<0.001), however, it did not change the cellular structure of C. albicans P34. Regarding the C. glabrata biofilm bioactivity and structure, no statistically significant differences were found between the control and experimental groups. CONCLUSION: FLZ, at the bioavailable concentration present in saliva, interferes with the development of C. albicans biofilms, but does not interfere with the development of C. glabrata biofilms. PMID- 21549351 TI - Magnetic resonance imaging of the temporomandibular joint in the rat compared with low-powered light microscopy. AB - OBJECTIVE: High magnetic field magnetic resonance imaging (MRI) was applied to the temporomandibular joint (TMJ) in the rat. The purpose of this study was the depiction of the internal structure of the TMJ, including the articular disc, articular cartilage, and the upper and lower joint cavities. We also proposed MRI settings and slices suitable for imaging the TMJ in the rat. METHODS: Temporomandibular joints from one female and eight male Sprague Dawley rats (5-8 weeks old) and four male Wistar-Hamamatsu rats (7-8 weeks old) were used. Using scout images, the horizontal plane was defined as being parallel to the body of the basisphenoid bone underneath the base of the brain. The coronal plane was defined as a slice vertical to the horizontal plane and vertical to the longitudinal fissure of the cerebrum. The sagittal plane was defined as a slice vertical to the horizontal plane and parallel to the longitudinal fissure of the cerebrum. RESULTS: T(1)-weighted MR images with a spatial resolution of 75 MUm were obtained for 5 min. The temporal bone and mandibular condyle were depicted as lower signal intensity images and the articular disc was depicted as an intermediate signal intensity image. In accordance with Gd-DTPA-enhanced MR or T(2)-weighted MR images, the articular disc, articular cartilage, and the upper and lower joint cavities could be assigned clearly. CONCLUSION: These MRI findings closely agreed with those observed with haematoxylin-eosin staining under light microscopy, suggesting that MRI is a useful method for analyzing the complex structure of the TMJ in the rat. PMID- 21549352 TI - A novel video game--based device for measuring stepping performance and fall risk in older people. AB - OBJECTIVE: To determine whether a dance mat test of choice stepping reaction time (CSRT) is reliable and can detect differences in fall risk in older adults. DESIGN: Randomized order, crossover comparison. SETTING: Balance laboratory, medical research institute, and retirement village. PARTICIPANTS: Older (mean age, 78.87+/-5.90y; range, 65-90y) independent-living people (N=47) able to walk in place without assistance. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Reaction (RT), movement, and response times of dance pad--based stepping tests, Physiological Profile Assessment (PPA) score, Digit Symbol Substitution Test (DSST) score, time to complete the Trail Making Test (TMT) A+B, Fall Efficacy Scale International (FES-I) score, Activities-specific Balance Confidence (ABC) Scale score, and Incidental and Planned Exercise Questionnaire (IPEQ) incidental IPEQ activity subscore. RESULTS: Test-retest reliability of the dance mat CSRT response time was high (intraclass correlation coefficient model 3,k=.90; 95% confidence interval [CI], .82-.94; P<.001) and correlated highly with the existing laboratory-based measure (r=.86; 95% CI, .75-.92; P<.001). Concurrent validity was shown by significant correlations between response time and measures of fall risk (PPA: r=.42; 95% CI, .15-.63; P<.01; TMT A: r=.61; 95% CI, .39-.77; TMT B: r=.55; 95% CI, .31-.72; DSST: r=-.53; 95% CI, -.71 to -.28; P<.001; FES-I: Spearman rho=.50; 95% CI, .25-.69; ABC Scale: Spearman rho=-.58; 95% CI, -.74 to -.35; P<.01). Participants with moderate/high fall-risk scores (PPA score >1) had significantly slower response times than people with low/mild fall-risk scores (PPA score <1) at 1146+/-182 and 1010+/-132ms, respectively (P=.005), and multiple fallers and single/nonfallers showed significant differences in RT (883+/-137 vs 770+/-100ms; P=.009) and response time (1180+/ 195 vs 1031+/-145ms; P=0.017). CONCLUSIONS: The new dance mat device is a valid and reliable tool for assessing stepping ability and fall risk in older community dwelling people. Because it is highly portable, it can be used in clinic settings and the homes of older people as both an assessment and training device. PMID- 21549353 TI - AKT signaling pathway in the nucleus accumbens mediates excessive alcohol drinking behaviors. AB - BACKGROUND: Neuroadaptations within the nucleus accumbens (NAc) have been implicated in molecular mechanisms underlying the development and/or maintenance of alcohol abuse disorders. We recently reported that the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in the NAc of rodents, after exposure to alcohol, contributes to alcohol drinking behaviors. The kinase AKT is a main upstream activator of the mTORC1 pathway. We therefore hypothesized that the activation of AKT in the NAc in response to alcohol exposure plays an important role in mechanisms that underlie excessive alcohol consumption. METHODS: Western blot analysis was used to assess the phosphorylation levels of enzymes. Acute exposure of mice to alcohol was achieved by the administration of 2 g/kg alcohol intraperitoneally (i.p.). Two-bottle choice and operant self administration procedures were used to assess drinking behaviors in rats. RESULTS: We found that acute systemic administration of alcohol and recurring cycles of excessive voluntary consumption of alcohol and withdrawal result in the activation of AKT signaling in the NAc of rodents. We show that inhibition of AKT or its upstream activator, phosphatidylinositol-3-kinase (PI3K), within the NAc of rats attenuates binge drinking as well as alcohol but not sucrose operant self administration. CONCLUSIONS: Our results suggest that the activation of the AKT pathway in the NAc in response to alcohol exposure is an important contributor to the molecular mechanisms underlying alcohol-drinking behaviors. AKT signaling pathway inhibitors are therefore potential candidates for drug development for the treatment of alcohol use and abuse disorders. PMID- 21549354 TI - White matter differences in monozygotic twins discordant or concordant for obsessive-compulsive symptoms: a combined diffusion tensor imaging/voxel-based morphometry study. AB - BACKGROUND: Neuroimaging studies of obsessive-compulsive disorder (OCD) patients point to deficits in cortico-striato-thalamo-cortical circuits that might include changes in white matter. The contribution of environmental and genetic factors to the various OCD-related changes in brain structures remains to be established. METHODS: White matter structures were analyzed in 140 subjects with both diffusion tensor imaging and voxel-based morphometry. We studied 20 monozygotic twin pairs discordant for obsessive-compulsive symptoms (OCS) to detect the effects of environmental risk factors for obsessive-compulsive (OC) symptomatology. Furthermore, we compared 28 monozygotic twin pairs concordant for low OCS scores with 23 twin pairs concordant for high OCS scores to detect the effects of genetic risk factors for OC symptomatology. RESULTS: Discordant pair analysis showed that the environmental risk was associated with an increase in dorsolateral-prefrontal white matter. Analysis of concordant pairs showed that the genetic risk was associated with a decrease in inferior frontal white matter. Various white matter tracts showed opposite effects of environmental and genetic risk factors (e.g., right medial frontal, left parietal, and right middle temporal), illustrating the need for designs that separate these classes of risk factors. CONCLUSIONS: Different white matter regions were affected by environmental and genetic risk factors for OC symptomatology, but both classes of risk factors might, in aggregate, create an imbalance between the indirect loop of the cortico-striato-thalamo-cortical network (to the dorsolateral-prefrontal region)-important for inhibition and switching between behaviors-and the direct loop (involving the inferior frontal region) that contributes to the initiation and continuation of behaviors. PMID- 21549356 TI - Effects of NMDA receptor modulators on a blood-brain barrier in vitro model. AB - Changes of the functionality of the blood-brain barrier (BBB) have been reported in the context of several brain related diseases such as multiple sclerosis, epilepsy, Alzheimer's disease and stroke. Several publications indicated the presence and functionality of the NMDA receptor (NMDAR) at the brain endothelium and a possible involvement of the NMDAR in the above-mentioned diseases. Recently, it was shown that the application of the NMDAR antagonist MK801 can block several adverse effects at the BBB in vitro, but also that MK801 can significantly change the proteome of brain endothelial cells without simultaneous stimulation of NMDAR by glutamate. Based on these reports we investigated if NMDAR antagonists MK801 and D-APV can affect the intracellular calcium level (Ca2+i) of an in vitro BBB model based on human cell line ECV304 on their own and compared these results to effects mediated by NMDAR agonists glutamate and NMDA. Treatment of ECV304 cells for 30 min with glutamate resulted in no significant change of Ca2+i. On the contrary, application of NMDA and NMDAR antagonists D-APV and MK801 led to a significant and concentration dependent decrease of Ca2+i. Further studies revealed that glutamate was able to decrease the transendothelial electrical resistance (TEER) of the BBB in vitro model, whereas NMDA and D-APV were able to increase TEER. Analysis of the protein expression levels of tight junctional molecules ZO-1 and occludin showed a complex regulation after application of NMDAR modulators. In summary, it was shown that NMDAR antagonists can alter BBB key properties in vitro on their own. Moreover, although qPCR results confirmed the presence of NMDA receptor subunits NR1, NR2A, NR2B and NR2C, membrane binding studies failed to prove the typical plasma membrane localization and functionality in human BBB cell line ECV304. PMID- 21549357 TI - "What you encode is not necessarily what you store": evidence for sparse feature representations from mismatch negativity. AB - The present study examines whether vowels embedded in complex stimuli may possess underspecified representations in the mental lexicon. The second goal was to assess the possible interference of the lexical status of stimuli under study. Minimal pairs of German nouns differing only in the stressed vowels [e], [o], and [o], and derived pseudowords, were used to measure the Mismatch Negativity (MMN) in a passive oddball-paradigm. The differing vowels were chosen such that the place of articulation information was conflicting vs. non-conflicting in the framework of models assuming underspecified representations in the mental lexicon (i.e. minimizing featural information by omitting redundant information in order to ensure efficient speech processing), whereas models assuming fully specified phonological representations would predict equal levels of conflict in all possible contrasts. The observed pattern of MMN amplitude differences was in accordance to predictions of models assuming underspecified phonological representations. As the possible interferences by other levels of linguistic processing was demonstrated, it seems favorable to use pseudowords for investigating phonological effects by means of MMN. PMID- 21549355 TI - Glutamatergic gene expression is specifically reduced in thalamocortical projecting relay neurons in schizophrenia. AB - BACKGROUND: Impairment of glutamate neurons that relay sensory and cognitive information from the medial dorsal thalamus to the dorsolateral prefrontal cortex and other cortical regions may contribute to the pathophysiology of schizophrenia. In this study, we have assessed the cell-specific expression of glutamatergic transcripts in the medial dorsal thalamus. METHODS: We used laser capture microdissection to harvest two populations of medial dorsal thalamic cells, one enriched with glutamatergic relay neurons and the other with gamma aminobutyric acidergic neurons and astroglia, from postmortem brains of subjects with schizophrenia (n = 14) and a comparison group (n = 20). Quantitative polymerase chain reaction of extracted RNA was used to assay gene expression in the different cell populations. RESULTS: The transcripts encoding the ionotropic glutamate receptor subunits NR2D, GluR3, GluR6, GluR7, and the intracellular proteins GRIP1 and SynGAP1 were significantly decreased in relay neurons but not in the mixed glial and interneuron population in schizophrenia. CONCLUSIONS: Our data suggest that reduced ionotropic glutamatergic expression occurs selectively in neurons, which give rise to the cortical projections of the medial dorsal thalamus in schizophrenia, rather than in thalamic cells that function locally. Our findings indicate that glutamatergic innervation is dysfunctional in the circuitry between the medial dorsal thalamus and cortex. PMID- 21549358 TI - Selective carboxypropionylation of chitosan: synthesis, characterization, blood compatibility, and degradation. AB - Two water-soluble chitosan (WSC) derivatives of N-succinyl-chitosan (NSCS) and N,O-succinyl-chitosan (NOSCS) with a degree of substitution (DS) that ranged form 0.28 to 0.61 were selectively synthesized by varying the molar ration of succinic anhydride and chitosan. The chemical structure and physical properties of the chitosan derivatives were characterized by FT-IR, 1H NMR, and XRD. XRD analysis showed that the derivatives were amorphous. The lysozyme enzymatic degradation results revealed that the NSCS was of higher susceptibility to lysozyme. The degradation rate and the solubility of the chitosan derivatives were strongly determined by the degree of substitution and the position of the substitution. The results of antithrombotic properties, hemolytic properties and anticoagulant properties of WSCs indicated that the blood compatibility was dramatically improved, and the carboxyl group introduced on the C-6 or C-2 hydroxyl group appeared to impact anticoagulant activity in different ways. PMID- 21549359 TI - Insights in starch acetylation in sub- and supercritical CO2. AB - An in-depth study on the acetylation of starch with acetic anhydride (Ac(2)O) and sodium acetate (NaOAc) as the catalyst in pressurized carbon dioxide (scCO(2)) in a broad pressure range (8-25MPa) and a temperature of 90 degrees C is provided. Highest degrees of substitution (DS) of 0.29 (1h reaction time) and 0.62 (24h reaction time) were found near the critical point of the mixture (15MPa). The phase behavior of the system CO(2), starch and acetic anhydride (Ac(2)O) was studied in a high pressure view cell. The critical points were a clear function of the temperature and increased from the range of 9.4-10MPa to 14.5-14.8MPa when going from 50 to 90 degrees C (Ac(2)O mole fraction at the critical point in the range of 0.08-0.09). Acetylation experiments with a range of starch particles sizes showed a clear relation between the DS and the particle size. PMID- 21549360 TI - Cognitive impairments due to focal cerebellar injuries in adults. AB - INTRODUCTION: It has been asserted that damage to the cerebellum produces a specific pattern of cognitive deficits, but clinical studies have had ambiguous results. There remains particular uncertainty about the effects of focal cerebellar injuries on cognition in adults. Clinical reports and anatomical connectivity studies have suggested a possible functional convergence of frontal lobes and cerebellum. This investigation was designed to assess whether focal cerebellar injuries in adults would cause impairment on tasks previously demonstrated to be sensitive to prefrontal lesions. METHOD: We investigated this question in 32 adults with either stroke or resection of benign tumours and 36 healthy control subjects. Patients underwent standard and experimental cognitive testing and an assessment of general health and well-being at least 3 months post onset. RESULTS: The group with right cerebellar lesions had lower performance on some tests of response control and verbal fluency than the controls and also the patients with left cerebellar lesions. On most tests, including most of the experimental tests sensitive to prefrontal lesions, the patients had no significant difference from the controls. The patient groups reported no health or functional decline. CONCLUSIONS: These results and the bulk of the clinical literature suggest that damage to some cerebellar sites may have specific cognitive consequences, but the cognitive impairment after focal cerebellar injury in adults is mild or transient. After the acute epoch, demonstration of deficits may require more demanding probes of specific domains of cognition. PMID- 21549361 TI - [EAHFE (Epidemiology Acute Heart Failure Emergency) study: analysis of the patients with echocardiography performed prior to an emergency visit due to an episode of acute heart failure]. AB - INTRODUCTION AND OBJECTIVES: Analyze the clinical profile and short-term evolution of the patients attended in the Spanish Hospital Emergency Services (SHES) due to an episode of acute heart failure (AHF) based on whether these patients had undergone or not an echocardiography and on the ventricular function estimated in said ultrasonography. PATIENTS AND METHODS: A total of 9 hospitals participated. They consecutively enrolled all the patients diagnosed of AHF during 2 months. Data were collected on the clinical profile and the short-term evolution (intra-hospital mortality and mortality and re-visits at 30 days). The existence of a previous echocardiography was retrospectively investigated and, if it existed, the quantification of the left ventricular ejection fraction (LVEF) as well. The ventricular function was considered to be depressed or conserved according to whether the LVEF was greater or equal to 45% or less than 45%, respectively. RESULTS: A total of 997 patients were enrolled. An echocardiography was available for 547 patients (54.9%). Of these, the type of ventricular function was known in 476: 273 (57.4%) had depressed function and 203 (42.6%) had conserved function. The patients who did not have an echocardiography were older, with fewer pathological backgrounds. They had less advanced forms of heart disease, used beta blockers less and, were treated less with bolus diuretics in the emergency service. The patients with depressed systolic function were more often males, younger, active smokers, with ischemic heart disease and had signs of left heart failure (orthopnea and paroxysmal nocturnal dyspnea). Less frequently, they were hypertense, with valvular heart disease, with chronic atrial fibrillation and their systolic blood pressure in the Emergency Service was lower. They were directly discharged from the SHES more frequently. Intra hospital mortality was 5.3%, mortality at 30 days 8.9% and re-visit at 30 days 27.2%. However, no significant differences were found in any of these evolution variables based on the existence or not of an echocardiography or on the type of dysfunction found in it. CONCLUSIONS: The patients who had an episode of AHF did not have any previous echocardiography in a high number of cases. This fact made it necessary in these cases to carry out the therapeutic management in the SHES guided only by the signs and symptoms, such as systolic blood pressure on their arrival to the emergency service. In spite of this, the fact that the functional state of the left ventricular was not known did not affect the intra-hospital mortality, at 30-days and readmission. PMID- 21549362 TI - [Hospital repercussion in 2009 of the influenza Av H1N1 pandemic in Murcia, Spain]. PMID- 21549363 TI - Ultrasound automated volume calculation in reproduction and in pregnancy. AB - OBJECTIVE: To review studies assessing the application of ultrasound automated volume calculation in reproductive medicine. DESIGN: We performed a literature search using the keywords "SonoAVC, sonography-based automated volume calculation, automated ultrasound, 3D ultrasound, antral follicle, follicle volume, follicle monitoring, follicle tracking, in vitro fertilization, controlled ovarian hyperstimulation, embryo volume, embryonic volume, gestational sac, and fetal volume" and conducted the search in PubMed, Medline, EMBASE, and the Cochrane Database of Systematic Reviews. Reference lists of identified reports were manually searched for other relevant publications. RESULT(S): Automated volume measurements are in very good agreement with actual volumes of the assessed structures or with other validated measurement methods. The technique seems to provide reliable and highly reproducible results under a variety of conditions. Automated measurements take less time than manual measurements. CONCLUSION(S): Ultrasound automated volume calculation is a promising new technology which is already used in daily practice especially for assisted reproduction. Improvements to the technology will undoubtedly render it more effective and increase its use. PMID- 21549364 TI - A case of diffuse uterine leiomyomatosis who had two successful pregnancies after medical management. AB - OBJECTIVE: To describe a case report of diffuse uterine leiomyomatosis who had successful pregnancy twice following conservative management. DESIGN: Retrospective report. SETTING: Private general hospital. PATIENT(S): A nulliparous woman 25 years of age presented with menorrhagia and infertility. She had innumerable small fibroids of 4-42 mm size throughout the myometrium. Size of the symmetrically enlarged uterus was 131*80*60 mm, clinically corresponding to that of 12 weeks of gestation. INTERVENTION(S): She received a GnRH analogue (GnRHa; leuprolide acetate) 3.75 mg per month for 6 months. MAIN OUTCOME MEASURE(S): Reduction of uterus size, menstrual amount, conception, pregnancy outcome. RESULT(S): Enlarged uterus reduced to almost normal size after 3 doses of GnRHa. She did not experience heavy bleeding during menstruation. She conceived spontaneously in the first cycle after discontinuation of GnRHa. Antenatal course was uneventful. A healthy male baby of 2.5 kg was delivered by cesarean section at 39 weeks. The placenta weighed 330 g. There was no postpartum hemorrhage. She conceived spontaneously for the second time in the first cycle after resumption of menses. Antenatal, intranatal (cesarean section), and postnatal courses of the second pregnancy were uneventful. The second neonate weighed 3.0 kg and the placenta 400 g. CONCLUSION(S): Conservative treatment may help to achieve successful pregnancy in case of diffuse uterine leiomyomatosis. PMID- 21549365 TI - Morphologic and mitochondrial characterization of human spermatogenic cells dispersed in wet preparation for testicular sperm extraction: establishment of a microscopic diagram of developing human spermatogenic cells. AB - The successful identification of spermatozoa at microdissection testicular sperm extraction is critical and can depend on the judgment of experienced reproductive clinicians. Therefore, we characterized human spermatogenic cells based on stage specific mitochondrial location and morphologic change by using a vital mitochondrion-specific fluorescent probe, Mitotracker, and stage-specific antibodies to make a useful microscopic diagram. PMID- 21549366 TI - Comparison of different diagnostic procedures for the staging of malformations associated with Mayer-Rokitansky-Kuster-Hauser syndrome. AB - OBJECTIVE: To compare different diagnostic procedures for staging malformations associated with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. DESIGN: Retrospective two-center cohort study (Canadian Task Force classification II-2). SETTING: University hospital. PATIENT(S): One hundred and thirty-eight women with MRKH. INTERVENTION(S): Clinical examinations, abdominal or perineal/rectal ultrasound, magnetic resonance imaging (MRI), and laparoscopy. MAIN OUTCOME MEASURE(S): Agreement between the results obtained with the other methods and the results obtained with the reference methods for correct staging of malformations, presented as kappa values (kappa). RESULT(S): The VCUAM (vagina cervix uterus adnex-associated malformation) classification system was used to classify genital malformations in 138 women with MRKH. The reference methods for examining the individual organs were: vagina-clinical examination; cervix/uterus and adnexa laparoscopy; and urinary tract malformations-MRI. The values obtained were as follows. Vagina was kappa 0.74 for MRI versus clinical examination; ultrasound and laparoscopy did not allow adequate description of vaginal malformations. Cervical findings were rarely detailed with any of the imaging methods. Uterus was kappa 0.93 for MRI versus laparoscopy, and kappa 0.83 for ultrasound. For adnexa, only laparoscopy was able to describe the morphology adequately. The urinary tract was kappa 0.87 for ultrasound versus MRI. CONCLUSION(S): For the correct staging of malformations associated with MRKH, MRI or a combination of clinical examination and ultrasound are equivalent. However, none of the imaging methods adequately describes adnexal morphology. PMID- 21549367 TI - Antimullerian hormone and polycystic ovary syndrome. AB - OBJECTIVE: To assess the relationship between antimullerian hormone (AMH) and parameters related to polycystic ovary syndrome (PCOS). DESIGN: Prospective study. SETTING: Academic tertiary care center. PATIENT(S): A total of 290 women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Parameters related to insulin resistance and metabolic syndrome. RESULT(S): Women with polycystic ovary morphology had significantly higher AMH levels than women in the control group. The prevalence of PCOS increased from 21% in the low-AMH (<4 ng/mL) group to 37% in the moderate-AMH (4-11 ng/mL) group and 80% in the high-AMH (>11 ng/mL) group. However, significant differences in insulin resistance parameters were not observed among groups. The results of the correlation analysis revealed that AMH levels were positively correlated with LH, total T, A, and total cholesterol content; however, AMH levels were negatively correlated with age, body mass index, and the number of menstrual cycles per year. AMH levels were not correlated with insulin resistance parameters. CONCLUSION(S): Elevated serum AMH levels increase the risk of PCOS but do not affect the risk of insulin resistance or metabolic syndrome. PMID- 21549368 TI - Catch-up growth in girls born small for gestational age precedes childhood progression to high adiposity. AB - OBJECTIVE: To study across childhood the features of small for gestational age (SGA) girls with spontaneous catch-up growth. DESIGN: Longitudinal study (age 2-8 years). SETTING: University hospital. PATIENT(S): Post-catch-up SGA girls (n = 18) versus healthy control girls born appropriate for gestational age (AGA; n = 13). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Height, weight, fasting glucose, insulin, IGF-I, high-molecular-weight (HMW) adiponectin, LDL and HDL cholesterol, triglycerides, body composition by absorptiometry (2-8 years); visceral fat by magnetic resonance imaging (6-8 years); bone age (by automated reading), sex hormone-binding globulin, DHEAS, and leptin (8 years). RESULT(S): At age 2 years, AGA and SGA girls were comparable for all study markers. Between 2 and 8 years, girls were prepubertal; AGA and SGA girls gained height, lean mass, and bone mineral content similarly; other outcomes diverged so that, at age 8, SGA girls had markedly higher levels of circulating insulin, IGF-I, DHEAS, LDL cholesterol, and leptin; lower HMW adiponectin and SHBG levels; more total and visceral fat (without being obese); and an older bone age. CONCLUSION(S): After completing catch-up growth and before starting puberty, SGA girls develop an ensemble that includes not only central adiposity, hyperinsulinemia, and hypoadiponectinemia but also hyperleptinemia, dyslipidemia, lower SHBG and higher DHEAS levels, and faster bone maturation. PMID- 21549369 TI - In vitro fertilization outcomes in Hispanics versus non-Hispanic whites. AB - The in vitro fertilization (IVF) outcomes, including clinical intrauterine gestation rate and live birth rate, between Hispanic and non-Hispanic white women were compared, and there were no differences. Hispanics were more likely to have a diagnosis of tubal factor infertility, whereas non-Hispanic white women were more likely to have endometriosis as their infertility diagnosis. PMID- 21549370 TI - Biliary leiomyoma diagnosed by Spyglass cholangioscopy (with video). PMID- 21549371 TI - Cryoablation of persistent Barrett's epithelium after definitive chemoradiation therapy for esophageal adenocarcinoma. AB - BACKGROUND: Dysplastic Barrett's epithelium (BE) persists after chemoradiation therapy for esophageal adenocarcinoma (EAC) arising in Barrett's esophagus. This phenomenon may present a significant risk for development of metachronous adenocarcinoma. OBJECTIVE: To analyze the safety and efficacy of endoscopic cryoablation therapy for persistent dysplastic BE in patients with complete clinical response after definitive chemoradiation therapy for EAC. DESIGN: Retrospective cohort study. SETTING: Single National Cancer Institute Comprehensive Cancer Center experience. PATIENTS: Radiation and endoscopic oncology treatment records were reviewed between January 2004 and September 2009. Fourteen patients with EAC who had been treated with definitive chemoradiation therapy followed by cryoablation were identified. INTERVENTION: Cryoablation therapy. MAIN OUTCOME MEASUREMENTS: Reduction in Prague Classification and dysplasia status following cryoablation therapy. Complications reported at 24 hour after the procedure telephone survey and at subsequent endoscopy. RESULTS: After complete clinical response of EAC to chemoradiation therapy, the median length of persistent BE was Prague classification C1M4 (C = circumferential extent, M = maximal extent). Cryoablation reduced the median length of persistent BE to Prague classification C0M1 (P = .009 with respect to circumferential extent and P = .004 with respect to maximal extent of BE). All 14 patients had dysplastic BE. Cryoablation resulted in histological downgrading in all 14 patients. Among patients with high-grade dysplasia, 20% (2/10) were reduced to low-grade dysplasia, 60% (6/10) to BE with no dysplasia, and 20% (2/10) to no BE. Among patients with low-grade dysplasia, 75% (3/4) were reduced to BE with no dysplasia, and 25% (1/4) to no BE. The median number of cryoablation treatments administered to the 14 patients evaluated was 1 (mean 1.5, range 1-5). Eighty-six percent (12/14) of patients reported no complaints during the 24 hours after cryoablation. No occurrences of perforation and no esophageal strictures were reported at surveillance endoscopy. LIMITATIONS: Single-center, retrospective design involving a small number of patients. CONCLUSION: Our observations suggest that cryoablation therapy is safe and effective for the treatment of persistent BE after definitive chemoradiation. PMID- 21549372 TI - Esophagitis dissecans superficialis. PMID- 21549373 TI - Fully covered self-expandable metal stents for benign esophageal disease: a multicenter retrospective case series of 31 patients. PMID- 21549374 TI - Acute cholecystitis after colonoscopy: a case series. PMID- 21549375 TI - Likelihood of missed and recurrent adenomas in the proximal versus the distal colon. AB - BACKGROUND: Colonoscopy may be less efficacious in reducing colorectal cancer mortality in the proximal compared with the distal colon. A greater likelihood for missed and recurrent adenomas in the proximal colon may contribute to this phenomenon. OBJECTIVE: To examine whether a proximal adenoma is associated with the risk and location of missed and recurrent adenomas. DESIGN: Prospective. SETTING: Polyp Prevention Trial. PARTICIPANTS: A total of 1864 patients with an adenoma at baseline underwent a follow-up colonoscopy 4 years later (adenoma recurrence). Of these, 1731 underwent a clearing colonoscopy 1 year after the baseline examination (missed adenoma). MAIN OUTCOME MEASUREMENTS: Association of baseline adenoma location with the risk and location of adenomas found at colonoscopy performed 1 year and 4 years later. RESULTS: At the year 1 colonoscopy, 598 patients (34.6%) had an adenoma (missed adenoma). Compared with those with a distal-only adenoma at baseline, patients with a proximal-only adenoma at baseline were more likely to have any missed adenomas (relative risk [RR] 1.28; 95% CI, 1.09-1.49) and a proximal-only missed adenoma (RR 2.05; 95% CI, 1.49-2.80). At the year 4 colonoscopy, 733 patients (39.3%) had adenoma recurrence. Patients with a baseline proximal-only adenoma were more likely to have any adenoma recurrence (RR 1.14; 95% CI, 1.00-1.31) and a proximal-only adenoma recurrence (RR 1.52; 95% CI, 1.15-2.02). Sensitivity analyses involving missed adenomas did not materially affect the risk or location of recurrent adenomas at year 4 colonoscopy. LIMITATION: Lesions may still be missed on repeated colonoscopies. CONCLUSIONS: Missed and recurrent adenomas are more likely to be in the proximal colon. PMID- 21549376 TI - Endoscopic removal of self-expandable metal stents from the esophagus (with video). AB - BACKGROUND: Self-expandable metals stents (SEMSs) have increasingly been used as a temporary device to bridge chemoradiotherapy in patients with malignant esophageal disease or in patients with benign esophageal defects or stenosis. OBJECTIVE: To evaluate the outcome of removal of SEMSs in a large cohort of patients with benign and malignant esophageal disease. DESIGN: Observational study with standardized treatment and follow-up. SETTING: Single university center. PATIENTS: Between 2001 and 2010, 95 consecutive patients referred for endoscopic SEMS extraction were included. INTERVENTIONS: Endoscopic stent removal. MAIN OUTCOME MEASUREMENTS: Technical and functional outcome and complications. RESULTS: A total of 124 stent extractions were undertaken in 95 patients; both partially covered (68%) and fully covered (32%) SEMSs were removed. Three patients had 2 overlapping SEMSs in place. Successful primary removal was achieved in 89%; the secondary removal rate was 96%. Uncomplicated primary removal rate was significantly higher for fully covered versus partially covered stents (P = .035) and for single versus overlapping stents (P = .033). Patients with a complicated stent removal had the stent in place significantly longer compared with patients with an uncomplicated primary stent removal (126 days vs 28 days; P = .01). Surgical removal was required in 3 patients (2.4%). Six moderate and severe complications (5%) related to the endoscopic extraction occurred. LIMITATIONS: Retrospective, nonrandomized study design. CONCLUSIONS: Primary endoscopic removal of an SEMS is feasible in the majority of patients with benign and malignant esophageal disease. A longer time that a stent is in place and the use of partially covered SEMSs both impede removal. Moreover, overlapping SEMSs should be avoided for temporary use because stent disintegration and subsequent complications may occur. PMID- 21549377 TI - 6 DOF synchronized control for spacecraft formation flying with input constraint and parameter uncertainties. AB - This paper treats the problem of synchronized control of spacecraft formation flying (SFF) in the presence of input constraint and parameter uncertainties. More specifically, backstepping based robust control is first developed for the total 6 DOF dynamic model of SFF with parameter uncertainties, in which the model consists of relative translation and attitude rotation. Then this controller is redesigned to deal with the input constraint problem by incorporating a command filter such that the generated control could be implementable even under physical or operating constraints on the control input. The convergence of the proposed control algorithms is proved by the Lyapunov stability theorem. Compared with conventional methods, illustrative simulations of spacecraft formation flying are conducted to verify the effectiveness of the proposed approach to achieve the spacecraft track the desired attitude and position trajectories in a synchronized fashion even in the presence of uncertainties, external disturbances and control saturation constraint. PMID- 21549378 TI - Are there any advantages in using a distal aiming device for tibial nailing? Comparing the Centro Nailing System with the Unreamed Tibia Nail. AB - INTRODUCTION: The distal locking of an intramedullary tibial nail can be challenging and time consuming when performed freehand. This study was conducted to evaluate if a distal aiming device would reduce surgical time. MATERIALS AND METHODS: A case-controlled study was performed between 2007 and 2009 with 30 patients receiving a reamed tibial nail (Centronail) with the use of a distal aiming device and 30 patients who were treated with an Unreamed Tibia Nail (UTN), with freehand distal locking, in the same period. The primary outcome in this study was operative time. Secondary outcomes were the need for fluoroscopy, time to consolidation and complications. RESULTS: Operation time was longer in the Centronail group compared with the UTN group (126 min vs. 96 min, p=0.000). Use of fluoroscopy for distal locking was needed in half of the cases (n=16) using a distal aiming device. No differences were found regarding time to consolidation, time to removal of the nail and complications. CONCLUSION: The use of an aiming device for distal locking of a tibia nail lengthens operation time rather than reducing it. Fluoroscopy was still needed in about half of the cases. No difference was seen in clinical outcomes. The use of a distal aiming device to lock a tibial nail appears to have no benefit. PMID- 21549379 TI - Asymmetric dimethylarginine and coronary artery calcium scores are increased in patients infected with human immunodeficiency virus. AB - OBJECTIVE: Patients infected with human immunodeficiency virus (HIV) have an increased risk for cardiovascular events and mortality. Elevated concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are associated with increased subclinical atherosclerosis and cardiovascular events. The objective of this study was to determine whether plasma ADMA levels are increased in patients infected with HIV and whether this is associated with cardiovascular risk factors, inflammatory/thrombotic biomarkers, and elevated coronary artery calcium scores (CACS). METHODS: HIV infected patients and control patients were recruited in a case-control study. Medical history and laboratory measurements including plasma ADMA and biomarkers for inflammation and thrombosis such as C-reactive protein (CRP), fibrinogen, and homocysteine were obtained in both cohorts. Using multidetector computed tomography, CACS were measured in Agatston Units (AU). Bivariate differences between HIV-infected and control patients were analyzed. RESULTS: HIV-infected patients (n=37, male=27, age=45 years) had significantly higher concentrations of ADMA (0.40+/-0.10 MUmol/l) compared to a similarly matched cohort of non-HIV infected patients (n=43, male=27, age=45 years), (0.35+/-0.07 MUmol/l, p=0.03). There were no significant differences in CRP, homocysteine, and fibrinogen between the two cohorts. However, HIV-infected patients had a higher CACS distribution compared to control patients [0.0 (8.5) vs. 0.0 (0.0) AU, p=0.01]. In a multivariable regression analysis HIV-infected patients with a relative CACS of 75-90% for age and gender had the highest ADMA concentrations (0.48+/-0.09 MUmol/l, p=0.04) among all CACS subgroups. CONCLUSION: HIV-infected patients have significantly higher ADMA concentrations compared to control patients. In addition, increased CACS was associated with elevated ADMA concentrations. Thus, increased ADMA levels appear to be associated with the presence of subclinical atherosclerosis in HIV-infected patients. PMID- 21549380 TI - Compressive properties of cd-HA-gelatin modified intrasynovial tendon allograft in canine model in vivo. AB - Although we sometimes use the intrasynovial tendon allograft as a donor, the gliding ability of allograft prepared by lyophilization is significantly decreased. The gliding ability of the grafted tendon after tendon reconstruction is very important because the high gliding resistance causes more adhesion and leads to poor clinical results. We recently revealed that tendon surface treatment with a carbodiimide derivatized HA (cd-HA)-gelatin mixture for intrasynovial tendon allograft significantly improved its gliding ability. The purpose of this study was to investigate whether this cd-HA-gelatin treatment affects the tendon mechanical property or not. A total of 40 flexor digitorum profundus (FDP) tendons from canines were evaluated for compressive property by using indentation test. Indentation stiffness was measured for normal tendon, rehydrated tendon after lyophilization, rehydrated tendon after lyophilization that was implanted 6 weeks in vivo, and cd-HA treated rehydrated tendon after lyophilization that was implanted 6 weeks in vivo. The results for all groups showed no significant difference in the tendon compressive properties. The findings of these results demonstrate that cd-HA treatment for intrasynovial tendon allograft is an excellent method to improve the tendon gliding ability after lyophilization without changing the compressive property of donor tendon. PMID- 21549381 TI - Estimation of centre of gravity movements in sitting posture: application to trunk backward tilt. AB - The aim of this study was to highlight, in sitting posture, the value of distinguishing between the movements of the vertical projection of the centre of gravity (CG(v)) and its difference from the centre of pressure (CP-CG(v)). A protocol for healthy, young, trained adults, consisting in tilting their trunk backward or keeping it vertical was used. A frequency analysis shows that statistically significant effects were only seen on CP-CG(v) movements: the RMS increased by 37% (p = 0.004), while the MPF decreased by 5% (p = 0.016), suggesting an increased muscular activity in these tilting postures. In contrast, no statistically significant effects on CP and CG(v) were reported. These data highlight the advantage, in sitting posture, of splitting overall CP displacements into basic components (i.e. CG(v) and CP-CG(v)), each of them having a biomechanical significance. PMID- 21549382 TI - A protocol for monitoring soft tissue motion under compression garments during drop landings. AB - This study used a single-subject design to establish a valid and reliable protocol for monitoring soft tissue motion under compression garments during drop landings. One male participant performed six 40 cm drop landings onto a force platform, in three compression conditions (none, medium high). Five reflective markers placed on the thigh under the compression garment and five over the garment were filmed using two cameras (1000 Hz). Following manual digitisation, marker coordinates were reconstructed and their resultant displacements and maximum change in separation distance between skin and garment markers were calculated. To determine reliability of marker application, 35 markers were attached to the thigh over the high compression garment and filmed. Markers were then removed and re-applied on three occasions; marker separation and distance to thigh centre of gravity were calculated. Results showed similar ground reaction forces during landing trials. Significant reductions in the maximum change in separation distance between markers from no compression to high compression landings were reported. Typical errors in marker movement under and over the garment were 0.1mm in medium and high compression landings. Re-application of markers showed mean typical errors of 1mm in marker separation and <3mm relative to thigh centre of gravity. This paper presents a novel protocol that demonstrates sufficient sensitivity to detect reductions in soft tissue motion during landings in high compression garments compared to no compression. Additionally, markers placed under or over the garment demonstrate low variance in movement, and the protocol reports good reliability in marker re-application. PMID- 21549383 TI - Dipyridine modified silica--a novel multi-interaction stationary phase for high performance liquid chromatography. AB - A novel multi-interaction stationary phase based on 4,4'-dipyridine modified silica was synthesized and characterized, by infrared spectra, X-ray photoelectron spectroscopy and elemental analysis. Mechanism involved in the chromatographic separation is the multi-interaction including pi-pi, hydrophobic, hydrogen-bonding, electrostatic and anion-exchange interactions. Based on these interactions, polycyclic aromatic hydrocarbons and phenols were successfully separated respectively in reversed-phase chromatography; inorganic and organic anions were also separated individually in anion-exchange chromatography by using the same column. Furthermore, the simultaneous separation of neutral organics, inorganic and organic anions was obtained on this stationary phase with the appropriate mobile phase. Therefore, such stationary phase has the characteristics of multi-interaction mechanism and multi-modal separation, and has potential application on complex samples. PMID- 21549384 TI - SBA-15 mesoporous silica coated with macrocyclic calix[4]arene derivatives: solid extraction phases for heavy transition metal ions. AB - A layer of macrocyclic calix[4]arene derivatives has been grafted on the internal surface of the mesochannels of the ordered mesoporous SBA-15 to develop highly efficient trap for heavy transition metal (HTM) ions. To ensure the successful anchoring of calix[4]arene derivatives on the surface of SBA-15, two different types of calix[4]arene derivatives, one with one trimethoxysilane functional group and another with two trimethoxysilane functional groups have been explored. XRD, N(2) adsorption and TEM results provide strong evidence that the mesoporous structure of the supporting materials retain their long range ordering throughout the grafting process. Solid-state NMR, TG and FT-IR spectroscopy indicate that both types of calix[4]arene derivatives can be well-anchored on the surface of the wall of SBA-15. Calix[4]arene derivative with only one trimethoxysilane functional group showed high grafting efficiency compared to that with two trimethoxysilane functional groups due to the intramolecular and intermolecular polycondensation between two trimethoxysilane functional groups. The HTM ions extraction capacity in aqueous solution of macrocycle functionalized SBA-15 nanohybrides for a series of HTM ions has been studied. The obtained materials demonstrated very high HTM ions extraction capacity up to 96% for Pb(2+) in aqueous solution. PMID- 21549385 TI - Tuning the self-assembled monolayer formation on nanoparticle surfaces with different curvatures: investigations on spherical silica particles and plane crystal-shaped zirconia particles. AB - The ordering of dodecyl-chain self-assembled monolayers (SAM) on different nanoscopic surfaces was investigated by FT-IR studies. As model systems plane crystal-shaped ZrO(2) nanoparticles and spherical SiO(2) nanoparticles were examined. The type of capping agent was chosen dependent on the substrate, therefore dodecylphosphonic acid and octadecylphosphonic acid were used for ZrO(2) and dodecyltrimethoxysilane for SiO(2) samples. The plane ZrO(2) nanocrystals yielded more ordered alkyl-chain structures whereas spherical SiO(2) nanoparticles showed significantly lower alkyl-chain ordering. Submicron-sized silica spheres revealed a significantly higher alkyl chain ordering, comparable to an analogously prepared SAM on a non-curved plane oxidized Si-wafer. In the case of ZrO(2) nanocrystals an intense alkyl-chain alignment could be disturbed by decreasing the grafting density from the maximum of 2.1 molecules/nm(2) through the variation of coupling agent concentration to lower values. Furthermore, the co-adsorption of a different coupling agent, such as phenylphosphonic acid for ZrO(2) and phenyltrimethoxysilane for SiO(2), resulted in a significantly lower alkyl-chain ordering for ZrO(2) plane crystals and for large SiO(2) spherical particles at high grafting density. An increasing amount of order-disturbing molecules leads to a gradual decrease in alkyl-chain alignment on the surface of the inorganic nanoparticles. In the case of the ZrO(2) nanoparticle system it is shown via dynamic light scattering (DLS) that the mixed monolayer formation on the particle surface impacts the dispersion quality in organic solvents such as n-hexane. PMID- 21549386 TI - Zeta potential of anoxygenic phototrophic bacteria and Ca adsorption at the cell surface: possible implications for cell protection from CaCO3 precipitation in alkaline solutions. AB - Electrophoretic mobility measurements and surface adsorption of Ca on living, inactivated, and heat-killed haloalkaliphilic Rhodovulum steppense, A-20s, and halophilic Rhodovulum sp., S-17-65 anoxygenic phototrophic bacteria (APB) cell surfaces were performed to determine the degree to which these bacteria metabolically control their surface potential equilibria. Zeta potential of both species was measured as a function of pH and ionic strength, calcium and bicarbonate concentrations. For both live APB in 0.1M NaCl, the zeta potential is close to zero at pH from 2.5 to 3 and decreases to -30 to -40 mV at pH of 5-8. In alkaline solutions, there is an unusual increase of zeta potential with a maximum value of -10 to -20 mV at a pH of 9-10.5. This increase of zeta potential in alkaline solutions is reduced by the presence of NaHCO(3) (up to 10 mM) and only slightly affected by the addition of equivalent amount of Ca. At the same time, for inactivated (exposure to NaN(3), a metabolic inhibitor) and heat-killed bacteria cells, the zeta potential was found to be stable (-30 to -60 mV, depending upon the ionic strength) between pH 5 and 11 without any increase in alkaline solutions. Adsorption of Ca ions on A-20s cells surface was more significant than that on S-17-65 cells and started at more acidic pHs, consistent with zeta potential measurements in the presence of 0.001-0.01 mol/L CaCl(2). Overall, these results indicate that APB can metabolically control their surface potential to electrostatically attract nutrients at alkaline pH, while rejecting/avoiding Ca ions to prevent CaCO(3) precipitation in the vicinity of cell surface and thus, cell incrustation. PMID- 21549387 TI - Effects of nonionic micelles on the rate of alkaline hydrolysis of N-(2' methoxyphenyl)phthalimide (1): kinetic and rheometric evidence for a transition from spherical to rodlike micelles under the typical reaction conditions. AB - Pseudo-first-order rate constants (k(obs)) for alkaline hydrolysis of N-(2' methoxyphenyl)phthalimide (1) decrease nonlinearly with increasing total concentration of nonionic surfactant C(m)E(n) (i.e. [C(m)E(n)](T) where m and n represent the respective number of methyl/methylene units in the tail and polyoxyethylene units in the headgroup of a surfactant molecule and m/n=16/20, 12/23 and 18/20) at constant 2% v/v CH(3)CN and 1.0 mM NaOH. The k(obs)vs. [C(m)E(n)](T) data follow the pseudophase micellar (PM) model at <= 50 mM C(16)E(20), <= 1.4 mM C(12)E(23) and <= 2.0 mM C(18)E(20) where rate of hydrolysis of 1 in micellar pseudophase could not be detected. The values of k(obs) fail to follow the PM model at > ~50 mM C(16)E(20), > ~1.4 mM C(12)E(23) and > ~2.0 mM C(18)E(20) which has been attributed to a micellar structural transition from spherical to rodlike which in turn increases C(m)E(n) micellar binding constant (K(S)) of 1 with increasing values of [C(m)E(n)](T). Rheological measurements show the presence of spherical micelles at <= 50 mM C(16)E(20), <= 1.4 mM C(12)E(23) and <= 3.0 mM C(18)E(20). The presence of rodlike micelles is evident from rheological measurements at > ~50 mM C(16)E(20), > ~1.4 mM C(12)E(23) and > ~3.0 mM C(18)E(20). PMID- 21549388 TI - Simulating the changes in carbon structure during the burn-off process. AB - Using a simple energetic criterion, we modelled the process of activation of 'soft' activated carbons. Eighteen carbon samples, differing in degree of graphitisation, and obtained using Molecular Dynamics annealing of an amorphous carbon precursor were studied. For all samples, the geometric pore size distribution was calculated using the method proposed by Bhattacharya and Gubbins. Adsorption isotherms for Ar at 87 K were simulated and analysed using different approaches widely applied in adsorption science (alpha(s), DA, APD, ND, BET). It is shown that our approach leads to similar changes in microporosity (with the rise in carbon burn-off) to those observed in real experiments. Moreover, the conclusions about the reality of popular methods of carbon porosity characterisation are given. PMID- 21549389 TI - Fabrication of superhydrophobic polymer films with hierarchical silver microbowl array structures. AB - Flexible superhydrophobic polyvinyl alcohol (PVA) films with silver bowl-like array structure are fabricated based on the thermal evaporation with sphere monolayer as templates and the modification of 1H, 1H, 2H, 2H perfluorodecanethiol on silver surface. The silver microbowl arrays were composed of silver nanoparticles with an average diameter size of ca. 10 nm. The polymer films exhibit excellent stability and remarkable superhydrophobicity with a high water contact angle (CA) of about 163 degrees and a low sliding angle (SA) of less than 3 degrees . PMID- 21549390 TI - Curcumin-loaded biocompatible thermoresponsive polymeric nanoparticles for cancer drug delivery. AB - This study aims at the formulation of curcumin with biodegradable thermoresponsive chitosan-g-poly (N-vinylcaprolactam) nanoparticles (TRC-NPs) for cancer drug delivery. The spherical curcumin-loaded nanoparticles of size 220 nm were characterized, and the biological properties were studied using flow cytometry and cytotoxicity by MTT assay. The in vitro drug release was higher at above LCST compared to that at below LCST. TRC-NPs in the concentration range of 100-1000 MUg/mL were non-toxic to an array of cell lines. The cellular localization of the curcumin-loaded TRC-NPs was confirmed from green fluorescence inside the cells. The time-dependent curcumin uptake by the cells was quantified by UV spectrophotometer. Curcumin-loaded TRC-NPs showed specific toxicity to cancer cells at above their LCST. Flow cytometric analysis showed increased apoptosis on PC3 compared to L929 by curcumin-loaded TRC-NPs. These results indicate that novel curcumin-loaded TRC-NPs could be a promising candidate for cancer drug delivery. PMID- 21549391 TI - Study of spectral behaviour and optical properties of cis/trans-bis(N methylpyridinium-4-yl)diphenyl porphyrin adsorbed on layered silicates. AB - The spectral properties of two dicationic porphyrins, cis- and trans-bis(N methylpyridinium-4-yl)diphenyl porphyrins, upon adsorption on clay mineral templates were investigated. A series of reduced charge Nanocor montmorillonites was used as host templates. The main impact was given on the influence of the layer charge on the absorption and fluorescence spectra. Adsorption of the porphyrins led to significant changes in their spectra but preserved the photoactivity of the dyes. The changes can be attributed to two phenomena: structural changes (flattening) of the porphyrin molecules and molecular aggregation. Latter one was more influenced by the molecular structure of the dyes and influenced the properties of mainly trans-isomer. The formation of the assemblies was significantly influenced by the layer charge of montmorillonite template. This study presents the example how one is able to influence the spectral properties and possibly also the functionality of adsorbed photoactive molecules via a strategy of appropriate combination of a photoactive component with specific inorganic templates. PMID- 21549392 TI - Effects of combat deployment on risky and self-destructive behavior among active duty military personnel. AB - Although research has documented negative effects of combat deployment on mental health, few studies have examined whether deployment increases risky or self destructive behavior. The present study addressed this issue. In addition, we examined whether deployment effects on risky behavior varied depending on history of pre-deployment risky behavior, and assessed whether psychiatric conditions mediated effects of deployment on risky behavior. In an anonymous survey, active duty members of the U.S. Marine Corps and U.S. Navy (N = 2116) described their deployment experiences and their participation in risky recreational activities, unprotected sex, illegal drug use, self-injurious behavior, and suicide attempts during three time frames (civilian, military pre-deployment, and military post deployment). Respondents also reported whether they had problems with depression, anxiety, or PTSD during the same three time frames. Results revealed that risky behavior was much more common in civilian than in military life, with personnel who had not deployed, compared to those who had deployed, reporting more risky behavior and more psychiatric problems as civilians. For the current time period, in contrast, personnel who had deployed (versus never deployed) were significantly more likely to report both risky behavior and psychiatric problems. Importantly, deployment was associated with increases in risky behavior only for personnel with a pre-deployment history of engaging in risky behavior. Although psychiatric conditions were associated with higher levels of risky behavior, psychiatric problems did not mediate associations between deployment and risky behavior. Implications for understanding effects of combat deployment on active duty personnel and directions for future research are discussed. PMID- 21549393 TI - Headache among mesial temporal lobe epilepsy patients: a case-control study. AB - Epilepsy and headache are two chronic disorders that are characterized by recurrent attacks, but the relationship between them is not completely understood. Using a structured questionnaire, we investigated the prevalence of headache during the previous year in a homogeneous group of 100 patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). The control group consisted of 100 age-matched individuals who were randomized from a nationwide Brazilian headache database. There was a significantly higher prevalence of headache (92%) among the MTLE-HS patients when compared with the controls (73%; p=0.001). Chronic daily headache (CDH) was significantly associated with MTLE-HS (OR 6.1, CI 95% 1.7-22, p=0.005). We did not find any association between the diagnosis of migraine or tension-type headache and MTLE HS. This study showed that MTLE-HS increases the likelihood of a headache diagnosis. In addition, CDH was more prevalent among the MTLE-HS patients, which supports a common pathophysiological mechanism for epilepsy and headache. PMID- 21549394 TI - Dysphagia screening decreases pneumonia in acute stroke patients admitted to the stroke intensive care unit. AB - Dysphagia increases the risk of pneumonia in stroke patients. This study aimed to evaluate bedside swallowing screening for prevention of stroke-associated pneumonia (SAP) in acute stroke patients admitted to the intensive care unit (ICU). Consecutive acute stroke patients admitted to the stroke ICU from May 2006 to March 2007 were included. Patients were excluded if they were intubated on the first day of admission or had a transient ischemic attack. A 3-Step Swallowing Screen was introduced since October 2006 and therefore patients were divided into pre-screen and post-screen groups. A binary logistic regression model was used to determine independent risk factors for SAP and in-hospital death. There were 74 and 102 patients included in the pre- and post-screen groups, respectively. Pneumonia was associated with higher National Institutes of Health Stroke Scale (NIHSS) score, older age, nasogastric and endotracheal tube placement. After adjusting for age, gender, NIHSS score and nasogastric and endotracheal tube insertion, dysphagia screening was associated with a borderline decrease in SAP in all stroke patients (odds ratio, 0.42; 95% CI, 0.18-1.00; p=0.05). However, dysphagia screening was not associated with reduction of in-hospital deaths. Systematic bedside swallowing screening is helpful for prevention of SAP in acute stroke patients admitted to the ICU. PMID- 21549395 TI - Needle type and the risk of post-lumbar puncture headache in the outpatient neurology clinic. AB - OBJECTIVE: Post-lumbar puncture headaches (PLPHs) are a common complication of diagnostic lumbar punctures (LPs) caused by a persistent leak of spinal fluid from the dural puncture site. We conducted a prospective study to determine risk factors associated with PLPHs in the neurology outpatient setting. METHODS: Clinical information from all diagnostic LPs performed at the Johns Hopkins Lumbar Puncture Clinic between September 2008 and June 2009 was reviewed. As standard of care, each patient was contacted by telephone by the attending physician within 2-5 days of having an LP to ascertain health status and the presence of PLPH. We performed multiple logistic regression analysis to evaluate the association between PLPH and needle type (traditional Quincke cutting needle 20 and 22 gauge, 20Q and 22Q, and Sprotte non-traumatic gauge 22 needle, 22S) adjusting for important variables such as traumatic LPs, number of attempts, positioning and volume of CSF drawn. RESULTS: The prevalence of PLPH was 32% with the popular gauge 20Q and 22Q needles compared to 19% with the 22S non-traumatic needle. Compared to the 20Q needle, the non-traumatic 22S needle was associated with 69% decreased odds of PLPH (adjusted OR: 0.31, 95% CI 0.12-0.82). In subset analysis, the odds of PLPH increased 4-fold when the 22Q needle was used compared to the 22S needle (adjusted OR=3.99, 95% CI 1.32-12.0). CONCLUSIONS: Our outpatient findings support the American Academy of Neurology recommendations to use smaller non-traumatic needles to reduce the risk of PLPH. PMID- 21549396 TI - Modified versus conventional ultrafiltration in pediatric cardiac surgery: a meta analysis of randomized controlled trials comparing clinical outcome parameters. AB - OBJECTIVE: Although previous studies have demonstrated that modified ultrafiltration improves laboratory parameters in pediatric cardiac surgery, the clinical outcome data have been inconsistent. We performed a meta-analysis of randomized controlled trials comparing modified versus conventional ultrafiltration. METHODS: We conducted a comprehensive search of the literature to identify clinical trials that met our inclusion criteria. To be included, studies had to be prospective randomized trials that compared modified ultrafiltration and conventional ultrafiltration in pediatric cardiac surgery using cardiopulmonary bypass. We focused on the following outcome variables: hematocrit and mean arterial blood pressure after cardiopulmonary bypass, amount of chest tube drainage after surgery, time to extubation, and length of stay in the intensive care unit. The random effects model was used to determine the pooled effect estimates. The estimators of treatment effects were expressed as the weighted mean difference with 95% confidence intervals. The heterogeneity of collected data was also evaluated. RESULTS: We screened 54 studies, 8 of which satisfied our inclusion criteria. Combined analysis revealed that modified ultrafiltration resulted in significantly higher postbypass hematocrit and higher mean arterial blood pressure. Benefits in postoperative blood loss, ventilator time, and intensive care unit stay were not apparent. There was significant heterogeneity among the studies surveyed. CONCLUSIONS: The advantage of modified ultrafiltration over conventional ultrafiltration consists of significant improvement of clinical conditions in the immediate postbypass period. The postoperative outcome parameters were not significantly influenced. We should also take into account possible clinical or methodologic variations in the currently available ultrafiltration studies. PMID- 21549397 TI - Bleeding and management of coagulopathy. AB - Bleeding after cardiac surgery remains a significant problem, increasing both length of stay and mortality, and is caused by multiple factors including dilutional changes, ongoing fibrinolysis, and platelet dysfunction. The evaluation of coagulopathy is problematic because of the long turnaround time of standard coagulation tests. Algorithms involving point of care testing, including thromboelastography and thromboelastometry, have been published; all have the potential to reduce transfusion requirements. Massive transfusion coagulopathy that occurs in trauma can also be seen in complex aortic surgery and other massive bleeding patients and should prompt consideration of a transfusion protocol involving fixed ratios of fresh frozen plasma, platelets, and red blood cells. Pharmacologic agents such as antifibrinolytics are commonly administered, but a multimodal approach to management is important. Recombinant and purified coagulation products are being studied and provide clinicians specific agents to treat targeted deficiencies. A general multi-modal approach is required and recommendations are made for the management of bleeding and coagulopathy in cardiac surgical patients. PMID- 21549399 TI - Spatial patterns of chemical contamination (metals, PAHs, PCBs, PCDDs/PCDFS) in sediments of a non-industrialized but densely populated coral atoll/small island state (Bermuda). AB - There is a recognized dearth of standard environmental quality data in the wider Caribbean area, especially on coral atolls/small island states. Extensive surveys of sediment contamination (n=109 samples) in Bermuda revealed a wide spectrum of environmental quality. Zinc and especially copper levels were elevated at some locations, associated with boating (antifouling paints and boatyard discharges). Mercury contamination was surprisingly prevalent, with total levels as high as 12mg kg(-1)DW, although methyl mercury levels were quite low. PAH, PCB and PCDD/PCDF contamination was detected a several hotspots associated with road run off, a marine landfill, and a former US Naval annexe. NOAA sediment quality guidelines were exceeded at several locations, indicating biological effects are possible, or at some locations probable. Overall, and despite lack of industrialization, anthropogenic chemicals in sediments of the atoll presented a risk to benthic biodiversity at a number of hotspots suggesting a need for sediment management strategies. PMID- 21549398 TI - Endovascular repair of complicated chronic distal aortic dissections: intermediate outcomes and complications. AB - INTRODUCTION: Patients with chronic distal aortic dissection (CDAD) remain at high risk for late aorta-related events and reinterventions, and the ideal management strategy remains undefined. Open surgical procedures carry morbidity, but scant data for thoracic endovascular aortic repair (TEVAR) of CDAD exist. This study reports our intermediate-term results with TEVAR for complicated CDAD. METHODS: All cases of TEVAR for complicated (aortic growth, malperfusion, intractable pain) CDAD at our institution between 2000 and 2007 were retrospectively reviewed. Demographic information, indications for repair, complications, and aortic morphologic changes were collected from medical records and imaging studies. Aortic morphology (aneurysm size, false lumen thrombosis) was assessed at multiple levels with 3-dimensional image analysis techniques. Kaplan-Meier analysis was used to estimate survival, freedom from reintervention, and likelihood of false lumen thrombosis, with log-rank tests used to discriminate between Kaplan-Meier curves. RESULTS: In total, 144 stent-grafts were implanted in 76 consecutive patients (49 male) with complicated CDAD. Early (<30 postoperative days) mortality was 5%. There was no paraplegia, and 1 patient died of stroke. At mean follow-up of 34 months, 12 patients had died (1 aorta related death). Seventeen patients (22%) underwent 19 secondary aortic reinterventions, mainly for enlargement of the untreated aorta remote to stent graft repair. Three secondary procedures treated retrograde proximal dissections. Estimated survivals were 86%, 82%, and 80% at 12, 24, and 36 months, respectively, and freedoms from both death and reintervention were 72%, 64%, and 59% at similar time points. Of 67 patients (88%) with complete imaging follow-up, TEVAR resulted in significantly decreased aortic diameter through the stent grafted segment but not untreated segments. Complete thrombosis of the entire false lumen was uncommon in patients with extensive dissections (13% vs 78% P < .001). CONCLUSIONS: Management of complicated CDAD remains challenging for clinicians. TEVAR is a reasonable treatment modality for dissections limited to the thoracic aorta and for prevention of focal aortic growth in extensive dissections. Late complications and the need for secondary interventions emphasize the complexity of this patient population and the need for long-term follow-up. PMID- 21549400 TI - A whole life cycle assessment on effects of waterborne PBDEs on gene expression profile along the brain-pituitary-gonad axis and in the liver of zebrafish. AB - Polybrominated diphenyl ethers (PBDEs) are now found ubiquitously in the aquatic environment and biota, and there is a growing concern that PBDEs may disrupt endocrine systems, leading to reproductive impairments of aquatic animals. In our study, zebrafish (Danio rerio) were exposed to the 5 ng/L, 1 MUg/L and 50 MUg/L of DE-71 for the duration of the whole life cycle (120 days, from eggs to adults). The expression of selected genes along the brain-pituitary-gonadal (BPG) axis and liver, and the levels of plasma sex hormones were examined. In male fish, up-regulation of GnRH in brain, FSHbeta and LHbeta in pituitary, FSH receptor, LH-receptor, and CYP19a in testis was clearly evident, while down regulation of CYP11a and 3beta-HSD was found in testis. In female fish, a 2.4 fold up-regulation of 3beta-HSD was found in ovary upon exposure to 50 MUg/L of DE-71. GnRH in brain, FSHbeta and LHbeta in pituitary were also up-regulated, while ERbeta, TH and TPH in brain and GnRH-receptor in pituitary were significantly down-regulated. Hepatic ERalpha, AR and VTG in males were all down regulated, while hepatic ERalpha and AR in female were up-regulated. Serum estradiol (E2) was reduced in both male and female upon exposure to DE-71, while significant increases in serum testosterone (T) and 11-keto-testosterone (11-KT) were only found in male but not female fish. The ratio of T/E2 as well as the ratio of 11-KT/E2 in male fish increased in a dose-dependent manner upon exposure to DE-71. Our overall results showed that whole life exposure of DE-71 altered the expression of regulatory genes and receptors at all three levels of the BPG axis in zebrafish, and the responses are sex dependent. The observed disruption of GnRH and GtHs can be further related to the subsequent disruption in both levels and balance sex steroid hormones. PMID- 21549401 TI - Reiterative and interruptive signaling in induced plant resistance to chewing insects. AB - Our understanding of induced resistance against herbivores has grown immeasurably during the last several decades. Based upon the emerging literature, we argue that induced resistance represents a continuum of phenotypes that is determined by the plant's ability to integrate multiple suites of signals of plant and herbivore origin. We present a model that illustrates the range of signals arising from early detection through herbivore feeding, and then through subsequent plant generations. PMID- 21549402 TI - Malaria control in a forest fringe area of Assam, India: a pilot study. AB - A study was conducted to evaluate the preventive efficacy of insecticide-treated mosquito nets (ITMNs) and mosquito repellent (MR) in a malaria-endemic foothill area of Assam, India, with forest ecosystem. During the first year, a survey was conducted in four demarcated sectors (A-D) to observe the malaria endemicity and vector prevalence patterns before implementing intervention measures. All four sectors were endemic for malaria. The prevalence of established malaria vectors such as Anopheles dirus, A. minimus and A. philippinensis was observed. During the second year, intervention measures were implemented in the four sectors as follows: A, ITMN + MR; B, ITMN; C, MR; D, no intervention. The most effective intervention was in sector A, followed by sectors B and C. Sectors A and B exhibited significantly higher (P < 0.001) malaria protective efficacy during both the first and second years of intervention compared with sector D. The total vector population in the three intervention sectors decreased significantly compared with that of the non-intervention one. Information-education communication activities motivated the residents to participate actively in the intervention programme. The finding could be an effective model for containment of high malaria morbidity in inaccessible forest fringe areas of the northeastern region of India. PMID- 21549403 TI - Laparoscopic surgery for chronic groin pain in athletes is more effective than nonoperative treatment: a randomized clinical trial with magnetic resonance imaging of 60 patients with sportsman's hernia (athletic pubalgia). AB - BACKGROUND: Chronic groin pain in athletes presents often a diagnostic and therapeutic challenge. Sportsman's hernia (also called "athletic pubalgia") is a deficiency of the posterior wall of the inguinal canal, which is often repaired by laparoscopic mesh placement. Endoscopic mesh repair may offer a faster recovery for athletes with sportsman's hernia than nonoperative therapy. METHODS: A randomized, prospective study was conducted on 60 patients with a diagnosis of chronic groin pain and suspected sportsman's hernia. Clinical data and MRI were collected on all patients. After 3 to 6 months of groin symptoms, the patients were randomized into an operative or a physiotherapy group (n = 30 patients in each group). Operation was performed using a totally extraperitoneal repair in which mesh was placed behind the symphysis and painful groin area. Conservative treatment included at least 2 months of active physiotherapy, including corticosteroid injections and oral anti-inflammatory analgesics. The outcome measures were pre- and postoperative pain using a visual analogue scale and partial or full recovery to sports activity at 1, 3, 6, and 12 months after randomization. RESULTS: The athletes in both treatment groups had similar characteristics and pain scores. Operative repair was more effective than nonoperative treatment to decrease chronic groin pain after 1 month and up to 12 months of follow-up (P < .001). Of the 30 athletes who underwent operation, 27 (90%) returned to sports activities after 3 months of convalescence compared to 8 (27%) of the 30 athletes in the nonoperative group (P < .0001). Of the 30 athletes in the conservatively treated group, 7 (23 %) underwent operation later because of persistent groin pain. CONCLUSION: This randomized controlled study indicated that the endoscopic placement of retropubic mesh was more efficient than conservative therapy for the treatment of sportsman's hernia (athletic pubalgia). PMID- 21549404 TI - Relationship between mucosa-associated microbiota and inflammatory parameters in the ileal pouch after restorative proctocolectomy for ulcerative colitis. AB - BACKGROUND: Our aim was to assess the relationship between the ileal-pouch microbiota and inflammatory parameters in patients operated on for ulcerative colitis. METHODS: In this cross-sectional study, 32 consecutive outpatients returning for follow-up endoscopy were recruited. Pouch biopsies were obtained during endoscopy for culture of bacteria adherent to the mucosa, histology, and analysis of local inflammation (IL-1beta, IL-6, and TNFalpha by immunometric assay; and toll-like receptor [TLR] 2 and 4 mRNA by quantitative real-time PCR). Fecal samples were collected for analysis of lactoferrin by ELISA. RESULTS: Granulocyte and monocyte mucosal infiltration correlated directly with mucosal Bacteriodiaceae spp. counts. Clostridiaceae spp. counts showed a direct correlation with mucosal ulceration and number of daily stools. In patients with pouchitis, Enterococcaceae spp. counts were less than in healthy patients. Enterobacteriaceae spp., Streptococcaceae spp. and Enterococcaceae spp. counts correlated inversely with immune cell infiltration. TLR-2 and TLR-4 mRNA, and mucosal levels of IL-1beta levels all correlated directly with Veilonella spp. counts. CONCLUSION: Bacteriodaceae spp. and, Clostridiaceae spp. may be associated with inflammation of the pouch mucosa. Conversely, Enterococcaceae spp., and possibly Enterobacteriaceae spp. and Streptococcaceae spp., may have an active role in maintaining immunologic homeostasis within the pouch mucosa. PMID- 21549405 TI - Traumatic abdominal wall hernia after blunt abdominal trauma caused by a handlebar in children: a well-visualized case report. PMID- 21549406 TI - PDZD8 is a novel moesin-interacting cytoskeletal regulatory protein that suppresses infection by herpes simplex virus type 1. AB - The host cytoskeleton plays a central role in the life cycle of many viruses yet our knowledge of cytoskeletal regulators and their role in viral infection remains limited. Recently, moesin and ezrin, two members of the ERM (Ezrin/Radixin/Moesin) family of proteins that regulate actin and plasma membrane cross-linking and microtubule (MT) stability, have been shown to inhibit retroviral infection. To further understand how ERM proteins function and whether they also influence infection by other viruses, we identified PDZD8 as a novel moesin-interacting protein. PDZD8 is a poorly understood protein whose function is unknown. Exogenous expression of either moesin or PDZD8 reduced the levels of stable MTs, suggesting that these proteins functioned as part of a cytoskeletal regulatory complex. Additionally, exogenous expression or siRNA-mediated knockdown of either factor affected Herpes Simplex Virus type 1 (HSV-1) infection, identifying a cellular function for PDZD8 and novel antiviral properties for these two cytoskeletal regulatory proteins. PMID- 21549407 TI - Cytotoxicity estimation of ionic liquids based on their effective structural features. AB - Cytotoxicity of a diverse set of 227 ionic liquids (taken from UFT/Merck Ionic Liquids Biological Effects Database) containing 94 imidazolium, 53 pyridinium, 23 pyrrolidinium, 22 ammonium, 15 piperidinium, 10 morpholinium, 5 phosphanium, and 5 quinolinium cations in combination with 25 different types of anions to Leukemia Rat Cell Line (IPC-81) was estimated from their structural parameters using quantitative structure - toxicity relationship "QSTR" methodology. Linear and nonlinear models were developed using genetic algorithm (GA), multiple linear regressions (MLR) and multilayer perceptron neural network (MLP NN) approaches. Robustness and reliability of the constructed models were evaluated through internal and external validation methods. Furthermore, chemical applicability domain was determined via leverage approach. In this work, it was revealed that the cationic moieties make the major contribution to cytotoxicity and the anionic parts play a secondary role in cytotoxicity of the ionic liquids studied here. Structural information represented in this work, can be used for a rational design of safer ILs. PMID- 21549408 TI - Theoretical study on hydrophilicity and thermodynamic properties of polyfluorinated dibenzofurans. AB - Logarithm values of octanol-water partition coefficients (logK(ow)) of polyfluorinated dibenzofurans (PFDFs) were calculated based on group contributions, and their thermodynamic properties in the ideal gas state at 298.15 K and 1.013 * 10(5) Pa were calculated using a combination of quantum mechanical computations performed with the Gaussian 03 program at the B3LYP/6 311G(*) level. The isodesmic reactions were designed to calculate standard enthalpy of formation (DeltaH(f)(theta)) and standard free energy of formation (DeltaG(f)(theta)) of PFDF congeners. By establishing relationships between these properties (including logK(ow), standard state entropy S(theta), DeltaH(f)(theta),DeltaG(f)(theta)) and the number and position of fluorine atom substituents (N(PFS)), it was found that the fluorine substitution pattern strongly influences all of these properties of the compounds. The relation curve of logK(ow) values varying with the fluorine substitution pattern presented a three-level sawtooth shape. Intramolecular repulsive forces exist between an oxygen-adjacent fluorine atom on phenyl ring and the oxygen of dibenzofuran, between ortho-substituted fluorine atoms on a phenyl ring, and between two adjacent fluorine atoms on different phenyl rings. Their repulsion energies were ascertained by comparing DeltaG(f)(theta) values to be approximately 14 kJ mol( 1)-17 kJ mol(-1), 18 kJ mol(-1)-22 kJ mol(-1) and 7 kJ mol(-1)-9 kJ mol(-1), respectively. According to the relative magnitude of their DeltaG(f)(theta), the relative stability order of PFDF congeners was theoretically proposed. PMID- 21549409 TI - Pollutants and the health of green sea turtles resident to an urbanized estuary in San Diego, CA. AB - Rapid expansion of coastal anthropogenic development means that critical foraging and developmental habitats often occur near highly polluted and urbanized environments. Although coastal contamination is widespread, the impact this has on long-lived vertebrates like the green turtle (Chelonia mydas) is unclear because traditional experimental methods cannot be applied. We coupled minimally invasive sampling techniques with health assessments to quantify contaminant patterns in a population of green turtles resident to San Diego Bay, CA, a highly urbanized and contaminated estuary. Several chemicals were correlated with turtle size, suggesting possible differences in physiological processes or habitat utilization between life stages. With the exception of mercury, higher concentrations of carapace metals as well as 4,4' dichlorodiphenyldichloroethylene (DDE) and gamma chlordane in blood plasma relative to other sea turtle studies raises important questions about the chemical risks to turtles resident to San Diego Bay. Mercury concentrations exceeded immune function no-effects thresholds and increased carapace metal loads were correlated with higher levels of multiple health markers. These results indicate immunological and physiological effects studies are needed in this population. Our results give insight into the potential conservation risk contaminants pose to sea turtles inhabiting this contaminated coastal habitat, and highlight the need to better manage and mitigate contaminant exposure in San Diego Bay. PMID- 21549410 TI - Removal processes for arsenic in constructed wetlands. AB - Arsenic pollution in aquatic environments is a worldwide concern due to its toxicity and chronic effects on human health. This concern has generated increasing interest in the use of different treatment technologies to remove arsenic from contaminated water. Constructed wetlands are a cost-effective natural system successfully used for removing various pollutants, and they have shown capability for removing arsenic. This paper reviews current understanding of the removal processes for arsenic, discusses implications for treatment wetlands, and identifies critical knowledge gaps and areas worthy of future research. The reactivity of arsenic means that different arsenic species may be found in wetlands, influenced by vegetation, supporting medium and microorganisms. Despite the fact that sorption, precipitation and coprecipitation are the principal processes responsible for the removal of arsenic, bacteria can mediate these processes and can play a significant role under favourable environmental conditions. The most important factors affecting the speciation of arsenic are pH, alkalinity, temperature, dissolved oxygen, the presence of other chemical species--iron, sulphur, phosphate--,a source of carbon, and the wetland substrate. Studies of the microbial communities and the speciation of arsenic in the solid phase using advanced techniques could provide further insights on the removal of arsenic. Limited data and understanding of the interaction of the different processes involved in the removal of arsenic explain the rudimentary guidelines available for the design of wetlands systems. PMID- 21549411 TI - Energy efficiency in Spanish wastewater treatment plants: a non-radial DEA approach. AB - Wastewater treatment plants (WWTPs) are energy-intensive facilities. Thus, reducing their carbon footprint is particularly important, both economically and environmentally. Knowing the real operating energy efficiency of WWTPs is the starting point for any energy-saving initiative. In this article, we applied a non-radial Data Envelopment Analysis (DEA) methodology to calculate energy efficiency indices for sampling of WWTPs located in Spain. In a second stage analysis, we examined the operating variables contributing to differences in energy efficiency among plants. It is verified that energy efficiencies of the analyzed WWTPs were quite low, with only 10% of them being efficient. We found that plant size, quantity of organic matter removed, and type of bioreactor aeration were significant variables in explaining energy efficiency differences. In contrast, age of the plant was not a determining factor in energy consumption. Lastly, we quantified the potential savings, both in economic terms and in terms of CO(2) emissions, that could be expected from an improvement in energy efficiency of WWTPs. PMID- 21549412 TI - Effects of exposure to halogenated organic compounds combined with dietary restrictions on the antioxidant defense system in herring gull chicks. AB - The Herring gull (HG) (Larus argentatus) is naturally exposed to halogenated organic compounds such as polychlorinated biphenyls (PCBs) through its diet. During periods of food scarcity, arctic seabirds experience lipid mobilization, allowing stored lipid soluble contaminants to re-enter the body circulation. In the present study, we investigated the effects of PCB exposure and fasting on the antioxidant defense system in HG chicks. Forty newly hatched chicks were exposed to contaminated cod liver oil for 6weeks and then fasted for 1week. We assessed the hepatic total oxyradical scavenging capacity (TOSC) against peroxynitrite, hydroxyl and peroxyl radicals, and measured glutathione (reduced: GSH, and oxidized: GSSG) levels and the enzymatic activities of catalase, glutathione peroxidase, glutathione reductase and superoxide dismutase. The results show that fasting significantly increased the HOC levels in the HG chick livers. Limited effects were observed on antioxidant responses; significant effects were only found for catalase (CAT) activity, Se-dependent GPX activity and the GSH/GSSG ratio in the exposed and fasted group. CAT and Se-dependent GPX activities correlated negatively with the PCB concentrations within this group, and a nonlinear relationship between glutathione and contaminant levels was also found. These effects were generally not observed after exposure or fasting alone and were likely related to the high PCB levels induced by the combination of exposure and fasting. PMID- 21549413 TI - Development of emission factors and emission inventories for motorcycles and light duty vehicles in the urban region in Vietnam. AB - This paper reports on a 2-year emissions monitoring program launched by the Centre for Environmental Monitoring of the Vietnam Environment Administration which aimed at determining emission factors and emission inventories for two typical types of vehicle in Hanoi, Vietnam. The program involves four major activities. A database for motorcycles and light duty vehicles (LDV) in Hanoi was first compiled through a questionnaire survey. Then, two typical driving cycles were developed for the first time for motorcycles and LDVs in Hanoi. Based on this database and the developed driving cycles for Hanoi, a sample of 12 representative test vehicles were selected to determine vehicle specific fuel consumption and emission factors (CO, HC, NOx and CO(2)). This set of emission factors were developed for the first time in Hanoi with due considerations of local driving characteristics. In particular, it was found that the emission factors derived from Economic Commission for Europe (ECE) driving cycles and adopted in some previous studies were generally overestimated. Eventually, emission inventories for motorcycles and LDVs were derived by combining the vehicle population data, the developed vehicle specific emission factors and vehicle kilometre travelled (VKT) information from the survey. The inventory suggested that motorcycles contributed most to CO, HC and NOx emissions while LDVs appeared to be more fuel consuming. PMID- 21549414 TI - Prognostic significance of STAT3 expression and its correlation with chemoresistance of non-small cell lung cancer cells. AB - Activation of signal transducer and activator of transcription 3 (STAT3) plays important roles in tumorigenesis and tumor development. Previously, we have reported that overexpression of STAT3 potentiates growth, survival and radioresistance of non-small cell lung cancer (NSCLC) cells. The aim of this study was to investigate the prognostic significance of STAT3 expression and its correlation with chemoresistance of NSCLC cells. Semi-quantitative RT-PCR was performed to detect the expression of STAT3 mRNA in 12 NSCLC and corresponding adjacent lung tissues. Immunohistochemistry was performed to detect the expression of STAT3 protein in 76 NSCLC tissue samples. Additionally, the correlation between STAT3 expression and prognosis of NSCLC patients was statistically analyzed. The role of STAT3 in chemoresistance of NSCLC cells was also assessed by the vector-based small interfering RNA. The expression level of STAT3 mRNA in NSCLC tissues was significantly higher than that in corresponding adjacent lung tissues (P<0.05). Positive immunostaining of STAT3 protein was mainly located in the cytoplasm of tumor cells. The expression of STAT3 protein was significantly correlated with tumor differentiation, clinical stage and lymph node metastasis of NSCLC patients. Moreover, the 5-year overall survival rate of patients with high STAT3 expression (42.3%) was significantly lower than that of patients with low STAT3 expression (58.8%; P<0.001). Multivariate analysis using the Cox proportional hazard model showed that high STAT3 protein expression was an independent prognostic factor for NSCLC patients (P=0.021). Furthermore, two stably transfected cell lines (A549/shSTAT3 and SPC-A1/shSTAT3) were successfully established, and RNAi-mediated STAT3 inhibition could significantly increase the sensitivity of NSCLC cells to cisplatin by enhancing caspase-3-dependent apoptosis. Together, the expression of STAT3 might be an independent prognostic marker for NSCLC patients and RNAi-mediated STAT3 inhibition would be a potential strategy for chemosensitization of NSCLC cells. PMID- 21549415 TI - A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. AB - We report the immediate effects of estrogen signaling on the transcriptome of breast cancer cells using global run-on and sequencing (GRO-seq). The data were analyzed using a new bioinformatic approach that allowed us to identify transcripts directly from the GRO-seq data. We found that estrogen signaling directly regulates a strikingly large fraction of the transcriptome in a rapid, robust, and unexpectedly transient manner. In addition to protein-coding genes, estrogen regulates the distribution and activity of all three RNA polymerases and virtually every class of noncoding RNA that has been described to date. We also identified a large number of previously undetected estrogen-regulated intergenic transcripts, many of which are found proximal to estrogen receptor binding sites. Collectively, our results provide the most comprehensive measurement of the primary and immediate estrogen effects to date and a resource for understanding rapid signal-dependent transcription in other systems. PMID- 21549416 TI - Injuries after Hurricane Katrina among Gulf Coast Evacuees sheltered in Houston, Texas. AB - INTRODUCTION: After Hurricane Katrina and a decline in the living conditions at a major temporary shelter in New Orleans, Louisiana, residents were offered transport to a Mega-Shelter in Houston, Texas. Approximately 200,000 Gulf Coast residents were transported to Houston's Astrodome/Reliant Center Complex for appropriate triage and transfer to other shelter facilities. The Katrina Clinic was quickly organized to treat evacuees with acute injuries and illnesses as well as chronic medical conditions. Clinic physicians documented 1130 hurricane related injuries during Katrina Clinic's operational interval, September 1-22, 2005. METHODS: This article documents the nature, extent, and location of injuries treated at that clinic. We compare the frequency of injury among Katrina evacuees who visited the clinic to that of injuries among clinic outpatient records recorded in a nationally representative database. Using the Barell Matrix system and codes from the International Classification of Diseases, Ninth Revision, we classify Katrina injuries by body region and nature of injury; we also document the large number of hurricane-related immunizations distributed at the temporary outpatient clinic. RESULTS: The results show a 42% higher injury proportion among Katrina evacuees and that approximately half of all of the evacuees required immunizations. Lower leg extremity injuries were among the most frequent injuries. DISCUSSION: Future planning for hurricanes should take into account nonfatal injuries requiring medical treatment and other supportive care. PMID- 21549417 TI - Situation, background, assessment, and recommendation (SBAR) may benefit individuals who frequent emergency departments: adults with sickle cell disease. PMID- 21549418 TI - Under-triage as a significant factor affecting transfer time between the emergency department and the intensive care unit. AB - INTRODUCTION: The purpose of the study was to identify factors that affect transfer times between the emergency department and the intensive care unit (ICU) in a community hospital. Patients who are transferred from the emergency department to the ICU are usually in critical condition and in need of prompt treatment by qualified personnel. As a result of delayed transfers, a patient may experience complications, such as increased mortality rates and longer hospital stays. METHODS: A quantitative descriptive correlational design was used in this study. Data were collected from the charts of 75 patients who were transferred from the emergency department to the ICU of a 142-bed community hospital in the eastern United States. "Delayed patients" were identified as those who were transferred after more than 4 hours. RESULTS: Forty-four patients (58.7%) spent more than 4 hours in the emergency department. Nineteen out of 25 patients (76%) with an Emergency Severity Index designation of 3 were identified as delayed. Delayed status and an Emergency Severity Index designation of 3 showed a significant correlation (r = -.339, P = .004). Eleven patients (64.7%) diagnosed with sepsis were delayed, compared with 6 who were not delayed. A total of 70.4% of female patients were delayed, compared with 52.1% of male patients. DISCUSSION: This study provides a more comprehensive view of the factors involved in delayed patient transfer and provides data needed for effective interventions to be developed. The results suggest significant problems with the under-triage of critically ill patients, specifically patients with sepsis. Future research should include a larger group of subjects and a multifactorial analysis. PMID- 21549419 TI - Pulp response after application of two resin modified glass ionomer cements (RMGICs) in deep cavities of prepared human teeth. AB - OBJECTIVES: This study evaluated the human pulp response to the application of two RMGICs in deep cavities in vivo. METHODS: The cavity floor prepared on the buccal surface of 34 premolars was lined with VBP (VBP), Vitrebond (VB) or Dycal(r) (DY), and restored with composite resin. Additional teeth were used as an intact control group. After 7 or 30-60 days, the teeth were extracted and processed for histological evaluation. The following histological events were scored: inflammatory response, tissue disorganization, reactionary dentin formation and presence of bacteria. RESULTS: At 7 days, VBP and VB elicited a mild inflammatory pulpal response in about 70% of specimens and in 1 specimen for DY. Only 1 specimen of each RMGICs exhibited moderate tissue disorganization. Bacteria and reactionary dentin formation were not found. At 30-60 days, about 20% of specimens lined with RMGICs showed a persistent mild inflammatory pulp response while no inflammatory reaction was observed for DY. Moderate tissue disorganization occurred with both materials. Bacteria were found only in 1 VBP specimen. The mean remaining dentin thickness (RDT) in specimens lined with VBP, VB or DY ranged from 342.3 to 436.1MUm, and no statistically significant differences in RDT were found among materials or periods (two-way ANOVA, p>0.05). Comparison of the two RMGICs tested for the histological events at each period showed statistically similar results (Kruskal-Wallis, p>0.05). SIGNIFICANCE: The use of the new Vitrebond formulation (VBP) in deep cavities in vivo caused mild initial pulp damage, which decreased with time, indicating acceptable biocompatibility. PMID- 21549420 TI - Pakistan prepares to abolish Ministry of Health. PMID- 21549422 TI - Quantum dot labeling using positive charged peptides in human hematopoetic and mesenchymal stem cells. AB - Quantum dots (QDs), as new and promising fluorescent probes, hold great potential in long term non-invasive bio-imaging, however there are many uncovered issues regarding their competency. In the present study, different QDs (525, 585 and 800 nm) were used to label CD133, CD34, CD14 and mesenchymal stem cells (MSCs) using positively charged peptides. Results demonstrated highly efficient internalization with the possible involvement of macropinocytosis. As indicated by LDH release and the TUNEL assay, no measurable effects on cell viability were detected at a concentration of 10 nM. QDs did not have any deleterious effects on normal cell functionality where both labeled CD133(+) cells and MSCs remarkably differentiated along multiple lineages with the use of the colony forming assay and adipo/osteo induction, respectively. Our results regarding QD maintenance revealed that these nano-particles are not properly stable and various excretion times have been observed depending on particle size and cell type. In vitro co culture system and transplantation of labeled cells to an animal model showed that QDs leaked out from labeled cells and the released nano-particles were able to re-enter adjacent cells over time. These data suggest that before any utilization of QDs in bio-imaging and related applications, an efficient intra cellular delivery technique should be considered to preserve QDs for a prolonged time as well as eliminating their leakage. PMID- 21549421 TI - Hybrid hydrogels self-assembled from graft copolymers containing complementary beta-sheets as hydroxyapatite nucleation scaffolds. AB - A biomimetic material that can assist bone tissue regeneration was proposed. A bone scaffold based on a hybrid hydrogel self-assembled from N-(2 hydroxypropyl)methacrylamide (HPMA) copolymers grafted with complementary beta sheet peptides was designed. Investigation of self-assembly by circular dichroism spectroscopy suggested that hydrogel formation was triggered through association of the complementary beta-sheet motifs. Congo Red and thioflavin T binding, as well as transmission electron microscopy confirmed the formation of a fibril network. Besides mimicking the natural bone extracellular matrix and maintaining preosteoblast cells viability, this hydrogel, as shown by scanning electron microscopy and Fourier transform infrared spectroscopy, provided surfaces characterized by epitaxy that favored hydroxyapatite-like crystal nucleation and growth potentially beneficial for biointegration. PMID- 21549423 TI - Surface-engineered quantum dots for the labeling of hydrophobic microdomains in bacterial biofilms. AB - Quantum dots (QDs) nanoprobes are emerging as alternatives to small-molecule fluorescent probes in biomedical technology. This paper reports an efficient and rapid method of producing highly dispersed and stable CdSe-core QDs with a hydrophobic gradient. Amphiphilic core/shell CdSe/ZnS QDs were prepared by ligand exchange at the surface of lipophilic CdSe/ZnS QDs using the dihydrolipoic acid (DHLA) dithiol ligand linked to leucine or phenylalanine amino acids. Contact angle relaxations on a hydrophobic surface and surface tension measurements indicated that aqueous dispersions of CdSe/ZnS@DHLA-Leu or CdSe/ZnS@DHLA-Phe QDs exhibit increased hydrophobicity compared to CdSe-core QDs capped by the hydrophilic 3-mercaptopropionic acid (MPA) ligand. We found that the surface functional groups and the ligand density at the periphery of these QDs significantly dictated their interactions with a complex biological matrix called biofilm. Using fluorescence confocal microscopy and an autocorrelation function (semi-variogram), we demonstrated that MPA-capped QDs were homogeneously associated to the biopolymers, while amphiphilic CdSe/ZnS@DHLA-Leu or CdSe/ZnS@DHLA-Phe QDs were specifically confined allowing identification of hydrophobic microdomains of the biofilms. Results obtained clearly point out that the final destination of QDs in biofilms can properly be controlled by an appropriate design of surface ligands. PMID- 21549424 TI - Designing a binding interface for control of cancer cell adhesion via 3D topography and metabolic oligosaccharide engineering. AB - This study combines metabolic oligosaccharide engineering (MOE), a technology where the glycocalyx of living cells is endowed with chemical features not normally found in sugars, with custom-designed three-dimensional biomaterial substrates to enhance the adhesion of cancer cells and control their morphology and gene expression. Specifically, Ac(5)ManNTGc, a thiol-bearing analog of N acetyl-d-mannosamine (ManNAc) was used to introduce thiolated sialic acids into the glycocalyx of human Jurkat T-lymphoma derived cells. In parallel 2D films and 3D electrospun nanofibrous scaffolds were prepared from polyethersulfone (PES) and (as controls) left unmodified or aminated. Alternately, the materials were malemided or gold-coated to provide bio-orthogonal binding partners for the thiol groups newly expressed on the cell surface. Cell attachment was modulated by both the topography of the substrate surface and by the chemical compatibility of the binding interface between the cell and the substrate; a substantial increase in binding for normally non-adhesive Jurkat line for 3D scaffold compared to 2D surfaces with an added degree of adhesion resulting from chemoselective binding to malemidede-derivatived or gold-coated surfaces. In addition, the morphology of the cells attached to the 3D scaffolds via MOE-mediated adhesion was dramatically altered and the expression of genes involved in cell adhesion changed in a time dependent manner. This study showed that cell adhesion could be enhanced, gene expression modulated, and cell fate controlled by introducing the 3D topograhical cues into the growth substrate and by creating a glycoengineered binding interface where the chemistry of both the cell surface and biomaterials scaffold was controlled to facilitate a new mode of carbohydrate-mediated adhesion. PMID- 21549425 TI - Effects of freezing-induced cell-fluid-matrix interactions on the cells and extracellular matrix of engineered tissues. AB - The two most significant challenges for successful cryopreservation of engineered tissues (ETs) are preserving tissue functionality and controlling highly tissue type dependent preservation outcomes. In order to address these challenges, freezing-induced cell-fluid-matrix interactions should be understood, which determine the post-thaw cell viability and extracellular matrix (ECM) microstructure. However, the current understanding of this tissue-level biophysical interaction is still limited. In this study, freezing-induced cell fluid-matrix interactions and their impact on the cells and ECM microstructure of ETs were investigated using dermal equivalents as a model ET. The dermal equivalents were constructed by seeding human dermal fibroblasts in type I collagen matrices with varying cell seeding density and collagen concentration. While these dermal equivalents underwent an identical freeze/thaw condition, their spatiotemporal deformation during freezing, post-thaw ECM microstructure, and cellular level cryoresponse were characterized. The results showed that the extent and characteristics of freezing-induced deformation were significantly different among the experimental groups, and the ETs with denser ECM microstructure experienced a larger deformation. The magnitude of the deformation was well correlated to the post-thaw ECM structure, suggesting that the freezing induced deformation is a good indicator of post-thaw ECM structure. A significant difference in the extent of cellular injury was also noted among the experimental groups, and it depended on the extent of freezing-induced deformation of the ETs and the initial cytoskeleton organization. These results suggest that the cells have been subjected to mechanical insult due to the freezing-induced deformation as well as thermal insult. These findings provide insight on tissue-type dependent cryopreservation outcomes, and can help to design and modify cryopreservation protocols for new types of tissues from a pre-developed cryopreservation protocol. PMID- 21549426 TI - Microstructured templates for directed growth and vascularization of soft tissue in vivo. AB - Tissue templates for reconstruction and regeneration in vivo have achieved clinical successes for homogeneous tissues in well vascularized regions. Outstanding challenges exist for applications in poorly vascularized regions and for spatially differentiated tissues. Here, we present a strategy to control the spatial patterns of cell and vascular ingrowth throughout the volume of a bioremodelable and resorbable matrix via well-defined micropores and networks of microchannels. Our presentation of this approach includes: a description of a lithographic technique to form deterministic microstructures within a matrix of native collagen; elucidation of multistep process by which microstructures drive rapid invasion and vascularization; and demonstration of long range guidance of invasion through the full thickness of patterned templates. Experiments were performed in a murine wound model. These microstructured tissue templates (MTTs) could improve outcomes in reconstructive surgery and open paths to directed regeneration of spatially heterogeneous tissues or organs. PMID- 21549427 TI - Differential roles of calcitonin family peptides in the dendrite formation and spinogenesis of the cerebral cortex in vitro. AB - We examined roles of calcitonin family peptides in the initial stages of dendrite formation and the maturation of dendritic spines in the rat cerebral cortex in vitro. Embryonic day 18 cortical neurons were dissociated and cultured for 2 3days in the presence of calcitonin gene-related peptide (CGRP), calcitonin, amylin or adrenomedullin. The treatment of cortical neurons with CGRP promoted the formation of primary dendrites of non-GABAergic neurons. In contrast, the treatment with amylin and adrenomedullin for 3days inhibited the dendritic elongation of non-GABAergic neurons. Calcitonin had no effect on the initial dendrite formation. Next, we examined roles of the peptides in the spine formation. Embryonic day 16 cortical neurons were cultured for 14days and then treated acutely with CGRP, amylin or adrenomedullin for 24h. The density of filopodia, puncta/stubby spines and spines were increased by the CGRP treatment, whereas decreased by amylin. Therefore, CGRP and amylin showed opposite effects on the formation of dendritic filopodia, puncta and spines. Adrenomedullin had no effects on the spine formation. In conclusion, the present study showed that calcitonin family peptides have differential effects both in the dendrite formation during the initial stages and the spine formation of cortical neurons in vitro. PMID- 21549428 TI - Effect of lifetime low dose exposure to heavy metals on selected serum proteins of Wistar rats during three subsequent generations. AB - The aim of the study was to assess the effects of exposure to low doses of lead, cadmium and mercury dissolved in drinking water (at a concentration 200-fold of maximum allowable concentration) on selected serum proteins of 120 Wistar rats during three subsequent generations. Animals were divided into four groups in all observed generation-control (C) and three experimental groups exposed to low doses of heavy metals (lead acetate in concentration 100 MUM; mercuric chloride in 1 MUM; cadmium chloride in 20 MUM of drinking water). We studied the biochemical parameters as well as total protein, albumin, transferrin and ferritin in the serum. Exposure to lead and mercury shortened life span, decreased body weight of the animals in each generation whereas cadmium had no such effect. Total protein increased after exposure to lead and mercury (P<0.001), albumin increased after exposure to lead and mercury in 1st filial and 2nd filial generation (P<0.05) and insignificantly decreased after exposure to cadmium in parental and 1st filial generation. Transferrin and ferritin increased in all exposed groups and generations (P<0.05). Transferrin and ferritin are good markers for intoxication of rats with heavy metals. For the results evaluation, not only data at the end of experiment should be taken into account, but entire duration of trials (i.e., more time steps), which makes results more objective. PMID- 21549429 TI - Inhibiting the C5-C5a receptor axis. AB - Activation of the complement system is a major pathogenic event that drives various inflammatory responses in numerous diseases. All pathways of complement activation lead to cleavage of the C5 molecule generating the anaphylatoxin C5a and, C5b that subsequently forms the terminal complement complex (C5b-9). C5a exerts a predominant pro-inflammatory activity through interactions with the classical G-protein coupled receptor C5aR (CD88) as well as with the non-G protein coupled receptor C5L2 (GPR77), expressed on various immune and non-immune cells. C5b-9 causes cytolysis through the formation of the membrane attack complex (MAC), and sub-lytic MAC and soluble C5b-9 also possess a multitude of non-cytolytic immune functions. These two complement effectors, C5a and C5b-9, generated from C5 cleavage, are key components of the complement system responsible for propagating and/or initiating pathology in different diseases, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia reperfusion injuries and neurodegenerative diseases. Thus, the C5-C5a receptor axis represents an attractive target for drug development. This review provides a comprehensive analysis of different methods of inhibiting the generation of C5a and C5b-9 as well as the signalling cascade of C5a via its receptors. These include the inhibition of C5 cleavage through targeting of C5 convertases or via the C5 molecule itself, as well as blocking the activity of C5a by neutralizing antibodies and pharmacological inhibitors, or by targeting C5a receptors per se. Examples of drugs and naturally occurring compounds used are discussed in relation to disease models and clinical trials. To date, only one such compound has thus far made it to clinical medicine: the anti-C5 antibody eculizumab, for treating paroxysmal nocturnal hemoglobinuria. However, a number of drug candidates are rapidly emerging that are currently in early-phase clinical trials. The C5-C5a axis as a target for drug development is highly promising for the treatment of currently intractable major human diseases. PMID- 21549430 TI - Rapid diagnosis of tuberculous peritonitis by T cell-based assays on peripheral blood and peritoneal fluid mononuclear cells. AB - OBJECTIVES: The utility of a newly-developed Mycobacterium tuberculosis-specific enzyme-linked immunosorbent spot (ELISPOT) assay for diagnosis of tuberculous peritonitis (TBP) has not been fully assessed. METHODS: All patients with suspected TBP in a tertiary care hospital in an intermediate TB burden country were prospectively enrolled over a 30-month period. ELISPOT assays were performed on peripheral mononuclear cells (PBMC) and mononuclear cells from peritoneal fluid (PF-MC). RESULTS: Sixty-four patients with suspected TBP were enrolled. Of these, 30 (47%) were classified as having TBP (27 confirmed and 3 probable cases), and 25 (39%) were classified as not having active tuberculosis. The remaining 9 (14%) with possible TBP were excluded from the final analysis. Five (8%) of the total 64 patients gave indeterminate PBMC ELISPOT results and 7 (18%) of 39 patients who underwent PF-MC ELISPOT assay revealed indeterminate PF-MC ELISPOT results. The sensitivity and specificity, respectively, of the tested methods for diagnosing TBP were as follows: PBMC ELISPOT (>= 6 spots), 86% and 67%; PF-MC ELISPOT (>= 14 spots), 92% and 86%; PF-MC ELISPOT/PBMC ELISPOT ratio (>= 2), 75% and 93%; and PF ADA levels (>= 38 IU/L), 95% and 100%. The areas under the receiver operating characteristics curves were as follows: PF-MC ELISPOT, 0.96; PF ADA, 0.96; PBMC ELISPOT, 0.88; and PF-MC ELISPOT/PBMC ELISPOT ratio, 0.87, respectively. CONCLUSIONS: Although the ELISPOT assay does not outperform PF ADA, the ELISPOT assay using PBMC and PF-MC is a useful adjunct for diagnosing TBP, especially for a rule-in test when PF/MC/PBMC ELISPOT ratio (>= 2) is used. However, the relatively high proportion of indeterminate results limits test utility, so further studies are needed to develop an optimized assay prototype. PMID- 21549431 TI - Inositol phosphoglycans and preeclampsia: from bench to bedside. AB - The metabolic syndrome that occurs in preeclampsia reflects the complex interactions between immunological alterations and the systemic inflammation that have been shown to take place during this complication of human pregnancy. Inositol phosphoglycans play a definite role in the insulin resistance in preeclampsia with a higher production and urinary excretion of this molecule before and during preeclampsia. Recent researches suggest that the feto-placental glucose metabolism in the first and early second trimester is mainly linked to the nonoxidative pathway of glycogen catabolism supporting the pivotal role of the inositol phosphoglycan P-type. In this article we present the results of a case-control study carried out in the first trimester to evaluate the potential of urinary P-IPG release as a early marker of the disease. A single mid-stream sample of maternal urine was collected at 11 weeks of gestation for this single centre retrospective study. Twenty-seven patients out of 331 women recruited (8.1%) went on to develop preeclampsia but no sample attained positivity. Further details about the development of the metabolic syndrome during preeclampsia were retrieved also from other studies to implement our knowledge about the pathophysiology of this syndrome and to identify biochemical aspects that could help in clinical practice. PMID- 21549432 TI - Regulatory T cells vary over bleeding segments in asthmatic and non-asthmatic women. AB - Sex hormones may play an important role in observed gender differences in asthma incidence and severity. Regulatory T cells (Treg cells) are presumed to be involved in asthma and may vary with hormone levels. To investigate the effects of sex hormones on levels of Treg cells (percentage of CD4+CD25+Foxp3+ lymphocytes that are CD127-), a cohort of 13 women (6 with and 7 without an asthma diagnosis) had blood drawn multiple times over the course of a bleeding segment (bleeding interval plus the following bleeding-free interval) and collected urine samples daily for measurement of estrogen (estrone E1C) and progesterone (pregnanediol-glucuronide PDG) metabolites. The samples from non asthmatic women indicated no association between bleeding segment day and Treg cells. Asthmatic women showed a 3% increase in Treg cell percentage with each successive day over the bleeding segment. Among non-asthmatic women, Treg cell percentages were not associated with PDG levels on the same day, or 1, 2 or 3 days before Treg cell measurement. E1C was positively correlated with the Treg cell percentage measured only on the same day - a 5% increase in E1C was associated with a 1.4% increase in Treg cell percentage. Among asthmatic women, only E1C was associated with Treg cell percentages after adjusting for PDG on the same day and 1 and 2 days before Treg cell measurement. A 5% increase in E1C was associated with a 2.3% increase in Treg cell percentage. A larger study of contiguous cycles to better determine within-woman cyclicity of the observed patterns is needed. PMID- 21549433 TI - Cognitive control in adults with attention-deficit/hyperactivity disorder. AB - The objective of the present study was to investigate the ability of adults with Attention-Deficit/Hyperactivity Disorder (ADHD) to direct their attention and exert cognitive control in a forced instruction dichotic listening (DL) task. The performance of 29 adults with ADHD was compared with 58 matched controls from the Bergen Dichotic Listening Database (N>1500). Participants in the Bergen DL task listen to and report from conflicting consonant-vowel combinations (two different syllables presented simultaneously, one to each ear). They are asked to report the syllable they hear (non-forced condition), or to focus and report either the right- or left-ear syllable (forced-right and forced-left condition). This procedure is presumed to tap distinct cognitive processes: perception (non-forced condition), orienting of attention (forced-right condition), and cognitive control (forced-left condition). Adults with ADHD did not show significant impairment in the conditions tapping perception and attention orientation, but were significantly impaired in their ability to report the left-ear syllable during the forced-left instruction condition, whereas the control group showed the expected left-ear advantage in this condition. This supports the hypothesis of a deficit in cognitive control in the ADHD group, presumably mediated by a deficit in a prefrontal neuronal circuitry. Our results may have implications for psychosocial adjustment for persons with ADHD in educational and work environments. PMID- 21549435 TI - Early repolarization and markers of ventricular arrhythmogenesis in patients referred to ambulatory 24-hour ECG recording. AB - BACKGROUND: Recent reports suggest that early repolarization, a common electrocardiographic (ECG) pattern that has been always considered benign, could be a substrate for ventricular arrhythmias and sudden cardiac arrest. METHODS: We examined the associations between early repolarization and markers of ventricular arrhythmogenesis as defined by presence of ventricular late potentials (LPs) in the Signal Averaged ECG (SA-ECG), depressed heart rate variability (HRV) and/or presence of ventricular ectopy in patients referred to ambulatory 24-hour ECG recording (Holter). RESULTS: This study included 687 patients (57% females) who were 51.2 +/- 5.1 years. In unadjusted and multivariable adjusted analyses, early repolarization was not significantly associated with any of the measures of SA ECG, HRV or ventricular ectopy. The lack of significant associations persisted in all subgroup analyses where different definitions of early repolarization in different groups of ECG leads were tested. CONCLUSIONS: Early repolarization has no significant association with markers of ventricular arrhythmogenesis as detected by SA-ECG, HRV and ventricular ectopy. These findings suggest that the mechanisms of arrhythmic events in early repolarization (if they truly exist), are not likely to be through pathological pathways that could be detected by these markers. PMID- 21549434 TI - Placing prediction into the fear circuit. AB - Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here, we review recent electrophysiological, molecular and behavioral evidence suggesting the existence of a distributed neural circuitry regulating amygdala synaptic plasticity during fear learning. This circuitry, which involves projections from the midbrain periaqueductal gray region, can be linked to prediction error and expectation modulation of fear learning, as described by associative and computational learning models. It controls whether, and how much, fear learning occurs by signaling aversive events when they are unexpected. Functional neuroimaging and clinical studies indicate that this prediction circuit is recruited in humans during fear learning and contributes to exposure based treatments for clinical anxiety. This aversive prediction error circuit might represent a conserved mechanism for regulating fear learning in mammals. PMID- 21549436 TI - Within-herd contact structure and transmission of Mycobacterium avium subspecies paratuberculosis in a persistently infected dairy cattle herd. AB - Within-herd transmission of pathogens occurs either by direct or by indirect contact between susceptible and infected animals. In dairy herds that are structured into groups, the way in which animals encounter each other and share an environment can affect pathogen transmission. Dairy cattle are heterogeneous in terms of susceptibility and infectivity with respect to Mycobacterium avium subspecies paratuberculosis (Map) transmission. It is mainly young animals that are susceptible and adults that are infectious. Both vertical and horizontal transmission through the ingestion of Map shed into the environment by adults and transiently infected calves can occur. Our objective was to assess the effect of contact structure on Map transmission in persistently infected dairy herds and to examine the effect of isolating calves from other calves or from adults before weaning. We developed a stochastic compartmental model of Map transmission in a closed dairy herd. The model reflects the Map infection process and herd management characteristics. Indirect transmission via the environment was modelled explicitly. Six infection states (susceptible, resistant, transiently infectious, latently infected, subclinically infected, and clinically affected) and two contaminated farm area environments (whole farm and calf area) were modelled. Calves were housed in hutches, individual indoor pens, or group indoor pens. Two different levels of exposure of calves to a farm environment contaminated by adults were possible: no exposure and indirect exposure through fomites. Three herd sizes were studied. We found that contacts between calves before weaning did not influence Map transmission in a herd, whereas the level of exposure of calves to an environment contaminated by adults and the starting age of exposure of calves to adults were pivotal. Early culling of clinically affected adults led to a lower prevalence of infectious adults over time. The results were independent of herd size. Despite the many transmission routes that are known, the best control approach is to limit the exposure of calves to adult faeces through the systematic separation of adults and calves in combination with hygiene measures. Reducing contact between calves does not appear effective. PMID- 21549437 TI - Micro- and nanoengineering for stem cell biology: the promise with a caution. AB - Current techniques used in stem cell research only crudely mimic the physiological complexity of the stem cell niches. Recent advances in the field of micro- and nanoengineering have brought an array of in vitro cell culture models that have enabled development of novel, highly precise and standardized tools that capture physiological details in a single platform, with greater control, consistency, and throughput. In this review, we describe the micro- and nanotechnology-driven modern toolkit for stem cell biologists to design novel experiments in more physiological microenvironments with increased precision and standardization, and caution them against potential challenges that the modern technologies might present. PMID- 21549439 TI - A national dosimetric audit of IMRT. AB - BACKGROUND AND PURPOSE: A dosimetric audit of IMRT has been carried out within the UK between June 2009 and March 2010 in order to provide an independent check of safe implementation and to identify problems in the modelling and delivery of IMRT. METHODS AND MATERIALS: A mail based audit involving film and alanine dosimeters was utilized. Measurements were made for each individual field in an IMRT plan isocentrically in a flat water-equivalent phantom at a depth of 5cm. The films and alanine dosimeters were processed and analysed centrally; additional ion chamber measurements were made by each participating centre. RESULTS: 57 of 62 centres participated, with a total of 78 plans submitted. For the film measurements, all 176 fields from the less complex IMRT plans (including prostate and breast plans) achieved over 95% pixels passing a gamma criterion of 3%/3mm within the 20% isodose. For the more complex IMRT plans (mainly head and neck) 8/245 fields (3.3%) achieved less than 95% pixels passing a 4%/4mm gamma criterion. Of the alanine measurements, 4/78 (5.1%) of the measurements differed by >5% from the dose predicted by the treatment planning system. Three of these were large deviations of -77.1%, -29.1% and 14.1% respectively. Excluding the three measurements outside 10%, the mean difference was 0.05% with a standard deviation of 1.5%. The out of tolerance results have been subjected to further investigations. CONCLUSIONS: A dosimetric audit has been successfully carried out of IMRT implementation by over 90% of UK radiotherapy departments. The audit shows that modelling and delivery of IMRT is accurate, suggesting that the implementation of IMRT has been carried out safely. PMID- 21549438 TI - Endothelialized biomaterials for tissue engineering applications in vivo. AB - Rebuilding tissues involves the creation of a vasculature to supply nutrients and this in turn means that the endothelial cells (ECs) of the resulting endothelium must be a quiescent non-thrombogenic blood contacting surface. Such ECs are deployed on biomaterials that are composed of natural materials such as extracellular matrix proteins or synthetic polymers in the form of vascular grafts or tissue-engineered constructs. Because EC function is influenced by their origin, biomaterial surface chemistry and hemodynamics, these issues must be considered to optimize implant performance. In this review, we examine the recent in vivo use of endothelialized biomaterials and discuss the fundamental issues that must be considered when engineering functional vasculature. PMID- 21549440 TI - Comparison of the planning target volume based on three-dimensional CT and four dimensional CT images of non-small-cell lung cancer. AB - BACKGROUND AND PURPOSE: To compare positional and volumetric differences of planning target volumes (PTVs) based on axial three-dimensional CT (3DCT) and four-dimensional CT (4DCT) for the primary tumor of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Twenty-eight patients with NSCLC underwent 3DCT and 4DCT scans of the thorax during normal free breathing. PTV(vector) was defined on 3DCT using the individual tumor motion vector measured by 4DCT accounting for tumor motion; PTV(4D) was defined on all phases of 4DCT images. In addition, a 7mm margin for microscopic disease and a 3mm setup margin were used for above PTVs, respectively. The differences in target position, volume and coverage between PTV(vector) and PTV(4D) were evaluated for tumors in different lobes, respectively. RESULTS: The median motion vector for tumors located in the upper lobe (group A) and in the middle lower lobe (group B) was 2.8 and 7mm, respectively. The mean centroid shifts between PTV(vector) and PTV(4D) in the LR, AP and CC directions for group A and B were close to zero. The median size ratio of PTV(4D) to PTV(vector) was 0.75 and 0.52 for group A and B. The motion vector showed a significant correlation to the ratio of PTV(4D) to PTV(vector) for group A and B (p=0.008 and 0.003). The median DI of PTV(vector) in PTV(4D) was 69.19% for group A and 51.60% for group B. The median DI of PTV(4D) in PTV(vector) was 98.99% for group A and 99.94% for group B. CONCLUSION: It is necessary to expand the internal margin isotropically in a single direction for 3DCT treatment planning due to the uncertainty of the 3DCT-based target position. The 3DCT-based PTV using individual margins provides a good coverage of the 4DCT-based PTV, meanwhile encompasses relatively large normal tissues, especially for middle and lower lobe tumors. We should be cautious about the use of the individual PTV derived from 3DCT in treatment planning. PMID- 21549441 TI - Toward an individualized target motion management for IMRT of cervical cancer based on model-predicted cervix-uterus shape and position. AB - BACKGROUND AND PURPOSE: To design and evaluate a 3D patient-specific model to predict the cervix-uterus shape and position. METHODS AND MATERIALS: For 13 patients lying in prone position, 10 variable bladder filling CT-scans were acquired, 5 at planning and 5 after 40Gy. The delineated cervix-uterus volumes in 2-5 pre-treatment CT-scans were used to generate patient-specific models that predict the cervix-uterus geometry by bladder volume. Model predictions were compared to delineations, excluding those used for model construction. The prediction error was quantified by the margin required around the predicted volumes to accommodate 95% of the delineated volume and by the predicted-to delineated surface distance. RESULTS: The prediction margin was significantly smaller (average 50%) than the margin encompassing the cervix-uterus motion. The prediction margin could be decreased (from 7 to 5mm at planning and from 10 to 8mm after 40Gy) by increasing (from 2 to 5) the number of CT-scans used for the model construction. CONCLUSION: For most patients, even with a model based on only two CT-scans, the prediction error was well below the margin encompassing the cervix-uterus motion. The described approach could be used to create prior to treatment, an individualized treatment strategy. PMID- 21549443 TI - A bootstrap approach for lower injury levels of the risk curves. AB - Survival analysis is widely applied to develop injury risk curves from biomechanical data. To obtain more accurate estimation of confidence intervals of parameters, bootstrap method was evaluated by a designed simulation process. Four censoring schemes and various sample sizes were considered to investigate failure time parameters corresponding to low-level injury probabilities. In the numerical simulations, the confidence interval ranges developed by bootstrapping were about two-third of the corresponding ranges calculated by asymptotical normal approximation and showed highest reduction for censored datasets with smaller sample size (<= 40). In analysis of two experimental datasets with reduced sample sizes and mixed censored data, it was shown that the bootstrapping reduce significantly the confidence intervals as well. The results presented in this study recommend using bootstrapping in development of more accurate confidence intervals for risk curves in injury biomechanics, which consequently will lead to better regulations and safer vehicle designs. PMID- 21549442 TI - Muscle coordination and force variability during static and dynamic tracking tasks. AB - This study examined muscular activity patterns of extensor and flexor muscles and variability of forces during static and dynamic tracking tasks using compensatory and pursuit display. Fourteen volunteers performed isometric actions in two conditions: (i) a static tracking task consisting of flexion/pronation, ulnar deviation, extension/supination and radial deviation of the wrist at 20% maximum voluntary contraction (MVC), and (ii) a dynamic tracking task aiming at following a moving target at 20% MVC in the four directions of contraction. Surface electromyography (SEMG) from extensor carpi ulnaris, extensor carpi radialis, flexor carpi ulnaris and flexor digitorum superficialis muscles and exerted forces in the transverse and sagittal plane were recorded. Normalized root mean square and mutual information (index of functional connectivity within muscles) of SEMGs and the standard deviation and sample entropy of force signals were extracted. Larger SEMG amplitudes were found for the dynamic task (p<.05), while normalized mutual information between muscle pairs was larger for the static task (p<.05). Larger size of variability (standard deviation of force) concomitant with smaller sample entropy was observed for the dynamic task compared with the static task (p<.01 for both). These findings underline a rescaling of the muscles' respective contribution influencing force variability relying on feedback and feed-forward control strategies in relation to display modes during static and dynamic tracking tasks. PMID- 21549444 TI - Reaction capacity characterization of shallow sedimentary deposits in geologically different regions of the Netherlands. AB - Quantitative insight into the reaction capacity of porous media is necessary to assess the buffering capacity of the subsurface against contaminant input via groundwater recharge. Here, reaction capacity is to be considered as a series of geochemical characteristics that control acid/base conditions, redox conditions and sorption intensity. Using existing geochemical analyses, a statistical regional assessment of the reaction capacity was performed for two geologically different areas in the Netherlands. The first area is dominated by Pleistocene aquifer sediments only, in the second area a heterogeneous Holocene confining layer is found on top of the Pleistocene aquifer sediments. Within both areas, two or more regions can be distinguished that have a distinctly different geological build-up of the shallow subsurface. The reactive compounds considered were pyrite, reactive Fe other than pyrite, sedimentary organic matter, carbonate and clay content. This characterization was complemented by the analysis of a dataset of samples newly collected, from two regions within the Pleistocene area, where the sedimentary facies of samples was additionally distinguished. The statistical assessment per area was executed at the levels of region, geological formation and lithology class. For both areas, significant differences in reaction capacities were observed between: 1. different lithology classes within a geological formation in a single region, 2. identical geological formations in different regions and 3. various geological formations within a single region. Here, the reaction capacity is not only controlled by lithostratigraphy, but also by post-depositional diagenesis and paleohydrology. Correlation coefficients among the reactive compounds were generally higher for sand than for clay, but insufficiently high to allow good estimation of reactive compounds from each other. For the sandy Pleistocene aquifer sediments, the content of reactive compounds was frequently observed to be below detection limits. From this, future characterization of sediment reaction capacity is best performed at the sublevel of lithology class, being the geochemically near-uniform unit identifiable for individual geological formations within geographic regions. Additional subdivision on facies provides particular insight in the spatial entity where relatively high reaction capacities may be encountered. To obtain quantitative insight into the reaction capacity of aquifer sediments, non-sandy minor subunits should be well characterised on their reaction capacity as well as their spatial occurrence in the geological formations. A straightforward approach is presented in which the regional statistics on geochemical reactivity become combined with a 3-dimensional geological voxel model. This results into 3-dimensional data fields on reactivity, which are suitable for, for example, groundwater transport modelling. The sedimentological architecture of the deposits becomes well maintained in the geochemical data field, which is an advantage in itself. PMID- 21549445 TI - [Multifocal electroretinography in follow-up of patients treated with hydroxychloroquine]. AB - INTRODUCTION: Ophthalmologic follow-up of hydroxychloroquine-treated patients is of major importance because of the risk for potentially irreversible retinal toxicity. The use of the multifocal electroretinogram for the follow-up of such patients has already been reported. We studied the capacity of the multifocal electroretinogram to detect early signs of retinal toxicity. PATIENTS AND METHODS: This study consisted of multifocal electroretinogram analysis of 28 patients treated with hydroxychloroquine for a period of 6-72 months. All patients selected had a normal clinical and paraclinical ophthalmological evaluation. A multifocal electroretinogram according to the international recommendations was obtained. We analyzed the amplitude and the implicit time for kernel 1 responses by quadrant and by ring. RESULTS: For both eyes, in both ring and quadrant analyses, the average implicit times of patients receiving hydroxychloroquine were significantly elevated (p<0.01). On the other hand, the amplitudes were not significantly attenuated. In a total of 28 patients, seven (25%) presented a significant prolongation of the implicit time and significant amplitude attenuation was found in only one patient. DISCUSSION: Implicit time prolongation in hydroxychloroquine-treated patients has already been reported. However, dissociation between amplitude and implicit time changes has, to our knowledge, never been previously described. This observation is important given that numerous studies focus exclusively on amplitude. CONCLUSION: The multifocal electroretinogram of patients receiving hydroxychloroquine can present lengthened kernel 1 implicit time, despite otherwise normal ophthalmological evaluation. Further studies are necessary to evaluate the prognostic value of mfERG responses in the early detection of patients presenting a retinotoxicity risk. PMID- 21549446 TI - Detection of viruses in used ventilation filters from two large public buildings. AB - BACKGROUND: Viral and bacterial pathogens may be present in the air after being released from infected individuals and animals. Filters are installed in the heating, ventilation, and air-conditioning (HVAC) systems of buildings to protect ventilation equipment and maintain healthy indoor air quality. These filters process enormous volumes of air. This study was undertaken to determine the utility of sampling used ventilation filters to assess the types and concentrations of virus aerosols present in buildings. METHODS: The HVAC filters from 2 large public buildings in Minneapolis and Seattle were sampled to determine the presence of human respiratory viruses and viruses with bioterrorism potential. Four air-handling units were selected from each building, and a total of 64 prefilters and final filters were tested for the presence of influenza A, influenza B, respiratory syncytial, corona, parainfluenza 1-3, adeno, orthopox, entero, Ebola, Marburg, Lassa fever, Machupo, eastern equine encephalitis, western equine encephalitis, and Venezuelan equine encephalitis viruses. Representative pieces of each filter were cut and eluted with a buffer solution. RESULTS: Attempts were made to detect viruses by inoculation of these eluates in cell cultures (Vero, MDCK, and RK-13) and specific pathogen-free embryonated chicken eggs. Two passages of eluates in cell cultures or these eggs did not reveal the presence of any live virus. The eluates were also examined by polymerase chain reaction or reverse-transcription polymerase chain reaction to detect the presence of viral DNA or RNA, respectively. Nine of the 64 filters tested were positive for influenza A virus, 2 filters were positive for influenza B virus, and 1 filter was positive for parainfluenza virus 1. CONCLUSION: These findings indicate that existing building HVAC filters may be used as a method of detection for airborne viruses. As integrated long-term bioaerosol sampling devices, they may yield valuable information on the epidemiology and aerobiology of viruses in air that can inform the development of methods to prevent airborne transmission of viruses and possible deterrents against the spread of bioterrorism agents. PMID- 21549447 TI - Impact of barrier precautions and antibiotic consumption on the incidence rate of acquired cases of infection or colonization with Acinetobacter baumannii: a 10 year multi-department study. AB - Following a previous investigation, this ecological study assessed the impact of barrier precautions and various factors on the annual incidence rate of acquired Acinetobacter baumannii cases in each of the 32 departments of the University Hospital of Besancon from 2000 to 2009. Ultimately, our study confirms the effectiveness of barrier precautions in addition to standard precautions for controlling A baumannii within our hospital departments. In comparison with the previous research, it emphasizes the significant role of fluoroquinolones in the emergence and the spread of this microorganism. PMID- 21549448 TI - [Causes, characteristics and mid-term course of acute urinary retention in women referred to a urodynamics unit]. AB - OBJECTIVES: Acute urinary retention (AUR) is uncommon in women and can be related to different conditions. Only some patients are referred to the urodynamics units for a more extensive study. We intend to describe the charcteristics and causes of AUR in women referred to our unit and to analyze their middle term evolution. MATERIAL AND METHODS: We performed a descriptive retrospective study (January 1982-December 2006), including the women referred to our Uro-Neurology and Urodynamics Unit after suffering an AUR. Medical charts were reviewed with special emphasis on medical history, physical examination, and also complete urodynamics study during the AUR event and after its resolution. RESULTS: A total of 202 women were included, median age of 57 years (12-87 years). Prior to the AUR, 59 women (28.7%) reported voiding symptoms. The urodynamics findings were: 65 (32.2%) detrusor hypocontractility; 64 (31.7%) normal study; 37 (18.3%) detrusor acontractility; 21 (10.4%) bladder outlet obstruction; 15 (7.4%) poor pelvic floor relaxation. The causes of the AUR were: 53 neurological (26.2%); 46 unknown (22.8%); 19 gynecological (9.4%); 22 diabetes mellitus (10.9%); 16 urological (7.9%). Renal insufficiency was observed in 14 patients (6.9%). After the AUR 106 women (52.4%) needed some kind of prolonged treatment. CONCLUSIONS: In our experience, AUR in the female is mainly related to underlying neurologic/urogynecologic disease, even though the etiology could not be known in a significant percentage of patients. Half of the patients recovered completely and did not require any treatment. PMID- 21549449 TI - [Physiopathology of acute renal failure during sepsis]. AB - Acute renal failure (ARF) is an independent risk factor associated with increased mortality during sepsis. Recent consensus definitions have allowed the standardization of research on the subject. The understanding of the physiopathology of ARF during sepsis is limited by the scarcity of histological studies and the inability to measure renal microcirculatory flows. Historically, ARF during sepsis has been considered to be a consequence of diminished renal blood flow (RBF). Indeed, in early stages of sepsis or in sepsis associated to cardiogenic shock, RBF may decrease. However, recent studies have shown that in resuscitated sepsis, in which cardiac output is characteristically normal or even elevated and there is systemic vasodilatation, RBF is normal or even increased, with no associated histological evidence of significant tubular necrosis. Thus, other factors may participate in the genesis of ARF in sepsis. These include apoptosis, glomerular and medullary microcirculatory disorders, cell changes in response to the pro-inflammatory cascade characteristic of sepsis, oxidative stress, mitochondrial dysfunction and damage induced by mechanical ventilation, among others. Sepsis associated ARF treatment is supportive. In general, renal replacement therapies can be grouped as intermittent or continuous, and as those whose primary objective is the replacement of impaired renal function, versus those whose main objective is to secure hemodynamic stability through the clearing of pro-inflammatory mediators. PMID- 21549450 TI - [The new generation of the Pillcam Colon Capsule: a non-invasive alternative in colorectal cancer screening?]. AB - The Pillcam colon capsule was first introduced in 2006 for the study of the colon. Colon capsule endoscopy is a new diagnostic technology to visualize the colorectal mucosa without sedation, intubation or insufflation and appears to be a safe and attractive alternative to colonoscopy. Since the introduction of this technology, numerous studies have been published on its diagnostic sensitivity and the regimen of colon preparation for better evaluation of the colon. Recently, a new generation of the capsule, Pillcam Colon 2, has been presented, with important innovations. PMID- 21549451 TI - [Lipomatous hypertrophy of the interatrial septum: findings in the (18)F-FDG PET/CT scan]. PMID- 21549452 TI - The role of FDG-PET/CT in ovarian cancer patients with high tumor markers or suspicious lesion on contrast-enhanced CT in evaluation of recurrence and/or in determination of intraabdominal metastases. AB - OBJECTIVES: This retrospective study was designed to investigate the role of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in determination of recurrence and/or intraabdominal metastasis in patients with ovarian cancer having increased tumor markers or suspicious lesion detected by a contrast-enhanced abdominal CT (ceCT). MATERIALS AND METHODS: A total of 34 female patients who were treated for histopathologically proven ovarian cancer, underwent PET/CT examination for restaging and suspected recurrence. Patients with pathology report, tumor marker levels, ceCT and PET/CT performed within one month were included in the study. RESULTS: A total of 34 patients were included in the study. 25 of 34 patients had high tumor marker (CA 125) level. The remaining 9 patients had suspected recurrence on ceCT imaging with normal tumor marker levels. Recurrence was confirmed by re-operation and biopsy (n=4), clinical and imaging follow-up (n=21) in 25 patients with elevated tumor markers. Recurrent disease was not shown in 5 of 25 patients on ceCT imaging and 1 of 25 patients on PET/CT imaging with high CA125 values. Both ceCT and PET/CT revealed recurrent disease in 19 of 25 patients. PET/CT showed more lesions in 11 of 19 patients. Sensitivity, specificity and accuracy of the PET/CT were 96.1%, 100% and 97%, respectively. CONCLUSION: PET/CT is found as a beneficial method for detection of the recurrence, in patients with increased serum CA 125 level and negative CT findings or with normal CA 125 level and recurrence detected by CT which was performed due to clinical symptoms. PMID- 21549453 TI - Prediction of future cardiac events using myocardial perfusion SPECT: a middle term follow-up study. AB - BACKGROUND: Myocardial perfusion imaging (MPI) provides highly valuable information for risk stratification and determination of optimal clinical management. The goal of the present study was to assess the prognostic value of myocardial perfusion SPECT for the prediction of future cardiac events in Asian population. METHODS: Five hundred and ten consecutive patients, who had undergone myocardial perfusion SPECT between 2005 and 2006, were prospectively followed-up. Patients' data were collected from recorded files. Follow-ups were performed by scripted telephone interviews by a physician blinded to the patients' MPI results and also from the hospital records. The total completed follow-ups consisted of 482 patients (follow-up rate, 94.5%). RESULTS: Over the mean follow-up period of 434 +/- 62 days, 14 out of 482 patients (2.9%) died from cardiac events. Also in 61 patients (12.7%), the clinical condition led to a cardiac intervention (Percutaneous coronary intervention or coronary artery bypass grafting). Those patients without cardiac events on follow-up (including cardiac death or myocardial infarction) were younger and with less severity of MPI abnormalities. Severe MPI abnormalities (Summed Stress Score > 13) were found in 42.9% of those with cardiac death, while in 17.2% of those with myocardial infarction. The rate of cardiac death had a direct relationship with the severity of scan abnormalities, however, the same association was not found between the severity of MPI abnormality and the rate of myocardial infarction. CONCLUSION: MPI is a valuable tool for risk stratification and prediction of future fatal cardiac events in Asian population. The risk of cardiac death as a mid-term outcome of coronary artery disease increases significantly with severity of MPI abnormalities. PMID- 21549454 TI - [SOD1-N196 mutation in a family with amyotrophic lateral sclerosis]. AB - INTRODUCTION: N19S mutation is produced by substitution in the 139 position of SOD1 and was described by Mayeux in a patient with amyotrophic lateral sclerosis (ALS). He suggested that it did not have a causal effect as it was found in asymptomatic and sporadic cases. Other authors in later articles did not agree. MATERIAL AND METHODS: We describe a family with 4 members with ALS patients and attempt to find the carrier of the N19S mutation of the propositus. Molecular studies were performed on 15 members of the family of a different order. RESULTS: The ALS cases were found in the maternal line of the propositus. The presence of the mutation was detected in 3 people, the other two were asymptomatic. One of patients with ALS in the family, who died previously, did not have the mutation. Two of the sons of this case and another of the other case did not show it. On the other hand, N19S mutation was only present in paternal branch of the propositus, where there were no cases. CONCLUSION: The described family supports the hypothesis by Mayeux and against that mutation N19S has pathological consequences, since mutation is only in the family line where there are no cases with ALS. In consequence, although the described case is included as a familiar form, it cannot be attributed to the mutation, and its relationship with N19S should be considered as casual. PMID- 21549455 TI - [From the evidence to the organisation of stroke care]. AB - INTRODUCTION: Acute stroke care in stroke units (SU) compared to care in general medicine wards provides benefits to the patient. DEVELOPMENT: Acute stroke care in an SU has shown benefits in reducing mortality, institutionalisation, dependency and costs compared to care in internal medicine wards, and even a lower risk of recurrence in the long term. The benefits are associated with specific treatments developed in the SU, such as thrombolytic therapy, development of clinical pathways, standardised procedures, and training and experience of professionals in the SU. This evidence should lead to the proper organisation of hospitals to ensure that all acute stroke patients may benefit from care in an SU. The introduction of SUs is a priority in Europe, although the number of stroke patients admitted to SUs is still low. CONCLUSIONS: Based on current evidence, acute stroke patients should be cared for in an SU due to the associated clinical benefits and hospitals should organise to provide this care to patients. PMID- 21549457 TI - New condensed pyrroles of potential biological interest syntheses and structure activity relationship studies. AB - The Pyrrole derivatives Ia-d were prepared and utilized for the preparation of pyrrolo[2,3-d]pyrimidine derivatives IIa-c, III, IVa-e, V and VIIIa-c; pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidine VI and pyrrolo[4,3e][1,2,4]triazolo[1,5 c]pyrimidine derivative derivatives VIIa-c. These some newly synthesized compounds were examined for their in vitro antimicrobial activity and in vivo anti-inflammatory. Result indicated that these compounds showed promising anti inflammatory activity in comparison to ibuprofen (the standard anti-inflammatory drug). The structure-activity relationships (SAR) and anti-inflammatory activities of these compounds are also discussed in this paper. PMID- 21549456 TI - Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-adrenergic receptor blocking properties. AB - We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl)-4-(2 methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [(3)H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (K(i) = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (K(B) = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (K(B) = 0.017 nM). PMID- 21549458 TI - [Tuberculosis of finger bones: three cases]. AB - Tuberculosis dactylis is exceptional. We report tuberculous dactylitis in three women who were 51, 44, and 62-year-old, respectively. The diagnosis was suspected on chronic and insidious clinical presentation, and confirmed by histology. Disease course was favourable with antibuberculosis regimen but two patients had permanent hand disability. Clinical and therapeutic issues are discussed in the context of an endemic country. PMID- 21549459 TI - [Genetic deafness]. PMID- 21549460 TI - Radioiodine and radiocesium in Thessaloniki, Northern Greece due to the Fukushima nuclear accident. AB - Radioiodine ((131)I) in air and rainwater as high as 497 MUBq m(-3) and 0.7 Bq L( 1), respectively, as well as (137)Cs and (134)Cs in air as high as 145 MUBq m(-3) and 126 MUBq m(-3), respectively were recorded in Thessaloniki, Northern Greece (40 degrees 38'N, 22 degrees 58'E) from March 24, 2011 through April 09, 2011, after a nuclear accident occurred at Fukushima, Japan (37 degrees 45'N, 140 degrees 28'E) on March 11, 2011. PMID- 21549461 TI - Zinc accumulation and synthesis of ZnO nanoparticles using Physalis alkekengi L. AB - A field survey and greenhouse experiments were conducted using Physalis alkekengi L. to investigate strategies of phytoremediation. In addition, ZnO nanoparticles were synthesized using P. alkekengi. P. alkekengi plants grew healthily at Zn levels from 50 to 5000 mg kg(-1) in soils. The plants incorporated Zn into their aerial parts (with mean dry weight values of 235-10,980 mg kg(-1)) and accumulated biomass (with a mean dry weight of 25.7 g plant(-1)) during 12 weeks. The synthesized ZnO nanoparticles showed a polydisperse behavior and had a mean size of 72.5 nm. The results indicate that P. alkekengi could be used for the remediation of zinc-contaminated soils. Moreover, the synthetic method of synthesizing ZnO nanoparticles from Zn hyperaccumulator plants constitutes a new insight into the recycling of metals in plant sources. PMID- 21549462 TI - Occurrence of arsenic in brown rice and its relationship to soil properties from Hainan Island, China. AB - The acquaintance of arsenic concentrations in rice grain is vital in risk assessment. In this study, we determined the concentration of arsenic in 282 brown rice grains sampled from Hainan Island, China, and discussed its possible relationships to the considered soil properties. Arsenic concentrations in the rice grain from Hainan Island varied from 5 to 309 MUg/kg, with a mean (92 MUg/kg) lower than most published data from other countries/regions and the maximum contaminant level (MCL) for As(i) in rice. The result of correlation analysis between grain and soil properties showed that grain As concentrations correlated significantly to soil arsenic speciation, organic matter and soil P contents and could be best predicted by humic acid bound and Fe-Mn oxides bound As fractions. Grain arsenic rises steeply at soil As concentrations lower than 3.6 mg/kg and gently at higher concentrations. PMID- 21549463 TI - High-normal albuminuria and risk of heart failure in the community. AB - BACKGROUND: Albuminuria has been associated with cardiovascular risk, but the relationship of high-normal albuminuria to subsequent heart failure has not been well established. STUDY DESIGN: Prospective observational study, the Atherosclerosis Risk in Communities (ARIC) Study. SETTING & PARTICIPANTS: 10,975 individuals free from heart failure were followed up from the fourth ARIC Study visit (1996-1998) through January 2006. PREDICTOR: Urinary albumin-creatinine ratio (UACR), analyzed continuously and categorically as optimal (<5 mg/g), intermediate-normal (5-9 mg/g), high-normal (10-29 mg/g), microalbuminuria (30 299 mg/g), and macroalbuminuria (>=300 mg/g). OUTCOMES & MEASUREMENTS: Incident heart failure was defined as a heart failure-related hospitalization or death. Cox proportional hazard models were used to calculate the HR of heart failure after adjustment for age, race, sex, estimated glomerular filtration rate (eGFR), and other cardiovascular risk factors. RESULTS: Individuals were followed up for a median of 8.3 years and experienced 344 heart failure events. Compared with normal UACR, albuminuria was associated with a progressively increased risk of heart failure from intermediate-normal (adjusted HR, 1.54; 95% CI, 1.12-2.11) and high-normal UACR (adjusted HR, 1.91; 95% CI, 1.38-2.66) to microalbuminuria (adjusted HR, 2.49; 95% CI, 1.77-3.50) and macroalbuminuria (adjusted HR, 3.47; 95% CI, 2.10-5.72). Results were similar in secondary analyses of participants censored at the time of coronary heart disease event and along a range of eGFRs. LIMITATIONS: UACR was measured as a single random sample. CONCLUSIONS: Albuminuria is associated with subsequent heart failure, even in individuals with few cardiovascular risk factors and UACR within the normal range. Our results suggest that the association between albuminuria and heart failure may not be mediated fully by ischemic heart disease or kidney disease, measured using eGFR. PMID- 21549464 TI - Retinal arteriolar narrowing and subsequent development of CKD Stage 3: the Multi Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Microvascular disease is a major pathogenic factor for chronic kidney disease (CKD) in persons with diabetes, but the role of microvascular disease in the development of CKD in the general population is unclear. The aim of this study is to examine whether microvascular disease precedes the development of CKD stage 3 in participants of the Multi-Ethnic Study of Atherosclerosis (MESA). STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: MESA is a prospective cohort study of adults aged 45-84 years living in 6 US communities; 4,594 adults with estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m(2) when they underwent retinal photography (visit 2: in 2002-2004) were examined. PREDICTOR: Retinal microvascular caliber measured from fundus photographs. OUTCOMES: Incident CKD stage 3 (ie, eGFR <60 mL/min/1.73 m(2)) at 2 subsequent follow-up examinations (visit 3 in 2004-2005, and visit 4 in 2005 2007) and an annual eGFR decrease >1 mL/min/1.73 m(2) computed using the CKD Epidemiology Collaboration (CKD-EPI) equation. RESULTS: After a median follow-up of 4.8 years, there were 232 incident CKD stage 3 cases. Overall, retinal microvascular caliber was not associated with incident CKD stage 3. However, in race-stratified analysis, narrower arterioles in whites was associated with a higher risk of developing CKD stage 3 after adjusting for age, sex, blood pressure, diabetes, and other factors (HR, 1.78; 95% CI, 1.01-3.15; P = 0.04, lowest vs highest arteriolar caliber tertile). This association was seen even in whites without hypertension and diabetes (HR, 2.95; 95% CI, 1.10-7.98; P = 0.03). Retinal arteriolar caliber was not associated with incident CKD stage 3 in African Americans, Chinese, or Hispanics. LIMITATIONS: Analyses were based on a single eGFR measurement, and retinal microvascular caliber and eGFR measurements were not ascertained concurrently. CONCLUSION: Microvascular changes as manifest in the eye may contribute to the development of CKD stage 3 in whites. PMID- 21549466 TI - Diagnosis, psychiatry and neurology: the case of Huntington Disease. AB - Although Huntington Disease (HD) is recognized as a neurological condition, it has a number of psychiatric effects, with recent studies suggesting that these effects can appear years prior to the telltale neurological symptoms. This trajectory has, in part, led to the misdiagnosis of HD as a psychiatric illness, as explicated in numerous case studies. This paper utilizes HD as a case study to investigate the social consequences of diagnosis by highlighting the tensions and ambiguities between neurology and psychiatry, while also discussing the difficulties that HD creates for psychiatry's diagnostic schema. Findings are based on 30 in-depth interviews conducted with both individuals with HD and informal caregivers (e.g., spouses) in British Columbia, Canada. The findings address numerous instances of misdiagnosis and the resulting negative impacts for individual health and well-being. The findings are further discussed in relation to the work of Bakhtin and Latour, with suggestions presented to ameliorate such misdiagnoses. PMID- 21549465 TI - Heart failure severity scoring system and medical- and health-related quality-of life outcomes: the HEMO study. AB - BACKGROUND: Cardiac disease is the leading cause of death in US prevalent hemodialysis (HD) patients. There is a lack of data about the impact of the severity of heart failure (HF) on outcomes and health-related quality of life (HRQoL) in HD patients. We aimed to determine the prognostic importance of the Index of Disease Severity (IDS) of the Index of Coexistent Disease (ICED) scoring system as an HF severity measure. STUDY DESIGN: Subanalysis of the Hemodialysis (HEMO) Study, a randomized controlled trial. Relationships between HF severity and mortality and cardiac hospitalizations were determined using Cox proportional hazards models. The relationship between HF severity and HRQoL scores was modeled using linear regression and generalized estimating equations. SETTING & PARTICIPANTS: 1,846 long-term HD patients at 15 clinical centers including 72 dialysis units. PREDICTOR OR FACTOR: HF severity classified using the IDS of the ICED scoring system. OUTCOMES: Mortality (all cause and cause specific), cardiac hospitalizations, and HRQoL. MEASUREMENTS: All-cause, cardiac, and infectious deaths; cardiac hospitalizations; and HRQoL scores from the Kidney Disease Quality of Life-Long Form. RESULTS: HF was present in 40% of HD patients. Increasing severity of HF was associated with older age, greater likelihood of diabetes, and lower serum albumin level (all P < 0.001). Adjusted HRs for all cause mortality were 1.31 (95% CI, 1.12-1.53), 1.48 (95% CI, 1.19-1.85), and 2.11 (95% CI, 1.43-3.11) for mild, moderate, and severe HF, respectively (P < 0.001). All-cause, cardiac, and infectious mortality and cardiac hospitalizations increased with increasing severity of HF. Increasing HF severity was associated with decreases in HRQoL, particularly in physical functioning and sleep quality. LIMITATIONS: This study is limited by the small sample size in the most severe HF group. CONCLUSIONS: Increasing severity of HF is associated with increased mortality and cardiac hospitalizations and worse HRQoL, especially in perceived physical limitations. These findings emphasize the utility of the IDS of the ICED score as a valid prognostic tool for medical and HRQoL outcomes in the HD population with HF. PMID- 21549467 TI - Enacting 'team' and 'teamwork': using Goffman's theory of impression management to illuminate interprofessional practice on hospital wards. AB - Interprofessional teamwork is widely advocated in health and social care policies. However, the theoretical literature is rarely employed to help understand the nature of collaborative relations in action or to critique normative discourses of teamworking. This paper draws upon Goffman's (1963) theory of impression management, modified by Sinclair (1997), to explore how professionals 'present' themselves when interacting on hospital wards and also how they employ front stage and backstage settings in their collaborative work. The study was undertaken in the general medicine directorate of a large NHS teaching hospital in England. An ethnographic approach was used, including interviews with 49 different health and social care staff and participant observation of ward-based work. These observations focused on both verbal and non verbal interprofessional interactions. Thematic analysis of the data was undertaken. The study findings suggest that doctor-nurse relationships were characterised by 'parallel working', with limited information sharing or effective joint working. Interprofessional working was based less on planned, 'front stage' activities, such as wards rounds, than on ad hoc backstage opportunistic strategies. These backstage interactions, including corridor conversations, allowed the appearance of collaborative 'teamwork' to be maintained as a form of impression management. These interactions also helped to overcome the limitations of planned front stage work. Our data also highlight the shifting 'ownership' of space by different professional groups and the ways in which front and backstage activities are structured by physical space. We argue that the use of Sinclair's model helps to illuminate the nature of collaborative interprofessional relations within an acute care setting. In such settings, the notion of teamwork, as a form of regular interaction and with a shared team identity, appears to have little relevance. This suggests that interventions to change interprofessional practice need to include a focus on ad hoc as well as planned forms of communication. PMID- 21549468 TI - Serial histologic and immunohistochemical changes in anterior digastric myocytes in response to distraction osteogenesis. AB - PURPOSE: To document histologic and immunohistochemical changes in the anterior digastric muscle during distraction osteogenesis (DO). MATERIALS AND METHODS: Nineteen Yucatan minipigs with mixed dentition were used for these experiments. Group A (n = 16) underwent unilateral mandibular distraction at a rate of 1 mm/day (no latency) for 12 days. Animals were killed at mid-DO (n = 5), end-DO (n = 5), mid-fixation (n = 4), and end-fixation (n = 2). Group B (n = 2) underwent acute 12-mm advancement, and group C (n = 1) dissection and osteotomy. Animals from groups B and C were killed at the end-DO time point. Digastric muscles from treatment and contralateral sides of all animals were harvested and embedded in paraffin. Specimens were stained with hematoxylin/eosin or immunohistochemically for proliferating cell nuclear antigen (PCNA; total cell proliferation), paired Box-7 gene protein (Pax7; satellite cells), or myogenic differentiation 1 protein (MyoD; differentiating myoblasts). Descriptive and bivariate statistics were computed to compare groups (P <= .05 statistically significant). RESULTS: All animals survived the operation and observation period; there were no device failures. Two animals (1 at mid-DO, 1 at mid-fixation) were eliminated from the study because of postoperative infection. There was minimal digastric inflammation, fibrosis, and muscle fiber size variability during active DO. Immunohistochemical analysis showed statistically significant increases in PCNA (cellular proliferation), Pax7 (satellite cells), and MyoD (differentiating myoblasts) positive nuclei in digastrics at mid-DO and end-DO. CONCLUSIONS: Results of this study indicate that there are minimal pathologic changes but significant increases in PCNA, Pax7, and MyoD positive nuclei during active distraction. This supports the hypothesis that the digastric muscle response to DO consists of proliferation and hypertrophy. PMID- 21549469 TI - Adrenal insufficiency with gingival mass--an unusual presentation of hepatocellular carcinoma. PMID- 21549470 TI - Transformation of benign fibrous histiocytoma into malignant fibrous histiocytoma in the mandible: case report. PMID- 21549471 TI - Comparison of the Ambu AuraFlex with the laryngeal mask airway Flexible: a manikin study. AB - PURPOSE: The present study compared the Ambu AuraFlex and the laryngeal mask airway (LMA) Flexible with regard to time required for and success rates of insertion on a manikin by dental students who had never used an LMA. In addition, participants' views on ease of insertion of each device were surveyed. MATERIALS AND METHODS: Subjects consisted of 30 dental students who inserted each airway device in a manikin. The time required for and success rates of insertion were measured. Subjects were then asked to rate the ease of insertion of each device using the 100-mm visual analog scale (from 0 mm = extremely easy to 100 mm = extremely difficult). RESULTS: Insertion time was shorter with the Ambu AuraFlex (26.6 +/- 7.1 seconds) than with the LMA Flexible (30.3 +/- 6.8 seconds; P = .045). The rate of successful insertion using the Ambu AuraFlex (28 of 30 attempts, 93.3%) was greater than that with the LMA Flexible (23 of 30 attempts, 76.7%), although the difference was not statistically significant (P = .145). Ambu AuraFlex insertion was considered less difficult (median, 41 mm; 10th to 90th percentiles, 18 to 78 mm) than LMA Flexible insertion (60 mm; 42 to 82 mm; P = .004), as rated using the 100-mm visual analog scale. CONCLUSIONS: The Ambu AuraFlex appears to be useful for inexperienced users because it enables quicker and easier insertion than the LMA Flexible. PMID- 21549472 TI - Keeping ether "en-vogue": the role of Nathan Cooley Keep in the history of ether anesthesia. AB - In this report, we explore the little known role of Dr Nathan Cooley Keep in the dissemination of ether anesthesia in Boston. Keep was a prominent Boston dentist who, for a short time, taught and employed both William Morton and Horace Wells. He used ether anesthesia for a variety of dental and other surgical procedures requiring pain control. Keep administered ether to anesthetize Henry Wadsworth Longfellow's wife during the delivery of their daughter. This was the first use of ether for obstetric anesthesia. Dr Keep was also the first Dean of the Harvard Dental School and convinced the Massachusetts General Hospital to appoint a dentist to the staff of the hospital for the first time. PMID- 21549473 TI - Submandibular gland MALT lymphoma associated with Sjogren's syndrome: case report. AB - Lymphoma is a common disease of the head and neck. Mucosal-associated lymphoid tissue (MALT) lymphoma constitutes a rare type of extranodal lymphoma. The Waldeyer's ring is one of the most common sites of occurrence, but MALT lymphoma may also arise in salivary glands, lung, stomach, or lacrimal glands. In the oral cavity, it may be confused with swellings from dental infection or sinus inflammation. Often, the patient will seek a dentist because of mobile teeth or because a denture no longer fits. We report a case of a female patient with salivary gland dysfunction and pain of several years' duration, who, after numerous tests and hospitalizations, was diagnosed with Sjogren's syndrome. She later developed mucosal-associated lymphoid tissue lymphoma. We discuss the diagnosis, treatment, and prognosis of this entity. MALT lymphoma is rare in salivary glands. In primary-Sjogren's syndrome, predisposition of the patient for development of malignant non-Hodgkin's lymphoma (4% to 10%) is well established. In this case, long-standing sialadenitis and Sjogren's syndrome seem to be the etiological factors. In cases of chronic infection of salivary glands and the presence of autoimmune syndromes, MALT lymphoma should be considered in the differential diagnosis. Consults should be called to ophthalmology, rheumatology, and head and neck oncologists for proper workup, staging, and treatment. PMID- 21549474 TI - Lemmo's flap for nasal dorsum reconstruction. AB - PURPOSE: Reconstruction of nasal defects is an antique challenge for surgeons. The first reported technique is dated 600 B.C. Since then a number of reconstructive options have been proposed in the literature. Some principles, first stated by Buget and Menick must be always taken into account when planning such reconstructions. In detail, every reconstruction should respect the subunit principle and the scars should always be well hidden in the passage between adjacent subunits. The flap proposed in the present paper adheres to the cited principles and leads to optimal nasal dorsum reconstruction in selected cases. MATERIALS AND METHODS: From April 2008 to March 2009, 5 patients were reconstructed with Lemmo's flap after local excision of 3 basal cell carcinomas and 2 squamous cell carcinomas affecting the the skin of the nasal dorsum in its caudal portion. RESULTS: In all cases a pleasing aesthetic result was obtained, no postoperative deformity was observed and all the scars were unnoticeable. CONCLUSIONS: The Lemmo's flap described in the present paper can be considered a valid choice for nasal dorsum skin reconstruction and is preferable over other techniques for reconstruction of small to medium sized defects of the skin of the caudal dorsum. PMID- 21549475 TI - Bronchogenic cyst with intraoral and extraoral components. PMID- 21549476 TI - Rhinoscleroma with involvement of the maxillary sinus, orbital floor, and temporomandibular joint: a case report. PMID- 21549477 TI - Desired characteristics of a potential oral and maxillofacial surgery practice associate: a Connecticut survey response. AB - PURPOSE: The goal of the survey was to identify the desired characteristics of recently graduated oral surgeons entering private practice in Connecticut and compare these results to a similar study conducted earlier in New Jersey. MATERIALS AND METHODS: An anonymous survey was mailed to all active members of the Connecticut Society of Oral and Maxillofacial Surgeons in February 2010. The response rate for the survey was 63%, with 69 of 110 surveys returned. CONCLUSIONS: The most valued characteristics of a new associate included board certification; clinical competence in dentoalveolar surgery, anesthesia, and implant surgery; and personal character. These results paralleled the results of the New Jersey survey. PMID- 21549478 TI - Fluorodeoxyglucose-positive Warthin tumor in a neck node mimicking metastasis in primary intraosseous left posterior mandibular cancer staging with positron emission tomography/computed tomography. PMID- 21549479 TI - Pericoronal ostectomy: an alternative surgical technique for management of mandibular third molars in close proximity to the inferior alveolar nerve. AB - PURPOSE: Close proximity of the inferior alveolar nerve (IAN) to mandibular third molars (MTMs) may result in nerve injury during the extraction of third molars. Alternative surgical techniques, such as coronectomy, have been suggested to decrease this risk. This study examined a new alternative technique, the pericoronal ostectomy (PO), that is intended to decrease IAN injury in high-risk cases. PATIENTS AND METHODS: This prospective clinical cohort study consisted of 14 patients with 17 MTMs in close relation to the IAN. All patients were subjected to 2- and 3-dimensional preoperative radiographic evaluations. Selected patients with mesioangular and vertical bone impactions were treated by the staged PO technique. An institutional review board approval from the University of the Pacific was given to this study. RESULTS: Because of the PO procedure, all 17 high-risk MTMs in the study erupted to a more occlusal position away from the danger zone of the IAN and were eventually removed (mean distance of eruption, 2.0 mm). Three patients reported a transient neurosensory deficit, 2 with the IAN and 1 with a lingual nerve. All 3 had a full resolution of symptoms within 3 months of the postoperative period. CONCLUSION: The PO technique appears to be an additional viable alternative technique to extraction of MTMs in intimate proximity to the IAN. PMID- 21549480 TI - Recombinant human bone morphogenetic protein 2 combined with an osteoconductive bulking agent for mandibular continuity defects in nonhuman primates. AB - PURPOSE: Recombinant human bone morphogenetic protein 2 (rhBMP-2) is an option for reconstructing mandibular continuity defects. A challenge of this technique is the need to maintain sufficient space to avoid compression of the defect. A compression-resistant matrix (CRM) provides a bulking agent that provides support during the bone formation phase. MATERIALS AND METHODS: Thirteen Rhesus Macaque monkeys were used to evaluate different forms of an osteoconductive bulking agent compared with an absorbable collagen alone placed into a critical-sized mandibular defect. A total of 5 groups (26 defects) were evaluated: group A, rhBMP-2/absorbable collagen sponge (ACS) (1.5 mg/mL); group B, rhBMP-2/ACS with ceramic granules (15% hydroxyapatite/85% beta-tricalcium phosphate) at 1.5 mg/mL; group C, rhBMP-2 (2.0 mg/mL) with a CRM; group D, rhBMP-2 (0.75 mg/mL) with a CRM; and group E, a CRM alone. RESULTS: Histology and micro computed tomography were used to evaluate and compare new bone formation in the defects. The reconstructed bone was evaluated with regard to the new bone formation, residual voids, and density. Animals treated with the CRM and rhBMP-2 at 2.0 mg/mL (group C) showed significantly higher amounts of new bone formation, bone density, and reduced voids when compared with rhBMP-2 and ACS (1.5 mg/mL) (P < .05). CONCLUSION: The carrier system CRM combined with rhBMP-2 and a reconstruction plate results in significantly higher bone density and better space maintenance than rhBMP-2 combined with ACS in a nonhuman primate mandibular bone repair model. PMID- 21549481 TI - Use of buccal fat pad for treatment of oral submucous fibrosis. AB - PURPOSE: The aim of this study was to clinically evaluate the application of pedicled buccal fat pad (BFP) in the surgical management of stage III and IV oral submucous fibrosis (OSMF). MATERIALS AND METHODS: Twenty-eight cases of clinically and histologically diagnosed cases of OSMF were divided into 2 groups: group I (n = 15) and group II (n = 13), corresponding to clinical stage III and stage IV, respectively. All the patients underwent incision of fibrotic bands and coverage of the buccal defect with a pedicled BFP flap. Both groups were analyzed separately for mouth opening (interincisal distance in millimeters) preoperatively and 1 year postoperatively, time taken for epithelialization of BFP, time taken for establishment of normal contour, and changes in symptoms (painful ulcerations, burning sensation, and intolerance to spices) 1 year after grafting. RESULTS: The mean preoperative mouth opening was 19.6 mm (SD, 2.43) in group I and 12.92 mm (SD, 1.21) in group II. The mean postoperative mouth opening after 1 year was 35 mm in group I (SD, 1.96) and 31.76 mm in group II (SD, 1.97). The time taken for epithelialization of BFP was 4 weeks in group I and 5 weeks in group II. The mean time taken for establishment of normal contour after grafting was 12.25 weeks (SD, 1.42) in group I and 15.07 weeks (SD, 1.26) in group II. In 2 cases in group II, there was remission of painful ulcerations, burning sensation, and intolerance to spices. CONCLUSION: BFP is reliable for the treatment of OSMF. PMID- 21549482 TI - Oral leukoplakia in a patient with Fanconi anemia: recurrence or a new primary lesion? PMID- 21549483 TI - Island osteoperiosteal flaps with interpositional bone grafting in rabbit tibia: preliminary study for development of new bone augmentation technique. AB - PURPOSE: Loss of alveolar vertical height is one of the most challenging conditions in the field of implantology. A few augmentation techniques have been proposed to address this challenge, including guided bone regeneration, alveolar distraction osteogenesis, sandwich osteotomies and autogenous block grafting. This is a pre-clinical study of lengthening the alveolar bone height using a thin osteoperiosteal bone flap, the "island bone flap" or i-flap, to establish vitality, stability and incorporation of the augmentation material after healing. MATERIALS AND METHODS: A rabbit tibia model was designed for this study and included 8 rabbits. An osteoperiosteal osteotomy was performed through the periosteum cutting 1 mm of the outer cortex of the bone in order to elevate a bone flap. The bone flap was detached, and remained attached to the periosteum as a free floating osteoperiosteal flap, and the resultant defect was filled with xenograft. RESULTS: The histological analysis demonstrates formation of maturing trabeculae in the site of the i-flap. In cases of trauma to the bone marrow during the surgical procedure, a centripetal gradient of bone remodeling from the surgical site toward the periphery was evident, while the bony component of the i flap maintained vital. CONCLUSIONS: Creating a free floating osteoperiosteal flap, used here with interpositional grafting in a rabbit tibia, appears to heal by both appositional modeling and creeping substitution remodeling. Volumetric augmentation persisted despite exuberant bone turnover in this animal model. This technique holds promise as a possible augmentation bone grafting approach for use in alveolar reconstruction. PMID- 21549484 TI - Transoral robotic surgery for tongue-base adenoid cystic carcinoma. PMID- 21549485 TI - A study of 2 bone plating methods for fractures of the mandibular symphysis/body. AB - PURPOSE: The purpose of this investigation was to evaluate outcomes for 2 bone plating techniques used in the treatment of mandibular symphysis/body fractures. PATIENTS AND METHODS: All patients with adequate records treated for fractures of the mandibular body or symphysis by 2 miniplates or 1 stronger plate over an 11 year period were included. Demographic and outcome variables were collected and statistically analyzed to determine if the 2 treatments produced different outcomes. RESULTS: Six hundred eighty-two patients had sufficient follow-up for inclusion in this study. There were no significant differences in demographic data for the 2 groups. There were no statistically significant differences in occlusal or osseous healing outcomes. However, there were significant differences in treatment outcomes for several variables, including wound dehiscence, plate exposure, the need for plate removal, and tooth root damage between the groups. CONCLUSION: The use of 2 miniplates was associated with more postoperative complications than the use of 1 stronger plate, but both techniques produced sufficient stability for healing. PMID- 21549486 TI - Effectiveness of postoperative antibiotics in orthognathic surgery: a meta analysis. AB - PURPOSE: To conduct a systematic review of published clinical trials on the effectiveness of extended postoperative antibiotics in orthognathic surgery. MATERIALS AND METHODS: Electronic databases were searched for randomized clinical trials. Data from relevant articles were extracted and assessed. The primary outcome variable was surgical site infection. Extracted data were analyzed using a meta-analytical program with a random effects model. RESULTS: In total 532 patients were assessed in 8 clinical trials. Wound infection occurred in 30 of 268 patients in the short-term prophylaxis group (frequency, 11.2%) and in 10 of 264 patients in the extended-term group (frequency, 3.8%). Extended antibiotic therapy was more effective in decreasing the risk of postoperative wound infection (odds ratio, 3.2; number needed to treat, 13.5). CONCLUSION: Extended postoperative antibiotic treatment does have a place in decreasing the risk of postoperative wound infection in orthognathic surgery. More trials are needed to standardize a proper regimen. PMID- 21549487 TI - Clinical importance of morphology and nomenclature of distal attachment of temporalis tendon. AB - PURPOSE: The objective of the present study was to examine and clinically relate the morphology of the anterior distal temporalis tendon attachment and describe its osseous nomenclature. The temporalis tendon muscle is arguably 1 of the 2 most important muscles of mastication. MATERIALS AND METHODS: Contemporary anatomy texts and atlases regarding the anterior distal temporalis tendon attachment demonstrate a coronoid process attachment and/or an extension inferiorly along the anterior border of the ramus, and its representation is often unclear and inconsistent. The osseous nomenclature of the retromolar triangle or fossa where the anterior distal temporalis tendon attaches is even less clear in most texts and atlases. We conducted a literature review and dissected 30 embalmed human cadavers to examine the morphology of the anterior distal temporalis tendon, including an analysis of commonly used anatomic texts and atlases. RESULTS: Only 2 of 24 texts described or illustrated a retromolar triangle area (although not labeled) for anterior distal temporalis tendon insertion. Including the variations, we observed that the distal insertion continues downward onto the retromolar triangle, posterior to the mandibular third molar. The dissection results revealed that the anterior distal temporalis tendon consistently attached onto the medial and lateral borders of the retromolar triangle or fossa. Clinically, the anterior distal temporalis tendon is a landmark for manual temporomandibular junction reduction and identifying the long buccal nerve. CONCLUSIONS: The results of the present study suggest the anterior distal temporalis tendon attachment could be further depicted and that the nomenclature of the retromolar triangle and fossa should be consistently included because of their clinical relevance. PMID- 21549488 TI - Treatment of intracapsular condylar fractures with resorbable pins. PMID- 21549489 TI - Risk factors for neurosensory disturbance after bilateral sagittal split osteotomy based on position of mandibular canal and morphology of mandibular angle. AB - PURPOSE: The aim of the present study was to evaluate the potential morphologic risk factors for postoperative neurosensory disturbance (NSD) after bilateral sagittal split osteotomy. PATIENTS AND METHODS: The study subjects were 30 skeletal Class III patients (9 males and 21 females), with a mean age of 22.0 years (range, 16-39 years). All patients underwent bilateral sagittal split osteotomy for setback to correct mandibular prognathism. The bone marrow space between the outer mandibular canal and the lateral cortex of the ramus was measured on transaxial computed tomography images, and the length at the mandibular angle between the retromolar and gonion was measured on the lateral cephalograms. The NSD was tested bilaterally using discrimination to touch with the sharp head of a mechanical probe. Each patient was evaluated at 1, 3, and 6 months postoperatively. RESULTS: The median bone marrow space was 1.96 mm (range, 0-4.5 mm), and median length of the mandibular angle was 30.93 mm (range, 23-37 mm). Neurosensory disturbance was present on 15 sides (25.0%) at 1 month postoperatively, 9 sides (15.0%) at 3 months postoperatively, and 7 sides (11.7%) at 6 months postoperatively. The difference in the incidence of NSD with a small bone marrow space and a long mandibular angle from that with a large bone marrow space and short mandibular angle was highly statistically significant (P = .006 and P < .01, respectively). CONCLUSIONS: The frequency of NSD after bilateral sagittal split osteotomy in Class III cases was dependent not only on the position of mandibular canal, but also on the length of the mandibular angle. A lateral course of the mandibular canal and a long mandibular angle appeared to result in a high risk of injury to the inferior alveolar nerve, resulting in NSD owing to a compromised splitting procedure. PMID- 21549490 TI - Use of cone beam computed tomography to volumetrically assess alveolar cleft defects--preliminary results. AB - PURPOSE: The purpose of this study was to determine the utility of cone beam computed tomographic (CBCT) imaging in assessing the volume of alveolar cleft defects in patients undergoing secondary cleft repair. MATERIALS AND METHODS: Fourteen patients with unilateral clefts were analyzed in a retrospective study. Preoperative CBCT imaging of patients preparing to undergo secondary repair of alveolar clefts was reviewed. Using anatomic landmarks, 3 measurements were collected from CBCT images for each patient: facial width (FW), facial height (FH), and facial-palatal length (FL). These values were used to calculate the estimated volume (EV) of the cleft and thus the amount of bone graft material that would be needed to fill the defect. RESULTS: The overall mean values of FW, FH, and FL were 9.7 +/- 3.1, 14.07 +/- 2.7, and 5.6 +/- 0.8 mm, respectively. Mean EV was 489.0 +/- 151.6 mm(3). The single (0.879) and average (0.956) measurements of the intraclass correlation coefficient for FH were very good to excellent. Similar data were observed for FH (single, 0.827; average, 0.935). For FL, a decreasing trend in the mean and variability over the 3 measurement times was reflected in low single (0.305) and moderate average (0.569) intraclass correlation coefficients. CONCLUSIONS: CBCT imaging can be used to reliably measure FW, FH, and FL and to calculate the EV of the cleft. These data can be used by oral and maxillofacial surgeons to quantitatively assess the volume of an alveolar cleft and aid in preoperative determination of the amount of bone that will be needed to adequately graft the cleft space. This will also aid in appropriate selection of an autogenous graft donor site before surgery. PMID- 21549491 TI - Dimensional analysis of the parietal bone in areas of surgical interest and relationship between parietal thickness and cephalic index. AB - PURPOSE: The aim of this study was to determine the thickness of the parietal bone in bone graft donor sites and to study the relationship between parietal bone thickness and gender or cephalic index. MATERIALS AND METHODS: We studied 300 parietal bones from 150 human skulls (84 male and 66 female) from individuals aged 18 to 60 years at the time of death. On each parietal bone, 9 areas were drawn by use of reference anatomic landmarks (bregma, lambda, asterion, and pterion), and bone thickness was determined in the areas adjoining the sagittal suture--superior-anterior (Sa), superior-medial (Sm), and superior-posterior (Sp). RESULTS: Mean thickness measurements ranged from 2.30 to 11.25 mm in the Sa area, from 3.08 to 13.32 mm in the Sm area, and from 2.88 to 12.26 in the Sp area. Smaller mean measurements were observed in the Sa area, with the smallest mean thickness being found in brachycephalic female specimens. The largest mean thickness was also found in female specimens in the Sm area. Statistically significant differences between genders were found only in the Sa area in dolichocephalic and mesocephalic specimens. CONCLUSION: Although the best bone graft donor site surgically is different in individuals of different genders and with different cephalic indexes, our findings suggest that harvesting from the anterosuperior area of the parietal bone should not be performed. PMID- 21549492 TI - Analysis of different treatment protocols for fractures of condylar process of mandible. AB - PURPOSE: The present study was conducted to provide an overall perspective on the diagnosis of condylar fractures, to analyze the technique and results of different treatment methods used, and to evolve a protocol for the selection of an appropriate treatment modality for an individual case. PATIENTS AND METHODS: A total of 28 patients with a condylar fracture were selected and were classified with the help of orthopantomogram and reverse Towne view radiographs. Of the 28 patients, 22 had unilateral fractures of the mandibular condyle process and 6 had bilateral fractures. They were treated with no invasive treatment, closed reduction with maxillomandibular fixation, or open reduction with internal semirigid fixation. RESULTS: No significant difference was observed in the occlusion, maintenance of fixation of anatomically reduced fractured bony segments, trismus index, movements of the mandible (ie, opening, protrusion, and lateral excursions), or masticatory efficiency. The only significant difference was the subjective discomfort of the surgically treated patients in terms of pain on movement and mastication, swelling, neurologic deficit, and parotid fistula formation. CONCLUSION: Patients with a condylar fracture with no displacement, dislocation, or derangement of occlusion seem best treated with medication only for symptomatic relief without any invasive treatment. Patients with derangement of occlusion or displacement of fractured fragments, especially in unilateral cases, seem best treated with closed reduction and maxillomandibular fixation, with medication for symptomatic relief and postoperative physiotherapy. Patients with deranged occlusion, displaced bony fractured fragments, and a dislocated condylar process out of the glenoid fossa, especially bilateral cases, seem best treated with open reduction with internal semirigid fixation. PMID- 21549493 TI - Extraction of 6 molars under general anesthesia in patient with fibrodysplasia ossificans progressiva. PMID- 21549494 TI - [Usefulness of coronary computed tomography in real practice]. PMID- 21549495 TI - Management of cardiac arrest in pregnancy: a systematic review. AB - OBJECTIVE: To describe the consensus on science pertaining to resuscitation of the pregnant patient. DESIGN: Systematic review. DATA SOURCES: EMBASE, Ovid MEDLINE, Evidence Based Reviews, American Heart Association library and bibliographies of selected articles. REVIEW METHODS: The following inclusion criteria were used: pregnancy and cardiac arrest out of hospital, pregnancy and cardiac arrest in hospital, cardiovascular, respiratory, fetal survival, and pharmacology as they relate to cardiac arrest and resuscitation. Non-English papers, case reports and reviews were excluded. Studies were selected through an independent review of titles, abstracts and full article. Two reviewers independently graded the methodological quality of selected articles. RESULTS: 1305 articles were identified and 5 were selected for further review. There were no randomized trials and overall the quality of the selected studies was good. Two studies examined chest compressions on a manikin in left lateral tilt from the horizontal and concluded that although feasible with increasing degrees of tilt forcefulness of the chest compressions decreases. The third study observed the transthoracic impedance was not altered during pregnancy. One case series and one retrospective cohort study reviewed perimortem cesarean section. Both reports concluded that perimortem cesarean section is rarely done within the recommended time frame of 5 min after the onset of maternal cardiac arrest. CONCLUSIONS: Usual defibrillation dosages are likely appropriate in pregnancy. Perimortem cesarean section is an intervention which is rarely done within 5 min to optimize maternal salvage from cardiac arrest. Chest compressions in left lateral tilt are less forceful compared to the supine position. PMID- 21549496 TI - Possible DRESS syndrome in a child with borreliosis. PMID- 21549497 TI - Case report: specific immunotherapy with dust mite allergens in a child with severe atopic dermatitis. PMID- 21549498 TI - Conformational heterogeneity and dynamics in a betagamma-crystallin from Hahella chejuensis. AB - Most of the betagamma-crystallins are structural proteins with high intrinsic stability, which gets enhanced by Ca(2+)-binding in microbial members. Functions of most of these proteins are yet to be known. However, a few of them were reported to be involved in Ca(2+)-dependent and stress-related functions. Hahellin, a microbial homolog, is a natively unfolded protein that acquires a well-folded structure upon Ca(2+) binding. Although the structure of betagamma crystallin domains is well understood, the dynamical features are yet to be explored. We have investigated for the first time the equilibrium dynamics, conformational heterogeneity and associated low-lying free-energy states of hahellin in its Ca(2+)-bound form using NMR spectroscopy to understand the dynamics of a betagamma-crystallin domain. Hahellin shows large conformational heterogeneity with nearly 40% of the residues, some of which are part of Ca(2+) binding loops, accessing alternative states. Further, out of the two Greek key motifs, which together constitute the betagamma-crystallin domain, the second Greek key motif is floppy as compared to its relatively rigid counterpart. Taken together, we believe that these characteristics might be of importance to understand the stability and functions of betagamma-crystallin domains. PMID- 21549499 TI - Determination of arsenic levels in the water resources of Aksaray Province, Turkey. AB - Arsenic levels were determined in 62 stations utilized as drinking and potable water resources by local community for Turkey's Aksaray Province (4589 km(2); 980 m above sea level). The samplings were implemented every two months for 1 year. The arsenic values were found to be ranging between 10 and 50 MUg/L in 22 points and were found to be >50 MUg/L in 5 stations, according to the mean value of the 6 samples. WHO and the Turkish Standards have permitted an arsenic concentration of 10 MUg/L in drinking waters. The multivariate statistical technique, cluster analysis (CA), followed by principal component analysis (PCA) were applied to the data on 17 water quality parameters in 47 stations that are used for drinking and other domestic resources. Two significant sampling locations were detected based on the similarity of their water quality. The chemical correlations were observed in the two sub-sampling locations by Principal Component Analysis. PMID- 21549500 TI - Performance of lime-BHA solidified plating sludge in the presence of Na2SiO3 and Na2CO3. AB - This research investigated the performance of lime-BHA (black rice husk ash) solidified plating sludge with 2 wt% NaO from Na(2)SiO(3) and Na(2)CO(3) at the level of 0, 30 and 50 wt%. The sludge was evaluated for strength development, leachability, solution chemistry and microstructure. The lime-BHA solidified plating sludge with Na(2)SiO(3) and Na(2)CO(3) had higher early strength when compared to the control. The addition of Na(2)SiO(3) and Na(2)CO(3) increased the OH(-) concentration and decreased the Ca(2+) and heavy metal ions in solution after the first minute. The XRD patterns showed that the addition of Na(2)SiO(3) resulted in the formation of calcium silicate hydrates, while the addition of Na(2)CO(3) resulted in CaCO(3). The heavy metals from the plating sludge, especially Zn, were immobilized in calcium zincate and calcium zinc silicate forms for the lime-BHA with and without Na(2)SiO(3) solidified wastes, while samples with Na(2)CO(3) contained Zn that was fixed in the form of CaZnCO(3). The cumulative leaching of Fe, Cr and Zn from the lime-BHA solidified plating sludge decreased significantly when activators were added, especially Na(2)CO(3). PMID- 21549502 TI - Environmental and health risks of chlorine trifluoride (ClF3), an alternative to potent greenhouse gases in the semiconductor industry. AB - The first accident involving chlorine trifluoride (ClF(3)) in the history of semiconductor fabrication processes occurred on 28 July 2006 at Hsinchu (Taiwan), resulting in a large release of the highly reactive material and causing the chemical burn to several workers. ClF(3) is used primarily as an in situ cleaning gas in the manufacture of semiconductor silicon-wafer devices in replacement of perfluorocompounds (PFCs) because they have the high potential to contribute significantly to the global warming. This article aimed at reviewing ClF(3) in the physicochemical properties, the industrial uses, and the environmental implications on the basis of its toxicity, reactivity, health hazards and exposure limits. The health hazards of probable decomposition/hydrolysis products from ClF(3) were also evaluated based on their basic physicochemical properties and occupational exposure limits. The occupational exposure assessment was further discussed to understand potentially hazardous risks caused by hydrogen fluoride and fluorides from the decomposition/hydrolysis products of ClF(3). PMID- 21549503 TI - Adsorption of dimethyl sulfide from aqueous solution by a cost-effective bamboo charcoal. AB - The adsorption of dimethyl sulfide from an aqueous solution by a cost-effective bamboo charcoal from Dendrocalamus was studied in comparison with other carbon adsorbents. The bamboo charcoal exhibited superior adsorption on dimethyl sulfide compared with powdered activated carbons at different adsorbent dosages. The adsorption characteristics of dimethyl sulfide onto bamboo charcoal were investigated under varying experimental conditions such as particle size, contact time, initial concentration and adsorbent dosage. The dimethyl sulfide removal was enhanced from 31 to 63% as the particle size was decreased from 24-40 to >300 mesh for the bamboo charcoal. The removal efficiency increased with increasing the adsorbent dosage from 0.5 to 10mg, and reached 70% removal efficiency at 10mg adsorbed. The adsorption capacity (MUg/g) increased with increasing concentration of dimethyl sulfide while the removal efficiency decreased. The adsorption process conforms well to a pseudo-second-order kinetics model. The adsorption of dimethyl sulfide is more appropriately described by the Freundlich isotherm (R(2), 0.9926) than by the Langmuir isotherm (R(2), 0.8685). Bamboo charcoal was characterized by various analytical methods to understand the adsorption mechanism. Bamboo charcoal is abundant in acidic and alcohol functional groups normally not observed in PAC. A distinct difference is that the superior mineral composition of Fe (0.4 wt%) and Mn (0.6 wt%) was detected in bamboo charcoal elements not found in PAC. Acidic functional group and specific adsorption sites would be responsible for the strong adsorption of dimethyl sulfide onto bamboo charcoal of Dendrocalamus origin. PMID- 21549504 TI - Combined effects of DOM extracted from site soil/compost and biosurfactant on the sorption and desorption of PAHs in a soil-water system. AB - The combined effects of DOM and biosurfactant on the sorption/desorption behavior of phenanthrene (PHE) and pyrene (PYR) in soil water systems were systematically investigated. Two origins of DOMs (extracted from soil and extracted from food waste compost) and an anionic biosurfactant (rhamnolipid) were introduced. The presence of DOM in the aqueous phase could decrease the sorption of PAHs, thus influence their mobility. Desorption enhancement for both PHE and PYR in the system with compost DOM was greater than that in the soil DOM system. This is due to the differences in specific molecular structures and functional groups of two DOMs. With the co-existence of biosurfactant and DOM, partitioning is the predominant process and the desorption extent was much higher than the system with DOM or biosurfactant individually. For PHE, the desorption enhancement of combined DOM and biosurfactant was larger than the sum of DOM or biosurfactant; however desorption enhancement for PYR in the combined system was less than the additive enhancement in two individual system under low PAH concentration. This could be explained as the competition sorption among PAHs, DOM and biosurfactant. The results of this study will help to clarify the transport of petroleum pollutants in the remediation of HOCs-contaminated soils. PMID- 21549505 TI - Environmental impact and site-specific human health risks of chromium in the vicinity of a ferro-alloy manufactory, China. AB - Previous studies often neglected the direct exposure to soil heavy metals in human health risk assessment. The purpose of this study was to assess the environmental impact and site-specific health risks of chromium (Cr) by both direct and indirect exposure assessment method. Results suggested that total Cr was shown a substantial buildup with a significant increase in the industrial and cultivated soils (averaged 1910 and 986 mg kg(-1), respectively). The Cr contents of vegetables exceeded the maximum permissible concentration by more than four times in every case. Human exposure to Cr was mainly due to dietary food intake in farming locations and due to soil ingestion in both industrial and residential sites. Soil ingestion was the main contributor pathway for direct exposure, followed by inhalation, and then dermal contact. The highest risks of vegetable ingestion were associated with consumption of Chinese cabbage. The results also indicated that plant tissues are able to convert the potentially toxic Cr (VI) species into the non-toxic Cr (III) species. The analyses of human health risks indicated that an important portion of the population is at risk, especially in the industrial site. PMID- 21549506 TI - Dorsal root entry zone lesioning for pain after brachial plexus avulsion: results with special emphasis on differential effects on the paroxysmal versus the continuous components. A prospective study in a 29-patient consecutive series. AB - Pain after brachial plexus avulsion (BPA) is generally characterized by 2 main different components: paroxysmal (electrical shooting-like) pain, and continuous (burning) pain. Dorsal root entry zone (DREZ) lesioning, namely, the microsurgical DREZotomy (MDT) used in our practice, has proved to be a worthwhile neurosurgical treatment for this indication. However, according to previous studies, the method does not seem to demonstrate as good effectiveness in patients in whom the continuous background of pain was predominant as in patients with the paroxysmal component predominating. To obtain more insight into this problem, a prospective study on an eventual differential effect of the MDT procedure on the 2 components was undertaken. The presented series included 29 consecutive patients affected with pain after BPA who underwent an operation over the 10 last years. Pain intensity was evaluated using a visual analogue scale (VAS). At last evaluation of the 26 patients followed for 12 to 122 months (60 months on average) after MDT, 76.9% had a good or excellent global pain relief after surgery, ie, pain control with or without additional nonopioid medications, respectively. According to the component types of pain, 84.6% of patients had good or excellent control of the paroxysmal pain, and 73.1% of the continuous pain. Kaplan-Meier prediction of lasting global pain control at 120 months of follow-up was calculated at 41.1%. Comparison of the 2 corresponding Kaplan-Meier curves at long term, namely, pain control in 76.2% for the paroxysmal component and in 43.1% for the continuous component, showed a statistically significant difference (P=.038). Hypotheses for this relative differential effect are discussed. PMID- 21549507 TI - Fibrin sealant improves graft adherence in a porcine full-thickness burn wound model. AB - INTRODUCTION: Autograft take and rapid wound closure is essential for the survival of severely burned patients. Loss of skin grafts typically occurs during the first few days after coverage, mainly due to shear forces and inadequate contact with the wound bed. Slow-clotting fibrin sealant, applied with a spray-on device, has been shown to improve healing of skin grafts in large wounds. However, its use in burn wounds has not been studied so far. STUDY AIM: To evaluate the effectiveness of sprayed fibrin sealant in excised and grafted full thickness burns. MATERIAL AND METHODS: Ten female Yorkshire pigs (30-45 kg) received a full-thickness contact burn of approximately 15% total body surface area. The burns were excised to the level of the muscular fascia after 24 h and covered with meshed skin autograft (mesh ratio 1:3). Wounds were randomized to either fibrin sealant (n=20) or standard skin staples (n=16) for graft fixation. Fibrin sealant was used as a slow-clotting spray (4 IU thrombin/ml). Outcome measurements included clinical scoring at days 2, 5, 9 and 14 postoperatively, planimetric analysis of wound closure, and histological examination of epidermal and dermal thickness 14 days after autografting. RESULTS: In the fibrin sealant group, graft adherence scores were significantly increased (p<0.02) and graft dislocation scores significantly decreased (p<0.01) at days 2 and 5 postoperatively, when compared to controls. Planimetric analysis of remaining open mesh interstices showed acceleration of wound closure in the fibrin sealant group but did not reach statistical significance (day 14 p=0.04 at significance level p<0.025). Wound contraction, occurrence of hematoma, and dermal as well as epidermal thickness were not different between the groups at 14 days postoperatively. CONCLUSION: The results indicate that the use of slow-clotting fibrin sealant spray for autograft fixation is advantageous over skin staples. Easy handling and reduced graft dislocation at early time points are key qualities of this method. PMID- 21549508 TI - HER2 shedding and serum HER2 extracellular domain: biology and clinical utility in breast cancer. AB - The transmembrane protein HER2 is over-expressed in approximately 15% of invasive breast cancers as a result of HER2 gene amplification. HER2 proteolytic cleavage (HER2 shedding) generates soluble truncated HER2 molecules that include only the extracellular domain and the concentration of which can be measured in the serum fraction of blood. HER2 shedding also generates a constitutively active truncated intracellular receptor of 95kDa (p95(HER2)). Another soluble truncated HER2 protein (Herstatin), which can also be found in serum, is the product of an alternatively spliced HER2 transcript. Recent preclinical findings may provide crucial insights into the biological and clinical relevance of increased sHER2 concentrations for the outcome of HER2-positive breast cancer and sensitivity to trastuzumab and lapatinib treatment. We present here the most recent findings about the role and biology of sHER2 based on data obtained using a standardized test, which has been cleared by FDA in 2000, for measuring sHER2. This test includes quality control assessments and has been already widely used to evaluate the clinical utility of sHER2 as a biomarker in breast cancer. We will describe in detail data concerning the assessment of sHER2 as a surrogate maker to optimize the evaluation of the HER2 status of a primary tumor and as a prognosis and predictive marker of response to therapies, both in early and metastatic breast cancer. PMID- 21549509 TI - Naloxone-induced cortisol predicts mu opioid receptor binding potential in specific brain regions of healthy subjects. AB - Investigators have administered the opioid receptor antagonist, naloxone, to interrogate the hypothalamic-pituitary-adrenal (HPA) axis response under the assumption that this technique provides a measure of endogenous opioid activity. However it has never been tested whether provocation of the HPA axis with naloxone provides a surrogate marker for direct measurement of endogenous opioid activity using PET imaging as the gold standard. To test this hypothesis, eighteen healthy subjects underwent a PET scan with the mu-opioid receptor (MOR) selective ligand [(11)C]carfentanil (CFN). The following day ACTH and cortisol responses were assessed using a technique which allows administration of 5 incremental doses of naloxone (0, 25, 50, 100 and 250MUg/kg) in a single session. Relationships between ACTH and cortisol responses and [(11)C]CFN binding potential (BP(ND)) were examined in 5 brain regions involved in the regulation of the HPA axis and/or regions with high concentrations of MOR. All subjects mounted graded ACTH and cortisol responses to naloxone administrations. There were significant negative relationships between cortisol response to naloxone and [(11)C]CFN BP(ND) in ventral striatum, putamen and caudate. When sex and smoking were added as covariates to the model, these correlations were strengthened and there was a significant correlation with the hypothalamus. There were no significant correlations between ACTH and any volumes of interest. The opioid receptor antagonist naloxone is not merely a non-specific pharmacologic activator of the HPA axis; it provides information about individual differences in opioid receptor availability. PMID- 21549510 TI - Sex steroids, insulin sensitivity and sympathetic nerve activity in relation to affective symptoms in women with polycystic ovary syndrome. AB - CONTEXT: Affective symptoms are poorly understood in polycystic ovary syndrome (PCOS). Clinical signs of hyperandrogenism and high serum androgens are key features in PCOS, and women with PCOS are more likely to be overweight or obese, as well as insulin resistant. Further, PCOS is associated with high sympathetic nerve activity. OBJECTIVE: To elucidate if self-reported hirsutism, body mass index (BMI) and waistline, circulating sex steroids, sex hormone-binding globulin (SHBG), insulin sensitivity and sympathetic nerve activity are associated with depression and anxiety-related symptoms in women with PCOS. DESIGN AND METHODS: Seventy-two women with PCOS, aged 21-37 years, were recruited from the community. Hirsutism was self-reported using the Ferriman-Gallway score. Serum estrogens, sex steroid precursors, androgens and glucuronidated androgen metabolites were analyzed by gas and liquid chromatography/mass spectroscopy (GC-MS/LC-MS/MS) and SHBG by chemiluminiscent microparticle immunoassay (CMIA). Insulin sensitivity was measured with euglycemic hyperinsulinemic clamp. Sympathetic nerve activity was measured with microneurography. Symptoms of depression and anxiety were self reported using the Montgomery Asberg Depression Rating Scale (MADRS-S) and the Brief Scale for Anxiety (BSA-S). RESULTS: Circulating concentrations of testosterone (T) (P=0.026), free T (FT) (P=0.025), and androstane-3alpha 17beta diol-3glucuronide (3G) (P=0.029) were lower in women with depression symptoms of potential clinical relevance (MADR-S>=11). The odds of having a MADRS-S score >=11 were higher with lower FT and 3G. No associations with BSA-S were noted. CONCLUSION: Lower circulating FT and 3G were associated with worse self-reported depression symptoms. The relationship between mental health, sex steroids and corresponding metabolites in PCOS requires further investigation. PMID- 21549511 TI - The possible role of hemochromatosis in testicular cancer. AB - Hemochromatosis is a genetic disorder of iron metabolism that results in elevated iron absorption in the intestines, which leads to progressive iron accumulation in a variety of organs. Studies have shown that excessive iron deposits in the liver due to hereditary hemochromatosis leads to cirrhosis, which can put an individual at increased risk for developing hepatocellular carcinoma. Testicular atrophy, sometimes caused by excessive iron deposition in the testes, is a risk factor for testicular cancer. Therefore, the possible role of hereditary hemochromatosis in testicular cancer is explored. PMID- 21549512 TI - Neurotransmitters in disorders of consciousness and brain damage. AB - Restorations from disorders of consciousness such as the minimally conscious state and the vegetative state have been achieved spontaneously or by pharmacological agents such as zolpidem, baclofen, dopaminergic agents and tricyclic antidepressants in some patients. Other restoration methods have included electric and magnetic nerve stimulation, oxygen, Kreb's cycle constituent substitution and axonal re-growth. Although apparently unrelated, these methods all influence neurotransmitter availability or production within the brain. This review proposes depleted neurotransmitter function as a cause for long term brain suppression and disorders of consciousness. It unifies fundamentally different treatment approaches and explores the restoration of neurotransmitter function as a common theme to improve brain function after brain damage. PMID- 21549513 TI - Role of systemic therapy in the development of lung sequelae after conformal radiotherapy in breast cancer patients. AB - PURPOSE: To analyze the risk of radiogenic lung damage in breast cancer patients after conformal radiotherapy and different forms of systemic treatment. METHODS AND MATERIALS: In 328 patients receiving sequential taxane-based chemotherapy, concomitant hormone therapy (tamoxifen or aromatase inhibitors), or no adjuvant systemic therapy, symptomatic and asymptomatic lung sequelae were prospectively evaluated via the detection of visible CT abnormalities, 3 months or 1 year after the completion of the radiotherapy. RESULTS: Significant positive associations were detected between the development of both pneumonitis and fibrosis of Grade 1 and patient age, ipsilateral mean lung dose, volume of the ipsilateral lung receiving 20 Gy, and irradiation of the regional lymph nodes. In multivariate analysis, age and mean lung dose proved to be independent predictors of early (odds ratio [OR] = 1.035, 95% confidence interval [CI] 1.011-1.061 and OR = 1.113, 95% CI 1.049-1.181, respectively) and late (OR = 1.074, 95% CI 1.042-1.107 and OR = 1.207, 95% CI 1.124-1.295, respectively) radiogenic lung damage, whereas the role of systemic therapy was significant in the development of Grade 1 lung fibrosis (p = 0.01). Among the various forms of systemic therapy, tamoxifen increased the risk of late lung sequelae (OR = 2.442, 95% CI 1.120-5.326, p = 0.025). No interaction was demonstrated between the administration of systemic therapy and the other above-mentioned parameters as regards the risk of radiogenic lung damage. CONCLUSIONS: Our analyses demonstrate the independent role of concomitant tamoxifen therapy in the development of radiogenic lung fibrosis but do not suggest such an effect for the other modes of systemic treatment. PMID- 21549514 TI - Phase I study of conformal radiotherapy and concurrent full-dose gemcitabine with erlotinib for unresected pancreatic cancer. AB - PURPOSE: To determine the recommended dose of radiotherapy when combined with full-dose gemcitabine and erlotinib for unresected pancreas cancer. METHODS AND MATERIALS: Patients with unresected pancreatic cancer (Zubrod performance status 0-2) were eligible for the present study. Gemcitabine was given weekly for 7 weeks (1,000 mg/m(2)) with erlotinib daily for 8 weeks (100 mg). A final toxicity assessment was performed in Week 9. Radiotherapy (starting at 30 Gy in 2-Gy fractions, 5 d/wk) was given to the gross tumor plus a 1-cm margin starting with the first dose of gemcitabine. A standard 3 plus 3 dose escalation (an additional 4 Gy within 2 days for each dose level) was used, except for the starting dose level, which was scheduled to contain 6 patients. In general, Grade 3 or greater gastrointestinal toxicity was considered a dose-limiting toxicity, except for Grade 3 anorexia or Grade 3 fatigue alone. RESULTS: A total of 20 patients were treated (10 men and 10 women). Nausea, vomiting, and infection were significantly associated with the radiation dose (p = .01, p = .03, and p = .03, respectively). Of the 20 patients, 5 did not complete treatment and were not evaluable for dose escalation purposes (3 who developed progressive disease during treatment and 2 who electively discontinued it). Dose-limiting toxicity occurred in none of 6 patients at 30 Gy, 2 of 6 at 34 Gy, and 1 of 3 patients at 38 Gy. CONCLUSION: The results of the present study have indicated that the recommended Phase II dose is 30 Gy in 15 fractions. PMID- 21549515 TI - Impact of gender, partner status, and race on locoregional failure and overall survival in head and neck cancer patients in three radiation therapy oncology group trials. AB - PURPOSE: We investigated the impact of race, in conjunction with gender and partner status, on locoregional control (LRC) and overall survival (OS) in three head and neck trials conducted by the Radiation Therapy Oncology Group (RTOG). METHODS AND MATERIALS: Patients from RTOG studies 9003, 9111, and 9703 were included. Patients were stratified by treatment arms. Covariates of interest were partner status (partnered vs. non-partnered), race (white vs. non-white), and sex (female vs. male). Chi-square testing demonstrated homogeneity across treatment arms. Hazards ratio (HR) was used to estimate time to event outcome. Unadjusted and adjusted HRs were calculated for all covariates with associated 95% confidence intervals (CIs) and p values. RESULTS: A total of 1,736 patients were analyzed. Unpartnered males had inferior OS rates compared to partnered females (adjusted HR = 1.22, 95% CI, 1.09-1.36), partnered males (adjusted HR = 1.20, 95% CI, 1.09-1.28), and unpartnered females (adjusted HR = 1.20, 95% CI, 1.09-1.32). White females had superior OS compared with white males, non-white females, and non-white males. Non-white males had inferior OS compared to white males. Partnered whites had improved OS relative to partnered non-white, unpartnered white, and unpartnered non-white patients. Unpartnered males had inferior LRC compared to partnered males (adjusted HR = 1.26, 95% CI, 1.09-1.46) and unpartnered females (adjusted HR = 1.30, 95% CI, 1.05-1.62). White females had LRC superior to non-white males and females. White males had improved LRC compared to non-white males. Partnered whites had improved LRC compared to partnered and unpartnered non-white patients. Unpartnered whites had improved LRC compared to unpartnered non-whites. CONCLUSIONS: Race, gender, and partner status had impacts on both OS and locoregional failure, both singly and in combination. PMID- 21549516 TI - Primary tumor volume is an important predictor of clinical outcomes among patients with locally advanced squamous cell cancer of the head and neck treated with definitive chemoradiotherapy. AB - PURPOSE: The tumor volume has been established as a significant predictor of outcomes among patients with head-and-neck cancer undergoing radiotherapy alone. The present study attempted to add to the existing data on tumor volume as a prognostic factor among patients undergoing chemoradiotherapy. METHODS AND MATERIALS: A total of 78 patients who had undergone definitive chemoradiotherapy for Stage III-IV squamous cell cancer of the hypopharynx, oropharynx, and larynx were identified. The primary tumor volumes were calculated from the treatment planning computed tomography scans, and these were correlated to the survival and tumor control data obtained from the retrospective analysis. RESULTS: The interval to progression correlated with the primary tumor volume (p = .007). The critical cutoff point for the tumor volume was identified as 35 cm(3), and patients with a tumor volume <35 cm(3) had a significantly better prognosis than those with a tumor volume >35 cm(3) at 5 years (43% vs. 71%, p = .010). Longer survival was also correlated with smaller primary tumor volumes (p = .022). Similarly, patients with a primary tumor volume <35 cm(3) had a better prognosis in terms of both progression-free survival (61% vs. 33%, p = .004) and overall survival (84% vs. 41%, p = < .001). On multivariate analysis, the primary tumor volume was the best predictor of recurrence (hazard ratio 4.7, 95% confidence interval 1.9-11.6; p = .001) and survival (hazard ratio 10.0, 95% confidence interval 2.9-35.1; p = < .001). In contrast, the T stage and N stage were not significant factors. Analysis of variance revealed that tumors with locoregional failure were on average 21.6 cm(3) larger than tumors without locoregional failure (p = .028) and 27.1-cm(3) larger than tumors that recurred as distant metastases (p = .020). CONCLUSION: The results of our study have shown that the primary tumor volume is a significant prognostic factor in patients with advanced cancer of the head and neck undergoing definitive chemoradiotherapy and correlated with the treatment outcomes better than the T or N stage. PMID- 21549517 TI - Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. AB - PURPOSE: This Phase II trial evaluated the toxicity, local control, and overall survival in patients treated with sequential gemcitabine and linear accelerator based single-fraction stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Twenty patients with locally advanced, nonmetastatic pancreatic adenocarcinoma were enrolled on this prospective single-institution, institutional review board-approved study. Gemcitabine was administered on Days 1, 8, and 15, and SBRT on Day 29. Gemcitabine was restarted on Day 43 and continued for 3-5 cycles. SBRT of 25 Gy in a single fraction was delivered to the internal target volume with a 2- 3-mm margin using a nine-field intensity modulated radiotherapy technique. Respiratory gating was used to account for breathing motion. Follow-up evaluations occurred at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. RESULTS: All patients completed SBRT and a median of five cycles of chemotherapy. Follow-up for the 2 remaining alive patients was 25.1 and 36.4 months. No acute Grade 3 or greater nonhematologic toxicity was observed. Late Grade 3 or greater toxicities occurred in 1 patient (5%) and consisted of a duodenal perforation (G4). Three patients (15%) developed ulcers (G2) that were medically managed. Overall, median survival was 11.8 months, with 1-year survival of 50% and 2-year survival of 20%. Using serial computed tomography, the freedom from local progression was 94% at 1 year. CONCLUSION: Linear accelerator-delivered SBRT with sequential gemcitabine resulted in excellent local control of locally advanced pancreatic cancer. Future studies will address strategies for reducing long-term duodenal toxicity associated with SBRT. PMID- 21549518 TI - Validation of EORTC prognostic factors for adults with low-grade glioma: a report using intergroup 86-72-51. AB - PURPOSE: A prognostic index for survival was constructed and validated from patient data from two European Organisation for Research and Treatment of Cancer (EORTC) radiation trials for low-grade glioma (LGG). We sought to independently validate this prognostic index with a separate prospectively collected data set (Intergroup 86-72-51). METHODS AND MATERIALS: Two hundred three patients were treated in a North Central Cancer Treatment Group-led trial that randomized patients with supratentorial LGG to 50.4 or 64.8 Gy. Risk factors from the EORTC prognostic index were analyzed for prognostic value: histology, tumor size, neurologic deficit, age, and tumor crossing the midline. The high-risk group was defined as patients with more than two risk factors. In addition, the Mini Mental Status Examination (MMSE) score, extent of surgical resection, and 1p19q status were also analyzed for prognostic value. RESULTS: On univariate analysis, the following were statistically significant (p<0.05) detrimental factors for both progression-free survival (PFS) and overall survival (OS): astrocytoma histology, tumor size, and less than total resection. A Mini Mental Status Examination score of more than 26 was a favorable prognostic factor. Multivariate analysis showed that tumor size and MMSE score were significant predictors of OS whereas tumor size, astrocytoma histology, and MMSE score were significant predictors of PFS. Analyzing by the EORTC risk groups, we found that the low-risk group had significantly better median OS (10.8 years vs. 3.9 years, p<0.0001) and PFS (6.2 years vs. 1.9 years, p<0.0001) than the high-risk group. The 1p19q status was available in 66 patients. Co-deletion of 1p19q was a favorable prognostic factor for OS vs. one or no deletion (median OS, 12.6 years vs. 7.2 years; p=0.03). CONCLUSIONS: Although the low-risk group as defined by EORTC criteria had a superior PFS and OS to the high-risk group, this is primarily because of the influence of histology and tumor size. Co-deletion of 1p19q is a prognostic factor. Future studies are needed to develop a more refined prognostic system that combines clinical prognostic features with more robust molecular and genetic data. PMID- 21549520 TI - Risk of carotid blowout after reirradiation of the head and neck: a systematic review. AB - PURPOSE: Carotid blowout (CB) is a rare but frequently fatal complication of head and-neck (H&N) cancer or its treatment. We sought to determine the reported rate of CB in patients receiving salvage reirradiation for H&N cancer. METHODS AND MATERIALS: A literature search identified 27 published articles on H&N reirradiation involving 1554 patients, and a pooled analysis was performed to determine the rate of CB. Treatment parameters, including prior radiation dose, interval from prior radiation, dose and fractionation of reirradiation, use of salvage surgery, and chemotherapy, were abstracted and summarized. The cumulative risk of CB was compared between groups using Fisher's exact test. RESULTS: Among 1554 patients receiving salvage H&N reirradiation, there were 41 reported CBs, for a rate of 2.6%; 76% were fatal. In patients treated in a continuous course with 1.8-2-Gy daily fractions or 1.2-Gy twice-daily fractions, 36% of whom received concurrent chemotherapy, the rate of CB was 1.3%, compared with 4.5% in patients treated with 1.5 Gy twice daily in alternating weeks or with delayed accelerated hyperfractionation, all of whom received concurrent chemotherapy (p = 0.002). There was no statistically significant difference in the rate of CB between patients treated with or without concurrent chemotherapy, or between patients treated with or without salvage surgery before reirradiation. CONCLUSION: Carotid blowout is an infrequent but serious complication of salvage reirradiation for H&N cancer. The rate of CB was lower among patients treated with conventional or hyperfractionated schedules compared with regimens of accelerated hyperfractionation, though heterogeneous patient populations and treatment parameters preclude definite conclusions. Given the high mortality rate of CB, discussion of the risk of CB is an important component of informed consent for salvage reirradiation. PMID- 21549519 TI - Concurrent androgen deprivation therapy during salvage prostate radiotherapy improves treatment outcomes in high-risk patients. AB - PURPOSE: To determine whether concurrent androgen deprivation therapy (ADT) during salvage radiotherapy (RT) improves prostate cancer treatment outcomes. METHODS AND MATERIALS: A total of 630 postprostatectomy patients were retrospectively identified who were treated with three-dimensional conformal RT. Of these, 441 were found to be treated for salvage indications. Biochemical failure was defined as prostate-specific antigen (PSA) of 0.2 ng/mL or greater above nadir with another PSA increase or the initiation of salvage ADT. Progression-free survival (PFS) was defined as the absence of biochemical failure, continued PSA rise despite salvage therapy, initiation of systemic therapy, clinical progression, or distant failure. Multivariate-adjusted Cox proportional hazards modeling was performed to determine which factors predict PFS. RESULTS: Low-, intermediate-, and high-risk patients made up 10%, 24%, and 66% of patients, respectively. The mean RT dose was 68 Gy. Twenty-four percent of patients received concurrent ADT (cADT). Regional pelvic nodes were treated in 16% of patients. With a median follow-up of 3 years, the 3-year PFS was 4.0 years for cADT vs. 3.4 years for cADT patients (p = 0.22). Multivariate analysis showed that concurrent ADT (p = 0.05), Gleason score (p < 0.001), and pre-RT PSA (p = 0.03) were independent predictors of PFS. When patients were stratified by risk group, the benefits of cADT (hazard ratio, 0.65; p = 0.046) were significant only for high-risk patients. CONCLUSIONS: This retrospective study showed a PFS benefit of concurrent ADT during salvage prostate RT. This benefit was observed only in high-risk patients. PMID- 21549521 TI - Surface replacement arthroplasty of the proximal interphalangeal joint using a volar approach: case series. AB - PURPOSE: To evaluate the outcomes (range of motion, function, and pain relief) of the volar approach to proximal interphalangeal (PIP) joint surface replacement arthroplasty (SRA) in active, high-demand patients. METHODS: A single surgeon performed PIP SRA in 6 joints using a volar approach. Patients with posttraumatic arthritis or osteoarthritis of the PIP joint were included. Range of motion, postoperative key pinch and grip strength, and Disabilities of the Arm, Shoulder, and Hand questionnaire data were collected. Complications, component integration, and use of cement were noted. Average follow-up was 35 months (range, 12-66 mo). RESULTS: Total arc of motion averaged 33 degrees before surgery and improved significantly in all patients, for an average postoperative arc of motion of 60 degrees . Grip strength averaged 30 kg in the affected hand and 35 kg in the contralateral hand after surgery. Postoperative key pinch strength averaged 6 and 7 kg in ipsilateral and contralateral hands, respectively. The average Disabilities of the Arm, Shoulder, and Hand score after surgery was 14. No coronal plane deformity or postural deformity was observed. Good component integration and stability were observed in all 5 cemented joints. The only noncemented joint demonstrated progressive subsidence of both components. CONCLUSIONS: The volar approach to PIP SRA can result in excellent range of motion, function, and pain relief with minimal complications in active patients with osteoarthritis or posttraumatic arthritis. The volar approach offers the advantages of maintaining the integrity of the extensor mechanism and allowing early postoperative motion. This case series demonstrates compelling data for a prospective, randomized study comparing dorsal and volar approaches to PIP SRA in patients with osteoarthritis and posttraumatic arthritis. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 21549523 TI - Use of a bilobed second dorsal metacarpal artery-based island flap for thumb replantation. AB - PURPOSE: An extensive traumatic defect at the level of the proximal phalanx of the thumb presents difficulty in replantation. We report bilobed second dorsal metacarpal artery-based island flap harvested from both the index and middle fingers for reconstruction of the defect and preservation of the normal thumb length. METHODS: From March 2004 to October 2008, 15 patients (11 men and 4 women; mean age, 35 y; range, 18 to 55 y) with completely or incompletely amputated thumbs associated with extensive defects in the proximal phalanx had replantation and reconstruction. In all cases, a bilobed second dorsal metacarpal artery-based island flap was used due to the large size of the defect. After flap transfer, anastomoses between the veins of the distal part of the thumb and the flap were performed. At the final follow-up, we assessed the mean active range of motion of the metacarpophalangeal and interphalangeal joints of the thumb and the span of the first web in the thumbs that survived. Active motion of the donor fingers was also assessed. RESULTS: In this series, 13 thumbs survived and 2 failed. All flaps survived completely. At the mean follow-up of 27 months (range, 24 to 29 mo), the mean active motion arcs of metacarpophalangeal and interphalangeal joints were 32 degrees (range, 15 degrees to 45 degrees ) and 31 degrees (range, 0 degrees to 47 degrees ), respectively. Full active range of motion was observed in all patients in both the metacarpophalangeal and the proximal interphalangeal joints of the donor index and middle fingers. CONCLUSIONS: Bilobed second dorsal metacarpal artery-based island flap transfer is a useful and reliable technique for thumb replantation when there is an extensive defect in the proximal phalanx and when a single-digit dorsal metacarpal artery island flap is too small. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 21549522 TI - Wrist denervation for painful conditions of the wrist. AB - PURPOSE: To evaluate the long-term (6-y) results of Wilhelm's wrist denervation technique used as an isolated procedure for painful conditions of the wrist. METHODS: We conducted a retrospective review of 49 wrist denervations that were performed as isolated procedures in patients with painful wrist conditions. Indication for surgery was degenerative osteoarthritis of the wrist caused by scaphoid nonunion advanced collapse in 19 patients, Kienbock's disease in 13 patients, and primary degenerative osteoarthritis in 17 patients. RESULTS: The results were analyzed as a group and by comparing the 3 etiologies. Average pain improvement after surgery for all groups was 68% +/- 8% after the first month and reached a plateau at the end of the first year, with the percentage remaining stable at 36 months at 79% +/- 4%. Grip strength on the treated side improved from 43% of the opposite side before denervation to 69% of the opposite side. The range of motion showed improvements in all axes of movement, without statistical differences between groups. Radiological evaluation after 72 months revealed worsening in 34 patients. There was no difference in results between the 3 groups with regard to grip strength, range of motion, or pain relief obtained. CONCLUSIONS: Wrist denervation resulted in improvement in pain scores in 39 patients despite radiological deterioration noted in 34 after 6 years. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 21549524 TI - Anticoagulation following digital replantation. PMID- 21549525 TI - Squamous cell carcinoma of the hand. PMID- 21549526 TI - Dorsal and volar 2.4-mm titanium locking plate fixation for AO type C3 dorsally comminuted distal radius fractures. AB - PURPOSE: In this retrospective, nonrandomized, single-surgeon study, we evaluated the clinical outcomes of dorsal and volar locking plate fixation for AO type C3 dorsally comminuted distal radius fractures. METHODS: We treated 41 consecutive patients who had sustained AO C3 dorsally comminuted fractures of the distal radius with 2.4-mm titanium locking plates between 2006 and 2008. Patients in group 1 (n = 22) were treated with dorsal locking plates, and those in group 2 (n = 19) with volar locking plates. We evaluated clinical outcomes at an average of 37 months and performed statistical analysis using the Mann-Whitney U test and Fisher's exact test. RESULTS: No significant difference was noted between the 2 groups in terms of radial inclination, volar tilt, and ulnar variance. At the 3- and 6-month follow-up, group 1 showed better clinical results with respect to wrist extension, grip strength, and Gartland and Werley score, whereas group 2 showed better wrist flexion during this period. The range of motion and grip strength progressively leveled out between the 2 groups, and no significant differences were observed at the 9- and 12-month assessments. One patient in group 1 had short-term complex regional pain syndrome, and 4 patients in group 2 had temporary median nerve numbness. CONCLUSIONS: Treatment with dorsal or volar locking plates can provide satisfactory radiographic and functional outcomes for AO type C3 dorsal comminuted distal radius fractures. The dorsal plate group showed an earlier recovery of wrist extension, grip strength, and functional score at the 3- and 6-month follow-up owing to direct reduction as well as fragmental-specific fixation of the dorsal fracture fragments. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 21549527 TI - Complications related to Artecoll injections for soft tissue augmentation of the hand: 3 case reports. AB - Rejuvenation of the aging hand has gained recent popularity. I report on 3 cases with complications related to the use of Artecoll (a permanent filler composed of polymethylmethacrylate) in soft tissue augmentation of the hand. All 3 patients had late-onset granuloma reactions, and the acute attacks were successfully treated with local injections of triamcinolone. However, recurrent reactions and hypopigmentation at the injection sites were noted. PMID- 21549528 TI - 30-year trajectories of heroin and other drug use among men and women sampled from methadone treatment in California. AB - BACKGROUND: This study examines 30-year trajectories of heroin and other drug use among men and women who were in methadone maintenance treatment in California in the late 1970s and interviewed in 1978-1981. METHODS: Nearly half (N=428; 46.8%) of the original study sample (N=914) was deceased. Of the remaining 486 subjects, 343 (44.3% female) completed a follow-up interview in 2005-2009 (70.6% of those not deceased). Average age at follow-up was 58.3 (SD=4.9) years for males and 55.0 (SD=4.1) years for females. Longitudinal data was obtained on their drug use, treatment participation, and criminal justice status over the follow-up period. Trajectory group modeling was used to identify distinctive trajectory groups based on monthly averages of heroin and other drug use per year; group differences were examined. RESULTS: Four heroin and five alcohol and other drug (AOD) trajectory groups were identified. A greater proportion of women (60%) were in the "rapid decrease" heroin group (odds of use less than 10% by 10 years following initiation of use) as compared with the other groups. More rapid decrease of heroin use was associated with increases in AOD use, whereas a gradual decrease in heroin use was associated with a gradual decrease in AOD use. More school problems and earlier age at onset of heroin use and first arrest were associated with more persistent heroin use. CONCLUSION: Heroin-use trajectories were linked with changes in AOD use. Childhood antecedents of heroin-use trajectories were identified as well as gender differences. PMID- 21549529 TI - Predictors of clinical trial dropout in individuals with co-occurring bipolar disorder and alcohol dependence. AB - BACKGROUND: Individuals with co-occurring bipolar disorder and alcohol dependence have particularly low rates of retention in clinical trials. Past research has identified a variety of factors associated with dropout in this population, but few have been replicated. The present study investigated the ability of several baseline variables to predict clinical trial dropout in a sample of individuals with co-morbid bipolar and alcohol use disorders. METHODS: Demographics, psychiatric diagnoses, recent alcohol use, mood pathology, and risk taking behavior (measured with the Balloon Analogue Risk Task) were evaluated as predictors of dropout from a randomized clinical trial of acamprosate for individuals with co-morbid bipolar and alcohol use disorders (n=30) using stepwise logistic regression. RESULTS: Risk taking behavior was the only significant predictor of dropout in the present study (OR=1.44, p=0.03); opiate dependence marginally predicted dropout as well (OR=13.46, p=0.08). A model consisting of these predictors, as well as acamprosate group status (p=0.13), provided excellent prediction of dropout (i.e., area under the ROC curve=0.94; R(2)=0.53). CONCLUSIONS: Given the robust relationship between risk taking and dropout in the present study, the Balloon Analogue Risk Task may represent a valuable tool for researchers to predict who will drop out of clinical trials for comorbid bipolar and substance use disorders. PMID- 21549530 TI - Molecular detection of Chlamydia-like organisms in cattle drinking water. AB - A substantial proportion of the causes of infectious bovine abortion remain largely undiagnosed, potentially due to the presence of previously unrecognised infectious agents. Recently, several reports have demonstrated the presence of Parachlamydia sp. in placental and foetal tissues derived from bovine abortions of unknown aetiology but the route of transmission remains undefined. The drinking water from one such recent case study was analysed for the presence of Parachlamydia sp. as a potential source of infection. Chlamydiales sp. 16S rRNA genes were PCR-amplified from the drinking water and a 16S rRNA gene clone library constructed. DNA sequencing of thirty-one clones indicated the presence of organisms belonging to the Parachlamydiaceae, specifically the genera Parachlamydia and Neochlamydia. Seven 16S rRNA gene sequences were identical to a Parachlamydia sp. sequence obtained from placental tissue from an abortion case originating from the same farm. These results raise the possibility that the drinking water is a source of Parachlamydia, which may play a role in infectious bovine abortion. PMID- 21549531 TI - Sensorimotor skills associated with motor dysfunction in children born extremely preterm. AB - BACKGROUND: Children born prematurely, despite being free of intellectual and sensorineural deficits, are at risk of motor dysfunction. AIM: To investigate the association of sensorimotor processing skills and Developmental Coordination Disorder (DCD) in "apparently normal" extreme preterm children. STUDY DESIGN: In a matched case-control study, 50 preterm children born less than 29 weeks or birthweight <1000 g, with an IQ>85 and no identified sensorineural disability, were assessed at 8 years of age along with 50 gender and birth date matched classroom controls born at full term. A battery of sensorimotor tests was administered, which examined visual-motor, visual perception, tactile perception, kinaesthesia, and praxis. RESULTS: For preterm children with DCD (n=21), significantly lower scores were found for the visual processing and praxis tests, with the exception of verbal command, in comparison to those 29 preterm children without DCD and term controls (median visual perception scores were 92, 96 and 108 respectively; design copying was 0.07, 0.46 and 0.95; constructive praxis was 0.09, 0.27 and 0.63; and sequencing praxis was 0.14, 0.73 and 0.96). There were no difference on the tactile sensitivity and kinaesthetic processing tests. CONCLUSIONS: Preterm children with DCD have difficulty with visual processing tasks. Praxis or motor planning poses a particular challenge for them. Motor dysfunction in extremely preterm children was related to poorer visual processing and motor planning and may relate to a cognitive processing problem. PMID- 21549532 TI - Stability of diazepam in blood samples at different storage conditions and in the presence of alcohol. AB - Diazepam is one of the mostly used benzodiazepines and it is frequently analyzed in different biological samples, especially blood samples. The diazepam stability in the sample matrices is an important factor regarding reliable data obtaining. The storage is the main factor determining the stability of diazepam in blood samples and it is the object of the study presented. Remaining diazepam amount in spiked whole blood and plasma samples were tested at different storage temperatures, in the absence or presence of sodium fluoride as stabilizer as well as the influence of ethanol on diazepam stability was evaluated. The results of the study indicated that the temperature is the main storage factor affecting diazepam stability. In the fluoride stabilized blood samples the amount of diazepam decreases up to 85% of initial level when stored at -20 degrees C for the period of testing (12 weeks). The presence of low (0.5 g/L) or high (3g/L) ethanol concentrations influences the stability of diazepam at -20 degrees C. In whole blood samples, the combination of sodium fluoride and ethanol decreases additionally (15-25%) the concentration of the analyte. Freeze-thaw experiments of whole blood samples show about 5-9% decrease in diazepam concentration after the first cycle. The freeze-thaw experiments on plasma samples, containing ethanol and/or fluoride show insignificant decreases of analyte concentration. Further experiments on benzodiazepines stability at different storage conditions or in combination of different factors should be undertaken in forensic toxicology to ensure the data quality, their reliability and reproducibility. PMID- 21549533 TI - [How can we improve the prognosis of infrapopliteal bypasses?]. AB - Infrapopliteal bypasses are often used for critical ischemia, in patients older than 80, in diabetics patients in 20% of cases, and patients with end-stage renal disease in 10% of cases. The goal of this paper is to analyze the systemic factors, which contribute to the clinical results, the technical aspects, which improve the patency of the bypass, and the role of postoperative follow-up. Postoperative mortality in those patients ranges from 3 to 10%, depending on several factors: age, global cardiovascular diffusion, diabetes mellitus, end stage renal disease. A complete evaluation of concomitant cardiovascular disease including coronary, renal and carotid disease is necessary to achieve the goal of reducing early and late mortality. Previous treatment of septic lesions of the foot is very important, before revascularisation. Technical aspects of infra inguinal revascularisations modalities are based on a complete analysis by duplex scan, magnetic resonance imaging and intra-arterial angiography, with asynchronous subtractions and lateral view of the foot. With the duplex scan, the quality and the length of the homolateral or controlateral long saphenous vein can be previewed, allowing an appropriate choice among bypass modalities. A surgically safe portion, free of proximal hemodynamic lesions, must be chosen for the proximal anastomosis: common femoral artery, superficial femoral artery (SFA), popliteal artery or tibial artery. In patients with poor arterial distal run off, and high peripheral resistances (diabetic foot, end-stage renal disease, foot infections) the proximal anastomosis must be made as distal as possible, on the popliteal or tibial artery. In case involving a short lesion of the superficial femoral artery, a combined strategy with angioplasty and distal bypass is a safe therapeutic option. The distal anastomosis must be made on an artery in continuity with the foot, and the plantar arch. In diabetic patients, the best artery is often the pedal artery. The graft is preferentially venous, which is better than prosthetic bypass. The long saphenous vein can be used in situ or reversed, or transposed, reversed after valvular disruption, when the proximal anastomosis is made below the common femoral artery. At 3 years, the primary patency of prosthetic bypasses is between 30 and 50%. Several technical artifices, (external route) or venous artifice at the distal anastomosis site (venous patch, venous cuff) can be useful. A distal arteriovenous fistula improves the flow in the grafts, but increases the distal resistances. Free tissue transfer increases outflow, allowing treatment of major tissue loss of the foot. Postoperative therapy must include a systemic heparinisation, until the patient is able to have a muscular activity. Antiplatelet therapy with aspirin is warranted for venous grafts. For prosthetic by-pass, some studies have shown that coumadin therapy provides a benefit. These bypasses require a duplex scan follow up at 1, 6, 12 months and then annually to search for stenosis of the venous grafts. If a significant hemodynamic lesion is found, a new procedure, via an endovascular or surgical approach can improve secondary patency. In cases of acute occlusions of the graft, an aggressive approach including thrombectomy, thrombolysis and distal angioplasty, can improve the patency. A global evaluation, with medical therapy, with antiplatelets, statins, diabetes control, annual evaluation of silent myocardial ischemia, and duplex scan follow-up of carotid artery disease, may improve the quality-of-life of these patients. PMID- 21549534 TI - [True or pseudo increase of antimicrobial use in hospitals?]. PMID- 21549535 TI - Utility of spiral CAT scan in the follow-up of patients with pulmonary Langerhans cell histiocytosis. AB - Pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease that occurs almost exclusively in smokers, generally young adults between 20 and 40 years old. Prognostic biomarkers of the disease are lacking. This study describes the clinical-radiological features of a group of PLCH patients and applies a semi quantitative CT score of the chest to verify the prognostic value of radiological findings in this disease. Clinical-radiological and immunological data from 12 Caucasian patients (6M, 7 smokers and 5 ex-smokers, mean age 36+/-8 years) were recorded at onset and after a follow-up period of 4 years. Application of the semi-quantitative CT score revealed a prevalently cystic pattern at onset and follow-up in the majority of the patients. Patients with a prevalently nodular pattern developed cystic lesions during follow-up. Interestingly, significant correlations were found between the extent of cystic lesions and DLCO values at onset (time 0: p<0.05) and at the end of follow-up (time 1, p<0.05) and with FEV1 values at time 0 (p<0.05) and time 1 (p<0.05). Patients with progressive functional decline were those with CT evidence of severe cystic alterations. The results suggest that high resolution CT scan of the chest is mandatory for characterizing PLCH patients at diagnosis and during follow-up. The proposed CT score of the chest showed potential prognostic value. PMID- 21549536 TI - Imaging of neuropathies about the hip. AB - Neuropathies about the hip may be cause of chronic pain and disability. In most cases, these conditions derive from mechanical or dynamic compression of a segment of a nerve within a narrow osteofibrous tunnel, an opening in a fibrous structure, or a passageway close to a ligament or a muscle. Although the evaluation of nerve disorders primarily relies on neurological examination and electrophysiology, diagnostic imaging is currently used as a complement to help define the site and aetiology of nerve compression and exclude other disease possibly underlying the patient' symptoms. Diagnosis of entrapment neuropathies about the hip with US and MR imaging requires an in-depth knowledge of the normal imaging anatomy and awareness of the anatomic and pathologic factors that may predispose or cause a nerve injury. Accordingly, the aim of this article is to provide a comprehensive review of hip neuropathies with an emphasis on the relevant anatomy, aetiology, clinical presentation, and their imaging appearance. The lateral femoral cutaneous neuropathy (meiralgia paresthetica), femoral neuropathy, sciatic neuropathy, obturator neuropathy, superior and inferior gluteal neuropathies and pudendal neuropathy will be discussed. PMID- 21549537 TI - Decreased hyperintense vessels on FLAIR images after endovascular recanalization of symptomatic internal carotid artery occlusion. AB - BACKGROUND AND PURPOSE: Hyperintense vessels (HV) on fluid-attenuated inversion recovery (FLAIR) images were assumed to be explained by slow antegrade or retrograde leptomeningeal collateral flow related to extracranial or intracranial artery steno-occlusion. The aim of this study was to investigate the effect of recanalization after endovascular therapy of symptomatic internal carotid artery (ICA) occlusion on the presence of HV. METHODS: Eleven patients with symptomatic ICA occlusion were retrospectively enrolled. Changes in the HV on FLAIR images were examined in affected hemisphere of each patient after successful treatment with endovascular recanalization (angioplasty, n = 3; stent-assisted angioplasty, n = 8). The relationship between postoperative changes in the HV and Thrombolysis In Cerebral Ischemia (TICI) scale (I-III) was assessed. RESULTS: After operation, HV of the 11 affected hemispheres were showed to be decreased (n = 3) or disappeared (n = 8) in treated side. The median interval between pre- and postoperative MRI examinations was 97.0 h (range, from 69. to 48.7h). Of the 8 patients with disappeared HV, 7 achieved high TICI grade flow (III) and 1 had relatively low TICI grade flow (IIc) in treated side. However, all the 3 patients with decreased HV were found to be relatively low TICI grade flow (IIc). CONCLUSION: Our data indicate that endovascular recanalization of ICA occlusion was effective for decreasing HV. Postoperative decrease in HV can be considered as a marker for hemodynamic improvement. PMID- 21549538 TI - Toward an optimal distribution of b values for intravoxel incoherent motion imaging. AB - The intravoxel incoherent motion (IVIM) theory provides a framework for the separation of perfusion and diffusion effects in diffusion-weighted imaging (DWI). To measure the three free IVIM parameters, DWIs with several diffusion weightings b must be acquired. To date, the used b value distributions are chosen heuristically and vary greatly among researchers. In this work, optimal b value distributions for the three parameter fit are determined using Monte-Carlo simulations for the measurement of a low, medium and high IVIM perfusion regime. The first 16 b values of a b value distribution, which was optimized to be appropriate for all three regimes, are {0, 40, 1000, 240, 10, 750, 90, 390, 170, 10, 620, 210, 100, 0, 530 and 970} in units of seconds per square meter. This distribution performed well for all organs and outperformed a distribution frequently used in the literature. In case of limited acquisition time, the b values should be chosen in the given order, but at least 10 b values should be used for current clinical settings. The overall parameter estimation quality depends strongly and nonlinearly on the signal-to-noise ratio (SNR): it is essential that the SNR is considerably higher than a critical SNR. This critical SNR is about 8 for medium and high IVIM perfusion and 50 for the low IVIM perfusion regime. Initial in vivo IVIM measurements were performed in the abdomen and were in keeping with the numerically simulated results. PMID- 21549539 TI - Determination of chamaechromone in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetic study. AB - A rapid, simple and accurate method was developed for the determination of chamaechromone in rat plasma using liquid chromatography tandem mass spectrometry (LC-MS-MS). Rosuvastatin was used as the internal standard. The plasma samples were extracted by liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on XbridgeTM C(18) column (2.1mm*50mm, 3.5MUm) with linear gradient elution using water and methanol, both of which were acidified with 0.1% aqueous formic acid. The flow rate was 0.4mL/min and the total run time was 6min. Detection was performed on a triple-quadrupole tandem mass spectrometer using positive ion mode electrospray ionization (ESI) in the multiple reaction monitoring (MRM) mode. The MS/MS ion transitions monitored were m/z 543.3->198.9 and 481.9->258.3 for chamaechromone and rosuvastatin, respectively. Good linearity was observed over the concentration range of 8-6400ng/mL in 0.1mL of rat plasma. The lowest concentration (8ng/mL) in the calibration curve was estimated as LLOQ with both deviation of accuracy and RSD of precision <20% (n=6). Intra-assay and inter-assay variability were less than 11% in plasma. This method was successfully applied to a pharmacokinetic study of chamaechromone in rats after intravenous (5mg/kg) and oral (100mg/kg) administration. Following oral administration the concentration-time curve of chamaechromone exhibited a biphasic absorption profile. The maximum mean concentration in plasma (C(max), 795.9+/-14.6ng/L) was achieved at 11.3+/-0.8h (T(max)) and the area under curve (AUC(0-60)) was 6976.7+/-1026.9ngh/L. After single intravenously administration of chamaechromone, the essential pharmacokinetic parameters C(max), AUC(0-48) were 4300.7+/-113.6ng/L and 3672.1+/-225.4ngh/L, respectively. The result showed that the compound was poorly absorbed with an absolute bioavailability being approximately 8.9%. PMID- 21549541 TI - Liquid paraffin as new dilution medium for the analysis of high boiling point residual solvents with static headspace-gas chromatography. AB - Residual solvents are volatile organic compounds which can be present in pharmaceutical substances. A generic static headspace-gas chromatography analysis method for the identification and control of residual solvents is described in the European Pharmacopoeia. Although this method is proved to be suitable for the majority of samples and residual solvents, the method may lack sensitivity for high boiling point residual solvents such as N,N-dimethylformamide, N,N dimethylacetamide, dimethyl sulfoxide and benzyl alcohol. In this study, liquid paraffin was investigated as new dilution medium for the analysis of these residual solvents. The headspace-gas chromatography method was developed and optimized taking the official Pharmacopoeia method as a starting point. The optimized method was validated according to ICH criteria. It was found that the detection limits were below 1MUg/vial for each compound, indicating a drastically increased sensitivity compared to the Pharmacopoeia method, which failed to detect the compounds at their respective limit concentrations. Linearity was evaluated based on the R(2) values, which were above 0.997 for all compounds, and inspection of residual plots. Instrument and method precision were examined by calculating the relative standard deviations (RSD) of repeated analyses within the linearity and accuracy experiments, respectively. It was found that all RSD values were below 10%. Accuracy was checked by a recovery experiment at three different levels. Mean recovery values were all in the range 95-105%. Finally, the optimized method was applied to residual DMSO analysis in four different Kollicoat((r)) sample batches. PMID- 21549540 TI - Quantitative determination and pharmacokinetic study of solamargine in rat plasma by liquid chromatography-mass spectrometry. AB - A sensitive and simple liquid chromatography-mass spectrometry (LC-MS) method has been developed and validated for the quantification of solamargine, a steroidal glycoalkaloid, in rat plasma. Vincristine was selected as the internal standard. Sample preparation involved simple liquid-liquid extraction by ethyl acetate with high efficiency. The chromatographical separation was performed on a Shimadzu C(18) column (150mm*2.0mm, 5MUm) with a gradient elution of acetonitrile and 0.02% (v/v) formic acid. The elutes were detected under positive electrospray ionization (ESI) and the target analytes quantified by selected ion monitoring (SIM) mode. The method was sensitive with the lowest limit of quantitation (LLOQ) at 0.5ng/mL in 50MUL of rat plasma. Good linearity (r(2)=0.9996) was obtained covering the concentration of 0.5-2000.0ng/mL. The intra- and inter-day assay precision ranged from 2.87 to 3.60% and 0.52 to 6.81%, respectively. In addition, the stability, extraction recovery and matrix effect involved in the method were also validated. The practical utility of the aforementioned method was successfully confirmed in the pharmacokinetic evaluation of solamargine in Sprague-Dawley rats after intravenous administration. PMID- 21549542 TI - Improved detection of AmpC beta-lactamases in Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis using new susceptibility breakpoints for third generation cephalosporins. PMID- 21549543 TI - The practice of cardiology and healthcare reform. AB - As reimbursement policies and healthcare reform legislation add pressure onto the independent practice of cardiology, many cardiology groups seek refuge in hospital employment. This has implications for healthcare costs and the future of the practice of cardiology, especially in the age of accountable care organizations. PMID- 21549544 TI - Cardiology integration challenge and opportunity. PMID- 21549545 TI - Two automobile collisions in one day. PMID- 21549546 TI - Early goal-directed therapy (EGDT) for severe sepsis/septic shock: which components of treatment are more difficult to implement in a community-based emergency department? AB - BACKGROUND: Early goal-directed therapy (EGDT) has been shown to reduce mortality in patients with severe sepsis/septic shock, however, implementation of this protocol in the emergency department (ED) is sometimes difficult. OBJECTIVES: We evaluated our sepsis protocol to determine which EGDT elements were more difficult to implement in our community-based ED. METHODS: This was a non concurrent cohort study of adult patients entered into a sepsis protocol at a single community hospital from July 2008 to March 2009. Charts were reviewed for the following process measures: a predefined crystalloid bolus, antibiotic administration, central venous catheter insertion, central venous pressure measurement, arterial line insertion, vasopressor utilization, central venous oxygen saturation measurement, and use of a standardized order set. We also compared the individual component adherence with survival to hospital discharge. RESULTS: A total of 98 patients presented over a 9-month period. Measures with the highest adherence were vasopressor administration (79%; 95% confidence interval [CI] 69-89%) and antibiotic use (78%; 95% CI 68-85%). Measures with the lowest adherence included arterial line placement (42%; 95% CI 32-52%), central venous pressure measurement (27%; 95% CI 18-36%), and central venous oxygen saturation measurement (15%; 95% CI 7-23%). Fifty-seven patients survived to hospital discharge (Mortality: 33%). The only element of EDGT to demonstrate a statistical significance in patients surviving to hospital discharge was the crystalloid bolus (79% vs. 46%) (respiratory rate [RR] = 1.76, 95% CI 1.11-2.58). CONCLUSION: In our community hospital, arterial line placement, central venous pressure measurement, and central venous oxygen saturation measurement were the most difficult elements of EGDT to implement. Patients who survived to hospital discharge were more likely to receive the crystalloid bolus. PMID- 21549547 TI - Infrarenal aortic aneurysm: an incidental radiological finding. PMID- 21549548 TI - Use of RIFLE criteria to predict the severity and prognosis of acute kidney injury in emergency department patients with rhabdomyolysis. AB - BACKGROUND: RIFLE criteria (Risk, Injury, Failure, Loss, End-stage) have not been evaluated in Emergency Department (ED) patients at risk of acute kidney injury (AKI). AKI occurs in rhabdomyolysis. STUDY OBJECTIVES: To use RIFLE criteria to stratify the severity of AKI and predict prognosis in ED patients with acute rhabdomyolysis. METHODS: This is a retrospective study of consecutive patients with rhabdomyolysis over a 44-month period. Data included ED admission anion gap, blood urea nitrogen (BUN), calcium, phosphate, potassium, urinalysis, toxicology screen, and hematocrit. Creatine kinase, creatinines, and hematocrits were followed serially. Hospital length of stay (LOS) and need for dialysis were also recorded. RESULTS: RIFLE categories were calculated for 135 patients. At admission, 60 (44%) had no AKI, 20 (15%) had Risk, 32 (24%) had Injury, and 23 (17%) had Failure. These categories were significantly associated with increasing magnitude of volume depletion, potassium, phosphate, BUN, and the anion gap. They predicted differences in LOS, dialysis, discharge creatinine, and the rate of normalization of the admission creatinine. Mortality was low (2%), as was morbidity. Only 8/132 surviving patients (6%) were discharged with a creatinine >2 mg/dL. CONCLUSIONS: The RIFLE categories correlated significantly with known markers of rhabdomyolysis and AKI. They also predicted LOS, dialysis, renal morbidity, and the timing of recovery. RIFLE criteria could be used to predict the outcome of ED patients and facilitate admission and discharge decisions. PMID- 21549549 TI - Alcohol-drinking patterns and metabolic syndrome risk: the 2007 Korean National Health and Nutrition Examination Survey. AB - Alcohol consumption has been known to be related to the prevalence of metabolic syndrome (MS). Although some studies have revealed that mild to moderate alcohol consumption reduces the risk of MS, most of these studies have focused the effect of alcohol consumption amount on MS. We examined the association between alcohol drinking patterns and MS by using the alcohol use disorders identification test (AUDIT) questionnaire to study 1,768 alcohol drinkers (847 men, 921 women) aged 20-75 years from Korean National Health and Nutrition Examination Survey in 2007. When compared with the subjects in the reference group (AUDIT score <= 7), the odds ratios (ORs, 95% confidence intervals [CIs]) for MS of subjects in the highest group (AUDIT score >= 16) were 3.92 (2.40-6.22) in men and 2.27 (0.87 5.89) in women after adjusting for confounding variables. Among the items of the AUDIT score, several alcohol-drinking patterns, including "drinking frequency," "usual drinking quantity," "frequency of high-risk drinking," "frequency of inability to stop drinking," "frequency of feeling guilty after drinking," and "frequency of inability to remember after drinking" were strongly associated with the prevalence of MS in men. In women, there were significant relationships between MS and "usual drinking quantity," "frequency of feeling guilty after drinking," and "frequency of inability to stop drinking." In summary, AUDIT score was strongly associated with MS in Korean adults, particularly in men. Accordingly, in addition to the amount of daily alcohol consumption, alcohol drinking patterns should be addressed in the prevention and treatment of MS. PMID- 21549550 TI - Validity and reliability of the MSKCC Bowel Function instrument in a sample of Italian rectal cancer patients. AB - AIMS: The purpose of this study was to translate the Memorial Sloan Kettering Cancer Centre (MSKCC) Bowel Function Instrument into Italian and to test its psychometric validity and reliability in a sample of Italian rectal cancer patients. METHODS: The MSKCC questionnaire was translated into Italian using a standard procedure of double-back translation. Construct validity was tested using a factor analysis and internal reliability was estimated using the Cronbach's alpha coefficient. Concurrent validity was determined by correlations with European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ CR38 quality of life scales. A non-parametric analysis of variance was used to establish the discriminant validity of the questionnaire. Test-retest reliability was assessed using the intra-class correlation coefficient. RESULTS: 124 rectal cancer patients participated in the validation study. The number of missing items was 2.2%. The factorial structure was found to be quite similar to the original one and the internal reliability was 0.7 for urgency, 0.6 for frequency, and 0.7 for dietary subscale. The test-retest reliability was acceptable with one exception: the dietary subscale showed a low reproducibility (ICC = 0.4). All three subscales showed a significant correlation with the QLQ-C30 and QLQ-CR38 domains and were able to discriminate several groups of clinical relevance. CONCLUSIONS: The Italian version of the MSKCC Bowel Function Instrument shows acceptable psychometric properties and can be considered a valuable and specific instrument to assess bowel functions in rectal cancer patients, both for research purposes and in clinical practise. PMID- 21549551 TI - Noninvasive skin measurements to monitor chronic renal failure pathogenesis. AB - BACKGROUND/AIMS: Cutaneous manifestations are common in hemodialysis (HD) patients with chronic renal failure (CRF). Associated with uremia, pruritus is a frequently observed symptom in CRF patients and increases with deteriorating renal function. Skin hydrophilic biomarkers (SHB) may be altered in CRF compared to healthy controls. METHODS: A noninvasive skin wash sampling technique to detect the expression of SHB, by measuring their secretion on skin surface, was used on HD patients and healthy controls. Hydrophilic antioxidants such as total antioxidant scavenging capacity (TSC) and uric acid (UA) content, and cytokine inflammatory biomarkers such as TNFalpha and IL-10 levels were estimated. RESULTS: Our findings demonstrate significant alterations of the SHB level between HD patients and healthy volunteers. Furthermore, such alterations of secreted SHB correlated markedly with detected changes in blood biochemistry and dermatology severity score. CONCLUSION: Skin wash sampling of SHB is a noninvasive technique that distinguishes between HD patients and healthy controls. In HD patients, SHB is associated with biochemical markers in blood and dermatologic symptom severity. This technique is also suggested, as a monitoring tool for diagnosis and treatments of various diseases, in which skin dysfunction is involved. PMID- 21549552 TI - [Prevalence of latent tuberculosis infection among health care workers from the emergency department of Meaux hospital using an interferon gamma release assay]. AB - OBJECTIVE: To determine the prevalence of the latent tuberculosis infection (LTBI) among health care workers (HCW) of the emergency ward of Meaux hospital, by comparing it with two witnesses units: the orthopaedic surgery ward (referral service to low risk) and the respiratory ward (referral service to high risk). METHODS: From July to December 2008, on a voluntary basis, anonymised blood samples of any HCW of the three departments were carried out by the occupational health service. Determination of interferon gamma was released by the test "QuantiFERON-TB Gold" (QFT). RESULTS: Of the 137 eligible subject sampled, 16 had a positive QFT test: nine in the emergency ward, six in the respiratory ward and one in the orthopaedic surgery ward. The proportion of HCW with a positive QFT test was not significantly different between the three wards. DISCUSSION: This study shows that HCWs of the emergency ward of the Meaux hospital are not working in a department where the risk of LTBI is high. CONCLUSION: Our study shows that, in a territory of health where the incidence of the tuberculosis disease is superior to the national average, the emergency department of Meaux hospital does not belong to an area at high risk of LTBI. It underlines the interest of QFT test for the screening of LTBI among vaccinated persons. PMID- 21549553 TI - [Children Lyme Borreliosis: retrospective study of 16 cases]. AB - OBJECTIVES: Lyme Borreliosis exists in an endemic way for adult's in Alsace and the clinical demonstrations are well known. For children, there are no data in France. The objective of this study was to list the cases of Lyme Borreliosis seen in pediatric consultation in the Bas-Rhin and to study the clinical presentation. METHODS: We realized an investigation with 70 pediatricians of the Bas-Rhin between April 2006 and March 2008 which allowed us to count 16 cases of Lyme Borreliosis. RESULTS: It is about nine girls and seven boys, seven-years-old on average. Thirteen had an erythema migrans, two a neuroborreliosis and one arthritis of Lyme. Tick injection (notion established in 81 % of the cases) sat in upper limbs in the majority of the cases (39 %). The delay between the injection and the first signs was established in seven cases on 13 and varied from five to 30 days. The first signs of the disease appeared in spring or in summer for 81 % of the children. Amoxicilline was the the most used treatment for the erythema migrans; ceftriaxone for neuroborreliosis or Lyme arthritis. Those treatments were effective in every cases. CONCLUSION: Lyme Borreliosis in children exists in Alsace. Its main demonstration is the erythema migrans, but there are also neurological and articular demonstrations. With an appropriate treatment, its evolution is excellent. PMID- 21549554 TI - [Torsades de pointes with methadone treatment]. PMID- 21549555 TI - [Arteritis in the young: diagnostic tools]. AB - Atherosclerosis is the main cause of lower limb claudication. Upper limb claudication is evocative of thromboangiitis obliterans, which is frequently a cause of peripheral artery disease in the young. Vascular compression could be searched for in patients with sport occupational activity. Ultrasonography, CT scan and MRI are useful for the diagnosis of inflammatory diseases, genetical diseases and radic arteriopathy. Blood count and search for thrombophilia are used for the diagnosis of antiphospholipid antibody syndrome or myeloproliferative disorders. PMID- 21549556 TI - [When do you implant a pacemaker in myotonic dystrophy?]. AB - Myotonic dystrophy is the most frequent adult form of hereditary muscular dystrophy caused by a mutation on the DMPK gene. Myotonic dystrophy leads to multiple systemic complications related to weakness, respiratory failure, cardiac arrhythmias and cardiac conduction disturbances. Age of death is earlier in myotonic dystrophy patients than in general population with a high frequency of sudden death. Several mechanisms are involved in sudden death: atrio-ventricular block, severe ventricular arrhythmias or non-cardiac mechanism. The high degree of atrio-ventricular block is a well-recognized indication of pacemaker implantation but the prophylactic implantation of pacemaker should be considered to prevent sudden death in asymptomatic myotonic dystrophy patients. A careful clinical evaluation needs to be done for the identification of patients at high risk of sudden death. The resting ECG and SA ECG are non-invasive tools useful to select the patients who need an electrophysiologic study. In presence of prolonged HV interval more than or equal to 70 ms one can discuss the implantation of a prophylactic pacemaker. The choice of an implantable cardiac defibrillator is preferred in presence of spontaneous ventricular tachycardia or an alteration of the left ventricular ejection fraction. PMID- 21549557 TI - Fixation and bone remodeling around a low-modulus stem seven-year follow-up of a randomized study with use of radiostereometry and dual-energy x-ray absorptiometer. AB - Thirty-eight patients (40 hips) randomly received either an uncemented fully porous-coated composite stem (Epoch; Zimmer, Warsaw, Ind) or an uncemented proximally porous-coated solid stem (Anatomic; Zimmer). Patients were followed up for 7 years using radiostereometry, dual-energy x-ray absorptiometry, conventional radiography, the Harris Hip Score, and a pain questionnaire. Both stem designs achieved excellent outcome for fixation (stem subsidence and stem rotations close to zero) and clinical outcome, without any difference between the 2 groups (P > .12). Median wear rates were low despite use of conventionally gamma-sterilized polyethylene. No stem was radiographically loose on the postoperative radiographs. The low-modulus composite stem had positive effects on early proximal bone remodeling in Gruen regions 1, 2, 6, and 7 (P < .04). However, at 7 years, this bone-sparing effect persisted in only the calcar region (Gruen region 7). PMID- 21549558 TI - Accuracy of the Holladay 2 intraocular lens formula for pediatric eyes in the absence of preoperative refraction. AB - PURPOSE: To evaluate the prediction error in pediatric eyes using the Holladay 2 formula in the absence of preoperative refraction and to compare it with the prediction error using the Holladay 1, Hoffer Q, and SRK/T formulas. SETTING: Storm Eye Institute, Charleston, South Carolina, USA. DESIGN: Evaluation of diagnostic test or technology. METHODS: Eyes having pediatric cataract surgery with intraocular lens (IOL) implantation were analyzed. One eye of bilateral cases was randomly selected for inclusion. Prediction error was calculated using the predicted postoperative refraction minus the actual postoperative refraction. RESULTS: Forty-five eyes were included. The median age at surgery was 3.56 years and the median follow-up, 28 days. Using the Holladay 2, Holladay 1, Hoffer Q, and SRK/T formulas, the mean prediction error was 0.02 diopter (D) +/- 0.91 (SD), -0.21 +/- 0.90 D, 0.07 +/- 1.01 D, and -0.47 +/- 0.98 D, respectively. The mean absolute prediction error was 0.68 +/- 0.61 D, 0.71 +/- 0.58 D, 0.72 +/- 0.71 D, and 0.84 +/- 0.69 D, respectively. The Holladay 2 formula had the least prediction error for shorter eyes (<22.0 mm). The mean difference between the actual versus the predicted refraction was -0.05 D using Holladay 2 (P=.71), 0.02 D using Holladay 1 (P= .89), -0.12 D using Hoffer Q (P=.44), and 0.04 D using SRK/T (P=.78). CONCLUSION: The Holladay 2 formula had the least prediction error and absolute prediction error even in the absence of preoperative refraction. PMID- 21549559 TI - Occurrence of posterior vitreous detachment after femtosecond laser in situ keratomileusis: Ultrasound evaluation. AB - PURPOSE: To analyze the modifications to the vitreous body after femtosecond laser-assisted laser in situ keratomileusis (LASIK) for myopia. SETTING: Centre Hospitalier National Des Quinze-Vingts, Paris, France. DESIGN: Case series. METHODS: B-scan ultrasonography of the posterior ocular segment was performed the day before and 48 hours after femtosecond LASIK for myopia. Posterior vitreous detachment (PVD) was diagnosed by the presence of a low-reflected mobile echogenic membrane partially or completely detached from the retina. Eyes with signs of partial or total PVD on preoperative examination were excluded. Occurrence of total or partial PVD after surgery was the main outcome measure. RESULTS: Thirty-one eyes of 18 patients (10 women; mean age 28 years +/- 5 [SD]) were included in the study. The mean preoperative spherical equivalent was -4.38 diopters (D) (range -2.88 to -6.75 D). After surgery, 5 eyes (16%) developed partial or total PVD. The remaining 26 eyes had no signs of PVD postoperatively. CONCLUSION: Although less vacuum is required to create a corneal flap with a femtosecond laser than with a conventional microkeratome, the incidence of PVD after femtosecond laser-assisted LASIK was similar to that reported for microkeratome-assisted LASIK. PMID- 21549560 TI - Termination of washing compulsions: a problem of internal reference criteria or 'not just right' experience? AB - Recent research suggests that obsessive-compulsive washers are more likely than individuals without washing compulsions to use conscious, internal reference criteria when deciding when to terminate compulsions (Wahl, Salkovskis, & Cotter, 2008). An alternative view is that they possess tendencies towards non-cognitive, automatic 'not just right' experiences (NJREs) that influence compulsion duration. The current study sought to investigate the latter explanation using valid behavioral tasks. Non-clinical participants (N=133) completed self-report measures, immersed their hands in a dirt mixture, and afterwards were allowed to wash their hands. Additionally, a subset of participants completed an in vivo assessment of NJRE using a pile of clutter. Total number and intensity of NJREs were predictive of hand-washing duration. Additionally, affective response to the clutter was uniquely predictive of hand-washing duration when controlling for pre wash anxiety. These results suggest that internal reference criteria as well as NJREs may influence compulsive washing, though the former may be a consequence of the latter. PMID- 21549561 TI - The foramen of Huschke: age and gender specific features after childhood. AB - The foramen of Huschke (FH) is an aperture that is formed in the tympanic plate of the temporal bone at the age of about 1 year. The FH usually closes before the age of 5 years; but it occasionally persists throughout life. A persistent FH may result in complications such as temporomandibular joint (TMJ) herniation and salivary fistula formation, and facilitate ear injury during TMJ arthroscopy. In this study, the authors examined 1994 temporal bones from 997 Japanese dry skulls, in order to define age and gender specific features of the persistent FH after childhood. A persistent FH was found in 12% of men and in 20% of women, representing a female predominance (P<0.0001). The incidence of a persistent FH decreased with age in both genders, suggesting that a persistent FH can close over time. PMID- 21549562 TI - Efficacy of topical benzydamine hydrochloride gel on oral mucosal ulcers: an in vivo animal study. AB - The aim of this study was to investigate the effect of benzydamine hydrochloride bioadhesive gel on healing of oral mucosal ulceration in an animal model. For in vivo determination of the effects of the bioadhesive gel, 36 rabbits were separated into three groups: the first group was treated with the gel formulation without active agent, the second group with the gel formulation containing benzydamine, and the third group received no treatment. Clinical healing was established by measuring the area of the ulcer in each test group on days 3, 6, 9 and 12. Histological healing was determined on the same days. Benzydamine containing gel applications resulted in a decrease in the ulcer area in 12 days (p=0.000). Histological evaluation showed that the benzydamine group had a higher mean histological score than the base and the control groups during the whole test period, and the difference between the benzydamine group and the control group was significant (p=0.04). The bioadhesive gel formulation of benzydamine hydrochloride showed a statistically significant increased rate of mucosal repair in this experimental standard mucosal wound animal study. It is a candidate for the topical treatment of oral mucosal ulcerative lesions. PMID- 21549564 TI - Seizure control: a secondary benefit of chemotherapeutic temozolomide in brain cancer patients. AB - The severity of brain tumor associated seizures often mirror the growth of the underlying tumor, and may be intractable to conventional antiepileptic drugs. We present a patient with intractable seizures in the setting of a low grade glioma who responded dramatically to temozolomide despite minimal radiographic change in tumor size. Temozolomide is an effective treatment for seizure control in patients with brain tumors. PMID- 21549563 TI - No effect of oral contraceptives on the metabolism of levetiracetam. AB - The effect on clearance of levetiracetam (LEV) was estimated in women with epilepsy of childbearing potential using oral contraceptives (OCs). The estimated clearance (plasma concentration/daily dose) was 39 nmol/L/mg (range 14-88 nmol/L/mg) among women who did not use OC (n=30) and 38 nmol/L/mg (range 18-103 nmol/L/mg) among OC users (n=23) (p=0.8). In conclusion, combing LEV and OCs seems safe from a pharmacokinetic perspective. PMID- 21549565 TI - Association of FAS, a TNF-alpha receptor gene, with treatment resistant schizophrenia. PMID- 21549566 TI - Symptom and functional outcomes for a 5 year early intervention program for psychoses. AB - There continues to be controversy concerning the long term benefits of specialized early intervention programs (SEI) for psychotic disorders. Recent reports of five year outcomes for SEI programs indicate that benefits of early intervention programs at two year follow-up have disappeared at five years. The Prevention and Early Intervention Program for Psychoses (PEPP) in London, Ontario offers continuity of care for five years, with a lower intensity level of specialized intervention after the initial two years. In this paper we examine whether the outcomes observed at two years were maintained at five year follow up. In addition, it was possible to compare PEPP outcomes with those of the OPUS project at two and five years. Results indicate that improvement of symptoms between entry into PEPP and two year follow-up were maintained at five years. In addition, there was further improvement in global functioning between two and five year follow-up. Comparison of PEPP outcomes at two and five year follow-up to those of OPUS suggest that longer term continuity of care within SEI is associated with continuing benefits at least with respect to level of positive symptoms and functioning. PMID- 21549567 TI - Association of impaired EEG mu wave suppression, negative symptoms and social functioning in biological motion processing in first episode of psychosis. AB - BACKGROUND: Event related desynchronization (ERD) of mu waves, or mu suppression, over sensorimotor cortex has been observed in response to self-generated movement, viewing movement, or imaging movement. Mu suppression is especially pronounced when the movement has social relevance and is being generated by a biological entity indicating successful social adaptation. And since social adaptation problems are common in schizophrenia, the authors designed a study to test mu wave suppression in a first episode of psychosis population. METHODS: A total of 32 subjects (first episode of psychosis patients N=20; healthy comparison subjects N=12) aged 13-34 watched movement videos with and without socially relevant cues, executed by biological or non-biological agents. Scalp electrode EEG recordings of mu rhythm (8-13 Hz) over sensorimotor cortex during the session were used to calculate mu wave suppression. Average mu suppression was compared within and between groups, as well as correlations between mu suppression and clinical measures. RESULTS: First episode patients showed significantly reduced mu wave suppression over sensorimotor cortex when viewing biological motion, compared to healthy subjects. In addition, negative symptom burden and poor social adjustment correlated with impaired mu wave suppression. CONCLUSIONS: Our finding provides the first description of impaired event related desynchronization of mu waves in response to biological motion and its correlation with negative symptoms and social adjustment in the first episode of psychosis. Future studies can be conducted to determine if mu wave suppression represents an endophenotype with potential applications in biological treatments of negative symptoms and social functioning deficits in schizophrenia. PMID- 21549568 TI - Cholesterol and cognition in schizophrenia: a double-blind study of patients randomized to clozapine, olanzapine and haloperidol. AB - OBJECTIVE: A positive relationship between cholesterol levels and cognition has been reported in various human and animal studies, but has never been investigated in schizophrenia. The goal of this study was to examine this relationship in schizophrenic patients randomized to clozapine, olanzapine or haloperidol. METHOD: This was a double-blind randomized prospective 12-week study. Participants received a baseline evaluation including a cognitive battery consisting of an evaluation of psychomotor function, general executive function, visual and verbal memory, and visuospatial ability. Their fasting serum cholesterol level was also assessed. The participants were then randomized to clozapine, olanzapine, or haloperidol. They were evaluated at the end of 12 weeks. A general cognitive index (GCI) derived from the cognitive battery was the primary variable. RESULTS: 82 patients had both baseline and endpoint neurocognitive assessments and cholesterol levels. There was a statistically and clinically significant positive association between change in cholesterol levels and change in GCI. This association was especially pronounced for verbal memory. There was no interaction between medication grouping and cholesterol level; the positive association was observable separately in each medication group. It was very robust and remained significant after we controlled for glucose and triglyceride levels, anticholinergic side effects, medication serum levels, cholesterol lowering medications, and pre-study antipsychotic medications. CONCLUSIONS: Cholesterol levels show a strong association with cognition in schizophrenia in all medication groups. Further research on the role of lipid metabolism in cognition may suggest new treatments for this core deficit of schizophrenia. PMID- 21549569 TI - Antiprotozoal compounds: state of the art and new developments. AB - Protozoa can cause severe diseases, including malaria, leishmaniasis, Chagas disease, sleeping sickness and amoebiasis, all being responsible for morbidity and mortality particularly in tropical countries. To date there are no protective vaccines against any of these diseases, and many of the available drugs are old or elicit serious adverse reactions. Moreover, parasite resistance to existing drugs has become a serious problem. Owing to lack of financial returns, research in this field is of limited interest to pharmaceutical companies and largely depends on funding by public authorities. This article aims to provide a concise overview of the state-of-the-art treatment for the most important tropical protozoal infections as well as new approaches. PMID- 21549570 TI - 'To bead or not to bead?' Treatment of osteomyelitis and prosthetic joint associated infections with gentamicin bead chains. AB - Gentamicin-containing polymethylmethacrylate (PMMA) beads are frequently used to prevent and treat orthopaedic infections. The beads are typically inserted to fill anatomical defects secondary to surgical debridement. Local gentamicin use results in low serum levels whilst achieving high concentrations at the site of infection. However, a systematic review of the available literature showed that, despite these theoretical advantages, no prospective study has thus far proven gentamicin-containing PMMA beads to be effective in treating orthopaedic infections. Available studies are based on small patient numbers and do not show significantly better results when local and parenteral antibiotics are combined compared with systemic therapy alone. These poor results may be explained partially by reduced aminoglycoside efficacy when biofilms or gentamicin resistant bacteria are present. Moreover, little is known regarding the potential side effects of gentamicin-containing beads. In this paper, the pros and cons regarding the use of gentamicin-containing PMMA beads are discussed. It is concluded that more well-executed, prospective studies are needed to settle the discussion on the use of gentamicin-containing beads in the treatment of orthopaedic infections. PMID- 21549571 TI - Two paediatric cases of skin and soft-tissue infections due to clindamycin resistant Staphylococcus aureus carrying a plasmid-encoded vga(A) allelic variant for a putative efflux pump. AB - Two clinical Staphylococcus aureus isolates were investigated due to their unusual antimicrobial susceptibility pattern, i.e. erythromycin-susceptible but clindamycin-resistant. These isolates harboured identical copies of a plasmid borne vga(A)(LC) gene not previously described in S. aureus. The native plasmids carrying vga(A)(LC) were transferable to a susceptible laboratory strain of S. aureus in vitro, in which they conferred resistance patterns similar to the parent isolates. PMID- 21549572 TI - Real-time TaqMan PCR for rapid detection of genes encoding five types of non metallo- (class A and D) carbapenemases in Enterobacteriaceae. AB - A real-time TaqMan multiplex polymerase chain reaction (PCR) assay was developed to detect genes encoding five types of serine carbapenemases (GES, IMI/NMC, KPC, OXA-48 and SME). The assay was validated using control strains known to produce each of these types of enzyme and was then further assessed by 'blindly' testing 59 previously characterised clinical isolates, including 19 with serine (KPC or OXA-48) carbapenemases, 22 with metallo- (IMP, VIM or NDM) carbapenemases, and 18 with carbapenem resistance contingent upon extended-spectrum beta-lactamase (ESBL) or AmpC production combined with porin loss. The assay detected and correctly assigned the serine carbapenemases in all five positive control strains and in 19 clinical isolates. No false-positive results were seen for isolates with metallo-enzymes or for those that lacked a carbapenemase. The five serine carbapenemase genotypes could also be distinguished by melt-curve analysis or the molecular size of the amplicons. PMID- 21549573 TI - Daptomycin: evaluation of a high-dose treatment strategy. AB - With a decreasing pipeline of novel antibiotics and increasing antibacterial resistance, the need to optimise the current antibiotics in our armamentarium has become vitally important. Daptomycin is a novel lipopeptide antibiotic that exhibits concentration-dependent activity. Currently, the daptomycin dosage is 4 mg/kg/day for treatment of complicated skin and soft-tissue infections and 6 mg/kg/day for Staphylococcus aureus bloodstream infections, including those with right-sided endocarditis, however higher doses (>6 mg/kg/day) have been explored as a possible alternative. A comprehensive review of published data identified through a MEDLINE search of the literature from 1967-2011 and a manual search of references was performed with the primary objective of critically evaluating the safety and efficacy of high-dose daptomycin. Search results yielded two prospective trials, three retrospective reviews, case reports and in vitro simulation studies on high-dose daptomycin. To date, clinical trials, retrospective reviews, case reports and in vitro simulation models have documented the safety and tolerability of high-dose daptomycin, even when administered for a prolonged duration. Additionally, in vitro benefits observed include suppression of the emergence of daptomycin resistance and increased rapidity of bactericidal activity. PMID- 21549574 TI - Prophylactic antibiotics: what does it mean to the obstetrician in a tertiary care setting? PMID- 21549576 TI - Lightweight hydrogen-storage material Mg(0.65)Sc(0.35)D2 studied with 2H and 2H {45Sc} MAS NMR exchange spectroscopy. AB - Using double-quantum (2)H MAS NMR with (45)Sc recoupling and Bloch-Siegert compensated (2)H-{(45)Sc} TRAPDOR we have identified the overlapping NMR signals of deuterium with and without scandium neighbors in Mg(0.65)Sc(0.35)D(2), a candidate lightweight material for hydrogen storage. At room temperature we also observe a third type of mobile deuterium. Deuterium mobility among the three NMR distinct sites has been investigated by means of one-and two-dimensional exchange spectroscopy (Exsy). Complete deuterium exchange within 0.1s is observed, which indicates that the three NMR-distinct sites are close together in the crystal lattice. The weak temperature- and MAS-rate dependences observed in Exsy are indicative for a combination of chemical exchange and spin diffusion. PMID- 21549575 TI - In vitro efficacy of antimicrobial agents against high-inoculum or biofilm embedded meticillin-resistant Staphylococcus aureus with vancomycin minimal inhibitory concentrations equal to 2 MUg/mL (VA2-MRSA). AB - Minimal inhibitory concentration (MIC) creep in meticillin-resistant Staphylococcus aureus (MRSA) isolates has been observed in recent years. The potential roles of vancomycin-based combination regimens as well as linezolid and tigecycline against five clinical MRSA isolates with vancomycin MICs of 2 MUg/mL (VA2-MRSA) were evaluated and compared in vitro. Antimicrobial susceptibility was studied by the agar dilution method. Anti-MRSA activities of linezolid, tigecycline, vancomycin, minocycline, rifampicin and fosfomycin alone as well as of three vancomycin-based combinations were studied by time-kill method and using a biofilm model. When VA2-MRSA at an inoculum of 1*10(5)colony-forming units (CFU)/mL was incubated with vancomycin, tigecycline, linezolid or rifampicin alone, bactericidal activity lasted for 48 h in time-kill analysis. At a higher inoculum of 1*10(7) CFU/mL, only linezolid demonstrated a bacteriostatic effect at 24 h and the inhibitory activity lasted for 36 h. However, bacterial growth was inhibited >=2log(10) at 24 h and was even undetectable at 48 h with vancomycin plus fosfomycin or rifampicin. In biofilm studies, vancomycin plus fosfomycin or minocycline at susceptible breakpoint concentrations demonstrated an enhanced antibacterial effect comparable with linezolid and better than tigecycline. In conclusion, vancomycin plus fosfomycin or rifampicin exhibited a synergistic and better antibacterial effect than linezolid or tigecycline alone against high-inoculum planktonic VA2-MRSA. Vancomycin plus fosfomycin or minocycline compared with linezolid exhibited a similar inhibitory effect, better than tigecycline alone, against biofilm-embedded VA2-MRSA. Evaluating the toxicity and efficacy of high-dose vancomycin monotherapy for VA2-MRSA, the fosfomycin combination exhibited a rapid killing effect in both conditions and may provide another therapeutic choice. PMID- 21549577 TI - An impedance QCM study on the partitioning of bioactive compounds in supported phospholipid bilayers. AB - The interaction of two drugs of small molecular size, propranolol and tetracaine, and the membrane-perturbing peptide melittin with a phospholipid bilayer supported on a SiO2 surface was studied with the quartz crystal microbalance. All three bioactive compounds interacted with the lipid bilayer and changed its viscoelastic properties. Adsorbed mass of the compounds was analyzed with a viscoelastic model as a function of the concentration of the compounds in the aqueous phase, as well as the effect of the compounds on the bilayer viscoelasticity. The analysis was based on the interpretation of the impedance of the crystal, utilizing the 5th, 7th and 9th overtone of the fundamental 5 MHz resonance frequency. PMID- 21549578 TI - [Scrofuloderma: a misleading lesion]. AB - We describe a case of scrofuloderma in an 8-year-old boy with a cutaneous tuberculosis lesion. CASE REPORT: The child had spent holidays in Morocco. He presented a cutaneous lesion of the thigh which turned into an abscess with suppuration, in spite of surgical drainage. The lymph node analysis showed Koch bacilli and granuloma, leading to the diagnosis of scrofuloderma. Further exams found no other lesion. The course was favorable under treatment. COMMENTS: With lupus vulgaris, scrofuloderma is the most common cutaneous tuberculosis lesion in children, particularly in developing countries. It is often associated with other organ lesions, such as bone or lung, and these must be sought. Scrofulodermas are unusual in Western countries, leading to misdiagnosis. Fortunately, adapted treatment most often results in recovery. PMID- 21549579 TI - Classification of healthy and abnormal swallows based on accelerometry and nasal airflow signals. AB - BACKGROUND: Dysphagia assessment involves diagnosis of individual swallows in terms of the depth of airway invasion and degree of bolus clearance. The videofluoroscopic swallowing study is the current gold standard for dysphagia assessment but is time-consuming and costly. An ideal alternative would be an automated abnormal swallow detection methodology based on non-invasive signals. OBJECTIVE: Building upon promising results from single-axis cervical accelerometry, the objective of this study was to investigate the combination of dual-axis accelerometry and nasal airflow for classification of healthy and abnormal swallows in a patient population with dysphagia. METHODS: Signals were acquired from 24 adult patients with dysphagia (17.8+/-8.8 swallows per patient). The abnormality of each swallow was quantified using 4-point videofluoroscopic rating scales for its depth of airway invasion, bolus clearance from the valleculae, and bolus clearance from the pyriform sinuses. For each scale, we endeavored to automatically discriminate between the 2 extreme ratings, yielding 3 separate binary classification problems. Various time, frequency, and time frequency domain features were extracted. A genetic algorithm was deployed for feature selection. Smoothed bootstrapping was utilized to balance the two classes and provide sufficient training data for a multidimensional feature space. RESULTS: A Euclidean linear discriminant classifier resulted in a mean adjusted accuracy of 74.7% for the depth of airway invasion rating, whereas Mahalanobis linear discriminant classifiers yielded mean adjusted accuracies of 83.7% and 84.2% for bolus clearance from the valleculae and pyriform sinuses, respectively. The bolus clearance from the valleculae problem required the lowest feature space dimensionality. Wavelet features were found to be most discriminatory. CONCLUSIONS: This exploratory study confirms that dual-axis accelerometry and nasal airflow signals can be used to discriminate healthy and abnormal swallows from patients with dysphagia. The fact that features from all signal channels contributed discriminatory information suggests that multi-sensor fusion is promising in abnormal swallow detection. PMID- 21549580 TI - Comparison of radiotherapy treatment plans for left-sided breast cancer patients based on three- and four-dimensional computed tomography imaging. AB - AIMS: The target volume for breast radiotherapy after conservative surgery for breast cancer may be affected by breathing motion. We investigated differences between conventional and four-dimensional computed tomography-based treatment planning and whether gating could improve dose volume parameters. MATERIALS AND METHODS: Ten patients with left-sided breast cancer and surgical clips at the excision site had conventional treatment planning computed tomography and four dimensional computed tomography. Treatment plans using two tangential beams (6 MV X-rays) were optimised for target coverage and homogeneity using a field in field technique for the three-dimensional scan. This plan was applied directly to four dimensional datasets representing individual phases of the breathing cycle and combinations thereof (average and maximum intensity projection). Optimised plans were generated for the maximum inhalation scan to study what could potentially be achieved in gated radiotherapy. RESULTS: Four-dimensional computed tomography with effective doses of around 10 mSv proved to be adequate for treatment planning in all patients. The average motion of the surgical clips was 3.7 mm (range 1.7-6.5mm), which was similar to the movement of the chest wall. With a margin of 7 mm for the whole breast to planning target volume, conventional three dimensional computed tomography-based planning was found to adequately cover the target as seen on four-dimensional computed tomography without significant differences in normal tissue sparing. Improved sparing of the heart and lung could only be achieved by reducing the posterior margin of the target volume, which may be justified if four-dimensional computed tomography is used to determine the target and its motion. CONCLUSION: No significant benefit has been shown for the use of four-dimensional computed tomography-based planning if motion management is not implemented concurrently with a reduced posterior margin between clinical and planning target volumes. PMID- 21549581 TI - Frequency and patterns of metastatic disease in locally advanced inflammatory and non-inflammatory breast cancer. AB - AIMS: To determine the frequency and pattern of metastatic disease as detected by staging computed tomography in patients presenting with locally advanced primary breast cancer, comparing non-inflammatory and inflammatory subtypes. MATERIALS AND METHODS: Patients who underwent staging computed tomography for locally advanced breast cancer were identified from the hospital's computerised radiology system. The computed tomography scans, breast imaging and pathology were reviewed. RESULTS: Over a 29 month period, 97 patients underwent staging computed tomography for locally advanced primary breast cancer. Sixteen patients (16%) were found to have metastatic disease at presentation. Thirty-eight patients (39%) presented with the inflammatory subtype and 59 patients (61%) with the non inflammatory subtype. Metastases were significantly more likely in patients with the inflammatory subtype, with 10 patients (26%) having metastases at presentation compared with six patients (10%) with the non-inflammatory subtype (P=0.034). Metastases to the lung and the pleura were the most commonly encountered sites, with pleural-based metastases more likely in patients with the inflammatory subtype (P=0.05). CONCLUSION: Routine computed tomography staging of patients with locally advanced breast cancer is worthwhile with the inflammatory subtype of locally advanced disease having the higher risk of metastatic disease at presentation. Pleural-based metastatic disease is more likely in patients with the inflammatory subtype. PMID- 21549582 TI - Biomarkers of dairy intake and the risk of heart disease. AB - BACKGROUND AND AIMS: Despite their relatively high content of saturated fat, studies of dairy product intake and the risk of cardiovascular disease have often yielded null or inverse results. The use of fatty acid biomarkers to reflect dairy intake could elucidate this association. This study aims to evaluate the association between dairy intake, assessed by adipose pentadecanoic (15:0) and heptadecanoic (17:0) fatty acids and food frequency questionnaire (FFQ), and the risk of nonfatal myocardial infarction (MI), in a matched case-control study of Costa Rican adults (n=3630). METHODS AND RESULTS: The association was examined using conditional logistic regression, adjusted for potential confounders. The associations of adipose tissue 15:0 and 17:0 with the risk of MI were not statistically significant (for 15:0: multivariate-adjusted OR for 5th quintile vs. 1st=1.14 (95% CI=0.85, 1.53), p-value for linear trend=0.77; for 17:0: multivariate-adjusted OR for 5th quintile vs. 1st=1.15 (95% CI=0.88, 1.51), p value for linear trend=0.18). The association between the FFQ measure of dairy intake and MI showed evidence of a possible threshold effect, with a protective association observed for all but the top quintile of the exposure distribution. CONCLUSION: Dairy product intake as assessed by adipose tissue 15:0, 17:0, and by FFQ is not associated with a linear increase in the risk of MI in the study population. It is possible that the adverse effect of saturated fat in dairy products on cardiovascular health is offset by presence of beneficial nutrients. PMID- 21549583 TI - Metabolic switching of human skeletal muscle cells in vitro. AB - In this review we will focus on external factors that may modify energy metabolism in human skeletal muscle cells (myotubes) and the ability of the myotubes to switch between lipid and glucose oxidation. We describe the metabolic parameters suppressibility, adaptability and substrate-regulated flexibility, and show the influence of nutrients such as fatty acids and glucose (chronic hyperglycemia), and some pharmacological agents modifying nuclear receptors (PPAR and LXR), on these parameters in human myotubes. Possible cellular mechanisms for changes in these parameters will also be highlighted. PMID- 21549584 TI - Quality of spirometry tests performed by 9893 adults in 14 countries: the BOLD Study. AB - OBJECTIVE: to determine the ability of participants in the Burden of Obstructive Lung Disease (BOLD) study to meet quality goals for spirometry test session quality and to assess factors contributing to good quality. METHODS: Following 2 days of centralized training, spirometry was performed pre- and post bronchodilator (BD) at 14 international sites, in random population-based samples of persons aged >=40 years, following a standardized protocol. The quality of each test session was evaluated by the spirometer software and an expert reading center. Descriptive statistics were calculated for key maneuver acceptability variables. A logistic regression model identified the predictors of acceptable quality test sessions. RESULTS: About 96% of test sessions met our quality goals for a low back-extrapolated volume (BEV), time to peak flow (PEFT), and end-of test volume (EOTV). The mean forced expiratory time (FET) was 10.4 s. Ninety percent of the maneuvers with the highest FVC had a forced expiratory time (FET) > 6.8 s. About 90% of test sessions had FEV(1) and FVC which were repeatable within 150 mL. Test quality was slightly better for post-BD test sessions when compared to pre-BD. Independent predictors of adequate test quality included female sex, younger age, higher education, lack of dyspnea, higher pre-BD FEV(1), less BD responsiveness, and study site. CONCLUSIONS: Quality goals for spirometry tests were met about 90% of the time in these population-based samples of adults from several countries. PMID- 21549585 TI - Effect of conductive polymers coated anode on the performance of microbial fuel cells (MFCs) and its biodiversity analysis. AB - Conductive polymer, one of the most attractive electrode materials, has been applied to coat anode of MFC to improve its performance recently. In this paper, two conductive polymer materials, polyaniline (PANI) and poly(aniline-co-o aminophenol) (PAOA) were used to modify carbon felt anode and physical and chemical properties of the modified anodes were studied. The power output and biodiversity of modified anodes, along with unmodified carbon anode were compared in two-chamber MFCs. Results showed that the maximum power density of PANI and PAOA MFC could reach 27.4 mW/m(2) and 23.8 mW/m(2), comparing with unmodified MFC, increased by 35% and 18% separately. Low temperature caused greatly decrease of the maximum voltage by 70% and reduced the sorts of bacteria on anodes in the three MFCs. Anode biofilm analysis showed different bacteria enrichment: a larger mount of bacteria and higher biodiversity were found on the two modified anodes than on the unmodified one. For PANI anode, the two predominant bacteria were phylogenetically closely related to Hippea maritima and an uncultured clone MEC_Bicarb_Ac-008; for PAOA, Clostridiales showed more enrichment. Compare PAOA with PANI, the former introduced phenolic hydroxyl group by copolymerization o aminophenol with aniline, which led to a different microbial community and the mechanism of group effect was proposed. PMID- 21549586 TI - Multi-day pre-clinical demonstration of glucose/galactose binding protein-based fiber optic sensor. AB - We report here the first pre-clinical demonstration of continuous glucose tracking by fluorophore-labeled and genetically engineered glucose/galactose binding protein (GGBP). Acrylodan-labeled GGBP was immobilized in a hydrogel matrix at the tip of a small diameter optical fiber contained in a stainless steel needle. The fiber optic biosensors were inserted subcutaneously into Yucatan and Yorkshire swine, and the sensor response to changing glucose levels was monitored at intervals over a 7-day period. Sensor mean percent error on day 7 was 16.4+/-5.0% using a single daily reference blood glucose value to calibrate the sensor. The GGBP sensor's susceptibility to common interferents was tested in a well-plate system using human sera. No significant interference was observed from the tested interferents except for tetracycline at the drug's maximum plasma concentration. The robust performance of the GGBP-based fiber optic sensor in swine models and resistance to interferents indicates the potential of this technology for continuous glucose monitoring in humans. PMID- 21549587 TI - Compact optical microfluidic uric acid analysis system. AB - We designed, fabricated and tested a novel compact fluorescence analysis system for quantification of uric acid (UA) in clinical samples at the point-of-care. To perform an analysis, diluted saliva, urine or blood samples are simply placed in a disposable thin-film sample holder using a dropper. A new enzyme immobilization technique was developed to retain within the sample holder two enzymes and a molecule, which transforms into a fluorescer in amounts depending on the UA concentration. The small instrument (7.5 cm * 5 cm * 5 cm) into which the sample holder is placed for analysis contains an LED, a narrow-band filter and an amplified photodiode. The analysis time is 30s, and the dynamic range of the system is 4-400 MUM of UA. The calibration curve for transparent saliva and urine was made using solutions of UA. The calibration curve for opaque blood was obtained with spiked samples of blood. The three different types of clinical samples were collected from three subjects and simply diluted before their measurements. Analysis with our instrument yielded UA concentrations within the expected concentration ranges. Development of instruments based on the current laboratory prototype is expected to result in products for clinical trials and point-of-care. PMID- 21549588 TI - The use of 24-h ambulatory blood pressure monitoring (ABPM) during the first cycle of sunitinib improves the diagnostic accuracy and management of hypertension in patients with advanced renal cancer. AB - AIM: Hypertension (HT) complicates treatment with antiangiogenic agents, including the tyrosine kinase inhibitor (TKI) sunitinib. To prospectively evaluate the prevalence and management of HT in patients with advanced renal cell carcinoma (RCC) receiving sunitinib we used 24-h ABPM and we treated HT according to guidelines of the Joint National Committee on Prevention, Detection and Evaluation and the Treatment of High Blood Pressure (JNC7). PATIENTS AND METHODS: Normal 24-h ABPM at the baseline and at 2, 4 and 6 weeks of the first cycle was ensured with the successive use of hydrochlorothiazide+irbesartan, nebivolol and amlodipine. Office BP measurements were used in subsequent cycles to monitor HT. Sunitinib dose was modified only if BP was not controlled with four anti hypertensive agents. RESULTS: Forty patients were included in this analysis. Twenty-one patients (53%) had baseline HT, while 12 of 14 (84%) normotensive patients required anti-HT treatment during the 1st cycle of sunitinib. HT was infrequent in subsequent cycles and increase of anti-HT medication was required in only 2 cases. Two patients permanently discontinued sunitinib due to HT. The remaining 34 (94%) required no dose modifications for HT. One cardiac event (2.8%) was observed. There was no correlation of HT with sunitinib efficacy. CONCLUSION: Sunitinib-associated HT is more frequent than previously reported. The use of 24-h ABPM for diagnosis and tailoring of HT according to JNC7 guidelines may achieve uninterrupted, full dose therapy in most patients. The substitution of such protocols for currently used Toxicity Criteria may be warranted. PMID- 21549589 TI - Choosing the relative survival method for cancer survival estimation. AB - BACKGROUND: The methods on how to calculate cumulative relative survival have been ambiguous and have given differences in empirical results. METHODS: The gold standard for the cumulative relative survival ratio is the weighted average of age-specific cumulative relative survival ratios, with weights proportional to numbers of patients at diagnosis. Mathematics and representative empirical materials from the population-based Finnish Cancer Registry were studied for the different relative survival methods and compared with the gold standard. RESULTS: The theoretical and empirical results show a good agreement between the method suggested in 1959 by Ederer and Heise (the so-called Ederer II method) and the gold standard. This result is in part due the fact that as follow-up time increases the conditional (annual) relative survival ratios become increasingly more independent of age. Moreover, the dependence between the excess mortality due to cancer and the baseline general mortality does not introduce an important enough selection in practice to cause a notable bias. CONCLUSION: The use of the method by Ederer and Heise, multiplication of the annual relative survival ratios, instead of direct standardisation, should be considered in future applications. This would be particularly important for the long-term follow-up when age-specific relative survival is not available in the oldest age categories. PMID- 21549590 TI - Simultaneous production of citric acid and invertase by Yarrowia lipolytica SUC+ transformants. AB - Simultaneous production of citric acid (CA) and invertase by Yarrowia lipolytica A-101-B56-5 (SUC(+) clone) growing from sucrose, mixture of glucose and fructose, glucose or glycerol was investigated. Among the tested substrates the highest concentration of CA was reached from glycerol (57.15 g/L) with high yield (Y(CA/S)=0.6g/g). When sucrose was used, comparable amount of CA was secreted (45 g/L) with slightly higher yield (Y(CA/S)=0.643 g/g). In all cultures amount of isocitrate (ICA) was below 2% of total citrates. Considering invertase production, the best carbon source appeared to be sucrose (72380 U/L). The highest yield of CA and invertase biosynthesis calculated for 1g of biomass was obtained for cells growing from glycerol (9.9 g/g and 4325 U/g, respectively). Concentrates of extra- and intracellular invertase of the highest activity were obtained from sucrose as substrate (0.5 and 1.8 * 10(6)U/L, respectively). PMID- 21549591 TI - Treatment of rice straw with selected Cyathus stercoreus strains to improve enzymatic saccharification. AB - Seventeen Cyathus stercoreus isolates were tested for their ability to treat rice straw for improved enzymatic saccharification. These isolates showed a negative correlation between cellulase and xylanase activity and enzymatic saccharification yields. Incubation of rice straw pretreated at 60 degrees C for 15 min with strain C. stercoreus TY-2 for 25 days resulted in an enzymatic saccharification yield of 57% as compared to a yield of 11% for the same straw in the absence of the fungus. These findings highlight the potential of this isolate for biological pretreatment of rice straw under conditions of low energy input. PMID- 21549592 TI - Material and energy balances of an integrated biological hydrogen production and purification system and their implications for its potential to reduce greenhouse gas emissions. AB - The materials and energy in an integrated biological hydrogen production and purification system involving hydrolysis, dark fermentation, photo fermentation, CO2 fixation and anaerobic digestion are balanced by integrating the results from multiple experiments, simulations and the literature. The findings are two fold. First, using 1000 kg rice straw as a substrate, 19.8 kg H2 and 138.0 kg CH4 are obtained. The net energy balance (NEB) and net energy ratio (NER) are -738.4 kWh and 77.8%, respectively, both of which imply an unfavorable energy production system. Opportunities to improve the performance particularly lie in the photo fermentation process. Second, greenhouse gas emissions are evaluated for various options. The results were comparable with the emission inventory of electricity generated from fossil fuels. NEB and NER under a zero-carbon-emission constraint were discussed in detail to clarify completely the implications of the energy and material balances on greenhouse gas emissions. PMID- 21549593 TI - Toward self-adjuvanting subunit vaccines: model peptide and protein antigens incorporating covalently bound toll-like receptor-7 agonistic imidazoquinolines. AB - Toll-like receptor (TLR)-7 agonists show prominent Th1-biased immunostimulatory activities. A TLR7-active N(1)-(4-aminomethyl)benzyl substituted imidazoquinoline 1 served as a convenient precursor for the syntheses of isothiocyanate and maleimide derivatives for covalent attachment to free amine and thiol groups of peptides and proteins. 1 was also amenable to direct reductive amination with maltoheptaose without significant loss of activity. Covalent conjugation of the isothiocyanate derivative 2 to alpha-lactalbumin could be achieved under mild, non-denaturing conditions, in a controlled manner and with full preservation of antigenicity. The self-adjuvanting alpha-lactalbumin construct induced robust, high-affinity immunoglobulin titers in murine models. The premise of covalently decorating protein antigens with adjuvants offers the possibility of drastically reducing systemic exposure of the adjuvant, and yet eliciting strong, Th1-biased immune responses. PMID- 21549594 TI - Radiosynthesis of [11C]Vandetanib and [11C]chloro-Vandetanib as new potential PET agents for imaging of VEGFR in cancer. AB - Vandetanib (ZD6474) and its chlorine analogue chloro-Vandetanib are potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with low nanomolar IC(50) values. [(11)C]Vandetanib and [(11)C]chloro Vandetanib, new potential PET agents for imaging of VEGFR in cancer, were first designed, synthesized and labeled at nitrogen and oxygen positions from their corresponding N- and O-des-methylated precursors, in 40-50% decay corrected radiochemical yield and 370-555GBq/MUmol specific activity at end of bombardment (EOB). PMID- 21549595 TI - Design and synthesis of an ER-specific fluorescent probe based on carboxylesterase activity with quinone methide cleavage process. AB - CEs are important enzymes that catalyze the hydrolysis of prodrugs. In this Letter, we present a new mechanistic ER-specific fluorescent probe 1 based on CE activity. Permeation of 1 into cells and subsequent hydrolytic activation by CEs causes spontaneously quinone methide cleavage, resulting in bright red fluorescence in ER with high specificity. Probe 1 was developed for CE activity imaging and inhibitor screening at the cellular level. PMID- 21549596 TI - Structure-activity relationship of cyclic thiacarbocyanine tau aggregation inhibitors. AB - Macrocyclic bis-thiacarbocyanines are efficacious inhibitors of tau protein aggregation. To extend the structure-activity relationship of this inhibitor class, N,N'-alkylene bis-thiacarbocyanines linked by chains of three to eight methylene carbons were synthesized and examined for inhibitory activity against recombinant human tau aggregation in vitro. At 10 micromolar concentration, inhibitory activity varied with linker length, with four methylene units being most efficacious. On the basis of absorbance spectroscopy measurements, linker length also affected compound folding and aggregation propensity, with a linker length of four methylene units being optimal for preserving open monomer conformation. These data suggest that inhibitory potency can be optimized through control of linker length, and that a contributory mechanism involves modulation of compound folding and aggregation. PMID- 21549597 TI - Synthesis and crystallographic analysis of new sulfonamides incorporating NO donating moieties with potent antiglaucoma action. AB - Several aromatic/heterocyclic sulfonamide scaffolds have been used to synthesize compounds incorporating NO-donating moieties of the nitrate ester type, which have been investigated for the inhibition of five physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms: hCA I (offtarget), II, IV and XII (antiglaucoma targets) and IX (antitumor target). Some of the new compounds showed effective in vitro inhibition of the target isoforms involved in glaucoma, and the X-ray crystal structure of one of them revealed factors associated with the marked inhibitory activity. In an animal model of ocular hypertension, one of the new compounds was twice more effective than dorzolamide in reducing elevated intraocular pressure characteristic of this disease, anticipating their potential for the treatment of glaucoma. PMID- 21549598 TI - Development of a fluorogenic sensor for activated Cdc42. AB - Cdc42, a member of the Rho GTPase family, is a fundamental regulator of the actin cytoskeleton during cell migration. To generate a sensor for Cdc42 activation, we employed a multi-pronged approach, utilizing cysteine labeling and expressed protein ligation, to incorporate the environment sensitive fluorophore 4-N,N dimethylamino-1,8-naphthalimide (4-DMN) into the GTPase binding domain of the WASP protein. These constructs bind only the active, GTP-bound conformation of Cdc42 to produce a fluorescence signal. Studies with a panel of five sensor analogs revealed a derivative that exhibits a 32-fold increase in fluorescence intensity in the presence of activated Cdc42 compared to incubation with the inactive GDP-bound form of the protein. We demonstrate that this sensor can be exploited to monitor Cdc42 nucleotide exchange and GTPase activity in a continuous, fluorescence assay. PMID- 21549600 TI - Improvement and impairment of visually guided behavior through LTP- and LTD-like exposure-based visual learning. AB - Cellular studies have focused on long-term potentiation (LTP) and long-term depression (LTD) to understand requirements for persistent changes in synaptic connections. Whereas LTP is induced through high-frequency intermittent stimulation, low-frequency stimulation evokes LTD. Because of the ubiquitous efficacy of these protocols, they are considered fundamental mechanisms underlying learning. Here we adapted LTP/LTD-like protocols to visual stimulation to alter human visually guided behavior. In a change-detection task, participants reported luminance changes against distracting orientation changes. Subsequently, they were exposed to passive visual high- or low-frequency stimulation of either the relevant luminance or irrelevant orientation feature. LTP-like high-frequency protocols using luminance improved ability to detect luminance changes, whereas low-frequency LTD-like stimulation impaired performance. In contrast, LTP-like exposure of the irrelevant orientation feature impaired performance, whereas LTD like orientation stimulation improved it. LTP-like effects were present for 10 days, whereas LTD-like effects lasted for a shorter period of time. Our data demonstrate that instead of electrically stimulating synapses, selective behavioral changes are evoked in humans by using equivalently timed visual stimulation, suggesting that both LTD- and LTP-like protocols control human behavior but that the direction of changes is determined by the feature incorporated into the stimulation protocol. PMID- 21549599 TI - Notch signaling modulates sleep homeostasis and learning after sleep deprivation in Drosophila. AB - The role of the transmembrane receptor Notch in the adult brain is poorly understood. Here, we provide evidence that bunched, a negative regulator of Notch, is involved in sleep homeostasis. Genetic evidence indicates that interfering with bunched activity in the mushroom bodies (MBs) abolishes sleep homeostasis. Combining bunched and Delta loss-of-function mutations rescues normal homeostasis, suggesting that Notch signaling may be involved in regulating sensitivity to sleep loss. Preventing the downregulation of Delta by overexpressing a wild-type transgene in MBs reduces sleep homeostasis and, importantly, prevents learning impairments induced by sleep deprivation. Similar resistance to sleep loss is observed with Notch(spl-1) gain-of-function mutants. Immunohistochemistry reveals that the Notch receptor is expressed in glia, whereas Delta is localized in neurons. Importantly, the expression in glia of the intracellular domain of Notch, a dominant activated form of the receptor, is sufficient to prevent learning deficits after sleep deprivation. Together, these results identify a novel neuron-glia signaling pathway dependent on Notch and regulated by bunched. These data highlight the emerging role of neuron-glia interactions in regulating both sleep and learning impairments associated with sleep loss. PMID- 21549601 TI - The requirement for the Dam1 complex is dependent upon the number of kinetochore proteins and microtubules. AB - The Dam1 complex attaches the kinetochore to spindle microtubules and is a processivity factor in vitro. In Saccharomyces cerevisiae, which has point centromeres that attach to a single microtubule, deletion of any Dam1 complex member results in chromosome segregation failures and cell death. In Schizosaccharomyces pombe, which has epigenetically defined regional centromeres that each attach to 3-5 kinetochore microtubules, Dam1 complex homologs are not essential. To determine why the complex is essential in some organisms and not in others, we used Candida albicans, a multimorphic yeast with regional centromeres that attach to a single microtubule. Interestingly, the Dam1 complex was essential in C. albicans, suggesting that the number of microtubules per centromere is critical for its requirement. Importantly, by increasing CENP-A expression levels, more kinetochore proteins and microtubules were recruited to the centromeres, which remained fully functional. Furthermore, Dam1 complex members became less crucial for growth in cells with extra kinetochore proteins and microtubules. Thus, the requirement for the Dam1 complex is not due to the DNA-specific nature of point centromeres. Rather, the Dam1 complex is less critical when chromosomes have multiple kinetochore complexes and microtubules per centromere, implying that it functions as a processivity factor in vivo as well as in vitro. PMID- 21549602 TI - Sustained elongation of sperm tail promoted by local remodeling of giant mitochondria in Drosophila. AB - BACKGROUND: Sperm length in Drosophilidae varies from a few hundred microns to 6 cm as a result of evolutionary selection. In postcopulatory competition, longer sperm have an advantage in positioning their head closer to the egg. Sperm cell elongation can proceed in the absence of an axoneme, suggesting that a mechanism besides intraflagellar transport emerged to sustain it. RESULTS: Here we report that sperm elongation in Drosophila melanogaster is driven by the interdependent extension of giant mitochondria and microtubule array that is formed around the mitochondrial surface. In primary cultures of elongating spermatids, we demonstrated that the mitochondrial integrity and local dynamics of microtubules at the tail tip region are essential for uniaxial elongation of the sperm tail. Mitochondria-microtubule linker protein Milton accumulated on mitochondria near the tail tip and is required for the sliding movement of microtubules. Disruption of Milton and its associated protein dMiro, and of potential microtubule crosslinkers Nebbish and Fascetto, caused strong elongation defects, indicating that mitochondria-microtubule association and microtubule crosslinking are required for spermatid tail elongation. CONCLUSIONS: Mitochondria play unexpected roles in sperm tail elongation in Drosophila by providing a structural platform for microtubule reorganization to support the robust elongation taking place at the tip of the very long sperm tail. The identification of mitochondria as an organizer of cytoskeletal dynamics extends our understanding of mechanisms of cell morphogenesis. PMID- 21549603 TI - TRPM channels modulate epileptic-like convulsions via systemic ion homeostasis. AB - Neuronal networks operate over a wide range of activity levels, with both neuronal and nonneuronal cells contributing to the balance of excitation and inhibition. Activity imbalance within neuronal networks underlies many neurological diseases, such as epilepsy. The Caenorhabditis elegans locomotor circuit operates via coordinated activity of cholinergic excitatory and GABAergic inhibitory transmission. We have previously shown that a gain-of-function mutation in a neuronal acetylcholine receptor, acr-2(gf), causes an epileptic like convulsion behavior. Here we report that the behavioral and physiological effects of acr-2(gf) require the activity of the TRPM channel GTL-2 in nonneuronal tissues. Loss of gtl-2 function does not affect baseline synaptic transmission but can compensate for the excitation-inhibition imbalance caused by acr-2(gf). The compensatory effects of removing gtl-2 are counterbalanced by another TRPM channel, GTL-1, and can be recapitulated by acute treatment with divalent cation chelators, including those specific for Zn(2+). Together, these data reveal an important role for ion homeostasis in the balance of neuronal network activity and a novel function of nonneuronal TRPM channels in the fine tuning of this network activity. PMID- 21549605 TI - Organization of voluntary stepping in response to emotion-inducing pictures. AB - The present experiment was conducted to examine the expectation that emotion stimuli influence the initiation and execution of voluntary stepping, a highly coordinated activity involving a sequence of medio-lateral and anterio-posterior weight shifts. Thirty participants made forward (approach) or backward (avoidance) steps on a forceplate in response to the valence of visual stimuli. Posturographic parameters of the steps, related to automatic stimulus evaluation, step initiation and step execution, were determined and analyzed as a function of stimulus valence and stimulus-response mapping. The results revealed marked effects of emotion on the step parameters of interest; unpleasant images caused an initial "freezing" response, and a tendency to move away from the stimuli. Pleasant stimuli, in contrast, were not found to induce approach tendencies. The results demonstrated that affect, especially negative emotions, and whole-body movements such as voluntary stepping are coupled. PMID- 21549606 TI - Morts d'amour: mitochondria are bacteria that sometimes become extinct through symbiosis. PMID- 21549604 TI - C. elegans Notch signaling regulates adult chemosensory response and larval molting quiescence. AB - BACKGROUND: The conserved DOS-motif proteins OSM-7 and OSM-11 function as coligands with canonical DSL (Delta, Serrate, and LAG-2) ligands to activate C. elegans Notch receptors during development. We report here that Notch ligands, coligands, and the receptors LIN-12 and GLP-1 regulate two C. elegans behaviors: chemosensory avoidance of octanol and quiescence during molting lethargus. RESULTS: C. elegans lacking osm-7 or osm-11 are defective in their response to octanol. We find that OSM-11 is secreted from hypodermal seam cells into the pseudocoelomic body cavity and acts non-cell autonomously as a diffusible factor. OSM-11 acts with the DSL ligand LAG-2 to activate LIN-12 and GLP-1 Notch receptors in the neurons of adult animals, thereby regulating octanol avoidance response. In adult animals, overexpression of osm-11 and consequent Notch receptor activation induces anachronistic sleep-like quiescence. Perturbation of Notch signaling alters basal activity in adults as well as arousal thresholds and quiescence during molting lethargus. Genetic epistasis studies reveal that Notch signaling regulates quiescence via previously identified circuits and genetic pathways including the egl-4 cGMP-dependent kinase. CONCLUSIONS: Our findings indicate that the conserved Notch pathway modulates behavior in adult C. elegans in response to environmental stress. Additionally, Notch signaling regulates sleep-like quiescence in C. elegans, suggesting that Notch may regulate sleep in other species. PMID- 21549607 TI - Twiddler's syndrome in a patient with a deep brain stimulation device for generalized dystonia. AB - Deep brain stimulation (DBS) is the technique of neurostimulation of deep brain structures for the treatment of conditions such as essential tremor, dystonia, Parkinson's disease and chronic pain syndromes. The procedure uses implanted deep brain stimulation electrodes connected to extension leads and an implantable pulse generator (IPG). Hardware failure related to the DBS procedure is not infrequent, and includes electrode migration and disconnection. We describe a patient who received bilateral globus pallidus internus DBS for dystonia with initially good clinical response, but the device eventually failed. Radiographs showed multiple twisting of the extension leads with disconnection from the brain electrodes and a diagnosis of Twiddler's syndrome was made. Twiddler's syndrome was first described in patients with cardiac pacemakers. Patients with mental disability, elderly and obese patients are at increased risk. Twiddler's syndrome should be suspected whenever there is a failure of the DBS device to relieve symptoms previously responsive to stimulation. Surgical correction is usually required. PMID- 21549608 TI - Aquaporin-4 expression after experimental contusional injury in an ovine impact acceleration head injury model. AB - Cerebral contusions are one of the principal lesions of traumatic brain injury and the attendant oedema formation contributes substantially to the clinicopathological manifestations. While it is now recognised that the membrane channel protein aquaporin-4 (AQP-4) plays a major role in the development and resolution of cerebral oedema, assessments of its expression in and around contusions have produced conflicting results. We used an ovine impact acceleration model of closed head injury to examine contusion-related AQP-4 expression and found that there was a heterogeneous AQP-4 response within contusions, with some astrocytes being nonviable and immunonegative, while others showed increased AQP-4 expression. Pericontusional astrocytes in the penumbra region generally showed more robust AQP-4 immunopositivity than intracontusional glia. Thus, manipulation of AQP-4 expression could have therapeutic applications in controlling cerebral oedema associated with contusions. PMID- 21549609 TI - Structural characteristics of nanocrystalline copper after carbon ion implantation. AB - A gradient structure was produced in a pure copper plate by means of surface mechanical attrition treatment (SMAT). The microstructure of the surface layer was reduced to nanoscale and the grain size increased gradually along the depth of the treated sample. In situ transmission electron microscopy (TEM) and high resolution transmission electron microscopy (HRTEM) observation was performed on the nanocrystalline copper after implantation of carbon. Carbon atoms first precipitated along the edges of the copper substrate or at the surface, then formed amorphous carbon layers. Subsequently, onion-like fullerenes were formed under electron-beam irradiation. The effects of ion implantation, electron beam irradiation, nanostructure of the substrate and interaction of C and Cu atoms on the formation of the onion-like fullerenes are discussed. PMID- 21549610 TI - Isolation and characterization of an oil palm constitutive promoter derived from a translationally control tumor protein (TCTP) gene. AB - We have characterized an oil palm (Elaeis guineensis Jacq.) constitutive promoter that is derived from a translationally control tumor protein (TCTP) gene. The TCTP promoter was fused transcriptionally with the gusA reporter gene and transferred to monocot and dicot systems in order to study its regulatory role in a transient expression study. It was found that the 5' region of TCTP was capable of driving the gusA expression in all the oil palm tissues tested, including immature embryo, embryogenic callus, embryoid, young leaflet from mature palm, green leaf, mesocarp and stem. It could also be used in dicot systems as it was also capable of driving gusA expression in tobacco leaves. The results indicate that the TCTP promoter could be used for the production of recombinant proteins that require constitutive expression in the plant system. PMID- 21549611 TI - Takayasu arteritis. PMID- 21549612 TI - Aortic valve translocation for treatment of a deteriorated stentless valve. AB - A 54-year-old woman was admitted to our hospital with recurrent chest pain for 1 month. She had a history of aortic root replacement with a stentless valve following aortic valve replacements done twice 12 years ago, and coronary artery bypass grafting 6 years ago. The stentless valve was implanted with the full-root technique. After admission, she was diagnosed with a saphenous vein graft aneurysm in the proximal anastomotic site and severe aortic regurgitation due to stentless valve deterioration. These lesions were successfully treated using aortic valve translocation. The advantage of this procedure is that it avoids dissection and removal of the stentless valve implanted using the full-root technique. Aortic valve translocation can be one of useful alternatives for stentless valve reoperation. PMID- 21549613 TI - A second prosthesis as a procedural rescue option in trans-apical aortic valve implantation. AB - OBJECTIVE: Trans-apical aortic valve implantation (TA-AVI) using the Edwards SAPIENTM prosthesis has evolved to a routine procedure for selected high-risk elderly patients. In rare cases, misplacement of the SAPIENTM valve (too low a position), dysfunction of the leaflets or perforation of the interventricular septum (ventricular septal defect, VSD) occurs and requires immediate implantation of a second prosthesis within the first one. Results of this 'bailout' maneuver have not been reported yet. METHODS: Of 305 TA-AVI procedures, 15 patients required a second prosthesis due to dysfunctional leaflets (n = 6), low position (n = 7), or VSD (n = 2). Mean age was 82.5 +/- 1.3 years, mean logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 45.5 +/- 5.4, and Society of Thoracic Surgeons (STS) Score was 13.5 +/- 1.5. RESULTS: All second SAPIENTM valves could be implanted successfully within the first one. The second prosthesis solved leaflet dysfunction, sealed the VSD (lower position of the second prosthesis), or corrected the initial misplacement (higher position of the second prosthesis) in all patients. Within 30 days, four patients died (low cardiac output n = 3, all with preoperative ejection fraction (EF) <35%; intestinal ischemia n = 1). Intra-operative echocardiogram and angiogram revealed mild paravalvular leak in three and none/trace in 12 patients. Transvalvular gradients were low despite the implantation of the second valve (P(max)/mean 13.7 +/- 4.3/6.4 +/- 2.0). CONCLUSION: Placement of a second SAPIENTM valve is a valuable 'bailout' technique in case of VSD, dysfunctional leaflets, or too low placement of the first prosthesis. The technique leads to an excellent functional result with low transvalvular gradients. The simple, straight, tubular stent design of the SAPIENTM prosthesis may be the ideal design for such valve-in-valve procedures. PMID- 21549614 TI - Glucocorticoid receptor mutants: man-made tools for functional research. AB - The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that can bind to glucocorticoids (GCs). Upon ligand binding, GR sheds its cytoplasmic chaperoning complex and translocates to the nucleus, where it can act as a ligand dependent transcription factor, transactivating or transrepressing specific gene promoters. Often, GR interacts with specific cofactors to implement a variety of gene promoter effects. GR activity and function is further modulated by post translational modifications. To assess the diverse aspects of GR mechanisms of activation and gene regulation, researchers continue to use a range of artificial GR mutants. In this review we analyze the characteristics of GR mutants with the aim of assisting the design and interpretation of GR mutant-based experiments. PMID- 21549615 TI - A comparative study of monosaccharide composition analysis as a carbohydrate test for biopharmaceuticals. AB - The various monosaccharide composition analysis methods were evaluated as monosaccharide test for glycoprotein-based pharmaceuticals. Neutral and amino sugars were released by hydrolysis with 4-7N trifluoroacetic acid. The monosaccharides were N-acetylated if necessary, and analyzed by high-performance liquid chromatography (HPLC) with fluorometric or UV detection after derivatization with 2-aminopyridine, ethyl 4-aminobenzoate, 2-aminobenzoic acid or 1-phenyl-3-methyl-5-pyrazolone, or high pH anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD). Sialic acids were released by mild acid hydrolysis or sialidase digestion, and analyzed by HPLC with fluorometric detection after derivatization with 1,2-diamino-4,5-methylenedioxybenzene, or HPAEC-PAD. These methods were verified for resolution, linearity, repeatability, and accuracy using a monosaccharide standard solution, a mixture of epoetin alfa and beta, and alteplase as models. It was confirmed that those methods were useful for ensuring the consistency of glycosylation. It is considered essential that the analytical conditions including desalting, selection of internal standards, release of monosaccharides, and gradient time course should be determined carefully to eliminate interference of sample matrix. Various HPLC based monosaccharide analysis methods were evaluated as a carbohydrate test for glycoprotein pharmaceuticals by an inter-laboratory study. PMID- 21549616 TI - Activation timing of postural muscles during bilateral arm flexion in self timing, oddball and simple-reaction tasks. AB - BACKGROUND: We investigated the effect of time constraint on activation timing of postural muscles during bilateral arm flexion in self-timing, oddball and simple reaction tasks. METHODS: Thirteen healthy adults flexed their arms from a suspended position with maximum speed and stopped at the shoulder level. For erector spinae-longissimus (ES), biceps femoris (BF), and gastrocnemius (GcM), onset timing of burst activation with respect to the anterior deltoid (AD), and the displacement of the center of pressure in the anteroposterior direction (CoPy) were analyzed. RESULTS: AD reaction time was significantly shorter in the simple-reaction task than oddball task, suggesting that time constraint would be lower in the task order noted above and affected the state of postural preparation. The following properties were found in the onset timing of postural muscle: (1) the onset timing of BF and GcM were earlier in the task order noted above, and (2) the earliest activated distal muscle in the self-timing task was activated later in the simple-reaction task. CoPy displacement was smaller in the same task order as the onset timing. CONCLUSIONS: It appears that with sufficient postural preparation, the focus of postural control is on the reduction of postural disturbance and earlier lower leg muscle activation. PMID- 21549617 TI - Activity modulations of trunk and lower limb muscles during impact-absorbing landing. AB - This study aimed to investigate the activity patterns of trunk and lower limb muscles during impact-absorbing landing. Electromyogram activities of the trunk and lower limb muscles along with kinematic and ground reaction forces were measured while subjects (n=17) performed 10 landings from a height of 35 cm. Landing motions were divided into three phases: 100 ms preceding ground contact (GC) (PRE phase), from GC through 100 ms (ABSORPTION phase), and from the end of the ABSORPTION phase until the vertical position of the center of mass was minimized (BRAKING phase). During the PRE phase, the rectus abdominis, external oblique, and medial gastrocnemius were highly activated. Upon GC, the hip and knee joints were in a flexed position; the ankle joints, in a plantarflexed position. After GC, peak timings of muscle activities and lower limb joint rotations were characterized by distal-to-proximal sequential patterns. The peak vertical ground reaction force in the ABSORPTION phase relative to body weight positively correlated with the activity levels of the vastus lateralis and gluteus maximus in the PRE phase and that of rectus abdominis in the ABSORPTION phase. These findings indicate that the intensities and peak timings of muscle activities in the trunk and lower limb are coordinated to absorb landing impact. PMID- 21549618 TI - Publication rates of manuscript presentations at the American College of Foot and Ankle Surgeons Annual Scientific Conference between 1999 and 2008. AB - Publication is the ultimate desired end point of scientific research. However, oral manuscript presentations of research studies are often referenced in textbooks, journal articles, and industry white papers, and, as a result, influence treatment care plans. No data exist for the actual publication rate of podiatric foot and ankle surgery oral manuscript presentations. Therefore, the objective of this study was to determine the actual publication rates of oral manuscript presentations at the American College of Foot and Ankle Surgeons (ACFAS) Annual Scientific Conference over 10 years. Print or electronic media for the ACFAS Annual Scientific Conference official program between 1999 and 2008 were obtained. Each year's official program was hand searched for any oral manuscript presentation, and, when identified, the title and authors were individually searched through electronic internet-based search engines to determine whether an oral manuscript presentation had been followed by publication of a full-text article. Additionally, pertinent journals were hand searched for potential articles. A total of 67.5% (139/206) oral manuscript presentations were ultimately published in 1 of 12 medical journals in a mean of 14.5 months. All journals except one (91.7%) represented peer-reviewed journals. The publication rate of oral manuscript presentations at the ACFAS Annual Scientific Conference is similar to or greater than orthopaedic subspecialties, including foot and ankle surgery, publication rates. Based on the above, attendees of the ACFAS Annual Scientific Conference should be aware that the majority of oral manuscript material presented at the ACFAS Annual Scientific Conference can be considered as accurate because they survive the rigors of the peer-review process more than two thirds of the time. PMID- 21549620 TI - Evaluation of hardware-related geometrical distortion in structural MRI at 7 Tesla for image-guided applications in neurosurgery. AB - RATIONALE AND OBJECTIVES: Geometrical distortion is a well-known problem in structural magnetic resonance imaging (MRI), leading to pixel shifts with variations up to several millimeters. Because the main factors of geometrical distortion are proportional to B(0), MRI spatial encoding distortions tend to increase with higher magnetic field strength. With the increasing prospects of utilizing ultra-high-field MRI (B(0) >= 7 Tesla) for neuroimaging and subsequently for image-guided neurosurgical therapy, the evaluation and correction of geometrical distortions occurring in ultra-high-field MRI are essential preconditions for the integration of these data. Hence, we conducted a phantom study to determine hardware-related geometrical distortion in clinically relevant sequences for structural imaging at 7 T MRI and compared the findings to 1.5 T MRI. MATERIAL AND METHODS: Hardware-related geometrical distortion was evaluated using a MRI phantom (Elekta, Sweden). Both applied scanner systems (Magnetom Avanto 1.5 T and Magnetom 7 T, Siemens Healthcare, Erlangen, Germany) were equipped with similar gradient coils capable of delivering 45 mT/m of maximum amplitude and a slew rate of 220 mT/m/ms. Distortion analysis was performed for various clinically relevant gradient echo and spin echo sequences. RESULTS: Overall, we found very low mean geometrical distortions at both 7 T and 1.5 T, although single values of up to 1.6 mm were detected. No major differences in mean distortion between the sequences could be found, except significantly higher distortions in turbo spin-echo sequences at 7 T, mainly caused by B(1) inhomogeneities. CONCLUSION: Hardware-related geometrical distortions at 7 T MRI are relatively small, which may be acceptable for image coregistration or for direct tissue-targeting procedures. Using a subject-specific correction of object related distortions, an integration of 7 T MRI data into image-guided applications may be feasible. PMID- 21549619 TI - Protective capacity of memory CD8+ T cells is dictated by antigen exposure history and nature of the infection. AB - Infection or vaccination confers heightened resistance to pathogen rechallenge because of quantitative and qualitative differences between naive and primary memory T cells. Herein, we show that secondary (boosted) memory CD8+ T cells were better than primary memory CD8+ T cells in controlling some, but not all acute infections with diverse pathogens. However, secondary memory CD8+ T cells were less efficient than an equal number of primary memory cells at preventing chronic LCMV infection and are more susceptible to functional exhaustion. Importantly, localization of memory CD8+ T cells within lymph nodes, which is reduced by antigen restimulation, was critical for both viral control in lymph nodes and for the sustained CD8+ T cell response required to prevent chronic LCMV infection. Thus, repeated antigen stimulation shapes memory CD8+ T cell populations to either enhance or decrease per cell protective immunity in a pathogen-specific manner, a concept of importance in vaccine design against specific diseases. PMID- 21549621 TI - Loss of APKC expression independently predicts tumor recurrence in superficial bladder cancers. AB - OBJECTIVES: Epithelial-mesenchymal transition (EMT) is known to play an important role in the development of tumor invasion and progression in tumors of epithelial origin. Our aim was to investigate the role of tight junction proteins, Par3/Par6/atypical protein kinase C (APKC), Discs large (Dlg), and Scribble in human bladder pathogenesis. METHODS: We evaluated levels of APKC, Dlg, and Scribble in 92 superficial bladder tumors using tissue microarrays and immunohistochemistry, and correlated expression with pathologic variables and clinical outcomes. RESULTS: There was a slight apparent enrichment in strong vs. weak staining for APKC (54.9% vs. 45.1%), Dlg (65.7% vs. 34.3%), and a marked enrichment for Scribble (75% vs. 25%) in the superficial bladder tumors. Univariate analysis determined that both tumor focality and APKC expression were significantly associated with tumor recurrence (P < 0.05). Multivariate analysis using the Cox's proportional hazards model revealed that only APKC (P = 0.025) as well as tumor focality (P = 0.018) were independent and significant prognostic factors for tumor recurrence in all patients. We found that no immunohistochemical staining of any of the cell polarity proteins significantly predicted for tumor progression on either univariate or multivariate analysis. CONCLUSIONS: Loss of APKC expression in superficial bladder tumors is a strong predictor of tumor recurrence. PMID- 21549622 TI - Computational study of haemodynamic effects of entry- and exit-tear coverage in a DeBakey type III aortic dissection: technical report. AB - OBJECTIVES: Outcome prediction in DeBakey Type III aortic dissections (ADs) remains challenging. Large variations in AD morphology, physiology and treatment exist. Here, we investigate if computational fluid dynamics (CFD) can provide an initial understanding of pressure changes in an AD computational model when covering entry and exit tears and removing the intra-arterial septum (IS). DESIGN: A computational mesh was constructed from magnetic resonance images from one patient (one entrance and one exit tear) and CFD simulations performed (scenario #1). Additional meshes were derived by virtually (1) covering the exit tear (false lumen (FL) thrombus progression) (scenario #2), (2) covering the entrance tear (thoracic endovascular treatment, TEVAR) (scenario #3) and (3) completely removing the IS (fenestration) (scenario #4). Changes in flow patterns and pressures were quantified relative to the initial mesh. RESULTS: Systolic pressures increased for #2 (300 Pa increase) with largest inter-luminal differences distally (2500 Pa). In #3, false lumen pressure decreased essentially to zero. In #4, systolic pressure in combined lumen reduced from 2400 to 800 Pa. CONCLUSIONS: CFD results from computational models of a DeBakey type III AD representing separate coverage of entrance and exit tears correlated with clinical experience. The reported results present a preliminary look at a complex clinical problem. PMID- 21549623 TI - PAX5 deletion is common and concurrently occurs with CDKN2A deletion in B-lineage acute lymphoblastic leukemia. AB - The PAX5 is essential in normal B-cell lymphopoiesis and deregulation of PAX5 function is believed to contribute to leukemogenesis in B-ALL. We performed a comprehensive study using FISH, G-banding and IHC to identify PAX5 deletion and expression in 102 CD19+ clinical B-ALL cases (79 children and 33 adults) and investigated its relationship with common cytogenetic changes including BCR-ABL1, ETV6-RUNX1 and MLL rearrangements, and CDKN2A deletion. The incidences of translocations and deletions were 2.5% and 10.0% in children, and 0.0% and 18.2% in adults, respectively. The incidence of PAX5 deletion was higher than those of BCR-ABL1 (8.9%) or MLL rearrangements (5.1%) in children and than that of MLL rearrangement (3.1%) in adults. Most patients with PAX5 deletion (83.3% of children and 100.0% of adults with PAX5 deletion) had concurrent CDKN2A deletion. PAX5 deletions were detected both in patients with positive and negative PAX5 expression. In this study, we found that PAX5 is a common target in leukemogenesis of B-ALL along with CDKN2A. Owing to its frequent deletion in B ALL, PAX5 could be used as one of the molecular markers in diagnosis and monitoring of the disease. No correlation between expression of PAX5 and deletion of PAX5 suggests allele-specific regulation. PMID- 21549624 TI - Comprehensive cDNA study and quantitative analysis of mutant HADHA and HADHB transcripts in a French cohort of 52 patients with mitochondrial trifunctional protein deficiency. AB - BACKGROUND: Deficiency of mitochondrial trifunctional protein (MTP) is caused by mutations in the HADHA and HADHB genes, which have been mostly delineated at the genomic DNA level and have not been always elucidated. AIM: To identify mutations in a French cohort of 52 MTP deficient patients and the susceptibility of mutations generating premature termination codons (PTCs) to the nonsense mRNA mediated decay (NMD). METHODS: Mutation screening in fibroblasts was performed at the cDNA level and real-time RT-PCR was used to compare the levels of the different PTC-bearing mRNAs before and after a treatment of fibroblasts by emetine, a translation inhibitor. RESULTS: A mutation detection rate of 100% was achieved. A total of 22 novel mutations were identified, including a large-sized genomic deletion in HADHB gene. A high proportion of all identified mutations were non-sense, frameshift and splicing mutations, generating (PTCs), distributed essentially on HADHA coding regions. We could demonstrate that the majority of mutations resulting in PTCs conform to the established rules governing the susceptibility to NMD. CONCLUSION: Our results emphasize the value of cDNA analysis in the characterization of HADHA and HADHB mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in MTP defects. PMID- 21549625 TI - 45-Year-old female with propionic acidemia, renal failure, and premature ovarian failure; late complications of propionic acidemia? AB - We describe a 45-year-old patient who was diagnosed with propionic acidemia in infancy, who experienced an unstable first two years of life but who eventually had a good developmental outcome. She developed severe renal failure requiring renal transplantation in her forties and premature ovarian failure. Renal failure and premature ovarian failure have not previously been associated with propionic acidemia. We hypothesize that propionic acidemia may have contributed to these complications, and discuss several possible mechanisms for this, emphasizing mainly the electron transport chain/mitochondrial energy deficiency hypothesis. PMID- 21549626 TI - CARD-mediated autoinhibition of cIAP1's E3 ligase activity suppresses cell proliferation and migration. AB - E3 ligases mediate the covalent attachment of ubiquitin to target proteins thereby enabling ubiquitin-dependent signaling. Unraveling how E3 ligases are regulated is important because miscontrolled ubiquitylation can lead to disease. Cellular inhibitor of apoptosis (cIAP) proteins are E3 ligases that modulate diverse biological processes such as cell survival, proliferation, and migration. Here, we have solved the structure of the caspase recruitment domain (CARD) of cIAP1 and identified that it is required for cIAP1 autoregulation. We demonstrate that the CARD inhibits activation of cIAP1's E3 activity by preventing RING dimerization, E2 binding, and E2 activation. Moreover, we show that the CARD is required to suppress cell proliferation and migration. Further, CARD-mediated autoregulation is also necessary to maximally suppress caspase-8-dependent apoptosis and vascular tree degeneration in vivo. Taken together, our data reveal mechanisms by which the E3 ligase activity of cIAP1 is controlled, and how its deregulation impacts on cell proliferation, migration and cell survival. PMID- 21549627 TI - [Loss of power of hospital nursing managers]. PMID- 21549628 TI - Secondary hyperaldosteronism in a patient with polyarteritis nodosa and renal artery aneurysms. AB - Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that affects medium- and small-sized arteries. We report the case of a 32-year-old female with PAN in which renal involvement was revealed by a secondary hyperaldosteronism. Hypokaliemia and arterial hypertension preceded rupture of renal artery aneurysm by several months. We believe that hyperreninemia resulted from diffuse renal necrotizing vasculitis with occlusive but non-stenotic lesions. Angiography or CT scan should be performed systematically in PAN to screen for aneurysms so as to be able to consider prophylactic treatment by embolization and intensification of the general treatment. Hyperaldosteronism may reveal renal involvement in PAN and warrants an angiography if it has not yet been done. PMID- 21549629 TI - Acute prepatellar and olecranon bursitis. Retrospective observational study in 46 patients. PMID- 21549630 TI - Frohse's arcade syndrome revealing sarcoidosic myopathy. AB - We report the first case of an unusual sarcoidosic muscular involvement, complicated with radial nerve palsy. A 58-year-old woman suffering from a mediastinopulmonary sarcoidosis, was admitted for a driving deficit of the hands with a radially deviation during the wrist extension. She had been given a diagnosis of motor branch radial nerve entrapment syndrome. The patient had neurolysis with many muscle biopsies compatible with multiples sarcoidosic nodules, especially at the level of supinator muscle at the origin of the radial nerve compression. PMID- 21549631 TI - Fibroblastic rheumatism: an addition to fibromatosis. AB - Fibroblastic rheumatism (FR) is a rare rheumatologic entity of unknown etiology. It is characterized by symmetrical polyarthritis associated with multiple cutaneous nodules. Bone erosion can occur as the disease progresses and destructive arthropathy is not rare. We report on an 18-year-old man with FR who presented a 6-year history of cutaneous nodules localized at para-articular sites with only minimal oligoarthralgia on exertion. There was no visceral involvement, and all the routine and immunological tests were normal. The diagnosis of FR was confirmed by histological examination of a nodule, which composed of myofibroblastic proliferation and thickened collagen fibers. Most skin lesions resolved after treated with IFN-alpha, however there was sequelae of permanent disability due to the progressive bone erosion despite weekly methotrexate treatment. PMID- 21549632 TI - Needle aponeurotomy in Dupuytren's disease. AB - Needle aponeurotomy (NA) is recommended as a nonsurgical treatment for Dupuytren's disease. The aim of the procedure is to cut the Dupuytren's cord by use of the bevel of a needle and to restore full extension of the metacarpophalageal or proximal interphalangeal joints. According to Lermusiaux's standard, NA is performed in an outpatient setting, with the patient under local anesthesia. It entails the use of a 25-gauge, 16 mm-long needle and an anesthetic mixture of lidocaine and acetate of prednisolone. Various modifications have been proposed since the description of Lermusiaux's standard. Lermusiaux's and modified standards demonstrated structural efficacy in Dupuytren's disease. Clinical studies indicate that the mean rate of good structural results of NA is 80% at short-term assessment and 69% at 5-year assessment. Most of the studies are case series and only one is a randomized trial. Better results are demonstrated in early stages of the disease. NA also reduces disability and patients are highly satisfied. The short-term results with Lermusiaux's standard do not appear to be impaired in digital involvement. This is not the case for modified standards providing better results with palmar involvement. Lermusiaux's standard appears to provide less recurrences and less adverse events. In the largest study, skin fissure was observed in 8% of hands, transient dysesthesia in 3%, local infection in 0.7%, and flexor tendon rupture in 0.2%. Values were lower if related to NA sessions or NAs during each session. We therefore recommend Lermusiaux's standard for safe and effective NA in patients with Dupuytren's disease. PMID- 21549633 TI - On the quantitative relationships between individual/occupational risk factors and low back pain prevalence using nonparametric approaches. AB - OBJECTIVES: To explore dual quantitative relationships between low back pain (LBP) prevalence and different individual and occupational risk factors, and detect the most important ones which can be used as weighted input data in LBP prediction diagnosis models, providing effective tools to help with the implementation of protection and prevention strategies among hospital staff. METHODS: Fourteen predictor individual risk factors (e.g., age, gender, body mass index BMI [kg/m(2)], domestic activity, etc.) and 17 occupational risk factors (e.g., job status, standing hours/day, sufficient break time, job dissatisfaction, etc.) were collected using self-reported questionnaire among the staff of Sacre-Coeur hospital - Lebanon (used as a case study), and correlated with LBP prevalence using Kendall's tau-b bivariate nonparametric approaches. RESULTS: This study indicates that among the investigated occupational risk factors, job status, working hours/day, and standing hours/day are the most influencing on LBP prevalence (highly correlated with other factors at 1 and 5% confidence levels). It also shows that strong positive (between 0.25 and 0.65)/negative (from -0.38 to -0.26) statistical correlations to LBP prevalence exist between these risk occupational factors and working days/week, sitting hours/day, job stress, job dissatisfaction, children care, and car driving. The weekly hours of domestic activity, the staff height, and gender type have proven also to be the strongest individual factors in aggravating LBP disease. These individual factors are highly correlated at 1% significance level (ranging between 0.28 and 0.49 for positive correlations, and from -0.49 to -0.25 for negative ones) to children care, weight, extra professional activity, and use of handling techniques. CONCLUSIONS: These obtained bivariate correlations can be used successfully by expert physicians in their decision making for LBP diagnosis. PMID- 21549635 TI - Analysis of RNA from brush cytology detects changes in B2M, CYP1B1 and KRT17 levels with OSCC in tobacco users. AB - RNA expression analysis of oral keratinocytes can be used to detect early oral cancer, but a limitation is the inability to obtain high quality RNA from oral tissue without using biopsies. While oral cytology cell samples can be obtained from patients in a minimally invasive manner, they have not been validated for quantitative analysis of RNA expression. Earlier we showed RNA from brush cytology of hamster Oral Squamous Cell Carcinoma (OSCC) demonstrated differential expression of B2M and CYP1B1 using real time RT-PCR in a dibenz[a,I]pyrene, tobacco carcinogen, induced model of this disease. Here we show reproducibility of this approach to measuring gene expression in humans. Cytology brush samples from 12 tobacco and betel related OSCC and 17 nonmalignant oral lesions revealed B2M mRNA was enriched in tumor samples while CYP1B1 mRNA was reduced, similar to what was seen in the model system. Additionally, we showed that KRT17 mRNA, a gene linked to OSCC in another brush cytology study, was also enriched in OSCC versus nonmalignant lesions, again supporting the promise of using RNA from brush oral cytology to reproducibly monitor oral gene expression. PMID- 21549634 TI - The interactive account of ventral occipitotemporal contributions to reading. AB - The ventral occipitotemporal cortex (vOT) is involved in the perception of visually presented objects and written words. The Interactive Account of vOT function is based on the premise that perception involves the synthesis of bottom up sensory input with top-down predictions that are generated automatically from prior experience. We propose that vOT integrates visuospatial features abstracted from sensory inputs with higher level associations such as speech sounds, actions and meanings. In this context, specialization for orthography emerges from regional interactions without assuming that vOT is selectively tuned to orthographic features. We discuss how the Interactive Account explains left vOT responses during normal reading and developmental dyslexia; and how it accounts for the behavioural consequences of left vOT damage. PMID- 21549636 TI - Investigation of structure, vibrational and NMR spectra of oxycodone and naltrexone: a combined experimental and theoretical study. AB - In this work, two important opioid antagonists, naltrexone and oxycodone, were prepared from thebaine and were characterized by IR, (1)H NMR and (13)C NMR spectroscopy. Moreover, computational NMR and IR parameters were obtained using density functional theory (DFT) at B3LYP/6-311++G** level of theory. Complete NMR and vibrational assignment were carried out using the observed and calculated spectra. The IR frequencies and NMR chemical shifts, determined experimentally, were compared with those obtained theoretically from DFT calculations, showed good agreements. The RMS errors observed between experimental and calculated data for the IR absorptions are 85 and 105 cm(-1), for the (1)H NMR peaks are 0.87 and 0.17 ppm and for those of (13)C NMR are 5.6 and 5.3 ppm, respectively for naltrexone and oxycodone. PMID- 21549637 TI - The effect of one left-sided dorsolateral prefrontal sham-controlled HF-rTMS session on approach and withdrawal related emotional neuronal processes. AB - OBJECTIVE: Although repetitive Transcranial Magnetic Stimulation (rTMS) is frequently used to examine emotional changes in healthy volunteers, it remains largely unknown how rTMS is able to influence emotion. METHODS: In this sham controlled, single-blind crossover study using fMRI, we examined in 20 right handed healthy females whether a single high frequency (HF)-rTMS session applied to the left dorsolateral prefrontal cortex could influence emotional processing while focussing on blocks of positively and negatively valenced baby faces. RESULTS: While positive information was being processed, we observed after one active HF-rTMS session enhanced neuronal activity in the left superior frontal cortex and right inferior parietal cortex. After sham HF-rTMS, we found significant decreases in neuronal activity in the left superior frontal cortex, the left inferior prefrontal cortex, as well as in the right posterior cingulate gyrus. When negative information was processed, one active stimulation attenuated neuronal activity in the right insula only. CONCLUSIONS: Our findings suggest that during the processing of positive information one active session enhanced the ability to empathize with the depicted emotional stimuli, while during the processing of negative information it resulted in decreased psychophysiological reactions. SIGNIFICANCE: These results provide new information on the working mechanism of left-sided HF-rTMS. PMID- 21549639 TI - Sentinel nodes in colorectal cancer: cul-de-sac or clarion call? PMID- 21549638 TI - Sentinel-lymph-node procedure in colon and rectal cancer: a systematic review and meta-analysis. AB - BACKGROUND: No consensus exists on the validity of the sentinel-lymph-node procedure for assessment of nodal status in patients with colorectal cancer. We aimed to assess the diagnostic performance of this procedure. METHODS: We searched Embase and PubMed databases for studies published before March 20, 2010. Eligible studies had a prospective design, a sample size of at least 20 patients, and reported the rate of sentinel-lymph-node positivity. Individual patient data were requested for localisation and T-stage stratification. A subset of reports with high methodological quality was selected and analysed. FINDINGS: We identified 52 eligible studies, which included 3767 sentinel-lymph-node procedures (2961 [78.6%] colon and 806 [21.4%] rectal carcinomas). Most tumours 2339 (62.1%) were stage T3 or T4. 1887 (50.1%) of patients were male, 1880 (49.9%) female. Mean overall weighted-detection rate was 0.94 (95% CI 0.92-0.95), at a pooled sensitivity of 0.76 (0.72-0.80) with limited heterogeneity (chi(2)=286.08, degrees of freedom=51; p=0.003). A mean weighted upstaging of 0.15 (95% CI 0.12-0.19) was noted. Individual patient data were available from 19 studies that included 1168 patients. Analysis of these data showed no significant difference in sensitivity between colon (0.86 [95% CI 0.83-0.90]) and rectal cancer (0.82 [0.77-0.88]; p=0.23). Also, there was no dependency of sensitivity on T stage for both colon (pT1: 0.79 [95% CI 0.73-0.84], pT2: 0.76 [0.62-0.90], pT3: 0.73 [0.59-0.87], pT4: 0.73 [0.53-0.93]) and rectal cancer (T1 or T2: 0.81 [0.52-0.94] vs T3 or T4: 0.80 [0.51-0.93]). The subgroup of eight studies with high methodological quality showed a mean detection rate of 0.96 (95% CI 0.90 0.99) for colonic tumours and 0.95 (0.75-0.99) for rectal tumours, and a mean sensitivity of 0.90 (95% CI 0.86-0.93) for colonic tumours and 0.82 (0.60-0.93) for rectal tumours. INTERPRETATION: The sentinel-lymph-node procedure shows a low sensitivity, regardless of T stage, localisation, or pathological technique. For every patient diagnosed with colon or rectal cancer without clinical evidence of lymph-node involvement or metastatic disease, this procedure in addition to conventional resection should be considered, since the prognostic information provided by this technique could be clinically significant. FUNDING: Cancer Center Amsterdam Foundation, Amsterdam, Netherlands. PMID- 21549640 TI - History of oocyte cryopreservation. AB - The potential advantages of being able to cryopreserve oocytes have been apparent for many decades. Technical difficulties associated with the unique properties of the mammalian oocyte initially retarded rapid development in this area but recent advances have overcome many of the problems. A stage has now been reached where oocyte cryopreservation can be considered an important component of human assisted reproductive technology. The potential advantages of being able to cryopreserve oocytes have been apparent for many decades. Technical difficulties associated with the unique properties of the mammalian oocyte initially retarded rapid development in this area but recent advances have overcome many of the problems. A stage has now been reached where oocyte cryopreservation can be considered an important component of human assisted reproductive technology. PMID- 21549641 TI - Management of Asherman's syndrome. AB - Intrauterine adhesions (IUA) or Asherman's syndrome is a multifaceted condition which is being diagnosed with increasing frequency. Although it usually occurs following curettage of the pregnant or recently pregnant uterus, any uterine surgery can lead to IUA. Most women with IUA have amenorrhoea or hypomenorrhoea, but some have normal menses. Those who have amenorrhoea may also have cyclic pelvic pain secondary to 'trapped' menses and the accompanying retrograde menstruation may lead to endometriosis. In addition to menstrual disorders, most women with IUA will present with infertility or recurrent spontaneous abortion. Over the last four decades hysteroscopy has become the standard method to diagnose and treat this condition. Various techniques for adhesiolysis and for prevention of scar reformation have been advocated. The most efficacious appears to be the use of miniature scissors for adhesiolysis and the placement of a balloon stent inside the uterus immediately after surgery. Post-operative oestrogen therapy is prescribed in order to stimulate endometrial regrowth. Follow-up studies to assure resolution of the IUA are mandatory before the patient attempts to conceive as is careful monitoring of pregnancies for cervical incompetence, placenta accreta and intrauterine growth restriction. PMID- 21549642 TI - Is another meta-analysis on the effects of intramural fibroids on reproductive outcomes needed? AB - Intramural fibroids when encountered in women undergoing fertility treatment present a clinical dilemma. Despite recent studies that have suggested a negative outcome for intramural fibroids on fertility outcomes, the evidence remains far from conclusive. The current study presents a systematic review and meta-analysis of the currently available evidence. Relevant articles were identified in MEDLINE and EMBASE. Ten studies reported the effects of intramural fibroids on assisted conception treatment including one study reporting the effect of myomectomy for these fibroids. Combined analysis of the included studies, after taking into account possible confounding factors, showed no evidence of a significant effect for intramural fibroids on clinical pregnancy rate (odds ratio (OR) 0.74, 95% confidence intervals (CI) 0.50-1.09), live birth rate (OR 1.17, 95% CI 0.62-2.22) or miscarriage rate (OR 1.61, 95% CI 0.61-4.20). There was also no evidence for a significant effect for myomectomy on the clinical pregnancy rate (OR 1.88, 95% CI 0.57-6.14) or the miscarriage rate (OR 0.89, 95% CI 0.14-5.48). These findings highlight the current deficiency in the literature and suggest that evidence is insufficient to draw any conclusions regarding the effect of intramural fibroids on reproductive outcomes. PMID- 21549643 TI - Patterns of fatigue in elderly heart failure patients measured by a quality of life scale (Minnesota living with heart failure). AB - BACKGROUND: Progression of fatigue in elderly heart failure patients is not well documented. AIM: To report on patterns and severity of fatigue in surviving patients (n = 112, mean age 75 years) of a 5 year heart failure programme (HFP). METHODS: Patients (n = 200 at baseline) participated in a 6 month trial of cardiac rehabilitation (CR versus standard care) followed by the same prescribed maintenance programme (Phase IV and/or independent exercise). Fatigue was rated by the MLHF questionnaire and compared to quality of life (QoL), physical and clinical measures. Patterns of fatigue are described in the whole sample. Data analysis is undertaken on sub-groups based on baseline randomisation, aetiology, gender, co-morbidity and survival. Heart failure patients (n = 29) newly diagnosed at the 5 year follow-up time point provided information on their experience of fatigue. RESULTS: At baseline and 5 years, 45% patients rated fatigue within the two highest categories of severity, whereas 10% reported no symptoms on assessment. Over 5 years, the fatigue patterns in the sample were unsustained improvement commensurate with the HFP (37%), an adverse pattern from baseline (37%), maintained improvement (18%) or no overall change (8%). Fatigue was higher in patients with joint problems and responded to the intervention. There was a significant increase (p < 0.05) in the proportion of patients with reduced haemoglobin level and severe fatigue at 5 years. Fatigue scores correlated significantly (p < 0.01) with QoL and physical measures. CONCLUSIONS: Severe fatigue progresses differently in elderly patients and is a modifiable symptom in the early phases of CR. PMID- 21549645 TI - Prevalence of psychotropic medication use among German and Austrian nursing home residents: a comparison of 3 cohorts. AB - BACKGROUND: Despite increasing knowledge about the limited effectiveness and severe adverse effects, the prescription rate of psychotropic medications in frail elderly persons remains high. Prescriptions are mainly made to control behavioral and psychological symptoms of dementia, although factors associated with prescriptions are rarely reported. However, such information is a prerequisite to develop intervention programs aiming to safely reduce psychotropic medication in nursing home residents. METHODS: We report the comparison of cross-sectional data of psychotropic medication prescription rates from 3 large studies including nursing home residents in Germany and Austria. We aimed to compare the prevalence of (1) psychotropic medication, (2) different classes of psychotropic medication, (3) psychotropic medication administered for bedtime use, and (4) associations between prescription of psychotropics and institutional and residents' characteristics. Confidence intervals of prevalences and multiple logistic regression analyses were adjusted for cluster correlation. RESULTS: Data from 5336 residents in 136 long term care facilities were included. In Austria, 74.6% (95% CI 72.0-77.2%) of all residents had a prescription of at least one psychotropic medication compared to Germany with about 51.8% (95% CI 48.3-55.2%) and 52.4% (95% CI 48.7-56.1%). Of all antipsychotics, 66% (Austria) and 47% (Germany) were prescribed for bedtime use. Most prescriptions were conventional, low-potency antipsychotics. In all 3 studies, there was no statistically significant association between psychotropic medication prescription and nursing home characteristics. On the level of residents, consistent positive associations were found for higher level of care dependency and permanent restlessness. Consistent negative associations were found for older age and male gender. CONCLUSION: Frequency of psychotropic and especially antipsychotic medication is substantial in nursing home residents in Germany and Austria. The high number of prescriptions is likely to be an indicator for a perceived or actual lack of strategies to handle behavioral and psychological symptoms of dementia. PMID- 21549646 TI - A novel method for accurate needle-tip identification in trans-rectal ultrasound based high-dose-rate prostate brachytherapy. AB - PURPOSE: In real-time trans-rectal ultrasound (TRUS)-based high-dose-rate prostate brachytherapy, the accurate identification of needle-tip position is critical for treatment planning and delivery. Currently, needle-tip identification on ultrasound images can be subject to large uncertainty and errors because of ultrasound image quality and imaging artifacts. To address this problem, we developed a method based on physical measurements with simple and practical implementation to improve the accuracy and robustness of needle-tip identification. METHODS AND MATERIALS: Our method uses measurements of the residual needle length and an off-line pre-established coordinate transformation factor, to calculate the needle-tip position on the TRUS images. The transformation factor was established through a one-time systematic set of measurements of the probe and template holder positions, applicable to all patients. To compare the accuracy and robustness of the proposed method and the conventional method (ultrasound detection), based on the gold-standard X-ray fluoroscopy, extensive measurements were conducted in water and gel phantoms. RESULTS: In water phantom, our method showed an average tip-detection accuracy of 0.7 mm compared with 1.6 mm of the conventional method. In gel phantom (more realistic and tissue-like), our method maintained its level of accuracy while the uncertainty of the conventional method was 3.4mm on average with maximum values of over 10mm because of imaging artifacts. CONCLUSIONS: A novel method based on simple physical measurements was developed to accurately detect the needle-tip position for TRUS-based high-dose-rate prostate brachytherapy. The method demonstrated much improved accuracy and robustness over the conventional method. PMID- 21549647 TI - Electrochemical determination of methimazole based on the acetylene black/chitosan film electrode and its application to rat serum samples. AB - A novel method has been developed for the determination of methimazole, which was based on the enhanced electrochemical response of methimazole at the acetylene black/chitosan composite film modified glassy carbon electrode. The electrochemical behavior of methimazole was studied at this film electrode by cyclic voltammetry and differential pulse voltammetry. The experimental results showed that methimazole exhibited a remarkable oxidation peak at 0.63V at the film electrode. Compared with the bare glassy carbon electrode, the oxidation peak current increased greatly, and the peak potential shifted negatively, which indicated that the acetylene black/chitosan film electrode had good catalysis to the electrochemical oxidation of methimazole. The enhanced oxidation current of methimazole was indebted to the nano-porus structure of the composite film and the enlarged effective electrode area. The influences of some experimental conditions on the oxidation of methimazole were tested and the calibration plot was examined. The results indicated that the differential pulse response of methimazole was linear with its concentration in the range of 1.0*10(-7) to 2.0*10(-5)mol/L with a linear coefficient of 0.998, and in the range of 4.0*10( 5) to 3.0*10(-4)mol/L with a linear coefficient of 0.993. The detection limit was 2.0*10(-8)mol/L (S/N=3). The film electrode was used to detect the content of methimazole in rat serum samples by the standard addition method with satisfactory results. PMID- 21549648 TI - RAD5a and REV3 function in two alternative pathways of DNA-damage tolerance in Arabidopsis. AB - DNA-damage tolerance (DDT) in yeast is composed of two parallel pathways and mediated by sequential ubiquitinations of PCNA. While monoubiquitination of PCNA promotes translesion synthesis (TLS) that is dependent on polymerase zeta consisted of a catalytic subunit Rev3 and a regulatory subunit Rev7, polyubiquitination of PCNA by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Inactivation of these two pathways results in a synergistic effect on DNA-damage responses; however, this two-branch DDT model has not been reported in any multicellular organisms. In order to examine whether Arabidopsis thaliana possesses a two-branch DDT system, we created rad5a rev3 double mutant plant lines and compared them with the corresponding single mutants. Arabidopsis rad5a and rev3 mutations are indeed synergistic with respect to root growth inhibition induced by replication-blocking lesions, suggesting that AtRAD5a and AtREV3 are required for error-free and TLS branches of DDT, respectively. Unexpectedly this study reveals three modes of genetic interactions in response to different types of DNA damage, implying that plant RAD5 and REV3 are also involved in DNA damage responses independent of DDT. By comparing with yeast cells, it is apparent that plant TLS is a more frequently utilized means of lesion bypass than error-free DDT in plants. PMID- 21549649 TI - Hepatic venous pressure gradient measurement in clinical hepatology. AB - Portal hypertension is key to the natural history of cirrhosis and the standard way to assess it is the hepatic venous pressure gradient. Hepatic venous pressure gradient is a strong predictor of variceal bleeding/survival and is the only suitable tool to assess the response of portal hypertension to medical treatment. The clinical applications, indications and timing for hepatic venous pressure gradient measurement, together with measurement principles and costs, are reviewed. PMID- 21549650 TI - [Application of the Porto criteria for the diagnosis of paediatric inflammatory bowel disease in a paediatric reference centre]. AB - INTRODUCTION: Inflammatory bowel diseases (IBD) have classically included two entities: Crohn's disease (CD) and ulcerative colitis (UC). The correct differentiation between these two diseases has important implications. The term inflammatory bowel disease unclassified (IBDu) describes inflammatory changes of the colon that cannot be classified as ulcerative colitis or Crohn's disease. This situation has been described in 20-30% of paediatric IBD at diagnosis. In order to reach a definitive diagnosis of suspicion of inflammatory bowel disease in children, the ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) established the Porto criteria (PC) in July 2005. The recommendations include: 1) total colonoscopy with ileal intubation, 2) upper endoscopy, 3) multiple biopsies and 4) complete small bowel exploration. AIM: To evaluate the diagnostic procedures used in our IBD patients regarding the PC. PATIENTS AND METHODS: Retrospective review of the data of our IBD patients diagnosed in the last ten years (1999-2008) in a Spanish tertiary hospital, differentiating two periods: before and after the publication of the PC. RESULTS: A total of 108 IBD patients had been diagnosed (51 UC, 52 CD, 5 IBDu), 43 girls (39.81%), 65 boys (60.18%). According to the Montreal classification: 1) UC, 40 (78%) extensive colitis, 5 left-sided colitis (9.8%), 6 proctitis (11%), 2) CD: 44 ileo-colonic (84%), 13 ileal, 7 colonic. Median age at diagnosis: 13 years 1 month (p25-p75: 10 years 3 months- 14 years 9months). The Porto criteria were followed in 49% of the cases (33.3% before its publication, 64.8% after, P=.001). Upper endoscopy was performed in 62 patients (58%): 38.9% versus 72.2%, P<.001. Upper involvement was found in 51% of our CD patients. Total colonoscopy with ileoscopy was achieved in 85.2% of the cases. The mean number of ileo-colonic segments biopsied was 6.6 (7 different segments). Granulomas at biopsies were present in 38% of our CD patients. Up to 38% of the CD patients had microscopic inflammation in endoscopically normal appearing segments. During the follow-up, initial diagnosis among the IBDu patients, was changed to CD in 1, to UC in 2 and the other 3 remained with the same diagnosis. We did not observe other changes in diagnosis in the remaining 103 patients (median follow-up: 4y 8mo). Thirty patients were discharged when becoming adults. CONCLUSIONS: Our clinical practice in IBD diagnosis has changed after the PC. Upper endoscopy is a useful tool to find upper involvement in CD. Total colonoscopy with ileoscopy and performance of multiple biopsies are essential to determine extension of the inflammatory changes. We have not observed changes in the final diagnosis in our CD and UC patients after a median follow-up of 4 years. PMID- 21549651 TI - Post-traumatic ear reconstruction using postauricular fascial flap combined with expanded skin flap. AB - INTRODUCTION: Post-traumatic ear reconstruction still remains a great challenge for plastic surgeons. In this article, we present the technique of post-traumatic ear reconstruction using a postauricular fascial flap combined with an expanded skin flap. METHODS: From May 2007 to June 2009, 91 cases of post-traumatic ear defect were treated using a postauricular fascial flap combined with an expanded skin flap. Surgical procedure included postauricular-skin-flap expansion, removal of tissue expander, autogenous rib-cartilage-framework implantation, postauricular-fascial-flap lifting and split-thickness free-skin grafting. RESULTS: With a follow-up duration of 6 months to 1 year, the described technique provided a nice final result, and the reconstructed ears showed good match in size, shape, colour and location to the contralateral normal ear. CONCLUSION: Post-traumatic ear reconstruction using a postauricular fascial flap combined with an expanded skin flap is an ideal approach with good final results. PMID- 21549654 TI - Osteodistraction of the maxilla in transverse deficiency in adults: analysis of the literature and clinical case. AB - Osteogenic distraction is a bone regeneration and reconstruction technique. Razdolsky et al. (2001) [1] have defined it as "the process of creating new bone by stretching". Disjunction entails separating two anatomical structures at their junction system and, therefore, at a suture. Usually, it involves separating two semi-maxillae in the transverse dimension by means of an osteotomy. Transverse maxillary distraction appears to offer an alternative of choice to orthognathic surgery alone, which is frequently prone to relapse (Betts et al., 2004) [2]. The greatest benefit of osteogenic distraction lies in its greater potential for expansion and concurrent growth of the soft tissues. Among other things, this technique increases arch length, thus precluding tooth extractions in cases of maxillary crowding, and appears to provide more stable results than conventional surgical intermaxillary disjunction. PMID- 21549655 TI - Evaluation of dentoskeletal parameters in Senegalese subjects using orthodontic architectural analysis. AB - INTRODUCTION: The aim of this study was to determine the morphological characteristics of a Senegalese population based on an architectural cephalometric analysis. PATIENTS AND METHODS: One hundred and five lateral cephalograms of Senegalese patients were assessed in a cross-sectional study. All lateral cephalometric films were traced on a transparent cellulose acetate sheet by the same operator. Danguy architectural analysis was performed with 11 measurements (seven linear and four angular). T-test was used to assess differences in cephalometric variables between subjects grouped according to gender (male and female) and age bracket (<12 years and >=12 years). Significance was set at p<=0.05. RESULTS: This study shows that this Senegalese sample had a skeletal class II tendency associated with backward mandibular rotation. The divergence of masticatory corner appears to be greater than in Caucasians with more vertical facial growth. No statistically significant differences were found between men and women. As compared to the under 12 years subgroup, the over 12 years subgroup shows significant increase in maxillary and mandibular lengths whereas skeletal divergence evidenced the opposite tendency and the difference with the under 12 subgroup was significant. Lastly, the first molar underwent significantly greater mesial drift in the 12 and over sub-group. CONCLUSION: Danguy architectural analysis provides a good reliable comparative assessment of facial structures and offers an addition to conventional dimensional or typological analytical methods. PMID- 21549656 TI - [Fatal evolution of a left brachio-cephalic vein perforation by a catheter for hemodialysis]. AB - Central venous catheterisation is a common procedure in intensive care and hemodialysis units. Tunnelled catheters of hemodialysis are a great contribution for patients for whom an arteriovenous fistula is not feasible, especially for prolonged use. However, multiple complications have been described from their practice. Through a case of perforation of the left brachio-cephalic vein with a venous catheter for dialysis and a review of the literature, the authors discuss the mechanisms and ways to prevent this complication. PMID- 21549657 TI - Genetic data for 17 Y-chromosomal STR loci in Macedonians in the Republic of Macedonia. AB - The population data were obtained for the 16 Y chromosomal STR loci included in the AmpFistr((r))YfilerTM PCR Amplification Kit (DYS456, DYS389I, DYS390, DYS389II, DYS458, DYS19, DYS385 a/b, DYS393, DYS391, DYS439, DYS635, DYS392, Y GATA H4, DYS437, DYS438, DYS448) in a sample of 262 unrelated men from the Republic of Macedonia. PMID- 21549658 TI - Posterior reversible encephalopathy syndrome in a context of isolated cervical spine fracture: CT angiogram as an early detector of blunt carotid artery trauma. AB - Blunt carotid injury associated with cervical spine fractures is a rare entity but potentially lethal. An initial, clinically silent period can be misleading. Prompt diagnosis and treatment are mandatory to avoid neurological damages and death. We present the case of a 36-year-old man diagnosed with an isolated cervical spine fracture, where an associated carotid artery lesion was initially overlooked and diagnosis was made after development of a neurological deterioration secondary to a posterior reversible encephalopathy syndrome (PRES). We discuss a simple algorithm that can be used to make the diagnosis, even during the clinically asymptomatic period of this injury. PMID- 21549659 TI - Liver transplantation for symptomatic centrohepatic biliary cystadenoma. AB - Biliary cystadenoma is a rare benign cystic tumor of the liver. The mainstay of treatment is complete resection, either by enucleation or by formal hepatectomy, since incomplete removal entails not only constant recurrence but also the risk of malignant transformation to cystadenocarcinoma. A case of symptomatic centrohepatic biliary cystadenoma involving the main vasculobiliary structures of the liver is reported. After an unsuccessful attempt at resection resulting in an intrahepatic biliary injury, relief of jaundice and radical excision were achieved by total hepatectomy and liver transplantation. The patient is now alive and well 4 years after transplant, disease-free, with normal liver and renal function while receiving everolimus monotherapy. This is the first report of liver transplantation performed for the treatment of this tumor. With the case on the background, diagnostic aspects and available therapeutic strategies for biliary cystadenoma are reviewed and discussed. PMID- 21549660 TI - Response and tolerance of root border cells to aluminum toxicity in soybean seedlings. AB - Root border cells (RBCs) and their secreted mucilage are suggested to participate in the resistance against toxic metal cations, including aluminum (Al), in the rhizosphere. However, the mechanisms by which the individual cell populations respond to Al and their role in Al resistance still remain unclear. In this research, the response and tolerance of RBCs to Al toxicity were investigated in the root tips of two soybean cultivars [Zhechun No. 2 (Al-tolerant cultivar) and Huachun No. 18 (Al-sensitive cultivar)]. Al inhibited root elongation and increased pectin methylesterase (PME) activity in the root tip. Removal of RBCs from the root tips resulted in a more severe inhibition of root elongation, especially in Huachun No. 18. Increasing Al levels and treatment time decreased the relative percent viability of RBCs in situ and in vitro in both soybean cultivars. Al application significantly increased mucilage layer thickness around the detached RBCs of both cultivars. Additionally, a significantly higher relative percent cell viability of attached and detached RBCs and thicker mucilage layers were observed in Zhechun No. 2. The higher viability of attached and detached RBCs, as well as the thickening of the mucilage layer in separated RBCs, suggest that RBCs play an important role in protecting root apices from Al toxicity. PMID- 21549661 TI - Impacts of ambient salinity and copper on brown algae: 1. Interactive effects on photosynthesis, growth, and copper accumulation. AB - The effect of copper enrichment and salinity on growth, photosynthesis and copper accumulation of two temperate brown seaweeds, Ascophyllum nodosum and Fucus vesiculosus, was investigated in laboratory experiments. A significant negative impact of reduced salinity on photosynthetic activity and growth was observed for both species. After 15 days at a salinity of 5, photosynthesis of A. nodosum was entirely inhibited and growth ceased at a salinity of 15. Increased copper concentration negatively affected photosynthetic activity of A. nodosum and F. vesiculosus resulting in chlorosis and reduced seaweed growth; 5 mg L-1 copper caused an inhibition of the photosynthesis and the degradation of seaweed tips. Under reduced salinity, copper toxicity was enhanced and caused an earlier impact on the physiology of seaweed tips. After exposure to copper and different salinities for 15 days, copper contents of seaweeds were closely related to copper concentration in the water; seaweed copper contents reached their maximum after 1 day of exposure; contents only increased again when additional, free copper was added to the water. At high water copper concentrations or low salinity, or a combination of both, copper content of A. nodosum decreased. By contrast, copper content of F. vesiculosus increased, suggesting that different binding sites or uptake mechanisms exist in the two species. The results suggest that when using brown seaweeds in biomonitoring in situ, any change in the environment will directly and significantly affect algal physiology and thus their metal binding capacity; the assessment of the physiological status of the algae in combination with the analysis of thallus metal content will enhance the reliability of the biomonitoring process. PMID- 21549662 TI - The relative importance of waterborne and dietborne arsenic exposure on survival and growth of juvenile rainbow trout. AB - Previous work demonstrated reduced growth of rainbow trout receiving diets containing environmentally relevant concentrations of arsenic, but did not address the relative and combined potency of waterborne and dietborne exposures. In the current study, juvenile rainbow trout were exposed for 28d to a range of arsenic concentrations in water and in a live oligochaete diet, separately and in combination. In clean water, fish fed worms previously exposed to arsenate at 4 or 8mg As/L showed pronounced reductions in growth, but fish exposed to these same water concentrations and a clean diet experienced less or no effect. Increasing waterborne arsenate to 16 or 32mg As/L had substantial effects on both growth and survival, and simultaneous exposure via both routes intensified growth effects, but not mortality. Growth reduction was strongly correlated to total arsenic accumulation in the fish tissue, regardless of the route of exposure, but mortality was better correlated to waterborne arsenic concentration. The relative concentration of total arsenic in fish viscera and in the remaining carcass was not a useful indicator of exposure route. Speciation analysis showed that most arsenate was converted to arsenite within the worms, but organoarsenic species were not found. The greater toxicity of dietborne exposure when fish and prey were exposed to the same waterborne arsenate concentration emphasizes the need to address dietborne exposure when assessing the aquatic risks of arsenic contamination. This is of particular concern because risk from dietary exposure may occur at even lower water concentrations than used here when prey organisms are exposed for longer periods and via multiple routes. PMID- 21549663 TI - The metacognitive beliefs account of hallucinatory experiences: a literature review and meta-analysis. AB - An influential model of hallucinations proposed by Morrison et al. (1995. Behavioural and Cognitive Psychotherapy, 23(3), 265-280) assumes that dysfunctional metacognitive beliefs lead to the misattribution of intrusive thoughts to external sources, therefore generating hallucinatory experiences. Following a comprehensive review of the literature, a series of meta-analyses was carried out to summarize the empirical findings on the association between hallucination-proneness and different metacognitive beliefs. The results of this research synthesis found little support for the existence of specific associations between hallucinations and dysfunctional metacognitive beliefs. While metacognitive beliefs are robustly associated with hallucination-proneness in non-clinical studies, they were only moderately associated with hallucinations in clinical samples. Additional analyses revealed that, after controlling for the effect of comorbid symptoms, hallucination-proneness was only weakly associated with metacognitive beliefs, suggesting that the large associations observed in previous research might stem from the failure to consider the covariation between different symptoms. These findings have important implications in relation to the role of metacognitive factors in psychopathological symptoms, as well as for the implementation of metacognitive-focused cognitive behavioural techniques for the treatment of psychosis. PMID- 21549664 TI - The efficacy of habit reversal therapy for tics, habit disorders, and stuttering: a meta-analytic review. AB - A meta-analysis based on 575 participants in 18 studies found Habit Reversal Therapy (HRT) to be an efficacious intervention for a wide variety of maladaptive repetitive behaviors, including stuttering, tics, nail biting, temporomandibular disorder, thumb sucking, and mixed repetitive oral-digital habits. Compared to control conditions, HRT showed a large effect size pre-treatment to final post treatment assessment, d=0.80. Moderator analyses revealed significant treatment effects for HRT for most moderator levels, indicating that HRT is efficacious in a number of variations for a variety of types of maladaptive behaviors, across a wide range of sample characteristics. The findings provide substantial support for the efficacy of HRT for disorders it is commonly used to treat. The findings are consistent with recent arguments for the classification of HRT as a well established treatment for tic and habit disorders. PMID- 21549665 TI - [Primary endobronchial leiomyoma--endoscopic laser resection]. AB - Leiomyomas account for less than 2% of all benign lung tumors. Only one third is endobronchial in location, usually presenting as primary solitary lesions and airway obstruction findings. Literature on primary endobronchial leiomyomas is therefore scarce, with a few more than 100 cases being reported. We describe a case of a 44-year-old female that presented with bronchial asthma like symptoms and an obstructive pneumonia, due to a right main bronchus primary leiomyoma that was successfully resected using Nd:YAG laser through rigid bronchoscopy. Purpose of this case is to enhance the rarity of primary endobronchial leiomyoma diagnosis and report the relevance of laser resection in its definitive treatment. A brief review on lung leiomyomas is discussed over the text. PMID- 21549666 TI - [A rich and blessed professional illness - organizing pneumonia due to gold dust]. AB - A 47-year-old man, restorer of religious art, presents a three week history of asthenia, myalgia, dry cough and fever, coinciding with recent, unprotected exposure, to golden dust. He had fever, crackles in lung bases, hypoxemia and elevation of inflammatory markers. Imaging studies showed areas of parenchymal consolidation with air bronchograms in posterior-basal regions of both lungs, suggesting a pneumonic process. Lung function tests: mild restrictive pattern. Bronchoalveolar lavage: lymphocytosis with low CD4/CD8 ratio. Lung biopsy: intraalveolar pneumonia with exsudative process and organization. Treatment with Prednisolone 40mg id was started with excellent response. First month follow-up CT scan showed areas of ground glass suggesting residual pneumonitis, and he resumed normal activities with excellent exercise tolerance, under appropriate protection measures. PMID- 21549667 TI - [Immediate and short term effects of smoking on nasal mucociliary clearance in smokers]. AB - BACKGROUND AND OBJECTIVES: The efficiency of mucociliary transport may vary in different conditions, such as in exposure to harmful particles of the cigarette smoke. The present study evaluated the acute and short term effects of smoking on nasal mucociliary clearance in current smokers by the quantification of the Saccharin Transit Time (STT), and to investigate its correlation with the history of tobacco consumption. METHODS: Nineteen current smokers (11 men, 51 +/- 16 years; BMI 23 +/- 9 kg/m(2), 27 +/- 11 cigarettes per day, 44 +/- 25 pack-years), entering a smoking cessation intervention program, responded to a questionnaire concerning smoking history and were submitted to lung function assessment (spirometry) and the STT test. STT was assessed immediately after smoking and 8 hours after smoking. The STT test was also performed in nineteen matched healthy non-smokers' who served as control group. RESULTS: When compared to STT in non smokers' (10 +/- 4 min; mean +/- standard deviation), smokers presented similar STT immediately after smoking (11 +/- 6 min; p=0.87) and slower STT 8 hours after smoking (16 +/- 6 min; p=0.005 versus non-smokers' and p=0.003 versus immediately after smoking). STT 8 hours after smoking correlated positively with age (r=0.59; p=0.007), cigarettes per day (r=0.53; p=0.02) and pack-years index (r=0.74; p=0.0003). CONCLUSIONS: In smokers, although the mucociliary clearance immediately after smoking is similar to non-smokers', eight hours after smoking it is reduced, and this reduction is closely related to the smoking habits. PMID- 21549668 TI - [Bronchial asthma is out of fashion!]. PMID- 21549669 TI - [Risk factors and prevalence of asthma and rhinitis among primary school children in Lisbon]. AB - AIMS: A cross-sectional study was carried out with the objective of identifying nutrition habits and housing conditions as risk factors for respiratory problems in schoolchildren in Lisbon. MATERIAL AND METHODS: Between October and December 2008, parents of 900 students of the basic schools of Lisbon were invited to answer a questionnaire of the International Study of Asthma and Allergies in Childhood Program (ISAAC). The response rate was 40%. Logistic regression was used in the analysis of results. RESULTS: The prevalence of asthma, allergic rhinitis and wheeze was 5.6%, 43.0% and 43.3%, respectively. Risk factors independently associated with asthma were wheezing attacks, and dry cough at night not related to common cold in the last 12 months. Wheezing crises were found to affect children daily activities. Risk factors for wheeze were hay fever and the presence of a pet at home. A risk factor for rhinitis was cough at night. The frequent consumption of egg was also associated with increased risk of rhinitis. CONCLUSION: Contrarily to asthma, the prevalence of allergic rhinitis and wheeze increased in comparison with previous ISAAC studies. Wheezing attacks were associated with asthma and hay fever was identified as a risk factor of manifesting wheezing symptoms. Having pets at home was pointed out as a significant risk factor for rhinitis, but not smoking exposure, mould, plush toys, diet (except egg consumption), breastfeeding or other conditions. PMID- 21549670 TI - [Positive bronchoalveolar lavage and quantitative cultures results in suspected late-onset ventilator associated penumonia evaluation--retrospective study]. AB - INTRODUCTION: Bronchoalveolar lavage (BAL) with quantitative cultures has been used in order to increase ventilator associated pneumonia (VAP) diagnosis specificity, although the accurate technique for this entity diagnosis remains controversial. OBJECTIVES: To evaluate the influence of using positive BAL and quantitative cultures results in microbiologic diagnosis and treatment of patients with suspected late VAP and prior antibiotherapy. MATERIAL AND METHODS: Retrospective analysis of intensive care unit (UCI) patients, during a one year period, with clinical suspicion of late VAP and prior use of antibiotics that presented a growth in BAL cultures. RESULTS: Of 243 BAL performed, there were 71 (29.2%) positive cultures (60 patients, 76.7% male, 54 +/- 19 years). BAL was done after 13 days (median) of invasive mechanical ventilation, 11 days of ICU antibiotherapy and in the day in which a new antibiotic for VAP suspicion was started. Colony forming units (CFU)/ml count was performed in 71.8% and endotracheal aspirate (ETA) simultaneously collected for qualitative analysis in 85.9%. Therapeutic approach was changed in 38.0%: correction (16.9%), de escalation (12.7%) and directed antibiotherapy start (8.4%). Therapeutic changes were made in the presence of CFU > 10(4) in 84.2% and in agreement with ETA in 70.8%. In cases in which antibiotherapy was maintained (62.0%), quantitative cultures would have allowed de-escalation in 9.1%. Changes in prescription were more frequent when CFU was > 10(4) (48.5%), comparing with situations in which counts were lower and BAL analysis was qualitative (28.9%), p = 0.091. There were no significant differences between patients submitted to different therapeutic approaches concerning to ICU mortality or length of stay. CONCLUSION: In late onset VAP, positive BAL and quantitative cultures allowed therapeutic changes, leading to antibiotic adequacy and consumption reduction, which can however be maximised. PMID- 21549671 TI - [Visualization of deep lung lymphatic network using radioliposomes]. AB - Deep lymphatic drainage plays an important role in the lung, as it removes foreign materials laying on the airways surface, such as pathogenic microorganisms. This drainage is also associated with lung tumour dissemination route. Liposomes with a specially tailored membrane were used as foreign particles to be removed by the lung lymphatics. We aim to obtain images of deep lung lymphatics in baboons using liposomes encapsulating (99m)Tc-HMPAO, as aerosols. Axillary lymph nodes were visualized 30 min post-inhalation, becoming more evident 1 hour after, when abdominal aortic and inguinal lymph nodes were also observed. Late images added no additional information. ROI's and their time activity curves were drawn to obtain biokinetic information. In conclusion, we can say that the proposed technique enables visualization of the deep lymphatic lung network and lymph nodes. This methodology may be an important tool for targeted lung delivery of cytotoxic drugs. PMID- 21549672 TI - [The importance of dyspnoea in the diagnosis of chronic obstructive pulmonary disease--a descriptive analysis of a stable cohort in Portugal (SAFE trial)]. AB - INTRODUCTION: The aim of this study was to determine patient-perceived characteristics of chronic obstructive pulmonary disease (COPD) in patients participating in a large trial evaluating tiotropium bromide. PATIENTS AND METHODS: Baseline symptoms were assessed by means of a standardized questionnaire. Patients reported symptoms that led to diagnosis as well as their current most troublesome symptom. RESULTS: Data were obtained from 298 patients, mostly male (95%), with mean (standard deviation) baseline forced expiratory volume in 1 second of 1.1 (0.4) L (40.6 [13.3] % of predicted), mean disease duration of 14.4 (10.1) years and smoking history of 55.1 (25.3) pack-years. Dyspnoea was the most frequently reported symptom leading to COPD diagnosis (55.0% of patients), followed by cough (33.2%). Dyspnoea was also the current most troublesome symptom (82.6%), followed by cough (8.4%). The presence of dyspnoea or cough was independent of COPD severity. The most commonly reported co morbidities were cardiovascular disorders (49% of patients), gastrointestinal disorders (20%) and metabolic disorders (16%), mainly diabetes mellitus. CONCLUSIONS: This analysis confirms the importance of dyspnoea as the most common symptom leading to initial COPD diagnosis and the symptom most troublesome to patients. Co-morbidities are common among COPD patients, and hence spirometric testing is appropriate in a patient who presents with dyspnoea associated with such a condition. PMID- 21549673 TI - [Successful pregnancy in a severely hypoxemic patient with pulmonary alveolar proteinosis]. AB - Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by abnormal accumulation of a lipoproteinaceous material in the alveoli, which may lead to respiratory failure and has an associated high risk for infections. The mainstay treatment for PAP is whole lung lavage. A pregnant woman, previously diagnosed with primary PAP, the most common form of PAP, was admitted with dyspnea and worsening respiratory function. In one month period, a whole-lung bronchopulmonary lavage was performed twice, with clinical and functional improvement. Pregnancy was carried to term and a healthy baby was delivered. The mechanisms of respiratory impairment are discussed as well as treatment options and response. PMID- 21549674 TI - About the role of indacaterol in obstructive airways disorder: CON. PMID- 21549676 TI - Dyslipidemia as a long-term marker for survival in pulmonary embolism. AB - OBJECTIVES: To analyse survival rate after 24 months in consecutive patients with a diagnosis of PE as well as associated factors. METHODS: Prospective cohort study during a follow-up period of two years in a series of consecutive patients with PE. RESULTS: During the follow-up period, 34 out of 148 patients died (23%). Factors independently associated with reduced survival rate were: creatinine levels > 2 (OR, 8.8; 95% CI, 1.1 - 70.87), previous neoplasm (OR, 8.8; 95% CI, 3.69 - 20.98), dementia (OR, 6.85; 95% CI, 2.1 - 22.33) and dyslipidemia (OR, 5.07; 95% CI, 1.92 - 13.44). Forty four percent of the patients with dyslipidemia died vs. 20.8% of patients without this condition. CONCLUSIONS: In our study dyslipidemia shows as a long-term negative prognostic marker for survival in patients with EP. PMID- 21549677 TI - How to write a scientific paper--and win the game scientists play! PMID- 21549678 TI - [The answer is blowing in the wind]. PMID- 21549679 TI - [Comment to the case: Successful pregnancy in a severely hypoxemic patient with alveolar proteinosis]. PMID- 21549680 TI - Effects of different temperature regimens on the development of Aedes aegypti (L.) (Diptera: Culicidae) mosquitoes. AB - This study was conducted to determine the effects of increased water temperatures on the development of Aedes aegypti immatures under laboratory conditions in Trinidad, West Indies using temperature regulated water baths to cover a range of temperatures from 24-25 degrees C to 34-35 degrees C at a relative humidity of 80%. Two experiments were designed: (1) at constant temperature regimens and (2) under diurnal temperature regimens ranging from 24-25 degrees C to 34-35 degrees C. At 24-25 degrees C egg hatching success was 98% at 48 h, however at 34-35 degrees C egg hatching rates declined to 1.6% after 48 h. Ae. aegypti larvae reared under constant temperature regimens showed pupation on day 4 with highest pupation occurring at 30 degrees C (78.4%) However, under diurnal temperature regimens, pupation began on day 4 but only at the higher temperatures of 30-35 degrees C. Under diurnal temperature regimens ranging from 24 degrees C to 35 degrees C significantly more females emerged at higher temperatures, than males. In contrast, at constant temperatures of 24-35 degrees C no significant difference in M/F ratios were observed. The body size of Ae. aegypti reared at constant temperature regimens was significantly larger than males and females larvae reared under diurnal temperature regimens of 25-30 degrees C. The results of this study are discussed in the context of changing or increasing water temperatures, seasonal changes in vector populations and vector competence. Using these key factors control strategies are recommended to manage vector populations as expected increases in temperatures impact the Caribbean region. PMID- 21549681 TI - Utility of a direct dual-mode development analysis on blotted protein mixtures. AB - Classic blotting methods remain a commonly applied approach to specific protein identification in gel electrophoresis of complex mixtures despite the inherent difficulty in band or spot matching due to significant variability of protein migration or localization in replicate blotting experiments. A direct application of both protein stain and protein blotting on a single membrane significantly reduces the complexity of the experiment and provides increased confidence of signal matching. Digital alignment of images acquired from both total protein stain and blotting development modes on a single membrane allows unambiguous spot or band assignments in these experiments as well as retention of quantitative information acquired from both modes of signal generation. A direct and simple method applying a fluorescent protein stain that is compatible with subsequent detection by antibody or lectin recognition factors along with common image adjustment software is examined. The utility of this blot dual-mode development method for direct protein recognition and quantification in one- and two dimensional electrophoresis is demonstrated for bioanalytical objectives where replicate experiments are challenged by sample complexity. PMID- 21549682 TI - A dual reporter cell assay for identifying serotype and drug susceptibility of herpes simplex virus. AB - A dual reporter cell assay (DRCA) that allows real-time detection of herpes simplex virus (HSV) infection was developed. This was achieved by stable transfection of cells with an expression cassette that contains the dual reporter genes, secreted alkaline phosphatase (SEAP) and enhanced green fluorescent protein (EGFP), under the control of an HSV early gene promoter. Baby hamster kidney (BHK) and Chinese hamster ovary (CHO) cell lines were used as parental cell lines because the former is permissive for both HSV serotypes, HSV-1 and HSV 2, whereas the latter is susceptible to infection only by HSV-2. The DRCA permitted differential detection of HSV-1 and HSV-2 by observation of EGFP positive cells, as substantiated by screening a total of 35 samples. The BHK based cell line is sensitive to a viral titer as low as a single plaque-forming unit with a robust assay window as measured by a chemiluminescent assay. Evaluations of the DRCA with representative acyclovir-sensitive and acyclovir resistant HSV strains demonstrated that their drug susceptibilities were accurately determined by a 48-h format. In summary, this novel DRCA is a useful means for serotyping of HSV in real time as well as a rapid screening method for determining anti-HSV susceptibilities. PMID- 21549683 TI - Ligand chirality effects on the dynamics of human 3-phosphoglycerate kinase: comparison between D- and L-nucleotides. AB - l-nucleoside analogues are now largely used as antiviral drugs for the treatment of viral infections like HBV, HCV and HIV. However, in order to be fully active, they need to be phosphorylated by cellular or viral kinases. Human 3 phosphogycerate kinase (hPGK) was shown to catalyze the last step of activation of l-enantiomers and thus constitutes an attractive target for theoretical predictions of its phosphorylation efficiency. Molecular dynamics simulations were carried out with four different nucleotides (d-/l-ADP and d-/l-CDP) in complex with hPGK and 1,3-bisphospho-d-glycerate (bPG). The binding affinities of CDPs (both enantiomers) for hPGK were found very weak while d- and l-ADP were better substrates. Interestingly, the binding affinity of the bPG substrate was found to be lower in presence of d-ADP than l-ADP which indicates a potential antagonistic effect on one substrate to the other. A detailed analysis of the simulations unravels important dynamic conditions for efficient phosphorylation. Indeed, as previously described for the natural substrate, the hinge bending motion of the domains upon substrates binding should be more correlated and directional. Interestingly, the unforeseen finding was the larger dynamics freedoms observed for the substrates that was favored by the protein atoms flexibility around the nucleobase binding site. PMID- 21549684 TI - Impact of inter-subunit interactions on the dimeric arginine kinase activity and structural stability. AB - Arginine kinase (AK) is a key enzyme for cellular energy metabolism, catalyzing the reversible phosphoryl transfer from phosphoarginine to ADP in invertebrates. In this study, the inter-subunit hydrogen bonds between the Q53 and D200 and between D57 and D200 were disrupted to explore their roles in the activity and structural stability of Stichopus japonicus (S. japonicus) AK. Mutating Q53 and/or D57 to alanine (A) can cause pronounced loss of activity and substrate synergism, and cause distinct conformational changes. Spectroscopic experiments indicated that mutations destroying the inter-subunit hydrogen bonds impaired the structure of dimer AK, and resulted in a partially unfolded state. The inability to fold to the functional compact state made the mutants prone to be inactivated and aggregate under environmental stresses. Restoring hydrogen bonds in Q53E and D57E mutants could rescue the loss of activity and substrate synergism, and conformational changes. All those results suggested that the inter-subunit interactions played a key role in keeping the activity, substrate synergism and structural stability of dimer AK. The result herein may provide a clue in understanding the folding and self-assembly processes of oligomeric proteins. PMID- 21549685 TI - SREBP-1c regulates glucose-stimulated hepatic clusterin expression. AB - Clusterin is a stress-response protein that is involved in diverse biological processes, including cell proliferation, apoptosis, tissue differentiation, inflammation, and lipid transport. Its expression is upregulated in a broad spectrum of diverse pathological states. Clusterin was recently reported to be associated with diabetes, metabolic syndrome, and their sequelae. However, the regulation of clusterin expression by metabolic signals was not addressed. In this study we evaluated the effects of glucose on hepatic clusterin expression. Interestingly, high glucose concentrations significantly increased clusterin expression in primary hepatocytes and hepatoma cell lines, but the conventional promoter region of the clusterin gene did not respond to glucose stimulation. In contrast, the first intronic region was transcriptionally activated by high glucose concentrations. We then defined a glucose response element (GlRE) of the clusterin gene, showing that it consists of two E-box motifs separated by five nucleotides and resembles carbohydrate response element (ChoRE). Unexpectedly, however, these E-box motifs were not activated by ChoRE binding protein (ChREBP), but were activated by sterol regulatory element binding protein-1c (SREBP-1c). Furthermore, we found that glucose induced recruitment of SREBP-1c to the E-box of the clusterin gene intronic region. Taken together, these results suggest that clusterin expression is increased by glucose stimulation, and SREBP-1c plays a crucial role in the metabolic regulation of clusterin. PMID- 21549686 TI - Insulin receptor mutation results in insulin resistance and hyperinsulinemia but does not exacerbate Alzheimer's-like phenotypes in mice. AB - Obesity is a risk factor for Alzheimer's disease (AD), which is characterized by amyloid beta depositions and cognitive dysfunction. Although insulin resistance is one of the phenotypes of obesity, its deleterious effects on AD progression remain to be fully elucidated. We previously reported that the suppression of insulin signaling in a mouse with a heterozygous mutation (P1195L) in the gene for the insulin receptor showed insulin resistance and hyperinsulinemia but did not develop diabetes mellitus [15]. Here, we generated a novel AD mouse model carrying the same insulin receptor mutation and showed that the combination of insulin resistance and hyperinsulinemia did not accelerate plaque formation or memory abnormalities in these mice. Interestingly, the insulin receptor mutation reduced oxidative damage in the brains of the AD mice. These findings suggest that insulin resistance is not always involved in the pathogenesis of AD. PMID- 21549687 TI - Formation of new bioactive organic nitrites and their identification with gas chromatography-mass spectrometry and liquid chromatography coupled to nitrite reduction. AB - Nitric oxide (NO) donors, notably organic nitrates and nitrites are used therapeutically but tolerance develops rapidly, making the use of e.g. nitroglycerin difficult. NO donation in the pulmonary vascular bed might be useful in critically ill patients. Organic nitrites are not associated with tachyphylaxis but may induce methaemoglobinemia and systemic hypotension which might hamper their use. We hypothesised that new lung-selective NO donors can be identified by utilizing exhaled NO as measure for pulmonary NO donation and systemic arterial pressure to monitor hypotension and tolerance development. Solutions of alcohols and carbohydrates were reacted with NO gas and administered to ventilated rabbits for evaluation of in vivo NO donation. Chemical characterization was made by liquid chromatography with on-line nitrite reduction (LC-NO) and by gas chromatography-mass spectrometry (GC-MS). In vivo experiments showed that the hydroxyl-containing compounds treated with NO gas yielded potent NO donors, via nitrosylation to organic nitrites. Analyses by LC-NO showed that the reaction products were able to release NO in vitro. In GC-MS the reaction products were determined to be the organic nitrites, where some are new chemical entities. Non-polar donors preferentially increased exhaled NO with less effect on systemic blood pressure whereas more polar molecules had larger effects on systemic blood pressure and less on exhaled NO. We conclude that new organic nitrites suitable for intravenous administration are produced by reacting NO gas and certain hydroxyl-containing compounds in aqueous solutions. Selectivity of different organic nitrites towards the pulmonary and systemic circulation, respectively, may be determined by molecular polarity. PMID- 21549688 TI - The tyrosine kinase inhibitor sorafenib sensitizes hepatocellular carcinoma cells to taxol by suppressing the HURP protein. AB - The hepatoma upregulated protein (HURP) represents a putative oncogene that is overexpressed in many human cancers, especially hepatocellular carcinoma (HCC). HURP plays an important role during mitotic spindle formation, a process that is targeted by various anti-cancer drugs like taxol. However, the role of HURP during the establishment of taxol chemoresistance in HCC remains unclear. In this study, we observed that high HURP protein level correlates with taxol resistance in HCC cells. Following HURP knockdown, HCC cells show a more sensitive response to taxol treatment. Notably, sorafenib, a tyrosine kinase inhibitor approved for the treatment of HCC, inhibits HURP expression primarily at the transcriptional level and sensitizes HCC cells to sub-lethal doses of taxol. By using real-time PCR and chromatin immunoprecipitation assays, we observed that the NF-kappaB family member c-Rel represents a putative transcription factor that activates HURP gene expression. In addition, the inhibitory effect of sorafenib on HURP expression was attributed to a reduced translation and nuclear translocation of c Rel. Accordingly, downregulation of c-Rel using short-hairpin RNA was shown to reduce HURP protein level and enhance taxol-induced cell death. Taken together, our results indicate that HURP acts as a novel survival protein that protects HCC cells against taxol-induced cell death. In addition, the regulation of HURP gene expression by NF-kappaB signaling appears to be critical for the response of HCC cells to taxol. PMID- 21549689 TI - Patient result median monitoring for clinical laboratory quality control. AB - BACKGROUND: Statistical process control is foundational in laboratory medicine. It typically uses artificial control specimens and can detect some, but not all, analytical defects. A practical, robust method to more directly detect trends in patient results, such as monitoring mean or median patient results, is desirable. METHODS: We generated a simulated set of laboratory results from a normal distribution, and also downloaded sequential patient results for serum sodium and CA 19-9. For each of the three data sets we calculated the standard error of the mean and estimated the standard error of the median by bootstrapping. RESULTS: The standard error of the mean is a practical, easily calculated summary statistic that can be used to construct control charts. The standard error of the median, cannot be reliably estimated without using bootstrap methods, but is more resistant to outliers. Our study confirms a simple relationship between the variance of the median and the variance of the mean, i.e., for Gaussian distributions, Var[Median]/Var[Mean]=pi/2. We also confirm that for skewed distributions, the median is more stable than the mean, implying Var[Median]/Var[Mean]<1. Finally, we establish a sample size of 200 individual patient results as sufficient for monitoring medians for data from approximately Gaussian distributions. CONCLUSIONS: Monitoring patient result medians represents a practical, statistically self-consistent approach to laboratory quality control. PMID- 21549690 TI - Analysis of the effects of iron and vitamin C co-supplementation on oxidative damage, antioxidant response and inflammation in THP-1 macrophages. AB - OBJECTIVES: The aims of the study were to test the susceptibility of THP-1 macrophages to develop oxidative stress and to deploy antioxidant defense mechanisms that insure the balance between the pro- and antioxidant molecules. DESIGN AND METHODS: Differentiated THP-1 were incubated in the presence or absence of iron-ascorbate (Fe/As) (100/1000MUM) and the antioxidants Trolox, BHT, alpha-Tocopherol and NAC. RESULTS: Fe/As promoted the production of lipid peroxidation as reflected by the formation of malondialdehyde and H(2)O(2) along with reduced PUFA levels and elevated glutathione disulfide/total glutathione ratio, a reliable index of cellular redox status. THP-1 macrophages developed an increase in cytoplasmic SOD activity due in part to high cytoplasmic SOD1. On the other hand, a decline was noted in mRNA and protein of extra-cellular SOD3, as well as the activity of GSH-peroxidase, GSH-transferase and ATOX-1 expression. CONCLUSIONS: Macrophages activated under conditions of oxidative stress do not adequately deploy a powerful endogenous antioxidant response, a situation that can lead to an enhanced inflammatory response. PMID- 21549691 TI - Development and validation of an enzyme-linked immunosorbent assay for the quantification of a specific MMP-9 mediated degradation fragment of type III collagen--A novel biomarker of atherosclerotic plaque remodeling. AB - OBJECTIVE: Degradation of collagen in the arterial wall by matrix metalloproteinases is the hallmark of atherosclerosis. We have developed an ELISA for the quantification of type III collagen degradation mediated by MMP-9 in urine. DESIGN AND METHODS: A monoclonal antibody targeting a specific MMP-9 generated fragment of collagen III was used in a competitive ELISA. The assay was validated in urine and arterial tissue of Apolipoprotein-E knockout (ApoE-KO) mice. RESULTS: The lower limit of detection was 0.5ng/mL, intra- and inter-assay coefficients of variation were below 10%. By the end of 20weeks of the study, urine levels of the novel CO3-610 biomarker in ApoE-KO mice increased by two-fold (p<0.0001) and were three-fold higher than in control mice. Western blots confirmed high expression of CO3-610 in arterial extracts of ApoE-KO mice. CONCLUSION: We have developed a novel competitive ELISA, capable of measuring a urine biomarker indicative of pathological extracellular matrix remodeling in a mouse model of atherosclerosis. PMID- 21549692 TI - Effects of bezafibrate in nonalcoholic steatohepatitis model mice with monosodium glutamate-induced metabolic syndrome. AB - Recently, we reported that monosodium glutamate-treated mice (MSG mice) developed severe hyperlipidemia and diabetes mellitus and several complications of obesity. MSG mice acquired fatty livers and subsequently underwent changes that are characteristic of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). In the present study, the effects of bezafibrate on obesity, diabetes mellitus, and NAFLD/NASH were examined in MSG mice. A single dose of MSG (4 mg/g) was administered subcutaneously to neonatal male mice within 24h of birth. Bezafibrate was mixed into the normal feed for 8 weeks. The weight and body mass index of MSG mice increased significantly despite the unchanged intake of food. Triglyceride and total cholesterol levels in blood, visceral adipose tissue, and interscapular adipose tissue rose significantly. In the livers of MSG mice, moderate centrilobular microvesicular steatosis, ballooning degeneration with Mallory bodies, and scattered infiltration of neutrophils and lymphocytes were observed. Centrilobular hepatocytes were 4-hydroxynonenal positive in MSG mice. Bezafibrate ameliorated the severity of diabetes mellitus, hyperinsulinemia, and hyperlipidemia. Adiponectin and leptin concentrations in blood improved, and the accumulation of visceral fat was inhibited. The expression of acyl-CoA oxidase, a beta-oxidation gene, and carnitine palmitoyl transferase, which regulates lipid metabolism, increased markedly on administration of bezafibrate. The liver pathology in MSG mice also improved with bezafibrate; specifically, macro- and microvesicles in hepatocytes nearly disappeared, and NAFLD activity score improved. It is concluded that bezafibrate inhibits the accumulation of visceral fat, following amelioration of hyperlipidemia, in MSG-induced obese mice, due to improvements in diabetes mellitus, fatty liver, and NAFLD. PMID- 21549693 TI - ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors. AB - 5-HT(6) receptor is one of the most recently cloned serotonin receptors, and it might play important roles in Alzheimer's disease, depression, and learning and memory disorders. Availability of only very few 5-HT(6) receptor agonists, however, does not allow examining their contribution in psychopharmacological processes. Therefore, a new 5-HT(6) receptor agonist, ST1936, was synthesized. ST1936 binds to human 5-HT(6) receptors with good affinity (K(i)=28.8 nM). ST1936 also exhibited some moderate binding affinity for 5HT(2B), 5HT(1A), 5HT(7) receptors and adrenergic alpha receptors. ST1936 behaved as a full 5-HT(6) agonist on cloned cells and was able to increase Ca(2+) concentration, phosphorylation of Fyn kinase, and regulate the activation of ERK1/2 that is a downstream target of Fyn kinase. These effects were completely antagonized by two 5-HT(6) receptor antagonists, SB271046 and SB258585. The other 5-HT(6) receptor agonist, WAY181187 also increased Fyn kinase activity. These results suggest that both ST1936 and WAY181187 mediate 5-HT(6) receptor-dependent signal pathways, such as cAMP, Fyn and ERK1/2 kinase, as specific agonists. PMID- 21549694 TI - Embelin reduces cutaneous TNF-alpha level and ameliorates skin edema in acute and chronic model of skin inflammation in mice. AB - Tumor necrosis factor-alpha (TNF-alpha) is known to play a crucial role in the pathogenesis of psoriasis. The present study was designed to investigate the effects of embelin on lipopolysachharide induced TNF-alpha production in mice and in human keratinocytes in vitro and also to study the effect of embelin on acute and chronic skin inflammation in mice. Production of pro-inflammatory cytokines (TNF-alpha and IL-1beta), activation of myeloperoxidase and histological assessment were examined in acute and chronic skin inflammation using 12-O tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear edema. Embelin inhibited topical edema in the mouse ear, leading to substantial reductions in skin thickness and tissue weight, inflammatory cytokine production, neutrophil mediated myeloperoxidase activity, and various histopathological indicators. Furthermore, embelin was effective at reducing inflammatory damage induced by chronic TPA exposure. Our data indicate that embelin has anti-inflammatory activities in both acute and chronic irritant contact dermatitis in vivo and this effect of embelin may be due, at least in part, to the inhibition of IL-1beta and TNF-alpha and to the subsequent blockade of leukocyte accumulation. PMID- 21549695 TI - Involvement of NCAM and FGF receptor signaling in the development of analgesic tolerance to morphine. AB - This study examined the involvement of neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily, in the development of tolerance to morphine. Furthermore, we focused on fibroblast growth factor (FGF) receptor and protein kinase C (PKC)-alpha as part of the intracellular signal transduction pathways underlying NCAM stimulation. The development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine (10mg/kg, s.c.) for 5 days. Morphine treatment gradually and significantly decreased the NCAM expression levels. However it returned to normal levels immediately after re treatment of morphine. Treatment of AS-ODN against NCAM completely inhibited analgesic tolerance to morphine. Protein expression levels of PKC-alpha were significantly increased by repeated morphine treatment in a NCAM-AS-ODN reversible manner. Interestingly, alterations of protein interactions between NCAM and FGF receptor were observed under repeated morphine treatment. In addition, SU5402 (2 MUg/mouse, i.c.v.), an inhibitor of FGF receptor, completely abolished the development of analgesic tolerance to morphine. Furthermore, kappa opioid receptor stimulation using U-50,488H, a kappa-opioid receptor agonist, or establishment of formalin-induced chronic pain can completely suppress these changes in protein expression levels of NCAM and PKC-alpha and inhibit development of analgesic tolerance to morphine. These findings suggest that NCAM and its interaction with FGF receptor in the mechanism of up-regulation of PKC alpha may contribute to the development of analgesic tolerance to morphine. Chronic pain or kappa-opioid receptor stimulation could modulate these phenomena and suppress the development of analgesic tolerance to morphine. PMID- 21549696 TI - Glial cells isolated from dorsal root ganglia express prostaglandin E(2) (EP(4)) and prostacyclin (IP) receptors. AB - Isolated cells from adult rat dorsal root ganglia (DRG) are frequently used as a model system to study responses of primary sensory neurons to nociceptor sensitizing agents such as prostaglandin E(2) and prostacyclin, which are presumed to act only on the neurons in typical mixed cell cultures. In the present study, we evaluated the expression of prostaglandin E(2) (EP(4)) and prostacyclin (IP) receptors in cultures of mixed DRG cells and in purified DRG glia. We show here that EP(4) and IP receptor agonists stimulated adenylyl cyclase activity in both mixed DRG cells and in purified DRG glia, and that these responses were specifically inhibited by EP(4) and IP receptor antagonists, respectively. The presence of EP(4) and IP receptors in DRG glia was further confirmed by the expression of EP(4) and IP receptor immunoreactivity and mRNA. With the increasing awareness of neuron-glial interactions within intact DRG and the use of isolated DRG cells in the study of mechanisms underlying nociception, it will be essential to consider the role played by EP(4) and IP receptor expressing glial cells when evaluating prostanoid-induced sensitization of DRG neurons. PMID- 21549697 TI - Protective effects of hemin in an experimental model of ventilator-induced lung injury. AB - Mechanical ventilation is an indispensable life-support modality for critically ill patients with acute lung injury or acute respiratory distress syndrome. Unfortunately, mechanical ventilation even the protective ventilation strategies may evoke ventilator-induced lung injury. Heme oxygenase-1 (HO-1) has recently exhibited anti-inflammatory and anti-oxidative properties in vitro and in vivo. The effect of HO-1 in ventilator-induced lung injury has not been fully characterized. In this study, rabbits were subjected to high tidal volume ventilation to induce ventilator-induced lung injury, which was confirmed by histopathological alterations, increased bronchoalveolar lavage fluid protein content and lung wet-to-dry ratio. In contrast to the level of HO-1 expression in high tidal volume group, pretreatment with hemin, an inducer of HO-1, further up regulated HO-1 expression. At the same time, these lung injury indexes were attenuated markedly. This pulmonary protection was accompanied by a decrease in bronchoalveolar lavage fluid neutrophil count and in lung myeloperoxidase activity. Besides, pretreatment with hemin prohibited the production of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-8, and up-regulated the level of anti-inflammatory cytokine interleukin (IL)-10 in bronchoalveolar lavage fluid. Furthermore, a decreased malondialdehyde activity, a marker of oxidative stress and a robust increase in total antioxidant capacity were observed in hemin-treated animals. Our findings suggest that HO-1 up-regulation by hemin plays a protective role in ventilator induced lung injury by suppression inflammatory process and oxidative stress. PMID- 21549698 TI - Proglumide enhances the antinociceptive effect of cyclooxygenase inhibitors in diabetic rats in the formalin test. AB - The purpose of this study was to assess the effect of the non-selective cholecystokinin receptor antagonist proglumide on the antinociceptive activity of ketorolac and meloxicam in non-diabetic and diabetic rats. Streptozotocin (60 mg/kg) injection caused hyperglycemia which was maintained for 2 weeks. Formalin evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Local peripheral ipsilateral, but not contralateral, administration of ketorolac and meloxicam produced antinociception in non-diabetic and diabetic rats. However, the antinociceptive effect of both drugs was significantly reduced in diabetic animals. Proglumide was ineffective by itself and it did not affect the antinociception induced by the cyclooxygenase inhibitors in non-diabetic rats. Contrariwise, proglumide reduced formalin-induced nociception and it increased ketorolac- or meloxicam-induced antinociception in diabetic rats. These results suggest that peripheral cholecystokinin plays an important role in diabetes induced sensitization as well as in the reduction of the antinociceptive effects of ketorolac and meloxicam in diabetic rats. The combination of cholecystokinin receptor antagonists and ketorolac or meloxicam may be a useful strategy to reduce nociception in diabetic patients. PMID- 21549699 TI - Effect of pioglitazone on altered expression of Abeta metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance. AB - Accumulation of beta-amyloid (Abeta) peptide in the brain is a major hallmark of Alzheimer's disease. An optimal brain insulin level promotes Abeta clearance, which may play protective roles against Alzheimer's disease. In this study we examined the role of dietary conditions leading to insulin resistance on amyloidosis in fructose-drinking rats. Further investigations tested pioglitazone, an insulin sensitizer, intervention on the altered amyloidosis in this rodent model of insulin resistance. Six-week-old male Wistar rats were fed a standard commercial diet and water without (control) or with 10% fructose for 16 weeks. The animals were randomly divided into 4 groups (n=10): non-treated and water-drinking rats (control group); pioglitazone treated and water-drinking (control treatment group); non-treated and fructose-drinking rats (fructose group) and pioglitazone-treated and fructose-drinking rats (fructose treatment group). Pioglitazone was given at the dose of 10mg/kgd by gavage for the last 12 weeks of the 16-week period. We found that diet-induced insulin resistance induced Abeta overproduction with altered expression of Abeta metabolism associated molecules, which corresponded with increased beta-secretase-1 (BACE1), gamma-secretase (PS-1) activities and decreased insulin degrading enzyme (IDE) activities, but not neprilysin in the cortex and hippocampus. Additionally, pioglitazone treatment prevented all these observed abnormalities. This study indicates that insulin resistance induced by fructose-drinking affects the expression of Abeta metabolism-associated molecules that are responsible for Abeta deposition and pioglitazone treatment negatively modulate amyloidogenesis. PMID- 21549700 TI - Pharmacological preconditioning with nicorandil and pioglitazone attenuates myocardial ischemia/reperfusion injury in rats. AB - The present investigation was designed to study the cardioprotective effects of nicorandil and pioglitazone preconditioning in myocardial ischemia/reperfusion induced hemodynamic, biochemical and histological changes in rats. Oral doses of nicorandil (3 or 6 mg/kg) and pioglitazone (10 or 20mg/kg) were administered once daily for 5 consecutive days. Rats were then subjected to myocardial ischemia/reperfusion (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during ischemia/reperfusion progress. At the end of reperfusion, plasma creatine kinase-MB activity and total nitrate/nitrite were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances, reduced glutathione and myeloperoxidase activity were estimated in the heart left ventricle. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments. Nicorandil (3 or 6 mg/kg) was effective in attenuating the ischemia/reperfusion-induced ventricular arrhythmias, creatine kinase-MB release, lactate accumulation and oxidative stress. Nicorandil (3 mg/kg) was more effective in improving the energy production and lowering the elevated myeloperoxidase activity. Both doses of pioglitazone (10 or 20 mg/kg) were equally effective in reducing lactate accumulation and completely counteracting the oxidative stress. Pioglitazone (10 mg/kg) was more effective in improving energy production and reducing ventricular arrhythmias, plasma creatine kinase-MB release and total nitrate/nitrite. It seems that selective mitochondrial K(ATP) channel opening by lower doses of nicorandil and pioglitazone in the present study provided more cardioprotection against ventricular arrhythmias and biochemical changes induced by ischemia/reperfusion. Histological examination revealed also better improvement by the lower dose of nicorandil than that of pioglitazone. PMID- 21549701 TI - Down-regulation of DDAH2 and eNOS induces endothelial dysfunction in sinoaortic denervated rats. AB - The aim of present study was to investigate whether downregulation of dimethylarginine dimethylaminohydrolase (DDAH2) and endothelial nitric oxide synthase (eNOS) induced endothelial dysfunction in sinoaortic-denervated (SAD) rats. SAD rats exhibited significantly higher blood pressure (BP) variability and markedly lower baroreflex sensitivity. However, there was no significant difference in BP between SAD rats and sham-operated rats. In SAD rats, ultrastructural analysis revealed that endothelial cells were degenerated and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) study showed that apoptotic aortic endothelial cells increased. Circulating angiotensinII (AngII), asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) levels in SAD rats were similar to sham-operated rats, but aortic AngII and MDA levels locally increased. Endothelium-mediated relaxation of thoracic aorta isolated from SAD rats was impaired compared to sham-operated rats, whereas the sodium nitroprusside-induced relaxation was quite similar. Western blotting results showed that DDAH2 and eNOS expressions decreased significantly in the aortae of SAD rats. Treatment of primary cultured rat aortic endothelial cells with AngII (1 MUM) resulted in a marked reduction of DDAH2 and eNOS expressions, and coadministration of losartan (1 MUM), an AT(1) receptor antagonist, abolished the effect. In conclusion, downregulation of DDAH2 and eNOS induced endothelial dysfunction in SAD rats. DDAH2 and eNOS may be the potential targets for treatment of endothelial dysfunction. PMID- 21549702 TI - Chronic type II diabetes mellitus leads to changes in neuropeptide Y receptor expression and distribution in human myocardial tissue. AB - Neuropeptide Y is one of the most abundant neurotransmitters in the myocardium, and is known to influence cardiovascular remodeling. We hypothesized that diabetic neuropathy could possibly be associated with altered neuropeptide Y and its receptor expression levels in myocardium and plasma. Plasma neuropeptide Y levels in diabetic (n=24, HgbA1c 7.9 +/- 1.1%) and non-diabetic (n=27, HgbA1c 5.8 +/- 0.5%) patients undergoing cardiac surgery utilizing cardiopulmonary bypass were analyzed. Right atrial tissue of these patients was used to determine the expression of neuropeptide Y, the receptors 1-5, and leptin by immunoblotting, real-time PCR and immunofluorescence. Apoptosis signaling and endostatin and angiostatin were measured to determine the effects of leptin. Plasma neuropeptide Y levels were significantly increased in patients with Type II diabetes mellitus as compared to non-diabetic patients (P=0.026). Atrial tissue neuropeptide Y mRNA levels were lower in diabetic patients (P=0.036). There was a significant up regulation of myocardial Y(2) and Y(5) receptors (P=0.009, P=0.01 respectively) in the diabetic patients. Leptin, involved with apoptosis and angiogenesis, was down regulated in diabetic patients (P=0.05). The levels of caspase-3, endostatin and angiostatin were significantly elevated in diabetic patients (P=0.003, P=0.008, P=0.01 respectively). Y(1) receptors were more likely to be localized within the nuclei of cardiomyocytes and vascular smooth muscle cells. Neuropeptide expression is altered differentially in the serum and myocardium by diabetes. Altered regulation of this system in diabetics may be in part responsible for the decreased angiogenesis, increased apoptosis, and increased vascular smooth muscle proliferation leading to coronary artery disease and heart failure in this patient population. PMID- 21549704 TI - Strategies for bypassing the membrane barrier in multidrug resistant Gram negative bacteria. AB - In Gram-negative bacteria, the envelope is a sophisticated barrier protecting the cell against external toxic compounds. Membrane transporters, e.g., porins or efflux pumps, are main filters regulating the internal accumulation of various hydrophilic molecules. Regarding bacterial susceptibility towards antibacterial agents, membrane permeability is part of the early bacterial defense. The bacterium manages the translocation process, influx and efflux, to control the intracellular concentration of various molecules. Antibiotics and biocides are substrates of these mechanisms and the continuing emergence of multidrug resistant isolates is a growing worldwide health concern. Different strategies could be proposed to bypass the bacterial membrane barrier, comprising influx and efflux mechanisms, in order to restore the activity of antibiotics against resistant bacteria. PMID- 21549705 TI - Featuring... Shiro Suetsugu: winner of the 2011 FEBS Letters Young Group Leader Award. Interview by Daniela Ruffell. PMID- 21549703 TI - Ovarian hormones influence corticotropin releasing factor receptor colocalization with delta opioid receptors in CA1 pyramidal cell dendrites. AB - Stress interacts with addictive processes to increase drug use, drug seeking, and relapse. The hippocampal formation (HF) is an important site at which stress circuits and endogenous opioid systems intersect and likely plays a critical role in the interaction between stress and drug addiction. Our prior studies demonstrate that the stress-related neuropeptide corticotropin-releasing factor (CRF) and the delta-opioid receptor (DOR) colocalize in interneuron populations in the hilus of the dentate gyrus and stratum oriens of CA1 and CA3. While independent ultrastructural studies of DORs and CRF receptors suggest that each receptor is found in CA1 pyramidal cell dendrites and dendritic spines, whether DORs and CRF receptors colocalize in CA1 neuronal profiles has not been investigated. Here, hippocampal sections of adult male and proestrus female Sprague-Dawley rats were processed for dual label pre-embedding immunoelectron microscopy using well-characterized antisera directed against the DOR for immunoperoxidase and against the CRF receptor for immunogold. DOR immunoreactivity (-ir) was found presynaptically in axons and axon terminals as well as postsynaptically in somata, dendrites and dendritic spines in stratum radiatum of CA1. In contrast, CRF receptor-ir was predominantly found postsynaptically in CA1 somata, dendrites, and dendritic spines. CRF receptor-ir frequently was observed in DOR-labeled dendritic profiles and primarily was found in the cytoplasm rather than at or near the plasma membrane. Quantitative analysis of CRF receptor-ir colocalization with DOR-ir in pyramidal cell dendrites revealed that proestrus females and males show comparable levels of CRF receptor-ir per dendrite and similar cytoplasmic density of CRF receptor-ir. In contrast, proestrus females display an increased number of dual-labeled dendritic profiles and an increased membrane density of CRF receptor-ir in comparison to males. We further examined the functional consequences of CRF receptor-ir colocalization with DOR-ir in the same neuron using the hormone responsive neuronal cell line NG108-15, which endogenously expresses DORs, and assayed intracellular cAMP production in response to CRF receptor and DOR agonists. Results demonstrated that short-term application of DOR agonist SNC80 inhibited CRF-induced cAMP accumulation in NG108-15 cells transfected with the CRF receptor. These studies provide new insights on opioid-stress system interaction in the hippocampus of both males and females and establish potential mechanisms through which DOR activation may influence CRF receptor activity. PMID- 21549708 TI - Characterization of melanocortin 4 receptor in Snakeskin Gourami and its expression in relation to daily feed intake and short-term fasting. AB - In this study, melanocortin 4 receptor (MC4R) was characterized in Snakeskin Gourami (Trichogaster pectoralis) and designated as TpMC4R. The TpMC4R contained predicted regions that were structural features of MC4R subtypes of vertebrates. In addition, phylogenetic analyses showed that TpMC4R were in MC4R orthologues and closely related to piscine MC4Rs. The TpMC4R transcripts were detected in embryos at all developmental stages. Further, its mRNA was detectable in unfertilized eggs, suggesting that TpMC4R could be classified as maternal mRNA. Using real-time RT-PCR, graded expression at each central and peripheral tissue was demonstrated. Localization of TpMC4R expression in the brain was performed by in situ hybridization. An experiment was conducted to determine the expression profile of TpMC4R during daily feeding in each region of the brain. Fish were fed twice a day at 10:00 and 16:00, and the level of TpMC4R expression was analyzed at 9:00, 11:00, 13:00 and 15:00. The expression level of TpMC4R was significantly reduced at 15:00 compared to that at all previous times (9:00, 11:00 and 13:00). Moreover, significantly higher expression levels of TpMC4R were observed at 18- and 24-h fasting periods. The finding of variation in MC4R expression level during daily feeding and fasting period revealed some direct and/or indirect relations of the MC4R expression to circadian feeding rhythm and short-term food deprivation in fish. PMID- 21549707 TI - MicroRNA regulation constrains the organization of target genes on mammalian chromosomes. AB - The regulation of microRNAs (miRNAs) is a complicated process requiring a large number of molecular events to be coordinated in both space and time. It is not known whether this complicated regulation process constrains the organization of target genes on mammalian chromosomes. We performed a genome-wide analysis to provide a better picture of chromosomal organization of miRNA target genes. Our results showed clustering of the target genes (TGs) of miRNAs on mammalian chromosomes, and further revealed that the particular gene organization is constrained by miRNA regulation. The clustering pattern of TGs provides an insight into the complexity of miRNA regulation. PMID- 21549706 TI - Changing the ubiquitin landscape during viral manipulation of the DNA damage response. AB - Viruses often induce signaling through the same cellular cascades that are activated by damage to the cellular genome. Signaling triggered by viral proteins or exogenous DNA delivered by viruses can be beneficial or detrimental to viral infection. Viruses have therefore evolved to dissect the cellular DNA damage response pathway during infection, often marking key cellular regulators with ubiquitin to induce their degradation or change their function. Signaling controlled by ubiquitin or ubiquitin-like proteins has recently emerged as key regulator of the cellular DNA damage response. Situated at the interface between DNA damage signaling and the ubiquitin system, viruses can reveal key convergence points in this important cellular pathway. In this review, we examine how viruses harness the diversity of the cellular ubiquitin system to modulate the DNA damage signaling pathway. We discuss the implications of viral infiltration of this pathway for both the transcriptional program of the virus and for the cellular response to DNA damage. PMID- 21549709 TI - Capacitance increases of dissociated tilapia prolactin cells in response to hyposmotic and depolarizing stimuli. AB - Prolactin (PRL) is the major hormonal mediator of adaptation to hyposmotic conditions. In tilapia (Oreochromis mossambicus), PRL cells are segregated to the rostral pars distalis of the anterior pituitary facilitating the nearly pure culture of dissociated PRL cells. Membrane capacitance (C(m)) was recorded at 1Hz or higher for tens of minutes as a surrogate monitor of PRL secretion by exocytosis from cells under perforated patch clamp. The study compares secretory responses to trains of depolarizing clamps (100 at 2.5 Hz, from -70 to +10 mV for 100 ms) to the physiological stimulus, exposure to hyposmotic medium, here a switch from 350 to 300 mOsm saline ([Ca2+] 15 mM). Two-thirds of cells tested with each stimulus responded. In response to depolarizing clamps, C(m) increased linearly at an average rate of 7.2 fF/s. The increase was also linear in response to hyposmotic perfusion, but the average rate was 0.68 fF/s. Response to depolarization was reversibly blocked in Ca2+-omitted saline, or in saline with 30 MUM Cd2+. It was unaffected by 0.1 MUM tetrodotoxin. By contrast, responses were reduced but not absent during perfusion of hyposmotic saline with Ca2+ omitted; 30 MUM Cd2+ appeared to enhance the hyposmotic response. BAPTA-AM eliminated responses to both stimuli, confirming that secretion was dependent on increases of intracellular [Ca2+]. Together with previous observations from this laboratory of [Ca2+](i) with simultaneous collection and immunoassay of perfusate for PRL, we conclude that depolarization and hyposmotic stimuli initiate secretion by independent mechanisms. PMID- 21549710 TI - Long-term in vivo resistin overexpression induces myocardial dysfunction and remodeling in rats. AB - We have previously reported that resistin induces hypertrophy and impairs contractility in isolated rat cardiomyocytes. To examine the long-term cardiovascular effects of resistin, we induced in vivo overexpression of resistin using adeno-associated virus serotype 9 injected by tail vein in rats and compared to control animals. Ten weeks after viral injection, overexpression of resistin was associated with increased ratio of left ventricular (LV) weight/body weight, increased end-systolic LV volume and significant decrease in LV contractility, measured by the end-systolic pressure volume relationship slope in LV pressure volume loops, compared to controls. At the molecular level, mRNA expression of ANF and beta-MHC, and protein levels of phospholamban were increased in the resistin group without a change in the level of SERCA2a protein expression. Increased fibrosis by histology, associated with increased mRNA levels of collagen, fibronectin and connective tissue growth factor were observed in the resistin-overexpressing hearts. Resistin overexpression was also associated with increased apoptosis in vivo, along with an apoptotic molecular phenotype in vivo and in vitro. Resistin-overexpressing LV tissue had higher levels of TNF-alpha receptor 1 and iNOS, and reduced levels of eNOS. Cardiomyocytes overexpressing resistin in vitro produced larger amounts of TNFalpha in the medium, had increased phosphorylation of IkappaBalpha and displayed increased intracellular reactive oxygen species (ROS) content with increased expression and activity of ROS-producing NADPH oxidases compared to controls. Long-term resistin overexpression is associated with a complex phenotype of oxidative stress, inflammation, fibrosis, apoptosis and myocardial remodeling and dysfunction in rats. This phenotype recapitulates key features of diabetic cardiomyopathy. This article is part of Special Issue Item Group entitled "Possible Editorial". PMID- 21549711 TI - Cardiac lipin 1 expression is regulated by the peroxisome proliferator activated receptor gamma coactivator 1alpha/estrogen related receptor axis. AB - Lipin family proteins (lipin 1, 2, and 3) are bifunctional intracellular proteins that regulate metabolism by acting as coregulators of DNA-bound transcription factors and also dephosphorylate phosphatidate to form diacylglycerol [phosphatidate phosphohydrolase activity] in the triglyceride synthesis pathway. Herein, we report that lipin 1 is enriched in heart and that hearts of mice lacking lipin 1 (fld mice) exhibit accumulation of phosphatidate. We also demonstrate that the expression of the gene encoding lipin 1 (Lpin1) is under the control of the estrogen-related receptors (ERRs) and their coactivator the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). PGC-1alpha, ERRalpha, or ERRgamma overexpression increased Lpin1 transcription in cultured ventricular myocytes and the ERRs were associated with response elements in the first intron of the Lpin1 gene. Concomitant RNAi-mediated knockdown of ERRalpha and ERRgamma abrogated the induction of lipin 1 expression by PGC-1alpha overexpression. Consistent with these data, 3-fold overexpression of PGC-1alpha in intact myocardium of transgenic mice increased cardiac lipin 1 and ERRalpha/gamma expression. Similarly, injection of the beta2-adrenergic agonist clenbuterol induced PGC-1alpha and lipin 1 expression, and the induction in lipin 1 after clenbuterol occurred in a PGC-1alpha-dependent manner. In contrast, expression of PGC-1alpha, ERRalpha, ERRgamma, and lipin 1 was down-regulated in failing heart. Cardiac phosphatidic acid phosphohydrolase activity was also diminished, while cardiac phosphatidate content was increased, in failing heart. Collectively, these data suggest that lipin 1 is the principal lipin protein in the myocardium and is regulated in response to physiologic and pathologic stimuli that impact cardiac metabolism. PMID- 21549713 TI - Interaction of human 3-phosphoglycerate kinase with its two substrates: is substrate antagonism a kinetic advantage? AB - Substrate antagonism has been described for a variety of enzymes with more than one substrate and is characterized by a lowering of the affinity of one substrate in the presence of the other(s). 3-Phosphoglycerate kinase (PGK) catalyzes phosphotransfer from 1,3-bisphosphoglycerate (bPG) to ADP to give 3 phosphoglycerate (PG) and ATP, and is subject to substrate antagonism. Because of the instability of bPG, antagonism has only been described between PG and ATP or ADP. Here, we show that antagonism also occurs between bPG and ADP. Using the stopped-flow method, we show that the dissociation constant for one substrate increases in the presence of the other, and that this decrease in affinity is mainly due to an increase in the dissociation rate constant. As a consequence, there is an increase in the overall interaction kinetics. Interestingly, in the presence of the mirror image of natural d-ADP, l-ADP (a good substrate for PGK), antagonism is absent. Using rapid-quench-flow, we studied the kinetics of ATP formation. The time courses present the following: (1) a lag with l-ADP, but not with d-ADP, the kinetics of which were similar to the interaction kinetics measured by stopped-flow; (2) a burst that is directed by the phosphotransfer; and (3) a steady-state that is rate limited by the release of product kinetics. Structural explanations for these results are proposed by analyzing the crystallographic structure of the fully closed conformation of PGK in complex with l-ADP, PG, and the transition-state analogue AlF(4)(-) compared to previously determined structures. PMID- 21549712 TI - Variable sequences outside the SAM-binding core critically influence the conformational dynamics of the SAM-III/SMK box riboswitch. AB - The S(MK) box (SAM-III) translational riboswitches were identified in S-adenosyl l-methionine (SAM) synthetase metK genes in members of Lactobacillales. This riboswitch switches between two alternative conformations in response to intracellular SAM concentration and controls metK expression at the level of translation initiation. We previously reported the crystal structure of the SAM bound S(MK) box riboswitch. In this study, we combined selective 2'-hydroxyl acylation analyzed by primer extension chemical probing with mutagenesis to probe the ligand-induced conformational switching mechanism. We revealed that while the majority of the apo S(MK) box RNA molecules exist in an alternatively base-paired (ON) conformation, a subset of them pre-organize into a SAM-bound-like (READY) conformation, which, upon SAM exposure, is selectively stabilized into the SAM bound (OFF) conformation through an induced-fit mechanism. Mutagenesis showed that the ON state is only slightly more stable than the READY state, as several single-nucleotide substitutions in a hypervariable region outside the SAM-binding core can alter the folding landscape to favor the READY state. Such S(MK) variants display a "constitutively OFF" behavior both in vitro and in vivo. Time resolved and temperature-dependent selective 2'-hydroxyl acylation analyzed by primer extension analyses revealed adaptation of the S(MK) box RNA to its mesothermal working environment. The latter analysis revealed that the SAM-bound S(MK) box RNA follows a two-step folding/unfolding process. PMID- 21549716 TI - Effect of environmental fluctuations on invasion fronts. AB - We determine the density profile and velocity of invasion fronts in one dimensional infinite habitats in the presence of environmental fluctuations. The population dynamics is reformulated in terms of a stochastic reaction-diffusion equation and is reduced to a deterministic equation that incorporates the systematic contributions of the noise. We obtain analytical expressions for the front profile and velocity by constructing a variational principle. The effect of the noise differs, depending on whether it affects the density-independent growth rate, the intraspecific competition term or the Allee threshold. Fluctuations in the density-independent growth rate increase the invasion velocity and the population density of the invaded area. Fluctuations in the competition term also change the population density of the invaded area, but modify the invasion velocity only for certain initial conditions. Fluctuations in the Allee threshold can induce pulled or pushed invasion fronts as well as invasion failure. We compare our analytical results with numerical solutions of the stochastic partial differential equations and show that our procedure proves useful in dealing with reaction-diffusion equations with multiplicative noise. PMID- 21549715 TI - Symmetry and asymmetry of the RING-RING dimer of Rad18. AB - The human ubiquitin-conjugating enzyme Rad6 (E2), with ubiquitin ligase enzyme Rad18 (RING E3), monoubiquitinates proliferating cell nuclear antigen at stalled replication forks in DNA translesion synthesis. Here, we determine the structure of the homodimeric Rad18 RING domains by X-ray crystallography and classify it to RING-RING dimers that dimerize through helices adjacent to the RING domains and through the canonical RING domains. Using NMR spectroscopy and site-directed mutagenesis, we demonstrate that the Rad6b binding site, for the Rad18 RING domain, strongly resembles that of other E2/E3 RING/U-box complexes. We show that the homodimeric Rad18 RING domain can recruit two Rad6b E2 enzymes, whereas the full-length Rad18 homodimer binds only to a single Rad6b molecule. Such asymmetry is a common feature of RING-RING heterodimers and has been observed for the CHIP U-box homodimer. We propose that asymmetry may be a common feature of dimeric RING E3 ligases. PMID- 21549718 TI - Mathematical modelling and assessment of the pH homeostasis mechanisms in Aspergillus niger while in citric acid producing conditions. AB - In this work we introduce an extended model of the Aspergillus niger metabolism while in citrate production conditions. The model includes many recent findings related to various transport processes. It now considers a new information about the fructose uptake system and the proton and amino acids carriers between cytoplasm and the external medium. It also accounts for recent information about both the malate-citrate antiport between mitochondria and cytoplasm and the dihydrogen citrate ion excretion symport with protons. Finally, the model also accounts for new information about the glycerol-3-phosphate shuttle and pH buffering systems. Provided with this updated representation and after having assessed its quality and dynamic behaviour, we were able to explain the observed pH homoeostasis found in A. niger while in citrate producing conditions. The model also serves to enhance our comprehension of the molecular mechanisms operating in order to keep homoeostasis of pH in A. niger and other fungi, bacteria and yeast of biotechnological relevance. PMID- 21549714 TI - Design and characterization of epitope-scaffold immunogens that present the motavizumab epitope from respiratory syncytial virus. AB - Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, but an effective vaccine has not yet been developed. An ideal vaccine would elicit protective antibodies while avoiding virus-specific T cell responses, which have been implicated in vaccine-enhanced disease with previous RSV vaccines. We propose that heterologous proteins designed to present RSV-neutralizing antibody epitopes and to elicit cognate antibodies have the potential to fulfill these vaccine requirements, as they can be fashioned to be free of viral T-cell epitopes. Here we present the design and characterization of three epitope-scaffolds that present the epitope of motavizumab, a potent neutralizing antibody that binds to a helix-loop-helix motif in the RSV fusion glycoprotein. Two of the epitope-scaffolds could be purified, and one epitope scaffold based on a Staphylococcus aureus protein A domain bound motavizumab with kinetic and thermodynamic properties consistent with the free epitope-scaffold being stabilized in a conformation that closely resembled the motavizumab-bound state. This epitope-scaffold was well folded as assessed by circular dichroism and isothermal titration calorimetry, and its crystal structure (determined in complex with motavizumab to 1.9 A resolution) was similar to the computationally designed model, with all hydrogen-bond interactions critical for binding to motavizumab preserved. Immunization of mice with this epitope-scaffold failed to elicit neutralizing antibodies but did elicit sera with F binding activity. The elicitation of F binding antibodies suggests that some of the design criteria for eliciting protective antibodies without virus-specific T-cell responses are being met, but additional optimization of these novel immunogens is required. PMID- 21549717 TI - Genome wide study of NF-Y type CCAAT boxes in unidirectional and bidirectional promoters in human and mouse. AB - A subset of CCAAT boxes is known as binding sites for the transcription factor NF Y. We characterize their number, mismatches to the consensus sequence, and locations in bidirectional and unidirectional promoter sequences in human and mouse. We confront the findings with an analytical null model of DNA sequences and find that NF-Y type CCAAT boxes play key, but distinct roles in the two types of promoters. They are found above chance in both, but in unidirectional only when having few mismatches. In bidirectional, the relative positions of multiple boxes differ from what is expected by chance, suggesting the need for contiguity. In agreement, when there are four boxes (four-box configurations), these have much lower number of mismatches than expected in bidirectional promoters alone. Positioning of the first box differs in the two types of promoters and the null model, and mismatches and positioning are found to be correlated. Finally, four box configurations are conserved between human and mouse, supporting the relevance of the findings. We conclude that bidirectional and unidirectional promoters, while sharing some similarities, appear to possess distinct regulatory mechanisms at the sequence level. PMID- 21549719 TI - Constant proportion harvest policies: dynamic implications in the Pacific halibut and Atlantic cod fisheries. AB - Overfishing, pollution and other environmental factors have greatly reduced commercially valuable stocks of fish. In a 2006 Science article, a group of ecologists and economists warned that the world may run out of seafood from natural stocks if overfishing continues at current rates. In this paper, we explore the interaction between a constant proportion harvest policy and recruitment dynamics. We examine the discrete-time constant proportion harvest policy discussed in Ang et al. (2009) and then expand the framework to include stock-recruitment functions that are compensatory and overcompensatory, both with and without the Allee effect. We focus on constant proportion policies (CPPs). CPPs have the potential to stabilize complex overcompensatory stock dynamics, with or without the Allee effect, provided the rates of harvest stay below a threshold. If that threshold is exceeded, CPPs are known to result in the sudden collapse of a fish stock when stock recruitment exhibits the Allee effect. In case studies, we analyze CPPs as they might be applied to Gulf of Alaska Pacific halibut fishery and the Georges Bank Atlantic cod fishery based on harvest rates from 1975 to 2007. The best fit models suggest that, under high fishing mortalities, the halibut fishery is vulnerable to sudden population collapse while the cod fishery is vulnerable to steady decline to zero. The models also suggest that CPP with mean harvesting levels from the last 30 years can be effective at preventing collapse in the halibut fishery, but these same policies would lead to steady decline to zero in the Atlantic cod fishery. We observe that the likelihood of collapse in both fisheries increases with increased stochasticity (for example, weather variability) as predicted by models of global climate change. PMID- 21549720 TI - Myricetin attenuated MPP(+)-induced cytotoxicity by anti-oxidation and inhibition of MKK4 and JNK activation in MES23.5 cells. AB - Increasing evidence suggests that oxidative stress may be implicated in the degeneration of dopaminergic neurons in Parkinson's disease (PD), and anti oxidation have been shown to be effective to PD treatment. Myricetin has been reported to have the biological functions of anti-oxidation, anti-apoptosis, anti inflammation and iron-chelation. The aim of the present study is to investigate the neuroprotective effect of myricetin on 1-methyl-4-phenylpyridinium (MPP(+)) treated MES23.5 cells and the underlying mechanisms. The results showed that myricetin treatment significantly attenuated MPP(+)-induced cell loss and nuclear condensation. Further experiments demonstrated that myricetin could suppress the production of intracellular reactive oxygen species (ROS), restore the mitochondrial transmembrane potential (?Psim), increase Bcl-2/Bax ratio and decrease caspase-3 activation that induced by MPP(+). Futhermore, we also showed myricetin decreased the phosphorylation of mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and c-Jun N-terminal kinase (JNK) caused by MPP(+). These results suggest that myricetin protected the MPP(+)-treated MES23.5 cells by anti oxidation and inhibition of MKK4 and JNK activation. PMID- 21549721 TI - The neural correlates of competition during memory retrieval are modulated by attention to the cues. AB - As people learn more facts about a concept, those facts become more difficult to remember. This is called the fan effect, where fan refers to the number of facts known about a concept. Increasing fan has been shown to decrease accuracy and increase response time and left ventrolateral prefrontal cortex (VLPFC) activity during retrieval. In this study, participants learned 36 arbitrary person location pairings and made recognition decisions while we recorded brain activity using fMRI. We separately manipulated the fan of each person and location, as well as the training procedure with which each pair was studied. In the person focus condition, participants studied pairs with a picture of the person's face and used the person as a retrieval cue during training. In the location focus condition, participants studied pairs with a picture of the location and used the location as a retrieval cue during training. We found that the fan of the focused cue had a greater effect on response time, accuracy, and left VLPFC activity during retrieval than the fan of the unfocused cue. We also found that the parahippocampal place area (PPA) was more active during the recognition of pairs studied in the location focus condition, but not when the fan of the location was high. Overall, we found opposite effects of fan on VLPFC and PPA that were modulated by cue focus. PMID- 21549722 TI - The time-course of global and local attentional guidance in Kanizsa-figure detection. AB - Object configurations can be perceptually represented at various hierarchical levels. For example, in visual search, global Kanizsa figures are detected efficiently, whereas search for local groupings is inefficient, with similarity dependent nontarget interference arising at the hierarchical level that defines the target (Conci, Muller, & Elliott, 2007). The present study was designed to examine the electrophysiological correlates of this global-local search asymmetry. The results revealed differences between hierarchical object levels to be evident throughout a number of processing stages: search for a global, versus a local, target elicited larger amplitudes in early sensory components (P1, N1). Moreover, the efficiency of attentional orienting towards a target was mirrored in the Posterior Contralateral Negativity (PCN), with PCN latencies being substantially delayed (by ~ 70 ms) with local, versus global, targets. Finally, late components (P3 and slow wave--SW) reflected the overall search efficiency, which was determined by both the hierarchical level at which the target was defined and the similarity-based nontarget interference. Taken together, this pattern shows that multiple, sequential processes of object completion contribute to the attentional precedence of a globally bound object over a mere local element grouping. PMID- 21549723 TI - Reduced hippocampal activity during encoding in cognitively normal adults carrying the APOE E4 allele. AB - Apolipoprotein (APOE) E4-related differences in memory performance have been detected before age 65. The hippocampus and the surrounding medial temporal lobe (MTL) structures are the first site affected by Alzheimer's disease (AD) and the MTL is the seat of episodic memory, including visuo-spatial memory. While reports of APOE E4-related differences in these brain structures are not consistent in either cross-sectional or longitudinal structural and functional magnetic resonance imaging (fMRI) studies, there is increasing evidence that brain activity at baseline (defined as activity during fixation or rest) may differ in APOE E4 carriers compared to non-carriers. In this fMRI study, cognitively normal APOE E4 carriers and non-carriers engaged in a perspective-dependent spatial learning task (Shelton & Gabrieli, 2002) previously shown to activate MTL structures in older participants (Borghesani et al., 2008). A low-level, visually engaging dot-control task was used for comparison, in addition to fixation. APOE E4 carriers showed less activation than non-carriers in the hippocampus proper during encoding. Specifically, when spatial encoding was contrasted against the dot-control task, encoding-related activation was significantly lower in carriers than non-carriers. By contrast, no E4-related differences in the hippocampus were found when spatial encoding was compared with fixation. Lower activation, however, was not global since encoding-related activation in early visual cortex (left lingual gyrus) was not different between APOE E4 carriers and non-carriers. The present data document APOE E4-related differences in the hippocampus proper during encoding and underscore the role of low-level control contrasts for complex encoding tasks. These results have implications for fMRI studies that investigate the default-mode network (DMN) in middle-aged to older APOE E4 carriers to help evaluate AD risk in this otherwise cognitively normal population. PMID- 21549725 TI - Gentle vs. aversive handling of pregnant ewes: I. Maternal cortisol and behavior. AB - The aim of the experiment was to study the effects of aversive vs. gentle handling in late pregnancy on maternal behavior of ewes. Sixteen Norwegian Dala ewes bearing twins were subjected to 10 min of either gentle (GEN--soft talking and calm behavior) or aversive (AVS--swift movements and shouting) handling twice a day during the last 5 weeks of pregnancy. Salivary cortisol was recorded before and after treatments. The following behaviors were recorded post-partum in the ewes: grooming duration, number of vocalizations and in the lambs: number of vocalizations, latency and duration of standing, latency and duration in udder directed position. The ability of the ewe to follow her lamb carried away by a human was scored on day 1 and 7. After the treatment sessions, cortisol levels tended to increase in AVS ewes but not GEN ewes. At parturition, AVS ewes groomed their offspring for a longer duration than GEN ewes. AVS lambs tended to be heavier than GEN lambs at 24 h of age. Follow Scores from GEN ewes were higher than for the AVS ewes at day one, but no difference between treatment groups was detected after one week. These results show that aversively treated ewes increased their grooming behavior towards their offspring, but that fear of humans disrupted their ability to follow their lambs closely when carried away by a human. We conclude that the type of handling of ewes during pregnancy may have some impact on important maternal behaviors. PMID- 21549724 TI - Cholinergic modulation of mesolimbic dopamine function and reward. AB - The substantial health risk posed by obesity and compulsive drug use has compelled a serious research effort to identify the neurobiological substrates that underlie the development these pathological conditions. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug-seeking and craving remains incomplete. Important work from the laboratory of Bart Hoebel has provided key information on neurochemical systems that interact with dopamine (DA) as potentially important components in both the development of addiction and the expression of compulsive behaviors such as binge eating. One such modulatory system appears to be cholinergic pathways that interact with DA systems at all levels of the reward circuit. Cholinergic cells in the pons project to DA-rich cell body regions in the ventral tegmental area (VTA) and substantial nigra (SN) where they modulate the activity of dopaminergic neurons and reward processing. The DA terminal region of the nucleus accumbens (NAc) contains a small but particularly important group of cholinergic interneurons, which have extensive dendritic arbors that make synapses with a vast majority of NAc neurons and afferents. Together with acetylcholine (ACh) input onto DA cell bodies, cholinergic systems could serve a vital role in gating information flow concerning the motivational value of stimuli through the mesolimbic system. In this report we highlight evidence that CNS cholinergic systems play a pivotal role in behaviors that are motivated by both natural and drug rewards. We argue that the search for underlying neurochemical substrates of compulsive behaviors, as well as attempts to identify potential pharmacotherapeutic targets to combat them, must include a consideration of central cholinergic systems. PMID- 21549726 TI - Age exacerbates sickness behavior following exposure to a viral mimetic. AB - Poly I:C, a viral mimetic, is a synthetic double-stranded RNA that is known to cause activation of the innate immune system, resulting in the emergence of sickness behaviors in otherwise healthy adult mice. However, the way in which such effects of poly I:C manifest themselves in aged mice are not currently known. We hypothesized that poly I:C administration would lead to burrowing deficits, but that these deficits would be exaggerated in aged subjects (19 months old) compared to young subjects (4-months old) that received the same dose. In order to associate these behavioral decrements with inflammatory factors, we measured mRNA expression of IL-1beta and IL-6 in the hippocampus and parietal cortex and peripheral protein expression of IL-6, TNF-alpha, MCP-1, MIP 1alpha, and IL-1beta in the serum. After exposure to poly I:C, aged subjects demonstrated significant impairments in their burrowing behavior, compared to younger subjects administered the same dose. These behavioral decrements coincided with increased expression of IL-6 among animals exposed to poly I:C and increased expression of IL-1beta among aged animals in the hippocampus and cortex. Furthermore, we observed an increase in peripheral poly I:C-induced IL-6, TNF-alpha, MCP-1, and MIP-1alpha, but not IL-1beta. These results indicate that virus-mediated immune activation in the aging body can lead to increased sickness behavior. Furthermore, these data indicated a possible dissociation between the effects of poly I:C on sickness behaviors in aged mice, with central expression of IL-1beta potentially playing a role in age-related impairments. PMID- 21549728 TI - Structure of motivation using food demand in mice. AB - Most animals have evolved to be foragers for food. We discriminate two types of foraging, the cost to locate or obtain access to the food, and the unit cost to consume the food once it is nearby. Using closed economy studies in normal weight and genetically obese mice, we have examined the effect of either access and/or unit cost on food demand and meal patterns. We also have included wheel running either as a voluntary activity or as an access cost. Our results showed that the demand functions differ between normal, exercising, and genetically obese mice, and that changes in intake normally occur via changes in the size of individual feeding bouts or meals. In contrast, changes in access cost have only a small effect on food demand but have large effects on the pattern of intake--on meal size and the number of meals taken. Thus, although food intake is sensitive to effort, the type of effort and the mode in which it is applied is critically important. These data are discussed in terms of potential economic strategies that could address the human obesity epidemic, for example by maximally targeting meal size and/or snacking behavior. PMID- 21549727 TI - Dopamine and learned food preferences. AB - An early study performed in Bart Hoebel's laboratory suggested that dopamine (DA) signaling in the nucleus accumbens was involved in learned flavor preferences produced by post-oral nutritive feedback. This paper summarizes our studies investigating the role of DA in flavor preference conditioning using selective DA receptor antagonists. Food-restricted rats were trained to prefer a flavored saccharin solution (CS+) paired with intragastric (IG) sugar infusions over a flavored saccharin solution (CS-) paired with water infusions. Systemic injections of a D1-like receptor antagonist (SCH23390), but not a D2-like receptor antagonist (raclopride) during training blocked flavor preference learning. Neither drug prevented the expression of an already learned preference except at high doses that greatly suppressed total intakes. Central sites of action were examined by local microinjections of SCH23390 (12 nmol) during flavor training or testing. Drug infusions in the nucleus accumbens, amygdala, medial prefrontal cortex, or lateral hypothalamus during training blocked or attenuated CS+ flavor conditioning by IG glucose infusions. The same drug dose did not suppress the expression of a learned CS+ preference. The findings suggest that DA signaling within different components of a distributed brain network is involved in sugar-based flavor preferences. A possible role of DA in conditioned increases in flavor acceptance is discussed. PMID- 21549729 TI - Obesogenic diets may differentially alter dopamine control of sucrose and fructose intake in rats. AB - Chronic overeating of obesogenic diets can lead to obesity, reduced dopamine signaling, and increased consumption of added sugars to compensate for blunted reward. However, the specific role of diet composition yet remains unknown. To study this, Sprague-Dawley male rats were fed a high-energy diet with high fat and low carbohydrate content (HFHE), a fat-sugar combination high-energy diet (FCHE), or standard chow for 24 weeks. We found that both high-energy diets produced substantial body weight gain compared to chow-fed controls. To investigate dopamine control of short (2-h) intake of palatable sucrose or fructose solutions, rats were pretreated peripherally (IP) with equimolar doses (0-600 nmol/kg) of the dopamine D1 (SCH23390) and D2 (raclopride) subtype specific receptor antagonists. The results showed an overall increase in the efficacy of D1 and D2 receptor antagonists on suppression of intake in obese rats compared to lean rats, with effects differing based on diets and test solutions. Specifically, SCH23390 potently reduced both sucrose and fructose intake in all groups; however, lower doses were more effective in HFHE rats. In contrast, raclopride was most effective at reducing fructose intake in the obese FCHE rats. Thus, it appears that obesity due to the consumption of combinations of dietary fat and sugar rather than extra calories from dietary fat alone may result in reduced D2 receptor signaling. Furthermore, such deficits seem to preferentially affect the control of fructose intake. These findings demonstrate for the first time a plausible interaction between diet composition and dopamine control of carbohydrate intake in diet-induced obese rats. It also provides additional evidence that sucrose and fructose intake is regulated differentially by the dopamine system. PMID- 21549730 TI - Learning and the motivation to eat: forebrain circuitry. AB - Appetite and eating are not only controlled by energy needs, but also by extrinsic factors that are not directly related to energy balance. Environmental signals that acquire motivational properties through associative learning-learned cues-can override homeostatic signals and stimulate eating in sated states, or inhibit eating in states of hunger. Such influences are important, as environmental factors are believed to contribute to the increased susceptibility to overeating and the rise in obesity in the developed world. Similarly, environmental and social factors contribute to the onset and maintenance of anorexia nervosa and other eating disorders through interactions with the individual genetic background. Nevertheless, how learning enables environmental signals to control feeding, and the underlying brain mechanisms are poorly understood. We developed two rodent models to study how learned cues are integrated with homeostatic signals within functional forebrain networks, and how these networks are modulated by experience. In one model, a cue previously paired with food when an animal was hungry induces eating in sated rats. In the other model, food-deprived rats inhibit feeding when presented with a cue that signals danger, a tone previously paired with footshocks. Here evidence will be reviewed that the forebrain network formed by the amygdala, lateral hypothalamus and medial prefrontal cortex mediates cue-driven feeding, while a parallel amygdalar circuitry mediates suppression of eating by the fear cue. Findings from the animal models may be relevant for understanding aspects of human appetite and eating, and maladaptive mechanisms that could lead to overeating and anorexia. PMID- 21549733 TI - Feeding behavior as seen through the prism of brain microdialysis. AB - The knowledge of feeding behavior mechanisms gained through brain microdialysis is reviewed. Most of the chemical changes so far reported concern to the limbic system in rodents. A picture showing increases and decreases of extracellular neurotransmitters correlating to different aspects of feeding behavior is gradually emerging. Depending on the region, the same neurotransmitter may signal opposite aspects of feeding. Dopamine (DA) in the nucleus accumbens (NAC) correlates with food reward, stimulus saliency, and goal directed hyperlocomotion but in the ventromedial hypothalamus DA correlates with satiety and hypolocomotion. The findings accumulated in the last 25 years suggest that the control of a particular function relies on the interaction of several neurotransmitters rather than on a single neurotransmitter. The poor sensitivity of most analytical techniques hinders time and spatial resolution of microdialysis. Therefore, neurochemical correlates of short lasting behaviors are hard to figure out. As new and more sensitive analytical techniques are applied, new neurochemical correlates of feeding show up. Sometimes the proper analytical techniques are simply not available. As a consequence, critical signals such as neuropeptides are not yet completely placed in the puzzle. Despite such limitations, brain microdialysis has yielded a great deal of knowledge on the neurochemical basis of feeding. PMID- 21549731 TI - Similarities in hypothalamic and mesocorticolimbic circuits regulating the overconsumption of food and alcohol. AB - Historically, studies of food intake regulation started with the hypothalamus and gradually expanded to mesocorticolimbic regions, while studies of drug use began with mesocorticolimbic regions and now include the hypothalamus. As research on ingestive behavior has progressed, it has uncovered more and more similarities between the regulation of palatable food and drug intake. It has also identified specific neurochemicals involved in palatable food and drug intake. Hypothalamic orexigenic neurochemicals specifically involved in controlling fat ingestion, including galanin, enkephalin, orexin and melanin-concentrating hormone, show positive feedback with this macronutrient, with these peptides both increasing fat intake and being further stimulated by its intake. This positive relationship offers some explanation for why foods high in fat are so often overconsumed. Research in Bart Hoebel's laboratory in conjunction with our own has shown that consumption of ethanol, a drug of abuse that also contains calories, is similarly driven by these neurochemical systems involved in fat intake, consistent with evidence closely relating fat and ethanol consumption. Both fat and ethanol intake are also regulated by dopamine and acetylcholine acting in mesocorticolimbic nuclei. This close relationship of fat and ethanol is likely driven in part by circulating lipids, which are increased by fat and ethanol intake, known to increase expression and levels of the neurochemicals, and found to promote further intake of fat and ethanol. Compellingly, recent studies suggest that these systems may already be dysregulated in animals prone to consuming excess fat or ethanol, even before they have ever been exposed to these substances. Further understanding of these systems involved in consummatory behavior will allow researchers to develop effective therapies for the treatment of overeating as well as drug abuse. PMID- 21549734 TI - Conditioned taste aversion from neostigmine or methyl-naloxonium in the nucleus accumbens. AB - An opioid antagonist injected in the nucleus accumbens of a morphine-dependent rat will lower extracellular dopamine and release acetylcholine (ACh), as also seen in opiate withdrawal. It was hypothesized that raising extracellular ACh experimentally would be aversive as reflected by the induction of a conditioned taste aversion. Rats were implanted with cannulas aimed above the nucleus accumbens (NAc) for injection of the opiate antagonist methyl-naloxonium in morphine-dependent animals or neostigmine to increase ACh in drug naive animals. Experiment 1 in addicted rats showed that local morphine withdrawal by local injection of methyl-naloxonium paired with the taste of saccharin induces a conditioned taste aversion. Experiment 2 in non-addicted rats demonstrated the same learned aversion after local administration of the cholinergic agonist neostigmine in the NAc. These results suggest that ACh released in the NAc during opiate withdrawal contributes to the dysphoric, aversive state characteristic of withdrawal. This accumbens system is implicated in the mechanism for generating the memory of an aversive event that is expressed as learned taste aversion. PMID- 21549735 TI - The winner and loser effect, serotonin transporter genotype, and the display of offensive aggression. AB - Aggressive behaviour results from a complex interplay between genetic and environmental factors. Key modulators of aggression include the serotonergic system on the molecular level and experience in prior aggressive contests as an environmental factor. The aim of this study was to elucidate the effects of fighting experience on the display of offensive aggressive behaviour in adult male mice varying in serotonin transporter (5-HTT) genotype. 5-HTT +/+, 5-HTT +/- and 5-HTT -/- mice were given either a winning or a losing experience on each of three consecutive days and were subsequently observed for their offensive aggressive behaviour as residents against a docile intruder from the C3H strain in a resident-intruder paradigm. The main findings were: There was no significant difference between the amount of offensive aggressive behaviour displayed by the genotypes. Winners showed more engagement with the intruder, attacked him faster and exhibited overall higher aggression scores than losers. There was no significant genotype * social experience interaction: winning and losing had a similar effect on offensive aggressive behaviour in all three 5-HTT genotypes. We conclude that social experience in terms of having been a winner or having been a loser rather than the 5-HTT genotype determines the behaviour towards a docile intruder. PMID- 21549732 TI - The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to opto-genetics. AB - As one of the evolutionary oldest parts of the brain, the diencephalon evolved to harmonize changing environmental conditions with the internal state for survival of the individual and the species. The pioneering work of physiologists and psychologists around the middle of the last century clearly demonstrated that the hypothalamus is crucial for the display of motivated behaviors, culminating in the discovery of electrical self-stimulation behavior and providing the first neurological hint accounting for the concepts of reinforcement and reward. Here we review recent progress in understanding the role of the lateral hypothalamic area in the control of ingestive behavior and the regulation of energy balance. With its vast array of interoceptive and exteroceptive afferent inputs and its equally rich efferent connectivity, the lateral hypothalamic area is in an ideal position to integrate large amounts of information and orchestrate adaptive responses. Most important for energy homeostasis, it receives metabolic state information through both neural and humoral routes and can affect energy assimilation and energy expenditure through direct access to behavioral, autonomic, and endocrine effector pathways. The complex interplays of classical and peptide neurotransmitters such as orexin carrying out these integrative functions are just beginning to be understood. Exciting new techniques allowing selective stimulation or inhibition of specific neuronal phenotypes will greatly facilitate the functional mapping of both input and output pathways. PMID- 21549736 TI - Poly (lactide-co-glycolide) acid nanoencapsulation of a synthetic coumarin: cytotoxicity and bio-distribution in mice, in cancer cell line and interaction with calf thymus DNA as target. AB - Several naturally occurring coumarin compounds, including scopoletin (7 hydroxy-6 methoxycoumarin), of plant origin have been reported to have anti-cancer potentials. A related but chemically synthesized coumarin, 4-methyl-7-hydroxy coumarin (SC), was also shown to have similar anti-cancer potentials. In the present study, to test if nano-encapsulated SC could be a more potent anti-cancer agent, we encapsulated SC with poly lactide-co-glycolide acid (PLGA) nanoparticles (Nano Coumarin; NC) and tested its potentials with a variety of protocols. NC demonstrated greater efficiency of drug uptake and showed anti cancer potentials in melanoma cell line A375, as revealed from scanning electronic and atomic force microscopies. To test its possible interaction with target DNA, the combined data of circular dichroism spectra (CD) and melting temperature profile (T(m)) of calf thymus DNA treated with NC were analyzed. Results indicated a concentration dependent interaction of NC with calf thymus DNA, bringing in effective change in structure and conformation, and forming a new complex that increased its stability. Particle size and morphology of NC determined through polydispersity index and zeta potential using dynamic light scattering qualified NC to be a more potent anti-cancer agent than SC. Further, SC and NC showed negligible cytotoxic effects on normal skin cells and peripheral blood mononuclear cells of mice. Distribution assay of PLGA nanoparticles in different tissues like brain, heart, kidneys, liver, lungs, and spleen in mice revealed the presence of nanoparticles in different tissues including brain, indicating that the particles could cross the blood brain barrier, significant information for drug design. PMID- 21549737 TI - Tityus serrulatus venom and toxins Ts1, Ts2 and Ts6 induce macrophage activation and production of immune mediators. AB - Scorpion envenomation induces a systemic immune response, and neurotoxins of venom act on specific ion channels, modulating neurotransmitter release or activity. However, little is known about the immunomodulatory effects of crude venom from scorpion Tityus serrulatus (TsV) or its toxins (Ts1, Ts2 and Ts6) in combination with lipopolysaccharide (LPS). To investigate the immunomodulatory effects of TsV and its toxins (Ts1, Ts2 and Ts6), J774.1 cells were stimulated with different concentrations (25, 50 and 100 MUg/mL) of venom or toxins pre stimulated or not with LPS (0.5 MUg/mL). Macrophage cytotoxicity was assessed, and nitric oxide (NO) and cytokine production were analyzed utilizing the culture supernatants. TsV and its toxins did not produce cytotoxic effects. Depending on the concentrations used, TsV, Ts1 and Ts6 stimulated the production of NO, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in J774.1 cells, which were enhanced under LPS co-stimulation. However, LPS + Ts2 inhibited NO, IL-6 and TNF-alpha production, and Ts2 alone stimulated the production of IL-10, suggesting an anti-inflammatory activity for this toxin. Our findings are important for the basic understanding of the mechanisms involved in macrophage activation following envenomation; additionally, these findings may contribute to the discovery of new therapeutic compounds to treat immune-mediated diseases. PMID- 21549738 TI - An alternative method for purifying and detoxifying diphtheria toxin. AB - Infections caused by Corynebacterium diphtheriae frequently induce situations in which very small doses of antigens injected intradermally can cause strong inflammatory reactions. This bacterium secretes the diphtheria toxin (DT), a virulence factor that can be lethal to the human organism at doses below 0.1 MUg/kg of body weight. The present work proposes alternative methods of DT purification using affinity chromatography and of DT detoxification through conjugating with the polymer methoxypolyethylene glycol activated (mPEG). Tests were performed to evaluate: the formation of edemas and the presence of dermonecrotic activity, in vitro cytotoxicity to Vero cells, the neutralizing activity of serum from guinea pigs immunized with the diphtheria toxoid inactivated with mPEG, and the immunogenic activity of the purified and modified toxin. The results indicated that purification with Blue Sepharose was an efficient method, yielding antigen purity equivalent to 2600 Lf/mg of protein nitrogen. The modification of the Purified Toxin with mPEG did not result in the formation of edema or necrosis although it was immunogenic and stimulated the formation of antibodies that could neutralize the Purified Toxin. The toxoid obtained from the purified toxin maintained its immunogenic characteristics, inducing antibodies with neutralizing activity; edema and necrosis were still observed, however. PMID- 21549740 TI - Grouping by Regularity and the perception of illumination. AB - The purpose of this work is to describe how the visual system groups surfaces of unequal lightness under complex patterns of illumination. We propose that the Gestalt principle of Grouping by Regularity explains this process better than the more often cited principle of Grouping by Similarity. In our first experiment we demonstrate that in a perceptual organization task, pitting proximity against illumination gradients, discounting the illuminant was contingent upon the periodicity of the illuminant. Traditional theories of lightness constancy and discounting the illuminant (Rock, Nijhawan, Palmer, & Tudor, 1992) cannot account for such effects. Three more experiments show that grouping is affected more by local luminance ratios than constant reflectance ratios. We conclude from these findings that Grouping by Regularity is a powerful grouping principle that operates pre-constancy. PMID- 21549739 TI - Chemical and biological characterization of four new linear cationic alpha helical peptides from the venoms of two solitary eumenine wasps. AB - Four novel peptides were isolated from the venoms of the solitary eumenine wasps Eumenes rubrofemoratus and Eumenes fraterculus. Their sequences were determined by MALDI-TOF/TOF (matrix assisted laser desorption/ionization time-of-flight mass spectrometry) analysis, Edman degradation and solid-phase synthesis. Two of them, eumenitin-R (LNLKGLIKKVASLLN) and eumenitin-F (LNLKGLFKKVASLLT), are highly homologous to eumenitin, an antimicrobial peptide from a solitary eumenine wasp, whereas the other two, EMP-ER (FDIMGLIKKVAGAL-NH(2)) and EMP-EF (FDVMGIIKKIAGAL NH(2)), are similar to eumenine mastoparan-AF (EMP-AF), a mast cell degranulating peptide from a solitary eumenine wasp. These sequences have the characteristic features of linear cationic cytolytic peptides; rich in hydrophobic and basic amino acids with no disulfide bond, and accordingly, they can be predicted to adopt an amphipathic alpha-helix secondary structure. In fact, the CD (circular dichroism) spectra of these peptides showed significant alpha-helical conformation content in the presence of TFE (trifluoroethanol), SDS (sodium dodecylsulfate) and asolectin vesicles. In the biological evaluation, all the peptides exhibited a significant broad-spectrum antimicrobial activity, and moderate mast cell degranulation and leishmanicidal activities, but showed virtually no hemolytic activity. PMID- 21549741 TI - Effects of adaptation on the temporal envelope of amplitude-modulated flickering light. AB - This study sought to investigate the way in which the temporal envelope of amplitude-modulated (AM) flickering light is processed in the visual system. To this end, we measured the effects of adaptation on a low-frequency (2 Hz) envelope of AM flickering light with a high carrier frequency (16 Hz). The results showed that sensitivity to the envelope of the AM flickering light was reduced by adaptation to the low temporal frequency, although the AM flickering light had a frequency component at the carrier frequency but not at the frequency corresponding to the envelope. These results suggest that the low-frequency temporal envelope, composed exclusively of high-frequency (first order) Fourier energy, is encoded by a low-frequency selective channel. PMID- 21549743 TI - Chromosomal aneuploidy in the aging brain. AB - Mechanisms that govern genome integrity and stability are major guarantors of viability and longevity. As people age, memory and the ability to carry out tasks often decline and their risk for neurodegenerative diseases increases. The biological mechanisms underlying this age-related neuronal decline are not well understood. Genome instability has been implicated in neurodegenerative processes in aging and disease. Aneuploidy, a chromosome content that deviates from a diploid genome, is a recognized form of genomic instability. Here, we will review chromosomal aneuploidy in the aging brain, its possible causes, its consequences for cellular homeostasis and its possible link to functional decline and neuropathies. PMID- 21549744 TI - Multiple suppression pathways of canonical Wnt signalling control thymic epithelial senescence. AB - Members of the Wnt family of secreted glyco-lipo-proteins affect intrathymic T cell development and are abundantly secreted by thymic epithelial cells (TECs) that create the specific microenvironment for thymocytes to develop into mature T cells. During ageing, Wnt expression declines allowing adipoid involution of the thymic epithelium leading to reduced naive T-cell output. The protein kinase C (PKC) family of serine-threonine kinases is involved in numerous intracellular biochemical processes, including Wnt signal transduction. In the present study, PKCdelta expression is shown to increase with age and to co-localise with Wnt receptors Frizzled (Fz)-4 and -6. It is also demonstrated that connective tissue growth factor (CTGF) is a Wnt-4 target gene and is potentially involved in a negative feed-back loop of Wnt signal regulation. Down-regulation of Wnt-4 expression and activation of multiple repressor pathways suppressing beta-catenin dependent signalling in TECs contribute to the initiation of thymic senescence. PMID- 21549745 TI - Lymphangiogenesis in post-natal tissue remodeling: lymphatic endothelial cell connection with its environment. AB - The main physiological function of the lymphatic vasculature is to maintain tissue fluid homeostasis. Lymphangiogenesis or de novo lymphatic formation is closely associated with tissue inflammation in adults (i.e. wound healing, allograft rejection, tumor metastasis). Until recently, research on lymphangiogenesis focused mainly on growth factor/growth factor-receptor pathways governing this process. One of the lymphatic vessel features is the incomplete or absence of basement membrane. This close association of endothelial cells with the underlying interstitial matrix suggests that cell-matrix interactions play an important role in lymphangiogenesis and lymphatic functions. However, the exploration of interaction between extracellular matrix (ECM) components and lymphatic endothelial cells is in its infancy. Herein, we describe ECM-cell and cell-cell interactions on lymphatic system function and their modification occurring in pathologies including cancer metastasis. PMID- 21549746 TI - Fermentation effects of oligosaccharides of Radix Ophiopogonis on alloxan-induced diabetes in mice. AB - In this study, oligosaccharides extracted from Ophiopogon japonicus vinegar (OOV) by alcoholic and acetic acid fermentation with water extracts from Radix Ophiopogon and oligosaccharides extracted from Radix Ophiopogonis (OOJ) were investigated. Characterization of the extracts indicated that OOV are proteoglycans, whereas OOJ are not. Moreover, compared with OOJ, monosaccharide compositions of OOV only include fructose and galactose and not glucose. MALDI TOF-mass spectrometric results showed that the molecular weight of OOV was smaller after fermentation. Changes in the characteristics of OOV would inevitably lead to changes in its hypoglycemic properties. The OOV inhibition activity against alpha-glucosidase was stronger than that of OOJ. The inhibition activity became stronger with higher dosages of OOV. The hypoglycemic effect of OOV on alloxan-induced diabetic mice was stronger than that of OOJ. More important, the ability of OOV to reduce damage on islets in diabetic mice was stronger than that of OOJ. Overall, alcoholic and acetic acid fermentation improved the hypoglycemic activity of OOJ. PMID- 21549748 TI - Optimization of ultrasonic circulating extraction of polysaccharides from Asparagus officinalis using response surface methodology. AB - Polysaccharides were extracted from Asparagus officinalis. A novel ultrasonic circulating extraction (UCE) technology was applied for the polysaccharide extraction. Three-factor-three-level Box-Behnken design was employed to optimize ultrasonic power, extraction time and the liquid-solid ratio to obtain a high polysaccharide yield. The optimal extraction conditions were as follows: ultrasonic power was 600 W, extraction time was 46 min, the liquid-solid ratio was 35 mL/g. Under these conditions, the experimental yield of polysaccharides was 3.134%, which was agreed closely to the predicted value. The average molecular weight of A. officinalis polysaccharide was about 6.18*10(4) Da. The polysaccharides were composed of glucose, fucose, arabinose, galactose and rhamnose in a ratio of 2.18:1.86:1.50:0.98:1.53. Compared with hot water extraction (HWE), UCE showed time-saving, higher yield and no influence on the structure of asparagus polysaccharides. The results indicated that ultrasonic circulating extraction technology could be an effective and advisable technique for the large scale production of plant polysaccharides. PMID- 21549747 TI - Preparation, characterization and antimicrobial activity of a bio-composite scaffold containing chitosan/nano-hydroxyapatite/nano-silver for bone tissue engineering. AB - In this study, a bio-composite scaffold containing chitosan/nano hydroxyapatite/nano-silver particles (CS/nHAp/nAg) was developed by freeze drying technique, followed by introduction of silver ions in controlled amount through reduction phenomenon by functional groups of chitosan. The scaffolds were characterized using SEM, FT-IR, XRD, swelling, and biodegradation studies. The testing of the prepared scaffolds with Gram-positive and Gram-negative bacterial strains showed antibacterial activity. The scaffold materials were also found to be non-toxic to rat osteoprogenitor cells and human osteosarcoma cell line. Thus, these results suggested that CS/nHAp/nAg bio-composite scaffolds have the potential in controlling implant associated bacterial infection during reconstructive surgery of bone. PMID- 21549749 TI - Non-mulberry silk sericin/poly (vinyl alcohol) hydrogel matrices for potential biotechnological applications. AB - This study reports a novel biopolymeric matrix fabricated by chemically cross linking poly (vinyl alcohol) with silk sericin protein obtained from cocoons of the tropical tasar silkworm Antheraea mylitta. Glutaraldehyde was used as a cross linking agent with hydrochloric acid acting as an initiator. The matrices were biophysically characterized and the cytocompatibility of the matrices was evaluated for their suitability as biomaterials. The surface morphology was assessed using atomic force microscopy while the changes taking place after cross linking were confirmed by Fourier transform infrared spectroscopy. The enhanced thermal stability of the constructs was assessed by thermogravimetric and differential scanning calorimetry. Fourier transform infrared spectroscopy analysis showed that sericin was chemically cross-linked with poly (vinyl alcohol) using glutaraldehyde. Silk sericin protein demonstrated a favorable effect on animal cell culture by successfully improving the adhering and spreading of cells on the poorly adhering surface of poly (vinyl alcohol). Confocal microscopy revealed cell spreading and actin filament development in sericin/poly (vinyl alcohol) hydrogel matrices. These findings prove the potential of non-mulberry silk sericin/poly (vinyl alcohol) hydrogel matrices to be used as biocompatible and biopolymeric material for tissue-engineering and biotechnological applications. PMID- 21549750 TI - Expression and function of triggering receptor expressed on myeloid cells-1 (TREM 1) on canine neutrophils. AB - The dog is both a valued veterinary species and a widely used translational model for sepsis research. However, relatively little work has been performed evaluating potential biomarkers present during canine infection. Triggering receptor expressed on myeloid cells-1 (TREM-1) has shown promise as a biomarker for infection and pneumonia in humans. Here we describe, for the first time, the expression and function of the canine orthologue of TREM-1. Expression of TREM-1 on canine neutrophils is significantly up-regulated by stimulation with microbial agonists of TLR2/6, TLR1/2, and TLR4/MD2. Kinetics of TREM-1 protein up regulation are rapid, with significant increases observed within 2 hr of neutrophil activation. Functionally, canine TREM-1 synergistically enhances LPS induced production of IL-8, TNF-alpha and a canine orthologue of CXCL1. Collectively, these data suggest that TREM-1 expression in dogs, as it is in humans, is an amplifier of pro-inflammatory responses to microbial products. These results have direct application to veterinary diagnostics as well as the potential to enhance the utility of canine disease models in the assessment of potential therapeutics in the treatment of human sepsis. PMID- 21549751 TI - Development of a compact and general-purpose experimental apparatus with a touch sensitive screen for use in evaluating cognitive functions in common marmosets. AB - Common marmosets have been used extensively in biomedical research and the recent advent of techniques to generate transgenic marmosets has accelerated the use of this model. New methods that efficiently assess the degree of cognitive function in common marmosets are needed in order to establish their suitability as non human primate models of higher brain function disorders. Here, we have developed a new apparatus suitable for testing the cognitive functions of common marmosets. Utilizing a mini laptop PC with a touch-sensitive screen as the main component, the apparatus is small and lightweight and can be easily attached to the home cages. The ease of designing and testing new paradigms with the flexible software is another advantage of this system. We have tested visual discrimination and its reversal tasks using this apparatus and confirmed its efficacy. PMID- 21549742 TI - Visual attention: the past 25 years. AB - This review focuses on covert attention and how it alters early vision. I explain why attention is considered a selective process, the constructs of covert attention, spatial endogenous and exogenous attention, and feature-based attention. I explain how in the last 25 years research on attention has characterized the effects of covert attention on spatial filters and how attention influences the selection of stimuli of interest. This review includes the effects of spatial attention on discriminability and appearance in tasks mediated by contrast sensitivity and spatial resolution; the effects of feature based attention on basic visual processes, and a comparison of the effects of spatial and feature-based attention. The emphasis of this review is on psychophysical studies, but relevant electrophysiological and neuroimaging studies and models regarding how and where neuronal responses are modulated are also discussed. PMID- 21549752 TI - Unified patch clamp protocol for the characterization of Pannexin 1 channels in isolated cells and acute brain slices. AB - In the central nervous system, Pannexin 1 (Panx1) channels are implicated in a variety of physiological and pathological conditions. One of the prerequisites to enlighten the role of Panx1 is the development and standardization of reliable methods. Here, we address the applicability of voltage clamp protocols to identify Panx1 channel mediated currents in neurons of acutely dissected brain slices. We improved an established protocol and report on a modified paradigm that robustly evokes Panx1 channel currents. Crucial advances are the use of physiologic ion gradient conditions and a preconditioning step of depolarizing membrane potential ramps of long duration. This new paradigm provides significant impact on membrane current generation at hypo- and depolarized holding potential steps post voltage ramp preconditioning in heterologous expression systems and primary hippocampal CA1 neurons of mouse brain slices in vitro. Finally, we demonstrate that under these conditions the analysis of tail currents elicited by repolarization of the cells from preconditioning holding potential depolarization permits an independent method to isolate Panx1 mediated channel activity. In summary, this study provides a comprehensive methodological improvement in the biophysical analysis of Panx1 channels with a particular focus on investigations under physiological conditions in complex tissues. PMID- 21549753 TI - An evaluation of the relationships between catheter design and tissue mechanics in achieving high-flow convection-enhanced delivery. AB - Convection-enhanced delivery (CED) is a rational technique for the direct intracranial administration of a range of therapeutic agents. CED critically depends on the use of a catheter with a narrow outer diameter and low infusion rate. Failure to adhere to these requirements can lead to reflux of infusate along the catheter-brain interface and damage at the catheter-tip. In this study we have tested the hypothesis that the relationship between infusion parameters and infusate distribution, including reflux, is critically dependent on the occurrence of tissue damage. The relationship between catheter outer diameter and the extent of blood-brain barrier disruption and subsequent tissue oedema was evaluated following catheter insertion into the striatum of rats. Three patterns of infusate distribution were observed: (1) Reflux restricted to the traumatised tissue around the catheter site. (2) Distribution in the white matter beyond the area of tissue trauma. (3) Widespread distribution in the striatum, which occurred only with catheters of an outer diameter of 0.35 mm or less. Extensive tissue damage occurred with a 0.2mm outer diameter catheter. This damage was completely prevented by rounding the catheter-tip. Infusions into pig brain demonstrated that high-flow CED could be performed in a large brain in both grey and white matter using a 0.2mm outer diameter catheter, with minimal reflux or MRI-evidence of tissue damage. This study demonstrates that by minimising tissue damage from catheter design and insertion, high flow-rate CED can be utilised to distribute therapeutic agents over large volumes of brain within clinically practical timescales. PMID- 21549754 TI - A rapid agonist application system for fast activation of ligand-gated ion channels. AB - The synaptic delay between neurotransmitter release across the synaptic cleft and activation of neurotransmitter gated ion channels is less than a ms. Nicotinic acetylcholine receptors (nAChRs), like many other classes of ligand-gated ion channels, are comprised of different protein subunits forming a variety of receptors with different activation and desensitization kinetics and pharmacological sensitivities. To measure and fully characterize ligand-gated ion channel currents accurately, one must apply agonists in a fraction of a ms and repeatedly at various concentrations without any prior desensitization of the receptors. In this paper, we describe an economical, easy to assemble and operate rapid drug application system. The drug applicator system consists of a parallel array of three pinch valves, which allow either agonist or wash solution into a theta tube. Solution exchanges of 0.16 ms can be achieved. In transfected cells, ACh elicited alpha4beta2 nicotinic currents with mean rise times of 55+/-13 ms. We recorded alpha7 nAChRs, which desensitize very rapidly, and obtained very fast rise times of 19+/-2 ms. With this novel drug applicator, agonists can be applied repeatedly without any loss of current. Hence, complete dose-response relations can be obtained for even alpha7 nAChRs, which are very sensitive to desensitization caused by agonist exposure on a ms time scale. The drug application system can also be extended to the study of ligand-gated ion channels in brain slices. The theta tube valve-driven drug applicator system can be applied to study other ligand-gated ion channels including glutamate and GABA receptors. PMID- 21549755 TI - Knee joint angular velocities and accelerations during the patellar tendon jerk. AB - Tendon jerk (TJ) is one of the most commonly used clinical tests in differential diagnosis of human motor disorders. There remains some ambiguity in the physiological interpretation of the test, especially with respect to its association to the functional status of patients. The TJ test inputs a non physiological stimuli, but it is unclear to what degree the kinematics generated during the TJ test exceed the ranges that muscles encounter in activities of daily living (ADLs). The aim of our pilot study was to determine the range of angular knee kinematics (angular velocities and accelerations) corresponding to the muscle stretch elicited by TJ. We measured the longitudinal kinematics (velocities and accelerations) of the rectus femoris muscle in vivo using vector tissue Doppler imaging, an ultrasound-based method, and measured the angular kinematics of the knee in response to tendon taps with an electrogoniometer. We concluded that muscle longitudinal elongation accelerations elicited during the standard TJ test exceed angular accelerations (104.40-4534.20 rads-2) encountered in typical ADLs, but the velocities (0.82-6.21 rads-1) elicited do not exceed those elicited by ADLs. PMID- 21549756 TI - Quantification of dynamic EMG patterns during gait in children with cerebral palsy. AB - Our goal was to simplify the representation and interpretation of surface electromyographic (EMG) activity during gait to develop a clinical method for evaluating gait disabilities in children with cerebral palsy (CP). EMG was recorded from four muscles of a lower extremity. Gait cycles were tracked from one force-sensing resistor signal that was recorded synchronously with EMG. The method is based on the comparison of a patient's dynamic EMG envelope shapes and the normative gait-related patterns (norms). Developed norms were based on EMG data obtained in 10 healthy children. Due to newly introduced techniques for time and amplitude normalization, norms were developed regardless of differences in subject age, gender, basic gait parameters and the EMG measurement process. The proposed gait metric quantifies the similarity between a patient's gait-related patterns and norms by a single global value suitable for gait analysis in general, including a detailed analysis using the 10 partial values. The gait metric was experimentally validated with a control group of healthy children and a group of children with CP with different degrees of motor deficits. Gait metric values obtained in children from the control group are high for all muscles, which means that gait-related patterns are close to norms, whereas in children with CP the higher the degree of motor deficit, the lower the gait metric values. The method could be a very useful clinical tool for the recognition and tracking of motor disorders of the lower extremities in children with CP as well as many other neuromotor pathologies. PMID- 21549758 TI - Mixed influenza A and B infections complicate the detection of influenza viruses with altered sensitivities to neuraminidase inhibitors. AB - Previously, three influenza A(H3N2) isolates with a reduced susceptibility to the neuraminidase inhibitors (NAIs) zanamivir and oseltamivir were identified during screening by the Neuraminidase Inhibitor Susceptibility Network (NISN). The isolates were from untreated patients from the first three years post licensure of the NAIs. We plaque-purified progeny from each of these isolates and determined the NAI sensitivity of each plaqued population. Sequencing and serology for each population revealed that the isolates contained a mix of wild type influenza A(H3N2) and influenza B. The NAI susceptibility reductions that had originally been reported were a consequence of influenza B neuraminidases that have lower relative NAI sensitivities, rather than being due to resistant influenza A(H3N2) viruses. Our study highlights the need to check for mixed influenza infections when isolates with potentially lower sensitivities to NAIs are identified. PMID- 21549757 TI - Biological functions of Mycobacterium tuberculosis-specific CD4+T cells were impaired by tuberculosis pleural fluid. AB - The local milieu at the site of Mycobacterium tuberculosis infection that modulates T-cell functions is the main battleground for the host to build counter M. tuberculosis immune responses. CD4+T cells are enriched predominantly in tuberculosis pleurisy and their roles are of considerable importance, but their nature and functional profiles linked with local condition remain elusive. Here we evaluated the functions of M. tuberculosis-specific CD4+T cells from the major three profiles: cytokines production, cell activation and division. Results showed that pleural fluid (PF) from tuberculosis patients in a dose dependent manner inhibited the production of IFN-gamma, IL-2 and TNF-alpha by M. tuberculosis-specific peptides or BCG activated CD4+T cells from pleural fluid mononuclear cells (PFMCs). Surface staining for activation molecules indicated that PF could also blunt cell activation process. CFSE labeling showed that antigen-specific CD4+T cell division ceased following co-incubation with PF. Pre- or post-treatment with PF could disturb subsequent cell activities. The strong inhibitory effect mediated by PF on CD4+T cells was functional predominance. Moreover, application of inhibitors of IDO, adenosine, neutralizing Abs to IL-10 and TGF-beta could partially reverse IFN-gamma production. Our current research provided novel information that the functions of antigen-specific CD4+T cells coincubated with PF were apparently impaired, which were distinct from cells that cultured in fresh culture medium. We concluded that CD4+T cell mediated antigen specific cellular immune response that occurred locally might be impaired by PF. PMID- 21549759 TI - Omission of the habituation procedure in the acquisition of a working memory task - evidence from Balb/c, C57/BL6J, and CD-1 mice. AB - Training animals in spatial mazes have always been preceded by prior habituation to the test apparatus and testing conditions with the main goal to reduce fear and anxiety from exposure to the unfamiliar maze environment. This approach makes assumptions about the baseline level of emotionality in animals without actual objective measurements. It also ignores that genetic factors and experimental manipulations can reduce or prolong fear and anxiety from novelty, hence affecting the acquisition of a memory task. In the present study, C57, CD-1 and Balb/c mice were introduced to a working memory task in a radial-arm maze without habituation. Fear-induced anxiety from exposure to the novelty in this maze is demonstrated by a very low number of arm entries. Animals have to climb onto a bridge in order to reach an arm of the maze. In the first session block, Bab/c mice made very few arm entries and made more arm repeats than CD-1 and C57 mice, and CD-1 made few arm entries and made more arm repeats than C57/BL6J mice. In the second session block, all three strains of mice did make 8 arm entries. Balb/c mice seem to perform better than C57 and CD-1 mice as shown by a low number of arm repeats in the second session block, a high number of correct choices before first errors in the third session block, and low number of errors and sessions to criterion. In the present case, a high baseline level of emotionality did not prevent Balb/c mice to perform better than C57 and CD-1 mice. PMID- 21549760 TI - Simultaneous multisite recordings of neural ensemble responses in the motor cortex of behaving rats to peripheral noxious heat and chemical stimuli. AB - Chronic motor cortex (MCx) stimulation (MCS) is an effective approach for patients with chronic, intractable neuropathic pain. However, the underlying neural mechanisms are less known. Combining an in vivo simultaneous multisite recording technique with a video-based behavioral tracker, simultaneous neuronal ensemble activities of the MCx and behavioral responses to noxious heat stimuli applied to bilateral hindpaw pads under naive and inflammatory pain state were studied in freely behaving rats receiving prior implantation of microwire multielectrode array (2 * 4). Totally, 81 active units were sorted and separated from 40 microwire electrodes pre-implanted in the MCx of 5 rats. Under naive state, 41% (33/81) units were responsive to contralateral, while 27% (22/81) were responsive to ipsilateral heat stimuli. However, the proportion of heat responsive units under inflammatory pain state induced by subcutaneous bee venom (BV) injection was significantly increased when compared with saline control (BV vs. saline: 60% vs. 48% for contralateral and 51% vs. 37% for ipsilateral, P < 0.05, n = 81 units) as a consequence of recruitment of some previously heat non responsive to heat sensitive units. Moreover, under the BV-inflamed condition, the discharge rate of the MCx neurons was significantly increased. The time course of increased spontaneous neuronal ensemble activities (n = 81) was in parallel with that of pain-related behaviors following BV injection. It is concluded that there are pain-related neurons in the MCx that can be functionally changed by peripheral inflammatory pain condition. PMID- 21549761 TI - Accurate performance of a rat model of schizophrenia in the water maze depends on visual cue availability and stability: a distortion in cognitive mapping abilities? AB - Rats were treated postnatally (PND 5-16) with BSO (l-buthionine-(S,R) sulfoximine) in an animal model of schizophrenia based on transient glutathione deficit. The BSO treated rats were impaired in patrolling a maze or a homing table when adult, yet demonstrated preserved escape learning, place discrimination and reversal in a water maze task [37]. In the present work, BSO rats' performance in the water maze was assessed in conditions controlling for the available visual cues. First, in a completely curtained environment with two salient controlled cues, BSO rats showed little accuracy compared to control rats. Secondly, pre-trained BSO rats were impaired in reaching the familiar spatial position when curtains partially occluded different portions of the room environment in successive sessions. The apparently preserved place learning in a classical water maze task thus appears to require the stability and the richness of visual landmarks from the surrounding environment. In other words, the accuracy of BSO rats in place and reversal learning is impaired in a minimal cue condition or when the visual panorama changes between trials. However, if the panorama remains rich and stable between trials, BSO rats are equally efficient in reaching a familiar position or in learning a new one. This suggests that the BSO accurate performance in the water maze does not satisfy all the criteria for a cognitive map based navigation on the integration of polymodal cues. It supports the general hypothesis of a binding deficit in BSO rats. PMID- 21549762 TI - A novel high-throughput imaging system for automated analyses of avoidance behavior in zebrafish larvae. AB - Early brain development can be influenced by numerous genetic and environmental factors, with long-lasting effects on brain function and behavior. The identification of these factors is facilitated by recent innovations in high throughput screening. However, large-scale screening in whole organisms remains challenging, in particular when studying changes in brain function or behavior in vertebrate model systems. In this study, we present a novel imaging system for high-throughput analyses of behavior in zebrafish larvae. The three-camera system can image 12 multiwell plates simultaneously and is unique in its ability to provide local visual stimuli in the wells of a multiwell plate. The acquired images are converted into a series of coordinates, which characterize the location and orientation of the larvae. The developed imaging techniques were tested by measuring avoidance behaviors in seven-day-old zebrafish larvae. The system effectively quantified larval avoidance and revealed an increased edge preference in response to a blue or red 'bouncing ball' stimulus. Larvae also avoid a bouncing ball stimulus when it is counter-balanced with a stationary ball, but do not avoid blinking balls counter-balanced with a stationary ball. These results indicate that the seven-day-old larvae respond specifically to movement, rather than color, size, or local changes in light intensity. The imaging system and assays for measuring avoidance behavior may be used to screen for genetic and environmental factors that cause developmental brain disorders and for novel drugs that could prevent or treat these disorders. PMID- 21549763 TI - Individual differences in novelty-seeking predict differential responses to chronic antidepressant treatment through sex- and phenotype-dependent neurochemical signatures. AB - Women experience major depression at roughly twice the rate of men. Inconclusive clinical evidences assist the notion that responsiveness to antidepressant pharmacotherapy is sexually dimorphic with the two sexes presenting differential responses when treated with tricyclic antidepressants (TCAs). Notably, responsiveness to antidepressive agents presents marked inter-individual variability, the biological basis of which remains elusive. Herein, we sought to investigate putative sex differences to chronic antidepressant treatment with the TCA clomipramine in rats selected on the basis of their reactions to novelty. Our data revealed that high novelty-seeker (HR) male rats were more responsive to clomipramine treatment as far as the alleviation of anxiety and nociception are concerned, compared to low novelty-seeker (LR) males and HR/LR female rats. Surprisingly, chronic clomipramine treatment attenuated depressive-like symptomatology in the forced swim test (FST) of behavioral despair in both sexes albeit in the opposite novelty-seeking phenotypes (i.e. in male HR and female LR). Interestingly in male HR rats, clomipramine treatment diminished serotonergic neurochemical responses post-FST exposure in all limbic brain regions examined, while these were boosted in their LR counterparts. Dopaminergic and glutamatergic neurochemistry also presented phenotype-related alterations. On the contrary, in females the neurochemical substrate was only modestly affected. Notably, corticosteroid responses were augmented in female but attenuated in male drug-treated rats. Overall, the current dataset lends further support that the male sex may benefit to a greater extent when treated with TCAs and reveals that individual differences are associated with qualitative and quantitative sex related behavioral and neurochemical manifestations in response to chronic antidepressant treatment. PMID- 21549764 TI - Expression of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) in the nucleus accumbens is critical for the acquisition, expression and reinstatement of morphine-induced conditioned place preference. AB - Activity-regulated cytoskeleton-associated protein (Arc), also known as activity regulated gene 3.1 (Arg3.1), is an immediate early gene whose mRNA is selectively targeted to recently activated synaptic sites, where it is translated and enriched. This unique feature suggests a role for Arc/Arg3.1 in coupling synaptic activity to protein synthesis, leading to synaptic plasticity. Although the Arc/Arg3.1 gene has been shown to be induced by a variety of abused drugs and its protein has been implicated in diverse forms of long-term memory, relatively little is known about its role in drug-induced reward memory. In this study, we investigated the potential role of Arc/Arg3.1 protein expression in reward related associative learning and memory using morphine-induced conditioned place preference (CPP) in rats. We found that (1) intraperitoneal (i.p.) injection of morphine (10mg/kg) increased Arc/Arg3.1 protein levels after 2h in the NAc core but not in the NAc shell. (2) In CPP experiments, Arc/Arg3.1 protein was increased in the NAc shell of rats following both morphine conditioning and the CPP expression test compared to rats that received the conditioning without the test or those that did not receive morphine conditioning. (3) Microinjection of Arc/Arg3.1 antisense oligodeoxynucleotide (AS) into the NAc core inhibited the acquisition, expression and reinstatement of morphine CPP; however, intra-NAc shell infusions of the AS only blocked the expression of CPP. These findings suggest that expression of the Arc/Arg3.1 protein in the NAc core is required for the acquisition, context-induced retrieval and reinstatement of morphine associated reward memory, whereas Arc/Arg3.1 protein expression in the NAc shell is only critical for the context-induced retrieval of memory. As a result, Arc/Arg3.1 may be a potential therapeutic target for the prevention of drug abuse or the relapse of drug use. PMID- 21549765 TI - Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice. AB - Endocannabinoid analogues exhibit antidepressant and anti-compulsive like effects similar to that of serotonin selective reuptake inhibitors (SSRIs) indicating a parallelism between the effects of serotonin and endocannabinoids. Therefore, the present study was designed to investigate the role of endocannabinoids in the antidepressant and anti-compulsive like effect of fluoxetine using mice model of forced swim test (FST) and marble-burying behavior (MBB). The results revealed that intracerebroventricular injections of endocannabinoid analogues, anandamide, a CB(1) agonist (AEA: 1-20 MUg/mouse); AM404, an anandamide transport inhibitor (0.1-10 MUg/mouse); and URB597, a fatty acid amide hydrolase inhibitor (0.05-10 MUg/mouse) produced antidepressant-like effect dose-dependently, whereas influenced the MBB in a biphasic manner (produced a U-shaped dose-response curve). Fluoxetine (2.5-20 mg/kg, i.p.) dose dependently decreased the immobility time as well as burying behavior. Co-administration of sub-effective dose of fluoxetine (2.5 mg/kg, i.p.) potentiated the effect of sub-effective dose of AEA (0.5 MUg/mouse, i.c.v.), AM404 (0.05 MUg/mouse, i.c.v) or URB597 (0.01 MUg/mouse, i.c.v) in both the paradigms. Interestingly, pretreatment with AM251, a CB(1) antagonist, blocked the effect of fluoxetine in FST and MBB at a dose (1 MUg/mouse, i.c.v) that per se had no effect on either parameter. Similar effects were obtained with endocannabinoid analogues in AM251 pretreated mice. However, AM251 increased the burying behavior in MBB at a highest dose tested (5 MUg/mouse). None of the treatments had any influence on locomotor activity. Thus, the study indicates an interaction between endocannabinoid and serotonergic system in regulation of depressive and compulsive-like behavior. PMID- 21549766 TI - Serotonin transporter genotype x construction stress interaction in rats. AB - A well-known example for gene x environment interactions in psychiatry is the one involving the low activity (s) allelic variant of the serotonin transporter (5 HTT) promoter polymorphism (5-HTTLPR) that in the context of stress increases risk for depression. In analogy, 5-HTT knockout rodents are highly responsive to early life, but also adult external stressors, albeit conflicting data have been obtained. In our study on emotion and cognition using homozygous 5-HTT knockout (5-HTT(-/-)) and wild-type (5-HTT(+/+)) rats we have been confronted with animal facility construction, which were associated with severe lifetime stress (noise and vibrations). To assess the impact of construction stress on well-established 5-HTT(-/-) rat phenotypes we conducted ad hoc analyses of 5-HTT(-/-) and 5 HTT(+/+) rats that grew up before and during the construction. The reproductive capacity of the parents of the experimental 5-HTT(+/-) rats was significantly decreased. Further, 5-HTT(-/-) anxiety-related phenotypes in the elevated plus maze and social interaction tests were abolished after construction noise exposure, due to increased anxiety in 5-HTT(+/+) rats and decreased anxiety in 5 HTT(-/-) rats (social interaction test only). In addition, reversal learning was improved in 5-HTT(+/+) and, to a milder extent, decreased in 5-HTT(-/-) rats. Finally, construction stress genotype-independently increased behavioural despair in the forced swim test. In conclusion, severe construction stress induces 5-HTT genotype-dependent 'for-better-and-for-worse' effects. These data importantly contribute to the understanding of 5-HTT gene x environment interactions and show the risk of losing genotype effects by construction stress. PMID- 21549767 TI - Secure attachment partners attenuate neural responses to social exclusion: an fMRI investigation. AB - Research has shown that social exclusion has devastating psychological, physiological, and behavioral consequences. However, little is known about possible ways to shield individuals from the detrimental effects of social exclusion. The present study, in which participants were excluded during a ball tossing game, examined whether (reminders of) secure attachment relationships could attenuate neurophysiological pain- and stress-related responses to social exclusion. Social exclusion was associated with activation in brain areas implicated in the regulation and experience of social distress, including areas in the lateral and medial prefrontal cortex, ventral anterior cingulate cortex, and hypothalamus. However, less activation in these areas was found to the extent that participants felt more securely attached to their attachment figure. Moreover, the psychological presence (i.e., salience) of an attachment figure attenuated hypothalamus activation during episodes of social exclusion, thereby providing insight into the neural mechanisms by which attachment relationships may help in coping with social stress. PMID- 21549768 TI - Ecology and management of whitefly-transmitted viruses of vegetable crops in Florida. AB - A variety of fresh market vegetables, including watermelon and tomato are economically important crops in Florida. Whitefly-transmitted Squash vein yellowing virus (SqVYV) was first identified in squash and watermelon in Florida in 2005 and shown to cause a severe decline of watermelon vines as crops approach harvest. Florida is most economically impacted by SqVYV, although the virus has been detected more recently in Indiana and South Carolina. The origin and evolutionary history of SqVYV, one of the few members of the genus Ipomovirus within the family Potyviridae, are not known. Sequence diversity of SqVYV isolates collected at different times, from different locations and from different plant species is being analyzed for insights into the origin of the virus. More recently, Cucurbit leaf crumple virus (CuLCrV) and Cucurbit yellow stunting disorder virus (CYSDV), also whitefly-transmitted, have been detected in watermelon in Florida. Tomato yellow leaf curl virus (TYLCV) was first detected in south Florida tomato crops in 1997. Several surveys have been conducted in the region to identify alternative hosts for these four viruses. Cucurbit weeds including Balsam-apple (Momordica charantia), creeping cucumber (Melothria pendula) and smellmelon (Cucumis melo var. dudaim) provide reservoirs for SqVYV, CuLCrV and/or CYSDV. Green bean (Phaseolus vulgaris) also can be a reservoir for CuLCrV. No wild hosts of TYLCV have been reported in Florida. The effectiveness of insecticides and silver plastic mulch to manage whiteflies and mitigate TYLCV has been demonstrated and is currently being evaluated for SqVYV, CuLCrV and CYSDV. In addition, potential sources of SqVYV resistance have been identified in greenhouse and field screening of watermelon germplasm. Further studies to refine these sources of resistance are underway. Lastly, a comprehensive map of 33,560 hectares (82,928 acres) of vegetable fields in the three counties comprising the majority of the southwest Florida vegetable production area has been developed to identify 'hot spots' and reservoir crops for viruses and whiteflies, and will be useful in evaluation of management strategies to decrease virus incidence in commercial fields. PMID- 21549769 TI - The influence of virus-induced changes in plants on aphid vectors: insights from luteovirus pathosystems. AB - Plant virus infection can alter the suitability of host plants for their aphid vectors. Most reports indicate that virus-infected plants are superior hosts for vectors compared to virus-free plants with respect to vector growth rates, fecundity and longevity. Some aphid vectors respond preferentially to virus infected plants compared to virus-free ones, while others avoid infected plants that are inferior hosts. Thus, it appears vectors can exploit changes in host plant quality associated with viral infection. Enhanced vector performance and preference for virus-infected plants might also be advantageous for viruses by promoting their spread and possibly enhancing their fitness. Our research has focused on two of the most important luteoviruses that infect wheat (Barley yellow dwarf virus), or potato (Potato leafroll virus), and their respective aphid vectors, the bird-cherry oat aphid, Rhopalosiphum padi, and the green peach aphid, Myzus persicae. The work has demonstrated that virus infection of host plants enhances the life history of vectors. Additionally, it has shown that virus infection alters the concentration and relative composition of volatile organic compounds in host plants, that apterae of each vector species settle preferentially on virus-infected plants, and that such responses are mediated by volatile organic compounds. The findings also indicate that plants respond heterogeneously to viral infection and as a result different plant parts change in attractiveness to vectors during infection and vector responses to virus infected plants are dynamic. Such dynamic responses could enhance or reduce the probability of virus acquisition by individual aphids searching among plants. Finally, our work indicates that compared to non-viruliferous aphids, viruliferous ones are less or not responsive to virus-induced host plant volatiles. Changes in vector responsiveness to plants after vectors acquire virus could impact virus epidemiology by influencing virus spread. The potential implications of these findings for virus ecology and epidemiology are discussed. PMID- 21549770 TI - Minimising losses caused by Zucchini yellow mosaic virus in vegetable cucurbit crops in tropical, sub-tropical and Mediterranean environments through cultural methods and host resistance. AB - Between 2006 and 2009, 10 field experiments were done at Kununurra, Carnarvon or Medina in Western Australia (WA) which have tropical, sub-tropical and Mediterranean climates, respectively. These experiments investigated the effectiveness of cultural control measures in limiting ZYMV spread in pumpkin, and single-gene resistance in commercial cultivars of pumpkin, zucchini and cucumber. Melon aphids (Aphis gossypii) colonised field experiments at Kununurra; migrant green peach aphids (Myzus persicae) visited but did not colonise at Carnarvon and Medina. Cultural control measures that diminished ZYMV spread in pumpkin included manipulation of planting date to avoid exposing young plants to peak aphid vector populations, deploying tall non-host barriers (millet, Pennisetum glaucum) to protect against incoming aphid vectors and planting upwind of infection sources. Clustering of ZYMV-infected pumpkin plants was greater without a 25m wide non-host barrier between the infection source and the pumpkin plants than when one was present, and downwind compared with upwind of an infection source. Host resistance gene zym was effective against ZYMV isolate Knx 1 from Kununurra in five cultivars of cucumber. In zucchini, host resistance gene Zym delayed spread of infection (partial resistance) in 2 of 14 cultivars but otherwise did not diminish final ZYMV incidence. Zucchini cultivars carrying Zym often developed severe fruit symptoms (8/14), and only the two cultivars in which spread was delayed and one that was tolerant produced sufficiently high marketable yields to be recommended when ZYMV epidemics are anticipated. In three pumpkin cultivars with Zym, this gene was effective against isolate Cvn-1 from Carnarvon under low inoculum pressure, but not against isolate Knx-1 under high inoculum pressure, although symptoms were milder and marketable yields greater in them than in cultivars without Zym. These findings allowed additional cultural control recommendations to be added to the existing Integrated Disease Management strategy for ZYMV in vegetable cucurbits in WA, but necessitated modification of its recommendations over deployment of cultivars with resistance genes. PMID- 21549771 TI - Antipredator behaviour of Myzus persicae affects transmission efficiency of Broad bean wilt virus 1. AB - Biological control has the potential to limit the population growth of arthropod vectors and consequently may be expected to reduce plant virus spread in a crop. However, reduction of vector abundance is not the only effect of biological control. Natural enemies might induce antipredator behaviour that affects feeding and dispersal of vectors, and therefore virus spread. Here we test the effect of two natural enemies on dispersal of the aphid vector Myzus persicae and transmission of Broad bean wilt virus 1 (BBWV-1), genus Fabavirus, which is non persistently transmitted by aphids. One of the predators tested, the syrphid Sphaerophoria rueppellii, is considered to induce low disturbance in aphid colonies, whereas the other, the coccinellid Adalia bipunctata, is assumed to induce high disturbance. Natural enemies enhanced aphid dispersal, but not virus transmission as compared to the control treatment without predators. However, transmission efficiency of BBWV-1 was higher in the presence of coccinellid adults than with syrphids. The behavioural observations of predators and the reactions of aphids to their presence indicate that a stronger antipredator behaviour is induced by coccinellid adults than by syrphids. The different antipredator behaviour displayed by aphids towards coccinellid adults and syrphids might explain the differences found in the rate of virus spread in their presence. PMID- 21549772 TI - Phylogenetic lineage of Tobacco leaf curl virus in Korea and estimation of recombination events implicated in their sequence variation. AB - New strains of Tobacco leaf curl virus (TbLCV) were isolated from tomato plants in four different local communities of Korea, and hence were designated TbLCV-Kr. Phylogenetic analysis of the sequences of the whole genome and of individual ORFs of these viruses indicated that they are closely related to the Tobacco leaf curl Japan virus (TbLCJV) cluster, which includes Honeysuckle yellow vein virus (HYVV), Honeysuckle yellow vein mosaic virus (HYVMV), and TbLCJV isolates. Four putative recombination events were recognized within these virus sequences, suggesting that the sequence variations observed in these viruses may be attributable to intraspecific and interspecific recombination events involving some TbLCV-Kr isolates, Papaya leaf curl virus (PaLCV), and a local isolate of Tomato yellow leaf curl virus (TYLCV). PMID- 21549773 TI - Visualization of resistance responses in Phaseolus vulgaris using reporter tagged clones of Bean common mosaic virus. AB - Reporter tagged virus clones can provide detailed information on virus-host interactions. In Phaseolus vulgaris (bean), four recessive and one dominant gene are known to control infection by strains of the potyvirus species Bean common mosaic virus (BCMV). To study the interactions between BCMV and bean genotypes with different resistance gene combinations, an infectious clone of the strain RU1 was tagged with the UidA gene encoding beta-glucuronidase (GUS). The clone was agroinoculated to bean genotypes with different combinations of the resistance genes bc-u, bc-1, bc-2, bc-3 and I. In situ histochemical GUS assays showed new details of the resistance responses, which were previously analysed by immunological methods and symptom descriptions. In some instances GUS assays suggested that resistance breaking strains appeared at single foci in uninoculated leaves. To allow recovery of resistance breaking strains for further studies, BCMV RU1 was tagged with the sequence encoding green fluorescent protein (GFP), which was visualized directly without destruction of the tissue. In this paper we present details of the construction of the infectious clone and discuss its application in studies of BCMV resistance in bean. PMID- 21549774 TI - Phylogeography and molecular epidemiology of Papaya ringspot virus. AB - Papaya ringspot virus (PRSV) is the most important virus affecting papaya and cucurbit plants in tropical and subtropical areas. PRSV isolates are divided into biotypes P and W: both the P and W types naturally infect plants in the family Cucurbitaceae, whereas the P type naturally infects papaya (Carica papaya). Understanding the origin and nature of the PRSV genetic diversity and evolution is critical for the implementation of control strategies based on cross protection and the deployment of transgenic plants that show resistance to virus isolates highly similar to the transgene. The molecular epidemiology of PRSV was evaluated by analyzing the nucleotide sequence of the capsid protein (CP) and helper component-proteinase (HC-Pro) genes of isolates from around the world, including newly characterized ones from Colombia and Venezuela, using a relaxed molecular clock-based approach and a phylogeographic study. Our results confirm previous estimates on the origin of PRSV around 400 years ago and suggest distinct dispersion events from the Indian Peninsula to the rest of Asia, via Thailand, and subsequently to the Americas. A historical reconstruction of the P- and W-type characters in the phylogenetic study supports the need to revise the hypothesis that PRSV-P derives from PRSV-W since our results suggest that the ancestral state could be either of the two biotypes. Moreover, estimates of epidemic growth predict an increasing genetic diversity of the virus over time that has direct implications for control strategies of PRSV based on cross protection and the use of transgenic plants. PMID- 21549775 TI - Banana bunchy top virus in sub-Saharan Africa: investigations on virus distribution and diversity. AB - Banana bunchy top virus (BBTV) was first reported from sub-Saharan Africa (SSA) from Democratic Republic of Congo (DRC) in the 1950s, has become invasive and spread into 11 countries in the region. To determine the potential threat of BBTV to the production of bananas and plantains (Musa spp.) in the sub-region, field surveys were conducted for the presence of banana bunchy top disease (BBTD) in the DRC, Angola, Cameroon, Gabon and Malawi. Using the DNA-S and DNA-R segments of the virus genome, the genetic diversity of BBTV isolates was also determined from these countries relative to virus isolates across the banana-growing regions around the world. The results established that BBTD is widely prevalent in all parts of DRC, Malawi, Angola and Gabon, in south and western part of Cameroon. Analysis of the nucleotide sequences of DNA-S and DNA-R indicate that BBTV isolates from these countries are genetically identical forming a unique clade within the 'South Pacific' phylogroup that includes isolates from Australia, Egypt, South Asia and South Pacific. These results imply that farmers' traditional practice of transferring vegetative propagules within and between countries, together with virus spread by the widely prevalent banana aphid vector, Pentalonia nigronervosa, could have contributed to the geographic expansion of BBTV in SSA. The results provided a baseline to explore sanitary measures and other 'clean' plant programs for sustainable management of BBTV and its vector in regions where the disease has already been established and prevent the spread of the virus to as yet unaffected regions in SSA. PMID- 21549776 TI - Comparing the regional epidemiology of the cassava mosaic and cassava brown streak virus pandemics in Africa. AB - The rapid geographical expansion of the cassava mosaic disease (CMD) pandemic, caused by cassava mosaic geminiviruses, has devastated cassava crops in 12 countries of East and Central Africa since the late 1980s. Region-level surveys have revealed a continuing pattern of annual spread westward and southward along a contiguous 'front'. More recently, outbreaks of cassava brown streak disease (CBSD) were reported from Uganda and other parts of East Africa that had been hitherto unaffected by the disease. Recent survey data reveal several significant contrasts between the regional epidemiology of these two pandemics: (i) severe CMD radiates out from an initial centre of origin, whilst CBSD seems to be spreading from independent 'hot-spots'; (ii) the severe CMD pandemic has arisen from recombination and synergy between virus species, whilst the CBSD pandemic seems to be a 'new encounter' situation between host and pathogen; (iii) CMD pandemic spread has been tightly linked with the appearance of super-abundant Bemisia tabaci whitefly vector populations, in contrast to CBSD, where outbreaks have occurred 3-12 years after whitefly population increases; (iv) the CMGs causing CMD are transmitted in a persistent manner, whilst the two cassava brown streak viruses appear to be semi-persistently transmitted; and (v) different patterns of symptom expression mean that phytosanitary measures could be implemented easily for CMD but have limited effectiveness, whereas similar measures are difficult to apply for CBSD but are potentially very effective. An important similarity between the pandemics is that the viruses occurring in pandemic-affected areas are also found elsewhere, indicating that contrary to earlier published conclusions, the viruses per se are unlikely to be the key factors driving the two pandemics. A diagrammatic representation illustrates the temporal relationship between B. tabaci abundance and changing incidences of both CMD and CBSD in the Great Lakes region. This emphasizes the pivotal role played by the vector in both pandemics and the urgent need to identify effective and sustainable strategies for controlling whiteflies on cassava. PMID- 21549777 TI - Maximum transepidermal flux for similar size phenolic compounds is enhanced by solvent uptake into the skin. AB - In principle, the maximum skin flux of solutes should be unaffected by the vehicle, unless that vehicle affects the skin. We recently showed that the maximum epidermal flux for 10 similarly sized phenolic compounds, with differing lipophilicities was defined by their solubility in the skin. Here, we extend these studies to examine how maximum fluxes are affected by cosolvents reported to enhance skin penetration. We compared in vitro human epidermal permeation and stratum corneum solubility for 10 phenols with similar molecular weights and hydrogen bonding but varying lipophilicity from 60% propylene glycol (PG)/water, 40% PG/water and water vehicles. We also measured solvent uptake into stratum corneum, investigated the changes in the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy of stratum corneum and the multiphoton microscopy (MPM) images of beta-naphthol for the various vehicles. We found that phenolic compounds maximum flux and stratum corneum solubilities generally increased with the percentage of PG in the binary solvent system but that the estimated diffusivities appeared to be vehicle independent. Maximum fluxes were related to vehicle-dependent stratum corneum solubilities. Theses solubilities, in turn, depended on the amount of vehicle absorbed into the stratum corneum and the amount of phenolic compounds dissolved in that absorbed vehicle. ATR-FTIR and MPM studies suggest that the vehicle-induced increased uptake of solutes into the stratum corneum occurred by an increased solubility in intercellular lipids of stratum corneum. PMID- 21549778 TI - Localized ultrasound enhances delivery of rapamycin from microbubbles to prevent smooth muscle proliferation. AB - Microbubble contrast agents have been shown to enhance reagent delivery when activated by ultrasound. We hypothesized that ultrasound would enhance delivery of rapamycin, an antiproliferative agent, from the shell of microbubbles, thus reducing proliferation of vascular smooth muscle cells. Our objective was to determine optimal ultrasound parameters that maximized therapeutic efficacy, maintained cell adherence, and minimized the drug exposure time. In vitro assays determined that ultrasound (1 MHz, 0.5% duty cycle) is required to successfully deliver rapamycin from microbubbles and reduce proliferation. Co-injection of rapamycin with control microbubbles did not result in a reduction in proliferation. Successful reduction in proliferation (>50%) required pulses at least 10 cycles in length and at least 300 kPa peak negative pressure at which point 90% of cells remained adherent. The anti-proliferative effect was also localized within a 6mm wide zone by focusing the ultrasound beam. PMID- 21549779 TI - Kinin generation from exogenous kininogens at the surface of retinoic acid differentiated human neuroblastoma IMR-32 cells after stimulation with interferon gamma. AB - Bradykinin-related peptides, kinins, ubiquitously occur in the nervous system and together with other pro-inflammatory mediators contribute to pathological states of that tissue such as edema and chronic pain. In the current work we characterized the kinin-forming system of neuronal cells obtained by differentiation of human neuroblastoma cell line IMR-32 with retinoic acid. These cells were shown to concentrate exogenous kinin precursors, kininogens, on the surface, release kinins from kininogens and subsequently convert kinins to their des-Arg metabolites. Significantly higher amounts of kinins and des-Arg-kinins were produced after cell stimulation with interferon-gamma, a potent pro inflammatory mediator involved in many neurological disorders. The expression of the major tissue kininogenase (the human kallikrein 1) and the major cell membrane-bound kininase (the carboxypeptidase M) also increased after cell stimulation with interferon-gamma, suggesting the involvement of these enzymes in the kinin production and degradation, respectively. Interferon-gamma was also able to up-regulate the expression of two known subtypes of kinin receptors. On the protein level, the changes were only observed in the expression of the des Arg-kinin-specific type 1 receptor which functions in the propagation of the inflammatory state. Taken together, these results suggest a novel way for local kinin and des-Arg-kinin generation in the nervous tissue during pathological states accompanied by interferon-gamma release. PMID- 21549780 TI - Protection provided by a recombinant ALVAC((r))-WNV vaccine expressing the prM/E genes of a lineage 1 strain of WNV against a virulent challenge with a lineage 2 strain. AB - The emergence of lineage 2 strains of WNV in Europe as a cause of clinical disease and mortality in horses raised the question whether the existing WNV vaccines, all based on lineage 1 strains, protect against circulating lineage 2 strains of WNV. In the present paper we have determined the level of cross protection provided by the recombinant ALVAC((r))-WNV vaccine in a severe challenge model that produces clinical signs of WNV type 2 disease. Ten horses were vaccinated twice at 4 weeks interval with one dose of the ALVAC-WNV vaccine formulated at the minimum protective dose. A further 10 horses served as controls. Two weeks after the second vaccination, all horses were challenged intrathecally with a recent neurovirulent lineage 2 strain of WNV. The challenge produced viraemia in 10 out of 10 and encephalitis in 9 out of 10 control horses. Three horses had to be euthanized for humane reasons. In contrast, none of the vaccinated horses developed WNV disease and only 1 vaccinated horse became viraemic at a single time point at low titre. The prevalence of WNV disease and viraemia were significantly lower in the vaccinated horses than in the control horses (P<0.0001 for both). Based on these results, the ALVAC-WNV vaccine will provide veterinarians with an effective tool to control infections caused by lineage 1 and 2 strains of WNV. PMID- 21549781 TI - The current perspective on tick-borne encephalitis awareness and prevention in six Central and Eastern European countries: report from a meeting of experts convened to discuss TBE in their region. AB - Tick-borne encephalitis (TBE) is a potentially life-threatening disease in humans and is caused by a flavivirus spread by infected ticks (Ixodes ricinus and Ixodes persulcatus). TBE is endemic across much of Central and Eastern Europe and the incidence is increasing, with numbers estimated to be as many as 8755 cases per year. The reasons for this increase are multi-faceted and may involve improvements in diagnosis and reporting of TBE cases, increases in recreational activities in areas inhabited by infected ticks and changes in climatic conditions affecting tick habitats. Vaccination is the most effective method of preventing TBE; following a successful nationwide vaccination campaign in Austria, the annual number of TBE cases fell to about 10% of those reported in the pre-vaccination era. This report describes the findings of a group of leading experts from six Central and Eastern European countries who convened to discuss TBE in their region during the 28th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID) Nice, France, 4-8 May 2010. PMID- 21549782 TI - Improved formulation and lyophilization cycle for rBCG vaccine. AB - To improve the conventional BCG vaccine in cake appearance and integrity, a new formulation with corresponding freeze drying cycle was developed for a recombinant BCG vaccine. The new formulation contains mannitol as a bulking agent, and trehalose, sucrose and sodium glutamate as stabilizers. The formulation and freeze drying cycle were tested with different super cooling rates and secondary drying temperatures, with or without an annealing process. Thermodynamic behavior was characterized using differential scanning calorimetry (DSC). Varying the secondary drying temperature and presence/absence of an annealing step caused marked differences in cake thermodynamic profiles irrespective of different cooling rates. The annealing process allowed efficient crystallization of the mannitol. Failure to crystallize the bulking agent had the potential to depress the Tg' and compromise storage stability in the final lyophile by crystallizing from the solid during storage, even when the secondary drying temperature was as high as 40 degrees C. The improved formulation and freeze drying cycle resulted in good recovery of 53.2% during lyophilization and a higher survival rate of 61.7% in an accelerated stability study than the conventional BCG formulation and cycle. In summary, full crystallization was necessary for the mannitol bulking formulation. The freeze dried rBCG vials obtained using the formulation and drying cycle developed here met the requirements of BCG vaccine in good cake appearance, high viability post freeze drying and heat stability during storage. PMID- 21549783 TI - Comparative effects of carrier proteins on vaccine-induced immune response. AB - The efficacy of vaccines against major encapsulated bacterial pathogens Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b (Hib) - has been significantly enhanced by conjugating the respective polysaccharides with different carrier proteins: diphtheria toxoid; non-toxic cross-reactive material of diphtheria toxin(197), tetanus toxoid, N. meningitidis outer membrane protein, and non-typeable H. influenzae-derived protein D. Hib, meningococcal, and pneumococcal conjugate vaccines have shown good safety and immunogenicity profiles regardless of the carrier protein used, although data are conflicting as to which carrier protein is the most immunogenic. Coadministration of conjugate vaccines bearing the same carrier protein has the potential for inducing either positive or negative effects on vaccine immunogenicity (immune interference). Clinical studies on the coadministration of conjugate vaccines reveal conflicting data with respect to immune interference and vaccine efficacy. PMID- 21549785 TI - Reported adverse events in girls aged 13-16 years after vaccination with the human papillomavirus (HPV)-16/18 vaccine in the Netherlands. AB - In 2009, human papillomavirus (HPV) vaccination was offered to girls born in 1993 1996 in a catch-up campaign, followed in 2010 by the implementation of the vaccination in the National Immunization Programme (NIP) for girls born in 1997. To monitor the tolerability of the 2009 catch-up campaign, we investigated the occurrence of adverse events within 7 days after vaccination with the bivalent HPV vaccine. A total of 6000 girls were asked to participate, including 1500 from each birth cohort from 1993 to 1996. One week after each of the required three successive doses, the participants received by e-mail a Web-based questionnaire focused on local reactions and systemic events. One or more questionnaires were returned by 4248 girls. Any local reaction was reported by 92.1% of the girls after the first dose, 79.4% after the second dose, and 83.3% after the third dose, and 91.7%, 78.7%, and 78.4% reported any systemic event after the three doses, respectively. Pain in the arm was the most frequently reported local reaction, of which 24.0%, 11.7%, and 14.7% was classified as pronounced. Myalgia was the most often reported systemic event. The proportion of local reactions and most systemic events was significantly lower after the second and third dose compared with the first dose (Odds ratio [OR], 0.33-0.76). Older girls reported a higher proportion of adverse events than younger girls. After vaccination with the bivalent HPV vaccine, girls 13-16 years of age reported a high proportion of short-term adverse events. These are maximum estimates and not necessarily caused by the vaccination itself. Although, girls experienced HPV vaccination as painful, no serious or unexpected adverse events were reported. The results of this survey are being communicated to health care workers and the public. PMID- 21549784 TI - Immunization of mice with the non-toxic HC50 domain of botulinum neurotoxin presented by rabies virus particles induces a strong immune response affording protection against high-dose botulinum neurotoxin challenge. AB - We previously showed that rabies virus (RABV) virions are excellent vehicles for antigen presentation. Here, a reverse genetic approach was applied to generate recombinant RABV that express a chimeric protein composed of the heavy chain carboxyterminal half (HC50) of botulinum neurotoxin type A (BoNT/A) and RABV glycoprotein (G). To promote surface expression and incorporation of HC50/A into RABV virions, the RABV glycoprotein (G) ER translocation sequence, various fragments of RABV ectodomain (ED) and cytoplasmic domain were fused to HC50/A. The HC50/A chimeric proteins were expressed on the surface of cells infected with all of the recombinant RABVs, however, the highest level of surface expression was detected by utilizing 30 amino acids of the RABV G ED (HV50/A-E30). Our results also indicated that this chimeric protein was effectively incorporated into RABV virions. Immunization of mice with inactivated RABV-HC50/A-E30 virions induced a robust anti-HC50/A IgG antibody response that efficiently neutralized circulating BoNT/A in vivo, and protected mice against 1000 fold the lethal dose of BoNT/A. PMID- 21549786 TI - Aerosol delivery of virus-like particles to the genital tract induces local and systemic antibody responses. AB - The induction of mucosal immune responses in the genital tract may be important for increasing the effectiveness of vaccines for sexually transmitted infections (STIs). In this study, we asked whether direct immunization of the mouse genital tract with a non-replicating virus-like particle (VLP)-based vaccine could induce local mucosal as well as systemic antibody responses. Using VLPs derived from two bacteriophages, Qbeta and PP7, and from a mammalian virus that normally infects the genital tract, human papillomavirus (HPV), we show that intravaginal aerosol administration of VLPs can induce high titer IgG and IgA antibodies in the female genital tract as well as IgG in the sera. Using a mouse model for HPV infection, we show that intravaginal immunization with either HPV type 16 VLPs or with PP7 bacteriophage VLPs displaying a peptide derived from the HPV minor capsid protein L2 could protect mice from genital infection with an HPV16 pseudovirus. These results provide a general method for inducing genital mucosal and systemic antibody responses using VLP-based immunogens. PMID- 21549787 TI - Active and passive surveillance of yellow fever vaccine 17D or 17DD-associated serious adverse events: systematic review. AB - PURPOSE: To identify the rate of serious adverse events attributable to yellow fever vaccination with 17D and 17DD strains reported in active and passive surveillance data. METHODS: We conducted a systematic review of published literature on adverse events associated with yellow fever. We searched 9 electronic databases for peer reviewed and grey literature in all languages. There were no restrictions on date of publication. Reference lists of key studies were also reviewed to identify additional studies. PRINCIPAL RESULTS: We identified 66 relevant studies: 24 used active, 17 a combination of passive and active (15 of which were pharmacovigilance databases), and 25 passive surveillance. ACTIVE SURVEILLANCE: A total of 2,660,929 patients in general populations were followed for adverse events after vaccination, heavily weighted (97.7%) by one large Brazilian study. There were no observed cases of viscerotropic or neurotropic disease, one of anaphylaxis and 26 cases of urticaria (hypersensitivity). We also identified four studies of infants and children (n=2199), four studies of women (n=1334), and one study of 174 HIV+, and no serious adverse events were observed. PHARMACOVIGILANCE DATABASES: 10 of the 15 databases contributed data to this review, with 107,621,154 patients, heavily weighted (94%) by the Brazilian database. The estimates for Australia were low at 0/210,656 for "severe neurological disease" and 1/210,656 for YEL-AVD, and also low for Brazil with 9 hypersensitivity events, 0.23 anaphylactic shock events, 0.84 neurologic syndrome events and 0.19 viscerotropic events cases/million doses. The five analyses of partly overlapping periods for the US VAERS database provided an estimate of 6.6 YEL-AVD and YEL-AND cases per million, and estimates between 11.1 and 15.6 of overall "serious adverse events" per million. The estimates for the UK were higher at 34 "serious adverse events" and also for Switzerland with 14.6 "neurologic events" and 40 "serious events not neurological"/million doses. PASSIVE SURVEILLANCE: Six studies of campaigns in general populations included 94,500,528 individuals, very heavily weighted (99%) by the Brazilian data, and providing an estimate of 0.51 serious AEFIs/million doses. Five retrospective reviews of hospital or clinic records included 60,698 individuals, and no serious AEFIs were proven. The data are heavily weighted (96%) by the data from the Hospital for Tropical Diseases, London. Two studies included 35,723 children, four studies included 138 pregnant women, six studies included 191 HIV+ patients, and there was one review of patients who were HIV+, and no serious AEFIs were proven. MAJOR CONCLUSIONS: The databases in each country used different definitions, protocols, surveillance mechanisms for the initial identification and reporting of cases, and strategies for the clinical and laboratory follow up of cases. The pharmacovigilance databases provide three sets of estimates: a low estimate from the Brazilian and Australian data, a medium estimate from the US VAERS data, and a higher estimate from the UK and Swiss data. The estimates from the active surveillance data are lower (and strongly influenced by the Brazilian data) and the estimates from the passive surveillance studies are also lower (strongly influenced by the London Hospital for Tropical Diseases data from the early 1950s). Sophisticated pathology, histopathology and tests such as PCR amplicon sequencing are needed to prove that serious adverse events were actually caused by the yellow fever vaccine, and the availability of such diagnostic capability is strongly biased towards recent reports from developed countries. Despite these variations in the estimation of serious harm, overall the 17D and 17DD yellow fever vaccine has proven to be a very safe vaccine and is highly effective against an illness with high potential mortality rates. PMID- 21549788 TI - Passive immunization with Leptospira LPS-specific agglutinating but not non agglutinating monoclonal antibodies protect guinea pigs from fatal pulmonary hemorrhages induced by serovar Copenhageni challenge. AB - Leptospira interrogans serovar Copenhageni causes pulmonary hemorrhages with respiratory failure, a major cause of death in leptospirosis patients. Protective immunity to Leptospira is known to correlate with the production of leptospiral lipopolysaccharide (L-LPS)-specific agglutinating antibodies. We generated L-LPS specific mouse monoclonal antibodies (MAbs) and investigated if these MAbs can protect guinea pigs against fatal pulmonary hemorrhages caused by serovar Copenhageni. The MAbs L8H4 and L9B11 against 22kDa L-LPS agglutinated leptospires and completely protected guinea pigs from the development of fatal pulmonary hemorrhages by serovar Copenhageni, whereas the MAb L4C1 against 8kDa L-LPS neither agglutinated the bacteria nor protected the animals against the fatal pulmonary hemorrhages. PMID- 21549789 TI - Protection of European domestic pigs from virulent African isolates of African swine fever virus by experimental immunisation. AB - African swine fever (ASF) is an acute haemorrhagic disease of domestic pigs for which there is currently no vaccine. We showed that experimental immunisation of pigs with the non-virulent OURT88/3 genotype I isolate from Portugal followed by the closely related virulent OURT88/1 genotype I isolate could confer protection against challenge with virulent isolates from Africa including the genotype I Benin 97/1 isolate and genotype X Uganda 1965 isolate. This immunisation strategy protected most pigs challenged with either Benin or Uganda from both disease and viraemia. Cross-protection was correlated with the ability of different ASFV isolates to stimulate immune lymphocytes from the OURT88/3 and OURT88/1 immunised pigs. PMID- 21549790 TI - A DNA vaccine encoding ubiquitinated Rift Valley fever virus nucleoprotein provides consistent immunity and protects IFNAR(-/-) mice upon lethal virus challenge. AB - Current vaccine candidates against Rift Valley fever virus (RVFV) incorporate the viral structural glycoproteins as antigens, since triggering antibody responses against them usually correlates with protection. Here, we have focused solely on the nucleoprotein of RVFV as a potential target for vaccine development. Previous studies in mouse models have already demonstrated that RVFV nucleoprotein can elicit partial protection when administered by means of a DNA vaccine or in recombinant, soluble, protein form. To determine whether this partially protective immune response could be augmented to a level comparable to DNA constructs encoding for RVFV glycoproteins, several targeting sequences were cloned adjacent to the RVFV nucleoprotein (N) gene. Immunization with a plasmid construct encoding for a ubiquitinated form of the viral nucleoprotein (pCMV-Ub N) significantly increased the survival of IFNAR(-/-) mice following viral challenge to levels comparable with a recombinant DNA-vaccine encoding both RVFV glycoproteins. Mice immunized with pCMV-Ub-N also displayed higher levels of non neutralizing anti-N antibodies and antigen-specific T-cell responses. This suggests a role for other cell mediated responses in protection against RVFV. These findings show the potential of RVFV N as a candidate antigen for vaccination, and present a new strategy in vaccine design against certain bunyaviruses, where glycoprotein variation may impede effective broad-based vaccination strategies. PMID- 21549791 TI - Development of an inactivated candidate vaccine against Chandipura virus (Rhabdoviridae: Vesiculovirus). AB - A Vero cell based vaccine candidate against Chandipura (CHP) virus (Rhabdoviridae: Vesiculovirus), was developed and evaluated for immunogenicity in mice. Virus was purified by ultracentrifugation on 30% glycerol cushion followed by differential centrifugation on 10-60% sucrose gradient and inactivated with beta-propio lactone at a concentration of 1:3500. The inactivated product was blended with aluminium phosphate (3%) and immunized 4-week-old Swiss albino mice. Neutralizing antibodies in the range of 1:10 to 160 and 1:80 to 1:320 was detected with 85% and 100% sero-conversion after 2nd and 3rd dose, respectively. All the immunized mice with antibody titer above 1:20 survived live virus challenge. The vaccine candidate has potential to be an efficient vaccine against CHP virus. PMID- 21549792 TI - Immune responses to an attenuated West Nile virus NS4B-P38G mutant strain. AB - The nonstructural (NS) proteins of West Nile virus (WNV) have been associated with participation in evasion of host innate immune defenses. In the present study, we characterized immune response to an attenuated WNV strain, which has a P38G substitution in the NS4B protein. The WNV NS4B-P38G mutant induced a lower level of viremia and no lethality in C57BL/6 (B6) mice following a systemic infection. Interestingly, there were higher type 1 IFNs and IL-1beta responses compared to mice infected by wild-type WNV. NS4B-P38G mutant-infected mice also showed stronger effector and memory T cell responses. WNV specific antibody responses were not different between mice infected with these two viruses. As a consequence, all mice were protected from a secondary infection with a lethal dose of wild-type WNV following a primary infection with NS4B-P38G mutant. Moreover, NS4B-P38G mutant infection in cultured bone-marrow derived dendritic cells (DCs) were shown to have a reduced replication rate, but a higher level of innate cytokine production than wild-type WNV, some of which were dependent on Myd88 signaling. In conclusion, the NS4B-P38G mutant strain induces higher protective innate and adaptive immune response in mice, which results in a lower viremia and no lethality in either primary or secondary infection, suggesting a high potential as an attenuating mutation in a vaccine candidate. PMID- 21549793 TI - Challenges and opportunities of a new HPV immunization program perceptions among Swedish school nurses. AB - AIM: To investigate school nurses' perceptions of HPV immunization, and their task of administering the vaccine in a planned school-based program in Sweden. METHOD: Data were collected through five focus group interviews with school nurses (n=30). The interviews were recorded, transcribed verbatim and analyzed using content analysis. FINDINGS: The theme Positive attitude to HPV immunization despite many identified problems and challenges summarizes the results. The school nurses saw the program as a benefit in that the free school-based HPV immunization program could balance out social inequalities. However, they questioned whether this new immunization program should be given priority given their already tight schedule. Some also expressed doubts regarding the effect of the vaccine. It was seen as challenging to obtain informed consent as well as to provide information regarding the vaccine. The nurses were unsure of whether boys and their parents should also be informed about the immunization. CONCLUSION: Although some positive aspects of the new HPV immunization program were mentioned, the school nurses primarily identified problems and challenges; e.g. regarding priority setting, informed consent, culture and gender. In order to achieve a good work environment for the school nurses, and obtain a high coverage rate for the HPV immunization, these issues need to be taken seriously, be discussed and acted upon. PMID- 21549794 TI - MyD88-dependent protective immunity elicited by adenovirus 5 expressing the surface antigen 1 from Toxoplasma gondii is mediated by CD8(+) T lymphocytes. AB - Toxoplasma gondii is an intracellular parasite widely spread around the world. The surface antigens (SAG) 1, 2 and 3 are the main proteins expressed on the surface of T. gondii tachyzoites. Replication-defective adenovirus serotype 5 (rAd5) is one of the most potent recombinant viral vectors for eliciting T cell mediated immunity in mice and humans. Here we show that vaccination with rAd5 expressing SAG1 (AdSAG1), but neither SAG2 nor SAG3, induces protective immunity in the highly susceptible C57BL/6 mice challenged with T. gondii. Furthermore, we evaluated different immunological components involved on viral induced protective immunity. We observed that host protection elicited by AdSAG1 is highly dependent on IL-12, IFN-gamma and CD8(+) T lymphocytes. Importantly, the induction of protective immunity (T cell-derived IFN-gamma) was also dependent on Myeloid Differentiation Factor 88 (MyD88), and thus, likely to involve Toll-like Receptors. We conclude that protective parasite specific-CD8(+) T cells are elicited by a mechanism that involves MyD88-dependent induction of IL-12. PMID- 21549796 TI - Pneumococcal colonisation following influenza infection. PMID- 21549795 TI - Extended safety and efficacy studies of a live attenuated double leucine and pantothenate auxotroph of Mycobacterium tuberculosis as a vaccine candidate. AB - We have previously described the development of a live, fully attenuated Mycobacterium tuberculosis (Mtb) vaccine candidate strain with two independent attenuating auxotrophic mutations in leucine and pantothenate biosynthesis. In the present work, those studies have been extended to include testing for protective efficacy in a long-term guinea pig survival model and safety testing in the highly tuberculosis susceptible Rhesus macaque. To model the safety of the DeltaleuD DeltapanCD strain in HIV-infected human populations, a Simian immunodeficiency virus (SIV)-infected Rhesus macaque group was included. Immunization with the non-replicating DeltaleuD DeltapanCD conferred long-term protection against challenge with virulent M. tuberculosis equivalent to that afforded by BCG as measured by guinea pig survival. In safety studies, clinical, hematological and bacteriological monitoring of both SIV-positive and SIV negative Rhesus macaques immunized with DeltaleuD DeltapanCD, revealed no vaccine associated adverse effects. The results support the further development of the DeltaleuD DeltapanCD strain as a viable tuberculosis (TB) vaccine candidate. PMID- 21549797 TI - A dose-response study in animals to evaluate the anticoagulant effect of the stage 2 unfractionated heparin USP monograph change. AB - The United States Pharmacopeia (USP) monograph for unfractionated heparin (UFH) was revised in October 2009. This revision was anticipated, based upon in vitro tests, to reduce UFH potency by approximately 10%. To study the potential in vivo consequences of the monograph change, we evaluated activated partial thromboplastin time (aPTT) and activated clotting time (ACT) responses in animals. Female mini-pigs and monkeys (n=8/species) were administered intravenously 60, 54, 48, or 42 U/kg and 50, 45, 40, or 35 U/kg "old" (pre-USP revision) UFH, respectively, in a Williams 4*4 crossover design. Blood samples for aPTT and ACT were collected at 15 min after dosing. The same study design was then repeated using "new" (post-USP revision) UFH. Mean "new" UFH aPTT and ACT values were generally lower than those for "old" UFH although individual animal responses varied considerably. The aPTT and ACT response was generally dose proportional for both "old" and "new" UFH. These studies indicate that the USP monograph alteration for UFH may result in a modest reduction in the anticoagulant response across a population, but the variability in animal responses underscores the importance of individualization of clinical UFH dosing and the importance of anticoagulant test monitoring. PMID- 21549799 TI - Olaquindox induces apoptosis through the mitochondrial pathway in HepG2 cells. AB - Olaquindox is used in China as feed additive for growth promotion in pigs. Recently, we have demonstrated that olaquindox induced genome DNA damage and oxidative stress in HepG2 cells. The aim of this study was to explore the molecular mechanism of cell cycle arrest and apoptosis induced by olaquindox in HepG2 cells. In the present study olaquindox induced cell cycle arrest to the S phase and dose-dependent apoptotic cell death in HepG2 cells, indicated by accumulation of sub-G1 cell population, nuclear condenstion, DNA fragmentation, caspases activation and PARP cleavage. Meanwhile, the data showed that olaquindox triggered ROS-mediated apoptosis in HepG2 cells correlated with both the mitochondrial DNA damage and nuclear DNA damage, collapse of Deltapsi(m), opening of mPTP, down-regulation of Bcl-2 and up-regulation of Bax. Furthermore, we also found that olaquindox increased the expression of p53 protein and induced the release of cytochrome C from mitochondria to cytosol. In conclusion, olaquindox induced apoptosis of HepG2 cells through a caspase-9 and -3 dependent mitochondrial pathway, involving p53, Bcl-2 family protein expression, Deltapsi(m) disruption and mPTP opening. PMID- 21549798 TI - Working memory and attention deficits in adolescent offspring of schizophrenia or bipolar patients: comparing vulnerability markers. AB - BACKGROUND: Working memory deficits abound in schizophrenia and attention deficits have been documented in schizophrenia and bipolar disorder. Adolescent offspring of patients may inherit vulnerabilities in brain circuits that subserve these cognitive domains. Here we assess impairments in offspring of schizophrenia (SCZ-Offspring) or bipolar (BP-Offspring) patients compared to controls (HC) with no family history of mood or psychotic disorders to the second degree. METHODS: Three groups (n=100 subjects; range: 10-20 yrs) of HC, SCZ-Offspring and BP Offspring gave informed consent. Working memory was assessed using a delayed spatial memory paradigm with two levels of delay (2s & 12s); sustained attention processing was assessed using the Continuous Performance Task-Identical Pairs version. RESULTS: SCZ-Offspring (but not BP-Offspring) showed impairments in working memory (relative to HC) at the longer memory delay indicating a unique deficit. Both groups showed reduced sensitivity during attention but only BP Offspring significantly differed from controls. CONCLUSIONS: These results suggest unique (working memory/dorsal frontal cortex) and potentially overlapping (attention/fronto-striatal cortex) vulnerability pathways in adolescent offspring of patients with schizophrenia and bipolar disorder. Working memory and attention assessments in these offspring may assist in the clinical characterization of the adolescents vulnerable to SCZ or BP. PMID- 21549800 TI - Trichloroacetic acid: updated estimates of its bioavailability and its contribution to trichloroethylene-induced mouse hepatomegaly. AB - Trichloroacetic acid (TCA) is a common drinking water disinfection byproduct that produces a spectrum of liver effects, including hepatomegaly and liver tumors, in mice. It is also an oxidative metabolite of trichloroethylene (TCE), a solvent used in degreasing with widespread environmental exposure, which also produces hepatomegaly and liver tumors in mice. Physiologically based pharmacokinetic (PBPK) modeling of TCE and TCA can be used to quantitatively compare the dose responses for hepatomegaly for these two chemicals on the basis of internal TCA dose, and thereby test the hypothesis that TCA could fully explain TCE-induced hepatomegaly. Previously, using a PBPK model calibrated using kinetic data from i.v. and gavage dosing of TCA and from TCA produced from TCE, it was concluded that TCA accounted for only about one-fifth of the degree of hepatomegaly produced by TCE. However, recently available data suggest a non-linear change in internal TCA dose attributed to a dose-dependent fractional absorption of TCA administered in drinking water, the primary route of exposure of TCA both environmentally and in experimental toxicity studies. Therefore, in the present reanalysis, the PBPK modeling of TCA was updated using these data and the comparison between TCA- and TCE-induced hepatomegaly was revisited using updated internal dose predictions. With respect to updated PBPK modeling results, incorporating less than complete absorption of TCA administered in drinking water substantially improves the PBPK model fit to the newly available data, based on goodness-of-fit comparison. However, inter-experimental variability is high, with nearly complete absorption estimated for some studies. With respect to the comparison of TCA and TCA-induced hepatomegaly, this reanalysis predicts that TCA can account for roughly one-third to one-half of the effect observed with TCE - greater than previously reported, but still inconsistent with TCA being the sole active moiety for this effect. However, given uncertainty as to the precise degree of contribution of TCA and due to high inter-experimental variability in estimated fractional absorption, a more precise quantitative estimate of the relative contribution of TCA may obtained through an appropriate experiment in mice simultaneously measuring TCA kinetics and TCE- and TCA-induced hepatomegaly. PMID- 21549801 TI - Influence of application time on penetration of an infiltrant into natural enamel caries. AB - OBJECTIVE: Caries infiltration is an innovative approach to treat medium stages of caries that bridges the gap between preventive and invasive measures, whereby hard tissues are preserved. Special low viscosity resins (infiltrants) showed almost complete penetration into natural lesions when applied for 5 min. Since shorter application times seem to be clinically more feasible, the aim of this in vitro study was to compare the penetration of an infiltrant (Icon pre-product; DMG, Hamburg, Germany) into natural caries lesions after various application times. METHODS: Extracted permanent human posterior teeth showing non-cavitated proximal caries lesions were infiltrated for either 0.5, 1, 3, or 5 min (n=20) and light-cured. Specimens were prepared and lesion (LD) as well as penetration depths (PD) were analysed using dual fluorescence confocal microscopy. RESULTS: PD [median (Q25;Q75)] at maximum LD after 0.5 min [159 (27;340) MUm] and 1 min [152 (69;375) MUm] were significantly lower compared to those after 3 min [414 (338, 518) MUm] and 5 min [407 (332;616) MUm] (p<0.05). Deep lesion parts (PD>500 MUm) could be penetrated almost completely after 3 min [98 (88;100)%] and 5 min [100 (81;100)%] application. CONCLUSIONS: Thus, 3 min application of an infiltrant seems to be sufficient to achieve an almost complete penetration of enamel caries. PMID- 21549802 TI - Role of hydration on the functionality of a proteolytic enzyme alpha-chymotrypsin under crowded environment. AB - Enzymes and other bio-macromolecules are not only sensitive to physical parameters such as pH, temperature and solute composition but also to water activity. A universally instructive way to vary water activity is the addition of osmotically active but otherwise inert solvents which also mimic the condition of an intercellular milieu. In the present contribution, the role of hydration on the functionality of a proteolytic enzyme alpha-chymotrypsin (CHT) is investigated by modulating the water activity with the addition of polyethylene glycols (PEG with an average molecular weight of 400). The addition of PEG increases the affinity of the enzyme to its substrate, however, followed by a decrease in the turnover number (k(cat)). Energetic calculations show that entrance path for the substrate is favoured, whereas the exit channel is restricted with increasing concentration of the crowding agent. This decrease is attributed to the thinning of the hydration shell of the enzyme due to the loss of critical water residues from the hydration surface of the enzyme as evidenced from volumetric and compressibility measurements. The overall secondary and tertiary structures of CHT determined from far-UV and near-UV circular dichroism (CD) measurements show no considerable change in the studied osmotic stress range. From kinetic and equilibrium data, we calculate 115 +/- 30 numbers of water molecules to be altered during the enzymatic catalysis of CHT. Spectroscopic observation of water relaxation and rotational dynamics of ANS-CHT complex at various concentrations of the osmoting agent also support the dehydration of the hydration layer. Such dehydration/hydration processes during turnover imply a significant contribution of solvation to the energetics of the conformational changes. PMID- 21549803 TI - A hybrid model to study pathological mutations of the human ADP/ATP carriers. AB - The adenine nucleotide carrier (Ancp) plays an essential role in the metabolism of cellular energy by catalyzing the transport of ADP and ATP across the inner mitochondrial membrane. Previous reports have indicated that mutations in the HANC1 gene, encoding the muscle isoform of human Ancp (HAnc1p), are directly involved in several diseases, including autosomal dominant progressive external ophthalmoplegia and cardiomyopathies. In this work, we studied three pathogenic HANC1 mutations at the biochemical level. To do so, we expressed the DdANCA gene, encoding the unique Ancp carrier of Dictyostelium discoideum (DdAncAp), in a yeast strain lacking all endogenous ANC genes. Our results indicate that DdAncAp is a good model for the human protein. It allows the carrier to be studied in yeast, and provides information on how the HANC1 mutations impair ADP/ATP transport in humans. A94D, A126D and V291M mutations, corresponding to A90D, A123D and V289M in HAnc1p, respectively, did not affect levels of DdAncAp in yeast mitochondria. However, while the wild-type DdAncAp fully restored growth of the ANC-null yeast strain on a non-fermentable carbon source, the carriers encompassing either the A94D or the A126D mutation failed to complement the null strain. The effect of the V291M mutation was not as pronounced, but led to impairment mainly of the nucleotide translocation process per se. These findings provide new insights into the mechanisms responsible for the diseases induced by HAnc1p mutations. PMID- 21549804 TI - Impaired preparatory re-mapping of stimulus-response associations and rule implementation in schizophrenic patients--the role for differences in early processing. AB - An accurate representation of task-set information is needed for successful goal directed behavior. Recent studies point to disturbances in the early processing stages as plausible causes for task-switching deficits in schizophrenia. A task cueing protocol was administered to a group of schizophrenic patients and compared with a sample of age-matched healthy controls. Patients responded slower and less accurate compared with controls in all conditions. The concurrent recording of event-related brain potentials to contextual cues and target events revealed abnormalities in the early processing of both cue-locked and target locked N1 potentials. Abnormally enhanced target-locked P2 amplitudes were observed in schizophrenic patients for task-switch trials only, suggesting disrupted stimulus evaluation and memory retrieval processes. The endogenous P3 potentials discriminated between task conditions but without further differences between groups. These results suggest that the observed impairments in task switching behavior were not specifically related to anticipatory set-shifting, but derived from a deficit in the implementation of task-set representations at target onset in the presence of irrelevant and conflicting information. PMID- 21549805 TI - Differential regulation of sense and antisense promoter activity at the Csf1R locus in B cells by the transcription factor PAX5. AB - OBJECTIVE: The transcription factor PAX5 is essential for the activation of B cell-specific genes and for the silencing of myeloid-specific genes. We previously determined the molecular mechanism by which PAX5 silences the myeloid specific colony-stimulating-factor-receptor (Csf1R) gene and showed that PAX5 directly binds to the Csf1r promoter as well as to an intronic enhancer that generates an antisense transcript in B cells. Here we examine the role of PAX5 in the regulation of sense and antisense transcription in B cells. MATERIALS AND METHODS: We performed PAX5-specific chromatin immunoprecipitation analyses across the Csfr1 locus. We investigated the role of PAX5 in regulating Csf1r sense and antisense promoter activity by transient transfections and by employing a Pax5(-/ ) pro-B-cell line expressing an inducible PAX5 protein. PAX5 interacting factors were identified by pull-down experiments. The role of the transcription factor Sp3 in driving antisense promoter expression was examined in B cells from Sp3 knockout mice. RESULTS: PAX5 differentially regulates the Csf1r promoter and the promoter of the antisense transcript. PAX5 interferes with PU.1 transactivation at the sense promoter by binding to a PAX5 consensus sequence. At the antisense promoter, PAX5 does not specifically recognize DNA, but interacts with Sp3 to upregulate antisense promoter activity. Antisense promoter activation by PAX5 is dependent on the presence of its partial homeo-domain. CONCLUSIONS: We demonstrate that PAX5 regulates Csf1r in B cells by reducing the frequency of binding of the basal transcription machinery to the promoter and by activating antisense RNA expression. PMID- 21549807 TI - Characterization of intracellular translocation of Forkhead transcription factor O (FoxO) members induced by NGF in PC12 cells. AB - Nuclear translocation of Forkhead transcription factors of the O class (FoxOs) is important for the action of growth factors. However it is not known if all members of the FOXO family have the same translocation properties. We examined the effects of nerve growth factor (NGF) on nuclear/cytoplasmic shuttling of FoxO1, FoxO3a and FoxO6 in PC12 cells and determined their translocation kinetics. Our data demonstrated that NGF could induce the nuclear exclusion of FoxO1-GFP and FoxO3a-GFP in PC12 cells with different properties, but had no effect on FoxO6-GFP's nuclear localization and FoxO6-GFP showed an exclusive nuclear localization. Translocat ould be blocked by K252a and LY294002 but not by PD98059. Moreover, FoxO3a returned to cytoplasm at a higher rate than FoxO1 after NGF stimulation and it was more sensitive than FoxO1 to NGF stimulation. PMID- 21549806 TI - Transcriptional regulation of type 11 17beta-hydroxysteroid dehydrogenase expression in prostate cancer cells. AB - Type 11 hydroxysteroid (17-beta) dehydrogenase (HSD17B11) catalyzes the conversion of 5alpha-androstan-3alpha,17beta-diol into androsterone suggesting that it may play an important role in androgen metabolism. We previously described that overexpression of C/EBPalpha or C/EBPbeta induced HSD17B11 expression in HepG2 cells but this process was not mediated by the CCAAT boxes located within its proximal promoter region. Here, we study HSD17B11 transcriptional regulation in prostate cancer (PC) cells. Transfection experiments showed that the region -107/+18 is sufficient for promoter activity in PC cells. Mutagenesis analysis indicated that Sp1 and C/EBP binding sites found in this region are essential for promoter activity. Additional experiments demonstrated that ectopic expression of Sp1 and C/EBPalpha upregulated HSD17B11 expression only in PC cell lines. Through DAPA and ChIP assays, specific recruitment of Sp1 and C/EBPalpha to the HSD17B11 promoter was detected. These results show that HSD17B11 transcription in PC cells is regulated by Sp1 and C/EBPalpha. PMID- 21549808 TI - Real-time evaluation of nitric oxide (NO) levels in cortical and hippocampal areas with a nanopore-based electrochemical NO sensor. AB - Nitric oxide (NO) is an important biomolecule for regulating various brain functions, such as the control of neurovascular tone. NO, however, cannot be stored inside cells where NO is produced and immediately diffuses through the cellular membrane and decays rapidly, which makes the detection of NO extremely hard in an in vivo setting. We constructed an amperometric NO nanosensor and utilized it to directly measure NO release in the living brain. The NO nanosensor uses nanopores (pores with an opening radii <500 nm) in which NO is oxidized at the porous platinum surface. The nanopore-based sensor was inserted vertically into the brains of anesthetized mice up to the end of the hippocampal CA 3 region, or to a depth of about 3mm. The sensor was slowly advanced in the brain in 0.5 MUm increments and in 0.05 s temporal steps. Different levels of NO release were monitored by the nanopore NO sensor during the course of the penetration. The hippocampal CA3 region had the highest level of NO release, which was followed by CA2 and CA1 of the hippocampus and the cortex. The levels of NO release were not uniformly distributed within the cortical and hippocampal areas of living brain. In sum, the nanopore-based NO sensor was able to grossly measure NO contents within living brain in real time and with high sensitivity. This study may provide good insights about the relationship between the distributions of NOS-immunoreactive neurons and the directly measured levels of NO release in brain. PMID- 21549809 TI - Respiratory responses to somatostatin microinjections into the Botzinger complex and the pre-Botzinger complex of the rabbit. AB - The respiratory responses to bilateral microinjections (30-50 nl) of 5mM somatostatin (SOM) or 10mM cyclosomatostatin (c-SOM, a SOM antagonist) into the Botzinger complex (BotC), the pre-Botzinger complex (preBotC) and the rostral inspiratory portion of the ventral respiratory group (iVRG) were investigated in urethane-chloralose anesthetized, vagotomized, paralysed and artificially ventilated rabbits. SOM microinjections into the BotC decreased respiratory frequency and the rate of rise of phrenic nerve activity without obvious changes in its peak amplitude. SOM microinjected into the preBotC caused increases in respiratory frequency and decreases in peak phrenic activity associated with increases in its rate of rise. No changes in respiration were induced by SOM microinjections into the iVRG. Microinjections of c-SOM into the preBotC caused decreases in respiratory frequency as well as in peak amplitude and rate of rise of phrenic nerve activity. The results show that endogenously released SOM within the preBotC contributes to shape the pattern of baseline respiratory activity and that SOM receptors within the BotC and the preBotC have a role in the modulation of respiration in the rabbit. PMID- 21549810 TI - Differences in the expression of transient receptor potential channel V1, transient receptor potential channel A1 and mechanosensitive two pore-domain K+ channels between the lumbar splanchnic and pelvic nerve innervations of mouse urinary bladder and colon. AB - The bladder and distal colon are innervated by lumbar splanchnic (LSN) and pelvic nerves (PN) whose axons arise from dorsal root ganglia (DRG) neurons at thoracolumbar (TL) and lumbosacral (LS) spinal levels, respectively. In an attempt to understand the molecular basis of differences between LSN and PN mechanosensitive afferents, we analyzed the gene expression of two potentially counteracting ion channel groups involved in mechanosensation, transient receptor potential channels (TRPV1 and TRPA1) and mechanosensitive two pore-domain K(+) (K(2P)) channels (TREK-1, TREK-2 and TRAAK), in TL and LS DRG neurons innervating mouse bladder or distal colon. The proportion of TRPV1-expressing cells (41~61%) did not differ between TL and LS neurons innervating bladder or colon. TRPA1 was seldom detected in bladder LS neurons whereas it was expressed in 64~66% of bladder TL, colon TL and colon LS neurons. Coexpression of TRPV1 and TRPA1 was frequent. TREK-1-expressing cells were more prevalent in LS than TL ganglia in both bladder- and colon-DRG neurons. All three K(2P) channels were detected more frequently in TRPV1-positive neurons in TL ganglia. More than half of TL neurons expressing only TRPA1 were devoid of any of the three K(2P) channels, whereas all TL neurons expressing both TRPA1 and TRPV1 expressed at least one of the K(2P) channels. These results reveal clear differences between LSN and PN sensory pathways in TRPA1 and TREK-1 gene expression and in the gene expression of K(2P) channels in TRPV1-expressing neurons. This study further documents heterogeneity of visceral afferents based on combinations of the five channels examined. PMID- 21549811 TI - ClC-2 contributes to tonic inhibition mediated by alpha5 subunit-containing GABA(A) receptor in experimental temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE), characterized by spontaneous recurrent seizures, learning and memory impairments is associated with neurodegeneration, abnormal reorganization of the circuitry and loss of functional inhibition in hippocampus. In adult hippocampus, the GABAergic cells mediate the major inhibitory function of the principal neurons, promoting the Cl(-) entry through the GABA(A) receptor, whether through phasic (synaptic) or tonic (extrasynaptic) conductance. Aside from classical synaptic component, tonic GABAergic inhibition mediated by extrasynaptic GABA(A) receptor received increasing attention over the past years. There is growing evidence that tonic inhibition plays an important role in epilepsy, memory and cognition. Since GABA(A) receptor-mediated inhibition depends on the maintenance of intracellular Cl(-) concentration at low levels in mature neurons, a shift in E(cl) is likely to participate in the generation and not merely a consequence of TLE. As we know, chloride channel-2 (ClC-2) is a member of the supergene family of voltage-gated chloride channels, it constitutes part of the background conductance and is involved in chloride extrusion. Here we show that ClC-2 were upregulated functionally in CA1 pyramidal cells in pilocarpine-treated rats, and that an observed increase in ClC-2 currents in CA1 pyramidal cells was reversed by L655,708, a specific antagonist of alpha5 subunit containing GABA(A) receptor. PMID- 21549812 TI - The PI/GLO-like locus in orchids: duplication and purifying selection at synonymous sites within Orchidinae (Orchidaceae). AB - Positive selection and relaxation of purifying constraints after duplication events have driven the functional diversification of gene families involved in development. One example of this occurred within the plant MADS-box genes. The evolution of the orchid flower was driven by duplication events followed by sub- and neo-functionalization of class B DEF-like MADS-box genes, which are present at three to four copies in the orchid genome. In contrast, the orchid PI/GLO-like class B MADS-box genes have been reported thus far as single-copy loci, with the only exception of Habenaria radiata. We isolated a novel PI/GLO-like gene (OrcPI2) in Orchis italica, which is different than the previously characterized OrcPI locus. The presence of two functional paralogs of PI/GLO-like genes in orchids is detectable only within the tribe Orchidinae. Evolutionary analyses revealed an apparent relaxation of purifying selection acting on the two PI/GLO like paralogs of the Orchidinae when compared to the single-copy PI/GLO-like genes found in other orchid species. Furthermore, by measuring dN/dS (omega) ratios, we show that a high percentage of sites between the two PI/GLO-like paralogs have different evolutionary pressures. Interestingly, the apparent relaxation of selective constraints on the two PI/GLO-like paralogs is due to strong purifying selection at synonymous sites rather than to a high value of nonsynonymous substitution rate. This peculiar evolutionary pattern might be related to molecular processes such as mRNA folding and/or translational efficiency control. These processes could potentially be involved in or predate the functional diversification of the two PI/GLO-like paralogs within Orchidinae. PMID- 21549813 TI - Involvement of oxidative stress-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic signals in methylmercury-induced neuronal cell injury. AB - Methylmercury (MeHg) is well-known for causing irreversible damage in the central nervous system as well as a risk factor for inducing neuronal degeneration. However, the molecular mechanisms of MeHg-induced neurotoxicity remain unclear. Here, we investigated the effects and possible mechanisms of MeHg in the mouse cerebrum (in vivo) and in cultured Neuro-2a cells (in vitro). In vivo study showed that the levels of LPO in the plasma and cerebral cortex significantly increased after administration of MeHg (50MUg/kg/day) for 7 consecutive weeks. MeHg could also decrease glutathione level and increase the expressions of caspase-3, -7, and -9, accompanied by Bcl-2 down-regulation and up-regulation of Bax, Bak, and p53. Moreover, treatment of Neuro-2a cells with MeHg significantly reduced cell viability, increased oxidative stress damage, and induced several features of mitochondria-dependent apoptotic signals, including increased sub-G1 hypodiploids, mitochondrial dysfunctions, and the activation of PARP, and caspase cascades. These MeHg-induced apoptotic-related signals could be remarkably reversed by antioxidant NAC. MeHg also increased the phosphorylation of ERK1/2 and p38, but not JNK. Pharmacological inhibitors NAC, PD98059, and SB203580 attenuated MeHg-induced cytotoxicity, ERK1/2 and p38 activation, MMP loss, and caspase-3 activation in Neuro-2a cells. Taken together, these results suggest that the signals of ROS-mediated ERK1/2 and p38 activation regulated mitochondria dependent apoptotic pathways that are involved in MeHg-induced neurotoxicity. PMID- 21549814 TI - Inferences from an ethnobotanical field expedition in the selected locations of Sivas and Yozgat provinces (Turkey). AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study was aimed to ascertain the present situation of the traditional knowledge on wild plant utilization for medicinal and dietary purposes in two neighboring provinces, Sivas and Yozgat located in the eastern threshold of Anatolia. MATERIALS AND METHODS: Information was collected by face-to-face interviews with 300 individuals in 20 selected sites. The demographic characteristics of the informants were evaluated and cross relationships with the recorded data were analyzed by SPSS statistical software. In order to justify the information reliability, "informant's consensus factor" (F(IC)) was estimated and to find the local importance of taxa "use value" (UV) were estimated. RESULTS: Altogether 166 utilizations recorded in the surveyed area were obtained from 100 taxa belonging to 38 plant families. Among these utilizations 89 were medicinal, 54 were used as foodstuff or spice, and 23 were for various other ethnobotanical (animal fodder, etc.) purposes. Those with the highest number of utilized taxa, Asteraceae, Rosaceae, Lamiaceae, Fabaceae and Polygonaceae members were employed for various purposes. Respiratory system disorders and gastrointestinal ailments were the most frequently referred to disease categories for which plant remedies were utilized for treatment. CONCLUSION: The area surveyed is known to have a high rate of migration from countrysides to metropolitan areas in Turkey or abroad to procure employment. Therefore, results of this ethnobotanical survey were important to find out the present situation of traditional knowledge in the area. Demographic data revealed that most of the inhabitants were remigrants from an urban area. Another encouraging point in terms of the Turkish ethnobotanical repository is that they still practice the information transmitted from their ancestors even after long dwelling in metropolitan areas. PMID- 21549815 TI - Investigation of Ehrlich ascites tumor cell death mechanisms induced by Synadenium umbellatum Pax. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Synadenium umbellatum Pax. is widely found in South America and empirically used in Brazil for the treatment of several diseases, mainly cancer. The aim of the study was to investigate cell death mechanisms induced by Synadenium umbellatum Pax. using Ehrlich ascites tumor (EAT) cells, as well as the myelotoxicity potential of this plant. MATERIALS AND METHODS: S. umbellatum cytotoxicity was evaluated in EAT cells by trypan blue exclusion and MTT reduction test and the mechanisms involved in EAT cell death were investigated by light and fluorescence microscopy, flow cytometry and immunocytochemistry. Investigation of S. umbellatum myelotoxicity was performed by clonogenic assay of colony forming unit- granulocyte macrophage (CFU-GM). RESULTS AND CONCLUSION: Our results demonstrated that S. umbellatum decreased the viability of EAT cells using both methods. Morphological analyses revealed that S. umbellatum-treatment induced EAT cell death by apoptotic pathway. We demonstrated the occurrence of reactive oxygen species (ROS) overgeneration, increased intracellular Ca(2+) concentration, alteration in mitochondrial membrane potential, phosphatydylserine externalization, and activation of caspases 3, 8, and 9. However, S. umbellatum produced myelotoxicity in bone marrow cells in a concentration-dependent manner. In comparison to EAT cells, the effects of S. umbellatum in bone marrow cells were 8-fold lower. Taken together, our results showed that S. umbellatum induced apoptosis in EAT cells at several levels and seems more toxic to tumor cells than to normal bone marrow cells. PMID- 21549816 TI - Subchronic administration of Catha edulis F. (khat) extract is marked by elevation of cardiac biomarkers and subendocardial necrosis besides blood pressure alteration in rats. AB - ETHNPHARMACOLOGICAL RELEVANCE: Khat is a widely chewed herb for its stimulant effect, however, its effects on the cardiovascular system are a source of growing concern, as prevalence of chewing is increasing and susceptible individuals may experience cardiovascular episodes. This study attempted to evaluate cardiovascular substrates that predispose individuals to these episodes by using both biochemical and morphologic-pathologic studies. MATERIALS AND METHODS: Rats were treated with either Tween 80 (2% in distilled water) (CON), or khat extract (100mg/kg, K100; 200mg/kg, K200; or 400mg/kg, K400 doses) orally for 6 weeks. Blood pressure (BP) in each group was measured before dosing and 1, 2 and 3h after-dose as well as weekly for 6 weeks using Tail cuff method. On day 45, blood was drawn for assessment of cardiac biomarkers and animals were sacrificed, and histological examination was undertaken for any overt damage on the myocardium. RESULTS: K400 was the only dose that significantly increased BP at 2 (p<0.05) and 3h (p<0.001) postdose compared to predose level. Likewise, the 3h postdose BP of each week was significantly greater (p<0.001) than baseline BP only at 400mg/kg. However, when the weekly values were compared among themselves, the difference was not statistically significant and a progressive change in postdose BP had not been observed. On the other hand, predose systolic BP of K400 rats tended to decline at week 3 and significantly decreased (p<0.05) beyond week 4 compared to baseline values, but the decline was not significant for the rest of the doses. Biomarker assessments revealed that whereas levels of total creatine kinase were found to be elevated significantly for K100 (p<0.05), K200 and K400 (p<0.001 in both cases); aspartate aminotransferease was increased in K200 (p<0.01) and K400 (p<0.001) compared to CON rats. By contrast, levels of cardiac troponin T was significantly increased (p<0.001) only in K400 rats. Heart tissues of CON and K100 rats were normal, while those from K200 showed signs of focal lesions but normal architecture of the myocardium was maintained. K400 rats, however, displayed fragmentation and segmentation of fibers, edema and mottled staining. CONCLUSIONS: These findings collectively indicate that the high dose of crude khat extract modulated most of the hemodynamic, biochemical and histopathological parameters in rats and hence chronic use of khat at higher dose and for longer sessions bear a significant risk for cardiovascular morbidities. PMID- 21549817 TI - Illicium verum: a review on its botany, traditional use, chemistry and pharmacology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Illicium verum Hook. f. (Chinese star anise) has long been used in traditional Chinese medicine and food industry with the actions of dispelling cold, regulating the flow of Qi and relieving pain. MATERIALS AND METHODS: A bibliographic investigation was carried out by analyzing recognized books including Chinese herbal classic, and worldwide accepted scientific databases (Pubmed, SciFinder, Scopus and Web of Science) were searched for the available information on I. verum. RESULTS: I. verum is an aromatic evergreen tree of the family Illiciaceae. It is sometimes contaminated with highly toxic Japanese star anise (I. anisatum L.) and poisonous star anise (I. lanceolatum A. C. Smith), which contain several neurotoxic sesquiterpenes. Traditional uses of I. verum are recorded throughout Asia and Northern America, where it has been used for more than 10 types of disorders. Numerous compounds including volatiles, seco-prezizaane-type sesquiterpenes, phenylpropanoids, lignans, flavonoids and other constituents have been identified from I. verum. Modern pharmacology studies demonstrated that its crude extracts and active compounds possess wide pharmacological actions, especially in antimicrobial, antioxidant, insecticidal, analgesic, sedative and convulsive activities. In addition, it is the major source of shikimic acid, a primary ingredient in the antiflu drug (Tamiflu). AIM OF THE REVIEW: This review summarizes the up-to-date and comprehensive information concerning the botany, traditional use, phytochemistry and pharmacology of I. verum together with the toxicology, and discusses the possible trend and scope for future research of I. verum. PMID- 21549818 TI - Panax ginseng ameliorates airway inflammation in an ovalbumin-sensitized mouse allergic asthma model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng (PG) is a medicinal herb that has been used to treat various immune diseases including asthma and COPD. In this study, we investigated the inhibitory mechanism of PG on asthma parameters in mice. MATERIALS AND METHODS: BALB/c mice were sensitized with 20 MUg/200 MUl OVA adsorbed on 1.0mg/50 MUl aluminum hydroxide gel adjuvant by i.p. injection on days 0 and 14. Mice were then challenged with 5% OVA in PBS to the nose for 30 min once a day for 3 days, from day 20 until day 22, using a nebulizer. PG (20mg/kg) or vehicle was administrated by i.p. injection once a day 10 min before every OVA challenge for 3 days. The recruitment of inflammatory cells into bronchoalveolar lavage fluid or lung tissues was measured. The expression of EMBP, Muc5ac, CD40, and CD40 ligand (CD40L) in lung tissues was investigated. In addition, the cytokines and mitogen activated protein (MAP) kinases were measured by RT-PCR and Western blot. RESULTS AND CONCLUSIONS: PG restored the expression of EMBP, Muc5ac, CD40, and CD40L, as well as the mRNA and protein levels of interleukin (IL)-1beta, IL-4, IL-5, and tumor necrosis factor (TNF)-alpha. In addition, PG inhibited the numbers of goblet cells and further small G proteins and MAP kinases in bronchoalveolar lavage cells and lung tissues increased in ovalbumin-induced allergic asthma in mice. These results suggest that PG may be used as a therapeutic agent in asthma, based on reductions of various allergic responses. PMID- 21549819 TI - Cordyceps sinensis promotes exercise endurance capacity of rats by activating skeletal muscle metabolic regulators. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps sinensis is a traditional Chinese medicine used for promotion of health, longevity and athletic power. However, the molecular mechanism for anti-fatigue activity and physical fitness has not yet been reported. AIM OF THE STUDY: The present study was conducted to evaluate the exercise endurance promoting activities of fungal traditional Chinese medicine (FTCM) Cordyceps sinensis cultured whole mycelium (CS) and the underlying mechanisms. MATERIALS AND METHODS: CS was orally supplemented (200mg/kg body weight/day) to rats for 15days with or without swimming exercise along with exercise and placebo groups. RESULTS: Both CS supplementation and supplementation concurrent with exercise improved exercise endurance by 1.79- (P<0.05) and 2.9 fold (P<0.01) respectively as compared to placebo rats. CS supplementation concurrent with exercise also increased the swimming endurance by 1.32-fold (P<0.05) over the exercise group. To study the molecular mechanism of the observed effect, we measured the expression levels of endurance responsive skeletal muscle metabolic regulators AMPK, PGC-1alpha and PPAR-delta as well as endurance promoting and antioxidant genes like MCT1, MCT4, GLUT4, VEGF, NRF-2, SOD1 and TRX in red gastrocnemius muscle. Our results indicate that CS supplementation significantly upregulates the skeletal muscle metabolic regulators, angiogenesis, better glucose and lactate uptake both in exercised and non-exercised rats. We have also observed increased expression of oxidative stress responsive transcription factor NRF-2 and its downstream targets SOD1 and TRX by CS supplementation. CONCLUSION: CS supplementation with or without exercise improves exercise endurance capacity by activating the skeletal muscle metabolic regulators and a coordinated antioxidant response. Consequently, CS can be used as a potent natural exercise mimetic. PMID- 21549820 TI - Cytotoxic and genotoxic effects of defence secretion of Ulomoides dermestoides on A549 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ulomoides dermestoides (Fairmaire, 1893) is a cosmopolitan tenebrionid beetle reared by Argentine people who consume them alive as an alternative medicine in the treatment of different illnesses such as asthma, Parkinson's, diabetes, arthritis, HIV and specially cancer. AIM OF THE STUDY: To evaluate the cytotoxicity and DNA damage of the major volatile components released by Ulomoides dermestoides on human lung carcinoma epithelial cell line A549. MATERIALS AND METHODS: The defence compounds of Ulomoides dermestoides were extracted with dichloromethane and analyzed and quantified by capillary gas chromatography. The toxicity effects of the beetle's extract against A549 cell line were evaluated. Cytotoxicity was evaluated by MTT test and Trypan blue assay and genotoxicity was evaluated by the comet assay. The synthetic compounds, individually or combined, were also tested in A549 cells and normal mononuclear human cells. RESULTS: The defence compounds of Ulomoides dermestoides extracted with dichloromethane (methyl-1,4-benzoquinones, ethyl-1,4 benzoquinones and 1-pentadecene as major components) showed cytotoxic activity on A549 cells demonstrated by MTT test and Trypan blue assay, with IC(50) values of 0.26equivalent/ml and 0.34equivalent/ml, respectively (1equivalent=amount of components extracted per beetle). The inhibition of A549 cell proliferation with the synthetic blend (1,4-benzoquinone and 1-pentadecene) or 1,4-benzoquinone alone was similar to that obtained with the insect extract. 1-Pentadecene showed no inhibitory effect. Low doses of insect extract or synthetic blend (0.15equivalent/ml) inhibited mononuclear cell proliferation by 72.2+/-2.7% and induced significant DNA damage both in tumor and mononuclear cells. CONCLUSION: Results of this study demonstrated that defence compounds of Ulomoides dermestoides reduced cell viability and induced DNA damage. We also concluded that the insect benzoquinones are primarily responsible for inducing cytotoxicity and genotoxicity in culture cells. PMID- 21549821 TI - Inhibitory effects of processed Aconiti tuber on morphine-induced conditioned place preference in rats. AB - AIM OF THE STUDY: Our previous studies indicated that processed Aconiti tuber (PAT), a traditional Chinese herbal medicine, had antinociceptive effects and inhibitory effects on morphine tolerance by activation of kappa-opioid receptor (KOR). Preclinical studies also demonstrated that KOR agonists functionally attenuate addictive behaviors of morphine, such as conditioned place preference (CPP). Therefore, we hypothesize that PAT may inhibit morphine-induced CPP in rats. MATERIALS AND METHODS: (1) Five groups of rats (n=8 for each group) were alternately subcutaneous (s.c.) injected with morphine 10mg/kg (one group receive normal saline as a control) and normal saline for 8 days and oral co administrated with distilled water or PAT 0.3, 1.0, or 3.0 g/kg daily on days 2-9 during CPP training, respectively. (2) Other four groups of rats were randomly s.c. injected with nor-binaltorphimine (nor-BNI; 5mg/kg) or normal saline (as a control) 120 min before alternately s.c. with morphine and normal saline and oral co-administrated with distilled water or PAT 3.0 g/kg daily. Each rat was acquired pre-conditioning and post-conditioning CPP data and assayed dynorphin concentrations by radioimmunoassay in rat's nucleus accumbens (NAc) after CPP training. RESULTS: (1) PAT 1.0 or 3.0 g/kg dose-dependently decreased the morphine-induced increase of CPP scores. (2) Nor-BNI completely antagonized the inhibition of PAT on morphine-induced CPP. (3) PAT dose-dependently increased dynorphin content in rats' NAc after CPP training. CONCLUSIONS: (1) PAT dose dependently inhibited morphine-induced CPP. (2) The inhibition of PAT on morphine induced CPP was probably due to activation of KOR by increasing dynorphin release in rats' NAc. PMID- 21549822 TI - Effects of Salvia miltorrhiza in neural differentiation of rat mesenchymal stem cells with optimized protocol. AB - AIM OF THE STUDY: The present study was aimed to explore the effects of Salvia miltorrhiza in inducing rMSCs to differentiate into functional neurons. MATERIALS AND METHODS: rMSCs were isolated and cultured in vitro, then Salvia miltorrhiza was added to induce rMSCs to differentiate repeatedly for 5 times with an optimized protocol, and neurophysiological functions such as action potential, endocytosis and exocytosis of the induced cells were investigated. RESULTS: About 98% of rMSCs expressed markers related to neural stem cells after treatment with preinduction medium, but they remained fibroform, the classical morphological state of MSCs, after exposure to induction medium for 2h, and the induced cells showed a neural shape. Next, fetal bovine serum (FBS) was added into the induction medium, transforming the neuron-like cells into fibroform cells. Finally, after exposure to induction medium, the cells could be transformed into neuron-like cells again. After the procedure was repeated 5 times, the induced cells displayed a classical neural shape and more than 95% of them expressed neural markers, including TUJ-1, NF and synaptophysin. Furthermore, the induced cells displayed neurophysiological functions, as characterized by action potential, endocytosis and exocytosis in response to a solution with a high concentration of potassium (K(+)). CONCLUSION: Salvia miltorrhiza can induce rMSCs to differentiate into neurons with neurophysiological functions efficiently by an optimized protocol. PMID- 21549823 TI - In vitro and in vivo antioxidant effects of the ethanolic extract of Swertia chirayita. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Swertia chirayita, a medicinal herb endemic to the Tibetan region, is used as a special remedy for liver disorders. The hepatoprotective activity of its plant extracts has been associated with its antioxidant activity. This paper aims to investigate the in vitro and in vivo antioxidant effects of Swertia chirayita extracts (SCE). MATERIALS AND METHODS: Antioxidant ability of Swertia chirayita was investigated by employing several established in vitro methods. In vivo antioxidant activity was tested against CCl(4)-induced toxicity in mice. The levels and activities of malondialdehyde (MDA) and antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), were then assayed using standard procedures. RESULTS: SCE exhibited strong antioxidant ability in vitro. The liver and kidney of CCl(4)-intoxicated animals exhibited a significant (p<0.001) decrease in SOD, CAT, and GSH levels. Additionally, these organs exhibited a significant (p<0.001) increase in MDA level. CCl(4) did not exhibit toxicity on mice treated with SCE and Vitamin E. The effects of Swertia chirayita (three dosages) were comparable to those of Vitamin E, except in MDA level in the liver and GSH level in the kidney (p<0.05). CONCLUSION: This study suggests that the ethanolic extract of Swertia chirayita possesses in vitro and in vivo antioxidant effects. This supports the traditional use of Swertia chirayita in Tibetan medicine to cure liver diseases. PMID- 21549824 TI - Vascular protective potential of the total flavanol glycosides from Abacopteris penangiana via modulating nuclear transcription factor-kappaB signaling pathway and oxidative stress. AB - ETHNOPHARMACOLOGICAL RELEVANCE: "Sanxuelian", the rhizome of Abacopteris penangiana (AP), is traditionally used in Chinese medicine for the treatment of blood circulation stasis, hemorheology barriers, edema and inflammation for patients of metabolic syndrome. This study was to investigate the protective effect of the total flavanol glycosides from AP (FAP) on diabetic vascular impairments by measuring the extents of oxidative stress and inflammatory response in mice. MATERIALS AND METHODS: The experimental aortic pathology in diabetic mice was induced by fed on high-fat diet and injected with streptozotocin. The activities of FAP on attenuating aortas injuries, hypoglycemic, hypolipidemic, inhibiting oxidative stress and anti-inflammation were investigated. Additionally, the aortic expressions of nuclear transcription factor-kappaB (NFkappaB) were determined by western blot and immunohistochemistry analysis. Furthermore, the effects of FAP on human umbilical vein endothelia cells (HUVECs) were studied. RESULTS: In animal study, the results showed that FAP enhanced the activities of antioxidant enzymes and attenuated the levels of proinflammatory cytokines. The plasma lipid profiles and glucose level in FAP treated groups were significantly decreased along with the vascular impairments were alleviated. Moreover, the aortic expression of NFkappaB was decreased. In cellular experiment, FAP could inhibit the apoptosis of HUVECs induced by H(2)O(2). CONCLUSIONS: The results indicated that FAP had hypolipidemic, hypoglycemic and vascular protective activities and represented a potential herb for the treatment of aortic pathology involved with metabolic syndrome. PMID- 21549825 TI - Aqueous extract of Tribulus terrestris Linn induces cell growth arrest and apoptosis by down-regulating NF-kappaB signaling in liver cancer cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A medicinal herb Tribulus terrestris Linn has been used to treat various diseases including hepatocellular carcinoma. The aim of the present study was to investigate the anticancer activity of Tribulus terrestris Linn (TT) in liver cancer cells. MATERIALS AND METHODS: The antitumor activity of aqueous TT extract was analyzed by testing the cytotoxicity and the effect on clonogenecity in HepG2 cells. Apoptosis and cell cycle arrest induced by TT were dissected by flow cytometry and its inhibitory effect on NF-kappaB activity was determined by analyzing the expression levels of NF-kappaB/IkappaB subunit proteins. The suppression of NF-kappaB-regulated gene expression by TT was assessed by RT-PCR. RESULTS: TT extract repressed clonogenecity and proliferation, induced apoptosis, and enhanced accumulation in the G0/G1 phase of liver cancer cells. It also turned out that TT extract inhibited NF-kappaB dependent reporter gene expression and NF-kappaB subunit p50 expression, while it enhanced the cellular level of IkappaBalpha by inhibiting the phosphorylation and degradation of IkappaBalpha. In addition, IKK activity was inhibited in a dose dependent manner. Furthermore, TT extract suppressed the transcription of genes associated with cell cycle regulation, anti-apoptosis, and invasion. CONCLUSION: These data showed that TT extract blocks proliferation and induces apoptosis in human liver cancer cells through the inhibition of NF-kappaB signaling. Aqueous TT extract can be used as an anticancer drug for hepatocellular carcinoma patients. PMID- 21549826 TI - Substitutes for endangered medicinal animal horns and shells exposed by antithrombotic and anticoagulation effects. AB - AIM OF THE STUDY: Cornu Saigae Tataricae (antelope horn), Manis Squama (pangolin scale), Cornu Cervi Pantotrichum (velvet antler) and Cornu Bovis grunniens (yak horn) are valuable medicinal animal horns and shells (MAHS). As the major source of biological agents and ethnodrugs, MAHS show pretty good bioactivities. However, with the increased demand for MAHS, some of the medicinal resources are endangered, and there has been a concomitant increase in the prevalence of adulterated or impostor MAHS. It is of great significance to exploit the substitutes for endangered medicinal animal resources. This study is going to provide a new mode for the exploitation of the substitutes of MAHS. MATERIALS AND METHODS: Plasma recalcification time, thrombin time and thrombin consumption were recorded to evaluate the anticoagulation effect of MAHS. Dissolution rate of thrombus in vitro and whole blood-gore were observed to appraise the antithrombotic effect of MAHS. RESULTS: All the MAHS involved in this study except Cornu Procaprae Gutturosae (argali horn), Cornu Saigae Tataricae and Cornu Bovis (cattle horn) could not only prolong recalcification time (P<0.01) and thrombin time (P<0.01), but also dissolve the thrombus in vitro (P<0.01) and whole blood-gore (P<0.01). The bioactivities among MAHS differed greatly from each other. CONCLUSIONS: The results indicate that Cornu Caprae Hircus (goat horn), Cornu Bubali (water buffalo horn) and Trionycis Carapax (turtle shell) are rational to be explored as the substitutes of Cornu Saigae Tataricae, Cornu Bovis grunniens and Manis Squama, respectively. On the contrary, velvet antler is not suitable to be substituted by Cornu Cervi (deerhorn). We presume that the bioactive evaluation methods are effective means of seeking substitutive resources of endangered medicinal animals with the advantages of close correlation to drug action, low dosage, and high sensitiveness. PMID- 21549827 TI - Macrophages, rather than T and B cells are principal immunostimulatory target cells of Lycium barbarum L. polysaccharide LBPF4-OL. AB - AIM OF THE STUDY: Lycium barbarum L. is a renowned Yin strengthening agent in traditional Chinese medicine. Lycium barbarum L. polysaccharide-protein complex is well-known for its immunoregulatory and antitumor effects. LBPF4-OL is the glycan part of Lycium barbarum L. polysaccharide-protein complex fraction 4 (LBPF4). LBPF4-OL's active contribution in LBPF4 is still blank. In the study, we enrich the polysaccharide part of Lycium barbarum L. polysaccharide-protein complex, and investigate its immunostimulatory effects on mouse spleen cells, T cells, B cells and macrophages. MATERIALS AND METHODS: Balb/C mice were used in vitro and in vivo studies. In in vitro study, lymphocyte proliferations were analyzed with (3)H-TdR incorporation method. Miltenyi MicroBeads were used in the purification of lymphocytes. Activation of T and B cells was analyzed by flow cytometry. In order to obtain the peritoneal macrophages, mice were injected i.p. with 1mL of sodium thioglycollate 3 days prior to killing. Spleen cells were stimulated with LBPF4-OL and cytokine concentrations in the supernatants were determined by multiplex bead analysis. In in vivo study, mice were injected i.p. with 1 mL of normal saline or 100 MUg/mL LBPF4-OL daily for 6 days. Peritoneal macrophage functions were analyzed by enzyme-linked immunosorbent assay and flow cytometry assay. RESULTS: Spleen cells and lymphocyte proliferation assay indicated that LBPF4-OL markedly induced the spleen cell proliferation, but could not induce proliferation of purified T and B lymphocytes. Further research revealed that B cell proliferation took place in the presence of activated macrophages or LPS. Multiplex bead analysis showed that LBPF4-OL can obviously induce IL-6, IL-8, IL-10 and TNF-alpha production of the spleen cells in a concentration-dependent manner. Flow cytometric analysis showed that LBPF4-OL (i.p.) prompts CD86 and MHC-II molecules expression on macrophages. ELISA assay showed that LBPF4-OL can greatly strengthen macrophage releasing of TNF-alpha and IL-1beta. CONCLUSION: These results suggested that glycan LBPF4-OL plays an important role in the immunopharmacological activity of Lycium barbarum L. polysaccharide-protein complex, and primary mouse macrophages, rather than T and B cells, are the principal target cells of it. PMID- 21549828 TI - Morphological development of dendritic spines on rat cerebellar Purkinje cells. AB - The posterior cerebellum is strongly involved in motor coordination and its maturation parallels the development of motor control. Climbing and mossy fibers from the spinal cord and inferior olivary complex, respectively, provide excitatory afferents to cerebellar Purkinje neurons. From post-natal day 19 climbing fibers form synapses with thorn-like spines located on the lower primary and secondary dendrites of Purkinje cells. By contrast, mossy fibers transmit synaptic information to Purkinje cells trans-synaptically through granule cells. This communication occurs via excitatory synapses between the parallel fibers of granule cells and spines on the upper dendritic branchlets of Purkinje neurons that are first evident at post-natal day 21. Dendritic spines influence the transmission of synaptic information through plastic changes in their distribution, density and geometric shape, which may be related to cerebellar maturation. Thus, spine density and shape was studied in the upper dendritic branchlets of rat Purkinje cells, at post-natal days 21, 30 and 90. At 90 days the number of thin, mushroom and thorn-like spines was greater than at 21 and 30 days, while the filopodia, stubby and wide spines diminished. Thin and mushroom spines are associated with increased synaptic strength, suggesting more efficient transmission of synaptic impulses than stubby or wide spines. Hence, the changes found suggest that the development of motor control may be closely linked to the distinct developmental patterns of dendritic spines on Purkinje cells, which has important implications for future studies of cerebellar dysfunctions. PMID- 21549829 TI - Oxidative stress in human lymphocytes treated with fatty acid mixture: role of carotenoid astaxanthin. AB - Fatty acids (FA) have been shown to alter leukocyte function, and depending on concentration and type, they can modulate both inflammatory and immune responses. Astaxanthin (ASTA) is a carotenoid that shows notable antioxidant properties. In the present study we propose to evaluate the oxidative stress in human lymphocytes induced by a FA mixture and the possible protective role of ASTA. The present study showed that the FA mixture at 0.3mM caused a marked increase in the production of superoxide anion, hydrogen peroxide and nitric oxide, which was accompanied by an increase in total-SOD activity, in TBARS levels and a reduction of catalase activity and content of GSH and free thiol groups. The FA mixture also promoted an increase in intracellular Ca(2+) mobilization and in the proliferative capacity of B-lymphocytes. The addition of ASTA (2 MUM) partially decreased the ROS production and TBARS levels and increased the levels of free thiol groups. ASTA decreased the proliferative capacity of cells treated with FA but not by reducing intracellular calcium concentration. Based on these results we can conclude that ASTA can partially prevent oxidative stress in human lymphocytes induced by a fatty acid mixture, probably by blenching/quenching free radical production. PMID- 21549830 TI - Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study. AB - Fatigue is a common complaint among adolescents. We investigated the course of fatigue in females during the transition from adolescence to young adulthood and examined psychological, immunological, and life style risk factors for development of fatigue and chronic fatigue syndrome (CFS)-related symptoms. Six hundred and thirty-three healthy females (age 14.63+/-1.37 years) filled out questionnaires measuring fatigue severity, depressive symptoms, anxiety, chronic fatigue syndrome (CFS)-related symptoms, sleep features, and life style characteristics at baseline and 41/2 years thereafter. Of 64 participants LPS- and CD2CD28-induced cytokine data at baseline were available. The best predictor of fatigue in young adulthood was previous fatigue severity. In participants who were non-fatigued during adolescence and who experienced a notable increase in fatigue, fatigue development was preceded by emotional problems and CFS-related complaints during adolescence. Increases as well as decreases in fatigue severity were accompanied by respectively increase and decrease in depressive symptoms and anxiety, suggesting that these symptoms cluster and co-vary over time. Higher interferon (IFN)-gamma, higher IFN-gamma/interleukin (IL)-4 ratio, lower tumor necrosis factor-alpha and lower IL-10 at baseline were related to fatigue severity at follow up. The rise in total number of CFS-related symptoms at follow up was predicted by anxiety and decreased physical activity during adolescence. Sleep and substance use were associated with fatigue severity and anxiety and depression. In conclusion, vulnerability to develop fatigue and associated symptoms in young adulthood can to a certain extent be identified already years before the manifestation of complaints. PMID- 21549831 TI - 17alpha-Ethinylestradiol and nonylphenol affect the development of forebrain GnRH neurons through an estrogen receptors-dependent pathway. AB - There is growing evidence that neuroendocrine circuits controlling development and reproduction are targeted by EDCs. We have previously demonstrated that low concentrations of 17alpha-ethinylestradiol (EE2) disrupt the development of forebrain GnRH neurons during zebrafish development. The objectives of the present study were to determine whether the weak estrogenic compound, nonylphenol (NP), could elicit similar effects to EE2 and to what extent the estrogen receptors are involved in mediating these effects. Using immunohistochemistry, we confirmed that EE2 exposure induces an increase in the number of GnRH-ir neurons and we demonstrated that NP is able to produce similar effects in a concentration dependent manner. The effects of both NP and EE2 were shown to be blocked by the estrogen receptors (ERs) antagonist ICI 182-780, demonstrating the involvement of functional ERs in mediating their effects. Altogether, these results highlight the need to consider neuroendocrine networks as critical endpoints in the field of endocrine disruption. PMID- 21549832 TI - Alteration of the CNS pathway to the hippocampus in a mouse model of Niemann Pick, type C disease. AB - Niemann-Pick type C disease (NPC) is an autosomal recessive disorder that results in premature death due to progressive neurodegeneration including dementia. To understand neuronal pathways connecting to the hippocampus, retrograde transneuronal labeling method with Bartha strain of pseudorabies virus (PRV) was employed in 40 NPC+/+, NPC+/- and NPC-/- mice. Immunohistochemistry using polyclonal antibody against PRV and streological counting were used. The number of neurons and synapse in CA2&3 regions of the hippocampus decreased dramatically in the NPC-/- mouse compared to the NPC+/+ or +/- mouse. The number of PRV positive cell was significantly decreased in several regions including the entorhinal and piriform cortex in the NPC-/- mouse. More severely, lateral septal dorsal nucleus, dorsal entorhinal cortex and medial geniculate body showed no positive labeling in the NPC-/- mouse. However, the hippocampus, medial septal and supramammilary nuclei showed increased immunoreactivity in the NPC-/- mouse. Our data suggest that the synaptic loss and discontinuity of the CNS hippocampal pathway may contribute to understanding the mechanism of symptoms and functional disabilities such as memory and learning disturbance in NPC patients. PMID- 21549833 TI - Translational research involving oxidative stress and diseases of aging. AB - There is ample mounting evidence that reactive oxidant species are exacerbated in inflammatory processes, many pathological conditions, and underlying processes of chronic age-related diseases. Therefore there is increased expectation that therapeutics can be developed that act in some fashion to suppress reactive oxidant species and ameliorate the condition. This has turned out to be more difficult than at first expected. Developing therapeutics for indications in which reactive oxidant species are an important consideration presents some unique challenges. We discuss important questions including whether reactive oxidant species should be a therapeutic target, the need to recognize the fact that an antioxidant in a defined chemical system may be a poor antioxidant operationally in a biological system, and the importance of considering that reactive oxidant species may accompany the disease or pathological system rather than being a causative factor. We also discuss the value of having preclinical models to determine if the processes that are important in causing the disease under study are critically dependent on reactive oxidant species events and if the therapeutic under consideration quells these processes. In addition we discuss measures of success that must be met in commercial research and development and in preclinical and clinical trials and discuss as examples our translational research effort in developing nitrones for the treatment of acute ischemic stroke and as anti-cancer agents. PMID- 21549834 TI - Reaction of hemoglobin with HOCl: mechanism of heme destruction and free iron release. AB - Hypochlorous acid (HOCl) is generated by myeloperoxidase using chloride and hydrogen peroxide as substrates. HOCl and its conjugate base (OCl(-)) bind to the heme moiety of hemoglobin (Hb) and generate a transient ferric species whose formation and decay kinetics indicate it can participate in protein aggregation and heme destruction along with subsequent free iron release. The oxidation of the Hb heme moiety by OCl(-) was accompanied by marked heme destruction as judged by the decrease in and subsequent flattening of the Soret absorbance peak at 405 nm. HOCl-mediated Hb heme depletion was confirmed by HPLC analysis and in-gel heme staining. Exposure of Hb to increasing concentrations of HOCl produced a number of porphyrin degradation products resulting from oxidative cleavage of one or more of the carbon-methene bridges of the tetrapyrrole ring, as identified by their characteristic HPLC fluorescence and LC-MS. A nonreducing denaturing SDS PAGE showed several degrees of protein aggregation. Similarly, porphyrin degradation products were identified after exposure of red blood cells to increasing concentrations of HOCl, indicating biological relevance of this finding. This work provides a direct link between Hb heme destruction and subsequent free iron accumulation, as occurs under inflammatory conditions where HOCl is formed in substantial amounts. PMID- 21549835 TI - Nrf2 expression modifies influenza A entry and replication in nasal epithelial cells. AB - Influenza infection is a major cause of morbidity and mortality worldwide, especially during pandemics outbreaks. Emerging data indicate that phase II antioxidant enzyme pathways could play a role in virus-associated inflammation and immune clearance. While Nrf2-dependent gene expression is known to modify inflammation, a mechanistic role in viral susceptibility and clearance has yet to be elucidated. Therefore, we utilized differentiated human nasal epithelial cells (NEC) and an enzymatic virus-like particle entry assay, to examine the role Nrf2 dependent gene expression has on viral entry and replication. Herein, lentiviral vectors that express Nrf2-specific short hairpin (sh)-RNA effectively decreased both Nrf2 mRNA and Nrf2 protein expression in transduced human NEC from healthy volunteers. Nrf2 knockdown correlated with a significant increase in influenza virus entry and replication. Conversely, supplementation with the potent Nrf2 activators sulforaphane (SFN) and epigallocatechin gallate (EGCG) significantly decreased viral entry and replication. The suppressive effects of EGCG on viral replication were abolished in cells with knocked-down Nrf2 expression, suggesting a causal relationship between the EGCG-induced activation of Nrf2 and the ability to protect against viral infection. Interestingly, the induction of Nrf2 via nutritional supplements SFN and EGCG increased antiviral mediators/responses: RIG I, IFN-beta, and MxA at baseline in the absence of infection. Our data indicate that there is an inverse relationship between the levels of Nrf2 expression and the viral entry/replication. We also demonstrate that supplementation with Nrf2 activating antioxidants inhibits viral replication in human NEC, which may prove to be an attractive therapeutic intervention. Taken together, these data indicate potential mechanisms by which Nrf2-dependent gene expression regulates susceptibility to influenza in human epithelial cells. PMID- 21549836 TI - Assessment of newly synthesized mitochondrial DNA using BrdU labeling in primary neurons from Alzheimer's disease mice: Implications for impaired mitochondrial biogenesis and synaptic damage. AB - The purpose of our study was to assess mitochondrial biogenesis and distribution in murine primary neurons. Using 5-bromo-2-deoxyuridine (BrdU) incorporation and primary neurons, we studied the mitochondrial biogenesis and mitochondrial distribution in hippocampal neurons from amyloid beta precursor protein (AbetaPP) transgenic mice and wild-type (WT) neurons treated with oxidative stressors, rotenone and H(2)O(2). We found that after 20h of labeling, BrdU incorporation was specific to porin-positive mitochondria. The proportion of mitochondrial area labeled with BrdU was 40.3+/-6.3% at 20h. The number of mitochondria with newly synthesized DNA was higher in AbetaPP neuronal cell bodies than in the cell bodies of WT neurons (AbetaPP, 45.23+/-2.67 BrdU-positive/cell body; WT, 32.92+/ 2.49 BrdU-positive/cell body; p=0.005). In neurites, the number of BrdU-positive mitochondria decreased in AbetaPP cultures compared to WT neurons (AbetaPP, 0.105+/-0.008 BrdU-positive/MUm neurite; WT, 0.220+/-0.036 BrdU-positive/MUm neurite; p=0.010). Further, BrdU in the cell body increased when neurons were treated with low doses of H(2)O(2) (49.6+/-2.7 BrdU-positive/cell body, p=0.0002 compared to untreated cells), while the neurites showed decreased BrdU staining (0.122+/-0.010 BrdU-positive/MUm neurite, p=0.005 compared to the untreated). BrdU labeling was increased in the cell body under rotenone treatment. Additionally, under rotenone treatment, the content of BrdU labeling decreased in neurites. These findings suggest that Abeta and mitochondrial toxins enhance mitochondrial fragmentation in the cell body, and may cause impaired axonal transport of mitochondria leading to synaptic degeneration. PMID- 21549837 TI - The 'stage-by-stage' deposition of drugs from commercial single-active and combination dry powder inhaler formulations. AB - Inhalation of salmeterol xinafoate (SX) and fluticasone propionate (FP) from a combination product is reported to produce superior clinical outcomes in comparison to the concurrent administration of 'similar' doses via separate single-active inhalers. For bioequivalence determination across different products, emphasis is currently placed on the assessment of drug deposition within inertial impactors on a 'stage-by-stage' basis as stipulated in a recent European Medicines Agency guidance. The aim of this study was to compare the stage-by-stage deposition of drugs aerosolised from the single-active Accuhaler(r) products Serevent(r) (SX) and Flixotide(r) (FP) with the SX-FP combination product Seretide(r) Accuhaler(r) in vitro. Drug deposition on a stage by-stage basis was assessed using the next generation impactor (NGI). Significant differences in drug deposition profiles were obtained following aerosolisation from the single-active versus combination products. The concurrent administration of the two single-active products: Serevent(r) and Flixotide(r) Accuhaler(r) may not be bioequivalent to inhalation of the combination product Seretide(r) Accuhaler(r). The observed differences may have resulted from different characteristics of the active pharmaceutical ingredient (APIs) and the carrier alpha-lactose monohydrate between the single-active and combination inhalers and/or a change in the drug-carrier inter-particulate interaction as a consequence of the presence of a second active. PMID- 21549838 TI - A new drug nanocarrier consisting of polyarginine and hyaluronic acid. AB - The purpose of this study was to produce and characterize a variety of nanostructures comprised of the polyaminoacid polyarginine (PArg) and the polysaccharide hyaluronic acid (HA) as a preliminary stage before evaluating their potential application in drug delivery. PArg was combined with high- or low molecular-weight HA (HMWHA or LMWHA, respectively) to form nanoparticles by simply mixing polymeric aqueous solutions at room temperature. The average size of the resulting nanocarriers was between 116 and 155 nm, and their zeta potential value ranged from +31.3 to -35.9 mV, indicating that the surface composition of the particle could be conveniently modified according to the mass ratio of the polymers. Importantly, the systems prepared with HMWHA remained stable after isolation by centrifugation and in conditions that mimic the physiological medium, whereas particles that incorporated LMWHA were unstable. Transmission electron microscopy showed that the nanostructures made with HMWHA were spherical. Finally, the systems were stable for at least three months at storage conditions (4 degrees C). PMID- 21549839 TI - Effect of the non-ionic surfactant Poloxamer 188 on passive permeability of poorly soluble drugs across Caco-2 cell monolayers. AB - Drug permeability of the model drugs ketoprofen and nadolol across Caco-2 cell monolayers was determined in the absence and presence of the non-ionic surfactant Poloxamer 188 (Pluronic(r) F68, P-188). Stringent controls confirmed that P-188 in concentrations up to 50 mg/ml did not adversely affect cell viability or monolayer integrity. Equilibrium experiments confirmed that the drugs were merely passively transported. Caco-2 permeability of both drugs was found to be decreased by the surfactant in a concentration-dependent manner. Ultrafiltration revealed that both drugs were associated with surfactant micelles. The systematic investigation of micellization on passive absorption showed that association of drugs with P-188 micelles appears to depress their passive permeability under conditions where other transport mechanisms can be neglected. PMID- 21549841 TI - Gene engineering, purification, crystallization and preliminary X-ray diffraction of cytochrome P450 p-coumarate-3-hydroxylase (C3H), the Arabidopsis membrane protein. AB - Cytochrome P450s (P450s) are the most versatile biological catalysts in plants; however, because the structure of the P450s has not been fully established, their broad substrate specificity has been limitedly discussed. p-coumarate-3 hydroxylase (C3H) is an essential enzyme for the biosynthesis of phenolic natural products in plants, but all attempts to express and purify C3H, have failed. In this research, we developed a bacterial expression of Arabidopsis C3H by combinational mutagenesis and purified C3H as a catalytically active form. The modified C3H could be purified in the absence of detergent, and crystallized in two forms (orthorhombic and trigonal space group) under different conditions. X ray diffraction was processed to a 4.0 A resolution (first type crystal) and a 3.8 A resolution (second type crystal). Although the diffraction results of C3H(mod) crystals are not enough to determine crystallographic structure due to low resolution, the simplicity and rapidity of this technology are competitive advantages in comparison with other methods, and may contribute to structural analyses of other membrane proteins including P450s family. PMID- 21549840 TI - Interaction of an intracellular pentraxin with a BTB-Kelch protein is associated with ubiquitylation, aggregation and neuronal apoptosis. AB - Neuronal pentraxin with chromo domain (NPCD) comprises a group of neuronally expressed pentraxins with both membrane and cytosolic isoforms; the functions of cytosolic NPCD isoforms are not clear. Here, we demonstrate that a cytosolic NPCD isoform selectively interacts with the BTB-Kelch protein Mayven/Kelch-like 2 (KLHL2), an actin-binding protein implicated in process outgrowth in oligodendrocytes. The KLHL2-NPCD interaction was identified by a yeast two-hybrid screen and confirmed through colocalization and co-immunoprecipitation studies. Truncation analysis indicates that the Kelch domains of KLHL2 interact with the pentraxin domain of NPCD. NPCD forms protein inclusion bodies (aggresomes) when overexpressed in tissue culture cells, KLHL2 localizes to these aggresomes, and overexpression of KLHL2 increases NPCD aggresome formation. Since other members of the BTB-Kelch family can act as Cullin-RING type E3 ubiquitin ligases, we tested the potential role of KLHL2 as a ubiquitin ligase for NPCD. We found that KLHL2 interacts selectively with Cullin 3, a key component of BTB-Kelch ubiquitin ligase complexes. Further, overexpression of KLHL2 promotes NPCD ubiquitylation. Together, these results suggest a novel E3 ubiquitin ligase function of KLHL2, with NPCD as a substrate. As the formation of aggresomes is often associated with protein aggregation in neurodegenerative diseases, we tested the effects of NPCD overexpression and KLHL2 coexpression on neuronal viability. Overexpression of NPCD in hippocampal neurons led to cell death and apoptosis; this effect was exacerbated by KLHL2 co-expression. Our findings implicate KLHL2 in ubiquitin ligase activity, and suggest potential roles of NPCD and KLHL2 in neurodegeneration. PMID- 21549842 TI - Overexpression, purification and assessment of cyclosporin binding of a family of cyclophilins and cyclophilin-like proteins of the human malarial parasite Plasmodium falciparum. AB - Malaria represents a global health, economic and social burden of enormous magnitude. Chemotherapy is at the moment a largely effective weapon against the disease, but the appearance of drug-resistant parasites is reducing the effectiveness of most drugs. Finding new drug-target candidates is one approach to the development of new drugs. The family of cyclophilins may represent a group of potential targets. They are involved in protein folding and regulation due to their peptidyl-prolyl cis-trans isomerase and/or chaperone activities. They also mediate the action of the immunosuppressive drug cyclosporin A, which additionally has strong antimalarial activity. In the genome database of the most lethal human malarial parasite Plasmodium falciparum, 11 genes apparently encoding cyclophilin or cyclophilin-like proteins were found, but most of these have not yet been characterized. Previously a pET vector conferring a C-terminal His6 tag was used for recombinant expression and purification of one member of the P. falciparum cyclophilin family in Escherichia coli. The approach here was to use an identical method to produce all of the other members of this family and thereby allow the most consistent functional comparisons. We were successful in generating all but three of the family, plus a single amino-acid mutant, in the same recombinant form as either full-length proteins or isolated cyclophilin-like domains. The recombinant proteins were assessed by thermal melt assay for correct folding and cyclosporin A binding. PMID- 21549843 TI - Biophysical model estimation of neurovascular parameters in a rat model of healthy aging. AB - Neuronal, vascular and metabolic factors result in a deterioration of the cerebral hemodynamic response with age. The interpretation of neuroimaging studies in the context of aging is rendered difficult due to the challenge in untangling the composite effect of these modifications. In this work we integrate multimodal optical imaging in biophysical models to investigate vascular and metabolic changes occurring in aging. Multispectral intrinsic optical imaging of an animal model of healthy aging, the LOU/c rat, is used in combination with somatosensory stimulation to study the modifications of the hemodynamic response with increasing age. Results are fitted with three macroscopic biophysical models to extract parameters, providing a phenomenological description of vascular and metabolic changes. Our results show that 1) biophysical parameters are estimable from multimodal data and 2) parameter estimates in this population change with aging. PMID- 21549844 TI - Impairment in explicit visuomotor sequence learning is related to loss of microstructural integrity of the corpus callosum in multiple sclerosis patients with minimal disability. AB - Sequence learning can be investigated by serial reaction-time (SRT) paradigms. Explicit learning occurs when subjects have to recognize a test sequence and has been shown to activate the frontoparietal network in both contralateral and ipsilateral hemispheres. Thus, the left and right superior longitudinal fasciculi (SLF), connecting the intra-hemispheric frontoparietal circuits, could have a role in explicit unimanual visuomotor learning. Also, as both hemispheres are involved, we could hypothesize that the corpus callosum (CC) has a role in this process. Pathological damage in both SLF and CC has been detected in patients with Multiple Sclerosis (PwMS), and microstructural alterations can be quantified by Diffusion Tensor Imaging (DTI). In light of these findings, we inquired whether PwMS with minimal disability showed impairments in explicit visuomotor sequence learning and whether this could be due to loss of white matter integrity in these intra- and inter-hemispheric white matter pathways. Thus, we combined DTI analysis with a modified version of SRT task based on finger opposition movements in a group of PwMS with minimal disability. We found that the performance in explicit sequence learning was significantly reduced in these patients with respect to healthy subjects; the amount of sequence-specific learning was found to be more strongly correlated with fractional anisotropy (FA) in the CC (r=0.93) than in the left (r=0.28) and right SLF (r=0.27) (p for interaction=0.005 and 0.04 respectively). This finding suggests that an inter hemispheric information exchange between the homologous areas is required to successfully accomplish the task and indirectly supports the role of the right (ipsilateral) hemisphere in explicit visuomotor learning. On the other hand, we found no significant correlation of the FA in the CC and in the SLFs with nonspecific learning (assessed when stimuli are randomly presented), supporting the hypothesis that inter-hemispheric integrity is specifically relevant for explicit sequence learning. PMID- 21549845 TI - Mitochondrial DNA analysis reveals a unique population structure of the amphidromous sculpin Cottus pollux middle-egg type (Teleostei: Cottidae). AB - In this study, we examined nucleotide sequences from the first half of the mitochondrial control region gene to test for genetic differentiation in an amphidromous sculpin, Cottus pollux middle-egg type (ME) (Cottidae), obtained from 19 localities across its distribution range. Spatial analysis of molecular variance revealed five divergent groups of related haplotypes among this populations. Analysis with Migrate software revealed that gene flow was quite restricted among the groups, although it occurred practically between neighboring groups. It has previously been reported that the population structure among the amphidromous fishes of the various islands is low or non-existent, and is characterized mainly by the duration of the pelagic larval life. However, the present study demonstrated that the various C. pollux ME populations were different both among the islands, and within the island of the Japanese Archipelago. Our finding indicate that the unique population structure of C. pollux ME may be influenced not only by the extent of the pelagic larval phase of the species but also by the seasonal differentiation of its dispersal phase. PMID- 21549846 TI - Use of matrix-assisted laser desorption/ionisation mass spectrometry in cancer research. AB - Cancer significantly affects millions of people worldwide. It is possible to use proteomic techniques to aid in detection, monitoring of treatment and progression, as well as gaining an increased understanding of cancer. Matrix assisted laser desorption/ionisation (MALDI) mass spectrometry can be utilised to detect the presence of proteins and peptides within various samples from the body, including blood, biological fluids and tumour tissue. This review aims to introduce MALDI mass spectrometry and discuss a range of applications in the field of cancer research, from quantitative to qualitative methods. Also described is MALDI imaging mass spectrometry which differs from typical sample preparation methods, as analytes are ionised directly from the tissue. Finally, presented is a brief summary of the status of biomarker discovery using blood/serum and biological fluids samples, and the implications in the clinic. PMID- 21549848 TI - The effect of addition of olive oil and "Aceto balsamico di Modena" wine vinegar in conjunction with active atmosphere packaging on the microbial and sensory quality of "Lollo Verde" lettuce and rocket salad. AB - Fresh rocket "Eruca Sativa" and lettuce "Lollo Verde" leaves were stored with the addition of olive oil and wine vinegar "Aceto balsamico di Modena" under modified atmosphere packaging (MAP) (5% O(2)/10% CO(2)/85% N(2) for MAP A and 2% O(2)/5% CO(2)/93% N(2) for MAP B). The microbial (mesophilic, psychrotrophic bacteria and Enterobacteriacae), physical (color and firmness) and sensory parameters of samples were studied in relation to storage time (up to 10 days at 5 +/- 1 degrees C). The effect of wine vinegar and the application of both MAP treatments reduced the growth of all bacteria populations (p < 0.05). Samples with olive oil stored under MAP A gave the best score for overall impression (3 and 2.1 for MAP A and B respectively at the 9th day of storage) while the addition of vinegar limited sensory shelf-life to 3 days (p < 0.05). Firmness was negatively affected by wine vinegar while samples with olive oil stored under MAP A maintained firmness close to normal. Color attributes were maintained better under both MAP treatments (p < 0.05). PMID- 21549849 TI - Effect of several MAP compositions on the microbiological and sensory properties of Graviera cheese. AB - The shelf life of Graviera cheese, a full fat cheese produced in Heraklion (Crete Greece), was investigated. Graviera cheese was stored at 4 degrees C for up to 90 days in polyamide packages under three different modified atmosphere compositions. Control cheeses were packaged in air whereas MAP mixtures were MAP(1): 40% CO(2)/55% N(2)/5% O(2), MAP(2): 60% CO(2)/40% N(2) and MAP(3): 50% CO(2)/50% N(2). Sampling of product was carried out every 10 days to investigate its sensory quality and microbiological characteristics. Ten trained panelists participated in the sensory panel to evaluate the cheeses for external appearance (color, texture), taste, and flavor in a scale from 1 to 10 (1 very poor, 10 very good). The microbiological analysis revealed that there were no colonies of Staphylococcus aureus and Listeria monocytogenes whereas both Escherichia coli and Total Viable Counts (TVC) increased strongly in control samples but were inhibited under all MAP compositions. PMID- 21549847 TI - Complex loading affects intervertebral disc mechanics and biology. AB - BACKGROUND: Complex loading develops in multiple spinal motions and in the case of hyperflexion is known to cause intervertebral disc (IVD) injury. Few studies have examined the interacting biologic and structural alterations associated with potentially injurious complex loading, which may be an important contributor to chronic progressive degeneration. OBJECTIVE: This study tested the hypothesis that low magnitudes of axial compression loading applied asymmetrically can induce IVD injury affecting cellular and structural responses in a large animal IVD ex-vivo model. METHODS: Bovine caudal IVDs were assigned to either a control or wedge group (15 degrees ) and placed in organ culture for 7 days under static 0.2MPa load. IVD tissue and cellular responses were assessed through confined compression, qRT-PCR, histology and structural and compositional measurements, including Western blot for aggrecan degradation products. RESULTS: Complex loading via asymmetric compression induced cell death, an increase in caspase-3 staining (apoptosis), a loss of aggrecan and an increase in aggregate modulus in the concave annulus fibrosis. While an up-regulation of MMP-1, ADAMTS4, IL-1beta, and IL-6 mRNA, and a reduced aggregate modulus were induced in the convex annulus. CONCLUSION: Asymmetric compression had direct deleterious effects on both tissue and cells, suggesting an injurious loading regime that could lead to a degenerative cascade, including cell death, the production of inflammatory mediators, and a shift towards catabolism. This explant model is useful to assess how injurious mechanical loading affects the cellular response which may contribute to the progression of degenerative changes in large animal IVDs, and results suggest that interventions should address inflammation, apoptosis, and lamellar integrity. PMID- 21549850 TI - Human herpesvirus 6 infection after hematopoietic cell transplantation: is routine surveillance necessary? AB - Human herpesvirus 6 (HHV6) may be an important pathogen following allogeneic hematopoietic cell transplantation (HCT). We prospectively evaluated weekly HHV6 viremia testing after allogeneic HCT using a quantitative polymerase chain reaction (PCR)-based assay. HHV-6 viremia was detected in 46 of 82 (56%) patients at a median of 23 days post-HCT (range: day +10 to +168). More males (65% vs females 39%, P = .03) and recipients of umbilical cord blood (UCB 69% vs unrelated donor [URD], 46% vs sibling donor [20%] grafts, P = 0.01) reactivated HHV-6. Patients with HHV6 viremia had more cytomegalovirus (CMV) reactivation (26% vs 5.5%, P = .01) and unexplained fever and rash (23.9% vs 2.7%, P = .01) compared with patients without HHV6 viremia. High-level HHV6 (>= 25,000 copies/mL) versus lower levels were associated with more culture-negative pneumonitis (72.7% vs 22.8%, P = .01). Twenty HHV6-positive patients were treated with foscarnet, ganciclovir, or cidofovir for HHV6 or other coexistent viruses. Within 2 weeks, HHV6 viremia resolved more commonly in treated (65%) than untreated patients (31%), P = .02. Survival at 3 months was similar in treated and untreated patients (90% vs 81%, P = .4). Survival at 3 and 6 months post-HCT were not affected by HHV6 positivity (3 months HHV6+ 85% vs 78%, P = .46; 6 months HHV6+ 70% vs 72%, P = .89) or by HHV6 level (3-month high level 73% vs 89%, P = .23; 6-month high level 64% vs 71%, P = .54). Neither the occurrence of HHV6, degree of viremia, nor use of antiviral drugs influenced short-term survival after HCT. PMID- 21549851 TI - Functional characterization of the oxaloacetase encoding gene and elimination of oxalate formation in the beta-lactam producer Penicillium chrysogenum. AB - Penicillium chrysogenum is widely used as an industrial antibiotic producer, in particular in the synthesis of beta-lactam antibiotics such as penicillins and cephalosporins. In industrial processes, oxalic acid formation leads to reduced product yields. Moreover, precipitation of calcium oxalate complicates product recovery. We observed oxalate production in glucose-limited chemostat cultures of P. chrysogenum grown with or without addition of adipic acid, side-chain of the cephalosporin precursor adipoyl-6-aminopenicillinic acid (ad-6-APA). Oxalate accounted for up to 5% of the consumed carbon source. In filamentous fungi, oxaloacetate hydrolase (OAH; EC3.7.1.1) is generally responsible for oxalate production. The P. chrysogenum genome harbours four orthologs of the A. niger oahA gene. Chemostat-based transcriptome analyses revealed a significant correlation between extracellular oxalate titers and expression level of the genes Pc18g05100 and Pc22g24830. To assess their possible involvement in oxalate production, both genes were cloned in Saccharomyces cerevisiae, yeast that does not produce oxalate. Only the expression of Pc22g24830 led to production of oxalic acid in S. cerevisiae. Subsequent deletion of Pc22g28430 in P. chrysogenum led to complete elimination of oxalate production, whilst improving yields of the cephalosporin precursor ad-6-APA. PMID- 21549852 TI - Two cases of Schizophyllum asthma: is this a new clinical entity or a precursor of ABPM? AB - BACKGROUND: There is a close link between fungal sensitization and asthma severity. Although Schizophyllum commune (S. commune, "suehirotake" in Japanese), one of the basidiomycetous (BM) fungi, is a fungus that can cause allergic bronchopulmonary mycosis (ABPM) and allergic fungal sinusitis (AFS), whether the fungus causes or sensitizes subjects to asthma is unclear. METHODS: The bronchial provocation test using S. commune antigen was performed in two asthmatics who had demonstrated positive skin reactions to the S. commune antigen, and low dose of itraconazole (50 mg/day) was prescribed as an adjunctive therapy for 2 weeks. The allergological features and clinical manifestations of these patients are herein evaluated and discussed. RESULTS: Case 1 was a 71-year-old female, and case 2 was a 69-year-old male. Both patients demonstrated positive reactions to the inhalation test. A diagnosis of AFS or ABPM was excluded in both patients because of the lack of a history of pulmonary infiltrates, central bronchiectasis, a history of expectoration of brown plugs or flecks, or sinusoidal findings. Although the efficacy of itraconazole in our cases was unclear, the elevated titer of the specific IgG-for S. commune in case 2 gradually decreased during the period of antifungal therapy. CONCLUSIONS: The two patients described herein were diagnosed to have bronchial asthma caused by S. commune; so-called Schizophyllum asthma. S. commune may also be a causative fungal antigen of bronchial asthma. PMID- 21549853 TI - Switching Clostridium acetobutylicum to an ethanol producer by disruption of the butyrate/butanol fermentative pathway. AB - Solventogenic clostridia are well-known since almost a century due to their unique capability to biosynthesize the solvents acetone and butanol. Based on recently developed genetic engineering tools, a targeted 3-hydroxybutyryl-CoA dehydrogenase (Hbd)-negative mutant of Clostridium acetobutylicum was generated. Interestingly, the entire butyrate/butanol (C(4)) metabolic pathway of C. acetobutylicum could be inactivated without a severe growth limitation and indicated the general feasibility to manipulate the central fermentative metabolism for product pattern alteration. Cell extracts of the mutant C. acetobutylicum hbd::int(69) revealed clearly reduced thiolase, Hbd and crotonase but increased NADH-dependent alcohol dehydrogenase enzyme activities as compared to the wildtype strain. Neither butyrate nor butanol were detected in cultures of C. acetobutylicum hbd::int(69), and the formation of molecular hydrogen was significantly reduced. Instead up to 16 and 20g/l ethanol were produced in glucose and xylose batch cultures, respectively. Further sugar addition in glucose fed-batch fermentations increased the ethanol production to a final titer of 33g/l, resulting in an ethanol to glucose yield of 0.38g/g. PMID- 21549854 TI - One-step production of lactate from cellulose as the sole carbon source without any other organic nutrient by recombinant cellulolytic Bacillus subtilis. AB - Although intensive efforts have been made to create recombinant cellulolytic microorganisms, real recombinant cellulose-utilizing microorganisms that can produce sufficient secretory active cellulase, hydrolyze cellulose, and utilize released soluble sugars for supporting both cell growth and cellulase synthesis without any other organic nutrient (e.g., yeast extract, peptone, amino acids), are not available. Here we demonstrated that over-expression of Bacillus subtilis endoglucanase BsCel5 enabled B. subtilis to grow on solid cellulosic materials as the sole carbon source for the first time. Furthermore, two-round directed evolution was conducted to increase specific activity of BsCel5 on regenerated amorphous cellulose (RAC) and enhance its expression/secretion level in B. subtilis. To increase lactate yield, the alpha-acetolactate synthase gene (alsS) in the 2,3-butanediol pathway was knocked out. In the chemically defined minimal M9/RAC medium, B. subtilis XZ7(pBscel5-MT2C) strain (DeltaalsS), which expressed a BsCel5 mutant MT2C, was able to hydrolyze RAC with cellulose digestibility of 74% and produced about 3.1g/L lactate with a yield of 60% of the theoretical maximum. When 0.1% (w/v) yeast extract was added in the M9/RAC medium, cellulose digestibility and lactate yield were enhanced to 92% and 63% of the theoretical maximum, respectively. The recombinant industrially safe cellulolytic B. subtilis would be a promising consolidated bioprocessing platform for low-cost production of biocommodities from cellulosic materials. PMID- 21549855 TI - Manifestation of Pig-a mutant bone marrow erythroids and peripheral blood erythrocytes in mice treated with N-ethyl-N-nitrosourea: direct sequencing of Pig a cDNA from bone marrow cells negative for GPI-anchored protein expression. AB - Our previous rat studies indicate that the endogenous Pig-a gene is a promising reporter of in vivo mutation and potentially useful as the basis for an in vivo genotoxicity assay. The function of the Pig-a protein in the synthesis of glycosylphosphatidyl inositol (GPI) anchors is conserved in variety of eukaryotic cells, including human and rodent cells, which implies that Pig-a mutants can be measured in a similar manner in different mammalian species. In the present study, we developed a flow cytometric Pig-a assay for rapidly measuring gene mutation in the mouse. An antibody to TER-119, a specific cell-surface marker of murine erythroid lineage, was used to identify erythrocytes in peripheral blood (PB) and erythroids in bone marrow (BM). An antibody to CD24, a GPI-anchored protein, was used to identify Pig-a mutants as CD24-negative cells. CD-1 mice were administered a single dose of 100mg/kgN-ethyl-N-nitrosourea (ENU), and PB and BM were collected at 1, 2, and 4 weeks after dosing. While the Pig-a mutant frequency (MF) in PB was increased moderately at 2 and 4 weeks after ENU dosing, the Pig-a MF in BM was strongly increased starting at 1 week after the dosing, with the elevated MF persisting for at least 4 weeks after the dosing. We also used flow cytometric sorting to isolate CD24-negative erythroids from the BM of ENU-treated mice. cDNA sequencing indicated that these cells have mutations in the Pig-a gene, with base-pair substitutions typical of ENU-induced mutation spectra. The results indicate that the Pig-a mutation assay can be adapted for measuring mutation in BM erythroids and PB of mice. Taken together, the data suggest that Pig-a mutants are fixed in the BM, where they further proliferate and differentiate; erythrocytes derived from these BM Pig-a mutants transit from the BM and accumulate in PB. PMID- 21549856 TI - Thin-layer chromatography, overlay technique and mass spectrometry: a versatile triad advancing glycosphingolipidomics. AB - Much effort is currently invested in the development of mass spectrometry-based strategies for investigating the entirety of glycosphingolipids (GSLs) of a certain cell type, tissue, organ or body encompassing the respective glycosphingolipidome. As part of the investigation of the vertebrate glycosphingolipidome, GSL analysis is undergoing rapid expansion owing to the application of novel mass spectrometry techniques acting as the linchpin in the network of collaborations challenged to unravel structural and functional aspects of GSLs. Difficulties may arise in the determination of the exact structures of GSLs due to the heterogeneity of the sugar moiety varying in the number and sequence of monosaccharides, and their anomeric configuration and linkage type, which make up the principal items of the glyco code of biologically active carbohydrate chains. The ceramide variability caused by the diversity of the long chain amino alcohol and the fatty acid, which both may vary in chain length, degree of unsaturation, and type and number of substituents, further contributes to the increasing number of possible GSL species. In view of this heterogeneity, a single-method analytical mass spectrometry (MS) technique without auxiliary tools yields limited data, providing only partial structural information of individual GSLs in complex mixtures. Approaching this challenge, current advances on a triad system matching three complementary methods are described in this review: (i) silica gel based TLC separation of GSLs, (ii) their overlay detection on the TLC plate (mostly based on antibody-mediated recognition), and (iii) direct and indirect MS based structural characterization, i.e. directly on the TLC plate or in lipid extracts from silica gel. We will focus on recent improvements by employing antibodies, AB(5) toxins and bacteria for direct IR MALDI-o-TOF MS and indirect ESI-QTOF MS analysis of GSLs. We believe that the combinatorial approach using conventional TLC and modern mass spectrometry provides a developmental advance in exploring the glycosphingolipidome of biological material. PMID- 21549857 TI - Deriving a probabilistic syntacto-semantic grammar for biomedicine based on domain-specific terminologies. AB - Biomedical natural language processing (BioNLP) is a useful technique that unlocks valuable information stored in textual data for practice and/or research. Syntactic parsing is a critical component of BioNLP applications that rely on correctly determining the sentence and phrase structure of free text. In addition to dealing with the vast amount of domain-specific terms, a robust biomedical parser needs to model the semantic grammar to obtain viable syntactic structures. With either a rule-based or corpus-based approach, the grammar engineering process requires substantial time and knowledge from experts, and does not always yield a semantically transferable grammar. To reduce the human effort and to promote semantic transferability, we propose an automated method for deriving a probabilistic grammar based on a training corpus consisting of concept strings and semantic classes from the Unified Medical Language System (UMLS), a comprehensive terminology resource widely used by the community. The grammar is designed to specify noun phrases only due to the nominal nature of the majority of biomedical terminological concepts. Evaluated on manually parsed clinical notes, the derived grammar achieved a recall of 0.644, precision of 0.737, and average cross-bracketing of 0.61, which demonstrated better performance than a control grammar with the semantic information removed. Error analysis revealed shortcomings that could be addressed to improve performance. The results indicated the feasibility of an approach which automatically incorporates terminology semantics in the building of an operational grammar. Although the current performance of the unsupervised solution does not adequately replace manual engineering, we believe once the performance issues are addressed, it could serve as an aide in a semi-supervised solution. PMID- 21549858 TI - The selective p38 mitogen-activated protein kinase inhibitor, SB203580, improves renal disease in MRL/lpr mouse model of systemic lupus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease accompanying excessive inflammatory responses in a wide range of organs. Abnormal activation of p38 MAPK has been postulated to contribute to the inflammation of SLE, leading to progressive tissue and organ damages to develop lupus nephritis and autoimmune hepatitis. In order to determine whether p38 MAPK inhibitor is effective in mouse model of SLE, a specific inhibitor of p38 MAPK SB203580 was orally administrated to MRL/lpr mice aged from 14 to 22 weeks. Renal and hepatic functions, as well as pathologic changes of important organs including kidney, liver and spleen of MRL/lpr mice were evaluated. As a result, we showed that SB203580 improved renal function by decreasing the levels of proteinuria and serum BUN, ameliorating the pathologic changes of kidney and reducing Ig and C(3) depositions in the kidney. Hepatocytes necrosis, recruitment and proliferation of leucocytes in liver and spleen were found to be inhibited by administration of SB203580. Therefore, p38 MAPK activation may be partially responsible for escalating autoimmune renal, hepatic and splenic destruction, and its inhibitor may lighten the autoimmune attack in these important organs and improve renal function. Our study reveals that the selective blockade of p38 MAPK is effective to prevent and treat the disease in this model of SLE. PMID- 21549859 TI - A 5-year prospective follow-up study in essential cryofibrinogenemia patients. AB - INTRODUCTION: Cryofibrinogenemia may be essential, or secondary to diseases such as neoplasia, infection, thrombosis, and collagen vascular diseases. In a previous study, we reported the occurrence of neoplasia in some essential cryofibrinogenemia patients after a short period of follow-up. PURPOSE: We performed a prospective multi-center 5-year follow-up study in essential cryofibrinogenemia patients (2005-2009). RESULTS: 23 patients with essential cryofibrinogenemia were included, mean age 59 years (range: 33-79), 14 males. After a mean follow-up period of 24 months, 11/23 (47%) of cases that were initially diagnosed as essential cryofibrinogenemia were found to have an underlying lymphoma (6 T lymphoma and 5 B lymphoma). CONCLUSION: This prospective study suggests that some cases of cryofibrinogenemia that are initially considered as essential, may have underlying lymphoma. Thus, we further suggest that regular follow-up should be performed in patients with essential cryofibrinogenemia. PMID- 21549860 TI - Kawasaki disease: current aspects on aetiopathogenesis and therapeutic management. AB - Kawasaki disease (KD) is a vasculitis that affects mainly children of 6 months to 4 years old. It is important to be early recognised so as to limit the inflammatory cascade that may lead to aneurysmatic dilatations of coronary arteries. The causative agent of KD has not been still indentified and the aetiopathogenetic theories are based on epidemiologic, laboratory and histological data. The management of the disease is divided according to the clinical stage and patients' follow up should be continued for years after the disease onset. The exact period is determined by the risk level of the KD. PMID- 21549861 TI - Angiogenic cytokines and growth factors in systemic sclerosis. AB - Systemic sclerosis is an autoimmune connective tissue disorder characterized by a widespread microangiopathy, autoimmunity and fibrosis of the skin and of various internal organs. Microangiopathy is characterized by a reduced capillary density and an irregular chaotic architecture that lead to chronic tissue hypoxia. Despite the hypoxic conditions, there is no evidence for a sufficient compensative angiogenesis in SSc. Furthermore, vasculogenesis is also impaired. An imbalance between angiogenic and angiostatic factors might explain the pathogenetic mechanisms of SSc vasculopathy. As far as angiogenic factors are concerned, within the most important are vascular endothelial growth factor (VEGF) and its receptors, platelet derived growth factor (PDGF), transforming growth factor beta (TGF-beta), fibroblast growth factor -2 (FGF-2), angiopoietin 1 (Ang-1), stromal cell-derived factor 1 (SDF-1/CXCL12), endothelin-1 (ET-1), monocyte chemoattractant protein -1 (MCP-1), urokinase type plasminogen activator receptors (uPAR) and kallikreins, vascular adhesion molecules. On the other hand, angiostatic factors include: endostatin, angiostatin, thrombospodin-1 (TSP-1), angiopoietin 2 (Ang-2). Our knowledge concerning the dysregulation of angiogenic homeostasis is largely incomplete and needs further research, for the future. PMID- 21549862 TI - m-Calpain activation in vitro does not require autolysis or subunit dissociation. AB - Calpains are Ca(2+)-dependent, intracellular cysteine proteases involved in many physiological functions. How calpains are activated in the cell is unknown because the average intracellular concentration of Ca(2+) is orders of magnitude lower than that needed for half-maximal activation of the enzyme in vitro. Two of the proposed mechanisms by which calpains can overcome this Ca(2+) concentration differential are autoproteolysis (autolysis) and subunit dissociation, both of which could release constraints on the core by breaking the link between the anchor helix and the small subunit to allow the active site to form. By measuring the rate of autolysis at different sites in calpain, we show that while the anchor helix is one of the first targets to be cut, this occurs in the same time frame as several potentially inactivating cleavages in Domain III. Thus autolytic activation would overlap with inactivation. We also show that the small subunit does not dissociate from the large subunit, but is proteolyzed to a 40-45k heterodimer of Domains IV and VI. It is likely that this autolysis-generated heterodimer has previously been misidentified as the small subunit homodimer produced by subunit dissociation. We propose a model for m-calpain activation that does not involve either autolysis or subunit dissociation. PMID- 21549863 TI - Bone healing of commercial oral implants with RGD immobilization through electrodeposited poly(ethylene glycol) in rabbit cancellous bone. AB - Immobilization of RGD peptides on titanium (Ti) surfaces enhances implant bone healing by promoting early osteoblastic cell attachment and subsequent differentiation by facilitating integrin binding. Our previous studies have demonstrated the efficacy of RGD peptide immobilization on Ti surfaces through the electrodeposition of poly(ethylene glycol) (PEG) (RGD/PEG/Ti), which exhibited good chemical stability and bonding. The RGD/PEG/Ti surface promoted differentiation and mineralization of pre-osteoblasts. This study investigated the in vivo bone healing capacity of the RGD/PEG/Ti surface for biomedical application as a more osteoconductive implant surface in dentistry. The RGD/PEG/Ti surface was produced on an osteoconductive implant surface, i.e. the grit blasted micro-rough surface of a commercial oral implant. The osteoconductivity of the RGD/PEG/Ti surface was compared by histomorphometric evaluation with an RGD peptide-coated surface obtained by simple adsorption in rabbit cancellous bone after 2 and 4 weeks healing. The RGD/PEG/Ti implants displayed a high degree of direct bone apposition in cancellous bone and achieved greater active bone apposition, even in areas of poor surrounding bone. Significant increases in the bone to implant contact percentage were observed for RGD/PEG/Ti implants compared with RGD-coated Ti implants obtained by simple adsorption both after 2 and 4 weeks healing (P<0.05). These results demonstrate that RGD peptide immobilization on a Ti surface through electrodeposited PEG may be an effective method for enhancing bone healing with commercial micro-rough surface oral implants in cancellous bone by achieving rapid bone apposition on the implant surface. PMID- 21549864 TI - Clay enriched silk biomaterials for bone formation. AB - The formation of silk protein/clay composite biomaterials for bone tissue formation is described. Silk fibroin serves as an organic scaffolding material offering mechanical stability suitable for bone-specific uses. Clay montmorillonite (Cloisite(r) Na(+)) and sodium silicate are sources of osteoinductive silica-rich inorganic species, analogous to bioactive bioglass like bone repair biomaterial systems. Different clay particle-silk composite biomaterial films were compared with silk films doped with sodium silicate as controls for the support of human bone marrow derived mesenchymal stem cells in osteogenic culture. The cells adhered to and proliferated on the silk/clay composites over 2 weeks. Quantitative real time polymerase chain reaction analysis revealed increased transcript levels for alkaline phosphatase, bone sialoprotein, and collagen type 1 osteogenic markers in the cells cultured on the silk/clay films in comparison with the controls. Early evidence of bone formation based on collagen deposition at the cell-biomaterial interface was also found, with more collagen observed for the silk films with higher contents of clay particles. The data suggest that silk/clay composite systems may be useful for further study for bone regenerative needs. PMID- 21549865 TI - Characterization of a newly isolated strain Rhodococcus erythropolis ZJB-09149 transforming 2-chloro-3-cyanopyridine to 2-chloronicotinic acid. AB - 2-Chloronicotinic acid is receiving much attention for its effective applications as a key precursor in the synthesis of pesticides and medicines. In this study, a strain ZJB-09149 converting 2-chloro-3-cyanopyridine to 2-chloronicotinic acid was newly isolated and identified as Rhodococcus erythropolis, based on its physiological and biological tests, and 16S rDNA sequence analysis. In addition, the effects of inducer, carbon source and nitrogen source were examined. Maximum activity was achieved when the above parameters were set as 8 g/l E-caprolactam, 7 g/l yeast extract and 5 g/l maltose. Moreover, the biotransformation pathway of 2-chloro-3-cyanopyridine to 2-chloronicotinic acid in strain ZJB-09149 was investigated as well. This study revealed that the nitrile hydratase (NHase) and amidase expressed in R. erythropolis ZJB-09149 are responsible for the conversion of 2-chloro-3-cyanopyridine. This is the first time to report on the biotransformation preparation of 2-chloronicotinic acid. PMID- 21549866 TI - Copper exposure effects on yeast mitochondrial proteome. AB - Mitochondria play an important role on the entire cellular copper homeostatic mechanisms. Alteration of cellular copper levels may thus influence mitochondrial proteome and its investigation represents an important contribution to the general understanding of copper-related cellular effects. In these study we have performed an organelle targeted proteomic investigation focusing our attention on the effect of non-lethal 1mM copper concentration on Saccharomyces cerevisiae mitochondrial proteome. Functional copper effects on yeast mitochondrial proteome were evaluated by using both 2D electrophoresis (2-DE) and liquid chromatography coupled with tandem mass spectrometry. Proteomic data have been then analyzed by different unsupervised meta-analysis approaches that highlight the impairment of mitochondrial functions and the activation of oxidative stress response. Interestingly, our data have shown that stress response generated by 1mM copper treatment determines the activation of S. cerevisiae survival pathway. To investigate these findings we have treated yeast cells responsiveness to copper with hydrogen peroxide and observed a protective role of this metal. These results are suggestive of a copper role in the protection from oxidative stress possibly due to the activation of mechanisms involved in cellular survival and growth. PMID- 21549867 TI - Relationship between abdominal fat and bone mineral density in white and African American adults. AB - Several studies have documented relationships between adipose tissue and bone mineral density (BMD); however, the degree to which there are racial differences in this relationship is not known. The purpose of this study was to examine the relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and BMD among white and African American adults. The sample included 330 white women, 328 African American women, 307 white men, and 116 African American men 18-74 years of age. Dual-energy X-ray absorptiometry scans were used to measure BMD and computed tomography scans were used to measure abdominal VAT and SAT. Linear regression was used to assess the relationships between abdominal adiposity and BMD and to explore possible sex and race differences in the associations. In the total sample as well as in all sex-by race groups, VAT and SAT were negatively related to BMD, after adjustment for lean body mass (LBM) and several covariates. The VAT model (including covariates) explained 33.3% of the variance in BMD and the SAT model (including covariates) explained 32.7% of the variance in BMD. Being African American, being male, and having high LBM were all associated with higher BMD. Race and sex interactions were not significant, indicating that the relationships were similar across race and sex groups. In conclusion, BMD was inversely related to abdominal VAT and SAT in white and African American adults after adjustment for LBM. PMID- 21549868 TI - Great Eastern Japan Earthquake--possible marine environmental contamination by toxic pollutants. PMID- 21549869 TI - Geriatricians differ from generalist physicians in that they focus on improving function as opposed to focusing on treating specific diseases. Preface. PMID- 21549870 TI - Treatment strategies for sarcopenia and frailty. AB - Sarcopenia is the key feature of frailty in older people and a major determinant of adverse health outcomes such as functional limitations and disability. Resistance training and adequate protein and energy intake are the key strategies for the management of sarcopenia. Management of weight loss and resistance training are the most relevant protective countermeasures to slow down the decline of muscle mass and muscle strength. The quality of amino acids in the diet is an important factor for stimulating protein synthesis. Vitamin D deficiency should be treated, and new pharmacologic approaches for sarcopenia are currently assessed. PMID- 21549872 TI - Revitalizing the aged brain. AB - Optimal cognitive and emotional function is vital to independence, productivity, and quality of life. Cognitive impairment without dementia may be seen in 16% to 33% of adults older than 65 years, and is associated with significant emotional distress. Cognitive and emotional well-being are inextricably linked. This article qualifies revitalizing the aged brain, discusses neuroplasticity, and suggests practical neuroplasticity-based strategies to improve the cognitive and emotional well-being of older adults. PMID- 21549871 TI - Chronic heart failure in older adults. AB - Assessment and management of heart failure (HF) in older adults may be simplified and structured by the mnemonic DEFEAT-HF: Diagnosis, Etiology, Fluid volume, Ejection fraction, And Treatment of Heart Failure. A clinical diagnosis and etiology of HF can often be established during history and physical examination. Fluid volume status must be assessed by estimating jugular venous pressure in centimeters of water by identifying the top of the jugular venous pulsation in the neck and estimating its vertical height from the right atrium. Left ventricular ejection fraction must be obtained to classify patients into systolic and diastolic HF and to guide evidence-based therapy. PMID- 21549873 TI - Nutritional strategies for successful aging. AB - With increasing life expectancy in developed and developing countries, maintaining health and function in old age has become an important goal, including avoidance or optimal control of chronic diseases; maintenance or retarding the decline of physical and cognitive function; optimizing psychological health; and maintaining independent functioning in tasks related to self-care and societal interaction. This article discusses all of those, as well as other components of successful aging such as social network and socioeconomic status. PMID- 21549874 TI - Falls, osteoporosis, and hip fractures. AB - Osteoporosis and falls are distinct conditions that share the potential clinical endpoint of fracture. This article explores the associations between osteoporosis and falls by examining the epidemiology, risk factors, risk prevention, and treatments. It outlines the evidence on falls prevention, osteoporosis diagnosis, and fracture risk assessment. It includes several studies that challenge the common view on the use of fall prevention tools, dual energy X-ray absorptiometry testing, and postfracture bisphosphonate treatment. By understanding the evidence, it becomes clearer how to target populations at risk, interpret screening methods, and promote disease prevention and treatment. PMID- 21549875 TI - Late-onset hypogonadism. AB - Late-onset hypogonadism is a clinical and biological syndrome associated with advancing age and characterized by typical symptoms and a deficiency in serum testosterone levels. It is a common condition but often underdiagnosed and undertreated. The main symptoms of hypogonadism are reduced libido/erectile dysfunction, reduced muscle mass and strength, increased adiposity, osteoporosis/low bone mass, depressed mood, and fatigue. Testosterone replacement therapy is only warranted in the presence of both clinical symptoms suggesting hormone deficiency and decreased hormone levels. It improves libido and sexual function, bone density, muscle mass, body composition, mood, erythropoiesis, cognition, quality of life, and cardiovascular disease. PMID- 21549876 TI - Hypertension: how does management change with aging? AB - Hypertension is a significant risk factor for cardiovascular morbidity and mortality in people older than 60 years. Isolated systolic hypertension and widened pulse pressure appear to be more important than diastolic hypertension. Very low blood pressure and orthostatic hypotension are associated with increased mortality, and should be checked for at every visit. Best evidence suggests that adjusting hypertension goals with age, and starting therapy when blood pressure is greater than 160/90 leads to improved outcomes. Therapy should start with a thiazide diuretic (best evidence) or an angiotensin-converting enzyme inhibitor. PMID- 21549877 TI - Incontinence. AB - Urinary incontinence is a common problem among older women and men. Older adults are reluctant to seek treatment, and health care providers should inquire about symptoms. Treatment of urinary incontinence includes multiple, office-based modalities, such as behavioral approaches, medications, and devices. Older adults may also consider surgical options to improve urinary incontinence. Special consideration should be given to older adults with cognitive impairment and incontinence. PMID- 21549878 TI - The evaluation and management of delirium among older persons. AB - This article reviews the pathophysiology, prevalence, incidence, and consequences of delirium, focusing on the evaluation of delirium, the published models of care for prevention in patients at risk of delirium, and management of patients for whom delirium is not preventable. Evidence on why physical restraints should not be used for patients with delirium is reviewed. Current available evidence on antipyschotics does not support the role for the general use in the treatment of delirium. An example of a restraint-free, nonpharmacologic management approach [called the TADA approach (tolerate, anticipate, and don't agitate)] is presented. PMID- 21549879 TI - Weight loss in older persons. AB - Weight loss is common in older people. It is associated with increased morbidity and mortality, particularly when unintentional, excessive (>5% body weight), or associated with low body weight (body mass index <22 kg/m(2)). It is often unrecognized, the associated adverse effects not appreciated, and underlying causes not addressed. Intentional weight loss by overweight older people is probably appropriate only when functional problems have resulted from the excess weight. It is important to include, wherever possible, exercise in weight-loss measures to preserve skeletal muscle mass. PMID- 21549880 TI - Medical care in the nursing home. AB - With the advent of the graying of the baby boomers, there is an urgent need to enhance care in the nursing home. This article focuses on the areas where high quality care can improve outcomes. PMID- 21549881 TI - Diabetes and insulin resistance in older people. AB - Diabetes is a common condition in older people. Diabetes significantly lowers the chances of successful aging, and notably increases functional limitations and impairs quality of life. Diabetes in older persons represents significant medical, human, and socioeconomic burden. Multiple interventions are now available to treat patients with diabetes. Clinicians have to weigh the risks and benefits of the treatments available to prevent these complications. This article discusses the pathophysiology, diagnosis, and vascular complications of diabetes and summarizes the various risk factors that are the focus of clinical care. PMID- 21549882 TI - [Renal failure]. PMID- 21549883 TI - [Measurement of renal function in clinical practice: principles and limitations]. AB - Methods for measurement of glomerular filtration rate (GFR) (clearance in plasma, urine or both of an " exogenous " tracer, usually radio labeled) often are considered impractical from a clinical standpoint. Alternate methods proposed to estimate the GFR are based on plasma levels of " endogenous " tracers (creatinine, cystatin C). These methods are so imprecise that they provide little if any true reassurance with regards to warnings and recommended GFR values for the use of iodinated and gadolinium based contrast agents. PMID- 21549884 TI - [Imaging evaluation of renal function: principles and limitations]. AB - The kidney performs multiple functions. Glomerular filtration is the most studied of these functions. In clinical practice, the surgical indication for patients with unilateral uropathy is frequently based on the split renal function as demonstrated by scintigraphy. MRI is not yet validated as a technique but nonetheless offers an interesting non-radiating alternative to achieve both morphological and functional renal evaluation. Recent pulse sequences such as diffusion, arterial spin labeling, and blood oxygenation dependent imaging may also provide additional information. CT and US remain of limited value for the evaluation of renal function. PMID- 21549885 TI - [Kidney and iodinated and gadolinium-based contrast agents]. AB - In patients with renal failure, iodinated contrast agents may cause acute deterioration of the renal function and gadolinium-based contrast agents (GBCAs) may cause nephrogenic systemic fibrosis (NSF). The administration of a contrast agent must thus be reviewed for each patient and evaluation of renal function is paramount even though its estimation using formulas derived from the creatinine level may fluctuate. For iodinated contrast agents, contrast induced nephropathy is reduced by hydratation, preferably intravenous, when the GFR is less than 60 ml/min. The risk for intravenous injections is less than the risk for arterial injections, and the GFR threshold may be reduced to 45 ml/min. For gadolinium based contrast agents, patients at risk for NSF are those with end-stage renal disease and patients undergoing dialysis. In such cases, the injection of a gadolinium-based contrast agent is only considered after a risk-benefit analysis has been completed, an alternate linear or macrocyclic agent issued and the dose limited to 0,1 mmol Gd/kg. Recently, recommendations from US and European agencies have converged. LEARNING OBJECTIVES: to be familiar with the risk factors of CIN with iodinated contrast agents; to be familiar with hydration procedures for patients at risk of CIN; to be familiar with the diagnostic criteria of NSF; to be familiar with the classification of GBCA with regards to the risk of NSF; to be familiar with the contraindications of the different groups of GBCA. PMID- 21549886 TI - [Renal failure: diagnostic work-up]. AB - The purpose of this article is to review the diagnostic work-up of renal failure, acute or chronic. The role of the radiologist is to exclude the presence of a curable etiology such as urinary tract obstruction or vascular thrombosis. Renal ultrasound with Doppler imaging is the imaging modality of choice for this indication, and the use of a contrast agent is useful to evaluate renal perfusion. Non-contrast CT remains valuable for the diagnosis of some urinary tract pathologies. Finally, MRI is the most comprehensive imaging modality for the evaluation of the urinary tract, but performed as a second line modality mainly for practical reasons but also due to the non-negligible risk of nephrogenic systemic fibrosis secondary to the intravenous administration of gadolinium based contrast agent. PMID- 21549887 TI - [Renal failure and cystic kidney diseases]. AB - Cystic kidney diseases often are discovered at the time of initial work-up of renal failure through ultrasound or family history, or incidentally at the time of an imaging test. Hereditary diseases include autosomal dominant or recessive polycystic kidney disease (PKD), tuberous sclerosis (TS) and medullary cystic kidney disease (MCKD). Autosomal dominant PKD is characterized by large renal cysts developing in young adults. Renal failure is progressive and becomes severe around 50-60 years of age. Atypical cysts (hemorrhagic or hyperdense) are frequent on CT and MRI examinations. Imaging plays a valuable role in the management of acute complications such as cyst hemorrhage or infection. Autosomal recessive PKD is often detected in neonates, infants or young adults. It is characterized by renal enlargement due to the presence of small cysts and liver disease (fibrosis and biliary ductal dilatation). Late manifestation or slow progression of autosomal recessive PKD may be more difficult to distinguish from autosomal dominant PKD. These cystic kidney diseases should not be confused with non-hereditary incidental multiple renal cysts. In tuberous sclerosis, renal cysts are associated with angiomyolipomas and sometimes pulmonary lymphangioleiomyomatosis. Renal failure is inconstant. Other hereditary cystic kidney diseases, including MCKD and nephronophtisis, are usually associated with renal failure. Non-hereditary cystic kidney diseases include multicystic renal dysplasia (due to complete pelvi-ureteric atresia or hydronephrosis), acquired multicystic kidney disease (chronic renal failure, chronic hemodialysis) and varied cystic kidney diseases (multicystic renal disease, glomerulocystic kidney disease, microcystic kidney disease). PMID- 21549888 TI - [Imaging and renal failure: from inflammation to fibrosis]. AB - Multiple chronic renal diseases evolve to end-stage kidney disease due to progressive renal tissue fibrosis at the level of the interstitium or glomeruli. Fibrosis often results from transformation of the extracellular matrix by cytokines and chemokines released by activated cells in the setting of recurrent episodes of acute inflammation. Newer techniques to image intrarenal inflammation and fibrosis are mandatory for the non-invasive evaluation of these processes to improve follow-up and monitoring of drug therapy. These techniques are based on methods of cellular and molecular imaging, and methods of functional, such as diffusion weighted imaging, and structural, such as elastography. PMID- 21549889 TI - [Urological and medical complications of renal transplant]. AB - Medical complications from renal transplant (acute tubular necrosis, acute rejection, chronic rejection) are mainly imaged with Doppler ultrasound to first exclude vascular or urological causes for renal function impairment. Once these causes are excluded, imaging features are nonspecific and imaging is mainly used for follow-up and biopsy remains essential. Urological complications include postsurgical collections, urinary fistulas, obstructive uropathy, vesicoureteric reflux, infections and malignancies. Imaging plays a leading role in the diagnostic and therapeutic management of these complications. PMID- 21549890 TI - [Vascular complications following renal transplantation: diagnostic evaluation]. AB - Vascular complications after renal transplantation are the most frequent type of complication following urological complications. They may affect the function of the transplant. Early vascular complications include renal artery or vein thrombosis, lesions to the iliac vessels and cortical necrosis. Delayed complications mainly include renal artery stenosis, arteriovenous fistula, and rarely false aneurysm. Doppler sonography, sometimes with the use of intravenous contrast, is the imaging modality of choice in the acute setting or routine follow-up. MRI may be performed for additional morphological and functional evaluation while CT may provide additional evaluation of the arterial supply. Angiography is performed prior to endovascular treatment. PMID- 21549891 TI - [Pre-kidney-transplant evaluation of donors and recipients]. AB - The pretransplant imaging evaluation of recipients is mainly achieved with CT and has two objectives: detection of iliac artery calcifications that may have an impact on the site of the transplant and the type of arterial anastomosis; detection of a primary malignancy that would be a contraindication to transplantation. The pretransplant imaging evaluation of living donors relies on noninvasive techniques. CT angiography and MR angiography both allow the simultaneous evaluation of arteries, excretory tract and renal parenchyma. The goal is to achieve anatomical and functional renal evaluation in order to select the best donor and plan the surgical procedure. PMID- 21549892 TI - [Dyspnea, a cardinal symptom for the respiratory physician]. PMID- 21549893 TI - [There may be more to breath than breathing]. PMID- 21549894 TI - [Lung development abnormalities should not be restricted to respiratory paediatricians]. PMID- 21549895 TI - [Tuberculosis and non-tuberculous mycobacteria: Respiratory medicine on pole position]. PMID- 21549896 TI - [Follow-up after occupational asbestos exposure. Public examination (texts of experts)]. PMID- 21549897 TI - [Sarcoidosis and genetics]. AB - Familial features of sarcoidosis and observations in monozygotic twins affected by the condition suggest the presence of a genetic predisposition. Various genetic associations have been described with genes coding for proteins involved in immune regulation in particular at the level of interaction between T lymphocyte and antigen presenting cell. We review the various genetic targets described with techniques ranging from classic human lymphocyte antigen genotype to genome wide linkage scans. The 6p21 region has been highlighted, which includes relevant genes such as MHC class II, BTNL2 and TNFalpha. These studies show that the genetics of sarcoidosis are complex, that patient sub-groups exist, which may explain some of the heterogeneity in the results of genetic studies and that the interactions between genetic and environmental factors remains to be elucidated. PMID- 21549898 TI - [The costs of asthma in France and the economic implications of its level of control]. AB - INTRODUCTION: The prevalence of asthma is increasing in France and the proportion of patients with poorly controlled or uncontrolled asthma remains significant. The economic impact of this public health issue is still poorly documented and this is addressed in the present literature review. STATE OF THE ART: Older identified studies aimed to estimate the use of asthma-related health care resources according to the asthma severity. Only more recent studies have taken into account the level of control of the disease as well. A consistent finding was that asthma-related medical costs were highly dependent both on the degree of severity and level of control. PERSPECTIVES: Studies identified in this review used the recommendations current at the time of their publication to define severity or levels of control in connection to asthma-related medical consumption, which leads to important methodological variation among them. Economic evaluation which is generally based on annual consumption estimates is hampered by the fact that the level of control reflects only a short-term situation. CONCLUSIONS: Although data in the literature are consistent in showing that improved control of the disease significantly reduces the costs of its management, there is a need for economic studies based on recent definitions of control and using appropriate methodology. PMID- 21549899 TI - [COPD and inflammation: Statement from a French expert group. How to treat inflammation?]. AB - INTRODUCTION: Management of chronic obstructive pulmonary disease (COPD) has made considerable progress over the last 15 years, with the development of pulmonary rehabilitation, new molecules to facilitate smoking cessation, and several medical treatments. Many therapeutic needs, however, remain to be met. STATE OF THE ART: Several lines of research on inflammation and COPD are promising, and some will probably result in new treatments. These may target specific populations, identified by clinical phenotype or by biomarkers. The forthcoming arrival of iPDE-4s on the market illustrates how knowledge of inflammation and remodeling and of some of the underlying mechanisms finally, after many years' development, has broadened the range of treatments available to help improve patients' daily life and outcomes. PERSPECTIVES AND CONCLUSIONS: The availability of such treatments, however, does not mean that knowledge of the disease in the general population and among healthcare workers can be neglected. Early detection (at a stage when treatment can already be effective) and patient education which promotes therapeutic compliance and lasting lifestyle change need to be developed further. PMID- 21549900 TI - [Cancer and venous thromboembolism]. AB - INTRODUCTION: Cancer and venous thromboembolism are frequently associated. STATE OF THE ART: Venous thromboembolism is associated with a worse prognosis in patients with cancer. Thrombosis in cancer patients is related to the expression of tissue factor and other procoagulants by tumour cells. Surgery, chemotherapy and antiangiogenic agents are also associated with an increased risk of thrombosis. Venous thromboembolism may be the first manifestation of cancer, the risk being especially increased during the first six months following an unexplained episode of idiopathic thrombosis. Current evidence does not suggest that a systematic screening for cancer after an unexplained thrombosis is associated with a clinical benefit. Risk factors for thrombosis specific to the cancer population have been identified. A recent controlled trial suggests that low-molecular weight heparin may reduce the incidence of venous thromboembolism in patients with cancer. These results need to be confirmed. Treatment of venous thromboembolism in cancer patients is primarily based on low-molecular weight heparin administered for three or six months. PERSPECTIVES: Low-molecular weight heparin may increase the survival of patients with cancer through a direct effect on tumour biology. Several clinical trials are underway to confirm this hypothesis. CONCLUSION: Thrombosis in cancer patients is a frequent and difficult to treat condition. The role of long-term prophylaxis remains to be defined. The treatment of venous thromboembolism in cancer patients is primarily based on low molecular weight heparin. Large clinical trials are currently assessing the effect of low-molecular weight heparin on the long-term survival of patients with cancer. PMID- 21549901 TI - [Risk factors for recurrent venous thromboembolism]. AB - Recurrent venous thromboembolism (VTE) is frequent and can be fatal. Long-term antithrombotic treatment reduces the risk of recurrent VTE but increases the risk of bleeding and, therefore, cannot be proposed for all patients. Predicting the probability of recurrence in an individual patient is of utmost importance for assessing the risk-benefit ratio of long-term anticoagulation. Multiple clinical risk factors for recurrent VTE have been identified which include: unprovoked first episode, anatomical proximal location, male gender, residual venous thrombosis, cancer and antiphospholipid syndrome. d-dimer level after discontinuation of oral anticoagulation can help to predict the risk of recurrence with a good negative predictive value. Finally, genetic polymorphisms and rare inherited deficiencies of natural anticoagulant proteins do not seem to be strongly associated to recurrence. New antithrombotic drugs may, in the near future, improve the safety and of long-term anticoagulation treatment. PMID- 21549902 TI - [Congenital diaphragmatic hernia - mechanisms of pulmonary hypoplasia]. AB - Congenital diaphragmatic hernia (CDH) is a common cause of severe neonatal respiratory distress. Mortality and morbidity are determined by the amount of pulmonary hypoplasia (PH) that occurs and by the development of therapy-resistant pulmonary hypertension. The pathogenesis and aetiology of CDH and its associated anomalies are still largely unknown despite all research efforts. The pathogenesis of CDH is based on an assumption linking herniation of abdominal viscera into the thorax with compression of the developing lung. PH, however, can also result from reduced distension of the developing lung secondary to impaired fetal breathing movements. Our understanding of CDH has also been aided by basic research with the use of dietary, teratogen-induced, and knockout models of CDH. These studies indicate that lung hypoplasia may involve disturbances of mitogenic signalling pathways fundamental to embryonic lung development. Recent data reveal the role of disruption of a retinoid-signalling pathway in the pathogenesis of CDH. Although multifactorial inheritance may best explain most cases of CDH in humans, much has been learned about the genetic factors that play a role in the development of CDH by studies of patients with CDH caused by specific genetic syndromes and chromosome anomalies. More research is warranted to improve our understanding of normal and abnormal lung development in relation to CDH. Such investigations will help in the design of new treatment strategies to improve the natural course or even to prevent this anomaly. PMID- 21549903 TI - [House dust mites allergens]. AB - INTRODUCTION: House dust mite allergens from the Pyroglyphidae family are one of the most frequent and potent causes of allergic sensitatisation. Since 1988, molecular knowledge has increased considerably and structures and functions have been determined for most of them. BACKGROUND: Of the 22 defined allergens, the major IgE-binding has been reported for groups 1 and 2 accounting for 40-60% of the anti-house dust mite titres. Der p 1, 2, 4, 5, 7 allergens account for about 80% of the IgE-response. Der p 4, 5, 7, 11, 14, 15 have a prevalence of sensitization of about 10% each. The IgE-binding to groups 3, 8, 10, 20 is low. Most of the allergens can be identified by amino-acid sequences and the tertiary structures of the major allergens have been solved. Most allergens are proteolytic enzymes: Der p1 for instance is a cysteine protease. Der p 2 has structural homology with MD-2, a co-receptor of the Toll-like receptor (TLR4) whose ligand is LPS. Knowledge of the structure of mite allergens has allowed better interpretation of cross-reactions between allergens from the same family or from more distant families. CONCLUSIONS: From a practical point of view: the occurrence of multisensitisation is better explained and molecular epidemiology has allowed a better choice of allergen molecules useful for diagnosis. Finally, new concepts of immunotherapy based on genetically engineered hypoallergenic variants of major allergens, used alone or in combination, may lead to useful therapeutic approach. PMID- 21549904 TI - [Health impact of indoor mineral particle pollution]. AB - Mineral particle air pollution consists of both atmospheric pollution and indoor pollution. Indoor pollution comes from household products, cosmetics, combustion used to heat homes or cook food, smoking, hobbies or odd jobs. There is strong evidence that acute respiratory infections in children and chronic obstructive pulmonary disease in women are associated with indoor biomass smoke. Detailed questioning is essential to identify at risk activities and sampling of airborne particles may help with the identification of pollution risks. Particle elimination depends on the standard of ventilation of the indoor environment. Five per cent of French homes have levels of pollution greater than 180 MUg/m3 for PM 10 and 2% for PM 2.5. The principal mineral particle air pollutants are probably silica, talc, asbestos and carbon, whereas tobacco smoke leads to exposure to various ultrafine particles. The toxicity of these particles could be more related to surface exchange than to density. Tissue measurements by electron microscopy and microanalysis of particle samples may identify an uptake of particles similar to those in the environmental sample. PMID- 21549905 TI - [Management of acute and severe complications in adults with cystic fibrosis]. AB - The natural history of cystic fibrosis (CF) may be associated both with acute respiratory complications (respiratory exacerbations, haemoptysis, pneumothorax) and with non-respiratory complications (distal intestinal obstruction syndrome, dehydration) that may result in hospitalizations. The aim of this article is to describe the main therapeutic approaches that are adopted in the management of acute complications occurring in CF adults, and to discuss indications for admission of these patients to intensive care units. Adult CF patients admitted to intensive care unit often benefit from antibiotic courses adapted to their chronic bronchial infection, especially when the hospitalization is related to respiratory disease (including haemoptysis and pneumothorax). Nutritional support, including hypercaloric diet, control of hyperglycemia and pancreatic enzyme supplementation is warranted. The recommended therapy for major haemoptysis is bronchial artery embolization. Patient with significant pneumothorax should have a chest tube inserted, while the treatment of distal intestinal obstruction syndrome will most often be medical. In case of respiratory failure, non-invasive ventilation is the preferred mode of ventilatory support because invasive ventilation is associated with poor outcomes. Therapeutic options should always have been discussed between the patient, family members and the CF medical team to allow for informed decision making. PMID- 21549906 TI - [Management of acute exacerbations of pulmonary fibrosis]. AB - INTRODUCTION: Acute exacerbation of idiopathic pulmonary fibrosis (IPF) is defined by an acute worsening of the respiratory status without any identified cause. STATE OF THE ART: IPF is the most frequent type of chronic interstitial pneumonia. In general, its course is a progressive worsening with a median survival at 3 years after diagnosis. Acute exacerbation is now recognized as a severe complication of IPF. It develops most often within less than 1 month and is characterized by a worsening of dyspnoea associated with the occurrence of new images on chest radiograph. Its diagnosis requires the exclusion of an identified cause for acute deterioration such as pulmonary embolism, bronchopulmonary infection, left heart failure or pneumothorax. The treatment of acute exacerbations of IPF is not well standardized and even though isolated cases of therapeutic success have been reported, its prognosis remains poor. In the most severe cases, mechanical ventilation is generally considered to be ineffective, thus leading most often to a conservative management strategy with no transfer to ICU. However, this attitude is now being questioned since it is now potentially possible to perform an urgent lung transplantation in some patients at least in several countries, including France. CONCLUSION: Acute exacerbation of IPF is a severe complication of IPF, but its optimal management is not yet clearly defined. PMID- 21549907 TI - [Specific features of tuberculosis in childhood]. AB - Primary infection with Mycobacterium tuberculosis usually occurs during childhood. The source of infection is most often an adult. The risk of infection in exposed children is modulated by various factors related to the infectiousness of the index case, exposure conditions, and the child himself. This review aims to describe the specific diagnostic and therapeutic features of latent TB infection and TB disease in childhood. PMID- 21549908 TI - [Managing the adverse events of antitubercular agents]. AB - Tuberculosis, an infectious disease which is curable by following a course of antibiotics, remains a major public health issue on a global scale. A therapeutic strategy has been standardised which calls for the use of four antibiotics. These are generally well-tolerated but, individually and in combination, frequently have undesirable effects. Isoniazid may cause hepatic toxicity and an also be an asue of peripheral neuropathy. Rifampin is a strong hepatic enzyme inducer and can be responsible for severe immunoallergic reactions in the case of interrupted treatment. Pyrazinamide sometimes results in severe hepatotoxicity. Ethambutol can be responsible for severe ocular toxicity. Both older antituberculous medications and new generation antibiotic medications used for the treatment of resistant bacilli can also be the source of adverse events. The treatment of tuberculosis is standardised but the decision to treat it is inseparable from the evaluation of possible side effects which require assessment prior to the initiation of therapy and close monitoring during treatment which includes ensuring that patients are aware of and vigilant for potential problems.This work describes the adverse events of different antibiotic medications so that, on an individual basis they can be anticipated and appropriately managed. PMID- 21549909 TI - [Follow-up after occupational asbestos exposure: terms and devices in foreign]. AB - INTRODUCTION: Diseases, including cancer induced by asbestos, usually occur after many years of latency. The follow-up of employees must therefore continue after the end of their employment (retirement, redundancy, etc.) and such an arrangement has existed in France since 1996. This article reviews the literature on the post-employment monitoring arrangements that exist outside of France, particularly in other European countries, and their characteristics. STATE OF ART: This research has revealed a limited number of national experiences in Germany, Spain, Finland, Italy, Norway, Poland, and Switzerland. The medical protocols generally involve: algorithm decisions, questionnaire, physical examination, chest radiography, CT scan, and/or spirometry. PERSPECTIVES: Internationally, various methods exist to select employees for follow-up and to determine the frequency of subsequent examinations. Unlike Germany, which has a long experience of such medical follow-up, several of these programs are more recent. CONCLUSIONS: Post-occupational medical surveillance of asbestos-related disease is uncommon, monitoring arrangements vary and depend on medical and also on social factors. The French system of post-occupational monitoring can undoubtedly improve but it bears comparison with arrangements in other countries, where these are even present. PMID- 21549910 TI - [A simple view on lung cancer biology: The EGFR pathway]. AB - Epidermal growth factor receptor (EGFR) is a cell membrane tyrosine kinase receptor. Activating mutations at exon 19 and 21 of the EGFR gene are associated with the occurrence and development of lung adenocarcinoma. These gain of function mutations predict responsiveness to EGFR tyrosine kinase inhibitors (TKis), erlotinib or gefitinib and are also a favorable prognostic factor in lung cancer. Sequencing is the recommended technique to detect the mutations, but other more sensitive technics are under evaluation. Treatment as first line therapy by gefitinib is limited to lung cancer patients harboring an EGFR mutation. Erlotinib can be given regardless of the EGFR status as second or third line therapy, as well as maintenance therapy in patients with a stable disease after platinum based chemotherapy. In EGFR mutated tumors, most patients present a recurrence of the disease, despite an initial response on EGFR TKis. Two mechanisms of secondary resistance have been identified, the selection of the T790M mutation in EGFR exon 20 and the MET amplification. Other molecular anomalies as the ras mutations or the EMLA-ALK protein fusion are mutually exclusive with the EGFR mutations and are associated with primary resistance to EGFR TKis. PMID- 21549911 TI - Upper extremity deep venous thrombosis: reassessing the risk for subsequent pulmonary embolism. AB - BACKGROUND: Although the incidence of upper extremity deep venous thrombosis (UEDVT) diagnoses has increased, anticoagulation therapy for UEDVT remains inconsistent and of variable duration. This study sought to analyze our institution's current treatment practices for UEDVT and assess the risk for subsequent pulmonary embolism (PE). METHODS: Between April 2005 and July 2007, 200 consecutively encountered patients with UEDVTs were identified in the Peripheral Vascular Laboratory. Then, UEDVT location and sonographic characteristics, patient demographics, anticoagulation treatment, and PE incidence and mortality were examined. RESULTS: Among the 200 patients with UEDVT, 156 (78%) had UEDVTs identified as clearly acute or acute on chronic, based on sonographic appearance. In all, 85% of the patients were symptomatic (n = 171). Among the patients, 71 (36%) had documented malignancy, 58 (29%) were postoperative or suffering from trauma, and 52 (26%) were obese (body mass index: >30). In addition, 153 (76%) had associated current or previous indwelling lines or leads. A total of 73 patients (36%) were put on anticoagulation therapy for variable periods. Younger age of the patient, duplex evidence of an acute deep venous thrombosis, and involvement of multiple named upper extremity venous segments were independent predictors of the decision to initiate anticoagulation therapy for patients with UEDVT. Two patients (1%) suffered PE, most likely the consequence of their UEDVTs. An additional two patients with UEDVT treated with coumadin died months after hospital discharge from intracranial bleedings after minor falls. CONCLUSION: Currently, the clinical decision to initiate anticoagulation therapy for patients with UEDVT is most associated with the documented acute nature of the deep venous thrombosis by duplex ultrasonography, involvement of multiple venous segments, and younger age of the patient. The incidence of PE attributable to previously documented UEDVT is very small (1%), regardless of anticoagulant therapy. Anticoagulation therapy for UEDVT is most likely to be best suited to address the symptoms of UEDVT; its proposed use to decrease the very small risk of PE may be rarely indicated, and must be carefully weighed with the risks associated with therapeutic anticoagulation in this patient population. PMID- 21549912 TI - Determining criteria for predicting stenosis with ultrasound duplex after endovascular intervention in infrainguinal lesions. AB - BACKGROUND: Studies examining duplex surveillance of lower extremity bypass grafts have defined a role for guiding graft re-intervention. The goal of this study is to determine the utility of duplex scanning to detect angiographic restenosis after endovascular therapy in patients with infrainguinal arterial disease. METHODS: A prospective registry including all patients treated for lower extremity atherosclerotic disease between February 2004 and September 2008 was established. Patients were followed up with duplex ultrasound at 1, 3, 6, 12 months, and then annually. Patients receiving repeat angiograms were identified and angiogram and duplex data were abstracted. Velocity ratios (Vr) were calculated for each lesion by dividing the peak velocity within the lesion by the peak velocity proximal to the lesion. Logarithmic regression and receiver operator characteristic (ROC) curve analyses were used. RESULTS: Repeat angiograms were performed on 345 lesions in 143 patients, and 254 lesions in 103 patients had a corresponding duplex ultrasound. Indications for the initial intervention were claudication (n = 62, 43.4%), rest pain (n = 23, 16.1%), and tissue loss (n = 58, 40.5%). A total of 178 superficial femoral artery (SFA) lesions, 59 popliteal lesions, and 17 tibial lesions were identified by surveillance duplex in 103 patients. In all, 70.5% of the intervened vessels that were studied were nonstented and the remaining 29.5% were stented. A total of 65% of the patients had diabetes. On determining correlations for peak systolic velocity (PSV) as measured by duplex ultrasound with degree of angiographic stenosis, strong correlation coefficients for SFA disease (R2 = 0.84) and popliteal disease (R2 = 0.88) were found. However, poor correlation was found in patients with tibial disease. When analyzing the lesions on the basis of Vr < 2.0, 11 of 86 (12.8%) had >70% angiographic stenosis. In lesions with ratios from 2 to 2.5, 12 of 13 (92.3%) had >70% angiographic stenosis and in lesions with ratios >2.5, 69 of 75 (92.0%) had >70% angiographic stenosis. ROC curve analysis showed that to detect >= 70% stenosis in the SFA, a PSV >= 204 cm/sec had a sensitivity of 97.6% and specificity of 94.7%. To detect >= 70% stenosis in the overall femoropopliteal region, a PSV >= 223 cm/sec had a sensitivity of 94.1% and specificity of 95.2%. CONCLUSIONS: Duplex ultrasound surveillance correlates to the degree of angiographic stenosis on the basis of PSV in the SFA and popliteal region. Correlation in the tibial vessels is poor. Vr > 2.0 appear to correlate to angiographic stenosis of > 70%. ROC analysis shows that PSV can have sufficiently high sensitivity and specificity to predict angiographic stenosis in the femoropopliteal region. PMID- 21549913 TI - Comparative predictors of mortality for endovascular and open repair of ruptured infrarenal abdominal aortic aneurysms. AB - BACKGROUND: The continued success of elective endovascular aneurysm repair (EVAR) has led to an extension of this technology to ruptured aortas. The purpose of this study was to evaluate our results of ruptured infrarenal aortic aneurysm (rAAA). METHODS: The treatment results of all patients who underwent repair of rAAAs between January 1990 and May 2008 were reviewed retrospectively. Comorbidities, intraoperative details, and postoperative complications were tabulated. EVAR and open repair were compared. RESULTS: Between January 1990 and May 2008, 160 patients underwent repair of rAAA. Of these, 32 (20%) underwent EVAR for rAAA; of 160 patients, 112 were considered to have free rupture (70%) and 48 had contained rupture (30%). The average Acute Physiology and Chronic Health Evaluation II score was 13.3 +/- 6.7. The Kaplan-Meier survival rates at 30 days, 6 months, 1 year, and 5 years were 69% (62,77), 57% (50,65), 50% (43,59), and 25% (19,34), respectively, with no difference seen in EVAR group as compared with open surgery (p = 0.24). Intraoperative mortality was 5.6%, with no patient undergoing EVAR suffering an intraoperative death (p = 0.03). However, 30 day mortality was 31.9% with no difference between EVAR and open surgery (31.2% vs. 32%; p = 0.93) results. Multivariate analysis for 30-day mortality found renal insufficiency (RI) odds ratio (OR): 2.4 (1.1, 5.3), p = 0.04; hypotension OR: 2.4 (1.1, 5.3), p = 0.02; and cardiac arrest OR: 3.8 (1.1, 11.6, p = 0.03), were all associated with the greatest mortality. Of all predictors analyzed, multivariate analysis found preoperative RI OR: 2.32 (1.55, 3.47), p < 0.001, was the only independent predictor of decreased long-term survival. CONCLUSIONS: Mortality rates for rAAA remain high. The use of EVAR for these procedures equals that for open repair with regard to 30-day and long-term mortality. Preoperative cardiac arrest and RI were associated with inferior results for both EVAR and open repair. Clinical judgment on when to use EVAR as a primary repair modality must be exercised. PMID- 21549914 TI - Is thromboangiitis obliterans presentation influenced by cannabis addiction? AB - BACKGROUND: Cannabis implication in the pathophysiology of distal arteritis remains controversial. The aim is to assess whether cannabis co-exposure influences presentation and outcome of thromboangiitis obliterans (TAO) in tobacco smokers. METHODS: All consecutive patients presenting with a definite TAO were retrospectively reviewed according to their tobacco and cannabis consumption status. RESULTS: A total of 38 patients with a definite TAO were included in this study. In all, 10 patients (26%) used tobacco together with cannabis (delta9 trans-tetrahydrocannabinol [THC], THC(+)), whereas 28 patients (74%) were only tobacco smokers (THC(-)). Tobacco exposure was comparable in both groups (21.7 +/ 12 vs. 26.7 +/- 17 pack-years). THC(+) patients were younger than THC(-) patients at onset of symptoms (28.5 +/- 7 years vs. 36.6 +/- 10.5 years, p = 0.02) and have more frequently unilateral involvement of lower limbs (44% vs. 7%, p = 0.02). Although 66% of patients presented with critical ischemia of lower limbs, THC(+) patients exhibited more often rest pain without ischemic ulcers (50% vs. 5%, p = 0.048). Upper limbs were clinically affected in 50% of THC(+) patients and 32% of THC(-) patients. Repeated infusions of iloprost were required in 84% of patients. Outcome and rate of minor and major amputations (10%) did not differ between groups. CONCLUSION: Cannabis exposure influences the age at onset and presentation of TAO, but not the outcome. The data of present study suggest that cannabis represent a co-factor of tobacco that may accelerate TAO onset and presentation. PMID- 21549915 TI - Traumatic aortic rupture: 30 years of experience. AB - BACKGROUND: To evaluate outcome differences in open surgical and endovascular treatment of traumatic aortic rupture (TAR) over a period of 30 years. METHODS: We retrospectively reviewed the diagnostic workup and management of all patients and compared outcome before and since the era of endovascular therapy. RESULTS: Between 1980 and 2010, 72 patients with a mean age of 38 years (range, 14-76) were treated for TAR. Of these, 48 (67%) were treated by open surgery and the remaining 24 (33%) by thoracic endovascular aortic repair (TEVAR). In the open surgery group, mortality was 16.7% and paraplegia occurred in 8.3% of patients, whereas mortality was 4.2% and no paraplegia occurred in the TEVAR group. Diagnostic workup consisted of chest X-ray and arteriography in the early period, whereas computed tomographic scan and transesophageal echography were preferred in the more recent period. CONCLUSIONS: Although our results could not reach statistical significance, mainly because of the gross oversizing of the open group in comparison with the TEVAR group, TEVAR has introduced a less invasive era in the treatment of TAR and has become the therapy of choice. The diagnostic workup has evolved from chest X-ray and arteriography to computed tomographic scanning and even transesophageal echography. PMID- 21549916 TI - Is use of a Continuous Autotransfusion System beneficial in emergency abdominal aortic aneursym (AAA) surgery? AB - BACKGROUND: Allogeneic blood products have become a limited and expensive resource. The Continuous Autotransfusion System (CATS) has been promoted as a method for reducing the need for allogeneic blood transfusion. This study was undertaken to ascertain whether the use of CATS in emergency open AAA surgery has any benefits. METHODS: This is a retrospective study of all patients undergoing emergency open AAA surgery in our center during a 5-year period (between July 2004 and July 2009). Patients were identified from a prospectively maintained vascular database, and data were obtained from patient records. RESULTS: CATS was used in 69 emergency open AAA repairs. The median total blood loss was 3,500 mL (range: 751-13,796 mL) but the median volume of packed red blood cells produced by CATS was only 493 mL (~ 2 U). An average of 7 U (range: 0-19 U) of bank blood was still used despite the availability of CATS. The mean hemoglobin 24 hours postoperatively was 10.3 g/dL (6.4-14.1) with a hematocrit of 0.30. CONCLUSION: The use of CATS in emergency AAA surgery does not seem to reduce the use of allogeneic blood transfusion. This may be because of over transfusion, as reflected by relatively high postoperative hemoglobin levels. PMID- 21549917 TI - Physiologic component of the estimation of physiologic ability and surgical stress scoring system as a predictor of immediate outcome after elective open abdominal aortic aneurysm repair. AB - BACKGROUND: Previous studies have shown a good predictive power of the risk scoring method, Estimation of Physiologic Ability and Surgical Stress, in predicting mortality after open elective aortic aneurysm repair. The aim of the present study was to evaluate the physiologic component of this method to assess mortality risk in a different geographic population from previously published reports. METHODS: Operative, morbidity and mortality data were collected retrospectively from charts of patients submitted to elective open repair of an abdominal aortic aneurysm over an 8-year period. There were 214 patients, the median age was 70 (range: 48-91) years; 179 (83.6%) patients were men. The Preoperative Physiologic Risk Score (PRS), Surgical Stress Score, and Comprehensive Risk Score (CRS) values were categorized and compared with morbidity and mortality rates. RESULTS: There were 27 deaths (12.6%), and 81 (37.9%) patients experienced a postoperative complication that required medical intervention. There was a significant statistical difference for the values of PRS and CRS for patients who survived (0.53/0.63, respectively) and for those who died (0.88/1.02, respectively), p < 0.0001 for both values. There is a strong correlation between PRS and CRS values and development of complications (p < 0.0001). Surgical Stress Score did not correlate as strongly to development of complications (p = 0.0028). For PRS, the area under the receiver-operator characteristic curve was 0.844 (95% confidence interval: 0.747-0.941) for mortality and 0.725 (95% confidence interval: 0.650-0.799) for morbidity. For CRS, the area under the curve was 0.812 (95% confidence interval: 0.734-0.891) for mortality and 0.719 (95% confidence interval: 0.645-0.792) for morbidity. There was also a significant positive correlation between length of hospital stay and PRS and CRS scores (p < 0.0001). In this study, it was found that renal impairment has a significant positive correlation with mortality (p = 0.0008), with an odds ratio of 4.3. In a multivariate regression analysis, renal impairment failed to increase the accuracy of the model when associated with the other parameters considered in PRS. CONCLUSION: This study corroborates with the previous findings that the Estimation of Physiologic Ability and Surgical Stress model seems to be a promising method of predicting death and postoperative complications in patients undergoing open abdominal aortic aneurysm repair. PMID- 21549918 TI - Longevity and outcomes of axillary valve transplantation for severe lower extremity chronic venous insufficiency. AB - BACKGROUND: To assess the efficacy of axillary vein transplantation in the treatment of severe chronic venous insufficiency (CVI). METHODS: Among 139 complex venous reconstructions performed between 1991 and 2007 for CVI, 18 patients underwent upper extremity to lower extremity venous valve transplantation. An upper extremity valve was transplanted to the popliteal vein in 13 cases, to the common femoral vein in six cases, and to the saphenofemoral junction in two cases for a total of 21 procedures. All patients had follow-up with duplex scanning to assess valve competency and clinical visits to assess clinical improvement. Mean follow-up period was 37 months. RESULTS: Mean patient age was 44 years, and 57% were men. Clinically, 57% of the limbs were Clincal (C) class C5-C6. The mean preoperative venous disability score was 2.95. Most of the patients (66%) had post-thrombotic valvular dysfunction. At the time of valve transplantation, there was no proximal venous obstruction documented. A successful operation was defined as a competent valve at the end of the procedure and was achieved in 20 of 21 (95%) patients. Eight patients had at least one postoperative complication, primarily bleeding. The mean postoperative venous disability score was 2.65 and this increased to 2.75 (p = not significant as compared with baseline) at the last postoperative visit. Median time to return of symptoms was 12 months, and median reflux-free survival period was 15 months. CONCLUSION: Despite initial technical and symptomatic success with venous valve transplantation, there is a poor long-term valve competency rate and symptomatic control. These data suggest that a better understanding and therapy for severe CVI associated with valvular incompetence needs to be found. PMID- 21549919 TI - Post-carotid endarterectomy hyperperfusion syndrome-is it predictable by lack of cerebral reserve? AB - BACKGROUND: Cerebral hyperperfusion syndrome (HS) is presumed to be because of an increase in postendarterectomy flow in patients with fixed cerebral vascular reserve. Severe headache is thought to be an early sign of possible HS. An increase in partial pressure CO2 (pCO2) is known to cause cerebral vasodilatation and is used to evaluate the presence of cerebral reserve. METHODS: A total of 45 patients undergoing carotid endarterectomy had internal carotid artery flow measured with a transonic flow probe as follows: F1, immediately after full dissection of the internal carotid artery; F2, after 30 seconds of breath holding; and F3, after restoration of flow. DeltaF2-F1 and DeltaF3-F2 were also evaluated. A 10% increase between F2 and F1 indicated normal cerebral reserve and between F3 and F2 indicated increased postoperative flow. Age, gender, medical comorbidities, indication for carotid endarterectomy, intraoperative cerebral oximetry values, and percentage of bilateral carotid stenosis were recorded. All patients were contacted after discharge about the presence of postoperative headache or other suggestions of HS. Fisher's exact test was used for categorical predictors and the rank-sum test for continuous predictors. RESULTS: Seven (16%) patients (group A) developed postoperative headache and 38 (group B) did not. No patient developed HS. No variables were associated with postoperative headache except for female gender (p = 0.005). There were no statistically significant differences in F1, F2, F3, and DeltaF (F2-F1 or F3-F2) between groups A and B (there was no descriptively significant DeltaF2-F1 in 17 patients). Only one of the nine patients who had no change between F2 and F1, who had a significant increase in F3, and who was thought to be at higher risk for HS developed a postoperative headache. CONCLUSIONS: Lack of cerebral reserve is common in patients undergoing endarterectomy. If headache is an early sign of hyperperfusion, it does not seem to be predicted by lack of cerebral reserve and an increase in postendarterectomy flow. PMID- 21549920 TI - Contemporary management of aberrant right subclavian arteries. AB - BACKGROUND: Aberrant origin of right subclavian arteries represents the most common of the aortic arch anomalies. This variant has few published series to guide management. Our goal was to review treatment options and results for these potentially complex reconstructions. METHODS: A retrospective review was performed on all patients with a diagnosis of aberrant right subclavian artery at our institution between January 2003 and July 2009. RESULTS: A total of 24 patients, which comprises one of the largest series reported, including 10 males and 14 females (mean age: 46.6 years, range: 7-77), were diagnosed with an aberrant right subclavian artery. Sixteen (66%) were diagnosed incidentally, but eight (33%) had symptoms of either dysphagia, upper extremity ischemia, or both. Computed tomography was most commonly used to establish the diagnosis (19 patients, 79%). Magnetic resonance imaging established the diagnosis in three patients (12%), upper gastrointestinal barium study in one (4%), and standard angiography in one (4%). A Kommerell's diverticulum (KD) was the most common associated anomaly (seven patients, 29%). All seven patients (100%) with a KD required intervention for either symptoms or aneurysmal degeneration. Intervention was performed in 10 patients (42%), including carotid subclavian bypass in five (50%), carotid subclavian transposition in three (30%), and ascending aorta to subclavian bypass in two (20%). Four patients (40%) had additional intervention for management of aneurysmal disease of the aorta or KD, with open aortic replacement in two (20%) and aortic endografting in two (20%). There was one perioperative death (10%) in a patient undergoing aortic arch debranching with placement of an aortic endograft. In all, 18 patients survived without symptoms after a mean follow-up of 38 months. CONCLUSIONS: Aberrant right subclavian arteries are most commonly found incidentally with computed tomography. The presence of a KD seemed to correlate with the need for intervention. Patients with no symptoms with the absence of a KD can safely be followed. PMID- 21549921 TI - Predictors of diagnostic success with renal artery duplex ultrasonography. AB - BACKGROUND: Renal artery duplex ultrasonography (RA-DUS) is commonly used for the evaluation and follow-up of renal artery atherosclerotic disease. In a complete study, renal artery flow is evaluated from the vessel origin to the intraparenchymal branches. The quality of RA-DUS is in part technologist dependent, but many factors may affect the ability to complete a diagnostic examination. This study evaluated the clinical and technical factors that predict the ability to obtain a complete RA-DUS examination. METHODS: A prospective evaluation of all patients undergoing RA-DUS between July 2008 and February 2009 was performed. Factors such as patient age, gender, body mass index, technologists' years of experience, patient care setting (inpatient vs. outpatient), bedside examination, smoking before the examination, fasting status, and recent abdominal surgery were all recorded. Multivariate logistic regression analysis was performed. A p value of <= 0.05 was considered significant. RESULTS: During the study period, 250 patients underwent RA-DUS (mean age: 59.9 +/- 17.8 years, 57% [143] female). A total of 87 (35%) examinations were incomplete. This included nondiagnostic examinations which did not exhibit any segment of the renal artery. Factors that were associated with an incomplete examination included technologists' years of experience (OR = 0.92, p = 0.042), bedside examination (OR = 4.17, p = 0.016), and recent abdominal surgery (OR = 3.45, p = 0.047). Body mass index, fasting status, and smoking before the examination did not affect the ability to obtain a complete study. CONCLUSIONS: One-third of the RA-DUS studies were classified as incomplete by the strict criteria used in this prospective study. An experienced ultrasound technologist is more likely to obtain a complete RA-DUS examination. Recent abdominal surgery and bedside examinations were predictive of a limited examination as well. Vascular laboratories should consider these factors when scheduling examinations so as to obtain complete RA-DUS studies, as well as improve the cost-effectiveness of resource utilization. PMID- 21549922 TI - One-year outcome after percutaneous rotational and aspiration atherectomy in infrainguinal arteries in patient with and without type 2 diabetes mellitus. AB - BACKGROUND: To compare the safety and efficacy of a rotational aspiration atherectomy system (Jetstream) for the treatment of infrainguinal arteries in diabetic versus nondiabetic patients. METHODS: A total of 172 patients with Rutherford stage 1-5 lower limb ischemia were treated with rotational aspiration atherectomy between February 2006 and February 2007. Of these, 80 patients with type 2 diabetes mellitus (DM: 46.5%) were compared with 92 nonDM (53.5%) patients. Overall, 210 target lesions (99 DM; 111 nonDM) were treated, located in the superficial femoral (67% DM; 61% nonDM), popliteal (25% DM; 30% nonDM), and tibial (8% DM; 9% nonDM) arteries. Lesion characteristics were comparable in both groups, mean lesion length was 28.5 mm (DM) and 26.2 mm (nonDM); total occlusions were present in 29% (DM) and 32% (nonDM), and 15% (DM) and 14% (nonDM) were restenotic. RESULTS: In the entire cohort, device success was 99% (all but two lesions). The major adverse event (MAE) rate (death, index limb amputation, myocardial infarction, target lesion revascularization [TLR] and target vessel revascularization) in DM at 30 days was 2.5% (n = 2 planned amputations) and 0% in nonDM. At 6 and 12 months, MAE in DM was seen in 13.8% (11/80) and 25% (20/80) compared with 21.7% (20/92) and 31.5% (29/92) in nonDM, respectively. TLR rate through 12 months was 20% (16/80) in DM and 28% in nonDM (26/92). Overall, 1 year restenosis rate was 38.2% based on duplex. The ankle-brachial index, mean Rutherford categories, and walking impairment questionnaire did not differ between groups at baseline and were increased significantly in both study cohorts at 12 months. CONCLUSION: Jetstream-assisted atherectomy in infrainguinal arteries is safe and effective in DM compared with nonDM patients. In this short lesion cohort, vessel patency in diabetics was as good as for non-DM at 1 year. TLR and MAE were higher by trend in nonDM, although planned amputations were seen only in DM. The clinical benefit was similar in both groups. PMID- 21549923 TI - Rapamycin-loaded nanoparticles for inhibition of neointimal hyperplasia in experimental vein grafts. AB - BACKGROUND: Nanoparticles (NPs) possess several advantages as a carrier system for intracellular delivery of therapeutic agents. Rapamycin is an immunosuppressive agent which also exhibits marked antiproliferative properties. We investigated whether rapamycin-loaded NPs can reduce neointima formation of vein graft disease in a rat model. METHODS: Poly(lactic-co-glycolic acid) (PLGA) NPs-containing rapamycin was prepared using an oil/water solvent evaporation technique. The size and morphology of the NP were determined by dynamic light scattering methodology and electron microscopy. In vitro cytotoxicity of blank, rapamycin-loaded PLGA NPs was studied using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay. Excised rat jugular vein was treated ex vivo with blank NPs, or rapamycin-loaded NPs, and then interposed back into the carotid artery position using a cuff technique. Grafts were harvested for 21 days and subjected to morphometric analysis as well as immunohistochemical analysis and Western blotting. RESULTS: Rapamycin was efficiently loaded in PLGA NPs with an encapsulation efficiency of 87.6%. The average diameter of NPs was 180.3 nm. The NPs-containing rapamycin at 1 ng/mL significantly inhibited vascular smooth muscular cells proliferation. Measurement of rapamycin levels in vein grafts showed that the concentration of rapamycin in vein grafts at 3 weeks after grafting was 0.9 +/- 0.1 MUg/g. In grafted veins without treatment, intima-media thickness was 300.4 +/- 181.5 MUm at 21 days after grafting, whereas veins treated with rapamycin-loaded NPs showed a reduction of intimal-media thickness of 150.2 +/- 62.5 MUm (p = 0.001). Cell proliferation was measured by proliferating cell nuclear antigen immunohistochemistry staining. As expected, proliferating cell nuclear antigen index declined from 83.4% +/- 7.4% to 66.2% +/ 4.5% in vein grafts after 3 weeks (p = 0.002). Platelet endothelial cell adhesion molecule (PECAM-1/CD31) staining was used to measure luminal endothelial coverage in grafts and indicated a high level of endothelialization at 21 days after grafting, with no significant effect of blank or rapamycin-loaded NPs group. Western blot analysis showed that treatment with rapamycin-loaded PLGA NPs markedly attenuated phosphorylation and activation of S6 kinase 1 phosphorylation and inactivation of 4E (eIF4E)-binding protein 1, both in vascular smooth muscular cells and vein grafts at 7 and 21 days after grafting. CONCLUSIONS: We conclude that sustained-release rapamycin from rapamycin-loaded NPs inhibits vein graft thickening without affecting the endothelial cells in rat carotid vein-to artery interposition grafts; thus, this may be a promising therapy for the treatment of vein graft disease. PMID- 21549924 TI - Eversion carotid endarterectomy for recurrent stenosis after carotid angioplasty/stenting. AB - Restenosis requiring treatment after carotid angioplasty/stenting is uncommon in clinical practice. Treatment options include repeat angioplasty (with or without another stent) or carotid endarterectomy. This report describes a patient with recurrent stenosis treated with eversion carotid endarterectomy and stent removal. PMID- 21549925 TI - Compartment syndrome as a rare complication of iloprost infusion for peripheral vascular disease. AB - We report a case of acute compartment syndrome associated with the use of iloprost in the treatment of Buerger's disease. After a four-compartmental fasciotomy of the affected lower limb, the patient made a complete recovery. PMID- 21549926 TI - Endovascular management of a ruptured thoracoabdominal aneurysm-damage control with superior mesenteric artery snorkel and thoracic stent-graft exclusion. AB - We report a case of a large ruptured thoracoabdominal aortic aneurysm, which was stabilized with endovascular aortic exclusion and snorkel bypass of the superior mesenteric artery (SMA). An 80-year-old African American woman with multiple medical comorbidities and previous open infrarenal abdominal aortic aneurysm repair presented with a ruptured 10.7 * 7.3 cm thoracoabdominal aortic aneurysm involving the origins of the renal and mesenteric vessels. The patient underwent emergent endovascular aortic repair with placement of a covered stent into the SMA coursing parallel to the aortic endograft. This technique was initially successful in clinically stabilizing the patient; however; 3 weeks after the initial procedure, she presented with recurrent rupture necessitating proximal extension of her snorkeled SMA bypass and aortic endograft into the mid descending thoracic aorta. The patient stabilized and was successfully discharged home. PMID- 21549927 TI - Aneurysmectomy and revascularization of a large hepatic artery aneurysm. AB - Aneurysms of the hepatic artery are rare, but are associated with significant mortality because of their lack of symptoms at presentation and risk of rupture. We report a case of an enlarging 4-cm hepatic artery aneurysm involving the proximal common hepatic artery to the bifurcation of the right and left hepatic arteries which was found incidentally on ultrasound examination. Endovascular treatment with a stent was considered, but because of the location of the aneurysm as well as the presence of significant thrombosis involving the right and left hepatic arteries, aneurysmectomy and revascularization using saphenous vein was performed. Doppler ultrasound measurements demonstrated good flow through the graft postoperatively and at 1-month follow-up. Although a variety of endovascular techniques exist to treat hepatic artery aneurysms, our results indicate that open excision and revascularization may be required and can have a good outcome. PMID- 21549928 TI - Splenic arteriovenous fistula: successful treatment with an Amplatz occlusion device. AB - Splenic artery and vein aneurysm with splenic arteriovenous fistula (SAVF) is a rare entity. We report the case of a 72-year-old woman who presented with signs and symptoms of portal hypertension after a laparoscopic Nissen fundoplication. The diagnosis of a 37-mm SAVF was confirmed by a computed tomographic angiogram. The arteriovenous fistula was successfully treated with placement of a 20-mm Amplatz occlusion device. Surgical ligation and percutaneous embolization have been reported to be equally successful in managing SAVF. We present a review of the literature and report on a novel approach to this rare and challenging diagnosis. PMID- 21549929 TI - Surgical treatment of complications associated with the Angio-Seal vascular closure device. AB - Vascular closure devices are used to provide quick hemostasis and early ambulation after percutaneous interventions. The Angio-Seal (AS) vascular closure device forms a mechanical seal by closing the puncture site located between a bioabsorbable anchor within the lumen and a collagen sponge on the adventitia. Although morbidities associated with AS are reportedly infrequent, even the slightest inaccuracy in device implantation may result in displacement of these device components, leading to sudden and severe complications. We report the surgical treatment of complications associated with the use of AS in four patients, including acute limb ischemia, pseudoaneurysm formation, significant hemorrhage, and hypovolemic shock. A common factor in all these cases was that the components of the AS device were displaced from their original site of implantation, stressing the importance of proper device placement. All patients underwent successful surgical vascular repair. Our report highlights the need for exercising extreme care during device implantation, and also the requirement for vigilant inspection for any associated vascular complications commencing immediately after device implantation. It is vital that these device components are actively looked for and removed during surgical exploration so as to prevent future complications. PMID- 21549930 TI - Graft-to-endograft anastomosis for emergency treatment of distal aortic arch aneurysm after endovascular stenting of thoracoabdominal type B dissection. AB - Emergency aortic arch surgery still remains a challenge, especially in elderly patients. We report a case about the open surgical management by graft-to endograft anastomosis of a complicated aortic arch aneurysm because of a type I endoleak after thoracic endovascular aortic repair of a chronic type B aortic dissection. PMID- 21549931 TI - Collapse of Viabahn stent-graft secondary to rheolytic thrombectomy: a rare complication of the AngioJet device. AB - There is increased use of percutaneous mechanical thrombectomy for treatment of occluded dialysis access. The AngioJet rheolytic thrombectomy device is one such device available. Reports have shown safety and efficacy of these techniques with relatively few complications. We describe a case report of a collapsed Viabahn endoprosthesis in an arteriovenous fistula during treatment with an AngioJet device. PMID- 21549932 TI - Leiomyosarcoma of the inferior vena cava: resection and vascular reconstruction using a dacron graft and an Adam DeWeese clip-three-year follow-up. AB - Leiomyosarcomas are rare malignant tumors that particularly affect women. In 2% of all cases, they involve the veins, and in 60% of the cases affecting veins, an involvement of the inferior vena cava (IVC) has been demonstrated. We report a case of IVC leiomyosarcoma operated by resection and reconstruction with a Dacron bypass and apposition of an Adams-DeWeese IVC filter. The latter procedure has never been reported before in association with a graft applied for this disease. Technical and clinical details are described. PMID- 21549933 TI - Nonresective repair for abdominal aortic aneurysm. AB - BACKGROUND: In this report, we present our experience with nonresective repair of abdominal aortic aneurysm in selected patients who were unsuited for other surgical approaches and would benefit from repair. METHODS: Seven patients with abdominal aortic aneurysm underwent nonresective repair comprising aneurysm embolization followed by the creation of an axillary-femoral, femoral-femoral bypass with a polytetrafluoroethylene (PTFE) graft. RESULTS: Between April 2006 and March 2009, seven patients (mean age: 85 years) underwent surgery. Of these, four (57%) are currently alive and healthy, with a mean follow-up of 15.7 months, the remaining three died. CONCLUSION: Nonresection may be used as an alternative surgical treatment in certain high-risk patients. PMID- 21549934 TI - Solitary profunda femoris artery aneurysm. AB - Solitary profunda femoris artery aneurysm (PFAA) is extremely rare but presents with symptoms related to rupture, distal embolization, or local compression of veins and nerves. We report two surgically treated cases of solitary PFAA. In case 1, a 69-year-old man presented with sudden onset of pain in the left groin. Computed tomography scan showed a large aneurysm with extravasation of the contrast medium in the left mid-thigh, indicating ruptured aneurysm of the profunda femoris artery. Case 2 involved a 70-year-old man whose computed tomography scan revealed a large, nonruptured PFAA. Both aneurysms were successfully resected with vascular reconstruction using the great saphenous vein. PMID- 21549936 TI - Cystic adventitial disease of the common femoral vein. AB - Cystic adventitial disease of blood vessels is a rare condition, more so when veins are involved. We report the case of a 36-year-old man who was referred to us after an intraoperative diagnosis of a left common femoral vein mass. This patient, who had a history of deep vein thrombosis and pulmonary embolism, had presented to an outside facility with recurrent left lower extremity pain and swelling. At our hospital, he underwent excision of the vein mass with interposition vein grafting using the left internal jugular vein. In this report, we discuss the presentation, diagnosis, treatment, and pathology of this rare condition. PMID- 21549935 TI - Periaortic inflammation after endovascular aneurysm repair. AB - BACKGROUND: The periaortitis seen with inflammatory abdominal aortic aneurysms usually resolves after repair by both open and endovascular techniques. Conversely, the de novo development of retroperitoneal fibrosis after endovascular aneurysm repair (EVAR) has also been rarely described, and we present a case and also review the literature. METHODS AND RESULTS: A 63-year-old man underwent EVAR for an asymptomatic, noninflammatory abdominal aortic aneurysm, presenting 9 months subsequently with left loin pain, raised inflammatory markers, and radiological evidence of periaortic inflammation causing significant left ureteric obstruction. Ureteric stenting resolved the hydronephrosis, and the periaortitis improved with combination of steroid and tamoxifen therapy. CONCLUSION: Periaortitis causing renal impairment after EVAR is a rare complication. Prompt recognition and ureteric stenting helps to prevent long-term renal damage. Steroid and tamoxifen therapy is recommended to treat and avoid recurrence of periaortitis. PMID- 21549937 TI - Acute forearm compressive myopathy syndrome secondary to upper limb entrapment: an unusual cause of renal failure. AB - Compressive myopathy syndrome (SCM) is a syndrome characterized by the lesion of skeletal muscle resulting in subsequent release of intracellular contents (myoglobin, creatine phosphokinase, potassium, etc.) into the circulatory system, which can cause potentially lethal complications. There are numerous causes that can lead to SCM resulting to acute rhabdomyolysis, and many patients present with multiple causes. The most common potentially lethal complication is acute renal failure. The occurrence of acute rhabdomyolysis should be considered as a possibility in any patient who can remain stationary for long periods, or is in a coma, or is intoxicated in any form. We report the rare case of a 26-year-old patient who developed SCM caused by ischemia reperfusion, with subsequent acute rhabdomyolysis and acute renal failure after prolonged compression of the right upper extremity. PMID- 21549938 TI - Mediastinal hemangioma arising in setting of partial anomalous pulmonary venous drainage to azygous vein in a 57-year-old woman. AB - Partial anomalous pulmonary venous drainage (PAPVD) to the azygous vein and benign posterior mediastinal hemangioma in adults are both rare entities in isolation. The coexistence of these two lesions in the same patient has not been reported. We describe a unique case of PAPVD to the azygous vein in an adult woman, where the anomalous left inferior pulmonary vein transited first through a large hemangioma, and then eventuated in the azygous vein. PMID- 21549939 TI - Management of flush superficial femoral artery occlusions with combined open femoral endarterectomy and endovascular femoral-popliteal angioplasty and stent grafting. AB - BACKGROUND: Flush occlusions of the superficial femoral artery (SFA) often preclude endovascular interventions for femoral-popliteal lesions. Furthermore, some investigators have found poor results with angioplasty and stenting or stent grafting of such lesions. For suitable patients with TransAtlantic Inter-Society Consensus (TASC) C and D femoral-popliteal lesions involving a flush occlusion of the SFA, we have adopted a technique to manage this disease pattern by combining femoral endarterectomy through a single, small groin incision with distal superficial femoral-popliteal stent-grafting. In this article we have described our technique and results in 14 consecutive patients. METHODS: A total of 14 patients who underwent this hybrid procedure between May 2005 and April 2009 were identified from our prospectively gathered registry. Data on indications, complications, length of hospital stay, pre- and postoperative ankle-brachial indices, patency determined by duplex ultrasonography, limb salvage rates, and functional results were collected. RESULTS: Of the 14 patients, nine were operated on for disabling claudication, two for rest pain, and three for tissue loss; three fit TASC C criteria and the remaining 11 fit TASC D. In all, 12 patients had stent-grafts placed and two had bare-metal stents inserted. The median ankle-brachial index of the affected leg was 0.61 (range, 0.23-1.71) before surgery and 0.99 (range, 0.63-1.39) after surgery (p = 0.034). There were no significant complications associated with the procedure. One patient died secondary to unrelated causes 5 months later, two did not return for follow-up after discharge, and three were lost to follow-up after primary patency was confirmed at 2, 4, and 4 months, respectively. Of the remaining eight patients, four still have primary patency of their stent-grafts at 52, 19, 17, and 4 months, respectively, and a fifth patient has secondary patency at 24 months. The remaining three patients occluded their stent-grafts with primary patency last confirmed at 0.5, 2.5, and 8 months, respectively; two have stable claudication and one has a nonhealing wound and rest pain, but all have limb salvage to date. CONCLUSION: Combined femoral endarterectomy and endovascular femoral-popliteal stent-grafting provides a viable option for revascularization of flush SFA occlusions with only a minimal groin incision. The technique described in this article allows for a larger number of patients with flush SFA occlusions to be treated primarily with endovascular techniques and helps avoid a traditional common femoral to above-the-knee popliteal prosthetic bypass. PMID- 21549944 TI - Neutrophil extracellular traps. PMID- 21549940 TI - Endovascular repair and pharmacotherapy of an inflammatory abdominal aortic aneurysm complicated by primary aortoduodenal fistula. AB - An inflammatory abdominal aortic aneurysm complicated by primary aortoduodenal fistula was successfully treated by stent grafting. Pharmacotherapy with octreotide after endovascular aneurysm repair was also performed with the expectation of spontaneous and rapid closure of the fistula. Gastrointestinal endoscopy performed 10 days after endovascular aneurysm repair showed closure of the large aortoduodenal fistula, and oral intake was started on the operative day 16. To date, 16 months after the initial operation, the patient is doing well without any symptoms or signs of infection and without any antibiotic therapy. PMID- 21549945 TI - Appetitive learning: memories need calories. AB - Recent studies of the way animals learn challenge the idea that food learning relies mainly on how food tastes. Work on Drosophila has now shown that flies must ingest food with a metabolic benefit to form a lasting memory for a learned odour. PMID- 21549946 TI - Cell migration: katanin gives microtubules a trim. AB - New evidence suggests that katanin - best known for severing microtubules in their more stable regions - localizes at the leading edge of migratory cells and trims microtubules at their dynamic plus ends. PMID- 21549947 TI - Circadian rhythms: biological clocks work in phospho-time. AB - The 24 hour molecular oscillator requires precisely calibrated degradation of core clock proteins, like PERIOD. New studies shed light on a sequential series of PERIOD phosphorylation events that first inhibits, then accelerates PERIOD degradation. PMID- 21549948 TI - Pollinator attraction: the importance of looking good and smelling nice. AB - Flowers entice animal pollinators using a complex array of attractions. Reciprocal transfer of traits between Petunia species now shows that colour and scent are equally important to hawkmoths in choosing between different flowers. PMID- 21549949 TI - Mechanotransduction: getting morphogenesis down pat. AB - Embryonic morphogenesis requires the coordination of forces across multiple tissues and their associated extracellular matrices. A new study reports a mechanical feedback loop in the Caenorhabditis elegans embryo between muscle and epidermis that may provide a model for understanding how tissues coordinate morphogenetic events in the embryo. PMID- 21549950 TI - Animal cognition: monkeys recall previously seen images. AB - A recent study has found that rhesus macaques can recall newly presented shapes: this demonstration of recall in non-human primates suggests that some animals have recollection processes similar to those of humans. PMID- 21549951 TI - Circadian biology: the supporting cast takes on a starring role. AB - Brain circuits are generally thought to consist solely of neurons communicating with other neurons. In Drosophila, glia-to-neuron signaling has now been shown to be critical to the function of the circadian circuit. PMID- 21549952 TI - Malaria: surprising mechanism of merozoite egress revealed. AB - A recent study reveals that the intraerythrocytic asexual reproduction cycle of Plasmodium falciparum ends with the ruptured erythrocyte membrane curling outwards, buckling, everting and vesiculating. Analogy with the sequence seen during spontaneous inside-out vesiculation of erythrocyte membranes suggests that the parasite co-opts pre-existing cytoskeletal conformations to facilitate terminal merozoite dispersal. PMID- 21549953 TI - Plant signalling pathways: a comparative evolutionary overview. PMID- 21549954 TI - Two-component systems and their co-option for eukaryotic signal transduction. AB - Two-component signaling pathways involve histidine kinases, response regulators, and sometimes histidine-containing phosphotransfer proteins. Prevalent in prokaryotes, these signaling elements have also been co-opted to meet the needs of signal transduction in eukaryotes such as fungi and plants. Here we consider the evolution of such regulatory systems, with a particular emphasis on the roles they play in signaling by the plant hormones cytokinin and ethylene, in phytochrome-mediated perception of light, and as integral components of the circadian clock. PMID- 21549955 TI - Auxin, self-organisation, and the colonial nature of plants. AB - Evolution has provided at least two particularly successful independent solutions to the problems of multicellularity - animals and higher plants. An obvious requirement for successful multicellularity is communication between different parts of the organism, both locally, for example between neighbouring cells, and over very long distances. Recent advances in understanding hormone signalling networks in plants are beginning to reveal how co-ordination of activity across the whole plant body can be achieved despite the lack of a control centre, typical of animal systems. Of particular importance in this distributed regulatory approach are the self-organising properties of the transport system for the plant hormone auxin. This review examines the integrative role of the auxin transport network in co-ordinating plant growth and development. PMID- 21549956 TI - The molecular mechanism and evolution of the GA-GID1-DELLA signaling module in plants. AB - Bioactive gibberellins (GAs) are diterpene phytohormones that modulate growth and development throughout the whole life cycle of the flowering plant. Impressive advances have been made in elucidating the GA pathway with the cloning and characterization of genes encoding most GA biosynthesis and catabolism enzymes, GA receptors (GIBBERELLIN INSENSITIVE DWARF1, GID1) and early GA signaling components. Recent biochemical, genetic and structural analyses demonstrate that GA de-represses its signaling pathway by GID1-induced degradation of DELLA proteins, which are master growth repressors, via a ubiquitin-proteasome pathway. Multiple endogenous signals and environmental cues also interact with the GA-GID1 DELLA regulatory module by affecting the expression of GA metabolism genes, and hence GA content and DELLA levels. Importantly, DELLA integrates different signaling activities by direct protein-protein interaction with multiple key regulatory proteins from other pathways. Comparative studies suggest that the functional GA-GID1-DELLA module is highly conserved among vascular plants, but not in the bryophytes. Interestingly, differentiation of the moss Physcomitrella patens is regulated by as yet unidentified ent-kaurene-derived diterpenes, which are distinct from the common active GAs in vascular plants. PMID- 21549957 TI - Evolution of abscisic acid synthesis and signaling mechanisms. AB - The plant hormone abscisic acid (ABA) mediates seed dormancy, controls seedling development and triggers tolerance to abiotic stresses, including drought. Core ABA signaling components consist of a recently identified group of ABA receptor proteins of the PYRABACTIN RESISTANCE (PYR)/REGULATORY COMPONENT OF ABA RECEPTOR (RCAR) family that act as negative regulators of members of the PROTEIN PHOSPHATASE 2C (PP2C) family. Inhibition of PP2C activity enables activation of SNF1-RELATED KINASE 2 (SnRK2) protein kinases, which target downstream components, including transcription factors, ion channels and NADPH oxidases. These and other components form a complex ABA signaling network. Here, an in depth analysis of the evolution of components in this ABA signaling network shows that (i) PYR/RCAR ABA receptor and ABF-type transcription factor families arose during land colonization of plants and are not found in algae and other species, (ii) ABA biosynthesis enzymes have evolved to plant- and fungal-specific forms, leading to different ABA synthesis pathways, (iii) existing stress signaling components, including PP2C phosphatases and SnRK kinases, were adapted for novel roles in this plant-specific network to respond to water limitation. In addition, evolutionarily conserved secondary structures in the PYR/RCAR ABA receptor family are visualized. PMID- 21549959 TI - Hormone signalling crosstalk in plant growth regulation. AB - The remarkable plasticity of plant ontogeny is shaped by hormone pathways, which not only orchestrate intrinsic developmental programs, but also convey environmental inputs. Several classes of plant hormones exist, and among them auxin, brassinosteroid and gibberellin are central for the regulation of growth in general and of cell elongation in particular. Various growth phenomena can be modulated by each of the three hormones, in a sometimes synergistic fashion, suggesting physiological redundancy and/or crosstalk between the different pathways. Whether this means that they target a common and unique transcriptome module, or rather separate growth-promoting transcriptome modules, remains unclear, however. Nevertheless, while surprisingly few molecular mediators of direct crosstalk in the proper sense have been isolated, evidence is accumulating for complex cross-regulatory relations between hormone pathways at the level of transcription, as exemplified in root meristem growth. The growing number of available genome sequences from the green lineage offers first glimpses at the evolution of hormone pathways, which can aid in understanding the multiple relationships observed between these pathways in angiosperms. The available analyses suggest that auxin, gibberellin and brassinosteroid signalling arose during land plant evolution in this order, correlating with increased morphological complexity and possibly conferring increased developmental flexibility. PMID- 21549958 TI - Peptide signaling in plant development. AB - Cell-to-cell communication is integral to the evolution of multicellularity. In plant development, peptide signals relay information coordinating cell proliferation and differentiation. These peptides are often encoded by gene families and bind to corresponding families of receptors. The precise spatiotemporal expression of signals and their cognate receptors underlies developmental patterning, and expressional and biochemical changes over evolutionary time have likely contributed to the refinement and complexity of developmental programs. Here, we discuss two major plant peptide families which have central roles in plant development: the CLAVATA3/ENDOSPERM SURROUNDING REGION (CLE) peptide family and the EPIDERMAL PATTERNING FACTOR (EPF) family. We discuss how specialization has enabled the CLE peptides to modulate stem cell differentiation in various tissue types, and how differing activities of EPF peptides precisely regulate the stomatal developmental program, and we examine the contributions of these peptide families to plant development from an evolutionary perspective. PMID- 21549961 TI - Quantifying the extent of emphysema "open the pod door, Hal". PMID- 21549960 TI - FT, a mobile developmental signal in plants. AB - Plants synchronise their flowering with the seasons to maximise reproductive fitness. While plants sense environmental conditions largely through the leaves, the developmental decision to flower occurs in the shoot apex, requiring the transmission of flowering information, sometimes over quite long distances. Interestingly, despite the enormous diversity of reproductive strategies and lifestyles of higher plants, a key component of this mobile flowering signal, or florigen, is contributed by a highly conserved gene: FLOWERING LOCUS T (FT). The FT gene encodes a small globular protein that is able to translocate from the leaves to the shoot apex through the phloem. Plants have evolved a variety of regulatory networks that control FT expression in response to diverse environmental signals, enabling flowering and other developmental responses to be seasonally timed. As well as playing a key role in flowering, recent discoveries indicate FT is also involved in other developmental processes in the plant, including dormancy and bud burst. PMID- 21549962 TI - Accurate prostate volume estimation using multifeature active shape models on T2 weighted MRI. AB - RATIONALE AND OBJECTIVES: Accurate prostate volume estimation is useful for calculating prostate-specific antigen density and in evaluating posttreatment response. In the clinic, prostate volume estimation involves modeling the prostate as an ellipsoid or a spheroid from transrectal ultrasound, or T2 weighted magnetic resonance imaging (MRI). However, this requires some degree of manual intervention, and may not always yield accurate estimates. In this article, we present a multifeature active shape model (MFA) based segmentation scheme for estimating prostate volume from in vivo T2-weighted MRI. MATERIALS AND METHODS: We aim to automatically determine the location of the prostate boundary on in vivo T2-weighted MRI, and subsequently determine the area of the prostate on each slice. The resulting planimetric areas are aggregated to yield the volume of the prostate for a given patient. Using a set of training images, the MFA learns the most discriminating statistical texture descriptors of the prostate boundary via a forward feature selection algorithm. After identification of the optimal image features, the MFA is deformed to accurately fit the prostate border. An expert radiologist segmented the prostate boundary on each slice and the planimetric aggregation of the enclosed areas yielded the ground truth prostate volume estimate. The volume estimation obtained via the MFA was then compared against volume estimations obtained via the ellipsoidal, Myschetzky, and prolated spheroids models. RESULTS: We evaluated our MFA volume estimation method on a total 45 T2-weighted in vivo MRI studies, corresponding to both 1.5 Tesla and 3.0 Tesla field strengths. The results revealed that the ellipsoidal, Myschetzky, and prolate spheroid models overestimated prostate volumes, with volume fractions of 1.14, 1.53, and 1.96, respectively. By comparison, the MFA yielded a mean volume fraction of 1.05, evaluated using a fivefold cross validation scheme. A correlation with the ground truth volume estimations showed that the MFA had an r(2) value of 0.82, whereas the clinical volume estimation schemes had a maximum value of 0.70. CONCLUSIONS: Our MFA scheme involves minimal user intervention, is computationally efficient and results in volume estimations more accurate than state of the art clinical models. PMID- 21549963 TI - Medicare started in 1966. PMID- 21549964 TI - A case of 'second rupture' following open repair of a ruptured Achilles tendon. AB - We present a case of Achilles tendon rupture in a 54-year-old man whilst rehabilitating following end-to-end open repair of an acute Achilles tendon rupture. Re-rupture following surgical repair of Achilles tendon is well known. This case however, is atypical as the second rupture occurred significantly proximal to the first rupture. To our knowledge this is the first time this has been described in the English literature. We have termed this incident a 'second rupture'. We describe the surgical technique used by the operating surgeon during open repair of this 'second rupture', involving a gastrocnemius flap turndown. This has lead to the patient making a good recovery, despite complications. This case report serves to inform surgeons of the existence of this type of Achilles tendon rupture, whilst considering possible aetiologies and suggesting a technique for repair of the injury. PMID- 21549965 TI - Osteochondroma of the calcaneus presenting as Haglund's deformity. AB - Haglund's deformity is a symptomatic osseous prominence of the posterosuperior corner of the calcaneus creating posterior heel pain and swelling around the insertion of the Achilles tendon. We have experienced an exceptionally huge Haglund's deformity in a 22-year-old female who initially presented to us with a large painful bony heel mass that had developed over the last decade. We performed the surgical resection of the prominence and the pathology confirmed the diagnosis of calcaneal osteochondroma. To our best knowledge, such a gigantic Haglund's deformity caused by calcaneal osteochondroma has never been reported in any medical literature. PMID- 21549966 TI - Septic arthritis of the ankle due to Salmonella enteritidis. AB - Salmonella septic arthritis in healthy, immunocompetent patients is extremely rare. We present the case of a 70-year-old man who presented with a one-day history of painful swelling of his ankle from which was aspirated pus which subsequently grew Salmonella enteritidis. There was no history of trauma or symptoms consistent with Salmonella enterocolitis. Our patient recovered fully after two weeks on intravenous ceftriaxone and six weeks on oral ciprofloxacin. Salmonella is a notifiable disease in the European Union and the United States of America, and is associated with outbreaks as a result of food contamination. The nature of Salmonella arthritis and its appropriate management are outlined. PMID- 21549967 TI - Intraosseous lipoma of the calcaneus mimicking plantar fascitis. AB - Benign lytic lesions of the calcaneus are rare and are usually asymptomatic. We report this case of a 55-year-old man with bilateral non-traumatic plantar heel pain, which was treated conservatively as plantar fasciitis. At three months follow-up, the patient had complete relief of symptoms in the left heel with partial relief of symptoms on the right side. However under the insistence of the patient an X-ray was taken, which revealed an expansile lytic lesion of the right calcaneus and a normal left heel. CT-scan revealed an expansile lytic lesion on the right calcaneus and an early lytic lesion in the left calcaneus. Following surgical intervention, the diagnosis was confirmed as intra-osseous lipoma and the patient was completely symptom free at two-year follow-up. Patients presenting with non-traumatic heel pain should be explained about the possible causes of heel pain, and should be offered X-ray at the first visit. In patients with X-ray showing unilateral lipoma of the calcaneus, CT scan should be offered to rule out involvement of the opposite side. PMID- 21549968 TI - Hallux valgus interphalangeus and a novel mutation in HOXA13. Part of the broadening spectrum of Hand-Foot-Genital syndrome. AB - When evaluating foot and hand malformations in children, the orthopaedic surgeon must always consider the possibility of a more serious underlying syndrome with other accompanying abnormalities of organogenesis. We report the case of a 13 year-old female with Hand-Foot-Genital syndrome presenting to our foot and ankle clinic with tarsal coalition and hallux valgus interphalangeus - an unusual variation on the previously reported hallux varus associated with the syndrome. She was subsequently found to have a novel mutation in the HOXA13 gene. To our knowledge, this is the first report of Hand-Foot-Genital syndrome in the orthopaedic literature. PMID- 21549969 TI - Dorsal dislocation of the first metatarsophalangeal joint associated with fractured second metatarsal head. AB - Traumatic dislocations of the first metatarsophalangeal joint were first described by Mouchet in 1931. The anatomical complexity of the first metatarsophalangeal joint makes this injury one of a kind. There have been a limited number of case reports of this injury. The ability to reduce the dislocation by nonoperative measures depends largely on the type of dislocation and involvement of the sesamoid complex. We report a case of a 35-year-old male with complete dorsal dislocation of the first metatarsophalangeal joint with second metatarsal head fracture. On review at 12 months he was pain free, fully mobile and pleased with the result. The papers principle message is that significant injuries to the metatarsophalangeal joint may be associated with fractures of adjacent bone segments, which may change diagnostic and therapeutic approaches. Also, the evolution of patients with this kind of injury after reduction is not well know today, at short, medium and long term. Thus could be considered to be a further development of Jahss's classification. PMID- 21549970 TI - Black bone disease of the foot. Minocycline related pigmentation. AB - Black bone disease is a rare manifestation of long term treatment with tetracyclines. We report the case of a patient who underwent surgery for bilateral hallux valgus and was found to have black discolouration of both first rays. This was subsequently related to previous long term Minocycline use. The unique features of this case relate to the location of the discolouration and the normal physical properties of the bone and soft tissues at surgery despite heavy pigmentation. Healing is now complete and follow-up at two years confirmed excellent clinical and radiological outcomes. PMID- 21549971 TI - Minimal invasive surgery (MIS) in foot and ankle surgery. PMID- 21549972 TI - Biomechanical changes associated with the osteoarthritic, arthrodesed, and prosthetic ankle joint. PMID- 21549973 TI - Stresses in the ankle joint and total ankle replacement design. AB - The ankle is a highly congruent joint with a surface area of 11-13 cm(2). Total ankle replacements have been attempted since the early 1970s and design has continually evolved as the early designs were a failure. This was because the stresses involved and the mutiaxial motion of the ankle has not been understood until recently. It has been shown that the talus slides as well as rolls during the ankle arc of motion from plantarflexion to dorsiflexion. Furthermore, the articular surfaces and the calcaneofibular and tibiocalcaneal ligaments have been shown to form a four bar linkage dictating ankle motion. A new design ankle replacement has been suggested recently which allows multiaxial motion at the ankle while maintaining congruency throughout the arc of motion. The early results of this ankle replacement have been encouraging without any reported failures due to mechanical loosening. PMID- 21549974 TI - A review of the STAR prosthetic system and the biomechanical considerations in total ankle replacements. AB - The ankle is a complex joint, anatomically and biomechanically. Pathologically diseased ankle joints, which require surgical intervention, now have the option of a total ankle replacement system rather than the long-standing arthrodesis procedure, first described by Albert in 1878. The anatomical features and forces acting across the joint are important when designing total ankle replacement (TAR) systems. This review discusses the history and evolution of TAR prosthetic systems and considers how the ankle's normal physiology and biomechanics is incorporated into their design. The Scandinavian total ankle replacement (STAR) is a three component prosthetic system and this review concludes that its size, shape and surgical insertion technique allows the biomechanical requirements of the ankle to be met with an adequate stress distribution in particular. PMID- 21549975 TI - Vira(r) system--a minimally invasive technique for severe fractures of the calcaneus treatment with primary subtalar fusion: a preliminary report. AB - OBJECTIVE: We presented the surgical technique and applicability of the Vira((r)) system for severe calcaneus fractures treatment. MATERIAL AND METHODOLOGY: The Vira((r)) system is a minimal invasive method for the reconstruction of severe calcaneal fractures with primary subtalar fusion. It comprises a fixation implant and a specific jig for the reduction of the fracture and placement of the holed nail and two screws for fixation to the talus. Additional advantages of this system are its high strength and stability allowing early weight bearing and the fact that additional bone grafting is not needed in most of the cases. The Vira((r)) system is a new concept in calcaneal surgery to provide a definitive solution for patients, low aggression and complication rates combined with high clinical effectiveness and sooner recovery. PMID- 21549976 TI - Determination of optimal screw positioning in flexor hallucis longus tendon transfer for chronic tendoachilles rupture. AB - BACKGROUND: Neglected ruptures of the tendoachilles pose a difficult surgical problem. There are no data to determine the optimal positioning of the FHL tendon to the calcaneus. METHODS: Two computer programmes (MSC.visualNastran Desktop 2002TM and Solid Edge((r)) V19) were used to generate a human ankle joint model. Different attachment points of FHL tendon transfer to the calcaneus were investigated. RESULTS: The lowest muscle force to produce plantarflexion (single stance heel rise) was 1355 N. Plantarflexion increased for a more anterior attachment point. The maximum range of plantarflexion was 33.4 degrees for anterior attachment and 24.4 degrees for posterior attachment. There was no significant difference in range of movement when the attachment point was moved to either a medial or lateral position. CONCLUSIONS: A more posterior attachment point is advantageous in terms of power and the arc of motion (24.4 degrees ) is physiological. We recommend that FHL is transferred to the calcaneus in a posterior position. PMID- 21549977 TI - Technique and results of arthroscopic treatment of posterior ankle impingement. AB - BACKGROUND: The aim of this study was to investigate the outcome after arthroscopic procedures for treatment of posterior ankle impingement. METHODS: From June 2006 to April 2009 36 patients were treated by hindfoot arthroscopy. Indication was posterior ankle impingement due to symptomatic os trigonum or osteophytes. Pain on the VAS was evaluated pre- and postoperatively. Minimum follow-up was 6 months. RESULTS: 30 patients were available for follow-up. Follow up averaged 9.7 months (range 6-14 months). Pain measured on the VAS improved significantly from 7.2 points to 1.3 points. One superficial (3.3%) and one deep wound infection (3.3%) occurred, 6.6% of our patients complained about impaired sensitivity of the sural nerve, and 6.6% required resurgery. CONCLUSIONS: Hindfoot arthroscopy is an elegant surgical technique in treatment of posterior ankle impingement. The minimally invasive procedure allows for low complication rates. PMID- 21549978 TI - Posttraumatic impingement syndrome of the ankle--indication and results of arthroscopic therapy. AB - BACKGROUND: Persisting pain after an ankle sprain is often caused by the development of intraarticular fibrous scars or even tibiotalar spurs due to repetitive trauma. This may result in a posttraumatic impingement syndrome of the ankle. Pain is typically provoked by dorsiflexion of the ankle and palpation of the tibiotalar anterior joint space. The study evaluates the outcome of arthroscopic treatment of the ankle impingement syndrome. METHODS: 32 patients are included (16-65 years, mean age 38 years) who underwent an arthroscopic operation because of an impingement syndrome of the ankle grades I-III (Scranton) due to a trauma without therapeutic response to conservative therapy over 3 months. Diagnostic criteria were palpatoric anterior ankle joint pain and pain provoked by dorsiflexion, in cases of grades II and III lesions spurs on the X ray as well. The mean follow-up time was 49 months. The evaluation of the results was done with the West Point Ankle Score. The study is designed as a retrospective case series. RESULTS: 26 patients reached more than 80 points in the West Point Ankle Score corresponding to a good or excellent result (mean result 86 points, ranging from 80 to 98 points). The preoperative mean score reached up to 64 points overall (57-70). Five patients rated the postoperative result fair, one bad with 73 points at mean (62-78). Preoperatively they reached 56 point on an average (48-62). The fair and the poor results were associated with severe ankle sprain leading to ligament ruptures or fractures where severe chondral lesions were to be found with arthroscopy. CONCLUSIONS: The results of the study show that ankle arthroscopy with resection of hypertrophic synovium and fibrous bands (type I) or tibial spurs (types II and III injuries) after an ankle sprain haven proven to be a reliable therapy for a posttraumatic impingement syndrome of the ankle that does not respond to conservative treatment. It is characterized by low morbidity and good to excellent results in most cases. The outcome of arthroscopic treatment was related to the extent of chondral lesions. PMID- 21549979 TI - Thromboprophylaxis in elective foot and ankle patients--current practice in the United Kingdom. AB - BACKGROUND: The incidence of venous thromboembolism (VTE) is unknown in elective foot and ankle surgery. The National Institute for Health and Clinical Excellence (NICE) recently published guidelines on reducing the risk of venous thromboembolism in surgical patients. This includes patients undergoing elective foot and ankle surgery. METHOD: In March 2010 we surveyed the current practice in VTE prophylaxis in elective foot and ankle surgery amongst members of the British Orthopaedic Foot and Ankle Society (BOFAS). RESULTS: The response rate was 84 (53%). The total number of elective foot and ankle operations performed by the surveyed group was 33,500 per annum. The estimated incidence of DVT, PE and fatal PE was 0.6%, 0.1% and 0.02%. In our study the number of patients needed to treat to prevent a single fatal PE is 10,000 although this figure is open to important bias. CONCLUSION: We question the applicability of the NICE guidelines to patients undergoing elective foot and ankle surgery. We consider that this data justifies the prospective study of the incidence of VTE in patients undergoing elective foot and ankle surgery, without the use of chemical thromboprophylaxis. PMID- 21549981 TI - Surgical training in an era of reduced working hours. PMID- 21549980 TI - Avulsion fracture of the medial malleolus following posterior tibialis tendon dislocation: a case report. AB - Dislocation of the posterior tibialis tendon as an isolated injury is rare. The diagnosis is often delayed due to its rarity and the need for various second line imaging modalities. We present a case of a dislocated posterior tibialis tendon that resulted in an avulsion type fracture of the medial malleolus. The fracture was openly reduced and internally fixed with inter-fragmentary screws. The patient was asymptomatic at 1 year follow-up. PMID- 21549982 TI - National curricula, certification and credentialing. AB - The education, certification, and credentialing of surgeons is undergoing change brought about by public expectations and by reform within the profession. In the United States, there is a clear trend towards standardization of education, as exemplified by the Surgical Council on Resident Education (SCORE) curriculum. There is an emerging effort to tie certification closely to the national curriculum. Finally, there is clarity emerging from the curriculum development process about the expected operative skills of graduating surgical trainees, and this will ultimately drive the process by which surgeons are credentialed by their hospitals or surgical centers. This period of change is being accompanied by a demand for more assessment of trainees and for outcomes-based training and residency program accreditation. PMID- 21549983 TI - Workplace-based assessment: the need for continued evaluation and refinement. AB - Workplace-Based Assessment (WBA) has been an integral part of the UK Intercollegiate Surgical Curriculum Programme (ISCP) since 2007 (www.iscp.ac.uk). The UK Postgraduate Medical Education and Training Board (now part of the General Medical Council) has defined WBA as 'the assessment of working practices based on what trainees actually do in the workplace, and predominantly carried out in the workplace itself' (www.gmc.org.uk). This article reviews the purpose of WBA and the methods in current use. It also discusses the misuse of WBA and possible solutions, including redesign of the rating scales. PMID- 21549984 TI - Use of the operative logbook to monitor trainee progress, and evaluate operative supervision provided by accredited training posts. AB - The Surgical Education and Training (SET) program of the Royal Australasian College of Surgeons (RACS) represents a change from a time-based program to a competency-based program and much greater emphasis is placed on formative assessment and timely feedback (to Surgical Training Boards - STBs - as well as to the trainee). It demands early recognition of the trainee who is struggling to progress, the so-called "marginal trainee". Many of these are simply failing to acquire the desired competencies at the desired or expected rate, although some have more profound underlying deficiencies. SET also places a demand on training posts--with the expectation that they are providing an environment that is conducive to learning and that the trainees are getting adequate learning opportunities. In the domain of operative skills, this largely implies that levels of operative teaching and supervision should be appropriate to the trainee's stage and ability. PMID- 21549985 TI - Surgical simulation: what is available and what is needed. AB - The reduction in working hours has driven interest in surgical simulation as a means of supplementing traditional training models. Simulation offers the opportunity for the rehearsal of a wide range of skills in a controlled, risk free environment, allowing for the development of mastery at a pace appropriate to the learner and offers a means for objective verification of skills. PMID- 21549986 TI - Credentialing of surgical skills centers. AB - Major imperatives regarding quality of patient care and patient safety are impacting surgical care and surgical education. Also, significant emphasis continues to be placed on education and training to achieve proficiency, expertise, and mastery in surgery. Simulation-based surgical education and training can be of immense help in acquiring and maintaining surgical skills in safe environments without exposing patients to risk. Opportunities for repetition of tasks can be provided to achieve pre-established standards, and knowledge and skills can be verified using valid and reliable assessment methods. Also, expertise and mastery can be attained through repeated practice, specific feedback, and establishment of progressively higher learning goals. Simulation based education and training can help surgeons maintain their skills in infrequently performed procedures and regain proficiency in procedures they have not performed for a period of time. In addition, warm-ups and surgical rehearsals in simulated environments should enhance performance in real settings. Major efforts are being pursued to advance the field of simulation-based surgical education. New education and training models involving validation of knowledge and skills are being designed for practicing surgeons. A competency-based national surgery resident curriculum was recently launched and is undergoing further enhancements to address evolving education and training needs. Innovative simulation-based surgical education and training should be offered at state-of the-art simulation centers, and credentialing and accreditation of these centers are key to achieving their full potential. PMID- 21549987 TI - Perspectives on performance assessment in medical simulation. AB - The work upon which this paper is based was supported by an award to Massachusetts General Hospital - CIMIT from the US Department of Defense. The opinions expressed herein are the sole responsibility of the author and do not represent the policy of the US Department of Defense. PMID- 21549988 TI - Objective assessment of technical skill. AB - Objective assessment of technical skill is an important component of skills training: trainees require that deficiencies are clearly and objectively identified if a model of deliberate practice with feedback on skill acquisition is to be employed. There are several types of reliable and valid assessments for technical skill currently available. PMID- 21549989 TI - The role of proximate feedback in skills training. AB - Skills training has been an increasingly important focus of surgical training and is ideally performed prior to reaching the operating room. Although our understanding of the role is increasing, and there are more publications describing endpoints with simulation and different training models, the optimal training methodology remains unclear. In this paper we discuss our experience with simulation and a variety of training models, primarily for teaching laparoscopic colorectal resection. Feedback during training is likely important, and the more proximate that feedback, the better its effectiveness. Optimal skills' training likely depends on a combination of having the optimal curriculum, in conjunction with an appropriate training model. PMID- 21549990 TI - Role of industry in development of surgical simulation centres: a medical education perspective. AB - The concept of simulation in medicine is derived from the industry. The industry plays an important role in the development production and assimilation of this technology throughout the medical profession however, it is up to the end-user to decide its' needs. Close interaction and cooperation between health care and industry professionals is imperative for successful dissemination of simulation in medicine. PMID- 21549991 TI - International consensus statement on surgical education and training in an era of reduced working hours. AB - An international consensus statement has been developed as a reference on the key principles to be considered during discussions on surgical education and training and the delivery of surgical care in an era of restricted hours. PMID- 21549992 TI - Innovation in surgical education--a driver for change. AB - The delivery of healthcare is undergoing a major transition period across the globe. Drivers for change range from the introduction of new technologies such as primary angioplasty and robotic surgery, to restriction in work hours of trainee doctors. PMID- 21549993 TI - Team training for surgical trainees. AB - Healthcare professionals work in teams but are rarely trained together. Realizing the adverse impact of poor teamwork on patient care, the Accreditation Council for Graduate Medical Education requires surgical trainees to demonstrate a mastery of teamwork-related competencies. A number of team training curricula are available in the USA, the best known of which is TeamSTEPPS - developed by the U.S. Department of Defense Patient Safety Program in collaboration with the Agency for Healthcare Research and Quality. PMID- 21549994 TI - Teaching and assessing non-technical skills. AB - The terms human factors and non-technical skills have recently been introduced to the language of surgical education. Both tend to be used interchangeably and yet each has a specific definition. More importantly, however, is the fact that the attributes and qualities contained within these headings relate to behaviours, attitudes and cognitive skills. They are recognised as crucially important in the practice of surgery, but are often poorly articulated during surgical performance, during training, during any assessment process and, indeed, seldom measured with reference to any metric in any of these activities. Most research in this area addresses non-technical skills in the operating theatre and it remains to be seen whether the same attributes and skills are used outwith theatre, particularly in the ward setting. However, the contribution that these aspects of performance make to a safe and successful outcome following surgery is being increasingly appreciated and there is increasing recognition of the need to train and assess. PMID- 21549995 TI - Developing a human factors and patient safety programme at the Royal College of Surgeons in Ireland. AB - Personal skills are now recognised to be important components of effective medical practice. These skills are explicit in the CANMED competencies from Canada, the recommendations of the ACGME from the United States and the recently revised 'Tomorrow's Doctors' paper from the Medical Council in the United Kingdom. The recommended core competencies which encompass personal skills in these international manifestos highlight a paradigm shift in a system which emphasised technical skills and knowledge to a recognition of the key role played by personal skills. PMID- 21549996 TI - Development and assessment of personal skills and aptitudes. AB - Professionalism is an inherent attribute to the practice of surgery. Historically, the importance of this quality arose later than the earliest three fundamental principles of medical knowledge, diagnostic ability, and technical skill. In the modern era, society has clearly come to require that its surgeons embrace professionalism as a fundamental principle. It now stands among the six core competencies that all United States training programs teach and measure. We define professionalism as the pursuit of excellence, the display of humanism, an altruistic commitment, and accountability to all interactions with society. Surgeons teach professionalism to their trainees every day, sometimes by formal curricula but more often by the unspoken and unsuspected modeling of behavior. These methods can be structured into a teaching program. To that program, active practice and engagement in continuous professionalism improvement ought to be added. In this way, a true method of professionalism training can be made that allows for formal assessment. PMID- 21549997 TI - Evaluation matters: lessons learned on the evaluation of surgical teaching. AB - The traditional system of academic promotion and tenure can make it difficult to reward those who excel at surgical teaching. A successful faculty evaluation process can provide the objective measures of teaching performance needed for performance appraisals and promotion decisions. Over the course of two decades, an extensive faculty evaluation process has been developed in the Department of Surgery at the University of Toronto. This paper presents some of the non psychometric characteristics of that system. Faculty awareness of the evaluation process, the consistency of its application, trainee anonymity and the materiality of the results are described key factors of a faculty evaluation system that meets the assessment needs of individual teachers and raises the profile of teaching in surgical departments. PMID- 21549998 TI - Characteristics of a surgical trainer 2010-2020. AB - The type of individual most commonly employed as a surgical trainer is a Clinical Instructor, usually in the junior stages of a faculty position, who has voiced an interest in education and who joins initially with a great deal of enthusiasm. Unfortunately, the lifespan of such an individual as a surgical trainer in a simulation center is relatively limited. PMID- 21549999 TI - Role models in surgery. AB - Our present training models date back almost 100 years. It is very apparent that trying to reshape an ageing system to meet the demands of today's patients and their physicians is just not going to be effective or efficient. In the past educators cared little about the working conditions for trainees such as the living and learning environment, social support and compensation models. You were just fortunate to be "chosen". Surgical educators in the 21st Century must reexamine their roles and consider what message they are sending to future generations on these and other critical issues that impact on safe patient care. PMID- 21550000 TI - Impact of reduced working time on surgical training in the United Kingdom and Ireland. AB - The European Working Time Directive (EWTD) 48 h working week has been law in European countries since 1998. A phased approach to implementation was agreed for doctors in training, which steadily brought down working hours to 58 in 2004, 56 in 2007 and 48 in 2009. Medical trainees can "opt out" to a 54 h working week but this has to be voluntary and rotas cannot be constructed that assume an opt out is taking place. A key component of the working week arrangements is that the maximum period of work for a resident doctor without rest is 13 h. Shorter sessions of work have led to complex rotas, frequent handovers with difficulties maintaining continuity of care with implications for patient safety. Although there has been over 10 years notice of the changes to the working week and progress has up to now been reasonable (helped, in part by a steady increase in consultant numbers) this latest reduction from 56 h to 48 h seems to have been the most difficult to manage. PMID- 21550001 TI - The impact of reduced working hours on surgical training in Australia and New Zealand. AB - There is a worldwide trend for reduced working hours for doctors, particularly in the developed western countries. This has been led by the introduction of the European Working Time Directive (EWTD) that has had a significant impact on work patterns and training. Australia currently has a more flexible working environment but this is changing. In New Zealand there is a contract for resident doctors defining a maximum 72 h of rostered work per week. PMID- 21550002 TI - Is OSCE valid for evaluation of the six ACGME general competencies? PMID- 21550003 TI - HIV in the elderly: an emergent challenge. PMID- 21550004 TI - Hiccups-functional or pathological? PMID- 21550005 TI - A core competence-based objective structured clinical examination (OSCE) in evaluation of clinical performance of postgraduate year-1 (PGY1) residents. AB - BACKGROUND: Clinical competency certifications are important parts of internal medicine residency training. This study aims to evaluate a composite objective structured clinical examination (OSCE) that assesses postgraduate year-1 (PGY(1)) residents' acquisition of the six core competencies defined by the Accreditation council for Graduate Medical Education (ACGME). METHODS: Six-core-competency based OSCE was used as examination of the clinical performance of 192 PGY(1) residents during their 3-month internal medicine training between 2007 January and 2009 December. For each year, the reliability of the entire examination was calculated with Cronbach's alpha. RESULTS: The reliability of six-core-competency based OSCE was acceptable, ranging from 0.69 to 0.87 between 2007 and 2009. In comparison with baseline scores, the summary scores and core-competency subscores all showed significant increase after PGY(1) residents finished their 3-month internal medicine training program. CONCLUSION: By using a structured development process, the authors were able to create reliable evaluation items for determining PGY(1) residents' acquisition of the ACGME core competencies. PMID- 21550006 TI - Evaluation of immune response to hepatitis A vaccination and vaccine safety in juvenile idiopathic arthritis. AB - BACKGROUND: Autoimmune mechanisms and drugs used in treatment increase the risk of liver disease in patients with juvenile idiopathic arthritis (JIA) and hepatitis A virus (HAV) vaccination is important, especially in intermediate endemicity areas like Turkey. In our study, we aimed to evaluate the immune response to hepatitis A vaccine and vaccine safety in children with JIA. METHODS: This study was carried out in our hospital's Pediatric Rheumatology outpatient clinic and Healthy Child clinic between the years 2003 and 2008. The study group consisted of 47 children with JIA (23 male and 24 female) diagnosed according to International League of Associations for Rheumatology diagnostic criteria. The control group consisted of 67 healthy children (31 female, 36 male) who did not have a history of hepatitis A infection or vaccination. Both groups were vaccinated with two doses of hepatitis A vaccine at 6-month intervals. Anti-HAV IgG >80 MIU was accepted as positive response. RESULTS: There was no significant difference between the groups in terms of age and sex. None of the patients with JIA had fever, clinical worsening, or disease activation after vaccination. Anti HAV IgG positivity rate was significantly higher in the control group (p < 0.05). Anti-HAV IgG was negative in only four cases, and they were all male patients with systemic JIA who had active disease under anti-tumor necrosis factor treatment. CONCLUSION: Hepatitis A vaccine was safe in patients with JIA, and response to vaccine did not differ between healthy children and patients with JIA except for children with active systemic JIA receiving anti-tumor necrosis factor alpha drugs. PMID- 21550007 TI - Third-line or fourth-line chemotherapy in non-small-cell lung cancer patients with relatively good performance status. AB - BACKGROUND: Our aim here was to explore treatment efficacy of pemetrexed and docetaxel in non-small-cell lung cancer patients who had failed previous chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor therapy. METHODS: We retrospectively reviewed clinical data of our non-small-cell lung cancer patients who received third- or fourth-line chemotherapy with pemetrexed or docetaxel in our institution from January 2006 to December 2009. RESULTS: One hundred and twenty-three patients received treatment, including 85 patients with pemetrexed treatment and 38 patients with docetaxel treatment. There was no difference in tumor response rate and toxicity profiles when using pemetrexed as third- or fourth-line treatment, neither was there difference in docetaxel treatment of third- versus fourth-line treatment. There was also no difference between docetaxel and pemetrexed in response rate and control rate when they were used as fourth-line treatment. However, docetaxel used in fourth line treatment had higher incidence of neutropenia and more frequent need of granulocyte colony-stimulating factor support compared with pemetrexed in fourth line treatment. Median progression-free survivals (PFSs) were 2.6 months and 3.8 months when using pemetrexed as third- and fourth-line treatment, respectively (p = 0.417). Median PFSs were 3.8 months and 4.8 months when using docetaxel as third- and fourth-line treatment, respectively (p = 0.882). There was also no difference in PFS between pemetrexed and docetaxel, both in third- and fourth line treatment. Median survivals were 13.4, 12.2, 13.2, and 13 months for pemetrexed in third-line, fourth-line, and docetaxel in third-line and fourth line treatment, respectively. CONCLUSION: This retrospective study of pemetrexed and docetaxel showed relatively safe toxicity profile, reasonable response rate, and long survival when used as third- and fourth-line chemotherapy. Thus, it is reasonable to give good performance status patients third- and fourth-line chemotherapy. A phase III randomized trial is needed for better clarification of these issues. PMID- 21550008 TI - Characteristics of human immunodeficiency virus infections among the elderly in Taiwan: a nationwide study. AB - BACKGROUND: Information regarding human immunodeficiency virus (HIV) infections and acquired immunodeficiency syndrome (AIDS) in the elderly of Taiwan is limited. This study looked into the aforementioned issues. METHODS: Data from the National HIV/AIDS Registry, relating to individuals diagnosed in 2007, were analyzed. RESULTS: Among 1,975 HIV-infected individuals diagnosed in 2007, the elderly group (age ?50 years) consisted of 153 subjects and the younger (control) group (age 15-39 years) consisted of 1,458 individuals. Some markers, such as primarily males/local Taiwanese, being unemployed, one third of subjects infected by means of intravenous drug use, and primarily diagnosed in hospitals, were similar between the two groups. The elderly group had more married, divorced, and separated individuals, and widows/widowers than the younger group. The causes of death differed insignificantly between the two groups. The younger group had more variety than the elderly group in distribution of occupations. Fewer prison diagnosed HIV, high ratio of individuals developing AIDS, heterosexuals, high mortality, and unsupported marital status were significant markers of elderly HIV infected subjects. CONCLUSION: In Taiwan, elderly HIV infections have reflected the aforementioned characteristics. Some specific issues concerning elderly HIV infections, such as heterosexual predominance, high mortality and fewer men who have sex with men, are similar with reports from other countries. These characteristics can guide possible directions of social and health care interventions. PMID- 21550009 TI - Management of base of tongue squamous cell carcinoma: experience with 85 patients in Taipei Veterans General Hospital. AB - BACKGROUND: The optimal treatment of base of tongue squamous cell carcinoma (BOTSCC) remains controversial. To optimize treatment planning, this study analyzed the outcomes of patients with BOTSCC treated in Taipei Veterans General Hospital. METHODS: Retrospective chart reviews were performed for 107 patients with BOTSCC from January 1990 to December 2004, and 85 patients were included, with a mean follow-up interval of 38 months. Patients were divided into surgical and radiotherapy/chemoradiation therapy (RT/CRT) groups. Potentially significant variables for survival were analyzed. RESULTS: The 3-year overall survival (OS) and disease-free survival rates were 40% and 37.1%, respectively. No significant differences in the patient and disease characteristics between the surgical (n = 39) and RT/CRT groups (n = 46) were found. Advanced overall stage (p = 0.034), cervical lymph node metastasis (p = 0.007), and regional recurrence (p = 0.024) were poor prognostic factors for OS. In early-stage disease (Stages I and II), the 3-year OS was higher in the surgical group (68.6%) than in the RT/CRT group (37.5%), but the significance was only borderline (p = 0.071). There was no significant difference in the 3-year OS between the patients in the surgical and CT/CRT groups with advanced-stage disease. In the surgical group, lymphovascular permeation (p = 0.015) and soft-tissue involvement (p = 0.01), determined by pathologic examination, were poor prognostic factors for OS. Recurrence occurred in 35 patients (41.2%), with no significant difference in local, regional, or distant control between the surgical and RT/CRT groups. CONCLUSION: These findings emphasize the importance of neck disease control in the treatment of BOTSCC. Although currently, RT/CRT is used more frequently, surgery may still have a role in the treatment of early-stage disease. Both surgery with adjuvant therapy and RT/CRT produced equivalent survival rates in the treatment of advanced-stage disease, but the recurrence rate was unsatisfactory. A more effective treatment modality with less early and late toxicity is needed. PMID- 21550010 TI - A long slanted transseptal accessory pathway. AB - A 63-year-old male with Wolff-Parkinson-White syndrome was admitted for ablation of accessory pathway. Intracardiac electrogram revealed a left-side accessory pathway during tachycardia, which was successfully ablated from the right posterior tricuspid annulus because of a long slanted transseptal accessory pathway (2.2 cm). PMID- 21550011 TI - Primary ovary transitional cell carcinoma after renal transplantation. AB - Transitional cell carcinoma (TCC) of the urinary tract is the most frequent malignancy following renal transplantation reported in Taiwan. A 67-year-old female underwent bilateral nephrouretectomy and bladder cuff excision because of bilateral hydronephrosis 5 years after cadaveric renal transplantation. The pathologic report was only atrophied kidney. Pelvic sonography and abdominal computed tomography showed a pelvic mass 8 years after transplantation. After gynecological surgery, the pathologic report of the left ovarian tumor was TCC, high grade, stage IIA. The patient then underwent four cycles of postoperative chemotherapy with carboplatin and gemcitabine. TCC of the ovary is a rare, recently recognized subtype of ovarian surface epithelial cancer. We present the first case of primary ovarian TCC following renal transplant. PMID- 21550012 TI - Duodenal duplication cyst: a rare cause of geriatric gastrointestinal bleeding. AB - Duodenal duplication cysts are rare congenital anomalies usually found in children, but rare cases, often presenting with pancreatitis, have been reported in adults. We report the case of a duodenal duplication cyst in an 81-year-old man who presented with gastrointestinal bleeding. Despite endoscopy and endoscopic ultrasonography, duodenal duplication was not diagnosed until exploratory laparotomy was performed to remove the lesion. To the best of our knowledge, this was the first case of a duodenal duplication cyst that presented with gastrointestinal bleeding in an elderly adult. The patient's recovery was uneventful. A high index of suspicion is required to diagnose duodenal duplication cysts, particularly in elderly patients with an atypical presentation. PMID- 21550013 TI - Primary pelvic hydatic cyst mimicking ovarian carcinoma. AB - Hydatic cyst is an illness that appears in consequence of the cystic form of small strap-shaped worm Echinococcus granulosis. Frequently, cysts exist in the lungs and liver. Peritoneal involvement is rare, and generally occurs as a result of second inoculation from rupture of a liver-located hydatic cyst. Primary ovarian hydatic cyst is very rare. A 56-year-old female patient was admitted to Emergency Service with the complaint of stomachache and swollen abdomen. From ultrasonographic examination, a right ovarian 52 * 45-mm heterogeneous semi-solid cystic mass and right hydronephrosis were detected. As a result of the tomographic examination, the right ovarian growth was judged to be a 60 * 45-mm lobule contoured, septal, heterogeneously cystic mass (ovarian carcinoma). Depending on these indicators and with the diagnosis of ovarian carcinoma, laparotomy was planned. During the observation, a mass that compressed on the right ureter and dilatation in the right ureter were determined. The mass was approximately 6 cm long and smoothly contoured, including widespread adhesions, and also obliteration of the pouch of Douglas. The mass was excised and total abdominal hysterectomy and bilateral salpingo-oopherectomy performed. After a pathological examination, hydatid cyst was diagnosed. Although pointing at the issue of the distinctive diagnosis of pelvic and peritoneal mass, it should be realized that the existence of primary peritoneal and pelvic involvement of the hydatic cyst is generally a result of the second inoculation, and is also more common in regions in which Echinococcus granulosa is endemic and livestock production is prevalent. PMID- 21550015 TI - Neonatal hyperoxia causes pulmonary vascular disease and shortens life span in aging mice. AB - Bronchopulmonary dysplasia is a chronic lung disease observed in premature infants requiring oxygen supplementation and ventilation. Although the use of exogenous surfactant and protective ventilation strategies has improved survival, the long-term pulmonary consequences of neonatal hyperoxia are unknown. Here, we investigate whether neonatal hyperoxia alters pulmonary function in aging mice. By 67 weeks of age, mice exposed to 100% oxygen between postnatal days 1 to 4 showed significantly a shortened life span (56.6% survival, n = 53) compared to siblings exposed to room air as neonates (100% survival, n = 47). Survivors had increased lung compliance and decreased elastance. There was also right ventricular hypertrophy and pathological evidence for pulmonary hypertension, defined by reduction of the distal microvasculature and the presence of numerous dilated arterioles expressing von Willebrand factor and alpha-smooth muscle actin. Consistent with recent literature implicating bone morphogenetic protein (BMP) signaling in pulmonary vascular disease, BMP receptors and downstream phospho-Smad1/5/8 were reduced in lungs of aging mice exposed to neonatal oxygen. BMP signaling alterations were not observed in 8-week-old mice. These data suggest that loss of BMP signaling in aged mice exposed to neonatal oxygen is associated with a shortened life span, pulmonary vascular disease, and associated cardiac failure. People exposed to hyperoxia as neonates may be at increased risk for pulmonary hypertension. PMID- 21550016 TI - Hematopoietic Fas deficiency does not affect experimental atherosclerotic lesion formation despite inducing a proatherogenic state. AB - The Fas death receptor (CD95) is expressed on macrophages, smooth muscle cells, and T cells within atherosclerotic lesions. Given the dual roles of Fas in both apoptotic and nonapoptotic signaling, the aim of the present study was to test the effect of hematopoietic Fas deficiency on experimental atherosclerosis in low density lipoprotein receptor-null mice (Ldlr(-/-)). Bone marrow from Fas(-/-) mice was used to reconstitute irradiated Ldlr(-/-) mice as a model for atherosclerosis. After 16 weeks on an 0.5% cholesterol diet, no differences were noted in brachiocephalic artery lesion size, cellularity, or vessel wall apoptosis. However, Ldlr(-/-) mice reconstituted with Fas(-/-) hematopoietic cells had elevated hyperlipidemia [80% increase, relative to wild-type (WT) controls; P < 0.001] and showed marked elevation of plasma levels of CXCL1/KC, CCL2/MCP-1, IL-6, IL-10, IL-12 subunit p70, and soluble Fas ligand (P < 0.01), as well as systemic microvascular inflammation. It was not possible to assess later stages of atherosclerosis because of increased mortality in Fas(-/-) bone marrow recipients. Our data indicate that hematopoietic Fas deficiency does not affect early atherosclerotic lesion development in Ldlr(-/-) mice. PMID- 21550018 TI - Effect of visual perspective on memory and interpretation in dysphoria. AB - When engaging in self-reflection, the visual perspective one adopts has important effects on emotional reactivity. Specifically, adopting a distanced stance, or viewing oneself from a third-person perspective, has been found to reduce emotional reactivity to negative autobiographical memories. The effect of adopting this perspective is moderated by depression such that reactivity is not reduced for individuals with particularly low levels of depressive symptoms. In the current study, we examine the effects of visual perspective on two forms of mental imagery in dysphoric and nondysphoric individuals. We attempt to replicate previous findings for recall of sad autobiographical memories and extend this research to interpretation of ambiguous situations. The results suggest that the effects of adopting a distanced stance are not moderated by depressive symptoms and do not extend from memories to interpretations of ambiguous situations. PMID- 21550017 TI - Pericyte requirement for anti-leak action of angiopoietin-1 and vascular remodeling in sustained inflammation. AB - Blood vessel leakiness is an early, transient event in acute inflammation but can also persist as vessels undergo remodeling in sustained inflammation. Angiopoietin/Tie2 signaling can reduce the leakiness through changes in endothelial cells. The role of pericytes in this action has been unknown. We used the selective PDGF-B-blocking oligonucleotide aptamer AX102 to determine whether disruption of pericyte-endothelial crosstalk alters vascular leakiness or remodeling in the airways of mice under four different conditions: i) baseline, ii) acute inflammation induced by bradykinin, iii) sustained inflammation after 7 day infection by the respiratory pathogen Mycoplasma pulmonis, or iv) leakage after bradykinin challenge in the presence of vascular stabilization by the angiopoietin-1 (Ang1) mimic COMP-Ang1 for 7 days. AX102 reduced pericyte coverage but did not alter the leakage of microspheres from tracheal blood vessels at baseline or after bradykinin; however, AX102 exaggerated leakage at 7 days after M. pulmonis infection and increased vascular remodeling and disease severity at 14 days. AX102 also abolished the antileakage effect of COMP-Ang1 at 7 days. Together, these findings show that pericyte contributions to endothelial stability have greater dependence on PDGF-B during the development of sustained inflammation, when pericyte dynamics accompany vascular remodeling, than under baseline conditions or in acute inflammation. The findings also show that the antileakage action of Ang1 requires PDGF-dependent actions of pericytes in maintaining endothelial stability. PMID- 21550019 TI - Catechol-O-methyltransferase valine158methionine polymorphism moderates methylphenidate effects on oppositional symptoms in boys with attention deficit/hyperactivity disorder. AB - BACKGROUND: The catechol-O-methyltransferase enzyme plays a key role in the function of prefrontal cortex, accounting for most of the degradation of dopamine. Previous studies have documented the improvement of oppositional symptoms in attention-deficit/hyperactivity disorder (ADHD) patients with methylphenidate (MPH) treatment. However, the effect of the COMT gene in the response to MPH on oppositional symptoms has not been investigated. METHODS: A total of 251 children with ADHD fulfilled inclusion criteria to participate in the study. Dosages of short-acting MPH were augmented until no further clinical improvement was detected or until there were significant adverse events (MPH dose always > .3 mg/kg/day). The outcome measure was the parent-rated oppositional subscale of the Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV). The scale was applied by child psychiatrists blinded to genotype at baseline and in the first and third months. The COMT valine158methionine polymorphism was genotyped by polymerase chain reaction based methods. RESULTS: We detected significant improvement in SNAP-IV oppositional scores from baseline to the first and three months of treatment [n = 112; F(2,231) = 5.35, p = .005]. A significant effect of the presence of methionine allele in oppositional defiant disorder scores during treatment [F(1,148) = 5.02, p = .027] and a significant interaction between the methionine allele and treatment over time for the SNAP-IV oppositional scores during this period of treatment [F(2,229) = 6.40, p = .002] were both observed. CONCLUSIONS: These results suggest an effect of the COMT genotype on the trajectory of oppositional defiant disorder symptoms improvement with MPH treatment in boys with ADHD. PMID- 21550020 TI - Changes in gray matter volume with rapid body weight changes in anorexia nervosa: a voxel-based morphometric study. PMID- 21550021 TI - The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. AB - Through neuromodulatory influences over fronto-striato-cerebellar circuits, dopamine and noradrenaline play important roles in high-level executive functions often reported to be impaired in attention-deficit/hyperactivity disorder (ADHD). Medications used in the treatment of ADHD (including methylphenidate, dextroamphetamine and atomoxetine) act to increase brain catecholamine levels. However, the precise prefrontal cortical and subcortical mechanisms by which these agents exert their therapeutic effects remain to be fully specified. Herein, we review and discuss the present state of knowledge regarding the roles of dopamine (DA) and noradrenaline in the regulation of corticostriatal circuits, with a focus on the molecular neuroimaging literature (both in ADHD patients and in healthy subjects). Recent positron emission tomography evidence has highlighted the utility of quantifying DA markers, at baseline or following drug administration, in striatal subregions governed by differential cortical connectivity. This approach opens the possibility of characterizing the neurobiological underpinnings of ADHD (and associated cognitive dysfunction) and its treatment by targeting specific neural circuits. It is anticipated that the application of refined and novel positron emission tomography methodology will help to disentangle the overlapping and dissociable contributions of DA and noradrenaline in the prefrontal cortex, thereby aiding our understanding of ADHD and facilitating new treatments. PMID- 21550022 TI - Studies on the stereoselective synthesis of a protected alpha-D-Gal-(1->2)-D-Glc fragment. AB - A novel 1,2-cis stereoselective synthesis of protected alpha-D-Gal-(1->2)-D-Glc fragments was developed. Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-alpha-D galactopyranosyl-(1->2)-3-O-benzoyl-4,6-O-benzylidene-alpha-D-glucopyranoside (13), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-alpha-D-galactopyranosyl-(1 >2)-3,4,6-tri-O-benzoyl-alpha-D-glucopyranoside (15), methyl 2-O-acetyl-3-O-allyl 4,6-O-benzylidene-alpha-D-galactopyranosyl-(1->2)-3-O-benzoyl-4,6-O-benzylidene beta-D-glucopyranoside (17), and methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene alpha-D-galactopyranosyl-(1->2)-3,4,6-tri-O-benzoyl-beta-D-glucopyranoside (19) were favorably obtained by coupling a new donor, isopropyl 2-O-acetyl-3-O-allyl 4,6-O-benzylidene-1-thio-beta-D-galactopyranoside (2), with acceptors, methyl 3-O benzoyl-4,6-O-benzylidene-alpha-D-glucopyranoside (4), methyl 3,4,6-tri-O-benzoyl alpha-D-glucopyranoside (5), methyl 3-O-benzoyl-4,6-O-benzylidene-beta-D glucopyranoside (8), and methyl 3,4,6-tri-O-benzoyl-beta-D-glucopyranoside (12), respectively. By virtue of the concerted 1,2-cis alpha-directing action induced by the 3-O-allyl and 4,6-O-benzylidene groups in donor 2 with a C-2 acetyl group capable of neighboring-group participation, the couplings were achieved with a high degree of alpha selectivity. In particular, higher alpha/beta stereoselective galactosylation (5.0:1.0) was noted in the case of the coupling of donor 2 with acceptor 12 having a beta-CH(3) at C-1 and benzoyl groups at C-4 and C-6. PMID- 21550023 TI - Chemical modification of chitosan by tetraethylenepentamine and adsorption study for anionic dye removal. AB - To utilize the contribution of introduced amino groups to the adsorption of an anionic dye (eosin Y), a batch adsorption system was applied to study the adsorption of eosin Y from aqueous solution by tetraethylenepentamine (TEPA) modified chitosan (TEPA-CS). Experiments were carried out as a function of particle size, initial pH, agitation rate, adsorbent dosage, agitation period, temperature and initial concentration of eosin Y. The Langmuir and Freundlich models were used to fit the adsorption isotherms. From the values of correlation coefficients (R2), it was observed that the experimental data fit very well to the Langmuir model, giving a maximum sorption capacity of 292.4mg/g at 298K. Kinetic studies showed that the kinetic data were well described by the pseudo second-order kinetic model. The thermodynamic study revealed negative value of enthalpy change (DeltaH degrees ) and free energy change (DeltaG degrees ), indicating spontaneous and endothermic nature of the adsorption of eosin Y on to TEPA-CS. PMID- 21550024 TI - Synthesis of 4-amino-4,5-dideoxy-L-lyxofuranose derivatives and their evaluation as fucosidase inhibitors. AB - The nitrone 4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-L-lyxofuranose) was synthesised from D-ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe two transformations of 4. Hydrolysis with aqueous sulfur dioxide gave the known potent nanomolar inhibitor 4-amino-4,5 dideoxy-L-lyxofuranose (3). 1,3-Dipolar cycloaddition with enol ethers led to the related 1,2,5,6-tetradeoxy-2,5-imino-L-altroheptonic ester 2a, acid 2b and the corresponding heptitol 2c. The new iminosugars have been evaluated for their inhibitory activity against alpha-L-fucosidase from bovine kidney. The alcohol 2c turned out to be a potent inhibitor in the same range as the amino-sugar 3 (K(i)=8 vs 10nM). PMID- 21550025 TI - A convenient synthesis of novel pyranosyl homo-C-nucleosides and their antidiabetic activities. AB - A series of pyranosyl homo-C-nucleosides have been synthesized by reaction of butenonyl C-glycosides (5a-5j, and 8) and cyanoacetamide in presence of t-BuOK followed by further modifications. The reaction proceeds by Michael addition of cyanoacetamide to the butenonyl C-glycosides and subsequent dehydrative cyclization and oxidative aromatization to give glycosylmethyl pyridones (6a-6j, 7a-7j, 9, and 10). The glycosylmethyl pyridones (6a-6e) on reaction with POCl(3) under reflux gave respective glycosylmethyl pyridines (11a-11e and 12a-12e) in good yields. The synthesized compounds were screened for their in vitro alpha glucosidase, glucose-6-phosphatase and glycogen phosphorylase inhibitory activities. One of the pyridylmethyl homo-C-nucleoside, compound 11d, displayed 52% inhibition of glucose-6-phosphatase as compared to the standard drug sodium orthovanadate while compound 12a showed a significant antihyperglycemic effect of 17.1% in the diabetic rats as compared to the standard drug metformin. PMID- 21550026 TI - A redox microenvironment is essential for MAPK-dependent secretion of pro inflammatory cytokines: modulation by glutathione (GSH/GSSG) biosynthesis and equilibrium in the alveolar epithelium. AB - The characterization of oxidant (glutathione)-dependent regulation of MAPK(p38/RK)-mediated TNF-alpha secretion was undertaken in vitro, and the ramifications of the influence of a redox microenvironment were unraveled. Intermittent exposure of alveolar epithelial cells (FATEII) to LPS (endotoxin) transiently and temporally induced the expression of MAPK(p38/RK). This upregulation was associated with the activation of MAPKAP-K(2), manifested by the specific phosphorylation of the downstream heat-shock protein (Hsp)-27. Selective blockading of the MAPK(p38/RK) pathway using the pyridinyl imidazole SB-203580 abrogated the LPS-dependent release of TNF-alpha. N-acetyl-l-cysteine (NAC), a precursor of glutathione, reduced TNF-alpha secretion and increased [GSH]. Conversely, l-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in the pathway mediating GSH biosynthesis, augmented the secretion of TNF-alpha and [GSSG] accumulation. Whereas NAC abrogated the phosphorylation of MAPK(p38/RK), BSO reversibly amplified this effect. Furthermore, intermittent exposure of FATEII cells to the exogenous oxidants X/XO and H(2)O(2) upregulated the secretion of pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha; this upregulation was correlated with increasing activity of key glutathione-related enzymes, closely involved with maintaining the cyclic GSH/GSSG equilibrium. These results indicate that a redox microenvironment plays a major role in regulating MAPK-dependent production of cytokines in the alveolar epithelium. PMID- 21550027 TI - Immunization with a poly (lactide co-glycolide) encapsulated plasmid DNA expressing antigenic regions of HPV 16 and 18 results in an increase in the precursor frequency of T cells that respond to epitopes from HPV 16, 18, 6 and 11. AB - A phase II trial was conducted in subjects with human papillomavirus (HPV) associated high-grade cervical dysplasia testing the safety and efficacy of a microparticle encapsulated pDNA vaccine. Amolimogene expresses T cell epitopes from E6 and E7 proteins of HPV types 16 and 18. An analysis was performed on a subset of HLA-A2+ subjects to test whether CD8+ T cells specific to HPV 16, 18, 6 and 11 were increased in response to amolimogene immunization. Of the 21 subjects receiving amolimogene, 11 had elevated CD8+ T cell responses to HPV 16 and/or 18 peptides and seven of these also had increases to corresponding HPV 6 and/or 11 peptides. In addition, T cells primed and expanded in vitro with an HPV 18 peptide demonstrated cross-reactivity to the corresponding HPV 11 peptide. These data demonstrate that treatment with amolimogene elicits T cell responses to HPV 16, 18, 6 and 11. PMID- 21550028 TI - Bulimia nervosa in overweight and normal-weight women. AB - The aim of the present study was to examine overweight bulimia nervosa (BN) in a community sample of women. Volunteers (n = 1964) completed self-report questionnaires of weight, binge eating, purging, and cognitive features. Participants were classified as overweight (body mass index >=25) or normal weight (body mass index <25). Rates of BN within the overweight and normal-weight classes did not differ (6.4% vs 7.9%). Of the 131 participants identified as BN, 64% (n = 84) were classified as overweight BN and 36% (n = 47) as normal-weight BN. The overweight BN group had a greater proportion of ethnic minorities and reported significantly less restraint than the normal-weight BN group. Otherwise, the 2 groups reported similarly, even in terms of purging and depression. In summary, rates of BN did not differ between overweight and normal-weight women. Among BN participants, the majority (two thirds) were overweight. Differences in ethnicity and restraint, but little else, were found between overweight and normal-weight BN. Findings from the present study should serve to increase awareness of the weight range and ethnic diversity of BN, and highlight the need to address weight and cultural sensitivity in the identification and treatment of eating disorders. PMID- 21550029 TI - Neuropsychological function in obsessive-compulsive disorder. AB - Obsessive-compulsive disorder (OCD) is a chronic disease characterized by repetitive, unwanted intrusive thoughts and ritualistic behaviors. Studies of neuropsychological functions in OCD have documented deficits in several cognitive domains, particularly with regard to visuospatial abilities, executive functioning, and motor speed. The objective of the present study was to investigate systematically the cognitive functioning of OCD patients who were free of medication and comorbid psychiatric disorders. In the present study, 72 OCD patients were compared with 54 healthy controls on their performance in a comprehensive neuropsychological battery. The Yale-Brown Obsessive Compulsive Scale and the Hamilton Depression Rating Scale were administered to the patients, and a semistructured interview form was used to evaluate the demographic features of the patients and control subjects. Overall, widespread statistically significant differences were found in tests related to verbal memory, global attention and psychomotor speed, and visuospatial and executive functions indicating a poorer performance of the OCD group. A closer scrutiny of these results suggests that the OCD group has difficulty in using an effective learning strategy that might be partly explained by their insufficient mental flexibility and somewhat poor planning abilities. PMID- 21550030 TI - The role of avoidance in the phenomenology of obsessive-compulsive disorder. AB - BACKGROUND: Pathologic levels of ritualistic avoidance (also known as active avoidance) are common in the clinical presentation of obsessive-compulsive disorder (OCD). Despite its clinical relevance, there has been little examination of active avoidance as a ritualistic compulsion in adults with OCD. OBJECTIVE: The objective of this study is to determine if adults with OCD who engage in ritualistic avoidance have greater obsessive-compulsive, anxiety, and depressive symptom severity and different comorbidity patterns than adults who do not engage in ritualistic avoidance. METHOD: Adults with OCD (n = 133) completed an evaluation that included clinician ratings of obsessive-compulsive severity; overall illness severity; and self-reported ratings of anxiety, depression, and obsessive-compulsive severity. RESULTS: Ritualized avoidance was endorsed by greater than 25% of the sample. Avoidant subjects and, more specifically, contaminant avoidant and reading-writing avoidant subjects presented with elevated levels of obsessive-compulsive symptom severity and greater overall clinical severity than comparison patients who did not engage in each respective avoidance ritual. CONCLUSIONS: Patients who engage in ritualized avoidance exhibited greater obsessive-compulsive symptom severity than patients who did not. These findings suggest that ritualized avoidance functions as a compulsion for adults with OCD and that avoidance should receive careful consideration in assessment and treatment. PMID- 21550031 TI - Overcoming the problem of diagnostic heterogeneity in applying measurement-based care in clinical practice: the concept of psychiatric vital signs. AB - Measurement-based care refers to the use of standardized scales to measure the outcome of psychiatric treatment. Diagnostic heterogeneity poses a challenge toward the adoption of a measurement-based care approach toward outcome evaluation in clinical practice. In the present article, we propose adopting the concept of psychiatric vital signs to facilitate measurement-based care. Medical vital signs are measures of basic physiologic functions that are routinely determined in medical settings. Vital signs are often a primary outcome measure, and they are also often adjunctive measurements. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we examined the frequency of depression and anxiety in a diagnostically heterogeneous group of psychiatric outpatients to determine the appropriateness of considering their measurement as psychiatric vital signs. Three thousand psychiatric outpatients were interviewed with the Structured Clinical Interview for DSM-IV supplemented with items from the Schedule for Affective Disorders and Schizophrenia. We determined the frequency of depression and anxiety evaluated according to the Schedule for Affective Disorders and Schizophrenia items. In the entire sample of 3000 patients, 79.3% (n = 2378) reported clinically significant depression of at least mild severity, 64.4% (n = 1932) reported anxiety of at least mild severity, and 87.4% (n = 2621) reported either anxiety or depression. In all 10 diagnostic categories examined, most patients had clinically significant anxiety or depression of at least mild severity. These findings support the routine assessment of anxiety and depression in clinical practice because almost all patients will have these problems as part of their initial presentation. Even for those patients without depression or anxiety, the case could be made that the measurement of depression and anxiety is relevant and analogous to measuring certain physiologic parameters in medical practice such as blood pressure and body temperature regardless of the reason for the visit. PMID- 21550032 TI - The relationship between illegal behaviors and borderline personality symptoms among internal medicine outpatients. AB - BACKGROUND: In psychiatric dysfunction, illegal behaviors are frequently associated with the traditional prison personality antisocial personality disorder. However, some empirical data indicate that illegal behaviors may also be associated with borderline personality, which is the focus of the present study. METHOD: Using a cross-sectional sample of consecutive internal medicine outpatients from a resident-provider clinic, we examined relationships between 27 illegal behaviors as delineated by the Federal Bureau of Investigation's crime cataloguing schema and 2 measures of borderline personality disorder (BPD), the BPD scale of the Personality Diagnostic Questionnaire-4 and the Self-Harm Inventory. RESULTS: The overall correlations between BPD and the number of the 27 illegal behaviors endorsed were r = 0.32 (P < .001, n = 375) for the Personality Diagnostic Questionnaire-4 and r = 0.47 (P < .001, n = 372) for the Self-Harm Inventory. Six specific illegal behaviors were endorsed by at least 12 participants each, and analyses indicated associations for each of these illegal behaviors with BPD (ie, aggravated and simple assault, disorderly conduct, driving under the influence, drug abuse violations, public drunkenness/intoxication). These 6 behaviors may be interrelated through alcohol/substance use. Participants who were male and younger were more likely to report having engaged in a greater number of different illegal behaviors. CONCLUSIONS: There appear to be associations between illegal behaviors and BPD, particularly in relation to alcohol/substance abuse and in young men. PMID- 21550033 TI - Suicide attempts are associated with worse quality of life in patients with bipolar disorder type I. AB - BACKGROUND: The association between suicidal behavior and quality of life (QoL) in bipolar disorder (BD) is poorly understood. Worse QoL has been associated with suicide attempts and suicidal ideation in schizophrenic patients, but this relationship has not been investigated in BD. This study tested whether a history of suicide attempts was associated with poor QoL in a well-characterized sample of patients with BD, as has been observed in other psychiatric disorders and in the general population. METHODS: One hundred eight patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition BD type I (44 with previous suicide attempts, 64 without previous suicide attempts) were studied. Quality of life was assessed using the World Health Organization's Quality of Life Instrument-Short Version. Depressive and manic symptoms were assessed using the Hamilton Depression Rating Scale-17 items and the Young Mania Rating Scale. RESULTS: Patients with BD and previous suicide attempts had significantly lower scores in all the 4 domains of the World Health Organization's Quality of Life Instrument-Short Version scale than did patients with BD but no previous suicide attempts (physical domain P = .001; psychological domain P < .0001; social domain P = .001, and environmental domain P = .039). In the euthymic subgroup (n = 70), patients with previous suicide attempts had significantly lower scores only in the psychological and social domains (P = .020 and P = .004). LIMITATIONS: This was a cross-sectional study, and no causal associations can be assumed. CONCLUSIONS: Patients with BD and a history of previous suicide attempts seem to have a worse QoL than did patients who never attempted suicide. Poorer QoL might be a marker of poor copying skills and inadequate social support and be a risk factor for suicidal behavior in BD. Alternatively, poorer QoL and suicidal behavior might be different expressions of more severe BD. PMID- 21550034 TI - [Primary non-Hodgkin's lymphoma of the bone. A retrospective analysis]. PMID- 21550035 TI - [Language in the medical practice]. PMID- 21550036 TI - Surgical management of cesarean scar ectopic pregnancy: hysterotomy by transvaginal approach. AB - OBJECTIVE: To report on the surgical management of a cesarean scar ectopic pregnancy (CSEP) by transvaginal hysterotomy. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 29-year-old woman, with previous cesarean delivery, presenting with vaginal bleeding, was transferred to our hospital at 5 weeks 4 days of gestation. Transvaginal ultrasonography confirmed the diagnosis of CSEP. INTERVENTION(S): Hysterotomy by transvaginal approach of the CSEP. MAIN OUTCOME MEASURE(S): During the operation, there were no significant complications. Postoperative ultrasonography showed complete disappearance of the ectopic gestational sac. RESULT(S): Good recovery of the patient and return of normal menstruation. CONCLUSION(S): Surgical removal of the ectopic mass by transvaginal hysterotomy may be a less invasive approach in cases of CSEP. This case report offers an alternative treatment to other proposed methods for CSEP, with a short operative time and minimum blood loss. PMID- 21550037 TI - Mild/minimal stimulation for in vitro fertilization: an old idea that needs to be revisited. AB - Mild ovarian stimulation for in vitro fertilization usually refers to the use of low-dose gonadotropins in conjunction with a gonadotropin-releasing hormone (GnRH) antagonist whereas minimal stimulation refers to the use of a sequential administration of clomiphene citrate followed by low-dose gonadotropins and a GnRH antagonist. These protocols offer important cost and tolerability advantages to all patients but specifically to high and low responders. PMID- 21550038 TI - The long-term outcome of 946 consecutive couples visiting a fertility clinic in 2001-2003. AB - OBJECTIVE: To describe the outcome of fertility work-up, treatment, and dropout in a cohort of subfertile couples in a well-defined area in Western Europe. DESIGN: Prospective cohort study. SETTING: Maastricht University Medical Center. PATIENT(S): Subfertile couples referred by their general physician between 2001 and 2003. INTERVENTION(S): Demographic data, findings of the fertility investigation, and outcome of treatment were entered prospectively into a database. Follow-up was performed until November 2008. MAIN OUTCOME MEASURE(S): Diagnosis, treatment, dropout rate, pregnancy rate, and live-birth rate. RESULT(S): During the study period, 946 couples were referred, of whom 17% dropped out. Follow-up was complete in 94% of couples. Spontaneous pregnancies occurred in 28% of all couples, and there were 32% treatment-dependent pregnancies. IVF (51% live births in couples treated) and no treatment/expectant management (50%) were the most effective treatments. CONCLUSION(S): After 5-8 years, 51% of couples referred for subfertility had at least one live birth. PMID- 21550039 TI - Expression of activated HER2 in human testes. AB - The HER2 messenger RNA (mRNA) was the most abundant among the erb type-1 tyrosine kinase receptors mRNA in human testis and was statistically significantly decreased in impaired spermatogenesis. Testicular HER2 was tyrosine phosphorylated and strongly expressed in spermatogonia, early spermatocytes, elongating/elongated spermatids, Sertoli cells, Leydig cells, and peritubular cells, suggesting that activated HER2 participates in mitosis and meiotic entry of germ cells, spermiogenesis, and steroidogenesis via mediating the epidermal growth factor-growth factor signaling. PMID- 21550040 TI - Child with Beckwith-Wiedemann syndrome born after assisted reproductive techniques to an human immunodeficiency virus serodiscordant couple. AB - OBJECTIVE: To report a child with Beckwith-Wiedemann syndrome (BWS) born after assisted reproductive technology (ART) to an HIV serodiscordant couple. DESIGN: Case report. SETTING: Academic medical center. PATIENT(S): A child with BWS born after ART to an HIV serodiscordant couple. INTERVENTION(S): Assisted reproductive techniques. MAIN OUTCOME MEASURE(S): ART and HIV. RESULT(S): Since 2003, it has been suggested that there is an association between ART and BWS, which is a congenital overgrowth syndrome characterized by macrosomia, macroglossia, visceromegaly, umbilical and abdominal wall abnormalities, and an increased risk of developing embryonal tumors in childhood. It is a multigenic disorder resulting from genetic or epigenetic alterations of genes on chromosome 11p15. Methylation errors account for 50%-60% of sporadic cases and almost 100% of cases born after ART. We report the birth of a child diagnosed with BWS arising from an ART cycle to an HIV serodiscordant couple with no history of infertility. This case cannot constitute conclusive evidence but it raises various questions. CONCLUSION(S): Assisted reproductive technology seems to be in the causal pathway but a male/female factor or an iatrogenic factor is also possible. PMID- 21550041 TI - Endometrial thickness predicts endometrial hyperplasia in patients with polycystic ovary syndrome. AB - Body mass index is predictive of sonographic endometrial stripe thickness, which in turn is predictive of endometrial hyperplasia in patients with polycystic ovary syndrome. For every 1-mm increase in endometrial stripe, the odds ratio of hyperplasia increased by 1.48 (95% confidence interval, 1.04-2.10). PMID- 21550042 TI - Comparison of "triggers" using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin. AB - This retrospective study of fresh autologous blastocyst transfers in high responders compared ongoing pregnancy rates in cycles that followed trigger with GnRH agonist (GnRHa) alone with standard luteal support, GnRHa alone with enhanced luteal support, or GnRHa with concomitant low-dose hCG (dual trigger). Ongoing pregnancy rates were significantly increased with the dual trigger or with enhanced luteal support, whereas the incidence of clinically significant ovarian hyperstimulation syndrome was 0.0% in the groups receiving only GnRHa and 0.5% (1 of 182) in patients receiving GnRHa with concomitant low-dose hCG. PMID- 21550043 TI - Fragmentation of embryos is associated with both necrosis and apoptosis. AB - OBJECTIVE: To explore the association between embryo fragmentation and necrosis and apoptosis. DESIGN: A prospective study. SETTING: Mizmedi Hospital. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Staining with annexin V (a marker of apoptosis) and propidium iodide (PI, a marker of necrosis), DNA integrity and mitochondrial distribution, and a beneficial effect of fragment removal in human fragmented embryos. RESULT(S): Most of the mouse and human fragmented embryos were stained with PI but not with annexin V. The comet assay revealed severe DNA fragmentation of the fragmented human embryos but not of the unfragmented embryos. Fewer mitochondria were observed in the fragmented compared with the normal blastomeres, indicating a rapid depletion of ATP in the fragmented embryos. Microsurgical fragment removal from the embryos had a beneficial effect on their subsequent development. CONCLUSION(S): Fragments of human embryos exhibited various characteristics of necrosis, such as staining with PI, DNA fragmentation, rapid depletion of ATP, and harmful effects on neighboring blastomeres. We suggest that the fragmentation of embryos is closely associated with both necrosis and apoptosis. Whether this fragmentation is associated with primary or secondary necrosis remains to be elucidated. PMID- 21550044 TI - Is anti-Mullerian hormone a marker of acute cyclophosphamide-induced ovarian follicular destruction in mice pretreated with cetrorelix? AB - OBJECTIVE: To define whether anti-Mullerian hormone (AMH) may be a marker of acute cyclophosphamide (CTX)-induced germ cell destruction in mice pretreated with the GnRH antagonist, cetrorelix. DESIGN: Controlled, experimental study. SETTING: Research laboratory in a federal research facility. ANIMAL(S): Balb/c female mice (6 weeks old). INTERVENTION(S): Mice were treated with GnRH antagonist (cetrorelix) or saline for 15 days followed by 75 mg/kg or 100 mg/kg of CTX or saline control on day 9. MAIN OUTCOME MEASURE(S): Number of primordial follicles (PMF), DNA damage, AMH protein expression, and AMH serum levels. RESULT(S): Ovaries in mice pretreated with cetrorelix had significantly more PMFs and reduced DNA damage compared with those exposed to CTX alone. Immunohistochemical staining for AMH expression and serum AMH levels did not differ significantly between treatment groups. CONCLUSION(S): Cetrorelix protected PMFs and reduced DNA damage in follicles of mice treated with CTX, but AMH levels in tissue and serum did not correlate with germ cell destruction. Further research is needed to determine the mechanism responsible for the protective effects on PMF counts observed with cetrorelix. PMID- 21550045 TI - Ramifications of adolescent menstrual cycles >=42 days in young adults. AB - OBJECTIVE: To determine to what degree annual reports from ages 14 to 19 years of menstrual cycles >=42 days would be associated with increased body mass index (BMI), waist circumference, glucose, insulin, and homeostasis model assessment insulin resistance (HOMA-IR) at ages 14-25 years. DESIGN: Prospective 11-year follow-up from ages 14 to 25 years. SETTING: Urban-suburban schools, post-high school. PATIENT(S): A total of 370 schoolgirls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): BMI, waist, insulin, glucose, HOMA-IR. RESULT(S): From ages 14 to 19 years, 269 girls had 0/6 annual reports of menstrual cycles >=42 days, 74 had 1, 19 had 2, and 8 had >=3. Among these four categories, girls with >=3 annual reports had highest free T and DHEAS at age 14, highest BMI and waist at ages 14, 19, and 25, highest insulin at age 25, and highest glucose and HOMA-IR at age 24 years. The number of annual reports of menstrual cycles >=42 days was positively related to change in BMI and waist and inversely with change in high density lipoprotein cholesterol from ages 14 to 25 years. CONCLUSION(S): Three or more annual reports of menstrual cycles >=42 days during ages 14-19 are associated with high BMI, waist circumference, insulin, glucose, and HOMA-IR at ages 14-25 years. PMID- 21550047 TI - Malreduction of syndesmosis--are we considering the anatomical variation? AB - Previous studies have demonstrated the need for accurate reduction of ankle syndesmosis. Measurement of syndesmosis is difficult on plain radiographs. A computed tomography (CT) scan allows better visualisation of the transverse relationship between the fibula and incisura fibularis. The difference ('G' a term we coined for ease of description) between the fibula and the anterior and posterior facets of the incisura fibularis was compared between normal and injured ankles following syndesmotic fixation in 19 patients. The mean diastasis (MD) was also calculated, representing the average measurement between the fibula and the anterior and posterior incisura. When compared with the normal side, eight out of 19 (42%) cases were found to have a residual diastasis even after fixation across the syndesmosis. However, if a standard value of G (2mm) was used for the injured leg only, all of the 19 cases would have abnormal values of 'G' following reduction. Our study has clearly demonstrated the need for individualising the assessment method to guide surgeons and radiologists prior to revision surgery. A standard value of 'G' of 2mm as the normal limit cannot be applied universally, as apparent from the data presented in this study. PMID- 21550046 TI - Clinical and biologic evaluation of ovarian function in women treated by bone marrow transplantation for various indications during childhood or adolescence. AB - OBJECTIVE: To evaluate which factors determine premature ovarian failure after bone marrow transplantation (BMT) during childhood and adolescence. DESIGN: Cross sectional study. SETTING: Academic teaching hospital. PATIENT(S): Thirty-five women with previous allogeneic (n = 19) or autologous (n = 16) BMT for benign (n = 12) or malignant disease (n = 23). Mean age at BMT was 9.8 +/- 5.2 years. Eighteen patients had received total body irradiation (TBI). Twenty-three (66%) were premenarchal at the time of BMT. INTERVENTION(S): Evaluation of ovarian function. MAIN OUTCOME MEASURE(S): Retrospective analysis of gynecologic history and hormone measurements (FSH, E(2), and antimullerian hormone [AMH]) in relation to initial pathology, treatment protocols, age, and menarchal status at the time of BMT and time elapsed since BMT. RESULT(S): Clinical evidence of persistent ovarian function after BMT was found in 46% of patients (16/35), but low AMH concentrations (<1.2 MUg/L) were observed in 85% of patients, including a large subset (2/3) of clinically eugonadal subjects. Age <=10 years at the time of BMT and absence of TBI were significantly and independently associated with higher rates of clinically proven persistent ovarian function at the time of evaluation. CONCLUSION(S): After BMT, ovarian function is impaired in the majority of women, even without clinical signs of premature ovarian failure. This impairment is mostly related to older age at the time of treatment and conditioning treatment with TBI. PMID- 21550048 TI - Implementation of the critical-care pain observation tool on pain assessment/management nursing practices in an intensive care unit with nonverbal critically ill adults: a before and after study. AB - BACKGROUND: The Critical-Care Pain Observation Tool (CPOT) is one of the few behavioural pain scales which have been developed and validated for the purpose of detecting pain in nonverbal critically ill adults. OBJECTIVES: This study aimed to complete a pre and post evaluation of the implementation of the CPOT on pain assessment/management nursing practices in the Intensive Care Unit (ICU) with nonverbal critically ill adults. DESIGN: A before-and-after study design was used. SETTING/PARTICIPANTS: The Intensive Care Unit (ICU) of a university affiliated health care centre in Monteregie (Canada) was selected for the implementation of the CPOT. All ICU nurses were trained to use the CPOT. Medical files were selected if the patient was 18 years or older, had been mechanically ventilated for a period >= 24hours, was unable to communicate, and had intact motor function. METHODS: This implementation study included three steps: 1) pre implementation phase, 2) implementation phase, and 3) post-implementation phase. The pre-implementation phase included the review of 30 medical files to describe the current nursing practice in pain assessment and management prior to the introduction of the CPOT. During the implementation phase, 60 ICU nurses attended standardized training sessions on the use of the CPOT and practiced the scoring with the CPOT using patients' videotapes. In the post-implementation phase, the interrater reliability of ICU nurses when using the CPOT was tested using three patients' videotapes. Also, pain assessment and management nursing practices were evaluated by reviewing 30 medical files at 3 months, and 30 others at 12 months post-implementation. RESULTS: Nurses' percentage of agreement when scoring patients with the CPOT by viewing the videotapes was high post-implementation of the tool (>87%). Reports of pain assessments were more frequently charted in the medical files in the post-implementation phase (10.5 to 12 assessments in a 24 hour period) compared with the pre-implementation phase (3 assessments in a 24 hour period). Interestingly, fewer analgesic and sedative agents were administered during the post-implementation phase. CONCLUSIONS: The CPOT was successfully implemented and seemed to have positive effects on pain assessment and management nursing practices in the ICU. Further research is warranted to look at its impact on patient outcomes. PMID- 21550049 TI - Morphology and interphase formation in epoxy/PMMA/glass fiber composites: effect of the molecular weight of the PMMA. AB - In this work ternary composites based on an epoxy thermoset modified with a thermoplastic polymer and reinforced with glass fibers were prepared. The aim of this study is to analyze the influence of the molecular weight of the thermoplastic polymer on the final morphologies. To obtain tailor made interphases four poly(methylmethacrylate), PMMA, which differ in their molecular weight (34,000, 65,000, 76,000 and 360,000 g/mol) were chosen to modify the epoxy resin. The amount of PMMA in the composites was fixed to 5 wt.%. Neat polymer matrices (epoxy-PMMA without fibers) were also prepared for comparison. To study all systems dynamic mechanical analysis (DMA), atomic force microscopy (AFM) and scanning electron microscopy (SEM) were used. Although all the systems showed the typical phase separation in the epoxy/PMMA blend, DMA experiments revealed a new phase with more restricted mobility when the glass fibers are present. The amount of this phase increases as molecular weight of PMMA does. The morphologies as well as the fracture surface in the immediate surroundings of the fibers were found to be different from those observed further away from the surface of the fiber, suggesting therefore that, in this case, different fracture mechanism operates. These observations allow us to conclude that an interphase with specific properties is formed. This interphase is based on a polymer or a polymer blend (epoxy-PMMA) enriched in the component with lower mobility. PMID- 21550050 TI - Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. AB - Brain-derived neurotrophic factor (BDNF) plays a central role in synaptic plasticity and neurogenesis. Bipolar disorder (BD) is among the most disabling of all psychiatric disorders and is associated with poor outcomes. Some studies suggest that BDNF levels decrease during mood states and remain normal during euthymia, but other studies have contradicted this paradigm. Therefore, the aim of this study was to perform a meta-analysis of all studies that measured peripheral BDNF levels in adults with BD. We conducted a systematic review using electronic databases. Inclusion criteria were studies that measured BDNF in plasma or serum in vivo in adult patients with BD. The resulting studies were compiled to measure the effect sizes (ESs) of the differences in BDNF levels between BD patients in different mood states and controls. Thirteen studies were included with a total of 1113 subjects. The BDNF levels were decreased in both mania and depression when compared to controls (ES -0.81, 95% CI -1.11 to -0.52, p < 0.0001 and ES -0.97, 95% CI -1.79 to -0.51, p = 0.02, respectively). The BDNF levels were not different in euthymia when compared to controls (ES -0.20, 95% CI -0.61 to 0.21, p = 0.33). Meta-regression analyses in euthymia showed that age (p < 0.0001) and length of illness (p = 0.04) influenced the variation in ES. There was also an increase in BDNF levels following the treatment for acute mania (ES 0.63, 95% CI -1.11 to -0.15, p = 0.01). In conclusion, BDNF levels are consistently reduced during manic and depressive episodes and recover after treatment for acute mania. In euthymia, BDNF decreases with age and length of illness. These data suggest that peripheral BDNF could be used as a biomarker of mood states and disease progression for BD. PMID- 21550051 TI - The attentional blink in schizophrenia: isolating the perception/attention interface. AB - Previous work has demonstrated that several aspects of visual processing are impaired in schizophrenia, including early perceptual processes and later higher order processes. However, it remains unclear whether the stage of processing where early perception and later higher-order processes interact is impaired in schizophrenia. The current research examined this interface in schizophrenia using the attentional blink (AB) paradigm. We administered two rapid serial visual processing (RSVP) tasks to 143 patients with schizophrenia or schizoaffective disorder and 80 healthy controls: 1) a single target detection task, to measure basic visual perception; and 2) a dual target detection task, to measure the AB effect. In the dual target task, the two target stimuli (T1 and T2) were presented at varying positions or "lags" within a rapid sequential stream of distractor stimuli. Participants verbally identified the target stimuli. Both groups showed the expected AB effect, with T2 accuracy being poorest 200-500 ms after presentation of T1. However, patients showed an exaggerated AB effect compared to the healthy controls, with significantly reduced detection of T2, even after correcting for performance on the single target task. The reduction in accuracy was steeper and more pronounced in the patients during the AB lags, and it extended to lags before and after the typical AB. This performance pattern on the AB task suggests that patients with schizophrenia exhibit both deficits in visual processing at the interface of perceptual and attentional processing and a general attentional deficit. PMID- 21550052 TI - Using HTK for prolonged pancreas preservation prior to human islet isolation. AB - BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) has been established as an alternative to University-of-Wisconsin solution (UWS) for abdominal organ preservation, but data about HTK efficiency to preserve pancreata during prolonged cold ischemia time (CIT) are conflicting. In human islet transplantation, HTK provided similar isolation outcomes after short CIT. The present study aimed to investigate whether islets can be successfully isolated from HTK-preserved pancreata after prolonged CIT compared with UWS. MATERIALS AND METHODS: Sixty-four human pancreata retrieved from donors meeting criteria for kidney donation were perfused utilizing either HTK or UWS and preserved for more or less than 10 h prior to islet isolation. Along with parameters related to isolation and islet quality assessment, the dry-to-wet weight ratio was evaluated. RESULTS: Donor- and procurement-related factors did not vary between HTK- and UWS-perfused pancreata. The dry-to-wet weight ratio was lower in HTK preserved pancreata indicated tissue edema (21.0% +/- 3.5% versus 24.8% +/- 2.0%, P = 0.007). Isolation-related variables differed between experimental groups after prolonged CIT with respect to purified packed tissue volume (9.1 +/- 5.0 versus 17.2 +/- 8.1 MUL/g, P = 0.004) and islet yield (1910 +/- 980 versus 3150 +/- 1420 IE/g, P = 0.012). Islet purity and survival after culture were similar after HTK or UWS perfusion. The preservation solution did not affect in vitro function and transplantability of isolated islets. CONCLUSIONS: Compared with UWS, HTK has similar efficiency to preserve human pancreata for subsequent islet isolation during <10 h CIT but seems to be limited for prolonged cold storage. PMID- 21550053 TI - Cross-transfusion of postshock mesenteric lymph provokes acute lung injury. AB - OBJECTIVE: Substantial investigation has implicated mesenteric lymph as the mechanistic link between gut ischemia/reperfusion (I/R) and distant organ injury. Specifically, lymph diversion prevents acute lung injury (ALI) in vitro, and bioactive lipids and proteins isolated from postshock mesenteric lymph (PSML) maintain bioactivity in vitro. However, Koch's postulates remain to be satisfied via direct cross-transfusion into a naive animal. We therefore hypothesized that real time cross-transfusion of postshock mesenteric lymph provokes acute lung injury. METHODS: One set of Sprague-Dawley rats (lymph donors) was anesthetized, with the mesenteric lymph ducts cannulated and exteriorized to drain freely into a siliconates plastic cup; concurrently, a second group of rats ( lymph recipients) was anesthetized, with a cannula inserted into the animal's right internal jugular vein. Blood was removed from the donor rats to induce hemorrhagic shock (MAP of 35 mmHg * 45 min). The recipient rats were positioned 10 cm below the plastic cup, which emptied into the jugular vein cannula. Thus, mesenteric lymph from the shocked donor rat was delivered to the recipient rat at the rate generated during shock and the subsequent 3 h of resuscitation. RESULTS: Neutrophil (PMN) accumulation in the lungs was substantially elevated in the postshock lymph cross-transfusion group compared to both sham lymph cross transfusion and instrumented control (MPO: 9.42 +/- 1.55 versus 2.81 +/- 0.82 U/mg lung tissue in postshock versus sham lymph cross-transfusion, n = 6 in each group, P = 0.02). Additionally, cross-transfusion of PSML induced oxidative stress in the lung (0.21 +/- 0.03 versus 0.10 +/- 0.01 micromoles MDA per mg lung tissue in lymph cross-transfusion versus instrumented control, n = 6 in each group, P = 0.046). Furthermore, transfusion of PSML provoked lung injury (BAL protein 0.77 +/- 0.18 versus 0.15 +/- 0.02 mg/mL protein in BALF, postshock versus sham lymph cross-transfusion, n = 6 in each group, P = 0.004). CONCLUSION: Cross-transfusion of PSML into a naive animal leads to PMN accumulation and provokes ALI. These data provide evidence that postshock agents released into mesenteric lymph are capable of provoking distant organ injury. PMID- 21550054 TI - Pitx2 is a critical early regulatory gene in normal cecal development. AB - BACKGROUND: The murine cecum is a critical digestive structure. Morphogenesis of the cecum involves several key genes, including Homeobox (Hox) d12. Ectopic expression of Hoxd12 has been shown to result in cecal agenesis and a down regulation of both Fibroblast growth factor 10 (Fgf10) and the Pituitary homeobox 2 gene (Pitx2). Homozygous null mutation of Fgf10 or its cognate receptor Fgfr2IIIb results in severe cecal defects where there is the initiation of mesodermal budding, but a failure of the endoderm to grow and extend into this structure. We examined the expression of Pitx2 in the cecum and hypothesized that homozygous null mutation of Pitx2 would result in cecal agenesis. METHODS: IACUC approval was obtained for these studies. Whole mount in situ hybridizations for Pitx2 were performed on wild-type embryos between embryonic d (E)11.0 and E12.5. Pitx2 -/- and Fgfr2IIIb -/- embryos were generated from n/+ heterozygote breedings and harvested at E10.5, E11.5, and E13.5. Genotypes were confirmed by PCR. Morphology of Pitx2 -/- cecae were compared with those of wild-type littermates and Fgfr2IIIb -/- embryos at identical stages. Embryos were fixed overnight and photographed the following day. RESULTS: Pitx2 is expressed in the cecal mesoderm and endoderm as early as E11.0. Expression becomes increasingly more robust by E12.5. Homozygous null mutation of Pitx2 results in agenesis of the cecum. In contrast to Fgfr2IIIb -/- embryos, which demonstrate a persistent mesodermal bud as late as E18.5, no mesodermal bud is present in Pitx2 -/- embryos. CONCLUSIONS: Our findings demonstrate that Pitx2 is a critical regulatory gene in cecal morphogenesis and suggest that Pitx2 is required for initiation of mesodermal budding and likely resides upstream of Fgf10-Fgfr2IIIb signaling in the normal development of this structure. PMID- 21550055 TI - Use of a third-generation perfluorocarbon for preservation of rat DCD liver grafts. PMID- 21550056 TI - The impact of postoperative abscess formation in perforated appendicitis. AB - BACKGROUND: Abscess after appendectomy for perforated appendicitis is the most common complication. We have completed three prospective trials and are conducting a fourth in which the included patients had either a hole in the appendix or a fecalith in the abdomen identified at the time of operation. The abscess rate in each of these trials was 20%. Multiple publications have focused on prevention and management of this postoperative complication but the total impact of an abscess on the hospital course has not been well documented. Therefore, we reviewed our experience with patients who developed a postoperative abscess to evaluate the total care received compared with those who recovered uneventfully. METHODS: Data from patients with abscess who have been enrolled in our prospective trials from April 2005 to December 2009 were utilized. Patients who recovered without complications in the most recent trial served as a comparison group, as this protocol offers the minimal length of stay without a predetermined length of stay. Data comparison included patient demographics, admission lab values, hospital length of stay, and hospital charges. RESULTS: There were 63 patients with a postoperative abscess and 61 patients without an abscess identified. Patients with an abscess were older (11.0 versus 9.7 y, P = 0.04) and had a higher mean body mass index (22.4 versus 19.5, P = 0.03). Total hospital length of stay was significantly longer in the abscess group (11.6 d versus 5.1 d, P <= 0.001). Total hospital charges doubled for patients who developed an abscess ($82,000 versus $40,000 P < 0.001). CONCLUSION: A postoperative abscess after appendectomy for perforated appendicitis translates into an average of an extra week in hospital care with double the total hospital cost. PMID- 21550057 TI - The usefulness of the upper gastrointestinal series in the pediatric patient before anti-reflux procedure or gastrostomy tube placement. AB - OBJECTIVE: Most children undergo an upper gastrointestinal study (UGI) before an anti-reflux (AR) procedure or gastrostomy tube placement (GT). Anatomic abnormalities detected by UGI are uncommon and we hypothesize that the value of routine preoperative use of this test is limited. METHODS: Five hundred and seventy-two patients who underwent either an AR or GT over a 10-y period at our institution were reviewed. Data including patient demographics, indications for surgery, preoperative testing, and type of operation were collected. RESULTS: Of the 572 cases, an UGI was performed in approximately 71%. The results were interpreted as normal in 63%, and abnormal in 37%. The most common abnormality noted was gastroesophageal reflux in approximately 80%, followed by an anatomic abnormality in 6%, most of which were expected. Of 36 anatomic abnormalities noted, only four were unexpected in the total cohort. In addition to an UGI, half of the subjects received additional evaluations that included pH probes and gastric emptying studies (GES). In these studies, 56% of pH probes and 45% of GES had findings in which reflux was noted. Compared with UGIs, these tests were significantly more likely to identify reflux in patients. CONCLUSION: These results suggest that the utility of an UGI before AR or GT procedures is low. Anatomic abnormalities were rare and changed clinical management in a total of four cases. A prospective trial would help to further validate these findings and help identify patients who would benefit from an UGI. PMID- 21550058 TI - Subnormothermic machine perfusion at both 20 degrees C and 30 degrees C recovers ischemic rat livers for successful transplantation. AB - BACKGROUND: Utilizing livers from donors after cardiac death could significantly expand the donor pool. We have previously shown that normothermic (37 degrees C) extracorporeal liver perfusion significantly improves transplantation outcomes of ischemic rat livers. Here we investigate whether recovery of ischemic livers is possible using sub-normothermic machine perfusion at 20 degrees C and 30 degrees C. METHODS: Livers from male Lewis rats were divided into five groups after 1 h of warm ischemia (WI): (1) WI only, (2) 5 h of static cold storage (SCS), or 5 h of MP at (3) 20 degrees C, (4) 30 degrees C, and (5) 37 degrees C. Long-term graft performance was evaluated for 28 d post-transplantation. Acute graft performance was evaluated during a 2 h normothermic sanguineous reperfusion ex vivo. Fresh livers with 5 h of SCS were positive transplant controls while fresh livers were positive reperfusion controls. RESULTS: Following machine perfusion (MP) (Groups 3, 4, and 5), ischemically damaged livers could be orthotopically transplanted into syngeneic recipients with 100% survival (N >= 4) after 4 wk. On the other hand, animals from WI only, or WI + SCS groups all died within 24 h of transplantation. Fresh livers preserved using SCS had the highest alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the lowest bile production during reperfusion, while at 28 d post-transplantation, livers preserved at 20 degrees C and 30 degrees C had the highest total bilirubin values. CONCLUSIONS: MP at both 20 degrees C and 30 degrees C eliminated temperature control in perfusion systems and recovered ischemically damaged rat livers. Postoperatively, low transaminases suggest a beneficial effect of sub normothermic perfusion, while rising total bilirubin levels suggest inadequate prevention of ischemia- or hypothermia-induced biliary damage. PMID- 21550059 TI - Reduced proliferation of aged human vascular smooth muscle cells--role of oxygen derived free radicals and BubR1 expression. AB - BACKGROUND: Aging is a risk factor for atherosclerosis. Recent studies suggest cell cycle events as well as reactive oxygen species (ROS) contribute to vascular cell dysfunction associated with aging. Mice expressing low levels of the spindle assembly checkpoint protein BubR1 develop aging-associated vascular changes at a young age, including decreased smooth muscle cells and increased reactive oxygen species (ROS) production. This study was designed to determine the effect of aging and production of oxygen-derived free radicals on expression of BubR1. MATERIALS AND METHODS: To assess cell proliferation capacity, human aortic smooth muscle cells (hAoSMC) derived from a young group (17-30 y) or an aged group (57 62 y) were cultured, and cell numbers were directly counted in using a Neubauer chamber. RT-PCR assay was used to evaluate BubR1 expression in cultured hAoSMC stimulated with Angiotensin II or H(2)O(2). RESULTS: No significant difference in BubR1 expression or hAoSMC proliferative ability was demonstrated at passage 5, but both were significantly decreased at passage 8 in the aged hAoSMC. Angiotensin II and H(2)O(2) up-regulated BubR1 expression in young hAoSMC, and the up-regulation was abrogated by a p38 MAPK inhibitor or an inhibitor of the NADH/NADPH oxidase. siRNA against BubR1 reduced proliferative activity and increased ROS production in hAoSMC. CONCLUSIONS: These findings demonstrate BubR1 mRNA expression decreases along with proliferation in aged hAoSMC. Aging-related loss of BubR1 and subsequent impairment of reactivity to ROS may explain reduced proliferative capacity of aged smooth muscle cells. PMID- 21550060 TI - Timing is everything: delayed intubation is associated with increased mortality in initially stable trauma patients. AB - BACKGROUND: The indications for immediate intubation in trauma are not controversial, but some patients who initially appear stable later deteriorate and require intubation. We postulated that initially stable, moderately injured trauma patients who experienced delayed intubation have higher mortality than those intubated earlier. METHODS: Medical records of trauma patients intubated within 3 h of arrival in the emergency department at our university-based trauma center were reviewed. Moderately injured patients were defined as an ISS < 20. Early intubation was defined as patients intubated from 10-24 min of arrival. Delayed intubation was defined as patients intubated >=25 min after arrival. Patients requiring immediate intubation, within 10 min of arrival, were excluded. RESULTS: From February 2006 to December 2007, 279 trauma patients were intubated in the emergency department. In moderately injured patients, mortality was higher with delayed intubation than with early intubation, 11.8% versus 1.8% (P = 0.045). Patients with delayed intubations had greater frequency of rib fractures than their early intubation counterparts, 23.5% versus 3.6% (P = 0.004). Patients in the delayed intubation group had lower rates of cervical gunshot wounds than the early intubation group, 0% versus 10.7% (P = 0.048) and a trend toward fewer of skull fractures 2.9% versus 16.1%, (P = 0.054). CONCLUSIONS: These findings suggest that delayed intubation is associated with increased mortality in moderately injured patients who are initially stable but later require intubation and can be predicted by the presence of rib fractures. PMID- 21550061 TI - The acute coagulopathy of trauma is due to impaired initial thrombin generation but not clot formation or clot strength. AB - BACKGROUND: Acute coagulopathy of trauma (ACOT) has been described as a very early hypocoagulable state, but the mechanism remains controversial. One proposed mechanism is tissue hypoperfusion leading to protein C activation, with subsequent inhibition of Factors V and VIII. Variability in trauma has impeded the use of clinical data towards the elucidation of the mechanisms of ACOT, but thrombelastography (TEG) may provide insight by assessing hemostatic function from initial thrombin activation to fibrinolysis. We hypothesized that in a controlled animal model of trauma/hemorrhagic shock, clotting factor dysfunction is the predominant mechanism in early ACOT. METHODS: Rats anesthetized by inhaled isoflurane (n = 6) underwent laparotomy, and hemorrhage was induced to maintain a MAP of 35 mm Hg for 30 min. Rats were then resuscitated with twice their shed blood volume in normal saline. TEG was performed at baseline, shock, and post resuscitation periods. No heparin was given. Statistical analysis was performed by ANOVA with post-hoc Fisher's test. RESULTS: Coagulation factor function was significantly impaired in the early stages of trauma/hemorrhagic shock. TEG R and SP-values were significantly increased from baseline to shock (P < 0.001) and from shock to post-resuscitation periods (P < 0.05). Delta (R-SP), a measure of thrombin generation, showed a significant increase (P < 0.05) from baseline to shock. No significant changes were found in K, Angle, MA, and LY30 values. CONCLUSION: Clotting factor derangement leading to impaired thrombin generation is the principle etiology of ACOT in this model and not the dynamics of clot formation, fibrin cross-linking, clot strength/platelet function, or fibrinolysis. PMID- 21550062 TI - Considering the patient's perspective in the injury severity score. AB - BACKGROUND: The injury severity score (ISS) assesses anatomical threat to life, but does not correlate with severity perceived by the patient. The purpose of this study was to assess how and why patients assign perceived injury severity. METHODS: One hundred twenty consecutive patients were asked "Would you say your injury is mild, moderate, severe or very severe?" and "Why do you rate your injury that way?" Explanations were categorized and compared by age, perceived injury severity, and injury mechanism. Categories were pain, injury assessment, injury description, and others. The age groups used were <55 and >= 55 y old. The data were analyzed with Wilcoxon rank sum, Spearman's correlation coefficient, and Mantel-Haenszel tests. RESULTS: The ISS was not significantly correlated with perceived injury severity scores (r(2) = 0.177, P = 0.0535, Spearman's correlation), and most patients reported a higher injury severity. Patients with penetrating injuries significantly overestimated their injury severity (P = 0.014, Wilcoxon rank sum). Patients with mild and moderate injuries gave more assessment explanations, whereas patients with severe or very severe injuries gave more description explanations (P = 0.0220, Mantel-Haenszel). CONCLUSIONS: Patients based perceived severity on their injuries, but it did not correlate with ISS, likely because ISS considers injuries graded events, while the patient considers them all or none events. Assessment responses suggested relief, whereas description responses indicated more distress. It is important to ask patients about their injury severity to help them better cope with their experience, which will likely improve quality of life outcomes. PMID- 21550063 TI - Total thyroidectomy: is morbidity higher for Graves' disease than nontoxic goiter? AB - BACKGROUND: Total thyroidectomy for treatment of Graves' disease is controversial and much of the debate centers on the concern for complications. The purpose of this study was to evaluate the morbidity of total thyroidectomy for Graves' disease and determine if it is different than for patients with nontoxic nodular goiter. METHODS: The rates of life threatening neck hematoma, recurrent laryngeal nerve (RLN) injury, transient hypocalcemia, and hypoparathyroidism were determined for consecutive patients with Graves' disease treated with total thyroidectomy from 1996 to 2010. Results were compared with patients who underwent total thyroidectomy for nontoxic nodular goiter during the same period, matched for the weight of the excised thyroid gland. RESULTS: Total thyroidectomy was performed in 111 patients with Graves' disease (group I) and 283 patients with nontoxic nodular goiter (group II). Parathyroid autotransplantation was performed in 31(28%) patients in group I and 98 (35%) patients in group II (P = NS). Comparative analysis of morbidity revealed no significant difference in neck hematoma, 0(0%) (I) versus 3(1%) (II); permanent RLN injury, 0(0%) (I) versus 2(1%) (II); and permanent hypoparathyroidism in 1(1%) (I) versus 1 (0.4%) (II) (P = NS). Transient hypocalcemia was more common in patients with Graves' disease, 80(72%) (I) versus 170 (60%) (II) (P < 0.05), but not when matched for thyroid weight. CONCLUSIONS: Total thyroidectomy can be performed with low morbidity in patients with Graves' disease; only transient hypocalcemia occurred more often than in patients with nodular goiter. Total thyroidectomy should be presented as a therapeutic option for all patients with Graves' disease. PMID- 21550064 TI - Utility of breast MRI for evaluation of residual disease following excisional biopsy. AB - BACKGROUND: Because benign postoperative changes may overlap those of malignancy, the utility of breast MRI following an excisional biopsy is unclear. We sought to investigate the ability of MRI to predict residual disease following an excisional biopsy for breast cancer. MATERIALS AND METHODS: We reviewed 93 patients who underwent surgical treatment for stage 0-III breast cancer at our institution from January 2005 to May 2008. All patients had previously undergone excisional biopsy with subsequent MRI. Patient, tumor, and treatment characteristics were collected. Descriptive statistics were utilized for data summary and data were compared using Fisher's exact or chi(2) tests. RESULTS: The mean age of the 84 patients who had additional surgery following MRI was 51 +/- 7 y. Thirteen (15%) patients had only postoperative changes on MRI; six had residual disease on final pathology. Of 71 patients with MRI findings suspicious for residual disease, 54 (76%) had pathologic confirmation, while 17 (24%) had only benign pathology. The sensitivity and specificity of MRI following excisional biopsy were 90% and 29%, respectively. Overall, 49 (58%) of the 84 patients underwent mastectomy, including 11 of 24 (46%) with negative final pathology. Patient age, tumor size, tumor grade, biomarker profile, nodal status, and MRI findings were not predictive of surgical treatment type (P > 0.05). CONCLUSION: Although excisional biopsy decreases the specificity of breast MRI, its sensitivity remains high. Nearly 50% of patients with a suspicious MRI and negative final pathology underwent mastectomy, suggesting that additional biopsy of all suspicious MRI findings is necessary to avoid surgical overtreatment. PMID- 21550065 TI - Sonographic optic nerve sheath diameter as an estimate of intracranial pressure in adult trauma. AB - BACKGROUND: Intracranial pressure (ICP) is currently measured with invasive monitoring. Sonographic optic nerve sheath diameter (ONSD) may provide a noninvasive estimate of ICP. Our hypothesis was that bedside ONSD accurately estimates ICP in acutely injured patients. The specific aims were (1) to determine the accuracy of ONSD in estimating elevated ICP, (2) to correlate ONSD and ICP in unilateral and bilateral head injuries, and (3) to determine the effect of ICP monitor placement on ONSD measurements. MATERIALS AND METHODS: A blinded prospective study of adult trauma patients requiring ICP monitoring was performed at a University-based urban trauma center. The ONSD was measured by ultrasound pre- and post-placement of an ICP monitor (Camino Bolt or Ventriculostomy). RESULTS: One-hundred fourteen measurements were obtained in 10 trauma patients requiring ICP monitoring. Pre- and post-ONSD were compared with side of injury in the presence of an ICP monitor. ROC analysis demonstrated ONSD poorly estimates elevated ICP (AUC = 0.36). Overall sensitivity, specificity, PPV, NPV, and accuracy for estimating ICP with ONSD were 36%, 38%, 40%, 16%, and 37%. Poor correlation of ONSD to ICP was observed with unilateral (R(2) = 0.45, P < 0.01) and bilateral (R(2) = 0.21, P = 0.01) injuries. ICP monitor placement did not affect ONSD measurements on the right (P = 0.5), left (P = 0.4), or right and left sides combined (P = 0.3). CONCLUSIONS: Sonographic ONSD as a surrogate for elevated ICP in lieu of invasive monitoring is not reliable due to poor accuracy and correlation. PMID- 21550066 TI - Significance of alanine aminopeptidase N (APN) in bile in the diagnosis of acute cellular rejection after liver transplantation. AB - BACKGROUND: Allograft dysfunction after liver transplantation requires histopathologic examination for confirmation of the diagnosis, however, the procedure is invasive and its interpretation is not always accurate. The aim of this study was to find novel protein markers in bile for the diagnosis of acute cellular rejection (ACR) after liver transplantation. MATERIALS AND METHODS: Quantitative proteomic analysis using the (18)O labeling method was used to search for bile proteins of interest. Nine recipients were selected who had liver dysfunction, diagnosed by liver biopsy, either with ACR (ACR group, n = 5) or without (LD group, n = 4). Donor bile samples were obtained from nine independent live liver donors. Enzyme activity in bile samples was assayed and liver biopsy specimens were immunostained for candidate protein of ACR. RESULTS: The analysis identified 78 proteins, among which alanine aminopeptidase N (APN/CD13) was considered a candidate marker of ACR. Comparative analysis of the ACR and LD groups showed high APN enzyme activity in three (60%) of five cases of the ACR group, while it was as low as donor level in all patients of the LD group. APN enzyme activity in bile samples of liver dysfunction liver transplantation (LDLT) recipients of the ACR group collected within 3 d before biopsy-confirmed ACR (n = 10) was significantly higher (584 +/- 434 U/g protein) than in those of recipients free of ACR (n = 96, 301 +/- 271 U/g protein) (P = 0.004). APN overexpression along bile canaliculi was observed during ACR in all five cases of the ACR group. CONCLUSION: APN in bile seems to be a useful and noninvasive biomarker of ACR after liver transplantation. PMID- 21550067 TI - Feasibility of endoscopic transoral thoracic surgical lung biopsy and pericardial window creation. AB - BACKGROUND: The thoracic cavity approach for natural orifice transluminal endoscopic surgery (NOTES) is technically challenging. The aim of this study was to evaluate the feasibility of a transoral endoscopic technique for a surgical lung biopsy and pericardial window creation METHODS: Under general anesthesia, a 12 mm incision was made over the vestibulum oris region. Under video guidance, a homemade metallic tube was introduced through the incision, extending along the pre-tracheal space to the substernal space with blunt dissection technique, and used as the entrance into the thoracic cavity. A surgical lung biopsy and a pericardial window creation were performed in 12 canines, using the transoral NOTES technique. RESULTS: The transoral endoscopic surgical lung biopsy and pericardial window creation were successfully completed in 11 of the 12 canines. Intraoperative bleeding and death from an injury to the pulmonary hilum developed in one animal during the electrosurgical excision of lung tissue. CONCLUSIONS: Transoral surgical lung biopsy and pericardial window creation in canine models is technically feasible and can be used as a novel experimental platform for studies of NOTES for intra-thoracic surgery. PMID- 21550068 TI - Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211 lumbar punctures. AB - BACKGROUND: Neuromyelitis optica (NMO, Devic disease) is a severely disabling autoimmune disorder of the CNS, which was considered a subtype of multiple sclerosis (MS) for many decades. Recently, however, highly specific serum autoantibodies (termed NMO-IgG or AQP4-Ab) have been discovered in a subset (60 80%) of patients with NMO. These antibodies were subsequently shown to be directly involved in the pathogenesis of the condition. AQP4-Ab positive NMO is now considered an immunopathogenetically distinct disease in its own right. However, to date little is known about the cerebrospinal fluid (CSF) in AQP4-Ab positive NMO. OBJECTIVE: To describe systematically the CSF profile of AQP4-Ab positive patients with NMO or its formes frustes, longitudinally extensive myelitis and optic neuritis. MATERIAL AND METHODS: Cytological and protein biochemical results from 211 lumbar punctures in 89 AQP4-Ab positive patients of mostly Caucasian origin with neuromyelitis optica spectrum disorders (NMOSD) were analysed retrospectively. RESULTS: CSF-restricted oligoclonal IgG bands, a hallmark of MS, were absent in most patients. If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, transient, and, importantly, restricted to acute relapses. CSF pleocytosis was present in around 50% of samples, was mainly mild (median, 19 cells/MUl; range 6-380), and frequently included neutrophils, eosinophils, activated lymphocytes, and/or plasma cells. Albumin CSF/serum ratios, total protein and CSF L-lactate levels correlated significantly with disease activity as well as with the length of the spinal cord lesions in patients with acute myelitis. CSF findings differed significantly between patients with acute myelitis and patients with acute optic neuritis at the time of LP. Pleocytosis and blood CSF barrier dysfunction were also present during remission in some patients, possibly indicating sustained subclinical disease activity. CONCLUSION: AQP4-Ab positive NMOSD is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and NMOSD and add to our understanding of the immunopathogenesis of this devastating condition. PMID- 21550069 TI - Seasonal and pollution-induced variations in biomarkers of transplanted mussels within the Beagle Channel. AB - The occurrence of biomarker variations linked to environmental factors makes it difficult to distinguish the effect of pollution. In an attempt to evaluate spatial and seasonal effects of environmental parameters on biomarker responses, mussels Mytilus edulis chilensis coming from an aquaculture farm were transplanted to several points within Ushuaia Bay (Beagle Channel) for 6 weeks in summer and winter. Activities of superoxide dismutase, catalase, glutathione-S transferase and levels of lipid peroxidation were measured in gills and digestive gland. Cu, Zn, Fe, Cd and Pb concentrations were also assessed. Results indicated a significant effect of seasons on biological responses as well as in metal bioaccumulation showing the influence of natural factors such as dissolved oxygen, temperature and food availability. The interdependence of those environmental factors is important for the homeostasis of thermoconformers, especially regarding their oxidative metabolism and should also be taken into consideration to distinguish natural from pollution-induced variations. PMID- 21550070 TI - Effects of macroalgal blooms on carbon and nitrogen biogeochemical cycling in photoautotrophic sediments: an experimental mesocosm. AB - The effects of floating macroalgae (250 g DW m(-2)) on photoautotrophic microbenthos were studied in a flow-through mesocosm with a parallel mesocosm without macroalgae serving as Control. Vertical microprofiles of O(2) at the sediment-water interface showed a immediate and complete suppression of photosynthetic activity of microphytobenthos (MPB) under the macroalgal canopy, resulting in a shift of benthic metabolism from autotrophic to heterotrophic. MPB abundance and chlorophyll a content decreased and a change from a diatom dominated to cyanobacteria-dominated community was observed. Inorganic nitrogen nutrients' concentrations increased in the porewater as a result of the inhibition of MPB nutrient demand, leading to an increase in net ammonification and anaerobic NO(x)(-) consumption rates. No organic matter transfer from macroalgae to the sediment was detected, resulting in a net consumption of the carbon and nitrogen stored in the sediment. In consequence, sediment was progressively impoverished in nitrogen, reducing sediment nutrient regeneration. PMID- 21550071 TI - The relationship between the concentrations and distribution of organic pollutants and black carbon content in benthic sediments in the Gulf of Gdansk, Baltic Sea. AB - The influence of the sediment's physico-chemical properties and black carbon content, on the distribution of polycyclic aromatic hydrocarbons and polychlorinated biphenyls in benthic sediments of the Gulf of Gdansk (Baltic Sea) was determined. Sediments from port, marine dump site of dredged spoils, the Vistula river mouth, Gdansk Deep were selected. The concentrations of ?PAHs (fluoranthene, pyrene, benzo(a)anthracene, benzo(k)fluoranthene, benzo(a)pyrene, dibenzo(ah)anthracene, benzo(ghi)perylene) were 294-2200 ng/g d.w. and for ?PCBs (28, 52, 101, 118, 138, 153, 180) were 2.4-11.3 ng/g d.w. The sediments content of loss on ignition was 1.13-16.15%, total organic carbon was 0.89-7.15%, black carbon was 0.20-1.15%. The highest correlation coefficient values (r=0.76-0.92, p<0.05) for a relationship between the concentrations of organic pollutants, and organic matter, organic and black carbon contents were obtained in harbor sediments with low content of organic matter (<5%) and high share of black carbon in total carbon (up to 40%). PMID- 21550072 TI - Pathogenic fungi: an unacknowledged risk at coastal resorts? New insights on microbiological sand quality in Portugal. AB - Whilst the potential impact on beach users from microorganisms in water has received considerable attention, there has been relatively little investigation into microbial contaminants in sand. Thirty three beaches across Portugal were analyzed during a five year period (2006-2010) to determine the presence of yeasts, pathogenic fungi, dermatophytes, total coliforms, Escherichia coli and intestinal enterococci in sand. Our results showed that 60.4% of the samples were positive for fungi and that 25.2% were positive for the bacterial parameters. The most frequent fungal species found were Candida sp. and Aspergillus sp., whereas intestinal enterococci were the most frequently isolated bacteria. Positive associations were detected among analyzed parameters and country-regions but none among those parameters and sampling period. Regarding threshold values, we propose 15 cfu/g for yeasts, 17 cfu/g for potential pathogenic fungi, 8 cfu/g for dermatophytes. Twenty-five cfu/g for E. coli, and 10 [corrected] cfu/g for intestinal enterococci. PMID- 21550073 TI - Phytoplankton pigments and epifluorescence microscopy as tools for ecological status assessment in coastal and estuarine waters, within the Water Framework Directive. AB - Inverted microscopy is widespread employed for the analysis of phytoplankton composition within water quality monitoring networks. However, the analysis at the lowest taxonomical level is not always required for ecological status assessment. In addition, inverted microscopy can underestimate the small phytoplankton, and not always distinguish photoautotrophic from heterotrophic cells. In this study, as alternative tools, epifluorescence microscopy and High Performance Liquid Chromatography (HPLC) were employed to characterize phytoplankton communities within waters of different trophic condition. Epifluorescence microscopy confirmed its effectiveness to count the small phytoplankton. Furthermore, significant correlations between nutrients of anthropogenic origin and nanoplankton abundances were found. However, this technique resulted very time-consuming. HPLC together with the CHEMTAX program was more appropriate than inverted microscopy, in terms of cost-effectiveness. Also, the main variability patterns observed in the phytoplankton community structure by HPLC coincided with previous findings in the study area. Nevertheless, a rapid screening at the inverted microscope is recommended. PMID- 21550074 TI - Ritonavir inhibits the two main prasugrel bioactivation pathways in vitro: a potential drug-drug interaction in HIV patients. AB - Prasugrel is an antiplatelet prodrug used in patients with acute coronary syndrome. Prasugrel is mainly bioactivated by cytochromes P450 3A4/5 and CYP2B6. HIV patients are at risk of cardiovascular disease, and the protease inhibitor ritonavir is a potent inhibitor of these 2 CYPs. The aim of this in vitro study was to determine the impact of ritonavir in prasugrel metabolism. Human liver microsomes (HLMs) and recombinant microsomes were used to identify the enzymes responsible for the bioactivation of prasugrel. Prasugrel concentrations of 5 to 200 MUM were used for Km determination. Inhibition by ritonavir was characterized using HLMs at concentrations of 0.1 to 30 MUM. Prasugrel active metabolite determination was performed with a validated liquid chromatography-mass spectrometry method. Using recombinant microsomes, prasugrel biotransformation was mainly performed by CYP2B6, CYP2D6, CYP2C19, CYP3A4, and CYP3A5. With specific inhibitors of CYP3A, CYP2B6, CYP2D6, CYP2C9, and CYP2C19, active metabolite production was decreased by 38% +/- 15% with 4-(4 chlorobenzyl)pyridine (CYP2B6 inhibitor) and by 45 +/- 16% with ketoconazole (CYP3A inhibitor). The Km value for prasugrel metabolism in HLMs was determined to be 92.5 MUM. Ritonavir at 0.1 to 30 MUM was shown to be a potent dose dependent inhibitor of prasugrel. In this in-vitro study, we found a potent inhibition of prasugrel bioactivation by ritonavir compared to the specific inhibitors of CYP3A and CYP2B6 due to the simultaneous inhibition of CYP2B6 and CYP3A by ritonavir. This finding suggests a potential significant drug-drug interaction between these two drugs. PMID- 21550075 TI - Cinnamon increases liver glycogen in an animal model of insulin resistance. AB - The objective of this study was to determine the effects of cinnamon on glycogen synthesis, related gene expression, and protein levels in the muscle and liver using an animal model of insulin resistance, the high-fat/high-fructose (HF/HFr) diet-fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with (1) HF/HFr diet to induce insulin resistance, (2) HF/HFr diet containing 20 g cinnamon per kilogram of diet, (3) control diet, and (4) control diet containing 20 g cinnamon per kilogram of diet. In the liver, cinnamon added to the HF/HFr diet led to highly significant increases of liver glycogen. There were no significant changes in animals consuming the control diet plus cinnamon. In the liver, cinnamon also counteracted the decreases of the gene expressions due to the consumption of the HF/HFr diet for the insulin receptor, insulin receptor substrates 1 and 2, glucose transporters 1 and 2, and glycogen synthase 1. In muscle, the decreased expressions of these genes by the HF/HFr diet and glucose transporter 4 were also reversed by cinnamon. In addition, the overexpression of glycogen synthase 3beta messenger RNA levels and protein observed in the muscle of HF/HFr fed rats was decreased in animals consuming cinnamon. These data demonstrate that, in insulin-resistant rats, cinnamon improves insulin sensitivity and enhances liver glycogen via regulating insulin signaling and glycogen synthesis. Changes due to cinnamon in control animals with normal insulin sensitivity were not significant. PMID- 21550076 TI - Treatment with the alpha-glucosidase inhibitor miglitol from the preonset stage in Otsuka Long-Evans Tokushima Fatty rats improves glycemic control and reduces the expression of inflammatory cytokine genes in peripheral leukocytes. AB - Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes mellitus, exhibit chronic and slowly progressive hyperglycemia with obesity. In this study, we examined whether dietary supplementation with the alpha-glucosidase inhibitor miglitol from the preonset stage improves glycemic control and reduces the gene expression of inflammatory cytokines in peripheral leukocytes. The OLETF rats were fed a control diet or a diet containing 800 ppm miglitol (miglitol diet) for 40 weeks from 5 weeks of age (preonset stage). We determined nonfasting blood glucose, blood 1,5-anhydroglucitol, and messenger RNA levels of inflammatory cytokines in peripheral leukocytes in these rats. Nonfasting blood glucose concentrations gradually increased in OLETF rats fed the control diet, with significant increases at weeks 28 and 40 compared with week 0. In contrast, nonfasting blood glucose levels did not increase in miglitol-treated rats during the experimental period. Miglitol-treated rats had lower nonfasting blood glucose levels and higher 1,5-anhydroglucitol levels, a marker for glucose fluctuations, at week 40 than control rats. The gene expression of inflammatory cytokines including interleukin-6, tumor necrosis factor-alpha, and interferon gamma in peripheral leukocytes gradually increased during the development of diabetes in control rats, but not in miglitol-treated rats. Our results suggest that dietary supplementation with miglitol from the preonset stage in OLETF rats improves glycemic control and reduces gene expression of cytokines related to inflammation in peripheral leukocytes. PMID- 21550077 TI - Metabolic imbalance of the insulin-like growth factor-I axis in Zucker diabetic fatty rats. AB - In healthy conditions, insulin-like growth factor-I (IGF-I) acts in a coordinated fashion with insulin to lower glycemia, mainly by increasing insulin sensitivity in peripheral tissues. The aim of this study was to explore the relationship between glucose homeostasis and the endocrine IGF-I axis in Zucker diabetic fatty (ZDF) rats. The plasma levels of glucose, insulin, growth hormone, free IGF-I, total IGF-I (associated to insulin-like growth factor binding proteins plus free), and corticosterone were measured in 13-week-old ZDF rats and in age matched controls under fasting and postprandial conditions. The plasma IGF-I binding capacity was measured by radioligand binding. In ZDF rats, fasting total and free IGF-I levels were reduced by 22% and 92%, respectively, compared with controls. Postprandial free IGF-I was reduced by 35%, whereas total IGF-I was unaffected. The plasma IGF-I binding capacity in ZDF rats was reduced by 24% after fasting and by 13% under postprandial conditions. A clear correlation between free IGF-I and insulin was observed in postprandial controls but not in ZDF rats. A principal component analysis clearly separated ZDF and control rats into 2 main components under both fasting and postprandial conditions. The first component was determined equally by total IGF-I, bound IGF-I, the free to total IGF-I ratio, and the IGF-I binding capacity. The second component was determined mostly by glucose and insulin. Our results show a marked alteration of the plasma IGF-I levels and of the capacity of plasma to bind IGF-I, and a disturbed relationship between IGF-I and postprandial insulinemia in a rat model of type 2 diabetes mellitus. PMID- 21550078 TI - Insulin improves beta-cell function in glucose-intolerant rat models induced by feeding a high-fat diet. AB - Insulin therapy has been shown to contribute to extended glycemia remission in newly diagnosed patients with type 2 diabetes mellitus. This study investigated the effects of insulin treatment on pancreatic lipid content, and beta-cell apoptosis and proliferation in glucose-intolerant rats to explore the protective role of insulin on beta-cell function. A rat glucose-intolerant model was induced by streptozotocin and a high-fat diet. Plasma and pancreatic triglycerides, free fatty acids, and insulin were measured; and pancreatic beta-cell cell apoptosis and proliferation were detected by a propidium iodide cell death assay and immunofluorescence for proliferating cell nuclear antigen. Relative beta-cell area was determined by immunohistochemistry for insulin, whereas insulin production in pancreas was assessed by reverse transcriptase polymerase chain reaction. Islet beta-cell secreting function was assessed by the index DeltaI30/DeltaG30. Glucose-intolerant rats had higher pancreatic lipid content, more islet beta-cell apoptosis, lower beta-cell proliferation, and reduced beta cell area in pancreas when compared with controls. Insulin therapy reduced blood glucose, inhibited pancreatic lipid accumulation and islet beta-cell apoptosis, and increased beta-cell proliferation and beta-cell area in glucose-intolerant rats. Furthermore, impaired insulin secretion and insulin production in glucose intolerant rats were improved by insulin therapy. Insulin can preserve beta-cell function by protecting islets from glucotoxicity and lipotoxicity. It can also ameliorate beta-cell area by enhancing beta-cell proliferation and reducing beta cell apoptosis. PMID- 21550079 TI - Genotype risk score of common susceptible variants for prediction of type 2 diabetes mellitus in Japanese: the Shimanami Health Promoting Program (J-SHIPP study). Development of type 2 diabetes mellitus and genotype risk score. AB - Recent genomewide association studies have successfully identified several genotypes susceptible to type 2 diabetes mellitus (T2DM). However, only a few studies have investigated whether these variations confer a risk of the future development of T2DM. We conducted a longitudinal genetic epidemiological study to clarify the prognostic significance of the T2DM-associated variants. The sample population consisted of 2037 middle-aged to elderly community residents. Personal health records were obtained from a clinical database administered by the local government. Genotype risk score was calculated by the following variants, namely, KCNQ1, TCF7L2, CDKAL1, HHEX, IGF2BP2, CDKN2AB, SLC30A8, KCNJ11, PPARG, and GCKR. Susceptibility of these variants in Japanese has been confirmed by association analysis. Among the 1824 subjects who did not have T2DM at baseline, 95 cases of T2DM were newly diagnosed during the 9.4-year follow-up period. Mean genotype risk score in these subjects was significantly higher than that in the subjects who remained nondiabetic (9.5 +/- 1.8 vs 9.1 +/- 2.0, P = .042). Although the initial mean body mass index (24.7 +/- 3.2 vs 23.0 +/- 2.8, P < .001) and initial glucose (106 +/- 18 vs 90 +/- 13, P < .001) were also significantly higher in those subjects who developed T2DM, the genotype risk score remained an independent determinant of the development of T2DM even after adjustment for these parameters and possible confounding factors. Per-allele odds ratio for the development of T2DM was 1.12 (95% confidence interval, 1.00-1.25; P = .049). Type 2 diabetes mellitus-susceptible genetic variants identified by a cross-sectional genomewide association study were significantly associated with the future development of T2DM in a general population sample. PMID- 21550080 TI - Micronucleus evaluation in mitogen-stimulated lymphocytes of patients with acromegaly. AB - Acromegaly is a syndrome characterized by a sustained elevation of circulating growth hormone and insulin-like growth factor-1 (IGF-1). Insulin-like growth factor-1 is a potent mitogen and has a role in the transformation of normal cells to malignant cells. This study aims to evaluate the spontaneous micronucleus (MN) frequency by using the cytokinesis-block MN assay to determine genetic damage in the lymphocytes of patients with acromegaly. The study was carried out in 20 patients who had active acromegaly and in 20 age- and sex-matched healthy controls. The MN values were measured in binucleated cells obtained from mitogen stimulated lymphocytes of patients and control subjects. The distribution of binucleated cells with 1, 2, 3, or more MNs was also measured. We found significantly higher MN frequency values in the lymphocytes of acromegalic patients than in those of the control subjects (2.23 +/- 0.68 vs 1.03 +/- 0.54, P = .001). The MN frequency increased with increasing IGF-1 levels of acromegalic patients (P = .036, R = 0.47). We observed that the number of binucleated cells with 2 MNs was higher for the majority of patients with acromegaly than for control subjects. Furthermore, the receiver operating characteristic curve (area under the curve = 0.914, P < .0001) was calculated to assess the discriminative power of the MN frequency. Our results indicate that increased MN frequency in the lymphocytes of patients with acromegaly may reflect genomic instability and this increased MN frequency may be associated with elevated levels of circulating growth hormone and IGF-1. PMID- 21550081 TI - Three novel CYP17A1 gene mutations (A82D, R125X, and C442R) found in combined 17alpha-hydroxylase/17,20-lyase deficiency. AB - The aim of this study was to analyze the structure and functional consequences of 3 novel mutations (A82D, R125X, and C442R) of the CYP17A1 gene found in 2 patients with combined 17alpha-hydroxylase/17,20-lyase deficiency (17OHD). Two Chinese 46, XY female patients were diagnosed with 17OHD based on clinical findings and biochemical results. The CYP17A1 gene was analyzed by polymerase chain reaction direct sequencing. An in vitro expression system was performed in HEK293 cells to analyze the mutant P450c17 activity compared with the wild type. Analysis of the CYP17A1 gene sequences in patient 1 showed compound heterozygous mutations A82D (g.417 C > A) in exon 1 and Y329fs (g.4869 T > A, 4871del) in exon 6; DNA sequencing analysis in patient 2 revealed compound heterozygous mutations R125X (g.2045 C > T) in exon 2 and C442R (g.6457 T > C) in exon 8. The mutations A82D, R125X, and C442R have not been reported previously. The functional study demonstrated that the A82D, R125X, and C442R mutations almost completely eliminate enzymatic activity. These results, which indicate that Ala 82 and Cys 442 are crucial for both 17-hydroxylase and 17,20-lyase activities, help define the structure-function relationship of the CYP17A1 gene. The novel mutations A82D, R125X, and C442R further clarify the patients' clinical manifestations of combined 17OHD. PMID- 21550082 TI - Diabetes mellitus, medications for type 2 diabetes mellitus, and cancer risk. PMID- 21550083 TI - Apolipoprotein A-II and adiponectin as determinants of very low-density lipoprotein apolipoprotein B-100 metabolism in nonobese men. AB - Data from cellular systems and transgenic animal models suggest a role of apolipoprotein (apo) A-II in the regulation of very low-density lipoprotein (VLDL) metabolism. However, the precise mechanism whereby apoA-II regulates VLDL metabolism remains to be elucidated in humans. In this study, we examined the associations between the kinetics of high-density lipoprotein (HDL)-apoA-II and VLDL-apoB-100 kinetics, and plasma adiponectin concentrations. The kinetics of HDL-apoA-II and VLDL-apoB-100 were measured in 37 nonobese men using stable isotope techniques. Plasma adiponectin concentration was measured using immunoassays. Total plasma apoA-II concentration was positively associated with HDL-apoA-II production rate (PR) (r = 0.734, P < .01); both were positively associated with plasma triglyceride concentration (r = 0.360 and 0.369, respectively) and VLDL-apoB-100 PR (r = 0.406 and 0.427, respectively), and inversely associated with plasma adiponectin concentration (r = -0.449 and 0.375, respectively). Plasma adiponectin was inversely associated with plasma triglyceride concentration (r = -0.327), VLDL-apoB-100 concentration (r = 0.337), and VLDL-apoB-100 PR (r = -0.373). In multiple regression models including waist circumference and plasma insulin, plasma adiponectin concentration was an independent determinant of total plasma apoA-II concentration (beta-coefficient = -0.508, P = .001) and HDL-apoA-II PR (beta coefficient = -0.374, P = .03). Conversely, total plasma apoA-II concentration (beta-coefficient = 0.348, P = .047) and HDL-apoA-II PR (beta-coefficient = 0.350, P = .035) were both independent determinants of VLDL-apoB-100 PR. However, these associations were not independent of plasma adiponectin. Variation in HDL apoA-II production, and hence total plasma apoA-II concentration, may exert a major effect on VLDL-apoB-100 production. Plasma adiponectin may also contribute to the variation in VLDL-apoB-100 production partly by regulating apoA-II transport. PMID- 21550084 TI - Resting energy expenditure and protein turnover are increased in patients with severe chronic obstructive pulmonary disease. AB - The mechanisms leading to weight loss in patients with chronic obstructive pulmonary disease (COPD) are poorly understood. Changes in protein metabolism and systemic inflammation may contribute to increased resting energy expenditure (REE) in COPD, leading to an energy imbalance and loss of fat and fat-free mass. The objective of this study was to determine first whether REE was increased in patients with COPD and, second, whether this was associated with increased protein turnover and/or systemic inflammation. Resting energy expenditure was determined using indirect calorimetry in 14 stable outpatients with severe COPD (7 with low and 7 with preserved body mass indices) and 7 healthy controls. Endogenous leucine flux, leucine oxidation, and nonoxidative disposal, indices of whole-body protein breakdown, catabolism, and synthesis, were measured using intravenous infusions of (13)C-bicarbonate and 1-(13)C-leucine. Total body water, from which fat-free mass and fat mass were calculated, was determined using an intravenous bolus of deuterated water. Plasma markers of systemic inflammation were also measured. As a group, subjects with COPD had increased REE adjusted for fat-free mass (P < .001) and faster rates of endogenous leucine flux (P = .006) and nonoxidative leucine disposal (P = .002) compared with controls. There was a significant correlation between REE and both endogenous leucine flux (P = .02) and nonoxidative leucine disposal (P = .008). Plasma concentrations of the inflammatory markers C-reactive protein and interleukin-6 were not different between COPD subjects and controls. Increased rates of protein turnover are associated with increased REE and loss of fat-free mass in COPD. PMID- 21550085 TI - Metabolic syndrome and pancreatic cancer risk: a case-control study in Italy and meta-analysis. AB - We assessed the relation between metabolic syndrome (MetS), its components, and pancreatic cancer risk in an Italian case-control study and performed a meta analysis of epidemiological studies published up to February 2011. The case control study included 326 patients with incident pancreatic cancer and 652 controls admitted to the same hospitals for acute, non-neoplastic conditions. MetS was defined as having at least 3 conditions among diabetes, drug-treated hypertension, hyperlipidemia, and body mass index at least 25 kg/m(2) at age 30 years. We computed multivariate odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) from logistic regression models adjusted for tobacco smoking, education, and other sociodemographic variables. For the meta-analysis, we calculated summary relative risks (RRs) using random-effects models. The OR of pancreatic cancer in the case-control study was 2.36 (95% CI, 1.43-3.90) for diabetes, 0.77 (95% CI, 0.55-1.08) for hypertension, 1.38 (95% CI, 0.94-2.01) for hypercholesterolemia, and 1.27 (95% CI, 0.91-1.78) for being overweight at age 30 years. The risk was significantly increased for subjects with 3 or more MetS components (OR = 2.13, 95% CI 1.01-4.49) compared with subjects with no component, the estimates being consistent among strata of sex, age, and alcohol consumption. The meta-analysis included 3 cohort studies and our case-control study, and found a summary RR of 1.55 (95% CI, 1.19-2.01) for subjects with MetS. Metabolic syndrome is related to pancreatic cancer risk. Diabetes is the key component related to risk. PMID- 21550086 TI - Different associations of apolipoprotein E polymorphism with metabolic syndrome by sex in an elderly Chinese population. AB - The metabolic syndrome (MetS) is characterized by a cluster of metabolic disorders including abnormal lipid and lipoprotein metabolism. Apolipoprotein E (ApoE) is involved in the regulation of the metabolism of cholesterol, lipoproteins, and triglycerides. The common ApoE polymorphism has been found to be associated with cardiovascular disease and diabetes. This study evaluated the ApoE genetic polymorphism and its relation to MetS defined by the modified National Cholesterol Education Program and International Diabetes Federation criteria in a population-based cross-sectional survey of an elderly Chinese population in Beijing, China. Genotypes of 937 men and 1385 women were included in the study. All participants were measured for blood pressure, anthropometric measurements, and fasting concentrations of glucose, triglycerides, cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. We applied a logistic regression model to derive adjusted odds ratios (ORs) and their 95% confidence intervals. In this Chinese population, the E2, E3, and E4 allele frequencies were 8.3%, 83.4%, and 8.3% for men and 8.7%, 82.9%, and 8.4% for women, respectively. In men, concentrations of fasting triglycerides were higher among the APOE2 and E4 subjects; and a lower level of high-density lipoprotein cholesterol was observed in the APOE4 group. There were approximately linear associations of low-density lipoprotein cholesterol levels with APOE genotype groups in both men and women. We observed that the E4 allele was associated with a significantly increased OR of MetS defined by the modified National Cholesterol Education Program criteria in men (OR, 1.75; 95% confidence interval, 1.17-2.63). In summary, our data show that common polymorphism of ApoE gene is associated with the presence of MetS in an elderly Chinese population. PMID- 21550087 TI - Ghrelin levels in patients with juvenile idiopathic arthritis: relation to anti tumor necrosis factor treatment and disease activity. AB - Studies in adults with rheumatoid arthritis reported low serum ghrelin that increased following anti-tumor necrosis factor (TNF) infusion. Data on juvenile idiopathic arthritis (JIA) are lacking. The aim of this pilot study was to explore serum ghrelin levels in patients with JIA and the possible association with anti-TNF treatment, disease activity, and nutritional status. Fifty-two patients with JIA (14/52 on anti-TNF treatment) were studied. Juvenile idiopathic arthritis was inactive in 3 of 14 anti-TNF-treated patients and in 11 of 38 non anti-TNF-treated patients. The nutritional status, energy intake/requirements, appetite, and fasting serum ghrelin levels were assessed. Ghrelin control values were obtained from 50 individuals with minor illness matched for age, sex, and body mass index. Ghrelin levels in patients with JIA were significantly lower than in controls (P < .001, confidence interval [CI] = -101 to -331). Analysis according to anti-TNF treatment and disease activity showed that ghrelin levels were comparable to control values only in 3 patients with anti-TNF-induced remission. Ghrelin in non-anti-TNF-treated patients in remission was low. Multiple regression analysis showed that disease activity (P = .002, CI = -84.16 to -20.01) and anti-TNF treatment (P = .003, CI = -82.51 to -18.33) were significant independent predictors of ghrelin after adjusting for other potential confounders. Ghrelin did not correlate with nutritional status, energy balance, and appetite. Serum ghrelin is low in patients with JIA and is restored to values similar to those in controls following anti-TNF-induced remission. Our study provides evidence that TNF blockade is independently associated with serum ghrelin, which possibly contributes to anti-TNF-induced remission. These preliminary results could form the basis for future research. PMID- 21550088 TI - Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome. AB - Both vitamin D deficiency and polycystic ovary syndrome (PCOS) are associated with aspects of metabolic syndrome, but it is unclear whether vitamin D deficiency contributes to the metabolic disturbances commonly found in women with PCOS. This study sought to investigate (1) the prevalence of vitamin D deficiency in PCOS women in Scotland and (2) the relationship between vitamin D status and metabolic risk factors. This was an observational study on 52 women (25 in PCOS group and 27 in control group). Serum 25-hydroxyvitamin D concentrations less than 25 nmol/L were classified as severe vitamin D deficiency and were found in 44.0% and 11.2% of subjects in the PCOS and control groups, respectively (P = .047). Among the PCOS subjects, 25-hydroxyvitamin D concentrations were negatively correlated with body mass index (P = .033), C-reactive protein (P = .027), and free androgen index (P = .025) and positively correlated with quantitative insulin sensitivity check index (P = .035), high-density lipoprotein cholesterol (HDL-C) (P = .033), and sex hormone binding globulin (P = .038). Associations of vitamin D deficiency with quantitative insulin sensitivity check index and HDL-C were independent of body mass index and waist-to-hip ratio. Vitamin D deficiency is highly prevalent in PCOS women in Scotland, and a larger proportion of PCOS patients than control women were found to be vitamin D deficient. We also demonstrate correlations of vitamin D status with insulin sensitivity, HDL-C, and C-reactive protein in PCOS patients, which support the increasing evidence that vitamin D deficiency is associated with multiple metabolic risk factors in PCOS women. PMID- 21550090 TI - Resistant starch promotes equol production and inhibits tibial bone loss in ovariectomized mice treated with daidzein. AB - Daidzein is metabolized to equol in the gastrointestinal tract by gut microflora. Equol has greater estrogenic activity than genistein and daidzein, with its production shown to be promoted by dietary fiber. It is known that resistant starch (RS) is not absorbed in the proximal intestine and acts as dietary fiber in the colon. In this study, we investigated the combined effects of daidzein and RS intake on equol production, bone mineral density, and intestinal microflora in ovariectomized (OVX) mice. Female mice of the ddY strain, aged 8 weeks, were either sham operated (n = 6) or OVX. The OVX mice were randomly divided into 5 groups: OVX control (n = 6), OVX fed 0.1% daidzein-supplemented diet (OVX + Dz, n = 8), OVX fed 0.1% daidzein- and 12% RS-supplemented diet (OVX + Dz + RS, n = 8), OVX fed 12% RS-supplemented diet (OVX + RS, n = 8), and OVX who received daily subcutaneous administration of 17 beta-estradiol (n = 6). After 6 weeks, urinary equol concentration was significantly higher in the OVX + Dz + RS group than in the OVX + Dz group. The bone mineral density of the whole tibia was higher in the OVX + Dz +RS group compared with the OVX + Dz group. The occupation ratios of Bifidobacterium spp in the cecal microflora in groups fed RS were significantly higher than those in the other groups. The present study demonstrated that RS may increase the bioavailability of daidzein. PMID- 21550091 TI - Characterization and identification of mycosporines-like compounds in cyanolichens. Isolation of mycosporine hydroxyglutamicol from Nephroma laevigatum Ach. AB - Mycosporine-like compounds, comprising mycosporines and mycosporine-like amino acids (MAAs) are UV protecting secondary metabolites described in organisms such as fungi, algae, cyanobacteria or animals. Lichens however, were only poorly investigated for such constituents so far. Here, a method for the characterization of mycosporines and MAAs in purified aqueous extracts, involving HPTLC coupled to spectrophotodensitometry, HPLC-DAD-MS(n) and UPLC-HRMS analysis, is described. This optimized protocol was validated on three algae and one cyanolichen containing known MAAs and mycosporines, and then applied to 18 cyanolichen species. Analyses revealed the presence of five already described mycosporine-like compounds in the investigated species, including mycosporine serinol in Lichina and Peltigera species and mycosporine glutamicol in Degelia plumbea. Apart from that, eight unknown mycosporine-like compounds were detected and tentatively characterized on the basis of their DAD spectra and their MS(n) and HRMS data: two in the alga Porphyra dioica and six in cyanolichen species belonging to the genera Degelia, Nephroma and Stereocaulon. From Nephroma laevigatum, the mycosporine hydroxyglutamicol was preparatively isolated and identified through HRMS, 1D and 2D NMR spectroscopic data. The optimized analytical protocol allowed the characterization of mycosporine-like compounds in small amounts of material and confirmed the potential of cyanolichens as a source of mycosporine compounds. It should also be applicable to investigate lichen species with green algae photobionts for mycosporine-like compounds. PMID- 21550092 TI - Pentacyclic polyketides from Endiandra kingiana as inhibitors of the Bcl-xL/Bak interaction. AB - An in vitro biological screening of Malaysian plants allowed the selection of several species with a significant binding affinity for the antiapoptotic protein Bcl-xL. The chemical investigation of Endiandra kingiana led to the isolation of a series of polyketides named kingianins A-N, having a pentacyclic carbon skeleton described for the first time in nature. Fourteen compounds were isolated as racemic mixtures, and characterized by mass spectrometryand extensive one- and two-dimensional NMR spectroscopy. The (-) and (+) enantiomers of kingianins A and G-L were separated using chiral HPLC, and the absolute configuration of four of them was clearly established by CD analysis. The levorotatory enantiomers showed the more potent binding affinity for Bcl-xL with Ki ranging from 1.0 to 12MUM. PMID- 21550093 TI - [Long-term psychiatric form of mixed connective tissue disease]. PMID- 21550094 TI - Declining HIV prevalence among women attending antenatal care in Pune, India. AB - A declining prevalence of HIV among young women has been reported by the public sector implementing prevention of mother-to-child transmission (PMTCT) programmes, sentinel surveillance sites and research institutions in India. However, there are no reports evaluating such trends from the private healthcare sector. This study is a retrospective analysis of data collected by PRAYAS as a part of the PMTCT programme at Sane Guruji Hospital (SGH), a secondary care hospital in Pune, India. Women attending the antenatal clinic at SGH were screened for HIV following a group counselling session, with an option to opt out. Between January 2003 and March 2008, the overall HIV prevalence was 111/17 578 (0.6%, 95% CI 0.5-0.7%). The HIV prevalence among antenatal women was 1.1% in 2003 and 0.2% in 2008 (i.e. 82% decline in HIV prevalence over the 5-year period) and the odds ratio (OR) of HIV prevalence declined by 0.24 per year from 2003 to March 2008 (OR=0.76, 95% CI 0.69-0.87; P<0.001). The risk of having HIV infection was significantly higher in women aged >= 24 years and those who were uneducated. To our knowledge, this is the first report from any private sector health system in India documenting a declining HIV prevalence among antenatal women. Characterising the risk profile of this small percentage of at-risk women will help in planning prevention strategies. PMID- 21550095 TI - Colloid transport in porous media: impact of hyper-saline solutions. AB - The transport of colloids suspended in natural saline solutions with a wide range of ionic strengths, up to that of Dead Sea brines (10(0.9) M) was explored. Migration of microspheres through saturated sand columns of different sizes was studied in laboratory experiments and simulated with mathematical models. Colloid transport was found to be related to the solution salinity as expected. The relative concentration of colloids at the columns outlet decreased (after 2-3 pore volumes) as the solution ionic strength increased until a critical value was reached (ionic strength > 10(-1.8) M) and then remained constant above this level of salinity. The colloids were found to be mobile even in the extremely saline brines of the Dead Sea. At such high ionic strength no energetic barrier to colloid attachment was presumed to exist and colloid deposition was expected to be a favorable process. However, even at these salinity levels, colloid attachment was not complete and the transport of ~ 30% of the colloids through the 30-cm long columns was detected. To further explore the deposition of colloids on sand surfaces in Dead Sea brines, transport was studied using 7-cm long columns through which hundreds of pore volumes were introduced. The resulting breakthrough curves exhibited a bimodal shape whereby the relative concentration (C/C(0)) of colloids at the outlet rose to a value of 0.8, and it remained relatively constant (for the ~ 18 pore volumes during which the colloid suspension was flushed through the column) and then the relative concentration increased to a value of one. The bimodal nature of the breakthrough suggests different rates of colloid attachment. Colloid transport processes were successfully modeled using the limited entrapment model, which assumes that the colloid attachment rate is dependent on the concentration of the attached colloids. Application of this model provided confirmation of the colloid aggregation and their accelerated attachment during transport through soil in high salinity solution. PMID- 21550096 TI - Removal of residual dissolved methane gas in an upflow anaerobic sludge blanket reactor treating low-strength wastewater at low temperature with degassing membrane. AB - In this study, we investigated the efficiency of dissolved methane (D-CH(4)) collection by degasification from the effluent of a bench-scale upflow anaerobic sludge blanket (UASB) reactor treating synthetic wastewater. A hollow-fiber degassing membrane module was used for degasification. This module was connected to the liquid outlet of the UASB reactor. After chemical oxygen demand (COD) removal efficiency of the UASB reactor became stable, D-CH(4) discharged from the UASB reactor was collected. Under 35 degrees C and a hydraulic retention time (HRT) of 10 h, average D-CH(4) concentration could be reduced from 63 mg COD L( 1) to 15 mg COD L(-1); this, in turn, resulted in an increase in total methane (CH(4)) recovery efficiency from 89% to 97%. Furthermore, we investigated the effects of temperature and HRT of the UASB reactor on degasification efficiency. Average D-CH(4) concentration was as high as 104 mg COD L(-1) at 15 degrees C because of the higher solubility of CH(4) gas in liquid; the average D-CH(4) concentration was reduced to 14 mg COD L(-1) by degasification. Accordingly, total CH(4) recovery efficiency increased from 71% to 97% at 15 degrees C as a result of degasification. Moreover, degasification tended to cause an increase in particulate COD removal efficiency. The UASB reactor was operated at the same COD loading rate, but different wastewater feed rates and HRTs. Although average D CH(4) concentration in the UASB reactor was almost unchanged (ca. 70 mg COD L( 1)) regardless of the HRT value, the CH(4) discharge rate from the UASB reactor increased because of an increase in the wastewater feed rate. Because the D-CH(4) concentration could be reduced down to 12 +/- 1 mg COD L(-1) by degasification at an HRT of 6.7 h, the CH(4) recovery rate was 1.5 times higher under degasification than under normal operation. PMID- 21550097 TI - Simultaneous dispersion-dissolution behavior of concentrated silver nanoparticle suspensions in the presence of model organic solutes. AB - The premise of the nanotechnology revolution is based on the increased surface reactivity of nanometer-sized particles. Thus, these newly realized applications of noble metal nanoparticles introduce new concerns about the environmental fate of these materials if released during use or product disposal. In this paper, the focus is on silver nanoparticles, a known biocidal agent. In particular, this work explores the effect of model solutes chosen for their simple chemical structure yet their ability to simulate chemical attributes common to soil humic material: a chelating molecule, EDTA; a nonionic surfactant, Brij 35; and a large polysaccharide, alginic acid. Batch systems containing concentrated (1600 mg L( 1)) silver nanoparticle (nAg) suspensions were equilibrated with varying additions of EDTA, Brij 35, or alginic acid to solutions containing 1 or 100 mM NaNO3 background electrolyte. In general, both EDTA and alginate were shown to exhibit poor control over nAg dispersion stability, while Brij 35 served as a good dispersant of nAg particles, showing little difference in particle size with respect to electrolyte concentration. The data also show that loading of the model organic compounds resulted in the supersaturation of dissolved Ag for most of the systems. Mechanisms by which these occurred are discussed in more detail. The evidence suggests that regardless of the effect of humics on the stability of nAg dispersions in aqueous systems, polymer loading may enhance the dissolution and release of dissolved Ag into the environment. PMID- 21550098 TI - Archaeological investigations in the Lower Omo Valley (Shungura Formation, Ethiopia): new data and perspectives. PMID- 21550099 TI - Interactions between endogenous and dietary antioxidants against Pb-induced oxidative stress in wild ungulates from a Pb polluted mining area. AB - Certain physiologic disorders, attributed to lead (Pb) exposure are related to the generation of oxidative stress. Organisms rely on a complex antioxidant system, composed of endogenously produced compounds such as glutathione (GSH), superoxide dismutase (SOD) and GSH peroxidase (GPX); and dietary antioxidants such as vitamins A and E. The aim of this work was to study the interactions between both groups of antioxidants and to evaluate their role in fighting Pb induced oxidative stress in wild ungulates living in a Pb mining area. We studied red deer (n=54) and wild boar (n=60) from mining and control sites. Liver Pb, copper (Cu) and selenium (Se) levels were measured in liver and bone. Levels of GSH, oxidized GSH (GSSG), lipid peroxidation (TBARS), alpha-tocopherol, free retinol and retinyl esters, and the activities of SOD and GPX were measured in liver. Wild boar and red deer from the mining sites had higher bone (geometric means: 7.36 vs. 1.23MUg/g dw for boar; and 0.46 vs. 0.11MUg/g dw for deer) and liver Pb levels (0.81 vs. 0.24MUg/g dw for boar; and 0.35 vs. 0.11MUg/g dw for deer) than the controls. Pb exposure in deer was associated with lower GSH, alpha tocopherol and retinyl esters, and higher free retinol and TBARS. A similar effect on vitamin A balance was observed in wild boar, but this was accompanied with an increase in GSH and alpha-tocopherol. GPX activity and Se levels were higher in wild boar (mean in controls: 670IU/mg protein and 1.3MUg/g dw, respectively) than in red deer (150IU/mg protein and 0.3MUg/g). These differences may indicate that red deer is more sensitive to Pb-induced oxidative stress than wild boar. Both endogenous and nutritional antioxidants may be negatively affected by Pb exposure, and their interactions are essential to fight against Pb mediated oxidative damage. PMID- 21550100 TI - Lead isotopes reveal different sources of lead in balsamic and other vinegars. AB - Fifty-eight brands of balsamic vinegars were analyzed for lead concentrations and isotopic compositions ((204)Pb, (206)Pb, (207)Pb, and (208)Pb) to test the findings of a previous study indicating relatively high levels of lead contamination in some of those vinegars--more than two thirds (70%) of them exceeded California's State Maximum Level (34 MUg/L) based on consumption rates >=0.5 MUg Pb per day. The lead isotopic fingerprints of all those vinegars with high lead concentrations were then found to be primarily anthropogenic. This isotopic analysis unquestionably reveals multiple contamination sources including atmospheric pollutant Pb and an unidentified contamination source, likely occurring after grape harvest. Organically grown grape vinegars display the same Pb content and isotopic signatures as other vinegars. This implies that pesticides might not be a significant source of pollutant Pb in vinegars. A significant post-harvest contamination would be inherited from chemicals added during production and/or material used during transport, processing or storage of these vinegars. This is consistent with the highest Pb levels being found in aged vinegars (112+/-112 MUg/L) in contrast to other vinegars (41.6+/-28.9 MUg/L) suggesting contamination during storage. It is, therefore, projected that lead levels in most vinegars, especially aged balsamic and wine vinegars, will decrease with improvements in their manufacture and storage processes consequential to recent concerns of elevated levels of lead in some vinegars. PMID- 21550101 TI - Evaluation of an animal protein-free semen extender for cryopreservation of epididymal sperm from North American bison (Bison bison). AB - The objective was to evaluate the suitability of an animal protein-free semen extender for cryopreservation of epididymal sperm from the two subspecies of North American bison: plains (Bison bison bison) and wood (Bison bison athabascae) bison. Both cauda epididymides (from six plains and five wood bison) were minced and incubated in Sp-TALPH buffer for approximately 2 h at 37 degrees C to release actively motile sperm. Sperm suspensions were filtered, centrifuged and the sperm pellet from each bull was divided into two fractions and diluted either in egg yolk containing extender, Triladyl, or in an animal protein-free extender, Andromed, and equilibrated for 20 min at 37 degrees C. Thereafter, samples were chilled and cryopreserved. Frozen-thawed sperm were evaluated for motility (computer assisted sperm analysis), viability (SYBR 14 and propidium iodide), acrosome integrity (FITC conjugated PSA), cryocapacitation (tyrosine phosphorylation of sperm proteins as a biomarker), and fertilizing ability (in a heterologous IVF system). There was no significant difference for progressive motility, viability, and acrosome integrity between the two extenders for plains bison (36.8 +/- 9.0, 60.5 +/- 17.4, and 77.3 +/- 4.6%; overall mean +/- SD) as well as for wood bison (11.7 +/- 8.1, 13.7 +/- 5.6, and 73.4 +/- 4.2%). Levels of tyrosine phosphorylation did not differ for sperm preserved in the two extenders for both subspecies, although an inter-bull variability in the response to tyrosine phosphorylation between extenders was suggested for plains bison. Fertilization percent did not differ significantly between extenders for plains bison (84.16 +/- 9.92%, overall mean +/- SD) and for wood bison (59.53 +/- 19.99%). In conclusion, in the absence of significant difference between extenders in post-thaw sperm characteristics, we inferred that Andromed (animal protein-free) was suitable for cryopreservation of epididymal sperm from North American bison. PMID- 21550102 TI - Ovarian hydrobursitis in female camels (Camelus dromedarius): clinical findings, histopathology and fertility after unilateral surgical ablation. AB - This study was undertaken to verify the clinical signs, incidence, location, etiology and pathology of ovarian hydrobursitis in infertile female camels and estimate the fertility after unilateral surgical ablation. Genital organs (n = 124) were examined in camels slaughtered at Makkah abattoir during Hajj of 2009. Infertile female camels (n = 142) presented for management to the Veterinary Teaching Hospital, Qassim University, Saudi Arabia, were clinically examined and ultrasound-scanned for the diagnosis of genital abnormalities. Twenty eight camels diagnosed with ovarian hydrobursitis were further investigated for the effect of unilateral surgical ablation on breeding outcomes. Surgical ablation was carried on 14 cases (treated group), the remaining 14 cases were followed as controls (control group). Both groups were observed for breeding results: 90 days non-return rate (90d NRR) and calving rate (CR). Removed bursae were sent to the laboratory for histopathological investigation. Results showed that the incidence of ovarian hydrobursitis was 6.5% in slaughtered camels and 33.8% in infertile females. Camels with hydrobursitis were concurrently affected with pyometra, uterine and vaginal adhesions or purulent endometritis. Histopathology reported degeneration and hyperplasia of the lining epithelium, mononuclear cells infiltration, focal aggregation of inflammatory cells, cystic dilatation of multi acinal structures, tiny hemorrhages, and presence of hemosiderin-laden macrophages. The 90d NRR and CR of the surgically-treated cases were 64.3% and 50%, respectively. None of the untreated cases conceived. These results confirmed that ovarian hydrobursitis causes infertility in dromedary female camels and is associated with inflammatory genital conditions and surgical ablation in unilaterally affected animals presents a potential treatment. PMID- 21550103 TI - Gene expression in placentation of farm animals: an overview of gene function during development. AB - Eutherian mammals share a common ancestor that evolved into two main placental types, i.e., hemotrophic (e.g., human and mouse) and histiotrophic (e.g., farm animals), which differ in invasiveness. Pregnancies initiated with assisted reproductive techniques (ART) in farm animals are at increased risk of failure; these losses were associated with placental defects, perhaps due to altered gene expression. Developmentally regulated genes in the placenta seem highly phylogenetically conserved, whereas those expressed later in pregnancy are more species-specific. To elucidate differences between hemotrophic and epitheliochorial placentae, gene expression data were compiled from microarray studies of bovine placental tissues at various stages of pregnancy. Moreover, an in silico subtractive library was constructed based on homology of bovine genes to the database of zebrafish - a nonplacental vertebrate. In addition, the list of placental preferentially expressed genes for the human and mouse were collected using bioinformatics tools (Tissue-specific Gene Expression and Regulation [TiGER] - for humans, and tissue-specific genes database (TiSGeD) - for mice and humans). Humans, mice, and cattle shared 93 genes expressed in their placentae. Most of these were related to immune function (based on analysis of gene ontology). Cattle and women shared expression of 23 genes, mostly related to hormonal activity, whereas mice and women shared 16 genes (primarily sexual differentiation and glycoprotein biology). Because the number of genes expressed by the placentae of both cattle and mice were similar (based on cluster analysis), we concluded that both cattle and mice were suitable models to study the biology of the human placenta. PMID- 21550104 TI - Tissue-specific selection of reference genes is required for expression studies in the mouse model of maternal protein undernutrition. AB - Suboptimal maternal nutrition during gestation results in the establishment of long-term phenotypic changes and an increased disease risk in the offspring. To elucidate how such environmental sensitivity results in physiological outcomes, the molecular characterisation of these offspring has become the focus of many studies. However, the likely modification of key cellular processes such as metabolism in response to maternal undernutrition raises the question of whether the genes typically used as reference constants in gene expression studies are suitable controls. Using a mouse model of maternal protein undernutrition, we have investigated the stability of seven commonly used reference genes (18s, Hprt1, Pgk1, Ppib, Sdha, Tbp and Tuba1) in a variety of offspring tissues including liver, kidney, heart, retro-peritoneal and inter-scapular fat, extra embryonic placenta and yolk sac, as well as in the preimplantation blastocyst and blastocyst-derived embryonic stem cells. We find that although the selected reference genes are all highly stable within this system, they show tissue, treatment and sex-specific variation. Furthermore, software-based selection approaches rank reference genes differently and do not always identify genes which differ between conditions. Therefore, we recommend that reference gene selection for gene expression studies should be thoroughly validated for each tissue of interest. PMID- 21550105 TI - Trisomy-X with estrous cycle anomalies in two female dogs. AB - Two female dogs were presented with a history of abnormal estrous cycles and infertility, despite multiple breedings. Medical therapy to correct the cycle anomalies did not result in pregnancy. Cytogenetic analysis of blood lymphocyte cultures in each dog revealed three copies of the X chromosome in each cell, constituting a 79,XXX karyotype (trisomy-X). Both dogs were eventually ovariohysterectomised and histological evaluation revealed hypoplastic ovaries and an absence of normal follicular structures. However, partial or immature follicles were noted, which may have been sufficient to cause both females to initiate cycling. The history and clinical characteristics found in these dogs were compared to those described in three other dogs reported with trisomy-X, as well as those reported in other species. These findings highlighted the importance of cytogenetic studies in fertility evaluation and achieving a definitive diagnosis for infertility in the bitch. PMID- 21550106 TI - Sex control by Zfy siRNA in the mouse. AB - The objective of this work was to detect the influence of Y sperm forming of Mus musculus by silencing the Zfy gene during spermatogenesis. The recombination expression vectors pSilencer5.1/Zfy215 and pSilencer5.1/Zfy2102 were constructed. 64 male KunMing Mus were divided into four groups randomly and averagely. The two recombination expression vectors were injected into two groups, respectively, through testis. The other two groups were injected with the same volume of physiological saline and empty vector pSilencer5.1-H1 Retro, respectively. They were injected every ten days for a total of four injections. Seventeen days after the fourth injection, 8 male Mus of each group mated with 8 female Mus. The testis tissue of the other 8 male Mus of each group was collected, and the expression level of Zfy mRNA was determined by fluorescence quantitation real time PCR (qRT-PCR). The result showed that the expression of Zfy mRNA decreased significantly after injection of pSilencer5.1/Zfy2102 (P < 0.01), and that 72.3% of the offspring were female, a number significantly higher than in the control group (P < 0.01). In the pSilencer5.1/Zfy215 group, the expression of Zfy mRNA was significantly lower than in the control group (P < 0.05), but the female rate of offspring was not. It was concluded that the Zfy gene could play a role in the process of Y sperm formation. PMID- 21550107 TI - Effect of tocopherol supplementation on serum 8-epi-prostaglandin F2 alpha and adiponectin concentrations, and mRNA expression of PPARgamma and related genes in ovine placenta and uterus. AB - The objectives were to determine the effects of tocopherol on serum concentrations of 8-epi-prostaglandin F2 alpha (isoprostane) and adiponectin, and to determine mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma), adiponectin (ADIPQ), and related genes in the uterus and placentome of tocopherol-supplemented ewes during late pregnancy. Pregnant ewes were individually given daily oral supplements of 500 mg of alpha-tocopherol (aT; N=6), 1000 mg of gamma-tocopherol (gT; N=7), or placebo (CON; N=5) from 107 to 137 d post breeding. Serum and tissue samples were collected weekly and at the end of the study, respectively. At the end of the study, in the aT, gT and CON groups, serum concentrations were 251.7 +/- 12.3, 232.5 +/- 6.8, and 285.8 +/- 9.4 etag/MUL, respectively, for isoprostane, and were 341.7 +/- 9.3, 358.7 +/- 11.5, and 305.2 +/- 2.8 etag/MUL for adiponectin (significantly different for aT and gT versus CON). The mRNA abundance for PPARgamma in the cotyledon and caruncle were similar in aT and gT ewes. The PPARgamma, ADIPQ and LEP mRNA expressions were reduced (P < 0.05) in the cotyledon and caruncle in aT versus CON ewes. However, associations of PPARgamma mRNA expression with ADIPQ and LEP mRNA expressions were negatively related in cotyledons, positively related in the caruncle, and positively downregulated in the uterus in gT supplemented ewes accounting for CON. The IGF-1 mRNA expression was downregulated in the cotyledon, caruncle and uterus in aT supplemented ewes. Expression of IGF-2 mRNA was upregulated in the cotyledon and caruncle, and downregulated in the uterus in gT supplemented ewes. In conclusion, oral supplementation of tocopherol during late gestation in ewes decreased isoprostane concentrations and increased adiponectin concentrations in the serum, and significantly affected PPARgamma- and ADIPQ related genes in the utero-placental network. Perhaps the pro-angiogenic tocopherol effect in the placental vascular network was via PPARgamma-mediated regulation of genes responsible for metabolism of glucose and fatty acid, as well as for angiogenesis. PMID- 21550108 TI - Hydatid pericardial tamponade: a grape soup. PMID- 21550109 TI - The use of mitochondrial targeting resveratrol liposomes modified with a dequalinium polyethylene glycol-distearoylphosphatidyl ethanolamine conjugate to induce apoptosis in resistant lung cancer cells. AB - Intrinsic multidrug resistance (MDR) of cancers remains a major obstacle to successful chemotherapy. A dequalinium polyethylene glycol distearoylphosphatidylethanolamine (DQA-PEG(2000)-DSPE) conjugate was synthesized as a mitochondriotropic molecule, and mitochondrial targeting resveratrol liposomes were developed by modifying DQA-PEG(2000)-DSPE on the surface of liposomes for overcoming the resistance. Evaluations were performed on the human lung adenocarcinoma A549 cells and resistant A549/cDDP cells, A549 and A549/cDDP tumor spheroids as well as the xenografted resistant A549/cDDP cancers in nude mice. The yield of DQA-PEG(2000)-DSPE conjugate synthesized was about 87% and the particle size of mitochondrial targeting resveratrol liposomes was approximately 70 nm. The mitochondrial targeting liposomes significantly enhanced the cellular uptake, and selectively accumulated into mitochondria when encapsulating coumarin as the fluorescent probe. Furthermore, mitochondrial targeting resveratrol liposomes induced apoptosis of both non-resistant and resistant cancer cells by dissipating mitochondria membrane potential, releasing cytochrome c and increasing the activities of caspase 9 and 3. They also exhibited significant antitumor efficacy in two kinds of cancer cells, in tumor spheroids by penetrating deeply into the core, and in xenografted resistant A549/cDDP cancers in nude mice. Mitochondrial targeting resveratrol liposomes co-treating with vinorelbine liposomes significantly enhanced the anticancer efficacy against the resistant A549/cDDP cells. In conclusion, mitochondrial targeting resveratrol liposomes would provide a potential strategy to treat the intrinsic resistant lung cancers by inducing apoptosis via mitochondria signaling pathway. PMID- 21550110 TI - The use of glass substrates with bi-functional silanes for designing micropatterned cell-secreted cytokine immunoassays. AB - It is often desirable to sequester cells in specific locations on the surface and to integrate sensing elements next to the cells. In the present study, surfaces were fabricated so as to position cytokine sensing domains inside non-fouling poly(ethylene glycol) (PEG) hydrogel microwells. Our aim was to increase sensitivity of micropatterned cytokine immunoassays through covalent attachment of biorecognition molecules. To achieve this, glass substrates were functionalized with a binary mixture of acrylate- and thiol-terminated methoxysilanes. During subsequent hydrogel photopatterning steps, acrylate moieties served to anchor hydrogel microwells to glass substrates. Importantly, glass attachment sites within the microwells contained thiol groups that could be activated with a hetero-bifunctional cross-linker for covalent immobilization of proteins. After incubation with fluorescently-labeled avidin, microwells fabricated on a mixed acryl/thiol silane layer emitted ~ 6 times more fluorescence compared to microwells fabricated on an acryl silane alone. This result highlighted the advantages of covalent attachment of avidin inside the microwells. To create cytokine immunoassays, micropatterned surfaces were incubated with biotinylated IFN-gamma or TNF-alpha antibodies (Abs). Micropatterned immunoassays prepared in this manner were sensitive down to 1 ng/ml or 60 pM IFN-gamma. To further prove utility of this biointerface design, macrophages were seeded into 30 MUm diameter microwells fabricated on either bi functional (acryl/thiol) or mono-functional silane layers. Both types of microwells were coated with avidin and biotin-anti-TNF-alpha prior to cell seeding. Short mitogenic activation followed by immunostaining for TNF-alpha revealed that microwells created on bi-functional silane layer had 3 times higher signal due to macrophage-secreted TNF-alpha compared to microwells fabricated on mono-functional silane. The rational design of cytokine-sensing surfaces described here, will be leveraged in the future for rapid detection of multiple cytokines secreted by individual immune cells. PMID- 21550111 TI - Elastin-like protein matrix reinforced with collagen microfibers for soft tissue repair. AB - Artificial composites designed to mimic the structure and properties of native extracellular matrix may lead to acellular materials for soft tissue repair and replacement, which display mechanical strength, stiffness, and resilience resembling native tissue. We describe the fabrication of thin lamellae consisting of continuous collagen microfiber embedded at controlled orientations and densities in a recombinant elastin-like protein polymer matrix. Multilamellar stacking affords flexible, protein-based composite sheets whose properties are dependent upon both the elastomeric matrix and collagen content and organization. Sheets are produced with properties that range over 13-fold in elongation to break (23-314%), six-fold in Young's modulus (5.3-33.1 MPa), and more than two fold in tensile strength (1.85-4.08 MPa), exceeding that of a number of native human tissues, including urinary bladder, pulmonary artery, and aorta. A sheet approximating the mechanical response of human abdominal wall fascia is investigated as a fascial substitute for ventral hernia repair. Protein-based composite patches prevent hernia recurrence in Wistar rats over an 8-week period with new tissue formation and sustained structural integrity. PMID- 21550112 TI - Environmental properties and aquatic hazard assessment of anionic surfactants: physico-chemical, environmental fate and ecotoxicity properties. AB - This paper summarizes the environmental hazard assessment of physicochemical properties, environmental fate and behavior and the ecotoxicity of a category of 61 anionic surfactants (ANS), comprised of alkyl sulfates (AS), primary alkane sulfonates (PAS) and alpha-olefin sulfonates (AOS) under the High Production Volume Chemicals Program of the Organisation for Economic Co-operation and Development (OECD). The most important common structural feature of the category members examined here is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate or sulfonate group, neutralized with a counter-ion. The hydrophobic hydrocarbon chain (with a length between C(8) and C(18)) and the polar sulfate or sulfonate groups confer surfactant properties and enable the commercial use of these substances as anionic surfactants. The close structural similarities lead to physico-chemical properties and environmental fate characteristics which follow a regular pattern and justify the applied read across within a category approach. Common physical and/or biological properties result in structurally similar breakdown products and are, together with the surfactant properties, responsible for similar environmental behavior. The structural similarities result in the same mode of ecotoxic action. Within each of the three sub-categories of ANS the most important parameter influencing ecotoxicity is the varying length of the alkyl chain. Although the counter-ion may also influence the physico-chemical properties, there is no indication that it significantly affects chemical reactivity, environmental fate and behavior or ecotoxicity of these chemicals. Deduced from physico-chemical and surfactancy properties, the main target compartment for the substances of the ANS category is the hydrosphere. They are quantitatively removed in waste water treatment plants, mainly by biodegradation. Quantitative removal in biological treatment plants is reflected by low AS concentrations measured in effluents of waste water treatment plants (mostly below 10 MUg/L). In addition, bioaccumulation of ANS does not exceed regulatory triggers based upon experimental data. A considerable number of reliable aquatic toxicity data for the whole ANS category are available, including chronic and subchronic data for species of all trophic levels. Based upon the highest quality data in hand, there appears to be no singularly most sensitive trophic level in tests on the toxicity of alkyl sulfates, with a large degree of overlap among algae, invertebrates and fish. Algae proved to be more variable in sensitivity to alkyl sulfate exposure compared to fish and daphnia. The key study for the aquatic hazard assessment is a chronic test on Ceriodaphnia dubia, which covers a range of the alkyl chain length from C(12) to C(18). A parabolic response was observed, with the C(14) chain length being the most toxic (7d-NOEC=0.045 mg/L). Responses of aquatic communities to C(12) AS and C(14-15) AS have been studied in high quality stream mesocosm studies containing a broad range of species and ecological interactions. These studies are regarded as a better approximation to reality when extrapolating to the environment. The 56-d chronic NOEC for C(12) AS and C(14-15) AS were 0.224 and 0.106 mg/L, respectively, based on integrated assessments of periphyton (algal, bacterial and protozoan) and invertebrate communities. Taking into account the rapid biodegradation of the ANS compounds as well as the low concentrations measured in different environmental compartments, this category of surfactants is of low concern for the environment. PMID- 21550113 TI - Chronic effects induced by ibuprofen on the freshwater bivalve Dreissena polymorpha. AB - The sub-lethal effects induced by the non-steroidal anti-inflammatory drug ((NSAID) ibuprofen (IBU; ((+/-)-2-(p-isobutylphenyl) propionic acid))) were investigated using a battery of biomarkers on the freshwater bivalve Dreissena polymorpha. According to the results from a semi-static in vivo approach, mussels were exposed for 96 h to increasing levels of environmentally relevant IBU concentrations (0.2, 2 and 8 MUg/l, corresponding to 1, 9 and 35 nM, respectively). Cyto-genotoxicity was evaluated via the single cell gel electrophoresis (SCGE) assay, the DNA diffusion assay, the micronucleus test (MN test) and lysosome membrane stability (Neutral Red Retention Assay) in mussel hemocytes. In addition, the activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and the phase II detoxifying enzyme glutathione S-transferase (GST) were measured in the cytosolic fraction that was extracted from a pool of entire bivalves to determine whether the oxidative status was imbalanced. The biomarker battery pointed out a slight cyto genotoxicity on zebra mussel hemocytes at the IBU concentration of 0.2 MUg/l, with higher IBU concentrations able to significantly increase both genetic and cellular damage. In addition, IBU seems to have a considerable effect on the activities of antioxidant and detoxifying enzymes as shown in the exposed specimens' notable oxidative status imbalances. PMID- 21550114 TI - Reduced body condition and enzymatic alterations in frogs inhabiting intensive crop production areas. AB - Parameters indicative of general condition and health were compared amongst adult frogs inhabiting uncultivated lands and fields subjected to agricultural practices typical of the humid pampas of Argentina. Whereas no significant differences existed in the parasite load and external malformations prevalence rate of adult frogs from either environments, a reduced condition factor was clearly demonstrated in frogs from agricultural lands. This conclusion was reached for four frog species of different life habits: the terrestrial fossorial Rhinella fernandezae, the terrestrial Leptodactylus latinasus, the semi-aquatic Leptodactylus ocellatus, and the arborescent Hypsiboas pulchellus. A distinct pattern of enzymatic modifications was furthermore observed in L. ocellatus and H. pulchellus from agricultural lands, including elevated hepatic activities of catalase and cholinesterase, and an inhibition of liver GST activity. Further studies should investigate the causes and consequences of the systematically low condition factor observed in frogs from agricultural fields of the humid pampas of Argentina. PMID- 21550115 TI - Prevention of sexual violence by those who have been sexually violent. AB - This article argues that indeterminate sentencing is the optimal means of preventing recidivism among sex offenders, both as an instrumental matter and jurisprudentially. Once a person is convicted of an offense, the duration and nature of sentence should be based on a back-end decision made by experts in recidivism reduction, within broad ranges set by the legislature. This position is defended against a number of objections, including claims that such a system relies on flawed risk assessments, ignores societal views of justice, denigrates offenders and victims, undermines deterrence and norm enforcement, depends too heavily on costly, uneven and demoralizing risk management schemes, and, as a result of one or more of these objections, is unconstitutional. PMID- 21550116 TI - Perfluorinated compounds in seafood from coastal areas in China. AB - Diet is an important source of perfluorinated compound (PFC) exposure and seafood is an important diet component for coastal populations. Therefore, it is necessary to monitor the concentrations of PFCs in seafood. In this study, we measured thirteen PFCs in 47 fatty fish and 45 shellfish samples collected from six coastal provinces in China (Liaoning, Shandong, Jiangsu, Zhejiang, Fujian, and Guangdong), using an ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). Perfluorooctanesulfonate (PFOS) was the dominant PFC in fatty fish which accounted for 38% of total PFCs, whereas perfluoroctanoic acid (PFOA) was the predominant PFC in shellfish. Concentrations of PFOS were ranged from less than 1.4 to 1627 pg/g wet weight in fatty fish, with the highest concentration in red drum from Jiangsu. Concentrations of PFOA in shellfish ranged from less than 5.4 to 7543 pg/g wet weight, with the maximum concentration found in briny clam also from Jiangsu. Compared with other studies, the PFC levels in seafood collected from our studied areas are relatively low. The estimated dietary intakes (EDI, pg/kg body weight /day) of PFOA, PFOS and total PFCs for the reference man (63 kg body weight) were calculated by multiplying the mean concentrations (pg/g wet weight) of PFOA, PFOS and total PFCs in six coastal provinces with the daily consumption data (g/day) from the fourth Chinese total diet study carried out in 2007. The highest EDI of PFOS and PFOA were found to be 694 pg/kg body weight/day and 914 pg/kg body weight/day in Guangdong and Jiangsu, respectively. However, the highest EDI of total PFCs was found in Fujian at 2513 pg/kg body weight/day. The EDI from seafood is much lower than the tolerable daily intake (TDI) recommended by the European Food Safety Authority in 2008 indicating low health risk of PFC exposure via eating seafood among the coastal populations in China. PMID- 21550117 TI - Increased expressions of DNA methyltransferases contribute to CD70 promoter hypomethylation and over expression of CD70 in ITP. AB - CD70 (TNFSF7), as a methylation susceptive immune gene, was hypomethylated in some autoimmune diseases. To investigate the status of CD70 methylation and the expressions of genes that regulated methylation in immune thrombocytopenia (ITP) patients, the expressions of CD70 mRNA and protein in CD4(+) T cells from ITP and controls were measured respectively by real-time PCR and flow cytometry. Methylation specific high resolution melting (MS-HRM) technology was applied to detect CD70 promoter methylation indices. Transcription levels of DNA methyltransferases (DNMTs), methylated CpG binding protein 2 (MBD2) were measured. The results showed that CD70, DNMTs and MBD2 was over expressed and methylation indices of CD70 promoter in CD4(+) T cells from ITP patients were lower than that from healthy controls. The transcription levels of CD70 showed significantly inverse correlation with methylation indices in ITP patients but significantly positive correlation with that of DNMTs. We concluded that DNMTs functioned as demethylases as MBD2, while increased DNMTs and MBD2 may cause demethylation and over expression of CD70 in CD4(+) T cells, potentially contributing to the pathogenesis of ITP. PMID- 21550118 TI - A prospective study of reticular macular disease. AB - PURPOSE: To determine the risk of progression to advanced age-related macular degeneration (AMD) conferred by reticular pseudodrusen (RPD), an imaging presentation of reticular macular disease (RMD), in high-risk fellow eyes of subjects with AMD and unilateral choroidal neovascularization (CNV) in a large, prospective study. DESIGN: Cohort study. PARTICIPANTS: Two hundred seventy-one subjects with AMD; 94 with RPD and 177 without RPD. METHODS: Images from a cohort of 271 subjects with AMD in the Nutritional AMD treatment phase II (NAT 2) Study, a 3-year prospective study of subjects with unilateral CNV and large soft drusen in the fellow eye, were studied. The fellow eye, at high risk for advanced AMD developing, was the study eye. There were 5 visits per subject. Imaging at each visit consisted of color, red-free, and blue-light photography and fluorescein angiography. The images were analyzed for the presence of RPD, following disease progression throughout the 3-year study. MAIN OUTCOME MEASURES: The development of advanced AMD (CNV or geographic atrophy). RESULTS: For the 271 subjects who completed the full 3-year study, there was a significantly higher rate of advanced AMD (56% or 53/94) in fellow eyes with RPD at any visit compared with eyes without RPD (32% or 56/177; P < 0.0001, chi-square test; relative risk [RR], 1.8; 95% confidence interval [CI], 1.4-2.4). The chance of developing advanced AMD in the fellow eye in women with RPD (66%) was more than double that of women without RPD (30%; P < 0.00001; RR, 2.2; 95% CI, 1.6-3.1). CONCLUSIONS: To the authors' knowledge, this is the first comprehensive prospective study of RMD, a distinct clinical phenotype of AMD that includes RPD. It provides strong confirmation that RMD, a disease entity with stereotypical presentations across imaging methods, is associated with a high risk of progression to advanced AMD, perhaps on an inflammatory or vascular basis. Reticular macular disease deserves wider recognition and consideration by clinicians caring for patients with AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21550119 TI - Early flap displacement after LASIK. AB - PURPOSE: To evaluate the risks of flap displacement after LASIK. DESIGN: Retrospective case series. PARTICIPANTS: We included 41 845 consecutive adults who underwent LASIK surgery at Optical Express in the United Kingdom, including 81 238 eyes, of which 14 555 were hyperopic and 66 681 myopic or mixed astigmatic. We treated 57 241 eyes with the IntraLase FS-60 femtosecond laser and 23 997 with the Moria S.A. ONE Use-Plus automated microkeratome. METHODS: We calculated the incidence of all flap displacements in the study population during an observational time period of >=12 months after surgery. Independent variables were entered into logistic regression models to identify risk factors. Postoperative outcomes were assessed. MAIN OUTCOME MEASURES: The incidence and odds ratios (OR) of flap displacement in the study population and in categories of refractive error and flap surgery technique. RESULTS: The incidence of flap displacements was 10 in 81 238 LASIK procedures (0.012%), including 8 hyperopic eyes (0.055%) and 2 myopic eyes (0.003%). All flap displacements occurred within 48 hours of surgery and none were preceded by ocular trauma. They were classified as "early flap displacements" (EFD). The incidence of EFD after microkeratome surgery was 0.033% (n = 8), and after femtosecond laser it was 0.003% (n = 2). In hyperopic eyes having microkeratome surgery, the incidence was 0.179% (n = 7). In a logistic regression model, the strongest predictor of EFD after LASIK was hyperopia, recording an OR of 19.29 (P<0.001). The OR of developing an EFD after microkeratomy was 10.53 times higher than after femtosecond laser (P<0.005). In hyperopes, the OR of an EFD was 18.87 times higher after microkeratomy than after femtosecond treatment. Four of 10 displaced flaps needed secondary surgery, and 1 eye lost 2 lines of best-corrected visual acuity. CONCLUSIONS: The incidence of flap displacements during a 12-month period after LASIK was extremely low (0.012%). Although the small number of displacements with the femtosecond laser limits conclusions, the risk of EFD was higher after microkeratome surgery than femtosecond laser. PMID- 21550120 TI - Factors associated with false positives in retinal nerve fiber layer color codes from spectral-domain optical coherence tomography. AB - PURPOSE: To determine the factors that contribute to false-positive retinal nerve fiber layer (RNFL) color code results from spectral-domain optical coherence tomography (OCT). DESIGN: A prospective, cross-sectional study. PARTICIPANTS: This study included 149 eyes from 77 healthy participants. METHODS: Participants, who were consecutively enrolled from June 2009 to December 2009, underwent Cirrus OCT. Recorded demographic and clinical factors included age, gender, eye side, intraocular pressure, central corneal thickness, spherical equivalent, axial length, anterior chamber depth, disc area, and the extent of retinal vasculature. MAIN OUTCOME MEASURES: An abnormal finding in RNFL color codes was defined as >=1 yellow or red sectors by quadrant and clock-hour maps and a wedge-shaped color pattern represented by yellow or red in the deviation map. The incidence of false positive color codes was determined. The influence of clinical and demographic factors on the incidence of false-positive RNFL color codes was assessed using generalized linear mixed model analysis. RESULTS: The false-positive rate for >=1 of the quadrant, clock-hour, and deviation maps was 26.2%. Longer axial length and smaller disc area were significantly associated with an increased incidence of false-positives when other factors were controlled (odds ratios, 2.422 and 0.165; P = 0.008 and 0.035, respectively). CONCLUSIONS: The factors that significantly affected the false-positive RNFL color code results using spectral domain OCT were axial length and disc area, which may significantly affect the specificity of spectral-domain OCT. Therefore, axial length and disc area should be considered during RNFL thickness profile analysis. PMID- 21550121 TI - Fungal eye disease at a tertiary care center: the utility of routine inpatient consultation. AB - PURPOSE: Hematogenous dissemination of fungus of the eyes can manifest as chorioretinitis or endophthalmitis. Early reports of this condition describe the prevalence to range from 10% to 40%; however, more recent studies have suggested a declining prevalence, presumably because of widespread use of prophylactic antifungal therapy and earlier diagnosis and treatment of systemic illness before ocular symptoms become apparent. This study estimates the current prevalence and microbial profile of fungal chorioretinitis and endophthalmitis among patients with positive fungal cultures at a tertiary care medical center. DESIGN: Retrospective case series. PARTICIPANTS: A total of 211 adult and pediatric inpatients with fungemia. METHODS: All inpatient consultations at our institution to evaluate for ocular involvement by fungal organisms from June 3, 2006, to September 3, 2009, were reviewed. MAIN OUTCOME MEASURES: The presence or absence of ocular lesions consistent with disseminated fungus. RESULTS: A total of 211 patients (83 pediatric, 128 adult) had consult requests indicating concern for ocular fungal infection. More than 97% of these patients had at least 1 positive fungal culture. In decreasing order of frequency, the organisms identified were Candida albicans, C. parapsilosis, C. glabrata, C. tropicalis, and others. More than 98% of all patients were receiving systemic antifungal therapy (average duration 6.5 days) at the time of examination. No pediatric patients and only 2 adult patients had positive findings (i.e., chorioretinitis or endophthalmitis); 1 of these 2 patients was able to verbalize symptoms and reported floaters and blurring, whereas the other patient was unable to verbalize. Visual symptoms were rare (3.5%) among patients with negative findings who could verbalize visual symptoms. Three adults had nonspecific fundus lesions that were considered inconsistent with chorioretinitis. CONCLUSIONS: Disseminated ocular fungal infection is rare in the current era of widespread prophylactic antifungal therapy. Less than 1% of patients in our study had ocular involvement from fungus, and no patients who were asymptomatic had involvement. We suggest that routine ophthalmic consultation on fungemic inpatients is not an efficient use of clinical resources; however, validation of these findings via a prospective study is desired. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21550122 TI - The 5-HTTLPR polymorphism, impulsivity and suicide behavior in euthymic bipolar patients. AB - BACKGROUND: Suicide behavior is very frequent in Bipolar Disorder (BD) and they are both closely associated with impulsivity. Furthermore they are, impulsivity, BD and suicide behavior, associated with serotonergic function, at least partially, under genetic determinism and somewhat associated with the serotonin transporter gene polymorphism, the 5-HTTLPR. We aimed to assess different impulsivity components in BD sub-grouped by suicidal attempt and healthy controls. We hypothesized that the non-planning/cognitive impulsivity, could be more closely associated with suicidal behavior. We further associated 5-HTTLPR genotypes with neuropsychological results to test the hypothesis that this polymorphism is associated with cognitive impulsivity. METHOD: We assessed 95 euthymic bipolar patients sub-grouped by suicidal attempt history in comparison with 94 healthy controls. All subjects underwent a laboratory assessment of impulsivity (Continuous Performance Test and Iowa Gambling Test). Furthermore the genotyping of 5-HTTLPR was performed in all subjects. RESULTS: We found that bipolar patients are more impulsive than healthy controls in all impulsivity dimensions we studied. Furthermore bipolar patients with a suicide attempt history have a greater cognitive impulsivity when compared to both bipolar patients without such a history as well when compared to healthy controls. No association was found between 5-HTTLPR genotypes and neuropsychological measures of impulsive behavior. LIMITATIONS: The sample studied can be considered small and a potentially confounding variable - medication status - was not controlled. CONCLUSION: A lifetime suicide attempt seems associated with cognitive impulsivity independently of the socio-demographic and clinical variables studied as well with 5-HTTLPR genotype. Further studies in larger samples are necessary. PMID- 21550124 TI - Past-year recreational gambling in a nationally representative sample: correlates of casino, non-casino, and both casino/non-casino gambling. AB - Data from the Gambling Impact and Behavior Study (GIBS), a national survey of 2417 U.S. adults, were examined by multivariate analysis to investigate characteristics of past-year recreational gamblers who participated in casino only, non-casino-only, and both casino and non-casino gambling. Compared to non casino-only gamblers, individuals who gambled in both locations had higher rates of alcohol use and abuse/dependence, lower rates of drug use, more frequent gambling, and larger wins and losses. Compared to casino-only gamblers, individuals who gambled in both locations reported less drug use, poorer subjective health, earlier age of gambling onset, greater frequency of gambling, and larger wins and losses. Compared to casino-only or non-casino-only gambling, gambling in both locations was associated with more frequent and heavier gambling. Findings suggest aspects of recreational gambling, such as gambling venue, may have important public health implications and should be considered in guidelines for responsible gambling. PMID- 21550125 TI - The effect of live, attenuated measles vaccine and measles infection on measles antibody levels in serum and CSF of patients with multiple sclerosis or clinically isolated syndrome. AB - High occurrence of measles, rubella and varicella zoster antibodies has been used as a biomarker for MS (the MRZ test). We analyzed measles antibody titres with respect to measles infection/measles vaccination status in 166 patients with MS or clinically isolated syndrome. Fifty blood donors served as controls. Measles vaccination yielded CSF measles antibodies in fewer patients (62%) than measles infection did (87%, p=0.001) and yielded lower measles titres in both serum and CSF (p<0.001). Controls had lower CSF measles titres than patients with measles vaccination alone (p<0.001). Childhood vaccinations probably reduce the sensitivity of the MRZ diagnostic test for MS. PMID- 21550123 TI - N4 component responses to pre-pulse startle stimuli in young adults: relationship to alcohol dependence. AB - Both physiological and behavioral studies provide evidence to suggest that deficits in frontal cortical control circuits may contribute to the risk for developing alcohol dependence. Event-related potential (ERP) and eye blink responses to startle and short delay prepulse-plus-startle stimuli, and psychiatric diagnoses were investigated in young adult (age 18-30 years) men (n=135) and women (n=205) Mexican Americans. Women displayed a significant increase in the amplitude of the eye blink response to both the startle and pre pulse-plus-startle stimuli. None of the psychiatric diagnoses were associated with differences in eye blink responses. ERP responses to the startle and prepulse-plus startle stimuli included a negative polarity wave at approximately 400 ms that was of the highest amplitude in the frontal leads (N4S). Women were found to have significantly higher amplitude N4S responses than men. Participants with alcohol dependence demonstrated significantly less inhibition and more facilitation of the N4S component by the pre-pulse stimuli. This finding was not associated with a diagnosis of: any other drug dependence disorder (including nicotine), anxiety or affective disorder, or conduct/antisocial personality disorder. The present study suggests that gender and a lifetime diagnosis of alcohol dependence may selectively contribute to this frontal late wave electrophysiological response to prepulse-plus-startle stimuli. PMID- 21550126 TI - Contact patterns as a risk factor for bovine tuberculosis infection in a free living adult brushtail possum Trichosurus vulpecula population. AB - The aim of this study was to identify risk factors for bovine tuberculosis (TB) in a free-roaming, capture-mark-recapture monitored possum Trichosurus vulpecula population in a 22-ha study site at Castlepoint, New Zealand from 1 April 1989 to 31 March 1994. A matched case-control design was used to evaluate the influence of sex, habitat and contact opportunities on TB risk. Cases comprised possums identified as TB-positive throughout the study period. Controls were selected from the group of possums that were captured and showed no clinical signs of TB throughout the study period. Measures derived from a social network analysis of possum capture locations such as degree, clustering coefficient (CC) and betweenness were used to represent potential contact opportunities among possums. Network analysis measures recorded for individual possums in the 12-month period before a diagnosis of TB were evaluated in a conditional logistic regression model. We found no evidence of an association between case status and the total number of possums with which there was potential contact (degree) (P=0.5). The odds of cases being exposed to unit increases in the number of TB-positive contacts was 2.50 (95% CI 1.24-5.05; P<0.01) times that of controls. This effect was conditional on the total number of potential contacts made, with a negative interaction with increasing degree. These findings indicate that potential contact with TB-positive possums increases the odds of disease whereas potential contact with large numbers of possums does not. This suggests that multiple contacts with TB-positive possum(s) are necessary for transmission of TB and this is more likely to occur in networks that are smaller. We challenge the hypothesis that contact with large numbers of individuals increases the probability of becoming TB infected and argue that individual contact behaviour is a determinant of the creation of TB foci within free-living possum populations. PMID- 21550127 TI - A functional model for monitoring equity and effectiveness in purchasing health insurance premiums for the poor: evidence from Cambodia and the Lao PDR. AB - OBJECTIVES: To assess the impact on equity and effectiveness of introducing targeted subsidies for the poor into existing voluntary health insurance schemes in Low Income Countries with special reference to cross-subsidisation. METHODS: A functional model was constructed using routine collected financial data to analyse changes in financial flows and resulting shifts in cross-subsidization between poor and non-poor. Data were collected from two sites, in Cambodia at Kampot operational health district and in the Lao People's Democratic Republic at Nambak district. RESULTS: Six key variables were identified as determining the financial flows between the subsidy and the insurance schemes and with health providers: population coverage, premium rate, facility contact rate, capitation rate, cost of treatment and changes in administration costs. Negative cross subsidization was revealed where capitation was used as the payment mechanism and where utilisation rates of the poor were significantly below the non-poor. The same level of access for the poor could have been achieved with a lower Health Equity Fund subsidy if used as a direct reimbursement of user charges by the Health Equity Fund to the provider rather than through the Community Based Health Insurance scheme. CONCLUSIONS: Purchasing premiums for the poor under these conditions is more costly than direct reimbursement to the provider for the same level of service delivery. Negative cross-subsidization is a serious risk that must be managed appropriately and the benefits of a larger risk pool (cross subsidization of the poor) are not evident. Benefits from combined coverage may accrue in the longer term with an expanded base of voluntary payers or when those with subsidized premiums are lifted out of poverty. PMID- 21550128 TI - Application of detector precision characteristics and histogram packing for compression of biological fluorescence micrographs. AB - Modern applications of biological microscopy such as high-content screening (HCS), 4D imaging, and multispectral imaging may involve collection of thousands of images in every experiment making efficient image-compression techniques necessary. Reversible compression algorithms, when used with biological micrographs, provide only a moderate compression ratio, while irreversible techniques obtain better ratios at the cost of removing some information from images and introducing artifacts. We construct a model of noise, which is a function of signal in the imaging system. In the next step insignificant intensity levels are discarded using intensity binning. The resultant images, characterized by sparse intensity histograms, are coded reversibly. We evaluate compression efficiency of combined reversible coding and intensity depth reduction using single-channel 12-bit light micrographs of several subcellular structures. We apply local and global measures of intensity distribution to estimate maximum distortions introduced by the proposed algorithm. We demonstrate that the algorithm provides efficient compression and does not introduce significant changes to biological micrographs. The algorithm preserves information content of these images and therefore offers better fidelity than standard irreversible compression method JPEG2000. PMID- 21550129 TI - Importance versus intensity of ecological effects: why context matters. AB - In any ecological study, target organisms are usually impacted by multiple environmental drivers. In plant interaction research, recent debate has focussed on the importance of competition; that is, its role in regulating plant success relative to other environmental drivers. Despite being clearly and specifically defined, the apparently simple concept of the importance of competition has been commonly overlooked, and its recognition has helped reconcile long-running debates about the dependence of competition on environmental severity. In this review, we argue that extending this formalised concept of importance to other aspects of ecology would be beneficial. We discuss approaches for measuring importance, and provide examples where explicit acknowledgement of this simple concept might promote understanding and resolve debate. PMID- 21550130 TI - The Arabidopsis thaliana natriuretic peptide AtPNP-A is a systemic regulator of leaf dark respiration and signals via the phloem. AB - Plant natriuretic peptides (PNPs) belong to a novel class of peptidic signaling molecules that share some structural similarity to the N-terminal domain of expansins and affect physiological processes such as water and ion homeostasis at nano-molar concentrations. Here we show that a recombinant Arabidopsis thaliana PNP (AtPNP-A) rapidly increased the rate of dark respiration in treated leaves after 5 min. In addition, we observed increases in lower leaves, and with a lag time of 10 min, the effect spread to the upper leaves and subsequently (after 15 min) to the opposite leaves. This response signature is indicative of phloem mobility of the signal, a hypothesis that was further strengthened by the fact that cold girdling, which affects phloem but not xylem or apoplastic processes, delayed the long distance AtPNP-A effect. We conclude that locally applied AtPNP A can induce a phloem-mobile signal that rapidly modifies plant homeostasis in distal parts. PMID- 21550131 TI - [Ocular biometry in children with hypermetropia: utility of the Lenstar LS 900 optical biometer (Haag-Streit((r)))]. AB - PATIENTS AND METHODS: Biometric measurements were recorded in the eyes of 238 children with hypermetropia (3-16 years of age), using the Lenstar 900 biometer (Haag-Streit((r))) with no contact. Four refractive groups were divided by objective refraction and spherical equivalent (group 1, more than 6.00 D; group 2, +4.50 to +99 D; group 3, +3.00 to +4.49 D; group 4, +1.50 to +2.99 D). Many parameters (i.e., axial length of the eye, anterior chamber depth, crystalline lens thickness, and central pachymetry) were analyzed in refractive groups. Two statistical analyzes were carried out: Pearson correlations on the various measurements and nonparametric tests (LSD tests). RESULTS: This statistical study showed the refractive characteristics of this pediatric population and the incidence of refraction on ocular biometry. There was a correlation between crystalline lens thickness, axial length, and anterior chamber depth. Axial length was significantly correlated in a positive way with age (r=0.332, p<0.001) and with anterior chamber depth (r=0.403, p<0.001), and in a negative way with crystalline lens thickness (r=-0.427, p<0.001). The study of refractive group parameters found a significant difference (p<0.01) between groups in axial length level. Anterior chamber depth decreased when the spherical equivalent increased. The study of crystalline lens thickness found a significant difference (p<0.01) between all four groups and pachymetry, as well as between groups 1 and 4 (p<0.05). CONCLUSION: The Lenstar LS 900 biometer (Haag-Streit((r))) provided a complete biometrical assessment of children's eye in a single and easy measurement procedure. In this pediatric population with hypermetropia, axial length of the eye was mainly correlated with spherical equivalent and other biometric parameters. The relation between these various parameters was influenced and modified by age. PMID- 21550132 TI - p16 expression: a marker of differentiation between childhood malignant melanomas and Spitz nevi. AB - BACKGROUND: Childhood malignant melanomas frequently present as nodular melanomas with Spitzoid features. Spitz nevus and Spitzoid melanoma overlap clinically and histopathologically and there have been many attempts to differentiate between them. Spitz nevi differ from melanomas by their immunohistochemical pattern of expression of cell cycle and apoptosis regulators such as the p16 protein. OBJECTIVE: The aim of this study was to evaluate in a childhood population the expression of p16 in nodular malignant melanoma of Spitzoid type, Spitz nevi, and a control group of benign compound melanocytic nevi. METHODS: We performed immunohistochemical studies for expression of p16 in 6 Spitzoid malignant melanomas, 18 Spitz nevi, and 12 compound melanocytic nevi in children younger than 18 years. Statistical analysis was used to compare p16 expression, mitotic count/mm(2), and Ki-67 index of childhood nodular malignant melanomas and Spitz nevi. RESULTS: All the childhood melanoma cases were associated with loss of p16 without any correlation with their Breslow thickness whereas all the Spitz nevi and benign melanocytic nevi had strong positive nuclear and cytoplasmic expression of p16 staining. We found a statistically significant difference in p16 expression, mitotic counts, and Ki-67 index when comparing the Spitzoid melanomas with the Spitz nevi. LIMITATIONS: This study is limited by the small number of malignant melanomas, which are known to be rare in childhood. CONCLUSION: p16 Expression in childhood nodular Spitzoid malignant melanomas and Spitz nevi, in conjunction with clinical and histopathological evaluation, may be a useful tool in differentiating between these two entities. PMID- 21550133 TI - Hereditary angioedema: diagnosis and management-a perspective for the dermatologist. AB - Hereditary angioedema (HAE) is a relatively rare, but potentially life threatening genetic disorder characterized by marked, diffuse mucosal edema that, in extreme cases, can affect the airway leading to asphyxiation. The clinical picture is similar to that of other forms of angioedema; therefore, misdiagnosis or delayed diagnosis is common. HAE is caused by a deficiency in, or a dysfunction of, C1 esterase inhibitor, which has a wide variety of physiologic functions, of which regulation of the contact (kallikrein-kinin) system is most relevant to this condition. Effective management of HAE must consider routine/long-term prophylaxis, short-term prophylaxis (in advance of predicted trauma, eg, surgical or dental procedures), and treatment of acute attacks. Historically, treatment options have been limited to controlling symptoms, but progress in understanding the pathophysiology of HAE has facilitated development of treatments, such as C1 inhibitor therapy, or drugs targeted at the bradykinin pathway, which address the underlying pathologic process. PMID- 21550134 TI - Evaluation of cutaneous angioimmunoblastic T-cell lymphoma. AB - BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) accounts for 18% of peripheral T-cell lymphomas worldwide. Skin involvement occurs in up to 50% of patients but poses a diagnostic dilemma because of the limited number of reported cases and subsequent lack of established diagnostic criteria. OBJECTIVE: The purpose of this review is to examine common clinical, histologic, and molecular findings in cases of AITL with the hope of improving the diagnostic accuracy of this challenging condition. METHODS: We present a case of AITL and conducted a review of the literature. RESULTS: The common clinical and histologic features in cases of AITL are nonspecific. However, newer immunohistochemical stains and gene rearrangement studies appear very promising at improving diagnostic capabilities. LIMITATIONS: There was a paucity of reported cases of AITL in the literature, and this review is retrospective. CONCLUSION: AITL presents with nonspecific clinical and histologic findings, but immunohistochemical stains and gene rearrangements can help establish the diagnosis. PMID- 21550135 TI - Ocular psoriasis. AB - BACKGROUND: Psoriasis is associated with several extracutaneous manifestations of which ocular complications are common. Signs and symptoms of ocular psoriasis may be subtle and overlooked. The dermatologic literature has generally underaddressed these complications; however, a thorough understanding of ophthalmic involvement is important to the comprehensive care of patients with psoriasis. OBJECTIVE: We sought to provide a complete and up-to-date clinical guide on the manifestations and diagnostic considerations of ocular psoriasis. METHODS: PubMed and Google Scholar were used to find primary resources. The MeSH database of PubMed was used to link key ocular terms with the words "psoriasis," "psoriatic arthritis," and/or various psoriasis medications. RESULTS: Ocular manifestations of psoriasis are discussed anatomically to allow for easy clinical reference. Complications include direct cutaneous effects such as eyelid involvement and blepharitis, and immune-mediated conditions such as uveitis. LIMITATIONS: Literature reviewed was primarily focused on English-language journals. In addition, older articles not included in the above electronic databases were underrepresented. CONCLUSION: Ophthalmic complications of psoriasis are numerous and affect almost any part of the eye; however, they may be easily missed. Physicians should maintain a high index of suspicion that ophthalmic symptoms in patients with psoriasis may be related to their underlying disease, even though signs and symptoms are often vague. Screening and evaluation guidelines for ocular disease should be more clearly incorporated into the already large academic framework of psoriasis research and care. PMID- 21550136 TI - Immunosuppression and sebaceous tumors: a confirmed diagnosis of Muir-Torre syndrome unmasked by immunosuppressive therapy. AB - Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis caused by mutations in the DNA mismatch repair genes MLH1 and MSH2. This case describes a patient with an extensive family history of colon cancer who experienced the onset of multiple sebaceous adenomas and carcinomas after undergoing kidney transplantation and receiving immunosuppressive therapy. The finding of deficient MSH2 expression in the immunohistochemical analysis of a sebaceous carcinoma prompted genetic testing for a systemic mutation in the mismatch repair gene. A systemic mutation of the MSH2 gene was detected and, despite the absence of a visceral malignancy, the diagnosis of MTS was made. Immunosuppression has previously been thought to play a possible role in unmasking a latent MTS phenotype in transplant recipients, but systemic mutations have not previously been analyzed. The relationship between immunosuppression and sebaceous tumors with the possibility of unmasking a MTS phenotype in transplant recipients is discussed. PMID- 21550137 TI - Use of topical tretinoin and the development of noncutaneous adverse events: evidence from a systematic review of the literature. AB - BACKGROUND: Topical retinoids have been in clinical use for the treatment of chronic skin conditions, including acne, photodamage, and psoriasis, for 30 years. OBJECTIVE: A systematic literature review was conducted to assess the incidence of noncutaneous adverse events (AE) among patients treated with topical retinoids with a focus on topical tretinoin studies reported before the Veterans Affairs Topical Tretinoin Chemoprevention trial. METHODS: Electronic literature searches were conducted in Embase and MEDLINE for literature reporting development of nonteratogenic, noncutaneous AE among patients treated with topical retinoids published through September 2008. RESULTS: The search yielded 2778 citations, of which 20 studies met inclusion criteria. Tretinoin was used in 14 of the studies. Other retinoids assessed included isotretinoin, adapalene, alitretinoin, and tazarotene. Within patients receiving topical tretinoin, 27.9% reported the occurrence of at least one noncutaneous AE. The majority of noncutaneous AE were transient and judged not to be related to tretinoin treatment. LIMITATIONS: The conclusions of this study apply largely to tretinoin compared with other topical retinoids. Many of the included trials were designed to evaluate the efficacy of topical treatment and reporting of safety events concentrated on incidence of localized AE, rather than systemic or noncutaneous events. CONCLUSION: We found no clear evidence of a relationship between the use of topical tretinoin and the development of noncutaneous AE before a recent report of excess mortality in a clinical trial. The majority of noncutaneous AE reported by patients receiving topical retinoids consisted of nonsevere, nonspecific symptoms that were judged not to be related to treatment. PMID- 21550138 TI - Screening for OPTN mutations in amyotrophic lateral sclerosis in a mainly Caucasian population. AB - Mutations in the optineurin (OPTN) gene cause amyotrophic lateral sclerosis (ALS). We previously reported 3 types of OPTN mutation in Japanese ALS subjects. Here, to identify the OPTN mutations in individuals of different ethnicity, we screened 563 sporadic ALS (SALS) subjects and 124 familial ALS (FALS) subjects who were mainly Caucasian. We found a c.964T>C synonymous variation in exon 8. However, we could not find the meaningful OPTN mutations. The results indicate that OPTN mutations causing ALS are rare, especially in mainly Caucasian ALS subjects. PMID- 21550139 TI - Reply to "Diagnosis of progressive supranuclear palsy: can measurement of tau forms help?". PMID- 21550140 TI - [Is there a safe cold ischemia time interval for the renal graft?]. AB - OBJECTIVE: It is aimed to characterize the true relationship of the cold ischemia time (CIT) with graft survival and with the principal post-transplantation events. MATERIAL AND METHODS: We analyzed 378 kidney transplants, studying the relationship of the CIT with graft survival using a univariate analysis according to the COX model and seeking the optimum cutoff according to the Kaplan-Meier method and log-rank test. The relationship between CIT and the principal events of the post-transplant was studied using the binary logistic regression. RESULTS: The mean follow-up of all the group was 77.8 months (+/- 51 SD) and the mean CIT was 14.8 hours (+/- 5.1 SD). The univariate analysis revealed that the CIT was not related with the graft survival as a continuous variable (OR=1.04; 95% CI: 0.9-1.08; p>0.05). On establishing the cutoff at 18 hours, we found differences in the actuarial survival. Survival at 5 years was 91% with CIT < 18 h versus 84% with CIT >18 h. Each hour of cold ischemia increased risk of delay in the graft function by 10% (OR=1.1; 95% CI: 1.05-1.15; p<0.001) and also conditioned a greater incidence of acute rejection (41.5% vs. 55.3%; p=0.02) and less time to the first rejection episode (72.6 days+/-137 vs. 272.2 days+/-614.8; p=0.023) after 18 hours. The CIT did not seem to be related (p<0.05) with the rest of the post-transplantation events, such as surgical complications or hospital admissions. CONCLUSIONS: In our experience, cold ischemia under 18 hours does not seem to negatively affect graft survival. PMID- 21550141 TI - [Bone mineral density change: comparison between prostate cancer patients with or without metastases and healthy men (a North African ethnic group)]. AB - AIM: To evaluate total body bone mineral density and regional bone mineral density in patients with prostate cancer with and without metastases, and to correlate them with bone scintigraphy findings. PATIENTS AND METHODS: 135 patients with prostatic carcinoma and 50 healthy subjects were investigated with bone scintigraphy and dual-energy X-ray absorptiometry. The bone scintigraphic findings were classified as normal (score 0: n=55), abnormal but not typical for metastases (score 1: n=45), and typical pattern of metastases (score 2: n=35). RESULTS: : The patients with bone metastases prostate cancer had significantly higher total bone mineral density and regional bone mineral density of trunk and pelvis than healthy controls and prostate cancer patients without bone metastases. There was a significant positive correlation between bone scan score and total bone mineral density and regional bone mineral density of trunk and pelvis (r=0.328; P<0.05; r=0.60; P<0.001; r=0.480; P<0.001, respectively). CONCLUSION: Bone metastasis is a major cause of morbidity in prostatic cancer, bone loss during hormonal treatment is currently effective. Our results show that patients of prostate cancer with bone metastases have increased bone mineral density (BMD) in the pelvis and trunk, possibly because of a predominance of osteoblastic over osteolytic metastases demonstrated by (99m)Tc MDP bone scan. PMID- 21550142 TI - [Risk factors for failure after transobturator vaginal tape for urinary incontinence]. AB - OBJECTIVE: To identify risk factors leading to treatment failure in a sample of 302 women with stress urinary incontinence (SUI) treated by transobturator vaginal tape (TOT) with a medium follow-up of 4 years (range 1-6). MATERIAL AND METHODS: A population based cohort study with prospectively data from 302 women, aged 41-81 years underwent TOT between April 2003-November 2010. Data were collected by validated questionnaire on urinary incontinence, the International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF), and clinical data-records. Continence was achieved in 262 (Group A) and 40 continued with incontinence (Group B). We investigated the relationship between age, SUI evolution time, type and number of childbirths (eutocic, dystocic, nulliparous, multiparous status) and medical and/or surgical backgrounds. The ICIQ-SF questionnaire was used to describe whether the surgery outcomes were successful or not. RESULTS: Group A were younger (p=0.0001), had less SUI evolution time (p=0.017); more eutocic childbirths (p=0.000018). Group B had more dystocic childbirth (p=0.022), previous tension free vaginal tape (TVT) or TOT (p=0.03.), antidepressant-anxiolytic drugs (p=0.003), antihypertensive drugs (p=0.0005), type 1 diabetes (p=0.02), arterial hypertension (p=0.0007), respiratory diseases (p=0.025). Differences were not found with regard to nulliparous (p=0.701), multiparous status (p=0.42), obesity (p=0.18), intestinal disorders (p=0.59), oophorectomy (p=0.19), caesarean (p=0.17), prolapse surgery (p=0.29), hysterectomy (p=0.57), allergies (p=0.48), arthritis (p=0.22), arthrosis (p=0.44), depression (p=0.74), type 2 diabetes (p=0.44), smoking patterns (p=0.28), fibromyalgia (p=0.47). CONCLUSIONS: Elderly women, with long evolution SUI, dystocic delivery, previous TVT or TOT appear as independent risk factors associated to TOT failure. These factors may make the indication of another surgical approach recommendable. PMID- 21550143 TI - [Risk factors in the failure of surgical repair of pelvic organ prolapse]. AB - INTRODUCTION: Pelvic organ prolapse (POP) surgery has variable results of recurrence and complications. We have aimed to analyze our outcomes in order to know the factors associated with anatomical and functional failure in POP surgery. MATERIAL AND METHODS: A retrospective study of 69 patients who underwent POP surgery at our hospital was performed. Registered variables were: Age, BMI, number of deliveries, previous pelvic surgery, menopause, quality of life, urinary incontinence, associated frequency-urgency symptoms, high POP stage, vaginal compartments repaired, type of mesh, urethro-suspension and vaginal hysterectomy during POP surgery and its complications. Patients were evaluated at 1, 6 and 12 months post-surgery. The technique was considered as failed when relapse or mesh erosion occurred and when the patient is not satisfied or there was relapse. The sample is described, analyzing the relationship of the variables studied by univariate analysis (Chi square and Mann-Whitney U test) and a study was made of which variables may have predictive value in the failure of the repair (multiple logistic regression). RESULTS: Surgery failed in 17 patients during the follow-up at one year. BMI (29.6+/-2.03 vs 27.1+/-3.32), delivery number (3.4+/-0.71 vs. 2.8+/-1.88), menopause, frequency- urgency symptoms and number of vaginal compartments repaired were associated with treatment failure although only BMI, delivery number and frequency-urgency symptoms were defined as independent predictive variables when the logistic regression was carried out. CONCLUSIONS: Overweightness-obesity, previous delivery number and frequency urgency symptoms before surgery are factors associated to anatomical and functional failure after POP repair. PMID- 21550144 TI - [Climate and epidemiological characteristics of renal colic attendances in an urban setting in Spain]. AB - OBJECTIVES: To address the real incidence of RC episodes in our setting and its relationship with several epidemiological, seasonal and climatic factors. MATERIAL AND METHODS: We analyzed 156,687 attendances in the emergency unit of Hospital Infanta Cristina (Parla, Madrid, Spain), from the opening of the unit in 07/04/2008 to the date of analysis (28/03/2010). Date of birth, sex, history of previous urinary lithiasis episodes, main cause and date of attendance were collected. Daily climate parameters (maximum daily temperature and percent relative humidity) were recorded. RESULTS: A total number of 1,866 RC episodes (1.19% of all attendances) were recorded during the study period. Age ranged from 15 to 94 years, median 39. RC episodes were more prevalent in male population (58.4% vs 41.6% in females respectively, p<0.001). No differences were observed with regard to previous history of RC. A modest but significant rise in RC incidence was observed during summer and autumn. No significant correlation was observed between monthly or seasonal number of RC attendances and the climatic parameters studied. CONCLUSIONS: RC incidence in our setting is similar to the previously reported in the literature. A modest but significant higher incidence of renal colic episodes were observed during summer and autumn seasons, although no significant relationship was attributed to temperature and humidity values. Absence of dramatic seasonal changes in incidence can be explained by the "non extreme" weather conditions in the studied setting. PMID- 21550145 TI - [Current treatment of hepatitis B infection: where do the new nucleos(t)ide analogues fit in?]. AB - One of the most important advances made in the treatment of chronic hepatitis B infection has been the development of nucleos(t)ide analogues. The first antiviral agents used had limited efficacy due to the high resistance rate. However, in the last few years, new agents (tenofovir, entecavir) have been developed with greater antiviral potency and a lower resistance rate. Consequently, these agents are considered to be the treatment of choice in the most recent clinical guidelines. Nevertheless, interferon may still play an important role in the treatment of hepatitis B in selected patients. Moreover, in some contexts, such as renal insufficiency, pregnancy or immunosuppression, the role of the new oral antiviral agents has not been precisely defined. The present review analyzes these aspects, as well as some of the particular features of the management of patients treated with nucleos(t)ide analogues. PMID- 21550146 TI - 99mTc-HMPAO labelled white blood cell scintigraphy in the diagnosis and monitoring of response of the therapy in patients with active bronchiectasis. AB - AIM: The aim of this study was to assess the role of labelled leukocyte scintigraphy in the diagnosis and monitorization of response to therapy of patients with active bronchiectasis. MATERIAL AND METHODS: Twenty patients underwent (99m)Technetium hexamethylpropyleneamine oxime ((99m)Tc-HMPAO) labelled white blood cell (WBC) scintigraphy. A second scintigraphy was performed in 13 patients at 10 day of the treatment. Regional (99m)Tc-HMPAO WBC uptake and radiologic imaging findings (high resolution computed tomography or Chest X-Ray) in the lungs were classified into 3 categories in 6 lung areas. scintigraphic, radiological and clinical disease scores were calculated for all patients. RESULTS: An abnormal accumulation was visually observed in 19 of 20 patients on the pre-treatment scans, the scintigraphy showing 95% sensitivity. A significant difference was found between early and late ratios (P=0.001) in the pre-treatment scans. The infected areas revealed a significant decrease in uptake ratios on the post-treatment scans compared to the pre-treatment scans (P=0.001). However, no significant correlation was determined between clinical and radiological scores, clinical and scintigraphic scores and also between scintigraphic and radiological scores (P >= 0.05). CONCLUSIONS: (99m)Tc-HMPAO WBC scintigraphy may be a useful tool to evaluate response to therapy in patients with active bronchiectasis. PMID- 21550147 TI - In search of patterns over physicochemical properties and pharmacological activities for a set of [MCl2(thiosemicarbazone)] complexes (M=Pt/Pd): support for multiple mechanisms of antichagasic action excluding DNA-bonding in vivo? AB - In order to rationalize the available data related to the antichagasic activity of Pt/Pd complexes containing 5-nitrofurylthiosemicarbazones, in the present work we carried out a PCM/DFT comparative characterization of 16 Pt(II)/Pd(II) compounds of general formula [MCl(2)L] and the corresponding 5 nitrofurylthiosemicarbazone ligands (L) using multivariate techniques to sort and classify them and to search for patterns correlating the biological activity with calculated physicochemical descriptors. The data allow us to rationally propose that these compounds might act through dual or even multiple mechanisms of action, with preferred paths that depend on both the nature of metal and ligand. Moreover, these results suggest that the complexes in the set would not react in vivo with DNA, being biotransformed earlier, before gaining access to nuclear DNA in the cell. The binding mode and inhibitory potency of a selection of metal complexes and ligands with Trypanosoma cruzi cruzipain and trypanothione reductase enzymes is also modeled through molecular docking. PMID- 21550148 TI - Possible effect of solar tides on radon signals. AB - Large temporal variations of radon ((222)Rn) are often encountered in air in the geologic environment, at time scales from diurnal to annual. Interpretations as to the nature of these variations, unique to (222)Rn, often invoke either above surface atmospheric variations, or the influence of subtle active geodynamic processes. So far the eventual geophysical drivers of the variation of (222)Rn as well as its specific qualities enabling this temporal variation are not known. New insight on the temporal variation of (222)Rn is gained by experimental simulation in confined air. Two short laboratory experiments, and one external experiment lasting over 3 years, were performed inside closed canisters and using natural and commercial (222)Rn sources. Internal and external gamma and alpha detectors recorded variations of the radiation, up to around 20% of the equilibrium level. Radon signals of different time scale occurred with: a) periodic annual and semi-annual signals; b) non-periodic multi-day signals; c) periodic daily signals. Similar, related, inversely-related and dissimilar temporal patterns were manifested in the measured time series of the different sensors. Diurnal periodicity was dominated by the solar tide components S1, S2 and S3, exhibiting unlike relative amplitudes and different phases at the different sensors. A compound association occurs among the amplitudes and phases of the diurnal and seasonal periodicities of the daily (222)Rn signal, linking the periodic phenomena to the rotation of earth around its axis and around the sun. (222)Rn variation patterns in the frequency-time domain cannot be driven by the corresponding atmospheric variation patterns. These results, obtained under static and isolated conditions, are in disagreement with the expected radioactive equilibrium and its spatially uniform expression within and around the experimental volume. The external influence which drives the daily signals evolving from (222)Rn inside the canister is non-atmospheric and seemed to be from a remote source and traversed a 5-cm thick lead shield. The similarities with observations on (222)Rn signals from upper crustal levels imply that such an external influence, possibly as a component of solar irradiance, drives the (222)Rn signals to a depth of at least 100 m. New combined prospects for the research are indicated in terms of the radioactive behavior of (222)Rn in air and in terms of an above surface geophysical driver for this behavior. PMID- 21550149 TI - The International Confederation of Midwives: Global Standards for Midwifery Education (2010) with companion guidelines. AB - OBJECTIVE: a 2-year study was conducted to develop Global Standards for Midwifery Education in keeping with core documents of the International Confederation of Midwives. Elements of the standards were based on evidence available in the published and unpublished literature. Companion Guidelines to assist in implementing the standards were also developed. DESIGN: a modified Delphi survey process was conducted in two rounds following item validation by a panel of midwifery education experts. SETTING: a global survey conducted in 88 countries. PARTICIPANTS: midwifery educators and clinicians associated with midwifery education located in any of the ICM member association countries. Additional participants included an Expert Midwifery Resource Group, other Key Stakeholders, midwifery regulators and policy makers. A total of 241 individuals from 46 ICM member association countries and ten non-member countries responded to one or both of the survey rounds. MEASUREMENTS: survey respondents expressed an opinion on whether to retain or to delete any of the proposed components of the standards. Version one had 109 proposed components and version two had 111 items for consideration. FINDINGS: a majority consensus of .80 was required to accept an item without further deliberation. The Education Standards Task Force (expert panel) made final decisions in the four instances where this level of consensus was not reached, retaining all four items. The panel also amended the wording of selected items or added new items based on feedback received from survey respondents. The final document contains 10 Preface items, 35 glossary terms, and 37 discrete standards with 27 sub-sections. PMID- 21550150 TI - Biosorption of divalent Pb, Cd and Zn on aragonite and calcite mollusk shells. AB - The potential of using mollusk shell powder in aragonite (razor clam shells, RCS) and calcite phase (oyster shells, OS) to remove Pb(2+), Cd(2+) and Zn(2+) from contaminated water was investigated. Both biogenic sorbents displayed very high sorption capacities for the three metals except for Cd on OS. XRD, SEM and XPS results demonstrated that surface precipitation leading to crystal growth took place during sorption. Calcite OS displayed a remarkably higher sorption capacity to Pb than aragonite RCS, while the opposite was observed for Cd. However, both sorbents displayed similar sorption capacities to Zn. These could be due to the different extent of matching in crystal lattice between the metal bearing precipitate and the substrates. The initial pH of the solution, sorbent's dosage and grain size affected the removal efficiency of the heavy meals significantly, while the organic matter in mollusk shells affected the removal efficiency to a lesser extent. PMID- 21550151 TI - Responses of a soil bacterium, Pseudomonas chlororaphis O6 to commercial metal oxide nanoparticles compared with responses to metal ions. AB - The toxicity of commercially-available CuO and ZnO nanoparticles (NPs) to pathogenic bacteria was compared for a beneficial rhizosphere isolate, Pseudomonas chlororaphis O6. The NPs aggregated, released ions to different extents under the conditions used for bacterial exposure, and associated with bacterial cell surface. Bacterial surface charge was neutralized by NPs, dependent on pH. The CuO NPs were more toxic than the ZnO NPs. The negative surface charge on colloids of extracellular polymeric substances (EPS) was reduced by Cu ions but not by CuO NPs; the EPS protected cells from CuO NPs toxicity. CuO NPs-toxicity was eliminated by a Cu ion chelator, suggesting that ion release was involved. Neither NPs released alkaline phosphatase from the cells' periplasm, indicating minimal outer membrane damage. Accumulation of intracellular reactive oxygen species was correlated with CuO NPs lethality. Environmental deposition of NPs could create niches for ion release, with impacts on susceptible soil microbes. PMID- 21550152 TI - Socioeconomic influences at different life stages on health in Guangzhou, China. AB - In long-term developed countries socioeconomic position across the life course is positively associated with health. We examined these associations in a developing country with a history of efforts to reorganize the social hierarchy. Taking a life course perspective, we used multi-variable logistic regression to assess the association of socioeconomic disadvantage at four life stages (measured by parental possessions, education, longest-held occupation and current household income) with self-rated health, chronic obstructive pulmonary disease (COPD) and metabolic syndrome in 20,086 Chinese adults aged >=50 years from the Guangzhou Biobank Cohort Study (2005-2008). Model comparisons were used to determine whether the number of exposures to disadvantage (accumulation of risk) was more important than the life stage of exposure (critical periods). Socioeconomic disadvantage across the life course was associated with poor self-rated health, COPD and, in women only, with metabolic syndrome. Adjusting for adult health related behavior (smoking, alcohol use and physical exercise) altered these associations very little. Associations between socioeconomic disadvantage and health in this Southern Chinese population were broadly similar to those found in Western countries in terms of the accumulation of disadvantage across the life course. However, longest-held occupation was not independently associated with adult health and socioeconomic disadvantage was not associated with metabolic syndrome in men. This suggests that the mechanisms linking socioeconomic position to health in China may be different from those in Western populations and may require context-specific policy interventions. PMID- 21550153 TI - Understanding the interplay of time, gender and professionalism in hospital medicine in the UK. AB - Regulation of time, management of gender equality and discourses of professionalism are often studied in isolation from one another in the context of hospital medicine. Drawing on qualitative analysis of 20 interviews with senior National Health Service (NHS) hospital doctors in Wales, UK, we demonstrate the complex interplay between professionalism and regulation of time and gender in hospital medicine. We examine the connectivity of gender and time in norms about professional behaviour in hospital medicine and demonstrate how a certain discourse of professionalism is used in turn to retain and reproduce a temporally regulated gender order at work. Based on our findings, and congruent with the spirit of modernisation of management of human resources in healthcare, we offer new directions for gender equality, regulation of time and development of professionalism in hospital medicine. PMID- 21550154 TI - Using the proximal ulna as a novel site for autogenous bone graft harvesting. PMID- 21550155 TI - Buccal to lingual transalveolar implant placement for all on four immediate function in posterior mandible: report of 10 cases. AB - PURPOSE: A retrospective study was done to evaluate the use of transalveolar implant placement in the mandible posterior to the mental nerve. MATERIALS AND METHODS: Ten patient charts were reviewed of twenty implants placed transalveolarly with evaluation of function, osseointegration, and bone level for 1 year by unregistered periapical x-rays. RESULTS: Ten patients which received twenty transalveolar implants were followed for 1 year. One implant failed. There were no significant complications encountered from the procedure. CONCLUSION: All On Four treatment of mandibles with relatively anterior mental nerve locations may be successfully treated with transalveolar implant placement posterior to the foramen. PMID- 21550156 TI - Leech therapy in reconstructive maxillofacial surgery. AB - PURPOSE: Corrective plastic surgery is indicated after accidents, burns, cancer surgery, or postoperative wound healing disorders with large tissue defects. The range of reconstructive techniques includes local skin flaps, pedicle grafts, and microvascular anastomosed flaps in the case of large defects. Main complications such as arterial and venous insufficiency caused by a vessel collapse or a vascular spasm are reported regularly in the area of anastomosed vessels and are the concern of any surgeon. Today, leeches are used if wound healing is at risk because of hemodynamic imbalance or a venous insufficiency. PATIENTS AND METHODS: A retrospective evaluation of 148 patients who underwent medical leech therapy in the case of local or pedicaled flaps and some patients who had undergone reconstruction with microvascular flaps from 2005 and 2010 was conducted. Our sample had the typical symptoms of venous congestions of their flaps, despite suture removal, relief of pressure on the flap, and the elimination of a hematoma beyond the flap after surgery. Medical leech therapy was used in these cases. RESULTS: Our series has confirmed the excellent and predictable healing after medical leech therapy for local and microsurgical anastomosed flaps in the case of venous congestion. CONCLUSION: Leech therapy should be considered as a reliable additional procedure and an advantage in maxillofacial and plastic reconstructive surgery to remedy complications resulting from a hemodynamic imbalance or venous insufficiency in the immediate postoperative period. PMID- 21550157 TI - Oral piercings: immediate and late complications. AB - PURPOSE: Oral piercings have a long history as part of religious, cultural, or sexual symbolism in many traditional tribes; currently, these ornaments have wide acceptance among young people. Several oral and systemic complications may be associated with this practice; however, limited data related to these complications can be obtained in the literature. PATIENTS AND METHODS: This study includes 42 cases of oral piercings in 39 young adults, who were using or had used oral piercings, and the complications associated with their use. RESULTS: Immediate complications occurred in 29 cases, including excessive bleeding (69%) and pain (52.3%) as the most representative. Two cases of syncope were found. Late complications related to the piercing insertion site were observed in 97.6% of cases, with pain and swelling being present in 92.9% and 61.9% of cases, respectively. Dental pain and lacerations on the tongue represented the most prevalent complications associated with the surrounding tissues, accounting for 33.3% and 31% of cases. CONCLUSIONS: The use of oral piercings is related to a series of mainly local complications, and individuals who decide to use piercings should be aware of such complications. Individuals wishing to get a part of their body pierced should do so with qualified professionals and should regularly visit the dentist so that a regular control is achieved, thus ensuring the early detection of the adverse effects associated with this practice. PMID- 21550158 TI - Can autologous platelet-rich plasma gel enhance healing after surgical extraction of mandibular third molars? AB - PURPOSE: This investigation assesses the effect of platelet-rich plasma (PRP) gel on postoperative pain, swelling, and trismus as well as healing and bone regeneration potential on mandibular third molar extraction sockets. PATIENTS AND METHODS: A prospective randomized comparative clinical study was undertaken over a 2-year period. Patients requiring surgical extraction of a single impacted third molar and who fell within the inclusion criteria and indicated willingness to return for recall visits were recruited. The predictor variable was application of PRP gel to the socket of the third molar in the test group, whereas the control group had no PRP. The outcome variables were pain, swelling, and maximum mouth opening, which were measured using a 10-point visual analog scale, tape, and millimeter caliper, respectively. Socket healing was assessed radiographically by allocating scores for lamina dura, overall density, and trabecular pattern. Quantitative data were presented as mean. Mann-Whitney test was used to compare means between groups for continuous variables, whereas Fischer exact test was used for categorical variables. Statistical significance was inferred at P < .05. RESULTS: Sixty patients aged 19 to 35 years (mean: 24.7 +/- 3.6 years) were divided into both test and control groups of 30 patients each. The mean postoperative pain score (visual analog scale) was lower for the PRP group at all time points and this was statistically significant (P < .05). Although the figures for swelling and interincisal mouth opening were lower in the test group, this difference was not statistically significant. Similarly, the scores for lamina dura, trabecular pattern, and bone density were better among patients in the PRP group. This difference was also not statistically significant. CONCLUSION: The PRP group recorded reduced pain, swelling, and trismus as well as enhanced and faster bone healing compared with those in the control. Hence the study showed that topical application of PRP gel has a beneficial effect in enhancing socket healing after third molar surgery. PMID- 21550160 TI - [Aortic valve sparing in 120 patients with aortic root aneurysms]. AB - INTRODUCTION AND OBJECTIVES: Several aortic valve sparing techniques have been described for the treatment of aortic root aneurysms. We report our experience using the reimplantation technique in 120 patients. METHODS: Between March 2004 and October 2010, 120 patients with aortic root aneurysms underwent David operations. Of these, 51 were diagnosed with Marfan syndrome. Mean patient age was 31 +/- 12 years. The mean diameter of the sinuses of Valsalva was 51 +/- 5 mm and moderate/severe aortic regurgitation was present in 16% of these patients. In the other 69 patients mean age was 56 +/- 14 years, the mean diameter of the sinuses of Valsalva was 53 +/- 7 mm and moderate/severe aortic regurgitation was present in 66%. A bicuspid aortic valve was presented in 14 cases. RESULTS: Hospital mortality was 1.7%. Mean follow-up was 37 +/- 21 months; 94% of the patients survived and 96% had an aortic regurgitation below grade II during 5 years of follow-up. One patient required re-operation because of severe aortic regurgitation. No endocarditis or thromboembolic complications have been documented, and 96% of the patients did not receive any anticoagulation therapy. CONCLUSIONS: Short- and mid-term results with the reimplantation technique for aortic root aneurysms are excellent. This technique prevents the need for chronic anticoagulation treatment as well as the complications arising from mechanical prostheses, and it should be the treatment of choice for young patients. PMID- 21550159 TI - Navigation-guided harvesting of autologous iliac crest graft for mandibular reconstruction. PMID- 21550161 TI - [Genetic variants, cardiovascular risk and genome-wide association studies]. AB - Genome-wide association studies have shown an association between single nucleotide polymorphisms (SNPs) and coronary artery disease and myocardial infarction in new chromosomal regions: 1p13.1, 2q36.3, 9p21 and 10q11.21. The SNPs from the 9p21 region constitute a risk haplotype due to the strong linkage disequilibrium in this area. These SNPs have been extensively replicated in several European and Asian populations, and are associated with other pathologies such as abdominal aortic and intracranial aneurysms, and with intermediate phenotypes such as arterial stiffness and coronary calcium. The risk haplotype of 9p21 is located in a region without annotated genes, near CDKN2A and CDKN2B, known tumor suppressor genes encoding for inhibitors of cell cycle kinases. In the remaining regions the SNPs are located in genes with known roles in atherosclerosis as well as others with new roles. It has been shown that the incorporation of genetic information in the form of SNPs slightly improves the prediction of long-term cardiovascular risk estimated by the Framingham function, allowing the reclassification of individuals into more precise categories. Gene expression studies have found that expression levels of CDKN2A/CDKN2B/ANRIL are co-regulated and associated with the risk haplotype and atherosclerosis severity. PMID- 21550162 TI - Effects of sustained abdominal aorta compression on coronary perfusion pressures and restoration of spontaneous circulation during cardiopulmonary resuscitation in swine. AB - OBJECTIVES: The present study was undertaken to explore whether sustained abdominal aorta compression-cardiopulmonary resuscitation (SAAC-CPR), as a means, can raise coronary perfusion pressure (CPP) as well as restoration of spontaneous circulation (ROSC) during CPR. In the present study, we hypothesised that SAAC CPR elevates CPP during CPR and improves ROSC, without causing liver laceration. METHODS: Animals were randomised into one of two groups (Standard CPR and SAAC CPR). Ten domestic swine (22-25 kg) were anaesthetised, intubated and mechanically ventilated. Ventricular fibrillation was induced, and after 3 min of untreated ventricular fibrillation, the animals were treated with standard CPR (with simplex chest compression (SCC) and epinephrine) or SAAC-CPR (SCC with sustained abdominal aorta compression, without epinephrine). CPP and ROSC were compared. RESULTS: SCC with sustained abdominal aorta compression (SCC+SAAC) significantly increased CPP in comparison with SCC during CPR (p<0.05). The increase in CPP with SCC+SAAC is equivalent to that achieved with epinephrine (p>0.05). All animals in the standard CPR and SAAC-CPR groups restored spontaneous circulation. No liver damage was found in post-mortem examinations of the swine subjects. CONCLUSIONS: During CPR, non-invasive SAAC can rapidly and reversibly raise the CPP as much as can epinephrine and is especially suitable for out-of-hospital CPR. PMID- 21550163 TI - Mite exposure in a Spanish Mediterranean region. AB - BACKGROUND: Knowledge of the domestic mite fauna and allergen levels is important for a correct diagnosis and treatment of mite allergy. Our objectives were to describe the domestic mite fauna in the region of Murcia, Spain, to quantify mite allergens in dust samples obtained from mattresses of this area and to assess the influence of geographical, climatic and dwelling factors. METHODS: Dust samples were collected in a transversal descriptive study from mattresses of 51 patients who went to the Allergology Service, and from mattress of 81 neighbours or family members of these patients. A questionnaire about home environment was filled in and obtained by all participants. Mite identification was done by light microscopy and allergen determinations (Der p 1 and Der f 1) by monoclonal antibodies. RESULTS: Sixteen mite species were identified in the 132 dust samples collected. The most frequent species were Dermatophagoides farinae (36% of the samples), Dermatophagoides pteronyssinus (32%) and Tyrophagus putrescentiae (5.3%). There were significant differences among climatic regions. The coastal sector had greater mite abundance, being D. pteronyssinus more frequent and abundant than D. farinae. In inland areas D. farinae was the predominant mite species. Allergen levels correlated with the concentration of Dermatophagoides, with higher levels detected in coastal regions. Average annual temperature was the main outdoor factor that correlated with higher mite concentrations. Indoor main predictor of higher levels of mites was the presence of obvious signs of humidity in the home. CONCLUSION: This study demonstrates the existence of a mite fauna dominated by D. pteronyssinus and D. farinae with a strong influence of climatic factors and residential characteristics. PMID- 21550164 TI - Oxidative stress status and plasma trace elements in patients with asthma or allergic rhinitis. AB - INTRODUCTION: This study was conducted to evaluate the oxidant/antioxidant balance (oxidative stress status) and plasma essential trace element levels in patients with bronchial asthma or allergic rhinitis. METHODS: A total of 94 individuals consisting of 19 allergic asthmatics; 17 non-allergic asthmatics; 22 patients with allergic rhinitis; and 36 healthy control people were enrolled into this study. Superoxide dismutase (CuZnSOD) and glutathione peroxidase (GSH-Px) activity as antioxidant defence mechanism parameters, along with malondialdehyde (MDA) as a marker of lipid peroxidation, were determined in erythrocytes of patient groups and controls. Plasma copper and zinc levels were also determined in all groups. RESULTS: CuZnSOD activity was significantly lower in all groups of patients (p<0.001 for allergic asthmatics, p=0.008 for allergic rhinitis patients, and p<0.001 for non-allergic asthmatics) when compared to those of controls. Erythrocyte GSH-Px enzyme activity was not different when compared to that of the control group. Similarly, the patient groups had no difference from those of the controls with respect to erythrocyte MDA levels. While plasma Cu levels in all asthmatic patients were not different from those of the controls, allergic rhinitis patients had significantly elevated (p<0.001) Cu levels compared to those of the controls. No statistically significant difference was established between patient groups and controls with respect to plasma zinc levels. CONCLUSION: While defective CuZnSOD activity observed in all patients groups was expected to cause an increase in lipid peroxidation indicated by high MDA levels in these patients groups, the fact that MDA levels were not different from those of controls in all patient groups indicates that other components of anti-oxidant defence system preserve their functions in these patients. On the other hand, statistically significant difference between all patients groups and controls with respect to trace elements was only observed in allergic rhinitis patients who had higher levels of Cu than those of controls. PMID- 21550165 TI - Framing community forestry challenges with a broader lens: case studies from the Brazilian Amazon. AB - Community forestry initiatives have been shown to reduce rural poverty while promoting the conservation and sustainable use of forests. However, a number of challenges face communities wanting to initiate or maintain formal, community based forest management. Through a grounded theory approach, this paper uses three case studies of community forest management models in the eastern Amazon to create a framework showing challenges faced by communities at different phases of formal management. The framework shows that, in the development phase, four root problems (land ownership, knowledge acquisition, community organization, and adequate capital) need to be addressed to obtain legal management permission. With this permission in hand, further challenges to operationalization are presented (deterring illegal loggers, maintaining infrastructure, obtaining necessary managerial skills and accessing markets). The interrelatedness of these challenges emphasizes that all challenges need to be addressed in a holistic manner for communities to maintain a profitable and self-sufficient operation. This contradicts current development approaches that only address part of this framework. The framework proposed here can be used as a starting point for community forestry initiatives in other regions. PMID- 21550166 TI - The role of abiraterone acetate in the management of prostate cancer: a critical analysis of the literature. AB - CONTEXT: The development of agents targeting androgen signalling holds promise for men with castration-resistant prostate cancer (CRPC). OBJECTIVE: The emerging role of abiraterone acetate (AA), a novel, orally administered androgen synthesis inhibitor, is critically analysed. EVIDENCE ACQUISITION: Data were acquired from critically important original research published in peer-reviewed literature or presented at conferences conducted by the American Society of Clinical Oncology and the European Society of Medical Oncology. EVIDENCE SYNTHESIS: The major findings are addressed in an evidence-based, objective, and balanced fashion. CONCLUSIONS: AA specifically inhibits CYP17 and substantially reduces serum androgen levels without inducing significant adrenal insufficiency. A phase 3 trial reported a significant extension of survival in metastatic CRPC with AA plus prednisone compared to prednisone alone following docetaxel. The primary toxicity of mineralocorticoid excess is manageable. The addition of low-dose corticosteroids to AA may be necessary for controlling symptoms of mineralocorticoid excess. PMID- 21550167 TI - Genital condylomata are not the human papilloma virus male infection burden. PMID- 21550168 TI - MicroRNA-143 functions as a tumor suppressor in human bladder cancer T24 cells. AB - MicroRNA (miR)-143 and -145 were down-regulated in human bladder cancer T24 cells. The enforced expression of miR-143 induced growth-suppression in T24 cells through down-regulation of ERK5 and Akt expression at translational level, and chemically-modified synthetic miR-143 (miR-143/BP) exhibited a greater growth inhibitory effect than wild-type miR-143. In addition, the synthetic miR-143/BP induced apoptotic cell death in some of the transfected cells. Furthermore, co treatment with the synthetic miR-143/BP and cisplatin showed the additive growth suppressing effect on T24 cells. These findings suggest that the chemically modified synthetic miR-143 functions as a tumor suppressor in T24 cells by targeting ERK5 and/or Akt. PMID- 21550169 TI - Assessment of the generation of chlorinated byproducts upon Fenton-like oxidation of chlorophenols at different conditions. AB - Homogeneous Fenton-like (H(2)O(2)/Fe(3+)) oxidation proved to be highly efficient in the degradation of monochlorophenols but some important issues need to be considered depending on the operating conditions. When using the stoichiometric amount of H(2)O(2) and a dose of Fe(3+) in the range of 10-20mg/L, complete breakdown of 4-CP up to CO(2) and short-chain acids was achieved. Nevertheless, when substoichiometric amounts of H(2)O(2) or lower concentrations of iron were used, significant differences between the TOC measured and the calculated from the identified species were found. These differences were attributed to condensation byproducts, including chlorinated species, formed by oxidative coupling reactions. PCBs, dioxins and dichlorodiphenyl ethers were identified. A solid residue was also formed consisting mainly in carbon, oxygen and chlorine including also Fe. The occurrence of these highly toxic species must be carefully considered in the application of Fenton oxidation to wastewaters containing chlorophenols. The possibility of reducing costs by lowering the H(2)O(2) dose below the stoichiometric one needs to take this into account. PMID- 21550170 TI - Translational challenges and analgesic screening assays. PMID- 21550172 TI - Evidence on acupuncture safety needs to be based on large-scale prospective surveys, not single case reports. PMID- 21550171 TI - Neonatal tissue damage facilitates nociceptive synaptic input to the developing superficial dorsal horn via NGF-dependent mechanisms. AB - Tissue injury during a critical period of early life can facilitate spontaneous glutamatergic transmission within developing pain circuits in the superficial dorsal horn (SDH) of the spinal cord. However, the extent to which neonatal tissue damage strengthens nociceptive synaptic input to specific subpopulations of SDH neurons, as well as the mechanisms underlying this distinct form of synaptic plasticity, remains unclear. Here we use in vitro whole-cell patch clamp recordings from rodent spinal cord slices to demonstrate that neonatal surgical injury selectively potentiates high-threshold primary afferent input to immature lamina II neurons. In addition, the increase in the frequency of miniature excitatory postsynaptic currents after hindpaw incision was prevented by neonatal capsaicin treatment, suggesting that early tissue injury enhances glutamate release from nociceptive synapses. This occurs in a widespread manner within the developing SDH, as incision elevated miniature excitatory postsynaptic current frequency in both GABAergic and presumed glutamatergic lamina II neurons of Gad GFP transgenic mice. The administration of exogenous nerve growth factor into the rat hindpaw mimicked the effects of early tissue damage on excitatory synaptic function, while blocking trkA receptors in vivo abolished the changes in both spontaneous and primary afferent-evoked glutamatergic transmission following incision. These findings illustrate that neonatal tissue damage can alter the gain of developing pain pathways by activating nerve growth factor-dependent signaling cascades, which modify synaptic efficacy at the first site of nociceptive processing within the central nervous system. PMID- 21550173 TI - Letter to the Editor in response to: Ernst E, Lee MS, Choi TY. Acupuncture: does it alleviate pain and are there serious risks? A review of reviews. Pain 2011;152:755-764. PMID- 21550174 TI - Cultured epithelial autografts in massive burns: a single-center retrospective study with 63 patients. AB - Cultured epithelial autografts (CEAs) have long been used to tackle limited donor site availability and difficulty of permanent skin coverage in massive burns, but this approach still has limited documentation. METHODS: In this retrospective, single-center study, medical records of patients treated with CEAs in our burn center from 1991 until 2008 were analyzed in search of factors associated with outcome. RESULTS: Out of 68 patients, 63 records were analyzable. Patients were aged 29 [17-41.5] years (seven children). Total body surface area (TBSA) burned was 81+/-10%, of which 69+/-14% TBSA full thickness. CEAs were first applied after 45+/-34 days, on a surface of 32+/-14% TBSA. Success rate at take down was 65+/-19%, correlating only with young age (r(2)=0.18; p=0.0006). At discharge, CEAs covered 26+/-15% TBSA. Infections (4.3+/-2 per patient), most frequently of skin, often complicated the clinical course. Mortality was 16% (10 patients). In multivariate analysis, the number of infections was the only factor associated with mortality (OR=2.05 per single infection, 95%CI 1.03-4.07, p=0.04). CONCLUSION: Although complex and costly, CEAs can be used with reasonable success and satisfying survival results for the treatment of massive burns. In this study, favorable outcome was principally associated with young age and low number of infectious complications. PMID- 21550175 TI - Distress conditions during pregnancy may lead to pre-eclampsia by increasing cortisol levels and altering lymphocyte sensitivity to glucocorticoids. AB - Psychological stress may affect up to 18% of all pregnant women, altering the function of both neuroendocrine and immune systems. Distress conditions may directly change the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased cortisol levels and associated changes in cellular immunity. Psychological events such as high stress levels, anxiety or depression may directly or indirectly affect pregnancy and may thus lead to pre-eclampsia (PE). Here, we suggest that distress conditions during pregnancy may lead the development of PE by enhancing in vivo cortisol levels. High cortisol levels are associated with hypertension and endothelial dysfunction, features often observed in patients with PE. Lymphocytes from patients with high cortisol levels may have a reduced sensitivity to the synthetic glucocorticoid dexamethasone (DEX). Stress related steroid resistance may disrupt the HPA axis, leading to post-natal detrimental effects such as increased allostatic load, increased pro-inflammatory cytokine levels and even depression in the offspring. PMID- 21550176 TI - Is tinnitus an acoasm? AB - Tinnitus and unspecific auditory hallucinations generally known as acoasms arise from identical or at least similar cerebral structures. Both phenomena can be interpreted as signs of an over activation of neuronal networks. Several pieces of evidence to underline this hypothesis as well as its implications are discussed. It is even speculated that both clinical entities might profit from treatment strategies that are normally employed for treatment of the other. PMID- 21550177 TI - An exposure driven functional model of carcinogenesis. AB - The understanding of general models of carcinogenesis have not advanced substantially over the last years despite a rapidly increasing amount of detailed knowledge in molecular biology, genetics and epidemiology, and it has been difficult to come up with specific hypotheses in order to test existing models. Current multistage models consider mutations per se as the driving forces of carcinogenesis. In contrast, novel knowledge in epidemiology and basic research combined with upcoming large scale technologies of transcriptomics and epigenetics offers a new model--the exposure driven functional model. In this model exposures to carcinogenic substances are the determinants of the carcinogenesis leading to functional changes in gene regulation and to mutations. The diversity of exposures and functional changes could give not one, but many different cancer phenotypes. Under this novel model, cessation of exposure could arrest or reverse the carcinogenic process. To test hypotheses based on this novel model, studies with valid exposures measurements, biological material suitable for all "-omics" analyses, and a design that takes into account the time order principle of causality are a prerequisite. In epidemiology, such designs have been proposed, while in basic genetic research most designs only comply with some, but not all of these conditions. The strength of the exposure driven functional model is the potential for testing specific hypothesis of the effect of many exposures on different stages or mutations. An example of such design would be the testing of the effect of continuing or stopping exposures in relation to the last stage of carcinogenesis in a prospective or globolomic design. If successful the exposure driven carcinogenic model and the use of functional genomics could improve the understanding of carcinogenesis and concomitantly the assessment of causality as part of systems epidemiology. PMID- 21550178 TI - Zinc lozenges for the common cold: Should we ignore the side-effects? PMID- 21550179 TI - Bioenergetic homeostasis decides neuroprotection or neurotoxicity induced by volatile anesthetics: a uniform mechanism of dual effects. AB - The commonly used volatile anesthetic isoflurane or sevoflurane has been shown to be both neuroprotective and neurotoxic in various cell cultures and animal models. Some possible mechanisms have been raised to elucidate volatile anesthetics-induced neuroprotection or neurotoxicity, respectively. However, none of these can reconcile the linkage between their dual effects. Similar to volatile anesthetics, some drugs and nonpharmacological factors also can produce neuroprotection and neurotoxicity, which is associated with bioenergetic metabolism of neuronal cells. Here we present a uniform mechanism, bioenergetic homeostasis hypothesis, to explain neuroprotection and neurotoxicity induced by volatile anesthetics. The numerous evidences have shown that volatile anesthetics could affect mitochondrial electron transport complexes and glycolysis related pathways in cells, which could alter intracellular calcium homeostasis, ROS production and adenosine triphosphate (ATP) synthesis. Duration and concentration of exposure to volatile anesthetics could play a role on severity of bioenergy inhibition. Mild bioenergetic metabolism inhibition trigger signaling events involving preconditioning on neurons, and further bioenergy impairment could lead to neuronal cellular apoptosis, inhibition of neurogenesis and elevated beta Secretase, which drive pathogenesis of neurodegeneration. PMID- 21550180 TI - Protracted hypofractionated radiotherapy for Graves' ophthalmopathy: a pilot study of clinical and radiologic response. AB - PURPOSE: To evaluate the clinical and radiologic response of patients with Graves' ophthalmopathy given low-dose orbital radiotherapy (RT) with a protracted fractionation. METHODS AND MATERIALS: Eighteen patients (36 orbits) received orbital RT with a total dose of 10 Gy, fractionated in 1 Gy once a week over 10 weeks. Of these, 9 patients received steroid therapy as well. Patients were evaluated clinically and radiologically at 6 months after treatment. Clinical response assessment was carried out using three criteria: by physical examination, by a modified clinical activity score, and by a verbal questionnaire considering the 10 most common signs and symptoms of the disease. Radiologic response was assessed by magnetic resonance imaging. RESULTS: Improvement in ocular pain, palpebral edema, visual acuity, and ocular motility was observed in all patients. Significant decrease in symptoms such as tearing (p < 0.001) diplopia (p = 0.008), conjunctival hyperemia (p = 0.002), and ocular grittiness (p = 0.031) also occurred. Magnetic resonance imaging showed decrease in ocular muscle thickness and in the intensity of the T2 sequence signal in the majority of patients. Treatments were well tolerated, and to date no complications from treatment have been observed. There was no statistical difference in clinical and radiologic response between patients receiving RT alone and those receiving RT plus steroid therapy. CONCLUSION: RT delivered in at a low dose and in a protracted scheme should be considered as a useful therapeutic option for patients with Graves' ophthalmopathy. PMID- 21550181 TI - Adjuvant radiotherapy for pediatric and young adult nonrhabdomyosarcoma soft tissue sarcoma. AB - PURPOSE: To evaluate the prognostic factors, outcomes, and complications in patients aged <=30 years with resectable nonrhabdomyosarcoma soft-tissue sarcoma treated at the University of Florida with radiotherapy (RT) during a 34-year period. METHODS AND MATERIALS: A total of 95 pediatric or young adult patients with nonrhabdomyosarcoma soft-tissue sarcoma were treated with curative intent with surgery and RT at the University of Florida between 1973 and 2007. The most common histologic tumor subtypes were synovial sarcoma in 22 patients, malignant fibrous histiocytoma in 19, and malignant peripheral nerve sheath tumor in 11 patients. The mean age at RT was 22 years (range, 6-30). Of the 95 patients, 73 had high-grade tumors; 45 had undergone preoperative RT and 50 postoperative RT. The prognostic factors for survival, local recurrence, and distant recurrence were analyzed. RESULTS: The median follow-up was 7.2 years (range, 0.4-30.5). The actuarial 5-year local control rate was 88%. A microscopically negative margin was associated with superior local control. Although 83% of local recurrence cases initially developed in the absence of metastases, all patients with local failure ultimately died of their disease. The actuarial estimate of 5-year overall survival and disease-free survival was 65% and 63%, respectively. Of all the deaths, 92% were disease related. An early American Joint Committee on Cancer stage, tumor<8 cm, and the absence of neurovascular invasion were associated with superior disease-free survival. The National Cancer Institute Common Toxicity Criteria, version 3, Grade 3-4 treatment complication rate was 9%. No secondary malignancies were observed. CONCLUSION: In the present large single-institution study, we found positive margins and locally advanced features to be poor prognostic factors for both local progression and survival. The results from the present study have helped to characterize the therapeutic ratio of RT in pediatric and young adult sarcoma patients and have provided a basis for identifying high-risk patients for whom treatment intensification might be justified. PMID- 21550182 TI - High-dose-rate brachytherapy as a monotherapy for favorable-risk prostate cancer: a Phase II trial. AB - PURPOSE: There are multiple treatment options for favorable-risk prostate cancer. High-dose-rate (HDR) brachytherapy as a monotherapy is appealing, but its use is still investigational. A Phase II trial was undertaken to explore the value of such treatment in low-to-intermediate risk prostate cancer. METHODS AND MATERIALS: This was a single-institution, prospective study. Eligible patients had low-risk prostate cancer features but also Gleason scores of 7 (51% of patients) and stage T2b to T2c cancer. Treatment with HDR brachytherapy with a single implant was administered over 2 days. One of four fractionation schedules was used in a dose escalation study design: 3 fractions of 10, 10.5, 11, or 11.5 Gy. Patients were assessed with the Common Terminology Criteria for Adverse Events version 2.0 for urinary toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring schema for rectal toxicity, and the Expanded Prostate Cancer Index Composite (EPIC) questionnaire to measure patient-reported health-related quality of life. Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/ml. RESULTS: Between 2003 and 2008, 79 patients were enrolled. With a median follow-up of 39.5 months, biochemical relapse occurred in 7 patients. Three- and 5-year actuarial biochemical control rates were 88.4% (95% confidence interval [CI], 78.0-96.2%) and 85.1% (95% CI, 72.5-94.5%), respectively. Acute grade 3 urinary toxicity was seen in only 1 patient. There was no instance of acute grade 3 rectal toxicity. Rates of late grade 3 rectal toxicity, dysuria, hematuria, urinary retention, and urinary incontinence were 0%, 10.3%, 1.3%, 9.0%, and 0%, respectively. No grade 4 or greater toxicity was recorded. Among the four (urinary, bowel, sexual, and hormonal) domains assessed with the EPIC questionnaire, only the sexual domain did not recover with time. CONCLUSIONS: HDR brachytherapy as a monotherapy for favorable-risk prostate cancer, administered using a single implant over 2 days, is feasible and has acceptable acute and late toxicities. Further follow-up is still required to better evaluate the efficacy of such treatment. PMID- 21550183 TI - Comparison of CT and MR-CT fusion for prostate post-implant dosimetry. AB - PURPOSE: The use of T2 MR for postimplant dosimetry (PID) after prostate brachytherapy allows more anatomically accurate and precise contouring but does not readily permit seed identification. We developed a reproducible technique for performing MR-CT fusion and compared the resulting dosimetry to standard CT-based PID. METHODS AND MATERIALS: CT and T1-weighted MR images for 45 patients were fused and aligned based on seed distribution. The T2-weighted MR image was then fused to the aligned T1. Reproducibility of the fusion technique was tested by inter- and intraobserver variability for 13 patients. Dosimetry was computed for the prostate as a whole and for the prostate divided into anterior and posterior sectors of the base, mid-prostate, and apex. RESULTS: Inter- and intraobserver variability for the fusion technique showed less than 1% variation in D90. MR-CT fusion D90 and CT D90 were nearly equivalent for the whole prostate, but differed depending on the identification of superior extent of the base (p = 0.007) and on MR/CT prostate volume ratio (p = 0.03). Sector analysis showed a decrease in MR CT fusion D90 in the anterior base (ratio 0.93 +/-0.25, p < 0.05) and an increase in MR-CT fusion D90 in the apex (p < 0.05). The volume of extraprostatic tissue encompassed by the V100 is greater on MR than CT. Factors associated with this difference are the MR/CT volume ratio (p < 0.001) and the difference in identification of the inferior extent of the apex (p = 0.03). CONCLUSIONS: We developed a reproducible MR-CT fusion technique that allows MR-based dosimetry. Comparing the resulting postimplant dosimetry with standard CT dosimetry shows several differences, including adequacy of coverage of the base and conformity of the dosimetry around the apex. Given the advantage of MR-based tissue definition, further study of MR-based dosimetry is warranted. PMID- 21550184 TI - Radiographic laxity of the trapeziometacarpal joint is correlated with generalized joint hypermobility. AB - PURPOSE: Increased joint laxity has been associated with the risk of ligament injury and development of osteoarthritis in large joints such as the knee, but this has not been investigated in depth in the hand. We hypothesized that generalized joint laxity would correlate with radiographic measures of trapeziometacarpal (TM) joint subluxation, as measured in carpometacarpal stress view radiographs. METHODS: We recruited volunteer subjects of all ages and examined them for generalized laxity using the Beighton-Horan index. A total of 163 subjects, 81 men and 82 women, with an average age of 48 years (range, 20-83 y), were examined. Each subject underwent a stress view radiograph of both TM joints using a previously described technique. Different examiners independently measured radial subluxation of the thumb metacarpal over the trapezium and the articular width of the thumb metacarpal and averaged them. The ratio of the radial subluxation to the articular width was calculated as a measure of radiographic TM laxity. RESULTS: The average Beighton score was 2 (range, 0-9). A total of 40 subjects had Beighton scores greater than 4. The mean stress view ratio was 0.31 (range, 0.06-0.58). When we calculated the Pearson correlation coefficient to assess the relationship between the stress view ratio and the Beighton score, a statistically significant correlation was demonstrated. CONCLUSIONS: In normal volunteers generalized joint laxity is positively correlated with increased mobility of the TM joint, as demonstrated on carpometacarpal stress view radiographs. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic I. PMID- 21550185 TI - Diagnosis of cubital tunnel syndrome. PMID- 21550186 TI - Mitogen-activated protein kinases p38 and JNK mediate Actinobacillus pleuropneumoniae exotoxin ApxI-induced apoptosis in porcine alveolar macrophages. AB - Actinobacillus pleuropneumoniae exotoxins (Apx) are major virulence factors that play important roles in the pathogenesis of pleuropneumonia in swine. A previous study has demonstrated that native ApxI at low concentrations induces apoptosis in primary porcine alveolar macrophages (PAMs) via a caspase-3-dependent pathway. However, the molecular mechanisms underlying ApxI-induced apoptosis remain largely unknown. In this study, it was shown that ApxI treatment in PAMs rapidly induced phosphorylation of both p38 and JNK, members of the mitogen-activated protein kinase family. Application of a selective p38 or JNK inhibitor significantly reduced ApxI-induced apoptosis, indicating the involvement of p38 and JNK pathways in this event. Furthermore, activation of both caspase-8 and -9 were observed in ApxI-stimulated PAMs. Inhibition of caspase-8 and caspase-9 activity significantly protected PAMs from ApxI-induced apoptosis. In addition, Bid activation was also noted in ApxI-treated PAMs, and inhibition of caspase-8 suppressed the activation of Bid and caspase-9, suggesting that ApxI was able to activate the caspases-8-Bid-caspase-9 pathway. Notably, inhibition of p38 or JNK pathway greatly attenuated the activation of caspases-3, -8, and -9. This study is the first to demonstrate that ApxI-induced apoptosis of PAMs involves the activation of p38 and JNK, and engages the extrinsic and intrinsic apoptotic pathways. PMID- 21550187 TI - Postnatal growth of preterm born children <= 750g at birth. AB - BACKGROUND: Extremely low birth weight (ELBW) infants are at risk of impaired postnatal growth. Impaired postnatal growth has been reported to be associated with delayed cognitive and motor development. AIMS: To describe postnatal growth patterns of appropriate and small for gestational age (AGA and SGA) ELBW children in relation to their cognitive and motor outcome at age 5.5. STUDY DESIGN: Retrospective cohort study. SUBJECTS: One hundred one children with a BW <= 750g, born between 1996 and 2005 in the University Hospital Utrecht, The Netherlands. OUTCOME MEASURES: Height (Ht), weight (Wt), occipital-frontal circumference (OFC) at birth, 15 months and 2 years corrected age and 3.5 and 5.5 years. Cognitive and motor outcome at 5.5 years of age, classified as normal (Z-score >=-1), mildly delayed (-2<=Z-score <-1) or severely delayed (Z-score <-2). AGA (Ht, Wt or OFC at birth >=-2 SDS) infants were compared with SGA (Ht, Wt or OFC at birth <-2 SDS) infants. RESULTS: Between birth and 5.5 years catch-up growth in Ht, weight for height (Wt/Ht), Wt and OFC was seen in 72.2%, 55.2%, 28.6% and 68.9% respectively of the SGA infants. For AGA infants we found substantial catch-down growth in Ht (15.4%) and Wt (33.8%). Cognitive and motor outcome was normal in 76.2% and 41.6% of the 101 children. A significantly higher percentage of normal cognitive outcome was found in AGA infants with Wt growth remaining at >=-2 SDS compared to AGA infants with catch-down growth (83% vs 63%). Next, SGA infants who caught-up in OFC had a higher prevalence of normal cognitive outcome compared to SGA infants who did not catch-up in OFC. Furthermore, a higher percentage of severely delayed motor outcome was found in SGA infants without catch-up growth in Wt compared to SGA infants who caught-up in Wt (61.5% vs 32.2%). CONCLUSIONS: Catch-up growth in Ht, Wt/Ht and OFC occurred in the majority of the SGA infants with a BW <= 750 g, but was less common in Wt. AGA children who remained their Wt at >=-2 SDS have a better cognitive and motor developmental outcome at 5.5 years of age. Catch-up growth in OFC was associated with a better cognitive outcome at 5.5 years of age. PMID- 21550188 TI - Biochemical markers of oxidative stress and retinopathy of prematurity. PMID- 21550189 TI - Seasonal influence on semen traits and freezability from locally adapted Curraleiro bulls. AB - Studies were conducted to characterize the effect of season of the year on testicular morphology, fresh and frozen/thawed semen quality from Curraleiro (Pe duro) bulls in the Brazilian Central west region. Five adult, healthy bulls underwent an andrological examination and semen collection using an electroejaculator, once a month for a year. Fresh and thawed semen were evaluated for progressive sperm motility and sperm vigor, sperm morphology and acrosomal integrity. Testicular length and volume were less (P<0.05) in April than in the other months of the year. For fresh semen, the ejaculate in April had less volume and sperm concentration (P<0.05), while sperm vigor was less (P<0.05) in June, increasing in January and February. With the frozen/thawed semen, the proportion of sperm was greater (P<0.05) in April to July, decreasing from October to December. Semen collected in December had the greatest (P<0.05) proportion of major defects while that collected in February/March had the highest proportion of minor defects. The proportion of live intact sperm reduced progressively from December to April/May. The marginal influence of the time of the year on testicular biometry and fresh semen in Curraleiro bulls shows the adaptation of this breed to the environmental conditions in the region. Thus, reproduction with natural mating should be successful at any time of year. For frozen semen collection for conservation programs, the best time of year is from June to September. PMID- 21550190 TI - Expression of wingless type (WNT) genes and their antagonists at mRNA levels in equine endometrium during the estrous cycle and early pregnancy. AB - WNT signaling pathway plays important roles in reproductive events. Aims were to (1) determine presence of WNT genes and their antagonists in equine endometrium; and (2) to evaluate their expression profiles during early pregnancy. Endometrial biopsies were obtained from mares on day of ovulation (d0, n=4) and on days of 14 (P14, n=4), 18 (P18, n=4), 22 (P22, n=4) of early pregnancy. Biopsies were also collected from cyclic mares during late diestrus (LD, on day of 13.5-14, n=4) and after luteolysis in estrus phase (AL, on day of 17.5-18, n=4) of the cycle. PCR was used to detect expression of genes studied and then relative expression levels were quantified using real-time PCR analysis. A mixed model was fitted on the normalized data and least significant difference test (alpha=0.05) was employed. Eleven WNT genes (WNT2, WNT2B, WNT4, WNT5A, WNT5B, WNT7A, WNT8A, WNT9B, WNT10B, WNT11 and WNT16) and their antagonists (SFRP1, SFRP2, SFRP5, DKK1, DKK2 and WIF-1) were detected in equine endometrium. Compared to d0, WNT2, WNT5B, WNT7A and SFRP1 expressions were downregulated by the pregnancy while DKK1 was upregulated. WNT5A, WNT11 and WIF-1 were upregulated on P14 and P18, but WNT2B increased only on P14. When LD and P14 were compared, level of WNT8A decreased on P14 while increase in WNT4 level on P14 was slightly significant (P<0.06). Levels of WNT7A and SFRP1 decreased while DKK1 and WIF-1 increased by the pregnancy on P18 compared to AL. Moreover, WNT2B, WNT5A, WNT9B, WNT10B, WNT11, WNT16 DKK1 and WIF-1 were upregulated on LD compared to AL whereas WNT4, WNT7A, SFRP1 were downregulated. In conclusion, the results demonstrate that WNT genes and their antagonists appear to be regulated during early pregnancy in equine endometrium possibly due to embryonic factors and/or maternal progesterone. PMID- 21550191 TI - Study of losses of volatile compounds from dynamites. Investigation of cross contamination between dynamites stored in polyethylene bags. AB - The purpose of this work was to study the appropriateness of polyethylene bags for the preservation of explosive specimens. To this end, specimens of two types of dynamites, Goma-2 EC, containing nitroglycol (EGDN) and dinitrotoluene (DNT), and Goma-2 ECO, containing only EGDN, were placed individually inside bags and introduced into hermetically sealed glass jars, which were stored for a period of time. Losses of volatile compounds were studied by headspace analysis using gas chromatography coupled to mass spectrometry (GC-MS). The cross-contamination between dynamites was studied by using high performance liquid chromatography with mass spectrometry (HPLC-MS) to analyse the extracts obtained after a sequential solvent extraction of these specimens. Polyethylene bags permit the loss of volatile compounds since EGDN and DNT were detected in the headspaces of the jars. Moreover, cross-contamination between dynamites was also demonstrated since DNT content decreased in the dynamite containing this compound and increased in the dynamite that had not contained it. PMID- 21550192 TI - In vitro activity of new antimicrobial agents against glycopeptide-resistant Enterococcus faecium clinical isolates from France between 2006 and 2008. AB - OBJECTIVE: The aim of this study was to determine the in vitro activity of six new antimicrobial agents against glycopeptide-resistant enterococci (GRE) strains from France. METHODS: Sixty epidemiologically unrelated clinical isolates of Enterococcus faecium (vanA or vanB), received at the National Reference Centre for Enterococci (CNR-Enc) between 2006 and 2008, were studied. The MICs of the following antibiotics were determined by broth microdilution according to Antibiogram Committee of the French Society for Microbiology (CA-SFM) guidelines: quinupristin-dalfopristin (Q-D), linezolid (LZD), daptomycin (DPT), tigecycline (TGC), ceftobiprole (CFT), and telavancin (TLV). Strains were classified using clinical breakpoints recommended by the CA-SFM (Q-D, LZD, TGC), or the Clinical and Laboratory Standards Institute (DPT). RESULTS: All strains were susceptible to LZD and DPT (MIC(90), 4 and 2MUg/ml, respectively) and only a single strain presented intermediate susceptibility to tigecycline (MIC(90), 0.25MUg/ml). Thirty percent of strains were resistant to Q-D (MIC(90), 4MUg/ml), and CFT was constantly inactive (MIC(90), 64MUg/ml). Finally, TLV showed low-level MICs (MIC(90), 0.5MUg/ml) against vanB-positive isolates but not against vanA-positive isolates (MIC(90), 8MUg/ml). CONCLUSION: Although several antibiotics are still active against GRE, it is essential to maintain an active antimicrobial resistance surveillance for these microorganisms considered as a model of multidrug resistance with a potential to transfer resistance to other bacterial species (e.g. Staphylococcus aureus). PMID- 21550193 TI - Differentiation between Birt-Hogg-Dube syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. AB - BACKGROUNDS: Since Birt-Hogg-Dube syndrome (BHDS) and lymphangioleiomyomatosis (LAM) share some clinical manifestations (multiple pulmonary cysts with pneumothorax, renal tumors, and sometimes skin lesions), the differential diagnosis of the two diseases becomes problem especially in female patients. This study aims to quantify pulmonary cysts in computed tomography (CT) of females with BHDS and those with LAM and also to identify the independent parameters for differentiating the two diseases. METHODS: Fourteen patients with BHDS and 52 with LAM were studied. In CT scans, lung fields were defined as areas with fewer than -200 Hounsfield units (HU) and pulmonary cysts as areas consisting of 10 or more consecutive pixels with fewer than -960 HU. The extent, number, size and circularity of cysts were calculated by using hand-made software and compared between the two diseases. Moreover, the lung fields were divided into six zones and analyzed for the distribution of cysts. Finally, a stepwise discriminant analysis employing quantitative measurements of cysts and clinical features was performed. RESULTS: The two diseases were significantly different in all quantitative measurements of cysts. Stepwise discriminant analysis accepted the following four variables: the family history of pneumothorax within the second degree relatives, lower-medial zone predominance of cysts, diffusing capacity and mean size of cysts in this order. CONCLUSION: The quantitative characteristics of pulmonary cysts are significantly different between BHDS and LAM. The independent parameters for differentiating the two diseases are the family history of pneumothorax, zonal predominance of cysts, diffusing capacity and size of cysts. PMID- 21550194 TI - Acute and chronic myocardial infarction in a pig model: utility of multi-slice cardiac computed tomography in assessing myocardial viability and infarct parameters. AB - OBJECTIVES: The aim of this study was to determine the feasibility of multi-slice computed tomography (MSCT) biphasic imaging in assessing myocardial viability and infarct parameters in both acutely and chronically infarcted pig models. MATERIALS AND METHODS: Seven pigs underwent ligation of the distal left anterior descending artery. Imaging was performed on the day of infarction and 3 months post-infarct, with contrast infusion followed by MSCT scan acquisition at different time-points. Left ventricular ejection fractions (LVEFs) were obtained by left ventriculography (LVG) after 3 months. Infarcted locations found using MSCT were compared with those obtained using SPECT. Infarcted areas were also analysed histopathologically and compared with the findings from MSCT. RESULTS: Chronic phase images had perfusion defects with lower CT values relative to normal myocardium (43+/-10HU vs. 156+/-13HU, p=0.001) on the early images but no residual defects on delayed images. However, we found hyperenhancing regions on delayed images (244+/-20HU vs. 121+/-25HU, p=0.001), and good correlation between MSCT- and LVG-derived LVEFs (60.56+/-7.56%). The areas identified by MSCT corresponded to the location of (201)Tl SPECT-/pathologic staining-derived regions in all models. Infarct size was in good agreement with MSCT and pathological analyses of chronic phase models. CONCLUSIONS: Necrotic myocardium in different stages after infarction could be qualitatively and quantitatively assessed using MSCT biphasic imaging, as could the status of microcirculation formation. MSCT-measured LVEFs matched well with other modalities, and hence MSCT is a useful tool in assessing post-infarct cardiac function. PMID- 21550195 TI - Qualitative and quantitative characterization of chemical constituents in Xin-Ke Shu preparations by liquid chromatography coupled with a LTQ Orbitrap mass spectrometer. AB - Xin-Ke-Shu (XKS), a traditional Chinese medicine (TCM) preparation containing five herbal medicines, has been commonly used for the treatment of coronary heart disease in China. However, the chemical constituents in XKS have not been clarified yet. In order to quickly define the chemical profiles and control the quality of XKS preparations, liquid chromatography coupled with electrospray ionization hybrid linear trap quadrupole orbitrap (LC-LTQ-Orbitrap) mass spectrometry was applied for simultaneous identification and quantification of multi-constituent. A total of 51 compounds, including phenolic acids, isoflavone C-glycosides, isoflavone-O-glycosides, flavonoids, and triterpenoid saponins, were identified or tentatively deduced on the base of their retention behaviors, MS and MS(n) data, or by comparing with reference substances and literatures. In addition, an optimized LC-ESI-MS method was established for quantitative determination of 15 marker compounds in XKS preparations from 7 independent pharmaceutical companies. The validation of the method, including spike recoveries, linearity, sensitivity (LOD and LOQ), precision, and repeatability, was carried out and demonstrated to be satisfied the requirements of quantitative analysis. This is the first report on the comprehensive determination of chemical constituents in XKS preparations by LC-LTQ-Orbitrap mass spectrometry. The results suggested that the established methods would be a powerful and reliable analytical tool for the characterization of multi-constituent in complex chemical system and quality control of TCM preparations. PMID- 21550196 TI - Patients' satisfaction with information and experiences with counseling on cardiovascular medication received at the pharmacy. AB - OBJECTIVE: To assess the extent to which patients feel they have received enough information on cardiovascular drugs and experienced counseling at the pharmacy. In addition, to identify factors that are predictors for patient satisfaction with the information received. METHODS: Fifteen community pharmacies participated. New and chronic users of cardiovascular medication received a questionnaire containing sociodemographic and health questions, a measure of satisfaction with information received (SIMS), beliefs about medication (BMQ), and frequency of pharmacy counseling. RESULTS: Of the 578 respondents, 335 (58%) indicated to be unsatisfied with the information received on 3 or more SIMS items. Patients' age, beliefs about medication, duration of cardiovascular treatment and use of antithrombotics predicted patients' satisfaction with information received. Two-thirds of patients reported 'never' to have experienced 5 of 8 counseling activities at the pharmacy. CONCLUSIONS: A considerable proportion of patients are unsatisfied with the information received on cardiovascular medication. The majority of patients have only received a limited scope of medication counseling at the pharmacy. PRACTICE IMPLICATIONS: Information and counseling should be tailored to patients' needs and concerns about cardiovascular medication and the experience patients already have with treatment. Pharmacists could enhance their role in supporting patients using cardiovascular medication. PMID- 21550197 TI - The feasibility of a multi-format Web-based assessment of physicians' communication skills. AB - OBJECTIVE: Little is known about the best approaches and format for measuring physicians' communication skills in an online environment. This study examines the reliability and validity of scores from two Web-based communication skill assessment formats. METHODS: We created two online communication skill assessment formats: (a) MCQ (multiple-choice questions) consisting of video-based multiple choice questions; (b) multi-format including video-based multiple-choice questions with rationales, Likert-type scales, and free text responses of what physicians would say to a patient. We randomized 100 general internists to each test format. Peer and patient ratings collected via the American Board of Internal Medicine (ABIM) served as validity sources. RESULTS: Seventy-seven internists completed the tests (MCQ: 38; multi-format: 39). The adjusted reliability was 0.74 for both formats. Excellent communicators, as based on their peer and patient ratings, performed slightly better on both tests than adequate communicators, though this difference was not statistically significant. Physicians in both groups rated test format innovative (4.2 out of 5.0). CONCLUSION: The acceptable reliability and participants' overall positive experiences point to the value of ongoing research into rigorous Web-based communication skills assessment. PRACTICE IMPLICATIONS: With efficient and reliable scoring, the Web offers an important way to measure and potentially enhance physicians' communication skills. PMID- 21550198 TI - Mortality rate among crack/cocaine-dependent patients: a 12-year prospective cohort study conducted in Brazil. AB - Mortality is a significant outcome among Brazilian crack/cocaine-dependent patients yet not well understood and is under investigated. This study examined a range of mortality indicators within a cohort of 131 crack/cocaine-dependent patients admitted into treatment and meeting criteria for dependence of crack (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). After 12 years of treatment discharge, 107 individuals were reassessed and 27 death cases were confirmed by official records, wherein in its majority were caused by homicide (n = 16). In this group, survival rate was 0.77 (95% confidence interval [CI] = 0.74-0.81) and previous history of IV cocaine use was identified as a predictor of mortality (2.5, 95% CI = 1.08-5.79). High mortality rates among Brazilian crack/cocaine-dependent patients, exposure to violence, and HIV/AIDS were topics discussed in this study. This research highlights the importance of ongoing programs to manage crack/cocaine use along with other treatment features within this population. PMID- 21550199 TI - Childhood sexual abuse and substance abuse treatment utilization among substance dependent incarcerated women. AB - Incarcerated women have high rates of substance abuse problems and trauma. A variety of variables may influence whether these women seek help or are referred for substance abuse problems. This study reports an exploratory project on service utilization among incarcerated substance-dependent women (N = 40) in southeastern Idaho. Using self-report and interview tools, most participants reported some substance abuse treatment history, although extent and types of treatment varied. Most of the women also reported some type of childhood abuse. Age, income, and consequences of alcohol and other drug use related positively to substance abuse treatment. However, severity of childhood sexual abuse and current trauma symptoms were negatively correlated with substance abuse treatment episodes. These women may use substances to cope with childhood trauma or may not perceive the substance abuse system as responsive to their co-occurring trauma symptoms. PMID- 21550200 TI - A phase I/II study of neoadjuvant chemotherapy with Pemetrexed (Alimta) in rectal cancer. AB - AIM: The aim was to assess the feasibility of preoperative chemotherapy and possible tumour response using Pemetrexed (Alimta) in rectal cancer. METHOD: The study was a prospective, non-randomized, single-centre phase I/II feasibility trial. 37 patients with resectable rectal cancer were recruited and given three 3 week cycles of preoperative Pemetrexed therapy. Tumour size and stage were assessed by MRI scans before and after chemotherapy. Treatment tolerability and response such as changes in tumour size and symptoms were assessed. RESULTS: All patients completed the chemotherapy. Whilst mild side effects were frequent (grade 1, 34/37), the risk of severe effects was limited (grade 3 or 4, 4/37). Overall, there was a significant reduction in tumour size (p < 0.001). By RECIST criteria, one patient had tumour progression, 23/36 had stable disease and 12 patients had a response of up to 65%. There was also a significant decrease in the number of pre-treatment symptoms (p < 0.018) including reduction of bleeding and diarrhoea/constipation. CONCLUSION: Preoperative (Neoadjuvant) treatment with Pemetrexed was feasible in studied patients. Serious side effects were limited and a radiological tumour response or stable disease was seen in a majority of patients. PMID- 21550201 TI - [Primary chondrosarcoma of stomach]. PMID- 21550202 TI - [Antagonists of interleukin-6 (tocilizumab), in adult refractory still disease]. AB - INTRODUCTION: The pathogenesis of Still's disease is best elucidated for the better recognition of the involvement of Many pro-inflammatory cytokines in the genesis of this condition. Publications have reported the contribution beneficial for certain biotherapeutics, such as anti-TNFa, the anti-CD20 or antagonists of interleukine1 (IL-1) tested successfully in the treatment of systemic Juvenile idiopathic arthritis (Still's disease the child), the tocilizumab is a humanized monoclonal antibody directed against the receptor for interleukin-6 and is beginning to be reported as effective in some refractory cases of Still's disease in adults. PATIENTS: We report two young patients with Still's disease in adults with refractory early and prolonged remission after the first infusion tocilizumab. CONCLUSION: The tocilizumab can be used in patients MSA with refractory after failure or intolerance conventional treatments. PMID- 21550203 TI - Atherosclerotic renal artery stenosis: review of pathophysiology, clinical trial evidence, and management strategies. AB - Renal artery stenosis is prevalent and commonly encountered by cardiovascular specialists. Recently published randomized studies have provoked tremendous controversies in the treatment strategy with regard to renal artery stenting. However, these studies are inconclusive because of major study limitations. As such, cardiovascular specialists are uncertain of the indications or utility of renal revascularization, with differing opinions on management by nephrologists and cardiologists. A greater understanding of this disease process, especially with regard to its functional significance and consequence and treatment strategies based on well-designed clinical trials, is sorely needed. Our review focuses on atherosclerotic renal artery stenosis, with an emphasis on indications for revascularization and review of current trial data. PMID- 21550204 TI - The Combat Experience Log: a web-based system for the in theater assessment of war zone stress. AB - This article presents preliminary data on the Combat Experience Log (CEL)--a web based prospective data collection system for the in theater assessment of war zone stressors and stress reactions. 177 U.S. Army soldiers deployed to Iraq took part in the study. The overall response rate was 90.1% and the majority of CEL responders perceived the CEL system to be quite easy and convenient to use, and relevant to their war-zone experiences. Preliminary data on stress reactions, CEL utilization and soldier satisfaction are encouraging and suggest that the CEL assessment system offers a potentially useful assessment tool for enhancing our understanding of war-zone stress experiences and their contribution to PTSD and other combat stress disorders. PMID- 21550205 TI - The Age of Blood Evaluation (ABLE) randomized controlled trial: study design. AB - Red blood cells (RBCs) are transfused to treat anemia and to maintain oxygen delivery to vital organs during critical illness. Laboratory and observational studies have raised the possibility that prolonged RBC storage may adversely affect clinical outcomes. Compared with RBCs stored less than 1 week, there are no clinical data demonstrating that RBCs stored longer remain as effective at carrying or releasing oxygen, and observational studies have risen to possibility that prolonged RBC storage might result in harm to vulnerable patients requiring blood transfusions. The "Age of Blood Evaluation" (ABLE) study (ISRCTN44878718) is a double-blind, multicenter, parallel randomized controlled clinical trial. It will test the hypothesis that the transfusion of prestorage leukoreduced RBCs stored for 7 days or less (fresh arm) as compared with standard-issue RBCs stored, on average, 15 to 20 days (control arm) will lead to lower 90-day all cause mortality and reduced morbidity in critically ill adults. We include adults in intensive care units (ICUs) who (1) have had a request for a first RBC unit transfusion during the first 7 days of ICU admission and (2) have an anticipated requirement for ongoing invasive and noninvasive mechanical ventilation exceeding 48 hours. Enrolled patients are randomized at the time of transfusion to receive either standard-issue RBC units or RBCs stored 7 days or less issued by the local hospital transfusion service. The primary outcome is 90-day all-cause mortality. Secondary outcomes include ICU and hospital mortality, organ failure, and serious nosocomial infections. With 2510 patients, we will be able to detect a 5% absolute risk reduction (from 25% to 20%). The ABLE study is currently enrolling patients in 23 university-affiliated and community-hospital ICUs across Canada; sites in France and United Kingdom are expected to start recruitment in 2011. Regardless of the results, ABLE study will have significant implications on the duration of RBC storage. A negative trial will reassure clinicians and blood bankers regarding the effectiveness and safety of standard-issue RBCs. A positive trial will have significant implications with respect to inventory management of RBCs given to critically ill adults with a high risk of mortality and will also prompt research to better understand the RBC storage lesion in the hopes of minimizing its clinical consequences through the development of better storage methods. PMID- 21550206 TI - Oral squamous cell carcinoma in a 7-year-old Brazilian boy. AB - Squamous cell carcinomas (SCCs) are amongst the commonest malignancies in adults but in paediatric patients are exceptionally rare, particularly those involving the oral mucosa. The aim of the present report is to describe the features of a gingival well-differentiated SCC in a 7-year-old Brazilian boy. Immunostaining for p53, Ki-67 and Mcm2 showed increased cellular proliferation compared with normal epithelium. In situ hybridization failed to identify human papilloma virus infection. Correct diagnosis of well-differentiated squamous carcinoma can be difficult in children and differentiation from pseudoepitheliomatous hyperplasia is essential to establish proper treatment. PMID- 21550207 TI - A preliminary study of the effect of low intensity pulsed ultrasound on new bone formation during mandibular distraction osteogenesis in rabbits. AB - This study assesses the effect of low intensity pulsed ultrasound (LIPUS) on new bone formation during mandibular distraction osteogenesis (DO) in rabbits. 24 rabbits underwent DO on the right side of the mandible. 12 rabbits received a daily 20-min LIPUS (1.5 MHz, 30 mW/cm2) treatment on the first day of the distraction until they were killed at week 0 (immediately after the distraction), week 2 and week 4 after the distraction. Four rabbits were killed at each time point. The other 12 rabbits followed the same protocol without the ultrasound treatment. A plain radiography, a micro-CT scan, a microhardness test and a histological examination were used to evaluate new bone formation in the distraction gap. At week 0 and week 2 after the distraction, the treatment groups showed higher radiopacity and microhardness (p<0.05), and more bone formation was detected by the histological examination. At week 4 after the distraction, there was no statistical difference between the two groups. In this study, LIPUS accelerated new bone formation during the distraction period and 2 weeks after the distraction, which implies that the effective time for using LIPUS is in the early stage of DO. PMID- 21550208 TI - Hippocampal T2 abnormalities in healthy adults. AB - We compared hippocampal abnormalities in 42 healthy adults identified by voxel based relaxometry (VBR) and by visual inspection. Hippocampal abnormalities were seen in 8 (19.0%) and 10 (23.8%) of subjects by VBR and visual inspection, respectively (p>0.05). Notably, 50% of the abnormalities seen by visual inspection were likely false positive. This suggests that VBR is a more specific measure and should be considered in subjects with questionable hippocampal abnormalities. PMID- 21550209 TI - Do surface DC-shifts affect epileptic hippocampal EEG activity? AB - Despite considerable research on EEG-feedback of slow cortical potentials (SCPs) for seizure control in epilepsy, the underlying mechanisms and the direct effects on intracerebral pathological activity within the focal area remain unclear. Intrahippocampal EEG recordings from four patients with temporal lobe epilepsy and implanted electrodes were analyzed with regard to spike activity and power in 10 frequency bands (0.5-148Hz) during SCP feedback based on surface recordings (position Cz). Trials with positive, negative and indifferent SCPs were contrasted. Three of the four patients showed changes in spike activity during SCPs, but these were inconsistent between patients, and resulted in increased and decreased activity in both positive and negative SCPs. Spectral analysis revealed that in all patients, positive surface shifts showed a bi-hemispheric higher power in the high-frequency activity above 40Hz. Two patients showed a higher power also during negative shifts, both in high-frequency activity and one in most other frequency bands. Feedback-related power effects did not differ between focal and non-focal side. The inconsistent change in spiking activity and the lack of decrease of power in pathology associated frequency bands during SCPs show that these SCPs do not decrease pathological activity within the epileptic focus. A possible relation of higher power in high-frequency activity during positive SCPs to cognitive processes, such as memory functions, is discussed. PMID- 21550210 TI - Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. AB - INTRODUCTION: HTR2A gene has been the subject of numerous studies in psychiatric genetics because LSD, which resembles serotonin causes psychosis and atypical antipsychotic drugs target the HTR2A receptor. However, evidence for the role of HTR2A polymorphism(s) in schizophrenia (SCZ) and bipolar disorder (BD) has been elusive. We hypothesized that epigenetic dysregulation of HTR2A may be involved in psycho-pathogenesis and analyzed promoter DNA methylome and expression of HTR2A in SCZ, BD and control subjects. METHOD: DNA derived from post-mortem brains of patients with SCZ and BD and matched control subjects (each 35) were obtained from the Stanley Medical Research Institute. While bisulfite DNA sequencing was used to screen and quantify cytosine methylation in the HTR2A promoter, corresponding gene expression was analyzed by qRT-PCR. RESULTS: We found strong evidence for epigenetic fine-tuning of HTR2A expression. In general, the expression of HTR2A in individuals carrying the C allele of T102C (or G allele of -1438A/G polymorphism) was higher than TT genotype. Interestingly, promoter DNA of HTR2A was hypermethylated at and around the -1438A/G polymorphic site, but was hypomethylated at and around T102C polymorphic site in SCZ and BD compared to the controls. Furthermore, epigenetic down-regulation of HTR2A was associated with early age of disease onset in SCZ and BD. CONCLUSION: Epigenetic dysregulation of HTR2A may contribute to SCZ, BD and earlier age of disease onset. Further research is required to delineate the dysregulation of other components of serotoninergic pathway to design new therapeutics based on the downstream effects of serotonin. PMID- 21550211 TI - MMN/P3a deficits in first episode psychosis: comparing schizophrenia-spectrum and affective-spectrum subgroups. AB - BACKGROUND: Reduced mismatch negativity (MMN) and P3a amplitudes are neurophysiological biomarkers for schizophrenia that index deviance detection and the orienting response, respectively. First-episode psychosis (FEP) patients show reduced amplitudes of the 'MMN/P3a complex', but it is unclear whether this occurs across the FEP spectrum. METHODS: Fifty-three young people (17-36 years) were assessed: 17 FEP affective-spectrum (bipolar disorder with psychotic features and major depressive disorder with psychotic features), 18 FEP schizophrenia-spectrum (schizophrenia, schizoaffective disorder, and schizophreniform disorder), and 18 healthy controls. MMN/P3a was acquired during a two-tone, auditory paradigm with 8% duration deviants. Clinical, psychosocial and neuropsychological assessments were also undertaken. RESULTS: FEP schizophrenia- and FEP affective-spectrum showed significantly reduced fronto central MMN and central P3a amplitudes compared to controls. FEP subgroups also showed significantly poorer cognitive and psychosocial functioning. The combined FEP sample showed significant correlations between fronto-central MMN amplitudes and cognitive measures. DISCUSSION: FEP schizophrenia-spectrum and FEP affective spectrum were similarly impaired in two biomarkers for schizophrenia. FEP subgroups showed impairments in fronto-central MMN consistent with chronic patients. Similarly, both subgroups showed reductions in P3a; although the affective subgroup showed an 'intermediate' frontal response. These findings suggest that FEP patients with both affective and schizophrenia spectrum diagnoses share common neurobiological disturbances in deviance detection/orienting processes in the early phase of illness. PMID- 21550212 TI - Second generation antipsychotics (SGAs) for non-psychotic disorders in children and adolescents: a review of the randomized controlled studies. AB - In children and adolescents the Second Generation Antipsychotics (SGAs) represent the class of psychotropic drugs whose use has grown more significantly in recent years: they are primarily used for treatment of patients with disruptive behavior disorders, mood disorders and pervasive developmental disorders or mental retardation. In order to compare the efficacy and tolerability of antipsychotics against placebo or each other, a systematic Medline/PubMed search for randomized, double blind studies on SGA in patients younger than 18 years of age at enrollment, was conducted. Papers on schizophrenia, discussed in another article of this specific issue, were excluded by the efficacy analysis. A set of standard efficacy and safety indices, such as treatment effect sizes (ES), the Numbers Needed to Treat (NNT) and Numbers Needed to Harm (NNH), was used to compare medications. 32 studies analyzing efficacy and/or tolerability of SGAs in children and adolescents with bipolar, autistic or disruptive behavior disorders, and Tourette syndrome were identified. SGAs efficacy on mania, extreme mood variability, irritability, aggression and disruptive behavior appears to be greater than for psychotic symptoms in schizophrenia: average NNT was 2-5, whereas for schizophrenia it varies between 3 for risperidone and 10 for olanzapine, quetiapine, and aripiprazole. As for schizophrenia, different SGAs show a similar efficacy for specific non-psychotic disorders, but they significantly differ in their safety profile. In randomized studies, adverse effects were usually relatively minor, easily predictable and manageable, whereas long-term open-label studies have indicated that some adverse event, such as the metabolic effects, may be severe and potentially life threatening on the long term. Taken together, these findings suggest that the choice of a specific treatment should be guided primarily by the safety profile of specific antipsychotics, considering specific risk factors (i.e. obesity and BMI, family history of diabetes or cardiovascular disorder, etc) for the single patient. PMID- 21550213 TI - Methylphenidate administration determines enduring changes in neuroglial network in rats. AB - Repeated exposure to psychostimulant drugs induces complex molecular and structural modifications in discrete brain regions of the meso-cortico-limbic system. This structural remodeling is thought to underlie neurobehavioral adaptive responses. Administration to adolescent rats of methylphenidate (MPH), commonly used in attention deficit and hyperactivity disorder (ADHD), triggers alterations of reward-based behavior paralleled by persistent and plastic synaptic changes of neuronal and glial markers within key areas of the reward circuits. By immunohistochemistry, we observe a marked increase of glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expression and a down-regulation of glial glutamate transporter GLAST in dorso lateral and ventro-medial striatum. Using electron microscopy, we find in the prefrontal cortex a significant reduction of the synaptic active zone length, paralleled by an increase of dendritic spines. We demonstrate that in limbic areas the MPH-induced reactive astrocytosis affects the glial glutamatergic uptake system that in turn could determine glutamate receptor sensitization. These processes could be sustained by NO production and synaptic rearrangement and contribute to MPH neuroglial induced rewiring. PMID- 21550214 TI - Study of cosurfactant effect on nanoemulsifying area and development of lercanidipine loaded (SNEDDS) self nanoemulsifying drug delivery system. AB - The present study deals with the development and characterization of self nanoemulsifying drug delivery system (SNEDDS) to improve the oral bioavailability of poorly soluble third generation calcium channel blocker lercanidipine (LER). Solubility of the LER was estimated in various oils, cosurfactants and surfactants which were grouped into two different combinations to construct pseudoternary phase diagrams. Various thermodynamic stability and dispersibility tests were performed on the formulations from phase diagram. After constructing phase diagram of two different combinations NL-I and NL-II, the effect of cosurfactants on the nanoemulsifying area was studied and the effect of number and length of hydrophobic alkyl chains of cosurfactant in its emulsification capacity was proved. Percentage transmittance, emulsification time, viscosity and droplet size analysis were used to characterize optimized formulations. The optimized formulation composed of Cremophor EL (45% wt/wt), (13.5% wt/wt) Caproyl 90 with (1.5% wt/wt) Transcutol(r) HP as per limits of inactive ingredients guidelines of FDA and Maisine oil (10% wt/wt). The mean droplet size in selected nanocarrier system was 20.01 nm. The in vitro dissolution profile of LER SNEDDS was found significant in comparison to the marketed LER (Zanidip) tablet and pure drug in pH 1.2, 4.5 and 6.8 buffers. Empty hard gelatin capsule shells were filled using Pfizer's Licap technology and charged on stability conditions of 30 degrees C/65% RH, 40 degrees C/65%RH and 50 degrees C/75% in glass bottles where no significant degradation (p>0.05) was observed in 3 months. The results indicate that SNEDDS of LER, owing to nanosized, has potential to enhance the absorption of drug. PMID- 21550215 TI - [Intussusception after congenital diaphragmatic hernia repair]. AB - INTRODUCTION: Bowel intussusception is a common complication of abdominal surgery. However, the literature on intussusception after congenital diaphragmatic hernia (CDH) repair is scarce. CASE REPORT: A 24-month-old female was admitted with vomiting, crying and leukocytosis, with no objective abdominal signs. The chest x-ray showed the presence of bowel in the left hemithorax. Surgical exposure reduced a hernia across a Bochdalek defect, involving part of the left colon and the transverse colon. On the 7th postoperative day, the patient had symptoms of intestinal obstruction with worsening of her general condition. The explorative laparotomy evidenced an ileoileal intussusception, 15 cm from the ileocecal valve, in absence of a leading point. CONCLUSION: A postoperative intussusception in a similar case could be explained by atony of the herniated bowel, possibly a functional leading point in the postoperative phase, when the peristalsis is reactivated. PMID- 21550216 TI - Late-onset bowel dysfunction after pelvic radiotherapy: a national survey of current practice and opinions of clinical oncologists. AB - AIMS: Seventeen thousand patients receive treatment with radical pelvic radiotherapy annually in the UK. It is common for patients to develop gastrointestinal symptoms after treatment. The aim of this study was to determine the current practice of clinical oncologists in the UK with respect to late-onset bowel dysfunction after pelvic radiotherapy, and to discuss the wider issues surrounding current and future service provision for this patient group. MATERIALS AND METHODS: A questionnaire was developed to establish current practice. This was sent to the 314 clinical oncologists in the UK who treat pelvic malignancies up to a maximum of three times. RESULTS: One hundred and ninety (61%) responses were received. Most oncologists (76%) screen for gastrointestinal dysfunction after pelvic radiotherapy, usually through history taking rather than formal tools. Clinical oncologists view toxicity as a significant problem, with most estimating that up to 24% of patients at 1 year have bowel symptoms. Most oncologists refer less than 50% of their symptomatic patients, with most referring less than 10%. These referrals are 31% to a gastroenterologist, 23% to a gastrointestinal surgeon and 33% to both. Most (58%) do not have access to a gastroenterologist or a gastrointestinal surgeon with a specialist interest in their area. Sixty-five per cent of oncologists think a service is required specifically for patients with bowel dysfunction after pelvic radiotherapy, but half (52%) think that the current service in their area is inadequate. CONCLUSIONS: Clinical oncologists recognise late-onset bowel dysfunction after pelvic radiotherapy as a significant problem, but one that is linked to poor recognition of symptoms and an inadequate patchy service. PMID- 21550217 TI - Priorities for the head and neck cancer patient, their companion and members of the multidisciplinary team and decision regret. AB - AIMS: To compare the treatment outcome priorities of patients, their companions and members of the multidisciplinary team (MDT), and also to determine if the former two groups suffered from regret of their decision. MATERIALS AND METHODS: Patients were eligible if attending with a companion at least 6 months after radiotherapy for head and neck cancer given with curative intent. They were interviewed by two clinicians separately with questions from the Chicago Priority Scale and Ottawa Decision Regret Scale. RESULTS: In total, 30 patients, 30 companions and 25 members of the MDT were evaluated. 'Being cured of my cancer', 'living as long as possible', 'having no pain' and 'being able to swallow all foods and drinks' were the top four priorities for all three groups. Patients ranked 'having no pain' lower than either companions (P=0.003) and members of the MDT (P=0.006). Patients ranked 'keeping my appearance unchanged' as less important than members of the MDT (P=0.013) and 'keeping my normal sense of taste and smell' as more important than members of the MDT (P=0.013). The post treatment regret score was 12.50 for patients and 10.33 for companions out of 100 (P value was not significant). CONCLUSIONS: There was a strong agreement between patients, their companions and members of the MDT with regards to priorities in head and neck cancer outcomes and low post-treatment regret for patients and their companions. These results suggest that the patients' companions and members of the MDT are able to exercise good judgment when it comes to supporting patients in decision making. PMID- 21550218 TI - Regular consumption of cocoa powder with milk increases HDL cholesterol and reduces oxidized LDL levels in subjects at high-risk of cardiovascular disease. AB - BACKGROUND AND AIMS: Epidemiological studies suggest that regular consumption of cocoa-containing products may confer cardiovascular protection, reducing the risk of coronary heart disease (CHD). However, studies on the effects of cocoa on different cardiovascular risk factors are still scarce. The aim of this study was too evaluate the effects of chronic cocoa consumption on lipid profile, oxidized low-density lipoprotein (oxLDL) particles and plasma antioxidant vitamin concentrations in high-risk patients. METHODS AND RESULTS: Forty-two high-risk volunteers (19 men and 23 women, mean age 69.7 +/- 11.5 years) were included in a randomized, crossover feeding trial. All received 40g of cocoa powder with 500 mL of skimmed milk/day(C + M) or only 500 mL/day of skimmed milk (M) for 4 weeks in a random order. Before and after each intervention period, plasma lipids, oxLDL and antioxidant vitamin concentrations were measured, as well as urinary cocoa polyphenols metabolites derived from phase II and microbial metabolisms. Compared to M, C + M intervention increases HDLc [2.67 mg/dL (95% confidence intervals, CI, 0.58-4.73; P = 0.008)] and decreases oxLDL levels [-12.3 U/L (CI,-19.3 to 5.2;P = 0.001)]. No changes between intervention groups were observed in vitamins B1, B6, B12, C and E, or folic acid concentrations. In addition, subjects who showed higher increments in urinary cocoa polyphenol metabolites exhibited significant increases in HDLc and significant decreases in oxLDL levels (P < 0.05; all). CONCLUSIONS: Consumption of cocoa power with milk modulates the lipid profile in high-risk subjects for CHD. In addition, the relationship observed between the urinary excretion of cocoa polyphenol metabolites and plasma HDLc and oxLDL levels suggests a beneficial role for cocoa polyphenols in lipid metabolism. PMID- 21550219 TI - Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes. AB - BACKGROUND AND AIMS: Vanin-1 (gene name VNN1) is an enzyme with pantetheinase activity generating the amino-thiol cysteamine which is implicated in the regulation of red-ox status through its effect on glutathione. We tested the hypothesis that the rs2294757 VNN1 T26I polymorphism could affect blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events. METHODS AND RESULTS: The VNN1 T26I polymorphism was genotyped in 5664 participants of the cardiovascular cohort of the "Malmo Diet and Cancer" (MDC CVA) study and successively in 17874 participants of the "Malmo Preventive project"(MPP). The incidence of cardiovascular events was monitored for an average of nearly 12 years of follow-up in the MDC-CVA and for 25 years in the MPP. Both before and after adjustment for sex, age and BMI in the MDC-CVA the polymorphism had a mild lowering effect on diastolic BP and hypertension, especially in females. However in MPP no effect on BP phenotypes was detectable. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events in the MDC-CVA was not significantly different in carriers of different genotypes. CONCLUSIONS: Our data do not support a major role for the VNN1 T26I variant in determining BP level and incident ischemic events. PMID- 21550220 TI - The association of fasting plasma sulfur-containing compounds with BMI, serum lipids and apolipoproteins. AB - BACKGROUND AND AIM: Sulfur amino acids are recognized as potent modulators of lipid metabolism. Plasma total cysteine (tCys) is associated with fat mass, obesity and serum LDL-cholesterol and apolipoprotein (Apo)-B in large population studies. It is not known how fasting plasma concentrations of cysteine precursors and products relate to these associations in humans, given that sulfur-containing compounds (SCC) influence rodent weight gain and serum lipids. METHODS AND RESULTS: We investigated the cross-sectional associations of fasting plasma SCC (methionine, total homocysteine, cystathionine, tCys, taurine and total glutathione) with BMI and fasting serum lipids and apolipoproteins in 854 men and women with and without cardiovascular disease (CVD). In multiple linear regression analysis adjusted for age, gender, CVD and other SCC, neither methionine, taurine, nor total glutathione was associated with BMI. Plasma taurine was, however, inversely related to HDL-cholesterol (partial r = -0.12, p = 0.004) and its associated apoA1 (partial r = -0.18, p < 0.001). Plasma cystathionine correlated positively with triglycerides and BMI, while tCys positively correlated with total cholesterol, LDL-cholesterol (partial r = 0.20, p < 0.001) and its associated apoB. The associations of SCC with serum lipids were independent of BMI. tCys was also independently associated with BMI (partial r = 0.20, p < 0.001) after adjustment for other SCC, glucose, lipids and apolipoproteins. CONCLUSIONS: Fasting tCys is associated with BMI independently of metabolically related SCC. Elevation of plasma SCC is generally associated with an unfavorable lipid profile. The negative relations of plasma taurine with HDL-C and apoA1 deserve further investigation. PMID- 21550221 TI - Lumbar vertebra morphometry and stereological assesment of intervertebral space volumetry: a methodological study. AB - The use of technology in the treatment of degenerative spinal diseases has undergone rapid clinical and scientific development. It has been extensively studied in combination with various techniques for spinal stabilization from both the anterior and posterior approach. Minimally invasive and instrumental approach via posterior fixation is increasingly being used for the treatment of adult degenerative disc disease, stenosis, and deformity of the lumbar vertebrae. Posterior access to the lumbar disc spaces for posterolateral fusion scan has been technically challenging, frequently requiring the use of an approach surgery for adequate exposure. For successful surgery and suitable instrumental design, adequate anatomical knowledge of the lumbar vertebra is also needed. Anatomic features of lumbar vertebrae are of importance for posterior screw fixation technique. The morphometry of L1-L5 has been studied to facilitate the safe application of pedicle screws. Thus, we aimed to evaluate the morphometric landmarks of lumbar vertebrae such as pedicle, vertebral body, vertebral foramen, intervertebral space height and volume for safe surgical intervention using a posterior fixation approach to offer anatomical supports for lumbar discectomy, stenosis and cases of deformity. The features of the L1-L5 vertebral body, the detailed morphometric parameters of lumbar vertebrae and the intervertebral space were analyzed using computerized tomography scan, magnetic resonance imaging and also dry lumbar vertebrae. Additionally, intervertebral space volumes were measured using stereological methods to ensure safe surgical intervention. PMID- 21550222 TI - Effect of aeration modes on the characteristics of composting emissions and the NH3 removal efficiency by using biotrickling filter. AB - A pilot biotrickling filter (BTF) packed with ZX02 fibrous balls as packing material was tested for the treatment of ammonia (NH(3)) released from a composting plant of dairy manure. In order to investigate the effects of three compost aeration modes (mode Co-I, Co-II and In-II) on the NH(3) removal efficiency, a field experiment was continuously carried out for more than eight months. The results demonstrated that under the intermittent aeration mode (In II), the NH(3) removal efficiency reached 99.2+/-0.1% when the inlet NH(3) concentration was 7.5-32.3mg m(-3) (9.8-42.5ppmv). The maximum and critical elimination capacity of the biotrickling filter was 22.6 and 4.9g NH(3)m(-3)h( 1), respectively. The effluent concentration of NH(3) was lower than 1.0mg m(-3), which meets the first class discharge standards of GB14554-93. When the concentration of free ammonia in the trickling liquid was varied from 0.1 to 0.4mg L(-1), the nitrification yield was between 47.9% and 103.8%. In addition, the optimum liquid tricking velocity (LTV) of the biotrickling filter was 0.5m(3)m(-2)h(-1) for low inlet concentrations and 2.2m(3)m(-2)h(-1) for high inlet concentrations. Therefore, the use of the biotrickling filter for the compost under the third aeration mode (In-II) yielded an effective optimum NH(3) removal and reduced the nitrogen loss in the compost. PMID- 21550223 TI - Towards zero industrial waste: Utilisation of brick dust waste in sustainable construction. AB - Laboratory investigations were carried out to establish the potential utilisation of brick dust (BD) in construction. The dust is a waste material from the cutting of fired clay bricks. Currently, the disposal of the dust is a problem to the brick fabrication company, and hence an environmental pollution concern. The dust was stabilised either used on its own or in combination with Pulverised Fuel Ash (PFA), a by-product material from coal combustion. The traditional stabilisers of lime and/or Portland Cement (PC) were used as controls. The main aim was to use a sustainable stabiliser material, where these stabilisers were partially replaced with Ground Granulated Blastfurnace Slag (GGBS), a by-product material from steel manufacture. Compacted cylinder test specimens were made at typical stabiliser contents and moist cured for up to 56 days prior to testing for compressive and California Bearing Ratio (CBR) strength tests, and to linear expansion during moist curing and subsequent soaking in water. The results obtained showed that partial substitution of the dust with PFA resulted in stronger material compared to using it on its own. The blended stabilisers achieved better performance. These results suggest technological, economic as well as environmental advantages of using the brick dust and similar industrial by-products to achieve sustainable infrastructure development with near zero industrial waste. PMID- 21550224 TI - Biodegradation of keratin waste: Theory and practical aspects. AB - Keratin-rich by-products, i.e. bristles, horns and hooves, chicken feathers and similar, are a source of nutrients for animals (amino acids) and plants (N, S). Contemporary developments in the management of keratin waste in feeds and fertilizers comply with human and animal health protection regulations and respect the principles of ecological development. Biotechnological methods employing keratinolytic bacteria and microscopic fungi play a key role in processing keratin waste. This study reviews the current knowledge on the ecology and physiology of keratinolytic microorganisms and presents the biodegradation mechanism of native keratin. The structure and chemical composition of keratin proteins are described, and methods of keratin waste biotransformation into products of practical industrial and natural value, especially composts, are discussed. PMID- 21550225 TI - Combining near-infrared-excited autofluorescence and Raman spectroscopy improves in vivo diagnosis of gastric cancer. AB - This study aims to evaluate the diagnostic utility of the combined near-infrared (NIR) autofluorescence (AF) and Raman spectroscopy for improving in vivo detection of gastric cancer at clinical gastroscopy. A rapid Raman endoscopic technique was employed for in vivo spectroscopic measurements of normal (n=1098) and cancer (n=140) gastric tissues from 81 gastric patients. The composite NIR AF and Raman spectra in the range of 800-1800 cm(-1) were analyzed using principal component analysis (PCA) and linear discriminant (LDA) to extract diagnostic information associated with distinctive spectroscopic processes of gastric malignancies. High quality in vivo composite NIR AF and Raman spectra can routinely be acquired from the gastric within 0.5s. The integrated intensity over the range of 800-1800 cm(-1) established the diagnostic implications (p=1.6E-14) of the change of NIR AF intensity associated with neoplastic transformation. PCA LDA diagnostic modeling on the in vivo tissue NIR AF and Raman spectra acquired yielded a diagnostic accuracy of 92.2% (sensitivity of 97.9% and specificity of 91.5%) for identifying gastric cancer from normal tissue. The integration area under the receiver operating characteristic (ROC) curve using the combined NIR AF and Raman spectroscopy was 0.985, which is superior to either the Raman spectroscopy or NIR AF spectroscopy alone. This work demonstrates that the complementary Raman and NIR AF spectroscopy techniques can be integrated together for improving the in vivo diagnosis and detection of gastric cancer at endoscopy. PMID- 21550226 TI - Sensitive detection of an anthrax biomarker using a glassy carbon electrode with a consecutively immobilized layer of polyaniline/carbon nanotube/peptide. AB - Sensitivity of Anthrax protective antigen (PA) detection has been improved by directly immobilizing a PA-specific peptide onto a multi-wall carbon nanotube (MWCNT). The MWCNT was covalently immobilized onto a polyaniline (PANI) electrode, which was prepared via electropolymerization of the aniline monomer onto a glassy carbon electrode (GCE). Then, the PA-specific peptide was covalently immobilized to the MWCNT layer for measurement. When comparing this technique to that of PA immobilization on an insulting self assembled organic layer, the advantages of the MWCNT are clear. The MWCNT sensor resulted in enhanced electron transfer across the sensing layer. The resulting limit of detection (LOD) was 0.4 pM, a 13-fold improvement over that of our previous self assembled organic layer was used for immobilization of the same peptide. Neither positive nor negative interferences were observed when a sample containing both 100 pM PA and bovine serum albumin (BSA) was measured, indicating good selectivity of the proposed sensor. PMID- 21550227 TI - Reusable evanescent wave DNA biosensor for rapid, highly sensitive, and selective detection of mercury ions. AB - Mercury ions (Hg(2+)) are a highly toxic and ubiquitous pollutants requiring rapid and sensitive on-site detection methods in the environment and foods. Herein, we report an envanescent wave DNA-based biosensor for rapid and very sensitive Hg(2+) detection based on a direct structure-competitive detection mode. In this system, a DNA probe covalently immobilized onto a fiber optic sensor contains a short common oligonucleotide sequences that can hybidize with a fluorescently labeled complementary DNA. The DNA probe also comprises a sequence of T-T mismatch pairs that binds with Hg(2+) to form a T-Hg(2+)-T complex by folding of the DNA segments into a hairpin structure. With a structure competitive mode, a higher concentration of Hg(2+) leads to less fluorescence labeled cDNA bound to the sensor surface and thus to lower fluorescence signal. The total analysis time for a single sample, including the measurement and surface regeneration, was under 6 min with a Hg(2+) detection limit of 2.1 nM. The high specificity of the sensor was demonstrated by evaluating its response to a number of potentially interfering metal ions. The sensor's surface can be regenerated with a 0.5% SDS solution (pH 1.9) over 100 times with no significant deterioration of performance. This platform is potentially applicable to detect other heavy metal ions or small-molecule analytes for which DNA/aptamers can be used as specific sensing probes. PMID- 21550228 TI - The foot represents a unique inter-professional forum for a world-wide focus. PMID- 21550229 TI - A systematic review and meta-analysis of KRAS status as the determinant of response to anti-EGFR antibodies and the impact of partner chemotherapy in metastatic colorectal cancer. AB - BACKGROUND: In the setting of metastatic colorectal cancer (CRC), anti-EGFR antibodies are not currently recommended for individuals with KRAS mutant tumours. This is based on subgroup analyses of individual clinical trials rather than a formal synthesis of evidence for KRAS status as a predictive biomarker, while newer trials report no benefit for anti-EGFR antibodies irrespective of KRAS status. This study systematically reviewed the evidence for KRAS mutation status as a treatment effect modifier of response to anti-EGFR antibodies and the influence of partner chemotherapy. METHODS: Medline (1966-2010), EMBASE and American and European oncology meeting abstracts were searched for randomised controlled trials reporting the influence of KRAS status on effectiveness of anti EGFR antibodies in metastatic CRC. The treatment efficacy was summarised by KRAS status using hazard ratios (HR) for progression-free survival (PFS) and risk differences (RD) for objective response. For each study, a measure of effect modification was calculated, and aggregated using random effects meta-analysis to assess the interaction between KRAS and treatment effect. FINDINGS: Eleven studies (8924 patients) were selected from 198 reports. Two studies assessed anti EGFR antibodies as monotherapy and nine their use with chemotherapy. KRAS status was reported in 7555 cases. In subgroup analysis, the progression HR for KRAS wild patients assigned to anti-EGFR antibodies was 0.80 (4436 patients 95%CI: 0.64, 0.99) and for mutant cases 1.11 (3119 patients, 95%CI: 0.97, 1.27). A significant treatment effect interaction between KRAS status and addition of anti EGFR antibodies to standard treatment was found for PFS (ratio of HRs 0.71, 95%CI: 0.57, 0.90 p=0.005) and response rate difference (difference in RDs 15%, 95%CI: 8, 22%, p<0.001). There was no evidence that the extent of effect modification differed between chemotherapeutic partners for both PFS (p=0.3) and response rate (p=0.6). INTERPRETATION: KRAS mutation status is a treatment effect modifier for anti-EGFR antibodies in metastatic CRC. Further evidence is needed to determine whether this is true for all chemotherapy partners and all clinical circumstances. PMID- 21550232 TI - Econometric models for biohydrogen development. AB - Biohydrogen is considered as an attractive clean energy source due to its high energy content and environmental-friendly conversion. Analyzing various economic scenarios can help decision makers to optimize development strategies for the biohydrogen sector. This study surveys econometric models of biohydrogen development, including input-out models, life-cycle assessment approach, computable general equilibrium models, linear programming models and impact pathway approach. Fundamentals of each model were briefly reviewed to highlight their advantages and disadvantages. The input-output model and the simplified economic input-output life-cycle assessment model proved most suitable for economic analysis of biohydrogen energy development. A sample analysis using input-output model for forecasting biohydrogen development in the United States is given. PMID- 21550231 TI - The pharmacoeconomics of spiralling cancer drug costs - is there a viable solution? PMID- 21550230 TI - Apigenin affects leptin/leptin receptor pathway and induces cell apoptosis in lung adenocarcinoma cell line. AB - BACKGROUND: Apigenin, a common edible plant flavonoid, is a well characterised antioxidant. The adipokine leptin exerts proliferative and anti-apoptotic activities in a variety of cell types. In cancer cells, apigenin may induce a pro apoptotic pathway whereas leptin has an anti-apoptotic role. The purpose of the study is to investigate the role of apigenin and of leptin/leptin receptor pathway on proliferation and on apoptosis in lung adenocarcinoma. METHODS: Immunocytochemistry, flow cytometry and RT-q-RT PCR, were used to investigate the expression and modulation of leptin receptors on the lung adenocarcinoma cell line A549 in presence or absence of apigenin and of leptin, alone or combined. Clonogenic test to evaluate cell proliferation was assessed. Exogenous leptin binding to its receptors by flow cytometry, reactive oxygen species (ROS) by dichlorofluorescein diacetate analysis, cell death by ethidium bromide and apoptosis by annexin V analysis were assessed. Apoptosis was assessed also in presence of lung adenocarcinoma pleural fluids (PF) (n=6). RESULTS: A549 express leptin/leptin receptor pathway and its expression is upregulated by apigenin. Apigenin alone or combined with leptin significantly decreases cell proliferation and significantly increases the spontaneous release of ROS, with augmented cell death and apoptosis, this latter also in the presence of lung adenocarcinoma PF. Leptin alone significantly increases cell proliferation and significantly decreases cell death. CONCLUSIONS: These results strongly suggest the potential utility of the flavonoid apigenin in the complementary therapeutic approach of patients with lung adenocarcinoma. PMID- 21550233 TI - Vermicomposting of distillation waste of citronella plant (Cymbopogon winterianus Jowitt.) employing Eudrilus eugeniae. AB - Laboratory experiment on vermicomposting of distillation waste of java citronella (Cymbopogon winterianus Jowitt.) was carried out employing Eudrilus eugeniae, in two seasonal trials, covering summer and winter periods. Two vermicomposting treatments were conducted in earthen pots, one with citronella plant waste only (CW) and the other, a mixture of citronella waste and cowdung in the proportion 5:1 (CW+CD). Vermicomposting of citronella waste resulted reduction in C/N ratio (83.5-87.7%), enhancement of ash content and a number of macro and micronutrients. The FT-IR spectroscopy of the vermicompost revealed the reduction in aliphatic and aromatic compound as well as increase in amide group after the 105 days stabilization process. The vermicompost output was significantly enhanced in CW+CD treatment than CW treatment. Even, nutrient content of the vermicompost was also higher in CW+CD treatment than CW alone indicating the positive role of cowdung in improvement of quantity and quality. PMID- 21550234 TI - Investigation on the removal of Mo(VI) from Mo-Re containing wastewater by chemically modified persimmon residua. AB - Persimmon waste was chemically modified by crosslinking with concentrated sulfuric acid to obtain a novel kind of adsorption gel, which was termed as crosslinked persimmon tannin (CPT), hereinafter. The adsorption behaviors of Mo(VI) with other coexisting metal ions onto the CPT gel were investigated. The gel exhibited selectivity only for Mo(VI) ions evidenced by the high value of separation factor of molybdenum and rhenium (beta(Mo/Re)=164.37), and the adsorption mechanism of Mo(VI) as a multispecies was studied. The molybdenum adsorption behavior conforms to the Langmuir model with a remarkably high adsorption capacity of 0.56 mol/kg. A kinetic study for the adsorption of molybdenum at various temperatures confirmed that the endothermic adsorption process followed pseudo-second order kinetics. Moreover, its excellent adsorption properties and applicability for Mo(VI) were demonstrated by the removal and separation of Mo(VI) from different Mo-Re containing industrial wastewaters. PMID- 21550235 TI - A bioelectrochemical reactor containing carbon fiber textiles enables efficient methane fermentation from garbage slurry. AB - A packed-bed system includes supporting materials to retain microorganisms and a bioelectrochemical system influences the microbial metabolism. In our study, carbon fiber textiles (CFT) as a supporting material was attached onto a carbon working electrode in a bioelectrochemical reactor (BER) that degrades garbage slurry to methane, in order to investigate the effect of combining electrochemical regulation and packing CFT. The potential on the working electrode in the BER containing CFT was set to -1.0 V or -0.8 V (vs. Ag/AgCl). BERs containing CFT exhibited higher methane production, elimination of dichromate chemical oxygen demand, and the ratio of methanogens in the suspended fraction than reactors containing CFT without electrochemical regulation at an organic loading rate (OLR) of 27.8 gCODcr/L/day. In addition, BERs containing CFT exhibited higher reactor performances than BERs without CFT at this OLR. Our results revealed that the new design that combined electrochemical regulation and packing CFT was effective. PMID- 21550236 TI - Orally active aminopyridines as inhibitors of tetrameric fructose-1,6 bisphosphatase. AB - A novel sulfonylureido pyridine series exemplified by compound 19 yielded potent inhibitors of FBPase showing significant glucose reduction and modest glycogen lowering in the acute db/db mouse model for Type-2 diabetes. Our inhibitors occupy the allosteric binding site and also extend into the dyad interface region of tetrameric FBPase. PMID- 21550237 TI - The discovery and structure-activity relationships of pyrano[3,4-b]indole-based inhibitors of hepatitis C virus NS5B polymerase. AB - We describe the structure-activity relationship of the C7-position of pyrano[3,4 b]indole-based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compounds 13 and 14. PMID- 21550238 TI - 4-Aminothiazolyl analogs of GE2270 A: design, synthesis and evaluation of imidazole analogs. AB - Imidazole analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and evaluated for gram positive bacteria growth inhibition. A recently reported, copper-mediated synthesis was exploited to prepare 4-thiazolyl imidazole analogs of 1. The synthesis described represents a structurally complex, natural product-based application of this recently reported synthetic methodology. In addition, the biological evaluation of the imidazole-based analogs further define the SAR of the 4-aminothiazolyl-based antibacterial template. PMID- 21550239 TI - Actin depolymerizing effect of trisoxazole-containing macrolides. AB - Oxazole-containing macrolides (1-5) isolated from the marine sponge Chondrosia corticata were evaluated for their actin depolymerizing activities by monitoring fluorescent intensity of pyrene F-actin. These studies led to the identification of (19Z)-halichondramide (5) as a new actin depolymerizing agent. The actin depolymerizing activity by (19Z)-halichondramide (5) was four times more potent than that of halichondramide (1). Compounds 1 and 5 also have potent antifungal activity. The preliminary structure-activity relationship of these compounds is described to elucidate the essential structural requirements. PMID- 21550240 TI - From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons. AB - Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30 fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC(50)<100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK. PMID- 21550241 TI - Recombinant human acid alpha-glucosidase (rhGAA) in adult patients with severe respiratory failure due to Pompe disease. AB - Pompe disease is a rare metabolic myopathy caused by lysosomal alpha-glucosidase deficiency. Pompe disease ranges from a rapidly progressive course when symptoms present in infancy to a more slowly progressive rate when symptoms present in childhood or adulthood. This open-label prospective exploratory study investigated the effect of 12 months of recombinant enzyme replacement therapy in 5 adult patients who had already advanced to a very severe stage of Pompe disease. Muscular and respiratory function, quantitative muscle testing and spirometry were assessed. Four patients were tracheostomized. Respiratory parameters did not deteriorate. A moderate improvement in sitting/supine slow vital capacity in 2 patients (from 7% to 11% and 28% to 32% of predicted) and reductions of ventilation support in 2 patients was observed. Three patients, wheelchair bound at baseline, improved sitting and proximal motor function; 2 patients improved in their ability to stand and transfer. The treatment was well tolerated. Alglucosidase alfa may stabilize or even slightly improve muscle strength and respiratory function among patients with severe Pompe disease. PMID- 21550242 TI - Fusing a lasting relationship between ER tubules. AB - Atlastin is an integral membrane GTPase localized to the endoplasmic reticulum (ER). In vitro and in vivo analyses indicate that atlastin is a membrane fusogen capable of driving membrane fusion, suggesting a role in ER structure and maintenance. Interestingly, mutations in the human atlastin-1 gene, SPG3A, cause a form of autosomal dominant hereditary spastic paraplegia (HSP). The etiology of HSP is unclear, but two predominant forms of the disorder are caused by mutant proteins that affect ER structure, formation and maintenance in motor neurons. In this review, we describe the current knowledge about the molecular mechanism of atlastin function and its potential role in HSP. Greater understanding of the function of atlastin and associated proteins should provide important insight into normal ER biogenesis and maintenance, as well as the pathology of disease. PMID- 21550244 TI - Long noncoding RNAs and human disease. AB - A new class of transcripts, long noncoding RNAs (lncRNAs), has been recently found to be pervasively transcribed in the genome. Multiple lines of evidence increasingly link mutations and dysregulations of lncRNAs to diverse human diseases. Alterations in the primary structure, secondary structure, and expression levels of lncRNAs as well as their cognate RNA-binding proteins underlie diseases ranging from neurodegeneration to cancer. Recent progress suggests that the involvement of lncRNAs in human diseases could be far more prevalent than previously appreciated. We review the evidence linking lncRNAs to diverse human diseases and highlight fundamental concepts in lncRNA biology that still need to be clarified to provide a robust framework for lncRNA genetics. PMID- 21550245 TI - Central gait control mechanisms and the stride length - cadence relationship. AB - The stride length - cadence relationship (SLCrel) was investigated to explore a theory of two alternate but inter-related pathways for gait control. Sixty-three healthy people in three age groups walked along a computerized walkway (GAITRite((r))) at five self-selected speeds from very slow to very fast, five cadences from 70 to 150 steps/min and five stride lengths from 0.8 to 1.6m. The data points from two walks in each level of each condition were examined for linear and quadratic relationships. In the self-selected speed condition 97% of participants had a positive linear or quadratic relationship of R(2)>=0.90. The quadratic relationships showed stride length decreased with very high cadences. When walks with cadences above 150 steps/min were removed, 95% of participants had a positive linear relationship of R(2)>=0.90. No age-related differences were found in slope or intercept of linear relationships or in maximum, minimum or range of stride length or cadence in the self-selected speed condition. In the cadence and stride length conditions, only 32% and 14% of positive linear or quadratic relationships were R(2)>=0.90. The near-invariant SLCrel, unaffected by ageing that exists for nearly all individuals when walking at self-selected speeds, indicates that the SLCrel may be used to simplify central control of automatic gait in healthy individuals. The current investigation also provides SLCrel data for healthy people which can be compared with patient populations. PMID- 21550243 TI - Rabs and the exocyst in ciliogenesis, tubulogenesis and beyond. AB - The exocyst, an octameric protein complex mediating vesicle tethering at the plasma membrane for exocytosis, is a downstream effector of the Rab proteins Rab8 and Rab11, which are key regulators of membrane trafficking from the trans-Golgi network and recycling endosome to the plasma membrane. Rab11 and Rab8 coordinate their actions via Rabin8, the guanine nucleotide exchange factor of Rab8. A cascade of protein-protein interactions involving the Rabs and the exocyst complex couples the generation of secretory vesicles at donor compartments to their docking and fusion at the plasma membrane. Here, we discuss recent work implicating Rab proteins and the exocyst in primary ciliogenesis and epithelial lumenogenesis. In addition, we discuss early work in the budding yeast Saccharomyces cerevisiae, which provided the initial insight into the molecular mechanisms of polarized exocytosis. PMID- 21550246 TI - A cross-sectional study about the relationship between morphology and kinematic parameters in children between 15 and 36 months. AB - Morphology and kinematic parameters were recorded for 31 children between 15 and 36 months to investigate the relation between morphology and the walking pattern. A full 3D gait analysis using a VICON motion system was performed to gather kinematic data. Next, the differences in kinematic parameters between four morphological classes were assigned with a multiple analysis of variance, with a correction for walking experience. Also stepwise linear regressions were performed, to examine the relation between detailed morphological measurements and kinematic parameters. The regression models showed relationships between kinematic parameters of the ankle, hip, thorax and morphology. All results indicated that the upper body played an important role in the coordination of the walking pattern, especially in the frontal plane. PMID- 21550247 TI - The role of tread fixations in the visual control of stair walking. AB - Although it is likely that foveal information on treads provides important sensory cues for stair walking, it is unclear how gaze stabilization on treads contribute to gait control on stairs. The aim of this study was to determine the extent to which (i) stair walking depends on foveal information on stepped treads, (ii) fixated treads correspond to future foot landing locations, and (iii) the distance looked ahead varies with stepping distance. Gaze and foot position was monitored from six healthy young adults when they ascended and descended a 10 tread long staircase, taking the stairs one or two treads at a time. The results showed that 55-68% of the total fixation time was aimed at treads, and that tread edges were fixated more intensively during stair descent (69% of the total time spent fixating treads) than during stair ascent (48%). A substantial 28-34% of the stepped treads was never fixated and, when the staircase was taken two treads a time, approximately 35% of the fixated treads was never stepped on. Subjects fixated 3.5-4.5 treads ahead in both stepping conditions, but when the staircase was taken 2 treads a time, stepped treads were fixated shorter ahead (2.7-2.9 treads) than treads that were not stepped (3.4-4.1 treads). These results provide new insights into the visual control of stair walking, and suggest that the stabilization of gaze on treads is not used solely to guide foot placement, but may serve other purposes as well, e.g., to facilitate postural control on the staircase. PMID- 21550248 TI - Atlantoaxial dislocation in a child with generalized primary dystonia. AB - We describe a 10-year-old boy with generalized dystonia who developed spastic quadriparesis within 1 month of dystonia onset. On neuroimaging, a craniovertebral junction anomaly with atlantoaxial dislocation and compressive myelopathy was present. We postulate that dystonia involving the neck led to atlantoaxial dislocation in this child with a craniovertebral junction anomaly. PMID- 21550249 TI - Unilateral optic neuritis in a Chinese population in three centers. AB - To describe the clinical profile of unilateral optic neuritis (ON) in a Chinese population, we reviewed retrospectively the records of 100 patients (66% female; age 18-74 years) diagnosed with unilateral ON between 2003 and 2009 at three hospitals in Guangxi Province, China. Ocular pain was noted in 40% and disc swelling in 48%. Periventricular plaques were found in 8% and multiple sclerosis in 6%. Visual loss varied at presentation, being mild (>= 0.5) in 15%, moderate (0.1-0.4) in 26%, and severe (< 0.1) in 59%. Visual acuity improved after a mean (+/- standard deviation) hospitalization of 12.5 +/- 5.3 days, with visual loss eing mild in 52%, moderate in 14% and severe in 34%. Our findings suggest that the characteristics and severity of initial visual loss of patients in our study are more similar to those of patients in Japan than to those of patients in the United States of America. It seems that visual recovery in our patients is relatively good. PMID- 21550250 TI - Selective bilateral hippocampal lesions after theophylline-induced status epilepticus causes a permanent amnesic syndrome. AB - Theophylline is known to increase the risk of epileptic seizures and might have a role in seizure-induced brain damage. We present a 55-year-old man who developed an amnesic syndrome after status epilepticus, caused by accidental theophylline intoxication. Imaging studies revealed acute, selective bilateral hippocampal damage, which corresponded to severe disturbances in bilateral temporal functions on neuropsychological testing. Three months later, the memory deficits persisted, while imaging exhibited bilateral atrophy of the hippocampus. Upon his long-term, 18-month follow-up, the patient demonstrated improvements in his daily living abilities, despite the persistence of bilateral temporal deficits. This report provides evidence that theophylline has the potential to provoke permanent seizure-induced neural damage, presumably via inhibition of adenosine receptors, and especially in vulnerable regions of the brain, such as the hippocampus. PMID- 21550251 TI - Brain abscess following intra-arterial thrombolytic treatment for acute brain ischemia. AB - Brain abscess formation is a rare complication of intracranial endovascular treatment. To our knowledge, all previous reports of brain abscess formation have been associated with treatments involving the introduction of foreign materials. A 75-year-old man was admitted to hospital for acute stroke. Cerebral angiography revealed occlusion of the left middle cerebral artery (MCA) at the origin of the M2 segment. Intra-arterial thrombolytic therapy was administered but a hemorrhagic event occurred during this process. A brain CT scan revealed a hematoma extending from the left basal ganglia to the left frontal lobe and expansion of the infarct in the left MCA territory. A brain abscess at the hemorrhagic site developed 3 months after symptom onset. This is the first report of a patient with brain abscess formation following intra-arterial thrombolytic treatment. It is important to ensure aseptic technique during endovascular procedures irrespective of the involvement of foreign materials. PMID- 21550252 TI - A novel human volunteer pain model using contact heat evoked potentials (CHEP) following topical skin application of transient receptor potential agonists capsaicin, menthol and cinnamaldehyde. AB - The discovery of transient receptor potential (TRP) receptors has advanced understanding of temperature sensation, and pre-clinical studies have identified TRP as major novel analgesic targets in inflammatory and neuropathic pain states. We systematically investigated the sensory effects and interactions of TRP agonists capsaicin (TRPV1), menthol (TRPM8) and cinnamaldehyde (TRPA1) applied topically to the skin in 14 healthy human participants. Capsaicin lowered heat pain thresholds while warm detection thresholds were unchanged, suggesting an effect purely on nociceptor nerve fibres. The amplitude of contact heat-evoked potentials (CHEP) and evoked pain ratings were negatively correlated after capsaicin, whereas CHEP had been correlated positively without capsaicin in a previous volunteer study. Menthol caused cold hypersensitivity and cinnamaldehyde caused heat hypersensitivity, but neither had an effect on evoked potentials. The CHEP after application of capsaicin show features observed in some patients with painful neuropathy, and could provide a model for development of novel analgesics, particularly TRPV1 antagonists. PMID- 21550253 TI - Indications for the use of temporary arterial occlusion during aneurysm repair: an institutional experience. AB - This study was undertaken to determine variables that could predict, in the preoperative period, the likelihood for the need for intraoperative temporary arterial occlusion using clips (temporary clipping) when surgically repairing intracranial aneurysms. Data collected prospectively between October 1989 and March 2010 of 1129 unruptured intracranial aneurysms in 934 patients who were managed surgically was examined retrospectively. Temporary clipping was used in 400 patients (35.4%). Regression analysis of putative predictive variables revealed that aneurysms of a larger size, irregular fundus shape or midline location were more likely to be treated with temporary clipping. Basilar caput aneurysms larger than 10mm were always managed with temporary clipping. There was no combination of factors studied that consistently predicted that temporary clipping would not be needed. Therefore, the potential need for temporary clipping must be considered for every patient with an aneurysm. PMID- 21550254 TI - Possible seizure suppression via deep brain stimulation of the thalamic ventralis oralis posterior nucleus. AB - Surgical treatment of intractable epilepsy with deep brain stimulation (DBS) has been shown to be of therapeutic benefit in some patients and with the recent publication of a randomised control study its use is likely to increase in the future. We describe a patient who developed a focal epileptic seizure within a few seconds of momentarily turning off the DBS stimulator in the nucleus ventralis oralis posterior, with which she was successfully treated for tremor. The seizure was the result of a newly diagnosed primary brain tumor. We suggest that the nucleus ventralis oralis posterior may be another thalamic target of DBS in epilepsy. PMID- 21550255 TI - Multifocal malignant optic glioma of adulthood presenting as acute anterior optic neuropathy. AB - We report a 63-year-old, previously healthy female patient with glioblastoma multiforme of the optic nerve and chiasm presenting as acute anterior optic neuropathy. She presented with a 3-week history of progressively increasing headaches, retrobulbar pain, rapidly progressive visual loss in the right eye and blurred vision in the left eye. Early clinical examination revealed right optic disc swelling and she was initially diagnosed with demyelinating optic neuritis. Her clinical course deteriorated with total visual loss in the right eye and progressive visual loss in the left eye despite treatment with intravenous (IV) methylprednisone and IV immunoglobulins. MRI revealed enhancement of the right optic nerve and optic chiasm, with multiple periventricular hyperintense foci. Six weeks later, the patient presented with left facial palsy and left hemiparesis. Follow-up MRI showed multiple enhancing lesions in addition to the previous lesions involving right lentiform and right thalamic nucleus, right cerebral peduncle, right temporal and parietal lobes. Although the optic nerve biopsy was inconclusive, the brain biopsy revealed glioblastoma multiforme. This report demonstrated that malignant glioma of adulthood may be multicentric and may mimic optic neuritis clinically, which might help explain the difficulties in diagnosis. PMID- 21550258 TI - Optimization of the radiosynthesis of the Alzheimer tracer 2-(4-N [11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB). AB - [(11)C]PIB is still the standard PET compound for Alzheimer imaging targeting beta-amyloid plaques. We aimed to establish a fully-automated procedure for the synthesis and purification of [(11)C]PIB with a high degree of reliability and improved specific activity as well as a suitable and fast quality control assay. The optimum reaction conditions were 75 degrees C, 4 mg/mL precursor yielding at 48.0+/-2.7% (EOS, based on [(11)C]CH(3)OTf, corrected for decay), 183+/-14 GBq/MUmol specific activity and >99% radiochemical purity. Time consumption was kept to a minimum (40 min from EOB) and overall yields were enough to serve 2 consecutive patients with a single preparation. PMID- 21550257 TI - Specific inhibitions of annonaceous acetogenins on class II 3-hydroxy-3 methylglutaryl coenzyme A reductase from Streptococcus pneumoniae. AB - 3-Hydroxy-3-methylglutaryl coenzyme A reductase (class II HMGR) could serve as a potential target to discover drugs fighting against the invasive diseases originated from Streptococcus pneumoniae, one of the major causes of bacterial disease in human. However, no strongly effective inhibitors of class II HMGR have been found so far. In the present study, for the first time, four annonaceous acetogenins (ACGs) were explored for the inhibition on S. pneumoniae HMGR. The results showed that the ACGs had higher inhibitory activities against S. pneumoniae HMGR with K(i) values in the range of 6.45-20.49 MUM than the statin drug lovastatin (K(i)=116.25 MUM), a classical inhibitor of class I HMGR. Then, three-dimensional modeling and docking simulations analyzed the possible binding mode of ACGs to S. pneumoniae HMGR and suggested a kind of novel structural and binding mode for designing promising inhibitor candidates of the targeted enzyme S. pneumoniae II HMGR. PMID- 21550256 TI - Diverse interactions of retroviral Gag proteins with RNAs. AB - Retrovirus particles are constructed from a single virus-encoded protein, termed Gag. Given that assembly is an essential step in the viral replication cycle, it is a potential target for antiviral therapy. However, such an approach has not yet been exploited because of the lack of fundamental knowledge concerning the structures and interactions responsible for assembly. Assembling an infectious particle entails a remarkably diverse array of interactions, both specific and nonspecific, between Gag proteins and RNAs. These interactions are essential for the construction of the particle, for packaging of the viral RNA into the particle, and for placement of the primer for viral DNA synthesis. Recent results have provided some new insights into each of these interactions. In the case of HIV-1 Gag, it is clear that more than one domain of the protein contributes to Gag-RNA interaction. PMID- 21550259 TI - Accuracy and borehole influences in pulsed neutron gamma density logging while drilling. AB - A new pulsed neutron gamma density (NGD) logging has been developed to replace radioactive chemical sources in oil logging tools. The present paper describes studies of near and far density measurement accuracy of NGD logging at two spacings and the borehole influences using Monte-Carlo simulation. The results show that the accuracy of near density is not as good as far density. It is difficult to correct this for borehole effects by using conventional methods because both near and far density measurement is significantly sensitive to standoffs and mud properties. PMID- 21550260 TI - Reproducibility of neutron activated Sm-153 oral dose formulations intended for human administration. AB - Neutron activation of Sm-152 offers a method of radiolabeling for the in vivo study of oral dose formulations by gamma scintigraphy. Reproducibility measurements are needed to ensure the robustness of clinical studies. 204 enteric coated guaifenesin core tablets (10mg of Sm(2)O(3)) were irradiated by thermal neutrons to achieve 1 MBq at 48 h. Administered activities were 0.86+/-0.03 MBq. Good reproducibility (CV=3.5%) was observed over 24 weeks ensuring that volunteer doses were within the dose reference level of 0.8 mSv. PMID- 21550261 TI - Off-label use of recombinant activated factor VII in intractable haemorrhage after cardiovascular surgery: an observational study of practices in 23 French cardiac centres (2005-7). AB - OBJECTIVES: The study aimed to describe French off-label use of rFVIIa for intractable bleeding in major cardiovascular surgery. METHODS: Retrospective observational analysis of data from 2005 to October 2007 (no formal guidelines were available) was employed. The collect request form was elaborated by a multidisciplinary committee. RESULTS: Data on 109 patients--37 mechanical cardiac assist devices--were collected, with repeated injection for 24%. Bleeding stopped, decreased or continued in 43%, 37% and 20% of the cases, respectively. For patients treated in the intensive care unit (ICU), hourly bleeding decreased from 365 +/- 212 to 115 +/- 106 ml h(-1) (p<0.001). The median number of transfused products was 25 (2-90) before and 6 (0-48) after rFVIIa (p<0.001). Most patients had been well compensated with fibrinogen (>1g.l(-1)) and platelets (>50 G.l(-1)) before rFVIIa. The bleeding outcome (cessation, decrease or no change) was associated with the infused dose (81 +/- 31, 71 +/- 24, 64 +/- 23 MUg.kg(-1); p = 0.044) and did not differ whether rFVIIa was administered in the operating room (49%) or ICU (51%). Thrombotic events occurred in 13% of patients without assist devices and in 27% of those with them (but without obvious intra device clotting). The overall 28-day survival rate was 60% and associated with bleeding outcome (p = 0.002). CONCLUSIONS: rFVIIa rescue therapy was followed by control of bleeding in a substantial number of the patients with seemingly acceptable safety; however, thrombotic risk remains a matter of concern. Our observational study suggests that the dose to be tested prospectively is at least 80 MUg.kg(-1). PMID- 21550262 TI - Surgical removal of fractured ATRIASEPT occluder 5 months after successful percutaneous closure of atrial septal defect. PMID- 21550263 TI - Is anterior mediastinum route a shorter choice for esophageal reconstruction? A comparative anatomic study. AB - OBJECTIVE: The reconstruction of the alimentary tract after esophagectomy is usually achieved by either anterior or posterior route through the mediastinum. Previous anatomic studies in comparing the length of both routes applied different methods and yielded inconsistent results. In order to resolve this important debate, we went back to cadavers to clarify the anatomic truth. METHODS: With strictly defined anatomic models, the distance of both routes between the proximal reference point (the cricoid cartilage) and the distal reference points (the celiac axis, the gastroduodenal artery, and the pyloric ring) was obtained on 20 cadavers. RESULTS: The length of the anterior route was significantly longer than the posterior route using the celiac axis (34.9 +/- 2.5 vs 32.4 +/- 2.3 cm, P < 0.0001), but was significantly shorter using either the gastroduodenal artery (35.4 +/- 2.6 vs 36.7 +/- 2 .7 cm, P = 0.0177) or the pyloric ring (34.9 +/- 2.8 vs 36.4 +/- 2.9 cm, P = 0.0168) as the distal reference point which is more clinically relevant. CONCLUSIONS: Compared with the posterior route, the anterior route may be considered as a shorter choice for the conduit to reach the cervical region for esophageal reconstruction. PMID- 21550264 TI - Realignment of the ventricular septum using partial direct closure of the ventricular septal defect in Tetralogy of Fallot. AB - OBJECTIVE: The aim is to describe our technique of partial direct closure of the ventricular septal defect (VSD) in Tetralogy of Fallot (TOF), and assess its influence on the realignment and remodeling of the left ventricular outflow tract. METHODS: Between 2004 and 2010, 32 non-consecutive patients with TOF underwent a direct or partial direct closure of VSD. Median age and weight were 5.2 months and 6.7 kg, respectively. An approach through the right atrium was used in 30 patients and through the infundibulum in two patients. The conal septum was mobilized by transecting the hypertrophic trabeculae to facilitate the approximation of the VSD. The membranous part of the VSD was closed (in the later part of the series) with a small xenopericardial patch to avoid tension on the suture line traversing the area of risk to the bundle of His. Follow-up was complete, with a median duration of 46.9 (range 12-75.3) months. RESULTS: The VSD could be closed successfully in all patients. A residual VSD was partly responsible for one early postoperative re-operation. There were no early or late deaths. At follow-up, all patients were in sinus rhythm. Three patients showed a small residual VSD. Thirty patients had none, one showed trivial, and one had mild aortic regurgitation. The left ventricular outflow showed a good realignment of the ventricular septum in all the patients. CONCLUSIONS: Partial direct closure of the VSD corrects the primary defect in TOF, that is, the malalignment of the septum. It results in a straight, wide open left ventricular outflow tract and brings better support to the aortic root. PMID- 21550265 TI - Different effects of (L)-arginine on the heat-induced unfolding and aggregation of proteins. AB - Circular dichroism spectroscopy was used to study the effect of l-arginine on the temperature related unfolding and aggregation of three growth hormones, i.e. human, porcine and mink growth hormones, and human interferon-alpha2b. (L) arginine can stabilize some proteins and suppress their aggregation as it was exemplified by porcine and mink growth hormones. For some other proteins, on the contrary, the effect of arginine can be negative. Even at low concentrations the amino acid is able to promote the aggregation as it was demonstrated by the experiments with human growth hormone and interferon-alpha2b. (L)-arginine seems not to be a universal excipient for preventing the temperature related aggregation of proteins in contrast to its widespread application in the refolding process. PMID- 21550266 TI - Influence of COX-inhibiting analgesics on the platelet function of patients with subarachnoid hemorrhage. AB - BACKGROUND: Platelet function of patients with subarachnoid hemorrhage (SAH) may play an important part in both rebleeding and delayed cerebral ischemia, but little is known about aggregation pathways during the acute phase of stroke. Analgesics are used regularly in the first days after bleeding, and some can potentially inhibit the cyclooxygenase (COX) enzyme. We examined the platelet function of patients with SAH in order to describe their basal situation and determine whether the administration of intravenous nonsteroidal antiinflammatory drugs (NSAIDs) affected platelet aggregation. METHODS: Arachidonic acid (AA) induced aggregation and the platelet function analyzer (PFA)-100 test with collagen/epinephrine cartridges were used to study a group of SAH patients that was treated with dexketoprofen and dipyrone and to compare them to patients that had received no analgesia. RESULTS: Ninety-six consecutive SAH patients prospectively enrolled in platelet studies. Twenty-seven patients were taking NSAIDs (10 on dexketoprofen and 17 on dipyrone), and there were 15 cases in the control group. AA-induced aggregation was 10% +/- 3.2% for NSAIDs (mean +/- standard error), specifically 17.2% +/- 7% for dexketoprofen and 5.7% +/- 1% for dipyrone. Aggregation in the control group was 72.4% +/- 6% (P = .001). Both analgesics slowed the platelet plug formation during the PFA-100 test, with closure times of 237.2 +/- 25 seconds for dexketoprofen and 198.4 +/- 22 seconds for dipyrone and 138.1 +/- 21 seconds in controls (P = .02). CONCLUSIONS: The administration of COX-inhibiting analgesics leads to an hypoaggregability state in the first days of SAH. Further insight into their impact on complications such as rebleeding and delayed cerebral ischemia is needed in order to optimize the headache treatment of SAH. PMID- 21550267 TI - Surgical treatment of patients with congenital vascular malformation-associated aneurysms. AB - OBJECTIVES: Aneurysms associated with congenital vascular malformation (CVM) comprise critical complication. We review our experience with extracranial CVM associated aneurysms and attempt to clarify their clinical features. PATIENTS AND METHODS: The prevalence, site, size and morphology of the accompanying aneurysms of 48 consecutive CVM patients, who were managed at our hospital from 1999 to 2008, were evaluated. After diagnosis or treatment, the patients were followed up, and the recurrence of aneurysms and patient survival were assessed. RESULTS: CVM-associated aneurysms were found in 14 patients (29%). CVMs were classified according to the Hamburg classification. The patients were classified into groups as follows: four (31%), in the 'predominantly arteriovenous (AV) shunting defect type'; eight (47%), 'combined vascular defects + predominantly AV shunting defects type'; and two (11%), 'combined vascular defects type'. All aneurysms except one situated at the CVM were saccular, whereas nine were fusiform aneurysms; all the ruptured aneurysms and seven out of the nine enlarging aneurysms were saccular. Surgical treatment was performed 8 times in six patients. During the postoperative follow-up period, recurrence and an aneurysm rupture were encountered in one patient each. CONCLUSION: Aneurysm is not a rare complication of CVM. It is important to treat CVM before the emergency presents. In addition to the treatment for malformation, regular screening for and proper management of the aneurysms in CVM patients are indispensable. PMID- 21550269 TI - Prevalence of radix entomolaris in mandibular permanent first molars: a study in a South Indian population. AB - OBJECTIVE: Anatomical racial variations are an acknowledged characteristic in permanent molars. Generally, mandibular first molars have 2 roots; however, the presence of a third root, radix entomolaris (RE), is a major anatomic variant among many population groups. This study evaluated the prevalence of permanent mandibular first molars featuring a distolingual root in a South Indian population. STUDY DESIGN: Five hundred patients of South Indian origin possessing bilateral mandibular first molars were selected. The radiographs of these patients were evaluated under optimal conditions. A total of 1000 mandibular first molars were screened and the incidence of 3-rooted mandibular first molars and the correlation between left and right side occurrence and between either gender was recorded. RESULTS: The prevalence of 3-rooted mandibular first molars was 18.6% of the patients examined and 13.3% of the teeth examined. There was no statistically significant difference between genders or side of occurrence (P > .05). The bilateral incidence of a symmetric distribution was 43.01%. CONCLUSIONS: RE is considered an Asiatic trait. The occurrence of this macrostructure in the South Indian population was 13.3%, which was lower than that of other patients of Mongoloid origin. The clinician must thoroughly examine the radiograph before initiation of endodontic therapy. PMID- 21550270 TI - Expression of the membrane-cytoskeletal linker Ezrin in salivary gland adenoid cystic carcinoma. AB - OBJECTIVE: The aim of this study was to investigate the relationship between membrane cytoskeleton linker protein Ezrin and CD44v6, iNOS, Ki-67, and clinicopathologic characteristics, and the prognostic significance of Ezrin expression in salivary gland adenoid cystic carcinoma (SACC). STUDY DESIGN: Immunohistochemistry and reverse-transcription polymerase chain reaction were used to quantify the expression of Ezrin, CD44v6, inducible nitric oxide synthase (iNOS), and Ki-67 in 75 primary SACCs, 25 tumor-free salivary tissues, and 2 SACC cell lines (ACC-M and ACC-2). Survival analysis was performed to find the prognostic significance of Ezrin expression. RESULTS: Expressions of Ezrin, CD44v6, iNOS, and Ki-67 in SACC tissues, especially with distant metastasis, were significantly higher than in tumor-free tissues. Ezrin mRNA and protein levels in ACC-M cells were significantly higher than in ACC-2 cells. Ezrin, CD44v6, iNOS, and Ki-67 expressions were significantly higher in solid pattern than in cribriform and tubular patterns. Ezrin and its partners, CD44v6, iNOS, and Ki-67, were significantly related to tumor size, clinical stage, perineural and vascular invasion, and recurrence. Furthermore, Ezrin had an independent prognostic effect on overall survival. CONCLUSIONS: The increased expression of Ezrin and its partners, CD44v6, iNOS, and Ki-67, in SACC correlated with histologic patterns, may play a role in distant metastasis, and might indicate poor clinical outcome. PMID- 21550271 TI - A survey of health care and disease in geriatric horses aged 30 years or older. AB - This study reports on aspects of preventive health care and on the prevalence of disease in geriatric (>=30 years old) horses and ponies in North-West England and North Wales. Of 128 questionnaires mailed to horse owners, 87 useable responses were received and 69 horses were subject to veterinary examination. Of the animals examined, 16% were underweight with body condition scores (BCS)<2/5, and 10% were overweight (BCS>3/5). This contrasted with the owner responses that reported 23% of the animals surveyed to be underweight and only 3% to be overweight. When assessed at trot, 77% of the horses were lame on at least one limb, with 97% having a reduced range of motion in at least one joint. Only 16% of these animals were reported by owners to have been lame within the previous 12 months. Owner-reported changes to hair coat were significantly associated with hirsutism or abnormal moulting detected at clinical examination (39%). At least one ophthalmic lesion was identified in all of the horses and ponies examined and 17% of owners reported that their animal had experienced visual problems within the previous year. Although dental abnormalities were detected in all animals where an oral examination was performed, only 42% of owners reported that their horse suffered from a known dental disorder. In general, despite a high prevalence of disease detected in these geriatric animals and with the majority having multiple abnormalities at clinical examination, there was under reporting/under-recognition of these health problems by owners. PMID- 21550272 TI - Field trial of six serological tests for bovine brucellosis. AB - Serum agglutination (SAT), complement fixation (CFT), indirect ELISA (iELISA), competitive ELISA (cELISA), Rose Bengal (RBT) and EDTA-modified agglutination (EDTA) tests were used in parallel on serological samples from 19,935 cattle in 301 herds. The study herds were selected according to putative exposure to Brucellaabortus with cases defined by bacteriological culture or test agreement. No single test identified all infected cattle and, at diagnostic thresholds, relative sensitivity was highest in the iELISA (67.9%) or RBT (78.1%), using bacteriological culture or test agreement, respectively, to define cases. As screening tests, the relative sensitivity of the SAT was highest (75.9% by culture or 84.9% by test agreement), with an optimal threshold of 31 IU. The relative specificity of the diagnostic tests ranged from 99.6% (SAT 31IU) to 100% (iELISA, RBT and CFT). The trial confirmed the value of the SAT as a screening test and the value of parallel testing. PMID- 21550273 TI - Unilateral pelvic mass presenting in postmenopausal patients: report of two unusual cases. AB - We encountered 2 unusual cases of polypoid endometriosis presenting as unilateral ovarian masses. The first was benign and was found in a 57-year-old postmenopausal patient; the second case gave rise to well-differentiated endometrioid carcinoma in an 80-year-old patient. The second patient also had a superficially invasive endometrioid adenocarcinoma of the endometrium arising in a background of complex atypical hyperplasia. Intraoperative evaluation was requested in both cases. PMID- 21550274 TI - Low-grade fibromyxoid sarcoma: a clinicopathologic study of 18 cases, including histopathologic relationship with sclerosing epithelioid fibrosarcoma in a subset of cases. AB - Low-grade fibromyxoid sarcoma (LGFMS) is an uncommon tumor with diverse histopathologic features. It has been found to be histopathologically and genetically related to hyalinizing spindle cell tumor with giant rosettes. Lately, sclerosing epithelioid fibrosarcoma (SEF) has been identified as another rare variant of fibrosarcoma. Very few studies have addressed the aspect of its histopathologic relationship with LGFMS. The present study was conducted to critically analyze the clinicopathologic features of a series of LGFMS cases, including identification of cases with histopathologic similarity with SEF. During a 7-year period, 18 LGFMS cases were diagnosed in 9 male and 9 female patients, had ages ranging from 10 to 69 years (median, 32.5 years), and were most commonly identified in the lower extremities (8 cases, or 44.4%). Most cases (16, 88.8%) showed "classic" features of LGFMS with mild (13 cases, or 72.2%) to moderate atypia (5 cases) and nil mitosis (12 cases, or 66.6 %). Variable features included whorling tumor growth pattern, small rosettes, perivascular hyalinization, and amianthoid-like collagen, along with epithelioid differentiation and nuclear pseudoinclusions within tumor cells. Four cases (22.2%) with large collagenous rosettes were diagnosed as hyalinizing spindle cell tumor with giant rosettes. Distinct SEF-like areas were observed in 6 cases (33.3%). On immunohistochemistry, consistent vimentin positively reinforced fibroblastic lineage of the tumor. Therapeutically, all 4 of 7 cases with available follow-up details, which underwent wide excisions, have been free of disease at 5 to 61 months. Eight excisions with unclear margins included 3 cases free of disease (24, 36, and 52 months) and 1 case with recurrence and metastasis. Two cases of marginal excision had tumor recurrences, including 1 case that recurred after 10 years. Low-grade fibromyxoid sarcoma is an uncommon sarcoma with diverse histopathologic features. Histopathologic relationship exists between LGFMS and SEF in a few cases. An LGFMS is optimally managed with surgical wide excision and follow-up. PMID- 21550275 TI - [Nursing diagnoses in children with congenital heart disease: differences by gender and age]. AB - AIMS: To assess the relationship between gender and age and development of nursing diagnoses in children with congenital heart disease. METHOD: Cross sectional study conducted on forty five children with congenital heart disease. Those nursing diagnoses with a frequency greater than 50% were selected for the association analysis, to which the chi-squared or Fisher tests were applied. The Levene test for homogeneity of variance and then the t-test was used to compare the mean age between children with and without the nursing diagnosis. RESULTS: The children had mean age of 4.74 months (SD=3.78 months) and 66.7% (30) were boys. The female gender was associated with the nursing diagnosis activity intolerance (P=.009) and delayed growth and development (P=.013). The presence of the nursing diagnoses impaired gas exchange, ineffective breathing pattern, ineffective tissue perfusion, decreased cardiac output and activity intolerance was associated with younger children. On the other hand, the children who presented risk of infection and delayed growth and development had higher mean of age. CONCLUSIONS: The population of girls had a higher risk for activity intolerance and delayed growth and development. Furthermore, younger children showed a higher risk for diagnoses related to respiratory and cardiovascular problems. PMID- 21550276 TI - [Faculties versus schools of nursing]. PMID- 21550277 TI - [Adjuvant radiotherapy in patients with endometrial cancers]. AB - The treatment of patients with endometrial cancer has been extensively modified in recent years. Several randomized studies have redefined the indications for adjuvant therapy in tumours staged 1. In the absence of poor prognostic factors, the management tends to be less aggressive than before, often limited to vaginal brachytherapy. Conversely, for more advanced lesions, for which prognosis is poor, combinations of chemoradiation are currently being evaluated. This literature review aims to provide an update on recent developments in the management of adjuvant radiotherapy for endometrial carcinoma. PMID- 21550278 TI - Atlanto-axial subluxation as the initial manifestation of spondyloarthritis. AB - Patients with spondyloarthritis (SpA) typically present with inflammatory back pain, peripheral arthritis and enthesitis, often with distinctive clinical features such as psoriasis and inflammatory bowel diseases. Atlanto-axial subluxation (AAS) is a complication occurring rarely in these patients, and usually is seen in patients with longstanding, severe disease. We present three cases of AAS whose initial presentation of AAS was followed by subsequent development of signs and symptoms meeting the European Spondyloarthropathy Study Group (ESSG) classification criteria for SpA. All three patients were less than 30 years of age and had no other explanation for the AAS. Significantly, all three patients required C1/C2 surgical fusion within 1 year of symptom onset due to severe pain, though none of them developed neurologic complications related to AAS such as myelopathy. Peripheral arthritis/tendonitis, the presence of HLA-B27 gene and family history of SpA appeared to be associated with higher risk of evolution to SpA in these patients. No medical therapy has been systematically examined in this condition. PMID- 21550279 TI - Numb chin syndrome as an early symptom of primary and secondary vasculitis. PMID- 21550280 TI - Intraradicular lumbar disc herniation. PMID- 21550281 TI - Anakinra: an effective treatment in the Schnitzler syndrome. AB - Schnitzler syndrome is a rare disease characterized by chronic urticarial eruption and a monoclonal gammapathy. The exact pathogenesis is still unclear and treatment remains a challenge. We report the case of a patient with a 2-year history of arthralgia, chronic urticaria rash and fever, not responding to different treatments including anti-histaminics, corticosteroids, colchicine and low dose methotrexate. A diagnostic of Schnitzler syndrome was suggested and treatment with anakinra, an interleukin-1 receptor antagonist, was started, leading to a rapid, complete and sustained remission of symptoms. Anakinra seems to constitute an efficient and safe therapeutic approach for this rare disease. PMID- 21550282 TI - HLA-DR17 is associated with enthesitis in psoriatic arthritis. PMID- 21550283 TI - Evaluation of self-report questionnaires for assessing rheumatoid arthritis activity: a cross-sectional study of RAPID3 and RADAI5 and flare detection in 200 patients. AB - OBJECTIVES: To assess the validity of the two self-report questionnaires RAPID3 and RADAI5 for measuring the activity of rheumatoid arthritis (RA) in everyday practice, comparatively to the DAS28, CDAI, and SDAI. To determine cutoffs for flare detection based on patients' and physicians' opinions. METHODS: The RAPID3 and RADAI5 questionnaires were completed by 200 consecutive patients with RA. The DAS28, CDAI, and SDAI were computed in each patient. Patients and physicians stated whether a flare was occurring. Pairwise Spearman correlation coefficients were computed between the two scores and three indices. The kappa coefficient was used to assess agreement between the patients and physicians regarding the presence of a flare. Receiver-operating characteristic (ROC) curves were constructed to determine cutoffs for flare detection. RESULTS: The 200 patients had a mean age of 57 +/- 11.5 years, a mean RA duration of 13 +/- 8.3 years, a mean DAS28 of 3.61 +/- 1.43, a mean CDAI of 12.7 +/- 9.89, and a mean SDAI of 13.4 +/- 10.45. The mean RAPID3 and RADAI5 scores were 3.45 +/- 2 and 3.93 +/- 2.18, respectively. The RAPID3 and RADAI5 scores correlated significantly with the three composite activity indices, with rho values ranging from 0.64 to 0.74. The flare rate was 35% according to the patients and 22% according to the physicians, with moderate agreement between patients and physicians (kappa=0.44). Flare cutoffs with satisfactory sensitivity and specificity values were obtained for the two scores and three indices. For the three indices, flare cutoffs according to the physicians were within the range indicating moderate disease activity: 4.04 for the DAS28, 14.5 for the CDAI, and 16.7 for the SDAI. The RAPID3 and RADAI5 flare cutoffs according to the physicians and patients were similar, 4.27 and 4.33 for RAPID3 and 4.5 and 4.7 for RADAI5, respectively. CONCLUSION: These results confirm the validity of the RAPID3 and RADAI5 self report questionnaires and support their widespread use in everyday practice in patients with RA. The self-report questionnaire scores correlate with the composite activity index values and allow the detection of activity peaks or flares. PMID- 21550284 TI - Systemic lupus erythematosus revealed by sweet syndrome. PMID- 21550285 TI - Animal models with pathological mineralization phenotypes. AB - Extracellular matrix mineralization is important for mechanical stability of the skeleton and for calcium and phosphate storage. Professional mineral-disposing cell types are hypertrophic chondrocytes, odontoblasts, ameloblasts and osteoblasts. Since ectopic mineralization causes tissue dysfunction mineralization inhibitors and promoting factors have to be kept in close balance. The most prominent inhibitors are fetuin-A, matrix-Gla-protein (MGP), SIGBLING proteins and pyrophosphate. In spite of their ubiquitous presence, their loss entails a specific rather than a stereotypic pattern of ectopic mineralization. Typical sites of pathological mineral accumulation are connective tissues, articular cartilage, and vessels. Associated common human pathologies are degenerative joint disorders and arteriosclerosis. This article gives a summary on what we have learned from different mouse models with pathologic mineralization phenotypes about the role of these inhibitors and the regulation of mineralization promoting factors. PMID- 21550286 TI - Tacrolimus (FK506) inhibits interleukin-1beta-induced angiopoietin-1, Tie-2 receptor, and vascular endothelial growth factor through down-regulation of JNK and p38 pathway in human rheumatoid fibroblast-like synoviocytes. AB - OBJECT: This study aimed to identify the regulatory effect of tacrolimus on the interleukin-1beta (IL-1beta)-induced expressions of angiopoietin-1 (Ang-1), Tie-2 receptor (Tie-2), and vascular endothelial growth factor (VEGF) in human rheumatoid fibroblast-like synoviocytes (FLS) and to determine the regulatory mechanism in the mitogen-activated protein kinases (MAPKs) signaling pathway. METHODS: IL-1beta-induced Ang-1, Tie-2, and VEGF expressions with and without tacrolimus were measured in cultured FLS using real time-polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining. The effect of tacrolimus on the regulation of Ang-1, Tie-2 and VEGF expressions through the MAPK signaling pathway was identified by Western blotting and immunofluorescence staining. RESULTS: IL-1beta appeared to induce marked expressions of Ang-1, Tie-2, and VEGF in cultured FLS. Tacrolimus significantly inhibited Ang-1, Tie-2, and VEGF mRNA and protein in cultured FLS treated with 10 ng/ml IL-1beta. In addition, expressions of these angiogenic molecules were shown to involve all three of the studied MAPK signaling pathways, including ERK, JNK, and p38. However, the inhibitory effects of tacrolimus on Ang 1, Tie-2, and VEGF proteins were regulated by blocking the phosphorylations of JNK and p38 MAPK, but not that of ERK. CONCLUSION: This study demonstrates that tacrolimus inhibits the expressions of Ang-1, Tie-2, and VEGF by blocking the activations of the IL-1beta-mediated JNK and p38 MAPK pathways in human FLS. This suggests that tacrolimus contributes to the suppression of angiogenesis in the pathogenesis of RA. PMID- 21550288 TI - The placebo effect: still under a cloud of confusion. Comments on the update by J.-M. Berthelot. PMID- 21550289 TI - Cold Pad-Batch dyeing method for cotton fabric dyeing with reactive dyes using ultrasonic energy. AB - Reactive dyes are vastly used in dyeing and printing of cotton fibre. These dyes have a distinctive reactive nature due to active groups which form covalent bonds with -OH groups of cotton through substitution and/or addition mechanism. Among many methods used for dyeing cotton with reactive dyes, the Cold Pad Batch (CPB) method is relatively more environment friendly due to high dye fixation and non requirement of thermal energy. The dyed fabric production rate is low due to requirement of at least twelve hours batching time for dye fixation. The proposed CPB method for dyeing cotton involves ultrasonic energy resulting into a one third decrease in batching time. The dyeing of cotton fibre was carried out with CI reactive red 195 and CI reactive black 5 by conventional and ultrasonic (US) method. The study showed that the use of ultrasonic energy not only shortens the batching time but the alkalis concentrations can considerably be reduced. In this case, the colour strength (K/S) and dye fixation (%F) also enhances without any adverse effect on colour fastness of the dyed fabric. The appearance of dyed fibre surface using scanning electron microscope (SEM) showed relative straightening of fibre convolutions and significant swelling of the fibre upon ultrasonic application. The total colour difference values DeltaE (CMC) for the proposed method, were found within close proximity to the conventionally dyed sample. PMID- 21550290 TI - fMRI brain mapping during motion capture and FES induced motor tasks: signal to noise ratio assessment. AB - Functional Electrical Stimulation (FES) is a well known clinical rehabilitation procedure, however the neural mechanisms that underlie this treatment at Central Nervous System (CNS) level are still not completely understood. Functional magnetic resonance imaging (fMRI) is a suitable tool to investigate effects of rehabilitative treatments on brain plasticity. Moreover, monitoring the effective executed movement is needed to correctly interpret activation maps, most of all in neurological patients where required motor tasks could be only partially accomplished. The proposed experimental set-up includes a 1.5 T fMRI scanner, a motion capture system to acquire kinematic data, and an electro-stimulation device. The introduction of metallic devices and of stimulation current in the MRI room could affect fMRI acquisitions so as to prevent a reliable activation maps analysis. What we are interested in is that the Blood Oxygenation Level Dependent (BOLD) signal, marker of neural activity, could be detected within a given experimental condition and set-up. In this paper we assess temporal Signal to Noise Ratio (SNR) as image quality index. BOLD signal change is about 1-2% as revealed by a 1.5 T scanner. This work demonstrates that, with this innovative set-up, in the main cortical sensorimotor regions 1% BOLD signal change can be detected at least in the 93% of the sub-volumes, and almost 100% of the sub volumes are suitable for 2% signal change detection. The integrated experimental set-up will therefore allows to detect FES induced movements fMRI maps simultaneously with kinematic acquisitions so as to investigate FES-based rehabilitation treatments contribution at CNS level. PMID- 21550291 TI - Objective assessment of walking environments in ultra-dense cities: development and reliability of the Environment in Asia Scan Tool--Hong Kong version (EAST HK). AB - The 91-item Environment in Asia Scan Tool--Hong Kong (EAST-HK) was developed to objectively assess aspects of the neighbourhood environment hypothesised to affect walking in Hong Kong and similar ultra-dense Asian metropolises. Reliability was assessed by four pairs of raters auditing 422 street segments, 204 on two occasions. Seventy-one items showed sufficient variability and reliability. These can be used to estimate neighbourhood walkability in Hong Kong. Fourteen items showed good reliability but limited variability and may be used in a more variable context. Auditing of only 50% of street segments may be sufficient to obtain representative estimates of neighbourhood walkability. PMID- 21550292 TI - Acquired melanosis of a conjunctival autograft following pterygium surgery. AB - Pterygium excision with conjunctival autografting is an established surgical treatment for symptomatic pterygia. Documented complications include wound dehiscence, Tenon's granuloma, inclusion cysts, graft oedema, and corneoscleral dellen. We illustrate a previously unreported complication of this technique. A 41 year old Sri Lankan man presented with selective hyperpigmentation of the conjunctival autograft approximately three months following pterygium excision. The possible biological mechanisms behind this complication are discussed. PMID- 21550293 TI - Tumor regression induced by photodynamic treatment with chlorin p(6) in hamster cheek pouch model of oral carcinogenesis: Dependence of mode of tumor cell death on the applied drug dose. AB - We investigated tumor regression and the mode of tumor cell death induced by photodynamic treatment (PDT) with chlorin p(6) (Cp(6)) in hamster cheek pouch model of oral squamous cell carcinoma. Cp(6) was administered systemically through intraperitoneal injection and after 4h the tumors were subjected to photodynamic treatment using red light (660+/-25nm, fluence ~100J/cm(2)). Tumor response to PDT was monitored by measuring the tumor volume before PDT and 1week after. Results show that smaller tumors (?80mm(3)) regressed completely after PDT with Cp(6) dose of 2.0mg/kg body weight and for the bigger tumors (~180mm(3)) higher dose of Cp(6) (4.0mg/kg) was more effective. Tumors treated with lower Cp(6) dose showed infiltration of immune cells, absence of TUNEL labeling, smeared pattern of DNA fragmentation and no significant increase in caspase-3 activity suggestive of necrotic cell death and inflammation. In tumors treated with higher Cp(6) dose, features characteristic of apoptotic cell death such as extensive TUNEL positive labeling, increase in caspase-3 activity and laddered pattern of DNA fragmentation were observed and there was no infiltration of immune cells. PDT with Cp(6) was also found to lead to expression of matrix metalloprotease-9 (MMP-9) which was greater at lower drug dose PDT as compared to higher drug dose PDT. These results suggest that drug dose plays an important role in determining the mechanism of tumor cell death and effectiveness of PDT. PMID- 21550294 TI - Decreased oral cancer risk by moderate alcohol consumption in non-smoker postmenopausal women. AB - OBJECTIVE: Alcohol consumption is a strong risk factor for oral cancer however; an ambiguous biphasic impact of moderate and excessive alcohol intake on the risk of upper aerodigestive tract cancers has also been published. The aim of the present study was to clarify the dose-related risk of alcohol consumption for oral cancer, in male and female cases. MATERIALS AND METHODS: Six-hundred and eight non-smoker patients (466 males and 142 females) with squamous cell oral carcinomas (OCs) and 406 non-smoker tumor free controls (264 males and 142 females) were included into the study. Data of three groups; abstinent cases, moderate and excessive alcohol consumers were recorded according to the drinking habits of both OC cases and their controls. Blood glucose levels in male and female cases and menopausal state of women were also registered. RESULTS: Mean age of female patients was significantly higher than of male cases (p<0.01). Excessive alcohol consumption was a strong risk factor for both sexes, however moderate alcohol intake proved to be an OC risk for men (OR: 1.4) and decreased the OC risk for women (OR: 0.7). Elevated blood glucose level proved to be an OC risk factor for the predominantly postmenopausal women (OR: 1.6), whereas did not affect the OC risk among men. CONCLUSION: The presented findings are controversial to the hypothesis that women are more vulnerable to alcohol-induced carcinogenesis as compared with men. Increased insulin sensitivity and higher estrogen levels are advantageous systemic effects of moderate ethanol intake and they might reduce the risk for OC in postmenopausal women. PMID- 21550295 TI - Many needles in a haystack: cell-type specific abiotic stress responses. AB - Plants react to abiotic stress with a number of physiological, biochemical, and developmental alterations. These responses include changes in signaling components, gene transcription, non-coding RNAs, proteins, and metabolites that occur in a cell-type and tissue-specific manner. Recent advances in cell-type specifically isolating protoplasts and nuclei from plants, extracting mRNA from targeted cells, and whole-genome transcriptional profiling have enabled scientists to gain insight into how cells and tissues respond transcriptionally to abiotic stress. Continued technological advances in profiling the proteomes, metabolomes, and other biological components of specific cells will continue to broaden our understanding of plant stress responses. PMID- 21550297 TI - Synthesis and spectroscopic studies of homo-binuclear, alkoxo bridged homo- and hetero-tetranuclear metal complexes of a bis-N2O4 Schiff base ligand derived from ethanolamine and macroacyclic tetranaphthaldehyde. AB - Three new homo-binuclear Ni(II), Cu(II), Zn(II) complexes (2-4), homo tetranuclear Cu(II) complex (5), and hetero-tetranuclear Cu(II)-Ni(II) complex (6) of a macroacyclic potentially bis-hexadentate N2O4 Schiff base have been synthesized. The imino-alcohol ligand, H4L was obtained by the condensation of ethanolamine with 2,2'-[2,3-bis(1-formyl-2-naphthyloxymethyl)-but-2-ene-1,4 diyldioxy]bis(naphthalene-1-carbaldehyde). The structures of both the Schiff base and its complexes have been proposed by elemental analyses, spectroscopic data i.e. IR, 1H and 13C NMR, UV-vis, electrospray ionisation mass spectra, molar conductivities and magnetic susceptibility measurements. The ligand has two similar compartments to bind first primary two metal ions, and acts bi- or tetra negative, bis-tetradentate forming five membered chelate ring. However, secondary two metal ions (either Cu2+ or Ni2+) are ligated with dianionic oxygen atoms of the alcohol groups and are linked to the 1,10-phenanthroline-nitrogen atoms in the tetranuclear complexes (5 and 6). PMID- 21550296 TI - Functional context, biosynthesis, and genetic encoding of pyrrolysine. AB - In Methanosarcina spp., amber codons in methylamine methyltransferase genes are translated as the 22nd amino acid, pyrrolysine. The responsible pyl genes plus amber-codon containing methyltransferase genes have been identified in four archaeal and five bacterial genera, including one human pathogen. In Escherichia coli, the recombinant pylBCD gene products biosynthesize pyrrolysine from two molecules of lysine and the pylTS gene products direct pyrrolysine incorporation into protein. In the proposed biosynthetic pathway, PylB forms methylornithine from lysine, which is joined to another lysine by PylC, and oxidized to pyrrolysine by PylD. Structures of the catalytic domain of pyrrolysyl-tRNA synthetase (archaeal PylS or bacterial PylSc) revealed binding sites for tRNAPyl and pyrrolysine. PylS and tRNAPyl are now being exploited as an orthogonal pair in recombinant systems for introduction of useful modified amino acids into proteins. PMID- 21550298 TI - Experimental (FT-IR and FT-Raman) and theoretical (HF and DFT) investigation, IR intensity, Raman activity and frequency estimation analyses on 1-bromo-4 chlorobenzene. AB - The FT-IR and FT-Raman spectra of 1-bromo-4-chlorobenzene (1-Br-4-CB) have been recorded using Bruker IFS 66V spectrometer in the region of 4000-100 cm(-1). Ab initio-HF (HF/6-311+G (d, p)) and DFT (B3LYP/6-31++G (d, p)/6-311++G (d, p)) calculations have been performed giving energies, optimized structures, harmonic vibrational frequencies, depolarization ratios, IR intensities, Raman activities. The vibrational frequencies are calculated and scaled values are compared with FT IR and FT-Raman experimental values. Comparison of simulated spectra with the experimental spectra provides important information, the computational method have the ability to describe the vibrational methods. The frequency estimation analysis on HF and DFT is made. The impact of di-substituted halogens on the benzene molecule has also been discussed. PMID- 21550299 TI - Glass formation and properties of Ge-Te-BiI3 far infrared transmitting chalcohalide glasses. AB - A novel series of Ge-Te-BiI(3) chalcogenide glasses were prepared by traditional melt-quenching method and the glass-forming region was determined. Properties measurements including density, Vis-NIR and infrared (IR) transmission spectra with FTIR, XRD, DSC were adopted to analyze the composition, structure and performance of the Ge-Te-BiI3 glass system. Based on the metallization criterion and band gap energy theory, the relationships between energy gap, metallization criterion and glass composition was investigated. The results show that with the addition of BiI3, the glasses-forming ability and thermal stability are improved. The values of energy band gap and metallization criterion are within the range of 0.627-0.343 eV and 0.177-0.131, respectively. These series of glasses have wide optical transmission window from 2.2 to 25 MUm and can offer an alternative solution for far infrared transmitting applications. PMID- 21550300 TI - FT-IR and FT-Raman investigation, computed vibrational intensity analysis and computed vibrational frequency analysis on m-Xylol using ab-initio HF and DFT calculations. AB - The FT-IR and FT-Raman spectra of m-Xylol molecule have been recorded using Bruker IFS 66V spectrometer in the range 4000-100cm(-1). The molecular geometry and vibrational frequencies in the ground state are evaluated using the Hartree fock (HF) and B3LYP with 6-31+G (d, p), 6-31++G (d, p) and 6-311++G (d, p) basis sets. The computed frequencies are scaled using a suitable scale factors to yield good agreement with the observed values. The HF and DFT analysis agree well with experimental observations. Comparison of the fundamental vibrational frequencies with calculated results by HF and B3LYP methods indicate that B3LYP/6-311++G (d, p) is superior to HF/6-31+G (d, p) for molecular vibrational problems. The complete data of this title compound provide some useful information for the study of substituted benzenes. The influences of Methyl groups on the geometry of benzene and its normal modes of vibrations have also been discussed. PMID- 21550302 TI - Assessment of DNA damage by comet assay and fast halo assay in buccal epithelial cells of Indian women chronically exposed to biomass smoke. AB - Genotoxicity of indoor air pollution from biomass burning was evaluated in buccal epithelial cells (BECs) of 85 pre-menopausal Indian women who were engaged in cooking with biomass (wood, dung, crop residues) and 76 age-matched control women who were cooking with cleaner fuel liquefied petroleum gas (LPG). DNA damage was evaluated by comet assay and fast halo assay (FHA). The concentrations of particulate matter with aerodynamic diameters of less than 10 and 2.5 MUm (PM(10) and PM(2.5), respectively) in indoor air were measured by real-time aerosol monitor. Generation of reactive oxygen species (ROS) was measured by flow cytometry and the level of superoxide dismutase (SOD) by spectrophotometry. Compared with control, BEC of biomass users illustrated 2.6-times higher comet tail % DNA (32.2 vs. 12.4, p < 0.001), 2.7-times greater comet tail length (37.8 MUm vs. 14.2 MUm, p < 0.001) and 2.2-times more olive tail moment (7.1 vs. 3.2, p < 0.001), suggesting marked increase in DNA damage. FHA also showed 5-times more mean nuclear diffusion factor (9.2 vs. 1.8, p < 0.0001) in BEC of biomass users, confirming sharp rise in DNA single strand breaks. Airway cells of biomass-using women showed 51% rise in ROS generation but 28% reduction in SOD, suggesting oxidative stress in the airways. Indoor air of biomass-using households had 3 times more PM(10) and PM(2.5) than LPG-using families, and DNA damage showed positive association with PM(10) and PM(2.5) levels controlling education, kitchen location and family income as potential confounders. In summary, chronic inhalation of biomass smoke elicits oxidative stress and extensive DNA damage in BEC. PMID- 21550301 TI - Ocular and cervical vestibular evoked myogenic potentials produced by air- and bone-conducted stimuli: comparative properties and effects of age. AB - OBJECTIVE: To compare amplitudes, latencies, symmetry and the effects of age for both ocular and cervical vestibular evoked myogenic potentials (oVEMPs and cVEMPs) produced by different types of air- (AC) and bone-conducted (BC) stimuli. METHODS: Sixty-one normal subjects aged 18-80 years participated. Both reflexes were recorded in response to AC clicks, AC and BC 500 Hz tone bursts, forehead taps and lateral mastoid accelerations. RESULTS: AC tone bursts, clicks and BC tone bursts evoked oVEMPs in 81%, 59% and 65% of ears, respectively. The AC stimuli had higher thresholds for oVEMPs than for cVEMPs and all three stimuli produced higher asymmetry for the oVEMP than for the cVEMP. Forehead taps and lateral pulses evoked oVEMPs in 96% and 92% of cases. AC click- and BC tone burst evoked oVEMPs showed a significant decline with age. CONCLUSIONS: AC stimulation and BC tone bursts delivered to the mastoid are less effective in evoking oVEMPs than in evoking cVEMPs, have high degrees of asymmetry in normals and appear to decline with age. Forehead taps and lateral accelerations produce more symmetrical effects and showed no significant decline with age. SIGNIFICANCE: Stimulus properties need to be considered when deciding the most appropriate way to investigate vestibular function using oVEMPs. PMID- 21550303 TI - Surgical management and mid-term outcomes of 108 patients with infective endocarditis. AB - This study evaluates the early and mid-term outcomes, predictors of mortality and morbidity and quality of life of patients operated for infective endocarditis. Data on 108 patients undergoing 113 surgical procedures during October 1998 to January 2010 was prospectively collected. NYHA Class was >III in 49 (43.4%) cases. Thirty-seven (33%) patients had isolated mitral valve procedures, 58 (51%) had aortic valve, two had tricuspid valve and 16 had multivalvular procedures. Active endocarditis was noted in 86 (76%) procedures, native valve endocarditis in 105 (93%) and prosthetic valve endocarditis in eight procedures. Logistic EuroSCORE at presentation was >14 in 18 (17%) patients. Staphylococcus aureus was the most common organism isolated. Follow-up was carried out in 76/85 (88.37%) of surviving patients, and the mean follow-up time was 37.2 months. Functional class and quality of life (using EQ-5D Health Questionnaire) were assessed by telephone interviews. NYHA Class on follow-up was I-II in 62/76 (83%). Multivariate predictor of 30-day mortality was peripheral vascular disease (p = 0.025) whilst multivariate predictors of long-term survival were male sex (p = 0.01), peripheral vascular disease (p = 0.02) and bypass time (p = 0.006). The overall survival was 87% at one year and 80% at five years. Thirty-three percent (25/76) patients reported a score reflecting full health. Optimal antibiotic therapy and timely surgical intervention were associated with improved functional class, quality of life and mid-term survival. PMID- 21550304 TI - Dealing with a troublesome body: a qualitative interview study of men's experiences living with prostate cancer treated with endocrine therapy. AB - PURPOSE: Endocrine therapy for prostate cancer causes substantial side effects, and previous studies have focused on the impacts on sexuality and masculinity. Little is known about how men experience bodily alterations in everyday life through the course of the prostate cancer and treatment. The aim of this study was to show how men with prostate cancer experience bodily changes and how these alterations influence daily life. METHOD: The study was conducted via qualitative interviews with a phenomenological hermeneutic approach. We interviewed ten men (aged 58-83) with prostate cancer who received endocrine therapy as the primary treatment method. RESULTS: The results showed that five themes were important for the men's experiences of their bodily alterations throughout the course of the illness: "something is 'wrong'", "when the body becomes troublesome", "to be well or to be ill", "dealing with the alterations" and "to talk about cancer and the intimate details". Initially, the shock of receiving a cancer diagnosis and the physical changes in their bodies were at the forefront of many patients' minds. Eventually, the impact of the side effects became more evident, which caused problems in everyday life. Yet, the men were able to reflect on the impact of treatment on their everyday lives. CONCLUSION: This study showed that hormone treatment has a significant influence, both directly and indirectly, on the bodies of prostate cancer patients. The experiences of men with prostate cancer may lead to feelings of loss of identity on an existential level. PMID- 21550305 TI - Retrospective analysis of outcomes following transfer of previously cryopreserved oocytes, pronuclear zygotes and supernumerary blastocysts. AB - Oocyte cryopreservation still bears the experimental label. Remarkable innovation in this field has led to immense improvement in clinical outcomes and has even resulted in outcomes comparable to those achieved following fresh embryo transfers. Such success has prompted this centre to investigate outcomes of cryopreservation options (oocyte versus pronuclear zygote versus supernumerary day-5 blastocyst after fresh embryo transfer). This study retrospectively analysed 200 cryopreservation cycles which were divided into three groups according to cryopreservation option, which were all cultured to blastocyst-stage post thaw/warming from January 2005 to December 2008, and compared them with 400 fresh embryo transfer cycles from the same time period. When compared with fresh embryo transfer, frozen embryo transfers originating from previously cryopreserved oocytes or pronuclear zygotes resulted in similar implantation, pregnancy and live-birth rates; however, frozen embryo transfers originating from supernumerary day-5 blastocysts resulted in lower outcomes. Thus, oocyte and/or pronuclear zygote cryopreservation appear to be the most viable options for women desiring fertility preservation. Cryopreservation of supernumerary blastocysts may lead to a slightly lower live-birth rate since the best-quality blastocysts are generally transferred during the fresh embryo transfer attempt. PMID- 21550306 TI - Cryopreservation of oocytes in experimental models. AB - Until recently, success in oocyte cryopreservation has been very limited mainly due to poor understanding of the complex physiological processes that lead to cell damage during cryopreservation. In the past three decades, however, a wealth of information has been collected using various different animal models, which has led to development of new technologies and optimization of existing ones. The use of these models has provided the opportunity for research that may not have been possible with human material. Today, results of these studies still continue to form the basis of oocyte cryobiology. This review discusses these studies, especially the physiological impacts of cryopreservation on oocyte biology. It will also focus on the role that animal models have played in improvement strategies, validation before translating new techniques into the human model and the advances made in the human in IVF because of these animal models. Finally, existing investigations and their potential impact in other areas of research will be discussed. Until recently, success in oocyte cryopreservation has been very limited mainly due to poor understanding of the complex physiological processes that lead to cell damage during cryopreservation. In the past three decades, however, a wealth of information has been collected using various different animal models, which has led to development of new technologies and optimization of existing ones. The use of these models provided the opportunity for research that may not have been possible with human material. Today, animal models still continuously provide imperative data that facilitate further advancements in oocyte cryobiology. This review will focus on the physiological impacts, current improvement strategies and future applications of oocyte cryopreservation using animal models as they benefit not only human oocyte cryopreservation procedures, but also the human species through their usefulness in agriculture, medicine and conservation. PMID- 21550308 TI - Factors influencing engraftment in HLA-haploidentical/mismatch related transplantation with combined granulocyte-colony stimulating factor-mobilized peripheral blood and bone marrow for patients with leukemia. AB - Unmanipulated HLA-haploidentical/mismatch related transplantation with combined granulocyte-colony stimulating factor-mobilized peripheral blood stem cells (G PBSCs) and granulocyte-colony stimulating factor-mobilized bone marrow (G-BM) has been used as an alternative transplantation strategy for patients without an HLA matched donor. In this transplantation setting, factors associated with hematopoietic recovery have not been defined completely. The aim of this study was to investigate the factors influencing the engraftment in this transplantation setting for patients with leukemia. The study group comprised 104 patients with leukemia who underwent transplantation at a single institution between 2005 and 2008. Factors correlating with neutrophil and platelet engraftment post-transplantation were analyzed retrospectively. All patients achieved an absolute neutrophil count of 500/MUL with a mean time of 13.6days (range 8-20days) and a platelet count over 20*10(9)/L with a mean time of 20.2days (range 16-26days). In univariate analysis, donor and age were associated with increased risk of neutrophil engraftment, but their significance was lost upon multivariate analysis. The sex, age, donor, CD34(+) cell dose, conditioning regimen, mismatched locus, ABO mismatched and diagnosis have no effect on platelet engraftment. Our results suggest that it is an ideal approach to treat patients with leukemia with HLA-haploidentical/mismatched related transplantation with combined G-PBSCs and G-BM for a high level of stem cells without delayed engraftment. PMID- 21550309 TI - Early diagnosis and management of postpartum hemolytic uremic syndrome with plasma exchange. AB - The likelihood of survival in cases of postpartum hemolytic uraemic syndrome (HUS) is as high as 80-90% with early diagnosis and aggressive treatment using plasma exchange (PE). The patients, referred to our center, diagnosed as postpartum HUS presented with thrombocytopenia, microangiopathic hemolytic anaemia with or without fever and severe renal failure, were managed aggressively with PE in conjunction with hemodialysis. All patients showed clinical improvement, along with laboratory indicators like normal renal function tests, increased platelet counts and decreased lactic dehydrogenase levels. Awareness amongst treating physicians, early diagnosis and treatment with PE could be the key factors in reducing maternal mortality due to postpartum HUS in developing countries. PMID- 21550310 TI - Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. AB - BACKGROUND: Chloroquine has in-vitro activity against influenza and could be an ideal candidate for worldwide prevention of influenza in the period between onset of a pandemic with a virulent influenza strain and the development and widespread dissemination of an effective vaccine. We aimed to assess the efficacy of such an intervention. METHODS: In this randomised, double-blind, placebo-controlled trial done at a single centre in Singapore, we randomly assigned (1:1) healthy adults to receive chloroquine phosphate (500 mg/day for 1 week, then once a week to complete 12 weeks) or matching placebo by use of a computer-generated randomisation list. Participants filled an online symptom diary every week, supplemented by daily diaries and self-administered nasal swabs when unwell. Haemagglutination-inhibition assays for influenza A (H1N1, H3N2) and B were done on blood samples taken at baseline and after 12 weeks. The primary outcome was laboratory-confirmed clinical influenza defined by specific symptoms accompanied by influenza RNA on nasal swabs or a four-fold increase in haemagglutination inhibition titres over the 12-week study period. Analysis was by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01078779. FINDINGS: From November, 2009, to February, 2010, we recruited 1516 eligible participants. 1496 (96%) returned at week 12 and were included in the efficacy analysis. Adherence to study intervention was 97%, and 94% of the scheduled weekly diaries were completed. Eight (1%) of 738 participants had laboratory confirmed clinical influenza in the placebo group and 12 (2%) of 724 in the chloroquine group (relative risk 1.53, 95% CI 0.63-3.72; p=0.376). 29 (4%) of 738 had laboratory-confirmed influenza infection (symptomatic or asymptomatic) in the placebo group and 38 (5%) of 724 in the chloroquine group (1.34, 0.83-2.14; p=0.261). 249 (33%) of 759 participants reported adverse events (mostly mild) in the placebo group and 341 (45%) of 757 in chloroquine group (p<0.0001). Headache, dizziness, nausea, diarrhoea, and blurred vision were more common in the chloroquine group, but rarely resulted in treatment discontinuation. One serious adverse event (hepatitis) was possibly related to chloroquine. INTERPRETATION: Although generally well tolerated by a healthy community population, chloroquine does not prevent infection with influenza. Alternative drugs are needed for large scale prevention of influenza. FUNDING: National Medical Research Council, Singapore. PMID- 21550311 TI - Bacterial meningitis: frapper fort ou frapper doucement? PMID- 21550312 TI - Use of chloroquine in viral diseases. PMID- 21550313 TI - Slow initial beta-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: a randomised, controlled trial. AB - BACKGROUND: New antimicrobials or adjunctive treatments have not substantially reduced mortality from acute childhood bacterial meningitis. Paracetamol seems to have beneficial effects in bacteraemic adults and some experts recommend initial slow beta-lactam infusion. We investigated whether these treatments had benefits in children with bacterial meningitis. METHODS: We did a prospective, double blind, single-centre study with a two-by-two factorial design in Luanda, Angola. 723 participants aged 2 months to 13 years were randomly assigned two 12 h intravenous infusions, without loading doses, of 125 mg/kg bodyweight cefotaxime (total dose 250 mg/kg) given over 24 h, or 250 mg/kg bodyweight cefotaxime given as four boluses, one every 6 h over 24 h. Patients also received oral paracetamol at an initial dose of 30 mg/kg then 20 mg/kg every 6 h for 48 h or placebo. Two primary endpoints, death or severe neurological sequelae and deafness, were analysed by intention to treat. The study was registered as ISRCTN62824827. FINDINGS: 183 patients were assigned cefotaxime infusion plus paracetamol and 180 patients to each of the other three treatment groups. Causative agents were identified in 63% of cases and were mostly Haemophilus influenzae type b, Streptococcus pneumoniae, or Neisseria meningitidis. Death or severe neurological sequelae were seen in 340 (47%) of 723 children and deafness in 45 (12%) of 374 tested, both distributed similarly across treatment groups. In a predefined subgroup analysis of death or any sequelae, by causative agent, a benefit was seen in favour of infusion over bolus in children with pneumococcal meningitis (infusion plus placebo, odds ratio 0.18, 95% CI 0.03-0.90, p=0.04). A similar effect was seen for children receiving cefotaxime infusion plus paracetamol, but the difference was not significant (OR 0.22, 95% CI 0.04-1.09, p=0.06). A post hoc analysis suggested that cefotaxime infusion plus paracetamol lowered mortality at least during the first 3 days, irrespective of cause. INTERPRETATION: Although no tested regimen improved the final outcomes of these very ill children, studies of longer courses of beta-lactam infusion plus paracetamol seem warranted. FUNDING: The Paivikki and Sakari Sohlberg, the Sigrid Juselius, and the Paediatric Research Foundations, and the daily newspaper Helsingin Sanomat. PMID- 21550315 TI - Should sex influence the choice between carotid stenting and carotid endarterectomy? PMID- 21550314 TI - Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). AB - BACKGROUND: In the randomised Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the primary endpoint did not differ between carotid artery stenting and carotid endarterectomy in patients with symptomatic and asymptomatic stenosis. A prespecified secondary aim was to examine differences by sex. METHODS: Patients who were asymptomatic or had had a stroke or transient ischaemic attack within 180 days before random allocation were enrolled in CREST at 117 clinical centres in the USA and Canada. The primary outcome was the composite of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke within 4 years. We used standard survival methods including Kaplan-Meier survival curves and sex-by-treatment interaction term to assess the relation between patient factors and risk of reaching the primary outcome. Analyses were by intention to treat. CREST is registered with ClinicalTrials.gov, NCT00004732. FINDINGS: Between Dec 21, 2000, and July 18, 2008, 2502 patients were randomly assigned to carotid endarterectomy (n=1240) or carotid artery stenting (n=1262), 872 (34.9%) of whom were women. Rates of the primary endpoint for carotid artery stenting compared with carotid endarterectomy were 6.2% versus 6.8% in men (hazard ratio [HR] 0.99, 95% CI 0.66-1.46) and 8.9% versus 6.7% in women (1.35, 0.82-2.23). There was no significant interaction in the primary endpoint between sexes (interaction p=0.34). Periprocedural events occurred in 35 (4.3%) of 807 men assigned to carotid artery stenting compared with 40 (4.9%) of 823 assigned to carotid endarterectomy (HR 0.90, 95% CI 0.57 1.41) and 31 (6.8%) of 455 women assigned to carotid artery stenting compared with 16 (3.8%) of 417 assigned to carotid endarterectomy (1.84, 1.01-3.37; interaction p=0.064). INTERPRETATION: Periprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy whereas there is little difference in men. Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women. FUNDING: National Institute of Neurological Disorders and Stroke and Abbott Vascular Solutions (formerly Guidant). PMID- 21550316 TI - A dialogue with historical concepts of epilepsy from the Babylonians to Hughlings Jackson: persistent beliefs. AB - Epilepsy is one of the few neurological disorders to be recognized in Antiquity. The etiology of epilepsy has evolved from affliction of evil spirits and bad omens to an organic disease of the brain. Geographically separate cultures have recognized the diverse symptomatology of epilepsy from vigorous convulsions to spontaneous localized jerking since times immemorial. Similarly, the diagnostic procedures and treatment options have varied in different milieus. In this review we have followed the course of history chronologically from Babylonians to Hughlings Jackson, mapping the conceptual development of epilepsy and the origin of some of the positive and negative attitudes inherited into today's epileptology. Original writings, such as Hughlings Jackson's letters, and English translations of early Latin work, where available, were used as primary sources of information. Where primary sources were not accessible, we consulted research articles, books, and commentaries by eminent historians and epileptologists. PMID- 21550317 TI - Patient-reported outcomes of prostate high-dose-rate brachytherapy boost comparing an outpatient and inpatient protocol: a two-center chronologic cohort study. AB - PURPOSE: To determine patients' self-reported experiences of outpatient high-dose rate prostate brachytherapy boost, and compare with previous cohort treated as inpatients. METHODS AND MATERIALS: Using the Prostate Brachytherapy Questionnaire, we previously examined patients' subjective experience of the brachytherapy procedure when it involved one implant and hospitalization with the template in situ for 2 days (Group 1). The protocol was subsequently changed to two implants, 2 weeks apart as outpatients. Fifty-eight patients treated with the new protocol (Group 2) completed the same questionnaire. We compared the self reported experiences between Groups 1 and 2 and also between the first and second implant for those in Group 2. Our hypothesis was that the worst rated issues in Group 1 might be reduced with the new approach. RESULTS: Group 2 patients were less troubled overall by the procedure (mean scores 2.3 vs. 3.2, p=0.0293). Specifically, they were less troubled by "discomfort" (2.8 vs. 3.8, p=0.0254); "being stuck in bed" (1.7 vs. 4.2 p<0.0001); "feeling helpless" (1.3 vs. 2.8, p=0.0009); "fear of opening my bowels" (2.1 vs. 3.3, p=0.0055); and "fear of coping with the implant" (1.3 vs. 2.5, p=0.0004). There was no significant increase in "thought of implant" or "fear of implant" before the second implant. However, more patients rated worse than expected "fear of passing urine" during the second implant. CONCLUSIONS: Patients rated high-dose-rate brachytherapy less troublesome when delivered as outpatient with two implants, 2 weeks apart than as inpatient over 3 days, despite the additional invasive procedure and anesthesia. PMID- 21550318 TI - Biomarkers in Alzheimer's disease drug development. AB - Developing new therapies for Alzheimer's disease (AD) is critically important to avoid the impending public health disaster imposed by this common disorder. Means must be found to prevent, delay the onset, or slow the progression of AD. These goals will be achieved by identifying disease-modifying therapies and testing them in clinical trials. Biomarkers play an increasingly important role in AD drug development. In preclinical testing, they assist in decisions to develop an agent. Biomarkers in phase I provide insights into toxic responses and drug metabolism and in Phase II proof-of-concept trials they facilitate go/no-go decisions and dose finding. Biomarkers can play a role in identifying presymptomatic patients or specific patient subgroups. They can provide evidence of target engagement before clinical changes can be expected. Brain imaging can serve as a primary outcome in Phase II trials and as a key secondary outcome in Phase III trials. Magnetic resonance imaging is currently best positioned for use in large multicenter clinical trials. Cerebrospinal fluid (CSF) measures of amyloid beta protein (Abeta), tau protein, and hyperphosphorylated tau (p-tau) protein are sensitive and specific to the diagnosis of AD and may serve as inclusion criteria and possibly as outcomes in clinical trials targeting relevant pathways. Plasma measures of Abeta are of limited diagnostic value but may provide important information as a measure of treatment response. A wide variety of measures of detectable products of cellular processes are being developed as possible biomarkers accessible in the cerebrospinal fluid and plasma or serum. Surrogate markers that can function as outcomes in pivotal trials and reliably predict clinical outcomes are needed to facilitate primary prevention trials of asymptomatic persons where clinical measures may be of limited value. Fit-for purpose biomarkers are increasingly available to guide AD drug development decisions. PMID- 21550319 TI - Electrochemical characterization of a bioceramic material: The shell of the Eastern oyster Crassostrea virginica. AB - The shell of the Eastern oyster (Crassostrea virginica) is composed of multiple incongruent mineralized layers. This bioceramic composite material was investigated to determine the effects of shell thickness, orientation and layer composition on its electrochemical behavior using electrochemical impedance spectroscopy, potentiodynamic polarization and scanning electron microscopy energy dispersive spectroscopy. SEM-EDS analysis of the oyster shell revealed that the multilayered biocomposite material is composed of calcium carbonate (CaCO(3)). EIS measurements in 3.5wt.% NaCl indicated that the impedance of the whole oyster shell in the low frequency region exhibited high impedance values which exhibited a decreasing trend with increasing immersion time. In terms of overall shell thickness, limiting currents measured by potentiodynamic techniques through the shell were observed to increase when the outer layers of the shell were sequentially removed by grinding, thus decreasing the shell thickness. These limiting current values remained relatively constant when the inner layers of the shell were removed. The impedance values of the oyster shell material as measured by EIS were shown to decrease with decreasing shell thickness. These findings suggest that the prismatic (outermost) shell layer in combination with the soluble organic matrix between all shell layers may influence the ionic conductivity through the oyster shell. PMID- 21550320 TI - Dynamics of mammalian NER proteins. AB - Despite detailed knowledge on the genetic network and biochemical properties of most of the nucleotide excision repair (NER) proteins, cell biological analysis has only recently made it possible to investigate the temporal and spatial organization of NER. In contrast to several other DNA damage response mechanisms that occur in specific subnuclear structures, NER is not confined to nuclear foci, which has severely hampered the analysis of its arrangement in time and space. In this review the recently developed tools to study the dynamic molecular transactions between the NER factors and the chromatin template are summarized. First, different procedures to inflict DNA damage in a part of the cell nucleus are discussed. In addition, technologies to measure protein dynamics of NER factors tagged with the green fluorescent protein (GFP) will be reviewed. Most of the dynamic parameters of GFP-tagged NER factors are deduced from different variants of 'fluorescence recovery after photobleaching' (FRAP) experiments and FRAP analysis procedures will be briefly evaluated. The combination of local damage induction, genetic tagging of repair factors with GFP and microscopy innovations have provided the basis for the determination of NER kinetics within living mammalian cells. These new cell biological approaches have disclosed a highly dynamic arrangement of NER factors that assemble in an orderly fashion on damaged DNA. The spatio-temporal analysis tools developed for the study of NER and the kinetic model derived from these studies can serve as a paradigm for the understanding of other chromatin-associated processes. PMID- 21550321 TI - Mitochondrial DNA toxicity compromises mitochondrial dynamics and induces hippocampal antioxidant defenses. AB - Mitochondria are highly dynamic organelles that can be actively transported within the cell to satisfy local requirements. They are vital for providing cellular energy, but are also an important endogenous source of reactive oxygen species. The distribution of mitochondria is particularly important for neurons because of the morphological complexity of these cells, and because neural processing is metabolically expensive. Defects in mitochondrial distribution, observed in several neurodegenerative diseases, can result in synaptic dysfunction. We have generated transgenic mice expressing an enzyme in forebrain neurons that causes mitochondrial DNA (mtDNA) damage in the form of abasic-sites, creating mtDNA toxicity. Here, we report that mitochondrial distribution is disturbed in hippocampal neurons of these mice. Moreover, mtDNA copy number and mitochondrial transcription are reduced, and oxidative stress is increased. There is also a loss of receptors at excitatory glutamatergic synapses in the dentate gyrus, and the size of the postsynaptic density in this region is abnormal. We speculate that the loss of synaptic mitochondria caused by accumulation in the neuronal cell body contributes to the observed synaptic abnormalities, as well as the overall loss of mtDNA and diminished mitochondrial transcription. Collectively, these changes lead to mitochondria with reduced function and increased oxidative stress. PMID- 21550322 TI - Highly sensitive and accurate screening of 40 dyes in soft drinks by liquid chromatography-electrospray tandem mass spectrometry. AB - A method combining solid phase extraction with high performance liquid chromatography-electrospray ionization tandem mass spectrometry was developed for the highly sensitive and accurate screening of 40 dyes, most of which are banned in foods. Electrospray ionization tandem mass spectrometry was used to identify and quantify a large number of dyes for the first time, and demonstrated greater accuracy and sensitivity than the conventional liquid chromatography ultraviolet/visible methods. The limits of detection at a signal-to-noise ratio of 3 for the dyes are 0.0001-0.01 mg/L except for Tartrazine, Amaranth, New Red and Ponceau 4R, with detection limits of 0.5, 0.25, 0.125 and 0.125 mg/L, respectively. When this method was applied to screening of dyes in soft drinks, the recoveries ranged from 91.1 to 105%. This method has been successfully applied to screening of illegal dyes in commercial soft drink samples, and it is valuable to ensure the safety of food. PMID- 21550323 TI - Music, meaning, and the brain: Comment on "Towards a neural basis of processing musical semantics" by Stefan Koelsch. PMID- 21550324 TI - Liver transplantation for patients with alcoholic liver disease: an open question. AB - End-stage alcoholic liver disease is a recognised indication for liver transplantation but some questions on the matter remain open. It is difficult to quantify alcohol consumption, and a single definition of post-transplant relapse is lacking. Moreover, there are no internationally accepted criteria for the selection of candidates for liver transplantation and the eligibility parameters for these patients are controversial. Additional clinical and psychological evaluations are necessary in this setting, especially to establish the risk of alcohol relapse. Nevertheless, patient and graft survival rates after liver transplantation in alcoholic liver disease are comparable to those after transplant for other aetiologies, alcohol consumption relapse being one of the most important problems in the post-transplant phase. In conclusion, alcohol related liver disease is a good indication for liver transplantation. The main future goals are to formulate a well-defined pre-transplant approach and a single definition of alcohol relapse and to improve prevention strategies. PMID- 21550325 TI - [What do paediatricians and mothers talk about in the well-child program visits?]. AB - AIMS: Paediatricians are the parents' main formal counselling source on their children's development and education. Unfortunately, there is limited knowledge on the content and the characteristics of their counselling practice. This study analyses the visit duration, topics discussed, and parent and paediatrician initiatives. MATERIAL AND METHODS: We performed a content analysis of 49 visits to 5 paediatricians. We classified the topics discussed into 7 categories: secondary prevention, primary prevention, health promotion, development, education, focused on the parents and family relationship. RESULTS: The duration of the visit was within the recommended limits (M=16.1; SD=5.6) and the content was very dense (14.3 topics per visit). The paediatricians' priorities were: feeding (100%), diseases (71%), psychomotor development (67%) and growth (53%), and those of the mothers were: minor health problems (37%), growth (33%), feeding (27%) and behaviour (24%). Significant differences among paediatricians were observed in all the studied dimensions. We observed a balance in the communication between paediatricians and mothers in the emission of words and in the introduction of topics. The mother's educational level had no effect on the studied parameters. CONCLUSIONS: There are different paediatric styles, and their study could help paediatricians to improve their professional practice. We observed a balance in the emission of words and the introduction of topics by paediatricians and mothers. We did not identify communication barriers as regards the mother's educational level. The introduction of more psychosocial topics could help to improve the program. PMID- 21550326 TI - An investigation of the relationship between thoracic outlet syndrome and the dimensions of the first rib and clavicle. AB - INTRODUCTION: Abnormalities of the first rib including rib width, rib shape and rib angulation were noted intra-operatively in our thoracic outlet syndrome (TOS) operative patients. The purpose of this study is to investigate the relationship between TOS and the first rib in TOS operative patients and normal population. METHODS: Between 1993 and 2003, 32 patients with TOS undergoing surgical decompression and 30 normal subjects as the control group were included in this investigation. The investigation was from posteroanterior chest and antero posterior C-spine radiographs. Sternal head width and vertebral head width of the first rib were measured. In addition, sternal head width, the acromion head width and the length of the clavicle were measured for comparison. Comparison between affected side and unaffected side first ribs was also performed in the unilateral TOS patients. RESULTS: In TOS patients, the widths of the vertebral end and sternal end of the first rib were significantly wider than the control group (both, P = 0.0001). CONCLUSION: Patients with wider vertebral end width of the first rib (>15 mm) or wider sternal end width of the first rib (>20 mm) may develop TOS. PMID- 21550327 TI - A comparison of stochastic variation in mixed and unmixed casework and synthetic samples. AB - Understanding the behaviour of mixed DNA profiles is of paramount importance in forensic DNA analysis. Key parameters are those of heterozygote balance and mixture proportion and its variability. These parameters have been previously explored as a function of the average peak height of the active alleles in single source and mixed samples derived from pristine DNA. Here we report a comparison of this data with data obtained from casework samples. This allows an assessment of the difference in the distribution of heterozygote balance between mixed and single source stains and between casework mixtures and synthetic mixtures constructed from pristine DNA. PMID- 21550328 TI - Effect of experimental horizontal mandibular deviation on dynamic balance. AB - PURPOSE: There are two aspects of human balance: static balance and dynamic balance. However, to the author's knowledge, no studies have investigated how changes in the stomatognathic system influence dynamic balance. This aim of this study was to determine the effect of horizontal mandibular deviation on stability of upright posture on an unstable platform in order to clarify the relationship between the stomatognathic system and the dynamic balance. METHODS: Fifteen healthy adult participants were selected. To determine the effect of changes in the stomatognathic system on dynamic balance, three experimental conditions were established: a resting mandibular position, a position in which experimental horizontal mandibular deviation was maintained by a splint, and a mandibular rest position maintained by a splint. Each participant was instructed to stand in a natural upright posture on an unstable board, and resulting variation in angle of the board was then measured. Measurements were taken 15 times under each condition. RESULTS: Variation in angle of inclination of the board as dynamic balance was the largest in the splint-maintained deviated mandibular position. CONCLUSION: Horizontal deviation in mandibular position interfered with stability of upright posture on an unstable platform, suggesting that changes in the stomatognathic system affect dynamic balance. PMID- 21550329 TI - Epidemiology of liver failure. AB - The etiology of fulminant hepatitis varies in different countries and at different times. The main causes of fulminant hepatitis are viruses, paracetamol, drugs (other than paracetamol), poisons and 15-30% remained of undetermined origin. The prevalence of these etiologies varies according to the geographic region and has changed over the past 10 years. Paracetamol has now overtaken viruses (particularly hepatitis B virus) as the leading cause of fulminant hepatitis. Establishing the cause of fulminant hepatitis is an important step in the management of acute liver failure, so that specific therapy can be initiated and any contraindications to liver transplantation be eliminated. PMID- 21550330 TI - Langerhans' cell histiocytosis of the liver in adults. AB - Among adults, liver involvement is relatively frequent in Langerhans' cell histiocytosis (LCH), even though it is often overlooked. In fact, the liver involvement may be missed in apparently localized LCH or when it is the sole site of involvement. We present 23 cases of liver involvement in LCH out of a cohort study of 85 adult patients included in the French Histiocytosis Study Group Registry. The most frequent clinical setting was multiorgan involvement (87% of our cases). The main histological pattern in liver LCH was sclerosing cholangitis (56% of the cases). The symptoms included hepatomegaly (48%) and/or liver biochemistry abnormalities (61%, including cholestasis associated with increased transaminases levels in 35% of cases, cholestasis only in 22% and increased transaminases levels only in 4% of the cases). Particularly suggestive of the diagnosis was the observation of biliary tree abnormalities through magnetic resonance imaging (MRI). The natural history of liver LCH fits into two stages: early infiltration by histiocytes and late sclerosis of the biliary tree. We found that liver involvement had a significant impact on survival. Thus we suggest that clinical and biological liver evaluation must be performed regularly onwards to screen every LCH adult patient from the time of the initial diagnosis. MRI and liver biopsy should be considered as soon as the data point to a possible liver localization. If this diagnosis is confirmed, we suggest a treatment with ursodesoxycholic acid, as in other cholestatic diseases, together with treatments specifically directed towards LCH. However, the ideal treatment of liver LCH remains to be found, and in advanced cases transplantation is the sole option. PMID- 21550331 TI - Towards a neurobiological model of offending. AB - In this paper we consider how disturbances in the neurobiological/neurochemical processes at a young age lead to problematic attachment styles in later life, and which can potentiate probability of offending behavior. In particular, we will contrast attachment and offending patterns of the more generalist type of offender (i.e., those who have a varied criminal career, committing both violent and non-violent offenses, in extremis the psychopathic type of offender), with the more specialist sexual offender (prototypically, the fixated pedophile), in the light of a preliminary neurobiological model. Here, we will argue that these two extremes of offenders show, or are predicted to show, differential patterns of neurochemical/neurobiological functioning. PMID- 21550332 TI - Community structure of ground-water breeding mosquitoes driven by land use in a temperate wetland of Argentina. AB - Wetlands have traditionally been associated with harbouring mosquitoes, but the effect of the land use on their communities has not been thoroughly studied. We characterized the ground-water habitat availability and mosquito species richness and composition during a year-round survey in the predominant land uses (domestic areas, Salicaceae plantations, secondary forests and Scirpus giganteus marshes) of the Parana Lower Delta, Argentina. Each land use presented a characteristically different number, composition, and diversity of ground-water habitats, and harboured mosquitoes throughout the year. Nearly half of the 824 habitats examined, consisting of 10 types, were positive for immatures. We identified 23 species from 7 genera, with Culex and Ochlerotatus species accounting for 81.7% of all samples. Species richness was significantly lower in marshes than in the other land uses. Some species such as Culex dolosus s.l. and Ochlerotatus crinifer exhibited no habitat-type restrictions, while Uranotaenia nataliae and Mansonia indubitans presented specific habitat requirements. Our results strongly suggest that land use within temperate wetlands drives species richness and composition of ground-water mosquito communities through larval habitat availability. PMID- 21550333 TI - A novel mechanical loading model for studying the distributions of strain and mechano-growth factor expression. AB - Mechano-growth factor (MGF), an insulin-like growth factor-I (IGF-I) splice variant, often serves as an important local tissue repair factor in response to the mechanical environment. However, there is no model for exhibiting the MGF expression in a series of strain distribution up to now. In this study, a novel mechanical loading model containing different stresses and strains simultaneously was developed to examine the MGF expression. The strain distributions were predicted by finite element modeling. The MC3T3-E1 cells on a silicone membrane with a central circular hole were exposed to a variable strain environment through stretching. The finite element analysis showed that, when the strain reached the magnitude of 10%, the strain concentration near the circular hole displayed along with the vertical stretch direction, while the minimum strain appeared in the parallel stretch direction. Furthermore, the results showed that MGF expression decreased gradually from high to low strain regions by immunocytochemistry. Meanwhile, the proliferation of osteoblasts increased significantly in the high strain region. In conclusion, this mechanical loading model can present the different distributions of the strain of osteoblasts in vitro. MGF expression and osteoblast proliferation have a high correlation with the levels of strain. PMID- 21550334 TI - Expression of a chloroplast ATP/ADP transporter in E. coli membranes: behind the Mistic strategy. AB - Eukaryotic membrane protein expression is still a major bottleneck for structural studies. Production in E. coli often leads to low expression level and/or aggregated proteins. In the last decade, strategies relying on new fusion protein expression revealed promising results. Fusion with the amphipatic Mistic protein has been described to favor expression in E. coli membranes. Although, this approach has already been reported for a few membrane proteins, little is known about the activity of the fused proteins. We used this strategy and obtained high expression levels of a chloroplast ATP/ADP transporter from A. thaliana (NTT1) and characterized its transport properties. NTT1 fused to Mistic has a very low transport activity which can be recovered after in vivo Mistic fusion cleavage. Moreover, detailed molecular characterization of purified NTT1 mature form, NTT1 fused to Mistic or NTT1 cleaved-off from this fusion highlights the correct fold of the latter one. Therefore, considering the higher quantity of purified NTT1 mature form obtained via the Mistic fusion approach, this is a valuable strategy for obtaining quantities of pure and active proteins that are adequate for structural studies. PMID- 21550336 TI - Effect of dinitrosyl iron complexes with glutathione on hemorrhagic shock followed by saline treatment. AB - It has been found that dinitrosyl iron complexes with glutathione (DNIC-GS) injected into the blood flow of rats at a dose of 0.05 MUmoles/kg prior to hemorrhage significantly improve cardiac function under conditions of hemorrhagic shock manifested in increased stroke volume, left ventricular work and cardiac output to a level exceeding control values 1.5-fold. Enhanced myocardial contractile activity leads to a situation where mean arterial pressure does not decrease further despite the significant decrease of total peripheral resistance. The decrease of total peripheral vascular resistance of the vascular system under vasodilating effects of DNIC-GS used as nitric oxide donors improves microcirculation in experimental rats judging from increased rates of blood flow and low degree of erythrocyte aggregation. Pretreatment of rats with the complexes significantly increases survival (by 21%) under conditions of hemorrhagic shock. It is suggested that beneficial effects of DNIC-GS on systemic circulation parameters under conditions of hemorrhagic shock are determined by their antioxidant activity and the ability to induce S-nitrosylation of proteins. PMID- 21550337 TI - Poncirin promotes osteoblast differentiation but inhibits adipocyte differentiation in mesenchymal stem cells. AB - Poncirin, flavanone glycoside, isolated from the fruit of Poncirus trifoliata, has anti-bacterial and anti-inflammatory activities. In this study, the effects of poncirin on the differentiation of mesenchymal stem cells were investigated. The C3H10T1/2 mesenchymal stem cells and primary bone marrow mesenchymal stem cells were studied. In the C3H10T1/2 cells, poncirin prevented adipocyte differentiation, as demonstrated by inhibition of cytoplasm lipid droplet accumulation and peroxisome proliferator-activating receptor-gamma (PPAR-gamma) and CCAAT-enhancer-binding protein-beta (C/EBP-beta) mRNA expression. By contrast, poncirin enhanced the expression of the key osteogenic transcription factors, runt-related transcription factor 2 (Runx2) and transcriptional coactivator with PDZ-binding motif (TAZ). Poncirin also enhanced expression of the osteogenic marker genes including alkaline phosphatase (ALP) and osteocalcin (OC). Poncirin increased mineral nodule formation in primary bone marrow mesenchymal stem cells. These results suggest that poncirin prevents adipogenesis and enhances osteoblast differentiation in mesenchymal stem cells. PMID- 21550335 TI - Topography of tyrosine residues and their involvement in peroxidation of polyunsaturated cardiolipin in cytochrome c/cardiolipin peroxidase complexes. AB - Formation of cytochrome c (cyt c)/cardiolipin (CL) peroxidase complex selective toward peroxidation of polyunsaturated CLs is a pre-requisite for mitochondrial membrane permeabilization. Tyrosine residues - via the generation of tyrosyl radicals (Tyr) - are likely reactive intermediates of the peroxidase cycle leading to CL peroxidation. We used mutants of horse heart cyt c in which each of the four Tyr residues was substituted for Phe and assessed their contribution to the peroxidase catalysis. Tyr67Phe mutation was associated with a partial loss of the oxygenase function of the cyt c/CL complex and the lowest concentration of H(2)O(2)-induced Tyr radicals in electron paramagnetic resonance (EPR) spectra. Our MS experiments directly demonstrated decreased production of CL hydroperoxides (CL-OOH) by Tyr67Phe mutant. Similarly, oxidation of a phenolic substrate, Amplex Red, was affected to a greater extent in Tyr67Phe than in three other mutants. Tyr67Phe mutant exerted high resistance to H(2)O(2)-induced oligomerization. Measurements of Tyr fluorescence, hetero-nuclear magnetic resonance (NMR) and computer simulations position Tyr67 in close proximity to the porphyrin ring heme iron and one of the two axial heme-iron ligand residues, Met80. Thus, the highly conserved Tyr67 is a likely electron-donor (radical acceptor) in the oxygenase half-reaction of the cyt c/CL peroxidase complex. PMID- 21550338 TI - Class I/B antiarrhythmic property of ranolazine, a novel antianginal agent, in dog and human cardiac preparations. AB - The aim of this study was to investigate the cellular electrophysiological effects of ranolazine on action potential characteristics. The experiments were carried out in dog and human cardiac preparations using the conventional microelectrode technique. In dog Purkinje fibres ranolazine produced a concentration- and frequency-dependent depression of the maximum rate of depolarization (V(max)) while action potential duration (APD) was shortened. In dog and human right ventricular papillary muscle ranolazine exerted no significant effect on APD, while it produced, like mexiletine, use-dependent depression of V(max) with relatively fast onset and offset kinetics. In dog midmyocardial preparations the drug did not exert statistically significant effect on repolarization at 10 MUM, although a tendency toward prolongation was observed at 20 MUM. A moderate lengthening of APD(90) by ranolazine was noticed in canine atrial preparations obtained from dogs in sinus rhythm and in tachypacing induced remodelled preparations. Use-dependent depression of V(max) was more pronounced in atria from dogs in sinus rhythm than those in remodelled atria or in the ventricle. These findings indicate that ranolazine, in addition to its known late sodium current blocking effect, also depresses peak I(Na) with class I/B antiarrhythmic characteristics. Although peak I(Na) inhibition by ranolazine is stronger in the atria, it is also substantial (at fast stimulation frequencies) in ventricular preparations. Ranolazine also decreased the dispersion of ventricular repolarization (the difference in APD(90) values between Purkinje fibres and papillary muscles), which can contribute to the antiarrhythmic property of the drug. PMID- 21550339 TI - Extracellular ATP through P2 receptors activates AMP-activated protein kinase and suppresses superoxide generation in cultured mouse podocytes. AB - Podocytes are an important constituent of the glomerular filtration barrier. The function of these glomerular cells is affected by extracellular nucleotides through P2 receptors. The activation of P2 receptors may lead to the activation of NAD(P)H oxidase, the key enzyme in oxidative stress, with the intracellular pathways leading to intracellular ATP depletion associated with an increase in the intracellular AMP:ATP ratio. This deregulation of the energy balance activates AMP-activated protein kinase (AMPK) to restore energy homeostasis. We investigated whether P2 receptor activation influences NAD(P)H oxidase-dependent rate of superoxide anion (O(2)(*-)) generation and AMPK activity in cultured mouse podocytes. The rate of O(2)(*-) generation was measured by chemiluminescence and changes in AMPK activity were determined by immunoblotting against AMPKalpha-Thr(172)-P. The addition of 100 MUM ATP induced a rapid and transient decrease in rate of O(2)(*-) generation and increased AMPK phosphorylation with maximal effects in the first minute (2.44+/-0.09 versus 1.62+/-0.06 nmol/mg protein/min, P<0.05 and 0.64+/-0.04 versus 0.97+/-0.07, P<0.05, respectively). Both parameters returned to control levels at 10 min. Suramin (300 MUM, P2 receptor antagonist) and compound C (100MUM, AMPK inhibitor) completely, and STO-609 (25 MUM, CaMKK-beta inhibitor) partially, prevented ATP action in rate of O(2)(*-) generation and AMPK phosphorylation. Various ATP analogues (10 MUM) mimicked the effects of ATP on rate of O(2)(*-) generation and AMPK phosphorylation. The data indicate that extracellular ATP, acting through P2 receptors upstream of CaMKK-beta, modulates podocyte function through simultaneous effects on AMPK and NAD(P)H oxidase activities. This mechanism may play a role in restoring energy homeostasis after oxidative stress. PMID- 21550340 TI - APOE epsilon3 attenuates experimental autoimmune neuritis by modulating T cell, macrophage and Schwann cell functions. AB - Human apolipoprotein E (apoE) is a 34.2kDa glycosylated protein with three isoforms (apoE2, apoE3 and apoE4). Experimental autoimmune neuritis (EAN), an animal model for human Guillain-Barre syndrome, is an immune-mediated experimental disorder of the peripheral nervous system (PNS). Increased susceptibility to EAN in apoE deficient mice has been previously found. To elucidate the isoform-dependent effects of apoE on EAN, we used human apoE2, E3 and E4 transgenic mice (Tg) immunized with P0 peptide 180-199, as well as T cell proliferation test, macrophage and Schwann cell (SC) cultures to investigate the effects of apoE isoforms on the functions of T cells, macrophages and SCs both under naive conditions and in EAN. Clinical signs of EAN were most severe in wild type (WT) C57BL/6 mice and apoE4 Tg mice, followed by apoE2 Tg mice and apoE3 Tg mice (WT~E4>E2>E3, p<0.01). At the nadir of EAN, spleen weight and lymphocyte proliferation were in line with the clinical severity of the disease. Proliferation tests of purified T cells from naive mice stimulated with phytohemagglutinin or interleukin-12 showed isoform-specific differences (WT~E4>E3~E2, p<0.01). Macrophages from both naive and EAN mice produced nitric oxide upon inflammatory stimulation with lipopolysaccharide, interferon-gamma, polyinosinic:polycytidylic acid or combinations thereof, in an isoform-dependent manner (WT~E4>E2>E3, p<0.01). Generalized intervention with 1400W, a specific inducible nitric oxide synthase inhibitor, significantly suppressed the clinical course of EAN in apoE2, E3 and E4 Tg mice and in WT mice. During the recovery stage of disease, the highest expression of CD178 (FasL) on SCs was found in apoE3 Tg mice. Our data support an isoform-dependent effect of apoE on EAN. This might be due to the isoform-specific effects of apoE on functions of T cells, macrophages and SCs, which contribute to the distinct clinical courses of EAN. ApoE3 might not only inhibit the onset and suppress the clinical severity of EAN, but also enhance the termination of immune responses in the PNS. PMID- 21550341 TI - Detecting UV-lesions in the genome: The modular CRL4 ubiquitin ligase does it best! AB - The DDB1-DDB2-CUL4-RBX1 complex serves as the primary detection device for UV induced lesions in the genome. It simultaneously functions as a CUL4 type E3 ubiquitin ligase. We review the current understanding of this dual function ubiquitin ligase and damage detection complex. The DDB2 damage binding module is merely one of a large family of possible DDB1-CUL4 associated factors (DCAF), most of which are substrate receptors for other DDB1-CUL4 complexes. DDB2 and the Cockayne-syndrome A protein (CSA) function in nucleotide excision repair, whereas the remaining receptors operate in a wide range of other biological pathways. We will examine the modular architecture of DDB1-CUL4 in complex with DDB2, CSA and CDT2 focusing on shared architectural, targeting and regulatory principles. PMID- 21550342 TI - The Nse2/Mms21 SUMO ligase of the Smc5/6 complex in the maintenance of genome stability. AB - There exist three highly-conserved structural maintenance of chromosomes (Smc) complexes that ensure genome stability during eukaryotic cell division. There are the well-characterized cohesin and condensin complexes and the third Smc complex, Smc5/6. Nse2/Mms21, a SUMO ligase, is a component of the Smc5/6 complex and recent data have indicated that Nse1 may function as a ubiquitin ligase. Smc5/6 regulates sister chromatid cohesion, homologous recombination and chromatin structure and conformation. This review examines the functions of Smc5/6 in DNA repair and the maintenance of genomic integrity and explores the roles of the associated SUMO and ubiquitin ligases. Recent findings have indicated that Smc5/6 may play a topological role in chromosome dynamics, which may help understand the complexity of its activities. PMID- 21550344 TI - How do immune cells overcome the blood-brain barrier in multiple sclerosis? AB - The presence of the blood-brain barrier (BBB) restricts the movement of soluble mediators and leukocytes from the periphery to the central nervous system (CNS). Leukocyte entry into the CNS is nonetheless an early event in multiple sclerosis (MS), an inflammatory disorder of the CNS. Whether BBB dysfunction precedes immune cell infiltration or is the consequence of perivascular leukocyte accumulation remains enigmatic, but leukocyte migration modifies BBB permeability. Immune cells of MS subjects express inflammatory cytokines, reactive oxygen species (ROS) and enzymes that can facilitate their migration to the CNS by influencing BBB function, either directly or indirectly. In this review, we describe how immune cells from the peripheral blood overcome the BBB and promote CNS inflammation in MS through BBB disruption. PMID- 21550343 TI - Progranulin: a promising therapeutic target for rheumatoid arthritis. AB - Progranulin (PGRN) is an autocrine growth factor with multiple functions. This review provides updates about the interplays of PGRN with extracellular matrix proteins, proteolytic enzymes, inflammatory cytokines, and cell surface receptors in cartilage and arthritis, with a special focus on the interaction between PGRN and TNF receptors (TNFR) and its implications in inflammatory arthritis. The paper also highlights Atsttrin, an engineered protein composed of three PGRN fragments that prevents inflammation in several inflammatory arthritis models. Identification of PGRN as a ligand of TNFR and an antagonist of TNFalpha signaling, together with the discovery of Atsttrin, not only betters our understanding of the pathogenesis of arthritis, but also provides new therapeutic interventions for various TNFalpha-mediated pathologies and conditions, including rheumatoid arthritis. PMID- 21550345 TI - Dissecting systemic control of metabolism and aging in the NAD World: the importance of SIRT1 and NAMPT-mediated NAD biosynthesis. AB - Many countries are facing social and economic problems due to increased elderly demographics. With these demands, it is now critical to understand the fundamental regulatory mechanism for aging and longevity in mammals. Our studies on the mammalian NAD-dependent deacetylase SIRT1 and nicotinamide phosphoribosyltransferase (NAMPT)-mediated systemic NAD biosynthesis led us to propose a comprehensive model for the systemic regulatory network connecting metabolism and aging, termed the "NAD World". In this article, I will discuss the importance of SIRT1 and NAMPT-mediated NAD biosynthesis in the NAD World and the system dynamics of this hierarchical network for the connection between metabolism and aging. PMID- 21550347 TI - NEMBASE4: the nematode transcriptome resource. AB - Nematode parasites are of major importance in human health and agriculture, and free-living species deliver essential ecosystem services. The genomics revolution has resulted in the production of many datasets of expressed sequence tags (ESTs) from a phylogenetically wide range of nematode species, but these are not easily compared. NEMBASE4 presents a single portal into extensively functionally annotated, EST-derived transcriptomes from over 60 species of nematodes, including plant and animal parasites and free-living taxa. Using the PartiGene suite of tools, we have assembled the publicly available ESTs for each species into a high-quality set of putative transcripts. These transcripts have been translated to produce a protein sequence resource and each is annotated with functional information derived from comparison with well-studied nematode species such as Caenorhabditis elegans and other non-nematode resources. By cross comparing the sequences within NEMBASE4, we have also generated a protein family assignment for each translation. The data are presented in an openly accessible, interactive database. To demonstrate the utility of NEMBASE4, we have used the database to examine the uniqueness of the transcriptomes of major clades of parasitic nematodes, identifying lineage-restricted genes that may underpin particular parasitic phenotypes, possible viral pathogens of nematodes, and nematode-unique protein families that may be developed as drug targets. PMID- 21550346 TI - Co-expression of reporter genes in the widespread pathogen Eimeria tenella using a double-cassette expression vector strategy. AB - The double-cassette expression vector strategy is valuable for many studies, including comparative analysis of the function of promoters and expression of genes in different compartments. In this study, we report co-expression of enhanced yellow fluorescent protein (EYFP) and red fluorescent protein (RFP) in Eimeria tenella transfected with two double-cassette expression vectors, pMIC EYFP/ACT-RFP and pMIC-EYFP/ACTss-RFP. The results showed that under regulation of the mic1 promoter, EYFP was expressed in sporulated oocysts but not in unsporulated ones, while under regulation of the actin promoter RFP was expressed in both forms. We found that the signal peptide of Toxoplasma gondii dense granule protein 8 (GRA8) located the RFP expression to the parasitophorous vacuoles of the parasites, the margins of the unsporulated oocysts and the cavities of the sporocysts. The feasibility of co-expression of exogenous proteins in E. tenella is important for the development of transgenic E. tenella as a novel vaccine vector. PMID- 21550348 TI - Circadian clock genes period and cycle regulate photoperiodic diapause in the bean bug Riptortus pedestris males. AB - The photoperiodic response is crucial for many insects to adapt to seasonal changes in temperate regions. It was recently shown that the circadian clock genes period (per) and cycle (cyc) are involved in the photoperiodic regulation of reproductive diapause in the bean bug Riptortus pedestris females. Here, we investigated the involvement of per and cyc both in the circadian rhythm of cuticle deposition and in the photoperiodic diapause of R. pedestris males using RNA interference (RNAi). RNAi of per and cyc disrupted the cuticle deposition rhythm and resulted in distinct cuticle layers. RNAi of per induced development of the male reproductive organs even under diapause-inducing short-day conditions, whereas RNAi of cyc suppressed development of the reproductive organs even under diapause-averting long-day conditions. Thus, the present study suggests that the circadian clock operated by per and cyc governs photoperiodism of males as that of females. PMID- 21550349 TI - Probability of freezing in the freeze-avoiding beetle larvae Cucujus clavipes puniceus (Coleoptera: Cucujidae) from interior Alaska. AB - Freeze-avoiding insects must resist freezing or die. A suite of adaptations to low temperatures, including the production of antifreeze proteins, colligative antifreezes (polyols), and dehydration allows most individuals to prevent freezing below the lowest ambient temperatures experienced in situ; however, there can be a wide variance in the minimum temperatures that individuals of freeze-avoiding species reach before freezing. We used logistic regression to explore factors that affect this variance and to estimate the probability of freezing in larvae of the freeze-avoiding beetle Cucujus clavipes puniceus. We hypothesized that water content <=0.5 mg mg(-1) dry mass would lead to deep supercooling (avoidance of freezing below -58 degrees C). We found a significant interaction between water content and ambient below-snow temperature and a significant difference between individuals collected from two locations in Alaska: Wiseman and Fairbanks. Individuals collected in Wiseman deep supercooled with greater water content and to a greater range of ambient temperatures than individuals collected in Fairbanks, leading to significantly different lethal water contents associated with 50% probability of freezing. PMID- 21550350 TI - Cross-resistance and mechanism of resistance to Cry1Ab toxin from Bacillus thuringiensis in a field-derived strain of European corn borer, Ostrinia nubilalis. AB - The cross-resistance spectrum and biochemical mechanism of resistance to the Bacillus thuringiensis Cry1Ab toxin was studied in a field-derived strain of Ostrinia nubilalis (Hubner) (Lepidoptera: Crambidae) that was further selected in the laboratory for high levels (>1000-fold) of resistance to Cry1Ab. The resistant strain exhibited high levels of cross-resistance to Cry1Ac and Cry1Aa but only low levels of cross-resistance (<4-fold) to Cry1F. In addition, there was no significant difference between the levels of resistance to full-length and trypsin-activated Cry1Ab protein. No differences in activity of luminal gut proteases or altered proteolytic processing of the toxin were observed in the resistant strain. Significantly reduced binding of radiolabeled Cry1Aa was observed in the resistant strain whereas binding of Cry1Ab and Cry1Ac was practically the same in both resistant and susceptible strains. The interpretation of the overall data seems to suggest the involvement of an alteration in the binding of Cry1A toxins to a common receptor, which is more clearly revealed by the binding assays using radiolabeled Cry1Aa. PMID- 21550351 TI - Competitive helping increases with the size of biological markets and invades defection. AB - Cooperation between unrelated individuals remains a puzzle in evolutionary biology. Recent work indicates that partner choice can select for high levels of helping. More generally, helping can be seen as but one strategy used to compete for partners within a broader biological market, yet giving within such markets has received little mathematical investigation. In the present model, individuals help others to attract attention from them and thus receive a larger share of any help actively or passively provided by those others. The evolutionarily stable level of helping increases with the size of the biological market and the degree of partner choice. Furthermore, if individuals passively produce some no-cost help to partners, competitive helping can then invade populations of non-helpers because helpers directly benefit from increasing their access to potential partners. This framework of competitive helping demonstrates how high helping can be achieved and why different populations may differ in helping levels. PMID- 21550352 TI - Episodic memory processes mediated by the medial temporal lobes contribute to open-ended problem solving. AB - The present study investigated the contribution of episodic memory processes mediated by the medial temporal lobes to solving open-ended problems: problems for which standard solutions or set procedures for arriving at solutions do not exist. Patients with unilateral temporal lobe epilepsy and excisions (TLE), older adults and control participants were asked to describe detailed solutions to various open-ended, social scenarios. TLE patients and older adults, both having deficits in episodic memory, provided fewer steps relevant to the given solution than their comparison group. Segmenting the descriptions into details using the methods of the Autobiographical Interview, we also found that patients with TLE and older adults provided fewer internal (episodic) details but a similar number of external (semantic) details compared to their control group. These findings are the first to demonstrate that processes underlying episodic memory, in particular those enabling the retrieval of experiential detail and episodic simulation may contribute to open-ended problem solving. Given that we examined groups with medial temporal lobe lesions and known episodic memory dysfunction, these results further suggest that the negative consequences of episodic memory loss resulting from damage to or deterioration of the medial temporal lobes extend beyond that of memory to include other domains, such as problem solving. PMID- 21550353 TI - Glutamate and GABA in lateral hypothalamic mechanisms controlling food intake. AB - By the 1990s a convergence of evidence had accumulated to suggest that neurons within the lateral hypothalamus (LH) play important roles in the stimulation of feeding behavior. However, there was little direct evidence demonstrating that neurotransmitters in the LH could, like electrical stimulation, elicit feeding in satiated animals. The present paper is a brief review in honor of Bartley Hoebel's scientific contributions, emphasizing the evidence from my lab that the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter gamma aminobutyric acid (GABA) in the LH mediate feeding stimulation and feeding inhibition respectively. Specifically, we summarize evidence that LH injection of glutamate, or agonists of its N-methyl-D-aspartate (NMDA) and non-NMDA receptors, elicits feeding in satiated rats, that NMDA receptor antagonists block the eating elicited by NMDA and, more importantly, that NMDA blockade suppresses natural feeding and can reduce body weight. Conversely, GABA(A) agonists injected into the LH suppress feeding and can also reduce body weight, while GABA(A) receptor antagonists actually elicit eating when injected into the LH of satiated rats. It is suggested that natural feeding may reflect the moment-to-moment balance in the activity of glutamate and GABA within the LH. PMID- 21550354 TI - Metabolic and humoral mechanisms of feeding and genesis of the ATP/ADP/AMP concept. AB - The organization of the regulatory system of feeding and of the parallel metabolic changes is schematized by a cyclical cartoon depicting the 8 phases of regulation. As I proposed in 1974, the cycle starts with the detection by hypothalamic sensors of decrease of the ATP/ADP/AMP turnover that reflects the post-prandial slow decline of general metabolic rate. That detection is translated into a signal of hunger. Experimental evidence is provided. Once initiated, this 'basic' signal follows the 7 remaining steps of the cycle, particularly the steps 2 and 4, where it receives multiple 'modulating' positive and negative signals (particularly peptides) that inform the central regulator, on the state of peripheral organs such as the adipocytes, stomach, intestine, and liver, on the outside world like day/light and on the available foods. Particular attention is given to the homeostatic and "homeoreutic" (see definition in the text) regulation of adipose reserves that are announced to brain specialized glio neuronal "lipo-counters". The role of insulin alongside leptin is shown. The conception of a part of the above mechanisms postulates and shows that some specialized glio-neuronal populations in the antero-ventral hypothalamus share metabolic properties along with somatic cells. Finally, the signal resulting from the algebraic sum of the main (the metabolic) signal and of the modulating pluses and minuses (peptides) leaves the integrative units and reaches the efferent phases (steps 5 and 6) that finish by inducing both metabolic adjustments and consequently food intake. The last steps (4 to 8) are only shortly commented. PMID- 21550355 TI - Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin. AB - Obesity results in the increased secretion of various hormones controlling food intake and body weight, such as leptin, and insulin; increased circulating levels of pancreatic amylin have also been described in obese humans and rodents. Because leptin-resistance is present in diet-induced obese (DIO) rats, and because hyperleptinemia seems necessary for the full development of leptin resistance, we tested whether amylin sensitivity is inversely correlated with adiposity, such that DIO reduces the anorectic action of acute amylin. We also determined if hyperamylinemia leads to a change in amylin sensitivity. In the first experiment, rats were chronically exposed to a high fat (HF; 60% fat) diet or fed standard chow for control. The anorectic response to amylin was tested on several occasions over a 14 week observation period. HF feeding led to the expected increase in body adiposity; the response to an acute amylin injection (5 50 MUg/kg s.c.) was unaltered for 10 weeks of HF feeding. Even after 12 weeks on a HF diet, which clearly caused obesity, acute administration of amylin (5 MUg/kg, s.c.) was still able to suppress food intake, although the suppression was not statistically significant. Further experiments using additional doses of amylin will be necessary to demonstrate possible amylin resistance after HF feeding or in DIO rats. In the second experiment, we tested more specifically whether hyperamylinemia that may result from HF feeding and subsequent obesity, reduces the sensitivity of the amylin signaling system. To avoid confounding factors, we chronically infused lean chow fed rats with amylin (5 or 10 MUg/kg/day s.c.) to elevate their plasma amylin concentration to levels observed in obese rats (30-40 pM). In the absence of obesity, hyperamylinemia did not lead to a reduced sensitivity to acute amylin (5-20 MUg/kg s.c.) injections; acute amylin reduced eating similarly in all groups of rats. Overall, we concluded that direct diet effects by short term exposure to HF appear to be of little importance for amylin sensitivity; further, long-term maintenance on a HF diet and the resulting obesity only slightly attenuated the anorectic response to acute amylin. Because we observed no marked changes in amylin sensitivity in lean, chow fed rats with induced hyperamylinemia, amylin receptor downregulation in chronic hyperamylinemia does not seem to occur. PMID- 21550358 TI - Introduction to special issue of Physiology and Behavior: a tribute to Bart Hoebel. PMID- 21550357 TI - Food anticipation and subsequent food withdrawal increase serum cortisol in healthy men. AB - The anticipation of food intake comprises endocrine changes that according to animal experiments include a rise in HPA axis activity. In humans, HPA axis responses to food anticipation and withdrawal, although of clinical relevance, have not been thoroughly examined. We assessed neuroendocrine and psychological effects of food anticipation and of withholding anticipated food in healthy human subjects. Food anticipation was induced in 14 men at 0800 h by the announcement and subsequent presentation of a breakfast buffet. The expected meal was surprisingly withheld at 1000 h under the pretense of an organizational problem. Fifteen fasted controls were informed at 0800 h that they would remain fasted throughout the experiments. In both groups, hunger, mood and circulating concentrations of glucose, insulin, cortisol, ACTH, leptin and ghrelin were assessed. At 1200 h, all subjects were allowed to eat from a plate of cookies. Compared to non-anticipation, food anticipation was associated with a relative increase in serum cortisol levels, an acute drop in plasma glucose and increased self-rated hunger. When anticipated food was withheld, self-rated mood deteriorated and cortisol levels remained elevated, while plasma glucose levels decreased with a delay of 50 min. Other endocrine parameters and cookie intake were comparable between groups. Our results indicate that food anticipation without subsequent food reward increases cortisol levels and reduces blood glucose availability. They support the assumption that dietary restraint, being associated with habitually extended periods of anticipating food that is temporarily withheld, may contribute to the development of overweight by detrimental effects on HPA-axis activity. PMID- 21550359 TI - The effect of recurrent mutation on the frequency spectrum of a segregating site and the age of an allele. AB - The sample frequency spectrum of a segregating site is the probability distribution of a sample of alleles from a genetic locus, conditional on observing the sample to be polymorphic. This distribution is widely used in population genetic inferences, including statistical tests of neutrality in which a skew in the observed frequency spectrum across independent sites is taken as a signature of departure from neutral evolution. Theoretical aspects of the frequency spectrum have been well studied and several interesting results are available, but they are usually under the assumption that a site has undergone at most one mutation event in the history of the sample. Here, we extend previous theoretical results by allowing for at most two mutation events per site, under a general finite allele model in which the mutation rate is independent of current allelic state but the transition matrix is otherwise completely arbitrary. Our results apply to both nested and nonnested mutations. Only the former has been addressed previously, whereas here we show it is the latter that is more likely to be observed except for very small sample sizes. Further, for any mutation transition matrix, we obtain the joint sample frequency spectrum of the two mutant alleles at a triallelic site, and derive a closed-form formula for the expected age of the younger of the two mutations given their frequencies in the population. Several large-scale resequencing projects for various species are presently under way and the resulting data will include some triallelic polymorphisms. The theoretical results described in this paper should prove useful in population genomic analyses of such data. PMID- 21550356 TI - Lateral thinking about leptin: a review of leptin action via the lateral hypothalamus. AB - The lateral hypothalamic area (LHA) was initially described as a "feeding center" but we are now beginning to understand that the LHA contributes to other aspects of physiology as well. Indeed, the best-characterized neuronal populations of the LHA (which contain melanin-concentrating hormone (MCH) or the hypocretins/orexins (OX)) are not strictly orexigenic, but also have roles in regulation of the autonomic and sympathetic nervous systems as well as in modulating motivated behavior. Leptin is an anorectic hormone that regulates energy homeostasis and the mesolimbic DA system (which transduces the wanting of food, drugs of abuse, and sex) in part, via actions at the LHA. At least three populations of LHA neurons are regulated by leptin: those containing MCH, OX or the long form of the leptin receptor, LepRb. The emerging picture of leptin interaction with these LHA populations suggests that the LHA is not merely regulating feeding, but is a crucial integrator of energy balance and motivated behavior. PMID- 21550361 TI - Role of adenosine A2A receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control. AB - Baroreflex dysfunction contributes to increased cardiovascular risk in cigarette smokers. Given the importance of adenosinergic pathways in baroreflex control, the hypothesis was tested that defective central adenosinergic modulation of cardiac autonomic activity mediates the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by i.v. doses (1-16MUg/kg) of phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed in conscious rats; slopes of the curves were taken as measures of baroreflex sensitivity (BRS). Nicotine (25 and 100MUg/kg i.v.) dose-dependently reduced BRS(SNP) in contrast to no effect on BRS(PE). BRS(SNP) was also attenuated after intracisternal (i.c.) administration of nicotine. Similar reductions in BRS(SNP) were observed in rats pretreated with atropine or propranolol. The combined treatment with nicotine and atropine produced additive inhibitory effects on BRS, an effect that was not demonstrated upon concurrent exposure to nicotine and propranolol. BRS(SNP) was reduced in preparations treated with i.c. 8-phenyltheophylline (8-PT, nonselective adenosine receptor antagonist), 8-(3-Chlorostyryl) caffeine (CSC, A(2A) antagonist), or VUF5574 (A(3) antagonist). In contrast, BRS(SNP) was preserved after blockade of A(1) (DPCPX) or A(2B) (alloxazine) receptors or inhibition of adenosine uptake by dipyridamole. CSC or 8-PT abrogated the BRS(SNP) depressant effect of nicotine whereas other adenosinergic antagonists were without effect. Together, nicotine preferentially impairs reflex tachycardia via disruption of adenosine A(2A) receptor-mediated facilitation of reflex cardiac sympathoexcitation. Clinically, the attenuation by nicotine of compensatory sympathoexcitation may be detrimental in conditions such as hypothalamic defense response, posture changes, and ventricular rhythms. PMID- 21550360 TI - Reduced cytochrome P4501A activity and recovery from oxidative stress during subchronic benzo[a]pyrene and benzo[e]pyrene treatment of rainbow trout. AB - This study assessed the role of aryl hydrocarbon receptor (AHR) affinity, and cytochrome P4501A (CYP1A) protein and activity in polyaromatic hydrocarbon (PAH) induced oxidative stress. In the 1-100nM concentration range benzo[a]pyrene (BaP) but not benzo[e]pyrene (BeP) competitively displaced 2nM [(3)H]2, 3, 7, 8 tetrachloro-dibenzo-p-dioxin from rainbow trout AHR2alpha. Based on appearance of fluorescent aromatic compounds in bile over 3, 7, 14, 28 or 50days of feeding 3MUg of BaP or BeP/g fish/day, rainbow trout liver readily excreted these polyaromatic hydrocarbons (PAHs) and their metabolites at near steady state rates. CYP1A proteins catalyzed more than 98% of ethoxyresorufin-O-deethylase (EROD) activity in rainbow trout hepatic microsomes. EROD activity of hepatic microsomes initially increased and then decreased to control activities after 50days of feeding both PAHs. Immunohistochemistry of liver confirmed CYP1A protein increased in fish fed both PAHs after 3days and remained elevated for up to 28days. Neither BaP nor BeP increased hepatic DNA adduct concentrations at any time up to 50days of feeding these PAHs. Comet assays of blood cells demonstrated marked DNA damage after 14days of feeding both PAHs that was not significant after 50days. There was a strong positive correlation between hepatic EROD activity and DNA damage in blood cells over time for both PAHs. Neither CYP1A protein nor 3-nitrotyrosine (a biomarker for oxidative stress) immunostaining in trunk kidney were significantly altered by BaP or BeP after 3, 7, 14, or 28days. There was no clear association between AHR2alpha affinity and BaP and BeP-induced oxidative stress. PMID- 21550362 TI - Metabolites of arsenic and increased DNA damage of p53 gene in arsenic plant workers. AB - Recent studies have shown that monomethylarsonous acid is more cytotoxic and genotoxic than arsenate and arsenite, which may attribute to the increased levels of reactive oxygen species. In this study, we used hydride generation-atomic absorption spectrometry to determine three arsenic species in urine of workers who had been working in arsenic plants,and calculated primary and secondary methylation indexes. The damages of exon 5, 6, 8 of p53 gene were determined by the method developed by Sikorsky, et al. Results show that the concentrations of each urinary arsenic species,and damage indexes of exon 5 and 8 of p53 gene in the exposed population were significantly higher, but SMI was significantly lower than in the control group. The closely positive correlation between the damage index of exon 5 and PMI,MMA, DMA were found, but there was closely negative correlation between the damage index of exon 5 and SMI. Those findings suggested that DNA damage of exon 5 and 8 of p53 gene existed in the population occupationally exposed to arsenic. For exon 5, the important factors may include the model of arsenic metabolic transformation, the concentrations of MMA and DMA, and the MMA may be of great importance. PMID- 21550363 TI - Candidate innate immune system gene expression in the ecological model Daphnia. AB - The last ten years have witnessed increasing interest in host-pathogen interactions involving invertebrate hosts. The invertebrate innate immune system is now relatively well characterised, but in a limited range of genetic model organisms and under a limited number of conditions. Immune systems have been little studied under real-world scenarios of environmental variation and parasitism. Thus, we have investigated expression of candidate innate immune system genes in the water flea Daphnia, a model organism for ecological genetics, and whose capacity for clonal reproduction facilitates an exceptionally rigorous control of exposure dose or the study of responses at many time points. A unique characteristic of the particular Daphnia clones and pathogen strain combinations used presently is that they have been shown to be involved in specific host pathogen coevolutionary interactions in the wild. We choose five genes, which are strong candidates to be involved in Daphnia-pathogen interactions, given that they have been shown to code for immune effectors in related organisms. Differential expression of these genes was quantified by qRT-PCR following exposure to the bacterial pathogen Pasteuria ramosa. Constitutive expression levels differed between host genotypes, and some genes appeared to show correlated expression. However, none of the genes appeared to show a major modification of expression level in response to Pasteuria exposure. By applying knowledge from related genetic model organisms (e.g. Drosophila) to models for the study of evolutionary ecology and coevolution (i.e. Daphnia), the candidate gene approach is temptingly efficient. However, our results show that detection of only weak patterns is likely if one chooses target genes for study based on previously identified genome sequences by comparison to homologues from other related organisms. Future work on the Daphnia-Pasteuria system will need to balance a candidate gene approach with more comprehensive approaches to de novo identify immune system genes specific to the Daphnia-Pasteuria interaction. PMID- 21550364 TI - Functional analysis of a small cryptic plasmid pYS1 from Nocardia. AB - Bacteria of the genus Nocardia cause opportunistic infections of lung, brain and central nervous system, and cutaneous tissue. They are also producers of antibiotics and industrially important enzymes. As studies describing plasmids in this genus are limited, we have characterized a 4326bp cryptic plasmid pYS1 from Nocardia aobensis IFM 10795. Three open reading frames (ORFs) were predicted. Both sequence analyses and detection of single-stranded intermediates suggested a rolling-circle mechanism as the mode of replication of pYS1. Mutageneses and deletion analyses revealed both the predicted double- and single-stranded origins to be indispensable in replication, suggesting a lack of secondary signals for leading and lagging strand synthesis. The replicon of pYS1 is broad-host-range and compatible to that of pAL5000 of mycobacteria, making it potentially useful in genetic manipulation of various actinomycetes. Insertion analyses showed orf1, despite its sequence similarity to plasmid transfer genes, is involved in plasmid stability rather than conjugation and is lethal in the absence of a functional orf3. This situation is somewhat analogous to the kil/kor system of pIJ101 of Streptomyces, except that orf3 was unrelated to korA and was shown by promoter probe assays to encode a novel transcriptional repressor negatively regulating orf1 expression. PMID- 21550365 TI - Can the neuroeconomics revolution revolutionize psychiatry? AB - Neuroeconomics is a rapidly growing new research discipline aimed at describing the neural substrate of decision-making using incentivized decisions introduced in experimental economics. The novel combination of economic decision theory and neuroscience has the potential to better examine the interactions of social, psychological and neural factors with regard to motivational forces that may underlie psychiatric problems. Game theory will provide psychiatry with computationally principled measures of cognitive dysfunction. Given the relatively high heritability of these measures, they may contribute to improving phenotypic definitions of psychiatric conditions. The game-theoretical concepts of optimal behavior will allow description of psychopathology as deviation from optimal functioning. Neuroeconomists have successfully used normative or near normative models to interpret the function of neurotransmitters; these models have the potential to significantly improve neurotransmitter theories of psychiatric disorders. This paper will review recent evidence from neuroeconomics and psychiatry in support of applying economic concepts such as risk/uncertainty preference, time preference and social preference to psychiatric research to improve diagnostic classification, prevention and therapy. PMID- 21550366 TI - Anatomical standardization of small animal brain FDG-PET images using synthetic functional template: experimental comparison with anatomical template. AB - Anatomical standardization (also called spatial normalization) of positron emission tomography (PET) small animal brain images is required to make statistical comparisons across individuals. Frequently, PET images are co registered to an individual MR or CT image of the same subject in order to transform the functional images to an anatomical space. In the present work, we evaluate the normalization of synthetic PET (synPET) images to a synthetic PET template. To provide absolute error in terms of pixel misregistration, we created a synthetic PET image from the individual MR image through segmentation of the brain into gray and white matter which produced functional and anatomical images in the same space. When comparing spatial normalization of synPET images to a synPET template with the gold standard (MR images to an MR template), a mean translation error of 0.24mm (+/-0.20) and a maximal mean rotational error of 0.85 degrees (+/-0.91) were found. Significant decrease in misregistration error was measured when achieving spatial normalization of functional images to a functional template instead of an anatomical template. This accuracy strengthens the use of standardization methods where individual PET images are registered to a customized PET template in order to statistically assess physiological changes in rat brains. PMID- 21550367 TI - Development of one-step multiplex RT-PCR method for simultaneous detection and differentiation of foot-and-mouth disease virus serotypes O, A, and Asia 1 circulating in Vietnam. AB - A one-step multiplex RT-PCR method using new primers was developed for the simultaneous detection and differentiation of Vietnamese FMDV serotypes O, A, and Asia 1 directly from clinical samples. The RT-PCR method used a cocktail of one universal minus-sense primer designed in the 2B gene and three serotype-specific plus-sense primers designed in the hypervariable regions of the capsid VP1 coding gene of FMDV. These serotype-specific primer pairs amplified 658, 535, and 427 bp PCR products corresponding to FMDV serotypes O, Asia 1, and A, respectively. In this study, six well-characterized FMDV strains belonging to serotypes O, A, and Asia 1 were used as reference strains for validation tests. Among these six FMDV strains were three vaccine strains for type O (O1/Manisa), A (A22/Iraq), and Asia 1 (As1/Shamir/89). The other reference strains included one pandemic strain of FMDV serotype Asia 1 (Asia1/MOG/05) and two pandemic strains of FMDV serotype O (O/UKG/34/2001 and O/SKR/2000). For field application, 37 positive-clinical samples and 18 cell culture-adapted viruses belonging to serotypes O, A, and Asia 1, as confirmed previously by antigen ELISA for FMDV detection, were used. The present method showed high sensitivity and specificity and can be adapted for detection and typing of FMDV serotypes O, A, and Asia 1 circulating in Vietnam. PMID- 21550368 TI - Hemocompatibility assessment of poly(2-dimethylamino ethylmethacrylate) (PDMAEMA) based polymers. AB - Poly(2-dimethylamino-ethylmethacrylate) (PDMAEMA), a cationic polymer, has been widely reported as a nonviral carrier. Despite the fact that the cytotoxicity of this polymer has been extensively studied, there is a lack of information about its blood compatibility. Hence, this work evaluates the hemocompatibility of free form PDMAEMA homopolymers differing in molecular weight (Mw) with or without a poly(ethylene glycol) (PEG) sequence in the form of a palm tree-like structure. Poly(ethylenimine) (PEI) was used as a reference in order to compare its hemoreactivity. Hemagglutination, hemolysis, platelet number, blood coagulation, and the complement systems were assessed in normal human whole blood according to the ISO 10993-4. Results showed that Mw, concentration, and incubation time strongly affected the hemocompatibility of the polymers evaluated. Our in vitro observations highlight that PDMAEMA homopolymers interacted strongly with the surface of the red blood cells but not with the inner structure of the membrane, while PEI behaved in the opposite way. No clear correlation has been evidenced between PDMAEMA-induced hemagglutination, PEI-induced hemagglutination, and hemolysis. Interestingly, if these polyelectrolytes strongly affect the platelets and blood coagulation cascades in a dose dependent way, none of them significantly affects the complement system. Our work reveals new knowledge on the toxicology of 2 families of polycations largely explored for gene delivery and on their mechanisms of cellular and humoral interactions. PMID- 21550369 TI - Consumers' acceptance of innovations in traditional cheese. A comparative study in France and Norway. AB - This study explores consumers' acceptance of innovations in traditional cheese in France (n=120) and Norway (n=119). The respondents were presented with 16 photographs of a traditional cheese from their respective countries, varying according to six factors: pasteurisation, organic production, omega-3, packaging, price and appropriateness. For each of the scenarios the consumers indicated their willingness to buy the cheese on a nine-point scale. Results show that consumers' willingness to buy traditional cheese is highly driven by price, appropriateness and pasteurisation in both countries. However, on average consumers in the French sample prefer buying raw milk cheese, while consumers in the Norwegian sample prefer buying pasteurised cheese. These general trends are led by a pro-raw milk segment in France and a pro-pasteurised milk segment in Norway. Several interaction effects involving appropriateness are detected, indicating the importance of the consumption context on the acceptance of innovations in traditional cheese. On a general level, the results indicate that well-accepted innovations in traditional cheese are those that reinforce the traditional and authentic character of the product. PMID- 21550370 TI - Isolation, antiproliferation on tumor cell and immunomodulatory activity of BSP I, a novel bursal peptide from chicken humoral immune system. AB - The bursa of Fabricius (BF) is acknowledged as central humoral immune organ unique to birds. Our purpose was to identify the potential function of a novel bursal-derived bioactive peptide. A bursal septpeptide (BSP-I), EPASGMM, first isolated from BF, reduced MCF and Hela tumor cells proliferation, and enhanced antitumor factor p53 luciferase activity and protein expression. Further, we found the significantly immune inducing function of BSP-I on antigen-specific immune response in BALB/c mice intraperitoneally immunized with inactivated avian influence virus (AIV, H(9)N(2) subtype) vaccine, including of enhancing the antibody (IgG, the isotypes IgG1 and IgG2a) production, and stimulating cytokines IL-4 and IFN-gamma level, and inducing T cell immunophenotyping and lymphocyte proliferation. These results suggested that as the bioactive peptide from avian humoral immune system, various biological function of BSP-I may have far-reaching implication on immune system significance, which might provide novel insight on linking between humoral immune system and development of effective immunotherapeutic strategies for treating human cancers diseases. PMID- 21550372 TI - Production and characterization of HCV particles from serum-free culture. AB - Hepatitis C virus (HCV) is a major cause of liver cancer, and it is therefore important to develop a prophylactic strategy for HCV infection. In recent years, a system for cell culture of the infectious HCV particle has been established, and the inactivated particle has potential as an antigen for vaccine development. In this study, we aimed to establish highly efficient HCV particle purification procedures using the following serum-free culture of HCV particles. First, naive human hepatoma Huh7 cells were grown in serum-free medium that was supplemented with human-derived insulin, transferrin and sodium selenite. Then, in vitro transcribed JFH-1 or J6/JFH-1 chimeric HCV-RNA was transfected into the serum free conditioned Huh7 cells. Infectious HCV was secreted into the culture supernatant with the same efficiency as that from cells cultured in FBS containing medium. The HCV-core protein and RNA continued to be detected in the culture supernatant when the infected cells were subcultured in serum-free medium. Sucrose gradient centrifugation analyses indicated that the profiles of HCV-core, HCV-RNA and the infectivity of HCV particles were almost identical between HCV from FBS-supplemented and serum-free cultures. We further determined that anti-CD81, anti-SR-BI and anti-E2 antibodies inhibited infection by serum free cultured HCV to a greater extent than infection by HCV from FBS-supplemented cultures. These HCV particles also differed in the level of associated apoplipoproteins: the ApoE level was lower in serum-free cultured HCV. ApoB and ApoE antibody-depletion assays suggested that infection of serum-free cultured HCV was independent of ApoB and ApoE proteins. These data suggest that lipids conjugated with HCV affect infection and neutralization. PMID- 21550373 TI - Evaluation of hha and hha sepB mutant strains of Escherichia coli O157:H7 as bacterins for reducing E. coli O157:H7 shedding in cattle. AB - Escherichia coli O157:H7 colonizes cattle intestines by using the locus of enterocyte effacement (LEE)-encoded proteins. The induction of systemic immune response against LEE-encoded proteins, therefore, will prove effective in reducing E. coli O157:H7 colonization in cattle. The previous studies have demonstrated that a hha (encodes for a hemolysin expression modulating protein) deletion enhances expression of LEE-encoded proteins and a sepB (encodes an ATPase required for the secretion of LEE-encoded proteins) deletion results in intracellular accumulation of LEE proteins. In this study, we demonstrate the efficacy of the hha and hha sepB deletion mutants as bacterins for reducing fecal shedding of E. coli O157:H7 in experimentally inoculated weaned calves. The weaned calves were injected intramuscularly with the bacterins containing 10(9) heat-killed cells of the hha(+) wild-type or hha or hha sepB isogenic mutants, and boosted with the same doses 2- and 4-weeks later. The evaluation of the immune response two weeks after the last booster immunization revealed that the calves vaccinated with the hha mutant bacterin had higher antibody titers against LEE proteins compared to the titers for these antibodies in the calves vaccinated with the hha sepB mutant or hha(+) wild-type bacterins. Following oral inoculations with 10(10) CFU of the wild-type E. coli O157:H7, the greater numbers of calves in the group vaccinated with the hha or hha sepB mutant bacterins stopped shedding the inoculum strain within a few days after the inoculations compared to the group of calves vaccinated with the hha(+) wild-type bacterin or PBS sham vaccine. Thus, the use of bacterins prepared from the hha and hha sepB mutants for reducing colonization of E. coli O157:H7 in cattle could represent a potentially important pre-harvest strategy to enhance post-harvest safety of bovine food products, water and produce. PMID- 21550371 TI - Amphipols stabilize the Chlamydia major outer membrane protein and enhance its protective ability as a vaccine. AB - The native major outer membrane protein (nMOMP) from Chlamydia was purified in its trimeric form using the zwitterionic detergent Z3-14. In aliquots from this preparation, Z3-14 was exchanged for amphipol (APol) A8-35. CD analysis showed that trapping with A8-35 improved the thermostability of nMOMP without affecting its secondary structure. Recombinant MOMP (rMOMP) was also formulated with Z3-14 or A8-35. Four groups of mice were vaccinated with nMOMP/Z3-14, nMOMP/A8-35, rMOMP/Z3-14 or rMOMP/A8-35 using CpG and Montanide as adjuvants. A positive control group was inoculated intranasally with live Chlamydia and a negative control group with culture medium. Mice were challenged intranasally with live Chlamydia and protection was assessed based on changes in body weight, the weight of the lungs and the number of chlamydial inclusion forming units recovered from the lungs 10 days after the challenge. Overall, vaccines formulated with nMOMP elicited better protection than those using rMOMP. Furthermore, the protection afforded by nMOMP/A8-35 was more robust than that achieved with nMOMP/Z3-14. In contrast, no differences in protection were observed between rMOMP/Z3-14 and rMOMP/A8-35 preparations. These findings suggest that the higher protection conferred by nMOMP/A8-35 complexes most likely results from a better preservation of the native structure of MOMP and/or from a more efficient presentation of the antigen to the immune system, rather than from an adjuvant effect of the amphipol. Thus, amphipols can be used in vaccine formulations to stabilize a membrane-protein component and enhance its immunogenicity. PMID- 21550374 TI - Mother-infant vaccination with pneumococcal polysaccharide vaccine: persistence of maternal antibodies and responses of infants to vaccination. AB - Protection against pneumococcal infection early in life is needed. This could be achieved by maternal vaccination or by starting infant vaccinations as early as possible. In an open controlled study, pregnant women received both 23-valent pneumococcal polysaccharide vaccine (PPV), Haemophilus influenzae type b conjugate vaccine and tetanus toxoid or tetanus toxoid alone. Infants received PPV at 7 or 17 weeks and the second dose at 3 years of age. Antibodies to six pneumococcal serotypes were measured with the non-22F and 22F enzyme immunoassays (EIA). Elevated antibody concentrations after maternal vaccination persisted in infants until 4 months of age. Infants responded to serotypes 1 and 5, but not to serotypes 6B, 14, 18C and 19F. High maternal antibody concentrations at early age reduced the responses, but not the antibody concentrations, of infants to PPV. The percentages of infants with concentrations >0.35 MUg/ml and >1 MUg/ml were high at birth, but decreased by age during the first 10 months of life. Revaccination with PPV at 3 years of age induced a good immune response. PMID- 21550375 TI - Formalin-inactivated vaccine provokes cross-protective immunity in a mouse model of human enterovirus 71 infection. AB - Human enterovirus 71 (HEV71) has emerged as a major cause of epidemics of hand, foot and mouth disease associated with severe neurological sequelae in the Asia Pacific region. In this study, a passive protection mouse model was used to evaluate the protective efficacy of formalin-inactivated HEV71 vaccines derived from a Chinese C4 genotype strain. Pregnant mice were immunised using a prime/boost strategy and >=50U of vaccine protected five-day-old pups from lethal challenge with a mouse-adapted (B3 genotype) strain of HEV71. Immunised mice developed a neutralising antibody response to both the immunising C4 strain and to the mouse-adapted strain. Mice born to immunised dams showed significantly less myositis and reduced viral loads in tissues. PMID- 21550376 TI - Seasonal influenza vaccination coverage in France during two influenza seasons (2007 and 2008) and during a context of pandemic influenza A(H1N1) in 2009. AB - OBJECTIVES: To measure the seasonal influenza vaccination coverage rate (VCR) in France in 2009, year of the A(H1N1) influenza pandemic, by age and target disease and compare it with the VCR for the 2007 and 2008 influenza seasons. METHOD: At the beginning of each annual seasonal vaccination campaign, the National Health Insurance, covering 86% of the French population, sends free influenza vaccination vouchers to at-risk beneficiaries aged under 65 suffering from diverse chronic diseases and to all individuals aged 65 and over (around 11 million). Vaccination is estimated from refund claims registered in the National Health Insurance Information System. RESULTS: The global VCR for the target population was 51% in 2007, 55.8% in 2008 and 56.9% in 2009. In 2009, the VCR for children under 10 years old was 24.3%, 28.1% in the 10-19 age range, 39.2% in the 20-64 age range and 63.3% for individuals aged 65 and over, of which 72.3% with a targeted chronic disease and 56.9% without. The inclusion of asthma as a target disease, lowered the global VCR for children under 10 years old (30.6% without asthma) but VCR increased proportionally with the number of annual refunds for drugs against asthma and chronic obstructive pulmonary disease. The 2009 vaccine uptake rates in target group children, adolescents, young adults and to a lesser extent the population aged 65 and over suffering from a chronic disease (particularly chronic respiratory disease), could have been positively impacted by the A(H1N1) influenza context. CONCLUSION: The influenza VCR varies considerably according to age and target disease but globally remains inferior to the recommended 75% coverage rate. These results permit the detailed analysis of VCR distribution by disease and target group and highlights areas for reflection and action. Specific studies should be conducted in order to understand why the VCR is lower in certain target groups. PMID- 21550377 TI - Influenza vaccine for pregnant women in resource-constrained countries: a review of the evidence to inform policy decisions. AB - Seasonal influenza is responsible for three to five million severe cases of disease annually, and up to 500,000 deaths worldwide. Pregnant women and infants suffer disproportionately from severe outcomes of influenza. The excellent safety profile and reliable immunogenicity of inactivated influenza vaccine support WHO recommendations that pregnant women be vaccinated to decrease complications of influenza disease during pregnancy. Nevertheless, influenza vaccine is not routinely used in most low-and middle-income countries and is not widely used in pregnant women worldwide. Two recent prospective, controlled trials of maternal influenza vaccination in Bangladesh and US Native American reservations demonstrated that inactivated influenza vaccine given to pregnant women can decrease laboratory-confirmed influenza virus infection in their newborn children. These studies support consideration of the feasibility of targeted influenza vaccine programs in resource-constrained countries. Platforms exist for the delivery of influenza vaccine to pregnant women worldwide. Even in the least developed countries, an estimated 70% of women receive antenatal care, providing an opportunity for targeted influenza vaccination. Challenges to the introduction of maternal influenza vaccination in resource-constrained countries exist, including issues regarding vaccine formulation, availability, and cost. Nonetheless, maternal influenza vaccination remains an important and potentially cost-effective approach to decrease influenza morbidity in two high-risk groups - pregnant women and young infants. PMID- 21550378 TI - Effect of red wine polyphenol dietary supplementation on two phase II enzymes in liver of hyperhomocysteinemic mice. AB - Hyperhomocysteinemia leads to diverse clinical manifestations, notably liver disease. The pathogenicity of homocysteine is believed to be due to its ability to produce oxidative stress. Paraoxonase-1 (Pon1), a phase I xenobiotic metabolizing enzyme (XME) synthesized by liver with anti-oxidative properties within the circulating system is down regulated in case of hyperhomocysteinemia. In a previous study, we have shown that red wine polyphenol extract (PE) supplementation induces a decrease in plasma homocysteine level and an increase in hepatic Pon1 gene expression concomitant with an increase in hepatic and plasma Pon1 activity in a murine model of hyperhomocysteinemia. In the present study, we analyzed the effect of PE supplementation on two phase II XME: NAD(P)H:quinone oxidoreductase (Nqo1) and arylamine-N-acetyltransferase (Nat) family. We found that hyperhomocysteinemia leads to a decrease of hepatic Nqo1 gene expression and activity with a reversal effect of PE supplementation. We also found that hyperhomocysteinemia-induced decrease of peroxynitrite level is associated with an increase of hepatic total Nat activity mainly due to the Nat2 isoform with a reversal effect of PE supplementation. Our results show a beneficial effect of PE supplementation on two phase II enzymes which are altered in case of hyperhomocysteinemia. PMID- 21550380 TI - An ancient frame-shifting event in the highly conserved KPNA gene family has undergone extensive compensation by natural selection in vertebrates. AB - One of the prevailing arguments in evolutionary theory is that the duplicates of genes can acquire novel functionality. This is because only one of the paralogs need maintain the ancestral function, leaving room for natural experimentation due to a respite in purifying selection. Although many duplicates can subsequently become disabled by nullifying mutations, a few may also go on to diverge along a novel evolutionary trajectory. Here, evidence is provided that demonstrates how this scenario may not always be true. Rather, in the case of the highly conserved KPNA importin family, an initial relaxation in selection induced a frameshift that was later suppressed and heavily compensated for as part of a reparative and optimizing process. Despite a resulting divergence, there remains a distinct preservation of both sequence and functionality among the paralogs. This would indicate that duplicates can be retained by selection for reasons related to their redundant functionality. It also shows that, even when positive selection is inferred in duplicate genes, this may be of a compensatory nature rather than one representing any biochemical innovation. Generally, this development would perhaps be a more common outcome for gene duplication than is currently maintained. PMID- 21550381 TI - Betaglycan: a multifunctional accessory. AB - Betaglycan is a co-receptor for the TGFbeta superfamily, particularly important in establishing the potency of its ligands on their target cells. In recent years, new insights have been gained into the structure and function of betaglycan, expanding its role from that of a simple co-receptor to include additional ligand-dependent and ligand-independent roles. This review focuses on recent advances in the betaglycan field, with a particular emphasis on its newly discovered actions in mediating the trafficking of TGFbeta superfamily receptors and as a determinant of the functional output of TGFbeta superfamily signalling. In addition, this review encompasses a discussion of the emerging roles of the betaglycan/inhibin pathway in reproductive cancers and disease. PMID- 21550382 TI - ReLA/P65-serine 536 nuclear factor-kappa B phosphorylation is related to vulnerability to status epilepticus in the rat hippocampus. AB - Although nuclear factor-kappa B (NF-kappaB) is essential for neuron survival and its activation may protect neuron against oxidative-stresses or ischemia-induced neurodegeneration, NF-kappaB activation can contribute to inflammatory reaction and apoptotic cell death after brain injury and stroke. However, there are little data concerning the specific pattern of NF-kappaB phosphorylations in neuronal damage/survival induced by status epilepticus (SE). In the present study, NF kappaB phosphorylation showed the cellular specific pattern in responses to SE. p52-S865, p52-Ser869, p65-Ser276, p65-Ser311, p65-Ser468, and p65-Ser529 NF kappaB phosphorylation was significantly decreased in the CA1 and CA3 pyramidal cells vulnerable to SE, although neuronal specific nuclear antigen immunoreactivity was strongly detected. In contrast, p65-Ser536 NF-kappaB phosphorylation was enhanced in these neurons accompanied by TUNEL- and Fluoro Jade B 244signals. These findings serve as the first comprehensive description of the cellular specific distribution of NF-kappaB phosphorylation in response to pilocarpine-induced SE in the rat hippocampus, and suggest that enhancement in p65-Ser536 NF-kappaB phosphorylation may be closely relevant to neuronal vulnerability to SE, while others may be involved in neuronal survival. PMID- 21550383 TI - Ultra-low exposure to alpha-7 nicotinic acetylcholine receptor partial agonists elicits an improvement in cognition that corresponds with an increase in alpha-7 receptor expression in rodents: implications for low dose clinical efficacy. AB - Alphalpha-7 neuronal nicotinic receptors (NNRs) are considered targets for cognitive enhancement in schizophrenia and Alzheimer's disease. AZD0328 is an alpha-7 NNR partial agonist that enhances cognition in rodents and nonhuman primates at sub-microgram to microgram doses. We hypothesized that increased expression of the alpha-7 receptor contributes to this beneficial activity at low doses and tested this by examining the effect of AZD0328 using in vivo and ex vivo binding, RT-PCR and cognitive function in rodents. AZD0328 (0.00178 mg/kg) was subcutaneously administered to mice 4, 24, 48 and 72 hours prior to testing in novel object recognition and produced a significant increase in cognition at 4, 24 and 48 h post-dosing. In vivo binding was examined in rat brain using [(3)H]AZ11637326 and there was a dose-dependent reduction in receptor binding at higher doses of AZD0328 (0.001-3 mg/kg), and a second alpha-7 partial agonist, SSR180711 (0.01-30 mg/kg). Lower doses of both compounds (0.0001 mg/kg) produced a significant increase in binding of [(3)H]AZ11637326. Ex vivo binding using [(125)I]-alpha-bungarotoxin, showed a significant increase in receptor number (B(max.)) in the frontal cortex or hippocampus with no significant effect on receptor affinity (K(d)) 2 h post administration of AZD0328. [(3)H]AZ11637326 administered 1.5 h following AZD0328 produced a significant increase in specific binding in rat brain regions. We found that the effect on receptor number was long-lasting, with [(125)I]-alpha-bungarotoxin binding increased in rats given AZD0328 for 2-48 h, but this was not accompanied by increased mRNA synthesis. SSR180711 produced a similar increase in B(max.) and specific binding with no effect on K(d). Therefore, trace dose of alpha-7 partial agonists has rapid onset and produces a profound, sustained effect on novel object recognition in mice that corresponds by dose to an increase in receptor number in rat brain. These findings provide an explanation for the acute and sustained benefit of alpha-7 receptor activation in working memory in nonhuman primates and guidance for drug development initiatives and treatment regimens for nicotinic partial agonists. PMID- 21550384 TI - Domain independence and stability in young and older adults' discounting of delayed rewards. AB - Individual discounting rates for different types of delayed reward are typically assumed to reflect a single, underlying trait of impulsivity. Recently, we showed that discounting rates are orders of magnitude steeper for directly consumable liquid rewards than for monetary rewards (Jimura et al., 2009), raising the question of whether discounting rates for different types of reward covary at the individual level. Accordingly, the present study examined the relation between discounting of hypothetical money and real liquid rewards in young adults (Experiment 1) and older adults (Experiment 2). At the group level, young adults discounted monetary rewards more steeply than the older adults, but there was no significant age difference with respect to liquid rewards. At the individual level, the rates at which young and older participants discounted each reward type were stable over a two- to fifteen-week interval (rs>70), but there was no significant correlation between the rates at which they discounted the two reward types. These results suggest that although similar decision-making processes may underlie the discounting of different types of rewards, the rates at which individuals discount money and directly consumable rewards may reflect separate, stable traits, rather than a single trait of impulsivity. PMID- 21550385 TI - Microsomal cytochrome P450-mediated metabolism of hypaconitine, an active and highly toxic constituent derived from Aconitum species. AB - Hypaconitine (HA), an active and highly toxic constituent derived from Aconitum species, is widely used to treat rheumatism. Little is known about the hepatic cytochrome P450-catalyzed metabolism of HA. The present study investigated the metabolism of HA in vitro using male human liver microsomes (MHLMS). Chemical inhibitors of specific CYP enzymes, CYP-specific inhibitory monoclonal antibodies (mAbs), and cDNA-expressed CYP enzymes were used to confirm the enzyme subtypes involved in the metabolism. Liquid chromatography-high resolution mass spectrometry (LC-MS) was used to detect and identify metabolites. A total of 11 metabolites were identified in MHLMS incubations. The major metabolic pathways included demethylation (M1-M3), demethylation-dehydrogenation (M4-M6), hydroxylation (M7, M8), and didemethylation (M9-M11). M8 was identified as mesaconitine (MA), another active and highly toxic constituent of Aconitum. The results of chemical inhibition, monoclonal antibody inhibition, and cDNA expressed CYP enzyme studies showed that the primary contributors toward HA metabolism were CYP3A4 and 3A5, with secondary contributions by CYP2C19, 2D6, and CYP2E1. CYP1A2 and 2C8 provided minor contributions. PMID- 21550386 TI - Granulocyte colony-stimulating factor treatment ameliorates liver injury and improves survival in rats with D-galactosamine-induced acute liver failure. AB - Only liver transplantation is currently available therapy for the patients with acute liver failure (ALF). This study was designed to determine whether administration of granulocyte colony-stimulating factor (G-CSF) has therapeutic efficacy in animals with ALF. Female Sprague-Dawley (SD) rats were intraperitoneally injected with a single dose of d-galactosamine (d-GalN, 1.4g/kg) to induce ALF. After 2h, the rats were randomized to receive G-CSF (50MUg/kg/day), or saline vehicle injection for 5 days. Rats were observed for survival and assessed for liver injury by serum alanine transaminase (ALT) measurement and histological analysis. CD34+ cells in bone marrow were assessed by flow cytometry. CD34+ cells and Ki-67+ hepatocytes in liver tissue were evaluated by immunohistochemistry. In the ALF model, 5-day survival after d-GalN injection was 33.3% (10/30), while G-CSF administration following d-GalN resulted in 53.3% (16/30) survival (p=0.027). G-CSF treated rats had lower ALT level and less hepatic injury compared with saline vehicle rats. The increases of CD34+ cells in bone marrow and liver tissue and Ki-67+ cells in liver tissue in G-CSF treated rats were higher than those in saline rats. No correlation was observed between CD34+ cells and Ki-67+ hepatocytes in liver tissue in both G-CSF and vehicle rats. It is suggested that G-CSF increases survival rate, decreases liver injury and enhances hepatocyte proliferation in rats with d-GalN-induced ALF possibly through actions including but not limiting to CD34+ cell mobilization, and that G-CSF may be of potential value in treating ALF. PMID- 21550387 TI - New functional degradable and bio-compatible nanoparticles based on poly(malic acid) derivatives for site-specific anti-cancer drug delivery. AB - Design of an efficient site-specific drug delivery system based on degradable functional polymers still remains challenging. In this work, we synthesized and characterized three degradable functional polyesters belonging to the poly(malic acid) family: the poly(benzyl malate) (PMLABe), the poly(ethylene glycol)-b poly(benzyl malate) (PEG(42)-b-PMLABe), the biotin-poly(ethylene glycol)-b poly(benzyl malate) (Biot-PEG(62)-PMLABe). Starting from these building blocks, we were able to prepare the corresponding well-defined degradable functional nanoparticles whose toxicity was evaluated in vitro on normal and cancer cell lines. Results have evidenced that the prepared nanoparticles did not show any significant cytotoxicity even at high concentrations. A model anti-cancer drug (doxorubicin, Dox) or a fluorescent probe (1,1'-dioctadecyl-3,3,3',3' tetramethylindodicarbocyanine, DiD oil) has been encapsulated into PMLABe, PEG(42)-PMLABe or Biot-PEG(62)-PMLABe based nanoparticles in order to evaluate, respectively, the in vitro cytotoxicity of Dox-loaded nanoparticles on normal and cancer cell lines and the ligand (biotin) effect on cellular uptake in vitro using mmt 060562 cell line. Dox-loaded PMLABe, PEG(42)-PMLABe or Biot-PEG(62) PMLABe nanoparticles showed an in vitro cytotoxicity similar to that of free Dox. Moreover, the DiD oil loaded Biot-PEG(62)-PMLABe based nanoparticles showed a better in vitro cellular uptake than ligand-free DiD oil loaded nanoparticles. Both results evidence the great potential of such degradable functional poly(malic acid) derivatives for the design of highly efficient site-specific anti-cancer nanovectors. PMID- 21550379 TI - DNA repair deficiency in neurodegeneration. AB - Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington's disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration. PMID- 21550388 TI - Effect of wheat germ agglutinin density on cellular uptake and toxicity of wheat germ agglutinin conjugated PEG-PLA nanoparticles in Calu-3 cells. AB - Wheat germ agglutinin (WGA) modified PEG-PLA nanoparticles (WGA-NP) have demonstrated its potential for enhancing delivery of peptides into brain following intranasal administration. However, the effect of ligand density is less well known. WGA density may affect nanoparticles uptake in nasal epithelial cells through ligand-receptor interactions, and the damage to nasal tissue since WGA showed cytotoxicity to cells in a dose-dependent manner. In this study, the effect of WGA density on WGA-NP was studied with regard to both the uptake and toxicity in vitro, using Calu-3 cells, which express a number of N acetylglucosamine on their cell surface. Nanoparticles containing different WGA ligand densities were prepared by controlling the molar ratio of thiolated WGA to maleimide-PEG-PLA (WGA/maleimide) and particles properties were examined. With the increase of WGA/maleimide ratio, the particle size, WGA density and the hemoagglutination increased, while the conjugation efficiency decreased. The in vitro study showed markedly enhanced endocytosis of WGA-NP compared to NP in Calu 3 cells and significant inhibition of uptake in the presence of chitin. Cytotoxicity of WGA-NP increased gradually with the increase of molar ratio of WGA to maleimide, nanoparticles concentration and incubation time. WGA-NP showed the highest efficiency of uptake and a mild cytotoxicity when the molar ratio of WGA to maleimide was 1:10. These results suggest that WGA density plays an important role in both cellular uptake and toxicity of WGA-NP via a receptor mediated mechanism. Therefore, to achieve a more rational approach of drug delivery system design, the surface density of the targeting moiety on the nanoparticles surface should be considered. PMID- 21550389 TI - Protective effects of Polygonatum sibiricum polysaccharide on ovariectomy-induced bone loss in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: To assess the ability of traditional Chinese medicine Polygonatum sibiricum polysaccharide to prevent bone loss in the ovariectomized rat. MATERIALS AND METHODS: PSP was administered intragastrically to the rats. After 35 days, the total body bone mineral density (BMD) was assessed in all of the rats. All sections were processed for immunohistochemistry and hematoxylin-eosin staining (H.E.). RESULTS: BMD was lower in the ovariectomized group (OVX, 0.163 g/cm(2)), the group that received a moderate dose of PSP on OVX animals (OVX+MP, 0.163 g/cm(2)) and the group that received a low dose of PSP on OVX animals (OVX+LP, 0.162 g/cm(2)) than in the sham-operated group (SHAM, 0.180 g/cm(2)), the OVX+E(2) group (OVX+E(2), 0.176 g/cm(2)) and the group that received a high dose of PSP on OVX animals (OVX+HP, 0.174 g/cm(2)) (P<0.05). Clear arrangements of bone trabeculae were observed in the OVX+E(2) and OVX+HP. The expression of bone morphogenetic proteins (BMP) and basic fibroblast growth factor (bFGF) in the OVX, OVX+MP and OVX+LP was down regulated compared to the SHAM, OVX+E(2) and OVX+HP (P<0.05). The rats in the OVX+E(2) and OVX+HP had lower levels of bone Gla protein (BGP), bone alkaline phosphatase (BALP), tartrate-resistant acid phosphatase (TRAP) and tumor necrosis factor alpha(TNF alpha) expression than the rats in the OVX, OVX+MP and OVX+LP (P<0.05). CONCLUSION: This experiment demonstrates that the administration of PSP to ovariectomized rats reverses bone loss and prevents osteoporosis. PMID- 21550390 TI - Traditional plants used for medicinal purposes by local communities around the Northern sector of Kibale National Park, Uganda. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The study was done to establish medicinal plants used in the treatment of various diseases by the people in the Northern sector of Kibale National Park in western Uganda. It was also aimed at establishing the plant parts used and the mode of preparation of remedies. These plants create a basis for phytochemical evaluation which can lead to the discovery of biologically active compounds that can be used as starting materials in the development of new drugs targeting selected diseases such as malaria. MATERIALS AND METHODS: The required information was obtained using open interviews, semi structured questionnaires, focus group discussions and transect walks. RESULTS: Different medicinal plants (131 species) distributed over 55 families were observed to be used by the local communities around the Northern sector of Kibale National Park. The plants as reported in this paper are used to treat 43 physical illnesses/diseases. The most used parts of the plants are the leaves. Water is the main medium used for the preparation of the remedies which are mostly administered orally. CONCLUSION: The people in the study area have a rich heritage of traditional plants that are used in the health care system to treat diseases. These medicinal plants have contributed significantly to several disease therapies. The most common diseases treated are malaria and cough, which are mostly treated by Vernonia amygdalina Del. and Albizia coriaria Welw. respectively. The main sources of medicinal plants include bush land, home gardens, grasslands, and the forest. PMID- 21550391 TI - TCM grammar systems: an approach to aid the interpretation of the molecular interactions in Chinese herbal medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Interpreting the molecular interactions in Chinese herbal medicine will help to understand the molecular mechanisms of Traditional Chinese medicines (TCM) and predict the new pharmacological effects of TCM. Yet, we still lack a method which could integrate the concerned pieces of parsed knowledge about TCM. MATERIALS AND METHODS: To solve the problem, a new method named TCM grammar systems was proposed in the present article. The possibility to study the interactions of TCM at the molecular level using TCM grammar systems was explored using Herba Ephedrae Decoction (HED) as an example. RESULTS: A platform was established based on the formalism of TCM grammar systems. The related molecular network of Herba Ephedrae Decoction (HED) can be extracted automatically. The molecular network indicates that Beta2 adrenergic receptor, Glucocorticoid receptor and Interleukin12 are the relatively important targets for the anti-anaphylaxis asthma function of HED. Moreover, the anti anaphylaxis asthma function of HED is also related with suppressing inflammation process. The results show the feasibility using TCM grammar systems to interpret the molecular mechanism of TCM. Although the results obtained depend on the database absolutely, recombination of existing knowledge in this method provides new insight for interpreting the molecular mechanism of TCM. CONCLUSIONS: TCM grammar systems could aid the interpretation of the molecular interactions in TCM to some extent. Moreover, it might be useful to predict the new pharmacological effects of TCM. The method is an in silico technology. In association with the experimental techniques, this method will play an important role in the understanding of the molecular mechanisms of TCM. PMID- 21550392 TI - Evaluation of anti-migraine potential of Areca catechu to prevent nitroglycerin induced delayed inflammation in rat meninges: possible involvement of NOS inhibition. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Areca catechu nut extract is a popular folk remedy for the treatment of migraine in Kerala and Tamil Nadu states of India. AIM OF THE STUDY: In order to prove the claimed utilization of plant, the effect of hydroalcoholic extract of Areca catechu nut (ANE) was investigated in nitroglycerine induced inflammation in rat meninges. In these models infusion of nitric oxide donor glyceryl trinitrate (GTN) produces augmented plasma protein extravasation (PPE) in dura mater, provides an important substrate for the development of migraine in rats. MATERIALS AND METHODS: The effect on plasma protein extravasation was assessed in both the models of intravenous and topical GTN application following oral administration of ANE (250 mg/kg and 500 mg/kg) in both curative and preventive treatment and compared with that of control positive. The l-NAME (15 mg/kg, i.v.) was used as reference standard. Plasma protein extravasation was measured using fluorescein as marker and was measured using a Perkin-Elmer LS-30 luminescence spectrometer. RESULTS: Expression of iNOS in the spleen after intravenous injection produced PPE into the dura mater in control positive group was significantly (P<0.01) reduced to 1.553+/-0.02499 and 1.398+/-0.01887 by preventive treatment with ANE at the dose of 250 and 500 mg/kg, orally, respectively. The extravasation produced by topical GTN due to expression of iNOS in dural macrophages was also reduced to 1.555+/-0.03384 and 1.425+/-0.01204 by preventive treatment with ANE at the dose of 250 and 500 mg/kg, orally, respectively. While ANE do not showed any significant results in curative treatment in both the models of i.v. and topical GTN application. CONCLUSION: These findings collectively indicate that the extract exhibited significant inhibition of iNOS, which may be the probable mechanism for its anti migraine activity, providing evidence, at least in part, for its folkloric use. PMID- 21550393 TI - Baculovirus as a gene delivery vector: recent understandings of molecular alterations in transduced cells and latest applications. AB - Baculovirus infects insects in nature and is non-pathogenic to humans, but can transduce a broad range of mammalian and avian cells. Thanks to the biosafety, large cloning capacity, low cytotoxicity and non-replication nature in the transduced cells as well as the ease of manipulation and production, baculovirus has gained explosive popularity as a gene delivery vector for a wide variety of applications. This article extensively reviews the recent understandings of the molecular mechanisms pertinent to baculovirus entry and cellular responses, and covers the latest advances in the vector improvements and applications, with special emphasis on antiviral therapy, cancer therapy, regenerative medicine and vaccine. PMID- 21550394 TI - The lipases from Yarrowia lipolytica: genetics, production, regulation, biochemical characterization and biotechnological applications. AB - Lipases are serine hydrolases that catalyze in nature the hydrolysis of ester bonds of long chain triacylglycerol into fatty acid and glycerol. However, in favorable thermodynamic conditions, they are also able to catalyze reactions of synthesis such as esterification or amidation. The non-conventional yeast Yarrowia lipolytica possesses 16 paralogs of genes coding for lipase. However, little information on all those paralogs has been yet obtained and only three isoenzymes, namely Lip2p, Lip7p and Lip8p have been partly characterized so far. Microarray data suggest that only a few of them could be expressed and that lipase synthesis seems to be dependent on the fatty acid or oil used as carbon source confirming the high adaptation of Y. lipolytica to hydrophobic substrate utilization. This review focuses on the biochemical characterization of those enzymes with special emphasis on the Lip2p lipase which is the isoenzyme mainly synthesized by Y. lipolytica. Crystallographic data highlight that this latter is a lipase sensu stricto with a lid covering the active site of the enzyme in its closed conformation. Recent findings on enzyme conditioning in dehydrated or liquid formulation, in enzyme immobilization by entrapment in natural polymers from either organic or mineral origins are also discussed together with long-term storage strategies. The development of various biotechnological applications in different fields such as cheese ripening, waste treatment, drug synthesis or human therapeutics is also presented. PMID- 21550395 TI - Classification and labeling of industrial products with extreme pH by making use of in vitro methods for the assessment of skin and eye irritation and corrosion in a weight of evidence approach. AB - Classification and labeling of products with extreme pH values (<= 2 or >= 11.5) is addressed in chemicals legislation. Following determination of pH and alkaline/acid reserve, additional in vitro tests are needed, especially to substantiate results less than corrosive. However, only limited experience with the practical application of in vitro methods to determine appropriate classifications for pH extreme products is available so far. Expert judgment and weight of evidence are given major roles under the globally harmonized system of classification and labeling of chemicals (GHS) and should be performed on a sound data basis. We have used a tiered testing strategy to assess 20 industrial products (cleaning and metal pretreatment) regarding their corrosive and irritating properties towards human skin models in vitro in the EpiDerm skin corrosion and/or skin irritation test. Nine dilutions of individual compounds were additionally tested. Non-corrosive samples were tested in the Hen's egg test chorioallantoic membrane (HET-CAM). We demonstrate how data is combined in a weight of evidence expert judgment, and give examples of classification decisions. To our knowledge this is the first comprehensive analysis of industrial products with extreme pH values to determine irritating and corrosive properties by making use of in vitro methods in a weight of evidence approach. PMID- 21550396 TI - Upgrading molecular diagnostics of myotonic dystrophies: multiplexing for simultaneous characterization of the DMPK and ZNF9 repeat motifs. AB - Myotonic dystrophy (DM) is a common neuromuscular disorder comprising at least two genetically different forms. DM1 is caused by expansion of a (CTG)(n) repeat in the DMPK gene, while DM2 is caused by expansion of a (CCTG)(n) part of a complex repetitive motif (TG)(n)(TCTG)(n)(CCTG)(n) in the ZNF9 gene. Detection of the responsible expansions is complicated in both cases because of the extremely variable length of the expanded alleles, which can contain even several thousands of repeats in both disorders. One of the commonly used detection approaches utilizes the combination of conventional PCR and "triplet" or "tetraplet" repeat primed PCR (TP-PCR). TP-PCR can be performed simultaneously or successively in both DM1 and DM2 testing. We have designed two multiplex reactions which include bi-directionally labelled conventional PCRs and TP-PCRs for both DM1 and DM2 loci. These two reactions can be used under the same amplification and electrophoretic conditions thus allowing their parallelisation into a one step method. Simultaneous analysis of the samples using these two multiplex reactions allows characterization of both the DM1 and DM2 repeat regions in the time usually required for the first screening step in conventional DM1 or DM2 testing. PMID- 21550398 TI - Candidate tumour suppressor Fau regulates apoptosis in human cells: an essential role for Bcl-G. AB - FAU, which encodes a ubiquitin-like protein (termed FUBI) with ribosomal protein S30 as a carboxy-terminal extension, has recently been identified as a pro apoptotic regulatory gene. This activity may be mediated by Bcl-G (a pro apoptotic member of the Bcl-2 family) which can be covalently modified by FUBI. FAU gene expression has been shown to be down-regulated in human breast, prostate and ovarian tumours, and this down-regulation is strongly associated with poor prognosis in breast cancer. We demonstrate here that ectopic FAU expression increases basal apoptosis in human T-cell lines and 293T/17 cells, whereas it has only a transient stimulatory effect on ultraviolet-C (UVC)-induced apoptosis. Conversely, siRNA-mediated silencing of FAU gene expression has no effect on basal apoptosis, but attenuates UV-induced apoptosis. Importantly, prior knockdown of Bcl-G expression ablates the stimulation of basal apoptosis by FAU, consistent with an essential downstream role for Bcl-G, itself a candidate tumour suppressor, in mediating the apoptosis regulatory role of FAU. In 293T/17 cells, Bcl-G knockdown also attenuates UV-induced apoptosis, so that Bcl-G may constitute a common factor in the pathways by which both FAU and UV-irradiation induce apoptosis. UV irradiation increases Bcl-G mRNA levels, providing an explanation for the transient nature of the effect of ectopic FAU expression on UV-induced apoptosis. Since failure of apoptosis is fundamental to the development of many cancers, the pro-apoptotic activity of the Fau/Bcl-G pathway offers an attractive explanation for the putative tumour suppressor role of FAU. PMID- 21550397 TI - Glutamatergic drive of the dorsal raphe nucleus. AB - The dorsal raphe nucleus (DR) contains the majority of serotonin (5 hydroxytryptamine, 5-HT) neurons in the brain that regulate neural activity in forebrain regions through their widespread projections. DR function is linked to stress and emotional processing, and is implicated in the pathophysiology of affective disorders. Glutamatergic drive of the DR arises from many different brain areas with the capacity to inform the nucleus of sensory, autonomic, endocrine and metabolic state as well as higher order neural function. Imbalance of glutamatergic neurotransmission could contribute to maladaptive 5-HT neurotransmission and represents a potential target for pharmacotherapy. Within the DR, glutamate-containing axon terminals can be identified by their content of one of three types of vesicular glutamate transporter, VGLUT1, 2 or 3. Each of these transporters is heavily expressed in particular brain areas such that their content within axons correlates with the afferent's source. Cortical sources of innervation to the DR including the medial prefrontal cortex heavily express VGLUT1 whereas subcortical sources primarily express VGLUT2. Within the DR, many local neurons responsive to substance P contain VGLUT3, and these provide a third source of excitatory drive to 5-HT cells. Moreover VGLUT3 is present, with or without 5-HT, in output pathways from the DR. 5-HT and non-5-HT neurons receive and integrate glutamatergic neurotransmission through multiple subtypes of glutamate receptors that have different patterns of expression within the DR. Interestingly, excitatory drive provided by glutamatergic neurotransmission is closely opposed by feedback inhibition mediated by 5-HT1A receptors or local GABAergic circuits. Understanding the intricacies of these local networks and their checks and balances, may help identify how potential imbalances could cause psychopathology and illuminate strategies for therapeutic manipulation. PMID- 21550399 TI - Real-time UV imaging of drug diffusion and release from Pluronic F127 hydrogels. AB - The objective of this study was to introduce and evaluate UV imaging technology for real-time characterization of drug diffusion in and release from hydrogels. Piroxicam and human serum albumin diffusion in Pluronic F127 hydrogel was monitored by measuring the absorbance of light passing through the diffusion cell at 26 degrees C, thus providing real-time concentration maps (7*3 mm imaging area) within the gel as a function of time. Apparent diffusion coefficients were obtained on the basis of Fick's second law. Piroxicam and human serum albumin diffusivities in 20% (w/w) F127 gel were 8 and 24 times lower than those determined in the phosphate buffer (pH 7.4). The effect of increasing polymer concentration (20%, 25% and 30% (w/w)) on piroxicam diffusion was further investigated. The decreasing diffusion rate with increasing F127 concentration agreed well with small-angle X-ray scattering (SAXS) measurements. UV imaging was also successfully applied to monitor piroxicam release from 30% (w/w) F127 gel into a stirred aqueous buffer solution, providing simultaneous information on gel dissolution rate, change in thickness of gel-aqueous boundary layer as well as the release of piroxicam into bulk aqueous phase. The current study indicates that UV imaging has great potential for measuring drug diffusion in and release from gel matrices. Compared to the currently used conventional techniques, this technology has several advantages including high information content, non intrusive measurements without the need for labeling, flexibility with respect to experimental design and simplicity of operation. PMID- 21550400 TI - Development and physico-chemical characterization of a liposomal formulation of istaroxime. AB - Istaroxime, an investigational new drug that targets defective Ca(2+) cycling without compromising cardiac efficiency, may represent a promising and safe treatment of both acute and chronic heart failure. Even though the compound demonstrated good tolerability in a phase I/II safety study, symptoms related to the gastro-intestinal tract and pain at the injection site were reported as the most frequent side effects. The aim of this study was to encapsulate istaroxime in a drug delivery system (DDS) that could minimize the pain perceived upon administration. The DDS was designed to be quickly destabilized in plasma, in order to minimize alteration of the pharmacokinetic profile of istaroxime. To meet those requirements, a balance between the encapsulation efficiency and the release rate was sought. Transmembrane pH-gradient liposomes formulated with different phosphatidylcholines were investigated as vehicles for an efficient active drug loading. Poly(ethylene glycol)-660-hydroxystearate (PEG-HS) was chosen as excipient to modulate the bilayer fluidity and the release properties of the liposomes. A fast and efficient encapsulation was obtained by modulating the drug-to-lipid ratio, the amount of PEG-HS, and the incubation temperature. High encapsulation efficiency was achieved by incubating the drug with liposomal dispersions at room temperature for 10 min. Almost complete release was obtained in physiological conditions in less than 10 min, suggesting a model formulation potentially useful for drugs presenting similar features and side effects. PMID- 21550401 TI - Solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein. AB - The objectives of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine (PC), an endogenous phospholipid with excellent in vivo solubilization capacity, as oil phase for the delivery of bioactive carotenoid lutein, by spray drying the SNEDDS (liquid system) containing PC using colloidal silica (Aerosil(r) 200 VV Pharma) as the inert solid carrier, and to evaluate the enhanced bioavailability (BA) of lutein from S-SNEDDS. The droplet size analyses revealed droplet size of less than 100 nm. The solid state characterization of S-SNEDDS by SEM, DSC, and XRPD revealed the absence of crystalline lutein in the S-SNEDDS. The bioavailability study performed in rabbits resulted in enhanced values of C(max) and AUC for S-SNEDDS. The enhancement of C(max) for S-SNEDDS was about 21-folds and 8-folds compared with lutein powder (LP) and commercial product (CP), respectively. The relative BA of S-SNEDDS compared with CP or LP was 2.74-folds or 11.79-folds, respectively. These results demonstrated excellent ability of S-SNEDDS containing PC as oil phase to enhance the BA of lutein in rabbits. Thus, S-SNEDDS containing PC as oil phase could be a useful lipid drug delivery system for enhancing the BA of lutein in vivo. PMID- 21550402 TI - Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease. AB - DAX-1 and SHP are two closely related atypical orphan members of the nuclear receptor (NR) family that make up the NR0B subfamily. They combine properties of typical NRs and of NR-associated coregulators: both carry the characteristic NR ligand-binding domain but instead of a NR DNA-binding domain they have unique N terminal regions that contain LxxLL-related NR-binding motifs often found in coregulators. Recent structural data indicate that DAX-1 lacks a ligand-binding pocket and thus should rely on ligand-independent mechanisms of regulation. This might be true, but remains to be proven, for SHP as well. DAX-1 and SHP have in common that they act as transcriptional corepressors of cholesterol metabolism pathways that are related on a molecular level. However, the expression patterns of the two NRs are largely different, with some notable exceptions, and so are the physiological processes they regulate. DAX-1 is mainly involved in steroidogenesis and reproductive development, while SHP plays major roles in maintaining cholesterol and glucose homeostasis. This review highlights the key similarities and differences between DAX-1 and SHP with regard to structure, function and biology and considers what can be learnt from recent research advances in the field. This article is part of a Special Issue entitled 'Orphan Receptors'. PMID- 21550403 TI - Structure-function analysis of vitamin D(2) analogs as potential inducers of leukemia differentiation and inhibitors of prostate cancer proliferation. AB - We characterized a structure-function relationships of four analogs of vitamin D(2) with extended and branched side-chains. We tested their ability to induce differentiation of human acute myeloid leukemia (AML) cells both in vitro and ex vivo. Our experiments on five human cell lines revealed substantial differences among tested analogs. Analogs with side-chains extended by one (PRI-1906) or two carbon units (PRI-1907) displayed similar or elevated cell-differentiating activity in comparison to 1,25-dihydroxyvitamin D(3) (1,25D), whereas further extending side-chain resulted in substantially lower biological activity (PRI 1908 and PRI-1909). Similar pattern of cell-differentiating activities to that observed in human cell lines has also been shown in blast cells isolated from patients diagnosed with AML. The ability of the analogs to activate expression of CYP24A1 gene has been studied in HL60 cell line. The analog PRI-1906 activated expression of CYP24A1 similarly to 1,25D, while PRI-1907 weaker than 1,25D. In addition, the analogs PRI-1906 and PRI-1907 were able to moderately inhibit proliferation and significantly activate expression of CYP24A1 mRNA in prostate cancer cells PC-3. Finally, we examined the molecular actions triggered by these analogs and found that their biological activity was related to their ability to induce expression and nuclear translocation of VDR and C/EBPbeta. PMID- 21550404 TI - Enzyme replacement reduces neuropathology in MPS IIIA dogs. AB - There is no treatment for the progressive neurodegenerative lysosomal storage disorder mucopolysaccharidosis type IIIA (MPS IIIA), which occurs due to a deficiency of functional N-sulfoglucosamine sulfohydrolase (SGSH), with subsequent accumulation of partially-degraded heparan sulfate and secondarily stored compounds including GM2 and GM3 gangliosides and unesterified cholesterol. The brain is a major site of pathology and affected children exhibit progressive cognitive decline and early death. In the present study, six MPS IIIA dogs received intravenous recombinant human SGSH (rhSGSH) from birth to either 8 or 12 weeks of age (1 mg/kg, up to 5 mg), with subsequent intra-cerebrospinal fluid injection of 3 or 15 mg rhSGSH (or vehicle) on a weekly or fortnightly basis to 23 weeks of age. All dogs completed the protocol without incident, and there was no clinically-relevant cellular or humoral immune response to rhSGSH delivery. Immunohistochemistry demonstrated rhSGSH delivery to widespread regions of the brain, and tandem mass spectrometry revealed an apparent dose-dependent decrease in the relative level of a heparan sulfate-derived disaccharide, with near normalization of substrate in many brain regions at the higher dose. Secondarily stored GM3 ganglioside and unesterified cholesterol, determined using histological methods, were also reduced in a dose-dependent manner, as was the number of activated microglia. We have demonstrated that pre-symptomatic treatment of this progressive neurodegenerative disorder via intra-cerebrospinal fluid injection of rhSGSH mediates highly significant reductions in neuropathology in this MPS IIIA model and clinical trials of this treatment approach in MPS IIIA patients are therefore indicated. PMID- 21550405 TI - Splice isoform-specific suppression of the Cav2.1 variant underlying spinocerebellar ataxia type 6. AB - Spinocerebellar ataxia type 6 (SCA6) is an inherited neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the Ca(V)2.1 voltage-gated calcium channel subunit (CACNA1A). There is currently no treatment for this debilitating disorder and thus a pressing need to develop preventative therapies. RNA interference (RNAi) has proven effective at halting disease progression in several models of spinocerebellar ataxia (SCA), including SCA types 1 and 3. However, in SCA6 and other dominantly inherited neurodegenerative disorders, RNAi based strategies that selectively suppress expression of mutant alleles may be required. Using a Ca(V)2.1 mini-gene reporter system, we found that pathogenic CAG expansions in Ca(V)2.1 enhance splicing activity at the 3'end of the transcript, leading to a CAG repeat length-dependent increase in the levels of a polyQ-encoding Ca(V)2.1 mRNA splice isoform and the resultant disease protein. Taking advantage of this molecular phenomenon, we developed a novel splice isoform-specific (SIS)-RNAi strategy that selectively targets the polyQ-encoding Ca(V)2.1 splice variant. Selective suppression of transiently expressed and endogenous polyQ-encoding Ca(V)2.1 splice variants was achieved in a variety of cell-based models including a human neuronal cell line, using a new artificial miRNA-like delivery system. Moreover, the efficacy of gene silencing correlated with effective intracellular recognition and processing of SIS-RNAi miRNA mimics. These results lend support to the preclinical development of SIS-RNAi as a potential therapy for SCA6 and other dominantly inherited diseases. PMID- 21550406 TI - Expression of soluble proteins in Escherichia coli by linkage with the acidic propiece of eosinophil major basic protein. AB - An expression method has been developed to produce soluble cationic polypeptides in Escherichia coli while avoiding inclusion body deposition. For this technique the recombinant product is linked through a thrombin or factor Xa susceptible bond to the amino-terminal domain of the precursor of eosinophil major basic protein (MBP). This N-terminal domain is strongly acidic and is apparently able to shield eosinophils from the potentially injurious activities of MBP. It was reasoned that constructs of this acidic domain with small heterologous cationic proteins expressed in E. coli could result in soluble expression while preventing trafficking and packaging into insoluble inclusion bodies. This has been demonstrated using four examples: complement C5a, CCL18, fibroblast growth factor beta, and leukemia inhibitory factor, whose isoelectric points range from 8.93 to 9.59. Further general applicability of this technique has been shown by using two different expression systems, one which encodes an amino-terminal oligo-histidine leash, and another that codes for an amino-terminal glutathione-S-transferase. Thus the utility of coupling MAP to cationic polypeptides for the purpose of soluble heterologous protein expression in E. coli has been demonstrated. PMID- 21550408 TI - Phylogenetic relationships and the temporal context for the diversification of African characins of the family Alestidae (Ostariophysi: Characiformes): evidence from DNA sequence data. AB - Phylogenetic relationships within the family Alestidae were investigated using parsimony, maximum likelihood, and Bayesian approaches based on a molecular dataset that included both nuclear and mitochondrial markers. Multiple representatives of all but two of the recognized alestid genera were included, which allowed for testing previous hypotheses of intergeneric relationships and the monophyly of several genera. The phylogenetic position of the Neotropical genus Chalceus with respect to the family Alestidae was also examined. In order to understand the temporal context of alestid diversification, Bayesian methods of divergence time estimation using fossil data in the form of calibration priors were used to date the nodes of the phylogenetic tree. Our results rejected the monophyly of the family as currently recognized (Alestidae sensu lato) and revealed several instances of poly- and paraphyly among genera. The genus Chalceus was recovered well nested within Neotropical characiforms, thus rejecting the hypothesis that this taxon is the most basal alestid. The estimated mean divergence time for the alestid clade (Alestidae sensu stricto) was 54 Mya with a 95% credibility interval of 63-49 Mya. These results are incongruent with the hypothesis that the origin of the family Alestidae predates the African-South American Drift-Vicariance event. PMID- 21550407 TI - Dynamic neural networks supporting memory retrieval. AB - How do separate neural networks interact to support complex cognitive processes such as remembrance of the personal past? Autobiographical memory (AM) retrieval recruits a consistent pattern of activation that potentially comprises multiple neural networks. However, it is unclear how such large-scale neural networks interact and are modulated by properties of the memory retrieval process. In the present functional MRI (fMRI) study, we combined independent component analysis (ICA) and dynamic causal modeling (DCM) to understand the neural networks supporting AM retrieval. ICA revealed four task-related components consistent with the previous literature: 1) medial prefrontal cortex (PFC) network, associated with self-referential processes, 2) medial temporal lobe (MTL) network, associated with memory, 3) frontoparietal network, associated with strategic search, and 4) cingulooperculum network, associated with goal maintenance. DCM analysis revealed that the medial PFC network drove activation within the system, consistent with the importance of this network to AM retrieval. Additionally, memory accessibility and recollection uniquely altered connectivity between these neural networks. Recollection modulated the influence of the medial PFC on the MTL network during elaboration, suggesting that greater connectivity among subsystems of the default network supports greater re experience. In contrast, memory accessibility modulated the influence of frontoparietal and MTL networks on the medial PFC network, suggesting that ease of retrieval involves greater fluency among the multiple networks contributing to AM. These results show the integration between neural networks supporting AM retrieval and the modulation of network connectivity by behavior. PMID- 21550409 TI - Evolution of a Neotropical marine fish lineage (Subfamily Chaenopsinae, Suborder Blennioidei) based on phylogenetic analysis of combined molecular and morphological data. AB - Phylogenetic relationships within tube blennies (Chaenopsinae) were reconstructed using Bayesian, maximum parsimony and likelihood analyses of multiple molecular markers (mitochondrial DNA: COI; nuclear DNA: TMO-4C4, RAG1, Rhodopsin, and Histone H3) and 148 morphological characters. This total-evidence based topology is well-resolved and congruent across analytical methods with strong support for the monophyly of the Chaenopsinae, all included genera and several internal nodes. A rapid radiation in the early evolution of chaenopsins is inferred from the relatively poor support values for relationships among basal lineages and their divergence into different habitats (rocky reefs, coral reefs and the reef/sand interface). Rates of molecular evolution in chaenopsins, as inferred by divergence among four putative transisthmian geminate species pairs, are rapid compared to other fishes. Conflicts among genetic markers and morphology are especially evident within the genus Coralliozetus, with different species relationships supported by morphology, TMO-4C4, and RAG1 plus Rhodopsin. This study hypothesizes a novel sistergroup relationship between Ekemblemaria and Hemiemblemaria, consistent with morphological, molecular and habitat use data. Our total evidence phylogenetic hypothesis indicates that previously hypothesized morphological characters supporting a close relationship between Hemiemblemaria and Chaenopsis plus Lucayablennius resulted from convergent evolution in these relatively free-swimming blennies. PMID- 21550410 TI - Isolation, phylogeny and evolution of the SymRK gene in the legume genus Lupinus L. AB - SymRK is one of the key genes involved in initial steps of legume symbiotic association with fungi (mycorrhization) and nitrogen-fixing bacteria (nodulation). A large portion of the sequence encoding the extracellular domain of SYMRK was obtained for 38 lupine accessions and 2 outgroups in order to characterize this region, to evaluate its phylogenetic utility, and to examine whether its molecular evolutionary pattern is correlated with rhizobial diversity and specificity in Lupinus. The data suggested that, in Lupinus, SymRK is a single copy gene that shows good phylogenetic potential. Accordingly, SymRK provided additional support to previous molecular phylogenies, and shed additional light on relationships within the Old World group of Lupinus, especially among the African species. Similar to results of other studies, analyses of SymRK sequences were unable to resolve placement of the Florida unifoliolate lineage, whose relationship was weakly supported to either the Old or the New World lupines. Our data are consistent with strong purifying selection operating on SymRK in Lupinus, preserving rather than diversifying its function. Thus, although SymRK was demonstrated to be a vital gene in the early stages of the root-bacterial symbiotic associations, no evidence from present analyses indicate that this gene is involved in changes in rhizobial specificity in Lupinus. PMID- 21550411 TI - Hip Osteoarthritis MRI Scoring System (HOAMS): reliability and associations with radiographic and clinical findings. AB - OBJECTIVE: To develop a semiquantitative MRI-based scoring system (HOAMS) of hip osteoarthritis (OA) and test its reliability and validity. DESIGN: Fifty-two patients with chronic hip pain were included. 1.5T magnetic resonance imaging (MRI) was performed on all patients. Pelvic radiographs were scored according to the Kellgren-Lawrence (KL) system. Clinical outcomes were assessed by the hip osteoarthritis outcome score (HOOS). MRIs were analyzed using a novel whole-joint MRI score that incorporated 13 articular features. Reliability was determined on a random subset of 15 cases. Weighted-kappa statistics and overall agreement were used as a measure of intra- and inter-observer reliability. Associations between MRI features and radiographic OA severity were calculated using Cochran-Armitage test for trend. Ordinal logistic regression was used to assess associations between MRI features and severity of pain and functional limitation. RESULTS: Distribution of radiographic grading was: KL 0=12 (27%), KL 1=11 (25%), KL 2=14 (32%), KL 3=5 (11%) and KL 4=2 (5%). Intra-reader reliability for the different features ranged from 0.18 (cysts) to 0.85 (cartilage). Inter-reader reliability ranged between 0.15 (cysts) and 0.85 (BMLs). Low kappas were due to low frequencies of some features as overall percent agreement was good to excellent (83.8% and 83.1%). There was a strong association between MRI-detected lesions and radiographic severity (P=0.002). Non-significant trends were observed between MRI features and clinical outcomes. CONCLUSION: MRI-based semiquantitative assessment of the hip shows adequate reliability. Presence of more severe MRI detected intraarticular pathology shows a strong association with radiographic OA. The results suggest possible associations between MRI-detected pathology and clinical symptoms. PMID- 21550413 TI - Modeling gas phase nitric oxide release in lung epithelial cells. AB - Nitric oxide (NO) is present in exhaled breath and is generally considered to be a noninvasive marker of airway inflammation, and is thus of particular relevance to monitoring asthma. NO is produced when L-arginine is converted to L-citrulline by NO synthase (NOS); however, L-arginine is also the substrate for arginase and both enzymes are upregulated in asthma. Recent reports have speculated that enhanced expression of one or both enzymes could lead to a limitation in substrate availability, and hence impact downstream targets or markers such as exhaled NO. The non-linear nature and vastly different kinetics of the enzymes make predictions difficult, particularly over the wide range of enzyme activity between baseline and inflammation. In this study, we developed a steady state model of L-arginine transmembrane transport, NO production, diffusion, and gas phase NO release from lung epithelial cells. We validated our model with experimental results of gas phase NO release and intracellular l-arginine concentration in A549 cells, and then performed a sensitivity analysis to determine relative impact of each enzyme on NO production. Our model predicts intracellular L-arginine and gas phase NO release over a wide range of initial extracellular L-arginine concentrations following stimulation with cytomix (10ng/ml TNF-alpha, IL-1beta, and INF-gamma). Relative sensitivity analysis demonstrates that enhanced arginase activity has little impact on l-arginine bioavailability for NOS. In addition, NOS activity is the dominant parameter which impacts gas phase NO release. PMID- 21550412 TI - Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. AB - Nitric oxide, generated by the nitric oxide synthase (NOS) enzymes, plays pivotal roles in cardiovascular homeostasis and in the pathogenesis of cardiovascular disease. The NOS cofactor, tetrahydrobiopterin (BH4), is an important regulator of NOS function, since BH4 is required to maintain enzymatic coupling of L arginine oxidation, to produce NO. Loss or oxidation of BH4 to 7,8 dihydrobiopterin (BH2) is associated with NOS uncoupling, resulting in the production of superoxide rather than NO. In addition to key roles in folate metabolism, dihydrofolate reductase (DHFR) can 'recycle' BH2, and thus regenerate BH4. It is therefore likely that net BH4 cellular bioavailability reflects the balance between de novo BH4 synthesis, loss of BH4 by oxidation to BH2, and the regeneration of BH4 by DHFR. Recent studies have implicated BH4 recycling in the direct regulation of eNOS uncoupling, showing that inhibition of BH4 recycling using DHFR-specific siRNA and methotrexate treatment leads to eNOS uncoupling in endothelial cells and the hph-1 mouse model of BH4 deficiency, even in the absence of oxidative stress. These studies indicate that not only BH4 level, but the recycling pathways regulating BH4 bioavailability represent potential therapeutic targets and will be discussed in this review. PMID- 21550414 TI - The endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) predicts LV mass independent of afterload. AB - BACKGROUND: Nitric oxide (NO) is a modulator of left ventricular hypertrophy (LVH) and myocardial relaxation. The impact of NO availability on development of LVH has never been demonstrated in humans. We tested the hypotheses that elevation of asymmetric dimethylarginine (ADMA) concentrations (biochemical marker of decreased NO generation), and impairment of vascular responsiveness to NO donor GTN, would each predict the presence of LVH and associated LV diastolic dysfunction in a normal aging population. METHODS AND RESULTS: In 74 subjects aged 68+/-6 years, LV volumes and mass indexed to height(2.7) (LVMI) were calculated from cardiac MRI. Despite the absence of clinically-defined LVH, there was a relationship (r=0.29; p=0.01) between systolic BP and LVMI. Both elevation of ADMA levels to the highest quartile or impairment of GTN responsiveness (determined by applanation tonometry) to the lowest quartile were determinants of LVMI independent of systolic BP (p=0.01 and p=0.03, respectively). Filling pressure (E/E' ratio from echocardiography) was increased in patients with impaired vascular NO responsiveness (p<0.05) irrespective of LVMI. ADMA remained a significant determinant of LVMI on multivariate analysis. CONCLUSIONS: These data imply that NO bioavailability within the myocardium modulates earliest stages of LVH development and facilitates development of diastolic dysfunction at a given LV mass. PMID- 21550415 TI - A flow-cytometry assisted segregation of responding and non-responding population of endothelial cells for enhanced detection of intracellular nitric oxide production. AB - Nitric oxide (NO) is an important paracrine substance released by the endothelium to regulate vasomotor tone. The constitutive levels of endothelium dependent NO production is low. However, it is induced significantly in response to certain environmental and biological stimuli. An accurate evaluation of such stimulus induced NO release is of pharmacological significance. We observed that the sensitivity of NO detection in endothelial cells is compromised by baseline fluorescence emanated from non-activated cells resulting in ambiguous detection. In order to measure NO levels in activated population independent of non activated cells, we segregated DAF-FM loaded cells based on their fluorescence intensity using flow-cytometry. Specific agonists like bradykinin, VEGF and insulin enhanced the proportion of activated cells. This effect was partially blocked in presence of NO synthase inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME). We demonstrate that the fluorescence yield of activated population serves as a sensitive measure to evaluate agonist induced nitric oxide production in endothelial cells. Such increase in NO production in activated cells was also associated with increased eNOS phosphorylation at Ser-1177. While the endothelial cells showed heterogeneity with respect to NO production, immuno-phenotyping for endothelial cell-surface markers revealed a homogenous population. PMID- 21550416 TI - T cell responses in experimental viral retinitis: mechanisms, peculiarities and implications for gene therapy with viral vectors. AB - T lymphocytes play a decisive role in the course and clinical outcome of viral retinal infection. This review focuses on aspects of the adaptive cellular immune response against viral pathogens in the retina. Two distinct models to study adaptive cell mediated immune responses in viral retinitis are presented: (i) experimental retinitis induced by murine cytomegalovirus (MCMV), where the immune system prevents necrotizing damage to the retina and (ii) retinitis induced by the non-cytopathic lymphocytic choriomeningitis virus (LCMV), where the retinal microanatomy is compromised not by the virus, but by the immune response itself. From these studies it is clear that, in the context of viral infections, the cytotoxic T cell response against a pathogen in the retina does not differ from that seen in other organs, and that once such a response has been initiated, clearing of virus from retinal tissue has priority over preservation of retinal architecture and function. Furthermore, implications drawn from these models for gene therapy in retinal diseases are discussed. PMID- 21550417 TI - Enhanced functional properties of corneal epithelial cells by coculture with embryonic stem cells via the integrin beta1-FAK-PI3K/Akt pathway. AB - Adult stem cells are important cell sources in regenerative medicine, but isolating them is technically challenging. This study employed a novel strategy to generate stem-like corneal epithelial cells and promote the functional properties of these cells by coculture with embryonic stem cells. The primary corneal epithelial cells were labelled with GFP and cocultured with embryonic stem cells in a transwell or by direct cell-cell contact. The embryonic stem cells were pre-transfected with HSV-tk-puro plasmids and became sensitive to ganciclovir. After 10 days of coculture, the corneal epithelial cells were isolated by treating the cultures with ganciclovir to kill the embryonic stem cells. The expression of stem cell-associated markers (ABCG2, p63) increased whereas the differentiation mark (Keratin 3) decreased in corneal epithelial cells isolated from the cocultures as evaluated by RT-PCR and flow cytometry. Their functional properties of corneal epithelial cells, including cell adhesion, migration and proliferation, were also enhanced. These cells could regenerate a functional stratified corneal epithelial equivalent but did not form tumors. Integrin beta1, phosphorylated focal adhesion kinase and Akt were significantly upregulated in corneal epithelial cells. FAK Inhibitor 14 that suppressed the expression of phosphorylated focal adhesion kinase and Akt inhibited cell adhesion, migration and proliferation. LY294002 that suppressed phosphorylated Akt but not phosphorylated focal adhesion kinase inhibited cell proliferation but had no effect on cell adhesion or migration. These findings demonstrated that the functional properties of stem-like corneal epithelial cells were enhanced by cocultured embryonic stem cells via activation of the integrin beta1-FAK-PI3K/Akt signalling pathway. PMID- 21550418 TI - NARP mutation and mtDNA depletion trigger mitochondrial biogenesis which can be modulated by selenite supplementation. AB - The importance of mitochondrial biogenesis in the pathogenesis of mitochondrial diseases has been widely recognised but little is known about it with regard to NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) syndrome. Since such knowledge would contribute to the understanding of the pathogenesis of this disease, we designed a study to provide comprehensive overview of mitochondrial biogenesis in cybrid cells harboring NARP mutation (8993T>G). We also used Rho0 cells with the same nuclear background to show that distinct mtDNA defects lead to distinct cellular responses irrespective of nuclear genome. Mitochondrial biogenesis is regulated by mitochondria-to-nucleus (retrograde) communication which depends on intracellular signaling pathways sensitive to ROS. Since we previously found that selenite lowered ROS in NARP cybrids, we hypothesised that selenite could also modulate mitochondrial biogenesis in these cells. Although the mitochondrial mass was not changed in NARP cybrids, we showed the compensatory upregulation of respiratory chain subunits which prompted us to investigate the transcription factors that regulate their expression such as PGC-1alpha, NRFs, and TFAM. Selenite supplementation increased the level of NRF1 and nuclear accumulation of NRF2, but we did not detect any major changes in the levels of investigated respiratory chain proteins. These subtle changes in mitochondrial biogenesis in response to selenite treatment support the hypothesis that selenite could be considered as a potential therapeutic agent of NARP syndrome due to its antioxidant properties. Moreover, it could also be tested with regard to other mitochondrial disorders associated with ROS overproduction. PMID- 21550419 TI - Knockdown of ribosomal protein S7 causes developmental abnormalities via p53 dependent and independent pathways in zebrafish. AB - Ribosomal proteins (RPs), structural components of the ribosome involved in protein synthesis, are of significant importance in all organisms. Previous studies have suggested that some RPs may have other functions in addition to assembly of the ribosome. The small ribosomal subunits RPS7, has been reported to modulate the mdm2-p53 interaction. To further investigate the biological functions of RPS7, we used morpholino antisense oligonucleotides (MO) to specifically knockdown RPS7 in zebrafish. In RPS7-deficient embryos, p53 was activated, and its downstream target genes and biological events were induced, including apoptosis and cell cycle arrest. Hematopoiesis was also impaired seriously in RPS7-deficient embryos, which was confirmed by the hemoglobin O dianisidine staining of blood cells, and the expression of scl, gata1 and alpha E1 globin were abnormal. The matrix metalloproteinase (mmp) family genes were also activated in RPS7 morphants, indicating that improper cell migration might also cause development defects. Furthermore, simultaneously knockdown of the p53 protein by co-injecting a p53 MO could partially reverse the abnormal phenotype in the morphants. These results strengthen the hypothesis that specific ribosomal proteins regulate p53 and that their deficiency affects hematopoiesis. Moreover, our data implicate that RPS7 is a regulator of matrix metalloproteinase (mmp) family in zebrafish system. These specific functions of RPS7 may provide helpful clues to study the roles of RPs in human disease. PMID- 21550420 TI - Regulation of progesterone receptor activity by cyclin dependent kinases 1 and 2 occurs in part by phosphorylation of the SRC-1 carboxyl-terminus. AB - We described previously a novel role for cyclin A2/Cdk2 as a progesterone receptor (PR) coactivator. In reporter gene assays, cyclin A2 overexpression enhanced PR activity while inhibition of Cdk2 activity using the chemical inhibitor roscovitine or Cdk2 siRNA strongly inhibited PR activity. We demonstrate here that both Cdk1 and Cdk2 contribute to maximal induction of endogenous progestin responsive genes in T47D breast cancer cells. Our earlier studies suggested that the mechanism by which cyclin A2/Cdk2 enhances PR activity is via phosphorylation of steroid receptor coactivator-1 (SRC-1), which increases PR-SRC-1 interactions. To assess the importance of SRC-1 phosphorylation in the regulation of PR activity, SRC-1 was phosphorylated by cyclin A2/Cdk2 in vitro and seventeen phosphorylation sites were identified using biochemical techniques. We show that one of these sites, T1426 (adjacent to the C-terminal LXXLL nuclear receptor interaction motif), is an in vivo target of Cdks in mammalian cells and an in vitro target of Cdk1 and Cdk2. Phosphorylation of T1426 also contributes to SRC-1 coactivation potential, as mutation of the threonine target site to alanine results in reduced stimulation of PR activity by SRC-1. Together, these results suggest a role for Cdk1 and Cdk2 in the regulation of endogenous PR activity in part through phosphorylation of SRC-1. PMID- 21550421 TI - Enabling enrichment analysis with the Human Disease Ontology. AB - Advanced statistical methods used to analyze high-throughput data such as gene expression assays result in long lists of "significant genes." One way to gain insight into the significance of altered expression levels is to determine whether Gene Ontology (GO) terms associated with a particular biological process, molecular function, or cellular component are over- or under-represented in the set of genes deemed significant. This process, referred to as enrichment analysis, profiles a gene set, and is widely used to make sense of the results of high-throughput experiments. Our goal is to develop and apply general enrichment analysis methods to profile other sets of interest, such as patient cohorts from the electronic medical record, using a variety of ontologies including SNOMED CT, MedDRA, RxNorm, and others. Although it is possible to perform enrichment analysis using ontologies other than the GO, a key pre-requisite is the availability of a background set of annotations to enable the enrichment calculation. In the case of the GO, this background set is provided by the Gene Ontology Annotations. In the current work, we describe: (i) a general method that uses hand-curated GO annotations as a starting point for creating background datasets for enrichment analysis using other ontologies; and (ii) a gene-disease background annotation set - that enables disease-based enrichment - to demonstrate feasibility of our method. PMID- 21550422 TI - Enhanced antiproliferative activity of Herceptin (HER2)-conjugated gemcitabine loaded chitosan nanoparticle in pancreatic cancer therapy. AB - Currently, effective drug delivery in pancreatic cancer treatment is a major challenge. Nanomedicine plays an essential role by delivering anticancer drugs in a targeted manner to the malignant tumor cells, leading to increased efficacy by reducing the toxicity of anticancer drugs to normal, sensitive sites. This study investigated the preparation and characterization of a targeted system represented by Herceptin-conjugated gemcitabine-loaded chitosan nanoparticles (HER2-Gem-CS-NPs) for pancreatic cancer therapy. The targeted NPs displayed superior antiproliferative activity along with an enhanced S-phase arrest, leading to apoptosis in comparison with unconjugated gemcitabine-loaded nanoparticles and free gemcitabine due to higher cellular binding with eventual uptake and prolonged intracellular retention. Thus, HER2-Gem-CS-NPs are able to provide an efficient and targeted delivery of gemcitabine for pancreatic cancer treatment. FROM THE CLINICAL EDITOR: This study investigated the preparation and characterization of a targeted drug delivery system consisting of Herceptin conjugated gemcitabine-loaded chitosan nanoparticles for pancreatic cancer therapy. PMID- 21550423 TI - Hepatitis E virus is prevalent in the pig population of Lao People's Democratic Republic and evidence exists for homogeneity with Chinese Genotype 4 human isolates. AB - The objective of this study was to determine the prevalence and genotypic range of Hepatitis E virus (HEV) in the pig population of northern Lao People's Democratic Republic (PDR). We collected 181 faecal samples from indigenous-breed pigs <= 6 months of age and the faeces was stored in RNA stabilisation buffer due to cold-chain and transport limitations. Twenty-one (11.6%) pigs had detectable HEV RNA and 43.5% of village pig herds were infected. Based on a 240 base pair nucleotide sequence flanking the junction of open reading frames 1, 2 and 3 (ORF1, ORF2 and ORF3) the isolates were phylogenetically classified within genotype 4. Phylogenetic analyses revealed distinct genetic groupings of the Lao HEV isolates and two groups clustered with human and pig HEV isolates from China. This was the first study to demonstrate genotype 4 HEV in Lao PDR and indicates pigs are a potential reservoir for human HEV infection. PMID- 21550424 TI - In vitro mineralization of dense collagen substrates: a biomimetic approach toward the development of bone-graft materials. AB - Bone is an organic-inorganic composite which has hierarchical structuring that leads to high strength and toughness. The nanostructure of bone consists of nanocrystals of hydroxyapatite embedded and aligned within the interstices of collagen fibrils. This unique nanostructure leads to exceptional properties, both mechanical and biological, making it difficult to emulate bone properties without having a bone-like nanostructured material. A primary goal of our group's work is to use biomimetic processing techniques that lead to bone-like structures. In our prior studies, we demonstrated that intrafibrillar mineralization of porous collagen sponges, leading to a bone-like nanostructure, can be achieved using a polymer-induced liquid precursor (PILP) mineralization process. The objective of this study was to investigate the use of this polymer-directed crystallization process to mineralize dense collagen substrates. To examine collagen scaffolds that truly represent the dense-packed matrix of bone, manatee bone was demineralized to isolate its collagen matrix, consisting of a dense, lamellar osteonal microstructure. This biogenic collagen scaffold was then remineralized using polyaspartate to direct the mineralization process through an amorphous precursor pathway. The various conditions investigated included polymer molecular weight, substrate dimension and mineralization time. Mineral penetration depths of up to 100 MUms were achieved using this PILP process, compared to no penetration with only surface precipitates observed for the conventional crystallization process. Electron microscopy, wide-angle X-ray diffraction and thermal analysis were used to characterize the resulting hydroxyapatite/collagen composites. These studies demonstrate that the original interpenetrating bone nanostructure and osteonal microstructure could be recovered in a biogenic matrix using the PILP process. PMID- 21550425 TI - Stem cell differentiation to epidermal lineages on electrospun nanofibrous substrates for skin tissue engineering. AB - Bone marrow (BM) mesenchymal stem cells (MSC) capable of differentiating along the epidermal lineage on engineered nanofibrous scaffolds have great potential for bionanomaterial-cell transplantation therapy of skin wounds. MSC have been the focus of many tissue engineering studies, mainly because of their multipotential properties. We investigated the potential of human BM-derived MSC for epidermal cell differentiation in vitro on electrospun collagen/poly(l-lactic acid)-co-poly(3-caprolactone) (Coll/PLLCL) nanofibrous scaffolds. PLLCL and Coll/PLLCL nanofibrous scaffolds were fabricated by an electrospinning process and their chemical and mechanical characterization carried out by scanning electron microscopy (SEM), water contact angle determination, Fourier transform infrared spectroscopy, and tensile testing. The differentiation of MSC was carried out using epidermis inducing factors, including epidermal growth factor (EGF) and 1,25-dihydroxyvitamin D(3), in culture medium. The proliferation of MSC evaluated by cell proliferation assay showed that the number of cells grown on Coll/PLLCL nanofibrous scaffolds was significantly higher than those on PLLCL scaffolds. The SEM results showed that MSC differentiated on Coll/PLLCL nanofibrous scaffolds showed a round keratinocyte morphology and expressed keratin 10, filaggrin and partial involucrin protein by immunofluorescent microscopic studies. The interaction of MSC and nanofibers was studied and we concluded that the electrospun Coll/PLLCL nanofibers could mimic the native skin extracellular matrix environment and are promising substrates for advanced skin tissue engineering. Our studies on the differentiation of MSC along the epidermal lineage on nanofibrous scaffolds suggest their potential application in skin regeneration without regional differentiation. PMID- 21550427 TI - Effect of post-harvest heat treatment on proteome change of peach fruit during ripening. AB - The extracted proteins from the heat-treated peach fruit (dipped in hot water at 48 degrees C for 10min and then stored at room temperature (20 degrees C-25 degrees C) for up to 6 days) were used for proteomic analysis in order to understand the response of post-harvest peach fruit to heat treatment during ripening stage at proteomic level. After two dimensional gels electrophoresis (2 DE) was conducted, more than 600 protein spots were detected. Among them, 35 differently expressed spots (P<0.05) were selected to be excised and analyzed using MALDI-TOF/TOF, and finally 30 protein spots were confidently identified according to NCBI database. The results demonstrated that among the thirty protein spots expressed particularly induced by heat treatment, 43% were related to stress response, 17% to cell structure, 13% to protein fate, 7% to glycolytic pathway, 3% to ripening and senescence and 17% to unclassified. All of them are involved in the regulation of peach fruit development and ripening. All these indicated that the self-defense capability of peach fruit was improved by heat treatment. The study will enable future detailed investigation of gene expression and function linked with peach fruit ripening. PMID- 21550426 TI - Heparin-decorated, hyaluronic acid-based hydrogel particles for the controlled release of bone morphogenetic protein 2. AB - We are interested in developing hydrophilic particulate systems that are capable of sequestering growth factors, regulating their release and potentiating their biological functions. To this end heparin (HP)-decorated, hyaluronic acid (HA) based hydrogel particles (HGPs) were synthesized using an inverse emulsion polymerization technique employing divinyl sulfone as the crosslinker. By varying the feed composition of the aqueous phase the amount of HP integrated in the particles can be systematically tuned. The resulting microscopic particles are spherical in shape and contain nanosized pores suitable for growth factor encapsulation. The covalently immobilized HP retained its ability to bind bone morphogenetic protein-2 (BMP-2) specifically, and its release kinetics can be adjusted by tuning the particle composition. Compared with pure HA particles the hybrid HA/HP HGPs show a higher BMP-2 loading capacity. While BMP-2 was released from HA HGPs with a significant initial burst, a near zero order release kinetics was observed from HA/HP hybrid particles with an optimized heparin content of 0.55 MUg per mg HGPs. The ability of HA/HP hybrid particles to present BMP-2 in a controlled manner, combined with the innate bioactivity of HA, induced robust and consistent chondrogenic differentiation of murine mesenchymal stem cells, as shown by up-regulation of the mRNA levels of chondrogenic markers and the production of cartilage-specific extracellular matrix components. The simplicity of the particle synthesis, combined with the defined biological activities of the constituent building blocks, renders the HP-decorated, HA-based hydrogel particle system an attractive candidate for the sustained release of BMP-2, possibly for cartilage repair and regeneration. PMID- 21550428 TI - Viral induction and suppression of RNA silencing in plants. AB - RNA silencing in plants and insects can function as a defence mechanism against invading viruses. RNA silencing-based antiviral defence entails the production of virus-derived small interfering RNAs which guide specific antiviral effector complexes to inactivate viral genomes. As a response to this defence system, viruses have evolved viral suppressors of RNA silencing (VSRs) to overcome the host defence. VSRs can act on various steps of the different silencing pathways. Viral infection can have a profound impact on the host endogenous RNA silencing regulatory pathways; alterations of endogenous short RNA expression profile and gene expression are often associated with viral infections and their symptoms. Here we discuss our current understanding of the main steps of RNA-silencing responses to viral invasion in plants and the effects of VSRs on endogenous pathways. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation. PMID- 21550429 TI - Effects of estrogen on osteoprogenitor cells and cytokines/bone-regulatory factors in postmenopausal women. AB - Decreases in estrogen levels contribute not only to early postmenopausal bone loss but also to bone loss with aging. While estrogen is critical for the maintenance of bone formation, the mechanism(s) of this effect remain unclear. Thus, we assessed the effects of 4months of transdermal estradiol treatment (0.05mg/day) of postmenopausal women as compared to no treatment (n=16 per group) on the expression of genes in pre-specified pathways in freshly isolated bone marrow osteoprogenitor cells (hematopoietic lineage [lin]-/Stro1+). We also evaluated whether estrogen treatment modulated peripheral blood or bone marrow plasma levels of the Wnt antagonists, sclerostin and DKK1, as well as serotonin, OPG, RANKL, adiponectin, oxytocin, and inflammatory cytokines (TNFalpha, IL 1beta, and IL-6), as each of these molecules have recently been shown to play an important role in regulating osteoblast function and/or being responsive to estrogen. We observed a significant decrease in the expression of several proliferation markers (cyclin B1, cyclin E1, E2F1) and increase in adhesion molecules (N-cadherin) in bone marrow lin-/Stro1+ cells from estrogen-treated compared to control women. None of the peripheral blood or bone marrow plasma marker levels differed between the two groups, with the exception of sclerostin levels, which were significantly lower in the estrogen-treated as compared to the control women in peripheral serum (by 32%, P=0.009) and in bone marrow plasma (by 34%, P=0.017). There were significant differences in bone marrow versus peripheral plasma levels of several factors: sclerostin and OPG levels were higher in bone marrow as compared to peripheral plasma, whereas serotonin and adiponectin levels were higher in peripheral as compared to bone marrow plasma. In summary, our data directly assessing possible regulation by estrogen of osteoprogenitor cells in humans indicate that, consistent with previous studies in mice, estrogen suppresses the proliferation of human bone marrow lin-/Stro1+ cells, which likely represent early osteoprogenitor cells. Further animal and human studies are needed to define the role of the changes we observed in mRNAs for adhesion molecules in these cells and in local sclerostin production in bone in mediating the effects of estrogen on bone metabolism in humans. PMID- 21550430 TI - Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. AB - The uncarboxylated form of the osteoblast-specific secreted molecule osteocalcin is a hormone favoring glucose handling and increasing energy expenditure. As a result, the absence of osteocalcin leads to glucose intolerance in mice, while genetically modified mice with an increase in uncarboxylated osteocalcin are protected from type 2 diabetes and obesity. Here, we tested in the mouse the therapeutic potential of intermittent administration of osteocalcin. We found that daily injections of osteocalcin at either 3 or 30 ng/g/day significantly improved glucose tolerance and insulin sensitivity in mice fed a normal diet. This was attributable, in part, to an increase in both beta-cell mass and insulin secretion. When mice were fed a high-fat diet (HFD), daily injections of osteocalcin partially restored insulin sensitivity and glucose tolerance. Moreover, mice treated with intermittent osteocalcin injections displayed additional mitochondria in their skeletal muscle, had increased energy expenditure and were protected from diet-induced obesity. Finally, the hepatic steatosis induced by the HFD was completely rescued in mice receiving osteocalcin daily. Overall, these results provide evidence that daily injections of osteocalcin can improve glucose handling and prevent the development of type 2 diabetes. PMID- 21550431 TI - Combination of radiograph-based trabecular and geometrical parameters can discriminate cervical hip fractures from controls in individuals with BMD in non osteoporotic range. AB - Majority of hip fractures occur in individuals with bone mineral density (BMD) in non-osteoporotic range. This suggests that factors other than BMD are associated with increased fracture risk in these individuals. The aim of this study was to investigate the combined ability of radiograph-based trabecular and geometrical parameters to discriminate cervical hip fractures from controls in individuals with non-osteoporotic BMD. A total of 39 postmenopausal females with non pathologic cervical hip fracture were recruited to the study. Nineteen of the fracture patients (48.7%) had non-osteoporotic BMD and they constituted the fracture group. The control group consisted of 35 BMD-matched non-osteoporotic females. Several geometrical and trabecular parameters were extracted from plain pelvic radiographs, and their combined ability to discriminate fracture patients from controls was studied using a receiver operating characteristics (ROC) analysis. Significant differences in several radiograph-based geometrical and trabecular parameters were found between the fracture patients and controls, whereas no statistically significant difference in BMD was observed (p=0.92) between the groups. Area under the ROC curve was 0.993 (95% CI 0.977-1.008) for the combined multiple regression model, which included both trabecular and geometrical parameters as explanatory factors. Here, the sensitivity of 100% was achieved with the specificity of 94%. In a cross-validation of the model, 94.4% of the fracture patients, and 94.1% of the controls were classified correctly. The combination of radiograph-based trabecular and geometrical parameters was able to discriminate the cervical hip fracture cases from controls with similar BMD, showing that the method can provide additional information on bone structure and fracture risk beyond BMD. PMID- 21550432 TI - The skeletal effects of the tyrosine kinase inhibitor nilotinib. AB - Nilotinib is a tyrosine kinase inhibitor (TKI) developed to manage imatinib resistance in patients with chronic myeloid leukemia (CML). It inhibits similar molecular targets to imatinib, but is a significantly more potent inhibitor of Bcr-Abl. Nilotinib exhibits off-target effects in other tissues, and of relevance to bone metabolism, hypophosphataemia has been reported in up to 30% of patients receiving nilotinib. We have assessed the effects of nilotinib on bone cells in vitro and on bone metabolism in patients receiving nilotinib for treatment of CML. We firstly investigated the effects of nilotinib on proliferating and differentiating osteoblastic cells, and on osteoclastogenesis in murine bone marrow cultures and RAW264.7 cells. Nilotinib potently inhibited osteoblast proliferation (0.01-1uM), through inhibition of the platelet-derived growth factor (PDGFR). There was a biphasic effect on osteoblast differentiation such that it was reduced by lower concentrations of nilotinib (0.1-0.5uM), with no effect at higher concentrations (1uM). Nilotinib also potently inhibited osteoclastogenesis, predominantly by stromal-cell dependent mechanisms. Thus, nilotinib decreased osteoclast development in murine bone marrow cultures, but did not affect osteoclastogenesis in RAW264.7 cells. Nilotinib treatment of osteoblastic cells increased expression and secretion of OPG and decreased expression of RANKL. In 10 patients receiving nilotinib, levels of bone turnover markers were in the low-normal range, despite secondary hyperparathyroidism, findings that are similar to those in patients treated with imatinib. Bone density tended to be higher than age and gender-matched normal values. These data suggest that nilotinib may have important effects on bone metabolism. Prospective studies should be conducted to determine the long-term effects of nilotinib on bone density and calcium metabolism. PMID- 21550433 TI - The differentiation of human adipose-derived stem cells (hASCs) into osteoblasts is promoted by low amplitude, high frequency vibration treatment. AB - Several studies have demonstrated that tissue culture conditions influence the differentiation of human adipose-derived stem cells (hASCs). Recently, studies performed on SAOS-2 and bone marrow stromal cells (BMSCs) have shown the effectiveness of high frequency vibration treatment on cell differentiation to osteoblasts. The aim of this study was to evaluate the effects of low amplitude, high frequency vibrations on the differentiation of hASCs toward bone tissue. In view of this goal, hASCs were cultured in proliferative or osteogenic media and stimulated daily at 30Hz for 45min for 28days. The state of calcification of the extracellular matrix was determined using the alizarin assay, while the expression of extracellular matrix and associated mRNA was determined by ELISA assays and quantitative RT-PCR (qRT-PCR). The results showed the osteogenic effect of high frequency vibration treatment in the early stages of hASC differentiation (after 14 and 21days). On the contrary, no additional significant differences were observed after 28days cell culture. Transmission Electron Microscopy (TEM) images performed on 21day samples showed evidence of structured collagen fibers in the treated samples. All together, these results demonstrate the effectiveness of high frequency vibration treatment on hASC differentiation toward osteoblasts. PMID- 21550434 TI - Cocaine and synaptic alterations in the nucleus accumbens. PMID- 21550435 TI - Merger fever: can two separate mechanisms work together to explain why we drink? PMID- 21550436 TI - Varenicline and the evaluation of neuropsychiatric adverse events in smokers. PMID- 21550437 TI - Live imaging of the cytoskeleton in early cleavage-stage zebrafish embryos. AB - The large and transparent cells of cleavage-stage zebrafish embryos provide unique opportunities to study cell division and cytoskeletal dynamics in very large animal cells. Here, we summarize recent progress, from our laboratories and others, on live imaging of the microtubule and actin cytoskeletons during zebrafish embryonic cleavage. First, we present simple protocols for extending the breeding competence of zebrafish mating ensembles throughout the day, which ensures a steady supply of embryos in early cleavage, and for mounting these embryos for imaging. Second, we describe a transgenic zebrafish line [Tg(bactin2:HsENSCONSIN17-282-3xEGFP)hm1] that expresses the green fluorescent protein (GFP)-labeled microtubule-binding part of ensconsin (EMTB-3GFP). We demonstrate that the microtubule-based structures of the early cell cycles can be imaged live, with single microtubule resolution and with high contrast, in this line. Microtubules are much more easily visualized using this tagged binding protein rather than directly labeled tubulin (injected Alexa-647-labeled tubulin), presumably due to lower background from probe molecules not attached to microtubules. Third, we illustrate live imaging of the actin cytoskeleton by injection of the actin-binding fragment of utrophin fused to GFP. Fourth, we compare epifluorescence-, spinning-disc-, laser-scanning-, and two-photon microscopic modalities for live imaging of the microtubule cytoskeleton in early embryos of our EMTB-3GFP-expressing transgenic line. Finally, we discuss future applications and extensions of our methods. PMID- 21550439 TI - Analysis of cilia structure and function in zebrafish. AB - The cilium, a previously little studied cell surface protrusion, has emerged as an important organelle in vertebrate cells. This tiny structure is essential for normal embryonic development, including the formation of left-right asymmetry, limb morphogenesis, and the differentiation of sensory cells. In the adult, cilia also function in a variety of processes, such as the survival of photoreceptor cells, and the homeostasis in several tissues, including the epithelia of nephric ducts. Human ciliary malfunction is associated with situs inversus, kidney cysts, polydactyly, blindness, mental retardation, obesity, and many other abnormalities. The genetic accessibility and optical transparency of the zebrafish make it an excellent vertebrate model system to study cilia biology. In this chapter, we describe the morphology and distribution of cilia in zebrafish embryonic and larval organs. We also provide essential protocols to analyze cilia formation and function. PMID- 21550438 TI - Analysis of cell proliferation, senescence, and cell death in zebrafish embryos. AB - Proper control of cell proliferation is critical for normal development, growth, differentiation, and tissue homeostasis. Dysregulation of cell division and cell death underlies almost all cancers, and contributes to the pathology of birth defects and degenerative diseases. The zebrafish has proved to be an excellent system for elucidating the roles of the cell cycle in normal development, and ways in which dysregulation of cell proliferation contributes to disease. This chapter describes the methods for studying the cell cycle in zebrafish embryos, including protocols to examine cell proliferation, DNA damage, senescence, and cell death. PMID- 21550440 TI - Cellular dissection of zebrafish hematopoiesis. AB - The zebrafish is an excellent model system to study vertebrate blood cell development due to a highly conserved hematopoietic system, optical transparency, and amenability to both forward and reverse genetic approaches. The development of functional assays to analyze the biology of hematopoietic mutants and diseased animals remains a work in progress. Here we discuss recent advances in zebrafish hematology, prospective isolation techniques, cellular transplantation, and culture-based assays that now provide more rigorous tests of hematopoietic stem and progenitor cell function. Together with the proven strengths of the zebrafish, the development and refinement of these assays further enable efforts to better understand the development and evolution of the vertebrate hematopoietic system. PMID- 21550441 TI - Zebrafish lipid metabolism: from mediating early patterning to the metabolism of dietary fat and cholesterol. AB - Lipids serve essential functions in cells as signaling molecules, membrane components, and sources of energy. Defects in lipid metabolism are implicated in a number of pandemic human diseases, including diabetes, obesity, and hypercholesterolemia. Many aspects of how fatty acids and cholesterol are absorbed and processed by intestinal cells remain unclear and present a hurdle to developing approaches for disease prevention and treatment. Numerous studies have shown that the zebrafish is an excellent model for vertebrate lipid metabolism. In this chapter, we review studies that employ zebrafish to better understand lipid signaling and metabolism. PMID- 21550442 TI - Development of the zebrafish enteric nervous system. AB - The enteric nervous system (ENS) is composed of neurons and glia that modulate many aspects of intestinal function. The ability to use both forward and reverse genetic approaches and to visualize development in living embryos and larvae has made zebrafish an attractive model in which to study mechanisms underlying ENS development. In this chapter, we review the recent work describing the development and organization of the zebrafish ENS and how this relates to intestinal motility. We also discuss the cellular, molecular, and genetic mechanisms that have been revealed by these studies and how they are providing new insights into human ENS diseases. PMID- 21550444 TI - Chemical approaches to angiogenesis in development and regeneration. AB - Research on blood vessel formation has provided a great deal of information regarding both normal and pathological forms of angiogenesis during development and in different disease states. Central to these studies is the role of the vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). VEGF stimulation promotes the division, survival, and migration of endothelial cells, and is necessary for the formation of blood and lymphatic vessels. The conserved functions of the VEGF ligands and receptors from fish to mammals have allowed a near-seamless translation of a cellular and molecular mechanism of vascular assembly between vertebrate models. An added advantage to the conserved gene function is the ability to apply chemical approaches to modulate zebrafish angiogenesis. In this chapter we will discuss current and potential future uses of chemical strategies in the zebrafish model to further our understanding of angiogenesis, lymphangiogenesis, and regenerative biology. PMID- 21550445 TI - Laser-induced thrombosis in zebrafish. AB - In the event of injury to the vasculature in vertebrate organisms bleeding is stopped by a defense mechanism called hemostasis. Even though biochemical studies characterized a number of factors, classical genetic methods have not been applied to study hemostasis. We introduced zebrafish as an animal model to study genetics of hemostasis. To conduct genetic studies of hemostasis, we required a global screening method to address all the factors of hemostasis such as those present in plasma, in platelets or those present in the endothelium. Therefore, we developed a global laser induced thrombosis method which can assay all these components. In this paper, we describe the principle of this method as well as provide the detailed protocol so this could be used as a screening tool to measure hemostasis in any laboratory. PMID- 21550443 TI - A guide to analysis of cardiac phenotypes in the zebrafish embryo. AB - The zebrafish is an ideal model organism for investigating the molecular mechanisms underlying cardiogenesis, due to the powerful combination of optical access to the embryonic heart and plentiful opportunities for genetic analysis. A continually increasing number of studies are uncovering mutations, morpholinos, and small molecules that cause striking cardiac defects and disrupt blood circulation in the zebrafish embryo. Such defects can result from a wide variety of origins including defects in the specification or differentiation of cardiac progenitor cells; errors in the morphogenesis of the heart tube, the cardiac chambers, or the atrioventricular canal or problems with establishing proper cardiac function. An extensive arsenal of techniques is available to distinguish between these possibilities and thereby decipher the roots of cardiac defects. In this chapter, we provide a guide to the experimental strategies that are particularly effective for the characterization of cardiac phenotypes in the zebrafish embryo. PMID- 21550446 TI - Endoderm specification, liver development, and regeneration. AB - The endoderm is the innermost germ layer that gives rise to the lining of the gut, the gills, liver, pancreas, gallbladder, and derivatives of the pharyngeal pouch. These organs form the gastrointestinal tract and are involved with the absorption, delivery, and metabolism of nutrients. The liver has a central role in regulating these processes because it controls lipid metabolism, protein synthesis, and breakdown of endogenous and xenobiotic products. Liver dysfunction frequently leads to significant morbidity and mortality; however, in most settings of organ injury, the liver exhibits remarkable regenerative capacity. PMID- 21550447 TI - Morphogenesis of the zebrafish jaw: development beyond the embryo. AB - The zebrafish has emerged as an important model for vertebrate development as it relates to human health and disease. Work in this system has provided significant insights into the variety of genetic signals that direct the cellular activities and tissue interactions necessary for proper assembly of the pharyngeal skeleton. Unfortunately our understanding of craniofacial development beyond embryonic stages is far less complete. Stated another way, we know a great deal about the early patterning of the skull, but we know comparatively little about how mature craniofacial shape is determined and maintained over time. Here we propose ways to expand the current molecular genetic paradigm beyond the embryo to gain an understanding of the processes and mechanisms that guide growth and remodeling of mineralized craniofacial, skeletal, and dental tissues. First, we discuss sources of adult mutant phenotypes that can be used to study of postembryonic development. Next, we review salient quantitative methods that are necessary to define complex adult phenotypes. We also discuss how other organismal systems can be used to inform and complement studies in zebrafish. We conclude by discussing the implications for such studies within the context of furthering an understanding of the etiology and pathophysiology of human craniofacial malformations, as well as informing an understanding of adaptive craniofacial variation among natural populations. PMID- 21550448 TI - Associative learning in zebrafish (Danio rerio). AB - The zebrafish has been one of the primary study species utilized in developmental biology. However, it is also gaining increasing amount of interest in other disciplines of biology including behavioral neuroscience; the numerous genetic tools developed and the large amount of genetic information accumulated for this species by now make it an excellent tool for the analysis of the mechanisms of complex central nervous system characteristics. Although several studies have investigated the biological and genetic underpinnings of associative learning (and memory), given the complexity of these phenomena, much remains to be discovered. In the past, the zebrafish has been employed particularly successfully in screening applications where a large number of mutations or drug effects had to be analyzed. Briefly, the practical simplicity and system complexity of the zebrafish may make this species an excellent tool also for the analysis of the mechanisms of associative learning. Screening, however, requires appropriate phenotypical (in this case behavioral) paradigms. A step in this direction is the characterization of learning abilities of zebrafish. The number of studies focused on cognitive and/or mnemonic characteristics of zebrafish is orders of magnitude smaller than those with rats or mice, but recently zebrafish has also started to be utilized in this research. The current chapter reviews these most recent developments. It also discusses certain unique features of zebrafish that must be taken into account when designing an associative learning task and how these tasks may be made high throughput. PMID- 21550449 TI - Are you a good witch or a bad witch? PMID- 21550450 TI - EBP, ENA, and ENRs. PMID- 21550451 TI - One nurse, one life, many legacies a tribute: Nancy Kostel-Donlon, July 10, 1958 September 17, 2010. PMID- 21550452 TI - Passing of a past president. PMID- 21550453 TI - Effect of education on a chest pain mnemonic on door-to-ECG time. AB - INTRODUCTION: Acute myocardial infarction (AMI) continues to contribute to both death and disability in both men and women. The first step in early intervention is an ECG. Atypically presenting patients, especially those who present by self transport, are more likely to experience delays. The purpose of this study was to evaluate the effect of a new chest pain mnemonic (CPM) as a teaching tool for rapid recognition of AMI patients arriving by self-transport in ED triage in an effort to improve door-to-ECG (DTE) time. METHODS: This study is a longitudinal, quasi-experimental quantitative study. Instruction and evaluation of nurses' knowledge related to identification of AMI before and after instruction on the CPM education (intervention) were coordinated by the emergency clinical nurse specialist. The study sample for the educational intervention included 26 nurses (15% of total population) from 4 emergency departments. Ad hoc queries of the National Registry for Myocardial Infarction database for patients arriving by self-transport to the emergency department were done to examine DTE before and after intervention. The pretests and post-tests of the nurses were analyzed with a paired t test, and the pre- and post-intervention DTE times were analyzed by log-linear modeling. RESULTS: Evaluation of nurses' knowledge before and after CPM education indicated an improvement in DTE time, although it was not statistically significant. There was a significant improvement in DTE time for 2 hospitals that was somewhat negated in the aggregate data. There was a noted trend that showed an advantage in DTE time associated with male patients. DISCUSSION: Inclusion of tools such as the CPM in education programs for emergency nurses improved rapid recognition of AMI patients presenting via self transport to the emergency department. Attention to gender differences in patient presentation should be included in future CPM education, and tools to assist nurses in the early recognition of AMI need to be developed. Investigation regarding intra-hospital differences is warranted. PMID- 21550454 TI - Who is sleeping in our beds? Factors predicting the ED boarding of admitted patients for more than 2 hours. AB - INTRODUCTION: Although the provision of inpatient care is not typically associated with emergency nursing, it is the new reality in many departments. Given the number of admitted patients boarded in the emergency department for part or all of their hospital stay, it is important to know who these patients are. The purpose of this analysis was to determine whether the occurrence of ED boarding could be predicted by factors specific to the type and timing of the ED visit or whether patient characteristics also affected these decisions. METHODS: A retrospective review of administrative data for a 1-year period was conducted. Chi-square and logistic regression analyses were used to determine whether the likelihood of being boarded for more than 2 hours could be predicted by factors specific to the type of visit (ie, triage level and admission type) and timing of the visit (ie, time of day and day of week) or whether patient characteristics (ie, sex and age group) also played a role. RESULTS: Slightly more than half of patients remained in the emergency department for more than 2 hours following receipt of an admission order. Results suggest the likelihood of boarding was highest for those who were medical admissions and admitted on a weekday or during the night shift. Even after accounting for these factors, patient characteristics improved the ability to predict ED boarding. Female patients and those 65 years of age or older were more likely to be boarded. CONCLUSIONS: Findings suggest that in addition to their usual responsibilities, emergency nurses are providing care to a group of inpatients who tend to have high medical and nursing care needs. PMID- 21550455 TI - The impact of education on provider attitudes toward family-witnessed resuscitation. AB - INTRODUCTION: The majority of acute care facilities have not developed policies or guidelines to facilitate family presence during cardiopulmonary resuscitation. Prior studies have shown that the personal beliefs and attitudes of hospital personnel involved in resuscitation efforts are the primary reasons family presence is not offered. METHODS: This 2-phase, before/after study was conducted in a 388-bed academic trauma center, and in a 143-bed community hospital in eastern Washington State in 2008. In phase I, a convenience sample of physicians and registered nurses from both facilities were surveyed about their opinions and beliefs regarding family-witnessed resuscitation (FWR). Spearman's rho and independent t-tests were used to compare support of FWR between and within roles and practice location subgroups. In phase II of the study, clinician subgroups in the community hospital were re-surveyed following an educational program that used evidence-based information. Independent t-test and one-way ANOVA were used to compare pre and post-education mean scores of subgroups on indicators of effective teaching strategies and improved FWR support. RESULTS: Opinions on FWR vary within and between practice roles and locations, with the strongest variable of support being prior experience with FWR. Following FWR education, mean scores improved for survey variables chosen as indicators of FWR support and teaching effectiveness. DISCUSSION: When CPR providers are presented with FWR education, their opinion-based beliefs may be modified, decreasing barriers to family witnessed resuscitation and improving overall support of FWR as an extension of family-centered care. PMID- 21550456 TI - Palliative and end-of-life care in the emergency department: guidelines for nurses. PMID- 21550457 TI - Emergency nursing resource: needle-related procedural pain in pediatric patients in the emergency department. PMID- 21550458 TI - A 30-year-old woman with acute leg pain. PMID- 21550460 TI - Education and culture: mitigation for workplace violence. PMID- 21550461 TI - Conducting triage research: lessons learned in a pediatric emergency department. PMID- 21550462 TI - Community solutions to the surge of psychiatric patients in emergency departments. PMID- 21550463 TI - An Australian audit of ED pain management patterns. AB - INTRODUCTION: Timely and appropriate pain management is an important quality indicator of ED performance. Emergency health care workers are well positioned to become active leaders and innovatively responsive in reducing human suffering. A pain management audit was conducted to determine Australia practice patterns. METHODS: A 12-month retrospective descriptive cohort audit was undertaken. Through the randomization process a medical record audit tool was completed for each record identified. Ethical approval for the study was obtained. RESULTS: Seventy-four hospitals agreed to conduct the audit, 36 (48%) provided data. The total number of patient notes reviewed was 2,066. Ninety-five percent (1,966) of patients arrived by ambulance. Of the patients (n=547; 56.4%) with a documented triage pain score the majority arrived in severe pain (n=300; 41.3%). Of the total number of patients (1,966) documented arriving in pain 1,473 (74.9%) received an analgesic. Six hundred and forty-four (32.7%) patients received an opioid. From time of emergency department arrival, the median time for analgesic administration was 70 minutes (IQR 58 minutes to 92 minutes). Twenty-five emergency departments (69.4%) had pain management policies that enabled nurses to initiate a pharmacological analgesia without medical consultation. DISCUSSION: The Australian pain management audit highlighted current practices and potential areas for further research. While the audit demonstrated that nurse initiated pain management interventions promoted better analgesic response, greater consistency of triage pain assessment, code allocation, and documentation of pain scores may go some way to improving the timeliness of analgesia. PMID- 21550464 TI - Prioritizing patients with acuity 3. PMID- 21550465 TI - Reducing road dangers. PMID- 21550466 TI - New guidelines for early detection of ovarian cancer. PMID- 21550467 TI - Financing HPV vaccination in developing countries. PMID- 21550468 TI - Appendicitis: is surgery the best option? PMID- 21550470 TI - Rebecca Ivers: driving down the toll of injury. PMID- 21550471 TI - Restricted elimination diet for ADHD. PMID- 21550472 TI - Restricted elimination diet for ADHD. PMID- 21550473 TI - Restricted elimination diet for ADHD. PMID- 21550474 TI - Towards universal health coverage in India. PMID- 21550476 TI - Towards universal health coverage in India. PMID- 21550477 TI - Towards universal health coverage in India. PMID- 21550478 TI - Towards universal health coverage in India. PMID- 21550479 TI - Health in southeast Asia. PMID- 21550480 TI - Making a difference to health in slums: an HIV and African perspective. PMID- 21550481 TI - Health in southeast Asia. PMID- 21550482 TI - Pricing the advance market commitment. PMID- 21550483 TI - Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. AB - BACKGROUND: Researchers have suggested that antibiotics could cure acute appendicitis. We assessed the efficacy of amoxicillin plus clavulanic acid by comparison with emergency appendicectomy for treatment of patients with uncomplicated acute appendicitis. METHODS: In this open-label, non-inferiority, randomised trial, adult patients (aged 18-68 years) with uncomplicated acute appendicitis, as assessed by CT scan, were enrolled at six university hospitals in France. A computer-generated randomisation sequence was used to allocate patients randomly in a 1:1 ratio to receive amoxicillin plus clavulanic acid (3 g per day) for 8-15 days or emergency appendicectomy. The primary endpoint was occurrence of postintervention peritonitis within 30 days of treatment initiation. Non-inferiority was shown if the upper limit of the two-sided 95% CI for the difference in rates was lower than 10 percentage points. Both intention to-treat and per-protocol analyses were done. This trial is registered with ClinicalTrials.gov, number NCT00135603. FINDINGS: Of 243 patients randomised, 123 were allocated to the antibiotic group and 120 to the appendicectomy group. Four were excluded from analysis because of early dropout before receiving the intervention, leaving 239 (antibiotic group, 120; appendicectomy group, 119) patients for intention-to-treat analysis. 30-day postintervention peritonitis was significantly more frequent in the antibiotic group (8%, n=9) than in the appendicectomy group (2%, n=2; treatment difference 5.8; 95% CI 0.3-12.1). In the appendicectomy group, despite CT-scan assessment, 21 (18%) of 119 patients were unexpectedly identified at surgery to have complicated appendicitis with peritonitis. In the antibiotic group, 14 (12% [7.1-18.6]) of 120 underwent an appendicectomy during the first 30 days and 30 (29% [21.4-38.9]) of 102 underwent appendicectomy between 1 month and 1 year, 26 of whom had acute appendicitis (recurrence rate 26%; 18.0-34.7). INTERPRETATION: Amoxicillin plus clavulanic acid was not non-inferior to emergency appendicectomy for treatment of acute appendicitis. Identification of predictive markers on CT scans might enable improved targeting of antibiotic treatment. FUNDING: French Ministry of Health, Programme Hospitalier de Recherche Clinique 2002. PMID- 21550484 TI - Recurrent pneumothorax. PMID- 21550485 TI - Triage is easy: sorting patients should be an extension of daily practice. PMID- 21550489 TI - CPR Debate. PMID- 21550490 TI - Cost. Access. Quality. PMID- 21550491 TI - A dollar a minute: wasting time is expensive. PMID- 21550492 TI - Scene safety situational: awareness saves lives. PMID- 21550493 TI - 'Cut yourself here': rethinking our view of suicide. PMID- 21550494 TI - The system works: prehospital ECG findings expedite patient care. PMID- 21550495 TI - Window to metabolism: studies analyze new use of end-tidal CO2 monitoring. PMID- 21550496 TI - Off-Road: EMS caring for racers south of the border. PMID- 21550497 TI - A whirlwind response tropical cyclone Yasi a success story for Australian EMS. PMID- 21550498 TI - Toxic transport treating inhalation injuries without becoming a patient. PMID- 21550499 TI - Broken freebirds EMS in hog heaven. PMID- 21550505 TI - Unmet needs in protein formulation science. PMID- 21550507 TI - Embolization during treatment of deep venous thrombosis: incidence, importance, and prevention. AB - The standard of care for the treatment of acute deep venous thrombosis (DVT) is anticoagulation, which often prevents the formation of new thrombus and reduces the risk of pulmonary embolism (PE) but fails to eliminate the clot burden. Patients who have thrombus remaining in their deep venous system despite therapeutic anticoagulation are at high risk for developing symptoms of the postthrombotic syndrome, a debilitating condition that adversely affects their quality of life. Strategies of thrombus removal for acute DVT, such as operative thrombectomy, catheter-directed thrombolysis, and pharmacomechanical techniques, are designed to avoid postthrombotic morbidity by restoring patency to the deep veins, but there is concern that these techniques may result in fragmentation of clot and pulmonary embolization. Careful patient evaluation before treatment is essential for preventing complications and often reveals asymptomatic pulmonary emboli in as many as 50% of patients. Nonobstructive or free-floating thrombus in the vena cava is a risk factor for procedure-related embolization and is frequently an indication for the use of vena caval filtration. A review of the literature on acute DVT treated by anticoagulation alone or with strategies of thrombus removal reveals that pulmonary embolization is an infrequent occurrence. Treatment with anticoagulation alone, however, increases the risk of patients developing symptoms of the postthrombotic syndrome, whereas thrombus removal strategies reduce postthrombotic morbidity without increasing the risk of embolization. PMID- 21550508 TI - The role of embolic protection in peripheral arterial atherectomy. AB - Embolic protection devices were initially developed for use in the treatment of saphenous vein aortocoronary bypass graft stenosis as well as in carotid artery stenting because of the significant risk of atheroembolism and their use is well accepted. The use of these devices for lower-extremity arterial interventions is becoming well accepted because of the significant consequences of embolization in patients with limited circulatory runoff. This is especially true in the use of mechanical atherectomy devices for femoropopliteal arterial lesions. PMID- 21550510 TI - Detection and treatment of acute thromboembolic events in the lower extremities. AB - Acute procedural thromboembolic events are serious complications affecting both short- and long-term outcome. Patients at high risk include those undergoing catheter-based interventions for acute limb ischemia and long segment de novo or stented occlusions of the lower limb arteries. Additionally, debulking procedures and angioplasty/stenting of complex lesions in patients with advanced disease have also been associated with a higher risk of distal embolization and in situ thrombosis. This article includes a discussion of detection methods as well as preventive and treatment strategies. PMID- 21550509 TI - A role for embolic protection in the management of acute limb ischemia. AB - Distal embolization is a complication during lower-extremity revascularization procedures that may occur when intervening on acute or subacute lesions. Several studies have demonstrated the safety and feasibility of using embolic protection devices (EPD) and some interventionalists have adapted this technology for use in infrainguinal revascularization procedures. At present, there are no randomized trials to indicate the benefit, safety, and cost-effectiveness of EPD for this application and its use in the United States is considered off-label. However, based on our experience and a review of the published literature, we consider the use of EPD in acute lower-extremity ischemia a reasonable strategy. PMID- 21550511 TI - Embolic protection in carotid artery stenting: new options. AB - Carotid artery stenting (CAS) has emerged as an attractive alternative to carotid endarterectomy (CEA) in patients with carotid disease who are at high risk for CEA. With increasing experience and improved technique, results in CAS patients have improved consistently over time in several clinical trials. Carotid stenting is clearly not inferior to CEA in appropriately selected high-CEA-risk patients treated by experienced operators. With improving results, CAS now has the potential to be considered "front-line therapy" even in standard-risk CEA patients, as demonstrated in CREST and as being studied in ongoing trials, such as the ACT I trial. Successful, low-risk CAS can only be performed if distal embolization is minimized during this procedure. This can be accomplished only with appropriate patient and case selection, adequate operator training and experience, and meticulous attention to procedural detail. Embolic protection devices (EPDs) are an important cornerstone of low-risk CAS. There are well established, study-validated embolic protection systems available for CAS. Four new EPD options have been introduced in the United States over the past 3 years. Results with these newer devices appear to be extremely promising, with low event rates seen in high-risk clinical patients. This article will offer a practical review of techniques to decrease distal embolization during CAS. We will review patient selection and provide a "cookbook" approach to procedural technique, emphasizing techniques unique to each of the various EPD systems currently available. We will also introduce the newer options in EPDs, provide practical tips on their use, and contrast their use and results with that of the existing EPD systems. We will provide practical procedural techniques that incorporate the use of various EPDs into strategies that will reduce distal embolization during CAS and also provide pertinent data referencing results of these devices seen in clinical trials. PMID- 21550512 TI - Is there an indication for embolic protection in renal artery intervention? AB - The role of endovascular treatment of atherosclerotic renal artery disease is uncertain, particularly after the publication of the Angioplasty and Stenting for Renal Artery Lesions trial and other randomized trials. These trials have shown that nonselective treatment of patients with renal artery stenosis does not result in a benefit when compared with best medical therapy. However, all trials have identified a subgroup of patients who do respond favorably to revascularization. In particular, patients with a degree of chronic renal insufficiency, critical renal artery stenosis, and a recent decline in renal function are likely to respond positively to revascularization. Endovascular treatment of renal artery stenosis must be performed safely, particularly in the high-risk patient group with background chronic renal insufficiency. Atheroembolization occurs during renal artery revascularization, as demonstrated by ex vivo studies and the high embolic yield obtained in published series of protected renal artery revascularization. The evidence supporting embolic protection includes single-center series wherein excellent results for renal function preservation have been reported. One small, randomized, controlled trial demonstrated a significant benefit if both embolic protection and abciximab were used. There are unique demands on an embolic protection device in the renal artery circulation and a dedicated device has not been developed. Both distal filters and occlusion balloons have been successfully used. Both devices can normally be primarily passed through the stenosis, allowing the remainder of the procedure to be protected. Filters have the advantage of maintaining renal perfusion throughout the procedure. Distal occlusion balloons can capture embolic particles of all sizes although the clinical advantage is uncertain. PMID- 21550513 TI - Pitfalls of embolic protection. AB - Some degree of distal embolization likely occurs during all transcatheter interventional procedures. The clinical sequela is defined by the sensitivity of the target organ to segmental ischemia and the burden of embolic load. The spectrum of clinical consequences varies from the extremes of stroke and no reflow phenomena in the carotid and coronaries, respectively, to silent renal insult following renal stenting. The clinical sequela of stroke and myocardial infarction in these most sensitive end-organ distributions led to the birth of embolic protection science. Over the past 2 decades embolic protection has matured and we now have a menu of devices to consider based on our specific patient clinical and anatomic needs. The goal of this narrative is to provide an update on protection device science and, more importantly, a very practical informal guide to the currently available technologies with emphasis on the pitfalls common to specific device families. PMID- 21550515 TI - Rapid endoscopic identification and destruction of degenerating Barrett's mucosal neoplasia. AB - There are distinct challenges implicit to the development of minimally invasive endoscopic surgery for the eradication of early neoplasia in Barrett's oesophagus. Endoscopic resection and ablation of high-grade dysplasia and mucosal cancer offer alternative therapeutic options to those unsuitable or unwilling to contemplate radical surgical excision. It may also become the treatment of choice in the future. Technological developments enable the instantaneous and non invasive diagnosis of microscopic tissue abnormalities in vivo. This is made possible by improving the level of information that can be obtained from the tissue. As well as the two-dimensional surface morphology image, which the traditional endoscope can view, we have used new techniques to enable structure at depth, using Optical Coherence Tomography, to be imaged in high resolution. Other advances, using Raman spectroscopy, enable the early endoscopic detection of biochemical and molecular changes in tissue that precede any changes in morphology, thus enabling earlier diagnosis of tissue abnormalities. This King James IV lecture details our recent work, to develop advanced imaging for the diagnosis of malignancy and pre-malignancy. After detection endoscopic photodynamic therapy and endoscopic mucosal resection can provide eradication of mucosal neoplasia. Following photodynamic therapy there was complete eradication of all high-grade dysplasia and intramucosal carcinoma in 40 of 42 patients with a maximum endoscopic follow-up period of 72 months. Following endoscopic resection of 95 patients, the mean survival for intramucosal adenocarcinoma and high-grade dysplasia was 40.6 and 60.8 months respectively. PMID- 21550516 TI - Effect of surgical approach for total hip replacement on hip function using Harris Hip scores and Trendelenburg's test. A retrospective analysis. AB - OBJECTIVE: A retrospective analysis of osteoarthritis patients undergoing primary hip arthroplasty, to assess which surgical approach produces the best functional results at one-year post-operatively, using common clinical scoring systems and tests. The aim of this study was to compare the anterolateral and the posterior approaches to total hip arthroplasty using Harris Hip scores and Trendelenburg's test by looking at pre-operative results and comparing them to post-operative results. METHODS: Data from 3416 consecutive cases were extracted from a multicentre database, maintained by the Tayside Arthroplasty Audit Group (TAAG) situated in Tayside, using only patients who had undergone a primary hip arthroplasty and had a clinical diagnosis of osteoarthritis. RESULTS: Analysis showed that there was statistically significant difference between the two approaches for Harris Hip score (p = 0.0344), Harris Hip function score (p = 0.0035) and Trendelenburg Test (p =< 0.00001). The posterior approach showed larger improvements in Harris Hip scores. There was an increased incidence of dislocation in the posterior approach group (6.9%) but an increased incidence of Trendelenburg gait in anterolateral approach group (5.7%). It was found that patients who suffered a dislocation had similar functional outcomes for both groups with no statistical difference. CONCLUSIONS: These results suggest that there may be benefit in using a posterior approach to primary total hip arthroplasty but due to limitations of the data within this study further more detailed research is required. PMID- 21550517 TI - Determinants of surgical delay for hip fracture. AB - BACKGROUND AND OBJECTIVE: Recent guidelines recommend early surgical treatment of hip fractures in the elderly. The aim of the present study is to analyse the factors delaying surgical treatment of hip fractures in elderly patients by more than 2 days and to investigate whether these factors are consistent between a teaching and a community hospital. METHODS: DESIGN: Retrospective cohort study using hospital discharge records and patients' charts. SETTING: Orthopaedics and traumatology departments of a teaching hospital and a small town hospital in Northern Italy. PARTICIPANTS: 1768 consecutive patients aged 65 years or more who underwent surgery for hip fractures between 2004 and 2007. INTERVENTIONS: Surgery for hip fracture. MAIN OUTCOME MEASURE(S): Surgery within two days from admission. RESULTS: 938 (53.1%) patients were operated within 2 days of admission to the hospital. Logistic regression models were used to examine potential predictors of surgery delay including gender, age, hospital, comorbidity, type of intervention (partial or total hip replacement, reduction and internal fixation), International Normalized Ratio (INR), Haemoglobin (Hb), American Society of Anaesthesiologists (ASA) score, and day of admission (categorized as Monday to Wednesday, Thursday-Friday, Saturday-Sunday). Age, type of intervention (partial or total hip replacement), INR score > 1.5 and an ASA score of 4 compared to 1-2, admission on Thursday-Friday or Saturday-Sunday and the interaction hospital * arrhythmia significantly predicted a surgery delay of more than 2 days. CONCLUSIONS: Both organization and medical problems accounted for delays of surgical treatment of hip fractures. Established protocols aimed to optimize the patient flow logistics and to manage comorbidities are crucial to make hospitals more patient-centred and to improve patient outcomes. PMID- 21550518 TI - Radical renal surgery (laparoscopic and open) in octogenarians. AB - AIM: An ageing population is at significant risk of developing of renal cell carcinoma (RCC). We evaluate our units experience in managing RCC in octogenarians using either laparoscopic or open radical nephrectomy, highlighting the postoperative complication rates and survival outcomes. MATERIALS AND METHODS: From June 2001 to June 2008, 65 octogenarians underwent a radical nephrectomy for suspected renal cell carcinoma. The procedure was performed laparoscopically (group 1) in 29 patients (44%) and via an open nephrectomy (group 2) in 36 patients (56%). The presenting age, sex distribution, ASA score, preoperative co-morbidities and indications for nephrectomy were statically comparable in both groups. Postoperative complications were recorded using the Clavien-Dindo classification. RESULTS: Both groups were similar preoperatively with respect to age of presentation, ASA score and co-morbidities such as hypertension, ischemic heart disease, and chronic respiratory disease. Group 1 showed better statistically significant operative parameters (operative time and blood loss), mean length of hospital stay and most importantly postoperative complications. Postoperative complication rates were lower in group 1 (48.3%) when compared with group 2 (80.5%) (p<0.05). CONCLUSION: Surgery for renal cancer in patient over the age of 80 should only be considered after a thorough work up. Chronological age itself should not be the only determining factor. If such a surgery was to be undertaken, then in our experience, patients who underwent laparoscopic radial nephrectomy had fewer complications than those had open radical nephrectomy. PMID- 21550519 TI - A comparison of Thiel and formalin embalmed cadavers for thyroid surgery training. AB - BACKGROUND: The European Working Time Directive has increased the need for surgical skills training which does not involve patients. Recent changes in the anatomy legislation now make it possible to perform surgical procedures on human cadavers. Standard formalin embalming, however does not provide a very realistic model and alternative approaches, such as Thiel soft-fix embalmed cadavers, should be explored and evaluated. METHODS: Two formalin and 3 Thiel embalmed cadavers were used at a senior trainee and consultant course in thyroid surgery. The 12 participants (8 trainees and 4 consultants) were asked to score 15 aspects, such as quality of different tissues, for each type of cadaver. Some of these aspects were specific to thyroid surgery, however many are equally applicable to other specialties. RESULTS: All participants rated the Thiel embalmed cadavers better or equal for all aspects. Of the 180 pairs of scores 33 were excluded, 10 were equal for formalin and Thiel, while in the remaining 137 Thiel scored better. The preference was particularly pronounced in aspects that require flexibility of tissues such as flap raising. CONCLUSIONS: Thiel embalmed cadavers provide a more realistic model for training of thyroid surgical skills; this is expected to be similar for many other types of surgery. PMID- 21550520 TI - The impact of the National Treatment Purchase Fund on numbers of core urology training cases at University Hospital Galway. AB - Since the National Treatment Purchase Fund (NTPF) scheme was introduced in 2002, public patients waiting longer than three months for investigations and treatment are offered care in the private medical sector. Our aim was to assess the impact of the NTPF scheme on the number of training cases performed at University Hospital Galway (UHG). The number and type of urological procedures performed in the private medical sector under the NTFP scheme in 2008 were obtained from the UHG waiting list office. The number of these procedures performed on public patients by trainees at UHG in 2008 was determined retrospectively by reviewing theatre records. A significant number of core urology procedures were performed in the private sector via the NTPF scheme. Cancer centre designation and implementation of the EWTD will also place further pressures on urological training opportunities in Ireland. PMID- 21550521 TI - Changing to endovenous treatment for varicose veins: how much more evidence is needed? AB - Surgical ligation and stripping of varicose veins has been the accepted treatment for almost a century but within the last decade this has been challenged by endovenous thermal and chemical ablation methods. Surgery is not without significant complications including paraesthesia and has reflux recurrence rates of up to 54% at five years, even though it has been shown to provide significant health-related quality of life benefits cost-effectively. Ultrasound-guided foam sclerotherapy, endovenous laser ablation and radiofrequency ablation are all consistently proving to be at least as beneficial as surgery, without the same complications and with less post-procedure morbidity and more rapid recovery. This article presents a review of the latest published evidence and comparative analysis of vein surgery and it's alternatives. Endovenous treatment under local anaesthesia in a clinic room or office-based setting is now being recognized internationally as an acceptable standard for dedicated venous practice in a cost effective environment. Although more long-term comparative trials of these innovative methods compared with surgery are desirable, many centres are now conducting trials testing the latest endovenous device technologies with each other to support the development of contemporary pathways of care. Patients are entitled to a range of treatment strategies, particularly when complex and recurrent venous disease has such unacceptably high surgical complication and recurrence rates compared to endovenous alternatives. There is questionable logic in procrastinating until there is more convincing evidence. Now is the time for vascular surgeons to enhance their ultrasound skills and future-proof their venous practice for the benefits of patients and institutions. PMID- 21550522 TI - Cardiac allograft rejection. AB - Success in cardiac transplantation has been achieved by the development of improved immunosuppressive therapies, which have led to a concomitant decrease in cardiac allograft rejection and infection. Rejection however continues to be the cause of significant morbidity and mortality particularly in the first year after cardiac transplantation. The endomyocardial biopsy remains an essential tool for its diagnosis. Acute cellular rejection has been a well recognized phenomenon although more recently, the diagnosis of antibody-mediated rejection has gained acceptance, a condition associated with greater graft dysfunction, subsequent development of cardiac allograft vasculopathy and mortality. In this article we review the current status of the diagnosis of cardiac allograft rejection as determined by the traditional endomyocardial biopsy, the more recent advances in the non-invasive evaluation of rejection, detection of circulating antibodies and the treatment of rejection. PMID- 21550523 TI - Inflammation to skin malignancy, time to rethink the link: SCC in skin graft donor sites. PMID- 21550524 TI - Oral erythromycin relieves dysphagia in a patient with known oesophageal hypomotility disorder who has had a Nissen's fundoplication. PMID- 21550525 TI - Vein cuffs facilitate removal of prosthetic dialysis access grafts. PMID- 21550526 TI - Touching hearts, touching minds. PMID- 21550527 TI - Insulin regimen-associated differences in diets of preadolescents with type 1 diabetes. PMID- 21550530 TI - The open-ended question. PMID- 21550531 TI - Determinants of children's use of and time spent in fast-food and full-service restaurants. AB - OBJECTIVE: Identify parental and children's determinants of children's use of and time spent in fast-food (FF) and full-service (FS) restaurants. DESIGN: Analysis of cross-sectional data. SETTING: Parents were interviewed by phone; children were interviewed in their homes. PARTICIPANTS: Parents and children ages 9-11 or 13-15 from 312 families were obtained via random-digit dialing. MAIN OUTCOME MEASURES: Dependent variables were the use of and the time spent in FF and FS restaurants by children. Determinants included parental work schedules, parenting style, and family meal ritual perceptions. ANALYSIS: Logistic regression was used for multivariate analysis of use of restaurants. Least squares regression was used for multivariate analysis of time spent in restaurants. Significance set at P < .05. RESULTS: Factors related to use of and time spent in FF and FS restaurants included parental work schedules, fathers' use of such restaurants, and children's time spent in the family automobile. CONCLUSIONS AND IMPLICATIONS: Parenting style, parental work, parental eating habits and perceptions of family meals, and children's other uses of their time influence children's use of and time spent in FF and FS restaurants. PMID- 21550532 TI - The Personal Nutrition Planner: a 5-week, computer-tailored intervention for women. AB - OBJECTIVE: To conduct a dietary intervention using the Personal Nutrition Planner (PNP), an on-line nutrition intervention tool. DESIGN: Randomized controlled trial with pretest, posttest, and 2-month follow-up self-report assessments. SETTING: Web/on-line. PARTICIPANTS: Female university staff (n = 307; 59.1% Caucasian) recruited via e-mail. Retention rate was 85.0% (118 treatment; 143 comparison). INTERVENTION: PNP on-line produces individualized nutrition feedback based on initial on-line assessment. Intervention lasted 5 weeks and included weekly e-mail reminders. MAIN OUTCOME MEASURES: Dietary intake frequencies, weight loss, opinions regarding intervention. ANALYSIS: Repeated-measures analysis of variance to determine intervention effects on dietary intake and weight loss (P < .05). RESULTS: Relative to the comparison group who received no program, the treatment group increased dairy intake frequency across the 3 assessments (F(2,304) = 3.15; P < .05). Among participants who wanted to lose weight, weight loss in the treatment group was significantly higher than that of the comparison group from pretest to posttest (F(1,92) = 4.50; P < .05). On a scale of 1-5, mean ratings of the PNP program characteristics ranged from 3-4. CONCLUSIONS AND IMPLICATIONS: PNP produced significant increases in dairy intake and decreases in weight. Further revisions will tailor PNP to better fit individuals' dietary goals and increase motivation. PMID- 21550533 TI - Can low-income Americans afford to satisfy MyPyramid fruit and vegetable guidelines? AB - OBJECTIVE: To estimate the costs of satisfying MyPyramid fruit and vegetable guidelines, with a focus on whether low-income households can bear these costs. DESIGN: Descriptive analysis of the 2008 National Consumer Panel with information on the food purchases of 64,440 households across the contiguous United States was used to analyze the cost of fruits and vegetables. Costs per MyPyramid cup equivalents were calculated by accounting for cooking yields and the portion of a food item's retail weight that is inedible. VARIABLES MEASURED: Costs per cup equivalent for less expensive fruits and vegetables by MyPyramid subgroup including whole and cut fruit, fruit juice, dark green vegetables, orange vegetables, starchy vegetables, other vegetables, and legumes. RESULTS: In 2008, a variety of fruits and vegetables was available for an average cost of $0.40 to $0.50 per cup-equivalent. MyPyramid fruit and vegetable recommendations could be satisfied at this cost level. CONCLUSIONS AND IMPLICATIONS: Low-income Americans facing national average food prices can satisfy MyPyramid fruit and vegetable guidelines with a budget equal to the Thrifty Food Plan allocation to fruits and vegetables. However, many low-income households spend too much money on food that is low in fruit and vegetable content. Some money should be reallocated to fruits and vegetables. PMID- 21550534 TI - How to help parents pack better preschool sack lunches: advice from parents for educators. AB - OBJECTIVES: This exploratory study obtained parent suggestions about messages and activities to guide parents to pack healthful sack lunches for preschool-aged children. METHODS: A facilitator conducted group interviews using a modified nominal group technique with a convenience sample of parents who pack daily lunches for their children. Interviews took place after hours at child care centers in group settings. Investigators reviewed written statements for common themes then calculated frequencies of references to identified themes. RESULTS: In total, 31 parents participated in 3 group interviews held at 3 centers. Interest in receiving written information and in activities stimulating parent interaction were dominant themes in 29% of the comments. Workshops and activity stations were suggested in 20% of the comments. Finally, recommendations for support from local supermarkets were present in 10% of the comments. CONCLUSIONS AND IMPLICATIONS: Parents provided helpful suggestions that can guide nutrition educators to implement effective program messages and strategies. PMID- 21550535 TI - FruitZotic: a sensory approach to introducing preschoolers to fresh exotic fruits at Head Start locations in Western Massachusetts. PMID- 21550536 TI - Patient safety in anaesthesiology. PMID- 21550537 TI - How do we know that we are doing a good job - can we measure the quality of our work? AB - There is an increasing demand for systems for measuring the quality of our medical work. In this article, we present a suggestion for how one can attempt to do this in a department of anaesthesia. It would be desirable to measure real clinical outcomes such as morbidity and mortality. However, such events are rare and not suitable for routine recording of work quality. Instead, we propose a system based on indicators of process quality and surrogate clinical outcomes. Surrogates may provide useful information if chosen carefully and checked for validity. We further suggest that such indicators be recorded routinely on every anaesthesia chart. The rate of the indicator can then be followed over time with the use of statistical process control methods. The foundation for such a system for measuring quality is the presence of a good quality culture in the department, with a good team spirit, communication and cooperation. PMID- 21550538 TI - Morbidity in anaesthesia: today and tomorrow. AB - Based on results recorded of perioperative mortality, anaesthetic care is often cited as a model for its improvements with regard to patient safety. However, anaesthesia-related morbidity represents a major burden for patients as yet in spite of major progresses in this field since the early 1980s. More than 1 out of 10 patients will have an intraoperative incident and 1 out of 1000 will have an injury such as a dental damage, an accidental dural perforation, a peripheral nerve damage or major pain. Poor preoperative patient evaluation and postoperative care often contribute to complications. Human error and inadequate teamwork are frequently identified as major causes of failures. To further improve anaesthetic care, high-risk technical procedures should be performed after systematic training, and further attention should be focussed on preoperative assessment and post-anaesthetic care. To minimise the impact of human errors, guidelines and standardised procedures should be widely implemented. Deficient teamwork and communication should be addressed through specific programmes that have been demonstrated to be effective in the aviation industry: crew resource management (CRM) and simulation. The impact of the overall safety culture of health-care organisations on anaesthesia should not be minimised, and organisational issues should be systematically addressed. PMID- 21550539 TI - High reliability organizations (HROs). AB - Academic and professional disciplines, such as organisation and management theory, psychology, sociology and engineering, have, for years, grappled with the multidisciplinary issues of safety and accident prevention. However, these ideas are just beginning to enrich research on safety in medicine. This article examines a domain of research on system safety - the High Reliability Organization (HRO) paradigm. HROs operate in hazardous conditions, but have fewer than their fair share of adverse events. HROs are committed to safety at the highest level and adopt a special approach to its pursuit. The attributes and operating dynamics of the best HROs provide a template on which to better understand how safe and reliable performance can be achieved under trying conditions, and this may be useful to researchers and caregivers who seek to improve safety and reliability in health care. PMID- 21550540 TI - The contribution of labelling to safe medication administration in anaesthetic practice. AB - The administration of medications is central to anaesthetists' care of patients. Errors are inevitable in any human endeavour, but should be distinguished from violations. The incidence of medication errors in anaesthesia has been estimated as 1 per 13,000 administrations, excluding errors in recording. Adverse medication events follow a proportion of these errors. Labelling is a key element of medication safety. There is a long-standing need for improvements in the labelling of ampoules and vials. An international standard exists for labelling syringes used during anaesthesia (ISO 26825). Australia has recently released national recommendations for labelling lines and injectable medications that complement this and other relevant standards. The provision of at least some medications in pre-filled syringes would reduce the number of steps involved in medication administration, increase the certainty that syringe labels are correct and probably reduce medication errors. Pre-printed, peel-off flag labels on ampoules and vials are a less expensive alternative to pre-filled syringes to facilitate correct labelling. The medication name on user-applied labels should be matched to that on the relevant ampoule or vial at the time of drawing up any medication. All lines and catheters should be labelled. Any medicine or fluid that cannot be identified (e.g., in an unlabelled syringe or other container) should be considered unsafe and discarded. Reducing adverse medication events will require the engagement of individual anaesthetists. PMID- 21550541 TI - The WHO surgical checklist. AB - Following the overwhelming evidence of adverse events in hospital practice, the World Health Organization (WHO)'s World Alliance for Patient Safety has launched the 'Safe Surgery Saves Lives' campaign, which has developed a surgical safety checklist aimed to improve patient safety. The implementation of this checklist has met with mixed reactions in different institutions. Many countries have still not adopted its use. In this article, a brief review is presented regarding the role of the WHO checklist, barriers to its implementation and strategies for successful adoption. PMID- 21550542 TI - Managing the aftermath of critical incidents: meeting the needs of health-care providers and patients. AB - Critical incidents may have serious psychological and health-related impact on patients, their families and the health-care providers involved. Exploring the needs of health-care providers and patients and their families in the aftermath of a critical incident, this article highlights a disconnect between the widely acknowledged ethical obligation for open disclosure and current practice, reviews the available evidence on effective disclosure and barriers to open disclosure and provides an overview of what health-care organisations can do to alleviate the impact of critical incidents on staff, patients and their families. The most critical elements are: (1) effective support systems for clinicians, (2) guidelines on critical incident management including immediate measures, disclosure standards and subsequent incident analysis and (3) educational interventions informing staff about disclosure standards and support systems and training critical disclosure skills. Significant leadership commitment is required to successfully implement such comprehensive incident management systems. PMID- 21550543 TI - Effective handover communication: an overview of research and improvement efforts. AB - In the recent patient safety literature, there is an increasing agreement that effective patient handover is critical to patient safety by ensuring appropriate coordination among health-care providers and continuity of care. It has repeatedly been pointed out that a lack of formal training and formal systems for patient handover impede the good practice necessary to maintain high standards of clinical care. Thus, patient handover has been defined a research priority for patient safety, and research in this field is increasing rapidly. In reviewing the current state of research and improvement, we identified key areas for future research. Despite the growing evidence at the descriptive level, future research will have to take a more systematic approach to establish valid measures of handover quality and safety, establish the causal effects of handover characteristics on safe care and identify best practices in safe handover and effective interventions within and across health-care settings. PMID- 21550544 TI - Human performance limitations (communication, stress, prospective memory and fatigue). AB - A key role in anaesthetic practice is gathering and assimilating information from a variety of sources to construct and maintain an accurate mental model of what is happening to the patient, a model that will influence subsequent decisions made by the anaesthetist on the patient's behalf, as part of a larger team. Effective performance of this role requires a set of mental functions that place great demands upon the physiology and psychology of anaesthetists, functions that are vulnerable to a wide range of factors including those affecting team performance and those affecting the anaesthetist specifically. The number of tasks, their complexity, the physical and mental demands of the job, the underlying health and well-being of the anaesthetist and the environment and context within which the team attempt to meet the demands placed on them will influence the outcome of patient care. PMID- 21550545 TI - Incident reporting in anaesthesiology. AB - Incident reporting can be a powerful tool to detect weaknesses in the complex system of anaesthesiology. Having its roots in aviation, incident reporting today is used in a variety of medical disciplines at the local and even on the national level. Strength of incident reporting is the potential for learning from rare and potentially dangerous events. To properly set up an incident reporting system requires certain conditions to support and motivate reporters. It, furthermore, needs a sound definition or a model of a critical incident as well as a strategy to analyse the reported events. In Europe, a number of countries already run a national reporting system in anaesthesiology with large collections of critical events. These national systems, furthermore, distribute hazard warnings to spread the information on critical incidents among all specialists in that country. PMID- 21550546 TI - Non-technical skills for anaesthetists: developing and applying ANTS. AB - This article examines the non-technical skills approach to enhancing operational safety, with particular reference to anaesthesia. Training and assessing the non technical skills of staff in safety-critical occupations is accepted by high-risk industries, most notably aviation, but has only recently been adopted in health care. These authors explain the background to the concept of non-technical skills that was first adopted in relation to the behaviours of airline pilots and could enhance or jeopardise safety. Then, this article considers one particular non technical skills framework for doctors, the Anaesthetists' Non-Technical Skills (ANTS) taxonomy and behaviour-rating tool. This was the first non-technical skills framework specifically designed for anaesthetists, and the authors explain how ANTS was designed as well as its use for selection, training and assessment. Finally, the article mentions similar tools available for surgeons (NOTSS) and scrub nurses (SPLINTS), as well as research activities to develop behavioural rating systems for obstetric anaesthetists and anaesthetic assistants. PMID- 21550547 TI - Safety culture in anaesthesiology: basic concepts and practical application. AB - This article starts from a social science viewpoint and reviews the concepts and measurement of safety culture and climate in their original industrial settings and in health care. Typical items measured and generic characteristics of a positive safety culture are described. The role of personality, professional group membership and anaesthesiology-specific knowledge and expertise in shaping notions of risk and safety and safety behaviour are discussed. The difficulties of changing human behaviour are outlined, and the pivotal role which anaesthesiologists can play in promoting a positive safety culture, both individually and within their teams and organisations, is highlighted. PMID- 21550548 TI - Simulation and CRM. AB - Patients are harmed as a result of incidents. Both poor interdisciplinary communication and teamwork are contributing factors to such events. The principles of crisis resource management are meant to help prevent and manage difficulties and reflect both, the social-team-oriented and cognitive-individual oriented aspects of human factors. This article explores the importance of human factors training for safe care of patients and the role of simulation. Based on the available literature, the need to integrate this type of training to increase awareness of the importance of human factors and to change attitudes appears obvious. A combination of different training methods appears to be useful. Simulation-based training appears to be favourable, although the number of studies demonstrating the impact of training is limited. It is important to develop training programmes for individual teams, based on the knowledge of challenges and deficiencies, and to monitor behavioural change. Several methods, including patient safety data, interviews, observational studies and simulations, can be used to specify learning objectives. The training should be established for the real team(s). Furthermore, leaders need to implement training in the organisation and establish databases to monitor the impact on patient outcome. PMID- 21550549 TI - Education, teaching & training in patient safety. AB - Patient Safety is not a side-effect of good patient care by skilled clinicians. Patient safety is a subject on its own, which was traditionally not taught to medical personnel. This must and will dramatically change in the future. The 2010 Helsinki Declaration for Patient Safety in Anaesthesiology states accordingly "Education has a key role to play in improving patient safety, and we fully support the development, dissemination and delivery of patient safety training". Patient safety training is a multidisciplinary topic and enterprise, which requires us to cooperate with safety experts from different fields (e.g. psychologists, educators, human factor experts). Anaesthesiology has been a model for the patient safety movement and its European organisations like ESA and EBA have pioneered the field up to now: Helsinki Patient Safety Declaration and the European Patient Safety Course are the newest establishments. But Anaesthesiology must continue in its efforts in order to stay at the top of the patient safety movement, as many other disciplines gain speed in this topic. We should strive to fulfill the Helsinki Declaration and move even beyond that. As the European Council states: "Education for patient-safety should be introduced at all levels within health-care systems" PMID- 21550550 TI - Closed claims' analysis. AB - The American Society of Anesthesiologists (ASA) Closed Claims database was started in 1985 to study anaesthesia injuries to improve patient safety, now containing 8954 claims with 5230 claims since 1990. Over the decades, claims for surgical anaesthesia decreased, while claims for acute and chronic pain management increased. In the 2000s, chronic pain management involved 18%, acute pain management 9% and obstetrical anaesthesia formed 8% of claims. Surgical anaesthesia claims with monitored anaesthesia care (MAC) increased in the 2000s to 10% of claims, while regional anaesthesia involved 19%. The most common complications were death (26%), nerve injury (22%) and permanent brain damage (9%). The most common damaging events due to anaesthesia in claims were regional block-related (20%), respiratory (17%), cardiovascular (13%) and equipment related events (10%). This review examines recent findings and clinical implications for injuries in management of the difficult airway, MAC, non operating room locations, obstetric anaesthesia and chronic pain management. PMID- 21550551 TI - The Helsinki Declaration on Patient Safety in Anaesthesiology: putting words into practice. AB - In June 2010, the European Board of Anaesthesiology (EBA) of the European Union of Medical Specialists (UEMS) and the European Society of Anaesthesiology (ESA) signed the Helsinki Declaration for Patient Safety in Anaesthesiology at the Euroanaesthesia meeting in Helsinki. The document had been jointly prepared by these two principal anaesthesiology organisations in Europe who pledged to improve the safety of patients being cared for by anaesthesiologists working in the medical fields of perioperative care, intensive care medicine, emergency medicine and pain medicine. The declaration stated their current heads of agreement on patient safety and listed a number of principle requirements as thought necessary for anaesthesiologists, anaesthesiology departments and institutions to introduce to improve patient safety. Good words are only as good as their implementation and this article explains the rationale behind them and expands the recommendations practically so anaesthesiologists caring for patients everywhere can follow the Helsinki Declaration and put the words into practice. PMID- 21550552 TI - Helsinki Declaration on patient safety in anaesthesiology: putting words into practice - experience in Germany. AB - For years now, the German Society of Anaesthesiology and Intensive Care Medicine and the Professional Association of German Anaesthesiologists have been actively involved in efforts to improve patient safety. To this end, a whole range of activities have been initiated in recent years and, since February 2011, collected together on our home page 'PATSI' (www.patientensicherheit-ains.de). Further, the implementation of syringe labelling (ISO 26825) with additional information on drugs frequently used in intensive care was carried out. Under the item Helsinki Declaration, all decisions and recommendations so far worked out by our speciality have, in structured form, been assigned to individual points and saved as PDF files. This has made it possible for every anaesthesiological department in Germany to integrate all the relevant instructions and conditions of the Helsinki Declaration into their own individual work structures. These systematic solutions represent a major contribution towards reducing the possibility of errors at the workplace. We are certainly still in the early stages of our efforts to achieve a nationwide integration of a cultural change in the way we deal with mistakes in medicine. We have incorporated the item 'learning from mistakes' in our project 'critical incident reporting system for anaesthesia, intensive care medicine, emergency care, and pain therapy, CIRS AINS', and have brought out a range of relevant illustrative publications. Accepting these 'mistakes' as an opportunity to critically examine ourselves and our work with a view to learning from them and further improving our speciality service is, we believe, a great challenge for future developments in anaesthesia. PMID- 21550553 TI - Preclinical efficacy of vascular disrupting agents in non-small-cell lung cancer. AB - There is increasing interest in the use of vascular targeted therapy for the treatment of non-small-cell lung cancer (NSCLC). Current approaches include antiangiogenic drugs, which prevent growth of new vessels, and tumor vascular disrupting drugs, which further compromise the function of tumor vasculature and induce vascular failure. Preclinical studies have led to the development of the two main classes of tumor vascular disrupting agent-tubulin polymerization inhibitors such as combretastatin A4 phosphate (CA4P) and the flavonoid class that includes flavone acetic acid (FAA) and ASA404 (vadimezan). Each class of drug has shown antitumor activity in preclinical models of lung cancer, including both rodent tumors and human tumor xenografts. Tubulin polymerization inhibitors act primarily by disrupting the tubulin network of the endothelial cell cytoskeleton, leading to shape changes and increased vascular permeability, but these agents also affect the actin cytoskeleton and endothelial cell junctions. Flavonoid vascular disrupting agents appear to accentuate pathologic signaling by cytokines such as tumor necrosis factor and vascular endothelial growth factor, leading to changes in the actin cytoskeleton, increased vascular permeability, and endothelial apoptosis. Several approaches to the measurement of vascular disrupting effects in preclinical models have been developed. They include measurement of tumor blood flow, the induction of tumor hypoxia, and the release of serotonin from platelets, measured in plasma as the metabolite 5 hydroxyindoleacetic acid. Both classes of agent combine with standard cytotoxic drugs in the treatment of experimental tumors, but consideration of the timing of combination administration is important because tumor vascular disruption will affect delivery of a second agent. PMID- 21550554 TI - History of small-cell lung cancer. AB - The history of small-cell lung cancer (SCLC) is one of the more fascinating stories of medicine, a story of hope and disappointment that characterizes it as 1 of the most elusive cancers. Its history can be divided into 3 intervals. The first interval encompassed the 30 years after the initial reports from Bernard in 1926 during which SCLC was characterized. The second interval, from the 1960s 1980s, introduced advances in staging and treatment of SCLC and the advent of chemotherapy and radiation therapy (RT) as the primary forms of therapy. The final interval covers the past 25 years, which is considered a dormant period, although there are some shimmers of hope from the emergence of several new active drugs that are currently undergoing clinical trials. PMID- 21550555 TI - Summary of presentations from the 46th annual meeting of the American Society Of Clinical Oncology (2010): focus on developmental therapeutics related to lung cancer. AB - A number of novel agents are currently being tested in clinical trials in patients with cancer. Results from early-phase trials, often in unselected groups of patients with a wide variety of cancer types, were reported at the 46th annual meeting of the American Society of Clinical Oncology (ASCO). We report on selected studies from the developmental therapeutics track (abstracts 2500-2613 and 3000-3108) that may be of interest to the thoracic oncology community. PMID- 21550556 TI - Second-line paclitaxel/carboplatin versus vinorelbine/carboplatin in patients who have advanced non-small-cell lung cancer pretreated with non-platinum-based chemotherapy: a multicenter randomized phase II study. AB - PURPOSE: This study evaluates the activity and toxicity of the paclitaxel/carboplatin (PC) doublet versus vinorelbine/carboplatin (VC) doublet as second-line treatment in patients who have advanced non-small-cell lung cancer (NSCLC). PATIENTS AND TREATMENT: Patients pretreated with front-line docetaxel and gemcitabine were randomized to receive either PC (n = 75), which consisted of paclitaxel at a dose of 140 mg/m(2) and carboplatin area under the curve (AUC3), or VC (n = 78), which consisted of vinorelbine at a dose of 45 mg/m(2) orally and carboplatin AUC3; both drugs were administered on days 1 and 15. RESULTS: The overall response rate was 18.6% (95% confidence interval, 9.85%-27.49%; one complete and 13 partial responses) in the PC arm and 7.7% (95% confidence interval, 1.78%-13.61%; one complete and five partial responses) in the VC arm (P = .056). Median time to tumor progression was 3.5 months (range, 0.3 - 23.73 months) and 3.07 months (range, 0.37-18.5) in the PC and VC arm, respectively (P = .287). Median overall survival was 7.83 months (range, 0.3-45.03 months) and 7.60 months (range, 0.5-30.27 months) for PC and VC arms, respectively (P value = .633). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed. CONCLUSIONS: Platinum-based doublets with either paclitaxel or vinorelbine in patients with advanced/metastatic NSCLC pretreated with front-line docetaxel/gemcitabine show comparable efficacy when used in the second-line setting. PMID- 21550557 TI - Prognostic impact of angiogenic markers in non-small-cell lung cancer is related to tumor size. AB - BACKGROUND: It is thought that different families of angiogenic factors stimulate angiogenesis at different stages of tumor development. Our aim was to study whether the prognostic impact of vascular endothelial growth factors (VEGFs) and receptors (VEGFRs), platelet-derived growth factors (PDGFs) and receptors (PDGFRs) and fibroblast growth factor-2 (FGF-2) were associated with tumor size in non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Tumor tissue samples were obtained from 335 patients who had undergone resection for stage I-IIIA NSCLC, and tissue microarrays (TMAs) were constructed. Immunohistochemical techniques were used to evaluate the expression of VEGF-A, VEGF-C, VEGFR-2, VEGFR 3, PDGF-A, PDGF-B, PDGFR-alpha, PDGFR-beta, and FGF-2. Tumor size was categorized using the same cutoffs as in the 7th TNM classification for lung cancer. RESULTS: In multivariate analysis, high VEGFR-2 (HR, 1.87, [95% CI, 1.02-3.45]; P = .043), VEGFR-3 (HR, 2.18 [95% CI, 1.28-3.71]; P = .004) and the combination of high VEGF A and high VEGFR-2 expression (low/low vs. high/high; HR, 3.28 [95% CI, 1.47 7.31]; P = .004) were independent negative prognostic factors in T2a tumors. High PDGF-B expression (HR, 11.72 [95% CI, 3.07-44.76]; P < .001) was an independent prognostic factor in T2b tumors. CONCLUSION: The prognostic impact of angiogenic factors depend in part on tumor size. VEGF-A/VEGFR-2 and VEGFR-3 seem to have their main impact in T2a tumors, while PDGF-B is a strong and independent prognostic factor in T2b tumors. PMID- 21550558 TI - First- or second-line gefitinib therapy in unknown epidermal growth factor receptor mutants of non-small-cell lung cancer patients treated in Taiwan. AB - Gefitinib is effective in treating patients with non-small-cell lung cancer (NSCLC). The response rate and improvement in survival are related to several aspects, including race, gender, smoking status, and histology; however, little is known about the relationship between survival and length of gefitinib treatment. We conducted this retrospective study to examine this relationship and identify the predictive factors influencing survival and tumor response in chemonaive and chemotherapy patients who had stage IIIb or IV NSCLC with unknown epidermal growth factor receptor mutants. This analysis was aimed to clarify the difference between first- and second-line gefitinib therapy. Among the 918 newly diagnosed, inoperable NSCLC patients from March 2003 to December 2006, 437 (47.6%) had ever received gefitinib therapy. One hundred forty-nine patients (34.0%) who selected gefitinib as first- or second-line therapy were included in the analysis. The overall survival rates of first- and second-line gefitinib therapy were 12.8 months and 20.7 months, respectively (P = .110). The shorter overall survival may be caused by the omission of platinum-based doublet chemotherapy in 37 patients from the first-line group (39.4%). There was also no significant difference in progression-free survival (6.8 months versus 4.9 months; P = .415), and the objective tumor response and disease control rates were similar. Better prognosis and tumor response was associated with female gender, adenocarcinoma, nonsmokers, and good performance status. The difference in overall survival between patients undergoing second-line treatment compared with those undergoing first-line treatment preceding chemotherapy was significant (P = .041). The overall survival, progression-free survival, and tumor response rates were similar in the patients who received gefitinib as initial therapy or after conventional chemotherapy. PMID- 21550559 TI - Phase I/II trial of a COX-2 inhibitor with limited field radiation for intermediate prognosis patients who have locally advanced non-small-cell lung cancer: radiation therapy oncology group 0213. AB - BACKGROUND: Treatment of patients who have locally advanced non-small-cell lung cancer and compromised performance status or weight loss (WL) is challenging. This study was conducted to test a low toxicity treatment regimen in this cohort. PATIENTS AND METHODS: Patients were treated with concurrent celecoxib and thoracic radiation therapy to 45 Gy in 15 fractions or 60 to 66 Gy in 30 to 33 fractions. Eligible patients had inoperable or unresectable stage IIB, IIIA/B NSCLC, performance status 2 and/or greater than 5% WL. In the phase I portion of the study, the starting dose of celecoxib was 200 mg twice daily with one dose escalation to 400 mg twice daily. Celecoxib was continued for 2 years or until progression. RESULTS: The phase I component accrued eight patients each at 200 mg twice daily and 400 mg twice daily. Twice daily 400 mg was chosen for the phase II component, which enrolled five patients and was closed early because of poor accrual. We were able to analyze 18 patients. Performance status ratings were 0, 1, and 2 in 7, 7, and 4 patients, respectively. Median age was 72 years. WL of greater than 5% was noted in 10 patients (56%). Four of 10 had WL greater than or equal to 20%. Median follow-up and survival was 10 months. Overall survival rates at 1 and 2 years were 44.4% [95% confidence interval (CI), 21.6%-65.1%] and 22.2% (95% CI, 6.9%-42.9%), respectively. Progression-free survival at 1 year was 33.3% (95% CI, 13.7%-54.5%). Toxicities matched those expected with thoracic radiotherapy alone. CONCLUSION: Concurrent thoracic radiation therapy and celecoxib was well tolerated. The sample size was too small to draw conclusions regarding efficacy. PMID- 21550560 TI - Baseline levels and decrease in serum soluble intercellular adhesion molecule-1 during chemotherapy predict objective response and survival in patients who have advanced non-small-cell lung cancer. AB - BACKGROUND: This study assesses the predictive and prognostic roles of serum soluble intercellular adhesion molecule-1 (sICAM-1) and vascular endothelial growth factor (VEGF) during chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Changes in serum levels of sICAM-1 and VEGF during first-line conventional chemotherapy were studied prospectively using an enzyme-linked immunosorbent assay at baseline and after every two courses of therapy in 124 patients who have advanced NSCLC. Data were correlated with radiologic objective response and survival. RESULTS: The prognostic values of serum sICAM-1and VEGF were explored in 115 advanced NSCLC patients and 61 patients were evaluated for radiologic and serologic responses after two chemotherapy courses. Of the 115 patients, 79 patients had baseline serum sICAM-1 levels greater than 232.84 ng/mL, which is the cut-off value for distinguishing malignant tumors from benign. Statistically significant correlations were observed between baseline sICAM-1 levels and odds ratios and between a sICAM-1 response and odds ratios (8.05 and 5.40, respectively). However, there was no correlation between baseline VEGF levels and odds ratios (P = .543). The median progression-free survival from response assessment was 4 months. In a multivariate analysis, performance status (hazard ratio [HR], 1.47; 95% confidence interval [CI] (95% CI), 1.03-2.10), disease stage (HR, 1.43; 95% CI, 1.07-1.90), baseline sICAM-1 (HR, 1.12; 95% CI, 1.01-1.21), and sICAM-1 response (HR, 0.58; 95%CI, 0.39-0.88), were confirmed as independent prognostic factors for survival. CONCLUSION: Baseline sICAM-1 and sICAM-1 responses appeared to be reliable surrogate markers of chemotherapy efficacy and were prognostic factors in patients with advanced NSCLC. PMID- 21550561 TI - Rationale for treatment and study design of tailor: a randomized phase III trial of second-line erlotinib versus docetaxel in the treatment of patients affected by advanced non-small-cell lung cancer with the absence of epidermal growth factor receptor mutations. AB - We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR) mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples. PMID- 21550562 TI - Pathophysiologic changes due to TASER(r) devices versus excited delirium: potential relevance to deaths-in-custody? AB - The syndrome of excited delirium has been implicated in some deaths-in-custody which also involved the use of electronic control devices (ECDs) (including those manufactured by TASER International) on subjects. This review is an update on recent studies of pathophysiologic changes related to these two separate but parallel topics: a) first, the use of ECDs during law-enforcement activities; and b) second, the occurrence of excited delirium during such activities. This is a narrative review of elements that may be of use in generating hypotheses relating to potential similarities or differences between the two topics. Differences between changes in most factors due to excited delirium versus those of ECD applications were not readily apparent in most cases. These factors include: direct and indirect effects on the cardiovascular system, respiration, rhabdomyolysis and muscle enzymes, hyperkalemia, acidosis, hyperglycemia, and increased hematocrit. One factor that may exhibit consistent differences, however, is increased body temperature, which is often evident during excited delirium (versus a lack of increase temperature during ECD exposures). Thus, on the basis of this review, a more detailed delineation of this factor could be a major focus for future forensic investigations of deaths-in-custody involving either excited delirium or ECD exposures. PMID- 21550563 TI - Human fatalities from wild elephant attacks--a study of fourteen cases. AB - Human-wild elephant conflicts are frequently reported from various parts of the country. Encroaching of animal habitat by human civilization is a primary reason for this. The present study comprises of fourteen autopsy cases conducted at the department of Forensic Medicine, B.S Medical College, Bankura, West Bengal, India over a period of three years. The study attempts to find out the nature of injuries caused by wild elephant attack and the common factors contributing to human-wild elephant conflict so that vulnerable population can be cautioned to avoid conflicts. A distinct seasonal as well as diurnal variation of attack incidences was noted. Attacks were sudden and unprovoked. Killer elephants were wild tuskers in all the cases. Victims were from the low socioeconomic group and the cause of death was due to trampling on the vital organs like chest and head. PMID- 21550564 TI - A satisfaction survey conducted on patients of a medico-legal consultation. AB - In 2006, a medico-legal consultation service devoted to adult victims of interpersonal violence was set up at the Lausanne University Hospital Centre, Switzerland: the Violence Medical Unit. Patients are received by forensic nurses for support, forensic examination (in order to establish medical report) and community orientation. In 2008, a telephone survey was conducted on patients. The objectives of the survey were to estimate the degree of patients' satisfaction and to document the use of the medical report by six questions. Among the 476 patients admitted to the VMU in 2007, 132 were interviewed. Their overall satisfaction was high with an average mark of 8.7/10. The medical report was used extensively by the interviewed victims (81%) for its primary function - to be produced as evidence. As the consultations are financed by public funds, these results were of interest for advocacy of long-lasting financial support. PMID- 21550565 TI - Challenges experienced by service providers in the delivery of medico-legal services to survivors of sexual violence in Kenya. AB - While much discussion has been devoted to defining the standards of care required when offering services to survivors of sexual violence, much less attention has been given to procedures for evidence collection to allow the successful prosecution of perpetrators. In Kenya there are no comprehensive guidelines that outline the roles of the survivor, the community, health care workers, and the police with regard to the handling of forensic evidence, a deficit that contributes to delays in prosecuting, or even a failure to prosecute sex offenders. This study examines some of the obstacles in Kenya to the adequate handling of forensic evidence in sexual violence cases. It was based on in-depth interviews with respondents drawn from health facilities, police stations, civil society organizations and with the Government Chemist in three Kenyan provinces. The study's objective was to examine the existing policy requirements regarding the maintenance of an evidence chain by the health and criminal justice systems, and how effectively they are being implemented. The findings indicate that the quality of the evidence obtained by the health care workers was often deficient, depending on the time elapsed before the rape survivor reports to the health facility; the equipment available at the health facility; the age of the survivor; and the level of knowledge of the service provider regarding the types of evidence to be collected from survivors of sexual violence. PMID- 21550566 TI - Estimation of stature from cephalo-facial dimensions by regression analysis in Indo-Mauritian population. AB - Determination of stature from fragmented human remains is vital part of forensic investigation for the purpose of identification. The present study was aimed to modelling the stature both for male and female separately on the basis of craniofacial dimensions. The study was conducted on 150 young and healthy students (75 males and 75 females) in the age group ranging from 20 to 28 years. The stature and fourteen cephalo-facial dimensions were measured on each subject by using standard anthropometric instruments. It is remarked that the stature and craniofacial measurements of males were significantly higher than that of females, except for nasal height where no significant difference was observed (p > 0.05). The correlation coefficients (r) of all cephalo-facial dimensions were less than 0.5. It means the estimation of stature is not reliable with the help of cephalo-facial dimensions. PMID- 21550567 TI - Sex identification on the basis of hand and foot measurements in Indo-Mauritian population--a model based approach. AB - Identification is the foremost issue in crime investigation. A few studies have been performed so far in order to identify sex on the basis of single foot or hand of the victim. Moreover, these studies provide only crude measures to indicate sex and there exists no concrete methodology to predict sex using the available information. In the present paper, we have developed statistical models to identify sex based on the dimensions of foot and hand. The models containing both length and breadth of hand or foot as independent variables are capable of predicting sex in Indo-Mauritian population with fairly high accuracy as compared to those containing hand or foot indices. PMID- 21550568 TI - Comparative analysis of sclerotic dentinal changes in attrited and carious teeth around pulp chamber for age determination. AB - AIM: The aim of this study was to estimate age by comparing sclerotic dentin thickness around coronal pulp chamber in carious and attrited teeth. METHODOLOGY: Inclusion criteria for teeth selection was eruption age around six to seven years (incisors and first molars). 100 teeth (50 carious + 50 attrited) were ground up to their pulp chamber, observed and photographed under an Olympus stereomicroscope. Image J 1.38 NIH software was employed to analyze dentinal thickness. STATISTICAL ANALYSIS: Regression formula was employed for evaluating age and compared with clinical age obtained at time of extraction. RESULTS: No matching values were found between calculated age and actual clinical age. CONCLUSION: Sclerotic dentin thickness values cannot be used as an indicator for the purpose of age estimation. PMID- 21550569 TI - Sudden death from an asymptomatic phaeochromocytoma: a case report. AB - A case of sudden death due to a phaeochromocytoma in an apparently healthy young man is presented. In cases of sudden death it is necessary to perform a complete and accurate autopsy also looking for alterations in other organs than the heart that could explain the death. PMID- 21550570 TI - Case report--death by subcutaneous injection of cyanide in Sri Lanka. AB - An elderly man was stabbed with a needle and syringe onto his abdomen while asleep. He progressively developed respiratory failure and coma and died an hour later. Autopsy findings and laboratory analysis confirmed the death as being due to poisoning by cyanide. This case highlights the need to consider cyanide as a possible agent where there is a rapid death with progressive respiratory failure after injection of an unknown substance. Cyanide poisoning by ingestion is frequently seen in suicidal, accidental and homicidal deaths. To our knowledge, this is the first reported case of cyanide poisoning by injection in Sri Lanka. PMID- 21550571 TI - Genetic composition of six miniSTR in a Brazilian Mulatto sample population. AB - The present study characterizes the genetic variability of Mulatto population based on the polymorphism of six miniSTR autosomal loci, known as Non Codis 01 and 02 (NC01 and NC02) and evaluate their applicability in forensic genetics. A sample of 102 unrelated Brazilian mulattoes were genotyped for miniSTR loci D1S1677, D2S441, D4S2364 (miniplex NC02) and 45 individuals for D10S1248, D14S1434, D22S1045 (miniplex NC01). No significant deviations from Hardy-Weinberg equilibrium expectations were detected. The combined power of discrimination (PD) and mean power of exclusion (PE) were 0.999996 and 0.98991, respectively. The results also support the effectiveness of the NC01and NC02 miniplexes for human identification. PMID- 21550572 TI - Authors reply to: Min Karen Lo et al., "A response to: Chlamydia trachomatis infection in children: do not forget perinatal acquisition." [J Forensic Legal Med 2010;17:450]. PMID- 21550573 TI - Three-dimensional echocardiographic characterization of left ventricular remodeling in Olympic athletes. AB - The aim of the present study was to assess, using 3-dimensioanl echocardiography, the morphologic characteristics, determinants, and physiologic limits of left ventricular (LV) remodeling in 511 Olympic athletes (categorized in skill, power, mixed, and endurance sport disciplines) and 159 sedentary controls matched for age and gender. All subjects underwent 3-dimensional echocardiography for the assessment of LV volumes, ejection fraction, mass, remodeling index (LV mass/LV end-diastolic volume), and systolic dyssynchrony index (obtained by the dispersion of the time to minimum systolic volume in 16 segments). Athletes had higher LV end-diastolic volumes (157 +/- 35 vs 111 +/- 26 ml, p <0.001) and mass (156 +/- 38 vs 111 +/- 25 g, p <0.001) compared to controls. Body surface area and age had significant associations with LV end-diastolic volume (R(2) = 0.49, p <0.001) and mass (R(2) = 0.51, p <0.001). Covariance analysis showed that also gender and type of sport were significant determinants of LV remodeling; in particular, the highest impact on LV end-diastolic volume and mass was associated with male gender and endurance disciplines (p <0.001). Regardless of the type of sport, athletes had similar LV remodeling indexes to controls (1.00 +/- 0.06 vs 1.01 +/- 0.07 g/mL, p = 0.410). No differences were found between athletes and controls for the ejection fraction (62 +/- 5% and 62 +/- 5%, p = 0.746) and systolic dyssynchrony index (1.06 +/- 0.40% and 1.37 +/- 0.41%, p = 0.058). In conclusion, 3-dimensional echocardiographic morphologic and functional assessment of the left ventricle in Olympic athletes demonstrated a balanced adaptation of LV volume and mass, with preserved systolic function, regardless of specific disciplines participated. PMID- 21550574 TI - Rate of progression of transthyretin amyloidosis. AB - Hereditary transthyretin (TTR) amyloidosis is an adult-onset disease characterized mainly by peripheral neuropathy and cardiomyopathy. Although disease progression is usually 5 to 15 years from time of diagnosis to death, no specific measurements of disease progression have been identified. The present study was designed to identify objective parameters to measure progression of hereditary TTR amyloidosis and determine if these parameters would show significant change within 1 year. Nine patients with biopsy-proved TTR amyloidosis and evidence of cardiac involvement were studied at baseline, 6 months, and 12 months by cardiac magnetic resonance imaging (MRI), electrocardiogram, and echocardiogram. Neurologic impairment score and electromyogram were determined at baseline and 12 months. Left ventricular mass determined by MRI and echocardiogram showed significant change at 12-month examination (p = 0.005 and p = 0.0009, respectively). Electrocardiogram and neurologic impairment score did not show significant change at 12 months. Measurement of left ventricular mass by MRI and echocardiographic techniques showed significant change in hereditary TTR cardiac amyloidosis within 1 year. In conclusion, these methods provide a means to clinically monitor progression of hereditary TTR amyloidosis and determine efficacy of therapeutic interventions. PMID- 21550575 TI - Circulating endothelial progenitor cells in patients with dysfunctional versus normally functioning congenitally bicuspid aortic valves. AB - Patients with bicuspid aortic valve (BAV) may gradually develop significant valve dysfunction, whereas others remain free of dysfunction. Factors that determine the prognosis of BAV remain unclear. Because endothelial progenitor cells (EPCs) have a role in the repair of endothelial surfaces after injury, we hypothesized that EPCs may also be involved in preventing BAV degeneration. Accordingly, we compared EPC level and function in patients with BAV with versus without valve dysfunction. The study group included 22 patients with BAV and significant valve dysfunction (at least moderate aortic regurgitation and/or at least moderate aortic stenosis). The control group included 28 patients with BAV without valve dysfunction. All patients had 1 blood sample taken. Proportion of peripheral mononuclear cells expressing vascular endothelial growth factor receptor 2, CD133 and CD34 was evaluated by flow cytometry. EPC colony-forming units (CFUs) were grown from peripheral mononuclear cells, characterized, and counted after 7 days of culture. The 2 groups had similar clinical characteristics except for higher prevalence of hypertension in the dysfunctional valve group. Number of EPC CFUs was smaller in the dysfunctional valve group (32 CFUs/plate, 15 to 42.5, vs 48 CFUs/plate, 30 to 62.5, respectively, p = 0.01), and the migratory capacity of the cells in this group was decreased. In addition, the proportion of cells coexpressing vascular endothelial growth factor receptor 2, CD133, and CD34 tended to be smaller in the dysfunctional valve group. In conclusion, patients with BAV and significant valve dysfunction appear to have circulating EPCs with impaired functional properties. These findings require validation by further studies. PMID- 21550576 TI - Older blood pressure medications-do they still have a place? AB - Hypertension is a major risk factor for cardiovascular disease, but control of hypertension remains inadequate, often because of poor patient adherence to prescribed medical regimens that are viewed as poorly tolerated and expensive. Physicians have largely stopped using some older blood pressure medications in favor of newer agents, mostly because of a presumed more favorable side effect profile. The investigators reviewed the pharmacologic properties and the evidence supporting the effectiveness and tolerability of several older blood pressure drugs: sympatholytic agents such as reserpine, methyldopa, and clonidine; diuretics such as chlorthalidone, ethacrynic acid and spironolactone; the vasodilators hydralazine and minoxidil; and others. In conclusion, some of these drugs are well studied and represent alternatives for patients who cannot afford or tolerate newer medications. PMID- 21550577 TI - Adiponectin and risk of coronary heart disease in apparently healthy men and women (from the EPIC-Norfolk Prospective Population Study). AB - The objective of the present study was to evaluate the association between adiponectin levels and incidence of coronary heart disease (CHD). We performed a prospective case-control analysis nested in the EPIC-Norfolk cohort. Participants were apparently healthy men and women 45 to 79 years of age who developed fatal or nonfatal CHD during an average follow-up period of 7.7 +/- 1.1 years. In total 1,035 participants with incident CHD were matched for age, gender, and enrollment time to 1,920 controls who remained free of CHD over the study follow-up. Baseline nonfasting plasma adiponectin concentrations were determined by enzyme linked immunosorbent assay. Adiponectin levels were lower in participants with CHD than in matched controls (men 8.74 vs 9.13 MUg/ml, p = 0.01; women 12.6 vs 13.4 MUg/ml, p = 0.03). A 1-MUg/ml increment in adiponectin was associated with decreased CHD risk (odds ratio 0.78, 95% confidence interval 0.63 to 0.96, p = 0.02, in men; odds ratio 0.73, 95% confidence interval 0.55 to 0.96, p = 0.03, in women). However, this association was no longer significant after adjustment for established cardiovascular risk factors. Stratification of participants according to metabolic syndrome status showed that men and women with metabolic syndrome had a higher CHD risk, irrespective of their adiponectin levels. In conclusion, although a low adiponectin concentration is associated with an increased CHD risk, findings of the present study do not suggest that its measurement is useful to refine CHD risk assessment once traditional risk factors and clinical features of the metabolic syndrome have been considered. PMID- 21550578 TI - Importance of adjunctive heart failure optimization immediately after implantation to improve long-term outcomes with cardiac resynchronization therapy. AB - Despite improvement in morbidity and mortality with cardiac resynchronization therapy (CRT), disease progression continues to affect a subset of patients and there is limited effort to identify contributing factors. Our objective was to investigate if a protocol-driven approach incorporated in a management strategy of heart failure immediately after implantation would provide incremental benefits beyond usual care after implantation. We reviewed 114 consecutive patients with CRT implanted from 2005 through 2009 who received usual care after implantation or underwent protocol-driven CRT care after implantation. Preimplantation characteristics in patients receiving usual versus protocol driven care were similar in left ventricular (LV) dimension (LV internal diastolic diameter 6.2 +/- 0.8 vs 6.4 +/- 1.0 cm), LV ejection fraction (26 +/- 8% vs 25% +/- 8%), QRS width, and medication usage. Major adjustments during the protocol-driven approach were uptitration of neurohormonal blockers (64%), echocardiographically guided atrioventricular optimization (50%), heart failure education (42%), arrhythmia management (19%), and LV lead repositioning (7%). Although positive LV remodeling was noted in the 2 groups at 6 months, extent was significantly greater in the protocol-driven approach compared to usual care (change in LV internal diastolic diameter 0.7 +/- 0.6 cm vs 0.2 +/- 1.2 cm, p = 0.01; change in LV ejection fraction 11 +/- 7% vs 7 +/- 9%, p = 0.01), which was associated with fewer major adverse events (14% vs 53%, p <0.001). In conclusion, a protocol-driven approach for patients with CRT started immediately after implantation is associated with incremental favorable effects on reverse remodeling and fewer adverse events compared to usual care after implantation. These effects appeared to be driven not only by changes in device settings and arrhythmia management but also by concomitant medication optimization and heart failure education. PMID- 21550579 TI - Usefulness of low-dose dobutamine echocardiography to predict response and outcome in patients undergoing cardiac resynchronization therapy. AB - A substantial proportion of patients who meet the current guidelines for cardiac resynchronization therapy (CRT) fail to respond to this pacing modality. Although appropriate patient selection and left ventricular (LV) lead location have been ascribed as determinants of CRT response, the interaction among contractile reserve, dynamics of dyssynchrony, and lead location is not well understood. The present study prospectively evaluated the effect of contractile reserve and dobutamine-induced changes in LV synchrony, in relation to the LV lead location, as predictors of the response to CRT. In the present study, 31 patients were prospectively evaluated and underwent low-dose dobutamine echocardiography. The dobutamine-induced increase in ejection fraction (contractile reserve [CR]) was measured, and the most mechanically delayed segment was identified to classify patients into 2 groups. Group 1 had a CR of >20% and a LV lead position concordant with the mechanically delayed segment. Group 2 included the remaining patients (i.e., low CR, discordant LV lead position, or both). Patients in group 1 were significantly more likely to have an echocardiographic response at 6 months (80% of group 1 vs 29% of group 2, p = 0.018) and had an improved 2-year heart failure hospitalization-free survival rate (90% in group 1 vs 33% in group 2, p = 0.006). In conclusion, low-dose dobutamine echocardiography provides information that can help to predict responders to CRT. The response rates and heart failure hospitalization-free survival were improved in those patients with a CR >20% and an LV lead tip concordant with the most delayed mechanical segment. PMID- 21550580 TI - Usefulness of exercise-induced hypertension as predictor of chronic hypertension in adults after operative therapy for aortic isthmic coarctation in childhood. AB - Chronic hypertension is a major concern in adults who have undergone resection of coarctation of the aorta (CoA) in childhood. In otherwise healthy subjects, exercise-induced hypertension is prognostic for chronic hypertension; however, the prognostic value in patients with CoA remains unknown. The aim of the present study was to evaluate the predictive value of exercise-induced hypertension for chronic hypertension in these patients. In the present prospective follow-up study, 74 patients with CoA (58% men, age 30.9 +/- 9.5 years) underwent ambulatory blood pressure (BP) monitoring and exercise testing twice from 2001 to 2009 with a follow-up period of 6.3 +/- 0.8 years. Hypertension was defined as a mean systolic BP >=140 mm Hg and/or mean diastolic BP >=90 mm Hg or the need for antihypertensive treatment. Exercise-induced hypertension was defined as a mean systolic BP of <140 mm Hg and peak exercise systolic BP of >=200 mm Hg. At baseline, 27 patients (36%) were hypertensive, 11 (15%) had exercise-induced hypertension, and 36 (49%) were normotensive. At follow-up, all 27 hypertensive patients remained hypertensive. Of the 11 with exercise-induced hypertension, 7 (64%) had developed chronic hypertension, and 4 (36%) continued to have exercise induced hypertension. Of the 36 normotensive patients, 7 (19%) had developed hypertension, 12 (33%) had developed exercise-induced hypertension, and 17 (47%) remained normotensive. On multivariate analysis, baseline maximum exercise systolic BP was independently associated with the mean systolic BP at follow-up (beta = 0.13, p = 0.005). In conclusion, the maximum exercise systolic BP was a predictor for chronic hypertension in patients with CoA. These findings demonstrate the clinical importance of exercise-induced hypertension and warrant additional study into the long-term consequences of exercise-induced hypertension and the potential beneficial role of early antihypertensive treatment in adult patients after CoA repair with exercise-induced hypertension. PMID- 21550581 TI - Clinical significance of prolonged QTc interval in Williams syndrome. PMID- 21550582 TI - Vascular complications in patients undergoing femoral cannulation for extracorporeal membrane oxygenation support. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a well-established treatment for severe cardiopulmonary failure. Patients undergoing ECMO support through femoral vessels are prone to vascular complications. The aim of this study was to evaluate such complications to outline basic technical principles for their prevention. METHODS: From January 2005 to December 2009, 174 patients underwent ECMO support through cannulation of the femoral vessels. The primary outcome was any vascular complication. Secondary outcomes were 30-day mortality and 1-year survival. A logistic regression analysis including ECMO duration, peripheral arterial disease, ECMO access (percutaneous versus open), and diabetes mellitus identified predictors for vascular complications. RESULTS: The venoarterial mode was used in 143 patients (82%), and venovenous in 31 patients (18%). Of the 17 (10%) observed vascular complications, 15 (88%) occurred in patients with venoarterial access, whereas 2 (12%) occurred after venovenous access (p=0.50) Two patients who had extremity ischemia required limb amputation. Thirty-day mortality and 1-year survival rates were 63% and 26%, respectively. Peripheral arterial disease was the only strong predictor of vascular complications (odds ratio, 6.95; 95% confidence interval, 1.89 to 25.59; p=0.003). Vascular complications were not associated with early or late mortality. CONCLUSIONS: The incidence of vascular complications in venovenous cannulation was low, whereas in arterial cannulation, it is still considerable. Peripheral arterial disease remains a risk factor, and early involvement of vascular surgeons for open vascular exposure or alternative vascular access sites can be recommended. Vascular complications after ECMO support are not associated with higher mortality rates. PMID- 21550583 TI - Risk factors for mortality and morbidity after the neonatal Blalock-Taussig shunt procedure. AB - BACKGROUND: Perioperative advances have led to significant improvements in outcomes after many complex neonatal open heart procedures. Whether similar improvements have been realized for the modified Blalock-Taussig shunt, the most common palliative neonatal closed-heart procedure, is not known. METHODS: Data were abstracted from The Society of Thoracic Surgeons Congenital Heart Surgery Database (2002 to 2009). Inclusion criteria were all neonates who received a modified Blalock-Taussig shunt with or without cardiopulmonary bypass, and with or without concomitant ligation of a patent ductus arteriosus. Discharge mortality was the primary end point. A composite morbidity end point one or more of the following: postoperative extracorporeal membrane oxygenation, low cardiac output, or unplanned reoperation. Associations with patient and procedural variables were assessed with univariable and multivariable analyses. RESULTS: The inclusion criteria were met by 1273 patients. The discharge mortality rate was 7.2%, and composite morbidity, as defined, was 13.1%. Primary diagnoses were classified as (1) those potentially amenable to biventricular repair (62%), (2) functionally univentricular hearts (22%), and (3) pulmonary atresia with intact ventricular septum (PA/IVS; 14%), and miscellaneous (2%). Discharge mortality stratified by primary diagnoses was PA/IVS (15.6%), functionally univentricular hearts (7.2%), and diagnoses potentially amenable to biventricular repair (5.1%). Need for preoperative ventilatory support, diagnosis of PA/IVS or functionally univentricular hearts, and any weight less than 3 kg, were risk factors for death. Preoperative acidosis or shock (resolved or persistent) and diagnosis of PA/IVS or functionally univentricular hearts were predictors of composite morbidity. Nearly 33% of the deaths occurred within 24 hours postoperatively, and 75% within the first 30 days. CONCLUSIONS: The mortality rate after the neonatal modified Blalock-Taussig shunt remains high, particularly for infants weighing less than 3 kg and those with the diagnosis of PA/IVS. PMID- 21550584 TI - Cultured epithelial grafting using human amniotic membrane: the potential for using human amniotic epithelial cells as a cultured oral epithelium sheet. AB - OBJECTIVE: Human amniotic cells are a valuable source of functional cells that can be used in various fields, including regenerative medicine and tissue engineering. The aim of this study was to investigate the utility of human amniotic epithelial (hAE) cells as a new cell source for culturing stratified epithelium sheets for intraoral grafting. METHODS: Enzymatically isolated hAE cells were submerged in a serum-free, low-calcium-supplemented MCDB 153 medium without a feeder layer. The hAE cells were seeded onto a Millicell cell culture plate insert and cultured while submerged in a high-calcium medium for 4 days. Then, they were cultured at an air-liquid interface for 3 weeks. Cultures of hAE cells proliferated at the air-liquid interface. RESULTS: After 3 weeks, the hAE cells cultivated using the air-liquid interface method lead to almost 10 continuous layers of stratified epithelium without parakeratinization or keratinization. It confirmed immunohistochemically that the presence of CK10/13 and Ki-67 positive cells were spread throughout almost all the epithelial layer, and that CK19 positive cells were expressed throughout the entire epithelial layer in the cultured hAE cell sheets. Cultured hAE cells sheets showed a staining pattern similar to that of uncultured oral mucosa: ZO-1 and occludin were located in the intercellular junctions throughout all the epithelial layers. It was suggested that the hAE sheets consisted of highly-active proliferating cells and undifferentiated cells, and had a barrier function. CONCLUSIONS: These results suggested that hAE cells may be a promising cell source for the development of stratified epithelium allograft sheets using a human cell strain. PMID- 21550585 TI - Face sensorimotor cortex and its neuroplasticity related to orofacial sensorimotor functions. AB - This review describes evidence in subprimates and primates that the face primary somatosensory cortex (face SI) and primary motor cortex (face MI) are involved in sensorimotor integration and control of orofacial motor functions that include semiautomatic movements (e.g., chewing, swallowing) and voluntary movements (e.g., jaw-opening). The review also notes that the neuroplastic capabilities of the face SI and face MI have recently been documented, and may reflect or allow for functional adaptation (or maladaptation) of the orofacial sensorimotor system to an altered oral state or oral motor behaviour. They may contribute to the processes whereby patients undergoing oral rehabilitation can (or cannot) restore the lost orofacial sensorimotor functions. Such understanding is important since pain, injuries to the oral tissues, and alterations to the dental occlusion induced by tooth loss or attrition are common occurrences in humans that may sometimes be accompanied by impaired oral sensorimotor functions. Furthermore, impaired oral sensorimotor functions are common in many neurological disorders, sometimes making the most vital functions of eating, swallowing and speaking difficult and thereby reducing the patient's quality of life. It has also been well documented that such negative consequences can be improved following oral rehabilitation as patients adapt, for example, to a new dental prosthesis aimed at restoring function. Therefore, understanding the mechanisms and cortical neuroplastic processes underlying orofacial sensorimotor functions and adaptation is also important for the development of new therapeutic strategies to facilitate recovery of patients suffering from orofacial pain and sensorimotor disorders and improve their quality of life. PMID- 21550586 TI - Increased expression of C-reactive protein gene in inflamed gingival tissues could be derived from endothelial cells stimulated with interleukin-6. AB - BACKGROUND: Epidemiological studies have suggested periodontitis as a risk factor for ischemic heart disease. High sensitive C-reactive protein (hs-CRP), a predictor of cardiovascular risk, is elevated in periodontitis patients. Therefore, local infection-induced elevation of systemic CRP could account for the relationship between the 2 diseases. However, the underlying mechanism of CRP production in the periodontal tissues has not been fully elucidated. Therefore, the aim of the present study was to clarify the mechanism of CRP production in periodontal tissues. METHODS: Gene expression of CRP in gingival biopsies was analysed by quantitative PCR. Human gingival epithelial cells (HGECs), human gingival fibroblasts (HGFBs), and human coronary artery endothelial cells (HCAECs) were characterized for CRP-producing ability by incubating with interleukin (IL)-1beta, IL-6, soluble IL-6 receptor (sIL-6R), and Porphyromonas gingivalis strain W83. RESULTS: Gene expression of CRP is significantly elevated in periodontitis lesions compared with gingivitis lesions. HCAECs, but not HGECs and HGFBs, produced CRP in response to IL-6 and IL-1beta in the presence of sIL 6R. In contrast to IL-6, the effect of IL-1beta on CRP production was indirect via induction of IL-6. IL-1beta was produced by HGECs and HGFBs with stimulation of P. gingivalis antigens. CONCLUSION: These results suggest that CRP induced locally by periodontal infection may play another role in the pathogenesis of periodontal disease, and to a much lesser extent, has the potential to modulate systemic CRP level by extra-hepatic CRP production. PMID- 21550587 TI - Effect of bone loss simulation and periodontal splinting on bone strain: Periodontal splints and bone strain. AB - OBJECTIVES: The influence of bone loss and periodontal splinting on strains in supporting bone is still not well understood. The aim of this study was to analyse the effect of bone loss and periodontal splints on strains in an anterior mandible structure. METHODS: Ten anterior mandible models were fabricated using polystyrene resin. Eighty human teeth were divided in 10 groups (right first premolar to left premolar) and embedded in simulated periodontal ligament. Strain gauges were attached to the buccal and lingual mandible surfaces. The models were sequentially tested for 7 conditions: no bone alterations and no splinting; 5mm of bone loss between canine teeth; bone loss associated with resin splint between canine teeth; bone loss with wire splint; bone loss with wire/resin splint; bone loss with extracoronal fibre-glass/resin splint; and bone loss with intracoronal fibre-glass/resin splint. Oblique loads (50, 100, and 150N) were applied on the teeth. Data were analysed using 3-way ANOVA and Scheffe's test (alpha=.05). RESULTS: Strains on buccal surface were higher than on lingual surface. Bone loss resulted in strain increase at 100 and 150N loading. Dental splinting with resin resulted in strain values similar to the control levels. CONCLUSIONS: Bone loss increased strain mainly in the buccal region. Dental splints with adhesive system and composite resin produced lower bone strains irrespective of occlusal load. PMID- 21550588 TI - Third molar development: measurements versus scores as age predictor. AB - Human third molar development is widely used to predict chronological age of sub adult individuals with unknown or doubted age. For these predictions, classically, the radiologically observed third molar growth and maturation is registered using a staging and related scoring technique. Measures of lengths and widths of the developing wisdom tooth and its adjacent second molar can be considered as an alternative registration. The aim of this study was to verify relations between mandibular third molar developmental stages or measurements of mandibular second molar and third molars and age. Age related performance of stages and measurements were compared to assess if measurements added information to age predictions from third molar formation stage. The sample was 340 orthopantomograms (170 females, 170 males) of individuals homogenously distributed in age between 7 and 24 years. Mandibular lower right, third and second molars, were staged following Gleiser and Hunt, length and width measurements were registered, and various ratios of these measurements were calculated. Univariable regression models with age as response and third molar stage, measurements and ratios of second and third molars as predictors, were considered. Multivariable regression models assessed if measurements or ratios added information to age prediction from third molar stage. Coefficients of determination (R(2)) and root mean squared errors (RMSE) obtained from all regression models were compared. The univariable regression model using stages as predictor yielded most accurate age predictions (males: R(2) 0.85, RMSE between 0.85 and 1.22 year; females: R(2) 0.77, RMSE between 1.19 and 2.11 year) compared to all models including measurements and ratios. The multivariable regression models indicated that measurements and ratios added no clinical relevant information to the age prediction from third molar stage. Ratios and measurements of second and third molars are less accurate age predictors than stages of developing third molars. PMID- 21550589 TI - A randomised controlled trial of cognitive-behaviour therapy for behavioural insomnia of childhood in school-aged children. AB - Chronic sleep problems can lead to the development of Behavioural Insomnia of Childhood - a sleep disorder involving problematic sleep-onset associations (i.e., parental presence), and resulting in impairments for children and family members. The aim of the present paper was to perform a controlled evaluation of cognitive-behaviour therapy (CBT) for Behavioural Insomnia. 42 children (M = 9.3 +/- 1.9 yrs, range 7-13 yrs, 18f, 24 m) were randomised to CBT (N = 21) or waitlist control (N = 21). CBT consisted of 6 sessions, and combined behavioural sleep medicine techniques (e.g., sleep restriction) with anxiety treatment techniques (e.g., cognitive restructuring). Compared to waitlist controls, children receiving CBT showed significant improvements in sleep latency, wake after sleep onset, and sleep efficiency (all p <= .003), but not total sleep time (p > .05). CBT was also associated with a reduction in problematic sleep associations (p <= .001), child-reported total and separation anxiety (both p <= .01), with all gains being maintained 6 months post-treatment. This is the first controlled study to demonstrate that multi-component CBT can be effective for the sleep, insomnia, and anxiety symptoms of Behavioural Insomnia of Childhood in school-aged children. Future research is needed to ascertain active treatment components. PMID- 21550591 TI - The effect of Mannose-6-Phosphate on recovery after sciatic nerve repair. AB - We have determined the effect of applying Mannose-6-Phosphate (M6P), a scar reducing agent, to a site of sciatic nerve repair. In anaesthetised C57-Black-6 mice, the left sciatic nerve was sectioned and repaired using 4 epineurial sutures. Either 100 MUl of 600 mM Mannose-6-Phosphate (29 animals), or 100 MUl of phosphate buffered saline as a placebo control (29 animals), was injected into and around the nerve repair site. A further group acted as sham-operated controls. After 6 or 12 weeks of recovery the extent of regeneration was assessed electrophysiologically and the percentage area of collagen staining at the repair site was analysed using picrosirius red and image analysis. Gait analysis was undertaken pre-operatively and at 1, 3, 6, 9 and 12 weeks postoperatively, to assess functional recovery. At 6 weeks the compound action potentials recorded from the regenerated nerves in the M6P group were significantly larger than in the placebo controls (P=0.015), and the conduction velocities were significantly faster (P=0.005), but there were no significant differences between these groups at 12 weeks. Gait analysis suggested better early functional recovery in the M6P group. In both repair groups there was a significant reduction in collagen staining between 6 and 12 weeks, suggestive of scar remodelling. We conclude that the normal scar remodelling process aids long term recovery in repaired nerves. Administration of 600 mM M6P to the nerve repair site enhances nerve regeneration and functional recovery in the early stages, and may lead to improved outcomes. PMID- 21550590 TI - Aversive imagery in panic disorder: agoraphobia severity, comorbidity, and defensive physiology. AB - BACKGROUND: Panic is characterized as a disorder of interoceptive physiologic hyperarousal, secondary to persistent anticipation of panic attacks. The novel aim of this research was to investigate whether severity of agoraphobia within panic disorder covaries with the intensity of physiological reactions to imagery of panic attacks and other aversive scenarios. METHODS: A community sample of principal panic disorder (n = 112; 41 without agoraphobia, 71 with agoraphobia) and control (n = 76) participants imagined threatening and neutral events while acoustic startle probes were presented and the eye-blink response (orbicularis oculi) recorded. Changes in heart rate, skin conductance level, and facial expressivity were also measured. RESULTS: Overall, panic disorder patients exceeded control participants in startle reflex and heart rate during imagery of standard panic attack scenarios, concordant with more extreme ratings of aversion and emotional arousal. Accounting for the presence of agoraphobia revealed that both panic disorder with and without situational apprehension showed the pronounced heart rate increases during standard panic attack imagery observed for the sample as a whole. In contrast, startle potentiation to aversive imagery was more robust in those without versus with agoraphobia. Reflex diminution was most dramatic in those with the most pervasive agoraphobia, coincident with the most extreme levels of comorbid broad negative affectivity, disorder chronicity, and functional impairment. CONCLUSIONS: Principal panic disorder may represent initial, heightened interoceptive fearfulness and concomitant defensive hyperactivity, which through progressive generalization of anticipatory anxiety ultimately transitions to a disorder of pervasive agoraphobic apprehension and avoidance, broad dysphoria, and compromised mobilization for defensive action. PMID- 21550592 TI - Neural compensation mechanisms to regulate motor output during physical fatigue. AB - Central fatigue refers to a progressive decline in the ability to activate muscles voluntarily. Although the neural mechanisms of central inhibition of the motor area during physical fatigue have been widely investigated, mechanisms supporting motor output during fatigue remain to be clarified. In this study, the compensation mechanisms to regulate physical fatigue were examined using a 160 channel whole-head-type magnetoencephalographic (MEG) system. The study group consisted of nine right-handed healthy participants. After enrollment, participants performed a fatigue-inducing physical task session in which they performed repetitive grips of the right hand at maximal voluntary contraction levels every second. Before and after the session, imagery of maximum grips of the right hand was performed for evaluation with MEG. Although beta-band event related desynchronization (ERD) level of the motor movement-evoked magnetic field in the left sensorimotor area showed a trend toward reduction after the fatigue session, the ERD level of the motor movement-evoked magnetic field in the right sensorimotor area was increased after the session. The ERD level in the prefrontal area was increased after the fatigue-inducing session. The ERD level in the left sensorimotor area was positively associated with that in the right sensorimotor area after the fatigue-inducing task session. In addition, ERD levels in the left and right sensorimotor areas had trends toward positive correlations with that in the prefrontal area. These results suggest that the ipsilateral sensorimotor and prefrontal areas are brain regions associated with compensation mechanisms to support motor output under the condition of physical fatigue. PMID- 21550593 TI - The respective and interaction effects of spinal GRs and MRs on radicular pain induced by chronic compression of the dorsal root ganglion in the rat. AB - High levels of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are colocalized in the substantia gelatinosa. This indicates that the pain pathways appear to be under a strong regulation of these receptors. However, their respective effects on pain behaviors and their interaction remain unclear. Here we show that the nociceptive behaviors induced by chronic compression of the lumbar dorsal root ganglion (CCD) are attenuated by either GR agonist dexamethasone (4=2 MUg>vehicle) or MR antagonist spironolactone (3 MUg) administered intrathecally twice daily for postoperative days 2-4, whereas the GR antagonist mifepristone (2 MUg) significantly exacerbated both mechanical hyperalgesia and thermal allodynia. Co-administration of spironolactone (3 MUg) with dexamethasone (2 MUg or 4 MUg) twice daily on days 2-4 after CCD surgery produced positive synergistic effects. Moreover, different from intrathecally administered dexamethasone alone [no difference was found between two dose levels of dexamethasone (4 MUg=2 MUg)], dexamethasone suppresses mechanical allodynia and thermal hyperalgesia in a dose-dependent manner (4 MUg>2 MUg>vehicle) when combined with spironolactone (3 MUg). These findings indicate that both central GRs and MRs play an important role in the regulation of pain behaviors and they have a perplexing interaction with each other. Spironolactone can enhance the analgesic effects of dexamethasone via complex mechanisms. PMID- 21550595 TI - Mitochondrial uncoupling agents antagonize rotenone actions in rat substantia nigra dopamine neurons. AB - Mild uncoupling of oxidative phosphorylation has been reported to reduce generation of reactive oxygen species (ROS) and therefore may be neuroprotective. We reported previously that the mitochondrial poison rotenone enhanced currents evoked by N-methyl-D-aspartate (NMDA) by a ROS-dependent mechanism in rat midbrain dopamine neurons. Thus, rotenone, which produces a model of Parkinson's disease in rodents, may increase the risk of dopamine neuron excitotoxicity. The purpose of this study was to test the hypothesis that oxidative phosphorylation uncoupling agents would antagonize the effect of rotenone on NMDA current. We used patch pipettes to record whole-cell currents under voltage-clamp (-60 mV) in substantia nigra dopamine neurons in slices of rat brain. Rotenone, NMDA and uncoupling agents were added to the brain slice superfusate. Inward currents evoked by NMDA (30 MUM) more than doubled in amplitude after slices were superfused for 30 min with 100 nM rotenone. Continuous superfusion with the uncoupling agent carbonyl cyanide-p-trifluoromethoxy-phenylhydrazone (1-3 nM) or 2,4-dinitrophenol (100 nM) significantly antagonized and delayed the ability of rotenone to potentiate NMDA currents. Coenzyme Q10 (1-10 nM), which has been reported to facilitate uncoupling protein activity, also antagonized this action of rotenone. These results suggest that mild uncoupling of oxidative phosphorylation may protect dopamine neurons against injury from mitochondrial poisons such as rotenone. PMID- 21550596 TI - A chemoenzymatic synthesis of 5a-carba-alpha-D-mannose-6-phosphate. AB - An efficient chemical synthesis of 5a-carba-alpha-D-mannose and its enzymatic elaboration to 5a-carba-alpha-D-mannose-6-phosphate, using yeast hexokinase, is described. PMID- 21550594 TI - Novel peptide ligands with dual acting pharmacophores designed for the pathophysiology of neuropathic pain. AB - The conventional design of high affinity drugs targeted to a single molecule has not resulted in clinically useful therapies for pain relief. Recent reviews have suggested that newly designed analgesic drugs should incorporate multiple targets. The distributions of cholecystokinin (CCK) and CCK receptors in the central nervous system (CNS) overlap significantly with endogenous opioid systems and can be dually targeted. CCK has been shown to act as an endogenous "anti analgesic" peptide and neuropathic pain conditions promote endogenous CCK release in CNS regions of pain modulation. Administration of CCK into nuclei of the rostral ventromedial medulla induces pronociceptive behaviors in rats. RSA 504 and RSA 601 are novel bifunctional compounds developed to target neuropathic pain by simultaneously acting as agonists at two distinct opioid receptors and antagonizing CCK receptors in the CNS. RSA 504 and RSA 601 demonstrate agonist activity in vitro and antihypersensitivity to mechanical and thermal stimuli in vivo using the spinal nerve ligation model of neuropathic pain. Intrathecal administration of RSA 504 and RSA 601 did not demonstrate antinociceptive tolerance over 7 days of administration and did not display motor impairment or sedation using a rotarod. These are the first behavioral studies that demonstrate how multi-targeted molecule design can address the pathology of neuropathic pain. These compounds with delta and MU opioid agonist activity and CCK antagonist activity within one molecule offer a novel approach with efficacy for neuropathic pain while lacking the side effects typically caused by conventional opioid therapies. PMID- 21550597 TI - The role of lic2B in lipopolysaccharide biosynthesis in Haemophilus influenzae strain Eagan. AB - Lipopolysaccharide (LPS) biosynthesis in Haemophilus influenzae involves genes from the lic2 locus that are required for chain extension from the middle heptose (HepII) of the conserved triheptosyl inner-core moiety. Lic2C initiates the process by attaching the first glucose to HepII, but the gene encoding for the enzyme adding the next beta-D-Glcp- is uncharacterized. Lic2B is the candidate glucosyltransferase; however, in previous investigations, mutation of lic2B resulted in no hexose extension from HepII, likely due to a polar effect on the lic2C gene. In this study we complemented a lic2B knock-out mutant of H. influenzae strain Eagan with a functional lic2C gene and investigated its LPS by mass spectrometry and 2D NMR spectroscopy. Lic2B was found to encode a glucosyltransferase responsible for the linkage of beta-D-Glcp-(1->4)-alpha-D Glcp-(1-> extending from O-3 of the central heptose of the triheptosyl inner-core moiety, l-alpha-D-Hepp-(1->2)-[PEtn->6]-l-alpha-D-Hepp-(1->3)-l-alpha-D-Hepp-(1 >5)-[PPEtn->4]-alpha-Kdo-(2->6)-lipid A. PMID- 21550598 TI - Regulation of NLRP3 and AIM2 inflammasome gene expression levels in gingival fibroblasts by oral biofilms. AB - Periodontal disease is an inflammatory condition that destroys the tooth supporting tissues. The inflammation is initiated by oral bacteria in the form of multi-species biofilms, and is dominated by cytokines of the IL-1 family. IL-1 activation and processing is regulated by Caspase-1, within intracellular protein complexes, known as "inflammasomes". The present study employed culture supernatants of in vitro supragingival and subgingival biofilms, to challenge human GF cultures for 6h. The gene expression of inflammasome complex components was investigated by TaqMan qPCR. NLRP1 expression was not affected, whereas NLRP2 was not expressed. Supragingival biofilm challenge increased the expression of Caspase-1, the adaptor ASC, AIM2, as well as IL-1beta and IL-18, but did not affect NLRP3 expression. Subgingival biofilm challenge enhanced Caspase-1, ASC, AIM2, IL-1beta and IL-18 gene expression at lower concentrations, followed by their down-regulation at higher concentrations, which was also evident for NLRP3 expression. Hence, supragingival and subgingival biofilms differentially regulate the gene expressions of NLRP3 and AIM2 inflammasomes and their down-stream IL-1 targets. Increased inflammasome transcription in response to supragingival biofilms is commensurate with early inflammatory events in periodontal disease, whereas decreased transcription in response to subgingival biofilms corroborates the dampening of host immune responses, in favour of pathogen survival and persistence. PMID- 21550599 TI - [Controversies in pancreatic cancer surgery]. PMID- 21550600 TI - [Intestinal obstruction due to a hernia across the broad ligament of the uterus]. PMID- 21550601 TI - [Efficacy, morbidity and mortality of surgical treatment of a primary spontaneous pneumothorax by videothorascopic talc pleurodesis]. AB - INTRODUCTION: A primary spontaneous pneumothorax (PSP) is due to the presence of air in the pleural space and is of unknown cause or aetiology. The main characteristic of this condition is its high tendency to re-occur. This study has two objectives: 1) to determine the efficacy of lung resection surgery using a videothorascope and talc pleurodesis, 2) to analyse the complications originating from the use of talc. MATERIAL AND METHODS: A review was carried out on a series of 130 PSP cases treated using videothorascopy, with or without parenchymal resection, and pleurodesis with 3g of asbestos-free talc (STERITAL(r)). Epidemiological data were collected, including the diagnostic method, surgical indication, mortality, general morbidity, and the specific morbidity due to talc pleurodesis, the number of recurrences, and their treatment. RESULTS: The patients had a mean age of 26.4 years, 84.3% were male, and 69% smoked. The surgical indication of the PSP was recurrence in 74.4% of cases. There was morbidity in 7% (9) cases, with the most frequent complication being an air leak. No specific complication, such as empyema, pachypleuritis or adult respiratory distress syndrome (ARDS, on the use of talc was recorded. The mean follow-up was 10.1 months, during which there was recurrence in 4 (3%) cases. CONCLUSIONS: PSP treatment by videothorascopic talc pleurodesis is highly effective, superior to other techniques use to produce pleurodesis, has a low general morbidity, no mortality, and no specific complications due to the talc. PMID- 21550603 TI - Methods of forward feature selection based on the aggregation of classifiers generated by single attribute. AB - Compared to backward feature selection (BFS) method in gene expression data analysis, forward feature selection (FFS) method can obtain an expected feature subset with less iteration. However, the number of FFS method is considerably less than that of BFS method. More efficient FFS methods need to be developed. In this paper, two FFS methods based on the pruning of the classifier ensembles generated by single attribute are proposed for gene selection. The main contributions are as follows: (1) a new loss function, p-insensitive loss function, is proposed to overcome the disadvantage of the margin Euclidean distance loss function in the pruning of classifier ensembles; (2) two FFS methods based on the margin Euclidean distance loss function and the p insensitive loss function, named as FFS-ACSA1 and FFS-ACSA2 respectively, are proposed; (3) the comparison experiments on four gene expression datasets show that FFS-ACSA2 obtains the best results among three FFS methods (i.e. signal-to noise ratio (SNR), FFS-ACSA1 and FFS-ACSA2), and is competitive to the famous support vector machine-based recursive feature elimination (SVM-RFE), while FFS ACSA1 is unstable. PMID- 21550604 TI - Prediction of pharmacologically induced baroreflex sensitivity from local time and frequency domain indices of R-R interval and systolic blood pressure signals obtained during deep breathing. AB - Pharmacological measurement of baroreflex sensitivity (BRS) is widely accepted and used in clinical practice. Following the introduction of pharmacologically induced BRS (p-BRS), alternative assessment methods eliminating the use of drugs were in the center of interest of the cardiovascular research community. In this study we investigated whether p-BRS using phenylephrine injection can be predicted from non-pharmacological time and frequency domain indices computed from electrocardiogram (ECG) and blood pressure (BP) data acquired during deep breathing. In this scheme, ECG and BP data were recorded from 16 subjects in a two-phase experiment. In the first phase the subjects performed irregular deep breaths and in the second phase the subjects received phenylephrine injection. From the first phase of the experiment, a large pool of predictors describing the local characteristic of beat-to-beat interval tachogram (RR) and systolic blood pressure (SBP) were extracted in time and frequency domains. A subset of these indices was selected using twelve subjects with an exhaustive search fused with a leave one subject out cross validation procedure. The selected indices were used to predict the p-BRS on the remaining four test subjects. A multivariate regression was used in all prediction steps. The algorithm achieved best prediction accuracy with only two features extracted from the deep breathing data, one from the frequency and the other from the time domain. The normalized L2-norm error was computed as 22.9% and the correlation coefficient was 0.97 (p=0.03). These results suggest that the p-BRS can be estimated from non pharmacological indices computed from ECG and invasive BP data related to deep breathing. PMID- 21550605 TI - N2O production pathways in the subtropical acid forest soils in China. AB - To date, N(2)O production pathways are poorly understood in the humid subtropical and tropical forest soils. A (15)N-tracing experiment was carried out under controlled laboratory conditions to investigate the processes responsible for N(2)O production in four subtropical acid forest soils (pH<4.5) in China. The results showed that denitrification was the main source of N(2)O emission in the subtropical acid forest soils, being responsible for 56.1%, 53.5%, 54.4%, and 55.2% of N(2)O production, in the GC, GS, GB, and TC soils, respectively, under aerobic conditions (40%-52%WFPS). The heterotrophic nitrification (recalcitrant organic N oxidation) accounted for 27.3%-41.8% of N(2)O production, while the contribution of autotrophic nitrification was little in the studied subtropical acid forest soils. The ratios of N(2)O-N emission from total nitrification (heterotrophic+autotrophic nitrification) were higher than those in most previous references. The soil with the lowest pH and highest organic-C content (GB) had the highest ratio (1.63%), suggesting that soil pH-organic matter interactions may exist and affect N(2)O product ratios from nitrification. The ratio of N(2)O N emission from heterotrophic nitrification varied from 0.02% to 25.4% due to soil pH and organic matter. Results are valuable in the accurate modeling of N2O production in the subtropical acid forest soils and global budget. PMID- 21550606 TI - Nutritional education for community dwelling older people: a systematic review of randomised controlled trials. AB - OBJECTIVES: To evaluate the effectiveness of nutritional education or advice on physical function, emotional health, quality of life, nutritional indices, anthropometric indicators, mortality, service use and costs of care in people over 65 years of age living at home. DESIGN: Systematic review of randomised controlled trials (RCTs). DATA SOURCES: PUBMED, CINAHL, PSYCINFO, the Cochrane Central Register of Controlled Trials and the National Research Register. METHODS: We included studies evaluating nutritional education or advice for people aged 65 and over living in their own homes that measured one or more of the following outcomes: physical function, emotional well being, service use, dietary change and other anthropometric indicators. Studies were assessed for risk of bias on six domains. Due to high heterogeneity, results were not pooled but are reported narratively. RESULTS: Twenty-three studies met our inclusion criteria. All but one of the interventions were delivered by health care professionals; ten were delivered by nurses. The review found evidence to suggest that nutritional education or advice can be used to positively influence diet and improve physical function. There was also evidence that some biochemical markers can be positively affected, although these are surrogate outcomes and are generally disease specific. Several studies indicated that complex interventions, with nutritional education as a component, also reduce depression. The evidence from this review on the impact on weight change was inconclusive. There was no evidence of an improvement in anxiety, quality of life, service use, costs of care or mortality. However, many studies were at moderate or high risk of bias, and for some outcomes the data were insufficient to make judgments about effectiveness. CONCLUSIONS: This review indicates that nutritional education or advice can positively affect physical function and diet, whilst complex interventions with nutritional education as a component, can reduce depression in people over 65 years who live at home. However, more research is needed to determine whether outcomes are influenced by types of intervention, morbidity, and socioeconomic circumstance of participants. RELEVANCE TO CLINICAL PRACTICE: Nutritional education, alone or as part of a complex intervention, can improve diet and physical function and may reduce depression in the over 65 s living at home. PMID- 21550608 TI - Elasticity and stress relaxation of a very small vocal fold. AB - Across mammals many vocal sounds are produced by airflow induced vocal fold oscillation. We tested the hypothesis that stress-strain and stress-relaxation behavior of rat vocal folds can be used to predict the fundamental frequency range of the species' vocal repertoire. In a first approximation vocal fold oscillation has been modeled by the string model but it is not known whether this concept equally applies to large and small species. The shorter the vocal fold, the more the ideal string law may underestimate normal mode frequencies. To accommodate the very small size of the tissue specimen, a custom-built miniaturized tensile test apparatus was developed. Tissue properties of 6 male rat vocal folds were measured. Rat vocal folds demonstrated the typical linear stress-strain behavior in the low strain region and an exponential stress response at strains larger than about 40%. Approximating the rat's vocal fold oscillation with the string model suggests that fundamental frequencies up to about 6 kHz can be produced, which agrees with frequencies reported for audible rat vocalization. Individual differences and time-dependent changes in the tissue properties parallel findings in other species, and are interpreted as universal features of the laryngeal sound source. PMID- 21550609 TI - Circumferential variations of mechanical behavior of the porcine thoracic aorta during the inflation test. AB - We developed an extension-inflation experimental apparatus with a stereo vision system and a stress-strain analysis method to determine the regional mechanical properties of a blood vessel. Seven proximal descending thoracic aortas were investigated during the inflation test at a fixed longitudinal stretch ratio of 1.35 over a transmural pressure range from 1.33 to 21.33 kPa. Four circumferential regions of each aorta were designated as the anterior (A), left lateral (L), posterior (P), and right lateral (R) regions, and the inflation test was repeated for each region of the aortas. We used continuous functions to approximate the surfaces of the regional aortic wall in the reference configuration and the deformed configuration. Circumferential stretch and stress at the four circumferential regions of the aorta were computed. Circumferential stiffness, defined as the tangent of the stress-stretch curve, and physiological aortic stiffness, named pressure-strain elastic modulus, were also computed for each region. In the low pressure range, the stress increased linearly with increased stretch, but the mechanical response became progressively stiffer in the high-pressure range above a transition point. At a transmural pressure of 12.00 kPa, mean values of stiffness were 416+/-104 kPa (A), 523+/-99 kPa (L), 634+/-91 kPa (P), and 489+/-82 kPa (R). The stiffness of the posterior region was significantly higher than that of the anterior region, but no significant difference was found in pressure-strain elastic modulus. PMID- 21550610 TI - Evaluation of residual stresses due to bone callus growth: a computational study. AB - Mechanical environment in callus is determinant for the evolution of bone healing. However, recent mechanobiological computational works have underestimated the effect that growth exerts on the mechanical environment of callus. In the present work, we computationally evaluate the significance of growth-induced stresses, commonly called residual stresses, in callus. We construct a mechanobiological model of a callus in the metatarsus of a sheep in two different stages: one week and four weeks after fracture. The magnitude of stresses generated during callus growth is compared with the magnitude of stresses when only external loads are applied to the callus. We predict that residual stresses are relevant in some areas, mainly located at the periosteal side far from the fracture gap. Therefore, the inclusion of these residual stresses could represent a significant impact on the callus growth and predict a different evolution of biological processes occurring during bone healing. PMID- 21550611 TI - Computation of hemodynamics in the left coronary artery with variable angulations. AB - The purpose of this study was to investigate the hemodynamic effect of variations in the angulations of the left coronary artery, based on simulated and realistic coronary artery models. Twelve models consisting of four realistic and eight simulated coronary artery geometries were generated with the inclusion of left main stem, left anterior descending and left circumflex branches. The simulated models included various coronary artery angulations, namely, 15 degrees , 30 degrees , 45 degrees , 60 degrees , 75 degrees , 90 degrees , 105 degrees and 120 degrees . The realistic coronary angulations were based on selected patient's data with angles ranging from narrow angles of 58 degrees and 73 degrees to wide angles of 110 degrees and 120 degrees . Computational fluid dynamics analysis was performed to simulate realistic physiological conditions that reflect the in vivo cardiac hemodynamics. The wall shear stress, wall shear stress gradient, velocity flow patterns and wall pressure were measured in simulated and realistic models during the cardiac cycle. Our results showed that a disturbed flow pattern was observed in models with wider angulations, and wall pressure was found to reduce when the flow changed from the left main stem to the bifurcated regions, based on simulated and realistic models. A low wall shear stress gradient was demonstrated at left bifurcations with wide angles. There is a direct correlation between coronary angulations and subsequent hemodynamic changes, based on realistic and simulated models. Further studies based on patients with different severities of coronary artery disease are required to verify our results. PMID- 21550612 TI - Self-assembly of short amyloidogenic peptides at the air-water interface. AB - Short peptide stretches in amyloidogenic proteins can form amyloid fibrils in vitro and have served as good models for studying amyloid fibril formation. Recently, these amyloidogenic peptides have gained considerable attention, as non amyloid ordered structures can be obtained from these peptides by carefully tuning the conditions of self-assembly, especially pH, temperature and presence of organic solvents. We have examined the effect of surface pressure on the self assembled structures of two amyloidogenic peptides, Pbeta(2)m (Ac-DWSFYLLYYTEFT am) and AcPHF6 (Ac-VQIVYK-am) at the air-water interface when deposited from different solvents. Both the peptides are surface-active and form Thioflavin T (ThT) positive structures at the air-water interface. There is considerable hysteresis in the compression and expansion isotherms, suggesting the occurrence of structural rearrangements during compression. Preformed Pbeta(2)m fibrillar structures at the air-water interface are disrupted as peptide is compressed to lower molecular areas but restored if the film is expanded, suggesting that the process is reversible. AcPHF6, on the other hand, shows largely sheet-like structures at lower molecular areas. The solvents used for dissolution of the peptides appear to influence the nature of the aggregates formed. Our results show that like hydrostatic pressure, surface pressure can also be utilized for modulating the self-assembly of the amyloidogenic and self-assembling peptides. PMID- 21550607 TI - Associations of birth weight with serum long chain polyunsaturated fatty acids in adolescents; the HELENA study. AB - OBJECTIVES: Nutritional factors in early life may have long-term physiologic effects in humans. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) play important roles in protecting against cardiovascular disease (CVD) risk. Our aim was to examine the association of birth weight (BW) with serum long chain polyunsaturated fatty acids (LCPUFA) profile in adolescents. SUBJECTS AND METHODS: A total of 772 European adolescents (56.3% females) aged 14.7 +/- 1.2 years were included in this study. Information on BW and gestational age was obtained from parental records. DHA, EPA and arachidonic acid (AA) concentrations were measured in serum phospholipids. Alfa-linolenic (ALA), linoleic (LA), AA, EPA and DHA intakes assessed by a computer based 24h dietary recall. Gender, gestational age, pubertal status, body mass index, center and total energy and LCPUFA intakes were used as confounders in all the analyses. RESULTS: BW was significantly associated with serum DHA and EPA (both adjusted P<0.05) independently of potential confounders including their main dietetic source. We did not observe any significant relationship between BW and serum AA levels. CONCLUSIONS: Our findings suggest that early metabolic changes, as a result from prenatal environmental influences, could affect long chain polyunsaturated fatty acid metabolism later in life. These results may contribute to explain the relationship between early nutrition and growth and later metabolic disorders as CVD. PMID- 21550613 TI - Deontic and epistemic reasoning in children. AB - It is widely accepted that adults show an advantage for deontic over epistemic reasoning. Two published studies (Cummins, 1996b; Harris and Nunez, 1996, Experiment 4) found evidence of this "deontic advantage" in preschool-aged children and are frequently cited as evidence that preschoolers show the same deontic advantage as adults. However, neither study has been replicated, and it is not clear from either study that preschoolers were showing the deontic advantage under the same conditions as adults. The current research investigated these issues. Experiment 1 attempted to replicate both Cummins's and Harris and Nunez's studies with 3- and 4-year-olds (N = 56), replicating the former with 4 year-olds and the latter with both 3- and 4-year-olds. Experiment 2 modified Cummins's task to remove the contextual differences between conditions, making it more similar to adult tasks, finding that 4-year-olds (n = 16) show no evidence of the deontic advantage when no authority figure is present in the deontic condition, whereas both 7-year-olds (n = 16) and adults (n = 28) do. Experiment 3 removed the authority figure from the deontic condition in Harris and Nunez's task, again finding that 3- and 4-year-olds (N = 28) show no evidence of the deontic advantage under these conditions. These results suggest that for preschoolers, the deontic advantage is reliant on particular contextual cues such as the presence of an authority figure, in the deontic condition. By 7 years of age, however, children are reasoning like adults and show evidence of the advantage when no such contextual cues are present. PMID- 21550614 TI - Effects of maternal-fetal hyperoxygenation on aortic arch flow in a late gestation human fetus with closed oval foramen at risk for coarctation. PMID- 21550616 TI - Bovine trypanosomosis in the Upper West Region of Ghana: entomological, parasitological and serological cross-sectional surveys. AB - Baseline surveys were conducted in the Upper West Region of Ghana to assess the distribution and densities of tsetse species, as well as the prevalence of bovine trypanosomosis. The entomological survey was designed to cover the suitable tsetse habitats along the three main rivers in the study area (i.e. Black Volta, Kulpawn and Sissili). Results indicated the presence of Glossina tachinoides in all three river basins, whilst Glossina palpalis gambiensis was only found close to the southern limit of the study area. A random sampling of 1800 cattle of the West African Short Horn, Sanga and Zebu breeds from 36 randomly selected grid cells covering the study area showed substantial differences between parasitological and serological prevalences. The average parasitological prevalence was estimated at 2.5% (95% CI: 1.06-5.77) with the majority of the infections due to Trypanosoma vivax. Most of the infected cattle were found close to the major river systems. The serological prevalence, measured using Enzyme Linked Immunosorbent Assay (ELISA), test was 19% (95% CI: 14.03-25.35). Cattle with anti-trypanosomal antibodies were also found throughout the study area. PMID- 21550615 TI - Metabolic fingerprinting of Leontopodium species (Asteraceae) by means of 1H NMR and HPLC-ESI-MS. AB - The genus Leontopodium, mainly distributed in Central and Eastern Asia, consists of ca. 34-58 different species. The European Leontopodium alpinum, commonly known as Edelweiss, has a long tradition in folk medicine. Recent research has resulted in the identification of prior unknown secondary metabolites, some of them with interesting biological activities. Despite this, nearly nothing is known about the Asian species of the genus. In this study, we applied proton nuclear magnetic resonance (1H NMR) spectroscopy and liquid chromatography-mass spectrometry (LC MS) metabolic fingerprinting to reveal insights into the metabolic patterns of 11 different Leontopodium species, and to conclude on their taxonomic relationship. Principal component analysis (PCA) of 1H NMR fingerprints revealed two species groups. Discriminators for these groups were identified as fatty acids and sucrose for group A, and ent-kaurenoic acid and derivatives thereof for group B. Five diterpenes together with one sesquiterpene were isolated from Leontopodium franchetii roots; the compounds were described for the first time for L. franchetii: ent-kaur-16-en-19-oic acid, methyl-15alpha-angeloyloxy-ent-kaur-16-en 19-oate, methyl-ent-kaur-16-en-19-oate, 8-acetoxymodhephene, 19-acetoxy-ent-kaur 16-ene, methyl-15beta-angeloyloxy-16,17-epoxy-ent-kauran-19-oate. In addition, differences in the metabolic profile between collected and cultivated species could be observed using a partial least squares-discriminant analysis (PLS-DA). PCA of the LC-MS fingerprints revealed three groups. Discriminating signals were compared to literature data and identified as two bisabolane derivatives responsible for discrimination of group A and C, and one ent-kaurenoic acid derivative, discriminating group B. A taxonomic relationship between a previously unidentified species and L. franchetii and Leontopodium sinense could be determined by comparing NMR fingerprints. This finding supports recent molecular data. Furthermore, Leontopodium dedekensii and L. sinense, two closely related species in terms of morphology and DNA-fingerprints, could be distinguished clearly using 1H NMR and LC-MS metabolic fingerprinting. PMID- 21550617 TI - Immunohistochemical detection of the orexin system in the placenta of cats. AB - The aim of the present study was to investigate the presence and distribution of cells containing orexin A (OXA), and orexin type 1 and 2 receptors (OX1R and OX2R, respectively) in the feline placenta by means of immunohistochemical technique. OXA was identified in several decidual and syncytiotrophoblastic cells present in the lamellar portion of the placenta. In the same placental structures, few decidual and syncytiotrophoblastic cells showed the presence of OX1R-like immunoreactivity. Characteristically, immunopositivity for OX2R, but not for OX1R, was evidenced in the cells of the glandular layer. The orexinic system was not expressed in the uterine structures that were not engaged by the chorion. Our results provide the first evidence of the presence of a placental orexinic system in a mammalian species. Orexin A and both OX1R and OX2R are unequally distributed within the cat placenta. Local OXA production and the presence of specific receptors, differentially expressed in the placental structures of the cat, suggest that the orexinic system may participate in placental growth and development as well as in the regulation of its steroidogenic capacity via endocrine, paracrine and/or autocrine mechanisms. PMID- 21550618 TI - Cloning and tissues expression of the pig CYP1B1 and CYP2J34. AB - Cytochrome P450 (CYP) 1B1 and CYP2J have been studied in various mammals, but not in pig. The sequences encoding pig CYP1B1 and CYP2J34 were isolated from liver cDNA by RACE and sequenced. The open reading frames of pig CYP1B1 showed a higher sequence homology to bovine 1B1 (89%) than to dog 1B1 (88%) or to human 1B1 (85%). On the other hand, the coding sequence of pig CYP2J34 showed a similar homology (83-85%) to CYP2J of these species. From the substrate recognition sites (SRS 1-6) analysis of the deduced proteins, it was found that the porcine CYP1B1, unlike CYP2J34, completely shared the six SRS with the bovine counterpart. RT-PCR analysis of CYP1B1 and CYP2J34 expression in ten porcine tissues revealed that CYP1B1 was principally expressed in adrenal gland, whereas CYP2J34 was predominantly expressed in small intestine. These results further support the pig as an useful model for human. PMID- 21550619 TI - Usefulness of detection of dengue NS1 antigen alongside IgM plus IgG, and concurrent platelet enumeration during an outbreak. PMID- 21550620 TI - Enhanced neogenic potential of Panc-1 cells supplemented with human umbilical cord blood serum--An alternative to FCS. AB - The promise(s) of using Fetal Calf Serum (FCS) as a supplement for the maintenance of cell cultures has been well documented. However, FCS forms the xenogenic source for any human derived cells/organ and limits its application. Recently, the usage of human umbilical cord blood serum (hUCBS) for maintenance of mesenchymal cells has been supportive. In the present study we investigated the effects of hUCBS and FCS on the proliferation (viability, proliferative) and its differentiation potential (DTZ staining, immunofluroscence) to generate islet like cellular aggregates (ICAs) using the human derived Panc-1 cell lines. A comparative analysis of hUCBS and FCS for each parameter demonstrated that hUCBS supplemented media was better for proliferation and differentiation of the Panc-1 cells. The ICAs obtained from hUCBS primed cultures showed a higher yield, increased islet size, and showed an increase for insulin staining compared to FCS. We suggest that hUCBS can be explored as an alternate serum supplement for FCS, making it more feasible in cell systems of human derived origin and can also find its application for the human transplantation programmes. PMID- 21550621 TI - Egg structure of Zorotypus caudelli Karny (Insecta, Zoraptera, Zorotypidae). AB - The structural features of eggs of Zorotypus caudelli Karny are described in detail. The egg is elliptic with long and short diameters of 0.6 and 0.3 mm respectively, and creamy white. The egg shows a honeycomb pattern on its surface, without any specialized structures for hatching such as an operculum or a hatching line. The fringe formed by a fibrillar substance secreted after the completion of the chorion encircles the lateral surface. The egg layer is composed of an exochorion, an endochorion, and a vitelline envelope. The exochorion and endochorion are electron-dense and homogeneous in structure. The exochorion shows a perforation of numerous branching aeropyles. The exo- and endochorion are connected by numerous small columnar structures derived from the latter. The vitelline envelope is very thin and more electron-dense than the chorion. A pair of micropyles is present at the equator on the dorsal side of the egg. Originating at the micropyle, the micropylar canal runs through the chorion obliquely. The structural features of the eggs of Zoraptera were compared with those of other polyneopteran and paraneopteran orders. PMID- 21550622 TI - Investigation of the function of the putative self-association site of Epstein Barr virus (EBV) glycoprotein 42 (gp42). AB - The Epstein-Barr virus (EBV) glycoprotein 42 (gp42) is a type II membrane protein essential for entry into B cells but inhibits entry into epithelial cells. X-ray crystallography suggests that gp42 may form dimers when bound to human leukocyte antigen (HLA) class II receptor (Mullen et al., 2002) or multimerize when not bound to HLA class II (Kirschner et al., 2009). We investigated this self association of gp42 using several different approaches. We generated soluble mutants of gp42 containing mutations within the self-association site and found that these mutants have a defect in fusion. The gp42 mutants bound to gH/gL and HLA class II, but were unable to bind wild-type gp42 or a cleavage mutant of gp42. Using purified gp42, gH/gL, and HLA, we found these proteins associate 1:1:1 by gel filtration suggesting that gp42 dimerization or multimerization does not occur or is a transient event undetectable by our methods. PMID- 21550624 TI - Degradation of 2,4,5-trichlorophenoxyacetic acid by a novel Electro-Fe(II)/Oxone process using iron sheet as the sacrificial anode. AB - A novel electrochemically enhanced advanced oxidation process for the destruction of organic contaminants in aqueous solution is reported in this study. The process involves the use of an iron (Fe) sheet as sacrificial anode and a graphite bar as cathode. In the oxidation process, once an electric current is applied between the anode and the cathode, a predetermined amount of Oxone is added to the reactor. Ferrous ions generated from the sacrificed Fe anode mediate the generation of highly powerful radicals (SO(4)(*-)) through the decomposition of Oxone. The coupled process of Fe(II)/Oxone and electrochemical treatment (Electro-Fe(II)/Oxone) was evaluated in terms of 2,4,5-Trichlorophenoxyacetic acid degradation in aqueous solution. Various parameters were investigated to optimize the process, including applied current, electrolyte and Oxone concentration. In addition, low solution pH facilitates the system performance due to the dual effects of weak Fenton reagent generation and persulfate ions generation, whereas the system performance was inhibited at basic pH levels through non-radical self-dissociation of Oxone and the formation of ferric hydroxide precipitates. Furthermore, the active radicals involved in the Electro Fe(II)/Oxone process were also identified. The Electro-Fe(II)/Oxone process demonstrates a very high 2,4,5-T degradation efficiency (over 90% decay within 10 min), which justifies the novel Electro-Fe(II)/Oxone a promising treatment process for herbicide removal in water. PMID- 21550623 TI - Occupancy of chromatin organizers in the Epstein-Barr virus genome. AB - The human CCCTC-binding factor, CTCF, regulates transcription of the double stranded DNA genomes of herpesviruses. The architectural complex cohesin and RNA Polymerase II also contribute to this organization. We profiled the occupancy of CTCF, cohesin, and RNA Polymerase II on the episomal genome of the Epstein-Barr virus in a cell culture model of latent infection. CTCF colocalizes with cohesin but not RNA Polymerase II. CTCF and cohesin bind specific sequences throughout the genome that are found not just proximal to the regulatory elements of latent genes, but also near lytic genes. In addition to tracking with known transcripts, RNA Polymerase II appears at two unannotated positions, one of which lies within the latent origin of replication. The widespread occupancy profile of each protein reveals binding near or at a myriad of regulatory elements and suggests context-dependent functions. PMID- 21550625 TI - Effects of hydrodynamics on the distribution of trace persistent organic pollutants and macrobenthic communities in Bohai Bay. AB - In recent years, the rapid economic development along Bohai Bay, has brought out continuous increasing of the pollution loads in the Bohai Sea, especially by the large coastal reclamation project, Tianjin Binhai New Area. In the period of 2007 2009, we collected the sediments of the main rivers, estuaries, intertidal zone, and near-shore area of Bohai Bay, and Macrobenthos associated with the marine sediments to assess the influence of hydrodynamics in the coastal environment on the pattern of trace contaminants and the macrobenthic community. Based on data derived from these samples, the levels of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) in sediments followed the order PAHs>OCPs>PCBs>PBDEs. The higher concentrations of PCBs, OCPs, PAHs and PBDEs were found in the estuarine and near-shore environment of the Dagu Drainage River. The spatial distribution of OCPs was different to that of PCBs due to the direction of the velocity field of Bohai Bay in its old and new topography, and the higher water-solubility of OCPs than that of PCBs. The results of the Pearson correlation and the PCA indicate that the medium diameter (MD) of sediments was the predominant factor influencing the distribution of PCBs and OCPs, most sampling sites were characterized mainly by TOC of sediments and biomass of macrobenthos. The results indicate that the distribution of trace contaminants and macrobenthic community in Bohai Bay are mainly affected by the hydrodynamic conditions. PMID- 21550626 TI - A simple McGowan specific volume correction for branching in hydrocarbons and its consequences for some other solvation parameter values. AB - Differences in molecular properties between linear and branched alkanes as well as between compounds with branched alkyl groups is of relevance due to the large number of branched isomers of environmentally relevant compounds (e.g. fuels, fuel additives, surfactants). For branched alkane vapor pressures, the McGowan specific volume is a poor predictor. Therefore, in this study a correction on the McGowan specific volume is derived in terms of the number of branches and the number of pairs of vicinal branches to improve the prediction of branched alkane vapor pressures. This branching correction also brought branched/alkane solvent accessible volumes, octanol/water partition coefficients, air/hexadecane partition coefficients, and aqueous solubilities as well as alkyl-branched substituted aliphatic hydrocarbon air/hexadecane partition coefficients more in line with corresponding linear hydrocarbon properties when compared on a McGowan specific volume basis. Even for air-hexadecane partition coefficients of substituted aliphatic hydrocarbons with substituents at non-terminal carbons, application of the branching correction to the carbon bearing the substituent caused these partition coefficients to be more in line with those for linear compounds. Values for the Abraham A and B solvation parameters for nonlinear aliphatic ethers, amines, and alcohols, recalculated using branching corrected McGowan specific volumes, turned out to be closer to chemical expectations based on linear aliphatic ether, amine and alcohol values compared to previously reported experimental values obtained using uncorrected McGowan specific volumes. A comparison of alkylbenzene and alkene partition coefficient estimates from two different linear solvation energy relations, one containing a McGowan specific volume term and one without such a term, suggests that no branching correction is needed for alkyl groups at sp2 carbons. The main advantage of using branching corrected McGowan specific volumes is that the values of other solvation parameters become chemically more consistent. PMID- 21550627 TI - Are exploited mangrove molluscs exposed to Persistent Organic Pollutant contamination in Senegal, West Africa? AB - The surface sediments, two bivalves (Arca senilis and Crassostera gasar) and three gastropods (Conus spp., Hexaplex duplex and Pugilina morio) from two Senegalese stations, Falia (Sine-Saloum Estuary) and Fadiouth (Petite Cote), were analyzed for their pollutant organic persistent contamination (polychlorinated biphenyls PCBs; organochlorinated pesticides OCPs; polybrominated diphenyl ethers PBDEs). Results revealed significant levels of PCBs, DDTs and lindane in mangrove sediments ranging from 0.3 to 19.1, 0.3 to 15.9, and 0.1 to 1.9 ng g(-1) d.w., respectively. Among the other POPs analysed, only hexachlorobenzene, heptachlor and trans-nonachlor for OCPs, as well as BDE47 and BDE99 congeners for PBDEs were detected at very low concentrations, generally not of concern. POP levels and patterns were in good accordance with literature data available for other tropical developing countries. A seasonal quantitative difference was highlighted with higher levels of PCBs and DDTs in sediments after the wet season, likely due to the strong wash-out of residues from inland to the marine ecosystems during the rainy season. The observed pattern of DDT and its metabolites pointed out probable recent applications of DDT for public health emergencies in Senegal. Exploited molluscs were exposed to the same POP compounds as those measured in sediments. They presented OCP levels within the same range as in sediments, while significant higher concentrations of PCBs were observed in shellfish soft tissues revealing a higher bioaccumulation potential mainly due to the lipophilicity of these compounds. Finally, the influence of the reproduction cycle on POP levels through lipid content variations was highlighted, minimizing potential differences in POP bioaccumulation between shellfish species. From an ecotoxicological and public health point of view, results from this study revealed that POPs in sediments from the Petite Cote and the Sine-Saloum Estuary would not cause toxic effects and impairments in molluscs from these regions, and that no potential risk exists for human, especially local populations, through mangrove shellfish consumption. PMID- 21550628 TI - Assessment of thyroid hormone activity of halogenated bisphenol A using a yeast two-hybrid assay. AB - The thyroid hormone agonist/antagonist activities of halogenated derivatives of bisphenol A (BPA) were assessed using a yeast two-hybrid assay incorporating the human thyroid hormone alpha (TRalpha), both with and without possible metabolic activation by rat liver S9 preparation. In the absence of the rat liver S9 preparation, 3,3',5,5'-tetrabromobisphenol A (TBBPA), 3,3',5,5' tetrachlorobisphenol A (TCBPA), and 3,3',5-trichlorobisphenol A (3,3',5-triClBPA) exhibited agonist activity, whereas 3-chlorobisphenol A (3-ClBPA), 3,5 dichlorobisphenol A (3,5-diClBPA), 3,3'-dichlorobisphenol A (3,3'-diClBPA), and BPA did not. The activities of TBBPA and TCBPA increased markedly (7.6-fold and 3.1-fold, respectively) after their metabolic activation with the rat liver S9 preparation. TBBPA, TCBPA, and 3,3',5-triClBPA inhibited the binding of triiodothyronine (T3) to TRalpha at 2*10(-5) M without rat liver S9 treatment and 4*10(-6) M with rat liver S9 treatment, demonstrating their T3 antagonist activity. These results revealed that metabolic activation by rat liver S9 significantly increased the agonist/antagonist potential of some halogenated BPAs. PMID- 21550629 TI - Production and use of DDT containing antifouling paint resulted in high DDTs residue in three paint factory sites and two shipyard sites, China. AB - This study provides the first intensive investigation of Dichlorodiphenyltrichloroethanes (DDT) distribution in typical paint factories and shipyards in China where DDT containing antifouling paint were mass produced and used respectively. DDTs were analyzed in soil, sludge and sediment samples collected from three major paint factories and two shipyards. The results showed that the total DDTs concentrations detected in paint factory and shipyard sites ranged from 0.06 to 8387.24 mg kg(-1). In comparison with paint factory sites, the shipyard sites were much more seriously contaminated. However, for both kinds of sites, the DDTs level was found to be largely affected by history and capacity of production and use of DDT containing antifouling paint. (DDE+DDD)/DDT ratios indicated that DDT containing antifouling paint could serve as important fresh input sources for DDTs. It can be seen that most samples in shipyards were in ranges where heavy contamination and potential ecological risk were identified. PMID- 21550630 TI - Levels of chemical and microbiological pollutants in the vicinity of a waste incineration plant and human health risks: temporal trends. AB - In 2007, a program was initiated to monitor air levels of volatile organic compounds (VOCs) and bioaerosols in the vicinity of a municipal solid waste incinerator (MSWI) (Tarragona, Catalonia, Spain). To investigate the temporal trends of chemical and microbiological pollutants, four 6-monthly campaigns were performed. Air samples were collected at different distances and directions from the facility, as well as in reference sites. In general terms, the concentrations of microbiological agents were very similar to those found in urban zones worldwide. The seasonal evaluation of the results showed higher levels of gram negative bacteria in winter, contrasting with the increase of the airborne amount of total bacteria in summer. On the other hand, the concentrations of VOCs (mean range: 7.6-18.2 MUg m(-3)) were typical of suburban zones. The current exposure to those compounds should not mean additional health risks for the population living nearby. PMID- 21550631 TI - Bioconcentration and depuration of endosulfan sulfate in mosquito fish (Gambusia affinis). AB - Endosulfan is an insecticide which has been widely used in agriculture. The technical grade material consists of two isomers (alpha and beta). Under natural environmental conditions, endosulfan is metabolized through oxidation and the main metabolite in the environment is endosulfan sulfate. Most ecotoxicology research has been conducted with technical grade endosulfan to determine effects on non-target aquatic organisms. Little data on the effects of endosulfan sulfate on aquatic organisms are available in the literature. This study characterizes endosulfan sulfate bioconcentration and depuration in mosquito fish (Gambusia affinis). During the study, G. affinis was exposed to an environmentally relevant endosulfan sulfate concentration of 0.25 MUg L(-1) for 5 weeks (uptake phase) followed by a 3-week period (depuration phase) in clean water. This study found that G. affinis bioconcentrated endosulfan sulfate. During the exposure phase, fish tissue concentrations of endosulfan sulfate increased with time up to 730 MUg kg(-1) dw or 215 MUg kg(-1) ww. The bioconcentration data followed Michaelis Menten kinetics better than the one-compartment first order kinetics (1-CFOK). Using these models, the bioconcentration factors for endosulfan sulfate-exposed G. affinis were from 687 to 888 L kg(-1) in wet weight or 2263 to 2936 L kg(-1) in dry weight. During the depuration phase, endosulfan sulfate concentrations in tissue significantly decreased and the data followed first order kinetics. The half-life of endosulfan sulfate in G. affinis was about 9 d. There was no significant difference in standard length or weight between control and exposed fish. The growth data followed the von Bertalanffy growth model. However, the condition factor of exposed fish increased with time during the exposure phase. PMID- 21550632 TI - PCDD/F enviromental impact from municipal solid waste bio-drying plant. AB - The present work indentifies some environmental and health impacts of a municipal solid waste bio-drying plant taking into account the PCDD/F release into the atmosphere, its concentration at ground level and its deposition. Four scenarios are presented for the process air treatment and management: biofilter or regenerative thermal oxidation treatment, at two different heights. A Gaussian dispersion model, AERMOD, was used in order to model the dispersion and deposition of the PCDD/F emissions into the atmosphere. Considerations on health risk, from different exposure pathways are presented using an original approach. The case of biofilter at ground level resulted the most critical, depending on the low dispersion of the pollutants. Suggestions on technical solutions for the optimization of the impact are presented. PMID- 21550633 TI - Pendrin mediates uptake of perchlorate in a mammalian in vitro system. AB - Perchlorate is a known endocrine disruptor present in groundwater, vegetables and dairy food products in many regions of the United States. It interferes with the uptake of iodide into the thyrocyte by the sodium-iodide symporter at the basolateral surface, thus potentially disrupting the synthesis of thyroid hormone. Because transport of iodide from the thyroid follicular cells to the follicular lumen is mediated by the protein pendrin at the apical surface, we hypothesized that perchlorate may also interact with this protein. Therefore, HeLa cells were transfected with the human SLC26A4 gene, which encodes pendrin, to generate an in vitro mammalian system expressing the recombinant pendrin protein (HeLa-PDS). The HeLa-PDS cells, along with untransfected cells, were then cultured in presence of iodide and/or perchlorate. Intracellular levels of these two chemicals were measured by ion chromatography tandem mass spectrometry. Results from this study show that iodide and perchlorate uptake increases significantly in HeLa-PDS cells as compared to untransfected cells. Thus, recombinant HeLa cells expressing pendrin protein accumulate iodide and perchlorate intracellularly, indicating that pendrin is involved in the uptake of perchlorate. Additional results from this study suggest that iodide and perchlorate competitively inhibit each other for uptake by pendrin. The ability of perchlorate to compete with iodide for uptake by both basal and apical transporters may increase the potential of perturbation of thyroid homeostasis and therefore the estimated risk posed to susceptible human populations. PMID- 21550634 TI - Cu/Zn- and Mn-superoxide dismutase (SOD) from the copepod Tigriopus japonicus: molecular cloning and expression in response to environmental pollutants. AB - Superoxide dismutase (SOD) is an important antioxidant enzyme which catalyzes conversion of superoxide to oxygen and hydrogen peroxide in aerobic organisms. Here, we cloned and sequenced the full-length cDNA and genomic DNA of two SODs from the copepod, Tigriopus japonicus: copper/zinc SOD (TJ-Cu/Zn-SOD) and manganese SOD (TJ-Mn-SOD). To define whether TJ-Mn-SOD is a cytosolic or a mitochondrial protein, a phylogenetic analysis was performed. The genomic structure of both TJ-SOD genes was determined with the promoter region sequences. In order to investigate their potential role in response to environmental pollutants, T. japonicus were treated with heavy metal (copper, zinc, and silver; 0, 10, 25, 50, and 100 MUg L(-1)) and industrial chemicals (benzo[alpha]pyrene, 4 nonylphenol, and tributyltin; 0, 1, 5, 10, and 20 MUg L(-1)) for 96 h. Subsequently, the TJ-Cu/Zn-SOD and TJ-Mn-SOD mRNA level was measured with quantitative real-time RT-PCR along with total SOD activity. The deduced amino acid residues of TJ-Cu/Zn-SOD and TJ-Mn-SOD possessed evolutionary conserved domains that are required for metal binding and Cu/ZnSOD-conserved signature sequences. The phylogenetic analysis revealed that TJ-Mn-SOD was closely clustered to mitochondrial Mn-SOD of another copepod, Lepeophtheirus salmonis. TJ Cu/Zn-SOD gene had four exons and three introns, while the TJ-Mn-SOD gene consisted of two exons interrupted by one intron. In the 5'-flanking region of TJ Cu/Zn-SOD and TJ-Mn-SOD, we observed several transcription regulatory elements such as p53, XRE, MRE, and ERE-half sites. In the response to heavy metals, Cu, Zn, and Ag, both TJ-Cu/Zn-SOD and TJ-Mn-SOD transcript levels along with enzyme levels were significantly increased at high concentrations (50 MUg L(-1) and 100 MUg L(-1)). Particularly, in the Cu- and Ag-exposed group, the expression of TJ Mn-SOD mRNA was regulated more sensitively than the TJ-Cu/Zn-SOD mRNA level, indicating that the chemical susceptibility would be not correlated with the form of chemicals. B[a]P treatment showed a significant increase in the expression of both TJ-SODs mRNA level and enzyme level from 5 MUg L(-1) concentration, while TBT decreased its expression at high concentrations (10 MUg L(-1) and 20 MUg L( 1)). 4-NP increased both TJ-SODs mRNA level at 1 MUg L(-1) concentration, and then inhibited its expression from 5 MUg L(-1) concentration to a lower level than the control. This finding suggests that TJ-Cu/Zn-SOD and TJ-Mn-SOD would be an inducible gene upon exposure to heavy metals and B[alpha]P, and could be used as a potential biomarker for the risk assessment of these environmental pollutants. This is the first report to elucidate response of SOD to environmental pollutants in copepods. Therefore, this study would give a clue to better understand the mode of action of antioxidant genes and enzymes under oxidative stress in marine invertebrates. PMID- 21550635 TI - Bacterially mediated mineralisation processes lead to biodeterioration of artworks in Maltese catacombs. AB - Mineral structures formed by bacterial and microalgal biofilms growing on the archaeological surface in Maltese hypogea were studied using Energy Dispersive X Ray Spectroscopy (EDS) coupled to Environmental Scanning Electron Microscopy (ESEM), X-ray micro-diffraction (XRD) and X-ray fluorescence (XRF). These techniques have shown that mineral structures having different morphologies and chemical composition were associated with the microorganisms in the subaerophytic biofilm. Salt efflorescences and mineral deposits on the archaeological surface were often formed from gypsum (CaSO(4)?2H(2)O), halite (NaCl) and calcite (CaCO(3)). Biogenic carbonates produced by microbial activities were a common occurrence. These assumed different forms, such as the production of mineral coats around cyanobacterial sheaths and the occurrence of calcite fibres with different morphologies on the surface of the biofilms. Moreover, vaterite (CaCO(3)) spherulites which appeared hollow in cross-section were observed. The presence of struvite was recorded from one catacomb site. These investigations have facilitated the study of the neoformation of metastable minerals by microbially mediated processes, which potentially contribute to a better understanding of the biodeterioration of artworks in Maltese palaeo-Christian catacombs. PMID- 21550636 TI - Thermal ablation vs surgery for localized kidney cancer: a Surveillance, Epidemiology, and End Results (SEER) database analysis. AB - OBJECTIVE: To evaluate contemporary national practice pattern trends in the use of thermal ablation (radiofrequency ablation and cryoablation) in the management of stage I renal cell carcinoma (RCC), and the factors that lead to using thermal ablation (TA) vs partial (PN) or radical nephrectomy (RN) in the United States. METHODS: Within the Surveillance, Epidemiology and End Results (SEER) database, we identified subjects with T1-N0M0 RCC treated with either PN, RN, or TA between 2004 and 2007. Proportions, trends, and multivariable logistic regression models tested the predictors of the use of TA. RESULTS: In total, 15,145 patients underwent a procedure for an RCC that was organ-confined and <=7 cm. Of these, 578 underwent TA, 4402 underwent PN, and 10,165 underwent RN. On unadjusted analyses, patients who received TA were more likely to be older, single, have smaller tumor size, be diagnosed in more recent years, and have more unspecified histologic subtype and tumor grade. In multivariable adjusted analyses, single status (P=.02), male gender (P=.01), increasing age (P<.01), year of diagnosis (P<.01), and smaller tumor size (P<.01) were strong independent predictors of TA use compared with surgery (PN or RN). Further adjusted analyses showed no statistical difference in cancer-specific or overall survival between TA vs PN or RN. CONCLUSIONS: TA use for stage I RCC increased over a relatively short period and was performed more commonly in patients of older age and with smaller tumor size. Longer follow-up is needed to assess the comparative effectiveness of TA vs surgery. PMID- 21550637 TI - Urethral steinstrasse with urethrocutaneous fistula. AB - A middle-age man presented with acute urinary retention and a history of passage of urine and stones through a fistula at the root of the penis of 7 years' duration. Computed tomography of the soft tissue penis revealed multiple calculi in the urethra. After an initial suprapubic cystostomy, he underwent Johanson's Stage I urethroplasty with excision of the fistulous tract and retrieval of the urethral stones. Intraoperatively, dense stricture of the distal penile urethra was found, with complete obliteration in places. A urethral stricture, if not promptly managed, can lead to devastating complications necessitating complex surgical management. PMID- 21550638 TI - 120-W GreenLight laser photoselective vaporization of prostate for benign prostatic hyperplasia: midterm outcomes. AB - OBJECTIVES: To evaluate the safety and efficacy of 120-W high-performance system (HPS) laser photoselective vaporization of the prostate (PVP) in the treatment of patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia. METHODS: Two experienced surgeons performed 120-W HPS laser PVP. The baseline characteristics, perioperative data, complications, and postoperative outcomes were evaluated at 3, 6, 12, 24, and 36 months postoperatively. RESULTS: A total of 550 consecutive patients, with a mean age of 67.6 years, underwent PVP with a 120-W HPS laser. The mean prostate volume was 72.93 cm3, with a mean prostate-specific antigen level of 3.57 ng/mL. The mean operative duration and the mean applied energy was 61.3 minutes and 164.06 kJ, respectively. No major complication occurred intraoperatively or postoperatively. The mean follow-up was 17.80 months. Significant improvements were observed postoperatively in the mean International Prostate Symptom Score, quality of life score, maximal urinary flow rate, and postvoid residual urine volume. The mean catheterization time was 18.5 hours. The complications included delayed hematuria in 26 (4.8%), recatheterization in 24 (4.4%), reoperation owing to residual prostatic adenoma in 46 (8.5%), urethral stricture in 19 (3.5%), and bladder neck contracture in 6 (1.1%) patients. CONCLUSIONS: PVP with a 120-W HPS laser for benign prostatic hyperplasia has been proved to be a safe and effective procedure for our patients, including those treated with oral anticoagulants. The functional outcome in larger prostates was similar to that in smaller glands. PMID- 21550639 TI - Trends and co-trends of prostate-specific antigen and body mass index in a screened population. AB - OBJECTIVES: This report investigated whether annual changes in body mass index (BMI) are associated with the opposite changes in prostate-specific antigen (PSA). Previous studies have confirmed lower PSA levels among men with higher BMI. METHODS: Normal linear mixed models were used to characterize annual PSA, BMI and the ratio of PSA to BMI profiles for 2641 men undergoing prostate cancer screening for up to 8 years as part of a San Antonio screening study. RESULTS: Among the 1898 participants (71.9%) who never received a prostate biopsy during the study and the 585 participants (22.1%) who had one or more biopsies, all negative for prostate cancer, BMI was higher for Hispanics than other racial groups, lower for older men at study entry, and increased every year during the study; and PSA and PSA/BMI ratios were higher for older men at study entry and increased each year on study (all P values<.05). Among the 158 men (6.0%) eventually diagnosed with prostate cancer, no trends in BMI were statistically significant, but PSA and PSA/BMI ratios were higher on average for older men at study entry and increased each year on study (both P values<.05). Correlations between BMI and PSA changes per year were negative but not statistically significantly different from zero. CONCLUSIONS: The individual man scrutinizing his PSA and weight year to year can expect a slight annual increase in both, but changes in PSA from one year to the next cannot be attributed to weight gain or loss. PMID- 21550640 TI - Fluoroscopy-guided renal access in supine percutaneous nephrolithotomy. AB - OBJECTIVE: To describe a standardized and easily reproducible method for fluoroscopy-guided renal access during supine percutaneous nephrolithotomy (sPCNL). PATIENTS AND METHODS: From January 2009 to January 2010, 35 patients underwent sPCNL. In 10 patients, ultrasound-guided puncture was unsuccessful. In these patients, we completed percutaneous access with a method based on fluoroscopy. We used a simple technique, adapted to sPCNL, consisting of cephalad tilting of the C-arm during puncture of the targeted calyx. We prospectively recorded the time necessary for the puncture, the success, and the complication rate of the puncture. RESULTS: Among the 10 study patients, the mean operative time for the puncture was 50 seconds (range 35-180). The puncture was successful after 1 attempt in 7 patients and in the remaining patients after a second or a third attempt. There were no complications related to the puncture technique. CONCLUSIONS: This technique is easy and reproducible for creating a fluoroscopy guided renal access adjunctive to ultrasound during sPCNL. It may also be useful for urologists not familiar with ultrasound-guided access. PMID- 21550641 TI - Factors determining stone-free rate in shock wave lithotripsy using standard focus of Storz Modulith SLX-F2 lithotripter. AB - OBJECTIVES: To calculate the efficiency quotient (EQ) of the latest mobile Storz Modulith SLX-F2 lithotripter and to identify the factors determining the stone free rate. METHODS: A retrospective review of a prospectively collected database of the first consecutive 533 patients undergoing shock wave lithotripsy (SWL) from June 2009 to February 2010 was performed. A total of 16 patients with radiolucent stones and 43 patients with incomplete follow-up were excluded. The patients were followed up with plain radiography to assess the stone-free status. Univariate and multivariate analyses were performed to identify the factors determining the stone-free rates. RESULTS: Follow-up was complete for 474 patients, with a mean age of 54.2 +/- 14.5 years. The success rate after a single SWL session was 82.7% (renal 82.2% and ureteral 83.3%; P = .81). The retreatment rate was 14.7% (renal 15.2% and ureteral 14.2%; P = .79). The stone-free rate was 77% (renal 74.1% and ureteral 80.9%; P = .10). Of the 474 patients, 43 had pre SWL ureteral stents, and 13 required post-SWL ureteral stenting; 35 patients required post-SWL curative procedures. The EQ was 0.66, and the modified EQ was 0.62. On multivariate analysis, the stone-free patients had a smaller stone size (9.5 vs 10.3 mm, P = .02), younger age (53.1 vs 58.0 years, P = .002), right sided stones (83.6% vs 71.0% P = .001), and the absence of a ureteral stent (78.7% vs 64.3%; P = .001). CONCLUSIONS: The mobile Storz Modulith SLX-F2 lithotripter has an acceptable EQ of 0.66. In the present study, smaller stones (<10 mm), younger age, right-sided stones, and the absence of ureteral stents were associated with significantly greater stone-free rates. PMID- 21550642 TI - Inadequacy of biopsy for diagnosis of upper tract urothelial carcinoma: implications for conservative management. AB - OBJECTIVE: To report changes in grade and stage between initial diagnostic and repeat biopsies or resection for urothelial carcinoma (UTUC) and investigate the consequences for endoscopic management. Ureteroscopic management of upper tract UTUC is an alternative to nephroureterectomy, which is less invasive and preserves renal function. However, concerns about potential understaging, inaccurate grading, incomplete resection, lack of effective tertiary chemoprevention, and need for ureteroscopic surveillance limits it appeal. METHODS: Clinicopathological records of patients with UTUC treated at our institution were reviewed. Fifty-six patients with a histologic diagnosis of UTUC and 2 or more consecutive biopsies or biopsy followed by surgical resection were included, resulting in 65 biopsy specimens. RESULTS: The median interval between diagnostic biopsy and subsequent biopsy or resection was 6 weeks (range, 1 week to 60 months). Change in grade from the diagnostic biopsy occurred in 24 of 65 biopsies (37%), including 9 in which diagnosis changed from low to high grade. Change in the stage from the diagnostic biopsy occurred in 25 of 65 biopsies (38%). Overall, 24 (43%) patients were reclassified from low-grade, noninvasive disease to high-grade and/or invasive disease. CONCLUSION: A change in grade and/or stage from the diagnostic biopsy occurred in more than one third of patients with UTUC managed conservatively. Because of the short median time interval between biopsies, this finding likely represents variability in tumor sampling on biopsy. Because of the concerns of undergrading and understaging, appropriate patient selection and vigilant endoscopic surveillance are mandatory for UTUC managed endoscopically. PMID- 21550643 TI - Is endoscopic injection therapy a reasonable treatment option for low-grade vesicoureteral reflux in association with overactive bladder? AB - OBJECTIVE: To assess the clinical outcome of endoscopic injection in children with vesicoureteral reflux (VUR) and concomittant overactive bladder (OAB). METHODS: A total of 41 patients with VUR and OAB underwent endoscopic injection of dextranomer/hyaluronic acid. At surgery, 13 patients had been successfully treated for their OAB (urgency with or without wetting) with behavior modification with or without anticholinergic therapy, and 28 had persistent OAB despite treatment. Voiding cystourethrogram was obtained 6-12 weeks postoperatively, and patients were followed up clinically for 1-5 years. RESULTS: Negative voiding cystourethrogram findings after a single treatment were seen in 34 (82.9%) of 41 patients. The radiographic success rate in patients with well controlled OAB was 76.9% (10 of 13) compared with 85.7% (24 of 28) of those with poorly controlled OAB. The overall clinical success rate, defined as no evidence of urinary tract infection in the setting of negative voiding cystourethrogram findings, reached 78.0% (32 of 41). After successful endoscopic treatment, an unanticipated return to normal voiding patterns without the need for postoperative anticholinergic therapy was seen in 4 of the children with well controlled OAB (40.0%) and in 4 with poorly controlled OAB (16.7%). CONCLUSION: Our data suggest that endoscopic injection is a viable treatment option for VUR in those with OAB, with postoperative rates of resolution comparable to those found in patients without OAB. Furthermore, 40.0% of children with well controlled OAB no longer required therapy for OAB after resolution of their VUR. PMID- 21550644 TI - Ovotesticular disorder of sex development with mosaic 45,X/46,X,idic(Y) (q11.23) karyotype and streak gonad. AB - An infant born at 38-weeks' gestation presented with ambiguous genitalia. Cytogenetic evaluation revealed an uncommon 45,X/46,X,idic(Y) mosaic karyotype. Pelvic ultrasonography, genitogram, and magnetic resonance imaging confirmed a long common urogenital sinus, vagina, cervix, unicornuate uterus, phallus, and bilateral intra-abdominal gonads resembling testes. The parents chose a male sex of rearing, and the infant underwent total abdominal hysterectomy, vaginectomy, bilateral gonadectomy, and first-stage hypospadias repair at 19 months of age. The histopathologic findings were consistent with ovotesticular disorder of sex development with a unique combination of testis and ovary on the left and testis and streak gonad on the right. PMID- 21550645 TI - Erectile dysfunction after anterior urethroplasty: a prospective analysis of incidence and probability of recovery--single-center experience. AB - OBJECTIVE: To evaluate the incidence and probability of recovery of erectile dysfunction after different types of one-stage urethroplasties for anterior urethral stricture disease. METHODS: Seventy-eight men undergoing single-stage anterior urethroplasty from January 1, 2008 to March 31, 2010 were followed prospectively. Patients were divided into 3 groups: group 1 (n=25)-penile substitution urethroplasty; group 2 (n=32)--primary excision anastomotic bulbar urethroplasty; and group 3 (n=21)--bulbar substitution urethroplasty. Patients willing to participate completed the International Index of Erectile Function (IIEF) preoperatively and then on subsequent follow-up visits at 3, 6, 9, 12, and 15 months after urethroplasty. Pre- and post-urethroplasty erectile functions were compared. RESULTS: Our mean follow-up period was 15.50+2.389 months. The mean age (years) was similar among groups. The mean stricture length (cm) was 4.78+/-0.747, 2.95+/-0.658, and 6.13+/-0.981 in-groups 1, 2, and 3, respectively (P=.001). Mean preoperative IIEF score was 24.60+/-2.365 (similar among groups). Erectile dysfunction (ED) was found in 15 (20%) patients: 4/25 (16%), 9/32 (28%), and 2/21 (10%) in groups 1, 2, and 3, respectively. Mean postoperative decline (3 months) in IIEF score was 22.54+/-4.823. Overall, the decline was not significant among groups (P=.502.) Recovery of erectile function was seen in 75/78 (96%) men at a mean follow-up time of 5.63+/-2.59 months. CONCLUSIONS: Anterior urethroplasty has a probability of causing ED in as much as 20% of patients. The type of urethroplasty has no significant effect on ED. Recovery of erectile function occurs within 6 months of urethroplasty. PMID- 21550646 TI - Prospective comparison of a new visual prostate symptom score versus the international prostate symptom score in men with lower urinary tract symptoms. AB - OBJECTIVE: To evaluate the correlation between the International Prostate Symptom Score (IPSS) and a new Visual Prostate Symptom Score (VPSS) using pictures rather than words to assess lower urinary tract symptoms (LUTS). METHODS: Four IPSS questions related to frequency, nocturia, weak stream, and quality of life (QoL) were represented by pictograms in the VPSS. Men with LUTS were given the IPSS and VPSS to complete. Peak (Qmax.) and average (Qave.) urinary flow rates were measured. Statistical analysis was performed using Student's t, Fisher's exact, and Spearman's correlation tests. RESULTS: The educational level of the 96 men (mean age 64, range 33-85 years) evaluated August 2009 to August 2010 was school grade 8-12 (62%), grade 1-7 (28%), university education (6%), and no schooling (4%). The IPSS was completed without assistance by 51 of 96 men (53%) and the VPSS by 79 of 96 men (82%) (P<.001). Comparing education grade<7 vs grade>10 groups, the IPSS required assistance in 27 of 31 men (87%) vs 9 of 38 men (24%) (P<.001), and the VPSS required assistance in 10 of 31 men (32%) vs 3 of 38 men (8%) (P=.014). There were statistically significant correlations between total VPSS, Qmax. and Qave., total VPSS and IPSS, and individual VPSS parameters (frequency, nocturia, weak stream and QoL) vs their IPSS counterparts. CONCLUSIONS: The VPSS correlates significantly with the IPSS, Qmax. and Qave., and can be completed without assistance by a greater proportion of men with limited education, indicating that it may be more useful than the IPSS in patients who are illiterate or have limited education. PMID- 21550647 TI - Urinary collecting system invasion is a predictor for overall and disease specific survival in locally invasive renal cell carcinoma. AB - OBJECTIVE: To examine the impact of urinary collecting system invasion (UCSI) on survival in patients with pathologic stage T3 renal cell carcinoma (RCC). MATERIALS AND METHODS: We identified 1420 patients who underwent nephrectomy at a single institution between 1988 and 2008. Patients with pT3 RCC and data on UCSI were examined (n=303). Clinicopathologic variables were compared using chi-square tests, and a multivariate analysis using the Cox proportional hazards method was used to evaluate the relationship between UCSI and survival. RESULTS: Of 303 patients with pT3 RCC, 67 (22.1%) had UCSI. UCSI was associated with higher T3 substage, tumor size, lymph node metastasis, and sarcomatoid features, as well as a shorter 5-year overall (51.9% vs 30.4%; P=.003) and disease-specific survival (59% vs 33.9%; P<.001) compared with those without USCI. On multivariate analysis, UCSI was independently associated with overall (HR 1.49; 95% CI, 1.02 2.17) and disease-specific survival (HR 1.76; 95% CI, 1.15-2.68). CONCLUSIONS: The presence of UCSI is independently associated with higher overall and disease specific mortality in patients undergoing nephrectomy for pT3 RCC. Locally advanced tumors crossing an additional anatomic boundary into the urinary collecting system appear to represent a particularly aggressive form of disease. These data suggest consideration for including UCSI in the next TNM staging system for RCC. PMID- 21550648 TI - An unusual case of right retrocaval ureter associated with ipsilateral ureterocele. AB - A 36-year-old man with right flank pain presented to our institution. Intravenous urography showed mild dilatation of the right pyelocaliceal system and large filling defect in the vesical lumen. Computed tomography revealed the right kidney to be smaller than the left, and with chronic pyelonephritis. The right ureter passed behind the inferior vena cava at the level of the pelvic-ureteral junction. The middle and lower ureter was dilated above a large ureterocele. Cystourethrography showed right vesicoureteral reflux. The patient underwent a resection of the ureterocele with reimplantation of the ureter. Follow-up at 3 months demonstrated resolution of the dilatation of the right ureter. PMID- 21550649 TI - Incomplete prenatal torsion of the testicle--a successful salvage. AB - The role of emergent intervention in prenatal testicular torsion is controversial. We report a case of successful testicular salvage of incomplete prenatal torsion. A 1-day-old male infant presented with a bluish-hued scrotum at birth. Testicular ultrasonography demonstrated right testicular torsion with minimal peripheral blood flow. Scrotal exploration was performed, confirming extravaginal torsion; both testes underwent orchiopexy. Subsequent imaging demonstrated normal bilateral testes with good vascular flow. Although intervention of prenatal torsion has been debated, the present case represents prenatal torsion saved by intervention. We propose the presence of any blood flow suggests incomplete torsion and the potential for salvage. PMID- 21550650 TI - A novel midline scroto-perineal approach facilitating innervation preserving sphincteroplasty and radical corporal detachment for reconstruction of exstrophy epispadias. AB - OBJECTIVE: To report a novel surgical approach for single-stage repair of exstrophy-epispadias, with the specific aim of innervation, preserving sphincteroplasty corporal detachment for penile lengthening and ischio-pubic ramotomy for Linia-alba approximation. MATERIAL AND METHODS: Twenty-five classic exstrophy with compliant bladder plate and 10 incontinent epispadias patients were selected. Preoperative magnetic resonance angiogram of urogenital diaphragm showed triangular space between ischio-cavernosus, bulbo-spongiosus, and transverse-perinei muscles containing sphincteric branch of perineal artery indicating the course of sphincteric nerve. Bladder plate was mobilized. Through a midline scrotal septal and transverse incision along the base of urogenital triangle, the urogenital diaphragm was exposed. Corpora were separated from the urethral plate while preserving the glanular continuity and innervation to striated urethral sphincter, using muscle stimulator and nerve integrity monitor. In the subperiosteal plane along the ischio-pubic rami, the corpora were detached. Repair included ureteric reimplantation; anatomic reconstruction of bladder, bladder neck, urethra, and striated sphincter; corporo-glanuloplasty; ischio-pubic ramotomy; and abdominal closure. Assessment included surgical problems, cosmetic satisfaction, erectile function, continence, and upper tract status at 2-year follow-up. RESULT: There was no corporal loss. Postoperative complications included 4 perineal suture line infections, 11 peno-pubic fistula, and 1 adhesive intestinal obstruction. Erectile function was good in 33 patients. Penile length was gratifying in 25. Of 28 patients, 20 (71.4%) had dry interval of two hours. Dimercaptosuccinic acid study demonstrated upper tract scarring in 2 patients. CONCLUSION: This approach facilitates innervation preserving sphincteroplasty and precise restoration of anatomy to near normal without operative accidents because of wide exposure gained, improving the functional and cosmetic results. PMID- 21550652 TI - Neural bases of language switching in high and early proficient bilinguals. AB - The left inferior frontal cortex, the caudate and the anterior cingulate have been proposed as the neural origin of language switching, but most of the studies were conducted in low proficient bilinguals. In the present study, we investigated brain areas involved in language switching in a sample of 19 early, high-proficient Spanish-Catalan bilinguals using a picture naming task that allowed contrasting switch and non-switch trials. Compared to the non-switching condition, language switching elicited greater activation in the head of the left caudate and the pre-SMA/ACC. When the direction of the switching was considered, the left caudate was more associated with forward switching and the pre-SMA/ACC with backward switching. The discussion is focused on the relevance of these brain structures in language control in early, high-proficient bilinguals, and the comparison with previous results in late bilinguals. PMID- 21550653 TI - The effect of anisotropic collagen-GAG scaffolds and growth factor supplementation on tendon cell recruitment, alignment, and metabolic activity. AB - Current surgical and tissue engineering approaches for treating tendon injuries have shown limited success, suggesting the need for new biomaterial strategies. Here we describe the development of an anisotropic collagen-glycosaminoglycan (CG) scaffold and use of growth factor supplementation strategies to create a 3D platform for tendon tissue engineering. We fabricated cylindrical CG scaffolds with aligned tracks of ellipsoidal pores that mimic the native physiology of tendon by incorporating a directional solidification step into a conventional lyophilization strategy. By modifying the freezing temperature, we created a homologous series of aligned CG scaffolds with constant relative density and degree of anisotropy but a range of pore sizes (55-243 MUm). Equine tendon cells showed greater levels of attachment, metabolic activity, and alignment as well as less cell-mediated scaffold contraction, when cultured in anisotropic scaffolds compared to an isotropic CG scaffold control. The anisotropic CG scaffolds also provided critical contact guidance cues for cell alignment. While tendon cells were randomly oriented in the isotropic control scaffold and the transverse (unaligned) plane of the anisotropic scaffolds, significant cell alignment was observed in the direction of the contact guidance cues in the longitudinal plane of the anisotropic scaffolds. Scaffold pore size was found to significantly influence tendon cell viability, proliferation, penetration into the scaffold, and metabolic activity in a manner predicted by cellular solids arguments. Finally, the addition of the growth factors PDGF-BB and IGF-1 to aligned CG scaffolds was found to enhance tendon cell motility, viability, and metabolic activity in dose-dependent manners. This work suggests a composite strategy for developing bioactive, 3D material systems for tendon tissue engineering. PMID- 21550654 TI - Vitamin E (D-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles superparamagnetic iron oxide nanoparticles for enhanced thermotherapy and MRI. AB - We synthesized vitamin E TPGS (d-alpha-Tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles for superparamagnetic iron oxides formulation for nanothermotherapy and magnetic resonance imaging (MRI), which showed better thermal and magnetic properties, and in vitro cellular uptake and lower cytotoxicity as well as better in vivo therapeutic and imaging effects in comparison with the commercial Resovist and the Pluronic F127 micelles reported in the recent literature. The superparamagnetic iron oxides originally coated with oleic acid and oleylamine were formulated in the core of the TPGS micelles using a simple solvent-exchange method. The IOs-loaded TPGS showed greatest colloidal stability due to the critical micelle concentration (CMC) of vitamin E TPGS. Highly monodisperse and water soluble suspension was obtained which were stable in 0.9% normal saline for a period of 12 days. The micelles were characterized for their size and size distribution. Their morphology was examined through transmission electron microscopy (TEM). The enhanced thermal and superparamagnetic properties of the IOs-loaded TPGS micelles were assessed. Cellular uptake and cytotoxicity were investigated in vitro with MCF-7 cancer cells. Relaxivity study showed that the IOs-loaded TPGS micelles can have better effects for T2-weighted imaging using MRI. T2 mapped images of xenograft grown on SCID mice showed that the TPGS micelle formulation of IOs had ~1.7 times and ~1.05 times T2 decrease at the tumor site compared to Resovist and the F127 micelle formulation, respectively. PMID- 21550655 TI - Controlled epi-cortical delivery of epidermal growth factor for the stimulation of endogenous neural stem cell proliferation in stroke-injured brain. AB - One of the challenges in treating central nervous system (CNS) disorders with biomolecules is achieving local delivery while minimizing invasiveness. For the treatment of stroke, stimulation of endogenous neural stem/progenitor cells (NSPCs) by growth factors is a promising strategy for tissue regeneration. Epidermal growth factor (EGF) enhances proliferation of endogenous NSPCs in the subventricular zone (SVZ) when delivered directly to the ventricles of the brain; however, this strategy is highly invasive. We designed a biomaterials-based strategy to deliver molecules directly to the brain without tissue damage. EGF or poly(ethylene glycol)-modified EGF (PEG-EGF) was dispersed in a hyaluronan and methylcellulose (HAMC) hydrogel and placed epi-cortically on both uninjured and stroke-injured mouse brains. PEG-modification decreased the rate of EGF degradation by proteases, leading to a significant increase in protein accumulation at greater tissue depths than previously shown. Consequently, EGF and PEG-EGF increased NSPC proliferation in uninjured and stroke-injured brains; and in stroke-injured brains, PEG-EGF significantly increased NSPC stimulation. Our epi-cortical delivery system is a minimally-invasive method for local delivery to the brain, providing a new paradigm for local delivery to the brain. PMID- 21550656 TI - A peptide-stainless steel reaction that yields a new bioorganic-metal state of matter. AB - A synthetic peptide derived from the native protein sequence of a metal binding bacterial pilus was observed to spontaneously react with stainless steel via a previously unreported type of chemical interaction to generate an altered form of stainless steel which we term bioorganic stainless steel. Bioorganic stainless steel has a significantly increased electron work function (4.9 +/- 0.05 eV compared to 4.79 +/- 0.07 eV), decreased material adhesive force (19.4 +/- 8.8 nN compared to 56.7 +/- 10.5 nN), and is significantly harder than regular 304 stainless steel (~40% harder). A formal or semi-formal organo-metallic covalent bond is generated between a pilin receptor binding domain and stainless steel based on XPS analysis which indicates that the electronic state of the surface is altered. Further, we establish that the peptide-steel reaction demonstrates a degree of stereospecificity as the reaction of native L-peptide, D-peptide and a retro-inverso-D-peptide yields bioorganic steel products that can be differentiated via the resulting EWF (4.867 +/- 0.008 eV, 4.651 +/- 0.008 eV, and 4.919 +/- 0.007 eV, respectively). We conclude that electron sharing between the peptide and steel surface results in the stabilization of surface electrons to generate bioorganic steel that displays altered properties relative to the initial starting material. The bioorganic steel generated from the retro-inverso D-peptide yields a protease stable product that is harder (41% harder at a 400 MUN load), and has a 50% lower corrosion rate compared with regular stainless steel (0.11 +/- 0.03 mpy and 0.22 +/- 0.04 mpy, respectively). Bioorganic steel is readily fabricated. PMID- 21550657 TI - Placentation in the African elephant (Loxodonta africana). V: the trophoblast secretes placental lactogen. AB - OBJECTIVES: To determine if elephant placenta secretes a lactogenic hormone which may function as the principal luteotrophin to maintain ovarian luteal function throughout gestation. STUDY DESIGN AND MAIN OUTCOME MEASURES: To label biopsies of endometrium and placenta recovered from African elephant culled professionally throughout gestation with an anti-human prolactin polyclonal antibody in a conventional immunocytochemical staining technique. RESULTS: All trophoblast cells covering the placental villi and forming 'plugs' in the apical endometrial glands stained strongly and precisely with the anti-human prolactin antiserum throughout gestation. CONCLUSIONS: Elephant trophoblast secretes a placental lactogen (elPL) which may stimulate both the development and secretory function of the large accessory corpora lutea of elephant pregnancy and provide the mitogenic stimulus for placental differentiation and development. PMID- 21550658 TI - Polymorphism of the thymidylate synthase gene and risk of relapse in childhood ALL. AB - Polymorphisms of genes encoding proteins involved in drug metabolism can influence the efficacy of leukemia treatment. In this population-wide study we aimed to evaluate selected, metabolically active genetic polymorphisms as prognostic markers of treatment efficacy in acute lymphoblastic leukemia (ALL). A total of 51 cases of leukemia relapse were diagnosed in a group of 354 patients with ALL. A strong association between promoter tandem repeat polymorphism of the thymidylate synthase gene and the relapse frequency was found. We believe that genotyping for this variant should be performed in patients treated for ALL to enable further optimizing of treatment protocols. PMID- 21550659 TI - Inhibition of PRAME expression causes cell cycle arrest and apoptosis in leukemic cells. AB - The preferentially expressed antigen of melanoma (PRAME) is known as a tumor associated antigen, but its function in leukemia remains unclear. We investigated the function with small interfering RNA (siRNA)-induced knockdown of PRAME in a K562 cell line. After PRAME siRNA transfection, proliferation was suppressed and cell cycle analysis showed G(0)/G(1) arrest, followed by apoptosis. PRAME siRNA treated cells also showed changes in the genes affecting erythroid differentiation. We examined the PRAME expression levels and the S phase population of 32 acute leukemia patients at the time of diagnosis and relapse. An increase of the S phase population was accompanied by an increase of PRAME expression at relapse. Our results suggest that PRAME plays an important role in disease progression in acute leukemia. PMID- 21550661 TI - Prospects for the international migration of U.S. sex offender registration and community notification laws. AB - Sex offender registration and community notification laws have proved enormously popular in the U.S. This is so even though the avowed sexual violence preventive benefits of the laws remain largely untested and unproven; indeed, it remains an open question whether the laws actually have anti-therapeutic and criminogenic effect. This article examines why this data deficit has characterized the social and political evolution of the laws and considers the prospects for their migration to other nations. PMID- 21550660 TI - Simultaneous inhibition of DNA methyltransferase and histone deacetylase induces p53-independent apoptosis via down-regulation of Mcl-1 in acute myelogenous leukemia cells. AB - We have recently established the MV4-11 acute myelogenous leukemia (AML) subline, designated as MV4-11 TP53 R248W, which possesses a missense mutation (CGG->TGG; R248W) in the TP53 gene, leading to inactivation of this transcription factor. DNA methyltransferase (DNMT) inhibitor 5-Aza-2'-deoxycytidine (5-AzadC) induced apoptosis in MV4-11, but not in MV4-11 TP53 R248W cells. Another class of anti epigenetic agent histone deacetylase inhibitor (HDACI) inhibited the proliferation of both MV4-11 and MV4-11 TP53 R248W cells. Notably, when 5-AzadC was combined with HDACI MS-275, apoptosis in MV4-11 TP53 R248W cells was significantly enhanced in parallel with activation of the caspase cascade, up regulation of p21waf1 and gamma-H2AX, and down-regulation of Mcl-1. Interestingly, inhibition of caspase 3 by the pan-caspase inhibitor attenuated the combination of 5-AzadC and MS-275-mediated apoptosis and down-regulation of Mcl-1 in MV4-11 TP53 R248W cells. Moreover, down-regulation of p21waf1 in MV4-11 R248W cells by a small interfering RNA blunted activation of caspase 3 after exposure to the combination of 5-AzadC and MS-275, indicating the role of p21waf1 to activate caspase 3. Taken together, TP53-independent up-regulation of p21waf1 activates caspase 3 and down-regulates Mcl-1 in AML cells. Combination of 5-AzadC and MS-275 may be a promising treatment strategy for individuals with leukemia in which TP53 is inactivated. PMID- 21550662 TI - A rhetoric of retribution and redemption: Burke's terms for order in the drama of child sexual abuse. AB - Law consists of a series of stories, narratives that embody the values and integrity of a culture. We define crimes, and label the individuals who commit them, along a continuum that moves from the merely unacceptable to the monstrous. One of the most heinous crimes in American society is considered to be child sexual abuse. The sexual abuser of children is firmly established in the public imagination as a modern-day bogeyman, and approaches to prevention and punishment reflect this artificially accelerated panic. Although public policies and correctional measures ostensibly are geared at preventing the crime, they reflect a fundamental misunderstanding as to the motivation of many offenders and the way in which child sexual abuse is perceived as a source of social anomie. This paper uses Kenneth Burke's interpretative framework to examine the social and legal perceptions and treatment of child sexual abusers. First discussed are Burke's conceptions of identity and orientation, which form the basis of human motivation and thus can illuminate the source of offenders' impulses. Next, Burke's "terms for order" are used to show the ways in which the dominant hierarchy compels us to scapegoat and sacrifice in the quest for social redemption. PMID- 21550663 TI - Levels and congener profiles of polybrominated diphenyl ethers (PBDEs) in breast milk from Shanghai: implication for exposure route of higher brominated BDEs. AB - Breast milk has been widely used as a bioindicator to assess the extent of human exposure to PBDEs via various exposure routes. In this study, 48 breast milk samples were collected from primiparous women in Shanghai city, and 14 PBDEs congeners (BDE-28, -47, -99, -100, -153, -154, -183, -196, -197, -203, -206, 207, -208, and -209) were quantified using gas chromatography-electron capture negative ionization-mass spectrometry. The mean concentration of total PBDEs was 8.6 ng/g lipid weight, and ranged from 1.8 to 26.7 ng/g lipid weight. These concentration levels were similar to those reported in Europe and Asia, but one order of magnitude lower than those in North America. The congener profiles in this study exhibited a specific pattern in human milk found worldwide, BDE-153 and BDE-28 accounted for a relatively higher proportion of lower brominated BDEs (from tri- to hepta-BDEs), whereas higher brominated BDEs (from octa- to deca BDEs) contributed more than 70% of the total PBDEs. The Spearman's correlation coefficient among higher brominated BDEs showed a positive relationship, and concentration levels of higher brominated BDEs were statistically different between office workers and housewives. Due to relatively higher proportion of PBDEs from octa- to deca-BDEs were detected, air inhalation and dust ingestion might be the major exposure routes of higher brominated BDEs. Further research is needed to clarify the major exposure route of higher brominated BDEs to humans. PMID- 21550664 TI - A conventional protein kinase C inhibitor targeting IRF-3-dependent genes differentially regulates IL-12 family members. AB - Protein kinase C (PKC) isoforms play a critical role in the regulation of innate immune responses. We have previously demonstrated that conventional PKC (cPKC) alpha is involved in interferon regulatory factor 3 (IRF-3) activation and IFN beta synthesis. Herein, we investigated the role of cPKCs in the regulation of IL 12 family members expression mediated by the Toll-like receptor 3 (TLR3) and TLR4. First, inhibition of cPKCs activity in human DCs by a cPKC-specific inhibitor, Go6976 downregulated the expression of IL-12p70 and IL-27p28 but not IL-12/IL-23p40, IL-23, IL-27EBI3 induced by LPS or poly(I:C). Furthermore, reporter gene assays in RAW 264.7 macrophages showed that cPKCs regulate IL-12p35 and IL-27p28 promoter activities since Go6976 repressed LPS and poly(I:C) mediated transcriptional activities of IL-12p35 and IL-27p28. In contrast, no effect was observed with IL-12/IL-23p40 and IL-23p19 reporter constructs. These results prompted us to study the role of IRF-3 on IL-23 expression. Bone marrow derived DC (BMDCs) from IRF-3(-/-) mice produced comparable levels of IL-23 induced by both LPS and poly(I:C) as compared to wild type BMDCs, indicating that IRF-3 is not involved in IL-23 production. Finally, BMDCs from PKCalpha(-/-) mice displayed a reduced synthesis of IL-27 induced by poly(I:C). Collectively, these data identify cPKCs as critical components that control IRF-3-dependent IL-12p35 and IL-27p28 gene expression downstream of TLR3 and TLR4. PMID- 21550665 TI - Newborn preference for a new face vs. a previously seen communicative or motionless face. AB - Newborn infants prefer to look at a new face compared to a known face (still face). This effect does not happen with the mother-face. The newborns could be attracted by the mother-face because, unlike the still-face, it confirms an expectation of communication. Fifty newborns were video-recorded. Sixteen of them were recruited in the final sample: nine were exposed to a communicative face and seven to a still-face. All the 16 newborns were successively exposed to two preference-tasks where a new face was compared with the known face. Only newborns previously exposed to a still-face preferred to look at a new face instead of the known face. The results suggest that the newborns are able to build a dynamic representation of faces. PMID- 21550666 TI - Friedreich's ataxia: past, present and future. AB - Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder characterized by progressive gait and limb ataxia, dysarthria, areflexia, loss of vibratory and position sense, and a progressive motor weakness of central origin. Additional features include hypertrophic cardiomyopathy and diabetes. Large GAA repeat expansions in the first intron of the FXN gene are the most common mutation underlying FRDA. Patients show severely reduced levels of a FXN-encoded mitochondrial protein called frataxin. Frataxin deficiency is associated with abnormalities of iron metabolism: decreased iron-sulfur cluster (ISC) biogenesis, accumulation of iron in mitochondria and depletion in the cytosol, enhanced cellular iron uptake. Some models have also shown reduced heme synthesis. Evidence for oxidative stress has been reported. Respiratory chain dysfunction aggravates oxidative stress by increasing leakage of electrons and the formation of superoxide. In vitro studies have demonstrated that Frataxin deficient cells not only generate more free radicals, but also show a reduced capacity to mobilize antioxidant defenses. The search for experimental drugs increasing the amount of frataxin is a very active and timely area of investigation. In cellular and in animal model systems, the replacement of frataxin function seems to alleviate the symptoms or even completely reverse the phenotype. Therefore, drugs increasing the amount of frataxin are attractive candidates for novel therapies. This review will discuss recent findings on FRDA pathogenesis, frataxin function, new treatments, as well as recent animal and cellular models. Controversial aspects are also discussed. PMID- 21550667 TI - CHRNA7 haplotypes are associated with impaired attention in euthymic bipolar disorder. AB - BACKGROUND: Bipolar disorder (BD) patients show a deficit in sustained attention during euthymic periods. This deficit may be relevant for genetic studies in these patients. The alpha7 cholinergic receptor plays an important role in attentional deficit in humans and animal models. Moreover, there is evidence suggesting the role of the alpha 7 nicotinic cholinergic receptor subunit gene (CHRNA7) in BD susceptibility. The aim of the present study was to investigate the impact of CHRNA7 in sustained attention performance. METHODS: We studied the association of a promoter variant (-86C/T) and three intronic polymorphisms, rs883473, rs6494223 and rs904952, in the non-duplicated region of CHRNA7 with sustained attention in 143 euthymic BD patients (based on DSM-IV criteria) and 101 healthy subjects. Sustained attention was assessed by the degraded stimulus (DS-CPT) version of Continuous Performance Test. Age, gender, years of education and IQ (WAIS vocabulary subtest) were controlled in the analyses as potential confounders. RESULTS: Several candidate polymorphisms showed significant associations with different measures of the neuropsychological task for bipolar group. The CTCT haplotype was associated with an improvement in the attentional task performance in the BD group (p <= 0.025). On the other hand, different low frequency haplotypes showed influence in bipolar attentional performance (p <= 0.026). LIMITATIONS: A replication study using larger samples may be required for conclusive results. CONCLUSIONS: Our results point toward a slight association of CHRNA7 genotypes and haplotypes with sustained attention performance in euthymic patients with BD. PMID- 21550668 TI - Cortical thickness and VBM-DARTEL in late-life depression. AB - BACKGROUND: Numerous studies have revealed structural brain changes in late life depression, mainly in white matter or whole lobes with few focussing just on grey matter (GM). The objective was to investigate GM changes in older depressed and similar aged healthy subjects using two different methods, cortical thickness in frontal lobe structures and voxel-based morphometry (VBM). METHODS: Sixty eight subjects participated (30 healthy comparison subjects, 38 depressed) and underwent 3T T1 MR imaging as well as clinical and cognitive assessments. Frontal cortical thickness was measured using FreeSurfer while VBM was undertaken using the DARTEL algorithm in SPM8. Group differences in cortical thickness and GM volumes were assessed using ANCOVA. Effects of cortical thickness and VBM results on cognitive and depression variables were also investigated. RESULTS: No significant differences in frontal lobe cortical thickness were observed between groups (F(1, 62) <= 2.7, p >= 0.1). In addition, no significant relationships of cortical thickness on cognitive and depression scores were identified (partial correlation |r'|=0.01-0.31, p >= 0.06). VBM showed that GM volumes were indistinguishable between groups but significant age effects were apparent, independent of diagnosis. CONCLUSIONS: Results suggest that cortical GM changes in late life depression (LLD) are similar to healthy older subjects and appear to be related to age rather than cognitive or depressive symptoms. Changes to white matter and subcortical GM structures may be more relevant in explaining the underlying neurobiology of LLD. PMID- 21550669 TI - Emotion recognition and experience in Huntington's disease: is there a differential impairment? AB - Findings on affective processing deficits in Huntington's disease (HD) have been inconsistent. It is still not clear whether HD patients are afflicted by specific deficits in emotion recognition and experience. We tested 28 symptomatic HD patients and presented them with pictures depicting facial expressions of emotions (Karolinska-Set) and with affective scenes (International Affective Picture System; IAPS). The faces were judged according to the displayed intensity of six basic emotions, whereas the scenes received intensity ratings for the elicited emotions in the viewer. Patients' responses were compared with those of 28 healthy controls. HD patients gave lower intensity ratings for facial expressions of anger, disgust and surprise than controls. Patients' recognition deficits were associated with reduced functional capacity, such as problems with social interactions. Moreover, their classification accuracy was reduced for angry, disgusted, sad and surprised faces. When judging affective scenes for the elicitation of happiness, disgust and fear, HD patients had a tendency to estimate them as more intense than controls. This finding points to a differential impairment in emotion recognition and emotion experience in HD. We found no significant correlations between emotion experience/recognition ratings and CAG repeats, symptom duration and UHDRS Motor Assessment in the patient group. PMID- 21550670 TI - Personalized smoking environment cue reactivity in smokers with schizophrenia and controls: a pilot study. AB - Exposure to smoking cues increases craving to smoke and negatively changes mood in smokers with schizophrenia (SWS). This pilot study compared reactivity to real world smoking environments versus neutral environments in SWS (n=10) and non psychiatric control smokers (CON; n=10). Results indicate that both SWS and CON experienced increases in smoking urges when viewing images of their smoking environments and that SWS tended to report greater increases in withdrawal related negative mood than CON when viewing images of their smoking environments. These findings signify that personalized smoking environments trigger smoking urges in SWS and suggest that extinguishing this reactivity may aid cessation efforts in this population. PMID- 21550671 TI - Resident B cells regulate thymic expression of myelin oligodendrocyte glycoprotein. AB - Thymic B cells represent a numerically minor cell population located primarily at the cortico-medullary junction. Their biological role is unclear. B cell deficient MUMT mice exhibited reduced medullary thymic epithelial cell (mTEC) numbers and reduced MOG and insulin mRNA expression. Lymphotoxin produced by B cells was critical for normal tissue restricted antigen (TRA) expression, suggesting that B cells regulate self-antigens through their production of LT. These results reveal an unexpected role of B cells in mTEC maintenance and expression of TRAs through their production of LT. PMID- 21550672 TI - Novel mechanisms of immune modulation of natalizumab in multiple sclerosis patients. AB - The goal of this study was to investigate the effects of natalizumab therapy on the immune cell composition and phenotype in the blood of relapsing MS patients treated over the course of 12 months. We collected peripheral blood from 26 RRMS patients before treatment onset, and then 6 and 12 months after therapy. PBMC was isolated and then analyzed for phenotypic characteristics by FACS and for cytokine production by ELISA. The results of our studies showed changes in both numbers and activation states of immune cells following therapy. These changes were observed at the 6 month timepoint and generally persisted through the 12 month timepoint. The proportions of NK cells (CD3-CD56+) and hematopoetic stem cells (CD34+lin-) were increased after natalizumab treatment. Decreases were noted in numbers of CD14+ monocytes, and possibly their migratory potential, since their expression levels of alpha4beta1 were decreased. Relative numbers of CD20+ B cells were increased, but the proportion of CD20+ cells expressing high levels of alpha4beta1 integrin was decreased. While proportions of CD4+ and CD8+ T cells did not change, the percentage of cells expressing alpha4beta1 integrin was significantly decreased for both subsets. Natalizumab therapy produces a number of phenotypic changes in the immune composition of peripheral blood. These changes may help to explain both the mechanisms of action of natalizumab and also shed light on the potential for the observed increase in PML in these patients. PMID- 21550673 TI - Myocardial extraction of intracellular magnesium and atrial fibrillation after coronary surgery. AB - BACKGROUND: The effects of magnesium loading on the incidence of atrial fibrillation following coronary artery bypass graft surgery (CAGB) are equivocal. None of the previous studies assessed the influence of myocardial extraction of magnesium in these settings. The current trial aims to elucidate whether the incidence of atrial fibrillation following CABG is affected by the preoperative rate of myocardial extraction of magnesium. METHODS: The ethical committee approved the study protocol. 113 patients (94 male, mean age 63 +/- 11 years) planned for elective CABG surgery under normothermic cardiopulmonary bypass were prospectively included. Preoperative independent variables included preoperative treatment, electrocardiographic abnormalities, left ventricular ejection fraction estimation, left atrial size, creatinine clearance and assays of plasma and intracellular magnesium, calcium, albumin, potassium and ionized calcium, drawn preoperatively from the coronary sinus and the aortic root. The covariates - including the rate of myocardial extraction of magnesium - were entered in a logistic regression model to predict the odds of atrial fibrillation. RESULTS: The incidence of post operative atrial fibrillation was 16%. A rate of myocardial extraction of intracellular magnesium >= 7% increases fivefold the multivariate risk of postoperative atrial fibrillation (p < .01). Advanced age was also significantly associated to postoperative atrial fibrillation. CONCLUSIONS: This study suggests that a preoperative rate of myocardial extraction of intracellular magnesium >= 7% could be a new and a potent predictive factor for postoperative atrial fibrillation. PMID- 21550674 TI - Gender differences in acute myocardial infarction, twenty-five years registration. AB - BACKGROUND/OBJECTIVES: The French-speaking Community of Belgium has set up a register of ischaemic cardiopathies (1983-2007). The aim consists in analyzing the evolution of fatal and non-fatal acute coronary events rates as well as the 28 days case fatality on a 25-year period and examine sex differences in lethality. METHODS: This register assures a standardized procedure according to the MONICA criteria. For each period, we present attack rates and trends analysis. Hospital lethality takes again in-patients and community lethality is calculated starting from all the cases. RESULTS: The total attack rate is rather stable between 1983 and 2007 for women (from 12 to 19 per 10,000 residents). For men, there is a distinct decline of the total attack rate since 1991 till 1993 (63 to 43 per 10,000 residents). We systematically observe a reduction in risk between men and women according to the age. For each 5-year period, this risk decreases significantly with age and this difference is strongest during the periods 1993-1997 and 1998-2002. The analysis shows also a significant decline in lethality between the 1983-1987 and 1993-1997 periods. Among women, lethality is systematically higher than in men in spite of the presence or the absence of antecedents of myocardial infarction. CONCLUSIONS: Favourable evolutions in the attack rates of acute coronary events in the study population appear clearly on the 25-year period of observation. The whole lethality rates decreased during the first 15 years of the register; after that, it stabilized. PMID- 21550675 TI - Coronary heart disease and stroke attributable to major risk factors is similar in Argentina and the United States: the Coronary Heart Disease Policy Model. AB - BACKGROUND: Cardiovascular disease is the leading cause of death in Argentina and the U.S. Argentina is 92% urban, with cardiovascular disease risk factor levels approximating the U.S. METHODS: The Coronary Heart Disease (CHD) Policy Model is a national-scale computer model of CHD and stroke. Risk factor data were obtained from the Cardiovascular Risk Factor Multiple Evaluation in Latin America Study (2003-04), Argentina National Risk Factor Survey (2005) and U.S. national surveys. Proportions of cardiovascular events over 2005-2015 attributable to risk factors were simulated by setting risk factors to optimal exposure levels [systolic blood pressure (SBP) 115 mm Hg, low-density lipoprotein cholesterol (LDL) 2.00 mmol/l (78 mg/dl), high-density lipoprotein cholesterol (HDL) 1.03 mmol/l (60 mg/dl), absence of diabetes, and smoking]. Cardiovascular disease attributable to body mass index (BMI) >21 kg/m2 was assumed mediated through SBP, LDL, HDL, and diabetes. RESULTS: Cardiovascular disease attributable to major risk factors was similar between Argentina and the U.S., except for elevated SBP in men (CHD 8% points higher in Argentine men, 6% higher for stroke). CHD attributable to BMI >21 kg/m2 was substantially higher in the U.S. (men 10-11% points higher; women CHD 13-14% higher). CONCLUSIONS: Projected cardiovascular disease attributable to major risk factors appeared similar in Argentina and the U.S., though elevated BMI may be responsible for more of U.S. cardiovascular disease. A highly urbanized middle-income nation can have cardiovascular disease rates and risk factor levels comparable to a high income nation, but fewer resources for fighting the epidemic. PMID- 21550676 TI - The effect of grazing on cow mortality in Danish dairy herds. AB - The effect of summer grazing in large Danish dairy herds and certain management characteristics of grazing were studied for their impact on dairy cow mortality. Mortality data (from the Danish Cattle Database) from 391 Danish dairy herds (>100 cows) were combined with information from a questionnaire survey of grazing procedures on these herds in 2008. In all, 131 of the herds were identified as summer grazing and 260 as zero-grazing herds. The mortality was affected by an interaction of summer grazing and milking system. The risk of a cow dying was reduced to 46% in a grazing compared to a zero-grazing herd having automatic milking system. In traditional milking system, mortality was reduced to 75% in grazing compared to zero-grazing herds. Within the grazing herds, the risk of mortality decreased with increasing number of hours on pasture during the season. Free access between barn and pasture was associated with increased cow mortality. PMID- 21550677 TI - Three-dimensional scapula kinematics and shoulder function examined before and after surgical treatment for breast cancer. AB - Shoulder motion loss following surgical treatment of breast cancer is common and may be associated with surgery-related soft tissue changes and altered shoulder kinematics. Knowledge of short term biomechanical changes at the shoulder will inform treatment decisions and may help prevent the development of shoulder pathology. Shoulder motion loss following surgery also impacts quality of life and shoulder function, and measuring function with a shoulder-specific tool may direct rehabilitation. This study examined the short term effects of surgery on scapula kinematics and function in breast cancer survivors. Bilateral three dimensional scapular kinematics were quantified before and after surgery for unilateral breast cancer and analyzed with repeated measures ANOVA. Shoulder function was assessed with the Shoulder Rating Questionnaire (SRQ) and analyzed with ANOVA. Subjects (n = 11) demonstrated statistically significant increases in scapula internal rotation on their involved side following surgery. An intention to treat analysis on all enrolled subjects supported this finding. The findings suggest that soft tissues restrictions impact short-term scapula motion following surgery for breast cancer. Significantly poorer shoulder function was reported for pain, recreation/athletic activities and total SRQ score after surgery. The SRQ appears sensitive enough to identify areas of life affected by changes in shoulder function following surgical intervention for breast cancer. PMID- 21550678 TI - Grasping possibilities for action: influence of object function and action capabilities. AB - The purpose of this study was to investigate the influence of object function and the observer's action capabilities on grasp facilitation. We used a stimulus response compatibility (SRC) protocol in which participants were asked to reach and grasp a drinking glass using one of two grasps - the thumb-up or the thumb down grasp. The reaction time (RT) was used as the index of grasp facilitation. In Experiment 1, we found evidence for the facilitation of "functionally relevant" grasps - where the type of grasp facilitated depended on the location of opening but not the shape of the object. However, this effect was found only when attention was directed toward the location of the opening. In Experiments 2 and 3, we found that this facilitation was also affected by whether participants had the ability to functionally interact with the object. These results show that S-R compatibilities are influenced both by the object's function and the actor's action capabilities, and are interpreted in Gibson's (1979) framework of affordances. PMID- 21550679 TI - Multiple-locus variable number of tandem repeat analysis (MLVA) of Listeria monocytogenes directly in food samples. AB - Listeria monocytogenes is the etiologic agent of listeriosis responsible for severe and fatal infections in humans. Listeria contamination occurs quite often in a wide range of foods due to its ubiquitous nature. Isolates need to be characterized to a strain level for accurate diagnosis of Listeria infection, epidemiological studies, investigation of outbreaks and effective prevention and control of food-borne listeriosis. The purpose of this research was to evaluate the multiple-locus variable number of tandem repeat analysis (MLVA) for sub typing L. monocytogenes isolates in pure cultures and in food matrices. Two multiplex PCR assays were formulated to amplify six specific loci using fluorescently-labeled primers; and the amplicons were analyzed by capillary electrophoresis. The MLVA method resulted in 34 unique DNA fingerprint patterns from 46 L. monocytogenes isolates of 10 serotypes which had 29 or 30 PFGE patterns with a single restriction enzyme and 34 AFLP patterns. The MLVA patterns of the 46 isolates remained unchanged in the presence of pre-enriched food matrices including sausage, ham, chicken, milk and lettuce. The MLVA method successfully typed L. monocytogenes strains spiked in cheese, roast beef, egg salad and vegetable samples after 48 h enrichment at the initial inoculation levels of 1-5 CFU per 25 g of food or higher. The limits of detection (typing) of the MLVA method were 10(3)-10(4)CFU/mL of pre-enriched food broth when evaluated using post-spiked sausage, ham, chicken, milk and lettuce samples. The MLVA method was simple, highly discriminatory, and easy to perform with portable (numerical) results. To our knowledge, this is the first report that describes the application of the MLVA method directly to food samples and demonstrates the possibility to obtain rapid and accurate subtyping results before an isolate is obtained. PMID- 21550680 TI - Identification and epidemiological relationships of Aeromonas isolates from patients with diarrhea, drinking water and foods. AB - A collection of Aeromonas isolates obtained over a three-year period in the same geographic area (Leon, NW of Spain) was characterized by (GTG)5-PCR fingerprinting, amplified fragment length polymorphism (AFLP) analysis and gyrB gene sequence analysis. The isolates originated from human diarrheal stools (29 isolates), potable water (13 isolates), rabbit meat (13 isolates) and marine fish (5 isolates). The distribution of Aeromonas species varied with the strain source. Aeromonas caviae HG4 and Aeromonas media HG5 were predominant in clinical and water isolates, respectively, whereas motile Aeromonas salmonicida HG3 strains were most frequently found in fish and meat. Molecular typing revealed several genotypic relationships among specific isolate subsets: (i) two clones of A. media HG5 persisted in drinking water over the study period, (ii) different patients harbored identical or closely related clones during several months, and (iii) clonal relatedness was observed in two sets of water and human isolates. The first of these sets comprised nine water isolates and two human A. media HG5 isolates, whereas the other one included a water isolate and a human isolate of A. caviae HG4. The latter finding suggests that Aeromonas transmission in the studied region followed a waterborne route. Interestingly, the three human isolates closely related to water isolates were recovered in a period of four days in June 2006 from non-related patients without underlying medical conditions that tested negative for other enteric pathogens. The data imply the transmission through contaminated water of strains of the A. caviae group that can produce disease in humans. PMID- 21550681 TI - Role of O-antigen on the Escherichia coli O157:H7 cells hydrophobicity, charge and ability to attach to lettuce. AB - Environmental factors encountered during growing and harvesting may contribute to Escherichia coli O157:H7 contamination of lettuce. Limited nutrients and extended exposure to water may cause E. coli O157:H7 to shed its O antigen. Absence of the O157-polysaccharide antigen could affect the cell's physicochemical properties (hydrophobicity and cell charge) and ultimately influence its attachment to surfaces. The objectives of this study were to evaluate the effect of the E. coli O157:H7 O-antigen on the cell's overall hydrophobicity, charge and ability to attach to cut edge and whole leaf iceberg lettuce surfaces. Three strains of E. coli O157:H7 (86-24 wild type; F-12, mutant lacking the O-antigen and pRFBE, plasmid for O157 gene reintroduced) were examined for their hydrophobicity, overall charge and ability to attach to lettuce. Overall, E. coli O157:H7 attached at higher levels to cut surfaces over whole leaf surfaces (P=0.008) for all strains and treatments. Additionally, the strain lacking the O-antigen (F12) attached significantly less to lettuce (P=0.015) than the strains expressing the antigen (WT and pRFBE). Cells lacking the O antigen (strain F-12) were also significantly more hydrophobic than strains 86-24 or pRFBE (P<=0.05). Surface charge differed among the strains tested (P<=0.05); however, it did not appear to influence bacterial attachment to lettuce surfaces. The charge was not fully restored in the pRFBE strain (expression of O-antigen reintroduced), therefore, no conclusions can be made pertaining to the effect of charge on attachment in this study. Results indicate that E. coli O157:H7 cells which lack the O-antigen have greater hydrophobicity and attach at lower concentrations than cells expressing the O-antigen, to iceberg lettuce surfaces. PMID- 21550683 TI - A new fibre optic pulse oximeter probe for monitoring splanchnic organ arterial blood oxygen saturation. AB - A new, continuous method of monitoring splanchnic organ oxygen saturation (SpO(2)) would make the early detection of inadequate tissue oxygenation feasible, reducing the risk of hypoperfusion, severe ischaemia, and, ultimately, death. In an attempt to provide such a device, a new fibre optic based reflectance pulse oximeter probe and processing system were developed followed by an in vivo evaluation of the technology on seventeen patients undergoing elective laparotomy. Photoplethysmographic (PPG) signals of good quality and high signal to-noise ratio were obtained from the small bowel, large bowel, liver and stomach. Simultaneous peripheral PPG signals from the finger were also obtained for comparison purposes. Analysis of the amplitudes of all acquired PPG signals indicated much larger amplitudes for those signals obtained from splanchnic organs than those obtained from the finger. Estimated SpO(2) values for splanchnic organs showed good agreement with those obtained from the finger fibre optic probe and those obtained from a commercial device. These preliminary results suggest that a miniaturized 'indwelling' fibre optic sensor may be a suitable method for pre-operative and post-operative evaluation of splanchnic organ SpO(2) and their health. PMID- 21550684 TI - Measurement error in statistical models of shape. AB - Active shape models (ASMs) are popular and sophisticated methods of extracting features in (especially medical) images. Here we analyse the error in placing ASM points on the boundary of the feature. By using replications, a corrected covariance matrix is presented that should reduce the effects of placement error. We show analytically and via simulations that the cumulative variability for a given number of eigenvalues retained in principal components analysis (PCA) ought to be reduced by increasing levels of point-placement error. Results for predicted errors are in excellent agreement with the set-up parameters of two simulated shapes and with anecdotal evidence from the trained experts for real data taken from the OSTEODENT project. We derive an equation for the reliability of placing the points and we find values of 0.79 and 0.85 (where 0=bad and 1=good) for the two clinical experts for the OSTEODENT data. These analyses help us to understand the sources and effects of measurement error in shape models. PMID- 21550685 TI - The Lindley distribution applied to competing risks lifetime data. AB - Competing risks data usually arises in studies in which the death or failure of an individual or an item may be classified into one of k >= 2 mutually exclusive causes. In this paper a simple competing risks distribution is proposed as a possible alternative to the Exponential or Weibull distributions usually considered in lifetime data analysis. We consider the case when the competing risks have a Lindley distribution. Also, we assume that the competing events are uncorrelated and that each subject can experience only one type of event at any particular time. PMID- 21550682 TI - Evolutionary genetics of plant adaptation. AB - Plants provide unique opportunities to study the mechanistic basis and evolutionary processes of adaptation to diverse environmental conditions. Complementary laboratory and field experiments are important for testing hypotheses reflecting long-term ecological and evolutionary history. For example, these approaches can infer whether local adaptation results from genetic tradeoffs (antagonistic pleiotropy), where native alleles are best adapted to local conditions, or if local adaptation is caused by conditional neutrality at many loci, where alleles show fitness differences in one environment, but not in a contrasting environment. Ecological genetics in natural populations of perennial or outcrossing plants can also differ substantially from model systems. In this review of the evolutionary genetics of plant adaptation, we emphasize the importance of field studies for understanding the evolutionary dynamics of model and nonmodel systems, highlight a key life history trait (flowering time) and discuss emerging conservation issues. PMID- 21550686 TI - Expression of thymidylate synthase, orotate phosphoribosyltransferase and dihydropyrimidine dehydrogenase in thymic epithelial tumors. AB - BACKGROUND: It remains unclear whether thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) expressions are associated with the pathogenesis of thymic epithelial tumors. Therefore, we investigated the expression of TS, OPRT and DPD in thymic epithelial tumors. PATIENTS AND METHODS: Fifty-six patients with thymic epithelial tumors were included in this study. Tumors sections were stained by immunohistochemistry for TS, OPRT, DPD, microvessel density (MVD) determined by CD34, and p53. We also conducted in vitro study of TS, OPRT and DPD expression using thymic carcinoma, thymic tumor and thymic fibroblast cell lines. RESULTS: TS, OPRT and DPD were expressed in 61%, 48% and 41%, respectively. High grade malignancy is significantly associated with higher expression of TS, OPRT and DPD in thymic epithelial tumors. These biomarkers were closely associated with p53 and MVD, and the overexpression of TS and DPD was a prognostic marker for predicting poor outcome in univariate analysis. Our in vitro study showed that marked overexpression of TS and OPRT was observed in thymic carcinoma cells, but not in thymic tumor cells, or thymic fibroblast cells. CONCLUSIONS: The expression of TS, OPRT and DPD was closely related to the grade of malignancy in thymic epithelial tumors. A positive expression of TS, DPD and OPRT might be an important factor in predicting the effectiveness of 5-FU based chemotherapy in this disease. PMID- 21550687 TI - [Efficacy of three intravitreal injections of bevacizumab in the treatment of exudative age-related macular degeneration]. AB - INTRODUCTION: To evaluate intravitreal bevacizumab therapy for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). MATERIAL AND METHODS: A retrospective review between June 2006 and May 2008 of patients with CNV secondary to AMD was conducted. All patients were treated with intravitreal injection of bevacizumab (1.25mg) once a month during a 3-month period. The mean evaluation criteria were the best-corrected visual acuity (BCVA) logMar testing before and one month after the third injection. All eyes underwent an angiography and an optical coherence tomography before injections to define the activity and the type of CNV and then to evaluate the persistence of leakage (macular edema, subretinal fluid, and pigment epithelial detachment) after treatment. Then treatments were left to the investigator's discretion during the following six months. RESULTS: Seventy-one eyes of 66 patients were enrolled. There were 65% occult CNV, 20% classic CNV, and 15% combined. A significant improvement in BCVA was observed, from 0.88+/-0.57 to 0.77+/-0.60 (p=0.001), one month after the third injection. At this time, 57.7% of the eyes required a reinjection because of leakage persistence. A concomitant treatment with intravitreal triamcinolone injection and/or photodynamic therapy was necessary for 8% of nonresponder eyes. Six months after initial treatment, a complete resolution of exudative signs was not obtained for 33.8% of eyes. The average number of injections was 3.85+/-0.96 during the 9-month follow-up. BCVA stability was observed at 4, 6 and 9-month follow-ups (F(71.2)=1.54; p=0.46). Three complications occurred: one endophthalmitis, one retinal tear, and one vitreous hemorrhage secondary to a macular hemorrhage. DISCUSSION: Mean BCVA significantly improved at one month after three consecutive monthly intravitreal injections of bevacizumab. However, most eyes required a reinjection. CONCLUSION: In spite of improvement in BCVA, leakage of the CNV persisted in most eyes after three monthly intravitreal injections of bevacizumab. Then retreatment and sometimes concomitant treatment was necessary to obtain complete resolution of exudative signs and BCVA stability. PMID- 21550688 TI - Perifoveal exudative vascular anomalous complex. AB - PURPOSE: To report the angiographic and optical coherence tomography (OCT) features of isolated "perifoveal exudative vascular anomalous complex (PEVAC)", a peculiar clinical entity. METHODS: A complete ophthalmologic examination was performed in two patients (a 82-year old woman [case 1]; a 52-year old man [case 2]) that were referred to our department for unilateral blurred vision. RESULTS: In both cases, fundus examination of the right eye showed a perifoveal isolated large aneurismal change, accompanied by small hemorrhages, intraretinal exudation, and small hard exudates accumulation. Both FA and ICGA revealed the absence of any other retinal or choroidal vascular abnormality associated. OCT showed a round hyperreflective lesion in correspondence of the perifoveal vascular anomalous complex, surrounded by intraretinal cystic spaces. In case 2, the lesion remained unchanged despite 3 monthly intravitreal injections of ranibizumab. CONCLUSION: PEVAC may develop in absence of capillary ischemia or inflammation, probably due to progressive retinal endothelial cell degeneration. This could explain the unresponsiveness to anti-VEGF treatments. PMID- 21550689 TI - [Small-incision, minimal dissection procedure (Frueh's procedure) in correction of involutional and congenital ptosis: A retrospective study of 119 cases]. AB - PURPOSE: To evaluate the efficacy and efficiency of the new small anterior incision, small-incision dissection procedure (Frueh's procedure) for the correction of involutional and congenital blepharoptosis. PATIENTS AND METHODS: This was a retrospective study to compare different parameters between Frueh's procedure and the traditional aponeurotic anterior approach in a group of 98 involutional blepharoptosis patients and between Frueh's procedure and Whitnall's sling in a group of 21 congenital blepharoptosis patients. The main criterion was recurrence requiring reintervention. RESULTS: In the adult's group, the rate of reoperation was not significantly different for the two surgical procedures (p=0.82). In the children's group, the rate of reoperation was not significantly different for the two surgical procedures (p=0.3). DISCUSSION: In adults, compared with the traditional aponeurotic approach, Frueh's procedure for blepharoptosis correction is equally efficacious in correcting eyelid height, superior in producing desirable eyelid contour, and much quicker to perform. In children, Frueh's procedure is a good technique for mild and moderate blepharoptosis with a good levator function. However, Frueh's procedure in severe blepharoptosis with low levator function seems not to be as efficient as the traditional surgical techniques. CONCLUSION: This study confirms Frueh's procedure as a reference for the treatment of adults and children with blepharoptosis. PMID- 21550690 TI - Dermatopathology workforce in the United States: a survey. AB - BACKGROUND: Although several studies have documented an undersupply of dermatologic services in the United States, little is known about the dermatopathology workforce. OBJECTIVE: Objectives included the following: (1) describe the dermatopathology workforce in the United States; (2) identify characteristics associated with academic dermatopathologists; and (3) explore issues surrounding dermatopathology training. METHODS: We conducted a cross sectional survey of all Fellows of the American Society of Dermatopathology (ASDP) practicing in the United States and its territories. RESULTS: Of 913 ASDP Fellows, 437 (48%) returned a completed questionnaire. Most were male (72%), Caucasian (85%), and had graduated from US/Canadian medical schools (88%). Approximately half (49%) had completed a dermatology residency and a quarter (24%) were in academia. As compared with those in private practice, academic dermatopathologists were more likely to be female (P = .0028), have a medical degree only (P = .0197), and earn $300,000 or less annually (P < .0001). No associations were identified for practice type with either location of medical school (United States/Canada vs other) or year of fellowship graduation (<=1996 vs >=1997). Although most respondents were satisfied overall with their training, the most common areas identified as inadequate included: coding/billing (47%), biostatistics (38%), pediatric clinical dermatology (27%), and electron microscopy (27%). LIMITATIONS: Moderate response rate and potential recall bias are limitations. CONCLUSIONS: This study of the US dermatopathology workforce provides benchmarks for future studies and strategies for workforce planning. PMID- 21550691 TI - Surgical smoke and the dermatologist. AB - BACKGROUND: The use of electrosurgery and lasers by dermatologists and dermatologic surgeons has increased in recent years with the growth of technology and procedures performed. These devices produce surgical smoke that has been demonstrated to harbor live viruses and bacteria in addition to hazardous chemicals. OBJECTIVE: We sought to review the literature on surgical smoke, its effects on those exposed, and measures that may be used to protect dermatologists and their staff. METHODS: We conducted a review of the literature on surgical smoke during the last 25 years. RESULTS: The studies reviewed indicate the potential for infection, carcinogenesis, and pulmonary damage as a result of exposure to surgical plume. LIMITATIONS: There is no inclusion of literature and subsequent findings published greater than 25 years prior. CONCLUSIONS: It is evident from our review that surgical smoke poses potential health risks to dermatologists who perform procedures using electrocautery and lasers. We recommend diligent use of high-filtration masks in addition to smoke evacuation systems to dermatologists performing laser surgery and using electrocautery. Furthermore, we advocate investigation into quantifying the exposure of dermatologists to surgical smoke in the outpatient setting. PMID- 21550692 TI - Activity assessment in morphea using color Doppler ultrasound. AB - BACKGROUND: Morphea (circumcripted cutaneous scleroderma) can be difficult to assess for lesion activity. Because variable-frequency ultrasound with color Doppler provides details of skin morphology and function, it may help in the categorization of morphea. OBJECTIVE: We sought to evaluate color Doppler ultrasound as a probing tool for assessing activity in morphea lesions. METHODS: Consecutive patients with cutaneous morphea referred by dermatologists were studied with color Doppler ultrasound, and the assessment of lesion activity was compared with histologic findings. Normal skin controls were obtained by performing ultrasound scans of healthy subjects or of unaffected areas of the patients themselves. Measurements included cutaneous layer thickness, relative echogenicity, and blood flow with peak systolic velocity. Ultrasound sensitivity and specificity were determined for each phase of morphea activity and the results correlated with histology. RESULTS: Fifty-one patients had a total of 104 morphea lesions. Of the lesions, 20% were active, 22% were atrophic, and 58% were inactive. Five of the patients had the Parry-Romberg syndrome with ipsilateral parotid gland inflammatory involvement, and one had an asymptomatic but sonographically active morphea lesion. Sensitivity and specificity for ultrasound diagnosis were 100% and 98.8%, respectively. The most accurate sonographic signs of lesion activity were increased subcutaneous tissue echogenicity and increased cutaneous blood flow (sensitivity and specificity 100% and 100% for each one). LIMITATIONS: Ultrasound cannot define lesions less than 0.1-mm deep. CONCLUSIONS: The morphologic and functional data obtained noninvasively and in real time with color Doppler ultrasound provide new insight into the pathogenesis of morphea. The technique represents a useful counterpart to histologic examination for the assessment of lesion activity. PMID- 21550693 TI - Correlates of low bone mass in children with generalized forms of epidermolysis bullosa. AB - BACKGROUND: Epidermolysis bullosa (EB) is a family of rare, heterogeneous, genetic disorders characterized by fragility of the skin and mucous membranes. Reduced bone mass and fractures have been recognized as complications of generalized forms of EB. OBJECTIVES: We sought to describe the range and to estimate the prevalence of low bone mass in children with generalized EB, and to identify correlates of low bone mass in this population. METHODS: This was a prospective, observational study of 24 patients with generalized EB. Each patient completed a history, physical examination, laboratory studies, bone age, and x rays of the lumbar spine. Those aged 6 years and older underwent dual energy x ray absorptiometry scans of the lumbar spine. Primary outcomes were areal bone mineral density (aBMD) based on chronologic age, bone age, and adjusted for height Z-score. Descriptive statistics were used to summarize results, and linear regression was used to determine factors associated with low aBMD. RESULTS: Mean lumbar spine aBMD Z-scores +/- SD were: -2.6 +/- 1.4 for chronologic age, -1.7 +/ 1.3 for bone age, and -1.0 +/- 1.2 after adjusting for height Z-score. aBMD Z scores were less than or equal to -2 in 64% for chronologic age, 50% for bone age, and 28% after adjusting for height Z-score. aBMD correlated with height Z score, weight Z-score, extensive blistering, immobility, albumin, hemoglobin, iron, erythrocyte sedimentation rate, and c-reactive protein values. LIMITATIONS: Small sample size was a limitation. CONCLUSIONS: Children with severe, generalized recessive dystrophic EB have low aBMD for age. Deficits in aBMD were reduced after adjusting for delayed skeletal maturation and small body size. PMID- 21550695 TI - Regional differences in age-related lipofuscin accumulation in the female hamster brainstem. AB - Lipofuscin accumulation is a characteristic feature of senescent postmitotic neuronal cells but estrogen may have protecting effects by inhibiting its formation. In the present ultrastructural study, lipofuscin accumulation was studied in 2 estrogen-alpha-receptive brainstem areas: nucleus pararetroambiguus (NPRA) and the commissural part of the solitary tract nucleus/A2 catecholaminergic group (NTScom/A2) and compared with the estrogen-insensitive medial tegmental field (mtf), in young (23 weeks) and aged (95 weeks) female hamsters. In the aged animals, extensive intracytoplasmic lipofuscin accumulation was observed. A total number of 6450 neurons were classified in 4 categories. Levels were significantly elevated in each of the brain areas studied. Lipofuscin accumulation was strongest in the mtf, less in NPRA, and remarkably less in the area of NTScom/A2. In conclusion, the observed differences in lipofuscin accumulation suggest: (1) considerable regional differences in the degree of neuronal vulnerability; and (2) a possible neuroprotective role for estrogen, because the degree of accumulation is inversely related to the density of the estrogen receptors, varying from nonreceptive (mtf) to NPRA and NTScom/A2 (most receptive). PMID- 21550694 TI - Lymphoma-associated hemophagocytic syndrome (LAHS) in advanced-stage mycosis fungoides/Sezary syndrome cutaneous T-cell lymphoma. AB - BACKGROUND: Lymphoma-associated hemophagocytic syndrome (LAHS) is a rare clinicopathological entity. It has been described with primary cutaneous lymphomas, mostly of the subcutaneous panniculitis-like T-cell type, and only once with cutaneous T-cell lymphoma (CTCL). METHODS: We report the cases of 5 patients with epidermotropic CTCL who developed LAHS and died shortly thereafter. Unlike LAHS associated with systemic lymphomas, these CTCL-associated LAHS were late events, occurring several years after the initial lymphoma diagnosis. LIMITATIONS: The small number of patients reported renders definite conclusions difficult. Further reports would be needed to confirm our statements. CONCLUSION: LAHS is probably underdiagnosed in CTCL patients with acute inflammatory symptoms suggestive of infections but should be considered, especially when cytopenia and elevated triglyceride and ferritin levels are present. PMID- 21550696 TI - [Comment to "Causes, characteristics and mid-term course of acute urinary retention in women referred to a Urodynamics Unit"]. PMID- 21550697 TI - Synthesis and biological evaluation of 4-nitro-substituted 1,3-diaryltriazenes as a novel class of potent antitumor agents. AB - We describe the synthesis and biological activity of a new class of 1,3 diaryltriazenes, namely 4-nitro-substituted 1,3-diaryltriazenes. Structure activity relationship analysis reveals that 1,3-diaryltriazenes can be modified from inactive to highly cytotoxic compounds by the introduction of two nitro groups at the para positions of benzene rings and two additional electron withdrawing groups (bromo, chloro, trifluoromethyl or fluoro substituents) at their ortho position. In order to increase the solubility of the modified compounds, we introduced various acyl groups to their triazene nitrogen. The results of LC-MS/MS analysis showed that N-acyltriazenes can be considered as prodrugs of non-acylated triazenes. Selected 3-acetyl-1,3-bis(2-chloro-4 nitrophenyl)-1-triazene (8b) is highly cytotoxic against different tumor cell lines, including cisplatin-resistant laryngeal carcinoma cells. Notably, its antiproliferative activity is significantly higher against tumor cells than against normal cells. DNA binding analysis suggests that neither 8b nor its non acylated derivative 8a bind into the minor groove of DNA. Instead, 8b induces reactive oxygen species that could provoke endoplasmic reticulum (ER(a)) stress finally leading to apoptosis. Our data suggest that 4-nitro-substituted 1,3 diaryltriazenes are a new class of anticancer molecules which preferentially target malignant cells and may serve as potential antitumor agents. PMID- 21550698 TI - Novel aliphatic N-oxide of naphthalimides as fluorescent markers for hypoxic cells in solid tumor. AB - A series of novel aliphatic N-oxide of naphthalimides (A1-A5) were designed and prepared. The N-O group was firstly introduced into the amine side chain tailed to planar naphthalimide chromophore as hypoxic bioreductive marker. Fluorescence image analysis showed that the compounds could be used as potential markers for hypoxic cells (V79) in vitro especially for A1 with 17 times hypoxic-oxic fluorescence differential, which was probably due to the bis-bioreduction mechanism. PMID- 21550699 TI - New 2-thioether-substituted apomorphines as potent and selective dopamine D2 receptor agonists. AB - A set of novel apomorphine derivatives were synthesized with diversely functionalized side chains in the proximity of position 2 of the aporphine skeleton. Amino and/or carboxylic functions were introduced to this region of the backbone to test their pharmacological effects. During the synthesis of 2-(S-3 mercaptopropionic acid)-derivative a heteroring-fused congener was also isolated. The structural elucidation confirmed that the formation of this product was in accordance with our previous observations on the reaction of thebaine (2) with thiosalycilic acid. All the novel apomorphine congeners 4a-g were neuropharmacologically characterized to discover their dopaminergic profiles. Two derivatives were identified as D(2) full agonists equipotent with apomorphine (1) having significantly increased D(2)/D(1) selectivity ratios. PMID- 21550700 TI - [Acute necrotizing pancreatitis and complete atrioventricular block complicating the course of ascaris infection in an adult patient]. AB - Ascaris lumbricoides, a large round nematode, which causes human ascariasis, is the most prevalent helminth in the world. Ascariasis is usually asymptomatic but can cause serious complications, with a mortality rate of 5%. We report a 55-year old woman from Comoros who presented with ascariasis complicated by occult cholangitis, severe acute pancreatitis, and transient complete heart-block. Cardiac damage due to migrating ascaris larvae was the likely explanation of the transient heart-block in this patient, although such a complication had never been described previously. PMID- 21550701 TI - Midwifery and the LGBT midwife. AB - OBJECTIVE: To identify, through searching the published literature, midwifery's attitudes to gay and lesbian midwives. DESIGN: A selective literature review. FINDINGS: UK-based material was sparse. Items on midwifery and nursing and medicine and on midwifery in non-UK countries were accessed. Issues emerging include the salience of 'coming out', of education, of culture, of forming relationships with childbearing women and the difficulty of authoritative research. KEY CONCLUSIONS: The midwifery literature on LGBT colleagues corresponds with that identified in nursing almost three decades ago. The lack of recognition of LGBT midwives carries personal and organisational implications. IMPLICATIONS FOR PRACTICE: Discriminatory attitudes may be difficult to resolve by education. Research on LGBT colleagues is fraught with difficulties. Various aspects of culture affect the acceptance of the colleague who is gay or lesbian. It is uncertain whether the midwife-woman relationship is less easily achieved by the gay or lesbian midwife. PMID- 21550702 TI - Preservation of the first rocker is related to increases in gait speed in individuals with hemiplegia and AFO. AB - BACKGROUND: Changes in impulse during the first rocker (braking force) and third rocker (propulsion force) may affect changes in gait speed after orthotic intervention. The purpose of this investigation was to objectively measure changes in impulse during double support and correlate those findings to changes in gait speed with and without ankle foot orthosis in individuals with hemiplegia. METHODS: Fifteen adults with stroke-related hemiplegia walked with and without ankle foot orthosis while foot pressure data was collected bilaterally. Outcome measures included: gait cycle time (s), mean force (N), and impulse (Ns) in the wholefoot, hindfoot, forefoot, and toe box during initial double support and terminal double support. FINDINGS: Time significantly decreased during the entire gait cycle, initial double support, and terminal double support, with the ankle foot orthosis. During initial double support, affected limb impulse significantly decreased with the ankle foot orthosis in the wholefoot (P=0.016), and hindfoot (P=0.006), and hindfoot impulse % change and gait speed % change were significantly correlated (P=0.007). During terminal double support, affected limb impulse was not significantly different in the wholefoot or forefoot and these changes were not significantly correlated to gait speed. INTERPRETATION: Previous research found that orthotics increase gait speed in individuals with hemiplegia. This research suggests that the increase in speed is not due to increased propulsive forces at the end of terminal double support, but due to decreased braking forces during initial double support. Therefore, the orthosis preserved the first ankle rocker and provided a more efficient weight acceptance which positively affected gait speed. PMID- 21550704 TI - Trace element uptake by Eleocharis equisetina (spike rush) in an abandoned acid mine tailings pond, northeastern Australia: implications for land and water reclamation in tropical regions. AB - This study was conducted to determine the uptake of trace elements by the emergent wetland plant species Eleocharis equisetina at the historic Jumna tin processing plant, tropical Australia. The perennial emergent sedge was found growing in acid waters (pH 2.45) and metal-rich tailings (SnAsCuPbZn). E. equisetina displayed a pronounced acid tolerance and tendency to exclude environmentally significant elements (Al, As, Cd, Ce, Co, Cu, Fe, La, Ni, Pb, Se, Th, U, Y, Zn) from its above-substrate biomass. This study demonstrates that geobotanical and biogeochemical examinations of wetland plants at abandoned mined lands of tropical areas can reveal pioneering, metal-excluding macrophytes. Such aquatic macrophytes are of potential use in the remediation of acid mine waters and sulfidic tailings and the reclamation of disturbed acid sulfate soils in subtropical and tropical regions. PMID- 21550703 TI - Tendon and nerve excursion in the carpal tunnel in healthy and CTD wrists. AB - BACKGROUND: During hand and finger motions, friction between flexor digitorum superficialis tendon and the median nerve is thought to play a role in the development of cumulative trauma disorders. This study investigated three methods to determine excursions of the flexor digitorum superficialis tendon and median nerve using several motions. METHODS: Twenty-five participants (mean age 37.2 years SD 13.4) were classified as healthy (n=16), self-reported distal upper extremity cumulative trauma disorders (6), or wheelchair users (3). Static carpal tunnel measurements were taken and displacements of the index flexor digitorum superficialis tendon and median nerve were determined via the velocity time integral and post hoc integration of the Doppler ultrasound waveform using a 12-5 MHz linear array transducer, as well as using predictive equations. FINDINGS: Median nerves in symptomatic wrists were larger than healthy wrists by 4.2 mm(2) (left) and 4.1 mm(2) (right) proximally to less than 1.4 mm(2) distally. In healthy wrists, left-right tendon excursion differences ranged from 0.7 mm to 4.3 mm depending on the motion while left to right differences in symptomatic wrists ranged over 22.2 mm. Ultrasound measures of tendon excursion overestimated those determined using predictive equations and were poorly correlated. The ratio of median nerve excursion to tendon excursion was lower in finger only motions compared to wrist motions with or without finger motion. INTERPRETATION: Spectral Doppler ultrasound imaging provided insights into tendon excursion that was not apparent with mathematical modeling. The difference in excursion between finger motions and wrist motions could be beneficial in therapeutic techniques. PMID- 21550705 TI - Accumulation, subcellular distribution and toxicity of inorganic mercury and methylmercury in marine phytoplankton. AB - We examined the accumulation, subcellular distribution, and toxicity of Hg(II) and MeHg in three marine phytoplankton (the diatom Thalassiosira pseudonana, the green alga Chlorella autotrophica, and the flagellate Isochrysis galbana). For MeHg, the inter-species toxic difference could be best interpreted by the total cellular or intracellular accumulation. For Hg(II), both I. galbana and T. pseudonana exhibited similar sensitivity, but they each accumulated a different level of Hg(II). A higher percentage of Hg(II) was bound to the cellular debris fraction in T. pseudonana than in I. galbana, implying that the cellular debris may play an important role in Hg(II) detoxification. Furthermore, heat-stable proteins were a major binding pool for MeHg, while the cellular debris was an important binding pool for Hg(II). Elucidating the different subcellular fates of Hg(II) and MeHg may help us understand their toxicity in marine phytoplankton at the bottom of aquatic food chains. PMID- 21550706 TI - Long-term outcome of trigeminal nerve injuries related to dental treatment. AB - PURPOSE: There is little information available on the long-term effects on patients of permanent involvement of the inferior alveolar or lingual nerve because of dental treatment. This study has attempted to document this information from patients who were reviewed between 3 and 9 years after injury. MATERIALS AND METHODS: All patients with an ICD-9 diagnosis of 951.2 (injury to the trigeminal nerve) because of dental treatment, seen in the Oral and Maxillofacial Surgery Clinic at the University of California, San Francisco between January 1, 2001 and December 31, 2006, were contacted in an attempt to complete a telephone survey of long-term effects. RESULTS: Of the 727 patients who were eligible for the study, 145 patients (95 female and 50 male) completed the telephone surveys. Many patients had sought both conventional and alternative treatments after consultation at University of California, San Francisco. A small number of patients had undergone subsequent surgery elsewhere. Many patients reported significant life changes, including adverse effects on employment (13%), relationship changes (14%), depression (37%), problems speaking (38%), and problems eating (43%). In general, however, patients reported improvement over time, often using a number of different coping mechanisms. Males had a greater decrease in symptoms than females, and those older than 40 years reported more pain in the long term than those under 40. Lingual nerve symptoms improved more than inferior alveolar nerve symptoms. CONCLUSIONS: Although most patients continue to have long-term problems that affect the overall quality of life, for most patients there has been improvement in symptoms over time. PMID- 21550707 TI - Utilization of the tympanomastoid fissure for intraoperative identification of the facial nerve: a cadaver study. AB - PURPOSE: Intraoperative identification of the facial nerve is an essential component of parotid gland surgery. Failure to visualize the facial nerve during the procedure can result in significant complications such as facial palsy. Several anatomic landmarks are used clinically to identify the facial nerve trunk; however, most of these structures have variable locations with respect to the nerve. The tympanomastoid fissure is the closest and least variable of the anatomic landmarks used in parotid gland surgery. The aim of this study was to evaluate the distance between the tympanomastoid fissure and the facial nerve trunk. MATERIALS AND METHODS: Thirty cadaver sides were dissected. A modified Blair incision exposed the facial nerve trunk, and the dissection was extended to the stylomastoid foramen and adjacent mastoid process. The distance between the most lateral aspect of the tympanomastoid fissure and facial nerve trunk was obtained using a digital caliper. RESULTS: The distance from the tympanomastoid fissure to the facial nerve trunk ranged from 3.3 to 9.2 mm with a mean of 4.9 mm. CONCLUSIONS: The results showed that the tympanomastoid fissure is a close and predictable anatomic landmark that can be used to identify the facial nerve trunk intraoperatively. PMID- 21550708 TI - [Induced sputum as a method for the study of bronchial inflammation]. PMID- 21550709 TI - Hypothermia and neuroprotection by sulfide after cardiac arrest and cardiopulmonary resuscitation. AB - BACKGROUND: Poor neurological outcome remains a major problem in patients suffering cardiac arrest. Recent data have demonstrated potent neuroprotective effects of the administration of sulfide donor compounds after ischaemia/reperfusion injury following cardiac arrest and resuscitation. Therefore, we sought to evaluate the impact of sodium sulfide (Na(2)S), a liquid hydrogen sulfide donor on core body temperature and neurological outcome after cardiac arrest in rats. METHODS: Fifty male Wistar rats were randomized into two groups (sulfide vs. placebo, n=25 per group). Cardiac arrest was induced by transoesophageal ventricular fibrillation during general anaesthesia. After 6 min of global cerebral ischaemia, animals were resuscitated by external chest compressions combined with defibrillation. An investigator blinded bolus of either Na(2)S (0.5 mg/kg body weight) or placebo 1 min before the beginning of CPR, followed by a continuous infusion of Na(2)S (1 mg/kg body weight/h) or placebo for 6 h, was administered intravenously. 1 day, 3 days, and 7 days after restoration of spontaneous circulation, neurological outcome was evaluated by a tape removal test. After 7 days of reperfusion, coronal brain sections were analyzed by TUNEL- and Nissl-staining. A caspase activity assay was used to determine antiapoptotic properties of Na(2)S. RESULTS: Temperature course was similar in both groups (mean minimal temperature in the sulfide group 31.3+/-1.2 degrees C vs. 30.8+/-1.9 degrees C in the placebo group; p=0.29). Despite significant neuroprotection demonstrated by the tape removal test after 3 days of reperfusion in the sulfide treated group, there was no significant difference in neuronal survival at day 7. Likewise results from TUNEL-staining revealed no differences in the amount of apoptotic cell death between the groups after 7 days of reperfusion. CONCLUSION: In our rat model of cardiac arrest, sulfide therapy was associated with only a short term beneficial effect on neurological outcome. PMID- 21550710 TI - A theoretical modeling for frequency modulation of Ca(2+) signal on activation of MAPK cascade. AB - It is known that Ca(2+) signal regulates mitogen-activated protein kinase (MAPK) cascade by a central Ras protein in GTPase-cycle. Therefore, we construct an integrated theoretical model comprising Ca(2+) oscillations, GTPase-cycle and MAPK cascade modules sequentially. Meanwhile, based on multiple feedback regulations in MAPK cascade, three operation modes of this model are introduced. An extended version of this model is further built when spatial heterogeneity is involved. These models allow us to investigate the very interesting and broad question about the effects of Ca(2+) oscillations on the activation of MAPK cascade in both the homogeneous and heterogeneous systems. When the Li-Rinzel model is adopted to simulate endogenous Ca(2+) oscillations, our theoretical results illustrate that the appropriate operation mode of MAPK cascade is required for the negative correlation between a decreasing frequency of Ca(2+) oscillations and activation of MAPK cascade, which was found in the experiment (S. Kupzig et al. PNAS 102 (2005) 7577-7582). While a piecewise function is used to generate Ca(2+) signal to explore much larger range of periods of Ca(2+) oscillations, it is found that the negative correlation feature is independent on the operation mode of MAPK cascade. In this case, different operation modes only influence the strength of negative correlation between activation of MAPK cascade and periods of Ca(2+) oscillations. The quantitative results may be of great use in analyzing interaction of IP3-Ca(2+) and Ras-MAPK signaling pathways, and motivate the further experimental research. PMID- 21550711 TI - Allowance for thermodynamic nonideality in the characterization of protein interactions by spectral techniques. AB - Theory is developed for the characterization of protein interactions by spectral techniques, where the constraints of constant temperature and pressure demand that thermodynamic activity be defined on the molal concentration scale. The customary practice of defining the equilibrium constant (K) on a molar basis is accommodated by developing expressions to convert those experimental values (K(molar)) to their thermodynamically more rigorous counterparts (K(molal)). Such procedures are illustrated by reanalysis of published results for the effects of molecular crowding agents on the isomerisation of alpha-chymotrypsin and reversible complex formation between catalase and superoxide dismutase. Although those reanalyses have led to only minor refinements of the quantitative interpretation, it is clearly preferable to adopt thermodynamic rigor throughout future spectral studies by employing the molal concentration scale from the outset. PMID- 21550712 TI - RNA polymerase pushing. AB - Molecular motors can exhibit Brownian ratchet or power stroke mechanisms. These mechanistic categories are related to transition state position: An early transition state suggests that chemical energy is stored and then released during the step (stroke) while a late transition state suggests that the release of chemical energy rectifies thermally activated motion that has already occurred (ratchet). Cellular RNA polymerases are thought to be ratchets that can push each other forward to reduce pausing during elongation. Here, by constructing a two dimensional energy landscape from the individual landscapes of active and backtracked enzymes, we identify a new pushing mechanism which is the result of a saddle trajectory that arises in the two-dimensional energy landscape of interacting enzymes. We show that this mechanism is more effective with an early transition state suggesting that interacting RNAPs might translocate via a power stroke. PMID- 21550713 TI - Adsorption of cadmium on carbonaceous adsorbents developed from used tire rubber. AB - Carbonaceous adsorbents (CAs) are developed from used tire rubber (UTR) and tested as adsorbents of Cd(2+) in aqueous solution. In the preparation of the CAs, UTR was treated thermally at 400-900 degrees C for 2 h in N(2) and at 850 degrees C for 2 h in steam. Concentrated NaOH, HCl, H(2)SO(4), HNO(3) and H(2)O(2) solutions were also used. UTR and H900 (i.e. UTR pyrolyzed at 900 degrees C) were treated with O(3) at 25 degrees C for 1 h and with air at 250 degrees C for 1 and 24 h. CAs were characterized texturally by N(2) adsorption at -196 degrees C, mercury porosimetry, and density measurements. The surface groups were analyzed by FT-IR spectroscopy. Using the batch method, the adsorption process of Cd(2+) was studied mainly from the kinetic standpoint at various pH values of the adsorptive solution. Significant porosity developments are achieved only when UTR is heat-treated, in particular in steam. However, the variety and concentration of surface groups are low in CAs. This is so even for CAs prepared using oxidizing agents as strong as O(3) and H(2)O(2), which has been associated with a lack of available or accessible surface active sites for oxidation in UTR and H900, respectively. Thermal and thermal-chemical treatments are usually more effective than chemical treatments to increase the adsorption of Cd(2+) in aqueous solution. The adsorption process of Cd(2+) is first fast and then much slower. Adsorption-time data fit better to a pseudo-second order kinetic equation than to a pseudo-first order kinetic equation. The extent to which the adsorption process occurs is strongly dependent on the pH of the Cd(2+) solution, being larger at pH 4.6 or 7.0 according to the adsorbent. PMID- 21550714 TI - Sellar paraganglioma: a unique route to a rare destination case report and literature review. AB - OBJECTIVE: Paragangliomas of the sella are rare; 14 cases have been reported in the literature. We describe here the unique case of a sellar paraganglioma that extended into the orbit through the superior orbital fissure. We have also reviewed all reported cases of sellar paragangliomas to better define best management strategies. CLINICAL PRESENTATION: A 63-year-old male presented with left eye proptosis and conjunctival vessel dilatation. INTERVENTION: Resection of the intraorbital component of the tumor was accomplished using a transcranial transorbital approach. CONCLUSION: This is the first report of a sellar/parasellar paraganglioma extending into the orbit through the superior orbital fissure. While an appropriate treatment paradigm has not been established, a review of all previously reported cases suggests that radiotherapy is an important consideration. PMID- 21550715 TI - Kinetic analysis of C.I. Acid Yellow 9 photooxidative decolorization by UV visible and chemometrics. AB - A kinetic study of the C.I. Acid Yellow 9 photooxidative decolorization process, using H(2)O(2) as oxidant, was carried out by chemometric analysis of the UV visible data recorded during the process. The number of chemical species involved in the photooxidative decolorization process was established by singular value decomposition (SVD) and evolving factor analysis (EFA). Information about the different chemical species along the process was obtained from the spectral and concentration profiles recovered by soft multivariate curve resolution with alternating least squares (MCR-ALS). This information was complemented by mass spectrometry (MS) to postulate a reaction pathway. The dye photooxidative decolorization process involved consecutive and parallel reactions. The consecutive pathway consists of a first stage of dye oxidation followed by the rupture of the azo linkage to form smaller molecules that are degraded in a subsequent stage. The parallel reactions form products that are undetectable in the UV-visible spectra. Kinetic constants of the reactions postulated in the photooxidative process were retrieved by applying a hybrid hard and soft MCR-ALS resolution. All constants were similar for the consecutive stages and higher than those obtained for the parallel reactions. PMID- 21550716 TI - Modified Ponorogo bentonite for the removal of ampicillin from wastewater. AB - The adsorption of ampicillin onto natural and organo-bentonite was studied. Organo-bentonite was obtained by modifying the natural bentonite obtained from Ponorogo, Indonesia, using CTAB surfactant by microwave heating. The temperature dependent form of the Langmuir, Freundlich, Sips and Toth equations was employed to correlate equilibrium data. Based on the evaluation of the physical meaning of fitted isotherm parameters of each model, it is clear that Toth equation can represent the equilibrium data better than other models. The adsorption performance of natural and organo-bentonite for the removal of ampicillin from pharmaceutical company wastewater was also studied. In real wastewater, both adsorbents could not completely remove the ampicillin due to the sorption competition with other substances which also present in the wastewater. PMID- 21550717 TI - Immobilization of polyethylenimine nanoclusters onto a cation exchange resin through self-crosslinking for selective Cu(II) removal. AB - Donnan membrane principle provides great opportunities for development of highly efficient adsorbents for toxic metals abatement. Based on the principle we prepared a new composite adsorbent by immobilizing polyethylenimine (PEI) nanoclusters within a macroporous cation exchanger D001 through self-crosslinking by glutaraldehyde upon Cu(II)-template process. Negligible PEI loss was observed from the resultant composite adsorbent D001-PEI-GA to solution of pHs 1-12. Increasing solution pH from 1 to 6 results in more favorable Cu(II) retention by D001-PEI-GA, and Cu(II) adsorption onto D001-PEI-GA follows the pseudo-second order kinetic model well. Compared to D001, D001-PEI-GA displays more preferable Cu(II) sequestration in the presence of co-ions Mg(2+), Ca(2+), Sr(2+) at higher levels. Fixed-bed adsorption of a synthetic solution containing Cu(II) and other co-ions showed that Cu(II) sequestration on D001-PEI-GA could result in its conspicuous decrease from 5mg/L to below 0.01 mg/L with the treatment volume as high as 630 BV per run, while that for D001 was only ~ 85 BV. Also, the spent composite adsorbent can be readily regenerated by HCl (0.3M)-NaCl (0.5M) binary solution for repeated use with negligible capacity loss. PMID- 21550718 TI - Characteristics and mechanisms of hexavalent chromium removal by biochar from sugar beet tailing. AB - Removal of Cr(VI) from aqueous solutions using biochar from sugar beet tailing (SBT) was investigated as a function of pH, contact time, and biochar mass via batch experiments. The surface characteristics of SBT biochar before and after Cr(VI) sorption was investigated with scanning electron microscopy equipped with energy dispersive X-ray spectroscopy and Fourier transform infrared spectroscopy. Desorption and X-ray photoelectron spectroscopy studies showed that most of the Cr bound to SBT biochar was Cr(III). These results indicated that the electrostatic attraction of Cr(VI) to positively charged biochar surface, reduction of Cr(VI) to Cr(III) ion, and complexation between Cr(III) ion and SBT's function groups were probably responsible for Cr(VI) removal by SBT biochar. An initial solution with a pH of 2.0 was most favorable for Cr(VI) removal. The sorption process can be described by the pseudo-second order equation and Langmuir isotherm. The maximum sorption capacity for Cr(VI) was 123 mg/g under an acidic medium, which was comparable to other low-cost sorbents. PMID- 21550719 TI - Comment on "Reductive dechlorination of gamma-hexachloro-cyclohexane using Fe-Pd bimetallic nanoparticles" by Nagpal et al. [J. Hazard. Mater. 175 (2010) 680 687]. AB - The author used a recent article on lindane (gamma-hexachloro-cyclohexane) reductive dechlorination by Fe/Pd bimetallics to point out that many other of published works in several journals do not conform to the state-of-the-art knowledge on the mechanism of aqueous contaminant removal by metallic iron (e.g. in Fe(0)/H(2)O systems). It is the author's view that the contribution of adsorbed Fe(II) to the process of contaminant reduction has been neglected while discussing the entire process of contaminant reduction in the presence of bimetallics. PMID- 21550720 TI - Detoxification of a carcinogenic paint preservative by Blumea malcolmii Hook cell cultures. AB - Phytoremediation is considered as an effective viable alternative to remediate the contaminated sites, industrially hazardous chemicals and other toxic pollutants. This bioremediation option offers a safe, cheap and eco friendly alternative to existing physical and chemical remediation technologies as well as other biological sources. The wall paint preservatives consist of several harmful and carcinogenic compounds causing serious environmental concerns. In the present study, an actively growing Blumea malcolmii Hook cell suspensions were established successfully on MS+CM (20%) +2,4-D (5 mg l(-1))+Gln (100 mg l( 1))+sucrose (3%) and were used to detoxify a paint preservative Troysan S 89 (a mixture of carbendazim, diuron and ochthilinone). FTIR and UV spectral analytical studies revealed the phytotransformation of Troysan S 89 by Blumea cell suspension cultures. The non-toxic nature of the products formed after phytotransformation was confirmed by phytotoxicity, cytogenotoxicity while non carcinogenic nature by Ames tests. The novelty of the present study is effective communal degradation of a mixture of three toxicants in Troysan S 89 by cell suspension cultures of Blumea. This work suggested that Blumea cell suspensions might be able to contribute to the wider and safer application of phytoremediation. PMID- 21550721 TI - A decade of effects on sickleave after multidisciplinary rehabilitation? PMID- 21550724 TI - WITHDRAWN: Response from authors. AB - This article has been withdrawn at the request of the author and has being approved by the editor. The Publisher apologizes for any inconvenience this may cause.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21550723 TI - Role of TRPV1 in nociception and edema induced by monosodium urate crystals in rats. AB - Gout is characterized by the deposition of monosodium urate (MSU) crystals. Despite being one of the most painful forms of arthritis, gout and the mechanisms responsible for its acute attacks are poorly understood. In the present study, we found that MSU caused dose-related nociception (ED(50) [ie, the necessary dose of MSU to elicit 50% of the response relative to the control value]=0.04 [95% confidence interval 0.01-0.11]mg/paw) and edema (ED(50)=0.08 [95% confidence interval 0.04-0.16]mg/paw) when injected into the hind paw of rats. Treatment with the selective TRPV1 receptor (also known as capsaicin receptor and vanilloid receptor-1) antagonists SB366791 or AMG9810 largely prevented nociceptive and edematogenic responses to MSU. Moreover, the desensitization of capsaicin sensitive afferent fibers as well as pretreatment with the tachykinin NK(1) receptor antagonist RP 67580 also significantly prevented MSU-induced nociception and edema. Once MSU was found to induce mast cell stimulation, we investigated the participation of these cells on MSU effects. Prior degranulation of mast cells by repeated treatment with the compound 48/80 decreased MSU-induced nociception and edema or histamine and serotonin levels in the injected tissue. Moreover, pretreatment with the mast cell membrane stabilizer cromolyn effectively prevented nociceptive and edematogenic responses to MSU. MSU induced a release of histamine, serotonin, and tryptase in the injected tissue, confirming mast cell degranulation. Furthermore, the antagonism of histaminergic H1 and serotoninergic receptors decreased the edema, but not the nociception of MSU. Finally, the prevention of the tryptase activity was capable of largely reducing both MSU-induced nociception and edema. Collectively, the present findings demonstrate that MSU produces nociceptive and edematogenic responses mediated by TRPV1 receptor activation and mast cell degranulation. PMID- 21550726 TI - Sexuality after burn in Brazil: survey of burn health-care workers. AB - Patients who survive a major burn must live with emotional and physical sequela. In a literature review, we found that sexuality concerns of burn victims are rarely a focus of therapy. After suggestions from Rimmer et al. [12], using their questionnaire translated into Portuguese, we held a survey of burn-care professionals at the VII Brazilian Burn Congress. More than 120 practitioners from 41 centres, aged in average 41.2 years (1 standard deviation 10.96), completed the survey. A proportion of 63.7% were female, and 58.1% were Caucasians; 37.1% were physicians, 20.9% nurse practitioners and 16.9 were occupational therapists/physical therapists (OTs/PT)s. Psychologists made up 3.2%. Only 28% of the respondents felt comfortable in initiating a conversation about sexual intimacy with their patients. The vast majority believed it should be done by the psychologist. Only 38% felt their burn centre did an adequate job in that area. When compared with a study of our country's general population, we find similar results indicating that intimacy, sexuality and sexual intercourse are considered most important in a relationship. There is a significant lack of literature in sexuality after burn; most likely meaning it is ignored by most centres. There is a need for other similar surveys to be performed, as well as a collective consciousness of the need for discussions about sexuality with patients and their partners, providing counselling and treatment, when need. PMID- 21550725 TI - Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain. AB - Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB(2) agonist to attenuate a neuropathic pain state. Self-medication of the CB(2) agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal thresholds in sham-operated or naive animals. The percentage of active lever responding was similar in naive groups self-administering vehicle or (R,S)-AM1241. The CB(2) antagonist SR144528 blocked both antiallodynic effects of (R,S)-AM1241 self-medication and the percentage of active lever responding in neuropathic (but not naive) rats. Neuropathic and sham groups exhibited similar percentages of active lever responding for (R,S)-AM1241 on a fixed ratio 1 (FR1) schedule. However, neuropathic animals worked harder than shams to obtain (R,S) AM1241 when the schedule of reinforcement was increased (to FR6). (R,S)-AM1241 self-medication on FR1, FR3, or FR6 schedules attenuated nerve injury-induced mechanical allodynia. (R,S)-AM1241 (900MUg intravenously) failed to produce motor ataxia observed after administration of the mixed CB(1)/CB(2) agonist WIN55,212-2 (0.5mg/kg intravenously). Our results suggest that cannabinoid CB(2) agonists may be exploited to treat neuropathic pain with limited drug abuse liability and central nervous system side effects. These studies validate the use of drug self administration methods for identifying nonpsychotropic analgesics possessing limited abuse potential. These methods offer potential to elucidate novel analgesics that suppress spontaneous neuropathic pain that is not measured by traditional assessments of evoked pain. PMID- 21550727 TI - Eribulin mesylate, a novel microtubule inhibitor in the treatment of breast cancer. AB - BACKGROUND: Microtubule-targeted agents are one of the most common classes of chemotherapeutic drug for the treatment of breast cancer. Limitations of current microtubule-targeted agents such as primary or secondary resistance of cancer cells and side effects like neuropathy prompted the discovery and introduction of newer more effective drugs. This review aims to provide a summary of the novel halichondrin B analog eribulin mesylate (E7389) and illustrate where it is placed in the treatment arena versus other agents that are approved or are currently in various stages of clinical development. METHODS: Preclinical and clinical trial (phases I-III) data for eribulin were obtained from scientific journals and meeting abstracts, posters, and oral presentations. The use of current and other emerging microtubule inhibiting agents in breast cancer was also surveyed and briefly reviewed. RESULTS: Eribulin mesylate at a dose of 1.4 mg/m(2) given on days 1 and 8 of a 21-day cycle increased overall survival in patients with metastatic breast cancer (MBC). Neutropenia, fatigue, alopecia, nausea and anemia were common adverse events (AEs) associated with eribulin in clinical studies. A low incidence of peripheral neuropathy was also associated with eribulin in clinical studies (21-26%). Other emerging microtubule targeted agents, such as vinflunine and larotaxel, also reported efficacy in patients with MBC who had received prior chemotherapy, with grade 3/4 neutropenia being the most common AEs for both agents. CONCLUSIONS: Eribulin mesylate offers clinical activity in advanced breast cancer through improved overall survival, its favorable side effect profile and convenience of preparation and administration. PMID- 21550729 TI - Sleep and muscle recovery: endocrinological and molecular basis for a new and promising hypothesis. AB - Sleep is essential for the cellular, organic and systemic functions of an organism, with its absence being potentially harmful to health and changing feeding behavior, glucose regulation, blood pressure, cognitive processes and some hormonal axes. Among the hormonal changes, there is an increase in cortisol (humans) and corticosterone (rats) secretion, and a reduction in testosterone and Insulin-like Growth Factor 1, favoring the establishment of a highly proteolytic environment. Consequently, we hypothesized that sleep debt decreases the activity of protein synthesis pathways and increases the activity of degradation pathways, favoring the loss of muscle mass and thus hindering muscle recovery after damage induced by exercise, injuries and certain conditions associated with muscle atrophy, such as sarcopenia and cachexia. PMID- 21550728 TI - A comparison of mandated versus volunteer adolescent participants in youth tobacco cessation programs. AB - A national evaluation of community-based youth cessation programs delivered in group format provided the opportunity to compare mandated and volunteer program participants on demographics, smoking patterns, other health behaviors and motivation to quit. A total of 857 youth participants completed surveys prior to the start of their treatment program. Mandated youth comprised 24% of the sample (n=202). Both bivariate and multivariate comparisons were conducted. Mandated participants reported lower levels of stress, higher extrinsic motivation and lower intrinsic motivation to quit, and were more likely to be in the earlier (precontemplation) stage of readiness to quit. Mandated and volunteer smokers did not differ in their smoking patterns, school-related smoking behaviors, or binge drinking. Rates of smoking, school problems, and binge drinking were higher among cessation program participants than in general samples of youth. Programs with mixed voluntary-mandatory participation may benefit from extra attention to motivational issues. PMID- 21550730 TI - Fatty acid profile and oxidative stability of the perirenal fat of bulls fattened on grass silage and maize silage supplemented with tannins, garlic, maca and lupines. AB - Carcass fat composition of cattle fed a forage-based diet might be inferior with maize silage compared to grass-silage based systems. This was quantified using complete diets with concentrate. To test whether supplements may influence carcass fat properties as well, the maize-silage diet was additionally supplemented either with Acacia mearnsii tannins, garlic, maca or lupines, feeds rich in secondary metabolites. The perirenal fat of 6*6 bulls fed these six diets was analysed for fatty acid profile and shelf life. The n-6/ n-3 ratio was always higher than 11 with the maize silage treatments and 2 with grass silage. The supplements did not affect the occurrence of biohydrogenation intermediates, including rumenic acid. Shelf life, being twice as long with maize compared to grass silage, was either unaffected or tended to be impaired, especially with supplementary garlic. Overall, supplementation was not efficient in improving carcass fat properties of maize-silage fed bulls. PMID- 21550731 TI - Usutu virus in Italy: an emergence or a silent infection? AB - A two year study (2008-2009) was carried out to monitor the Usutu virus (USUV) circulation in Italy. Sentinel horses and chickens, wild birds and mosquitoes were sampled and tested for the presence of USUV and USUV antibodies within the WND National Surveillance plan. Seroconversion evidenced in sentinel animals proved that in these two years the virus has circulated in Tuscany, Emilia Romagna, Veneto and Friuli Venezia Giulia regions. In Veneto USUV caused a severe blackbird die-off disease involving at least a thousand birds. Eleven viral strains were detected in organs of 9 blackbirds (52.9%) and two magpies (0.5%) originating from Veneto and Emilia Romagna regions. USUV was also detected in a pool of Culex pipiens caught in Tuscany. According to the alignment of the NS5 partial sequences, no differences between the Italian USUV strains isolated from Veneto, Friuli and Emilia Romagna regions were observed. The Italian North Eastern strain sequences were identical to those of the strain detected in the brain of a human patient and shared a high similarity with the isolates from Vienna and Budapest. Conversely, there were few differences between the Italian strains which circulated in the North Eastern regions and the USUV strain detected in a pool of C. pipiens caught in Tuscany. A high degree of similarity at both nucleotide and amino acid level was also found when the full genome sequence of the Italian North Eastern isolate was compared with that of the strains circulating in Europe. The North Eastern Italian strain sequence exhibited 97% identity to the South African reference strain SAAR-1776. The deduced amino acid sequences of the Italian strain differed by 10 and 11 amino acids from the Budapest and Vienna strains, respectively, and by 28 from the SAAR 1776 strain. According to this study two strains of USUVs are likely to have circulated in Italy between 2008 and 2009. They have developed strategies of adaptation and evolution to spread into new areas and to become established. PMID- 21550732 TI - Discriminatory potential of a novel set of Variable Number of Tandem Repeats for genotyping Mycobacterium marinum. AB - Mycobacterium marinum is a free-living bacterium that infects fish and amphibians, but is also an opportunistic pathogen in humans. Although in previous studies, the bacterium has shown a small number of Variable Number of Tandem Repeat (VNTR) polymorphic loci, the discriminatory power of the known VNTR loci is unlikely to be sufficient to distinguish such a globally ubiquitous waterborne microorganism, which has a presumably high genetic variance. The object of this study was to test M. marinum isolates from east China for strain diversity using previously described loci as well as novel VNTR loci, and to identify more discriminating VNTR loci that could enrich the genotyping tools for M. marinum. We found that 7 of the 12 tested VNTR loci, of which 5 were known loci and 2 loci were newly identified, showed good discriminatory power for the 14 M. marinum clinical isolates (Hunter-Gaston Index [HGI] value=0.990). The pathogenicity of isolates representing different VNTR clusters was also studied in a zebrafish (Danio rerio) infection model; in this model, 6 isolates representing 4 VNTR clusters induced chronic infections, whereas the American strain ATCC BAA-535 caused acute and lethal infections. PMID- 21550733 TI - Natural progression of Bovine Leukemia Virus infection in Argentinean dairy cattle. AB - We describe the progression of Bovine Leukemia Virus (BLV) infection from birth until the first lactation in 61 animals from a typical large dairy herd of Argentina, with more than 85% of prevalence. The purpose was to identify potential points to effectively break the BLV cycle of transmission in our dairy productive system. We detected early infection in 11.47% of newborn calves by nested PCR. From birth to 12 months, no evidence of new infections was observed. After 12 months of age, the detection of new reactors increased slowly with time, from 15.09% at 15 months to 24% at 27 months. After that, the number of reactors increased rapidly up to 40% and 60.76% at 30 and 36 months, respectively. This last 9-month period coincided with parturition and the entry into the milking herd. Real-time PCR showed that more than 75% of adult animals had low peripheral blood proviral load. Complementary, all infected animals showed low levels of provirus in milk and colostrum. The most important finding was that even when management procedures to prevent BLV iatrogenic transmission were followed, no significant change was observed in the prevalence after three years, strongly suggesting that other way/s of transmission play a key role under natural conditions. This study showed an interesting baseline to draw an alternative approach based on selective segregation according to the peripheral-blood proviral load as a potential indicator of risk transmission, and as an alternative to classical control measures. PMID- 21550734 TI - Myocardial function in offspring 5-8years after pregnancy complicated by preeclampsia. AB - INTRODUCTION: Preeclampsia and diabetic pregnancies share pathophysiological features suggested to influence epigenetic changes during foetal life with importance for later development and metabolic and cardiovascular diseases. AIM: Our objective was to study the myocardium in offspring after pregnancy complications. METHODS: Forty-five children (age 5-8 years) delivered from pregnancies complicated by preeclampsia (n = 25), diabetes mellitus type 1 (n = 8) or gestational diabetes mellitus (n = 12) were included. Fifteen children from uneventful pregnancies served as controls. Myocardial functions of right and left ventricle were examined by conventional Doppler and tissue Doppler imaging (TDI). RESULTS: No major differences were found in the myocardial function between offspring of pregnancy complications and control group. However, the preeclampsia group had smaller hearts, increased heart rate and increased late diastolic velocity (A'-wave) at mitral valve attachments shown by both pulsed wave and colour TDI compared to the control and diabetic groups together (p <= 0.01). CONCLUSION: Children born after preeclampsia may show effects of a negative impact on the heart already at the age of 5 to 8 years. The numbers of examined children were, however, limited. PMID- 21550735 TI - Mammary duct ectasia in children: report of a short series and review of the literature. AB - BACKGROUND: Mammary duct ectasia is uncommon in children, and is usually considered to be an acquired disease in adults. However the occurrence in infants and children suggest it may be developmental. AIMS: To report a case series of mammary duct ectasia, and review the published literature to ascertain the common findings and histological findings in children. STUDY DESIGN: Case series report and review of the literature. RESULTS: We report three cases of mammary duct ectasia, an unusual disease in children. The most common presenting features are a bloody nipple discharge; there may also be a palpable mass or general breast enlargement. Two patients in this series presented with large masses simulating other conditions. Summary of all reported cases in children found that symptoms can arise from infancy, but is most common around the age of 3 years (range 2 months to 13 years), with a 5:2 male:female ratio. Histology centres on peri ductal inflammation and dilation. Haemosiderin laden macrophages were seen commonly in this series; and may represent a histological marker in children. The disease is often self-limiting. Patients may require surgery for persistent nipple discharge or lump. CONCLUSIONS: Duct ectasia should be entertained in small infants and children presenting with both small and large peri-areolar breast masses and/or bleeding. The occurrence of the disease in infants suggests that mammary duct ectasia may represent a developmental anomaly in the paediatric population. PMID- 21550736 TI - Effect of empty uterine space on birth intervals and fetal and placental development in pigs. AB - A substantial loss of embryos occurs between Days 30 and 40 of pregnancy in the pig under crowded intrauterine conditions, but it is not clear whether this loss affects the growth of adjacent conceptuses. Birth intervals are known to increase with decreasing litter size, but the factors responsible are unknown. Two possibilities are that increased birth weight associated with reduced litter size and the empty uterine space and resulting constricted uterine regions that occur in pigs with small litters may impair piglet delivery. To address these, pregnant gilts were laparotomized on Day 35 of pregnancy and one or two fetuses were manually crushed through the uterine wall on the ovarian or cervical end of each uterine horn to create an empty uterine space behind or in front of the litter of piglets, respectively, in relation to the route of delivery from the uterus. A subset of gilts was slaughtered at 105 days of gestation to confirm that the empty uterine spaces were successfully created and to determine their effects on placental and fetal weights of adjacent conceptuses. At slaughter, the lengths of all externally visible empty constricted regions of the uterus were measured. The uterine horns were opened and the lengths of each placenta were measured from the umbilicus toward the ovary and toward the cervix to assess whether placentas developed symmetrically, and then each fetus and placenta was weighed. Fetal crushing successfully created constricted empty uterine regions on the ovarian and cervical ends of the uterine horns. Ovarian-side placental lengths were greater than cervical-side for conceptuses adjacent to fetuses crushed on the ovarian end of the horn. Cervical-side placental lengths were greater than ovarian-side for conceptuses adjacent to fetuses crushed on the cervical end. Both placental and fetal weights were greater (10% and 6%, respectively, P<0.05) for conceptuses adjacent to crushed fetuses compared to nonadjacent conceptuses. Remaining gilts were farrowed to determine the effect of litter size, average birth weights, and treatment on birth intervals of piglets, which were monitored using 24-h video surveillance. The negative association between number of piglets born alive and average birth interval was confirmed and was not explained by litter size-induced reduction in litter average birth weights. Birth intervals and stillbirth rate did not differ between cervically- and ovarian-treated gilts. These results indicate that conceptus loss on Day 35 of gestation can benefit the growth of adjacent placentas and fetuses, but the benefit is small. Increased average birth weight and the presence of empty uterine space that occurs when litter size is reduced does not fully explain the effect of litter size on birth intervals. PMID- 21550737 TI - Risk assessment of porcine reproductive and respiratory syndrome virus (PRRSV) transmission via somatic cell nuclear transfer (SCNT) embryo production using oocytes from commercial abattoirs. AB - Somatic cell nuclear transfer (SCNT) technology has become a powerful tool for reproductive biology to preserve and propagate valuable genetics for livestock. Embryo production through SCNT involves enucleation of the oocyte and insertion of a somatic donor cell into the oocyte. These procedures lead to a few small openings on the zona pellucida that may elevate risk of viral infection for the produced SCNT embryos. The oocytes used for SCNT are mainly obtained from abattoirs where viral contamination is almost inevitable. Therefore, a systematic evaluation of risk of disease transmission through SCNT embryo production is necessary prior large scale implementation of this technology in the livestock industry. The objective of the current study was to evaluate the risk of disease transmission via SCNT embryo production and transfer by testing for the presence of porcine reproductive and respiratory syndrome virus (PRRSV) throughout the process of SCNT embryo production. The presence of PRRSV in each step of SCNT embryo production, from donor cells to pre-implantation SCNT embryo culture, was carefully examined using a real-time PCR assay with a sensitivity of five copies per-reaction. All 114 donor cell lines derived from pig skin tissue over a period of 7 years in our facility tested negative for PRRSV. Out of the 68 pooled follicular fluid samples collected from 736 ovaries, only four (5.9%) were positive indicating a small amount of viral molecule present in the oocyte donor population. All 801 Day 7 SCNT embryos produced in four separate trials and over 11,571 washed oocytes obtained in 67 batches over 10 months tested negative. These oocytes were collected from multiple abattoirs processing animals from areas with high density of pig population and correspond to a donor population of over 5828 individuals. These results indicate that the oocytes from abattoirs were free of PRRSV infection and therefore could be safely used for in vitro embryo production. Additionally, the established SCNT embryo production system, including donor cell testing, oocytes decontamination, and pathogen free embryo reconstruction and culturing, bears no risk of PRRSV transmission. PMID- 21550738 TI - Profiles of blood biomarkers in alternating hemiplegia of childhood--increased MMP-9 and decreased substance P indicates its pathophysiology. AB - Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by repeated plegic attacks, movement disorders, autonomic phenomena, and developmental delay. To obtain insights into the pathophysiology of AHC, we determined the concentrations of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of MMP-1 (TIMP-1), calcitonin gene-related peptide (CGRP), and substance P (SP) in the serum/plasma of AHC patients (n=6) and control subjects (n=11) by performing enzyme-linked immunosorbent assay (ELISA). Decreased levels of serum SP (382+/-161 pg/ml), increased levels of plasma MMP-9 (111.0+/-99.3 ng/mL) and increased MMP-9/TIMP-1 ratio (0.65+/-0.44) were revealed, compared to those in control subjects (SP: 620+/-223 pg/mL, p<0.05; MMP-9: 33.5+/-20.3 ng/mL, p<0.05; MMP-9/TIMP-1 ratio 0.21+/-0.09, p<0.005). Serum CGRP levels in AHC patients (32.6+/-14.4 pg/mL) were comparable to those in control subjects (37.0+/ 17.0 pg/mL). Increased MMP-9 levels may be linked to the vascular insult and is common in migraineurs. However, because AHC patients showed different changes in SP and CGRP levels compared to those shown by migraineurs, these results suggest that AHC has a pathomechanism different from the hypothesis of trigeminovascular theory. Decreased SP may represent the autonomic dysfunction in AHC, for which an etiology with progressive neuronal damage can be hypothesized. PMID- 21550739 TI - Repeated seizures induce prefrontal growth disturbance in frontal lobe epilepsy. AB - BACKGROUND: The possible consequences of seizures in the immature brain have been the subject of much conjecture. We prospectively measured frontal and prefrontal lobe volumes using three-dimensional (3D) magnetic resonance imaging (MRI)-based volumetry in patients with frontal lobe epilepsy (FLE) presenting with the same seizure semiology. The pathogenesis of repeated seizure-induced brain damage is discussed herein. METHODS: Serial changes in regional cerebral volumes were measured in two patients with FLE presenting with intractable clinical courses and cognitive impairments/behavioral problems (FLE(+)) and four FLE patients without cognitive impairments/behavioral problems (FLE(-)). Eleven normal subjects (4-13 years old) served as controls. Volumes of the frontal and prefrontal lobes were determined using a workstation, and the prefrontal-to frontal lobe volume ratio was calculated. RESULTS: Frontal and prefrontal lobe volumes revealed growth disturbance in FLE(+) compared with those of FLE(-) and control subjects. In addition, prefrontal-to-frontal lobe volume ratio increased serially in FLE(-) similarly to controls, but was stagnant or decreased in FLE(+). Prefrontal growth also revealed more rapid recovery in a FLE(+) patient with shorter active seizure period. CONCLUSION: These findings suggest that repeated seizures may lead to prefrontal growth disturbance. The occurrence of frequent seizures in patients with FLE may be associated with prefrontal lobe growth retardation, which relates to neuropsychological problems and ultimate neuropsychological outcome. PMID- 21550740 TI - Technical innovation: wire guided ductography. AB - To introduce an easy and improved technique for performing ductography using inexpensive easily available intravenous cannula. Guide wire: Prolene/Surgipro 3 0 (Polypropylene mono filament non-absorbable surgical suture). A plastic 26 G intravenous cannula. Disposable syringe 2 ml. Non-ionic contrast (low density like Omnipaque 240 mg I/I). The guide wire (Prolene 3-0) is introduced into the orifice of the duct heaving discharge and 26 G intravenous plastic cannula is then passed over the guide wire. The cannula is advanced in the duct over guide wire by spinning around it. When the cannula is in place the guide wire is removed. Any air bubbles present in the hub of the cannula can be displaced by filling the hub from bottom upwards with needle attached to contrast filled syringe. 0.2-0.4 ml non-ionic contrast is gently injected. Injection is stopped if the patient has pain or burning. Magnified cranio-caudal view is obtained with cannula tapped in place and gentle compression is applied with the patient sitting. If duct filling is satisfactory a 90* lateral view is obtained. A successful adaptation of the technique for performing ductography is presented. The materials required for the technique are easily available in most radiology departments and are inexpensive, thus making the procedure comfortable for the patient and radiologist with considerable cost effectiveness. PMID- 21550741 TI - Diffusion-weighted imaging of the brain at 7 T with echo-planar and turbo spin echo sequences: preliminary results. AB - Ultra-high-field clinical MRI scanners (e.g., 7 T and above) are becoming increasingly prevalent and can potentially enhance diagnostic ability through higher contrast, resolution and/or sensitivity. Diffusion-weighted MRI is a highly valued component in today's radiological exam and may benefit from the enhanced signal-to-noise ratio provided by high field with the appropriate imaging strategy. The most common diffusion pulse sequence readout (echo-planar imaging (EPI)) has been widely employed for in vivo human 7 T diffusion tensor imaging (DTI). In this article, we present results of brain DTI at 7 T with two diffusion-weighted imaging pulse sequence readouts: echo-planar imaging (EPI-DTI) and turbo spin echo (TSE-DTI). Results indicate that analogous coverage, quality and resolution typical of lower field (2 mm) can be obtained by properly processed EPI-DTI at 7 T, and, with some reduction in efficiency and sharpness, TSE-DTI at 7 T. Furthermore, 7 T TSE-DTI shows promise in obtaining higher resolution results in targeted acquisitions of specific brain areas. PMID- 21550742 TI - Magnetic resonance diffusion-weighted imaging: quantitative evaluation of age related changes in healthy liver parenchyma. AB - The purpose of this study was to verify in healthy liver parenchyma the possible influence of age on DwI-related parameters: apparent diffusion coefficient (ADC), perfusion fraction (PF), diffusion and pseudodiffusion coefficient (D and D*). Forty healthy adult volunteers (age range 26-86 years), divided into four age groups, were prospectively submitted to a breath-hold magnetic resonance diffusion imaging (MR-DwI) (two b values, 0-300 and 0-1000 s/mm2). A smaller cohort of 16 subjects underwent a free-breath multi-b acquisition (16 b values, 0 750 s/mm2). Quantitative analysis was performed by two observers with manually defined regions of interest, on the most homogeneous portion of the right liver lobe. Individual and group statistical analysis of data was performed: ANOVA to establish differences between groups and Pearson correlation coefficient to investigate the association between DwI parameters and age. The mean, S.D. and 95% limits of agreement of ADC values for each age-defined group are reported. ANOVA showed no significant differences between group means (P always >.05). No significant correlation between subjects' age and DwI parameters was established, both in breath-hold and free-breath acquisitions, on the whole range of adopted b values. Our study conducted on healthy liver parenchyma shows that there are no significant differences in ADC, PF, D and D* of younger or older subjects. PMID- 21550743 TI - Quantification of Gd-DTPA concentration in neuroimaging using T13D MP-RAGE sequence at 3.0 T. AB - PURPOSE: To propose a simple and accurate quantitative method based on the linear relationship between magnetic resonance (MR) signal enhancement (DeltaSI=SI(postcontrast)-SI(precontrast)) and gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) concentration (C) by using T1 weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo (T13D MP-RAGE) sequence for the in vivo measurement of Gd-DTPA concentration in real-time neuroimaging at 3.0 T. METHODS: Phantom experiment was carried out to study the linear fitting of signal intensity change vs. Gd-DTPA concentration (DeltaSI-C) curve. A goodness-of-fit test was performed to compare the accuracy between the proposed method and the conventional method based on longitudinal relaxation rate (R1=1/T1) measurement. The influences on the goodness of fit (R2) and the signal-to-noise ratio (SNR) by sequence parameters were explored. Six human subjects with different brain tumors, who underwent a Gd-DTPA-enhanced MRI, were enrolled for in vivo application of the novel method. RESULTS: A good linear relationship between DeltaSI and Gd-DTPA concentration existed over the concentration range of 0-1 mM (R2=0.985). The linearity of the DeltaSI-C curve was as good as that of the 1/T1-C curve (R2=0.988). Concentrations calculated by both methods had a strong correlation (R2=0.920). An improved linearity of the DeltaSI-C curve and an increased SNR can be achieved using sequences with a shorter inversion time (TI) and a higher flip angle. The concentration range of Gd-DTPA in human brain tumors was within the quantitative scope of 0-1 mM. CONCLUSIONS: The proposed quantitative method based on DeltaSI measurement is accurate and applicable for real-time neuroimaging at 3.0 T. PMID- 21550744 TI - Reconstructing very short TE phase rotation spectral data collected with multichannel phased-array coils at 3 T. AB - Phased-array volume coils were used in conjunction with the phase rotation STEAM (PR-STEAM) spectroscopy technique to acquire very short TE data from the anterior cingulate gyrus at 3 T. A method for combining PR-STEAM data from multiple subcoils is presented. The data were acquired from seven healthy participants using PR-STEAM (repetition time/mixing time/echo time=3500/10/6.5 ms, 6 cm(3), NEX=128, spectral width=2000 Hz, 2048 complex points, Deltaphi(1)=135 degrees , Deltaphi(2)=22.5 degrees , Deltaphi(3)=112.5 degrees and Deltaphi(ADC)=0 degrees ). In addition to the primary metabolites, LCModel fit results suggest that glutathione and glutamate can also be identified with Cramer-Rao lower bounds of 10% or less. PMID- 21550745 TI - A diffusion gradient optimization framework for spinal cord diffusion tensor imaging. AB - The uncertainty in the estimation of diffusion model parameters in diffusion tensor imaging (DTI) can be reduced by optimally selecting the diffusion gradient directions utilizing some prior structural information. This is beneficial for spinal cord DTI, where the magnetic resonance images have low signal-to-noise ratio and thus high uncertainty in diffusion model parameter estimation. Presented is a gradient optimization scheme based on D-optimality, which reduces the overall estimation uncertainty by minimizing the Rician Cramer-Rao lower bound of the variance of the model parameter estimates. The tensor-based diffusion model for DTI is simplified to a four-parameter axisymmetric DTI model where diffusion transverse to the principal eigenvector of the tensor is assumed isotropic. Through simulations and experimental validation, we demonstrate that an optimized gradient scheme based on D-optimality is able to reduce the overall uncertainty in the estimation of diffusion model parameters for the cervical spinal cord and brain stem white matter tracts. PMID- 21550746 TI - Evaluation of an edge-based registration method: application to magnetic resonance first-pass myocardial perfusion data. AB - PURPOSE: Quantification of cardiac magnetic resonance (CMR) myocardial perfusion remains time consuming since it requires manual interventions to compensate for motion. Thus, the aim of this study was to evaluate a semiautomated registration method. MATERIALS AND METHODS: A rigid edge-based registration algorithm was applied on 10 patients who had rest and stress CMR acquisitions on three slice levels (apical, midventricular and basal slices). Registration efficiency was assessed qualitatively by evaluating the quality of k-means maps in terms of symmetry and heart structures identification before and after registration and quantitatively by estimating noise amplitude within the myocardium. Finally, residual registration errors were manually estimated. RESULTS: Before registration, k-means maps were satisfactory for 15 of 30 slices at rest and for only 5 of 30 slices during stress. After registration, the k-means maps quality was satisfactory for 29 of 30 slices at rest and for 30 of 30 slices during stress. Moreover, registration reduced noise amplitude from 49+/-26 to 29+/-11 at rest (P<.01) and from 52+/-14 to 30+/-10 during stress (P<.01). The residual horizontal and vertical shifts were 0.06+/-0.12 and 0.04+/-0.08 mm at rest and 0.32+/-0.69 and 0.28+/-0.53 mm at stress. CONCLUSION: The registration was successfully tested on rest and stress CMR perfusion data. It provides a valuable basis for quantitative evaluation of myocardial perfusion. PMID- 21550747 TI - Geometric analysis of the b-dependent effects of Rician signal noise on diffusion tensor imaging estimates and determining an optimal b value. AB - The optimal diffusion weighting (DW) factor, b, for use in diffusion tensor imaging (DTI) studies remains uncertain. In this study, the geometric relations of DW quantities are examined, in particular, the effects of Rician noise in the measured magnetic resonance signal. This geometric analysis is used to make theoretical predictions for selecting a b value to reduce the influence of noise. It is shown that the optimal b value for DTI studies in healthy human parenchyma is approximately b=1200 s mm(-2), with a simple relation given as well for a given expected apparent diffusion coefficient. Monte-Carlo simulations on sets of realistic DTI measures are then performed, verifying the optimal DW for minimizing estimate errors. The effects of noise on various DTI parameters such as anisotropy indices (fractional anisotropy and scaled relative anisotropy), mean diffusivity, radial diffusivity, eigenvalues and the direction of the first eigenvector are investigated as well. PMID- 21550748 TI - An empirical investigation of motion effects in eMRI of interictal epileptiform spikes. AB - We recently developed a functional neuroimaging technique called encephalographic magnetic resonance imaging (eMRI). Our method acquires rapid single-shot gradient echo echo-planar MRI (repetition time=47 ms); it attempts to measure an MR signal more directly linked to neuronal electromagnetic activity than existing methods. To increase the likelihood of detecting such an MR signal, we recorded concurrent MRI and scalp electroencephalography (EEG) during fast (20-200 ms), localized, high-amplitude (>50 MUV on EEG) cortical discharges in a cohort of focal epilepsy patients. Seen on EEG as interictal spikes, these discharges occur in between seizures and induced easily detectable MR magnitude and phase changes concurrent with the spikes with a lag of milliseconds to tens of milliseconds. Due to the time scale of the responses, localized changes in blood flow or hemoglobin oxygenation are unlikely to cause the MR signal changes that we observed. While the precise underlying mechanisms are unclear, in this study, we empirically investigate one potentially important confounding variable - motion. Head motion in the scanner affects both EEG and MR recording. It can produce brief "spike like" artifacts on EEG and induce large MR signal changes similar to our interictal spike-related signal changes. In order to explore the possibility that interictal spikes were associated with head motions (although such an association had never been reported), we had previously tracked head position in epilepsy patients during interictal spikes and explicitly demonstrated a lack of associated head motion. However, that study was performed outside the MR scanner, and the root-mean-square error in the head position measurement was 0.7 mm. The large inaccuracy in this measurement therefore did not definitively rule out motion as a possible signal generator. In this study, we instructed healthy subjects to make deliberate brief (<500 ms) head motions inside the MR scanner and imaged these head motions with concurrent EEG and MRI. We compared these artifactual MR and EEG data to genuine interictal spikes. While per-voxel MR and per-electrode EEG time courses for the motion case can mimic the corresponding time courses associated with a genuine interictal spike, head motion can be unambiguously differentiated from interictal spikes via scalp EEG potential maps. Motion induces widespread changes in scalp potential, whereas interictal spikes are localized and have a regional fall-off in amplitude. These findings make bulk head motion an unlikely generator of the large spike-related MR signal changes that we had observed. Further work is required to precisely identify the underlying mechanisms. PMID- 21550749 TI - Expression of sigma receptors of human urinary bladder tumor cells (RT-4 cells) and development of a competitive receptor binding assay for the determination of ligand affinity to human sigma(2) receptors. AB - A selective competitive binding assay for the determination of the affinity of compounds to the human sigma(2) receptor using 96-well multiplates and a solid state scintillator was developed. In the assay system, [(3)H]ditolylguanidine (DTG) was used as radioligand and membrane homogenates from human RT-4 cells physiologically expressing sigma(2) receptors served as receptor material. In order to block the interaction of the unselective radioligand [(3)H]DTG with sigma(1) receptors, all experiments were performed in the presence of the sigma(1) selective ligand (+)-pentazocine. The density of sigma(2) receptors of the cells was analyzed by a saturation experiment with [(3)H]DTG. The radioligand [(3)H]DTG was bound to a single, saturable site on human sigma(2) receptors, resulting in a B(max) value of 2108+/-162fmol/mg protein and K(d)-value of 8.3+/ 2.0nM. The expression of competing sigma(1) receptors was evaluated by performing a saturation experiment using the sigma(1) selective radioligand [(3)H](+) pentazocine, which resulted in a B(max) value of 279+/-40fmol/mg protein and K(d) value of 13.4+/-1.6nM. For validation of the sigma(2) binding assay, the K(i) values of four sigma(2) ligands (ditolylguanidine, haloperidol, rimczole and BMY 14802) were determined with RT-4 cell membrane preparations. The K(i) values obtained from these experiments are in good accordance with the K(i)-values obtained with rat liver membrane preparations as receptor material and with K(i) values given in the literature. PMID- 21550750 TI - The bougie: an inexpensive lifesaving airway device. AB - BACKGROUND: "Bougies," otherwise known as endotracheal tube introducers, remain preferred devices for the emergency physician when faced with a difficult airway. Bougies have high success rates for the prehospital provider and the first-time emergency department (ED) user, with few reported complications. Inexpensive, disposable models provide simple yet valuable tools in the challenging patient with an anterior airway or limited neck mobility. OBJECTIVES: Use of the bougie is similar to standard endotracheal intubation. Correct placement is determined by feeling "clicks" as the device passes over the tracheal rings and a "hold up" when entering the distal airways. CASE REPORTS: Three recent cases from our ED are briefly reported, in which the bougie was invaluable in the management of the difficult airway. All patients had limited visualization of the glottis but were intubated successfully. CONCLUSION: This article discusses three example cases, and then reviews the history of the bougie, placement technique, and current evidence for use. PMID- 21550751 TI - Left-sided acute appendicitis: a pitfall in the emergency department. AB - BACKGROUND: Acute appendicitis continues to be a condition at high risk for missed and delayed diagnosis. It characteristically presents with right lower quadrant pain after vague epigastric or periumbilical discomfort. Left-sided appendicitis is an atypical presentation and has been reported rarely. The majority of these cases have been described to be associated with congenital midgut malrotation, situs inversus, or an extremely long appendix. We report a case of left-sided acute appendicitis occurring in a patient with a redundant and hypermobile ascending colon. OBJECTIVES: To alert emergency physicians to an anatomical anomaly that could delay the diagnosis of appendicitis. CASE REPORT: A 50-year-old man presented with fever and left lower abdominal pain. Physical examination revealed local tenderness over the left lower quadrant. Abdominal computed tomography scan revealed a redundant, floating, ascending colon and inflammatory appendix adhering to the descending colon over the left lower abdomen. Exploratory laparotomy was performed and perforated appendicitis with turbid ascites was found during the surgery. Appendectomy was performed and the patient recovered uneventfully. CONCLUSION: This case is presented to increase awareness among emergency physicians of this anatomical variant and atypical presentation of appendicitis. PMID- 21550752 TI - Angiotensin-converting enzyme inhibitor angioedema. PMID- 21550753 TI - Basilar artery occlusion. PMID- 21550754 TI - Factors influencing emergency medicine physicians' management of sports-related concussions: a community-wide study. AB - BACKGROUND: Numerous guidelines to grade and manage sports-related concussions have been published. However, little is known about how frequently they are implemented in the emergency department. This study evaluates the current practices of emergency physicians (EPs) in managing sports-related concussions. OBJECTIVES: To evaluate the current practice of EP evaluation and management of sports-related concussions. METHODS: All EPs and emergency medicine residents in Kalamazoo County were surveyed regarding their management of sports-related concussions. The surveys obtained demographic data, participants' use of guidelines, and the importance of clinical and non-clinical factors in deciding when to allow a player to return to play. RESULTS: Of the 73 EP respondents, only 23% used a nationally recognized guideline, with no significant difference between attending and resident EPs. The symptomatic complaints of loss of consciousness, amnesia of the event, and difficulty concentrating were ranked most important by EPs in assessing patients with sports-related concussions. Among non-clinical factors, residents were significantly more likely than attendings to report that medical-legal, parental, and players' concerns were more likely to influence their decision in allowing a patient to return to play. CONCLUSION: EPs take into consideration important clinical factors in assessing patients with sports-related concussion. However, almost 75% do not use any nationally recognized guideline in their evaluation. Residents are more likely than attendings to be influenced by non-clinical factors. PMID- 21550755 TI - Tracheal perforation after thyroidectomy. PMID- 21550756 TI - Dedicated emergency department ultrasound rotation improves residents' ultrasound knowledge and interpretation skills. AB - BACKGROUND: Graduates of Emergency Medicine (EM) residency training programs are expected to be proficient in ultrasound. However, best practices for teaching residents ultrasonography has yet to be determined. STUDY OBJECTIVES: To determine if a dedicated Emergency Department (ED) ultrasound rotation objectively improves residents' EM ultrasound knowledge, interpretation accuracy, and clinical decision-making based on ultrasound findings. METHODS: EM residents completing a required ED-based ultrasound rotation were prospectively studied. Before the start of the rotation, each resident completed a 20-question pre-test. At the end of the rotation, residents completed a 20-question post-test. Both tests covered physics, trauma (focused assessment with sonography for trauma), first-trimester pregnancy, aorta, biliary, echocardiography, and vascular sonography, using a multiple-choice format. In both tests, ultrasound images were included in 11 of the 20 questions. The questions were divided into three categories: knowledge-based (8 questions), interpretation (9 questions), and clinical decision-making (3 questions), for both tests. Scores on pre-tests and post-tests were compared using a Wilcoxon signed-rank test. RESULTS: During the 2 year study period, 21 residents completed the rotation. The median pre-test score was 16 (interquartile range [IQR] 14.5-17), compared to a median post-test score of 19 (IQR 18-20), p < 0.001. CONCLUSIONS: A dedicated ED ultrasound rotation improves residents' EM ultrasound knowledge and interpretation accuracy based on ultrasound findings, as measured by improvement on ultrasound test scores. PMID- 21550757 TI - Tailored information for cancer patients on the Internet: effects of visual cues and language complexity on information recall and satisfaction. AB - OBJECTIVE: This study was designed to investigate the effects of visual cues and language complexity on satisfaction and information recall using a personalised website for lung cancer patients. In addition, age effects were investigated. METHODS: An experiment using a 2 (complex vs. non-complex language)*3 (text only vs. photograph vs. drawing) factorial design was conducted. In total, 200 respondents without cancer were exposed to one of the six conditions. RESULTS: Respondents were more satisfied with the comprehensibility of both websites when they were presented with a visual cue. A significant interaction effect was found between language complexity and photograph use such that satisfaction with comprehensibility improved when a photograph was added to the complex language condition. Next, an interaction effect was found between age and satisfaction, which indicates that adding a visual cue is more important for older adults than younger adults. Finally, respondents who were exposed to a website with less complex language showed higher recall scores. CONCLUSION: The use of visual cues enhances satisfaction with the information presented on the website, and the use of non-complex language improves recall. PRACTICE IMPLICATIONS: The results of the current study can be used to improve computer-based information systems for patients. PMID- 21550758 TI - Drug assertiveness and sexual risk-taking behavior in a sample of HIV-positive, methamphetamine-using men who have sex with men. AB - Drug assertiveness skills have been demonstrated to be effective in reducing substance use behaviors among patients with alcohol or heroin use disorders. This study examined the association between drug assertiveness and methamphetamine use, psychological factors, and sexual risk behaviors in a sample of 250 HIV positive men who have sex with men enrolled in a safer sex intervention in San Diego, CA. Less assertiveness in turning down drugs was associated with greater frequency and larger amounts of methamphetamine use, lower self-esteem, higher scores on a measure of sexual sensation seeking, and greater attendance at risky sexual venues. These data suggest that drug assertiveness training should be incorporated into drug abuse treatment programs and other risk reduction interventions for methamphetamine users. PMID- 21550759 TI - Expression of leptin, leptin receptor, and connective tissue growth factor in degenerative disk lesions in the wrist. AB - PURPOSE: The purpose of this study was to identify whether leptin and connective tissue growth factor (CTGF) occur in the degenerative fibrocartilage disk and whether cartilage cells express leptin receptors. METHODS: The study included 23 patients diagnosed with degenerative articular disk tears of the triangular fibrocartilage (TFC) (Palmer type 2C). Patients were divided into 2 groups based on ulna length: 1 group consisted of patients with an ulna-positive variance (group A), and the other group included patients with ulna-negative or -neutral variance (group B). After arthroscopic debridement of the TFC, histologic sections of biopsy specimens were prepared. The biopsy specimens were immunohistochemically analyzed, and the quantity of leptin-, CTGF-, and leptin receptor-positive cells was assessed. RESULTS: Cells positive for leptin, leptin receptor, and CTGF were found. The number of cells positive for leptin was significantly increased in specimens of patients with an ulna-negative variance (group B). In contrast, no significant difference was found for leptin receptor and CTGF in biopsy specimens of patients with ulna-positive or ulna negative/neutral variance. The inner, middle, and outer zones of the disk do not express significantly different quantities of marker-positive cells. CONCLUSIONS: Degenerative fibrocartilage disk tissue cells exhibit leptin receptors and are exposed to the markers leptin and CTGF, providing evidence of a local paracrine system and regenerative processes. Cells of disks from patients with an ulna neutral/negative length express significantly higher numbers of leptin-positive cells. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 21550760 TI - Comparison of the clinical outcome of double-bundle, anteromedial single-bundle, and posterolateral single-bundle anterior cruciate ligament reconstruction using hamstring tendon graft with minimum 2-year follow-up. AB - PURPOSE: The purpose of this study was to obtain more than 2 years' follow-up after surgery to investigate the effect of the difference in rotatory stability based on our previous data on the clinical outcome among 3 groups: double-bundle (DB) reconstruction group, anteromedial (AM) single-bundle reconstruction group, and posterolateral (PL) single-bundle reconstruction group. METHODS: We randomly separated 55 patients with anterior cruciate ligament rupture into 3 groups: 18 in DB group, 18 in AM group, and 19 in PL group. The mean follow-up period is 33.7 months for the DB group, 31.9 months for the AM group, and 33.2 months for the PL group. We evaluated the Lysholm score, Tegner score, anterior laxity with the KT-1000 arthrometer (MEDmetric, San Diego, CA), rotator instability with the pivot-shift test, and muscle strength with knee extensor and flexor isokinetic peak torques at 60 degrees /s. RESULTS: There were no significant differences in postoperative Lysholm score and Tegner score. Anterior stability of the knee, as measured by the KT-1000 arthrometer, was significantly better in the DB group than the PL group (P < .05). The negative rate of the manual pivot-shift test in the DB group was significantly superior to the PL group (P < .05). Muscle strength of the extensor in the DB group was significantly superior to that in the AM group (P < .05), and muscle strength of the flexor in the PL group was significantly inferior to that in both the DB and AM groups (P < .05). Two patients in the PL group had rerupture; however, there was no graft failure in the other groups. CONCLUSIONS: At 2 years' follow-up, patients undergoing DB anterior cruciate ligament reconstruction had greater extension strength than patients receiving an AM single-bundle reconstruction. The DB and AM groups had greater flexion strength than the PL group. The DB and AM groups had a similar rate of negative pivot-shift test results, whereas the PL group had fewer negative pivot-shift test results than the DB group. There were no KT-1000 side to-side differences between the DB and AM groups, whereas the DB group had better results than the PL group. Overall, the clinical outcome as measured by Lysholm and Tegner scores was not different between groups. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 21550761 TI - The use of a novel "conservative hip replacement" to reconstruct an osteoarthritic hip with an occluded femoral canal. AB - This case report describes the successful use of a novel "conservative hip replacement" in conditions precluding the use of a standard total hip arthroplasty in a 70-year-old man. The femoral canal was occluded because of previous surgery for a bone tumor in the subtrochanteric region. The patient continues to do well at 4 years with minimal discomfort. At this interval, the Oxford Hip Score was 35. This conservative hip replacement has been developed to preserve bone stock and produce more physiologic loading of the proximal femur. Its design has been produced, using plain radiographs and computed tomography, to maximize "fit and fill" of the femur. The neck supports standard modular heads, allowing the use of any bearing surface. The prosthesis has been rigorously laboratory tested. PMID- 21550762 TI - Knee simulator wear of vitamin E stabilized irradiated ultrahigh molecular weight polyethylene. AB - Wear and damage of ultrahigh molecular weight polyethylene (UHMWPE) tibial inserts used in total knee arthroplasty are accelerated by oxidation. Radiation crosslinking reduces wear but produces residual free radicals adversely affecting stability. One alternative to stabilize radiation-crosslinked UHMWPE is to infuse the material with vitamin E (vit E). We investigated the properties of 100-kGy e beam-irradiated UHMWPE that was subsequently doped with vitamin E in comparison with conventional UHMWPE. Both polymers were sterilized with gamma irradiation in vacuum packaging. Vitamin E-doped UHMWPE showed lower wear before and after aging (2.4 +/- 0.5 and 2.5 +/- 0.8 mg/million cycle, respectively, vs 26.9 +/- 3.5 and 40.8 +/- 3.0 mg/million cycle for conventional UHMWPE). Conventional UHMWPE showed oxidation after accelerated aging, and its mechanical properties were adversely affected, whereas vit E-doped UHMWPE showed no oxidation or changes in its mechanical properties. Vitamin E stabilization of radiation-crosslinked UHMWPE resulted in low wear and high oxidation resistance; it is an alternative load-bearing material for total knee applications. PMID- 21550763 TI - Initial experience of the Journey-Deuce bicompartmental knee prosthesis: a review of 36 cases. AB - We evaluated the effectiveness of a novel bicompartmental knee arthroplasty prosthesis for the treatment of degenerative disease affecting the medial and patellofemoral compartments. The study included 36 knees in 32 patients with a mean follow-up of 21 months. The mean Knee Society functional survey and Western Ontario McMaster Osteoarthritic Index Survey scores were 65.4 and 75.8, respectively. Thirty-one percent of patients were unsatisfied with the surgery, and 53% stated that they would not repeat the surgery. We report an overall survival rate of 86% with one catastrophically failed tibial baseplate. We conclude that this prosthesis provides inconsistent pain relief and unacceptable functional results for bicompartmental arthritis. Short-term survival of this prosthesis was unacceptably low, and therefore, we no longer implant it at our institution. PMID- 21550764 TI - Early failure of articular surface replacement XL total hip arthroplasty. AB - The ASR (articular surface replacement) XL (DePuy, Warsaw, Ind) metal-on-metal hip arthroplasty offers the advantage of stability and increased motion. However, an alarming number of early failures prompted the evaluation of patients treated with this system. A prospective study of patients who underwent arthroplasty with the ASR XL system was performed. Patients with 2-year follow-up or any revision were included. Failure rates, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and radiographs were evaluated. Ninety-five patients (105 hips) were included. There were 16 revisions. Thirteen (12%) were aseptic acetabular failures. Eight were revised for aseptic loosening; 4, for metallosis; 1, for malposition; 2, for infection; and 1, for periprosthetic fracture. Mean time to revision was 1.6 years (0.18-3.4 years). The ASR XL with a revision rate of 12% is the second reported 1 piece metal-on-metal system with a significant failure rate at early follow-up. This particular class of implants has inherent design flaws that lead to early failure. PMID- 21550765 TI - Dilute betadine lavage before closure for the prevention of acute postoperative deep periprosthetic joint infection. AB - This study evaluated the efficacy of a dilute Betadine (Purdue Pharma, Stamford, Conn) lavage in preventing early deep postoperative infection after total hip (THA) and knee (TKA) arthroplasty. A protocol of dilute Betadine lavage (0.35%) for 3 minutes was introduced to the practice of the senior author in June 2008. A total of 1862 consecutive cases (630 THA and 1232 TKA) performed before this were compared with 688 consecutive cases (274 THA and 414 TKA) after for the occurrence of periprosthetic infections within the first 90 days postoperatively. Eighteen early postoperative infections were identified before the use of dilute Betadine lavage, and 1 since (0.97% and 0.15%, respectively; P = .04). There were no significant demographic differences between the 2 groups. Betadine lavage before wound closure may be an inexpensive, effective means of reducing acute postoperative infection after total joint arthroplasty. PMID- 21550766 TI - Periacetabular osteolysis is the problem in contemporary total hip arthroplasty in young patients. AB - We retrospectively reviewed 474 patients (492 hips) with a contemporary cemented total hip arthroplasty (THA) (mean age, 38.9 years) and 504 patients (532 hips) with a cementless THA (mean age, 39.3 years). Patients were evaluated clinically and radiographically. The mean follow-up was similar (14.5 vs 14.8 years) in both groups. The mean postoperative Harris hip scores (93.6 vs 94.7 points), the mean Western Ontario and McMaster Universities Osteoarthritis Index scores (12 vs 13 points), and the mean University of California, Los Angeles activity scores (6.9 vs 7.1 points) were similar between the 2 groups. Incidence of acetabular osteolysis (16% vs 20%) and femoral osteolysis (8% vs 9%) was similar between the 2 groups. Survivorship of cup (86% vs 82%) and stem (98% vs 98.5%) was similar between the 2 groups. Periacetabular osteolysis constitutes the major challenge in modern THAs in young patients. PMID- 21550767 TI - Management of a pelvic mass following a worn uncemented total hip arthroplasty. AB - Intrapelvic granulomatous masses from polyethylene wear debris can easily be misdiagnosed if orthopaedic etiology is not considered. This article presents the case of a 50 year old woman with history of hip joint trauma and total hip arthroplasty (THA) revisions who presented to her gynecologist with a large intrapelvic cyst. Prolonged use of an indwelling drain and failure to recognize the orthopaedic origin of the mass resulted in articular infection that required an antibiotic spacer and subsequent THA revision. This patient did not have pain or evidence of medial wall defects, but did have a history of trauma, revision arthroplasty and acetabular allograft. In the presence of these findings, wear induced polyethylene debris should be considered in the differential diagnosis of the pelvic mass. PMID- 21550768 TI - Revision for recurrent instability: what are the predictors of failure? AB - Dislocation is a common complication following total hip arthroplasty (THA). In this study, we evaluated treatment strategies in patients undergoing revision THA for instability. A total of 156 hips in 154 patients underwent revision THA for instability between 2000 and 2007 at our institution. Demographic data and surgical treatment used were analyzed to determine risk factors for failure. Revision treatments included acetabular components in 100 hips, liner exchange in 56 hips, and femoral and acetabular components in 13 hips. Thirty-three (21.2%) had further dislocation. Isolated liner revision (P = .004), previous revision arthroplasty (P < .05), and the use of a 28-mm femoral head were associated with higher failure rates. A total of 20.3% (12/59) of constrained liners failed. Isolated liner exchange, history of revision, and use of a 28-mm head were associated with failure in revision THA for instability. PMID- 21550769 TI - Assessment of second language proficiency in bilingual children with specific language impairment: a clinical perspective. AB - The goal of this study was to examine to what extent the conditions of restricted input of L2 and SLI have an additive impact on language acquisition. Therefore, the Dutch language achievement of 6-, 7-, and 8-year-old bilingual children with SLI was compared with that of typically developing monolingual Dutch children, typically developing bilingual children, and monolingual Dutch children with SLI. Assuming that speaking a language in varying environments involves distinct subskills that can be acquired in differential patterns, the achievement of phonological, lexical, morphosyntactic and textual abilities were assessed separately. For each of these abilities, it was determined to what extent the conditions of restricted input (first vs. second language) and language deficit (typically developing vs. SLI) cause stagnation or a delay in language acquisition. Bilingual children with SLI perform at a lower level than the other groups in almost all aspects of achievement in Dutch. For language tasks related to the mental lexicon and grammar, an additional disadvantage was evidenced as a result of the combination of learning Dutch as second language and having SLI. PMID- 21550770 TI - Sensory processing dysfunctions as expressed among children with different severities of intellectual developmental disabilities. AB - High frequency of sensory processing dysfunctions (SPD) is prevalent among children with intellectual developmental disabilities and contributes to their maladaptive behaviors. However, the knowledge about the expressions of SPD in different levels of IDD severity is limited. As SPD may reduce adaptive responses and limit participation, this knowledge should be elaborated. The purpose of the present study was to examine the specific expressions of sensory processing among children with different severity levels of IDD. Participants were 91 children aged 4-9 years with mild, moderate severe-profound and IDD. Their parents completed the short sensory profile (SSP). According the results, SPD were manifested across all levels of IDD. Groups differed in specific behaviors related to sensory stimuli. The highest percentage of children with severe sensory processing difficulties was found among children with mild and sever IDD level. SPD may characterize children with all severity levels of IDD. Nevertheless, the probability that children with a specific IDD level will be more vulnerable to specific aspects of SPD emphasizes the need for early evaluation and intervention to address the specific sensory needs of children with different IDD levels. This may enhance their development, performance and participation in daily living. PMID- 21550771 TI - (Instrumental) activities of daily living in older adults with intellectual disabilities. AB - Daily living skills are important to ageing adults with intellectual disabilities (ID). The purpose of this study was to investigate the level of these skills in older adults with ID and to investigate the influence of gender, age, level of ID and mobility on these skills. Daily living skills were measured with the Barthel Index (for Activities of Daily Living, ADL) and the Lawton IADL scale (for Instrumental Activities of Daily Living, IADL) in 989 adults with ID aged 50 years and over living in community-based and institutional settings. Descriptives were presented by categories of gender, age, level of ID and mobility. Regression analysis was used to investigate the influence of these variables on total and item scores of ADL and IADL questionnaires. ADL and IADL scores in older adults with ID are comparable to those of vulnerable patient groups. Total ADL score was mainly determined by mobility, while total IADL score was mainly determined by level of ID. Of all 18 separate items of these questionnaires, 11 were determined more by mobility than level of ID. The Barthel Index and Lawton IADL scale are recommended for future use in research and clinical practice in this group. This study stresses the need to support mobility older adults with ID as much as possible, in order to optimize independency in this group. PMID- 21550772 TI - A comprehensive vowel space for whispered speech. AB - Whispered speech is a relatively common form of communications, used primarily to selectively exclude or include potential listeners from hearing a spoken message. Despite the everyday nature of whispering, and its undoubted usefulness in vocal communications, whispers have received relatively little research effort to date, apart from some studies analyzing the main whispered vowels and some quite general estimations of whispered speech characteristics. In particular, a classic vowel space determination has been lacking for whispers. For voiced speech, this type of information has played an important role in the development and testing of recognition and processing theories over the past few decades and can be expected to be equally useful for whisper-mode communications and recognition systems. This article aims to redress the shortfall by presenting a vowel formant space for whispered speech and comparing the results with corresponding phonated samples. In addition, because the study was conducted using speakers from Birmingham, the analysis extends to discuss the effect of the common British West Midlands accent in comparison with Standard English (Received Pronunciation). Thus, the article presents the analysis of formant data showing differences between normal and whispered speech while also considering an accentual effect on whispered speech. PMID- 21550773 TI - Passaggio in the professional tenor voice--evaluation of perturbation measures. AB - PURPOSE: Vocal stability throughout the passaggio region in professional singers is an unclarified area of research. METHOD: The acoustic and electroglottographic signals of ascending and descending frequency transitions from 220 to 440 Hz (and vice versa) on the vowels /a, e, i, o, u, ae/ were analyzed in eight professional tenors. The frequency transitions were accompanied by shifts in register conditions, from modal to unmodulated naive falsetto and modal to voix mixte (and vice versa). RESULTS: For ascending tasks, it was found that frequency perturbation values (jitter and relative average perturbation) were higher for the frequency transition and upper frequency produced in naive falsetto or voix mixte compared with lower frequency produced in modal register. No such higher values were found for descending tasks. Shimmer was increased during frequency transitions between modal and naive falsetto. The electroglottographic contact quotient showed a positive correlation with the sound pressure level for the modal register and voix mixte but not for the naive falsetto. CONCLUSION: In our study, ascending tasks, including register transitions, are different from descending tasks with regard to frequency perturbation in professional tenors. PMID- 21550774 TI - Laryngeal aerodynamic analysis in assisting with the diagnosis of muscle tension dysphonia. AB - OBJECTIVE/HYPOTHESIS: To estimate the aerodynamic multiparameters for patients with muscular tension dysphonia (MTD) and evaluate voice aerodynamic analysis for assisting the diagnosis of this disorder. STUDY DESIGN: A prospective study. METHODS: Voice aerodynamic parameters, including subglottal pressure (SGP) level, glottal resistance (GR), mean airflow rate (MFR), and maximum phonation time (MPT), for 26 MTD patients and 27 normal adults were analyzed using receiver operating characteristics (ROC) analysis and multivariate logistic regression. RESULTS: For male samples, MTD patients had higher SGP (P=0.001), higher GR (P=0.012), lower MFR (P=0.042), and shorter MPT (P=0.027), whereas for female samples, the difference between cases and controls was statistically significant only in SGP (P<0.001) and MPT (P<0.001). ROC analysis showed that the threshold of 8.175 cm H(2)O for SGP achieved a good classification for MTD, with an adequate sensitivity (76.9%) and the perfect specificity (100%). Finally, multivariate logistic regression established a credible model (with SGP and MPT as the predictors) for classifying MTD, with a 92.5% percentage correct. CONCLUSIONS: This analysis indicates that aerodynamics evaluation could help the diagnosis of MTD patients, jointly with medical history scrutiny, physical examination, fibrolaryngoscopy, and/or videoendostroboscopy. PMID- 21550775 TI - Three-dimensional morphometric analysis of cricoarytenoid subluxation. AB - OBJECTIVES: To create a high-resolution three-dimensional (3D) reconstruction of a case of cricoarytenoid subluxation and perform quantitative analysis to understand its anatomy and functional consequence. STUDY DESIGN: Computational, with image processing and analysis. METHODS: High-resolution axial computed tomography images of the larynx of a patient with an anteriorly subluxed arytenoid were processed with custom MATLAB routines to create a versatile 3D reconstruction. The geometries of the subluxed and nonsubluxed arytenoids were quantitatively compared. RESULTS: The anteriorly subluxed arytenoid has an inferoposteriorly displaced vocal process (VP), resulting in an elongated and inferiorly positioned vocal fold. The paradoxical posterior displacement of the VP with elongation of the vocal fold has not been described previously. Quantitative analysis reveals significant rotational components and a unidirectional translational component in anterior arytenoid subluxation. CONCLUSIONS: Quantitative 3D analysis yielded insight into the biomechanics of anterior arytenoid subluxation. Subluxation in this case appeared to involve more pure rotational than translational motion. Overrocking of the subluxed arytenoid can produce paradoxical elongation of the involved vocal fold. PMID- 21550776 TI - Cooperative regulation of vocal fold morphology and stress by the cricothyroid and thyroarytenoid muscles. AB - Voice is produced by vibrations of vocal folds that consist of multiple layers. The portion of the vocal fold tissue that vibrates varies depending primarily on laryngeal muscle activity. The effective depth of tissue vibration should significantly influence the vibrational behavior of the tissue and resulting voice quality. However, thus far, the effect of the activation of individual muscles on the effective depth is not well understood. In this study, a three dimensional finite element analysis is performed to investigate the effect of the activation of two major laryngeal muscles, the cricothyroid (CT) and thyroarytenoid (TA) muscles, on vocal fold morphology and stress distribution in the tissue. Because structures that bear less stress can easily be deformed and involved in vibration, information on the morphology and stress distribution may provide a useful estimate of the effective depth. The results of the analyses indicate that the two muscles perform distinct roles, which allow cooperative control of the morphology and stress. When the CT muscle is activated, the tip region of the vocal folds becomes thinner and curves upward, resulting in the elevation of the stress magnitude all over the tissue to a certain degree that depends on the stiffness of each layer. On the other hand, the TA muscle acts to suppress the morphological change and controls the stress magnitude in a position dependent manner. Thus, the present analyses demonstrate quantitative relationships between the two muscles in their cooperative regulation of vocal fold morphology and stress. PMID- 21550777 TI - The effectiveness of group voice therapy: a group climate perspective. AB - OBJECTIVES/HYPOTHESIS: Group therapy has frequently been adopted as a service delivery model for providing voice therapy. However, currently no literature has focused on understanding the underlying processes that are unique to group therapy, which contribute to treatment success. This study aimed at investigating the role of group climate in voice group therapy. STUDY DESIGN: Prospective case series. METHODS: Twelve teachers with hyperfunctional dysphonia attended eight sessions of group voice therapy. Treatment comprised both direct and indirect voice therapy. Therapy techniques were introduced and practiced in a large group and small group format. Outcome measures were taken using perceptual evaluation, videostroboscopy measures, voice-related quality-of-life (V-RQOL) measures, and vocal symptom scores. The Group Climate Questionnaire was used to measure the underlying process of group therapy. Treatment outcome was measured immediately posttreatment and at 6-months posttreatment. RESULTS: Results indicated statistically significant improvement in the participants' V-RQOL measures and the vocal symptom scores. Treatment gain was noted to sustain up to 6-months posttreatment. The Group Climate Questionnaire indicated that the treatment group is considered as "engaging" rather than "conflicting," which is considered to be associated with positive treatment outcome. CONCLUSION: Group therapy as a service delivery model possesses many advantages from the psychosocial, clinical, health resources allocation perspective. This study demonstrated that group climate plays a significant role in determining treatment success in group voice therapy. PMID- 21550778 TI - Coping strategies in voice disorders of a Brazilian population. AB - The purpose of this research is to explore coping strategies of individuals with and without vocal complaint and to examine relationships between the type of coping and vocal complaint; vocal symptoms; vocal self-assessment; perceptual analysis and states of depression, anxiety, and aspects related to self-esteem; and locus of control. One hundred seventy-eight subjects with (n=87) and without vocal (n=91) complaint completed the following analysis: identification and characterization questionnaire, vocal self-assessment, perceptual analysis, Voice Disability Coping Questionnaire (VDCQ)-Brazilian Version, Beck Depression Inventory, Rosenberg Self-esteem Scale, Spielberger State-Trait Anxiety Inventory, and Health Locus of Control Scale. Age (P=0.219) and sex (P=0.132) were similar for both groups. The groups were statistically different for the following vocal characterization: number of symptoms, voice complaint, vocal self assessment, and perceptual analysis. Conversely, the groups did not differ on states of depression, anxiety, and aspects related to self-esteem; and locus of control. Mean coping scores for the group with vocal complaint was 51.86 and for the group without vocal complaint was 23.18. Furthermore, men and women did not differ on the coping strategies reported (P=0.750); however, individuals with vocal complaint reported statistically more strategies than the individuals without vocal complaint (P<0.001). Problem-focused strategies were more frequently reported by individuals with vocal complaint (46.7%). Coping results correlated (Spearman's r) positively with vocal perceptual analysis (P=0.036), depression (P=0.006), and anxiety (P=0.022), and correlated negatively with locus of control (P=0.001). No correlation was found between coping and the other variables studied. These findings indicate that people with vocal complaint use a variety of coping strategies, problem focused in particular, to deal with their voice problems. Coping results appear to be associated with perceptual characteristics of voice and some traits, such as depression, anxiety, and locus of control. PMID- 21550779 TI - The effect of resonance tubes on glottal contact quotient with and without task instruction: a comparison of trained and untrained voices. AB - Phonation into narrow tubes or straws has been used as a voice training and voice therapy technique and belongs to a group of techniques known as semi-occluded vocal tract exercises. The use of what are called resonance tubes has received renewed attention in the voice research literature, in both theoretical and empirical studies. The assumption is that the partially occluded and lengthened vocal tract alters supraglottal acoustics in such a way as to allow phonation near a lowered first vocal tract formant, which has been suggested as a way to bring about a more efficient glottal closure pattern for sustained oscillation. In this study, two groups of male participants, 10 with no vocal training and 10 with classical vocal training, phonated into a resonance tube for approximately 1 minute. Electroglottography was used to estimate glottal contact quotient (CQ) during spoken /a/ vowels before tube phonation, during tube phonation, and again during spoken /a/ vowels after tube phonation. Half of each group of participants was made to keep pitch and loudness consistent for all phases of the experiment, replicating the method of a previous study by this author. The other half was instructed to practice phonating into the resonance tube before collecting data and was encouraged to find a pitch and loudness combination that maximized ease of phonation and a sense of forward oral resonance. Glottal CQ altered considerably from baseline for almost all participants during tube phonation, with a larger variability than that during vowel production. Small differences in glottal CQ were found as a function of training and instruction, with most participants' CQ increasing during tube phonation. A small post-tube phonation effect was found primarily for the trained and instructed group. Secondary single subject analyses revealed large intersubject variation, highlighting the highly individualized response to the resonance tube task. Continued study of resonance tubes is recommended, comparing both male and female as well as vocally trained and untrained participants. Future studies should continue to examine systematic variations in task instruction, length of practice, and resonance tube dimensions. PMID- 21550780 TI - Study on the simplified Chinese version of the voice handicap index. AB - OBJECTIVES: To investigate the characteristics of the simplified Chinese versions of the Voice Handicap Index (VHI). METHODS: Cluster analysis was performed on the VHI scores of 1766 dysphonic patients to screen for items to compile different simplified Chinese VHI versions. The VHI scores of 3825 dysphonic patients (in which 424 patients have undertaken surgical treatment) and 120 control subjects were assessed using the simplified versions, and the results were compared between the simplified versions and the original version. RESULTS: Two simplified versions of VHI-10 (10 items) and VHI-13 (13 items) were compiled after the cluster analysis. Their internal consistency reliabilities were 0.939 and 0.936, the test-retest reliability coefficients were 0.995 and 0.993, and their correlation coefficients to the original VHI questionnaire were 0.972 and 0.973, respectively. The scores of VHI-10 and VHI-13 were significantly higher in dysphonic patients than in control subjects (Z=17.42, Z=17.46; P=0.000). The mean ratios of the VHI-10 and VHI-13 scores to the original VHI questionnaire scores in dysphonic groups were found to be consistently greater than expected (0.333 and 0.433, respectively). The VHI scores from the simplified versions were classified on the basis of the overall grade severity of dysphonia according to the physicians' subjective auditory assessment, and when the scores among the different groups were compared, there was a statistical difference between the VHI-10 and VHI-13 scores (Z=5.735-9.861, P=0.000). The VHI-10 and VHI-13 patient scores declined significantly after treatment (P<0.05). CONCLUSIONS: Both of the simplified Chinese versions, VHI-10 and VHI-13, had good reliability and validity. They could be used in the dysphonic self-assessment as the simplified Chinese VHI questionnaire. VHI-10 was found to be more concise and more widely applicable than VHI-13. PMID- 21550781 TI - Voice-related quality of life in adults with neurofibromatosis type 1. AB - OBJECTIVE: Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder, which occurs in about one in 3000-4000 people. Its hallmark features include multiple cafe-au-lait spots and neurofibromas. Voice characteristics of NF1 patients have been documented using both subjective and objective evaluations. However, the relative impact of these voice characteristics on daily activities has, as far as we know, not been examined yet. METHODS: Thirty adults with NF1 were asked to complete the Flemish Dutch version of the Voice Handicap Index (VHI). Additionally, the level of severity of NF1 was rated and Dysphonia Severity Indices (DSIs) were collected. The results of the patient group were compared with those of a healthy control group frequency matched for age, gender, smoking behavior, and vocal usage. RESULTS: NF1 patients obtained significantly higher VHI scores compared with healthy controls. Differences between the patient and control group were especially marked for daily functioning and affective responses. Men and women with NF1 had similar VHI scores, but total VHI score did increase with age. An apparent association between VHI, DSI, and severity of NF1 could not be demonstrated. CONCLUSION: It is likely that the elevated VHI scores observed in the patient group were not merely caused by the voice characteristics associated with NF1. A flow over from other psychophysical issues relating to the disease might have played a role. PMID- 21550782 TI - Temporalis muscle flap for immediate reconstruction of maxillary defects: review of 39 cases. AB - This study evaluated the advantages and complications associated with immediate reconstruction of maxillary defects after maxillectomy and the relationship between defect tissues classification and postoperative results after using the temporalis muscle flap. In this retrospective study, the records of 39 patients who underwent immediate reconstruction surgery using temparolis myofascial flap following maxillectomy from April 1989 to February 2009 were reviewed. Demographic data, features of the disease, follow-up, outcome and complications were analysed. Patients were classified into three groups, to ascertain the influence between defect classification and functional results, aesthetic outcomes and complications in each group. Of the 39 cases, all tissue flaps survived. 5 patients underwent postoperative radiotherapy, which did not seem to influence the outcome of the reconstructive procedure. There was one case of oroantral fistula, which could easily be obturated with the prosthesis. One patient developed haematoma in the donor site 5 days after surgery. Postoperative speech was good, facial appearance was normal and ocular function remained unchanged. Postoperative aesthetic and functional results were satisfying. The temporalis muscle flap can be considered as a first-line reconstructive option for maxillary defects. Acceptable functional and aesthetic outcomes can be expected in high rates. PMID- 21550783 TI - Inequalities in the provision of cardiovascular screening to people with severe mental illnesses in primary care: cohort study in the United Kingdom THIN Primary Care Database 2000-2007. AB - BACKGROUND: People with severe mental illnesses (SMI), including schizophrenia, are at increased risk of cardiovascular disease (CVD). Guidelines recommend regular CVD screening and in the United Kingdom, since 2004, General Practitioners are remunerated for annual reviews. OBJECTIVES: To compare annual rates of CVD screening provision in people with and without SMI between 2000 and 2008. METHOD: We identified 18,696 people with SMI and 95,512 people without SMI in the UK The Health Improvement Network (THIN) primary care database. We compared the rates of measurement of blood pressure (BP), glucose, cholesterol and body mass index (BMI). RESULTS: Prior to 2004, all people with SMI, were significantly less likely to receive each measurement, (including people above and below 60 years of age). In 2003; adjusted incidence rate ratios (95% CI) for screening in people with SMI under 60 years compared to people without SMI were: BMI: 0.62 (0.58-0.65); BP: 0.59 (0.56-0.62); glucose: 0.66 (0.61-0.70) and cholesterol: 0.54 (0.49-0.59). By 2007 people with SMI under 60 were equally likely receive a measurement of BMI: 1.00 (0.96-1.04), glucose: 1.00 (0.96-1.05) and cholesterol: 0.95 (0.90-1.0); the gap in screening for BP had narrowed 0.87 (0.83-0.90). However people with SMI over 60 years of age remained significantly less likely to be screened. There was little difference in screening according to social deprivation. CONCLUSIONS: In UK primary care, people with SMI over 60 years of age remain less likely than the general population to receive annual CVD screening despite higher risk of developing CVD. PMID- 21550784 TI - Effects of galanin message-associated peptide and neuropeptide Y against various non-albicans Candida strains. AB - Antimicrobial peptides (AMPs) could represent promising therapeutic agents against fungal pathogens, especially in cases of pathogen resistance to common antifungal substances. The neuropeptides galanin message-associated peptide (GMAP) and neuropeptide Y (NPY) are both potent AMPs against certain microbes. The objective of this study was to test clinically relevant non-albicans Candida strains (C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis, C. pelliculosa, C. tropicalis and C. utilis) with regard to their susceptibilities to NPY and GMAP. GMAP showed a higher potency than NPY, which only inhibited growth of some isolates of C. krusei, C. tropicalis and C. utilis. Interestingly, the fluconazole-resistant C. krusei was susceptible to both AMPs. In summary, we show that these neuropeptides have Candida strain-dependent antifungal activity, which in some cases does not match the susceptibility of the strains to the positive controls fluconazole and magainin I. Thus, the findings demonstrate the therapeutic potential of these AMPs in cases of resistance to traditional antifungal substances. This study also confirms the research on neuropeptides as potential fungicides, which are still in the early stages. The results also suggest that testing of strain-specific susceptibility is mandatory. PMID- 21550785 TI - Class 2 integrons in multidrug-resistant Acinetobacter baumannii circulating in different Brazilian geographic regions. PMID- 21550786 TI - Meticillin-resistant Staphylococcus aureus in pigs from Thailand. PMID- 21550787 TI - Large-scale fabrication of two-dimensional spider-web-like gelatin nano-nets via electro-netting. AB - For the first time, two-dimensional (2D) gelatin nano-nets are fabricated by regulating the solution properties and several process parameters during electrospinning/electro-netting. The spider-web-like nano-nets that comprise interlinked one-dimensional (1D) ultrathin nanowires (10-35 nm) are stacked layer by-layer and widely distributed in the three-dimensional (3D) porous membranes. The final morphology of the gelatin nano-nets, including nanowire diameter, area density and pore-width of the nano-nets, is highly dependent on the solution concentration, salt concentration, kinds of solvents, applied voltage, ambient temperature and relative humidity (RH). The occurrence of rapid phase separation on the splitting-film and the formation of hydrogen bond among gelatin molecules during electro-netting are proposed as the possible mechanisms for the formation of these spider-web-like nano-nets. PMID- 21550788 TI - Invadosome regulation by adhesion signaling. AB - Invadosomes are adhesive mechanosensory modules composed of a dense F-actin core surrounded by a ring of adhesion molecules and able to infiltrate compact tissue environment in physiological and pathological conditions. These structures comprise podosomes that are found in a variety of cells under physiological conditions and invadopodia in transformed or cancer cells. Invadosomes are regulated by extracellular matrix signals and are endowed with degradative machinery for extracellular matrix. The ability of extracellular matrix signals to orchestrate the building, dynamics, and function of invadosomes is based on mechano-chemical integrin outside-in signaling and requires integrin cross-talk. This review highlights recent findings that place Src as an inducer and PKC as an amplifier in the assembly of integrin stimulated invadosome through mechanotransduction and polarized endo/exocytic trafficking pathways for key proteolytic and enzymatic activities in a temporally and spatially confined manner. PMID- 21550789 TI - Exit from the trans-Golgi network: from molecules to mechanisms. AB - The trans-Golgi network is a major sorting platform of the secretory pathway from which proteins and lipids, both newly synthesized and retrieved from endocytic compartments, are targeted to different destinations. These sorting processes occur during the formation of pleomorphic tubular-vesicular carriers. The past years have provided insights into basic mechanisms coordinating the spatial and temporal organization of machineries necessary for the segregation of membrane components into distinct microdomains, for the bending, elongation, and fission of corresponding membranes, thus revealing a complex interplay of protein-protein and protein-lipid interactions. PMID- 21550790 TI - Use of respondent-driven sampling to enhance understanding of injecting networks: a study of people who inject drugs in Sydney, Australia. AB - BACKGROUND: Respondent-driven sampling (RDS) is a method for recruiting hidden populations, such as people who inject drugs (PWID). In RDS, participants recruit their peers into the study; who recruited who into the study is tracked, and thus information is gathered on the population's social networks. The purpose of this study was to use information collected from an RDS study of PWID to determine the size and structure of injecting networks and whether network characteristics are associated with sharing injecting equipment. METHODS: A study was launched in Sydney, Australia in 2009 with five seeds, who were asked to recruit three participants each into the survey. This process was repeated until the target sample size was reached. The median size of injecting networks and the homophily (a measure of in-group affiliation) of different subgroups were calculated. Participants' information was linked with that of their recruiter to form dyads, and multivariate analysis was conducted to determine whether dyad and injecting network characteristics were associated with sharing injecting equipment within the dyads. RESULTS: The injecting networks were large, the lowest median subgroup network size being 12. Homophily estimates indicated a lack of strong ties both within and across groups. In the multivariate analysis, factors significantly associated with sharing injecting equipment within dyads were feeling very close to their recruiter and having one or both members of the dyad identify as Aboriginal or Torres Strait Islander and one or both members having not been tested for hepatitis C in the previous year. CONCLUSION: RDS provided valuable information on injecting networks in Sydney. PWID were shown to be socially connected with a large number of other injectors, and affiliations were formed without regard to demographic or drug use characteristics. Linking information from the recruits with that of their recruiter was a useful way of organizing information to gain a more complete understanding of risk behaviour. PMID- 21550791 TI - Abstinence and harm reduction: can they work together? PMID- 21550792 TI - Rhetoric, reality and research: what they mean for achieving the best possible treatment system for addiction-related problems. PMID- 21550793 TI - Minicells: versatile vectors for targeted drug or si/shRNA cancer therapy. AB - Effective cancer therapy continues to be a daunting challenge due mainly to considerable tumor cell heterogeneity, drug-resistance, and dose-limiting toxicity of therapeutics. Here we review a versatile nano-cellular (minicell) delivery vehicle that can be packaged with therapeutically effective concentrations of chemotherapeutic drugs, siRNAs or shRNAs and can be targeted to tumors via minicell-surface attached bispecific antibodies. A range of minicell based therapeutics have shown highly effective tumor stabilization/regression in the murine xenograft model and in case studies in canines with late-stage endogenous tumors. Repeat intravenous dosing shows absence of toxicity or immunogenicity in both species. The minicell-based therapeutic has potential applications in personalized cancer medicine. PMID- 21550794 TI - Current strategies for osteochondral regeneration: from stem cells to pre clinical approaches. AB - Damaged cartilage tissue has no functional replacement alternatives and current therapies for bone injury treatment are far from being the ideal solutions emphasizing an urgent need for alternative therapeutic approaches for osteochondral (OC) regeneration. The tissue engineering field provides new possibilities for therapeutics and regeneration in rheumatology and orthopaedics, holding the potential for improving the quality of life of millions of patients by exploring new strategies towards the development of biological substitutes to maintain, repair and improve OC tissue function. Numerous studies have focused on the development of distinct tissue engineering strategies that could result in promising solutions for this delicate interface. In order to outperform currently used methods, novel tissue engineering approaches propose, for example, the design of multi-layered scaffolds, the use of stem cells, bioreactors or the combination of clinical techniques. PMID- 21550795 TI - Dr jeffrey page. PMID- 21550796 TI - Responsiveness of the foot and ankle ability measure (FAAM) in individuals with diabetes. AB - BACKGROUND: The impact of diabetes on physical function pose a challenge in assessing clinical outcomes. OBJECTIVE: The purpose of this study was to provide evidence of responsiveness for the foot and ankle ability measures (FAAM) in individuals with diabetes mellitus. METHODS: The two most recent FAAM scores of 155 diabetic patients treated for foot/ankle pathology were analyzed. Based on physical component summary (PCS) scores of the SF-36, subjects were categorized as improved (>7-point positive change), worsened (>7-point negative change), or unchanged (<7-point change). Analyses of the worsened and improved groups were compared to the unchanged group using two-way repeated measures ANOVAs and ROC curve analyses. RESULTS: The ANOVAs demonstrated a significant difference between groups (P = 0.001). ROC curves analysis for detecting an improvement or decline in status were 0.73 (95% CI 0.62-0.84) and 0.70 (95% CI 0.59-0.81), respectively. An increase in FAAM score of 9 points represented the minimal clinically important difference (MCID) with 0.64 sensitivity and 0.78 specificity. A decrease in FAAM score of 2 points represented a MCID with 0.65 sensitivity and 0.61 specificity. CONCLUSIONS: The FAAM demonstrated responsiveness to change in individuals with orthopedic foot and ankle dysfunction complicated by diabetes and can be used to measure patient outcomes over a 6-month period. PMID- 21550797 TI - Nonsense-mediated mRNA decay (NMD) in animal embryogenesis: to die or not to die, that is the question. AB - Nonsense-mediated mRNA decay (NMD) is a well-studied cellular quality-control pathway. It decreases the half-lives of eukaryotic mRNAs that aberrantly contain premature termination codons and additionally regulates an estimated 10-20% of normal transcripts. NMD factors play crucial roles during embryogenesis in many animals. Here, we review data indicating that NMD factors are required for proper embryogenesis by discussing the abnormal developmental phenotypes that result when the abundance of individual NMD factors is either downregulated or completely eliminated. We conclude that while NMD per se affects the embryogenesis of all animals, it is required to avoid embryonic lethality in only some animals. The critical roles of many NMD factors in other metabolic pathways undoubtedly also contribute to embryonic development if not viability. PMID- 21550800 TI - Efficiency of combined process of ozone and bio-filtration in the treatment of secondary effluent. AB - The present work was aimed at studying the efficiency of the combined process of biofiltration with ozonation to improve the quality of secondary effluent. The secondary effluent from the Dinapur Sewage Treatment Plant Varanasi, India was used in this work. The process of biofiltration with the plant species of Eichornia crassipes and Lemna minor, at a flow rate of 262 ml min(-1) and plant density of 30 mg L(-1) for 48 h, in combination with the process of ozonation with ozone dose of 10 mg L(-1) and contact time of 5 min was applied. Results revealed that combined process was statistically most suitable for the highest degradation of physico-chemical and microbial parameters with improving BDOC value. The biofiltration process is able to remove highest percentage of toxic heavy metals from the secondary effluent without production of toxicity. This technique is highly recommendable for tropical wastewater where sewage is mixed with industrial effluents. PMID- 21550798 TI - Cholinergic modulation of synaptic integration and dendritic excitability in the striatum. AB - Modulatory interneurons such as, the cholinergic interneuron, are always a perplexing subject to study. Far from clear-cut distinctions such as excitatory or inhibitory, modulating interneurons can have many, often contradictory effects. The striatum is one of the most densely expressing brain areas for cholinergic markers, and actylcholine (ACh) plays an important role in regulating synaptic transmission and cellular excitability. Every cell type in the striatum has receptors for ACh. Yet even for a given cell type, ACh affecting different receptors can have seemingly opposing roles. This review highlights relevant effects of ACh on medium spiny neurons (MSNs) of the striatum and suggests how its many effects may work in concert to modulate MSN firing properties. PMID- 21550801 TI - Osteogenic activity of diphenyl ether-type cyclic diarylheptanoids derived from Acer nikoense. AB - Osteogenic activity of six diarylheptanoids, acerogenin A (1), (R)-acerogenin B (2), aceroside I (3), aceroside B(1) (4), aceroside III (5) and (-)-centrolobol (6) and two phenolic compounds; (+)-rhododendrol (7) and (+)-cathechin (8), isolated from the stem bark of Acer nikoense (Nikko maple) was evaluated using alkaline phosphatase (ALP) activity as a marker for early osteoblast differentiation. We found that the diphenyl ether-type cyclic diarylheptanoids 1 5 promoted ALP activity in mouse preosteoblastic MC3T3-E1 cells without affecting cell proliferation, but linear-type diarylheptanoid 6 and phenolic compounds 7 and 8 did not. Diphenyl ether-type cyclic diarylheptanoids 1-4 also increased protein production of osteocalcin, a late stage maker for osteoblast differentiation, and induced osteoblastic mineralization. Structure-activity relationships of these compounds demonstrated that the stimulative efficacy of aglycones was higher than that of its glycosides. Taken together, diphenyl ether type cyclic diarylheptanoids promote early- and late-stage osteoblastogenesis, which may open the possibility for the development of novel osteogenic agents. PMID- 21550799 TI - One-month relative dose intensity of not less than 50% predicts favourable progression-free survival in sorafenib therapy for advanced renal cell carcinoma in Japanese patients. AB - BACKGROUND: Sorafenib is a multikinase inhibitor used as a second-line treatment for metastatic renal cell carcinoma (mRCC). However, it is very difficult to estimate sorafenib dosage because it is difficult to maintain stable administration and dosage intervals due to several side-effects. We examined the correlation between relative dose intensity (RDI) and clinical outcome of sorafenib therapy in a multi-institutional study. METHODS: A study population of 70 first-line therapy-refractory patients with pathologically confirmed RCC was eligible for this investigation. Clinical outcomes were evaluated according to clinicopathological features and RDI for 1 month (1M-RDI). RESULTS: There was significant difference in progression-free survival (PFS) time but not overall survival (OS) time when the 1M-RDI cut-off value was >= 50%. In 15 patients (21.4%) with 1M-RDI of <50%, median PFS time was 4.1 months (95% I collagen (95% CI): 2.0-6.2), whereas it was 10.5 months (95% CI: 7.6-13.4) in the patients with 1M-RDI of ?50% (P=0.022). Multivariate analysis showed 1M-RDI status to be significantly associated with PFS (HR: 3.838, 95% CI: 1.658-8.883, P=0.002) but not OS (P=0.328). CONCLUSION: Although this study was retrospective, a 1M-RDI cut off value of >= 50% for sorafenib may be the first factor to predict PFS but not OS in cytokine pretreated mRCC patients. The data indicate that a dose of 400mg/day of sorafenib administered successively for the first one month was necessary to prolong disease stabilisation and could be tolerated by Japanese patients. PMID- 21550802 TI - Part 3: Design and synthesis of proline-derived alpha2delta ligands. AB - A potent series of substituted (2S,4S)-benzylproline alpha(2)delta ligands have been designed from the readily available starting material (2S,4R)-hydroxy-L proline. The ligands have improved pharmacokinetic profile over the (4S) phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development. PMID- 21550803 TI - Part 2: Design, synthesis and evaluation of hydroxyproline-derived alpha2delta ligands. AB - Conformational constraint has been used to design a potent series of alpha(2)delta ligands derived from the readily available starting material (2S,4R)-hydroxy-l-proline. The ligands have improved physicochemistry and potency compared to their linear counterparts (described in our earlier publication) and the lead compound has been progressed to clinical development. PMID- 21550804 TI - Relative frequency of known causes of multiple mtDNA deletions: two novel POLG mutations. AB - Diseases affecting mtDNA stability, termed nuclear-mitochondrial intergenomic communication disorders, are caused by a primary nuclear gene defect resulting in multiple mtDNA deletions. The aim of this study was to estimate the frequency of known etiologies and the spectrum of mutations in a cohort of 21 patients harboring multiple mtDNA deletions in skeletal muscle. We showed that 10 cases (48%) display mutations in POLG, including eight previously reported variants and two novel mutations (namely, p.Trp585X and p.Arg1081Gln). The novel mutations affect evolutionary conserved residues and were absent in a large set of control chromosomes. These findings expand the array of mutations associated with multiple rearranged mtDNA attributed to mutations in POLG. The relatively high diagnostic yield (about one in two cases) supports the notion that it is recommended to test POLG routinely in diagnostic laboratories whenever multiple mtDNA deletions are present, regardless of the age of onset of patients and their clinical phenotype. PMID- 21550805 TI - Evaluation of a single leg stance balance test in children. AB - Balance is a major determinate of gait. In high functioning individuals without significant vestibular or vision impairments, a ceiling effect may be present when using a double limb support protocol to assess balance function. For these populations, a single leg stance protocol may be more suitable. 47 typically developing (TD) subjects and 10 patients with CEV performed a single leg stance test on a force plate. The center of pressure (COP) was determined and several COP derived variables were calculated. Included measurements were: standard deviation, maximum excursion, area, average radial displacement, path velocity and frequency of the COP. Directional components of suitable variables were used to analyze anterior/posterior and medial/lateral contributions. Correlations with age of TD subjects indicated that all balance variables except frequency were significantly correlated. Most parameters were highly inter-correlated. Age adjusted COP balance variables also correlated to the Bruininks-Oseretsky balance subtest. Highest correlations were determined by the maximum excursion and velocity of the COP in the anterior/posterior direction. Statistical comparisons between the CEV group and a 4-6 TD group indicated significant differences between groups for most COP balance parameters. These results indicated that a single limb balance assessment may be a useful assessment for determining balance impairments in higher functioning children with orthopedic impairments. PMID- 21550806 TI - Outcome of meniscal repair prior compared with concurrent ACL reconstruction. AB - Meniscal tears are commonly associated with traumatic rupture of the anterior cruciate ligament (ACL). At our centre, if a patient presents with locked knee in conjunction with an ACL injury we perform an initial arthroscopy to remove the cause of locking and schedule ACL reconstruction once a full range of motion has returned. The aim of this study was to assess the outcome of meniscal tears stabilised prior to ACL reconstruction. We identified 24 patients who underwent repair of a torn meniscus before having their ACL reconstruction (group 1). As a comparison group we identified 148 patients who underwent meniscal repair at the time of ACL reconstruction (group 2). Twelve of the patients in group 1 underwent meniscectomy, seven at the time of reconstruction and five subsequently. This gives a success rate of 50% (12/24) in the ACL deficient patients. In comparison forty two of the patients in group 2 went on to have a meniscectomy representing a success of 72% (106/148). The odds ratio for meniscectomy in an ACL deficient meniscal repair is 2.52 (95% CI 1.07-5.97) and there is a relative risk of 1.76 (95% CI 1.05-2.63). The difference in success of the meniscal repair between the groups was significant (Fisher's exact test p=0.05). Meniscal repair and delayed ACL reconstruction is more likely to fail than a combined repair and ACL reconstruction. PMID- 21550807 TI - Gait analysis in patients with a preformed articulated knee spacer. AB - Two-stage revision is one of the most widely accepted procedures to eradicate infection and restore function in infected knee prosthesis; while the use of an articulated spacers is advocated by many as a means to preserve function between stages, no data are available regarding gait parameters after spacer implant. The aim of present study was to assess and compare the gait parameters of patients with articulated knee spacers with a normal reference population and with the sound limb. Computerised gait analysis, was performed 8 to 14 weeks after the infected knee prosthesis had been removed and a preformed, articulated, knee spacer had been implanted, in 10 consecutive patients. Kinematic data show a mean gait velocity reduction of 70% and a decrease of the range of motion of the operated knee of 59%, compared with controls. While ground reaction forces were only slightly reduced, frontal and sagittal moments and calculated powers around the affected knees were near zero or zero. Our findings point out the ability of a preformed articulated spacer to preserve, although reduced, the normal gait parameters and joint range of motion and the capacity of the human body to provide useful postural modifications, even in the absence of the proprioceptive input from a normal knee or from a traditional total knee replacement. PMID- 21550808 TI - 1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane: further insights into a class of triple re-uptake inhibitors. AB - Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area. PMID- 21550810 TI - Stereostructure-based differences in the interactions of cardiotoxic local anesthetics with cholesterol-containing biomimetic membranes. AB - Amide-type pipecoloxylidide local anesthetics, bupivacaine, and ropivacaine, show cardiotoxic effects with the potency depending on stereostructures. Cardiotoxic drugs not only bind to cardiomyocyte membrane channels to block them but also modify the physicochemical property of membrane lipid bilayers in which channels are embedded. The opposite configurations allow enantiomers to be discriminated by their enantiospecific interactions with another chiral molecule in membranes. We compared the interactions of local anesthetic stereoisomers with biomimetic membranes consisting of chiral lipid components, the differences of which might be indicative of the drug design for reducing cardiotoxicity. Fluorescent probe labeled biomimetic membranes were prepared with cardiolipin and cholesterol of varying compositions and different phospholipids. Local anesthetics were reacted with the membrane preparations at a cardiotoxically relevant concentration of 200 MUM. The potencies to interact with biomimetic membranes and change their fluidity were compared by measuring fluorescence polarization. All local anesthetics acted on lipid bilayers to increase membrane fluidity. Chiral cardiolipin was ineffective in discriminating S(-)-enantiomers from their antipodes. On the other hand, cholesterol produced the enantiospecific membrane interactions of bupivacaine and ropivacaine with increasing its composition in membranes. In 40 mol% and more cholesterol-containing membranes, the membrane interacting potency was S(-)-bupivacaine 0.05). Compared with the male/male group, 10-year actuarial survival was significantly lower in the sex mismatch groups: 58% in the male/female group (p = 0.03) and 59% in the female/male group (p = 0.01). There was no significant difference in 10-year freedom from CAV or NF-MACE among the groups. CONCLUSIONS: Heart transplant patients with donor-recipient sex mismatch have lower survival, extending the results of prior studies to suggest that sex mismatch is undesirable in female, as well as male, recipients. This may impact donor selection and recipient wait time to transplantation. PMID- 21550825 TI - Immediate and long-term priming effects are independent of prime awareness. AB - Subliminal primes are assumed to produce weaker and short-lived effects on subsequent behavior compared to clearly visible primes. However, this difference in priming effect may be due to differences in signal strength, rather than level of awareness. In the present study we manipulated prime discriminability by using metacontrast masks and pseudomasks, while keeping the prime strength equal. This manipulation resulted in large differences in discriminability of the primes. However, both immediate response priming and long-term response priming (measured with conflict adaptation) was equal for the poorly discriminable and well discriminable primes, and equal for groups that differed markedly in terms of how well they could discriminate the primes. Our findings imply that discriminability of information is independent of both the immediate and long-term effects that information can have on behavior. PMID- 21550826 TI - Following the trail of an HIV-prevention Web site enhanced for mobile cell phone text messaging delivery. PMID- 21550827 TI - Non-bladder cancer mortality in patients with urothelial cancer of the bladder. AB - OBJECTIVES: Because bladder cancer (BC) patients often have comorbidities that adversely affect their health, we wanted to determine whether grade and stage of BC at diagnosis are associated with the hazard of death from causes other than BC. MATERIALS AND METHODS: Cancer records for 93,033 patients diagnosed with urothelial BC during 1988-2002 were obtained from the Surveillance Epidemiology and End Results (SEER) database. The grade-stage categories were defined as follows: (1) low grade, stage 0/I (Ta/T1, N0/Nx), (2) high grade, stage 0/I (Ta/Tis/T1, N0/Nx), (3) any grade, stage II (T2, N0/Nx), (4) any grade, stage III (T3-T4a, N0/Nx), (5) any grade, stage IV (T4b and/or N+). Patients with known distant metastases at presentation were excluded. Other covariates were age, gender, and race. The outcome measures were defined as the hazard of death from all causes, from BC, and from non-BC causes. Cox regression model was used to estimate the effect of grade-stage categories on over-all and cause-specific hazards with adjustment for covariates. RESULTS: The 5-year mortality proportions by grade-stage category were as follows: low grade, stage 0/I: all-causes 25%, BC 3%, non-BC 22%; high grade stage 0/I: all-causes 38%, BC 13%, non-BC 25%; stage II: all-causes 63%, BC 36%, non-BC 27%; stage III: all-causes 69%, BC 45%, non-BC 24%; stage IV: all-causes 83%, BC 68%, non-BC 15%. Using low grade, stage 0/I as a reference category, the hazard ratios for increasing grade-stage categories (high grade 0/I, II, III, IV) were as follows: all-cause mortality 1.30, 2.37, 3.07, 6.14; BC-related hazard 3.31, 10.02, 14.65, 32.04; non-BC-related hazard: 1.05, 1.37, 1.49, 1.65 (all P < 0.001). CONCLUSION: Grade-stage categories were associated with the hazard of death from non-BC causes. However, their influence on BC-related hazard was much greater in magnitude. Because BC (rather than co morbidities) is the main cause of death in patients with muscle-invasive disease, aggressive BC-directed therapies in these patients, when feasible, are justified. PMID- 21550828 TI - Phase II study of biweekly gemcitabine as first line therapy in CIS of the bladder: what does an aborted trial tell us? AB - OBJECTIVE: The objective of this study was to challenge the activity of a promising intravesical drug (gemcitabine), administered at an intensive regimen (2,000 mg twice a week for 6 weeks) in treatment naive CIS of the bladder and to observe side-effects. The statistical design was conceived to provide sufficient information through the enrollment of a low number of patients. MATERIAL AND METHODS: Primary, secondary, and concurrent CIS with no prior intravesical therapy were eligible. Treatment schedule: 2000 mg gemcitabine in 50 ml saline, unbuffered, for 1 hour twice a week for 6 weeks. Complete response (CR) = negative cytology and negative cystoscopy + bladder mapping at 3 months. Failure (FA) = all other situations. Side-effects were recorded according to Common Terminology Criteria for Adverse Events (CTCAE). STUDY DESIGN: A 3-stage design. After testing the drug on 11 patients in the first stage, the trial had to be terminated if 3 or fewer CRs. After testing the drug on 21 patients in the first and second stages, the trial had to be terminated if 7 or fewer CRs. After testing the drug on 32 patients in all 3 stages, the drug was considered active in case of >12 CRs. Survival data up to 4 years from trial closure were collected. RESULTS: The study proceeded to stage II since 5/11 responded at stage I but it was stopped after including 18 patients due to side-effects; 6/18 had primary CIS, 7 had secondary CIS, and 5 concomitant CIS; 6/18 (33.3%) had grade 3 side-effects (4 G3 cystitis, 3 G3 leucopenia), leading to stopping the treatment in all 6 cases. CRs were observed in 8/18 patients (44.4%), FA in 10/18 (55.5%). Median overall survival (OS) was 44 months with a 4-year cancer-specific survival of 100%. CONCLUSION: Biweekly gemcitabine as first line treatment for CIS led to excess toxicity and suboptimal activity. Due to the peculiar statistical design, a negative response was generated enrolling a low number of patients. The absolute 4-year CSS suggests that no window of opportunity for disease cure may have been lost by assessing a new, non standard, treatment for CIS. PMID- 21550829 TI - Embolisation for vascular injuries complicating elective orthopaedic surgery. AB - OBJECTIVES: The study aims to present the indications and emphasise the role of embolisation for vascular injuries in orthopaedic surgery. METHODS: Thirty-one patients with vascular injuries complicating elective orthopaedic surgery had embolisation from 2003 to 2010. N-2-butyl cyano-acrylate (NBCA) was used as embolic agent in 28 patients, gelatin sponge in three and coil embolisation in addition to NBCA or gelatin sponge in two patients. The mean follow-up period was 37 months (range, 4-96 months). RESULTS: The most common orthopaedic operations associated with vascular injuries amenable to embolisation were hip-joint procedures; and the most common injuries were arterial tears of branch vessels or non-critical axial vessels, most commonly of the superior glutaeal artery. In all cases, angiography showed the bleeding point, and a single embolisation session effectively stopped bleeding. Embolisation-related complications were not observed. CONCLUSIONS: Embolisation should be considered the treatment of choice for vascular injuries of branch vessels or non-critical axial vessels following elective orthopaedic surgery because of the advantages of minimally invasive therapy and the lack of complications. PMID- 21550830 TI - Neutrophil-derived azurocidin cleaves insulin-like growth factor-binding protein 1, -2 and -4. AB - OBJECTIVE: Azurocidin is an important inflammatory mediator and considered to be an inactive serine protease homologue. It has previously been reported that azurocidin is a possible IGFBP-1 specific protease; however, the protease activity of azurocidin was not isolated in its active form. The aim of this study was to determine the effect of neutrophil-derived azurocidin on the six different IGFBPs, focusing especially on IGFBP-1. METHODS: IGFBPs were incubated with azurocidin in phosphate-buffered saline for 2 h and proteolysis was studied by SDS-PAGE. Analysis of azurocidin was performed by MALDI-TOF peptide mass fingerprint and MALDI-TOF/TOF peptide sequencing. RESULTS: The neutrophil-derived preparation of azurocidin cleaved IGFBP-1, IGFBP-2 and IGFBP-4. IGFBP-1 bound to IGF-I was also degraded whereas IGF-II was shown to have an inhibitory effect on proteolysis of IGFBP-1. The proteolytically active preparation of neutrophil derived azurocidin was found to be glycosylated and determined to be 31 kDa by SDS-PAGE. CONCLUSIONS: Our results indicate that the neutrophil-derived preparation of azurocidin contains a protease activity which cleaves IGFBP-1, IGFBP-2 and IGFBP-4. These findings are of interest since both IGFBP-1 and azurocidin increase during inflammation. The effect of azurocidin on IGFBP- and IGF-activity needs to be further investigated. PMID- 21550831 TI - Patients' impatience is an independent determinant of poor diabetes control. AB - AIMS: Some individuals have a preference for the present rather than for the future. We investigated the impact of this impatient relationship to temporality on adherence to medication and HbA(1c) level in type 2 diabetic patients. METHODS: An observational, cross-sectional monocenter study in 90 patients consulting for a health check-up at a Center for Preventive Medicine. We used questionnaires assessing adherence to medication, impatience in a fictive monetary choice (preferring a smaller amount now to a higher amount later) and in daily life situations, foresight, locus of control, and social deprivation. RESULTS: Impatience in the monetary choice was associated with non-adherence to medication (P=0.005). In a multivariate logistic regression model, the risk of observing HbA(1c)>=7% was associated with a long duration of diabetes (OR 5.2, CI 1.7-15.7, P=0.003), monetary impatience (OR=5.1, CI 1.7-15.4, P=0.004), a high "chance and other people" score of the locus of control (OR=5.1, CI 1.7-15.7, P=0.004), a suboptimal foresight (OR 3.9, CI 1.2-12.0, P=0.02). A decision-tree analysis (CHAID algorithm) showed that in this cohort of 90 patients, the 11 people who were adherent to medication, patient in the monetary scenario, had optimal foresight, and gave importance neither to chance nor to other people, had all HbA(1c) below 7%. CONCLUSION: An impatient relationship to temporality was found associated with non-adherence to medication and uncontrolled HbA(1c) in type 2 diabetic patients. Treatment strategies for chronic diseases should be tailored according to this novel dimension of psychology. PMID- 21550832 TI - Non-traumatic rhabdomyolysis and diabetes. AB - The present clinical report describes the case of a spontaneously resolving rhabdomyolysis episode in a type 1 diabetic patient, who presented with multiple risk factors of this muscle complication, including uncontrolled brittle diabetes with sequences of hyper- and hypoglycaemic episodes in the same day, caloric restriction and intensive exercise. It should be borne in mind that rhabdomyolysis is not particularly rare in diabetes and can be severe. To raise clinicians' awareness of a possible rhabdomyolysis diagnosis, the various clinical conditions that are likely to lead to this complication in diabetic patients are also reviewed here. PMID- 21550833 TI - Abatacept for treatment of refractory polymyositis. PMID- 21550834 TI - Sonication improves kasturi lime (Citrus microcarpa) juice quality. AB - Freshly squeezed kasturi lime fruit juice was sonicated (for 0, 30 and 60min at 20 degrees C, 25kHz frequency) to evaluate its impact on selected physico chemical and antioxidant properties, such as pH, degrees Brix, titratable acidity, Hunter color values (L(*), a(*), b(*)), ascorbic acid, DPPH radical scavenging activity, total phenolics, antioxidant capacity, flavonoids and flavonols. Additionally, the effect of sonication treatments on the microbial load (TPC, yeast and mold) were also evaluated. Sonication of juice samples for 60min showed enhancement in most of the bioactive compounds compared to samples treated for 30min and control samples (untreated). Significant reductions in the microbial load corresponding to sonication time were also recorded. Results of the present study indicate that sonication may be employed as a suitable technique for kasturi lime juice processing, where antioxidant and other bioactive compound retention or enhancement is desired, along with the achievement of safety and quality standards. PMID- 21550835 TI - Ferritin as an important player in neurodegeneration. AB - Oxidative stress is considered one of the pathways leading to neuronal death in neurodegenerative disease. Many published studies aimed to assess the possible role of iron in this process but no consensus has been reached. On the other hand little is known about the role played by the main iron storage protein - ferritin. In this review we discuss the data obtained using several methods - Mossbauer spectroscopy, electron microscopy and ELISA - from human brain tissue both in controls and in four neurodegenerative disorders - Parkinson's (PD) and Alzheimer's disease, progressive supranuclear palsy and neuroferritinopathy. Iron may only cause oxidative stress injury when it is available as labile iron for Fenton reaction. This may be related to the decreased ability of ferritin to retain iron within the iron core of ferritin. This happens in PD and in neuroferritinopathy. In PD there is a decrease in the concentration of L ferritin, while in neuroferritinopathy there is a genetically induced mutation in L ferritin causing its loss of function. We discuss the importance of the ratio H/L ferritin and its changes in neurodegeneration. PMID- 21550836 TI - Active children use more locations for physical activity. AB - We examined frequency of use of 11 physical activity (PA) locations among 539 San Diego children (45.0% males, 41.2% Latinos; mean +/- SD age: 6.6 +/- 0.7 years) and explored associations between location use, PA and potential correlates. Parents reported child's use (visits/week) of 11 locations. Child PA was assessed by accelerometry (subsample n = 178). The most frequently used locations (mean +/ SD times/week) were homes (3.2 +/- 2.3) and parks/playground (1.6 +/- 1.3). Children used 4.0 +/- 2.0 locations in a typical week, and made a total of 12.5 +/- 6.8 visits/week to all locations. Latinos used fewer locations regularly (3.6 +/- 2.1 vs. 4.3 +/- 1.9 locations; p < 0.001) and had fewer visits to all locations (11.4 +/- 7.4 vs. 13.2 +/- 6.4 visits/week; p = 0.003) than non Latinos. Accelerometry-assessed vigorous PA (VPA) was positively associated with the number of locations regularly used (beta = 0.04, p = 0.03) and total visits to all locations among Latinos (beta = 0.09, p = 0.005). Parental PA support was positively associated with locations used (beta = 0.64, p < 0.001) and visits to all locations (beta = 2.56, p < 0.001). Children using a greater variety of locations did more VPA. Latinos making more total visits to all locations had higher VPA. PMID- 21550837 TI - Effects of household, workplace, and public place smoking restrictions on smoking cessation. AB - The aim of this study was to evaluate the association between environmental smoking restrictions, distinguished by site, and smoking cessation by Chinese urban residents. Recruited through multi-stage quota-sampling, residents in six Chinese cities were surveyed. Data were both individual-level and city-level. Among 4735 respondents, 715 were identified as successful quitters and 405 as unsuccessful. Multilevel logistic regression analysis showed smoking cessation to be associated with city-level public place and workplace restrictions and individual-level workplace and household restrictions. Results offer justification for decision-makers to implement environmental tobacco control policies and related public health interventions aimed at markedly diminishing the high smoking prevalence in China. PMID- 21550839 TI - Archaea: very diverse, often different but never bad? PMID- 21550840 TI - Metallation of ethylenediamine based Schiff base with biologically active Cu(II), Ni(II) and Zn(II) ions: synthesis, spectroscopic characterization, electrochemical behaviour, DNA binding, photonuclease activity and in vitro antimicrobial efficacy. AB - A new ligand [C28H20N6O8] (L2) has been synthesized by the condensation reaction of 3-hydroxy-4-nitrobenzaldehydenephenylhydrazine (L1) with diethyloxalate. This ligand L2 is allowed to react with bis(ethylenediamine)Cu(II)/Ni(II)/Zn(II) complexes. It affords [(L2)Cu(en)2]Cl2(1)/[(L2)Ni(en)2]Cl2(2)/[(L2)Zn(en)2]Cl2(3) complexes, respectively. These complexes (1-3) have been characterized by the spectral and analytical techniques. The interaction of these complexes with calf thymus (CT) DNA is characterized by the absorption spectra which exhibit a slight red shift with hypochromic effect. Electrochemical analyses and viscosity measurements have also been carried out to determine the mode of binding. The shift in DeltaEp, E1/2 and Ipc values explores the interaction of CT DNA with the above metal complexes. The slight increase in the viscosity of CT DNA indicates that these complexes bind to CT DNA through a partial non-classical intercalative mode. Cleavage experiments using pBR322 DNA in presence of H2O2 indicate that these complexes behave as efficient artificial chemical nucleases in the order of 1>2>3. Moreover, the antibacterial and antifungal studies reveal that complex 1 is highly active against the bacterial and fungal growth. PMID- 21550841 TI - pKa determinations of xanthene derivates in aqueous solutions by multivariate analysis applied to UV-Vis spectrophotometric data. AB - Xanthenes form to an important class of dyes which are widely used. Most of them present three acid-base groups: two phenolic sites and one carboxylic site. Therefore, the pKa determination and the attribution of each group to the corresponding pKa value is a very important feature. Attempts to obtain reliable pKa through the potentiometry titration and the electronic absorption spectrophotometry using the first and second orders derivative failed. Due to the close pKa values allied to strong UV-Vis spectral overlap, multivariate analysis, a powerful chemometric method, is applied in this work. The determination was performed for eosin Y, erythrosin B, and bengal rose B, and also for other synthesized derivatives such as 2-(3,6-dihydroxy-9-acridinyl) benzoic acid, 2,4,5,7-tetranitrofluorescein, eosin methyl ester, and erythrosin methyl ester in water. These last two compounds (esters) permitted to attribute the pKa of the phenolic group, which is not easily recognizable for some investigated dyes. Besides the pKa determination, the chemometry allowed for estimating the electronic spectrum of some prevalent protolytic species and the substituents effects evaluation. PMID- 21550843 TI - Seizure produced by 20 Hz transcranial magnetic stimulation during isometric muscle contraction in a healthy subject. PMID- 21550842 TI - Sustained elite suppression of replication competent HIV-1 in a patient treated with rituximab based chemotherapy. AB - The mechanism of elite control of HIV-1 replication is not fully understood. While immunosuppression due to rituximab based chemotherapy has been associated with increased replication of HBV, CMV, and HIV-1, control of replication competent HIV-1 was maintained in an elite controller/suppressor treated with a regimen that included vincristine, cyclophosphamide, prednisone, four rounds of plasmapheresis and ten cycles of rituximab. The data suggests that de-novo antibody responses do not play a significant role in the control of viral replication in these patients. PMID- 21550844 TI - The use of conventional EEG for the assessment of hypoxic ischaemic encephalopathy in the newborn: a review. AB - Neonatal hypoxic ischaemic encephalopathy continues to be one of the leading causes of morbidity and mortality among neonates around the globe. With the advent of therapeutic hypothermia, the need to accurately classify the severity of injury in the early neonatal period is of great importance. As clinical measures cannot always accurately estimate the severity early enough for treatment to be initiated, clinicians have become more dependent on conventional and amplitude integrated EEG. Despite this, there is currently no single agreed classification scheme for the neonatal EEG in hypoxic ischaemic encephalopathy. In this review we discuss classification schemes of neonatal background EEG, published over the past 35 years, highlighting the urgent need for a universal visual analysis scheme. PMID- 21550845 TI - Theta power as a marker for cognitive interference. AB - OBJECTIVE: The present study aimed at investigating whether theta activity within medio-frontal cortex (MFC) serves as a marker for increased cognitive control demands such as performance monitoring. METHODS: We confronted participants with at least two incompatible sources of information in a Simon task, a flanker task, and a NoGo task to assess whether changes in EEG theta activity correspond to executive control demands across different sources of cognitive interference. RESULTS: Overall, increases of theta power were to a different extent observed in all interference situations: (1) differences in theta power were largest between successful response inhibition in NoGo events compared to Go responses, (2) incongruent and congruent events in the flanker task differed to a lesser extent, and (3) differences in theta power were smallest comparing incompatible and compatible Simon events. Scalp-topographies and dipole modeling of theta activity pointed to different sources across interference conditions that encompassed various MFC areas within anterior cingulate cortex and (pre-) supplementary motor areas. CONCLUSIONS: Our results indicate that theta power amplitude is sensitive to the recruitment of executive control in interference situations, whereas the MFC sources of theta power varied across different interference situations. SIGNIFICANCE: This study shows for the first time theta power enhancement related to the recruitment of cognitive control across different types of conflicts in the stream of information processing. PMID- 21550846 TI - Interaction of the mucosal barrier with accessory immune cells during fungal infection. AB - The mucosal epithelium is of central importance in host defence and immune surveillance, as it is the primary cell layer that initially encounters environmental microorganisms. Induction of antifungal innate immune responses depends on recognition of fungal components by host pattern recognition receptors. Members of the Toll-like receptor family have emerged as key sensors that recognize fungal pathogens and trigger defence responses. During oral infection with the fungal pathogen Candida albicans, a large number of cytokines is secreted by oral epithelial cells, which in turn activate myeloid cells in the submucosal layers to clear the invading pathogen. Recent data provide novel insights into the complex molecular mechanisms of innate immune responses initiated by cooperation between epithelial cells and neutrophils. In this review, we discuss the role of epithelial TLRs and how the immunological crosstalk between C. albicans-infected oral epithelium and neutrophils protects the mucosal surface from fungal invasion and cell injury. PMID- 21550847 TI - The parasitophorous vacuole of Encephalitozoon cuniculi: biogenesis and characteristics of the host cell-pathogen interface. AB - Microsporidia are obligate intracellular fungal pathogens of increasing importance in immunocompromised patients. They have developed a unique invasion mechanism, which is based on the explosive discharge of a hollow tubulus, the so called polar tube. The infectious sporoplasm is subsequently extruded through this flexible tube and injected into the host cell. The model microsporidium Encephalitozoon cuniculi is a paradigm of a fungus with an extreme host cell dependency. This human pathogen possesses one of the smallest eukaryotic genomes (<3MB) identified so far and has reduced its own biosynthetic pathways to a minimum, thus depending on an efficient supply of metabolites from the host cell. E. cuniculi spends its entire intracellular life cycle inside a parasitophorous vacuole (PV), which is formed during invasion. We have provided here an overview of the biogenesis and characteristics of this important host cell-pathogen interface and suggest in this context a modified model for E. cuniculi invasion. According to the model, the host cell plasma membrane is not pierced by the polar tube, but is pushed at the contact site into the cell interior by the mechanical force of the expelled polar tube. This results in a channel-like invagination of the plasma membrane, from which finally the parasitophorous vacuole is pinched off. PMID- 21550848 TI - Nutrient acquisition by pathogenic fungi: nutrient availability, pathway regulation, and differences in substrate utilization. AB - All pathogenic microorganisms have in common that they need to feed on nutrients available from their host. Therefore, the specific interruption of metabolic pathways is a promising approach which could lead to the discovery of new antimicrobial drugs. However, nutrient availability strongly varies in respect to the infected host niche and pathogens may possess different strategies to acquire nutrients. This review focuses on the differences in regulation and use of key metabolic pathways during infection by pathogenic fungi, especially in the filamentous fungus Aspergillus fumigatus and the dimorphic yeast Candida albicans. Besides universal metabolic pathways, emphasis is given on pathways, which are absent in humans and might, therefore, suit as antifungal drug targets. Niche-specific nutrient availability and different physiological strategies complicate the identification of metabolic pathways, which are essential for all pathogens at each step of the infection process. PMID- 21550849 TI - Genetic susceptibility to Aspergillus fumigatus infections. AB - Invasive aspergillosis mostly caused by the opportunistic mould Aspergillus fumigatus is characterized by high morbidity and mortality in risk group patients. Several ethno-pathological factors promote the development and the course of this fungal infection like neutropenia, T-cell depletion, CD34-selected stem cell products, corticosteroid therapy, or cytomegalovirus infections. Furthermore, a growing number of defined single nucleotide polymorphisms affiliated to genes affecting the innate immune response has been described which genetically determine susceptibility to A. fumigatus. Thereby, it concerns a broad band ranging from genes encoding for cytokines or chemokines, their respective receptors to those of toll-like receptors including further genes involved in recognition and defence of pathogens by the innate immune system. Here, we summarize in detail the current knowledge about genetic markers correlated with invasive aspergillosis and their relevance for the developing and outcome of infections with A. fumigatus. PMID- 21550850 TI - Specialist breast care and research nurses' attitudes to adjuvant chemotherapy in older women with breast cancer. AB - PURPOSE: Breast cancer largely affects older women (>= 70 y) who have historically been excluded from clinical trials; consequently, treatment is often not evidence-based. Older women may not be offered adjuvant chemotherapy due to assumptions that they would not benefit, cannot tolerate it or do not wish to have it. Specialist breast care nurses (BCN) and research nurses (RN) play an important role influencing decisions. We report the roles, attitudes and involvement of such nurses regarding adjuvant chemotherapy in older women. METHOD: A questionnaire examined 259 UK BCN and RN's views about efficacy and desirability of chemotherapy in older women, participation in decision-making in MDTs, and roles when chemotherapy was discussed with patients. RESULTS: 72% of BCN and 48% of RN agreed that age should not be a factor influencing who is offered chemotherapy. BCNs indicated involvement in decision-making with older breast cancer patients, discussing chemotherapy with patients at different points following diagnosis and during treatment, and proposing chemotherapy in MDT meetings. RNs were involved to a lesser extent. 69% of all nurses had not received specific training in the area and 70% thought training would be beneficial. Nurses disagreed that older patients would not tolerate or did not want chemotherapy but 1/3 agreed or were uncertain that burdens of chemotherapy outweighed benefits. A third felt that older women had less control over treatment decisions than younger women. CONCLUSIONS: This study suggests a need to develop the role of specialist nurses to facilitate treatment decision-making relating to chemotherapy in older women. PMID- 21550852 TI - Meta-analysis of letrozole versus clomiphene citrate in polycystic ovary syndrome. AB - The aim of this study was to systematically compare the clinical efficacy and safety of letrozole with clomiphene citrate for ovulation induction in women with polycystic ovary syndrome (PCOS). The Cochrane Central Register of Controlled Trials, PubMed, EMbase, CBMdisc and CNKI were searched for eligible randomized controlled trials (RCT) comparing letrozole with clomiphene citrate in PCOS patients. Two reviewers independently extracted information and evaluated methodological quality according to the Cochrane Handbook 5.0. Meta-analysis was performed with the fixed-effects model or random-effects model according to the heterogeneity. Six eligible RCT involving 841 patients were included. Letrozole was associated with a number of lower mature follicles per cycle (standardized mean difference (SMD) -1.41; 95% confidence intervales (CI) -1.54 to -1.28; P<0.00001) compared with clomiphene citrate. There were no significant differences in pregnancy rate (relative risk (RR) 0.97; 95% CI 0.79 to 1.18), abortion rate (RR 1.38; 95% CI 0.48 to -3.96) and multiple pregnancy rate (RR 0.34; 95% CI 0.07 to -1.72) between the two groups. The evidence from ovulation rates was not enough to support either letrozole or clomiphene citrate. In conclusion, letrozole is as effective as clomiphene citrate for ovulation induction in patients with PCOS. PMID- 21550853 TI - Current opinion on use of luteinizing hormone supplementation in assisted reproduction therapy: an Asian perspective. AB - LH and FSH have complementary functions in ensuring optimal oocyte maturation and ovulation. In women undergoing assisted reproduction technology protocols with gonadotrophin-releasing hormone analogues, LH and FSH concentrations are reduced. While FSH use in assisted reproduction technology is well established, there is no published consensus on the need for exogenous LH in Asian patients. Having reviewed the concept of the LH therapeutic window and differences between recombinant human LH (r-HLH) and human menopausal gonadotrophin, a consensus was reached on which patient subgroups may benefit from LH supplementation. Adjuvant r-HLH gives clinicians precise control over the dose of LH bioactivity administered to target the therapeutic window. The use of r-HLH is recommended in women with poor response in a previous cycle or suboptimal follicular progression in a current cycle by day 6-8 of stimulation. r-HLH should also be considered in women at risk of suboptimal response, specifically age > 35 years. Other risk markers that suggest the need for LH supplementation, which include baseline/day 6 serum LH and anti-Mullerian hormone concentrations, antral follicle count and LH polymorphisms require further research and verification. For measurement of LH response adequacy, the monitoring of follicular progression, oestradiol concentrations and endometrial thickness is recommended. PMID- 21550851 TI - Innate responses to Toxoplasma gondii in mice and humans. AB - Primary infection with Toxoplasma gondii stimulates production of high levels of interleukin 12 (IL-12) and interferon gamma (IFN-gamma) by cells of the innate immune system. These two cytokines are central to resistance to T. gondii. Signaling through the Toll-like receptor (TLR) adaptor protein MyD88 is indispensible for activating early innate immune responses. Recent studies have established that TLR11 plays a dominant role in sensing T. gondii. At the same time, TLR11 is represented in humans only by a pseudogene, and the major question of how innate and adaptive immune responses occur in the absence of TLR11 remains unanswered. In this article, similarities and differences in sensors and effector molecules that determine host resistance to the parasite in humans and mice are discussed. PMID- 21550854 TI - Current practice in tubal surgery and adhesion management: a review. AB - The diminished role of tubal surgery in infertile women following widespread access to IVF is now being reviewed as more patients and surgeons today consider tubal surgery as an effective alternative to assisted reproduction treatment in certain circumstances. The limitations of and lack of patient acceptance of assisted reproduction treatment for ethical and moral reasons have contributed to this change as well as advances in surgical techniques and instrument technology, notably developments in endoscopic surgery. Strategies in tubal surgery are largely unchanged but the mini-invasive nature of the endoscopic approach has added value because of less tissue trauma, better visualization of the operative field and more rapid healing, which make surgery using today's techniques an integral part of the treatment strategy in infertile couples. PMID- 21550855 TI - Innate immune responses to M. tuberculosis infection. AB - A prerequisite for successful establishment of Mycobacterium tuberculosis in the host is its ability to survive after internalization in alveolar macrophages that they encounter after inhalation. The innate immune response protects some individuals to the extent that they remain uninfected. In others, the innate immune system is not sufficient and an adaptive immune response is generated. This is usually protective, but not sterilizing, and individuals remain latently infected. In susceptible individuals, M. tuberculosis successfully escapes immune surveillance. The interplay between the host innate immune response and the bacterial mechanisms in play to offset this response, is of considerable importance in dictating the course of the disease. In order to gain an understanding of this interplay it is of importance to analyze how M. tuberculosis interacts with innate immune receptors and makes its entry into macrophages, how it subverts the bactericidal effects of macrophages, and dampens processes required for protective immunity, including cytokine and chemokine induction. This review will focus on some of the Indian efforts in these areas, concentrating mainly on the interaction of M. tuberculosis with macrophages and dendritic cells (DCs). The role of the PE/PPE family of proteins in regulating the immune response, will not be discussed in this chapter. The genome-wide approaches of analyzing host-M. tuberculosis interactions will also be discussed elsewhere. PMID- 21550856 TI - Induction of type B synoviocyte-like cells from plasmacytoid dendritic cells of the bone marrow in rheumatoid arthritis and osteoarthritis. AB - We examined the capacities of bone marrow (BM) plasmacytoid dendritic cells (pDC) to differentiate into type B synoviocyte-like cells. BM aspiration samples were obtained from 24 rheumatoid arthritis (RA) patients and 19 osteoarthritis (OA) patients during joint operations from the iliac crest. CD34+ cells and pDC purified from BM mononuclear cells were cultured with or without SCF, GM-CSF, and TNF-alpha for 2-4 weeks. RA BM pDC as well as OA BM pDC comparably differentiated into fibroblast-like cells (FLC), expressing cadherin-11 and producing MMP-1, especially in the presence of TNF-alpha. Of note, depletion of BDCA4+ pDC from RA BM CD34+ cells significantly diminished their capacities to differentiate into FLC, which were restored by addition of BDCA4+cells in a dose-response manner. These results indicate that pDC is one of the progenitors of type B synoviocytes, suggesting that BM pDC might be involved in the pathogenesis of RA and OA. PMID- 21550857 TI - Immune mechanisms of new therapeutic strategies in multiple sclerosis-A focus on alemtuzumab. AB - Alemtuzumab is a humanized monoclonal antibody targeting CD52, a broadly expressed cell surface molecule on immune cells. Application results in a rapid and long-lasting removal of lymphocyte populations from the circulation. Alemtuzumab-treatment of MS patients with relapsing-remitting forms of the disease significantly reduced the risk of relapse and accumulation of disability compared to interferon beta-1a treatment in a phase II trial. Interestingly, further analysis together with parallel experimental studies suggested that alemtuzumab not only reduces disease activity due to its immune cell-depleting effect, but also confers neuroprotective effects, presumably by inducing production of neurotrophic factors in autoreactive T cells. However, alemtuzumab treated MS patients experienced increased rates of novel autoimmunity and a slight increase in infections, demonstrating that alemtuzumab-mediated skewing of the immune cell compartment has a broad influence on immune functions. This review discusses the current concepts about the underlying mechanisms causing these altered immune responses in alemtuzumab-treated MS patients. PMID- 21550859 TI - The complex dance between parents and child: the sex of all 3 modifies phenotype. PMID- 21550858 TI - Primary care providers' perspectives on psychoactive medication disorders in older adults. AB - BACKGROUND: Compared with younger adults, older adults consume a disproportionate percentage of pain and sleep medications. Some studies have reported that psychoactive medication misuse and abuse in older populations is a significant problem. OBJECTIVES: The aim of this study was to understand the perspective of primary care providers (PCPs) regarding the extent and clinical presentations of misuse and abuse of psychoactive medications in older patients and to explore PCPs' perceived barriers to identifying affected individuals. METHODS: Seventeen physicians and 5 nurse practitioners from 2 ambulatory care practices serving older adults in New York City participated in this study. Six focus group discussions were audiotaped and transcribed. Two raters coded transcripts to identify recurring themes. Qualitative analysis software was employed for data coding and sorting purposes. RESULTS: Although PCPs indicated that only a small percentage of older patients were actively misusing or abusing their psychoactive medications (average estimate given by providers, 8%), they felt that these patients placed significant time burdens on them. Perceived risk factors included psychiatric disorders, previous substance abuse history, and cognitive impairment, but many PCPs found it impossible to predict which patients were at increased risk. PCPs identified multiple barriers to identifying affected patients, including lack of communication (between provider and patient, provider and patients' caregivers, and between different providers), nonspecific symptoms, and the lack of a clear definition of misuse and abuse. CONCLUSIONS: The lack of a clear definition, absence of well-defined risk factors, and ambiguous clinical manifestations of psychoactive medication misuse and abuse present substantial barriers to diagnosis. A standard, age-appropriate definition could help PCPs establish a diagnosis, clarify what constitutes appropriate psychoactive medication use, define the extent of the problem, and pave the way for the development of effective screening and diagnostic tools. PMID- 21550860 TI - Mathematical modeling of cardiovascular coupling: Central autonomic commands and baroreflex control. AB - The cross-correlation function (CCF) yields the correlation coefficient between spontaneous fluctuations of heart period and blood pressure as a function of the time shift between these variables. Two CCF patterns occur in humans: I) positive correlation between heart period and previous pressure values; II) negative correlation between heart period and subsequent pressure values. These patterns may result from the baroreflex and central autonomic commands (CAC), respectively. The aim of this study was to test this interpretation with a non linear mathematical model of the human cardiovascular system. CAC were modeled as either phasic changes or random fluctuations of vagal and sympathetic activities with opposite sign. CCF pattern I resulted from baroreflex buffering of blood pressure changes elicited by vascular resistance fluctuations. When cardiac baroreflex control was absent or outweighed by CAC to the heart, simulations resulted in CCF pattern II only. In intermediate conditions when cardiac baroreflex interacted with CAC to the heart, CCF patterns I and II coexisted because the coupling between heart period and blood pressure varied with time. CAC to the heart decreased in magnitude the correlation coefficient and lengthened the time shift of CCF pattern I, thus apparently slowing and blunting baroreflex effects. Conversely, the baroreflex decreased in magnitude the correlation coefficient of CCF pattern II, thus blunting CAC effects. These results provide theoretical evidence in favor of application of the CCF analysis to investigate the balance between central autonomic and baroreflex cardiac control. PMID- 21550861 TI - Transient elastography and portal hypertension in pediatric patients with cystic fibrosis Transient elastography and cystic fibrosis. AB - BACKGROUND: Esophageal varices (EV) are a complication of cystic fibrosis associated liver disease. Esophagogastroduodenoscopy (EGD) is currently used to diagnose varices but is invasive for pediatric patients. The goal of this study was to explore the relationship between transient elastography (FibroScan(r)) and the presence of EV in patients with liver disease defined by clinical, laboratory, sonographic, and/or endoscopic criteria. METHODS: 18 patients with cystic fibrosis underwent EGD and transient elastography. 12 patients had EV. RESULTS: Patients with EV had higher FibroScan values than those without varices with median values of 22.4 kPa (14.4-30.4 kPa) vs. 7.9 kPa (4.4-13.7 kPa) (p=0.01). Using a threshold of 12 kPa, four of six patients without EV would not have needed EGD. CONCLUSIONS: Elastography should be recommended for all cystic fibrosis patients with liver disease to follow its progression. A prospective study is needed to define an elastography threshold value that predicts the presence of EV. PMID- 21550862 TI - Simultaneous determination of lipoic acid (LA) and dihydrolipoic acid (DHLA) in human plasma using high-performance liquid chromatography coupled with electrochemical detection. AB - A fast, simple, and a reliable high-performance liquid chromatography linked with electrochemical detector (HPLC-ECD) method for the assessment of lipoic acid (LA) and dihydrolipoic acid (DHLA) in plasma was developed using naproxen sodium as an internal standard (IS) and validated according to standard guidelines. Extraction of both analytes and IS from plasma (250 MUl) was carried out with a single step liquid-liquid extraction applying dichloromethane. The separated organic layer was dried under stream of nitrogen at 40 degrees C and the residue was reconstituted with the mobile phase. Complete separation of both compounds and IS at 30 degrees C on Discovery HS C18 RP column (250 mm * 4.6 mm, 5 MUm) was achieved in 9 min using acetonitrile: 0.05 M phosphate buffer (pH 2.4 adjusted with phosphoric acid) (52:48, v/v) as a mobile phase pumped at flow rate of 1.5 ml min(-1) using electrochemical detector in DC mode at the detector potential of 1.0 V. The limit of detection and limit of quantification for lipoic acid were 500 pg/ml and 3 ng/ml, and for dihydrolipoic acid were 3 ng/ml and 10 ng/ml, respectively. The absolute recoveries of lipoic acid and dihydrolipoic acid determined on three nominal concentrations were in the range of 93.40-97.06, and 93.00-97.10, respectively. Similarly coefficient of variations (% CV) for both intra-day and inter-day were between 0.829 and 3.097% for lipoic acid and between 1.620 and 5.681% for dihydrolipoic acid, respectively. This validated method was applied for the analysis of lipoic acid/dihydrolipoic acid in the plasma of human volunteers and will be used for the quantification of these compounds in patients with oxidative stress induced pathologies. PMID- 21550863 TI - Defining modularity: A comment on "The emergence of modularity in biological systems" by Lorenz, Jeng, and Deem. PMID- 21550864 TI - Linear array ultrasonography to stage rectal neoplasias suitable for local treatment. AB - BACKGROUND: Because of the many therapeutic options available, a reliable staging is crucial for rectal neoplasia management. Adenomas and cancers limited to the submucosa without lymph node involvement may be treated locally. AIMS: The aim of this study is to evaluate the diagnostic accuracy of endorectal ultrasonography in the staging of neoplasias suitable for local treatment. METHODS: We considered all patients who underwent endorectal ultrasonography between 2001 and 2010. The study population consisted of 92 patients with 92 neoplasias (68 adenocarcinomas and 24 adenomas). A 5 and 7.5MHz linear array echoendoscope was used. The postoperative histopathologic result was compared with the preoperative staging defined by endorectal ultrasonography. Adenomas and cancers limited to the submucosa were considered together (pT0-1). RESULTS: The sensitivity, specificity, overall accuracy rate, positive predictive value, and negative predictive value of endorectal ultrasonography for pT0-1 were 86%, 95.6%, 91.3%, 94.9% and 88.7%. Those for nodal involvement were 45.4%, 95.5%, 83%, 76.9% and 84%, with 3 false positive results and 12 false negative. For combined pT0-1 and pN0, endorectal ultrasonography showed an 87.5% sensitivity, 95.9% specificity, 92% overall accuracy rate, 94.9% positive predictive value and 90.2% negative predictive value. CONCLUSION: Endorectal linear array ultrasonography is a reliable tool to detect rectal neoplasias suitable for local treatment. PMID- 21550865 TI - New microvascular anastomotic ring-coupling device using negative pressure. AB - INTRODUCTION: Many microvascular anastomoses have been performed with Unilink devices, and their advantages have been discussed in the literature over the past few decades. However, there are two drawbacks that have not been addressed and that have limited the development of next-generation microvascular anastomotic devices. First, the Unilink device has metallic pins for fixing vessel walls that remain permanently in the body. Second, the surgeon must manually attach vessel walls to the device. A novel microvascular anastomotic ring device, which uses negative pressure as an atraumatic force to semiautomatically fix the vessel walls, was built and tested in rats. METHODS: The device was designed with three dimensional computer-aided design (3D-CAD) software, constructed with laser lithography, and tested in the femoral veins of eight rats. At 2 weeks' post implantation, the vein was exposed again, and the patency was examined subjectively. The specimens were examined with light and scanning electron microscopy. RESULTS: Of the eight devices, one broke during the implantation procedure and was omitted from the study. The other seven veins were successfully anastomosed by the devices. Two weeks later, six of the seven veins remained patent, and one had separated. In the patent specimens, endothelialisation was complete, and no thrombus formation was found. CONCLUSIONS: A novel microvascular anastomotic ring device that uses negative pressure to semiautomatically fix the vessel walls without requiring metallic pins was successfully designed. PMID- 21550866 TI - Three-dimensional evaluation of breast contour and volume changes following subpectoral augmentation mammaplasty over 6 months. AB - BACKGROUND: Changes in breast-morphology occur after all types of breast surgery, but a systematic and objective surgical result assessment is currently lacking. Three-dimensional (3-D) surface imaging offers the ability to quantitatively evaluate breast contour, shape, surface and volume changes after surgery. This study evaluates 3-D breast contour and volume changes after breast augmentation over time. METHODS: 3-D surface imaging of 14 subpectoral breast-augmentation patients (n = 28 breasts) were accomplished over six time periods (preoperative (OP), post-OP 1: 2-3 days; post-OP 2: 1 week; post-OP 3: 1 month; post-OP 4: 3 months; and post-OP 5: 6 months after surgery) and linear-distance measurement, breast volume and surface changes were analysed. 3-D breast-contour- and volume variations are expressed in percentage changes over time. RESULTS: All breast measurements changed significantly between pre-OP and post-OP 1 (Friedmann test, p = 0.001-0.025). First significant postoperative changes over time compared with post-OP 1 for breast volume, surface, sternal notch to nipple and nipple to inframammary-fold-distance measurements are quantifiable after 1 month (post hoc Wilcoxon test, p = 0.001 for all) with further relevant breast volume (post hoc Wilcoxon test, p = 0.041) and surface changes (post hoc Wilcoxon test, p = 0.037) between months 1 and 3 after surgery. The inframammary fold dropped by 1.4 cm after 6 months and final breast volume +/- 0.5% is reached between months 1 and 3 after surgery. Valuable reductions in breast contour and volume by nearly 85% are also reached after 1 month (Wilcoxon test, p = 0.001) and changed to 98% after 3 months and 100% after 6 months. CONCLUSIONS: Breast morphological changes following subpectoral breast augmentation are completed after 3 months. 3-D surface imaging may play a part in comparing different breast-augmentation techniques. PMID- 21550867 TI - Children ankle valgus deformity treatment using a transphyseal medial malleolar screw. AB - INTRODUCTION: Ankle valgus deformity is rare in children. It generally leads to difficulties wearing shoes, walking instability and mechanical pain. No medical treatment is effective and the only option is surgical correction of the deformity. Two main options are available: supramalleolar osteotomy and medial malleolar epiphysiodesis. We report our experience with epiphysiodesis using a transphyseal medial malleolar screw. PATIENTS AND METHODS: This is a retrospective study of all children followed for ankle valgus and treated by transphyseal medial malleolar screw epiphysiodesis in our department. The study included 10 cases of ankle valgus deformity in seven children (four with multiple extostoses, two type 1 neurofibromatosis, one Larsen's syndrome) who completed skeletal maturity. At surgery, median bone age was 12 years (10 to 13 years and 6 months) and the median tibiotalar angle was 17.5 degrees (10 degrees to 30 degrees ). RESULTS: At skeletal maturity, preoperative valgus was corrected in six patients (9/10 ankles). The median tibiotalar angle was 5 degrees (0 degrees to 25 degrees ). Valgus was not corrected in one patient (30 degrees to 25 degrees ). No postoperative complications occurred. DISCUSSION: Epiphysiodesis by transphyseal medial malleolar screw is a simple, efficient and safe procedure to correct a significant or symptomatic ankle valgus deformity in children before skeletal maturity. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 21550868 TI - Capstone projects and national student design competitions. PMID- 21550869 TI - The dream factory. PMID- 21550870 TI - Wireless diagnostics. PMID- 21550871 TI - Technology and innovative services: toward a megamarket response to aging. PMID- 21550872 TI - Measurement of blood pressure. PMID- 21550873 TI - A novel rotate-and-fire digital spiking neuron and its neuron-like bifurcations and responses. AB - A novel rotate-and-fire digital spiking neuron is presented. The digital neuron is a wired system of shift registers and thus it is suited to on-chip learning unlike many other analog spiking neuron models. By adjusting the wiring pattern among the registers, the digital neuron can generate spike trains with various spike patterns and can exhibit related bifurcations. A discrete-continuous hybrid map, which describes the neuron dynamics without any approximation, is derived analytically. Using the hybrid map, it is shown that the digital spiking neuron can mimic typical bifurcation phenomena and various nonlinear responses of biological neurons. PMID- 21550874 TI - Moving-horizon state estimation for nonlinear systems using neural networks. AB - Moving-horizon (MH) state estimation is addressed for nonlinear discrete-time systems affected by bounded noises acting on system and measurement equations by minimizing a sliding-window least-squares cost function. Such a problem is solved by searching for suboptimal solutions for which a certain error is allowed in the minimization of the cost function. Nonlinear parameterized approximating functions such as feedforward neural networks are employed for the purpose of design. Thanks to the offline optimization of the parameters, the resulting MH estimation scheme requires a reduced online computational effort. Simulation results are presented to show the effectiveness of the proposed approach in comparison with other estimation techniques. PMID- 21550875 TI - Modeling of complex-valued wiener systems using B-spline neural network. AB - In this brief, a new complex-valued B-spline neural network is introduced in order to model the complex-valued Wiener system using observational input/output data. The complex-valued nonlinear static function in the Wiener system is represented using the tensor product from two univariate B-spline neural networks, using the real and imaginary parts of the system input. Following the use of a simple least squares parameter initialization scheme, the Gauss-Newton algorithm is applied for the parameter estimation, which incorporates the De Boor algorithm, including both the B-spline curve and the first-order derivatives recursion. Numerical examples, including a nonlinear high-power amplifier model in communication systems, are used to demonstrate the efficacy of the proposed approaches. PMID- 21550876 TI - Spectral analysis of accelerometry signals from a directed-routine for falls-risk estimation. AB - Injurious falls are a prevalent and serious problem faced by a growing elderly population. Accurate assessment and long-term monitoring of falls-risk could prove useful in the prevention of falls, by identifying those at risk of falling early so targeted intervention may be prescribed. Previous studies have demonstrated the feasibility of using triaxial accelerometry to estimate the risk of a person falling in the near future, by characterizing their movement as they execute a restricted sequence of predefined movements in an unsupervised environment, termed a directed routine. This study presents an improvement on this previously published system, which relied explicitly on time-domain features extracted from the accelerometry signals. The proposed improvement incorporates features derived from spectral analysis of the same accelerometry signals; in particular the harmonic ratios between signal harmonics and the fundamental frequency component are used. Employing these additional frequency-domain features, in combination with the previously reported time-domain features, an increase in the observed correlation with the clinical gold-standard risk of falling, from = 0:81 to = 0:96, was achieved when using manually annotated event segmentation markers; using an automated algorithm to segment the signals gave corresponding results of = 0:73 and = 0:99, before and after the inclusion of spectral features. The strong correlation with falls-risk observed in this preliminary study further supports the feasibility of using an unsupervised assessment of falls-risk in the home environment. PMID- 21550877 TI - A multiscale graph theoretical approach to gene regulation networks: a case study in atrial fibrillation. AB - The changes in between gene expression correlation structure induced in heart tissue by atrial fibrillation are studied by means of a graph theoretical approach. As expected by general statistical mechanics principles, the disease increases the general connectivity of the gene regulation network; the multiscale character of the analysis allows us to get both a general appreciation of regulation network connectivity and the sketching of a biological interpretation of the studied disease. The presence of a still largely unknown, scale invariant, global correlation field encompassing the entire genome is demonstrated as well. PMID- 21550878 TI - A nonrigid registration framework using spatially encoded mutual information and free-form deformations. AB - Mutual information (MI) registration including spatial information has been shown to perform better than the traditional MI measures for certain nonrigid registration tasks. In this work, we first provide new insight to problems of the MI-based registration and propose to use the spatially encoded mutual information (SEMI) to tackle these problems. To encode spatial information, we propose a hierarchical weighting scheme to differentiate the contribution of sample points to a set of entropy measures, which are associated to spatial variable values. By using free-form deformations (FFDs) as the transformation model, we can first define the spatial variable using the set of FFD control points, and then propose a local ascent optimization scheme for nonrigid SEMI registration. The proposed SEMI registration can improve the registration accuracy in the nonrigid cases where the traditional MI is challenged due to intensity distortion, contrast enhancement, or different imaging modalities. It also has a similar computation complexity to the registration using traditional MI measures, improving up to two orders of magnitude of computation time compared to the traditional schemes. We validate our algorithms using phantom brain MRI, simulated dynamic contrast enhanced mangetic resonance imaging (MRI) of the liver, and in vivo cardiac MRI. The results show that the SEMI registration significantly outperforms the traditional MI registration. PMID- 21550879 TI - Automatic nonrigid calibration of image registration for real time MR-guided HIFU ablations of mobile organs. AB - Real time magnetic resonance imaging (MRI) is rapidly gaining importance in interventional therapies. An accurate motion estimation is required for mobile targets and can be conveniently addressed using an image registration algorithm. Since the adaptation of the control parameters of the algorithm depends on the application (targeted organ, location of the tumor, slice orientation, etc.), typically an individual calibration is required. However, the assessment of the estimated motion accuracy is difficult since the real target motion is unknown. In this paper, existing criteria based only on anatomical image similarity are demonstrated to be inadequate. A new criterion is introduced, which is based on the local magnetic field distribution. The proposed criterion was used to assess, during a preparative calibration step, the optimal configuration of an image registration algorithm derived from the Horn and Schunck method. The accuracy of the proposed method was evaluated in a moving phantom experiment, which allows the comparison with the known motion pattern and to an established criterion based on anatomical images. The usefulness of the method for the calibration of optical-flow based algorithms was also demonstrated in vivo under conditions similar to thermo-ablation for the abdomen of twelve volunteers. In average over all volunteers, a resulting displacement error of 1.5 mm was obtained (largest observed error equal to 4-5 mm) using a criterion based on anatomical image similarity. A better average accuracy of 1 mm was achieved using the proposed criterion (largest observed error equal to 2 mm). In both kidney and liver, the proposed criterion was shown to provide motion field accuracy in the range of the best achievable. PMID- 21550880 TI - Improvements on twin support vector machines. AB - For classification problems, the generalized eigenvalue proximal support vector machine (GEPSVM) and twin support vector machine (TWSVM) are regarded as milestones in the development of the powerful SVMs, as they use the nonparallel hyperplane classifiers. In this brief, we propose an improved version, named twin bounded support vector machines (TBSVM), based on TWSVM. The significant advantage of our TBSVM over TWSVM is that the structural risk minimization principle is implemented by introducing the regularization term. This embodies the marrow of statistical learning theory, so this modification can improve the performance of classification. In addition, the successive overrelaxation technique is used to solve the optimization problems to speed up the training procedure. Experimental results show the effectiveness of our method in both computation time and classification accuracy, and therefore confirm the above conclusion further. PMID- 21550881 TI - Hyperellipsoidal statistical classifications in a reproducing kernel Hilbert space. AB - Standard support vector machines (SVMs) have kernels based on the Euclidean distance. This brief extends standard SVMs to SVMs with kernels based on the Mahalanobis distance. The extended SVMs become a special case of the Euclidean distance when the covariance matrix in a reproducing kernel Hilbert space is degenerated to an identity. The Mahalanobis distance leads to hyperellipsoidal kernels and the Euclidean distance results in hyperspherical ones. In this brief, the Mahalanobis distance-based kernel in a reproducing kernel Hilbert space is developed systematically. Extensive experiments demonstrate that the hyperellipsoidal kernels slightly outperform the hyperspherical ones, with fewer SVs. PMID- 21550882 TI - A new automatic parameter setting method of a simplified PCNN for image segmentation. AB - An automatic parameter setting method of a simplified pulse coupled neural network (SPCNN) is proposed here. Our method successfully determines all the adjustable parameters in SPCNN and does not need any training and trials as required by previous methods. In order to achieve this goal, we try to derive the general formulae of dynamic threshold and internal activity of the SPCNN according to the dynamic properties of neurons, and then deduce the sub-intensity range expression of each segment based on the general formulae. Besides, we extract information from an input image, such as the standard deviation and the optimal histogram threshold of the image, and attempt to build a direct relation between the dynamic properties of neurons and the static properties of each input image. Finally, the experimental segmentation results of the gray natural images from the Berkeley Segmentation Dataset, rather than synthetic images, prove the validity and efficiency of our proposed automatic parameter setting method of SPCNN. PMID- 21550883 TI - Feature selection using probabilistic prediction of support vector regression. AB - This paper presents a new wrapper-based feature selection method for support vector regression (SVR) using its probabilistic predictions. The method computes the importance of a feature by aggregating the difference, over the feature space, of the conditional density functions of the SVR prediction with and without the feature. As the exact computation of this importance measure is expensive, two approximations are proposed. The effectiveness of the measure using these approximations, in comparison to several other existing feature selection methods for SVR, is evaluated on both artificial and real-world problems. The result of the experiments show that the proposed method generally performs better than, or at least as well as, the existing methods, with notable advantage when the dataset is sparse. PMID- 21550884 TI - Kernel map compression for speeding the execution of kernel-based methods. AB - The use of Mercer kernel methods in statistical learning theory provides for strong learning capabilities, as seen in kernel principal component analysis and support vector machines. Unfortunately, after learning, the computational complexity of execution through a kernel is of the order of the size of the training set, which is quite large for many applications. This paper proposes a two-step procedure for arriving at a compact and computationally efficient execution procedure. After learning in the kernel space, the proposed extension exploits the universal approximation capabilities of generalized radial basis function neural networks to efficiently approximate and replace the projections onto the empirical kernel map used during execution. Sample applications demonstrate significant compression of the kernel representation with graceful performance loss. PMID- 21550885 TI - Image segmentation using local variation and edge-weighted centroidal Voronoi tessellations. AB - The classic centroidal Voronoi tessellation (CVT) model and its generalizations work quite well at extracting uniformly colored objects, but often fail to handle images with distinct color distribution or strong inhomogeneous intensity. To resolve this problem within the CVT methodology, in this paper we incorporate the information of local variation of colors/intensities and the length of boundaries into the energy functional and develop a new model called the Local Variation and Edge-Weighted Centroidal Voronoi Tessellation (LVEWCVT) for image segmentation. Its mathematical formulation and practical implementations are also discussed and given. We test the LVEWCVT method on various type of segments and also compare it with several state-of-art algorithms using extensive segmentation examples, the results demonstrate excellent performance and competence of the proposed method. PMID- 21550886 TI - Image deconvolution with multi-stage convex relaxation and its perceptual evaluation. AB - This paper proposes a new image deconvolution method using multi-stage convex relaxation, and presents a metric for perceptual evaluation of deconvolution results. Recent work in image deconvolution addresses the deconvolution problem via minimization with non-convex regularization. Since all regularization terms in the objective function are non-convex, this problem can be well modeled and solved by multi-stage convex relaxation. This method, adopted from machine learning, iteratively refines the convex relaxation formulation using concave duality. The newly proposed deconvolution method has outstanding performance in noise removal and artifact control. A new metric, transduced contrast-to distortion ratio (TCDR), is proposed based on a human vision system (HVS) model that simulates human responses to visual contrasts. It is sensitive to ringing and boundary artifacts, and very efficient to compute. We conduct comprehensive perceptual evaluation of image deconvolution using visual signal-to-noise ratio (VSNR) and TCDR. Experimental results of both synthetic and real data demonstrate that our method indeed improves the visual quality of deconvolution results with low distortions and artifacts. PMID- 21550887 TI - Generalized random walks for fusion of multi-exposure images. AB - A single captured image of a real-world scene is usually insufficient to reveal all the details due to under- or over-exposed regions. To solve this problem, images of the same scene can be first captured under different exposure settings and then combined into a single image using image fusion techniques. In this paper, we propose a novel probabilistic model-based fusion technique for multi exposure images. Unlike previous multi-exposure fusion methods, our method aims to achieve an optimal balance between two quality measures, i.e., local contrast and color consistency, while combining the scene details revealed under different exposures. A generalized random walks framework is proposed to calculate a globally optimal solution subject to the two quality measures by formulating the fusion problem as probability estimation. Experiments demonstrate that our algorithm generates high-quality images at low computational cost. Comparisons with a number of other techniques show that our method generates better results in most cases. PMID- 21550888 TI - Efficient reversible watermarking based on adaptive prediction-error expansion and pixel selection. AB - Prediction-error expansion (PEE) is an important technique of reversible watermarking which can embed large payloads into digital images with low distortion. In this paper, the PEE technique is further investigated and an efficient reversible watermarking scheme is proposed, by incorporating in PEE two new strategies, namely, adaptive embedding and pixel selection. Unlike conventional PEE which embeds data uniformly, we propose to adaptively embed 1 or 2 bits into expandable pixel according to the local complexity. This avoids expanding pixels with large prediction-errors, and thus, it reduces embedding impact by decreasing the maximum modification to pixel values. Meanwhile, adaptive PEE allows very large payload in a single embedding pass, and it improves the capacity limit of conventional PEE. We also propose to select pixels of smooth area for data embedding and leave rough pixels unchanged. In this way, compared with conventional PEE, a more sharply distributed prediction-error histogram is obtained and a better visual quality of watermarked image is observed. With these improvements, our method outperforms conventional PEE. Its superiority over other state-of-the-art methods is also demonstrated experimentally. PMID- 21550889 TI - Multivariate compressive sensing for image reconstruction in the wavelet domain: using scale mixture models. AB - Most wavelet-based reconstruction methods of compressive sensing (CS) are developed under the independence assumption of the wavelet coefficients. However, the wavelet coefficients of images have significant statistical dependencies. Lots of multivariate prior models for the wavelet coefficients of images have been proposed and successfully applied to the image estimation problems. In this paper, the statistical structures of the wavelet coefficients are considered for CS reconstruction of images that are sparse or compressive in wavelet domain. A multivariate pursuit algorithm (MPA) based on the multivariate models is developed. Several multivariate scale mixture models are used as the prior distributions of MPA. Our method reconstructs the images by means of modeling the statistical dependencies of the wavelet coefficients in a neighborhood. The proposed algorithm based on these scale mixture models provides superior performance compared with many state-of-the-art compressive sensing reconstruction algorithms. PMID- 21550890 TI - Revisiting intensity-based image registration applied to mammography. AB - The detection of architectural distortions and abnormal structures in mammographic images can be based on the analysis of bilateral and temporal cases using image registration. This paper presents a quantitative evaluation of state of-the art intensity based image registration methods applied to mammographic images. These methods range from a global and rigid transformation to local deformable paradigms using various metrics and multiresolution approaches. The aim of this study is to assess the suitability of these methods for mammographic image analysis. Evaluation using temporal cases based on quantitative analysis and a multiobserver study is presented which gives an indication of the accuracy and robustness of the different algorithms. Although previous studies suggested that local deformable methods were not suitable due to the generation of unrealistic distortions, in this work we show that local deformable paradigms (multiresolution B-Spline deformations) obtain the most accurate registration results. PMID- 21550891 TI - Vascular system modeling in parallel environment - distributed and shared memory approaches. AB - This paper presents two approaches in parallel modeling of vascular system development in internal organs. In the first approach, new parts of tissue are distributed among processors and each processor is responsible for perfusing its assigned parts of tissue to all vascular trees. Communication between processors is accomplished by passing messages, and therefore, this algorithm is perfectly suited for distributed memory architectures. The second approach is designed for shared memory machines. It parallelizes the perfusion process during which individual processing units perform calculations concerning different vascular trees. The experimental results, performed on a computing cluster and multicore machines, show that both algorithms provide a significant speedup. PMID- 21550892 TI - Generalizing common tasks in automated skin lesion diagnosis. AB - We present a general model using supervised learning and MAP estimation that is capable of performing many common tasks in automated skin lesion diagnosis. We apply our model to segment skin lesions, detect occluding hair, and identify the dermoscopic structure pigment network. Quantitative results are presented for segmentation and hair detection and are competitive when compared to other specialized methods. Additionally, we leverage the probabilistic nature of the model to produce receiver operating characteristic curves, show compelling visualizations of pigment networks, and provide confidence intervals on segmentations. PMID- 21550895 TI - Indirect mitral annuloplasty: a feasible or a mirage technology. PMID- 21550896 TI - Patrick W. Serruys and the roots of PCR. PMID- 21550897 TI - Patrick Washington Serruys: a view from across the Atlantic. PMID- 21550898 TI - The concept of participatory learning and group development. PMID- 21550899 TI - EuroPCR May 2011 plenary session: coronary revascularisation, Asia Pacific perspectives. PMID- 21550900 TI - Patrick W. Serruys and the EAPCI. PMID- 21550901 TI - Transapical versus transfemoral aortic valve implantation. PMID- 21550902 TI - Outcomes and complications of transcatheter aortic valve replacement using a balloon expandable valve according to the Valve Academic Research Consortium (VARC) guidelines. AB - AIMS: There is heterogeneity in the reporting of procedural outcomes and complications following transcatheter aortic valve replacement (TAVR). Recently, new definitions have been proposed by the Valve Academic Research Consortium (VARC) in an effort to standardise these outcomes and improve the quality of future clinical research. The aim of this study is to report the procedural outcomes and complication rates following TAVR in a large sequential patient cohort using a balloon expandable valve according to the new VARC definitions. METHODS AND RESULTS: Three hundred and ten consecutive patients undergoing TAVR were assessed, including patients forming our early historical series at the infancy of TAVR. All complication rates were re-evaluated according to VARC definitions. Mean age was 82.2 +/- 8.1 years and the Society of Thoracic Surgeons score was 9.4 +/- 5.7%. Transfemoral 30-day mortality was 6.8% (3.8% in the second half of the cohort) and transapical 30-day mortality was 13.7% (9.4% in the second half of the cohort). Cardiovascular 30-day mortality was 7.4% and the composite safety endpoint at 30-days was 18.4%. Device success was 80% (post procedural valve area <= 1.2 cm2 in 9.7%). Failure to deliver and deploy a valve occurred in only 3.5%, with 82% (nine cases) occurring in the first half of the experience. Of those who did not meet echocardiographic criteria for device success (valve area <= 1.2 cm2, transaortic gradient >= 20 mmHg or >= moderate aortic incompetence), 90% achieved a New York Heart Association class I/II. Life threatening bleeding complications occurred in 8.4%. In 7.7% of patients, red blood cell transfusions were given without evidence of overt bleeding. Major strokes occurred in 2.3% and acute kidney injury occurred in 6.5%. CONCLUSIONS: The VARC consensus guidelines provide a standardised reporting framework for clinical endpoints and complications post TAVR. We report the first series to our knowledge of 30-day outcomes using these definitions utilising a balloon expandable valve system. PMID- 21550903 TI - Reappraisal of percutaneous aortic balloon valvuloplasty as a preliminary treatment strategy in the transcatheter aortic valve implantation era. AB - AIMS: To assess the results of percutaneous aortic balloon valvuloplasty (PABV) as a potential bridge to further intervention in patients referred for transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Two hundred and fifty-three patients referred for TAVI were studied: 41 (16%) were considered transiently unsuitable for either aortic valve replacement (AVR) or TAVI and underwent PABV as a bridge to intervention. In the others, primary TAVI or AVR was performed in 140 cases, and medical therapy alone in 72.The overall population was at high risk: 82 +/- 8 years, logistic EuroSCORE: 28 +/- 16%, STS score: 16 +/- 10%. There was no PABV-related death. Twenty-three patients underwent secondary TAVI (n=19) or AVR (n=4), 18 did not undergo further intervention. One and two year survival rates were respectively 94 +/- 5% and 85 +/- 10% after bridge PABV, and 33 +/- 11 and 6 +/- 5% after PABV alone. There was no difference in survival between the primary TAVI / AVR and bridge PABV (p=0.08), and between medical treatment and PABV alone (p=0.36). CONCLUSION: In high-risk patients with aortic stenosis and temporary contraindications to AVR or TAVI, PABV may be used as a bridge to intervention with good mid-term outcomes. In others, PABV can be safely used but is associated with a poor outcome. PMID- 21550904 TI - Haemodynamic evaluation of aortic regurgitation after transcatheter aortic valve implantation using cardiovascular magnetic resonance. AB - AIMS: Echocardiography may underestimate the degree of paravalvular aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) using the Medtronic CoreValve bioprosthesis due to inherent limitations of ultrasound imaging in the evaluation of implanted cardiac prostheses. We aimed to evaluate the accuracy and feasibility of cardiovascular magnetic resonance (CMR) in quantifying regurgitant volume (RV) and regurgitant fraction (RF) in patients treated with this bioprosthesis for severe calcific aortic stenosis, and to compare the results with echocardiography and aortography. METHODS AND RESULTS: This study included 16 patients with a mean age of 78.7 years (eight women, eight men) who underwent successful TAVI using Medtronic CoreValve bioprosthesis. AR was evaluated by CMR, echocardiography, and aortography. Angiography was performed immediately after valve implantation. CMR and echocardiography were performed four weeks after valve implantation. There was a highly significant correlation between the CMR-derived and the angiographically-estimated degree of AR (r=0.86, p<0.001). On the other hand, there was only a limited correlation between CMR and echocardiography (r=0.374, p=0.15) as well as angiography and echocardiography (r=0.319, p=0.23) regarding the degree of AR. The weighted kappa for agreement between echocardiography and angiography was 0.14, for agreement between echocardiography and CMR 0.20, and for agreement between angiography and CMR 0.72. Echocardiography underestimated AR by one degree compared to CMR in five patients and 2 degrees in two patients; in six of these, the degree of AR obtained by CMR was similar to angiography. CONCLUSIONS: In patients undergoing TAVI, comparisons between purely quantitative measurements of AR by CMR and qualitative assessment by angiography showed better correlations than those with echocardiography. This suggests that echocardiography may underestimate the degree of AR and CMR in these circumstances has a great potential in reliably measuring the severity of AR in a quantitative manner. PMID- 21550905 TI - Effect of paclitaxel elution from reservoirs with bioabsorbable polymer compared to a bare metal stent for the elective percutaneous treatment of de novo coronary stenosis: the EUROSTAR-II randomised clinical trial. AB - AIMS: To compare the angiographic and clinical performance of a paclitaxel eluting stent using reservoirs technology and a bioabsorbable polymer, without surface coating (CoStar), vs. an equivalent bare metal stent (BMS) using an identical metallic platform. METHODS AND RESULTS: Three hundred and three (303) patients (335 lesions) with de novo coronary artery stenosis suitable for elective percutaneous treatment were randomised in an international multicentre single-blind trial to receive the CoStar stent (n=152) or the equivalent BMS (n=151). At eight months, the primary endpoint of in-segment binary restenosis was significantly lower in the CoStar than in the BMS group (17.6 vs. 30.3%, p=0.029). In-stent late loss (0.41 vs. 0.81 mm; p<0.0001) and all the other angiographic secondary endpoints also favoured CoStar. The composite of cardiac death, myocardial infarction related to the target vessel and target lesion revascularisation was significantly lower at eight months in the CoStar arm (19.7 vs. 29.1%; hazard ratio 0.54, 95% CI: 0.34-0.87; p=0.010), mainly due to lower incidence of target lesion revascularisation (15.1 vs. 26.5%; 95% CI: hazard ratio 0.45, 95% CI: 0.27-0.76; p=0.002). CONCLUSIONS: As compared with a bare metal stent of identical design, the paclitaxel elution from reservoirs results in significantly less binary restenosis, less late loss and lower revascularisation rates at eight months. Therefore, based on these data, the CoStar paclitaxel-eluting stent was found to be effective and safe. PMID- 21550906 TI - Predictors of death or myocardial infarction, ischaemic-driven revascularisation, and major adverse cardiovascular events following everolimus-eluting or paclitaxel-eluting stent deployment: pooled analysis from the SPIRIT II, III, IV and COMPARE trials. AB - AIMS: Although clinical trials have demonstrated superior clinical efficacy and improved safety of the everolimus-eluting stent (EES) compared with paclitaxel eluting stents (PES) the clinical, angiographic and procedural factors associated with adverse clinical outcomes following drug-eluting stent (DES) deployment have not been carefully analysed. METHODS AND RESULTS: We performed a patient-level pooled database analysis from the SPIRIT II, III, IV and COMPARE prospective randomised (EES versus PES) trials which enrolled 6,789 patients undergoing coronary stenting with follow-up through two years. To determine independent predictors of death, myocardial infarction (MI), ischaemia-driven revascularisation (target lesion [ID-TLR] or target vessel [ID-TVR]), and major adverse cardiovascular events ([MACE]; composite occurrence of cardiovascular death, MI, ID-TLR), we analysed clinical, angiographic and procedural variables using Cox proportional hazard stepwise regression analysis. Treatment with EES (versus PES) was a powerful, independent predictor of relative freedom from MI (HR [95% CI]= 0.54 [0.41, 0.71]; p<0.0001), cardiac death or MI (0.63 [0.49, 0.80]; p=0.0002), ID-TLR (0.59 [0.47, 0.74]; p<0.0001), ID-TVR (0.70 [0.58,0.84]; p=0.0002) and MACE (0.64 [0.54, 0.77]; p<0.0001). Both diabetes and the extent of coronary artery disease as reflected by the number of lesions treated were predictive of cardiac death, ID-TLR, ID-TVR, MI and MACE. CONCLUSIONS: This multivariate analysis identified independent predictors of adverse outcomes to two years following DES deployment. Treatment with EES (versus PES) is an independent predictor of freedom from MI, cardiac death or MI, ID-TLR, ID-TVR and MACE. PMID- 21550907 TI - PLATINUM QCA: a prospective, multicentre study assessing clinical, angiographic, and intravascular ultrasound outcomes with the novel platinum chromium thin-strut PROMUS Element everolimus-eluting stent in de novo coronary stenoses. AB - AIMS: Assess clinical, angiographic, and intravascular ultrasound results in lesions treated with the PROMUS Element platinum chromium everolimus-eluting stent (EES). METHODS AND RESULTS: Patients (N=100) with one de novo target lesion <= 34 mm long and reference vessel diameter (RVD) >= 2.25-<= 4.25 mm were enrolled at 14 sites. The primary endpoint was the 30-day composite of cardiac death, myocardial infarction, target lesion revascularisation (TLR), or definite/probable stent thrombosis (ST). The efficacy endpoint of 9 month in stent late loss in workhorse lesions (defined as RVD >= 2.5-<= 4.25 mm, lesion <= 24 mm) was compared to a performance goal based on historical results with TAXUS Express paclitaxel-eluting stents. Post-procedure incomplete stent apposition (ISA) was compared to a performance goal based on results with the PROMUS/XIENCE V EES in SPIRIT III. Mean age was 61.8 +/- 9.9 years; 77.0% were male; 19% had medically treated diabetes. Baseline RVD was 2.72 +/- 0.53 mm; lesion length was 15.4 +/- 7.0 mm. The primary endpoint occurred in one patient (periprocedural ST with TLR) with no additional major clinical events through one year. Nine-month in-stent late loss in workhorse lesions (0.17 +/- 0.25 mm, N=73) and post procedure ISA (5.7%, 5/88) were below performance goals (p<0.001). CONCLUSIONS: Through one year, PROMUS Element EES had an acceptable safety and efficacy profile with low in-stent late loss and post-procedure ISA. PMID- 21550908 TI - Impact of transradial and transfemoral coronary interventions on bleeding and net adverse clinical events in acute coronary syndromes. AB - AIMS: The aim of the present study was to examine the impact of the transradial approach (TRA), in comparison to the transfemoral approach (TFA), on PCI-related bleeding and patient outcomes in acute coronary syndrome patients who underwent PCI in the OASIS-5 trial. METHODS AND RESULTS: The primary outcome (death, myocardial infarction, refractory ischaemia) at nine days was similar in both groups (7.1% in 872 TRA and 7.7% in 7,013 TFA). Major bleeding was significantly lower in patients who underwent PCI with TRA by comparison to TFA (1.6% vs 3.5%, p<0.003, respectively). No difference between patients treated by fondaparinux or enoxaparin was noted for ischaemic events at nine days according to the access site. The rate of major bleeding at nine days was markedly reduced with fondaparinux when compared to enoxaparin for both access sites (from 4.8% to 2.3%, HR 0.48 [0.37-0.62], p< 0.0001 for TFA and from 2.4 to 0.9%, HR 0.36 [0.11- 1.16], p<0.08 for TRA). CONCLUSIONS: TRA is associated with substantial decrease of PCI-related bleeding in current contemporary pharmacological environment in comparison to TFA. Even in the context of low access site complication rate provided by TRA, fondaparinux was effective in reducing major bleeding. PMID- 21550909 TI - Preliminary experience with optical coherence tomography imaging to evaluate carotid artery stents: safety, feasibility and techniques. AB - AIMS: Optical coherence tomography (OCT) is an increasingly used intravascular imaging modality to assess coronary stent implantation and vessel healing. A recently developed catheter (C7 Dragonfly; LightLab Imaging Inc.,Westford, MA, USA) allows visualisation of peripheral arteries up to 10 mm of diameter with high speed pullback. Safety, feasibility and the technique of OCT following carotid artery stenting (CAS) were evaluated in the present study. METHODS AND RESULTS: OCT was performed in seven consecutive patients following successful CAS using proximal cerebral protection devices, occluding the common and external carotid artery and gentle manual injection of a total of 8-14 ml of 50% diluted contrast media with normal saline in order to displace the blood from the artery. Once the blood was displaced, pullback was started through the stented segment continuing the gentle contrast injection. After completion of the pullback all injected contrast was aspirated and discarded. In the first three patients, OCT was also performed without internal carotid artery flow blockage. Due to the high blood flow in the ICA it was not possible to replace all residual blood and obtain adequate OCT images. No procedural, in-hospital, or 30-day follow-up complications occurred. One patient experienced transient intolerance to vessel occlusion without any neurological sequels. OCT images were of good quality providing important information regarding stent geometry, presence and lack of strut apposition, plaque fracture, and plaque prolapse. CONCLUSIONS: Intravascular OCT under occlusive proximal protection appears feasible and safe to assess stent implantation in carotid arteries. PMID- 21550910 TI - Treatment of iatrogenic occlusive coronary dissections: a novel approach. AB - AIMS: Iatrogenic occlusive coronary dissection (IOCD) is a rare but high-risk complication of percutaneous coronary intervention (PCI) with limited data on options for management. The aim of this study was to describe a novel approach to the treatment of IOCD in order to gain access to the true coronary lumen. This technique may be feasible in cases in which conventional methods of PCI have failed. METHODS AND RESULTS: We performed a retrospective analysis of 11 patients with PCI complicated by IOCD. In all cases, IOCD was treated using the contrast guided subintimal tracking and re-entry "rescue" (STAR-R) procedure. Angiographic success with TIMI 3 flow was achieved in all patients and stent implantation was performed in 81.8% (n=9). At clinical follow-up (mean 186 +/- 79 days), target lesion revascularisation was required in 9% (n=1), with target vessel revascularisation in 27.3% (n=3), and a major adverse cardiac event rate of 27.3% (n=3). Angiographic follow-up was obtained in 81.8% (n=9) with a restenosis rate of 11% (n=1). CONCLUSIONS: The STAR-R procedure is a feasible option for the treatment of IOCD following failure of conventional techniques of treatment. PMID- 21550911 TI - In vivo assessment of optimal viewing angles from X-ray coronary angiography. AB - AIMS: To propose and validate a novel approach to determine the optimal angiographic viewing angles for a selected coronary (target) segment from X-ray coronary angiography, without the need to reconstruct the entire coronary tree in three-dimensions (3D), such that subsequent interventions are carried out from the best view. METHODS AND RESULTS: The approach starts with standard quantitative coronary angiography (QCA) of the target vessel in two angiographic views. Next, the target vessel is reconstructed in 3D, and in a very simple and intuitive manner, the possible overlap of the target vessel and other vessel segments can be assessed, resulting in the best view with minimum foreshortening and overlap. A retrospective study including 67 patients was set up for the validation. The overlap prediction result was compared with the true overlap on the available angiographic views (TEST views). The foreshortening for the views proposed by the new approach software viewing angle (SVA) and the views used during the stent deployment software viewing angle (EVA) were compared. Two experienced interventional cardiologists visually evaluated the success of SVA with respect to EVA. The evaluation results were graded into five values ranging from -2 to 2. The overlap prediction algorithm successfully predicted the overlap condition for all 235 TEST views. EVA was associated with more foreshortening than SVA (8.9% +/- 8.2% vs. 1.6% +/- 1.5%, p<0.001). The average evaluated point for the success of SVA was 0.94 +/- 0.80 (p <0.001), indicating that the evaluators were in favor of the optimal views determined by the proposed approach versus the views used during the actual intervention. CONCLUSIONS: The proposed approach is able to accurately and quickly determine the optimal viewing angles for the online support of coronary interventions. PMID- 21550912 TI - High shear stress induces a strain increase in human coronary plaques over a 6 month period. AB - AIMS: Atherosclerotic plaques develop in low shear stress regions. In the more advanced phase of the disease, plaques are exposed to altered shear stress levels, which could influence plaque composition. We investigated changes in plaque composition in human coronary arteries over a 6-month period and how these changes are related to shear stress. METHODS AND RESULTS: We took images of eight coronary arteries to obtain the 3D shape of the arteries. Lumen data were combined with computational fluid dynamics to obtain shear stress. Palpography was applied to measure strain at baseline and at 6-month follow-up. The change in strain from baseline to follow-up served as a marker for the change in plaque composition. We identified 17 plaques, and each plaque was divided into four regions: the upstream, throat, shoulder and downstream region. Shear stress and strain in the downstream region was significantly lower than in the other regions. There was no significant change in strain for the four different plaque regions. However, we observed that those plaque regions exposed to high shear stress showed a significant increase in strain. CONCLUSIONS: Plaque regions exposed to high shear stress showed an increase in strain over time. This indicates that shear stress may modulate plaque composition in human coronary arteries. PMID- 21550913 TI - Impact of perfusion restoration at epicardial and tissue levels on markers of myocardial necrosis and clinical outcome of patients with acute myocardial infarction. AB - AIMS: To assess the impact of reperfusion after primary percutaneous coronary intervention (PCI) on myocardial salvage and outcome of patients with acute ST segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: This study included 1,406 patients with STEMI undergoing primary PCI. Blood flow restoration at epicardial and tissue levels was assessed by Thrombolysis in Myocardial Infarction (TIMI) and myocardial perfusion grade (MPG). Patients had paired scintigraphic examinations before, and 7-14 days after intervention. Based on TIMI and MPG grades, patients were divided into three groups: patients with optimal epicardial/optimal tissue perfusion (TIMI=3/MPG=3; n=801), patients with optimal epicardial/suboptimal tissue reperfusion (TIMI=3/MPG <= 2; n=412) and patients with suboptimal epicardial/suboptimal tissue reperfusion (TIMI <= 2/MPG <= 2; n=193). In these groups, the median infarct size (25th-75th quartiles) in the 7-14 days scintigraphy was: 7.0% (1.0%-19.0%), 12.6% (5.0%-27.6%) and 18.7% (10.4%-33.7%) of the left ventricle (p<0.001); frequency of aborted myocardial infarction was: 15.5%, 10.0% and 4.7%, (p<0.001); estimates of 5-year mortality were: 7.8%, 16.0% and 20.1% (adjusted hazard ratio=0.43, 95% confidence interval 0.21-0.89; p=0.02 for optimal epicardial/optimal tissue vs suboptimal epicardial/suboptimal tissue reperfusion). CONCLUSIONS: In patients with STEMI undergoing primary PCI, restoration of blood flow at epicardial and tissue levels was associated with increased myocardial salvage and improved long-term survival. PMID- 21550914 TI - Impact of drug-eluting stent type on periprocedural myocardial necrosis. AB - AIMS: The relationship between stent design and periprocedural myocardial infarction is unclear. The newest type of drug-eluting stent (DES), the everolimus-eluting stent (EES), has thinner strut and polymer thickness and a small amount of drug. EES use, therefore, could be related to less myocardial necrosis post-percutaneous coronary intervention (PCI). This study was undertaken to compare the amount of myocardial necrosis associated with implantation of the four DES types currently approved in the U.S. METHODS AND RESULTS: A cohort of 7,259 consecutive patients who underwent elective PCI with DES implantation from 2003 to 2010 was studied. Sirolimus-eluting stents were deployed in 4420, paclitaxel-eluting stents in 1858, zotarolimus-eluting stents in 308, and EES in 673. The maximum creatine phosphokinase-MB (CPK-MB) was measured post-procedure and served as the primary endpoint. Patients who received EES had the smallest CPK-MB rise (p<0.0001) among the four groups. Further, a post-PCI increase was less often large enough to meet any of the usual criteria for periprocedural myocardial infarction used in clinical studies. After adjustment for baseline and angiographic characteristics, paclitaxel-, sirolimus-, and zotarolimus-eluting stent groups more frequently exceeded the CPK-MB >5x normal limit compared with EES-treated patients (OR=2.44, p=0.01; OR=2.01, p=0.05; OR=1.80, p=0.2, respectively). CONCLUSIONS: It is plausible that EES with their superior design are associated with less periprocedural myocardial injury compared with older generation DES. PMID- 21550915 TI - Impact factors: scientific and career assessment by numbers. AB - The most used scientific evaluation parameters today are: 1) The impact factor (IF) of scientific journals in which the papers of researchers, and their collaborators, are published and 2) The so-called H-factor which is used to evaluate the work of individual scientists. We explore in detail these particular parameters. Also we briefly discuss alternative forms of assessment in the modern age. PMID- 21550916 TI - Fatal coronary sinus and aortic erosions following percutaneous transvenous mitral annuloplasty device. PMID- 21550917 TI - How should I treat acute valve regurgitation? AB - BACKGROUND: An 81-year-old male with symptoms of angina and dyspnoea (NYHA 3), a history of coronary bypass surgery, a transaortic peak gradient of 109 mmHg on transthoracic echocardiography and a logistic Euro-SCORE of 21.6 was deemed suboptimal for surgery by a multidisciplinary team and was accepted for TAVI. INVESTIGATION: Preprocedural diameter of the native aortic root was 24.4 mm on transthoracic echocardiography (TTE), 26.9 mm on contrast angiography and 26.8 mm by 30.2 mm on multislice computed tomography (MSCT). DIAGNOSIS: heavy calcification of the aortic root and coronary arteries by MSCT. TREATMENT: Transcatheter aortic calve replacement with an 29 mm CoreValve prosthesis. PMID- 21550918 TI - Tools & Techniques: PCI in coronary bifurcations lesions. PMID- 21550919 TI - Transcatheter indirect mitral annuloplasty with the PTMA system: a technical report. PMID- 21550920 TI - Valve thrombosis after transcatheter heart valve implantation. PMID- 21550921 TI - [Community-based distribution of injectable contraceptives in an African setting: community trial in Madagascar]. AB - Community-based distribution of family planning provides a way of reaching underserved populations in developing countries. This article reports findings from an introductory trial of community-based distribution of Depot Medroxyprogesterone Acetate (DMPA), a progestin-only injectable contraceptive. The project, conducted in Madagascar in 2007 in collaboration with the Malagasy government, was intended to test the safety, acceptability, and contribution to policy goals of adding contraceptive injections to the range of methods already offered by paraprofessional community-based health workers in rural areas. In total, 61 agents in 13 communities were trained and initiated service offering DMPA. The intervention was evaluated after 7 months. Data collection included interviews with agents, their supervisors, and a sample of 303 clients, and review of agents' records. In support of the objectives, the descriptive analysis primarily examined the quality of agents' services (safety), three-month reinjection rates (acceptability), and DMPA uptake (contribution). Interviews with agents to test knowledge about correct practices indicated that they are able to provide high quality services. To capture mastery of essential techniques, a composite quality score was calculated from agents' answers. The average score was 23.3 out a maximum possible of 27. All agents scored at least 18 points, and 80% of them received 22 points or more. Interviews with clients further confirmed that agents were competent. The majority of clients were satisfied with the services they received, and a very large proportion (94%) of the women eligible for a second injection received it from the agent. There were no complaints from the communities, and women reported that acceptability among their partners was also high. Finally, the program attracted new users: the 61 agents recruited a total of 1,662 women over six months, 41% of whom were not using family planning when they initiated DMPA. Encouraged by the findings from the pilot project, the Malagasy government has proceeded to expand the program. As of March 2010, a total of 1,109 agents had been trained. At the international level, this study further contributes to the growing body of evidence that well trained community-based health workers can safely provide injectable contraceptives, potentially helping to increase contraceptive coverage in rural areas with a nationally scaled-up program. While community-based family planning services in Latin America and Asia have included injectables since the 1970s, experiences in sub-Saharan Africa have been very limited. Madagascar was one of the first countries, and several others (Ethiopia, Kenya, Nigeria, Malawi, Rwanda, Uganda, and Zambia) are beginning to include injectables in community based family planning programs. Furthermore, a recent technical consultation convened by the World Health Organization concluded that global evidence supports the introduction, continuation, and scale-up of community-based provision of injectable contraceptives. Despite this momentum, further efforts are required to expand this approach and increase the choice of contraceptive methods available to underserved populations. PMID- 21550922 TI - Non-convulsive status epilepticus characterised exclusively by a language disorder induced by non-ketotic hyperglycaemia. AB - Non-ketotic hyperglycaemia is an endocrine emergency characterised by elevated blood glucose levels and high plasma osmolarity. While hypoglycaemia-induced seizures are usually generalised, hyperglycaemia-induced seizures are often focal and secondary to the presence of brain lesions. Moreover, in the few studies in which language disorders of epileptic origin have been reported as a clinical manifestation of non-ketotic hyperglycaemia, the disorders were usually not isolated but were followed by partial motor seizures. We describe a patient who presented with non-convulsive partial status epilepticus and whose only sign was a fluctuating language disorder induced by non-ketotic hyperglycaemia. There were no accompanying brain lesions and the patient responded optimally to diazepam. Neurophysiological EEG evaluation was fundamental for the diagnosis. PMID- 21550923 TI - Benzodiazepine receptor imaging in an adult with Rasmussen's encephalitis and epilepsia partialis continua. AB - We describe an adult with Rasmussen's encephalitis associated with widespread decreased accumulation of tracer on 123-I iomazenil (IMZ) SPECT. The patient had a form of epilepsia partialis continua and neurological deterioration associated with hemiatrophy. Cranial MRI showed cerebral atrophy in the left frontal, parietal, and temporal lobes, without abnormal intensity. Delayed IMZ SPECT showed widespread decreased accumulation of tracer in the left temporal and frontal regions. An early scan showed mildly decreased accumulation in the left temporal and frontal regions. Three-dimensional stereotactic surface projection (3D-SSP) analysis showed that the decreased regions on delayed IMZ images were slightly larger as compared with the previous IMZ study performed. Some regions without decreased accumulation of tracer on Tc-ECD or early IMZ images showed decreased accumulation on delayed IMZ images. This case study suggests that benzodiazepine receptors may be reduced in the affected hemisphere of patients with Rasmussen's encephalitis. PMID- 21550924 TI - [Pregnancy and medical follow-up of women living with HIV/AIDS in Guadeloupe and Martinique (French West Indies): medical progress and social problems]. AB - After sub-Saharan Africa, the Caribbean is the region of the world most affected by HIV/AIDS. Guadeloupe and Martinique (French West Indies) are located in the heart of this region. Although the AIDS incidence here is lower than in other Caribbean countries, it is much higher than in mainland France. Transmission is mostly heterosexual, and the proportion of women infected is high, almost half of all those infected. Moreover, in Guadeloupe a large proportion of them are foreigners (mainly from Haiti). This qualitative study was conducted in 2009 among health professionals, advocacy and support groups, and women living with HIV/AIDS. It analysed the characteristics of women's follow-up during and after their pregnancy. It also analysed the practices that health professionals have developed to provide follow-up for these women, despite various obstacles. Antiretroviral therapy makes it possible to health professionals to reduce the risk of mother-to-child transmission of HIV infection. They inform their patients of the possibilities for infected women to have a child with less risk of infection provided that she has a medical follow-up and that she is treated. But they note that the pregnancies are rarely planned in consultation with them: patients are generally already pregnant when they discuss the subject with their doctors. The pregnancy is nevertheless a special moment for medical monitoring: women are particularly compliant during their pregnancy, because their priority is the protection of the child's health. After the child's birth, however, the social and administrative difficulties of many of these women serve as obstacles to their continued medical care. Some women stop treatment and medical follow-up after delivery, even when they make sure the child has medical follow-up. To continue the follow-up of women and their children, or to contact women who have been lost to follow-up, professionals resort to various practices: compliance consultations, house calls, hospitalization... These practices are based on multidisciplinary collaboration, between medical departments (infectious diseases, obstetrics/gynaecology, and paediatrics), as well as with social services and support groups for persons living with HIV/AIDS. PMID- 21550925 TI - [Profile of immunoglobulins A, G, and M during breast milk maturation in a tropical area (Gabon)]. AB - OBJECTIVES: To study the maturation of breast milk by the course of immunoglobulins A, G and M during the first three weeks of breast feeding. MATERIAL AND METHODS: This longitudinal and prospective survey took place from August to October, 2007, in Libreville, the capital of Gabon. The population comprised women with no significant medical history who had given birth in the obstetrics department of Center Hospital of Libreville. Women who delivered at home, had stillbirths, or infants positive for HIV hepatitis B virus were excluded. Three samples were taken, on D1 for colostrum, D7 for the transitional milk and D21 for mature milk. Immunoglobulins were determined by nephelometry, with the Turbox Plus((r)) system from Diagnostica Orion. Variables were compared with Spearman's non-parametric test. The survey of the kinetic has been made from the test of Friedman's test was used to assess the kinetics. Significance was set at p<0.05. RESULTS: This survey included 60 mother-child pairs. The mean IgA concentration on D1 was 13.4 +/- 5.9 g/L. This concentration fell very quickly by the end of the first week, to 2.3 +/- 2.0 g/L on D8, and then stabilized through D21. This rapid drop explains the need for early breast feeding after birth. On the other hand, IgG and IgM concentrations varied less and about one-sixth as high as the IgA. This finding confirms that they were minor components of breast milk. CONCLUSION: This work shows the importance of the early immune protection provided by the mother to her child during the first week of life. PMID- 21550926 TI - [Reactivity of GST-SAPA antigen of Trypanosoma cruzi against sera from patients with Chagas disease and leishmaniasis]. AB - Serologic diagnosis of Trypanosoma cruzi infection is important due to the limited sensitivity of direct parasitologic methods for diagnosis in the indeterminate and chronic phases of disease. SAPA antigen has been used in several studies and has been shown to be a good marker for use in the diagnosis of T. cruzi infection. Chagas disease and leishmaniasis are endemic in northern Salta with overlapping zones of transmission, which frequently leads to T. cruzi Leishmania spp. mixed infections. Diagnosis is complicated by the fact that there is significant cross-reactivity when non-specific antigens are used. We evaluated the reactivity of GST-SAPA antigen in the ELISA test (ELISA-SAPA) against sera from persons infected with T. cruzi (n = 154), leishmaniasis (n = 66), mixed infections (29), and healthy controls (n = 28) using commercial ELISA and IHA kits as reference tests. For ELISA-SAPA the sensitivity, specificity and kappa index were calculated for detection of T. cruzi infection. Among sera from patients infected with leishmaniasis, 30.5% of co-infections were detected. ELISA SAPA sensitivity was 97.1% (confidence interval 95%: 94.5-99.9), specificity was 100% (confidence interval 95%: 99.4-100), and kappa index was 96% (confidence interval 95%: 93-99%), for detection of T. cruzi infection. Sensitivity, specificity and kappa indices have shown a high efficiency of ELISA-SAPA. PMID- 21550927 TI - [Training response in COPD. Differences between fatigue-limited and dyspnea limited patients]. AB - Our objective was to study the post-training response to exercise, comparing fatigue-limited (FL) vs. dyspnea-limited (DL) COPD patients. Moderate and severe COPD patients (GOLD definition) were included. They were classified as FL if Borg score of fatigue at maximal exercise testing was >= 2 points vs. dyspnea; and DL if it was the reverse. Also, each patient was evaluated with submaximal cycloergometry, 6 minutes walking test and quality of life score (SGRQ). All patients were trained 3 times/week, 90 min/session with aerobic and strength exercises by 8 weeks. A total of 14 patients in LF and 11 in LD group were evaluated with same tools. Means of age were 69 and 66 years respectively. They presented severe airway flow obstruction (FEV1: 49%). There was not any baseline difference between both groups, except body-mass index, which was lower in FL. Both groups significantly improved p exercise variables post-training in comparison with baseline and SGRQ, except maximal workload in DL. Comparing both groups, FL had the highest maximal workload (48.7 +/- 9.2 vs. 40.04 +/- 15.48 watts, p = 0.033), 6 minute walking test (505.42 +/- 50.75 vs. 454.9 +/- 64.3 meters, p = 0.048) and endurance time (14.57 +/- 9.55 vs. 6.71 +/- 4.18 min, p = 0.025), respectively. It can be concluded that FL patients had better response after training in maximal and submaximal exercise tests in comparison with DL. Perhaps, different training strategies would be performed to train different COPD phenotypes. PMID- 21550928 TI - [Community acquired pneumonia and pulmonary hemorrhage in leptospirosis in the Buenos Aires metropolitan area]. AB - The aim of this paper is to report the epidemiological, clinical and diagnosis findings of pneumonia and pulmonary hemorrhage observed in patients with leptospirosis in the period January 2007 to October 2009. A 64% (20/31) of patients diagnosed with leptospirosis presented pneumonia. Fifteen of them (75%) had severe pneumonia, of which seven (35%) were pulmonary hemorrhage. In ten patients (32%) reason for consultation and clinical early stage was a secretory gastroenteritis with fever and abdominal pain. Jaundice was only expressed in eleven patients (35%). The technique of chain reaction (PCR) was useful for diagnosis in samples obtained post mortem. A strain classified in serogroup canicola was isolated from blood culture. Pneumonia was classified into three types: non-severe pneumonia course with little overall impact; severe pneumonia associated with systemic clinical forms with jaundice, renal failure, thrombocytopenia, and pulmonary hemorrhage, and of serious course, not associated with jaundice, kidney failure or thrombocytopenia. Antibiotic treatment started in the early stages of disease (average 3.2 days) had no influence on the development of severe pneumonia. It is puggested to consider three clinical forms of leptospirosis: anicteric, icteric (with its evolutionary variants) and pulmonary hemorrhage. PMID- 21550929 TI - [Discrepancies between clinical diagnoses and autopsy findings]. AB - The main objective of this study was to identify the clinical-pathological discrepancies in autopsies performed in the institution. We reviewed autopsies of clinical cases in 53 adults in the period between January 2005 and June 2009, carried out in the Pathology Service at the Hospital Privado de Cordoba, Argentina. Six autopsies were excluded due to insufficient information. The Goldman et al. classification was applied to establish clinico-pathologic discrepancies between clinical diagnoses and autopsy findings. Frequently clinical diagnoses were respiratory infections and acute pulmonary embolism. The most frequently reported postmortem diagnoses were respiratory infections and acute myocardial infarction. There were 17 major discrepancies and 30 coincidences. No any minor discrepancy was detected. Respiratory infections were the main cause of error, followed by myocardial infarction. We conclude that in 17/47 (37%) of cases the pre-mortem and postmortem diagnoses were different, and that respiratory infections were the main cause of error. We suggest to adopt educational and informative strategies, to revalue the importance of autopsy, and traditional clinical practices. PMID- 21550930 TI - In vivo effects of adenosine 5'-triphosphate on rat preneoplastic liver. AB - The utilization of adenosine 5'-triphosphate (ATP) infusions to inhibit the growth of some human and animals tumors was based on the anticancer activity observed in in vitro and in vivo experiments, but contradictory results make the use of ATP in clinical practice rather controversial. Moreover, there is no literature regarding the use of ATP infusions to treat hepatocarcinomas. The purpose of this study was to investigate whether ATP prevents in vivo oncogenesis in very-early-stage cancer cells in a well characterized two-stage model of hepatocarcinogenesis in the rat. As we could not preclude the possible effect due to the intrinsic properties of adenosine, a known tumorigenic product of ATP hydrolysis, the effect of the administration of adenosine was also studied. Animals were divided in groups: rats submitted to the two stage preneoplasia initiation/promotion model of hepatocarcinogenesis, rats treated with intraperitoneal ATP or adenosine during the two phases of the model and appropriate control groups. The number and volume of preneoplastic foci per liver identified by the expression of glutathione S-transferase placental type and the number of proliferating nuclear antigen positive cells significantly increased in ATP and adenosine treated groups. Taken together, these results indicate that in this preneoplastic liver model, ATP as well as adenosine disturb the balance between apoptosis and proliferation contributing to malignant transformation. PMID- 21550931 TI - [NT-Pro-BNP levels performance before and after reversion to sinus rhythm in patients with preserved ventricular function]. AB - Our objective was to evaluate changes of N-terminal pro-BNP (NT-Pro-BNP) levels at baseline and after restoration to sinus rhythm in hemodynamic stable patients with lone atrial fibrillation (LAF) with preserved left ventricular function. NT Pro-BNP levels were obtained before and after cardioversion in thirty hemodynamic stable patients with LAF and preserved left ventricular function. At baseline levels of NT-Pro BNP levels were significatively higher than a normal control group. NT-Pro-BNP levels decreased significantly following cardioversion from 529 (157-1763) to 318 (98-870) pg/ml, p < 0.0001. Decreasing of N-terminal pro-BNP concentrations was observed after any mode of cardioversion: electrical or pharmacologic, 345 (153-1151) pg/ml to 169 (86-407) pg/ml, p: 0.02 and from 1624 (541-4010) pg/ml to 856 (532-1160) pg/ml, p < 0.001, respectively. N-terminal pro BNP decreasing was observed mainly in patients with length of LAF longer than 8 hours: 1289 (338-2103) to 410 (169-905) pg/ml, p < 0.001 but no difference was detected when such length was less than 8 hours: 274 (137-2300) to 286 (82-1440), p = NS. Our study showed that baseline levels of NT-pro-BNP decreased shortly after reversion of patients with LAF to sinus rhythm. This performance occurs predominantly in patients with LAF length of at least eight hours. PMID- 21550932 TI - [Numeric alterations in the dys gene and their association with clinical features]. AB - The Duchenne/Becker muscular dystrophy is a hereditary miopathy with a recessive sex-linked pattern. The related gene is called DYS and the coded protein plays a crucial role in the anchorage between the cytoskeleton and the cellular membrane in muscle cells. Different clinical manifestations are observed depending on the impact of the genetic alteration on the protein. The global register of mutations reveals an enhanced frequency for deletions/duplications of one or more exons affecting the DYS gene. In the present work, numeric alterations have been studied in the 79 exons of the DYS gene. The study has been performed on 59 individuals, including 31 independent cases and 28 cases with a familial link. The applied methodology was Multiplex Ligation Dependent Probe Amplification (MLPA). In the 31 independent cases clinical data were established: i.e. the clinical score, the Raven test percentiles, and the creatininphosphokinase (CPK) blood values. Our results reveal a 61.3% frequency of numeric alterations affecting the DYS gene in our population, provoking all of them a reading frame shift. The rate for de novo mutations was identified as 35.2%. Alterations involving a specific region of one exon were observed with high frequency, affecting a specific region. A significant association was found between numeric alterations and a low percentile for the Raven test. These data contribute to the local knowledge of genetic alterations and their phenotypic impact for the Duchenne/Becker disease. PMID- 21550933 TI - [Tumor lysis syndrome in a patient with a renal carcinoma treated with sunitinib]. AB - The tumor lysis syndrome (TLS) is a metabolic disorder resulting from a massive tumor breakdown. It is characterized by hyperuricemia, hyperphosphatemia, hypocalcemia and hyperkalemia and predisposes to acute renal failure. TLS usually occurs after the initiation of cytotoxic therapy and is more frequent in the case of neoplasias with a high proliferative rate or that are highly chemo-sensitive. We report the case of a man with a recurrent kidney cancer who presented with a TLS and acute renal failure after initiation of sunitinib. PMID- 21550934 TI - [Transverse myelitis associated with anti-influenza A (H1N1) vaccination]. AB - Transverse myelitis is an inflammatory disorder characterized by spinal cord dysfunction. Infectious, autoimmune, postinfectious and postvaccination diseases are the most common recognized causes of transverse myelitis, but near 50% of the cases are finally assumed as idiopathic. Rubeolla, mumps, rabies and influenza vaccines were associated with many neurologic complications, such as Guillain Barre Syndrome, acute disseminated encephalomyelitis (ADEM) and transverse myelitis. As a prevention measure after the 2009 pandemia, in February 2010 a National Campaigne of Vaccination against the Influenza A (H1N1) was started in our country. We report a case of a woman who received a monovalent Influenza A (H1N1) vaccine and four days after, began with sensory symptoms that progressed to a clear defined sensory level. She reached the clinical criteria of transverse myelitis, according to the Transverse Myelitis Consortium Working Group. One month later, the patient remained clinically stable and the MRI showed an improvement of the image without corticosteroids treatment. We discuss diagnostic, prognostic and therapeutic aspects of this clinical entity. PMID- 21550935 TI - [Aquagenic keratoderma]. PMID- 21550936 TI - [Unexpected pause. What's the mechanism?]. PMID- 21550937 TI - [Published papers in biomedicine from Argentina. Data on clinical research]. AB - The aim of this paper was to provide quantitative data about clinical investigation in Argentina. We searched MEDLINE which is the U.S. National Library of Medicine's bibliographic database that contains more than 18 million references to journal articles in life sciences; 5400 journals in 39 languages are listed. In 2009 almost 850,000 papers were cited in MEDLINE and Argentina provided 0.33% of them, 90% of these in English. The number of papers published in Spanish is diminishing every year and similar results are observed with the German, French and other languages. Using the tools provided by MEDLINE we searched for papers that could be classified as clinical. We restricted our search to the word "patients" in the text and "hospital" in the address provided by the authors. Along the last 10 years, from 2000 to 2009, about 16% of the papers published from Argentina contain the word "patient" and this percentage is reduced to half if we combine the word "patient" with the word "hospital" in the address. If we search for papers written in Spanish with these two restrictions the number is much lower. The number of articles from Argentina followed the upward trend in the total of articles cited in MEDLINE in the last 10 years. This local increase was due to basic investigation papers because the percentage of clinical articles was relatively constant during these years. In conclusion, these data provide a survey of an area with scanty quantitative information. PMID- 21550938 TI - [Cardiac implantable devices and physiotherapy practices interaction: myth or real?]. AB - Several reports of negative interactions between physiotherapy practices and cardiac rhythm devices (CRDs) have been described in the literature. In spite of this, there is very little evidence to suggest the extent to which it is safe to use physiotherapy practices in this patient population. Here we summarize the documented interactions between physiotherapy and CRDs, discuss the current standard of practice for treating CRD patients, and outline the main considerations that exist from the arrhythmia service perspective in terms of patient and device factors. Finally, we advocate for a stronger cooperation between physiotherapists and the electrophysiology service team in order to safely and effectively deliver optimal physiotherapy care to CRD patients. PMID- 21550939 TI - [Amiloride sensitive sodium channels (ENaC) and their regulation by proteases]. AB - ENaC is a channel that mediates entry of Na+ from the luminal fluid into the cells in many reabsorbing epithelia and it is also expressed in human placenta. ENaC is crucial in the control of electrolyte and extracellular volume homeostasis. ENaC is regulated by several hormones, including aldosterone and blocked by amiloride and its analogs. ENaC channels are composed by three homologous subunits, alpha, beta and gamma that form the pore where Na ions are transported. Two factors regulate the activity of ENaC channels: 1) the number of channels inserted in the membrane and 2) the open probability of the channels or time that the channel is open. The number of channels is the result of a balance between the synthesis and degradation of ENaC channels. The open probability depends on the proteolysis of specific segments in the alpha and gamma subunits of ENaC by multiple proteases inside of the cell or in the extracellular space. Among the most studied proteases are furin, prostasin, elastase, plasmin and trypsin. There are endogenous substances that block the activity of these proteases such as aprotinin, bikunin and nexin-1 and the expression of both, proteases and their inhibitors are controlled by the rate of Na+ movement, aldosterone and TFG-beta levels. In this work we present some examples of this regulation and the potential role that this process may play under normal and pathological conditions such as cystic fibrosis, kidney diseases and hypertension. PMID- 21550940 TI - [Mycobacterium vaccae and intelligence. Sensationalism and propaganda in press releases]. PMID- 21550941 TI - [Mycobacterium vaccae and tuberculosis]. PMID- 21550942 TI - [Brain drain. The ones who left and the ones who came back]. PMID- 21550943 TI - [Argentine science and its diaspora]. PMID- 21550944 TI - Natural history of IgE-dependent food allergy diagnosed in children during the first three years of life. AB - PURPOSE: The aim of the study was to analyze: the course of allergy diagnosed during first three years of life, frequency of food tolerance development and impact of factors which have potential meaning in that process. MATERIAL AND METHODS: The study was performed in 115 children with IgE-dependent allergy, diagnosed during first three years of life, treated in 2nd Department of Pediatrics and Allergology of Polish Mothers Health Center in Lodz. All children were invited to our clinic in order to analyze course of the allergy after period of minimum 5 years since diagnosis. RESULTS: The results of the study revealed that food tolerance was acquired by high percentage of examined children (87.9%) among 83 children with food allergy. However among 32 children with initial inhalant allergy there were still no food sensitizations. The frequency of this process increased with age of examined children. The study revealed that such factors as lack of family history of atopy, clinical manifestation limited to one system, lack of inhalant allergy, type of allergen, good social conditions, have positive impact on tolerance development. CONCLUSIONS: High percentage of children with food allergy is able to develop the status of food immunotolerance. Factors which predispose to development of food allergy have also negative impact on ability to acquiring tolerance to harmful food. The study indicates the need of constant and wide education about decreasing exposure to allergy predisposing factors which could increase chance of food tolerance development. PMID- 21550945 TI - Parathyroid hormone-related protein: an unusual mechanism for hypercalcemia in sarcoidosis. AB - OBJECTIVE: To describe parathyroid hormone-related protein (PTHrP) as a mediator of hypercalcemia in sarcoidosis. METHODS: We present a detailed case report including history, physical, laboratory testing, pathology findings, and follow up data over 2 years. We also propose a possible mechanism for PTHrP-mediated hypercalcemia in sarcoidosis. RESULTS: A 56-year-old man presented with abdominal pain, fatigue, and excess thirst. Routine laboratory testing demonstrated severe hypercalcemia. The patient was admitted for treatment and work-up. Inpatient work up was significant for suppressed parathyroid hormone, low 25-hydroxyvitamin D, normal 1,25-dihydroxyvitamin D, and elevated PTHrP. The patient was treated for hypercalcemia and discharged for follow-up. Malignancy screening included computed tomography of the chest, which revealed parenchymal nodules and diffuse lymphadenopathy. Biopsy revealed nonnecrotizing granulomatous inflammation with positive PTHrP staining by immunohistochemistry. After treatment with intravenous hydration and glucocorticoids, the hypercalcemia resolved and on subsequent follow-up, PTHrP levels had normalized to 0.5 pmol/L. CONCLUSION: PTHrP may be a possible mediator of hypercalcemia in sarcoidosis. The differential diagnosis of PTHrP-induced hypercalcemia should include sarcoidosis, and further research is needed to establish the incidence and source of PTHrP in sarcoidosis. PMID- 21550946 TI - Preimplantation genetic diagnosis for hereditary endocrine disease. AB - OBJECTIVE: To describe the process of preimplantation genetic diagnosis (PGD), which allows the selection of embryos without mutations for implantation, with specific application for mutations in GNAS. METHODS: We identified a GNAS mutation in a patient with a severe form of Albright hereditary osteodystrophy and pseudohypoparathyroidism type 1a with phocomelia and performed PGD on embryos derived by in vitro fertilization in order to deliver an unaffected infant. RESULTS: After in vitro fertilization, embryos that were homozygous normal for GNAS were identified and implanted into the mother. Ultrasonography 34 days after embryo transfer showed a viable singleton intrauterine pregnancy. A normal appearing male infant was born at 36.5 weeks of gestation. Newborn screening revealed normal results of thyroid function tests, and a buccal swab obtained when the child was 1 year old verified normal GNAS gene sequences. CONCLUSION: PGD is an alternative that can be offered for many genetic diseases and represents a method to decrease and potentially eliminate the transmission of severe genetic diseases. Patients with multiple endocrine neoplasia (MEN) type 2 with known RET gene mutations as well as those with other heritable disorders are candidates for PGD. Successful PGD in patients with MEN has not yet been reported and has met with some early difficulties, but it is believed that this technique will eventually be successful for MEN and other hereditary endocrine disorders. PMID- 21550947 TI - Update on inpatient glycemic control in hospitals in the United States. AB - OBJECTIVE: To provide data on glucose control in hospitals in the United States, analyzing measurements from the largest number of facilities to date. METHODS: Point-of-care bedside glucose (POC-BG) test results were extracted from 575 hospitals from January 2009 to December 2009 by using a laboratory information management system. Glycemic control for patients in the intensive care unit (ICU) and non-ICU areas was assessed by calculating patient-day-weighted mean POC-BG values and rates of hypoglycemia and hyperglycemia. The relationship between POC BG levels and hospital characteristics was determined. RESULTS: A total of 49,191,313 POC-BG measurements (12,176,299 ICU and 37,015,014 non-ICU values) were obtained from 3,484,795 inpatients (653,359 in the ICU and 2,831,436 in non ICU areas). The mean POC-BG was 167 mg/dL for ICU patients and 166 mg/dL for non ICU patients. The prevalence of hyperglycemia (>180 mg/dL) was 32.2% of patient days for ICU patients and 32.0% of patient-days for non-ICU patients. The prevalence of hypoglycemia (<70 mg/dL) was 6.3% of patient-days for ICU patients and 5.7% of patient-days for non-ICU patients. Patient-day-weighted mean POC-BG levels varied on the basis of hospital size (P<.01), type (P<.01), and geographic location (P<.01) for ICU and non-ICU patients, with larger hospitals (>=400 beds), academic hospitals, and US hospitals in the West having the lowest mean POC-BG values. The percentage of patient-days in the ICU characterized by hypoglycemia was highest among larger and academic hospitals (P<.05) and least among hospitals in the Northeast (P<.001). CONCLUSION: Hyperglycemia is common in hospitals in the United States, and glycemic control may vary on the basis of hospital characteristics. Increased hospital participation in data collection may support a national benchmarking process for the development of optimal practices to manage inpatient hyperglycemia. PMID- 21550948 TI - Cushing syndrome secondary to a thymic carcinoid tumor due to multiple endocrine neoplasia type 1. AB - OBJECTIVE: To present an Iranian patient with a nonclassic form of multiple endocrine neoplasia type 1 (MEN 1) who presented with ectopic Cushing syndrome (CS) secondary to a corticotropin (ACTH)-producing thymic neuroendocrine tumor (NET), recurrent renal stones, and a giant cell granuloma of the jaw due to primary hyperparathyroidism (PHPT) without involvement of the pituitary or pancreas. METHODS: Relevant imaging and hormonal evaluations were performed. The patient was operated on 2 occasions for a thymic NET and on 3 occasions for PHPT. DNA from a peripheral blood sample was extracted for sequencing of the MEN1 gene. RESULT: Histopathologic evaluation of the thymic tumor removed during the first surgery showed an atypical carcinoid tumor with a Ki-67 labeling index of 5%. Evaluation after the second surgery revealed an invasive carcinoid tumor with a Ki-67 labeling index of 30%. Parathyroid pathology was suggestive of glandular hyperplasia. Menin gene sequencing revealed a novel frameshift mutation c.1642_1648dup in exon 10. CONCLUSION: This case of MEN 1 is unusual because most thymic NETs in MEN 1 are nonfunctional, and secretion of ACTH or other ectopic hormones rarely occurs. In patients presenting with thymic NETs, the possibility of MEN 1 should be considered, especially in the presence of hyperparathyroidism. This case also demonstrates that the behavior of thymic NETs can change over time from slow-growing tumors to highly invasive neoplasia, and that ectopic ACTH can be produced by these tumors in the context of MEN 1. PMID- 21550949 TI - A bridge to insulin pump therapy: twice-daily regimen with NPH and detemir insulins during initial treatment of youth with type 1 diabetes mellitus. AB - OBJECTIVE: To describe clinical outcomes in youth with new-onset type 1 diabetes mellitus (T1DM) treated with a modified, twice-daily regimen of a mixture of NPH insulin and rapid-acting insulin analogue at breakfast and separate injections of rapid-acting insulin analogue and insulin detemir at dinner. METHODS: Our clinic database was used to describe changes in insulin doses, hemoglobin A1c (A1C) levels, and frequency of severe hypoglycemia during the first year of therapy in young patients with T1DM diagnosed between September 2006 and April 2009. Data are presented as median values (25%, 75%). RESULTS: Overall, 108 patients (62 girls; mean age, 10.0 +/- 0.4 years) were eligible for inclusion. Total daily insulin doses at 3, 6, and 12 months were 0.6 (0.4, 0.8), 0.7 (0.4, 0.9), and 0.8 (0.6, 0.9) U/kg, respectively. A1C levels were 9.8% (8.5%, 10.8%) at 2 weeks (baseline). Of the 108 patients, 19 had switched to insulin pump therapy by 3 months and 49 had switched by 12 months after initial diagnosis of T1DM. The 49 pump-treated patients had an A1C of 6.9% (6.6%, 7.3%), whereas the 59 injection treated patients had an A1C of 7.2% (6.7%, 7.7%) by 12 months. There were only 6 severe hypoglycemic events in 5 patients; none occurred during the first 3 months, none occurred during the night, and all occurred in patients receiving insulin injection treatment. CONCLUSION: A twice-daily insulin regimen that uses insulin detemir for overnight basal replacement and morning NPH insulin to avoid lunch and afternoon snack doses is an effective initial treatment for young patients with new-onset T1DM that can provide a smooth transition to intensive basal/bolus insulin pump therapy. PMID- 21550950 TI - Comparison of 3 algorithms for Basal insulin in transitioning from intravenous to subcutaneous insulin in stable patients after cardiothoracic surgery. AB - OBJECTIVE: To determine the effectiveness of an algorithm containing 1 of 3 initial subcutaneous doses of insulin detemir and flexible prandial and supplemental insulin aspart in stable patients who have undergone cardiac surgery and are being transitioned off intravenous insulin infusion. METHODS: Patients were extubated, were not taking vasopressors, and were otherwise stable, requiring at least 1 unit per hour of intravenous insulin at least 48 hours after surgery. Patients were randomly assigned to once-daily insulin detemir at 50%, 65%, or 80% of intravenous basal insulin requirements and received insulin aspart according to carbohydrate intake. The dose of insulin detemir was adjusted daily over 72 hours. RESULTS: Eighty-two patients were included. The percentages of patients with an initial morning glucose concentration of 80 to 130 mg/dL were 36%, 63%, and 56% of patients at the 50%, 65%, and 80% doses, respectively (P = .12). However, the mean overall glucose value at 24 and 72 hours was similar between groups, and 86%, 93%, and 92% of patients in each group, respectively, achieved a mean glucose concentration of 80 to 180 mg/dL at 72 hours (P = .60). Hypoglycemia (glucose <65 mg/dL) only occurred in the 65% group (21%) and the 80% group (12%) over the first 72 hours (P = .02 in the 50% group compared with the 65% and 80% groups combined) with 1 event of a glucose concentration less than 40 mg/dL in the 80% group. There was no loss of glycemic control by the end of the once-daily dosing interval. CONCLUSIONS: Glycemic targets can be achieved without hypoglycemia by 72 hours in most patients who have undergone cardiac surgery and require intravenous insulin with a regimen consisting of an initial insulin detemir dose of 50% of basal intravenous insulin requirements and prandial and supplemental insulin. PMID- 21550951 TI - Sitagliptin compared with thiazolidinediones as a third-line oral antihyperglycemic agent in type 2 diabetes mellitus. AB - OBJECTIVE: To compare sitagliptin and thiazolidinediones as third-line oral antihyperglycemic agents among ethnic minority patients with poorly controlled type 2 diabetes mellitus. METHODS: In an open-label, single-arm design, we treated type 2 diabetic patients who had suboptimal diabetes control on maximum tolerated dosages of metformin plus sulfonylureas with the addition of sitagliptin, 100 mg daily, and compared their responses with findings from a historical control group of similar patients treated with rosiglitazone, 8 mg daily, or pioglitazone, 45 mg daily, as their third-line oral agent. Patients were assessed bimonthly, and those who achieved hemoglobin A1c levels less than 7.5% at 4 months continued through 1 year of follow-up. RESULTS: One hundred eight patients were treated with sitagliptin, and 104 patients constituted the historical control group treated with rosiglitazone or pioglitazone. At baseline, sitagliptin- and thiazolidinedione-treated patients had identical hemoglobin A1c levels (mean +/- SD) (9.4 +/- 1.8% and 9.4 +/- 1.9%, respectively) and similar known diabetes duration (6.7 +/- 5.0 years and 7.6 +/- 5.8 years, respectively). Hemoglobin A1c was reduced in both groups at 4 months (P<.001), but the reduction was greater with thiazolidinediones than with sitagliptin (-2.0 +/- 1.7% vs -1.3 +/- 1.8%; P = .006), as was the proportion of patients achieving a hemoglobin A1c level less than 7.5% (62% vs 46%; P = .026). Of all patients achieving a hemoglobin A1c level less than 7.5% at 4 months, the same proportions in each group sustained their hemoglobin A1c level less than 7.5% by 12 months (59% vs 58%). Sitagliptin was well tolerated. CONCLUSIONS: Among ethnic minority patients with poorly controlled type 2 diabetes while taking maximum tolerated dosages of metformin and sulfonylureas, third-line add-on therapy with a thiazolidinedione controlled hyperglycemia more effectively than sitagliptin after 4 months. PMID- 21550952 TI - Clinical impact of initiating insulin glargine therapy with disposable pen versus vial in patients with type 2 diabetes mellitus in a managed care setting. AB - OBJECTIVE: To investigate health care utilization, cost, and clinical outcomes among non-insulin-treated patients with type 2 diabetes mellitus who initiated insulin glargine therapy with use of either a disposable pen or vial and syringe in a managed care setting in the United States. METHODS: This retrospective cohort study of a large national claims database consisted of a 6-month baseline period and a follow-up period extending 12 months from the date of the patient's first filled insulin glargine prescription. Outcomes included medication persistence, hypoglycemic events, health care utilization and costs, and glycosylated hemoglobin A1c (A1C) levels. RESULTS: There were 3,842 matched patients (n = 1,921 per group). Patients initiating insulin glargine therapy with a disposable pen were significantly less likely to discontinue or switch treatment during the 12-month follow-up period versus patients in the vial and syringe group (P<.001). Disposable pen use was also associated with a reduced hypoglycemia risk. The disposable pen group had overall health care utilization similar to the vial and syringe group; however, the pen group had significantly fewer diabetes-related hospitalizations (P = .04) and significantly more diabetes related endocrinologist visits (P = .04). Overall health care costs were similar between the 2 groups, despite higher pharmacy costs in the disposable pen group. In a subgroup of patients with available baseline and follow-up A1C values (n = 511), the disposable pen group achieved similar A1C control at follow-up despite a higher baseline A1C value than in the vial and syringe group. CONCLUSION: Initiation of insulin glargine therapy with a disposable pen in patients with type 2 diabetes was associated with better treatment persistence and decreased hypoglycemia in comparison with the vial and syringe method, without any increase in total health care utilization or costs. PMID- 21550953 TI - Coordinated primary and specialty care for type 2 diabetes mellitus, guidelines, and systems: an educational needs assessment. AB - OBJECTIVE: To determine knowledge, competence, and attitudinal issues among primary care providers (PCPs) and diabetes specialists regarding the use and application of evidence-based clinical guidelines and the coordination of care between PCPs and diabetes specialists specifically related to referral practices for patients with diabetes. METHODS: A survey tool was completed by 491 PCPs and 249 diabetes specialists. Data were collected from specialists online and from PCP attendees at live symposia across the United States. Results were analyzed for frequency of response and evaluation of significant relationships among the variables. RESULTS: Suboptimal practice patterns and interprofessional communication as well as gaps in diabetes-related knowledge and processes were identified. PCPs reported a lack of clarity about who, PCP or specialist, should assume clinical responsibility for the management of diabetes after a specialty referral. PCPs were most likely to refer patients to diabetes specialists for management issues relating to insulin therapy and use of advanced treatment strategies, such as insulin pens and continuous glucose monitoring. A minority of PCPs and even fewer specialists reported the routine use of clinical guidelines in practice. CONCLUSION: This research-based assessment identified critical educational needs and gaps related to coordinated care for patients with diabetes as well as the need for quality- and performance-based educational interventions. PMID- 21550954 TI - Correlation of findings from iodine 123 scan and ultrasonography in the recommendation for thyroid fine-needle aspiration biopsy. AB - OBJECTIVE: To assess the impact of correlating findings from iodine I 123 (123I) radionuclide scans and thyroid ultrasonography on the decision to perform fine needle aspiration (FNA) biopsy of thyroid nodules. METHODS: Iodine 123 scans and sonographic images of adult patients who had both examinations performed within 6 months of each other at our institution were retrospectively reviewed. The presence of 1 or more nodules satisfying imaging-specific criteria for recommending FNA biopsy was recorded. Iodine 123 scan and sonographic images were then directly compared to determine how frequently the FNA recommendation would be affected by discordant findings. RESULTS: The study included 97 adult patients, with a total of 291 thyroid lobes (right thyroid lobe, left thyroid lobe, and isthmus). Recommendations for FNA biopsy were concordant in 231 of 291 lobes (79.4%), with both modalities recommending FNA biopsy in 55 lobes and not recommending FNA biopsy in 176 lobes. A discordant recommendation occurred in 60 of 291 lobes (20.6%). Using only ultrasonography findings, a recommendation for FNA biopsy was not indicated for 11 of the 291 lobes (3.8%) with functioning nodules. Using only 123I findings, a recommendation for FNA biopsy was not indicated for 23 of the 291 lobes (7.9%); 13 had nodules, but none that fulfilled sonographic criteria, and 10 had no identifiable nodule on ultrasonography. Iodine 123 scan did not identify 26 lobes with nodules (8.9%) for which FNA biopsy was recommended based on ultrasonography findings. CONCLUSION: Recommendations for FNA biopsy should not be based on the presence of hypofunctioning regions on 123I scan without sonographic confirmation. PMID- 21550955 TI - Non-islet cell tumor hypoglycemia associated with uterine leiomyomata. AB - OBJECTIVE: We report a case of non-islet cell tumor hypoglycemia (NICTH) in a patient with large leiomyomata. METHODS: We present the clinical, laboratory, and pathologic findings of a diabetic patient who presented with recurrent hypoglycemia later linked to uterine leiomyomata. RESULTS: An 80-year-old woman with diabetes was admitted after falling at home. She reported dizziness and had recorded low capillary blood glucose despite discontinuing her diabetic medication prior to admission. Her physical examination was remarkable for nonorthostatic vital signs, normal cardiovascular and lung examination, and a pelvi-abdominal mass the size of a gravid uterus at 28 weeks of gestation. After receiving a 50% dextrose infusion, she became alert with no focal neurological deficit. Capillary blood glucose rose from 31 mg/dL to 110 mg/dL. A pelvic sonogram confirmed fibromyomata. She was initially treated with steroids after a hormonal profile suggested NICTH (normal fasting insulin, C-peptide, cosyntropin and glucagon stimulation tests, and negative insulin antibodies). Insulinlike growth factor (IGF) levels were IGF-1, 69 ng/mL and IGF-2, 782 ng/mL, and the IGF 2/IGF-1 ratio was 10.8. The patient underwent a total abdominal hysterectomy. Pathology reported a 3-kg uterus with multiple, large cellular fibromyomas. After steroids were discontinued, she became hyperglycemic requiring insulin and oral diabetic agents. Repeat IGF-2 and IGF-1 measurements were 261 ng/mL and 36 ng/mL, respectively. She was discharged 2 weeks after surgery. CONCLUSION: NICTH is a rare complication associated with large neoplasms. Leiomyomata should be included in the differential diagnoses of NICTH. Surgery is curative in such cases. PMID- 21550956 TI - Pancreatic endocrine tumors in multiple endocrine neoplasia type 1 syndrome: review of literature. AB - OBJECTIVE: To analyze the surgical approach to multiple endocrine neoplasia type 1 (MEN 1)-related pancreatic endocrine tumors (PETs). METHODS: We reviewed selected publications and our personal experience with MEN 1-associated PETs to delineate their general characteristics, current practice and controversies, preoperative imaging and intraoperative assessment, and appropriate therapeutic strategies including radical surgical procedures. RESULTS: The penetrance of PETs in the setting of MEN 1 is similar to that of parathyroid tumors, even though hyperparathyroidism is usually the first manifestation of MEN 1 syndrome. In contrast with the sporadic counterparts, MEN 1-related PETs are characterized by an early onset, multiplicity of lesions, variable expression of the tumors, and propensity for malignant degeneration. Both the histologic type and the size of these tumors correlate with malignant potential. CONCLUSION: The rationale for surgical considerations for these tumors is to curtail the malignant progression of the disease and to cure or aid in management of the associated biochemical syndromes. A surgical procedure is often the treatment of choice for PETs in patients with MEN 1. Monitoring of pancreatic peptides and use of diagnostic imaging allow an early pancreatic resection, in conjunction with prevention of metastatic PETs and improvement of long-term survival. Hepatic metastatic lesions can be successfully treated by surgical resection. PMID- 21550957 TI - Comparison of 2 intensification regimens with rapid-acting insulin aspart in type 2 diabetes mellitus inadequately controlled by once-daily insulin detemir and oral antidiabetes drugs: the step-wise randomized study. AB - OBJECTIVE: To compare the efficacy and safety of 2 intensification strategies for stepwise addition of prandial insulin aspart in patients with type 2 diabetes mellitus treated with insulin detemir. METHODS: This randomized, controlled, parallel-group, open-label, 48-week trial compared the stepwise addition of insulin aspart to either the largest meal (titration based on premeal glucose values [SimpleSTEP]) or to the meal with the largest prandial glucose increment (titration based on postmeal glucose values [ExtraSTEP]) in patients with type 2 diabetes inadequately controlled on basal insulin and oral antidiabetes drugs. After 12 weeks of basal insulin detemir dosage optimization, participants with a hemoglobin A1c level of 7% or greater entered three 12-week treatment periods with stepwise addition of a first insulin aspart bolus, then a second, and then a third, if hemoglobin A1c remained at 7% or greater after 12 and 24 weeks of treatment, respectively. Endpoints included hemoglobin A1c (primary endpoint), fasting plasma glucose, self-measured plasma glucose, adverse events, and hypoglycemia. RESULTS: Two hundred ninety-six patients were randomly assigned to treatment with insulin aspart in the SimpleSTEP (n = 150) and ExtraSTEP (n = 146) groups. Hemoglobin A1c decreased by approximately 1.2% in both groups, to 7.5 +/- 1.1% (Simple-STEP) and 7.7 +/- 1.2% (ExtraSTEP) at end of trial (estimated treatment difference, SimpleSTEP - ExtraSTEP: -0.06% [95% confidence interval, 0.29 to 0.17]). Self-measured plasma glucose levels decreased with both regimens. At trial end, approximately 75% of patients in each group were using 3 prandial injections. The frequency of adverse events and hypoglycemia was low and similar between groups. CONCLUSION: The SimpleSTEP and ExtraSTEP strategies for stepwise addition of insulin aspart to 1 or more meals were equally effective at intensifying therapy in patients with type 2 diabetes not achieving glycemic control on basal insulin and oral antidiabetic drugs. PMID- 21550958 TI - Kaposi sarcoma in the setting of cushing disease. AB - OBJECTIVE: To report a case of a human immunodeficiency virus (HIV)-negative Kaposi sarcoma (KS) associated with Cushing disease (CD). METHODS: The details of case presentation, evaluation, diagnosis, and treatment are presented and cases of KS and CD published before November 1, 2010 on PubMed and Scopus are reviewed. RESULTS: A 54-year-old Hispanic HIV-negative man presented with typical signs and symptoms of CD (easy bruisability, proximal muscle wasting, and abdominal fat pads). Numerous raised, purplish, nonblanching plaques 0.5 to 2 cm in diameter extended throughout his lower extremities. Biochemical tests and pituitary magnetic resonance imaging confirmed CD. A lesion biopsy showed atypical vascular proliferation positive by immunohistochemistry for human herpesvirus 8 (HHV-8), consistent with KS. He underwent 2 transsphenoidal surgeries followed by a bilateral adrenalectomy. After recovery, his KS was treated with a systemic combination of liposomal doxorubicin and paclitaxel. CONCLUSION: The occurrence of CD and KS is rare. Specific therapy for CD and chemotherapy for KS are effective in the treatment of KS associated with CD. PMID- 21550959 TI - Concomitant oral antihyperglycemic agent use and associated treatment outcomes after initiation of insulin therapy. AB - OBJECTIVE: To compare outcomes in patients with type 2 diabetes initiating insulin lispro mix 75/25 (75% insulin lispro protamine suspension and 25% lispro) or insulin glargine therapy, stratified by baseline oral antihyperglycemic agent (OHA) use. METHODS: We performed a post hoc analysis of 6-month data from the DURABLE clinical trial, which enrolled patients with hemoglobin A1c (A1C) levels >7.0% treated with 2 or more OHAs (metformin, sulfonylurea, and thiazolidinedione), and randomly assigned them to treatment with twice-daily insulin lispro 75/25 or once-daily glargine. RESULTS: In both insulin treatment groups, metformin/thiazolidinedione-treated patients had significantly greater improvement in A1C levels (-2.19% to -2.36%), lower end point A1C values, and lower rates of occurrence of hypoglycemia in comparison with metformin/sulfonylurea-treated patients (all P<.05). Patients treated with sulfonylurea/thiazolidinedione or metformin/sulfonylurea/thiazolidinedione did not differ significantly from metformin/sulfonylurea-treated patients in A1C change (-1.56% to -1.84%) or rates of occurrence of hypoglycemia. CONCLUSION: In these post hoc analyses, patients with type 2 diabetes initiating premixed or basal insulin therapy and treated concomitantly with the OHA combination of metformin/thiazolidinedione at baseline demonstrated significantly greater A1C improvement with less hypoglycemia in comparison with patients treated with metformin/sulfonylurea. PMID- 21550960 TI - Effect of vitamin D therapy on bone turnover markers in postmenopausal women with osteoporosis and osteopenia. AB - OBJECTIVE: To (1) assess the rate of reduction in bone turnover with vitamin D and bisphosphonate therapies and (2) evaluate the clinical utility of bone specific alkaline phosphatase (BSAP) in monitoring treatment response. METHODS: We retrospectively reviewed medical records of patients with newly diagnosed osteopenia and osteoporosis from 2002 to 2009 at Loyola University Medical Center. A cohort of postmenopausal women with hip or spine T-scores of less than 1, normal serum creatinine, and no prior vitamin D or bisphosphonate therapy was divided into vitamin D-deficient (n = 29) and vitamin D-sufficient (n = 13) groups. Vitamin D-deficient patients received high-dose vitamin D, whereas vitamin D-sufficient patients received orally administered bisphosphonates. BSAP levels at baseline and 1 year were compared. RESULTS: Vitamin D therapy in the group with vitamin D deficiency led to a 26.7% decrease in BSAP (P<.01). Bisphosphonate therapy in the vitamin D-sufficient group led to a 32.7% decrease in BSAP (P = .01). The magnitude of BSAP change in the 2 study groups (6.74 +/- 6.48 MUg/L and 8.72 +/- 9.94 MUg/L) did not differ significantly (P = .45). CONCLUSION: The results of this study suggest that correction of vitamin D deficiency in patients with osteopenia and osteoporosis can lead to a decrease in bone turnover as measured by BSAP and that the magnitude of this reduction is similar to that achieved with orally administered bisphosphonates. PMID- 21550961 TI - A smartphone client-server teleradiology system for primary diagnosis of acute stroke. AB - BACKGROUND: Recent advances in the treatment of acute ischemic stroke have made rapid acquisition, visualization, and interpretation of images a key factor for positive patient outcomes. We have developed a new teleradiology system based on a client-server architecture that enables rapid access to interactive advanced 2 D and 3-D visualization on a current generation smartphone device (Apple iPhone or iPod Touch, or an Android phone) without requiring patient image data to be stored on the device. Instead, a server loads and renders the patient images, then transmits a rendered frame to the remote device. OBJECTIVE: Our objective was to determine if a new smartphone client-server teleradiology system is capable of providing accuracies and interpretation times sufficient for diagnosis of acute stroke. METHODS: This was a retrospective study. We obtained 120 recent consecutive noncontrast computed tomography (NCCT) brain scans and 70 computed tomography angiogram (CTA) head scans from the Calgary Stroke Program database. Scans were read by two neuroradiologists, one on a medical diagnostic workstation and an iPod or iPhone (hereafter referred to as an iOS device) and the other only on an iOS device. NCCT brain scans were evaluated for early signs of infarction, which includes early parenchymal ischemic changes and dense vessel sign, and to exclude acute intraparenchymal hemorrhage and stroke mimics. CTA brain scans were evaluated for any intracranial vessel occlusion. The interpretations made on an iOS device were compared with those made at a workstation. The total interpretation times were recorded for both platforms. Interrater agreement was assessed. True positives, true negatives, false positives, and false negatives were obtained, and sensitivity, specificity, and accuracy of detecting the abnormalities on the iOS device were computed. RESULTS: The sensitivity, specificity, and accuracy of detecting intraparenchymal hemorrhage were 100% using the iOS device with a perfect interrater agreement (kappa=1). The sensitivity, specificity, and accuracy of detecting acute parenchymal ischemic change were 94.1%, 100%, and 98.09% respectively for reader 1 and 97.05%, 100%, and 99.04% for reader 2 with nearly perfect interrater agreement (kappa=.8). The sensitivity, specificity, and accuracy of detecting dense vessel sign were 100%, 95.4%, and 96.19% respectively for reader 1 and 72.2%, 100%, and 95.23% for reader 2 using the iOS device with a good interrater agreement (kappa=.69). The sensitivity, specificity, and accuracy of detecting vessel occlusion on CT angiography scans were 94.4%, 100%, and 98.46% respectively for both readers using the iOS device, with perfect interrater agreement (kappa=1). No significant difference (P<.05) was noted in the interpretation time between the workstation and iOS device. CONCLUSION: The smartphone client-server teleradiology system appears promising and may have the potential to allow urgent management decisions in acute stroke. However, this study was retrospective, involved relatively few patient studies, and only two readers. Generalizing conclusions about its clinical utility, especially in other diagnostic use cases, should not be made until additional studies are performed. PMID- 21550962 TI - Understanding the effect of different assay formats on agonist parameters: a study using the u-opioid receptor. AB - The correct interpretation of data is fundamental to the study of G-protein coupled receptor pharmacology. Often, new assay technologies are assimilated into the drug discovery environment without full consideration of the data generated. In this study, the authors look at u-opioid receptor agonists in three different assays: (1) [(35)S]GTPgammaS binding, (2) inhibition of forskolin-stimulated cAMP production, and (3) beta-arrestin recruitment. Agonist-concentration effect curves were performed before and after treatment with the irreversible antagonist beta-funaltrexamine, and where appropriate, these data were fitted to the operational model of agonism. The Z' value was highest in the beta-arrestin assay, followed by the [(35)S]GTPgammaS and cAMP assays. The cAMP data fitted well to the operational model, as did the [(35)S]GTPgammaS data, but the [(35)S]GTPgammaS assay led to an apparent overestimation of K(A) values. However, in the beta-arrestin assay, data did not fit the operational model, as treatment with beta-funaltrexamine reduced the Emax proportionally to receptor number, with no change in EC(50). In addition, the EC(50) values generated correlated well with affinity values. In conclusion, the beta-arrestin recruitment assay does not fit with traditional pharmacological theory but is of great utility as the EC(50) value generated is a good approximation of affinity. PMID- 21550965 TI - Texting the doctor. PMID- 21550966 TI - Pathways: a road to restriction? PMID- 21550967 TI - Why, when, and how to prevent hepatitis B virus reactivation in cancer patients undergoing chemotherapy. AB - Hepatitis B virus (HBV) reactivation is a serious clinical problem in HBV carriers undergoing chemotherapy. The clinical course of HBV reactivation can be separated into 2 phases: 1) an increase in HBV replication and 2) hepatic injury. Patients with resolved HBV infections (negative for hepatitis B surface antigen [HBsAg], and positive for both hepatitis B core antibody [anti-HBc] and/or hepatitis B surface antibody) can experience HBV reactivation, and Western guidelines recommend that not only HBsAg but also anti-HBc be screened before initiation of chemotherapy or immunosuppressive therapy. Several meta-analyses have repeatedly confirmed the prophylactic role of lamivudine in preventing HBV reactivation. In conclusion, screening for HBV is required before chemotherapy, and prophylactic antiviral therapy can reduce not only the incidence of HBV reactivation but also HBV-related morbidity and mortality. PMID- 21550968 TI - Non-Hodgkin's lymphomas. PMID- 21550969 TI - Optimization of postremission therapy in follicular lymphoma: efficacy of rituximab maintenance. AB - Rituximab has been proven to be an important part of the treatment of newly diagnosed and relapsed or refractory follicular lymphoma both alone and in combination with chemotherapy. Given its tolerability, rituximab has now been investigated in the maintenance setting in an effort to further improve progression-free and overall survival in patients with follicular lymphoma. PMID- 21550970 TI - Role of routine imaging in lymphoma. AB - Patients with lymphoma commonly undergo routine imaging studies after treatment completion, yet the appropriate interval, duration, and modality of follow-up, and the overall efficacy of various approaches is unclear. Existing guidelines are vague and not evidence-based, and consequently, practice patterns are varied. Most surveillance approaches in lymphoma have focused on early detection of recurrence, with the hope of prolonged survival and potential cure. Concerns regarding the prognostic value of frequent scanning, cost-effectiveness, and long term risks associated with prolonged radiation exposure have led many to question the role of routine imaging in this setting. Given the multiple lymphoma subtypes and the clinical heterogeneity of these entities, a single approach to follow-up may not be reasonable. Much of the available literature focuses on Hodgkin lymphoma, and may not be generalizable. Retrospective series show that most relapses are detected by signs and symptoms regardless of the imaging schedule. In summary, clinicians are still left with "expert opinion" to guide them. This article examines the available data outlining the role of surveillance imaging in lymphoma. PMID- 21550972 TI - L-threonine regulates G1/S phase transition of mouse embryonic stem cells via PI3K/Akt, MAPKs, and mTORC pathways. AB - Although amino acids can function as signaling molecules in the regulation of many cellular processes, mechanisms surrounding L-threonine involvement in embryonic stem cell (ESC) functions have not been explored. Thus, we investigated the effect of L-threonine on regulation of mouse (m)ESC self-renewal and related signaling pathways. In L-threonine-depleted mESC culture media mRNA of self renewal marker genes, [(3)H]thymidine incorporation, expression of c-Myc, Oct4, and cyclins protein was attenuated. In addition, resupplying L-threonine (500 MUM) after depletion restores/maintains the mESC proliferation. Disruption of the lipid raft/caveolae microdomain through treatment with methyl-beta-cyclodextrin or transfection with caveolin-1 specific small interfering RNA blocked L threonine-induced proliferation of mESCs. Addition of L-threonine induced phosphorylation of Akt, ERK, p38, JNK/SAPK, and mTOR in a time-dependent manner. This activity was blocked by LY 294002 (PI3K inhibitor), wortmannin (PI3K inhibitor), or an Akt inhibitor. L-threonine-induced activation of mTOR, p70S6K, and 4E-BP1 as well as cyclins and Oct4 were blocked by PD 98059 (ERK inhibitor), SB 203580 (p38 inhibitor) or SP 600125 (JNK inhibitor). Furthermore, L-threonine induced phosphorylation of raptor and rictor binding to mTOR was completely inhibited by 24 h treatment with rapamycin (mTOR inhibitor); however, a 10 min treatment with rapamycin only partially inhibited rictor phosphorylation. L threonine induced translocation of rictor from the membrane to the cytosol/nuclear, which blocked by pretreatment with rapamycin. In addition, rapamycin blocked L-threonine-induced increases in mRNA expressions of trophoectoderm and mesoderm marker genes and mESC proliferation. In conclusion, L threonine stimulated ESC G(1)/S transition through lipid raft/caveolae-dependent PI3K/Akt, MAPKs, mTOR, p70S6K, and 4E-BP1 signaling pathways. PMID- 21550971 TI - Disruption of the murine protein kinase Cbeta gene promotes gallstone formation and alters biliary lipid and hepatic cholesterol metabolism. AB - The protein kinase C (PKC) family of Ca(2+) and/or lipid-activated serine threonine protein kinases is implicated in the pathogenesis of obesity and insulin resistance. We recently reported that protein kinase Cbeta (PKCbeta), a calcium-, diacylglycerol-, and phospholipid-dependent kinase, is critical for maintaining whole body triglyceride homeostasis. We now report that PKCbeta deficiency has profound effects on murine hepatic cholesterol metabolism, including hypersensitivity to diet-induced gallstone formation. The incidence of gallstones increased from 9% in control mice to 95% in PKCbeta(-/-) mice. Gallstone formation in the mutant mice was accompanied by hyposecretion of bile acids with no alteration in fecal bile acid excretion, increased biliary cholesterol saturation and hydrophobicity indices, as well as hepatic p42/44(MAPK) activation, all of which enhance susceptibility to gallstone formation. Lithogenic diet-fed PKCbeta(-/-) mice also displayed decreased expression of hepatic cholesterol-7alpha-hydroxylase (CYP7A1) and sterol 12alpha hydroxylase (CYP8b1). Finally, feeding a modified lithogenic diet supplemented with milk fat, instead of cocoa butter, both increased the severity of and shortened the interval for gallstone formation in PKCbeta(-/-) mice and was associated with dramatic increases in cholesterol saturation and hydrophobicity indices. Taken together, the findings reveal a hitherto unrecognized role of PKCbeta in fine tuning diet-induced cholesterol and bile acid homeostasis, thus identifying PKCbeta as a major physiological regulator of both triglyceride and cholesterol homeostasis. PMID- 21550973 TI - Identification of novel anionic phospholipid binding domains in neutral sphingomyelinase 2 with selective binding preference. AB - Sphingolipids such as ceramide are recognized as vital regulators of many biological processes. Neutral sphingomyelinase 2 (nSMase2) is one of the key enzymes regulating ceramide production. It was previously shown that the enzymatic activity of nSMase2 was dependent on anionic phospholipids (APLs). In this study, the structural requirements for APL-selective binding of nSMase2 were determined and characterized. Using lipid-protein overlay assays, nSMase2 interacted specifically and directly with several APLs, including phosphatidylserine and phosphatidic acid. Lipid-protein binding studies of deletion mutants identified two discrete APL binding domains in the N terminus of nSMase2. Further, mutagenesis experiments pinpointed the core sequences and major cationic amino acids in the domains that are necessary for the cooperative activation of nSMase2 by APLs. The first domain included the first amino-terminal hydrophobic segment and Arg-33, which were essential for nSMase2 to interact with APLs. The second binding domain was comprised of the second hydrophobic segment and Arg-92 and Arg-93. Moreover, mutation of one or both domains decreased APL binding and APL-dependent catalytic activity of nSMase2. Further, mutation of both domains in nSMase2 reduced its plasma membrane localization. Finally, these binding domains are also important for the capability of nSMase2 to rescue the defects of yeast lacking the nSMase homologue, ISC1. In conclusion, these data have identified the APL binding domains of nSMase2 for the first time. The analysis of interactions between nSMase2 and APLs will contribute to our understanding of signaling pathways mediated by sphingolipid metabolites. PMID- 21550974 TI - Identification of a proline-rich inositol polyphosphate 5-phosphatase (PIPP)*collapsin response mediator protein 2 (CRMP2) complex that regulates neurite elongation. AB - Neuron polarization is essential for the formation of one axon and multiple dendrites, establishing the neuronal circuitry. Phosphoinositide 3-kinase (PI3K) signaling promotes axon selection and elongation. Here we report in hippocampal neurons siRNA knockdown of the proline-rich inositol polyphosphate 5-phosphatase (PIPP), which degrades PI3K-generated PtdIns(3,4,5)P(3), results in multiple hyperelongated axons consistent with a polarization defect. We identify collapsin response mediator protein 2 (CRMP2), which regulates axon selection by promoting WAVE1 delivery via Kinesin-1 motors to the axon growth cone, as a PIPP interacting protein by Y2H screening, direct binding studies, and coimmunoprecipitation of an endogenous PIPP, CRMP2, and Kinesin-1 complex from brain lysates. The C-terminal growth cone-targeting domain of PIPP facilitates its interaction with CRMP2. PIPP growth cone localization is CRMP2-dependent. PIPP knockdown in PC12 cells promotes neurite elongation, WAVE1 and Kinesin-1 growth cone localization, whereas knockdown of CRMP2 exhibits the opposite phenotype, with shorter neurites and decreased WAVE1/Kinesin-1 at the growth cone. In contrast, CRMP2 overexpression promotes neurite elongation, a phenotype rescued by full-length PIPP, or expression of the CRMP2-binding PIPP domain. Therefore this study identifies PIPP and CRMP2 exert opposing roles in promoting axon selection and neurite elongation and the complex between these proteins serves to regulate the localization of effectors that promote neurite extension. PMID- 21550975 TI - Immobilized pool of NCAM180 in the postsynaptic membrane is homeostatically replenished by the flux of NCAM180 from extrasynaptic regions. AB - Homeostatic mechanisms maintaining high levels of adhesion molecules in synapses over prolonged periods of time remain incompletely understood. We used fluorescence recovery after photobleaching experiments to analyze the steady state turnover of the immobile pool of green fluorescent protein-labeled NCAM180, the largest postsynaptically accumulating isoform of the neural cell adhesion molecule (NCAM). We show that there is a continuous flux of NCAM180 to the postsynaptic membrane from nonsynaptic regions of dendrites by diffusion. In the postsynaptic membrane, the newly delivered NCAM180 slowly intermixes with the immobilized pool of NCAM180. Preferential immobilization and accumulation of NCAM180 in the postsynaptic membrane is reduced after disruption of the association of NCAM180 with the spectrin cytoskeleton and in the absence of the homophilic interactions of NCAM180 in synapses. Our observations indicate that the homophilic interactions and binding to the cytoskeleton promote immobilization of NCAM180 and its accumulation in the postsynaptic membrane. Flux of NCAM180 from extrasynaptic regions and its slow intermixture with the immobile pool of NCAM180 in the postsynaptic membrane may be important for the continuous homeostatic replenishment of NCAM180 protein at synaptic contacts without compromising the long term synaptic contact stability. PMID- 21550976 TI - Functional and metabolic effects of adaptive glycerol kinase (GLPK) mutants in Escherichia coli. AB - Herein we measure the effect of four adaptive non-synonymous mutations to the glycerol kinase (glpK) gene on catalytic function and regulation, to identify changes that correlate to increased fitness in glycerol media. The mutations significantly reduce affinity for the allosteric inhibitor fructose-1,6 bisphosphate (FBP) and formation of the tetramer, which are structurally related, in a manner that correlates inversely with imparted fitness during growth on glycerol, which strongly suggests that these enzymatic parameters drive growth improvement. Counterintuitively, the glpK mutations also increase glycerol induced auto-catabolite repression that reduces glpK transcription in a manner that correlates to fitness. This suggests that increased specific GlpK activity is attenuated by negative feedback on glpK expression via catabolite repression, possibly to prevent methylglyoxal toxicity. We additionally report that glpK mutations were fixed in 47 of 50 independent glycerol-adapted lineages. By far the most frequently mutated locus (nucleotide 218) was mutated in 20 lineages, strongly suggesting this position has an elevated mutation rate. This study demonstrates that fitness correlations can be used to interrogate adaptive processes at the protein level and to identify the regulatory constraints underlying selection and improved growth. PMID- 21550978 TI - N-linked glycosylation regulates human proteinase-activated receptor-1 cell surface expression and disarming via neutrophil proteinases and thermolysin. AB - Proteinase-activated receptor 1 (PAR(1)) induces activation of platelet and vascular cells after proteolytic cleavage of its extracellular N terminus by thrombin. In pathological situations, other proteinases may be generated in the circulation and might modify the responses of PAR(1) by cleaving extracellular domains. In this study, epitope-tagged wild-type human PAR(1) (hPAR(1)) and a panel of N-linked glycosylation-deficient mutant receptors were permanently expressed in epithelial cells (Kirsten murine sarcoma virus-transformed rat kidney cells and CHO cells). We have analyzed the role of N-linked glycosylation in regulating proteinase activation/disarming and cell global expression of hPAR(1). We reported for the first time that glycosylation in the N terminus of hPAR(1) downstream of the tethered ligand (especially Asn(75)) governs receptor disarming to trypsin, thermolysin, and the neutrophil proteinases elastase and proteinase 3 but not cathepsin G. In addition, hPAR(1) is heavily N-linked glycosylated and sialylated in epithelial cell lines, and glycosylation occurs at all five consensus sites, namely, Asn(35), Asn(62), Asn(75), Asn(250), and Asn(259). Removing these N-linked glycosylation sequons affected hPAR(1) cell surface expression to varying degrees, and N-linked glycosylation at extracellular loop 2 (especially Asn(250)) of hPAR(1) is essential for optimal receptor cell surface expression and receptor stability. PMID- 21550977 TI - Sialylation of the Fas death receptor by ST6Gal-I provides protection against Fas mediated apoptosis in colon carcinoma cells. AB - The glycosyltransferase, ST6Gal-I, adds sialic acid in an alpha2-6 linkage to the N-glycans of membrane and secreted glycoproteins. Up-regulation of ST6Gal-I occurs in many cancers, including colon carcinoma, and correlates with metastasis and poor prognosis. However, mechanisms by which ST6Gal-I facilitates tumor progression remain poorly understood due to limited knowledge of enzyme substrates. Herein we identify the death receptor, Fas (CD95), as an ST6Gal-I substrate, and show that alpha2-6 sialylation of Fas confers protection against Fas-mediated apoptosis. Intriguingly, differences in ST6Gal-I activity do not affect the function of DR4 or DR5 death receptors upon treatment with TRAIL, implicating a selective effect of ST6Gal-I on the Fas receptor. Using ST6Gal-I knockdown and forced overexpression colon carcinoma cell models, we find that alpha2-6 sialylation of Fas prevents apoptosis stimulated by FasL as well as the Fas-activating antibody, CH11, as evidenced by decreased activation of caspases 8 and 3. We also show that alpha2-6 sialylation of Fas does not alter the binding of CH11, but rather inhibits the capacity of Fas to induce apoptosis by blocking the association of FADD with Fas cytoplasmic tails, an event that initiates death inducing signaling complex formation. Furthermore, alpha2-6 sialylation of Fas inhibits Fas internalization, which is required for apoptotic signaling. Although dysregulated Fas activity is a well known mechanism through which tumors evade apoptosis, the current study is the first to link Fas insensitivity to the actions of a specific sialyltransferase. This finding establishes a new paradigm by which death receptor function is impaired for the self-protection of tumors against apoptosis. PMID- 21550979 TI - Identification of a gene essential for the first committed step in the biosynthesis of bacteriochlorophyll c. AB - Bacteriochlorophylls (BChls) c, d, and e are the major chlorophylls in chlorosomes, which are the largest and one of the most efficient antennae produced by chlorophototrophic organisms. In the biosynthesis of these three BChls, a C-13(2)-methylcarboxyl group found in all other chlorophylls (Chls) must be removed. This reaction is postulated to be the first committed step in the synthesis of these BChls. Analyses of gene neighborhoods of (B)Chl biosynthesis genes and distribution patterns in organisms producing chlorosomes helped to identify a gene (bciC) that appeared to be a good candidate to produce the enzyme involved in this biochemical reaction. To confirm that this was the case, a deletion mutant of an open reading frame orthologous to bciC, CT1077, was constructed in Chlorobaculum tepidum, a genetically tractible green sulfur bacterium. The CT1077 deletion mutant was unable to synthesize BChl c but still synthesized BChl a and Chl a. The deletion mutant accumulated large amounts of various (bacterio)pheophorbides, all of which still had C-13(2)-methylcarboxyl groups. A C. tepidum strain in which CT1077 was replaced by an orthologous gene, Cabther_B0081 [corrected] from "Candidatus Chloracidobacterium thermophilum" was constructed. Although the product of Cabther_B0081 [corrected] was only 28% identical to the product of CT1077, this strain synthesized BChl c, BChl a, and Chl a in amounts similar to wild-type C. tepidum cells. To indicate their roles in the first committed step of BChl c, d, and e biosynthesis, open reading frames CT1077 and Cabther_B0081 [corrected] have been redesignated bciC. The potential mechanism by which BciC removes the C-13(2)-methylcarboxyl moiety of chlorophyllide a is discussed. PMID- 21550980 TI - Characterization of prefibrillar Tau oligomers in vitro and in Alzheimer disease. AB - Neurofibrillary tangles, composed of insoluble aggregates of the microtubule associated protein Tau, are a pathological hallmark of Alzheimer disease (AD) and other tauopathies. However, recent evidence indicates that neuronal dysfunction precedes the formation of these insoluble fibrillar deposits, suggesting that earlier prefibrillar Tau aggregates may be neurotoxic. To determine the composition of these aggregates, we have employed a photochemical cross-linking technique to examine intermolecular interactions of full-length Tau in vitro. Using this method, we demonstrate that dimerization is an early event in the Tau aggregation process and that these dimers self-associate to form larger oligomeric aggregates. Moreover, using these stabilized Tau aggregates as immunogens, we generated a monoclonal antibody that selectively recognizes Tau dimers and higher order oligomeric aggregates but shows little reactivity to Tau filaments in vitro. Immunostaining indicates that these dimers/oligomers are markedly elevated in AD, appearing in early pathological inclusions such as neuropil threads and pretangle neurons as well as colocalizing with other early markers of Tau pathogenesis. Taken as a whole, the work presented herein demonstrates the existence of alternative Tau aggregates that precede formation of fibrillar Tau pathologies and raises the possibility that these hierarchical oligomeric forms of Tau may contribute to neurodegeneration. PMID- 21550981 TI - The Dsl1 protein tethering complex is a resident endoplasmic reticulum complex, which interacts with five soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptors (SNAREs): implications for fusion and fusion regulation. AB - Retrograde vesicular transport from the Golgi to the ER requires the Dsl1 tethering complex, which consists of the three subunits Dsl1, Dsl3, and Tip20. It forms a stable complex with the SNAREs Ufe1, Use1, and Sec20 to mediate fusion of COPI vesicles with the endoplasmic reticulum. Here, we analyze molecular interactions between five SNAREs of the ER (Ufe1, Use1, Sec20, Sec22, and Ykt6) and the Dsl1 complex in vitro and in vivo. Of the two R-SNAREs, Sec22 is preferred over Ykt6 in the Dsl-SNARE complex. The NSF homolog Sec18 can displace Ykt6 but not Sec22, suggesting a regulatory function for Ykt6. In addition, our data also reveal that subunits of the Dsl1 complex (Dsl1, Dsl3, and Tip20), as well as the SNAREs Ufe1 and Sec20, are ER-resident proteins that do not seem to move into COPII vesicles. Our data support a model, in which a tethering complex is stabilized at the organelle membrane by binding to SNAREs, recognizes the incoming vesicle via its coat and then promotes its SNARE-mediated fusion. PMID- 21550982 TI - Arsenite interacts selectively with zinc finger proteins containing C3H1 or C4 motifs. AB - Arsenic inhibits DNA repair and enhances the genotoxicity of DNA-damaging agents such as benzo[a]pyrene and ultraviolet radiation. Arsenic interaction with DNA repair proteins containing functional zinc finger motifs is one proposed mechanism to account for these observations. Here, we report that arsenite binds to both CCHC DNA-binding zinc fingers of the DNA repair protein PARP-1 (poly(ADP ribose) polymerase-1). Furthermore, trivalent arsenite coordinated with all three cysteine residues as demonstrated by MS/MS. MALDI-TOF-MS analysis of peptides harboring site-directed substitutions of cysteine with histidine residues within the PARP-1 zinc finger revealed that arsenite bound to peptides containing three or four cysteine residues, but not to peptides with two cysteines, demonstrating arsenite binding selectivity. This finding was not unique to PARP-1; arsenite did not bind to a peptide representing the CCHH zinc finger of the DNA repair protein aprataxin, but did bind to an aprataxin peptide mutated to a CCHC zinc finger. To investigate the impact of arsenite on PARP-1 zinc finger function, we measured the zinc content and DNA-binding capacity of PARP-1 immunoprecipitated from arsenite-exposed cells. PARP-1 zinc content and DNA binding were decreased by 76 and 80%, respectively, compared with protein isolated from untreated cells. We observed comparable decreases in zinc content for XPA (xeroderma pigmentosum group A) protein (CCCC zinc finger), but not SP-1 (specificity protein-1) or aprataxin (CCHH zinc finger). These findings demonstrate that PARP-1 is a direct molecular target of arsenite and that arsenite interacts selectively with zinc finger motifs containing three or more cysteine residues. PMID- 21550983 TI - Crystal structures of SlyA protein, a master virulence regulator of Salmonella, in free and DNA-bound states. AB - SlyA is a master virulence regulator that controls the transcription of numerous genes in Salmonella enterica. We present here crystal structures of SlyA by itself and bound to a high-affinity DNA operator sequence in the slyA gene. SlyA interacts with DNA through direct recognition of a guanine base by Arg-65, as well as interactions between conserved Arg-86 and the minor groove and a large network of non-base-specific contacts with the sugar phosphate backbone. Our structures, together with an unpublished structure of SlyA bound to the small molecule effector salicylate (Protein Data Bank code 3DEU), reveal that, unlike many other MarR family proteins, SlyA dissociates from DNA without large conformational changes when bound to this effector. We propose that SlyA and other MarR global regulators rely more on indirect readout of DNA sequence to exert control over many genes, in contrast to proteins (such as OhrR) that recognize a single operator. PMID- 21550984 TI - Chromatin-modifying complex component Nurf55/p55 associates with histones H3 and H4 and polycomb repressive complex 2 subunit Su(z)12 through partially overlapping binding sites. AB - Drosophila Nurf55 is a component of different chromatin-modifying complexes, including the PRC2 (Polycomb repressive complex 2). Based on the 1.75-A crystal structure of Nurf55 bound to histone H4 helix 1, we analyzed interactions of Nurf55 (Nurf55 or p55 in fly and RbAp48/46 in human) with the N-terminal tail of histone H3, the first helix of histone H4, and an N-terminal fragment of the PRC2 subunit Su(z)12 using isothermal calorimetry and pulldown experiments. Site directed mutagenesis identified the binding site of histone H3 at the top of the Nurf55 WD40 propeller. Unmodified or K9me3- or K27me3-containing H3 peptides were bound with similar affinities, whereas the affinity for K4me3-containing H3 peptides was reduced. Helix 1 of histone H4 and Su(z)12 bound to the edge of the beta-propeller using overlapping binding sites. Our results show similarities in the recognition of histone H4 and Su(z)12 and identify Nurf55 as a versatile interactor that simultaneously contacts multiple partners. PMID- 21550985 TI - Furin is the major processing enzyme of the cardiac-specific growth factor bone morphogenetic protein 10. AB - Bone morphogenetic protein 10 (BMP10) is a member of the TGF-beta superfamily and plays a critical role in heart development. In the postnatal heart, BMP10 is restricted to the right atrium. The inactive pro-BMP10 (~60 kDa) is processed into active BMP10 (~14 kDa) by an unknown protease. Proteolytic cleavage occurs at the RIRR(316)? site (human), suggesting the involvement of proprotein convertase(s) (PCs). In vitro digestion of a 12-mer peptide encompassing the predicted cleavage site with furin, PACE4, PC5/6, and PC7, showed that furin cleaves the best, whereas PC7 is inactive on this peptide. Ex vivo studies in COS 1 cells, a cell line lacking PC5/6, revealed efficient processing of pro-BMP10 by endogenous PCs other than PC5/6. The lack of processing of overexpressed pro BMP10 in the furin- and PACE4-deficient cell line, CHO-FD11, and in furin deficient LoVo cells, was restored by stable (CHO-FD11/Fur cells) or transient (LoVo cells) expression of furin. Use of cell-permeable and cell surface inhibitors suggested that endogenous PCs process pro-BMP10 mostly intracellularly, but also at the cell surface. Ex vivo experiments in mouse primary hepatocytes (wild type, PC5/6 knock-out, and furin knock-out) corroborated the above findings that pro-BMP10 is a substrate for endogenous furin. Western blot analyses of heart right atria extracts from wild type and PACE4 knock-out adult mice showed no significant difference in the processing of pro-BMP10, implying no in vivo role of PACE4. Overall, our in vitro, ex vivo, and in vivo data suggest that furin is the major convertase responsible for the generation of BMP10. PMID- 21550986 TI - Phospholipase C epsilon scaffolds to muscle-specific A kinase anchoring protein (mAKAPbeta) and integrates multiple hypertrophic stimuli in cardiac myocytes. AB - To define a role for phospholipase Cepsilon (PLCepsilon) signaling in cardiac myocyte hypertrophic growth, PLCepsilon protein was depleted from neonatal rat ventricular myocytes (NRVMs) using siRNA. NRVMs with PLCepsilon depletion were stimulated with endothelin (ET-1), norepinephrine, insulin-like growth factor-1 (IGF-1), or isoproterenol and assessed for development of hypertrophy. PLCepsilon depletion dramatically reduced hypertrophic growth and gene expression induced by all agonists tested. PLCepsilon catalytic activity was required for hypertrophy development, yet PLCepsilon depletion did not reduce global agonist-stimulated inositol phosphate production, suggesting a requirement for localized PLC activity. PLCepsilon was found to be scaffolded to a muscle-specific A kinase anchoring protein (mAKAPbeta) in heart and NRVMs, and mAKAPbeta localizes to the nuclear envelope in NRVMs. PLCepsilon-mAKAP interaction domains were defined and overexpressed to disrupt endogenous mAKAPbeta-PLCepsilon complexes in NRVMs, resulting in significantly reduced ET-1-dependent NRVM hypertrophy. We propose that PLCepsilon integrates multiple upstream signaling pathways to generate local signals at the nucleus that regulate hypertrophy. PMID- 21550987 TI - Comparative fluorescence resonance energy transfer analysis of metabotropic glutamate receptors: implications about the dimeric arrangement and rearrangement upon ligand bindings. AB - Dimerization of G protein-coupled receptors has received much attention as a regulatory system of physiological function. Metabotropic glutamate receptors (mGluRs) are suitable models for studying the physiological significance of G protein-coupled receptor dimers because they form constitutive homodimers and function through dimeric rearrangement of their extracellular ligand binding domains. However, the molecular architecture of the transmembrane domains (TMDs) and their rearrangement upon agonist binding are still largely unknown. Here we show that the two helix Vs are arranged as the closest part in the dimeric TMDs and change their positions through synergistic control by the binding of two glutamates. The possibility that helix V is involved in an inter-protomer communication was first suggested by the finding that constitutively active mutation sites were identified on both sides of helix V. Then, comprehensive fluorescence resonance energy transfer (FRET) analysis using mGluRs whose cytoplasmic loops were labeled with donor and acceptor fluorescent proteins revealed that the third intracellular loop connecting helices V and VI of one protomer was in close proximity to the second and third intracellular loops of the other protomer and that all the intracellular loops became closer during the activation. Furthermore, FRET analysis of heterodimers in which only one protomer had ligand binding ability revealed the synergistic effect of the binding of two glutamates on the dimeric rearrangements of the TMD. Thus, the glutamate dependent synergistic relocation of the helix Vs in the dimer is important for the signal flow from the extracellular ligand binding domain to the cytoplasmic surface of the mGluR. PMID- 21550988 TI - Differential distribution, clustering, and lateral diffusion of subtypes of the inositol 1,4,5-trisphosphate receptor. AB - Regulation of inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)R) by IP(3) and Ca(2+) allows them to initiate and regeneratively propagate intracellular Ca(2+) signals. The distribution and mobility of IP(3)R determines the spatial organization of these Ca(2+) signals. Until now, there has been no systematic comparison of the distribution and mobility of the three mammalian IP(3)R subtypes in a uniform background. We used confocal microscopy and fluorescence recovery after photobleaching to define these properties for each IP(3)R subtype expressed heterologously in COS-7 cells. IP(3)R1 and IP(3)R3 were uniformly distributed within the membranes of the endoplasmic reticulum (ER), but the distribution of IP(3)R2 was punctate. The mobile fractions (M(f) = 84 +/- 2 and 80 +/- 2%) and diffusion coefficients (D = 0.018 +/- 0.001 and 0.016 +/- 0.002 MUm(2)/s) of IP(3)R1 and IP(3)R3 were similar. Other ER membrane proteins (ryanodine receptor type 1 and sarco/endoplasmic reticulum Ca(2+)-ATPase type 1) and a luminal protein (enhanced GFP with a KDEL retrieval sequence) had similar mobile fractions, suggesting that IP(3)R1 and IP(3)R3 move freely within an ER that is largely, although not entirely, continuous. IP(3)R2 was less mobile, but IP(3)R2 mobility differed between perinuclear (M(f) = 47 +/- 4% and D = 0.004 +/- 0.001 MUm(2)/s) and near-plasma membrane (M(f) = 64 +/- 6% and D = 0.013 +/- 0.004 MUm(2)/s) regions, whereas IP(3)R3 behaved similarly in both regions. We conclude that IP(3)R1 and IP(3)R3 diffuse freely within a largely continuous ER, but IP(3)R2 is more heterogeneously distributed and less mobile, and its mobility differs between regions of the cell. PMID- 21550989 TI - Anterior knee laxity increases gapping of posterior horn medial meniscal tears. AB - BACKGROUND: Meniscal tears often occur in association with anterior cruciate ligament (ACL) lesions or in chronically lax knees. It is also known that meniscal repairs are less likely to heal in ACL-deficient knees. PURPOSE: To test the effect of different knee joint motion and loading conditions on the gapping behavior of longitudinal posterior horn meniscal tears in stable and ACL deficient knee joints. STUDY DESIGN: Controlled laboratory study. METHODS: Longitudinal tears of 3 cm were set in the posterior horn of the medial menisci in 10 human cadaveric joints. The medial plateau of the knees was replaced by a transparent replica, and an arthroscope was placed underneath to observe the gapping phenomenon of the meniscal tears. The maximum gap width occurring during flexion-extension under various motion and loading situations was registered in intact and ACL-deficient joints before and after meniscal repair with FasT-Fix suture anchors. RESULTS: Longitudinal meniscal tears gapped significantly wider after ACL transection under 30-N axial joint load (P < .05). Increasing the axial load to 200 N or applying external moments to the knee did not lead to further alterations in the gap size. Gapping was significantly reduced after meniscal repair (P < .01). However, after meniscal repair, gapping under 30-N and 200-N axial joint load was still increased significantly after ACL transection compared with the ACL-intact state (P < .05). CONCLUSION: Anterior knee laxity increases gapping across both unrepaired and repaired vertical peripheral medial meniscal posterior horn tears. CLINICAL RELEVANCE: Repairing such meniscal tears without reconstructing the ACL may affect meniscus healing rates or increase the risk of retears. Moderate rehabilitation regimens can be recommended, allowing at least for partial weightbearing and knee motion from extension to 120 degrees of flexion in a stable knee. However, caution should be recommended if meniscal repair is performed in a knee joint with persistent anterior laxity due to ACL deficiency. PMID- 21550991 TI - Glucosylceramide synthase in the fat body controls energy metabolism in Drosophila. AB - Glucosylceramide synthase (GlcT-1) catalyzes the synthesis of glucosylceramide (GlcCer), the core structure of major glycosphingolipids (GSLs). Obesity is a metabolic disorder caused by an imbalance between energy uptake and expenditure, resulting in excess stored body fat. Recent studies have shown that GSL levels are increased in obese rodents and that pharmacologically reducing GSL levels by inhibiting GlcCer synthesis improves adipocyte function. However, the molecular mechanism underlying these processes is still not clearly understood. Using Drosophila as a model animal, we report that GlcT-1 expression in the fat body, which is equivalent to mammalian adipose tissue, regulates energy metabolism. Overexpression of GlcT-1 increases stored nutrition (triacylglycerol and carbohydrate) levels. Conversely, reduced expression of GlcT-1 in the fat body causes a reduction of fat storage. This regulation occurs, at least in part, through the activation of p38-ATF2 signaling. Furthermore, we found that GlcCer is the sole GSL of the fat body, indicating that regulation of GlcCer synthesis by GlcT-1 in the fat body is responsible for regulating energy homeostasis. Both GlcT-1 and p38-ATF2 signaling are evolutionarily conserved, leading us to propose an evolutionary perspective in which GlcT-1 appears to be one of the key factors that control fat metabolism. PMID- 21550992 TI - Implications for double-row rotator cuff repair. PMID- 21550990 TI - Altered vitamin E status in Niemann-Pick type C disease. AB - Vitamin E (alpha-tocopherol) is the major lipid-soluble antioxidant in many species. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene, which regulates lipid transport through the endocytic pathway. NPC disease is characterized by massive intracellular accumulation of unesterified cholesterol and other lipids in lysosomal vesicles. We examined the roles that NPC1/2 proteins play in the intracellular trafficking of tocopherol. Reduction of NPC1 or NPC2 expression or function in cultured cells caused a marked lysosomal accumulation of vitamin E in cultured cells. In vivo, tocopherol significantly accumulated in murine Npc1-null and Npc2-null livers, Npc2-null cerebella, and Npc1-null cerebral cortices. Plasma tocopherol levels were within the normal range in Npc1-null and Npc2-null mice, and in plasma samples from human NPC patients. The binding affinity of tocopherol to the purified sterol-binding domain of NPC1 and to purified NPC2 was significantly weaker than that of cholesterol (measurements kindly performed by R. Infante, University of Texas Southwestern Medical Center, Dallas, TX). Taken together, our observations indicate that functionality of NPC1/2 proteins is necessary for proper bioavailability of vitamin E and that the NPC pathology might involve tissue-specific perturbations of vitamin E status. PMID- 21550993 TI - Endoscopic anterior cruciate ligament reconstruction. PMID- 21550994 TI - Kids will be kids. PMID- 21550996 TI - Thermodynamic analysis of hepatitis C virus vitality in syringes. PMID- 21550997 TI - Grading schemes for placental malaria. PMID- 21551000 TI - Second neoplasms after cancers of unknown primary. PMID- 21550999 TI - Escherichia coli isolates causing bacteremia via gut translocation and urinary tract infection in young infants exhibit different virulence genotypes. AB - Escherichia coli bacteremia in young infants may arise via either urinary tract infection or gut translocation (GT). E. coli GT isolates have rarely been investigated. Molecular analysis of 100 E. coli isolates recovered from bacteremic infants revealed that GT isolates had multilocus sequence types similar to those of urosepsis isolates but different prevalences of PapGII adhesin, TcpC protectin, and ibeA invasin. Compared with late-onset GT isolates, early-onset isolates were associated with significantly different rates of the conserved virulence plasmidic region common to human and avian pathogenic strains and alpha-hemolysin. We identified genetic determinants potentially involved in specific pathophysiological steps preceding E. coli bloodstream invasion. PMID- 21551001 TI - The potential role of cyclooxygenase-2 (COX-2) during early breast cancer therapy. PMID- 21551002 TI - Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: implications for adjuvant therapy of breast cancer. AB - BACKGROUND: Zoledronic acid (ZA) reduces locoregional and distant metastases in estrogen receptor (ER)-positive breast cancer patients. Since ZA rapidly concentrates in the bone following i.v. administration, we hypothesized that this phenomenon involves the mechanism of action of ZA in bone tissue. MATERIALS AND METHODS: Migration assays were carried out in fibronectin-coated Boyden chambers. Activation of signaling proteins was analyzed with a phosphoprotein array. Chemokines and growth factors were measured by immunoassays and real-time PCR. RESULTS: ZA significantly reduced in bone marrow-derived mesenchymal stem cells (MSCs) the activation of AKT and mitogen-activated protein kinase and their ability to migrate. Conditioned medium (CM) from ZA-treated MSCs showed a reduced capacity to promote the migration of ER-positive MCF-7 breast cancer cells as compared with CM from untreated MSCs. The levels of the chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES - Regulated upon Activation, Normal T-cell Expressed, and Secreted) and interleukin (IL)-6 were significantly reduced in MSC CM following treatment with ZA. Anti-RANTES and anti-IL-6 antibodies almost completely abolished the migration of MCF-7 cells induced by MSC-CM. Recombinant RANTES and IL-6 significantly induced MCF-7 cell migration and their combination showed a cooperative effect. Similar results were observed in different breast cancer cell lines. CONCLUSION: ZA might exert its antitumor activity by inhibiting MSC migration and blocking MSCs' secretion of factors involved in breast cancer progression. PMID- 21551003 TI - Biomarkers and efficacy: are we nearly there yet? PMID- 21551004 TI - A meta-analysis on alcohol drinking and esophageal and gastric cardia adenocarcinoma risk. AB - BACKGROUND: In order to provide a precise quantification of the association between alcohol drinking and esophageal and gastric cardia adenocarcinoma risk, we conducted a meta-analysis of available data. PATIENTS AND METHODS: We identified 20 case-control and 4 cohort studies, including a total of 5500 cases. We derived meta-analytic estimates using random-effects models, taking into account correlation between estimates, and we carried out a dose-risk analysis using nonlinear random-effects meta-regression models. RESULTS: The relative risk (RR) for drinkers versus nondrinkers was 0.96 [95% confidence interval (CI) 0.85 1.09] overall, 0.87 (95% CI 0.74-1.01) for esophageal adenocarcinoma and 0.89 (95% CI 0.76-1.03) for gastric cardia adenocarcinoma. Compared with nondrinkers, the pooled RRs were 0.86 for light (<= 1 drink per day), 0.90 for moderate (1 to < 4 drinks per day), and 1.16 for heavy (>= 4 drinks per day) alcohol drinking. The dose-risk model found a minimum at 25 g/day, and the curve was < 1 up to 70 g/day. CONCLUSIONS: This meta-analysis provides definite evidence of an absence of association between alcohol drinking and esophageal and gastric cardia adenocarcinoma risk, even at higher doses of consumption. PMID- 21551006 TI - Stem-cell transplantation in T-cell non-Hodgkin's lymphomas. AB - BACKGROUND: T-cell lymphomas are a heterogeneous group of non-Hodgkin's lymphomas (NHLs). With the exception of anaplastic lymphoma kinase protein-positive large cell lymphoma, standard chemotherapy provides dismal long-term outcomes when compared with NHLs with B-cell immunophenotype. DESIGN: We review the literature on the role of high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in T-cell NHLs both as up-front treatment and in the salvage setting. The role of allogeneic transplantation will also be reviewed. RESULTS: Results from five prospective, nonrandomized and six retrospective studies evaluating the role of HDT and ASCT in the up-front setting show that patients in first complete or partial remission especially those who present with advanced disease and high prognostic index of peripheral T-cell lymphoma score may benefit from this approach. In the relapsed and/or refractory setting, most series show results that are comparable with those seen in patients with B-cell lymphomas if transplanted with chemosensitive disease. There is limited evidence to suggest that an immune-mediated graft-versus-lymphoma effect may result in long-term disease remissions in some patients after allogeneic transplantation. CONCLUSIONS: Randomized studies comparing HDT and ASCT with conventional chemotherapy are needed in T-cell lymphomas. PMID- 21551005 TI - Risk of hepatitis B reactivation and the role of novel agents and stem-cell transplantation in multiple myeloma patients with hepatitis B virus (HBV) infection. AB - BACKGROUND: The purpose of the study is to analyse the prevalence of hepatitis B virus (HBV) infection and its incidence of reactivation among multiple myeloma (MM) patients treated in the era of novel therapy in an endemic Asian setting. PATIENTS AND METHODS: From 2000 to 2008, 273 patients with newly diagnosed MM were screened for the presence of hepatitis B virus surface antigen and HBV core antibody. HBV-infected patients were prospectively followed for reactivation with serial monitoring of serum alanine transferase and HBV DNA load. The patterns of HBV reactivation in relation to treatment received, exposure to high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) and novel agents were studied. RESULTS: The prevalence of HBV infection was 5.5%. Three cases of HBV reactivation despite lamivudine prophylaxis were reported. Two patients reactivated 3-5 months after HDT/ASCT while receiving thalidomide maintenance and one reactivated 3 years after HDT/ASCT and shortly after bortezomib salvage therapy. Emergence of a mutant HBV strain was documented in one patient. CONCLUSIONS: Use of prophylaxis may reduce but will not preclude HBV reactivation. Highest risk occurs during immune reconstitution phase of HDT/ASCT. The role of immunomodulatory agents in HBV reactivation needs to be further elucidated. Separate HBV prophylaxis and surveillance guidelines ought to be developed for patients with MM. PMID- 21551007 TI - High-fat diet overrules the effects of training on fiber-specific intramyocellular lipid utilization during exercise. AB - In this study, we compared the effects of endurance training in the fasted state (F) vs. the fed state [ample carbohydrate intake (CHO)] on exercise-induced intramyocellular lipid (IMCL) and glycogen utilization during a 6-wk period of a hypercaloric (~+30% kcal/day) fat-rich diet (HFD; 50% of kcal). Healthy male volunteers (18-25 yrs) received a HFD in conjunction with endurance training (four times, 60-90 min/wk) either in F (n = 10) or with CHO before and during exercise sessions (n = 10). The control group (n = 7) received a HFD without training and increased body weight by ~3 kg (P < 0.001). Before and after a HFD, the subjects performed a 2-h constant-load bicycle exercise test in F at ~70% maximal oxygen uptake rate. A HFD, both in the absence (F) or presence (CHO) of training, elevated basal IMCL content by ~50% in type I and by ~75% in type IIa fibers (P < 0.05). Independent of training in F or CHO, a HFD, as such, stimulated exercise-induced net IMCL breakdown by approximately twofold in type I and by approximately fourfold in type IIa fibers. Furthermore, exercise-induced net muscle glycogen breakdown was not significantly affected by a HFD. It is concluded that a HFD stimulates net IMCL degradation by increasing basal IMCL content during exercise in type I and especially IIa fibers. Furthermore, a hypercaloric HFD provides adequate amounts of carbohydrates to maintain high muscle glycogen content during training and does not impair exercise-induced muscle glycogen breakdown. PMID- 21551008 TI - AMPKalpha2 deficiency uncovers time dependency in the regulation of contraction induced palmitate and glucose uptake in mouse muscle. AB - AMP-activated protein kinase (AMPK) is a fuel sensor in skeletal muscle with multiple downstream signaling targets that may be triggered by increases in intracellular Ca(2+) concentration ([Ca(2+)]). The purpose of this study was to determine whether increases in intracellular [Ca(2+)] induced by caffeine act solely via AMPKalpha(2) and whether AMPKalpha(2) is essential to increase glucose uptake, fatty acid (FA) uptake, and FA oxidation in contracting skeletal muscle. Hindlimbs from wild-type (WT) or AMPKalpha(2) dominant-negative (DN) transgene mice were perfused during rest (n = 11), treatment with 3 mM caffeine (n = 10), or muscle contraction (n = 11). Time-dependent effects on glucose and FA uptake were uncovered throughout the 20-min muscle contraction perfusion period (P < 0.05). Glucose uptake rates did not increase in DN mice during muscle contraction until the last 5 min of the protocol (P < 0.05). FA uptake rates were elevated at the onset of muscle contraction and diminished by the end of the protocol in DN mice (P < 0.05). FA oxidation rates were abolished in the DN mice during muscle contraction (P < 0.05). The DN transgene had no effect on caffeine-induced FA uptake and oxidation (P > 0.05). Glucose uptake rates were blunted in caffeine treated DN mice (P < 0.05). The DN transgene resulted in a greater use of intramuscular triglycerides as a fuel source during muscle contraction. The DN transgene did not alter caffeine- or contraction-mediated changes in the phosphorylation of Ca(2+)/calmodulin-dependent protein kinase I or ERK1/2 (P > 0.05). These data suggest that AMPKalpha(2) is involved in the regulation of substrate uptake in a time-dependent manner in contracting muscle but is not necessary for regulation of FA uptake and oxidation during caffeine treatment. PMID- 21551009 TI - Hypoxic exercise training causes erythrocyte senescence and rheological dysfunction by depressed Gardos channel activity. AB - Despite enhancing cardiopulmonary and muscular fitness, the effect of hypoxic exercise training (HE) on hemorheological regulation remains unclear. This study investigates how HE modulates erythrocyte rheological properties and further explores the underlying mechanisms in the hemorheological alterations. Twenty four sedentary males were randomly divided into hypoxic (HE; n = 12) and normoxic (NE; n = 12) exercise training groups. The subjects were trained on 60% of maximum work rate under 15% (HE) or 21% (NE) O(2) condition for 30 min daily, 5 days weekly for 5 wk. The results demonstrated that HE 1) downregulated CD47 and CD147 expressions on erythrocytes, 2) decreased actin and spectrin contents in erythrocytes, 3) reduced erythrocyte deformability under shear flow, and 4) diminished erythrocyte volume changed by hypotonic stress. Treatment of erythrocytes with H(2)O(2) that mimicked in vivo prooxidative status resulted in the cell shrinkage, rigidity, and phosphatidylserine exposure, whereas HE enhanced the eryptotic responses to H(2)O(2). However, HE decreased the degrees of clotrimazole to blunt ionomycin-induced shrinkage, rigidity, and cytoskeleton breakdown of erythrocytes, referred to as Gardos effects. Reduced erythrocyte deformability by H(2)O(2) was inversely related to the erythrocyte Gardos effect on the rheological function. Conversely, NE intervention did not significantly change resting and exercise erythrocyte rheological properties. Therefore, we conclude that HE rather than NE reduces erythrocyte deformability and volume regulation, accompanied by an increase in the eryptotic response to oxidative stress. Simultaneously, this intervention depresses Gardos channel-modulated erythrocyte rheological functions. Results of this study provide further insight into erythrocyte senescence induced by HE. PMID- 21551010 TI - Effects of 8 wk of voluntary unloaded wheel running on K+ tolerance and excitability of soleus muscles in rat. AB - During intense exercise, efflux of K(+) from working muscles increases extracellular K(+) ([K(+)](o)) to levels that can compromise muscle excitability and hence cause fatigue. In this context, the reduction in the exercise-induced elevation of [K(+)](o) observed after training in humans is suggested to contribute to the increased performance after training. Although a similar effect could be obtained by an increase in the tolerance of muscle to elevated [K(+)](o), this possibility has not been investigated. To examine this, isolated soleus muscles from sedentary (sedentary) rats and from rats that had voluntarily covered 13.1 +/- 0.7 km/day in an unloaded running wheel for 8 wk (active) were compared. In muscles from active rats, the loss of force induced by exposure to an elevated [K(+)](o) of 9 mM was 42% lower than in muscles from sedentary rats (P < 0.001). This apparent increase in K(+) tolerance in active rats was associated with an increased excitability as evident from a 33% reduction in the electrical current needed to excite individual muscle fibers (P < 0.0009). Moreover, muscles from active rats had lower Cl(-) conductance, higher maximal rate of rise of single-fiber action potentials (AP), and higher Na(+)/K(+) pump content. When stimulated intermittently at 6.5 mM K(+), muscles from active rats displayed better endurance than muscles from sedentary rats, whereas no difference was found when the muscles were stimulated continuously at 30 or 120 Hz. We conclude that voluntary running increases muscle excitability, leading to improved tolerance to elevated [K(+)](o). PMID- 21551011 TI - PKB signaling and atrogene expression in skeletal muscle of aged mice. AB - The purpose of this study was to determine if PKB signaling is decreased and contractile protein degradation is increased in extensor digitorum longus (EDL) and soleus (SOL) muscles from middle-aged (MA) and aged (AG) mice. We also examined the effect of age on atrogene expression in quadriceps muscle. PKB activity, as assessed by Thr(308) and Ser(473) phosphorylation, was significantly higher in EDL and SOL muscles from AG than MA mice. The age-related increase in PKB activity appears to be due to an increase in expression of the kinase, as PKB alpha and PKB-beta levels were significantly higher in EDL and SOL muscles from AG than MA mice. The phosphorylation of forkhead box 3a (FOXO3a) on Thr(32), a PKB target, was significantly higher in EDL muscles from AG than MA mice. The rate of contractile protein degradation was similar in EDL and SOL muscles from AG and MA mice. Atrogin-1 and muscle-specific RING finger protein 1 (MuRF-1) mRNA levels did not change in muscles from AG compared with MA mice, indicating that ubiquitin-proteasome proteolysis does not contribute to sarcopenia. A significant decrease in Bcl-2 and 19-kDa interacting protein 3 (Bnip3) and GABA receptor associated protein 1 (Gabarap1) mRNA was observed in muscles from AG compared with MA mice, which may contribute to age-related contractile dysfunction. In conclusion, the mechanisms responsible for sarcopenia are distinct from experimental models of atrophy and do not involve atrogin-1 and MuRF-1 or enhanced proteolysis. Finally, a decline in autophagy-related gene expression may provide a novel mechanism for impaired contractile function and muscle metabolism with advancing age. PMID- 21551012 TI - Less is more: standard warm-up causes fatigue and less warm-up permits greater cycling power output. AB - The traditional warm-up (WU) used by athletes to prepare for a sprint track cycling event involves a general WU followed by a series of brief sprints lasting >= 50 min in total. A WU of this duration and intensity could cause significant fatigue and impair subsequent performance. The purpose of this research was to compare a traditional WU with an experimental WU and examine the consequences of traditional and experimental WU on the 30-s Wingate test and electrically elicited twitch contractions. The traditional WU began with 20 min of cycling with a gradual intensity increase from 60% to 95% of maximal heart rate; then four sprints were performed at 8-min intervals. The experimental WU was shorter with less high-intensity exercise: intensity increased from 60% to 70% of maximal heart rate over 15 min; then just one sprint was performed. The Wingate test was conducted with a 1-min lead-in at 80% of optimal cadence followed by a Wingate test at optimal cadence. Peak active twitch torque was significantly lower after the traditional than experimental WU (86.5 +/- 3.3% vs. 94.6 +/- 2.4%, P < 0.05) when expressed as percentage of pre-WU amplitude. Wingate test performance was significantly better (P < 0.01) after experimental WU (peak power output = 1,390 +/- 80 W, work = 29.1 +/- 1.2 kJ) than traditional WU (peak power output = 1,303 +/- 89 W, work = 27.7 +/- 1.2 kJ). The traditional track cyclist's WU results in significant fatigue, which corresponds with impaired peak power output. A shorter and lower-intensity WU permits a better performance. PMID- 21551013 TI - Primary ciliary dyskinesia: evaluation using cilia beat frequency assessment via spectral analysis of digital microscopy images. AB - Ciliary beat frequency (CBF) measurements provide valuable information for diagnosing of primary ciliary dyskinesia (PCD). We developed a system for measuring CBF, used it in association with electron microscopy to diagnose PCD, and then analyzed characteristics of PCD patients. The CBF measurement system was based on power spectra measured through digital imaging. Twenty-four patients suspected of having PCD (age 1-19 yr) were selected from a group of 75 children and adolescents with pneumopathies of unknown causes. Ten healthy, nonsmoking volunteers (age >= 17 yr) served as a control group. Nasal brush samples were collected, and CBF and electron microscopy were performed. PCD was diagnosed in 12 patients: 5 had radial spoke defects, 3 showed absent central microtubule pairs with transposition, 2 had outer dynein arm defects, 1 had a shortened outer dynein arm, and 1 had a normal ultrastructure. Previous studies have reported that the most common cilia defects are in the dynein arm. As expected, the mean CBF was higher in the control group (P < 0.001) and patients with normal ultrastructure (P < 0.002), than in those diagnosed with cilia ultrastructural defects (i.e., PCD patients). An obstructive ventilatory pattern was observed in 70% of the PCD patients who underwent pulmonary function tests. All PCD patients presented bronchial wall thickening on chest computed tomography scans. The protocol and diagnostic techniques employed allowed us to diagnose PCD in 16% of patients in this study. PMID- 21551014 TI - Early neural responses to strength training. AB - The neural adaptations that accompany strength training have yet to be fully determined. Here we sought to address this topic by testing the idea that strength training might share similar mechanisms with some forms of motor learning. Since ballistic motor learning is accompanied by a shift in muscle twitches induced by transcranial magnetic stimulation (TMS) toward the training direction, we sought to investigate if these changes also occur after single isometric strength training sessions with various contraction duration and rate of force development characteristics (i.e., brief or sustained ballistic contractions or slow, sustained contractions). Twitch force resultant vectors and motor-evoked potentials (MEPs) induced by TMS were measured before and after single sessions of strength training involving the forearm muscles. Participants (n = 12) each performed three training protocols (each consisting of 4 sets of 10 repetitions) and served as their own control in a counterbalanced order. All three training protocols caused a significant (P < 0.05) shift in TMS-induced twitch force resultant vectors toward the training direction, followed by a gradual shift back toward the pretraining direction. The strongest effect was found when training involved both ballistic and sustained force components. There were no large or consistent changes in the direction of twitches evoked by motor nerve stimulation for any of the three training protocols. We suggest that these early neural responses to strength training, which share similar corticospinal changes to motor learning, might reflect an important process that precedes more long-term neural adaptation that ultimately enhance strength. PMID- 21551016 TI - Cutaneous thermal hyperemia: more than skin deep. PMID- 21551015 TI - Differential responses of targeted lung redox enzymes to rat exposure to 60 or 85% oxygen. AB - Rat exposure to 60% O(2) (hyper-60) or 85% O(2) (hyper-85) for 7 days confers susceptibility or tolerance, respectively, of the otherwise lethal effects of exposure to 100% O(2). The objective of this study was to determine whether activities of the antioxidant cytosolic enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) and mitochondrial complex III are differentially altered in hyper-60 and hyper-85 lungs. Duroquinone (DQ), an NQO1 substrate, or its hydroquinone (DQH(2)), a complex III substrate, was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of DQH(2) and DQ were measured. Based on inhibitor effects and kinetic modeling, capacities of NQO1 mediated DQ reduction (V(max1)) and complex III-mediated DQH(2) oxidation (V(max2)) increased by ~140 and ~180% in hyper-85 lungs, respectively, compared with rates in lungs of rats exposed to room air (normoxic). In hyper-60 lungs, V(max1) increased by ~80%, with no effect on V(max2). Additional studies revealed that mitochondrial complex I activity in hyper-60 and hyper-85 lung tissue homogenates was ~50% lower than in normoxic lung homogenates, whereas mitochondrial complex IV activity was ~90% higher in only hyper-85 lung tissue homogenates. Thus NQO1 activity increased in both hyper-60 and hyper-85 lungs, whereas complex III activity increased in hyper-85 lungs only. This increase, along with the increase in complex IV activity, may counter the effects the depression in complex I activity might have on tissue mitochondrial function and/or reactive oxygen species production and may be important to the tolerance of 100% O(2) observed in hyper-85 rats. PMID- 21551017 TI - What's in a name? PMID- 21551018 TI - Relaxin regulates vascular wall remodeling and passive mechanical properties in mice. AB - Administration of recombinant human relaxin (rhRLX) to conscious rats increases global arterial compliance, and small renal arteries (SRA) isolated from these rats demonstrate increased passive compliance. Here we characterize relaxin induced vascular remodeling and examine its functional relevance. SRA and external iliac arteries (EIA) were examined in rhRLX-treated (1.0 MUg/h for 5 days) and relaxin knockout mice. Arterial geometric remodeling and compositional remodeling were quantified using immunohistochemical and biochemical techniques. Vascular mechanical properties were quantified using an ex vivo preparation wherein pressure-diameter data were obtained at various axial lengths. Compared with vehicle-treated mice, SRA from rhRLX-treated mice showed outward geometric remodeling (increased unstressed wall area and wall-to-lumen area ratio), increased smooth muscle cell (SMC) density, reduction in collagen-to-total protein ratio, and unchanged elastin-to-tissue dry weight ratio. Compared with wild-type mice, relaxin knockout mice exhibited the opposite pattern: decreased unstressed wall area and wall-to-lumen area ratio, decreased SMC density, and increased collagen-to-total protein ratio. Although tissue biaxial strain energy of SRA was not different between rhRLX- and vehicle-treated groups at low-to physiological circumferential and axial strains, it was lower for the rhRLX treated group at the highest circumferential strain. In contrast to SRA, relaxin administration was not associated with any vascular remodeling or changes in passive mechanics of EIA. Thus relaxin induces both geometric and compositional remodeling in vessel-specific manner. Relaxin-induced geometric remodeling of SRA is responsible for the increase in passive compliance under low-to-physiological levels of circumferential and axial strains, and compositional remodeling becomes functionally relevant only under high circumferential strain. PMID- 21551019 TI - Long-term effects of kidney donation on renal function and blood pressure in African Americans. AB - BACKGROUND AND OBJECTIVES: African Americans (AAs) have four times higher prevalence of ESRD than Caucasians. Therefore, long-term effects of kidney donation are of considerable importance in this patient population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: GFR was measured by (125)I-iothalamate clearance, 24-hour urine albumin excretion, and 24-hour BP monitoring in 33 AAs and 11 CAs who donated kidneys for transplantation 5 to 23 years previously. RESULTS: Mean GFRs were 76 +/- 13 and 78 +/- 11 ml/min per 1.73 m(2) for AA and CA donors, respectively. Nine percent of the AA donors and none of the CA donors had GFRs below 60 ml/min per 1.73 m(2). AA donors had a tendency for lower prevalence of microalbuminuria compared with CA donors (18.1% versus 36.3%) and a tendency for higher prevalence of macroalbuminuria compared with CAs (12.1% versus 0.0%). Twenty-four percent of the AAs, and 45% of the CAs were hypertensive with mean daytime BP >=135/85 mmHg. Only 6% of AAs had a decrease in mean nocturnal systolic BP of 10% or more as compared with daytime readings. Older age at time of donation was associated (P = 0.046) with lower GFR values compared with younger ages. CONCLUSION: Carefully selected AA kidney donors have well preserved renal function and a low prevalence of hypertension many years after kidney donation. Abnormal albumin excretion and loss of physiologic decrease in nocturnal BP is more prevalent in AA donors than the general AA population. Older age at donation may predict lower GFR after donation. PMID- 21551020 TI - The future nephrology workforce: will there be one? AB - Interest in nephrology as a career is declining and has been on the decline for nearly one decade. From 2002 to 2009, all internal medicine subspecialties except geriatric medicine increased the number of available fellowship positions. However, only two subspecialties attracted fewer United States medical graduates (USMGs) in 2009 than in 2002: geriatric medicine and nephrology. This drop occurred at a time when demand for nephrologists is increasing and when the specialty is having a harder time benefiting from the substantial contribution of international medical graduates (IMGs). Today's USMGs possess fundamentally different career and personal goals from their teachers and mentors. Medical students report receiving minimal exposure to nephrology in clinical rotations, and they perceive that the specialty is too complex, uninteresting, and lacks professional opportunity. Meanwhile, the demographics of kidney disease in the United States, as well as recent national health policy developments, indicate a growing need for nephrologists. Efforts to improve the educational continuum in nephrology and enhance mentorship are essential to restoring interest in nephrology for USMGs, maintaining its appeal among IMGs, and developing a workforce sufficient to meet future demand for renal care. PMID- 21551021 TI - Clinical efficacy and cost-effectiveness of lanthanum carbonate as second-line therapy in hemodialysis patients in Japan. AB - BACKGROUND AND OBJECTIVES: Lanthanum carbonate (LC) is a nonaluminum, noncalcium phosphate binder that is effective for hyperphosphatemia in dialysis patients. However, its efficacy and cost-effectiveness as second-line therapy have not been fully examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We first conducted a multicenter, open-label, 16-week clinical trial to examine the effect of additive LC in 116 hemodialysis patients who had uncontrolled hyperphosphatemia with conventional phosphorus-lowering therapy alone. Based on these clinical data, a state transition model was developed to evaluate the benefits and costs associated with LC as second-line therapy. Reduced risks for cardiovascular morbidity and mortality among patients treated with LC arise through more of the population achieving the target phosphorus levels. Uncertainty was explored through sensitivity analysis. RESULTS: After 16 weeks of additive LC treatment, mean serum phosphorus levels decreased from 7.30 +/- 0.90 to 5.71 +/- 1.32 mg/dl, without significant changes in serum calcium or intact parathyroid hormone levels. A subsequent cost-effectiveness analysis showed that compared with conventional treatment, additive LC incurred an average additional lifetime cost of $22,054 per person and conferred an additional 0.632 quality-adjusted life years (QALYs). This resulted in an incremental cost-effectiveness ratio of $34,896 per QALY gained. Applying a cost-effectiveness threshold of $50,000 per QALY, a probabilistic sensitivity analysis showed that additive LC had a 97.4% probability of being cost-effective compared with conventional treatment. CONCLUSIONS: Our results indicate that the use of LC as second-line therapy would be cost-effective among hemodialysis patients with uncontrolled hyperphosphatemia in Japan. PMID- 21551023 TI - Patterns and prognostic value of total and differential leukocyte count in chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to evaluate the levels and patterns of total and differential leukocyte counts and their prognostic importance in a cohort of people with and without chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 153 veterans without CKD and 267 with, blood leukocyte count was measured at baseline and then repeatedly over a decade. The patterns of change in leukocyte count between the two groups were compared. In the CKD cohort, the spikes in leukocyte counts were compared to the combined endpoint of ESRD and death. RESULTS: Patients with CKD had more granulocytes and eosinophils and fewer lymphocytes. Over time, granulocytes increased and lymphocytes decreased in those with and without CKD. In addition, in those with CKD, over time eosinophils fell and monocytes increased. Compared with their non-CKD counterparts, patients with CKD had between 1.5- and 3.0-fold more spikes in leukocyte counts. Independent risk factors for the combined endpoint were associated with spikes in the leukocyte counts of absolute and percent eosinophil count, percent granulocyte, and percent monocyte counts. In a multivariate adjusted joint model, both granulocyte and monocyte spikes were independently associated with ESRD and death (hazard ratio 1.67 and 1.52 respectively, P < 0.05). CONCLUSIONS: Compared with those without CKD, patients with CKD have more eosinophils and granulocytes and fewer lymphocytes. Greater variation in leukocytes is seen. Spikes in granulocyte and monocyte percentages among patients with CKD are of independent prognostic importance. PMID- 21551022 TI - Inflammatory markers and risk of cerebrovascular events in patients initiating dialysis. AB - BACKGROUND AND OBJECTIVES: Stroke remains a leading cause of morbidity and mortality for patients on dialysis; however, its risk factors in this population and measures to prevent it are not well understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We investigated whether inflammation was associated with cerebrovascular events in a national US cohort of 1041 incident dialysis patients enrolled from October 1995 to June 1998 and followed until January 31, 2004. Incident cerebrovascular events were defined as nonfatal (hospitalized stroke, carotid endarterectomy) and fatal (stroke death) events after dialysis initiation. With Cox proportional hazards regression analysis accounting for the competing risk of nonstroke death, we assessed the independent event risk associated with baseline levels of multiple inflammatory markers (high sensitivity C-reactive protein [hsCRP], interleukin-6 (IL-6), matrix metalloproteinase-3 [MMP-3], and P-selectin) and hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) use, which may have pleiotropic inflammatory effects. RESULTS: 165 patients experienced a cerebrovascular event during 3548 person-years of follow-up; overall incidence rate was 4.9/100 person years. None of the inflammatory markers were associated with cerebrovascular event risk (adjusted hazard ratios [HRs] per log unit [95% confidence interval]: hsCRP, 0.97 [0.85 to 1.11]; IL-6, 1.04 [0.85 to 1.26]; MMP-3, 1.02 [0.70 to 1.48]; P-selectin, 0.98 [0.57 to 1.68]). Statin use was also not associated with significant risk of events in unadjusted (HR 1.07 [0.69 to 1.68]) or propensity score adjusted analyses (HR 0.98 [0.61 to 1.56]). CONCLUSIONS: In conclusion, neither inflammatory markers nor statin use was associated with risk of cerebrovascular events. Further studies are needed to understand the pathophysiology and prevention of stroke in patients on dialysis. PMID- 21551024 TI - Paradoxical embolism after declotting of hemodialysis fistulae/grafts in patients with patent foramen ovale. AB - BACKGROUND AND OBJECTIVES: The safety of percutaneous endovascular declotting procedures for thrombosed hemodialysis fistulae/grafts is well described in the general population; however, its safety in the presence of a patent foramen ovale (PFO) is not known. The objective of this study is to assess the incidence of symptomatic paradoxical embolic events associated with declotting procedure of thrombosed arteriovenous (AV) graft or fistula in patients with documented PFO. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective study in a hospital-based, academic practice. It included 23 patients (10 men; mean age, 65) with PFO and thrombosed hemodialysis graft/fistula who underwent a standardized declotting procedure with 2 mg of Alteplase and balloon thrombectomy. Twenty patients (87%) had AV grafts, and three (13%) had AV fistulae. The PFO shunt was right to left in two (9%), left to right in eight (34%), and bidirectional in ten (44%). The shunt direction was not specified in three patients (13%). The technical success of the declotting procedure and the frequency of clinically manifested paradoxical embolic events in this patient population were calculated. RESULTS: Fifty declotting procedures were performed on 23 patients with a technical success rate of 96% (48 of 50, 96%). No symptomatic paradoxical embolic events were found in any of the 23 patients with PFO. CONCLUSIONS: Symptomatic paradoxical embolic events after percutaneous endovascular declotting procedures of thrombosed AV grafts and fistulae in patients with documented PFO are rare. This procedure appears to be safe in patients with a PFO. PMID- 21551025 TI - Prevalence and demographic and clinical associations of health literacy in patients on maintenance hemodialysis. AB - BACKGROUND AND OBJECTIVES: Although limited health literacy is estimated to affect over 90 million Americans and is recognized as an important public health concern, there have been few studies examining this issue in patients with chronic kidney disease. We sought to characterize the prevalence of and associations of demographic and clinical characteristics with limited health literacy in patients receiving maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: As part of a prospective clinical trial of symptom management strategies in 288 patients treated with chronic hemodialysis, we assessed health literacy using the Rapid Estimate of Adult Literacy in Medicine (REALM). We defined limited health literacy as a REALM score <=60 and evaluated independent associations of demographic and baseline clinical characteristics with limited health literacy using multivariable logistic regression. RESULTS: Of the 260 patients who completed the REALM, 41 demonstrated limited health literacy. African-American race, lower educational level, and veteran status were independently associated with limited health literacy. There was no association of limited health literacy with age, gender, serologic values, dialysis adequacy, overall symptom burden, quality of life, or depression. CONCLUSIONS: Limited health literacy is common among patients receiving chronic hemodialysis. African American race and socioeconomic factors are strong independent predictors of limited health literacy. These findings can help inform the design and implementation of interventions to improve health literacy in the hemodialysis population. PMID- 21551027 TI - Transitional gene expression profiling in ovarian follicle during ovulation in normal-cycle rats. AB - Evaluation of ovarian toxicity requires an understanding of the physiological changes related to the estrous cycle in the ovary. The authors investigated the transitional gene expression profile of ovulatory follicles in rats that show normal estrous cyclicity. Ovaries were collected at 10:00 and 22:00 on the proestrus day and at 10:00 on the estrus day. Ovarian follicles or early corpora lutea were isolated using laser microdissection, and extracted total RNA was analyzed using microarray technology. Clustering analysis revealed four different expression patterns: transient up- or down-regulation only at 22:00 on the proestrus day (pattern 1), up- or down-regulation only at 10:00 on the estrus day (pattern 2), continuous increase at 22:00 on the proestrus day and at 10:00 on the estrus day (pattern 3), and up- or down-regulation at 22:00 on the proestrus day and level maintenance at 10:00 on the estrus day (pattern 4). In addition, these probe sets were functionally categorized in each pattern using the Ingenuity Pathways Analysis database. These data will aid in understanding the physiology of ovulation and may be useful in assessing ovarian toxicity and its mechanism, such as in investigations of chemical-induced ovulatory impairment. PMID- 21551026 TI - Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease. AB - BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) patients have an increased risk for intracranial aneurysms (IAs). The importance of screening for unruptured IAs (UIAs) depends on their risks for growth and rupture. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: ADPKD patients with UIAs found by presymptomatic screening with magnetic resonance angiography (MRA) during 1989 to 2009 were followed initially at 6 months and annually, and less frequently after demonstration of stability. RESULTS: Forty-five saccular aneurysms were detected in 38 patients from 36 families. Most were small (median diameter 3.5 mm) and in the anterior circulation (84%). Median age at diagnosis was 49 years. During cumulative imaging follow-up of 243 years, one de novo UIA was detected and increased in size from 2 to 4.4 mm over 144 months and two UIAs grew from 4.5 to 5.9 mm and 4.7 to 6.2 mm after 69 and 184 months, respectively. Seven patients did not have imaging follow-up. No change was detected in the remaining 28 patients. During cumulative clinical follow-up of 316 years, no aneurysm ruptured. Five patients died from unrelated causes and two were lost to follow-up after 8 and 120 months. Three patients underwent surgical clipping. CONCLUSIONS: Most UIAs detected by presymptomatic screening in ADPKD patients are small and in the anterior circulation. Growth and rupture risks are not higher than those of UIAs in the general population. These data support very selective screening for UIAs in ADPKD patients, and widespread screening is not indicated. PMID- 21551028 TI - Characterization of xenobiotic-induced hepatocellular enzyme induction in rats: anticipated thyroid effects and unique pituitary gland findings. AB - During routine safety evaluation of RO2910, a non-nucleoside reverse transcriptase inhibitor for HIV infection, histopathology findings concurrent with robust hepatocellular induction occurred in multiple organs, including a unique, albeit related, finding in the pituitary gland. For fourteen days, male and female rats were administered, by oral gavage vehicle, 100, 300, or 1000 mg/kg/day of RO2910. Treated groups had elevated serum thyroid-stimulating hormone and decreased total thyroxine, and hypertrophy in the liver, thyroid gland, and pituitary pars distalis. These were considered consequences of hepatocellular induction and often were dose dependent and more pronounced in males than in females. Hepatocellular centrilobular hypertrophy corresponded with increased expression of cytochrome P450s 2B1/2, 3A1, and 3A2 and UGT 2B1. Bilateral thyroid follicular cell hypertrophy occurred concurrent to increased mitotic activity and sometimes colloid depletion, which were attributed to changes in thyroid hormone levels. Males had hypertrophy of thyroid-stimulating hormone-producing cells (thyrotrophs) in the pituitary pars distalis. All findings were consistent with the well-established adaptive physiologic response of rodents to xenobiotic-induced hepatocellular microsomal enzyme induction. Although the effects on the pituitary gland following hepatic enzyme induction mediated hypothyroidism have not been reported previously, other models of stress and thyroid depletion leading to pituitary stimulation support such a shared pathogenesis. PMID- 21551029 TI - Realizing all-spin-based logic operations atom by atom. AB - An ultimate goal of spintronic research is the realization of concepts for atomic scale all-spin-based devices. We combined bottom-up atomic fabrication with spin resolved scanning tunneling microscopy to construct and read out atomic-scale model systems performing logic operations. Our concept uses substrate-mediated indirect exchange coupling to achieve logical interconnection between individual atomic spins. Combined with spin frustration, this concept enables various logical operations between inputs, such as NOT and OR. PMID- 21551030 TI - Climate trends and global crop production since 1980. AB - Efforts to anticipate how climate change will affect future food availability can benefit from understanding the impacts of changes to date. We found that in the cropping regions and growing seasons of most countries, with the important exception of the United States, temperature trends from 1980 to 2008 exceeded one standard deviation of historic year-to-year variability. Models that link yields of the four largest commodity crops to weather indicate that global maize and wheat production declined by 3.8 and 5.5%, respectively, relative to a counterfactual without climate trends. For soybeans and rice, winners and losers largely balanced out. Climate trends were large enough in some countries to offset a significant portion of the increases in average yields that arose from technology, carbon dioxide fertilization, and other factors. PMID- 21551032 TI - Deciphering the rhizosphere microbiome for disease-suppressive bacteria. AB - Disease-suppressive soils are exceptional ecosystems in which crop plants suffer less from specific soil-borne pathogens than expected owing to the activities of other soil microorganisms. For most disease-suppressive soils, the microbes and mechanisms involved in pathogen control are unknown. By coupling PhyloChip-based metagenomics of the rhizosphere microbiome with culture-dependent functional analyses, we identified key bacterial taxa and genes involved in suppression of a fungal root pathogen. More than 33,000 bacterial and archaeal species were detected, with Proteobacteria, Firmicutes, and Actinobacteria consistently associated with disease suppression. Members of the gamma-Proteobacteria were shown to have disease-suppressive activity governed by nonribosomal peptide synthetases. Our data indicate that upon attack by a fungal root pathogen, plants can exploit microbial consortia from soil for protection against infections. PMID- 21551033 TI - Indigenous genomics. PMID- 21551038 TI - Demography. China's population growing slowly, changing fast. PMID- 21551031 TI - The Selaginella genome identifies genetic changes associated with the evolution of vascular plants. AB - Vascular plants appeared ~410 million years ago, then diverged into several lineages of which only two survive: the euphyllophytes (ferns and seed plants) and the lycophytes. We report here the genome sequence of the lycophyte Selaginella moellendorffii (Selaginella), the first nonseed vascular plant genome reported. By comparing gene content in evolutionarily diverse taxa, we found that the transition from a gametophyte- to a sporophyte-dominated life cycle required far fewer new genes than the transition from a nonseed vascular to a flowering plant, whereas secondary metabolic genes expanded extensively and in parallel in the lycophyte and angiosperm lineages. Selaginella differs in posttranscriptional gene regulation, including small RNA regulation of repetitive elements, an absence of the trans-acting small interfering RNA pathway, and extensive RNA editing of organellar genes. PMID- 21551039 TI - Stem cells. NIH wins in appeals court, but legal battle continues. PMID- 21551040 TI - Biotechnology. EPA proposal would exempt some GMOs from registry. PMID- 21551041 TI - Addiction research. Anonymous alcoholic bankrolls trial of controversial therapy. PMID- 21551042 TI - Literary criticism. Red in tooth and claw among the literati. PMID- 21551043 TI - Profile: Jin Huiqing. Car-crash epidemiologist pushes systemic attack on bad driving. PMID- 21551044 TI - Profile: Zenobia Jacobs and Richard Roberts. New light on ancient samples. PMID- 21551045 TI - Profile: Zenobia Jacobs and Richard Roberts. Dating duo illuminates modern humans' journey. PMID- 21551046 TI - New university plan skips crucial steps. PMID- 21551047 TI - An unexpected spotlight. PMID- 21551048 TI - Symmetrical transparency in science. PMID- 21551049 TI - Bringing research into the classroom. PMID- 21551050 TI - Agriculture. Transforming U.S. agriculture. PMID- 21551051 TI - Astronomy. Twisted disks. PMID- 21551052 TI - Cell biology. Ancient neurons regulate immunity. PMID- 21551053 TI - Chemistry. Designing the next generation of chemical separation membranes. PMID- 21551054 TI - Applied physics. Hot electrons cross boundaries. PMID- 21551055 TI - Immunology. Flow cytometry, amped up. PMID- 21551056 TI - Retrospective. Jurg Tschopp (1951-2011). PMID- 21551057 TI - Scaffold proteins: hubs for controlling the flow of cellular information. AB - The spatial and temporal organization of molecules within a cell is critical for coordinating the many distinct activities carried out by the cell. In an increasing number of biological signaling processes, scaffold proteins have been found to play a central role in physically assembling the relevant molecular components. Although most scaffolds use a simple tethering mechanism to increase the efficiency of interaction between individual partner molecules, these proteins can also exert complex allosteric control over their partners and are themselves the target of regulation. Scaffold proteins offer a simple, flexible strategy for regulating selectivity in pathways, shaping output behaviors, and achieving new responses from preexisting signaling components. As a result, scaffold proteins have been exploited by evolution, pathogens, and cellular engineers to reshape cellular behavior. PMID- 21551059 TI - Photodetection with active optical antennas. AB - Nanoantennas are key optical components for light harvesting; photodiodes convert light into a current of electrons for photodetection. We show that these two distinct, independent functions can be combined into the same structure. Photons coupled into a metallic nanoantenna excite resonant plasmons, which decay into energetic, "hot" electrons injected over a potential barrier at the nanoantenna semiconductor interface, resulting in a photocurrent. This dual-function structure is a highly compact, wavelength-resonant, and polarization-specific light detector, with a spectral response extending to energies well below the semiconductor band edge. PMID- 21551058 TI - Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. AB - Flow cytometry is an essential tool for dissecting the functional complexity of hematopoiesis. We used single-cell "mass cytometry" to examine healthy human bone marrow, measuring 34 parameters simultaneously in single cells (binding of 31 antibodies, viability, DNA content, and relative cell size). The signaling behavior of cell subsets spanning a defined hematopoietic hierarchy was monitored with 18 simultaneous markers of functional signaling states perturbed by a set of ex vivo stimuli and inhibitors. The data set allowed for an algorithmically driven assembly of related cell types defined by surface antigen expression, providing a superimposable map of cell signaling responses in combination with drug inhibition. Visualized in this manner, the analysis revealed previously unappreciated instances of both precise signaling responses that were bounded within conventionally defined cell subsets and more continuous phosphorylation responses that crossed cell population boundaries in unexpected manners yet tracked closely with cellular phenotype. Collectively, such single-cell analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention. PMID- 21551060 TI - Single-cell genomics reveals organismal interactions in uncultivated marine protists. AB - Whole-genome shotgun sequence data from three individual cells isolated from seawater, followed by analysis of ribosomal DNA, indicated that the cells represented three divergent clades of picobiliphytes. In contrast with the recent description of this phylum, we found no evidence of plastid DNA nor of nuclear encoded plastid-targeted proteins, which suggests that these picobiliphytes are heterotrophs. Genome data from one cell were dominated by sequences from a widespread single-stranded DNA virus. This virus was absent from the other two cells, both of which contained non-eukaryote DNA derived from marine Bacteroidetes and large DNA viruses. By using shotgun sequencing of uncultured marine picobiliphytes, we revealed the distinct interactions of individual cells. PMID- 21551061 TI - A family of IFN-gamma-inducible 65-kD GTPases protects against bacterial infection. AB - Immune interferon gamma (IFN-gamma) is essential for mammalian host defense against intracellular pathogens. IFN-gamma induces nearly 2000 host genes, yet few have any assigned function. Here, we examined a complete mouse 65-kilodalton (kD) guanylate-binding protein (Gbp) gene family as part of a 43-member IFN-gamma inducible guanosine triphosphatase (GTPase) superfamily in mouse and human genomes. Family-wide loss-of-function analysis found that at least four Gbps- Gbp1, Gbp6, Gbp7, and Gbp10--conferred cell-autonomous immunity to listerial or mycobacterial infection within macrophages and gene-deficient animals. These Gbps solicited host defense proteins, including the phagocyte oxidase, antimicrobial peptides, and autophagy effectors, to kill intracellular bacteria. Thus, specific 65-kD Gbps coordinate a potent oxidative and vesicular trafficking program to protect the host from infection. PMID- 21551062 TI - Normalization for sparse encoding of odors by a wide-field interneuron. AB - Sparse coding presents practical advantages for sensory representations and memory storage. In the insect olfactory system, the representation of general odors is dense in the antennal lobes but sparse in the mushroom bodies, only one synapse downstream. In locusts, this transformation relies on the oscillatory structure of antennal lobe output, feed-forward inhibitory circuits, intrinsic properties of mushroom body neurons, and connectivity between antennal lobe and mushroom bodies. Here we show the existence of a normalizing negative-feedback loop within the mushroom body to maintain sparse output over a wide range of input conditions. This loop consists of an identifiable "giant" nonspiking inhibitory interneuron with ubiquitous connectivity and graded release properties. PMID- 21551063 TI - Relationship between clinical signs and transmission of an infectious disease and the implications for control. AB - Control of many infectious diseases relies on the detection of clinical cases and the isolation, removal, or treatment of cases and their contacts. The success of such "reactive" strategies is influenced by the fraction of transmission occurring before signs appear. We performed experimental studies of foot-and mouth disease transmission in cattle and estimated this fraction at less than half the value expected from detecting virus in body fluids, the standard proxy measure of infectiousness. This is because the infectious period is shorter (mean 1.7 days) than currently realized, and animals are not infectious until, on average, 0.5 days after clinical signs appear. These results imply that controversial preemptive control measures may be unnecessary; instead, efforts should be directed at early detection of infection and rapid intervention. PMID- 21551064 TI - Transient activation of the HOG MAPK pathway regulates bimodal gene expression. AB - Mitogen-activated protein kinase (MAPK) cascades are conserved signaling modules that control many cellular processes by integrating intra- and extracellular cues. The p38/Hog1 MAPK is transiently activated in response to osmotic stress, leading to rapid translocation into the nucleus and induction of a specific transcriptional program. When investigating the dynamic interplay between Hog1 activation and Hog1-driven gene expression, we found that Hog1 activation increases linearly with stimulus, whereas the transcriptional output is bimodal. Modeling predictions, corroborated by single-cell experiments, established that a slow stochastic transition from a repressed to an activated transcriptional state in conjunction with transient Hog1 activation generates this behavior. Together, these findings provide a molecular mechanism by which a cell can impose a transcriptional threshold in response to a linear signaling behavior. PMID- 21551065 TI - The LRRK2-related Roco kinase Roco2 is regulated by Rab1A and controls the actin cytoskeleton. AB - We identify a new pathway that is required for proper pseudopod formation. We show that Roco2, a leucine-rich repeat kinase 2 (LRRK2)-related Roco kinase, is activated in response to chemoattractant stimulation and helps mediate cell polarization and chemotaxis by regulating cortical F-actin polymerization and pseudopod extension in a pathway that requires Rab1A. We found that Roco2 binds the small GTPase Rab1A as well as the F-actin cross-linking protein filamin (actin-binding protein 120, abp120) in vivo. We show that active Rab1A (Rab1A GTP) is required for and regulates Roco2 kinase activity in vivo and that filamin lies downstream from Roco2 and controls pseudopod extension during chemotaxis and random cell motility. Therefore our study uncovered a new signaling pathway that involves Rab1A and controls the actin cytoskeleton and pseudopod extension, and thereby, cell polarity and motility. These findings also may have implications in the regulation of other Roco kinases, including possibly LRRK2, in metazoans. PMID- 21551066 TI - Regulation of Greatwall kinase during Xenopus oocyte maturation. AB - Greatwall kinase has been identified as a key element in M phase initiation and maintenance in Drosophila, Xenopus oocytes/eggs, and mammalian cells. In M phase, Greatwall phosphorylates endosulfine and related proteins that bind to and inhibit protein phosphatase 2A/B55, the principal phosphatase for Cdk phosphorylated substrates. We show that Greatwall binds active PP2A/B55 in G2 phase oocytes but dissociates from it when progesterone-treated oocytes reach M phase. This dissociation does not require Greatwall kinase activity or phosphorylation at T748 in the presumptive T loop of the kinase. A mutant K71M Greatwall, also known as Scant in Drosophila, induces M phase in the absence of progesterone when expressed in oocytes, despite its reduced stability and elevated degradation by the proteasome. M phase induction by Scant Greatwall requires protein synthesis but is not associated with altered binding or release of PP2A/B55 as compared to wild-type Greatwall. However, in vitro studies with Greatwall proteins purified from interphase cells indicate that Scant, but not wild-type Greatwall, has low but detectable activity against endosulfine. These results demonstrate progesterone-dependent regulation of the PP2A/B55-Greatwall interaction during oocyte maturation and suggest that the cognate Scant Greatwall mutation has sufficient constitutive kinase activity to promote M phase in Xenopus oocytes. PMID- 21551067 TI - Exposed hydrophobicity is a key determinant of nuclear quality control degradation. AB - Protein quality control (PQC) degradation protects the cell by preventing the toxic accumulation of misfolded proteins. In eukaryotes, PQC degradation is primarily achieved by ubiquitin ligases that attach ubiquitin to misfolded proteins for proteasome degradation. To function effectively, PQC ubiquitin ligases must distinguish misfolded proteins from their normal counterparts by recognizing an attribute of structural abnormality commonly shared among misfolded proteins. However, the nature of the structurally abnormal feature recognized by most PQC ubiquitin ligases is unknown. Here we demonstrate that the yeast nuclear PQC ubiquitin ligase San1 recognizes exposed hydrophobicity in its substrates. San1 recognition is triggered by exposure of as few as five contiguous hydrophobic residues, which defines the minimum window of hydrophobicity required for San1 targeting. We also find that the exposed hydrophobicity recognized by San1 can cause aggregation and cellular toxicity, underscoring the fundamental protective role for San1-mediated PQC degradation of misfolded nuclear proteins. PMID- 21551068 TI - Signal sequence-independent SRP-SR complex formation at the membrane suggests an alternative targeting pathway within the SRP cycle. AB - Protein targeting by the signal recognition particle (SRP) and the bacterial SRP receptor FtsY requires a series of closely coordinated steps that monitor the presence of a substrate, the membrane, and a vacant translocon. Although the influence of substrate binding on FtsY-SRP complex formation is well documented, the contribution of the membrane is largely unknown. In the current study, we found that negatively charged phospholipids stimulate FtsY-SRP complex formation. Phospholipids act on a conserved positively charged amphipathic helix in FtsY and induce a conformational change that strongly enhances the FtsY-lipid interaction. This membrane-bound, signal sequence-independent FtsY-SRP complex is able to recruit RNCs to the membrane and to transfer them to the Sec translocon. Significantly, the same results were also observed with an artificial FtsY-SRP fusion protein, which was tethered to the membrane via a transmembrane domain. This indicates that substrate recognition by a soluble SRP is not essential for cotranslational targeting in Escherichia coli. Our findings reveal a remarkable flexibility of SRP-dependent protein targeting, as they indicate that substrate recognition can occur either in the cytosol via ribosome-bound SRP or at the membrane via a preassembled FtsY-SRP complex. PMID- 21551069 TI - Sequential assembly of translesion DNA polymerases at UV-induced DNA damage sites. AB - In response to DNA damage such as from UV irradiation, mammalian Y-family translesion synthesis (TLS) polymerases Poleta and Rev1 colocalize with proliferating cell nuclear antigen at nuclear foci, presumably representing stalled replication sites. However, it is unclear whether the localization of one polymerase is dependent on another. Furthermore, there is no report on the in vivo characterization of the Rev3 catalytic subunit of the B-family TLS polymerase Polzeta. Here we describe the detection of endogenous human Poleta, Rev1, and Rev3 by immunocytochemistry using existing or newly created antibodies, as well as various means of inhibiting their expression, which allows us to examine the dynamics of endogenous TLS polymerases in response to UV irradiation. It is found that Rev1 and Poleta are independently recruited to the nuclear foci, whereas the Rev3 nuclear focus formation requires Rev1 but not Poleta. In contrast, neither Rev1 nor Poleta recruitment requires Rev3. To further support these conclusions, we find that simultaneous suppression of Poleta and Rev3 results in an additive cellular sensitivity to UV irradiation. These observations suggest a cooperative and sequential assembly of TLS polymerases in response to DNA damage. They also support and extend the current polymerase switch model. PMID- 21551070 TI - Focal adhesion kinase protein regulates Wnt3a gene expression to control cell fate specification in the developing neural plate. AB - Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase protein localized to regions called focal adhesions, which are contact points between cells and the extracellular matrix. FAK protein acts as a scaffold to transfer adhesion dependent and growth factor signals into the cell. Increased FAK expression is linked to aggressive metastatic and invasive tumors. However, little is known about its normal embryonic function. FAK protein knockdown during early Xenopus laevis development anteriorizes the embryo. Morphant embryos express increased levels of anterior neural markers, with reciprocally reduced posterior neural marker expression. Posterior neural plate folding and convergence-extension is also inhibited. This anteriorized phenotype resembles that of embryos knocked down zygotically for canonical Wnt signaling. FAK and Wnt3a genes are both expressed in the neural plate, and Wnt3a expression is FAK dependent. Ectopic Wnt expression rescues this FAK morphant anteriorized phenotype. Wnt3a thus acts downstream of FAK to balance anterior-posterior cell fate specification in the developing neural plate. Wnt3a gene expression is also FAK dependent in human breast cancer cells, suggesting that this FAK-Wnt linkage is highly conserved. This unique observation connects the FAK- and Wnt-signaling pathways, both of which act to promote cancer when aberrantly activated in mammalian cells. PMID- 21551071 TI - Release mode of large and small dense-core vesicles specified by different synaptotagmin isoforms in PC12 cells. AB - Many cells release multiple substances in different proportions according to the specific character of a stimulus. PC12 cells, a model neuroendocrine cell line, express multiple isoforms of the exocytotic Ca(2+) sensor synaptotagmin. We show that these isoforms sort to populations of dense-core vesicles that differ in size. These synaptotagmins differ in their Ca(2+) sensitivities, their preference for full fusion or kiss-and-run, and their sensitivity to inhibition by synaptotagmin IV. In PC12 cells, vesicles that harbor these different synaptotagmin isoforms can be preferentially triggered to fuse by different forms of stimulation. The mode of fusion is specified by the synaptotagmin isoform activated, and because kiss-and-run exocytosis can filter small molecules through a size-limiting fusion pore, the activation of isoforms that favor kiss-and-run will select smaller molecules over larger molecules packaged in the same vesicle. Thus synaptotagmin isoforms can provide multiple levels of control in the release of different molecules from the same cell. PMID- 21551072 TI - The two actin-interacting protein 1 genes have overlapping and essential function for embryonic development in Caenorhabditis elegans. AB - Disassembly of actin filaments by actin-depolymerizing factor (ADF)/cofilin and actin-interacting protein 1 (AIP1) is a conserved mechanism to promote reorganization of the actin cytoskeleton. We previously reported that unc-78, an AIP1 gene in the nematode Caenorhabditis elegans, is required for organized assembly of sarcomeric actin filaments in the body wall muscle. unc-78 functions in larval and adult muscle, and an unc-78-null mutant is homozygous viable and shows only weak phenotypes in embryos. Here we report that a second AIP1 gene, aipl-1 (AIP1-like gene-1), has overlapping function with unc-78, and that depletion of the two AIP1 isoforms causes embryonic lethality. A single aipl-1 null mutation did not cause a detectable phenotype. However, depletion of both unc-78 and aipl-1 arrested development at late embryonic stages due to severe disorganization of sarcomeric actin filaments in body wall muscle. In vitro, both AIPL-1 and UNC-78 preferentially cooperated with UNC-60B, a muscle-specific ADF/cofilin isoform, in actin filament disassembly but not with UNC-60A, a nonmuscle ADF/cofilin. AIPL-1 is expressed in embryonic muscle, and forced expression of AIPL-1 in adult muscle compensated for the function of UNC-78. Thus our results suggest that enhancement of actin filament disassembly by ADF/cofilin and AIP1 proteins is critical for embryogenesis. PMID- 21551074 TI - Regulation of dendritic spine growth through activity-dependent recruitment of the brain-enriched Na+/H+ exchanger NHE5. AB - Subtle changes in cellular and extracellular pH within the physiological range have profound impacts on synaptic activities. However, the molecular mechanisms underlying local pH regulation at synapses and their influence on synaptic structures have not been elucidated. Dendritic spines undergo dynamic structural changes in response to neuronal activation, which contributes to induction and long-term maintenance of synaptic plasticity. Although previous studies have indicated the importance of cytoskeletal rearrangement, vesicular trafficking, cell signaling, and adhesion in this process, much less is known about the involvement of ion transporters. In this study we demonstrate that N-methyl-D aspartate (NMDA) receptor activation causes recruitment of the brain-enriched Na(+)/H(+) exchanger NHE5 from endosomes to the plasma membrane. Concomitantly, real-time imaging of green fluorescent protein-tagged NHE5 revealed that NMDA receptor activation triggers redistribution of NHE5 to the spine head. We further show that neuronal activation causes alkalinization of dendritic spines following the initial acidification, and suppression of NHE5 significantly retards the activity-induced alkalinization. Perturbation of NHE5 function induces spontaneous spine growth, which is reversed by inhibition of NMDA receptors. In contrast, overexpression of NHE5 inhibits spine growth in response to neuronal activity. We propose that NHE5 constrains activity-dependent dendritic spine growth via a novel, pH-based negative-feedback mechanism. PMID- 21551073 TI - The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells. AB - Previous studies using in vitro cell culture systems have shown the role of the dynamin-related GTPase Opa1 in apoptosis prevention and mitochondrial DNA (mtDNA) maintenance. However, it remains to be tested whether these functions of Opa1 are physiologically important in vivo in mammals. Here, using the Cre-loxP system, we deleted mouse Opa1 in pancreatic beta cells, in which glucose-stimulated ATP production in mitochondria plays a key role in insulin secretion. Beta cells lacking Opa1 maintained normal copy numbers of mtDNA; however, the amount and activity of electron transport chain complex IV were significantly decreased, leading to impaired glucose-stimulated ATP production and insulin secretion. In addition, in Opa1-null beta cells, cell proliferation was impaired, whereas apoptosis was not promoted. Consequently, mice lacking Opa1 in beta cells develop hyperglycemia. The data suggest that the function of Opa1 in the maintenance of the electron transport chain is physiologically relevant in beta cells. PMID- 21551076 TI - Which comes first in fragile X syndrome, dendritic spine dysgenesis or defects in circuit plasticity? AB - The salient neuropathological defect in fragile X syndrome is the overabundance of immature dendritic spines in cortical pyramidal neurons. This review examines this anatomical synaptic defect in the context of other alterations in synaptic and circuit plasticity in fragile X mice. In theory, abnormal spines could lead to dysfunctional circuits and vice versa, so it is still not clear which problem comes first. Because of the tight structure-function relationships at the synapse, and given the significant overlap between signaling pathways that regulate spine shape/dynamics and long-term synaptic plasticity (both of which involve proteins regulated by fragile X mental retardation protein [FMRP]), it is argued that the two defects cannot be separated. It will be critical to determine whether neurons that lack FMRP and demonstrate alterations in long-term potentiation/depression also fail to undergo the expected enlargement/shrinkage of dendritic spines associated with those forms of synaptic plasticity or to establish clear links from FMRP signaling to either spine instability or defective synaptic plasticity, especially during critical periods of brain development. The resulting data will be vital in guiding translational research that can identify novel molecular targets for therapy in this devastating disorder. PMID- 21551075 TI - Glioblastoma motility occurs in the absence of actin polymer. AB - In fibroblasts and keratocytes, motility is actin dependent, while microtubules play a secondary role, providing directional guidance. We demonstrate here that the motility of glioblastoma cells is exceptional, in that it occurs in cells depleted of assembled actin. Cells display persistent motility in the presence of actin inhibitors at concentrations sufficient to fully disassemble actin. Such actin independent motility is characterized by the extension of cell protrusions containing abundant microtubule polymers. Strikingly, glioblastoma cells exhibit no motility in the presence of microtubule inhibitors, at concentrations that disassemble labile microtubule polymers. In accord with an unconventional mode of motility, glioblastoma cells have some unusual requirements for the Rho GTPases. While Rac1 is required for lamellipodial protrusions in fibroblasts, expression of dominant negative Rac1 does not suppress glioblastoma migration. Other GTPase mutants are largely without unique effect, except dominant positive Rac1-Q61L, and rapidly cycling Rac1-F28L, which substantially suppress glioblastoma motility. We conclude that glioblastoma cells display an unprecedented mode of intrinsic motility that can occur in the absence of actin polymer, and that appears to require polymerized microtubules. PMID- 21551079 TI - China's success in increasing per capita food production. AB - China has to feed 20% of the global population with only about 5% of the planet's water resources and 7% of its arable land. With such limited natural conditions, however, China's grain production has increased from about 200 kg per capita in 1949 to about 400 kg in the early 1990s. Hunger as a social problem has largely disappeared after being prevalent in China for several thousand years with the rise and decline of dynasties. This achievement has been accompanied by a 2.5 fold increase in the population and a 4.5-fold increase in total grain production. Although total cropped land has increased slightly in some areas, land used for cropping has decreased from 0.18 hectare per capita in the 1950s to less than 0.1 hectare per capita today. Apparently, yield increase or improved land productivity is the major contributor to the increase of food production per capita. What are the major reasons for the unprecedented achievement in China's food production? Political decisions, good or bad, on land distribution and ownership changes, have caused unusual fluctuation in grain production. Technical progress, however, has maintained a long-term increasing trend. The semi-dwarf cultivars of rice and wheat, the use of heterosis in rice and maize, and the alleviation of salinized soil stress in the major grain-producing areas have all played significant roles in increasing China's food production capability. PMID- 21551078 TI - Rubisco mutagenesis provides new insight into limitations on photosynthesis and growth in Synechocystis PCC6803. AB - Orthophosphate (Pi) stimulates the activation of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) while paradoxically inhibiting its catalysis. Of three Pi-binding sites, the roles of the 5P- and latch sites have been documented, whereas that of the 1P-site remained unclear. Conserved residues at the 1P-site of Rubisco from the cyanobacterium Synechocystis PCC6803 were substituted and the kinetic properties of the enzyme derivatives and effects on cell photosynthesis and growth were examined. While Pi-stimulated Rubisco activation diminished for enzyme mutants T65A/S and G404A, inhibition of catalysis by Pi remained unchanged. Together with previous studies, the results suggest that all three Pi-binding sites are involved in stimulation of Rubisco activation, whereas only the 5P-site is involved in inhibition of catalysis. While all the mutations reduced the catalytic turnover of Rubisco (K(cat)) between 6- and 20-fold, the photosynthesis and growth rates under saturating irradiance and inorganic carbon (Ci) concentrations were only reduced 40-50% (in the T65A/S mutants) or not at all (G404A mutant). Analysis of the mutant cells revealed a 3-fold increase in Rubisco content that partially compensated for the reduced K(cat) so that the carboxylation rate per chlorophyll was one-third of that in the wild type. Correlation between the kinetic properties of Rubisco and the photosynthetic rate (P(max)) under saturating irradiance and Ci concentrations indicate that a >60% reduction in K(cat) can be tolerated before P(max) in Synechocystsis PCC6803 is affected. These results indicate that the limitation of Rubisco activity on the rate of photosynthesis in Synechocystis is low. Determination of Calvin cycle metabolites revealed that unlike in higher plants, cyanobacterial photosynthesis is constrained by phosphoglycerate reduction probably due to limitation of ATP or NADPH. PMID- 21551077 TI - In utero electroporation as a tool for genetic manipulation in vivo to study psychiatric disorders: from genes to circuits and behaviors. AB - Many genetic risk factors for major mental disorders have key roles in brain development. Thus, exploring the roles for these genetic factors for brain development at the molecular, cellular, and neuronal circuit level is crucial for discovering how genetic disturbances affect high brain functions, which ultimately lead to disease pathologies. However, it is a tremendously difficult task, given that most mental disorders have genetic complexities in which many genetic risk factors have multiple roles in different cell types and brain regions over a time-course dependent manner. Furthermore, some genetic risk factors are likely to act epistatically in common molecular pathways. For this reason, a technique for spatial and temporal manipulation of multiple genes is necessary for understanding how genetic disturbances contribute to disease etiology. Here, the authors will review the said technique, in utero electroporation, which investigates the molecular disease pathways in rodent models for major mental disorders. This technique is also useful to examine the effect of genetic risks at the behavioral level. Furthermore, the authors will discuss the recent progress of this technology, such as inducible and cell type specific targeting, as well as nonepisomal genetic manipulation, which provide further availability of this technique for research on major mental disorders. PMID- 21551080 TI - Urinary screening for renal disease among apparently healthy school children in Qatar. PMID- 21551081 TI - The challenge of modeling human acute respiratory distress syndrome: a new model of lung injury due to sepsis with impaired alveolar edema fluid removal. PMID- 21551082 TI - Ankle--brachial index, vascular calcifications and mortality in dialysis patients. AB - BACKGROUND: The ankle-brachial index (ABI) is a noninvasive method to evaluate peripheral artery disease (PAD). ABI <0.9 diagnoses PAD; ABI >1.3 is a false negative caused by noncompressible arteries. The aim of this study is to evaluate the association between ABI with vascular calcifications (VC) and with mortality, in haemodialysis (HD) patients. METHODS: We studied 219 HD patients (60% male; 20% diabetic). At baseline, ABI was evaluated by a Doppler device. VCs were evaluated by two methods: the abdominal aorta calcification score (AACS) in a lateral plain X-ray of the abdominal aorta and the simple vascular calcification score (SVCS) in plain X-rays of the pelvis and hands. VC were also classified by their anatomical localization in main vessels (aorta and iliac-femoral axis) and in peripheral or distal vessels (pelvic, radial or digital). The cutoff values for the different VC scores in relation with ABI were determined by receiver operating characteristic curve analysis. Biochemical parameters were time averaged for the 6 months preceding ABI evaluation. RESULTS: An ABI <0.9, an ABI >1.3 or a normal ABI were found, respectively, in 90 (41%), in 42 (19%) and in 87 (40%) patients. AACS >=6 and SVCS >3 were found, respectively, in 98 (45%) and 95 (43%) patients. The adjusted odds ratio (OR) for having an ABI <0.9 was 2.5 (P = 0.007) for AACS >=6 and 4.5 (P < 0.001) for iliac-femoral calcification score (CS) >=2. The adjusted OR for having an ABI >1.3 was 4.2 (P = 0.003) for pelvic CS and 3.7 (P = 0.006) for hand CS >=2. During an observational period of 28.9 months, all-cause and cardiovascular mortality occurred, respectively, in 50 (23%) and in 29 (13%) patients. Adjusting for age, diabetes, P levels, HD duration and cardiovascular disease at baseline, an ABI <0.9 [hazard ratio (HR) = 3.9, P < 0.001] and an ABI >1.3 (HR = 2.7, P = 0.038) were associated with all cause mortality; an ABI <0.9 (HR = 7.2, P = 0.002) and an ABI >1.3 (HR = 5.1, P = 0.028) were associated with cardiovascular mortality. CONCLUSIONS: Both low and high ABI were independent predictors of all-cause and cardiovascular mortality. VC in main arteries were associated with an ABI <0.9. VC in peripheral and distal arteries were associated with an ABI >1.3. ABI is a simple and noninvasive method that allows the identification of high cardiovascular risk patients. PMID- 21551083 TI - Protective effect of N-acetylcysteine from drug-induced ototoxicity in uraemic patients with CAPD peritonitis. AB - AIM: Peritonitis is currently one of the leading complications of continuous ambulatory peritoneal dialysis (CAPD) treatment. Aminoglycosides and vancomycin are used in the treatment of CAPD peritonitis despite their potential risk for ototoxicity. N-acetylcysteine (NAC) is a molecule used in the treatment and prophylaxis of many diseases related to oxidative stress. The aim of this study was to examine whether ototoxicity due to antibiotics used in the treatment of CAPD peritonitis can be prevented by NAC. METHODS: Sixty patients, who first developed CAPD peritonitis attacks from February 2008 to April 2010 were included in this study. Patients were divided into two groups, those taking an additional NAC treatment (n = 30) and a control group (n = 30). Low- and high-frequency hearing function tests were performed on the two groups before treatment (baseline), at the end of the first (early follow-up) and the fourth week after the treatment (late follow-up). Total doses of vancomycin and amikacin were recorded. RESULTS: There was no statistically significant difference between the groups in terms of hearing functions at the beginning. However, patients taking NAC had better hearing function test results 4 weeks after the treatment compared with those of the control group (P < 0.05). There were no statistical differences between posttreatment low-frequency hearing function tests conducted at the baseline and the first and the fourth weeks in patients taking NAC. The first and the fourth week's low-frequency hearing functions worsened when compared with the baseline low-frequency results in the control group (P < 0.001). It was found that NAC had a protective effect against ototoxicity on low-frequency (0.25-8 KHz) hearing functions. The first and the fourth week's high-frequency hearing functions improved when compared with baseline high-frequency hearing functions in patients taking NAC (P < 0.05), while they worsened. The first and fourth week's high-frequency tests worsened when compared with the baseline high frequency tests in the control group (P < 0.001). CONCLUSIONS: The present study suggests that intraperitoneal aminoglycoside and vancomycin administration in CAPD patients may cause low- and high-frequency hearing loss, and this ototoxic effect is related to the dose given. It was found that when the antioxidant NAC is administered alone, it prevents ototoxicity, associated with intraperitoneal amikacin and vancomycin in patients with CAPD peritonitis. In addition, it was revealed that NAC may also have a curative effect on impaired high-frequency hearing functions. PMID- 21551084 TI - Ayurvedic medicine and NADPH oxidase: a possible approach to the prevention of ESRD in hyperoxaluria. PMID- 21551085 TI - Albuminuria increases cystatin C excretion: implications for urinary biomarkers. AB - BACKGROUND: Low-molecular weight (LMW) proteins, including albumin and novel urinary biomarkers of acute kidney injury (AKI) such as cystatin C and neutrophil gelatinase-associated lipocalin (NGAL), are normally absorbed from the glomerular filtrate by receptor-mediated transport. We evaluated the effect of albuminuria on urinary excretion of novel biomarkers. METHODS: Sprague-Dawley rats given four injections over 2 days of 5 mg/g body wt/day bovine serum albumin (BSA) in saline were compared with controls given saline alone. Urinary cystatin C, albumin and protein excretion rates were compared prior to treatment (Day -1), after treatment (Day 2) and 4 days later (Day 6). A preliminary assessment of the clinical effect of proteinuria on the filtered urinary biomarkers cystatin C and NGAL was made by comparison with the effect on urinary interleukin-18 (IL-18) that is not absorbed from the glomerular filtrate, in a cohort of intensive care unit patients. RESULTS: BSA induced transient increases in albuminuria, proteinuria and cystatinuria (P < 0.01, P < 0.001 and P < 0.001, respectively). Beyond a threshold 6-fold increase in albuminuria, cystatin C absorption was reduced by competitive inhibition. The excretion rates of all analytes returned to preinjection levels by Day 6. Clinical proteinuria was associated with increasing cystatin C and NGAL concentrations (n = 90, P < 0.0001) but not IL-18 (P = 0.12). CONCLUSIONS: Proteinuria may increase the threshold for detection of AKI by increasing the excretion of LMW protein biomarkers. PMID- 21551086 TI - When to start dialysis: updated guidance following publication of the Initiating Dialysis Early and Late (IDEAL) study. PMID- 21551087 TI - The exchangeable calcium pool: physiology and pathophysiology in chronic kidney disease. AB - Excessive soft tissue and vascular calcifications are typical complications of chronic kidney disease (CKD) and disorders of phosphate homeostasis are considered to be a major contributor to the pathogenesis. However, at least in some individuals, calcium administration also increases the risk, and furthermore, it is widely accepted that there is a link between bone disease and vascular pathology. In this review, we discuss the role of the bone exchangeable calcium pool (ECP) in the acute regulation of the serum calcium concentration (Ca(s)) in health and CKD. This pool is able to buffer an acute calcium load as well as to maintain a stable Ca(s) during acute calcium deprivation. Indeed, the minute-to-minute regulation of Ca(s) appears to depend exclusively on this mechanism without any obvious contribution of other factors like parathyroid hormone, which nonetheless define the Ca(s) steady state set point. It is tempting to speculate that a reduction of the bone ECP plasticity in some patients with CKD leads to short-lasting increases in Ca(s) above the individual mid- to long-term set point as observed during haemodialysis or after the ingestion of calcium-containing phosphate binders. This could contribute to and partially explain the propensity of these subjects to develop extraosseous calcifications. An improved understanding of the processes involved and the availability of new techniques to assess the capacity of this pool, at least in dialysis patients, will make this area an attractive target for new investigations. PMID- 21551088 TI - Validation of the CKD-EPI formula in patients after renal transplantation. AB - BACKGROUND: Accurate calculation of glomerular filtration rate (GFR) is crucial in the management of patients after kidney transplantation (KTx). Recently, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was introduced to estimate GFR in chronic kidney disease patients. However, to date the diagnostic value of this equation remains to be determined in patients after KTx. METHODS: We analysed the CKD-EPI formula in comparison to the re-expressed Modification of Diet in Renal Disease (MDRD) equation in 170 stable patients after renal transplantation. Correlation, bias, precision and accuracy within 30 and 50% of true GFR were determined. GFR was measured by technetium diethylenetriamine pentaacetic acid clearance [39.6, 95% confidence interval (CI): 37.3-42.0 mL/min/1.73m(2)]. RESULTS: The results for the MDRD and CKD-EPI equations correlated well with GFR (0.82; 0.83, respectively). GFR calculated by MDRD (44.1, 95% CI: 41.6-46.8 mL/min/1.73m(2)) and CKD-EPI (47.7, 95% CI: 44.7 50.7 mL/min/1.73m(2)) overestimated true GFR significantly (P < 0.001). Precision was not significantly different between MDRD and CKD-EPI (10.9 versus 10.0 mL/min/1.73m(2), respectively). Accuracy within 30% of true GFR was significantly higher for MDRD (71.8%) than for CKD-EPI (64.1%, P = 0.0014). Accuracy within 50% of true GFR did not differ significantly (MDRD: 89.4% versus CKD-EPI: 84.7%, P = 0.06). CONCLUSION: The new CKD-EPI formula did not improve the estimation of GFR in Caucasian patients after renal transplantation in this study. PMID- 21551089 TI - CKD-MBD: comfort in the trough of the U. PMID- 21551090 TI - Pathology of idiopathic nephrotic syndrome in children: are the adolescents different from young children? AB - BACKGROUND: There is no specific data on the pathological lesions underlying idiopathic nephrotic syndrome (INS) in adolescents in Pakistan. Moreover, it is not known whether the pathological lesions in adolescents differ significantly from young children with INS in our setup. Materials and methods. A retrospective analysis was carried out on all patients with INS with onset <= 18 years of age. They were split into two groups: patients with onset of INS <= 12 years (young children group) and patients with onset >= 13 through 18 years of age (adolescent group). Renal biopsies were evaluated by light microscopy, immunoflourescence and electron microscopy. The histopathological lesions on renal biopsies were analyzed and compared between the two groups. RESULTS: The adolescents comprised 173 (32.1%) patients, and there were 365 young children (67.8%). The mean age of adolescents at the time of onset of INS was 15.12 +/- 1.5 years and there were 113 boys (65.3%) and 60 girls (34.6%). The mean age of young children was 7.26 +/ 3.24 years and there were 231 boys (63.2%) and 134 girls (36.7%). Focal segmental glomerulosclerosis was the most common histopathological lesion in adolescents (36.4%) followed by minimal change disease (MCD) (28.9%). Adolescent onset INS had a significantly higher frequency of membranous glomerulonephritis and membranoproliferative glomerulonephritis (MPGN) (P < 0.05) and significantly lower frequency of MCD (P < 0.05) than early childhood-onset INS. CONCLUSIONS: Our data indicate that the pathological lesions in adolescent INS are different from younger children and resemble more closely those seen in adults. Our findings are concordant with the few previously published studies on this subject. PMID- 21551091 TI - Will fish foster regenerative medicine in man? PMID- 21551092 TI - Mycobacterial-immune reconstitution inflammatory syndrome: a cause of acute interstitial nephritis during HIV infection. AB - Kidney injury during HIV infection encompasses a wide variety of disorders, including acute interstitial nephritis. We report a case of acute granulomatous interstitial nephritis related to a mycobacterial-triggered immune reconstitution inflammatory syndrome (IRIS) in an HIV-infected patient. IRIS is an emerging health concern during HIV infection and should be considered in the diagnostic frame of acute renal failure during immune restoration. PMID- 21551093 TI - Incidence of stroke symptoms among adults with chronic kidney disease: results from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. AB - BACKGROUND: Reduced glomerular filtration rate and albuminuria are associated with an increased risk for stroke. Their association with stroke symptoms is not known. METHODS: The incidence of stroke symptoms was determined in 20 386 participants >=45 years of age in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study who were free of a history of stroke, transient ischemic attack and stroke symptoms at baseline. Six stroke symptoms were assessed via telephone interviews at baseline and every 6 months. Participants were followed over a median of 2.1 years (maximum follow-up of 6 years). Estimated glomerular filtration rate (eGFR) was calculated using the CKD EPI equation and the albumin-to-creatinine ratio from spot urine samples. RESULTS: The incidence of any stroke symptom (n = 2548 cases) was 10.8, 12.9, 18.2 and 20.7% among participants with an eGFR >=90, 60-89, 45-59 and <45 mL/min/1.73m(2), respectively, and 10.8, 14.4, 17.0 and 18.8 for participants with albumin-to-creatinine ratios <10, 10-29, 30-299 and >=300 mg/g, respectively (each P-trend < 0.001). The multivariable-adjusted hazard ratio (95% confidence interval) for any stroke symptom was 1.02 (0.91-1.14), 1.22 (1.01-1.48) and 1.26 (0.98-1.62) for those with an eGFR of 60-89, 45-59 and <45 mL/min/1.73m(2), respectively, versus >=90 mL/min/1.73m(2) (P-trend = 0.022) and 1.16 (1.03-1.31), 1.29 (1.12-1.50) and 1.11 (0.82-1.49) for those with albumin-to-creatinine ratios of 10-29, 30-299 and >=300 versus <10 mg/g, respectively (P-trend = 0.005). CONCLUSIONS: Reduced eGFR and higher albuminuria levels are associated with an increased risk for incident stroke symptoms. PMID- 21551094 TI - Tracking single coccolith dissolution with picogram resolution and implications for CO2 sequestration and ocean acidification. AB - Coccoliths are micrometer scale shields made from 20 to 60 individual calcite (CaCO(3)) crystals that are produced by some species of algae. Currently, coccoliths serve as an important sink in the global carbon cycle, but decreasing ocean pH challenges their stability. Chalk deposits, the fossil remains of ancient algae, have remained remarkably unchanged by diagenesis, the process that converts sediment to rock. Even after 60 million years, the fossil coccolith crystals are still tiny (< 1 MUm), compared with inorganically produced calcite, where one day old crystals can be 10 times larger, which raises the question if the biogenic nature of coccolith calcite gives it different properties than inorganic calcite? And if so, can these properties protect coccoliths in CO(2) challenged oceans? Here we describe a new method for tracking dissolution of individual specimens, at picogram (10(-12) g) resolution. The results show that the behavior of modern and fossil coccoliths is similar and both are more stable than inorganic calcite. Organic material associated with the biogenic calcite provides the explanation. However, ancient and modern coccoliths, that resist dissolution in Ca-free artificial seawater at pH > 8, all dissolve when pH is 7.8 or lower. Ocean pH is predicted to fall below 7.8 by the year 2100, in response to rising CO(2) levels. Our results imply that at these conditions the advantages offered by the biogenic nature of calcite will disappear putting coccoliths on algae and in the calcareous bottom sediments at risk. PMID- 21551095 TI - Sensitivity, robustness, and identifiability in stochastic chemical kinetics models. AB - We present a novel and simple method to numerically calculate Fisher information matrices for stochastic chemical kinetics models. The linear noise approximation is used to derive model equations and a likelihood function that leads to an efficient computational algorithm. Our approach reduces the problem of calculating the Fisher information matrix to solving a set of ordinary differential equations. This is the first method to compute Fisher information for stochastic chemical kinetics models without the need for Monte Carlo simulations. This methodology is then used to study sensitivity, robustness, and parameter identifiability in stochastic chemical kinetics models. We show that significant differences exist between stochastic and deterministic models as well as between stochastic models with time-series and time-point measurements. We demonstrate that these discrepancies arise from the variability in molecule numbers, correlations between species, and temporal correlations and show how this approach can be used in the analysis and design of experiments probing stochastic processes at the cellular level. The algorithm has been implemented as a Matlab package and is available from the authors upon request. PMID- 21551096 TI - In vitro evolution goes deep. PMID- 21551097 TI - End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment. AB - The axon initial segment (AIS) plays a key role in maintaining the molecular and functional polarity of the neuron. The relationship between the AIS architecture and the microtubules (MTs) supporting axonal transport is unknown. Here we provide evidence that the MT plus-end-binding (EB) proteins EB1 and EB3 have a role in the AIS in addition to their MT plus-end tracking protein behavior in other neuronal compartments. In mature neurons, EB3 is concentrated and stabilized in the AIS. We identified a direct interaction between EB3/EB1 and the AIS scaffold protein ankyrin G (ankG). In addition, EB3 and EB1 participate in AIS maintenance, and AIS disassembly through ankG knockdown leads to cell-wide up regulation of EB3 and EB1 comets. Thus, EB3 and EB1 coordinate a molecular and functional interplay between ankG and the AIS MTs that supports the central role of ankG in the maintenance of neuronal polarity. PMID- 21551098 TI - Emergence of segregation in evolving social networks. AB - In many social networks, there is a high correlation between the similarity of actors and the existence of relationships between them. This paper introduces a model of network evolution where actors are assumed to have a small aversion from being connected to others who are dissimilar to themselves, and yet no actor strictly prefers a segregated network. This model is motivated by Schelling's [Schelling TC (1969) Models of segregation. Am Econ Rev 59:488-493] classic model of residential segregation, and we show that Schelling's results also apply to the structure of networks; namely, segregated networks always emerge regardless of the level of aversion. In addition, we prove analytically that attribute similarity among connected network actors always reaches a stationary distribution, and this distribution is independent of network topology and the level of aversion bias. This research provides a basis for more complex models of social interaction that are driven in part by the underlying attributes of network actors and helps advance our understanding of why dysfunctional social network structures may emerge. PMID- 21551099 TI - Genome-wide remodeling of the epigenetic landscape during myogenic differentiation. AB - We have examined changes in the chromatin landscape during muscle differentiation by mapping the genome-wide location of ten key histone marks and transcription factors in mouse myoblasts and terminally differentiated myotubes, providing an exceptionally rich dataset that has enabled discovery of key epigenetic changes underlying myogenesis. Using this compendium, we focused on a well-known repressive mark, histone H3 lysine 27 trimethylation, and identified novel regulatory elements flanking the myogenin gene that function as a key differentiation-dependent switch during myogenesis. Next, we examined the role of Polycomb-mediated H3K27 methylation in gene repression by systematically ablating components of both PRC1 and PRC2 complexes. Surprisingly, we found mechanistic differences between transient and permanent repression of muscle differentiation and lineage commitment genes and observed that the loss of PRC1 and PRC2 components produced opposing differentiation defects. These phenotypes illustrate striking differences as compared to embryonic stem cell differentiation and suggest that PRC1 and PRC2 do not operate sequentially in muscle cells. Our studies of PRC1 occupancy also suggested a "fail-safe" mechanism, whereby PRC1/Bmi1 concentrates at genes specifying nonmuscle lineages, helping to retain H3K27me3 in the face of declining Ezh2-mediated methyltransferase activity in differentiated cells. PMID- 21551100 TI - NifEN-B complex of Azotobacter vinelandii is fully functional in nitrogenase FeMo cofactor assembly. AB - Assembly of nitrogenase FeMoco is one of the key processes in bioinorganic chemistry. NifB and NifEN are two essential elements immediately adjacent to each other along the biosynthetic pathway of FeMoco. Previously, an 8Fe-precursor of FeMoco was identified on NifEN; however, the identity of the biosynthetic intermediate on NifB has remained elusive to date. Here, we present a combined biochemical and spectroscopic investigation of a His-tagged NifEN-B fusion protein of Azotobacter vinelandii. Our data from the EPR and activity analyses confirm the presence of the 8Fe-precursor in the NifEN entity of NifEN-B; whereas those from the metal, EPR, and UV/Vis experiments reveal the presence of additional [Fe(4)S(4)]-type cluster species in the NifB entity of NifEN-B. EPR-, UV/Vis- and metal-based quantitative analyses suggest that the newly identified cluster species in NifEN-B consist of both SAM-motif (CXXXCXXC)- and non-SAM motif-bound [Fe(4)S(4)]-type clusters. Moreover, EPR and activity experiments indicate that the non-SAM-motif [Fe(4)S(4)] cluster is a NifB-bound intermediate of FeMoco assembly, which could be converted to the 8Fe-precursor in a SAM dependent mechanism. Combined outcome of this work provides the initial insights into the biosynthetic events of FeMoco on NifB. More importantly, the full capacity of NifEN-B in FeMoco biosynthesis demonstrates the potential of this fusion protein as an excellent platform for further investigations of the role of NifB and its interaction with NifEN during the process of FeMoco assembly. PMID- 21551101 TI - Concerted heavy-atom bond cleavage and proton and electron transfers illustrated by proton-assisted reductive cleavage of an O-O bond. AB - Electron transfer may be concerted with proton transfer. It may also be concerted with the cleavage of a bond between heavy atoms. All three events may also be concerted. A model is presented to analyze the kinetics of these all-concerted reactions for homogeneous or electrochemical reduction or oxidation processes. It allows the estimation of the kinetic advantage that derives from the increase of the bond-breaking driving force resulting from the concerted proton transfer. Application of the model to the electrochemical reductive cleavage of the O-O bond of an organic peroxide in the presence of a proximal acid group illustrates the applicability of the model and provides an example demonstrating that electron transfer, heavy-atom bond breaking, and proton transfer may be all concerted. Such analyses are expected to be useful for the invention, analysis, and optimization of reactions involved in contemporary energy challenges as well as for the comprehension of major biochemical processes, a number of which involve electron and proton transfer together with cleavage of bonds between heavy atoms. PMID- 21551102 TI - Direct involvement of leucine-rich repeats in assembling ligand-triggered receptor-coreceptor complexes. PMID- 21551103 TI - Single nucleotide mutation in the barley acetohydroxy acid synthase (AHAS) gene confers resistance to imidazolinone herbicides. AB - Induced mutagenesis can be an effective way to increase variability in self pollinated crops for a wide variety of agronomically important traits. Crop resistance to a given herbicide can be of practical value to control weeds with efficient chemical use. In some crops (for example, wheat, maize, and canola), resistance to imidazolinone herbicides (IMIs) has been introduced through mutation breeding and is extensively used commercially. However, this production system imposes plant-back restrictions on rotational crops because of herbicide residuals in the soil. In the case of barley, a preferred rotational crop after wheat, a period of 9-18 mo is required. Thus, introduction of barley varieties showing resistance to IMIs will provide greater flexibility as a rotational crop. The objective of the research reported was to identify resistance in barley for IMIs through induced mutagenesis. To achieve this objective, a sodium azide treated M(2)/M(3) population of barley cultivar Bob was screened for resistance against acetohydroxy acid synthase (AHAS)-inhibiting herbicides. The phenotypic screening allowed identification of a mutant line showing resistance against IMIs. Molecular analysis identified a single-point mutation leading to a serine 653 to asparagine amino acid substitution in the herbicide-binding site of the barley AHAS gene. The transcription pattern of the AHAS gene in the mutant (Ser653Asn) and WT has been analyzed, and greater than fourfold difference in transcript abundance was observed. Phenotypic characteristics of the mutant line are promising and provide the base for the release of IMI-resistant barley cultivar(s). PMID- 21551104 TI - It seemed like a good idea at the time: a brief history of Journal of Vision. PMID- 21551106 TI - The future of neurology services in the UK. PMID- 21551107 TI - The posterior reversible encephalopathy syndrome: what's certain, what's new? AB - The posterior reversible encephalopathy syndrome is an increasingly recognised disorder. Most patients have several symptoms; seizures are the most frequent, often multiple or status epilepticus. A combination of seizures, visual disturbance and/or headache, in particular, should lead to an early brain MRI to reveal the typical pattern of bilateral hyperintensities on fluid attenuated inversion recovery imaging, predominantly in the parieto-occipital region. There seem to be many possible triggers, including abrupt arterial hypertension, impaired renal function, pregnancy, immunosuppressive therapies and various inflammatory conditions. The clinical outcome is excellent, with recovery within a few days, while the MRI abnormalities resolve much more slowly. Little is known about the best management. Seizures do not normally progress to chronic epilepsy so antiepileptic drugs should be discontinued after about 3 months. PMID- 21551108 TI - The treatment of early Parkinson's disease: levodopa rehabilitated. AB - Many clinicians regard levodopa as a last resort in the symptomatic treatment of Parkinson's disease. Here we critically review the arguments that are typically used to postpone the start of levodopa for as long as possible. We will point out that most concerns are invalid. Levodopa remains the most effective and best tolerated Parkinson's drug to date, and should have an important role in all therapeutic strategies, both as monotherapy in early Parkinson's disease and as part of combination therapy in advanced disease. Regardless of disease stage, the choice of a particular drug should not be driven by fear of long term complications but by the clinical condition of the patient at the time, with an emphasis on functioning in everyday life and any comorbidity. A 'phobia' for levodopa-or, indeed, for any other antiparkinsonian medication-is unacceptable according to current evidence. PMID- 21551109 TI - South Wales joint neuroscience meeting, Bridgend, 29 April 2010: a 66-year-old man who suddenly couldn't drive. PMID- 21551110 TI - The opsoclonus-myoclonus syndrome. AB - The opsoclonus-myoclonus syndrome is a rare and distinct neurological disorder characterised by rapid multidirectional conjugate eye movements (opsoclonus), myoclonus and ataxia, along with behavioural changes in adults and irritability in children. Sometimes it is due to a self-limiting presumed para-infectious brainstem encephalitis but it may also represent a non-metastatic manifestation of neuroblastoma in children and small cell carcinoma of the lung in adults. In this article, we will describe the clinical features, diagnosis, pathogenesis and management. PMID- 21551111 TI - Work out where the problem is in the brainstem using 'the rule of 4'. AB - The brainstem is incredibly complex. It contains nuclei, pathways and structures, many with unusual names such as the olives, medial longitudinal fasciculus and the superior and inferior colliculi. The neurological examination can only assess some of them. This article is designed to help make sense of the signs in the more common brainstem syndromes using 'the rule of 4'. PMID- 21551112 TI - The Pulfrich phenomenon; clumsiness and collisions which can be ameliorated. AB - The Pulfrich phenomenon has been described many times but usually just as an interesting academic issue with only diagnostic significance. The phenomenon is due to the fact that patients with unilateral optic neuropathy due to ischaemia, facial injury or multiple sclerosis may have delayed transmission of retinal responses to light from one eye to the brain. This leads to an altered and incorrect interpretation of the pathway and direction of moving targets. Clinicians should be aware of the unique symptomatology of the Pulfrich phenomenon because it is often difficult for patients to describe their symptoms which can be both unpleasant and troublesome. An appropriate tint in either a spectacle or contact lens over the normal eye delays retinal conduction, so re establishing visual processing symmetry and ameliorating the symptoms. PMID- 21551113 TI - A middle road between physics and literature. PMID- 21551115 TI - "The eye altering alters all", William Blake. PMID- 21551116 TI - Recurrent subarachnoid haemorrhage. PMID- 21551117 TI - Gloucester. PMID- 21551118 TI - Neuro-ophthalmology. PMID- 21551119 TI - Neurologists and head injury. PMID- 21551120 TI - 10 best resources on ... the current effects of global health initiatives on country health systems. PMID- 21551121 TI - Holding health providers in developing countries accountable to consumers: a synthesis of relevant scholarship. AB - Health care providers in low-income countries often treat consumers poorly. Many providers do not consider it their responsibility to listen carefully to consumer preferences, to facilitate access to care, to offer detailed information, or to treat patients with respect. A lack of provider accountability to health consumers may have adverse effects on the quality of health care they provide, and ultimately on health outcomes. This paper synthesizes relevant research on health provision in low-, middle- and high-income countries with the aim of identifying factors that shape health provider accountability to consumers, and discerning promising interventions to enhance responsiveness. Drawing on this scholarship, we develop a framework that classifies factors into two categories: those concerning the health system and those that pertain to social influences. Among the health systems factors that may shape provider accountability are oversight mechanisms, revenue sources, and the nature of competition in the health sector-all influences that may lead providers to be accountable to entities other than consumers, such as governments and donors. Among the social factors we explore are consumer power, especially information levels, and provider beliefs surrounding accountability. Evidence on factors and interventions shaping health provider accountability is thin. For this reason, it is not possible to draw firm conclusions on what works to enhance accountability. This being said, research does suggest four mechanisms that may improve provider responsiveness: 1. Creating official community participation mechanisms in the context of health service decentralization; 2. Enhancing the quality of health information that consumers receive; 3. Establishing community groups that empower consumers to take action; 4. Including non-governmental organizations in efforts to expand access to care. This synthesis reviews evidence on these and other interventions, and points to future research needs to build knowledge on how to enhance health provider accountability to consumers. PMID- 21551122 TI - Inferring the time-invariant topology of a nonlinear sparse gene regulatory network using fully Bayesian spline autoregression. AB - We propose a semiparametric Bayesian model, based on penalized splines, for the recovery of the time-invariant topology of a causal interaction network from longitudinal data. Our motivation is inference of gene regulatory networks from low-resolution microarray time series, where existence of nonlinear interactions is well known. Parenthood relations are mapped by augmenting the model with kinship indicators and providing these with either an overall or gene-wise hierarchical structure. Appropriate specification of the prior is crucial to control the flexibility of the splines, especially under circumstances of scarce data; thus, we provide an informative, proper prior. Substantive improvement in network inference over a linear model is demonstrated using synthetic data drawn from ordinary differential equation models and gene expression from an experimental data set of the Arabidopsis thaliana circadian rhythm. PMID- 21551123 TI - Coparenting in relation to children's psychosocial and diabetes-specific adjustment. AB - OBJECTIVE: To explore the potential utility of a general and diabetes-specific measure of coparenting by evaluating linkages between coparenting and both the psychosocial and medical adjustment of children with type 1 diabetes (TID). METHOD: Mothers and fathers of children (ages 8-12 years; n=61) with TID completed questionnaires including measures of general and diabetes-specific coparenting, and children's internalizing and externalizing problems. Medical adjustment included parent-reported diabetes management behaviors, children's self-reported diabetes quality of life (QOL), and metabolic control (HbA1c) assessed during clinic appointments. RESULTS: Coparenting conflict around general child rearing tasks was significantly related to children's internalizing and externalizing problems. Diabetes-specific coparenting conflict was linked to poorer diabetes management behaviors and children's reports of poorer diabetes specific quality of life, but not HbA1c. CONCLUSIONS: Significant findings offer preliminary support for the inclusion of coparenting assessments among children with TID and warrant further exploration. PMID- 21551124 TI - Anxiety, coping, and disability: a test of mediation in a pediatric chronic pain sample. AB - OBJECTIVE: To evaluate pain coping as a mediator of associations between anxiety and functional disability and anxiety and somatic symptoms in adolescents with chronic pain. METHOD: Participants (mean age = 14.76 years, range: 12-17 years) included 280 patients (212 girls) with chronic pain who underwent multidisciplinary evaluation at a tertiary pain clinic in a northeast pediatric hospital. Patients completed measures of current pain, anxiety, active, passive, and accommodative pain coping, functional disability, and somatic symptoms. RESULTS: Structural equation modeling was employed. The association between anxiety and disability was fully mediated by passive coping. The association between anxiety and somatic symptoms was not mediated by coping. CONCLUSIONS: Links between anxiety symptoms and pain-related outcomes in adolescents with chronic pain are complex. Assessing how an adolescent copes with his/her pain provides further understanding of this relationship. PMID- 21551125 TI - Phylogenetic inference of reciprocal effects between geographic range evolution and diversification. AB - Geographic characters--traits describing the spatial distribution of a species may both affect and be affected by processes associated with lineage birth and death. This is potentially confounding to comparative analyses of species distributions because current models do not allow reciprocal interactions between the evolution of ranges and the growth of phylogenetic trees. Here, we introduce a likelihood-based approach to estimating region-dependent rates of speciation, extinction, and range evolution from a phylogeny, using a new model in which these processes are interdependent. We demonstrate the method with simulation tests that accurately recover parameters relating to the mode of speciation and source-sink dynamics. We then apply it to the evolution of habitat occupancy in Californian plant communities, where we find higher rates of speciation in chaparral than in forests and evidence for expanding habitat tolerances. PMID- 21551126 TI - A phylogenetic analysis of pygmy perches (Teleostei: Percichthyidae) with an assessment of the major historical influences on aquatic biogeography in southern Australia. AB - The biogeography of southern Australia is characterized by a repeated pattern of relatedness between the biota of southwestern and southeastern Australia. Both areas possess a temperate climate but are separated by a vast arid region, currently lacking permanent freshwater habitats, which has become increasingly drier since about 15 Ma. Aquatic organisms have thus potentially remained isolated for a considerable time. Pygmy perches (Nannatherina and Nannoperca, Percichthyidae) provide an excellent scenario for investigating biogeographic relationships between southwestern and southeastern regions as multiple species occur on either side of Australia. This allows us to potentially differentiate between "Multiple Invasion" and "Endemic Speciation," the two major hypotheses proposed to account for current distributions. The first suggests that multiple east-west movements have occurred, whereas the second suggests a single east-west split, with current biodiversity in each region being reciprocally monophyletic. Systematic relationships within this group were investigated with the mitochondrial cytochrome b gene; nuclear intron and exon sequences from S7, RAG1, and RAG2; and 53 allozyme loci. Our data supported the hypothesis of multiple movements across southern Australia based on a consistent lack of support for reciprocal monophyly of eastern and western species. This study appears to be the first example of an animal group displaying clear multiple east-west movement in southern Australia, as all other aquatic and terrestrial fauna previously examined displayed a single east-west split. Despite a high degree of sympatry within each region, the only evidence for hybridization was found between Nannoperca australis and N. obscura, with the latter having its mitochondrial genome completely replaced by that of N. australis, with no evidence for nuclear introgression. This is one of only a few confirmed examples of complete replacement of the mitochondrial genome in one species with that of another. Cryptic differentiation was also evident within the two most widespread species, N. australis and N. vittata, indicating that these likely consist of multiple species. We also highlight the need for multiple molecular markers with different strengths in order to obtain a more robust phylogeny, despite problems resulting from potential incongruences between data sets. PMID- 21551127 TI - Genome-wide copy-number variation analysis identifies common genetic variants at 20p13 associated with aggressiveness of prostate cancer. AB - The genetic determinants for aggressiveness of prostate cancer (PCa) are poorly understood. Copy-number variations (CNVs) are one of the major sources for genetic diversity and critically modulate cellular biology and human diseases. We hypothesized that CNVs may be associated with PCa aggressiveness. To test this hypothesis, we conducted a genome-wide common CNVs analysis in 448 aggressive and 500 nonaggressive PCa cases recruited from Johns Hopkins Hospital (JHH1) using Affymetrix 6.0 arrays. Suggestive associations were further confirmed using single-nucleotide polymorphisms (SNPs) that tagged the CNVs of interest in an additional 2895 aggressive and 3094 nonaggressive cases, including those from the remaining case subjects of the JHH study (JHH2), the NCI Cancer Genetic Markers of Susceptibility (CGEMS) Study, and the CAncer of the Prostate in Sweden (CAPS) Study. We found that CNP2454, a 32.3 kb deletion polymorphism at 20p13, was significantly associated with aggressiveness of PCa in JHH1 [odds ratio (OR) = 1.30, 95% confidence interval (CI): 1.01-1.68; P = 0.045]. The best-tagging SNP for CNP2454, rs2209313, was used to confirm this finding in both JHH1 (P = 0.045) and all confirmation study populations combined (P = 1.77 * 10(-3)). Pooled analysis using all 3353 aggressive and 3584 nonaggressive cases showed the T allele of rs2209313 was significantly associated with an increased risk of aggressive PCa (OR = 1.17, 95% CI: 1.07-1.27; P = 2.75 * 10(-4)). Our results indicate that genetic variations at 20p13 may be responsible for the progression of PCa. PMID- 21551128 TI - Increased incidence of endometrioid tumors caused by aberrations in E-cadherin promoter of mismatch repair-deficient mice. AB - Loss of E-cadherin expression is a critical step in the development and progression of gynecological tumors. Study of the precise role of E-cadherin has been hampered by the lack of satisfactory mouse model for E-cadherin deficiency. Likewise, DNA mismatch repair (MMR) is implicated in gynecological tumorigenesis, but knockout of MMR in mice predominantly causes hematologic neoplasms. Here, we show that combined disruption of E-cadherin and DNA MMR pathways increases incidence of endometrioid tumors in mice. Twenty percent of mice knockout for Msh2 enzyme and hemizygous for E-cadherin [Msh2(-/-)/Cdh1(+/-)] developed endometrioid-like tumors in the ovary, uterus and genital area. Characteristic of these tumors was a complete loss of E-cadherin expression. Sequence analysis of E cadherin promoter region demonstrated that the loss of E-cadherin expression is caused by inactivating mutations, implying that E-cadherin is a mutational target in Msh2-deficient mice. In addition, Msh2(-/-)/Cdh1(+/-) mice showed a reduction in overall survival as compared with their Msh2(-/-) counterparts due to the development of more aggressive lymphomas, suggesting a specific role of E cadherin in lymphomagenesis. In conclusion, Msh2(-/-)/Cdh1(+/-) mice provide a good model of gynecological tumorigenesis and may be useful for testing molecular target-specific therapies. PMID- 21551129 TI - c-Src dependency of NSAID-induced effects on NF-kappaB-mediated apoptosis in colorectal cancer cells. AB - Long-term aspirin or related non-steroidal anti-inflammatory drugs (NSAIDs) ingestion can protect against colorectal cancer (CRC). NSAIDs have a pro apoptotic activity and we have shown that stimulation of the nuclear factor kappaB (NF-kappaB) pathway is a key component of this pro-apoptotic effect. However, the upstream pathways have yet to be fully elucidated. Here, we demonstrate that aspirin activates the c-Src tyrosine kinase pathway in CRC cells. We show that c-Src activation occurs in a time- and dose-dependent manner, preceding aspirin-mediated degradation of IkappaBalpha, nuclear/nucleolar translocation of NF-kappaB/RelA and induction of apoptosis. Furthermore, inhibition of c-Src activity, by chemical inhibition or expression of a kinase dead form of the protein abrogates aspirin-mediated degradation of IkappaBalpha, nuclear translocation of RelA and apoptosis, suggesting a causal link. Expression of constitutively active c-Src mimics aspirin-induced stimulation of the NF kappaB pathway. The NSAIDs sulindac, sulindac sulphone and indomethacin all similarly activate a c-Src-dependent NF-kappaB and apoptotic response. These data provide compelling evidence that c-Src is an upstream mediator of aspirin/NSAID effects on NF-kappaB signalling and apoptosis in CRC cells and have relevance to the development of future chemotherapeutic/chemopreventative agents. PMID- 21551130 TI - miR-29c induces cell cycle arrest in esophageal squamous cell carcinoma by modulating cyclin E expression. AB - Cyclin E is reported to be an important cell cycle regulator, and its dysregulation is implicated in tumorigenesis including esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) regulate gene expression at the posttranscriptional level and play important roles in tumor initiation and progression. However, the regulation of cyclin E by miRNAs is still unclear in ESCC. In the present study, we found that overexpression of miR-29c inhibited cyclin E expression by targeting 3' untranslated region of cyclin E messenger RNA in ESCC cells. Moreover, overexpression of miR-29c induced cell cycle G(1)/G(0) arrest through suppression of cyclin E expression, without affecting other G(1) phase-related proteins level, such as cyclin D1, cyclin D2, cyclin dependent kinase (CDK) 2 and CDK6. Furthermore, we demonstrated that overexpression of miR 29c inhibited proliferation of ESCC cells in vitro and in vivo. In addition, we detected miR-29c expression in 26 pairs of esophageal tumor-in-site-tissues and 60 pairs of ESCC tissues. The result showed that miR-29c level significantly decreased in ESCC tumor tissues and cell lines compared with normal esophageal epithelia. Taken together, our findings indicated that miR-29c was frequently downregulated in ESCC tissues and cells and suppressed tumor growth by inducing cell cycle G(1)/G(0) arrest mainly through modulating cyclin E expression. PMID- 21551131 TI - Epidemiological associations of hearing impairment and health among a national cohort of 87 134 adults in Thailand. AB - Studies on socioeconomic and epidemiological effects of hearing impairment in middle-income countries of Southeast Asia are still quite scarce. This study examines the association between hearing impairment and health outcomes in Thailand. Data derived from a cohort of 87 134 Open University adults aged 15 to 87 years residing throughout Thailand. Approximately 8.5% of cohort members reported trouble hearing and 0.13% reported being deaf. After adjusting for age and gender, poor self-assessed health was strongly associated with some trouble hearing (odds ratio [OR] = 2.70, 95% confidence interval [CI] = 2.48-2.93) and deafness (OR = 3.08, 95% CI = 1.73-5.50). Population attributable fractions for hearing impairment were 12.9% for poor self-assessed health, 9.8% for poor psychological health, 3.3% for metabolic disorders, and 4.1% for cardiovascular conditions. More attention needs to be paid on hearing impairment with regular check-ups and early detections. PMID- 21551132 TI - Pandemic preparedness in Asia: a role for law and ethics? AB - Management of pandemic influenza relies on complex coordination of many different dimensions of the health and social care systems, emergency services, levels of national and local government, civil society, communications and media, and cultural expectations. Law is one small but important component of those arrangements, which touch on fundamental ethical debates. This review demonstrates that the Asian region is actively engaging those issues in diverse ways in light of their varied socioeconomic and cultural backgrounds, but scope remains for prioritising further research into these relationships. PMID- 21551133 TI - Trends in socioeconomic and nutritional status of children younger than 6 years in India. AB - The main aims of this study are to find out the trends in the (a) prevalence of undernutrition and severe anemia and (b) degree of association of undernutrition and severe anemia in children younger than 6 years in India with some socioeconomic variables. Using the Reproductive and Child Health Survey data, z score of weight for age and hemoglobin status were analyzed to understand the state and agewise variation and their association with the sociodemographic variables through logistic regression. The prevalence of malnutrition according to both the criteria was first seen to increase, attain a maximum value at some age between 12 and 48 months, and then decrease. Statewise distribution showed a close link between the stage of development and the prevalence of malnutrition prevalence rate being less for developed states. The rates were also less for the Northeastern states of India. The regression analysis clearly points out that children with illiterate mothers, of lower age groups, or from low standard of living households are more prone to become malnourished. The economic growth alone is not sufficient for substantially reducing malnutrition. It is necessary to improve the rate of literacy, especially of women, to reduce the prevalence of malnutrition and anemia among children. It is not only economic development but also overall human development that is needed in India. PMID- 21551134 TI - The characteristics of imported cases and the effectiveness of outbreak control strategies of pandemic influenza A (H1N1) in China. AB - The aim of this article was to describe the epidemiological characteristics of imported cases of pandemic influenza A (H1N1) and to assess the effectiveness of public health intervention measures in Beijing, China. Data on imported cases were collected via border entry screening, influenza-like illness screening in hospitals, medical follow-up of travelers from overseas, and quarantined close contacts. The characteristics of these cases were investigated. Pharyngeal swabs were collected and tested using polymerase chain reaction. A total of 609 imported cases were confirmed in Beijing from May 16 to September 30, 2009. Subjects aged <20 years accounted for 47.3%, and females represented 49.1%. Most cases were from North America and South America (27.3%). There were 21.8%, 18.7%, 3.1%, and 56.3% of cases detected separately via border entry screening, quarantined close contacts, medical follow-up of travelers from overseas, and influenza-like illness screening in hospitals, respectively. The 4 strategies were able to detect the cases efficiently but the use of resources was high. PMID- 21551135 TI - Unsafe abortion as a birth control method: maternal mortality risks among unmarried cambodian migrant women on the Thai-Cambodia border. AB - Reproductive health research and policies in Cambodia focus on safe motherhood programs particularly for married women, ignoring comprehensive fertility regulation programs for unmarried migrant women of reproductive age. Maternal mortality risks arising due to unsafe abortion methods practiced by unmarried Cambodian women, across the Thai-Cambodia border, can be considered as a public health emergency. Since Thailand has restrictive abortion laws, Cambodian migrant women who have irregular migration status in Thailand experimented with unsafe abortion methods that allowed them to terminate their pregnancies surreptitiously. Unmarried migrant women choose abortion as a preferred birth control method seeking repeat "unsafe" abortions instead of preventing conception. Drawing on the data collected through surveys, in-depth interviews, and document analysis in Chup Commune (pseudonym), Phnom Penh, and Bangkok, the authors describe the public health dimensions of maternal mortality risks faced by unmarried Cambodian migrant women due to various unsafe abortion methods employed as birth control methods. PMID- 21551136 TI - BINOCh: binding inference from nucleosome occupancy changes. AB - Transcription factor binding events are frequently associated with a pattern of nucleosome occupancy changes in which nucleosomes flanking the binding site increase in occupancy, while those in the vicinity of the binding site itself are displaced. Genome-wide information on enhancer proximal nucleosome occupancy can be readily acquired using ChIP-seq targeting enhancer-related histone modifications such as H3K4me2. Here, we present a software package, BINOCh that allows biologists to use such data to infer the identity of key transcription factors that regulate the response of a cell to a stimulus or determine a program of differentiation. AVAILABILITY: The BINOCh open source Python package is freely available at http://liulab.dfci.harvard.edu/BINOCh under the FreeBSD license. PMID- 21551137 TI - A cautionary note for retrocopy identification: DNA-based duplication of intron containing genes significantly contributes to the origination of single exon genes. AB - MOTIVATION: Retrocopies are important genes in the genomes of almost all higher eukaryotes. However, the annotation of such genes is a non-trivial task. Intronless genes have often been considered to be retroposed copies of intron containing paralogs. Such categorization relies on the implicit premise that alignable regions of the duplicates should be long enough to cover exon-exon junctions of the intron-containing genes, and thus intron loss events can be inferred. Here, we examined the alternative possibility that intronless genes could be generated by partial DNA-based duplication of intron-containing genes in the fruitfly genome. RESULTS: By building pairwise protein-, transcript- and genome-level DNA alignments between intronless genes and their corresponding intron-containing paralogs, we found that alignments do not cover exon-exon junctions in 40% of cases and thus no intron loss could be inferred. For these cases, the candidate parental proteins tend to be partially duplicated, and intergenic sequences or neighboring genes are included in the intronless paralog. Moreover, we observed that it is significantly less likely for these paralogs to show inter-chromosomal duplication and testis-dominant transcription, compared to the remaining 60% of cases with evidence of clear intron loss (retrogenes). These lines of analysis reveal that DNA-based duplication contributes significantly to the 40% of cases of single exon gene duplication. Finally, we performed an analogous survey in the human genome and the result is similar, wherein 34% of the cases do not cover exon-exon junctions. Thus, genome annotation for retrogene identification should discard candidates without clear evidence of intron loss. CONTACT: mlong@uchicago.edu; zhangy@uchicago.edu PMID- 21551139 TI - MPEA--metabolite pathway enrichment analysis. AB - We present metabolite pathway enrichment analysis (MPEA) for the visualization and biological interpretation of metabolite data at the system level. Our tool follows the concept of gene set enrichment analysis (GSEA) and tests whether metabolites involved in some predefined pathway occur towards the top (or bottom) of a ranked query compound list. In particular, MPEA is designed to handle many to-many relationships that may occur between the query compounds and metabolite annotations. For a demonstration, we analysed metabolite profiles of 14 twin pairs with differing body weights. MPEA found significant pathways from data that had no significant individual query compounds, its results were congruent with those discovered from transcriptomics data and it detected more pathways than the competing metabolic pathway method did. AVAILABILITY: The web server and source code of MPEA are available at http://ekhidna.biocenter.helsinki.fi/poxo/mpea/. PMID- 21551138 TI - Identification of prokaryotic small proteins using a comparative genomic approach. AB - MOTIVATION: Accurate prediction of genes encoding small proteins (on the order of 50 amino acids or less) remains an elusive open problem in bioinformatics. Some of the best methods for gene prediction use either sequence composition analysis or sequence similarity to a known protein coding sequence. These methods often fail for small proteins, however, either due to a lack of experimentally verified small protein coding genes or due to the limited statistical significance of statistics on small sequences. Our approach is based upon the hypothesis that true small proteins will be under selective pressure for encoding the particular amino acid sequence, for ease of translation by the ribosome and for structural stability. This stability can be achieved either independently or as part of a larger protein complex. Given this assumption, it follows that small proteins should display conserved local protein structure properties much like larger proteins. Our method incorporates neural-net predictions for three local structure alphabets within a comparative genomic approach using a genomic alignment of 22 closely related bacteria genomes to generate predictions for whether or not a given open reading frame (ORF) encodes for a small protein. RESULTS: We have applied this method to the complete genome for Escherichia coli strain K12 and looked at how well our method performed on a set of 60 experimentally verified small proteins from this organism. Out of a total of 11 407 possible ORFs, we found that 6 of the top 10 and 27 of the top 100 predictions belonged to the set of 60 experimentally verified small proteins. We found 35 of all the true small proteins within the top 200 predictions. We compared our method to Glimmer, using a default Glimmer protocol and a modified small ORF Glimmer protocol with a lower minimum size cutoff. The default Glimmer protocol identified 16 of the true small proteins (all in the top 200 predictions), but failed to predict on 34 due to size cutoffs. The small ORF Glimmer protocol made predictions for all the experimentally verified small proteins but only contained 9 of the 60 true small proteins within the top 200 predictions. CONTACT: jsamayoa@jhu.edu PMID- 21551140 TI - Application of the Bayesian MMSE estimator for classification error to gene expression microarray data. AB - MOTIVATION: With the development of high-throughput genomic and proteomic technologies, coupled with the inherent difficulties in obtaining large samples, biomedicine faces difficult small-sample classification issues, in particular, error estimation. Most popular error estimation methods are motivated by intuition rather than mathematical inference. A recently proposed error estimator based on Bayesian minimum mean square error estimation places error estimation in an optimal filtering framework. In this work, we examine the application of this error estimator to gene expression microarray data, including the suitability of the Gaussian model with normal-inverse-Wishart priors and how to find prior probabilities. RESULTS: We provide an implementation for non-linear classification, where closed form solutions are not available. We propose a methodology for calibrating normal-inverse-Wishart priors based on discarded microarray data and examine the performance on synthetic high-dimensional data and a real dataset from a breast cancer study. The calibrated Bayesian error estimator has superior root mean square performance, especially with moderate to high expected true errors and small feature sizes. AVAILABILITY: We have implemented in C code the Bayesian error estimator for Gaussian distributions and normal-inverse-Wishart priors for both linear classifiers, with exact closed-form representations, and arbitrary classifiers, where we use a Monte Carlo approximation. Our code for the Bayesian error estimator and a toolbox of related utilities are available at http://gsp.tamu.edu/Publications/supplementary/dalton11a. Several supporting simulations are also included. CONTACT: ldalton@tamu.edu PMID- 21551141 TI - The strength of chemical linkage as a criterion for pruning metabolic graphs. AB - MOTIVATION: A metabolic graph represents the connectivity patterns of a metabolic system, and provides a powerful framework within which the organization of metabolic reactions can be analyzed and elucidated. A common practice is to prune (i.e. remove nodes and edges) the metabolic graph prior to any analysis in order to eliminate confounding signals from the representation. Currently, this pruning process is carried out in an ad hoc fashion, resulting in discrepancies and ambiguities across studies. RESULTS: We propose a biochemically informative criterion, the strength of chemical linkage (SCL), for a systematic pruning of metabolic graphs. By analyzing the metabolic graph of Escherichia coli, we show that thresholding SCL is powerful in selecting the conventional pathways' connectivity out of the raw network connectivity when the network is restricted to the reactions collected from these pathways. Further, we argue that the root of ambiguity in pruning metabolic graphs is in the continuity of the amount of chemical content that can be conserved in reaction transformation patterns. Finally, we demonstrate how biochemical pathways can be inferred efficiently if the search procedure is guided by SCL. PMID- 21551142 TI - TVNViewer: an interactive visualization tool for exploring networks that change over time or space. AB - The relationship between genes and proteins is a dynamic relationship that changes across time and differs in different cells. The study of these differences can reveal various insights into biological processes and disease progression, especially with the aid of proper tools for network visualization. Toward this purpose, we have developed TVNViewer, a novel visualization tool, which is specifically designed to aid in the exploration and analysis of dynamic networks. AVAILABILITY: TVNViewer is freely available with documentation and tutorials on the web at http://sailing.cs.cmu.edu/tvnviewer. CONTACT: epxing@cs.cmu.edu. PMID- 21551143 TI - A multiple network learning approach to capture system-wide condition-specific responses. AB - MOTIVATION: Condition-specific networks capture system-wide behavior under varying conditions such as environmental stresses, cell types or tissues. These networks frequently comprise parts that are unique to each condition, and parts that are shared among related conditions. Existing approaches for learning condition-specific networks typically identify either only differences or only similarities across conditions. Most of these approaches first learn networks per condition independently, and then identify similarities and differences in a post learning step. Such approaches do not exploit the shared information across conditions during network learning. RESULTS: We describe an approach for learning condition-specific networks that identifies the shared and unique subgraphs during network learning simultaneously, rather than as a post-processing step. Our approach learns networks across condition sets, shares data from different conditions and produces high-quality networks that capture biologically meaningful information. On simulated data, our approach outperformed an existing approach that learns networks independently for each condition, especially for small training datasets. On microarray data of hundreds of deletion mutants in two, yeast stationary-phase cell populations, the inferred network structure identified several common and population-specific effects of these deletion mutants and several high-confidence cases of double-deletion pairs, which can be experimentally tested. Our results are consistent with and extend the existing knowledge base of differentiated cell populations in yeast stationary phase. AVAILABILITY AND IMPLEMENTATION: C++ code can be accessed from http://www.broadinstitute.org/~sroy/condspec/ . PMID- 21551144 TI - Pathway analysis of high-throughput biological data within a Bayesian network framework. AB - MOTIVATION: Most current approaches to high-throughput biological data (HTBD) analysis either perform individual gene/protein analysis or, gene/protein set enrichment analysis for a list of biologically relevant molecules. Bayesian Networks (BNs) capture linear and non-linear interactions, handle stochastic events accounting for noise, and focus on local interactions, which can be related to causal inference. Here, we describe for the first time an algorithm that models biological pathways as BNs and identifies pathways that best explain given HTBD by scoring fitness of each network. RESULTS: Proposed method takes into account the connectivity and relatedness between nodes of the pathway through factoring pathway topology in its model. Our simulations using synthetic data demonstrated robustness of our approach. We tested proposed method, Bayesian Pathway Analysis (BPA), on human microarray data regarding renal cell carcinoma (RCC) and compared our results with gene set enrichment analysis. BPA was able to find broader and more specific pathways related to RCC. AVAILABILITY: Accompanying BPA software (BPAS) package is freely available for academic use at http://bumil.boun.edu.tr/bpa. PMID- 21551145 TI - Exploiting maximal dependence decomposition to identify conserved motifs from a group of aligned signal sequences. AB - Bioinformatics research often requires conservative analyses of a group of sequences associated with a specific biological function (e.g. transcription factor binding sites, micro RNA target sites or protein post-translational modification sites). Due to the difficulty in exploring conserved motifs on a large-scale sequence data involved with various signals, a new method, MDDLogo, is developed. MDDLogo applies maximal dependence decomposition (MDD) to cluster a group of aligned signal sequences into subgroups containing statistically significant motifs. In order to extract motifs that contain a conserved biochemical property of amino acids in protein sequences, the set of 20 amino acids is further categorized according to their physicochemical properties, e.g. hydrophobicity, charge or molecular size. MDDLogo has been demonstrated to accurately identify the kinase-specific substrate motifs in 1221 human phosphorylation sites associated with seven well-known kinase families from Phospho.ELM. Moreover, in a set of plant phosphorylation data-lacking kinase information, MDDLogo has been applied to help in the investigation of substrate motifs of potential kinases and in the improvement of the identification of plant phosphorylation sites with various substrate specificities. In this study, MDDLogo is comparable with another well-known motif discover tool, Motif-X. CONTACT: francis@saturn.yzu.edu.tw PMID- 21551146 TI - Sim4db and Leaff: utilities for fast batch spliced alignment and sequence indexing. AB - The large number of genomes that will be sequenced will need to be annotated with genes and other functional features. Aligning gene sequences from a related species to the target genome is an economical and highly reliable method to identify genes; unfortunately, existing tools have been lacking in sensitivity and speed. A program we reported, sim4cc, was shown to be highly accurate but is limited to comparing one cDNA with one genomic sequence. We present here an optimization of the tool, implemented in the packages sim4db and leaff. The new tool performs batch alignments of cDNA and genomic sequences in a fraction of the time required by its predecessor, and thus is very well suited for genome-wide analyses. AVAILABILITY: Sim4db and leaff are written in C, C++ and Perl for Linux and other Unix platforms. Source code is distributed free of charge from http://sourceforge.net/projects/kmer/. CONTACT: florea@umiacs.umd.edu PMID- 21551147 TI - The role of indirect connections in gene networks in predicting function. AB - MOTIVATION: Gene networks have been used widely in gene function prediction algorithms, many based on complex extensions of the 'guilt by association' principle. We sought to provide a unified explanation for the performance of gene function prediction algorithms in exploiting network structure and thereby simplify future analysis. RESULTS: We use co-expression networks to show that most exploited network structure simply reconstructs the original correlation matrices from which the co-expression network was obtained. We show the same principle works in predicting gene function in protein interaction networks and that these methods perform comparably to much more sophisticated gene function prediction algorithms. AVAILABILITY AND IMPLEMENTATION: Data and algorithm implementation are fully described and available at http://www.chibi.ubc.ca/extended. Programs are provided in Matlab m-code. CONTACT: paul@chibi.ubc.ca PMID- 21551148 TI - Genome-wide DNA sequence polymorphisms facilitate nucleosome positioning in yeast. AB - MOTIVATION: The intrinsic DNA sequence is an important determinant of nucleosome positioning. Some DNA sequence patterns can facilitate nucleosome formation, while others can inhibit nucleosome formation. Nucleosome positioning influences the overall rate of sequence evolution. However, its impacts on specific patterns of sequence evolution are still poorly understood. RESULTS: Here, we examined whether nucleosomal DNA and nucleosome-depleted DNA show distinct polymorphism patterns to maintain adequate nucleosome architecture on a genome scale in yeast. We found that sequence polymorphisms in nucleosomal DNA tend to facilitate nucleosome formation, whereas polymorphisms in nucleosome-depleted DNA tend to inhibit nucleosome formation, which is especially evident at nucleosome disfavored sequences in nucleosome-free regions at both ends of genes. Sequence polymorphisms facilitating nucleosome positioning correspond to stable nucleosome positioning. These results reveal that sequence polymorphisms are under selective constraints to maintain nucleosome positioning. CONTACT: zhimdai@gmail.com; issdxh@mail.sysu.edu.cn PMID- 21551149 TI - An MCMC algorithm for detecting short adjacent repeats shared by multiple sequences. AB - MOTIVATION: Repeats detection problems are traditionally formulated as string matching or signal processing problems. They cannot readily handle gaps between repeat units and are incapable of detecting repeat patterns shared by multiple sequences. This study detects short adjacent repeats with interunit insertions from multiple sequences. For biological sequences, such studies can shed light on molecular structure, biological function and evolution. RESULTS: The task of detecting short adjacent repeats is formulated as a statistical inference problem by using a probabilistic generative model. An Markov chain Monte Carlo algorithm is proposed to infer the parameters in a de novo fashion. Its applications on synthetic and real biological data show that the new method not only has a competitive edge over existing methods, but also can provide a way to study the structure and the evolution of repeat-containing genes. AVAILABILITY: The related C++ source code and datasets are available at http://ihome.cuhk.edu.hk/%7Eb118998/share/BASARD.zip. CONTACT: xfan@sta.cuhk.edu.hk PMID- 21551150 TI - Creating views on integrated multidomain data. AB - MOTIVATION: Modern data acquisition methods in biology allow the procurement of different types of data in increasing quantity, facilitating a comprehensive view of biological systems. As data are usually gathered and interpreted by separate domain scientists, it is hard to grasp multidomain properties and structures. Consequently, there is a need for the integration of biological data from different sources and of different types in one application, providing various visualization approaches. RESULTS: In this article, methods for the integration and visualization of multimodal biological data are presented. This is achieved based on two graphs representing the meta-relations between biological data and the measurement combinations, respectively. Both graphs are linked and serve as different views of the integrated data with navigation and exploration possibilities. Data can be combined and visualized multifariously, resulting in views of the integrated biological data. AVAILABILITY: http://vanted.ipk gatersleben.de/hive/. CONTACT: rohn@ipk-gatersleben.de. PMID- 21551151 TI - Integrative gene network construction for predicting a set of complementary prostate cancer genes. AB - MOTIVATION: Diagnosis and prognosis of cancer and understanding oncogenesis within the context of biological pathways is one of the most important research areas in bioinformatics. Recently, there have been several attempts to integrate interactome and transcriptome data to identify subnetworks that provide limited interpretations of known and candidate cancer genes, as well as increase classification accuracy. However, these studies provide little information about the detailed roles of identified cancer genes. RESULTS: To provide more information to the network, we constructed the network by incorporating genetic interactions and manually curated gene regulations to the protein interaction network. To make our newly constructed network cancer specific, we identified edges where two genes show different expression patterns between cancer and normal phenotypes. We showed that the integration of various datasets increased classification accuracy, which suggests that our network is more complete than a network based solely on protein interactions. We also showed that our network contains significantly more known cancer-related genes than other feature selection algorithms. Through observations of some examples of cancer-specific subnetworks, we were able to predict more detailed and interpretable roles of oncogenes and other cancer candidate genes in the prostate cancer cells. AVAILABILITY: http://embio.yonsei.ac.kr/~Ahn/tc.php. CONTACT: sanghyun@cs.yonsei.ac.kr PMID- 21551152 TI - Effect of improvement in left ventricular ejection fraction on long-term survival in revascularized patients with ischaemic left ventricular systolic dysfunction. AB - AIMS: The importance of improvement in the ejection fraction to the prognosis of revascularized patients with ischaemic left ventricular (LV) dysfunction is uncertain. METHODS AND RESULTS: Eighty-seven patients with ischaemic LV dysfunction (mean ejection fraction 29 +/- 8% by biplane Simpson's) had dobutamine echocardiography before revascularization (coronary bypass graft surgery-81, percutaneous intervention-6). Follow-up echocardiograms were performed a mean of 4.8 +/- 6.2 months after revascularization. An 8% increase in the ejection fraction was considered significant (two times the inter-observer difference of 3.7%). Patients were followed for cardiac death. During a mean follow-up of 5.2 +/- 3.9 years, there were 20 (23%) cardiac deaths. Class 3/4 heart failure, increasing low-dose wall motion score, increasing % non-viable myocardium, and digoxin use in follow-up were univariate predictors of death. Beta-blocker use, ejection fraction improvement, angina, aspirin use, and increasing fractional shortening were univariate predictors of survival. Ejection fraction improvement [P= 0.02, hazard ratio (HR) = 0.26], digoxin use in follow up (P= 0.006, HR = 5.85), and low-dose wall motion score (P= 0.017, HR = 4.78) were independent predictors of outcome. In step-wise analysis, low-dose wall motion score added incremental prognostic value to ejection fraction improvement (P= 0.003), and digoxin use in follow-up (P= 0.003) added incremental value to a low-dose score and ejection fraction improvement. CONCLUSION: Ejection fraction improvement is an independent predictor of long-term outcome in revascularized patients but viability (low-dose wall motion score) and digoxin use in follow-up are also independent predictors and add incremental prognostic value to ejection fraction improvement. PMID- 21551153 TI - Advanced right lung adenocarcinoma invading left atrium and left ventricle via right superior pulmonary vein and partially occluding mitral valve in diastole. PMID- 21551154 TI - Multimodality cardiac imaging of a giant left ventricular pseudoaneurysm. PMID- 21551155 TI - Infective ascending aortic graft pseudoaneurysm after Bentall surgery for type A aortic dissection diagnosed with magnetic resonance. PMID- 21551157 TI - It makes SENSE to take a safer road. PMID- 21551158 TI - XMRV, prostate cancer and chronic fatigue syndrome. AB - BACKGROUND: A new retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), was identified in 2006 and an association was claimed between it and a genetic polymorphism predisposing to cancer of the prostate. In 2009 the same virus was identified in a cohort of patients with chronic fatigue syndrome (CFS). In 2010 a second related virus was identified in a separate group of CFS patients. A series of studies from disparate geographical areas have failed to substantiate this work. Most recently several papers have suggested that the detection of these viruses was explained by laboratory contamination. SOURCES OF DATA: All papers including the wording XMRV were abstracted from the NIH library of medicine database and included in the analysis. AREAS OF AGREEMENT: XMRV is a newly described retrovirus whose nucleic acid has been identified in samples from patients with both prostate cancer and CFS. AREAS OF CONTROVERSY: Opinions differ as to whether the detected nucleic acid indicates infection with this virus in this disease or whether laboratory contamination of samples accounts for its presence. GROWING POINTS: An increasing number of papers now refute the association of XMRV with human disease in humans although there is some evidence of serological reactivity to the virus. While it is unlikely that XMRV is a major cause of either prostate cancer or CFS, it can infect human cells and might yet have a role in human disease. AREAS TIMELY FOR DEVELOPING RESEARCH: Further studies to either prove or disprove the disease association of the virus are ongoing. PMID- 21551160 TI - Effect of hypoxic acclimation on anoxia tolerance in Vitis roots: response of metabolic activity and K+ fluxes. AB - The effect of a hypoxic pre-treatment (HPT) on improving tolerance to prolonged anoxia conditions in two contrasting Vitis species (V. riparia, anoxia tolerant; V. rupestris, anoxia sensitive) was evaluated. The energy economy of root cells was studied by measuring heat production, the activity of pyruvate decarboxylase (PDC) and alcohol dehdrogenase (ADH), ethanol and ATP production, and K(+) fluxes. The results showed that HPT is an effective tool in order to maintain a sustainable metabolic performance in both the species under anoxia conditions, especially in sensitive species such as V. rupestris. Our results showed that the improved tolerance was mainly driven by: (i) an enhanced activity of key enzymes in alcohol fermentation (ADC and PDC); (ii) the capability to maintain a higher level of respiration, evidenced by a lesser decrease in heat development and ATP production; and (iii) the maintenance of a better ion homeostasis (highlighted by measurement of K(+) fluxes) and K(+) channel functionality. PMID- 21551161 TI - Influence of order and type of drug (bisoprolol vs. enalapril) on outcome and adverse events in patients with chronic heart failure: a post hoc analysis of the CIBIS-III trial. AB - AIMS: Angiotensin-converting enzyme inhibitors (ACE-Is) and beta-blockers are associated with improved outcome in patients with chronic heart failure (CHF). In this post hoc analysis of the CIBIS III trial, we examined the influence of the order of drug administration on clinical events and achieved dose. We also assessed the relations between dose levels and baseline variables or adverse events. METHODS AND RESULTS: In the CIBIS III trial, 1010 patients (mean age: 72.4 years; mean ejection fraction: 28.8%; male: 68.2%) with stable CHF were randomized to up-titration of monotherapy with either bisoprolol (target dose 10 mg o.d.) or enalapril (target dose 10 mg b.i.d.) for 6 months, followed by their combination for 6-24 months. Endpoints were mortality or all-cause hospitalization, mortality alone and mortality or cardiovascular hospitalization. The study drug (ACE-I or beta-blocker) was last prescribed at >=50% of target dose to significantly more patients for the first initiated drug in both treatment groups (both P< 0.001). Sixty per cent of endpoints were reached during the monotherapy phase and randomized treatment during monotherapy was not a predictor of the three assessed outcomes. Monotherapy phase was the strongest independent predictor of outcome (P< 0.0001 for all endpoints). Older age, NYHA class III, impaired renal function, lower body weight and blood pressure at baseline, and hypotension, bradycardia and heart failure during treatment were associated with the inability to reach high dose of both study drugs. CONCLUSION: The order of drug administration plays an important role in whether CHF patients reach target doses of bisoprolol and enalapril. For both study drugs, the dose level reached was associated with baseline characteristics and adverse events. In CHF patients not treated with an ACE-I or a beta-blocker, the duration of monotherapy with either type of drug should be shorter than 6 months. PMID- 21551159 TI - Rice debranching enzyme isoamylase3 facilitates starch metabolism and affects plastid morphogenesis. AB - Debranching enzymes, which hydrolyze alpha-1 and 6-glucosidic linkages in alpha polyglucans, play a dual role in the synthesis and degradation of starch in plants. A transposon-inserted rice mutant of isoamylase3 (isa3) contained an increased amount of starch in the leaf blade at the end of the night, indicating that ISA3 plays a role in the degradation of transitory starch during the night. An epitope-tagged ISA3 expressed in Escherichia coli exhibited hydrolytic activity on beta-limit dextrin and amylopectin. We investigated whether ISA3 plays a role in amyloplast development and starch metabolism in the developing endosperm. ISA3-green fluorescent protein (GFP) fusion protein expressed under the control of the rice ISA3 promoter was targeted to the amyloplast stroma in the endosperm. Overexpression of ISA3 in the sugary1 mutant, which is deficient in ISA1 activity, did not convert water-soluble phytoglycogen to starch granules, indicating that ISA1 and ISA3 are not functionally redundant. Both overexpression and loss of function of ISA3 in the endosperm generated pleomorphic amyloplasts and starch granules. Furthermore, chloroplasts in the leaf blade of isa3 seedlings were large and pleomorphic. These results suggest that ISA3 facilitates starch metabolism and affects morphological characteristics of plastids in rice. PMID- 21551162 TI - The effect of ventricular assist devices on long-term post-transplant outcomes: a systematic review of observational studies. AB - AIMS: Ventricular assist device (VAD) therapy is widely used as a bridge to cardiac transplant. Studies addressing the effect of VADs on post-transplant outcomes have shown conflicting results. It is imperative to review this evidence to inform clinical decision making and future research. Our aim was to systematically evaluate the effect of VAD therapy on long-term post-transplant outcomes in heart transplant recipients. METHODS AND RESULTS: We searched online databases (Medline, PubMed, Embase, and CINAHL) and references of included articles. Comparative studies evaluating the effect of VADs on post-transplant outcomes in adults were included and study results were meta-analysed using random-effects models. We conducted subgroup analyses to assess the effect estimate of extra- vs. intra-corporeal VADs and to evaluate the impact of transplant era and listing status. Overall, we identified 31 observational studies. One-year post-transplant mortality in recipients bridged with an extra corporeal VAD was significantly higher than in non-bridged recipients (RR 1.8, 95% CI 1.53-2.13, I(2)= 1%), while patients supported with an intra-corporeal VAD had similar mortality to non-bridged recipients (RR 1.08, 95% CI 0.95-1.22, I(2)= 0%). The risks of rejection within the first post-transplant year and coronary allograft vasculopathy were not significantly different between patients with or without VAD support prior to transplant. Publication bias was low; however, the risk of bias across studies was moderate to high. CONCLUSION: Intra-corporeal VAD support does not have a deleterious impact on post-transplant outcomes. However, post-transplant survival may be poorer in the subgroup of patients supported with extra-corporeal devices. Studies with greater methodological rigour are warranted. PMID- 21551163 TI - Soluble ST2, high-sensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure. AB - AIM: To investigate the use of biomarkers providing independent information regarding physiology in acutely decompensated heart failure (ADHF) for assessment of risk. METHODS AND RESULTS: This was a prospective study of 107 patients hospitalized with ADHF (mean age 72 +/- 13 years, 44% male, left ventricular ejection fraction 47 +/- 15%). Blood samples were collected on presentation to measure soluble (s)ST2, high-sensitivity troponin T (hsTnT), and amino-terminal pro-B type natriuretic peptide (NT-proBNP) levels. Clinical follow-up was obtained for all patients over a median period of 739 days, and all-cause mortality was registered. Concentrations of sST2 [per 10 ng/mL, hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.04-1.13; P< 0.001], hsTnT (per 0.1 ng/mL, HR 1.16, 95% CI 1.09-1.24; P< 0.001), and NT-proBNP (per 100 pg/mL, HR 1.01, 95% CI 1.003-1.01; P< 0.001) were each predictive of a higher risk of death. In bootstrapped models, each biomarker retained independent predictive value for mortality. Patients with all three biomarkers below their optimal cut-off at presentation were free of death (0%) during follow-up, whereas 53% of those with elevations of all three biomarkers had died. For each elevated marker (from 0 to 3) adjusted analysis suggested a tripling of the risk of death (for each elevated marker, HR 2.64, 95% CI 1.63-4.28, P< 0.001). Integrated discrimination analyses indicated that the use of these three markers in a multimarker approach uniquely improved prediction of death. CONCLUSIONS: Biomarkers reflecting remodelling (sST2), myonecrosis (hsTnT), and myocardial stretch (NT-proBNP) provide complementary prognostic information in patients with ADHF. When used together, these novel markers provide superior risk stratification. PMID- 21551164 TI - Life-threatening metabolic alkalosis in Pendred syndrome. AB - INTRODUCTION: Pendred syndrome, a combination of sensorineural deafness, impaired organification of iodide in the thyroid and goitre, results from biallelic defects in pendrin (encoded by SLC26A4), which transports chloride and iodide in the inner ear and thyroid respectively. Recently, pendrin has also been identified in the kidneys, where it is found in the apical plasma membrane of non alpha-type intercalated cells of the cortical collecting duct. Here, it functions as a chloride-bicarbonate exchanger, capable of secreting bicarbonate into the urine. Despite this function, patients with Pendred syndrome have not been reported to develop any significant acid-base disturbances, except a single previous reported case of metabolic alkalosis in the context of Pendred syndrome in a child started on a diuretic. CASE REPORT: We describe a 46-year-old female with sensorineural deafness and hypothyroidism, who presented with severe hypokalaemic metabolic alkalosis during inter-current illnesses on two occasions, and who was found to be homozygous for a loss-of-function mutation (V138F) in SLC26A4. Her acid-base status and electrolytes were unremarkable when she was well. CONCLUSION: This case illustrates that, although pendrin is not usually required to maintain acid-base homeostasis under ambient condition, loss of renal bicarbonate excretion by pendrin during a metabolic alkalotic challenge may contribute to life-threatening acid-base disturbances in patients with Pendred syndrome. PMID- 21551165 TI - Testicular size development and reproductive hormones in boys and adult males with Noonan syndrome: a longitudinal study. AB - OBJECTIVE: To characterise changes in testicular size and reproductive hormones and to investigate the aetiology of delayed puberty and impaired fertility in males with Noonan syndrome (NS). DESIGN: In this study, 12 males with NS were longitudinally followed from pre/early puberty until adulthood. Of the 12 males, ten had no medical history other than NS and were divided into two groups, undescended testes (UT), and descended testes (DT) and compared with a reference population. METHODS: Hormone concentrations in serum were determined by immunoassays and testicular volume was measured using an orchidometer. RESULTS: Before puberty, reproductive hormone levels were within the expected range in almost all cases. In some cases, LH, FSH and testosterone and oestradiol (E(2)) concentrations started to increase during puberty and inhibin B and anti Mullerian hormone (AMH) declined to subnormal levels. Most of the boys studied had small testes that, in the majority of cases, progressed to normal size in adulthood. No difference in reproductive hormones was observed between the UT and DT groups either during puberty or at adulthood. However, as adults, males with NS had higher LH (5.7 vs 4.0 U/l, P<0.01), FSH (7.1 vs 2.5 U/l, P<0.001), testosterone (18.7 vs 15.6 nmol/l, P<0.01) and E(2) (66 vs 46 pmol/l, P<0.001) levels and lower AMH (33 vs 65 pmol/l, P<0.01) and inhibin B (median 108 vs 187 pg/ml, P<0.01) levels than the reference population. CONCLUSIONS: In NS males, both Sertoli and Leydig cell dysfunction is common with reproductive hormone levels deteriorating progressively to adulthood. PMID- 21551166 TI - Analysis of expression and function of the inhibitory receptor ILT2 in lymphocytes from patients with autoimmune thyroid disease. AB - OBJECTIVE: Autoimmune thyroid disease (AITD) is characterized by different defects in immunoregulatory mechanisms. The immunoglobulin-like transcript receptor 2 (ILT2) or leukocyte Ig-like receptor 1 (LIRB1/CD85j) exerts an important immunoregulatory role. We hypothesized that the lymphocytes from AITD patients have a diminished expression and function of ILT2. The aim of this study was to investigate the expression and function of ILT2 in lymphocytes from patients with AITD. DESIGN AND METHODS: In this study, 18 patients with Hashimoto's thyroiditis (HT), 20 with Graves' disease, and 26 healthy controls were studied. ILT2 expression was analyzed by flow cytometry and immunohistochemistry in peripheral blood mononuclear cells (PBMC) and thyroid tissue. The regulatory function of ILT2 was assessed by an assay of inhibition of lymphocyte proliferation and by an analysis of cell cycle progression. The effect of ILT2 on cytokine synthesis was also evaluated. RESULTS: We found a significant increased expression of ILT2 by lymphocytes in AITD patients. ILT2 was also detected in the leukocyte infiltrate of thyroid tissue from HT patients. On the contrary, a significant diminished inhibitory activity of ILT2 on cell proliferation was observed in AITD patients. In addition, PBMC from AITD patients showed a diminished synthesis of interleukin 10 on ILT2 engagement. CONCLUSIONS: The abnormal expression and function of ILT2 detected in AITD suggests that this receptor may participate in the pathogenesis of this condition. PMID- 21551168 TI - Long-term outcome following interstitial laser photocoagulation of benign cold thyroid nodules. AB - AIM: To evaluate the long-term efficacy of interstitial laser photocoagulation (ILP) in solitary benign thyroid nodules. DESIGN AND METHODS: A total of 78 euthyroid outpatients (45 participating in randomized trials) with a benign solitary solid and scintigraphically cold thyroid nodule causing local discomfort were assigned to ILP. ILP (using one laser fiber) was performed under continuous ultrasound (US) guidance and with an output power of 1.5-3.5 W. Thyroid nodule volume was assessed by US and thyroid function determined by routine assays, before and during follow-up. Pressure symptoms and cosmetic complaints were evaluated on a visual analogue scale (0-10 cm). Of the total patients, six had thyroid surgery 6 months after ILP and three were lost to follow-up. The median follow-up for the remaining 69 patients was 67 months (range 12-114). RESULTS: The overall median nodule volume decreased from 8.2 ml (range 2.0-25.9) to 4.1 ml (range 0.6-33.0; P<0.001) at the final evaluation, corresponding to a median reduction of 51% (range: -194 to 95%). This correlated with a significant decrease in pressure as well as cosmetic complaints. After 12--96 months (median 38 months) of ILP, 21 patients (29%) had thyroid surgery because of an unsatisfactory result. All had benign histology. Thyroid function was unaltered throughout and side effects were restricted to mild local pain. CONCLUSION: US guided ILP results in a satisfactory long-term clinical response in the majority of patients with a benign solitary solid cold thyroid nodule. Further large-scale studies should aim at optimizing selection criteria for ILP, preferably in randomized studies. PMID- 21551167 TI - Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'etude des Tumeurs Endocrines. AB - CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed. OBJECTIVE: The aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1. DESIGN: Data regarding a study of 734 cases of MEN1 from the multicenter 'Groupe d'etude des Tumeurs Endocrines' were analyzed. RESULTS: There were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (P=0.06, P=0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P<0.001, P<0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (P=0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%). CONCLUSION: The phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia. PMID- 21551169 TI - Increased risk of stroke after Bell's palsy: a population-based longitudinal follow-up study. PMID- 21551170 TI - Amyotrophic lateral sclerosis and vascular risk: a metabolic conundrum. PMID- 21551171 TI - Keeping it simple: is there a need for the various subtyping of axonal forms of Guillain-Barre syndrome? PMID- 21551172 TI - The real onset of amyotrophic lateral sclerosis. PMID- 21551173 TI - Low index-to-ring finger length ratio in sporadic ALS supports prenatally defined motor neuronal vulnerability. AB - BACKGROUND: The aetiology of apparently sporadic amyotrophic lateral sclerosis (ALS) is unknown, but prenatal factors are known to influence disease development. In both men and women, motor neurons require testosterone for survival and axonal regeneration after injury, and androgen insensitivity leads to a form of motor neuron degeneration in men. Reduction in the ratio of index to ring finger length (2D:4D ratio) is considered a surrogate marker for high prenatal testosterone levels in both men and women. The authors therefore tested the hypothesis that prenatal testosterone irrespective of gender is an independent risk factor for the development of ALS later in life, and that this would be reflected in a lower 2D:4D ratio in both men and women with ALS. METHODS: Patients and unrelated control individuals attending a specialist tertiary referral centre for ALS were studied. A digital camera was used to photograph hands. Finger lengths were measured by four independent scorers blind to case-control status, and the mean 2D:4D ratio derived. Analysis was by linear regression and receiver-operator-curve analysis. RESULTS: Controlling for differences in sex ratio between groups, the 2D:4D ratio was lower for people with ALS (n=47) than for controls (n=63) (r=-0.25, two-tailed p=0.009). CONCLUSIONS: Patients with ALS have a lower 2D:4D ratio, consistent with higher prenatal circulating levels of testosterone, and possibly a prenatal influence of testosterone on motor-neuron vulnerability in later life. PMID- 21551174 TI - Non-conventional practices and immune functioning among individuals receiving conventional care for HIV. AB - OBJECTIVE: to examine the relationships among non-conventional practices, adherence and immune functioning in individuals with HIV. METHODS: 92 participants completed an interview on non-conventional practices (complementary and alternative medicines (CAM), psychosocial therapies, and religious practice). They also completed the Psychiatric Symptom Index and the AIDS Clinical Trials Group Adherence Follow-up Questionnaire. Medical chart reviews determined CD4 count and viral load. RESULTS: Hierarchical logistic regressions revealed religious practice was associated with adherence and CAM was associated with viral load. CONCLUSION: Participation in non-conventional practices in HIV populations may lead to positive health and health behaviors. Clinical implications are discussed. PMID- 21551176 TI - Feasibility study of a randomized controlled trial protocol to examine clinical effectiveness of shoulder strapping in acute stroke patients. AB - OBJECTIVE: The majority of stroke patients experience upper limb motor impairment and reduced ability to perform basic activities. Shoulder strapping has been reported as a beneficial adjunct to rehabilitation therapies but has not been rigorously trialled. This study tested the feasibility of recruitment, intervention and outcome assessment protocols for future trial of the clinical effectiveness of shoulder strapping. DESIGN AND SETTING: Feasibility study using a randomized controlled trial in an East London stroke service. SUBJECTS: Fourteen acute stroke patients with mild to moderate upper limb hemiparesis were recruited between October 2004 and July 2005. INTERVENTION: Five strapping methods and criteria for use were identified from the literature. Shoulder strapping applied for one month in addition to routine rehabilitation was compared to routine rehabilitation only. MAIN MEASURES: The Motor Assessment Scale, Fugl Meyer Scale - Arm section and the Nine Hole Peg Test were measured at baseline and 1, 2, 3 and 5 weeks later. The Stroke-specific Quality of Life questionnaire was delivered at 6 and 12 weeks post stroke. RESULTS: Useful findings were demonstrated in relation to the feasibility of all elements of the protocol. Motor Assessment Scale findings showed a small-moderate (0.27) effect size for the strapping intervention used as an adjunct to routine rehabilitation compared to routine rehabilitation alone. Sample size calculation indicated 312 participants would be adequate to test a null hypothesis of nil benefit additional to routine rehabilitation. CONCLUSION: Findings supported the value of pilot-testing, and enabled revision of the study protocol for future definitive trial. PMID- 21551175 TI - Eukaryotic-like Ser/Thr protein kinases SpkC/F/K are involved in phosphorylation of GroES in the Cyanobacterium synechocystis. AB - Serine/threonine protein kinases (STPKs) are the major participants in intracellular signal transduction in eukaryotes, such as yeasts, fungi, plants, and animals. Genome sequences indicate that these kinases are also present in prokaryotes, such as cyanobacteria. However, their roles in signal transduction in prokaryotes remain poorly understood. We have attempted to identify the roles of STPKs in response to heat stress in the prokaryotic cyanobacterium Synechocystis sp. PCC 6803, which has 12 genes for STPKs. Each gene was individually inactivated to generate a gene-knockout library of STPKs. We applied in vitro Ser/Thr protein phosphorylation and phosphoproteomics and identified the methionyl-tRNA synthetase, large subunit of RuBisCO, 6-phosphogluconate dehydrogenase, translation elongation factor Tu, heat-shock protein GrpE, and small chaperonin GroES as the putative targets for Ser/Thr phosphorylation. The expressed and purified GroES was used as an external substrate to screen the protein extracts of the individual mutants for their Ser/Thr kinase activities. The mutants that lack one of the three protein kinases, SpkC, SpkF, and SpkK, were unable to phosphorylate GroES in vitro, suggesting possible interactions between them towards their substrate. Complementation of the mutated SpkC, SpkF, and SpkK leads to the restoration of the ability of cells to phosphorylate the GroES. This suggests that these three STPKs are organized in a sequential order or a cascade and they work one after another to finally phosphorylate the GroES. PMID- 21551177 TI - Painting the picture. PMID- 21551178 TI - Do sons reduce parental mortality? AB - BACKGROUND: Although sons are thought to impose greater physiological costs on mothers than daughters, sons may be advantageous for parental survival in some social contexts. The authors examined the relationship between the sex composition of offspring and parental survival in contemporary China and Taiwan. Because of the importance of sons for the provision of support to elderly parents in these populations, the authors hypothesised that sons would have a beneficial effect on parental survival relative to daughters. METHODS: The authors used data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and the Taiwan Longitudinal Study of Aging (TLSA). The CLHLS sample consisted of 4132 individuals aged 65 years and over in 2002. The TLSA sample comprised two cohorts: 3409 persons aged 60 years and over in 1989 and 2193 persons aged 50-66 years in 1996. These cohorts were followed up for 3, 18 and 11 years, respectively. The Cox proportional hazards model was used to estimate the relationship between the sex composition of offspring and parental mortality. RESULTS: Based on seven measures of sex composition, no protective effect of sons was found in either China or Taiwan. For example, in the 1989 Taiwan sample, the hazard ratio (HR) for maternal mortality associated with having an eldest son was 0.979 (95% CI 0.863 to 1.111). In Taiwan, daughters may have been more beneficial than sons in reducing mortality in recent years. CONCLUSION: The authors offer several explanations for these findings, including possible benefits associated with emotional and interpersonal forms of support provided by daughters and negative impacts of conflicts arising between parents and resident daughters-in law. PMID- 21551179 TI - Timeliness of childhood vaccinations in 31 low and middle-income countries. AB - BACKGROUND: This study assessed the extent of delays in childhood vaccinations and examined sociodemographic correlates of delayed and missing vaccinations. METHODS: Datasets from the 2005-7 Multiple Indicator Cluster Surveys from 31 countries were used. Information on vaccinations was based on vaccination cards. Survival analysis was applied to assess age-specific vaccination rates, and multilevel logistic regression analysis was used to assess factors associated with delayed and missing vaccinations. RESULTS: The median vaccination coverage across all countries varied from 91% measles-containing vaccine (MCV) to 98% bacille Calmette-Guerin vaccine (BCG). The median fraction of timely administered vaccinations was 65% (range 14.5-97.2%) for BCG, 67% (11.6-89.3%) for the first dose of vaccine against diphtheria, tetanus and pertussis (DTP1), 41% (10.8 82.1%) for DTP3, 68% (29.7-90.3%) for the first dose of polio vaccine (polio1), 38% (10.5-81.0%) for polio3 and 51% (22.3-91.1%) for MCV. The median of the median delays across all countries was 2.1 weeks (IQR 0.9-3.0) for BCG, 2.4 weeks (1.5-3.1) for DTP1; 6.3 weeks (3.3-9.0) for DTP3; 2.0 weeks (1.3-3.1) for polio1, 6.6 weeks (4.3-9.3) for polio3 and 4.1 weeks (2.5-5.8) for MCV. A higher number of children in households and lower socioeconomic status were associated with delayed and missing vaccinations; however, the effects of socioeconomic gradient varied by country. CONCLUSION: Most countries achieved high up-to-date vaccination coverage. However, there were substantial vaccination delays. Collecting information on the timeliness of vaccination in national surveillance systems will provide a more complete view of vaccination coverage. Missing and delayed vaccinations can be addressed jointly in prevention programmes. PMID- 21551180 TI - New European rules require all herbal medicines to be registered. PMID- 21551181 TI - Full smoking ban is needed in Germany as study finds four out of five pubs flout regulations. PMID- 21551184 TI - Comparisons within randomised groups can be very misleading. PMID- 21551185 TI - Investigating suspected subarachnoid haemorrhage in adults. PMID- 21551187 TI - Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell 'stemness' via the bone morphogenetic protein pathway. AB - BACKGROUND: Promoter hypermethylation is an important and potentially reversible mechanism of tumour suppressor gene silencing in cancer. Compounds that demethylate tumour suppressor genes and induce differentiation of cancer cells, but do not have toxic side effects, would represent an exciting option in cancer therapy. Statins are cholesterol-lowering drugs with an excellent safety profile and associated with a reduced incidence of various cancers including colorectal cancer (CRC). The authors have previously shown that statins act by activating tumour suppressive bone morphogenetic protein (BMP) signalling in CRC, increasing expression of BMP2. BMP2 is silenced by hypermethylation in gastric cancer. AIM: To investigate whether BMP2 is methylated in CRC, whether statins can reverse this, and what implications this has for the use of statins in CRC. METHODS: Methylation-specific PCR, bisulphite sequencing, immunoblotting, reverse transcription PCR, quantitative PCR, fluorescence-activated cell sorting analysis, an in vitro DNA methyltransferase (DNMT) assay, and cell viability studies were performed on CRC cells. The effect of statins was confirmed in a xenograft mouse model. Results BMP2 is silenced by promoter hypermethylation in cell lines with the hypermethylator phenotype and in primary tumours. Treatment with lovastatin downregulates DNMT activity, leading to BMP2 promoter demethylation and to upregulation of expression of BMP2 as well as other genes methylated in CRC. Statins alter gene expression, indicating a shift from a stem like state to a more differentiated state, thereby sensitising cells to the effects of 5-fluorouracil. In a xenograft mouse model, simvastatin treatment induces BMP2 expression, leading to differentiation and reduced proliferation of CRC cells. CONCLUSIONS: Statins act as DNMT inhibitors, demethylating the BMP2 promoter, activating BMP signalling, inducing differentiation of CRC cells, and reducing 'stemness'. This study indicates that statins may be able to be used as differentiating agents in combined or adjuvant therapy in CRC with the CpG island methylator phenotype. PMID- 21551188 TI - Role of acute diverticulitis in the development of complicated colonic diverticular disease and 1-year mortality after diagnosis in the UK: population based cohort study. AB - OBJECTIVE: To determine the risk of developing complicated colonic diverticular disease (CCDD) with prior episodes of acute diverticulitis and determine the mortality of the spectrum of CCDD. DESIGN: Population-based cohort study. SETTING: Computerised records from the General Practice Research Database linked to Hospital Episode Statistics data from the UK. PARTICIPANTS: Patients and controls registered in the General Practice Research Database from 1990 to 2007. MAIN OUTCOME MEASURES: Mortality was calculated and Cox regression modelling used to provide adjusted HRs and 95% CI. Logistic regression was used to model the effect of prior acute diverticulitis on the development of complications. RESULTS: 2950 patients (1872 (63.5%) female) had a diagnosis of CCDD (8739 controls). A total of 1042 (35.3%) patients died compared with 2062 (23.6%) controls. Most excess deaths occurred in the first year after the complication. Patients with a perforation/abscess had a 4.5-fold increase in 1-year mortality (HR 4.55, 95% CI 3.74 to 5.52) compared with the general population, whereas those with a fistula or stricture had a 2.5-fold increase in mortality (fistula HR 2.60, 95% CI 1.47 to 4.62; stricture HR 2.41, 95% CI 1.86 to 3.11). Although most patients (2133 (72.3%)) had suffered no prior episodes of acute diverticulitis, increasing episodes of acute diverticulitis were associated with an increased risk of developing a fistula (two or more prior episodes, OR 1.54 95%, CI 1.08 to 2.19), but there was no clear relationship with stricture or perforation/abscess. CONCLUSIONS: Although most patients have experienced no prior episodes of acute diverticulitis, fistula formation is preceded by bouts of inflammation. Excess 1-year mortality across the spectrum of CCDD compared with the general population is substantial. PMID- 21551189 TI - IBD and arthropathies: a practical approach to its diagnosis and management. AB - Arthropathies are a major clinical problem in patients with inflammatory bowel disease (IBD). Often it is difficult to control the articular symptoms with the anti-inflammatory strategies used for IBD. Studies evaluating specific treatments aimed at articular manifestations in patients with IBD are rare. Although there has been considerable interest in the gut-joint axis over the last decade, the pathophysiological mechanisms driving IBD-associated arthropathy are still unknown. Recently, interest in the multidisciplinary approach to patients with IBD and arthropathy has been increasing. New research and clinical projects aimed at understanding the mechanisms of disease may advance the development of effective therapies. In this review, the pathophysiology of IBD-associated arthropathy is discussed, as well as clinical manifestations, the classification and current therapeutic strategies. PMID- 21551191 TI - Defra announces new animal health and welfare board. PMID- 21551190 TI - Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection. AB - BACKGROUND AND AIMS: CD8 T cells are central to the control of hepatitis C virus (HCV) although the key features of a successful CD8 T cell response remain to be defined. In a cohort of Irish women infected by a single source, a strong association between viral clearance and the human lecucocyte (HLA)-A*03 allele has been described, and the aim of this study was to define the protective nature of the associated CD8 T cell response. METHODS: A sequence-led approach was used to identify HLA-A*03-restricted epitopes. We examine the CD8 T cell response associated with this gene and address the likely mechanism underpinning this protective effect in this special cohort, using viral sequencing, T cell assays and analysis of fitness of viral mutants. RESULTS: A strong 'HLA footprint' in a novel NS3 epitope (TVYHGAGTK) was observed. A lysine (K) to arginine (R) substitution at position 9 (K1088R) was seen in a significant number of A*03 positive patients (9/12) compared with the control group (1/33, p=0.0003). Threonine (T) was also substituted with alanine (A) at position 8 (T1087A) more frequently in A*03-positive patients (6/12) compared with controls (2/33, p=0.01), and the double substitution of TK to AR was also observed predominantly in HLA-A*03-positive patients (p=0.004). Epitope-specific CD8 T cell responses were observed in 60% of patients three decades after exposure and the mutants selected in vivo impacted on recognition in vitro. Using HCV replicons matched to the viral sequences, viral fitness was found to be markedly reduced by the K1088R substitution but restored by the second substitution T1087A. CONCLUSIONS: It is proposed that at least part of the protective effect of HLA-A*03 results from targeting of this key epitope in a functional site: the requirement for two mutations to balance fitness and escape provides an initial host advantage. This study highlights the potential protective impact of common HLA-A alleles against persistent viruses, with important implications for HCV vaccine studies. PMID- 21551193 TI - Dietary changes reduce environmental impact of cows and sheep. PMID- 21551194 TI - BSAVA award winners 2011. PMID- 21551196 TI - Veterinary medicines: product update. PMID- 21551197 TI - VN qualifications: how the new system is bedding in. PMID- 21551198 TI - Vaccination of dogs and cats: no longer so controversial? PMID- 21551199 TI - Use of broiler litter as a bedding material for livestock. PMID- 21551200 TI - Treating mud fever in horses. PMID- 21551201 TI - Improving dairy cow welfare. PMID- 21551202 TI - Controlling bovine TB and valuing reactors. PMID- 21551211 TI - Pulmonary alveolar microlithiasis. PMID- 21551212 TI - Lung function and exposure to workplace second-hand smoke during exemptions from smoking ban legislation: an exposure-response relationship based on indoor PM2.5 and urinary cotinine levels. AB - BACKGROUND: The effects of workplace second-hand smoke (SHS) on lung function remain uncertain because of a lack of objective measures for SHS exposures. OBJECTIVE: To determine whether an exposure-response association exists between lung function and two different markers of SHS based on indoor fine particulate (PM(2.5)) and urinary cotinine levels in non-smoking catering workers. DESIGN: A cross-sectional study during a 1.5-year exemption of licensed catering premises from smoke-free legislation. Participants 186 non-smoking catering workers aged 18-65 years in Hong Kong were recruited. A declared non-smoking status was accepted in workers with exhaled breath carbon monoxide levels <6 ppm and urinary cotinine levels <100 ng/ml. MAIN OUTCOME MEASURES: Lung function measures of forced expiratory volume in 1s (FEV(1) in litres), forced vital capacity (FVC in litres) and forced expiratory flow as 25-75% of FVC (FEF(25-75) in l/s) were recorded. RESULTS: Indoor fine particulate (PM(2.5)) concentrations were 4.4 times as high in smoking premises (267.9 MUg/m(3)) than in non-smoking premises (60.3 MUg/m(3)) and were strongly associated with the probability of permitted smoking (R(2)=0.99). Smoking was the dominant source of particulates (R(2)=0.66). Compared with workers exposed to the lowest indoor PM(2.5) stratum (<25 MUg/m(3)), lung function was lower in the three higher PM(2.5) strata (25-75, 75 175, >175 MUg/m(3)) with FEV(1) -0.072 (95% CI -0.123 to -0.021), -0.078 (95% CI 0.132 to -0.024), -0.101 (95% CI -0.187 to -0.014); FEF(25-75) -0.368 (95% CI 0.660 to -0.077), -0.489 (95% CI -0.799 to -0.179), -0.597 (95% CI -0.943 to 0.251); and FEV(1)/FVC (%) -2.9 (95% CI -4.8 to -1.0), -3.2 (95% CI -5.1 to -1.4) and -4.4 (95% CI -7.4 to -1.3), respectively. Urinary cotinine was associated positively with indoor PM(2.5) but negatively with lung function. Consistently lower values for lung function per unit increase of indoor PM(2.5) were found. CONCLUSION: Lung function is inversely associated with workplace SHS. Workplace exemptions and delays in implementing smoke-free policies and current moves to relax legislation are a major threat to the health of workers. PMID- 21551213 TI - Law enforcement officers' attitudes about domestic violence. AB - This exploratory study examines attitudes about domestic violence among officers from a large urban police department. Additionally, this study examines whether attitudes vary according to officer characteristics. A total of 309 police officers responded to a survey that explored their attitudes and perceptions of domestic violence incidents. The results show that officers are well versed in handling domestic violence, though self-reports indicate that police personnel who respond to the calls are concerned about their limited amount of discretion. Additionally, when comparing attitudes based on officer characteristics, more similarities are found than differences. Implications for future research are discussed. PMID- 21551214 TI - Risk prediction of incident coronary heart disease in The Netherlands: re estimation and improvement of the SCORE risk function. AB - AIMS: To re-estimate the SCORE risk function using individual data on risk factors and coronary heart disease (CHD) incidence from the Dutch Cardiovascular Registry Maastricht (CAREMA) population-based cohort study; to evaluate changes that may improve risk prediction after re-estimation; and to compare the performance of the resulting CAREMA risk function with that of existing risk scores. METHODS AND RESULTS: The cohort consisted of 21,148 participants, born in 1927-1977 and randomly sampled from the Maastricht region in 1987-1997. After follow-up (median 10.9 years), 783 incident CHD cases occurred. Model performance was assessed by discrimination and calibration. The additional value of including other risk factors or current risk factors in a different manner was evaluated using the net reclassification index (NRI). The c statistic of the re-estimated SCORE model was 0.799 (95% CI 0.782-0.816). Separating the total/high-density lipoprotein (HDL) cholesterol ratio into total and HDL cholesterol levels did not improve the c statistic (p = 0.22), but reclassified 6.0% of the participants into a more appropriate risk category (p < 0.001) compared with the re-estimated model. The resulting CAREMA function reclassified 28% of the participants into a more appropriate risk category than the Framingham score. Compared with the SCORE functions for high- and low-risk regions, the NRIs were 28% and 35%, respectively, which can largely be explained by the difference in outcome definition (CHD incidence vs. CHD mortality). CONCLUSION: In this Dutch population, a re-estimated SCORE function with total and HDL cholesterol levels instead of the cholesterol ratio can be used for the risk prediction of CHD incidence. PMID- 21551215 TI - Glucose levels are associated with cardiovascular disease and death in an international cohort of normal glycaemic and dysglycaemic men and women: the EpiDREAM cohort study. AB - AIMS: In an international prospective cohort study we assessed the relationship between glucose levels and incident cardiovascular events and death. METHODS AND RESULTS: 18,990 men and women were screened for entry into the DREAM clinical trial from 21 different countries. All had clinical and biochemical information collected at baseline, including an oral glucose tolerance test (OGTT), and were prospectively followed over a median (IQR) of 3.5 (3.0-4.0) years for incident cardiovascular (CV) events including coronary artery disease (CAD), stroke, congestive heart failure (CHF) requiring hospitalization, and death. After OGTT screening, 8000 subjects were classified as normoglycaemic, 8427 had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), and 2563 subjects had newly diagnosed type 2 diabetes mellitus (DM). There were incident events in 491 individuals: 282 CAD, 54 strokes, 19 CHF, and 164 died. The annualized CV or death event rate was 0.79/100 person-years in the overall cohort, 0.51/100 person years in normoglycaemics, 0.92/100 person-years among subjects with IFG and/or IGT at baseline, and 1.27/100 person-years among those with DM (p for trend <0.0001). Among all subjects, a 1 mmol/l increase in fasting plasma glucose (FPG) or a 2.52 mmol/l increase in the 2-h post-OGTT glucose was associated with a hazard ratio increase in the risk of CV events or death of 1.17 (95% CI 1.13 1.22). CONCLUSIONS: In this large multiethnic cohort, the risk of CV events or death increased progressively among individuals who were normoglycaemic, IFG or IGT, and newly diagnosed diabetics. A 1 mmol/l increase in FPG was associated with a 17% increase in the risk of future CV events or death. Therapeutic or behavioural interventions designed to either prevent glucose levels from rising, or lower glucose among individuals with dysglycaemia should be evaluated. PMID- 21551216 TI - Latitudinal prevalence gradient of multiple sclerosis in Latin America. AB - BACKGROUND: Multiple sclerosis (MS) has a unique geographical distribution that reflects both genetic and environmental factors. Many studies have shown a positive correlation between MS frequency and latitude across both large and small geographical regions. However, scarce data have been published on the epidemiology of MS in Latin America and no study has evaluated latitudinal variation. OBJECTIVE: To evaluate the effect of latitude on MS prevalence in Latin America. METHODS: We conducted a systematic review of MS prevalence during January 2011. Prevalence rates were collected from eligible publications. The effect of latitude on prevalence was analyzed using linear regression. RESULTS: A total of ten studies were eligible for analysis, corresponding to six countries, spanning from Panama to Argentina. The crude prevalence of MS ranged from 0.75 to 21.5 per 100,000. We found a strong and significant association between prevalence and latitude (r(2) 0.8; p < 0.001) and determined an increase in prevalence of 0.33 per 100,000 per degree latitude. CONCLUSION: Our findings suggest a latitudinal prevalence gradient of MS in Latin American countries between Panama and Argentina. PMID- 21551217 TI - Use of mobile telemedicine for cervical cancer screening. AB - Visual inspection of the cervix with application of 4% acetic acid (VIA) is an inexpensive alternative to cytology-based screening in areas where resources are limited, such as in many developing countries. We have examined the diagnostic agreement between off-site (remote) expert diagnosis using photographs of the cervix (photographic inspection with acetic acid, PIA) and in-person VIA. The images for remote evaluation were taken with a mobile phone and transmitted by MMS. The study population consisted of 95 HIV-positive women in Gaborone, Botswana. An expert gynaecologist made a definitive positive or negative reading on the PIA results of 64 out of the 95 women whose PIA images were also read by the nurse midwives. The remaining 31 PIA images were deemed insufficient in quality for a reading by the expert gynaecologist. The positive nurse PIA readings were concordant with the positive expert PIA readings in 82% of cases, and the negative PIA readings between the two groups were fully concordant in 89% of cases. These results suggest that mobile telemedicine may be useful to improve access of women in remote areas to cervical cancer screening utilizing the VIA 'see-and-treat' method. PMID- 21551218 TI - msl2 mRNA is bound by free nuclear MSL complex in Drosophila melanogaster. AB - In Drosophila, the global increase in transcription from the male X chromosome to compensate for its monosomy is mediated by the male-specific lethal (MSL) complex consisting of five proteins and two non-coding RNAs, roX1 and roX2. After an initial sequence-dependent recognition by the MSL complex of 150-300 high affinity sites, the spread to the majority of the X-linked genes depends on local MSL-complex concentration and active transcription. We have explored whether any additional RNA species are associated with the MSL complex. No additional roX RNA species were found, but a strong association was found between a spliced and poly adenylated msl2 RNA and the MSL complex. Based on our results, we propose a model in which a non-chromatin-associated partial or complete MSL-complex titrates newly transcribed msl2 mRNA and thus regulates the amount of available MSL complex by feedback. This represents a novel mechanism in chromatin structure regulation. PMID- 21551219 TI - Highly fluorescent guanosine mimics for folding and energy transfer studies. AB - Guanosines with substituents at the 8-position can provide useful fluorescent probes that effectively mimic guanine residues even in highly demanding model systems such as polymorphic G-quadruplexes and duplex DNA. Here, we report the synthesis and photophysical properties of a small family of 8-substituted-2' deoxyguanosines that have been incorporated into the human telomeric repeat sequence using phosphoramidite chemistry. These include 8-(2-pyridyl)-2' deoxyguanosine (2PyG), 8-(2-phenylethenyl)-2'-deoxyguanosine (StG) and 8-[2 (pyrid-4-yl)-ethenyl]-2'-deoxyguanosine (4PVG). On DNA folding and stability, 8 substituted guanosines can exhibit context-dependent effects but were better tolerated by G-quadruplex and duplex structures than pyrimidine mismatches. In contrast to previously reported fluorescent guanine analogs, 8-substituted guanosines exhibit similar or even higher quantum yields upon their incorporation into nucleic acids (Phi = 0.02-0.45). We have used these highly emissive probes to quantify energy transfer efficiencies from unmodified DNA nucleobases to 8 substituted guanosines. The resulting DNA-to-probe energy transfer efficiencies (eta(t)) are highly structure selective, with eta(t)(duplex) < eta(t)(single strand) < eta(t)(G-quadruplex). These trends were independent of the exact structural features and thermal stabilities of the G-quadruplexes or duplexes containing them. The combination of efficient energy transfer, high probe quantum yield, and high molar extinction coefficient of the DNA provides a highly sensitive and reliable readout of G-quadruplex formation even in highly diluted sample solutions of 0.25 nM. PMID- 21551220 TI - DIANA-microT Web server upgrade supports Fly and Worm miRNA target prediction and bibliographic miRNA to disease association. AB - microRNAs (miRNAs) are small endogenous RNA molecules that are implicated in many biological processes through post-transcriptional regulation of gene expression. The DIANA-microT Web server provides a user-friendly interface for comprehensive computational analysis of miRNA targets in human and mouse. The server has now been extended to support predictions for two widely studied species: Drosophila melanogaster and Caenorhabditis elegans. In the updated version, the Web server enables the association of miRNAs to diseases through bibliographic analysis and provides insights for the potential involvement of miRNAs in biological processes. The nomenclature used to describe mature miRNAs along different miRBase versions has been extensively analyzed, and the naming history of each miRNA has been extracted. This enables the identification of miRNA publications regardless of possible nomenclature changes. User interaction has been further refined allowing users to save results that they wish to analyze further. A connection to the UCSC genome browser is now provided, enabling users to easily preview predicted binding sites in comparison to a wide array of genomic tracks, such as single nucleotide polymorphisms. The Web server is publicly accessible in www.microrna.gr/microT-v4. PMID- 21551221 TI - Patient preferences for a hospital-based rheumatology Interactive Health Communication Application and factors associated with these preferences. AB - OBJECTIVES: To examine current disease-related Internet use and intentions to use various online support services on a hospital-based Interactive Health Communication Application (IHCA) of patients with rheumatic diseases. Furthermore, to examine which variables are associated with the intentions to use different services. METHODS: Questionnaires were sent to a random sample of 484 patients of a large hospital's rheumatology clinic: response was 47% (n = 227). Questions included socio-demographics, health characteristics, health literacy, patients' current disease-related Internet use and their intentions to use eight different support services: (i) information about disease and treatment; (ii) information about care and support; (iii) peer communication; (iv) e consultation; (v) autonomous symptom monitoring; (vi) symptom monitoring with telemonitoring; (vii) self-management support; and (viii) access to their electronic medical records. RESULTS: Although most patients with Internet access had used it in relation to their disease (82%), Internet use was mainly limited to searching information. Many patients (45-68%), however, intended to use seven out of eight possible online services if offered on a hospital-based rheumatology IHCA. An exception was peer communication; only 11% intended to use this service. Of all the services, access to the electronic medical record was mostly preferred, followed by information provision. Demographics, health characteristics and health literacy did not show clear significant relationships with the reported intentions. CONCLUSION: Results show that patients with rheumatic diseases are interested in online support from the hospital and that they intend to use an IHCA, if it is available. Clear associating variables with reported intentions to use the different services were not found. PMID- 21551222 TI - Consistent avoidance of human disturbance over large geographical distances by a migratory bird. AB - Recent work on animal personalities has demonstrated that individuals may show consistent behaviour across situations and contexts. These studies were often carried out in one location and/or during short time intervals. Many animals, however, migrate and spend their life in several geographically distinct locations, and they may either adopt behaviours specific to the local environment or keep consistent behaviours over ecologically distinct locations. Long-distance migratory species offer excellent opportunities to test whether the animals maintain their personalities over large geographical scale, although the practical difficulties associated with these studies have hampered such tests. Here, we demonstrate for the first time consistency in disturbance tolerance behaviour in a long-distance migratory bird, using the common crane Grus grus as an ecological model species. Cranes that hatched in undisturbed habitats in Finland choose undisturbed migratory stop-over sites in Hungary, 1300-2000 km away from their breeding ground. This is remarkable, because these sites are not only separated by large distances, they also differ ecologically: the breeding sites are wooded bogs and subarctic tundra, whereas the migratory stop-over sites are temperate zone alkaline grasslands. The significance of our study goes beyond evolutionary biology and behavioural ecology: local effects on behaviour may carry over large distances, and this hitherto hidden implication of habitat selection needs to be incorporated into conservation planning. PMID- 21551223 TI - Leeches run cold, then hot. AB - Food processing is costly, potentially limiting the energy and time devoted to other essential functions such as locomotion or reproduction. In ectotherms, post prandial thermophily, the selection of a warm environmental temperature after feeding, may be advantageous in minimizing the duration of this elevated cost. Although present in many vertebrate taxa, this behaviour had not previously been observed in invertebrates. Sanguivorous leeches ingest large blood meals that are costly to process and limit mobility until excess fluid can actively be expelled to reduce body volume. When presented with a temperature gradient from 10 degrees C to 30 degrees C, leeches select a temperature that is significantly warmer (24.3 +/- 0.9 degrees C, n = 6) than their acclimation temperature (T(a), 21 degrees C). Unfed leeches preferred temperatures that were significantly cooler than ambient (12.8 +/- 0.9 degrees C, n = 6). This behavioural strategy is consistent with minimizing the time course of elevated post-feeding energy costs and reducing energy expenditure during fasting. Our observations raise the possibility that thermoregulatory behaviour of this type is an unrecognized feature of other invertebrate taxa. PMID- 21551224 TI - Commentary: Intelligence in youth and all-cause mortality: some problems in a recent meta-analysis. PMID- 21551225 TI - NFBD1/MDC1 regulates Cav1 and Cav2 independently of DNA damage and p53. AB - NFBD1/MDC1 is involved in DNA damage checkpoint signaling and DNA repair. NFBD1 binds to the chromatin component gammaH2AX at sites of DNA damage, causing amplification of ataxia telangiectasia-mutated gene (ATM) pathway signaling and recruitment of DNA repair factors. Residues 508-995 of NFBD1 possess transactivation activity, suggesting a possible role of NFBD1 in transcription. Furthermore, NFBD1 influences p53-mediated transcription in response to adriamycin. We sought to determine the role of NFBD1 in ionizing radiation (IR) responsive transcription and if NFBD1 influences transcription independently of p53. Using microarray analysis, we identified genes altered upon NFBD1 knockdown. Surprisingly, most NFBD1 regulated genes are regulated in both the absence and presence of IR, thus pointing toward a novel function for NFBD1 outside of the DNA damage response. Furthermore, NFBD1 knockdown regulated genes mostly independent of p53 knockdown. These genes are involved in pathways including focal adhesion signaling, carbohydrate metabolism, and insulin signaling. We found that CAV1 and CAV2 mRNA and protein levels are reduced by both NFBD1 knockdown and knockout independently of IR and p53. NFBD1-depleted cells exhibit some similar phenotypes to Cav1-depleted cells. Furthermore, like Cav1-depletion, NFBD1 shRNA increases Erk phosphorylation. Thus, Cav1 could act as a mediator of the DNA-damage independent effects of NFBD1 in mitogenic signaling. PMID- 21551226 TI - The association between financial hardship and amygdala and hippocampal volumes: results from the PATH through life project. AB - This study examined whether middle-aged adults exposed to poverty in childhood or current financial hardship have detectable brain differences from those who have not experienced such adversity. Structural magnetic resonance imaging (MRI) was conducted as one aspect of the Personality and Total Health (PATH) through life study: a large longitudinal community survey measuring the health and well-being of three cohorts from south-eastern Australia. This analysis considers data from 431 middle-aged adults in the aged 44-48 years at the time of the interview. Volumetric segmentation was performed with the Freesurfer image analysis suite. Data on socio-demographic circumstances, mental health and cognitive performance were collected through the survey interview. Results showed that, after controlling for well-established risk factors for atrophy, adults who reported financial hardship had smaller left and right hippocampal and amygdalar volumes than those who did not report hardship. In contrast, there was no reliable association between hardship and intra-cranial volume or between childhood poverty and any of the volumetric measures. Financial hardship may be considered a potent stressor and the observed results are consistent with the view that hardship influences hippocampal and amygdalar volumes through hypothalamic pituitary-adrenal axis function and other stress-related pathways. PMID- 21551227 TI - Influence of wheat milling on low-hydration bread quality developed by sheeting rolls. AB - It is well known that milling influences the characteristics of flour and products made from it. This article analyzed the influence of milling on the quality of low-hydration bread. In general, milling influenced the quality of these products more than the type of wheat selected. Among the various mill streams, the last break and reduction streams produced lower quality bread and must be eliminated in milling. These streams had a higher protein and ash content, showing the presence of components of the outer layers of the grain. The flour was able to absorb more water, but had less extensibility in kneading and the dough generated was weaker due the poorer quality of its proteins and the influence of elements from the outer layers. Thus, bread made from these streams had smaller volume, had a firmer texture and had both darker crumb and crust. These differences, along with the effect of the kind of flour on the flavor and aroma of the bread, made it less acceptable than flour from the rest of the streams studied. PMID- 21551228 TI - A phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605. AB - Older acute myeloid leukemia (AML) patients with a chromosome 5q deletion have poor outcomes with conventional chemotherapy. This phase 2 study explored the safety and efficacy of single-agent lenalidomide in previously untreated older AML patients with del(5q) who declined standard chemotherapy. Patients were treated with lenalidomide 50 mg daily for 28 days as induction therapy and 10 mg daily for 21 days of a 28-day cycle as maintenance until disease progression or unacceptable toxicity. Among 37 evaluable patients, the median age was 74 years (range, 60-94), 21 (57%) were female, 19 (51%) had prior myelodysplastic syndrome, and 30 (81%) had pretreatment cytogenetic studies evaluated centrally. Six had isolated del(5q), 1 had del(5q) and +8, 23 had complex cytogenetics, and 7 others had del(5q) identified locally. Fourteen patients (38%) completed induction therapy: 7 patients died during induction therapy, 8 had disease progression, 7 had nonfatal adverse events, and 1 entered hospice. Eight patients started maintenance therapy. Five patients (14%) achieved a partial or complete response, 2 with isolated del(5q) and 3 with complex cytogenetics. Relapse-free survival was 5 months (range, 0-19). Median overall survival was 2 months for the entire population. In conclusion, lenalidomide as a single agent has modest activity in older del(5q) AML patients. Southwest Oncology Group Study S0605 is registered at www.clinicaltrials.gov as NCT00352365. PMID- 21551229 TI - The RacGAP ArhGAP15 is a master negative regulator of neutrophil functions. AB - In phagocytes, GTPases of the Rac family control crucial antimicrobial functions. The RacGAP ArhGAP15 negatively modulates Rac activity in leukocytes, but its in vivo role in innate immunity remains largely unknown. Here we show that neutrophils and macrophages derived from mice lacking ArhGAP15 presented higher Rac activity but distinct phenotypes. In macrophages, the loss of ArhGAP15 induced increased cellular elongation and membrane protrusions but did not modify chemotactic responses. Conversely, the lack of ArhGAP15 in neutrophils affected critical Rac-dependent antimicrobial functions, specifically causing enhanced chemotactic responses, straighter directional migration, amplified reactive oxygen species production, increased phagocytosis, and improved bacterial killing. In vivo, in a model of severe abdominal sepsis, these effects contributed to increase neutrophil recruitment to the site of infection, thereby limiting bacterial growth, controlling infection spread, reducing systemic inflammation, and ultimately improving survival in ArhGAP15-null mice. Altogether, these results demonstrate the relevance of ArhGAP15 in the selective regulation of multiple neutrophil functions, suggesting that ArhGAP15 targeting might be beneficial in specific pathologic settings like severe sepsis. PMID- 21551230 TI - Ex vivo characterization and isolation of rare memory B cells with antigen tetramers. AB - Studying human antigen-specific memory B cells has been challenging because of low frequencies in peripheral blood, slow proliferation, and lack of antibody secretion. Therefore, most studies have relied on conversion of memory B cells into antibody-secreting cells by in vitro culture. To facilitate direct ex vivo isolation, we generated fluorescent antigen tetramers for characterization of memory B cells by using tetanus toxoid as a model antigen. Brightly labeled memory B cells were identified even 4 years after last immunization, despite low frequencies ranging from 0.01% to 0.11% of class-switched memory B cells. A direct comparison of monomeric to tetrameric antigen labeling demonstrated that a substantial fraction of the B-cell repertoire can be missed when monomeric antigens are used. The specificity of the method was confirmed by antibody reconstruction from single-cell sorted tetramer(+) B cells with single-cell RT PCR of the B-cell receptor. All antibodies bound to tetanus antigen with high affinity, ranging from 0.23 to 2.2 nM. Furthermore, sequence analysis identified related memory B cell and plasmablast clones isolated more than a year apart. Therefore, antigen tetramers enable specific and sensitive ex vivo characterization of rare memory B cells as well as the production of fully human antibodies. PMID- 21551231 TI - Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150. AB - Ontogenesis of T cells in the thymus is a complex process whose molecular control is poorly understood. The present study investigated microRNAs involved in human thymocyte differentiation by comparing the microRNA expression profiles of thymocytes at the double-positive, single-positive CD4(+) and single-positive CD8(+) maturation stages. Microarray analysis showed that each thymocyte population displays a distinct microRNA expression profile that reflects their developmental relationships. Moreover, analysis of small-RNA libraries generated from human unsorted and double-positive thymocytes and from mature peripheral CD4(+) and CD8(+) T lymphocytes, together with the microarray data, indicated a trend toward up-regulation of microRNA expression during T-cell maturation after the double-positive stage and revealed a group of microRNAs regulated during normal T-cell development, including miR-150, which is strongly up-regulated as maturation progresses. We showed that miR-150 targets NOTCH3, a member of the Notch receptor family that plays important roles both in T-cell differentiation and leukemogenesis. Forced expression of miR-150 reduces NOTCH3 levels in T-cell lines and has adverse effects on their proliferation and survival. Overall, these findings suggest that control of the Notch pathway through miR-150 may have an important impact on T-cell development and physiology. PMID- 21551232 TI - Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory disorder with a poor prognosis for affected individuals. To find a means of suppressing the clinical phenotype, we investigated the cellular and molecular mechanisms leading to HLH in Unc13d(jinx/jinx) mice, in which cytolytic function of NK and CD8(+) T cells is impaired. Unc13d(jinx/jinx) mutants infected with lymphochoriomeningitis virus (LCMV) present typical clinical features of HLH, including splenomegaly, elevated serum IFNgamma, and anemia. Proteins mediating cell-cell contact, cytokine signaling or Toll-like receptor (TLR) signaling were analyzed. We show that neither the integrin CD18, which is involved in adhesion between antigen presenting cells and effector T cells, nor tumor necrosis factor (TNF) made nonredundant contributions to the disease phenotype. Disruption of IFNgamma signaling reduced immune cell activation in Unc13d(jinx/jinx) mice, but also resulted in uncontrolled viral proliferation and exaggerated release of inflammatory cytokines. Abrogating the function of myeloid differentiation primary response gene 88 (MyD88) in Unc13d(jinx/jinx) mice suppressed immune cell activation and controlled cytokine production in an IL-1 receptor 1 (IL-1R1) independent way. Our findings implicate MyD88 as the key initiator of myeloid and lymphoid proliferation in HLH, and suggest that blockade of this signaling molecule may reduce immunopathology in patients. PMID- 21551233 TI - Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: results of an international study. AB - We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as >= 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied. PMID- 21551234 TI - HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy. AB - Hodgkin lymphoma (HL) incidence with HIV infection may have increased with the introduction of combination antiretroviral therapy (cART), suggesting that immune reconstitution may contribute to some cases. We evaluated HL risk with cART during the first months of treatment. With 187 HL cases among 64 368 HIV patients in France, relative rates (RRs) and 95% confidence intervals (CIs) of HL were estimated using Poisson models for duration of cART, CD4 count, and HIV load, with and without adjustment for demographic/clinical covariates. HL risk was unrelated to cART use overall, but it was related to time intervals after cART initiation (P = .006). Risk was especially and significantly elevated in months 1 3 on cART (RR 2.95, CI 1.64-5.31), lower in months 4-6 (RR 1.63), and null with longer use (RR 1.00). CD4 count was strongly associated with HL risk (P < 10-6), with the highest HL incidence at 50-99 CD4 cells/mm3. With adjustment for CD4 count and covariates, HL risk was elevated, but not significantly (RR 1.42), in months 1-3 on cART. HIV load had no added effect. HL risk increased significantly soon after cART initiation, which was largely explained by the CD4 count. Further studies of HIV-associated HL are needed. PMID- 21551235 TI - Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1-mediated transcriptional events. AB - Most antiangiogenic therapies currently being evaluated in clinical trials target the vascular endothelial growth factor pathway; however, the tumor vasculature can acquire resistance to vascular endothelial growth factor-targeted therapy by shifting to other angiogenesis mechanisms. Insulin-like growth factor binding protein-3 (IGFBP-3) has been reported to suppress tumor growth and angiogenesis by both IGF-dependent and IGF-independent mechanisms; however, understanding of its IGF-independent mechanisms is limited. We observed that IGFBP-3 blocked tumor angiogenesis and growth in non-small cell lung cancer and head and neck squamous cell carcinoma. Conditioned media from an IGFBP-3-treated non-small cell lung cancer cell line displayed a significantly decreased capacity to induce HUVEC proliferation and aortic sprouting. In cancer cells, IGFBP-3 directly interacted with Erk1/2, leading to inactivation of Erk1/2 and Elk-1, and suppressed transcription of early growth response protein 1 and its target genes, basic fibroblast growth factor and platelet-derived growth factor. These data suggest that IGF-independent Erk1/2 inactivation and decreased IGFBP-3-induced Egr-1 expression block the autocrine and paracrine loops of angiogenic factors in vascular endothelial and cancer cells. Together, these findings provide a molecular framework of IGFBP-3's IGF-independent antiangiogenic antitumor activities. Future studies are needed for development of IGFBP-3 as a new line of antiangiogengic cancer drug. PMID- 21551236 TI - Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. AB - Human mesenchymal stem/progenitor cells (hMSCs) repair tissues and modulate immune systems but the mechanisms are not fully understood. We demonstrated that hMSCs are activated by inflammatory signals to secrete the anti-inflammatory protein, TNF-alpha-stimulated gene 6 protein (TSG-6) and thereby create a negative feedback loop that reduces inflammation in zymosan-induced peritonitis. The results demonstrate for the first time that TSG-6 interacts through the CD44 receptor on resident macrophages to decrease zymosan/TLR2-mediated nuclear translocation of the NF-kappaB. The negative feedback loop created by MSCs through TSG-6 attenuates the inflammatory cascade that is initiated by resident macrophages and then amplified by mesothelial cells and probably other cells of the peritoneum. Because inflammation underlies many pathologic processes, including immune responses, the results may explain the beneficial effects of MSCs and TSG-6 in several disease models. PMID- 21551237 TI - PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia. AB - We have recently reported inactivation of the tyrosine phosphatase PTPN2 (also known as TC-PTP) through deletion of the entire gene locus in ~ 6% of T-cell acute lymphoblastic leukemia (T-ALL) cases. T-ALL is an aggressive disease of the thymocytes characterized by the stepwise accumulation of chromosomal abnormalities and gene mutations. In the present study, we confirmed the strong association of the PTPN2 deletion with TLX1 and NUP214-ABL1 expression. In addition, we found cooperation between PTPN2 deletion and activating JAK1 gene mutations. Activating mutations in JAK1 kinase occur in ~ 10% of human T-ALL cases, and aberrant kinase activity has been shown to confer proliferation and survival advantages. Our results reveal that some JAK1 mutation-positive T-ALLs harbor deletions of the tyrosine phosphatase PTPN2, a known negative regulator of the JAK/STAT pathway. We provide evidence that down-regulation of Ptpn2 sensitizes lymphoid cells to JAK1-mediated transformation and reduces their sensitivity to JAK inhibition. PMID- 21551238 TI - Secondary coenzyme Q10 deficiency triggers mitochondria degradation by mitophagy in MELAS fibroblasts. AB - Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mtDNA. Here, we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from 2 patients with MELAS who harbored the A3243G mutation. Both mitochondrial respiratory chain enzyme activities and coenzyme Q(10) (CoQ) levels were significantly decreased in MELAS fibroblasts. A similar decrease in mitochondrial membrane potential was found in intact MELAS fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and the activation of mitochondrial permeability transition (MPT), which triggered the degradation of impaired mitochondria. Furthermore, we found defective autophagosome elimination in MELAS fibroblasts. Electron and fluorescence microscopy studies confirmed a massive degradation of mitochondria and accumulation of autophagosomes, suggesting mitophagy activation and deficient autophagic flux. Transmitochondrial cybrids harboring the A3243G mutation also showed CoQ deficiency and increased autophagy activity. All these abnormalities were partially restored by CoQ supplementation. Autophagy in MELAS fibroblasts was also abolished by treatment with antioxidants or cyclosporine, suggesting that both reactive oxygen species and MPT participate in this process. Furthermore, prevention of autophagy in MELAS fibroblasts resulted in apoptotic cell death, suggesting a protective role of autophagy in MELAS fibroblasts. PMID- 21551239 TI - Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. AB - Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions for which new therapeutic approaches are needed. Genetic and pharmacological data point to a protective role of CB(1) and CB(2) cannabinoid receptor activation in IBD experimental models. Therefore, increasing the endogenous levels of 2 arachidonoylglycerol, the main full agonist of these receptors, should have beneficial effects on colitis. 2-Arachidonoylglycerol levels were raised in the trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model by inhibiting monoacylglycerol lipase (MAGL), the primary enzyme responsible for hydrolysis of 2-arachidonoylglycerol, using the selective inhibitor JZL184. MAGL inhibition in diseased mice increased 2-arachidonoylglycerol levels, leading to a reduction of macroscopic and histological colon alterations, as well as of colonic expression of proinflammatory cytokines. The restored integrity of the intestinal barrier function after MAGL inhibition resulted in reduced endotoxemia as well as reduced peripheral and brain inflammation. Coadministration of either CB(1) (SR141716A) or CB(2) (AM630) selective antagonists with JZL184 completely abolished the protective effect of MAGL inhibition on TNBS-induced colon alterations, thus demonstrating the involvement of both cannabinoid receptors. In conclusion, increasing 2-arachidonoylglycerol levels resulted in a dramatic reduction of colitis and of the related systemic and central inflammation. This could offer a novel pharmacological approach for the treatment of IBD based on the new protective role of 2-arachidonoylglycerol described here. PMID- 21551241 TI - Prospective study of UV exposure and cancer incidence among Swedish women. AB - BACKGROUND: Except for skin melanoma and nonmelanoma skin cancer, little evidence from prospective studies is available on the association between UV exposure and cancer risk. METHODS: We followed prospectively 49,261 women aged 30 to 49 years at enrollment in 1991 to 1992 for 15 years. Cancer incidence was analyzed by fitting Cox models, and estimating hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: 2,303 incident cases of cancer were diagnosed (breast: 1,053, ovary: 126, lung: 116, colon-rectum: 133, and brain: 116). No associations were found between any cumulative measure of UV exposure at ages 10 to 39 years and overall cancer risk. However, spending >=1 week/year between ages 10 and 29 years on sunbathing vacations led to an inverse association with overall cancer risk (HR: 0.70, 95% CI: 0.53-0.93) and breast cancer risk (HR: 0.56, 95% CI: 0.36 0.89) when compared with women who never went on such vacations. Solarium use was inversely associated with breast cancer risk, whereas >=2 sunburns/year was inversely associated with lung cancer risk. No other associations were found between sun exposure or solarium use at ages 10 to 39 years and cancer risk. CONCLUSION: We found no evidence of an association between any cumulative measure of UV exposure at ages 10 to 39 years and overall cancer risk. UV exposure earlier in life was related to reduced overall and breast cancer risk. IMPACT: Further research is needed to define the amount of solar or artificial UV exposure that may, or may not, be beneficial for cancer prevention. PMID- 21551240 TI - Intraplantar-injected ceramide in rats induces hyperalgesia through an NF-kappaB- and p38 kinase-dependent cyclooxygenase 2/prostaglandin E2 pathway. AB - Inflammatory pain represents an important unmet clinical need with important socioeconomic implications. Ceramide, a potent proinflammatory sphingolipid, has been shown to elicit mechanical hyperalgesia, but the mechanisms remain largely unknown. We now demonstrate that, in addition to mechanical hyperalgesia, intraplantar injection of ceramide (10 MUg) led to the development of thermal hyperalgesia that was dependent on induction of the inducible cyclooxygenase (COX 2) and subsequent increase of prostaglandin E(2) (PGE(2)). The development of mechanical and thermal hyperalgesia and increased production of PGE(2) was blocked by NS-398 (15-150 ng), a selective COX-2 inhibitor. The importance of the COX-2 to PGE(2) pathway in ceramide signaling was underscored by the findings that intraplantar injection of a monoclonal PGE(2) antibody (4 MUg) blocked the development of hyperalgesia. Our results further revealed that COX-2 induction is regulated by NF-kappaB and p38 kinase activation, since intraplantar injection of SC-514 (0.1-1 MUg) or SB 203580 (1-10 MUg), well-characterized inhibitors of NF kappaB and p38 kinase activation, respectively, blocked COX-2 induction and increased formation of PGE(2) and thermal hyperalgesia in a dose-dependent manner. Moreover, activation of NF-kappaB was dependent on upstream activation of p38 MAPK, since SB 203580 (10 MUg) blocked p65 phosphorylation, whereas p38 kinase phosphorylation was unaffected by NF-kappaB inhibition by SC-514 (1 MUg). Our findings not only provide mechanistic insight into the signaling pathways engaged by ceramide in the development of hyperalgesia, but also provide a potential pharmacological basis for developing inhibitors targeting the ceramide metabolic-to-COX-2 pathway as novel analgesics. PMID- 21551242 TI - MicroRNA signatures: novel biomarker for colorectal cancer? AB - Aberrant microRNA (miRNA) expression might be of potential use as diagnostic and prognostic biomarker for cancers. We reviewed studies published until March 2011 which assessed expression of miRNAs in colorectal cancer (CRC)/adenoma tissue and normal colorectal mucosa and in plasma of CRC/adenoma patients and healthy controls. Overall, 20 studies that investigated miRNA expression in tissue and 3 studies that investigated miRNA levels in plasma were included. A total of 160 miRNAs were found to be dysregulated in CRC. MiR-20a and miR-31 were found to be significantly upregulated in more than one study, and miR-143 and miR-145 were found to be significantly downregulated in CRC tissue in six or more studies. MiR 92a was significantly upregulated in CRC patients in two of the plasma-based studies and in CRC tissue in one of the tissue-based studies. Our results provide timely and relevant information for miRNAs as potential diagnostic biomarkers for CRC. The expression of miRNAs in plasma may be indicative of presence of CRC. Larger diagnostic studies are needed to evaluate potential use of miRNA expression in early detection and diagnosis of CRC. PMID- 21551243 TI - Parent attitudes about school requirements for human papillomavirus vaccine in high-risk communities of Los Angeles, California. AB - BACKGROUND: Human papillomavirus (HPV) immunization requirements for school entry could increase HPV vaccine uptake but are controversial. This study assessed parents' attitudes about HPV immunization requirements. METHODS: During October 2007 to June 2008, we conducted telephone surveys with 484 parents of girls attending middle/high schools serving communities in Los Angeles County with elevated cervical cancer rates. RESULTS: Parents were mostly Hispanic (81%) or African American (15%); 71% responded in Spanish. Many parents did not know if HPV vaccine works well (42%) or is unsafe (41%). Overall, 59% of parents agreed that laws requiring HPV vaccination for school attendance "are a good idea." In multivariable analysis, African Americans and Hispanics responding in English were less likely than Hispanics responding in Spanish to agree (aOR 0.1, 95% CI: 0.1-0.3; aOR 0.4, 95% CI: 0.2-0.8, respectively). Parents were less likely to agree with these laws if they did not believe the vaccine works well (aOR 0.2, 95% CI: 0.1-0.5) but more likely to agree if they believed the vaccine is not "too new for laws like these" (aOR 4.5, 95% CI: 2.6-8.0). Agreement with laws increased to 92% when including agreement that "these laws are okay only if parents can opt out." CONCLUSIONS: In this at-risk community, more than half of the parents agreed with HPV immunization requirements generally, and the vast majority agreed when including opt-out provisions. IMPACT: Support for HPV vaccine requirements may depend on race/ethnicity and inclusion of opt-out provisions. Information about vaccine efficacy and safety may increase support and reduce uncertainty about HPV vaccine in high-risk populations. PMID- 21551244 TI - Oral contraceptive use and survival in women with invasive breast cancer. AB - BACKGROUND: Oral contraceptives (OC) are widely used in the United States. Although the relation between OC use and breast cancer incidence has been widely studied, the few studies examining associations between OC use prior to breast cancer diagnosis and survival are inconsistent. METHODS: Women with invasive breast cancer participating in the Women's Contraceptive and Reproductive Experiences (CARE) Study, a population-based case-control study (4565 women ages 35-64 years), and the California Teachers Study (CTS) cohort (3929 women ages 28 91 years) were followed for vital status. A total of 1,064 women died in the CARE Study (median follow-up, 8.6 years) and 523 died in the CTS (median follow-up, 6.1 years). Cox proportional hazards regression provided hazard rate ratio estimates [(relative risk, RR)] with 95% confidence intervals (CIs) for risk of death from any cause and from breast cancer. RESULTS: No association was observed for any OC use prior to diagnosis and all-cause mortality [CARE Study: RR = 1.01 (95% CI = 0.86-1.19); CTS: RR = 0.84 (95% CI = 0.67-1.05)]. A decreased risk of all-cause mortality was observed in the CTS among women with more than 10 years of OC use (RR = 0.67, 95% CI = 0.47-0.96); however, no trend of decreasing risk with increasing OC duration was observed (P(trend) = 0.22), and no association was observed in the CARE study. No associations were observed for breast cancer specific mortality. CONCLUSIONS: OC use is not associated with all-cause or breast cancer-specific mortality among women with invasive breast cancer. IMPACT: These 2 independent studies demonstrated no overall association between OC use and survival among women with breast cancer. PMID- 21551245 TI - The B lineage transcription factor E2A regulates apoptosis in chronic lymphocytic leukemia (CLL) cells. AB - Chronic lymphocytic leukemia (CLL) is a common malignancy characterized by the accumulation of B lymphocytes with an antigen-experienced activated CD19(+)CD5(+) clonal phenotype. Clinically, ~50% of cases will behave more aggressively. Here, we investigate the role of the major B-cell transcription factor E2A, a known regulator of B-cell survival and proliferation, to CLL persistence. We show that E2A is elevated at the mRNA and protein levels relative to normal B-cell subsets. E2A silencing in primary CLL cells leads to a significant increase in spontaneous apoptosis in both CD38(+) (aggressive) and CD38(-) (indolent) cases. Moreover, E2A knockdown synergizes with the immunomodulatory drug lenalidomide to reduce CLL viability. E2A is known to restrain the proliferation of primary B and T lymphocytes at multiple stages of maturation and we report that targeted E2A disruption increases the frequency of Ki-67(+) CLL cells in the absence of effects on de novo proliferation. At the molecular level, E2A siRNA-treated CLL cells display reduced expression of key genes associated with survival and cell cycling including p27, p21 and mcl-1, of which the former two are known E2A target genes. Thus, E2A, a key transcription factor associated with the B-cell activation profile, regulates apoptosis in CLL and may contribute to disease pathology. PMID- 21551246 TI - SclR, a basic helix-loop-helix transcription factor, regulates hyphal morphology and promotes sclerotial formation in Aspergillus oryzae. AB - Most known basic-region helix-loop-helix (bHLH) proteins belong to a superfamily of transcription factors often involved in the control of growth and differentiation. Therefore, inappropriate expression of genes encoding bHLH proteins is frequently associated with developmental dysfunction. In our previously reported study, a novel bHLH protein-encoding gene (AO090011000215) of Aspergillus oryzae was identified. The gene-disrupted strain was found to produce dense conidia, but sparse sclerotia, relative to the parent strain. Here, to further analyze its function, we generated an overexpressing strain using the A. oryzae amyB gene promoter. Genetic overexpression led to a large number of initial hyphal aggregations and then the formation of mature sclerotia; it was therefore designated sclR (sclerotium regulator). At the same time, the sclR overexpressing strain also displayed both delayed and decreased conidiation. Scanning electron microscopy indicated that the aerial hyphae of the sclR overexpressing strain were extremely branched and intertwined with each other. In the generation of the SclR-enhanced green fluorescent protein (EGFP) expression strain, the SclR-EGFP protein fusion was conditionally detected in the nuclei. In addition, the loss of sclR function led to rapid protein degradation and cell lysis in dextrin-polypeptone-yeast extract liquid medium. Taken together, these observations indicate that SclR plays an important role in hyphal morphology, asexual conidiospore formation, and the promotion of sclerotial production, even retaining normal cell function, at least in submerged liquid culture. PMID- 21551247 TI - Live imaging of disseminated candidiasis in zebrafish reveals role of phagocyte oxidase in limiting filamentous growth. AB - Candida albicans is a human commensal and a clinically important fungal pathogen that grows in both yeast and hyphal forms during human infection. Although Candida can cause cutaneous and mucosal disease, systemic infections cause the greatest mortality in hospitals. Candidemia occurs primarily in immunocompromised patients, for whom the innate immune system plays a paramount role in immunity. We have developed a novel transparent vertebrate model of candidemia to probe the molecular nature of Candida-innate immune system interactions in an intact host. Our zebrafish infection model results in a lethal disseminated disease that shares important traits with disseminated candidiasis in mammals, including dimorphic fungal growth, dependence on hyphal growth for virulence, and dependence on the phagocyte NADPH oxidase for immunity. Dual imaging of fluorescently marked immune cells and fungi revealed that phagocytosed yeast cells can remain viable and even divide within macrophages without germinating. Similarly, although we observed apparently killed yeast cells within neutrophils, most yeast cells within these innate immune cells were viable. Exploiting this model, we combined intravital imaging with gene knockdown to show for the first time that NADPH oxidase is required for regulation of C. albicans filamentation in vivo. The transparent and easily manipulated larval zebrafish model promises to provide a unique tool for dissecting the molecular basis of phagocyte NADPH oxidase-mediated limitation of filamentous growth in vivo. PMID- 21551248 TI - Motivating smokers in the hospital pulmonary function laboratory to quit smoking by use of the lung age concept. AB - INTRODUCTION: The purpose of this study was to investigate the use of lung age to motivate a quit attempt among smokers presenting to a hospital pulmonary function testing (PFT) laboratory. METHODS: Participants were randomized to receive a lung age-based motivational strategy (intervention group) versus standard care (control group). At 1 month, all participants were interviewed by telephone to determine whether they made a quit attempt. RESULTS: A total of 67 participants were enrolled, and 51 completed the study. Baseline mean data included age = 52 years, 70% women, 40 pack-years of smoking, FEV(1) = 69% predicted, and lung age = 83 years. The quit attempt rates were not different between the intervention and control groups (32% vs. 24%, respectively, p = .59). There was a near significant interaction between lung age and intervention strategy (p = .089), with quit attempt rates among those with normal lung age of 18% in the intervention group versus 33% in the control group and among those with high (worse) lung age of 39% in the intervention group versus 17% in the control group; p = .38. CONCLUSIONS: Using lung age to motivate smokers presenting to the PFT laboratory to quit may succeed in patients with high lung age but may undermine motivation in smokers with normal lung age. Further work is needed to refine the approach to smokers with normal lung age. PMID- 21551249 TI - Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. AB - Plexiform neurofibromas are peripheral nerve sheath tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. To understand whether neurofibroma formation is possible after birth, we induced Nf1 loss of function with an inducible proteolipid protein Cre allele. Perinatal loss of Nf1 resulted in the development of small plexiform neurofibromas late in life, whereas loss in adulthood caused large plexiform neurofibromas and morbidity beginning 4 months after onset of Nf1 loss. A conditional EGFP reporter allele identified cells showing recombination, including peripheral ganglia satellite cells, peripheral nerve S100beta+ myelinating Schwann cells, and peripheral nerve p75+ cells. Neurofibromas contained cells with Remak bundle disruption but no recombination within GFAP+ nonmyelinating Schwann cells. Extramedullary lympho hematopoietic expansion was also observed in PlpCre;Nf1fl/fl mice. These tumors contained EGFP+/Sca-1+ stromal cells among EGFP-negative lympho-hematopoietic cells indicating a noncell autonomous effect and unveiling a role of Nf1-deleted microenvironment on lympho-hematopoietic proliferation in vivo. Together these findings define a tumor suppressor role for Nf1 in the adult and narrow the range of potential neurofibroma-initiating cell populations. PMID- 21551250 TI - Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development. AB - Stem cells are under strict regulation by both intrinsic factors and the microenvironment. There is increasing evidence that many cancers initiate through acquisition of genetic mutations (loss of intrinsic control) in stem cells or their progenitors, followed by alterations of the surrounding microenvironment (loss of extrinsic control). In neurofibromatosis type 1 (NF1), deregulation of Ras signaling results in development of multiple neurofibromas, complex tumors of the peripheral nerves. Neurofibromas arise from the Schwann cell lineage following loss of function at the NF1 locus, which initiates a cascade of interactions with other cell types in the microenvironment and additional cell autonomous modifications. In this study, we sought to identify whether a temporal "window of opportunity" exists during which cells of the Schwann cell lineage can give rise to neurofibromas following loss of NF1. We showed that acute loss of NF1 in both embryonic and adult Schwann cells can lead to neurofibroma formation. However, the embryonic period when Schwann cell precursors and immature Schwann cells are most abundant coincides with enhanced susceptibility to plexiform neurofibroma tumorigenesis. This model has important implications for understanding early cellular events that dictate neurofibroma development, as well as for the development of novel therapies targeting these tumors. PMID- 21551251 TI - Endogenous PMN sialidase activity exposes activation epitope on CD11b/CD18 which enhances its binding interaction with ICAM-1. AB - Diapedesis is a dynamic, highly regulated process by which leukocytes are recruited to inflammatory sites. We reported previously that removal of sialyl residues from PMNs enables these cells to become more adherent to EC monolayers and that sialidase activity within intracellular compartments of resting PMNs translocates to the plasma membrane following activation. We did not identify which surface adhesion molecules were targeted by endogenous sialidase. Upon activation, beta2 integrin (CD11b/CD18) on the PMN surface undergoes conformational change, which allows it to bind more tightly to the ICAM-1 and ICAM-2 on the EC surface. Removal of sialyl residues from CD18 and CD11b, by exogenous neuraminidase or mobilization of PMN sialidase, unmasked activation epitopes, as detected by flow cytometry and enhanced binding to ICAM-1. One sialidase isoform, Neu1, colocalized with CD18 on confocal microscopy. Using an autoperfused microflow chamber, desialylation of immobilized ICAM-1 enhanced leukocyte arrest in vivo. Further, treatment with a sialidase inhibitor in vivo reversed endotoxin-induced binding of leukocytes to ICAM-1, thereby suggesting a role for leukocyte sialidase in the cellular arrest. These data suggest that PMN sialidase could be a physiologic source of the enzymatic activity that removes sialyl residues on beta2 integrin and ICAM-1, resulting in their enhanced interaction. Thus, PMN sialidase may be an important regulator of the recruitment of these cells to inflamed sites. PMID- 21551252 TI - Modulation of human beta-defensin-1 (hBD-1) in plasmacytoid dendritic cells (PDC), monocytes, and epithelial cells by influenza virus, Herpes simplex virus, and Sendai virus and its possible role in innate immunity. AB - hBD comprise a family of antimicrobial peptides that plays a role in bridging the innate and adaptive immune responses to infection. The expression of hBD-2 increases upon stimulation of numerous cell types with LPS and proinflammatory cytokines. In contrast, hBD-1 remains constitutively expressed in most cells in spite of cytokine or LPS stimulation; however, its presence in human PDC suggests it plays a role in viral host defense. To examine this, we characterized the expression of hBD-1 in innate immune cells in response to viral challenge. PDC and monocytes increased production of hBD-1 peptide and mRNA as early as 2 h following infection of purified cells and PBMCs with PR8, HSV-1, and Sendai virus. However, treatment of primary NHBE cells with influenza resulted in a 50% decrease in hBD-1 mRNA levels, as measured by qRT-PCR at 3 h following infection. A similar inhibition occurred with HSV-1 challenge of human gingival epithelial cells. Studies with HSV-1 showed that replication occurred in epithelial cells but not in PDC. Together, these results suggest that hBD-1 may play a role in preventing viral replication in immune cells. To test this, we infected C57BL/6 WT mice and mBD-1((-/-)) mice with mouse-adapted HK18 (300 PFU/mouse). mBD-1((-/ )) mice lost weight earlier and died sooner than WT mice (P=0.0276), suggesting that BD-1 plays a role in early innate immune responses against influenza in vivo. However, lung virus titers were equal between the two mouse strains. Histopathology showed a greater inflammatory influx in the lungs of mBD-1((-/-)) mice at Day 3 postinfection compared with WT C57BL/6 mice. The results suggest that BD-1 protects mice from influenza pathogenesis with a mechanism other than inhibition of viral replication. PMID- 21551253 TI - Association of CHFR promoter methylation with disease recurrence in locally advanced colon cancer. AB - PURPOSE: This study was designed to determine whether DNA methylation biomarkers are associated with recurrence and survival in colon cancer patients. EXPERIMENTAL DESIGN: A retrospective analysis of 82 patients who received curative surgical resection for American Joint Committee on Cancer (AJCC) high risk stage II or III colon cancer (1999-2007) was conducted. DNA methylation status was quantitatively evaluated by the pyrosequencing method. We preselected three tumor suppressor genes and one locus of interest; CHFR, ID4, RECK, and MINT1. Mean methylation levels of multiple CpG sites in the promoter regions were used for analysis; 15% or more was defined as methylation positive. The association of recurrence-free survival (RFS) and overall survival (OS) with methylation status was analyzed by the log-rank test, Kaplan-Meier method, and Cox proportional hazards model. RESULTS: Methylation levels of ID4, MINT1, and RECK did not correlate with RFS or OS. CHFR was methylation positive in 63% patients. When methylation status was dichotomized (negative or low: <30%, high: >=30%), patients with CHFR methylation-high (44%) had worse RFS (P = 0.006) and reduced OS (P = 0.069). When stratified by stage, CHFR methylation-high was associated with reduced RFS (P = 0.004) and OS (P = 0.010) in stage III patients. CHFR methylation-high was commonly associated with N2 disease (P = 0.04) and proximal tumors (P = 0.002). Multivariate analysis indicated AJCC T4 disease and CHFR methylation-high (P = 0.001 and P = 0.015, respectively) were independent predictors for recurrence. CONCLUSIONS: The extent of CHFR promoter methylation correlates with RFS, indicating it is a promising epigenetic marker for recurrence. PMID- 21551254 TI - Integrated, genome-wide screening for hypomethylated oncogenes in salivary gland adenoid cystic carcinoma. AB - PURPOSE: Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy that is poorly understood. To look for relevant oncogene candidates under the control of promoter methylation, an integrated, genome-wide screen was conducted. EXPERIMENTAL DESIGN: Global demethylation of normal salivary gland cell strains using 5-aza-2'-deoxycytidine (5-aza-dC) and trichostatin A (TSA), followed by expression array analysis was conducted. ACC-specific expression profiling was generated using expression microarray analysis of primary ACC and normal samples. Next, the two profiles were integrated to identify a subset of genes for further validation of promoter demethylation in ACC versus normal. Finally, promising candidates were further validated for mRNA, protein, and promoter methylation levels in larger ACC cohorts. Functional validation was then conducted in cancer cell lines. RESULTS: We found 159 genes that were significantly re-expressed after 5-aza-dC/TSA treatment and overexpressed in ACC. After initial validation, eight candidates showed hypomethylation in ACC: AQP1, CECR1, C1QR1, CTAG2, P53AIP1, TDRD12, BEX1, and DYNLT3. Aquaporin 1 (AQP1) showed the most significant hypomethylation and was further validated. AQP1 hypomethylation in ACC was confirmed with two independent cohorts. Of note, there was significant overexpression of AQP1 in both mRNA and protein in the paraffin-embedded ACC cohort. Furthermore, AQP1 was upregulated in 5-aza-dC/TSA-treated SACC83. Finally, AQP1 promoted cell proliferation and colony formation in SACC83. CONCLUSIONS: Our integrated, genome-wide screening method proved to be an effective strategy for detecting novel oncogenes in ACC. AQP1 is a promising oncogene candidate for ACC and is transcriptionally regulated by promoter hypomethylation. PMID- 21551255 TI - Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis. AB - PURPOSE: Currently, there are no approved targeted therapies for the treatment of ovarian cancer, despite the fact that it is the most lethal gynecological malignancy. One proposed target is c-Met, which has been shown to be an important prognostic indicator in a number of malignancies, including ovarian cancer. The objective of this study was to determine whether an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) blocks ovarian cancer growth. EXPERIMENTAL DESIGN: The effect of foretinib was tested in a genetic mouse model of endometrioid ovarian cancer, several ovarian cancer cell lines, and an organotypic 3D model of the human omentum. RESULTS: In the genetic mouse model, treatment with foretinib prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. In 2 xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced overall tumor burden (86% inhibition, P < 0.0001) and metastasis (67% inhibition, P < 0.0001). The mechanism of inhibition by foretinib involved (a) inhibition of c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, (c) a block in migration and invasion, (d) reduced proliferation mediated by a G(2)-M cell-cycle arrest, and (e) induction of anoikis. CONCLUSIONS: This study shows that foretinib blocks tumorigenesis and reduces invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions. We believe that it provides a rationale for the further clinical development of foretinib for the treatment of ovarian cancer. PMID- 21551256 TI - Obstacles to colorectal screening in general practice: a qualitative study of GPs and patients. AB - BACKGROUND: The faecal occult blood test (FOBT) has proven efficiency at screening populations for an average risk of colorectal cancer. Mortality related to this cancer decreases by 15-18% among adults, 50-74 years old, tested every 2 years. A participation rate of at least 50% is desirable. This rate has not yet been reached in most French regions. OBJECTIVE: To explore the obstacles to mass colorectal screening in France. METHOD: In 2009, five focus groups were conducted in different areas to explore physicians' obstacles to FOBT screening. The patients' obstacles were assessed in semi-structured interviews. A purposive sampling had been carried out for both GPs and patients. The focus groups were coded using Nvivo 8((r)) software by three researchers; the interviews manually coded by two researchers. RESULTS: GPs reported insufficient training and some doubted the relevance of screening. They expressed concern of having insufficient time for the test during a consultation, as well as practical and administrative obstacles. Some GPs experienced difficulty persuading patients who had no signs of colorectal disease. Obstacles for patients were mainly difficulties in doing screening themselves and a perception of health care that didn't match with screening. Information and organization were also important points to improve. The screening process was considered complex both by GPs and by patients. CONCLUSIONS: Numerous obstacles to colorectal screening, from both the physicians' and the patients' perspectives, were found. The major goal to improve mass screening may be to increase awareness and understanding of both physicians and patients regarding this process. PMID- 21551257 TI - Effects of ketamine on human UDP-glucuronosyltransferases in vitro predict potential drug-drug interactions arising from ketamine inhibition of codeine and morphine glucuronidation. AB - In this study, the selectivity of UDP-glucuronosyltransferase (UGT) enzyme inhibition by ketamine (KTM) and the kinetics of KTM inhibition of human liver microsomal morphine (MOR) and codeine (COD) glucuronidation were characterized to explore a pharmacokinetic basis for the KTM-opioid interaction. With the exception of UGT1A4, KTM inhibited the activities of recombinant human UGT enzymes in a concentration-dependent manner. However, IC(50) values were <100 MUM only for UGT2B4, UGT2B7, and UGT2B15. UGT2B7 catalyzes MOR 3- and 6 glucuronidation and the 6-glucuronidation of COD, with an additional substantial contribution of UGT2B4 to the latter reaction. Consistent with the effects of KTM on the activities of recombinant UGT2B enzyme activities, KTM competitively inhibited human liver microsomal MOR and COD glucuronidation. K(i) values for KTM inhibition of MOR 3- and 6-glucuronidation and COD 6-glucuronidation by human liver microsomes supplemented with 2% bovine serum albumin were 5.8 +/- 0.1, 4.6 +/- 0.2, and 3.5 +/- 0.1 MUM, respectively. Based on the derived inhibitor constants, in vitro-in vivo extrapolation was used to predict the effects of anesthetic and analgesic doses of KTM on MOR and COD clearances. Potentially clinically significant interactions (>50% increases in the in vivo area under the curve ratios) with MOR and COD were predicted for anesthetic doses of KTM and for a subanesthetic dose of KTM on COD glucuronidation. PMID- 21551258 TI - The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells. AB - One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemo-resistant tumors. The aim of this study is to evaluate the role of Palomid 529 (P529), a novel TORC1/TORC2 inhibitor, in association with docetaxel (DTX) and cisplatin (CP). This work utilizes a wide panel of prostatic cancer cell lines with or without basal activation of Akt as well as two in vivo models of aggressive HRPC. The blockade of Akt/mTOR activity was associated to reduced cell proliferation and induction of apoptosis. Comparison of IC50 values calculated for PTEN-positive and PTEN-negative cell lines as well as the PTEN transfection in PC3 cells or PTEN silencing in DU145 cells revealed that absence of PTEN was indicative for a better activity of the drug. In addition, P529 synergized with DTX and CP. The strongest synergism was achieved when prostate cancer (PCa) cells were sequentially exposed to CP or DTX followed by treatment with P529. Treatment with P529 before the exposure to chemotherapeutic drugs resulted in a moderate synergism, whereas intermediated values of combination index were found when drugs were administered simultaneously. In vivo treatment of a combination of P529 with DTX or CP increased the percentage of complete responses and reduced the number of mice with tumor progression. Our results provide a rationale for combinatorial treatment using conventional chemotherapy and a Akt/mTOR inhibitor as promising therapeutic approach for the treatment of HRPC, a disease largely resistant to conventional therapies. PMID- 21551259 TI - In vitro transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu, and Arg886Trp. AB - Multiple endocrine neoplasia type 2 and a subset of apparently sporadic medullary thyroid carcinoma (AS-MTC) are caused by germ line activating point mutations of the rearranged during transfection (RET) proto-oncogene. RET encodes a receptor with tyrosine kinase activity that targets several intracellular signaling cascades, such as RAS-RAF-ERK1/2, PIK3-AKT, and STAT transcription factors. The objective of this study was to assess the function of three germ line RET variants Arg886Trp, Ser649Leu, and Glu511Lys of undetermined pathogenic significance, which were found in three kindreds of isolated AS-MTC. For this purpose, we employed vectors expressing each of the RET variants and measured the number of NIH3T3 transformation foci and soft agar colonies, the degree of activation of known RET intracellular signaling targets (ERK1/2, STAT1, STAT3, and TCF4), and the extent of ERK1/2 inhibition on sorafenib treatment. We found that RET variants Arg886Trp and Glu511Lys have shown increased in vitro transforming potential in a glial-derived neurotrophic factor-dependent manner. In contrast, the Ser649Leu variant did not significantly increased the number of foci and agar colonies relative to wild-type RET (RET-WT). The variants Glu511Lys and Arg886Trp showed 10- and 12.5-fold ERK1/2 activation respectively, that was significantly higher than that observed for RET-WT (fivefold). Increased levels of STAT1 and TCF4 activation were only observed for RET Arg886Trp (2.5- and 3 fold versus 1.2- and 2-fold in RET-WT respectively). The three RET variants analyzed here were sensitive to treatment with sorafenib. In conclusion, our results allow to classify previously uncharacterized RET genotypes, which may be of use to define follow-up and therapeutic regimens. PMID- 21551260 TI - E7080 suppresses hematogenous multiple organ metastases of lung cancer cells with nonmutated epidermal growth factor receptor. AB - While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors improve the prognosis of patients with EGFR mutant lung cancer, the prognosis of patients with nonmutant EGFR lung cancer, especially those with metastases, is still extremely poor. We have assessed the therapeutic efficacy of E7080, an orally available inhibitor of multiple tyrosine kinases including VEGF receptor 2 (VEGFR 2) and VEGFR-3, in experimental multiple organ metastasis of lung cancer cell lines without EGFR mutations. E7080 markedly inhibited the in vitro proliferation of VEGF-stimulated microvascular endothelial cells. Intravenous inoculation into natural killer cell-depleted severe combined immunodeficient mice of the small cell lung cancer cell lines H1048 (producing low amounts of VEGF) and SBC-5 (producing intermediate amounts of VEGF) resulted in hematogenous metastases into multiple organs, including the liver, lungs, kidneys, and bones, whereas intravenous inoculation of PC14PE6, a non-small cell lung cancer cell line producing high amounts of VEGF, resulted in lung metastases followed by massive pleural effusion. Daily treatment with E7080 started after the establishment of micrometastases significantly reduced the number of large (>2 mm) metastatic nodules and the amount of pleural effusion, and prolonged mouse survival. Histologically, E7080 treatment reduced the numbers of endothelial and lymph endothelial cells and proliferating tumor cells and increased the number of apoptotic cells in metastatic nodules. These results suggest that E7080 has antiangiogenic and antilymphangiogenic activity and may be of potential therapeutic value in patients with nonmutant EGFR lung cancer and multiple organ metastases. PMID- 21551261 TI - Expression signatures of the lipid-based Akt inhibitors phosphatidylinositol ether lipid analogues in NSCLC cells. AB - Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphoinositide-3-kinase (PI3K) that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of five active PIAs and the PI3K inhibitor LY294002 (LY) was conducted in non-small cell lung carcinoma cells using high-density oligonucleotide arrays. Gene ontology analysis revealed that genes involved in apoptosis, wounding response, and angiogenesis were upregulated by PIAs, whereas genes involved in DNA replication, repair, and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3, and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB), and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity. PMID- 21551263 TI - Chemotherapy dosing schedule influences drug resistance development in ovarian cancer. AB - Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of patients with metastatic, late-stage ovarian cancer. The present study addressed whether changes in the chemotherapy dosing schedule affect the development, further worsening, or circumvention of drug resistance in chemosensitive and chemoresistant ovarian cancer. Severe combined immunodeficient mice bearing HeyA8 and HeyA8-MDR xenografts were treated with docetaxel intermittently (1*/wk or 3*/wk) or continuously for 21 days. Tumor mRNA expression of genes implicated in docetaxel resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters mdr1 and mrp7 and for molecules that interfere with or overcome the effects of docetaxel, including beta-tubulinIII, actinin4, stathmin1, bcl2, rpn2, thoredoxin, and akt2. In both models, continuous docetaxel resulted in greater antitumor efficacy than 1*/wk or 3*/wk dosing and did not induce upregulation of any analyzed genes. Once weekly dosing caused upregulation of various drug resistance-related genes, especially in chemoresistant xenografts. More frequent, 3*/wk dosing diminished this effect, although levels of various genes were higher than for continuous chemotherapy. Drug efflux transporter expression was further examined by Western blotting, confirming that intermittent, but not continuous, docetaxel induced significant upregulation. Overall, our results show that the presence and length of treatment-free intervals contribute to the development of drug resistance. Elimination of these intervals by continuous dosing resulted in superior antitumor efficacy and prevented drug resistance induction in chemosensitive and chemoresistant disease. These results encourage the clinical implementation of continuous chemotherapy to overcome and/or prevent drug resistance in newly diagnosed and recurrent, refractory ovarian cancer. PMID- 21551262 TI - Sorafenib enhances the antitumor effects of chemoradiation treatment by downregulating ERCC-1 and XRCC-1 DNA repair proteins. AB - Head and neck squamous cell carcinoma remains a challenging clinical problem because of the persisting high rate of local and distant failure due to the acquisition of chemo- and radioresistance. In this study, we examined if treatment with sorafenib, a potent inhibitor of Raf kinase and VEGF receptor, could reverse the resistant phenotype in tumor and tumor-associated endothelial cells, thereby enhancing the therapeutic efficacy of currently used chemoradiation treatment. We used both in vitro and in vivo models to test the efficacy of sorafenib either as a single agent or in combination with chemoradiation. Sorafenib, as a single agent, showed antitumor and angiogenesis properties, but the effects were more pronounced when used in combination with chemoradiation treatment. Sorafenib significantly enhanced the antiproliferative effects of chemoradiation treatment by downregulating DNA repair proteins (ERCC-1 and XRCC-1) in a dose-dependent manner. In addition, combination treatment significantly inhibited tumor cell colony formation, tumor cell migration, and tumor cell invasion. Combination treatment was also very effective in inhibiting VEGF-mediated angiogenesis in vitro. In a severe combined immunodeficient mouse xenograft model, combination treatment was very well tolerated and significantly inhibited tumor growth and tumor angiogenesis. Interestingly, following combination treatment, low-dose sorafenib treatment alone was highly effective as a maintenance regimen. Taken together, our results suggest a potentially novel strategy to use sorafenib to overcome chemo- and radioresistance in tumor and tumor-associated endothelial to enhance the effectiveness of the chemoradiation therapy. PMID- 21551264 TI - DNA methylation in cancer development, diagnosis and therapy--multiple opportunities for genotoxic agents to act as methylome disruptors or remediators. AB - The role of DNA methylation and recently discovered hydroxymethylation in the function of the human epigenome is currently one of the hottest topics in the life sciences. Progress in this field of research has been further accelerated by the discovery that alterations in the methylome are not only associated with key functions of cells and organisms, such as development, differentiation and gene expression, but may underlie a number of human diseases, including cancer. This review describes both well established and more recent observations concerning alterations in the methylome, i.e. the global and local distribution of 5 methylcytosines, involved in its normal functions. Then, the changes in DNA methylation pattern seen in cancer cells are discussed in the context of their utilisation in cancer diagnostics and treatment. On this basis, comparisons are made between natural covalent DNA modification and that induced by genotoxic agents, chemical carcinogens and antitumour drugs as regards their impact on epigenetic mechanisms. The available data suggest that DNA damage by genotoxins can mimic epigenetic markers and in consequence disrupt the proper function of the epigenome. On the other hand, the same processes in cancer cells, e.g. DNA demethylation as a result of DNA methyltransferase blocking or the induction of DNA repair by DNA adducts, may restore the activity of hypermethylated anticancer genes. The observed multiple mechanisms by which genotoxic agents directly affect methylome function suggest that chemical carcinogens act primarily as epigenome disruptors, whereas mutations are secondary events that occur at later stages of cancer development when genome-protecting mechanisms have already been deregulated. PMID- 21551265 TI - Shear stress increases endothelial hyaluronan synthase 2 and hyaluronan synthesis especially in regard to an atheroprotective flow profile. AB - Recent studies revealed that in vivo the inner blood vessel surface is lined with an endothelial surface layer at least 0.5 MUm thick, which serves as an aegis, protecting the vessel wall from arteriosclerosis. Hyaluronan seems to be a constitutive component in regard to the atheroprotective properties of this surface structure. It has been shown that arterial pulsatile laminar blood flow increases the thickness of this surface layer in vivo, while it is significantly reduced at atheroprone regions with disturbed flow. This study was undertaken to reveal whether endothelial hyaluronan synthesis via hyaluronan synthase 2 (HAS2) can be changed by different shear stress conditions in vitro, especially in regard to an undisturbed, arterial-like pulsatile flow profile. Human umbilical vein endothelial cells, exposed to constant or pulsatile shear stress in a cone and-plate system, were analysed for HAS2 expression by real-time RT-PCR and immunoblotting, and for hyaluronan by ELISA. Hyaluronan synthase 2 mRNA and protein were found to be transiently increased in a shear stress-dependent manner via the phosphatidylinositol 3-kinase-Akt pathway. Especially pulsatile, arterial like shear stress conditions induced enzyme and hyaluronan effectively, while lower shear stress that continuously changed its direction did not induce any differences in comparison with control cultures not exposed to shear stress. These experiments provide a link between the production of a constitutive component of the endothelial surface layer by endothelial cells and blood flow. PMID- 21551266 TI - Ion channels as target effectors for carbon monoxide. AB - Our understanding of carbon monoxide (CO) as an endogenous signalling molecule has expanded enormously in recent years, to the point where it can now be safely exploited therapeutically. In more recent years, the ability of CO to modulate ion channel activity has added further diversity to its activity. Here, I summarize briefly the established ion channel targets of CO and describe in more detail its actions on two example ion channels (the cardiac L-type Ca(2+) channel and the neuronal delayed rectifier, Kv2.1). The physiological consequences of such modulation are also considered. It is clear that our knowledge of the cellular effects of this gas is incomplete, and further study is required to further understand and so more fully exploit its therapeutic potential. PMID- 21551267 TI - Liver glutathione S-transferase expression is decreased by 3,5,3-triiodothyronine in hypothyroid but not in euthyroid mice. AB - As previously reported, the activity of liver glutathione S-transferases, an important family of enzymes for detoxification processes, is regulated by thyroid hormone levels. Here, we specifically studied glutathione S-transferase alpha (Gsta) gene expression in livers of mice. First, in wild-type (WT) mice, hypothyroidism was induced by 5 weeks of a diet containing 5-propyl-2-thiouracil plus water containing metimazole, whereas hyperthyroidism was induced by daily injections of 50 MUg (100 g body weight)(-1) of 3,3, 5-triiodo-L-thyronine (L T(3)) for 15 days. Importantly, hypothyroidism induced liver Gsta mRNA (>500%) and protein levels (70%; P < 0.01), indicating an important role of baseline thyroid hormone levels to repress this gene; however, surprisingly, no differences were seen in hyperthyroid mice. To further investigate Gsta repression by T(3), we used animals expressing a naturally occurring mutation of the gene for thyroid hormone receptor (TR)-beta (Delta337T), which prevents T(3) binding and causes a general resistance to thyroid hormone. At baseline, homozygous animals showed increased Gsta levels (mRNA 3.5 times, protein 1.3 times) similar to those found in hypothyroid animals. After a T(3) suppression test, we found a blunted response of liver Gsta after the lower doses of T(3) in homozygous animals, as expected. However, after the highest dose of T(3), we observed a decrease in Gsta expression (80%), similar to normal animals, explained by a higher expression of TR-alpha1 (60%; P < 0.01) and a lower expression of Src1 (steroid coactivator receptor) in the mutant animals (50% decrease). In summary, a decrease in Gsta expression caused by T(3) was observed only in the hypothyroid state. In addition, an essential role of TR-beta1 is to mediate Gsta suppression in response to T(3) and, in the absence of a functional TR-beta, there is a compensatory action of TR-alpha1 that depends on low levels of Src1. PMID- 21551268 TI - The sympathetic nervous system through the ages: from Thomas Willis to resistant hypertension. AB - The 17th century London neuroanatomical school headed by Thomas Willis provided us with the first identifiable images of the sympathetic nervous system. Nineteenth century giants of European physiology (Bernard, Waller and Brown Sequard) identified these as the 'pressor nerves'. Von Euler's demonstration that the sympathetic transmitter was noradrenaline brought the field into the modern era. The development of ganglion-blocking drugs by Paton, whose name this review commemorates, allowed comprehensive pharmacological antagonism of this system in patients. With the development of contemporary techniques for recording from human sympathetic nerves and quantifying rates of noradrenaline release, the sympathetic nervous system became accessible to clinical scientists investigating possible contributions to cardiovascular and other diseases. Sympathetic nervous system responses typically are regionally differentiated, with activation in one outflow sometimes accompanying no change or sympathetic inhibition in another. Regional sympathetic activity is best studied in humans by recording from postganglionic sympathetic efferents (multi-unit or single-fibre recording) and by isotope dilution-derived measurement of organ-specific noradrenaline release to plasma from sympathetic nerves (regional 'noradrenaline spillover'). With the application of these techniques, evidence has been assembled in the past three decades which indicates that sympathetic nervous system activation is crucial in the development of cardiovascular disorders, most notably heart failure and essential hypertension. An important goal for clinical scientists is translation of knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this 'mechanisms to management' transition is mature in cardiac failure, with knowledge of cardiac neural pathophysiology having led to introduction of beta-adrenergic blockers, an effective therapy. Perhaps we are now on the cusp of effective translation in patients with essential hypertension, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on prior demonstration in them of activation of the renal sympathetic outflow. PMID- 21551269 TI - The origins, evolution, and functional potential of alternative splicing in vertebrates. AB - Alternative splicing (AS) has the potential to greatly expand the functional repertoire of mammalian transcriptomes. However, few variant transcripts have been characterized functionally, making it difficult to assess the contribution of AS to the generation of phenotypic complexity and to study the evolution of splicing patterns. We have compared the AS of 309 protein-coding genes in the human ENCODE pilot regions against their mouse orthologs in unprecedented detail, utilizing traditional transcriptomic and RNAseq data. The conservation status of every transcript has been investigated, and each functionally categorized as coding (separated into coding sequence [CDS] or nonsense-mediated decay [NMD] linked) or noncoding. In total, 36.7% of human and 19.3% of mouse coding transcripts are species specific, and we observe a 3.6 times excess of human NMD transcripts compared with mouse; in contrast to previous studies, the majority of species-specific AS is unlinked to transposable elements. We observe one conserved CDS variant and one conserved NMD variant per 2.3 and 11.4 genes, respectively. Subsequently, we identify and characterize equivalent AS patterns for 22.9% of these CDS or NMD-linked events in nonmammalian vertebrate genomes, and our data indicate that functional NMD-linked AS is more widespread and ancient than previously thought. Furthermore, although we observe an association between conserved AS and elevated sequence conservation, as previously reported, we emphasize that 30% of conserved AS exons display sequence conservation below the average score for constitutive exons. In conclusion, we demonstrate the value of detailed comparative annotation in generating a comprehensive set of AS transcripts, increasing our understanding of AS evolution in vertebrates. Our data supports a model whereby the acquisition of functional AS has occurred throughout vertebrate evolution and is considered alongside amino acid change as a key mechanism in gene evolution. PMID- 21551270 TI - Insights into the evolution of vitamin B12 auxotrophy from sequenced algal genomes. AB - Vitamin B(12) (cobalamin) is a dietary requirement for humans because it is an essential cofactor for two enzymes, methylmalonyl-CoA mutase and methionine synthase (METH). Land plants and fungi neither synthesize or require cobalamin because they do not contain methylmalonyl-CoA mutase, and have an alternative B(12)-independent methionine synthase (METE). Within the algal kingdom, approximately half of all microalgal species need the vitamin as a growth supplement, but there is no phylogenetic relationship between these species, suggesting that the auxotrophy arose multiple times through evolution. We set out to determine the underlying cellular mechanisms for this observation by investigating elements of B(12) metabolism in the sequenced genomes of 15 different algal species, with representatives of the red, green, and brown algae, diatoms, and coccolithophores, including both macro- and microalgae, and from marine and freshwater environments. From this analysis, together with growth assays, we found a strong correlation between the absence of a functional METE gene and B(12) auxotrophy. The presence of a METE unitary pseudogene in the B(12) dependent green algae Volvox carteri and Gonium pectorale, relatives of the B(12) independent Chlamydomonas reinhardtii, suggest that B(12) dependence evolved recently in these lineages. In both C. reinhardtii and the diatom Phaeodactylum tricornutum, growth in the presence of cobalamin leads to repression of METE transcription, providing a mechanism for gene loss. Thus varying environmental conditions are likely to have been the reason for the multiple independent origins of B(12) auxotrophy in these organisms. Because the ultimate source of cobalamin is from prokaryotes, the selective loss of METE in different algal lineages will have had important physiological and ecological consequences for these organisms in terms of their dependence on bacteria. PMID- 21551271 TI - Gene loss and parallel evolution contribute to species difference in flower color. AB - Although the importance of regulatory and functional sequence evolution in generating species differences has been studied to some extent, much less is known about the role of other types of genomic changes, such as fluctuation in gene copy number. Here, we apply analyses of gene function and expression of anthocyanin pigment pathway genes, as well as cosegregation analyses in backcross populations, to examine the genetic changes involved in the shift from blue to red flowers in Andean Iochroma (Solanaceae). We demonstrate that deletion of a gene coding for an anthocyanin pathway enzyme was necessary for the transition to red floral pigmentation. The downregulation of a second pathway gene was also necessary for the novel flower color, and this regulatory pattern parallels the genetic change in the two other red-flowered species in the sister family Convolvulaceae in which flower color change has been examined genetically. Finally, we document a shift in enzymatic function at a third locus, but the importance of this change in the transition to red flowers depends on the exact order with which the three changes occurred. This study shows that gene inactivation or loss can be involved in the origin of phenotypic differences between species, thereby restricting the possibility of reversion to the ancestral state. It also demonstrates that parallel evolution of red flowers in three different species occurs via a common developmental/regulatory change but by mutations in different genes. PMID- 21551272 TI - Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones. AB - Thirty years ago, De Bold et al. (20) reported that atrial extracts contain some biologically active peptides, which promote a rapid and massive diuresis and natriuresis when injected in rats. It is now clear that the heart also exerts an endocrine function and in this way plays a key role in the regulation of cardiovascular and renal systems. The aim of this review is to discuss some recent insights and still-debated findings regarding the cardiac natriuretic hormones (CNHs) produced and secreted by cardiomyocytes (i.e., atrial natriuretic peptide and B-type natriuretic peptide). The functional status of the CNH system depends not only on the production/secretion of CNHs by cardiomyocytes but also on both the peripheral activation of circulating inactive precursor of natriuretic hormones and the transduction of the hormone signal by specific receptors. In this review, we will discuss the data supporting the hypothesis that the production and secretion of CNHs is the result of a complex integration among mechanical, chemical, hemodynamic, humoral, ischemic, and inflammatory inputs. The cross talk among endocrine function, adipose tissue, and sex steroid hormones will be discussed more in detail, considering the clinically relevant relationships linking together cardiovascular risk, sex, and body fat development and distribution. Finally, we will review the pathophysiological role and the clinical relevance of both peripheral maturation of the precursor of B-type natriuretic peptides and hormone signal transduction. PMID- 21551274 TI - Effect of age on high-fat diet-induced hypertension. AB - Aging and obesity both have a significant impact on central blood pressure (BP) regulation, and previous studies indicated that changes in central redox signaling with age may affect high-fat (HF) diet-induced cardiovascular responses. Therefore, we investigated the effects of 60% HF feeding on BP regulation in young adult (5 mo) and old (26 mo) Fischer-344 * Brown-Norway rats. Radiotelemetric transmitters were implanted to measure BP, heart rate (HR), locomotor activity, and spontaneous baroreflex sensitivity. Expression and activity of NADPH oxidase and ANG II type 1 receptor were assessed in the hypothalamus and in the nucleus tractus solitarii. Old animals gained more weight on HF diet compared with young, whereas central NADPH oxidase expression and activity elevated similarly in the two age groups. After an initial hypotensive and tachycardic response during the first week of HF feeding, BP in young animals increased and became significantly elevated after 6 wk of HF feeding. In contrast, BP in old animals remained depressed. Nighttime HR and locomotor activity decreased in both young and old rats fed with HF diet, but these changes were more significant in young rats. As a result, amplitudes of circadian variation of BP, HR, and activity that were originally higher in young rats declined significantly and became similar in the two age groups. In conclusion, our experiments led to the surprising finding that HF diet has a more serious impact on cardiovascular regulation in young animals compared with old. PMID- 21551273 TI - Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats. AB - Uridine adenosine tetraphosphate (Up(4)A) was reported as a novel endothelium derived contracting factor. Up(4)A contains both purine and pyrimidine moieties, which activate purinergic (P2)X and P2Y receptors. However, alterations in the vasoconstrictor responses to Up(4)A in hypertensive states remain unclear. The present study examined the effects of Up(4)A on contraction of isolated renal arteries (RA) and pulmonary arteries (PA) from DOCA-salt rats using isometric tension recording. RA from DOCA-salt rats exhibited increased contraction to Up(4)A versus arteries from control uninephrectomized rats in the absence and presence of N(G)-nitro-l-arginine (nitric oxide synthase inhibitor). On the other hand, the Up(4)A-induced contraction in PA was similar between the two groups. Up(4)A-induced contraction was inhibited by suramin (nonselective P2 antagonist) but not by diinosine pentaphosphate pentasodium salt hydrate (Ip(5)I; P2X(1) antagonist) in RA from both groups. Furthermore, 2-thiouridine 5'-triphosphate tetrasodium salt (2-ThioUTP; P2Y(2) agonist)-, uridine-5'-(gamma-thio) triphosphate trisodium salt (UTPgammaS; P2Y(2)/P2Y(4) agonist)-, and 5 iodouridine-5'-O-diphosphate trisodium salt (MRS 2693; P2Y(6) agonist)-induced contractions were all increased in RA from DOCA-salt rats. Protein expression of P2Y(2)-, P2Y(4)-, and P2Y(6) receptors in RA was similar between the two groups. In DOCA-salt RA, the enhanced Up(4)A-induced contraction was reduced by PD98059, an ERK pathway inhibitor, and Up(4)A-stimulated ERK activation was increased. These data are the first to indicate that Up(4)A-induced contraction is enhanced in RA from DOCA-salt rats. Enhanced P2Y receptor signaling and activation of the ERK pathway together represent a likely mechanism mediating the enhanced Up(4)A induced contraction. Up(4)A might be of relevance in the pathophysiology of vascular tone regulation and renal dysfunction in arterial hypertension. PMID- 21551275 TI - Catalase overexpression in aortic smooth muscle prevents pathological mechanical changes underlying abdominal aortic aneurysm formation. AB - The causality of the associations between cellular and mechanical mechanisms of abdominal aortic aneurysm (AAA) formation has not been completely defined. Because reactive oxygen species are established mediators of AAA growth and remodeling, our objective was to investigate oxidative stress-induced alterations in aortic biomechanics and microstructure during subclinical AAA development. We investigated the mechanisms of AAA in an angiotensin II (ANG II) infusion model of AAA in apolipoprotein E-deficient (apoE(-/-)) mice that overexpress catalase in vascular smooth muscle cells (apoE(-/-)xTg(SMC-Cat)). At baseline, aortas from apoE(-/-)xTg(SMC-Cat) exhibited increased stiffness and the microstructure was characterized by 50% more collagen content and less elastin fragmentation. ANG II treatment for 7 days in apoE(-/-) mice altered the transmural distribution of suprarenal aortic circumferential strain (quantified by opening angle, which increased from 130 +/- 1 degrees at baseline to 198 +/- 8 degrees after 7 days of ANG II treatment) without obvious changes in the aortic microstructure. No differences in aortic mechanical behavior or suprarenal opening angle were observed in apoE(-/-)xTg(SMC-Cat) after 7 days of ANG II treatment. These data suggest that at the earliest stages of AAA development H(2)O(2) is functionally important and is involved in the control of local variations in remodeling across the vessel wall. They further suggest that reduced elastin integrity at baseline may predispose the abdominal aorta to aneurysmal mechanical remodeling. PMID- 21551276 TI - Development of a preclinical model of ischemic cardiomyopathy in swine. AB - A number of promising therapies for ischemic cardiomyopathy are emerging, and the role of translational research in testing the efficacy and safety of these agents in relevant clinical models has become important. The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a large animal model. In this study, 40 consecutive pigs were initially enrolled. To induce progressive stenosis, a plastic occluder with a fixed diameter of 1.0 mm fitted with an 18 gauge copper wire was placed around the proximal left anterior descending (LAD) coronary artery. Coronary angiography, hemodynamic measurements, and echocardiography were performed at 2 wk and 1, 2, and 3 mo. Overall mortality was 26% at 3 mo, and up to 80% of the pigs showed total occlusion of LAD at 1 mo. A significant depression of peak LV pressure rate of rise (+dP/dt(max)) was observed in the animals showing total artery occlusion throughout the study. Left ventricular ejection fraction was also impaired, and the left ventricular volumes tended to be larger in the pigs with occlusion. Approximately 10% of scar tissue was found in the LAD occluded pigs, whereas the coronary flow pattern in the rest of the area took the pattern of hibernating myocardium. At the same time, histological and protein analysis established the presence of fibrosis and ongoing apoptosis in the ischemic area. In this model, the timing and incidence of total occlusion and low mortality offer significant advantages over other ischemic cardiomyopathy models in conducting preclinical studies. PMID- 21551277 TI - New method to measure coronary velocity and coronary flow reserve. AB - Coronary flow reserve (CFR) is an important index of coronary microcirculatory function. The objective of this study was to validate the reproducibility and accuracy of intravascular conductance catheter-based method for measurements of baseline and hyperemic coronary flow velocity (and hence CFR). The absolute coronary blood velocity was determined by measuring the time of transit of a saline injection between two pairs of electrodes (known distance) on a conductance catheter during a routine saline injection without the need for reference flow. In vitro validation was made in the velocity range of 5 to 70 cm/s in reference to the volume collection method. In 10 swine, velocity measurements were compared with those from a flow probe in coronary arteries at different CFR attained by microsphere embolization. In vitro, the mean difference between the proposed method and volume collection was 0.7 +/- 1.34 cm/s for steady flow and -0.77 +/- 2.22 cm/s for pulsatile flow. The mean difference between duplicate measurements was 0 +/- 1.4 cm/s. In in vivo experiments, the flow (product of velocity and lumen cross-sectional area that is also measured by the conductance catheter) was determined in both normal and stenotic vessels and the mean difference between the proposed method and flow probe was -1 +/- 12 ml/min (flow ranged from 10 to 130 ml/min). For CFR, the mean difference between the two methods was 0.06 +/- 0.28 (range of 1 to 3). Our results demonstrate the reproducibility and accuracy of velocity and CFR measurements with a conductance catheter by use of a standard saline injection. The ability of the combined measurement of coronary lumen area (as previously validated) and current velocity and CFR measurements provides an integrative diagnostic tool for interventional cardiology. PMID- 21551278 TI - Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats. AB - Matrix metalloproteases (MMPs) are a family of zinc peptidases involved in extracellular matrix turnover. There is evidence that increased MMP activity is involved in remodeling of resistance vessels in chronic hypertension. Thus we hypothesized that inhibition of MMP activity with doxycycline (DOX) would attenuate vascular remodeling. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with DOX (50 mg.kg(-1).day(-1) in the drinking water) for 6 wk. Untreated SHRSP were controls. Blood pressure was measured by telemetry during the last week. Middle cerebral artery (MCA) and mesenteric resistance artery (MRA) passive structures were assessed by pressure myography. MMP-2 expression in aortas was measured by Western blot. All results are means +/- SE. DOX caused a small increase in mean arterial pressure (SHRSP, 154 +/- 1; SHRSP + DOX, 159 +/- 3 mmHg; P < 0.001). Active MMP-2 expression was reduced in aorta from SHRSP + DOX (0.21 +/- 0.06 vs. 0.49 +/- 0.13 arbitrary units; P < 0.05). In the MCA, at 80 mmHg, DOX treatment increased the lumen (273.2 +/- 4.7 vs. 238.3 +/- 6.3 MUm; P < 0.05) and the outer diameter (321 +/- 5.3 vs. 290 +/- 7.6 MUm; P < 0.05) and reduced the wall-to-lumen ratio (0.09 +/- 0.002 vs. 0.11 +/- 0.003; P < 0.05). Damage after transient cerebral ischemia (transient MCA occlusion) was reduced in SHRSP + DOX (20.7 +/- 4 vs. 45.5 +/- 5% of hemisphere infarcted; P < 0.05). In the MRA, at 90 mmHg DOX, reduced wall thickness (29 +/- 1 vs. 22 +/- 1 MUm; P < 0.001) and wall-to-lumen ratio (0.08 +/ 0.004 vs. 0.11 +/- 0.008; P < 0.05) without changing lumen diameter. These results suggest that MMPs are involved in hypertensive vascular remodeling in both the peripheral and cerebral vasculature and that DOX reduced brain damage after cerebral ischemia. PMID- 21551279 TI - Xenia Forsselliana 2010. PMID- 21551282 TI - Composition and variability of biofouling organisms in seawater reverse osmosis desalination plants. AB - Seawater reverse osmosis (SWRO) membrane biofouling remains a common challenge in the desalination industry, but the marine bacterial community that causes membrane fouling is poorly understood. Microbial communities at different stages of treatment processes (intake, cartridge filtration, and SWRO) of a desalination pilot plant were examined by both culture-based and culture-independent approaches. Bacterial isolates were identified to match the genera Shewanella, Alteromonas, Vibrio, and Cellulophaga based on 16S rRNA gene sequencing analysis. The 16S rRNA gene clone library of the SWRO membrane biofilm showed that a filamentous bacterium, Leucothrix mucor, which belongs to the gammaproteobacteria, accounted for nearly 30% of the clone library, while the rest of the microorganisms (61.2% of the total clones) were related to the alphaproteobacteria. 16S rRNA gene terminal restriction fragment length polymorphism (T-RFLP) analysis indicated that bacteria colonizing the SWRO membrane represented a subportion of microbes in the source seawater; however, they were quite different from those colonizing the cartridge filter. The examination of five SWRO membranes from desalination plants located in different parts of the world showed that although the bacterial communities from the membranes were not identical to each other, some dominant bacteria were commonly observed. In contrast, bacterial communities in source seawater were significantly different based on location and season. Microbial profiles from 14 cartridge filters collected from different plants also revealed spatial trends. PMID- 21551281 TI - Anaerobic oxidation of methane in sediments of Lake Constance, an oligotrophic freshwater lake. AB - Anaerobic oxidation of methane (AOM) with sulfate as terminal electron acceptor has been reported for various environments, including freshwater habitats, and also, nitrate and nitrite were recently shown to act as electron acceptors for methane oxidation in eutrophic freshwater habitats. Radiotracer experiments with sediment material of Lake Constance, an oligotrophic freshwater lake, were performed to follow 14CO2 formation from 14CH4 in sediment incubations in the presence of different electron acceptors, namely, nitrate, nitrite, sulfate, or oxygen. Whereas 14CO2 formation without and with sulfate addition was negligible, addition of nitrate increased 14CO2 formation significantly, suggesting that AOM could be coupled to denitrification. Nonetheless, denitrification-dependent AOM rates remained at least 1 order of magnitude lower than rates of aerobic methane oxidation. Using molecular techniques, putative denitrifying methanotrophs belonging to the NC10 phylum were detected on the basis of the pmoA and 16S rRNA gene sequences. These findings show that sulfate-dependent AOM was insignificant in Lake constant sediments. However, AOM can also be coupled to denitrification in this oligotrophic freshwater habitat, providing first indications that this might be a widespread process that plays an important role in mitigating methane emissions. PMID- 21551284 TI - Regulation of the Edwardsiella ictaluri type III secretion system by pH and phosphate concentration through EsrA, EsrB, and EsrC. AB - A recently described Edwardsiella ictaluri type III secretion system (T3SS) with functional similarity to the Salmonella pathogenicity island 2 T3SS is required for replication in channel catfish head-kidney-derived macrophages (HKDM) and virulence in channel catfish. Quantitative PCR and Western blotting identified low pH and phosphate limitation as conducive to expression of the E. ictaluri T3SS, growth conditions that mimic the phagosomal environment. Mutagenesis studies demonstrated that expression is under the control of the EsrAB two component regulatory system. EsrB also induces upregulation of the AraC-type regulatory protein EsrC, which enhances expression of the EscB/EseG chaperone/effector operon in concert with EsrB and induces expression of the pEI1 encoded effector, EseH. EsrC also induces expression of a putative type VI secretion system translocon protein, EvpC, which is secreted under the same low pH conditions as the T3SS translocon proteins. The pEI2-encoded effector, EseI, was upregulated under low-pH and low-phosphate conditions but not in an EsrB- or EsrC-dependent manner. Mutations of EsrA and EsrB both resulted in loss of the ability to replicate in HKDM and full attenuation in the channel catfish host. Mutation of EsrC did not affect intracellular replication but did result in attenuation in catfish. Although EsrB is the primary transcriptional regulator for E. ictaluri genes within the T3SS pathogenicity island, EsrC regulates expression of the plasmid-carried effector eseH and appears to mediate coordinated expression of the T6SS with the T3SS. PMID- 21551285 TI - Validation of heavy-water stable isotope probing for the characterization of rapidly responding soil bacteria. AB - Rapid responses of bacteria to sudden changes in their environment can have important implications for the structure and function of microbial communities. In this study, we used heavy-water stable isotope probing (H2(18)O-SIP) to identify bacteria that respond to soil rewetting. First, we conducted experiments to address uncertainties regarding the H2(18)O-SIP method. Using liquid chromatography-mass spectroscopy (LC-MS), we determined that oxygen from H2(18)O was incorporated into all structural components of DNA. Although this incorporation was uneven, we could effectively separate 18O-labeled and unlabeled DNAs derived from laboratory cultures and environmental samples that were incubated with H2(18)O. We found no evidence for ex vivo exchange of oxygen atoms between DNA and extracellular H2O, suggesting that 18O incorporation into DNA is relatively stable. Furthermore, the rate of 18O incorporation into bacterial DNA was high (within 48 to 72 h), coinciding with pulses of CO2 generated from soil rewetting. Second, we examined shifts in the bacterial composition of grassland soils following rewetting, using H2(18)O-SIP and bar-coded pyrosequencing of 16S rRNA genes. For some groups of soil bacteria, we observed coherent responses at a relatively course taxonomic resolution. Following rewetting, the relative recovery of Alphaproteobacteria, Betaproteobacteria, and Gammaproteobacteria increased, while the relative recovery of Chloroflexi and Deltaproteobacteria decreased. Together, our results suggest that H2(18)O-SIP is effective at identifying metabolically active bacteria that influence soil carbon dynamics. Our results contribute to the ecological classification of soil bacteria while providing insight into some of the functional traits that influence the structure and function of microbial communities under dynamic soil moisture regimes. PMID- 21551286 TI - Monitoring the metabolic status of geobacter species in contaminated groundwater by quantifying key metabolic proteins with Geobacter-specific antibodies. AB - Simple and inexpensive methods for assessing the metabolic status and bioremediation activities of subsurface microorganisms are required before bioremediation practitioners will adopt molecular diagnosis of the bioremediation community as a routine practice for guiding the development of bioremediation strategies. Quantifying gene transcripts can diagnose important aspects of microbial physiology during bioremediation but is technically challenging and does not account for the impact of translational modifications on protein abundance. An alternative strategy is to directly quantify the abundance of key proteins that might be diagnostic of physiological state. To evaluate this strategy, an antibody-based quantification approach was developed to investigate subsurface Geobacter communities. The abundance of citrate synthase corresponded with rates of metabolism of Geobacter bemidjiensis in chemostat cultures. During in situ bioremediation of uranium-contaminated groundwater the quantity of Geobacter citrate synthase increased with the addition of acetate to the groundwater and decreased when acetate amendments stopped. The abundance of the nitrogen-fixation protein, NifD, increased as ammonium became less available in the groundwater and then declined when ammonium concentrations increased. In a petroleum-contaminated aquifer, the abundance of BamB, an enzyme subunit involved in the anaerobic degradation of mono-aromatic compounds by Geobacter species, increased in zones in which Geobacter were expected to play an important role in aromatic hydrocarbon degradation. These results suggest that antibody-based detection of key metabolic proteins, which should be readily adaptable to standardized kits, may be a feasible method for diagnosing the metabolic state of microbial communities responsible for bioremediation, aiding in the rational design of bioremediation strategies. PMID- 21551283 TI - The genotype of the calcium/calmodulin-dependent protein kinase gene (CCaMK) determines bacterial community diversity in rice roots under paddy and upland field conditions. AB - The effects of the Oryza sativa calcium/calmodulin-dependent protein kinase OsCCaMK genotype (dominant homozygous [D], heterozygous [H], recessive homozygous [R]) on rice root-associated bacteria, including endophytes and epiphytes, were examined by using a Tos17 rice mutant line under paddy and upland field conditions. Roots were sampled at the flowering stage and were subjected to clone library analyses. The relative abundance of Alphaproteobacteria was noticeably decreased in R plants under both paddy and upland conditions (0.8% and 3.0%, respectively) relative to those in D plants (10.3% and 17.4%, respectively). Population shifts of the Sphingomonadales and Rhizobiales were mainly responsible for this low abundance in R plants. The abundance of Anaerolineae (Chloroflexi) and Clostridia (Firmicutes) was increased in R plants under paddy conditions. The abundance of a subpopulation of Actinobacteria (Saccharothrix spp. and unclassified Actinosynnemataceae) was increased in R plants under upland conditions. Principal coordinate analysis revealed unidirectional community shifts in relation to OsCCaMK gene dosage under both conditions. In addition, shoot length, tiller number, and plant weight decreased as the OsCCaMK gene dosage decreased under upland conditions. These results suggest significant impacts of OsCCaMK on both the diversity of root-associated bacteria and rice plant growth under both paddy and upland field conditions. PMID- 21551288 TI - Effect of chemical chaperones in improving the solubility of recombinant proteins in Escherichia coli. AB - The recovery of active proteins from inclusion bodies usually involves chaotrope induced denaturation, followed by refolding of the unfolded protein. The efficiency of renaturation is low, leading to reduced yield of the final product. In this work, we report that recombinant proteins can be overexpressed in the soluble form in the host expression system by incorporating compatible solutes during protein expression. Green fluorescent protein (GFP), which was otherwise expressed as inclusion bodies, could be made to partition off into the soluble fraction when sorbitol and arginine, but not ethylene glycol, were present in the growth medium. Arginine and sorbitol increased the production of soluble protein, while ethylene glycol did not. Production of ATP increased in the presence of sorbitol and arginine, but not ethylene glycol. A control experiment with fructose addition indicated that protein solubilization was not due to a simple ATP increase. We have successfully reproduced these results with the N-terminal domain of HypF (HypF-N), a bacterial protein which forms inclusion bodies in Escherichia coli. Instead of forming inclusion bodies, HypF-N could be expressed as a soluble protein in the presence of sorbitol, arginine, and trehalose in the expression medium. PMID- 21551289 TI - Generic exposure scenarios: their development, application, and interpretation under REACH. AB - The European Union Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) Regulation (EC 1907/2006) places significant new obligations on the manufacturers or importers (M/Is) of chemicals in Europe. It also places new responsibilities on downstream users (DUs) of these chemicals i.e. those that purchase and use chemical products. In particular, for registered classified substances, the M/I is expected to communicate how any substance can be safely used without risk to man or the environment. This communication is in the form of an exposure scenario (ES), which is included in an Annex to the REACH extended safety data sheet. DUs then have certain obligations relating to adopting the control conditions described in the ES. The REACH Technical Guidance Documents lay down the expectations for the process of risk assessment that M/Is should adopt when developing ESs. But with many thousands of chemicals in daily commerce, it is also necessary to ensure that what is communicated to DUs not only meets the requirements of REACH but is also understandable to these groups, as well as being consistent across different chemical suppliers and supply chains. In cooperation with relevant DU groups, the European solvents industry has developed generic approaches for describing how solvents are commonly used, in order that these can subsequently be used as the basis for REACH registrations and related safety data sheet communications on health risk control. The utility of these approaches (termed 'generic exposure scenarios') is acknowledged under REACH and they are now publicly available for use both by M/Is and DUs. PMID- 21551287 TI - Significant alteration of gene expression in wood decay fungi Postia placenta and Phanerochaete chrysosporium by plant species. AB - Identification of specific genes and enzymes involved in conversion of lignocellulosics from an expanding number of potential feedstocks is of growing interest to bioenergy process development. The basidiomycetous wood decay fungi Phanerochaete chrysosporium and Postia placenta are promising in this regard because they are able to utilize a wide range of simple and complex carbon compounds. However, systematic comparative studies with different woody substrates have not been reported. To address this issue, we examined gene expression of these fungi colonizing aspen (Populus grandidentata) and pine (Pinus strobus). Transcript levels of genes encoding extracellular glycoside hydrolases, thought to be important for hydrolytic cleavage of hemicelluloses and cellulose, showed little difference for P. placenta colonizing pine versus aspen as the sole carbon source. However, 164 genes exhibited significant differences in transcript accumulation for these substrates. Among these, 15 cytochrome P450s were upregulated in pine relative to aspen. Of 72 P. placenta extracellular proteins identified unambiguously by mass spectrometry, 52 were detected while colonizing both substrates and 10 were identified in pine but not aspen cultures. Most of the 178 P. chrysosporium glycoside hydrolase genes showed similar transcript levels on both substrates, but 13 accumulated >2-fold higher levels on aspen than on pine. Of 118 confidently identified proteins, 31 were identified in both substrates and 57 were identified in pine but not aspen cultures. Thus, P. placenta and P. chrysosporium gene expression patterns are influenced substantially by wood species. Such adaptations to the carbon source may also reflect fundamental differences in the mechanisms by which these fungi attack plant cell walls. PMID- 21551290 TI - Complete genome sequence of Carnobacterium sp. 17-4. AB - Members of the carnobacteria have been extensively studied as probiotic cultures in aquacultures and protective cultures in seafood, diary, and meat. We report on the finished genome sequence of Carnobacterium sp. 17-4, which has been isolated from permanently cold seawater. The genetic information reveals a new circular bacteriocin biosynthesis cluster. PMID- 21551291 TI - The lysis-lysogeny decision of bacteriophage 933W: a 933W repressor-mediated long distance loop has no role in regulating 933W P(RM) activity. AB - Our data show that unlike bacteriophage lambda, repressor bound at O(L) of bacteriophage 933W has no role in regulation of 933W repressor occupancy of 933W O(R)3 or the transcriptional activity of 933W P(RM). This finding suggests that a cooperative long-range loop between repressor tetramers bound at O(R) and O(L) does not form in bacteriophage 933W. Nonetheless, 933W forms lysogens, and 933W prophage display a threshold response to UV induction similar to related lambdoid phages. Hence, the long-range loop thought to be important for constructing a threshold response in lambdoid bacteriophages is dispensable. The lack of a loop requires bacteriophage 933W to use a novel strategy in regulating its lysis lysogeny decisions. As part of this strategy, the difference between the repressor concentrations needed to bind O(R)2 and activate 933W P(RM) transcription or bind O(R)3 and repress transcription from P(RM) is <2-fold. Consequently, P(RM) is never fully activated, reaching only ~25% of the maximum possible level of repressor-dependent activation before repressor-mediated repression occurs. The 933W repressor also apparently does not bind cooperatively to the individual sites in O(R) and O(L). This scenario explains how, in the absence of DNA looping, bacteriophage 933W displays a threshold effect in response to DNA damage and suggests how 933W lysogens behave as "hair triggers" with spontaneous induction occurring to a greater extent in this phage than in other lambdoid phages. PMID- 21551292 TI - Genome sequence of Vibrio rotiferianus strain DAT722. AB - Vibrio rotiferianus is a marine pathogen capable of causing disease in various aquatic organisms. We announce the genome sequence of V. rotiferianus DAT722, which has a large chromosomal integron containing 116 gene cassettes and is a model organism for studying the role of this system in vibrio evolution. PMID- 21551293 TI - Genome sequence of Gluconacetobacter sp. strain SXCC-1, isolated from Chinese vinegar fermentation starter. AB - Gluconacetobacter strains are prominent bacteria during traditional vinegar fermentation. Here, we report a draft genome sequence of Gluconacetobacter sp. strain SXCC-1. This strain was isolated from a fermentation starter (Daqu) used for commercial production of Shanxi vinegar, the best-known vinegar of China. PMID- 21551294 TI - Genome sequence of the clinical O4:K12 serotype Vibrio parahaemolyticus strain 10329. AB - Vibrio parahaemolyticus is the leading cause of food-borne illnesses worldwide. Here, we report a draft genome of V. parahaemolyticus strain 10329 of the O4:K12 serotype. It belongs to the main U.S. West Coast clonal complex of V. parahaemolyticus (sequence type 36 [ST36]) causing oyster-associated human illness. It contains the virulence determinants tdh and trh but appears to infect at much lower doses than V. parahaemolyticus strains with these same determinants from other areas, such as the U.S. Gulf and Atlantic coasts. PMID- 21551295 TI - Complete genome sequence of Staphylococcus aureus T0131, an ST239-MRSA-SCCmec type III clone isolated in China. AB - We report here the complete genome sequence of Staphylococcus aureus T0131, which is a multiresistant clinical isolate recovered in China and the first sequenced epidemic ST239-MRSA-SCCmec type III strain obtained in Asia. Comparison with two published genomes of ST239 reveals the polymorphism among strains of this type from different continents. PMID- 21551296 TI - Complete genome sequence of Aeromonas veronii strain B565. AB - Aeromonas veronii strain B565 was isolated from aquaculture pond sediment in China. We present here the complete genome sequence of B565 and compare it with 2 published genome sequences of pathogenic strains in the Aeromonas genus. The result represents an independent stepwise acquisition of virulence factors of pathogenic strains in this genus. PMID- 21551297 TI - Streptococcus pneumoniae serotype 6C: an intra- and interclonal complex comparison. AB - We report the annotated draft genome sequences of four serotype 6C Streptococcus pneumoniae isolates of differing genetic backgrounds. Serotype 6C isolates are increasing in prevalence and becoming progressively more resistant to antibiotics. As a result, these strains are likely to become more important in the near future. PMID- 21551298 TI - Draft genome sequence of the marine bacterium Streptomyces griseoaurantiacus M045, which produces novel manumycin-type antibiotics with a pABA core component. AB - Streptomyces griseoaurantiacus M045, isolated from marine sediment, produces manumycin and chinikomycin antibiotics. Here we present a high-quality draft genome sequence of S. griseoaurantiacus M045, the first marine Streptomyces species to be sequenced and annotated. The genome encodes several gene clusters for biosynthesis of secondary metabolites and has provided insight into genomic islands linking secondary metabolism to functional adaptation in marine S. griseoaurantiacus M045. PMID- 21551299 TI - Complete genome of Pseudomonas mendocina NK-01, which synthesizes medium-chain length polyhydroxyalkanoates and alginate oligosaccharides. AB - Pseudomonas mendocina NK-01 can synthesize medium-chain-length polyhydroxyalkanoate (PHA(MCL)) and alginate oligosaccharides (AO) simultaneously from glucose under conditions of limited nitrogen. Here, we report the complete sequence of the 5.4-Mbp genome of Pseudomonas mendocina NK-01, which was isolated from farmland soil in Tianjin, China. PMID- 21551300 TI - Genome sequences of Listeria monocytogenes strains J1816 and J1-220, associated with human outbreaks. AB - Listeria monocytogenes has caused numerous human outbreaks. Here we report draft genomes of L. monocytogenes J1816 and J1-220, which belong to epidemic clones II and IV, respectively. Whole-genome sequence analysis of these strains provides a tool for studying the short-term evolution of these epidemic clones. PMID- 21551301 TI - Identity gene expression in Proteus mirabilis. AB - Swarming colonies of independent Proteus mirabilis isolates recognize each other as foreign and do not merge together, whereas apposing swarms of clonal isolates merge with each other. Swarms of mutants with deletions in the ids gene cluster do not merge with their parent. Thus, ids genes are involved in the ability of P. mirabilis to distinguish self from nonself. Here we have characterized expression of the ids genes. We show that idsABCDEF genes are transcribed as an operon, and we define the promoter region upstream of idsA by deletion analysis. Expression of the ids operon increased in late logarithmic and early stationary phases and appeared to be bistable. Approaching swarms of nonself populations led to increased ids expression and increased the abundance of ids-expressing cells in the bimodal population. This information on ids gene expression provides a foundation for further understanding the molecular details of self-nonself discrimination in P. mirabilis. PMID- 21551302 TI - Complete genome sequence of Bacillus amyloliquefaciens LL3, which exhibits glutamic acid-independent production of poly-gamma-glutamic acid. AB - Bacillus amyloliquefaciens is one of most prevalent Gram-positive aerobic spore forming bacteria with the ability to synthesize polysaccharides and polypeptides. Here, we report the complete genome sequence of B. amyloliquefaciens LL3, which was isolated from fermented food and presents the glutamic acid-independent production of poly-gamma-glutamic acid. PMID- 21551303 TI - Pantethine rescues phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency in Escherichia coli but not in Pseudomonas aeruginosa. AB - Coenzyme A (CoA) plays a central and essential role in all living organisms. The pathway leading to CoA biosynthesis has been considered an attractive target for developing new antimicrobial agents with novel mechanisms of action. By using an arabinose-regulated expression system, the essentiality of coaBC, a single gene encoding a bifunctional protein catalyzing two consecutive steps in the CoA pathway converting 4'-phosphopantothenate to 4'-phosphopantetheine, was confirmed in Escherichia coli. Utilizing this regulated coaBC strain, it was further demonstrated that E. coli can effectively metabolize pantethine to bypass the requirement for coaBC. Interestingly, pantethine cannot be used by Pseudomonas aeruginosa to obviate coaBC. Through reciprocal complementation studies in combination with biochemical characterization, it was demonstrated that the differential characteristics of pantethine utilization in these two microorganisms are due to the different substrate specificities associated with endogenous pantothenate kinase, the first enzyme in the CoA biosynthetic pathway encoded by coaA in E. coli and coaX in P. aeruginosa. PMID- 21551304 TI - Genome sequence of strain TW15, a novel member of the genus Ruegeria, belonging to the marine Roseobacter clade. AB - Ruegeria sp. TW15, which belongs to the family Rhodobacteraceae, was isolated from an ark clam in the South Sea of Korea. Here is presented the draft genome sequence of Ruegeria sp. TW15 (4,490,771 bp with a G+C content of 55.7%), a member of the marine Roseobacter clade, which comprises up to 20% of the bacterioplankton in the coastal and oceanic mixed layer. PMID- 21551305 TI - Complete genome sequence of Metallosphaera cuprina, a metal sulfide-oxidizing archaeon from a hot spring. AB - The genome of the metal sulfide-oxidizing, thermoacidophilic strain Metallosphaera cuprina Ar-4 has been completely sequenced and annotated. Originally isolated from a sulfuric hot spring, strain Ar-4 grows optimally at 65 degrees C and a pH of 3.5. The M. cuprina genome has a 1,840,348-bp circular chromosome (2,029 open reading frames [ORFs]) and is 16% smaller than the previously sequenced Metallosphaera sedula genome. Compared to the M. sedula genome, there are no counterpart genes in the M. cuprina genome for about 480 ORFs in the M. sedula genome, of which 243 ORFs are annotated as hypothetical protein genes. Still, there are 233 ORFs uniquely occurring in M. cuprina. Genome annotation supports that M. cuprina lives a facultative life on CO(2) and organics and obtains energy from oxidation of sulfidic ores and reduced inorganic sulfuric compounds. PMID- 21551306 TI - Genetic transformation of the relapsing fever spirochete Borrelia hermsii: stable integration and expression of green fluorescent protein from linear plasmid 200. AB - Tick-borne relapsing fever (TBRF) is a spirochetal disease caused by at least 15 different Borrelia species. It is a serious human health concern in regions of endemicity throughout the world. Transmission to humans occurs through the bites of infected Ornithodoros ticks. In North America, the primary Borrelia species associated with human disease are B. hermsii and B. turicatae. Direct demonstration of the role of putative TBRF spirochete virulence factors in the disease process has been hindered by the lack of a genetic manipulation system and complete genome sequences. Expanding on recent developments in these areas, here we demonstrate the successful generation of a clone of B. hermsii YOR that constitutively produces green fluorescent protein (GFP) (B. hermsii YOR::kan gfp). This strain was generated through introduction of a kan-gfp cassette into a noncoding region of the 200-kb B. hermsii linear plasmid lp200. Genetic manipulation did not affect the growth rate or trigger the loss of native plasmids. B. hermsii YOR::kan gfp retained infectivity and elicited host seroconversion. Stable production of GFP was demonstrated both in vitro and in vivo. This study represents a significant step forward in the development of tools that can be employed to study the virulence mechanisms of TBRF spirochetes. PMID- 21551307 TI - Complete genome sequence of Bacillus thuringiensis subsp. chinensis strain CT-43. AB - Bacillus thuringiensis has been widely used as an agricultural biopesticide for a long time. As a producing strain, B. thuringiensis subsp. chinensis strain CT-43 is highly toxic to lepidopterous and dipterous insects. It can form various parasporal crystals consisting of Cry1Aa3, Cry1Ba1, Cry1Ia14, Cry2Aa9, and Cry2Ab1. During fermentation, it simultaneously generates vegetative insecticidal protein Vip3Aa10 and the insecticidal nucleotide analogue thuringiensin. Here, we report the finished, annotated genome sequence of B. thuringiensis strain CT-43. PMID- 21551308 TI - Complete genome sequence of the plant growth-promoting endophyte Burkholderia phytofirmans strain PsJN. AB - Burkholderia phytofirmans PsJN(T) is able to efficiently colonize the rhizosphere, root, and above-ground plant tissues of a wide variety of genetically unrelated plants, such as potatoes, canola, maize, and grapevines. Strain PsJN shows strong plant growth-promoting effects and was reported to enhance plant vigor and resistance to biotic and abiotic stresses. Here, we report the genome sequence of this strain, which indicates the presence of multiple traits relevant for endophytic colonization and plant growth promotion. PMID- 21551309 TI - DMS3-42: the secret to CRISPR-dependent biofilm inhibition in Pseudomonas aeruginosa. PMID- 21551310 TI - Genome sequence of strain IMCC3088, a proteorhodopsin-containing marine bacterium belonging to the OM60/NOR5 clade. AB - Strain IMCC3088, cultivated from the Yellow Sea, is a novel isolate belonging to the OM60/NOR5 clade and is closely related to clone OM241, Congregibacter litoralis, and strain HTCC2080. Here, the genome sequence of strain IMCC3088 is presented, showing the absence of photosynthetic gene clusters and the presence of proteorhodopsin. PMID- 21551311 TI - Genome sequence of the abyssomicin- and proximicin-producing marine actinomycete Verrucosispora maris AB-18-032. AB - Verrucosispora maris AB-18-032 is a marine actinomycete that produces atrop abyssomicin C and proximicin A, both of which have novel structures and modes of action. In order to understand the biosynthesis of these compounds, to identify further biosynthetic potential, and to facilitate rational improvement of secondary metabolite titers, we have sequenced the complete 6.7-Mb genome of Verrucosispora maris AB-18-032. PMID- 21551312 TI - Genome Sequence of the ethene- and vinyl chloride-oxidizing actinomycete Nocardioides sp. strain JS614. AB - Nocardioides sp. strain JS614 grows on ethene and vinyl chloride (VC) as sole carbon and energy sources and is of interest for bioremediation and biocatalysis. Sequencing of the complete genome of JS614 provides insight into the genetic basis of alkene oxidation, supports ongoing research into the physiology and biochemistry of growth on ethene and VC, and provides biomarkers to facilitate detection of VC/ethene oxidizers in the environment. This is the first genome sequence from the genus Nocardioides and the first genome of a VC/ethene oxidizing bacterium. PMID- 21551313 TI - Draft genome of Phaeobacter gallaeciensis ANG1, a dominant member of the accessory nidamental gland of Euprymna scolopes. AB - Phaeobacter gallaeciensis strain ANG1 represents the dominant member of the bacterial consortium within the reproductive accessory nidamental gland (ANG) of the squid Euprymna scolopes. We present a 4.59-Mb assembly of its genome, which may provide clues as to how it benefits its host. PMID- 21551314 TI - Health promotion and risk behaviors among adolescents in Turkey. AB - Adolescents experience the onset and development of several health-related behaviors. The purpose of this study is to determine health risk and promotion behaviors of adolescents between the ages of 11 and 19 who were attending and to test the reliability and validity analysis of the Turkish version of Adolescent Health Promotion Scale (AHPS). The study was a cross-sectional survey and the sample consisted of 1,351 participants. A questionnaire that included demographic information, health risk behaviors, and AHPS was used to collect data. In the current study, the Cronbach's alpha coefficient for the AHPS was calculated as .92. Female students had significantly higher mean total scale scores than males (p < .05). The 11-14 age group had a statistically significant higher scale total mean score than the 15-19 age group (p = .001). International directives highlight the important function nurses fulfill in health promotion. Nurses may play a key role in school health services. PMID- 21551316 TI - Population pharmacokinetics and exposure-response of albinterferon alfa-2b. AB - Albinterferon alfa-2b (albIFN) has been studied for treatment of chronic hepatitis C virus (HCV). A population pharmacokinetics model was developed using nonlinear mixed-effects modeling. Efficacy/safety exposure-response relationships were assessed for subcutaneous albIFN doses (900-1800 ug once every 2 or 4 weeks) administered for either 24 weeks (HCV genotypes 2/3) or 48 weeks (genotype 1), plus daily oral ribavirin. Sustained virologic response (SVR) exposure-response was modeled using logistic regression. Adverse event incidence was tabulated versus exposure quartiles. First-order absorption rate constant (0.0148 h(-1)), apparent clearance (38.9 mL/h), and apparent volume of distribution (11.6 L) had interindividual variances (coefficient of variation) of 21%, 34%, and 24%, respectively. Residual variance estimates were 27% (coefficient of variation) and 1.51 ng/mL (standard deviation). For the only explanatory covariate-body weight exposure decreased as weight increased. Important SVR predictors included baseline HCV RNA, fibrosis score, and black race (genotype 1); SVR was minimally related to exposure. Most adverse events had similar incidence rates across exposure quartiles. Some adverse events had a higher incidence in the upper exposure quartile without evidence of exposure-response across the lower quartiles. Given the lack of consistent efficacy/safety exposure-response relationships, further investigation is necessary to optimize albIFN dosing. PMID- 21551317 TI - Influence of a fat-rich meal on bioavailability of extended-release and immediate release propiverine. AB - The muscarinic receptor antagonist propiverine is unique insofar as extended release (ER) tablets are of higher bioavailability than immediate-release (IR) tablets; this is caused by lower "first-pass" elimination of propiverine via CYP3A4 and efflux transporters in the distal small intestine and colon. Food may influence gastrointestinal transiting and, in turn, may affect regional absorption of propiverine IR and ER. Therefore, food effects on disposition of 30 mg IR and 45 mg ER were measured in a randomized, open, 4-period interaction study in 24 healthy participants. In fasting participants, ER had higher bioavailability than IR (F(rel) = 169%, P = .03). Fat-rich meal did not change the disposition of ER markedly (AUC(0-infinity) ratio, 1.00 [90% confidence interval (CI), 0.90-1.11], C(max) ratio, 0.97 [0.87-1.09]). However, C(max) and renal A(e) of the major N-oxidized metabolite (M-5) significantly increased, whereas t(1/2) decreased. By eating a fat-rich meal before administration, the differences in absorption of IR and ER were nearly abolished (AUC(0-infinity) ratio for propiverine, 1.12 [90% CI, 0.95-1.33]; AUC(0-infinity) ratio for M-5, 0.89 [0.82-0.95]). In conclusion, propiverine ER has higher bioavailability than IR and no positive food effect because it reaches, independently of food, intestinal absorption areas with lower metabolism and efflux transport, which results in constant absorption rates. PMID- 21551318 TI - Pharmacodynamic modeling of the effects of lanreotide Autogel on growth hormone and insulin-like growth factor 1. AB - Acromegaly arises from excessive levels of growth hormone (GH), many of whose effects are mediated by stimulation of secretion of insulin-like growth factor 1 (IGF-1). Synthetic somatostatin analogues inhibit GH secretion. The objective of the study was to develop a population pharmacodynamic model describing the relationship between serum concentrations of lanreotide (C(P)) and its GH and IGF 1 effects in patients with acromegaly receiving lanreotide Autogel (LA) at doses of 60, 90, or 120 mg by deep subcutaneous route every 28 days. Data were analyzed from 104 patients. The GH and IGF-1 profiles were fit simultaneously using the population approach with NONMEM. The GH vs C(P) and the IGF-1 vs GH relationships were described using inhibitory I(max) and E(max) models, respectively. Results indicated that lanreotide cannot abolish GH completely. C(P) levels of 3.4 ng/mL are required to achieve percentages of hormonal control (GH and IGF-1) of 21% and 36% in not treated and previously treated patients. If the focus is only GH, a C(P) of 3.4 ng/mL corresponds to 33% and 56% controlling rates. Simulations showed that there is a possible clinical benefit if the highest dose of 120 mg LA is administered to patients who are not well controlled by lower doses of LA. PMID- 21551319 TI - Accurate determination of S-phase fraction in proliferative cells by dual fluorescence and peroxidase immunohistochemistry with 5-bromo-2'-deoxyuridine (BrdU) and Ki67 antibodies. AB - To ensure the maintenance of tissues in mammals, cell loss must be balanced with cell production, the proliferative activity being different from tissue to tissue. In this article, the authors propose a new method for the quantification of the proliferative activity, defined as the S-phase fraction of actively cycling cells, by dual labeling with fluorescence and peroxidase immunohistochemistry using BrdU (marker of S-phase) and Ki67 antibodies (marker of G(1)-, S-, G(2)-, and M-phases) after a one-step antigen retrieval. In the generative cell zones of fundic and pyloric glandular stomachs, where the majority of cells were cycling, the authors measured a proliferative activity of 31%. In the epithelium of the forestomach and the skin, where cycling cells are intermingled with G(0) and differentiated cells, proliferative activities were 21% and 13%, respectively. In the adrenal cortex, in which cycling cells were sparsely distributed, the proliferative activity reached 32%. During the regenerative process in the skin after a lesion, the proliferative activity increased in proximity to the wound. The present one-step dual-labeling method has revealed that the proliferative activity is different between tissues and depends on the physiological or pathological state. PMID- 21551320 TI - Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. AB - Trop2 is a cell-surface glycoprotein reported to be overexpressed in various types of adenocarcinomas with minimal expression in normal tissues. Recent findings that Trop2 expression correlates with tumor aggressiveness have increased interest in Trop2 as a potential target for cancer immunotherapy. The goal of this study was to extensively evaluate Trop2 expression at the transcript and protein levels in normal and tumor tissues. It was determined that Trop2 is overexpressed on some carcinomas relative to the corresponding normal tissue. However, in human and mouse, Trop2 is highly expressed at both the transcript and protein levels on several essential normal tissues. The findings suggest that the development of therapeutic agents to target Trop2 may require strategies that target Trop2 on malignant tissues in order to minimize potential toxicities to essential normal tissues that also express high levels of Trop2. PMID- 21551321 TI - Proteomic analysis yields an unexpected trans-acting point in control of the human sympathochromaffin phenotype. AB - BACKGROUND: The secretory protein chromogranin A (CHGA) plays a necessary role in formation of catecholamine storage vesicles and gives rise to a catecholamine release-inhibitory fragment. Because genetic variation in the proximal human CHGA promoter predicts autonomic function and blood pressure, we explored how a common genetic variant alters transcription of the gene. METHODS AND RESULTS: Bioinformatic analysis suggested that the common G-462A promoter variant (rs9658634) may disrupt as many as 3 transcriptional control motifs: LEF1, COUP TF, and PPARgamma-RXRalpha. During electrophoretic mobility shifts, chromaffin cell nuclear proteins bound specifically to the A (though not G) allele of CHGA promoter G-462A. On oligonucleotide affinity chromatography followed by electrospray ionization followed by 2-dimensional (tandem) mass spectrometry analysis of A allele eluates, the transcription factor LEF1 (lymphoid enhancer binding factor-1) was identified. Interaction of LEF1 with the A allele at G-462A was confirmed by supershift. On cotransfection, LEF1 discriminated between the allelic variants, especially in chromaffin cells. Allele specificity of trans activation by LEF1 was transferable to an isolated G-462A element fused to a heterologous (SV40) promoter. Because beta-catenin (CTNNB1) can heterodimerize with LEF1, we tested the effect of cotransfection of this factor and again found A allele-specific perturbation of CHGA transcription. CONCLUSIONS: Common genetic variation within the human CHGA promoter alters the interaction of specific factors in trans with the promoter, with LEF1 identified by proteomic analysis and confirmed by supershift. Coexpression experiments show functional effects of LEF1 and CTNNB1 on CHGA promoter. The findings document a novel role for components of the immune and WNT pathways in control of human sympathochromaffin phenotypes. PMID- 21551322 TI - Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. AB - BACKGROUND: Left ventricular noncompaction of the myocardium (LVNC) has been recognized as a cardiomyopathy with a genetic etiology. Mutations in genes encoding sarcomere proteins were shown to be associated with LVNC. We evaluated the potential clinical impact of genetic analysis of sarcomere genes in patients with LVNC. METHODS AND RESULTS: We identified 5 mutations in cardiac myosin binding protein C (MYBPC3) and 2 mutations in alpha-tropomyosin (TPM1) in a cohort of unrelated adult probands with isolated LVNC. The mutations in MYBPC3 and TPM1 and in 6 other previously reported sarcomere genes in this cohort resulted in a total of 18 (29%) heterozygous mutations in 63 probands. beta myosin heavy chain (MYH7) was the most prevalent disease gene and accounts for 13% of cases, followed by MYBPC3 (8%). Comparing sarcomere mutation-positive and mutation-negative LVNC probands showed no significant differences in terms of average age, myocardial function, and presence of heart failure or tachyarrhythmias at initial presentation or at follow-up. Familial disease was found in 16 probands of whom 8 were sarcomere mutation positive. Nonpenetrance was detected in 2 of 8 mutation-positive families with LVNC. CONCLUSIONS: Mutations in sarcomere genes account for a significant (29%) proportion of cases of isolated LVNC in this cohort. The distribution of disease genes confirms genetic heterogeneity and opens new perspectives in genetic testing in patients with LVNC and their relatives at high risk of inheriting the cardiomyopathy. The presence or absence of a sarcomere gene mutation in LVNC cannot be related to the clinical phenotype. PMID- 21551323 TI - A successful, voluntary, multicomponent statewide effort to reduce health care associated infections. AB - Health care-associated infections (HAIs) increase morbidity, mortality, and hospital costs. Multiple organizations have worked independently to reduce HAIs. Regional collaborative efforts to reduce HAIs have been less common but may be particularly effective. The authors describe a statewide multicomponent approach implemented by the Iowa Healthcare Collaborative (IHC) to reduce HAIs. IHC's initiatives helped providers improve patient care by becoming engaged in specific projects, improving communication, sharing data, and implementing best practices. Other states could use this approach as a model to engage clinicians in patient safety initiatives and thereby accelerate the rate at which clinical care and health care outcomes are improved. PMID- 21551324 TI - Devosia psychrophila sp. nov. and Devosia glacialis sp. nov., from alpine glacier cryoconite, and an emended description of the genus Devosia. AB - Two psychrophilic strains, Cr7-05(T) and Cr4-44(T), isolated from alpine glacier cryoconite, were characterized by using a polyphasic approach. Both strains were psychrophilic, showing good growth over a temperature range of 1-20 degrees C. The chemotaxonomic characteristics of these isolates included the presence of C(18:1)omega7c and summed feature 3 (C(16:1)omega7c and/or C(16:1)omega6c) as the major cellular fatty acids, Q-10 as the predominant ubiquinone and diphosphatidylglycerol, phosphatidylglycerol and unknown glycolipids as major polar lipids. The DNA G+C contents of strains Cr7-05(T) and Cr4-44(T) were 61.4 and 63.6 mol%, respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the two isolates belong to the genus Devosia. The 16S rRNA gene sequence similarity between the two strains was 98.6%, but DNA-DNA hybridization indicated 54% relatedness. Strains Cr7-05(T) and Cr4-44(T) exhibited 16S rRNA gene sequence similarity of 94.7-97.2 and 94.9-96.9%, respectively, to the type strains of recognized Devosia species. On the basis of phenotypic characteristics, phylogenetic analysis and DNA-DNA relatedness data, strains Cr7-05(T) and Cr4-44(T) represent two novel species within the genus Devosia, for which the names Devosia psychrophila sp. nov. (type strain Cr7-05(T) =DSM 22950(T) =CGMCC 1.10210(T) =CIP 110130(T)) and Devosia glacialis sp. nov. (type strain Cr4-44(T) =CGMCC 1.10691(T) =LMG 26051(T)) are proposed. An emended description of the genus Devosia is also provided. PMID- 21551325 TI - Description of Belnapia rosea sp. nov. and emended description of the genus Belnapia Reddy et al. 2006. AB - A novel alphaproteobacterial strain, designated CPCC 100156(T), was isolated from a forest soil sample collected from Hainan Island, South China, and subjected to taxonomic investigation using a polyphasic approach. The pink- to rosy-coloured colonies on TSA and YM agar were smooth and moist. Good growth occurred at 28-32 degrees C and at pH 7.0-7.5. The respiratory quinone was ubiquinone-9. The polar lipids consisted of phosphatidylcholine (PC), hydroxyphosphatidylethanolamine (OH PE), phosphatidylglycerol (PG), diphosphatidylglycerol (DPG) and two unidentified aminolipids (AL1, AL2), with a minor amount of ninhydrin-positive phosphoglycolipid. (NPG). The major cellular fatty acids were summed feature 8 (C(18:1)omega7c /C(18:1)omega6c) (49.5%), summed feature 3 (C(16:1)omega7c/C(16:1)omega6c) (22.5%), and C(16:0) (14.0%). The G+C content of the genomic DNA was 70.3 mol%. The organism showed 16S rRNA gene sequence similarity of 97.37% with Belnapia moabensis DSM 16746(T). Phylogenetic analyses based on 16S rRNA gene sequences showed that the isolate belonged to the family Acetobacteraceae and consistently formed a robust cluster with Belnapia moabensis DSM 16746(T) in the phylogenetic tree. The DNA-DNA hybridization value between the new isolate and Belnapia moabensis DSM 16746(T) was 45.6%. On the basis of the taxonomic evidence, it is proposed that strain CPCC 100156(T) represents a novel species, for which the name Belnapia rosea sp. nov. is proposed. The type strain is CPCC 100156(T) (=DSM 23312(T)=CGMCC 1.10758(T)). The description of the genus Belnapia is emended accordingly. PMID- 21551326 TI - Aquabacterium limnoticum sp. nov., isolated from a freshwater spring. AB - A Gram-negative, facultatively anaerobic, short-rod-shaped, non-motile and non spore-forming bacterial strain, designated ABP-4(T), was isolated from a freshwater spring in Taiwan and was characterized using the polyphasic taxonomy approach. Growth occurred at 20-40 degrees C (optimum, 30-37 degrees C), at pH 7.0-10.0 (optimum, pH 7.0-9.0) and with 0-3% NaCl (optimum, 0%). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain ABP-4(T), together with Aquabacterium fontiphilum CS-6(T) (96.4% sequence similarity), Aquabacterium commune B8(T) (96.1%), Aquabacterium citratiphilum B4(T) (95.5%) and Aquabacterium parvum B6(T) (94.7%), formed a deep line within the order Burkholderiales. Strain ABP-4(T) contained summed feature 3 (comprising C(16:1) omega7c and/or C(16:1) omega6c), C(18:1) omega7c and C(16:0) as predominant fatty acids. The major cellular hydroxy fatty acid was C(10:0) 3-OH. The major isoprenoid quinone was Q-8 and the DNA G+C content was 68.6 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, diphosphatidylglycerol and several uncharacterized phospholipids. The DNA-DNA relatedness of strain ABP-4(T) with respect to recognized species of the genus Aquabacterium was less than 70%. On the basis of the genotypic, chemotaxonomic and phenotypic data, strain ABP-4(T) represents a novel species in the genus Aquabacterium, for which the name Aquabacterium limnoticum sp. nov. is proposed. The type strain is ABP-4(T) (=BCRC 80167(T)=KCTC 23306(T)). PMID- 21551327 TI - Nocardia grenadensis sp. nov., isolated from sand of the Caribbean Sea. AB - A Gram-stain-positive, non-spore-forming bacterium (GW5-5797(T)) was isolated on soil extract agar from sand collected at a depth of 5 m in the Caribbean Sea near Grenada. 16S rRNA gene sequence analysis and similarity studies showed that strain GW5-5797(T) belongs to the genus Nocardia, and is most closely related to Nocardia speluncae N2-11(T) (99.2% similarity) and Nocardia jinanensis 04-5195(T) (99.2%) and more distantly related to Nocardia rhamnosiphila 202GMO(T) (98.6%) and other Nocardia species. Strain GW5-5797(T) could be distinguished from all other recognized Nocardia species by sequence similarity values less than 98.5%. The peptidoglycan diamino acid was meso-diaminopimelic acid. Strain GW5-5797(T) exhibited a quinone system with the predominant compounds MK-8(H(4)omega-cyclo) and MK-8(H(2)). The polar lipid profile of GW5-5797(T) consisted of the major compounds diphosphatidylglycerol, phosphatidylethanolamine and an unidentified glycolipid, moderate amounts of phosphatidylinositol and a phosphatidylinositol mannoside and minor amounts of several lipids including a second phosphatidylinositol mannoside. The polyamine pattern contained the major compound spermine and moderate amounts of spermidine. The major fatty acids were C(16:0,) C(18:1)omega9c and 10-methyl C(18:0). These chemotaxonomic traits are in excellent agreement with those of other Nocardia species. The results of DNA-DNA hybridizations and physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain GW5-5797(T) from the most closely related species, showing 16S rRNA gene sequence similarities >98.5%. Strain GW5-5797(T) therefore merits separate species status, and we propose the name Nocardia grenadensis sp. nov., with the type strain GW5-5797(T) (=CCUG 60970(T) =CIP 110294(T)). PMID- 21551328 TI - Psychrobacter isolates of human origin, other than Psychrobacter phenylpyruvicus, are predominantly Psychrobacter faecalis and Psychrobacter pulmonis, with emended description of P. faecalis. AB - Human Psychrobacter isolates, other than Psychrobacter phenylpyruvicus, are predominantly designated Psychrobacter immobilis. Phenotypic and genotypic testing of Psychrobacter isolates that have been deposited in different culture collections as P. immobilis indicates that most of these human isolates belong to the species Psychrobacter faecalis and Psychrobacter pulmonis. PMID- 21551329 TI - Bryocella elongata gen. nov., sp. nov., a member of subdivision 1 of the Acidobacteria isolated from a methanotrophic enrichment culture, and emended description of Edaphobacter aggregans Koch et al. 2008. AB - An aerobic, pink-pigmented, chemo-organotrophic bacterium, designated strain SN10(T), was isolated from a methanotrophic enrichment culture obtained from an acidic Sphagnum peat. This isolate was represented by Gram-negative, non-motile rods that multiply by normal cell division and form rosettes. Strain SN10(T) is an obligately acidophilic, mesophilic bacterium capable of growth at pH 3.2-6.6 (with an optimum at pH 4.7-5.2) and at 6-32 degrees C (with an optimum at 20-24 degrees C). The preferred growth substrates are sugars and several heteropolysaccharides of plant and microbial origin, such as pectin, lichenan, fucoidan and gellan gum. While not being capable of growth on C(1) compounds, strain SN10(T) can develop in co-culture with exopolysaccharide-producing methanotrophs by utilization of their capsular material. The major fatty acids determined in strain SN10(T) using the conventional lipid extraction procedure are iso-C(15:0) and C(16:1)omega7c. Upon hydrolysis of total cell material, substantial amounts of the uncommon membrane-spanning lipid 13,16-dimethyl octacosanedioic acid (isodiabolic acid) were also detected. The polar lipids are two phosphohexoses, phosphatidylethanolamine, phosphatidylglycerol and several phospholipids of unknown structure. The major quinone is MK-8. Pigments are carotenoids. The G+C content of the DNA is 60.7 mol%. Strain SN10(T) forms a separate lineage within subdivision 1 of the phylum Acidobacteria and displays 94.0-95.4% 16S rRNA gene sequence similarity to members of the genera Edaphobacter and Granulicella, 93.0-93.7% similarity to members of the genus Terriglobus and 92.2-92.3 % similarity to the type strains of Telmatobacter bradus and Acidobacterium capsulatum. Therefore, strain SN10(T) is classified within a novel genus and species, for which the name Bryocella elongata gen. nov., sp. nov. is proposed. Strain SN10(T) (=LMG 25276(T) =DSM 22489(T)) is the type strain of Bryocella elongata. An emended description of Edaphobacter aggregans Koch et al. 2008 is also given. PMID- 21551330 TI - Mongoliitalea lutea gen. nov., sp. nov., an alkaliphilic, halotolerant bacterium isolated from a haloalkaline lake. AB - Two bacterial isolates from the surface water of a haloalkaline lake on the Mongolia Plateau, strains MIM18(T) and MIM19, were characterized; their morphological, physiological and chemotaxonomic characters, and phylogenetic position based on 16S rRNA gene sequences, were determined. The two strains were alkaliphilic, halotolerant, non-motile, aerobic, Gram-negative, orange-red, rod shaped and oxidase-positive. Growth was observed in 0-5.5% (w/v) NaCl, with optimum growth at 1%. The temperature range for growth was 0-41 degrees C, with good growth at 28-37 degrees C and optimum growth at 30-33 degrees C. The DNA G+C content was 39.8-41.2 mol%. The strains contained menaquinone MK-7 as the major respiratory quinone and phosphatidylcholine, phosphatidylglycerol and phosphatidylethanolamine as the major polar lipids. Predominant cellular fatty acids were iso-C(15:0) (28.1-29.3%), iso-C(17:0) 3-OH (14.6-18.8%), C(15:1)omega6c (5.3-8.6%), C(14:0) 2-OH and/or iso-C(15:0) 2-OH (5.4-6.1%), and iso-C(17:1)omega9c and/or C(16:0) 10-methyl (5.0-6.8%). 16S rRNA gene sequence analysis showed that Belliella and Nitritalea of the family Cyclobacteriaceae were the closest related species with sequence similarities of 91.7-92.3% and 88.2%, respectively, with strains of these genera; other members of the Cyclobacteriaceae had sequence similarities lower than 88%. Phylogenetic analysis indicated that the strains formed a deep-rooted lineage distinct from the clades represented by the genera Belliella, Nitritalea, Indibacter, Aquiflexum, Echinicola, Litoribacter, Cyclobacterium and Algoriphagus. Based on the phenotypic and phylogenetic characteristics mentioned above, the two strains are representatives of a single novel species in a new genus; the name Mongoliitalea lutea gen. nov., sp. nov. is proposed, with MIM18(T) (=ACCC 05421(T)=KCTC 23224(T)) as the type strain. PMID- 21551331 TI - Algoriphagus aquaeductus sp. nov., isolated from a freshwater pipe. AB - A Gram-staining-negative, aerobic to microaerophilic, rod-shaped, red-coloured bacterium, strain T4(T), was isolated from a freshwater pipe on Tenerife island. A polyphasic taxonomic study was performed in order to characterize the strain in detail. The isolate is surrounded by a slime capsule, occurs singly, in the form of short chains, or in aggregates, and exhibits catalase and oxidase activities. Growth was observed at 15-42 degrees C. Optimum growth occurred at pH 8 with mono- and disaccharides, followed by polysaccharides and deoxysaccharides, but the bacterium utilized only a restricted spectrum of alcohols, alditols, amides, amines, carboxylic acids and amino acids. Strain T4(T) tolerated concentrations of 0-4% (w/v) NaCl and contained MK-7 as predominant isoprenoid quinone as well as carotenoids, but lacked pigments of the flexirubin type. The predominant fatty acids were iso-C(15:0) (32.2%), summed feature 3 (C(16:1)omega6c and/or C(16:1)omega7c; 22.5%), and iso-C(17:0) 3-OH (7.9%). Major polar lipids were phosphatidylethanolamine, phospholipids, aminophospholipids and other lipids of unknown character. The DNA G+C content was approximately 41.8 mol%. The sequence of the 16S-rRNA gene assigned strain T4(T) to the CFB group, forming a coherent cluster with species of the genus Algoriphagus with the highest similarity of 98.8% to Algoriphagus aquatilis A8-7(T). DNA-DNA hybridization revealed 37.5% relatedness to strain A8-7(T). Based on morphological, physiological and molecular properties as well as on phylogenetic distinctiveness, strain T4(T) should be placed into the genus Algoriphagus as a novel species, for which the name Algoriphagus aquaeductus sp. nov. (type strain T4(T) =DSM 19759(T) =LMG 24398(T) =NCIMB 14399(T)) is proposed. PMID- 21551332 TI - Pontibacter populi sp. nov., isolated from the soil of a Euphrates poplar (Populus euphratica) forest. AB - A Gram-negative-staining, rod-shaped, non-motile and pink bacterial strain was isolated from the soil of a Populus euphratica forest located in Xinjiang, China. The strain, designated strain HYL7-15(T), was subjected to a taxonomic analysis using a polyphasic approach. 16S rRNA gene sequence analyses indicated that the isolate belonged to the phylum Bacteroidetes and was related to the genus Pontibacter, with sequence similarities ranging from 93.1 to 95.0% with other species of the genus Pontibacter. Strain HYL7-15(T) contained MK-7 as the predominant menaquinone and its DNA G+C content was 44.9 mol%. The major cellular fatty acids of the novel strain were iso-C(15:0) (16.49%), iso-C(17:0) 3-OH (10.96%) and summed feature 4 (comprising anteiso-C(17:1) B and/or iso-C(17:1) I, 18.46%). The major polar lipids were phosphatidylethanolamine (PE) and phosphatidylglycerol (PG); diphosphatidylglycerol (DPG), three unknown aminophospholipids (APLs) and two unknown phospholipids (PLs) were also detected. On the basis of the evidence presented, it is concluded that strain HYL7-15(T) represents a novel species of the genus Pontibacter, for which the name Pontibacter populi sp. nov. is proposed. The type strain is HYL7-15(T) (=CCTCC AB 206239(T)=NRRL B-59488(T)). PMID- 21551333 TI - Sphingobacterium wenxiniae sp. nov., a cypermethrin-degrading species from activated sludge. AB - A Gram-negative, non-motile, non-spore-forming, non-flagellated rod capable of degrading cypermethrin, designated LQY-18(T), was isolated from activated sludge of a wastewater treatment plant in China. Strain LQY-18(T) grew at 8-40 degrees C (optimum 30 degrees C), at pH 5.0-10.0 (optimum pH 7.0) and with 0-5% (w/v) NaCl (optimum 1%). The predominant menaquinone was MK-7 (97%) and the major fatty acids were summed feature 3 (comprising C(16:1)omega6c and/or C(16:1)omega7c), iso-C(15:0) and iso-C(17:0) 3-OH. The DNA G+C content was 40.3 mol%. Phylogenetic analysis revealed that the isolate belonged to the genus Sphingobacterium of the phylum Bacteroidetes and showed low 16S rRNA gene sequence similarity with recognized members of the genus Sphingobacterium. The closest neighbour was Sphingobacterium mizutaii ATCC 33299(T) (92.9% 16S rRNA gene sequence similarity). On the basis of phenotypic, genetic and phylogenetic data, strain LQY-18(T) (=ACCC 05410(T)=CCTCC AB 2010005(T)=KCTC 23009(T)) should be classified as a representative of a novel species of the genus Sphingobacterium, for which the name Sphingobacterium wenxiniae sp. nov. is proposed. PMID- 21551334 TI - Tropicimonas aquimaris sp. nov., isolated from seawater, and emended description of the genus Tropicimonas Harwati et al. 2009. AB - A Gram-staining-negative, aerobic, non-motile and rod-shaped bacterial strain, designated DPG-21(T), was isolated from seawater from the South Sea in Korea, and investigated using a polyphasic taxonomic approach. Strain DPG-21(T) grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2% (w/v) NaCl. In a neighbour-joining phylogenetic tree based on 16S rRNA gene sequences, strain DPG-21(T) clustered with Tropicimonas isoalkanivorans B51(T) (with a sequence similarity of 97.1%); the novel strain showed lower 16S rRNA gene sequence similarities (<95.4%) with the other species included in the tree. The mean DNA DNA relatedness value between strain DPG-21(T) and T. isoalkanivorans DSM 19548(T) was 12%. The predominant ubiquinones of strain DPG-21(T) were Q-10 and Q 9 while C(18:1)omega7c was the strain's major fatty acid. The polar lipid profile of strain DPG-21(T) was similar to that of T. isoalkanivorans DSM 19548(T). The genomic DNA G+C content of the novel strain was 69.6 mol%. Some phenotypic properties and the phylogenetic and genetic data indicated that strain DPG-21(T) was distinct from T. isoalkanivorans and represents a novel species of the genus Tropicimonas, for which the name Tropicimonas aquimaris sp. nov. is proposed. The type strain is DPG-21(T) (=KCTC 23424(T)=CCUG 60524(T)). PMID- 21551335 TI - Hasllibacter halocynthiae gen. nov., sp. nov., a nutriacholic acid-producing bacterium isolated from the marine ascidian Halocynthia roretzi. AB - A Gram-negative, aerobic, ovoid to rod-shaped bacterial strain, KME 002(T) was isolated from a marine ascidian, Halocynthia roretzi, off the coast of Gangneung, Korea. Phylogenetic analyses based on 16S rRNA gene sequences showed that this strain belonged to the family Rhodobacteraceae in the class Alphaproteobacteria and was closely related to the type strains of Dinoroseobacter shibae, Roseovarius crassostreae and Pseudoruegeria aquimaris with 95.0, 94.7 and 94.5% 16S rRNA gene sequence similarities, respectively. KME 002(T) was an obligately halophilic bacterium requiring 1 to 5% (w/v) NaCl, with an absolute requirement for magnesium chloride for growth. Cells were motile by means of a single polar flagellum and showed budding fission. The predominant cellular fatty acid of the isolate was C(18:1)omega7c and Q-10 was the major ubiquinone. The DNA G+C content of the strain was 71.6 mol%. The major secondary metabolites from cultures in liquid medium were cholic acid derivatives, including 3alpha,12alpha-hydroxy-3 keto-glycocholanic acid, 12-hydroxy-3-keto-glycocholanic acid, nutriacholic acid and deoxycholic acid. These characteristics determined in this polyphasic study suggest that strain KME 002(T) represents a novel species in a new genus of the family Rhodobacteraceae. The name Hasllibacter halocynthiae gen. nov., sp. nov. is proposed for this isolate, and the type strain is KME 002(T) (=JCM 16214(T)=KCCM 90082(T)). PMID- 21551336 TI - Methylorosula polaris gen. nov., sp. nov., an aerobic, facultatively methylotrophic psychrotolerant bacterium from tundra wetland soil. AB - Three strains of Gram-negative, aerobic, motile bacteria with bipolar flagella were isolated from acidic tundra wetland soils near the city of Vorkuta and from the Chukotka and Yugorsky Peninsulas and designated strains V-022(T), Ch-022 and Ju-022. The cells were rod-shaped, 0.5-0.6 um in width and 1.3-4.5 um in length and reproduced by irregular fission. These bacteria were facultative methylotrophs that used methanol, methylamines and a wide range of other sources of carbon and energy such as sugars and polysaccharides, ethanol and amino acids. The isolates used the Calvin-Benson pathway for the assimilation of one-carbon compounds and were unable to fix nitrogen. The new strains were moderately acidophilic and psychrotolerant, capable of growth over a pH range of 4.0 to 7.8, with optimum growth at pH 5.5-6.0. Growth occurred between 4 and 30 degrees C (optimum 20-25 degrees C). The principal phospholipid fatty acid was C(18:1)omega7c. The DNA G+C content of strain V-022(T) was 65.2 mol%. Analysis of the 16S rRNA gene sequences revealed that all three isolates V-022(T), Ch-022 and Yu-022 exhibited almost identical 16S rRNA gene sequences (99.9% gene sequence similarity) and formed a new lineage within the class Alphaproteobacteria. The name Methylorosula polaris is suggested to accommodate this new genus and novel species with strain V-022(T) (=DSM 22001(T)=VKM V-2485(T)) as the type strain of the type species. PMID- 21551337 TI - Sphingobium lucknowense sp. nov., a hexachlorocyclohexane (HCH)-degrading bacterium isolated from HCH-contaminated soil. AB - A yellow-pigmented, hexachlorocyclohexane (HCH)-degrading bacterium, designated F2(T), was isolated from an HCH dumpsite at Ummari village in Lucknow, India. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolate belonged to the genus Sphingobium. Its closest neighbour was Sphingobium japonicum UT26(T) (99.2% 16S rRNA gene sequence similarity). The DNA G+C content was 65.7 mol%. The polyamine profile showed the presence of spermidine. The respiratory pigment was ubiquinone Q-10. The predominant cellular fatty acids were C(16:0) (12.5%), C(14:0) 2-OH (8.1%), summed feature 3 (consisting of C(16:1)omega7c and/or C(16:1)omega6c; 5.8%) and summed feature 8 (consisting of C(18:1)omega7c and/or C(18:1)omega6c; 53.1%). The major polar lipids of strain F2(T) were phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and sphingoglycolipid. DNA-DNA relatedness and biochemical and physiological characters clearly distinguished the isolate from its closest phylogenetic neighbours. Thus, strain F2(T) represents a novel species of the genus Sphingobium, for which the name Sphingobium lucknowense sp. nov. is proposed. The type strain is strain F2(T) (=MTCC 9456(T) =CCM 7544(T)). PMID- 21551339 TI - Distinguishing blocking from attenuation in visual selective attention. AB - Sensory information must be processed selectively in order to represent the world and guide behavior. How does such selection occur? Here we consider two alternative classes of selection mechanisms: In blocking, unattended stimuli are blocked entirely from access to downstream processes, and in attenuation, unattended stimuli are reduced in strength but if strong enough can still access downstream processes. Existing evidence as to whether blocking or attenuation is a more accurate model of human performance is mixed. Capitalizing on a general distinction between blocking and attenuation-blocking cannot be overcome by strong stimuli, whereas attenuation can-we measured how attention interacted with the strength of stimuli in two spatial selection paradigms, spatial filtering and spatial monitoring. The evidence was consistent with blocking for the filtering paradigm and with attenuation for the monitoring paradigm. This approach provides a general measure of the fate of unattended stimuli. PMID- 21551338 TI - Bisphosphonates inhibit expression of p63 by oral keratinocytes. AB - Osteonecrosis of the jaw (ONJ), a side-effect of bisphosphonate therapy, is characterized by exposed bone that fails to heal within eight weeks. Healing time of oral epithelial wounds is decreased in the presence of amino-bisphosphonates; however, the mechanism remains unknown. We examined human tissue from individuals with ONJ and non-bisphosphonate-treated control individuals to identify changes in oral epithelium and connective tissue. Oral and intravenous bisphosphonate treated ONJ sites had reduced numbers of basal epithelial progenitor cells, as demonstrated by a 13.8+/-1.1% and 31.9+/-5.8% reduction of p63 expression, respectively. No significant differences in proliferation rates, vessel density, or macrophage number were noted. In vitro treatment of clonal and primary oral keratinocytes with zoledronic acid (ZA) inhibited p63, and expression was rescued by the addition of mevalonate pathway intermediates. In addition, both ZA treatment and p63 shRNA knock-down impaired formation of 3D Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) and closure of an in vitro scratch assay. Analysis of our data suggests that bisphosphonate treatment may delay oral epithelial healing by interfering with p63-positive progenitor cells in the basal layer of the oral epithelium in a mevalonate-pathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone. PMID- 21551340 TI - Banking on a bad bet. Probability matching in risky choice is linked to expectation generation. AB - Probability matching is the tendency to match choice probabilities to outcome probabilities in a binary prediction task. This tendency is a long-standing puzzle in the study of decision making under risk and uncertainty, because always predicting the more probable outcome across a series of trials (maximizing) would yield greater predictive accuracy and payoffs. In three experiments, we tied the predominance of probability matching over maximizing to a generally adaptive cognitive operation that generates expectations regarding the aggregate outcomes of an upcoming sequence of events. Under conditions designed to diminish the generation or perceived applicability of such expectations, we found that the frequency of probability-matching behavior dropped substantially and maximizing became the norm. PMID- 21551341 TI - The ease-of-processing heuristic and the stability bias: dissociating memory, memory beliefs, and memory judgments. AB - Judgments about memory are essential in promoting knowledge; they help identify trustworthy memories and predict what information will be retained in the future. In the three experiments reported here, we investigated the mechanisms underlying predictions about memory. In Experiments 1 and 2, single words were presented once or multiple times, in large or small type. There was a double dissociation between actual memory and predicted memory: Type size affected predicted but not actual memory, and future study opportunities affected actual memory but scarcely affected predicted memory. The results of Experiment 3 suggest that beliefs and judgments are largely independent, and neither consistently resembles actual memory. Participants' underestimation of future learning-a stability bias-stemmed from an overreliance on their current memory state in making predictions about future memory states. The overreliance on type size highlights the fundamental importance of the ease-of-processing heuristic: Information that is easy to process is judged to have been learned well. PMID- 21551342 TI - The presence of inositol phosphates in gastric pig digesta is affected by time after feeding a nonfermented or fermented liquid wheat- and barley-based diet. AB - The objective was to quantify the retention of digesta and evaluate the degradation of phytate or inositol hexakisphosphate (InsP(6)) and lower inositol phosphates (InsP5, InsP4, InsP3, and InsP2) in the stomach at different times after feeding pigs a fermented liquid diet with microbial phytase or a nonfermented diet with or without microbial phytase. Six barrows fitted with gastric cannulas were used. The experiment was a 3 * 3 Latin square with 3 pigs fed 3 diets during 3 wk in 2 replicates. Each experimental period lasted for 7 d, comprising 3 d of adaptation and 4 d of total collection of gastric digesta. For each pig, the digesta was collected once daily at 1, 2, 3, or 5 h after feeding the morning meal. A basal wheat- and barley-based diet was steam-pelleted at 90 degrees C. The dietary treatments were a nonfermented basal diet (NF-BD), the NF BD with microbial phytase (750 phytase units of phytase/kg, as-fed basis; NF-BD + phytase), and the NF-BD + phytase fermented for 17.5 h (F-BD + phytase). Gastric InsP6-P was not detected at all in pigs fed F-BD + phytase because of complete InsP6 degradation during fermentation of the feed before feeding. Gastric InsP6-P decreased over time (P < 0.05) in pigs fed NF-BD and NF-BD + phytase. The decreases were 45, 54, 56, and 61 percentage points greater at 1, 2, 3, and 5 h, respectively, in pigs fed NF-BD + phytase compared with NF-BD. However, substantial amounts of InsP6 still passed into the small intestine in pigs fed NF BD + phytase, especially within the first hour (estimated to 17% of InsP6-P intake). The accumulation of lower inositol phosphates in gastric digesta was very small for all treatments and at all times because of a rapid and almost complete degradation. In conclusion, phytase addition to the nonfermented diet increased the degradation of gastric InsP6. However, considerable amounts of intact InsP6 still passed into the small intestine because of a shortage of time for InsP6 degradation in the stomach. Therefore, to increase the apparent digestibility of plant P in dry wheat- and barley-based diets, the development of phytases that can degrade InsP6 effectively immediately after ingestion of the feed at an initial gastric pH from 6.5 to 5.0 is needed. Feeding F-BD + phytase compensated for the shortage of time because the InsP6 degradation was completed during fermentation before feeding. The degradation of InsP6 to InsP5 is the bottleneck for plant P utilization in pigs because the degradation of the lower inositol phosphates is rapid and almost complete. PMID- 21551343 TI - Modulation of nicotinamide adenine dinucleotide phosphate oxidase activity through sequential posttranslational modifications of p22 phagocytic oxidase during capacitation and acrosome reaction in goat spermatozoa. AB - Superoxide anion radical, produced in low quantities, plays a positive role in sperm function. Spermatozoa produce superoxide anion radical during posttesticular development, which shows an abrupt increase during capacitation. The NAD phosphate oxidase (NOX) family members NOX2 and NOX5 are the 2 enzymes implicated in superoxide production in spermatozoa. We examined the organization of NOX2 in goat spermatozoa during epididymal maturation, capacitation, and acrosome reaction. Spermatozoa from testis, caput epididymidis, corpus epididymidis, and cauda epididymidis possessed components of the phagocytic oxidase (PHOX; i.e., gp91phox, p22phox, p67phox, p47phox, p40phox), and ras related C3 botulinum toxin substrate 1/2 (Rac1/2) on spermatozoa, and their concentrations did not show significant alterations during epididymal maturation. During capacitation in vitro, p22phox underwent Thr-phosphorylation, which resulted in a mobility shift of the corresponding band toward greater molecular mass. The Rac1/2 also showed a mobility shift from 32 to 23 kDa during capacitation. During progesterone-induced acrosome reaction, the spermatozoa experienced a total loss of p22phox and p47phox. The p47phox, but not p22phox, was detected in the exocytic vesicles of the acrosome. The Thr-phosphorylated form of p22phox was ubiquitinated and degraded through proteasome-mediated pathways in goat sperm cell lysates. Thus, Thr phosphorylation of p22phox acts as a regulatory switch in goat spermatozoa that transiently activates the NOX2 system during capacitation and subsequently directs it for degradation through the ubiiquitin-proteasomal pathway during progesterone-induced acrosome reaction. PMID- 21551344 TI - Mechanistic modeling of turkey growth response to genotype and nutrition. AB - Along with the fast genetic improvement, nutritional and environmental effects on poultry growth performance have made it necessary to develop growth models that have the flexibility to adapt to different genotypes and growing conditions. A mechanistic simulation model of energy and nutrient utilization in growing turkeys is presented herein. The model consists of simulating the average homeorhetic and homeostatic regulations associated with the utilization of circulating glucose, fatty acid, AA, and acetyl-CoA for protein and lipid retention in carcass, viscera, and feathers in a turkey population. Homeorhesis plays a major role in the control of protein and lipid turnover for the definition of genetic potential and feed intake, whereas homeostasis adjusts growth rate through protein and lipid turnover rates and, therefore, BW gain and feed intake to the growing conditions. Also, homeostasis enables the maintenance of a dynamic balance state during all the growing period through the control of circulating nutrient concentration. The model was developed and calibrated with experimental data that described energy utilization in male and female growing turkeys. Then, the ability of the model to adapt to genotypes and to predict the average response of a turkey population to dietary energy was evaluated. Model calibration showed simulations of energy and nutrient utilization that fitted well with the experimental data because ME was satisfyingly partitioned into heat production and energy retention as protein and lipid, and nutrient intake accurately partitioned BW gain into carcass, viscera, and feathers. The evaluation of the model was also satisfactory because BW gain and feed-to-gain ratio were globally in accordance with the observations in different male and female genotypes, in spite of an overestimation of the feed-to-gain ratio during the first weeks of age. Model evaluation showed that the BW gain and feed intake response of growing turkeys to dietary energy was accurately predicted. The model can therefore be used in different growing conditions as it is capable of simulating the growth of different turkey genotypes fed under changing environmental and nutritional contexts. PMID- 21551345 TI - Localization of gene and protein expressions of tumor necrosis factor-{alpha} and tumor necrosis factor receptor types I and II in the bovine corpus luteum during the estrous cycle. AB - One of the many roles of tumor necrosis factor (TNF)-alpha is to control mammalian corpus luteum (CL) PG synthesis and apoptotic cell death. Here, the cellular localization of TNF-alpha and its type I (TNF-RI) and type II (TNF-RII) receptors in bovine luteal tissue were analyzed using in situ hybridization, immunohistochemistry, and quantitative real-time PCR. Transcripts for TNF-alpha were expressed in bovine CL throughout the estrous cycle, but were significantly more abundant (P < 0.01) at the regressed luteal stage than at the other stages. Localization of TNF-alpha transcripts and protein were observed in large and small bovine luteal cells, as well as in immune cells. Moreover, transcripts for TNF-RI and TNF-RII were expressed in bovine CL throughout the estrous cycle. The abundance of TNF-RII transcripts was greater (P < 0.01) at the regressed luteal stage than at the other stages, whereas TNF-RI transcript abundance did not significantly change. Expression of TNF-RI and TNF-RII transcripts and proteins were observed in both the large and small luteal cells, and the proteins were also expressed in the immune cells and vascular endothelial cells. These results suggest that TNF-alpha sources include immune cells, as well as large and small luteal cells, and that TNF-RI and TNF-RII are present in the luteal cells of the bovine CL. PMID- 21551346 TI - Effects of adding polyclonal antibody preparations on ruminal fermentation patterns and digestibility of cows fed different energy sources. AB - Nine ruminally cannulated cows fed different energy sources were used to evaluate an avian-derived polyclonal antibody preparation (PAP-MV) against the specific ruminal bacteria Streptococcus bovis, Fusobacterium necrophorum, Clostridium aminophilum, Peptostreptococcus anaerobius, and Clostridium sticklandii and monensin (MON) on ruminal fermentation patterns and in vivo digestibility. The experimental design was three 3 * 3 Latin squares distinguished by the main energy source in the diet [dry-ground corn grain (CG), high-moisture corn silage (HMCS), or citrus pulp (CiPu)]. Inside each Latin square, animals received one of the feed additives per period [none (CON), MON, or PAP-MV]. Dry matter intake and ruminal fermentation variables such as pH, total short-chain fatty acids (tSCFA), which included acetate, propionate, and butyrate, as well as lactic acid and NH(3)-N concentration were analyzed in this trial. Total tract DM apparent digestibility and its fractions were estimated using chromic oxide as an external marker. Each experimental period lasted 21 d. Ruminal fluid sampling was carried out on the last day of the period at 0, 2, 4, 6, 8, 10, and 12 h after the morning meal. Ruminal pH was higher (P = 0.006) 4 h postfeeding in MON and PAP-MV groups when compared with CON. Acetate:propionate ratio was greater in PAP-MV compared with MON across sampling times. Polyclonal antibodies did not alter (P > 0.05) tSCFA, molar proportion of acetate and butyrate, or lactic acid and NH(3)-N concentration. Ruminal pH was higher (P = 0.01), 4 h postfeeding in CiPu diets compared with CG and HMCS. There was no interaction between feed additive and energy source (P > 0.05) for any of the digestibility coefficients analyzed. Starch digestibility was less (P = 0.008) in PAP-MV when compared with CON and MON. In relation to energy sources, NDF digestibility was greater (P = 0.007) in CG and CiPu vs. the HMCS diet. The digestibility of ADF was greater (P = 0.002) in CiPu diets followed by CG and HMCS. Feeding PAP-MV or monensin altered ruminal fermentation patterns and digestive function in cows; however, those changes were independent of the main energy source of the diet. PMID- 21551347 TI - Concentrations of airborne endotoxin and microorganisms at a 10,000-cow open freestall dairy. AB - Confined animal production systems produce increased bioaerosol concentrations, which are a potential respiratory health risk to individuals on site and downwind. In this longitudinal study, airborne endotoxin and microorganisms were collected during the spring, summer, and fall at a large, open-freestall dairy in southern Idaho. Compared with the background ambient atmosphere, both endotoxin and culturable heterotrophic bacteria concentrations were up to several-hundred fold greater 50 m downwind from the facility, then decreased to near background concentrations at 200 m. However, downwind fungi concentrations were not increased above background concentrations. At 50 m downwind, the average inhalable endotoxin concentration ranged from 5 to 4,243 endotoxin units per m-3, whereas bacteria concentrations ranged from 102 to 104 cfu per m-3 of air. Although the bioaerosol concentrations did not follow a seasonal trend, they did significantly correlate with meteorological factors. Increasing temperature was found to be positively correlated with increasing bacteria (r = 0.15, P < 0.05), fungi (r = 0.14, P < 0.05), and inhalable endotoxin (r = 0.32, P < 0.001) concentrations, whereas an inverse relationship occurred between the concentration and solar radiation. The airborne concentrations at 50 m were also found to be greatest at night, which can likely be attributed to changes in animal activity and wind speed and reduced exposure of the airborne microorganisms to UV radiation. PMID- 21551348 TI - Genetic analysis of the longevity of French sport horses in jumping competition. AB - The longevity of sport horses is an economic and ethical issue. The aim of this study was to analyze the duration of the competitive life of jumping horses in France to assess the potential for genetic evaluation and to propose rules of management for sport horses. Data included lifetimes spent in jumping competitions for the 209,296 horses born from 1968 onward with performances between 1972 and 2008; the data set contained 22% right-censored records. Longevity was measured in years. Discrete survival analysis included fixed effects of region of birth, month of birth, year of recording, age at first competition, interaction between sex and level of jumping performance as measured by the logarithm of earnings adjusted for sex, age, year, and random sire and maternal grand-sire effects. There were 16,668 sires and maternal grand-sires. All fixed effects were highly significant (P < 0.001). Management of the sports career had an important effect on longevity: against common belief, the younger the horse started competing, the longer it stayed in competition. For horses that started competing at an age of 6 yr, the risk of culling was 1.33-fold that of horses having started at 4 yr of age. The less success in competition, the greater was the chance for leaving competition, especially for horses without earnings. For a gelding without earnings, the risk of culling was 1.40-fold that of an average-performance gelding and 2.57-fold that of a top-rated gelding (performance at least 2 SD above the mean). Mares always had greater relative risk than geldings or stallions because they may be culled from competition to be used for breeding. The risk of culling for females was 1.45-fold that of a gelding with the same performance. The heritability of the length of competitive life was 0.10. Breeding values were predicted for sires, and 3,303 sires showed an accuracy greater than 0.60. Among these sires, 262 were used for breeding in 2008. PMID- 21551349 TI - Factors affecting pregnancy rate to estrous synchronization and fixed-time artificial insemination in beef cattle. AB - Application of AI in extensive beef cattle production would be facilitated by protocols that effectively synchronize ovarian follicular development and ovulation to enable fixed-time AI (TAI). The objectives were to determine whether use of a controlled internal drug release (CIDR) device to administer progesterone in a GnRH-based estrous synchronization protocol would optimize blood progesterone concentrations, improve synchronization of follicular development and estrus, and increase pregnancy rates to TAI in beef cows. Beef cows (n = 1,240) in 6 locations within the US Meat Animal Research Center received 1 of 2 treatments: 1) an injection of GnRH [100 ug intramuscularly (i.m.)] followed by PGF(2alpha) (PGF; 25 mg i.m.) 7 d later (CO-Synch), or 2) CO Synch plus a CIDR during the 7 d between GnRH and PGF injections (CO-Synch + CIDR). Cows received TAI and GnRH (100 ug i.m.) at 60 h after PGF. Progesterone was measured by RIA in blood samples collected 2 wk before and at initiation of treatment (d 0) and at PGF injection (d 7). Estrous behavior was monitored by Estrotect Heat Detectors. Pregnancy was diagnosed by ultrasonography 72 to 77 d after TAI. Plasma progesterone concentrations did not differ (P > 0.10) between synchronization protocols at first GnRH injection (d 0), but progesterone was greater (P < 0.01) at PGF injection (d 7) in cows receiving CO-Synch + CIDR vs. CO-Synch as a result of fewer CIDR-treated cows having progesterone <=1 ng/mL at PGF (10.7 vs. 29.6%, respectively). A greater (P < 0.01) proportion of CO-Synch + CIDR vs. CO-Synch cows were detected in estrus within 60 h after PGF (66.7 vs. 57.8 +/- 2.6%, respectively) and a greater (P < 0.01) proportion were pregnant to TAI (54.6 vs. 44.3 +/- 2.6%, respectively). For both synchronization protocols, cows expressing estrus within 60 h before TAI had a greater pregnancy rate than cows without estrus. For cows with plasma progesterone <=1 ng/mL at PGF injection, CO-Synch + CIDR increased pregnancy rate (65.2 +/- 5.9 vs. 30.8 +/- 3.4% with vs. without CIDR), whereas pregnancy rates did not differ (P > 0.10) between protocols (52.1 +/- 2.1 vs. 50.0 +/- 2.4%, respectively) when progesterone was >1 ng/mL (treatment * progesterone; P < 0.01). Inclusion of a CIDR in the synchronization protocol increased plasma progesterone concentration, proportion of cows detected in estrus, and pregnancy rate; however, the increase in pregnancy rate from inclusion of the CIDR was primarily in cows with decreasing or low endogenous progesterone secretion during treatment. PMID- 21551351 TI - Integration of the genetic map and genome assembly of fugu facilitates insights into distinct features of genome evolution in teleosts and mammals. AB - The compact genome of fugu (Takifugu rubripes) has been used widely as a reference genome for understanding the evolution of vertebrate genomes. However, the fragmented nature of the fugu genome assembly has restricted its use for comparisons of genome architecture in vertebrates. To extend the contiguity of the assembly to the chromosomal level, we have generated a comprehensive genetic map of fugu and anchored the scaffolds of the assembly to the 22 chromosomes of fugu. The map consists of 1,220 microsatellite markers that provide anchor points to 697 scaffolds covering 86% of the genome assembly (http://www.fugu-sg.org/). The integrated genome map revealed a higher recombination rate in fugu compared with other vertebrates and a wide variation in the recombination rate between sexes and across chromosomes of fugu. We used the extended assembly to explore recent rearrangement events in the lineages of fugu, Tetraodon, and medaka and compared them with rearrangements in three mammalian (human, mouse, and opossum) lineages. Between the two pufferfishes, fugu has experienced fewer chromosomal rearrangements than Tetraodon. The gene order is more highly conserved in the three teleosts than in mammals largely due to a lower rate of interchromosomal rearrangements in the teleosts. These results provide new insights into the distinct patterns of genome evolution between teleosts and mammals. The consolidated genome map and the genetic map of fugu are valuable resources for comparative genomics of vertebrates and for elucidating the genetic basis of the phenotypic diversity of ~25 species of Takifugu that evolved within the last 5 My. PMID- 21551352 TI - Evolutionary patterns of the mitochondrial genome in Metazoa: exploring the role of mutation and selection in mitochondrial protein coding genes. AB - The mitochondrial genome is a fundamental component of the eukaryotic domain of life, encoding for several important subunits of the Respiratory Chain, the main energy production system in cells. The processes by means of which mtDNA replicates, expresses itself and evolves have been explored over the years, although various aspects are still debated. In this review, we present several key points in modern research on the role of evolutionary forces in affecting mitochondrial genomes in Metazoa. In particular, we assemble the main data on their evolution, describing the contributions of mutational pressure, purifying and adaptive selection, and how they are related. We also provide data on the evolutionary fate of the mitochondrial synonymous variation, related to the non synonymous variation, in comparison with the pattern detected in the nucleus. Elevated mutational pressure characterises the evolution of the mitochondrial synonymous variation, whereas purging selection, physiologically due to phenomena such as cell atresia and intracellular mtDNA selection, guarantees coding sequence functionality. This enables mitochondrial adaptive mutations to emerge and fix in the population, promoting mito-nuclear coevolution. PMID- 21551353 TI - 1,3-Dinitrobenzene-induced metabolic impairment through selective inactivation of the pyruvate dehydrogenase complex. AB - Prolonged exposure to the chemical intermediate, 1,3-dinitrobenzene (1,3-DNB), produces neuropathology in the central nervous system of rodents analogous to that observed in various conditions of acute energy deprivation including thiamine deficiency and Leigh's necrotizing encephalopathy. Increased production of reactive intermediates in addition to induction of oxidative stress has been implicated in the neurotoxic mechanism of 1,3-DNB, but a clear metabolic target has not been determined. Here we propose that similar to thiamine deficiency, the effects of 1,3-DNB on metabolic status may be due to inhibition of the thiamine dependent alpha-ketoacid dehydrogenase complexes. The effects of 1,3-DNB on astroglial metabolic status and alpha-ketoacid dehydrogenase activity were evaluated using rat C6 glioma cells. Exposure to 1,3-DNB resulted in altered morphology and biochemical dysfunction consistent with disruption of oxidative energy metabolism. Cotreatment with acetyl-carnitine or acetoacetate attenuated morphological and metabolic effects of 1,3-DNB exposure as well as increased cell viability. 1,3-DNB exposure inhibited pyruvate dehydrogenase complex (PDHc) and the inhibition correlated with the loss of lipoic acid (LA) immunoreactivity, suggesting that modification of LA is a potential mechanism of inhibition. Treatment with antioxidants and thiol-containing compounds failed to protect against loss of LA. Alternatively, inhibition of dihydrolipoamide dehydrogenase, the E3 component of the complex attenuated loss of LA. Collectively, these data suggest that 1,3-DNB impairs oxidative energy metabolism through direct inhibition of the PDHc and that this impairment is due to perturbations in the function of protein-bound LA. PMID- 21551355 TI - Let's not forget the critical role of surface tension in xylem water relations. PMID- 21551354 TI - Perturbation of mitosis through inhibition of histone acetyltransferases: the key to ochratoxin a toxicity and carcinogenicity? AB - Ochratoxin A (OTA) is one of the most potent rodent renal carcinogens studied to date. Although controversial results regarding OTA genotoxicity have been published, it is now widely accepted that OTA is not a mutagenic, DNA-reactive carcinogen. Instead, increasing evidence from both in vivo and in vitro studies suggests that OTA may promote genomic instability and tumorigenesis through interference with cell division. The aim of the present study was to provide further support for disruption of mitosis as a key event in OTA toxicity and to understand how OTA mediates these effects. Immortalized human kidney epithelial cells (IHKE) were treated with OTA and monitored by differential interference contrast microscopy for 15 h. Image analysis confirmed that OTA at concentrations >= 5 MUM, which correlate with plasma concentrations in rats under conditions of carcinogenesis, causes sustained mitotic arrest and exit from mitosis without nuclear or cellular division. Mitotic chromosomes were characterized by aberrant condensation and premature sister chromatid separation associated with altered phosphorylation and acetylation of core histones. To test if OTA directly interferes with histone acetyltransferases (HATs) which regulate lysine acetylation of histones and nonhistone proteins, a cell-free HAT activity assay was conducted using total nuclear extracts of IHKE cells. In this assay, OTA significantly blocked HAT activity in a concentration-dependent manner Overall, results from this study provide further support for a mechanism of OTA carcinogenicity involving interference with the mitotic machinery and suggest HATs as a primary cellular target of OTA. PMID- 21551350 TI - The microevolution of V1r vomeronasal receptor genes in mice. AB - Vomeronasal sensitivity is important for detecting intraspecific pheromonal cues as well as environmental odorants and is involved in mating, social interaction, and other daily activities of many vertebrates. Two large families of seven transmembrane G-protein-coupled receptors, V1rs and V2rs, bind to various ligands to initiate vomeronasal signal transduction. Although the macroevolution of V1r and V2r genes has been well characterized throughout vertebrates, especially mammals, little is known about their microevolutionary patterns, which hampers a clear understanding of the evolutionary forces behind the rapid evolutionary turnover of V1r and V2r genes and the great diversity in receptor repertoire across species. Furthermore, the role of divergent vomeronasal perception in enhancing premating isolation and maintaining species identity has not been evaluated. Here we sequenced 44 V1r genes and 25 presumably neutral noncoding regions in 14 wild-caught mice belonging to Mus musculus and M. domesticus, two closely related species with strong yet incomplete reproductive isolation. We found that nucleotide changes in V1rs are generally under weak purifying selection and that only ~5% of V1rs may have been subject to positive selection that promotes nonsynonymous substitutions. Consistent with the low functional constraints on V1rs, 18 of the 44 V1rs have null alleles segregating in one or both species. Together, our results demonstrate that, despite occasional actions of positive selection, the evolution of V1rs is in a large part shaped by purifying selection and random drift. These findings have broad implications for understanding the driving forces of rapid gene turnovers that are often observed in the evolution of large gene families. PMID- 21551356 TI - Vertical and seasonal variation in the delta13C of leaf-respired CO2 in a mixed conifer forest. AB - The C-isotopic composition (delta13C) of leaf respiration (delta(LR)) has previously been shown to vary among functional groups, plant organs and times of day. We here investigated vertical and seasonal variation in delta(LR) through deep (~35 m) forest canopies. We measured delta(LR), delta13C of leaf bulk organic matter (delta(LB)), specific leaf area, net photosynthesis (A) and dark respiration in shade, middle and sun foliage in four conifer species from May to August. We used Keeling plots to estimate delta(LR); we developed a novel technique for ensuring that the respiratory substrate was not changing over the course of the measurement. Variables delta(LR) and delta(LB) displayed a vertical pattern in Abies grandis, Pseudotsuga menziesii and Thuja plicata, but were independent of canopy position in Larix occidentalis. Vertical gradients in delta(LB) (3.60/00) and delta(LR) (2.80/00) were similar. The respiratory enrichment (delta(LR)-delta(LB)) was smaller in expanding (30/00) than mature (4 80/00) foliage. There was a linear relationship between the respiratory enrichment and A. Our data support the hypothesis that delta(LR) values are related to patterns of C allocation among metabolic pathways. We demonstrated that considerable variation in delta(LR) occurs vertically through the canopy (30/00 gradient) and seasonally (3-70/00). Understanding sources of variation in respiratory signals is fundamental to comprehending C dynamics and for global model applications. PMID- 21551357 TI - Limited response of ponderosa pine bole defenses to wounding and fungi. AB - Tree defense against bark beetles (Curculionidae: Scolytinae) and their associated fungi generally comprises some combination of constitutive (primary) and induced (secondary) defenses. In pines, the primary constitutive defense against bark beetles consists of preformed resin stored in resin ducts. Induced defenses at the wound site (point of beetle entry) in pines may consist of an increase in resin flow and necrotic lesion formation. The quantity and quality of both induced and constitutive defenses can vary by species and season. The inducible defense response in ponderosa pine is not well understood. Our study examined the inducible defense response in ponderosa pine using traumatic mechanical wounding, and wounding with and without fungal inoculations with two different bark beetle-associated fungi (Ophiostoma minus and Grosmannia clavigera). Resin flow did not significantly increase in response to any treatment. In addition, necrotic lesion formation on the bole after fungal inoculation was minimal. Stand thinning, which has been shown to increase water availability, had no, or inconsistent, effects on inducible tree defense. Our results suggest that ponderosa pine bole defense against bark beetles and their associated fungi is primarily constitutive and not induced. PMID- 21551358 TI - Response of living tissues of Pinus sylvestris to the saprotrophic biocontrol fungus Phlebiopsis gigantea. AB - The saprotrophic fungus Phlebiopsis gigantea has been used for several years as a biocontrol agent against the conifer pathogen Heterobasidion annosum. Although the effectiveness of P. gigantea in biocontrol has been shown empirically, the long-term effect on living conifer trees as well as the mechanism underlying its antagonistic activity is still unknown. An additional concern is the potential of P. gigantea to acquire a necrotrophic habit through adaptation to living wood tissues. By using a combination of histochemical, molecular and transcript profiling (454 sequencing), we investigated under in vitro conditions the necrotrophic capability of P. gigantea and induced localized resistance as a mechanism for its biocontrol action. Pinus sylvestris seedlings (10 years old) were challenged on the xylem surface with P. gigantea or H. annosum. Both fungi provoked strong necrotic lesions, but after prolonged incubation, P. gigantea lesions shrank and ceased to expand further. Tree seedlings pre-treated with P. gigantea further restricted H. annosum-induced necrosis and had more lignified cells. The 454 sequencing revealed elevated transcript levels of genes important for lignification, cell death regulation and jasmonic acid signalling. The results suggest that induced localized resistance is a contributory factor for the biocontrol efficacy of P. gigantea, and it has a limited necrotrophic capability compared with H. annosum. PMID- 21551359 TI - Recruitment of dendritic cells is responsible for intestinal epithelial damage in the pathogenesis of necrotizing enterocolitis by Cronobacter sakazakii. AB - Cronobacter sakazakii is a Gram-negative pathogen associated with the cases of necrotizing enterocolitis (NEC) that result from formula contamination. In a mouse model of NEC, we demonstrate that C. sakazakii infection results in epithelial damage by recruiting greater numbers of dendritic cells (DCs) than macrophages and neutrophils in the gut and suppresses DC maturation, which requires outer membrane protein A (OmpA) expression in C. sakazakii. Pretreatment of intestinal epithelial cell monolayers with supernatant from OmpA(+) C. sakazakii/DC culture markedly enhanced membrane permeability and enterocyte apoptosis, whereas OmpA(-) C. sakazakii/DC culture supernatant had no effect. Analysis of OmpA(+) C. sakazakii/DC coculture supernatant revealed significantly greater TGF-beta production compared with the levels produced by OmpA(-) C. sakazakii infection. TGF-beta levels were elevated in the intestinal tissue of mice infected with OmpA(+) C. sakazakii. Cocultures of CaCo-2 cells and DCs in a "double-layer" model followed by infection with OmpA(+) C. sakazakii significantly enhanced monolayer leakage by increasing TGF-beta production. Elevated levels of inducible NO synthase (iNOS) were also observed in the double layer infection model, and abrogation of iNOS expression prevented the C. sakazakii-induced CaCo-2 cell monolayer permeability despite the presence of DCs or OmpA(+) C. sakazakii/DC supernatant. Blocking TGF-beta activity using a neutralizing Ab suppressed iNOS production and prevented apoptosis and monolayer leakage. Depletion of DCs in newborn mice protected against C. sakazakii-induced NEC, whereas adoptive transfer of DCs rendered the animals susceptible to infection. Therefore, C. sakazakii interaction with DCs in intestine enhances the destruction of the intestinal epithelium and the onset of NEC due to increased TGF-beta production. PMID- 21551361 TI - Calcitonin gene-related peptide is an important regulator of cutaneous immunity: effect on dendritic cell and T cell functions. AB - Some cutaneous inflammations are induced by percutaneous exposure to foreign Ags, and many chemical mediators regulate this inflammation process. One of these mediators, calcitonin gene-related peptide (CGRP), is a neuropeptide released from nerve endings in the skin. CGRP binds to its receptors composed of receptor activity-modifying protein 1 and calcitonin receptor-like receptor to modulate immune cell function. We show that CGRP regulates skin inflammation under physiological conditions, using contact hypersensitivity (CHS) models of receptor activity-modifying protein 1-deficient mice. CGRP has different functions in CHS responses mediated by Th1 or Th2 cells; it inhibits Th1-type CHS, such as 2,4,6 trinitrochlorobenzene-induced CHS, but promotes Th2-type CHS, such as FITC induced CHS. CGRP inhibits the migration of Langerin(+) dermal dendritic cells to the lymph nodes in 2,4,6-trinitrochlorobenzene-induced CHS, and upregulates IL-4 production of T cells in the draining lymph nodes in FITC-CHS. These findings suggest that CGRP regulates several types of CHS reactions under physiological conditions and plays an important role in cutaneous immunity. PMID- 21551360 TI - CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis. AB - CD44 is expressed by a variety of cells, including glial and T cells. Furthermore, in the demyelinating lesions of multiple sclerosis, CD44 expression is chronically elevated. In this study, we demonstrate that targeted deletion of CD44 attenuated myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalitomyelitis (EAE) through novel regulatory mechanisms affecting Th differentiation. Specifically, by developing chimeras and using adoptive transfer experiments, we noted that CD44 deficiency on CD4(+) T cells, but not other cells, conferred protection against EAE induction. CD44 expression played a crucial role in Th differentiation, inasmuch as deletion of CD44 inhibited Th1/Th17 differentiation while simultaneously enhancing Th2/regulatory T cell differentiation. In contrast, expression of CD44 promoted Th1/Th17 differentiation. When osteopontin and hyaluronic acid, the two major ligands of CD44, were tested for their role in Th differentiation, osteopontin, but not hyaluronic acid, promoted Th1/Th17 differentiation. Furthermore, activation of CD44(+) encephalitogenic T cells with myelin oligodendrocyte glycoprotein peptide led to demethylation at the ifngamma/il17a promoter region while displaying hypermethylation at the il4/foxp3 gene promoter. Interestingly, similar activation of CD44-deficient encephalitogenic T cells led to increased hypermethylation of ifngamma/il17a gene and marked demethylation of il4/foxp3 gene promoter. Together, these data suggested that signaling through CD44, in encephalitogenic T cells, plays a crucial role in the differentiation of Th cells through epigenetic regulation, specifically DNA methylation of Th1/Th17 and Th2 cytokine genes. The current study also suggests that molecular targeting of CD44 receptor to promote a switch from Th1/Th17 to Th2/regulatory T cell differentiation may provide a novel treatment modality against EAE. PMID- 21551362 TI - Aim2 deficiency in mice suppresses the expression of the inhibitory Fcgamma receptor (FcgammaRIIB) through the induction of the IFN-inducible p202, a lupus susceptibility protein. AB - Murine Aim2 and Ifi202 genes (encoding for the Aim2 and p202 proteins) are members of the IFN-inducible Ifi200 gene family. The Aim2 deficiency in mice activates IFN signaling and stimulates the expression of the lupus susceptibility gene, the Ifi202, located within the NZB autoimmunity 2 (Nba2) interval. Given that the deficiency in the expression of the Fcgr2b gene (encoding for the inhibitory FcgammaRIIB receptor) is associated with increased lupus susceptibility in mice, we investigated whether the Aim2 protein could regulate the expression of Fcgr2b gene. In this article, we report that Aim2 deficiency in mice suppresses the expression of the FcgammaRIIB receptor. Interestingly, the Fcgr2b-deficient cells expressed increased levels of the IFN-beta, activated IFN signaling, and expressed reduced levels of the Aim2 protein. Treatment of splenic cells with IFN-alpha or -gamma reduced levels of the FcgammaRIIB mRNA and protein and also decreased the activity of the FcgammaRIIB p(-729/+585) Luc reporter. Moreover, levels of the FcgammaRIIB receptor were significantly higher in the Stat1-deficient splenic cells than in the wild-type cells. Accordingly, increased expression of IFN-beta in lupus-prone B6.Nba2-ABC mice, as compared with non lupus-prone C57BL/6 (B6) or B6.Nba2-C mice, was associated with reduced expression of the FcgammaRIIB receptor. Notably, overexpression of the p202 protein in cells decreased the expression of the Aim2 gene, activated the IFN response, and suppressed the expression of the Fcgr2b gene. These observations demonstrate that the expression of Aim2 protein is required to maintain the expression of the Fcgr2b gene and also predict epistatic interactions between the Ifi200 genes and the Fcgr2b gene within the Nba2 interval. PMID- 21551363 TI - HIV-1 reduces Abeta-degrading enzymatic activities in primary human mononuclear phagocytes. AB - The advent and wide introduction of antiretroviral therapy has greatly improved the survival and longevity of HIV-infected patients. Unfortunately, despite antiretroviral therapy treatment, these patients are still afflicted with many complications including cognitive dysfunction. There is a growing body of reports indicating accelerated deposition of amyloid plaques, which are composed of amyloid-beta peptide (Abeta), in HIV-infected brains, though how HIV viral infection precipitates Abeta accumulation is poorly understood. It is suggested that viral infection leads to increased production and impaired degradation of Abeta. Mononuclear phagocytes (macrophages and microglia) that are productively infected by HIV in brains play a pivotal role in Abeta degradation through the expression and execution of two endopeptidases, neprilysin (NEP) and insulin degrading enzyme. In this study, we report that NEP has the dominant endopeptidase activity toward Abeta in macrophages. Further, we demonstrate that monomeric Abeta degradation by primary cultured macrophages and microglia was significantly impaired by HIV infection. This was accompanied with great reduction of NEP endopeptidase activity, which might be due to the diminished transport of NEP to the cell surface and intracellular accumulation at the endoplasmic reticulum and lysosomes. Therefore, these data suggest that malfunction of NEP in infected macrophages may contribute to acceleration of beta amyloidosis in HIV-inflicted brains, and modulation of macrophages may be a potential preventative target of Abeta-related cognitive disorders in HIV affected patients. PMID- 21551364 TI - IL-32gamma induces the maturation of dendritic cells with Th1- and Th17 polarizing ability through enhanced IL-12 and IL-6 production. AB - IL-32, a newly described multifunctional cytokine, has been associated with a variety of inflammatory diseases, including rheumatoid arthritis, vasculitis, and Crohn's disease. In this study, we investigated the immunomodulatory effects of IL-32gamma on bone marrow-derived dendritic cell (DC)-driven Th responses and analyzed the underlying signaling events. IL-32gamma-treated DCs exhibited upregulated expression of cell-surface molecules and proinflammatory cytokines associated with DC maturation and activation. In particular, IL-32gamma treatment significantly increased production of IL-12 and IL-6 in DCs, which are known as Th1- and Th17-polarizing cytokines, respectively. This increased production was inhibited by the addition of specific inhibitors of the activities of phospholipase C (PLC), JNK, and NF-kappaB. IL-32gamma treatment increased the phosphorylation of JNK and the degradation of both IkappaBalpha and IkappaBbeta in DCs, as well as NF-kappaB binding activity to the kappaB site. The PLC inhibitor suppressed NF-kappaB DNA binding activity and JNK phosphorylation increased by IL-32gamma treatment, thereby indicating that IL-32gamma induced IL 12 and IL-6 production in DCs via a PLC/JNK/NF-kappaB signaling pathway. Importantly, IL-32gamma-stimulated DCs significantly induced both Th1 and Th17 responses when cocultured with CD4(+) T cells. The addition of a neutralizing anti-IL-12 mAb abolished the secretion of IFN-gamma in a dose-dependent manner; additionally, the blockage of IL-1beta and IL-6, but not of IL-21 or IL-23p19, profoundly inhibited IL-32gamma-induced IL-17 production. These results demonstrated that IL-32gamma could effectively induce the maturation and activation of immature DCs, leading to enhanced Th1 and Th17 responses as the result of increased IL-12 and IL-6 production in DCs. PMID- 21551365 TI - Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer. AB - Within the ovarian cancer microenvironment, there are several mechanisms that suppress the actions of antitumor immune effectors. Delineating the complex immune microenvironment is an important goal toward developing effective immune based therapies. A dominant pathway of immune suppression in ovarian cancer involves tumor-associated and dendritic cell (DC)-associated B7-H1. The interaction of B7-H1 with PD-1 on tumor-infiltrating T cells is a widely cited theory of immune suppression involving B7-H1 in ovarian cancer. Recent studies suggest that the B7-H1 ligand, programmed death receptor-1 (PD-1), is also expressed on myeloid cells, complicating interpretations of how B7-H1 regulates DC function in the tumor. In this study, we found that ovarian cancer infiltrating DCs progressively expressed increased levels of PD-1 over time in addition to B7-H1. These dual-positive PD-1(+) B7-H1(+) DCs have a classical DC phenotype (i.e., CD11c(+)CD11b(+)CD8(-)), but are immature, suppressive, and respond poorly to danger signals. Accumulation of PD-1(+)B7-H1(+) DCs in the tumor was associated with suppression of T cell activity and decreased infiltrating T cells in advancing tumors. T cell suppressor function of these DCs appeared to be mediated by T cell-associated PD-1. In contrast, ligation of PD-1 expressed on the tumor-associated DCs suppressed NF-kappaB activation, release of immune regulatory cytokines, and upregulation of costimulatory molecules. PD-1 blockade in mice bearing ovarian cancer substantially reduced tumor burden and increased effector Ag-specific T cell responses. Our results reveal a novel role of tumor infiltrating PD-1(+)B7-H1(+) DCs in mediating immune suppression in ovarian cancer. PMID- 21551366 TI - IL-17A-dependent CD4+CD25+ regulatory T cells promote immune privilege of corneal allografts. AB - IL-17A is a proinflammatory cytokine that has received attention for its role in the pathogenesis of several autoimmune diseases. IL-17A has also been implicated in cardiac and renal allograft rejection. Accordingly, we hypothesized that depletion of IL-17A would enhance corneal allograft survival. Instead, our results demonstrate that blocking IL-17A in a mouse model of keratoplasty accelerated the tempo and increased the incidence of allograft rejection from 50 to 90%. We describe a novel mechanism by which CD4(+)CD25(+) regulatory T cells (Tregs) respond to IL-17A and enhance corneal allograft survival. Our findings suggest the following: 1) IL-17A is necessary for ocular immune privilege; 2) IL 17A is not required for the induction of anterior chamber-associated immune deviation; 3) Tregs require IL-17A to mediate a contact-dependent suppression; 4) corneal allograft Tregs suppress the efferent arm of the immune response and are Ag specific; 5) Tregs are not required for corneal allograft survival beyond day 30; and 6) corneal allograft-induced Treg-mediated suppression is transient. Our findings identify IL-17A as a cytokine essential for the maintenance of corneal immune privilege and establish a new paradigm whereby interplay between IL-17A and CD4(+)CD25(+) Tregs is necessary for survival of corneal allografts. PMID- 21551367 TI - An evolutionarily conserved TNF-alpha-responsive enhancer in the far upstream region of human CCL2 locus influences its gene expression. AB - Comparative cross-species genomic analysis has served as a powerful tool to discover novel noncoding regulatory regions that influence gene expression in several cytokine loci. In this study, we have identified several evolutionarily conserved regions (ECRs) that are shared between human, rhesus monkey, dog, and horse and that are upstream of the promoter regions that have been previously shown to play a role in regulating CCL2 gene expression. Of these, an ECR that was ~16.5 kb (-16.5 ECR) upstream of its coding sequence contained a highly conserved NF-kappaB site. The region encompassing the -16.5 ECR conferred TNF alpha responsiveness to homologous and heterologous promoters. In vivo footprinting demonstrated that specific nucleotide residues in the -16.5 ECR were protected or became hypersensitive after TNF-alpha treatment. The footprinted regions were found to bind NF-kappaB subunits in vitro and in vivo. Mutation/deletion of the conserved NF-kappaB binding site in the -16.5 ECR led to loss of TNF-alpha responsiveness. After TNF-alpha stimulation, the -16.5 ECR showed increased sensitivity to nuclease digestion and loss of histone signatures that are characteristic of a repressive chromatin. Chromosome conformation capture assays indicated that -16.5 ECR physically interacts with the CCL2 proximal promoter after TNF-alpha stimulation. Taken together, these results suggest that the -16.5 ECR may play a critical role in the regulation of CCL2. PMID- 21551368 TI - Novel TGF-beta antagonist inhibits tumor growth and angiogenesis by inducing IL-2 receptor-driven STAT1 activation. AB - Carcinoma derived TGF-beta acts as a potent pro-oncogenic factor and suppresses antitumor immunity. To antagonize TGF-beta-mediated effects in tandem with a proinflammatory immune stimulus, we generated a chimeric protein borne of the fusion of IL-2 and the soluble extracellular domain of TGF-betaR II (FIST). FIST acts as a decoy receptor trapping active TGF-beta in solution and interacts with IL-2-responsive lymphoid cells, inducing a distinctive hyperactivation of STAT1 downstream of IL-2R, which in turn promotes SMAD7 overexpression. Consequently, FIST-stimulated lymphoid cells are resistant to TGF-beta-mediated suppression and produce significant amounts of proinflammatory cytokines. STAT1 hyperactivation further induces significant secretion of angiostatic CXCL10. Moreover, FIST upregulates T-bet expression in NK cells promoting a potent Th1-mediated antitumor response. As a result, FIST stimulation completely inhibits pancreatic cancer (PANC02) and melanoma (B16) tumor growth in immunocompetent C57BL/6 mice. In addition, melanoma cells expressing FIST fail to form tumors in CD8(-/-), CD4( /-), B cell-deficient (MUMT), and beige mice, but not in NOD-SCID and Rag2/gammac knockout mice, consistent with the pivotal role of FIST-responsive, cancer killing NK cells in vivo. In summary, FIST constitutes a novel strategy of treating cancer that targets both the host's angiogenic and innate immune response to malignant cells. PMID- 21551369 TI - Impact of anticoagulation on the short-term outcome in a population of neonates with cerebral sinovenous thrombosis: a retrospective study. AB - To investigate the impact of anticoagulation on short-term outcome (1 month) in neonates with cerebral sinovenous thrombosis, the authors conducted a retrospective chart review of neonates admitted to 2 tertiary hospitals over a 5- and 8-year period, respectively. Neonates with confirmed radiographic evidence of cerebral sinovenous thrombosis were included. Eighteen total patients treated with hydration only were identified. Approximately 50% of these neonates showed clot extension or other complications on follow-up imaging that were obtained within 72 hours with either magnetic resonance imaging or computed topography. Five neonates were treated with anticoagulation, and none of these patients developed new infarcts or hemorrhages. The results of this retrospective study suggest that anticoagulation is safe in neonates with cerebral sinovenous thrombosis. Early follow-up scans can help treatment decision. Larger studies are needed to develop standardized guidelines for the evaluation and treatment of neonatal cerebral sinovenous thrombosis. PMID- 21551370 TI - A case of neurobrucellosis presenting with isolated intracranial hypertension. AB - Despite being a treatable and preventable zoonosis, brucellosis is still endemic in certain areas of the world. Nervous system involvement is a rare but an important complication of brucellosis in childhood. Neurobrucellosis should be taken into consideration in the differential diagnosis of any kind of neurological signs, particularly in endemic areas. The authors present a patient with neurobrucellosis who presented with isolated intracranial hypertension without any other systemic symptoms of brucellosis. PMID- 21551371 TI - Reorganization of the right arcuate fasciculus following left arcuate fasciculus resection in children with intractable epilepsy. AB - The authors evaluated postsurgical reorganization of the arcuate fasciculus longitudinally using diffusion tensor imaging in 10 children with intractable epilepsy, whose resections included the left arcuate fasciculus. Evaluation of fractional anisotropy before and after surgery (mean follow-up: 7.5 months) showed a significant increase (P = .002) in the right arcuate fasciculus during follow-up. There was marked enlargement of the right arcuate fasciculus postsurgically in 8 patients. The change in right arcuate fasciculus fractional anisotropy values showed a positive correlation with interval between resection and postsurgical magnetic resonance imaging (MRI) (P = .044). Comparison of 10 age-matched controls to patients pre- and postsurgery showed significantly reduced presurgery fractional anisotropy in the left (P = .018) and right (P = .036) arcuate fasciculus and no difference in postsurgery fractional anisotropy in the right arcuate fasciculus (P = .399) in patients. These findings suggest a compensatory reorganization in the right arcuate fasciculus in children with intractable epilepsy following left arcuate fasciculus resection. PMID- 21551372 TI - Ethics in health care services for young persons with neurodevelopmental disabilities: a focus on cerebral palsy. AB - In this article we review and discuss some of the key ethical and social challenges that young persons with cerebral palsy face in health care delivery. We identify and explain these challenges, some of which are rarely discussed in contemporary medicine and biomedical ethics, partly because they are not considered genuine "ethical" challenges per se. Most of these challenges are heavily shaped by broader social context and institutional practices, which highlights the importance of nonbiological aspects of the care of young persons with cerebral palsy from an ethics standpoint. PMID- 21551373 TI - YouTube videos as a teaching tool and patient resource for infantile spasms. AB - The purpose of this study was to assess YouTube videos for their efficacy as a patient resource for infantile spasms. Videos were searched using the terms infantile spasm, spasm, epileptic spasm, and West syndrome. The top 25 videos under each term were selected according to set criteria. Technical quality, diagnosis of infantile spasms, and suitability as a teaching resource were assessed by 2 neurologists using the Medical Video Rating Scale. There were 5858 videos found. Of the 100 top videos, 46% did not meet selection criteria. Mean rating for technical quality was 4.0 of 5 for rater 1 and 3.9 of 5 for rater 2. Raters found 60% and 64% of videos to accurately portray infantile spasms, respectively, with significant agreement (Cohen kappa coefficient = 0.75, P < .001). Ten videos were considered excellent examples (grading of 5 of 5) by at least 1 rater. YouTube may be used as an excellent patient resource for infantile spasms if guided search practices are followed. PMID- 21551374 TI - Botulinum toxin type A on oral health in treating sialorrhea in children with cerebral palsy: a randomized, double-blind, placebo-controlled study. AB - Intrasalivary gland injection of botulinum toxin type A is known to treat sialorrhea effectively in children with cerebral palsy. However, oral health may be compromised with escalating dose. In this randomized, double-blind, and placebo-controlled pilot trial, the authors aim to determine the therapeutic effect of low-dose, ultrasonography-controlled botulinum toxin type A injection to bilateral parotid and submandibular glands on oral health in the management of sialorrhea. Twenty children diagnosed with cerebral palsy were randomly assigned to 2 groups. The treatment group received botulinum toxin type A injections, whereas the control received normal saline in the same locations. The authors evaluated subjective drooling scales, salivary flow rate, and oral health (salivary compositions and cariogenic bacterial counts). A significant decrease was found in salivary flow rate at the 1- and 3-month follow-up in the botulinum toxin-treated group. The authors suggest that current protocol can effectively manage sialorrhea while maintaining oral health. PMID- 21551376 TI - Lessons learned from a decade of focused recruitment and training to develop minority public health professionals. AB - From 1999 to 2009, the Eliminating Health Disparities Pre-doctoral Fellowship Program provided specialized education and mentoring to African American graduate students in public health. Fellows received a public health degree, coursework in understanding and eliminating health disparities, experiential learning, mentored research, and professional network building with African American role models. We describe successful strategies for recruiting and training fellows and make 5 recommendations for those seeking to increase workforce diversity in public health: (1) build a community of minority students, not a string of individual recruits; (2) reward mentoring; (3) provide a diverse set of role models and mentors; (4) dedicate staffing to assure a student-centered approach; and, (5) commit to training students with varying levels of academic refinement. PMID- 21551375 TI - Inactivation of multidrug resistance proteins disrupts both cellular extrusion and intracellular degradation of cAMP. AB - In addition to xenobiotics and several other endogenous metabolites, multidrug resistance proteins (MRPs) extrude the second-messenger cAMP from various cells. Pharmacological and/or genetic inactivation of MRPs has been shown to augment intracellular cAMP signaling, an effect assumed to be a direct consequence of the blockade of cAMP extrusion. Here we provide evidence that the augmented intracellular cAMP levels are not due exclusively to the prevention of cAMP efflux because MRP inactivation is also associated with reduced cAMP degradation by phosphodiesterases (PDEs). Several prototypical MRP inhibitors block PDE activity at concentrations widely used to inhibit MRPs. Their dose-dependent effects in several paradigms of cAMP signaling are more consistent with their potency in inhibiting PDEs than MRPs. Moreover, genetic manipulation of MRP expression results in concomitant changes in PDE activity and protein levels, thus affecting cAMP degradation in parallel with cAMP efflux. These findings suggest that the effects of MRP inactivation on intracellular cAMP levels reported previously may be due in part to reduced degradation by PDEs and identify MRP-dependent transport mechanisms as novel regulators of cellular PDE expression levels. Mathematical simulations of cAMP signaling predict that selective ablation of MRP-dependent cAMP efflux per se does not affect bulk cytosolic cAMP levels, but may control cAMP levels in restricted submembrane compartments that are defined by small volume, high MRP activity, limited PDE activity, and limited exchange of cAMP with the bulk-cytosolic cAMP pool. Whether this regulation occurs in cells remains to be confirmed experimentally under conditions that do not affect PDE activity. PMID- 21551377 TI - Secondhand smoke and periodontal disease: atherosclerosis risk in communities study. AB - OBJECTIVES: We investigated the relationship between secondhand smoke and periodontal disease in nonsmokers. METHODS: We undertook a cross-sectional analysis of the Atherosclerosis Risk in Communities study with 2739 lifetime nonsmokers aged 53-74 years, unexposed to other sources of tobacco, who received a complete periodontal examination at visit 4. Exposure was reported as average hours per week in close contact with a smoker in the preceding year. We defined severe periodontitis as 5 or more periodontal sites with probing pocket depth of 5 millimeters or more and clinical attachment levels of 3 millimeters or more in those sites. Other outcomes were extent of periodontal probing depths of 4 millimeters or more and extent of clinical attachment levels of 3 millimeters or more. RESULTS: In a binary logistic regression model, adjusted odds of severe periodontitis for those exposed to secondhand smoke 1 to 25 hours per week increased 29% (95% confidence interval = 1.0, 1.7); for those exposed to secondhand smoke 26 hours per week, the odds were twice as high (95% confidence interval = 1.2, 3.4) as for those who were unexposed. CONCLUSIONS: Exposure to secondhand smoke and severe periodontitis among nonsmokers had a dose-dependent relationship. PMID- 21551378 TI - Environmental health disparities in housing. AB - The physical infrastructure and housing make human interaction possible and provide shelter. How well that infrastructure performs and which groups it serves have important implications for social equity and health. Populations in inadequate housing are more likely to have environmental diseases and injuries. Substantial disparities in housing have remained largely unchanged. Approximately 2.6 million (7.5%) non-Hispanic Blacks and 5.9 million Whites (2.8%) live in substandard housing. Segregation, lack of housing mobility, and homelessness are all associated with adverse health outcomes. Yet the experience with childhood lead poisoning in the United States has shown that housing-related disparities can be reduced. Effective interventions should be implemented to reduce environmental health disparities related to housing. PMID- 21551379 TI - Conceptual environmental justice model for evaluating chemical pathways of exposure in low-income, minority, native American, and other unique exposure populations. AB - Risk assessment determines pathways, and exposures that lead to poor health. For exposures that fall disproportionately on urban low-income communities, minorities, and Native Americans, these pathways are often more common than in the general population. Although risk assessors often evaluate these pathways on an ad hoc basis, a more formal way of addressing these nonstandard pathways is needed to adequately inform public health policy. A conceptual model is presented for evaluating nonstandard, unique, or excessive exposures, particularly for environmental justice communities that have an exposure matrix of inhalation, dermal, ingestion, and injection. Risk assessment can be improved by including nonstandard and unique exposure pathways as described in this conceptual model. PMID- 21551380 TI - Physical and mental health, cognitive development, and health care use by housing status of low-income young children in 20 American cities: a prospective cohort study. AB - OBJECTIVES: We assessed the independent effect of homeless and doubled-up episodes on physical and mental health, cognitive development, and health care use among children. METHODS: We used data from 4 waves of the Fragile Families and Child Wellbeing Study, involving a sample of 2631 low-income children in 20 large US cities who have been followed since birth. Multivariate analyses involved logistic regression using the hybrid method to include both fixed and random effects. RESULTS: Of the sample, 9.8% experienced homelessness and an additional 23.6% had a doubled-up episode. Housing status had little significant adverse effect on child physical or mental health, cognitive development, or health care use. CONCLUSIONS: Family and environmental stressors common to many children in poverty, rather than just homeless and doubled-up episodes, were associated with young children's poor health and cognitive development and high health care use. Practitioners need to identify and respond to parental and family needs for support services in addition to housing assistance to effectively improve the health and development of young children who experience residential instability, particularly those in homeless families. PMID- 21551381 TI - Community-based participatory research and policy advocacy to reduce diesel exposure in West Oakland, California. AB - We conducted a multimethod case study analysis of a community-based participatory research partnership in West Oakland, California, and its efforts to study and address the neighborhood's disproportionate exposure to diesel air pollution. We employed 10 interviews with partners and policymakers, participant observation, and a review of documents. Results of the partnership's truck count and truck idling studies suggested substantial exposure to diesel pollution and were used by the partners and their allies to make the case for a truck route ordinance. Despite weak enforcement, the partnership's increased political visibility helped change the policy environment, with the community partner now heavily engaged in environmental decision-making on the local and regional levels. Finally, we discussed implications for research, policy, and practice. PMID- 21551383 TI - Characterizing workplace exposures in Vietnamese women working in California nail salons. AB - OBJECTIVES: We engaged Vietnamese nail salon workers in a community-based participatory research (CBPR) study to measure personal and area concentrations of solvents in their workplace. METHODS: We measured average work-shift concentrations of toluene, ethyl acetate, and isopropyl acetate among 80 workers from 20 salons using personal air monitors. We also collected area samples from 3 salons using summa canisters. RESULTS: For personal measurements, the arithmetic mean was 0.53 parts per million (range = 0.02-5.50) for ethyl acetate, 0.04 parts per million (range = 0.02-0.15) for isopropyl acetate, and 0.15 parts per million (range = 0.02-1.0) for toluene. Area measurements were lower in comparison, but we detected notable levels of methyl methacrylate, a compound long banned from nail products. Predictors of solvent levels included different forms of ventilation and whether the salon was located in an enclosed building. CONCLUSIONS: Using a CBPR approach that engaged community members in the research process contributed to the successful recruitment of salon workers. Measured levels of toluene, methyl methacrylate, and total volatile organic compounds were higher than recommended guidelines to prevent health symptoms such as headaches, irritations, and breathing problems, which were frequently reported in this workforce. PMID- 21551382 TI - Associations of fast food restaurant availability with dietary intake and weight among African Americans in the Jackson Heart Study, 2000-2004. AB - OBJECTIVES: We examined the associations of fast food restaurant (FFR) availability with dietary intake and weight among African Americans in the southeastern United States. METHODS: We investigated cross-sectional associations of FFR availability with dietary intake and body mass index (BMI) and waist circumference in 4740 African American Jackson Heart Study participants (55.2 +/- 12.6 years, 63.3% women). We estimated FFR availability using circular buffers with differing radii centered at each participant's geocoded residential location. RESULTS: We observed no consistent associations between FFR availability and BMI or waist circumference. Greater FFR availability was associated with higher energy intake among men and women younger than 55 years, even after adjustment for individual socioeconomic status. For each standard deviation increase in 5-mile FFR availability, the energy intake increased by 138 kilocalories (confidence interval [CI] = 70.53, 204.75) for men and 58 kilocalories (CI = 8.55, 105.97) for women. We observed similar associations for the 2-mile FFR availability, especially in men. FFR availability was also unexpectedly positively associated with total fiber intake. CONCLUSIONS: FFR availability may contribute to greater energy intake in younger African Americans who are also more likely to consume fast food. PMID- 21551385 TI - Health disparities and health equity: the issue is justice. AB - Eliminating health disparities is a Healthy People goal. Given the diverse and sometimes broad definitions of health disparities commonly used, a subcommittee convened by the Secretary's Advisory Committee for Healthy People 2020 proposed an operational definition for use in developing objectives and targets, determining resource allocation priorities, and assessing progress. Based on that subcommittee's work, we propose that health disparities are systematic, plausibly avoidable health differences adversely affecting socially disadvantaged groups; they may reflect social disadvantage, but causality need not be established. This definition, grounded in ethical and human rights principles, focuses on the subset of health differences reflecting social injustice, distinguishing health disparities from other health differences also warranting concerted attention, and from health differences in general. We explain the definition, its underlying concepts, the challenges it addresses, and the rationale for applying it to United States public health policy. PMID- 21551384 TI - Disproportionate exposures in environmental justice and other populations: the importance of outliers. AB - We examined traditional environmental justice populations and other groups whose exposure to contaminants is often disproportionately high. Risk assessment methods may not identify these populations, particularly if they are spatially dispersed. We suggest using a National Health and Nutrition Examination Survey approach to oversample minority communities and develop methods for assessing exposure at different distances from pollution sources; publishing arithmetic and geometric means and full distributions for minority populations; and paying particular attention to high-end exposures. Means may sufficiently characterize populations as a whole but are inadequate in identifying vulnerable groups and subgroups. The number of individuals above the 95th percentile of any distribution may be small and unrepresentative, but these outliers are the ones who need to be protected. PMID- 21551386 TI - Cumulative risk assessment for combined health effects from chemical and nonchemical stressors. AB - Cumulative risk assessment is a science policy tool for organizing and analyzing information to examine, characterize, and possibly quantify combined threats from multiple environmental stressors. We briefly survey the state of the art regarding cumulative risk assessment, emphasizing challenges and complexities of moving beyond the current focus on chemical mixtures to incorporate nonchemical stressors, such as poverty and discrimination, into the assessment paradigm. Theoretical frameworks for integrating nonchemical stressors into cumulative risk assessments are discussed, the impact of geospatial issues on interpreting results of statistical analyses is described, and four assessment methods are used to illustrate the diversity of current approaches. Prospects for future progress depend on adequate research support as well as development and verification of appropriate analytic frameworks. PMID- 21551387 TI - Walking and cycling in the United States, 2001-2009: evidence from the National Household Travel Surveys. AB - OBJECTIVES: To assess changes in walking and cycling in the United States between 2001 and 2009. METHODS: The 2001 and 2009 National Household Travel Surveys were used to compute the frequency, duration, and distance of walking and cycling per capita. The population-weighted person and trip files were merged to calculate the prevalence of any walking and cycling and of walking and cycling at least 30 minutes per day. RESULTS: The average American made 17 more walk trips in 2009 than in 2001, covering 9 more miles per year, compared with only 2 more bike trips, and 5 more miles cycling. At the population level, the prevalence of "any walking" remained unchanged (about 18%), whereas walking at least 30 minutes per day increased from 7.2% to 8.0%. The prevalence of "any cycling" and cycling 30 minutes per day remained unchanged (1.7% and 0.9%, respectively). Active travel declined for women, children, and seniors, but increased among men, the middle aged, employed, well-educated, and persons without a car. CONCLUSIONS: Walking increased slightly, whereas cycling levels stagnated, and the overall prevalence of active travel remained low. Improved infrastructure for walking and cycling must be combined with programs to encourage active travel among more groups, especially children, seniors, and women. PMID- 21551388 TI - The Jasmonate-ZIM-domain proteins interact with the WD-Repeat/bHLH/MYB complexes to regulate Jasmonate-mediated anthocyanin accumulation and trichome initiation in Arabidopsis thaliana. AB - Jasmonates (JAs) mediate plant responses to insect attack, wounding, pathogen infection, stress, and UV damage and regulate plant fertility, anthocyanin accumulation, trichome formation, and many other plant developmental processes. Arabidopsis thaliana Jasmonate ZIM-domain (JAZ) proteins, substrates of the CORONATINE INSENSITIVE1 (COI1)-based SCF(COI1) complex, negatively regulate these plant responses. Little is known about the molecular mechanism for JA regulation of anthocyanin accumulation and trichome initiation. In this study, we revealed that JAZ proteins interact with bHLH (Transparent Testa8, Glabra3 [GL3], and Enhancer of Glabra3 [EGL3]) and R2R3 MYB transcription factors (MYB75 and Glabra1), essential components of WD-repeat/bHLH/MYB transcriptional complexes, to repress JA-regulated anthocyanin accumulation and trichome initiation. Genetic and physiological evidence showed that JA regulates WD-repeat/bHLH/MYB complex mediated anthocyanin accumulation and trichome initiation in a COI1-dependent manner. Overexpression of the MYB transcription factor MYB75 and bHLH factors (GL3 and EGL3) restored anthocyanin accumulation and trichome initiation in the coi1 mutant, respectively. We speculate that the JA-induced degradation of JAZ proteins abolishes the interactions of JAZ proteins with bHLH and MYB factors, allowing the transcriptional function of WD-repeat/bHLH/MYB complexes, which subsequently activate respective downstream signal cascades to modulate anthocyanin accumulation and trichome initiation. PMID- 21551389 TI - Microtubule-associated proteins MAP65-1 and MAP65-2 positively regulate axial cell growth in etiolated Arabidopsis hypocotyls. AB - The Arabidopsis thaliana MAP65-1 and MAP65-2 genes are members of the larger eukaryotic MAP65/ASE1/PRC gene family of microtubule-associated proteins. We created fluorescent protein fusions driven by native promoters that colocalized MAP65-1 and MAP65-2 to a subset of interphase microtubule bundles in all epidermal hypocotyl cells. MAP65-1 and MAP65-2 labeling was highly dynamic within microtubule bundles, showing episodes of linear extension and retraction coincident with microtubule growth and shortening. Dynamic colocalization of MAP65-1/2 with polymerizing microtubules provides in vivo evidence that plant cortical microtubules bundle through a microtubule-microtubule templating mechanism. Analysis of etiolated hypocotyl length in map65-1 and map65-2 mutants revealed a critical role for MAP65-2 in modulating axial cell growth. Double map65-1 map65-2 mutants showed significant growth retardation with no obvious cell swelling, twisting, or morphological defects. Surprisingly, interphase microtubules formed coaligned arrays transverse to the plant growth axis in dark grown and GA(4)-treated light-grown map65-1 map65-2 mutant plants. We conclude that MAP65-1 and MAP65-2 play a critical role in the microtubule-dependent mechanism for specifying axial cell growth in the expanding hypocotyl, independent of any mechanical role in microtubule array organization. PMID- 21551391 TI - Exciting research studies on practical medical problems and health services delivery. PMID- 21551390 TI - Clathrin mediates endocytosis and polar distribution of PIN auxin transporters in Arabidopsis. AB - Endocytosis is a crucial mechanism by which eukaryotic cells internalize extracellular and plasma membrane material, and it is required for a multitude of cellular and developmental processes in unicellular and multicellular organisms. In animals and yeast, the best characterized pathway for endocytosis depends on the function of the vesicle coat protein clathrin. Clathrin-mediated endocytosis has recently been demonstrated also in plant cells, but its physiological and developmental roles remain unclear. Here, we assessed the roles of the clathrin mediated mechanism of endocytosis in plants by genetic means. We interfered with clathrin heavy chain (CHC) function through mutants and dominant-negative approaches in Arabidopsis thaliana and established tools to manipulate clathrin function in a cell type-specific manner. The chc2 single mutants and dominant negative CHC1 (HUB) transgenic lines were defective in bulk endocytosis as well as in internalization of prominent plasma membrane proteins. Interference with clathrin-mediated endocytosis led to defects in constitutive endocytic recycling of PIN auxin transporters and their polar distribution in embryos and roots. Consistent with this, these lines had altered auxin distribution patterns and associated auxin transport-related phenotypes, such as aberrant embryo patterning, imperfect cotyledon specification, agravitropic growth, and impaired lateral root organogenesis. Together, these data demonstrate a fundamental role for clathrin function in cell polarity, growth, patterning, and organogenesis in plants. PMID- 21551393 TI - Guest family physician commentaries. PMID- 21551394 TI - Patient-centered care is associated with decreased health care utilization. AB - PURPOSE: This article uses an interactional analysis instrument to characterize patient-centered care in the primary care setting and to examine its relationship with health care utilization. METHODS: Five hundred nine new adult patients were randomized to care by family physicians and general internists. An adaption of the Davis Observation Code was used to measure a patient-centered practice style. The main outcome measures were their use of medical services and related charges monitored over 1 year. RESULTS: Controlling for patient sex, age, education, income, self-reported health status, and health risk behaviors (obesity, alcohol abuse, and smoking), a higher average amount of patient-centered care recorded in visits throughout the 1-year study period was related to a significantly decreased annual number of visits for specialty care (P = .0209), less frequent hospitalizations (P = .0033), and fewer laboratory and diagnostic tests (P = .0027). Total medical charges for the 1-year study were also significantly reduced (P = .0002), as were charges for specialty care clinic visits (P = .0005), for all patients who had a greater average amount of patient-centered visits during that same time period. For female patients, the regression equation predicted 15.47% of the variation in total annual medical charges compared with male patients, for whom 31.18% of the variation was explained by the average percent of patient-centered care, controlling for sociodemographic variables, health status, and health risk behaviors. CONCLUSIONS: Patient-centered care was associated with decreased utilization of health care services and lower total annual charges. Reduced annual medical care charges may be an important outcome of medical visits that are patient-centered. PMID- 21551395 TI - The Colorado Asthma Toolkit Program: a practice coaching intervention from the High Plains Research Network. AB - INTRODUCTION: Asthma is often under-diagnosed and under-treated in primary care. The Colorado Asthma Toolkit Program was initiated to establish a method for improving asthma care by providing to primary care practices coaching, training, and support for (1) evidence-based asthma diagnosis and treatment, and (2) education and activation of patients toward effective self-management of their illness. METHODS: A collaborative program was initiated involving 2 academic medical institutions and the High Plains Research Network, a primary care practice-based research network in eastern Colorado. Focus groups were conducted with rural Colorado patients and health care clinicians to assess need and determine the most effective intervention strategies. Two intertwined training programs, or "toolkits," were subsequently developed, one each for health care clinicians and patients. Clinicians received 3 coaching sessions conducted by 2 nurses in the practice that included training in guideline-based methods for evaluation and treatment of asthma, coaching to assist practices in implementing these methods, and training in communication techniques to promote asthma self management. Practices were also given a spirometer and trained in its use and interpretation. Patient self-management toolkits were provided to clinicians, who were trained to use the materials to educate patients and increase treatment adherence. Evaluations were based on practice interviews 1 to 3 months after coaching. RESULTS: Coaching occurred in 57 of the 58 primary care offices in eastern rural and semirural Colorado. Practices reported changes in their asthma management behaviors: (1) 40.4% of practices increased their use of inhaled corticosteroids, with the median percent of patients taking inhaled corticosteroids rising from 25% to 50%; (2) 53.2% of practices increased their use of asthma action plans, with the median percent of patients with action plans rising from 0% to 20%; and (3) 78.7% of practices initiated or increased their use of spirometry, resulting in a rise in median use from 0% to 30%. CONCLUSION: The Colorado Asthma Toolkit Program successfully disseminated asthma care training into a majority of area rural health care practices. Acceptance by practices was attributable to flexible, in-office coaching and provision of spirometry. Significant shifts seen in asthma-management practices are likely to reduce hospitalizations and emergency department visits. PMID- 21551397 TI - Prevalence of depressive symptoms in the immediate postpartum period. AB - PURPOSE: There is currently little information about rates of positive maternal depression screens immediately after delivery; rather, most studies have assessed the prevalence of major depression between 1 and 6 months postpartum. This study investigated the rate of positive 9-item Patient Health Questionnaire (PHQ-9) surveys within 1 to 2 days after delivery. METHODS: A retrospective chart review of PHQ-9 results obtained within 1 to 2 days after childbirth was performed on 441 women who delivered at 3 St. Paul, MN, hospitals during February 2010. RESULTS: Out of 441 deliveries recorded during the study period, PHQ-9 results were available for 361 women (81.9%). A total of 9 women (2.5%) had positive PHQ 9 scores within 1 to 2 days after delivery. CONCLUSION: We found very low rates of depressive symptoms during the immediate postpartum period, which leads us to suggest that this is not an ideal time for postpartum depression screening or evaluation. PMID- 21551396 TI - Maternal depressive symptomatology: 16-month follow-up of infant and maternal health-related quality of life. AB - PURPOSE: The purpose of this study was to document risk factors for depressive symptoms during the postpartum period among working mothers and to determine longitudinal effects of depressive symptoms on maternal health-related quality of life and infant health and development. METHODS: Mother-infant dyads from a community-based cohort study of working mothers were recruited when infants were 4 months old and were interviewed every 4 months until infants were 16 months old. Depressive symptoms and health-related quality of life were assessed using the Center for Epidemiologic Studies Depression Scale and the Short Form-12 Health Survey, respectively. Infant development and health-related quality of life were measured with the Ages and Stages Questionnaire and the Infant-Toddler Quality of Life Questionnaire, respectively. RESULTS: Depressive symptoms were elevated among mothers who were younger, less educated, African American, unmarried, and impoverished. Mothers with significant depressive symptoms had significantly poorer physical and mental health-related quality of life, reported greater pain for their infant, and had more health-related concerns about their child. Maternal depressive symptoms at 4 months predicted infant poorer health related quality of life at 8, 12, and 16 months. CONCLUSIONS: Several characteristics, including age, education level, race, marital status, and poverty, can help primary care physicians identify working mothers at risk for depressive symptoms. Identification of these symptoms is important; they are correlated with poorer maternal health-related quality of life and they predict poorer children's health-related quality of life. PMID- 21551398 TI - Teratogen use in women of childbearing potential: an intervention study. AB - PURPOSE: The purpose of this study was to quantify the number of women of childbearing potential who are prescribed angiotensin-converting enzyme inhibitor (ACE inhibitor), angiotensin receptor blocker (ARB), or HMG-coenzyme A reductase inhibitor (statin) and to determine the number of documented teratogenic risk discussions (risk documentation) before and after educational interventions. METHODS: The institutional review board-approved retrospective chart review included female patients ages 15 to 45 years who were prescribed an ACE inhibitor, ARB, or statin between January 1, 2007, and March 1, 2009. Exclusion criteria were tubal ligation and hysterectomy. A survey determined physician knowledge of teratogenic risks and prescribing practices for targeted medications. Educational interventions were implemented. Data was reviewed and analyzed quarterly for 1 year. RESULTS: Baseline analysis included 200 patients. A total of 129 (64.5%) patients were prescribed an ACE inhibitor, 29 (14.5%) were prescribed an ARB, and 88 (44.0%) were prescribed a statin. Risk documentation occurred for 40 (20%) patients. Analysis after intervention of 131 patients revealed that risk documentation was 2.4 times greater than before intervention (odds ratio, 2.4; 95% CI, 1.5-3.9). No significant difference identified in survey responses before and after intervention; however, resident physicians overestimated risk documentation. CONCLUSIONS: Physicians' baseline awareness of ACE inhibitor, ARB, or statin teratogenic risks and risk documentation was lacking. Improvement in risk documentation was seen after intervention; however, continual improvement is essential. PMID- 21551399 TI - Acceptability of behavioral treatments for insomnia. AB - BACKGROUND: Behavioral treatments for insomnia are safe and efficacious but may not be embraced by patients in primary care. Understanding factors associated with acceptability can enhance successful use of these modalities. The objective of this study was to identify demographic and clinical/psychosocial correlates of behavioral insomnia treatment acceptability. METHODS: This nonexperimental, inventory-based, cross-sectional study enrolled patients from a hospital sponsored primary care clinic and 2 urban academic family practices. Participants (n = 236) were 18 years of age or older who had clinically significant insomnia (Insomnia Severity Index score >= 8) and were recruited consecutively at these sites. A study coordinator obtained informed consent then distributed survey materials. Participants received a $10 honorarium. The main outcome measure was the Acceptability Insomnia Treatment Acceptability Scale-Behavioral subscale (ITAS-B). RESULTS: Only acceptability of medications (r = 0.259) and dysfunctional beliefs (r = 0.234) scores had significant bivariate correlations with ITAS-B scores (P < .001). Medication acceptability, dysfunctional beliefs, and self-efficacy accounted for 12.45% of ITAS-B variance in linear regression. CONCLUSIONS: Screening for dysfunctional beliefs about sleep may identify patients with interest in behavioral approaches. Improving self-efficacy for sleep may improve acceptance of behavioral insomnia therapies. Interest in behavioral and medication treatments are not mutually exclusive. However, the modest variance reported here suggests other factors impact acceptance of behavioral treatments. PMID- 21551400 TI - Time, costs, and clinical utilization of screening for health literacy: a case study using the Newest Vital Sign (NVS) instrument. AB - PURPOSE: Difficulties in identifying and caring for patients with limited health literacy have prompted interest in clinical screening to assess health literacy. Little agreement exists, however, on the utility of such screening. In this case study we explore the business and clinical cases for screening for health literacy using the Newest Vital Sign (NVS), a brief instrument specifically developed for use in primary care settings. METHODS: Data were collected in 2008 in the Morehouse School of Medicine Department of Family Medicine Primary Care Clinic, where health literacy screening was implemented as part of routine intake procedures within an ongoing quality improvement effort to improve cardiovascular disease and diabetes outcomes. Specifically, we monitored time requirements, administrative and training costs, and clinician utilization associated with the NVS. RESULTS: Results identified only small time and cost constraints associated with implementing NVS screening. Clinical utility was more problematic, however, because refresher trainings were needed to ensure continued staff and clinician buy-in, use of the NVS data, and implementation of best practices to communicate with at-risk patients. CONCLUSIONS: Though the time and cost constraints associated with screening for health literacy were small, clinician utilization of this data in decision making and care processes may require further training and/or support. PMID- 21551401 TI - Urinary symptoms after a routine pelvic exam. AB - PURPOSE: To determine if urinary symptoms are more common in women during the 4 weeks after a routine pelvic examination. METHODS: This was a 4-week, prospective, observational cohort study in a Family Medicine residency clinic at an urban university. Participants included women ages 18 to 40 years who identified themselves as sexually active and who presented for a routine pelvic examination. Controls were women presenting for other health maintenance with no pelvic examination. Independent variables included age, pelvic examination/no pelvic examination, intercourse frequency, and condom use. Dependent variables included dysuria and urinary frequency. Relative rates of dysuria and frequency were compared using chi(2) analysis. Mean rates of dysuria, frequency, intercourse, and condom use were compared using 2-tailed t tests. RESULTS: Sixty three subjects and 87 controls completed the study. More subjects had days with dysuria (17% vs 7%; P < .01), days with frequency (27% vs 14%; P < .01), days with both dysuria and frequency (13% vs 3%; P < .01), and days with either dysuria or frequency (32% vs 17%; P < .01). Subjects had less intercourse than controls (1.6 times per week vs 2.2 times per week; P < .01) and used condoms less frequently (33% vs 41%; P < .01). CONCLUSIONS: Dysuria and urinary frequency are more common among sexually active women during the month after a routine pelvic examination. PMID- 21551402 TI - Genitourinary infections after a routine pelvic exam. AB - PURPOSE: To determine if genitourinary problems are more common in women in the first 1 to 2 months after a routine pelvic examination. METHODS: This was a historical cohort study in 2 family medicine teaching clinics at an urban university. Participants included all women who received a Papanicolaou smear during calendar year 2006. Subjects included all participants for weeks 1 to 7 after their Papanicolaou smear. Controls were all participants in weeks 8 to 52 after their Papanicolaou smear. The independent variable was time after Papanicolaou smear, and dependent variables included frequency of visits for urinary complaints, diagnosed urinary tract infections (UTIs), vaginal complaints, diagnosed vaginitis, and sexually transmitted diseases. Relative frequencies compared using 2-tailed t tests. RESULTS: UTIs and urinary complaints were significantly more frequent during the first 7 weeks after a Papanicolaou smear compared with weeks 8 to 14, 8 to 48, and 8 to 52. The overall rate of UTIs was 7.33 per 100 person-years; the attributable risk during the first 7 weeks was 0.82 per 100 person-years, or 11% of observed UTIs. Combined Candidal and bacterial vaginitis was marginally more frequent during the first 7 weeks compared with weeks 8 to 48 and 8 to 52 only. The incidence of sexually transmitted diseases combined was 1.13 per 100 person-years, distributed evenly over the study period unrelated to time. CONCLUSIONS: The risk of UTI is increased in the 7 weeks after a Papanicolaou smear. PMID- 21551403 TI - Uninsured patient opinions about a reduced-fee retainer program at academic health center clinics. AB - BACKGROUND: Access Assured, an experimental program to deliver primary care to uninsured patients using a monthly retainer payment system, has been shown to provide a financially viable method of delivering primary care services to people without health insurance. This qualitative study was designed to assess patient attitudes and concerns about this program and to identify ways to improve it. METHODS: We conducted telephone interviews with 40 purposefully selected Access Assured members between May and June of 2009. This population was stratified to include a sample of 20 patients from those who had elected to renew enrollment in the program after their first 6-month enrollment period. The other 20 patients were selected from those enrollees who had not re-enrolled in the program after this initial period. The semistructured interviews were based on an original list of 19 standardized questions, which were asked of each participant. All interviews were audio taped. The interview tapes were transcribed verbatim and content analysis was conducted using immersion-crystallization methods. RESULTS: Content analysis identified 9 themes related to patient attitudes and concerns about this program. (1) Patients could not understand why they needed to remain enrolled if they were healthy. (2) Patients had variable levels of personal agency or responsibility for their own care. (3) Patients reported they had no choice and needed to enroll in the program to have access to care. (4) Patients liked that the program allowed them to choose their provider and see that provider with continuity from visit to visit. (5) Patients felt they were respected and treated the same as other patients. (6) Patients expressed appreciation for the program. (7) Patients had a range of comments about the quality of care and service they received. (8) Patients reported confusion about the rules of the program and often did not understand its terms and benefits. (9) Patients were under personal and family economic stress. Twenty of the subjects in our study had re-enrolled in Access Assured and 11 of the 20 patients who had not re-enrolled expressed an intention to do so. CONCLUSIONS: Our study population expressed gratitude and other positive opinions about the retainer based program for uninsured patients in 2 academic family medicine clinics. Conversely, some were concerned about the perceived lack of choice related to enrollment. Significant gaps in patient understanding about the program were identified. Based on these results, we have made improvements to the program and plan to continue to offer this care model to uninsured patients in our practices. PMID- 21551404 TI - Smoking and asthma. AB - BACKGROUND: The purpose of this review is to describe the current understanding of the prevalence and adverse effects of cigarette smoking and secondhand smoke (SHS) in asthmatics in terms of patient outcomes and response to inhaled corticosteroids. METHODS: We searched the English biomedical literature via PubMed, Embase, and Scopus using the terms "smoking and asthma," "secondhand smoke and asthma," "environmental tobacco smoke and asthma," and "smoking/secondhand smoke and corticosteroids." We also reviewed reference lists of identified articles for relevant citations. RESULTS: In asthmatic patients who smoke, disease control is poorer than in asthmatic nonsmokers. Of all forms of SHS, maternal exposure seems to have the largest impact on asthma by increasing the frequency and severity of the disease and decreasing lung function. Asthmatic children exposed to multiple household smokers face an increased risk for respiratory illness-related absences from school, and these effects persist during adolescence but weaken during adulthood. Airway mucosal permeability is increased in smokers, which could lead to increased clearance of inhaled corticosteroids from the airways. Smokers also have decreased histone deacetylase activity, which is necessary for corticosteroids to fully suppress cytokine production, and can lead to corticosteroid resistance. CONCLUSIONS: Cigarette smoking and SHS in asthmatics lead to detrimental effects in patient outcomes and effectiveness of steroid therapy. PMID- 21551405 TI - Night transport in Port-au-Prince. AB - The author leaves a rural clinic in Fort Morgan, CO, to briefly join a medical relief team responding to the Haitian January 2010 earthquake. While transporting an ill newborn, he reflects on similarities between the Haitians' displacement and resulting vulnerability and that of his patients back home. "Jeff! Jeff! Get up!" Elias' headlamp pierces the thin tent and catches me in the eyes, blinding me. "There's a sick baby at the hospital they want to transport...they need someone to go." PMID- 21551406 TI - Shared medical appointments: promoting weight loss in a clinical setting. AB - INTRODUCTION: Shared medical appointments (SMAs) are 90-minute group appointments for patients with similar medical complaints. SMAs include components of a traditional office visit but provide further emphasis on health education. The effectiveness of SMAs on weight-loss in an outpatient setting has not been studied. METHODS: Weight-loss SMAs were offered by one physician at the Palo Alto Medical Foundation. Teaching content included Diabetes Prevention Program materials. This analysis includes patients who attended at least one SMA (n = 74) compared with patients in the same physician's practice who had at least one office visit and a body mass index >= 25 kg/m(2) (n = 356). RESULTS: The SMA group had a higher proportion of women than the comparison group (76% vs 64%) and were older (mean, 52.4 years; SD, 13.1 years vs mean, 47.0 years; SD, 13.3 years). SMA patients on average lost 1.0% of their baseline weight. Patients in the comparison group on average gained 0.8% of their baseline weight. DISCUSSION: SMAs may be a viable option for physicians to promote weight loss in the clinical setting. PMID- 21551407 TI - Coding and obesity: room to grow. AB - INTRODUCTION: Obesity is the leading health problem in the United States. Providers often fail to document obesity in patients whose body mass index (BMI) is more than 30. METHODS: Using a structured data query of the military health system electronic medical record, we determined the BMI and presence of an associated International Classification of Disease code in a cohort of more than 3 million patients. RESULTS: Fifteen percent of patients (482,628) had a BMI exceeding 30. Of those patients with a BMI more than 30,78,776 (16%) had an associated International Classification of Disease 9 code documenting obesity in their record. CONCLUSION: Coding and documentation of obesity is inadequate. This has implications for delivery of preventive counseling and efforts to mitigate rising trends in obesity. PMID- 21551408 TI - Re: Trimethoprim-sulfamethoxazole or clindamycin for community-associated MRSA (CA-MRSA) skin infections. PMID- 21551409 TI - Expression and regulation of antimicrobial peptide psoriasin (S100A7) at the ocular surface and in the lacrimal apparatus. AB - PURPOSE: Psoriasin, originally isolated from psoriasis as an overexpressed molecule of unknown function, has recently been identified as a principal Escherichia coli-killing antimicrobial peptide of healthy skin. The purpose of this study was to investigate the expression and antimicrobial role of psoriasin at the ocular surface and in the lacrimal apparatus. METHODS: Different tissues of the lacrimal apparatus and ocular surface were systematically analyzed by means of RT-PCR, Western blot, and immunohistochemistry for their ability to express and produce psoriasin. The inducibility and regulation of psoriasin were studied in human corneal as well as conjunctival epithelial cell lines after challenge with ocular pathogens and proinflammatory cytokines. Real-time RT-PCR was performed to evaluate the expression and induction of psoriasin. In addition, tear fluid obtained from different healthy volunteers was examined by ELISA for its psoriasin concentration. RESULTS: RT-PCR and Western blot analyses revealed a constitutive expression of psoriasin in cornea, conjunctiva, nasolacrimal ducts, and lacrimal gland. Immunohistochemistry showed strong staining of meibomian glands for psoriasin. No induction of psoriasin was observed after stimulation with supernatants of E. coli, whereas supernatants of Staphylococcus aureus and Haemophilus influenzae significantly increased the psoriasin mRNA expression. Stimulation with IL-1beta and VEGF also strongly increased psoriasin transcription. The highest amounts of psoriasin protein were detected in the tear fluid (~170 ng/mL) of healthy volunteers. CONCLUSIONS: The results suggest that psoriasin is produced by the structures of the ocular surface and is part of the innate immune system at the ocular surface and tear film. PMID- 21551410 TI - Understanding clinically undetected macular changes in early retinopathy of prematurity on spectral domain optical coherence tomography. AB - PURPOSE: To investigate macular changes in acute retinopathy of prematurity (ROP). METHODS: Fifty-four premature infants with ROP and 20 controls underwent routine ROP screening with indirect ophthalmoscopy and imaging. A tabletop spectral domain optical coherence tomography (SD-OCT) scanner (Spectralis; Heidelberg Engineering, Heidelberg, Germany) was converted into a handheld device to image infants in the office sans sedation. RESULTS: SD-OCT images were obtained in all infants in the office. On SD-OCT, 23 of 79 eyes (29.1%) with stage 2 ROP showed abnormal foveal changes despite clinically normal foveae. Of the 23 eyes, 2 distinct patterns of foveal involvement were observed: "pattern A," which was characterized by dome-shaped foveal elevation and cystoid spaces with highly reflective intervening vertical septae, and "pattern B," which was characterized by preservation of the foveal depression with fewer intraretinal cystoid spaces. These patterns were seen in 12 (52.2%) and 11 (47.8%) eyes, respectively. All eyes (100%) belonging to stage 1 ROP (27) and the normal group (40) had no abnormal SD-OCT changes. The mean central foveal thickness was 156.9 +/- 28.3 MUm, 206.5 +/- 98.7 MUm, and 135.9 +/- 17.6 MUm for stage 1, 2, and normal eyes, respectively (P < 0.001). Nineteen of the 23 eyes underwent serial imaging at 52 weeks' postmenstrual age (PMA), and all of them revealed normalization of foveal contours at this visit. CONCLUSIONS: SD-OCT changes of the macula in mild ROP have not been previously described. Our method reveals that infants may be imaged supine and unanesthetized in the office. We hypothesize that these transient foveal changes at the critical time of fovealization in premature infants may influence their visual acuity in the adult life. PMID- 21551412 TI - Shadow removal and contrast enhancement in optical coherence tomography images of the human optic nerve head. AB - PURPOSE: To improve the quality of optical coherence tomography (OCT) images of the optic nerve head (ONH). METHODS: Two algorithms were developed, one to compensate for light attenuation and the other to enhance contrast in OCT images. The former was borrowed from developments in ultrasound imaging and was proven suitable with either time- or spectral-domain OCT. The latter was based on direct application of pixel intensity exponentiation. The performances of these two algorithms were tested on spectral-domain OCT images of four adult ONHs. RESULTS: Application of the compensation algorithm significantly reduced the intralayer contrast (from 0.74 +/- 0.16 to 0.17 +/- 0.12; P < 0.001), indicating successful blood vessel shadow removal. Furthermore, compensation dramatically improved the visibility of deeper ONH tissues, such as the peripapillary sclera and lamina cribrosa. Application of the contrast-enhancement algorithm significantly increased the interlayer contrast (from 0.48 +/- 0.22 to a maximum of 0.89 +/- 0.05; P < 0.001) and thus allowed a better differentiation of tissue boundaries. Contrast enhancement was robust only when compensation was considered. CONCLUSIONS: The proposed algorithms are simple and can significantly improve the quality of ONH images clinically captured with OCT. This study has important implications, as it will help improve our ability to perform automated segmentation of the ONH; quantify the morphometry and biomechanics of ONH tissues in vivo; and identify potential risk indicators for glaucoma. PMID- 21551411 TI - Comparison of ocular pathologies in vitamin A-deficient mice and RPE65 gene knockout mice. AB - PURPOSE: RPE65 gene knockout (Rpe65-/-) mice showed abolished isomerohydrolase activity in the visual cycle and were considered a model for vitamin A deficiency in the retina. The purpose of this study was to compare the retinal phenotypes between vitamin A-deficient (VAD) mice and Rpe65-/- mice under normal diet. METHODS: The VAD mice were fed with a vitamin A-deprived diet after birth. The age-matched control mice and Rpe65-/- mice were maintained under normal diet. The structure of photoreceptor outer segment was compared using electron microscopy. Photoreceptor-specific gene expression was determined using real-time RT-PCR. The isomerohydrolase and lecithin-retinol acyltransferase (LRAT) activities were measured using an in vitro enzymatic activity assay. Endogenous retinoid profiles were analyzed by HPLC in mouse eyecup homogenates. RESULTS: Compared to wild-type mice under normal diet, scanning and transmission electron microscopy showed that the outer segments of photoreceptors were disorganized in VAD mice and were not disorganized in Rpe65-/- mice, although they were shortened in the latter. VAD mice showed more prominent downregulation of middle wavelength cone opsin, whereas Rpe65-/- mice displayed more suppressed expression of short wavelength cone opsin. In vitro enzymatic activity assay and Western blot analysis showed that vitamin A deprivation downregulated LRAT expression and activity in the eyecup, but Rpe65-/- mice showed unchanged LRAT expression and activity. The depressed LRAT activity in VAD mice was partially rescued by the intraperitoneal injection of retinoic acid. CONCLUSIONS: VAD and Rpe65-/- mice are different in cone photoreceptor degeneration, photoreceptor-specific gene regulation, isomerohydrolase activity, endogenous retinoid profile, and LRAT activity. PMID- 21551413 TI - Preventive effects of ethyl pyruvate on endotoxin-induced uveitis in rats. AB - PURPOSE: Recent studies indicate that ethyl pyruvate (EP) exerts anti inflammatory properties; however, the effect of EP on ocular inflammation is not known. The efficacy of EP in endotoxin-induced uveitis (EIU) in rats was investigated. METHODS: EIU in Lewis rats was developed by the subcutaneous injection of lipopolysaccharide (LPS; 150 MUg). EP (30 mg/kg body weight) or its carrier was injected intraperitoneally 1 hour before or 2 hours after lipopolysaccharide injection. Animals were killed after 3 and 24 hours followed by enucleation of eyes and collection of the aqueous humor (AqH). The number of infiltrating cells and levels of proteins in the AqH were determined. The rat cytokine/chemokine multiplex method was used to determine level of cytokines and chemokines in the AqH. TNF-alpha and phospho-nuclear factor kappa B (NF-kappaB) expression in ocular tissues were determined immunohistochemically. Human primary nonpigmented ciliary epithelial cells (HNPECs) were used to determine the in vitro efficacy of EP on lipopolysaccharide-induced inflammatory response. RESULTS: Compared to controls, AqH from the EIU rat eyes had a significantly higher number of infiltrating cells, total protein, and inflammatory cytokines/chemokines, and the treatment of EP prevented EIU-induced increases. In addition, EP also prevented the expression of TNF-alpha and activation of NF kappaB in the ciliary bodies and retina of the eye. Moreover, in HNPECs, EP inhibited lipopolysaccharide-induced activation of NF-kappaB and expression of Cox-2, inducible nitric oxide synthase, and TNF-alpha. CONCLUSIONS: Our results indicate that EP prevents ocular inflammation in EIU, suggesting that the supplementation of EP could be a novel approach for the treatment of ocular inflammation, specifically uveitis. PMID- 21551414 TI - Significant inhibition of corneal scarring in vivo with tissue-selective, targeted AAV5 decorin gene therapy. AB - PURPOSE: This study tested a hypothesis that tissue-selective targeted decorin gene therapy delivered to the stroma with adeno-associated virus serotype 5 (AAV5) inhibits corneal fibrosis in vivo without significant side effects. METHODS: An in vivo rabbit model of corneal fibrosis was used. Targeted decorin gene therapy was delivered to the rabbit cornea by a single topical application of AAV5 (100 MUL; 6.5 * 10(12) MUg/mL) onto the bare stroma for 2 minutes. The levels of corneal fibrosis were determined with stereomicroscopy, slit lamp biomicroscopy, alpha-smooth muscle actin (alphaSMA), fibronectin, and F-actin immunocytochemistry, and/or immunoblotting. CD11b, F4/80 immunocytochemistry, and TUNEL assay were used to examine immunogenicity and cytotoxicity of AAV5 to the cornea. Transmission electron microscopy (TEM) was used to investigate ultrastructural features. Slot-blot-quantified the copy number of AAV5-delivered decorin genes. RESULTS: Selective decorin delivery into the stroma showed a significant (P < 0.01) decrease in corneal haze (1.3 +/- 0.3) compared with the no-decorin-delivered control rabbit corneas (3 +/- 0.4) quantified using slit lamp biomicroscopy. Immunostaining and immunoblot analyses detected significantly reduced levels of alphaSMA, F-actin, and fibronectin proteins (59%-73%; P < 0.001 or <0.01) in decorin-delivered rabbit corneas compared with the no-decorin delivered controls. The visual clinical eye examination, slit lamp clinical studies, TUNEL, CD11b, and F4/80 assays revealed that AAV5-mediated decorin gene therapy is nonimmunogenic and nontoxic for the cornea. TEM studies suggested that decorin gene delivery does not jeopardize collagen fibrillogenesis as no significant differences in collagen fibril diameter and arrangement were observed in decorin-delivered and no-decorin-delivered control corneas. CONCLUSIONS: Tissue-targeted AAV5-mediated decorin gene therapy is effective and safe for treating corneal fibrosis in vivo. PMID- 21551415 TI - What to do about occult metastases in breast cancer? Standards shift, but doubts linger. PMID- 21551416 TI - Half-match bone marrow transplants may raise odds for more recipients. PMID- 21551417 TI - Immunotherapies in clinical trials: do they demand different evaluation tools? PMID- 21551418 TI - AACR highlights: promise for treating pancreatic cancer. PMID- 21551419 TI - StatBite. AML survival after bone marrow transplant by type of donor. PMID- 21551420 TI - Noninvasive vascular function measurement in the community: cross-sectional relations and comparison of methods. AB - BACKGROUND: Several methods of noninvasive vascular function testing have been suggested for cardiovascular risk screening in the community. A direct comparison of the different methods and their relation to classical cardiovascular risk factors in a large cohort is missing. METHODS AND RESULTS: In 5000 individuals (mean age, 55.5 +/- 10.9 years; age range, 35 to 74 years; women, 49.2%) of the population-based Gutenberg Heart Study, we performed simultaneous measurement of flow-mediated dilation (FMD) and peripheral arterial volume pulse determined by infrared photo (reflection index) and pneumatic plethysmography (PAT) and explored their associations. All function measures were recorded at baseline and after reactive hyperemia induced by 5-minute brachial artery occlusion. Correlations between different measures of vascular function were statistically significant but moderate. The strongest association for hyperemic response variables was observed for PAT ratio and FMD (Spearman r = 0.17; age- and sex adjusted partial correlation, 0.068). Classical risk factors explained between 15.8% (baseline reflection index) and 58.4% (brachial artery diameter) of the baseline values but only accounted for 3.2% (reflection index), 15.4% (FMD), and 13.9% (PAT ratio) of the variability of reflective hyperemic response. Regression models varied in their relations to classical risk factors for the individual vascular function measures. Consistently associated with different vascular function methods were age, sex, body mass index, and indicators of hypertension. Peripheral tonometry also showed a relation to fasting glucose concentrations. CONCLUSIONS: Noninvasive measures of conduit artery and peripheral arterial function are modestly correlated, differ in their relation to classical cardiovascular risk factors, and may thus reflect different pathologies. PMID- 21551422 TI - Sex educators and self-efficacy: toward a taxonomy of enactive mastery experiences. AB - Enactive mastery experiences have been identified as the most influential source of self-efficacy beliefs. Yet little is known about enactive mastery experiences, including how such experiences manifest in naturally occurring situations (as opposed to simulated situations). This study draws from semistructured interviews (N = 50) with sex educators working in public secondary schools throughout Indiana to explicate distinct categories of enactive mastery experiences. Three types of enactive mastery experiences--growth, interactive, and endorsed--emerged from the data and are delineated. This formative taxonomy provides detailed targets for those working to foster individuals' perceived self-efficacy in a variety of contexts, including the health education classroom. PMID- 21551421 TI - A family and community focused lifestyle program prevents weight regain in Pacific Islanders: a pilot randomized controlled trial. AB - Preventing weight regain after the loss of excess weight is challenging for people, especially for ethnic minorities in the United States. A 6-month weight loss maintenance intervention designed for Pacific Islanders, called the PILI Lifestyle Program (PLP), was compared with a 6-month standard behavioral weight loss maintenance program (SBP) in a pilot randomized controlled trial using a community-based participatory research approach. Adult Pacific Islanders (N = 144) were randomly assigned to either PLP (n = 72) or SBP (n = 72) after completing a 3-month weight loss program. Successful weight maintenance was defined as participants' postintervention weight change remaining <= 3% of their preintervention mean weight. Both PLP and SBP participants achieved significant weight loss maintenance (p <= .05). Among participants who completed at least half of the prescribed sessions, PLP participants were 5.1-fold (95% confidence interval = 1.06, 24; p = .02) more likely to have maintained their initial weight loss than SBP participants. The pilot PLP shows promise as a lifestyle intervention to address the obesity disparities of Pacific Islanders and thus warrants further investigation. PMID- 21551423 TI - Mexican American mothers' perceptions of childhood obesity: a theory-guided systematic literature review. AB - Childhood obesity continues to increase, disproportionately affecting Mexican American children. The aims of this review are to (a) assess the literature regarding Mexican American mothers' knowledge and perceptions of childhood obesity, prevention, and their role in prevention; (b) critically evaluate the methodological quality of the research conducted on mothers' perceptions of childhood obesity; and (c) make recommendations for future research on parental perceptions of childhood obesity. Four databases were searched for relevant articles and 22 studies met inclusion criteria and were included in the review. Social cognitive theory was used to sort findings across studies. Major findings included the following: (a) barriers to childhood obesity prevention included lack of education regarding prevention and role modeling, (b) only 23% of studies explicitly used a theoretical framework to guide their study, and (c) most studies used heterogeneous groups to examine perceptions. Implications for future research and practice are presented. PMID- 21551425 TI - Abstracts of the International Anesthesia Research Society 2010 Annual Meeting. Honolulu, Hawaii, USA. March 20-23, 2010. PMID- 21551424 TI - Effectiveness of Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) methods in Medicaid-supported prenatal care: Trial III. AB - This two-phase evaluation documented the delivery and effectiveness of evidence based health education methods by regular staff to pregnant smokers. During Phase 1, a total of 436 Medicaid patients were screened and 416 (95%) gave consent: 334 nonsmokers and 102 smokers. This historical Comparison (C) group was assessed to document the "normal" pretrial smoking prevalence, patient nondisclosure (deception), and cessation rates at the first prenatal visit and during care. After this study, a formative evaluation of SCRIPT methods was conducted among 139 experimental group patients and 126 control group patients. During Phase 2, a total of 6,514 patients were screened over a 36-month period: 1,736 (27%) were smokers and 1,340 (77%) gave consent. After randomization, 247 became ineligible. The remaining 1,093 smokers received brief routine advice to quit. The experimental group (n = 544) also received a Commit to Quit video, A Pregnant Woman's Guide to Quit Smoking, and counseling. Self-reports and saliva were collected at baseline, >=60 days, and <=90 days postpartum for cotinine analyses to document cessation and significant reduction (SR) rates. The Phase 1 formative evaluation documented a 24% nondisclosure rate at the onset of care. It also confirmed a significantly higher experimental (17.3%) versus control group (8.8%) cessation rate and experimental versus control group SR rates of 22% and 16%. During Phase 2, unplanned policy changes, and delivery of experimental group counseling procedures to 15% to 20% of control group patients, resulted in a final experimental group cessation rate of 12% and a control group rate of 10%. The experimental group SR rate of 18%, however, was significantly higher than the control group SR rate of 13%. Effectiveness varied by the stability of clinic infrastructure, and degree of fidelity of staff performance of assessment and intervention procedures. The methods and results of this study will assist future health education programs for pregnant smokers to plan and conduct process and impact evaluations in prenatal care. PMID- 21551426 TI - Characterization of the microanatomy and histopathology of placentas from aborted, stillborn, and normally delivered alpacas (Vicugna pacos) and llamas (Lama glama). AB - From 2002 to 2007, 101 camelid abortions and stillbirths were submitted to the Veterinary Diagnostic Laboratory at Oregon State University (84 alpacas [Vicugna pacos], 13 llamas [Lama glama], 4 unknown). For most cases (n = 67), a cause was not determined by routine testing. Eighty-five submissions included placenta for microscopic examination, of which 55 were from abortions to unknown causes (idiopathic). Microscopic features of placentas from abortion/stillbirth were compared with those from 19 camelids delivered normally (6 alpacas, 12 llamas, 1 unknown) and with those from 4 alpaca fetuses of known gestational age collected during the dam's necropsy. The most common microscopic findings in abortion/stillbirth placentas were mineralization (n = 57) and mucinous edema (n = 27) of the chorioallantoic stroma. One or more of these features were also observed in 22 of 23 placentas from normal pregnancies/deliveries and therefore interpreted as incidental findings. The comparison of alpaca placentas after matching for gestational parameters (crown-rump length, weight, days of gestation; n = 41) revealed hypoplasia of placental villi in 5 of 22 idiopathic abortions and in 1 abortion due to umbilical torsion; hypoplasia was further suspected in an additional 6 abortions of unknown cause and 2 abortions of known cause. The identified villous hypoplasia is assumed to have resulted in placental insufficiency. When placental insufficiency is included as cause, idiopathic abortions are reduced from 66.2 to 47.9% of alpaca cases with histopathologic examination of placenta and from 66.3 to 52.5% of alpaca and llama abortions overall. This study also permitted the generation of a linear regression curve correlating alpaca fetal crown-rump length with fetal age. PMID- 21551427 TI - Association of porcine circovirus type 2 with vascular lesions in porcine pneumonia. AB - The aim of this study was to evaluate the vasculature in porcine circovirus type 2-infected (PCV2-infected) lungs and to identify the PCV2 subtypes involved in porcine pneumonia. Pulmonary samples from 140 pigs, 2 weeks to 7 months of age, from 36 Hungarian commercial herds with clinical signs of respiratory disease were examined for the presence of respiratory pathogens, with bacterial culture, pathologic evaluation, and immunohistochemistry for PCV2, porcine reproductive respiratory syndrome virus, and swine influenza virus. PCV2 was the most commonly identified pathogen (49 cases) among the 74 of 140 cases (53%) with respiratory pathogens. PCV2 was detected immunohistochemically in the wall of 13% to 100% of pulmonary vessels (mean, 89%) in 38 of 49 cases (78%). Detection of PCV2 antigen was positively correlated with the presence of vascular lesions (P < .001, odds ratio [OR]: 159.54). Other pathogens capable of vascular injury in swine were found in 29 of 49 of the PCV2-positive cases (59%). The probability of detecting vascular lesions in PCV2-infected lung was higher than in infection with porcine reproductive respiratory syndrome virus (P < .002, OR: 14.63), Pasteurella multocida infection (P < .001, OR: 5.75), or Streptococcus spp. infection (not significant, OR: 1.45). Sequence analysis of open reading frame 2 amplicons was possible in 6 PCV2-positive cases, from which 5 cases proved to be PCV2b subtype and 1 case, PCV2a subtype. In conclusion, PCV2 antigen was commonly colocalized with pulmonary vascular lesions in pneumonia in Hungarian swine, and PCV2b was the dominant subtype. PMID- 21551428 TI - Abstracts of the International Anesthesia Research Society 2009 Annual Meeting. San Diego, California, USA. March 14 -17, 2009. PMID- 21551429 TI - Comprehensive surgical aesthetic enhancement and rejuvenation of the perioral region. AB - There has been minimal attention paid in the literature to the aesthetics of the perioral area, either in youth or in senescence. Aging around the lips traditionally was thought to result from a combination of thinning skin surrounding the area, ptosis, and loss of volume in the lips. The atrophy of senescence was treated by adding volume to the lips and filling the deep nasolabial creases. There is now a growing appreciation for the role of volume enhancement in the perioral region and the sunken midface, as well as for dentition, in the resting and dynamic appearance of the perioral area (particularly in youth). In this article, the authors describe the senior author's (BG) preferred methods for aesthetic enhancement of the perioral region and his rejuvenative techniques developed over the past 28 years. The article describes the etiologies behind the dysmorphologies in this area and presents a problem-oriented algorithm for treating them. PMID- 21551430 TI - Evaluation of the effects of transaxillary breast augmentation on sentinel lymph node integrity. AB - BACKGROUND: The transaxillary approach for breast augmentation has gained popularity because of the absence of scarring on the breast. However, the effects of this procedure on breast cancer detection and treatment (which rely heavily on the results of axillary status studies) remain under debate. Specifically, sentinel lymph node biopsy is not indicated for patients who have undergone axillary surgery, due to controversy about the interference of the axillary approach with evaluation of the axillary drainage. OBJECTIVES: The authors evaluate changes in axillary lymphatic drainage in patients who underwent transaxillary breast augmentation. METHODS: Twenty-seven patients who presented to Rio de Janeiro State University for breast augmentation were selected for this study. All patients underwent preoperative mammary lymphoscintigraphy, a subsequent transaxillary breast augmentation, and postoperative lymphoscintigraphy at 21 days and six months after the procedure. The postoperative imaging results examining the axillary lymphatic chain and the first axillary lymph node were analyzed and compared to the preoperative images. RESULTS: One of the 27 patients (4.5%) demonstrated a lower rate of lymphatic drainage at 21 days postoperatively compared to preoperative values, but the flow rate had recovered by her six-month follow-up visit. All other patients showed no changes between the preoperative and postoperative images at either time point. The sentinel lymph node remained visible in all patients at all time points, and all breasts showed drainage primarily to the axillary lymphatic chain. Two patients experienced hematoma and one patient experienced late infection at four months postoperatively. The sentinel lymph node was still evident in both axillae. CONCLUSIONS: The data showed preservation of lymphatic drainage and visible sentinel lymph nodes even after transaxillary breast augmentation. Therefore, the authors believe that this procedure does not alter the integrity of mammary drainage for properly selected patients. These data provide surgeons with a less invasive treatment option for patients with early breast cancer, even when they have undergone prior breast augmentation through a transaxillary approach. PMID- 21551431 TI - Evaluation of a novel high-intensity focused ultrasound device for ablating subcutaneous adipose tissue for noninvasive body contouring: safety studies in human volunteers. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) is an energy-based medical technology with many clinical applications. A device under clinical investigation in the United States (LipoSonix; Medicis Technologies Corporation, Bothell, Washington) uses HIFU to reduce localized deposits of abdominal adipose tissue. OBJECTIVES: The authors describe the results from their clinical trial investigating the safety of this HIFU device in human patients. METHODS: Over the course of three studies evaluating the safety of the HIFU device for ablating human subcutaneous adipose tissue (SAT), 152 healthy patients were treated with total HIFU energy doses of 47 to 331 J/cm(2)), including patients who presented for elective abdominoplasty and underwent treatment to areas identified for subsequent excision. The safety of each treatment regimen was confirmed before the energy levels were raised. Abdominoplasty was performed up to 14 weeks following the HIFU procedure, and a pathologist performed histopathological analyses of excised tissues. Safety evaluations included an assessment of clinical chemistry and hematology profiles, physical examinations, and adverse events. RESULTS: Posttreatment ultrasound confirmed that the HIFU effects were limited to targeted SAT layers. Histopathology revealed well-demarcated disruption of adipocytes within the targeted SAT. Phagocytosis of released lipids and cellular debris occurred after 14 to 28 days. Phagocytized lipids underwent normal hepatic metabolism. Healing progressed normally and was 95% complete after eight to 14 weeks. Adverse events consisted primarily of temporary treatment discomfort, edema, erythema, dysesthesia, and ecchymosis. There were no changes in clinical laboratory parameters, and no serious device-related adverse events occurred. Optimal clinical outcomes were achieved with lower energy levels, which provided beneficial effects with the least amount of discomfort. CONCLUSIONS: HIFU appears to provide a safe means for removing and remodeling unwanted deposits of abdominal SAT. PMID- 21551432 TI - Fractional nonablative 1540-nm laser treatment of striae distensae in Fitzpatrick skin types II to IV: clinical and histological results. AB - BACKGROUND: Current striae treatments are limited in their ability to deliver long-lasting improvements for all skin types. The success of fractional nonablative lasers for surgical scars has been attributed to the controlled wound healing response stimulated by microscopic columns of epidermal and dermal thermal damage. OBJECTIVES: The authors describe the safety and efficacy results of treatment with a fractional nonablative 1540-nm erbium:glass laser in patients with Fitzpatrick skin types II to IV for both striae rubra and striae alba. METHODS: A 51-person clinical study was conducted on striae ranging in duration from one to 40 years. Nine different anatomical locations were treated, including the breasts, hips, and abdomen. Treatment parameters included two to three passes with the 1540-nm laser, with energy settings from 35 to 55 mJ/mb with the 10-mm optical tip or 12 to 14 mJ/mb with the 15-mm optical tip. Two to four total treatments were performed at four- to six-week intervals. Nonblinded efficacy evaluations were performed on all 51 patients; blinded evaluations were conducted by three independent clinicians on 14 randomized sets of pre- and posttreatment images on a 0% to 100% quartile improvement scale. Skin reactions were assessed by the treating physician and recorded at multiple time points, and histology was conducted with hemotoxylin and eosin as well as Orcein-Giemsa staining. RESULTS: Nonblinded clinical assessments rated overall improvement as 50% or greater for all patients at six months or longer after the last treatment. Blinded evaluators reported an overall mean improvement score of 51% to 75% on properly selected images taken at least three months after treatment (n = 11). In all patients examined at either 18 or 24 months after treatment, there was no recurrence of striae. Typical side effects included transient erythema and edema. A small minority of patients experienced transient cases of trace postinflammatory hyperpigmentation (PIH), which all resolved. Histologic observations showed thickening of the epidermis and dermis, neocollagenesis, and increased elastin deposition one month after the last treatment. CONCLUSIONS: Positive safety and efficacy results with the fractional nonablative 1540-nm erbium:glass laser for the treatment of striae rubra and striae alba ranging in maturation age from one to 40 years was demonstrated in Fitzpatrick skin types II to IV. PMID- 21551433 TI - Effects of coagulase-negative staphylococci and fibrin on breast capsule formation in a rabbit model. AB - BACKGROUND: The etiology and ideal clinical treatment of capsular contracture (CC) remain unresolved. Bacteria, especially coagulase-negative staphylococci, have been previously shown to accelerate the onset of CC. The role of fibrin in capsule formation has also been controversial. OBJECTIVE: The authors investigate whether fibrin and coagulase-negative staphylococci (CoNS) modulate the histological, microbiological, and clinical outcomes of breast implant capsule formation in a rabbit model and evaluate contamination during the surgical procedure. METHODS: Thirty-one New Zealand white female rabbits were each implanted with one tissue expander and two breast implants. The rabbits received (1) untreated implants and expanders (control; n = 10), (2) two implants sprayed with 2 mL of fibrin and one expander sprayed with 0.5 mL of fibrin (fibrin; n = 11), or (3) two implants inoculated with 100 uL of a CoNS suspension (10(8)CFU/mL 0.5 density on the McFarland scale) and one expander inoculated with a CoNS suspension of 2.5 * 10(7) CFU/mL (CoNS; n = 10). Pressure/volume curves and histological and microbiological evaluations were performed. Operating room air samples and contact skin samples were collected for microbiological evaluation. The rabbits were euthanized at four weeks. RESULTS: In the fibrin group, significantly decreased intracapsular pressures, thinner capsules, loose/dense (<25%) connective tissue, and negative/mild angiogenesis were observed. In the CoNS group, increased capsular thicknesses and polymorph-type inflammatory cells were the most common findings. Similar bacteria in capsules, implants, and skin were cultured from all the study groups. One Baker grade IV contracture was observed in an implant infected with Micrococcus spp. CONCLUSIONS: Fibrin was associated with reduced capsule formation in this preclinical animal model, which makes fibrin an attractive potential therapeutic agent in women undergoing breast augmentation procedures. Clinical strategies for preventing bacterial contamination during surgery are crucial, as low pathogenic agents may promote CC. PMID- 21551434 TI - Evaluation of a novel high-intensity focused ultrasound device: preclinical studies in a porcine model. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) has been applied clinically for the noninvasive treatment of pathological conditions in various organs for over 50 years; however, there are little data describing the use of thermal HIFU to ablate fat for body contouring and treatment of collagen-rich layers. A novel device under clinical investigation (LipoSonix; Medicis Technologies Corporation, Bothell, Washington) uses HIFU to eliminate unwanted adipose tissue. OBJECTIVES: The authors describe the results of HIFU treatment in a series of preclinical studies performed in a validated porcine model. METHODS: Preclinical research included in vivo treatment of the abdominal subcutaneous adipose tissue of swine with transcutaneous HIFU therapy. Endpoint analyses included thermocouple temperature data, full-body necropsy, local pathology and histology studies, clinical hematology, urinalysis, and blood chemistry parameters, including lipid panels. RESULTS: The application of HIFU energy levels of 166 to 372 J/cm(2) generated tissue temperature approaching 70 degrees C, which was restricted to the focal area (n = seven). Application of 68 and 86 J/cm(2) did not produce clinically-significant changes in serum liver function tests, free fatty acids, or cholesterol (n = eight). Gross examination of tissue from various organs showed no evidence of fat emboli or accumulation (n = two). Histology demonstrated well-preserved vasculature and intact nerve fibers within the HIFU focal area (n = three). Following treatment with 85.3 to 270 J/cm(2), normal healing response included the migration of macrophages into the damaged tissue and removal of disrupted cellular debris and lipids (n = 8). CONCLUSIONS: In a preclinical swine model, the controlled thermal effect of HIFU appears to provide a safe and effective means for ablating subcutaneous adipose tissue. PMID- 21551435 TI - Social media in plastic surgery practices: emerging trends in North America. AB - BACKGROUND: Social media is a common term for web-based applications that offer a way to disseminate information to a targeted audience in real time. In the current market, many businesses are utilizing it to communicate with clients. Although the field of plastic surgery is constantly changing in response to innovative technologies introduced into the specialty, the utilization of social media in plastic surgery practices is currently unclear. OBJECTIVES: The authors evaluate the current attitudes and practices of aesthetic surgeons to emerging social media technology and compare these to attitudes about more traditional modes of communication. METHODS: A 19-question web-based survey was disseminated by e-mail to all board-certified or board-eligible American plastic surgeons (n = 4817). Respondents were asked to answer questions on three topics: (1) their use of social media in their personal and professional lives, (2) their various forms of practice marketing, and (3) their demographic information. RESULTS: There were 1000 responses (20.8%). Results showed that 28.2% of respondents used social media in their practice, while 46.7% used it in their personal life. Most plastic surgeons managed their social media themselves or through a staff member. The majority of respondents who used social media in their practice claimed that their efforts were directed toward patient referrals. The typical plastic surgery practice that used social media was a solo practice in a large city with a focus on cosmetic surgery. Local competition of plastic surgeons did not correlate with social media use. Most plastic surgeons (88%) advertised, but the form of marketing varied. The most common forms included websites, print, and search engine optimization, but other modalities, such as television, radio, and billboards, were still utilized. CONCLUSIONS: Social media represents a new avenue that many plastic surgeons are utilizing, although with trepidation. As social media becomes commonplace in society, its role in plastic surgery practice development and communication will become more prominent and defined. PMID- 21551436 TI - Commentary on: Social media in plastic surgery practices: emerging trends in North America. PMID- 21551437 TI - Commentary on: Social media in plastic surgery practices: emerging trends in North America. PMID- 21551438 TI - Cosmetic surgery training in plastic surgery residency programs in the United States: how have we progressed in the last three years? AB - BACKGROUND: In 2006, a survey performed by Morrison et al analyzed the experience of aesthetic surgery training from the perspective of residents and their program directors in plastic surgery programs across the United States. OBJECTIVES: The authors conducted a survey to follow-up on the Morrison results three years after publication, to assess the changes in plastic surgery residency programs. METHODS: In December 2009, a 17-question survey was sent to program directors, and a 19-question survey was sent to senior residents in all Accreditation Council for Graduate Medical Education-approved plastic surgery residency programs in the United States. The questions were posed in a five-point ranking format. The two additional questions included in the senior resident survey related to career aspirations and desirable areas of additional training. Ninety two program directors and 397 senior residents received the survey. RESULTS: Forty-four program director surveys (47.8%) and 117 (29.5%) senior resident surveys were returned. Two-thirds of programs offered a residents' clinic, which was considered the preferred method of cosmetic surgery education by residents. Residents reported increased exposure to nonsurgical procedures such as lasers and injectables. Abdominoplasty, breast augmentation, and breast reduction remained the procedures most frequently performed by residents with confidence, as in the 2006 survey. Facial aesthetic procedures, including rhinoplasty and facelift, remained challenging to residents. Many residents (55.7%) felt confident integrating cosmetic surgery into their practice. One-third of residents reported that they would apply for a cosmetic fellowship. CONCLUSIONS: This survey shows an improvement in cosmetic surgery training for plastic surgery residents in the United States, particularly in that noninvasive cosmetic treatments are being increasingly taught. Since 2006, steps have been taken to provide more comprehensive cosmetic surgery education to residents, encouraging the delivery of the safe, high-quality care expected of a board-certified plastic surgeon. PMID- 21551439 TI - Dorsal reduction and spreader flaps. AB - Dorsal reduction (humpectomy) is a simple maneuver in principle, yet it commonly results in irregularities and general inaccuracies, along with occasional internal valve compromise. Traditionally, spreader grafts have been applied to reconstruct an internal valve disrupted during dorsal reduction. Imbricating the dissected ends of the upper lateral cartilages at their interface with the septum (spreader flaps) allows the surgeon to use this tissue, which would otherwise be discarded, to reconstruct the internal valve and design an aesthetically pleasing nasal line. The application of a spreader flap is not only an easily reproducible technique to restore middle vault structure but allows for precise incremental control when performed at the time of humpectomy. To that end, the authors provide a detailed description of their internal valve reconstruction technique, which has been honed over the past 15 years. PMID- 21551440 TI - Electronic medical records: rising out of the sand. PMID- 21551441 TI - Anaplastic large cell lymphoma and breast implants: FDA report. PMID- 21551442 TI - Dynamic risk groups among adult male sexual offenders. AB - In the present study, the 16-item Stable-2000 was used to identify different dynamic risk groups among 419 adult male sexual offenders who were referred for assessments between 2000 and 2007. Using a two-stage cluster analysis, four dynamic risk groups were identified: (a) a low needs group who scored below the overall sample mean on all of the Stable-2000 items; (b) a typical group who had intermediate scores on many items; (c) a sexually deviant group who scored relatively high on deviant sexual interests, sexual preoccupation, emotional identification with children, and child molester attitudes; and (d) a pervasive high-needs group who scored relatively high on many Stable-2000 items, reflecting a variety of problems in both general and sexual self-regulation. These dynamic risk groups were not redundant with offender type based on victim age, relatedness, or gender, and did not differ in terms of age at time of assessment, marital status, number of sexual victims, or long-term risk, estimated using the Static-99. The implications for treating and supervising sexual offenders with different dynamic risk profiles are discussed. PMID- 21551443 TI - Herman Melville, marine biologist. PMID- 21551444 TI - Orientation to Objects in the Sea Urchin Strongylocentrotus purpuratus depends on apparent and not actual object size. PMID- 21551445 TI - Isolation and ultrastructural characterization of squid synaptic vesicles. AB - Synaptic vesicles contain a variety of proteins and lipids that mediate fusion with the pre-synaptic membrane. Although the structures of many synaptic vesicle proteins are known, an overall picture of how they are organized at the vesicle surface is lacking. In this paper, we describe a better method for the isolation of squid synaptic vesicles and characterize the results. For highly pure and intact synaptic vesicles from squid optic lobe, glycerol density gradient centrifugation was the key step. Different electron microscopic methods show that vesicle membrane surfaces are largely covered with structures corresponding to surface proteins. Each vesicle contains several stalked globular structures that extend from the vesicle surface and are consistent with the V-ATPase. BLAST search of a library of squid expressed sequence tags identifies 10 V-ATPase subunits, which are expressed in the squid stellate ganglia. Negative-stain tomography demonstrates directly that vesicles flatten during the drying step of negative staining, and furthermore shows details of individual vesicles and other proteins at the vesicle surface. PMID- 21551446 TI - Influence of cortisol on the attachment and metamorphosis of larval Utterbackia imbecillis on bluegill sunfish (Lepomis macrochirus). AB - The larvae of unionid freshwater mussels (i.e., glochidia) undergo a parasitic stage requiring their attachment to the external epithelia of fish hosts, where they metamorphose into free-living juveniles. We describe the physiological effects in bluegill sunfish (Lepomis macrochirus) of infection with glochidia from the paper pondshell (Utterbackia imbecillis). Glochidia accumulation on bluegill increased dramatically at concentrations of 2000 glochidia liter(-1) and above, reaching a maximum attachment density of about 30 glochidia g(-1) fish at 4000 glochidia liter(-1). Plasma cortisol was the most sensitive indicator of biological effect to glochidial exposure, increasing significantly in hosts exposed to 2000 glochidia liter(-1) or greater. Glochidia were 31% more likely to undergo successful juvenile metamorphosis when attached to bluegill with elevated plasma cortisol, largely due to the enhanced survivorship of these larvae during the first 48 h after infection. We tested the hypothesis that glochidial attachment and juvenile metamorphosis were stimulated directly by plasma cortisol in fish hosts. Bluegill were given an intraperitoneal injection of cortisol, then infected with 1000 glochidia liter(-1) at 48 h after hormone supplementation. Cortisol-injected fish had a 42% increase in the number of attached glochidia g( 1) fish and a 28% increase in larval metamorphosis compared to sham-injected and control fish. We provide evidence that cortisol enhances glochidial metamorphosis on hosts by improving the retention of attached glochidia. This study gives insights into the influence of host physiology on glochidial attachment and juvenile mussel transformation. PMID- 21551447 TI - Preference versus performance: body temperature of the intertidal snail Chlorostoma funebralis. AB - Evolutionary theory predicts that, in variable environments, it is advantageous for ectothermic organisms to prefer a body temperature slightly below the physiological optimum. This theory works well for many terrestrial organisms but has not been tested for animals inhabiting the hypervariable physical environment of intertidal shores. In laboratory experiments, we allowed the intertidal snail Chlorostoma funebralis to position itself on a temperature gradient, then measured its thermal preference and determined an index of how its performance varied with temperature. Snails performed a biased random walk along the temperature gradient, which, contrary to expectations, caused them to aggregate where body temperature was 15 to 17 degrees C below their temperature of optimum performance and near the species' lower thermal limit. This "cold-biased" behavioral response may guide snails to refuges in shaded cracks and crevices, but potentially precludes C. funebralis from taking full advantage of its physiological capabilities. PMID- 21551448 TI - Phylogenetic characterization of episymbiotic bacteria hosted by a hydrothermal vent limpet (lepetodrilidae, vetigastropoda). AB - Marine invertebrates hosting chemosynthetic bacterial symbionts are known from multiple phyla and represent remarkable diversity in form and function. The deep sea hydrothermal vent limpet Lepetodrilus fucensis from the Juan de Fuca Ridge complex hosts a gill symbiosis of particular interest because it displays a morphology unique among molluscs: filamentous bacteria are found partially embedded in the host's gill epithelium and extend into the fluids circulating across the lamellae. Our objective was to investigate the phylogenetic affiliation of the limpet's primary gill symbionts for comparison with previously characterized bacteria. Comparative 16S rRNA sequence analysis identified one gamma- and three epsilon-Proteobacteria as candidate symbionts. We used fluorescence in situ hybridization (FISH) to test which of these four candidates occur with the limpet's symbiotic gill bacteria. The gamma-proteobacterial probes consistently hybridized to the entire area where symbiotic bacteria were found, but fluorescence signal from the epsilon-proteobacterial probes was generally absent. Amplification of the gamma-proteobacterial 16S rRNA gene using a specific forward primer yielded a sequence similar to that of limpets collected from different ridge sections. In total, direct amplification or FISH identified a single gamma-proteobacterial lineage from the gills of 23 specimens from vents separated by a distance up to about 200 km and collected over the course of 2 years, suggesting a highly specific and widespread symbiosis. Thus, we report the first filamentous gamma-proteobacterial gill symbiont hosted by a mollusc. PMID- 21551449 TI - The Osedax trophosome: organization and ultrastructure. AB - The polychaete family Siboglinidae, which is currently construed as comprising the Frenulata, Monilifera (composed of Sclerolinum), Vestimentifera, and Osedax, has become known for its specialized symbiont-housing organ called the trophosome. This organ replaced the digestive system of the worms and is located in the elongated trunk region in Frenulata, Sclerolinum, and Vestimentifera. Currently two types of trophosomes have been described: in the taxa Frenulata and Sclerolinum the bacteriocytes originate from endoderm, and in Vestimentifera they originate from mesoderm. In Osedax, a trophosome was described as lacking (Rouse et al., 2004), but bacteriocytes are located in Osedax's characteristic root tissue. Here, we argue for a consistent name for the symbiont-housing tissue, namely trophosome, as in other siboglinids. In this study we provide morphological evidence that in Osedax the bacteriocytes are derived from somatic mesoderm. We show that the trophosome in Osedax is an apolar tissue composed of bacteriocytes and nonsymbiotic cells. As in vestimentiferans, a specific cell cycle was identified; however, in this case it is directed from the posterior to the anterior end of the worms instead of from the center toward the periphery. Comparison of all siboglinid trophosomes and re-evaluation of their body regions allows us to discuss whether the trophosomes are homologous and to hypothesize about the organization of the last common ancestor of Siboglinidae. PMID- 21551450 TI - Organization and microanatomy of the Sclerolinum contortum trophosome (Polychaeta, Siboglinidae). AB - The trophosome-an organ especially evolved to accommodate symbiotic bacteria-is a key character of the polychaete family Siboglinidae. Astonishingly, the trophosomes vary in organization and origin between the different siboglinid taxa. The trophosome of the small genus Sclerolinum was nearly unknown until now. Here we investigated the trophosome of S. contortum from the Gulf of Mexico, using light and electron microscopy. We show that this organ derives from the visceral mesoderm and propose that the trophosome of the sister clade Vestimentifera and Sclerolinum is a homologous character. Like that of juvenile vestimentiferans, the trophosome of Sclerolinum trophosome is simply organized. This study reveals that the Sclerolinum trophosome exhibits two regions that differ in the organization of host tissue and the size and shape of the symbionts. We suggest that a specific cell cycle within the symbiont-housing organ is directed along the longitudinal body axis, with a region of proliferation anteriorly and a region of degradation posteriorly. Using Raman microspectroscopy we demonstrate that the endosymbionts of S. contortum from the Gulf of Mexico contain sulfur vesicles, and we argue for a chemoautotrophic sulfur-oxidizing metabolism. PMID- 21551451 TI - Dyssynchrony contributes to false-positive myocardial perfusion SPECT results in patients with stable angina. AB - AIM: We designed this study to evaluate the possibility that dyssynchrony might lead to false-positive myocardial perfusion single photon emission computed tomography myocardial perfusion image (MPS) results in stable angina patients. METHODS AND RESULTS: This study included 61 patients with both clinically diagnosed stable angina and quantitative MPS results who underwent coronary angiography. The patients were divided into two groups: those who had positive MPS results and normal coronary angiography (Group I, n = 28, 64.05 +/- 10.14 years, 11 males and 17 females) and those who had positive MPS results and significant coronary lesions as determined by coronary angiography (Group II, n = 33, 69.2 +/- 10.4 years, 14 males and 19 females). The maximal difference in time to-peak myocardial sustained systolic velocity among all 12 left ventricular (LV) segments (maximal difference in TS) was significantly delayed in Group I as compared with Group II (125.00 +/- 46.10 vs. 87.33 +/- 40.53 ms, P=0.001). The standard deviation of the time-to-peak myocardial sustained systolic velocity of all 12 LV segments (TS-SD) was also significantly different in the two groups (45.12 +/- 19.25 vs. 30.10 +/- 15.80 , P=0.002). CONCLUSION: Dyssynchrony may be a cause of false-positive quantitative MPS results, even if patients have narrow QRS complexes on ECG. Dyssynchrony index can increase the specificity of quantitative MPS in stable angina patients. PMID- 21551452 TI - Spermatogenetic inhibition in men taking a combination of oral medroxyprogesterone acetate and percutaneous testosterone as a male contraceptive method. AB - BACKGROUND: We previously demonstrated in a small pilot study that oral medroxyprogesterone acetate and percutaneous testosterone (OMP/PT) induce reversible spermatogenesis suppression. The aims of this study were to determine the rate of spermatogenetic inhibition and recovery and to obtain preliminary data on efficacy for a larger population under OMP/PT. METHODS: A total of 35 healthy men with normal spermiograms requesting male hormonal contraception were treated with OMP (20 mg/day) and PT (50-125 mg/day) for periods up to 18 months. Couples were included in a contraceptive efficacy phase after a value of <=1 million/ml spermatozoa was reached between 1 and 3 months of treatment. RESULTS: Sperm counts decreased by 47% at 1 month, reaching 90% at 2 months and 98-100% between 4 and 8 months. At 3 months, 80% of men had <=1 million/ml spermatozoa. Follicle-stimulating hormone and luteinizing hormone decreased to 35% of pretreatment levels after 1 month of treatment and to 75-80% at 2 and 6 months, respectively. Plasma testosterone and estradiol levels were in the eugonadal range at 3, 6, 9 and 12 months of treatment. Dihydrotestosterone concentrations were 2-4 times higher than pretreatment values. The rate of spermatogenetic recovery was rapid (73 +/- 29.5 days). During the efficacy phase (211 months for 25 couples), one pregnancy attributable to poor compliance of the male partner was observed. CONCLUSIONS: OMP/PT efficiently inhibits spermatogenesis in 80% of men, maintains testosterone at physiological levels and avoids the need for parenteral administration, which is poorly accepted by French men. These results justify larger studies to define a more adequate dosage of OMP/PT and to confirm its efficacy and safety. PMID- 21551453 TI - Association of Sly with sex-linked gene amplification during mouse evolution: a side effect of genomic conflict in spermatids? AB - In common with other mammalian sex chromosomes, the mouse sex chromosomes are enriched for genes with male-specific function such as testis genes. However, in mouse there has been an unprecedented expansion of ampliconic sequence containing spermatid-expressed genes. We show via a phylogenetic analysis of gene amplification on the mouse sex chromosomes that multiple families of sex-linked spermatid-expressed genes are highly amplified in Mus musculus subspecies and in two further species from the Palaearctic clade of mouse species. Ampliconic X linked genes expressed in other cell types showed a different evolutionary trajectory, without the distinctive simultaneous amplification seen in spermatid expressed genes. The Palaearctic gene amplification occurred concurrently with the appearance of Sly, a Yq-linked regulator of post-meiotic sex chromatin (PMSC) which acts to repress sex chromosome transcription in spermatids. Despite the gene amplification, there was comparatively little effect on transcript abundance, suggesting that the genes in question became amplified in order to overcome Sly-mediated transcriptional repression and maintain steady expression levels in spermatids. Together with the known sex-ratio effects of Yq/Sly deficiency, our results suggest that Sly is involved in a genomic conflict with one or more X-linked sex-ratio distorter genes. The recent evolution of the novel PMSC regulator Sly in mouse lineages has significant implications for the use of mouse-model systems in investigating sex chromosome dynamics in spermatids. PMID- 21551454 TI - Seipin ablation in mice results in severe generalized lipodystrophy. AB - Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance and fatty liver. Here, we create the first murine model of BSCL2 by targeted disruption of seipin, the causative gene for BSCL2. Compared with their wild-type littermates, the seipin(-/-) mice are viable and of normal weight but display significantly reduced adipose tissue mass, hepatic steatosis, glucose intolerance and hyperinsulinemia. The levels of leptin and adiponectin were both significantly decreased in seipin(-/-) mice, so were non-esterified fatty acids upon fasting. Surprisingly, however, hypertriglyceridemia which is common in human BSCL, was not observed in seipin(-/-) mice. Our findings suggest a possible tissue-autonomous role of seipin in liver lipid storage. The availability of the seipin(-/-) mice should help elucidate the molecular function of seipin and lead to a better understanding of the many metabolic consequences of human BSCL2. PMID- 21551455 TI - A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility. AB - Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1.48, 95% confidence interval (CI) 1.23, 1.78; P = 2.52 * 10(-5)] compared with controls, while the association with rs755383 persisted (per allele OR = 1.26, 95% CI 1.08, 1.47, P = 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR = 14.1, 95% CI 5.12, 38.6; P = 2.98 * 10(-7)) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility. PMID- 21551456 TI - Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. AB - Schizophrenia is a severe chronic mental disorder with a high genetic component in its etiology. Several lines of study have suggested that synaptic dysfunction may underlie the pathogenesis of schizophrenia. Neuroligin proteins function as cell-adhesion molecules at post-synaptic membrane and play critical roles in synaptogenesis and synaptic maturation. In this study, we systemically sequenced all the exons and promoter region of neuroligin-2 (NLGN2) gene in a sample of 584 schizophrenia patients and 549 control subjects from Taiwan. In total, we identified 19 genetic variants, including six rare missense mutations such as R215H (one patient), V510M (two patients), R621H (one patient), A637T (two patients), P800L (one patient and one control) and A819S (one patient and one control). In silico analysis predicted that two patient-specific missense mutations, R215H and R621H, had damaging effect, whereas the other missense mutations were benign. Importantly, functional analysis with immunocytochemistry and electrophysiological recordings identified the R215H mutant as a loss-of function mutant in inducing GABAergic synaptogenesis. Mechanistically, the synaptogenic deficiency of R215H mutant was due to its retention inside the endoplasmic reticulum and inability to be transported to cell membrane. Our study suggests that defects in GABAergic synapse formation in the brain may be an important contributing factor for the onset of schizophrenia. In the family study of this mutation, we found his elder brother also carried this mutation but did not have psychiatric symptoms, indicating that this mutation has incomplete penetrance, and thus the clinical relevance of this mutation should be interpreted with caution. PMID- 21551457 TI - Occurrence of the human tumor-specific antigen structure Galbeta1-3GalNAcalpha- (Thomsen-Friedenreich) and related structures on gut bacteria: prevalence, immunochemical analysis and structural confirmation. AB - The Thomsen-Friedenreich antigen (TF; CD176, Galbeta1-3GalNAcalpha-) is a tumor specific carbohydrate antigen and a promising therapeutic target. Antibodies that react with this antigen are frequently found in the sera of healthy adults and are assumed to play a role in cancer immunosurveillance. In this study, we examined the occurrence of alpha-anomeric TF (TFalpha) on a large variety of gastrointestinal bacteria using a novel panel of well-characterized monoclonal antibodies. Reactivity with at least one anti-TF antibody was found in 13% (16 of 122) of strains analyzed. A more in-depth analysis, using monoclonal antibodies specific for alpha- and beta-anomeric TF in combination with periodate oxidation, revealed that only two novel Bacteroides ovatus strains (D-6 and F-1), isolated from the faeces of healthy persons by TF-immunoaffinity enrichment, possessed structures that are immunochemically identical to the true TFalpha antigen. The TF-positive capsular polysaccharide structure of strain D-6 was characterized by mass spectrometry, monosaccharide composition analysis, glycosidase treatments and immunoblot staining with TFalpha- and TFbeta-specific antibodies. The active antigen was identified as Galbeta1-3GalNAc-, which was alpha-anomerically linked as a branching structure within a heptasaccharide repeating unit. We conclude that structures immunochemically identical to TFalpha are extremely rare on the surface of human intestinal bacteria and may only be identifiable by binding of both antibodies, NM-TF1 and NM-TF2, which recognize a complete immunomolecular imprint of the TFalpha structure. The two novel B. ovatus strains isolated in this study may provide a basis for the development of TF-based anti-tumor vaccines. PMID- 21551458 TI - Gamma-irradiated EPR response of nano-structure hydroxyapatite synthesised via hydrolysis method. AB - In this paper, the gamma-irradiated EPR responses of hydroxyapatite (HAP) samples were investigated from a dosimetric point of view. For this purpose, nano structure hydroxyapatite was synthesised via a hydrolysis method. A portion of the produced powder was annealed at 600 degrees C for 4 h. All the samples were irradiated under the (60)Co gamma-ray source at different absorbed doses from 0.1 to 45 kGy. EPR signal intensities of HAP samples were measured at room temperature in air. Subsequently, the EPR signal intensities were constructed as a function of radiation dose and were compared with the results of bone powder samples. The results show that the EPR responses of non-annealed HAP samples are higher than others for several times. PMID- 21551460 TI - Long-term effect on mortality of a multicomponent cognitive behavioural group intervention to reduce fear of falling in older adults: a randomised controlled trial. PMID- 21551459 TI - Handgrip strength among older American Indians: the Native Elder Care Study. PMID- 21551461 TI - Giant right coronary aneurysm: a case of mistaken identity. PMID- 21551463 TI - Incidence and regression of Charles Bonnet syndrome in vascular age-related macular degeneration. PMID- 21551462 TI - Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. AB - AIM: After an acute coronary syndrome, patients remain at risk of recurrent ischaemic events, despite contemporary treatment, including aspirin and clopidogrel. We evaluated the safety and indicators of efficacy of the novel oral direct thrombin inhibitor dabigatran. METHODS AND RESULTS: In this double-blind, placebo-controlled, dose-escalation trial, 1861 patients (99.2% on dual antiplatelet treatment) in 161 centres were enrolled at mean 7.5 days (SD 3.8) after an ST-elevation (60%) or non-ST-elevation (40%) myocardial infarction and randomized to twice daily treatment with dabigatran 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406), 150 mg (n = 347), or placebo (n = 371). Primary outcome was the composite of major or clinically relevant minor bleeding during the 6 month treatment period. There were 96 primary outcome events and, compared with placebo, a dose-dependent increase with dabigatran, hazard ratio (HR) 1.77 (95% confidence intervals 0.70, 4.50) for 50 mg; HR 2.17 (0.88, 5.31) for 75 mg; HR 3.92 (1.72, 8.95) for 110 mg; and HR 4.27 (1.86, 9.81) for 150 mg. Compared with placebo, D-dimer concentrations were reduced in all dabigatran dose groups by an average of 37 and 45% at weeks 1 and 4, respectively (P< 0.001). Fourteen (3.8%) patients died, had a myocardial infarction or stroke in the placebo group compared with 17 (4.6%) in 50 mg, 18 (4.9%) in 75 mg, 12 (3.0%) in 110 mg, and 12 (3.5%) in the 150 mg dabigatran groups. CONCLUSIONS: Dabigatran, in addition to dual antiplatelet therapy, was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent myocardial infarction. PMID- 21551464 TI - Two concepts of therapeutic optimism. AB - Researchers and ethicists have long been concerned about the expectations for direct medical benefit expressed by participants in early phase clinical trials. Early work on the issue considered the possibility that participants misunderstand the purpose of clinical research or that they are misinformed about the prospects for medical benefit from these trials. Recently, however, attention has turned to the possibility that research participants are simply expressing optimism or hope about their participation in these trials. The ethical significance of this therapeutic optimism remains unclear. This paper argues that there are two distinct phenomena that can be associated with the term 'therapeutic optimism'-one is ethically benign and the other is potentially worrisome. Distinguishing these two phenomena is crucial for understanding the nature and ethical significance of therapeutic optimism. The failure to draw a distinction between these phenomena also helps to explain why different writers on the topic often speak past one another. PMID- 21551465 TI - Molecular identification of Pentatrichomonas hominis in two patients with gastrointestinal symptoms. PMID- 21551466 TI - Clinicopathologic significances of nuclear expression of nuclear factor-kappaB transcription factors in retinoblastoma. AB - AIMS: The nuclear factor-kappaB (NF-kappaB) transcription factors family is thought to play an important role in the development of certain cancers. In this study, the clinical significance of NF-kappaB transcription factor expression and the MIB-1 labelling index (MIB-1 LI) were studied in retinoblastoma. METHODS: Immunohistochemical analysis of normal retina (n=6) and retinoblastoma tumour (n=62) specimens obtained from multiple centres was performed in order to evaluate the pathological associations of NF-kappaB subunits and retinoblastoma. RESULTS: Expression of NF-kappaB proteins was frequently detected in retinoblastoma but not in normal retina samples with c-Rel being the most commonly detected (61%). This protein was more frequently detected in poorly differentiated and invasive tumours than in well-differentiated and non-invasive tumours. RelA expression in invasive tumours was also significantly higher. Furthermore, expression of c-Rel correlated positively with the MIB-1 LI in retinoblastoma, and RelA/c-Rel revealed positive correlation with RelA/RelB. CONCLUSIONS: This study demonstrated that expression of RelA and c-Rel proteins represents a reliable prognostic marker of retinoblastoma and that NF-kappaB is related to retinoblastoma tumorigenesis and progression through a non conventional pathway. This data suggests that therapeutic strategies targeting NF kappaB combined with other therapies may represent a novel approach to retinoblastoma therapy. PMID- 21551467 TI - Ochronosis and calcification in the mediastinal mass of a patient with alkaptonuria. PMID- 21551468 TI - Adaptive motion processing in bilateral vestibular failure. AB - BACKGROUND: Patients with bilateral vestibular failure (BVF) suffer from oscillopsia during head movements. This is secondary to the loss of the vestibulo ocular reflex which is responsible for stabilising retinal images during head movements of high frequency or velocity. Previous studies documented decreased visual motion sensitivity in such patients at low velocities. The authors now examine motion coherence tasks, which have two advantages: (1) the task is associated with the functions of the middle temporal area; and (2) it affords testing at low and high motion velocities, as relevant for patients with oscillopsia due to BVF. METHODS: Nine BVF patients and nine healthy control subjects were examined with a random dot pattern with variable percentages of dots moving in the target direction. Participants were asked to indicate in which of two possible directions they perceived the coherent motion. Horizontal and vertical planes were tested at speeds from 0.156 to 40 degrees /s. RESULTS: Motion coherence thresholds were lower at higher speeds in both groups (p<0.0001). BVF patients had raised motion coherence thresholds (p=0.002) across all velocities as compared with the control subject group. CONCLUSION: In a motion coherence paradigm, BVF patients show raised thresholds. This is the first demonstration of diminished visual motion processing at high velocities, supporting the view that the changes allow BVF patients to partly compensate for the oscillopsia. The findings are interpreted as an adaptive process likely to involve the middle temporal visual motion processing areas. PMID- 21551469 TI - Neurology at the airport. AB - OBJECTIVES: Neurological problems are reported to be common in air travellers. The authors aimed to study neurological problems which might be associated with air traffic in a systematic way. METHODS: The authors analysed a prospective registry of all the patients referred from Madrid-Barajas International Airport to the emergency department of their tertiary university hospital (Hospital Universitario Ramon y Cajal), for whom a neurological consultation was required, during a period of 21 months. RESULTS: 77 patients with a history of air travel presented with neurological problems and were included in the analysis. Fifty nine (76.6%) were male, and the mean age was 45.9 (range 8-89, SD 17.5). Onset of symptoms was after landing in 44 subjects (58.7%), during the flight in 31 (41.3%), and unknown in two (5.1%). Thirty-nine (50.9%) had seizures, 18 (23.4%) had a stroke, and 20 (26%) other diagnosis. Sixty-one per cent of the patients with seizures had no previous history of epilepsy. Seizures on presentation were significantly associated with the use of drugs (p = 0.0008), and most of the cases with known epilepsy admitted non-adherence to treatment. Three 'body packers' were admitted with seizures secondary to intra-abdominal cocaine pack rupture. Of eight ischaemic strokes, five had high-grade carotid stenosis, and one case had economy-class stroke syndrome. Six patients with stroke were eligible and treated with intravenous thrombolysis. CONCLUSION: In our series of neurological problems among air travellers, drug-induced seizures and ischaemic strokes due to large-artery atherosclerosis were the commonest observed diagnoses. PMID- 21551470 TI - Familial recurrence risks for multiple sclerosis in Australia. AB - BACKGROUND: Genetic susceptibility to multiple sclerosis (MS) has been recognised for many years. Considerable data exist from the northern hemisphere regarding the familial recurrence risks for MS, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. To investigate the interaction between environmental and genetic causative factors in MS, the authors undertook a familial recurrence risk study in three latitudinally distinct regions of Australia. METHODS: Immediate and extended family pedigrees have been collected for three cohorts of people with MS in Queensland, Victoria and Tasmania spanning 15 degrees of latitude. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates. RESULTS: Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.13% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the sibling recurrence-risk ratio (lambda(s)) was similar across all sites. DISCUSSION: The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the lambda(s) is similar to the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture. PMID- 21551471 TI - Feeling of presence in Parkinson's disease. AB - BACKGROUND: A feeling of presence (FP), that is, the vivid sensation that somebody (distinct from oneself) is present nearby, is commonly reported by patients with Parkinson's disease (PD), but its phenomenology has not been described precisely. The objective of this study was to provide a detailed description of FP in PD and to discuss its possible mechanisms. PATIENTS AND METHODS: The authors studied 52 non-demented PD patients reporting FP in the preceding month (38 consecutive outpatients and 14 inpatients). FP characteristics were recorded with a structured questionnaire. The outpatients with FP were compared with 78 consecutive outpatients without FP. RESULTS: About half the patients said they recognised the 'identity' of the presence. More than 75% of patients said the FP were not distressing, were short-lasting, were felt beside and/or behind the patient, and occurred while indoors; most patients checked for a real presence, but their insight was generally preserved. In 31% of cases, the patients had an unformed visual hallucination simultaneously with the FP. A higher daily levodopa-equivalent dose and the presence of visual illusions or hallucinations were independently associated with FP. DISCUSSION: Although FP is not a sensory perception, projection of the sensation into the extrapersonal space, along with the frequent co-occurrence of elementary visual hallucinations and the strong association with visual hallucinations or illusions, supports its hallucinatory nature. FP may be viewed as a 'social' hallucination, involving an area or network specifically activated when a living being is present, independently of any perceptual clue. PMID- 21551472 TI - Factors associated with quality of life in 7-year survivors of stroke. AB - BACKGROUND: Little is known about health-related quality of life (HRQoL) in the long term after stroke. AIM: The aim of this study was to assess the level of, and factors associated with, HRQoL at 7 years post-stroke. METHODS: All stroke cases from a prospective community-based stroke incidence study (excluding subarachnoid haemorrhage) were assessed 7 years after stroke. HRQoL was measured with the Assessment of Quality of Life instrument. Proportional odds ordinal logistic regression was used to determine factors associated with HRQoL at 7 years post-stroke. RESULTS: Overall, 1321 stroke cases were recruited. Seven years after stroke, 413 (31.2%) were alive and 328 (79.4%) were assessed. Those assessed were less often current smokers pre-stroke than those not assessed (p<0.01). Seventy-six survivors (23%) had very poor HRQoL (range: -0.038 to 0.100). Factors present at 7 years that were associated with better 7-year HRQoL were independence in instrumental activities of daily living (IADL) (estimated OR=11.2, 95% CI 4.87 to 25.6, p<0.001), independence in basic activities of daily living (BADL) (OR=4.53, 95% CI 2.03 to 10.1, p<0.001), independence in IADL and BADL (OR=9.90, 95% CI 4.51 to 21.7, p<0.001), male gender (OR=1.89, 95% CI 1.21 to 2.96, p=0.005) and lesser handicap (trend: OR=3.47, 95% CI 2.51 to 4.79, p<0.001). Participants' HRQoL scores tended to be lower when HRQoL assessments were completed by proxy (OR=0.13, 95% CI 0.06 to 0.31, p<0.001). CONCLUSION: At 7 years post-stroke, 68.8% had died and a substantial proportion of survivors had poor HRQoL. Factors such as handicap, BADL and IADL could be targeted to improve HRQoL in long-term survivors of stroke. PMID- 21551473 TI - MRI guides diagnostic approach for ischaemic stroke. AB - BACKGROUND AND AIM: Identification of ischaemic stroke subtype currently relies on clinical evaluation supported by various diagnostic studies. The authors sought to determine whether specific diffusion-weighted MRI (DWI) patterns could reliably guide the subsequent work-up for patients presenting with acute ischaemic stroke symptoms. METHODS: 273 consecutive patients with acute ischaemic stroke symptoms were enrolled in this prospective, observational, single-centre NIH-sponsored study. Electrocardiogram, non-contrast head CT, brain MRI, head and neck magnetic resonance angiography (MRA) and transoesophageal echocardiography were performed in this prespecified order. Stroke neurologists determined TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification on admission and on discharge. Initial TOAST stroke subtypes were compared with the final TOAST subtype. If the final subtype differed from the initial assessment, the diagnostic test deemed the principal determinant of change was recorded. These principal determinants of change were compared between a CT-based and an MRI based classification schema. RESULTS: Among patients with a thromboembolic DWI pattern, transoesophageal echocardiography was the principal determinant of diagnostic change in 8.8% versus 0% for the small vessel group and 1.7% for the other group (p<0.01). Among patients with the combination of a thromboembolic pattern on MRI and a negative cervical MRA, transoesophageal echocardiography led to a change in diagnosis in 12.1%. There was no significant difference between groups using a CT-based scheme. CONCLUSIONS: DWI patterns appear to predict stroke aetiologies better than conventional methods. The study data suggest an MRI-based diagnostic algorithm that can potentially obviate the need for echocardiography in one-third of stroke patients and may limit the number of secondary extracranial vascular imaging studies to approximately 10%. PMID- 21551474 TI - Pacemaker sensitivity to 50 Hz noise voltages. AB - AIMS: European standards specify that pacemakers (PM) should be resistant to electromagnetic interference (EMI) up to an upper borderline voltage as a function of frequency. Electromagnetic interference fields should either remain below this upper borderline voltage level or be identified and isolated from the general population. Physicians caring for PM patients need to be aware of potential problems relating to EMI. For example, sensitivity should be programmed to avoid sensing EMI below the recommended borderline voltage level. The susceptibility of a pacemaker (PM) to 50 Hz noise is an important parameter of EMI and depends on the programmed sensitivity [sensitivity setting (SS)]. We studied SS and 50 Hz noise thresholds in a large population and determined the borderline SS, defined as the SS below which 50 Hz noise was sensed. Our results should be taken into consideration in programming the SS to protect patients from the adverse effects of EMI. METHODS AND RESULTS: Measurements were performed on 189 PMs explanted after death. All PMs studied were implanted in 1998 or later. Sensitivity setting and sensing configuration (unipolar or bipolar) were left as programmed during lifetime. The ventricular SS and 50 Hz noise thresholds were measured according to the European pacemaker standard. The signal-to-noise ratios (S/N) were derived from the heart test and noise test signal thresholds. The S/N for pulsed 50 Hz noise of five manufacturers tested ranged from 0.435 to 0.59. The S/N for 50 Hz continuous noise for four manufactures other than Medtronic was higher, ranging from 0.458 to 0.623. No PM showed a ratio of 1 or better. Medtronic PMs reacted differently to 50 Hz continuous noise than the other brands. In 24 Medtronic PMs, the continuous noise threshold was evaluated with two heart test signal amplitudes: either 10 mV or threshold level. In tests at threshold amplitudes, voltages between 0.1 and 0.85 mV elicited interference proving that Medtronic PM reacted extremely sensitively to noise. At 10 mV heart test amplitude, the noise threshold was inversely proportional to the SS, i.e. higher SS resulted in lower noise thresholds. Noise immunity increases with increasing heart test signal amplitude. CONCLUSION: All tested PMs reacted to pulsed 50 Hz waves as if they were heart signals and were inhibited. Continuous noise above noise threshold evoked asynchronous pacing at noise rate. All PMs had an S/N ratio <1, indicating that the heart signals were amplified less than noise. The European Standard requires that unipolarly sensing PMs tolerate noise up to 2 mV. However, an SS of 2 mV does not guarantee a noise tolerance of 2 mV. In order to fulfil this requirement, SS in the majority of PMs must be programmed >2 mV. In Medtronic PMs, the continuous noise threshold is paradoxical as it is higher with decreasing SS. As a good compromise in Medtronic PMs, SS should be ~3 mV to guarantee sufficient protection from pulsed and continuous noise, assuming ventricular heart signals of 10 mV or more. PMID- 21551475 TI - Rate responsive pacing using cardiac resynchronization therapy in patients with chronotropic incompetence and chronic heart failure. AB - AIMS: Chronotropic incompetence (CI) is a common finding in patients with advanced chronic heart failure (CHF) and is associated with a worse functional capacity. Whether rate responsive pacing with cardiac resynchronization therapy (CRT) would acutely improve exercise performance in patients with advanced CHF and severe CI (<70% age-predicted maximum heart rate) is unknown. METHODS AND RESULTS: Patients (n = 13) with CHF, a CRT device, and severe CI were randomized in a double-blind crossover pilot study to either DDD (control) or DDDR (rate responsive) pacing. Six minutes walk test (6MWT) distance, oxygen consumption at anaerobic threshold (VO(2) @ AT), and maximal oxygen consumption (VO(2) max) were measured. One week later, testing was repeated in the alternate pacing mode. Rate responsive pacing commenced with standard settings in only 9 of 13 (69%) patients. In these 9 subjects, 6MWT distance improved acutely from 358.5 +/- 40.7 to 376.8 +/- 24.5 m with DDDR pacing (P< 0.05). VO(2) max did not improve with DDDR pacing (14.0 +/- 3.2 mL/kg/min) compared with DDD pacing (13.9 +/- 3.0 mL/kg/min; P= 0.69). VO(2) @ AT tended towards improvement with DDDR pacing (10.8 +/- 2.9 mL/kg/min) compared with DDD pacing (9.6 +/- 1.8 mL/kg/min; P= 0.29). There was a linear relationship between the increase in heart rate at minute 3 during rate responsive pacing and improvement in VO(2) @ AT (r = 0.83, P< 0.05). CONCLUSION: When rate responsive pacing using a CRT device is achieved in patients with advanced CHF and severe CI, parameters of aerobic exercise performance improve acutely. Routine exercise testing to ensure successful restoration of heart rate response may be beneficial to optimize CRT settings in this patient population. PMID- 21551476 TI - Type I Brugada electrocardiogram pattern induced by metoclopramide. PMID- 21551477 TI - Right ventricular dilatation: an often neglected component in the electrocardiographic assessment of patients with heart failure. PMID- 21551478 TI - Trends in the incidence and prevalence of atrial fibrillation in Iceland and future projections. AB - AIMS: Data are scarce on the epidemiology of atrial fibrillation (AF) in Europe. The aim of this study was to examine recent trends in the incidence and prevalence of AF and project the prevalence to the year 2050. METHODS AND RESULTS: From 1991 to 2008 a total of 4905 residents of Reykjavik, Iceland were diagnosed with AF at the city's main health care centre. The age-standardized incidence of AF increased in women (0.9% per year, 95% CI 0.1-1.8) but not in men (0.1% per year, 95% CI -0.6 to 0.9). The age-standardized prevalence increased per year by 1.8% (95% CI 1.3-2.3) in men and 2.3% (95% CI 1.7-2.9) in women from 1998 to 2008. The number of adults with AF in Iceland is projected to increase from 4495 (prevalence 2.0%) in 2008 to 11 088 (prevalence 3.5%) in 2050, if the incidence of AF and mortality remain constant beyond 2008. However, if the incidence continues to increase as it has and mortality decreases according to projections for the general population, the projected number will rise to 13 583 (prevalence 4.3%). CONCLUSION: In this study in a northern European population, the incidence of AF increased in women but not men from 1991 to 2008. The prevalence of AF is currently high and the number of patients with AF is expected to triple in the next four decades. AF is already a serious public health problem and the burden of this disease could reach epidemic proportions in the coming years. PMID- 21551479 TI - Beneficial effect of pioglitazone on the outcome of catheter ablation in patients with paroxysmal atrial fibrillation and type 2 diabetes mellitus. AB - AIMS: Pioglitazone, one of the peroxisome proliferator-activated receptor-gamma activators, possesses anti-inflammatory and antioxidant properties. In the present study, we sought to identify the impact of pioglitazone on the outcome of catheter ablation for paroxysmal atrial fibrillation (PAF). METHODS AND RESULTS: We conducted a prospective observational cohort study of 150 consecutive patients undergoing catheter ablation of drug-refractory PAF. All patients had a history of type 2 diabetes mellitus (T2DM) and were divided based on whether they received pioglitazone before ablation or not. After grouping, 51 patients treated with pioglitazone and 99 control subjects were followed up at least 15 months after ablation. After a single ablation, sinus rhythm was maintained in 44 patients (86.3%) of the pioglitazone group vs. 70 patients (70.7%) of the control group (P = 0.034) without antiarrhythmic drug during a mean follow-up of 22.9 +/- 5.1 months. The second ablation was performed in 5 patients (9.8%) from the pioglitazone group and in 24 patients (24.2%) from the control group (P = 0.034). Multivariate logistic analysis showed left atrium diameter was associated with a high risk of atrial tachyarrhythmias recurrence, and treatment with renin angiotensin system inhibitor as well as pioglitazone was associated with a reduced atrial tachyarrhythmias recurrence rate. CONCLUSION: Pioglitazone improved the preservation of sinus rhythm and reduced the reablation rate in patients with PAF and T2DM after catheter ablation. PMID- 21551480 TI - Transcriptional profile of diuron-induced toxicity on the urinary bladder of male Wistar rats to inform mode of action. AB - Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide that induces rat urinary bladder urothelial tumors at high dietary levels (2500 ppm). The specific mode of action and molecular alterations triggered by diuron, however, have not been clarified. The present study evaluated the dose-dependent effects of mucosal alterations and transcriptional changes in the urinary bladder of rats exposed to diuron. Six-week-old male Wistar rats were treated with 0, 60, 125, 1250, and 2500 ppm of diuron in the diet for 20 weeks. Histologic examination showed urothelial hyperplasia present in rats treated with either 1250 or 2500 ppm of diuron but not 60 or 125 ppm. Comprehensive gene expression analyses of urothelial cell RNA were conducted using Affymetrix microarrays. The numbers of differentially expressed transcripts between each treatment group and control increased with diuron dose. Based on similar histology and gene expression responses, the treatment groups were regrouped into a high-dose (1250 and 2500 ppm) and low-dose group (60 and 125 ppm). These data suggest that persistent exposure to high dietary concentrations of diuron induces oxidative stress, increases cellular metabolism, and enhances cell death that is associated with sustained urothelial hyperplasia. PMID- 21551505 TI - In patients with early inflammatory polyarthritis, ACPA positivity, younger age and inefficacy of the first non-biological DMARD are predictors for receiving biological therapy: results from the Norfolk Arthritis Register. AB - OBJECTIVES: To identify baseline disease-related predictors in patients with early inflammatory polyarthritis (IP) for starting subsequent biological therapy and to determine if patients who failed their first non-biological disease modifying antirheumatic drug (DMARD) within 6 months were more likely to need biological therapy. METHODS: Patients with early IP recruited between 1990 and 1994 (cohort 1) and between 2000 and 2004 (cohort 2) in the Norfolk Arthritis Register were included in this study. The association between possible predictors with the start of biological therapy was assessed using Cox proportional hazards regression models. RESULTS: 32/407 (7.9%) patients in cohort 1 and 45/416 (10.8%) patients in cohort 2 received biological therapy during follow-up. In both cohorts, anti-citrullinated protein antibody (ACPA) positivity (cohort 1, HR 7.62, 95% CI 2.46 to 23.58; cohort 2, HR 4.68, 95% CI 2.23 to 9.78) was the strongest predictor for starting biological therapy. In cohort 2, younger patients (HR 0.97, 95% CI 0.95 to 0.99) and patients who failed their first non biological DMARD within 6 months due to inefficacy were also more likely to receive biological therapy (HR 2.35, 95% CI 1.05 to 5.27). CONCLUSION: Patients with early IP who are ACPA positive, are younger or who fail their first non biological DMARD due to inefficacy within 6 months are more likely to need biological therapy. PMID- 21551504 TI - Correct interpretation of comprehensive phosphorylation dynamics requires normalization by protein expression changes. AB - The interpretation of quantitative phosphoproteomics studies is complicated because each differential phosphorylation event integrates both changes in protein expression and phosphorylation. Here we investigated this phenomenon by performing parallel comparisons of protein expression and phosphorylation in S. cerevisiae. In each of two experiments comparing yeast mutants bearing deletions in FUS3 or STE7 with their wild-type counterparts, we quantified over 4100 proteins, including all members of the yeast mating pathway. We also identified 12,499 unique phosphorylation sites in this work. We demonstrate the critical importance of controlling the protein-level false-discovery rate and provide a novel method to assess the accuracy of protein false-discovery rate estimates. For the first time, 96% of nonredundant phosphopeptide ratios could be calibrated by protein levels, allowing truly differential phosphorylation to be distinguished from altered protein expression. This revealed a starkly different view, with 25% of seemingly differential phosphopeptides now attributed to changes in protein expression. Combined protein expression and phosphorylation surveys uncovered both independent and concerted changes in protein expression and phosphorylation, while highlighting the partially redundant role of a second MAPK (Kss1) in the mating pathway. PMID- 21551506 TI - Risk factors predictive of joint replacement in a 2-year multicentre clinical trial in knee osteoarthritis using MRI: results from over 6 years of observation. AB - OBJECTIVE: To identify predictive factors for total knee replacement (TKR) using data from MRI of knee osteoarthritis patients in a phase III multicentre disease modifying osteoarthritis drug (DMOAD) study. METHODS: Knee osteoarthritis patients from a 2-year clinical trial evaluating licofelone versus naproxen were investigated for the incidence of TKR of the study knee. Patients (n=161) who completed the study according to protocol were selected. Incidence of TKR was assessed blindly to the treatment following telephone interviews (n=123). RESULTS: 18 TKR (14.6%) were performed in 4-7 years following enrolment in the original study. More TKR were performed within the naproxen than the licofelone group (61% vs 39%, p=0.232). Baseline score of bone marrow lesions (BML) in the medial compartment (p=0.0001), medial joint space width (JSW) as assessed by standardised radiographs (p=0.0008), presence of severe medial meniscal tear (p=0.004), medial meniscal extrusion (p=0.013), and C-reactive protein level (p=0.049) were strong predictors of TKR. Changes at the end of the study also yielded strong predictors: change in cartilage volume of the medial compartment (p=0.005) and of the global knee (p=0.034), reduction in the JSW of greater than 7% (p=0.009), and WOMAC pain (p=0.009) and function (p=0.023) scores. Multivariate analysis showed that baseline severe medial meniscal tear (p=0.023) and presence of medial BML (p=0.025) were the strongest independent long-term predictors of TKR. CONCLUSION: This study shows that in the context of osteoarthritis trials, clinical data and structural changes identified by MRI allow prediction of a 'hard' outcome such as TKR. The findings support the usefulness and predictive value of MRI in defining study outcome in DMOAD trials. PMID- 21551508 TI - Simplified versions of the original disease activity score: validation in the BeSt trial. AB - OBJECTIVE: To evaluate three disease activity score (DAS) alternatives without the Ritchie articular index (RAI). To compare the use of patient global assessment (PGA) of disease activity versus global assessment of health (GH) in DAS, DAS alternatives and DAS28. METHODS: Data from the BeSt study were used, a treatment strategy trial in early rheumatoid arthritis patients aiming at a DAS <=2.4. DAS alternatives were DAS 0-1, with the RAI (0-3) reduced to a no-yes (0 1) score, DAS tender joint count 53 (DAS TJC53), with a 0-1 TJC in 53 separate joints and DAS TJC44 in 44 joints. Correlation patterns, mean difference from original DAS, classification differences in disease activity level and patient percentages with radiological damage progression per level were determined for all scores. RESULTS: In the majority of patients the scores were equal and correlation was high. Mean difference with the DAS at year 1 was -0.03 for DAS 0 1, 0.18 for DAS TJC53 and 0.11 for DAS TJC44. Classification agreement between scores was high (kappa year 1 0.76-0.98). Patient percentages with joint damage progression were similar for all scores. DAS, DAS alternative and DAS28 perform similarly using either PGA or GH. CONCLUSION: DAS without the RAI perform comparably to the original DAS and may be chosen as alternatives. PGA can replace GH in the DAS, the alternatives and DAS28. PMID- 21551507 TI - Relationship between active inflammatory lesions in the spine and sacroiliac joints and new development of chronic lesions on whole-body MRI in early axial spondyloarthritis: results of the ESTHER trial at week 48. AB - AIM: To investigate the relationship between active inflammatory lesions on whole body MRI (wb-MRI) and new development of chronic lesions on T1 MRI in patients with early axial spondyloarthritis (SpA) treated either with etanercept (ETA) or sulfasalazine (SSZ). METHODS: Wb-MRIs of 65 patients treated either with ETA (n=35) or SSZ (n=30) over 1 year were scored for active inflammation, fatty lesions, erosions and ankylosis in the 23 vertebral units (VUs) of the spine and in the sacroiliac joints (SI joints). Scoring was performed by two blinded radiologists. RESULTS: If there was no previous inflammation in the bone no new fatty lesions occurred in SI joint quadrants and only a few (0.6%) in spine VUs. There was a significant relationship between disappearance of inflammation and the appearance of fatty lesions: if baseline inflammation resolved fatty lesions occurred in 10.5% of SI joint quadrants and 17.9% of VUs. If inflammation did not resolve over 1 year, fatty lesions occurred less frequently: 2.4% (SI joint quadrants) and 7.2% (VUs). There was a significantly higher increase of the mean fatty lesion score between baseline and week 48 in the ETA (4.0 vs 4.8 for the SI joints and 1.9 vs 2.7 for the spine) compared to the SSZ (3.0 vs 3.2 for the SI joints and 1.1 vs 1.2 for the spine, respectively) group (p=0.001 and p=0.020 for the differences). No significant changes in the erosion or ankylosis score were observed in any of the two groups during this time. CONCLUSIONS: These data indicate that there is a close interaction between inflammation, tumour necrosis factor blockade and the development of fatty lesions in subchondral bone marrow of patients with axial SpA. PMID- 21551509 TI - Impact of IL-6 receptor inhibition on human memory B cells in vivo: impaired somatic hypermutation in preswitch memory B cells and modulation of mutational targeting in memory B cells. AB - OBJECTIVE: Interleukin 6 (IL-6) receptor (IL-6R) inhibition by tocilizumab is a novel anti-inflammatory therapy for rheumatoid arthritis (RA) patients. As IL-6 is a late differentiation factor of B cells the authors asked if IL-6R inhibition impacts on the mutational differentiation of human memory B-cell antigen receptors in vivo. METHODS: 1733 immunoglobulin receptors (IgR) of single cell sorted preswitch and postswitch memory B cells were prospectively analysed from 11 RA patients under IL-6R inhibition (7 patients) or tumour necrosis factor (TNF) inhibition (4 patients). RESULTS: The results show a reduced mutational frequency in IgR of preswitch memory B cells (p=0.0001) during week 12, week 24 and 1 year of tocilizumab therapy. Mutational hotspot RGYW/WRCY motifs indicated significantly decreased targeting (p<0.05) in preswitch and postswitch memory B cells. Anti-TNFalpha therapy had no effect on mutational frequency and mutational hotspot targeting motifs in memory B-cell subsets. CONCLUSIONS: These data suggest that preswitch and postswitch memory B cells are susceptible to IL-6R inhibition in vivo. Acquisition of mutations was substantially altered in preswitch memory B cells, while targeting of mutational hotspots affected preswitch and postswitch memory B cells. The results indicate that preswitch and postswitch memory B cells have a differential dependence on the IL-6/IL-6R system for differentiation, which can be influenced by tocilizumab in vivo. PMID- 21551510 TI - The effects of doxycycline on reducing symptoms in knee osteoarthritis: results from a triple-blinded randomised controlled trial. AB - OBJECTIVES: Evidence suggests that doxycycline might have disease-modifying properties in osteoarthritis. However, the clinically relevant question as to whether doxycycline also modifies symptoms in knee osteoarthritis is unanswered. The objective of this study was to investigate the effectiveness of doxycycline on pain and daily functioning in symptomatic knee osteoarthritis. METHODS: A 24 week, randomised, triple-blind, placebo controlled trial on the symptomatic effectiveness of doxycycline twice a day 100 mg in knee osteoarthritis patients according to the clinical and radiological American College of Rheumatology classification criteria. The primary endpoint was the difference in the proportion of participants in both study groups achieving a clinical response defined by the OMERACT-OARSI set of responder criteria. Secondary endpoints included pain, stiffness, daily functioning, patient global assessment, quality of life, osteoarthritis-related medication and side effects. RESULTS: 232 patients were randomly assigned. At study end, 31% of participants met the primary endpoint in both groups. Except for more adverse events in the doxycycline group, no differences were also found on the secondary endpoints. CONCLUSIONS: Doxycycline is not effective in reducing symptoms in knee osteoarthritis patients over a 24-week study period, but is associated with an increased risk of adverse events. Although a possible structure-modifying effect of doxycycline was previously suggested, this is not accompanied by symptom relief in the short and medium term. Dutch Trial Register no NTR1111. PMID- 21551511 TI - ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFalpha inhibitors. AB - OBJECTIVES: To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFalpha) inhibitor therapy. METHODS: ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFalpha inhibitor therapy. RESULTS: Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP 3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/high differences in responsiveness for major versus no/clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. CONCLUSION: Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFalpha therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. ClinicalTrials.gov identifier NCT00133315. PMID- 21551512 TI - Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry. AB - OBJECTIVES: To describe drug survival, disease activity and clinical response in patients with rheumatoid arthritis (RA) treated with abatacept or tocilizumab in routine care, based on prospectively registered observational data from the nationwide Danish DANBIO registry. METHODS: 150 Patients with RA treated with abatacept and 178 treated with tocilizumab were identified. Drug survival was investigated. Response data were available in 104 and 97 patients, respectively. Changes in 28-joint Disease Activity Score (DAS28) based on C-reactive protein (CRP) and European League Against Rheumatism (EULAR) response after 24 and 48 weeks were investigated. No direct comparison of drugs was made. RESULTS: Median (IQR) disease duration was 8.5 (3-14)/9 (3-12) years (abatacept/tocilizumab). 95%/93% of patients had previously received one or more tumour necrosis factor inhibitor (TNFi). After 48 weeks, 54%/64% of patients (abatacept/tocilizumab) maintained treatment. Among patients with available response data, DAS28 was 5.3 (4.7-6.1), 3.4 (2.7-4.9) and 3.3 (2.5-4.3) at baseline, weeks 24 and 48, respectively, in the abatacept group and 5.4 (4.7-6.2), 2.9 (2.3-4.0) and 2.5 (1.9-4.5) in the tocilizumab group. At weeks 24 and 48, the remission rates for abatacept/tocilizumab were 19%/39% and 26%/58%, respectively. EULAR good-or moderate response rates were 70%/88% and 77%/84%, respectively. The decline in DAS28 variables over time appeared similar between drugs, except for CRP, which seemed to decline more rapidly among tocilizumab-treated patients. CONCLUSIONS: In patients with RA (>=90% TNFi failures), a good-or-moderate EULAR response was achieved in >=70% of patients treated with abatacept or tocilizumab for 24 weeks in routine care. Apparent declines in DAS28 variables over time were similar between drugs, except for the more rapid CRP decline among tocilizumab-treated patients, directly caused by interleukin 6 inhibition. PMID- 21551513 TI - Early decline and late restoration of spinal cord binding and transganglionic transport of isolectin B4 from Griffonia simplicifolia I after peripheral nerve transection or crush. AB - Isolectin B4 from Griffonia simplicifolia I (B4) has a high binding affinity to a large population of unmyelinated primary sensory neurons (Wang et al., Neuroscience 62 (1994) 539-551). Using immunohistochemical techniques, binding and transganglionic transport of B4 in the spinal cord was investigated, both at short and long survival times, after sciatic nerve transection and ligation or crush in the adult rat. Nerve transection and ligation resulted in nearly complete disappearance of B4 immunolabelling in the sciatic nerve territory of the superficial dorsal horn after B4 binding, as well as after transganglionic transport of B4 by 2 weeks postinjury. Partial recovery of both B4 binding and B4 transport was found by 8 months, and nearly complete recovery by 16 months, indicating that reappearance of B4 binding is not critically dependent on peripheral reinnervation. Crush injury made by jeweller's forceps resulted in partial depletion of binding and transport by 2 weeks and a nearly complete recovery by 10 weeks. The results show that binding and transganglionic transport of B4 can be used to label dorsal horn connections of unmyelinated primary afferents during the process of regeneration after crush injury. Furthermore, as B4 binding and transport recover at long survival times in the absence of reestablished peripheral connections, the same techniques can be used to study central primary afferent connections at long survival times after nerve transection. Binding and transganglionic transport of B4 offer alternatives to the use of previous techniques such as transganglionic transport of wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP) to study central connections of fine primary afferents after injury. PMID- 21551514 TI - Neurochemical and behavioral recovery after colchicine lesions of the nucleus basalis magnocellularis in rats. AB - Experimentally-induced lesions of the basal forebrain have been used to test the hypothesis that the cholinergic system plays a critical role in learning and memory. In the present study, a basal forebrain infusion of colchicine, a microtubule assembly inhibitor, was used to characterize the relationship between a cholinergic marker and behavioral function. Bilateral infusions were made in the nucleus basalis magnocellularis (NBM) of male Long-Evans rats. At 4 weeks post-lesion, behavioral assessments were made on half of the rats in each group. These rats were sacrificed 1 week later and regional choline acetyltransferase (ChAT) activity was measured. The remaining rats were behaviorally tested 11 weeks post-lesion and sacrificed 12 weeks post-lesion. The brains of additional rats were studied for Nissl-staining, ChAT-, GAD- and metEnk immunoreactivity (IR) and AChE histochemistry. At 5 weeks after colchicine infusion, there was a significant decrease in parietal and frontal cortical ChAT activity, impaired acquisition of a water maze spatial navigation task and decreased passive avoidance cross-over latency. At 12 weeks after colchicine infusion, ChAT activity was decreased in frontal but not parietal cortex; acquisition of the water maze task was not significantly different from vehicle-infused rats, and a significant deficit was observed in passive avoidance latency. ChAT-IR in the NBM showed a significant decrease at both time points, while changes in AChE-stained cortical fibers paralleled the ChAT activity. GAD- and metEnk-IR were decreased but were not different between the two time points. These data show task-specific behavioral recovery associated in time with recovery of regional cholinergic markers. PMID- 21551515 TI - The dose-related effect of monoclonal antibodies against adhesion molecules ICAM 1 and LFA-1 on peripheral nerve allograft rejection in a rat model. AB - Donor-specific immunosuppression using anti-intercellular adhesion molecule-1 (ICAM-1) and anti-lymphocyte function-associated antigen-1 (LFA-1) has been shown to inhibit nerve allograft rejection without side effects. This dose-response study evaluated several dosing regimens using a 2-week course of three monoclonal antibodies (mAbs) against ICAM-1 and LFA-1 in combination on peripheral nerve allograft rejection in a rat model. Assessments of regeneration included walking track, electrophysiological, and histomorphologic analyses. Donor (ACI)-specific tolerance induction was assessed. Toxicity and mAb serum levels were monitored. At 18 weeks post engraftment, intermediate and high-dose groups were histologically indistinguishable from isograft controls, and superior to the untreated allograft group which demonstrated a significantly lower percent nerve tissue than all other groups. There were no differences in print length factor after 12 weeks or conduction velocity at sacrifice between any groups. Tolerance induction was not demonstrated. During mAb administration, animals in higher dose groups experienced temporary systemic side effects. This study demonstrated that a short course of mAb therapy directed against ICAM-1/LFA-1 inhibits rejection in rat peripheral nerve allografts by an unknown mechanism. The use of immune modulation in nerve transplantation may eliminate the need for systemic immunosuppression. PMID- 21551516 TI - Basic FGF partially prevents degeneration of paraventricular vasopressin neurons after hypophysectomy. AB - This experiment was designed to determine if basic fibroblast growth factor (bFGF) had neurotrophic effects on vasopressin neurons after hypophysectomy. Adult male Sprague-Dawley rats received 1 MUg bFGF (bFGF group) or 0.1% bovine serum albumin (BSA group) to the sellar cavity immediately after hypophysectomy via parapharyngeal approach. Seven sham-operated non-hypophysectomized rats were used as control. Later (7 weeks) the number of arginine vasopressin (AVP) neurons was quantitatively examined in the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) by immunohistochemistry. AVP neurons in both the PVN and SON of the hypophysectomy groups exhibited a significant reduction in number, compared with the control group. In the PVN, the number of AVP neurons was significantly greater in the FGF group than in the BSA group. Particularly, the difference was confirmed in the posterior magnocellular division, that consists of AVP neurons mainly projecting their axons to the posterior pituitary. In the SON, however, there was no difference in the number of AVP neurons between the bFGF group and BSA group. These results suggest that bFGF has a preserving effect on AVP neurons in the PVN following hypophysectomy. PMID- 21551517 TI - Abstracts of the 11th annual meeting of the Japanese society for neural growth, regeneration and transplantation. PMID- 21551518 TI - Corrigendum to "Expression of the proto-oncogene bcl-2 is increased in the rat brain following kainate-induced seizures" [Restor. Neurol. Neurosci. 9 (1996) 243]. PMID- 21551519 TI - Histologic assessment of sciatic nerve regeneration following resection and graft or tube repair in the mouse. AB - The present study determines the number and morphology of myelinated fibers that regenerate after resection of the mouse sciatic nerve. In different groups of mice, a resection of 4 or 6 mm of the sciatic nerve was left unrepaired, repaired with silicone or collagen guides or by an autologous nerve graft of the same or smaller calibre. Regeneration was examined, under light microscopy, 3 months after operation and quantified by morphometric analysis of light micrographs of cross-sectional nerve fibers. The results show that, without repair, few nerve fibers reach the distal nerve stump, while tubulization or autografts allowed better regeneration. Tube repair allowed a comparable degree of regeneration to that of an autograft with 4 mm gaps, but lower with 6 mm gaps. Regeneration was limited with a gap of 6 mm in silicone tubes, but was successful in half the mice with collagen tubes. The size and myelination of regenerated fibers were below normal values in all experimental groups, although they were closer to normal with sciatic autografts than after smaller grafts and tubulization. There were no signs of secondary degeneration in the nerve regenerates within silicone and collagen tubes. (c) 1996 Elsevier Science Ireland Ltd. All rights reserved. PMID- 21551520 TI - Transcutaneous electrical stimulation of the neck muscles and hemineglect rehabilitation. AB - In four patients with left visuo-spatial hemineglect and right brain- damage, the therapeutic effects of Transcutaneous Electrical Nervous Stimulation (TENS) of the left neck muscles, associated with a non-specific treatment, and of a specific rehabilitation paradigm were investigated. The two treatments were given for an 8-week period each. TENS had positive effects on hemineglect in two out of four patients, whereas the specific treatment produced a major improvement of the disorder in all four cases. The suggestion is made that an effective treatment of neglect requires a paradigm comprising a range of visuo-spatial exploratory tasks of increasing complexity and a systematic feedback as to the success of the patients' performance. This is the case of the specific treatment. By contrast a procedure confined to a sensory stimulation, which produces a short-term improvement in the range of minutes, does not have comparable long-term effects. (c) 1996 Elsevier Science Ireland Ltd. All rights reserved. PMID- 21551521 TI - Axonal regeneration by chronically injured supraspinal neurons can be enhanced by exposure to insulin-like growth factor, basic fibroblast growth factor or transforming growth factor beta. AB - To test whether known growth factors could promote the regenerative reponse of chronically injured neurons, we exposed the injured adult rat spinal cord to insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF) or transforming growth factor beta 1 + 2 (TGFbetas) 1 month after creation of a hemisection lesion. At 1 week later an autologous peripheral nerve graft was apposed to the rostral cavity wall and 1 month later Nuclear Yellow (NY) was used to retrogradely label neurons that had grown an axon into the graft. Neurons capable of axonal regeneration after a long term (5 weeks) injury were double labeled with True Blue (TB, provided at the time of hemisection lesion) and NY. Exposure to any of the three growth factors, compared to a PBS-treated control, resulted in a significant increase in the total number of regenerating supraspinal neurons, with the greatest increase after treatment with TGFbetas. Treatment with TGFbetas or bFGF led to a significant increase in the number of regenerating neurons in 6 out of 7 major regions (excluding the motor cortex) contributing to descending spinal pathways. Treatment with IGF-1 promoted significant regeneration only by reticular formation neurons. These results indicate that exposure to specific growth factors can enhance axonal regeneration by chronically injured neurons, thus overcoming one significant challenge to the repair of long standing structural damage to the spinal cord. (c) 1996 Elsevier Science Ireland Ltd. All rights reserved. PMID- 21551522 TI - Abstracts selected from Excerpta Medica's EMBASE. PMID- 21551523 TI - Extract of Ginkgo biloba (EGb 761) improves behavioral performance and reduces histopathology after cortical contusion in the rat. AB - Male rats received bilateral frontal cortex contusions and were injected with 100 mg/kg of EGb 761 or an equal volume of vehicle beginning 5 min after injury and then with 1 injection/day for 7 days. The rats were tested for spontaneous motor behavior on days 1, 5, 10, and 15 postinjury and then for 10 days of spatial navigation performance in the Morris Water Maze (MWM), beginning on the day 8 after the contusion. Brain tissue was removed for examination on the 18th day after injury. Contused rats given EGb 761 performed more like intact rats on measures of spontaneous motor activity while vehicle-treated counterparts remained more active than either shams or EGb 761-treated animals by the conclusion of testing. Contusion-only rats were worse than shams on spatial performance, while those given EGb 761 were less impaired. Histological analyses indicated that EGb 761 failed to prevent loss of tissue at the primary site of impact. However, the extract reduced retrograde degeneration of neurons, gliosis in the thalamus, and ex vacuo hydrocephalus. EGb 761 treatment also decreased the loss of ChAT-positive neurons in the dorsomedial caudate-putamen and in the nucleus basalis magnocellularis (NBM). The results of this study indicate that EGb 761 could be a possible treatment for traumatic brain injury. PMID- 21551524 TI - Intrastriatal grafts of fetal ventral mesencephalic tissue restore quantitative and qualitative D1/D2 dopamine receptor synergism in the striatum. AB - Grafts of fetal ventral mesencephalic (VM) tissue into the striatum of unilaterally 6-hydroxydopamine lesioned rats reduce many of the behavioural and neural changes associated with the lesion. In this report, the ability of such grafts to restore the qualitative and quantitative synergistic relationship between Dl-like and D2-like receptors in the striatum was investigated. In animals with a unilateral 6-hydroxydopamine lesion of the nigrostriatal bundle, there was a loss of qualitative and quantitative DA receptor coupling in the striatum, consistent with previous reports. Intrastriatal fetal VM grafts restored both qualitative and quantitative DA receptor synergism to the same level as was observed in the intact striatum. Thus, the ability of intrastriatal grafts to ameliorate some behavioural deficits observed after unilateral lesion may be due to the recoupling of DA D1/D2 synergisms within the striatum. PMID- 21551525 TI - Intraventricular encapsulated calf adrenal chromaffin cells: viable for at least 500 days in vivo without detectable adverse effects on behavioral/cognitive function or host immune sensitization in rats. AB - Numerous studies have reported that adrenal chromaffin cell transplants, including encapsulated xenogeneic adrenal chromaffin cells, have analgesic effects. However, in addition to efficacy, the clinical utility of encapsulated xenogeneic adrenal chromaffin cells for treatment of chronic pain is dependent on the duration of cell viability in vivo, and their relative safety. The objectives of the present study in rats were to: (1) examine encapsulated calf adrenal chromaffin (CAC) cells for evidence of viable cells and continued release of analgesic agents after an extended period in vivo; (2) determine if intraventricular encapsulated CAC cells produce detectable adverse effects on behavioral/cognitive function; and (3) test for evidence of host immune sensitization after an extended period of exposure to encapsulated xenogeneic adrenal chromaffin cells. Results of the present study suggest that some encapsulated CAC cells remain viable for nearly 1.5 years in vivo and continue to produce catecholamines and met-enkephalin. Post-explant device norepinephrine output was equivalent to amounts previously shown to produce analgesic effects with intrathecal implants. Encapsulated adrenal chromaffin cells also appeared relatively safe, even when implanted in the cerebral ventricals, with a lower side-effect profile than systemic morphine (4 mg/kg). There was no evidence that encapsulated CAC-cells implanted in the ventricles affected body weight, spontaneous activity levels, or performance in the delayed matching to position operant task which is sensitive to deficits in learning, memory, attention, motivation, and motor function. Finally, encapsulated CAC cells produced no detectable evidence of host immune sensitization after 16.7 months in vivo, although unencapsulated CAC cells produced a robust immune response even in aged rats. The results of the present study suggest that adrenal chromaffin cells remain viable in vivo for long periods of time, and that long-term exposure to encapsulated xenogeneic adrenal chromaffin cell implants appears relatively safe. PMID- 21551526 TI - Reinnervation of rat muscles via volkensin-affected and normal peripheral nerve conduits. AB - Volkensin is a neurotoxic lectin which, when injected into a peripheral nerve is retrogradely transported to the cell body and causes it to die. Accordingly, volkensin-affected peripheral nerves rapidly degenerate. It is, however, not clear whether axonal growth can take place within these degenerated nerves. In this study the ability of volkensin-treated and untreated degenerated peripheral nerves to support regeneration of healthy axons was compared. Four groups of animals were used, in Group 1 the peroneal nerve was cut and 10 days later the proximal stump of the deep tibial nerve was sutured to the distal stump of the peroneal nerve (10 days after axotomy). In the second group of animals the peroneal nerve was treated with volkensin, 10 days later the proximal stump of the deep tibial nerve was connected to the distal section of the cut, thus giving a volkensin-treated peroneal nerve. In the third group, 10 days after the peroneal nerve was treated with volkensin, the proximal stump of the deep tibial nerve was connected directly to the extensor digitorum longus (EDL) muscle. In Group 4 the volkensin-treated peroneal nerve was left intact. Six weeks after surgical intervention the tension of both EDL muscles was recorded and the muscles were processed for histological visualisation of endplates and axons. EDL muscles from Group 1 animals produced 36.5 +/- 11.3% S.E.M of maximal tetanic tension produced by the contralateral EDL muscle. Significantly less recovery of function was achieved by EDL muscles in Group 2 animals (9.3 +/- 2.5%). Muscles from Group 3, where the healthy nerve was sutured directly into the EDL muscle that had been denervated by volkensin treatment had a significantly better recovery than Group 2 muscles (23 +/- 3%). Sprouting of nerve fibres and proliferation of Schwann cells was observed in the muscles from Groups 1 and 3, but not in Group 2. Thus, volkensin-treated peripheral nerves provide a poor conduit for regenerating nerve fibres though muscles denervated, by treatment with volkensin, and can accept reinnervation by healthy nerves. The possible mechanisms that render the volkensin treated peripheral stump a poor conduit for healthy axons is discussed. PMID- 21551527 TI - Expression of choline acetyltransferase within spinal motoneurons following brachial plexus avulsion. AB - Avulsion of the brachial plexus is considered the most severe injury of the peripheral nerve. The present study provides a description of the response of ChAT within the ventral horn of the rat cervical spinal cord following avulsion of the brachial plexus. The result demonstrates that the intensity of immunoreactivity of ChAT positive neurons and neuropil background increases in the first 3 days following avulsion and then decreases. The number of ChAT positive motorneurons in the ventral horn in the lesion side is 84.4% compared to the normal side during the first 3 days post-avulsion, at 7 days the number of ventral horn neurons drops to 64.4% and at 21 days post-avulsion it becomes 44.1%. In the sixth week post-avulsion, only 24.8% of the ventral horn neurons still persist. PMID- 21551528 TI - Effects of bilateral and unilateral locus coeruleus lesions on beam-walking recovery after subsequent unilateral sensorimotor cortex suction-ablation in the rat. AB - The recovery of beam-walking ability following a unilateral sensorimotor cortex lesion in the rat is hypothesized to be noradrenergically-mediated. We carried out two experiments to further test this hypothesis. In the first experiment, bilateral 6-hydroxydopamine locus coeruleus (LC) lesions or sham LC lesions were made 2 weeks prior to a right sensorimotor cortex suction-ablation lesion or sham cortex lesion. In the second experiment, unilateral left or right LC lesions or sham LC lesions were made 2 weeks prior to a right sensorimotor cortex lesion or sham cortex lesion. Beam-walking recovery was measured over the 12 days following cortex lesioning in each experiment. Bilateral, unilateral left, and unilateral right LC lesions resulted in impaired recovery. These data provide additional support for the hypothesis that beam-walking recovery after sensorimotor cortex injury is, at least in part, noradrenergically mediated. PMID- 21551529 TI - Resorbable filament structures as a scaffold for matrix formation and axonal growth in bioartificial nerve grafts: long term observations. AB - Gaps, 10 mm wide, in rat sciatic nerves were bridged by bioartificial nerve grafts consisting of a silicone tube containing seven longitudinally placed synthetic filaments, which were expected to serve as a scaffold for axonal growth. The filaments were made of non-resorbable material (polyamide [Ethilon(r)]) or resorbable material (polydioxanon [PDS(r)], polyglactin [Vicryl(r)] or catgut). The purpose was to study the influence of resorbable materials on axonal regeneration and to choose, in the long term, the best filament material among the four. After 3 and 6 months, histological techniques were used to study the regenerated nerve structure. The total axon number in the nerve segment distal to the silicone chamber was counted in all specimens at 6 months. The histological findings were different depending on the filament materials; all the three resorbable materials showing significantly larger numbers of axons than polyamide (non-resorbable). All materials were covered with several layers of more or less flattened cells. These results indicate that resorbable filaments are superior to non-resorbable filaments when used as a scaffold inside a silicone tube, and polyglactin seems ideal for this purpose. PMID- 21551530 TI - Non-competitive NMDA antagonists and anti-oxidant drugs reduce striatal atrophy and facilitate recovery of function following lesions of the rat cortex. AB - Following brain injury there is an excessive release of glutamate, a reduction in levels of cellular Mg+ +, and the generation of oxygen free radicals. These processes may contribute to the severity of the behavioral impairments seen following brain injury by leading to secondary neuronal degeneration. The present experiment investigates the relative effects of three drugs (MK-801, an NMDA antagonist; magnesium chloride, an NMDA antagonist; and N-tert-butyl-alpha phenylnitrone (PBN), an anti-oxidant and free radical scavenger) which disrupt different aspects of the pathophysiological process, in reducing these impairments. Direct comparisons of these drugs may determine if one treatment is more effective than another, or if one is detrimental. In addition, the effects of combination treatments including PBN and MK-801 or MgCl2 were examined. These combination treatment were aimed at the possibility of potentiating the beneficial effects observed after administration of these agents alone. Rats received unilateral electrolytic lesions of the somatic sensorimotor cortex followed by a regimen of MK-801 (1 mg/kg), MgCl2 (1 mmol/kg), PBN (100 mg/kg), MK 801 + PBN (1 mg/kg, 100 mg/kg), MgCl2 + PBN (1 mmol/kg, 100 mg/kg), or saline (1 ml/kg) beginning 15 min following injury. Rats were tested on several sensorimotor tasks (i.e. forelimb placing and foot-fault) for 43 days following the cortical lesions. Rats receiving any of the single or combination drug treatments showed a significant facilitation of recovery on the sensorimotor tasks compared to saline control rats. On one behavioral test (i.e. foot-fault) there was a significant further enhancement of the recovery by combination treatments compared to the single treatment groups. These data are consistent with the idea that excessive release of glutamate, reduction in Mg+ + levels, and free radical generation contribute to the severity of the behavioral impairments following cortical injury, and that arresting these processes results in a facilitation of behavioral recovery. Anatomical analysis showed that all drug treatments decreased the amount of atrophy seen in the ipsilateral striatum. PMID- 21551531 TI - Vitamin E attenuates the effects of both reversible and irreversible inhibitors of high-affinity choline transport in vivo. AB - High-affinity choline transport (HAChT) is the rate limiting step in the synthesis of acetylcholine (ACh). The activity of HAChT and the binding of its selective inhibitor, [3H]hemicholinium-3 (HC-3) are affected by a number of exogenous and endogenous factors. Previous experiments demonstrated that Vitamin E pretreatment could prevent the decrease in HAChT and the cognitive deficits induced by the cholinotoxin AF64A [38]. To further examine this effect these experiments determined whether Vitamin E would alter the efficacy of both irreversible (AF64A) and reversible (HC-3) inhibitors of HAChT. In Experiment 1, rats were pretreated with Vitamin E (50 mg/kg), 24 h and 15 min, prior to bilateral icv injection of AF64A (0, 0.75, 1.5, or 3.0 nmol). HAChT was assessed in hippocampal synaptosomes, 14 days following surgery. Vitamin E prevented the dose-dependent AF64A-induced inhibition of HAChT in the hippocampus (HPC). In a second experiment, rats were pretreated with Vitamin E as above, and infused (icv) with the reversible inhibitor of HAChT, HC-3 (20 MUg), or CSF. HAChT in the HPC was assessed 30 min, 4, 12, or 24 h after injection. HC-3 produced a significant decrease of HAChT (58%) that was maximal at 4 h and recovered by 24 h. Vitamin E significantly attenuated, but did not prevent, the inhibition of HAChT produced by HC-3. These experiments demonstrate that Vitamin E pretreatment can attenuate the effects of both reversible and irreversible inhibitors of HAChT. These data are discussed in terms of potential underlying mechanisms. It is possible that the neuroprotectant effects of Vitamin E on both reversible and irreversible inhibitors of HAChT reflect an action at the choline carrier and not an antioxidant effect. PMID- 21551532 TI - Development of pyramidal cells in medial frontal cortex following neonatal lesions of anterior midline cortex. AB - The anterior midline cortex of rats was removed on postnatal day 10. The development of layer II, III and V pyramidal cells in the tissue that subsequently formed the presumptive medial frontal cortex in these animals was studied in Golgi-Cox stained material on postnatal days 15, 25, 35, and 120. The results showed that the number of branch segments of both basilar and apical dendrites were significantly reduced relative to controls at the early developmental stages but by adulthood all regions analyzed were similar in operates and controls. Thus, the cells migrating into the lesion area were delayed in development but did eventually grow to resemble cells that were in the same region in normal controls. This anatomical development correlates with the functional recovery of animals with day 10 frontal lesions in other studies, and suggests that the growth of this tissue may play a role in functional recovery. PMID- 21551533 TI - Specificity of fiber innervation by cholinergic neurons transplanted into the retrosplenial cortex of adult rats as revealed by choline acetyltransferase immunocytochemistry. AB - The retrosplenial cortex (RSC) is a target of the forebrain cholinergic projecting system. It receives extensive cholinergic innervation from the medial septal nucleus and the diagonal band of Broca. These cholinergic afferents travel along the paths of cingulate bundle and fornix. In the present study we investigated the ability of cholinergic fetal septal grafts to reinnervate the deafferented RSC. Four groups of rats were used: (1) normal control rats (NC); (2) rats with bilateral transections of the cingulate bundle (CgX); (3) rats with simultaneous lesions of both the cingulate bundle and the fornix (FX), and (4) rats with intra-retrosplenial fetal septal grafts and lesions in both cingulate bundle and the fornix (RSCsep-TPL). We found that lesions in the cingulate bundle alone produced a modest reduction of cholinergic innervation whereas lesions in both the fornix and cingulate bundle resulted in a complete loss of cholinergic inputs in this area, indicating that both the cingulate bundle and the fornix are involved in mediating cholinergic projections from the septal-diagonal area to the RSC. Transplantation of cholinergic fetal septal neurons into the RSC of animals with simultaneous lesions in both the fornix and cingulate bundle restored the cholinergic innervation pattern to that which is typical of the normal septo-retrosplenial inputs. These results provide the neuroanatomical basis for behavioral studies which have documented graft-mediated recovery of spatial memory function in rats with lesions of the cholinergic septo retrosplenial pathways. PMID- 21551534 TI - Nimodipine-accelerated hypoglossal sprouting prevents the postoperative hyperinnervation of target muscles after hypo glossal-facial anastomosis in the rat. AB - Hypoglossal-facial anastomosis (HFA), used for the treatment of facial palsy, was performed in adult Wistar rats. For 7-224 days post operation (DPO), half of the animals were kept on standard laboratory food and half received food pellets containing 1000 ppm of the Ca2+ channel blocker nimodipine. The postoperative neurotization of facial muscles in these two groups was traced by comparing numbers of all retrogradely labeled neurons after injection of HRP into the whiskerpad muscles. In unoperated animals, injection of HRP labeled 1254 +/- 54 neurons. Immediately after HFA, this number dropped to zero. The treatment with nimodipine yielded two beneficial effects. (1) In the early phase of regeneration (until 28 DPO), it accelerated the sprouting of hypoglossal axons into the facial periphery; (2) In the final phase, it suppressed the axonal sprouting from both, hypoglossal and facial stumps. In this way nimodipine fully prevented the postoperative hyperinnervation, i.e. the projection of more hypoglossal plus facial motoneurons to the whiskerpad muscles than under normal conditions. PMID- 21551535 TI - Editorial: A turning point for Restorative Neurology and Neuroscience. PMID- 21551536 TI - Editorial: New editorial office and publisher. PMID- 21551537 TI - Oxidative stress does not appear to be involved in the aetiology of Friedreich's ataxia. AB - The purpose of this study was to investigate the hypothesis that the gene for Friedreich's ataxia (FA) may be involved in the metabolism of alpha-tocopherol (vitamin E) or in other antioxidant systems. Concentrations of alpha-tocopherol, parameters of endogenous lipid peroxidation and susceptibility to in vitro oxidative stress were measured in neural tissues from four patients with FA and four controls. In general there were no significant differences in any of the parameters studied, although the brainstem whole homogenate from the FA patients was significantly (p < 0.02) less susceptible to in vitro oxidative stress than control material. These results, therefore, do not support the suggestion that abnormal metabolism of alpha-tocopherol or increased oxidative stress is involved in the aetiology of FA. PMID- 21551538 TI - Efferent connections of homotopic and heterotopic transplants of embryonic neocortical tissue placed in the occipital neocortex of newborn rats. AB - We examined (i) the capacity of transplants of embryonic neocortex to restore corticofugal systems disrupted following neonatal damage to the occipital cortex and (ii) the influence of the embryonic origin of the transplanted neurons on the reconstruction of the corticofugal circuitry. Transplants of embryonic occipital or frontal cortex were grafted homo- or heterotopically into the damaged occipital cortex of newborn rats. Several months after grafting, an anterograde tracer was injected into each category of transplants. Homotopic transplants developed a set of projections directed exclusively towards most of the cortical and subcortical visual targets normally contacted by occipital cortical neurons. Heterotopic transplants formed a hybrid system of efferent projections that reflected both their embryonic origin and their new location within the host cortex. These findings are consistent with previous results indicating that fetal frontal and occipital neurons are not interchangeable. Consequently, transplantations aiming at the reconstruction of neural circuits disrupted following neonatal damage affecting a given cortical area should only use fetal cortical cells taken from the same cortical locale. PMID- 21551539 TI - Marked alteration of c-fos and c-jun but not hsp70 messenger RNA expression in rat brain after cold-induced trauma: An in situ hybridization study. AB - Immediate early gene (IEG) mRNA induction by cryogenic injury was examined using an in situ hybridization approach and the results compared with the heat shock protein mRNA expression. Hybridization signals for c-fos and c-jun mRNA were found after 30 min in the ipsilateral cortex, the hippocampal dentate granule cells and the piriform cortex, c-jun mRNA was also detected in the contralateral dentate gyrus and the piriform cortex, but was less extensive. Return to baseline values was observed at the 24 h time point. Peak induction, with silver grains observed mainly over the neurons on emulsion autoradiograms, was demonstrated in all cases 30 min to 1 h post-injury. In contrast, only slight hsp70 mRNA expression by the neurons surrounding the cold-injured site could be detected by microautoradiography, at 6 h following the trauma. The results indicate that cryogenic brain injury induces IEGs in a similar way to mechanical modes of injury such as lateral fluid percussion, but that hsp70 mRNA is hardly expressed, implying the possible existence of differences in stress response pathways. PMID- 21551540 TI - An experimental study of nerve grafting combined with silicone tubes in the rat model: Functional outcome and specificity of muscle reinnervation. AB - Bridging large defects in mixed nerves is still an unsolved problem in reconstructive microsurgery. Two main aspects may be distinguished: one is to obtain an appropriate substitute for the lost neural tissue, the second to direct fibers toward their previous end-organs with the highest possible specificity. In the present study, sural nerve block grafts were combined with enclosed gaps at one or both ends of the grafts. Functional outcome at the muscle level as well as the number of motor axons and their cross-sectional distribution were assessed after 3 months. The presence of a proximally placed tube was found to decrease significantly the maximal tetanic force of the tibialis anterior muscle, whereas a distally placed one tended to improve it. Morphological data from acetylcholinesterase histochemistry correlated poorly with functional results but they gave some clues about possible roles played by the chambers, according to their position relatively to the grafts. No definitive evidence for an improved regeneration by use of silicone tubes in addition to the conventional grafts could be demonstrated. PMID- 21551541 TI - Altered expression of Growth Inhibitory Factor (GIF / MT-III) mRNA in the rat facial nucleus after facial nerve injury is closely related with facial function. AB - Growth inhibitory factor / metallothionein III (GIF / MT-III) is reported to have the unique property of suppressing neuronal survival and neurite promotion in vitro. We investigated changes in the expression of GIF mRNA within the facial nucleus using in situ hybridization as well as changes in the function of the facial nerve after nerve injury. Following crushing injury just distal to the stylomastoid foramen, movement of the ipsilateral whiskers was eliminated but returned by the 7th day. GIF mRNA expression decreased at 3 days after injury and returned in 7 days. However, when the nerve was cut and sutured immediately, it took one month for the facial function to recover. In this case, GIF mRNA expression decreased 3 days after injury, remained at a low level for 14 days, and finally returned in 3-4 weeks. Thus, changes in the expression of GIF mRNA were found to be closely related to the facial nerve function. PMID- 21551542 TI - Tissue culture studies of neural plasticity. AB - Exposure of cerebellar cultures derived from neonatal mice to cytosine arabinoside for the first 5 days in vitro results in destruction of cerebellar granule cells and inhibition of glial maturation. Such cultures undergo reorganizational changes, primary features of which are a sprouting of Purkinje cell recurrent axon collaterals and the formation of recurrent axon collateral Purkinje cell dendritic spine synapses. Such heterotypical synapses are inhibitory, in contrast to the excitatory parallel fiber-Purkinje cell dendritic spine synapses normally present. If locus coeruleus neurons are included with the cerebellar cultures, the catecholaminergic axons also sprout, and tissue levels of catecholamines are increased. Purkinje cell survival is enhanced in Ara C treated cultures, as the target field for Purkinje cell axonal projections is expanded. Oligodendrocyte inhibition results in failure of myelination, and astrocyte inhibition, when it occurs, is associated with a failure of Purkinje cell ensheathment and a hypennnervation of Purkinje cell somata by sprouted recurrent axon collateral terminals. Transplantation of such cultures with granule cells and glia reverses many of these changes. Parallel fiber-Purkinje cell dendritic spine synapses are formed, and most heterotypical synapses disappear. The Purkinje cell population is reduced to normal, and most of the sprouted recurrent axon collaterals are eliminated. However, sprouted catecholaminergic axons are not significantly reduced. Transplanted cultures become myelinated and Purkinje cells acquire astrocytic sheaths, with an associated reduction of axosomatic synapses. Transplantation with glia alone does not reduce the sprouted recurrent axon collaterals, but does result in astrocytic ensheathment of Purkinje cells and an associated decrease of axosomatic synapses. These tissue culture models illustrate some of the plastic changes that the nervous system may undergo following injury and transplantation. PMID- 21551543 TI - Fetal neocortical transplants grafted into cortical lesion cavities made in newborn rats receive multiple host afferents. A retrograde fluorescent tracer analysis. AB - Several reports have demonstrated efferent projections from fetal neocortical transplants placed in the cerebral cortex of newborn rats. Fewer studies have examined transplant afferents, and these have primarily used techniques based on the axonal transport of horseradish peroxidase. In the present study, we extend these initial findings on transplant afferent connections by using retrogradely transported fluorescent dyes to demonstrate a topographic and more extensive pattern of cortical transplant afferents than has been previously reported. Fetal neocortical tissue was grafted into frontal cortical lesion cavities made by aspiration in newborn rats. At 1.5-10 months later, the fluorescent dyes Fast blue and Diamidino yellow were injected into the transplants. Subsequent histological analysis demonstrated numerous retrogradely labeled fluorescent neurons within the host thalamus and cerebral cortex as well as several other areas of the host brain. The neurons were primarily single-labeled and generally found in areas that normally project to the ablated area of the cortex. The topographic distribution of retrograde labeling in several animals with non overlapping dye injections confined to the transplants suggests that the host projections were distributed selectively within the grafts. These results support and extend previous studies suggesting the use of fetal neocortical tissue in repair of the neonatally damaged central nervous system. PMID- 21551544 TI - Expression of growth-associated proteins (GAPs) in injured sensory axons of frogs acclimatized to 15 degrees C and 25 degrees C. AB - Labelled proteins conveyed by fast axonal transport into the sensory axons of frog sciatic nerve following axotomy have been studied by 2D gel electrophoresis. Previous work showed that in frogs acclimatized to 25 degrees C a cell body reaction occurs, along with regeneration of axons to their targets. In contrast, frogs acclimatized to 15 degrees C showed no cell body reaction and though regeneration began, it stalled after approximately 35 days. We found that axotomy at 25 degrees C was followed by an increase in transport of specific labelled proteins corresponding to growth-associated proteins (GAPs) identified in other regenerating systems. Surprisingly, axotomy at 15 degrees C also induced a similar increase, though with a slower onset, so that the highest levels of expression of GAPs occurred during the time when the axons had stalled. We conclude that sensory neurons in 15 degrees C frogs do detect that their axons have been injured, as shown by their ability to increase GAP synthesis. Slow and limited axonal growth is possible during a period when GAP synthesis is low compared to levels in rapidly regenerating nerves, but even when the ability to produce GAPs increases, this alone is not sufficient to sustain regeneration in the absence of other components of the cell body reaction to injury. PMID- 21551545 TI - Rabbit retinal ganglion cells survive optic nerve transection and entubulation repair with type I collagen nerve guide tubes. AB - The major objective of the experiments reported in this paper was to qualitatively test the hypothesis that rabbit retinal ganglion cells survive optic nerve transection and entubulation repair of the proximal optic nerve stump. The optic nerve of rabbits was transected immediately behind the globe, and a 1-cm length of a Type I collagen nerve guide tube was sutured onto the short proximal stump. The nerve guide was either left empty or was filled with a Type I collagen gel (Vitrogen, Collagen Corp.). Following 8-12 weeks survival time, the animals were sacrificed and the retinae were prepared as whole mounts and processed for immunocytochemistry using an antibody which selectively labels the retinal ganglion cells. Although no formal cell counts were carried out, the animals which received Vitrogen within the nerve guide showed a qualitative enhancement of retinal ganglion cell survival compared to the group with the nerve guide alone. The results suggest that specific manipulations of the central nervous system microenvironment may enhance neuronal survival following axonal transection. PMID- 21551546 TI - The effects of 4-aminopyridine on focal nerve conduction block. AB - In order to test whether 4-aminopyridine (4-AP), a potassium channel blocker, may be of therapeutic value in demyelinating neuropathies, a focal tibial nerve conduction block with demyelination was produced in adult rats by an intraneural microinjection of potassium tellurite. Onset and recovery of the lesion were monitored by evoked compound muscle action potentials (CMAP) activated from the proximal and distal nerve one day before and 1, 4, 7, 14, 21 and 28 days after the injection. Intraperitoneal 4-AP (2 mg/kg) or buffered saline were injected prior to the potassium tellurite and 6 days per week for 28 days. The data show that 4-AP is tolerated, it does not prevent conduction block, and only has a modest effect on increasing its recovery from day 4 to 7 (91 % increase in CMAP ratio compared with control of 35%). Recovery is similar by day 28 in 4-AP treated or untreated animals. These results suggest that 4-AP will have limited use in the therapy of subacute demyelinating neuropathies. PMID- 21551547 TI - Rehabilitation training of homonymous visual field defects in patients with postgeniculate damage of the visual system. AB - Training-dependent improvement of visual behavior after postgeniculate damage of the visual system was studied in 10 patients. The patients, all with computer tomographically proven damage and a lesion chronicity of 8 weeks to 4.7 years, were subjected to a special exploration training of at least 10 sessions or 1100 trials. Before and after training, extensive perimetric tests were performed to determine possible training-related visual changes. It was found that the training program improved visual exploration considerably and induced qualitative shifts in exploration strategy even for patients who had failed to adopt these strategies for more than 3 years postlesion. On the other hand, a training-based visual field enlargement was not supported when applying strict criteria. It is concluded that specific and systematic exploration training can be of significant help for improving visuo-spatial behavior in hemianopic patients, but that a reliable visual field enlargement is unlikely to occur in unselected patients trained and examined under standard conditions. PMID- 21551548 TI - Comparison of the synthesis and axonal transport of fucosylated glycoproteins by intact and regenerating sensory neurons in the frog. AB - Peripheral nerve regeneration requires a reorganization of neuronal synthesis and axonal transport to replace the degenerating axon. This study examines the time course, the extent and the molecular components which comprise the observed increases in protein fucosylation and fast axonal transport of fucosylated proteins in regenerating frog peripheral nerves. The in vitro spinal ganglia sciatic nerve preparation used in these experiments allowed comparisons to be made between axotomized and intact neurons from the same animal, incubated in the same [3H]fucose-containing solution, and subjected to the same axonal transport conditions. Thus, we were able to show that the fucosylation of constituent proteins increased in axotomized neurons without an increase in the membrane transport of fucose or neuronal protein synthesis. An increase in the amount of newly fucosylated protein conveyed by fast transport preceded the apparent increase in neuronal synthesis by approximately 3 days. The increase in anterograde transport was initiated just subsequent to a transient increase in retrograde or 'turnaround' transport, suggesting a possible association between the two responses. The protein (distinguished on the basis of molecular weight) undergoing the most pronounced increase in fucosylation in the cell body was different from that in the nerve, but there was no evidence for the production of novel glycoproteins. The data indicate that protein fucosylation increases significantly in regenerating neurons and that an increase in the incorporation of newly fucosylated protein into the fast axonal transport system precedes an increase in synthesis. The increase in transport of fucosylated protein may be one of the earliest responses directed toward the generation of a new axon. PMID- 21551549 TI - Recovery of preoptic-anterior hypothalamic functions after transplantation. AB - Kainic acid lesion of the medial preoptic area resulted in the impairment of the thermoregulation and disruption of the reproductive cycle in female rats. The preoptic-anterior hypothalamic area from fetal donor was transplanted into the lesioned area ofthe host. After transplantation, these animals showed signs of estrus cyclicity and a recovery in basal temperature towards normal. They also showed a reduced shift of body temperature on exposure to a hot environment. Thus the female rats, which received transplantation, showed some degree of recovery of functions which were disrupted by kainic acid lesions. PMID- 21551550 TI - Factors affecting septal graft amelioration of differential reinforcement of low rates (DRL) and activity deficits after fimbria-fornix lesions. AB - Wound-derived trophic factors released by the injured brain are thought to reach a peak 1-2 weeks after injury. It has been proposed that such factors can promote the survival, growth and functional capacity of embryonic tissue grafts. To test the generality of this hypothesis, control rats and rats with aspirative fimbria fornix lesions were compared with 5 groups of rats with lesions and septal grafts implanted either in the same session as the lesion or after delays from 10 days to 9 months. Animals were assessed 3 months post-transplantation on an operant differential reinforcement of low rates (DRL) task and on a test of spontaneous locomotor activity. Lesions produced impairments on all measures of DRL performance. Two graft groups showed amelioration of the DRL deficits, one graft group was unchanged, and the deficits were exacerbated in two others. There was no clear relationship between lesion-graft interval and recovery. An inverse relationship was seen, however, between recovery and the developmental age of the donor tissue. In contrast, significant recovery from lesion-induced hyperactivity was observed in the two graft groups with tissue derived from the oldest embryos. There were no clear relationships between recovery on either test, lesion-graft interval, and AChE-positive reinnervation of the host brain. The results provide further evidence that septal grafts can reverse behavioural deficits induced by fimbria-fornix lesions under some conditions, but suggest that the timing of graft surgery may not be as important a factor as donor age in this model system. PMID- 21551551 TI - Abstract Selection from Excerpta Medica's EMBASE. PMID- 21551552 TI - IIIrd International Symposium On Neural Transplantation from Molecular Bases to Clinical Application. AB - IIIrd International Symposium On Neural Transplantation from Molecular Bases to Clinical Application(6th - 11th August 1989, Cambridge, U.K.)International Organising Committee: A. Aguayo, A. Bjorklund, S.B. Dunnett, WJ. Freed, F.H. Gage, D.M. Gash, S.D. Iversen, R.D. Lund, C.D. Marsden, L. Olson, J. Sladek, C. Sotelo.Local Organising Committee: L.E. Annett, DJ. Clarke, S.B. Dunnett, P.C. Emson, B.J. Everitt, O. Isacson, S.D. Iversen, S.-J. Richards, J.D. Rowell, D.J.S. Sirinathsinghji. PMID- 21551553 TI - Expression and distribution of microtubule proteins in neurites of dorsal root ganglion neurons in culture. AB - The expression and distribution of beta-tubulin gene products and post translationally modified forms of alpha-tubulin in dorsal root ganglion neurons in culture were examined. The neurons in culture rapidly regenerated neurites and expressed multiple beta-tubulin genes (Mbeta2, Mbeta3/4, Mbeta5, Mbeta6). The gene products were present in the neurites and growth cones. Unmodified tyrosinated alpha-tubulin was present in the neurites and growth cones but modified alpha-tubulins (detyrosinated and acetylated) were largely absent from growth cones. The distribution of the alpha-tubulin forms is consistent with assembly of tubulin occurring behind the growth cone after transport of non polymeric subunits. Distal assembly of microtubules would provide a pool of unmodified alpha-tubulin subunits for the assembly of labile microtubules in the growth cone. Subsequent modification behind the advancing growth cone would stabilise the newly formed neurite. PMID- 21551554 TI - Alteration of cytoskeletal organization during axonal elongation and its role in regulating the growth process. AB - The composition and organization of the axonal cytoskeleton vary from neuron to neuron and the ability of a nerve to regenerate may, at least in part, depend on the pre-existing nature of the cytoskeleton. In axons, where the cytoskeletal elements are loosely organized enough material may be mobilized after an injury to allow elongation to proceed. However, if microtubules and neurofilaments interact closely with each other, it may not be possible for enough material to be released from or to migrate through a complex network. As a consequence material is not provided to the growing tip and elongation cannot proceed beyond the initial sprouting. PMID- 21551555 TI - Cytoskeletal protein synthesis and regulation of nerve regeneration in PNS and CNS neurons of the rat. AB - Following injury to the facial nerve, facial motoneurons respond with a rapid suppression of neurofilament synthesis, and an increase in actin and tubulin synthesis. In situ hybridization studies show that these changes are the result of alterations in levels of the corresponding mRNAs. The increased ratio of neurofilament to tubulin expression is also characteristic of developing neurons, and direct evidence for the idea that axon injury provokes a partial return to a developmental state is provided by the finding that there is rapid re-expression of a developmentally regulated alpha-tubulin gene. In magnocellular rubrospinal neurons, whose axons do not regenerate after injury, the same initial changes in gene expression occurred, but they were not sustained. We do not know whether this is cause or effect of the failure to regenerate, but we can conclude that injured CNS neurons have the potential to respond to injury by initiating a 'regeneration programme'. Failure to sustain this programme is presumably due to differences in the trophic environment of central and peripheral axons. PMID- 21551556 TI - Some hypotheses concerning axon regeneration. AB - We review evidence related to several hypotheses concerning the mechanism of axon regeneration and present new data addressing one hypothesis. That one hypothesis concerns the signal that initiates changes in the cell bodies of neurons after axon damage. We identify a molecule that has a number of the properties expected of such a signal. We also review the hypothesis that induction of some genes is tightly correlated with nerve regeneration, and conclude that such a correlation is not so 'tight'. Nevertheless, proteins whose rate of synthesis or transport is increased in some systems are good candidates for playing important roles in regrowth. A third hypothesis, that mammalian CNS neurons fail to regenerate because of a failure to induce growth-associated proteins, is probably not true. Growth-associated proteins appear to be induced, at least transiently, in some cases where regeneration is abortive. The state of the neuron undoubtedly is important in regeneration, but many neurons, even in the CNS, appear to be able to support axon regrowth given the proper environment. Thus, support seems stronger for the view that the environment at the site of damage (including surfaces and growth factors) determines whether significant regrowth occurs in most cases. PMID- 21551557 TI - Insulin-like growth factor II gene expression: relationship to the development and regeneration of neuromuscular synapses. AB - The mechanisms responsible for the formation, loss, and regeneration of vertebrate synapses are still shrouded in mystery. Recent data suggesting that insulin-like growth factor II (IGF-II) may play a special role in the nervous system are reviewed. In particular, studies now show that the IGF-II gene is selectively expressed in a manner consistent with its involvement in the formation of the neural circuitry. The prenatal up-regulation and postnatal down regulation of IGF-II transcripts in muscle are closely correlated with the prenatal accumulation and postnatal elimination, respectively, of polyneuronal innervation at the neuromuscular junction. Use and disuse of nerve and muscle can profoundly alter the developmental rate at which superfluous synapses are eliminated. Such alteration may result through modification of the rate at which postnatal down-regulation of IGF-II mRNA content occurs. Moreover, IGF-II mRNA content is correlated with the capacity of muscle to regenerate synapses. The IGF II gene may be the first example of a gene which can regulate the development and turnover of vertebrate synapses. PMID- 21551558 TI - Insulin-like growth factor I (IGF-I) and regeneration of the sciatic nerve of the rat. AB - We have found that insulin-like growth factor I (IGF-I) stimulates regeneration of the rat sciatic nerve. This paper reviews and adds some new data to our investigations on the effects of local administration of IGF-I to the sciatic nerve after infliction of a crush or freeze injury. PMID- 21551559 TI - The expression of growth factor receptors during nerve regeneration. AB - Growth factors and their receptors play a central role in the regulation of normal and injury-induced regenerative cell growth. In this article we review the data on the expression of growth factor receptors for beta-nerve growth factor, platelet-derived growth factor and serum transferrin during regeneration following peripheral nerve injury. Particular emphasis is put on the pathophysiological mechanisms leading to the expression of these growth factor receptors, their interaction with their respective ligands and their specific role in this regenerative process. PMID- 21551560 TI - Increase in protein and tubulin mRNA synthesis in frog sensory neurons treated with the adenylate cyclase activator, forskolin. AB - We are interested in the role cyclic AMP may play as a mediator of growth factor induced gene expression in regenerating peripheral nerves. As a first step, we investigated mRNA levels and protein synthesis in intact frog dorsal root ganglia (DRG) treated with the adenylate cyclase activator, forskolin in vitro. Forskolin (10-7 M) increased intraganglionic cyclic AMP concentration 3-fold within 40 min of application and maintained this concentration through 60 min, when the drug was withdrawn. Addition of forskolin to isolated DRG neurons for 1 h increased the incorporation of [3H]leucine into TCA-insoluble material beginning 12 h after the withdrawal of forskolin. Axonally transported labeled material was increased almost 2-fold by 12 h. The effect of forskolin could be blocked by the simultaneous addition of actinomycin D, but not if actinomycin D was added 1 h later. Northern and dot-blot analysis of RNA extracted from the treated ganglia indicated that an mRNA coding for an alpha-subunit of tubulin was increased by treatment with forskolin. 2D PAGE also demonstrated an increase in an alpha subunit of tubulin. An increase in neuronal cyclic AMP appears to selectively increase the production of specific proteins and may contribute to the production of macromolecules involved in the initiation and stimulation of axonal regeneration. PMID- 21551561 TI - Effects of human growth hormone on peripheral nerve regeneration. AB - Systemic administration of human growth hormone (hGH) to intact or hypophysectomized rats was found to stimulate regeneration of the crush-lesioned sciatic nerve. The IGF-I levels of serum of the treated rats did not correlate with regeneration of the nerve but hGH treatment increased the IGF-I content of the nerve. The results suggest that a GH-mediated increase of IGF-I in the sciatic nerve could be involved in the stimulatory effect of GH on neurite outgrowth. PMID- 21551562 TI - B-50/GAP-43 in neuronal development and repair. AB - The protein kinase C substrate B-50 is identical to the growth-associated protein GAP-43. Although as yet no causal relationship has been established between B 50/GAP-43 and neurite outgrowth, evidence accumulates that the function of the protein relates to neuronal plasticity. Stimulation of PC12 cells by NGF results in translocation of the protein from cytosolic stores to the membrane of newly formed neurite-like extensions. The protein is associated with the inner leaflet of the growth cone membrane isolated from neonatal rat brain and was used as a marker to study the development of the rat pyramidical tract and olfactory system. In the adult rat, crush lesion of the sciatic nerve results in a rapid expression of B-50/GAP-43 mRNA followed by synthesis of B-50/GAP-43 protein in dorsal root ganglia and transport of the protein into the newly formed sprouts. Presumably, the neurotrophic effect of melanocortins on peripheral nerve repair is not brought about by enhancement of B-50/GAP-43 synthesis per se. Bulbectomy (central) or Triton X-100 lesioning (peripheral) of the olfactory epithelium results in a differential expression of B-50/GAP-43 and the olfactory marker protein characterizing two stages in the regeneration of this epithelium. Evidence that the degree of phosphorylation may co-determine the role of B-50/GAP 43 in neurite outgrowth is discussed. PMID- 21551563 TI - Posttranslational modification of nerve proteins by amino acids. AB - Both axonal and glial components of nerve are capable of carrying out reactions in which Arg, Lys, Leu, Pro, Val, AJa and Ser can be covalently linked to endogenous proteins in reactions which require tRNA but occur in the absence of ribosomes and ribosomal RNA. These posttranslational protein modifications appear to play important roles in nerve regeneration since they are increased more than 10-fold within 2 h of a crush injury in nerves which are capable of regeneration, but are not activated in nerves not capable of regrowth following injury. The regulation of the modification of proteins by Arg and Lys in vivo appears to be the function of separate peptides. The exogenous application of serine protease inhibitors (but not other protease inhibitors) mimics the effect of the endogenous peptides, suggesting that the endogenous regulators have serine protease inhibitory activity. The targets for modification are proteins of low abundance and thus far have been identified only in terms of their molecular weights and isoelectric points. The site of addition of Arg, but not the other amino acids, to target proteins is to the amino terminus. The addition of Arg to an amino terminus is likely to be involved in the ubiquitin mediated proteolysis of the modified protein. One of the most unusual findings in these series of experiments is that in regenerating sciatic nerves, amino acid modified proteins aggregate to form complexes of greater than 2 * 106 Da. The significance of this finding is not known. But we speculate that the aggregate may result from the assembly of an insoluble functional unit of the cell from soluble precursor proteins, and that the trigger for their assembly is amino acid modification. PMID- 21551564 TI - Regeneration of the rat sciatic nerve in the silicone chamber model. AB - The silicone nerve regeneration chamber is a useful model to investigate the cellular and molecular events underlying successful regeneration in the peripheral nervous system. In this model a transected rat sciatic nerve with a 10 mm interstump gap, is repaired with a silicone chamber. The spatial-temporal sequence of regeneration in the silicone chamber has been examined in detail. The chamber rapidly becomes filled with fluid which contains neurotrophic activity for neurons in vitro. The second event to occur is the formation of a fibrin matrix connecting the two nerve stumps. This matrix is then invaded by cellular elements in the following order: perineurial-like cells, vasculature, Schwann cells, and axons. The silicone chamber model also allows manipulation of the regeneration process. Prefilling the chamber at the time of implantation with phosphate-buffered saline or dialyzed plasma stimulates nerve regeneration. Multiple injections into the chamber of a mixture containing laminin, testosterone, and ganglioside GM1 increase the size and the vascularization of the regenerate. Specially designed chambers divided into two compartments by a longitudinally inserted nitrocellulose strip have been used to examine the effects of substrate-bound trophic factors on nerve regeneration. Fibroblast growth factor containing chambers have an improved regeneration and vascularization as compared to controls. PMID- 21551565 TI - Regeneration in vitro of the adult frog sciatic sensory axons. AB - The adult frog sciatic nerve offers several advantages as an in vitro model to study nerve regeneration. The nerve with the attached dorsal root ganglia can easily be isolated and incubated in a culture medium for several days. If the nerve is subjected to a crush immediately after dissection there is a delay of 3.4 days after which the sensory axons start to regenerate into the distal nerve stump at a constant rate of about 1.1 mm . day-1 in serum-containing and 1.0 mm . day-1 in serum-free medium. Serum-free cultures may be used in future studies to examine the effect of various neurotrophic factors. The existence of an accurate method for examining the outgrowth distance, based on axonal transport of labelled proteins, contributes to the attractiveness of the model. A compartmental culture system permits separate exposure of the ganglia and the nerve to different agents. Taking advantage of this, pharmacological studies suggest that Schwann cells produce signals, dependent on newly transcribed RNA, which transform the preparation into a growth state. The present model system offers favourable conditions to learn more about the early events and also the subsequent steps of the regeneration process. PMID- 21551566 TI - Regeneration in vitro of axolotl peripheral and central axons. AB - Peripheral nerves and spinal cords of axolotls were maintained in organ culture for periods of up to 2 weeks. Sensory axons in peripheral nerves and the dorsal funiculus of the spinal cord showed regeneration through the crush site within about 2 days. Axonal regeneration also occurred in peripheral nerves after cutting but was dependent on close contact between proximal and distal stumps of nerve. When cells in the distal stump of nerve were killed by freezing, axonal regeneration was inhibited. PMID- 21551567 TI - Specificity in regenerative outgrowth and target reinnervation by mammalian peripheral axons. AB - There are indications that specific factors are present in the distal stump of transected nerves which preferentially attract axons of the corresponding proximal stump into the distal nerve stumps. However, the impact of these factors is unclear, since there is abundant evidence that numerous regenerating motor and sensory axons are topographically misdirected after nerve transection and repair. Topographic reinnervation is improved after fascicular repair of fasciculated nerves, and quite precise after nerve crush. The latter may not be true, however, for non-myelinated axons, which show a high degree of aberrant growth even after crush. In contrast, regenerative outgrowth appears to be topographically specific after neonatal nerve transection. Reinnervation of muscle fibers appears to be unspecific in adult mammals, but specific after neonatal injury under certain circumstances. Some preference for reinnervation of the appropriate sensory receptors seems to exist although this preference does not preclude reinnervation of receptors by 'foreign' sensory fibers. In conclusion, incorrect topographic and target reinnervation commonly occurs after peripheral regeneration in adult mammals, and most certainly explains some of the functional disturbances after peripheral nerve lesions. Topographic regeneration appears to be better after nerve injury in developing mammals indicating that mechanisms from the developmental period may persist and aid in accurate regenerative outgrowth. PMID- 21551568 TI - Preferential motor reinnervation: a sequential double-labeling study. AB - Previous experiments have shown that motor axons regenerating in mixed nerve will preferentially reinnervate a distal motor branch. The present experiments examine the mechanism through which this sensory-motor specificity is generated. An enclosed 0.5 mm gap was created in the proximal femoral nerves of juvenile rats. Two, three or eight weeks later the specificity of motor axon regeneration was evaluated by simultaneous application of horseradish peroxidase (HRP) to one distal femoral branch (sensory or motor) and Fluoro-Gold to the other. Motoneurons were then counted as projecting (i) correctly to the motor branch, (ii) incorrectly to the sensory branch, and (iii) simultaneously to both branches (double-labeled). Motor axon regeneration was random at 2 weeks, with equal numbers of motoneurons projecting to sensory and motor branches. However, the number of correct projections increased dramatically between 2 and 3 weeks. Twenty-six percent of neurons labeled at 2 weeks contained both tracers, indicating axon collateral projections to both sensory and motor branches. This number decreased significantly at each time period. Axon collaterals were thus 'pruned' from the sensory branch, increasing the number of correct projections at the expense of double-labeled neurons. These findings suggest random reinnervation of the distal stump, with specificity generated through trophic interaction between axons and the pathway and/or end organ. PMID- 21551569 TI - Regeneration after spinal nerve root injury. AB - Spinal nerve root avulsion has been considered as a central nervous type of injury and therefore not repaired surgically in man. The possibility for axonal regeneration after root avulsion or root lesion has been investigated in laboratory animals by means of up to date neurophysiological, morphological and tracing techniques. It is shown that, after ventral root avulsion and implantation into the spinal cord, alpha and probably also gamma motoneurons are able to regenerate within the spinal cord for a considerable distance before entering the implanted root and reinnervate previously denervated skeletal muscles. The regenerated neurons were found to respond to afferent activity with excitatory or inhibitory responses, and the regenerated axons could conduct action potentials that elicited muscle twitch responses. After dorsal root injury in the adult animal, regeneration into the spinal cord does not occur. However, regeneration of primary sensory neurons into appropriate locations of the spinal cord can be demonstrated in immature animals. PMID- 21551570 TI - Nerve regeneration problems in a clinical perspective. AB - Injuries to peripheral nerves represent a challenging clinical problem. In spite of the use of microsurgical techniques, repair of severed nerves seldom results in complete recovery of motor and sensory functions. Misdirection of axons at the suture line as well as a slow axonal outgrowth contribute to the bad results. Recent experimental data indicate that growth factors, synthesized by the damaged nerve tissue as well as protein-associated neurite-promoting factors in the local micro-environment play an important role for the regulation of axonal growth and directionality. Future studies should aim at an application of this knowledge to the clinical treatment of nerve injuries. PMID- 21551571 TI - Pulsed electromagnetic fields stimulate nerve regeneration in vitro and in vivo. AB - The influence of non-invasive, low level, pulsed electromagnetic fields (PEMF) on regeneration was tested on in vitro and in vivo models. Cultures of dorsal root ganglia were exposed to 2 Hz PEMF, amplitude of 0.05 mTesla while rats after a 'crush' lesion of sciatic nerves were exposed to 2 Hz PEMF, amplitude of 0.3 mTesla. In in vitro experiments, relative to controls, cultures treated with PEMF exhibited a significant increase in neurite outgrowth with dense labeling of neurons and neurites on autoradiographs after incorporation of [3H]proline into new proteins. In vivo exposure of rats to PEMF for 3, 4 or 6 days after lesioning produced a 22% increase in the regeneration rate relative to controls with no effect on the initial delay period. When rats were exposed to PEMF before lesioning without further treatment, the same degree of stimulation of axonal sprouting was obtained. Reduction of the amplitude from 0.3 mTesla to 0.06 mTesla eliminated this pre-exposure response. Alterations in the distribution of new proteins synthesized 2 weeks after PEMF treatment provide additional evidence for its influence at the whole body and cellular levels. PMID- 21551572 TI - Post-lesion practice and amphetamine-facilitated recovery of beam-walking in the rat. AB - Treatment with amphetamine increases the rate of recovery of beam-walking in rats when administered after a unilateral suction-ablation lesion of the sensorimotor cortex. It is thought that amphetamine treatment must be combined with postlesion practice on the beam since confinement to prevent locomotion blocks amphetamine facilitated recovery. However, rats which are confined are also isolated and not handled. In the present experiment, beam-walking recovery was compared among groups of rats which were treated with either amphetamine or saline and then either handled and allowed to walk in a home cage or given practice on the beam. Although amphetamine treatment and postlesion practice had independent beneficial effects on recovery, the group of rats given both treatments had the greatest improvement in beam-walking scores. PMID- 21551573 TI - Effects of adrenal medulla grafts in neonatal rat hosts on subsequent bilateral substantia nigra lesions. AB - Bilateral lesioning of rat substantia nigra results in a syndrome of aphagia, adipsia, and akinesia. Rats can be protected from the development of this syndrome if they have previously received intraventricular fetal substantia nigra grafts as neonates. In this experiment, we determined whether neonatal adrenal medulla grafts would offer similar protection. One day old Sprague-Dawley rat pups received bilateral intraventricular allografts of either adrenal medulla or sciatic nerve from adult donors. At 3-4 months of age the rats received bilateral lesions of the substantia nigra with 6-hydroxydopamine. After lesioning, food and water consumption were greater in the rats receiving adrenal medulla grafts, as compared to the sciatic nerve control group. Nevertheless, food and water consumption was markedly decreased in both groups, and activity levels did not differ between the two groups. Histology showed consistently surviving grafts with large numbers of surviving catecholamine-containing cells. Thus adrenal medulla grafts in neonatal hosts offer partial protection against the syndrome of adipsia and aphagia produced by subsequent substantia nigra lesions, but this protection is much less than that produced by substantia nigra grafts. PMID- 21551574 TI - Long-term impairment of behavioral recovery from cortical damage can be produced by short-term GABA-agonist infusion into adjacent cortex. AB - Diazepam and other GABA-related agents can prevent or delay recovery from an otherwise short-term somatosensory asymmetry caused by unilateral cortical lesions. Postrecovery treatment does not affect behavior. One possible contributive site of action for these agents is remaining cortical tissue. In the present study, following unilateral anteromedial cortex (AMC) lesions or sham operations, the GABA agonist muscimol or saline was infused once a day for 7 days into the adjacent sensorimotor cortex (SMC) or, as a control, into the more remote occipital cortex (OC) of the ipsilateral hemisphere. Each day the animals were given somatosensory and motor coordination tests at 21 h postinfusion. The SMC-muscimol regimen, but not the SMC-saline or OC-muscimol, retarded recovery from somatosensory asymmetry. The disruptive effect on recovery was enduring, greatly outlasting the week of exposure to muscimol. In sham-operated animals, SMC-muscimoI did not yield a chronic effect on behavior, although during the first hour after each infusion, in which the muscimol presumably was still present in the SMC, somatosensory asymmetry could be observed. Although the AMC lesion created a vulnerability to muscimol in the SMC, no detectable difference in the extent of cortical damage in this group could account for the prolongation of behavioral asymmetry. SMC-muscimol (but not SMC-saline) led to atrophy of SMC projection areas in the ipsilateral thalamus. However, in sham-operated animals, SMC-muscimol did not affect thalamic size. These behavioral and anatomical data suggest that systemically delivered GABAergic drugs might interfere with restoration of function after AMC lesions in part by adversely influencing events in the SMC. PMID- 21551575 TI - Long-term effects of thyroid hormone deficiency on noradrenergic circuitry: electrophysiological changes in intraocular hippocampus-locus coeruleus double transplants. AB - The effects of thyroid hormone deficiency on the noradrenergic innervation of hippocampus from locus coeruleus (LC) were examined using intraocular double transplants in albino rats. Fetal brainstem pieces containing the nucleus LC were transplanted to the anterior chamber of the eye of thyroidectomized and normal recipients and the brain grafts were allowed to mature for 8 weeks. Pieces of fetal hippocampal formation were introduced into the anterior eye chamber and placed in contact with the LC grafts or placed in previously operated eyes. As evidenced by high performance liquid chromatography, hippocampal transplants in contact with a brainstem graft gradually became hyperinnervated by noradrenergic fibers from these grafts. The levels of norepinephrine were lower in single control grafts and in double grafts in thyroidectomized animals than in control double grafts. Extracellular recordings of single neuronal activity were performed in hippocampal transplants in all 3 groups after 10-14 months in oculo. Superfusion with the alpha2- adrenergic agonist clonidine and the alpha adrenergic antagonist phentolamine elicited significant increases in discharge rate of hippocampal neurons in control double transplants, but not in single hippocampal grafts or in double grafts in thyroidectomized hosts. The beta adrenergic antagonist timolol did not change the neuronal firing rate in any of the 3 groups. Superfusion with penicillin over single hippocampal transplants caused long-lasting increases in slow-wave activity. This increased bioelectric activity remained after the cessation of drug application. A similar increase in slow-wave activity was found in hyperinnervated control double transplants only when penicillin was combined with clonidine or phentolamine. However, the hippocampal portion of double grafts in thyroidectomized recipients readily responded to penicillin with seizures and/or interictal spiking. The data presented here suggest that chronic lack of thyroid hormones leads to significant disturbances of the central noradrenergic transmission in isolated LC-hippocampal circuits. PMID- 21551576 TI - A collagen and fibrin tube for nerve repair. AB - A biodegradable tube consisting of alternating laminae of aldehyde and heat treated collagen and fibrin was tested as a nerve repair device. Tubes placed around intact nerves for 3 weeks showed a high degree of biocompatibility as evidenced by the absence of reactive or toxic alterations of epineurium contacting the implant and the presence of normal perineurial and endoneurial components. Tubes used to bridge a 5 mm gap in the rat tibial nerve showed good vascularization of the collagen laminae, a well-confined nerve regenerate, and advanced resorption of the fibrin component at 3 months. One year after being used to bridge 5-12 mm gaps in the cat radial and saphenous nerves, the tubes were replaced by well-vascularized connective tissue which surrounded a dense nerve regenerate. However, inadequate stabilization of the implants by the small anchoring sutures apparently caused some of the repairs to fail. In sum, the implants appear to promote regeneration of axons across a nerve gap by providing an oriented, well-vascularized physical substrate for neurite outgrowth. PMID- 21551577 TI - MHC antigen expression and cellular response in spontaneous and induced rejection of intracerebral neural xenografts in neonatal rats. AB - Fetal mouse retinae transplanted to the mesencephalon of neonatal rats generally survive for prolonged periods of time without immune suppression suggesting that such grafts enjoy a degree of immunological privilege. A small, but consistent percentage of these transplants, however, ultimately undergo spontaneous rejection. In addition, rejection can be induced by (1) systemically sensitizing the host to the donor antigens by placing a mouse skin graft or (2) producing a local degenerative process adjacent to the graft by removing the host eye contralateral to the side of the retinal transplant. To elucidate the immunological events that underly spontaneous and induced rejection in this system, we examined the distribution of lymphocytes, astrocytes, microglia, and cells expressing major histocompatibility complex (MHC) antigens in unrejected grafts, in transplants showing spontaneous rejection, and in grafts undergoing induced rejection. In unrejected grafts, increased astrocytic and microglial staining was seen around the photoreceptor layer of the graft and at the graft host interface, but no lymphocytes and only occasional cells expressing MHC antigens were detected. In contrast, spontaneously rejecting grafts showed widespread MHC, lymphocytic, astrocytic, and microglial immunoreactivity that extended well beyond the limits of the transplant into the surrounding host brain. Skin graft-induced rejection produced a temporally consistent, comparatively localized enhancement of astrocytic, microglial and MHC immunoreactivity and infiltration of lymphocytes. Four to five days after skin grafting, before neural graft rejection was detectable histologically, MHC immunoreactivity was demonstrated within the transplant coinciding with the presence of small numbers of lymphocytes and an increase in microglial staining. By 8 days, grafts had undergone profound necrosis. Intense astrocytosis, microglial staining, MHC immunoreactivity, and perivascular lymphocytic cuffing were present within the graft and at the graft-host interface. With longer survival times, several of these changes were also detected within the visual pathways, suggesting that the regions to which the graft projected were also involved, though in a delayed fashion. After eye removal, the temporal pattern of rejection was more protracted and considerably less uniform than that seen after skin grafting. At 7 days, prominent microglial, astrocytic, and MHC immunoreactivity was seen in the area of distribution of the host optic axons within the superior colliculus and to a lesser extent around the graft itself, however, no infiltration of lymphocytes was detected. With longer survival times, an increasing percentage of grafts showed signs of overt rejection with perivascular cuffing by lymphocytes; however, even at 21 days, a small number of grafts remained free of lymphocytic infiltration, despite the presence of intense MHC, astrocytic, and microglial staining. We conclude that the different rejection models studied may involve fundamentally different triggers of the host immune system, but that in each case MHC expression may be the precedent step to graft rejection. PMID- 21551578 TI - Chronic spinal cord transection does not affect peripheral nerve regeneration. AB - Spinal cord transection is known to cause progressive changes in motor neurons and hind limb muscles. In the present study, regeneration of the peroneal nerve was examined in rats 25 weeks after a T9 spinal cord transection. Successful regeneration and innervation of the target muscle was observed after crush injury to the nerve in the spinal cord transected animals. It is concluded that the ability of peripheral nerve to regenerate remains preserved after spinal cord injury. PMID- 21551580 TI - A 16th century request for brain tissue transplantation. PMID- 21551581 TI - Brain tissue and neural graft reactivity to the implantation of in situ self assembled collagen matrices. AB - The extracellular matrices of living tissue provide scaffolding supports for cell migration and interaction during tissue remodelling and regeneration and therefore may also be relevant to processes of regeneration in the injured central nervous system. We implanted in artificially made cavities of the neostriatum or cortex of adult rats a fluid collagen gelling system into which fetal grafts from either the substantia nigra or cortex were introduced. The collagen polymerizes to form a fibrillar matrix (organogel) which restitutes a physical continuity to the neural tissue. The host tissue reaction consisted of the ingrowth of blood vessels, the migration of mesenchymatous cells, of reactive astrocytes and of microglia within the bioimplant which became the substrate of heterogeneous cell interactions. As a result, newly formed collagen and carbohydrate-rich materials were deposited upon the collagen matrix while the bioimplant underwent remodelling. After 2 months, the original matrix was replaced by a glial-mesenchymal matrix into which nerve fibers of the lesioned striatum regenerated. The neural transplants survived and differentiated according to the stability of collagen matrices. We conclude that a collagen gelling system can be used to introduce a scaffolding structure into open brain wounds, and suggest that instead of sealing off the lesion, the ensuing scarring process rather favors tissue repair by establishing a glial-mesenchymal matrix well-suited for inducing intrinsic and extrinsic (grafts) neural regeneration. PMID- 21551582 TI - Increased levels of basic fibroblast growth factor (bFGF) following focal brain injury. AB - Focal injury to the mammalian central nervous system (CNS) results in a cascade of cellular responses - including glial and capillary proliferation and neural sprouting - that contribute to the repair of neural tissue and to the recovery of neurological function. Fibroblast growth factors (FGFs) are heparin-binding polypeptides with potent trophic effects on CNS glia, endothelia, and neurons; both acidic and basic forms are found in the mammalian CNS. We used heparin affinity chromatography coupled to Balb/c 3T3 mitogenic assay to show a marked increase in levels of bioactive FGFs in tissue surrounding focal cortical lesions of the mature rat brain at one week after injury. Heparin-affinity HPLC showed that this increase was due to a large increase in levels of basic FGF (bFGF), and a much smaller increase in levels of acidic FGF (aFGF) after injury. Increased bFGF bioactivity was paralleled by increased levels of immunoreactive bFGF, as assessed by Western blotting techniques. Increased bFGF levels may play an important role in the cascade of cellular reactions occurring after focal brain injury. PMID- 21551583 TI - Dynamic analysis of the righting reflex in toads; recovery after hemilabyrinthectomy. AB - Static and dynamic measurements of the righting reflex were performed in intact toads (Bufo arenarum platensis) and at different stages of recovery from hemilabyrinthectomy. Reflex activity was evaluated by the toad's capacity to maintain a horizontal head position while rolled sideways. Static data were obtained from frontal photographs. In dynamic experiments platform position (stimulus) was measured through a potentiometer, while a linear accelerometer glued to the cranium was used to record head tilts. The dynamic study included a linear systems analysis using sinusoids of 0.5-3 Hz with rolls of up to 30 degrees to each side. Hemilabyrinthectomy produced a head tilt towards the lesioned side, and gain decay and phase lag increase in the dynamic response. All postural defects recovered progressively within 30-60 days as already described in other species. Nevertheless, the tonic head deviation produced by dynamic stimuli of frequencies above 1 Hz did not recover. This remnant defect has not been observed in previous studies in which only static observations were performed. The involvement of a frequency-dependent rectifying mechanism in postural compensation is discussed. PMID- 21551585 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551586 TI - Post-translational modification of proteins by arginine and lysine following crush injury and during regeneration of rat sciatic nerves. AB - Following crush injury to rat sciatic nerves, a crude fraction of the 150,000 g supernatant can post-translationally incorporate [3H]Arg and [3H]Lys into endogenous proteins in amounts approximately 10 times uninjured control nerves. These increases occur in the proximal nerve stump within 2 h of injury and 2 weeks later in a distal segment of nerve containing the tips of the regenerating axons. In the present experiments, the endogenous nerve proteins modified by Arg or Lys in these nerve segments have been identified using two-dimensional polyacrylamide gel electrophoresis. The fraction used to assay for protein modification, the void volume of a Sephacryl S-300 column, was found to contain only a few proteins visible by Coomassie blue staining, one of which is likely to be albumin (68 kDa, pI 6.4). While this protein was modified by both Arg and Lys, the majority of label was found in areas not showing Coomassie blue staining. This indicates that of the many potential targets of post-translational arginylation and lysylation, most are proteins of relatively low abundance. A variety of proteins were modified by Arg or Lys alone while others were modified by both Arg and Lys. A high molecular weight protein (175 kDa, pI 9.0) was modified only by Lys and only at 2 h post crush. Of a variety of modified proteins of approximately 17 kDa one (pI 6.3) was modified by both Arg and Lys and at both time points, while another (pI 9.0) was modified at both time points, but only by Lys. The results show that Arg and Lys can be added post translationally to a large number of low abundance, soluble sciatic nerve proteins, and that some of those proteins are modified only by Arg or Lys while others are modified by both Arg and Lys. Also, the modification of certain proteins appears to be associated specifically with the immediate response of a nerve to injury (e.g. 88 kDa, pI 7.1) while others are associated with the regenerative period (e.g. 56 kDa, pI 7.4). PMID- 21551587 TI - Fetal tectal transplants in the cortex of adult rats become innervated both by retinal ganglion cell axons regenerating through peripheral nerve grafts and by cortical neurons. AB - The present work elucidates the connectivity of adult retinal ganglion cell axons regenerating through grafted peripheral nerve segments with co-grafted immature brain target cells. The optic nerve of rats was transected intraorbitally and its segment distal to the transection was replaced by a 3 cm length of peroneus communis graft, that is known to permit regeneration of a certain proportion of the severed axonal population. Five weeks after optic nerve transection and peripheral nerve transplantation the regenerating optic tract axons were guided into rat fetal mesencephalic co-grafts (E14-16) placed in superficial cavities prepared in the occipital cortex. The rationale of the experimental setup was based on the fact that regrowth of retinal axons started at the 6th day after transection, whereas the fastest-growing axons reached the distal end of the transplanted peripheral nerve 4 weeks later growing with a velocity of about 1.33 mm/day. Therefore, grafting the fetal superior colliculus at the time axons arrive distally resulted in ingrowth of several hundreds of retinal axons into this immature, retinoreceptive brain tissue. Retinal axons which penetrated the fetal grafts contacted tectal neurons and GFAP-immunoreactive glia and formed typical retinocollicular axonal arbors as detected by anterograde labeling with RITC from the retina. In addition, sprouting fibers from the adjacent adult cortical neurons penetrated frequently the fetal transplants. By 'bridging' lesions with peripheral nerve pieces and providing immature neurons as targets for growing neurites, this transplantation model is suitable for investigations on whether regenerating adult neurites are capable of reforming connections. The co-transplantation technique may serve as a tool for understanding whether interrupted circuitries in the central nervous system can be functionally restored over long distances by the use of peripheral nerve grafts and immature nervous system tissue. PMID- 21551588 TI - Influence of needle lumen size on viability of injected dispersed and clumped foetal brain cells. AB - Foetal tissue from cortex, striatum, cerebellum and mesencephalon of human foetuses of gestational age 18 weeks have been examined for cell viability pre- and postpassage through needles of varying dimensions. Fully dispersed cells have less viability than cell clumps, but needle lumenar sizes employed in this study do not appear to have any significant influence on viability as measured by the vital staining method. There is a tendency of narrower needles to adversely affect viability of both dispersed and clumped cells; the vulnerability of component cells, i.e. neurones or glia has not been determined. PMID- 21551589 TI - Modifications in the cytoskeleton transported by slow component A during axonal regeneration. AB - We studied the modifications occurring in the parent cytoskeleton carried by SCa (the slower of the two slow axonal transport subcomponents) after peripheral nerve crush. The proteins transported in rat sciatic motor axons were radiolabelled by injecting [35S]methionine into the ventral horn of the spinal cord, and the nerve was crushed so as to entrap only the proteins transported by SCa along the parent axon. Two weeks after the crush, the regenerating nerve was removed and the distributions of the polymerized and unpolymerized radiolabelled cytoskeletal proteins were compared with those in normal, non-regenerating nerves. We found that in the parent axons, most of the radioactive neurofilaments were arrested by the crush, but microtubules, soluble tubulin, insoluble and soluble actin were normally transported. Thus, when the resulting cytoskeleton transported by SCa entered the daughter axon, it was enriched in microtubules and actin, and partially depleted of neurofilaments. This cytoskeleton contained larger proportions of soluble tubulin and insoluble actin than the parent cytoskeleton, but retained its coordinated progression and transport velocity, suggesting that after axotomy, the main destiny of the parent cytoskeleton carried by SCa is to become the equivalent cytoskeleton in the daughter axons. PMID- 21551590 TI - Preliminary experiments in nerve regeneration through laser-drilled holes in silicon chips. AB - Many of the present limitations of peripheral nerve repair might be overcome by performing nerve repairs at the axon level. One approach to nerve repair at this level would be to implant a neuroprosthesis in the form of a microelectronic switchboard which could route the connections of regenerated axons to their correct destinations. This requires a merger of microsurgery and microelectronics. Three steps are needed to achieve this goal. (1) The achievement of in vivo compatibility and electrical contact between axons and a material compatible with microelectronics. (2) The fabrication of a microelectronic neuroprosthesis with electrodes to establish communication with the axon. (3) The development of signal processing hardware and software to control the mapping of the regenerated axons. This report describes preliminary experiments in regenerating peripheral nerve axons through an electronic-grade silicon chip with laser-drilled holes small enough to capture either one or a few axons per hole. We have observed the viability of such nerves in 4 rats for 6 months to 1 year, and in two primates for more than 3 months. As our experiments show, this technique is not yet as effective as suture repair, but the development of a neuroprosthesis that communicates with peripheral nerve axons could have applications including nerve repair, neuroma, and nerve grafts, as well as interfacing the peripheral nervous system to prostheses of other kinds. PMID- 21551591 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551592 TI - Neuronal activity of the septum transplanted into the neocortical barrel field of the rat. AB - Embryonic (E16-17) septal solid grafts were transplanted into acute cavities in the barrel field of somatosensory neocortex of adult rats. Extracellular recording of the graft's neuronal activity was performed in lightly anesthetized rats, or in brain slices in vitro 8-10 months after grafting. Analysis of Nissl and Golgi-Cox stained preparations showed that 81% of the grafts survived. Judging by combined histological and electrophysiological criteria, 69% of surviving grafts were integrated with the host brain. All septal grafts contained neurons with high spontaneous activity (mean 14.9 +/- 8.3 spikes . s -1). Irregular bursts or rhythmic theta-bursts were present in background activity. The frequency of theta-bursts varied in parallel with the state of the animal from 3 Hz (deep barbiturate sleep) up to 7-8 Hz (arousal). Somatosensory stimulation evoked initial bursts or suppression of activity, often followed by a period of rhythmic theta-bursts. Though a high level of convergence for stimulation of vibrissae and body surface was typical of the grafted neurons, a certain spatial gradient of body representation was present. Many neurons responded also by initial burst or prolonged suppression of activity to electrical stimulation of thalamus and homolateral motor cortex. In the frontal slices of neocortex the neurons of septal grafts were highly reactive to stimulation of adjacent neocortex, but usually when the distance between the stimulating electrodes and the graft border did not exceed 1-1.5 mm. The data obtained in the septal slices are compared to the results described earlier in homotopic neocortical and heterotopic hippocampal grafts to the barrel field. It is concluded that heterotopic embryonic septal grafts can successfully develop and establish functional afferent connections with the host brain. Their neurons can participate in processing of sensory information, appropriate to the substituted cortical area, though the characteristics of responses are to a great extent determined by intrinsic properties of the septal neurons. PMID- 21551593 TI - Effects of cool storage on survival and function of intrastriatal ventral mesencephalic grafts. AB - Ongoing clinical trials with fetal tissue transplants in Parkinson's disease would be facilitated by an effective tissue storage technique that would allow for temporal separation of the procurement of the fetal donor tissue and implantation surgery. In order to develop such a method, we grafted rat or human fetal ventral mesencephalic tissue to the dopamine-depleted striatum of rats either directly, or following pregraft refrigeration in a 'hibernation' medium at 4 degrees C. Rat tissue transplants were found to normalize amphetamine-induced circling behavior at 6 weeks post-transplantation after having been hibernated for either 2 or 5 days. The number of tyrosine hydroxylase immunoreactive neurons in these hibernated grafts did not differ significantly from that found in matched grafts of fresh tissue. Hibernation for 10 days resulted both in an absence of functional effects and in decreases of graft survival down to 10-20% of control values. Volume assessment of fresh and hibernated grafts prepared from human fetal tissue revealed no adverse effects of a 3 day hibernation interval at 3 weeks after transplantation into immunosuppressed rats. The results indicate that hibernation of neural tissue may be a convenient and simple tool, which can help to guarantee tissue availability at the planned time of implantation in patients and facilitate transport and bacteriological examination. Furthermore, the method offers a simple means which permits prolonged exposure of the neural tissue to trophic factors and specific markers prior to grafting in experimental animals. PMID- 21551594 TI - Functional repair of transected spinal cord in embryonic chick. AB - The purpose of this study was to determine the developmental stage of the chick embryo when descending spinal tracts lose the capacity for anatomical and functional repair after complete transection of the thoracic spinal cord. Previous studies have demonstrated that the first reticulospinal projections descend to the lumbar cord by embryonic day (E) 5. A comparison of the distribution and density of retrogradely labelled brainstem-spinal neurons in embryos versus hatchling chicks suggests that the descent of all brainstem-spinal projections is essentially complete to lumbar levels between E10 and El2. Transections and control sham operations were performed on different embryos from E3 through E14 of development. After a recovery period of 5-18 days, the extent of anatomical repair was assessed by injecting a small volume of a retrograde tract-tracing chemical into the upper lumbar spinal cord, caudal to the transection site. The brainstem nuclei were then examined for the number and distribution of retrogradely labelled brainstem-spinal neurons. In comparison to control animals, anatomical recovery appeared to be complete for embryos transected as late as E12, whereas thoracic cord transections conducted on E13 E14 resulted in reduced labelling of most brainstem-spinal nuclei. In addition, a number of E3-E6 transected embryos were allowed to hatch and with some assistance a few E7-E14 transected embryos also hatched. Functional recovery was assessed by behavioral observations and by focal electrical stimulation of brainstem locomotor regions (known to have direct projections to the lumbar spinal cord). Brainstem stimulation experiments were undertaken on transected and control embryos, either in ovo on E18-E20 or after hatching. Leg and wing muscle electromyographic recordings were used to monitor any brainstem evoked motor activity. Voluntary open-field locomotion (hatchling chicks) or brainstem evoked locomotion (embryonic or hatchling) in animals transected on or before E12 was indistinguishable from that observed in control (i.e. sham-operated or unoperated) chicks, indicating that complete functional recovery had occurred. In contrast, chicks transected on or after El3 showed reduced functional recovery. Since a previous study has shown that neurogenesis in chick brainstem-spinal neurons is complete prior to E5, the possible intrinsic neuronal mechanisms underlying the repair of descending supraspinal pathways are: (1) subsequent projections from later developing (undamaged) neurons, or (2) regrowth of previously axotomized projections (regeneration). For the E5-E12 chick embryos examined in this study, significant descending supraspinal fibers are present within the thoracic cord at the time of transection. Even if the transection is made at E12, when descending projections have completed their development to the lumbar cord, there is still a similar number and distribution of brainstem-spinal neurons labelled afterward (when compared to controls). This suggests that regeneration of previously axotomized projections may account for some of the observed anatomical and functional repair of brainstem-spinal pathways. PMID- 21551595 TI - Impairment of memory and affect in a patient with reversible bilateral thalamic lesions due to internal cerebral vein thrombosis. AB - A 39-year-old woman suffered from an extensive bilateral lesion in the region of the thalamus. The damage, caused by a primary thrombosis of the internal cerebral veins, turned out to be reversible to a considerable degree detected by repeated CT-and MR-imaging after 2, 4 and 9 months. In spite of the partial, structural recovery the patient remained severely impaired on both cognitive and affective levels. The key functions involved were an anterograde verbal and figural memory impairment, depressed arousal and attentional levels, affective flattening, lack of prosody and a depressive irritable mood. These findings illustrate that thalamic lesions of a certain extent not only influence memory functioning, but have in addition, severe consequences for emotional behavior. PMID- 21551597 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551598 TI - Foreword. PMID- 21551599 TI - Preface. PMID- 21551600 TI - Antioxidant therapy in experimental spinal cord injury. AB - We have tested the capacity of several compounds with in vitro and/or in vivo antioxidant or antilipolytic activity to ameliorate locomotor function in cats subjected to static loading (i.e. compression) injury of the spinal cord. These include the synthetic glucocorticoid, methylprednisolone sodium succinate (MP), and the new 21-aminosteroid antioxidant, U74006F. Treatment of spinal cord injured cats with high doses of MP promoted or spared locomotor function and preserved spinal cord tissue. Extending these findings in cats to humans, it was recently demonstrated that high doses of MP administered within 8 h of injury significantly improved neurologic recovery in human spinal cord-injured patients. The compound U74006F is one of a series of 21-aminosteroids that, unlike MP, lack glucocorticoid, mineralocorticoid or other hormonal activity yet are potent inhibitors of lipid perioxidation. Over a 100-fold range of doses, U74006F promoted recovery of locomotor function in spinal cord-injured cats. The lowest effective dose for U74006F was 100 times lower than the maximally effective dose for MP. The efficacy of U74006F is unchanged if treatment is initiated within 4 h of injury. However, if treatment is delayed for 8 h, the therapeutic potency of U74006F is substantially reduced. These findings suggest that antioxidant therapy can successfully limit the effects of both experimental and clinical spinal cord injury especially if the treatment is initiated shortly after injury. PMID- 21551601 TI - Sex differences in the effect of MK-801 on normal and spinal cord injured rats. AB - The induction of functional paraplegia in female rats by contusive spinal cord injury was not prevented by compound MK-801. However, the treatment reduced cavitation around the lesion epicenter to 14 mm3 compared to 17 mm3 in untreated controls t-test, P < 0.28) and conserved more neurons in defined regions outside the lesion epicenter (drug-treated animals vs untreated controls: 299 vs 73 neurons/mm2; t-test, P < 0.009). Thus, although MK-801 was only partially effective in preventing neuronal death secondary to contusion injury it appeared to have a definite neuroprotective effect. In view of the variety of side effects of MK-801 and the controversy on the mechanism of neuroprotection, we examined the action of the drug on non-injured animals. The effects of the drug were strongly sex-dependent. One hour after subcutaneous injection (0.5 mg/kg), female rats were hypothermic (36.8 degrees C treated vs 38.3 degrees C control) whereas male rats were hyperthermic (39.6 degrees C treated vs 38.4 degrees C control). In females, MK-801 caused cessation of cycling and appearance of numerous polymorphonuclear (PMN) phagocytes in vaginal frotis. Also, beginning 24 h after MK-801 injection, the proportion of PMN increased 400% in female blood, whereas males maintained control values. Arthritis-like joint inflammation was prominent in the toes of female rats, but males were unaffected. After continued treatment with the drug for 15 days, PMN count in female rats decreased and the animals resumed cycling. However, during this period female rats lost 20% of their weight, whereas males gained 26%. One hour after MK-801 injection large increases in blood pressure occurred in both sexes, returning to normal values 2 h later. Hypothermia does not appear to be a factor in the neuroprotective effect of MK-801, but the drug has a number of potentially dangerous side effects, particularly in female rats. Because polymorphonuclear cells are known sources of oxygen free radicals, neuroprotection by MK-801 treatment ought to be much more efficient in males than in females and the drug should be used in combination with a free-radical scavenger. PMID- 21551602 TI - Spinal cord microglial cells and DRG satellite cells rapidly respond to transection of the rat sciatic nerve. AB - Transection of the rat sciatic nerve induces retrograde changes in the dorsal root ganglia (DRG) neurons and in the motoneurons in the ventral grey matter of the lumbar L4-L6 spinal cord segments. In the ipsilateral dorsal grey matter and in the ipsilateral nucleus gracilis, transganglionic changes occur in the terminal fields of the centrally projecting axons of injured DRG neurons. As revealed by immunocytochemistry, the neuronal reactions were associated with a rapid proliferation and activation of microglial cells in the lumbar spinal cord as well as in the nucleus gracilis. Reactive microglial cells were detected as early as 24 h after sciatic axotomy. The microglial reaction had a maximum around day 7 postlesion and disappeared around 6 weeks after axotomy. In addition to light microscopy, activated, perineuronal microglia were identified by immuno electron microscopy in the ventral grey matter. In the DRG, satellite cells constitutively expressed major histocompatibility complex (MHC) class II antigens. Sciatic axotomy led to a proliferation of satellite cells and an increased expression of MHC class II molecules in particular. This satellite cell reaction started 24 h after axotomy and continued to increase gradually until about 6 weeks after the lesion. Resident macrophages, detected in the DRG interstitial tissue by their expression of monocyte/macrophage markers, also reacted to sciatic axotomy. Our data suggest that (1) sciatic axotomy leads to a rapid microglial reaction in both the ventral and dorsal grey matter of the lumbar spinal cord and in the ipsilateral nucleus gracilis; (2) the immunophenotype of activated microglia following sciatic axotomy is comparable with that observed after axotomy of cranial nerves, e.g. the facial nerve; (3) satellite cells in DRG constitutively express MHC class II molecules; and (4) sciatic axotomy leads to a rapid activation of satellite cells and interstitial macrophages in the axotomized DRG. PMID- 21551603 TI - Intraspinal cellular responses after spinal cord transection in rats: neuronal expression of growth-associated protein (GAP-43). AB - The methods of non-radioisotopic in situ hybridization and immunocytochemistry were used to visualize sites of GAP-43 expression after a mid-thoracic spinal cord transection in adult rats. Neurons which expressed moderate to high levels of GAP-43 mRNA and showed strong GAP-43-like immunoreactivity were located immediately above the lesion site as well as at greater distances from the lesion site in the lower cervical and mid-lumbar spinal cord. The results of this study suggest a widespread occurrence of lesion-induced neuroplastic changes and may indicate that the increase in GAP-43 expression can be caused by axotomy, deafferentation and increased compensatory motor activity in the spinal cord of paraplegic rats. PMID- 21551604 TI - The axonal response after ventral root avulsions at the cervical 7 level in the cat spinal cord. AB - The ventral cervical 7th root was avulsed from the adult cat spinal cord and the reaction of the torn axons in the underlying white matter was studied by light microscopy using histochemical staining for acetylcholinesterase and immunocytochemical staining for neurofilament and by electron microscopy, after different survival times. One day postoperatively some of the torn axonal ends were enlarged in the intraspinal trajectory of the root fibers in the white matter between the ventral horn and the pial surface as observed by acetylcholinesterase staining. The formation of terminal clubs had accordingly started at this postlesional survival time. From day 2, terminal clubs positive to neurofilament antibody were found. The number of terminal clubs increased during the first 4 days after the avulsion, remained present at 30 days and then disappeared gradually during the next months. One such unmyelinated axonal terminal club was studied at the ultrastructural level. From its distal end an unmyelinated protrusion emanated which appeared myelinated on the most distal part. This protrusion may be the ultrastructural parallel of the ramifications from terminal axonal clubs described by Ramon Y Cajal after avulsion. PMID- 21551605 TI - The neurotrophin family of NGF-related neurotrophic factors. AB - The recent molecular cloning of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) has established the existence of an NGF-related family of neurotrophic factors - the neurotrophins. Purification and recombinant production of BDNF and NT-3 has allowed the initiation or extension of in vitro studies of the neuronal specificity of each of these factors. We have found that NT-3, like NGF and BDNF, promotes survival and neurite outgrowth from certain populations of sensory neurons. There appear to be both distinct and overlapping specificities of the 3 neurotrophins towards peripheral neurons - sympathetic neurons and subpopulations of neural crest and neural placode-derived sensory neurons. Using cultures of central nervous system neurons, we have recently established that BDNF: (i) promotes the survival and phenotypic differentiation of rat septal cholinergic neurons, a property consistent with the discovery of high levels of BDNF mRNA expression within the hippocampus; (ii) promotes the survival of rat nigral dopaminergic neurons and furthermore protects these neurons from two dopaminergic neurotoxins, 6-hydroxydopamine (6-OHDA) and MPTP. Thus the neurotrophic effects of these factors towards peripheral neurons and neuronal populations known to degenerate in two of the major human neurodegenerative diseases - Alzheimer's and Parkinson's disease - provokes the question of whether neurotrophic factors may have therapeutic potential in halting the progression and ameliorating the symptoms of devastating neurological disorders of the CNS or PNS, or improving regeneration of neurons of CNS or PNS after traumatic injury. PMID- 21551606 TI - Neurite outgrowth over resting and reactive astrocytes. AB - A classic problem in CNS fiber regeneration is that the glial scar, generated after a lesion, is not crossed by regenerating axons. We know that reactive astrocytes are important in the formation of this barrier and that the barrier is not mechanical. However, its precise nature remains unclear. To study interactions of normal and reactive astrocytes with central neurites, we have attempted to create an in vitro model of the glial scar. We found the following: (1) Cultured astrocytes, independently of their lineage, morphology, immunological type and treatment with differentiating agents, induced profuse neurite outgrowth from various kinds of embryonic CNS neurons. The outgrowth was comparable to that elicited by laminin. (2) Membranes from isomorphic gliotic tissue (induced by deafferentation or excitotoxic injury and containing a large number of reactive astrocytes), inhibited central neurite outgrowth as powerfully as myelin. Reactive astrocyte membranes from areas of anisomorphic gliosis (following penetrating trauma) were permissive for neurite outgrowth, but growth was more limited than on cultured astrocyte membranes. (3) When given a choice, growing neurites actively avoided membranes from isomorphic gliosis (similar to myelin), while they seemed to follow anisomorphic membrane boundaries and crossed unhindered into membranes of cultured astrocytes. In conclusion, reactive glia seem to contain both inhibitory and neurite promoting molecules, the proportion of which depends on the way gliosis has been generated. For isomorphic reactive astrocytes the balance is inhibitory for central neurite outgrowth, while anisomorphic reactive astrocytes probably express inhibitory components at lower levels and the growth promoting factors predominate. Overall, our observations suggest that reactive astrocytes are still the major problem for axonal regeneration in the CNS. PMID- 21551607 TI - Glial support of CNS neuronal survival, neurite growth and regeneration. AB - In an attempt to identify specific molecular and cellular requirements necessary to support long-term maintenance and differentiation of central neurons we have identified laminin-HSPG and free fibronectin as two major neurite promoting substrate adhesion factors released by immature cerebral astrocytes in serum-free culture. Astrocytes further secrete diffusible neurotrophic protein factor(s) which are permanently required for survival of cultured neurons from various brain regions. However, both the presence of substrate-bound neurite-promoting factors and diffusible neurotrophic activities were not sufficient to support long-term maintenance of central neurons in culture. Cell contact-mediated interactions which appear to be cell type-restricted (e.g. to neurons and astrocytes, but not to fibroblasts) are further required for neuronal stabilization. The implantation of immature astroglial cells into the injured adult CNS should provide a supportive environmental condition for damaged neurons to enhance their recovery and stimulate regenerative responses. PMID- 21551608 TI - Regrowth of lesioned retinal axons associated with the transplantation of Schwann cells to the brachial region of the rat optic tract. AB - Attempts were made to enhance the regrowth of retinal axons which had been lesioned in the brachial region of the rat optic tract. Pieces of nitrocellulose paper (Millipore) were placed into the lesioned area between the dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC) in 13- to 18-day-old Wistar rats. Five types of implant were used: (1) uncoated implants, (2) coated with Poly-l-lysine (PLL), (3) coated on one side with cortical astrocytes, (4) coated with tectal astrocytes and (5) coated with Schwann cells. About half the Schwann cell-covered implants were precoated with PLL. Schwann cell-coated implants (16-40 * 103 cells per implant) were placed with the cells lying on either the dorsal or ventral (inverted) surface of the paper. 5-7 weeks after surgery, eyes were injected with WGA-HRP, the animals were perfused and frozen or vibratome sections (40-50 MUm) processed for TMB histochemistry. Selected sections containing retinal axons were osmicated and prepared for electron microscopic examination. 45 out of 86 implants were found attached to the caudal dLGN. A small number of retinal axons were found growing onto the rostral end of one uncoated implant, two PLL-coated implants and over the surface of 4 of the astrocyte-coated implants. The densest and most extensive growth was seen on the Schwann cell-coated implants. In 15 of the 30 animals with such implants attached to the dLGN, retinal axons were found regrowing for 50-1120 MUm (mean 530 MUum). In about half of these rats (8 out of 15), the regrowth involved relatively large numbers of optic axons which were sometimes densely packed together. In the subgroup of Schwann cell-coated implants where the cells were placed upwards, retinal axons regrew on the dorsal surface of the paper for more than 500 MUm in 7 animals. Almost no growth was seen on the uncoated (ventral) surface of the implants. In the subgroup of inverted implants, where the Schwann cells were placed downwards, in 4 animals retinal axon regrowth was densest on the ventral surface and extended for 300-550 MUm. In 3 cases, occasional axons were also seen on the dorsal implant surface. Myelin sheaths surrounding some of the regenerating axons had PNS characteristics, suggesting that they were formed by the implanted Schwann cells, but most of the myelin appeared to be of central origin. The data suggest that Schwann cells placed just caudal to the dLGN and adjacent to lesioned retinal axons can enhance and direct the regrowth of these axons in the rat optic tract. PMID- 21551609 TI - Rat corticospinal tract fibers regenerate in the presence of antibodies to myelin associated neurite growth inhibitors. PMID- 21551610 TI - Anatomical and physiological assessments of peripheral nerve grafts in the dorsal columns of the spinal cord. AB - Portions of 1 cm length of the sensory radial nerve from the cat forelimb were used to replace an excised portion of the dorsal columns in the upper lumbar spinal cord. Observations were made on the clinical recovery of the animals, and cine recordings were made of their ability to traverse a horizontal ladder 5 months after the grafting procedure. Evoked sensory potential studies performed 6 months after grafting showed that an impulse arising from a stimulus applied to the sciatic nerve could be recorded in the spinal cord caudal to the graft, in the graft and in the spinal cord rostral to the graft in 5 out of 8 animals. Tracing of nerve connections with injection of horseradish peroxidase into the grafts resulted in labelling of nerve cell bodies in dorsal root ganglia and the grey matter of the lumbar spinal cord up to a distance of 10 mm away from the graft. These results confirm that peripheral nerve grafts can provide a satisfactory environment for the regrowth of ascending fibres in the dorsal columns of the spinal cord. However, there is as yet no evidence that the regenerated fibres succeed in forming useful synaptic connections with other nerve cell bodies. PMID- 21551611 TI - Vertebrectomy and its possible use in repair of spinal cord injuries by neural transplantation. AB - Spinal cord (SC) injury followed by autodestruction and resection of damaged tissue necessarily leads to the formation of a gap between the disconnected cord stumps. For any attempts to reconstruct the transected cord it may accordingly be useful to narrow or close this gap. Physically this can be achieved by vertebral resection with shortening of the spinal column. In cats and rabbits the dynamics of SC autodestruction was examined, and a technique for removal of autodestructed tissue developed, together with a surgical technique for resection of the second lumbar vertebra. By means of these techniques the volume of the gap between the SC stumps in rabbits was reduced from 200 mm3 to almost zero. In future research this should allow use of neural grafts of a reasonably small volume. PMID- 21551612 TI - Grafted fetal astrocyte migration can prevent host neuronal atrophy: comparison of astrocytes from cultures and whole piece donors. AB - In a 'double blind' study, 2 series of adult rats were trained to traverse a narrow bar or a horizontal ladder for a water reward. Hindlimb placement (measured as hindlimb foot slips) of the subjects trained on the narrow platform was ranked. The subjects traversing the ladder were videotaped and the number of hindlimb slips counted. After reaching criterion (10 complete traverses on each of 2 consecutive days), all animals had the fasciculus gracilis (FG) of the third cervical spinal cord segment (C3) aspirated to sever hindlimb dorsal column afferents. After aspiration of C3FG the subjects were randomly placed in an aspiration-only (controls) or aspiration + graft group. All grafts were prelabeled with the plant lectin Phaseolus vulgaris leucoagglutinin (PHAL) as a graft-derived cell marker. The grafts were either unoriented whole pieces of E14 fetal spinal cord or 105 purified, cultured, E14 fetal spinal cord astrocytes. Subjects were tested at intervals over 90 days. Aspiration of C3FG and a graft of whole pieces of E14 fetal spinal cord resulted in a statistically significant improvement in hindlimb placement at 21 and 90 days (P < 0.05) when compared to controls. In contrast, animals with cultured, purified, E14 fetal spinal cord astrocyte grafts had significantly worse (P < 0.05) hindlimb placement than controls. Immunohistochemical double staining for PHAL and glial fibrillary acidic protein in the same cell showed that astrocytes from both types of grafts migrated to the nucleus gracilis (NG) of the medulla of the host. The grafted fetal astrocytes from the whole piece grafts prevented denervation atrophy of the host NG neurons, whereas cultured grafted fetal astrocytes did not demonstrate this effect. After grafting donor tissue that contained astrocytes into the injured spinal cord there were two accompanying classes of astrocytes. One class derived from whole piece, E14, fetal spinal cord grafts migrated to the NG of the host, prevented atrophy of host NG cluster and interneurons, and improved hindlimb placement. The other class, derived from cultures of E14 fetal spinal cord astrocytes, migrated to the NG of the host, failed to maintain the size of cluster neurons and interneurons of the host NG, and resulted in a greater hindlimb placement deficit when compared to controls. These data suggest that improvement of hindlimb placement due to graft-derived fetal astrocytes in injured host spinal cord was due to the ability of the astrocytes to maintain host neurons and neuronal networks. PMID- 21551613 TI - Immunological reactions to neural grafts in the central nervous system. AB - Immunological rejection is a lasting, although highly variable, threat to allo- and xenogeneic neural tissue grafted to the CNS of rodents, monkeys and man. One major determinant for rejection of intracerebral CNS grafts appears to be induction of major histocompatibility complex (MHC) antigens on the donor CNS cells. We have previously examined the cellular immune response against neural mouse xenografts undergoing rejection in the adult rat brain. In this study we focus on the astro- and microglial reactions within and around the graft, and the potential of individual host rat and donor mouse brain cells to express MHC antigens. Previous light microscopical observations of expression of rat MHC antigen class I by endothelial cells, microglial cells, and invading leukocytes were extended to the ultrastructural level and found to include a few astrocytes. Rat and mouse MHC antigen class II was only detected on leukocytes and activated microglial cells. The findings imply that within grafts of brain or spinal cord tissue donor astrocytes, microglial cells and endothelial cells can be induced to act as target cells for class I specific host T cytotoxic cells, while only (graft and host) microglial cells can be induced to express MHC antigen class II and present antigen to sensitized (and possibly also resting) host T helper cells. PMID- 21551614 TI - Fetal neural transplants into an area of neurodegeneration in the spinal cord of the adult rat. AB - Lesioning the spinal cord with an excitotoxic agent provides a model of neuronal degeneration while sparing afferent axons. The present study has been undertaken to determine whether homotypic fetal neurons transplanted as a cell suspension were able to rebuild a neural circuitry in the neuron-depleted adult cord. Fetal spinal cords, taken from rat embryos (gestational day E12-13), were transplanted as cell suspensions into an area of the lumbar cord previously depleted of neurons using kainic acid. The excitotoxic lesion extended over ventral and intermediate horns, implying the death of all motoneurons with consequent paralysis and muscular atrophy of corresponding hindlimb. During the first month after injection, the damaged cord was characterized by proliferation and recruitment of various glial cell and Schwann cell populations. First to appear were activated microglia/macrophages and next reactive astrocytes which entered the lesion from its borders with the intact tissue. Schwann cells also ensheathed central axons. Differential sensitivity of various afferents to loss of postsynaptic target neurons was observed: rubrospinal and corticospinal afferents decreased in density while no conspicuous changes were observed for immunostained CGRP-containing or monoaminergic fibers. Two to fourteen months after surgery, transplants occupied most of the neuron-depleted area. The grafts did not display a laminar organization. Monoaminergic afferents grew for a long distance and formed a network within transplants. Similarly, primary sensory CGRP immunoreactive fibers entering in the dorsal roots penetrated deeply into transplants. In contrast, cortico- and rubrospinal afferents entered only the most peripheral portion of transplants. Our results indicate that fetal spinal neurons can be successfully transplanted into the adult neuron-depleted spinal cord. Host-to-graft connections can be formed, although their spatial extent in the transplants may depend upon features of the afferent fiber systems. PMID- 21551615 TI - Co-transplantation of embryonic neural tissue and autologous peripheral nerve segments to severe spinal cord injury of the adult rat. Guided axogenesis from transplanted neurons. AB - The present study is the first of a series of experiments designed to investigate the possibilities of reconstructing the severely injured spinal cord by means of transplantation techniques. Special attention has been given here to the capability of transplanted embryonic neurons to extend axons into autologous peripheral nerve grafts (PNGs). A cavity, made unilaterally in the cervical enlargement of the spinal cord of adult rats, was filled with solid pieces of different embryonic tissues: spinal cord (SC), cortex (CT) or dorsal root ganglia (DRG). In more than half of the transplanted animals, one end of a PNG was inserted into the center of the transplants, while the other, extraspinal end, was crushed and tied to peripheral tissues. After a postgrafting period ranging from 1 to 6 months, we found that the 3 types of transplants in general had survived and become integrated with the host spinal cord, although their overall organization remained atypical. Surviving graft neurons had developed processes, some of which had become myelinated. The ability of the grafted neurons to extend axons into the PNG differed strikingly from one type of graft to another, being apparently non-existent for cortical grafts, moderate for spinal cord grafts and quite extensive for dorsal root ganglia transplants. Interestingly, these differences reflected what was observed for the corresponding, fully differentiated qeurons in adult animals, when their cut axons were put in contact with non-neuronal components of peripheral nerves. PMID- 21551616 TI - Embryonic motoneurones grafted into the spinal cord of an adult rat can innervate a muscle. AB - We have previously shown that motoneurone-like cells from embryonic grafts survive and migrate into the host neuropil of adult rat spinal cord, depleted of some of its own motoneurones. We moreover demonstrated that a muscle, when connected at the site of the graft to the spinal cord of the host by its own nerve, was reinnervated by motoneurones that could be identified by retrograde labelling with HRP [11]. However, it was not clear whether these retrogradely labelled motoneurones were of graft origin. In this study we combined the use of an embryonic marker with retrograde labelling to demonstrate that grafted neurones of embryonic origin can indeed innervate a soleus muscle implant. Embryonic donor cells were labelled with bromodeoxyuridine (BrDU) by its incorporation into replicating DNA during neurogenesis. The nuclei of grafted cells were then identified in host cords by immunocytochemistry, visualising the BrDU positive nuclei with the fiuorophore Texas Red, while the fluorescent dyes Fast Blue and Diamidino Yellow were used for retrograde labelling. Examination of frozen spinal cord sections by fluorescence microscopy, at wavelengths appropriate to each fiuorophore, showed that about 12% of the neurones innervating the muscle implant also contained detectable amounts of BrDU and therefore were of graft origin. PMID- 21551617 TI - Transplants of syngeneic adult dorsal root ganglion neurons to the spinal cord of rats with acute traumatic paraplegia: morphological analyses. AB - Neurons and non-neuronal cells were harvested from adult rat dorsal root ganglia and transplanted to syngeneic adult rat spinal cord. Transplants were performed in intact rats and after acute traumatic paraplegia induced by inflation of a subdural microballoon. Only the first histopathological results are presented here. Transplants were well tolerated and fused with the surrounding host tissue. Survival of neurons within the grafts appeared better in the injured cords than in the intact ones. Some of them expressed neuropeptides known to be present in DRG in situ. Few interactions were found with morphological methods between the transplants and the host spinal cord. Some peptidergic fibers were seen crossing the graft-host interface; most fibers probably originated from host spinal fiber systems. The perspectives and limitations of the presently described type of spinal transplantation are discussed. PMID- 21551618 TI - Delayed grafting of fetal CNS tissue into chronic compression lesions of the adult cat spinal cord. AB - This review summarizes a series of experiments involving transplants of embryonic feline CNS tissue into chronic compression lesions of the adult cat spinal cord. Fetal spinal cord (FSC), caudal brainstem (BSt), neocortex (NCx) or a combination of either FSC/NCx or FSC/BSt was transplanted as solid pieces or as a suspension of dissociated cells into the developed cystic cavities produced by static-load compression trauma 2-10 weeks prior to grafting. All cats were immunosuppressed with cyclosporin A and their locomotor function was assessed for 6-30 weeks. Following the period of evaluation, all recipients were perfused with fixative and tissue specimens, taken at the transplantation site, were processed for general histological and/or immunocytochemical analysis. Viable graft tissue was found in all animals with the exception of two cats which showed active rejection of their transplants. All of the viable intraspinal grafts were extensively vascularized and did not show any signs of imminent or on-going tissue rejection. Fetal cat CNS grafts showed an extended maturational phase in that features of immature neural tissue (e.g. a paucity of myelination) were still seen even 6-9 weeks after transplantation. By 20-30 weeks, FSC and BSt grafts had attained a more advanced stage of maturation. Transplants in these chronic lesions were extensively blended with both the gray and white matter of the host spinal cord and could be visualized by magnetic resonance imaging (MRI). MRI could also detect regions of cavitation at the graft-host interface, as well as within some transplants. While preliminary evidence from behavioral studies suggest that the FSC and BSt grafts may improve or spare locomotor function in some recipients, a more rigorous analysis of post-grafting locomotor function is required to determine conclusively the functionality of these transplants. PMID- 21551619 TI - CNS transplants promote anatomical plasticity and recovery of function after spinal cord injury. AB - We are using neural tissue transplantation after spinal cord injury to identify the rules which determine the response of young neurons to injury, to identify the mechanisms underlying anatomical plasticity and recovery of function following spinal cord injury, and to determine the conditions which change during development, leading to the more restricted growth capacity of mature neurons following injury. Spinal cord lesions at birth interrupt different pathways at different relative stages in their development. Neural tissue transplants modify the response of the immature central nervous system neurons to injury. In the current studies, we have used neuroanatomical and behavioral methods to compare the response of the late-developing corticospinal pathway with that of brainstem spinal pathways which are intermediate in their development and that of the relatively mature dorsal root pathway. We find that both late-developing and regenerating neuronal populations contribute to the transplant-induced anatomical plasticity, and suggest that this anatomical plasticity underlies the transplant mediated sparing and recovery of function. PMID- 21551621 TI - Restitution of function; a research goal for the decade of the brain. PMID- 21551620 TI - The use of behavioral methods to predict spinal cord plasticity. AB - The mechanisms underlying recovery of function following damage to the CNS, although suspected, are virtually unknown. After damage to the adult cat spinal cord, recovery of motor behavior depends on which systems have been interrupted and which remain intact. For example, following hemisection, overground (voluntary) and reflex locomotion recover and, although a normal kinematic pattern recovers, accurate placement of the limb during locomotion does not return to normal levels. This recovery is associated with lowering of thresholds for postural reflexes suggesting that increased afferent input may compensate for diminished descending control. In contrast, after unilateral loss of afferent input by lumbosacral deafferentation, (L1-S2 dorsal roots cut) overground locomotion recovers but a permanently abnormal kinematic pattern is used; reflex locomotion (bipedal locomotion on a treadmill) does not recover at all in the deafferented hindlimb. The specificity of the recovery suggests that increased input from descending pathways, which is required for overground but not reflex locomotion may compensate for loss of afferent input. Anatomical sequellae of these two lesion types have been examined. Studies after hemisection support the notion of a permanently increased dorsal root input as mapped by monoclonal antibody 'rat 102'. This is associated with a transient increase in GAP-43 labeling in the dorsal horn. In contrast, after deafferentation an increase is found in the descending serotonergic input to the deafferented side. These observations suggest that recovery of specific locomotor behavior can be used to predict compensatory changes in spared pathways. For the study of the effects of transplants, we have used complete spinal transections in newborn kittens with transplantation of E26 cat spinal cord into the transection site. The normal kitten develops overground locomotion beginning the end of the first week postnatal but reflex locomotion is delayed until the end of the second week. After transection on the first day of life, with or without a transplant, reflex locomotion begins precociously. Overground locomotion fails to develop in transection-only animals but does develop in animals with transection and transplant. This locomotion although clearly abnormal, shows postnatal development in terms of weight support and lateral stability. Furthermore, there is some indication of coordination between fore and hind limbs. These observations suggest that the transplants permit the development of some descending control although the anatomical correlates of this sparing/recovery of function are uncertain; the transplant rescues neurons caudal to the transection and also permits regeneration of some descending pathways into the transplant and caudally into host spinal cord. PMID- 21551622 TI - Susceptibility to pentylenetetrazol-induced and audiogenic seizures in rats given aspirative lesions of the fimbria-fornix pathways followed by intrahippocampal grafts: a time-course approach. AB - Long-Evans female rats sustained aspirative lesions of the fimbria-fornix pathways and part of the overlying structures (Lesion). Eight or 9 days later, one third of these lesioned rats received intrahippocampal septal cell suspension grafts (Sept-G) and another third received grafts of hippocampal origin (Hipp-G). Sham-operated rats (Sham) served as controls. For each surgical treatment, 3 subgroups were assigned to one of 3 experiments which differed by the delay separating grafting from testing. Three months (EXP1), seven months (EXP2) and twelve months (EXP3) after grafting, rats were tested for reactivity to pentylenetetrazol (PTZ, 30 mg/kg, i.p.) and to sound (10-20 kHz peaks, 120 dB, 90 s), two models of generalized convulsive seizures. Three months after grafting, lesion-only rats showed increased reactivity to PTZ as compared to Sham rats; both types of grafts (Sept-G, Hipp-G) attenuated this lesion-induced effect. Whether 7 or 12 months after grafting, no significant between-group differences were observed anymore. Three months after grafting, reactivity to sound tended to increase in lesion-only rats and was significantly increased in both groups with grafts (Sept-G, Hipp-G) as compared to the Sham group. Seven months after grafting, only Hipp-G rats showed increased reactivity to sound compared to Sham or lesion-only rats. No significant between-group difference was observed at 12 months post-grafting. At all 3 delays, histological analyses revealed well integrated grafts, but only septal grafts provided the denervated hippocampus with an AChE-positive fiber ingrowth. Reactivity to PTZ or to sound was correlated neither with the size of the graft, nor with the acetylcholinesterase (AChE)-positive graft-derived reinnervation of the dorsal hippocampus. The present results suggest that hippocampal denervation may result in a temporary increase in reactivity to PTZ and susceptibility to sound, the former being transitorily attenuated and the latter being transitorily increased by both kinds of grafts. Our data confirm earlier reports showing that grafts may influence sensitivity to convulsive seizure-inducing treatments. In addition, these data indicate that this influence is not necessarily lasting and that the kind and duration of this influence is dependent upon the model of convulsive seizures used. PMID- 21551623 TI - Changes in myelinated and unmyelinated axon numbers in the proximal parts of rat sural nerves after two types of injury. AB - Counts of myelinated and unmyelinated axon profiles have been made from normal, uninjured rat sural nerves and from nerves injured 6 months earlier in one of two ways. In one group of rats the nerve was simply cut and left to regenerate, leading to the development of a neuroma in continuity, while in the second group the nerve was cut but then ligated as well to prevent regeneration; this led to stump neuroma formation. After nerve transection and regeneration, with subsequent formation of a neuroma in continuity, there was no change in the number of myelinated axon profiles found 25 mm proximal to the old injury site when compared with control, but there was an 18% reduction (P < 0.05) in the number of unmyelinated axon profiles. Immediately proximal to the injury site the picture was similar, with there still being the same number of myelinated axon profiles as in control material but here the reduction in unmyelinated axon numbers was slightly greater at 24% (P < 0.05). In the proximal part of nerves that had been cut and stump neuroma formation induced there was a large increase (33%) in myelinated axon profiles over and above control values (P < 0.001) but the number of unmyelinated profiles was the same as in controls. Closer to the stump neuroma the number of myelinated axon profiles had increased yet further to be 88% (P < 0.001) above control while the number of unmyelinated ones remained no different from control. Our interpretation of these results is that after nerve transection and regeneration there is no loss of peripheral neurons supporting myelinated axons but some loss of those supporting unmyelinated ones. If a cut nerve is prevented from regenerating and a stump neuroma forms, however, a vigorous sprouting response is triggered in neurons with myelinated axons while those supporting unmyelinated axons are possibly prevented from dying. The reaction of peripheral neurons to injury is such that the number of axons they support varies along the nerve as one goes disto-proximally away from the injury site. Thus discrepancies in results from different laboratories have come about because material for axon counting has been taken from different points along the nerve relative to the injury site and also because the material has been taken from nerves injured in different ways. PMID- 21551624 TI - Comparison of fibrin glue, bioresorbable tubing and sutures in peripheral nerve repair. AB - Regeneration of severed rat tibial nerves was functionally and morphologically compared with repair following the use of 3 anastomosis techniques: collagen guide tubes, fibrin glue and conventional microsurgical sutures. In addition, one tibial nerve was crushed in some rats. At ten weekly intervals, functional recovery, assessed by sciatic nerve stimulated evoked contraction of the flexor digitorum muscle, was quicker and more complete following nerve crush than following the anastomosis techniques which were not different from each other. Ten weeks following the surgery, the retrograde transport morphological technique indicated that the anastomosis techniques were not different from each other. The number of labeled tibial motoneurons (tube and suture groups) was significantly less than the crush group, but the glue group was intermediate. Thus, although having less extensive recovery following crush, the quicker and easier techniques of nerve repair, i.e., collagen tubes or fibrin glue, produced comparable anatomical and functional recovery as the more time-consuming, technically demanding microsurgical repair with fine sutures. PMID- 21551625 TI - A computational test of the requirements for conduction in demyelinated axons. AB - Conduction in demyelinated and remyelinating axons has been simulated with a computational model. The calculations made use of recent determinations of ionic channel densities in the internodal axolemma of Xenopus fibers. Several new morphological measurements reduced the number of parameters not directly obtained from experimental data. Action potentials and ionic currents were calculated for a wide range of fiber diameters and internodal lengths. The earliest stage of remyelination, characterized by Schwann cell attachment and extension of processes, was simulated by covering just a small percentage of the internode by a single cell layer. Conduction invariably failed if the internodal Na+ channel density was zero. The minimum density required for successful propagation agreed well with that measured in loose patch clamp experiments. Lateral diffusion of Na+ channels from nodes of Ranvier into the demyelinated internode did not restore conduction in blocked axons, and this was true regardless of the initial internodal Na+ channel density. Decreases in the internodal K+ channel density improved the safety factor for conduction, but this was significant only in the largest axons. Simulating minimal paranodal demyelination by eliminating the axo glial junctional seals did not result in conduction block, but did produce large conduction delays. PMID- 21551626 TI - Collagen-cliondroitin-6-sulfate hydrogel implants in CNS lesion cavities favor glial repair, the differentiation of co-implanted neurons and the growth of axons. AB - Collagen chondroitin-6-sulfate hydrogels containing embryonic striatal neurons were implanted into premade brain cavities of the rat striatum. The bioimplant was progressively transformed into a new matrix mostly by the deposition of newly formed collagen and by the ingrowth of glial cells and glial cell processes. At two months, the new matrix has partly restructured the lesion cavity. Cells co implanted with the hydrogels attached, survived and differentiated while nerve fibers of the host striatum grew into the biomatrix. PMID- 21551627 TI - Repair and Regeneration of the Cochlea (RNID Symposium Number 4). PMID- 21551628 TI - Effect of MPTP on primate chromaffin cells in vitro: relevance for adrenal medullary cell transplantation. AB - Primate adrenal medullary cells were exposed to l-methyl-4-phenyl-l,2,3,6 tetrahydropyridine (MPTP) in vitro to examine the effect of this neurotoxic agent on chromaffin cells. Chromaffin cells from monkey and humans were cultured in the presence of 100 ng/ml nerve growth factor for 1 week and then exposed to 150 MUM MPTP or its active metabolite methylpyridinium ion (MPP+) for an additional week. Cells which had extended neurites in the presence of NGF showed no morphological effect in response to MPTP or MPP+ at the light microscopic level. However, there was a significant loss in catecholamines as seen by histofluorescence and high performance liquid chromotography (HPLC). Electron microscopy revealed a depletion in dense-core vesicles in chromaffin cells after chronic exposure to MPTP while the mitochondria appeared similar to those observed in control cells. Replacement of MPTP medium with standard medium stimulated restoration of catecholamine histofluorescence after 7 days. An acute 15 min pretreatment of chromaffin cells with MPTP or MPP+ induced secretion of catecholamines over a 1 h pulse, with MPP+ producing the maximum and more rapid secretion as determined by HPLC. These data indicate that MPTP induces a dramatic loss in catecholamines in primate chromaffin cells in vitro after both acute and chronic exposures; however, removal of the toxic agent permits restoration of catecholamines without permanent effect on the integrity of these cells. PMID- 21551629 TI - The behavioral and anatomical effects of prenatal umbilical cord clamping in the rat and their alteration by the prior maternal administration of nimodipine. AB - This study investigated the effects of fetal rat umbilical cord compression on anatomical, biochemical, and behavioral parameters of development. Further, the study examined the ability of the calcium channel antagonist nimodipine to afford protection from this insult. Near the day of birth (E21), the umbilical cord of individual fetuses was not clamped or clamped for 2, 6, or 12 min. Before clamping, mothers were given 70 MUg/kg (i.p.) nimodipine in a polyethylene glycol (PEG) vehicle or the vehicle alone. Selected animals were sacrificed for cytochrome oxidase histochemistry. The remainder of the pups were given to foster mothers and allowed to develop through adulthood. At the end of testing all animals were sacrificed and the brains weighed and measured. Histochemical analysis revealed that clamping resulted in a decrease in cytochrome oxidase reaction product in the hippocampus. The reduction in this marker of oxidative metabolism was not as pronounced in animals from drug-treated mothers. Alterations in behavior produced by clamping were detectable as early as the third day after birth (P3). At this age, pups subjected to cord clamping exhibited impaired righting and diminished avoidance of a 'cliff' on which they had been placed. On P67-P75, clamped animals exhibited hyperactivity in an open field, low rates of spontaneous alternation in a T-maze, and impaired learning and memory in a Pavlovian conditioned aversion-to-brightness test. The calcium channel blocker afforded protection from the effects of cord clamping, since the nimodipine-treated animals were less impaired in these behavioral tests. Animals that had been subjected to cord clamping showed reduced brain volumes and dimensions on P80. Nimodipine treatment normalized these parameters of brain development relative to non-clamped controls. Taken together, these results indicate that brief periods of umbilical cord occlusion near the time of birth can have both immediate and long-term effects on different parameters of development. In addition, the calcium channel blocker nimodipine affords partial protection from damage induced by compression of the fetal umbilical cord. PMID- 21551630 TI - Morphology of embryonic hippocampus transplants and generation of long-distance extrinsic graft fiber connections to the lateral septum and the entorhinal cortex in the mature rat brain. AB - Pyramidal neurons inside transplants of embryonic nervous tissue are capable of generating axonal extrinsic hippocampal fiber connections over considerable distances to appropriate target areas in the mature brain. The establishment of long-distance graft efferents to the lateral septum and to the entorhinal cortex was shown by retrograde transport of the tracers HRP and bisbenzimide which were injected into these areas after bilateral neurotoxic lesions of the hippocampus. Additional AChE-staining demonstrated the presence of an afferent cholinergic graft input mainly from the medial septum via the fornix. Morphological analysis of the transplants grafted as cell suspensions showed typical details of the original hippocampus cytoarchitecture with bands of pyramidal and granule cells. PMID- 21551631 TI - Cerebrovascular permeability in intracerebral implants of foetal basal forebrain cell suspensions. AB - Blood-brain barrier permeability was measured using [14C]-labelled a aminoisobutyric acid (AIB) quantitative auto-radiography in rats which had previously received unilateral ibotenate-induced lesions of the nucleus basalis followed by intracortical implantation of foetal basal forebrain cell suspensions. The permeability characteristics of intracortical transplants were found to be dependent upon the site of implantation. Superficial transplants were invariably associated with AIB transfer constants (Ki) 3- to 4-fold higher than those in corresponding contralateral host cortex. In transplants sited deep in host neocortex, Ki values were not significantly different from those measured in surrounding host brain tissue. PMID- 21551633 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551632 TI - Norepinephrine depletion impairs motor recovery following sensorimotor cortex injury in the rat. AB - Beam-walking in the rat provides a method for investigating the effects of drugs on motor recovery following unilateral injury to the sensorimotor cortex. In the present experiment, the impact of norepinephrine depletion on beam-walking recovery was investigated. Groups of rats were first given either the neurotoxin DSP-4 or saline. Two weeks later, the animals were trained at the beam-walking task. Rats were then subjected to either a unilateral sensorimotor cortex lesion or sham operation. Recovery of beam-walking performance was measured over the next 12 days. Pretreatment with DSP-4 significantly slowed the rate of recovery but did not significantly affect sham-operated rats. Norepinephrine was significantly diminished in both lesioned and sham-operated rats that had been given DSP-4. These results are consistent with the hypothesis that recovery of beam-walking in the rat is mediated, at least in part, through noradrenergic neurons. PMID- 21551634 TI - Collagen nerve guide tubes in the rat septohippocampal pathway. AB - Synthetic porous collagen tubes were implanted into the rat fimbria in order to determine whether such prostheses will permit axonal growth in the mature mammalian central nervous system (CNS). The tubes were found to slowly degrade over 4 weeks. In the majority of cases a distinct tissue core occupied the lumen of the tube and extended from the rostral (septal) end to the caudal (hippocampal) end. The core consisted of cellular aggregates of various cell types and blood vessels. In addition, the presence of axons within the tube lumen was demonstrated at both light and electron microscopic levels. Fibers within the tubes were visualized with noradrenergic histofluorescence and with neurofilament immunohistochemistry. Pretreatment of the tubes with nerve growth factor (NGF) resulted in circumferential disposition of the tissue core and an increase in acetylcholinesterase activity associated with the tube but no obvious change in axonal regeneration. No evidence was obtained for reinnervation of the hippocampal formation by cholinergic or noradrenergic fibers. These results indicate that porous collagen tubes will persist for several weeks within the mature rat CNS and can support axonal growth. PMID- 21551635 TI - Fetal substantia nigra and adrenal medullary grafts placed contralateral to the nigrostriatal lesion side induce a decrease in turning behavior but not in dopamine receptor density. AB - Motor asymmetries as well as changes in the density of postsynaptic dopamine receptors produced by unilateral denervation of the striatum have been reduced by both substantia nigra (SN) and adrenal medullary (AM) grafts. Since to this date all studies have placed the grafts on the side ipsilateral to the lesion, the purpose of this study was to determine whether similar effects can be obtained when grafts are placed contralateral to the denervated side. The results of this study showed that 6-hydroxydopamine-lesioned rats followed up to 150 days with contralaterally placed intraventricular fetal substantia nigra grafts and fetal adrenal medulla grafts have a reduction of turning behavior of 41% and 34% respectively. However, contrary to ipsilateral grafts no normalization of dopamine receptor density as measured by [3H]spiperone autoradiography was observed 6 months after SN grafts, however, after AM grafts normalization did occur except in the anterior portion of the striatum. These results suggest that the compensatory motor changes induced by the grafted tissues could be mediated by mechanisms unrelated to changes in receptor density. PMID- 21551636 TI - Behavioral effects of fetal substantia nigra tissue grafted into the dopamine denervated striatum: responses to selective D1 and D2 dopamine receptor agonists. AB - Grafts of fetal ventral mesencephalon/substantia nigra cell suspensions into the dopamine-denervated striatum have been shown to reduce many of the behavioral alterations associated with striatal dopamine depletion. In this report, the behavioral response to amphetamine, apomorphine, the D1 receptor agonist SKF82958, and the D2 receptor agonist LY171555 were tested before and after intrastriatal grafts of fetal substantia nigra, of fetal striatum or no implantation procedure in animals with unilateral dopamine denervation. Grafts of fetal substantia nigra tissue were associated with significant behavioral recovery, as indicated by decreased turning induced by amphetamine (P <= 0.005), SKF82958 (P < 0.005), and LY171555 (P < 0.002). These effects were significantly different from the response in animals that did not receive grafts (P < 0.05) and occurred in the absence of decreased apomorphine-induced turning. These data suggest that the response to selective D1 or D2 dopamine receptor agonists is diminished following grafts of fetal dopaminergic tissue and that this behavioral effect is dissociable from the phenomena of behavioral supersensitivity to apomorphine. In a subset of substantia nigra grafted animals, it was found that D1 or D2 dopamine receptor antagonists administered 30 min prior to apomorphine could significantly reduce apomorphine-induced turning. PMID- 21551637 TI - Quantification of synaptic density changes in the medial vestibular nucleus of the cat following vestibular neurectomy. AB - The synaptic density in the medial vestibular nuclei of the cat was analyzed after section of the ipsilateral vestibular nerve, using an anti-synaptophysin antibody as a nerve terminal marker. Synaptic areas of nuclei ipsilateral (test) and contralateral (control) to the lesion were measured to quantify synaptic loss (one week post-lesion) and synaptic site reoccupation during vestibular compensation (3 weeks and 5 months post-lesion). The results indicate that only 35% of the immunoreactive synaptic profiles in the media) vestibular nucleus were due to vestibular nerve input: the mean synaptic profile loss in the deafferented nucleus one week post-lesion was 35.25% (+/- 13.83). This loss was rapidly compensated overtime since it was reduced to 14% (+/- 13.25) 3 weeks post-lesion, corresponding to a synaptic restoration of approximately 60%. The synaptic density in the deafferented nucleus 5 months after neurectomy was not significantly different from that of the intact vestibular nuclei. These results suggest that vestibular neurectomy is followed by an axonal sprouting in the partially deafferented medial vestibular nuclei, which raises the question concerning the origins and the functional role of the new axon terminals in vestibular compensation. PMID- 21551638 TI - Extension of dorsal horn neurons into the severed and implanted dorsal root. AB - After dorsal root ganglionectomy in adult rats, the dorsal root was cut close to the spinal cord and implanted into the dorsal horn. Outgrowth from neurons in he dorsal horn of the spinal cord into the implanted dorsal root could be demonstrated after 3 months by means of retrograde HRP labeling. Double-labeling experiments showed that some of these neurons had retained their central projections while extending new processes into the implanted root. The possibility to reconstruct the sensory pathway by replacing the damaged primary sensory neuron with peripheral outgrowth from secondary sensory neurons is discussed. PMID- 21551639 TI - Nimodipine-enhanced survival of suboptimal neural grafts. AB - The present experiment was conducted to see whether nimodipine, a calcium channel blocker with the potential to protect vulnerable neurons, could improve the survival rate of striatal grafts under suboptimal conditions. The drug markedly improved graft viability of rats with near-term (E21) striatal implants. Untreated rats showed no surviving neurons while all treated rats showed surviving grafts rich in neuron. It did not affect the survival of striatal grafts from E14/15 donors into the striatum, in which the high rates of survival are normally obtained. PMID- 21551641 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551642 TI - Adverse effects of catecholaminergic drugs following unilateral cerebellar ablations. AB - The following experiment was designed to examine the effects of unilateral cerebellar cortex lesions and pharmacological postinjury treatments with catecholamine drugs on recovery of beam walking ability in rats. Rats trained on a beam walking task were initially given either amphetamine, haloperidol, or a combination of the drugs at 24 h after injury, and tested at various intervals after drug administration. Six total doses were given to animals at 5d intervals during recovery. All drugs retarded recovery of function on the beam walking task compared to saline controls. Animals with cortical lesions that involved the deep cerebellar nuclei showed no recovery on the beam, regardless of group assignment. Phenoxybenzamine and propranalol were both ineffective in reinstating the beam walking deficit in those animals that demonstrated recovery on the beam walking task. The results indicate that the cerebellum plays a particularly important role in recovery of beam walking ability, and may contribute to beam walking recovery commonly observed after sensorimotor cortex ablations. PMID- 21551643 TI - Morphological changes of retinal ganglion cells regenerating axons along peripheral nerve grafts: a Lucifer Yellow and silver staining study. AB - The morphology of the retinal ganglion cells (RGCs) with their axons regenerating along a peripheral nerve graft at different post-grafting periods was studied by the intracellular injection of Lucifer yellow (LY) and silver staining methods. Several morphological features which were observed on developing RGCs, but not mature RGCs, have also been observed in the regenerating RGCs studied by the intracellular injection of LY. These morphological features observed on the regenerating RGCs included intraretinal axonal branches and collaterals, spine like processes on the dendrites and soma, and short processes on the soma. These results suggest that damaged mammalian RGCs may be able to recapitulate certain cellular events which occur during normal development provided the regenerating cells are given the proper stimulus and a favorable environment for regrowth. From the results of both LY injection and silver staining experiments, it was found that the dendrites of the regenerating RGCs were, in general, much simpler than that of control Type I RGCs. However, regenerating RGCs with different degree of dendritic complexity could be observed in all post-grafting periods studied, and the dendritic complexity seems to decrease continuously with the increase in the post-grafting time. These results suggest that the ability to regenerate an axon is not closely related to dendritic responses and the peripheral nerve does not seem to be able to prevent the deterioration and retraction of the dendrites. PMID- 21551644 TI - Reduction of lesion-induced deficits in visual reversal learning following cross modal training. AB - Two experiments examined the effects of postoperative auditory intensity training on serial brightness reversal learning of visual decorticate rats. In Experiment 1 rats learned an avoidance response cued by a high intensity light prior to visual decortication. Six days later the rats were given either avoidance training with an auditory intensity cue, additional training with the preoperative visual cue, or no training. The next day all rats began a series of 8 brightness discrimination reversals. The no-training lesion group failed the early reversals but reached criterion in later reversals. Lesion rats retrained with visual cues failed early reversals with the low intensity light cue but not reversals with the high intensity cue. In contrast, lesion rats given auditory training easily reached criterion in all reversals. Experiment 2 followed a similar training sequence except auditory training was given after the second reversal. All rats showed rapid acquisition of all visual reversals subsequent to auditory training. These data suggest that generalization of a learning set by cross-modal transfer training with an intact modality can reduce reversal learning deficits following brain damage more efficiently than comparable training with the damaged system. PMID- 21551645 TI - Beneficial effect of the opioid receptor antagonist naltrexone on hyper sensitivity induced by spinal cord ischemia in rats: disassociation with MK-801. AB - In this study we examined the effect of the long-acting opioid antagonist naltrexone on the allodynia-like effect of spinal ischemia in rats. The spinal cord ischemia was induced at midthoracic level by a recently developed photochemical technique using laser irradiation and photoactivatable intravascular dyes. An allodynia-like sensory disturbance, where the animals reacted by vocalization to non-noxious mechanical stimuli in the flank area, was consistently seen during several days after ischemia. Pretreatment with 10 and 20 mg/kg, but not 5 mg/kg naltrexone i.v. 10 min before irradiation decreased the incidence of allodynia. However, even the effect of the highest dose of naltrexone (20 mg/kg) was incomplete, which is in contrast to the effect of the NMDA receptor antagonist MK-801, which has been tested in the same model and found to completely prevent the incidence of allodynia at a dose of 0.5 mg/kg. Pretreatment with sub- or suprathreshold doses of naltrexone (5 and 20 mg/kg respectively) combined with a subthreshold dose of MK-801 (0.1 mg/kg) did not produce a synergistic effect. When naltrexone (20 mg/kg) was administered 10 min after induction of ischemia, it was totally ineffective in decreasing the occurrence and severity of allodynia. In contrast, MK-801 (0.5 mg/kg) still had a good protective effect when injected as this time. Histological examination showed slight morphological damage in the spinal cord in 38% of control rats after 1 min laser irradiation without pretreatment with naltrexone. No morphological abnormalities were observed in rats after pretreatment with naltrexone (20 mg/kg). The results suggest that opioid receptor antagonists and NMDA receptor antagonists prevent a consequence of transient spinal cord ischemia through different mechanisms. High doses of opioid antagonists may have anti ischemic effects by improving local spinal cord microcirculation and therefore may have a role in preventing ischemia after traumatic spinal cord injury. On the other hand, the NMDA receptor may have a role in the secondary neuronal death resulting from ischemia. Thus, NMDA receptor antagonists may contribute to the prevention of tissue damage by antagonizing the excitotoxic action of glutamate and/or aspartate released by ischemia into the spinal cord. Finally, since only high doses of naltrexone had an effect in the present study, we cannot rule out the possiblity that this drug may act through non-opioid mechanisms. PMID- 21551646 TI - Effects of a Ginkgo biloba extract on two models of cortical hemiplegia in rats. AB - To screen drugs potentially useful in the pharmacological treatment of subjects with brain lesions, we studied the effects of chronic (7 and 30 days) treatments with a Ginkgo biloba extract (EGb761-IPSEN; EGb) in two animal models of cortical hemiplegia: one induced by motor cortex aspiration and another using a reversible inactivation of the motor cortex through chronic, localized infusion of y aminobutyric acid (GABA), via osmotic minipumps. The elevated beam test was used in water-deprived animals trained to drink saccharin-sweetened solutions (with or without EGb) and to perform to criteria before the surgical procedures. From the day after surgery, the rats were administered 100 mg/kg of EGb daily for 7 or 30 days. In all groups with motor impairment in which the extract was administered, a faster and more complete recovery was observed, which was significantly different from that of rats which received only saccharin solutions. The salutary effect of EGb was more marked in ablation-induced hemiplegia than in the GABA treated group. In the former injury model, EGb-treated animals had smaller ventricular diameters than non-treated rats. No differences concerning sensory deficits were detected among groups. EGb was also acutely administered during the epileptic syndrome that follows interruption of chronic GABA infusions (the GABA withdrawal syndrome). No anticonvulsant effects of EGb were observed. These results suggest a potential use of EGb in brain-injured patients as this product shows little toxicity in animals and man after chronic administration. The active principles among terpenes (ginkgolides, bilobalides and flavonolheterosides present in the EGb) and the mechanisms for this beneficial effects remain to be elucidated. PMID- 21551647 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551648 TI - alpha-Noradrenergic agonists and antagonists affect recovery and maintenance of beam-walking ability after sensorimotor cortex ablation in the rat. AB - Rats trained to traverse a narrow elevated beam were given a single intraperitoneal injection of either D-amphetamine, clonidine, L-phenylephrine, prazosin, yohimbine, or saline 24 h after ablation of the right sensorimotor cortex and tested for recovery of beam-walking (BW) ability to day 16 postsurgery. Clonidine, prazosin and L-phenylephrine did not significantly affect BW recovery. A 10 mg/kg dose of yohimbine significantly accelerated BW recovery, as did D-amphetamine (2 mg/kg). Since D-amphetamine and yohimbine both increase norepinephrine (NE) release and prior research has implicated NE but not dopamine in BW recovery, these data support the hypothesis that increased NE release benefits functional recovery in this model of cortical injury. However, a possible role of dopaminergic or serotonergic influences of D-amphetamine or yohimbine treatment cannot be ruled out. To investigate the role of the NE system in maintenance of recovery, animals recovered from BW deficits 18 days after injury were administered clonidine, prazosin, or yohimbine and retested on the BW task. Both the alpha1-NE antagonist prazosin (2 or 4 mg/kg) and the alpha2-NE agonist clonidine (0.1 or 0.4 mg/kg) produced a dose-dependent, transient worsening of BW performance. This reinstatement of deficits in recovered rats suggests that integrity of the alpha-NE system is necessary for maintaining functional recovery. PMID- 21551649 TI - Axonal projections and functional recovery following fascicular repair of the rat sciatic nerve with Y-tunnelled silicone chambers. AB - The projection of regenerating axons and the specificity of motor reinnervation were studied after repair of the transected rat sciatic nerve with Y-tunnelled silicone chambers. This geometry was used experimentally to face either the proximal tibial or peroneal fascicle with two distal fascicular options usually the distal peroneal and tibial fascicle. A 4 mm gap separated the proximal and distal fascicles. Four weeks after the repair, preferential motor reinnervation could be demonstrated and there were always more axons projecting towards the distal homonymous fascicle. In contrast, if the distal stumps were disconnected from the target no fascicle specific projection of axons was observed. This was true even if segments from the median and ulnar nerve were used to replace either the distal tibial or peroneal segments. It appeared as though the size and not the type of fascicle determined the number of attracted axons. The results suggest that there is no fascicle specific guidance of regenerating nerve fibers. PMID- 21551650 TI - Sabeluzole accelerates neurite outgrowth in different neuronal cell lines. AB - The outgrowth of neurites in neuronal cell cultures reflects the intrinsic capacity for neurite regeneration and morphological rearrangements after axotomy and in plasticity. The role of fast axonal transport in these neurite outgrowth responses has not been investigated. We have recently shown that sabeluzole (R58735), a new neuro-active compound increases fast axonal transport in cultures of hippocampal neurons. In rat hippocampal neurons, N4 neuroblastoma cells and adult rat dorsal root ganglion cultures, incubation with sabeluzole at an optimal concentration of between 0.1 MUM and 0.5 MUM enhances neurite outgrowth between 10 and 30%. The relative number of cells with neurite length greater than twice the cell body, is also increased dose-dependently. Time-dependent studies further indicate that the rate of neurite elongation is markedly enhanced during the first 24-48 h. This neurite enhancing effect of sabeluzole is discussed in relation to the enhancement of fast axonal transport. PMID- 21551651 TI - Radial maze performance after hippocampal lesions: beneficial effects of nimodipine. AB - Rats trained in an 8-arm radial maze were given electrolytic lesions of the dorsal hippocampus or sham operations. Within 24 h of surgery, approximately half of the rats in each groups began 14 daily oral treatments with the central calcium channel blocker, nimodipine. Retention testing began seven days after surgery. The untreated rats that received the larger hippocampal lesions did not relearn the maze within one month (2.5 times the preoperative mean number of days). The untreated rats that received the smaller lesions relearned within the allotted time but still showed clear deficits. Nimodipine improved the maze scores of the animals with the smaller lesions, but not those of the animals with the larger lesions. It was unclear whether nimodipine led to the sparing of more cells in the hippocampal region, or whether spared-but-affected cells were returning to normal modes of functioning more rapidly in the group with the smaller lesions. These findings suggest that spared hippocampus was mediating behavior, and extend previous findings from this laboratory showing that nimodipine can enhance recovery of function on higher cognitive tasks after hippocampal lesions. PMID- 21551652 TI - Phenotypic plasticity of 'mature' human foetal mesencephalic dopaminergic neurons and glial cells. AB - Human mesencephalic neurons from the second trimester have been cultured and characterised. Fresh, non-cultured cells were rounded and without processes post dispersion but in culture differentiated with neurite outgrowth when treated with 2 mMdibutyryl cyclic AMP in the absence of serum. This morphological differentiation could be reversed by the addition of the serine protease, prothrombin. Immunocytochemical staining for dopamine, tyrosine hydroxylase, neuron-specific enolase and glial fibrillary acid protein, demonstrated that dopaminergic, non-dopaminergic and glial elements responded similarly. The conditioned medium contained quantifiable levels of catecholamines as measured by HPLC. These findings are relevant to both developmental neurobiology and clinical neural transplantation, evidencing the considerable plasticity and functional integrity of mesencephalic cells in the second trimester as well as the influence of environmental factors. PMID- 21551653 TI - Use of amphetamine in the treatment of aphasia. AB - The effects of d-amphetamine on the recovery of aphasia following stroke was examined in 6 patients. Patients entered the study between 10 and 30 days post onset and were followed for 3 months. The Porch Index of Communicative Ability was used to project a 6 month recovery score. By 3 months post onset, 5 of the 6 patients obtained scores in excess of 100% of the 6 month projections. PMID- 21551654 TI - Interactive effects of insulin, IGF-I and GMl ganglioside on growth of PC12 cells. AB - PC12 cells grow in serum-free medium (SFM) if high doses of insulin (5-50 MUg/ml), or combined insulin (5 MUg/ml) and insulin-like growth factor-I (3 ng/ml) are added daily. Ganglioside GMl counteracts these effects in a dose responsive fashion between 10 nM and 50 MUM. This provides a serum-free system to study the interactive effects of gangliosides on growth and neuritogenesis in PC12 cells. PMID- 21551655 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551656 TI - Factors influencing structure and function of intracerebral grafts in the mammalian brain: a review. AB - After twenty years of intensive research, the possibility to induce recovery from various disorders in brain damaged mammals by means of intracerebral grafts of fetal CNS tissue is well documented and largely accepted by the scientific community. However, there are several reports on animal research suggesting that intracerebral grafts may fail to induce the expected recovery after brain injury or even that they may cause deficits which are actually more pronounced than those induced by the lesions alone. In addition, attempts to produce functional benefits with catecholamine-releasing tissue grafts in the brain of Parkinsonian patients have given limited and variable results; graft-induced deleterious effects have also been occasionally reported in a few clinical cases. One way to progress towards a better understanding of such disappointing, although informative, discrepancies between successful and less successful experimental studies and clinical trials would be to consider that there are several factors which may influence, in one direction or the other, the survival, development, integration and functional expression of intracerebral fetal CNS grafts. The present review considers the following factors: (i) some of the technical factors such as the constraints of transplantation surgery, the origin of donor tissue, the implantation site, the age of both the donor and the recipient, and tissue manipulations prior to grafting (i.e., cryopreservation, culture, genetic modification); (ii) exogenous and endogenous neurotrophic factors, the latter being distinguished by whether they may be host- or graft-derived; (iii) immunological factors (from the particular immunological status of the brain to some effects of immunosuppression in the case of xenografting)', (iv) pharmacological factors, with a particular focus on experimental data suggesting that administration of drugs may or might contribute to elicit, enhance or block some functional effects of grafts. It is concluded that all these factors may become simultaneously operative and interacting, thereby presiding over the functional outcome of intracerebral grafting in both experimental research and clinical trials. PMID- 21551657 TI - Target regulation of synaptic number in the expanded retinotectal projection of goldfish: the half-retinal preparation. AB - The nature of the expansion of the visual field projection was studied in goldfish in which size disparities were created between the retina and the tectum. After removal of one-half of the retina, the remaining retinal ganglion cells expand their projections so that the entire contralateral optic tectum is encompassed (Schmidt et al.1978). We wished to determine whether this expansion is accompanied by increased arborization including proliferation of synaptic terminals by the spared retinal ganglion axons or whether field expansion is accomplished by increased arborization without changes in synaptic number. Portions of the retina were ablated and the animals were allowed to survive for at least 5 months, the time at which expansion can be demonstrated, before sacrifice. We mapped retinotectal projections to determine the extent of the expanded visual fields and used stereological and morphometric analyses of synaptic contacts in the retinal target lamina, the stratum fibrosum et griseum superficialis (SFGS), in the optic tectum to estimate synaptic number. Numbers of synaptic terminals in the SFGS contralateral to the lesioned retina were not different from numbers in the comparable portion of control tecta. These observations indicate that the surviving retinal axons increased the number of synaptic contacts on tectal target cells in response to removal of other retinal ganglion cells. PMID- 21551658 TI - Calcitonin gene-related peptide (CGRP) in the regenerating rat sciatic nerve. AB - Calcitonin-gene related peptide (CGRP) is a neuromodulatory peptide present in motoneurons and a subpopulation of sensory neurons of the adult peripheral nervous system. Here we have investigated the changes in axonal transport of CGRP and CGRP receptor expression in the injured and regenerating rat sciatic nerve using CGRP-immunocytochemistry, radioimmunoassay and quantitative in situ receptor autoradiography techniques. Axotomy led to a gradual and prolonged, 2.5- to 3.5-fold increase in specific CGRP binding to the distal part of the crushed sciatic nerve, beginning 4-6 days after axotomy. An even stronger, up to 30-fold increase was observed after 30-42 day denervation in the distal part of the transected sciatic nerve, where neurite reinnervation was prevented by retroversion and ligation of the proximal nerve stump. Reconnection of the proximal and distal nerve stumps 21 days after transection did not lead to a major reduction in specific CGRP binding but prevented a further increase that occurred between 21 and 42 days after transection without reconnection. In contrast, the anterograde axonal transport of CGRP decreased after axotomy to 40 50% of the control values 6-8 days after nerve crush but recovered towards normal levels during successful regeneration. Interestingly, the retrograde axonal transport of CGRP appeared to amount to only 10-20% of the anterograde transport, suggesting that the peptide may be released by the regenerating neurites into the endoneurium of the injured peripheral nerve. In view of the persistent upregulation in endoneural CGRP binding after axotomy these data indicate that axonal CGRP could play a regulatory role in mediating axonal-endoneural cell interaction during peripheral nerve regeneration. PMID- 21551659 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551660 TI - IVth International Symposium on Neural Transplantation. AB - IVth International Symposium on Neural TransplantationEdited by William J. Freed and Jeffrey M. RosensteinThe George Washington University, Washington, DC, USAJuly 12-16, 1992. PMID- 21551661 TI - Intracerebral transplantation of the A7 immortalized astrocytic cell line. AB - The A7 cell line is an astrocyte-like cell immortalized by SV40 large T antigen, using retroviral-mediated gene transfer. These cells were transplanted into rat brains, and the graft-host interaction was investigated immunohistochemically. The A7 cells survived focally 2, 6 and 8 weeks after transplantation and retained the immunocytochemical properties observed in vitro. No immunological response was observed. GAP-43 and N-cadherin immunoreactivities were not expressed by A7 cells, but were seen in the matrix within the area of the graft and in the surrounding brain tissue. This indicates that A7 cells may stimulate expression of GAP-43 and N-cadherin immunoreactivity by host tissue. Expression of Thy 1.1 was not observed within the graft site after 2 weeks of survival, but 6 and 8 weeks after transplantation Thy 1.1 was observed within the graft area, indicating the possible co-existence of grafted cells and host tissue. Although indirect, these observations suggest that the A7 cells induce changes in host brain, including possible growth or regeneration of host tissue into the graft area. PMID- 21551662 TI - Implantation of the myenteric plexus into the corpus striatum of adult rats: survival of the neurons and glia and interactions with host brain. AB - Live or freeze-killed syngeneic adult muscularis externa, comprising myenteric plexus sandwiched between two layers of smooth muscle, was implanted into the corpus striatum of adult Fischer rats and examined electron microscopically 10 days to 6 weeks after operation. Living grafts contained healthy neurons and glial cells at all time-periods examined, although some areas of necrosis were observed. After 10 days, the glia limitans around the grafts were poorly developed and the adjacent brain tissue contained only a small number of small non-myelinated axons. After 3 and 6 weeks, the brain surrounding the living grafts contained many clusters of small non-myelinated axons. Bundles of putative central nervous system (CNS) axonal sprouts had invaded the grafts, making contact with enteric glia, despite the presence of a well-developed glia limitans at the interface with the brain. In the longer-term grafts some CNS axonal sprouts in the myenteric plexus enlarged and became myelinated. A few astrocyte processes but no axons were found in the freeze-kilied grafts. The brain surrounding the freeze-killed grafts appeared to contain fewer axonal sprouts than were present around the living grafts. The possibility that the living grafts may promote both the sprouting and the elongation of CNS axons is discussed. PMID- 21551663 TI - Changes in somatosensory circuits after subcortical infarct in rats. AB - We compared the functional and anatomical alterations of somatosensory circuits in the acute (1-3 days after infarct) and chronic (3 months after infarct) stage after subcortical striatal infarct in Wistar rats. Occlusion of the left middle cerebral artery produced subcortical striatal infarct in approximately 69% of the rats. The others developed cortical infarct. The function of the somatosensory circuits was evaluated by [14C]2-deoxyglucose autoradiography during physiological stimulation of the right vibrissae and face. In rats with subcortical infarct, the areas activated by sensory stimulation of the right vibrissae and face, applied 1 and 3 days after occlusion, were reduced compared to sham-operated controls (P < 0.05). In the chronic stage of subcortical infarct, the areas of metabolic activation of the left anterior vibrissal and facial sensory area were increased compared to rats with acute subcortical infarct (P < 0.05). To evaluate the anatomical changes in the somatosensory pathway, at 1 day and 3 months after occlusion, we injected wheat germ agglutinin horseradish peroxidase solution as an axonal transport substance bilaterally into the anterior vibrissal and facial sensory area. Tract tracing studies in both the acute and chronic stage of subcortical infarct showed a reduction in the peroxidase-positive area in the left thalamus compared to the control hemispheres (P < 0.01). The functional disturbance and recovery of the somatosensory circuits after subcortical infarct are discussed. PMID- 21551664 TI - Muscle force recovery after continuous direct current stimulation of a crushed nerve. AB - The purpose of this work was to examine whether, after sciatic axonotmesis, continuous low-amplitude direct current stimulation across the nerve crush lesion could affect the overall regeneration rate and shorten the time necessary to restore muscle force. Rats were randomly divided into cathode-stimulated (7 animals with a cathode stimulating electrode at the distal end of the nerve crush), anode-stimulated (6 animals with an anode stimulating electrode at the distal end of the nerve crush) and sham-treated (6 animals) groups. The recovery of muscle force was assessed by measuring the isometric tetanic contraction of the plantar flexor muscles once weekly, for five weeks in all groups. There was no statistically significant difference (P > 0.05) among the three groups from the first to the third week after the nerve crush. The cathode-stimulated animals had a statistically significantly enhanced muscle force recovery in the fourth (P = 0.023) and fifth week (P = 0.003) after the nerve crush, when compared to the anode-stimulated and sham-treated groups. From the first to the fifth week after the nerve crush there was no statistically significant difference (P > 0.05) in muscle force between the anode-stimulated and sham groups. After axonotmesis, the average ratio of normalized muscle force to normalized body weight in the cathode stimulated group reached the pre-crush control value in the fourth week following the nerve injury. This ratio was significantly lower all five weeks compared to the initial one before axonotmesis in anode-stimulated and sham-treated groups. Placing the cathode-stimulating electrode at the distal end of the nerve crush seems to have shortened the overall time of muscle force recovery. A possible mechanism for the enhancement of muscle force recovery in the cathode-stimulated group is proposed. PMID- 21551665 TI - Directional specificity of regenerating primary sensory neurons after peripheral nerve crush or transection and epineurial suture A sequential double-labeling study in the rat. AB - Clinical and experimental observations have demonstrated that peripheral nerve transection generally results in lasting disturbed sensory discrimination whereas nerve crush is followed by more or less complete functional restoration. This has been explained by an increased misdirection of regenerating fibers after transection as compared to crush injury. In the present study, sequential double labeling was used to investigate the relative proportions of peripherally misdirected sensory fibers in the sural and tibial nerve branches after crush or transection of the parent sciatic nerve in the rat. Control experiments showed that 0.21% +/- 0.12 (mean +/- S.D.) of all labeled tibial and sural neurons normally send axons to both nerves. After sciatic nerve crush or transection, 1.31% +/- 0.78 and 3.79% +/- 3.01, respectively, of all labeled tibial and sural axons were double-labeled indicating previously sural axons now having an axon in the tibial. Statistically significant differences in the percentages of bidirectional sciatic sensory neurons were found between the normal controls and after crush injury (P < 0.01) or transection injury (P < 0.001), respectively, but not between transection and crush (P > 0.05). The results indicate that the number of sensory neurons having an axon in two peripheral nerves is normally very small, that a substantial number of sensory axons become misdirected after both crush and transection with resuture, and that the number of misdirected fibers in the major sciatic branches after these types of injury is similar. PMID- 21551666 TI - On the late failure of spinal cord stimulation for deafferentation pain. AB - Two cases are described in which spinal cord stimulation was effective in abolishing previously intractable deafferentation pain for a number of years, but in which late failure occurred for non-technical reasons. A possible explanation for this is advanced; namely that the dorsal column fibres have altered electrical properties due to a form of transganglionic degeneration. PMID- 21551668 TI - Abstracts Selected From Excerpta Medica's EMBASE. PMID- 21551670 TI - Prolonged T1 values of the crushed nerve are not exclusively attributable to Wallerian degeneration or endoneurial edema. AB - Axonotmesis of the left sciatic nerve was performed on adult male Wistar rats. T1 values of the crushed nerve samples were determined with proton magnetic resonance spectroscopy. Denervation changes of the dependent hind plantar flexor muscles were assessed with proton magnetic resonance imaging of their cross sectional area and muscle force measurements. However, Tl relaxation time of the crushed nerve samples remained prolonged implying the absence of nerve regeneration. This would be in contradiction with what is known about regeneration after simple crash and the muscle force and magnetic resonance imaging measurements of the dependent plantar flexor muscles. These studies indicated that sufficient nerve regeneration had taken place to restore their muscle force and volume. A model is suggested to explain the persistence of prolonged Tl values in the presence of muscle force recovery. PMID- 21551671 TI - Physiological and behavioral consequences of delayed septal grafts in the subcortically denervated hippocampus. AB - The present experiments examined whether cholinergic grafts reverse the physiological and behavioral deficits of the damaged hippocampus. Fimbria-fornix lesions were performed in young rats and 3 months later half of the lesioned rats received cholinergic-rich basal forebrain transplants. Eight months after grafting we tested the animals behaviorally in the water maze. Following the behavioral experiments, the animals were implanted with chronic recording and stimulating electrodes and the electrical properties of the hippocampus, including spontaneous EEG, interictal spikes, evoked responses, long-term potentiation, and sensitivity to induced seizures were examined. Grafted rats did not show statistically reliable behavioral recovery (swim latencies, swim path lengths) and their performance was identical to the lesion-only group. Acetylcholinesterase reinnervation of the host hippocampus in grafted animals was similar to intact rats; the grafts also contained numerous parvalbumin immunoreactive neurons. The most striking physiological change was the significant elevation of seizure threshold in the grafted group, but other physiological parameters did not improve consistently. The findings suggest that the presence of septal tissue grafts and restoration of cholinergic reinnervation in animals with previous subcortical denervation of the hippocampus are not sufficient to restore normal hippocampal electrical patterns or to improve behavioral performance. PMID- 21551672 TI - Spiny interneurons identified in the normal mouse spinal cord show alterations in the Wobbler mouse: a model for inherited motoneuron disease. AB - Presumed interneurons are described in the Golgi-impregnated cervical spinal cord taken from normal phenotype and motoneuron-diseased mice of the Wobbler mouse strain (NFR/wr), as well as from the spinal cord of two related normal mouse strains (C57B1/6N and NFR/N). The interneurons, distributed throughout Rexed's laminae V-VIII, are characterized by numerous spines clustered along the distal dendrites. Quantitatively, the soma size (MUm2) of the interneurons in the Wobbler specimens studied late in the motoneuron disease is smaller than that measured in the pair-matched (3-week-old) normal phenotype littermates. Early in the disease, the spine density (number of spines per 100 MUm length dendrite) is greater compared with the normal phenotype littermates, perhaps implying that sprouting may occur. At a later stage in the disease process, the spine density does not differ significantly. However the increase in the spine density expected with advancing age is not observed for the Wobbler interneurons. It is proposed that perhaps the normal age-related proliferation of spines is impaired in the Wobbler mice. Since the measurements for spine length are lower in the Wobbler interneurons studied late in the motoneuron disease compared with the pair matched (3-month-old) normal phenotype littermates, the normal age-related lengthening of the spines seems to be lacking. In addition, the spine length measured in the normal phenotype littermates is significantly greater compared with the normal mice (NFR/N, C57B1/6N). Thus the growth patterns of the spines may differ in the Wobbler mouse strain compared with the normal (C57B1/6N, NFR/N) mouse strains. It is proposed that the Wobbler motoneuron disease affects interneurons as well as motoneurons. PMID- 21551673 TI - Fetal neocortical transplants in rats: blood-brain barrier development and partial permeability to IgG in long-surviving grafts. AB - In previous work, allografts of fetal (E13-16) neocortical tissue transplanted into neocortical lesion cavities in newborn (PND 0-1) rats developed an impermeable blood-brain barrier (BBB) as shown by intravascular administration of horseradish peroxidase and by immunohistochemical staining for endogenous IgG. The present study examines the time course for the formation of the graft BBB by staining for endogenous IgG and also looks at transplants with extended survival times of 1-2 years. At two weeks post-transplantation, the grafts of all ten animals of this group showed evidence of IgG immunoreactivity within the graft parenchyma. This was greatest at the pial surface and adjacent to the ventricular surface of the transplant. By three weeks after transplantation, only four of nine grafts showed graft vessel permeability and this was confined to the area under the pia. At four weeks survival, one of nine grafts showed a small rostral patch of IgG reactivity, and a second animal showed very light, diffuse transplant labeling. The remaining seven animals were devoid of transplant IgG reactivity. At 11.5-28 months, three out of seven grafts had reaction product in the graft, indicating BBB permeability to IgG. In two of these older transplants, permeability was confined to the area around larger blood vessels, while one additional animal (28 months) showed dense labeling immediately below the pial surface. As in normal rats, host brain labeling was only found in circumventricular organs. These results show that circulating macromolecules are excluded from most CNS grafts within the first month of transplantation. This process progresses from the center of grafts and requires the longest time to complete in subpial regions possibly associated with healing of the pia. Some older grafts show leakage of protein which may relate to aging of the transplant or to a low-level graft rejection. PMID- 21551674 TI - Stroke rehabilitation - who benefits? A comparison of medical wards and rehabilitation units. AB - This prospective, multicentre, population study, of all first-stroke survivors in one year referred for in-patient rehabilitation, compares the efficiency and effectiveness of functional recovery following ad hoc and routine rehabilitation of general medical wards with intensive and comprehensive rehabilitation of mixed disability geriatric/rehabilitation units. After controlling for potential confounding variables, no significant differences were recorded in terms of Barthel discharge function scores, effectiveness or efficiency of rehabilitation. Conventional rehabilitation in general medical wards of acute hospitals was 35% more efficient than comprehensive rehabilitation in geriatric/rehabilitation units (1.08 vs. 0.70, P < 0.001), this being due to unnecessarily long rehabilitation stays (44 vs. 70 days, P < 0.000). Contrary to other studies, geriatric/rehabilitation units did not significantly increase the discharge scores, did not accelerate the process of rehabilitation, and did not decrease the demand for extended-care beds. PMID- 21551675 TI - NGF receptor (p75)-immunoreactivity within hypoglossal motor neurons following axotomy in monkeys. AB - The expression of the p75 nerve growth factor receptor (NGFR) was examined in Rhesus and Cebus monkeys following complete unilateral transections of the hypoglossal nerve. In unoperated and sham-lesioned monkeys, NGF receptor immunoreactivity was always undetectable within hypoglossal motor neurons. In contrast, monkeys receiving unilateral transections of the hypoglossal nerve displayed numerous NGFR-immunoreactive neurons within ipsilateral hypoglossal motor neurons 1 week post-lesion. The peak expression of NGFR-immunoreactive hypoglossal neurons was seen 4 weeks following the lesion and although fewer, these neurons were still observed in large numbers 10 weeks post-lesion. By 16 weeks post-lesion only a few NGFR-immunoreactive motor neurons were observed. A small number of NGF receptor-immunoreactive neurons were also seen within the contralateral hypoglossal nucleus at post-lesion weeks 4 and 10. These data demonstrate that adult hypoglossal motor neurons express detectable levels of p75 nerve growth factor receptor following hypoglossal nerve transection in monkeys in a manner similar to that previously reported in non-primate species. The synthesis of p75 NGF receptors in these neurons may represent a regeneration mediated re-expression of NGF receptors which only normally occurs during development. PMID- 21551676 TI - Modulation of locomotion by a nerve graft across a spinal transection in rat. AB - Adult rats received a complete mid-lower thoracic spinal cord transection and a peripheral nerve autograft was inserted across the transection site. Testing 3-4 months later showed that, after decerebration, stimulation of the mesencephalic locomotor region (MLR) induced forelimb but not hindlimb locomotion. However, in 5/7 animals, tail pinch interrupted MLR stimulation-induced forelimb stepping, while pinna pinch induced hindlimb muscle twitch. These effects were not present following complete section of the nerve graft or in 6 control animals which did not receive a graft. Exposure of the cut mid-portion of the grafts to DiI revealed the presence of labeled axons entering the spinal cord through both ends of the graft in those animals which showed the above effects. There was no transport in the 2 cases in which tail pinch interruption of MLR-induced stepping or pinna pinch-induced hindlimb muscle twitch did not occur. We conclude that non specific information which can modulate locomotion may be flowing through the graft. PMID- 21551677 TI - Progesterone treatment attenuates brain edema following contusion injury in male and female rats. AB - To assess the effectiveness of progesterone as a treatment for edema following traumatic brain injury, male and female rats were injected with progesterone or the oil vehicle over a 3-day period following a cortical contusion injury. Oil treated rats showed significant localized edema as measured by the wet weight/dry weight tissue punch technique. Progesterone-treated rats, both male and female, showed marked attenuation, or in some cases, absence of this post-injury edema. We conclude that progesterone shows promise as a treatment for edema following traumatic brain injury. PMID- 21551679 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551680 TI - Foreword. PMID- 21551681 TI - Perspectives on the autocrine and paracrine functions of trans-activating factors. AB - It is a more and more widespread observation that growth factors can, on occasion, be found within nuclei where they may serve as trans-activating factors. This dual action raises the possibility that, on their side, trans activating factors might be secreted and act both at the membrane and at the nuclear level of target cells. At the same time it has now been clearly demonstrated that the classical growth factors bFGF and TGF-b are good in vitro mesodermal inducers and may have in vivo counterparts. Neural inducers, unfortunately, remain much more elusive even though the phenomenon of neural induction was described almost 60 years ago. Here, we present a short review on the development of the nervous system in which we focus on the importance of homeobox proteins in inductive phenomena. We follow on to propose that some trans activating factors belonging to the homeoprotein family may have paracrine and autocrine functions and might thus participate directly in neural induction. This highly hypothetical proposal is based on evidence from the literature and on experiments carried out in our laboratory showing that the antennapedia homeobox peptide (pAntp) added to neurons in culture is internalised by these cells, conveyed to their nuclei and provokes their morphological differentiation. PMID- 21551682 TI - The development and plasticity of peripheral and central connections of primary sensory neurons. PMID- 21551683 TI - Hox genes: a molecular code for patterning regional diversity in the nervous system and branchial structures. PMID- 21551684 TI - Neurotrophic factors in development and plasticity of spinal neurons. AB - Factors affecting neuronal growth may be considered to fall into two major categories: those required for neuronal survival during development or following a lesion, and those which enhance growth or regeneration of axonal or dendritic processes. We briefly review here some recent studies on the former in spinal cord development and plasticity as an introduction to other papers in the session on Factors controlling Neural Growth, and then present in more detail work on factors affecting motoneuron development in vitro. The neurotrophins are a closely-related family of basic neurotrophic factors including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and neurotrophins -3, 4 and -5 that enhance neuronal survival by binding to surface receptors whose major components are the trk tyrosine kinases and p75NGF-R. Only the latter has been studied in the context of spinal cord neuroplasticity: its levels on motoneurons are up-regulated following central or peripheral trauma, although its function there remains unknown. Much evidence exists for the existence of 'motoneuron growth factors' involved in regulation of survival and development of spinal motoneurons. Following a critical comparison of techniques for their purification, we review results obtained in vitro and in vivo using known growth factors such as ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF) and transforming growth factor (TGF/beta1). Although none of them satisfies all the criteria for the embryonic 'motoneuron growth factor', CNTF is of potential interest for reducing motoneuron loss in pathological situations. PMID- 21551685 TI - Molecular control of neuronal survival. PMID- 21551686 TI - The nerve growth factor family of neurotrophic factors. PMID- 21551687 TI - Myelin associated neurite growth inhibitors. PMID- 21551688 TI - Plasticity in the spinal cord: the dorsal root connection. AB - There is considerable evidence supporting a naturally occuring increase in the density of projections by intact systems induced by partial denervation of targets within the spinal cord. The phenomenon of sprouting in the spinal cord appears to be quite similar to the denervation evoked sprouting shown elsewhere in the CNS. Sprouting appears to be regulated rather than random since not all systems projecting to a denervated region may show demonstrable sprouting. In adults, the extent of sprouting is usually limited to the normal target zone of the intact systems and thus reasonably rigorous quantitative methods may be required to provide a clear demonstration of the increased projection. Greater plasticity, including regenerative like changes can be elicited in the undamaged processes of DRGs within the CNS by lesion to the peripheral process. Expansion of terminal fields into novel territories in adults has been demonstrated most convincingly in cases where additional manipulations are made, e.g. addition of peripheral nerve injury to the lesion paradigm. This suggests that the limitation on sprouting in adults can be overridden by increasing the metabolic drive of the sprouting neurons. In contrast there appear to be fewer limitations on sprouting in the neonate, since extensive sprouting into aberrant targets occurs if denervation occurs before development has ceased. Changing patterns of synaptic activity can also evoke quite dramatic modifications of the synthetic activity of neurons. Some of these changes appear to be long lasting and may lead to modifications in the activity of spinal neurons. Naturally occurring plasticity thus represents a major compensatory response to CNS lesions which needs to be taken into account in considering the consequences of CNS lesions, the extent of recovery of function and ways of improving the extent of recovery of function. PMID- 21551689 TI - Regulation of levels of SP and CGRP in dorsal root ganglia and dorsal horn after neonatal sciatic nerve lesion. PMID- 21551690 TI - Neurotransmitter phenotype plasticity in adult dorsal root ganglia neurons. PMID- 21551691 TI - Differential patterns of immediate early gene expression following sensory stimulation or nerve damage. PMID- 21551692 TI - Factors controlling the expression of GAP-43 in dorsal root ganglia cells: implications for plasticity and growth of central terminals. PMID- 21551693 TI - The use of a highly selective opioid MU ligand to gauge the plasticity of small caliber primary afferent fibers that project to the superficial layers of the rat dorsal horn. PMID- 21551694 TI - Dynamic changes in motoneurons during regeneration. AB - Axonally injured neurons demonstrate profound changes in morphology, in metabolism and in housekeeping functions. Specifically, changes in cytoskeletal proteins, in neurotransmitter metabolism, in growth and maintenance factors seem to be correlated to the growth of the new axons as part of the regeneration program. Significant changes have been described in the perineuronal glial cells of a motor nucleus undergoing retrograde axonal reaction, the so-called chromatolysis. Microglia become activated, augmented, mobile and instrumental in the synaptic stripping process. Astrocytes become first hypertrophic and, in a delayed reaction, form insulating lamellae around the recovering neurons. The molecular signals that could mediate the accompanying glial reactions are presumed to be produced by the injured neurons. Cytokines, but also neuropeptides and nitric oxide, are likely candidates. PMID- 21551695 TI - Development of motoneurons in spinal transplants. PMID- 21551696 TI - Transplant mediated mechanisms of locomotor recovery. PMID- 21551697 TI - Grafts and functional recuperation. AB - Plasticity of undamaged projections (axonal sprouting) in the adult and neonatal mammalian spinal cord has been documented many times. It has been associated, in some paradigms, with recovery of specific functions and motor behavior. This mutually occurring recovery of function appears to be enhanced by transplants of fetal tissue. PMID- 21551698 TI - Anatomical and behavioral outcome after spinal cord contusion injury produced by a displacement controlled impact device. PMID- 21551699 TI - Plasticity in sacral spinal cord reflex circuits. PMID- 21551700 TI - Changes in lower urinary tract function following spinal cord injury. PMID- 21551701 TI - The effects of locomotor training in spinal cord injured subjects: a preliminary study. PMID- 21551703 TI - Comments. PMID- 21551702 TI - Neuroplasticity as a basis for therapeutics in spinal cord injuries and diseases. AB - The concept of neuroplasticity in the adult is now well accepted. Amongst the most striking neuroplastic phenomena are those that systematically follow a lesion in the neural system itself. The work reported in this symposium emphatically illustrates the plasticity of neurons participating in spinal cord networks in various conditions that involve axonal lesions and neuronal degeneration. The purpose of this paper is to evaluate the potential for post lesion neuroplastic changes to serve as a basis for future therapeutics with specific emphasis on two important pathologies observed in humans: spinal cord injuries and degenerative motoneuronal diseases. Spontaneous attempts at axonal regeneration and growth of axotomized neurons can be seen after a spinal trauma although the number of neurons involved is often low and variable from one population to another. In any case, axons fail to cross the scar tissue, most probably due to specific neurono-glial interactions. Successful recovery of neural systems (and therefore possible functional recovery) that can be expected as a result of these spontaneous attempts at regeneration of axotomized axons is, overall, very poor. Innumerable attempts have been made to provide severed axons in the spinal cord with a suitable substrate. Altogether, the results obtained when regeneration is facilitated in the adult through a series of different ways point to several remarkable conclusions: (i) adult neurons are indeed able to grow an axon; (ii) the failure to grow an axon after axotomy which is normally observed depends, at least in part, on an unsuitable substrate; (iii) growth ability seems to be much more restricted for neurons with large myelinated axons than for neurons with unmyelinated ones. Several therapeutic avenues can be considered that can be grouped in three different endeavors: to fill in the gap, and to change the nature of the gap, to protect fibers that have not been directly injured. An additional possibility is that compensation of lost inputs by transplants of monoaminergic neurons below the level of the lesion can be of therapeutic value. Experimental models of spinal neurodegeneration have been less intensely studied than those of spinal cord injuries. Data suggesting the existence of spontaneous neuronal plasticity in the aftermath of motoneuronal loss are, however, available. Two types of neuronal attempts at regeneration can be considered: sprouting of surviving motoneurons leading to the reoccupation of vacant motor endplates and possible attempts to grow by afferents that have been deprived of their postsynaptic target cells. These attempts may be facilitated experimentally by the use of growth factors and fetal neural transplants. The use of growth factors may be of therapeutic value and preliminary studies are presently in progress. The therapeutic value of neural transplants to replace lost motoneurons in amyotrophic lateral sclerosis or spinal muscular atrophies is not easily determined. It seems excluded that transplanted motoneurons replace lost neurons at all levels of the neuraxis. In contrast, neural transplantation may be interesting to replace a specific set of motoneurons, namely those controlling respiratory muscles. PMID- 21551704 TI - Axonal regeneration after peripheral nerve grafting and fibrin-fibronectin containing matrix implantation on the injured septohippocampal pathway of the adult rat: a light and electron microscopic study. AB - The damaged septohippocampal pathway was utilized to study the axonal regeneration of injured neurons. Semipermeable tubes, 2-mm long, were placed in the axis of the transected septohippocampal pathway of adult rats. In a first series of experiments, empty tubes were implanted. Even six weeks after the operation, no regenerated axons were observed in the conduit. In a second series of experiments, in order to validate our approach, segments of pre-degenerated sciatic nerves were introduced into the tubes. Under these experimental conditions, acetylcholinesterase (AChE)-containing regenerated axonal processes were detected in the grafted sciatic nerves. Glial fibrillary acidic protein (GFAP)-immunodetection showed that astroglial cells and astrocyte processes were able to progress on and into the peripheral grafts. At the electron microscopic level, axons were observed in close contact with Schwann cells which myelinated some of them. In some other cases, unmyelinated axons were also present at the surface of reactive astroglial cells filled by numerous intermediate filaments. These central glial cells had migrated among the sciatic nerve collagen fibers. No axon was detected without glial cell contact. In a third series of experiments, we implanted semipermeable tubes previously filled with a fibrin fibronectin-containing matrix provided by peripheral regeneration chambers. One week after the implantation of the tubes containing this peripheral substrate, different cell types were observed migrating into the conduit and replacing the fibrin-fibronectin-containing matrix. Among these cells astrocytes were present as revealed by GFAP-immunocytochemistry and electron microscopic examinations. During the following weeks, axons were detected in contact with the reactive astroglial cells. AChE-histochemistry showed that axons were able to cross the two millimeter distance separating the septal part and the hippocampal part of the lesion site. GABA (gamma-aminobutyric acid)-ergic fibers were also detected in the regenerated structure. These experiments show that cellular or acellular substrates provided by the PNS can promote the regeneration of CNS GABAergic and cholinergic neurons. Our observations suggest that astrocytes can take an important part, after their migration or after extending processes, in the axonal regeneration in the adult CNS of the rat, possibly in furnishing a cellular terrain for the progression of growth cones over a distance of two millimeters and in maintaining regenerated axons at least until the sixth week after the operation. PMID- 21551705 TI - Characteristics of the vibratory reflex in humans with reduced suprasegmental influence due to spinal cord injury. AB - The tonic stretch reflex elicited by vibration of a muscle or tendon provides a means of studying segmental reflex activity in humans with impaired volitional motor activity due to spinal cord injury (SCI). Vibration applied to the achilles or patellar tendon in a group of 51 SCI subjects elicited motor unit activity different from that found in 12 healthy subjects. Four distinct features of motor unit responses to vibration of a single tendon (achilles or patellar) could be seen in the SCI subjects: (i) a rapid onset, tonic response, frequently beginning with a single burst analogous to a tendon jerk, in 72% of vibrated sites; (ii) repetitive, phasic bursts of activity or vibratory-induced clonus in 23% of the tonic responses; (iii) spread of activity to muscles distant from the vibration in 44% of the tonic responses; and vibratory-induced withdrawal reflexes (VWR) which occurred after vibration of 37% of the sites. Overall, 81% of stimulated sites responded to vibration in SCI subjects. In contrast, only 54% of vibrated sites responded in control subjects, always with a gradual onset tonic response, never accompanied by a VWR. The VWR in SCI subjects was typically of much larger amplitude than the tonic responses and involved a mean of 5 muscles (41% bilaterally). Features of these responses provide an insight into underlying neurocontrol mechanisms which may provide guidance in the selection of appropriate intervention or management strategies. PMID- 21551706 TI - The effect of a short-course treatment with FK506 on the survivability of rat-to mouse cross-species neural graft. AB - We examined the effect of a short-course treatment with a new immunosuppressive agent FK506 (FK) on the survivability of neural xenografts. Pieces of ventral mesencephalic tissues from rat embryos were transplanted into the right lateral ventricle of adult mice. The mice were either assigned to a 4-day FK (10 mg/kg/day) immunosuppressive scheme or were given no immunosuppression. The 4-day course treatment with FK was started on postoperative day 0, 2, 4, 6 or 8. The incidence of graft rejection 28 days after transplantation was 82%, 55%, 55%, 100% and 100% when FK was given on days 0-3, 2-5, 4-7, 6-9 and 8-11, respectively. As a separate group, we examined the cellular infiltration in neural xenografts of the non-immunosuppressed recipients at two different time points (3 days and 7 days) after transplantation. The infiltration of T lymphocytes was not detected 3 days after transplantation, but had occurred by 7 days after transplantation. We speculate that FK is more effective in preventing the rejection of neural xenografts when it is given just before the initiation of the T-lymphocytic infiltration. PMID- 21551707 TI - Functional consequences of transplantation of frontal neocortex vary with age of donor tissue and behavioral task. AB - The spatial learning of rats with medial prefrontal lesions was compared to that of animals with cortical transplants of frontal tissue from donors of embryonic age 17, 19, 21, or 23 days. The age of the donor tissue significantly affected the extent that the transplanted tissue developed as the E17 and E19 grafts were markedly larger than those from E21 or E23 animals. Nonetheless, transplants were viable at all ages. Rats with E19 grafts, but not rats with grafts at other ages, showed significant reduction of the expected deficit on the Morris water task. In contrast, only rats with E21 grafts showed enhanced performance on a T-maze alternation task. The contrasting effects of the grafts of different aged tissue suggests that there may be some specific contributions of cortical grafts of different ages that leads to partial restoration of function. PMID- 21551708 TI - Effect of highly concentrated gels of sodium hyaluronate on early phases of regeneration in the transected and tubulized rat sciatic nerve. AB - Silicone regeneration chambers prefilled with sodium hyaluronate (HA) gels of different molecular weight (MW) and at different concentrations were used to tubulize the transected rat sciatic nerve. After two weeks, the tissue cables bridging the severed nerve ends within the silicone tubes were examined. Low MW HA gels had no significant effect while high MW HA gels reduced the diameter of the growing bridges. PMID- 21551709 TI - GABA-ergic component of rat embryonic ventral mesencephalic grafts: an in-vitro study. AB - In order to establish the number, the viability and the developmental potential of GABAergic neurons present in dopaminergic ventral mesencephalic (VM) grafts from embryonic rat, we have studied the survival and development of these neurons in culture. The GABAergic fraction demonstrated a highly disproportionate survival in culture in relation to other VM neurons resulting in a drastic change in the neuronal composition of the dissociated VM grafts. The occurrence of a similar gradual dominance of GABAergic neurons at the site of intracerebral implantation, may affect the development of grafted dopaminergic VM neurons and their interaction with host striatal cells. PMID- 21551710 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551711 TI - The distribution of C-Fos protein immunolabeled cells in the spinal cord of the rat after electrical and noxious thermal stimulation following sciatic nerve crush, or transection and repair. AB - The distribution of stimulus evoked Fos protein-like immunoreactivity in spinal cord neurons was studied in adult rats at different survival times after sciatic nerve crush or transection and epineural repair. Fos protein-like immunoreactivity was induced either by electrical stimulation of the sciatic nerve central to the injury, at C-fiber strength, at 21, 39, and 92 days post lesion, or by noxious heat applied to the skin of the hind paw 92 days post lesion. The contralateral uninjured side served as control. The results with electrical stimulation showed, with some exceptions, that the distribution of c fos expressing cells in the spinal cord on the normal and on the previously injured side were similar after both crush and transection with repair. The main finding was an up-regulation of the number of Fos protein immunoreactive neurons in the inner portion of Rexed's lamina II. The results following heat stimulation 92 days post-lesion showed a decrease in the number of labeled neurons in most laminae after both types of injury. This was more pronounced in cases with sciatic nerve transection with repair compared to cases with crush. The results indicate time-dependent alterations in the distribution of stimulus evoked c-fos expression in spinal cord neurons during regeneration after nerve injury. Furthermore, the results from heat stimulation may indicate a slower and perhaps more incomplete restoration process after transection with repair than after crush. PMID- 21551712 TI - Septal grafts improve acquisition of an operant timing task after fimbria-fornix lesions in rats: Role of the interval between lesion and transplantation surgeries. AB - In a previous study we evaluated the conditions under which septal grafts could ameliorate performance of rats with fimbria-fornix lesions in an operant differential reinforcement of low rates of responding (DRL) task. Although the best recovery was demonstrated by the group in which the grafts were made 10 days following the lesion surgery, this factor (lesion-graft interval) was confounded with the developmental stage of the donor tissue, and it was suggested that the age of the embryonic donor was a more significant factor than the lesion graft interval in achieving good recovery. The present study provides a better control of embryonic age of the donor tissues, and we report that cholinergic rich septal grafts implanted into the host hippocampus either immediately or 11 days following fimbria-fornix lesion yielded better recovery than when the grafts were implanted after longer (8 weeks) lesion-graft intervals. In addition, grafts implanted into the intact hippocampus were without significant effect when the host rats were subjected to a delayed fimbria-fornix lesion made 10 weeks after graft implantation. These results corroborate the hypothesis of Nieto-Sampedro, Manthorpe and colleagues that 'wound-derived neurotrophic factors' can promote the functional viability of embryonic septal grafts in the hippocampus, even if such factors are not absolutely necessary for graft survival. PMID- 21551713 TI - Sprout formation at nodes of Ranvier of crush-injured peripheral nerves. AB - Sprouting from crush-injured rat sciatic nerves was studied by electron microscopy to clarify how regenerating sprouts are generated at the node of Ranvier and extended distally in the injured nerves. Three hours after injury, sprouting had already begun in a few nodes: part of the dense submembranous undercoat had disappeared from the nodal axolemma, and the axolemma was slightly evaginated where the undercoat was avoided. The sprout contained clear vesicles of about 50 nm in diameter in an amorphous axoplasm. In addition, vacuoles measuring 100-200 nm in diameter and multivesicular bodies were commonly found within or near these early sprouts. Six to 12 h after injury, nodes of Ranvier with sprouts increased in number in the region 1-1.5 mm proximal to the lesion. Sprouts grew toward the overlying Schwann cell basal lamina, and extended through the space between the basal lamina and Schwann cell plasmalemma (or myelin sheath). In the stem region continuous with the parent axon, regenerating sprouts displayed prominent neurofilaments, which were randomly arranged at 1 day post injury, but oriented longitudinally by 5 days post-injury. PMID- 21551714 TI - Reinstatement of motor deficits in recovered brain-injured animals: the role of cerebellar norepinephrine. AB - Previous research has indicated that antagonists of locus ceruleus functioning, when administered during the acute phase of an injury, slow recovery of motor function following unilateral sensorimotor cortex injury. Following a recovery plateau in animals, it is possible to pharmacologically reinstate unilateral motor deficits in recovered animals with similar acting drugs given intraperitoneally. The present study was designed to localize the brain systems responsible for the reinstatement of the deficit after recovery from the cortical injury. The results indicate that maintaining functional recovery after injury is modulated by NE in the cerebellum contralateral to the injury, since microinfusions of phenoxybenzamine into this structure reinstate motor deficits. Additionally, removal of the noradrenergic projection to contralateral cerebellum through unilateral lesions of the locus ceruleus reinstate unilateral deficits more severely than the drug administration. PMID- 21551715 TI - Ventral root avulsion versus transection at the cervical 7 level of the cat spinal cord. AB - The results of unilateral ventral root avulsions at the cervical 7 (C7) level were compared using light microscopy with unilateral transactions of the ventral root C7 at the surface of the cat spinal cord after survival times ranging from one to 90 days. Sections were stained for Nissl, acetylcholinesterase, neurofilaments, glial fibrillary acidic protein, and B-50/GA P43. A distinct difference in neuronal reaction was found between the effects of avulsion and transection of ventral root C7. After avulsion, changes in the Nissl-and acetylcholinesterase-stained sections and the sections stained with antibodies against neurofilaments remained present up to 90 days, although the number of neurons in the ventral horn on the avulsed side had significantly decreased at 60 and 90 days. This was in contrast to the transection where the changes in the stainings tended to return to the normal situation between 30 and 60 days and showed the normal pattern 90 days after transection. No decrease in the number of neurons was found. Both lesions were situated in the transitional region of the nerve roots. After avulsion axons break in the white matter of the CNS, while the axons were transected in the PNS compartment of the CNS-PNS transitional region. After avulsion, not only were the axons disconnected, as in transection, but the connections of recurrent motor axon collaterals probably were damaged. This may explain the different reaction after avulsion and transection. PMID- 21551717 TI - Effects of applied electric fields on clinical cases of complete paraplegia in dogs. AB - A clinical trial of applied, slowly oscillating, weak electric fields was performed in dogs with naturally occurring spinal cord injuries due to intervertebral disc herniation. Criteria for admission to the study were: complete paraplegia, defined by neurological examination and electrophysiological testing; intact segmental reflexes; radiologic and myelographic evidence of spinal cord compression due to disc herniation and a focal lesion, without appreciable rostrocaudal spread of necrosis; weight less than 16 kg; onset of paralysis less than 1 month before surgery. The injured cord was exposed by laminectomy, and decompressed by aspiration of disc material. Active (n = 13) or sham (n = 11) stimulators were implanted subcutaneously, with platinum/iridium electrodes sutured to muscle several millimeters above the cord surface, at either end of the laminectomy site. Active stimulators delivered 200 MUA of direct current, switching polarity every 15 min, for 3, 6, or 15 weeks. Neurological and electrophysiological examinations were repeated approximately 6 weeks and 6 months after implantation. Few complications were noted. None were attributable to current application. The group of dogs with active stimulators showed greater improvement in function than the group with sham implants, with a trend towards greater recovery in all neurological measures, and evoked potentials. The combined neurological score derived from these separate tests was significantly different from controls at 6 weeks and 6 months (P < 0.05). Application of slowly oscillating electric fields thus appears to be beneficial in the treatment of paraplegia in dogs. PMID- 21551718 TI - Comparison of the Semmes-Weinstein monofilaments with the Pressure-Specifying Sensory Device. AB - Measuring human sensibility remains a challenge, with the primary limitation being the instrumentation traditionally available. The Pressure-Specifying Sensory Device (PSD) permits quantitation of the human pressure perception threshold by means of transducers that couple two rounded prongs to a personal computer. If just one prong is perceived in constant contact with the skin, the cutaneous pressure threshold is directly obtained, scaling along a continuum from .05 to 100 g/mm2 (readout on computer monitor). This measurement is analogous to that obtained with the series of Semmes-Weinstein monofilaments (SWM) (readout in logarithmic marking on nylon rod). The present study evaluated twenty normal volunteers and ten nerve-impaired patients with both the PSD and the SWM. There was a poor correlation between the measurement offeree (r = 0.21) and pressure (r = 0.29) obtained with the PSD and the SWM. This study reaffirms the value of measuring pressure perception threshold during the sensibility evaluation, while calling attention to selection of instrumentation for obtaining this measurement. PMID- 21551719 TI - Pharmacological manipulation of the NMDA receptor differentially protects from systemic kainic acid neuropathology: evaluation through ornithine decarboxylase induction, morphology and GFAP immunohistochemistry. AB - The excitotoxic brain damage caused by systemic administration of kainic acid requires the activation of N-methyl-D-aspartate (NMDA) receptors in order to fully express its neurotoxic potency. We have tested the relative efficacy of different manipulations of the NMDA receptor on morphological, immunohistochemical and neurochemical parameters in this experimental model. A competitive (CGP 39551) and a non-competitive (MK 801) antagonist of the NMDA receptor, granted full protection against neuronal degeneration and consequent glial proliferation in the hippocampus and olfactory cortex, two regions severely affected by systemic administration of kainic acid. In addition, CGP 39551 completely counteracted the dramatic induction of the enzyme ornithine decarboxylase which occurs shortly after kainic acid administration. Systemic administration of high amounts of MgSO4 concomitantly and after kainic acid injection, appeared to partially prevent neuronal degeneration but had no clear effects on glial reaction and ornithine decarboxylase induction. Finally administration of an antagonist of the polyamine site present in the NMDA receptor (SL 82.0715), did not appear to have any protective effect at the dose used here. The present results help to better understand the ways by which it could be possible to counteract excitotoxic brain injuries. PMID- 21551720 TI - Visualization of outgrowing axons of grafted neurons by anterograde labelling with Phaseolus vulgaris leucoagglutinin in the motor cortex of the rat. AB - Fetal cerebral cortical tissue was transplanted into an aspirated lesion cavity made in the sensorimotor cortex of adult rats. Ten weeks after grafting, outgrowing fibers from the graft were visualized by an anterograde tracing technique using Phaseolus vulgaris leucoagglutinin (PHA-L). It was demonstrated that the efferent fibers grew into the neighboring host cortical tissue, the corpus callosum and in some cases approached caudate/putamen. Characteristic axon arborization with abundant boutons were found in the host cortical tissue, but only in close vicinity to the grafts. It is concluded that the PHA-L anterograde tracing technique can be a useful tool to assess the degree of anatomical integration of the transplants into the host tissue. PMID- 21551721 TI - Effects of microglia-derived cytokines on astrocyte proliferation. AB - Recent studies have suggested that cytokines, such as interleukin-l(IL-l), tumor necrosis factor(TNF)alpha, or interferon(IFN) gamma, play a role in the development of astrocytic gliosis. In this study, we examined the effects of these cytokines on the proliferation of purified astrocytes in vitro, using the colorimetric assay, bromodeoxyuridine uptake by astrocytes, and changes in the amount of the S-100 beta protein as markers of astrocyte proliferation. The effects of a crude supernatant from microglia enriched cultures (Mi-Sup) also were examined. In contrast to previous reports, these recombinant cytokines did not induce proliferation of purified mouse astrocytes. However, stimulation of astrocytes with Mi-Sup increased all the markers for astrocyte proliferation, which could not be blocked by the addition of anti-IL-1, IL-6, IFNgamma or TGFbeta antibodies. Thus, it appears that microglia produce factors, other than the above cytokines, which induce the proliferation of astrocytes in vitro. These factors may have a role in the development of gliosis in various pathologic conditions of the central nervous system. PMID- 21551722 TI - Synthetic nerve graft containing collagen and synthetic Schwann cells inproves functional, electrophysiological, and histological parameters of peripheral nerve regeneration. AB - Current methods of peripheral nerve repair are to directly suture cut nerve stumps, or to bridge large gaps with an autograft repair. Autograft-associated problems include donor site morbidity and limited supply. Many of the present limitations of nerve repair might be overcome by expanding the patients own Schwann cells in vitro, then combining the cells with other neuro-tropic and trophic materials into an Artificial Nerve Graft (ANG) for bridging a nerve gap. In this 4.5 month experiment, a rat peroneal nerve model with a 10 mm gap was used to evaluate the effect of live Schwann cells on peripheral nerve regeneration. Nerve gaps were repaired with cellular ANGs containing live Schwann cell, dead Schwann cell, or mixed fibroblast/Schwann cell populations suspended in a collagen I matrix, and with sutured autografts or ANGs containing just collagen or medium. Regenerated nerves were evaluated by walking track analysis, qualitative and quantitative histology, and electrophysiology. Overall, the autograft was the best repair method, while the ANG containing live Schwann cells was statistically superior to other ANG repair methods. This study demonstrates that an ANG containing cultured syngeneic Schwann cells improves functional, histological, and electrophysiological parameters of peripheral nerve regeneration. PMID- 21551723 TI - Amantadine and ketamine-induced improvement of motor coordination in lurcher mutant mice. AB - The effects of amantadine and ketamine were compared to a placebo in a coat hanger test on lurcher mutant mice. This test measures motor coordination and is dependent on cerebellar functioning. Both drugs improved motor coordination of the cerebellar mutants in that the time taken to reach the side-bar according to a 2 paw criterion was decreased during the drugged condition in comparison to the non-drugged condition. This result indicates that NMDA receptor antagonists may improve motor coordination in animals with cerebellar disease. PMID- 21551724 TI - Acute unilateral sensorimotor cortex injury in the rat blocks d-amphetamine induced norepinephrine release in cerebellum. AB - Pharmacologic studies have implicated norepinephrine in amphetamine-facilitated motor recovery following sensorimotor cortex injury in rats. We studied the acute effects of unilateral sensorimotor cortex ablation on the release of norepinephrine in cerebellum with in vivo dialysis. In rats without a cortex lesion, the administration of a single dose of d-amphetamine (2.6 mg/kg base weight, i.p.) resulted in a substantial increase in dialyzable norepinephrine in cerebellum reaching its peak 30-40 min later (~ 14 pg/MUl, not corrected for recovery). The administration of the same dose of d-amphetamine to rats 60 min following a suction-ablation lesion of the right sensorimotor cortex did not result in norepinephrine release into the cerebellar dialysates. These data provide evidence for an acute remote effect of sensorimotor cortex injury on amphetamine-induced norepinephrine release in the cerebellum (diaschisis). PMID- 21551725 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551726 TI - Transplantation of dorsal root ganglion into the olfactory bulb of neonatal rats: a histochemical study. AB - We have transplanted encapsulated dorsal root ganglia (DRG) from adult Wistar albino rats unilaterally into partially bulbectomized (n = 20) neonatal (P3-5) rats of the same strain. Three months postoperatively the animals were perfused and their brains processed by direct thiocholine method for cholinesterases (Ch), specific acetylcholinesterase (AChE) and nonspecific butyrylcholinesterase (BuChE) or stained by Cresyl violet. Selected sections were immunohistochemically stained for olfactory marker protein (OMP). In 17 cases we found surviving transplanted DRG. Fifteen transplants were well integrated with the spared portion of the olfactory bulb (OB) as clearly demonstrated by AChE and BuChE histochemistry, while two did not integrate. Regenerated OMP positive olfactory axons originating from neuroepithelium and AChE positive fibres from OB remnant penetrated into the transplants. In one case, fibers connected with BuChE positive Schwann cells grew from the transplanted DRG into the host OB. Individual sensory neurons of the transplants revealed variable intensity of the AChE staining, thus resembling the pattern of AChE activity in normal DRG. BuChE activity was mostly localized on the surface of sensory neurons in the ring of satellite cells. Some BuChE positive blood vessels penetrated into the DRG, and were observed around sensory neurons. The results showed a considerable viability and adaptability of the sensory neurons in the new environment after a long-term transplantation. PMID- 21551727 TI - Partial recovery of skilled forelimb reaching after transplantation of fetal cortical tissue in adult rats with motor cortex lesion - anatomical and functional aspects. AB - We have studied the effect of transplantation of embryonic frontal cortex on the motor deficit resulting from motor cortex lesion in the adult rat. Twenty-four 2 month-old rats were first trained in a food reaching task with right and left forelimbs. Then, at 4 months of age, the subjects were divided into two equal groups. In the lesion group, the animals sustained a lesion of the left motor cortex, whereas in the graft group the animals received a fetal cell suspension of embryonic (E16) frontal cortical tissue three days after the lesion. Postoperative reaching ability was assessed every week during eight weeks and then every two months until the age of one year. The results indicate that the deficit resulting from the lesion is bilateral but mainly affects the limb contralateral to the lesion. During the first 3 weeks of postoperative testing, both groups displayed comparable evolution of performance with contralateral forelimb, characterized by an initial large drop followed by progressive recovery. But, whereas in the lesion group performance did not increase after the fourth postoperative week, in the graft group the reaching scores further improved, without recovering, however, preoperative levels. This improvement was still observed eight months after transplantation. However, no improvement appeared using the limb ipsilateral to the transplant. An anatomical study of the volumes of transplant and/or lesion revealed that the importance of the recovery or deficit varied as a function of the sizes of the transplant and/or lesion within the rostral part of the motor cortex, approximately corresponding to the rostral forelimb area of Neafsey et al. [37]. It is therefore suggested that in adult rats, some components of the motor deficit resulting from a lesion of the motor cortex can be partially reduced by transplantation of homotopic embryonic cortex. PMID- 21551728 TI - Sprouting of axon-like processes from axotomized retinal ganglion cells is influenced by the distance of axotomy from the cell body and the mode of transplantation of the peripheral nerve. AB - It is a well known fact that the proximity of an axonal lesion from the cell body influences the degree of neuronal survival: a lesion close to the cell body leads to more severe cell death and vice versa. On the other hand, experiments involving transplantation of a peripheral nerve (PN) to various central nervous system (CNS) regions to induce axonal regeneration have suggested that axonal regrowth is more vigorous when the grafting is performed closer to the cell body. It is not clear, however, whether it is the distance of the site of axotomy or the location of the trophic source (PN graft) or both from the cell body which dictates the vigorousness of axonal regrowth. Using either a model of transplantation of a PN to the retina or implantation of a short PN into the vitreous body of the eye of the adult hamster, we have demonstrated that sprouting of axon-like processes from retinal ganglion cells (RGCs) depends on the distance of axotomy from the cell body when the PN graft is maintained at a constant distance from the cell body. Moreover, it was found that the distance of axotomy at which sprouting of axon-like processes could be induced was different for the 2 paradigms: with the intravitreal PN model, sprouting was observed even after intracranial ON cut whereas it was absent in the PN grafting-to-retina paradigm. This suggests that extrinsic influence (in this case an intravitreal PN) can overcome to a certain extent the growth-suppressive effects due to a long distance of axotomy. PMID- 21551729 TI - Upregulation of B-50/GAP-43 in Schwann cells at denervated motor endplates and in motoneurons after rat facial nerve crush. AB - Crush or transection of peripheral nerves of the adult rat is accompanied by changes in protein expression, including the growth associated protein (GAP-43) B 50. Following peripheral nerve crush in rat enhanced B-50 immunoreactivity was observed in regenerating nerve fibres and in newly formed axon terminals. However, before reinnervation was apparent, an unexpected transient increase in B 50 immunoreactivity was observed at denervated motor endplates [J. Neurosci. 8 (1988) 1759]. This study was performed to clarify this observation. Four days following facial nerve crush B-50 immunoreactivity was detected by double immunofluorescence microscopy in Sl00-positive Schwann cells covering the denervated endplates. Using diluted polyclonal and monoclonal B-50 antibodies we found that B-50 immunoreactivity at the denervated motor endplates was strongly increased in comparison to innervated motor endplates in which B-50 immunoreactivity was hardly detectable. However, when a high concentration of B 50 antibodies was applied the normal innervated motor endplates were also B-50 immunoreactive. Muscle fibres did not display B-50 immunoreactivity. Northern blot analysis revealed elevated B-50 mRNA in denervated muscle and in degenerating nerve with respect to the controls. The B-50 mRNA levels in these non-neuronal tissues were very low compared to the intact and injured facial nucleus containing the neuronal cell bodies. Electron microscopy demonstrated that the B-50 protein was localized in the processes of Schwann cells covering axon terminals of intact and vacant motor endplates and in axon varicosities of sympathetic nerves. This study has confirmed that prior to reinnervation B-50 immunoreactivity is increased at denervated motor endplates and shows that B-50 is co-localized with S100 in Schwann cells. Therefore, upregulation of B-50 expression in Schwann cells may explain the early occurrence of B-50 immunoreactivity at the motor endplate. PMID- 21551730 TI - Transient improvement of amphetamine-induced rotational behavior by PC12 cell grafts: studies with microdialysis. AB - The effects of striatal transplantation of PC12 cells on amphetamine-induced rotational behavior and monoamine levels were examined in rats with unilateral 6 hydroxydopamine (6-OHDA) lesions in the nigrostriatal pathway. A total of 9 * 104 or 9 * 105 cells of PC12 was implanted into 3 sites in the striatum and changes in amphetamine (3 mg/kg, i.p.)-induced rotational behavior were observed for 8 weeks. Two weeks after transplantation, a significant reduction in rotation was observed. However, this improvement disappeared after 3 weeks. Three of 7 rats implanted with 9 * 104 cells and 6 of 7 rats with 9 * 105 cells died between 3 and 4 weeks after transplantation. In 6-OHDA-injected control rats, the levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in brain dialysates were profoundly reduced to between 0 and 11% of normal rats, while the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) level remained unchanged. These reductions in DA and its metabolites did not recover at 2 or 8 weeks after the transplantation of 9 * 104 PC12 cells. 5 HIAA was reduced at 2 weeks and recovered to nearly control levels at 8 weeks. Histologically, PC12 cells proliferated to form a large tumor mass at 2 weeks. There were almost no processes growing from the aggregated PC12 cells into the host tissue. These results indicate that PC12 grafts do not release detectable quantities of DA into the deafferented striatum, and suggest that the transient improvements in rotational behavior may be due to a non-specific suppression in neuronal function induced by the growing tumor mass. PMID- 21551731 TI - Experimental hyperthyroidism enhances the regeneration of central neurites promoted by peripheral nerve grafts in the hippocampus. AB - The aim of the present paper was to ascertain whether experimental hyperthyroidism promotes the regenerative action of predegenerated peripheral nerve grafts implanted into the transected hippocampus. Hyperthyroidism was induced by subcutaneous injections of T4. Autologous peripheral nerve grafts were implanted immediately, 7 and 35 days following transection of the sciatic nerve. Cells extending their neurites into the grafts were traced by means of horseradish peroxidase conjugated with fluoresceine isothiocyanate (FITC-HRP). Fluorescence microscope examination revealed that experimentally induced hyperthyroidism considerably enhanced the regenerative influence of peripheral nerve grafts. This effect was particularly pronounced in hyperthyrotic animals treated with either nonpredegenerated or 35 day predegenerated nerve grafts. PMID- 21551732 TI - Treadmill running combined with microdialysis can evaluate motor deficit and improvement following dopaminergic grafts in 6-OHDA lesioned rats. AB - To evaluate the physiological role of striatal dopamine (DA) during exercise and the mechanism of functional recovery mediated by grafted DAergic neurons, the locomotor ability (treadmill running) and DA turnover were investigated using treadmill running combined with in vivo microdialysis in the intact control rats, 6-hydroxydopamine (6-OHDA) lesioned rats (hemi-parkinsonian model rats) and DAergic cell grafted rats. The 3 groups of rats were trained to run on a straight treadmill at a speed of 1,800 cm/min for 20 min every day for 7 consecutive days. If the rats could not follow the speed they got electrostimulation (ES) from the grid behind the treadmill belt. The numbers of ES rats received during treadmill running were counted to quantify the locomotor ability. Control rats could keep up with the treadmill easily (0-1 ES/10 min), whereas lesioned rats could not follow the speed (80-100 ES/10 min). Most of the grafted rats received only a few ES, but a few received over 100 ES/10 min. Extracellular DA and its metabolites, dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA), were measured by in vivo microdialysis and high-performance liquid chromatography (HPLC) during and after treadmill running. In control rats the basal levels of DA, DOPAC and HVA were 2.3 fmol/MUl, 1,109.8 fmol/MUl and 612.2 fmol/MUl, respectively. They increased up to 130%, 140% and 160% by running. In 6-OHDA lesioned rats basal values of DA, DOPAC and HVA were less than 10% of controls. We did not perform microdialysis in these rats since they got too much ES during running. In grafted rats that showed good recovery in locomotor ability, DA returned to almost control level (1.9 fmol/MUl), but those of DOPAC (127.8 fmol/MUl) and HVA (100.2 fmol/MUl) were still low. DA, DOPAC and HVA increased up to 130%, 130% and 150% by running in a similar pattern as in intact rats. These results suggest that grafted neurons can release and metabolize DA in the host striatum both tonically and phasically in relation with internal and external stimuli and also suggest that treadmill running ability is a good indicator of DA turnover in the striatum. Thus, the treadmill running test with microdialysis is useful for quantitative evaluation of motor function in grafted animals. PMID- 21551733 TI - Improved cryopreservative medium suitable for the freeze-storage and transplantation of fetal neural tissues. AB - Techniques to maintain viable fetal neural tissue might be an important tool for a successful neural transplantation by giving enough time for preparation, storage, and transportation of donor tissue. In the present study, we examined the effect of freeze-storage (cryopreservation) for 7 days at liquid nitrogen temperature on the survivability of intraventricular rat fetal mesencephalic grafts (gestational day 15) when using 10% dimethyl sulfoxide (DMSO), 0.1% methylcellulose, or 10% DMSO with additional 0.1% methylcellulose (m-DMSO) as a cryoprotective agent. As a control group, the survivability of grafts transplanted immediately after dissection was examined. The volume of grafts treated with m-DMSO was 3 times as large as that of grafts treated with 10% DMSO alone. While the number of surviving neurons in 10% DMSO-treated transplants decreased down to 15% of the control value, there was no statistically significant difference in the number of surviving neurons between the m-DMSO treated group and control group. In the group treated with m-DMSO, there were a lot of well developed tyrosine hydroxylase positive neurons and fibers in the graft, and a few reactive astrocytes were observed only in the peripheral region of the grafts. In the group treated with 0.1% methylcellulose alone, no graft survival was observed in any of the animals. We conclude that the addition of methylcellulose to the commonly used cryoprotective agent (DMSO) is beneficial for the freeze-storage of fetal neural tissue. PMID- 21551734 TI - Glucocorticoid effects on axonal regeneration of retinal ganglion cells in vitro. AB - Although glucocorticoids are commonly used for the treatment of optic nerve inflammations, little is known about direct effects of steroids on retinal nerve cells. In this study, the neuritogenic effect of prednisolone on retinal ganglion cells was investigated using retinal organ cultures derived from adult rats and embryonic chickens. The numbers of axons growing from retinal ganglion cells (RGC) in vitro were counted to measure the regenerative propensity at various corticosteroid concentrations. Prednisolone exerted a dose-dependent neuritogenic influence on RGC of either origin. The effect was highest at a concentration of 25 MUg/ml culture medium, where axon numbers increased to 237% (rat) and 166% (chick) of the control values. This was highly significant (t-test: P < 0.01 and P < 0.005, respectively). High corticosteroid concentrations (>125 MUg/ml) produced toxic effects, as revealed by low axon numbers as well as morphological alterations of the explants. PMID- 21551735 TI - Immunological reactions following intracerebroventricular transplantation of adrenal medulla. AB - Immunological reactions after intracerebroventricular syn-, allo- and xenogenic transplantation of adrenal medulla were investigated histologically. In xenografts only, T cell infiltration and graft rejection were observed. Syngrafts and allografts were not rejected and were not infiltrated by T cells, although expression of MHC class II antigen was observed at all survival times. Major histocompatibility complex (MHC) class I immunoreactivity was strongly expressed in adrenal cortex syngrafts, which could play a role in the rejection of grafts containing mixed cell populations. The survival of chromaffin cells in allografts was decreased as compared to syngrafts, and there were fewer allograft animals with large numbers of surviving chromaffin cells. There was some increased cellularity (microglia and macrophages) in allografts even though no T cell infiltration was found. Therefore, it appears that this limited survival of intracerebral adrenal medulla allografts is not due to T cell-mediated graft rejection. PMID- 21551736 TI - A long term follow-up of fetal dopaminergic neurons transplantation into the brain of three parkinsonian patients. AB - In three parkinsonian patients ages 48, 53, and 50, human fetal dopaminergic cells taken from the ventral part of mesencephalon of 11-12-week-old fetuses were implanted into the head of caudate nucleus. The operation was carried out with a specially designed device to enable safe and precise graft implantation. All patients had been suffering from severe Parkinson's disease for about 10-15 years (stage 4/5 according to Hoehn and Yahr scale) with bradykinesia, rigidity and tremor as the main symptoms. Long-lasting L-dopa therapy resulted in side effects with ON/OFF syndrome and dyskinesias. A detailed clinical examination was performed before and every 3 months after the operation according to the CAPIT battery of standarized tests. The patients were under post-operational observation lasting 30, 20 and 12 months, respectively. Improvement was observed in all patients starting between 3 and 6 months after operation and is still sustained. Significant increases in movement speed for repeated pronation supination, finger dexterity and foot lifting tests were found. The speed of walking also increased with decreased rigidity. The OFF phase during the day is of shorter duration and less severe; dyskinesias are markedly reduced. Our results indicate that fetal grafting seems to be a valuable experimental approach towards the treatment of selected parkinsonian patients. PMID- 21551737 TI - Long term exposure to heat protects against brain damage induced by closed head injury in the rat. AB - Closed head injury leads to delayed tissue-edema, necrosis and impaired neurological function. In the present study the effect of chronic exposure to heat on the outcome of head injury in rats was investigated. Rats were held at ambient temperature of 24 degrees C (CON) or 34 degrees C (heat acclimated, ACC) for one month, before induction of trauma. Injury was induced by a weight drop device, falling over the left cerebral hemisphere. Twenty-four or 48 h later the rats were sacrificed and their brains removed for evaluation of edema (specific gravity or water content). Blood-brain barrier integrity (Evans blue extravasation) was evaluated 4 h after injury. One, 24 and 48 h after injury the rats were evaluated by a set of criteria which yields their clinical status (Neurological Severity Score - NSS). Forty-eight hours after trauma specific gravity of the contused hemispheres was 1.0389 +/- 0.0019 and 1.0364 +/- 0.0007 (P < 0.01) and water content 81.44 +/- 1.28 and 84.17 +/- 1.03% (P < 0.001), for ACC and CON rats, respectively. Lower degree of edema was also evident at 24 h suggesting slower rate of edema formation in ACC rats. Evans blue uptake by the contused hemisphere was 315 +/- 61 and 50 +/- 23 ng/g tissue in the CON and ACC rats, respectively (P < 0.001). Clinical recovery of the ACC rats was significantly better (P < 0.001) than that of the matched controls as exhibited at 48 h by median NSS values of: 10.8 (range 6-16) and 5 (range 4-6) for CON and ACC, respectively. Based on the present results we suggest that heat acclimation offers protection to rats subjected to head trauma. PMID- 21551738 TI - Fetal transplants in rat hippocampus following kainic acid lesions: influence of post-lesion delay on graft survival and integration. AB - Host brain receptivity to fetal hippocampal grafts was investigated following transplantation into unilateral kainic acid (KA) lesions of adult rat hippocampus. E18-E19 hippocampal cell suspensions were labeled with rhodamine dextran amine and transplanted bilaterally into hosts at various times following the KA-lesion. After one to three and one half months survival the grafts (contained within host hippocampal slices) were analyzed using intracellular electrophysiological techniques. A nonparametric graft index was developed which assessed the overall size and distribution of the graft. Using this grading system graft development was noted to be significantly enhanced for grafts placed into hosts with KA lesions at either 2-4 days or 11-12 days following the lesion, compared to grafts placed at either 6-7 days or 27-33 days after the lesion. Also, grafts implanted at delays of either 14-16 or 28-33 days appeared to have fewer surviving cells but were more dispersed within the host brain than grafts at shorter post-lesion implant times. Synaptic responses to host stimulation were noted in most grafts. Intracellular staining of transplanted neurons showed considerable development of cell processes but atypical pyramidal cell morphology and ectopic location; numerous axons traveled into the host tissue. The time course of lesion-induced host receptivity appeared to significantly influence graft development and maturation. In this study graft survival was partially independent from cell migration. This differential effect may be due to various aspects of host brain receptivity, which in turn is influenced by the delay between the host brain lesion and grafting. PMID- 21551739 TI - Traumatic injury of spinal cord cells in vitro reduced by GM1 ganglioside. AB - GM1 ganglioside (monosialoganglioside) is a significant endogenous component of central nervous system (CNS) cellular membranes, thereby contributing to the membranes' integrity and function. Exogenous gangliosides have been shown to be incorporated into plasma membranes and can exert neuroprotective effects on damaged neuronal tissue(s). An in vitro method of physical injury (trauma) previously described which used cultures derived from fetal mouse spinal cord [38] was adapted for these studies in order for us to assess GMl's neuroprotective efficacy. Injury was induced by uniformly crosshatching the spinal cell cultures with a 1 mm plastic pipette tip. The extent of injury and the effects of GM1 ganglioside posttreatment (80 MUM) was assessed after 48 h by measuring lactate dehydrogenase (LDH) released and by observing changes in the plasma membrane surface distribution of endogenous GM1 using cholera toxin/antitoxin/fluorescent antibody immunohistochemistry. A gradient of injury, from the zone of maximum injury to partially traumatized or non-injured areas, was seen using immunohistochemistry. The primary injury zone in this gradient was characterized by areas of swollen or dead cells and abnormal or degenerating cell processes. At further distances, cells were observed to be nearly normal, with intact fibers. This gradient of injury may reflect proximate (at the locus of trauma) and distant effects of the release of neurotoxic levels of endogenous glutamate (Glu) and other excitatory amino acids. Ganglioside GM1 treatment resulted in a significantly reduced (>75%) release of LDH as well as enhanced cell and process integrity indicative of reduced tissue injury. These initial results indicate that GMl's previously documented neuroprotective effects using neuronal culture systems can be generalized to injured spinal cells in vitro wherein there is evidence for preservation (rescue) of cellular plasma membranes after injury as reflected by reduced cell loss, swelling, and process degeneration, as well as decreased LDH release. PMID- 21551740 TI - Suprachiasmatic nucleus lesions abolish and fetal grafts restore circadian gnawing rhythms in hamsters. AB - It is widely accepted that the suprachiasmatic nuclei (SCN) of the hypothalamus serve as biological pacemakers, organizing daily activities. However some circadian rhythms are controlled by extra-SCN structures. Transplantation of fetal donor SCN in SCN-lesioned rodents induces recovery of rhythmic locomotor and drinking activities. Such grafts do not however, restore appropriate gonadal responses to photoperiodic stimuli. It is not known whether other behavioral rhythms are restored by fetal tissue grafts, or whether various responses are restored simultaneously. In the present study, we established that circadian rhythms of gnawing behavior are abolished following SCN lesions. Next, we measured both gnawing and wheel-running activity in SCN-lesioned hamsters following transplantation of fetal hypothalamic grafts containing the SCN. The results indicate that such grafts restore circadian rhythms of gnawing behavior, and that gnawing and wheel-running rhythms re-emerge at about the same time. PMID- 21551741 TI - Visualization of axonal degeneration after optic nerve lesion in rat by immunohistochemical labelling for myelin basic protein (MBP). AB - Immunohistochemical staining of myelin basic protein (MBP) was followed during axonal degeneration of rat retinal fibers within the first 3 weeks after injury. Wallerian degeneration of rat retinal fibers was elicited by unilateral transection or crush injury of optic nerve. MBP-labelled fibers in central retinal pathways and visual nuclei showed sequential changes of the myelin sheath, such as swelling at 1-2 days post lesion (dpi), granular staining at 4-8 dpi, and granular debris formation at 21 dpi. Consequently, immunostaining for MBP could be used to identify early stages of degenerating myelin and persisting myelin debris which is known to contain neurite growth inhibitors. PMID- 21551742 TI - Autotomy prevention by amitriptyline after peripheral nerve section in different strains of mice. AB - This study evaluates the degree of autotomy induced by anesthesia dolorosa after transection of the sciatic and saphenous nerves in four different strains of mice, and the effectiveness of amitriptyline administration in two of them. The self-mutilating lesions were assessed by means of an autotomy score for one month after denervation. The onset of lesions generally occurred during the first week, starting in the nails and progressing proximally. Autotomy behavior developed differently in the mouse strains studied, involving 88% of the paw areas in OF1 mice, 61% in Balb-C, 35% in NMRI, and 15% in B6CBAF1. Two selected strains, OF1 and NMRI, were treated with amitriptyline (8 mg/kg/day, p.o.) from different intervals pre-operation. Administration starting 14 days before nerve lesion was the most effective treatment schedule for reducing autotomy in both strains. PMID- 21551744 TI - Erratum. PMID- 21551745 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551746 TI - Developmental plasticity after spinal cord lesions and transplants at birth. PMID- 21551747 TI - Electrical stimulation of nerve regeneration in the rat: functional evaluation by a twitch tension method. AB - The effect of D.C. electrical fields on in vivo nerve regeneration following rat sciatic nerve transection was assessed by a toe-twitch tension method for motor recovery. Two groups for baseline comparisons received either a nerve transection and a neutral battery implant or a nerve crush and no implant. Two treatment groups each received a nerve transection and an implant delivering either cathodal (-10 MUA) or anodal (+10 MUA) current via electrodes positioned on either side of the transection site. The contralateral nerve was exposed but not given a lesion. The functional recovery was assessed at weekly intervals by comparing the amplitude and area of the twitch tension curves on both sides, expressed as a ratio (index of motor recovery = IMR). By 28-35 days postoperative (dpo) the crushed/untreated group had mean IMR values not significantly different than the preoperative values. The transected/neutral group appeared to have the worst recovery throughout the study. Compared to these two groups, both the cathodal and anodal treatment groups with a transected nerve showed intermediate IMR values, but by 63 dpo the group differences were less. These results indicate that following a nerve transection lesion steady D.C. electrical fields may temporarily enhance the early functional recovery of motor nerve regeneration compared to conventional nerve repair alone. PMID- 21551748 TI - Axonal sprouting at the node of Ranvier of the peripheral nerve disconnected with the cell body. AB - In order to examine whether the axonal sprouting at the node of Ranvier is a local event reactive to the lesion independent of influences from the cell body, the sciatic nerve of mouse (ddY strain) was freeze-injured at the mid-thigh and at the same time transected at the level 2 cm proximal to the frozen site. Within 5 h after freeze-transection, sprouts were formed at some nodes of Ranvier located within 0.5 mm proximal to the frozen site. These sprouts had almost the same ultrastructural features as those found in ordinary freeze-injury, showing a tendency to grow toward the overlying Schwann cell basal lamina. However, the sprouts thus formed ceased to grow and became atrophic within 10 h after freeze transection. This fact indicates that the axon has a property of sprouting at the node of Ranvier in the absence of the cell body. However, nutritional as well as constitutive substances from the cell body are needed to maintain the growth of the sprout. PMID- 21551749 TI - Improved footprint analysis using video recording to assess functional recovery following injury to the rat sciatic nerve. AB - Footprint analysis is a non-invasive method to quantitate functional recovery after crush injury in the rat sciatic nerve model. Traditional methods of producing the footprints for measurement are limited by inability to reliably produce clear prints when the injury is severe. We describe the use of video technique with image analysis to record and measure these prints. Video had fewer unmeasurable prints than ink. For the 1-5 and 2-4 toe spreads, there was good correlation of video measurements with ink method and better repeatability using video as compared with ink. However, the print length parameter determined by video had poorer repeatability and poorly correlated with that measured by ink. Therefore, calculation of a Sciatic Function Index by video is not appropriate. Since the print length also varies with gait velocity, we believe that a ratio of injured:uninjured hindfoot 1-5 toe spreads as measured by video is a more reliable and repeatable measure of functional recovery in this model. PMID- 21551750 TI - Fos-like immunoreactivity in the rat spinal cord induced by formalin injection in the forelimb to gauge possible plasticity of primary afferent fibers following partial deafferentation. AB - The aim of this study was to gauge the possible sprouting of primary afferent fibers following dorsal rhizotomies using Fos-like immunoreactivity (Fos-LI) in order to label neurons activated by formalin injection into the rat forepaw. To assess the functional consequences of possible sprouting of fine diameter primary afferents, we monitored the behavioral responses and to visualize fine afferent fiber sprouting, we examined calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) in the superficial laminae of the dorsal horn. Two types of dorsal rhizotomies and two delays post-rhizotomy were used: one dorsal root, C7 (C7 cut) or three consecutive dorsal roots, C6, C7 and C8 (C6, C7, C8 cut), were sectioned on the right side three months or 7 days before the day when formalin was injected in the extremity of the ipsilateral forelimb. Control animals had no rhizotomy but received the formalin injection. In control animals, following the formalin injection the greatest number of Fos-LI neurons was encountered in the superficial laminae and in the neck of the dorsal horn of segments C5-T1. In the C7 cut group, the number of Fos-LI neurons was slightly decreased in all segments 7 days after the lesion whereas it was slightly increased 3 months after the lesion as compared to 7 days. In C6, C7 C8 cut group, the number of Fos-LI significantly decreased (90% of the control values) 7 days after the lesion, but after three months, it significantly increased in segments C7 and C8 as compared to 7 days. In parallel in this latter group, a marked depletion of CGRP-LI fibers was observed in the medial part of the superficial laminae at 7 days whereas a clear increase in CGRP-LI occured in the same region at 3 months. Behavioral observations showed a slight decrease in the licking time induced by the formalin injection in the C7 cut group both at 7 days and 3 months after the lesion as compared to the control group. The significant decrease of this behavior observed in C6, C7, C8 cut group at 7 days was not changed after 3 months. The increase in the number of Fos-LI neurons after 3 months in the C6, C7, C8 cut group is discussed in terms of collateral sprouting of thin primary afferent fibers and/or central compensatory mechanisms in response to peripheral deafferentation. Our data favor the first hypothesis, and in addition, support the use of the Fos-LI technique to assess the functional post-synaptic changes at the dorsal horn level. PMID- 21551751 TI - Expression of cholinergic phenotype by embryonic ventral horn neurons transplanted into the spinal cord in the rat. AB - Solid grafts of E12 embryonic spinal ventral horn were transplanted into motoneuron-depleted adult lumbar spinal cord in the rat. A muscle was implanted parallel to the vertebral column with its nerve inserted into the lumbar cord at the site of transplantation so as to provide a target for innervation by the grafted neurons. Previous retrograde labelling studies have shown that modest numbers of grafted motoneuron-like cells participate in the muscle's reinnervation and these are often found outside the graft within the host spinal cord. However, Nissl stained sections show that larger numbers of neurons survive within tissue recognisable as being of graft origin. In this study we have examined the expression of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) by neurons within the graft. These enzymes are involved in cholinergic neurotransmission and are characteristic of motoneurons. Thirty four to seventy days following transplantation the grafts contained numerous neurons with acetylcholinesterase (AChE) activity. Different patterns of AChE staining were observed which probably reflected the degree of differentiation and maturation within the graft. AChE positive neurons were found in isolation or in groups resembling developing motor pools. Most of the AChE-positive neurons appeared immature with scant cytoplasm. However, neurons could be found which appeared relatively mature with a regularly shaped nucleus, prominent nucleolus and Nissl bodies. The grafts contained few AChE-positive axons and no dense plexuses of varicose fibres around the neurons such as are found around motoneurons in the mature ventral horn. Comparisons between the size of AChE positive neurons in the graft and the size of AChE-positive neurons in the developing ventral horn found that the size of grafted neurons to be intermediate between the sizes of spinal motoneurons at E19 and P0. Far fewer grafted neurons were found to be immunoreactive for choline acetyltransferase (ChAT) than histochemically reactive for AChE. This was consistent with our findings in the spinal cord during normal development where we found that fixation and staining procedures which labelled adult motoneurons failed to reliably demonstrate ChAT immunoreactivety in normal motoneurons prenatally, although AChE histochemical reactivity could be demonstrated as early as E16. We conclude that the grafts contain numbers of immature motoneurons which fail to proceed beyond a certain stage of development, perhaps because of a failure to form appropriate efferent and afferent connections. PMID- 21551752 TI - Regrowth of axons within Schwann cell-filled polycarbonate tubes implanted into the damaged optic tract and cerebral cortex of rats. AB - The efficacy of Schwann cell-filled polycarbonate tubes as a bridging substrate for regrowing axons following lesions of the rat optic tract or cerebral cortex has been assessed after short (11-31 days) or long (82-119 days) survival times. Tubes were impregnated with Iaminin and poly-L-lysine, soaked in basic FGF and filled with Schwann cells. They were implanted into optic tract lesions in 34 rats aged 15-21 days and into cortical lesion cavities in 3 adult rats. Gelfoam soaked in basic FGF and Schwann cell conditioned medium was placed over the tubes. In one group of rats, axon regrowth into implants was assessed using neurofilament antibody RT97; antibodies to proteolipid protein, Po, Iaminin, the low-affinity nerve growth factor receptor (NGFr), S-100 and EDI were also used to study myelination and the cellular content of the tubes. In a second group of rats, anterograde tracing techniques were used to specifically identify host retinal axons within the implanted polymers. After long survival times, the relationships between regrown axons and cells inside the tubes were also examined ultrastructurally. In all implants examined immunohistochemically at short survival times, large numbers of RT97+ axons were found throughout the tubes, usually in association with Iaminin+, NGFr+ Schwann cells. At longer survival times, viable Schwann cells were still present, but tubes contained fewer axons and less cellular material. This material often formed a cord (200-250 MUm thick) which extended the length of the implant. In the second group of rats, labelled retinal axons were found in 11 of the 16 implants that were attached to the dLGN. Axons regrew up to 1 mm but did not reach the distal (tectal) end of the implants. Interestingly, there was no evidence of myelinogenesis by either implanted Schwann cells or by host-derived oligodendroglia which had migrated into the tubes. Oligodendroglia were usually encircled by processes, many of which originated from Schwann cells, suggesting that the grafted cells may have been involved in isolating the central glia. The data show that Schwann cell filled polycarbonate tubes provided a favourable milieu for axonal regeneration in the short term; however over time there was a decrease in the cellular and fibre content of the tubes. After intracranial implantation, an additional supporting matrix inside the polycarbonate tubes may aid in providing an environment conducive to the long term maintenance of regenerated retinal and other axons. PMID- 21551753 TI - Transient forebrain ischemia-induced neuronal degeneration in fascia dentata transplants. AB - Fascia dentata tissue blocks from newborn rats were grafted into one-week-old, ibotenic acid-induced lesions of the fascia dentata, or the normal fascia dentata of adult rats. After at least 2 months survival the recipient rats were subjected to 10 min of forebrain ischemia (4-vessel occlusion), and examined 2 or 4 days later for neuronal degeneration in the host hippocampi and the transplants, by silver staining and immunohistochemistry. Transplants survived well in both normal and lesioned host brains, with easily recognizable subfields and layers and presence of normal types of principal and non-principal neurons. As expected, argyrophilic, degenerating neurons were present in the pyramidal cell layer of CAl and CA3c of the non-grafted contralateral host hippocampus and in the contralateral dentate hilus (CA4). In the hilus the degeneration corresponded to the loss of somatostatin-immunoreactive neurons, while parvalbumin-immunoreactive neurons were spared. In the dentate transplants degenerating neurons were observed in the granule cell layer, the hilus and the adjacent CA3 pyramidal cell layer. There was no obvious loss of either somatostatin- or parvalbumin immunoreactive neurons. The degeneration varied considerably between transplants, from a few to large groups of silver stained neurons, but this difference did not display any obvious relation to grafting into normal or lesioned hosts, the exact location of the grafts or the general organization and distribution of intrinsic or extrinsic host afferents in the grafts. The results demonstrate that both ischemia-susceptible and -resistant types of neurons grafted to normal and lesioned adult rat brains are susceptible to transient forebrain ischemia after transplantation. In spite of an extensive reorganization of transplant nerve connections, the physiologicalbiochemical mechanisms necessary for the induction of ischemic cell death were accordingly present in the transplants. PMID- 21551754 TI - Influence of fetal hippocampal grafts on lesions induced by intraventricular infusion of N-methyl-D-aspartate (NMDA) into rats. AB - Effects of fetal hippocampal transplants were evaluated following a prolonged intraventricular excitotoxic lesion (1.0 mg of N-methyl-D-aspartate over two weeks infusion) in F344 rats. The septum and ipsilateral hippocampus (CA1 and dentate regions) showed extensive cell loss, decreased acquisition of spatial memory was observed and a decrease in AChE positive fiber innervation to the hippocampus was noted following the lesion. Fetal hippocampal transplants into the posterior lateral ventricle resulted in moderate graft survival and physiological analysis of graft-host interconnection in vitro demonstrated evoked field potentials. However, the transplants did not lead to significant improvement in behavior, possibly due to poor synaptic integration of the intraventricular transplants into the host hippocampus. The prolonged intraventricular NMDA lesion may be helpful to understand a mixed lesion model of both septal areas and hippocampus and also as a background lesion in which to assess the connectivity and development of various types of neural grafts. PMID- 21551756 TI - 4-Aminopyridine and spinal cord injury: a review. AB - Demyelination of axons within the spinal cord represents a significant component of the pathology of contusive and compressive spinal cord injury (SCI) and the associated conduction deficits most probably contribute to the paralysis and sensory loss experienced by SCI patients. 4-Aminopyridine (4-AP) is a potassium (K+) channel blocking agent that has been shown capable of restoring conduction across demyelinated internodes in neurons of the spinal cord. Recent clinical trials of 4-AP provide evidence that limited and transient neurological gain may be derived by some SCI patients with longstanding injury. The present review traces the historical development of 4-AP, describes the mechanism of action and rationale for use in SCI, and provides an overview of the clinical trials conducted to date. The early trials give rise to optimism that pharmaceutical management of conduction deficits may have a role to play in restoring neurological function in some patients with SCI. PMID- 21551757 TI - Influence of dihydropyridines on the recovery of sensory function after a caudal nerve crush in the rat. AB - Nimodipine, a Ca2+ antagonist of the dihydropyridine type, is known to display a variety of neuropharmacological effects including facilitation of functional recovery following a crush of the sciatic nerve in the rat. In the present study, we investigated the effect of nimodipine, nifedipine (another Ca2+ antagonist with a lesser penetration in neural parenchyma) and Bay K 8644 (a Ca2+ agonist) treatment following a crush of the major caudal nerve. The caudal nerve crush model was used because this model provided the opportunity for longitudinal evaluation of nerve repair. Recovery of sensory function was tested by vocal reaction following local stimulation with a small electric current. The results suggest that nimodipine (20 mg/kg) both enhances the initial sprouting response and exerts an effect on the outgrowth rate of newly developed sprouts. Neither nifedipine (20 mg/kg) nor Bay K 8644 (0.5 mg/kg) had any influence on the recovery of nerve function. Furthermore, it was demonstrated that nimodipine, nifedipine and Bay K 8644 had no influence on nerve conduction velocity of the non-injured sciatic nerve indicating that there was no general beneficial effect of these agents on the peripheral nerve. PMID- 21551758 TI - Persistence of functional neuromuscular junctions formed in a denervated skeletal muscle of the adult rat by axons that have regrown from the injured spinal cord through a peripheral nerve autograft. AB - In previous 'short-term' (2 to 7 months) experiments, we had demonstrated, in the adult rat, that motoneurons of the injured cervical spinal cord could extend lengthy axons into an autologous peripheral nerve segment which was connected to a nearby denervated skeletal muscle. In addition, we had shown that new functional motor endplates were formed by these axons both at the original sites of innervation and at ectopic locations of the denervated muscle. This substitution motor system, although quite functional, was anatomically very different from the original model of innervation in the intact animal, relating to its motoneuronal pool, the course of its motor axons and the sites of terminal innervation. The present 'long-term' (11 to 21 months) experiments demonstrate the anatomical and functional permanency of the new motor circuitry, despite a lack of strict specificity in the new neuromuscular connections. However, some minor modifications or adjustments were observed with time: (i) the maintenance of functional ectopic endplates could be consistently demonstrated, while functional reinnervated endplates at the initial sites of innervation were rare or even lacking; (ii) there was a definitive withdrawal of all non target specific regenerated axons from the vicinity of the muscle. It is now necessary to address the question to what extent this substitution motor system is actually controlled by central and/or peripheral inputs. PMID- 21551759 TI - The immunosuppressant FK506 increases functional recovery and nerve regeneration following peripheral nerve injury. AB - Regeneration of peripheral nerve fibers over long distances often requires extended periods of convalescence. Loss to society can be measured in terms of increased health care costs, decreased productivity and, in the case of job related injuries, larger workers' compensation claims. The availability of drugs to increase axonal regeneration would be beneficial not only to patients but also to society in general by decreasing these costs. In the present paper, we present our initial studies on the regenerative effects of the new immunosuppressive agent FK506. Rats given a sciatic nerve crush (axotomy) received daily subcutaneous injections of FK506 (1.0 mg/kg); axotomized control animals received saline. Clinical signs of recovery in the hind feet were manifested two days earlier in FK506-treated than in saline-treated animals; movement in the toes, and walking on the hind feet and toes were observed at 16 and 17 days, respectively, in saline-treated rats and at 14 and 15 days, respectively, in FK506-treated rats. Measurement of interdigit distances in the hind feet at 18 days following axotomy showed a return toward normal position of the toes (increased interdigit distances) during walking in FK506-treated rats. Light and electron microscopy performed at 18 days following axotomy confirmed the clinical appearance of increased functional recovery in FK506-treated rats. Distal to the crush site, the sciatic nerve and its terminal branches from FK506-treated animals contained more myelinated fibers compared to saline-treated animals; in the soleus nerve, the numbers of myelinated axons was increased 2.75-fold. Taken together, the present results suggest that FK506 enhances recovery of function in the rat by increasing the rate of axonal regeneration following a sciatic nerve crush. PMID- 21551760 TI - The effect of propranolol on the desipramine-induced regeneration of brain noradrenergic axons in the rat. AB - The antagonizing effect of the beta-adrenoceptor antagonist propranolol (PRP) on the desipramine (DMI)-induced regeneration of brain noradrenergic fibers was examined. The symmetrical sites of the rat frontal cortex were pretreated with 6 hydroxydopamine (6-OHDA). Then, the same cortical site of one hemisphere was infused with DMI, while the corresponding site of the other hemisphere was infused with DMI (1 mM) plus PRP (1 mM). The DMI-induced axonal regeneration was attenuated by PRP. This finding suggests that activation of beta-adrenoceptors is involved at least in part in the regeneration of brain noradrenergic axons. PMID- 21551761 TI - The role of the habenula-interpeduncular pathway in modulating levels of circulating adrenal hormones. AB - The fasciculus retroflexus (FR) is the major pathway by which the medial and lateral habenular nuclei project to the interpeduncular nucleus (IPN) and ventral tegmentum. Recent work has suggested that the habenula-interpeduncular system may be involved in the regulation of states of arousal. Bilateral FR lesions have been shown to disrupt chronically, and habenula transplants have been shown to restore normal sleep patterns in rats [J. NeuroscL, 12 (1992) 3282-3290]. In this study, we examined whether FR lesions and habenula cell transplants would also modify chronically the circulating plasma levels of the stress-related hormones, norepinephrine (NE), epinephrine (EPI) and corticosterone. When plasma samples were obtained via retro-orbital eye-bleed during anesthesia, animals with FR lesions had significantly increased levels of plasma NE, EPI and corticosterone 2 3 months postoperatively compared to unoperated controls. Transplants of embryonic habenula cells placed near the denervated IPN in FR-lesioned animals restored levels of NE and EPI to normal, but did not attenuate elevated corticosterone levels. When plasma samples were obtained in conscious animals via indwelling arterial cannulae, FR-lesioned rats likewise exhibited increased basal levels of corticosterone but plasma levels of catecholamines were similar to those of unoperated controls. Differences in our results obtained using the two methods of blood sampling may be explained by the effects of anesthesia and stress associated with the eye-bleed method. Thus, the effect of FR lesions in increasing plasma levels of catecholamines may not reflect a difference in basal hormone levels, but a heightened sympathetic adrenomedullary response to stress. While these results indicate that the integrity of the habenular efferent pathway is important in modulating circulating levels of hormones associated with the stress response, two separate mechanisms appear to control its interactions with sympathetic-adrenal medullary and adrenocortical pathways. PMID- 21551762 TI - Recombinant basic fibroblast growth factor spares thalamic neurons from retrograde degeneration after ablation of the somatosensory cortex in rats. AB - Retrograde degeneration of thalamic neurons after cortical ablation has long been recognized. Neuronal loss following axotomy eliminates the possibility of regeneration and might prevent the recovery from axonal injury in patients with brain trauma. We investigated whether CS23, a stable recombinant variant of human basic fibroblast growth factor (bFGF), could protect neurons from retrograde degeneration. Four weeks after ablation of the somatosensory cortex in young female rats, there was extensive neuronal degeneration and loss in the lateral ventro-posterior nucleus (VPL) of the ipsilateral thalamus. When Gelfoam soaked in bFGF(CS23) (1 MUg/0.l ml) was applied topically at the time of surgery, this neuronal degeneration in the VPL was markedly reduced and macroscopic atrophy of the lateral and medial ventroposterior nucleus (VPL + VPM) was significantly reduced. In contrast, application of bFGF at three days after surgery failed to prevent retrograde degeneration. These resuts indicate that bFGF can prevent thalamic atrophy after ablation of the somatosensory cortex and that administration of bFGF is only effective in the very early period after brain injury. PMID- 21551764 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551763 TI - The effects of delayed nerve repair on nerve regeneration in a silicone chamber model. AB - The silicone chamber model for nerve regeneration is suitable to test the effects of exogenous agents or surgical manipulations on nerve regeneration. The total 16 day regeneration period used in this model makes it possible to analyze the effects of certain manipulations on the sequential advancement of the individual cellular components (circumferential perineurial-like cells, vessels, Schwann cells, axons, and myelin) into the chamber fibrin matrix. In the present study we compared the effects on cellular migration of a 7 day delayed chamber repair vs. chamber repair immediately after transection (control chambers) of the rat sciatic nerve. Regeneration was evaluated with light and electron microscopic techniques. Chambers implanted after a delay of 7 days had a statistically significant more advanced migration of vessels, Schwann cells, and axons from the proximal nerve stump and also a significantly increased vascular density as compared to control chambers. We conclude that a 7 day delayed nerve repair stimulates nerve regeneration in this specific silicone chamber model. PMID- 21551765 TI - No adverse effects of cyclosporin A on cellular and functional development of foetal rat dopaminergic mesencephalic neurones grafted into the 6-hydroxydopamine rat model of Parkinson's disease. AB - This study investigated the potential neurotoxic effects of cyclosporin A (CyA) on allogeneic foetal rat ventral mesencephalic (VM) grafts in the 6 hydroxydopamine rat model of Parkinson's disease. Despite its use in the clinical neural grafting situation, the safety of the CyA treatment concerning graft survival and function has not been demonstrated in systematical animal studies. Three groups of grafted rats were treated with either 10 or 20 mg/kg cylcosporin A daily for 6 weeks. Analysis of graft function and development within the different immunosuppression regimes showed no significant differences between any parameters assessed (rotational behaviour and graft survival). It is concluded that high doses of cyclosporin A do not adversely influence survival and function of rat-to-rat foetal allogeneic VM grafts. PMID- 21551766 TI - Chronic alterations in rat brain alpha-adrenoceptors following traumatic brain injury. AB - Norepinephrine (NE) has been implicated in cerebral plasticity and recovery of function after brain injury. To examine the status of noradrenergic mechanisms in the brain following traumatic brain injury (TBI), male Sprague-Dawley rats underwent right sensorimotor cortex contusions and were observed for the next 30 days for recovery of motor function by measurement of the time taken to perform a modified beam walking task! At 30 days, their brains were assayed by receptor autoradiography for alphar- and alpha2-adrenoceptor binding with 1 nM [3H]prazosin and 1 nM [3H]paraminoclonidine, respectively. One day after contusion, TBI rats took 60% longer to run the beam than sham-lesioned controls. Run times were directly proportional (r = 0.784; P = 0.012) to lesion volume determined at 30 days. The motor deficit persisted for 8 days, after which TBI and control rats had similar run times, largely due to increased run times in sham rats. At 30 days, TBI rats had a generalized, bilateral decrease in [3H]prazosin binding across all brain areas read (F[l,13] = 9.23; P = 0.009) with specific 12%-21% decreases in the cortex contralateral to the lesion and bilaterally in the dorsomedial hypothalamic and three thalamic nuclei. On the other hand, [3H]paraminoclonidine binding did not differ from sham lesion controls in any brain area of TBI rats. Thus, unilateral TBI is followed by widespread, bilateral changes in alpha1-adrenoceptor binding which would leave the animal vulnerable to any factors which reduced the access of NE to its postsynaptic adrenoceptors. This is compatible with the observation that alpha1 antagonists and alpha2-agonists can transiently reinstate the motor deficit after recovery has occurred. PMID- 21551767 TI - Production of terminally differentiated neuroblastoma cells in culture. AB - The use of fetal central nervous system (CNS) tissue in neural transplants has ethical, availability and some biological limitations. In order to overcome these problems, homogeneous populations of specific neurons in vitro should be established. Transformed nerve cells such as neuroblastoma cells (NBP2) in culture can serve as one of the sources of donor neurons in neural transplants provided they can be induced to differentiate terminally. This study showed that treatment of murine neuroblastoma (NBP2) cells with 4-(3-butoxy-4-methoxybenzyl) 2-imidazolidinone (R020-1724, an inhibitor of cyclic nucleotide phosphodiesterase), and beta-carotene for a period of 3 days followed by X irradiation with 20 Gy or above produced 100% terminally differentiated cells. These differentiated NB cells had long and extensive neurites, contained elevated levels of tyrosine hydroxylase (TH) activity and very low levels of MHC class I and II antigens, and were non-tumorigenic. The viability of differentiated NB cells when determined on the criteria of attachment efficiency, re-extension of neurites and presence of TH after replating was only 9%. This was in contrast to the trypan blue exclusion technique which showed that over 90% of differentiated NB cells in culture were viable. PMID- 21551768 TI - Axonal regeneration in the foot branch of the superficial peroneal nerve and the lateral plantar nerve of the rat after sciatic nerve lesions. AB - Hand injuries with nerve lesions often leave the patient with a persistent sensory deficit, particularly with respect to glabrous skin. The present study examines axonal regeneration in the foot branch of the superficial peroneal nerve (fSPN) and the lateral plantar nerve (LPN), supplying hairy skin and glabrous skin together with some intrinsic muscles, respectively, after sciatic nerve lesions in the rat. Following crush lesions, the number of myelinated axons is normal in the fSPN, and the occurrence of C-fibers appears slightly reduced. In the LPN, the numbers of myelinated axons and C-fibers are both significantly increased. Post-crush regenerated myelinated fSPN and LPN axons show normal size ranges, but the proportion of small myelinated axons is increased. After neurotomy and suture, the numbers of myelinated axons and C-fibers in the fSPN are not significantly different from normal. The LPN exhibits a significantly increased number of myelinated axons, but the number of C-fibers is not significantly abnormal. In both nerves, the myelinated axons present an abnormally narrow size range. These findings show that the quantitative outcome of regeneration in a nerve innervating glabrous skin (and some intrinsic muscles) differs significantly from that of branches to hairy skin of the foot, with respect to myelinated as well as unmyelinated axons. To what extent these differences mirror functional differences awaits elucidation. PMID- 21551769 TI - Expression of basic fibroblast growth factor receptor messenger RNA in the periinfarcted brain tissue. AB - The present study examined whether expression of basic fibroblast growth factor receptor (bFGFR) messenger ribonucleic acid (mRNA) was upregulated by focal ischemia. We have studied the in situ hybridization autoradiography for bFGFR mRNA in the rat model of middle cerebral artery (MCA) occlusion. Male Wistar rats were used for occlusion of the left MCA, and were sacrificed 1, 3, 7 and 14 days after MCA occlusion. In situ hybridization was performed on the brain sections of these animals and sham controls by using 35S-labeled antisense and sense (control) RNA probes for rat bFGFR. Expression of bFGFR mRNA was observed in the periinfarcted area of the rats within 1-14 days after MCA occlusion. Expression was evident in the whole hemisphere of the infarcted side, especially at 1 and 3 days after ischemia, but no expression was detected in the contralateral side. On microautoradiograms, the signals of bFGFR mRNA were detected in both neurons and non-neural cells located in the periinfarcted area. Upregulation of bFGFR mRNA detected in the periinfarcted brain tissue suggests that receptor-mediated action of bFGF may be related to preservation of neurons injured by ischemia. PMID- 21551770 TI - Experimentally induced autonomic neuropathy: beneficial effect of a systemic ACTH4-9 analogue on oculomotor nerve regeneration. AB - While the regenerating capacity of peripheral nerves has been the subject of intensive study, little is known about the regenerative capacity of the autonomic nervous system. Using an animal model, where the pupil diameter of the eye in the rat serves as a parameter of autonomic function, we studied whether systemic treatment with the neuropeptide Org 2766, a synthetic ACTH4-9, analogue, facilitates the functional recovery of parasympathetic nerve fibres after transection, and after a crush lesion of the oculomotor nerve. By simply photographing the rat's pupil under standardised conditions, we show that sectioning the oculomotor nerve leads to an immediate mydriasis, followed by spontaneous regeneration in 30 days. Systemic treatment with an ACTH4-9 analogue had no effect on the rate or quality of recovery. However, systemic treatment with an ACTH4-9 analogue after a crush lesion of the oculomotor nerve (spontaneous regeneration time 16 days) did enhance the speed of recovery of the parasympathetic nerve fibres in the oculomotor nerve, especially in the initial stages of regeneration. We conclude that the animal model used in this study is valuable for studying the regenerative capacity of the autonomic nervous system and the influence of neurotrophic peptides on autonomic neuropathies. Evidence is presented that synthetic ACTH4-9 analogue exerts beneficial neurotrophic effects, not only in peripheral sensorimotor neuropathies but also in autonomic neuropathies. PMID- 21551772 TI - Erratum. PMID- 21551771 TI - Rejection and regeneration through peripheral nerve allografts: immunoperoxidase studies with laminin, S100 protein and neurofilament antisera. AB - The pattern and temporal sequence of histopathological events in a rat nerve allograft model were evaluated. Following grafting and varying survival periods (from 1 to 30 weeks), the host and donor nerve were removed and assessed by light and electron microscopy. Nerve allografts underwent Wallerian degeneration and rejection. Wallerian degeneration was the dominant pathologic process at weeks 1 and 2 after engraftment. Histologic rejection started as an epineurial process at weeks I and 2, became progressively endoneurial and was most prominent at 4 and 6 weeks after engraftment. Rejection was accompanied by evidence of graft Schwann cell and endoneurial tube loss. The rejection process delayed, but did not prevent, nerve regeneration by the host. Regeneration of fine neurofilament positive axonal sprouts into the proximal portions of the graft was observed as early as week 2. Subsequently, regeneration occurred through the periphery and around the exterior of the rejected nerve allograft fascicle. Regenerating axons were accompanied by S100 protein reactive Schwann cells and newly synthesized laminin-positive endoneurial tubes. Regenerating axons reinnervated the distal host segment at week 8 and increased in number and myelination thereafter. The observations of rejection and regeneration through nerve allograft segments are discussed in reference to previous studies. PMID- 21551773 TI - Neuroprotection of completely lacerated spinal cord of adult rats by homotopic and heterotopic transplantation. AB - To evaluate the neuroprotective effect of transplants placed in the lesion zone after a complete spinal cord (SC) laceration, two independent series of experiments were carried out. In the first, allogeneic or xenogeneic fetal SC was transplanted into the gaps of the damaged lower thoracic SC of adult rats. In the transplanted rats the incidence of life-threatening complications was reduced, and the survival rate was increased compared with the control group (lesion, without implant). Histological examination showed less damage to the neighboring SC parenchyma in the transplanted rats. The measurement of this neuroprotective effect was made in a second series of experiments. Using the same model of SC injury, allogeneic fetal SC, autologous peripheral nerve and/or adipose tissue were implanted. Rats with implants of Gelfoam and damaged rats without implants were the controls. The implanted rats of all groups, including the Gelfoam group, showed a better survival rate than the nonimplanted rats. Significantly less damage to the neighboring SC parenchyma was measured in implanted rats with any of the live tissues tested compared with non-implanted rats, although no significant differences were observed between the Gelfoam group and the nonimplanted rats. Histological evidence of tissue implant survival was observed in all corresponding groups. It is concluded that the transplanted tissues tested here have a neuroprotective effect, possibly by acting as a buffer to neurotoxic substance(s) released by the stumps, and/or by exerting trophic effect(s) on the host. PMID- 21551774 TI - Neurotrophic effect of submicrosomal fractions obtained from pre-degenerated peripheral nerves. AB - Submicrosomal fractions obtained from pre-degenerated distal stumps of sciatic nerves were implanted by means of connective tissue chambers into the injured hippocampus for 8 and 18 weeks. The nerve stumps were allowed to pre-degenerate for 7, 28 and 35 days. The neuronal outgrowth was examined by means of FITC-HRP injected into the chamber. Eight weeks postoperatively the greatest number of traced cells was present in brains treated with the fraction obtained from nerves pre-degenerated for 7 days. Eighteen weeks following implantation the greatest number of FITC-HRP positive cells was found in brains grafted with the fraction from nerves pre-degenerated for 35 days. PMID- 21551775 TI - Proliferation and differentiation of transplanted embryonic diencephalon in the brain of adult rats. AB - The survival, proliferation potential, differentiation, and host tissue reaction of allografts of undifferentiated embryonal diencephalic tissue (E12.5, E17.5) transplanted into or around the third ventricle of adult rats were investigated. Rats harboring grafts were sacrificed at three, six, and nine weeks after transplantation. The proliferative activity of the grafts was assessed by injection of 5'-bromo-2'-deoxyuridine (BrdU) into pregnant rats before the removal of fetuses for transplantation, and staining the grafts using an anti BrdU antibody. The proliferative activity of the transplanted grafts was evaluated by immunostaining using an anti-proliferating cell nuclear antigen (PCNA) antibody. The differentiation of the grafts into neurons was estimated by double immunostaining using anti-BrdU and anti-neuron-specific enolase (NSE) antibodies. The survival rate of the grafts was strongly related to the proliferative activity of the graft. Surviving E17.5 grafts contained immunoreactive BrdU cells. E12.5 grafts could survive without immunoreactive BrdU cells. Undifferentiated El2.5 grafts proliferated up to six weeks after transplantation. Thereafter, most graft cells differentiated into mature neurons. E12.5 diencephalic allografts survived well with minimal rejection reactions and resulted in substantial neurite ingrowth into the host brain, while El7.5 allografts caused substantial reactive gliosis and little ingrowth. PMID- 21551776 TI - Continuous low amplitude direct current stimulation of the crushed peripheral nerve accelerates the early recovery of choline acetyltransferase but not of acetylcholinesterase activity in fast and slow muscles. AB - We investigated if continuous 1 uA direct current stimulation of the injured nerve, with the cathode electrode at the distal end of the nerve crush injury (cathode stimulation), accelerated the recovery of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity in transiently denervated extensor digitorum longus (EDL) and soleus (SOL) rat muscles. ChAT is a specific marker of cholinergic nerve terminals and may reflect axon ingrowth, and AChE reflects the re-establishment of neuromuscular junctions and recovery of muscle activity. Compared to sham operated animals, the cathode (CA) stimulated rats had a statistically significant larger ChAT activity in the EDL and SOL muscles on days 12 and 14 after nerve crush (P < 0.01, n = 6). The difference in ChAT activity between the groups decreased thereafter. Regarding recovery of muscle AChE, CA stimulation of the crushed sciatic nerve did not detectably accelerate the normalization of activity and pattern of AChE molecular forms in the EDL and SOL muscles. This means that the early rise in ChAT muscle activity in CA stimulated rats was not followed by an accelerated normalization of the neuromuscular transmission in the same group. It is more likely that the higher ChAT activity observed after cathode stimulation indicates a higher ChAT content in regenerating motor nerve endings, rather than a greater number of motor axons entering the muscles. It seems possible that cathode stimulation increased ChAT axonal transport, causing the early increase of ChAT content in the nerve endings. This raises the possibility that the axon transport and subsequent secretion of a trophic factor(s) from the nerve to the reinnervated muscle are enhanced as well, thus shortening the overall time of muscle force recovery in the absence of an appreciable acceleration of recovery of the neuromuscular transmission. PMID- 21551777 TI - Differential recovery of bipedal and overground locomotion following complete spinal cord hemisection in cats. AB - We used behavioral assessment techniques to investigate the recovery of locomotion after spinal cord injury. Complete hemisec-tions were made at T13 and LI in the cat spinal cord. Observational and high-speed kinematic analyses of bipedal treadmill and overground locomotion were made from 1 to 5 weeks postoperatively. Both bipedal and overground locomotion showed partial recovery. The early stage of recovery was characterized by an increased range of joint movement in a proximal to distal progression. During later stages, hindlimb movements became more complex and interjoint coordination markedly improved. Overground locomotion recovered faster and to a greater extent than bipedal locomotion, as indicated by the time course of recovery, joint angular excursions and intralimb coordination. We propose that the recovery of bipedal locomotion may be more limited by reorganization of segmenta) sensory systems than overground locomotion, perhaps because alternate strategies for overground locomotion are available. PMID- 21551778 TI - Forebrain and midbrain astrocytes promote neuritogenesis in cultured chromaffin cells. AB - Adrenal chromaffin cells from immature or adult rats were grown in one of the following 'in vitro' conditions: (1) on coverslips placed on top of confluent, fetal, regional glia cultures; (2) in conditioned media from similar confluent cultures; (3) after direct seeding on top of such confluent cultures. Astroglia was obtained from cerebral cortex, septum, striatum and ventral mesen-cephalon from El6-17 pregnant-dated rats. All regions succesfully generated conditions for the early (less than 24 h) expression of neuritogenesis in about 15% of cells, which was more apparent in immature adrenal cell dissociates than in adult ones. The former grew long neurites compared with their adult counterparts. In addition to the known effects of glioma conditioned medium and isolated trophic factors described by other authors, it is concluded that adrenal chromaffin cells are responsive to the neuritogenic activity of (central) astroglial diffusible factor(s) in non-supplemented, defined culture media conditioned by astrocytes from various brain regions. Additionally, evidence is offered that adult chromaffin cells show a reduced responsiveness towards such astroglial factor(s). Possible implications for cell trasplantation chimeras are discussed. PMID- 21551779 TI - Pruning of dendrites and restoration of function after brain damage: Role of the NMDA receptor. AB - Following unilateral injury to the forelimb-representation area of the sensorimotor cortex (FL-SMC) in adult rats, there occurs a biphasic process of overgrowth and partial elimination of neuronal dendrites in layer V pyramidal cells of the homotopic cortex of the opposite hemisphere. These neural events are associated with hyper-reliance on the non-impaired forelimb for postural supporting and related movements that compensate for impaired function in the other forelimb. The overgrowth appears to be use-dependent because it can be prevented by one-sleeve casts that restrict the range of movements of the unimpaired limb during the period of expected neural growth. In development, "exuberant" growth of neurons is often followed by pruning, a process that has been associated with activity-dependency and a glutamatergic N-methyl-D-aspartate (NMDA) mechanism. To determine whether a related mechanism might be operating in adult animals recovering from brain damage, MK-801, a non-competitive NMDA receptor antagonist, was administered during the pruning phase in adult rats that had sustained FL-SMC lesions. MK-801 prevented the elimination of dendrites in the FL-SMC rats and had no effect on dendritic arborization in Sham-operated rats. MK-801 reinstated dysfunction in the previously-recovered forelimb in FL SMC rats, and had no effect in Sham-operated rats. These data are consistent with the possibility that there may be a functionally important pruning mechanism with a glutamatergic component in adults with FL-SMC lesions, just as in the developing brain. PMID- 21551780 TI - Biochemical and anatomical analysis of cholinergic, noradrenergic and serotonergic innervation of fetal neocortical transplants placed in excitotoxin induced neocortical lesions of adult rats. AB - Fetal neocortical block transplants were implanted into the excitotoxically ablated sensorimotor cortex of adult rats in order to examine the density of innervation and distribution of presumptive host derived afferent fibers within these transplants. Cholinergic fiber innervation was examined at 3 months post grafting by measuring acetylcholinesterase (AChE) and choline acetyl-transferase (ChAT) enzyme activities within the grafts and within the corresponding host cortex by radiochemical enzyme assays as well as by AChE histochemistry for the visualization of AChE positive fibers. Noradrenergic and serotonergic inputs were examined by high performance liquid chromatography (HPLC) measurements of noradrenaline (NA) and serotonin (5-hydroxytryp-tamine, 5-HT) concentrations as well as by tyrosine hydroxylase (TH) and 5-HT immunocytochemistry for the visualization of monoaminergic fiber distribution. Our results demonstrated that the grafts contained significantly lower levels of neurotransmitter markers when compared to normal unablated cortex. The anatomical analysis showed an unequal fiber distribution within the transplants. Areas adjacent to the host tissue revealed a relatively dense fiber innervation when compared to the density observed within the more central parts of the transplants, and the anatomical data therefore supported the biochemical data in suggesting an overall lower cholinergic and monoaminergic innervation of fetal neocortical transplants placed into the lesioned adult cortex when compared to normal cortex. PMID- 21551781 TI - N-CAM promotes recovery in injured nerves. AB - The neural cell adhesion molecule, N-CAM, makes critical contributions to the development of the nervous system. It mediates the stability of homophilic adhesion in embryonic neurons and participates in morphologic differentiation. The goal of these studies was to determine N-CAM contributions to nerve regeneration and recovery of function in two species with an excised segment of sciatic nerve. N-CAM was isolated from embryonic brains, affinity purified and admixed in collagen gel for administration. Recovery was compared 30 days after surgery for two types of N-CAM delivery: entubulization versus direct application. For control nerves, tubes contained gel only. In preliminary chicken studies, latency of nerve responses was measured to demonstrate N-CAM's ability to improve upon spontaneous recovery. In subsequent studies of rodent nerves, the direct application of N-CAM significantly improved recovery in evoked nerve response amplitude, number of regenerated axons and behavioral activity. Results demonstrate N-CAM's ability to augment nerve regeneration and suggest a potential for therapeutic use. PMID- 21551782 TI - Sciatic nerve stimulation increases the degree of histopathological damage in lumbosacral segments after short lasting spinal cord ischemia in rabbit. AB - To characterize the influence of primary afferent activation on the development of histopathological changes in the spinal cord after reversible ischemia, the left sciatic nerve was stimulated at the intensity of myelinated fibers before, during and for 1 h after 10 min of abdominal aortic ligation in halothane anesthetized rabbits. In control animals, only 10 min of spinal cord ischemia or sciatic nerve stimulation was employed. One hour after reperfusion all animals were perfusion fixed with 4% paraformaldehyde. Histopathological analysis using the suppressive Nauta method revealed significantly higher number of argyrophilic neurons in dorsal horns and in the intermediate zone in animals in which spinal cord ischemia was combined with sciatic nerve stimulation in comparison with the animals with spinal cord ischemia, but without stimulation. These histopathological changes corresponded with signs of irreversible damage analyzed on the ultrastructural level. Stimulation of sciatic nerve, but without ischemia did not evoke any detectable neuronal changes. The data from the present study suggest that increased activity of spinal cord neurons evoked by peripheral nerve stimulation can be an important factor in determining the extent of irreversible damage after short lasting ischemia. PMID- 21551783 TI - False recovery from auditory hemineglect produced by source misattribution of auditory stimuli (the ventriloquist effect). AB - Right-hemisphere-damaged (RHD) patients with contralesional neglect in the visual modality (n = 8) were found to differ from normal controls (n = 8), and also from RHD patients without visual neglect (n = 7), in their ability to identify auditory stimuli delivered through a loudspeaker on the left side. When the same stimuli on the left were administered in the presence of a fictitious source of sound (a dummy loudspeaker) visible in the homolesional space, a significant increase in the identification score was obtained (the 'ventriloquist effect'). The result is in keeping with a notion of a strong coupling between auditory and visual systems. It is attributed to the activation by the fictitious stimulus of the audio-visual map in the left hemisphere. We draw attention to the possibility that the symptomatic relief associated with the above effect could be translated into certain clinical gains over time. PMID- 21551784 TI - Structural and functional regeneration in hairy and glabrous skin after fibrin sealing of transected peripheral nerves in the rat. AB - Fibrin sealing of nerves has become a commonly used technique in the treatment of brachial plexus injuries as it is quicker than microsuture, but the tensile strength of the fibrin has been in question. A new fibrin (Tisseel-DUO(r), Immuno; Austria) is now available which we have previously studied and with which we had no anastomotic failures. This study is a continuation of our previous work and the aim was to evaluate further the histological and functional outcome after repair with this new product. The sciatic nerves in 15 rats were divided and rejoined with fibrin. The animals were allowed to survive for 3 months and their movement was unrestricted from immediately after the operation. The numbers of myelinated and unmyelinated axons were evaluated after regeneration at * 5000 and * 14 000 respectively. Regenerated function of polymodal nociceptors and low threshold mechano-receptors were evaluated in hairy and glabrous skin. Results from normal rats (n = 15) and rats that had undergone neurotomy and microsuture (n = 15) were used for comparison. After regeneration, counts of myelinated and unmyelinated axons in branches to hairy and glabrous skin differed significantly (P <= 0.05) when fibrin was used compared with microsuture, but this difference was not reflected in the functional regeneration. We conclude that this product may be a time saving alternative to microsuture of peripheral nerves in patients. PMID- 21551785 TI - Nerve regeneration in nerve grafts conditioned by vibration exposure. AB - Regeneration distances were studied in nerves from vibration-exposed limbs. One hind limb of anaesthetized rats was attached to a vibration exciter and exposed to vibration (80 Hz/32 m/s2) for 5 h/day for 2 or 5 days. Seven days after the latest vibration period a 10-mm long nerve graft was taken from the vibrated sciatic nerve and sutured into a corresponding defect in the con-tralateral sciatic nerve and vice versa, thereby creating two different models within the same animal: (i) regeneration from a freshly transected unvibrated nerve into a vibrated graft and (ii) regeneration from a vibrated nerve into a fresh nerve graft (vibrated recipient side). Four, 6 or 8 days postoperatively (p.o.) the distances achieved by the regenerating axons were determined using the pinch reflex test. Two days of vibration did not influence the regeneration, but 5 days of vibration reduced the initial delay period and a slight reduction of regeneration rate was observed. After 5 days of vibration an increased regeneration distance was observed in both models at day 4 p.o. and at day 6 p.o. in vibrated grafts. This study demonstrates that vibration can condition peripheral nerves and this may be caused by local changes in the peripheral nerve trunk and in the neuron itself. PMID- 21551786 TI - The effect of injection technique on the passive spread of astrocytes following transplantation into rat spinal cord white matter. AB - Bisbenzimide-labelled astrocytes were transplanted into the spinal white matter of the rat using three different injection techniques and the variability of the longitudinal distance over which they were found was compared 30 min later. Cells spread up to 5.02 mm and the greatest variability was seen when they were injected as a bolus (54%), compared with 26% when injected over 2 min. These results show the importance of establishing the extent of passive spread of cells and its variability when performing studies in cell migration. PMID- 21551787 TI - Abstracts selected from Excerpta Medica's EMBASE. PMID- 21551789 TI - Peripheral nerve injury and immune response in rat. AB - The effect of peripheral nerve axotomy on cellular and humoral immunity after bovine serum albumin (BSA) sensitization was examined. Arthus and delayed hypersensitivity skin reactions and anti-BSA antibody production in 7, 14 and 21 days after immunization were significantly increased after axotomy of n. saphenus, n. tibialis and n. fibularis. The results indicate that peripheral nerves are also involved in the regulation of immune homeostasis from the place of peripheral immunization to or out the central nervous system (CNS). PMID- 21551790 TI - Fetal porcine ventral mesencephalon grafts: dissection procedure and cellular characterization in culture. AB - The objective of this study was to develop an optimal dissection procedure for fetal porcine ventral mesencephalon (VM) grafts and to characterize the cellular composition of such an explant, in particular with respect to the dopaminergic and GABAergic components. We have used a monolayer cell culture system to study and identify the various VM cell types. The in vitro development of the fetal VM cells and the effect of the addition of brain-derived neurotrophic factor (BDNF) was investigated during a culture period of 5 days. Extracellular dopamine levels were measured by means of high performance liquid chromatography (HPLC) with electrochemical detection (LCEC). Our results indicate that the ratio of dopaminergic to GABAergic neurons changed in favour of the dopaminergic component when a more selective dissection technique was used. Although addition of BDNF to the cultures appeared to exert trophic influences on all the cellular components of pig fetal VM, this effect was most pronounced on the TH-positive cells. Highest extracellular DA levels were found in the VM culture with the addition of BDNF and when a more selective dissection method was used. Our in vitro findings suggest that porcine fetal dopaminergic cells retain their potential for development and outgrowth after proper explantation and dissociation. Anticipating on the results of ongoing transplantation studies in rat, they suggest that pig fetal VM can be a suitable alternative for the use of fetal human VM as a graft for Parkinson's disease. PMID- 21551791 TI - Trauma-induced opening of the the blood-spinal cord barrier is reduced by indomethacin, an inhibitor of prostaglandin biosynthesis. Experimental observations in the rat using [131I]-sodium, Evans blue and lanthanum as tracers. AB - The possibility that prostaglandins participate in opening of the blood-spinal cord barrier (BSCB) after trauma was investigated by comparing rats given indomethacin (an inhibitor of prostaglandin synthesis) before trauma with untreated animals. The trauma was produced by making an incision into the right dorsal horn of the T10-11 segment. The BSCB was examined after 5 h using Evans blue, [131I]-sodium and lanthanum as tracers. A focal trauma to the cord resulted in widespread opening of the BSCB to [l3lI]-sodium in the C5 to L5 segments of the untreated rats. Evans blue extravasation was limited to the T9-T12 segments. Electron microscopy of microvessels in the T9 and T12 segments showed lanthanum diffusely in some endothelial cells, in vesicular profiles and basal lamina. On the other hand, indomethacin pretreatment prevented the extravasation of [131I] sodium in segments located far away from the trauma. In segments closer to the trauma, the extravasation of radiotracer was markedly reduced. Extravasation of Evans blue was less pronounced. Spread of lanthanum into the basal lamina of microvessels was not present. The diffuse passage into the capillary endothelium was reduced and the incidence of cytoplasmic vesicles loaded with lanthanum was lower. Our results for the first time provide direct morphological evidence that prostaglandins are involved in the early, widespread opening of the BSCB after trauma to the cord. PMID- 21551792 TI - Recovery of cellular activity in cryopreserved human foetal brain tissue. AB - Since long-term cryopreservation can cause losses in neural tissue viability and function a prerequisite would be the ability to monitor and promote functional recovery in donor tissue intended for neural transplantation. Rapid assessment of cryopreserved tissue's functional status prior to grafting is presently difficult in a clinical setting. A convenient indicator of functional status may be the level of DNA synthesis activity taking place in the tissue. Using immunocytochemical detection of incorporated bromodeox-yuridine we have quantified and compared DNA synthesis activity (expressed as proliferative capacity (PC)) in human foetal mesencephalic, striatal, cortical and cerebellar tissue before and after a 275-376 day storage in liquid nitrogen. There was a post-storage reduction in viability of 48-73% and in PC of 26-59%; the higher the PC before storage the greater the reduction after. Incubation of cryopreserved tissue with fetal calf serum resulted in 2-4-fold higher PC levels than serum untreated controls and reached 80% of fresh tissue levels in mesencephalic cells after 3-4 h incubation. Assuming that quantification of proliferative activity is a practical indicator of the tissue's functional status, these findings suggest that treatment of the tissue with serum can largely restore the lost function caused by cryopreservation. PMID- 21551793 TI - Neurophysiological assessment of the motor and sensory spinal pathways in chronic spinal cord injury. AB - Introduction of transcranial magnetic stimulation (TMS) has provided means to study non-invasively corticospinal functions in humans. The purpose of the present study was to obtain an objective evaluation of spinal cord functions in spinal cord injury (SCI) subjects using TMS, multichannel surface EMG and somatosensory-evoked potentials (SSEP). Multichannel surface EMG recording was performed during reinforcement manoeuvres and during vibratory tonic reflex. Twenty-five post-traumatic clinically incomplete (ambulatory, AMB, and non ambulatory, nAMB) SCI subjects were studied and compared to a control group of seven subjects. After preliminary analysis of neurophysiological studies they were divided into four groups according to presence or absence of motor-evoked potentials (MEP) in response to TMS in muscles below the level of the lesion and according to their ability to ambulate. TMS was delivered at vertex at 100% intensity and recorded from the large muscles of the upper and lower limbs. Surface EMG was recorded during reinforcement manoeuvres (RM) in the leg muscles and EMG activity was scored. SSEP were recorded at T12, L2, L4 and SI spinous processes and at Cz' on the scalp following tibial nerve stimulation at popliteal fossa. The prevalence of EMG responses during RM was higher in group with present MEPs (AMB/MEP+ and nAMB/MEP+) than in the group without MEPs. The group with present MEPs also showed better preserved functions of the ascending tracts compared to subjects without MEPs. Groups with present MEPs had 5/10 normal, 2/10 abnormal and 3/10 absent cortical SSEPs, whereas groups without MEPs showed 1/11 normal, 4/11 abnormal and 6/11 absent cortical SSEPs. Sustained function of ascending tracts was also positively correlated with preserved ability to ambulate. It was concluded that TMS in combination with multichannel surface EMG monitoring and sensory evoked potentials may prove feasible in assessing the functional capacity of the spinal cord after spinal cord lesion. PMID- 21551794 TI - Visual experience during a sensitive period plays a critical role in vestibular compensation: neuronal substrates within Deiters' nucleus in the alert cat. AB - In a previous study [31], we showed that Deiters' neurons ipsilateral to a vestibular neurectomy temporarily exhibit increased sensitivity to visual cues about fast movement. It was proposed that this change in the deafferented vestibular neuron response observed only during the first 3 weeks post-lesion plays an important role in the vestibular compensation process. The present study was aimed at analyzing the potential influence over the first 2 weeks post-lesion of visual motion cue deprivation (cats housed in stroboscopic light) and passive visual experience (visual information not correlated to head or body movement) on the visually induced activity of Deiters' cells. The extra-cellular response of single units was recorded during sinusoidal translation of a whole field optokinetic stimulus in six alert cats. Following the deprivation of visual motion cues, vestibular unit responses were found to be tuned to low frequencies of visual stimulation, as in intact cats, and to display a phase lag re. velocity during rapid visual stimulation. Passive visual stimulation was also found to impede the increase in neuronal sensitivity to visual input, although the cats had benefited from normal vision from the 15th day post-lesion. These results are discussed in relation to the functional implication of interactive visual experience within the early stages (sensitive period) of the vestibular compensation process. PMID- 21551795 TI - The therapeutic trend of neurosciences. PMID- 21551796 TI - Internalization of macromolecules by live cells. AB - The membrane of eukaryotic cells represents a barrier normally impermeable to non lipophilic substances. In consequence, internalization of extracellular compounds requires the presence of specific channels, or of specialized endocytic mechanisms. Recently, several groups have reported that some growth factors and transcription factors can be internalized by cells in culture and addressed to the cytoplasmic and nuclear compartments. In the latter case, they have been shown to interfere directly with gene transcription. Among these factors are fibroblast growth factor-1 and -2 (FGF-1 and FGF-2), schwannoma-derived growth factor (SDGF), Tat protein and homeodomain or homeodomain containing polypeptides. In the present paper, we present the available data concerning these unconventional uptake mechanisms and speculate on their potential interest to target macromolec-ular structures into live cells. PMID- 21551798 TI - Diphtheria toxin can be used as a vehicle for bringing other proteins into cells. PMID- 21551797 TI - Tat-mediated delivery of heterologous macromolecules into living cells. PMID- 21551799 TI - Vitamin-mediated delivery of proteins, antisense oligonucleotides and genes into living cells. PMID- 21551800 TI - Antennapedia homeodomain third helix as a peptide and oligonucleotide vector. PMID- 21551801 TI - Virus vectors for gene delivery to the nervous system. AB - A number of virus vectors have been developed for gene delivery to the nervous system. Virus vectors still provide the most efficient means of gene delivery, and this is critical as only a small volume of inoculum can be used without damaging neurons. Each of the four types of vectors currently in use have their advantages and disadvantages. Highest titers can be achieved with herpes virus and adenovirus vectors, with retrovirus and adeno-associated virus (AAV) vectors currently yielding lower titers. The transgene capacity of each from highest to lowest is: herpes virus (30 kb), adenovirus (8-10 kb), retrovirus (7-8 kb) and AAV (4.5 kb). All can infect a broad range of cell types in the nervous system, including neurons, glia and endothelial cells. Herpes, adenovirus and AAV vectors can deliver genes to postmitotic, as well as mitotic cells, while retrovirus vectors depend on cell mitosis for gene delivery. Herpes virus can assume a stable extrachromosomal configuration in the nuclei of some neurons (termed latency), while both retrovirus and AAV can integrate into the cell genome. Both integrate at random sites, but AAV can also integrate at a specific chromosomal location. Adenovirus neither assumes a stable state nor integrates, still its genome can persist and be expressed in the host cell for some time (up to a month or so). Stability of gene expression is a problem for all the vectors, due in part to the use of viral promoters which tend to be down-regulated by the host cell over a month or so. Both herpes virus vectors and adenovirus vectors have some toxicity in their current configurations, while retrovirus and AAV tend to be associated with less neuropathogenicity. Many developments in vectors should be occurring over the next few years that should increase the potential of these vectors for therapeutic gene delivery. PMID- 21551802 TI - Third-generation adenovectors for gene therapy. PMID- 21551803 TI - Cell type-specific expression from viral promoters within replication-deficient adenovirus recombinants in primary neocortical cultures. PMID- 21551804 TI - HSV-1 amplicons. Advantages and disadvantages of a versatile vector system. PMID- 21551805 TI - Using adenoviral vectors to transfer the CNTF gene into the CNS. PMID- 21551806 TI - Engineered cells: a promising therapeutic approach for neural disease. AB - The transplantation technique has been invaluable for studying the CNS. Recently, the use of genetically modified cells for CNS grafting has further increased the utility of this technique. Studies conducted during the past 10 years have shown that a variety of genes can be successfully expressed in both neural and non neural populations. Depending on the cell type used for gene transfer, engineered cells survive well within the CNS and continue to synthesize engineered products. In addition to providing insights into CNS development and plasticity, genetically modified cells have revealed the therapeutic role of different factors in neural disease. Cells engineered to produce growth factors have been shown to prevent and/or minimize neural degeneration following an experimental damage while the intracerebral transplantation of cells genetically modified to produce neurotransmit-ters have successfully reversed behavioral impairments of animals with experimental Parkinson's disease or Alzheimer's disease. Recent results with engineered cells transplanted into the brain of non-human primates suggest the potential of engineered cells for human therapy. Work with encapsulation techniques to isolate engineered cells from a host brain offers one of several approaches for ensuring the safety of genetically modified cells grafted into the CNS. Identifying factors that influence the survival and gene expression of engineered cells following transplantation will enhance the usefulness of these cells for studying and repairing the CNS. PMID- 21551807 TI - Cell-mediated delivery of neurotrophic factors and neuroprotection in the neostriatum and substantia nigra. PMID- 21551808 TI - Transplantation of cells genetically modified and direct intracerebral gene transfer with an adenoviral vector expressing tyrosine hydroxylase in a rat model of Parkinson's disease. PMID- 21551809 TI - Encapsulation of neurotrophic factor-releasing cells for the treatment of neurodegenerative diseases. PMID- 21551810 TI - Delivery of therapeutic proteins from genetically-modified cells. PMID- 21551812 TI - Inhibition of tumor growth by dominant negative inhibition of growth factor receptor signals. PMID- 21551811 TI - Methodological aspects of clinical trials in diseases of the nervous system: conventional drug treatment versus gene therapy. PMID- 21551813 TI - Antisense IGF-1 gene transfer and immunotherapy of glioblastoma. PMID- 21551814 TI - Novel non-viral systems for in vivo cancer gene therapy and delivery of trophic factors. PMID- 21551815 TI - Neurotrophic factors: repair and regeneration in the central nervous system. AB - Neurotrophic factors promote maintenance, repair and regeneration of selected neurons in vitro and in vivo. They include nerve growth factor (NGF) and other neurotrophins, ciliary neurotrophic factor (CNTF) and other cytokines, and a number of growth factors. Molecular properties of the trophic proteins and their transducing receptors are increasingly well characterized. Interest in the neurotrophic factors has greatly accelerated over the past decade with accumulating evidence that they play important roles in the adult mammalian CNS as well as in its development. Adult in vivo models for degenerative CNS conditions have demonstrated the ability of exogenous neurotrophic factors (NTFs) to protect against neuronal damage induced by traumatic or chemical experimental lesions, particularly with regard to easily identifiable neurons such as cholinergic and dopaminergic ones. Other models have shown beneficial effects of NTF administration with regard to axonal regeneration inside CNS tissue. PMID- 21551816 TI - Ciliary neurotrophic factor (CNTF): physiological and pharmacological effects. PMID- 21551817 TI - The role of NGF in the peripheral nervous system. PMID- 21551818 TI - Neurotrophins and neurotrophin antagonists as potential therapeutics. PMID- 21551819 TI - Trophic factors made by adrenal chromaffin cells and their putative clinical implications. PMID- 21551820 TI - Gender, progesterone and the early stages of brain injury. PMID- 21551821 TI - Acceleration of functional recovery from motor cortex ablation by two Ginkgo biloba extracts in rats. AB - We studied the effects of two extracts of Ginkgo biloba, with and without terpenes, on motor recovery from cortical hemiplegia. Both extracts of the reference product (EGb761-IPSEN) produced a dose-dependent acceleration of behavioral recovery and diminished ventricular dilation in lesion rats. These results indicate that the active substance(s) participating in the beneficial effect of EGb761 is (are) contained in the non-terpenic fraction of the extract. PMID- 21551822 TI - Dendritic outgrowth from neural cells transplanted to the hippocampal fissure. AB - Transplants of cell suspensions that were either selective for granule cells or contained all hippocampal cell types were placed in the hippocampal fissure or in the infragranular cleavage plane (IGCP) of the dentate gyrus. Several transplants were found in both areas in the same dentate gyrus. After a variety of post transplant survival times, neurons of both the donor and the host were filled with lucifer yellow in fixed sections. Sections were also immunoreacted with antibodies to glial fibrillary acidic protein (GFAP), vimentin, neural cell adhesion molecule (NCAM and HNK-1/NCAM) and were histochemically reacted for ACHE. Dendrites of neurons from transplants of cells of the whole hippocampus usually stayed within the transplant. If a dendrite from such transplants did grow out of the transplant, it grew into the molecular layer (ML) of the host dentate gyrus and not into the hilus of the host. Dendrites from granule cell selective transplants grew into the ML of the host and those that grew from fissure transplants were inverted from the normal orientation of host granule cell dendrites. Dendrites also grew out of the transplant in the absence of reactive gliosis. Transplants of cells from the whole hippocampus placed in the IGCP showed the greatest ingrowth of acetylcholinesterase (ACHE) fibers. In granule cell transplants made concurrently into the fissure and the IGCP, donor granule cell dendrites grew into the host ML from both sites, demonstrating that a gradient of tropic factors across the ML could not account for the direction and orientation of the dendritic outgrowth, since a gradient that directed the growth of one set of dendrites would work against the dendrites growing in the opposite direction. PMID- 21551823 TI - Activation of non-neuronal cells in the rat sciatic nerve in response to inflammation caused by implanted silicone tubes. AB - The presence of macrophages and the induction of c-jun protein and proliferation of non-neuronal cells were studied following implantation of silicone tubes with different diameters (i.e. 0.8 or 1.6 mm) around the rat sciatic nerve. Three days after implantation, numerous EDI and ED2 positive macrophages could be observed around the nerve beneath the 1.6 mm tubes. Some EDI and ED2 positive macrophages were also present in the endoneurium. In contrast, there were numerous EDI and ED2 positive macrophages in the endoneurium beneath the tube and distally in nerves surrounded by the 0.8 mm tube. In these experiments, there was also a massive induction of c-jun protein and DNA synthesis in non-neuronal cells, as visualised by c-jun and BrdU antibodies respectively (e.g. a response similar to that observed after a crush lesion). Such activated cells, albeit few, were also present in the endoneurium beneath the tube of nerves with a 1.6 mm tube, but not distal to the tube in the endoneurium. At 7 days, the responses were somewhat amplified but essentially the same as at 3 days. The results showed that the large diameter implants, which do not cause axonal damage, as does the small diameter tube, but result in conditioning of the nerve [4], induced invasion of macrophages around the nerve and activation of some cells in the endoneurium beneath the tube. We suggest that cell activation is caused by factors released from macrophages and that endoneurial cell activation is important for the conditioning of the nerve by the silicone tube implant. PMID- 21551824 TI - Microtubule-associated protein 2 as a sensitive marker for dendrite lesions after spinal cord trauma: an immunohistochemical study in the rat. AB - We evaluated, by irnmunohistochemistry, the changes of microtubule-associated protein 2 (MAP2) of rat spinal cord following compression injury of mild, moderate and severe degrees at the Th8-9 level. The spinal cord of normal rats and animals subjected to laminectomy only, presented immunoreactivity to MAP2 in nerve cell bodies and dendrites but not in axons and other structures. Following moderate and severe compression resulting in reversible paraparesis or irreversible paraplegia, respectively, the compressed segment showed loss of MAP2 immunoreactivity in dendrites and nerve cell bodies already 4 h after injury. This phenomenon remained throughout the experimental period of 9 days. Our findings indicate that there is a rapid and long-lasting reduction of MAP2 in nerve cell bodies and dendrites of the compressed segment and that this alteration is related to the degree of the impact to the cord. The reduction of MAP2 may well have functional implications by interfering with neurotransmission. MAP2 immuno-staining is an excellent way of studying dendritic changes in spinal cord trauma and can be used in future experiments designed to investigate the influence of various therapeutic measures on secondary lesions after trauma. PMID- 21551825 TI - Nerve regeneration in silicone tubes: distribution of macrophages and interleukin 1beta in the formed fibrin matrix. AB - Macrophages have been regarded as important sources for different growth stimulating factors in nerve regeneration. The distribution of macrophages in the fibrin matrix, which is formed between the proximal and distal nerve stumps in silicone tubes [29], was investigated in rats. The sciatic nerves of rats were transected and the stumps were introduced into a silicone tube. After 3, 6, 14 or 28 days, the distribution of macrophages (ED1 and ED2), the cytokine Interleukin 1beta (IL-1beta), fibrin/fibrinogen, fibronec-tin, neurofilament and 5-100 protein was investigated using immunocytochemistry. The pattern of fibrin/fibrinogen, fibronectin, neurofilament and 5-100 protein was similar to previously published data [29]. The matrices at 3 and 6 days, as well as the later regenerate, contained both ED 1 and ED2 positive macrophages which was one of the cell types present. These cells were evenly distributed along the fibrin fibers or migrating cell columns. At the proximal and distal nerve stumps, macrophages were more abundant in the perineurial tissue which was close to the silicone tube, except for more macrophages in the distal part. IL-1beta was also present, especially at 3 and 6 days and evenly distributed in the matrix, but the intensity of the staining decreased later. There was however no specific relation of ED1 or ED2 macrophage to the detected IL-1beta. It is concluded that macrophages are trapped and present in the fibrin matrix formed between the proximal and distal nerve stumps at an early stage of the regeneration process and one of their products, IL-1beta, was distributed in the matrix. PMID- 21551826 TI - Scopolamine facilitates recovery of function following unilateral electrolytic sensorimotor cortex lesions in the rat. AB - Following brain injury there is an excessive release of excitatory neurotransmitters that may lead to secondary cell death. Although much research has focused on glutamate-NMDA receptor interactions, acetylcholine-muscarinic receptor interactions may also prove to be important for an understanding of the pathophysiological events that lead to secondary degeneration after brain damage. Previous experiments have shown that the muscarinic receptor antagonist scopolamine facilitates recovery from very transient (1 h-10 days) behavioral deficits after fluid percussion injury. The present study extends these findings by investigating whether scopolamine can facilitate recovery from the more enduring behavioral deficits (14-60 days) that follow electrolytic lesions of the rat somatic sensorimotor cortex (SMC). Rats received unilateral lesions of the SMC and a regimen of scopolamine (1 mg/kg) or saline beginning 15 min after surgery. Following SMC lesions rats exhibited an impairment in placing the forelimb contralateral to the lesion as well as an ipsilateral somatosensory asymmetry on a bilateral tactile stimulation test. Rats treated with scopolamine showed a reduction in the initial magnitude of the contralateral placing deficit and an accelerated rate of recovery compared with saline-treated control rats. In contrast, scopolamine had no effect on recovery from the ipsilateral somatosensory asymmetry. These data are consistent with the idea that muscarinic receptor stimulation plays a role in the production of secondary brain damage, that blockade of this receptor leads to a facilitation of recovery on some behavioral tasks, and that electrolytic lesions may trigger some of the same posttraumatic events described in other models of neural trauma. PMID- 21551827 TI - Abstracts selected from Excerpta Medica's EMBASE. PMID- 21551828 TI - Effects of delayed nerve repair on regeneration of rat sciatic nerve. AB - The optimal time for nerve suture in transected rat sciatic nerve was investigated. The sciatic nerve on both side nerves were transected and repaired by an epineurial suture technique 0-28 days after nerve transection. The regeneration distance was measured by the sensory pinch reflex test 2-6 days after nerve repair. The initial delay period and the regeneration rate were calculated by using a new mathematical model. One day delayed repair was sufficient to reduce the initial delay period and the largest reduction on the initial delay period was observed in the three day delayed repair group. The initial delay period was reduced to 0.87 days as compared to 2.31 days for nerves repaired immediately (controls). The seven day and ten day delayed repair had similar effects but they also showed a decrease of the regeneration rate. The regeneration rate was not affected except for these two time points. The results suggest that the repair delay period can influence the initial delay as well as the regeneration rate. In our model an optimal effect was achieved on both these measures with a one or three day delay between transection and repair. PMID- 21551829 TI - Does monocular viewing improve target detection in hemispatial neglect? AB - Experimental animals with large posterior-cortical lesions develop disturbances of visual perception and visually-guided behavior in the contralateral space, resembling the syndrome of unilateral spatial neglect (USN) in humans. The visuo motor performance in the ignored space is recovered some time following additional lesion inflicted to the contralesional superior colliculus (SC) or section of the intercollicular pathways. Based on the model that explains this recovery by disinhibition of the ipsilesional SC (the 'Sprague effect') Posner and Rafal [37] proposed that ipsilesional monocular occlusion could possibly reduce the 'tone' of contralesional collicular neurons thereby removing an important contributor of hemineglect. A group of twenty-six right-hemisphere damaged patients with USN was given a cancellation task under binocular and monocular (left and right) viewing conditions. Thirteen patients showed amelioration of left hemineglect in conditions of left-monocular viewing, as compared to the baseline binocular state. Although this result superficially resembles the Sprague effect, two patients benefited from right-monocular viewing whereas eleven patients showed no significant change in either right or left viewing conditions. The possible role of structures mediating interocular differences in target detection in cases of right hemisphere damage is discussed. It is suggested that even if the Sprague effect contributes to the salubrious influence of monocular viewing it is hardly the single factor involved. PMID- 21551830 TI - Asymmetrical behavior in rats following striatal lesions and fetal transplants: the elevated body swing test. AB - Animals with unilateral neurotoxic lesions in the striatum exhibit a stereotypical biased rotational behavior in response to dopamine agonists. We recently argued that the rotational test may be subject to sensitization effects of the drug. Accordingly, we proposed the drug-free elevated body swing test (EBST) as an alternative behavioral index of motor asymmetry in striatal lesioned animals. EBST involves elevating the animal from the ground by holding its tail and simply recording the number of swings to either side made by the animal over 30 s. We previously reported that Sprague-Dawley, male 8-week-old rats, intrastriatally lesioned with 500 nanomoles of 3-nitropropionic acid or 225 nanomoles of quinolinic acid, exhibit biased swing activity at 7, 14, 21 and 28 days post-lesion. In the present study, we extended the efficacy of the EBST in measuring the recovery of motor function following fetal striatal transplants. At 2 months post-lesion, lesioned animals which show 70% or higher biased swing activity were transplanted with rat fetal striatal lateral eminence (16-day-old gestational age). When tested in the EBST at 1 and 3 months post-transplant, these transplanted animals displayed normalization of the biased swing activity. In contrast, animals transplanted with medium alone continued to exhibit a biased swing activity. The present study thus extends our previous EBST data to include successful behavioral characterization by EBST of recovery of motor function in lesioned animals receiving fetal transplants. PMID- 21551831 TI - Reactive changes in the adult rat superior colliculus after deafferentation. AB - We have recently shown that optic nerve transection is followed by a delayed appearance (7-14 days after lesion) of putative guidance activities for retinal axons in the superior colliculus (SC) of adult rats. In the present study we analysed with immunohistological methods whether there is a correlation between localized reactive changes in the cellular compartment of the SC after deafferentation and the reappearance of putative guidance activities. The optic nerve of adult female Sprague-Dawley rats was transected. After 1 day to 1 year the contralateral SC was sectioned sagitally and examined with antibodies directed against Vimentin and glial fibrillary acidic protein (GFAP) to label astrocytes, myelin basic protein (MBP) to detect oligodendrocytes, OX-42 to stain microglia and SMI-31 to determine degeneration of afferent retinal ganglion cell axons. These stainings were performed in order to detect differences in the cellular composition of macro- and microglial cells between the anterior and posterior regions of the SC. All cell populations we examined in the SC showed reactive changes after optic nerve transection. Microglia activation occurred as soon as 2 days after optic nerve transection in the anterior part of the SC. After 4 days, a homogeneous distribution of activated microglia was seen in the whole SC. GFAP upregulation occurred without a specific regional distribution. Only Vimentin-expressing astrocytes appeared with a delay of 1-2 weeks after deafferentation and were strongly restricted to the afferent optic tract and the very anterior region of the SC. In conclusion, a temporo-spatial correlation between the re-expression of guidance activities and changes in the cellular compartment of the SC exists in the delayed re-expression of Vimentin in astrocytes and their strong spatial restriction. Activated microglia might be involved in triggering regional changes in an anterior-posterior graded fashion in the deafferented SC. PMID- 21551832 TI - Implantation of cultured rat foetal adrenal gland cells reverses amphetamine induced rotation in the 6-hydroxydopamine-lesioned rat striatum: behavioural, ultrastructural and voltammetric data. AB - Roller tube cultures of foetal rat adrenal gland grown in the presence of nerve growth factor were implanted into the 6-hydroxydopamine-lesioned rat striatum to assess the ability of such cells to release catecholamine and restore function. Fast cyclic voltammetry was used to demonstrate that the lesions significantly reduced dopamine overflow following electrical stimulation of brain slices of the ipsilateral caudate putamen and nucleus accumbens. Viable reaggregates caused a significant reduction in the amphetamine-induced rotational behaviour over a period of 33 days, but no reduction of rotation was observed after the implantation of control materials. Fast cyclic voltammetry within and around the site of the implant was unable to demonstrate electrically stimulated dopamine overflow. Transmission electron microscopy of sections taken from the lesioned and implanted striatum failed to demonstrate any transformation by the implants towards a neuronal phenotype. PMID- 21551833 TI - The Japanese society for neural growth, regeneration and transplantation. PMID- 21551834 TI - Amphetamine affects the behavioral outcome of lateral fluid percussion brain injury in the rat. AB - This study examined the effects of (D)-amphetamine, methoxamine (an al-adrenergic receptor agonist), and prazosin (an al-adrenergic receptor antagonist) on the behavioral outcome of lateral fluid percussion brain injury. Rats trained to perform a beam walking task were subjected to brain injury of moderate severity (2.1-2.2 atm). At 10 min after injury, rats were treated with amphetamine, methoxamine or prazosin at two different dose levels. Amphetamine-treated animals displayed significantly lower impairment in beam walking ability from days 1 to 5 after brain injury. Neither methoxamine nor prazosin significantly affected the impairment in beam walking ability from day 1 to day 7 after injury. However, prazosin treatment at both dose levels increased the post-injury mortality and the incidences of failure to recovery from hemiplegia. Amphetamine-treatment at 4 mg/kg, but not at 2 mg/kg, improved the spatial learning abilities of the injured animals. Neither methoxamine nor prazosin affected the spatial learning abilities. These results indicate that amphetamine facilitated beam walking recovery and improved cognitive function after concussive fluid percussion injury. Although the methoxamine experiments suggest that the norepinephrine alpha1-adrenergic receptor system may not be involved in the pathophysiology of fluid percussion brain injury, our results with amphetamine (beneficial effects) and prazosin (deleterious effects) and the results observed in other models of brain injury point out that further investigations are necessary to understand the role of a1-adrenergic receptors in brain injury. PMID- 21551835 TI - Does monocular viewing improve target detection in hemispatial neglect? AB - Experimental animals with large posterior-cortical lesions develop disturbances of visual perception and visually-guided behavior in the contralateral space, resembling the syndrome of unilateral spatial neglect (USN) in humans. The visuo motor performance in the ignored space is recovered some time following additional lesion inflicted to the contralesional superior colliculus or section of the intercollicular pathways. Based on the model that explains this recovery by disinhibition of the ipsilesional superior colliculus (the 'Sprague effect') Posner and Rafal [37] proposed that ipsilesional monocular occlusion could possibly reduce the 'tone' of contralesional collicular neurons thereby removing an important contributor of hemineglect. A group of twenty-six right-hemisphere damaged patients with USN was given a cancellation task under binocular and monocular (left and right) viewing conditions. Thirteen patients showed amelioration of left hemineglect in conditions of left-monocular viewing, as compared to the baseline binocular state. Although this result superficially resembles the Sprague effect, two patients benefited from right-monocular viewing whereas eleven patients showed no significant change in either right or left viewing conditions. The possible role of structures mediating interocular differences in target detection in cases of right hemisphere damage is discussed. It is suggested that even if the Sprague effect contributes to the salubrious influence of monocular viewing it is hardly the single factor involved. PMID- 21551836 TI - No evidence for enhancement of recovery from a crush lesion of a motor nerve in rats by Org2766. AB - The present study was undertaken to investigate the effect of Org2766 on the recovery of lesioned motor nerve fibres. The facial nerve of Wistar rats was crush lesioned and the process of recovery was assessed by functional and histological methods. Functional recovery was examined in two experiments and was assessed by quantifying blind the return of eyelid and whisker movements. No difference could be demonstrated between Org2766-treated and saline-treated groups of animals. The histological investigations involved quantifying the number of reinnervated motor endplates in the whisker muscle. On days 10 to 12 in male rats and on days 12 and 13 in female rats, there was no difference in reinnervation between the two treatment groups. It was concluded that with the methods used in this study, no significant effect of Org2766 on the axonal regeneration of motor nerve fibres could be established. PMID- 21551837 TI - Metabolic profile of fetal dopamine neurons transplanted to the adult rat striatum. AB - In the present study, we have examined the expression and distribution of the metabolic marker neuron-specific enolase (NSE) in solid-tissue transplants of fetal substantia nigra (SN) to the striatum of intact and 6-hydroxydopamine lesioned mature rats. Immunocytochemistry was applied to label NSE and tyrosine hydroxylase (TH) respectively. Cellular content of NSE is indicative of metabolic activity as well as synaptogenesis/maturation. Three months after implantation, the fetal grafts exhibited intensely TH-immunoreactive neurons, typically organized in elongated clusters, especially along the graft-host border and along blood vessels penetrating into the graft interior. Moderate to high metabolic activity as indicated by NSE immunoreactivity was observed in neuronal perikarya, principally in non-TH immunoreactive areas. In contrast to these immunohistochemical findings, in situ hybridization for TH mRNA, carried out exclusively on grafts into the intact striatum, demonstrated DA cell bodies both at the graft-host interface and, significantly, throughout the graft interior. The number of transcripts per cell, moreover, did not differ significantly in these two locations. We propose that conditions at the graft-host border promote tissue-specific regulation of nigral DA neurons, and that this regulation occurs post-transcriptionally. Thus, DA neurons relatively distant from the host parenchyma are underregulated, resulting in a higher level of metabolic activity and an increased turnover of TH in the grafted neurons. PMID- 21551838 TI - Functional N-methyl-D-aspartate receptors develop and persist in heterotopic cortical grafts and regulate expression of transcription factor KROX-24. AB - N-Methyl-D-aspartate (NMDA) receptors are a major subfamily of glutamate receptors and thought to play a pivotal role in developmental plasticity and synaptogenesis, neuronal migration and differentiation. NMDA receptors have also been implicated in neuronal degeneration, as glutamate binding to the receptor initiates rapid excitotoxic signal transduction. Molecular cloning of cDNAs has yielded different NMDA receptor subtypes with an essential NR1 subunit associated with various modulatory NR2 subunits. The NR1 gene is expressed at high levels in virtually all brain structures, but to a distinctly higher extent in cortex than in striatum. Here we report on the development, maintenance and function of glutamate receptors in intrastriatally located cortical grafts. Cortical primordia of rat fetuses (El4) were stereotactically grafted into the rostral striatum of adult recipient rats. Expression of NR1 mRNA was examined by in situ hybridization after post transplantation periods of 2, 6 and 12 months. Analysis of NR1 mRNA expression in grafts after a differentiation period of 2 months revealed equal levels compared to the intact neocortex of the host rats and that of rats with the same ontogenetic age. No downregulation of NR1 mRNA was seen 6 and 12 months after transplantation. To ensure normal function of NMDA receptors in grafts, we studied the effects of a blockade of receptor dependent gene expression, using Krox-24 as a reporter gene. In normal brain tissue, constitutive expression of KROX-24 protein is thought to be maintained by NMDA receptor mediated physiological synaptic activity and can be abolished by the non competitive NMDA receptor antagonist MK-801. Immunostaining of KROX-24 protein was almost identical in grafts compared to the corresponding neocortex. This constitutive expression of KROX-24 could be abolished by treatment with MK-801. Thus, our data indicate normal development and long term persistence of glutamate receptors with intrinsic excitatory activity in transplants. PMID- 21551840 TI - Abstracts selected from Excerpta Medica's EMBASE. PMID- 21551839 TI - Localization of gliosis in the corpus striatum of mice following cortical lesions. AB - Localized lesions of the medial and lateral frontal cortex were used to study gliosis, neurofilament content and changes in synaptic density in the mouse striatum. Relationships between the sites of cortical lesions and the localization of changes in different regions of the striatum were examined after 3 and 12 weeks. Independent of the location of frontal cortex lesions, glial fibrillary acidic protein (GFAP) immunoreactivity was increased throughout the entire striatum after 3 weeks. Twelve weeks after lesioning, increases in GFAP were confined to the dorsomedial (DM) striatum following medial cortical lesions, and to the dorsolateral (DL) striatum following lateral cortical lesions, suggesting persistent gliosis only in areas of striatal deafferentation. It appears, therefore, that the mechanisms which induce gliosis after short and long time periods are different. PMID- 21551841 TI - Memory rehabilitation - recent developments and future directions. AB - Memory impairment is a frequent effect of different forms of brain injuries and may be even more handicapping than severe physical problems. The purpose of this article is to critically review empirical studies on the effectiveness of different procedures of memory rehabilitation. Traditionally memory rehabilitation has focused on direct training of memory functioning. The problem of these programs is that training effects hardly generalize to patients' everyday life memory problems. As a consequence of this transfer problem, strategies have been developed (method of vanishing cues, errorless learning) which are restricted to the aim of teaching patients domain specific knowledge. Another aspect of memory rehabilitation concentrates on coping with memory impairment. This may be done by alleviating demands on the patient and by including external resources into the process of recovery. On the other hand, teaching the patient to actively cope with memory related difficulties, has recently become an essential objective of memory rehabilitation. In order to pursue this aim, traditional mnemonic techniques are embedded into training of problem solving abilities and metamemory knowledge. Future perspectives and questions open to research are outlined for each of the different procedures. PMID- 21551842 TI - Stimulation of nerve regeneration by macrophages in granulation tissue. AB - The effects of granulation tissue exposure on regeneration of sensory axons after a test crush lesion in rat sciatic nerves were studied. Chromic catgut threads were applied subcutaneously in the back of rats. Three weeks later the surrounding granulation tissue was isolated and transposed to the sciatic or tibial nerve in the same rat. Immunocytochemical, light and electron microscopic evaluation of the isolated granulation tissue revealed numerous EDI and ED2 positive macrophages. After an additional three weeks the sciatic nerves were crushed and the axonal outgrowth lengths were measured by the pinch reflex test and by neurofilament staining 3 or 6 days later. The regeneration distances in the sciatic nerve exposed to granulation tissue were significantly longer compared with that of nerves to which only subcutaneous tissue was transposed. Thus, the nerve had become conditioned by the transposure of macrophage rich tissue. After the transposure macrophages were present close to the nerve at the time point of the test crush lesion, but no signs of degeneration or inflammation in the endoneurial space were observed. It was also found that the outgrowth lengths in the tibial nerve branch were consistently longer than in the peroneal branch of the sciatic nerve. It is concluded that granulation tissue, containing macrophages, can induce a conditioning effect in the sciatic nerve. We suggest that this effect is related to factors emanating from macrophages in the transposed tissue. PMID- 21551843 TI - Peripheral nerve regeneration through microelectrode arrays based on silicon technology. AB - This paper describes some developments, made to obtain a chronic neural interface to record signals from regenerated peripheral nerves. Microperforated silicon dices, fabricated by techniques compatible with CMOS processes, were coupled in silicone nerve chambers and implanted between the severed ends of peripheral nerves in rats. Three configurations of perforated dices with 25 via-holes of 100 MUm diameter, 121 via-holes of 40 MUm and 400 via-holes of 10 MUm were assessed. The feasibility of axonal regeneration through the dices via-holes was proved by histological and physiological methods over 3 months post-implantation. The regenerated nerves were organized in fascicles corresponding to the grid pattern of the via-holes. However, nerve regeneration was difficult and distal re innervation delayed with respect to simple tubulization repair. The size of the via-holes and the total open area are determinants of the degree and quality of regeneration. Further improvements are needed in both the microelectrode dice design and in neurobiological stimulation of regeneration. PMID- 21551844 TI - Invading and resident macrophages in the regenerating rat vagus nerve in vivo and in vitro. AB - Invading and resident macrophages were studied in the regenerating rat vagus nerve in vivo and in vitro, using antibodies to invading (EDI) and resident (ED2) macrophages. Fresh vagus nerves contained no EDI positive macrophages as revealed by immunocytochemical staining. In crush lesioned nerves in vivo, the number of EDI positive cells around and distal to the crush lesion, increased dramatically with time. Interestingly, EDI positive cells, although few, appeared in the cultured vagus nerves subjected to a crush lesion. Resident ED2 positive macrophages were abundant in fresh nerves. In vivo, there was a small increase of ED2 positive macrophages at the crush area as regeneration proceeded. In contrast, no increase was observed in vitro and after 3 days no ED2 stained macrophages were found. Immunocytochemical staining for low-affinity NGF receptors showed a dramatic increase at the crush and distal to it in vivo, while in vitro, the receptors were upregulated along the entire nerve. The results suggest that invading macrophages may not be crucial for the initial and early outgrowth of sensory nerve fibres in peripheral nerves. PMID- 21551845 TI - Temporal relationship between the recovery of longitudinal reflex systems and motor recovery in chronic spinally-lesioned rats. AB - This study was performed to determine whether a correlation exists in the functional recovery of the longitudinal reflex systems and recovery of quadrupedal locomotion in chronic spinally-lesioned rats. Partial spinal lesions sparing only the right ventral quadrant (VQ) or dorsal quadrant (DQ) of the spinal cord at the lower thoracic (T9-10) levels were performed aseptically under Nembutal anesthesia. Quadrupedal locomotion reappeared within 2-3 weeks after the initial operations in VQ rats. However, no recovery of hindlimb movement was observed in DQ rats. In terminal experiments with VQ and DQ rats, the right brachial plexus (C6-T1) was dissected and mounted on a bipolar stimulating electrode. Spino-bulbo-spinal and interlimb reflex potentials were recorded from bilateral hindlimb muscles under urethane-chloralose anesthesia and Nembutal anesthesia, respectively. In VQ rats, these longitudinal reflex potentials could not be evoked for several days post-operatively. However, the early threshold elevation for evoking the reflex potentials returned gradually to the normal range in accordance with locomotor recovery. In DQ rats, on the other hand, disappearance of the reflex potentials persisted over 1 month observation period. These results suggest that the functional recovery of these longitudinal reflex systems in the ventral quadrant parallels the quadrupedal locomotor recovery after partial spinal cord lesions in rats. PMID- 21551846 TI - Abstracts selected from Excerpta Medica's EMBASE. PMID- 21551847 TI - Conservation of space and energy in the brain. PMID- 21551848 TI - Muscle fiber type reorganization and behavioral functional recovery of rat median nerve repair with vascularized or conventional nerve grafts. AB - In 1921, Ney introduced the concept of nerve grafts with preservation of the vascular blood supply. Today, over 70 years later, the use of vascularized nerve grafts in clinical practice is still controversial. Although the results of experiments with vascularized and conventional nerve grafts have been compared on the basis of electrophysiological and histological observations, the literature includes no vaJid comparison of the clinical and behavioral significance of these results. Therefore, in the experiments reported here, the rat median nerve was repaired using either a vascularized or a conventional ulnar nerve graft. The rates behavior between 0 and 360 days after surgery was assessed by the grasping test. Nienty-five, 120, 150, 210 and 360 days after surgery rats were submitted to retrograde labeling studies and muscle samples were removed and studied using routine hematoxilin-eosin and ATPase histochemistry. The present study provides evidence that autografting is a reliable procedure for nerve repair. Motor axons were able to reinnervate and largely respecify muscle properties. Reinnervation was not selective either at the nerve trunk level or at the muscle fiber. A mechanism of collateral pruning might have been present in the early phases of reinnervation. This mechanism was, however, self limiting and unable to correct all wrong projections. A mechanism of terminal sprouting was in part responsible for time-related improvement in muscle force recovery. While the present study does provide evidence that recovery was 20% faster in rats with vascularized grafts than in those with conventional grafts (P < 0.0001), it does not, however, provide evidence for better functional recovery in long-term assessment. PMID- 21551849 TI - Connective integration of hippocampal grafts in excitotoxic hippocampal lesions in adult rats: an anterograde axonal tracing study. AB - Exchange of nerve connections between developing neural grafts and adult recipient brains is enhanced for grafts placed in excitotoxic lesions, which spare recipient brain afferent axons in otherwise neuron-depleted lesion areas. In previous studies of hippocampal grafts placed in such lesions, we have used anterograde axonal degeneration, histochemical Timm staining and acetylcholinesterase to demonstrate host-graft interconnectivity. In this study, we have now used three anterograde axonal tracers, Phaseoulus vulgaris leukoaglutinin (PHA-L), biocytin and biotinylated dextran amine (BDA), which allow individual fibers to be traced. Adult male rats with 1-week-old axon sparing ibotenic acid lesions of the dorsal CA3 region or fascia dentata were grafted into the respective lesions with suspensions of fetal (El8-19) CA3 cells or a block of neonatal fascia dentata tissue. One to twelve months later, recipients were injected with Phaseoulus vulgaris-leukoaglutinin or biocytin in the hippocampus contralateral to the graft to trace the possible ingrowth and distribution within the transplants of host commissural axons, or into the transplants with biotinylated dextran amine in order to trace outgrowing graft fibers. In rats with succesfull host Phaseoulus vulgaris-leukoaglutinin or biocytin injections, the CA3 and fascia dentata transplants were innervated by labelled host commissural fibers. In the dentate transplants, most commissural fibers projected as normally to the inner part of the molecular layer, with fewer aberrant fibers extending more superficially into the molecular layer. Following injections into the fascia dentata and CA3 grafts of biotinylated dextran amine, labelled graft fibers were traced into the ipsilateral host dentate hilus, CA3 and CA1. From some CA3 containing grafts, a few labelled fibers were also observed passing through the host fimbria-fornix to the lateral septum on the grafted side. A few fibers were projected as far as to the most septal levels of the contralateral CA1. PMID- 21551850 TI - Ensheathing cells: Large scale purification from adult olfactory bulb, freeze preservation and migration of transplanted cells in adult brain. AB - Regenerating nerve fiber sprouts enveloped by olfactory bulb (OB) ensheathing cells (ECs) seem to escape the inhibitory influence of gliotic tissue. Accordingly, these cells may be useful for general repair of injured CNS. Relatively large numbers of ECs could be purified from confluent cultures of adult rat olfactory bulb using immunomagnetic beads. Viable ECs could be cultured and purified in good yield from OB dissected up to 18 h post-mortem. Purified ECs could be stored frozen at -75 degrees C for at least 6 months, while maintaining 95% viability. ECs labelled with the fluorescent cell-linker PKH-26 neither shed the label nor exchanged it with other cells. The migration of labelled ECs transplanted to adult hippocampus was examined at intervals ranging from 3 h to 30 days. Active migration from the injection site was first observed 4 days after transplantation, when ECs appeared intercalated between the neurons of the hippocampal and dentate cell layers. Some ECs remained in that location after 30 days but, at that time, the olfactory glial cells could be observed in loci as distant and diverse as the laterodorsal thalamic nuclei, internal capsule, arcuate nucleus, cerebral aqueduct walls and choroid plexus. ECs seemed to have preferences for the dentate hilus, the pyramidal and granular cell layers, choroid plexus, blood vessels and putative peptidergic loci. PMID- 21551851 TI - Re-innervation of muscles after nerve injury in neonates. AB - Three-day-old neonatal rats had their common peroneal nerve crushed 3 mm from the extensor digitorum longus (EDL) muscle. At periodic intervals of 7, 10, 14, 21 and 28 days following nerve injury the EDL muscles were removed, weighed, stained using the silver cholinesterase method and their muscle fibres counted. In these rats during the re-innervation process, the bands of Biingner were absent, some endplates disintegrated and a large proportion of the muscle fibres were lost. This study has shown that interruption of the normal nerve-muscle interaction during the neonatal period is highly detrimental to the subsequent growth and development of the muscle. PMID- 21551852 TI - Interleukin-1beta and tumor necrosis factor-alpha co-operatively enhance a novel trophic activity of astrocytes for pontine cholinergic neurons in vitro. AB - Insulin and insulin-like growth factors (IGFs) are the only known trophic factors for pontine cholinergic neurons. The present study revealed that astrocyte extract pretreated with IL-1beta and TNF-alpha significantly enhanced choline acetyltransferase (ChAT) activity of the pontine neurons in the presence of a supramaximal dose of insulin, while various trophic factors including IGFs failed to increase the ChAT activity under the same culture conditions, suggesting that IL-1beta and TNF-alpha co-operatively enhanced the expression of a novel trophic factor for pontine cholinergic neurons in astrocytes. PMID- 21551853 TI - Dissociation of p75 receptors and nerve growth factor neurotrophic effects: lack of p75 immunoreactivity in striatum following physical trauma, excitotoxicity and NGF administration. AB - While the function and regulation of the low affinity (p75) nerve growth factor (NGF) receptor in the central nervous system (CNS) remains a mystery, one of the more intriguing observations involves its response to injury in the adult rat striatum. Following mechanical injury to the striatum, a re-expression of striatal p75 receptors and mRNA purportedly occurs (apparently mediated by elevations in NGF), thus reversing the natural loss of these phenotypic markers that is known to occur during development. This observation has important implications for understanding both the regulation of NGF neurotrophic activity and the role of the p75 receptor, for it implies that the presence of this receptor may be required for NGF trophic activity in the CNS. In an effort to gain a greater understanding of the function and regulation of the low affinity p75 NGF receptor, we performed a series of experiments to study the injury induced, re-expression phenomenon in the striatum. In the first experiment, we duplicated the mechanical, cannula-induced injury used in the original study. In a follow-up study, we exacerbated that injury by infusing quinolinic acid directly into the striatum. In a third study, the mechanical injury was complemented with chronic striatal infusions of NGF. In a final study, we examined striatal tissue from rats who had been protected from striatal quinolinic acid neurotoxicity by administration of NGF. In no instance was the re expression of p75 striatal receptors observed, despite positive controls for (a) effective neural trauma, confirmed by histologic and immunocytochemical methods, (b) effective antibody staining, confirmed by appropriate basal forebrain p75 immunoreactivity, and (c) effective biological activity of exogenous NGF, confirmed by hypertrophy of choline acetyltransferase (ChAT)-positive striatal neurons and protection of ChAT-positive striatal neurons against excitotoxicity. At least two important conclusions can be drawn from these studies: (1) the presence or induction of low affinity p75 receptors is not necessary, while the presence of constitutive high affinity tropomyosin related kinase (trk) NGF receptors seem sufficient for NGF trophic activity in the CNS, and (2) the variables necessary to induce re-expression of p75 striatal receptors in adult rats have not yet been elucidated and are apparently complex. PMID- 21551854 TI - Basic fibroblast growth factor treatment partially protects from visual deficits but does not increase retinal ganglion cell survival following controlled optic nerve crush. AB - Lack of trophic support after axonal injury leads to the degeneration of neurons. To study whether the application of trophic factor can improve functional recovery and retinal ganglion cell (RGC) survival after unilateral controlled optic nerve crush injury, we have now treated adult rats intraocularly (i.o.) with basic fibroblast growth factor (bFGF). To monitor visual deficits, rats were trained in a two-choice pattern discrimination test. Immediately after the crush, and on postoperative days 3 and 6, either 1.1 MUg recombinant bFGF or phosphate buffered saline (PBS) was injected i.o. Sham-operated controls received intraocular injection of PBS or bFGF. Within the first few days after the crush, all animals showed a loss of discrimination ability which was followed by a significant recovery within 2-3 weeks. Animals treated with bFGF had a significantly smaller initial deficit and thus recovered earlier compared to PBS controls. Retrograde RGC death was evaluated using retrograde HRP-tracing technique, but bFGF-treatment had no neuroprotective effect. Thus, the behavioral effects of bFGF could not be related to neuroprotection of RGCs and therefore other mechanisms may have to be considered. PMID- 21551855 TI - Glucose-6-phosphate dehydrogenase and glutathione reductase support antioxidant enzymes in nerves and muscles of rats during nerve regeneration. AB - The effects of the rat sciatic nerve crush on the activities of glucose-6 phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT) were examined in regenerating nerve and in two reinnervating muscles: the slow twitch soleus and the fast twitch extensor digitorum longus (edl). The enzyme activities in the crushed side, were compared with the contralateral homologue tissues and basal values, determined in uncrushed animals. In the crushed side, the activity of G6PD, GR, GPX and CAT of the sciatic nerve and both muscles markedly increased in comparison with the uncrushed side. In the nerve and in both muscles, SOD activity decreased at 13 days, then rose to values higher than normal, but the pattern of the crushed side was not significantly different from that of the uncrushed. In the uncrushed side, we observed a significant increase of nerve G6PD, GPX and CAT activities compared to basal values, while in both muscles, values fluctuated around the normal without any significant variation. The mechanism of these enzymatic changes is unknown, however our work suggests that: (i) during nerve regeneration, an oxidative stress occurs in nerve and muscle, which causes adaptive responses in antioxidant enzymes; (ii) the maximum antioxidant power is expressed during the period of synaptic retraction; (iii) G6PD and GR activities are synergistically modulated with GPX and CAT, while SOD activity appears independently regulated. PMID- 21551856 TI - Studies on the regenerative recovery of long-term denervated muscle in rats. AB - Denervated extensor digitorum longus (EDL) muscles in rats rapidly lose mass and contractile force. After two months of denervation, mass and maximum tetanic force have fallen to 31% and 2% of the values of contralateral control muscles. Our purpose was to determine if grafting a long-term denervated muscle into an innervated site provides an effective means of restoring its structure and function. EDL muscles that had been denervated for periods of 2-12 months were freely grafted into innervated sites of EDL muscles in 4-month inbred host animals. Contralateral normally innervated EDL muscles from the same donors were implanted into the opposite legs of the same hosts. Two months after grafting, the muscles were removed and measurements were made in vitro of isometric contractile properties. The grafts were then prepared for morphological analysts. In all cases, the maximum forces generated by innervated grafts of denervated muscles were greater than those generated by denervated muscles. However, when compared with grafts of control muscles in the contralateral limb, grafts of previously denervated muscles showed a steady decline in structural and functional recovery corresponding to the time of previous denervation. The decline was especially pronounced for muscles denervated between 2 and 7 months prior to grafting. Grafts of 7-month denervated muscles were restored to only 17% of the maximum tetanic force of contralateral control grafts compared with 83% for grafts of 2-month denervated muscles. The longer a muscle had been denervated prior to grafting, the higher proportion of thin atrophic muscle fibers it contained. We conclude that grafting into an innervated site improves the mass and maximum force of a muscle over the denervated state, but the longer the period of prior denervation the poorer the recovery of the grafted muscles. PMID- 21551857 TI - Effect of exercise training on acute (crush lesion) and chronic (diabetes mellitus) peripheral neuropathy in the rat. AB - The effect of moderate exercise training on acute and chronic neuropathy in two separate experiments was examined. Acute nerve dysfunction was induced by sciatic nerve crush lesion and chronic neuropathy by streptozotocin-induced diabetes mellitus (experimental diabetic neuropathy; EDN). Moderate exercise training was achieved by placing food and water, separately, at either end of a U-shaped tubular home cage (8 m). Recovery from the crush lesion and the development of EDN were monitored by evaluating the free walking pattern and nerve conduction velocity (NCV), respectively. In the acute neuropathy model, 24 days of exercise after the crush lesion resulted in an enhanced return of motor function in the early phase of recovery (P < 0.01) and an increased sensory NCV after 250 days in the late phase (P < 0.001). Diabetic rats benefited from this exercise training by showing fewer signs of EDN, as evidenced by a superior motor function (toespreading, calculated from the free walking pattern; P < 0.05) and an improvement in both motor and sensory NCV (both P < 0.05). We conclude that moderate exercise training is effective in enhancing recovery from acute peripheral neuropathy and in ameliorating the consequences of experimental chronic neuropathy in diabetic rats. PMID- 21551858 TI - The effect of a chronic breakdown of the blood-optic nerve barrier on the severed optic nerve in adult rat. AB - The changes brought about in the severed optic nerve of an adult rat when the blood-optic nerve barrier was chronically broken down by the local application of a solution of mannitol is described. Axonal labelling indicated that axons did not regenerate across the lesion site, refuting the suggestion that breakdown of the blood-optic nerve barrier can stimulate axonal regeneration. However, we observed that blood vessels were dilated and, between the eye and lesion site, provided a substrate for regenerating axonal sprouts. We suggest that blood-borne agents may directly or indirectly influence the navigation of the growth cones of regrowing axons. PMID- 21551860 TI - Abstracts selected from Excerpta Medica's EMBASE. PMID- 21551859 TI - Age-dependent neurobehavioral responses by young and mature adult rats to systemic kainic acid. AB - Neurobehavioral effects caused by the excitotoxin kainic acid (KA) have been characterized by convulsions including 'wet dog shakes' (WDS) with accompanying hippocampal degeneration in experimental animals. Accordingly, this model has been proposed for putative excitotoxin-mediated disorders, such as the temporal lobe epilepsy. There have been reports on age-dependent neurobehavioral effects of KA; however, little is known about possible correlations between neuropathology and behavioral responses to KA. The present study demonstrates that mature adult rats (12 months old) injected subcutaneously (s.c.) with KA (12 mg/kg) had severer damage to the hippocampal formation, i.e. CA3 region, compared with KA-treated young adult rats (2 months old). The mature adult animals also exhibited an earlier onset of WDS, a significantly higher number of WDS (P > 0.01), and severer convulsions compared with young adult rats. These findings indicate a positive correlation between KA-induced hippocampal damage and behavioral responses in young and mature adult rats. PMID- 21551861 TI - Corrigendum to "In vivo protection against kainate-induced apoptosis by the pineal hormone melatonin: effect of exogenous melatonin and circadian rhythm" [Restor. Neurol. Neurosci. 9 (1996) 251]. PMID- 21551862 TI - Immunohistochemical analysis on the rejection of xenogeneic brain grafts. AB - The central nervous system (CNS) of mammals has long been thought of as an immunologically privileged site. However, this concept is now changing because the rejection of histo-incompatible neural grafts has been frequently observed in the CNS. In neural transplantation used as therapy for some human neurodegenerative diseases, it is important to determine which factors are related to brain graft rejection. In this study, we examined immunological reactions in brains that had received isogeneic (rat to rat) and xenogeneic (mouse to rat) neural transplants. In the immunohistochemical analysis, antibodies against T cell receptor alphabeta (R73), macrophage and microglia (0X42), MHC class II antigens (0X6), CD4 (W3/25), CD8 (0X8), NK cell (3.2.3), B cell (RLN-9D3), T cell receptor (TCR) Vbeta8.2 (R78), TCR Vbeta8.5 (B73) and TCR Vbetal0 (G101) were used. At the early stage of both isogeneic and xenogeneic transplantation, a nonspecific inflammatory reaction characterized by macrophage infiltration was observed along the needle track which was produced by the grafting procedure. From the day 7 stage onwards, the non-specific inflammatory reaction was replaced by the specific immune reactions of T cell infiltration, neovascularization and necrosis of xenogeneic grafts. Marked T cell infiltration was detected in the lesions, whereas NK and B cells were not. Quantitative analysis of T cell subsets revealed that both CD4+ and CD8+ T cells were found in the xenogeneic transplants. Microglia became activated and strongly expressed MHC class II antigens at the time of graft rejection. Isogeneic transplants, in contrast, showed no histological characteristics of rejection, and numerous dopaminergic neurons with several neurites were observed in the grafts. Based on these findings, we concluded that T cells are the principal effectors in the rejection of xenogeneic neural grafts, and that activated microglia may have some role in presenting antigens to the infiltrating T cells during the rejection process. PMID- 21551863 TI - Restoration of trimethyltin induced hippocampal degeneration by single and multiple transplantation. AB - Trimethyltin produces a selective loss of pyramidal neurons in the hippocampus resulting in functional deficits. The present study was aimed to assess the comparative restoration of behavioural and neurochemical deficits in trimethyltin chloride (7.5 mg/Kg body weight, i.p) treated rats following single or multiple site fetal hippocampal transplants. Exposure to trimethyltin caused a decrease in learning ability (51 %), an increase in locomotor activity (92 %) and decrease in acetylcholinesterase activity (36%) and muscarinic receptor binding (31%). Trimethyltin treated rats receiving multiple transplants of fetal hippocampal cell suspension (0.25 MUl at 8 stereotaxic coordinates) showed significant restoration of the functional deficits 4 weeks post transplantation. This restoration by multiple site transplants persisted upto 16 weeks post transplantation. Restoration of the above deficits by single site transplants (2 MUl at a single coordinate), 4 weeks post transplantation was less marked in comparison to multiple transplants and was evident only in learning ability and muscarinic receptor binding after 16 weeks of transplantation. The results suggest that multiple site transplants provide better restoration , on long term basis, in chemical induced neurodegeneration. PMID- 21551864 TI - Flunarizine enhances survival and regeneration of sensory and motor neurons after peripheral nerve injury. AB - The diphenylpiperazine, flunarizine, partially prevents apoptosis after trophic factor deprivation in neural crest-derived neurons. Flunarizine protects dorsal root ganglion neurons (DRG) after nerve growth factor (NGF) withdrawal in vitro and after peripheral nerve injury in newborn rats in vivo. We have further studied the mechanisms of neuronal protection by flunarizine. Oligosomal DNA fragmentation, a hallmark of apoptosis, was significantly decreased by treatment of DRG neurons with flunarizine after NGF deprivation. We examined the effect on survival of the timing of administration of flunarizine to DRG neurons both in vitro and in vivo. Flunarizine effectively rescued dissociated DRG neurons if administered up to six hours after NGF withdrawal. In vivo, flunarizine prevented DRG neuronal death after sciatic axotomy in newborn rats if given soon after injury. Long-term experiments were done to test the ability of flunarizine to protect neurons and enhance regeneration after sciatic nerve injury. Newborn rats were subjected to peripheral nerve injury and administered flunarizine for four weeks; no further treatment was given for an additional 12 weeks. The group treated with flunarizine demonstrated a significantly increased number of DRG and spinal motor neurons that had regenerated axons into the distal sciatic nerve as determined by retrograde labeling with HRR Myelinated axons in the sural nerve in the group treated with flunarizine increased by nearly two-fold compared to control animals. Thus, flunarizine was able to enhance survival and promote long term regeneration of sensory and motor spinal neurons after peripheral nerve injury. PMID- 21551865 TI - Cervical spinal cord injury in the adult rat: assessment of forelimb dysfunction. AB - Traumatic injury to the adult human spinal cord most frequently occurs at the mid to-low cervical segments and produces tetraplegia. To investigate treatments for improving upper extremity function after cervical spinal cord injury (SCI), three behavioral tests were examined for their potential usefulness in evaluating forelimb function in an adult rat model that mimics human low cervical SCI. Testing was conducted pre- and up to 4 weeks post-operation in adult female rats subjected to either contusion injury at the C7 spinal cord segment or sham surgery. Modified Forelimb Tarlov scales revealed significant proximal and distal forelimb extension dysfunction in lesion rats at l-to-4 weeks post-cervical SCI. The Forelimb Grip Strength Test showed a significant decrease in forelimb grip strength of lesion rats throughout the 4 weeks post-cervical SCI. Significant deficits in reach and pellet retrieval by lesion rats were measured at l-to-4 weeks post-cervical SCI with the conditioned pellet retrieval Staircase Test. The results demonstrate that these qualitative and quantitative forelimb behavioral tests can be used to evaluate forelimb function following low cervical SCI and may be useful to investigate treatments for improving forelimb function in these lesions. PMID- 21551866 TI - Abstracts of the 12th annual meeting of the Japanese society for neural growth, regeneration and transplanation. PMID- 21551867 TI - Effects of nimodipine on medial septal area cells after section of the fimbria fornix. AB - In rats, sectioning the fimbria-fornix leads to a decrease in cells reactive for acetylcholinesterase and choline acetyltransferase, as well as other types of cells, in the medial septal area that project to the hippocampus. In this study cells in the medial septal area were stained for acetylcholinesterase reaction product or by a Nissl method two weeks after unilateral section of the fimbria fornix. Counts were made of cells on each side of the midline by independent observers. The counts of the cells on the two sides of the brain were compared in rats that had been given nimodipine (70 MUg/kg) just after the lesion and for 7 additional days and in rats that had been given only the vehicle for an equivalent amount of time. The number of cells reactive for acetylcholinesterase was reduced in the medial septal area on the side of the brain in which the forebrain fornix was sectioned, but this occurred to a significantly less extent in the nimodipine-treated rats. No differences were noted in the number of cells on the two sides of the medial septal area when counted in Nissl-stained sections. PMID- 21551868 TI - Transplantation of human embryonic retina to adult rat retina. AB - Human embryonic retinas (postconceptional age 3-10 weeks) with or without retinal pigment epithelium were grafted to the retina of immuno-suppressed adult rat hosts. The development of the xenografts was followed up to 37 weeks of total age by histology and by immunohistochemistry for S-antigen. The donor tissue became rearranged in folded sheets with rosettes. The grafts developed approximately according to their intrinsic timetable, but with a developmental delay in the later stages. Occasionally, the grafts were well fused with the host retina. At 13 weeks of total age, the grafts contained areas of inner plexiform layer with presumptive ganglion cells, one neuroblastic layer, and cone precursor cells around rosettes. At 19 weeks, an outer plexiform layer and inner segments of the cones started to form. At 20 weeks, the first immunoreactivity for S-antigen was observed in photoreceptor precursors. Cone inner segments were clearly distinguishable at 28 weeks, and more S-antigen-positive rods were seen. At 31 weeks, rods were more differentiated, showing S-antigen-positive inner and outer segments. An inner limiting membrane with an apparent ganglion cell layer was only seen in one cograft of retina and retinal pigment epithelium at 37 weeks, indicating an important role of retinal pigment epithelium for graft differentiation. This study shows that human embryonic retina can be grafted to immuno-suppressed adult rat retina with long-term survival. A high degree of maturation can be obtained in the grafted tissue comparable to the layering of newborn human retina. It appears that most cell types develop. This model opens up possibilities for studying human retinal development with the goal of reaching a treatment for human degenerative retinal disorders. PMID- 21551869 TI - Restoration of denervated skeletal muscle transplants after reinnervation in rats. AB - The present study describes reinnervation and restoration of rat skeletal muscle denervated for the duration of 3, 6 or 12 months. Denervation of extensor digitorum longus (EDL) muscle was achieved by cutting and ligating the donor rat sciatic nerve in situ. At 3, 6 and 12 months, the denervated EDL muscles were removed and transplanted into an innervated normal leg of another rat. In addition, normal (i.e., no prior denervation) muscles were transplanted as controls for comparison. The muscles were analyzed at 4 and 12 weeks after transplantation. The EDL muscle weight and myofiber size decreased with extended denervation times. After transplantation, the muscles underwent regeneration and reinnervation, and recovered as determined by an increase in muscle mass and myofiber size. The 3-month denervated muscle regenerates recovered completely, and were similar to the non-denervated normal muscle regenerates. Reinnervation, and partial recovery of muscle weight and myofiber size was observed in 6- and 12 month denervated muscle transplants. These results document that while regeneration and reinnervation does occur in denervated muscles after transplantation, the extent of recovery is related to the duration of denervation. PMID- 21551870 TI - Graded crush of the rat optic nerve as a brain injury model: combining electrophysiological and behavioral outcome. AB - In the present study, we have developed an animal model for central nervous system (CNS) damage using the graded crush injury of the adult rat optic nerve. This injury model has the following characteristics: (a) the injuries are reproducible; (b) the injuries can be created with controlled severity; and (c) variations in the severity of the injuries correlate with definable electrophysiological and behavioral outcomes. Self-closing forceps, modified by attaching a screw to the handle, were used as a lesion-causing device. Rat optic nerves were crushed in vitro. The severity of the injury, calibrated by a measured applied force, was determined, electrophysiologically, in vitro. Compound action potential was assessed and recorded by suction electrodes connected to both sides of the nerve. In vivo studies correlated the calibrated crush injuries with behavioral outcome. After severe crush (applied force: 205 g or higher), the rats were unable to orient towards visual stimuli presented in the visual field of the damaged nerve and only minor transient recovery was observed. After moderate crush (applied force: 120 g), however, there was a significant recovery of orienting performance up to the 6th postoperative day, followed by a gradual, secondary loss of function. In the mildly injured group (applied force lower than 30 g), functional improvement continued for up to 10 days and remained stable thereafter, with only minor secondary loss. This CNS graded injury model may be valuable to study the molecular and anatomical mechanisms underlying secondary degeneration and the potency of various posttraumatic treatments in leading to recovery of function. PMID- 21551871 TI - The effect of lateralized dynamic stimuli on unilateral spatial neglect following right hemisphere lesions. AB - Patients with unilateral (left-sided) spatial neglect following right-hemisphere stroke were tested for the effects of visual stimulation on performance of a line bisection task. As predicted from research on brain mechanisms of spatial orientation and attention, dynamic visual stimuli presented on the left side substantially reduced neglect in the task. In contrast, left sided static stimuli reduced neglect significantly less and dynamic stimuli presented in the center had no effect on neglect. Neglect patients with hemianopia did not show significantly less benefit of left-sided dynamic stimuli compared to neglect patients without hemianopia, suggesting that the effect of these stimuli was unconscious and automatic. The potential advantages of lateralized dynamic stimuli in the rehabilitation of neglect are discussed. PMID- 21551872 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551873 TI - Substantia nigra grafts and Parkinson's disease: from animal experiments to human therapeutic trials. AB - During the decade since the first reports of functional effects of substantia nigra (SN) transplantation in animal models of Parkinson's disease, the procedure has progressed to human clinical trials. There is evidence that SN grafts can produce some alleviation of the manifestations of SN lesions in animal models, and by several measures these grafts appear to function in a manner similar to the normal SN. There do, however, appear to be limitations on the efficacy of SN allografts in rodent models, that may be related to an inability of fetal SN transplants to fully integrate into the host brain structure. No method of overcoming this limitation has yet been found. Studies of transplantation of human fetal SN to immunosuppressed rat hosts suggest that human donor tissue exerts proportionately greater effects than rat tissue, and is similarly effective when transplanted as solid tissue fragments or as dissociated cells. Only recently, a few controlled studies have obtained evidence for positive effects of SN grafts in primate models of Parkinson's disease. In the few clinical studies reported thus far, there are indications that some clinical improvements can be produced by SN grafts, although there is little or no evidence that the clinical changes found so far are larger than the changes that have been seen after adrenal medulla grafts. The possibility of a role of striatal injury in the clinical changes has not been resolved. It is noteworthy that nearly all of the studies of SN transplantation in rodents, primates, and humans have employed methodologies similar to those developed in the course of the first few reports on SN transplantation, and that the effects obtained by these methods are limited, even in rats. The possibility is raised that fundamental advances in SN transplantation techniques may be important for the development of a more efficacious clinical procedure. PMID- 21551874 TI - Skilled forelimb use in the rat: amelioration of functional deficits resulting from neonatal damage to the frontal cortex by neonatal transplantation of fetal cortical tissue. AB - Limb preference and dexterity of right and left forelimbs were studied in a food reaching task in normal rats (control group), in rats that sustained a neonatal lesion of the left frontal cortex (lesion group) and in animals that received a transplant obtained from the frontal cortex of 16-day-old embryos immediately after the lesion (graft group). In addition, an anatomical study of host transplant interconnections was performed in several transplanted animals. The results indicate that the lesion slightly increased the preference for the limb ipsilateral to the lesion and transplantation of fetal cortical tissue did not restore the preference for the contralateral limb. Furthermore, lesion of the motor cortex induced a deficit in the dexterity of limb use in the food-reaching task. This motor deficit was more pronounced when the limb contralateral to the lesion was used. Transplantation of embryonic cortical tissue led to a reduction of the motor deficit. Compared to the lesion group, the graft group had a higher success rate and a lower percentage of motor abnormalities, whichever forelimb was used, ipsi- or contralateral to the transplant. Nevertheless, larger improvement was noted with contralateral forelimb usage. Functional recovery was not complete since the control group still performed significantly better than the graft group, although almost complete sparing in skilled reaching was noted when the limb ipsilateral to the transplant was used. Analysis of host-transplant interconnections indicates that the transplants sent fibers to the host spinal cord, caudate-putamen, thalamus and homotopic contralateral cortex and received projections from the host thalamus and contralateral cortex. It is therefore suggested that neonatal transplantation of fetal cortical tissue promotes functional recovery from damage to the motor cortex occurring at birth. PMID- 21551875 TI - Accumulation of neurofilament proteins in the regenerating facial nerve. AB - In order to compare the extent of axonal regeneration in two surgical nerve repair procedures, we measured the levels of the neurofilament (NF) proteins in the regenerating facial nerve of adult New Zealand rabbits. The animals were operated on bilaterally, with a chamber model placed on one side and a cable graft model inserted on the contralateral side. Normal nerve from unoperated animals or nerve removed during nerve repair surgery served as controls. Using immunoblot techniques and densitometric measurement, we examined specific changes in the individual NF [High (H), Medium (M), and Low (L) molecular weight (MW)] in the regenerating nerve at 3 and 7 weeks postoperation time. Linearity of the densitometric system was established by separation of serial dilutions of known NF on the gel, and blotting for immunostaining. The amount of all 3 NF's decreased during the regeneration process compared to normal nerve, but there were differences between the two procedures. The NFH in the distal segment of the chamber repaired nerve at 7 weeks was 60-70% of the preoperative state, which correlated with a previous morphological study of axona) caliber during regeneration. At 3 weeks, NF content was lower in the distal segment of the chamber than in the distal cable graft. By 7 weeks, NF content was similar in proximal and distal segments of both models. Thus, although initial regeneration is slower in the chamber model, the eventual outcome is similar in both chamber and graft. PMID- 21551876 TI - The pia mater - a conduit for regenerating axons after ventral root replantation. AB - Previous studies have shown that replantation of avulsed ventral roots may lead to functional reinnervation of hindleg muscles. Regenerating motor axons may regrow for a considerable distance within the spinal cord before entering the replanted ventral root. In this study we show, in the rat and monkey, that many regenerating axons utilize an alternative pathway along the surface of the spinal cord, i.e. the pia mater. This type of reinnervation takes place entirely in the peripheral nervous system. PMID- 21551877 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551878 TI - Progress in understanding recovery of function after brain damage: the need for collaboration. PMID- 21551879 TI - Rehabilitation of homonymous scotomata in patients with postgeniculate damage of the visual system: saccadic compensation training. AB - A systematic training procedure for patients with disturbed visual search was evaluated in 92 patients with postchiasmatic visual field disorders (VFD) and 30 VFD patients with additional leftsided visual neglect (VFD +). Visual fields and areas of visual search via saccadic eye movements in the scotomatous field (search field) were mapped perimetrically in all patients before and after training and after a follow-up interval (mean follow-up interval: 22 months). A significant increase of more than 20 degrees of visual angle was found in visual search field in the scotomatous field during training. Search field remained stable at follow-up in both patient groups. In contrast, only minor, though significant increases in visual field size were obtained during search field training in some patients. Multiple baseline designs in 5 patients revealed that search field enlargements were training dependent and not related to spontaneous recovery, adaptation to test procedures or measurement variability. VFD + Neglect patients needed some 25% more therapy sessions than VFD patients to achieve the same amount of increase in visual search field. Frequent head movements had a deleterious effect on training progress. It is concluded that the presented training procedure can lead to a significant and stable improvement in visual search within 15 to 25 training sessions and hence to a better compensation of visual deficits in daily living in most patients with VFD and/or visual neglect. PMID- 21551880 TI - Correlation between vestibular habituation and postural recovery in cerebellar patients. AB - Vestibular habituation was studied in normal subjects and in patients with cerebellar disease using a stimulation paradigm proposed in this paper. Six caloric stimuli were repeated daily in the same ear during six days and electronystagmographic responses at the beginning and the end of that period were compared. The normal behaviour was a clear reduction of the response across time. Two groups of cerebellar patients were identified by their ability to recover from positional imbalance after treatment. Compensated patients responded to repeated caloric stimulation in the same way as normal subjects. Conversely, uncompensated patients increased their response after the stimulation paradigm. The role played by the cerebellum in vestibular plasticity is discussed together with the observed correlation between vestibular habituation and the ability for postural recovery to occur. PMID- 21551881 TI - Grafted fetal suprachiasmatic nucleus cells survive much better in tissue pieces than in suspension. AB - A comparison was made between the survival of fetal suprachiasmatic nucleus (SCN) grafted either in tissue pieces or as tissue suspension. Donor tissue was obtained from day 15, 16 or 17 Wistar fetuses, and stereotaxically placed in the dorsal thalamus of the brain of vasopressin(VP)-deficient Brattleboro adult rats. One month post-grafting, the suspension grafts largely failed to show the immunocytochemical presence of VP- and vasoactive intestinal polypeptide(VIP) producing SCN cells, but solid piece grafts did. In the suspension grafts only a few tiny clusters of surviving VP SCN neurons were seen and hardly any VIP cells. This suggests that intrinsic contacts are necessary for SCN cells to survive and/or to express their genotype. Efferent VP fiber growth was observed to run from the tissue piece derived SCN grafts towards the periventricular area of the thalamus, a nearby SCN projection area. However, the number of VP efferents was very limited and not consistently present. Surprisingly, magnocellular VP neurons, also present in the fetal SCN grafts, showed an opposite survival pattern. Several of such cells were seen in day 15 suspension grafts, whereas hardly any were found in day 15 tissue piece grafts. These results indicate that the type of graft preparation might be important when survival of particular cells is desired. PMID- 21551882 TI - Infantile right hemisphere injury: a case report with MRI and 13 year follow-up. AB - Serial neuropsychological findings were obtained in a case of infantile right parietal injury who was studied over a 13 year follow-up period. Magnetic resonance imaging at age 13 years documented extensive injury to the right hemisphere, particularly the parietal region. Serial examinations at age 7 and 13 years showed intact visual attention, normal expression and processing of affect and variable visuospatial abilities. However, intellectual development was generally depressed. Implications of these findings for recovery from early brain injury are discussed. PMID- 21551883 TI - Sensory deprivation prevents integration of neocortical grafts with the host brain. AB - The histological and electrophysiological properties of embryonic neocortical grafts transplanted into the barrel field of adult rats were compared between the side receiving normal vibrissae input vs. chronic deprivation of input produced by clipping of the recipients vibrissae. Each animal received ablation of the neocortex and transplantation of neocortical tissue bilaterally. Vibrissae were clipped unilaterally immediately after surgery and were trimmed for up to 4 months. Significant differences were found between volume of the grafts as well as the number of grafts showing contact with the wall of the lesion cavity, indicating that the tissue growth was directly influenced by sensory deprivation. Decrements in functional integration with the host brain measured electrophysiologically were also observed. PMID- 21551885 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551884 TI - Differential sound-evoked metabolic activity in fetal tectum grafted into damaged adult rat inferior colliculus. AB - Long-Evans rats with unilateral lesions of the dorsal inferior colliculus (IC) received transplants of fetal tectal tissue to determine functional efficacy. Acoustic stimulation increases metabolic activity in both graft and host tissues relative to spontaneous activity in these regions. During periods of quiescence, graft tissue shows basal metabolic activity similar to that found in host IC. Coupled with previous anatomical findings, the results suggest that tectal grafts not only possess a neural structure resembling normal adult IC, but also contain cellular constituents which are responsive to sound. Given the apparent system appropriate function of implanted fetal tectum, the graft tissue may be able to have a restorative effect within the damaged central auditory pathway. PMID- 21551886 TI - Postischemic hyperoxia enhances vulnerability in the rabbit spinal cord ischemic model. AB - This study evaluated whether or not reperfusion of the rabbit ischemic spinal cord under conditions of varying blood oxygen tension combined with low blood viscosity can alter the neurological outcome after 15 min of infrarenal aortic occlusion. In group A (n = 20), hyperoxic reperfusion was performed during the initial 30 min of recirculation (pO2 = 460 +/- 72 mmHg). In group B (n = 20), no attempt was made to manipulate the physiological arterial pO2 tension. In group C (n = 20), graded postischemic reoxygenation was applied during 15 min of recirculation beginning with 48 +/- 12 mmHg as the initial arterial pO2. Neurological analysis revealed a high incidence of paraplegic animals after hyperoxic reperfusion as opposed to relatively undamaged animals after normoxic or graded postischemic reoxygenation. The possible role of different pathobiochemical events, specifically the high molecular oxygen availability and oxygen free-radical overproduction, is discussed below with attention to the interneuronal destructive process, detected during the early reoxygenation phase by means of the Nauta method permitting the visualization of the early signs of somatic and dendritic argyrophilia. PMID- 21551887 TI - Autoradiographic analysis of muscarinic receptors and choline-uptake mechanisms within foetal basal forebrain transplants. AB - The pharmacological characteristics of both muscarinic receptors and high affinity choline uptake sites were examined within intracerebral implants of foetal basal forebrain cell suspensions. Approximately 12 weeks after implantation, the transplants were identified by acetylcholinesterase histochemistry. Muscarinic receptors were labelled by [3H]quinuclidinyl benzylate (QNB) autoradiography. The M1 and M2 receptor components of QNB binding were differentiated by pirenzepine competition. The distribution of the high-affinity choline uptake site was examined using [3H]hemicholinium-3 (HC3) autoradiography. Unilateral lesion of the nucleus basalis reduced [3H]QNB (8-25%) and [3H]HC3 (19 43%) binding throughout host frontoparietal cortex ipsilateral to the lesion but did not significantly alter these cholinergic markers within cingulate cortex, subcortical white matter, striatum or septum. Saturation analysis of the implanted tissue revealed the presence of a single population of [3H]QNB and [3H]HC3 binding sites with affinities similar to those of the host tissue (KD = 0.43 nM and 20.4 nM respectively). However, the receptor profile which developed appeared to be intrinsic to the implant; it was unaffected by the site of implantation and was dissimilar to that which ultimately developed in the donor tissue when left in situ. PMID- 21551888 TI - Retinal synthesis and axonal transport of gangliosides during regeneration of the goldfish optic nerve. AB - In the present study, the left optic nerve of the goldfish was transected between eye bulb and optic chiasm. One to 39 days after lesion, the fish received an intraperitoneal injection of [3H]proline or [3H]NAc-glucosaraine. After one or two days of incorporation, both retinae and optic nerves were analyzed for protein- and ganglioside-bound radioactivity. A transient enhancement of label incorporation into proteins (up to 2-fold) and gangliosides (up to 1.5-fold) of the regenerating retina was found. Simultaneously, a transiently enhanced accumulation (up to 4.5-fold) of protein- and ganglioside-bound radioactivity in the regenerating optic nerve took place. These regeneration-related 'metabolic' changes came to a maximum at 6-8 days after nerve transection and were still measurable after 40 days. In the regenerating retina, there were no changes either of the ganglioside pattern or of the relative distribution of radioactivity of individual gangliosides. In the regenerating optic nerve, however, ganglioside GPlc, identified by immuno-TLC, and a fraction migrating like GD3/GM1 were enhanced with respect to their relative proportion of total ganglioside sialic acid and radioactivity. The radioactivity proportion of a ganglioside migrating like GDlb was decreased. PMID- 21551889 TI - Transplant and ganglioside GM1 mediated neuronal recovery in rats with brain lesions. AB - Transplants of fetal brain tissue or injections of ganglioside GM1, given to rats with unilateral, left medial frontal cortex lesions, altered the concentrations of neuronal and glial marker proteins in cortex both adjacent and contralateral to the lesion. The markers were: the neural cell adhesion molecule (NCAM) and D3 protein, both present in neuronal and synaptic membranes; synaptophysin, present in synaptic vesicles; glial fibrillary acidic protein (GFAP) enriched in reactive astrocytes, and the astrocytic glutamine synthetase. After 21 days the concentrations of NCAM, D3 and synaptophysin in brain tissue adjacent to the lesions were decreased by 39, 32 and 42%, respectively, indicating neuronal damage. In the injured rats the GFAP concentration was increased 77%, indicating activation of astrocytes. However, astroglial proliferation was not altered as indicated by the nearly unchanged glutamine synthetase concentrations. The levels of the neuronal markers NCAM, D3 and synaptophysin showed significantly less decline in injured rats treated 7 days after the lesions with transplants or with daily injections of 30 mg/kg GM1. The decrease respectively constituted 23 (NCAM), 31 (D3) and 41% (synaptophysin) in rats with transplants and 23 (NCAM), 16 (D3) and 28% (synaptophysin) in rats treated with GM1. In another group of rats the efficacy of transplants was studied 34 days after lesions. NCAM and D3 in tissue adjacent to the lesions were decreased by 50 and 29%, respectively. In rats which received transplants the decrease was only 27 and 16%, respectively. Moreover, as measured by GFAP concentration, activation of astrocytes was less in rats with transplants (93% increased) compared with rats with lesions only (163%). In contralateral frontal cortex, the effects of lesions were similar but less pronounced. In this brain area also the treatments significantly counteracted the loss of neuronal and glial markers. Previous studies have demonstrated that synaptic remodelling is reflected by the ratios of NCAM to marker proteins for mature synapses. Twenty-one days after the initial injury to the brain the ratios of NCAM to D3 and synaptophysin were significantly increased in frontal cortex ipsilateral to the injury in rats with transplants (26 and 33%, respectively). In contrast, compared with values for injured rats, the calculated ratios were not changed, whereas all neuronal marker proteins were significantly increased in rats treated with GM1. The results suggest that transplants mediate neuronal recovery by inducing dendritic sprouting followed by synaptic remodelling whereas gangliosides mediate recovery by counteracting neuronal degeneration. PMID- 21551890 TI - Fate of afferents to the dentate gyrus following destruction of granule cells with colchicine. AB - Granule cells of the dentate gyrus can be selectively destroyed by intrahippocampal injections of colchicine. The present study evaluates the consequences of this selective neuronal destruction on the afferent axon terminals which have been deprived of their normal targets. The area of the neuropil in the dentate gyrus (the molecular layer) was evaluated in sections stained using the Timm's method for heavy metals, which selectively marks the terminal fields of the different afferent systems. The molecular layer was examined electron microscopically to determine the fate of afferent terminals. Anterograde transport of HRP or [3H]proline was used to define the location and extent of afferent terminal fields of the entorhinal and commissural projections to the dentate gyrus in which the granule cells had been destroyed. There was a substantial reduction in the size of the dentate gyrus molecular layer after destruction of granule cells with colchicine. Electron microscopic analyses revealed that there were very few axon terminals or synapses remaining in the shrunken molecular layer. Tract tracing methods revealed that both the entorhinal and commissural pathways were still present in their normal terminal zones in the dentate gyrus, however, the density of the projections was greatly reduced. There was no evidence to suggest the formation of ectopic projections to unusual locations, such as the contralateral dentate gyrus. Pathways passing through the hippocampus appeared to survive the colchicine injections. These results suggest that target destruction in adult animals leads to the disappearance of the afferent axon terminals which normally innervate the cells which die. PMID- 21551891 TI - Retrograde regulation of neuronal size in the entorhinal cortex: consequences of the destruction of dentate gyrus granule cells with colchicine. AB - Studies in developing animals have documented that manipulations which increase or decrease the size of a neuron's axon arbor lead to increases or decreases respectively in the size of the neuron's soma. The present study evaluates whether similar dependencies exist in adult animals, by analyzing changes in cell size in the entorhinal cortex after selective destruction of dentate granule cells with colchicine. Neurons in layer II of the entorhinal cortex which had been deprived of their normal targets decreased in size by 32% relative to their contralateral homologs. Neurons in layer III which project to regio superior of the hippocampus were affected to only a slight extent, decreasing in size by 8% relative to their contralateral homologs. Neurons in layer V, which do not project to the hippocampus, were unaffected by colchicine injections into the hippocampus. These results indicate that neurons in adult animals which retract terminal arbors as a consequence of target loss also decrease in size. PMID- 21551892 TI - Comparison of the effects of adrenocorticotropic hormone fragment 4-10 (ACTH(4 10)) and [D-Phe7]ACTH(4-10) on the compensation of spontaneous nystagmus in guinea pig. AB - Following unilateral labyrinthectomy (UL), spontaneous nystagmus (SN) was measured in guinea pigs which received i.m. injections of 100 or 400 ug/kg ACTH(4 10) or 800 ug/kg [D-Phe7]ACTH(4-10), every 4 h for 48 h post-UL. The results were compared to those from a previous study, conducted under identical conditions, in which guinea pigs received similar injections of 200 ug/kg ACTH(4-10) or 0.1 ml/kg saline. ACTH(4-10) significantly accelerated the rate of compensation of SN at 100, 200, and 400 ug/kg doses, although the average effects were larger for the 200 ug/kg condition. [D-Phe7]ACTH(4-10) significantly increased the frequency of SN following UL compared to saline-treated animals; however, it also accelerated the rate of SN compensation. These results indicate that the acceleration of SN compensation in guinea pig by ACTH(4-10) follows an inverted U shaped dose-response curve and that [D-Phe7]ACTH(4-10) increases the frequency of SN. PMID- 21551893 TI - Bridging of peripheral nerve defects with exogenous laminin-fibrin matrix in silicone tubes in a rat model. AB - Fibrin matrix (FM) is a biological substance involved in the comprehensive wound healing process, and has been used in local applications as a carrier of nerve growth factor (NGF) to achieve an effective local neurotrophic concentration by slow release of the factor. In the present experiment, an exogenous fibrin matrix enriched with laminin (LM) and tubulized by a silicone conduit was used to improve the bridging effect of a peripheral nerve defect in a rat model. A 10 mm nerve defect was bridged with a 14 mm silicone conduit which was prefilled either with 25 MUl fibrin matrix enriched without or with laminin (0.1 MUg/ml), serving as groups FM and LM-FM, or with the same amount of saline solution for control (CTR group) (n = 10). After 12 weeks, the nerve conduction velocity and the distal latency were calculated from the electromyographic recordings. In addition, morphological semi-quantitative evaluations in longitudinal and transversal sections were carried out by immuno-histochemical staining with a monoclonal antibody against neurofilament. An improvement in nerve conduction velocity and distal latency, and a better orientation of the regenerated nerve fibers in the gap area were achieved in the LM-FM group than in the CTR and FM groups. These results indicate that the bridging of peripheral nerve defect in a rat model may be improved by the use of exogenous fibrin matrix enriched with laminin (as a filling material) in a silicone conduit. PMID- 21551894 TI - Visual field enlargement after computer training in brain-damaged patients with homonymous deficits: an open pilot trial. AB - Brain damage is often accompanied by homonymous hemianopia, but few therapeutic approaches exist for visual field deficits. In this open pilot study we describe a computerized training program which may possibly reduce the size of the 'blind' visual field in patients with homonymous visual field deficits. Various stimuli to test light perception and discrimination of colors and shapes were presented on a monitor which permitted the examination or training of the central section of the visual field up to about 25 degrees vertical and 40 degrees horizontal eccentricity. Eleven patients trained at home for 1 h each day for a total of 80 300 h. Their results were compared with those of three patients who opted not to participate in the training procedure or those with very little therapy. These latter subjects had a slight decrease in the visual field size after about 1 year. In contrast, the treatment group displayed a reliable enlargement of visual field size. This was revealed by a significant improvement in the detection of small light stimuli, an increase in the ability to discriminate colors and a minor, but notable, improvement of shape discrimination in the blind areas of the visual field. Additional training of shape recognition led to further improvement of shape discriminations, even when the patients trained with very different kinds of shapes, e.g. lines or letters. Outcome depended on age of the patients and the size of the lesion, but it was independent of on-set of treatment and cause of the lesion. Only two of the 11 patients with treatment showed no significant improvement. This study suggests that regular home training of the 'blind' visual field with computer-controlled stimuli may lead to improvement in vision. However, because of the following methodological limitations results are only preliminary: (1) the trial did not contain a true placebo group, (2) the patients were not assigned randomly to a control or treatment condition, (3) the lack of defined inclusion criteria considerably increased the variance in neuropsychological performance, (4) because the experimental design was not double blind, experimenter bias cannot be ruled out, and (5) the conditions of the home training could not be standardized. The results warrant a larger randomized, double-blind controlled trial. PMID- 21551895 TI - Rat striatal astroglia induce morphological and neurochemical changes in adult bovine, adrenergic-enriched adrenal chromaffin cells in vitro. AB - Adult bovine chromaffin cells are generally resistant to plastic changes when exposed to various culture media. Here, we demonstrate that adrenergic-enriched bovine chromaffin cell populations show significant process extension when co cultured with fetal rat brain glial fibrillary acid protein (GFAP)+, fibronectin astroglia. Basal medium was ineffective in promoting such growth in chromaffin cells. Initial process formation could be observed about 24 h after seeding, while well developed processes were seen after 3-4 days. Intimate contacts of cytoplasmic extensions with adrenergic chromaffin cells, or with astroglial cells, were frequently observed. Both co-culture with glial cells or exposure to glia-conditioned medium led to a significant increase in noradrenaline and adrenaline, but not in dopamine content. Since bovine chromaffin cells are widely used as models to study fundamental mechanisms of neurosecretion and phenotype transformation, their co-culture with astroglia may provide a useful strategy to study such phenomena. PMID- 21551896 TI - Differential expression of the electrophysiological responses to axotomy in bullfrog sympathetic neurons following nerve injury at 15 degrees C. AB - In frogs maintained at 15 degrees C, there is a partial failure of the cell body reaction (CBR) to axotomy. We investigated, in the sympathetic B-cells of the bullfrog, the effects of axotomy at 15 degrees C on the changes in electrophysiological properties which we found previously to follow axotomy at 21 degrees C. While the increase in action potential (AP) duration was delayed by about 14 days, it increased by the normal amount. In contrast, the reduction in after-hyperpolarization (AHP) duration was both delayed and attenuated. These results show that there is a differential expression of these two components of the CBR, with changes in AHP duration more sensitive to lowered temperature. In attempts to determine if the effect of reduced temperature was on the signalling of axotomy or on the cell body response to the signal, we performed experiments where the 15 degrees C frogs were maintained at 21 degrees C for 7 days, immediately after axotomy, or after various delays. These results suggest that at 15 degrees C, there is an increased delay in signalling that the injury has occurred, but we were not able to show conclusively that maintained expression of the CBR requires an ambient temperature of 21 degrees C. This study emphasizes that the CBR to axotomy is not a unitary response to a single signal, but can be dissected, by lowered ambient temperature, into differentially regulated components. PMID- 21551898 TI - Abstracts selected from Excerpta Medica's EMBASE. PMID- 21551897 TI - Bilateral paramedian thalamic infarction with persisting signs of frontal lobe dysfunction. AB - Cognition and behavior of a 46-year-old woman with a bilateral paramedian thalamic infarction is discussed with regard to dysfunctions of executive behaviors associated with frontal lobe function. The patient displayed marked disturbances in traditional neuropsychological tests measuring frontal lobe functions, as well as in attentional and mnemonic tasks depending on strategic behavior or on response flexibility, response shifting, or response inhibition. Behaviorally, the patient showed considerable apathy, confusion and perseverative tendencies in the acute state, and a diminished psychic self-activation in the chronic state. In spite of long-lasting rehabilitation efforts, the patients' neurobehavioral deficits remained and became obvious in situations with high cognitive demands. PMID- 21551899 TI - Delayed application of direct current electric fields in experimental spinal cord injuries. AB - The cutaneus trunci muscle (CTM) reflex of guinea pigs depends on an ascending afferent pathway within the ventrolateral funiculus of the thoracic spinal cord. The expression of this reflex is a phasic contraction of back skin in response to tactile stimulation, which is permanently eliminated by transection of the ventrolateral funiculus. It was shown previously that when a polarized (rostrally negative), weak (300-400 MUV/mm) DC electric field is placed across a lateral hemisection of the spinal cord in adult guinea pigs at the time of injury, approximately 13% recover the reflex, while sham-treated animals remain unchanged. In this study, a similar approach was used, except that three months were allowed to pass between the time of hemisection and experimental treatment. No recovery of the CTM reflex was observed in 13 animals with rostrally negative fields, 8 of which were followed for at least 9 months, 5 for 3 months; or in 11 animals with caudally negative applied fields, 8 of which were followed for 9 months and 3 for 3 months. PMID- 21551900 TI - Nerve regeneration is improved by insulin-like growth factor I (IGF-I) and basic flbroblast growth factor (bFGF). AB - In rat sciatic nerves, IGF-I or bFGF was applied distal to a crush to evaluate their effects upon the restoration of the neuromuscular function. In comparison with the recovery following a simple crush, treatment with growth factors resulted in (i) enhanced elongation of regenerating axons ( + 24%) up to day 3 post lesion (PL); (ii) more sprouts at early times; (iii) reduced participation of macrophages in the removal of the degenerating myelin in the first week PL; (iv) restoration of the neuromuscular transmission 2 days earlier; (v) a prolonged relaxation time and a reduced specific tetanic tension at week 3 PL but not at week 7 PL. Other indicators of recovery such as conduction velocity of nerve impulse, muscle weight, specific twitch tension, and time to peak were not affected by bFGF or IGF-I. Results suggest that IGF-I and bFGF affect locally Schwann cells and axons, and also the neuron as a whole, including its trophic function. We conclude that IGF-I and bFGF applied to the nerve, albeit moderately, improve the recovery of the neuromuscular function. PMID- 21551901 TI - Muscle coordination in hindlimbs of mice after bilateral nerve regeneration. AB - The common peroneal nerve was transected bilaterally in 25 adult mice. Nerve stumps were immediately readapted without nerve suture. Before transection and after nerve regeneration the muscle coordination of tibialis anterior (TA) and medial gastrocnemius (MG) muscle was examined by electromyographic recordings from both muscles (EMG) during free running. Using a personal computer, the degree of muscle coordination between TA and MG was determined by calculating a coordination index. In normal mice an antagonistic innervation pattern was observed. After nerve transection and regeneration the degree of muscle coordination of TA and MG substantially decreased with great interindividual but also great intraindividual variation. In 16 mice there was no correlation between the coordination index of the left and right hindlimbs. In nine out of 25 mice reinnervation was absent on one side. These results suggest that nerve regeneration by axonal sprouting to appropriate or foreign muscles occurs at random and that there are no intraindividual factors which might promote the finding of the proper target muscle. PMID- 21551902 TI - Repair of the transected rat sciatic nerve: matrix formation within implanted silicone tubes. AB - Matrix formation within silicone tubes of different geometries implanted between the stumps of the transected rat sciatic nerve was studied. A matrix, composed of longitudinally oriented fibrin strands containing fibronectin, was formed within one day. The matrix then increased in size. The matrix contained macrophages and other inflammatory cells. Matrix size could be increased if the diameter of the tube was increased or if holes were made in the implanted tube. In contrast, matrix diameter decreased if the tube length was increased or if circulation was compromised in the inserts. The results suggest that the size, orientation and cellular components of the matrix have profound effects on the regenerative response of the transected nerve. PMID- 21551903 TI - Improvement of passive avoidance task after grafting of fetal striatal cell suspensions in ischemic striatum in the rat. AB - Behavioral recovery and cell survival/growth after grafting of fetal striatal cell suspensions in the ischemic striatum of rats were investigated. Ischemia was induced by one hour intraluminal occlusion of the right middle cerebral artery under halothane anesthesia. During the ischemia rats usually manifested signs of hemiparesis and sometimes rotations. Behavioral function was measured by a passive avoidance task and radial arm maze test at 1-2 weeks and 6-7 weeks after ischemia. The size of the ischemic lesions depended on each animal, but the ischemic animals showed deficits in both passive avoidance task and radial maze test. Two weeks after ischemia, fetal striatal cells, marked with DiI, were transplanted into the ischemic striatum. The transplantation improved the ischemia-induced deficit in the passive avoidance task but not in radial maze test. Although there were variations in the size of the grafts, many DiI-positive cells with dendritic outgrowth were detected under fluorescent microscopy. Immunohistochemical study revealed that many choline acetyltransferase (ChAT) positive cells and GABA-positive cells survived in the grafts. However, striosome matrix compartments were not evident inside the grafts. Thus, partial recoveries in both cytoarchitectural and behavioral aspects were obtained by striatal cell grafts, suggesting that neural transplantation could be a useful approach in reconstructing ischemic brain function. PMID- 21551904 TI - Persisting axonal degeneration in the hippocampus after transection of the fimbria-fornix. AB - Degeneration within the hippocampus was examined at the light microscopic level using the Gallyas silver stain two, four or nine months after bilateral transection of the fimbria-fornix and commissural connections. At two or four months after the lesion the strata oriens and radiatum of the subicular end of the CA1 subfields were strongly argyrophilic as was the inner third of the molecular layer of the dentate gyrus. At nine months post-lesion argyrophilia diminished but clearly persisted in the same layers. Electron microscopic examination revealed a large number of electron-dense axon terminals in the argyrophilic areas, most of them making asymmetric synaptic contacts with dendritic spines. These findings suggest that at least a portion of the Schaffer collaterals of the CA3 pyramidal cells and associational collaterals of hilar neurons were in a process of acute degeneration at all time points after the initial surgical trauma. This persistent synaptic reorganization of intrahippocampal circuits may be related to abnormal electrical activity observed several months after fimbria-fornix transection. PMID- 21551905 TI - The regeneration of axons through normal and reversed peripheral nerve grafts. AB - The effect of proximo-distal orientation of peripheral nerve grafts upon axonal regeneration has been investigated using the sciatic nerve of the rat as a model. To test the hypothesis that the presence of nerve branches within a graft will cause misdirection of axons in normally oriented grafts but not in reversed grafts, all grafts studied contained branches. Qualitative electron microscopic examination of graft ultrastructure revealed no differences in nerve structure related to graft orientation. In most normally oriented grafts, branches persisted up to 12 months after surgery. These branches contained axons which terminated at the end of the branch. In all reverse oriented grafts, and in a small number of normally oriented ones, the branches could not be seen after two or more months of regeneration. Axons sprouting outside of the epineurium of the graft caused the branch to be incorporated into the nerve structure. Axon counts in the distal stump of grafted nerves after twelve months recovery revealed that normally oriented grafts with persistent branches led to poorer peripheral regeneration, especially of unmyelinated fibers. The results indicate that regeneration of axons to their peripheral targets may be facilitated by reversing the graft orientation. PMID- 21551906 TI - Abstracts Selected from Excerpta Medica's EMBASE. PMID- 21551907 TI - Programmed cell life: anti-apoptotic signaling and therapeutic strategies for neurodegenerative disorders. AB - Injury to the nervous system initiates a cascade of signal transduction events that mobilize survival-promoting gene products and post-translational modifications of existing proteins involved in neuronal injury responses. These 'cell life programs' appear to converge on gene products involved in maintenance of calcium homeostasis and suppression of free radical accumulation. Central to the hypothesis of 'programmed cell life' is that neurons die (either by apoptosis or necrosis) when the severity or duration of the insult overcomes the ability of the cell life programs to protect the cell. Whether cell death manifests as apoptosis or necrosis depends upon the severity and duration of the insult, the cell type encountering the insult, and the state of the cell rather than the type of insult. For example, activation of glutamate receptors and oxidative insults can kill neurons by a rapid necrotic mode or a delayed apoptotic mode. In either case, calcium and free radicals mediate the cell injury. Several categories of anti-apoptotic signaling molecules (AASMs) are released from neurons and/or glia in response to brain injury including: classic neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor and basic fibroblast growth factor; cytokines such as tumor necrosis factor and interleukin-1; protease inhibitors such as protease nexin-1; and novel AASMs such as secreted forms of the beta-amyloid precursor protein. The specific ways in which AASMs promote cell survival range from induction of antioxidant enzymes to regulation of glutamate receptor expression to stimulation of calcium-binding protein expression to activation of K+ channels. The intracellular messengers mediating programmed cell life pathways include intermediate kinases. cyclic nucleotides and transcription factors such as NFkappaB. As details of AASM signal transduction pathways emerge so do novel therapeutic approaches to reducing neuronal degeneration. Because neuronal degeneration in many, if not all, neurodegenerative conditions results from excessive accumulation of free radicals and disruption of calcium homeostasis, activiation of AASM signaling pathways has broad applicability to both acute and chronic neurodegenerative disorders. PMID- 21551908 TI - Oxidative stress in the production and expression of neurotoxic beta-amyloid. AB - Although there is not yet any in vivo evidence of the neurotoxic action of beta amyloid in humans, it is well established that the insoluble form of full length beta-amyloid 1-40, and the fragment comprised of amino acids 25-35, are both toxic in vitro to neurons in tissue culture. beta-amyloid 25-35 increases cytosolic calcium in rat PC12 cells and in rat cortical neurons in primary culture by facilitating the entry of extracellular calcium into the cell. This effect is not altered by calcium channel blocking drugs but is prevented by U 83836E, one of the lazaroid anti-oxidant drugs, and by vitamin E. Similarly, the neurotoxic actions of beta-amyloid 25-35 are also prevented by U-83836E and by vitamin E. These observations indicate that the actions of beta-amyloid 25-35 are mediated by free radicals. In vivo, beta-amyloid 1-40 is cleaved from a precursor protein that appears to be synthesized and inserted into cellular membranes following damage to cells. To form neurotoxic beta -amyloid, the precursor protein must be cleaved within the transmembrane portion of its structure. In spite of extensive world-wide effort, an enzyme capable of doing this has not been found. However, a peroxidation cascade propagated through the lipid bilayer of the cellular membrane would cleave the precursor protein at a site needed to form beta-amyloid. If this is the case, then free radicals would play a role both in the formation of beta-amyloid and in its neurotoxic actions. PMID- 21551909 TI - Elastase is associated with the neurofibrillary pathology of Alzheimer disease: a putative link between proteolytic imbalance and oxidative stress. AB - This study demonstrates elastase immunoreactivity in the neurofibrillary pathology of Alzheimer disease. Using an antiserum against elastase, we show that elastase immunoreactivity is restricted to neurons and is markedly elevated in a proportion of neurofibrillary tangle-bearing neurons. Elastase is a proteolytic enzyme that might be a candidate protease for the generation of amyloid-beta from beta-protein precursor. These findings support the hypothesis that proteases play an important role in Alzheimer disease and furthers the notion that an imbalance in proteolytic regulation contributes towards the pathogenic presentation of the disease. Moreover, since alpha1-antitrypsin, the principal inhibitor of elastase, is highly susceptible to oxidative stress, our findings suggest a link between proteolytic imbalance and oxidative stress in the pathogenesis of Alzheimer disease. PMID- 21551910 TI - Role of apoptosis in acute neurodegenerative disorders. AB - Many toxic factors are generated during stroke that contribute directly to the death of neurons. Several recent studies suggest that a suicide-like phenomena similar to apoptosis or programmed cell death also contributes to the loss of neurons in stroke. The evidence implicating apoptosis in stroke can be divided into three categories; biochemical, molecular and pharmacological. Biochemical evidence: One hallmark of apoptosis is the early activation of destructive enzymes, including endonucleases and proteases. Endonuclease-mediated DNA fragmentation can be observed within 4 h after focal cerebral ischemia and precedes morphological evidence of cell death. Cells with damaged DNA appear to concentrate in the salvageable tissue of the penumbra while necrosis predominates in areas where the sustained lack of blood flow may make tissue salvage impossible. Molecular evidence: Bcl-2 is an anti-apoptotic gene that confers the ability to block apoptosis from a wide variety of stimuli. The levels of bcl-2 can be enhanced by viral gene delivery or transgenic methodology. In cortical tissue where bcl-2 was elevated, neurons were protected from a subsequent ischemic attack. In contrast to bcl-2, p53 is a pro-apoptotic protein. Levels of p53 are elevated after cerebral ischemia and transgenic p53 knockouts exhibit smaller infarcts than wild type control mice. Pharmacological evidence: The process of apoptosis typically involves the activation of enzymes and genes, leading to an irreversible committment to die. Inhibition of new protein synthesis by cycloheximide reduces brain damage after a stroke, suggesting that newly synthesized proteins are contributing to the death of neurons. In addition, inhibition of calpain (an enzyme implicated in certain forms of apoptosis) protects neurons in models of global ischemia, focal ischemia, and hypoxia. In conclusion, the observation that an apoptotic-like process contributes to stroke may have important therapeutic implications since therapies that inhibit apoptosis improve outcome in experimental stroke. PMID- 21551911 TI - Apoptosis associated genes are induced in gerbil hippocampus following global ischemia. AB - Numerous studies have demonstrated evidence of DNA nick end-labeling and DNA laddering following cerebral ischemia. To determine whether genes directly implicated in apoptosis were induced by ischemia, the expression of bcl-2, bcl-x and ICE mRNAs were examined using oligonucleotide probes. Northern blots demonstrated induction of bcl-2 mRNA and bcl-x mRNAs in hippocampus 24 and 72 h following 5 min of global ischemia. In situ hybridization demonstrated induction of bcl-2 and bcl-x mRNAs in CAl pyramidal neurons of hippocampus at 24 h following ischemia which decreased by 72 h. ICE-like mRNA was induced in non neuronal cells in the CAl region at 72 h following global ischemia. The data show that genes implicated in either protecting against or promoting programmed cell death in other systems are induced following cerebral ischemia. It is hypochesized that CAl neuronal cell death could be accounted for by the failure of the ischemic cells to make protective proteins that protect the cells from an ischemic induced apoptotic-like cell death. PMID- 21551912 TI - Excitotoxic damage in neurotrauma: fact or fiction. AB - Secondary brain injury is a well-demonstrated contributor to the morbidity and mortality of severe head injury. At least ten new compounds which antagonize the effects of glutamate in the brain are currently undergoing clinical evaluation as putative protectants against this secondary injury. None have yet shown clear benefit in humans. It is accepted that excitatory amino acids, glutamate in particular, have 'neurotoxic' effects on the brain, especially when present in excessive amounts. Whether or not this excitatory amino acid toxicity represents the major pathway for secondary damage is disputed. In the laboratory, over 300 studies have now demonstrated the ability of glutamate antagonist drugs of various types to prevent ischemic and post-traumatic acute brain damage. The magnitude and consistency of protection afforded by this group of compounds exceeds that which has ever been shown with any other mechanisms. Laboratory studies using in vitro neuronal models have implicated glutamate as a promoter of ionic flux and calcium entry across the cell membrane, which may then initiate astrocytic swelling and neuronal necrosis. In vivo animal models of brain trauma and ischemia have demonstrated glutamate release and potassium efflux into the extracellular fluid (ECF). Outcome in these models is improved, as assessed by both histopathology and behavioral studies, when glutamate antagonists are used. Additionally, presynaptic glutamate blockade in animal models such as middle cerebral artery (MCA) occlusion and subdural hematoma, creates reduction in lesion size which is paralleled by reduced glutamate production. In bridging the gap between the laboratory and the patient care setting, human microdialysis studies have shown massive release of excitatory amino acids into the ECF after severe head injury. Early studies with TV-methyl-D-aspartate (NMDA) antagonists in head injured humans have demonstrated a reduction of intracranial pressure and an improvement in cerebral perfusion. Future studies are needed to examine further the value of protection from excitatory amino acid induced injury. PMID- 21551913 TI - Expression of the proto-oncogene bcl-2 is increased in the rat brain following kainate-induced seizures. AB - The proto-oncogene bcl-2 is an important suppressor of apoptotic cell death in development and of both apoptotic and necrotic cell death in mature neurons. We studied expression of bcl-2 and the related gene, bax, which may promote cell death, after seizures induced by systemic kainate injection in rats. Expression of bcl-2 mRNA was studied by in situ hybridization. Bax and bcl-2 protein expression was studied by immunocytochemistry. Histologic analysis of cresyl violet-stained paraffin sections was performed at 72 h. bcl-2 protein was expressed in CA1 neurons, a region that is injured, yet survives after seizures. Bcl-2 mRNA was expressed in CA3, a region where there is extensive neuronal death at 72 h, but the bcl-2 protein was not translated. However, bax protein expression in CA3 was increased at 24 h. These results support a possible role for bcl-2 in promoting survival of CA3 after seizures. PMID- 21551914 TI - In vivo protection against kainate-induced apoptosis by the pineal hormone melatonin: effect of exogenous melatonin and circadian rhythm. AB - We recently reported that the pineal hormone melatonin protected neuronal cultures from excitotoxicity mediated via kainate-sensitive glutamate receptors and from oxidative stress-induced apoptosis. It has been shown that in rats, a systemic administration of kainate induces apoptotic cell death in various brain regions. In this study, we assayed the extent of brain injury after intraperitoneal (i.p.) administration of 10 mg/kg kainate to rats, using the quantitative TUNEL technique and Nissl staining. We examined the role of melatonin on kainate-induced brain injury by (a) injecting melatonin (4 * 2.5 mg/kg i.p.) prior to and after kainate injection and (b) injecting kainate at the time of low circulating melatonin levels (day/light), and high melatonin levels (night/dark). The extent of kainate-triggered DNA damage and the loss of Nissl staining were lower in animals treated with melatonin, or when kainate was injected at night, i.e. in the presence of high endogenous levels of melatonin. Our results suggest that both the pharmacological use of melatonin and the circadian secretion of endogenous melatonin during the night may reduce the extent of excitotoxic brain injury. Further studies are needed to fully characterize the relevance of our findings for the treatment of progressive neurodegenerative processes which involve excitotoxicity and apoptotic neuronal death. PMID- 21551915 TI - Suffering and death among early American Roentgenologists: the power of remotely anatomizing the living body in fin de siecle America. AB - This manuscript has two aims. First, I extend the historiography on early American roentgenology that demonstrates that dozens of early adopters knowingly suffered intense pain, mutilation, and death for the sake of the X-ray. The objective is to pinpoint as precisely as possible when and to what extent the roentgenologists knew of the life-threatening risks of X-ray exposure. Second, I articulate a partial explanation for their behavior that is rooted in the social power of remotely anatomizing the living body in fin de siecle American scientific and medical culture. PMID- 21551916 TI - "In the last stages of irremediable disease": American hospitals and dying patients before World War II. AB - After a brief discussion of early- and mid-nineteenth-century hospitals, this article focuses on the years between 1880 and 1939, when those facilities underwent a major transformation and the proportion of hospital deaths steadily increased. During both periods, private hospitals refused admission to many seriously ill people and discharged others when death approached. City hospitals dumped poor patients with advanced disease on chronic care facilities and especially on almshouses. With each transfer, the quality of care sharply declined. And trips from one institution to another often inflicted additional suffering; some accelerated death. PMID- 21551917 TI - Men of dreams and men of action: neurologists, neurosurgeons, and the performance of professional identity, 1920-1950. AB - In the 1930s and 1940s, neurosurgeons and clinical neurologists engaged in a fierce exchange on the scope of their specialties. Neurosurgeon Wilder Penfield's rhetoric of therapeutic superiority had a strong impact both on the Rockefeller Foundation's support for his institute and on the self-fashioning of neurologists. Neurologists articulated their identity in spirited performances at the meetings of specialist societies, their response shifting from a combative approach to a focus on internal organization. In light of the neurosurgeons' discourse, by the 1950s a new generation of neurologists created a revisionist narrative that inaccurately portrayed the clinical neurologists of the past as having been uninterested in therapeutics. PMID- 21551919 TI - A note from the editor. PMID- 21551918 TI - Bioequivalence: the regulatory career of a pharmaceutical concept. AB - Generic drugs cannot be marketed without regulatory and clinical demonstration of "bioequivalence." The authors argue that the concept of "bioequivalence" is a joint regulatory and scientific creation, not purely a technical concept, and not purely a legal concept. It developed at the interstices of networks of pharmacologists, regulators, food and drug lawyers, and American and European policy makers interested in "generic" drugs. This article provides a situated perspective on the history of bioequivalence, which emphasizes the shaping role of the state upon scientific processes, networks of regulators and scientists, and the centrality of transnational dynamics in the formation of drug regulatory standards. PMID- 21551920 TI - Trans-disciplinary care: a new approach to improving the effectiveness of tobacco use interventions. PMID- 21551921 TI - Access to abortion services: a neglected health disparity. AB - Minority and low SES women have persistently and disproportionately higher rates of abortion than White and higher SES women, yet have limited access to these services. The response of governmental health agencies to these disparities in abortion has focused solely on decreasing the number of abortions, without attention to access to needed health services. This commentary seeks to build an understanding of how access to abortion care is currently impeded for low-income women and women of color and calls for an end to that omission. PMID- 21551922 TI - Still missing: undocumented immigrants in health care reform. AB - The health care reform signed by President Obama in March 2010 mirrors the Clinton reform proposal of 1993 in that both excluded undocumented immigrants from federal insurance coverage. In both cases substantive discussion of their possible inclusion was stifled by political timidity. This paper begins with a brief descriptive overview of undocumented immigrants in the U.S. and their health care and insurance coverage. It highlights the most common moral, economic, and public health arguments made for and against the inclusion of undocumented immigrants in the 2010 health care reform. The paper then asserts that undocumented immigrants are part of the U.S. health care community and urges health care workers to become more active participants in this policy arena. PMID- 21551923 TI - Improving the lives of patients with chronic diseases: pharmacists as a solution. AB - Positive health outcomes hinge on the effective use of medications especially among vulnerable, chronically ill, and aging populations. Yet, increasingly powerful and complex drug combinations are used to treat patients with chronic diseases and multiple health conditions. As treatment complexity increases the potential grows for non-adherence to medications due to side-effects, drug disease interactions, costs, and patient confusion about medicines. Pharmacists are the medication experts on a health care team. Working in collaboration with the patient and the prescriber, pharmacists offer solutions that foster medication adherence, improve clinical outcomes and decrease drug-related adverse events. Their accessibility, extensive knowledge of drug therapy, and trustworthiness in the minds of consumers open many opportunities for pharmacists to expand their reach in preventing drug-related problems in patients with chronic diseases. PMID- 21551924 TI - Improving medical care for detained immigrants: a call for a legislative solution. AB - Health care services provided to detained immigrants are inadequate to provide for the needs of this population. We analyzed the medical care policies and procedures for immigrants in detention, government reports on detainee medical care, and available mortality and morbidity data. We conclude that the current system of medical care for this vulnerable population needs improvement. We suggest that a federal legislative solution is one essential component to address this issue and improve medical care. Principles to be embodied in a legislative proposal necessary to address the inadequacies in the current system are presented. PMID- 21551925 TI - Bone mineral density in Hispanic women: a review of the literature with implications for promoting culturally relevant osteoporosis education. AB - Osteoporosis is a disease that primarily affects postmenopausal women of all ethnicities. Demographic projections indicate that the number of Hispanics over age 65 in the U.S. will increase from 2.9 million currently, to 17.5 million in 2050. A majority will be women. Recent research has increased understanding about biocultural correlates of osteoporosis in Hispanic women, and indicates that their risk for the disease is about equal to that of non-Hispanic White (NHW) women. Although Hispanics living in the U.S. share many biological and cultural characteristics with the general population, there are important differences in disease pre-disposition and associated morbidity that present challenges to osteoporosis prevention efforts. The purpose of this article is to provide a review of selected bone density studies that have included Hispanic women, to summarize the findings, and to discuss implications of these findings for osteoporosis prevention education for this population. PMID- 21551926 TI - Impact of closure of mental health center: emergency department utilization and length of stay among patients with severe mental illness. AB - This paper demonstrates the impact of closure of a local mental health center on patients who suffer from severe mental illness. The authors analyze electronic health record data to show that these patients not only use emergency department services more than the general medical population, but also experience an increased length of stay in the emergency department. PMID- 21551927 TI - Breastfeeding in an inner-city patient population. AB - In order to determine the proportion of infants seen in safety-net health clinics whose mothers initiated and sustained breastfeeding and to assess predictors of breastfeeding in this largely minority patient population, charts were reviewed for infants treated in the eight Philadelphia Health Centers. Breastfeeding was initiated by 42%; 7.5% breastfed for 180 or more days. Race/ethnicity, mother's age, birth weight, and prematurity were not associated with breastfeeding initiation or maintenance. There were differences in initiation rates between patients born in different hospitals, and between patients seen in different health centers. Hospital and health center differences in breastfeeding initiation and health center differences in breastfeeding maintenance may reflect practice variations and unmeasured differences in patient populations. While breastfeeding rates in this population remain far below targets, the substantial proportion of mothers who did breastfeed and large variations between facilities demonstrate that breastfeeding is possible and can be successfully promoted among economically disadvantaged mothers. PMID- 21551928 TI - Hispanic women's health care provider control expectations: the influence of fatalism and acculturation. AB - In order to understand how culture influences Hispanic women's views about their health care provider (HCP), we examined the relationship between acculturation and fatalism in the HCP control expectations of Hispanic women. (A HCP control expectation is the extent to which an individual believes that her HCP has control over her health.) We predicted that acculturation would be negatively associated with HCP control expectations, and fatalism would be positively associated with HCP control expectations. A group of 1,027 young Hispanic women (mean age 21.24 years; SD=2.46) who were University of Texas Medical Branch clinic patients completed a comprehensive survey. Structural equation modeling was employed and, as predicted, acculturation was negatively associated with HCP control expectations (p<.001) and fatalism was positively associated (p<.001). Understanding fatalism, acculturation, and their influence on HCP control expectations will help us understand this population's perceptions of their HCPs. This knowledge will assist HCPs in providing culturally competent care which will increase adherence to medical treatment and screening guidelines. PMID- 21551929 TI - Satisfaction with health care among Latinas. AB - Despite growing interest in disparities in access to health care, relatively little is known about different facets of care among Latinas, their satisfaction with the care they receive, and the predictors of satisfaction. This study examined whether various health care access and context factors, the quality of the patient-physician interaction, and medical mistrust predict satisfaction with health care among Latina immigrants in New York City. Structured interviews were conducted with 220 Latinas predominantly from the Dominican Republic and aged 40 years or over. Of the access to health care variables examined, greater waiting time predicted dissatisfaction with health care. Greater quality of the patient physician interaction predicted less dissatisfaction. The effect of the patient physician interaction on dissatisfaction was mediated, in part, by waiting time. The results illustrate the important role of specific health care factors in satisfaction with care. PMID- 21551930 TI - Barriers to health care access among refugee asylum seekers. AB - OBJECTIVE: Asylum seekers have poor access to health care. Qualitative data portraying their experience is lacking. METHODS: We conducted focus groups and comprehensive interviews with 35 asylum seekers and 15 expert providers/advocacy organization representatives. Purposive sampling was used to recruit subgroups. Interviews were recorded, coded, and analyzed. RESULTS: PARTICIPANTS: 85% male, mostly from African countries. Major barriers: a) Internal, including mental illness, fatalism, mistrust, and perceived discrimination; b) Structural, including affordability, limited services, inadequate interpretation, resettlement challenges such as shelter, food, and employment insecurity; health care for urgent care only; and poor cultural competency; c) Barriers in social assimilation, including difficulty navigating a complex system and inadequate community support. CONCLUSION: Significant inter-related barriers exist at the individual, provider, and system levels. Strategies to improve access include targeting social programs and mental health services, expanding Medicaid eligibility/enrollment, promoting community-based organizations, enforcing the use of trained medical interpreters, and improving cultural competency. PMID- 21551931 TI - A framework to identify the costs of providing language interpretation services. AB - The availability of language services for patients with limited English proficiency has become a standard of care in the United States. Finding the resources to pay for language programs is challenging for providers, payers, and policymakers. There is no federal payment policy and states are developing policies using different methodologies for determining costs and reimbursement rates. This paper establishes a conceptual framework that identifies program costs, can be used across health care entities, and can be understood by administrators, researchers, and policymakers to guide research and analysis and establish a common ground for informed strategic discussion of payment and reimbursement policy. Using case study methods, a framework was established to identify costs and included determining the perspective of the cost analysis as well as distinguishing between the financial accounting costs (direct, indirect, and overhead costs) and the economic opportunity and subsequent utilization costs. PMID- 21551932 TI - Health disparities and the social context of health disparity between the poorest and wealthiest quintiles in a developing country. AB - BACKGROUND: Previous studies that have examined social determinants of health have done so for the general population or elderly, but none have explored socio biological determinants between the poorest and wealthiest income quintiles. More specifically, health disparity and socio-biological determinants of the poorest quintile and the wealthiest quintile have never been examined for Jamaica. OBJECTIVES: The current study will bridge this gap in the literature by examining health status, illness, age at which the lower and upper classes indicate having illness and particular illnesses, and parameters that explain health status of the upper and lower quintiles in Jamaica as well as the social context of disparities between the two groups. METHODS: A sample of 2,725 respondents from the wealthiest quintile and poorest quintile was extracted from a cross-sectional survey of 6,783 respondents. Stepwise logistic regression was used to determine the contribution of significant socio-biological determinants of the health status model. Health status here corresponds to self-rated general health of respondents. RESULTS: The wealthiest quintile reported good health status 62% more than for the poorest quintile. CONCLUSION: This study is far-reaching and can be used to lessen the health disparities between and among social hierarchies in Jamaica. Health policies in Jamaica must be adopted that will address the social determinants of health. They should aim at making the health system more effective in reaching the poorest in the nation, especially those in rural areas. PMID- 21551933 TI - Working to close the gap: identifying predictors of HPV vaccine uptake among young African American women. AB - Factors associated with greater likelihood of human papillomavirus (HPV) vaccination among women who experience excess cervical cancer incidence and mortality requires further study. The purpose of this study was to assess factors associated with HPV vaccine uptake among young African American women. Three hundred sixty-three African American women aged 18-26 were recruited from Historically Black Colleges/Universities to complete a questionnaire to assess health beliefs associated with HPV vaccination. One quarter of participants reported uptake of the HPV vaccine. Women who reported uptake had significantly higher HPV knowledge, lower perceived barriers to vaccination, and were younger (all p<.05). Factors significantly associated with HPV vaccine uptake included HPV knowledge (OR=1.22), perceived severity of health outcomes (OR=0.48), perceived barriers to vaccination (OR=0.49), cues to action (OR=1.94), and age (OR=0.68). Findings can be used to inform the development of targeted HPV vaccine promotion programs for African American women to prevent continued cervical cancer disparities. PMID- 21551934 TI - Defining and targeting health care access barriers. AB - The impact of social and economic determinants of health status and the existence of racial and ethnic health care access disparities have been well-documented. This paper describes a model, the Health Care Access Barriers Model (HCAB), which provides a taxonomy and practical framework for the classification, analysis and reporting of those modifiable health care access barriers that are associated with health care disparities. The model describes three categories of modifiable health care access barriers: financial, structural, and cognitive. The three types of barriers are reciprocally reinforcing and affect health care access individually or in concert. These barriers are associated with screening, late presentation to care, and lack of treatment, which in turn result in poor health outcomes and health disparities. By targeting those barriers that are measurable and modifiable the model facilitates root-cause analysis and intervention design. PMID- 21551935 TI - Children's health insurance and access to care during and after the CHIP expansion period. AB - OBJECTIVE/METHODS: We used national data from the Medical Expenditure Panel Survey and multivariate linear spline regression models to compare trends in children's health insurance coverage and access to care by income and race/ethnicity during (1998-2002) and after (2002-2006) major expansions of state insurance programs. RESULTS: During expansions, coverage and access for children in low-income and middle-income families improved, but these gains ceased thereafter for middle-income children, most of whom remained ineligible for public insurance. Racial and ethnic differences narrowed from 1998-2002, but persisted-and in at least one case tended to widen-from 2002-2006. Non-White children in families with incomes above most states' eligibility thresholds experienced significant declines in coverage and access to care after 2002. CONCLUSIONS: Gains in children's coverage and access to care during CHIP expansions have since stagnated or even reversed for some groups. Recent legislation to expand coverage for uninsured children (the PPACA of 2010) may redress these adverse changes in trends. PMID- 21551936 TI - Birthplace, language use, and body size among Mexican American women and men: findings from the National Health and Nutrition Examination Survey (NHANES) 2001 2006. AB - INTRODUCTION: Mexican immigrant status has been associated with decreased obesity, but this pattern may be changing. We draw from 2001-2006 NHANES data on Mexican Americans to examine whether body mass index (BMI) and waist circumference vary by country of birth and among the U.S.-born by language. RESULTS: Among women, U.S.-born Spanish speakers had the highest mean BMI, followed by immigrant women, while U.S.-born English speakers had the lowest mean BMI. Immigrant men had a lower mean BMI than U.S.-born men. These patterns were similar for waist circumference and persisted after adjusting for socioeconomic status (SES) and other covariates. CONCLUSION: Immigrant women do not appear to be protected against a large body size, compared with immigrant men. Among the U.S.-born, women who retain Spanish are at higher risk for larger body size than exclusive English speakers. Initiatives targeting obesity should address differentials in body size patterns among immigrant and U.S.-born Mexican American men and women. PMID- 21551937 TI - Race/ethnicity-related and payer-related disparities in the timeliness of emergency care in U.S. emergency departments. AB - Our study objectives were to examine race/ethnicity-related and insurance-related differences in the timeliness of emergency care for a nationally representative sample of adults and to explore the role of uncertainty and location of care in explaining overall differences. We estimated a logistic regression model with hospital fixed effects to derive estimates of within-hospital group differences in the likelihood of waiting for more than 60 minutes to see a physician for several presenting conditions. We further estimated a model without hospital fixed effects to derive overall group differences. We observed race/ethnicity related and payer-related differences in the timeliness of a medical screening exam for abdominal pain and chest pain visits but not for extremity laceration visits. Overall (within- and between-hospitals) differences in waiting time were due to patients receiving different care from the same hospital and from patients receiving care from different hospitals. PMID- 21551938 TI - Racial/ethnic differences in access to substance abuse treatment. AB - A secondary dataset, Collaborative Psychiatric Epidemiology Surveys (CPES), 2001 2003, was employed to examine racial/ethnic differences in access to specialty and non-specialty substance abuse treatment (compared with no access to treatment). The study found that non-Hispanic White Americans were (1) likelier than members of all racial/ethnic minority groups (other than Hispanics) to address substance abuse by accessing care through specialty addiction-treatment facilities, and were (2) also less likely to access substance abuse care through non-specialty facilities. Because non-specialty facilities may have staffs whose professional training does not target treating chronic, bio-psycho-social illness such as substance abuse, our results imply that treatment facilities deemed non specialty may need to enhance staff training, in order to ensure individuals are properly screened for substance use conditions and are referred for or provided with effective counseling and medications as appropriate. PMID- 21551939 TI - Medicare's policy to limit payment for hospital-acquired conditions: the impact on safety net providers. AB - In 2008, Medicare implemented a policy limiting reimbursement to hospitals for treating avoidable hospital-acquired conditions (HACs). Although the policy will expand nationally to Medicaid programs in 2011, little is known about the impact on safety-net hospitals. Using data from the 2006 American Hospital Association Annual Survey and MEDPAR, we compared the incidence of cases that met the HACs criteria at safety-net and non-safety-net hospitals. We found that safety-net hospitals had an average of 65.5 HACs per 1,000 Medicare discharges compared with 57.6 at non-safety-net hospitals. Hospitals in the lowest quintile for financial margins had higher rates of HACs on average than other hospitals. Safety-net hospitals and hospitals with the lowest financial margins may be more likely than others to be affected by policies that reduce payment for HACs. PMID- 21551940 TI - Dental caries in underprivileged children of Los Angeles. AB - OBJECTIVES: The purpose of this study is to investigate the disease of dental caries among a population of poor, migrant, minority children in Los Angeles County. METHODS: The study team developed an instrument to be completed by parents about their children's determinants of oral health, and adapted the Association of State and Territorial Dental Directors (ASTDD) protocol for conducting clinical examinations. The target groups were 2-5, 6-8 and 14-16 year old children. Subjects were selected from public schools and early childhood programs. RESULTS: The study recruited 2,313 children and found that 73% of all children had untreated caries (29% of them had white spot lesions only), 53% had fillings or crowns, and 81% needed dental care. CONCLUSIONS: This is the most comprehensive study of oral health among disadvantaged children of Los Angeles County. The study documented an epidemic of dental caries in the County, the oral health profiles of disadvantaged children, and prepared for the design of appropriate intervention programs. PMID- 21551941 TI - Socioeconomic inequalities in access to health care: examining the case of Burkina Faso. AB - The past decade has recorded remarkable interest in socioeconomic inequalities in health care. A multivariate analysis of the World Health Survey data for Burkina Faso was conducted using STATA. This included questions on household economic factors, perceived need, and access to health care. Poverty was defined using Principal Components Analysis. There was no significant difference in perceived need on the basis of poverty or gender. The less poor accessed health care more than the poor, but this difference was significant only among males. Respondents who lived in urban areas accessed health care more than those in rural areas, but this difference was significant only among females. We argue that health care financing arrangements affect self-reported need and access to health care. Even when they perceive need, the poor do not access care, probably because of cost, exacerbated by non-availability of readily accessible health care facilities. PMID- 21551942 TI - Explaining public support (or lack thereof) for extending health coverage to undocumented immigrants. AB - While the recent passage of health care reform is estimated to provide millions of currently uninsured Americans with access to health coverage, undocumented immigrants are excluded from federal mandates. Since federal reform excludes undocumented immigrants, state governments will largely decide the fate of this vulnerable population. This article investigates public support for including undocumented immigrants in state health care reform efforts in New Mexico. Understanding the public's perception of extending health coverage to this population is important because public opinion influences health policy formation at the state and federal levels. Our results suggest that there is little support for including undocumented immigrants (or recent migrants from other parts of the United States) in state health care reform, particularly when compared with other segments of the New Mexican population, such as the homeless or unemployed. Our discussion highlights the economic and public health consequences of excluding undocumented immigrants from coverage options. PMID- 21551943 TI - Left ventricular hypertrophy is associated with inflammation in sodium loaded subtotal nephrectomized rats. AB - The pathological influences of inflammation on left ventricular hypertrophy (LVH) were studied in subtotal nephrectomized (SNx) rats after 0.3% NaCl loading for 5 weeks. We found that mild hypertension, increased plasma levels of creatinine, inorganic phosphate, asymmetric dimethylarginine (ADMA), and parathyroid hormone (PTH) were observed in the present SNx rats without LVH. In the present study, the NaCl-loaded SNx (SNx + NaCl) rats were characterized by significant LVH and hypertension with aggravated values of all the parameters. We further confirmed that glomerular sclerosis, tubulointerstitial fibrosis, and inflammatory cell infiltration into the tubulointerstitial area, observed in the SNx rats, were more severely caused in the SNx + NaCl rats. In addition, plasma interleukin-6 (IL-6) levels in the SNx + NaCl rats were significantly increased compared to those in the SNx rats. These findings indicated that NaCl-loaded SNx rats developed LVH and hypertension, which were accompanied with increased plasma levels of PTH, creatinine, inorganic phosphorus, ADMA, and IL-6. Thus, these results suggest that inflammation as well as endothelial dysfunction would be correlated with LVH as non-traditional risk factors at the early stage in the present renal failure model. PMID- 21551944 TI - Proteomic analysis of rat brains in a model of neuropathic pain following exposure to electroconvulsive stimulation. AB - Some reports have shown that electroconvulsive shock therapy is effective for treating refractory neuropathic pain. However, its mechanism of action remains unknown. This study analyzes changes in protein expression in the brainstems of neuropathic pain model rats with or without electroconvulsive stimulation (ECS). A neuropathic pain model rat is produced by chronic constrictive injury (CCI) of the sciatic nerve. An ECS was administered to rodents once daily for 6 days after the CCI operation. After ECS, the latency to withdrawal from thermal stimulation was significantly increased. The expression of several proteins was changed after CCI. Ten proteins that increased after CCI then had decreased expression levels (close to control) after ECS, and 8 proteins that decreased after CCI then had increased expression levels (close to control) after ECS. In conclusion, ECS improved thermal hypersensitivity in a rat CCI model. Proteomic analysis showed that altered expression levels of proteins in the brainstem of CCI model rats returned to close to control levels after ECS, including many proteins associated with pain. This trend suggests an association of ECS with improved hypersensitivity, and these results may help elucidate the mechanism of this effect. PMID- 21551945 TI - Increased alpha-taxilin protein expression is associated with the metastatic and invasive potential of renal cell cancer. AB - Intracellular vesicle trafficking is the principal transportation system in eukaryotic cells, and is considered to be involved in a variety of processes related to cell proliferation. A protein named alpha-taxilin has been identified as a binding partner of the syntaxin family, which coordinates intracellular vesicle trafficking. To clarify the role of alpha-taxilin in renal cell carcinoma (RCC), we investigated alpha-taxilin protein expression in clear cell RCC tissues. We analyzed alphataxilin protein in matched sets of tumor and non-tumor tissues from the surgical specimens of 52 Japanese RCC patients by Western blotting. We also studied the relation between alpha-taxilin protein expression in tumor tissues and various clinicopathological features. The alpha-taxilin protein level was higher in tumor tissues than in non-tumor tissues (P < 0.05). Increased expression of alpha-taxilin protein in primary tumors was related to local invasion (P < 0.001), pathological vessel invasion (P < 0.001), and metastasis (P < 0.0001). Kaplan-Meier plots of survival for patients with low versus high alpha-taxilin expression revealed that high expression in tumor tissues was associated with shorter overall survival in all patients (P < 0.05) and with shorter disease-free survival in patients without metastasis (P < 0.01). These findings suggest that alpha-taxilin influences the metastatic and invasive potential of RCC. PMID- 21551946 TI - Sexual dimorphism in LEC rat liver: suppression of carbonic anhydrase III by copper accumulation during hepatocarcinogenesis. AB - We examined age-related changes in the protein expression of carbonic anhydrase III (CAIII) in livers of Long-Evans with a cinnamon-like color (LEC) rats using an agouti color (LEA) rats as controls. The levels of the protein of CAIII in the liver of LEC male rats increased before 20 weeks of age, at the stage of acute hepatitis, and were decreased at 54 weeks of age, while those of CAIII in the liver of LEA male rats were highly expressed at all ages. In the normal LEA rats, CAIII showed sexual dimorphism. The level of CAIII in LEA male rat liver relative to female was four times higher. On the other hand, young LEC rat (at 4-12 weeks) showed a higher protein level of CAIII than LEA rats, and then decreased during development of hepatitis. CAIII mRNA also decreased in the LEC rat liver during hepatocarcinogenesis. The level of CAIII in the tumor region was lower than that in the tumor-free region. Immunohistochemical analysis showed that glutathione S transferase P (GST-P) was positive and CAIII was negative in the precancerous region. The expression of CAIII was suppressed in cancerous lesions in hepatoma bearing LEC rat liver compared to uninvolved surrounding tissues. These results indicated that suppression of CAIII accompanied hepatocarcinogenesis and it is a secondary consequence of the high copper levels in the liver. PMID- 21551947 TI - Effects of a catechin-free fraction derived from green tea on gene expression of gluconeogenic enzymes in rat hepatoma H4IIE cells and in the mouse liver. AB - Many biological activities of green tea have been attributed to a major constituent, (-)-epigallocatechin gallate (EGCG). We previously reported that EGCG and a catechin-rich green tea beverage modulated the gene expression of gluconeogenic enzymes, glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), in the mouse liver. However, it remains to be examined whether or not a constituent other than EGCG contributes to the change in gene expression of these enzymes. In this study, we separated the hot water infusion of green tea leaves (GT) into an ethanol-soluble fraction (GT-E) and an EGCG-free water-soluble fraction (GT-W), and examined their effects using rat hepatoma H4IIE cells. The inclusion of GT, GT-E, and GT-W in the culture medium reduced the gene expression of G6Pase and PEPCK. GT-W caused a decrease in expression of the transcription factor HNF4alpha. Reduced levels of PEPCK and HNF4alpha proteins were demonstrated in the cells treated with GT-W. GT-W showed an activity similar to insulin, but different from EGCG. Administration of GT-W to mice for 4 weeks reduced the hepatic expression of G6Pase, PEPCK, and HNF4alpha. These results suggest that green tea contains some component(s) with insulin-like activity distinguishable from EGCG and that drinking green tea may help to prevent diabetes. PMID- 21551948 TI - Histopathological phenotypes of early gastric cancer and its background mucosa. AB - Recent advances in endoscopic submucosal dissection (ESD) techniques contribute to endoscopic treatment of early gastric cancer (EGC). Recognition of chronic atrophic gastritis as the background is important for high-quality detection and diagnosis of EGC. But, relationships between EGC and atrophy of the background gastric mucosa caused by Helicobacter pylori are not well understood. The present study demonstrated histopathological phenotypes of EGC, as well as chronic atrophic gastritis as background mucosa of EGC. We evaluated mucosal heights, number of glands, and degree of intestinal metaplasia (IM) of the background gastric mucosa, using 81 cases of EGC resected by ESD. Gastric phenotype cancer cases showed IM of the background gastric mucosa less frequently, compared with intestinal phenotype cancer cases (score of IM, 1.15 vs. 1.65, P = 0.012). The average mucosal heights around EGC were lower in moderately to poorly differentiated adenocarcinoma cases than well differentiated adenocarcinoma cases (442.6 um vs. 500.2 um, P = 0.011). The mucosal atrophy indicated by average heights of background mucosa was low in the gastric phenotype cancer cases, compared with the intestinal phenotype cancercases (452.8 um vs. 505.6 um, P = 0.018). In the fundic gland area, the mucosal heights were low in the gastric phenotype cancer cases, compared with the intestinal phenotype cancer cases (413.2 um vs. 495.5 um, P = 0.015). Our results using EGC specimens indicated that gastric phenotype cancer and moderately to poorly differentiated adenocarcinoma had atrophic background mucosa with lower mucosal heights and less IM. The atrophic gastric mucosa with less IM is thought to play an important role in gastric carcinogenesis, especially tumoriogenesis of gastricphenotype cancer. PMID- 21551949 TI - Plasma miR-124 as a biomarker for cerebral infarction. AB - MicroRNAs (miRNAs) are endogenous small RNAs that play an important role in various physiological processes by downregulating target genes. Recently, plasma miRNAs have been investigated as biomarkers for various diseases. In this study, miRNA array analysis in various tissues showed that miR-124 is almost exclusively expressed in the central nervous system and neuronal cells, suggesting that it might be useful as a potential biomarker for neurological diseases. We examined whether plasma concentrations of brain-specific miRNA can serve as a biomarker for cerebral infarction, where the cerebral infarction was modeled by middle cerebral artery occlusion (MCAO) in the rat. Plasma concentrations of miR-124 were significantly elevated at 6 h, and remained elevated at 48 h after MCAO introduction. Thus, plasma concentration of miR-124 provides a promising candidate biomarker for early detection of cerebral infarction. PMID- 21551950 TI - Expression of human factors CD81, claudin-1, scavenger receptor, and occludin in mouse hepatocytes does not confer susceptibility to HCV entry. AB - No suitable mouse model is available for studying chronic liver disease caused by hepatitis C virus (HCV). CD81, claudin-1, scavenger receptor class B type I, and occludin were recently reported to be the important factors in HCV entry into hepatocytes. We made transgenic mice (Alb-CCSO) expressing the four human proteins and examined whether HCV from a patient serum or HCV pseudoparticles (HCVpp) were capable of infecting them. HCV was not detected in the mouse serum after injecting the mice with HCV from a patient serum. We also found no indications of HCVpp entry into primary hepatocytes from Alb-CCSO mice. In addition, HCV-infectible Hep3B cells were fused with HCV-resistant primary mouse hepatocytes and the fused cells showed 35-fold lower infectivity compared to wild type Hep3B cells, indicating that primary mouse hepatocytes have the inhibitory factor(s) in HCVpp entry. Our results suggest that the expression of the human factors does not confer susceptibility to HCV entry into the liver. PMID- 21551951 TI - (-)-Bornyl acetate induces autonomic relaxation and reduces arousal level after visual display terminal work without any influences of task performance in low dose condition. AB - (-)-Bornyl acetate is the main volatile constituent in numerous conifer oils and has a camphoraceous, pine-needle-like odor. It is frequently used as the conifer needle composition in soap, bath products, room sprays, and pharmaceutical products. However, the psychophysiological effects of (-)-bornyl acetate remained unclear. We investigated the effects of breathing air mixed with (-)-bornyl acetate at different doses (low-dose and high-dose conditions) on the individuals during and after VDT (visual display terminal) work using a visual discrimination task. The amounts of (-)-bornyl acetate through our odorant delivery system for 40 min were 279.4 ug in the low-dose and 716.3 ug in the high-dose (-)-bornyl acetate condition. (-)-Bornyl acetate induced changes of autonomic nervous system for relaxation and reduced arousal level after VDT work without any influences of task performance in low-dose condition, but not in high-dose condition. PMID- 21551952 TI - One-step simple assay to determine antigen-specific cytotoxic activities by single-color flow cytometry. AB - Assays for cytotoxicity of CTLs in vivo using a fluorescent-based dye, 5- (and 6 ) carboxyfluorescein diacetate succinimydyl ester (CFSE), have been established and widely used. On the basis of this experience, we applied it to in vitro assay system and established a simpe, highly sensitive flow cytometric assay for CTL activity. In our assay, specific activities of CTLs could be detected by a reduction in sensitive target cell numbers on single-color histogram plot analysis. By using this assay, we could determine the changes in cytotoxic activity by single amino acid substitution within an epitope peptide. Adherent cells were also used as target cells in this assay by treatment with excess EDTA and trypsin reagents after incubation with effector CTLs. Furthermore, when fluorescent calibration beads were used as a control, we could determine the cytotoxicity of CTLs against tumor cells. The results obtained from our assay were almost consistent with those from the conventional ( 51)Cr-release assay.Because our assay uses only a stable non-radioactive reagent, CFSE, this assay is safe, inexpensive and extremely easy. These results indicated that this new assay (FACS-CTL assay) would be sufficiently acceptable alternative to classical (51)Cr-release assay. PMID- 21551953 TI - Pancreatic beta-cells are generated by neogenesis from non-beta-cells after birth. AB - The mass of pancreatic beta-cells is maintained throughout lifetime to control blood glucose levels. Although the major mechanism of the maintenance of beta cell mass after birth is thought to be selfreplication of pre-existing beta cells, it is possible that pancreatic beta-cells are also generated from non-beta cells. Here, we address this issue by using the inducible Cre/loxP system to trace beta-cells. We generated Ins2-CreERT2/R26R-YFP double knock-in mice, in which pancreatic beta-cells can be labeled specifically and permanently upon injection of the synthetic estrogen analog tamoxifien, and then traced the beta cells by pulse and chase experiment in several different conditions. When beta cells were labeled in adults under physiological and untreated conditions, the frequency of the labeling (labeling index) was not altered significantly throughout the 12-month experimental period. In addition, the labeling index was not changed after ablation of beta-cells by streptozotocin treatment. However, when tamoxifen was injected to pregnant mothers just before they gave birth, the labeling index in the neonates was decreased significantly around weaning, suggesting that beta-cells are generated from non-beta-cells. These results indicate that various mechanisms are involved in the maintenance of beta-cells after birth, and that the present system using knock-in mice is useful for investigation of beta-cell fate. PMID- 21551954 TI - The "Senobi" breathing exercise ameliorates depression in obese women through up regulation of sympathetic nerve activity and hormone secretion. AB - Obese individuals have an increased risk of developing depression. This study aimed to determine whether the "Senobi" breathing exercise (SBE), a stretching breathing exercise that we have established, could relieve depression, especially in obese women. Forty premenopausal women, aged 40 to 49 years, participated in the present study. Twenty were healthy, and the other 20 were obese (body mass index > 25 and body fat > 30%) and in a depressive state (OWD). Sympathetic nerve activity determined by analyzing heart rate variability, and the hormone levels in the urine were investigated before and 30 min after one minute of SBE. The relative proportion of sympathetic nerve activity among healthy women in the daytime was 79.2 +/- 2.3%, whereas that in OWD group was 30.4 +/- 1.9%. After one minute of SBE, significant up-regulation of sympathetic nerve activity and increased concentrations of catecholamines, estradiol, and growth hormone (all P values < 0.001) were observed in OWD group. After 30 days of SBE, the sympathetic nerve activity and hormone levels had recovered in OWD group, and the depressive state, as evaluated by the Hamilton Depression Scale, had ameliorated. The "Senobi" breathing exercise was found to be effective for amelioration of depression in obese women possibly through up-regulation of sympathetic nerve activity and hormone secretion. PMID- 21551955 TI - Intraluminal administration of zingerol, a non-pungent analogue of zingerone, inhibits colonic motility in rats. AB - Zingerone, a pungent component of ginger, may exert beneficial therapeutic effects on hypermotility-induced diarrhea because it has the ability to inhibit contractions of colonic smooth muscles. However, the pungency is undesirable for possible therapeutic use. The purpose of this study was to examine effects of zingerol, a non-pungent analogue of zingerone, in rats. Colonic motility in vivo was evaluated by measuring intraluminal pressure changes and expelled fluid volume from the colon in anesthetized rats. Mechanical contractile activities of isolated colonic segments were also recorded. Intracolonic administration of zingerol attenuated colonic motility in vivo without affecting blood pressure and heart rate in a manner similar to that of zingerone. Zingerol also inhibited spontaneous contractile movements in isolated colonic segments, suggesting that zingerol directly acts on the colon. Zingerol had no effect on jejunal motility, although zingerone showed an inhibitory effect to the jejunum. These findings suggest that zingerol can inhibit colonic motility without adverse effects on small intestinal motility and the cardiovascular system. The non-pungent property of zingerol will be useful as an oral or suppository medicine for treating diarrhea and other gastrointestinal disorders. PMID- 21551956 TI - Congener-specific polychlorinated biphenyls and the prevalence of diabetes in the Saku Control Obesity Program (SCOP). AB - The prevalence of diabetes is increasing globally. In addition to established risk factors for diabetes, such as diet, inactivity, overweight and obesity, the involvement of persistent organic pollutants, including dioxins and polychlorinated biphenyls (PCBs), has also been suggested to be a possible, but controversial, cause of this epidemic. The present study investigated the association between blood PCB congener levels and the prevalence of diabetes among middle-aged, overweight and obese Japanese participants in the Saku Control Obesity Program. One hundred seventeen participants had their congener-specific PCB levels measured in addition to undergoing routine blood analyses at the time of a medical checkup. Prevalent diabetes was defined according to two methods: definite diabetes was defined as people with an HbA1c level >= 6.9% or who were taking medication for diabetes, and all diabetes was defined as people with an HbA1c level >= 6.5%, a fasting plasma glucose level >= 126 mg/dL, or a history of doctor-diagnosed diabetes. A multiple logistic regression analysis was performed to analyze the association between the PCB levels and the prevalence of diabetes, with adjustments for sex, age, body mass index and total lipids. As a result, PCB 146 and 180 were positively associated and PCB 163/164 and 170 were negatively associated with the prevalence of definite diabetes. The significance of the association of PCB 180 and 163/164 with the prevalence of diabetes persisted regardless of the definition of diabetes or adjustments for total lipids, suggesting the possibility that these parameters may modify the risk of diabetes. PMID- 21551957 TI - Reference limits for serum thyrotropin in a Japanese population. AB - The aim of the present study was to establish new reference intervals for serum thyrotropin (TSH) levels in Japanese subjects without antithyroid antibodies. We reviewed the serum TSH level of all patients 20 years of age and over who attended the outpatient clinic of our hospital between January 1, 2003, and September 20, 2010. The thyroid gland of every patient was examined by ultrasonography, and subjects found to have a normal thyroid were chosen. The following subjects were excluded: subjects with past history of thyroid diseases; subjects whose serum was positive for antithyroid antibodies; pregnant women; patients taking medication that might affect their free thyroxine (fT(4)) level or TSH levels. Ultimately, 1388 subjects were included in the reference population. The serum TSH levels shifted to higher ranges as the age of the groups increased. The calculated reference range was 0.39-4.29 mIU/L in the 20-29 year-old group, 0.34-3.90 mIU/L in the 30-39-year-old group, 0.56-5.02 mIU/L in the 40-49-year-old group, 0.51-5.30 mIU/L in the 50-59-year-old group, 0.60-4.85 mIU/L in the 60-69-year-old group, 0.62-6.15 mIU/L in the over 70-year-old group. The results of this study showed that the upper limit of the normal range of serum TSH levels increased with age in a Japanese population. Since the number of elderly reference subjects was relatively small, further study is needed. Setting the age- and race-specific reference limits for serum TSH levels is important in order to prevent significant misclassifications of patients with abnormal TSH levels. PMID- 21551958 TI - Combined Cerenkov luminescence and nuclear imaging of radioiodine in the thyroid gland and thyroid cancer cells expressing sodium iodide symporter: initial feasibility study. AB - Radioiodine (RI) such as (131)I or (124)I, can generate luminescent emission and be detected with an optical imaging (OI) device. To evaluate the possibility of a novel Cerenkov luminescence imaging (CLI) for application in thyroid research, we performed feasibility studies of CLI by RI in the thyroid gland and human anaplastic thyroid carcinoma cells expressing sodium iodide symporter gene (ARO NIS). For in vitro study, FRTL-5 and ARO-NIS were incubated with RI, and the luminometric and CLI intensity was measured with luminometer and OI device. Luminescence intensity was compared with the radioactivity measured with gamma counter. In vivo CLI of the thyroid gland was performed in mice after intravenous injection of RI with and without thyroid blocking. Mice were implanted with ARO NIS subcutaneously, and CLI was performed with injection of (124)I. Small animal PET or gamma-camera imaging was also performed. CLI intensities of thyroid gland and ARO-NIS were quantified, and compared with the radioactivities measured from nuclear images (NI). Luminometric assay and OI confirmed RI uptake in the cells in a dose-dependent manner, and luminescence intensity was well correlated with radioactivity of the cells. CLI clearly demonstrated RI uptake in thyroid gland and xenografted ARO-NIS cells in mice, which was further confirmed by NI. A strong positive correlation was observed between CLI intensity and radioactivity assessed by NI. We successfully demonstrated dual molecular imaging of CLI and NI using RI both in vitro and in vivo. CLI can provide a new OI strategy in preclinical thyroid studies. PMID- 21551959 TI - A case of fulminant type 1 diabetes mellitus accompanied by myocarditis. AB - This report presents the case of a 47-year-old female patient with fulminant type 1 diabetes mellitus and myocarditis. Following a high fever, nausea, vomiting and diarrhea, diabetic ketoacidosis occurred and she was transferred to the hospital. The plasma glucose level was 63.6 mmol/L and HbA1c was 7.0%. C-peptide was undetectable in her plasma. Blood gas analysis showed a pH of 6.99. Antibodies to glutamic acid decarboxylase nor insulinoma associated antigen-2 were not detected. She was diagnosed to have fulminant type 1 diabetes mellitus. Her electrocardiogram showed diffuse ST-segment elevations on the second day of admission, along with a positive troponin test. However coronary angiography revealed neither occlusion nor stenosis of the cardiac arteries. An endomyocardial biopsy revealed hypertrophic cardiomyocytes with a disarrangement of myofibers and the focal accumulation of mononuclear cells in the stroma, thus suggesting myocarditis or mild myocarditic change. Viruses are an important cause of myocarditis and the preceding flu-like symptoms indicate the association of viral infection with myocarditis in this case. The mechanisms by which fulminant type 1 diabetes mellitus occurs is still uncertain, but the presence of islet injury accompanied by myocardial inflammation in the current case suggested that a viral infection accounted for the onset of this type of diabetes. PMID- 21551960 TI - Adipokines and aging. AB - Dysregulation of adipose tissue-derived bioactive molecules, termed adipokines, is recognized as common ground for insulin resistance and metabolic syndrome associated with obesity. However, adipokine dysregulation is paradoxically associated with lipodystrophy and lipoatrophy with aging. In familial partial lipodystrophic syndromes and Hutchinson-Gilford progeria syndrome, both of which are caused by mutations in the LMNA gene, loss of adipose tissue is associated with adipokine dysregulation, insulin resistance, and atherosclerosis, suggesting a critical role of adipose tissue function in controlling whole body energy metabolism, age-related pathologies, and longevity. Centenarians, a model of healthy aging and longevity, are reported to exhibit preserved insulin sensitivity as well as favorable adipokine profiles, particularly high levels of circulating adiponectin. Furthermore, adipose tissue dysfunction indicated by dysregulation of leptin, tumor necrosis factor-alpha, and adiponectin is associated with poor prognosis in centenarians. In contrast to results obtained for obesity, adipokine dysregulation in centenarians is associated with very low leptin levels, suggesting that age-related lipoatrophy is the major factor for adipose tissue dysfunction at an advanced age. These observations suggest that adipose tissue excess as well as its aging is implicated in the regulation of adipokines, insulin sensitivity, and lifespan in humans. PMID- 21551961 TI - Osteo-progenitors in vascular calcification: a circulating cell theory. AB - Vascular calcification has been associated with the incidence of cardiovascular events and thus there has been interest in better understanding its pathogenesis. Early theories considered vascular calcification to be a passive process which occurred as a non-specific response to tissue injury or necrosis. More recent theories propose vascular calcification results from loss of molecular inhibitors or via an active cell mediated process. The origin of the cells responsible for vascular calcification is controversial and may vary in different sites and patients. Calcification has been reported as result of apoptosis or death of vascular smooth muscle cells for example. One novel source of cells controlling vascular calcification is from the bone marrow. A circulating immature bone marrow derived population has been identified and a small subset of this bone marrow population has been reported to possess bone forming properties in vitro and hence termed osteo-progenitors. This article reviews evidence supporting the contribution of these naive bone marrow derived circulating osteo-progenitor cells in vascular calcification. PMID- 21551962 TI - Epitope-grafted and antigenized antibodies can be used for versatile vaccination strategies to induce epitope-specific immune responses. PMID- 21551963 TI - Clinical applications of basic research that shows reducing skin tension could prevent and treat abnormal scarring: the importance of fascial/subcutaneous tensile reduction sutures and flap surgery for keloid and hypertrophic scar reconstruction. AB - We use evidence-based algorithms to treat abnormal scarring, including keloids and hypertrophic scars (HSs). This involves a multimodal approach that employs traditional methods such as surgical removal, postoperative radiotherapy, corticosteroid injection, laser, and silicone gel sheets. As a result, the rate of abnormal scarring recurrence has decreased dramatically over the past 10 years. However, several problems remain to be solved. First, despite the optimization of a radiotherapy protocol, over 10% of cases who are treated with surgery and postoperative radiotherapy still recur in our facility. Second, the treatment options for cases with huge keloids are very limited. To address these problems, we performed basic research on the mechanisms that drive the formation of keloids and HSs. Extrapolation of these research observations to the clinic has led to the development of two treatment strategies that have reduced the rate of abnormal scar recurrence further and provided a means to remove large scars. Our finite element analysis of the mechanical force distribution around keloids revealed high skin tension at the keloid edges and lower tension in the keloid center. Moreover, when a sophisticated servo-controlled device was used to stretch wounded murine dorsal skin, it was observed that the stretched samples exhibited upregulated epidermal proliferation and angiogenesis, which are also observed in keloids and HSs. Real-time RT-PCR also revealed that growth factors and neuropeptides are more strongly expressed in cyclically stretched skin than in statically stretched skin. These findings support the well-established notion that mechanical forces on the skin strongly influence the cellular behavior that leads to scarring. These observations led us to focus on the importance of reducing skin tension when keloids/HSs are surgically removed to prevent their recurrence. Clinical trials revealed that subcutaneous/fascial tensile reduction sutures, which apply minimal tension on the dermis, are more effective in reducing recurrence than the three-layered sutures used by plastic surgeons. Moreover, we have found that by using skin flaps (e.g., perforator flaps and propeller flaps), which release tension on the wound, in combination with postoperative radiotherapy, huge keloids can be successfully treated. PMID- 21551964 TI - Utility of the orbitocranial approach for clipping of anterior communicating artery aneurysms: significance of dissection of the interhemispheric fissure and the sylvian fissure. AB - OBJECTIVE: To investigate the importance of sufficient dissection of the interhemispheric and sylvian fissures, an orbitocranial approach was used for clipping of ruptured anterior communicating artery aneurysms. PATIENTS AND METHODS: From January 1998 through March 2009, 41 patients underwent surgery for subarachnoid hemorrhage caused by rupture of an anterior communicating artery aneurysm. Their mean age was 58.4 years, with a range of 37 to 84 years. The preoperative World Federation of Neurosurgical Societies grade was I to III in 32 patients and IV to V in 9 patients. The direction of the aneurysm was upward in 23 patients, forward in 14 patients, and backward in 4 patients. Seven patients had a large aneurysm. RESULTS: All patients underwent surgery during the acute stage following the subarachnoid hemorrhage (day 0-2). A right orbitocranial approach was used for most patients, but a left orbitocranial approach was used for 9 patients because of the presence of a complicated aneurysm and the positional relationship of the left-right A2 segment. In 12 patients, external decompression was performed. The outcome, using the Glasgow Outcome Scale, was good recovery in 24 patients, moderately disabled in 8 patients, and severely disabled in 4 patients, and 5 patients died. Temporary eye movement disorders developed after surgery in 5 patients but resolved in all patients within 2 months. No patients had olfactory disturbance. DISCUSSION: Using the orbitocranial approach and sufficient dissection of the interhemispheric and sylvian fissures, we could secure a broad field of vision and surgical field, which contributed to a safe operation. The only postoperative complication caused by the surgical approach was temporary eye movement disorder. Thus, for some patients with aneurysms of the anterior communicating artery, the orbitocranial approach contributes to improved outcomes. PMID- 21551965 TI - Determining best potential predictor during high-dose progestin therapy for early staged and well-differentiated endometrial adenocarcinoma using semiquantitative analysis based on image processing and immunohistochemistry. AB - This study aimed to examine whether morphological changes during the early stage of treatment or indices of proliferation, apoptosis, or hormone receptors are reliable predictors of the hormonal response to uterus-preserving high-dose progestin therapy in patients with endometrial adenocarcinoma. Seven patients (5 good responders and 2 poor responders) with presumptive stage IA endometrial adenocarcinoma treated with 600 mg/day of medroxyprogesterone acetate were reviewed. Epithelial cell size and stromal area observable on microscopic examination of hematoxylin and eosin-stained sections, and immunostaining labeling indices for Ki-67 nuclear antigen, single-stranded DNA, estrogen receptor, and progesterone receptor were semiquantitatively analyzed before treatment and after 4, 8, 12, and 16 weeks of treatment using computer imaging programs. The mean ratio of cell size after 4 weeks of treatment to that before treatment in good responders was 3.83, whereas the ratios in the 2 poor responders were 1.08 and 0.98. The mean Ki-67 nuclear antigen labeling index before treatment was 37.2% for the 5 good responders but was 51.0% in the 2 poor responders. The indices of the poor responders remained high (20%-77%), even after 16 weeks of treatment; in contrast, the indices of the good responders were low (0.4%-7.3%) throughout the treatment period. No definitive differences in labeling indices for single-stranded DNA, estrogen receptor, or progesterone receptor were observed between good and poor responders or at different stages of treatment (p>0.05). In conclusion, a higher epithelial cell size ratio after 4 weeks of treatment in conjunction with lower Ki-67 nuclear antigen labeling indices could be a potential predictor of hormonal response. PMID- 21551966 TI - Evaluation of sentinel lymph node biopsy in clinically node-negative breast cancer. AB - BACKGROUND: In patients with clinically node-negative breast cancer, diagnosed with palpation and several types of imaging examination, sentinel lymph nodes accurately predict the status of the other axillary nodes, which determine the nature of subsequent adjuvant treatment. In addition, compared with axillary lymph node dissection, sentinel-node biopsy results in less postoperative morbidity, including pain, numbness, swelling, and reduced mobility in the ipsilateral arm. METHODS: We analyzed the validity of the sentinel node biopsy procedure using dual-agent injection of blue dye and radioactive colloid performed in our hospital from May 2006 through March 2010. A total of 258 breasts of 253 patients were studied. Simultaneous axillary lymph node dissection was performed only if rapid intraoperative diagnosis identified metastasis in sentinel lymph nodes. The identification rate, accuracy, provisional false negative rate, which was calculated with data from all 65 patients whose sentinel lymph nodes had metastasis, and axillary recurrence rate of sentinel node biopsy were calculated. RESULTS: The sentinel node identification rate was 99.2%, and the accuracy of sentinel lymph node status was 98.0%. The provisional false negative rate was 7.7%. During an observation period averaging 24 months, axillary recurrence was observed in only 1 of 256 cases (0.4%), and there were no cases of parasternal recurrence. In patients who underwent sentinel-node biopsy without axillary lymph node dissection, there was no obvious morbidity. CONCLUSION: Our sentinel-node biopsy procedure yielded satisfactory results, which were not inferior to the results of previous clinical trials. Thus, we conclude our sentinel-node biopsy procedure is feasible. If the efficacy and safety of sentinel-node biopsy are confirmed in several large-scale randomized controlled trials in Europe and the United States, sentinel-node biopsy will become a standard surgical technique in the management of clinically node negative breast cancer. PMID- 21551967 TI - A 6-year-old girl with hemoglobin H disease. AB - Hemoglobin H (HbH) disease is the severe nonfatal form of alpha-thalassemia syndrome. It is usually caused by molecular defects of 3 of 4 alpha-globin genes (--/-alpha) which cause alpha-globin expression to be decreased. HbH disease is rare in Japan. Here, we report on a 6-year-old girl with HbH disease who had profound hypochromatic and microcytic anemia. Analysis of the alpha-globin genes of the patient's family showed that the father, who was Japanese, had an abnormal gene with a 3.7-kb deletion (-alpha(3.7)/alphaalpha), and the mother, who was Filipino, had a deletion removing both alpha-globin genes of the Filipino type (- (FIL)/alphaalpha). Neither parent had anemia. The patient was found to have HbH disease with a heterozygous genetic abnormality (--(FIL)/-alpha(3.7)). Recently, the number of marriages of Japanese to natives of areas where thalassemia is epidemic has increased. Therefore, the incidence of HbH disease can be expected to increase in Japan. Long-term follow-up will be needed to evaluate the long term complications and to improve the quality of life of patients with HbH disease. PMID- 21551968 TI - Biliary obstruction due to a huge simple hepatic cyst treated with laparoscopic resection. AB - Most hepatic cysts are asymptomatic, but complications occasionally occur. We describe a patient with biliary obstruction due to a huge simple hepatic cyst treated with laparoscopic resection. A 60-year-old Japanese woman was admitted to our hospital because of a nontender mass in the right upper quadrant of the abdomen. Laboratory tests revealed the following: serum total bilirubin, 0.6 mg/dL; serum aspartate aminotransferase, 100 IU/L; serum alanine aminotransferase, 78 IU/L; serum alkaline phosphatase, 521 IU/L; and serum gamma glutamic transpeptidase, 298 IU/L. Abdominal computed tomography, ultrasonography, and magnetic resonance cholangiopancreatography revealed a huge hepatic cyst, 13 cm in diameter, at the hepatic hilum, accompanied by dilatation of the intrahepatic bile duct and obstruction of the common bile duct. We diagnosed biliary obstruction due to a huge hepatic cyst at the hepatic hilum, and laparoscopic surgery was performed. A huge hepatic cyst was seen at the hepatic hilum. After needle puncture of the huge cyst, the anterior wall of the cyst was unroofed, and cholecystectomy was done. Intraoperative cholangiography through a cystic duct revealed stenosis of the duct. Subsequent decapsulation of the cyst was performed in front of the common bile duct. After this procedure, cholangiography revealed that the stenosis of the common bile duct had resolved. Histopathological examination of the surgical specimen confirmed the hepatic cyst was benign. The postoperative course was uneventful, and the results of liver function tests normalized. The patient was discharged 7 days after operation. Computed tomography 3 months after operation revealed disappearance of the hepatic cyst and no dilatation of the intrahepatic bile duct. PMID- 21551969 TI - Visceral ischemia caused by acute aortic dissection following blunt aortic injury: report of a case. AB - The diagnosis and management of blunt thoracic aortic injuries have seen significant changes over the last decade. The purposeful delay of definitive repair by aggressive blood pressure management has been suggested to be safe, and deliberate nonoperative management may be a reasonable alternative in selected patients with minimal aortic injuries detected with contrast-enhanced computed tomography. We report a case of acute aortic dissection due to blunt thoracic aortic injury resulting in splanchnic ischemia, for which we selected primarily nonoperative management, because the aortic tear was small but was complicated by multiple trauma. Although acute aortic dissection is an uncommon presentation of blunt injuries of the thoracic aorta and the poor prognosis has not been adequately emphasized, close observation, to evaluate the dissection and to determine whether splanchnic ischemia has developed, is recommended for patients for whom delayed definitive repair or nonoperative management has been selected. PMID- 21551970 TI - Postoperative course after simple ligation for superior mesenteric vein injury caused by blunt abdominal trauma: report of a case. AB - Traumatic injury of the superior mesenteric vein (SMV) by blunt trauma is a rare but frequently fatal injury. Although simple ligation should be considered for a patient in unstable condition, its complications have not been reported in detail. A 47-year-old man was struck on the abdomen during a fight. When he was transferred to a local hospital, he complained of severe abdominal pain. Computed tomography (CT) of the abdomen showed fluid accumulation in the peritoneal cavity and a hematoma around the root of the mesentery, with leakage of contrast material. When the patient was transferred to our emergency department, the hemodynamic status did not improve after rapid fluid resuscitation with 1,500 mL of crystalloid. Emergency laparotomy was performed 4 hours after the injury. Two lacerations of the proximal SMV were observed. The SMV was ligated owing to the unstable hemodynamic status. On postoperative day (POD) 5, abdominal radiography showed dilated loops of bowel, suggesting ileus of the small bowel. A CT scan with contrast enhancement showed that the wall of the small bowel was thickened. On POD 11, a CT scan showed that the collateral vessels that drain the mesenteric circulation had not developed. However, collateral vessels were revealed on a 3 dimensional CT scan, and, on POD 23, a CT scan showed that the collateral vessels had developed. The patient was discharged on POD 37. This case demonstrates that simple ligation of the proximal SMV leads to the development of collateral vessels and is useful for preventing side effects and improving outcomes. PMID- 21551971 TI - A case report of complete chorioamniotic membrane separation. AB - We describe a patient with complete chorioamniotic membrane separation (CMS). During embryologic development, the chorionic and amniotic membranes each arise from their own germ layers and form a celomic cavity in the first trimester of pregnancy. By the early second trimester, the cavity has shrunk and the membranes become conjugated. However, the membranes may separate spontaneously or because of an invasive intrauterine procedure. This pathologic condition is referred to as CMS. Extensive CMS can lead to miscarriage, fetal death, neonatal death, amniotic band syndrome, umbilical cord complications, and preterm delivery. In this case, CMS was detected in the 29th week of pregnancy with a routine ultrasonographic examination in the absence of a distinct non-reassuring fetal status or an abnormality of the intrauterine environment. The patient had undergone amniocentesis at 16 weeks of pregnancy for chromosomal analysis. Ultrasonography showed a floating membranous structure in almost every view of the intra-amniotic cavity. Thus, complete CMS was believed to have occurred. Therefore, precautionary checkups and examinations were periodically performed. Childbirth took place uneventfully by means of elective cesarean section in the 37th week of pregnancy. Because pathological examination showed complete CMS, the validity of the prenatal diagnosis was confirmed. PMID- 21551972 TI - Does the use of labor-inducing drugs cause adverse perinatal outcomes? AB - There have been several studies of adverse perinatal outcomes associated with the indiscriminate use of labor-inducing drugs. However, the present results indicate that the appropriate use of labor-inducing drugs is not unsafe and improves neonatal outcomes in abnormal deliveries. PMID- 21551974 TI - Role of cell-death ligand-receptor system of granulosa cells in selective follicular atresia in porcine ovary. AB - In the mammalian ovary, more than 99% of follicles degenerate without ovulation and few oocytes ovulate and succeed to the next generation. Granulosa cell apoptosis plays a critical role in this process, follicular atresia. However, the molecular mechanisms responsible for the regulation of granulosa cell apoptosis have not been clarified. Death ligand and receptor systems are major apoptosis inducing factors. This review describes the granulosa cell apoptosis via death ligand and receptor systems during follicular atresia in the porcine ovary. PMID- 21551973 TI - Myosin light chain kinase/actin interaction in phorbol dibutyrate-stimulated smooth muscle cells. AB - Previous work has suggested that in addition to its kinase activity, myosin light chain kinase (MLCK) exhibits non-kinase properties within its N-terminus that could influence cytoskeletal organization of smooth muscle cells (A. Nakamura et al. Biochem Biophys Res Commun. 2008;369:135-143). Myosin ATPase activity measurements indicate that the 26-41 peptide of MLCK significantly decreases ATPase activity as the concentration of this peptide increases. Sliding velocity of actin-filaments on myosin and stress responses in skinned smooth muscle tissue are also inhibited. Peptide-mediated uptake and the microinjection technique in cells indicate that the peptide was necessary for actin-filament stabilization. Fluorescence resonance energy transfer analysis indicated that in the presence of MLCK, alpha-actin but not beta-actin remodeled during phorbol 12,13-dibutyrate (PDBu)-induced contractions. PDBu also induced podosomes in the cell. When MLCK expression was down-regulated by introduction of RNAi for MLCK by lentivirus vector into the cells, we failed to observe the podosome induction upon PDBu stimulation. Rescue experiments indicate that the non-kinase activity of MLCK plays an important role in maintaining actin stress fibers and in the PDBu induced reorganization of actin-filaments in smooth muscle cells. PMID- 21551975 TI - A study on freeze-drying as a method of preserving mouse sperm. AB - This review describes the study of freeze-dried mouse sperm for practical application in preserving and transporting genetic resources. Freeze-dried sperm can be used to preserve and transport genetic resources; however, there still remain many areas which need to be studied. In particular, it is essential to assure long-term preservation over several decades or centuries. Recently, the theory of accelerated degradation kinetics to freeze-dried mouse sperm has been applied, and found that long-term preservation by conventional methods requires temperatures lower than -80 C. When the relationship between the pressure at primary drying and the preservation potential of freeze-dried mouse sperm was examined, a pressure of 0.37 mbar at primary drying significantly improved the developmental rate to the blastocyst stage. In addition, it has been shown that freeze-dried sperm stored at -80 C with and without transportation can retain their ability to generate viable offspring after storage for up to 2 years. Sperm chromatin structure assay (SCSA) was applied to mouse sperm freeze-dried under several conditions and compared the results with the embryonic developmental rates of freeze-dried sperm after intracytoplasmic sperm injection (ICSI) and with comet assay results. Furthermore, SCSA might be useful for estimation of developmental potential of fertilized eggs derived from ICSI using freeze-dried sperm in mice. PMID- 21551976 TI - Factors affecting fertilization and embryonic development during intracytoplasmic sperm injection in pigs. AB - In intracytoplasmic sperm injection (ICSI) technique, a sperm was injected into ooplasm directly using a glass pipette. The fertilization physiology in ICSI is considered quite different from that of the natural fertilization. The different mechanisms for fertilization may be the causes of various results in ICSI. In this paper, we focus on the state of sperm membranes, nuclear or DNA integrity during ICSI procedure and discuss the influence of these factors on fertilization and embryonic development. We also introduce some examples in application of ICSI for new technologies in pigs. PMID- 21551977 TI - Lectin histochemistry of respiratory mucosa in the Pacific white-sided dolphin. AB - Sugars in the glycocalyx play an important role in the attachment of infectious agents to the respiratory mucosa. We examined the histochemistry of 23 lectins to survey the sugar expression in the glycocalyx of the respiratory mucosa of the Pacific white-sided dolphin, Lagenorhynchus obliquidens. The ciliated and basal cells were positive for all of the lectins studied. SBA, WFA, GSL-II, STL, S-WGA, and PNA staining in the cytoplasm showed different intensities between basal cells and ciliated cells. These results suggest that multiple terminal glycosylation occurs on ciliated and basal cells, such as GalNAc, GlcNAc, NeuNAc, galactose, glucose/mannose, oligosaccharide, and fucose, and that sugar residue expression changes during cell differentiation. The Pacific white-sided dolphin respiratory mucosa might express multiple sugar residues in the glycocalyx, to prevent the attachment and colonisation of infectious agents. PMID- 21551978 TI - CYP1B1 is polymorphic in cynomolgus and rhesus macaques. AB - Cytochrome P450 (CYP) 1B1 is involved in the metabolic activation of various procarcinogens, and some CYP1B1 genetic variants alter CYP1B1-dependent procarcinogen metabolism. Cynomolgus and rhesus macaques are frequently used in toxicity tests due to their evolutionary closeness to humans. In this study, we attempted to identify CYP1B1 genetic variants in 13 cynomolgus and 4 rhesus macaques. A total of 17 genetic variants were identified, including 8 non synonymous genetic variants, indicating that, similar to humans, CYP1B1 is polymorphic in macaques. These CYP1B1 genetic variants could be the basis for understanding potential inter-animal differences in macaque CYP1B1-dependent metabolism of promutagens. PMID- 21551979 TI - Direct detection of equine herpesvirus type 1 DNA in nasal swabs by loop-mediated isothermal amplification (LAMP). AB - We evaluated loop-mediated isothermal amplification (LAMP) as a means of detecting equine herpesvirus type 1 (EHV-1) DNA directly from nasal swabs. To increase the sensitivity, we added a step in which the samples were heat-treated to the original LAMP procedure. The detection limit of the LAMP assay with heat treatment was 10 times more sensitive than the original LAMP assay even when the DNA extraction step was omitted. In addition, the LAMP assay with heat treatment was more sensitive than the original LAMP assay and the polymerase chain reaction using clinical samples. The LAMP assay with heat treatment is easy to perform and so should be applicable to the diagnosis of EHV-1 infections in clinical laboratories. PMID- 21551980 TI - Cutaneous lymphoplasmacytic lymphoma with systemic metastasis in a cat. AB - A lymphoplasmacytic lymphoma was diagnosed in a 12- year-old domestic cat that had a primary cutaneous mass involving the stomach, liver, kidneys, heart, abdominal wall, diaphragm, bone marrow and several lymph nodes. Histopathologically, the most characteristic feature of this tumor was the heterogeneity of cell components, such as small lymphocytes, well-differentiated plasma cells and plasmacytoid transformed lymphocytes. Amyloid was deposited in the skin, stomach, and several lymph nodes. Immunohistochemically, neoplastic small lymphocytes were positive for CD20, and well-differentiated plasma cells and plasmacytoid transformed lymphocytes were positive for lambda-Ig light chains and MUM1/IRF-4. These results emphasize the importance of lymphoplasmacytic lymphoma as a differential diagnosis of extramedullary cutaneous plasmacytoma in cats. PMID- 21551981 TI - Endometrial injury increases side population cells in the uterine endometrium: a decisive role of estrogen. AB - Normal endometrial growth is essential for embryonic implantation and maintenance of pregnancy. The uterine endometrium contains stem cells that are involved in tissue regeneration. Side population cells (SP cells) are an emerging cell population that may be responsible for the regeneration process of uterine endometrium. In this study, we investigated the changes in the distribution of SP cells using a mouse model of uterine endometrial injury that was induced by peritoneal injection of lipopolysaccharide (LPS). The uterine horns were collected 0, 6, 12, and 18 hours after LPS injection. ATP-binding cassette and sub-family G member 2 (Abcg2) is highly expressed on the cellular membrane of some stem and progenitor cells, and was used as a marker for SP cells. Immunohistochemistry demonstrated that Abcg2-positive cells were increased around the uterine endometrial glands from 6 to 12 h after LPS injection. The percentage of Abcg2-positive cells was calculated using flow cytometry. The percentage of stromal SP cells was significantly higher at 6 h after LPS injection, compared with the value before the injection (3.01 +/- 0.41% vs. 1.63 +/- 0.31%, P < 0.05). To evaluate the influence of ovarian hormones, we implanted pellets containing 17beta-estradiol (0.1 mg), progesterone (10 mg), or a combination of 17beta-estradiol and progesterone in the bilaterally ovariectomized mice. Ovariectomy abolished the increase in SP cells, which was restored by estradiol, but not by progesterone or the combination treatment. In conclusion, estrogen is required for the increase of SP cells, thereby leading to the regeneration of the uterine endometrium. PMID- 21551982 TI - Adult human parvovirus-B19 infection presenting with hearing difficulty and dizziness. AB - Human parvovirus B19 (HPV-B19), a small and non-enveloped DNA virus, causes erythema infectiosum (EI) in children. In adults, however, it is known to cause a variety of symptoms. A 39-year-old woman visited our hospital because of low grade fever, diarrhea, bilateral leg edema, and numbness in the right arm, one and a half months after her daughter developed EI. We diagnosed her as HPV-B19 infection after her daughter's history and positive test for serum HPV-B19 IgM antibody, together with the continued observations. Two weeks later, she developed dizziness and left hearing difficulty. However, we did not give her any medication. HPV-B19 IgM antibody value (2.4) measured after one month of the onset was decreased to 1.7, 1.1, and 0.9 after two, three, and five months of the onset, respectively. Thus, it took 5 months for the IgM antibody value to become negative. Her symptoms gradually improved along with the decrease in HPV-B19 antibody without any medication. Hearing difficulty and dizziness are not categorized as manifestations of HPV-B19 infection, because these symptoms are very rare. The present report indicates that the symptoms related to inner ear dysfunctions should be added to those associated with adult HPV-B19 infection. In conclusion, we should consider HPV-B19 infection when we evaluate patients with causeless hearing difficulty and dizziness. PMID- 21551983 TI - Clinical features of bacteremia caused by methicillin-resistant Staphylococcus aureus in a tertiary hospital. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has become a leading cause of infections in both the community and in hospitals. MRSA bacteremia is a serious infection with a very high mortality rate. The aim of this study was to assess the clinical features of MRSA bacteremia and to evaluate predictors of mortality in patients with this infection. The medical records of 83 patients with MRSA bacteremia, who had been admitted to Nagasaki University Hospital between January 2003 and December 2007, were retrospectively reviewed. Underlying disease, presumed source, MRSA sensitivity, Staphylococcal cassette chromosome mec (SCCmec) types, virulence genes and prognosis were evaluated. Of the 83 patients (44 men and 39 women; mean age: 63.7 years) with MRSA bacteremia, 30 (36.1%) had malignancy and 25 (30.1%) had been treated with immunosuppressive drugs. Fifteen patients (18.1%) were intravascular catheter related. SCCmec typeII accounted for 80% of SCCmec types of MRSA isolates. The mortality rate was 39.8% (33/83), which is similar to that of previous reports. The ratio of males to females, the mean age or the body temperature did not differ between survivors and nonsurvivors. Independent predictors associated with mortality in the multivariate analyses are pneumonia (P = 0.016), treatment with VCM (P = 0.039), and transplantation (P = 0.021). We suggest that poor prognosis achieved with VCM is in part due to its low blood concentration and poor tissue penetration. VCM should not be selected when presumed source of MRSA bacteremia is pneumonia. PMID- 21551984 TI - Delayed administration of D-Ala2-D-Leu5-enkephalin, a delta-opioid receptor agonist, improves survival in a rat model of sepsis. AB - Sepsis is the major cause of death in intensive care units, despite enormous efforts in the development of antimicrobial therapies. Sepsis is mediated by early [e.g., tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta] and late [e.g., high-mobility group box 1 protein (HMGB1)] proinflammatory cytokines. HMGB1, which is secreted into extracellular milieu by activated macrophages or passively released by destroyed macrophages, stimulates intensive inflammatory responses. D-Ala2-D-Leu5-enkephalin (DADLE), a synthetic delta-opioid receptor agonist, has been shown to protect rats from sepsis. Here we elucidated the mechanism for protective effect of DADLE against sepsis. Sepsis was established in Sprague-Dawley rats by means of cecal ligation and puncture (CLP). In this model, the serum levels of TNF-alpha and IL-1beta were increased after 2-3 h, while those of HMGB1 were increased after 18 h. Administration of DADLE (5 mg/kg) concurrently with CLP improved survival, which was associated with the decreases in the serum levels of TNF-alpha, IL-1beta and HMGB1. Importantly, DADLE administrated 4 h after CLP showed comparable protective effect as the concurrent administration, with decreased serum HMGB1 levels. Moreover, peritoneal macrophages isolated from rats were challenged with lipopolysaccharide (LPS). Concurrent or delayed DADLE administration at 10(-6) M suppressed the LPS-induced cell death. DADLE also suppressed the release of HMGB1 from macrophages that was induced by LPS, TNF-alpha or interferon-gamma. In conclusion, DADLE protects rats from sepsis probably by decreasing the serum level of HMGB1. We propose DADLE as a candidate for septic shock therapy, even if it is administered after the onset of sepsis. PMID- 21551985 TI - [Chronic obstructive pulmonary disease in Korea: prevalence, risk factors, and quality of life]. AB - PURPOSE: This study seeks to examine prevalence, risk factors, and quality of life of Korean adults with Chronic Obstructive Pulmonary Disease (COPD). METHODS: From the database of the Fourth Korean National Health and Nutrition Examination Survey (KNHANES IV-1, 2008), the researchers selected 1,458 adults over the age of 45. The original study was a population-based epidemiological survey of health and nutrition with a stratified multistage clustered probability design. Prevalence of COPD was computed on the basis of the sampling weight. Data were analyzed using descriptive statistics, chi(2) test, t-test and multiple logistic regression with the SPSS WIN 18.0 and SAS Ver. 9.1 program. RESULTS: The prevalence of COPD was 18.0% among people older than 45 yr. The prevalence of current smokers was 19.7% in this population and 26.3% in individuals with COPD. Age, gender, education, and smoking levels were found to be risk factors for COPD. Significant difference in quality of life was founded between adults with COPD and the healthy controls. CONCLUSION: The results of this study indicate that COPD is a highly prevalent disease in Korea. To reduce the prevalence of COPD and improve health-related quality of life in patients with COPD, nursing interventions must focus on prevention of risk factors. PMID- 21551986 TI - [Influence of pre-operative fasting time on blood glucose in older patients]. AB - PURPOSE: This study was performed to identify changes in blood glucose at preoperative fasting time in surgical patients over 60 yr. METHODS: Data collection was performed from July, 2008 through July, 2009. Participants consisted of 80 nondiabetic surgical patients. Blood glucose was checked from 3 to 5 times. The 5 times were 2-hr fasting on the pre-operative day (T1, n=80), 8 hr (T2, n=80), 10 hr (T3, n=17), 12 hr (T4, n=34) and 14 hr fasting on the day of the operation (T5, n=29). RESULTS: Of the patients, 27.5% had a blood glucose level of less than 79 mg/dL at T2; 17.6% at T3; 32.4% at T4; and 17.2% at T5. Mean blood glucose levels were 93.8 mg/dL at T1; 88.4 mg/dL at T2; 91.7 mg/dL at T3; 87.4 mg/dL at T4: and 94.1 mg/dL at T5. Blood glucose was the lowest at T2 (p<.001). CONCLUSION: As 17.6-32.4% of the patients showed the blood glucose level of less than 79 mg/dL at 8-14 hr pre-operative fasting, the authors recommend that surgical patients >60 yr-of-age be observed for hypoglycemia during pre-operative fasting of more than 10 hr and that surgical patients >60 yr of-age with risks for hypoglycemia be scheduled for operation within 10 hr preoperative fasting. PMID- 21551987 TI - [Effects of a fall prevention program on physical fitness and psychological functions in community dwelling elders]. AB - PURPOSE: This study was done to identify effects of a fall prevention program on physical fitness and psychological functions in community dwelling elders. METHODS: A quasi-experimental study was carried out with a nonequivalent control group pre & post-test design. The program, which included exercises and education, consisted of a 12-week group program and an 8-week self-management program using a health calendar. An experimental group (32) and a control group (21) participated. RESULTS: There were significant differences in SPPB (t=-3.92, p<.001), TUG test (t=4.94, p<.001), standing with right leg (t=-3.60, p=.001), standing with left leg (t=-3.74, p<.001), front and rear maximum step length test (t=-4.34, p<.001), right-left maximum step length test (t=-2.65, p=.011), and fall efficacy (t=-2.42, p=.019). Fall efficacy, fear of falling and depression showed significant differences following the 12-week exercise program and 8-week self-management program in the experimental group. CONCLUSION: Study findings indicate that the fall prevention program is an effective nursing intervention to enhance physical fitness and psychological functions for elders. Using a health calendar, the self-management program was more effective for psychological functions compared to only the group program. Therefore, health providers should develop diversified fall prevention programs which include motivation plans to encourage clients in participating. PMID- 21551988 TI - [Endotracheal colonization and ventilator-associated pneumonia in mechanically ventilated patients according to type of endotracheal suction system]. AB - PURPOSE: This study was conducted to identify endotracheal colonization and the incidence of ventilator-associated pneumonia related to the type of endotracheal suction system. METHODS: The participants in this study were ICU patients hospitalized between October 2009 to March 2010 who used ventilators for over 48 hr with closed (CSS, n=30) or open (OSS, n=32) suction systems. To standardize the pre-intervention suction system, a suctioning protocol was taught to the ICU nurses. Collected data were analyzed using Chi(2)-test, Fisher's exact test, Wilcoxon rank sums test, Wilcoxon test, Log-rank test and Poisson regression. RESULTS: Endotracheal colonization was higher in OSS than CSS from day 1 to day 8 while using a ventilator and there was a significant difference between the two groups. The CSS reached 50% of endotracheal colonization by the 4th day, whereas for the OSS, it was the 2nd day (p=.04). The incidence of ventilator-associated pneumonia showed no significant difference. CONCLUSION: For patients with a high risk of pneumonia, CSS must be used to lower endotracheal colonization. PMID- 21551989 TI - [Relationship of daily activity and biochemical variables in the elderly with diabetes mellitus]. AB - PURPOSE: This study was done to identify correlates and variables predicting daily activity among elders with Diabetes Mellitus (DM). METHODS: Seventy-six elders registered in the Department of Endocrine Medicine at C university hospital participated in data collection. Data on daily activity and biochemical variables were collected via actigraph accelerator (Actical) and blood tests between September 2009 and July 2010. Data analysis was done using SPSS WIN 15.0 program and included one-way ANOVA, independent t-test, Pearson correlation coefficients, and stepwise multiple regression. RESULTS: This study showed a positive correlation between daily activity and High Density Lipoprotein Cholesterol (HDL-C) and a negative correlation among Total Cholesterol (TC), Triglyceride (TG), and Low Density Lipoprotein Cholesterol (LDL-C). The variables predicting daily activity were frequency of exercise, HDL-C, and TC. These factors accounted for 40.0% of the variance of daily activity in elders with DM. CONCLUSION: The results indicate that it is necessary to improve daily activity to reduce Fasting Blood Glucose (FBG), TC, and TG in elders with DM. PMID- 21551990 TI - [Estrogen attenuates the pressor response mediated by the group III mechanoreflex]. AB - PURPOSE: We investigated the effects of group III mechanoreceptors to cardiovascular responses in both pre-menopausal woman and post-menopausal woman during passive ankle dorsiflexion (PAD). METHODS: Twenty healthy volunteers (10 post-menopausal women and 10 pre-menopausal women) were recruited for this study. Stroke volume (SV), heart rate (HR), cardiac output (CO), and total vascular conductances (TVC) were measured continuously throughout the experiment. To stimulate the group III mechanoreceptors, PAD was performed for one minute. RESULTS: The results showed that mean arterial pressure (MAP) mediated by the mechanoreflex activation was significantly increased in both groups. However, this pressor response was significantly higher in post-menopausal women. This reflex significantly increased both SV and CO in pre-menopausal women, while there were no differences in post-menopausal women. There was no difference in HR in either group. The mechanoreflex significantly decreased TVC in post-menopausal woman, while there was no difference in pre-menopausal woman. CONCLUSION: The results indicate that the excessive pressor response mediated by the mechanoreflex occurs due to overactivity of group III mechanorecptors and the mechanism is produced mainly via peripheral vasoconstriction in post-menopausal women. PMID- 21551991 TI - [The effect of treadmill exercise on ischemic neuronal injury in the stroke animal model: potentiation of cerebral vascular integrity]. AB - PURPOSE: This study was done to identify whether pre-conditioning exercise has neuroprotective effects against cerebral ischemia, through enhance brain microvascular integrity. METHODS: Adult male Sprague-Dawley rats were randomly divided into four groups: 1) Normal (n=10); 2) Exercise (n=10); 3) Middle cerebral artery occlusion (MCAo), n=10); 4) Exercise+MCAo (n=10). Both exercise groups ran on a treadmill at a speed of 15 m/min, 30 min/day for 4 weeks, then, MCAo was performed for 90 min. Brain infarction was measured by Nissl staining. Examination of the remaining neuronal cell after MCAo, and microvascular protein expression on the motor cortex, showed the expression of Neuronal Nuclei (NeuN), Vascular endothelial growth factor (VEGF) & laminin. RESULTS: After 48 hr of MCAo, the infarct volume was significantly reduced in the Ex+MCAo group (15.6+/ 2.7%) compared to the MCAo group (44.9+/-3.8%) (p<.05), and many neuronal cells were detected in the Ex+MCAo group (70.8+/-3.9%) compared to the MCAo group (43.4+/-5.1%) (p<.05). The immunoreactivity of laminin, as a marker of microvessels and Vascular endothelial growth factor (VEGF) were intensively increased in the Ex+MCAo group compared to the MCAo group. CONCLUSION: These findings suggest that the neuroprotective effects of exercise pre-conditioning reduce ischemic brain injury through strengthening the microvascular integrity after cerebral ischemia. PMID- 21551992 TI - [Development of the competency model for prevention of adolescent risk behavior]. AB - PURPOSE: This study was done to identify fundamental data on competency reinforcement programs to prevent adolescent risk behavior by developing and examining a competency model. METHODS: In this study, competences on prevention of adolescent risk behavior were identified through competency modeling, and a competency model was developed and tested for validity. RESULTS: Competences for prevention of adolescent risk behavior defined by the competency model included the following: self-control, positive mutual understanding between parents and adolescents, and positive connectedness with peer group. Validation of the competency model showed the model to be appropriate. CONCLUSION: The competency model for prevention of adolescent risk behavior through competency modeling is expected to be the foundation of an integral approach to enhance competency in adolescents and prevent adolescent risk behavior. This kind of approach can be a school-centered, cost-efficient strategy, which not only reduces adolescent risk behavior but also improves quality of adolescent resources. PMID- 21551993 TI - [Life experience of inpatients with recurrent breast cancer]. AB - PURPOSE: Understanding daily life experiences of patients admitted to hospital with recurrent breast cancer. METHODS: The grounded theory method was used for this study. RESULTS: Consistent comparative analysis was used throughout the study to obtain the results. Results showed that inpatients with recurrent breast cancer experience 'a co-existence of life suffering and fear of death'. The causal condition of this result was determined to be 'patient's response to cancer recurrence (acceptance/despair)', including contextual conditions such as, 'previous experience with cancer treatment', 'patient's current physical condition', and 'treatment methods for recurrent cancer'. Intervening conditions, such as 'a strong will to live', 'family support', 'moral support providers', and action/interaction strategies were found to provide patients with 'a strength to live'. Shown in these results, inpatients with recurrent breast cancer were seen to have a simultaneous 'hope for life and fear of death'. CONCLUSION: When providing nursing services to inpatients with recurrent breast cancer, people must recognize there is a notable difference between individual patients' contextual conditions and interactive strategies. Henceforth, proper cognitive nursing must be provided which encourages patients to maintain a strong will to overcome the many hardships of treatment as well as physical nursing, such as management of side effects caused by chemotherapy. PMID- 21551994 TI - [Psychosocial adjustment of low-income Koreans with cancer]. AB - PURPOSE: To describe psychosocial adjustment of low-income Koreans who have cancer. METHODS: Data were collected during 2008 using individual in-depth interviews with 18 Korean people with cancer. The income status of the participants was low, 11 were recipients of the National Basic Livelihood Protection program. Mean age was 58.3 yr and 11 were female. Five participants had stomach cancer, five, colorectal cancer, and four, breast cancer. Data were analyzed using grounded theory methodology. RESULTS: The core category emerged as 'bearing up alone with double suffering'. 'Poverty and cancer: A double suffering' emerged as a causal condition. The adjustment process consisted of three stages: 'forming a treatment will to live' ,'practicing for the cure',and 'restructuring self and repaying favors'. Each stage indicated action-interaction strategies which were employed to bear up alone with double suffering during the illness process. Self-reflection, parental responsibility, and support from the public sector played important roles in overcoming the double suffering. Two types of consequences were identified: Transcended life and strained life suppressed by poverty and cancer. CONCLUSION: The results provide insights into the psychosocial adjustment process for low income Korean with cancer and can be used in developing and implementing efficient home-care services for these people. PMID- 21551995 TI - [Impact of pro-environmental behavior on dysmenorrhea]. AB - PURPOSE: In this study the impact of pro-environmental behavior, well-being oriented behavior, and use of cloth menstrual pads on dysmenorrhea in Korean female adults was examined according to the theory of reasoned action. METHODS: A cross-sectional study was conducted with 195 Korean female adults. Data were collected from June to August, 2010 using self-report questionnaires. Data were analyzed using t-test, one-way ANOVA, Pearson correlation coefficients, multiple regression, and logit regression with STATA 10.0. RESULTS: Pro-environmental behavior explained 48% of well-being oriented behavior. Well-being oriented behavior explained 10% of cloth pad use. Use of cloth pad explained 4% of dysmenorrhea and 5% of menstrual pain. The path through well-being oriented behavior had a significant effect from pro-environmental behavior to cloth pad use. CONCLUSION: Use of cloth pad was significantly related with well-being oriented behavior, pro-environmental behavior, social influence, dysmenorrhea, and menstrual pain. The results of this study suggest that pro-environmental strategies can help health care providers diminish clients' menstrual symptoms. Nursing intervention can support pro-environmental behavioral strategies. PMID- 21551996 TI - [Effect of a simulation-based education on cardio-pulmonary emergency care knowledge, clinical performance ability and problem solving process in new nurses]. AB - PURPOSE: This study was conducted to examine the effects of simulation-based education regarding care in a cardio-pulmonary emergency care as related to knowledge, clinical performance ability, and problem solving process in new nurses. METHODS: An equivalent control group pre-post test experimental design was used. Fifty new nurses were recruited, 26 nurses for the experimental group and 24 nurses for the control group. The simulation-based cardio-pulmonary emergency care education included lecture, skill training, team-based practice, and debriefing, and it was implemented with the experimental group for a week in May, 2009. Data were analyzed using frequency, ratio, chi-square, Fisher's exact probability and t-test with the SPSS program. RESULTS: The experimental group who had the simulation-based education showed significantly higher know-ledge (t=5.76, p<.001) and clinical performance ability (t=5.86, p<.001) for cardio pulmonary emergency care compared with the control group who had traditional education but problem solving process was not included (t=1.11, p=.138). CONCLUSION: The results indicate that a simulation-based education is an effective teaching method to improve knowledge and clinical performance ability in new nurses learning cardio-pulmonary emergency care. Further study is needed to identify the effect of a simulation-based team discussion on cognitive outcome of clinical nurses such as problem solving skills. PMID- 21551997 TI - [Meta analysis of variables related to attention deficit hyperactivity disorder in school-age children]. AB - PURPOSE: The purpose of this study was to use meta-analysis to examine recent domestic articles related to attention deficit hyperactivity disorder (ADHD) in school-age children. METHODS: After reviewing 213 articles published between 1990 and 2009 from and cited in RISS, KISS, and DBpia, the researchers identified 24 studies with 440 research variables that had appropriate data for methodological study. SPSS 17.0 program was used. The outcome variables were divided into five types: Inattention, hyperactive impulsive, intrinsic, extrinsic, and academic ability variables. RESULTS: Effects size of overall core symptoms was 0.47 which is moderate level in terms of Cohen criteria and effects size of overall negative variables related ADHD was 0.27 which is small level. The most dominant variable related to ADHD was obtained from hyperactive-impulsive (0.70). Also academic ability (0.45), inattention (0.37), and intrinsic variables (0.29) had a small effect whereas extrinsic variables (0.13) had little effect on descriptive ADHD study. CONCLUSION: The results reveal that ADHD core symptoms have moderate effect size and peripheral negative variables related ADHD have small effect size. To improve the reliability of the meta-analysis results by minimizing publication bias, more intervention studies using appropriate study designs should be done. PMID- 21551998 TI - [Effects of carbonated water intake on constipation in elderly patients following a cerebrovascular accident]. AB - PURPOSE: This study was done to identify effects of carbonated water intake on constipation in elders who have experienced a cerebrovascular accident (CVA) and are bed-ridden. METHODS: Forty elderly patients with CVA were randomly assigned to one of two groups in a double-blind study. Patients in the experimental group drank carbonated water and those in the control group drank tap water for two weeks. Six patients dropped out during the study period. Data were analyzed by repeated measured ANCOVA and the covariance was the dose of laxatives used for the two weeks. RESULTS: Frequency of defecation increased significantly and symptoms of constipation decreased significantly for patients in the experimental group. CONCLUSION: The study results suggest that the intake of carbonated water is an effective method for the intervention of constipation in elderly patients with CVA. PMID- 21551999 TI - [Relationship of prenatal stress and depression to maternal-fetal attachment and fetal growth]. AB - PURPOSE: Prenatal depression is associated with potential negative consequences for the mother and infant. The purpose of this study was to examine pregnant women's stress, and depression and their impact on maternal-fetal attachment and fetal growth. METHODS: Data were collected by means of a questionnaire and fetal sonogram from a convenience sample of 166 pregnant women. RESULTS: Women who have a low educational level, poor health and are dissatisfied with their marriage showed low maternal-fetal attachment. Prenatal depression had significant correlations with length of pregnancy and level of stress. Even though correlation between maternal stress and fetal weight (r=-.15, p=.099) and correlation between maternal depression and maternal-fetal attachment (r=-.13, p=.095) were not statistically significant, the impact of the prenatal psychological state of mothers can not be ignored as it relates to fetal health. CONCLUSION: Maternal-fetal attachment and fetal growth can be affected by maternal emotional state, including stress or depression. These findings suggest that primary care nurses in hospitals and public health centers should provide prenatal depression screening and nursing intervention programs for management and prevention of prenatal stress and depression. PMID- 21552000 TI - The written description rejection as a barrier to biotech patent prosecution. AB - Biotech firms always pursue broad claims to secure new discoveries, new technologies and even as yet undiscovered results of future research. However, expansive claims without sufficient description violate the principal of granting the patentee the right to exclude others from using the technical development for a certain amount of time in return for disclosing the innovation. Based on this investigation, a written description can be a barrier to biotech patents with broad claims. To avoid a written description rejection during patent prosecution or invalidation in litigation, the patent applicant or assignee should demonstrate possession of the claimed invention by describing the claimed invention with all of its limitations using descriptive means such as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Although the court cases analyzed in this study were not directly related to vaccines, the guideline indeed is applicable to patents of vaccine. Furthermore, a vaccine patent application is also demonstrated. PMID- 21552001 TI - Application of PHEL (Public Health Epidemiological Logic) in devising a vaccination policy: a broad public health criteria-for routine Immunization. AB - There is a need to develop clear cut public health criteria for consideration of new vaccines for use in public health. Most of the vaccines which have become recently available or will soon be available are mostly recommended for use in clinical/office practice. A new vaccine that is highly recommended for use in clinical setting may not be effective at all for larger public health use or may even lack rationale to put it in use for public health. It is stressed that a new vaccine which is proven to be good clinical tool for preventing particular disease at individual level need not necessarily be good public health tool in combating the same disease at community level. The present paper takes a closer look at the logical basis for use of any vaccine in public health. Rabies vaccine is used as a case study to set the background to scrutinize the criteria for eligibility for considering any new vaccine to be included in routine immunization program A rough & ready algorithm is proposed as a check list for a new vaccine as a likely candidate for inclusion in Universal immunization programme.The suggested new algorithm is basically a public health criteria called as Public Health Epidemiological Logic (PHEL) Criteria. The public health debate and the arguments against inclusion of Rabies vaccine in routine national immunization programme in India is a argued in the frame work of PHEL criteria in this paper Rabies vaccine to drive home the point, that a vaccine which is a good clinical tool need not always be a good public health tool, where as a vaccine which is proven to be a good public health tool will always invariably be a good clinical tool as well. PMID- 21552002 TI - Considerations on the clinical application of the human papillomavirus vaccine in Spain. AB - The circumstances that in the opinion of the authors influence the lower than expected uptake of the vaccine against human papillomavirus in Spain are analyzed. Among others, aspects related to doubts about efficacy and safety, the attitude of the Spanish health authorities or the role of media and the antivaccine groups, as well as the vaccination "culture" of the gynecologist, are discussed. The authors conclude that only with the coordinated effort of all involved bodies in the vaccination process (health authorities, scientific societies, social agents, media...) wide coverage of HPV vaccine will be achieved. PMID- 21552003 TI - Inverse correlation between varicella severity and level of anti-Varicella Zoster Virus maternal antibodies in infants below one year of age. AB - Varicella, a widespread disease of childhood, is usually benign but may in some instances lead to complications and eventually death. The aim of this study was to assess whether varicella severity in infants below one year of age was associated with the level of anti-varicella zoster virus (VZV) maternal antibodies. Two different data sets were used. Data on varicella-associated complications were collected through a national surveillance network involving 175 hospital-based pediatric wards. Data on levels of maternal acquired antibodies according to infants' age were extracted from a cohort of 345 full term infants enrolled in a prospective multicenter study in seven pediatric wards and/or pediatric emergency units. Among infants hospitalized for varicella complications, the overall prevalence of complications increased regularly from 10.4% in infants below 1 month of age to over 72.4% at 5 months of age. Conversely, the mean antibody titre decreased from 536 mIU/mL in the [0-1 [month group to below the 150 mIU/mL threshold at 3-4 months [Pearson coefficient = 0.956 (p < 0.001)]. Based on large numbers of infants, our results show for the first time, a strong inverse correlation between the levels of circulating anti VZV maternal antibodies in full term infants and occurrence of varicella complications below one year of age. Infant protection could be optimized by increasing herd immunity, reducing the susceptibility of women in childbearing age and lowering the age of routine vaccination to 9 months. Additional vaccination for unprotected persons in close contact with infants below 12 months of age could be promoted. PMID- 21552005 TI - Response to commentaries. PMID- 21552006 TI - Cost of pneumococcal vaccine underestimated ten-fold. PMID- 21552007 TI - GM130, a cis-Golgi protein, regulates meiotic spindle assembly and asymmetric division in mouse oocyte. AB - GM130, a cis-Golgi protein, plays key roles in various mitotic events, but its function in mammalian oocyte meiosis remains unknown. In this study, we found that GM130 was localized to the spindle poles at both metaphase I and metaphase II stages and associated with the midbody at telophase I stage. The association of GM130 with spindle poles was further confirmed by its colocalization with the centrosome-associated proteins, MEK1/2. By nocodazole treatment, we clarified that GM130 localization was consistently dependent on spindle assembly. Then we investigated the possible function of GM130 by specific morpholino microinjection. This treatment caused abnormal spindle formation, and decreased first polar body extrusion. Our results showed that knockdown of GM130 impaired the localization of MTOCs proteins gamma-tubulin and Plk1. Using live cell imaging we observed that depletion of GM130 affected spindle migration and resulted in elongated spindle and large polar body extrusion. We further found that depletion of GM130 blocked p-MEK1/2 accumulation at the spindle poles. And, it was shown that GM130 detached from the spindle poles in oocytes treated with MEK specific inhibitor U0126. Taken together, our results suggested that GM130 regulates microtubule organization and might cooperate with the MAPK pathway to play roles in spindle organization, migration and asymmetric division during mouse oocyte maturation. PMID- 21552008 TI - Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. AB - Recent evidence suggests that enhanced aldehyde dehydrogenase (ALDH) activity is a hallmark of cancer stem cells (CSC) measurable by the aldefluor assay. ALDH1A1, one of 19 ALDH isoforms expressed in humans, was generally believed to be responsible for the ALDH activity of CSCs. More recently, experiments with murine hematopoietic stem cells, murine progenitor pancreatic cells, and human breast CSCs indicate that other ALDH isoforms, particularly ALDH1A3, significantly contribute to aldefluor positivity, which may be tissue and cancer specific. Therefore, potential prognostic application involving the use of CSC prevalence in tumor tissue to predict patient outcome requires the identification and quantification of specific ALDH isoforms. Herein we review the suggested roles of ALDH in CSC biology and the immunohistological studies testing the potential application of ALDH isoforms as novel cancer prognostic indicators. PMID- 21552009 TI - Lack of autophagy in the hematopoietic system leads to loss of hematopoietic stem cell function and dysregulated myeloid proliferation. AB - The regulated lysosomal degradation pathway of autophagy prevents cellular damage and thus protects from malignant transformation. Autophagy is also required for the maturation of various hematopoietic lineages, namely the erythroid and lymphoid ones, yet its role in adult hematopoietic stem cells (HSCs) remained unexplored. While normal HSCs sustain life-long hematopoiesis, malignant transformation of HSCs or early progenitors leads to leukemia. Mechanisms protecting HSCs from cellular damage are therefore essential to prevent hematopoietic malignancies. By conditionally deleting the essential autophagy gene Atg7 in the hematopoietic system, we found that autophagy is required for the maintenance of true HSCs and therefore also of downstream hematopoietic progenitors. Loss of autophagy in HSCs leads to the expansion of a progenitor cell population in the bone marrow, giving rise to a severe, invasive myeloproliferation, which strongly resembles human acute myeloid leukemia (AML). PMID- 21552010 TI - Oncogene-induced autophagy and the Goldilocks principle. AB - Although several oncogenes enhance autophagic flux, the molecular mechanism and consequences of oncogene-induced autophagy remain to be clarified. We have recently shown that expression of oncogenic H-Ras (V12) promotes autophagy through upregulation of Beclin 1 and the BH3-only protein Noxa. H-Ras-expressing cells undergo autophagic cell death as a result of Noxa-mediated displacement of Mcl-1 and Bcl-xL from Beclin 1. Oncogenic H-Ras-induced death is attenuated through knockdown of BECLIN 1, ATG5, or ATG7, or through overexpression of Mcl-1, Bcl-2, Bcl-xL and their close relatives. These observations suggest that high intensity oncogene activation may be selected against by promoting excessive autophagy, leading to cell death. Consequently, such oncogenes may select for cells with a reduced capacity for autophagy, either through loss of a BECLIN 1 allele or through upregulation of negative regulators of Beclin 1, such as Bcl-2 family members. PMID- 21552011 TI - Denys-Drash syndrome and gonadoblastoma in a patient with Klinefelter syndrome. PMID- 21552012 TI - Tc-99m exametazime (HMPAO)-labeled leukocyte scintigraphy in premature infants: detection and localization of necrotic enterocolitis and osteomyelitis. AB - Two cases of successful detection of inflammatory foci using Tc-99m exametazime (HMPAO)-labeled leukocyte scintigraphy in premature infants were reported. Necrotizing enterocolitis was detected in a child with a body weight of 1.6 kg. Scintigraphy confirmed a neonatal osteomyelitis in the distal part of the leg of another patient weighing 2.2 kg. These 2 cases indicate that it is feasible to perform Tc-99m HMPAO-labeled leukocyte scintigraphy even if the blood sample volume is lower than the minimal volumes required by the guidelines for pediatric patients. PMID- 21552013 TI - Histiocytic sarcoma involving lymph nodes: imaging appearance on gallium-67 and F 18 FDG PET/CT. AB - This report of an 82-year-old man who presented with a 3-week history of an enlarging left axillary mass and mild fevers, highlights the usefulness of both gallium-67 and F-18 FDG PET/CT imaging in the staging of histiocytic sarcoma. While PET/CT was superior in determining the extent of the disease, gallium can be used to help stage the disease in centers where PET/CT is not available. PMID- 21552014 TI - Intramuscular metastasis of uterine cervix cancer on F-18 FDG PET/CT. AB - We report F-18 FDG PET/CT images of biopsy-proven intramuscular metastasis from primary uterine cervix cancer. A 70-year-old woman was admitted because of a mass in the left axilla. She was diagnosed with uterine cervix cancer and underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic node dissection and received adjuvant chemotherapy and radiation therapy 9 years ago. Magnetic resonance imaging showed a large soft tissue mass in the intramuscular region of the left axilla. The mass showed intense F-18 FDG uptake with a central necrotic portion on F-18 FDG PET/CT. Hypermetabolic lymph nodes were also noted in the left axilla, interpectoral, and left supraclavicular areas. Additionally, several hypermetabolic nodules were noted in both lungs. The lesion in the left axilla was excised and the pathologic results were consistent with metastasis from uterine cervix cancer. PMID- 21552015 TI - Be aware of disseminated sarcoidosis with diffuse subcutaneous nodules on F-18 FDG PET. AB - Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that typically affects young adults. Definitive diagnosis requires compatible clinical and radiologic manifestations and histopathologic detection of noncaseating granulomas. In recent years, F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has been proposed to play a role in the diagnosis and management of sarcoidosis. Although disseminated sarcoidosis has been reported in nearly all organs including the skin, subcutaneous sarcoidosis is relatively rare with few reports using F-18 FDG PET. We report a case of disseminated sarcoidosis with diffuse subcutaneous nodules demonstrating avid F-18 FDG uptake on PET. PMID- 21552016 TI - Use of F-18 FDG PET/CT in non-Hodgkin lymphoma with central nervous system involvement. AB - Central nervous system (CNS) is a rare site of involvement by non-Hodgkin lymphoma (NHL). Therapeutic approach for primary and secondary CNS NHL is different and remains challenging. Therefore imaging data are essential at staging to discriminate these 2 clinical entities and during follow-up to assess therapy response. The adjunct role of positron emission tomography using F-18 fluorodeoxyglucose to morphologic imaging is still undefined. We report 2 didactic cases of primary and secondary CNS NHL assessed by F-18 fluorodeoxyglucose positron emission tomography. Metabolic imaging seems to be complementary to conventional imaging techniques for the extent-of-disease evaluation and therapy monitoring of CNS lesions. PMID- 21552017 TI - Impact of dual-time-point F-18 FDG PET/CT in the assessment of pleural effusion in patients with non-small-cell lung cancer. AB - AIM: The aim of this study was to assess the utility of dual-time-point F-18 fluorodeoxyglucose positron emission tomography (F-18 FDG PET) in differentiating benign from malignant pleural disease, in patients with non-small-cell lung cancer. METHODS: A total of 61 patients with non-small-cell lung cancer and pleural effusion were included in this retrospective study. All patients had whole-body FDG PET/CT imaging at 60 +/- 10 minutes post-FDG injection, whereas 31 patients had second-time delayed imaging repeated at 90 +/- 10 minutes for the chest. Maximum standardized uptake values (SUV(max)) and the average percent change in SUV(max) (%SUV) between time point 1 and time point 2 were calculated. Malignancy was defined using the following criteria: (1) visual assessment using 3-points grading scale; (2) SUV(max) >=2.4; (3) %SUV >= +9; and (4) SUV(max) >=2.4 and/or %SUV >= +9. Analysis of variance test and receiver operating characteristic analysis were used in statistical analysis. P < 0.05 was considered significant. RESULTS: Follow-up revealed 29 patient with malignant pleural disease and 31 patients with benign pleural effusion. The average SUV(max) in malignant effusions was 6.5 +/- 4 versus 2.2 +/- 0.9 in benign effusions (P < 0.0001). The average %SUV in malignant effusions was +13 +/- 10 versus -8 +/- 11 in benign effusions (P < 0.0004). Sensitivity, specificity, and accuracy for the 5 criteria were as follows: (1) 86%, 72%, and 79%; (2) 93%, 72%, and 82%; (3) 67%, 94%, and 81%; (4) 100%, 94%, and 97%. CONCLUSIONS: Dual-time point F-18 FDG PET can improve the diagnostic accuracy in differentiating benign from malignant pleural disease, with high sensitivity and good specificity. PMID- 21552018 TI - Value of dual-time-point FDG PET/CT for mediastinal nodal staging in non-small cell lung cancer patients with lung comorbidity. AB - PURPOSE: To evaluate the efficacy of dual-time-point F-18 fluorodeoxyglucose positron emission tomography (FDG PET)/ computed tomography (CT) for mediastinal nodal staging in non-small-cell lung cancer patients with lung comorbidity. MATERIALS AND METHODS: Fifty-three pathologically proven non-small-cell lung cancer patients with pulmonary comorbidity and 49 patients as controlled group without comorbidity were enrolled. PET/CT was performed at 1-hour (whole body) post-FDG injection and repeated 2 hours (thoracic) after injection. All patients received radical surgery with system mediastinal lymph node (LN) dissection. The results of LN detection by single-time-point and dual-time-point scan were compared with the histopathologic findings. RESULTS: On a per-patient basis, in patients with pulmonary comorbidity, the sensitivity, specificity, accuracy, and positive predictive values (PPV), and negative predictive values of single-time point scan were 87.5%, 59.5%, 67.9%, 48.3%, and 91.7%, respectively. Those values of dual-time-point scan were 93.8%, 67.6%, 75.5%, 55.6%, and 96.2%, respectively. In patients without comorbidity, dual-time-point scan was similar in those values to single-time-point. On a per-nodal station basis, the specificity, accuracy, and PPV of dual-time-point scan were better than those of single-time-point with statistically significant differences (P = 0.017, 0.002, and 0.027, respectively) in patients with pulmonary comorbidity, but the difference was not statistically significant in patients with no pulmonary comorbidity. CONCLUSIONS: Dual-time point FDG PET/CT is more effective for mediastinal nodal staging than single-time point in patients with pulmonary comorbidity. Dual-time-point scan was useful for diagnosis of mediastinal LN metastases in reducing the false-positive results in all patients, but improved specificity, accuracy, and PPV only in patients with pulmonary comorbidity. PMID- 21552019 TI - Limited predictive value of dual-time-point F-18 FDG PET/CT for evaluation of pathologic N1 status in NSCLC patients. AB - OBJECTIVE: The aim of the current study was to investigate the predictive value of dual-time-point F-18 FDG PET/CT for pathologic N1 metastasis in patients with non-small cell lung cancer (NSCLC). METHODS: A retrospective review identified 70 patients with NSCLC patients who received dual-time-point F-18 FDG PET/CT at diagnosis of cancer. The F-18 FDG PET/CT findings for all primary NSCLC and mediastinal lymph node involvement were compared with the pathologic diagnosis within 5 weeks after surgical resection. The pathologic diagnoses of N1 state were confirmed by surgical resection. Univariate and multivariate analyses were used to analyze the associations among the pathologic N1 status and age, sex, tumor size, histology, standardized uptake value (SUV(maxE)), SUV(maxD), and %DeltaSUV(max). RESULTS: The N1 (+) group showed statistically significant higher value of SUV(maxE) and SUV(maxD) than N1 (-) group. The %DeltaSUV(max) did not show the statistical difference between pathologic N1 (+) and N1 (-) groups. Receiver operating characteristic analyses showed that the SUV(maxE) was superior to the %DeltaSUV(max) for the prediction of pathologic N1 involvement in NSCLC. In univariate analysis, pathology (adenocarcinoma or nonadenocarcinoma), SUV(maxE) (>6.9 or <=6.9), SUV(maxD) (>7.1 or <=7.1) were factors significantly associated with pathologic N1 involvement. However, in multivariate analysis, only the SUV(maxE) was factor significantly associated with pathologic N1 involvement in NSCLC. CONCLUSIONS: Based on the presented results, the dual-time point F-18 FDG PET/CT is not a useful method for the prediction of pathologic N1 status in NSCLC patients. Further studies are needed to confirm these results and improve statistical accuracy. PMID- 21552020 TI - Outpatient radioiodine therapy for thyroid cancer: a safe nuclear medicine procedure. AB - PURPOSES: To evaluate the dosimetric effect of outpatient radioiodine therapy for thyroid cancer in members of a patient's family and their living environment, when using iodine-131 doses reaching 7.4 GBq. The following parameters were thus defined: (a) whole-body radiation doses to caregivers, (b) the production of contaminated solid waste, and (c) radiation potential and surface contamination within patients' living quarters. METHODS: In total, 100 patients were treated on an outpatient basis, taking into consideration their acceptable living conditions, interests, and willingness to comply with medical and radiation safety guidelines. Both the caregivers and the radiation dose potentiality inside patients' residences were monitored by using thermoluminescent dosimeters. Surface contamination and contaminated solid wastes were identified and measured with a Geiger-Muller detector. RESULTS: A total of 90 monitored individuals received a mean dose of 0.27 (+/-0.28) mSv, and the maximum dose registered was 1.6 mSv. The mean value for the potential dose within all living quarters was 0.31 (+/-0.34) mSv, and the mean value per monitored surface was 5.58 Bq/cm(2) for all the 1659 points measured. The overall production of contaminated solid wastes was at a low level, being about 3 times less than the exemption level indicated by the International Atomic Energy Agency. CONCLUSIONS: This study indicates that the treatment of thyroid cancer by applying radioiodine activities up to 7.4 GBq, on an outpatient basis, is a safe procedure, especially when supervised by qualified professionals. This alternative therapy should be a topic for careful discussion considering the high potential for reducing costs in healthcare and improving patient acceptance. PMID- 21552021 TI - Commentary on Willegaignon et al.: outpatient radioiodine therapy for thyroid cancer: a safe nuclear medicine procedure. PMID- 21552022 TI - Primary tumor volume measured by FDG PET and CT in nasopharyngeal carcinoma. AB - BACKGROUND: The prognostic value of CT-derived primary tumor volume in patients with nasopharyngeal carcinoma (NPC) has been demonstrated in our previous serial studies. The purpose of the present study is to compare the primary tumor volume measured by FDG PET and traditional CT in NPC, and to ascertain their prognostic value. MATERIALS AND METHODS: From 2007 to 2008, 32 patients with newly diagnosed NPC were prospectively studied. All patients underwent a CT scan, followed by a FDG PET/CT scan. CT-derived primary tumor volume (VolumeCT) was measured using the summation-of-area technique. PET-volume was measured using 3 methods: delineating the contour of tumor with the threshold of standardized uptake value (SUV) ?2.5 (Volume2.5), ?40% of maximal SUV (Volume40%), and ?50% of maximal SUV (Volume50%). The primary tumor volumes derived from the 4 methods, VolumeCT, Volume2.5, Volume40%, and Volume50%, were compared. Univariate Cox regression was used to identify the above parameters as prognosticators. RESULTS: The volumes derived from the VolumeCT, Volume2.5, Volume40%, and Volume50% methods were 16.48 +/- 12.46 cm(3), 25.87 +/- 16.96 cm(3), 13.66 +/- 6.90 cm(3), and 8.25 +/- 4.52 cm(3), respectively. There was decent correlation between VolumeCT and Volume2.5 (r = 0.64, P = 0.0001), and Volume2.5 was systemically larger than VolumeCT. No significant difference was noted between VolumeCT and Volume40% (P = 0.24), but the correlation was poor (r = 0.15, P = 0.39). For VolumeCT and Volume50%, the difference was significant (P = 0.0006) and the correlation was poor (r = 0.23, P = 0.20). Larger tumor volumes presented as VolumeCT, Volume2.5, and Volume50% were associated with shorter overall survival. CONCLUSION: PET-derived primary tumor volumes are substantially different from CT-derived tumor volumes, only decent correlation is noted between VolumeCT and Volume2.5. Volume2.5 and Volume50% seem to be reasonable alternatives for VolumeCT in predicting the patient outcomes. PMID- 21552023 TI - Increased F-18 FDG intestinal uptake in diabetic patients on metformin: a matched case-control analysis. AB - PURPOSE: A matched case-control study was performed to assess the relationship between metformin use and the degree of F-18 fluorodeoxyglucose (FDG) bowel activity in diabetic patients. MATERIALS AND METHODS: Seventy-seven diabetic patients referred to our department for a positron emission tomography/computed tomography study, including 45 on metformin, were compared with nondiabetic controls matched for sex, age, and body mass index. Positron emission tomography studies were obtained in a standard manner and reviewed in a blinded fashion. F 18 FDG uptake in the GI tract was evaluated quantitatively using maximal standardized uptake values and visually using a previously published semiquantitative scale. RESULTS: F-18 FDG uptake in small and large bowel was significantly increased in metformin patients compared with nondiabetic controls both visually and quantitatively (all P < 0.0001), as well as compared with nonmetformin patients with diabetes. Control sites (liver, fat, muscle) showed similar uptake. Multiple regression analysis confirmed that metformin was the variable most strongly associated with bowel uptake. CONCLUSION: Physiologic accumulation of F-18 FDG in bowel is increased in diabetic patients maintained on metformin. PMID- 21552024 TI - What is professionalism and how can we promote it? AB - Professionalism is understood differently by members of different professions and within the medical profession itself. In its broadest sense, medical professionalism encompasses all of the aspects of the higher attributes of being a physician. This article explores some of the characteristics of being a professional, some of its challenges, and what we can do to promote professionalism. PMID- 21552025 TI - Whole-body FDG PET/CT in diagnosis of internal mammary nodal metastasis of ovarian carcinosarcoma. AB - Internal mammary lymph node is rare metastatic site in ovarian neoplasm. In this study, we report an ovarian carcinosarcoma with peritoneal carcinomatosis initially. Annually, whole-body FDG PET/CT is indicated during 4 years. Tiny peritoneal nodules are found on the first-time FDG PET/CT imaging. A high grade of FDG-avid internal mammary nodal activity is shown on the secondary time of FDG PET/CT imaging. Pathologic result of excision biopsy demonstrates carcinoma metastasis. On the recent imaging, significant FDG-avid peritoneal and subphrenic carcinomatosis has happened again. After surgery and chemotherapy, the patient is still followed up in clinic. PMID- 21552026 TI - FDG PET/CT findings of a glomangiopericytoma. AB - Glomangiopericytoma (GPC) is a rare vascular neoplasm that arises almost exclusively from the nasal cavity or paranasal sinuses. GPC is also called sinonasal-type hemangiopericytoma, although current nomenclature, as well as classification in a group with myopericytomas, better emphasizes the relatively indolent behavior of this tumor. The authors present the FDG PET/CT findings of GPC in a 53-year-old with symptoms of nasal congestion and facial pressure. CT and MRI showed a nasal mass to extend along the sphenoid ridge from the posterior nasal cavity into the posterior nasopharynx. PET showed the mass to have uniformly low-grade FDG hypermetabolism. Pathologic examination of the surgical specimen showed classic features of GPC. PMID- 21552027 TI - Benign intrapulmonary schwannoma: aspect on F-18 fluorodeoxyglucose PET/CT. AB - A 75-year-old man, with no significant symptoms, was referred after the incidental finding of a left hilar pulmonary mass of 30 * 30 * 50 mm on a chest CT. F-18 fluorodeoxyglucose (FDG) PET/CT demonstrated a heterogeneous, moderate radiotracer uptake in the mass (SUV 3.5 g/mL). Bronchoscopy revealed a discrete extrinsic compression of the superior bronchus without endobronchial lesion. Endobronchial fine-needle biopsies could not deliver a final diagnosis. The patient underwent upper lobectomy by thoracotomy. Histopathology revealed a benign intrapulmonary schwannoma. Although rare, intermediate FDG uptake in the settings of a pulmonary mass should include schwannoma in the differential diagnosis. PMID- 21552028 TI - PET/CT in a patient with adenoma malignum of the uterine cervix. AB - The findings of positron emission tomography combined with computed tomography (PET/CT) in a patient with FIGO stage IIA adenoma malignum of the uterine cervix are described in this article. PET/CT showed that the cervical tumor was intensely hypermetabolic with no evidence of disease spread. However, lymphadenectomy revealed metastatic spread to paraaortic lymph nodes. PET/CT may be useful in identifying primary site of disease in patients with adenoma malignum; however, the utility in detecting metastatic nodal disease remains to be determined. PMID- 21552029 TI - Metastasis of malignant melanoma to common biliary duct demonstrated with F-18 FDG PET/CT. AB - Malignant melanoma is well known for its propensity to spread to unpredictable sites. F-18 FDG PET can highlight metastases at unusual sites that may be missed with conventional imaging modalities. In this study, we present the case of a 57 year-old male patient who was referred to our department for PET/CT imaging because of metabolic characterization of the lesion located in distal common biliary duct and biopsied as malignant melanoma. His PET/CT images revealed a hypermetabolic lesion at the mentioned site. Interestingly, his images also showed mild FDG accumulation on right frontoparietal skin, and the biopsy of this lesion was also reported as malignant melanoma. PMID- 21552030 TI - F-18 FDG PET/CT findings of primary sinonasal hemangiopericytoma: rare location in a young adult patient. AB - Hemangiopericytoma is an unusual tumor that arises from vascular smooth muscle cells. It is mainly experienced in 4th to 5th decades of life and soft-tissue masses are frequently located in lower extremity, pelvis, and retroperitoneum. A 29-year-old man presented with a mass lesion in the right nasal cavity associated with shortness of breath as a result of nasal obstruction. An incisional biopsy was reported as sinonasal type hemangiopericytoma. The initial staging F-18 flourodeoxyglucose PET/CT successfully demonstrated severe hypermetabolism in the primary tumor location and mild-to-moderate hypermetabolism in the right upper jugular lymph node. PMID- 21552031 TI - F-18 FDG PET/CT imaging of metastatic extrarenal Wilms tumor arising in the inguinal canal. AB - Extrarenal Wilms tumor (ERWT) is rare, and has been reported sporadically in the literatures. ERWT can arise anywhere from the renal bed to the testes; reported locations of ERWTs include the retroperitoneum, inguinal canal, endocervix, uterus, epididymis, and sigmoid mesocolon. We report the F-18 FDG PET/CT imaging findings of an ERWT arising from the inguinal canal in a 9-year-old boy. F-18 FDG accumulated in the metastatic lesions of the lung and mediastinal lymph nodes, as well as the primary ERWT. After chemotherapy, a follow-up PET/CT showed complete metabolic remission. F-18 FDG PET/CT is useful in detecting primary and metastatic ERWTs and in evaluating treatment response. PMID- 21552032 TI - Pancreatic metastasis detected by F-18 FDG PET/CT in a patient with breast cancer. AB - Pancreatic involvement by metastasis from other primaries is rare and accounts for approximately 2% to 4% of pancreatic tumors. In this article, we describe FDG avid pancreatic involvement in a patient with diagnosis of breast cancer. We conclude that FDG PET can be a convenient noninvasive method of early detection of recurrence and in monitoring metastatic disease during follow-up in such patients. A positive FDG PET warrants histopathologic correlation for appropriate treatment. PMID- 21552033 TI - Simultaneous occurrence of typical carcinoid and non-small-cell lung cancer in the same lung lobe: value of nuclear medicine. AB - The present report demonstrates the usefulness of nuclear medicine in differentiating different pulmonary tumors. A 79-year-old woman presented with a suspicious peripherally located lesion of the right lower lobe in the costophrenic angle. During bronchoscopic evaluation, a centrally located intrabronchial lesion was found, which was positive on a subsequent In-111 octreotide examination. The histologic examination of this central lesion confirmed a typical bronchial carcinoid. The FDG PET examination revealed a high uptake just in the peripherally located lesion, which was then confirmed to be non-small-cell lung cancer. This is the first report of nuclear medicine methods evaluating simultaneous occurrence of a typical bronchial carcinoid and a non small-cell lung cancer in the same lung lobe. PMID- 21552034 TI - PET/CT appearance of appendiceal adenocarcinoma. AB - Appendiceal cancer is rare and is associated with a poor prognosis because it is usually found at an advanced stage. We report the case of a 58-year-old man with appendiceal adenocarcinoma, who complained of right lower abdominal malaise for a couple of months. The tumor was detected early on contrast-enhanced computed tomography and F-18 FDG PET/CT. It appeared as an obvious enhancement and intense abnormal tracer uptake focus in front of the right psoas major, which was easily misinterpreted as an enlarged lymph node. PMID- 21552035 TI - Ectopic parathyroid carcinoma presenting with hypercalcemic crisis, ectopic uptake in bone scan and obstruction of superior vena cava. AB - A 28-year-old Chinese man diagnosed with hypercalcemic crisis was referred for Tc 99m sestamibi parathyroid imaging, which revealed a massive sestamibi-avid lesion in right-site of upper mediastinum. Contrast-enhanced CT demonstrated the lesion encroached and obstructed bilateral innominate veins and superior vena cava. Tc 99m methylene diphosphonate (MDP) bone scan and SPECT displayed ectopic uptakes in the lungs and stomach. Preoperative suspicion of parathyroid carcinoma prompted an en bloc surgery, which was confirmed in histopathology. Our case showed that although ectopic parathyroid carcinoma causing hypercalcemic crisis, extraskeletal microcalcifications, and great vessel obstruction is rare, parathyroid imaging and bone scan can help solve these diagnostic challenges. PMID- 21552036 TI - Liver herniation through the foramen of Morgagni: a pitfall in oncologic F-18 FDG PET/CT evaluation of the anterior mediastinum. AB - Diaphragmatic hernias are characterized by defects in the diaphragm that allow herniation of abdominal contents into the thorax. Herniation through the retrosternal foramen of Morgagni is rare, with less than 300 adult cases reported in the literature. This is a case of a 90-year-old woman who was diagnosed with herniation of the liver through the foramen of Morgagni on F-18 FDG PET/CT scan, which was done for the evaluation of a lung mass. Herniation of liver through the foramen of Morgagni is a potential pitfall in oncologic F-18 FDG PET/CT imaging, as it may mimic any FDG-avid anterior mediastinal mass, benign or malignant, especially in the presence of significant respiratory artifacts that commonly degrade image quality at the lung bases. PMID- 21552037 TI - Schmorl's node may cause an increased FDG activity. AB - Schmorl's node is an intraspongious disc herniation, which is formed within the vertebral body through a cartilaginous endplate. Schmorl's nodes are commonly seen at radiographic examination or autopsy. Schmorl's nodes are generally considered to be asymptomatic. In this article, we demonstrate the incidental findings of moderate FDG uptake in the Schmorl's node. PMID- 21552038 TI - FDG PET/CT incidental diagnosis of a synchronous bladder cancer as a fourth malignancy in a patient with head and neck cancer. AB - A 74-year-old man with 40-year history of smoking and known history of chronic lymphocytic leukemia and cutaneous T-cell lymphoma underwent FDG PET/CT examination for a recent diagnosis of squamous cell carcinoma diagnosed from right frontal crown and left posterior ear skin biopsy. PET images revealed multiple FDG-avid lesions in the head and neck, highly suspicious for nodal metastases. Reviewing CT portion of PET/CT examination revealed a hyperattenuating density in the posterior bladder wall. This lesion was not noticed initially due to the intense physiologic bladder uptake. On lowering the intensity, this lesion showed intense FDG avidity on the PET portion of the examination. Cytoscopic biopsy revealed low-grade papillary urothelial cell carcinoma. PMID- 21552039 TI - Use of Ga-68 DOTATATE PET/CT to confirm portal vein tumor thrombosis in a patient with pancreatic neuroendocrine tumor. AB - A 37-year-old man complained of increasing severity and frequency of abdominal pain over a 2-year period. Initial contrast-enhanced computed tomography of the abdomen demonstrated diffuse enlargement of the pancreas associated with a filling defect in the portal vein, splenomegaly with wedge-shaped peripheral splenic hypodensities and multiple hepatic hypodensities. Findings were suggestive of a pancreatic malignancy complicated by hepatic metastases, splenic infarcts, and portal vein thrombosis. We describe the use of gallium-68 DOTA DPhe1, Tyr3-octreotate positron emission tomography/computed tomography (Ga-68 DOTATATE PET/CT) in confirming the diagnosis of a pancreatic neuroendocrine tumor with portal vein tumor thrombosis. PMID- 21552040 TI - Current readings in nuclear medicine. PMID- 21552042 TI - Can intraoperative technical difficulty predict the long-term outcome in laparoscopic surgery for colorectal cancer? PMID- 21552046 TI - The impact of smoking on perianal disease. PMID- 21552047 TI - Single incision laparoscopic colectomy: boutique surgery or the new standard? PMID- 21552049 TI - The efficacy of nonoperative management of acute complicated diverticulitis. AB - BACKGROUND: The surgical management of acute complicated diverticulitis has evolved to avoid emergency surgery in favor of elective resection. The optimal manner to accomplish this goal remains debatable. OBJECTIVE: The purpose of this study was to examine the efficacy of nonoperative management of acute diverticulitis with abscess or perforation. DESIGN: A retrospective review was performed of an institutional review board-approved database of patients admitted with a diagnosis of acute complicated diverticulitis from 1995 to 2008. Patient demographics, disease manifestation, management, and outcomes were collected. SETTINGS: This study was conducted at a tertiary care hospital/referral center. PATIENTS: Patients were included who presented with complicated diverticulitis defined as having an associated abscess or free air diagnosed by CT scan. MAIN OUTCOME MEASURES: Primary end points were the success of nonoperative management and need for surgery during the initial admission. RESULTS: One hundred thirty six patients were identified with perforated diverticulitis: 19 had localized free air, 45 had abscess <4 cm or distant free air measuring <2 cm, 66 had abscess >4 cm or distant free air >2 cm, and 6 had distant free air with free fluid. Thirty-eight patients (28%) required percutaneous abscess drains and 37 (27%) required parenteral nutrition. Only 5 patients (3.7%) required urgent surgery at the time of admission, and 7 (5%) required urgent surgery for failed nonoperative management. Thus, the overall success rate of nonoperative management was 91%. One hundred twenty-four of 131 (95%) patients were treated with nonoperative management successfully. Twenty-five of 27 (92.5%) patients with free air remote from the perforation site were successfully treated nonoperatively. CONCLUSIONS: Nonoperative management of acute complicated diverticulitis is highly effective. For patients with free air remote from the site of perforation, nonoperative management is able to convert an emergent situation into an elective one in 93% of cases. The decision to attempt nonoperative therapy must be made based on the patient's physiologic state and associated comorbidities. PMID- 21552050 TI - The effects of short-course preoperative irradiation on local recurrence rate and survival in rectal cancer: a population-based nationwide study. AB - BACKGROUND: Preoperative irradiation with 5 * 5 Gy in randomized trials reduces local recurrence rate and may improve survival in patients with resectable rectal cancer. OBJECTIVE: The aim of this study was to determine whether the same favorable effects could be observed in a population-based study. DESIGN: This study was conducted via a retrospective analysis of prospectively collected data from the Swedish Rectal Cancer Registry. SETTINGS: This study examined population based data from Sweden. PATIENTS: All newly diagnosed rectal cancers in Sweden are reported to the Swedish Rectal Cancer Registry. INTERVENTIONS: Between 1995 and 2001, 6878 patients (stages I-III) were operated on with an anterior resection, an abdominoperineal resection, or a Hartmann's procedure. Short-course irradiation was given to 41% of patients preoperatively. To reduce bias, patients operated on with a Hartmann procedure or older than 75 years were excluded when 5 year survival was analyzed (n = 3466). Tumors were analyzed according to height (0-5 cm, 6-10 cm, 11-15 cm). MAIN OUTCOME MEASURES: Five-year cumulative local recurrence and survival rates. RESULTS: The 5-year cumulative local recurrence rate was 6.3% (95% CI 5.4-7.4) for patients receiving preoperative irradiation and 12.1% (95% CI 10.8-13.5) for patients not receiving preoperative irradiation. Multivariate analyses indicated the risk of local recurrence was 50% lower for patients receiving preoperative irradiation compared with patients not receiving irradiation (hazard ratio = 0.50; 95% CI 0.40-0.62). Among patients younger than 76 years and operated on with an anterior resection or abdominoperineal resection, the 5-year cumulative survival rate was 0.70 (95% CI 0.69-0.72). Disease-free and overall survivals were higher in irradiated patients, and the difference was statistically significant in low tumors. CONCLUSIONS: In this population-based analysis, the favorable effect of preoperative short-course irradiation on local recurrence rates, seen in randomized trials, was confirmed for the entire Swedish population irrespective of tumor height and stage. Data also suggested an effect on 5-year survival, especially in patients with low tumors (0-5 cm). PMID- 21552051 TI - Recent smoking is a risk factor for anal abscess and fistula. AB - BACKGROUND: Smoking is a risk factor for inflammatory, fistulizing cutaneous diseases. It seems reasonable that smoking might be a risk factor for anal abscess/fistula. OBJECTIVE: This study aimed to test the hypothesis that recent smoking is a risk factor for development of anal abscess/fistula. DESIGN: This is a case-control study. SETTINGS: This study was conducted at a Department of Veterans Affairs general surgical clinic. PATIENTS: Included in the study were 931 patients visiting the general surgical clinic over a 6-month period. INTERVENTIONS: A tobacco use questionnaire was administered. MAIN OUTCOME MEASURES: Patients with anal abscess/fistula history were compared with controls, who had all other general surgical conditions. To investigate the temporal relation between smoking and the clinical onset of anal abscess/fistula, we compared the group consisting of current smokers and former smokers who had recently quit, against the group consisting of nonsmokers and former smokers who had quit a longer time ago (ie, not recently). We excluded patients with IBD and HIV. RESULTS: Cases and controls were comparable in age (57 and 59 y) and sex (93% and 97% male). After exclusions, there were 74 anal abscess/fistula cases and 816 controls. Among the anal abscess/fistula cases, 36 patients had smoked within 1 year before the onset of anal abscess/fistula symptoms, and 38 had not smoked within the prior year; among controls, 249 had smoked within 1 year before seeking surgical treatment, and 567 had not (OR 2.15, 95% CI 1.34-3.48, 2-tail P = .0025). Using a 5-year cutoff for recent smoking, the association was less pronounced but still significant (OR 1.72, 95% CI 1.03-2.86, P = .0375), and the association was insignificant at 10 years (OR 1.34, 95% CI 0.78-2.21, P = .313). LIMITATIONS: Limitations of the study included self-selection bias, recall bias, convenience sample, and noninvestigation of the dose-response relationship. CONCLUSIONS: Recent smoking is a risk factor for anal abscess/fistula development. As in other smoking-related diseases, the influence of smoking as a risk factor for anal abscess/fistula diminishes to baseline after 5 to 10 years of smoking cessation. Anal abscess/fistula can be added to the list of chronic, inflammatory cutaneous conditions associated with smoking. PMID- 21552052 TI - Prospective multicenter trial comparing echodefecography with defecography in the assessment of anorectal dysfunction in patients with obstructed defecation. AB - BACKGROUND: Defecography is the gold standard for assessing functional anorectal disorders but is limited by the need for a specific radiologic environment, exposure of patients to radiation, and inability to show all anatomic structures involved in defecation. Echodefecography is a 3-dimensional dynamic ultrasound technique developed to overcome these limitations. OBJECTIVE: This study was designed to validate the effectiveness of echodefecography compared with defecography in the assessment of anorectal dysfunctions related to obstructed defecation. DESIGN: Multicenter, prospective observational study. PATIENTS: Women with symptoms of obstructed defecation. SETTING: Six centers for colorectal surgery (3 in Brazil, 1 in Texas, 1 in Florida, and 1 in Venezuela). INTERVENTIONS: Defecography was performed after inserting 150 mL of barium paste in the rectum. Echodefecography was performed with a 2050 endoprobe through 3 automatic scans. MAIN OUTCOME MEASURES: The kappa statistic was used to assess agreement between echodefecography and defecography in the evaluation of rectocele, intussusception, anismus, and grade III enterocele. RESULTS: Eighty six women were evaluated: median Wexner constipation score, 13.4 (range, 6-23); median age, 53.4 (range, 26-77) years. Rectocele was identified with substantial agreement between the 2 methods (defecography, 80 patients; echodefecography, 76 patients; kappa = 0.61; 95% CI = 0.48-0.73). The 2 techniques demonstrated identical findings in 6 patients without rectocele, and in 9 patients with grade I, 29 with grade II, and 19 patients with grade III rectoceles. Defecography identified rectal intussusception in 42 patients, with echodefecography identifying 37 of these cases, plus 4 additional cases, yielding substantial agreement (kappa = 0.79; 95% CI = 0.57-1.0). Intussusception was associated with rectocele in 28 patients for both methods (kappa = 0.62; 95% CI = 0.41-0.83). There was substantial agreement for anismus (kappa = 0.61; 95% CI = 0.40-0.81) and for rectocele combined with anismus (kappa = 0.61; 95% CI = 0.40-0.82). Agreement for grade III enterocele was classified as almost perfect (kappa = 0.87; 95% CI = 0.66-1.0). LIMITATIONS: Echodefecography had limited use in identification of grade I and II enteroceles because of the type of probe used. CONCLUSIONS: Echodefecography may be used to assess patients with obstructed defecation, as it is able to detect the same anorectal dysfunctions found by defecography. It is minimally invasive and well tolerated, avoids exposure to radiation, and clearly demonstrates all the anatomic structures involved in defecation. PMID- 21552053 TI - The hemorrhoid laser procedure technique vs rubber band ligation: a randomized trial comparing 2 mini-invasive treatments for second- and third-degree hemorrhoids. AB - BACKGROUND: Hemorrhoid laser procedure is a new laser procedure for outpatient treatment of hemorrhoids in which hemorrhoidal arterial flow feeding the hemorrhoidal plexus is stopped by means of Doppler-guided laser coagulation. OBJECTIVE: Our aim was to compare the hemorrhoid laser procedure with rubber band ligation for outpatient treatment of symptomatic hemorrhoids with moderate mucosal prolapse. DESIGN: This was a randomized controlled trial with balanced allocation to hemorrhoid laser procedure or rubber band ligation, with stratification by study center. SETTING: This study was conducted at 2 teaching hospitals in Italy. PATIENTS: Patients with symptomatic grade II or grade III hemorrhoids with minimal mucosal prolapse were eligible for the study. INTERVENTIONS: In the hemorrhoid laser procedure operation, a Doppler probe was inserted into the anal canal through a dedicated disposable proctoscope to identify the terminal branches of superior hemorrhoidal arteries approximately 3 cm above the dentate line. Five pulsed laser shots were delivered to each identified artery through the proctoscope to close the terminal branches. The procedure was repeated for each artery through clockwise rotation of the proctoscope. Absence of a Doppler signal after treatment confirmed arterial coagulation. Rubber band ligation was performed by positioning rubber bands at the base of left lateral, right anterior, and right posterior piles. No anesthesia was given for either technique. MAIN OUTCOME MEASURES: Operative time, complications, postoperative pain (visual analog scale), postoperative downgrading of hemorrhoids, resolution of symptoms, and quality of life were evaluated. RESULTS: A total of 60 patients (35 women, 25 men; mean age, 46 years) entered the trial and were analyzed. No significant differences between rubber band ligation and hemorrhoid laser procedure were observed in operative time or intraoperative morbidity. The median postoperative pain score was 2.9 (range, 1 5) with rubber band ligation vs 1.1 (range, 0-2) for hemorrhoid laser procedure (P < .001). At 6 months, resolution of symptoms was observed in 16 patients (53%) with ligation vs 27 (90%) with hemorrhoid laser procedure (P < .001), and reduction of hemorrhoids by at least 1 grade was observed in 12 patients (40%) with ligation vs 24 (80%) with hemorrhoid laser procedure (P < .001). Significantly higher quality of life was seen in the hemorrhoid laser procedure group (P = .002). LIMITATIONS: Follow-up was not longer than 1 year (median, 6 mo). CONCLUSIONS: Despite higher cost, the hemorrhoid laser procedure technique was more effective than rubber band ligation in reducing postoperative pain, resolving symptoms, and improving quality of life in patients with grade II or III hemorrhoids with incomplete mucosal prolapse. PMID- 21552054 TI - Topical sucralfate treatment of anal fistulotomy wounds: a randomized placebo controlled trial. AB - BACKGROUND: Sucralfate is a cytoprotective agent which adheres to mucoproteins and forms a protective barrier at wound sites. In oral form it is a common ulcer medication, and as a topical preparation it has been used to treat a wide variety of wounds. OBJECTIVE: The present study was designed to evaluate the effectiveness and safety of topical sucralfate in wound healing after anal fistulotomy. DESIGN: Double-blind, randomized controlled study comparing topical application of sucralfate or placebo. SETTING: Private outpatient clinic specializing in anorectal disease in Nagpur, India. PATIENTS: Patients with a wound length of at least 5 cm after low anal fistulotomy were eligible for the study. INTERVENTION: Patients were randomly assigned to receive ointment containing 7% sucralfate or a placebo ointment consisting of petroleum jelly. Patients were instructed to apply approximately 3 g of ointment to the wound twice daily after a sitz bath for 6 weeks or until the wound had healed. MAIN OUTCOME MEASURES: The wounds were examined by a blinded independent observer at 2, 4, and 6 weeks after the operation. The primary end point was the proportion of patients with wounds that had completely healed. Secondary end points included amount of mucosal covering (scored by the observer), adverse events, and postoperative pain (self-rated on a visual analog scale). RESULTS: Of 80 participants (29 women, 51 men; median age, 23 (range, 17-49) years), 76 participants completed the trial (sucralfate, 39; placebo, 37). At 6-week follow up, complete wound healing was achieved in 37 patients (95%) in the sucralfate group and 27 patients (73%) in the placebo group (P = .009). Mucosal coverage of the wound was significantly greater with sucralfate than with placebo at each measurement point (P = .01). No adverse events were observed. Postoperative pain scores were significantly lower for sucralfate than for placebo at 2 and 4 weeks after the start of treatment. LIMITATIONS: Wound tissue specimens were not available for morphological and ultrastructural analysis. CONCLUSIONS: The results of this study add support to the evidence that topical sucralfate is a safe and effective method for promoting mucosal healing and for providing analgesia during wound treatment. Patients undergoing anal fistulotomy can benefit from the use of topical application of sucralfate. PMID- 21552055 TI - Single-incision laparoscopic colectomy for colon cancer: early experience with 31 cases. AB - BACKGROUND: Transumbilical single-port surgery has been developed with the aim to further reduce the invasiveness of conventional laparoscopy. OBJECTIVE: This study aimed to report our experience with 31 patients who were treated with transumbilical single-incision laparoscopic colectomy for colon cancer. DESIGN: This is a retrospective review of prospectively gathered data. SETTINGS: This study was conducted at the Department of Surgery of Juntendo University Urayasu Hospital between April 2009 and April 2010. Data were obtained from a prospectively maintained single-institution laparoscopic colon cancer database. PATIENTS: Thirty-one consecutively selected patients (mean BMI, 22.5 +/- 2.3) were evaluated. INTERVENTIONS: All patients underwent single-incision laparoscopic colectomy for colon cancer. Two different approaches were used for single-incision laparoscopic colectomy: the trocar insertion method and the SILS port method. The trocar insertion method was adopted in 22 of 31 patients, and the SILS port method was used in 9 patients. MAIN OUTCOME MEASURES: The main measures of outcomes were intraoperative findings, postoperative course, and oncological outcomes. RESULTS: The most common procedure was sigmoid colon resection performed in 12 of 31 (39%) patients. The mean skin incision was 2.72 +/- 0.79 (range, 3-5) cm. The operating time ranged from 101 to 263 (mean, 156 +/ 45) minutes. The volume of bleeding ranged from 5 to 60 (mean, 27 +/- 19) mL. No intraoperative complications were observed in this series. Postoperatively, there was no mortality. Wound infection was observed in 1 patient. The number of harvested lymph nodes was 18 +/- 2.1, and the mean tumor-free resection margin was 11 +/- 4.8 cm. CONCLUSION: Our experience indicates that single-incision laparoscopic colectomy is feasible for selected patients with colon cancer. PMID- 21552056 TI - Perineal repair after extralevator abdominoperineal excision for low rectal cancer. AB - BACKGROUND: Extralevator abdominoperineal excision for low rectal cancer includes resection of the pelvic floor as a part of the operative technique to reduce the risk of tumor-involved section margins. OBJECTIVE: This study aimed to compare perineal defect reconstruction with a fasciocutaneous gluteal flap vs biological mesh regarding healing and occurrence of perineal hernia. DESIGN: Retrospective review of medical records comparing surgical methods during 2 consecutive periods. SETTINGS: Tertiary care university medical center (Colorectal Section, Surgical Department P, Aarhus University Hospital, Denmark). PATIENTS: Patients with low rectal cancer who underwent extralevator abdominoperineal excision from December 2005 through October 2008 were included. INTERVENTION: The perineum was reconstructed with a fasciocutaneous gluteal flap in the first period and with a biological mesh in the second period. MAIN OUTCOME MEASURES: We assessed rates of perineal wound infection requiring surgical intervention and perineal hernia diagnosed by clinical examination. RESULTS: The study comprised 57 patients: 33 patients with gluteal flap and 24 with biological mesh reconstruction. Perineal hernia developed in 7 (21%) patients in the gluteal flap group and in none (0%) of the patients in the mesh group (P < .01). Median follow-up was 3.2 (1.7-4.3) years for gluteal flap and 1.7 (0.4-2.2) years for biologic mesh. All hernias occurred within the first postoperative year (median, 6 months; range, 1-12 months). Infectious complications were seen in 2 patients (6%) with a gluteal flap and in 4 patients (17%) with mesh repair (P = .26). After 3 months, all patients were completely healed except for 1 patient in each group with a persistent perineal sinus. The median (range) hospital stay was 14 (8-23) days in the flap group and 9 days (6-35) in the mesh group (P < .05). LIMITATIONS: This was a nonrandomized retrospective observational study comparing 2 methods used in different time periods. CONCLUSION: We recommend biological mesh reconstruction of the pelvic floor after extralevator abdominoperineal resection because this method can achieve a high healing rate with an acceptable risk of infection, a low hernia rate, and a shorter hospital stay without donor-site morbidity. PMID- 21552057 TI - Modified pseudocontinent perineal colostomy: a special technique. AB - BACKGROUND: Innovative techniques created to restore gastrointestinal perineal continuity after abdominoperineal resection in patients with anorectal cancer include pseudocontinent perineal colostomy, in which the colon is pulled to the perineum and wrapped with a sleeve of stretched colon segment to act as a new sphincter. OBJECTIVE: We investigated perineal reconstruction with a modified pseudocontinent perineal colostomy technique. DESIGN: Prospective cohort study. SETTINGS: Tertiary care university hospital in Egypt. PATIENTS: Patients with T2 or T3 anorectal cancer invading the sphincter who underwent Miles abdominoperineal resection and immediate total pelvic reconstruction between 2003 and 2007. INTERVENTION: Reconstruction consisted of a vertical rectus abdominis myocutaneous flap with modified perineal colostomy pulled through the flap to add the high-pressure zone of the flap to that of the colostomy and to create a persistent new anorectal angle. MAIN OUTCOME MEASURES: Early and late complications were recorded. Functional results were evaluated at regular intervals by questionnaire, physical examination, and balloon manometry. Continence was graded according to Kirwan. Satisfaction with continence was assessed by questionnaire. RESULTS: A total of 14 patients (3 women) were included. Tumors were adenocarcinoma (n = 11), squamous-cell carcinoma (n = 2), and melanoma (n = 1). Complete (R0) resection was achieved in all patients without perioperative deaths, major postoperative morbidity, or conversion to permanent iliac colostomy. Early postoperative complications (perineal wound infection, flap dehiscence, and partial perineal stoma necrosis) occurred in the first 4 patients. Late complications occurred in 7 patients, with mucosal prolapse in 3, stomal stricture in 4, and tumor recurrence in 1. Fecal continence progressed consistently with time, and by the end of the first year 8 patients (57%) had complete continence (grade A), 5 (36%) were continent with minor soiling (grade C), and 1 (7%) still had major soiling (grade D). After 6 months, 9 patients (64%) were satisfied with continence; after 1 year, 13 patients (93%) were satisfied. Regular enemas were necessary during the first year to improve soiling, and 8 patients (57%) were not in need after that. At 37 months median follow-up, 8 of 9 evaluable patients (89%) were satisfied with continence (grade A) without regular enemas. LIMITATIONS: This was a preliminary observational study with no control group. CONCLUSIONS: Total orthotopic pelvic reconstruction with autologous tissue transposition to rebuild the principle anorectal continence elements is feasible with minor complications, and is oncologically safe. This new technique offered high continence satisfaction independent of regular enemas and electrical stimulation. PMID- 21552058 TI - Anal carcinoma in HIV-infected patients in the era of antiretroviral therapy: a comparative study. AB - BACKGROUND: Before the introduction of highly active antiretroviral therapy, prognosis of anal squamous-cell carcinoma was worse when patients were infected with HIV. Since then, contradictory results have been reported. OBJECTIVE: To compare the results of chemoradiotherapy in HIV-infected and uninfected patients with anal carcinoma. DESIGN: Retrospective analysis of medical records. SETTING: Tertiary care center in France. PATIENTS: Patients with invasive anal carcinoma treated from 2001 through 2006. INTERVENTIONS: Chemoradiotherapy included 60 Gy pelvic irradiation and cisplatin-based chemotherapy. Surgery was performed for local failures or complications. MAIN OUTCOME MEASURES: Tolerance for chemoradiotherapy, tumor control, and survival were evaluated. RESULTS: A total of 46 patients (20 HIV-infected and 26 uninfected) were treated for nonmetastatic anal carcinoma. Median follow-up was 32.5 (range, 7-84) months. HIV-infected patients were more likely to be men (95% vs 23%, P < .001) and were younger (median age, 46 vs 62 years, P < .001) than uninfected patients. The viral load was less than 200 copies/mL in 15 (75%) of the HIV-infected patients. The duration of chemoradiotherapy was longer in HIV-infected than in uninfected patients (median, 103 vs 84 days, P = .027). Chemoradiotherapy failed to achieve local control in 10 (50%) HIV-infected and in 6 (23%) uninfected patients (P = .057). In HIV-infected patients, failure rates were higher in patients who required prolonged chemoradiotherapy than in those who received treatment as scheduled (7/11, 64% vs 1/7, 14%; P = .039). During follow-up, 7 (35%) of the HIV infected and 3 (12%) of the uninfected patients died, all from anal carcinoma. The 5-year overall survival rate was 39% for HIV-infected and 84% for uninfected patients (P = .026); 5-year disease-free survival was 37% in HIV-infected and 75% in uninfected patients (P = .06). LIMITATIONS: Retrospective design, lack of data regarding precise toxicity grading, and use of cisplatin-based chemoradiotherapy. CONCLUSIONS: Even in the era of highly active antiretroviral therapy, HIV infected patients with anal squamous-cell carcinoma show impaired tolerance to chemoradiotherapy, have a lower survival rate, and may have a higher rate of local failure compared with uninfected patients. PMID- 21552059 TI - Improved clinical outcomes with a new contour-curved stapler in the surgical treatment of obstructed defecation syndrome: a mid-term randomized controlled trial. AB - BACKGROUND: Stapled transanal rectal resection has become the primary surgical procedure for surgical treatment of obstructed defecation syndrome caused by rectocele or rectal intussusception. The procedure is generally performed with 2 circular staplers. Recently, a dedicated contour-curved stapler was developed. OBJECTIVE: This study was designed to compare the effects of these stapler types on relief of symptoms. DESIGN AND SETTING: A randomized controlled trial was conducted at a regional referral center in Naples, Italy. PATIENTS: Patients with obstructed defecation syndrome and rectocele or rectal intussusception, treated from November 2005 through September 2007. INTERVENTIONS: Participants were randomly assigned to undergo stapled transanal rectal resection with 2 circular staplers or the contour-curved stapler. MAIN OUTCOME MEASURES: The primary end point was success rate at 24 months, defined by symptom improvement on an obstructed defecation syndrome scale. Secondary end points included success rate at 12 months, Agachan-Wexner constipation score, and rates of early and late complications at 12 and 24 months. RESULTS: Of 198 patients evaluated, 63 patients (31.8%) satisfied criteria. Follow-up data were available for 61 patients: 30 patients (28 women) in the circular stapler group (mean age, 53; range, 41-75 years) and 31 (29 women) in the contour-curved stapler group (mean age, 55; range, 38-69 years). At 24-month follow-up, success was achieved in 21 patients (70.0%) with the circular staplers and in 27 (87.0%) with the contour curved stapler (P = .10). Symptom scores improved significantly in both groups from baseline to 12 months (P < .0001). Improvement was maintained in the contour curved stapler group: mean score, 5.0 (SD, 1.6) at 12 months and 5.5 (1.5) at 24 months (P = .20). In the circular stapler group, symptom scores worsened from 4.5 (1.5) at 12 months to 9.0 (1.3) at 24 months (P < .0001). At 24 months, the groups differed significantly in symptom scores (P < .0001) and constipation scores (P = .03). No significant differences were seen in duration of postoperative hospital stay or rate of early or late complications. CONCLUSIONS: Stapled transanal rectal resection with either circular or contour-curved staplers can achieve relief of symptoms in patients with obstructed defecation syndrome. The contour-curved stapler appears to result in more stable clinical results over time. PMID- 21552060 TI - The effect of alvimopan on recovery after laparoscopic segmental colectomy. AB - BACKGROUND: Alvimopan, a peripherally acting MU-opioid receptor antagonist, was recently approved for the reduction of postoperative ileus after open colectomy. No data are available regarding the use of alvimopan following laparoscopic segmental colectomy. OBJECTIVE: This study was designed to evaluate the effectiveness of alvimopan in patients undergoing laparoscopic segmental colectomy. DESIGN: A retrospective review of segmental laparoscopic colectomy was conducted in a population of patients using an accelerated postcolectomy care pathway. Patients that received alvimopan were identified from an institutional review board-approved database and matched with nonalvimopan patients for age, sex, procedure, and diagnosis. Patients with a diverting ileostomy or with contraindications for alvimopam were excluded. RESULTS: One hundred patients undergoing laparoscopic colectomy received alvimopan perioperatively and were matched with a similar group of nonalvimopan patients. Although patients on alvimopan were significantly less likely to develop postoperative ileus (4% vs 12%; P = .04), there was no difference in length of hospital stay (3.63 days in the alvimopan group vs 3.78 in the nonalvimopan group; P = .84) or 30-day readmission rate (4.0% vs 4.2%; P = .95). CONCLUSIONS: As the cost of providing health care continues to increase, reductions in perioperative complications and hospital stay are important to hospital efficiency and patient care. Alvimopan effectively reduces the incidence of postoperative ileus in patients undergoing open colectomy; however, hospital stay and readmission rates were not altered in this laparoscopic group. Further study is required before alvimopan can be routinely used in patients undergoing laparoscopic colectomy. PMID- 21552061 TI - Does a defunctioning stoma affect anorectal function after low rectal resection? Results of a randomized multicenter trial. AB - BACKGROUND: Anorectal function is often impaired after low anterior resection of the rectum. Many factors affect the functional outcome and not all are known. OBJECTIVE: This trial aimed to assess whether a temporary defunctioning stoma affected anorectal function after the patients had been stoma-free for a year. DESIGN: Multicenter randomized controlled trial. SETTING: Twenty-one Swedish hospitals performing surgery for rectal cancer participated. PATIENTS: Patients who had undergone low anterior resection for adenocarcinoma of the rectum were eligible. INTERVENTIONS: Patients were randomly assigned to receive a defunctioning stoma or no stoma. MAIN OUTCOME MEASURES: Anorectal function was evaluated with a questionnaire after patients had been without a stoma for 12 months. Questions pertained to stool frequency, urgency, fragmentation of bowel movements, evacuation difficulties, incontinence, lifestyle alterations, and whether patients would prefer a permanent stoma. RESULTS: After exclusion of patients in whom stomas became permanent, a total of 181 (90%) of 201 patients answered the questionnaire (90 in the stoma group and 91 in the no-stoma group). The median number of stools was 3 during the day and 0 at night in both groups. Inability to defer defecation for 15 minutes was reported in 35% of patients in the stoma group and 25% in the no stoma group (P = .15). Median scores were the same in each group regarding need for medication, evacuation difficulties, fragmentation of bowel movements, incontinence, and effects on well-being. Two patients (2.2%) in the stoma group and 3 patients (3.3%) in the no-stoma group would have preferred a permanent stoma. LIMITATIONS: Because this study was an analysis of secondary end points of a randomized trial, no prestudy power calculation was performed. CONCLUSIONS: A defunctioning stoma after low anterior resection did not affect anorectal function evaluated after 1 year. Many patients experienced impaired anorectal function, but nearly all preferred having impaired anorectal function to a permanent stoma. PMID- 21552062 TI - Treatment for right colon polyps not removable using standard colonoscopy: combined laparoscopic-colonoscopic approach. AB - BACKGROUND: For complex right colon polyps, not removable using colonoscopy, right colon resection is considered the optimal treatment. Combined endoscopic laparoscopic surgery, using both laparoscopy and CO2 colonoscopy, has been introduced as a new approach for these complex colon polyps with intent to avoid bowel resection. OBJECTIVE: This study aimed to evaluate the safety and outcomes of combined endoscopic-laparoscopic surgery used for treatment of complex right colon polyps. DESIGN: This is a retrospective study of patients undergoing combined endoscopic-laparoscopic surgery for treatment of benign right colon polyps from 2003 to 2008. SETTINGS: This is a single-institution study. PATIENTS: Twenty-three patients with complex right colon polyps were included. MAIN OUTCOME MEASURES: The main outcome measures included the length of hospital stay, postoperative complications, and polyp recurrence. RESULTS: Of 23 patients, 20 (87%) patients had their polyp removed successfully by combined endoscopic laparoscopic surgery and 3 (13%) needed laparoscopic resection, after laparoendoscopic evaluation. The median length of hospital stay was 2 days (range, 1-5), and there were no postoperative complications. Median follow-up time was 12 months. Three patients had recurrent polyps, and the recurrence-free interval at 36 months was 55.7% (95% CI = 8.6%, 87.0%). All recurrences were benign polyps and were removed by colonoscopic snaring. CONCLUSIONS: Combined endoscopic-laparoscopic surgery can be safely offered to selected patients with benign right colon polyps that can not be removed by colonoscopy. This combined approach may provide a viable alternative to right colon resection for complex benign colon lesions and warrants future investigation. PMID- 21552063 TI - Anal canal vector volume manometry. AB - BACKGROUND: Anal manometry is routinely used in the assessment of the anal sphincters in patients with fecal incontinence or suspected sphincter injury. Such physiological information is complementary to the anatomical assessment provided by anal endosonography. The evolution of 3-dimensional anal endosonography provides more diagnostically useful information in complex cases. Vector volume manometry has been developed to give a 3-dimensional view of the anal sphincters. OBJECTIVE: We reviewed the published literature on this technique, with the intention of deriving a system of standardization based on the published literature and to summarize the derivation and physiological meaning of the parameters measurable by vector volume studies, as well. DATA SOURCES: We undertook a MEDLINE search using the terms "vector volume" or "vector manometry" and "anal canal." We also reviewed further publications found from references cited in the original articles identified from the above search. STUDY SELECTION: Only English language articles of studies performed on humans were reviewed. INTERVENTION: Anal canal vector volume manometry was the intervention. RESULTS: With the development of automated puller systems and associated software, parameters such as total vector volume, maximum pressure, mean pressure, anal canal symmetry, anal canal length, and the length of the high pressure zone can be readily calculated. LIMITATIONS: There are conflicting studies related to the clinical value of both anal manometry and vector volume manometry, in part, because of the lack of standardization of equipment and technique. CONCLUSIONS: The vector volume parameters have been shown to correlate with both imaging results and incontinence scores with automated puller systems. The clinical utility of vector volume manometry would be improved further by the standardization of equipment and technique. The main clinical utility may lie in the treatment selection and preoperative assessment of patients awaiting surgery for anal pathology that has yet to be evaluated. PMID- 21552064 TI - Psychiatric diagnoses after hospitalization with work-related burn injuries in Washington State. AB - This study aims to describe workers who were hospitalized with work-related burn injuries and their psychiatric sequelae in Washington State. Psychiatric sequelae of interest were depression, posttraumatic stress disorder, and other anxiety disorders. Workers' compensation claims meeting a definition for a hospitalized burn patient from Washington State from January 2001 through April 2008 were analyzed. The resulting claims were searched for the presence of certain psychiatric diagnoses or treatment codes, and descriptive analyses performed. In Washington State during the time period, the prevalence of claims with psychiatric diagnoses after hospitalization with burn injury was 19%. Claims with psychiatric diagnoses had higher medical costs and more days of time loss than those without these diagnoses. Workers with electrical burns in the construction industry and in construction and extraction occupations had a higher proportion of psychiatric sequelae. Burns are devastating yet preventable injuries. Workers who were hospitalized with work-related burn injuries, particularly those in certain industries and occupations and those with electrical burns, are at high risk for developing serious psychiatric sequelae with major costs to both the individual and the society. PMID- 21552066 TI - Principles of learning in TBI rehabilitation. PMID- 21552067 TI - The impact of verbal memory encoding and consolidation deficits during recovery from moderate-to-severe traumatic brain injury. AB - OBJECTIVE: Encoding and consolidation deficits appear to account for verbal memory impairment following traumatic brain injury (TBI). It is unknown whether these abilities vary during TBI recovery. We sought to determine the pattern and impact of verbal encoding and consolidation deficits following TBI. METHODS: Twenty-three participants with moderate-to-severe TBI and 25 age- and education matched control participants' verbal memory abilities were assessed at 2 time points approximately 1 year apart; assessments occurred at acute and chronic visits for TBI survivors. MAIN OUTCOME MEASURES: Rey Auditory Verbal Learning Test and Item Specific Deficit Approach indices of encoding, consolidation, and retrieval deficits. RESULTS: In contrast to the controls, participants with TBI showed impaired verbal memory characterized by encoding and consolidation deficits at both time points. The TBI group's short-delayed recall and consolidation scores improved between the acute and chronic assessments. Encoding (primary) and consolidation (secondary) deficits emerged as predictors of acute and chronic recall in the TBI group. Also, acute visit encoding deficits predicted chronic visit delayed recall in TBI survivors, but acute consolidation deficits did not. CONCLUSIONS: These findings suggest that memory rehabilitation efforts focused on improving encoding of verbal material may be useful during both the acute and chronic phases of recovery following TBI. PMID- 21552068 TI - Impairments in learning, memory, and metamemory following childhood head injury. AB - OBJECTIVE: To assess postinjury changes in learning, memory, and metamemory abilities following childhood traumatic brain injury. DESIGN: Prospective, longitudinal with 5 assessments made from baseline to 24 months postinjury. PARTICIPANTS: A total of 167 children (aged 5-15 years) with traumatic brain injury (TBI; 64 severe, 55 moderate, and 48 mild). METHODS: Children completed a judgment of learning task with 4 recall trials and made 3 metamemory judgments. RESULTS: Relative to those with mild TBI, children with moderate or severe TBI performed worse at earlier times postinjury and had a greater change in performance over time. Performance for moderate and severe groups peaked at 12 months and the performance gap between them and mild TBI group increased slightly from 12 to 24 months. Traumatic brain injury severity did not affect initial study-recall trial performance, but groups did diverge in performance with repeated study. Greater TBI severity was associated with poorer performance on prospective metamemory judgments, but not retrospective judgments. CONCLUSIONS: Traumatic brain injury severity affected prospective judgments of memory performance and learning strategies, but did not appear to affect either word retention or the forgetting of words over a delay. Implications for rehabilitation are discussed. PMID- 21552069 TI - Applications of operant learning theory to the management of challenging behavior after traumatic brain injury. AB - For more than 3 decades, interventions derived from learning theory have been delivered within a neurobehavioral framework to manage challenging behavior after traumatic brain injury with the aim of promoting engagement in the rehabilitation process and ameliorating social handicap. Learning theory provides a conceptual structure that facilitates our ability to understand the relationship between challenging behavior and environmental contingencies, while accommodating the constraints upon learning imposed by impaired cognition. Interventions derived from operant learning theory have most frequently been described in the literature because this method of associational learning provides good evidence for the effectiveness of differential reinforcement methods. This article therefore examines the efficacy of applying operant learning theory to manage challenging behavior after TBI as well as some of the limitations of this approach. Future developments in the application of learning theory are also considered. PMID- 21552070 TI - Self-regulated learning in a dynamic coaching model for supporting college students with traumatic brain injury: two case reports. AB - OBJECTIVE: To describe a program that integrates self-regulated learning theory with supported education for college students with traumatic brain injury using a dynamic coaching model; to demonstrate the feasibility of developing and implementing such a program; and to identify individualized outcomes. DESIGN: Case study comparisons. SETTING: University setting. PARTICIPANTS: Two severely injured students with cognitive impairments. INTERVENTIONS: A dynamic coaching model of supported education which incorporated self-regulated learning was provided for students with traumatic brain injury while attending college. OUTCOMES: Outcomes were both short and long term including decontextualized standardized test scores, self-reported academic challenges, number and specificity of reported strategies, grades on assignments, number of credits completed versus attempted, and changes in academic status and campus life. RESULTS: Students improved on graded assignments after strategy instruction and reported using more strategies by the end of the year. Students completed most of the credits they attempted, were in good academic standing, and made positive academic decisions. Performance on decontextualized tests pre- and postintervention was variable. CONCLUSIONS: It is feasible to deliver a hybrid supported education program that is dynamically responsive to individual students' needs and learning styles. Reasons for including both functional and standardized test outcomes are discussed. PMID- 21552071 TI - Higher-order reasoning training years after traumatic brain injury in adults. AB - OBJECTIVE: To conduct a feasibility study to compare the effects of top-down Strategic Memory and Reasoning Training (SMART) versus information-based Brain Health Workshop (BHW, control) on gist-reasoning (ie, abstracting novel meaning from complex information), memory, executive functions, and daily function in adults with traumatic brain injury. PARTICIPANTS: Twenty-eight participants (of the 35 recruited), 16 men & 12 women, aged 20 to 65 years (M = 43, SD = 11.34) at chronic stages posttraumatic brain injury (2 years or longer) completed the training. Fourteen participants that received SMART and 14 participants that completed BHW were assessed both pre- and posttraining. Thirteen of the SMART trained and 11 from BHW participated in a 6-month testing. DESIGN: The study was a single blinded randomized control trial. Participants in both groups received a minimum of 15 hours of training over 8 weeks. RESULTS: The SMART group significantly improved gist-reasoning as compared to the BHW group. Benefits of the SMART extended to untrained measures of working memory and participation in functional activities. Exploratory analyses suggested potential transfer effects of SMART on memory and executive functions. The benefits of the SMART program as compared to BHW were evident at immediately posttraining and 6 months posttraining. CONCLUSION: This study provides preliminary evidence that short term intensive training in top-down modulation of information benefits gist reasoning and generalizes to measures of executive function and real life function at chronic stages of post-TBI. PMID- 21552072 TI - Making progress. PMID- 21552073 TI - The effect of suit wear during an intensive therapy program in children with cerebral palsy. AB - PURPOSE: To examine the effects of suit wear during an intensive therapy program on motor function among children with cerebral palsy. METHOD: Twenty children were randomized to an experimental (TheraSuit) or a control (control suit) group and participated in an intensive therapy program. The Pediatric Evaluation of Disability Inventory (PEDI) and Gross Motor Function Measure (GMFM)-66 were administered before and after (4 and 9 weeks). Parent satisfaction was also assessed. RESULTS: No significant differences were found between groups. Significant within-group differences were found for the control group on the GMFM 66 and for the experimental group on the GMFM-66, PEDI Functional Skills Self care, PEDI Caregiver Assistance Self-care, and PEDI Functional Skills Mobility. No adverse events were reported. CONCLUSIONS: Children wearing the TheraSuit during an intensive therapy program did not demonstrate improved motor function compared with those wearing a control suit during the same program. PMID- 21552074 TI - Commentary on "The effect of suit wear during an intensive therapy program in children with cerebral palsy". PMID- 21552075 TI - The relationship between body mass index and gross motor development in children aged 3 to 5 years. AB - PURPOSE: To investigate the relationship between obesity and gross motor development in children who are developing typically and determine whether body mass index (BMI) predicts difficulty in gross motor skills. METHODS: BMIs were calculated and gross motor skills examined in 50 children who were healthy aged 3 to 5 years using the Peabody Developmental Motor Scales, 2nd edition (PDMS-2). Pearson chi-square statistic and stepwise linear hierarchical regression were used for analysis. RESULTS: A total of 24% of the children were overweight/obese, whereas 76% were found not to be overweight/obese. Fifty-eight percent of the overweight/obese group scored below average on the PDMS-2 compared to 15% of the nonoverweight group. Association between BMI and gross motor quotients was identified with significance of less than 0.002. Regression results were nonsignificant with all 50 subjects, yet showed significance (P = 0.018) when an outlier was excluded. CONCLUSIONS: Children aged 3 to 5 years with high BMIs may have difficulty with their gross motor skills. Further research is needed. PMID- 21552076 TI - Commentary on "The relationship between body mass index and gross motor development in children aged 3 to 5 years". PMID- 21552077 TI - Effect of weight-bearing in abduction and extension on hip stability in children with cerebral palsy. AB - PURPOSE: : To study the effect of 1 year of daily, straddled weight-bearing on hip migration percentage (MP) and muscle length in children with cerebral palsy who were nonambulatory. METHODS: : Participants stood upright in maximum tolerated hip abduction and hip and knee extension 1/2 to 11/2 hours per day for 1 year. Controls, matched for age, motor ability, and surgery, were derived from a national cerebral palsy follow-up program. RESULTS: : Participants using straddled weight-bearing after surgery had the largest decrease in MP (n = 3, 20 controls; P = .026). Children using straddled weight-bearing at least 1 hour per day for prevention also improved (n = 8, 63 controls; P = .029). Hip and knee contractures were found only in controls. CONCLUSION: : Straddled weight-bearing, 1 hour per day, may reduce the MP after adductor-iliopsoas-tenotomies or prevent an MP increase and preserve muscle length in children with cerebral palsy who did not need surgery. Larger studies are needed to confirm the results. PMID- 21552078 TI - Commentary on "Effect of weight-bearing in abduction and extension on hip stability in children with cerebral palsy". PMID- 21552079 TI - Effects of positioning on respiratory measures in individuals with cerebral palsy and severe scoliosis. AB - PURPOSE: To examine the effect of positioning on respiratory measurements in individuals with cerebral palsy and severe scoliosis. METHODS: Five individuals aged 17 to 37 years participated in an alternating treatment, single-subject design. Oxygen saturation, respiratory rate, heart rate, and chest wall excursion measurements were obtained in supine, sitting, and sidelying positions. RESULTS: Level of support for hypotheses varied on the basis of the respiratory measurement and participants' status. Respiratory rate appeared to be most sensitive to change in the positions. Severity of respiratory compromise and age may be associated with less tolerance for supine position versus sitting and sidelying positions. CONCLUSIONS: The use of therapeutic positioning in sitting and sidelying positions should be considered as a noninvasive intervention for a population with respiratory compromise. Further research with a larger sample is needed to empirically link specific positions with improved respiratory efficiency. PMID- 21552080 TI - Commentary on "Effects of positioning on respiratory measures in individuals with cerebral palsy and severe scoliosis". PMID- 21552081 TI - Examination of the functional mobility assessment tool for children and adolescents with lower extremity amputations. AB - PURPOSE: To assess the validity of the Functional Mobility Assessment (FMA) for children and adolescents with lower extremity amputations. METHODS: Twenty-five subjects (mean age = 12.36 +/- 1.42 years) with lower extremity amputations and 12 subjects (mean age = 10.25 +/- 1.42 years) with typical development were examined using the FMA, which includes the Timed Up and Go, Timed Up and Down Stairs, 9-minute walk/run, heart rate, and Borg Rating of Perceived Exertion. A subjective interview was also performed including questions related to pain, walking satisfaction, and participation in and challenges with various physical activities. RESULTS: Significant differences were identified between the control and amputation groups in FMA score and 3 individual items (P < .05). However, no differences were identified between groups for other items on the FMA. CONCLUSION: Discriminant validity of the FMA as a whole is supported. However, reevaluation of the items within the FMA is warranted. PMID- 21552082 TI - Commentary on "Examination of the functional mobility assessment tool for children and adolescents with lower extremity amputations". PMID- 21552083 TI - Relationship of therapy to postsecondary education and employment in young adults with physical disabilities. AB - PURPOSE: The relationship of therapy services to postsecondary education and paid employment in young adults with physical disabilities was examined. METHODS: A sample of 1510 youth from the National Longitudinal Transition Study 2 categorized with orthopedic impairment including cerebral palsy and spina bifida was analyzed using weighted sampling multivariate regression. RESULTS: At follow up, 48% participated in postsecondary education and 24% had paid employment. Receiving physical and/or occupational therapy at ages 13 to 16 years was significantly associated with higher levels of enrollment in postsecondary education at ages 19 to 21 years. Social interactions and expressive language skills but not therapy services were associated with paid employment. CONCLUSIONS: Results suggest that therapy services that focus on improvement of upper extremity function, self-care skills, and social skills are associated with participation in postsecondary education. Longer follow-up is needed to effectively examine paid employment. PMID- 21552084 TI - Commentary on "Relationship of therapy to postsecondary education and employment in young adults with physical disabilities". PMID- 21552085 TI - The effects of aerobic exercise on academic engagement in young children with autism spectrum disorder. AB - PURPOSE: To determine whether participation in aerobic exercise before classroom activities improves academic engagement and reduces stereotypic behaviors in young children with autism spectrum disorder. METHODS: This study employed a within-subjects crossover design, using a treatment condition (aerobic exercise) and a control condition, across 4 classrooms. The treatment condition included 15 minutes of running/jogging followed by a classroom task. The control condition included a classroom task not preceded by exercise. The number of stereotypic behaviors, percentage of on-task behavior, and correct/incorrect responses were measured. The Wilcoxon signed rank test was used to compare differences between conditions. RESULTS: Statistically significant improvements were found in correct responding following exercise (P < .05). No significant differences were found for on-task behavior or stereotypic behaviors. CONCLUSIONS: Consistent with findings in older children, these results indicate that aerobic exercise prior to classroom activities may improve academic responding in young children with autism spectrum disorder. PMID- 21552086 TI - Commentary on "The effects of aerobic exercise on academic engagement in young children with autism spectrum disorder". PMID- 21552087 TI - Retrospective case report: evaluation of pain in a child with pervasive developmental disorder. AB - PURPOSE: To describe how a nurse and a physical therapist in an interprofessional (IP) school-based clinic collaborated to meet the needs of a child with pervasive developmental disorder-not otherwise specified, with atypical classroom behaviors and declining student performance. SUMMARY: The IP team sought answers for atypical classroom behaviors with declining student performance. Student sensory perceptions masked and delayed the ability to recognize infection. OBSERVATIONS: Cumulative observations by the team generated serial referrals until a diagnosis of dental abscess was identified. CONCLUSIONS: An IP team in this school setting generated a positive outcome for a student demonstrating absence of clear indicators of pain or infection, with additional positive outcomes for the clinic. RECOMMENDATIONS FOR CLINICAL PRACTICE: Further studies are needed to recognize illness earlier in the absence of pain or pain perception in children with a form of autism spectrum disorder and to develop reliable and valid metrics for pain identification. PMID- 21552088 TI - A description of professional pediatric physical therapy education. AB - PURPOSE: The purpose of this work was to reexamine the status of professional pediatric physical therapy education in the United States. METHODS: A task force designed a 16-item survey and contacted representatives from all professional physical therapy programs. RESULTS: Surveys were gathered from 151 programs for a return rate of 75%. Much variability exists across programs in total number of hours devoted to pediatrics (range, 35-210 hours). In addition, almost 60% of respondents indicated that the individual responsible for delivering the pediatric content will be retiring within the next 15 years. CONCLUSION: These results describe current pediatric professional education and provide numerous opportunities and challenges for the development of optimal professional pediatric education. PMID- 21552089 TI - Commentary on "A description of professional pediatric physical therapy education". PMID- 21552092 TI - American Pediatric Society 2009 presidential address--the complexity of pediatric education in the 21st century: what can we do? PMID- 21552093 TI - Introduction of the American Pediatric Society's 2010 John Howland Award recipient, Charles R. Scriver, MDCM. PMID- 21552094 TI - American Pediatric Society's 2010 John Howland Award acceptance lecture: some things considered. PMID- 21552095 TI - Semantic dementia versus nonfluent progressive aphasia: neuropsychological characterization and differentiation. AB - BACKGROUND: Early progressive nonfluent aphasia (PNFA) may be difficult to differentiate from semantic dementia (SD) in a nonspecialist setting. There are descriptions of the clinical and neuropsychological profiles of patients with PNFA and SD but few systematic comparisons. METHOD: We compared the performance of groups with SD (n=27) and PNFA (n=16) with comparable ages, education, disease duration, and severity of dementia as measured by the Clinical Dementia Rating Scale on a comprehensive neuropsychological battery. Principal components analysis and intergroup comparisons were used. RESULTS: A 5-factor solution accounted for 78.4% of the total variance with good separation of neuropsychological variables. As expected, both groups were anomic with preserved visuospatial function and mental speed. Patients with SD had lower scores on comprehension-based semantic tests and better performance on verbal working memory and phonological processing tasks. The opposite pattern was found in the PNFA group. CONCLUSIONS: Neuropsychological tests that examine verbal and nonverbal semantic associations, verbal working memory, and phonological processing are the most helpful for distinguishing between PNFA and SD. PMID- 21552096 TI - Laparoscopic versus open resection of gastric gastrointestinal stromal tumors. AB - OBJECTIVES: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. There is some controversy as to the effectiveness and feasibility of laparoscopic versus open resection of these tumors. We hypothesized that laparoscopic resection of gastric GISTs would offer better perioperative outcomes compared with the traditional open approach. METHODS: A retrospective review was conducted of all GISTs treated at a tertiary care urban teaching hospital between January 1999 and August 2008. The medical records were examined for demographic and clinicopathological features. RESULTS: Forty-six gastric GISTs were identified (17 treated laparoscopically and 29 treated via laparotomy). The median age of patients in these groups were comparable at 62 and 60, respectively. Body mass index of these patients were also similar at 28.2 kg/m(2) for the laparoscopic and 29.9 kg/m(2) for the open group. The average size of tumor was slightly smaller in the laparoscopic group at 4.27 cm versus the open group at 6.39 cm (NS). The estimated blood loss for the laparoscopic group was lower at 94 mL versus 169 mL (P = 0.059). Operative times for the 2 surgical approaches were not significantly different at 135 minutes for laparoscopic and 157.4 minutes for open. Laparoscopic resection yielded a significantly shorter length of stay compared with open at 2.68 versus 6.25 days (P < 0.001). CONCLUSIONS: Laparoscopic resection of gastric GISTs offers a decreased length of stay, a trend to decreased blood loss, and comparable oncologic outcomes indicating that a laparoscopic approach should be considered in all patients with gastric GISTs who do not have a contraindication to this approach. PMID- 21552097 TI - Phase II study of gemcitabine, oxaliplatin, and cetuximab in advanced pancreatic cancer. AB - OBJECTIVE: Little progress has been made in the treatment of pancreatic cancer (PC). This study evaluated the clinical activity of gemcitabine, oxaliplatin, and cetuximab (GOC) in patients with locally advanced or metastatic PC. METHODS: The study primary endpoint was progression-free survival (PFS). Eligible, chemotherapy-naive PC patients were treated with gemcitabine (1000 mg/m(2) over 100 min) on day 1, oxaliplatin (100 mg/m(2)) on day 2, every 2 weeks, and weekly cetuximab, (loading dose of 400 mg/m(2) on cycle 1 day 1 and 250 mg/m(2) thereafter). It was expected that GOC treatment would extend the median PFS from 5.8 to 7.54 months, a relative increase of 30%, compared with gemcitabine and oxaliplatin (historical control). RESULTS: A total of 41 evaluable patients were enrolled. The overall response rate was 24%. Median PFS time was 6.9 months and median overall survival (OS) was 11.3 months. Patients with locally advanced disease had longer median PFS (12.4 vs. 4.7 mo) and OS (15.7 vs. 6.4 mo) compared with patients with metastatic disease. The most common grade 3 to 4 toxicities included neutropenia (32%), infection (with normal or grade 1 to 2 neutropenia, in 24%), neuropathy (17%), fatigue (15%), and rash (7%). Five patients (12%) discontinued study treatment without evidence of progression. Rash was not a significant prognostic factor affecting PFS or OS. CONCLUSIONS: GOC is a feasible combination with an acceptable toxicity profile. However, GOC did not significantly extend PFS in the overall patient population to consider it for further development. PMID- 21552098 TI - Primary cutaneous anaplastic large-cell lymphoma. AB - Since the recognition of the anaplastic large-cell lymphomas in the 1980s, much has been learned about the diagnosis, clinical presentation, and treatment of these malignant conditions. The systemic and primary cutaneous types of anaplastic large cell lymphomas have been differentiated on clinical and immunophenotypical findings, but further research is required to elucidate their exact etiologies and pathogeneses. Primary cutaneous anaplastic large-cell lymphoma has a 95% disease-specific 5-year survival, owing partly to the relatively benign course of the disease and partly to the variety of effective treatments that are available. As with many other oncological diseases, new drugs are continually being tested and developed, with immunotherapy and biological response modifiers showing promise. PMID- 21552099 TI - Optimizing the administration of fixed-dose rate gemcitabine plus capecitabine using an alternating-week schedule: a dose finding and early efficacy study in advanced pancreatic and biliary carcinomas. AB - OBJECTIVES: This multisite study sought to optimize the dosing, schedule, and administration of fixed-dose rate (FDR) gemcitabine plus capecitabine for advanced pancreatic and biliary tract cancers using an alternating-week dose schedule of both agents. METHODS: Patients with previously untreated advanced pancreatic and biliary tract cancers with Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. For the dose-finding portion, a standard 3+3 dose-escalation schema was used, with the gemcitabine dose kept at 1000 mg/m(2) administered by FDR (10 mg/m(2)/min) on day 1 of each 14-day cycle, and capecitabine given on days 1 to 7 at doses ranging from 800 to 1500 mg/m(2) twice daily. Primary study objective was determination of maximum tolerated dose (MTD). The cohort at MTD was expanded for further efficacy assessment. RESULTS: A total of 45 patients (median age 61 y; 93% pancreatic/7% biliary; 84% with metastatic disease) were enrolled. Median number of cycles received was 11.5. The MTD using this dose schedule was FDR gemcitabine 1000 mg/m(2) plus capecitabine 1000 mg/m(2) bid, due to a high incidence of late hand-foot syndrome observed at the next higher dose level. Most common nonhematologic adverse events related to treatment included nausea/vomiting (overall rate, 64%; all grade 1/2) and hand foot syndrome (overall rate, 60%; grade 3, 22%). The incidence of grade 3/4 hematologic adverse events was 24%. Six of 41 evaluable patients (14.6%) had a partial response; 18 of 31 patients (58%) with elevated baseline CA 19-9 level had >=50% biomarker decline during treatment. Estimated median time to tumor progression and overall survival were 5.5 and 9.8 months, respectively (5.5 and 10.1 mo in the metastatic pancreatic cancer cohort). CONCLUSIONS: This dosing schedule of FDR gemcitabine plus capecitabine is active in patients with advanced pancreatobiliary cancers. Given its favorable toxicity profile and convenience, this regimen represents an appropriate front-line option for this patient population and may serve as the foundation on which new investigational agents are added in future trial design. PMID- 21552100 TI - Where do antiangiogenic agents belong in the treatment algorithm for ovarian cancer? AB - Although epithelial ovarian cancer responds well to chemotherapy, patients presenting with advanced disease still have a poor prognosis. The clear role of angiogenesis in the development and progression of ovarian tumorigenesis has led to the development of several novel antiangiogenic agents; however, questions remain as how to best incorporate such agents into current treatment algorithms. Searches of PubMed (terms: angiogenesis, VEGF, tyrosine kinase inhibitor, bevacizumab and ovarian cancer) and of recent results from key oncology congresses (terms: drug names and ovarian cancer) were performed to identify relevant articles and abstracts. Clinical trials are ongoing to evaluate investigational antiangiogenic agents as a component of first-line chemotherapy, as a treatment option for recurrent disease, and as maintenance therapy for ovarian cancer. The antiangiogenic monoclonal antibody bevacizumab has demonstrated a progression-free survival benefit in combination with first-line paclitaxel/carboplatin and continued as maintenance therapy, and phase II data suggest therapeutic potential for several multitargeted tyrosine kinase inhibitors in ovarian cancer, with phase III results forthcoming for BIBF 1120, cediranib, and pazopanib. Antiangiogenic therapy remains a promising strategy for ovarian cancer, and it is hoped that results from ongoing trials will inform their optimal placement in the treatment paradigm. PMID- 21552101 TI - Impact of transarterial therapy in hepatitis C-related hepatocellular carcinoma on long-term outcomes after liver transplantation. AB - OBJECTIVES: To evaluate the impact of long-term outcomes of transarterial embolization (TAE) therapy in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) on the waiting list for liver transplantation (LT). METHODS: We retrospectively evaluated the post-LT patients with HCV-related HCC who received TAE intervention (n=33) and those who had no treatment (n=47) while on the waiting list to determine long-term outcomes. RESULTS: Over a 10 year period, of the 424 patients transplanted with HCV, 80 patients had HCC with a tumor burden within Milan criteria. For the entire study cohort, the mean duration of post-LT follow-up was 3.5 years; mean time of transplant waiting list was 120 days; and median post-LT survival was 8.9 years. The survival rates at 1, 3, 5, and 10 years were 82%, 70%, 55%, and 35%, respectively. From the study cohort, 33 patients received TAE and 47 patients did not while on the waiting list. The 2 groups were well matched, except, that the intervention patients received post-LT interferon more often and had a shorter time on the waiting list (56.2 d) when compared with the no treatment group (164.6 d, P<0.001). Median survival in the TAE group was 4.8 years and 8.9 years in the no treatment group. The recurrence rate was 15.6% in the treatment group and 6.9% in the no therapy group (P=0.275). CONCLUSIONS: Pre-LT transarterial therapy has no benefit on post LT survival and tumor recurrence in patients with HCV-related HCC who underwent a mean waiting period of <3 months to transplant. PMID- 21552102 TI - Flow cytometric evaluation of skin biopsies for mycosis fungoides. AB - Multicolor flow cytometry (FC) is indispensable for lymphoma diagnosis and classification, but its utility in evaluating skin biopsies for mycosis fungoides (MF) is not well established. We describe the largest series to date of skin biopsies evaluated by FC for MF (n = 33), and we compare the flow cytometric results with the histologic, molecular, and clinical findings. Abnormal T-cell populations were identified by FC in 14 of 18 patients (78%) having histologically confirmed MF and in no patient whose histology was negative or indeterminate for MF (n = 14). One patient had histologic, flow cytometric, and molecular findings compatible with MF, but this patient's clinical course was more suggestive of a drug eruption. Fourteen of 15 abnormal T-cell populations showed definitive aberrant expression of at least 2 surface antigens, including CD2 (47%), CD3 (67%), CD4, CD5 (87%), CD7, and CD45 (67%); most cases (67%) had light scatter properties suggesting increased cell size and/or cytoplasmic complexity. The high specificity of FC suggests that it will be a useful adjunct to routine histology in the evaluation of diagnostic skin biopsies for MF. PMID- 21552103 TI - Identification of nodal metastases in melanoma using sox-10. AB - The presence of S100-positive dendritic cells hinders the identification of isolated melanoma tumor cells and micrometastases in sentinel lymph nodes. Sox 10, a transcription factor that plays an important role in schwannian and melanocytic cell development, is not expressed in dendritic cells. We investigated the diagnostic utility of Sox-10 in the identification of metastases in sentinel and nonsentinel lymph nodes for melanoma. We examined the expression pattern of Sox-10, as compared with S100, Melan-A, and HMB-45 in 93 lymph nodes (40 originally reported as positive and 53 originally reported as negative for metastasis) from 33 sentinel lymph node biopsies and regional lymphadenectomies. Sox-10 and S100 both highlighted metastases in 43 of 43 (100%) positive lymph nodes identified in this study; however, Sox-10 immunohistochemical staining significantly improved the detection of nodal metastases. The nuclear staining of Sox-10 promoted improved distinction between heavily pigmented melanophages and melanocytic metastases in 3 positive lymph nodes. In 2 lymph nodes, Sox-10 was critical in distinguishing S100-positive atypical nodal dendritic cells from tumor cells. Also, Sox-10 significantly improved the identification of micrometastases and isolated tumor cells as compared with S100 in 10 positive lymph nodes. Most importantly, Sox-10 identified micrometastases in 2 lymph nodes, originally reported as negative on S100, Melan-A, and HMB-45 immunostains. Therefore, Sox-10 is a comparable marker to S100 in identifying nodal metastases in melanoma and is especially useful in the setting of lymph nodes with heavily pigmented metastases, numerous S100-positive nodal dendritic cells, micrometastases, and isolated tumor cells. PMID- 21552104 TI - Characteristic distribution of melanin columns in the cornified layer of acquired acral nevus: an important clue for histopathologic differentiation from early acral melanoma. AB - Clinical and histopathologic differentiation between early acral melanoma and acral nevus is often difficult. Dermoscopy is helpful in this differentiation. On dermoscopy, early acral melanoma shows the parallel ridge pattern showing band like pigmentation on the ridges of the surface skin markings, whereas a representative dermoscopic pattern in acquired acral nevus is the parallel furrow pattern showing parallel linear pigmentation along the surface furrows. The parallel furrow pattern suggests that melanocytes of acral nevus preferentially proliferate in the crista profunda limitans, an epidermal rete ridge underlying the surface furrow. In the present study, however, we found that in 13 of 18 acquired acral nevi, proliferation of melanocytes were detected not only in the crista profunda limitans but also in the crista profunda intermedia (CPI), an epidermal rete ridge underlying the surface ridge. Very interestingly, Fontana Masson staining of these acral nevi revealed that even when proliferation of melanocytes was prominent in the CPI, melanin granules in the cornified layer were observed as regular melanin columns situated under the surface furrows and were hardly detected under the surface ridges. These findings indicate that in acral nevus, melanin granules produced by melanocytes in the CPI are not transferred to the upper epidermis. Hence, we must be careful not to overdiagnose an acral melanocytic lesion in which an increased number of melanocytes are detected in the CPI. Even in such a case, if melanin granules in the cornified layer are detected as melanin columns regularly distributed under the surface furrows, the lesion is strongly suggested to be a benign acral nevus. PMID- 21552105 TI - Histopathology of scarring alopecia in Indian patients. AB - OBJECTIVES: Diagnosis of scarring alopecias (SAs) are challenging, especially when lesions late in the process of development are met with. There is a paucity of literature that profiles the role of histopathology in unscrambling this puzzle, especially in Indian patients. Our aim is to review the histological features of SA in Indian patients and attempt to assign a specific diagnosis. MATERIALS AND METHODS: We reviewed 37 cases of SA from 2005 to 2009. Sections were assessed for various histological parameters. RESULTS: There were 18 of 37 cases (49%) of lupus erythematosus, 15 of 37 (41%) lichen planopilaris (LPP), 1 folliculitis, and 3 alopecia areata. The important findings in lupus erythematosus are epidermal atrophy, papillary dermal fibrosis, mucin, peribulbar inflammation, and haphazard spacing of scars. LPP shows an essentially normal epidermis, peri-infundibular infiltrate, and even spacing of scars. Twelve cases had total absence of follicles and yet could be classified based on the connective tissue changes. Alcian blue-periodic acid-Schiff stain highlighted follicular remnants within scars in 9 cases. Three cases of alopecia areata demonstrated peribulbar inflammation, evenly spaced scars, and remnants of catagenic basement membrane. Cases termed as "pseudopelade" clinically were predominantly LPP on histology. CONCLUSIONS: Histopathology is a dependable tool in identifying the underlying cause in SA. Even in cases that show a complete loss of follicles, it is possible to suggest the etiology based on epidermal and connective tissue changes. PMID- 21552106 TI - Comparing a transrectal ultrasound-guided with a cystoscopy-guided botulinum toxin a injection in treating detrusor external sphincter dyssynergia in spinal cord injury. AB - OBJECTIVE: The aim of this study was to compare the results of a transrectal ultrasound-guided botulinum toxin injection with those of a cystoscopy-guided method to the external urethral sphincter in treating detrusor external sphincter dyssynergia. DESIGN: A total of 18 suprasacral spinal cord-injured patients with detrusor external sphincter dyssynergia were included in the present study. A single dose of 100 IU botulinum toxin A was applied into the external urethral sphincter via a transrectal ultrasound-guided transperineal route. We retrospectively compared the outcome measurements with 20 suprasacral spinal cord injured patients previously treated with the same dose of botulinum toxin through a cystoscopy-guided procedure. RESULTS: There were significant reductions in integrated electromyography and urethral pressure but not in detrusor pressure and leak point pressure after treatment. Postvoiding residuals were significantly decreased in the first, second, and third months in the cystoscopy group and in the first and second months in the transrectal ultrasound group. There were no significant differences between the groups in all of the outcome measures. CONCLUSIONS: This study demonstrates that transrectal ultrasound-guided transperineal botulinum toxin injection may be an alternative for a cystoscopy guided injection. This alternative procedure provides clinicians with an innovative and less invasive method that is performed without requiring anesthesia or cystoscopy. PMID- 21552107 TI - Clavicle-induced narrowing of the thoracic outlet during shoulder abduction as imaged by computed tomographic angiography and enhanced by three-dimensional reformation. AB - OBJECTIVE: This study aimed to confirm the location and degree of compromise of the subclavian vessels within the thoracic outlet during ipsilateral arm abduction in patients with clinical evidence of thoracic outlet syndrome and to identify both the physical and physiologic source of neurovascular compromise that induces the symptoms of thoracic outlet syndrome. DESIGN: After a neuromuscular and vascular examination, all of the subjects underwent a two-part high-resolution computed tomographic angiography with three-dimensional reformation. The initial study was performed with the arm held at the side in an anatomical neutral position. Subsequently, the arm was abducted to 90 degrees with external rotation (ABER). In each position, 60 ml of iodinated nonionic contrast medium was injected in the opposite arm at 4 ml/sec. Three-dimensional volume-rendered images were obtained. Each image was subsequently reviewed by a musculoskeletal radiologist (S. Yadavalli). Patients were initially evaluated in the physiatrist's private office (M.M. LaBan). The computed tomographic scans were obtained from the participants as outpatients in an academic community-based medical center (William Beaumont Hospital). Seventeen outpatients with clinical signs and symptoms of thoracic outlet syndrome were evaluated, including seven men and ten women. This group has an average age of 48 yrs (range, 17-73 yrs). RESULTS: The level of vessel occlusion varied in the costoclavicular space as well as in demonstrating the alterations in the diameter of both the subclavian artery and vein both in the neutral and ABER positions. The possible levels of occlusions included the costoclavicular space, the interscalene triangle, and the retropectoralis minor space. The narrowing of the subclavian vessel was considered significant if the percentage change of the vessel's diameter between the neutral and the ABER positions was 30% or greater for the subclavian artery and 50% or greater for the subclavian vein. CONCLUSIONS: The average change in the costoclavicular space between the neutral and ABER positions was 18.2 mm or 55.6%. The degree of subclavian artery occlusion was significant in 8 (47%) of the 17 patients. The average change in artery diameter was 28% (5.5 to 7.5 mm). Significant subclavian vein occlusion was present in 12 (75%) of 16 patients. The average change in venous diameter was 54.1% (5.7 to 12.6 mm). In two cases, venous occlusion occurred in the retropectoralis minor space, one of which was significant at 79%. The vast majority of patients, that is, 13 (76.5%) of 17, demonstrated a compression of either the subclavian vein or artery, whereas 6 (35.3%) of 17 demonstrated a compression in both. In each of these cases, the asymptomatic side failed to demonstrate a significant change in either the venous and/or arterial caliber. PMID- 21552108 TI - Effect of therapeutic ultrasound on tendons. AB - Ultrasound is a therapeutic agent commonly used to treat sports-related musculoskeletal conditions, including tendon injuries or tendinopathy. Despite the widespread popularity of therapeutic ultrasound, few clinical studies have proved its efficacy. Several animal studies have been conducted to explore its effectiveness. In addition, a number of in vitro studies investigating the mechanisms underlying the ability of this physical modality to enhance tendon healing or to treat tendinopathy are in progress. There is strong supporting evidence from animal studies about the positive effects of ultrasound on tendon healing. In vitro studies have also demonstrated that ultrasound can stimulate cell migration, proliferation, and collagen synthesis of tendon cells that may benefit tendon healing. These positive effects of therapeutic ultrasound on tendon healing revealed by in vivo and in vitro studies help explain the physiologic responses to this physical modality and could serve as the foundation for clinical practice. PMID- 21552109 TI - Application of real-time sonoelastography in musculoskeletal diseases related to physical medicine and rehabilitation. AB - Real-time sonoelastography is a recently developed ultrasound-based technique that evaluates tissue elasticity in real time, and it is based on the principle that the compression of tissue produces a strain (displacement) that is lower in hard tissue and higher in soft tissue. Real-time sonoelastography provides information on tissue elasticity, in addition to the shape or vascularity, which is obtained via B-mode ultrasound. Similar to B-mode ultrasound, freehand manipulation with the transducer and real-time visualization are now available for real-time sonoelastography in actual clinical practice. Tissue elasticity not only varies among different tissues but also seems to reflect disease-induced alternations in tissue properties. Real-time sonoelastography was recently applied to the normal and pathologic tissues in muscle and tendon disorders, and it showed promising results and new potentialities. Therefore, it is expected to be a useful modality for providing novel diagnostic information in musculoskeletal diseases because tissue elasticity is closely related to its pathology. It can also be used as a research tool to provide insight into the biomechanics and pathophysiology of tissue abnormality. PMID- 21552110 TI - Mechanical ventilation, paradigm shifts, and the prefrontal cortex. PMID- 21552111 TI - Digital slide repositories for publications: lessons learned from the microarray community. PMID- 21552112 TI - Benefits of a combined approach to sampling of renal neoplasms as demonstrated in a series of 351 cases. AB - Percutaneous radiofrequency ablation is increasingly used for curative treatment of primary cancers of the kidney. We reviewed our experience of percutaneous sampling performed under computed tomographic guidance with fine needle aspiration biopsy (FNAB) and core biopsy (CB), and we report on the complementary roles of these 2 techniques in a series of 351 consecutive patients undergoing radiofrequency ablation for renal neoplasms. Both FNAB and CB were obtained in 290 cases, of which 156 patients (54%) were positive for neoplasm in both specimens, and 27 (9%) were negative for tumor in both specimens. In 58 (20%) patients, the FNABs were positive, but the CBs were negative, and the reverse occurred in 11 patients (4%). When suspicious interpretations by FNAB and CB are included as positives in the calculations, both their complementary nature and the relative higher diagnostic yield of FNAB persisted. In 25 cases with FNABs positive for neoplasm, the CB allowed a more specific tumor classification. The 19 cases of FNAB which were read as negative/benign had corresponding CBs that were also negative/benign in 13 cases; yet, 6 were diagnostic of renal cell carcinoma not otherwise specified (1 case), renal cell carcinoma clear cell/conventional (4 cases), and non-Hodgkin lymphoma (1 case). These and additional findings illustrate the complementary value of the combination of the 2 biopsy methods for a reliable pretherapy morphologic confirmation of specific renal neoplasms. FNAB has relatively greater sensitivity and utility for on-site evaluation, whereas CB provides an additional sample for more specific subclassification and additional studies. PMID- 21552113 TI - EBV-positive extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in the posttransplant setting: a distinct type of posttransplant lymphoproliferative disorder? AB - The 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues defines monomorphic posttransplant lymphoproliferative disorders (M-PTLDs) as lymphoid or plasmacytic proliferations that fulfill the criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent patients. However, indolent B-cell lymphomas, such as extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), are specifically excluded from this category. In this study, we describe the clinicopathologic features of 4 posttransplant lymphoma-like proliferations that were Epstein-Barr virus (EBV) positive, but were otherwise completely typical for a MALT lymphoma. The 4 patients (age, 12 to 71 y) had received solid organ transplants (2 hearts, 1 kidney, 1 kidney/pancreas) at a median of 116 months before presentation, and had been maintained on varying immunosuppressive regimens that included cyclosporine, azathioprine, tacrolimus, and sirolimus. Three of the 4 patients presented with solitary subcutaneous masses, whereas the fourth patient presented with a solitary orbital soft tissue mass. All the 4 cases were morphologically typical for MALT lymphoma, demonstrated plasmacytic differentiation with IgA heavy chain restriction (3 cases kappa positive, 1 case lambda positive), and were diffusely EBV-encoded small RNA positive. Patients were followed for a median of 44.9 months, and all achieved a complete response following various regimens that included reduced immunosuppression with or without antiviral therapy, local surgical excision, rituximab, or local radiation therapy. The uniform EBV positivity and response to immune reconstitution in some cases suggest that EBV-positive MALT lymphomas arising in the posttransplant setting should be included among PTLDs. Whether their distinctive subcutaneous/soft tissue localization and IgA positivity are uniform features will require identification of additional cases. PMID- 21552114 TI - Oligodendroglial tumors with marked desmoplasia: clinicopathologic and molecular features of 7 cases. AB - Oligodendroglial tumors may rarely display striking desmoplasia resulting in unusual histologic patterns that have not been completely characterized. We reviewed the clinicopathologic findings of 7 such cases. Patients included 4 men and 3 women. Mean age at the time of primary surgery was 49 years (range, 31 to 57 y). All tumors were of World Health Organization grade III (4 anaplastic oligodendrogliomas and 3 anaplastic oligoastrocytomas). Characteristic morphologic features included tumor nests/nodules with surrounding fibrosis/desmoplasia (n=5), cords/single-cell infiltration (n=2), minigemistocytes (n=5), endothelial hypertrophy (n=6), and necrosis (n=1). Mean mitotic index was 9 mitoses per 10 high-power fields. Immunohistochemical studies demonstrated immunoreactivity for PDGFRalpha 1 to 3+ (5 of 6), PDGFRbeta 3+ (n=3 of 3), and EGFR 1 to 2+ (n=5 of 6). p53 protein expression was 1-2+ and MIB-1 labeling index was moderate. Four tumors showed 1p19q codeletion, 1 tumor showed 1p deletion only, and 2 tumors showed intact 1p19q loci. t(1:19) was identified in 2 (of 3) tested cases, both also with 1p19q codeletion, and was absent in the case with 1p loss only. IDH1R132H mutant protein was detected in 3 (of 6) cases, and an IDH mutation (R132S) was identified in an additional case by pyrosequencing. Clinical follow-up was available in 6 (of 7) patients (mean follow-up of 64.2 mo). Five (of 6) developed recurrence/progression at a mean interval of 49.2 months after primary diagnosis. Only 1 patient died of disease, 22.5 months after primary diagnosis. Oligodendroglial tumors with prominent desmoplasia are rare. Most cases demonstrate 1p19q codeletion and IDH1 mutations, and behave as expected for anaplastic oligodendroglial tumors. PMID- 21552115 TI - A comprehensive analysis of PAX8 expression in human epithelial tumors. AB - PAX8 is a paired-box gene important in embryogenesis of the thyroid, Mullerian, and renal/upper urinary tracts, and expression of PAX8 has been previously described in carcinomas from each of these sites. However, a large study including a wide variety of epithelial neoplasms from multiple organ sites other than the thyroid, kidney, or Mullerian system has not been performed. The goal of this study was to evaluate the utility of PAX8 immunostaining based on the evaluation of a wide range of epithelial tumors. PAX8 immunohistochemistry was performed on 1357 tumors (486 tumors in whole-tissue sections and 871 tumors in tissue microarrays, predominantly epithelial) from multiple organs. Only nuclear staining was scored as positive, and tumors were evaluated for the extent and intensity of staining. Western blot analysis with PAX8 was also performed on multiple tumor cell lines. Nuclear PAX8 staining was present in 91% (60 of 66) of thyroid tumors, 90% (158 of 176) of renal cell carcinomas (RCCs), 81% (13 of 16) of renal oncocytomas, 99% (164 of 165) of high-grade ovarian serous carcinomas, 71% (32 of 49) of nonserous ovarian epithelial neoplasms, 91% (10 of 11) of cervical epithelial lesions, and 98% (152 of 155) of endometrial adenocarcinomas. Of the remaining 719 evaluated tumors, only 30 cases (4%), including 12 thymic neoplasms, 3 bladder urothelial carcinomas, 4 lung squamous cell carcinomas, 2 esophageal adenocarcinomas, 1 pancreatic adenocarcinoma, 2 cholangiocarcinomas, 1 ovarian Sertoli-Leydig cell tumor, 1 ovarian sex cord stromal tumor, 3 testicular mixed germ cell tumors, and 1 acinic cell carcinoma, showed at least weak or focal PAX8 positivity. The unexpected finding was diffuse, moderate staining of PAX8 in a subset of thymomas and thymic carcinomas. The 689 remaining tumors, including but not limited to those from the prostate, colon, stomach, liver, adrenal gland, and head and neck, and small cell carcinomas from the lung, cervix, and ovary, were PAX8 negative. PAX8 specificity was confirmed by Western blot analysis, as expression was detected only in ovarian and RCC cell lines. These results show that PAX8 is a highly sensitive marker for thyroid, renal, Mullerian, and thymic tumors. Importantly, all lung adenocarcinomas, breast and adrenal neoplasms, and the majority of gastrointestinal tumors were negative for PAX8. Therefore, PAX8 is an excellent marker for confirming primary tumor site. In a subset of cases, additional markers, including but not limited to thyroid transcription factor-1, RCC, and Wilms tumor-1, may be needed to distinguish between the 3 most common PAX8-positive tumors. PMID- 21552116 TI - Independent predictors and outcomes of unanticipated early postoperative tracheal intubation after nonemergent, noncardiac surgery. AB - BACKGROUND: Although the risk of hypoxemia is greatest during the first 72 h after surgery, little is known of the incidence of respiratory failure during this period. The authors studied the incidence and predictors of unanticipated early postoperative intubation (within 3 days) and its role in mortality. METHODS: A total of 222,094 adult patients undergoing nonemergent, noncardiac surgery in the American College of Surgeons-National Surgical Quality Improvement Program database were studied to determine the incidence and independent predictors of unanticipated early postoperative intubation. A risk-class model was developed and subsequently validated in 109,636 patients. RESULTS: Overall, 2,828 of 5,725 (49.4%) unanticipated tracheal intubations in a period of 30 days occurred within the first 3 days after surgery. The incidence of unanticipated early postoperative intubation was 0.83-0.9% in the derivation and validation cohorts. Independent predictors of unanticipated early postoperative intubation included current ethanol use, current smoker, dyspnea, chronic obstructive pulmonary disease, diabetes mellitus needing insulin therapy, active congestive heart failure, hypertension requiring medication, abnormal liver function, cancer, prolonged hospitalization, recent weight loss, body mass index less than 18.5 or >= 40 kg/m, medium-risk surgery, high-risk surgery, very-high-risk surgery, and sepsis. Unanticipated early postoperative intubation was an independent predictor of 30-day mortality, with an adjusted odds ratio of 9.2. Higher risk classes were associated with increasing incidence of unanticipated early postoperative intubation and death. CONCLUSIONS: One half of unanticipated tracheal intubations in a period of 30 days occurred within the first 3 days after nonemergent, noncardiac surgery and were independently associated with a 9 fold increase in mortality. The authors present a validated perioperative risk class index for determining risk of unanticipated early postoperative intubation. PMID- 21552117 TI - A description of intraoperative ventilator management in patients with acute lung injury and the use of lung protective ventilation strategies. AB - BACKGROUND: The incidence of acute lung injury (ALI) in hypoxic patients undergoing surgery is currently unknown. Previous studies have identified lung protective ventilation strategies that are beneficial in the treatment of ALI. The authors sought to determine the incidence and examine the use of lung protective ventilation strategies in patients receiving anesthetics with a known history of ALI. METHODS: The ventilation parameters that were used in all patients were reviewed, with an average preoperative PaO2/Fio2 [corrected] ratio of <= 300 between January 1, 2005 and July 1, 2009. This dataset was then merged with a dataset of patients screened for ALI. The median tidal volume, positive end-expiratory pressure, peak inspiratory pressures, fraction inhaled oxygen, oxygen saturation, and tidal volumes were compared between groups. RESULTS: A total of 1,286 patients met criteria for inclusion; 242 had a diagnosis of ALI preoperatively. Comparison of patients with ALI versus those without ALI found statistically yet clinically insignificant differences between the ventilation strategies between the groups in peak inspiratory pressures and positive end expiratory pressure but no other category. The tidal volumes in cc/kg predicted body weight were approximately 8.7 in both groups. Peak inspiratory pressures were found to be 27.87 cm H2O on average in the non-ALI group and 29.2 in the ALI group. CONCLUSION: Similar ventilation strategies are used between patients with ALI and those without ALI. These findings suggest that anesthesiologists are not using lung protective ventilation strategies when ventilating patients with low PaO2/Fio2 [corrected] ratios and ALI, and instead are treating hypoxia and ALI with higher concentrations of oxygen and peak pressures. PMID- 21552118 TI - Evaluation of methods for preserving PTEN antigenicity in stored paraffin sections. AB - Reduced phosphatase and tensin homolog (PTEN) expression in breast cancer confers susceptibility to phosphatidylinositol 3 kinase/Akt pathway inhibitors. As inhibitors of this pathway are in development for treatment of breast and other cancers, it is of interest to minimize the frequency at which PTEN signal is reduced because of poor antigen preservation, rather than to decreased protein expression. Methods for preserving antigenicity include coating sections in paraffin, refrigerated storage, desiccation, and storage in nitrogen. This study examined various combinations of the first 2 methods with respect to PTEN immunoreactivity. This was assessed semiquantitatively in freshly cut sections of paraffin blocks from 26 breast cancer specimens. The histoscore was compared with that observed in cut sections stored for 2 to 6 months with or without paraffin coating at room temperature (RT; 20 to 25 degrees C) or at 2 to 8 degrees C. At 2 months, the histoscore was strongest in freshly cut sections. Among the other treatments, refrigerated paraffin-coated sections had the highest histoscore followed by refrigerated uncoated sections. It was lower in RT paraffin-coated sections. Uncoated sections stored at RT showed the greatest signal loss. The greatest magnitude of changes between the various storage conditions and freshly cut slides ranged from 15% for refrigerated paraffin-coated slides to 75% for RT uncoated slides at 4 months. Although freshly cut paraffin-embedded sections were optimal, sections can be stored with adequate antigen preservation for 2 months using refrigeration with or without paraffin coating, and for 4 months using refrigeration with paraffin coating. PMID- 21552119 TI - Detection of high-risk HPV in head and neck squamous cell carcinomas: comparison of chromogenic in situ hybridization and a reverse line blot method. AB - Human papillomaviruses (HPVs) have been etiologically linked to a subset of head and neck squamous cell carcinomas (HNSCCs), generally arising in young patients without a history of tobacco smoking or alcohol use. These tumors typically lack mutations in TP53 and may show enhanced sensitivity to chemoradiation therapy with a correspondingly better overall prognosis. The determination of the HPV status in HNSCC therefore has therapeutic implications. We compared the Ventana ISH iView Blue Plus Detection Kit in situ hybridization (ISH) system and the Roche Linear Array HPV Genotyping Test for the detection of HPV in 98 formalin fixed, paraffin-embedded HNSCC samples. A moderate concordance rate (70.4%) was observed between ISH and the Linear Array assays. ISH detected HPV in 39.8% of cases, whereas Linear Array detected HPV in 57.1% of cases. Sensitivity and specificity of ISH for detecting HPV in HNSCC specimens were determined to be 58.9% and 85.7%, respectively, using the Linear Array as the method of comparison (McNemar test, P=0.003). ISH offers the advantage of visual cell-type localization of viral infection but overall it is less sensitive than the polymerase chain reaction-based detection of HPV in HNSCC. PMID- 21552120 TI - Vacuum sealing and cooling as methods to preserve surgical specimens. AB - Recently, vacuum-based preservation of surgical specimens has been proposed as a safe alternative to formalin fixation at the surgical theater. The method seems feasible from a practical point of view, but no systematic study has examined the effect of vacuum sealing alone with respect to tissue preservation. In this study, we therefore subjected tissue samples from 5 different organs to treatments with and without vacuum sealing and cooling at 4 degrees C to study the effect of vacuum sealing of surgical specimens with respect to tissue preservation and compare it with the effect of cooling. No preserving effect of vacuum sealing was observed with respect to cellular morphology, detection of immunohistochemical epitopes, or RNA integrity. In contrast, storage at 4 degrees C was shown to preserve tissue to a higher degree than storage at room temperature for all included endpoints, independently of whether the tissue was subjected to vacuum sealing or not. We, therefore, conclude that vacuum sealing is not an alternative to cooling on ice. PMID- 21552121 TI - Reduced brain edema and functional deficits after treatment of diffuse traumatic brain injury by carbamylated erythropoietin derivative. AB - OBJECTIVE: To investigate the effects of carbamylated erythropoietin, a modified erythropoietin lacking erythropoietic activity, on brain edema and functional recovery in a model of diffuse traumatic brain injury. DESIGN: Adult male Wistar rats. SETTING: Neurosciences and physiology laboratories. INTERVENTIONS: Thirty minutes after diffuse traumatic brain injury (impact-acceleration model), rats were intravenously administered with either a saline solution (traumatic brain injury-saline) or carbamylated erythropoietin (50 MUg/kg; traumatic brain injury carbamylated erythropoietin). A third group received no traumatic brain injury insult (sham-operated). MEASUREMENTS AND MAIN RESULTS: Three series of experiments were conducted to investigate: 1) the effect of carbamylated erythropoietin on brain edema before and 1 hr after traumatic brain injury using diffusion-weighted magnetic resonance imaging and measurements of apparent diffusion coefficient (n = 10 rats per group), and the phosphorylation level of brain extracellular-regulated kinase-1/-2 was also determined to indicate the presence of an activated cell signaling pathway; 2) the time course of brain edema using magnetic resonance imaging between 4 and 6 hrs postinjury and the gravimetric technique at 6 hrs (n = 10 rats per group); and 3) motor and cognitive function over 10 days post traumatic brain injury, testing acute somatomotor reflexes, adhesive paper removal, and two-way active avoidance (n = 8 rats per group). Compared to traumatic brain injury-saline rats, rats receiving traumatic brain injury-carbamylated erythropoietin showed a significant reduction in brain edema formation at 1 hr that was sustained until 6 hrs when results were comparable with sham-operated rats. This antiedematous effect of carbamylated erythropoietin was possibly mediated through an early inhibition of extracellular regulated kinase-1/-2 phosphorylation. Compared to traumatic brain injury-saline rats, traumatic brain injury-carbamylated erythropoietin rats showed improved functional recovery of the acute somatomotor reflexes post traumatic brain injury, took less time to remove adhesive from the forelimbs, and showed higher percentages of correct avoidance responses. CONCLUSION: Our findings indicate that early posttraumatic administration of carbamylated erythropoietin reduces brain edema development until at least 6 hrs postinjury and improves neurologic recovery. Carbamylated erythropoietin can thus be considered as a potential agent in the treatment of traumatic brain injury-induced diffuse edema. PMID- 21552122 TI - Epithelial inducible nitric oxide synthase causes bacterial translocation by impairment of enterocytic tight junctions via intracellular signals of Rho associated kinase and protein kinase C zeta. AB - OBJECTIVE: Gut barrier dysfunction and bacterial translocation occur in various disorders, including intestinal obstruction. Overexpression of inducible nitric oxide synthase is implicated in the pathogenesis of bacterial translocation, of which the molecular mechanism remains unclear. Epithelial permeability is regulated by tight junction reorganization and myosin light chain phosphorylation. Our aim was to investigate the roles of Rho-associated kinase and protein kinase C zeta in epithelial nitric oxide synthase-mediated barrier damage. DESIGN: Animal study and cell cultures. SETTING: Research laboratory. SUBJECTS: BALB/c mice. INTERVENTIONS: : Mouse distal small intestine was obstructed in vivo by a 10-cm loop ligation in which vehicle, L-Nil (a nitric oxide synthase inhibitor), or Y27632 (a Rho-associated kinase inhibitor) was luminally administered. After obstruction for 24 hrs, intestinal tissues were mounted on Ussing chambers for macromolecular flux. Liver and spleen tissues were assessed for bacterial counts. Caco-2 cells were exposed to 1 mM S-nitroso-N acetylpenicillamine (a nitric oxide donor) for 24 hrs, and transepithelial resistance and permeability were evaluated. MEASUREMENTS AND MAIN RESULTS: Mice with intestinal obstruction displayed epithelial barrier dysfunctions, such as permeability rise and bacterial translocation, associated with tight junction disruption and myosin light chain phosphorylation. Increased inducible nitric oxide synthase and phosphorylated protein kinase C zeta were observed in villus epithelium. Enteric instillation of L-Nil and Y27632 attenuated the functional and structural barrier damage caused by intestinal obstruction. L-Nil decreased intestinal obstruction-induced myosin light chain, myosin phosphatase target subunit 1, and protein kinase C zeta phosphorylation, suggesting that inducible nitric oxide synthase is upstream of Rho-associated kinase and protein kinase C zeta signaling. The intestinal phosphorylated myosin light chain level did not increase in inducible nitric oxide synthase(-/-) mice following intestinal obstruction. In vitro studies showed that S-nitroso-N-acetylpenicillamine-induced transepithelial resistance drop and permeability rise was independent of cell apoptosis. Y27632 inhibited S-nitroso-N-acetylpenicillamine-induced myosin light chain phosphorylation and permeability rise. S-nitroso-N-acetylpenicillamine also triggered phosphorylation and membrane translocation of protein kinase C zeta. Inhibitory protein kinase C zeta pseudosubstrate blocked S-nitroso-N acetylpenicillamine-induced tight junction reorganization, but not myosin light chain phosphorylation. CONCLUSIONS: Epithelial inducible nitric oxide synthase activates two distinct signals, protein kinase C zeta and Rho-associated kinase, to disrupt tight junctions leading to bacterial influx. PMID- 21552123 TI - Nutritional intervention for improving treatment tolerance in cancer patients. AB - PURPOSE OF REVIEW: This study aims to assess various types of nutritional intervention for improving treatment tolerance in patients with malnutrition related to the cancer anorexia-cachexia syndrome. RECENT FINDINGS: Malnutrition in cancer patients is associated with a poor prognosis, whereas weight loss is an important predictor of mortality. Disease and treatments have a major impact on nutritional status. By improving the latter, we can change the prognosis, quality of life and functional status, facilitating improved tolerance to treatment. Dietary counselling, recommended for patients at risk of malnutrition, should be introduced early in close collaboration with the patient. Administering oral nutritional supplements to malnourished patients has been shown to lead to a reduction in mortality, in complications and in the length of hospital stay. Supplementation with enteral nutrition has demonstrated an increase in appetite, energy intake, nutritional status and, above all, reduced gastrointestinal toxicity from cancer treatments due to a better response to them. Supplementation with home parenteral nutrition in aphagic and terminal patients has shown improved quality of life, energy balance, body composition and prolonged survival. SUMMARY: Supplementation with omega3 fatty acids appears to offer benefits that are verifiable at a biochemical, clinical and functional level. Related literature, however, provides conflicting results; therefore further studies will be required to confirm their efficacy. Supplementation with glutamine appears to support the efficacy of chemoradiotherapy treatment while reducing toxicity of the tissues and improving outcomes. Oral supplementation with branched amino acid appears to reduce the length of hospital stay, decrease morbidity and improve the quality of life, without any changes in mortality. Perioperative supplementation with arginine has shown a reduced incidence of complications and a significant increase in long-term survival. PMID- 21552124 TI - Clinical and molecular approaches to well differentiated and dedifferentiated liposarcoma. AB - PURPOSE OF REVIEW: Liposarcoma, a rare disease, is classified into five histologic subtypes. These include well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS), both characterized by chromosome 12q13-15 amplification. This review will focus on the clinical management of WDLS and DDLS and examine recent molecular studies that have the potential to affect clinical management. RECENT FINDINGS: Outcome of patients with WDLS and DDLS depends on completeness of surgical resection as well as tumor location and histologic subtype. Risk of recurrence is high for patients with dedifferentiated histology or retroperitoneal location. We now understand that surgical outcomes are poor for patients with rapidly growing or incompletely resectable tumors, so these patients should be managed nonoperatively. Radiation and chemotherapy have low response rates in WDLS and DDLS, but novel agents targeted at chromosome 12 gene products MDM2 and CDK4 have shown promise in preclinical studies and are being tested in clinical trials. Cell line, tissue microarray, and genomic analyses have identified additional targets including ZIC1, TOP2A, AURKA, and IGF-1R, which could form the basis of future therapies. SUMMARY: Although complete surgical resection is currently the most effective treatment for WDLS and DDLS, the majority of patients with retroperitoneal liposarcoma will eventually have recurrence and die of disease. It is hoped that a multimodality approach, which incorporates targeted therapies and complete surgical resection, will significantly improve patient outcomes. PMID- 21552125 TI - Laser in-situ keratomileusis infection: review and update of current practices. AB - PURPOSE OF REVIEW: To review new clinically relevant data regarding the prevention cause and treatment of laser in-situ keratomileusis (LASIK) infections. RECENT FINDINGS: Many recent studies of post-LASIK infectious keratitis show the predominance of atypical mycobacteria and Gram-positive cocci and the growing number of other rare pathogens. The American Society of Cataract and Refractive Surgery White Paper treatment paradigm remains the model for initial treatment of LASIK-associated infectious keratitis. SUMMARY: Improved understanding of the risk factor, different causes, along with a high degree of suspicion on initial presentation is crucial in order to provide the appropriate management in LASIK-associated infectious keratitis. PMID- 21552126 TI - Femtosecond laser in-situ keratomileusis flap configurations. AB - PURPOSE OF REVIEW: The corneal flap laser in-situ keratomileusis (LASIK) is among the most important determinants in the successful outcome of the surgery. Femtosecond lasers have evolved over the last decade to all but replace the mechanical microkeratome as the preferred method to create these flaps. With improvements in femtosecond laser technology, there has been a reduction in the time taken for the cut and the quality of the stromal bed has improved. Improved predictability has led surgeons to explore the possibility of thin flap LASIK. RECENT FINDINGS: Corneal flaps created with the femtosecond laser have been shown to be more predictable in depth and have a more desirable planar morphology. Corneal flaps created by the femtosecond laser can be customized according to depth, profile, morphology, and side-cut configuration. Changes in the angulation of the side cut, to reduce the incidence of epithelial ingrowth, have not been corroborated by clinical evidence as yet. Thin flap LASIK, also referred to as sub-Bowman's keratomileusis, has the advantage of preserving more stroma and potentially reducing the incidence of corneal ectasia but seems to be associated with an increased incidence of interface haze. SUMMARY: This review examines the advantages of creating a flap with the femtosecond laser and the various configurations of these flaps. It also explores the advantages of varying the thickness and profile of femtosecond flaps. PMID- 21552127 TI - Refractive surgery and the glaucoma patient. AB - PURPOSE OF REVIEW: Patients considering corneal refractive surgery undergo extensive preoperative testing, but current protocols may not address the management of glaucoma appropriately. This review outlines the current body of literature on the diagnostic and management challenges that exist in the treatment of glaucoma patients undergoing laser ablative surgery, and makes recommendations to improve current perioperative protocols. RECENT FINDINGS: As permanent structural alterations to the cornea after laser-assisted in-situ keratomileusis surgery make Goldmann applanation tonometry inaccurate, the advent of new diagnostic modalities and recommendations to accurately measure postoperative intraocular pressure (IOP) and subtle damage to the optic nerve have been further analyzed and tested. SUMMARY: As IOP is the only modifiable risk factor in the treatment of glaucoma to date, traditional diagnostic and treatment algorithms may not be appropriate for refractive surgery patients. Glaucoma remains a relative contraindication to refractive procedures, but as new diagnostic modalities emerge, our ability to diagnose and manage these patients may improve. More uniform recommendations need to be implemented to improve our long-term management of these patients. PMID- 21552128 TI - Binaural directivity patterns for normal and aided human hearing. AB - OBJECTIVE: The aim of this brief report was to investigate binaural directivity patterns for normal and aided hearing, as opposed to conventional monaural measures. DESIGN: Head-related transfer functions for an artificial head measured at the entrance to the ear canal and above the pinnae and a binaural loudness model for directional sounds were used to estimate binaural directivity patterns for normal human hearing and behind-the-ear (BTE) hearing devices in the horizontal plane. RESULTS: The results show that binaural directivity patterns are smoother than the corresponding monaural patterns, and that there are clear frequency-dependent differences in binaural directivity between the two measurement positions. CONCLUSION: The data can be used in the signal processing of BTE hearing aid systems to mimic the binaural directivity of normal, unoccluded ears. PMID- 21552129 TI - Direct and indirect effects in a survival context. AB - A cornerstone of epidemiologic research is to understand the causal pathways from an exposure to an outcome. Mediation analysis based on counterfactuals is an important tool when addressing such questions. However, none of the existing techniques for formal mediation analysis can be applied to survival data. This is a severe shortcoming, as many epidemiologic questions can be addressed only with censored survival data. A solution has been to use a number of Cox models (with and without the potential mediator), but this approach does not allow a causal interpretation and is not mathematically consistent. In this paper, we propose a simple measure of mediation in a survival setting. The measure is based on counterfactuals, and measures the natural direct and indirect effects. The method allows a causal interpretation of the mediated effect (in terms of additional cases per unit of time) and is mathematically consistent. The technique is illustrated by analyzing socioeconomic status, work environment, and long-term sickness absence. A detailed implementation guide is included in an online eAppendix (http://links.lww.com/EDE/A476). PMID- 21552130 TI - Factors influencing adherence to an emergency department national protocol. AB - The objective of this study was to identify factors that influence emergency nurses' adherence to an emergency department national protocol (EDNP). A survey of emergency nurses (n=200) and physicians with medical end responsibility on an emergency department (n=103) was carried out. Emergency nurses' self-reported adherence to the EDNP was 38%, 55% of the nurses and 44% of the physicians were aware of the protocol. Interference with professional autonomy, insufficient organizational support and the EDNP's applicability were indicated as barriers for adherence. The main influencing factor seems awareness. Other factors related to the individual, the organization and to protocol characteristics. Solely disseminating the EDNP is not enough to get the protocol used in clinical practice. PMID- 21552131 TI - Contrast-induced nephropathy risk due to emergency contrast-enhanced computed tomography. AB - OBJECTIVE: In this study, we aimed to compare serum creatinine, blood urea, and glomerular filtration rate (GFR) levels of patients at baseline and 48 h after the administration of radiocontrast agent in the emergency department. METHOD: We prospectively enrolled 114 patients who underwent contrast-enhanced computed tomography scan and had a baseline creatinine level of 1.5 mg/dl or less. Serum creatinine and blood urea levels were measured at baseline and 48 h after the administration of radiocontrast agent. GFR and Mehran risk score were calculated at baseline and 48 h after the administration of radiocontrast agent. RESULTS: Baseline mean serum creatinine was 1.03+/-0.25 mg/dl. Forty-eight hours after the administration of radiocontrast agent, mean serum creatinine was 1.04+/-0.31 mg/dl, baseline mean blood urea was 8.14+/-4.04 mmol/l, mean blood urea was 8.42+/-4.42 mmol/l, baseline mean GFR was 76.74+/-27.08 ml/min, and mean GFR was 77.21+/-27.92 ml/min. There were no significant differences between baseline and 48 h after the administration of radiocontrast agent serum creatinine, blood urea levels, and GFR (P>0.05). CONCLUSION: There was no statistically significant difference between basal and 48 h after the administration of radiocontrast agent serum creatinine and GFR levels of patients who were enrolled in this study. Results had shown that administration of intravenous radiocontrast agent (<=100 ml) for emergency imaging in the emergency department did not produce a risk for contrast-induced nephropathy in patients with serum creatinine levels of 1.5 mg/dl or less. PMID- 21552132 TI - Transformational teaching and physical activity engagement among adolescents. AB - The integrative hypothesis presented in this paper is that transformational leadership, as displayed by school physical education teachers, leads to improved engagement in physical activity behaviors among adolescents. A conceptual framework is proposed that includes salient intrapersonal mediators (psychological mechanisms) and boundary conditions (moderators). PMID- 21552133 TI - Policy statement on folic acid and neural tube defects. AB - It now recognized that the use of folate fortification and/or supplementation before initiation of pregnancy can impact the risk of the fetus developing a neural tube defect. This document serves to update the policy statement issued by the American College of Medical Genetics and published in 2005. PMID- 21552134 TI - Multiple endocrine neoplasia type 2: an overview. AB - Multiple endocrine neoplasia type 2 is historically composed of three clinical subtypes, all of which are associated with germline mutations in the RET proto oncogene. Multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and multiple endocrine neoplasia type 2B are collectively associated with a 70-100% risk of medullary thyroid carcinoma by age 70 years. Pheochromocytomas are identified in 50% of individuals with multiple endocrine neoplasia type 2A and multiple endocrine neoplasia type 2B. Furthermore, those with multiple endocrine neoplasia type 2A have a 20-30% risk for primary hyperparathyroidism. Individuals with multiple endocrine neoplasia type 2B often have distinct physical features including mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, ganglioneuromatosis of the gastrointestinal tract, distinctive facies with enlarged lips, and a "Marfanoid" body habitus. Clinical recognition and accurate diagnosis of individuals and families who are at risk of harboring a germline RET mutation is critical for the prevention and management of potentially life-threatening neoplasms. This overview summarizes the clinical description of multiple endocrine neoplasia type 2, diagnosis and testing strategies, management and surveillance, and differential diagnosis for other related syndromes. PMID- 21552136 TI - Should the treatment of anal carcinoma be adapted in the elderly? A retrospective analysis of toxicities in a French center. PMID- 21552135 TI - Gastric cancer in individuals with Li-Fraumeni syndrome. AB - PURPOSE: Li-Fraumeni syndrome is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. Although sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as Li Fraumeni syndrome-associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer in Li-Fraumeni syndrome. METHODS: Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute Li-Fraumeni syndrome registry. We identified subjects with gastric cancer documented either by pathology report or death certificate and performed pathology review of the available specimens. RESULTS: Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. Gastric cancer was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at gastric cancer diagnosis were 43 and 36 years, respectively (range: 24-74 years), significantly younger compared with the median age at diagnosis in the general population based on Surveillance Epidemiology and End Results data (71 years). Five (8.1%) families reported two or more cases of gastric cancer, and six (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies. CONCLUSIONS: Early-onset gastric cancer seems to be a component of Li-Fraumeni syndrome, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of gastric cancer. PMID- 21552137 TI - Qualitative assessment of patient-reported outcomes in adults with eosinophilic esophagitis. AB - GOALS: This study aims to qualitatively describe experiences of adult patients diagnosed with eosinophilic esophagitis (EoE). Specifically, we aim to identify disease-specific concerns related to patient-reported outcomes in this population to inform clinical care and assessment. BACKGROUND: EoE is a chronic inflammatory disease of the esophagus and is increasingly recognized as a cause of dysphagia in adults. On the basis of its symptoms, limited and restrictive treatment options and potential for social and psychological impact, it is logical to expect that the health related quality of life of EoE patients would be an important outcome marker for assessment. STUDY: Twenty-four EoE patients participated in semistructured interviews about their illness experiences. Participants also provided demographic and clinical data, and completed the Medical Outcome Study Short Form 12 to assess mental and physical function. RESULTS: Six themes emerged from qualitative analyses which centered around 3 main points: concerns about the illness itself, concerns about swallowing difficulty, and concerns about the impact of EoE on social interactions. Patients were generally open to disclosing their illness status and reported relief at receipt of the EoE diagnosis. EoE patients did not differ from healthy norms for physical well-being, and were similar to comparable illness groups for mental functioning. CONCLUSIONS: Our study demonstrated that EoE has substantial impact on several psychosocial domains that are not adequately addressed by focused assessment of physical complaints of dysphagia. The results support the importance of development of disease-specific instruments pertaining to quality of life in EoE patients. PMID- 21552138 TI - A randomized, double-blind, placebo-controlled pilot study of Lactobacillus reuteri ATCC 55730 for the prevention of antibiotic-associated diarrhea in hospitalized adults. AB - GOALS: The purpose of the study was to evaluate Lactobacillus reuteri for the prevention of antibiotic-associated diarrhea (AAD) in hospitalized adults. BACKGROUND: AAD is a problem in hospitalized adults, contributing to increased length of stay, cost, and mortality. Probiotics have been proposed as a way to prevent AAD. L. reuteri decreases acute infectious diarrhea in children; however, L. reuteri has never been evaluated for the prevention of AAD. STUDY: In a randomized, double-blind, placebo-controlled pilot study, in-patients receiving antibiotics were given L. reuteri 1*10 colony-forming units twice daily or an identical placebo for 4 weeks. Stool frequency, consistency, and gastrointestinal symptoms were monitored during the 4-week treatment period and during a 2-week follow-up period. RESULTS: A total of 31 patients were enrolled. Eight patients were excluded in the data analysis because of length of study participation less than 14 days. Mean age was 51 +/- 18 years; 63% were female and 37% male. Most frequent primary diagnosis was pneumonia (20%), followed by abscess (10%), chronic obstructive pulmonary disease (6.7%), and bronchitis (6.7%). Thirteen patients received L. reuteri and 10 received placebo. Patients treated with L. reuteri had a significantly lower frequency of diarrhea compared with placebo (50% in the placebo group vs. 7.7% in the probiotic group, P=0.02). There were no differences in the frequency or severity of gastrointestinal symptoms. CONCLUSIONS: In this placebo-controlled, pilot study, L. reuteri twice daily for 4 weeks significantly decreased AAD among hospitalized adults. L. reuteri was safe and well tolerated. PMID- 21552139 TI - "Tac"kling a difficult problem: using tacrolimus to maintain remission in ulcerative colitis. PMID- 21552140 TI - The prevalence and efficacy of ganciclovir on steroid-refractory ulcerative colitis with cytomegalovirus infection: a prospective multicenter study. AB - BACKGROUND: It remains controversial whether or not cytomegalovirus infection in patients with active ulcerative colitis reflects a nonpathogenic colonization or a pathogenic disease warranting antiviral therapy. GOALS: The aim of this study was to determine the prevalence of cytomegalovirus infection in patients with active ulcerative colitis and the therapeutic efficacy of ganciclovir against cytomegalovirus infection in patients with steroid-refractory ulcerative colitis. STUDY: A prospective, multicenter study was conducted in 72 patients with moderate-to-severe ulcerative colitis who were treated with intravenous steroids. The presence of cytomegalovirus was evaluated serologically and histopathologic examination, including immunohistochemical staining. In patients with steroid refractory ulcerative colitis, cytomegalovirus infections were treated with intravenous ganciclovir. In patients with steroid-responsive ulcerative colitis, steroid therapy was continued irrespective of cytomegalovirus infection. RESULTS: The evidence of cytomegalovirus infection was found in 31 patients (43%) with moderate-to-severe active ulcerative colitis. In patients with steroid-refractory ulcerative colitis, the cytomegalovirus infection rate increased to 67% (14 of 21). No significant clinical and endoscopic differences existed between patients with and without a cytomegalovirus infection; however, the amount of steroids used during the flare-up period was significantly higher in patients with a cytomegalovirus infection (P = 0.013). Eleven of 14 patients (79%) with steroid refractory ulcerative colitis and a cytomegalovirus infection improved with ganciclovir treatment. Cytomegalovirus infections in the steroid-responsive group (17 of 31) did not require ganciclovir therapy. CONCLUSIONS: Cytomegalovirus infections are frequently observed in patients with moderate-to-severe ulcerative colitis, especially steroid-refractory ulcerative colitis. Ganciclovir was effective in patients with steroid-refractory ulcerative colitis who had a cytomegalovirus infection. PMID- 21552141 TI - Jejunal adaptation in a prepubertal boy after total ileal resection and jejunostomy placement: a four-year follow-up. AB - Intestinal adaptation is the process that attempts to restore total gut absorption after intestinal resection. In humans, the ileum and the colon can undergo adaptation without the jejunum. However, there is little evidence for the jejunum to undergo adaptation in the absence of the ileum. Here, we report the unusual case of a prepubertal boy who underwent total ileal resection, right hemicolectomy, and jejunostomy after a motor vehicle accident. Despite ileal resection, he showed evidence of successful structural and functional jejunal adaptation. PMID- 21552142 TI - Modeling for the decision process to implement an educational intervention: an example of a central venous catheter insertion course. AB - INTRODUCTION: The Center for Medicare and Medicaid Services recently declared that central venous catheter-associated bloodstream infections (CLABs) are preventable and no longer reimbursable. The new penalty paradigm creates substantial economic incentives for hospitals to eliminate infections. Modeling exercises offer the opportunity to justify expenditures for the prevention of rare patient safety events. METHODS: We constructed a decision analytic model of the theoretical impact of an educational intervention to improve the safety of central venous catheter insertion. This methodology allows for decision nodes representing procedure urgency, procedure locations, and effects of education on both infectious and mechanical complications. We performed deterministic sensitivity analyses to estimate effects of changes in complication rates, educational impact, and cost. RESULTS: In an already safety system (CLAB rate of 1:1000 line days or 0.7%), the initial sensitivity results suggest that if education results in a 50% reduction in CLAB and a 25% reduction in mechanical complications, survival is equal, and cost is increased by $92,400 in a large hospital system annually. If all CLAB and mechanical complications are eliminated, survival improves slightly, and cost is reduced by $64,800 annually. CONCLUSIONS: These results suggest that if the educational intervention is effective, a small increase in cost can reduce complications. Our analysis does not consider increased revenue generated by virtual bed capacity increases or dynamic changes in practice. This model serves as a template for other health care institutions to estimate the costs and benefits of their own proposed educational interventions. PMID- 21552143 TI - Continuing response to subsequent treatment lines with tyrosine kinase inhibitors in an adolescent with metastatic renal cell carcinoma. AB - A 14-year-old girl with metastatic renal cell carcinoma was treated with nephrectomy, interferon, and several lines of the targeted agents sorafenib, bevacizumab, sunitinib, and everolimus, either alone or in combination. Treatment was well tolerated, but the patient developed hypothyroidism and significant hypertension with bevacizumab and sunitinib. She responded to all agents and was given radiation treatment twice at the time of symptomatic disease progression; she died 33 months from diagnosis. PMID- 21552144 TI - JAK2V617F mutation in a 9-year-old girl with polycythemia vera and Budd-Chiari syndrome: a case report. PMID- 21552145 TI - High aromatase activity and overexpression of epidermal growth factor receptor in fibrolamellar hepatocellular carcinoma in a child. AB - An 11-year-old boy was admitted with a liver tumor and underwent right trisegmentectomy for a diagnosis of fibrolamellar hepatocellular carcinoma. He had suffered from bilateral gynecomastia for a year, which improved after complete resection of the tumor. The tumor cells had significant aromatase activity (8.03 pmol/g/h) and contained high levels of estradiol (82.1 pg/mL), which contributed to gynecomastia. Furthermore, overexpression of epidermal growth factor receptor was determined in the tumor cells, which suggests that antitumor strategies using epidermal growth factor receptor antagonists may be effective. PMID- 21552146 TI - Isolated esophageal ulcerations in immunocompromised patients: mycophenolate mofetil or foscarnet, who is guilty? PMID- 21552147 TI - ASPS-1, a novel cell line manifesting key features of alveolar soft part sarcoma. AB - In vitro growth of alveolar soft part sarcoma (ASPS) and establishment of an ASPS cell line, ASPS-1, are described in this study. Using a recently developed xenograft model of ASPS derived from a lymph node metastasis, organoid nests consisting of 15 to 25 ASPS cells were isolated from ASPS xenograft tumors by capture on 70 MUm filters and plated in vitro. After attachment to the substratum, these nests deposited small aggregates of ASPS cells. These cells grew slowly and were expanded over a period of 3 years and have maintained characteristics consistent with those of both the original ASPS tumor from the patient and the xenograft tumor including (1) presence of the alveolar soft part locus-transcription factor E3 type 1 fusion transcript and nuclear expression of the alveolar soft part locus-transcription factor E3 type 1 fusion protein; (2) maintenance of the t(X;17)(p11;q25) translocation characteristic of ASPS; and (3) expression of upregulated ASPS transcripts involved in angiogenesis (ANGPTL2, HIF 1-alpha, MDK, c-MET, VEGF, and TIMP-2), cell proliferation (PRL, PCSK1), metastasis (ADAM9), as well as the transcription factor BHLHB3 and the muscle specific transcripts TRIM63 and ITGbeta1BP3. This ASPS cell line forms colonies in soft agar and retains the ability to produce highly vascularized ASPS tumors in NOD.SCID/NCr mice. Immunohistochemistry of selected ASPS markers on these tumors indicated similarity to those of the original patient tumor as well as to the xenografted ASPS tumor. We anticipate that this ASPS cell line will accelerate investigations into the biology of ASPS including identification of new therapeutic approaches for treatment of this slow growing soft tissue sarcoma. PMID- 21552148 TI - A common symptom of an uncommon disease. AB - Cancer of the colon is the second most common visceral cancer in the United States (lung cancer is the first). It is usually diagnosed in patients older than 40 years, with a peak incidence at 70 years of age. Rarely, are cases seen in the pediatric population. In this study, we report a case of a 13-year-old girl with an 11-month history of intermittent abdominal pain whose diagnosis was delayed due to vague symptoms and a low index of suspicion for this condition. PMID- 21552149 TI - Elbow arthrography in children with an ulnar fracture and occult subluxation of the radial head. AB - The purpose of this study was to investigate the use of elbow arthrography for detecting an occult subluxation of the radial head and for verifying the quality of reduction in children with ulnar fractures. The study involved 15 children who underwent closed reduction (with or without percutaneous pinning) based on arthrography for minimally displaced fractures with or without radial head subluxation. The mean age of the patient at the time of surgery was 6 years (range, 3-12 years). Initial diagnoses based on conventional radiographs were compared with arthrographically confirmed final diagnoses in groups of children with ulnar fractures of the olecranon, proximal, and diaphysis. Arthrography confirmed initial radiographic diagnoses in 10 and altered diagnoses in five patients. We conclude that arthrography can be useful for detecting an occult subluxation of the radial head and for evaluating adequate reduction in children of less than 6 years with ulnar fractures. PMID- 21552150 TI - Potential of delayed gadolinium enhancement magnetic resonance imaging for quantification of reverse remodeling of the peri-infarct zone in patients with ischemic cardiomyopathy treated with chronic vasodilator therapy: initial experience. AB - PURPOSE: The peri-infarct zone represents the morphologic substrate for reentry ventricular tachycardia after myocardial infarction, and its extent is a strong predictor of major cardiac events. Although delayed gadolinium enhancement magnetic resonance imaging (DGE-MRI) was shown to allow for detailed characterization of myocardial infarction by quantifying infarct core zone and peri-infarct zone volume, potentials of DGE-MRI for measuring changes in peri infarct zone volume are unknown. Therefore, we aimed to assess changes in volume of the peri-infarct zone among patients with ischemic cardiomyopathy treated with chronic vasodilator therapy. MATERIALS AND METHODS: Core and peri-infarct zone volumes as assessed with DGE-MRI were measured in 5 patients at baseline and after 6 months treatment with sustained-release dipyridamole. RESULTS: Core zone volume remained stable during follow-up [median (range), 19 mL (9 to 42) vs. 16 mL (11 to 46); P=0.785]. The ratio between the peri-infarct zone and the core zone volume decreased significantly at 6 months compared with baseline [median (range), 0.22 (0.19 to 0.42) vs. 0.18 (0.09 to 0.32); P=0.043], and a trend toward reduction in peri-infarct zone volume was found [median (range), 5 mL (2 to 8) vs. 3 mL (2 to 6); P=0.059]. The peri-infarct zone volume decreased in all but 1 patient over the follow-up. CONCLUSIONS: This initial experience suggests that reverse remodeling of the peri-infarct zone with reduction in peri-infarct zone volume may take place in patients with ischemic cardiomyopathy. Quantification of this process may be feasible with DGE-MRI, but further studies are needed to confirm this hypothesis and to further clarify the role of DGE-MRI for the assessment of changes in peri-infarct zone volume in patients with ischemic cardiomyopathy. PMID- 21552151 TI - Noninvasive estimation of myosin heavy chain composition in human skeletal muscle. AB - PURPOSE: Information on muscle fiber type composition is of great importance in muscle physiology and athletic performance. Because there are only a few techniques available that noninvasively and accurately provide an estimate of muscle fiber type composition, the development of additional and alternative approaches is required. METHODS: Twenty-seven participants (21 men, 6 women) with an average age of 43 +/- 18 yr, height of 175 +/- 7 cm, and mass of 74 +/- 12 kg participated in the study. Delay, contraction, and half relaxation times were calculated from tensiomyographic radial twitch responses of the vastus lateralis muscle. Univariate and multiple linear regression analyses were used to correlate the proportion of myosin heavy chain I (%MHC-I) in a biopsy obtained from the same muscle with a single and all three radial twitch parameters. RESULTS: Delay, contraction, and half relaxation times all correlated with %MHC-I (r = 0.612, 0.878, and 0.669, respectively, at P <= 0.001). When all three parameters were included in a multiple linear regression, the correlation with the %MHC-I was even better (R = 0.933, P < 0.001). CONCLUSIONS: These data suggest that time parameters of the skeletal muscle mechanical radial twitch response, measured with a contact linear displacement sensor, can be used as an accurate noninvasive predictor of the %MHC-I in a muscle. PMID- 21552152 TI - Effects of salmeterol on skeletal muscle cells: metabolic and proapoptotic features. AB - PURPOSE: Salmeterol is a beta2-adrenergic receptor agonist widely used for the treatment of asthma and chronic obstructive pulmonary disease. It has been shown that salmeterol is also used at supratherapeutic doses as performance-enhancing substance in sport practice. Although the abuse of beta-agonists might determine some adverse effects, the molecular effects of salmeterol on skeletal muscle cells remain unclear. METHODS: We evaluated the effects of salmeterol (0.1-10 MUM) on both proliferative and differentiated rat L6C5 and mouse C2C12 skeletal muscle cell lines. The metabolic effects were evaluated by glyceraldehyde phosphate dehydrogenase, lactate dehydrogenase, citrate synthase, 3-OH acyl-CoA dehydrogenase, and alanine transglutaminase activities. Cytotoxic and apoptotic effects were analyzed by 3-(4,5-dimethylthiazol-1)-5-(3-carboxymeth-oxyphenyl)-2H tetrazolium, trypan blue exclusion assay, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, Western blot analysis, and immunofluorescence staining. RESULTS: We showed that salmeterol reduced the growth rate of proliferating cells in a dose- and time-dependent manner (6-48 h). An increase in oxidative metabolism was found after 6 h in C2C12 and L6C5 myoblasts and in C2C12 myotubes with respect to control cells, while in L6C5 myotubes, anaerobic metabolism prevailed. Exposure of myoblasts and myotubes for 48 and 72 h at high salmeterol concentrations induced apoptosis by the activation of the intrinsic apoptotic pathway, as confirmed by the modulation of the apoptotic proteins Bcl xL, caspase-9, and poly (ADP-ribose) polymerase and by the cytoplasmic release of Smac/DIABLO. CONCLUSIONS: Altogether, our results demonstrate that short-term supratherapeutic salmeterol exposure increased oxidative metabolic pathways on skeletal muscle cells, whereas prolonged treatment inhibits cell growth and exerts either a cytostatic or a proapoptotic effect in a time- and dose-dependent way. PMID- 21552153 TI - Physical activity, sedentary behavior, and the metabolic syndrome in minority youth. AB - PURPOSE: This study aimed to determine the associations among physical activity, sedentary behavior, and the metabolic syndrome (MetS) in Latino and African American youth using both subjective and objective measures of activity levels. METHODS: Cross-sectional data from 105 participants from three pediatric obesity studies that share a core set of methods and measures (Latino 74%, female 75%, mean age = 13 +/- 3 yr) were used. Measures included moderate-to-vigorous physical activity and sedentary behavior by accelerometry and 3-Day Physical Activity Recall (3DPAR), fat and lean tissue mass by BodPodTM, fasting glucose, lipids, blood pressure, and waist circumference. Associations between physical activity, sedentary behavior, and MetS were examined using ANCOVA, Pearson correlations, partial correlations, and logistic regressions with adjustments for age, sex, ethnicity, fat and lean mass, and pubertal Tanner stage. RESULTS: Accelerometry data showed that greater time engaging in moderate-to-vigorous physical activity was related to lower odds of the MetS (odds ratio = 0.49, 95% confidence interval = 0.25-0.98), independent of sedentary behavior and covariates, and inversely correlated with fasting glucose (r = -0.21, P = 0.03) and systolic blood pressure (r = -0.25, P = 0.01), adjusting for covariates. Data from the 3DPAR showed that higher levels of sedentary behavior were related to higher odds of the MetS (odds ratio = 4.44, 95% confidence interval = 1.33 14.79), independent of moderate-to-vigorous physical activity and covariates, negatively correlated with HDL-cholesterol (r = -0.21, P = 0.04) and positively correlated systolic blood pressure (r = 0.26, P = 0.009), adjusting for covariates. CONCLUSIONS: Future interventions aiming to improve metabolic health in youth should target both the promotion of physical activity and the reduction of sedentary behavior. Subjective and objective measures should be used in conjunction to better capture activity behaviors. PMID- 21552155 TI - Study of injury and illness rates in multiday ultramarathon runners. AB - PURPOSE: This study aimed to describe injury and illness rates in runners competing in 7-d, 250-km off-road ultramarathon events. METHODS: Three hundred ninety-six runners competing in the RacingThePlanet(c) 4 Desert Series ultramarathon races from 2005 to 2006 were prospectively followed. Descriptive analyses were used to evaluate overall injury/illness rates, types of injuries/illnesses, and diagnoses for all medical encounters. Multivariate linear regression was used to estimate the risk of number of injuries/illnesses and 95% confidence intervals associated with age, sex, and race completion time. RESULTS: Eight-five percent of runners representing a total of 1173 medical encounters required medical care. The overall injury/illness rates were 3.86 per runner and 65 per 1000-h run. Almost 95% were minor in nature, owing to skin-related disorders (74.3%), musculoskeletal injuries (18.2%), and medical illnesses (7.5%). Medical illnesses were more likely on the first day of the race, whereas musculoskeletal and skin injuries were more likely on day 3 or 4. A 10-yr increase in age was associated with 0.5 fewer injuries/illnesses, and females had 0.16 more medical illnesses compared with males. CONCLUSIONS: Despite the extreme nature and harsh environments of multiday ultramarathon races, the majority of injuries or illnesses are minor in nature. Future studies are needed to evaluate additional factors contributing to injuries. PMID- 21552154 TI - Common genetic variation in the IGF1 associates with maximal force output. AB - PURPOSE: We clarified the effect of insulin-like growth factor-1 (IGF1), IGF binding protein-3 (IGFBP3), interleukin-6 (IL6), and its receptor (IL6R) gene variants on muscular and aerobic performance, body composition, and on circulating levels of IGF-1 and IL-6. Single nucleotide polymorphisms (SNPs) may, in general, influence gene regulation or its expression, or the structure and function of the corresponding protein, and modify its biological effects. IGF-1 is involved in the anabolic pathways of skeletal muscle. IL-6 plays an important role in muscle energy homeostasis during strenuous physical exercise. METHODS: Eight hundred forty-one healthy Finnish male subjects of Caucasian origin were genotyped for IGF1 (rs6220 and rs7136446), IGFBP3 (rs2854744), IL6 (rs1800795), and IL6R (rs4537545) SNPs, and studied for associations with maximal force of leg extensor muscles, maximal oxygen consumption, body fat percent, and IGF-1 and IL 6 levels. Analytic methods included dynamometer, bicycle ergometer, bioimpedance, ELISA, and polymerase chain reaction assays. RESULTS: All investigated SNPs conformed to Hardy-Weinberg equilibrium with allele frequencies validated against CEU population. Genotype CC of rs7136446 associated with higher body fat and increased maximal force production. Genotype CC of the IGFBP3 SNP rs2854744 and TT genotype of the IL6R SNP rs4537545 associated with higher IL-6 levels. In logistic regression analysis, allele C of the rs2854744 decreased odds for lower body fat. None of the studied SNPs associated with aerobic performance. CONCLUSIONS: Our data suggest that common variation in the IGF1 gene may affect maximal force production, which can be explained by the role of IGF-1 in the anabolic pathways of muscle and neurotrophy. Variations in the IGF1 and IGFBP3 gene may result in higher body fat and be related to alterations of IGF-1 mediated tissue growth. PMID- 21552156 TI - Effect of exercise intensity on the cytokine response to an acute bout of running. AB - PURPOSE: We compared the effects of exercise intensity (EI) on the cytokine response to an acute bout of running. METHODS: Ten males (mean +/- SD VO(2max)= 56.2 +/- 8.1 mL.min(-1).kg(-1)) completed three, counterbalanced, 8-d trials. After three control days, on day 4, participants completed 60 min of running at 55%, 65%, and 75% VO(2max). The cytokines tumor necrosis factor (TNF)-alpha, interleukin-1beta (IL-1beta), IL-6, and IL-1 receptor antagonist (ra), and creatine kinase were measured during and for 3 h after exercise and on four follow-up days (FU1-FU4). RESULTS: RER was higher at 75% V(O2max) compared with both 55% (P < 0.001) and 65% (P < 0.01) VO(2max). IL-1beta was undetectable in six participants. There was a small (18%-27%) increase in TNF-alpha during exercise but no effect of EI. IL-6 concentrations peaked at the end of exercise, with a greater increase at 75% VO(2max), resulting in higher concentrations at the end of exercise and at 30 min after exercise compared with 55% (P < 0.001) and 65% VO(2max) (P < 0.01). IL-1ra concentrations peaked at the end of exercise at 75% VO(2max), resulting in higher (P < 0.05) concentrations at 1-2 h after exercise compared with 55% and 65% VO(2max). Creatine kinase was increased at FU1 and FU2, but there was no effect of EI. CONCLUSIONS: Sixty minutes of treadmill running at 75% VO(2max) results in a greater increase in IL-6 but not TNF-alpha compared with 55% and 65% V(O2max). The higher IL-1ra concentrations at 75% VO(2max) might be related to the higher IL-6 concentrations that precede them. PMID- 21552157 TI - Spin on fastballs thrown by elite baseball pitchers. AB - PURPOSE: In this study, we analyzed the direction of the spin axis angles and the spin rate of baseballs pitched by elite collegiate and professional pitchers. METHOD: The video image of a ball being pitched was taken from the period just before release until 200 ms after release with a high-speed video camera at a rate of 1000 frames per second. A custom-made device was used to analyze the spin axis angle and the spin rate. RESULTS AND CONCLUSION: There were no significant differences in the direction of the spin axis angles or the spin rate between collegiate and professional pitchers. A significant correlation was obtained between spin rate and ball speed; that is, the higher the ball speed, the greater the spin rate. In addition, the spin rate deviated more across subjects than did ball speed. For all subjects, the azimuth and elevation of spin axis were 19 degrees +/- 14 degrees and -32 degrees +/- 9 degrees , respectively. Some of the pitchers were able to put a characteristic spin on their fastball; the nature of this spin could be related to their pitching success. PMID- 21552158 TI - Association between knee extensor strength and EMG activities during squat movement. AB - PURPOSE: The present study aimed to clarify how the force-generating capability of quadriceps femoris (QF) is associated to its surface EMG activity during a body mass-based squat movement. METHODS: Isometric knee extension torque (KET) during maximal voluntary contraction and EMG activities of the rectus femoris and vastus lateralis muscles during a body mass-based squat movement were determined in 53 men and 48 women age 19-90 yr, including 18 frail elderly persons who used the long-term care insurance system. The rectified EMG signals during the squat movement were averaged and normalized as the relative value (%EMG(max)) to that during maximal voluntary contraction. The %EMG(max) values for rectus femoris and vastus lateralis were averaged and used as an index representing the level of muscular activities of QF during the squat movement (QF %EMG(max)). RESULTS: QF %EMG(max) was nonlinearly related to KET relative to body mass (KET/BM). Linear piecewise continuous regression analysis showed that there was a breakpoint of 1.9 N.m.kg(-1) in the relationship between the two variables. In individuals with KET/BM less than 1.9 N.m.kg(-1), QF %EMG(max) rapidly increased as KET/BM decreased. CONCLUSIONS: The current results indicate that the activity level of QF during a body mass-based squat movement is influenced by its force generation capability. For individuals with a KET/BM less than 1.9 N.m.kg(-1), body mass based squat movement is considered to be a fairly high-intensity exercise. The breakpoint of 1.9 N.m.kg(-1) may be assumed to be a threshold level of knee extensor strength, which should be maintained for performing the activities of daily living without great difficulty. PMID- 21552159 TI - Effect of orthoses on changes in neuromuscular control and aerobic cost of a 1-h run. AB - PURPOSE: The study's purpose was to determine the effect of foot orthoses on neuromuscular control and the aerobic cost of running. METHODS: Twelve recreational athletes ran for 1 h on a treadmill at a constant velocity (i.e., 10% higher than their first ventilatory threshold) with and without custom-molded foot orthoses, in a counterbalanced order. Surface EMG activity of five lower limb muscles, together with oxygen consumption and HR, was recorded at 8-min intervals, starting after 2 min, during the run. A series of neuromuscular tests including voluntary and electrically evoked contractions of the ankle plantar flexors was performed before and after running. RESULTS: Peroneus longus root mean square amplitude decreased with time, independently of the condition ( 18.9%, P < 0.01). Lower root mean square signal amplitude for vastus medialis ( 13.3%, P < 0.02) and gastrocnemius medialis (-10.7%, P < 0.05), combined with increased peroneus longus burst duration (+14.7%, P < 0.05), occurred when running with orthoses. There was no main effect of the condition for oxygen consumption (P > 0.05), whereas HR was significantly lowered while wearing foot orthoses (-3%, P < 0.02). Maximal strength capacity (-9%, P < 0.01), normalized EMG activity (-17%, P < 0.001), and peak twitch torque (-14%, P < 0.01) declined from before to after exercise, independently of the condition. Smaller fatigue induced decrements in the rate of torque development within the first 200 ms (-6% vs -33%, P < 0.01) were reported after running with foot orthoses. CONCLUSIONS: Wearing foot orthoses alters neuromuscular control during a submaximal 1-h treadmill run and partly protects from the resulting fatigue-induced reductions in rapid force development characteristics of the plantar flexors. However, these changes may be too small to alter the aerobic cost of running. PMID- 21552160 TI - Cardiac magnetic resonance imaging during pulmonary hyperinflation in apnea divers. AB - PURPOSE: Apnea divers hyperinflate the lung by taking a deep breath followed by glossopharyngeal insufflation. The maneuver can lead to symptomatic arterial hypotension. We tested the hypotheses that glossopharyngeal insufflation interferes with cardiac function further reducing cardiac output (CO) using cardiac magnetic resonance imaging (MRI) to fully sample both cardiac chambers. METHODS: Eleven dive athletes (10 men, 1 woman; age = 26 +/- 5 yr, body mass index = 23.5 +/- 1.7 kg.m(-2)) underwent cardiac MRI during breath holding at functional residual capacity (baseline), at total lung capacity (apnea), and with submaximal glossopharyngeal insufflation. Lung volumes were estimated from anatomic images. Short-axis cine MR images were acquired to study biventricular function. Dynamic changes were followed by long-axis cine MRI. RESULTS: Left and right ventricular end-diastolic volumes (LVEDV, RVEDV) decreased during apnea with and without glossopharyngeal insufflation (baseline: LVEDV = 198 +/- 19 mL, RVEDV = 225 +/- 30 mL; apnea: LVEDV = 125 +/- 38 mL, RVEDV = 148 +/- 37 mL, P < 0.001; glossopharyngeal insufflation: LVEDV = 108 +/- 26 mL, RVEDV = 136 +/- 29 mL, P < 0.001 vs baseline). CO decreased during apnea (left = -29 +/- 4 %, right = -29 +/- 4 %) decreasing further with glossopharyngeal insufflation (left = -38% +/- 4%, right = -39% +/- 4%, P < 0.05). HR increased 16 +/- 4 bpm with apnea and 17 +/- 5 bpm with glossopharyngeal insufflation (P < 0.01). Ejection fraction moderately decreased (apnea: left = -5% +/- 2%, right = -7% +/- 2%, glossopharyngeal insufflation: left = -6% +/- 2%, right = -10% +/- 2%, P < 0.01). With continued apnea with and without glossopharyngeal insufflation, LVEDV and CO increased over time by a similar but small amount (P < 0.01). CONCLUSIONS: The major finding of our study was that submaximal glossopharyngeal insufflation decreased CO further albeit by a small amount compared to maximal inspiratory apnea. The response was not associated with severe biventricular dysfunction. PMID- 21552161 TI - Effects of priming exercise on VO2 kinetics and the power-duration relationship. AB - PURPOSE: This study aimed to investigate the influence of prior heavy- and severe intensity exercise on the oxygen uptake (V.O2) kinetics and the power-duration relationship. METHODS: Ten cyclists performed 13 exercise tests during a 4-wk period, consisting of a ramp test to determine the gas exchange threshold (GET) and the peak V.O2, followed by a series of square-wave tests to exhaustion under three conditions: no prior exercise (control), prior heavy exercise (6 min at a work rate above GET but below critical power [CP)], and prior severe exercise (6 min at a work rate above the CP). Pulmonary gas exchange was measured throughout the exhaustive exercise bouts and the parameters of the power-duration relationship (CP and the curvature constant, W') were determined from the linear work-time model. RESULTS: Prior heavy exercise increased the amplitude of the primary V.O2 response (by ~ 0.19 +/- 0.28 L.min(-1), P = 0.001), reduced the V.O2 slow component trajectory (by 0.04 +/- 0.09 L.min(-2), P = 0.002), and increased the time to exhaustion (by ~ 52 +/- 92 s, P = 0.005). The CP was unchanged (control vs prior heavy: 284 +/- 47 vs 283 +/- 44 W; 95% confidence interval, -7 to 5 W), whereas the W' was increased by heavy-intensity priming (16.0 +/- 4.8 vs 18.7 +/- 4.8 kJ; 95% confidence interval, 0.3-5.2 kJ). Severe-intensity exercise had a similar effect on the V.O2 kinetics but had no effect on the time to exhaustion, the CP (275 +/- 45 W), or the W' (16.7 +/- 4.7 kJ). CONCLUSIONS: Prior heavy-intensity exercise primes the V.O2 kinetics and increases the amount of work that can be performed above the CP. PMID- 21552162 TI - Slow component of VO2 kinetics: mechanistic bases and practical applications. AB - The V.O2 slow component, a slowly developing increase in V.O2 during constant work-rate exercise performed above the lactate threshold, represents a progressive loss of skeletal muscle contractile efficiency and is associated with the fatigue process. This brief review outlines the current state of knowledge concerning the mechanistic bases of the V.O2 slow component and describes practical interventions that can attenuate the slow component and thus enhance exercise tolerance. There is strong evidence that, during constant-work-rate exercise, the development of the V.O2 slow component is associated with the progressive recruitment of additional (type II) muscle fibers that are presumed to have lower efficiency. Recent studies, however, indicate that muscle efficiency is also lowered (resulting in a "mirror-image" V.O2 slow component) during fatiguing, high-intensity exercise in which additional fiber recruitment is unlikely or impossible. Therefore, it seems that muscle fatigue underpins the V.O2 slow component, although the greater fatigue sensitivity of recruited type II fibers might still play a crucial role in the loss of muscle efficiency in both situations. Several interventions can reduce the magnitude of the V.O2 slow component, and these are typically associated with an enhanced exercise tolerance. These include endurance training, inspiratory muscle training, priming exercise, dietary nitrate supplementation, and the inspiration of hyperoxic gas. All of these interventions reduce muscle fatigue development either by improving muscle oxidative capacity and thus metabolic stability or by enhancing bulk muscle O2 delivery or local Q.O2-to-V.O2 matching. Future honing of these interventions to maximize their impact on the V.O2 slow component might improve sports performance in athletes and exercise tolerance in the elderly or in patient populations. PMID- 21552163 TI - Bone quality and muscle strength in female athletes with lower limb stress fractures. AB - PURPOSE: Lower limb stress fractures (SF) have a high prevalence in female athletes of running-related sports. The purpose of this study was to investigate bone quality, including bone microarchitecture and strength, and muscle strength in athletes diagnosed with SF. METHODS: Female athletes with lower limb SF (SF subjects, n = 19, 18-45 yr, premenopausal) and healthy female athletes (NSF subjects, n = 19) matched according to age, sport, and weekly training volume were recruited. Bone microarchitecture of all participants was assessed using high-resolution peripheral quantitative computed tomography at two skeletal sites along the distal tibia of the dominant leg. Bone strength and load distribution between cortical and trabecular bone was estimated by finite element analysis. Using dual-energy x-ray absorptiometry, areal bone mineral density (aBMD) at the hip, femoral neck, and spine was measured. Muscle torque (knee extension, plantarflexion, eversion/inversion) was assessed (Biodex dynamometer) as a measure of lower leg muscle strength. RESULTS: SF subjects, after adjusting for body weight, had thinner tibia compared with NSF subjects as indicated by a lower tibial cross-sectional area (-7.8%, P = 0.02) and higher load carried by the cortex as indicated by finite element analysis (4.1%, P = 0.02). Further site specific regional analysis revealed that, in the posterior region of the tibia, SF subjects had lower trabecular BMD (-19.8%, P = 0.02) and less cortical area ( 5.2%, P = 0.02). The SF group exhibited reduced knee extension strength (-18.3%, P = 0.03) compared with NSF subjects. CONCLUSIONS: These data suggest an association of impaired bone quality, particularly in the posterior region of the distal tibia, and decreased muscle strength with lower limb SF in female athletes. PMID- 21552164 TI - Pregnancy in a woman with premature ovarian insufficiency undergoing intracytoplasmic sperm injection after pretreatment with estrogens followed by therapy with estrogens associated with ovarian stimulation with gonadotropins: remarks about oocyte and embryo quality. AB - OBJECTIVE: The aim of this study was to achieve pregnancy in a woman with premature ovarian insufficiency (POI) by means of estrogen pretreatment, a combination of estrogen therapy and gonadotropin ovarian stimulation, and intracytoplasmic sperm injection (ICSI). METHODS: A 34-year-old woman with POI who failed to achieve follicular growth in two previous ovarian stimulation protocols using high doses of gonadotropins alone underwent an ICSI trial after estrogen pretreatment (ethinyl estradiol 0.05 mg three times a day for 10 d) followed by estrogens (at the same dose) and recombinant beta-follicle stimulating hormone (250 IU/d for 12 d). RESULTS: Delivery of a healthy female baby was achieved. CONCLUSIONS: Stimulation with gonadotropins plus estrogens after pretreatment with estrogen can be considered a useful intervention in women with POI trying to conceive. PMID- 21552165 TI - Effects of reproductive history on symptoms of menopause: a brief report. AB - OBJECTIVE: The aim of this study was to examine the relationship between reproductive history and menopausal symptoms among urban women. METHODS: This was a cohort study of women aged 35 to 47 years recruited in Philadelphia, PA. Two hundred ninety-one premenopausal women meeting the study eligibility criteria and contributing reproductive health history and infertility information completed the assessments of occurrence and severity of several menopausal symptoms over a 14-year period. Reproductive history included the number of pregnancies, live births, preterm deliveries, and miscarriages. Trying to get pregnant for more than 1 year was used as an assessment of infertility. The occurrence of severe hot flashes, vaginal dryness, and decreased libido was evaluated. RESULTS: Women scoring positive on the infertility index were significantly more likely to report severe decreased libido (odds ratio [OR], 1.86; 95% CI, 1.05-3.31) and were more than twice as likely to report severe vaginal dryness (OR, 2.79; 95% CI, 1.19-6.94) in multivariable models. None of the other reproductive health indices were related to the report of severe hot flashes, vaginal dryness, or decreased libido. The race-specific models continued to find a significant increased risk of severe vaginal dryness (OR, 2.79; 95% CI, 1.22-6.36) and decreased libido (OR, 1.87; 95% CI, 1.04-3.34) among white women scoring positive on the infertility index; however, the relationship did not remain significant among African American women. CONCLUSIONS: Severe vaginal dryness and decreased libido are common and important considerations of the menopausal transition, and the experience of infertility problems may influence the report of severe vaginal dryness and decreased libido particularly among white women. PMID- 21552166 TI - Changes in self-reported hot flashes and their association with concurrent changes in insomnia symptoms among women with breast cancer. AB - OBJECTIVE: The aim of this study was to assess longitudinally the relationship between hot flashes and insomnia symptoms in women receiving adjuvant treatments for breast cancer. METHODS: Fifty-eight participants completed a 7-day daily diary assessing hot flashes, the Menopause-Specific Quality of Life Questionnaire, and the Insomnia Severity Index, before and after chemotherapy or radiotherapy and at a 3-month follow-up evaluation. RESULTS: A first canonical correlation analysis (n = 55) revealed a marginally significant relationship between pretreatment versus posttreatment change scores in hot flashes and sleep (R = 0.39), and a second analysis (n = 51) showed a significant relationship between posttreatment and follow-up changes in hot flash activity and sleep (R = 0.59). CONCLUSIONS: These results show that increases in vasomotor symptoms occurring within the few months after the termination of initial adjuvant treatments for breast cancer are significantly associated with concurrent increases in insomnia symptoms and vice versa. PMID- 21552167 TI - Long-term outcomes after gamma knife stereotactic radiosurgery for nonfunctional pituitary adenomas. AB - BACKGROUND: Nonfunctional pituitary adenomas (NFPAs) represent approximately 50% of all pituitary tumors. OBJECTIVE: To evaluate the long-term outcomes of stereotactic radiosurgery for NFPAs. METHODS: We evaluated the management outcomes of Gamma Knife radiosurgery in 125 patients with NFPAs over an interval of 22 years. The median patient age was 54 years (range, 16-88 years). One hundred ten patients (88%) had residual or recurrent tumors after >= 1 surgical procedures, and 17 (14%) had undergone prior fractionated radiation therapy. The median target volume was 3.5 cm3 (range, 0.4-28.1 cm3), and the median tumor margin dose was 13.0 Gy (range, 10-25 Gy). RESULTS: Tumor volume decreased in 66 patients (53%), remained stable in 46 (37%), and increased in 13 (10.4%) during a median of 62 months (maximum, 19 years) of imaging follow-up. The actuarial tumor control rates at 1, 5, and 10 years were 99%, 94%, and 76%, respectively. Factors associated with a reduced progression-free survival included larger tumor volume (>= 4.5 cm3) and >= 2 prior recurrences. Of 88 patients with residual pituitary function, 21 (24%) suffered new hormonal deficits at a median of 24 months (range, 3-114 months). Prior radiation therapy increased the risk of developing new pituitary hormonal deficits. One patient (0.8%) had a decline in visual function, and 2 (1.6%) developed new cranial neuropathies without tumor progression. CONCLUSION: Stereotactic radiosurgery can provide effective management for patients with newly diagnosed NFPAs and for those after prior resection and/or radiation therapy. PMID- 21552168 TI - Midterm clinical and angiographic follow-up for the first Food and Drug Administration-approved prospective, Single-Arm Trial of Primary Stenting for Stroke: SARIS (Stent-Assisted Recanalization for Acute Ischemic Stroke). AB - BACKGROUND: Although early data demonstrate encouraging angiographic results following intracranial stent deployment for acute ischemic stroke, longer-term follow-up is necessary to evaluate the clinical outcomes, as well as the durability of angiographic results. OBJECTIVE: We report 6-month clinical and radiologic follow-up data of the 20 patients prospectively enrolled in the Stent Assisted Recanalization in acute Ischemic Stroke (SARIS) trial. METHODS: Twenty patients were prospectively enrolled to receive self-expanding intra-arterial stents as first-line therapy for acute ischemic stroke treatment. Patients were scheduled for follow-up 6-months after treatment for clinical evaluation (modified Rankin Scale [mRS] score obtained by a trained certified research nurse/nurse practitioner) and repeat cerebral angiography. Angiographic interpretation was performed by an independent adjudicator. RESULTS: At 6 months, the mRS score was <=3 in 60% of patients (n = 12) and was <=2 in 55% of patients (n = 11). Mortality at the 6-month follow-up was 35% (n = 7). Follow-up angiography was performed for 85% (11 of 13) of surviving patients. All patients undergoing angiographic follow-up demonstrated Thrombolysis in Myocardial Infarction 3 flow on digital subtraction angiography or stent patency on computed tomographic angiography. None of the patients demonstrated evidence of in-stent stenosis (>=50% vessel narrowing). CONCLUSION: The midterm angiographic and clinical results following intracranial stent deployment for acute ischemic stroke are encouraging. Further study of primary stent-for-stroke treatment is warranted. PMID- 21552170 TI - Fiducial registration with spoiled gradient-echo magnetic resonance imaging enhances the accuracy of subthalamic nucleus targeting. AB - BACKGROUND: A variety of imaging strategies may be used to derive reliable stereotactic coordinates when performing deep brain stimulation lead implants. No single technique has yet proved optimal. OBJECTIVE: To compare the relative accuracy of stereotactic coordinates for the subthalamic nucleus (STN) derived either from fast spin echo/inversion recovery (FSE/IR) magnetic resonance imaging MRI alone (group 1) or FSE/IR in conjunction with T1-weighted spoiled gradient echo MRI (group 2). METHODS: A retrospective analysis of 145 consecutive STN deep brain stimulation lead placements (group 1, n = 72; group 2, n = 73) was performed in 81 Parkinson disease patients by 1 surgical team. From the operative reports, we recorded the number of microelectrode recording trajectories required to localize the desired STN target and the span of STN traversed along the implantation trajectory. In addition, we calculated the 3-dimensional vector difference between the initial MRI-derived coordinates and the final physiologically refined coordinates. RESULTS: The proportion of implants completed with just 1 microelectrode recording trajectory was greater (81% vs 58%; P < .001) and the 3-dimensional vector difference between the anatomically selected target and the microelectrode recording-refined target was smaller (0.6 +/- 1.2 vs 0.9 +/- 1.3; P = .04) in group 2 than in group 1. At the same time, the mean expanse of STN recorded along the implantation trajectory was 8% greater in group 2 (4.8 +/- 0.6 vs 5.2 +/- 0.6 mm; P < .001). CONCLUSION: A combination of stereotactic FSE/IR and spoiled gradient-echo MRI yields more accurate coordinates for the STN than FSE/IR MRI alone. PMID- 21552169 TI - Dipyrone inhibits neuronal cell death and diminishes hypoxic/ischemic brain injury. AB - BACKGROUND: Dipyrone is an analgesic and antipyretic drug usually prescribed for patients with inflammatory conditions. We recently identified dipyrone as an antiapoptotic agent by screening a library of 1040 compounds for their ability to inhibit cytochrome c release from isolated mitochondria. OBJECTIVE: We investigated the potential neuroprotective properties of dipyrone in cerebral ischemia. METHODS: We evaluated the protective effects of dipyrone in experimental models of neuronal hypoxia/ischemia, including an oxygen/glucose deprivation model in primary cerebrocortical neurons and a focal cerebral ischemia model in mice. RESULTS: Dipyrone reduced hypoxia/ischemia injury in both cellular and animal models. Dipyrone inhibited the release of cytochrome c and other mitochondrial apoptogenic factors from mitochondria into the cytoplasm, and attenuated subsequent caspase-9 and caspase-3 activation both in vitro and in vivo. Moreover, dipyrone prevented ischemia-induced changes in Bcl-2 and tBid, and ameliorated oxygen/glucose deprivation-mediated loss of mitochondrial membrane potential. Dipyrone also inhibited ischemia-induced reactive microgliosis. In the cellular models evaluated, dipyrone did not inhibit oxygen/glucose deprivation-induced cyclooxygenase-2 activation. CONCLUSION: Dipyrone is remarkably neuroprotective in cerebral ischemia, and its cyclooxygenase-independent protective properties are, at least in part, due to the inhibition of mitochondrial cell death cascades. PMID- 21552171 TI - Accuracy of image-guided pedicle screw placement using intraoperative computed tomography-based navigation with automated referencing, part I: cervicothoracic spine. AB - BACKGROUND: Image-guided spinal instrumentation reduces the incidence of implant misplacement. OBJECTIVE: To assess the accuracy of intraoperative computed tomography (iCT)-based neuronavigation (iCT-N). METHODS: In 35 patients (age range, 18-87 years), a total of 248 pedicle screws were placed in the cervical (C1-C7) and upper and midthoracic (T1-T8) spine. An automated iCT registration sequence was used for multisegmental instrumentation, with the reference frame fixed to either a Mayfield head clamp and/or the most distal spinous process within the instrumentation. Pediculation was performed with navigated drill guides or Jamshidi cannulas. The angular deviation between navigated tool trajectory and final implant positions (evaluated on postinstrumentation iCT or postoperative CT scans) was calculated to assess the accuracy of iCT-N. Final screw positions were also graded according to established classification systems. Mean follow-up was 16.7 months. RESULTS: Clinically significant screw misplacement or iCT-N failure mandating conversion to conventional technique did not occur. A total of 71.4% of patients self-rated their outcome as excellent or good at 12 months; 99.3% of cervical screws were compliant with Neo classification grades 0 and 1 (grade 2, 0.7%), and neurovascular injury did not occur. In addition, 97.8% of thoracic pedicle screws were assigned grades I to III of the Heary classification, with 2.2% grade IV placement. Accuracy of iCT-N progressively deteriorated with increasing distance from the spinal reference clamp but allowed safe instrumentation of up to 10 segments. CONCLUSION: Image guided spinal instrumentation using iCT-N with automated referencing allows safe, highly accurate multilevel instrumentation of the cervical and upper and midthoracic spine. In addition, iCT-N significantly reduces the need for reregistration in multilevel surgery. PMID- 21552173 TI - Evaluation of fibrin sealants for central nervous system sealing in the mongrel dog durotomy model. AB - BACKGROUND: Watertight repair of the dura is imperative after neurosurgical procedures involving the brain or spinal cord because inadequately treated leakage of cerebrospinal fluid (CSF) from punctured dura can have serious consequences such as meningitis, arachnoiditis, or epidural abscess. OBJECTIVE: To assess the efficacy of Evicel Fibrin Sealant (Human) to prevent CSF leakage using a 2.0-cm durotomy mongrel dog repair model and to compare the tissue response with Tisseel (a fibrin sealant) and Duraseal (a synthetic polyethylene glycol [PEG] hydrogel sealant). METHODS: The canine durotomy repair model was used. This well-characterized model assesses the ability of sealants to achieve intraoperative watertight seals of the dura mater, as well as long-term safety and efficacy. This study included 27 mongrel dogs and had a 28-day duration. RESULTS: The 3 sealants were 100% effective in preventing CSF leakage intraoperatively at 15 mm Hg. The 2 fibrin sealants were 100% effective in postoperative sealing; the PEG hydrogel was not. Microscopically, the tissue changes induced by Evicel at the durotomy site were similar in nature except for foamy macrophages seen only with the PEG hydrogel. The extent and severity of adhesions at 28 days were less with the fibrin sealants than with the PEG hydrogel. CONCLUSION: Evicel, a fibrin sealant, was safe and effective in achieving and maintaining a watertight seal of the dura. The performance of the fibrin sealants was similar to that of the synthetic PEG hydrogel sealant with the exception of a Duraseal seal, which leaked. PMID- 21552174 TI - New drugs 2011 part 2. PMID- 21552175 TI - Spectral domain optical coherence tomography as a predictor of visual function in chronic solar maculopathy. AB - PURPOSE: Solar maculopathy can be a diagnostic challenge as clinical findings are often subtle and resemble other macular pathologies. Recent reports of chronic solar maculopathy have described characteristic loss of outer retinal layers. With the advent of spectral domain optical coherence tomography (SD-OCT), higher resolution of the chorioretinal architecture is possible and provides a unique means of assessing the organization and integrity of the retinal layers in cases of solar maculopathy. Two cases (four eyes) of chronic solar maculopathy were examined using Cirrus SD-OCT imaging (Carl Zeiss Meditec, Dublin, CA). RESULTS: OCT scans revealed a large fragment of hyporeflectance at the level of the outer and inner photoreceptor layer with an abrupt discontinuation of the inner segment/outer segment junction. Visual acuity was minimally but permanently reduced in both cases. CONCLUSIONS: These two cases demonstrate the reliability of SD-OCT as a biomarker of visual function in chronic solar maculopathy. The characteristic fragmented loss of the photoreceptor inner segment/outer segment junction correlates with decreased visual function in cases of solar maculopathy. PMID- 21552176 TI - Membrane array analysis of tear proteins in ocular cicatricial pemphigoid. AB - PURPOSE: To explore non-invasive, protein-based, membrane array technology as a means to evaluate the global immune and angiogenic profile of tear proteins in patients with active ocular cicatricial pemphigoid (OCP). METHODS: Forty-three proteins consisting of cytokines, angiogenic/growth factors, and immunoinflammatory modulators were measured by membrane array in tear samples of four control patients and four OCP patients during active disease and after treatment. RESULTS: Signals for several distinct and consistent molecular entities were upregulated in all four active OCP tear samples relative to controls. In particular, interleukin-8 and matrix metalloproteinase-9 were elevated during active disease and decreased after systemic immunomodulatory therapy. CONCLUSIONS: Protein array analysis may provide a well-tolerated assay to monitor levels of inflammatory markers in the tears of OCP patients in response to therapy. PMID- 21552177 TI - Effect of cholesterol deposition on bacterial adhesion to contact lenses. AB - PURPOSE: To examine the effect of cholesterol on the adhesion of bacteria to silicone hydrogel contact lenses. METHODS: Contact lenses, collected from subjects wearing Acuvue Oasys or PureVision lenses, were extracted in chloroform:methanol (1:1, v/v) and amount of cholesterol was estimated by thin layer chromatography. Unworn lenses were soaked in cholesterol, and the numbers of Pseudomonas aeruginosa strains or Staphylococcus aureus strains that adhered to the lenses were measured. Cholesterol was tested for effects on bacterial growth by incubating bacteria in medium containing cholesterol. RESULTS: From ex vivo PureVision lenses, 3.4 +/- 0.3 MUg/lens cholesterol was recovered, and from Acuvue Oasys lenses, 2.4 +/- 0.2 to 1.0 +/- 0.1 MUg/lens cholesterol was extracted. Cholesterol did not alter the total or viable adhesion of any strain of P. aeruginosa or S. aureus (p > 0.05). However, worn PureVision lenses reduced the numbers of viable cells of P. aeruginosa (5.8 +/- 0.4 log units) compared with unworn lenses (6.4 +/- 0.2 log units, p = 0.001). Similarly, there were fewer numbers of S. aureus 031 adherent to worn PureVision (3.05 +/- 0.8 log units) compared with unworn PureVision (4.6 +/- 0.3 log units, p = 0.0001). Worn Acuvue Oasys lenses did not affect bacterial adhesion. Cholesterol showed no effect on the growth of any test strain. CONCLUSIONS: Although cholesterol has been shown to adsorb to contact lenses during wear, this lipid does not appear to modulate bacterial adhesion to a lens surface. PMID- 21552178 TI - Lenstar versus ultrasound for ocular biometry in a pediatric population. AB - PURPOSE: To compare the central corneal thickness (CCT), axial length (AL), anterior chamber depth (ACD), and lens thickness (LT) measured with Lenstar with those obtained with ultrasound pachymetry and A-scan contact ultrasound (ASU) in children. METHODS: ODs of 565 school children were included. All measurements were obtained 30 min after instilling 1% tropicamide. For each instrument, three consecutive measurements per each child were performed. Initially, examiner 1 performed measurements with Lenstar to obtain CCT, AL, ACD, and LT. Later, examiner 2 performed measurements with corneal pachymetry to obtain CCT. Finally, ASU was used by examiner 2 to obtain AL, ACD, and LT. Four parameters obtained with Lenstar were compared with those obtained with pachymetry and ASU using Pearson correlation coefficients (r) and Bland-Altman analyses. RESULT: Lenstar measurements were obtained in 557 of 565 subjects(mean age; 10.48 +/- 2.11 years, mean spherical equivalent of the ODs; +0.47 +/- 1.18 diopters) whereas ASU and pachymetry could be performed in 530 of 565. Four hundred seventy-nine subjects were statistically assessed after 41 subjects were extracted as outliers from 530 subjects in whom all instruments could be performed. Mean difference between pachymetry and Lenstar was 13.20 +/- 13.13 MUm [95% confidence interval (CI): 12.01 to 14.37]. Mean difference between ASU and Lenstar was -0.72 +/- 0.35 mm (95% CI: -0.75 to -0.69) for AL, -0.27 +/- 0.32 mm (95% CI: -0.30 to -0.24) for ACD, and 0.24 +/- 0.28 mm (95% CI: 0.22 to 0.27) for LT. R values were 0.912 (p < 0.001), 0.904 (p < 0.001), 0.487 (p < 0.001), 0.369 (p < 0.001) for CCT, AL, ACD, and LT respectively. CONCLUSIONS: AL and ACD were found to be greater with Lenstar, whereas CCT and LT measures were smaller. It is concluded that there was agreement between instruments for CCT and ACD, because the small differences between measures were clinically insignificant. AL and LT values cannot be used interchangeably. If these differences are considered, Lenstar can replace ASU and pachymetry for the majority of children. PMID- 21552179 TI - Accommodative functions with multifocal contact lenses: a pilot study. AB - PURPOSE: To evaluate accommodative response and facility in presbyopic patients fitted with several types of simultaneous-image multifocal contact lenses (CLs). METHODS: Six presbyopic patients, unadapted wearers of simultaneous-image bifocals, were fitted with the Focus Progressives and the low- and high-addition Pure Vision simultaneous vision multifocal CLs. Each individual wore each of the three types of lenses in successive random order. Accommodative response, accommodative facility, visual acuity, and contrast sensitivity at distance and near were evaluated in all cases. A control group of eight non-presbyopic patients was also studied. RESULTS: The mean age was 28.6 +/- 2.72 and 51.2 +/- 5.81 years in the non-presbyopes and presbyopic patients, respectively. For the presbyopic group, statistically significant differences were not found for distance visual acuity between the baseline situations and with the three different CLs types. For the near visual acuity, there were no statistically significant differences between baseline situation (without add) compared with patients wearing the Focus Progressives and with PureVision Low Add. With the Purevision High Add, the near visual acuity was slightly better than baseline situation (p = 0.03). Non-presbyopic subjects showed relatively linear 1:1 stimulus response functions for all situations. Presbyopic subjects showed an increasing lag of accommodation with amplitude as they approach to the maximum amplitude for all situations. Distance and near accommodative facility rate for the presbyopic patients was zero for all conditions. CONCLUSIONS: The results of this study suggest that simultaneous-image multifocal CLs studied do not alter accommodative functions. The high add of the Purevision CL enhances near vision for advanced presbyopes compared with the other models studied. PMID- 21552180 TI - High mortality in patients with influenza A pH1N1 2009 admitted to a pediatric intensive care unit: a predictive model of mortality. AB - OBJECTIVE: To describe the clinical characteristics and outcome of patients admitted to pediatric intensive care with influenza A (pH1N1) 2009 in Argentina. DESIGN: Retrospective observational study. SETTING: Thirteen pediatric intensive care units in Argentina. SUBJECTS: One hundred and forty-two patients with confirmed or suspected influenza A (H1N1). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 142 critically ill patients. The median age was 19 months (range, 2-110 months) with 39% of the patients <24 months of age. Ninety nine patients (70%) had an underlying disease. Influenza A (pH1N1) 2009 infection was confirmed in 90 patients and the remaining 52 had a positive direct immunofluorescence assay for influenza A. The median length of stay in the pediatric intensive care unit was 12 days (range, 2-52 days). One hundred eighteen patients (83%) received invasive mechanical ventilation and 19 patients were treated with noninvasive ventilation; however, seven of the patients receiving noninvasive ventilation later needed mechanical ventilation. Sixty eight patients died (47%) with the most frequent cause refractory hypoxemia. Multivariate logistic regression analysis showed that age <24 months (odds ratio, 2.87; 2.35-3.93), asthma (odds ratio, 1.34; 1.20-2.91), and respiratory coinfection with respiratory syncytial virus (odds ratio, 2.92; 1.20-4.10) were associated with higher mortality. As expected, mechanical ventilation and treatment with inotropes were also associated with increased mortality. CONCLUSIONS: The mortality of children admitted to the pediatric intensive care unit with 2009 pH1N1 influenza was high (47%) in our population. Age <24 months, asthma, respiratory coinfection, need of mechanical ventilation, and treatment with inotropes were predictors of poorer outcome. PMID- 21552181 TI - Comparison of clinical and biologic features of Kingella kingae and Staphylococcus aureus arthritis at initial evaluation. AB - We conducted a retrospective study comparing the presenting clinical and biologic features of 64 children who had septic arthritis caused by Kingella kingae with 26 children who had septic arthritis caused by Staphylococcus aureus. Children with K. kingae septic arthritis were significantly younger than those with S. aureus septic arthritis. Otherwise, there were no significant differences between the 2 groups with respect to fever, location, white blood cell count, synovial fluid cell count, C-reactive protein, or serum fibrinogen. However, the clinical course was significantly better for children with septic arthritis caused by K. kingae as evidenced by shorter hospitalization and fewer adverse events. Presumptive antibiotic therapy for septic arthritis in young infants should take into account both of these pathogens, even in case of mild presentation. PMID- 21552182 TI - Dengue antibody in Thai children from maternally transferred antibody to acquired infection. AB - This prospective cohort study examined serotype-specific neutralizing serum antibodies to dengue in 55 maternal-newborn pairs, at 3, 6, 9, 12, 18, and 24 months, and again at 4 to 8 years of age. In all, 95% of the mothers had neutralizing antibody to at least one dengue serotype, and 92.7% of the maternally transferred antibody had disappeared in 12-month-old infants. In all, 31 infants had serologically confirmed dengue infection; 5 symptomatic and 29 inapparent infections were reported. The increasing trend of inapparent infections among the older age group warrants further study of the need for effective dengue vaccination beyond 2 years of age. PMID- 21552183 TI - Safety and immunogenicity of a modified process hepatitis B vaccine in healthy infants. AB - BACKGROUND: A modified process hepatitis B vaccine (mpHBV) uses higher phosphate content in the manufacturing process relative to the current product, Recombivax HB. The higher phosphate is thought to improve antigen presentation, and thereby, increase antibody production. The mpHBV was previously shown to be well tolerated and immunogenic in adults. The current study tested a 2-, 4-, 6-month vaccination schedule and a higher dose formulation (10 MUg mpHBV) in healthy infants. METHODS: In a randomized, double-blind study, healthy infants (N = 1718), approximately 2 months of age, received a 0.5-mL intramuscular dose of 5-MUg mpHBV, Recombivax-HB (5 MUg), 10-MUg mpHBV, or Engerix-B (10 MUg) at day 1, month 2, and month 4 (2, 4, 6 months of age). Serum antibody to hepatitis B surface antigen (anti-HBs) was analyzed at month 7. The geometric mean titer (GMT) and seroprotection rate (SPR; % subjects with anti-HBs titer >= 10 mIU/mL) were determined 1 month after the third dose. RESULTS: Month 7 SPRs were 99.3% (402/405, 95% confidence interval [CI]: 98.3, 100) in the 5 MUg mpHBV group, 100.0% (398/398, 95% CI: 99.9, 100) in the 10 MUg mpHBV group, 98.5% (400/406, 95% CI: 97.2, 99.8) in the Recombivax-HB group, and 99.5% (398/400, 95% CI: 98.7, 100) in the Engerix-B group. Month 7 GMTs (mIU/mL) were 748.2 (95% CI: 672.0, 833.1) in the 5 MUg mpHBV group, 981.5 (95% CI: 891.0, 1081.2) in the 10 MUg mpHBV group, 376.8 (95% CI: 331.4, 428.5) in the Recombivax-HB group, and 556.6 (95% CI: 491.8, 629.9) in the Engerix-B group. The percentages of subjects reporting injection-site or systemic adverse events were similar across the vaccination groups. CONCLUSIONS: All 4 hepatitis B vaccines elicited high anti HBs SPRs. After dose 3, anti-HBs GMT were highest in the 10 MUg mpHBV group, but did not meet the predefined criteria for superiority. All vaccines were well tolerated. PMID- 21552184 TI - Increased incidence and severity of Kawasaki disease among Filipino-Americans in San Diego county. AB - This study compared characteristics of Kawasaki disease (KD) in Filipino and non Filipino children. Filipino KD patients had a higher coronary artery Z-score (P = 0.016) and aneurysm rate (P = 0.021) than KD patients of non-Filipino Asian and non-Asian descent. PMID- 21552186 TI - Optimization of the selective monohydrolysis of diethyl 4-aryl-4H-pyran-3,5 dicarboxylates. AB - A simple, efficient and eco-friendly procedure for the selective monohydrolysis of diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates under quaternary ammonium salt catalysis conditions is presented. The catalytic activities of various quaternary ammonium salts were investigated using different molar ratios of NaOH and water-organic solvent mixtures. The results indicate that the combination of 1.0 equivalent of tetraethyl-ammonium bromide (TEAB) with 1.2 equivalents of NaOH in a 10% water-ethanol media at 40 degrees C displays remarkable selectivity for the monohydrolysis of diethyl 2,6-dimethyl-4-aryl-4H pyran-3,5-dicarboxylates. The utility of this process is demonstrated by the monohydrolysis of a series of 4-aryl-4H-pyran-3,5-dicarboxylate esters to afford the corresponding monoesters in 20-80% yields under the optimized conditions. PMID- 21552185 TI - Increased microbial translocation in <= 180 days old perinatally human immunodeficiency virus-positive infants as compared with human immunodeficiency virus-exposed uninfected infants of similar age. AB - BACKGROUND: The effect of early versus deferred antiretroviral treatment (ART) on plasma concentration of lipopolysaccharide (LPS) and host LPS-binding molecules in human immunodeficiency virus (HIV)-infected infants up to 1 year of age was investigated. METHODS: We evaluated 54 perinatally HIV-infected and 22 HIV exposed uninfected infants (controls) at the first and second semester of life. All HIV-infected infants had a baseline CD4 of >= 25%, participated in the Comprehensive International Program of Research on AIDS Children with HIV Early Antiretroviral Therapy trial in South Africa, and were randomized in the following groups: group 1 (n = 20), ART deferred until CD4 < 25% or severe HIV disease; and group 2 (n = 34), ART initiation within 6 to 12 weeks of age. LPS, endotoxin-core antibodies, soluble CD14 (sCD14), and LPS-binding protein (LBP) were measured in cryopreserved plasma. T-cell activation was measured in fresh whole blood. RESULTS: At the first semester, LPS concentration was higher in HIV infected infants than in controls; sCD14, LBP, and T-cell activation were higher in group 1 than in group 2 and controls. Although LPS was not correlated with study variables, viral load was positively associated with sCD14, LBP, or endotoxin-core antibodies. At the second semester, LPS was not detectable and elevated host LPS-control molecules values were sustained in all groups and in conjunction with ART in all HIV-infected infants. CONCLUSIONS: Although plasma concentration of LPS was higher in perinatally HIV-infected infants 0 to 6 months of age than in controls independent of ART initiation strategy, concentration of LPS-control molecules was higher in infants with deferred ART, suggesting the presence of increased microbial translocation in HIV-infected infants with sustained early viral replication. PMID- 21552187 TI - Weight Gain Risk Factor assessment checklist: overview and recommendation for use. AB - OBJECTIVES: Patients with mental illness are at risk for weight gain. Evidence based risk assessment checklists have the potential to identify patients at risk early in treatment and improve patient outcomes. METHODS: The 16-item Weight Gain Risk Factor (WGRF-16) checklist has been developed as a simple brief assessment of key weight gain risk factors during antipsychotic treatment. It consists of factors that were collected on the basis of published research on predictors to be assessed at initiation of, and early in treatment with antipsychotics. RESULTS: The factors in the WGRF-16 checklist included age, sex, body mass index, race, appetite, energy intake, a diagnosis of undifferentiated schizophrenia, early clinical response, comorbiditites, social activity, patient insight, housing conditions, weight satisfaction, eating habits, and physical activity level. The WGRF-16 is designed to be repeated 2-3 weeks after initiation of treatment to help to predict an individual's risk of clinically significant weight gain (>7%) during long-term treatment. Further research is required to assess the predictive validity of the checklist. CONCLUSIONS: The WGRF-16 checklist is not intended to replace other required monitoring of patients with severe mental disorders but is a facilitator of weight monitoring in conjunction with clinical guidelines. PMID- 21552188 TI - Valproate inhibits GnRH-induced gonadotropin release from anterior pituitary cells of male rat in vitro. AB - OBJECTIVE: Valproate (VPA) a potent antiepileptic drug has been claimed to induce reproductive disturbances in men. Long-term VPA treatment can affect sperm morphology and induce testicular atrophy in non-epileptic rats. It has been reported that VPA reduced testosterone secretion stimulated by hCG in isolated rat Leydig cells. These results suggest direct effect of VPA on testes in rats. However centrally mediated effects at hypothalamo-pituitary level can therefore not be excluded. This study focused on the dose and time-dependent effects of VPA on basal and GnRH-induced LH and FSH release from the primary anterior pituitary cells culture of male rats. MATERIAL AND METHODS: The dose-dependent effect of 10 nM-100 mM of VPA on basal LH release from anterior pituitary cells after 3h of incubation was examined. To determine the time-dependent effects on LH, FSH, TSH and PRL release short (3 h) and long-term (24 h) incubations in the presence of 10 nM, 100 nM and 1 MUM of VPA were maintained.To assess whether VPA can affect GnRH-induced LH and FSH release, cells were incubated for 3 h with 10 nM, 100 nM and 1 MUM of VPA in the presence of GnRH. The concentration of rLH, rFSH, rPRL and rTSH in incubation medium was determined by RIA method. RESULTS: VPA did not affect the basal LH, FSH, PRL and TSH release from the primary anterior pituitary cells culture of male rats. VPA in concentration 1uM significantly suppressed GnRH-induced LH secretion. However VPA at all tested doses diminished GnRH induced FSH release. CONCLUSIONS: VPA may diminish gonadotropin release in vitro but this effect can only be achieved after GnRH-dependent specific receptor activation. Both gonadotropins differ in their pattern of response for increasing doses of VPA. PMID- 21552189 TI - The role of renal function loss on circadian misalignment of cytokines EPO, IGF 1, IL-6 and TNF-alfa in chronic renal disease. AB - OBJECTIVE: Chronic inflammation plays a pivotal role in the development of renal disease. Circadian sleep-wake rhythm is disturbed in renal disease. Awareness of other disturbed rhythms, such as inflammation processes, can affect the treatment of patients with renal disease. Knowledge of possibly related circadian misalignment of the cytokines erythropoietin (EPO), Insulin Growth Factor-1 (IGF 1) and interleukins (IL) however is limited. We therefore performed an observational study. The objective of this study was to characterize levels of EPO, IGF-1 and inflammation markers IL-6 and TNF-alpha, related to renal function. METHODS: The study population consisted of patients with various degrees of renal function, admitted to our hospital. During 24 hours, blood of 28 subjects with various degrees of renal function was collected every 2 hours. The patients were stable, not acutely ill and they were waiting for a procedure, such as elective surgery. Circadian parameters of EPO, IGF-1, IL-6 and TNF-alpha were measured in serum and were correlated with glomerular filtration rate (GFR) and Hb, using Pearson correlations. RESULTS: Although diurnal variations in EPO level were found in 15 out of 28 patients, the curves did not show a consistent phase. The presence of an EPO rhythm was not related to GFR. No diurnal rhythm could be detected for IGF-1, IL-6 and TNF-alpha. Mean levels of IGF-1 were correlated inversely to mean levels of EPO (p=0.03). When divided based on GFR and Hb subjects with GFR 10-30 ml/min and lower Hb had the highest IGF-1 levels (p=0.02). A relationship between Il-6, TNF-alpha and EPO or GFR was not found. CONCLUSION: The existence of a circadian (mis)alignment of EPO, IGF-1, IL-6 and TNF-alpha was not found. The association between high IGF-1 and low Hb suggests that EPO and IGF-1 have an alternating role, dependent on GFR, in stimulating erythropoiesis. These results could have consequences for the treatment of anemia. PMID- 21552191 TI - Repetitive transcranial magnetic stimulation and treatment of negative symptoms of schizophrenia. AB - One of the fundamental prerequisites of the successful schizophrenia treatment is represented by an adequately significant impact on the negative symptoms of schizophrenia. Since the present pharmacotherapy has probably reached its limit in this area, there is a logical effort to utilize other, non-pharmacological methods. One of the most promising supplements that has been for a long time verified in the clinical practice is rTMS. Most of the studies have arrived at the conclusion that rTMS is an efficient method in the treatment of negative symptoms of schizophrenia. A valuable contribution to the assessment of the rTMS application in the treatment of negative symptoms is represented by meta analyses. The meta-analyses indicate that the effect is mild to moderate (d=0.43 to 0.68). To sum it up, there will be higher probability of the rTMS effect on negative symptoms if 10 Hz stimulating frequency and a longer stimulation period in the extent at least three, ideally four to six weeks is used. PMID- 21552190 TI - The impact of light from computer monitors on melatonin levels in college students. AB - OBJECTIVES: Self-luminous electronic devices emit optical radiation at short wavelengths, close to the peak sensitivity of melatonin suppression. Melatonin suppression resulting from exposure to light at night has been linked to increased risk for diseases. The impact of luminous cathode ray tube (CRT) computer monitors on melatonin suppression was investigated. DESIGN: Twenty-one participants experienced three test conditions: 1) computer monitor only, 2) computer monitor viewed through goggles providing 40 lux of short-wavelength (blue; peak lambda ~ 470 nm) light at the cornea from light emitting diodes (LEDs), and 3) computer monitor viewed through orange-tinted safety glasses (optical radiation <525 nm ~ 0). The blue-light goggles were used as a "true positive" experimental condition to demonstrate protocol effectiveness; the same light treatment had been shown in a previous study to suppress nocturnal melatonin. The orange-tinted glasses served as a "dark" control condition because the short-wavelength radiation necessary for nocturnal melatonin suppression was eliminated. Saliva samples were collected from subjects at 23:00, before starting computer tasks, and again at midnight and 01:00 while performing computer tasks under all three experimental conditions. RESULTS: Melatonin concentrations after exposure to the blue-light goggle experimental condition were significantly reduced compared to the dark control and to the computer monitor only conditions. Although not statistically significant, the mean melatonin concentration after exposure to the computer monitor only was reduced slightly relative to the dark control condition. CONCLUSIONS: Additional empirical data should be collected to test the effectiveness of different, brighter and larger screens on melatonin suppression. PMID- 21552192 TI - Pain in Paget's disease: a retrospective study of treatment efficacy. AB - The authors addressed the role and the management of pain in Paget's disease by a retrospective study. The objectives were: to assess the presence of pain in Paget's disease; to look for a relationship between pain and the levels of total alkaline phosphatase (total ALP); to verify if the most commonly used drugs in Paget's disease, calcitonin and bisphosphonates, were able to reduce the pain and the levels of total ALP. The study analyzed 107 Italian patients with Paget's disease who were hospitalized at the same Institute between 1970 and 2010; all patients affected by severe arthritis were excluded. From the analysis of the clinical records it emerged that as many as 85% of patients had pain and that total ALP was also increased in most of the patients with pain in comparison with patients without pain. The clinical and metabolic effects of different therapies were then assessed: many patients had not received any specific therapy (58%), others had been treated with calcitonin (25%) and others with bisphosphonates (17%). In fact, the patients treated with bisphosphonates had significantly lower levels both of pain and total ALP. The authors hypothesize that the pain in Paget's disease has a primary origin and is correlated to the degree of bone metabolic hyperactivity. Finally, treatment with bisphosphonates appeared to be the most appropriate treatment, having been able to control both the pain and the metabolic hyperactivity. PMID- 21552193 TI - Neuro- and immunomodulatory steroids and other biochemical markers in drug-naive schizophrenia patients and the effect of treatment with atypical antipsychotics. AB - OBJECTIVE: Serum levels of neuro- and immunomodulatory adrenal steroids together with selected hormonal, lipid and other relevant biochemical parameters were investigated to examine the differences between first-episode schizophrenia patients and age-matched healthy subjects, and the effect of treatment with atypical antipsychotics. METHODS: The patient's group consisted of 22 drug-naive patients (13 men and 9 women), diagnosed with schizophrenia according to ICD-10 criteria, before and after six-months treatment with atypical antipsychotics of olanzapine or non-olanzapine type. Biochemical markers included steroids cortisol, dehydroepiandrosterone, its sulfate, 7-hydroxylated metabolites of dehydroepiandrosterone, prolactin, thyrotropin, free thyroxine, autoantibodies against thyroid peroxidase and thyroglobulin, glucose levels, four major lipid parameters, homocysteine and three other aminothiols. Steroids, prolactin and thyroid parameters were determined by radioimmunoassays, the other markers by standard biochemical methods. RESULTS: Significantly lower dehydroepiandrosterone sulfate and of 7alpha-hydroxy- dehydroepiandrosterone levels than in controls were found in male patients. In the female group, the only difference in steroid spectra was significantly higher cortisolemia in the patients. The patients had also higher titres of autoantibodies against thyroid peroxidase. Compared to controls, the patients displayed worse lipid spectra, and higher homocysteinemia. Medication did not lead to significant changes in the parameters, with the exception of expected increase in prolactin levels in non-olanzapine treated subgroups. CONCLUSION: Lower levels of 7alpha-hydroxydehydroepiandrosterone, abundant especially in brain, determined for the first time in schizophrenia patients, are in agreement with recent opinion of their neuroprotective and immunoprotective role. High levels of autoantibodies against thyroid peroxidase in the patients support the autoimmunity hypothesis of schizophrenia. PMID- 21552194 TI - Lower whole blood glutathione peroxidase (GPX) activity in depression, but not in myalgic encephalomyelitis / chronic fatigue syndrome: another pathway that may be associated with coronary artery disease and neuroprogression in depression. AB - BACKGROUND: Major depression and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are two disorders accompanied by an upregulation of the inflammatory and oxidative and nitrosative (IO&NS) pathways and a decreased antioxidant status. Moreover, depression is accompanied by disorders in inflammatory and neuroprogressive (IN-PRO) pathways. METHODS: This study examines whole blood glutathione peroxidase (GPX) in depression and in ME/CFS; GPX is an enzyme that reduces hydroperoxides by oxidizing glutathione and consequently protects the cells from oxidative damage. Blood was sampled in 39 patients with depression, 40 patients with ME/CFS and 24 normal volunteers. Whole blood was analysed for GPX activity using the Ransel assay (Randox). Severity of illness was measured by means of the Hamilton Depression Rating Scale (HDRS) and the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF scale). RESULTS: We found that whole blood GPX activity was significantly (p=0.001) lower in depressed patients than in normal controls and that there were no significant differences between ME/CFS and controls. In depression and ME/CFS, there were significant and inverse relationships between GPX activity and the FF items, depressed mood and autonomic symptoms. In depression, there were significant and negative correlations between whole blood GPX and the HDRS score and autonomic symptoms. DISCUSSION: The results show that lowered whole blood GPX activity contributes to the lowered antioxidant status in depression. Since GPX activity is a predictor of neuroprogression and coronary artery disease (CAD), lowered GPX activity in depression contributes to the IN-PRO pathways and the comorbidity between depression and CAD. Our results suggest that patients with depression would benefit from Ebselen or a supplementation with glutathione, N-Acetyl-l Cysteine and selenium. PMID- 21552195 TI - Immunolocalization of the PP family and its receptors in the gastrointestinal tract of house musk shrew, Suncus murinus. AB - OBJECTIVES: To investigate the immunolocalization of the pancreatic polypeptide (PP)-fold peptide family, important regulatory factors for food intake, in the gastrointestinal tract of Suncus murinus, and to discuss the relation with the obesity-resistance, visceral fat accumulation-resistance phenomenon in Suncus murinus. METHODS: The gastrointestinal tract of adult Suncus murinus, except for the stomach and pylorus, was divided into five sections (S1, corresponding to the duodenum, S2, S3 and S4, corresponding to the jejunum and ileum, and S5, corresponding to the colon and rectum in other mammals), to investigate the PP family and their receptor-producing cells by means of immunohistochemistry. RESULTS: NPY, PYY, Y1 and Y4-immunoreactive cells were distributed widely throughout the gastrointestinal tract, moreover, the PP family and their receptor immunoreactive cells were predominantly distributed at the end of the gastrointestinal tract, the rectum. CONCLUSION: In this study, we investigated the distribution of the PP family and their receptor-producing cells in the gastrointestinal tract of Suncus murinus in detail for the first time. It was presumed that the wide distribution of Y4 in the gastrointestinal tract may be related to (associated with) the phenomenon of natural obesity-resistance, visceral fat accumulation-resistance in aging Suncus murinus. PMID- 21552196 TI - Extreme elevation of placental alkaline phosphatase as a marker of preterm delivery, placental insufficiency and low birth weight. AB - OBJECTIVE: Clinical case of extremely elevated levels of alkaline phosphatase (ALP) enzyme detected in the 3rd trimester of gestation, the diagnostic and therapeutic procedures, delivery and puerperium are presented. The paper also offers a review of the currently available bibliographical data of the issue. METHODS AND RESULTS: The case presents a 23-year-old secundipara with clinical problems in her 3rd trimester, namely a generalized pruritus. The gestation had signs of asymmetrical fetal hypotrophy induced by placental insufficiency. Laboratory tests showed elevated (as much as a 10.5-fold increase) values of alkaline phosphatase enzyme, 94.05% of which was placental isoenzyme. The patient also had clinical symptoms of a preterm delivery. The spontaneous delivery occurred in 36 week of gestation. The postpuerperium values of alkaline phosphatase returned to normal. CONCLUSION: The authors point out the potential relationship between elevated placental isoenzyme of alkaline phosphatase levels and placental insufficiency and the onset of a preterm delivery. PMID- 21552197 TI - Dopamine selectively modulates lipopolysaccharide-induced TNF-alpha, IFN-gamma and IL-10 within mice tissues. AB - OBJECTIVES: Dopamine (DA) administration in sepsis is used to modulate the hypotensive condition and to normalize the blood vessels perfusion. However, whether this administration of DA has an effect on the release of cytokines in vivo deserves investigation. METHODS AND RESULTS: Pre-exposure of DA (1 ug/ml) to whole blood enhanced IL-10 (30%) production level following LPS stimulation. This IL-10 enhancement became statistically significant (p<0.001) upon the addition of D2-DA receptor (DAR) antagonists, Clozapine or Haloperidol. Furthermore, systemic administration of DA (0.5-50 mg/kg) in mice suppressed significantly LPS-induced TNF-alpha levels in blood, liver, spleen, brain, and lungs; IL-10 levels in blood, brain and liver; and IFN-gamma levels in blood, liver, brain, and lungs. On the other hand, DA enhanced significantly LPS-induced IL-10 production in the lungs and spleen, and IFN-gamma levels in the spleen. Administration of Clozapine (54 mg/kg) or Haloperidol (62 mg/kg) with LPS (1 ug) and DA (5 mg/kg) reversed DA suppressive effects on LPS-induced cytokines in blood, IFN-gamma in brain and lungs, and enhanced significantly LPS-induced IL-10 production in blood, spleen, liver, and lungs. CONCLUSIONS: These results indicate that DA modulatory effect on LPS-induced blood cytokines-producing cells is mediated mainly by D2-DAR (D2/ D3/D4) through enhancing immune cells migration and extravasation into tissues. Furthermore, DA selectivity on cytokines modulation is tissue specific, mediated by the type of DAR expressed and on the immune cells lodged in each tissue. PMID- 21552198 TI - Detection of atrial natriuretic peptide and its receptor in marginal cells and cochlea tissues from the developing rats. AB - OBJECTIVE: Atrial natriuretic peptide (ANP) regulates the homeostasis of body fluid and blood pressure as a neuropeptide in the central nervous system. To assess the possible physiological role in the inner ear, we investigated the expression of ANP in primary culture of marginal cells, and then we detected the expression of ANP and its receptor (NPR-A) in cochlear tissues derived from neonatal and adult rats of various ages. METHODS: Marginal cells were isolated from cochlear stria vascularis of the neonatal rats. The cultured cells were subsequently characterized by morphology, immunocytochemistry, and scanning electron microscope (SEM) analysis. In order to examine the expression of ANP in marginal cells as well as in the developing rats' cochleae, immunocytochemistry and reverse-transcription polymerase chain reaction (RT-PCR) were applied respectively. RESULTS: The present study demonstrated typical characteristics of marginal cells, including cobblestone, polygonal monolayer, pleomorphic growth pattern and the expression of cell type-specific marker, and SEM analysis. Subsequently, immunoreactive product of ANP were found in cultured marginal cells. The mRNAs encoding ANP and NPR-A receptor was expressed in rats' cochleae from postembryonic stage to early postnatal period. During the maturation stage, ANP expression was gradually down-regulated, while the expression of NPR-A receptor was relatively stable. CONCLUSION: ANP might be synthesized and secreted by marginal cells of stria vascularis, and could play an important role in modulating the microenvironment of the inner ear. In addition, ANP might contribute to development and growth process of cochlea. PMID- 21552199 TI - Corticotropin-releasing factor (CRF) over-expression down-regulates hippocampal dopamine receptor protein expression and CREB activation in mice. AB - BACKGROUND: Stress results in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by increased central CRF activity, elevated circulating glucocorticoid levels, impaired glucocorticoid-mediated negative feedback and abnormal hippocampal functions, possibly contributing to the development of behavioral pathologies, such as depression. The hippocampus is critically involved in the control of the HPA axis as well as in explicit memory, contextual aspects of fear, organization of the behavioral response to environmental novelty and in habituation. We have previously shown that mice that over-express CRF in the brain exhibit impaired novelty detection and altered psychophysiological and behavioral habituation, functions linked to dopamine receptor-dependent hippocampal plasticity. OBJECTIVE AND METHODS: Therefore, the aim of the present study was to measure D1 and D2 dopamine receptor expression and related signaling, such as CREB and ERK protein levels and phosphorylation, in the hippocampus and other brain regions of mice with post-natal CRF over-expression (CRF-OE mice). RESULTS: We found a region-specific down-regulation of both D1 and D2 protein expression, without altered CRF receptor protein expression, in the hippocampus in CRF-OE mice. This was accompanied by an impaired phosphorylation of hippocampal CREB, but not ERK1 and ERK2, in the same animals. CONCLUSIONS: These results suggest that post-natal onset CRF over-expression results in an impairment of dopamine signaling in the hippocampus, which may underlie cognitive and motivational aspects of stress-related, CRF-driven mood disorders. PMID- 21552200 TI - Codeine did not increase analgesic efficacy of coxibs in contrast to that of paracetamol or ibuprofen: isobolographic analysis in mice. AB - OBJECTIVES: There is good evidence that opioids can potentiate analgesic activity of some older non-opioid analgesics (such as paracetamol or ibuprofen) but it is not known whether this also holds true for newer non-opioid analgesics that selectively inhibit cyclooxygenase 2 (coxibs). This study was undertaken to determine the nature of the interaction between codeine and celecoxib or etoricoxib in peritoneal irritation-induced visceral pain in mice. For comparison, interactions of codeine with paracetamol and ibuprofen were also tested using the same method. MATERIAL AND METHODS: A small volume of a weak acetic acid (0.6%) was injected into the peritoneal cavity and the number of writhes (contractions of abdominal muscles) was counted. All drugs were given orally. Their interaction was characterized using isobolographic analysis. RESULTS: Codeine, etoricoxib, celecoxib, ibuprofen and paracetamol all independently produced dose-dependent suppression of writhing. The isobolographic analysis carried out using equipotent dose ratios showed that the interactions between codeine and etoricoxib or celecoxib were sub-additive or additive, respectively. This was in contrast to combinations of codeine with ibuprofen or paracetamol, which were supra-additive. Interaction indexes gamma, determined as a ratio between experimental and theoretical ED50 values of the mixture, were as follows: 2.7 for codeine + etoricoxib, 0.62 for codeine + celecoxib, 0.43 for codeine + ibuprofen and 0.33 for codeine + paracetamol. CONCLUSIONS: These and other results suggest that opioids do not seem to potentiate analgesic effects of selective COX-2 inhibitors, in contrast to nonselective COX inhibitors or paracetamol. PMID- 21552201 TI - Chronic alcohol administration increases serum prolactin level and pituitary cell proliferation, and alters hypothalamus neurotransmitters in rat. AB - OBJECTIVES: Alcohol induces hyperprolactinemia in both alcoholic men and women, but the mechanism is not fully established. The aim is to investigate the mechanism involved in elevation of serum prolactin level after chronic alcohol administration. METHODS: In this study, healthy female SD rats were given alcohol for 8 weeks and checked for serum prolactin level by radioimmunoassay. Interior pituitary cell proliferation was determined by immunohistochemistry score of Ki 67, and hypothalamic neurotransmitters were detected by Coulomb HPLC electrochemical array. RESULTS: We demonstrated that serum prolactin level and wet pituitary weight of alcohol-fed rats were significantly increased. Interior pituitary cell proliferation was significantly enhanced; hypothalamic dopamine, 5 HT and GABA levels were reduced while glutamate level was increased by chronic alcohol administration; hypothalamic noradrenalin level remained unchanged. CONCLUSION: Our study suggested that chronic alcohol administration resulted in elevated serum prolactin level in normal SD rats probably through enhancing pituitary gland cell proliferation combined with altered hypothalamic neurotransmitters that regulate prolactin level. PMID- 21552202 TI - Attachment in integrative neuroscientific perspective. AB - Attachment theory is a very influential general concept of human social and emotional development, which emphasizes the role of early mother-infant interactions for infant's adaptive behavioural and stress copying strategies, personality organization and mental health. Individuals with disrupted development of secure attachment to mother/primary caregiver are at higher risk of developing mental disorders. This theory consists of the complex developmental psycho-neurobiological model of attachment and emerges from principles of psychoanalysis, evolutionary biology, cognitive-developmental psychology, ethology, physiology and control systems theory. The progress of modern neuroscience enables interpretation of neurobiological aspects of the theory as multi-level neural interactions and functional development of important neural structures, effects of neuromediattors, hormones and essential neurobiological processes including emotional, cognitive, social interactions and the special key role of mentalizing. It has multiple neurobiological, neuroendocrine, neurophysiological, ethological, genetic, developmental, psychological, psychotherapeutic and neuropsychiatric consequences and is a prototype of complex neuroscientific concept as interpretation of modern integrated neuroscience. PMID- 21552203 TI - The 2'-OH group of the peptidyl-tRNA stabilizes an active conformation of the ribosomal PTC. AB - The ribosome accelerates the rate of peptidyl transfer by >10(6)-fold relative to the background rate. A widely accepted model for this rate enhancement invokes entropic effects whereby the ribosome and the 2'-OH of the peptidyl-tRNA substrate precisely position the reactive moieties through an extensive network of hydrogen bonds that allows proton movement through them. Some studies, however, have called this model into question because they find the 2'-OH of the peptidyl-tRNA to be dispensable for catalysis. Here, we use an in vitro reconstituted translation system to resolve these discrepancies. We find that catalysis is at least 100-fold slower with the dA76-substituted peptidyl-tRNA substrate and that the peptidyl transferase centre undergoes a slow inactivation when the peptidyl-tRNA lacks the 2'-OH group. Additionally, the 2'-OH group was found to be critical for EFTu binding and peptide release. These findings reconcile the conflict in the literature, and support a model where interactions between active site residues and the 2'-OH of A76 of the peptidyl-tRNA are pivotal in orienting substrates in this active site for optimal catalysis. PMID- 21552204 TI - The RSC chromatin remodelling ATPase translocates DNA with high force and small step size. AB - ATP-dependent chromatin remodelling complexes use the energy of ATP hydrolysis to reposition and reconfigure nucleosomes. Despite their diverse functions, all remodellers share highly conserved ATPase domains, many shown to translocate DNA. Understanding remodelling requires biophysical knowledge of the DNA translocation process: how the ATPase moves DNA and generates force, and how translocation and force generation are coupled on nucleosomes. Here, we characterize the real-time activity of a minimal RSC translocase 'motor' on bare DNA, using high-resolution optical tweezers and a 'tethered' translocase system. We observe on dsDNA a processivity of ~35 bp, a speed of ~25 bp/s, and a step size of 2.0 (+/-0.4, s.e.m.) bp. Surprisingly, the motor is capable of moving against high force, up to 30 pN, making it one of the most force-resistant motors known. We also provide evidence for DNA 'buckling' at initiation. These observations reveal the ATPase as a powerful DNA translocating motor capable of disrupting DNA-histone interactions by mechanical force. PMID- 21552205 TI - Galactose-modified iNKT cell agonists stabilized by an induced fit of CD1d prevent tumour metastasis. AB - Invariant natural killer T (iNKT) cells are known to have marked immunomodulatory capacity due to their ability to produce copious amounts of effector cytokines. Here, we report the structure and function of a novel class of aromatic alpha galactosylceramide structurally related glycolipids with marked Th1 bias in both mice and men, leading to superior tumour protection in vivo. The strength of the Th1 response correlates well with enhanced lipid binding to CD1d as a result of an induced fit mechanism that binds the aromatic substitution as a third anchor, in addition to the two lipid chains. This induced fit is in contrast to another Th1-biasing glycolipid, alpha-C-GalCer, whose CD1d binding follows a conventional key-lock principle. These findings highlight the previously unexploited flexibility of CD1d in accommodating galactose-modified glycolipids and broaden the range of glycolipids that can stimulate iNKT cells. We speculate that glycolipids can be designed that induce a similar fit, thereby leading to superior and more sustained iNKT cell responses in vivo. PMID- 21552207 TI - The transcription factor Pax5 regulates its target genes by recruiting chromatin modifying proteins in committed B cells. AB - Pax5 is a critical regulator of B-cell commitment. Here, we identified direct Pax5 target genes by streptavidin-mediated ChIP-chip analysis of pro-B cells expressing in vivo biotinylated Pax5. By binding to promoters and enhancers, Pax5 directly regulates the expression of multiple transcription factor, cell surface receptor and signal transducer genes. One of the newly identified enhancers was shown by transgenic analysis to confer Pax5-dependent B-cell-specific activity to the Nedd9 gene controlling B-cell trafficking. Profiling of histone modifications in Pax5-deficient and wild-type pro-B cells demonstrated that Pax5 induces active chromatin at activated target genes, while eliminating active chromatin at repressed genes in committed pro-B cells. Pax5 rapidly induces these chromatin and transcription changes by recruiting chromatin-remodelling, histone-modifying and basal transcription factor complexes to its target genes. These data provide novel insight into the regulatory network and epigenetic regulation, by which Pax5 controls B-cell commitment. PMID- 21552206 TI - Histone variant macroH2A confers resistance to nuclear reprogramming. AB - How various layers of epigenetic repression restrict somatic cell nuclear reprogramming is poorly understood. The transfer of mammalian somatic cell nuclei into Xenopus oocytes induces transcriptional reprogramming of previously repressed genes. Here, we address the mechanisms that restrict reprogramming following nuclear transfer by assessing the stability of the inactive X chromosome (Xi) in different stages of inactivation. We find that the Xi of mouse post-implantation-derived epiblast stem cells (EpiSCs) can be reversed by nuclear transfer, while the Xi of differentiated or extraembryonic cells is irreversible by nuclear transfer to oocytes. After nuclear transfer, Xist RNA is lost from chromatin of the Xi. Most epigenetic marks such as DNA methylation and Polycomb deposited H3K27me3 do not explain the differences between reversible and irreversible Xi. Resistance to reprogramming is associated with incorporation of the histone variant macroH2A, which is retained on the Xi of differentiated cells, but absent from the Xi of EpiSCs. Our results uncover the decreased stability of the Xi in EpiSCs, and highlight the importance of combinatorial epigenetic repression involving macroH2A in restricting transcriptional reprogramming by oocytes. PMID- 21552208 TI - The oligomeric state sets GABA(B) receptor signalling efficacy. AB - G protein-coupled receptors (GPCRs) have key roles in cell-cell communication. Recent data suggest that these receptors can form large complexes, a possibility expected to expand the complexity of this regulatory system. Among the brain GPCRs, the heterodimeric GABA(B) receptor is one of the most abundant, being distributed in most brain regions, on either pre- or post-synaptic elements. Here, using specific antibodies labelled with time-resolved FRET compatible fluorophores, we provide evidence that the heterodimeric GABA(B) receptor can form higher-ordered oligomers in the brain, as suggested by the close proximity of the GABA(B1) subunits. Destabilizing the oligomers using a competitor or a GABA(B1) mutant revealed different G protein coupling efficiencies depending on the oligomeric state of the receptor. By examining, in heterologous system, the G protein coupling properties of such GABA(B) receptor oligomers composed of a wild type and a non-functional mutant heterodimer, we provide evidence for a negative functional cooperativity between the GABA(B) heterodimers. PMID- 21552210 TI - Biomarkers and microsatellite instability analysis of curettings can predict the behavior of FIGO stage I endometrial endometrioid adenocarcinoma. AB - The prognostic value of molecular biomarkers, microsatellite instability, DNA ploidy and morphometric mean shortest nuclear axis in endometrial cancer is conflicting, possibly due to the fact that different studies have used mixtures of histotypes, FIGO stages and different non-standardized non-automated methods. We have evaluated the prognostic value of classical prognostic factors, molecular biomarkers, microsatellite instability, DNA ploidy and morphometric mean shortest nuclear axis in a population-based cohort of FIGO stage I endometrial endometrioid adenocarcinomas. Curettings of 224 FIGO stage I endometrial endometrioid adenocarcinoma patients were reviewed. Clinical information, including follow-up, was obtained from the patients' charts. Microsatellite instability and morphometric mean shortest nuclear axis were obtained in whole tissue sections and molecular biomarkers using tissue microarrays. DNA ploidy was analyzed by image cytometry. Univariate (Kaplan-Meier method) and multivariate (Cox model) survival analysis was performed. With median follow-up of 66 months (1-209), 14 (6%) patients developed metastases. Age, microsatellite instability, molecular biomarkers (p16, p21, p27, p53 and survivin) and morphometric mean shortest nuclear axis had prognostic value. With multivariate analysis, combined survivin, p21 and microsatellite instability overshadowed all other variables. Patients in which any of these features had favorable values had an excellent prognosis, in contrast to those with either high survivin or low p21 (97 vs 78% survival, P<0.0001, hazard ratio=7.8). Combined high survivin and low p21 values and microsatellite instability high identified a small subgroup with an especially poor prognosis (survival rate 57%, P=0.01, hazard ratio=5.6). We conclude that low p21 and high survivin expression are poor prognosis indicators in FIGO stage I endometrial endometrioid adenocarcinoma, especially when high microsatellite instability occurs. PMID- 21552209 TI - Loss of E-cadherin expression and outcome among patients with resectable pancreatic adenocarcinomas. AB - Only a minority of patients who undergo surgical resection for pancreatic ductal adenocarcinoma are cured. Since patient outcome is not reliably predicted using pathological factors (tumor stage, differentiation, and resection margin status) alone, markers of tumor behavior are needed. One candidate predictor of pancreatic cancer outcome is E-cadherin status. CDH1 is a tumor suppressor gene encoding an important cell adhesion molecule (E-cadherin). The aim of this study was to determine if, among patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, loss of E-cadherin expression was an independent predictor of poor outcome. We examined patterns of loss of E-cadherin by immunohistochemistry in tissue microarrays of 329 surgically resected pancreatic ductal adenocarcinomas. E-cadherin expression was then correlated with outcome. Kaplan-Meier analysis and Cox proportional hazards regression modeling were used to assess the mortality risk. One hundred forty-one pancreatic adenocarcinomas (43%) had partial or complete loss of E-cadherin expression within the analyzed tissue cores. In most instances (134 cases, 41%), this loss was partial. Patients whose pancreatic adenocarcinomas had either complete loss (n=7; median survival, 5.5 months) or partial loss (n=134; 12.7 months) of E-cadherin expression had significantly worse median survival than those with uniformly intact E-cadherin expression (n=188; 18.5 months) by univariate (P=0.002) and multivariate (P=0.006) analyses. In subgroup analysis, patients with poorly differentiated cancers had a worse prognosis if their cancers had partial loss of E-cadherin expression (P=0.02). Among patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, partial loss of tumoral E-cadherin expression is an independent predictor of poor outcome. PMID- 21552211 TI - Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. AB - Immunohistochemical staining for p53 is used as a surrogate for mutational analysis in the diagnostic workup of carcinomas of multiple sites including ovarian cancers. Strong and diffuse immunoexpression of p53 is generally interpreted as likely indicating a TP53 gene mutation. The immunoprofile that correlates with wild-type TP53, however, is not as clear. In particular, the significance of completely negative immunostaining is controversial. The aim of this study was to clarify the relationship of the immunohistochemical expression of p53 with the mutational status of the TP53 gene in ovarian cancer. A total of 57 ovarian carcinomas (43 high-grade serous ovarian/peritoneal carcinomas, 2 malignant mesodermal mixed tumors (carcinosarcomas), 2 low-grade serous carcinomas, 4 clear cell carcinomas, 1 well-differentiated endometrioid carcinoma, and 5 carcinomas with mixed epithelial differentiation) were analyzed for TP53 mutations by nucleotide sequencing (exons 4-9), and subjected to immunohistochemical analysis of p53 expression. Thirty six tumors contained functional mutations and 13 had wild type TP53. Five tumors were found to harbor known TP53 polymorphism and changes in the intron region were detected in three. Tumors with wild-type TP53 displayed a wide range of immunolabeling patterns, with the most common pattern showing <=10% of positive cells in 6 cases (46%). Mutant TP53 was associated with 60-100% positive cells in 23 cases (64% of cases). This pattern of staining was also seen in three cases with wild-type TP53. Tumors that were completely negative (0% cells staining) had a mutation of TP53 in 65% of cases and wild-type TP53 in 11%. Combining two immunohistochemical labeling patterns associated with TP53 mutations (0% and 60-100% positive cells), correctly identified a mutation in 94% of cases (P<0.001). Immunohistochemical analysis can be used as a robust method for inferring the presence of a TP53 mutation in ovarian carcinomas. In addition to a strong and diffuse pattern of p53 expression (in greater than 60% of cells), complete absence of p53 immunoexpression is commonly associated with a TP53 mutation. Accordingly, this latter pattern, unlike low-level expression (10-50% cells), should not be construed as indicative of wild-type TP53. PMID- 21552213 TI - Classification of epithelial-mesenchymal transition phenotypes in esophageal squamous cell carcinoma is strongly associated with patient prognosis. AB - Epithelial-mesenchymal transition is characterized by a loss of cell adhesion and increased cell mobility due to cells gaining a mesenchymal phenotype. During the epithelial-mesenchymal transition process, tumor cells are expected to lose their epithelial phenotype and gradually and sequentially acquire a mesenchymal phenotype. Epithelial-mesenchymal transition is a dynamic and reversible process, which has been observed in patient tissues to display a wide spectrum of phenotypes. However, very little is known about the clinical significance of the different phenotypes of the epithelial-mesenchymal transition. Based on the expression pattern of various epithelial-mesenchymal transition-related proteins, we divided 168 esophageal squamous cell carcinomas into different phenotypes, including complete type; incomplete type, including hybrid type and null type; and a wild type. The clinical significance of each phenotype was investigated. Of the 168 cases, 31 were categorized as complete type, 53 as incomplete type (hybrid type, 26 cases; null type, 27 cases), and 84 as wild type. Epithelial mesenchymal transition phenotype was significantly associated with tumor size (P=0.021), differentiation (P=0.001), and invasion depth (P<0.001). Overall survival and disease-free survival rates were significantly worse in the complete type, better in the incomplete type, and best in the wild type. Within the incomplete type group, the hybrid type survival curve was similar to that of the complete type, whereas the overall survival of the null type was similar to the wild type. Complete type had a noticeable poorer prognostic effect on survival in patients with early invasion (pT<=2) than it had on survival among patients with advanced invasion (pT>=3). The complete phenotype was an independent prognostic factor for both overall (P=0.009) and disease-free survival (P<0.001). In conclusion, classification of epithelial-mesenchymal transition phenotypes has novel clinical implications, and identification of a specific phenotype might provide a tool to better stratify and predict patient outcomes. PMID- 21552212 TI - Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study. AB - Previous studies have demonstrated that androgen receptor is expressed in many breast cancers, but its expression in relation to the various breast cancer subtypes as defined by molecular profiling has not been studied in detail. We constructed tissue microarrays from 3093 breast cancers that developed in women enrolled in the Nurses' Health Study. Tissue microarray sections were immunostained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6, epidermal growth factor receptor (EGFR) and androgen receptor (ER). Immunostain results were used to categorize each cancer as luminal A or B, HER2 and basal like. The relationships between androgen receptor expression and molecular subtype were analyzed. Overall, 77% of the invasive breast carcinomas were androgen receptor positive. Among 2171 invasive cancers, 64% were luminal A, 15% luminal B, 6% HER2 and 11% basal like. The frequency of androgen receptor expression varied significantly across the molecular phenotypes (P<0.0001). In particular, androgen receptor expression was commonly observed in luminal A (91%) and B (68%) cancers, but was less frequently seen in HER2 cancers (59%). Despite being defined by the absence of ER and PR expression and being considered hormonally unresponsive, 32% of basal-like cancers expressed androgen receptor. Among 246 cases of ductal carcinoma in situ, 86% were androgen receptor positive, but the frequency of androgen receptor expression differed significantly across the molecular phenotypes (P=0.001), and high nuclear grade lesions were less likely to be androgen receptor positive compared with lower-grade lesions. Androgen receptor expression is most commonly seen in luminal A and B invasive breast cancers. However, expression of androgen receptor is also seen in approximately one-third of basal-like cancers, providing further evidence that basal-like cancers represent a heterogeneous group. Our findings raise the possibility that targeting the androgen receptor pathway may represent a novel therapeutic approach to the management of patients with basal-like cancers. PMID- 21552214 TI - Evaluation of the WHO criteria for the classification of patients with mastocytosis. AB - Diagnosis and classification of mastocytosis is currently based on the World Health Organization (WHO) criteria. Here, we evaluate the utility of the WHO criteria for the diagnosis and classification of a large series of mastocytosis patients (n=133), and propose a new algorithm that could be routinely applied for refined diagnosis and classification of the disease. Our results confirm the utility of the WHO criteria and provide evidence for the need of additional information for (1) a more precise diagnosis of mastocytosis, (2) specific identification of new forms of the disease, (3) the differential diagnosis between cutaneous mastocytosis vs systemic mastocytosis, and (4) improved distinction between indolent systemic mastocytosis and aggressive systemic mastocytosis. Based on our results, a new algorithm is proposed for a better diagnostic definition and prognostic classification of mastocytosis, as confirmed prospectively in an independent validation series of 117 mastocytosis patients. PMID- 21552219 TI - Inadequately met needs. PMID- 21552220 TI - PARP inhibitors stumble in breast cancer. PMID- 21552221 TI - Human iPSC and ESC translation potential debated. PMID- 21552225 TI - Chinese biotechs wrestle with transparency, cultural hurdles. PMID- 21552227 TI - Sequencing firms eye pathology labs as next big market opportunity. PMID- 21552229 TI - Flawed arithmetic on drug development costs. PMID- 21552230 TI - Q1 strong out of the gates. PMID- 21552231 TI - Drug pipeline: Q111. PMID- 21552232 TI - Peering inside Alzheimer's brains. PMID- 21552233 TI - Overhauling the reimbursement system for molecular diagnostics. PMID- 21552234 TI - Interaction databases on the same page. PMID- 21552235 TI - PathSeq: software to identify or discover microbes by deep sequencing of human tissue. PMID- 21552236 TI - Reforming direct-to-consumer advertising. PMID- 21552237 TI - Mandating race: how the USPTO is forcing race into biotech patents. PMID- 21552239 TI - Building stronger microvessels. PMID- 21552240 TI - Sialidase inhibitors DAMPen sepsis. PMID- 21552241 TI - Auxin boost for cotton. PMID- 21552242 TI - A self-assembling retina. PMID- 21552250 TI - First-quarter biotech job picture. PMID- 21552244 TI - Minimum information about a marker gene sequence (MIMARKS) and minimum information about any (x) sequence (MIxS) specifications. AB - Here we present a standard developed by the Genomic Standards Consortium (GSC) for reporting marker gene sequences--the minimum information about a marker gene sequence (MIMARKS). We also introduce a system for describing the environment from which a biological sample originates. The 'environmental packages' apply to any genome sequence of known origin and can be used in combination with MIMARKS and other GSC checklists. Finally, to establish a unified standard for describing sequence data and to provide a single point of entry for the scientific community to access and learn about GSC checklists, we present the minimum information about any (x) sequence (MIxS). Adoption of MIxS will enhance our ability to analyze natural genetic diversity documented by massive DNA sequencing efforts from myriad ecosystems in our ever-changing biosphere. PMID- 21552252 TI - In situ formation of highly conducting covalent Au-C contacts for single-molecule junctions. AB - Charge transport across metal-molecule interfaces has an important role in organic electronics. Typically, chemical link groups such as thiols or amines are used to bind organic molecules to metal electrodes in single-molecule circuits, with these groups controlling both the physical structure and the electronic coupling at the interface. Direct metal-carbon coupling has been shown through C60, benzene and pi-stacked benzene, but ideally the carbon backbone of the molecule should be covalently bonded to the electrode without intervening link groups. Here, we demonstrate a method to create junctions with such contacts. Trimethyl tin (SnMe(3))-terminated polymethylene chains are used to form single molecule junctions with a break-junction technique. Gold atoms at the electrode displace the SnMe(3) linkers, leading to the formation of direct Au-C bonded single-molecule junctions with a conductance that is ~100 times larger than analogous alkanes with most other terminations. The conductance of these Au-C bonded alkanes decreases exponentially with molecular length, with a decay constant of 0.97 per methylene, consistent with a non-resonant transport mechanism. Control experiments and ab initio calculations show that high conductances are achieved because a covalent Au-C sigma (sigma) bond is formed. This offers a new method for making reproducible and highly conducting metal organic contacts. PMID- 21552253 TI - Quantum measurement and orientation tracking of fluorescent nanodiamonds inside living cells. AB - Fluorescent particles are routinely used to probe biological processes. The quantum properties of single spins within fluorescent particles have been explored in the field of nanoscale magnetometry, but not yet in biological environments. Here, we demonstrate optically detected magnetic resonance of individual fluorescent nanodiamond nitrogen-vacancy centres inside living human HeLa cells, and measure their location, orientation, spin levels and spin coherence times with nanoscale precision. Quantum coherence was measured through Rabi and spin-echo sequences over long (>10 h) periods, and orientation was tracked with effective 1 degrees angular precision over acquisition times of 89 ms. The quantum spin levels served as fingerprints, allowing individual centres with identical fluorescence to be identified and tracked simultaneously. Furthermore, monitoring decoherence rates in response to changes in the local environment may provide new information about intracellular processes. The experiments reported here demonstrate the viability of controlled single spin probes for nanomagnetometry in biological systems, opening up a host of new possibilities for quantum-based imaging in the life sciences. PMID- 21552254 TI - Fast, three-dimensional super-resolution imaging of live cells. AB - We report super-resolution fluorescence imaging of live cells with high spatiotemporal resolution using stochastic optical reconstruction microscopy (STORM). By labeling proteins either directly or via SNAP tags with photoswitchable dyes, we obtained two-dimensional (2D) and 3D super-resolution images of living cells, using clathrin-coated pits and the transferrin cargo as model systems. Bright, fast-switching probes enabled us to achieve 2D imaging at spatial resolutions of ~25 nm and temporal resolutions as fast as 0.5 s. We also demonstrated live-cell 3D super-resolution imaging. We obtained 3D spatial resolution of ~30 nm in the lateral direction and ~50 nm in the axial direction at time resolutions as fast as 1-2 s with several independent snapshots. Using photoswitchable dyes with distinct emission wavelengths, we also demonstrated two color 3D super-resolution imaging in live cells. These imaging capabilities open a new window for characterizing cellular structures in living cells at the ultrastructural level. PMID- 21552255 TI - In vivo protein trapping produces a functional expression codex of the vertebrate proteome. AB - We describe a conditional in vivo protein-trap mutagenesis system that reveals spatiotemporal protein expression dynamics and can be used to assess gene function in the vertebrate Danio rerio. Integration of pGBT-RP2.1 (RP2), a gene breaking transposon containing a protein trap, efficiently disrupts gene expression with >97% knockdown of normal transcript amounts and simultaneously reports protein expression for each locus. The mutant alleles are revertible in somatic tissues via Cre recombinase or splice-site-blocking morpholinos and are thus to our knowledge the first systematic conditional mutant alleles outside the mouse model. We report a collection of 350 zebrafish lines that include diverse molecular loci. RP2 integrations reveal the complexity of genomic architecture and gene function in a living organism and can provide information on protein subcellular localization. The RP2 mutagenesis system is a step toward a unified 'codex' of protein expression and direct functional annotation of the vertebrate genome. PMID- 21552256 TI - Combining quantitative proteomics data processing workflows for greater sensitivity. AB - We here describe a normalization method to combine quantitative proteomics data. By merging the output of two popular quantification software packages, we obtained a 20% increase (on average) in the number of quantified human proteins without suffering from a loss of quality. Our integrative workflow is freely available through our user-friendly, open-source Rover software (http://compomics rover.googlecode.com/). PMID- 21552257 TI - Sequence-based identification of 3D structural modules in RNA with RMDetect. AB - Structural RNA modules, sets of ordered non-Watson-Crick base pairs embedded between Watson-Crick pairs, have central roles as architectural organizers and sites of ligand binding in RNA molecules, and are recurrently observed in RNA families throughout the phylogeny. Here we describe a computational tool, RNA three-dimensional (3D) modules detection, or RMDetect, for identifying known 3D structural modules in single and multiple RNA sequences in the absence of any other information. Currently, four modules can be searched for: G-bulge loop, kink-turn, C-loop and tandem-GA loop. In control test sequences we found all of the known modules with a false discovery rate of 0.23. Scanning through 1,444 publicly available alignments, we identified 21 yet unreported modules and 141 known modules. RMDetect can be used to refine RNA 2D structure, assemble RNA 3D models, and search and annotate structured RNAs in genomic data. PMID- 21552258 TI - Structure of C3PO and mechanism of human RISC activation. AB - Assembly of the RNA-induced silencing complex (RISC) consists of loading duplex (guide-passenger) siRNA onto Argonaute (Ago2) and removing the passenger strand. Ago2 contributes critically to RISC activation by nicking the passenger strand. Here we reconstituted duplex siRNA-initiated RISC activity using recombinant human Ago2 (hAgo2) and C3PO, indicating that C3PO has a critical role in hAgo2 RISC activation. Consistently, genetic depletion of C3PO compromised RNA silencing in mammalian cells. We determined the crystal structure of hC3PO, which reveals an asymmetric octamer barrel consisting of six translin and two TRAX subunits. This asymmetric assembly is critical for the function of C3PO as an endonuclease that cleaves RNA at the interior surface. The current work supports a Dicer-independent mechanism for human RISC activation, in which Ago2 directly binds duplex siRNA and nicks the passenger strand, and then C3PO activates RISC by degrading the Ago2-nicked passenger strand. PMID- 21552259 TI - Alternative splicing of SYK regulates mitosis and cell survival. AB - Most human genes produce multiple mRNA isoforms through alternative splicing. However, the biological relevance of most splice variants remains unclear. In this study, we evaluated the functional impact of alternative splicing in cancer cells. We modulated the splicing pattern of 41 cancer-associated splicing events and scored the effects on cell growth, viability and apoptosis, identifying three isoforms essential for cell survival. Specifically, changing the splicing pattern of the spleen tyrosine kinase gene (SYK) impaired cell-cycle progression and anchorage-independent growth. Notably, exposure of cancer cells to epithelial growth factor modulated the SYK splicing pattern to promote the pro-survival isoform that is associated with cancer tissues in vivo. The data suggest that splicing of selected genes is specifically modified during tumor development to allow the expression of isoforms that promote cancer cell survival. PMID- 21552260 TI - Nemo kinase phosphorylates beta-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin-beta-catenin. AB - Frizzled planar cell polarity (PCP) signaling regulates cell motility in several tissues, including ommatidial rotation in Drosophila melanogaster. The Nemo kinase (Nlk in vertebrates) has also been linked to cell-motility regulation and ommatidial rotation but its mechanistic role(s) during rotation remain obscure. We show that nemo functions throughout the entire rotation movement, increasing the rotation rate. Genetic and molecular studies indicate that Nemo binds both the core PCP factor complex of Strabismus-Prickle, as well as the E-cadherin-beta catenin (E-cadherin-Armadillo in Drosophila) complex. These two complexes colocalize and, like Nemo, also promote rotation. Strabismus (also called Vang) binds and stabilizes Nemo asymmetrically within the ommatidial precluster; Nemo and beta-catenin then act synergistically to promote rotation, which is mediated in vivo by Nemo's phosphorylation of beta-catenin. Our data suggest that Nemo serves as a conserved molecular link between core PCP factors and E-cadherin-beta catenin complexes, promoting cell motility. PMID- 21552261 TI - Multimeric assembly and biochemical characterization of the Trax-translin endonuclease complex. AB - Trax-translin heteromers, also known as C3PO, have been proposed to activate the RNA-induced silencing complex (RISC) by facilitating endonucleolytic cleavage of the siRNA passenger strand. We report on the crystal structure of hexameric Drosophila C3PO formed by truncated translin and Trax, along with electron microscopic and mass spectrometric studies on octameric C3PO formed by full length translin and Trax. Our studies establish that Trax adopts the translin fold, possesses catalytic centers essential for C3PO's endoRNase activity and interacts extensively with translin to form an octameric assembly. The catalytic pockets of Trax subunits are located within the interior chamber of the octameric scaffold. Truncated C3PO, like full-length C3PO, shows endoRNase activity that leaves 3'-hydroxyl-cleaved ends. We have measured the catalytic activity of C3PO and shown it to cleave almost stoichiometric amounts of substrate per second. PMID- 21552262 TI - A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. AB - Oncogene activation has been shown to generate replication-born DNA damage, also known as replicative stress. The primary responder to replicative stress is not Ataxia-Telangiectasia Mutated (ATM) but rather the kinase ATM and Rad3-related (ATR). One limitation for the study of ATR is the lack of potent inhibitors. We here describe a cell-based screening strategy that has allowed us to identify compounds with ATR inhibitory activity in the nanomolar range. Pharmacological inhibition of ATR generates replicative stress, leading to chromosomal breakage in the presence of conditions that stall replication forks. Moreover, ATR inhibition is particularly toxic for p53-deficient cells, this toxicity being exacerbated by replicative stress-generating conditions such as the overexpression of cyclin E. Notably, one of the compounds we identified is NVP BEZ235, a dual phosphatidylinositol-3-OH kinase (PI3K) and mTOR inhibitor that is being tested for cancer chemotherapy but that we now show is also very potent against ATM, ATR and the catalytic subunit of DNA-dependent protein kinase (DNA PKcs). PMID- 21552263 TI - Genome partitioning of genetic variation for complex traits using common SNPs. AB - We estimate and partition genetic variation for height, body mass index (BMI), von Willebrand factor and QT interval (QTi) using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate that ~45%, ~17%, ~25% and ~21% of the variance in height, BMI, von Willebrand factor and QTi, respectively, can be explained by all autosomal SNPs and a further ~0.5-1% can be explained by X chromosome SNPs. We show that the variance explained by each chromosome is proportional to its length, and that SNPs in or near genes explain more variation than SNPs between genes. We propose a new approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein. PMID- 21552264 TI - KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. AB - KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies. PMID- 21552265 TI - Complex interactions between genes controlling trafficking in primary cilia. AB - Cilia-associated human genetic disorders are striking in the diversity of their abnormalities and their complex inheritance. Inactivation of the retrograde ciliary motor by mutations in DYNC2H1 causes skeletal dysplasias that have strongly variable expressivity. Here we define previously unknown genetic relationships between Dync2h1 and other genes required for ciliary trafficking. Mutations in mouse Dync2h1 disrupt cilia structure, block Sonic hedgehog signaling and cause midgestation lethality. Heterozygosity for Ift172, a gene required for anterograde ciliary trafficking, suppresses cilia phenotypes, Sonic hedgehog signaling defects and early lethality of Dync2h1 homozygotes. Ift122, like Dync2h1, is required for retrograde ciliary trafficking, but reduction of Ift122 gene dosage also suppresses the Dync2h1 phenotype. These genetic interactions illustrate the cell biology underlying ciliopathies and argue that mutations in intraflagellar transport genes cause their phenotypes because of their roles in cilia architecture rather than direct roles in signaling. PMID- 21552266 TI - Mutations in CEP57 cause mosaic variegated aneuploidy syndrome. AB - Using exome sequencing and a variant prioritization strategy that focuses on loss of-function variants, we identified biallelic, loss-of-function CEP57 mutations as a cause of constitutional mosaic aneuploidies. CEP57 is a centrosomal protein and is involved in nucleating and stabilizing microtubules. Our findings indicate that these and/or additional functions of CEP57 are crucial for maintaining correct chromosomal number during cell division. PMID- 21552267 TI - Genetic analysis of basophil function in vivo. AB - Contributions by basophils to allergic and helminth immunity remain incompletely defined. Using sensitive interleukin 4 (Il4) reporter alleles, we demonstrate here that basophil IL-4 production occurs by a CD4(+) T cell-dependent process restricted to the peripheral tissues affected. We genetically marked and achieved specific deletion of basophils and found that basophils did not mediate T helper type 2 (T(H)2) priming in vivo. Two-photon imaging confirmed that basophils did not interact with antigen-specific T cells in lymph nodes but engaged in prolonged serial interactions with T cells in lung tissues. Although targeted deletion of IL-4 and IL-13 in either CD4(+) T cells or basophils had a minimal effect on worm clearance, deletion from both lineages demonstrated a nonredundant role for basophil cytokines in primary helminth immunity. PMID- 21552269 TI - Control and characterization of individual grains and grain boundaries in graphene grown by chemical vapour deposition. AB - The strong interest in graphene has motivated the scalable production of high quality graphene and graphene devices. As the large-scale graphene films synthesized so far are typically polycrystalline, it is important to characterize and control grain boundaries, generally believed to degrade graphene quality. Here we study single-crystal graphene grains synthesized by ambient chemical vapour deposition on polycrystalline Cu, and show how individual boundaries between coalescing grains affect graphene's electronic properties. The graphene grains show no definite epitaxial relationship with the Cu substrate, and can cross Cu grain boundaries. The edges of these grains are found to be predominantly parallel to zigzag directions. We show that grain boundaries give a significant Raman 'D' peak, impede electrical transport, and induce prominent weak localization indicative of intervalley scattering in graphene. Finally, we demonstrate an approach using pre-patterned growth seeds to control graphene nucleation, opening a route towards scalable fabrication of single-crystal graphene devices without grain boundaries. PMID- 21552268 TI - Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. AB - The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30 dependent tumor necrosis factor-alpha (TNF-alpha) and CD107a release, and defective interferon-gamma (IFN-gamma) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation. PMID- 21552270 TI - Highly active oxide photocathode for photoelectrochemical water reduction. AB - A clean and efficient way to overcome the limited supply of fossil fuels and the greenhouse effect is the production of hydrogen fuel from sunlight and water through the semiconductor/water junction of a photoelectrochemical cell, where energy collection and water electrolysis are combined into a single semiconductor electrode. We present a highly active photocathode for solar H(2) production, consisting of electrodeposited cuprous oxide, which was protected against photocathodic decomposition in water by nanolayers of Al-doped zinc oxide and titanium oxide and activated for hydrogen evolution with electrodeposited Pt nanoparticles. The roles of the different surface protection components were investigated, and in the best case electrodes showed photocurrents of up to -7.6 mA cm(-2) at a potential of 0 V versus the reversible hydrogen electrode at mild pH. The electrodes remained active after 1 h of testing, cuprous oxide was found to be stable during the water reduction reaction and the Faradaic efficiency was estimated to be close to 100%. PMID- 21552271 TI - Single-molecule analysis reveals three phases of DNA degradation by an exonuclease. AB - lambda exonuclease degrades one strand of duplex DNA in the 5'-to-3' direction to generate a 3' overhang required for recombination. Its ability to hydrolyze thousands of nucleotides processively is attributed to its ring structure, and most studies have focused on the processive phase. Here we have used single molecule fluorescence resonance energy transfer (FRET) to reveal three phases of lambda exonuclease reactions: the initiation, distributive and processive phases. The distributive phase comprises early reactions in which the 3' overhang is too short to stably engage with the enzyme. A mismatched base is digested one-fifth as quickly as a Watson-Crick-paired base, and multiple concatenated mismatches have a cooperatively negative effect, highlighting the crucial role of base pairing in aligning the 5' end toward the active site. The rate-limiting step during processive degradation seems to be the post-cleavage melting of the terminal base pair. We also found that an escape from a known pausing sequence requires enzyme backtracking. PMID- 21552272 TI - Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. AB - We have systematically compared copy number variant (CNV) detection on eleven microarrays to evaluate data quality and CNV calling, reproducibility, concordance across array platforms and laboratory sites, breakpoint accuracy and analysis tool variability. Different analytic tools applied to the same raw data typically yield CNV calls with <50% concordance. Moreover, reproducibility in replicate experiments is <70% for most platforms. Nevertheless, these findings should not preclude detection of large CNVs for clinical diagnostic purposes because large CNVs with poor reproducibility are found primarily in complex genomic regions and would typically be removed by standard clinical data curation. The striking differences between CNV calls from different platforms and analytic tools highlight the importance of careful assessment of experimental design in discovery and association studies and of strict data curation and filtering in diagnostics. The CNV resource presented here allows independent data evaluation and provides a means to benchmark new algorithms. PMID- 21552273 TI - Transitions in neural oscillations reflect prediction errors generated in audiovisual speech. AB - According to the predictive coding theory, top-down predictions are conveyed by backward connections and prediction errors are propagated forward across the cortical hierarchy. Using MEG in humans, we show that violating multisensory predictions causes a fundamental and qualitative change in both the frequency and spatial distribution of cortical activity. When visual speech input correctly predicted auditory speech signals, a slow delta regime (3-4 Hz) developed in higher-order speech areas. In contrast, when auditory signals invalidated predictions inferred from vision, a low-beta (14-15 Hz) / high-gamma (60-80 Hz) coupling regime appeared locally in a multisensory area (area STS). This frequency shift in oscillatory responses scaled with the degree of audio-visual congruence and was accompanied by increased gamma activity in lower sensory regions. These findings are consistent with the notion that bottom-up prediction errors are communicated in predominantly high (gamma) frequency ranges, whereas top-down predictions are mediated by slower (beta) frequencies. PMID- 21552274 TI - A normalization model of multisensory integration. AB - Responses of neurons that integrate multiple sensory inputs are traditionally characterized in terms of a set of empirical principles. However, a simple computational framework that accounts for these empirical features of multisensory integration has not been established. We propose that divisive normalization, acting at the stage of multisensory integration, can account for many of the empirical principles of multisensory integration shown by single neurons, such as the principle of inverse effectiveness and the spatial principle. This model, which uses a simple functional operation (normalization) for which there is considerable experimental support, also accounts for the recent observation that the mathematical rule by which multisensory neurons combine their inputs changes with cue reliability. The normalization model, which makes a strong testable prediction regarding cross-modal suppression, may therefore provide a simple unifying computational account of the important features of multisensory integration by neurons. PMID- 21552275 TI - Auditory aversive learning increases discrimination thresholds. AB - Animal studies of discriminative fear conditioning traditionally use stimuli that are distant in physical features and thus easily distinguished perceptually. Independently, human studies have shown that training mostly improves discrimination thresholds. We found that aversive learning actually induced an increase in discrimination thresholds in humans and that subjective aversion during conditioning predicted the individual threshold change. This counterintuitive performance deterioration occurred when using odors or sounds as aversive reinforcers and was not a result of attentional distraction or decision bias. In contrast, positive reinforcement or mere exposure induced the typically reported decrease in thresholds. Our findings indicate that aversive outcomes induce wider stimulus generalization by modulating perceptual thresholds, suggesting the engagement of low-level mechanisms. We suggest that for risk- or loss-related stimuli, less specificity could be a benefit, as it invokes the same mechanisms that respond quickly and efficiently in the face of danger. PMID- 21552276 TI - Behavior and neural basis of near-optimal visual search. AB - The ability to search efficiently for a target in a cluttered environment is one of the most remarkable functions of the nervous system. This task is difficult under natural circumstances, as the reliability of sensory information can vary greatly across space and time and is typically a priori unknown to the observer. In contrast, visual-search experiments commonly use stimuli of equal and known reliability. In a target detection task, we randomly assigned high or low reliability to each item on a trial-by-trial basis. An optimal observer would weight the observations by their trial-to-trial reliability and combine them using a specific nonlinear integration rule. We found that humans were near optimal, regardless of whether distractors were homogeneous or heterogeneous and whether reliability was manipulated through contrast or shape. We present a neural-network implementation of near-optimal visual search based on probabilistic population coding. The network matched human performance. PMID- 21552277 TI - A graphene-based broadband optical modulator. AB - Integrated optical modulators with high modulation speed, small footprint and large optical bandwidth are poised to be the enabling devices for on-chip optical interconnects. Semiconductor modulators have therefore been heavily researched over the past few years. However, the device footprint of silicon-based modulators is of the order of millimetres, owing to its weak electro-optical properties. Germanium and compound semiconductors, on the other hand, face the major challenge of integration with existing silicon electronics and photonics platforms. Integrating silicon modulators with high-quality-factor optical resonators increases the modulation strength, but these devices suffer from intrinsic narrow bandwidth and require sophisticated optical design; they also have stringent fabrication requirements and limited temperature tolerances. Finding a complementary metal-oxide-semiconductor (CMOS)-compatible material with adequate modulation speed and strength has therefore become a task of not only scientific interest, but also industrial importance. Here we experimentally demonstrate a broadband, high-speed, waveguide-integrated electroabsorption modulator based on monolayer graphene. By electrically tuning the Fermi level of the graphene sheet, we demonstrate modulation of the guided light at frequencies over 1 GHz, together with a broad operation spectrum that ranges from 1.35 to 1.6 um under ambient conditions. The high modulation efficiency of graphene results in an active device area of merely 25 um(2), which is among the smallest to date. This graphene-based optical modulation mechanism, with combined advantages of compact footprint, low operation voltage and ultrafast modulation speed across a broad range of wavelengths, can enable novel architectures for on-chip optical communications. PMID- 21552278 TI - Earliest evidence of mammalian social behaviour in the basal Tertiary of Bolivia. AB - The vast majority of Mesozoic and early Cenozoic metatherian mammals (extinct relatives of modern marsupials) are known only from partial jaws or isolated teeth, which give insight into their probable diets and phylogenetic relationships but little else. The few skulls known are generally crushed, incomplete or both, and associated postcranial material is extremely rare. Here we report the discovery of an exceptionally large number of almost undistorted, nearly complete skulls and skeletons of a stem-metatherian, Pucadelphys andinus, in the early Palaeocene epoch of Tiupampa in Bolivia. These give an unprecedented glimpse into early metatherian morphology, evolutionary relationships and, especially, ecology. The remains of 35 individuals have been collected, with 22 of these represented by nearly complete skulls and associated postcrania. These individuals were probably buried in a single catastrophic event, and so almost certainly belong to the same population. The preservation of multiple adult, sub adult and juvenile individuals in close proximity (<1 m(2)) is indicative of gregarious social behaviour or at least a high degree of social tolerance and frequent interaction. Such behaviour is unknown in living didelphids, which are highly solitary and have been regarded, perhaps wrongly, as the most generalized living marsupials. The Tiupampan P. andinus population also exhibits strong sexual dimorphism, which, in combination with gregariousness, suggests strong male-male competition and polygyny. Our study shows that social interactions occurred in metatherians as early as the basal Palaeocene and that solitary behaviour may not be plesiomorphic for Metatheria as a whole. PMID- 21552279 TI - Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. AB - 5-hydroxymethylcytosine (5hmC) is a modified base present at low levels in diverse cell types in mammals. 5hmC is generated by the TET family of Fe(II) and 2-oxoglutarate-dependent enzymes through oxidation of 5-methylcytosine (5mC). 5hmC and TET proteins have been implicated in stem cell biology and cancer, but information on the genome-wide distribution of 5hmC is limited. Here we describe two novel and specific approaches to profile the genomic localization of 5hmC. The first approach, termed GLIB (glucosylation, periodate oxidation, biotinylation) uses a combination of enzymatic and chemical steps to isolate DNA fragments containing as few as a single 5hmC. The second approach involves conversion of 5hmC to cytosine 5-methylenesulphonate (CMS) by treatment of genomic DNA with sodium bisulphite, followed by immunoprecipitation of CMS containing DNA with a specific antiserum to CMS. High-throughput sequencing of 5hmC-containing DNA from mouse embryonic stem (ES) cells showed strong enrichment within exons and near transcriptional start sites. 5hmC was especially enriched at the start sites of genes whose promoters bear dual histone 3 lysine 27 trimethylation (H3K27me3) and histone 3 lysine 4 trimethylation (H3K4me3) marks. Our results indicate that 5hmC has a probable role in transcriptional regulation, and suggest a model in which 5hmC contributes to the 'poised' chromatin signature found at developmentally-regulated genes in ES cells. PMID- 21552280 TI - Glutamate induces de novo growth of functional spines in developing cortex. AB - Mature cortical pyramidal neurons receive excitatory inputs onto small protrusions emanating from their dendrites called spines. Spines undergo activity dependent remodelling, stabilization and pruning during development, and similar structural changes can be triggered by learning and changes in sensory experiences. However, the biochemical triggers and mechanisms of de novo spine formation in the developing brain and the functional significance of new spines to neuronal connectivity are largely unknown. Here we develop an approach to induce and monitor de novo spine formation in real time using combined two-photon laser-scanning microscopy and two-photon laser uncaging of glutamate. Our data demonstrate that, in mouse cortical layer 2/3 pyramidal neurons, glutamate is sufficient to trigger de novo spine growth from the dendrite shaft in a location specific manner. We find that glutamate-induced spinogenesis requires opening of NMDARs (N-methyl-D-aspartate-type glutamate receptors) and activation of protein kinase A (PKA) but is independent of calcium-calmodulin-dependent kinase II (CaMKII) and tyrosine kinase receptor B (TrkB) receptors. Furthermore, newly formed spines express glutamate receptors and are rapidly functional such that they transduce presynaptic activity into postsynaptic signals. Together, our data demonstrate that early neural connectivity is shaped by activity in a spatially precise manner and that nascent dendrite spines are rapidly functionally incorporated into cortical circuits. PMID- 21552282 TI - Retraction: Safety and efficacy of sildenafil citrate in the treatment of Parkinson-emergent erectile dysfunction: a double-blind, Placebo-controlled, randomized study. PMID- 21552281 TI - Non-apoptotic role of BID in inflammation and innate immunity. AB - Innate immunity is a fundamental defence response that depends on evolutionarily conserved pattern recognition receptors for sensing infections or danger signals. Nucleotide-binding and oligomerization domain (NOD) proteins are cytosolic pattern-recognition receptors of paramount importance in the intestine, and their dysregulation is associated with inflammatory bowel disease. They sense peptidoglycans from commensal microorganisms and pathogens and coordinate signalling events that culminate in the induction of inflammation and anti microbial responses. However, the signalling mechanisms involved in this process are not fully understood. Here, using genome-wide RNA interference, we identify candidate genes that modulate the NOD1 inflammatory response in intestinal epithelial cells. Our results reveal a significant crosstalk between innate immunity and apoptosis and identify BID, a BCL2 family protein, as a critical component of the inflammatory response. Colonocytes depleted of BID or macrophages from Bid(-/-) mice are markedly defective in cytokine production in response to NOD activation. Furthermore, Bid(-/-) mice are unresponsive to local or systemic exposure to NOD agonists or their protective effect in experimental colitis. Mechanistically, BID interacts with NOD1, NOD2 and the IkappaB kinase (IKK) complex, impacting NF-kappaB and extracellular signal-regulated kinase (ERK) signalling. Our results define a novel role of BID in inflammation and immunity independent of its apoptotic function, furthering the mounting evidence of evolutionary conservation between the mechanisms of apoptosis and immunity. PMID- 21552284 TI - Prostate cancer: an emerging threat to the health of aging men in Asia. AB - The aim of this study was to determine and examine the possible reasons for the difference in prostate cancer incidence between Asian men and North American men by literature review. Data regarding cancer incidence and mortality were obtained from the database of the International Agency for Research on Cancer (IARC). A literature review was conducted by studying related articles published in peer reviewed journals such as the The New England Journal of Medicine, Journal of Clinical Oncology, A Cancer Journal for Clinicians and Asian Journal of Andrology. To evaluate the early diagnosis and survival rates, the mortality-to incidence rate ratio (MR/IR) was calculated from the IARC data. By comparing prostate cancer data between Asian men and North American men, we found that differences in the incidence rate and MR/IR could be attributed largely to a lack of annual prostate cancer screening with serum prostate-specific antigen (PSA) in most Asian countries. It is likely that PSA screening also contributes significantly to the differences in prostate cancer mortality rates. Prostate cancer has the highest incidence rate among five common malignancies in Asian Americans. However, the MR/IR ratio of prostate cancer is the lowest among cancers. These data seem to further support the usefulness of PSA screening, even though the percentage of low risk cancers is greater in prostate cancer than in other cancers. The low incidence rate of prostate cancer does not reflect the actual statistics of this disease in Asia. The data from limited institutions in many Asian countries seem to bias the true incidence and mortality rates. To improve this situation, incorporating PSA screening for prostate cancer, as well as constructing a nationwide cancer registration system, will be helpful. PMID- 21552285 TI - An essential role for TAK1 in the contact hypersensitivity response. AB - Contact hypersensitivity (CHS) is a delayed-type hypersensitivity that can be induced by haptens, such as 2,4-dinitrofluorobenzene (DNFB). Innate and adaptive immunities are both important for the development of CHS. To treat CHS-related diseases, such as allergic contact dermatitis, a disease prevalent in industrialized countries, ways of interfering with improper immune function during CHS responses need to be identified. Transforming growth factor-beta activated kinase-1 (TAK1), a member of mitogen-activated protein kinase kinase kinase family, is important for both innate and adaptive immunities. We thus hypothesized that the CHS response could be inhibited by interfering with TAK1 activity. Using a mouse model in which TAK1 deletion can be locally induced, we observed that TAK deficiency led to an impaired CHS response and was associated with defective T-cell expansion, activation and interferon (IFN)-gamma production. In addition, we investigated the effect of deleting TAK1 specifically in dendritic cells (DC) on the CHS response. We found that when TAK1 is deficient in DC, the CHS response was abolished and hapten-elicited T-cell responses were defective. Collectively, this study demonstrates an essential role of TAK1 in the induction of CHS and suggests that targeting TAK1 could be a viable approach to treat CHS. PMID- 21552287 TI - Bacterial physiology: Motor helps gliders to gain traction. PMID- 21552286 TI - Evolution and classification of the CRISPR-Cas systems. AB - The CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR associated proteins) modules are adaptive immunity systems that are present in many archaea and bacteria. These defence systems are encoded by operons that have an extraordinarily diverse architecture and a high rate of evolution for both the cas genes and the unique spacer content. Here, we provide an updated analysis of the evolutionary relationships between CRISPR-Cas systems and Cas proteins. Three major types of CRISPR-Cas system are delineated, with a further division into several subtypes and a few chimeric variants. Given the complexity of the genomic architectures and the extremely dynamic evolution of the CRISPR-Cas systems, a unified classification of these systems should be based on multiple criteria. Accordingly, we propose a 'polythetic' classification that integrates the phylogenies of the most common cas genes, the sequence and organization of the CRISPR repeats and the architecture of the CRISPR-cas loci. PMID- 21552288 TI - miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo. AB - Cancer cell resistance to paclitaxel continues to be a major clinical problem. In this study, we utilized microRNA (miRNA) arrays to screen for differentially expressed miRNAs in paclitaxel-resistant cell lines established in vitro. We observed concordant upregulation of miR-135a in paclitaxel-resistant cell lines representing three human malignancies. Subsequently, the role of miRNA-135a was evaluated in an in vivo model of paclitaxel resistance. In this model, mice were inoculated subcutaneously with a non-small cell lung carcinoma cell line and treated with paclitaxel for a prolonged period. In paclitaxel-resistant cell lines, established either in vitro or in vivo, blockage of miR-135a sensitized resistant cell lines to paclitaxel-induced cell death. We further demonstrated a correlation between paclitaxel response and miR-135a expression in paclitaxel resistant subclones that were established in vivo. The paclitaxel-resistant phenotype of these subclones was maintained upon retransplantation in new mice, as shown by decreased tumor response upon paclitaxel treatment compared with controls. Upregulation of miR-135a was associated with reduced expression of the adenomatous polyposis coli gene (APC). APC knockdown increased paclitaxel resistance in parental cell lines. Our results indicate that paclitaxel resistance is associated with upregulation of miR-135a, both in vitro and in vivo, and is in part determined by miR-135a-mediated downregulation of APC. PMID- 21552289 TI - Shared acquired genomic changes in zebrafish and human T-ALL. AB - T-cell acute lymphoblastic leukemia (T-ALL) is a challenging clinical entity with high rates of induction failure and relapse. To discover the genetic changes occurring in T-ALL, and those contributing to relapse, we studied zebrafish (Danio rerio) T-ALL samples using array comparative genomic hybridization (aCGH). We performed aCGH on 17 T-ALLs from four zebrafish T-ALL models, and evaluated similarities between fish and humans by comparing all D. rerio genes with copy number aberrations (CNAs) with a cohort of 75 published human T-ALLs analyzed by aCGH. Within all D. rerio CNAs, we identified 893 genes with human homologues and found significant overlap (67%) with the human CNA dataset. In addition, when we restricted our analysis to primary T-ALLs (14 zebrafish and 61 human samples), 10 genes were recurrently altered in > 3 zebrafish cancers and >= 4 human cases, suggesting a conserved role for these loci in T-ALL transformation across species. We also conducted iterative allo-transplantation with three zebrafish malignancies. This technique selects for aggressive disease, resulting in shorter survival times in successive transplant rounds and modeling refractory and relapsed human T-ALL. Fifty-five percent of original CNAs were preserved after serial transplantation, demonstrating clonality between each primary and passaged leukemia. Cancers acquired an average of 34 new CNAs during passaging. Genes in these loci may underlie the enhanced malignant behavior of these neoplasias. We also compared genes from CNAs of passaged zebrafish malignancies with aCGH results from 50 human T-ALL patients who failed induction, relapsed or would eventually relapse. Again, many genes (88/164) were shared by both datasets. Further, nine recurrently altered genes in passaged D. rerio T-ALL were also found in multiple human T-ALL cases. These results suggest that zebrafish and human T-ALLs are similar at the genomic level, and are governed by factors that have persisted throughout evolution. PMID- 21552291 TI - p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1. AB - A variety of cellular insults activate the tumour suppressor p53, leading generally to cell-cycle arrest or apoptosis. However, it is not inconceivable that cellular protective mechanisms may be required to keep cells alive while cell-fate decisions are made. In this respect, p53 has been suggested to perform functions that allow cells to survive, by halting of the cell-cycle, and thus preventing immediate cell death. Nonetheless, the existence of direct pro survival p53 target genes regulating cellular survival is lacking. We show here evidence for p53-dependent cellular survival in a context-dependent manner. Both mouse and human cells lacking p53 are hypersensitive to hydrogen peroxide (H(2)O(2))-induced cell death compared with their isogenic wild-type counterparts. By contrast, p53(-/-) cells are expectedly resistant to cell death upon exposure to DNA-damaging agents such as cisplatin (CDDP) and etoposide. Although p53 and its classical targets such as p21 and Mdm2 are activated by both H(2)O(2) and CDDP, we found that the expression of haeme-oxygenase-1 (HO-1)-an antioxidant and antiapoptotic protein-was directly induced only upon H(2)O(2) treatment in a p53-dependent manner. Consistently, p53, but not its homologue p73, activated HO-1 expression and was bound to the HO-1 promoter specifically only upon H(2)O(2) treatment. Moreover, silencing HO-1 expression enhanced cell death upon H(2)O(2) treatment only in p53-proficient cells. Finally, H(2)O(2) mediated cell death was rescued significantly in p53-deficient cells by antioxidant treatment, as well as by bilirubin, a by-product of HO-1 metabolism. Taken together, these data demonstrate a direct role for p53 in promoting cellular survival in a context-specific manner through the activation of a direct transcriptional target, HO-1. PMID- 21552290 TI - Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours. AB - Individuals with germline mutations in the tumour-suppressor gene CYLD are at high risk of developing disfiguring cutaneous appendageal tumours, the defining tumour being the highly organised cylindroma. Here, we analysed CYLD mutant tumour genomes by array comparative genomic hybridisation and gene expression microarray analysis. CYLD mutant tumours were characterised by an absence of copy number aberrations apart from LOH chromosome 16q, the genomic location of the CYLD gene. Gene expression profiling of CYLD mutant tumours showed dysregulated tropomyosin kinase (TRK) signalling, with overexpression of TRKB and TRKC in tumours when compared with perilesional skin. Immunohistochemical analysis of a tumour microarray showed strong membranous TRKB and TRKC staining in cylindromas, as well as elevated levels of ERK phosphorylation and BCL2 expression. Membranous TRKC overexpression was also observed in 70% of sporadic BCCs. RNA interference mediated silencing of TRKB and TRKC, as well as treatment with the small-molecule TRK inhibitor lestaurtinib, reduced colony formation and proliferation in 3D primary cell cultures established from CYLD mutant tumours. These results suggest that TRK inhibition could be used as a strategy to treat tumours with loss of functional CYLD. PMID- 21552292 TI - Metformin attenuates pressure overload-induced cardiac hypertrophy via AMPK activation. AB - AIM: To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect. METHODS: Wild type and AMPKalpha2 knockout (AMPKalpha2-/-) littermates were subjected to left ventricular pressure overload caused by transverse aortic constriction. After administration of metformin (200 mg.kg-1.d-1) for 6 weeks, the degree of cardiac hypertrophy was evaluated using echocardiography and anatomic and histological methods. The antihypertrophic mechanism of metformin was analyzed using Western blotting. RESULTS: Metformin significantly attenuated cardiac hypertrophy induced by pressure overload in wild type mice, but the antihypertrophic actions of metformin were ablated in AMPKalpha2-/- mice. Furthermore, metformin suppressed the phosphorylation of Akt/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in response to pressure overload in wild type mice, but not in AMPKalpha2-/- mice. CONCLUSION: Long-term administration of metformin may attenuate cardiac hypertrophy induced by pressure overload in nondiabetic mice, and this attenuation is highly dependent on AMPK activation. These findings may provide a potential therapy for patients at risk of developing pathological cardiac hypertrophy. PMID- 21552293 TI - TRPM7 in cerebral ischemia and potential target for drug development in stroke. AB - Searching for effective pharmacological agents for stroke treatment has largely been unsuccessful. Despite initial excitement, antagonists for glutamate receptors, the most studied receptor channels in ischemic stroke, have shown insufficient neuroprotective effects in clinical trials. Outside the traditional glutamate-mediated excitotoxicity, recent evidence suggests few non-glutamate mechanisms, which may also cause ionic imbalance and cell death in cerebral ischemia. Transient receptor potential melastatin 7 (TRPM7) is a Ca(2+) permeable, non-selective cation channel that has recently gained attention as a potential cation influx pathway involved in ischemic events. Compelling new evidence from an in vivo study demonstrated that suppression of TRPM7 channels in adult rat brain in vivo using virally mediated gene silencing approach reduced delayed neuronal cell death and preserved neuronal functions in global cerebral ischemia. In this review, we will discuss the current understanding of the role of TRPM7 channels in physiology and pathophysiology as well as its therapeutic potential in stroke. PMID- 21552294 TI - Aquaporins in sperm osmoadaptation: an emerging role for volume regulation. AB - Upon ejaculation, mammalian sperm experience a natural osmotic decrease during male to female reproductive tract transition. This hypo-osmotic exposure not only activates sperm motility, but also poses potential harm to sperm structure and function by inducing unwanted cell swelling. In this physiological context, regulatory volume decrease (RVD) is the major mechanism that protects cells from detrimental swelling, and is essential to sperm survival and normal function. Aquaporins are selective water channels that enable rapid water transport across cell membranes. Aquaporins have been implicated in sperm osmoregulation. Recent discoveries show that Aquaporin-3 (AQP3), a water channel protein, is localized in sperm tail membranes and that AQP3 mutant sperm show defects in volume regulation and excessive cell swelling upon physiological hypotonic stress in the female reproductive tract, thereby highlighting the importance of AQP3 in the postcopulatory sperm RVD process. In this paper, we discuss current knowledge, remaining questions and hypotheses about the function and mechanismic basis of aquaporins for volume regulation in sperm and other cell types. PMID- 21552295 TI - Calcium-permeable ion channels involved in glutamate receptor-independent ischemic brain injury. AB - Brain ischemia is a leading cause of death and long-term disabilities worldwide. Unfortunately, current treatment is limited to thrombolysis, which has limited success and a potential side effect of intracerebral hemorrhage. Searching for new cell injury mechanisms and therapeutic interventions has become a major challenge in the field. It has been recognized for many years that intracellular Ca(2+) overload in neurons is essential for neuronal injury associated with brain ischemia. However, the exact pathway(s) underlying the toxic Ca(2+) loading remained elusive. This review discusses the role of two Ca(2+)-permeable cation channels, TRPM7 and acid-sensing channels, in glutamate-independent Ca(2+) toxicity associated with brain ischemia. PMID- 21552297 TI - Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. AB - Alpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1-23) years and underwent HSCT at a median of 3.6 (1.3-23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1-12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients' developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha mannosidosis. PMID- 21552296 TI - Aquaporin-4: orthogonal array assembly, CNS functions, and role in neuromyelitis optica. AB - Aquaporin-4 (AQP4) is a water-selective transporter expressed in astrocytes throughout the central nervous system, as well as in kidney, lung, stomach and skeletal muscle. The two AQP4 isoforms produced by alternative spicing, M1 and M23 AQP4, form heterotetramers that assemble in cell plasma membranes in supramolecular structures called orthogonal arrays of particles (OAPs). Phenotype analysis of AQP4-null mice indicates the involvement of AQP4 in brain and spinal cord water balance, astrocyte migration, neural signal transduction and neuroinflammation. AQP4-null mice manifest reduced brain swelling in cytotoxic cerebral edema, but increased brain swelling in vasogenic edema and hydrocephalus. AQP4 deficiency also increases seizure duration, impairs glial scarring, and reduces the severity of autoimmune neuroinflammation. Each of these phenotypes is likely explicable on the basis of reduced astrocyte water permeability in AQP4 deficiency. AQP4 is also involved in the neuroinflammatory demyelinating disease neuromyelitis optica (NMO), where autoantibodies (NMO-IgG) targeting AQP4 produce astrocyte damage and inflammation. Mice administered NMO IgG and human complement by intracerebral injection develop characteristic NMO lesions with neuroinflammation, demyelination, perivascular complement deposition and loss of glial fibrillary acidic protein and AQP4 immunoreactivity. Our findings suggest the potential utility of AQP4-based therapeutics, including small-molecule modulators of AQP4 water transport function for therapy of brain swelling, injury and epilepsy, as well as small-molecule or monoclonal antibody blockers of NMO-IgG binding to AQP4 for therapy of NMO. PMID- 21552298 TI - The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries. AB - Between 1982 and 2009 a total of 92 patients with myelofibrosis (MF) in chronic phase underwent allo-SCT in nine Nordic transplant centers. Myeloablative conditioning (MAC) was given to 40 patients, and reduced intensity conditioning (RIC) was used in 52 patients. The mean age in the two groups at transplantation was 46+/-12 and 55+/-8 years, respectively (P<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (P=0.003). Among the RIC patients, the survival was significantly (P=0.003) better for the patients with age <60 years (a 10-year survival close to 80%) than for the older patients. The type of stem cell donor did not significantly affect the survival. No significant difference was found in TRM at 100 days between the MAC- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MAC-treated patients and 59% in the RIC group (P=0.125). Patients treated with RIC experienced significantly less aGVHD compared with patients treated with MAC (P<0.001). The OS at 5 years was 70, 59 and 41% for patients with Lille score 0, 1 and 2, respectively (P=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MAC-treated patients (P<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups. Our conclusions are (1) allo-SCT performed with RIC gives a better survival compared with MAC. (2) age over 60 years is strongly related to a worse outcome and (3) patients with higher Lille score had a shorter survival. PMID- 21552299 TI - Recombinant human soluble thrombomodulin for the treatment of hepatic sinusoidal obstructive syndrome post allogeneic hematopoietic SCT. PMID- 21552300 TI - Mesenchymal stromal cells: a novel and effective strategy for facilitating engraftment and accelerating hematopoietic recovery after transplantation? AB - MSCs are multipotent cells that can be isolated from several human tissues and expanded ex vivo for clinical use. They comprise a heterogeneous population of cells, which, through production of growth factors, cell-to-cell interactions and secretion of matrix proteins, has a role in the regulation of hematopoiesis. In recent years, several experimental studies have shown that MSCs are endowed with immunomodulatory properties and with the capacity to promote graft survival in animal models. In view of these properties, MSCs have been tested in pilot studies aimed at preventing/treating graft rejection and at accelerating recovery after hematopoietic cell transplantation (HCT). The available clinical evidence deriving from these studies indicates that MSC infusion is safe and promising in terms of capacity of preventing graft failure. More debated is the effect of MSCs for what concerns their capacity of accelerating hematopoietic reconstitution after HCT. Whether the favorable effect of MSCs largely depends on the type of transplantation remains also a field of future investigation. Moreover, future researches should be oriented to gain more insights on MSC biological and functional mechanisms relevant for exploiting their use in the modulation of alloreactivity and in the promotion of hematopoietic reconstitution. PMID- 21552301 TI - Salivary secretion in children after fractionated or single-dose TBI. AB - The incidence of long-term oral complications after hematopoietic SCT (HSCT) varies between 60 and 100%. The aim of this study was to compare the salivary secretion rate and the contribution of known risk factors for a low salivary secretion rate 1 year after HSCT in children conditioned with fractionated TBI (fTBI) and in children conditioned with single-dose TBI (sTBI). The study involved 44 patients, 27 conditioned with sTBI and 17 conditioned with fTBI. The unstimulated and stimulated salivary secretion rates (USSRs and SSSRs) were estimated before HSCT and at 1-year follow-up. Risk factors that may have influenced the salivary secretion rate were recorded. An SSSR of <=0.5 mL/min and a USSR of <=0.1 mL/min were chosen as cut-off points for salivary dysfunction. The median reduction in stimulated salivary flow 1 year after HSCT was 56% in the sTBI group and 12% in the fTBI group (P=0.003). The median reduction in unstimulated salivary flow 1 year after HSCT was 74% in the sTBI group and 33% in the fTBI group (P=0.003). In the multivariate model, a significant correlation between both sTBI (odds ratio (OR)=6.49, 95% confidence interval (CI)=1.40-30, P=0.014) and seropositivity of the recipient for 3-4 herpesviruses (OR=6.57, 95% CI=1.26-34, P=0.021) and a low stimulated salivary secretion rate (<0.5 mL/min) was found 1 year after HSCT. PMID- 21552303 TI - Single-agent high-dose melphalan followed by auto-SCT for relapsed and refractory Hodgkin lymphoma in children and adolescents. AB - Hodgkin lymphoma (HL) is cured in the majority of children and adolescents. However, there remains a group of patients with primary refractory or relapsed disease for whom cure is more difficult to achieve. Most of these patients receive high-dose chemotherapy followed by auto-SCT, with expected cure rates ranging from 40 to 60%. Conditioning regimens often consist of multiple non-cross resistant agents, with well-described risks of morbidity and mortality. The use of single-agent high-dose melphalan (HDM) as conditioning, before autologous rescue, has been described in adult patients at our center, with comparable efficacy and less morbidity. We present a series of eight pediatric patients conditioned with single-agent HDM before autologous stem cell rescue for relapsed and primary refractory HL. All patients engrafted with a median of 12 days to neutrophil engraftment. Two patients subsequently relapsed. Seven patients are currently alive, and seven of eight patients have no evidence of disease (one in CR3). Toxicities included grade 4 hematologic in 8/8, grade 3 mucositis in 3/8, grade 3 infectious in 2/8 and grade 4 infectious in 1/8. Our analysis suggests that this regimen is feasible in pediatric patients with acceptable engraftment and toxicity. PMID- 21552302 TI - Sirolimus and mycophenolate mofetil as GVHD prophylaxis in myeloablative, matched related donor hematopoietic cell transplantation. AB - We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD. PMID- 21552304 TI - Rituximab treatment may disturb the normal pattern of lymphopoiesis after cord blood SCT. PMID- 21552305 TI - CT60 single-nucleotide polymorphism as a surrogate marker for donor lymphocyte infusion outcome after allogeneic cell transplantation for acute leukemia. AB - The benefit of survival at the expense of new GVHD after DLI for acute leukemia following human allogeneic hematopoietic cell transplantation (allo-HCT) remains a matter of controversy. The detection of biological markers predicting this outcome would be an enormous breakthrough. The purpose of this study was the analysis of CT60 single-nucleotide polymorphism (SNP) of the CTLA-4 T-regulatory gene as a surrogate marker for DLI outcome in this difficult setting. Using Pyrosequencing, we genotyped the alleles of the CT60 SNP of 79 DLI donors and correlated them with the post-DLI outcome of their matching recipients. The presence of a donor 'AA' or 'AG' CT60 genotype vs a 'GG' genotype was an independent factor for remaining in complete chimerism/remission post-DLI (odds ratio (OR) 2.61 vs 0.42, respectively, P=0.05). Further, in cases with evident post-DLI allo-reactivity the importance of an 'AA' or 'AG' vs a 'GG' genotype gained significance for ongoing complete chimerism (OR 4.35 vs 0.32, P=0.03). Neither alterations in cumulative DLI dose nor any other clinical parameter significantly weakened the importance of CT60 SNP. Our results provide evidence for the necessity of genotyping CT60 SNP prior to DLI administration in patients with acute leukemia. PMID- 21552306 TI - Genetic and epigenetic association studies suggest a role of microRNA biogenesis gene exportin-5 (XPO5) in breast tumorigenesis. AB - Given strong evidence implicating an important role of altered microRNA expression in cancer initiation and progression, the genes responsible for microRNA biogenesis may also play a role in tumorigenesis. Exportin-5 (XPO5) is responsible for exporting pre-miRNAs through the nuclear membrane to the cytoplasm, and is thus critical in miRNA biogenesis. In the current study, we performed both genetic and epigenetic association studies of XPO5 in a case control study of breast cancer. We first genotyped two missense SNPs in XPO5, rs34324334 (S241N) and rs11544382 (M1115T), and further analyzed methylation levels in the XPO5 promoter region for blood DNA samples from a breast cancer case-control study. We found the variant genotypes of rs11544382 to be associated with breast cancer risk (OR=1.59, 95% CI: 1.06 -2.39), compared to the homozygous common genotype. When stratified by menopausal status, the variant alleles of both rs11544382 (OR=1.82, 95% CI: 1.09-3.03) and rs34324334 (OR=1.76, 95% CI: 1.10-2.83) were significantly associated with breast cancer risk in post menopausal women. The methylation analysis showed that the "high" and combined "high/middle" tertiles of methylation index were associated with reduced risk of breast cancer (OR=0.34, 95% CI:0.15-0.81 and OR=0.47, 95% CI:0.24-0.94, respectively; P(trend)=0.015). These results were corroborated by data from a publicly available tissue array, which showed lower levels of XPO5 expression in healthy controls relative to tumor or adjacent tissues from breast cancer patients with tumor tissue exhibiting the highest expression levels. These findings support the hypothesis that variations in components of the miRNA biogenesis pathway, in this case XPO5, may affect an individual's risk of developing breast cancer. PMID- 21552307 TI - An effective model of institutional taxation: lunatic asylums in nineteenth century England. AB - The compulsory establishment of large public lunatic asylums under Act of parliament in the nineteenth century to address the enormous increase in the number of the insane raised legal and practical challenges in relation to their status within the law of tax. As a result of their therapeutic and custodial objectives, these novel institutions required extensive landed property and very specific systems of governance, the fiscal consequences of which potentially undermined those very objectives. This article examines and analyses the nature and legal process of the application of the tax regime to these asylums, concluding that it constituted a rare and effective model of institutional taxation. PMID- 21552308 TI - How do albino fish hear? AB - Pigmentation disorders such as albinism are occasionally associated with hearing impairments in mammals. Therefore, we wanted to investigate whether such a phenomenon also exists in non-mammalian vertebrates. We measured the hearing abilities of normally pigmented and albinotic specimens of two catfish species, the European wels Silurus glanis (Siluridae) and the South American bronze catfish Corydoras aeneus (Callichthyidae). The non-invasive auditory evoked potential (AEP) recording technique was utilized to determine hearing thresholds at 10 frequencies from 0.05 to 5 kHz. Neither auditory sensitivity nor shape of AEP waveforms differed between normally pigmented and albinotic specimens at any frequency tested in both species. Silurus glanis and C. aeneus showed the best hearing between 0.3 and 1 kHz; the lowest thresholds were 78.4 dB at 0.5 kHz in S. glanis (pigmented), 75 dB at 1 kHz in S. glanis (albinotic), 77.6 dB at 0.5 kHz in C. aeneus (pigmented) and 76.9 dB at 1 kHz in C. aeneus (albinotic). This study indicates no association between albinism and hearing ability. Perhaps because of the lack of melanin in the fish inner ear, hearing in fishes is less likely to be affected by albinism than in mammals. PMID- 21552309 TI - Double-blind comparison of ziprasidone and risperidone in the treatment of Chinese patients with acute exacerbation of schizophrenia. AB - BACKGROUND: The aim of the study was to evaluate the efficacy and safety of ziprasidone versus risperidone in Chinese subjects with acute exacerbation of schizophrenia. METHODS: In patients meeting the Chinese Classification of Mental Disorders criteria for schizophrenia and with a Positive and Negative Syndrome Scale (PANSS) total score >=60 were randomly assigned to six weeks of double blind treatment with ziprasidone 40-80 mg twice daily or risperidone 1-3 mg bid, flexibly dosed. Noninferiority was demonstrated if the upper limit of the two sided 95% confidence interval (CI) for the difference in PANSS total score improvement from baseline in the evaluable population was smaller than the prespecified noninferiority margin of 10 units. RESULTS: The intent-to-treat population comprised 118 ziprasidone-treated and 121 risperidone-treated subjects. Improvement (reduction) from baseline to week 6 in PANSS total score was (-35.6 [95% CI: -38.6, -32.6]) for ziprasidone and (-37.1 [95% CI: -39.9, 34.4]) for risperidone. Noninferiority was demonstrated in the evaluable population with a difference score of 1.5 [95% CI: -2.5, 5.5]. Mean prolactin levels decreased at week 6 compared with baseline for ziprasidone (-3.5 ng/mL), but significantly increased for risperidone (61.1 ng/mL; P < 0.001). More risperidone-treated subjects (14.9%) than ziprasidone-treated subjects (4.2%) reported weight gain >=7%. Akathisia and somnolence in the ziprasidone group and akathisia and insomnia in the risperidone group were the most common side effects. Treatment-related/treatment-emergent adverse events were reported by 79.7% and 71.1% of ziprasidone-treated and risperidone-treated subjects, respectively. CONCLUSION: In Chinese subjects, ziprasidone was as effective as risperidone, with less weight gain and less prolactin elevation. PMID- 21552310 TI - The role of ziprasidone in adjunctive use with lithium or valproate in maintenance treatment of bipolar disorder. AB - OBJECTIVES: This article addresses the clinical role for ziprasidone used adjunctively with a mood stabilizer in maintenance treatment of bipolar disorder. This review also addresses the strengths and limitations of design features in adjunctive studies of second-generation antipsychotic drugs added to mood stabilizers. METHODS: The principal study relevant to this review enrolled subjects who were >=18 years of age, experiencing a recent or current manic or mixed bipolar I episode, with at least moderately severe current manic symptoms. To meet criteria for randomization to 6 months maintenance treatment, patients had to have failed a short course of treatment with either lithium or valproate and achieved benefit with added ziprasidone for 8 consecutive weeks. RESULTS: Time to intervention for a new mood episode as well as time to discontinuation for any reason was significantly longer with adjunctive ziprasidone treatment than with monotherapy treatment with mood stabilizer. Three dosages of ziprasidone augmentation were studied. Patients treated with 120 mg/day had better efficacy and overall outcomes than did patients who received 80 or 160 mg/day of ziprasidone. CONCLUSIONS: Good evidence exists that adjunctive ziprasidone will likely provide greater overall efficacy coupled with good tolerability for at least a 6-month period than a strategy of continued monotherapy with a mood stabilizer. Changes in open phases of maintenance studies to reduce study enrichment, in study endpoints, and in statistical approaches to analysis of data are warranted. PMID- 21552312 TI - Do neurologists in Germany adhere to the national Parkinson's disease guideline? AB - Implementation of guidelines can improve clinical practice. The aim in this study was to investigate whether neurologists in Germany adhered to the national Parkinson's disease guideline. Data were obtained from a cross-sectional survey of 60 neurologists. Analyses were performed on 320 patients with idiopathic Parkinson's disease with either low grades of functional impairment (Hoehn and Yahr stage I) or higher grades of functional impairment (stage II-V) but without motor complications. The sample was divided into four groups depending on age and grade of functional impairment. For each group, a biometric parameter on the use of dopamine agonists and L-dopa was defined based on the guideline. In patients aged <70 years, the recommendation to use dopamine agonists without L-dopa (parameter 1) was observed in 53% of patients with lower grades of functional impairment, whilst recommended use of dopamine agonists in more functionally impaired patients (parameter 2) was followed to a greater extent (84%). In patients aged >=70 years, recommendations to use L-dopa without dopamine agonists were adhered to in only 50% of less functionally impaired (parameter 3) and 52% of more functionally impaired (parameter 4) patients. In conclusion, our results indicated there was moderate but not full adherence to the guideline. PMID- 21552311 TI - Number needed to treat and number needed to harm with paliperidone palmitate relative to long-acting haloperidol, bromperidol, and fluphenazine decanoate for treatment of patients with schizophrenia. AB - BACKGROUND: We analyzed data retrieved through a PubMed search of randomized, placebo-controlled trials of first-generation antipsychotic long-acting injectables (haloperidol decanoate, bromperidol decanoate, and fluphenazine decanoate), and a company database of paliperidone palmitate, to compare the benefit-risk ratio in patients with schizophrenia. METHODS: From the eight studies that met our selection criteria, two efficacy and six safety parameters were selected for calculation of number needed to treat (NNT), number needed to harm (NNH), and the likelihood of being helped or harmed (LHH) using comparisons of active drug relative to placebo. NNTs for prevention of relapse ranged from 2 to 5 for paliperidone palmitate, haloperidol decanoate, and fluphenazine decanoate, indicating a moderate to large effect size. RESULTS: Among the selected maintenance studies, NNH varied considerably, but indicated a lower likelihood of encountering extrapyramidal side effects, such as akathisia, tremor, and tardive dyskinesia, with paliperidone palmitate versus placebo than with first-generation antipsychotic depot agents versus placebo. This was further supported by an overall higher NNH for paliperidone palmitate versus placebo with respect to anticholinergic use and Abnormal Involuntary Movement Scale positive score. LHH for preventing relapse versus use of anticholinergics was 15 for paliperidone palmitate and 3 for fluphenazine decanoate, favoring paliperidone palmitate. CONCLUSION: Overall, paliperidone palmitate had a similar NNT and a more favorable NNH compared with the first-generation long-acting injectables assessed. PMID- 21552313 TI - Psychiatric disorders in primary focal dystonia and in Parkinson's disease. AB - BACKGROUND: Primary focal dystonia and Parkinson's disease are movement disorders that have contrasting motor phenotypes. The aim of this study was to compare the frequency and the severity of psychiatric disorders in primary focal dystonia and Parkinson's disease. METHODS: Two groups of 30 patients matched by gender and age underwent a neurological and psychiatric assessment. RESULTS: Parkinson's disease patients were diagnosed with higher rates of major depression (P = 0.02) and generalized anxiety disorder (P = 0.02), and greater severity of depressive symptoms (P = 0.04), while patients with primary focal dystonia exhibited increased severity of obsessive-compulsive symptoms (P = 0.02). DISCUSSION: The difference in pathophysiology of primary focal dystonia and Parkinson's disease may explain the different psychiatric profiles of these two diseases. The increased frequency of affective symptoms in Parkinson's disease may be related to the fact that Parkinson's disease is a neurodegenerative disease marked by the loss of monoaminergic neurons which does not happen in primary focal dystonia. CONCLUSION: The psychiatric profile differs in movement disorders with distinct neurobiological bases. PMID- 21552314 TI - Performance of Cpred/Cobs concentration ratios as a metric reflecting adherence to antidepressant drug therapy. AB - BACKGROUND: Nonadherence is very common among subjects undergoing pharmacotherapy for schizophrenia and depression. This study aimed to evaluate the performance of the ratio of the nonlinear mixed effects pharmacokinetic model predicted concentration to observed drug concentration (ratio of population predicted to observed concentration (Cpred/Cobs) and ratio of individual predicted to observed concentration (Cipred/Cobs) as a measure of erratic drug exposure, driven primarily by variable execution of the dosage regimen and unknown true dosage history. METHODS: Modeling and simulation approaches in conjunction with dosage history information from the Medication Event Monitoring System (MEMS, provided by the "Depression: The search for treatment relevant phenotypes" study), was applied to evaluate the consistency of exposure via simulation studies with scenarios representing a long half-life drug (escitalopram). Adherence rates were calculated based on the percentage of the prescribed doses actually taken correctly during the treatment window of interest. The association between Cpred/Cobs, Cipred/Cobs ratio, and adherence rate was evaluated under various assumptions of known dosing history. RESULTS: Simulations for those scenarios representing a known dosing history were generated from historical MEMS data. Simulations of a long half-life drug exhibited a trend for overprediction of concentrations in patients with a low percentage of doses taken and underprediction of concentrations in patients taking more than their prescribed number of doses. Overall, the ratios did not predict adherence well, except when the true adherence rates were extremely high (greater than 100% of prescribed doses) or extremely low (complete nonadherence). In general, the Cipred/Cobs ratio was a better predictor of adherence rate than the Cpred/Cobs ratio. Correct predictions of extreme (high, low) 7-day adherence rates using Cipred/Cobs were 73.8% and 64.0%. CONCLUSION: This simulation study demonstrated the limitations of the Cpred/obs and Cipred/obs ratios as metrics for actual dosage intake history, and identified that use of MEMS dosing history monitoring combined with sparse pharmacokinetic sampling is a more reliable approach. PMID- 21552315 TI - Management of traumatic events: influence of emotion-centered coping strategies on the occurrence of dissociation and post-traumatic stress disorder. AB - Our aim was to assess the influence of the coping strategies employed for the management of traumatic events on the occurrence of dissociation and traumatic disorders. We carried out a 1-year retrospective study of the cognitive management of a traumatic event in 18 subjects involved in the same road vehicle accident. The diagnosis of post-traumatic stress disorder (PTSD) was made for 33.3% of the participants. The participants with a PTSD diagnosis 1 year after the event used emotion-centered strategies during the event more often than did those with no PTSD, P < 0.02. In the year after the traumatic event, our results show a strong link between the intensity of PTSD and the severity of the post traumatic symptoms like dissociation (P = 0.032) and the use of emotion-centered strategies (P = 0.004). Moreover, the participants who presented Peritraumatic Dissociative Experiences Questionnaire scores above 15 made greater use of emotion-centered coping strategies than did those who did not show dissociation, P < 0.04. Our results confirm that the cognitive management of traumatic events may play an essential role in the development of a state of post-traumatic stress in the aftermath of a violent event. PMID- 21552316 TI - Pharmacotherapy for treatment-resistant schizophrenia. AB - Schizophrenia is a disabling mental illness with a lifetime prevalence of 0.7% worldwide and significant, often devastating, consequences on social and occupational functioning. A range of antipsychotic medications are available; however, suboptimal therapeutic response in terms of psychotic symptoms is common and affects up to one-third of people with schizophrenia. Negative symptoms are generally less amenable to treatment. Because of the consequences of inadequate symptom control, effective treatment strategies are required for people with treatment-resistant schizophrenia. Clozapine has been shown to be more effective than other antipsychotics in treatment-resistant populations in several studies; however, the occurrence of adverse effects, some of which are potentially life threatening, are important limitations. In addition to those who are intolerant to clozapine, only 30% to 50% experience clinically significant symptom improvement. This review describes the recent evidence for treatment strategies for people not responding to nonclozapine antipsychotic agents and people not responding or only partially responding to clozapine. PMID- 21552317 TI - Current and emerging therapies for the treatment of myasthenia gravis. AB - Myasthenia gravis (MG) is an autoimmmune disease in which autoantibodies to different antigens of the neuromuscular junction cause the typical weakness and fatigability. Treatment includes anticholinesterase drugs, immunosuppression, immunomodulation, and thymectomy. The autoimmune response is maintained under control by corticosteroids frequently associated with immunosuppressive drugs, with improvement in the majority of patients. In case of acute exacerbations with bulbar symptoms or repeated relapses, modulation of autoantibody activity by plasmapheresis or intravenous immunoglobulins provides rapid improvement. Recently, techniques removing only circulating immunoglobulins have been developed for the chronic management of treatment-resistant patients. The rationale for thymectomy relies on the central role of the thymus. Despite the lack of controlled studies, thymectomy is recommended as an option to improve the clinical outcome or promote complete remission. New videothoracoscopic techniques have been developed to offer the maximal surgical approach with the minimal invasiveness and hence patient tolerability. The use of biological drugs such as anti-CD20 antibodies is still limited but promising. Studies performed in the animal model of MG demonstrated that several more selective or antigen-specific approaches, ranging from mucosal tolerization to inhibition of complement activity or cellular therapy, might be feasible. Investigation of the transfer of these therapeutic approaches to the human disease will be the challenge for the future. PMID- 21552318 TI - Status epilepticus in the elderly: differential diagnosis and treatment. AB - Seizures are not an uncommon occurrence in older adults, and the incidence of status epilepticus is much greater in the elderly than in younger populations. Status epilepticus is a neurologic emergency and requires prompt intervention to minimize morbidity and mortality. Treatment involves both supportive care as well as initiation of medications to stop all clinical and electrographic seizure activity. Benzodiazepines are used as first-line agents, followed by antiepileptic drugs when seizures persist. In refractory status epilepticus, urgent neurologic consultation is indicated for the titration of anesthetic agents to a level of appropriate background suppression on EEG. In light of our aging population, physician awareness and competence in the management of status epilepticus is imperative and should be recognized as a growing public health concern. PMID- 21552320 TI - Population-based study of acquired cerebellar ataxia in Al-Kharga district, New Valley, Egypt. AB - BACKGROUND: The aim of this research was to determine the prevalence and etiology of acquired ataxia in Al-Kharga district, New Valley, Egypt. METHODS: A population-based study of acquired ataxia was conducted in a defined geographical region with a total population of 62,583. A door-to-door survey was used to identify cases of acquired cerebellar ataxia. Patients with acquired cerebellar ataxia at any age and of both genders were included. Cases of known inherited cerebellar ataxia, acquired neurological disorders with ataxia as a minor feature, or pure acquired sensory ataxia, were excluded. RESULTS: We identified 17 cases of acquired ataxia, of which eight were vascular, six were an ataxic cerebral palsy subtype, and three involved postencephalitic ataxia. The crude prevalence rate for acquired ataxia was 27.16/100,000 (95% confidence interval [CI]: 14.3-40.1). The mean age of the patients at interview was 31.8 (range 4-72) years, with a male to female ratio of 2.1:1. The most frequent presenting complaint was disturbance of gait (90.7%). The majority (92%) were ambulatory, but only 9.3% were independently self-caring. CONCLUSION: This population-based study provides an insight into acquired cerebellar ataxia within a defined region, and may inform decisions about the rational use of health care resources for patients with acquired cerebellar ataxia. The most common causes of acquired cerebellar ataxia in this region were cerebrovascular injury and cerebral palsy. PMID- 21552319 TI - Cognitive behavioral therapy for the treatment of post-traumatic stress disorder: a review. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a psychiatric sequel to a stressful event or situation of an exceptionally threatening or catastrophic nature. Cognitive behavioral therapy (CBT) has been used in the management of PTSD for many years. This paper reviews the effectiveness of CBT for the treatment of PTSD following various types of trauma, its potential to prevent PTSD, methods used in CBT, and reflects on the mechanisms of action of CBT in PTSD. METHODS: Electronic databases, including PubMed, were searched for articles on CBT and PTSD. Manual searches were conducted for cross-references in the relevant journal sites. RESULTS: The current literature reveals robust evidence that CBT is a safe and effective intervention for both acute and chronic PTSD following a range of traumatic experiences in adults, children, and adolescents. However, nonresponse to CBT by PTSD can be as high as 50%, contributed to by various factors, including comorbidity and the nature of the study population. CBT has been validated and used across many cultures, and has been used successfully by community therapists following brief training in individual and group settings. There has been effective use of Internet-based CBT in PTSD. CBT has been found to have a preventive role in some studies, but evidence for definitive recommendations is inadequate. The effect of CBT has been mediated mostly by the change in maladaptive cognitive distortions associated with PTSD. Many studies also report physiological, functional neuroimaging, and electroencephalographic changes correlating with response to CBT. CONCLUSION: There is scope for further research on implementation of CBT following major disasters, its preventive potential following various traumas, and the neuropsychological mechanisms of action. PMID- 21552321 TI - The phylogenetic origin of oskar coincided with the origin of maternally provisioned germ plasm and pole cells at the base of the Holometabola. AB - The establishment of the germline is a critical, yet surprisingly evolutionarily labile, event in the development of sexually reproducing animals. In the fly Drosophila, germ cells acquire their fate early during development through the inheritance of the germ plasm, a specialized maternal cytoplasm localized at the posterior pole of the oocyte. The gene oskar (osk) is both necessary and sufficient for assembling this substance. Both maternal germ plasm and oskar are evolutionary novelties within the insects, as the germline is specified by zygotic induction in basally branching insects, and osk has until now only been detected in dipterans. In order to understand the origin of these evolutionary novelties, we used comparative genomics, parental RNAi, and gene expression analyses in multiple insect species. We have found that the origin of osk and its role in specifying the germline coincided with the innovation of maternal germ plasm and pole cells at the base of the holometabolous insects and that losses of osk are correlated with changes in germline determination strategies within the Holometabola. Our results indicate that the invention of the novel gene osk was a key innovation that allowed the transition from the ancestral late zygotic mode of germline induction to a maternally controlled establishment of the germline found in many holometabolous insect species. We propose that the ancestral role of osk was to connect an upstream network ancestrally involved in mRNA localization and translational control to a downstream regulatory network ancestrally involved in executing the germ cell program. PMID- 21552322 TI - ESR1 is co-expressed with closely adjacent uncharacterised genes spanning a breast cancer susceptibility locus at 6q25.1. AB - Approximately 80% of human breast carcinomas present as oestrogen receptor alpha positive (ER+ve) disease, and ER status is a critical factor in treatment decision-making. Recently, single nucleotide polymorphisms (SNPs) in the region immediately upstream of the ER gene (ESR1) on 6q25.1 have been associated with breast cancer risk. Our investigation of factors associated with the level of expression of ESR1 in ER+ve tumours has revealed unexpected associations between genes in this region and ESR1 expression that are important to consider in studies of the genetic causes of breast cancer risk. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with an aromatase (oestrogen synthase) inhibitor was analyzed on Illumina 48K microarrays. Multiple-testing corrected Spearman correlation revealed that three previously uncharacterized open reading frames (ORFs) located immediately upstream of ESR1, C6ORF96, C6ORF97, and C6ORF211 were highly correlated with ESR1 (Rs = 0.67, 0.64, and 0.55 respectively, FDR<1 * 10(-7)). Publicly available datasets confirmed this relationship in other groups of ER+ve tumours. DNA copy number changes did not account for the correlations. The correlations were maintained in cultured cells. An ERalpha antagonist did not affect the ORFs' expression or their correlation with ESR1, suggesting their transcriptional co activation is not directly mediated by ERalpha. siRNA inhibition of C6ORF211 suppressed proliferation in MCF7 cells, and C6ORF211 positively correlated with a proliferation metagene in tumours. In contrast, C6ORF97 expression correlated negatively with the metagene and predicted for improved disease-free survival in a tamoxifen-treated published dataset, independently of ESR1. Our observations suggest that some of the biological effects previously attributed to ER could be mediated and/or modified by these co-expressed genes. The co-expression and function of these genes may be important influences on the recently identified relationship between SNPs in this region and breast cancer risk. PMID- 21552323 TI - Completion of hepatitis C virus replication cycle in heterokaryons excludes dominant restrictions in human non-liver and mouse liver cell lines. AB - Hepatitis C virus (HCV) is hepatotropic and only infects humans and chimpanzees. Consequently, an immunocompetent small animal model is lacking. The restricted tropism of HCV likely reflects specific host factor requirements. We investigated if dominant restriction factors expressed in non-liver or non-human cell lines inhibit HCV propagation thus rendering these cells non-permissive. To this end we explored if HCV completes its replication cycle in heterokaryons between human liver cell lines and non-permissive cell lines from human non-liver or mouse liver origin. Despite functional viral pattern recognition pathways and responsiveness to interferon, virus production was observed in all fused cells and was only ablated when cells were treated with exogenous interferon. These results exclude that constitutive or virus-induced expression of dominant restriction factors prevents propagation of HCV in these cell types, which has important implications for HCV tissue and species tropism. In turn, these data strongly advocate transgenic approaches of crucial human HCV cofactors to establish an immunocompetent small animal model. PMID- 21552324 TI - Genomic instability, defective spermatogenesis, immunodeficiency, and cancer in a mouse model of the RIDDLE syndrome. AB - Eukaryotic cells have evolved to use complex pathways for DNA damage signaling and repair to maintain genomic integrity. RNF168 is a novel E3 ligase that functions downstream of ATM,gamma-H2A.X, MDC1, and RNF8. It has been shown to ubiquitylate histone H2A and to facilitate the recruitment of other DNA damage response proteins, including 53BP1, to sites of DNA break. In addition, RNF168 mutations have been causally linked to the human RIDDLE syndrome. In this study, we report that Rnf168(-/-) mice are immunodeficient and exhibit increased radiosensitivity. Rnf168(-/-) males suffer from impaired spermatogenesis in an age-dependent manner. Interestingly, in contrast to H2a.x(-/-), Mdc1(-/-), and Rnf8(-/-) cells, transient recruitment of 53bp1 to DNA double-strand breaks was abolished in Rnf168(-/-) cells. Remarkably, similar to 53bp1 inactivation, but different from H2a.x deficiency, inactivation of Rnf168 impairs long-range V(D)J recombination in thymocytes and results in long insertions at the class-switch junctions of B-cells. Loss of Rnf168 increases genomic instability and synergizes with p53 inactivation in promoting tumorigenesis. Our data reveal the important physiological functions of Rnf168 and support its role in both gamma-H2a.x-Mdc1 Rnf8-dependent and -independent signaling pathways of DNA double-strand breaks. These results highlight a central role for RNF168 in the hierarchical network of DNA break signaling that maintains genomic integrity and suppresses cancer development in mammals. PMID- 21552325 TI - NF-kappaB hyper-activation by HTLV-1 tax induces cellular senescence, but can be alleviated by the viral anti-sense protein HBZ. AB - Activation of I-kappaB kinases (IKKs) and NF-kappaB by the human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, is thought to promote cell proliferation and transformation. Paradoxically, expression of Tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors, p21(CIP1/WAF1) and p27(KIP1), which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21(CIP1/WAF1)-/p27(KIP1)-mediated senescence constitutes a checkpoint against IKK/NF-kappaB hyper-activation. Senescence induced by Tax in HeLa cells is attenuated by mutations in Tax that reduce IKK/NF-kappaB activation and prevented by blocking NF-kappaB using a degradation-resistant mutant of I-kappaBalpha despite constitutive IKK activation. Small hairpin RNA-mediated knockdown indicates that RelA induces this senescence program by acting upstream of the anaphase promoting complex and RelB to stabilize p27(KIP1) protein and p21(CIP1/WAF1) mRNA respectively. Finally, we show that down-regulation of NF-kappaB by the HTLV-1 anti-sense protein, HBZ, delay or prevent the onset of Tax-induced senescence. We propose that the balance between Tax and HBZ expression determines the outcome of HTLV-1 infection. Robust HTLV-1 replication and elevated Tax expression drive IKK/NF-kappaB hyper activation and trigger senescence. HBZ, however, modulates Tax-mediated viral replication and NF-kappaB activation, thus allowing HTLV-1-infected cells to proliferate, persist, and evolve. Finally, inactivation of the senescence checkpoint can facilitate persistent NF-kappaB activation and leukemogenesis. PMID- 21552326 TI - Genetic assignment methods for gaining insight into the management of infectious disease by understanding pathogen, vector, and host movement. AB - For many pathogens with environmental stages, or those carried by vectors or intermediate hosts, disease transmission is strongly influenced by pathogen, host, and vector movements across complex landscapes, and thus quantitative measures of movement rate and direction can reveal new opportunities for disease management and intervention. Genetic assignment methods are a set of powerful statistical approaches useful for establishing population membership of individuals. Recent theoretical improvements allow these techniques to be used to cost-effectively estimate the magnitude and direction of key movements in infectious disease systems, revealing important ecological and environmental features that facilitate or limit transmission. Here, we review the theory, statistical framework, and molecular markers that underlie assignment methods, and we critically examine recent applications of assignment tests in infectious disease epidemiology. Research directions that capitalize on use of the techniques are discussed, focusing on key parameters needing study for improved understanding of patterns of disease. PMID- 21552327 TI - PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease. AB - Lafora disease is the most common teenage-onset neurodegenerative disease, the main teenage-onset form of progressive myoclonus epilepsy (PME), and one of the severest epilepsies. Pathologically, a starch-like compound, polyglucosan, accumulates in neuronal cell bodies and overtakes neuronal small processes, mainly dendrites. Polyglucosan formation is catalyzed by glycogen synthase, which is activated through dephosphorylation by glycogen-associated protein phosphatase 1 (PP1). Here we remove PTG, one of the proteins that target PP1 to glycogen, from mice with Lafora disease. This results in near-complete disappearance of polyglucosans and in resolution of neurodegeneration and myoclonic epilepsy. This work discloses an entryway to treating this fatal epilepsy and potentially other glycogen storage diseases. PMID- 21552328 TI - Deficiency of huntingtin has pleiotropic effects in the social amoeba Dictyostelium discoideum. AB - Huntingtin is a large HEAT repeat protein first identified in humans, where a polyglutamine tract expansion near the amino terminus causes a gain-of-function mechanism that leads to selective neuronal loss in Huntington's disease (HD). Genetic evidence in humans and knock-in mouse models suggests that this gain-of function involves an increase or deregulation of some aspect of huntingtin's normal function(s), which remains poorly understood. As huntingtin shows evolutionary conservation, a powerful approach to discovering its normal biochemical role(s) is to study the effects caused by its deficiency in a model organism with a short life-cycle that comprises both cellular and multicellular developmental stages. To facilitate studies aimed at detailed knowledge of huntingtin's normal function(s), we generated a null mutant of hd, the HD ortholog in Dictyostelium discoideum. Dictyostelium cells lacking endogenous huntingtin were viable but during development did not exhibit the typical polarized morphology of Dictyostelium cells, streamed poorly to form aggregates by accretion rather than chemotaxis, showed disorganized F-actin staining, exhibited extreme sensitivity to hypoosmotic stress, and failed to form EDTA resistant cell-cell contacts. Surprisingly, chemotactic streaming could be rescued in the presence of the bivalent cations Ca(2+) or Mg(2+) but not pulses of cAMP. Although hd(-) cells completed development, it was delayed and proceeded asynchronously, producing small fruiting bodies with round, defective spores that germinated spontaneously within a glassy sorus. When developed as chimeras with wild-type cells, hd(-) cells failed to populate the pre-spore region of the slug. In Dictyostelium, huntingtin deficiency is compatible with survival of the organism but renders cells sensitive to low osmolarity, which produces pleiotropic cell autonomous defects that affect cAMP signaling and as a consequence development. Thus, Dictyostelium provides a novel haploid organism model for genetic, cell biological, and biochemical studies to delineate the functions of the HD protein. PMID- 21552329 TI - Reciprocal sign epistasis between frequently experimentally evolved adaptive mutations causes a rugged fitness landscape. AB - The fitness landscape captures the relationship between genotype and evolutionary fitness and is a pervasive metaphor used to describe the possible evolutionary trajectories of adaptation. However, little is known about the actual shape of fitness landscapes, including whether valleys of low fitness create local fitness optima, acting as barriers to adaptive change. Here we provide evidence of a rugged molecular fitness landscape arising during an evolution experiment in an asexual population of Saccharomyces cerevisiae. We identify the mutations that arose during the evolution using whole-genome sequencing and use competitive fitness assays to describe the mutations individually responsible for adaptation. In addition, we find that a fitness valley between two adaptive mutations in the genes MTH1 and HXT6/HXT7 is caused by reciprocal sign epistasis, where the fitness cost of the double mutant prohibits the two mutations from being selected in the same genetic background. The constraint enforced by reciprocal sign epistasis causes the mutations to remain mutually exclusive during the experiment, even though adaptive mutations in these two genes occur several times in independent lineages during the experiment. Our results show that epistasis plays a key role during adaptation and that inter-genic interactions can act as barriers between adaptive solutions. These results also provide a new interpretation on the classic Dobzhansky-Muller model of reproductive isolation and display some surprising parallels with mutations in genes often associated with tumors. PMID- 21552330 TI - Fluctuations in spo0A transcription control rare developmental transitions in Bacillus subtilis. AB - Phosphorylated Spo0A is a master regulator of stationary phase development in the model bacterium Bacillus subtilis, controlling the formation of spores, biofilms, and cells competent for transformation. We have monitored the rate of transcription of the spo0A gene during growth in sporulation medium using promoter fusions to firefly luciferase. This rate increases sharply during transient diauxie-like pauses in growth rate and then declines as growth resumes. In contrast, the rate of transcription of an rRNA gene decreases and increases in parallel with the growth rate, as expected for stable RNA synthesis. The growth pause-dependent bursts of spo0A transcription, which reflect the activity of the spo0A vegetative promoter, are largely independent of all known regulators of spo0A transcription. Evidence is offered in support of a "passive regulation" model in which RNA polymerase stops transcribing rRNA genes during growth pauses, thus becoming available for the transcription of spo0A. We show that the bursts are followed by the production of phosphorylated Spo0A, and we propose that they represent initial responses to stress that bring the average cell closer to the thresholds for transition to bimodally expressed developmental responses. Measurement of the numbers of cells expressing a competence marker before and after the bursts supports this hypothesis. In the absence of ppGpp, the increase in spo0A transcription that accompanies the entrance to stationary phase is delayed and sporulation is markedly diminished. In spite of this, our data contradicts the hypothesis that sporulation is initiated when a ppGpp-induced depression of the GTP pool relieves repression by CodY. We suggest that, while the programmed induction of sporulation that occurs in stationary phase is apparently provoked by increased flux through the phosphorelay, bet-hedging stochastic transitions to at least competence are induced by bursts in transcription. PMID- 21552332 TI - Long-lost relative claims orphan gene: oskar in a wasp. PMID- 21552331 TI - Beyond missing heritability: prediction of complex traits. AB - Despite rapid advances in genomic technology, our ability to account for phenotypic variation using genetic information remains limited for many traits. This has unfortunately resulted in limited application of genetic data towards preventive and personalized medicine, one of the primary impetuses of genome-wide association studies. Recently, a large proportion of the "missing heritability" for human height was statistically explained by modeling thousands of single nucleotide polymorphisms concurrently. However, it is currently unclear how gains in explained genetic variance will translate to the prediction of yet-to-be observed phenotypes. Using data from the Framingham Heart Study, we explore the genomic prediction of human height in training and validation samples while varying the statistical approach used, the number of SNPs included in the model, the validation scheme, and the number of subjects used to train the model. In our training datasets, we are able to explain a large proportion of the variation in height (h(2) up to 0.83, R(2) up to 0.96). However, the proportion of variance accounted for in validation samples is much smaller (ranging from 0.15 to 0.36 depending on the degree of familial information used in the training dataset). While such R(2) values vastly exceed what has been previously reported using a reduced number of pre-selected markers (<0.10), given the heritability of the trait (~ 0.80), substantial room for improvement remains. PMID- 21552333 TI - Arabidopsis HDA6 regulates locus-directed heterochromatin silencing in cooperation with MET1. AB - Heterochromatin silencing is pivotal for genome stability in eukaryotes. In Arabidopsis, a plant-specific mechanism called RNA-directed DNA methylation (RdDM) is involved in heterochromatin silencing. Histone deacetylase HDA6 has been identified as a component of such machineries; however, its endogenous targets and the silencing mechanisms have not been analyzed globally. In this study, we investigated the silencing mechanism mediated by HDA6. Genome-wide transcript profiling revealed that the loci silenced by HDA6 carried sequences corresponding to the RDR2-dependent 24-nt siRNAs, however their transcript levels were mostly unaffected in the rdr2 mutant. Strikingly, we observed significant overlap of genes silenced by HDA6 to those by the CG DNA methyltransferase MET1. Furthermore, regardless of dependence on RdDM pathway, HDA6 deficiency resulted in loss of heterochromatic epigenetic marks and aberrant enrichment for euchromatic marks at HDA6 direct targets, along with ectopic expression of these loci. Acetylation levels increased significantly in the hda6 mutant at all of the lysine residues in the H3 and H4 N-tails, except H4K16. Interestingly, we observed two different CG methylation statuses in the hda6 mutant. CG methylation was sustained in the hda6 mutant at some HDA6 target loci that were surrounded by flanking DNA-methylated regions. In contrast, complete loss of CG methylation occurred in the hda6 mutant at the HDA6 target loci that were isolated from flanking DNA methylation. Regardless of CG methylation status, CHG and CHH methylation were lost and transcriptional derepression occurred in the hda6 mutant. Furthermore, we show that HDA6 binds only to its target loci, not the flanking methylated DNA, indicating the profound target specificity of HDA6. We propose that HDA6 regulates locus-directed heterochromatin silencing in cooperation with MET1, possibly recruiting MET1 to specific loci, thus forming the foundation of silent chromatin structure for subsequent non-CG methylation. PMID- 21552335 TI - Toddler Emotion Regulation with Mothers and Fathers: Temporal Associations Between Negative Affect and Behavioral Strategies. AB - The present study investigated temporal associations between putative emotion regulation strategies and negative affect in 20-month-old toddlers. Toddlers' parent-focused, self-distraction, and toy-focused strategies, as well as negative affect, were rated on a second-by-second basis during laboratory parent-toddler interactions. Longitudinal mixed-effects models were conducted to determine the degree to which behavioral strategy use predicts subsequent negative affect and negative affect predicts subsequent strategy use. Results with mother-toddler and father-toddler dyads indicated that parent-focused strategies with an unresponsive parent were followed by increases in negative affect, whereas toy focused strategies were followed by decreases in negative affect. Results also indicated that toddler negative affect serves to regulate behavioral strategy use within both parent contexts. PMID- 21552334 TI - A stochastic model of latently infected cell reactivation and viral blip generation in treated HIV patients. AB - Motivated by viral persistence in HIV+ patients on long-term anti-retroviral treatment (ART), we present a stochastic model of HIV viral dynamics in the blood stream. We consider the hypothesis that the residual viremia in patients on ART can be explained principally by the activation of cells latently infected by HIV before the initiation of ART and that viral blips (clinically-observed short periods of detectable viral load) represent large deviations from the mean. We model the system as a continuous-time, multi-type branching process. Deriving equations for the probability generating function we use a novel numerical approach to extract the probability distributions for latent reservoir sizes and viral loads. We find that latent reservoir extinction-time distributions underscore the importance of considering reservoir dynamics beyond simply the half-life. We calculate blip amplitudes and frequencies by computing complete viral load probability distributions, and study the duration of viral blips via direct numerical simulation. We find that our model qualitatively reproduces short small-amplitude blips detected in clinical studies of treated HIV infection. Stochastic models of this type provide insight into treatment-outcome variability that cannot be found from deterministic models. PMID- 21552336 TI - Second-order Poisson Nernst-Planck solver for ion channel transport. AB - The Poisson Nernst-Planck (PNP) theory is a simplified continuum model for a wide variety of chemical, physical and biological applications. Its ability of providing quantitative explanation and increasingly qualitative predictions of experimental measurements has earned itself much recognition in the research community. Numerous computational algorithms have been constructed for the solution of the PNP equations. However, in the realistic ion-channel context, no second order convergent PNP algorithm has ever been reported in the literature, due to many numerical obstacles, including discontinuous coefficients, singular charges, geometric singularities, and nonlinear couplings. The present work introduces a number of numerical algorithms to overcome the abovementioned numerical challenges and constructs the first second-order convergent PNP solver in the ion-channel context. First, a Dirichlet to Neumann mapping (DNM) algorithm is designed to alleviate the charge singularity due to the protein structure. Additionally, the matched interface and boundary (MIB) method is reformulated for solving the PNP equations. The MIB method systematically enforces the interface jump conditions and achieves the second order accuracy in the presence of complex geometry and geometric singularities of molecular surfaces. Moreover, two iterative schemes are utilized to deal with the coupled nonlinear equations. Furthermore, extensive and rigorous numerical validations are carried out over a number of geometries, including a sphere, two proteins and an ion channel, to examine the numerical accuracy and convergence order of the present numerical algorithms. Finally, application is considered to a real transmembrane protein, the Gramicidin A channel protein. The performance of the proposed numerical techniques is tested against a number of factors, including mesh sizes, diffusion coefficient profiles, iterative schemes, ion concentrations, and applied voltages. Numerical predictions are compared with experimental measurements. PMID- 21552337 TI - A Multilevel Perspective on the Climate of Bullying: Discrepancies Among Students, School Staff, and Parents. AB - Although many bullying prevention programs aim to involve multiple partners, few studies have examined perceptual differences regarding peer victimization and the broader bullying climate among students, staff, and parents. The present study utilized multilevel data from 11,674 students, 960 parents, and 1,027 staff at 44 schools to examine the association between school-level indicators of disorder, norms regarding bullying and bullies, and students, parents, and staff perceptions of safety, belonging, and witnessing bullying. Results revealed several important discrepancies between adults and youth with regard to their perceptions. Moreover, results highlight the significance of normative beliefs about bullies, retaliation, and the influence of school contextual factors on students' risk for exposure to bullying. PMID- 21552338 TI - N-Benzyl-3-sulfonamidopyrrolidines are a New Class of Bacterial DNA Gyrase Inhibitors. AB - This paper characterizes N-benzyl-3-sulfonamidopyrrolidines (gyramides) as DNA gyrase inhibitors. Gyramide A was previously shown to exhibit antimicrobial activity that suggested it inhibited bacterial cell division. In this study, we conducted target identification studies and identified DNA gyrase as the primary target of gyramide A. The gyramide A resistance-determining region in DNA gyrase is adjacent to the DNA cleavage gate and is a new site for inhibitor design. We studied the antibiotic effects of gyramides A-C in combination with the Gram negative efflux pump inhibitor MC-207,110 (60 MUM). The gyramides had a minimum inhibitory concentration of 10-40 MUM against Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, Staphylococcus aureus, and Streptococcus pneumoniae; the compounds were ineffective against Enterococcus faecalis. The IC(50) of gyramides A-C against E. coli DNA gyrase was 0.7- 3.3 MUM. The N-benzyl 3-sulfonamidopyrrolidines described in this manuscript represent a starting point for development of antibiotics that bind a new site in DNA gyrase. PMID- 21552339 TI - Higher Order Inference On A Treatment Effect Under Low Regularity Conditions. AB - We describe a novel approach to nonparametric point and interval estimation of a treatment effect in the presence of many continuous confounders. We show the problem can be reduced to that of point and interval estimation of the expected conditional covariance between treatment and response given the confounders. Our estimators are higher order U-statistics. The approach applies equally to the regular case where the expected conditional covariance is root-n estimable and to the irregular case where slower non-parametric rates prevail. PMID- 21552340 TI - Treating anterior cruciate ligament tears in skeletally immature patients. AB - PURPOSE: To systematically review the current evidence for conservative and surgical treatment of anterior cruciate ligament (ACL) tears in skeletally immature patients. METHODS: A systematic search of PubMed, CINAHL, EMBASE, CCTR, and CDSR was performed for surgical and/or conservative treatment of complete ACL tears in immature individuals. Studies with less than six months of follow-up were excluded. Study quality was assessed and data were collected on clinical outcome, growth disturbance, and secondary joint damage. RESULTS: We identified 48 studies meeting the inclusion criteria. Conservative treatment was found to result in poor clinical outcomes and a high incidence of secondary defects, including meniscal and cartilage injury. Surgical treatment had only very weak evidence for growth disturbance, yet strong evidence of good postoperative stability and function. No specific surgical treatment showed clearly superior outcomes, yet the studies using physeal-sparing techniques had no reported growth disturbances at all. CONCLUSIONS: The current best evidence suggests that surgical stabilization should be considered the preferred treatment in immature patients with complete ACL tears. While physeal-sparing techniques are not associated with a risk of growth disturbance, transphyseal reconstruction is an alternative with a beneficial safety profile and a minimal risk of growth disturbance. Conservative treatment commonly leads to meniscal damage and cartilage destruction and should be considered a last resort. LEVEL OF EVIDENCE: Level IV, systematic review of Level II, III, and IV studies. PMID- 21552341 TI - N,N,N-Trimethyl chitosan nanoparticles for the delivery of monoclonal antibodies against hepatocellular carcinoma cells. AB - N,N,N-Trimethyl chitosan chloride is capable of forming nanocomplexes with protein through ionotropic gelation. A monoclonal antibody, raised against human liver heparan sulfate proteoglycan and specifically inhibiting hepatocellular carcinoma in vitro, was prepared in nanocomplexes of this modified chitosan. The smallest nanocomplexes (59 +/- 17 nm, zeta-potential 16.5 +/- 0.5 mV) were obtained at polysaccharide:antibody ratios of 5:0.3. Spherical particles with a smooth surface and compact structure having a mean diameter of ~11.2 +/- 0.09 nm were investigated by Atomic Force Microscopy. Cellular uptake of fluorescently labeled nanocomplexes was studied in mouse monocyte models of cancer and normal cells. External and internal fluorescence was analyzed by flow cytometry. The results demonstrate that the nanocomplexes could enter cells and were retained for a longer period of time in cancer cells where they exhibited greater toxicity. These nanocomplexes appear safe and could potentially enhance the half life of added antibodies. PMID- 21552342 TI - Healthcare-Related Financial Burden among Families in the U.S.: The Role of Childhood Activity Limitations and Income. AB - This study examined the impact of childhood activity limitations on family financial burden in the U.S. We used ten complete panels (1996-2006) of the Medical Expenditure Panel Survey (MEPS) to evaluate the burden of out-of-pocket healthcare expenditures for 17,857 families with children aged 0-17 years. Multivariate generalized linear models were used to examine the relationship between childhood activity limitation status and both absolute and relative financial burden. Families of children with limitations had higher absolute out of-pocket healthcare expenditures than families of children without limitations ($594.36 higher; p<0.05), and were 54% more likely to experience relative burden (p<0.05). Substantial socioeconomic disparities in financial burden were observed. Policies are needed to enable these families to access appropriate and affordable healthcare services. PMID- 21552343 TI - An Inversion Recovery NMR Kinetics Experiment. AB - A convenient laboratory experiment is described in which NMR magnetization transfer by inversion recovery is used to measure the kinetics and thermochemistry of amide bond rotation. The experiment utilizes Varian spectrometers with the VNMRJ 2.3 software, but can be easily adapted to any NMR platform. The procedures and sample data sets in this article will enable instructors to use inversion recovery as a laboratory activity in applied NMR classes and provide research students with a convenient template with which to acquire inversion recovery data on research samples. PMID- 21552344 TI - Neuro-QOL and the NIH Toolbox: implications for epilepsy. AB - The impact of neurological disorders on the lives of patients is often far more complex than what is measured in routine examination. Measurement of this impact can be challenging owing to a lack of brief, psychometrically sound and generally accepted instruments. Two NIH-funded initiatives are developing assessment tools, in English and Spanish, which address these issues, and should prove useful to the study and treatment of epilepsy and other neurological conditions. The first, Neuro-QOL, has created a set of health-related quality of life measures that are applicable for people with common neurological disorders. The second, the NIH Toolbox for the Assessment of Neurological and Behavioral Function, is assembling measures of cognitive, emotional, motor and sensory health and function that can be used across all ages, from 3 to 85 years. This article describes both the projects and their potential value to epilepsy treatment and research. PMID- 21552345 TI - Alcohol and Other Drug Resistance Strategies Employed by Rural Adolescents. AB - This study seeks to identify how rural adolescents make health decisions and utilize communication strategies to resist influence attempts in offers of alcohol, tobacco, and other drugs (ATOD). Semi-structured interviews were conducted with 113 adolescents from rural school districts to solicit information on ATOD norms, past ATOD experiences, and substance offer-response episodes. Rural youths' resistance strategies were similar to previous findings with urban adolescents - refuse, explain, avoid, and leave (the REAL typology) - while unique features of these strategies were identified including the importance of personal narratives, the articulation of a non-user identity, and being "accountable" to self and others. PMID- 21552347 TI - Influence of Domain Size on the Scaling Effects in Pb(Mg1/3Nb2/3)O3-PbTiO3 Ferroelectric Crystals. AB - The property degradation observed in thin Pb(Mg(1/3)Nb(2/3))O(3)-PbTiO(3) (PMN PT) crystals is believed to relate to large domains and subsequent clamping induced by surface-boundary. In this work, the properties were investigated as function of domain size, using controlled poling. The degraded piezoelectric and dielectric properties of thin PMN-PT were found to increase significantly, by decreasing domain size. Furthermore, the fine domain structure was found to be stable at 3kV/cm after 7.0*10(5) negative-pulse cycles, hence, enabling PMN-PT crystals for high-frequency (>20 MHz) ultrasound-transducers. PMID- 21552346 TI - In Silico Augmentation of the Drug Development Pipeline: Examples from the study of Acute Inflammation. AB - The clinical translation of promising basic biomedical findings, whether derived from reductionist studies in academic laboratories or as the product of extensive high-throughput and -content screens in the biotechnology and pharmaceutical industries, has reached a period of stagnation in which ever higher research and development costs are yielding ever fewer new drugs. Systems biology and computational modeling have been touted as potential avenues by which to break through this logjam. However, few mechanistic computational approaches are utilized in a manner that is fully cognizant of the inherent clinical realities in which the drugs developed through this ostensibly rational process will be ultimately used. In this article, we present a Translational Systems Biology approach to inflammation. This approach is based on the use of mechanistic computational modeling centered on inherent clinical applicability, namely that a unified suite of models can be applied to generate in silico clinical trials, individualized computational models as tools for personalized medicine, and rational drug and device design based on disease mechanism. PMID- 21552348 TI - Parental investment without kin recognition: Simple conditional rules for parent offspring behavior. AB - Species differ widely with regard to parental investment strategies and mechanisms underlying those strategies. The passing of benefits to likely offspring can be instantiated with a number of different computational and behavioral systems. We report results from an agent-based model in which offspring maintain proximity with parents and parents transmit benefits to offspring without the capacity of either parent or offspring to 'recognize' one another. Instead, parents follow a simple rule to emit benefits after reproducing and offspring follow a simple rule of moving in the direction of positive benefit gradients. This model differs from previous models of spatial kin-based altruism in that individuals are modeled as having different behavioral rules at different life stages and benefits are transmitted unidirectionally from parents to offspring. High rates of correctly directed parental investment occur when mobility and sociality are low and parental investment occurs over a short period of time. We suggest that strategies based on recognition and bonding/attachment might serve to increase rates of correctly directed parental investment under parameters that are shown here to otherwise lead to high rates of misdirected and wasted parental investment. PMID- 21552350 TI - Reduced-Rank Approximations to the Far-Field Transform in the Gridded Fast Multipole Method. AB - The fast multipole method (FMM) has been shown to have a reduced computational dependence on the size of finest-level groups of elements when the elements are positioned on a regular grid and FFT convolution is used to represent neighboring interactions. However, transformations between plane-wave expansions used for FMM interactions and pressure distributions used for neighboring interactions remain significant contributors to the cost of FMM computations when finest-level groups are large. The transformation operators, which are forward and inverse Fourier transforms with the wave space confined to the unit sphere, are smooth and well approximated using reduced-rank decompositions that further reduce the computational dependence of the FMM on finest-level group size. The adaptive cross approximation (ACA) is selected to represent the forward and adjoint far field transformation operators required by the FMM. However, the actual error of the ACA is found to be greater than that predicted using traditional estimates, and the ACA generally performs worse than the approximation resulting from a truncated singular-value decomposition (SVD). To overcome these issues while avoiding the cost of a full-scale SVD, the ACA is employed with more stringent accuracy demands and recompressed using a reduced, truncated SVD. The results show a greatly reduced approximation error that performs comparably to the full scale truncated SVD without degrading the asymptotic computational efficiency associated with ACA matrix assembly. PMID- 21552349 TI - Apolipoprotein E-Deficient Lipoproteins Induce Foam Cell Formation by Activation of PERK-EIF-2alpha Signaling Cascade. AB - Transformation of macrophages into foam cells by apolipoprotein (Apo) E deficient, ApoB48-containing (E(-)/B48) lipoproteins has been shown to be associated with increased phosphorylation of eukaryotic initiation factor-2alpha (eIF-2alpha). The present report examined the causal relationship between eIF 2alpha phosphorylation and lipid accumulation in macrophages induced by E(-)/B48 lipoproteins. E(-)/B48 lipoproteins increased eIF-2alpha phosphorylation and cholesterol ester accumulation, while lipoprotein degradation decreased and lysosomal acid lipase and cathepsin B mRNA translation was inhibited in mouse peritoneal macrophages (MPMs). These responses were overcome by overexpression of a nonphosphorylatable eIF-2alpha mutant in MPMs. Incubation of MPMs with E(-)/B48 lipoproteins also increased the phosphorylation of RNA-dependent protein kinase like endoplasmic reticulum kinase (PERK), but not other eIF-2alpha kinases. Overexpression of a nonphosphorylatable PERK mutant inhibited PERK and eIF-2alpha phosphorylation, and alleviated cholesterol ester accumulation induced by E( )/B48 lipoproteins. PERK is an eIF-2alpha kinase activated by endoplasmic reticulum (ER) stress. Taken together, findings from this report suggest that induction of ER stress, i.e., activation of the PERK-eIF2alpha signaling cascade, is a mechanism by which E(-)/B48 lipoproteins down-regulate lysosomal hydrolase synthesis, inhibit lysosomal lipoprotein degradation, and increase intracellular lipoprotein and cholesterol ester accumulation, resulting in foam cell formation. PMID- 21552351 TI - THE ONGOING STRUGGLE FOR PSYCHOANALYTIC RESEARCH: SOME STEPS FORWARD. PMID- 21552352 TI - A C Symmetric Nitrate Complex with a Thiophene-Based Tripodal Receptor. AB - A thiophene-based tripodal receptor has been synthesized and its complexes with nitrate and iodide have determined by single-crystal X-ray analysis. In the nitrate complex, one nitrate is encapsulated in a selective orientation forming a C(3) symmetric complex, which is bonded to three protonated secondary amines with six NH...O bonds. The anion is coordinated in a plane perpendicular to the principal rotation axis passing through the tertiary nitrogen of the receptor and the nitrogen of the encapsulated nitrate. High-level DFT calculations support the crystallographic results demonstrating that an adduct with trigonal binding of three oxygen atoms is more stable than that of one oxygen atom of the encapsulate nitrate. On the other hand, in the structure of the iodide complex, all three iodides lie outside the cavity. (1)H NMR titration studies indicate that the receptor forms a 1:1 complex with nitrate with a binding constant of K = 315 M( 1) in chloroform, showing a moderate selectivity over halides and perchlorate. PMID- 21552353 TI - Middle School Friendships and Academic Achievement in Early Adolescence: A Longitudinal Analysis. AB - Early adolescence is a critical transition period for the maintenance of academic achievement. One factor that school systems often fail to take into account is the influence of friends on academic achievement during middle school. This study investigated the influence of friends' characteristics on change in academic achievement from Grade 6 through 8, and the role of students' own characteristics as moderators of this relationship. The sample included 1,278 participants (698 girls). Linear regressions suggest that students with academically engaged friends may achieve to levels higher than expected in Grade 8. However, when considering the significant, negative influence of friends' problem behavior, the role of friend's school engagement became nonsignificant. Low-achieving girls who had high-achieving friends in Grade 6 had lower academic achievement than expected by Grade 8. In contrast, high-achieving girls seemed to benefit from having high-achieving friends. Implications for theory and prevention efforts targeting young adolescents are discussed. PMID- 21552354 TI - Experimental evaluation of an adaptive Joule-Thomson cooling system including silicon-microfabricated heat exchanger and microvalve components. AB - This article reports the evaluation of a Joule-Thomson (JT) cooling system that combines two custom micromachined components-a Si/glass-stack recuperative heat exchanger and a piezoelectrically actuated expansion microvalve. With the microvalve controlling the flow rate, this system can modulate cooling to accommodate varying refrigeration loads. The perforated plate Si/glass heat exchanger is fabricated with a stack of alternating silicon plates and Pyrex glass spacers. The microvalve utilizes a lead zirconate titanate actuator to push a Si micromachined valve seat against a glass plate, thus modulating the flow passing through the gap between the valve seat and the glass plate. The fabricated heat exchanger has a footprint of 1 * 1 cm(2) and a length of 35 mm. The size of the micromachined piezoelectrically actuated valve is about 1 * 1 * 1 cm(3). In JT cooling tests, the temperature of the system was successfully controlled by adjusting the input voltage of the microvalve. When the valve was fully opened (at an input voltage of -30 V), the system cooled down to a temperature as low as 254.5 K at 430 kPa pressure difference between inlet and outlet at steady state and 234 K at 710 kPa in a transient state. The system provided cooling powers of 75 mW at 255 K and 150 mW at 258 K. Parasitic heat loads at 255 K are estimated at approximately 700 mW. PMID- 21552355 TI - Biodegradable Multiblock Poly[N-(2-hydroxypropyl)methacrylamide] via Reversible Addition-Fragmentation Chain Transfer Polymerization and Click Chemistry. AB - A new bifunctional chain transfer agent (CTA) containing alkyne end groups was designed, synthesized and used for direct synthesis of clickable telechelic polymers. Good control of reversible addition-fragmentation chain transfer (RAFT) polymerization of N-(2-hydroxypropyl)methacrylamide (HPMA) was achieved by using the new CTA, as indicated by a linear increase of number average molecular weight (Mn) with conversion and low polydispersity (PDI) (<1.1). In particular, enzymatically degradable multiblock HPMA polymers were readily prepared by subsequent reaction with alphaomega, -diazido oligopeptide (GFLG) sequence via Cu(I) catalyzed alkyne-azide cycloaddition. Upon exposure of high molecular weight fractions of multiblock polyHPMA to papain or cathepsin B, the polymer was degraded into segments of molecular weight and narrow polydispersity similar to those of the initial telechelic polyHPMA. PMID- 21552356 TI - Quasi- and pseudo-maximum likelihood estimators for discretely observed continuous-time Markov branching processes. AB - This article deals with quasi- and pseudo-likelihood estimation in a class of continuous-time multi-type Markov branching processes observed at discrete points in time. "Conventional" and conditional estimation are discussed for both approaches. We compare their properties and identify situations where they lead to asymptotically equivalent estimators. Both approaches possess robustness properties, and coincide with maximum likelihood estimation in some cases. Quasi likelihood functions involving only linear combinations of the data may be unable to estimate all model parameters. Remedial measures exist, including the resort either to non-linear functions of the data or to conditioning the moments on appropriate sigma-algebras. The method of pseudo-likelihood may also resolve this issue. We investigate the properties of these approaches in three examples: the pure birth process, the linear birth-and-death process, and a two-type process that generalizes the previous two examples. Simulations studies are conducted to evaluate performance in finite samples. PMID- 21552357 TI - Erosion and physical transport via overland flow of arsenic and lead bound to silt-sized particles. AB - Understanding of the transport mechanisms of contaminated soils and sediment is essential for the sustainable management of contaminated lands. In New England and elsewhere, vast areas of agricultural lands are contaminated by the historical application of lead-arsenate pesticides. Left undisturbed the physical and chemical mobility of As and Pb in these soils is limited due to their strong affinity for adsorption onto solid phases. However, soil disturbance promotes erosion and overland flow during intense rainstorms. Here we investigate the event-scale transport of disturbed As and Pb contaminated soils through measurement of concentrations of As and Pb in suspended sediment and changes in Pb isotopic ratios in overland flow. Investigation of several rain events shows that where land disturbance has occurred, physical transport of silt-sized particles and aggregates is the primary transport vector of As and Pb derived from pesticide-contaminated soil. Although both As and Pb are associated with similarly-sized particles, we find that solid-phase As is more effectively mobilized and transported than Pb. Our results demonstrate that anthropogenic land disturbance of historical lands contaminated with lead-arsenate pesticides may redistribute, through physical transport, significant amounts of As, and lesser amounts of Pb, to riparian and stream sediments, where they are potentially more bioavailable. PMID- 21552358 TI - Induction Plasma Sprayed Nano Hydroxyapatite Coatings on Titanium for Orthopaedic and Dental Implants. AB - This paper reports preparation of a highly crystalline nano hydroxyapatite (HA) coating on commercially pure titanium (Cp-Ti) using inductively coupled radio frequency (RF) plasma spray and their in vitro and in vivo biological response. HA coatings were prepared on Ti using normal and supersonic plasma nozzles at different plate powers and working distances. X-ray diffraction (XRD) and Fourier transformed infrared spectroscopic (FTIR) analysis show that the normal plasma nozzle lead to increased phase decomposition, high amorphous calcium phosphate (ACP) phase formation, and severe dehydroxylation of HA. In contrast, coatings prepared using supersonic nozzle retained the crystallinity and phase purity of HA due to relatively short exposure time of HA particles in the plasma. In addition, these coatings exhibited a microstructure that varied from porous and glassy structure at the coating-substrate interface to dense HA at the top surface. The microstructural analysis showed that the coating was made of multigrain HA particles of ~200 nm in size, which consisted of recrystallized HA grains in the size range of 15- 20 nm. Apart from the type of nozzle, working distance was also found to have a strong influence on the HA phase decomposition, while plate power had little influence. Depending on the plasma processing conditions, a coating thickness between 300 and 400 MUm was achieved where the adhesive bond strengths were found to be between 4.8 MPa to 24 MPa. The cytotoxicity of HA coatings was examined by culturing human fetal osteoblast cells (hFOB) on coated surfaces. In vivo studies, using the cortical defect model in rat femur, evaluated the histological response of the HA coatings prepared with supersonic nozzle. After 2 weeks of implantation, osteoid formation was evident on the HA coated implant surface, which could indicate early implant- tissue integration in vivo. PMID- 21552359 TI - Cross-coupling of C(sp)-H Bonds with Organometallic Reagents via Pd(II)/Pd(0) Catalysis** AB - Palladium-catalyzed C-H activation/C-C bond-forming reactions have emerged as a promising class of synthetic tools in organic chemistry. Among the many different means of forging C-C bonds using Pd-mediated C-H activation, a new horizon in this field is Pd(II)-catalyzed cross-coupling of C-H bonds with organometallic reagents via a Pd(II)/Pd(0) catalytic cycle. While this type of reaction has proven to be effective for the selective functionalization of aryl C(sp(2))-H bonds, the focus of this review is on Pd(II)-catalyzed C(sp(3))-H activation/C-C cross-coupling, a topic of particular importance because reactions of this type enable fundamentally new methods for bond construction. Since our laboratory's initial report on cross-coupling of C-H bonds in 2006, this area has expanded rapidly, and the unique ability of Pd(II) catalysts to cleave and functionalize alkyl C(sp(3))-H bonds has been exploited to develop protocols for forming an array of C(sp(3))-C(sp(2)) and C(sp(3))-C(sp(3)) bonds. Furthermore, enantioselective C(sp(3))-H activation/C-C cross-coupling has been achieved through the use of chiral amino acid-derived ligands, offering a novel technique for producing enantioenriched molecules. Although this nascent field remains at an early stage of development, further investigations hold the potential to revolutionalize the way in which chiral molecules are synthesized in industrial and academic laboratories. PMID- 21552360 TI - Do Parent Education Programs Promote Healthy Post-Divorce Parenting? Critical Distinctions and a Review of the Evidence. AB - Most parent education programs are designed to improve child well-being following divorce by changing some aspect of parenting. However, there has been relatively little discussion of what aspects of parenting are most critical and the effectiveness of programs to change different aspects of parenting. This paper addresses these issues by: 1. Distinguishing three aspects of post-divorce parenting that have been targeted in parent education programs; 2. Reviewing evidence of the relations between each aspect of parenting and the well-being of children and; 3. Critically reviewing evidence that parent education programs have been successful in changing each aspect of post-divorce parenting. PMID- 21552361 TI - Tobacco Dependence: Insights from Investigations of Self-Reported Smoking Motives. AB - The Wisconsin Inventory of Smoking Dependence Motives (WISDM) assesses 13 theoretically-derived dimensions of smoking motivation. These 13 subscales were intended to index comprehensively the severity of tobacco dependence and provide insight into the disorder. Recent studies indicate that four subscales (Automaticity, Craving, Loss of Control, and Tolerance) represent the core features of tobacco dependence and have been dubbed the Primary Dependence Motives (PDM). The remaining nine subscales, the Secondary Dependence Motives (SDM), may be clinically relevant but index less essential features of dependence. PMID- 21552362 TI - Academic Self-Concept in Black Adolescents: Do Race and Gender Stereotypes Matter? AB - We examined the relation between race- and gender-group competence ratings and academic self-concept in 252 Black seventh- and eighth-graders. On average, youth reported traditional race stereotypes, whereas gender stereotypes were traditional about verbal abilities and were nontraditional regarding math/science abilities. Among boys, in-group gender and in-group race-based competence ratings (i.e. ratings of boys and Blacks) were related to math/science and verbal self concepts. However, only gender-based ratings (i.e. ratings of girls' abilities for reading/writing) were related to girls' self-concepts. These findings suggest that the influence of race stereotypes on Black adolescents' academic self concepts is different for girls than boys. Whereas self-relevant gender groups were associated with both Black girls' and boys' academic self-concept, race based competence ratings were only relevant for the academic self-views of Black boys. PMID- 21552363 TI - Bioimpedance spectroscopy for the estimation of fat-free mass in end-stage renal disease. AB - BACKGROUND #ENTITYSTARTX00026; AIMS: Bioimpedance spectroscopy may provide reliable estimates of fat-free mass in end-stage renal disease patients. We aimed to evaluate the ability of bioimpedance spectroscopy to estimate fat-free mass in end-stage renal disease patients using dual-energy X-ray absorptiometry as a reference. METHODS: Fat-free mass measured by bioimpedance spectroscopy was compared to fat-free mass measured by dual-energy X-ray absorptiometry in 16 end stage renal disease patients on hemodialysis, 12 undialysed end-stage renal disease patients and 23 control subjects. RESULTS: Methods were highly correlated for fat-free mass in all subject groups (r = 0.87, P < 0.001). Mean bioimpedance spectroscopy measures of fat-free mass were not different from the dual-energy X ray absorptiometry measures in any subject group. Individual comparisons revealed wide limits of agreement between methods in hemodialysis (11.6 to -9.72 kg) and undialysed patients (10.95 to -14.73 kg). CONCLUSIONS: Although bioimpedance spectroscopy estimates of fat-free mass in the end-stage renal disease patient groups were not different from dual-energy X-ray absorptiometry and the methods were highly correlated, there was great individual variability. From these data it is clear that future studies are warranted before bioimpedance spectroscopy can be recommended as a valid clinical tool for assessing fat-free mass in end stage renal disease patients. PMID- 21552364 TI - Constructing semantic representations from a gradually-changing representation of temporal context. AB - Computational models of semantic memory exploit information about cooccurrences of words in naturally-occurring text to extract information about the meaning of the words that are present in the language. Such models implicitly specify a representation of temporal context. Depending on the model, words are said to have occurred in the same context if they are presented within a moving window, within the same sentence or within the same document. The temporal context model (TCM), a specific quantitative specification of temporal context has proved useful in the study of episodic memory. The predictive temporal context model (pTCM) uses the same definition of temporal context to generate semantic memory representations. Taken together pTCM and TCM may prove to be part of a general model of declarative memory. PMID- 21552365 TI - Tyrosine Phosphatase TpbA of Pseudomonas aeruginosa Controls Extracellular DNA via Cyclic Diguanylic Acid Concentrations. AB - Inactivating the tyrosine phosphatase TpbA of Pseudomonas aeruginosa PA14 induces biofilm formation by 150-fold via increased production of the second messenger cyclic diguanylic acid (c-di-GMP). Here, we show the tpbA mutation reduces extracellular DNA (eDNA) and that increased expression of tpbA increases eDNA; hence, eDNA is inversely proportional to c-di-GMP concentrations. Mutations in diguanylate cyclases PA0169, PA4959, and PA5487 and phosphodiesterase PA4781 corroborate this trend. The tpbA mutation also decreases cell lysis while overexpression of tpbA increases cell lysis. To further link c-di-GMP concentrations and eDNA, the gene encoding phosphodiesterase PA2133 was overexpressed which increased eDNA and decreased biofilm formation by decreasing c-di-GMP. Furthermore, the effect of the tpbB mutation along with the tpbA mutation was examined because loss of TpbB restored the phenotypes controlled by enhanced c-di-GMP in the tpbA mutant. The tpbA tpbB double mutations restored eDNA to that of the PA14 wild-type level. These findings suggest that c-di-GMP, rather than TpbA, controls eDNA. Hence, TpbA acts as a positive regulator of eDNA and cell lysis by reducing c-di-GMP concentrations. PMID- 21552366 TI - RBC storage and avoiding hyperkalemia from transfusions to neonates & infants. PMID- 21552367 TI - Impact of Scaffold Micro and Macro Architecture on Schwann Cell Proliferation under Dynamic Conditions in a Rotating Wall Vessel Bioreactor. AB - Over the last decade tissue engineering has emerged as a powerful alternative to regenerate lost tissues owing to trauma or tumor. Evidence shows that Schwann cell containing scaffolds have improved performance in vivo as compared to scaffolds that depend on cellularization post implantation. However, owing to limited supply of cells from the patients themselves, several approaches have been taken to enhance cell proliferation rates to produce complete and uniform cellularization of scaffolds. The most common approach is the application of a bioreactor to enhance cell proliferation rate and therefore reduce the time needed to obtain sufficiently significant number of glial cells, prior to implantation.In this study, we show the application of a rotating wall bioreactor system for studying Schwann cell proliferation on nanofibrous spiral shaped scaffolds, prepared by solvent casting and salt leaching techniques. The scaffolds were fabricated from polycaprolactone (PCL), which has ideal mechanical properties and upon degradation does not produce acidic byproducts. The spiral scaffolds were coated with aligned or random nanofibers, produced by electrospinning, to provide a substrate that mimics the native extracellular matrix and the essential contact guidance cues.At the 4 day time point, an enhanced rate of cell proliferation was observed on the open structured nanofibrous spiral scaffolds in a rotating wall bioreactor, as compared to static culture conditions. However, the cell proliferation rate on the other contemporary scaffolds architectures such as the tubular and cylindrical scaffolds show reduced cell proliferation in the bioreactor as compared to static conditions, at the same time point. Moreover, the rotating wall bioreactor does not alter the orientation or the phenotype of the Schwann cells on the aligned nanofiber containing scaffolds, wherein, the cells remain aligned along the length of the scaffolds. Therefore, these open structured spiral scaffolds pre cultured with Schwann cells, in bioreactors could potentially shorten the time needed for grafts for peripheral nerve regeneration. PMID- 21552368 TI - Making Sense of Posttraumatic Stress Disorder: Illness Perceptions Among Traumatic Injury Survivors. AB - More than 1.5 million persons in the United States sustain traumatic physical injuries each year. A significant proportion of traumatic injury survivors develop serious mental health problems such as posttraumatic stress disorder (PTSD), yet few obtain professional mental health care. According to the commonsense model of self-regulation (Leventhal, Diefenbach, & Leventhal, 1992), illness-related perceptions can influence coping responses including the use of professional treatment. Using the commonsense model as a guiding framework, we conducted semi-structured interviews with non-treatment seeking trauma injury survivors with PTSD (N = 23). Illness perceptions regarding the following key conceptual dimensions were examined: PTSD symptoms (identity), experienced or perceived consequences of PTSD symptoms, and beliefs about the causes, controllability, and course of PTSD symptoms. Results revealed that no respondents identified their symptoms as indicative of PTSD. Common illness perceptions included believing that symptoms would be short-lived, that symptoms were reflective of poor physical health or were a natural reaction to life in a violent community, and that symptoms were functionally adaptive. Respondents also reported exerting some limited control over symptoms by relying on religious forms of coping. None of the respondents perceived professional treatment as being able to completely control symptoms. Findings indicated that respondents' conceptualizations of PTSD symptoms may have inhibited the recognition of symptoms as a serious mental health condition that warrants professional treatment. PMID- 21552369 TI - PREPARATIVE ISOLATION AND PURIFICATION OF CHEMICAL CONSTITUENTS OF BELAMCANDA BY MPLC, HSCCC AND PREP-HPLC. AB - Combined with medium-pressure liquid chromatography (MPLC) and preparative high pressure liquid chromatography (Prep-HPLC), high-speed countercurrent chromatography (HSCCC) was successfully applied for separation and purification of isoflavonoids from the extract of belamcanda. HSCCC separation was performed on a two-phase solvent system composed of methyl tert-butyl ether -ethyl acetate n-butyl alcohol - acetonitrile -0.1% aqueous trifluoroacetic acid at a volume radio of 1:2:1:1:5. Semi-purified peak fractions from HSCCC separation were further purified by Prep-HPLC. Nine well-separated fractions were analyzed by HPLC-UV absorption spectrometry to determine their purities and characterized with ESI-MS(n). Except for peaksland VII (unknown) seven compounds were identified as apocynin (peak II), mangiferin (peak III), 7-O-methylmangiferin (peak IV), hispidulin (peak V), 3'-hydroxyltectoridin (peak VI), iristectorin B (peak VII), isoiridin (peak IX). PMID- 21552370 TI - Stochastic modeling of animal epidemics using data collected over three different spatial scales. AB - A stochastic, spatial, discrete-time, SEIR model of avian influenza epidemics among poultry farms in Pennsylvania is formulated. Using three different spatial scales wherein all the birds within a single farm, ZIP code, or county are clustered into a single point, we obtain three different views of the epidemics. For each spatial scale, two parameters within the viral-transmission kernel of the model are estimated using simulated epidemic data. We show that simulated epidemics modeled using data collected on the farm and ZIP-code levels behave similar to the actual underlying epidemics, but this is not true using data collected on the county level. Such analyses of data collected on different spatial scales are useful in formulating intervention strategies to control an ongoing epidemic (e.g., vaccination schedules and culling policies). PMID- 21552371 TI - Colorectal Cancer Stem Cells: Biology and Therapeutic Implications. AB - The hypothesis that cancer is driven by a subpopulation of tumor-initiating or cancer stem cells (CSC), defined by their selective ability for extensive self renewal and capacity to give rise to nontumorigenic cancer cell progeny through differentiation, has been validated experimentally in diverse human malignancies. Translational relevance of the CSC hypothesis is underlined by emerging novel strategies designed to target all subpopulations within a given tumor in order to effect cancer eradication and improve patient outcomes. Colorectal cancer stem cells (CRSCs) have been identified and successfully isolated by several research groups based on distinct cell-surface marker characteristics. Identification of CRSC populations has led to a wave of discoveries describing novel self-renewal and drug resistance mechanisms in colorectal cancer that represent novel future therapeutic targets. In this review, we will discuss emerging CRSC-specific pathways and the therapeutic promise of targeting this cancer population in colorectal cancer patients. PMID- 21552372 TI - A Transferable Non-bonded Pairwise Force Field to Model Zinc Interactions in Metalloproteins. AB - Herein we introduce a novel practical strategy to overcome the well-known challenge of modeling the divalent zinc cation in metalloproteins. The main idea is to design short-long effective functions (SLEF) to describe charge interactions between the zinc ion and all other atoms. This SLEF approach has the following desired features: (1). It is pairwise, additive and compatible with widely used atomic pair-wise force fields for modeling biomolecules; (2). It only changes interactions between the zinc ion and other atoms, and does not affect force field parameters that model other interactions in the system; (3). It is a non-bonded model that is inherently capable to describe different zinc ligands and coordination modes. By optimizing two SLEF parameters as well as zinc vdW parameters through force matching based on Born-Oppenheimer ab initio QM/MM molecular dynamics simulations, we have successfully developed the first SLEF force field (SLEF1) to describe zinc interactions. Extensive molecular dynamics simulations of seven zinc enzyme systems with different coordination ligands and distinct chelation modes (4-,5-,6-fold), including the binuclear zinc active site, yielded zinc coordination numbers and binding distances in good agreement with the corresponding crystal structures as well as ab initio QM/MM MD results. This not only demonstrates the transferability and adequacy of the new SLEF1 force field in describing a variety of zinc proteins, but also indicates that this novel SLEF approach is a promising direction to explore for improving force field description of metal ion interactions. PMID- 21552373 TI - Poly(Acrylic Acid-b-Styrene) Amphiphilic Multiblock Copolymers as Building Blocks for the Assembly of Discrete Nanoparticles. AB - In order to expand the utility of current polymeric micellar systems, we have developed amphiphilic multiblock copolymers containing alternating blocks of poly(acrylic acid) and poly(styrene). Heterotelechelic poly(tert-butyl acrylate-b styrene) diblock copolymers containing an alpha-alkyne and an omega-azide were synthesized by atom transfer radical polymerization (ATRP), allowing control over the molecular weight while maintaining narrow polydispersity indices. The multiblock copolymers were constructed by copper-catalyzed azide-alkyne cycloaddition of azide-alkyne end functional diblock copolymers which were then characterized by (1)H NMR, FT-IR and SEC. The tert-butyl moieties of the poly(tert-butyl acrylate-b-styrene) multiblock copolymers were easily removed to form the poly(acrylic acid-b-styrene) multiblock copolymer ((PAA-PS)(9)), which contained up to 9 diblock repeats. The amphiphilic multiblock (PAA-PS)(9) (M(n) = 73.3 kg/mol) was self-assembled by dissolution into tetrahydrofuran and extensive dialysis against deionized water for 4 days. The critical micelle concentration (CMC) for (PAA-PS)(9) was determined by fluorescence spectroscopy using pyrene as a fluorescent probe and was found to be very low at 2 * 10(-4) mg/mL. The (PAA PS)(9) multiblock was also analyzed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The hydrodynamic diameter of the particles was found to be 11 nm. Discrete spherical particles were observed by TEM with an average particle diameter of 14 nm. The poly(acrylic acid) periphery of the spherical particles should allow for future conjugation of biomolecules. PMID- 21552374 TI - Toward a Model of Social Influence that Explains Minority Student Integration into the Scientific Community. AB - Students from several ethnic minority groups are underrepresented in the sciences, such that minority students more frequently drop out of the scientific career path than non-minority students. Viewed from a perspective of social influence, this pattern suggests that minority students do not integrate into the scientific community at the same rate as non-minority students. Kelman (1958, 2006) describes a tripartite integration model of social influence (TIMSI) by which a person orients to a social system. To test if this model predicts integration into the scientific community, we conducted analyses of data from a national panel of minority science students. A structural equation model framework showed that self-efficacy (operationalized consistent with Kelman's 'rule-orientation') predicted student intentions to pursue a scientific career. However, when identification as a scientist and internalization of values are added to the model, self-efficacy becomes a poorer predictor of intention. Additional mediation analyses support the conclusion that while having scientific self-efficacy is important, identifying with and endorsing the values of the social system reflect a deeper integration and more durable motivation to persist as a scientist. PMID- 21552375 TI - Polymer Mechanics as a Model for Short-Term and Flow-Independent Cartilage Viscoelasticity. AB - Articular cartilage is the load bearing soft tissue that covers the contacting surfaces of long bones in articulating joints. Healthy cartilage allows for smooth joint motion, while damaged cartilage prohibits normal function in debilitating joint diseases such as osteoarthritis. Knowledge of cartilage mechanical function through the progression of osteoarthritis, and in response to innovative regeneration treatments, requires a comprehensive understanding of the molecular nature of interacting extracellular matrix constituents and interstitial fluid. The objectives of this study were therefore to (1) examine the timescale of cartilage stress-relaxation using different mechanistic models and (2) develop and apply a novel (termed "sticky") polymer mechanics model to cartilage stress-relaxation based on temporary binding of constituent macromolecules. Using data from calf cartilage samples, we found that different models captured distinct timescales of cartilage stress-relaxation: monodisperse polymer reptation best described the first second of relaxation, sticky polymer mechanics best described data from ~1-100 seconds of relaxation, and a model of inviscid fluid flow through a porous elastic matrix best described data from 100 seconds to equilibrium. Further support for the sticky polymer model was observed using experimental data where cartilage stress-relaxation was measured in either low or high salt concentration. These data suggest that a complete understanding of cartilage mechanics, especially in the short time scales immediately following loading, requires appreciation of both fluid flow and the polymeric behavior of the extracellular matrix. PMID- 21552376 TI - Repeated Names, Overt Pronouns, and Null Pronouns in Spanish. AB - In two self-paced, sentence-by-sentence reading experiments we examined the difference in the processing of Spanish discourses with repeated names, overt pronouns, and null pronouns in emphatic and non-emphatic contexts. In Experiment 1, repeated names and overt pronouns caused a processing delay when they referred to salient antecedents in non-emphatic contexts. In Experiment 2, both processing delays were eliminated when an emphatic cleft-structure was used. The processing delay caused by overt pronouns referring to salient antecedents in non-emphatic contexts in Spanish contrasts with previous findings in Chinese, where null and overt pronouns elicited similar reading times. We explain both our Spanish findings and the Chinese findings in a unified framework based on the notion of balance between processing cost and discourse function in line with the Informational Load Hypothesis. PMID- 21552377 TI - MALDI-TOF Mass Spectral Characterization of Polymers Containing an Azide Group: Evidence of Metastable Ions. PMID- 21552378 TI - MR and CT imaging of Arrhythmogenic Cardiomyopathy. PMID- 21552379 TI - Detection of impervious surface change with multitemporal Landsat images in an urban-rural frontier. AB - Mapping and monitoring impervious surface dynamic change in a complex urban-rural frontier with medium or coarse spatial resolution images is a challenge due to the mixed pixel problem and the spectral confusion between impervious surfaces and other non-vegetation land covers. This research selected Lucas do Rio Verde County in Mato Grosso State, Brazil as a case study to improve impervious surface estimation performance by the integrated use of Landsat and QuickBird images and to monitor impervious surface change by analyzing the normalized multitemporal Landsat-derived fractional impervious surfaces. This research demonstrates the importance of two step calibrations. The first step is to calibrate the Landsat derived fraction impervious surface values through the established regression model based on the QuickBird-derived impervious surface image in 2008. The second step is to conduct the normalization between the calibrated 2008 impervious surface image with other dates of impervious surface images. This research indicates that the per-pixel based method overestimates the impervious surface area in the urban-rural frontier by 50-60%. In order to accurately estimate impervious surface area, it is necessary to map the fractional impervious surface image and further calibrate the estimates with high spatial resolution images. Also normalization of the multitemporal fractional impervious surface images is needed to reduce the impacts from different environmental conditions, in order to effectively detect the impervious surface dynamic change in a complex urban-rural frontier. The procedure developed in this paper for mapping and monitoring impervious surface area is especially valuable in urban-rural frontiers where multitemporal Landsat images are difficult to be used for accurately extracting impervious surface features based on traditional per-pixel based classification methods as they cannot effectively handle the mixed pixel problem. PMID- 21552380 TI - LIGHT-SENSITIVE VISUALIZATION OF MULTIMODAL DATA FOR NEUROSURGICAL APPLICATIONS. AB - We present a technique for enhancing multimodal visualizations for image-guided neurosurgery in the presence of adverse lighting conditions. In the surgical environment, images used for real time navigation are displayed in suboptimal conditions due to the varying lighting conditions. Our approach actively monitors the incoming light on the display and appropriately enhances the visualization based on the change in light. Based on the results of a user study to evaluate our approach, we found that our enhanced visualization techniques were mostly preferred over regular visualizations. PMID- 21552381 TI - Synthesis and characterization of mixed-ligand diimine-piperonal thiosemicarbazone complexes of ruthenium(II): Biophysical investigations and biological evaluation as anticancer and antibacterial agents. AB - We have used a novel microwave-assisted method developed in our laboratories to synthesize a series of ruthenium-thiosemicarbazone complexes. The new thiosemicarbazone ligands are derived from benzo[d][1,3]dioxole-5-carbaldehyde (piperonal) and the complexes are formulated as [(diimine)(2)Ru(TSC)](PF(6))(2) (where the TSC is the bidentate thiosemicarbazone ligand). The diimine in the complexes is either 2,2'-bipyridine or 1,10-phenanthroline. The complexes have been characterized by spectroscopic means (NMR, IR and UV-Vis) as well as by elemental analysis. We have studied the biophysical characteristics of the complexes by investigating their anti-oxidant ability as well as their ability to disrupt the function of the human topoisomerase II enzyme. The complexes are moderately strong binders of DNA with binding constants of 10(4) M(-1). They are also strong binders of human serum albumin having binding constants on the order of 10(4) M(-1). The complexes show good in vitro anticancer activity against human colon cancer cells, Caco-2 and HCT-116 and indeed show some cytotoxic selectivity for cancer cells. The IC(50) values range from 7 - 159 MUM (after 72 h drug incubation). They also have antibacterial activity against Gram-positive strains of pathogenic bacteria with IC(50) values as low as 10 MUM; little activity was seen against Gram-negative strains. It has been established that all the compounds are catalytic inhibitors of human topoisomerase II. PMID- 21552382 TI - Ischemic colitis of the left colon in a diabetic patient. AB - Diabetes mellitus may affect the gastrointestinal tract possibly as a result of autonomic neuropathy. Here we present a 68-year-old male with non-insulin dependent diabetes mellitus who presented with prolonged watery diarrhea and in whom imaging studies demonstrated ischemic colitis of the left colon. Resection of the affected colon resulted in sustained disappearance of symptoms. PMID- 21552383 TI - Unusual ovarian stromal tumor with radiation changes mimicking carcinoma. AB - Radiation-related changes including fibrosis, nuclear enlargement, hyperchromasia and cytoplasmic vacuolization may alter the appearance of normal ovarian tissue and ovarian tumors. We describe radiation-related changes in ovarian stromal neoplasm with mixed features of sclerosing stromal tumor and fibrothecoma. The right ovarian mass was discovered in a 38 year-old woman with past history of invasive squamous cell carcinoma of the cervix treated with cone biopsy and brachytherapy. The low power architecture of cellular pseudolobules and small sheets of tumor cells with scattered hyaline plaques was consisted with the pattern of combined sclerosing stromal tumor and fibrothecoma. However, the presence of severe cytologic atypia, as well as clear cell and signet ring differentiation and arrangements of tumor cells in single files and nests, raised a possibility of primary or metastatic carcinoma. The tumor cells were positive for calretinin, vimentin, inhibin, and WT1 and negative for AE1/3, cytokeratin 7 and 20, CD99, estrogen and progesterone receptors, mammaglobin, chromogranin, and S100 protein. Based on the results of immunostains and a subsequently provided history of radiation, a diagnosis of sex cord stromal tumor with mixed fibrothecoma and sclerosing stromal differentiation was made. Radiation-related atypia and fibrosis in sex cord stromal tumor may create a pattern mimicking carcinoma and therefore, in the presence of unusual histology, the use of immunohistochemistry is recommended. PMID- 21552385 TI - Cellular and phenotypic characterization of canine osteosarcoma cell lines. AB - Canine and human osteosarcoma (OSA) have many similarities, with the majority of reported cases occurring in the appendicular skeleton, gender predominance noted, high rate of metastasis at the time of presentation, and a lack of known etiology for this devastating disease. Due to poor understanding of the molecular mechanisms underlying OSA, we have characterized seven different OSA canine cell lines: Abrams, D17, Grey, Hughes, Ingles, Jarques, and Marisco and compared them to U2, a human OSA cell line, for the following parameters: morphology, growth, contact inhibition, migrational tendencies, alkaline phosphatase staining, heterologous tumor growth, double-strand DNA breaks, and oxidative damage. All results demonstrated the positive characteristics of the Abrams cell line for use in future studies of OSA. Of particular interest, the robust growth of a subcutaneous tumor and rapid pulmonary metastasis of the Abrams cell line in an immunocompromised mouse shows incredible potential for the future use of Abrams as a canine OSA model. Further investigations utilizing a canine cell model of OSA, such as Abrams, will be invaluable to understanding the molecular events underlying OSA, pharmaceutical inhibition of metastasis, and eventual prevention of this devastating disease. PMID- 21552384 TI - Biological Markers in DCIS and Risk of Breast Recurrence: A Systematic Review. AB - Understanding of the biology and clinical behavior of ductal carcinoma in situ (DCIS) is currently inadequate. The aim of this comprehensive review was to identify important molecular biological markers associated with DCIS and candidate markers associated with increased risk of ipsilateral recurrence after diagnosis of DCIS. A comprehensive systematic review was performed to identify studies published in the past 10 years that investigated biological markers in DCIS. To be included in this review, studies that investigated the rate of biological expression of markers had to report on at least 30 patients; studies that analyzed the recurrence risk associated with biomarker expression had to report on at least 50 patients. There were 6,252 patients altogether in our review. Biological markers evaluated included steroid receptors, proliferation markers, cell cycle regulation and apoptotic markers, angiogenesis-related proteins, epidermal growth factor receptor family receptors, extracellular matrix related proteins, and COX-2. Although the studies in this review provide valuable preliminary information regarding the expression and prognostic significance of biomarkers in DCIS, common limitations of published studies (case-series, cohort, and case-control studies) were that they were limited to small patient cohorts in which the extent of surgery and use of radiotherapy or endocrine therapy varied from patient to patient, and variable methods of determining biomarker expression. These constraints made it difficult to interpret the absolute effect of expression of various biomarkers on risk of local recurrence. No prospective validation studies were identified. As the study of biomarkers are in their relative infancy in DCIS compared with invasive breast cancer, key significant prognostic and predictive markers associated with invasive breast cancer have not been adequately studied in DCIS. There is a critical need for prospective analyses of novel and other known breast cancer molecular markers in large cohorts of patient with DCIS to differentiate indolent from aggressive DCIS and better tailor the need and extent of current therapies. PMID- 21552386 TI - A Qualitative Exploration of Trajectories Among Suburban Users of Methamphetamine. AB - The goal of this exploratory study was to gain a better understanding of methamphetamine use among suburban users. We know very little about the mechanisms of initiation and trajectory patterns of methamphetamine use among this under-researched and hidden population. This study employed qualitative methods to examine the drug career of suburban methamphetamine users. Analysis of in-depth interviews with 48 former and current users indicated that suburban users often initiate and continue use for functional purposes. Turning points into dysfunctional use included loss of work, broken relationships, and stress related to a suburban lifestyle. The route to cessation included frequent relapses. Findings call for treatment and prevention programs targeted for specific patterns of suburban use. PMID- 21552387 TI - Comparison of Displacement-Based and Force-Based Mapped Meshing. AB - The finite element (FE) method is a powerful tool for the study of biomechanics. One of the limiting factors in transitioning this tool into the clinic is the time required to generate high quality meshes for analysis. Previously, we developed a mapped meshing technique that utilized force control and a finite element solver to warp a template mesh onto subject specific surfaces. This paper describes a displacement based method that directly warps the template mesh onto subject specific surfaces using distance as the driving measure for the deformable registration. The resulting meshes were evaluated for mesh quality and compared to the force based method. An initial evaluation was performed using a mathematical phantom. The algorithm was then applied to generate meshes for the phalanx bones of the human hand. The algorithm successfully mapped the template bone to all of the bony surfaces, with the exception of the distal phalanx bone. In this one case, significant differences existed between the geometries of the template mesh and the distal phalanx. Further refinement of the algorithm may allow the algorithm to successfully generate meshes even in the presence of large geometric shape differences. PMID- 21552388 TI - Response to Letter from Shin and Lee, entitled "FDDNP PET patterns in nondemented populations" PMID- 21552389 TI - Conducting-Polymer Nanotubes for Controlled Drug Release. PMID- 21552390 TI - Synthesizing complex sensations from simple components. AB - The target article suggests that taste is not based on the traditional four basic tastes, but rather is a continuum subserved by cross-fiber integration. This commentary describes evidence indicating that the traditional concept is valid, and that with suitable precautions, it is possible to match natural substances using mixtures representing fundamental tastes. PMID- 21552391 TI - Cadaveric Renal Transplantation in Diabetics in the 1980's: with Special Reference to Cyclosporine. PMID- 21552392 TI - THE IMMUNOSUPPRESSIVE EFFECTS OF FR 900506 IN RATS RECEIVING HETEROTOPIC CARDIAC ALLOGRAFTS. AB - The immunosuppressive effects of FR 900506 were studied in Lewis rats given ACI heterotopic heart allografts. Intramuscular doses of 0.02 mg/kg daily for 2 weeks extended graft survival slightly, and with doses up to 1.28 mg/kg for 2 weeks, there is long-term graft survival. If only 3 daily doses were given starting on day 4 after transplantation, graft survival for almost 3 months was accomplished in 4 of 6 animals who still bear functioning hearts. PMID- 21552393 TI - IMMUNOSUPPRESSION WITH FR 900506 FOR CANINE KIDNEY AND LIVER TRANSPLANTATION. AB - The immunosuppressive effects of FR 900506 were investigated for one month after canine kidney and liver transplantation. Eight untreated kidney recipients lived for 8 to 19 days, mean 12.1. In contrast, the one month survival of dogs given FR 900506 in daily oral doses of 0.5, 1.0, and 1.5 mg/kg was 2/6, 3/6, and 4/6 respectively. The one month survival of liver recipients was 4/5 compared to one month survival of 1/8 in historical untreated controls. There was no evidence from biochemical tests of hepatotoxicity or nephrotoxicity. PMID- 21552394 TI - Does the response to alcohol taxes differ across racial/ethnic groups? Some evidence from 1984-2009 Behavioral Risk Factor Surveillance System. AB - BACKGROUND: Excessive alcohol use remains an important lifestyle-related contributor to morbidity and mortality in the U.S. and worldwide. It is well documented that drinking patterns differ across racial/ethnic groups, but not how those different consumption patterns would respond to tax changes. Therefore, policy makers are not informed on whether the effects of tax increases on alcohol abuse are shared equally by the whole population, or policies in addition to taxation should be pursued to reach certain sociodemographic groups. AIMS OF THE STUDY: To estimate differential demand responses to alcohol excise taxes across racial/ethnic groups in the U.S. METHODS: Individual data from the Behavioral Risk Factor Surveillance System 1984-2009 waves (N= 3,921,943, 39.3% male; 81.3% White, 7.8% African American, 5.8% Hispanic, 1.9% Asian or Pacific Islander, 1.4% Native American, and 1.8% other race/multi-race) are merged with tax data by residential state and interview month. Dependent variables include consumption of any alcohol and number of drinks consumed per month. Demand responses to alcohol taxes are estimated for each race/ethnicity in separate regressions conditional on individual characteristics, state and time fixed effects, and state-specific secular trends. RESULTS: The null hypothesis on the identical tax effects among all races/ethnicities is strongly rejected (P < 0.0001), although pairwise comparisons using t-test are often not statistically significant due to a lack of precision. Our point estimates suggest that the tax effect on any alcohol consumption is largest among White and smallest among Hispanic. Among existing drinkers, Native American and other race/multi-race are most responsive to tax effects while Hispanic least. For all races/ethnicities, the estimated tax effects on consumption are large and significant among light drinkers (1-40 drinks per month), but shrink substantially for moderate (41-99) and heavy drinkers (>= 100). DISCUSSION: Extensive research has been conducted on overall demand responses to alcohol excise taxes, but not on heterogeneity across various racial/ethnic groups. Only one similar prior study exists, but used a much smaller dataset. The authors did not identify differential effects. With this much larger dataset, we found some evidence for different responses across races/ethnicities to alcohol taxes, although we lack precision for individual group estimates. Limitations of our study include the absence of intrastate tax variations, no information on what type of alcohol is consumed, lack of controls for subgroup baseline alcohol consumption rates, and measurement error in self reported alcohol use data. IMPLICATIONS FOR HEALTH POLICIES: Tax policies aimed to reduce alcohol-related health and social problems should consider whether they target the most harmful drinking behaviors, affect subgroups in unintended ways, or influence some groups disproportionately. This requires information on heterogeneity across subpopulations. Our results are a first step in this direction and suggest that there exists a differential impact across races/ethnicities, which may further increase health disparities. Tax increases also appear to be less effective among the heaviest consumers who are associated with highest risk. IMPLICATIONS FOR FURTHER RESEARCH: More research, including replications in different settings, is required to obtain better estimates on differential responses to alcohol tax across races/ethnicities. Population heterogeneity is also more complex than our first cut by race/ethnicity and needs more fine-grained analyses and model structures. PMID- 21552395 TI - Alterations in phospholipid catabolism in Mycobacterium tuberculosis lysX mutant. AB - Mycobacterium tuberculosis lysX mutant, defective for production of lysinylated phosphatidylglycerol (L-PG), is sensitive to cationic antimicrobial peptides, is not proficient for proliferation in mice lungs and exhibits altered membrane potential (17). In the present study we show that a lysX complement strain expressing lysX from inducible tet promoter is proficient in restoring lysX phenotypes, confirming that the observed phenotypes are specific to lysX. To evaluate the correlation between changes in membrane potential and lysX activity, we visualized regions of cardiolipin (CL), one of the abundant phospholipids of mycobacteria, by staining with fluorescent dye 10-N-nonyl-acridine orange (NAO) and found that CL is localized as bright spots at septal regions and poles of actively dividing cells, but not in stationary phase cells. lysX mutants were elongated and showed more numerous and brighter CL staining at both midcell and quarter cell septa, compared with wild type, indicating a defect in the cell division process. Evaluation of (14)C-acetic acid incorporation into major phospholipids such as CL, phosphatidylethanolamine (PE), phosphatidylinositol and their degradation between lysX mutant and its parent revealed differences in the turnover of PE and PI. Our results favor a hypothesis that alterations in phospholipids metabolism could be contributing to changes in membrane potential, hence the observed phenotype of lysX mutant. PMID- 21552396 TI - IN VITRO IMMUNOSUPPRESSIVE EFFECTS OF FR 900506 ON HUMAN T LYMPHOCYTE ALLOACTIVATION. AB - FR 900506 (FR) is a new immunosuppressive drug which prolongs allograft survival. Our studies have compared the in vitro inhibitory effects of FR and Cyclosporine (CsA) on human lymphocyte proliferation. Considerably lower doses of FR were required to induce inhibition of lymphocyte proliferation induced by concanavalin A (ConA) stimulation or in primary mixed lymphocyte reactions (MLR) Similar differences between FR and CsA were observed with the secondary stimulation of alloactivated T cells generated in MLR or propagated from liver transplant biopsies These observations provide further evidence that FR is about 500 fold more potent than CsA and may be a useful immunosuppressive agent in organ transplantation. PMID- 21552397 TI - THE DUAL-FOCUS APPROACH TO CREATING BILINGUAL MEASURES. AB - The dual-focus approach to creating bilingual research protocols requires a bilingual/bicultural research team, including indigenous researchers from the cultures being studied. The presence of indigenous researchers as full and equal members of the research team can guard against an unexamined exportation of ideas and methods developed in one culture to other cultural/linguistic communities. The team develops the research plan and a research protocol that express a given concept with equal clarity, affect, and level of usage simultaneously in two languages. The dual-focus method employs a concept-driven rather than a translation-driven approach to attain conceptual and linguistic equivalence. Examples of the application of this approach to creating new measures in Spanish and English, adapting existing measures, revising instructions to research participants, and correcting official translations are provided. PMID- 21552398 TI - Androgen Receptor regulation of Vitamin D receptor in response of castration resistant prostate cancer cells to 1alpha-Hydroxyvitamin D5 - a calcitriol analog. AB - Calcitriol (1,25(OH)(2)D3) is cytostatic for prostate cancer (CaP), but had limited therapeutic utility due to hypercalcemia-related toxicities, leading to the development of low-calcemic calcitriol analogs. We show that one analog, 1 alpha-Hydroxyvitamin-D5 (1alpha(OH)D5), induced apoptosis in castration-sensitive LNCaP prostate cancer cells, but unlike calcitriol, did not increase androgen receptor (AR) transcriptional activity. LNCaP-AI, a castrate-resistant (CRCaP) LNCaP subline, was resistant to 1alpha(OH)D5 in the presence of androgens; however, androgen withdrawal (AWD), although ineffective by itself, sensitized LNCaP-AI cells to 1alpha(OH)D5. Investigation of the mechanism revealed that the vitamin D receptor (VDR), which mediates the effects of 1alpha(OH)D5, is downregulated in LNCaP-AI cells compared to LNCaP in the presence of androgens, whereas AWD restored VDR expression. Since LNCaP-AI cells expressed higher AR compared to LNCaP and AWD decreased AR, this indicated an inverse relationship between VDR and AR. Further, AR stimulation (by increased androgen) suppressed VDR, while AR downregulation (by ARsiRNA) stimulated VDR levels and sensitized LNCaP-AI cells to 1alpha(OH)D5 similar to AWD. Another cell line, pRNS-1-1, although isolated from a normal prostate, had lost AR expression in culture and adapted to androgen-independent growth. These cells expressed the VDR and were sensitive to 1alpha(OH)D5, but restoration of AR expression suppressed VDR levels and induced resistance to 1alpha(OH)D5 treatment. Taken together, these results demonstrate negative regulation of VDR by AR in CRCaP cells. This effect is likely mediated by prohibitin (PHB), which was inhibited by AR transcriptional activity and stimulated VDR in CRCaP, but not castrate-sensitive cells. Therefore, in castration sensitive cells, although the AR negatively regulates PHB, this does not affect VDR expression, whereas in CRCaP cells, negative regulation of PHB by the AR results in concomitant negative regulation of the VDR by the AR. These data demonstrate a novel mechanism by which 1alpha(OH)D5 prolong the effectiveness of AWD in CaP cells. PMID- 21552399 TI - Fine needle aspiration cytology of pilomatrixoma. AB - AIM: To delineate and characterize the cytomorphologic features of pilomatrixoma (PMX) helpful in correct diagnosis of the lesion on fine needle aspiration cytology (FNAC). MATERIALS AND METHODS: Archival records of clinical findings, FNAC and histopathological reports of PMX cases were analyzed. Aspirate findings in 14 cases of PMX were correlated with detailed clinical data and subsequent histopathology on excisional biopsy. Different morphological findings were graded semiquantitatively from 0 to 3+. RESULTS: The series showed female preponderance, with head and neck being the commonest site. Majority patients had a single tumor with mean size of 1.6 cm. Out of 14 biopsy proven cases of PMX, cytology findings revealed PMX in 7 cases on the basis of ghost cells, groups of basaloid cells, squamous cells in combination with multinucleated giant cells and calcium deposits in a background of debris. The main reasons for erroneous diagnosis were predominance of one component over the others and non-representative aspirated material. CONCLUSIONS: The cytological features of PMX are characteristic and allow a conclusive diagnosis provided the smears are examined keenly bearing in mind the diagnostic traps that can mislead a cytopathologist. PMID- 21552400 TI - Micronuclei: An essential biomarker in oral exfoliated cells for grading of oral squamous cell carcinoma. AB - BACKGROUND: Micronuclei in exfoliated oral epithelial cells have been shown in some studies to correlate with severity of this genotoxic damage. This severity can be measured in terms of grading of the lesions. AIM: To correlate frequency of micronuclei (MN) in oral exfoliated cells in clinically diagnosed cases of oral squamous cell carcinoma (OSCC) followed by a histopathological grading. MATERIALS AND METHODS: The study subjects consisted of clinically diagnosed cases of OSCC. Healthy subjects without any tobacco consumption habits formed the control group. The cytosmears from both groups were stained with rapid Papanicolaou stain. MN were identified according to the criteria given by Countryman and Heddle with some modifications. RESULTS: The frequency of MN was three to four times higher in patients with OSCC as compared to patients in the control group and the difference was found to be highly significant. In 75% cases, the cytological grade as determined by the frequency of micronuclei correlated with the histopathological grade and this observation was statistically significant. CONCLUSIONS: MN can be a candidate to serve as a biomarker for prediction of the grade of OSCC. PMID- 21552401 TI - The value of systematic pattern analysis in FNAC of breast lesions: 225 cases with cytohistological correlation. AB - BACKGROUND: Fine needle aspiration cytology (FNAC) has a high rating in the assessment of breast lesions. Various methods have been used to diagnose cytology of breast lesions. AIMS: Present study was undertaken to evaluate the feasibility of application of systematic pattern analysis based on morphology in diagnosing breast aspirates. MATERIALS AND METHODS: This is a retrospective study of FNAC of the breast done over a period of 4 years in a tertiary care centre. A total of 225 cases of breast lesions for which FNAC was done with histological follow-up were included in the study. Breast aspirates were provisionally diagnosed based on systematic pattern analysis. Aspirates were grouped into six categories based on predominant cellular pattern, and correlation between cytological and histological diagnosis was assessed. RESULTS: Application of pattern analysis on FNAC of breast lesions in our study had a sensitivity of 94.5%, specificity of 98%, diagnostic accuracy of 97%, positive predictive value of 95.8%, and negative predictive value of 97.4%. CONCLUSIONS: Systematic pattern analysis based on morphology of FNAC smears was found to be highly reliable and could be easily reproducible in the assessment of breast masses. PMID- 21552402 TI - Guided fine needle aspiration cytology of retroperitoneal masses - Our experience. AB - BACKGROUND: Early pathological classification of retroperitoneal masses is important for pin-point diagnosis and timely management. AIMS: This study was done to evaluate the usefulness and drawbacks of guided fine needle aspiration cytology (FNAC) of retroperitoneal masses covering a period of two years with an intention to distinguish between neoplastic and non-neoplastic lesions and to correlate with histologic findings. MATERIALS AND METHODS: FNAC was done under radiological guidance in all cases using long needle fitted with disposable syringe. Appropriate staining was done and cytology was correlated with histology which was taken as the gold standard for comparison. RESULTS: Fifty-one patients who presented with retroperitoneal masses were studied. Forty-four lesions were malignant cytologically and 7 were inflammatory (tuberculous). According to radiological and cytologic findings, we classified our cases into four groups: renal tumors, retroperitoneal lymphadenopathy, germ cell tumors, soft tissue tumors. Except for cases of non-Hodgkin lymphoma (NHL) and metastatic lesions, we had sensitivity and specificity of 100%. In NHL the sensitivity and specificity were both 50%. In cases of metastatic adenocarcinoma, the sensitivity and specificity were 84.6% and 81.8%, respectively. CONCLUSIONS: Ignoring the pitfalls, guided FNAC is still an inexpensive and reliable method of early diagnosis of retroperitoneal lesions. PMID- 21552403 TI - Cytodiagnosis of coexistent cryptococcal and mycobacterial lymphadenitis in a case of AIDS. AB - Multiple infections are a common feature of acquired immunodeficiency syndrome (AIDS), but coexistent infections at the same site are rare. In this report, we describe a 35-year-old human immunodeficiency virus infected male with coexistent cryptococcal and mycobacterial lymphadenitis. He presented with generalised lymphadenopathy. Fine needle aspiration cytology of enlarged cervical lymph node, aided by special stains, revealed coexistent cryptococcal and mycobacterial infection. Coexistent infections pose diagnostic problems in AIDS patients and are likely to be missed. Special stains are valuable for accurate diagnosis of coexistent infections. PMID- 21552404 TI - Cytological diagnosis of adamantinoma of long bone in a 78-year-old man. AB - A clinicohistopathological study of a rare case of adamantinoma of long bone in a 78-year-old patient is presented. The cytological features when evaluated in conjunction with clinical and radiologic features are sufficiently diagnostic. The primary knowledge of its existence and knowledge of its cytological features are important for a correct preoperative cytological diagnosis. PMID- 21552405 TI - Cytodiagnosis of cutaneous metastasis from renal cell carcinoma: A case report with review of literature. AB - Cytodiagnosis of cutaneous metastasis of renal cell carcinoma (RCC) in the absence of history of primary tumor is difficult as it can be confused with other clear cell tumors. We report here a case of cytodiagnosis of cutaneous metastasis of RCC in a patient who had nephrectomy done 9 years back at some other centre, but did not have any records with him. Clinicians should be aware of the possibility of primary internal organ malignancy in patients presenting with cutaneous lesions and therefore conduct a careful examination and get necessary investigations. Prompt diagnosis and treatment will have its bearing on the eventual outcome. PMID- 21552406 TI - Metastatic myxoid liposarcoma of lung and mediastinum diagnosed by fine needle aspiration. AB - Myxoid liposarcomas metastatic to lungs and mediastinum are infrequent lung neoplasms. The tumor has an aggressive course and needs to be recognized cytologically. A 60-year-old male smoker presented with gradually progressive left-sided chest pain, cough, and expectoration for the past one month. Chest radiograph and computed tomography of thorax revealed a lung mass in left apical region extending into the posterior mediastinum, which was subjected to ultrasound-guided fine needle aspiration (FNA). Smears showed a cellular tumor with ovoid to spindle shaped tumor cells in a myxoid background having a rich vascular network. The possibility of a myxoid liposarcoma metastatic to lung and mediastinum was suggested and confirmed by histopathology. A previous history of excision of a tumor in the thigh one and half years ago was present. The importance of recognizing the cytological picture by FNA is discussed. PMID- 21552407 TI - Hemophagocytic syndrome secondary to cytomegalovirus infection in an infant. AB - Virus associated hemophagocytic syndrome is a non-neoplastic, generalized histiocytic proliferation with prominent hemophagocytosis associated with a systemic viral infection. We report a case of cytomegalovirus (CMV) associated hemophagocytic syndrome in a 2 month old male child presenting with rashes, fever, hepatosplenomegaly, cervical lymphadenopathy and pancytopenia. Fine needle aspiration cytology and biopsy from cervical lymph nodes revealed prominent hemophagocytosis. Serology for CMV IgM was positive in both the mother and the child, suggesting recent infection. Possibly there was intrauterine transmission of the infection. PMID- 21552408 TI - Fine needle aspiration cytology and cell block in the diagnosis of seminoma testis. AB - Testicular neoplasms which show a wide variety of morphologic types, comprise a small proportion of malignancies. Early identification and treatment is essential for achieving long term survival. The cytologic findings in fine needle aspiration smears from left testicular swelling of a 49 year old male suggestive of a germ cell tumor was complimented by cell block preparation as seminoma. This was confirmed by histopathologic studies. We are presenting this case to emphasize that cell block can be used for diagnosis of testicular tumors. PMID- 21552409 TI - Mucinous carcinoma of breast: Cytodiagnosis of a case. AB - Mucinous carcinoma of the breast is a relatively rare, pure form accounting for 2% of all breast cancers. Pure mucinous carcinoma of the breast has a favorable prognosis. The common age is postmenopausal group. Here, we report a 30-year-old female patient diagnosed on cytology as mucinous carcinoma of the breast with lymph node metastasis and subsequently confirmed by histopathology. In 1 year follow-up, the patient did not show pulmonary or distant metastasis and received adjuvant chemotherapy at every 3 weeks interval. PMID- 21552410 TI - Tamoxifen in early-stage estrogen receptor-positive breast cancer: overview of clinical use and molecular biomarkers for patient selection. AB - Tamoxifen was the first targeted anticancer agent for breast cancer patients and its effects on reduction of breast cancer events and improvement in overall survival are undisputed. Hence, it has long been considered an essential part of patient care. Recent results of several large adjuvant hormonal trials evaluating the use of aromatase inhibitors in comparison with the previous standard of five years of tamoxifen has led to a paradigm shift, ensuring the inclusion of an aromatase inhibitor as part of standard endocrine therapy for most postmenopausal women diagnosed today with estrogen receptor-positive breast cancer. However, one could argue that despite statistically significant improvements in breast cancer events, an overall survival advantage has not been clear. In this review, we discuss recent genomic and molecular data pertaining to estrogen receptor positive breast cancer and how this knowledge may aid clinicians to prescribe adjuvant hormonal treatment in the future. A combination of gene expression and genetic aberration markers may be most useful in discerning a population that is still appropriate for adjuvant tamoxifen treatment. PMID- 21552411 TI - Electronic brachytherapy as adjuvant therapy for early stage breast cancer: a retrospective analysis. AB - PURPOSE: This multicenter, retrospective study evaluated treatment and clinical outcomes of patients with early stage breast cancer who received adjuvant high dose rate (HDR) electronic brachytherapy (EBT) treatment post-lumpectomy using the Axxent((r)) EBT system. Dosimetric data from the EBT treatment plans were compared with those based on iridium-192 HDR brachytherapy. MATERIAL AND METHODS: Medical records of 63 patients with early stage breast cancer (Tis, T1a, T1b, T1c, and T2) who were treated post-lumpectomy with EBT alone or in combination with external beam radiation therapy were reviewed. The prescribed EBT dose was 34 Gy (10 fractions over 5 days, 3.4 Gy each) to 1 cm from the balloon surface. Dosimetry data from 12 patients were compared with these of treatment plans using an iridium-192 source prepared for the same 12 patients. RESULTS: The majority of patients (90.5%) were older than 50 years and had one or more risk factors for breast cancer (80.6%). Tumor sizes were 0.1 cm to 3.5 cm (mean 1.3 cm). Median follow-up was 7 months (1 to 18 months) post-EBT. Balloon applicators were implanted 0 to 85 days (mean 13.4 days) post-lumpectomy/re-excision. The most common adverse events were erythema, rash dermatitis, and pain or breast tenderness. No recurrences were reported. Dosimetric analyses demonstrated comparable target coverage, increased high-dose regions, and a significantly reduced dose to the ipsilateral breast and lungs as well as the heart with EBT as compared with the iridium-192 treatment plans. CONCLUSION: This retrospective, multicenter study showed that postsurgical adjuvant radiation therapy for early stage breast cancer can be administered using the EBT system with similar toxicity outcomes to those reported with iridium-192 brachytherapy. EBT offers a convenient, portable, nonisotope alternative to HDR brachytherapy using iridium 192. PMID- 21552413 TI - Expression of organic anion-transporting polypeptides 1B3, 1B1, and 1A2 in human pancreatic cancer reveals a new class of potential therapeutic targets. AB - BACKGROUND: Organic anion-transporting polypeptides (OATPs) are influx transporters that mediate intracellular uptake of selective endogenous and xenobiotic compounds. Identification of new molecular targets and discovery of novel targeted therapies is top priority for pancreatic cancer, which lacks any effective therapy. MATERIALS AND METHODS: We studied expression of OATP 1A2, 1B1, and 1B3 in pancreatic cancer tissue and in cell lines. Formalin-fixed paraffin embedded biopsy material of 12 human pancreatic cancers was immunohistochemically assessed for protein expression of the three studied influx transporters. Immunohistochemistry was evaluated by experienced pathologists and quantified by use of an automated image analysis system. BxPC-3 and MIA PaCa-2 pancreatic cancer cell lines were used to quantify transcripts of OATP 1B1 and 1B3. RESULTS: OATP 1A2, 1B1, and 1B3 proteins were found ubiquitously expressed in all studied cases. Quantification performed by HistoQuest system revealed that mean intensity was 53 for 1A2, 45 for 1B1, and 167 for OATP 1B1/1B3 on a range scale 0-250 units. At mRNA level, 1B1 and 1B3 were overexpressed in both studied cancer cell lines but not in normal pancreatic tissue. CONCLUSION: OATPs 1A2, 1B1, and 1B3 are highly expressed in pancreatic adenocarcinoma. We suggest that expression of these transporters in pancreatic cancer justify research efforts towards discovery of novel therapeutics targeting OATPs. PMID- 21552412 TI - New developments in the treatment of metastatic gastric cancer: focus on trastuzumab. AB - Patients with metastatic gastric cancer have a poor outcome. The development of new combinations of chemotherapy has led to steady but only modest gains in overall survival with largest effects reported with two- and three-drug regimens. Trastuzumab, a fully humanized monoclonal antibody directed at the human epidermal growth factor receptor-2 (HER2), has been found to improve response rate and survival in patients with advanced gastric cancer. This update will review the role of HER2 and summarize therapeutic advances in the use of trastuzumab in advanced gastric cancer. PMID- 21552414 TI - Long term effects of cyclophosphamide treatment on lung function and survival in scleroderma patients with interstitial lung disease. AB - BACKGROUND: Scleroderma (SSc) patients with active interstitial lung disease (ILD) experience a decline in lung function and increased mortality; cyclophosphamide (CYC) therapy may stabilize lung function at one and two years follow-up. Long-term lung function and survival outcomes of SSc patients with ILD following CYC treatment remain largely unknown. METHODOLOGY: We reviewed records of SSc patients with active ILD who had received at least six months of CYC treatment and had pulmonary function tests (PFTs) performed at least two years from the onset of treatment. PRINCIPAL FINDINGS: Thirty eight patients meeting eligibility criteria had a mean follow-up period from start of CYC to the last follow-up PFT of 5.1 years (range 2.3 -10.8 years). At a median of 4.1 years (range 9 months - 8.4 years), 12/38 (32%) patients had a significant decline in % predicted Forced Vital Capacity from their baseline PFT. At a median of 3.9 years (range 7 months - 8.4 years); 12/36 (33%) patients experienced a significant decline in their % predicted carbon monoxide diffusing capacity. Three patients died at a follow-up between 4.5-6 years and two received bilateral lung transplants because of severe restrictive lung disease. CONCLUSIONS: While the majority of SSc patients treated with CYC for active ILD experience long-term lung function stability and survive, greater than 1/3 of patients will experience either lung function decline, death, or require a lung transplant. This suggests that despite aggressive immune suppressing therapy, a subset of patients will have continued lung function decline, highlighting the need for ongoing monitoring and better therapeutic options. PMID- 21552415 TI - Hand Osteoarthritis Severity is Associated with Total Knee Joint Replacements Independently of BMI. The Ages-Reykjavik Study. AB - OBJECTIVE: To identify factors associated with having total knee replacement due to osteoarthritis in the AGES-Reykjavik Study, a large population based study of elderly Icelanders. METHODS: Information about total knee and hip joint replacements (TKR,THR) and hand OA (HOA) severity was available in 2195 males and 2975 females, mean age 76+/-6 years. The prevalence of TKR was 223 (4.3%) and THR 316 (6.1%). We performed a backwards binary logistic regression analysis of possible OA associated variables including age, gender, abdominal circumference, BMI, hs-CRP, cholesterol, statin use, bone mineral density of the spine, education and smoking history as well as HOA severity and the presence of THR. RESULTS: Only three factors showed significant associations with TKR; BMI (p=3.5x10(-17)), HOA severity (p=2.9x10(-8)) and THR (p=0.0002). The highest quintile of BMI was associated with a fivefold risk of TKR compared with the lowest (8% vs 1.6%), and severe HOA had a 2.4 fold risk compared with those with no HOA (8% vs 3.3%). There was no statistical interaction between BMI and HOA. Thus, individuals with BMI<23.5 with no evidence of HOA had a prevalence of TKR of 1.1%, while those with BMI>30.3 and severe HOA had a prevalence of 13.4%. CONCLUSIONS: Hand and hip osteoarthritis in conjunction with BMI are strongly associated with the prevalence of TKR due to osteoarthritis. Together, BMI and HOA severity seem to contribute to the majority of the total TKR prevalence. While BMI has long been recognized as the major risk factor for TKR, the influence of osteoarthritis at other sites may have been underestimated. PMID- 21552416 TI - Melatonin and its day and night rhythm of alterations in familial mediterranean Fever: a brief research letter. AB - OBJECTIVE: The pineal hormone melatonin plays a crucial role in immunomodulation, mainly by effecting T cells. The aims of the present study were to compare the melatonin levels in patients with Familial Mediterranean Fever (FMF) and healthy controls and to find out if it associates with interferon(IFN)gamma and interleukin(IL)-10. MATERIALS AND METHODOLOGY: Twenty five patients with FMF and 16 healthy donors were enrolled into the study. Melatonin, IFN gamma and IL-10 measurements were assayed by using enzyme immunoassay (EIA) method. RESULTS: Serum melatonin levels at 03.30 am in both patients during attack-free phase and healthy controls were significantly higher than those levels of corresponding groups measured at 10.00 am. The melatonin levels at 03.30 and 10.00 am in patients during attack-free phase were higher than those levels measured in healthy controls at the same time points. IFNgamma and IL-10 did not show any day and night rhythm in both patients and healthy controls. In addition, there was no association among day and night levels of melatonin, IFNgamma and IL-10. CONCLUSIONS: We conclude that melatonin may play a role in FMF pathogenesis. However, its modulatory effect on immune response most likely does not depend on T cells. Further comprehensive studies should be performed in order to reveal the role of melatonin in the pathogenesis of this disease. PMID- 21552417 TI - Overexpression of Grb2-associated binder 2 in human lung cancer. AB - OBJECTIVE: Grb2-associated binder 2 (Gab2), a member of the family of Gab scaffolding adaptors, transmits and amplifies the signals from receptor tyrosine kinases. A recent study demonstrated that Gab2 was over-expressed in breast cancers and metastatic melanomas, and Gab2 was an oncogenic protein. However, the roles of Gab2 in lung cancers are largely unknown. METHOD: In this study, to investigate whether Gab2 expression could be a characteristic of lung cancers, we analyzed the expression of Gab2 in 88 lung frozen tissue samples and 122 paraffin embedded tissue specimens, using quantitative real-time-PCR, immunohistochemistry and western blot. RESULTS: We found that the positive expression rate of Gab2 in the tumor tissues, as detected by immunohistochemistry, 62.5% in squamous cell cancers, 51.35% in adenocarcinomas, and 75% in other types of lung cancers, was significantly higher than that (12%) in normal lung tissues. The mRNA expression detected by quantitative real-time-PCR and protein expression detected by western blotting in different groups were consistent with the immunohistochemical results. CONCLUSION: Our data indicate that Gab2 is over-expressed in malignant lung tissues compared with that in normal lung tissues, and suggest that Gab2 expression may play a role in lung cancer development. PMID- 21552418 TI - Identification and characterization of the alternatively spliced nuclear receptor coactivator-6 isoforms. AB - The nuclear receptor coactivator-6 (NCOA6, AIB3, PRIP, ASC-2, TRBP, RAP250 or NRC) is a co-activator for nuclear hormone receptors and certain other transcription factors. NCOA6 plays an important role in embryonic development, adipocyte differentiation, metabolism and breast carcinogenesis. The human and mouse NCOA6 genes had 15 and 14 previously identified exons, respectively. This study further identified an alternatively spliced exon 11b (E11b) in human or E10b in mouse, which codes a short polypeptide and a Stop codon, resulting in splicing variants lacking the last four exon-coded polypeptide. Analyses of mouse testis NCOA6 mRNAs identified four alternatively spliced variants, NCOA6-alpha (without E10b), -beta (without E10a and E10b), -gamma (with E10a and E10b) and delta (without E10a but with E10b). These isoforms were detected in multiple mouse tissues and in MDA-MB-435 human cells. NCOA6-alpha and -beta are mainly located in the nucleus; NCOA6-gamma is located in both cytoplasm and nucleus; and NCOA6-delta is mainly located in mitochondria. The C-terminus coded by the last four exons was responsible for locating NCOA6-alpha and -beta into the nucleus. The human E11a or mouse E10a-coded region is responsible for distributing NCOA6 gamma in both cytoplasm and nucleus, while the region coded by E8-E9 in human or E7-E8 in mouse is responsible for directing NCOA6-delta to mitochondria. Our assays also demonstrated that NCOA6-alpha and -beta could significantly enhance estrogen receptor alpha-mediated transcription, but NCOA6-gamma and -delta were unable to do so. These results suggest that the diverse physiological function of NCOA6 may be mediated by multiple isoforms expressed in different tissues and localized in different subcellular compartments. PMID- 21552421 TI - Varied pathways of stage IA lung adenocarcinomas discovered by integrated gene expression analysis. AB - BACKGROUND: Discovery of the progression-associated genes and pathways in lung adenocarcinoma (LAD) has important implications in understanding the molecular mechanism of tumor development. However, few studies had been performed to focus on the changes of pathways in lung adenocarcinoma development using microarray expression profile. RESULT: We performed a meta-analysis of 4 LAD microarray datasets encompassing 353 patients to reveal differentially expressed genes (DEGs) between normal lung tissues and LAD of different stages. Overall, 1 838 genes were found to be dys-regulated, and the adipogenesis, circadian rhythm, and Id pathways were significantly changed. Interestingly, most of the genes from the same gene family (such as Interleukin receptor, Matrix metallopeptidase, Histone cluster and Minichromosome maintenance complex component families) were found to be up-regulated (or down-regulated). Real-time PCR (qRT-PCR) was applied to validate the expression of randomly selected 18 DEGs in LAD cell lines. In the pathway analysis among stages, Oxidative stress, Glycolysis/Gluconeogenesis and Integrin-mediated cell adhesion pathways, which were involved in cancer cell proliferation and metastasis, were showed to be significantly regulated in stages other than IA. CONCLUSION: Genes involved in adipogenesis and Id pathways might play important roles in development of LADs. The similar trend of expression of the gene family members suggested coordinate regulation in tumor progression. Three pathways (Oxidative stress, Glycolysis/Gluconeogenesis and Integrin mediated cell adhesion pathways) significantly regulated in stages other than stage IA suggested that genes and pathways conferring invasive character might be activated in the preinvasive stage IB, while the Oxidative stress and the Glycolysis/Gluconeogenesis pathways might have strong connections to cisplatin based chemotherapy. The insignificantly regulated three pathways in stage IA might be used in early-stage detection of LAD. PMID- 21552420 TI - Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target. AB - Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated by many cytokines and growth factors and plays a key role in cell survival, proliferation, and differentiation. STAT3 activation is detected virtually in all rodent models of liver injury and in human liver diseases. In this review, we highlight recent advances of STAT3 signaling in liver injury, steatosis, inflammation, regeneration, fibrosis, and hepatocarcinogenesis. The cytokines and small molecules that activate STAT3 in hepatocytes may have therapeutic benefits to treat acute liver injury, fatty liver disease, and alcoholic hepatitis, while blockage of STAT3 may have a therapeutic potential to prevent and treat liver cancer. PMID- 21552419 TI - Novel therapeutic strategies for targeting liver cancer stem cells. AB - The cancer stem cell (CSC) hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment.Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It is believed that hepatic progenitor cells (HPCs) could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/beta-catenin, TGF-beta, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC. Here we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for targeting liver CSCs. PMID- 21552422 TI - miR-148a promoted cell proliferation by targeting p27 in gastric cancer cells. AB - Accumulating evidence has shown that miRNAs are aberrantly expressed in human gastric cancer and crucial to tumorigenesis. Herein, we identified the role of miR-148a in gastric cell proliferation. miR-148a knockdown inhibited cell proliferation in gastric cancer cell lines. Conversely, miR-148a overexpression promoted cell proliferation and cell cycle progression. p27, a key inhibitor of cell cycle, was verified as the target of miR-148a, indicating miR-148a might downregulate p27 expression to promote gastric cell proliferation. Moreover, we confirmed that miR-148a expression was frequently and dramatically downregulated in human advanced gastric cancer tissues, and observed a good inverse correlation between miR-148a and p27 expression in tumor samples. Thus, our results demonstrated that miR-148a downregulation might exert some sort of antagonistic function in cell proliferation, rather than promote cell proliferation in gastric cancer. PMID- 21552424 TI - Bayesian model-based tight clustering for time course data. AB - Cluster analysis has been widely used to explore thousands of gene expressions from microarray analysis and identify a small number of similar genes (objects) for further detailed biological investigation. However, most clustering algorithms tend to identify loose clusters with too many genes. In this paper, we propose a Bayesian tight clustering method for time course gene expression data, which selects a small number of closely-related genes and constructs tight clusters only with these closely-related genes. PMID- 21552423 TI - Internet-based behavioral interventions for obesity: an updated systematic review. AB - The objective of this systematic review is to update a previous systematic review on the effectiveness of internet-based interventions for weight loss and weight loss maintenance in overweight and obese people with new or additional studies. A literature search from 2008 to March 2010 was conducted. Studies were eligible for inclusion if: participants were adults with a body mass index <= 25, at least one study arm involved an internet-based intervention and the primary aims were weight loss or maintenance. Eight additional studies over the eighteen included in the previous review met the inclusion criteria. Data were extracted on sample characteristics, attrition, weight loss, duration of treatment and maintenance of weight loss. Effect sizes (Hedges g) and relative 95% confidence intervals were calculated for all two-way comparisons within each study. No attempt was made to pool the data in a meta-analysis because of the great heterogeneity of designs among studies. An examination of effect sizes show that the higher significant effects pertain studies that found a superiority of behavioral internet-based programs enhanced by features such as tailored feedback on self-monitoring of weight, eating and activity over education only internet-based interventions. However, control groups are very different among studies and this heterogeneity probably accounts for much of the variance in effect sizes. Hence, questions still remain as to the effectiveness of web-based interventions in achieving weight loss or maintenance. Implications for further research include using a "real" control group in order to make meta-analysis possible and developing multi factorial design in order to separate components of interventions and identify which of them or patterns of them are keys to success. PMID- 21552425 TI - There's more to emotion than meets the eye: A processing bias for neutral content in the domain of emotional prosody. AB - Research on emotion processing in the visual modality suggests a processing advantage for emotionally salient stimuli, even at early sensory stages; however, results concerning the auditory correlates are inconsistent. We present two experiments that employed a gating paradigm to investigate emotional prosody. In Experiment 1, participants heard successively building segments of Jabberwocky "sentences" spoken with happy, angry, or neutral intonation. After each segment, participants indicated the emotion conveyed and rated their confidence in their decision. Participants in Experiment 2 also heard Jabberwocky "sentences" in successive increments, with half discriminating happy from neutral prosody, and half discriminating angry from neutral prosody. Participants in both experiments identified neutral prosody more rapidly and accurately than happy or angry prosody. Confidence ratings were greater for neutral sentences, and error patterns also indicated a bias for recognising neutral prosody. Taken together, results suggest that enhanced processing of emotional content may be constrained by stimulus modality. PMID- 21552426 TI - Comparison of the Lunar DPX-L and Prodigy dual-energy X-ray absorptiometers for assessing total and regional body composition. AB - The purpose of this study was to assess the agreement of the Lunar DPX-L with the newer Prodigy dual-energy X-ray absorptiometer (DXA) for determining total-body and regional (arms, legs, trunk) bone mineral density (BMD), bone mineral content (BMC), fat mass (FM), lean tissue mass (LTM), total body mass (BM) and percent fat. A total of 106 apparently healthy males (n=34) and females (n=72) between the ages of 8-72 years were scanned consecutively on the DPX-L (software version 1.35) and Prodigy DXA (enCORE v. 3.6 software). Paired t-tests indicated significantly higher measures by Prodigy for BM (percent difference= 1.1%) and total-body BMD (2.2%), BMC (2.9%), FM (3.5%), and percent fat (2.8%; P<0.001), but not LTM (-0.2%). Regional estimates of FM and bone tended to be overestimated by Prodigy relative to DPX-L. The percent difference was most pronounced for FM in the arms (14.2%) and trunk (8.5%), BMD in the legs (4.9%), LTM in arms (5.6%), and BMC in the trunk (5.9%); but all total-body and regional measures were strongly and significantly correlated (P<0.001). The method of Bland and Altman indicated that the Prodigy overestimated DPX-L for BM (r=0.343; P<0.001), and total-body measures of BMD (r=0.460; P<0.001), and BMC (r=0.321; P<0.001) at higher values, as indicated by the significant, positive association between difference (Prodigy-DPX-L) versus mean ((Prodigy+DPX-L)/2). Regionally, Prodigy overestimated DPX-L for BMD in the legs, BMC in the legs and trunk, and FM in the arms at higher values (P<0.001). In contrast, FM in the legs was underestimated by Prodigy relative to DPX-L at higher values (P<0.001), and no regional bias was observed for LTM. In conclusion, we recommend that correction equations be used for comparing BM, total-body BMD and BMC, and regionally for BMD in the legs, BMC in the legs and trunk, and FM in the arms and legs. The use of correction equations for other estimates is not required for making direct comparisons. PMID- 21552428 TI - An Exploratory Study of Inhalers and Injectors Who Used Black Tar Heroin. AB - AIMS: To undertake an exploratory study to examine the characteristics of patients in narcotic treatment programs who started their use of black tar heroin either as inhalers or as injectors and to compare them with those who started as inhalers but shifted to injecting. Other studies in this area have used subjects using other forms of heroin more amenable to inhaling. PARTICIPANTS, DESIGN, AND MEASUREMENT: A purposive sample of 199 patients in 6 methadone programs in Texas were interviewed in 2002-2003 using a structured instrument. FINDINGS: At admission to treatment, those who were heroin inhalers were more likely to be African American, to live with their families, to have income from wages, and to report fewer days of problems on most of the ASI measures. Those who shifted from inhaling to injecting were more likely to be Hispanic and to have had mental health problems that interfered with their lives and to have had less nurturing while growing up. Injectors were older at this treatment admission, had more treatment episodes and more times in jail, and were more likely to have hepatitis C, AIDS, or gonorrhea. There were high levels of physical and mental problems and histories of traumatization as children and adults for almost all the respondents. Males were as likely as females to have been sexually abused as children or as adults. CONCLUSIONS: The high rates of mental and physical problems among all the clients interviewed showed the need for comprehensive services to be delivered within the substance abuse treatment programs. Histories of trauma and sexual abuse should be addressed for both male and female clients. PMID- 21552427 TI - Macrophages and Cell-Cell Spread of HIV-1. AB - Macrophages have been postulated to play an important role in the pathogenesis of HIV-1 infection. Their ability to cross the blood-brain barrier and their resistance to virus-induced cytopathic effects allows them to serve as reservoirs for long-term infection. Thus, exploring the mechanisms of virus transmission from macrophages to target cells such as other macrophages or T lymphocytes is central to our understanding of HIV-1 pathogenesis and progression to AIDS, and is vital to the development of vaccines and novel antiretroviral therapies. This review provides an overview of the current understanding of cell-cell transmission in macrophages. PMID- 21552429 TI - Using Blur to Affect Perceived Distance and Size. AB - We present a probabilistic model of how viewers may use defocus blur in conjunction with other pictorial cues to estimate the absolute distances to objects in a scene. Our model explains how the pattern of blur in an image together with relative depth cues indicates the apparent scale of the image's contents. From the model, we develop a semiautomated algorithm that applies blur to a sharply rendered image and thereby changes the apparent distance and scale of the scene's contents. To examine the correspondence between the model/algorithm and actual viewer experience, we conducted an experiment with human viewers and compared their estimates of absolute distance to the model's predictions. We did this for images with geometrically correct blur due to defocus and for images with commonly used approximations to the correct blur. The agreement between the experimental data and model predictions was excellent. The model predicts that some approximations should work well and that others should not. Human viewers responded to the various types of blur in much the way the model predicts. The model and algorithm allow one to manipulate blur precisely and to achieve the desired perceived scale efficiently. PMID- 21552430 TI - Trapping of Thiol Terminated Acrylate Polymers with Divinyl Sulfone to Generate Well-Defined Semi-Telechelic Michael Acceptor Polymers. AB - Herein we report the synthesis of vinyl sulfone end functionalized PEGylated polymers by reversible addition-fragmentation chain transfer (RAFT) polymerization for conjugation to proteins. Poly(ethylene glycol) methyl ether acrylate (PEGA) was polymerized in the presence of 1-phenylethyl dithiobenzoate with 2,2'-azobis(2-methylpropionitrile) as the initiator to generate well-defined polyPEGAs with number-average molecular weights (M(n)) by gel permeation chromatography (GPC) of 6.7 kDa, 11.8 kDa and 16.1 kDa. Post-polymerization, the majority of polymer chains contained the dithioester functional group at the omega chain end, and the polydispersity indexes (PDI) of the polymers ranged from 1.08 to 1.24. The dithioester was subsequently reduced via aminolysis, and the resulting thiol was trapped with a divinyl sulfone in situ to produce semi telechelic, vinyl sulfone polyPEGAs with efficiencies ranging between 85% and 99%. It was determined that the retention of vinyl sulfone was directly related to reaction time, with the maximum dithioester being transformed into a vinyl sulfone within 30 minutes. Longer reaction times resulted in slow decomposition of the vinyl sulfone end group. The resulting semi-telechelic vinyl sulfone polymers were then conjugated to a protein containing a free cysteine, bovine serum albumin (BSA). Gel electrophoresis demonstrated that the reaction was highly efficient and that conjugates of increasing size were readily prepared. After polymer attachment, the activity of the BSA was 92% of the unmodified biomolecule. PMID- 21552431 TI - Shear thickening of F-actin networks crosslinked with non-muscle myosin IIB. AB - The material properties of cytoskeletal F-actin networks facilitate a broad range of cellular behaviors, whereby in some situations cell shape is preserved in the presence of force and, at other times, force results in irreversible shape change. These behaviors strongly suggest that F-actin networks can variably deform elastically or viscously. While a significant amount is known about the regulation of the elastic stiffness of F-actin networks, our understanding of the regulation of viscous behaviors of F-actin networks is largely lacking. Here, we study the rheological behavior of F-actin networks formed with heavy meromyosin non-muscle IIB (NMMIIB). We show that NMMIIB quenched with ADP crosslinks F-actin into networks that, for sufficient densities, display stress stiffening behavior. By performing a series of creep tests, we show that densely crosslinked actin/NMMIIB-ADP networks undergo viscous deformation over a wide range of stresses, ranging from 0.001 to 10 Pa. At high stresses, networks that stress stiffen are also observed to shear thicken, whereby the effective viscosity increases as a function of stress. Shear thickening results in a reduction in the extent of irreversible, viscous deformation in actin/NMMIIB-ADP networks at high stresses compared to that expected for a linear viscoelastic material. Thus, viscous deformation contributes less to the overall mechanical response at high levels of applied force. Our results indicate mechanisms by which the fluid-like nature of the actomyosin cytoskeleton can be reduced under high load. PMID- 21552432 TI - The Product Operator Formalism: A Physical and Graphical Interpretation. AB - The product-operator formalism is the most commonly used tool for describing and designing multidimensional NMR experiments. In spite of its relative simplicity and sound theoretical underpinnings, however, students and practitioners often find it difficult to relate the mathematical manipulations to a physical picture. In an effort to address this pedagogical challenge, the present paper begins with a quantum-mechanical treatment of pure populations of scalar-coupled spin-pairs, rather than the equilibrium population of spin-pairs in different quantum states, which is the usual starting point for treatments based on the density matrix and product operators. In the context of pure populations, the product operators are shown to represent quantum correlations between the nuclei in individual molecules, and a new variation on the classical vector diagram is introduced to represent these correlations. The treatment is extended to mixed populations that begin at thermal equilibrium, and the density matrix is introduced as an efficient means of carrying out quantum calculations for a mixed population. Finally, it is shown that the operators for observable magnetization and correlations can be used as a basis set for the density matrix, providing the formal justification for the widely-used rules of the product-operator treatment. Throughout the discussion, the vector diagrams are used to help maintain a connection between the mathematics and the sometimes subtle physical principles. An electronic supplement created with the Mathematica computer program is used to provide additional mathematical details and the means to carry out further calculations. PMID- 21552433 TI - Comparison of software versions for body composition analysis using the PIXImus dual-energy X-ray absorptiometer. AB - We have previously validated the use of dual-energy X-ray absorptiometry (DXA) for measuring body composition of mice using the GE-Lunar PIXImus and software version 1.42 [1]. Since that report, newer versions of the software have been released. The purpose of the present study was to compare results from our original study with results analyzed using two newer versions of software (versions 1.44 and 1.45). Body composition data (lean tissue mass [LTM], fat mass [FM], bone mineral content [BMC], and bone mineral density [BMD]) were obtained from DXA scans of twenty-five, anesthetized male C57Bl/6J mice (6-11 weeks old; 19 to 29g). Relative to version 1.42, versions 1.44 and 1.45 significantly (P<0.001) overestimated LTM and BMD and underestimated FM and BMC. However, compared to carcass analysis, versions 1.44 and 1.45 significantly overestimated both FM and LTM and underestimated BMC. Results from 1.44 and 1.45 were highly correlated with carcass values for all body composition parameters. Prediction equations were developed for the two new software versions. Applying the prediction equation from 1.42, to the data obtained from 1.44 and 1.45 resulted in FM and LTM that were worse than if no equation was used. However, using their own developed equations resulted in data that were not significantly different than that from carcass analysis. These data suggest that software-specific equations are necessary for comparing DXA-derived data to that of chemical analysis. PMID- 21552434 TI - A new crystal form of mouse thiamin pyrophosphokinase. AB - Thiamin pyrophosphokinase (TPK) transfers a pyrophosphate group from ATP to the hydroxyl group of thiamin and produces thiamin pyrophosphate (TPP). TPP is the cofactor of metabolically important enzymes such as pyruvate dehydrogenase, alpha ketoglutarate dehydrogenase, branched-chain alpha-keto acid dehydrogenase, transketolase and 2-hydroxyphytanoyl-CoA lyase. Thiamin deficiency results in Wernike-Korsakof Syndrome (WKS) due to neurological disorder and wet beriberi, a potentially fatal cardiovascular disease. Mouse TPK associates as a dimer revealed by previous solved crystallographic structures. In this study, we report mouse TPK complexed with TPP-Mg(2+) and thiamin -Mg(2+), respectively, in a new crystal form. In these two structures, four mouse TPK molecules were found in each asymmetric unit. Although we cannot rule out this tetramer form can be an artifact from crystal packing, mouse TPK tetramer has a more closed ATP binding pocket and has the potential to provide specific interactions between mouse TPK and ATP compared with the previous dimeric structure and is likely to be an active form. PMID- 21552435 TI - An extremely uncommon case of parasitic infection presenting as eosinophilic ascites in a young patient. AB - We report the case of a 24-year-old male patient admitted for recent ascites and splenomegaly of unknown origin. The patient was referred to our institution with complaints of diarrhea, epigastric pain, abdominal cramping and weight loss over the past three weeks. The acute onset presented with colicky abdominal pain and peritoneal effusion. History revealed reduced appetite and weight gain of 7 kg over the last one month. His past medical history and family history was negative. He had no history of alcohol abuse or viral hepatitis infection. Laboratory data revealed normal transaminases and bilirubin levels, and alkaline phosphatase and gammaglutamyltransferase were within normal range. A diagnostic laparoscopy was performed which showed free peritoneal fluid and normal abdominal viscera. Upper gastrointestinal system endoscopy performed a few days later revealed diffuse severe erythematous pangastritis and gastroduodenal gastric reflux. Duodenal biopsies showed chronic nonspecific duodenitis. Antrum and corpus biopsies showed chronic gastritis. The ascitic fluid was straw-colored and sterile with 80% eosinophils. Stool exam was negative for parasitic infection. Treatment with albendazole 400 mg twice daily for 5 days led to the disappearance of ascites and other signs and symptoms. Three months after albendazole treatment the eosinophilic cell count was normal. The final diagnosis was consistent with parasitic infection while the clinical, sonographic and histological findings suggested an eosinophilic ascites. We emphasize the importance of excluding parasitic infection in all patients with eosinophilic ascites. We chose an alternative way (albendazole treatment) to resolve this clinical picture. With our alternative way for excluding this parasitic infection, we treated the patient and then found the cause. PMID- 21552436 TI - A complicated case of tacrolimus-induced rapid remission after cesarean section in the early third trimester for refractory severe ulcerative colitis flaring in the initial period of gestation. AB - A 36-year-old woman who had been diagnosed with ulcerative colitis at the age of 17 years was referred to our hospital because of severe abdominal pain and repeated bloody diarrhea that persisted during pregnancy despite combination therapy with high-dose corticosteroids and weekly granulocyte and monocyte adsorptive apheresis (GMA). She underwent combination therapy consisting of high dose corticosteroids, intensive GMA (two sessions per week) and vancomycin, which was used to eradicate Clostridium difficile, under total parenteral nutrition control until the estimated weight of her fetus reached 1,000 g. This combination therapy was partially successful, resulting in almost complete disappearance of abdominal pain and a marked decrease in stool frequency. However bloody diarrhea persisted and the patient developed anemia and hypoalbuminemia and was unable to prolong her gestation time. Cesarean section was conducted at 28 weeks of gestation without any congenital abnormalities or neurological defects. Oral administration of tacrolimus was begun 7 days after cesarean section, which was followed by rapid induction of remission. Corticosteroids were then gradually tapered off. Tacrolimus is one therapeutic option after cesarean section in pregnant patients who do not respond well to GMA and high-dose corticosteroids for persistent active ulcerative colitis. PMID- 21552437 TI - Hepatic sarcoidosis mimicking hilar cholangiocarcinoma: case report and review of the literature. AB - Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. Hepatic involvement was reported in about 11% of patients with sarcoidosis. However, cases of sarcoidosis in which the granuloma is solitary and limited in the liver are very rare. A 51-year-old woman with tumors in the liver underwent extended left lobectomy with caudate lobectomy and bile duct resection. The tumor was located between segment 4 and the hilar region. Some daughter nodules were found in the left lobe, which were regarded as intrahepatic metastasis. Our case displayed clinical and radiologically distinct findings, which are very similar to those of hilar cholangiocarcinoma restricted to the liver. This report demonstrates that sarcoidosis can show solitary hepatic involvement in the absence of thoracic lymphadenopathy. In such a case, it is difficult to distinguish the diagnosis from other malignant neoplasms. In conclusion, the diagnosis of hepatic sarcoidosis has to be made through prudent and comprehensive investigations that include a full clinical history of sarcoidosis in other organs. Despite utilizing several detailed diagnostic modalities, the definitive diagnosis of cases of solitary sarcoidosis may remain difficult. In these cases, surgical treatment including liver resection should be considered in order to avoid missing a suitable opportunity for treatment. PMID- 21552438 TI - Exacerbation of bloody diarrhea as a side effect of mesalamine treatment of active ulcerative colitis. AB - Mesalamine has been used as the first-line therapy for the treatment of ulcerative colitis (UC) because of its efficacy and fewer side effects. However, earlier study showed that mesalamine occasionally causes diarrhea. We are presenting a patient with active UC in whom bloody diarrhea accompanied by abdominal pain and fever occurred and the symptoms were aggravated after administration of mesalamine. In order to clarify the reason of symptoms aggravation, drug lymphocyte stimulation test and rechallenge trial with mesalamine were performed. The results indicated the possibility that aggravation was related to allergic reaction and was dose-dependent. Furthermore, we examined colonoscopic views but there was no remarkable change in before and after rechallenge trial. Based on the above result, the patient was diagnosed with mesalamine intolerance. In order to differentiate whether the exacerbation of bloody diarrhea is due to the side effects of the mesalamine or a true relapse of UC, taking careful history before and after increasing mesalamine dosage as well as being aware of side effects of mesalamine are required. Clinicians should be aware of diarrhea as a side effect of mesalamine particularly after onset of mesalamine formulation, change in mesalamine formulation, or change in mesalamine dose. PMID- 21552439 TI - Isolated splenic metastasis from renal cell carcinoma: case report and review. AB - This report presents the case of a 70-year-old woman with a previous history of a left nephrectomy for renal cell carcinoma (RCC), who developed general malaise and fatigue. Abdominal computed tomography demonstrated an enhancing 6 * 7 cm necrotic lesion in the lower pole of the spleen suggestive of a metastasis. Given the highly suspicious nature of the lesion we proceeded to splenectomy. The tumour did not breach the splenic capsule, and there was no local diaphragmatic involvement. The mass was concluded to be a true metastasis of the original RCC rather than local recurrence of the disease. The causes of isolated solid splenic lesions are wide and varied, however a past or present history of malignancy should lead to a high index of suspicion for a splenic metastasis. We report an extremely unusual case of spread from a RCC. PMID- 21552440 TI - Adenocarcinoma of the minor duodenal papilla: report of a case. AB - An 81-year-old male was found to have a duodenal tumor by screening upper gastrointestinal endoscopy. The tumor was located in the minor duodenal papilla. Pathological examination of the biopsy specimen revealed adenocarcinoma, and endoscopic ultrasound showed an elevated hypoechoic mass in the minor duodenal papilla. The preoperative diagnosis was therefore considered to be either adenocarcinoma of the minor duodenal papilla or duodenal cancer. We performed a subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination of the resected specimen showed the tumor cells to be primarily located in the submucosa of the minor duodenal papilla, with slight invasion into the pancreatic parenchyma through the accessory pancreatic duct. We therefore diagnosed a primary adenocarcima of the minor duodenal papilla. Adenocarcinoma of the minor duodenal papilla is considered to be a rare disease, but it may be underestimated because of the difficulty in distinguishing advanced adenocarcinoma of the minor duodenal papilla from primary duodenal cancer and cancer of the pancreatic head. PMID- 21552441 TI - Spontaneous splenic rupture: a rare complication of acute pancreatitis in a patient with Crohn's disease. AB - Crohn's disease (CD) is an idiopathic inflammatory bowel disease which can involve any part of the gastrointestinal tract. It frequently involves the ileum, colon and the anorectum. Although rare, acute pancreatitis as a complication of CD involving the duodenum has been described in the literature. We describe a 37 year-old male with CD presenting with acute pancreatitis and spontaneous splenic rupture. The potential mechanisms associated with acute pancreatitis along with spontaneous rupture of the spleen in this patient population and its treatment will be discussed. Common complaints such as upper abdominal pain in a patient with CD should undergo workup to exclude less commonly involved sites such as the pancreas and spleen. Close monitoring in the critical care setting is recommended in carefully selected and hemodynamically stable patients with splenic rupture. Surgical treatment is considered as the standard of care in hemodynamically unstable patients. PMID- 21552442 TI - An unusual cause of gastrointestinal bleeding: duodenal lipoma. AB - Common causes of chronic upper gastrointestinal bleeding include oesophageal varices, gastroduodenal ulcers and malignancy, and patients mostly present with iron deficiency type anaemia. We present the case of a 60-year-old lady who presented with iron deficiency anaemia and on investigation was found to have a large duodenal polyp requiring surgical excision. On histological examination, the polyp was revealed to be a lipoma. We review the recent literature and formulate a management plan for this rare entity. PMID- 21552443 TI - Diagnosis of metastatic breast cancer to an intraabdominal lymph node by endoscopic ultrasound. AB - Breast cancer can present with metastatic disease initially or as a systemic relapse despite seemingly adequate initial treatment. We report a case of suspected metastatic breast cancer to an intraabdominal lymph node based on imaging, which was subsequently confirmed by tissue sampling at the time of endoscopic ultrasound (EUS). While previous studies have shown the utility of EUS in the diagnosis of metastatic breast cancer, this is the first case to our knowledge that describes the use of EUS in diagnosing recurrent breast cancer to an intraabdominal lymph node. PMID- 21552445 TI - Esophageal small cell carcinoma with synchronous renal cell carcinoma: a case report with review of the literature. AB - Synchronous malignancies with an esophageal malignancy are not uncommon. However synchronous esophageal and renal cell carcinoma (RCC) is rare with only 11 cases reported in the world literature, the esophageal malignancies being adenocarcinomas or squamous cell carcinomas. Here, we report the first case of synchronous small cell carcinoma (SCC) of the esophagus with a RCC. SCC of the esophagus is an aggressive malignancy with poor prognosis constituting 0.8-2.4% of all esophageal malignancies, currently treated with induction chemotherapy followed by chemoradiotherapy. Our patient underwent chemoradiotherapy for the SCC of the esophagus followed by radical nephrectomy for the RCC. He developed metastatic disease and died 8 months after diagnosis. Larger case series are required to develop a treatment algorithm for such a rare presentation. The key points of this report are: (1) Synchronous RCC with a primary esophageal carcinoma is a rare presentation. (2) This is the first described case report of a SCC of the esophagus with a synchronous RCC. (3) Overall prognosis in a synchronous presentation is determined by the primary esophageal malignancy. (4) Esophageal carcinomas with synchronous malignancies have a poorer prognosis compared to isolated esophageal carcinoma. PMID- 21552444 TI - Rapid development of intestinal type gastric adenocarcinoma. AB - Intestinal type gastric adenocarcinoma is felt to develop over a protracted time period through a series of defined steps. Several potential risk factors for the development of gastric cancer have been identified, including a family history of gastric cancer and Helicobacter pylori infection. We present the case of a patient with neither risk factor who progressed in a 14 month time frame from histologically normal gastric mucosa to early stage intestinal type gastric adenocarcinoma in the setting of diffuse gastric intestinal metaplasia and atrophic gastritis. This patient's presentation conflicts with our current understanding of the development of intestinal type gastric adenocarcinoma. PMID- 21552446 TI - An unusual digestive foreign body. AB - Foreign digestive bodies present unusual circumstances because they are associated with various degrees of local trauma and may lead to direct perforation or delayed local injury. Patients with foreign bodies should be evaluated upon admission for signs of impaction and perforation. While all objects impacted in the esophagus require urgent treatment, rectal foreign bodies are usually removable through the anus. The current case illustrates successful endoscopic retrieval of a proximally located foreign body in a particular legal situation where physicians had to work closely with police officers and court members. PMID- 21552447 TI - Post-traumatic intra-cocoon mesenteric tear: a case report. AB - Sclerosing peritonitis, more commonly called abdominal cocoon, is a rare intra peritoneal disease that is characterized by complete or partial encapsulation of the small intestine by a thick collagenous membrane. This disease mostly presents in the form of small bowel obstruction, however in our case the patient presented with intra-cocoon bleeding following a motor vehicle accident. PMID- 21552448 TI - Proton Pump Inhibitors in the Management of Tachypnoea following Panproctocolectomy: A Case of High Output Ileostomy. AB - High output ileostomies are important complications of stoma formation following bowel surgery. Adequate management of such stomas might prevent severe morbidity and mortality when this potentially fatal complication develops. In this case report, we describe a female patient with a recent ileostomy formation following panproctocolectomy for ulcerative colitis who presented with progressively increasing shortness of breath. The patient was found to have a hypochloraemic metabolic acidosis on arterial blood gases. She rapidly improved with adequate sodium and fluid replacement and with the use of a course of proton pump inhibitors. This case highlights the importance of recognising high output ileostomies early and important management issues in their regard. PMID- 21552449 TI - A Case of Drug-Induced Hepatitis due to Lenalidomide. AB - Lenalidomide is a recent thalidomide analog used for the treatment of refractory multiple myeloma. The main toxicity of this drug consists in severe neutropenia and thrombocytopenia. Lenalidomide-associated liver injury is rare, manifesting itself as elevated liver enzymes and hyperbilirubinemia reversible upon weeks after drug withdrawal. We report here in detail the clinical course as well as the biological and histological alterations of an acute lenalidomide-induced liver injury. Findings on liver biopsy allowed us to discriminate acute inflammatory changes due to the drug and minor associated lesions of graft-versus host disease in this patient with recurrent myeloma after allogeneic bone marrow transplantation. PMID- 21552450 TI - An obscure case of hepatic subcapsular hematoma. AB - Spontaneous liver bleeding is often reported in preeclampsia. It is otherwise rare and has been linked to gross anatomical lesions and coagulopathy. We report a case of subcapsular hematoma of the liver without any apparent lesion and in the absence of coagulopathy. A 41-year-old male, paraplegic for 16 years, presented to the emergency department 3 days after sudden onset of right upper quadrant and shoulder pain. He had been on vitamins and 5,000 units subcutaneous heparin 12-hourly at the nursing home for the last month. He was in no distress, afebrile, with stable vitals. Physical examination showed a diverting colostomy, tender hepatomegaly and sacral decubiti. A fecal occult blood test was negative. There was spastic paraplegia below the level of T12. Two days after admission, the patient was afebrile and hemodynamically stable. PTT, PT, liver profile, BUN and creatinine were all normal, however his hemoglobin had dropped from 11.3 to 7.6 g/dl. An abdominal CT scan revealed an isolated 9.0 * 1.8 cm subcapsular hematoma. The patient received blood transfusion in the intensive care unit and was discharged 7 days later. In conclusion, spontaneous liver hemorrhage occurs in the nonobstetrical population in the setting of gross anatomical lesions or coagulopathy. This is the first report of an isolated subcapsular liver hematoma. PMID- 21552451 TI - Bacteremia caused by a swallowed toothpick impacted in the gastric mucosa. AB - Although most ingested foreign bodies usually pass through the gastrointestinal tract asymptomatically, toothpick injury to the gastrointestinal tract is often associated with significant morbidity and mortality. Toothpick perforation of the gastrointestinal tract is frequently reported but, to the best of our knowledge, bacteremia caused by an impacted toothpick within the gastric mucosa has not yet been described. Here, we report the case of bacteremia caused by an accidentally swallowed toothpick. The toothpick was impacted deeply in the gastric mucosa and was first seen and localized on contrast-enhanced computed tomography (CT). CT scan is a very useful imaging technique in such situations since we lack typical and relevant physical findings or laboratory studies that go with accidentally swallowed objects, in this case a toothpick. Flexible endoscopy was successful in extracting the whole toothpick. In cases without free perforation, flexible endoscopy is the treatment of choice in toothpick removal from the upper gastrointestinal tract. PMID- 21552452 TI - Composite adenocarcinoma and carcinoid gastric tumor in chronic atrophic gastritis and pernicious anemia. AB - A 42-year-old Hispanic female was referred for investigation of unexplained weight loss. Initial upper endoscopy showed atrophic gastritis. Repeat endoscopy one year later revealed the presence of mixed composite tumor consisting of gastric adenocarcinoma and carcinoid tumors. Treatment was accomplished by surgical excision. Such cases are extremely rare and few such reports are available in the literature. We discuss the pathologies and means by which these tumors are classified and treated. PMID- 21552453 TI - Integrated, Multidisciplinary and Technology-Enhanced Science Education: The Next Frontier. AB - Contemporary science education at all levels presents several critical pedagogical and social challenges to educators and learners alike. Among these challenges are the widening Intergenerational Information Technology (IIT) divide and the need for a comprehensive and balanced multidisciplinary training. In the past few years, it has become clear that one significant hurdle impedes the efforts to integrate information technology in the classroom - the Intergenerational IT divide. The IIT gap reflects a different growing misalignment between providers and recipients of the science and technology educational content in terms of the expected vs. supplied, needed vs. perceived and contextual vs. abstract specialized learning. The common K-12 teacher or college instructor is much less familiar with, and slower to adapt to, the new ether of communication and novel IT resources. The transfer and blending of data, research challenges and methodologies between diverse areas of science is also critical in motivating wider spectra of students, demonstrating cross disciplinary methodological concepts and synergies, as well as for engaging students in research projects. This article discusses the problems faced by modern science educators and suggests some methods and vision for coping with the increasing IIT divide and the social need to train "complete" and broadly educated citizens. PMID- 21552454 TI - Evaluation of a rotary laser body scanner for body volume and fat assessment. AB - This paper reports the evaluation tests on the reliability and validity of a 3 dimensional (3D) laser body scanner for estimation of body volume and % fat. Repeated measures of body imaging were performed for reproducibility analysis. Validity of the instrument was assessed by comparison of measures of body volume by imaging to hydrodensitometry, and body fat was compared to hydrodensitometry and dual energy X-ray absorptiometry. Reproducibility analysis showed little difference between within-subjects measurements of volume (ICC >= 0.99, p < 0.01). Body volume estimations by laser body scanner and hydrodensitometry were strongly related (r = 0.99, p < 0.01), and agreement was high (ICC = 0.99, p < 0.01). Measurements of % body fat also agreed strongly with each other between methods (ICC = 0.86, p < 0.01), and mean % fat estimates by body imaging did not differ from criterion methods (p > 0.05). These findings indicate that the 3D laser body scanner is a reliable and valid technique for the estimation of body volume. Furthermore, body imaging is an accurate measure of body fat, as compared to dual energy X-ray absorptiometry. This new instrument is promising as a quick, simple to use, and inexpensive method of body composition analysis. PMID- 21552455 TI - A textual representation scheme for identifying clinical relationships in patient records. AB - The identification of relationships between clinical concepts in patient records is a preliminary step for many important applications in medical informatics, ranging from quality of care to hypothesis generation. In this work we describe an approach that facilitates the automatic recognition of relationships defined between two different concepts in text. Unlike the traditional bag-of-words representation, in this work, a relationship is represented with a scheme of five distinct context-blocks based on the position of concepts in the text. This scheme was applied to eight different relationships, between medical problems, treatments and tests, on a set of 349 patient records from the 4th i2b2 challenge. Results show that the context-block representation was very successful (F-Measure = 0.775) compared to the bag-of-words model (F-Measure = 0.402). The advantage of this representation scheme was the correct management of word position information, which may be critical in identifying certain relationships. PMID- 21552456 TI - On the Importance of the Aromatic Ring Parameter in Studies of the Solvolyses of Cinnamyl and Cinnamoyl Halides. AB - In solvolysis studies using Grunwald-Winstein plots, dispersions were observed for substrates with aromatic rings at the alpha-carbon. Several examples for the unimolecular solvolysis of monoaryl benzylic derivatives and related diaryl- or naphthyl- substituted derivatives have now been reported, where the application of the aromatic ring parameter (I) removes this dispersion. A recent claim suggesting the presence of an appreciable nucleophilic component to the I scale, has now been shown, in a review of the solvolysis of highly-hindered alkyl halides, to be unlikely to be correct. Attention is now focused on the application of the hI term for the solvolysis of compounds containing a double bond in the vicinity of any developing carbocation. Available specific rates of solvolysis (plus some new values) at 25 degrees C of cinnamyl chloride, cinnamyl bromide, cinnamoyl chloride, p-chlorocinnamoyl chloride, and p-nitrocinnamoyl chloride are analyzed using the simple and extended (including the hI term) Grunwald-Winstein equations. PMID- 21552457 TI - Feasibility of Neural Stimulation With Floating-Light-Activated Microelectrical Stimulators. AB - Neural microstimulation is becoming a powerful tool for the restoration of impaired functions in the central nervous system. Microelectrode arrays with fine wire interconnects have traditionally been used in the development of these neural prosthetic devices. However, these interconnects are usually the most vulnerable part of the neuroprosthetic implant that can eventually cause the device to fail. In this paper, we investigate the feasibility of floating-light activated microelectrical stimulators (FLAMES) for wireless neural stimulation. A computer model was developed to simulate the micro stimulators for typical requirements of neural activation in the human white and gray matters. First, the photon densities due to a circular laser beam were simulated in the neural tissue at near-infrared (NIR) wavelengths. Temperature elevation in the tissue was calculated and the laser power was retrospectively adjusted to 325 and 250 mW/cm(2) in the gray and white matters, respectively, to limit DeltaT to 0.5 degrees C. Total device area of the FLAMES increased with all parameters considered but decreased with the output voltage. We conclude that the number of series photodiodes in the device can be used as a free parameter to minimize the device size. The results suggest that floating, optically activated stimulators are feasible at submillimeter sizes for the activation of the brain cortex or the spinal cord. PMID- 21552458 TI - Effect of a direct thrombin inhibitor compared with dalteparin and unfractionated heparin on human osteoblasts. AB - PURPOSE: Osteoporosis is a relevant problem after long term administration of unfractionated heparin (UFH) and low molecular weight heparin. Melagatran is a representative of a new group of direct thrombin inhibitors with comparable data in the prevention of thromboembolic events after orthopaedic surgery. The aim of our in vitro study was to investigate the effect of a direct thrombin inhibitor compared with dalteparin and UFH on human osteoblasts. MATERIALS AND METHODS: Melagatran, dalteparin and UFH were added to primary osteoblast cultures in their therapeutic range and two decimal powers below and above. Cell number, protein synthesis, mitochondrial and alkaline phosphatase activity and collagen type I synthesis were evaluated. RESULTS: Melagatran showed the least influence on protein synthesis and cell proliferation with a reduction of cell number to 83.5 +/- 9% (p = 0.027) of the control group only in the highest investigated concentration after 15 days of incubation. Mitochondrial and alkaline phosphatase activity and collagen type I synthesis in osteoblasts incubated with melagatran and dalteparin showed similar patterns. UFH showed the most pronounced influence on cellular metabolism. CONCLUSIONS: Melagatran showed less inhibitory in vitro effects on human osteoblasts than dalteparin or UFH. The presented study gives first hints that direct thrombin inhibitors may help prevent heparin-induced negative effects on bone metabolism. PMID- 21552459 TI - Early changes in bone specific turnover markers during the healing process after vertebral fracture. AB - BACKGROUND: The present study measured longitudinal changes in bone turnover markers in elderly patients with vertebral fracture and investigated the relationship among bone turnover markers, duration of bed rest and bone mineral density (BMD). METHODS: Criteria for patient selection were 50 years in age and older, and presence of VF. Serum bone-specific alkaline phosphatase (BAP) was measured as a marker of bone formation. Urinary crosslinked N-terminal telopeptides of type I collagen (NTX) was measured as a marker of bone resorption. In principle, samples were collected just after injury, within 24 h, and 1, 2, 3, 5 and 8 weeks after. We also measured duration of bed rest and BMD. RESULTS: The study population consisted of 42 cases. The average BMD of the lumbar vertebrae was 0.670 +/- 0.174 g/cm2. Bed rest period was 17.9 +/- 8.8 days. BAP showed significantly higher values at 2 and 3 weeks compared with the baseline value. Thereafter, BAP progressively decreased until 8 weeks. Urinary NTX was increased soon after the onset of pain with the same patterns in BAP. Urinary NTX values reached a peak at 3 weeks, and then they kept significantly higher values until 8 weeks. The peak value of serum BAP was affected by the duration of bed rest, although that of the urinary NTX was not. The peak values of serum BAP and urinary NTX showed negative correlations with the initial BMD values. CONCLUSIONS: Bone turnover markers remained higher at 8 weeks, even patients symptom was healed after VF. Bone turnover markers were affected on physical activity and BMD. PMID- 21552460 TI - Lateral clavicular autograft for repair of reverse hill-sachs defect. AB - Posterior dislocations of the shoulder joint can result in an impression fracture over the anteromedial humeral head, termed the reverse Hill-Sachs lesion, the presence of which can contribute to recurrent dislocations. Methods described to repair this defect include using allografts, iliac crest and coracoid process autografts, and bone graft substitutes. We describe a novel technique using the lateral end of the ipsilateral clavicle as an autograft in a 78 year old man with a reverse Hill Sachs lesion. This graft can be harvested through the same incision and does not compromise the stability of the acromioclavicular joint or any future shoulder arthroplasty. PMID- 21552461 TI - Socioeconomic Differentials Between HIV Caregivers and Noncaregivers: Is There a Selection Effect? A Case of Older People Living in Nairobi City Slums. AB - This article seeks to investigate the association between caregiving to someone with an HIV-related illness and the socioeconomic status of the caregiver using a population-based survey of 1,587 older people living in Nairobi slums. Findings indicate significant differences in living arrangements, wealth, income, and expenditure between HIV caregivers and noncaregivers. HIV caregivers lived in larger households and were also more likely to live in households with a large number of children younger than the age of 15 years. Whereas a high proportion of HIV caregivers were ranked highly in terms of wealth status, differences in per capita income and expenditure were not significant when household size and other confounders were accounted for. The financial costs associated with caring for someone with a chronic illness and the reliance on family members with financial ability for material support, a common feature of African extended family systems, may account for the relative economic advantage of HIV caregivers. PMID- 21552462 TI - Prospective single-arm, multi-center trial of a patient-specific interpositional knee implant: early clinical results. AB - BACKGROUND: The treatment of unicompartmental arthritis in younger patients is challenging. The aim of this study is to report final safety and efficacy analysis results for the iForma patient-specific interpositional device, which is designed for the treatment of isolated medial or lateral compartment arthritis of the knee. METHODS: From June 2005 to June 2008 78 subjects (42 men, 36 women) received an iForma implant. The mean age was 53 years, the mean Body Mass Index 29.0. We surveyed the WOMAC scores, the visual analog pain scale and the Knee Society Scores. RESULTS: The mean follow up was 16.4 months. The mean WOMAC knee scores increased from 48.3 before surgery to 71.3 after 24 months. A reduction in pain was achieved for all five pain measures using a standard visual analog scale (VAS). Knee Society Knee Score improved from 39.2 before to 61.9 24 month after surgery. The Knee Society Function Scores improved form preoperative 64.5 to 82.5 2 years postoperative. The preoperative range of motion could be restored. The overall revision rate was 24%. 15 implants were removed early, 4 knees were revised without implant removal. CONCLUSION: Within narrow indication of patients with unicompartmental disease, the iForma device can provide improvement in knee function and reduction in pain, however, with a significant higher risk of early revision compared to traditional arthroplasty. Respecting this limitation it may be an alternative option for arthritic patients with unicompartmental disease who have contraindications to High Tibial Osteotomy or are too young for knee replacement; the iForma device further has the distinct advantage of time and cost saving compared to those procedures. PMID- 21552463 TI - An Iterative Time Windowed Signature Algorithm for Time Dependent Transcription Module Discovery. AB - An algorithm for the discovery of time varying modules using genome-wide expression data is present here. When applied to large-scale time serious data, our method is designed to discover not only the transcription modules but also their timing information, which is rarely annotated by the existing approaches. Rather than assuming commonly defined time constant transcription modules, a module is depicted as a set of genes that are co-regulated during a specific period of time, i.e., a time dependent transcription module (TDTM). A rigorous mathematical definition of TDTM is provided, which is serve as an objective function for retrieving modules. Based on the definition, an effective signature algorithm is proposed that iteratively searches the transcription modules from the time series data. The proposed method was tested on the simulated systems and applied to the human time series microarray data during Kaposi's sarcoma associated herpesvirus (KSHV) infection. The result has been verified by Expression Analysis Systematic Explorer. PMID- 21552464 TI - Inferring the Sign of Kinase-Substrate Interactions by Combining Quantitative Phosphoproteomics with a Literature-Based Mammalian Kinome Network. AB - Protein phosphorylation is a reversible post-translational modification commonly used by cell signaling networks to transmit information about the extracellular environment into intracellular organelles for the regulation of the activity and sorting of proteins within the cell. For this study we reconstructed a literature based mammalian kinase-substrate network from several online resources. The interactions within this directed graph network connect kinases to their substrates, through specific phosphosites including kinasekinase regulatory interactions. However, the "signs" of links, activation or inhibition of the substrate upon phosphorylation, within this network are mostly unknown. Here we show how we can infer the "signs" indirectly using data from quantitative phosphoproteomics experiments applied to mammalian cells combined with the literature-based kinase-substrate network. Our inference method was able to predict the sign for 321 links and 153 phosphosites on 120 kinases, resulting in signed and directed subnetwork of mammalian kinase-kinase interactions. Such an approach can rapidly advance the reconstruction of cell signaling pathways and networks regulating mammalian cells. PMID- 21552465 TI - Spectral Regularization Algorithms for Learning Large Incomplete Matrices. AB - We use convex relaxation techniques to provide a sequence of regularized low-rank solutions for large-scale matrix completion problems. Using the nuclear norm as a regularizer, we provide a simple and very efficient convex algorithm for minimizing the reconstruction error subject to a bound on the nuclear norm. Our algorithm Soft-Impute iteratively replaces the missing elements with those obtained from a soft-thresholded SVD. With warm starts this allows us to efficiently compute an entire regularization path of solutions on a grid of values of the regularization parameter. The computationally intensive part of our algorithm is in computing a low-rank SVD of a dense matrix. Exploiting the problem structure, we show that the task can be performed with a complexity linear in the matrix dimensions. Our semidefinite-programming algorithm is readily scalable to large matrices: for example it can obtain a rank-80 approximation of a 10(6) * 10(6) incomplete matrix with 10(5) observed entries in 2.5 hours, and can fit a rank 40 approximation to the full Netflix training set in 6.6 hours. Our methods show very good performance both in training and test error when compared to other competitive state-of-the art techniques. PMID- 21552466 TI - Developing a multivariable prognostic model for pancreatic endocrine tumors using the clinical data warehouse resources of a single institution. AB - OBJECTIVE: Current staging systems are not accurate for classifying pancreatic endocrine tumors (PETs) by risk. Here, we developed a prognostic model for PETs and compared it to the WHO classification system. METHODS: We identified 98 patients diagnosed with PET at NewYork-Presbyterian Hospital/Columbia University Medical Center (1999 to 2009). Tumor and clinical characteristics were retrieved and associations with survival were assessed by univariate Cox analysis. A multivariable model was constructed and a risk score was calculated; the prognostic strength of our model was assessed with the concordance index. RESULTS: Our cohort had median age of 60 years and consisted of 61.2% women; median follow-up time was 10.4 months (range: 0.1-99.6) with a 5-year survival of 61.5%. The majority of PETs were non-functional and no difference was observed between functional and non-functional tumors with respect to WHO stage, age, pathologic characteristics or survival. Distant metastases, aspartate aminotransferase-AST and surgical resection (HR=3.39, 95% CI: 1.38-8.35, p=0.008, HR=3.73, 95% CI: 1.20-11.57, p=0.023 and HR=0.20, 95% CI: 0.08-0.51, p<0.001 respectively) were the strongest predictors in the univariate analysis. Age, perineural and/or lymphovascular invasion, distant metastases and AST were the independent prognostic factors in the final multivariable model; a risk score was calculated and classified patients into low (n=40), intermediate (n=48) and high risk (n=10) groups. The concordance index of our model was 0.93 compared to 0.72 for the WHO system. CONCLUSION: Our prognostic model was highly accurate in stratifying patients by risk; novel approaches as such could thus be incorporated into clinical decisions. PMID- 21552467 TI - Predicting Neoplastic Progression in Barrett's Esophagus. AB - Patients with Barrett's esophagus have a significantly increased risk of esophageal adenocarcinoma, 40-125 times higher than the general population. Since only a small fraction of Barrett's esophagus patients will actually progress to esophageal adenocarcinoma, there is a need to develop markers that may accurately predict which patients with Barrett's esophagus are likely to have aggressive disease and progress to cancer versus patients who will remain histologically stable and have a benign course. This would allow for better risk stratification of patients with Barrett's esophagus in order to target aggressive surveillance and intervention towards only those patients at highest risk for neoplastic progression. Predictive biomarkers may thus have significant clinical utility in the management of Barrett's esophagus patients. The detection of dysplasia in esophageal biopsies is currently the only standard method used in clinical practice as a marker for increased risk of cancer. However, dysplasia has not been a accurate or reliable marker for predicting malignant progression and suffers from poor interobserver agreement among pathologists and sampling error. A multitude of potential biomarkers have been studied over the years. It is likely that the best model for predicting progression to esophageal adenocarcinoma in Barrett's esophagus patients will ultimately involve a combination of biomarkers, dysplasia grade and other pathological characteristics, as well as clinical and demographic attributes. In this review, we will discuss the most promising biomarkers that have been studied thus far. PMID- 21552469 TI - Effect of Regularization Parameter and Scan Time on Crossing Fibers with Constrained Compressed Sensing. AB - Diffusion tensor imaging (DTI) is an MR imaging technique that uses a set of diffusion weighted measurements in order to determine the water diffusion tensor at each voxel. In DTI, a single dominant fiber orientation is calculated at each measured voxel, even if multiple populations of fibers are present within this voxel. A new approach called Crossing Fiber Angular Resolution of Intra-voxel structure (CFARI) for processing diffusion weighted magnetic resonance data has been recently introduced. Based on compressed sensing, CFARI is able to resolve intra-voxel structure from limited number of measurements, but its performance as a function of the scan and algorithm parameters is poorly understood at present. This paper describes simulation experiments to help understand CFARI performance tradeoffs as a function of the data signal-to-noise ratio and the algorithm regularization parameter. In the compressed sensing criterion, the choice of the regularization parameter beta is critical. If beta is too small, then the solution is the conventional least squares solution, while if beta is too large then the solution is identically zero. The correct selection of beta turns out to be data dependent, which means that it is also spatially varying. In this paper, simulations using two random tensors with different diffusivities having the same fractional anisotropy but with different principle eigenvalues are carried out. Results reveal that for a fixed scan time, acquisition of repeated measurements can improve CFARI performance and that a spatially variable, data adaptive regularization parameter is beneficial in stabilizing results. PMID- 21552468 TI - Blood loss control with two doses of tranexamic Acid in a multimodal protocol for total knee arthroplasty. AB - Average blood loss after total knee arthroplasty (TKA) usually ranges from 1500 to 1900 cc, including both the postoperative drain and hidden blood loss. This represents about 46% of TKA patients requiring postoperative blood transfusion. Not only the risks of disease transmission but also those of ABO incompatibility, infection due to immunosupression, increased procedure costs, and increased length of hospital stay, are potential problems that foster blood saving strategies. In this study, 71 unilateral TKAs using a multimodal protocol to decrease blood loss were compared to 61 historical cases. Patients in both groups underwent cemented TKA with the same system, surgical technique, and multimodal protocol (MIS approach, plug in the femoral canal, tourniquet removal after wound closure and compressive bandage, analgesic periarticular infiltration with vasoconstrictor, postoperative drain at atmospheric pressure, opened 2 hours after the end of the surgical procedure and removed after 24 hours). The study series incorporated intravenous tranexamic acid (TXA) infusion in 2 doses of 10 15 mg/kg, 15 minutes before tourniquet release and 3 hours later. Results showed no transfusion requirements in the TXA series (0%), with 23/61 (37.7%) transfusions in the control, with an average cost decrease of 240 euros per patient. Visible bleeding in 24h significantly decreased from 553.36 cc (range 50 1500) to 169.72 cc (range 10-480) in the TXA series. As a conclusion, implementing a TXA-based multimodal protocol produced significant decrease in the transfusion rate, visible blood loss, and cost per patient, thus proving effectiveness and efficiency in the surgical management of TKA. PMID- 21552470 TI - Compton Scattering in Clinical PET/CT With High Resolution Half Ring PET Insert Device. AB - The integration of a high resolution PET insert into a conventional PET system can significantly improve the resolution and the contrast of its images within a reduced imaging field of view. For the rest of the scanner imaging field of view, the insert is a highly attenuating and scattering media. In order to use all available coincidence events (including coincidences between 2 detectors in the original scanner, namely the scanner-scanner coincidences), appropriate scatter and attenuation corrections have to be implemented. In this work, we conducted a series of Monte Carlo simulations to estimate the composition of the scattering background and the importance of the scatter correction. We implemented and tested the Single Scatter Simulation (SSS) algorithm for a hypothetical system and show good agreement between the estimated scatter using SSS and Monte Carlo simulated scatter contribution. We further applied the SSS to estimate scatter contribution from an existing prototype PET insert for a clinical PET/CT scanner. The results demonstrated the applicability of SSS to estimate the scatter contribution within a clinical PET/CT system even when there is a high resolution half ring PET insert device in its imaging field of view. PMID- 21552471 TI - Targeted suppression of HO-2 gene expression impairs the innate anti-inflammatory and repair responses of the cornea to injury. AB - PURPOSE: Heme oxygenase (HO)-2 is highly expressed in the corneal epithelium and is a component of the heme oxygenase system that represents an intrinsic cytoprotective and anti-inflammatory system based on its ability to modulate leukocyte migration and to inhibit expression of inflammatory cytokines and proteins via its products biliverdin/bilirubin and carbon monoxide (CO). We have shown that in HO-2 null mice epithelial injury leads to unresolved corneal inflammation and chronic inflammatory complications including ulceration, perforation and neovascularization. In this study, we explore whether a localized corneal suppression of HO-2 is sufficient for disrupting the innate anti inflammatory and repair capability of the cornea. METHODS: Silencing hairpin RNA (shRNA) against HO-2 was administered subconjunctivally (100 ng/eye) as well as topically (100 ng/eye) starting one day before corneal epithelial debridement and once daily, thereafter. The corneal epithelium was removed using an Alger Brush in anesthetized mice. Re-epithelialization was assessed by fluorescein staining using a dissecting microscope and image analysis. Inflammatory response was quantified by myeloperoxidase activity. Levels of mRNA were measured by RT-PCR. RESULTS: Local injection of HO-2-specific shRNA led to a 50% reduction in corneal HO-2 mRNA. Administration of HO-2-specific shRNA delayed corneal re epithelialization when compared with the control shRNA-treated group by 14%, 20%, and 12% at days 3, 4, and 7 after injury, respectively (n=18-24). The observed delay in the wound repair process in HO-2 shRNA treated mice was accompanied by a threefold and 3.5 fold increase in the neovascular response at days 4 and 7 after injury. Further, local knockdown of HO-2 lead to an aberrant chronic inflammatory response, as shown by presence of high numbers of inflammatory cells still present in the cornea at day 7 after injury; 1.04+/-0.45*10(6) in HO-2 knockdown mice versus 0.14+/-0.03*10(6) inflammatory cells in control mice. Matrix metalloproteinase-2 (MMP-2) but not MMP-9 increased following injury and remained elevated in the injured corneas of the HO-2 shRNA-treated eyes. CONCLUSIONS: Corneal knockdown of HO-2 via local administration of HO-2-specific shRNA leads to delayed re-epithelialization, increased neovascularization and an aberrant inflammatory response similar to what is observed in the HO-2 null mouse. The elevated MMP-2 expression may contribute to the increase in neovascularization in corneas in which HO-2 expression is suppressed. PMID- 21552472 TI - Analysis of an extended chromosome locus 2p14-21 for replication of the 2p16.3 association with glaucoma susceptibility. AB - PURPOSE: Susceptibility to primary open-angle glaucoma (POAG) has recently associated with three intergenic single-nucleotide polymorphisms (SNPs) on human chromosome 2p16.3, just outside of the POAG-linkage locus GLC1H (2p15-16.2), in an Afro-Caribbean population. Especially, association of one SNP (rs12994401) was very strong (odds ratio 35) and later replicated in Afro-Americans but not in Ghanaians or Japanese. An extended region was examined in this study to look for SNPs of cross-population association. METHODS: The three reported SNPs and all 63 SNPs considerably correlating with rs12994401 (r(2)>=0.3) in the African descendent Yoruba were examined for POAG susceptibility association in a Korean population of 1,159 unrelated participants including 226 cases with glaucoma. As these 66 SNPs were spread from 2p14 to 2p21, all SNPs in this extended region were imputed for susceptibility association tests. RESULTS: No susceptibility association was detected with rs12994401 in comparisons between 933 controls and 188 POAG (or 175 high-tension glaucoma) cases (statistical power of 100%), as well as with all 19 other typed SNPs, using logistic regression with adjustment for age and gender. The other 46 SNPs were deemed non-polymorphic in Koreans. Among 21,201 SNPs located in 2p14-21, only 4,260 were imputed to be non monomorphic, but none of them passed a significance level of multiple testing. No association was observed when the samples were stratified by age or gender. CONCLUSIONS: No typed or imputed SNPs within 2p14-21 showed association with susceptibility to POAG, suggesting that the population inconsistency in 2p16.3 association was unlikely due to linkage disequilibrium differences. PMID- 21552473 TI - Quantifying transduction efficiencies of unmodified and tyrosine capsid mutant AAV vectors in vitro using two ocular cell lines. AB - PURPOSE: With the increasing number of retinal gene-based therapies and therapeutic constructs, in vitro bioassays characterizing vector transduction efficiency and quality are becoming increasingly important. Currently, in vitro assays quantifying vector transduction efficiency are performed predominantly for non-ocular tissues. A human retinal pigment epithelial cell line (ARPE19) and a mouse cone photoreceptor cell line, 661W, have been well characterized and are used for many retinal metabolism and biologic pathway studies. The purpose of this study is to quantify transduction efficiencies of a variety of self complementary (sc) adeno-associated virus (AAV) vectors in these biologically relevant ocular cell lines using high-throughput fluorescence-activated cell sorting (FACS) analysis. METHODS: ARPE19 and 661W cells were infected with sc smCBA-mCherry packaged in unmodified AAV capsids or capsids containing single/multiple tyrosine-phenylalanine (Y-F) mutations at multiplicity of infections (MOIs) ranging from 100 to 10,000. Three days post infection fluorescent images verified mCherry expression. Following microscopy, FACS analysis was performed to quantify the number of positive cells and the mean intensity of mCherry fluorescence, the product of which is reported as transduction efficiency for each vector. The scAAV vectors containing cone specific (sc-mCARpro-green fluorescent protein [GFP]), rod-specific (sc-MOPS500 eGFP), retinal pigment epithelium (RPE)-specific (sc-VMD2-GFP), or ubiquitous (sc smCBA-GFP) promoters were used to infect both cell lines at an MOI of 10,000. Three days post infection, cells were immunostained with an antibody raised against GFP and imaged. Finally, based on our in vitro results, we tested a prediction of transduction efficiency in vivo. RESULTS: Expression from unmodified scAAV1, scAAV2, scAAV5, and scAAV8 vectors was detectable by FACS in both ARPE19 and 661W cells, with scAAV1 and scAAV2 being the most efficient in both cell lines. scAAV5 showed moderate efficiency in both ARPE19 and 661W cells. scAAV8 was moderately efficient in 661W cells and was by comparison less so in ARPE19 cells; however, transduction was still apparent. scAAV9 performed poorly in both cell types. With some exceptions, the Y-F capsid mutations generally increased the efficiency of scAAV vector transduction, with the increasing number of mutated residues improving efficiency. Results for single scAAV1 and scAAV8 capsid mutants were mixed. In some cases, efficiency improved; in others, it was unchanged or marginally reduced. Retinal-specific promoters were also active in both cell lines, with the 661W cells showing a pattern consistent with the in vivo activity of the respective promoters tested. The prediction based on in vitro data that AAV2 sextuple Y-F mutants would show higher transduction efficiency in RPE relative to AAV2 triple Y-F capsid mutants was validated by evaluating the transduction characteristics of the two mutant vectors in mouse retina. CONCLUSIONS: Our results suggest that this rapid and quantifiable cell based assay using two biologically relevant ocular cell lines will prove useful in screening and optimizing AAV vectors for application in retina-targeted gene therapies. PMID- 21552474 TI - Mutation analysis at codon 838 of the Guanylate Cyclase 2D gene in Spanish families with autosomal dominant cone, cone-rod, and macular dystrophies. AB - PURPOSE: Heterozygous mutations around codon 838 of the guanylate cyclase 2D (GUCY2D) gene have recently been associated with more than a third of autosomal dominant macular dystrophy patients. The aim of our study was to evaluate the prevalence of these mutations in Spanish families with autosomal dominant cone, cone-rod, and macular dystrophies. METHODS: Mutation analysis was performed by PCR amplification of exon 13 of GUCY2D and subsequent restriction analysis. To confirm the results, automatic sequencing analysis was also performed. RESULTS: Among the 22 unrelated Spanish families included in the study, we found two associated disease mutations at codon 838 of the GUCY2D gene, one of which had not been previously described (p.R838P). This novel mutation exhibited phenotypic variability. CONCLUSIONS: The prevalence of mutations around codon 838 of GUCY2D in our group of families (9.09%) is lower than that previously reported in other populations. However, the discovery of a novel mutation at codon 838 further suggests that this locus is a mutation hotspot within the GUCY2D gene, and confirms the importance of analyzing this codon to characterize molecularly these autosomal dominant retinal disorders. PMID- 21552475 TI - Novel TSPAN12 mutations in patients with familial exudative vitreoretinopathy and their associated phenotypes. AB - PURPOSE: Mutations in tetraspanin 12 (TSPAN12) have recently been identified as a cause of autosomal dominant familial exudative vitreoretinopathy (FEVR). The purpose of this study was to detect TSPAN12 mutations in Chinese patients with FEVR and to describe the associated phenotypes. METHODS: Sanger sequencing was used to analyze the seven coding exons and their adjacent regions of TSPAN12 in 49 unrelated FEVR patients. Clinical phenotypes of the patients with TSPAN12 mutations were documented. RESULTS: Three novel heterozygous mutations in TSPAN12 were identified in three patients from unrelated families: c.146C>T (p.Thr49Met), c.313T>C (p.Cys105Arg), and c.601delC (p.Leu201PhefsX14). All three mutations involved highly conserved residues and were not present in 180 normal individuals. Ocular phenotypes included retinal folds, inferotemporal dragging of the optic disc and macula, increased vessels in the equatorial region, and a peripheral avascular zone. A father and his daughter had the same mutation but the father only had mild peripheral fundus changes while his daughter had obvious dragged disc and macular ectopia. CONCLUSIONS: Our results suggest that TSPAN12 mutations are responsible for FEVR. Similar to patients with mutations in NDP, LRP5, or FZD4, the phenotypes associated with TSPAN12 mutations showed great variations between different individuals within a family and between the two eyes in individual patients. PMID- 21552477 TI - Initial stage of crystalline rubrene thin film growth on mica (0 0 1). AB - We have studied the morphology and the spatially resolved photoluminescence of rubrene thin films at the early stage of crystallization. The initial growth proceeds via the formation of a wetting layer and the nucleation of islands with an amorphous structure. Crystallization starts when the amorphous islands coalesce and needle like crystalline fibers are formed in the gap between islands. The crystalline fibers then grow on top and in between the original amorphous islands leading to an "open network" of islands. The latter acts as the basis for the growth of semi-crystalline spherulites. PMID- 21552476 TI - Degeneration of the mouse retina upon dysregulated activity of serum response factor. AB - PURPOSE: Our aim was to generate and phenotypically characterize a transgenic mouse line expressing a constitutively active variant of the transcription regulatory protein serum response factor (SRF), namely the SRF-VP16 protein. This new mouse strain has been registered under the designation Gt(ROSA)26Sor(tm1(SRF VP16)Antu). We found phenotypic changes upon ectopic expression of SRF-VP16, especially in the mouse retina. METHODS: Using homologous recombination, we integrated an SRF-VP16 conditional (i.e., "flox-STOP" repressed) expression transgene into the Rosa26 locus of murine embryonic stem (ES) cells. These engineered ES cells were used to derive the Gt(ROSA)26Sor(tm1(SRF-VP16)Antu) mouse strain. Semiquantitative real-time PCR was used to determine expression of the SRF-VP16 transgene at the mRNA level, both in young (P20 and P30) and adult (six months old) Gt(ROSA)26Sor(tm1(SRF-VP16)Antu) mice. We also investigated the transcript levels of endogenous Srf and several SRF target genes. Retinal function was tested by electroretinography in both young and adult mice. Morphological abnormalities could be visualized by hematoxylin and eosin staining of sectioned, paraffin-embedded eye tissue samples. Scanning-laser ophthalmoscopy was used to investigate retinal vascularization and degeneration in adult mice. RESULTS: We show that the SRF-VP16 mRNA is expressed to a low but significant degree in the retinas of young and adult animals of the Gt(ROSA)26Sor(tm1(SRF VP16)Antu) mouse strain, even in the absence of Cre-mediated deletion of the "flox-STOP" cassette. In the retinas of these transgenic mice, endogenous Srf displays elevated transcript levels. Ectopic retinal expression of constitutively active SRF-VP16 is correlated with the malfunction of retinal neurons in both heterozygous and homozygous animals of both age groups (P20 and adult). Additionally, mislamination of retinal cell layers and cellular rosette formations are found in retinas of both heterozygous and homozygous animals of young age. In homozygous individuals, however, the cellular rosettes are more widespread over the fundus. At adult age, retinas both from animals that are heterozygous and homozygous for the floxSTOP/SRF-VP16 transgene display severe degeneration, mainly of the photoreceptor cell layer. Wild-type age-matched littermates, however, do not show any degeneration. The severity of the observed effects correlates with dosage of the transgene. CONCLUSIONS: This is the first report suggesting an influence of the transcription factor SRF on the development and function of the murine retina. Ectopic SRF-VP16 mRNA expression in the retinas of young animals is correlated with photoreceptor layer mislamination and impaired retinal function. At an advanced age of six months, degenerative processes are detected in SRF-VP16 transgenic retinas accompanied by impaired retinal function. The Gt(ROSA)26Sor(tm1(SRF-VP16)Antu) mouse strain represents a genetic SRF gain-of-function mouse model that will complement the current SRF loss-of-function models. It promises to provide new insight into the hitherto poorly defined role of SRF in retinal development and function, including potential contributions to ophthalmologic disorders. Furthermore, using conditional Cre-mediated activation of SRF-VP16, the described mouse strain will enable assessment of the impact of dysregulated SRF activity on the physiologic functions of various other organs. PMID- 21552478 TI - Metallic-Nanostructure-Enhanced Fluorescence of Single Flavin Cofactor and Single Flavoenzyme Molecules. AB - The enzyme cofactors are intrinsically fluorescent and participate directly in the single molecule enzymology studies. Due to photobleaching, one cannot follow kinetics continuously by cofactor fluorescence for more than several minutes typically. Modification of spectral properties of fluorophores, such as the amplification of emission intensity, can be achieved through coupling with surface plasmons in close proximity to metallic nanostructures. This process, referred to as metal-enhanced fluorescence, offers promise for a range of applications, including bioassays, sensor technology, microarrays, and single molecule studies. Here, we demonstrated up to a 100-fold increase in the emission of the single cofactors and flavoenzymes near silver nanostructures. Amplified fluorescence of different types of flavins and flavoenzymes has been interpreted by using time-resolved single molecule fluorescence data. The results show considerable promise for the studies of enzyme kinetics using the intrinsic fluorescence from the cofactors. PMID- 21552480 TI - Changes in antipsychotic medication in clients of assertive community treatment in Japan: a one-year follow up. AB - The purpose of the present one-year follow-up study was to describe and investigate the change in the amount of antipsychotic drugs prescribed for ACT (assertive community treatment) clients in Japan. Subjects were 52 clients of ACT from January 2009 to December 2009. Prescription data were collected each month from the time the clients entered into ACT. The results of a Wilcoxon signed-rank test show that the dosage of antipsychotics significantly decreased from 1,131.3 mg to 731.3 mg over the course of the 12 months (Z = -2.505, p = 0.012). PMID- 21552481 TI - Stop Kissing and Steaming!': Tuberculosis and the Occupational Health Movement in the Massachusetts and Lancashire Cotton Weaving Industries, 1870-1918. PMID- 21552479 TI - Biochemistry of eukaryotic homologous recombination. AB - The biochemistry of eukaryotic homologous recombination caught fire with the discovery that Rad51 is the eukaryotic homolog of the bacterial RecA and T4 UvsX proteins; and this field is still hot. The core reaction of homologous recombination, homology search and DNA strand invasion, along with the proteins catalyzing it, are conserved throughout evolution in principle. However, the increased complexity of eukaryotic genomes and the diversity of eukaryotic cell biology pose additional challenges to the recombination machinery. It is not surprising that this increase in complexity coincided with the evolution of new recombination proteins and novel support pathways, as well as changes in the properties of those eukaryotic recombination proteins that are evidently conserved in evolution. In humans, defects in homologous recombination lead to increased cancer predisposition, underlining the importance of this pathway for genomic stability and tumor suppression. This review will focus on the mechanisms of homologous recombination in eukaryotes as elucidated by the biochemical analysis of yeast and human proteins. PMID- 21552482 TI - Acceptance and efficacy of a guided internet self-help treatment program for obese patients with binge eating disorder. AB - INTRODUCTION: A significant percentage of obese patients suffer from binge eating disorder (BED), with negative consequences on psychological health, quality of life, weight loss treatment and maintenance. Cognitive behavioral therapy (CBT), delivered in traditional or self-help format, is effective in reducing BED symptoms. To improve dissemination, a self-help treatment program composed of eleven CBT based modules was implemented on the Internet and evaluated in a population of adult obese patients with BED. METHOD: Forty-two obese BED patients wait-listed for a multi-disciplinary obesity treatment took part in the study. Twenty-two patients completing the six-month online guided self-help treatment program were compared to a control group of twenty patients without intervention. Both groups were evaluated before and after six months of Internet self-help treatment or waiting list. A follow-up evaluation was carried out six months later. RESULTS: Participants in the online self-help treatment program showed higher binge eating abstinence rates, lower EDE-Q shape and weight concerns, and improved TFEQ disinhibition of eating and hunger scores compared to the control group. They also scored better on psychological health and quality of life measures after intervention, and gains were maintained at follow-up. No effect was found regarding BMI. The number of modules completed was correlated with a better quality of life improvement at post evaluation. Participants rated the program as useful and easy to use. CONCLUSION: The Internet seems to be a valuable tool for disseminating CBT for BED obese patients. Acceptance of new technology was good in this population. Further research is needed with a larger sample to corroborate these results. PMID- 21552483 TI - The complete genome sequence of 'Candidatus Liberibacter solanacearum', the bacterium associated with potato zebra chip disease. AB - Zebra Chip (ZC) is an emerging plant disease that causes aboveground decline of potato shoots and generally results in unusable tubers. This disease has led to multi-million dollar losses for growers in the central and western United States over the past decade and impacts the livelihood of potato farmers in Mexico and New Zealand. ZC is associated with 'Candidatus Liberibacter solanacearum', a fastidious alpha-proteobacterium that is transmitted by a phloem-feeding psyllid vector, Bactericera cockerelli Sulc. Research on this disease has been hampered by a lack of robust culture methods and paucity of genome sequence information for 'Ca. L. solanacearum'. Here we present the sequence of the 1.26 Mbp metagenome of 'Ca. L. solanacearum', based on DNA isolated from potato psyllids. The coding inventory of the 'Ca. L. solanacearum' genome was analyzed and compared to related Rhizobiaceae to better understand 'Ca. L. solanacearum' physiology and identify potential targets to develop improved treatment strategies. This analysis revealed a number of unique transporters and pathways, all potentially contributing to ZC pathogenesis. Some of these factors may have been acquired through horizontal gene transfer. Taxonomically, 'Ca. L. solanacearum' is related to 'Ca. L. asiaticus', a suspected causative agent of citrus huanglongbing, yet many genome rearrangements and several gene gains/losses are evident when comparing these two Liberibacter. species. Relative to 'Ca. L. asiaticus', 'Ca. L. solanacearum' probably has reduced capacity for nucleic acid modification, increased amino acid and vitamin biosynthesis functionalities, and gained a high-affinity iron transport system characteristic of several pathogenic microbes. PMID- 21552484 TI - A transient expression of Prospero promotes cell cycle exit of Drosophila postembryonic neurons through the regulation of Dacapo. AB - Cell proliferation, specification and terminal differentiation must be precisely coordinated during brain development to ensure the correct production of different neuronal populations. Most Drosophila neuroblasts (NBs) divide asymmetrically to generate a new NB and an intermediate progenitor called ganglion mother cell (GMC) which divides only once to generate two postmitotic cells called ganglion cells (GCs) that subsequently differentiate into neurons. During the asymmetric division of NBs, the homeodomain transcription factor PROSPERO is segregated into the GMC where it plays a key role as cell fate determinant. Previous work on embryonic neurogenesis has shown that PROSPERO is not expressed in postmitotic neuronal progeny. Thus, PROSPERO is thought to function in the GMC by repressing genes required for cell-cycle progression and activating genes involved in terminal differentiation. Here we focus on postembryonic neurogenesis and show that the expression of PROSPERO is transiently upregulated in the newly born neuronal progeny generated by most of the larval NBs of the OL and CB. Moreover, we provide evidence that this expression of PROSPERO in GCs inhibits their cell cycle progression by activating the expression of the cyclin-dependent kinase inhibitor (CKI) DACAPO. These findings imply that PROSPERO, in addition to its known role as cell fate determinant in GMCs, provides a transient signal to ensure a precise timing for cell cycle exit of prospective neurons, and hence may link the mechanisms that regulate neurogenesis and those that control cell cycle progression in postembryonic brain development. PMID- 21552485 TI - Living bacterial sacrificial porogens to engineer decellularized porous scaffolds. AB - Decellularization and cellularization of organs have emerged as disruptive methods in tissue engineering and regenerative medicine. Porous hydrogel scaffolds have widespread applications in tissue engineering, regenerative medicine and drug discovery as viable tissue mimics. However, the existing hydrogel fabrication techniques suffer from limited control over pore interconnectivity, density and size, which leads to inefficient nutrient and oxygen transport to cells embedded in the scaffolds. Here, we demonstrated an innovative approach to develop a new platform for tissue engineered constructs using live bacteria as sacrificial porogens. E.coli were patterned and cultured in an interconnected three-dimensional (3D) hydrogel network. The growing bacteria created interconnected micropores and microchannels. Then, the scafold was decellularized, and bacteria were eliminated from the scaffold through lysing and washing steps. This 3D porous network method combined with bioprinting has the potential to be broadly applicable and compatible with tissue specific applications allowing seeding of stem cells and other cell types. PMID- 21552486 TI - Update on role of agalsidase alfa in management of Fabry disease. AB - Fabry disease (FD) is an X-linked lysosomal storage disorder that affects both men and women. The manifestations of this heterogeneous disease are multisystemic and progressive. Prior to the development of enzyme replacement therapy, the management and treatment for Fabry disease was largely nonspecific and supportive. Because enzyme replacement therapy became commercially available in 2001, a variety of clinical benefits in Fabry patients have been consistently reported, including improved renal pathology and cardiac function, and reduced severity of neuropathic pain and improved pain-related quality of life. This update focuses on published data on the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa, and gives a brief overview on some of the outstanding management issues in the treatment of this complex disease. PMID- 21552487 TI - Drug discovery and development for neglected diseases: the DNDi model. AB - New models of drug discovery have been developed to overcome the lack of modern and effective drugs for neglected diseases such as human African trypanosomiasis (HAT; sleeping sickness), leishmaniasis, and Chagas disease, which have no financial viability for the pharmaceutical industry. With the purpose of combining the skills and research capacity in academia, pharmaceutical industry, and contract researchers, public-private partnerships or product development partnerships aim to create focused research consortia that address all aspects of drug discovery and development. These consortia not only emulate the projects within pharmaceutical and biotechnology industries, eg, identification and screening of libraries, medicinal chemistry, pharmacology and pharmacodynamics, formulation development, and manufacturing, but also use and strengthen existing capacity in disease-endemic countries, particularly for the conduct of clinical trials. The Drugs for Neglected Diseases initiative (DNDi) has adopted a model closely related to that of a virtual biotechnology company for the identification and optimization of drug leads. The application of this model to the development of drug candidates for the kinetoplastid infections of HAT, Chagas disease, and leishmaniasis has already led to the identification of new candidates issued from DNDi's own discovery pipeline. This demonstrates that the model DNDi has been implementing is working but its DNDi, neglected diseases sustainability remains to be proven. PMID- 21552490 TI - Self-calibrated warping for mass spectra alignment. AB - With recent advances in mass spectrometry (MS) technologies, it is now possible to study protein profiles over a wide range of molecular weights in small biological specimens. However, MS spectra are usually not aligned or synchronized between samples. To ensure the consistency of the subsequent analysis, spectrum alignment is necessary to align the spectra such that the same biological entity would show up at the same m/z value for different samples. Although a variety of alignment algorithms have been proposed in the past, most of them are developed based on chromatographic data and do not address some of the unique characteristics of the serum or other body fluid MS data. In this work, we propose a self-calibrated warping (SCW) algorithm to address some of the challenges associated with serum MS data alignment. In addition, we compare the proposed algorithm with five existing representative alignment methods using a clinical surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) data set. PMID- 21552489 TI - Current and emerging drugs for the treatment of inflammatory bowel disease. AB - During the last decade a large number of biological agents against tumor necrosis factor-alpha (TNF-alpha), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-alpha inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn's disease and ulcerative colitis. PMID- 21552491 TI - Extension of cox proportional hazard model for estimation of interrelated age period-cohort effects on cancer survival. AB - In the frame of the Cox proportional hazard (PH) model, a novel two-step procedure for estimating age-period-cohort (APC) effects on the hazard function of death from cancer was developed. In the first step, the procedure estimates the influence of joint APC effects on the hazard function, using Cox PH regression procedures from a standard software package. In the second step, the coefficients for age at diagnosis, time period and birth cohort effects are estimated. To solve the identifiability problem that arises in estimating these coefficients, an assumption that neighboring birth cohorts almost equally affect the hazard function was utilized. Using an anchoring technique, simple procedures for obtaining estimates of interrelated age at diagnosis, time period and birth cohort effect coefficients were developed.As a proof-of-concept these procedures were used to analyze survival data, collected in the SEER database, on white men and women diagnosed with LC in 1975-1999 and the age at diagnosis, time period and birth cohort effect coefficients were estimated. The PH assumption was evaluated by a graphical approach using log-log plots. Analysis of trends of these coefficients suggests that the hazard of death from LC for a given time from cancer diagnosis: (i) decreases between 1975 and 1999; (ii) increases with increasing the age at diagnosis; and (iii) depends upon birth cohort effects.The proposed computing procedure can be used for estimating joint APC effects, as well as interrelated age at diagnosis, time period and birth cohort effects in survival analysis of different types of cancer. PMID- 21552492 TI - Reproducibility of SELDI Spectra Across Time and Laboratories. AB - This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.The reproducibility of mass spectrometry (MS) data collected using surface enhanced laser desorption/ionization-time of flight (SELDI-TOF) has been questioned. This investigation was designed to test the reproducibility of SELDI data collected over time by multiple users and instruments. Five laboratories prepared arrays once every week for six weeks. Spectra were collected on separate instruments in the individual laboratories. Additionally, all of the arrays produced each week were rescanned on a single instrument in one laboratory. Lab-to-lab and array-to array variability in alignment parameters were larger than the variability attributable to running samples during different weeks. The coefficient of variance (CV) in spectrum intensity ranged from 25% at baseline, to 80% in the matrix noise region, to about 50% during the exponential drop from the maximum matrix noise. Before normalization, the median CV of the peak heights was 72% and reduced to about 20% after normalization. Additionally, for the spectra from a common instrument, the CV ranged from 5% at baseline, to 50% in the matrix noise region, to 20% during the drop from the maximum matrix noise. Normalization reduced the variability in peak heights to about 18%. With proper processing methods, SELDI instruments produce spectra containing large numbers of reproducibly located peaks, with consistent heights. PMID- 21552493 TI - In silico analysis of combinatorial microRNA activity reveals target genes and pathways associated with breast cancer metastasis. AB - Aberrant microRNA activity has been reported in many diseases, and studies often find numerous microRNAs concurrently dysregulated. Most target genes have binding sites for multiple microRNAs, and mounting evidence indicates that it is important to consider their combinatorial effect on target gene repression. A recent study associated the coincident loss of expression of six microRNAs with metastatic potential in breast cancer. Here, we used a new computational method, miR-AT!, to investigate combinatorial activity among this group of microRNAs. We found that the set of transcripts having multiple target sites for these microRNAs was significantly enriched with genes involved in cellular processes commonly perturbed in metastatic tumors: cell cycle regulation, cytoskeleton organization, and cell adhesion. Network analysis revealed numerous target genes upstream of cyclin D1 and c-Myc, indicating that the collective loss of the six microRNAs may have a focal effect on these two key regulatory nodes. A number of genes previously implicated in cancer metastasis are among the predicted combinatorial targets, including TGFB1, ARPC3, and RANKL. In summary, our analysis reveals extensive combinatorial interactions that have notable implications for their potential role in breast cancer metastasis and in therapeutic development. PMID- 21552494 TI - PCCR: Pancreatic Cancer Collaborative Registry. AB - The Pancreatic Cancer Collaborative Registry (PCCR) is a multi-institutional web based system aimed to collect a variety of data on pancreatic cancer patients and high-risk subjects in a standard and efficient way. The PCCR was initiated by a group of experts in medical oncology, gastroenterology, genetics, pathology, epidemiology, nutrition, and computer science with the goal of facilitating rapid and uniform collection of critical information and biological samples to be used in developing diagnostic, prevention and treatment strategies against pancreatic cancer. The PCCR is a multi-tier web application that utilizes Java/JSP technology and has Oracle 10 g database as a back-end. The PCCR uses a "confederation model" that encourages participation of any interested center, irrespective of its size or location. The PCCR utilizes a standardized approach to data collection and reporting, and uses extensive validation procedures to prevent entering erroneous data. The PCCR controlled vocabulary is harmonized with the NCI Thesaurus (NCIt) or Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT). The PCCR questionnaire has accommodated standards accepted in cancer research and healthcare. Currently, seven cancer centers in the USA, as well as one center in Italy are participating in the PCCR. At present, the PCCR database contains data on more than 2,700 subjects (PC patients and individuals at high risk of getting this disease). The PCCR has been certified by the NCI Center for Biomedical Informatics and Information Technology as a cancer Biomedical Informatics Grid (caBIG((r))) Bronze Compatible product. The PCCR provides a foundation for collaborative PC research. It has all the necessary prerequisites for subsequent evolution of the developed infrastructure from simply gathering PC-related data into a biomedical computing platform vital for successful PC studies, care and treatment. Studies utilizing data collected in the PCCR may engender new approaches to disease prognosis, risk factor assessment, and therapeutic interventions. PMID- 21552495 TI - Physicochemical Studies and Anticancer Potency of Ruthenium eta-p-Cymene Complexes Containing Antibacterial Quinolones. AB - With the aim of exploring the anticancer properties of organometallic compounds with bioactive ligands, Ru(arene) compounds of the antibacterial quinolones nalidixic acid (2) and cinoxacin (3) were synthesized, and their physicochemical properties were compared to those of chlorido(eta(6)-p-cymene)(ofloxacinato kappa(2)O,O)ruthenium(II) (1). All compounds undergo a rapid ligand exchange reaction from chlorido to aqua species. 2 and 3 are significantly more stable than 1 and undergo minor conversion to an unreactive [(cym)Ru(MU OH)(3)Ru(cym)](+) species (cym = eta(6)-p-cymene). In the presence of human serum albumin 1-3 form adducts with this transport protein within 20 min of incubation. With guanosine 5'-monophosphate (5'-GMP; as a simple model for reactions with DNA) very rapid reactions yielding adducts via its N7 atom were observed, illustrating that DNA is a possible target for this compound class. A moderate capacity of inhibiting tumor cell proliferation in vitro was observed for 1 in CH1 ovarian cancer cells, whereas 2 and 3 turned out to be inactive. PMID- 21552496 TI - Myocilin mutations in black South Africans with POAG. AB - PURPOSE: Myocilin (MYOC) mutations are associated with primary open-angle glaucoma (POAG) in multiple populations. Here we examined the role of MYOC mutations in a black South African population with primary open-angle glaucoma (POAG). METHODS: Unrelated black South African subjects with POAG and unaffected controls were recruited from the St. John Eye Hospital (Soweto, Johannesburg, South Africa) and East London Hospital Complex (Eastern Cape, South Africa). A complete eye examination including visual field assessment was performed in all subjects. Blood samples were obtained for DNA extraction. The complete coding region of MYOC was sequenced using the PCR-based Sanger method. Identified mutations were compared to known MYOC mutations. RESULTS: One hundred-thirteen POAG cases and 131 controls were recruited for analysis. A total of 19 variants were observed. Probable glaucoma-causing mutations were observed in 4.4% of POAG cases. A previously reported glaucoma-causing mutation, Tyr453MetfsX11, was observed in three cases and one control. Two other sequence variants, Gly374Val and Lys500Arg, occurred only in cases. Other sequence variants, including 6 novel variants, occurred in at least one control. CONCLUSIONS: A small minority of black South Africans with POAG carry MYOC mutations. The Gly374Val mutation might represent a novel glaucoma-causing mutation. The Tyr453MetFSX11 mutation appears to be a glaucoma-causing mutation with incomplete penetrance. PMID- 21552497 TI - A recurrent mutation in CRYGD is associated with autosomal dominant congenital coralliform cataract in two unrelated Chinese families. AB - PURPOSE: Congenital cataract is a clinically and genetically heterogeneous lens disorder. The purpose of this study was to identify the mutation responsible for autosomal dominant congenital coralliform cataracts in two Chinese families and to investigate the relationship between virulence genes and lens morphology. METHODS: Patients received a physical examination, and blood samples were collected for DNA extraction. Mutation analysis was performed by direct sequencing of the candidate genes: gammaC-crystallin (CRYGC), gammaD-crystallin (CRYGD), gammaS-crystallin (CRYGS), gap-junction protein, alpha 8 (GJA8), gap junction protein, alpha 3 (GJA3), and alphaA-crystallin (CRYAA). RESULTS: The affected individuals in two families had congenital coralliform cataracts. Mutational analysis of the CRYGD identified a C->A transversion at nucleotide position c.70 in exon 2, which resulted in a threonine substitution for proline at amino-acid residue 24 (P24T). This mutation was identified in all affected individuals but was not found in healthy relatives or 100 control chromosomes from the same ethnic background. CONCLUSIONS: Our results indicated that the P24T mutation of CRYGD was responsible for two Chinese pedigrees with congenital coralliform cataracts. CRYGD and coralliform cataracts are highly related, and P24T may be a hot-point mutation for this disorder. PMID- 21552498 TI - A novel mutation in the GJA3 (connexin46) gene is associated with autosomal dominant congenital nuclear cataract in a Chinese family. AB - PURPOSE: Congenital cataract is both a clinically and genetically heterogeneous lens disorder. The purpose of this study is to map and identify the mutation in an autosomal dominant congenital nuclear cataract in a Chinese family. METHODS: Patients were given physical examinations and their blood samples were collected for DNA extraction. Genotyping was performed by microsatellite markers and logarithm of odds (LOD) scores were calculated using the LINKAGE programs. Mutation detection was performed by direct sequencing. RESULTS: Linkage to the gap-junction protein alpha3 (GJA3) locus was verified. Sequencing of GJA3 revealed a G>A transition at nucleotide position c.139, which causes an Asn substitution for the conservative Asp at codon 47 (P.D47N).This mutation is identified in all affected individuals but is not found in 100 control chromosomes. CONCLUSIONS: Our results identify that the mutation (D47N) in GJA3 is responsible for this Chinese pedigree. It is further identified that GJA3 is responsible for congenital cataract. In our study, the novel mutation broadens the spectrum of GJA3 mutations. PMID- 21552499 TI - Effects of apelin and vascular endothelial growth factor on central retinal vein occlusion in monkey eyes intravitreally injected with bevacizumab: a preliminary study. AB - PURPOSE: To examine the intraocular distribution of bevacizumab at four weeks after intravitreal bevacizumab (IVB) injection and to investigate the effects of IVB on apelin and vascular endothelial growth factor (VEGF) in the central retinal vein occlusion (CRVO) of monkey eyes. METHODS: Direct laser coagulation was performed on all branch retinal veins in the right eyes of six Rhesus monkeys to establish a CRVO model. The eyes of the first three monkeys were enucleated one week, two weeks, and 24 weeks after the establishment of the CRVO model; this was the CRVO group. Subsequently, IVB was injected into the eyes of the last three monkeys one week, two weeks, and 24 weeks after laser coagulation; this was the IVB group. The left eye of the first monkey was used as normal control. Immunohistochemistry and reverse-transcription PCR was used to examine the expression of apelin and VEGF. The penetration of bevacizumab into the retina and iris was investigated by fluorescence immunostaining. RESULTS: Immunoreactivity for bevacizumab could be detected in the vessel walls of the iris and choroid on day 28 after injecting IVB: apelin and VEGF staining had been more prominent than normal in the CRVO eye, but these decreased following IVB injection. Expression of apelin mRNA (p<0.01) was lower in the IVB group than the CRVO group and did not vary significantly between groups. CONCLUSIONS: Bevacizumab could be detected in the iris and choroid after four weeks of intravitreal injection. Apelin may be partially suppressed by bevacizumab, and it may play a role in retinal neovascularization during the development of CRVO. PMID- 21552500 TI - A method to extract cytokines and matrix metalloproteinases from Schirmer strips and analyze using Luminex. AB - PURPOSE: The Schirmer's test is commonly used in the clinic for the diagnosis of dry eye disease by measuring tear volume. This report describes a procedure which can be used to recover tears from the Schirmer strip for the measurement of multiple tear cytokines as well as matrix metalloproteinases (MMPs) by Luminex technology. METHODS: Cytokine and MMP recovery was determined by using spiked Schirmer strips presoaked with known cytokines or MMPs prepared in PBS with 1% BSA. In a clinical study, tears were collected from 5 subjects using Schirmer strips. Strips were stored on ice immediately after removal from the subject and stored dry at -20 degrees C for 16-24 h. Cytokines were extracted from the Schirmer strip in 0.5 M NaCl with 0.5% Tween-20. Concentrations of cytokines and MMPs in collected tear samples were analyzed by Luminex using both a 10-cytokine and a 5-MMP kit. RESULTS: The standard curves for the assay in both the kit assay buffer and extraction buffer were identical for 9 of the 10 cytokines and all 5 MMPs. In the clinical sample all the cytokines (interleukin 1alpha [IL-1alpha], IL-1beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-13, monocyte chemotactic protein-1 [MCP-1], and tumor necrosis factor-alpha [TNF-alpha]) and 5 MMPs (MMP-1, MMP-2, MMP-7, MMP-9, and MMP-10) tested were detected in at least 50% of the 10 subject samples. Recoveries from extracted Schirmer strips were >60% for 8 of the 10 cytokines and all MMPs. CONCLUSIONS: Numerous cytokines and MMPs were detected in the tear samples collected using the Schirmer strip, including many that have been implicated in ocular surface disease. This procedure may be used to evaluate the cytokine and MMP content in tear samples in clinical studies, especially for the evaluation of dry eye therapeutics. Because the Schirmer test is routine in the assessment of dry eye, this method offers the opportunity to evaluate both the quantity and quality of the tears. PMID- 21552501 TI - Down-regulation of OPA1 in patients with primary open angle glaucoma. AB - PURPOSE: Heterozygous optic atrophy type1 (OPA1) mutations are responsible for dominant optic atrophy, and the down regulation of OPA1 expression in patients with Leber hereditary optic neuropathy may imply that Opa1 protein levels in mitochondria play a role in other spontaneous optic neuropathies as well. Mitochondrial and metabolic abnormalities may put the optic nerve at risk in primary open angle glaucoma (POAG), and this preliminary study was designed to investigate whether altered OPA1 expression might be present in the progressive optic neuropathy of POAG. METHODS: Patients were eligible for inclusion if they met standard clinical criteria for POAG, including age greater than 40 years, intraocular pressure >= 21 mmHg in at least one eye before treatment, normal appearing anterior chamber angles bilaterally on gonioscopy, and optic nerve injury characteristic of POAG. RNA was extracted from leukocytes and converted to cDNA by reverse transcriptase enzyme, and real time PCR was used to assess expression levels of OPA1 and the beta-globulin (HBB) housekeeping gene. The ratio of OPA1 expression to HBB expression (OPA1/HBB) for POAG patients was compared to that of controls and to clinical characteristics of POAG patients. RESULTS: Forty-three POAG patients and 27 controls were completely phenotyped with a full ophthalmologic examination and static perimetry. Mean age (POAG 67.9 years; controls 61.8 years) and sex (POAG 26 males/17 females; controls 11/16) were similar for the two groups. Mean OPA1/HBB of POAG patients (1.16, SD 0.26) was 18% lower than controls (1.41, SD 0.50), and this difference was statistically significant (p<=0.021). OPA1 expression differed between the groups (p<=0.037), but HBB expression did not differ (p<=0.24). OPA1/HBB was not correlated with any clinical feature of POAG patients. CONCLUSIONS: Transcriptional analysis of peripheral blood leucocytes is a limited model system for studying the consequences of mitochondrial abnormalities in the optic nerve. Nevertheless, OPA1 is known to affect mitochondrial stability and has now been implicated in several spontaneous optic neuropathies. Decreased OPA1 expression in POAG patients is another indication that mitochondrial function, and possibly mitochondrially-induced apoptosis, may play a role in the development of POAG. PMID- 21552503 TI - New Drimane Sesquiterpenoids from Tidestromia oblongifolia. AB - From an acetone extract of the aerial parts of Tidestromia oblongifolia (Amaranthaceae), a new drimane sesquiterpenoid bearing an 11,12,13 trihydroxydrimene skeleton (1) as well as the 11,12 acetonide of 1 were isolated. Three known stigmastane triterpenoids were also isolated. Structures were elucidated with the aid of 1D and 2D NMR spectroscopic techniques. The absolute configuration of 1 was confirmed by single-crystal x-ray crystallography. This is the first report on phytochemical constituents from any plant of the genus Tidestromia and is the first report of the occurrence of drimanes in the Amaranthaceae. PMID- 21552504 TI - Alexander Disease: An Important Mimicker of Focal Brainstem Glioma-Response. PMID- 21552502 TI - Inhibition of proliferation of rat lens epithelial cell by overexpression of KLF6. AB - PURPOSE: Proliferation of lens epithelial cell (LEC) is main principle for posterior capsular opacity (PCO) following surgery. We investigated whether overexpression of Kruppel-like factor 6 (KLF6) can be employed to increase protein 21 (p21) and protein 27 kinase inhibition protein 1 (p27(kip1)) levels and its effect on proliferation of LEC. METHODS: A plasmid containing KLF6 cDNA was used to increase the level of KLF6 protein in rat lens epithelial cells (rLEC) which can lead to consequent degradation of p21 and p27(kip1). Cell proliferation was assayed by cell counts and bromodeoxyuridine (BrdU) Incorporation. RESULTS: western blot analysis showed increased levels of KLF6, p21, and p27(kip1) in cells transfected with pKLF6 cDNA. pKLF6 cDNA transfected cells showed less compared with control cells in vitro. CONCLUSIONS: pKLF6 cDNA inhibited cell proliferation and decreased cell viability of LEC by unregulation of p21 and p27(kip1). PMID- 21552505 TI - Preference Heterogeneity and Insurance Markets: Explaining a Puzzle of Insurance. PMID- 21552506 TI - The French Heritage in Clinical Kidney Transplantation. PMID- 21552507 TI - Effect based monitoring of seasonal ambient air exposures in Australia sampled by PUF passive air samplers. AB - There has been relatively little bioanalytical effect based monitoring conducted using samples derived from polyurethane foam (PUF) passive air samplers. Combining these techniques may provide a more convenient and cost effective means of monitoring the potential for biological effects resulting from exposure to complex mixtures in a range of scenarios. Seasonal polycyclic aromatic hydrocarbon (PAH) levels were monitored at sites around Australia using direct chemical analysis. In addition, both indirect acting genotoxicity (umuC assay) and aryl hydrocarbon receptor (AhR) activity (chemically activated fluorescent gene expression [CAFLUX assay]), which are effects potentially relevant to subsequent carcinogenesis for these compounds, were measured. The levels of PAHs as well as genotoxicity and AhR activity were all higher in winter compared to summer and for sites in urban capital cities compared to other locations. Statistically significant relationships were found between the levels of PAHs and both genotoxicity and AhR activity. The dominant contributors to the total AhR activity, were found to be for compounds which are not resistant to H(2)SO(4)/silica gel treatment and were relatively rapidly metabolised that is consistent with a PAH type response. Relative potency estimates for individual PAHs determined for the first time on the CAFLUX assay were used to estimate the proportion of total AhR activity (<= 3.0%) accounted by PAHs monitored. Observed responses are thus largely due to non-quantified AhR active compounds. PMID- 21552509 TI - Amide-Amide and Amide-Water Hydrogen Bonds: Implications for Protein Folding and Stability. AB - Amide-amide hydrogen bonds have been implicated in directing protein folding and enhancing protein stability. Inversion transfer (13)C NMR spectroscopy and IR spectroscopy were used to compare the ability of various amide solvents and of water to alter the rate of the cis-trans isomerization of the prolyl peptide bond of Ac-Gly-[beta,delta-(13)C]Pro-OMe and the amide I vibrational mode of [(13)C=O]Ac-Pro-OMe. The results indicate that secondary amides are significantly weaker hydrogen bond donors than is formamide or water. These results are most consistent with models for protein folding in which the formation of secondary structure is a cooperative process that follows hydrophobic collapse. These results also suggest that a hydrogen bond between a main-chain oxygen and an asparagine or glutamine sidechain may contribute more to protein stability than does a main-chain-main-chain hydrogen bond. PMID- 21552510 TI - Motivational Influences on Cognitive Performance in Children: Focus Over Fit. AB - Cognitive psychologists have begun to address how motivational factors influence adults' performance on cognitive tasks. However, little research has examined how different motivational factors interact with one another to affect behavior across the lifespan. The current study examined how children perform on a classification task when placed in a regulatory fit or mismatch. Nine-year-old children performed a classification task in which they either gained or lost points for each response. Additionally, children were given either a global promotion focus (trying to earn a gift card) or a prevention focus (trying to avoid losing a gift card). Previous work indicates that adults in this task tend to perform better when there is a match (or fit) between the overall incentive to earn or avoid losing the incentive and the task reward structure to maximize points gained or minimize points lost. Unlike adults, nine-year-olds perform better in the promotion condition than in the prevention condition regardless of task reward structure. Possible explanations for the differences between adults' and children's performance are discussed as well as possible applications for academic settings. PMID- 21552512 TI - Integrating utilization-focused evaluation with business process modeling for clinical research improvement. AB - New discoveries in basic science are creating extraordinary opportunities to design novel biomedical preventions and therapeutics for human disease. But the clinical evaluation of these new interventions is, in many instances, being hindered by a variety of legal, regulatory, policy and operational factors, few of which enhance research quality, the safety of study participants or research ethics. With the goal of helping increase the efficiency and effectiveness of clinical research, we have examined how the integration of utilization-focused evaluation with elements of business process modeling can reveal opportunities for systematic improvements in clinical research. Using data from the NIH global HIV/AIDS clinical trials networks, we analyzed the absolute and relative times required to traverse defined phases associated with specific activities within the clinical protocol lifecycle. Using simple median duration and Kaplan-Meyer survival analysis, we show how such time-based analyses can provide a rationale for the prioritization of research process analysis and re-engineering, as well as a means for statistically assessing the impact of policy modifications, resource utilization, re-engineered processes and best practices. Successfully applied, this approach can help researchers be more efficient in capitalizing on new science to speed the development of improved interventions for human disease. PMID- 21552513 TI - Serum levels of adipocyte fatty acid-binding protein are associated with the severity of coronary artery disease in Chinese women. AB - BACKGROUND: Adipocyte fatty acid-binding protein (A-FABP) has been described as a novel adipokine, playing an important role in the development of metabolic syndrome, type 2 diabetes and atherosclerosis. In this study, we investigated the relationship between serum levels of A-FABP and the presence and severity of coronary artery disease (CAD) in Chinese subjects. METHODOLOGY/PRINCIPAL FINDINGS: Circulating A-FABP level was determined by ELISA in 341 Chinese subjects (221 men, 120 women) who underwent coronary angiography. A-FABP levels in patients with CAD were significantly higher compared with non-CAD subjects (P = 0.029 in men; P = 0.031 in women). Serum A-FABP increased significantly in multi-vessel diseased patients than in non-CAD subjects (P = 0.011 in men, P = 0.004 in women), and showed an independent correlation with coronary atherosclerosis index (standardized beta = 0.173, P = 0.025). In multiple logistic regression analysis, serum A-FABP was an independent risk factor for CAD in women (OR = 5.637, 95%CI: 1.299-24.457, P = 0.021). In addition, amino terminal pro-brain natriuretic peptide (NT-proBNP) was demonstrated to be positively and independently correlated with A-FABP (standardized beta = 0.135, P = 0.027). CONCLUSIONS/SIGNIFICANCE: Serum A-FABP is closely associated with the presence and severity of CAD in Chinese women. PMID- 21552515 TI - Variation in the structure of bird nests between northern Manitoba and southeastern Ontario. AB - Traits that converge in appearance under similar environmental conditions among phylogenetically independent lineages are thought to represent adaptations to local environments. We tested for convergence in nest morphology and composition of birds breeding in two ecologically different locations in Canada: Churchill in northern Manitoba and Elgin in southeastern Ontario. We examined nests from four families of passerine birds (Turdidae: Turdus, Parulidae: Dendroica, Emberizidae: Passerculus and Fringillidae: Carduelis) where closely related populations or species breed in both locations. Nests of American Robins, Yellow Warblers, and Carduelis finches had heavier nest masses, and tended to have thicker nest-walls, in northern Manitoba compared with conspecifics or congenerics breeding in southeastern Ontario. Together, all species showed evidence for wider internal and external nest-cup diameters in northern Manitoba, while individual species showed varying patterns for internal nest-cup and external nest depths. American Robins, Yellow Warblers, and Carduelis finches in northern Manitoba achieved heavier nest masses in different ways. American Robins increased all materials in similar proportions, and Yellow Warblers and Common Redpolls used greater amounts of select materials. While changes in nest composition vary uniquely for each species, the pattern of larger nests in northern Manitoba compared to southeastern Ontario in three of our four phylogenetically-independent comparisons suggests that birds are adapting to similar selective pressures between locations. PMID- 21552514 TI - The stress response factors Yap6, Cin5, Phd1, and Skn7 direct targeting of the conserved co-repressor Tup1-Ssn6 in S. cerevisiae. AB - Maintaining the proper expression of the transcriptome during development or in response to a changing environment requires a delicate balance between transcriptional regulators with activating and repressing functions. The budding yeast transcriptional co-repressor Tup1-Ssn6 is a model for studying similar repressor complexes in multicellular eukaryotes. Tup1-Ssn6 does not bind DNA directly, but is directed to individual promoters by one or more DNA-binding proteins, referred to as Tup1 recruiters. This functional architecture allows the Tup1-Ssn6 to modulate the expression of genes required for the response to a variety of cellular stresses. To understand the targeting or the Tup1-Ssn6 complex, we determined the genomic distribution of Tup1 and Ssn6 by ChIP-chip. We found that most loci bound by Tup1-Ssn6 could not be explained by co-occupancy with a known recruiting cofactor and that deletion of individual known Tup1 recruiters did not significantly alter the Tup1 binding profile. These observations suggest that new Tup1 recruiting proteins remain to be discovered and that Tup1 recruitment typically depends on multiple recruiting cofactors. To identify new recruiting proteins, we computationally screened for factors with binding patterns similar to the observed Tup1-Ssn6 genomic distribution. Four top candidates, Cin5, Skn7, Phd1, and Yap6, all known to be associated with stress response gene regulation, were experimentally confirmed to physically interact with Tup1 and/or Ssn6. Incorporating these new recruitment cofactors with previously characterized cofactors now explains the majority of Tup1 targeting across the genome, and expands our understanding of the mechanism by which Tup1 Ssn6 is directed to its targets. PMID- 21552511 TI - Magnetic resonance imaging of cells in experimental disease models. PMID- 21552516 TI - Inactivation of the DNA repair genes mutS, mutL or the anti-recombination gene mutS2 leads to activation of vitamin B1 biosynthesis genes. AB - Oxidative stress generates harmful reactive oxygen species (ROS) that attack biomolecules including DNA. In living cells, there are several mechanisms for detoxifying ROS and repairing oxidatively-damaged DNA. In this study, transcriptomic analyses clarified that disruption of DNA repair genes mutS and mutL, or the anti-recombination gene mutS2, in Thermus thermophilus HB8, induces the biosynthesis pathway for vitamin B(1), which can serve as an ROS scavenger. In addition, disruption of mutS, mutL, or mutS2 resulted in an increased rate of oxidative stress-induced mutagenesis. Co-immunoprecipitation and pull-down experiments revealed previously-unknown interactions of MutS2 with MutS and MutL, indicating that these proteins cooperatively participate in the repair of oxidatively damaged DNA. These results suggested that bacterial cells sense the accumulation of oxidative DNA damage or absence of DNA repair activity, and signal the information to the transcriptional regulation machinery for an ROS detoxifying system. PMID- 21552517 TI - 4-aminobutyrate aminotransferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease. AB - Gastro-esophageal reflux disease (GERD) is partly caused by genetic factors. The underlying susceptibility genes are currently unknown, with the exception of COL3A1. We used three independent GERD patient cohorts to identify GERD susceptibility genes. Thirty-six families, demonstrating dominant transmission of GERD were subjected to whole genome microsatellite genotyping and linkage analysis. Five linked regions were identified. Two families shared a linked region (LOD 3.9 and 2.0) on chromosome 16. We used two additional independent GERD patient cohorts, one consisting of 219 trios (affected child with parents) and the other an adult GERD case control cohort consisting of 256 cases and 485 controls, to validate individual genes in the linked region through association analysis. Sixty six single nucleotide polymorphism (SNP) markers distributed over the nine genes present in the linked region were genotyped in the independent GERD trio cohort. Transmission disequilibrium test analysis followed by multiple testing adjustments revealed a significant genetic association for one SNP located in an intron of the gene 4-aminobutyrate aminotransferase (ABAT) (P(adj) = 0.027). This association did not replicate in the adult case-control cohort, possibly due to the differences in ethnicity between the cohorts. Finally, using the selective ABAT inhibitor vigabatrin (gamma-vinyl GABA) in a dog study, we were able to show a reduction of transient lower esophageal sphincter relaxations (TLESRs) by 57.3 +/- 11.4 % (p = 0.007) and the reflux events from 3.1 +/- 0.4 to 0.8 +/- 0.4 (p = 0.007). Our results demonstrate the direct involvement of ABAT in pathways affecting lower esophageal sphincter (LES) control and identifies ABAT as a genetic risk factor for GERD. PMID- 21552518 TI - Effects of subthalamic nucleus stimulation on emotional prosody comprehension in Parkinson's disease. AB - BACKGROUND: Although impaired decoding of emotional prosody has frequently been associated with Parkinson's disease (PD), to date only few reports have sought to explore the effect of Parkinson's treatment on disturbances of prosody decoding. In particular, little is known about how surgical treatment approaches such as high frequency deep brain stimulation (DBS) affect emotional speech perception in patients with PD. Accordingly, the objective of this study was to evaluate the effect of subthalamic nucleus (STN) stimulation on prosody processing. METHODOLOGY/PRINCIPAL FINDINGS: To this end the performance of 13 PD patients on three tasks requiring the decoding of emotional speech was assessed and subsequently compared to the performance of healthy control individuals. To delineate the effect of STN-DBS, all patients were tested with stimulators turned on as well as with stimulators turned off. Results revealed that irrespective of whether assessments were made "on" or "off" stimulation, patients' performance was less accurate as compared to healthy control participants on all tasks employed in this study. However, while accuracy appeared to be unaffected by stimulator status, a facilitation of reactions specific to highly conflicting emotional stimulus material (i.e. stimulus material presenting contradicting emotional messages on a verbal and non-verbal prosodic level) was observed during "on" stimulation assessments. CONCLUSION: In sum, presented results suggest that the processing of emotional speech is indeed modulated by STN-DBS. Observed alterations might, on the one hand, reflect a more efficient processing of highly conflicting stimulus material following DBS. However, on the other hand, given the lack of an improvement in accuracy, increased impulsivity associated with STN stimulation needs to be taken into consideration. PMID- 21552519 TI - Antibody engineering using phage display with a coiled-coil heterodimeric Fv antibody fragment. AB - A Fab-like antibody binding unit, ccFv, in which a pair of heterodimeric coiled coil domains was fused to V(H) and V(L) for Fv stabilization, was constructed for an anti-VEGF antibody. The anti-VEGF ccFv showed the same binding affinity as scFv but significantly improved stability and phage display level. Furthermore, phage display libraries in the ccFv format were constructed for humanization and affinity maturation of the anti-VEGF antibody. A panel of V(H) frameworks and V(H)-CDR3 variants, with a significant improvement in affinity and expressibility in both E. coli and yeast systems, was isolated from the ccFv phage libraries. These results demonstrate the potential application of the ccFv antibody format in antibody engineering. PMID- 21552520 TI - Survey of activated FLT3 signaling in leukemia. AB - Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 is therefore an attractive drug target. However, the molecular mechanisms by which FLT3 mutations lead to cell transformation in AML remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream effectors, we performed detailed phosphoproteomic analysis of FLT3 signaling in human leukemia cells. We identified over 1000 tyrosine phosphorylation sites from about 750 proteins in both AML (wild type and mutant FLT3) and B cell acute lymphoblastic leukemia (normal and amplification of FLT3) cell lines. Furthermore, using stable isotope labeling by amino acids in cell culture (SILAC), we were able to quantified over 400 phosphorylation sites (pTyr, pSer, and pThr) that were responsive to FLT3 inhibition in FLT3 driven human leukemia cell lines. We also extended this phosphoproteomic analysis on bone marrow from primary AML patient samples, and identify over 200 tyrosine and 800 serine/threonine phosphorylation sites in vivo. This study showed that oncogenic FLT3 regulates proteins involving diverse cellular processes and affects multiple signaling pathways in human leukemia that we previously appreciated, such as Fc epsilon RI-mediated signaling, BCR, and CD40 signaling pathways. It provides a valuable resource for investigation of oncogenic FLT3 signaling in human leukemia. PMID- 21552521 TI - HIV-infected children in rural Zambia achieve good immunologic and virologic outcomes two years after initiating antiretroviral therapy. AB - BACKGROUND: Many HIV-infected children in sub-Saharan Africa reside in rural areas, yet most research on treatment outcomes has been conducted in urban centers. Rural clinics and residents may face unique barriers to care and treatment. METHODS: A prospective cohort study of HIV-infected children was conducted between September 2007 and September 2010 at the rural HIV clinic in Macha, Zambia. HIV-infected children younger than 16 years of age at study enrollment who received antiretroviral therapy (ART) during the study were eligible. Treatment outcomes during the first two years of ART, including mortality, immunologic status, and virologic suppression, were assessed and risk factors for mortality and virologic suppression were evaluated. RESULTS: A total of 69 children entered the study receiving ART and 198 initiated ART after study enrollment. The cumulative probabilities of death among children starting ART after study enrollment were 9.0% and 14.4% at 6 and 24 months after ART initiation. Younger age, higher viral load, lower CD4+ T-cell percentage and lower weight-for-age z-scores at ART initiation were associated with higher risk of mortality. The mean CD4(+) T-cell percentage increased from 16.3% at treatment initiation to 29.3% and 35.0% at 6 and 24 months. The proportion of children with undetectable viral load increased to 88.5% and 77.8% at 6 and 24 months. Children with longer travel times (>= 5 hours) and those taking nevirapine at ART initiation, as well as children who were non-adherent, were less likely to achieve virologic suppression after 6 months of ART. CONCLUSIONS: HIV-infected children receiving treatment in a rural clinic experienced sustained immunologic and virologic improvements. Children with longer travel times were less likely to achieve virologic suppression, supporting the need for decentralized models of ART delivery. PMID- 21552522 TI - Differences in mouse maternal care behavior - is there a genetic impact of the glucocorticoid receptor? AB - Depressive episodes are frequently preceded by stressful life events. Evidence from genetic association studies suggests a role for the glucocorticoid receptor (GR), an essential element in the regulation of stress responses, in the pathophysiology of the disorder. Since the stress response system is affected by pregnancy and postpartum-associated changes, it has also been implicated in the pathophysiology of postpartum depression. Using a 2 * 2 factorial design, we investigated whether a heterozygous deletion of GR would influence maternal care behavior in C57BL/6 and Balb/c mice, two inbred strains known to display qualitative differences in this behavior. Behavioral observation was carried out between postnatal days 1 and 7, followed by a pup retrieval test on postnatal days 7 or 8. While previously noted inter-strain differences were confirmed for different manifestations of caring behavior, self-maintenance and neglecting behaviors as well as the pup retrieval test, no strain-independent effect of the GR mutation was noted. However, an interaction between GR genotype and licking/grooming behavior was observed: it was down-regulated in heterozygous C57BL/6 mice to the level recorded for Balb/c mice. Home cage observation poses minimal disturbance of the dam and her litter as compared to more invasive assessments of dams' emotional behavior. This might be a reason for the absence of any overall effects of the GR mutation, particularly since GR heterozygous animals display a depressive-like phenotype under stressful conditions only. Still, the subtle effect we observed may point towards a role of GR in postpartum affective disorders. PMID- 21552523 TI - Absence of aquaporin-4 in skeletal muscle alters proteins involved in bioenergetic pathways and calcium handling. AB - Aquaporin-4 (AQP4) is a water channel expressed at the sarcolemma of fast-twitch skeletal muscle fibers, whose expression is altered in several forms of muscular dystrophies. However, little is known concerning the physiological role of AQP4 in skeletal muscle and its functional and structural interaction with skeletal muscle proteome. Using AQP4-null mice, we analyzed the effect of the absence of AQP4 on the morphology and protein composition of sarcolemma as well as on the whole skeletal muscle proteome. Immunofluorescence analysis showed that the absence of AQP4 did not perturb the expression and cellular localization of the dystrophin-glycoprotein complex proteins, aside from those belonging to the extracellular matrix, and no alteration was found in sarcolemma integrity by dye extravasation assay. With the use of a 2DE-approach (BN/SDS-PAGE), protein maps revealed that in quadriceps, out of 300 Coomassie-blue detected and matched spots, 19 proteins exhibited changed expression in AQP4(-/-) compared to WT mice. In particular, comparison of the protein profiles revealed 12 up- and 7 down regulated protein spots in AQP4-/- muscle. Protein identification by MS revealed that the perturbed expression pattern belongs to proteins involved in energy metabolism (i.e. GAPDH, creatine kinase), as well as in Ca(2+) handling (i.e. parvalbumin, SERCA1). Western blot analysis, performed on some significantly changed proteins, validated the 2D results. Together these findings suggest AQP4 as a novel determinant in the regulation of skeletal muscle metabolism and better define the role of this water channel in skeletal muscle physiology. PMID- 21552524 TI - GPVI and GPIbalpha mediate staphylococcal superantigen-like protein 5 (SSL5) induced platelet activation and direct toward glycans as potential inhibitors. AB - BACKGROUND: Staphylococcus aureus (S. aureus) is a common pathogen capable of causing life-threatening infections. Staphylococcal superantigen-like protein 5 (SSL5) has recently been shown to bind to platelet glycoproteins and induce platelet activation. This study investigates further the interaction between SSL5 and platelet glycoproteins. Moreover, using a glycan discovery approach, we aim to identify potential glycans to therapeutically target this interaction and prevent SSL5-induced effects. METHODOLOGY/PRINCIPAL FINDINGS: In addition to platelet activation experiments, flow cytometry, immunoprecipitation, surface plasmon resonance and a glycan binding array, were used to identify specific SSL5 binding regions and mediators. We independently confirm SSL5 to interact with platelets via GPIbalpha and identify the sulphated-tyrosine residues as an important region for SSL5 binding. We also identify the novel direct interaction between SSL5 and the platelet collagen receptor GPVI. Together, these receptors offer one mechanistic explanation for the unique functional influences SSL5 exerts on platelets. A role for specific families of platelet glycans in mediating SSL5-platelet interactions was also discovered and used to identify and demonstrate effectiveness of potential glycan based inhibitors in vitro. CONCLUSIONS/SIGNIFICANCE: These findings further elucidate the functional interactions between SSL5 and platelets, including the novel finding of a role for the GPVI receptor. We demonstrate efficacy of possible glycan-based approaches to inhibit the SSL5-induced platelet activation. Our data warrant further work to prove SSL5-platelet effects in vivo. PMID- 21552525 TI - Functional interaction of nuclear domain 10 and its components with cytomegalovirus after infections: cross-species host cells versus native cells. AB - Species-specificity is one of the major characteristics of cytomegaloviruses (CMVs) and is the primary reason for the lack of a mouse model for the direct infection of human CMV (HCMV). It has been determined that CMV cross-species infections are blocked at the post-entry level by intrinsic cellular defense mechanisms, but few details are known. It is important to explore how CMVs interact with the subnuclear structure of the cross-species host cell. In our present study, we discovered that nuclear domain 10 (ND10) of human cells was not disrupted by murine CMV (MCMV) and that the ND10 of mouse cells was not disrupted by HCMV, although the ND10-disrupting protein, immediate-early protein 1 (IE1), also colocalized with ND10 in cross-species infections. In addition, we found that the UL131-repaired HCMV strain AD169 (vDW215-BADrUL131) can infect mouse cells to produce immediate-early (IE) and early (E) proteins but that neither DNA replication nor viral particles were detectable in mouse cells. Unrepaired AD169 can express IE1 only in mouse cells. In both HCMV-infected mouse cells and MCMV infected human cells, the knocking-down of ND10 components (PML, Daxx, and SP100) resulted in significantly increased viral-protein production. Our observations provide evidence to support our hypothesis that ND10 and ND10 components might be important defensive factors against the CMV cross-species infection. PMID- 21552526 TI - A deletion in exon 9 of the LIPH gene is responsible for the rex hair coat phenotype in rabbits (Oryctolagus cuniculus). AB - The fur of common rabbits is constituted of 3 types of hair differing in length and diameter while that of rex animals is essentially made up of amazingly soft down-hair. Rex short hair coat phenotypes in rabbits were shown to be controlled by three distinct loci. We focused on the "r1" mutation which segregates at a simple autosomal-recessive locus in our rabbit strains. A positional candidate gene approach was used to identify the rex gene and the corresponding mutation. The gene was primo-localized within a 40 cM region on rabbit chromosome 14 by genome scanning families of 187 rabbits in an experimental mating scheme. Then, fine mapping refined the region to 0.5 cM (Z = 78) by genotyping an additional 359 offspring for 94 microsatellites present or newly generated within the first defined interval. Comparative mapping pointed out a candidate gene in this 700 kb region, namely LIPH (Lipase Member H). In humans, several mutations in this major gene cause alopecia, hair loss phenotypes. The rabbit gene structure was established and a deletion of a single nucleotide was found in LIPH exon 9 of rex rabbits (1362delA). This mutation results in a frameshift and introduces a premature stop codon potentially shortening the protein by 19 amino acids. The association between this deletion and the rex phenotype was complete, as determined by its presence in our rabbit families and among a panel of 60 rex and its absence in all 60 non-rex rabbits. This strongly suggests that this deletion, in a homozygous state, is responsible for the rex phenotype in rabbits. PMID- 21552527 TI - From isotropic to anisotropic side chain representations: comparison of three models for residue contact estimation. AB - The criterion to determine residue contact is a fundamental problem in deriving knowledge-based mean-force potential energy calculations for protein structures. A frequently used criterion is to require the side chain center-to-center distance or the -to- atom distance to be within a pre-determined cutoff distance. However, the spatially anisotropic nature of the side chain determines that it is challenging to identify the contact pairs. This study compares three side chain contact models: the Atom Distance criteria (ADC) model, the Isotropic Sphere Side chain (ISS) model and the Anisotropic Ellipsoid Side chain (AES) model using 424 high resolution protein structures in the Protein Data Bank. The results indicate that the ADC model is the most accurate and ISS is the worst. The AES model eliminates about 95% of the incorrectly counted contact-pairs in the ISS model. Algorithm analysis shows that AES model is the most computational intensive while ADC model has moderate computational cost. We derived a dataset of the mis estimated contact pairs by AES model. The most misjudged pairs are Arg-Glu, Arg Asp and Arg-Tyr. Such a dataset can be useful for developing the improved AES model by incorporating the pair-specific information for the cutoff distance. PMID- 21552528 TI - The phosphodiesterase-5 inhibitor vardenafil is a potent inhibitor of ABCB1/P glycoprotein transporter. AB - One of the major causes of chemotherapy failure in cancer treatment is multidrug resistance (MDR) which is mediated by the ABCB1/P-glycoprotein. Previously, through the use of an extensive screening process, we found that vardenafil, a phosphodiesterase 5 (PDE-5) inhibitor significantly reverses MDR in ABCB1 overexpressing cancer cells, and its efficacy was greater than that of tadalafil, another PDE-5 inhibitor. The present study was designed to determine the reversal mechanisms of vardenafil and tadalafil on ABC transporters-mediated MDR. Vardenafil or tadalafil alone, at concentrations up to 20 uM, had no significant toxic effects on any of the cell lines used in this study, regardless of their membrane transporter status. However, vardenafil when used in combination with anticancer substrates of ABCB1, significantly potentiated their cytotoxicity in ABCB1 overexpressing cells in a concentration-dependent manner, and this effect was greater than that of tadalafil. The sensitivity of the parenteral cell lines to cytotoxic anticancer drugs was not significantly altered by vardenafil. The differential effects of vardenafil and tadalafil appear to be specific for the ABCB1 transporter as both vardenafil and tadalafil had no significant effect on the reversal of drug resistance conferred by ABCC1 (MRP1) and ABCG2 (BCRP) transporters. Vardenafil significantly increased the intracellular accumulation of [(3)H]-paclitaxel in the ABCB1 overexpressing KB-C2 cells. In addition, vardenafil significantly stimulated the ATPase activity of ABCB1 and inhibited the photolabeling of ABCB1 with [(125)I]-IAAP. Furthermore, Western blot analysis indicated the incubation of cells with either vardenafil or tadalafil for 72 h did not alter ABCB1 protein expression. Overall, our results suggest that vardenafil reverses ABCB1-mediated MDR by directly blocking the drug efflux function of ABCB1. PMID- 21552530 TI - Gelechiidae moths are capable of chemically dissolving the pollen of their host plants: first documented sporopollenin breakdown by an animal. AB - BACKGROUND: Many insects feed on pollen surface lipids and contents accessible through the germination pores. Pollen walls, however, are not broken down because they consist of sporopollenin and are highly resistant to physical and enzymatic damage. Here we report that certain Microlepidoptera chemically dissolve pollen grains with exudates from their mouthparts. METHODOLOGY/PRINCIPAL FINDINGS: Field observations and experiments in tropical China revealed that two species of Deltophora (Gelechioidea) are the exclusive pollinators of two species of Phyllanthus (Phyllanthaceae) on which their larvae develop and from which the adults take pollen and nectar. DNA sequences placed the moths and plants phylogenetically and confirmed that larvae were those of the pollinating moths; molecular clock dating suggests that the moth clade is younger than the plant clade. Captive moths with pollen on their mouthparts after 2-3 days of starvation no longer carried intact grains, and SEM photographs showed exine fragments on their proboscises. GC-MS revealed cis-beta-ocimene as the dominant volatile in leaves and flowers, but GC-MS analyses of proboscis extracts failed to reveal an obvious sporopollenin-dissolving compound. A candidate is ethanolamine, which occurs in insect hemolymphs and is used to dissolve sporopollenin by palynologists. CONCLUSIONS/SIGNIFICANCE: This is the first report of any insect and indeed any animal chemically dissolving pollen. PMID- 21552531 TI - Critical factors governing the difference in antizyme-binding affinities between human ornithine decarboxylase and antizyme inhibitor. AB - Both ornithine decarboxylase (ODC) and its regulatory protein, antizyme inhibitor (AZI), can bind with antizyme (AZ), but the latter has a higher AZ-binding affinity. The results of this study clearly identify the critical amino acid residues governing the difference in AZ-binding affinities between human ODC and AZI. Inhibition experiments using a series of ODC mutants suggested that residues 125 and 140 may be the key residues responsible for the differential AZ-binding affinities. The ODC_N125K/M140K double mutant demonstrated a significant inhibition by AZ, and the IC(50) value of this mutant was 0.08 uM, three-fold smaller than that of ODC_WT. Furthermore, the activity of the AZ-inhibited ODC_N125K/M140K enzyme was hardly rescued by AZI. The dissociation constant (K(d)) of the [ODC_N125K/M140K]-AZ heterodimer was approximately 0.02 uM, which is smaller than that of WT_ODC by approximately 10-fold and is very close to the K(d) value of AZI_WT, suggesting that ODC_N125K/M140K has an AZ-binding affinity higher than that of ODC_WT and similar to that of AZI. The efficiency of the AZI_K125N/K140M double mutant in the rescue of AZ-inhibited ODC enzyme activity was less than that of AZI_WT. The K(d) value of [AZI_K125N/K140M]-AZ was 0.18 uM, nine-fold larger than that of AZI_WT and close to the K(d) value of ODC_WT, suggesting that AZI_K125N/K140M has an AZ-binding affinity lower than that of AZI_WT and similar to that of ODC. These data support the hypothesis that the differences in residues 125 and 140 in ODC and AZI are responsible for the differential AZ-binding affinities. PMID- 21552532 TI - An operational definition of a statistically meaningful trend. AB - Linear trend analysis of time series is standard procedure in many scientific disciplines. If the number of data is large, a trend may be statistically significant even if data are scattered far from the trend line. This study introduces and tests a quality criterion for time trends referred to as statistical meaningfulness, which is a stricter quality criterion for trends than high statistical significance. The time series is divided into intervals and interval mean values are calculated. Thereafter, r(2) and p values are calculated from regressions concerning time and interval mean values. If r(2) >= 0.65 at p <= 0.05 in any of these regressions, then the trend is regarded as statistically meaningful. Out of ten investigated time series from different scientific disciplines, five displayed statistically meaningful trends. A Microsoft Excel application (add-in) was developed which can perform statistical meaningfulness tests and which may increase the operationality of the test. The presented method for distinguishing statistically meaningful trends should be reasonably uncomplicated for researchers with basic statistics skills and may thus be useful for determining which trends are worth analysing further, for instance with respect to causal factors. The method can also be used for determining which segments of a time trend may be particularly worthwhile to focus on. PMID- 21552533 TI - Alternative splicing of the cardiac sodium channel creates multiple variants of mutant T1620K channels. AB - Alternative splicing creates several Na(v)1.5 transcripts in the mammalian myocardium and in various other tissues including brain, dorsal root ganglia, breast cancer cells as well as neuronal stem cell lines. In total nine Na(v)1.5 splice variants have been discovered. Four of them, namely Na(v)1.5a, Na(v)1.5c, Na(v)1.5d, and Na(v)1.5e, generate functional channels in heterologous expression systems. The significance of alternatively spliced transcripts for cardiac excitation, in particular their role in SCN5A channelopathies, is less well understood. In the present study, we systematically investigated electrophysiological properties of mutant T1620K channels in the background of all known functional Na(v)1.5 splice variants in HEK293 cells. This mutation has been previously associated with two distinct cardiac excitation disorders: with long QT syndrome type 3 (LQT3) and isolated cardiac conduction disease (CCD). When investigating the effect of the T1620K mutation, we noticed similar channel defects in the background of hNa(v)1.5, hNa(v)1.5a, and hNa(v)1.5c. In contrast, the hNa(v)1.5d background produced differential effects: In the mutant channel, some gain-of-function features did not emerge, whereas loss-of-function became more pronounced. In case of hNa(v)1.5e, the neonatal variant of hNa(v)1.5, both the splice variant itself as well as the corresponding mutant channel showed electrophysiological properties that were distinct from the wild-type and mutant reference channels, hNa(v)1.5 and T1620K, respectively. In conclusion, our data show that alternative splicing is a mechanism capable of generating a variety of functionally distinct wild-type and mutant hNa(v)1.5 channels. Thus, the cellular splicing machinery is a potential player affecting genotype-phenotype correlations in SCN5A channelopathies. PMID- 21552534 TI - alphaA-crystallin peptide SDRDKFVIFLDVKHF accumulating in aging lens impairs the function of alpha-crystallin and induces lens protein aggregation. AB - BACKGROUND: The eye lens is composed of fiber cells that are filled with alpha-, beta- and gamma-crystallins. The primary function of crystallins is to maintain the clarity of the lens through ordered interactions as well as through the chaperone-like function of alpha-crystallin. With aging, the chaperone function of alpha-crystallin decreases, with the concomitant accumulation of water insoluble, light-scattering oligomers and crystallin-derived peptides. The role of crystallin-derived peptides in age-related lens protein aggregation and insolubilization is not understood. METHODOLOGY/PRINCIPAL FINDINGS: We found that alphaA-crystallin-derived peptide, (66)SDRDKFVIFLDVKHF(80), which accumulates in the aging lens, can inhibit the chaperone activity of alpha-crystallin and cause aggregation and precipitation of lens crystallins. Age-related change in the concentration of alphaA-(66-80) peptide was estimated by mass spectrometry. The interaction of the peptide with native crystallin was studied by multi-angle light scattering and fluorescence methods. High molar ratios of peptide-to crystallin were favourable for aggregation and precipitation. Time-lapse recordings showed that, in the presence of alphaA-(66-80) peptide, alpha crystallin aggregates and functions as a nucleus for protein aggregation, attracting aggregation of additional alpha-, beta- and gamma-crystallins. Additionally, the alphaA-(66-80) peptide shares the principal properties of amyloid peptides, such as beta-sheet structure and fibril formation. CONCLUSIONS/SIGNIFICANCE: These results suggest that crystallin-derived peptides such as alphaA-(66-80), generated in vivo, can induce age-related lens changes by disrupting the structure and organization of crystallins, leading to their insolubilization. The accumulation of such peptides in aging lenses may explain a novel mechanism for age-related crystallin aggregation and cataractogenesis. PMID- 21552535 TI - Deep sequencing of organ- and stage-specific microRNAs in the evolutionarily basal insect Blattella germanica (L.) (Dictyoptera, Blattellidae). AB - BACKGROUND: microRNAs (miRNAs) have been reported as key regulators at post transcriptional level in eukaryotic cells. In insects, most of the studies have focused in holometabolans while only recently two hemimetabolans (Locusta migratoria and Acyrthosiphon pisum) have had their miRNAs identified. Therefore, the study of the miRNAs of the evolutionarily basal hemimetabolan Blattella germanica may provide valuable insights on the structural and functional evolution of miRNAs. METHODOLOGY/PRINCIPAL FINDINGS: Small RNA libraries of the cockroach B. germanica were built from the whole body of the last instar nymph, and the adult ovaries. The high throughput Solexa sequencing resulted in approximately 11 and 8 million reads for the whole-body and ovaries, respectively. Bioinformatic analyses identified 38 known miRNAs as well as 11 known miRNA*s. We also found 70 miRNA candidates conserved in other insects and 170 candidates specific to B. germanica. The positive correlation between Solexa data and real-time quantitative PCR showed that number of reads can be used as a quantitative approach. Five novel miRNA precursors were identified and validated by PCR and sequencing. Known miRNAs and novel candidates were also validated by decreasing levels of their expression in dicer-1 RNAi knockdown individuals. The comparison of the two libraries indicates that whole-body nymph contain more known miRNAs than ovaries, whereas the adult ovaries are enriched with novel miRNA candidates. CONCLUSIONS/SIGNIFICANCE: Our study has identified many known miRNAs and novel miRNA candidates in the basal hemimetabolan insect B. germanica, and most of the specific sequences were found in ovaries. Deep sequencing data reflect miRNA abundance and dicer-1 RNAi assay is shown to be a reliable method for validation of novel miRNAs. PMID- 21552536 TI - Multiplex fluorescence melting curve analysis for mutation detection with dual labeled, self-quenched probes. AB - Probe-based fluorescence melting curve analysis (FMCA) is a powerful tool for mutation detection based on melting temperature generated by thermal denaturation of the probe-target hybrid. Nevertheless, the color multiplexing, probe design, and cross-platform compatibility remain to be limited by using existing probe chemistries. We hereby explored two dual-labeled, self-quenched probes, TaqMan and shared-stem molecular beacons, in their ability to conduct FMCA. Both probes could be directly used for FMCA and readily integrated with closed-tube amplicon hybridization under asymmetric PCR conditions. Improved flexibility of FMCA by using these probes was illustrated in three representative applications of FMCA: mutation scanning, mutation identification and mutation genotyping, all of which achieved improved color-multiplexing with easy probe design and versatile probe combination and all were validated with a large number of real clinical samples. The universal cross-platform compatibility of these probes-based FMCA was also demonstrated by a 4-color mutation genotyping assay performed on five different real-time PCR instruments. The dual-labeled, self-quenched probes offered unprecedented combined advantage of enhanced multiplexing, improved flexibility in probe design, and expanded cross-platform compatibility, which would substantially improve FMCA in mutation detection of various applications. PMID- 21552537 TI - RhoE deficiency produces postnatal lethality, profound motor deficits and neurodevelopmental delay in mice. AB - Rnd proteins are a subfamily of Rho GTPases involved in the control of actin cytoskeleton dynamics and other cell functions such as motility, proliferation and survival. Unlike other members of the Rho family, Rnd proteins lack GTPase activity and therefore remain constitutively active. We have recently described that RhoE/Rnd3 is expressed in the Central Nervous System and that it has a role in promoting neurite formation. Despite their possible relevance during development, the role of Rnd proteins in vivo is not known. To get insight into the in vivo function of RhoE we have generated mice lacking RhoE expression by an exon trapping cassette. RhoE null mice (RhoE gt/gt) are smaller at birth, display growth retardation and early postnatal death since only half of RhoE gt/gt mice survive beyond postnatal day (PD) 15 and 100% are dead by PD 29. RhoE gt/gt mice show an abnormal body position with profound motor impairment and impaired performance in most neurobehavioral tests. Null mutant mice are hypoactive, show an immature locomotor pattern and display a significant delay in the appearance of the hindlimb mature responses. Moreover, they perform worse than the control littermates in the wire suspension, vertical climbing and clinging, righting reflex and negative geotaxis tests. Also, RhoE ablation results in a delay of neuromuscular maturation and in a reduction in the number of spinal motor neurons. Finally, RhoE gt/gt mice lack the common peroneal nerve and, consequently, show a complete atrophy of the target muscles. This is the first model to study the in vivo functions of a member of the Rnd subfamily of proteins, revealing the important role of Rnd3/RhoE in the normal development and suggesting the possible involvement of this protein in neurological disorders. PMID- 21552538 TI - Dbx1-expressing cells are necessary for the survival of the mammalian anterior neural and craniofacial structures. AB - Development of the vertebrate forebrain and craniofacial structures are intimately linked processes, the coordinated growth of these tissues being required to ensure normal head formation. In this study, we identify five small subsets of progenitors expressing the transcription factor dbx1 in the cephalic region of developing mouse embryos at E8.5. Using genetic tracing we show that dbx1-expressing cells and their progeny have a modest contribution to the forebrain and face tissues. However, their genetic ablation triggers extensive and non cell-autonomous apoptosis as well as a decrease in proliferation in surrounding tissues, resulting in the progressive loss of most of the forebrain and frontonasal structures. Targeted ablation of the different subsets reveals that the very first dbx1-expressing progenitors are critically required for the survival of anterior neural tissues, the production and/or migration of cephalic neural crest cells and, ultimately, forebrain formation. In addition, we find that the other subsets, generated at slightly later stages, each play a specific function during head development and that their coordinated activity is required for accurate craniofacial morphogenesis. Our results demonstrate that dbx1 expressing cells have a unique function during head development, notably by controlling cell survival in a non cell-autonomous manner. PMID- 21552539 TI - Genetic analysis reveals an unexpected role of BMP7 in initiation of ureteric bud outgrowth in mouse embryos. AB - BACKGROUND: Genetic analysis in the mouse revealed that GREMLIN1 (GREM1)-mediated antagonism of BMP4 is essential for ureteric epithelial branching as the disruption of ureteric bud outgrowth and renal agenesis in Grem1-deficient embryos is restored by additional inactivation of one Bmp4 allele. Another BMP ligand, BMP7, was shown to control the proliferative expansion of nephrogenic progenitors and its requirement for nephrogenesis can be genetically substituted by Bmp4. Therefore, we investigated whether BMP7 in turn also participates in inhibiting ureteric bud outgrowth during the initiation of metanephric kidney development. METHODOLOGY/PRINCIPAL FINDINGS: Genetic inactivation of one Bmp7 allele in Grem1-deficient mouse embryos does not alleviate the bilateral renal agenesis, while complete inactivation of Bmp7 restores ureteric bud outgrowth and branching. In mouse embryos lacking both Grem1 and Bmp7, GDNF/WNT11 feedback signaling and the expression of the Etv4 target gene, which regulates formation of the invading ureteric bud tip, are restored. In contrast to the restoration of ureteric bud outgrowth and branching, nephrogenesis remains aberrant as revealed by the premature loss of Six2 expressing nephrogenic progenitor cells. Therefore, very few nephrons develop in kidneys lacking both Grem1 and Bmp7 and the resulting dysplastic phenotype is indistinguishable from the one of Bmp7 deficient mouse embryos. CONCLUSIONS/SIGNIFICANCE: Our study reveals an unexpected inhibitory role of BMP7 during the onset of ureteric bud outgrowth. As BMP4, BMP7 and GREM1 are expressed in distinct mesenchymal and epithelial domains, the localized antagonistic interactions of GREM1 with BMPs could restrict and guide ureteric bud outgrowth and branching. The robustness and likely significant redundancy of the underlying signaling system is evidenced by the fact that global reduction of Bmp4 or inactivation of Bmp7 are both able to restore ureteric bud outgrowth and epithelial branching in Grem1-deficient mouse embryos. PMID- 21552540 TI - Vitamin E supplementation increases the attractiveness of males' scent for female European green lizards. AB - BACKGROUND: In spite that chemoreception is important in sexual selection for many animals, such as reptiles, the mechanisms that confer reliability to chemical signals are relatively unknown. European green lizards (Lacerta viridis) have substantial amounts of alpha-tocopherol ( = vitamin E) in their femoral secretions. Because vitamin E is metabolically important and can only be attained from the diet, its secretion is assumed to be costly. However, its role in intraspecific communication is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here, we experimentally show that male European green lizards that received a dietary supplement of vitamin E increased proportions of vitamin E in their femoral secretions. Furthermore, our experiments revealed that females preferred to use areas scent marked by males with experimentally increased vitamin E levels in their secretions. Finally, female preferences were stronger when vitamin E differences between a pair of males' secretions were larger. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that female green lizards are able to discriminate between males based on the vitamin E content of the males' femoral secretions. We suggest that the possible cost of allocating vitamin E to secretions, which might be dependent on male quality, may be a mechanism that confers reliability to scent marks of green lizards and allows their evolution as sexual signals. PMID- 21552541 TI - Modulation of COUP-TF expression in a cnidarian by ectopic Wnt signalling and allorecognition. AB - BACKGROUND: COUP transcription factors are required for the regulation of gene expression underlying development, differentiation, and homeostasis. They have an evolutionarily conserved function, being a known marker for neurogenesis from cnidarians to vertebrates. A homologue of this gene was shown previously to be a neuronal and nematocyte differentiation marker in Hydra. However, COUP-TFs had not previously been studied in a colonial cnidarian. METHODOLOGY/PRINCIPAL FINDINGS: We cloned a COUP-TF homologue from the colonial marine cnidarian Hydractinia echinata. Expression of the gene was analysed during normal development, allorecognition events and ectopic Wnt activation, using in situ hybridisation and quantitative PCR. During normal Hydractinia development, the gene was first expressed in post-gastrula stages. It was undetectable in larvae, and its mRNA was present again in putative differentiating neurons and nematocytes in post-metamorphic stages. Global activation of canonical Wnt signalling in adult animals resulted in the upregulation of COUP-TF. We also monitored a strong COUP-TF upregulation in stolons undergoing allogeneic interactions. COUP-TF mRNA was most concentrated in the tissues that contacted allogeneic, non-self tissues, and decreased in a gradient away from the contact area. Interestingly, the gene was transiently upregulated during initial contact of self stolons, but dissipated rapidly following self recognition, while in non self contacts high expression levels were maintained. CONCLUSIONS/SIGNIFICANCE: We conclude that COUP-TF is likely involved in neuronal/nematocyte differentiation in a variety of contexts. This has now been shown to include allorecognition, where COUP-TF is thought to have been co-opted to mediate allorejection by recruiting stinging cells that are the effectors of cytotoxic rejection of allogeneic tissue. Our findings that Wnt activation upregulates COUP TF expression suggests that Wnts' role in neuronal differentiation could be mediated through COUP-TF. PMID- 21552543 TI - The complete spectrum of yeast chromosome instability genes identifies candidate CIN cancer genes and functional roles for ASTRA complex components. AB - Chromosome instability (CIN) is observed in most solid tumors and is linked to somatic mutations in genome integrity maintenance genes. The spectrum of mutations that cause CIN is only partly known and it is not possible to predict a priori all pathways whose disruption might lead to CIN. To address this issue, we generated a catalogue of CIN genes and pathways by screening ~ 2,000 reduction-of function alleles for 90% of essential genes in Saccharomyces cerevisiae. Integrating this with published CIN phenotypes for other yeast genes generated a systematic CIN gene dataset comprised of 692 genes. Enriched gene ontology terms defined cellular CIN pathways that, together with sequence orthologs, created a list of human CIN candidate genes, which we cross-referenced to published somatic mutation databases revealing hundreds of mutated CIN candidate genes. Characterization of some poorly characterized CIN genes revealed short telomeres in mutants of the ASTRA/TTT components TTI1 and ASA1. High-throughput phenotypic profiling links ASA1 to TTT (Tel2-Tti1-Tti2) complex function and to TORC1 signaling via Tor1p stability, consistent with the role of TTT in PI3-kinase related kinase biogenesis. The comprehensive CIN gene list presented here in principle comprises all conserved eukaryotic genome integrity pathways. Deriving human CIN candidate genes from the list allows direct cross-referencing with tumor mutational data and thus candidate mutations potentially driving CIN in tumors. Overall, the CIN gene spectrum reveals new chromosome biology and will help us to understand CIN phenotypes in human disease. PMID- 21552542 TI - Structural basis for variant-specific neuroligin-binding by alpha-neurexin. AB - Neurexins (Nrxs) are presynaptic membrane proteins with a single membrane spanning domain that mediate asymmetric trans-synaptic cell adhesion by binding to their postsynaptic receptor neuroligins. alpha-Nrx has a large extracellular region comprised of multiple copies of laminin, neurexin, sex-hormone-binding globulin (LNS) domains and epidermal growth factor (EGF) modules, while that of beta-Nrx has but a single LNS domain. It has long been known that the larger alpha-Nrx and the shorter beta-Nrx show distinct binding behaviors toward different isoforms/variants of neuroligins, although the underlying mechanism has yet to be elucidated. Here, we describe the crystal structure of a fragment corresponding to the C-terminal one-third of the Nrx1alpha ectodomain, consisting of LNS5-EGF3-LNS6. The 2.3 A-resolution structure revealed the presence of a domain configuration that was rigidified by inter-domain contacts, as opposed to the more common flexible "beads-on-a-string" arrangement. Although the neuroligin binding site on the LNS6 domain was completely exposed, the location of the alpha Nrx specific LNS5-EGF3 segment proved incompatible with the loop segment inserted in the B+ neuroligin variant, which explains the variant-specific neuroligin recognition capability observed in alpha-Nrx. This, combined with a low resolution molecular envelope obtained by a single particle reconstruction performed on negatively stained full-length Nrx1alpha sample, allowed us to derive a structural model of the alpha-Nrx ectodomain. This model will help us understand not only how the large alpha-Nrx ectodomain is accommodated in the synaptic cleft, but also how the trans-synaptic adhesion mediated by alpha- and beta-Nrxs could differentially affect synaptic structure and function. PMID- 21552544 TI - A mathematical framework for estimating pathogen transmission fitness and inoculum size using data from a competitive mixtures animal model. AB - We present a method to measure the relative transmissibility ("transmission fitness") of one strain of a pathogen compared to another. The model is applied to data from "competitive mixtures" experiments in which animals are co-infected with a mixture of two strains. We observe the mixture in each animal over time and over multiple generations of transmission. We use data from influenza experiments in ferrets to demonstrate the approach. Assessment of the relative transmissibility between two strains of influenza is important in at least three contexts: 1) Within the human population antigenically novel strains of influenza arise and compete for susceptible hosts. 2) During a pandemic event, a novel sub type of influenza competes with the existing seasonal strain(s). The unfolding epidemiological dynamics are dependent upon both the population's susceptibility profile and the inherent transmissibility of the novel strain compared to the existing strain(s). 3) Neuraminidase inhibitors (NAIs), while providing significant potential to reduce transmission of influenza, exert selective pressure on the virus and so promote the emergence of drug-resistant strains. Any adverse outcome due to selection and subsequent spread of an NAI-resistant strain is exquisitely dependent upon the transmission fitness of that strain. Measurement of the transmission fitness of two competing strains of influenza is thus of critical importance in determining the likely time-course and epidemiology of an influenza outbreak, or the potential impact of an intervention measure such as NAI distribution. The mathematical framework introduced here also provides an estimate for the size of the transmitted inoculum. We demonstrate the framework's behaviour using data from ferret transmission studies, and through simulation suggest how to optimise experimental design for assessment of transmissibility. The method introduced here for assessment of mixed transmission events has applicability beyond influenza, to other viral and bacterial pathogens. PMID- 21552546 TI - Minimum Information About a Simulation Experiment (MIASE). PMID- 21552545 TI - Alkylation base damage is converted into repairable double-strand breaks and complex intermediates in G2 cells lacking AP endonuclease. AB - DNA double-strand breaks (DSBs) are potent sources of genome instability. While there is considerable genetic and molecular information about the disposition of direct DSBs and breaks that arise during replication, relatively little is known about DSBs derived during processing of single-strand lesions, especially for the case of single-strand breaks (SSBs) with 3'-blocked termini generated in vivo. Using our recently developed assay for detecting end-processing at random DSBs in budding yeast, we show that single-strand lesions produced by the alkylating agent methyl methanesulfonate (MMS) can generate DSBs in G2-arrested cells, i.e., S-phase independent. These derived DSBs were observed in apn1/2 endonuclease mutants and resulted from aborted base excision repair leading to 3' blocked single-strand breaks following the creation of abasic (AP) sites. DSB formation was reduced by additional mutations that affect processing of AP sites including ntg1, ntg2, and, unexpectedly, ogg1, or by a lack of AP sites due to deletion of the MAG1 glycosylase gene. Similar to direct DSBs, the derived DSBs were subject to MRX (Mre11, Rad50, Xrs2)-determined resection and relied upon the recombinational repair genes RAD51, RAD52, as well as on the MCD1 cohesin gene, for repair. In addition, we identified a novel DNA intermediate, detected as slow moving chromosomal DNA (SMD) in pulsed field electrophoresis gels shortly after MMS exposure in apn1/2 cells. The SMD requires nicked AP sites, but is independent of resection/recombination processes, suggesting that it is a novel structure generated during processing of 3'-blocked SSBs. Collectively, this study provides new insights into the potential consequences of alkylation base damage in vivo, including creation of novel structures as well as generation and repair of DSBs in nonreplicating cells. PMID- 21552547 TI - Drug discovery using chemical systems biology: weak inhibition of multiple kinases may contribute to the anti-cancer effect of nelfinavir. AB - Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent. PMID- 21552548 TI - A comparison of mathematical models for polarization of single eukaryotic cells in response to guided cues. AB - Polarization, a primary step in the response of an individual eukaryotic cell to a spatial stimulus, has attracted numerous theoretical treatments complementing experimental studies in a variety of cell types. While the phenomenon itself is universal, details differ across cell types, and across classes of models that have been proposed. Most models address how symmetry breaking leads to polarization, some in abstract settings, others based on specific biochemistry. Here, we compare polarization in response to a stimulus (e.g., a chemoattractant) in cells typically used in experiments (yeast, amoebae, leukocytes, keratocytes, fibroblasts, and neurons), and, in parallel, responses of several prototypical models to typical stimulation protocols. We find that the diversity of cell behaviors is reflected by a diversity of models, and that some, but not all models, can account for amplification of stimulus, maintenance of polarity, adaptation, sensitivity to new signals, and robustness. PMID- 21552549 TI - The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case-control study. AB - BACKGROUND: In the recently published meta-analysis of multiple sclerosis genome wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin. PRINCIPAL FINDINGS: We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19 * 10-7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35 * 10-10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19 * 10-5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios). CONCLUSIONS: Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis. PMID- 21552550 TI - Apolipoprotein E4 frequencies in a Japanese population with Alzheimer's disease and dementia with Lewy bodies. AB - BACKGROUND: The apolipoprotein E (APOE) epsilon4 allele has been reported to be a risk factor for Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Previous neuropathological studies have demonstrated similar frequencies of the APOE epsilon4 allele in AD and DLB. However, the few ante-mortem studies on APOE allele frequencies in DLB have shown lower frequencies than post-mortem studies. One reason for this may be inaccuracy of diagnosis. We examined APOE genotypes in subjects with AD, DLB, and a control group using the latest diagnostic criteria and MRI, SPECT, and MIBG myocardial scintigraphy. METHODS: The subjects of this study consisted of 145 patients with probable AD, 50 subjects with probable DLB, and a control group. AD subjects were divided into two groups based on age of onset: early onset AD (EOAD) and late onset AD (LOAD). All subjects had characteristic features on MRI, SPECT, and/or myocardial scintigraphy. RESULTS: The rate of APOE4 carrier status was 18.3% and the frequency of the epsilon4 allele was 9.7% in controls. The rate of APOE4 carrier status and the frequency of the epsilon4 allele were 47% and 27% for LOAD, 50% and 31% for EOAD, and 42% and 31% for DLB, respectively. CONCLUSION: The APOE4 genotypes in this study are consistent with previous neuropathological studies suggesting accurate diagnosis of AD and DLB. APOE4 genotypes were similar in AD and DLB, giving further evidence that the epsilon4 allele is a risk factor for both disorders. PMID- 21552551 TI - Y-like retinal ganglion cells innervate the dorsal raphe nucleus in the Mongolian gerbil (Meriones unguiculatus). AB - BACKGROUND: The dorsal raphe nucleus (DRN) of the mesencephalon is a complex multi-functional and multi-transmitter nucleus involved in a wide range of behavioral and physiological processes. The DRN receives a direct input from the retina. However little is known regarding the type of retinal ganglion cell (RGC) that innervates the DRN. We examined morphological characteristics and physiological properties of these DRN projecting ganglion cells. METHODOLOGY/PRINCIPAL FINDINGS: The Mongolian gerbils are highly visual rodents with a diurnal/crepuscular activity rhythm. It has been widely used as experimental animals of various studies including seasonal affective disorders and depression. Young adult gerbils were used in the present study. DRN projecting RGCs were identified following retrograde tracer injection into the DRN, characterized physiologically by extracellular recording and morphologically after intracellular filling. The result shows that DRN-projecting RGCs exhibit morphological characteristics typical of alpha RGCs and physiological response properties of Y-cells. Melanopsin was not detected in these RGCs and they show no evidence of intrinsic photosensitivity. CONCLUSIONS/SIGNIFICANCE: These findings suggest that RGCs with alpha-like morphology and Y-like physiology appear to perform a non-imaging forming function and thus may participate in the modulation of DRN activity which includes regulation of sleep and mood. PMID- 21552552 TI - Climate change, precipitation and impacts on an estuarine refuge from disease. AB - BACKGROUND: Oysters play important roles in estuarine ecosystems but have suffered recently due to overfishing, pollution, and habitat loss. A tradeoff between growth rate and disease prevalence as a function of salinity makes the estuarine salinity transition of special concern for oyster survival and restoration. Estuarine salinity varies with discharge, so increases or decreases in precipitation with climate change may shift regions of low salinity and disease refuge away from optimal oyster bottom habitat, negatively impacting reproduction and survival. Temperature is an additional factor for oyster survival, and recent temperature increases have increased vulnerability to disease in higher salinity regions. METHODOLOGY/PRINCIPAL FINDINGS: We examined growth, reproduction, and survival of oysters in the New York Harbor-Hudson River region, focusing on a low-salinity refuge in the estuary. Observations were during two years when rainfall was above average and comparable to projected future increases in precipitation in the region and a past period of about 15 years with high precipitation. We found a clear tradeoff between oyster growth and vulnerability to disease. Oysters survived well when exposed to intermediate salinities during two summers (2008, 2010) with moderate discharge conditions. However, increased precipitation and discharge in 2009 reduced salinities in the region with suitable benthic habitat, greatly increasing oyster mortality. To evaluate the estuarine conditions over longer periods, we applied a numerical model of the Hudson to simulate salinities over the past century. Model results suggest that much of the region with suitable benthic habitat that historically had been a low salinity refuge region may be vulnerable to higher mortality under projected increases in precipitation and discharge. CONCLUSIONS/SIGNIFICANCE: Predicted increases in precipitation in the northeastern United States due to climate change may lower salinities past important thresholds for oyster survival in estuarine regions with appropriate substrate, potentially disrupting metapopulation dynamics and impeding oyster restoration efforts, especially in the Hudson estuary where a large basin constitutes an excellent refuge from disease. PMID- 21552553 TI - A role for the immediate early gene product c-fos in imprinting T cells with short-term memory for signal summation. AB - T cells often make sequential contacts with multiple DCs in the lymph nodes and are likely to be equipped with mechanisms that allow them to sum up the successive signals received. We found that a period of stimulation as short as two hours could imprint on a T cell a "biochemical memory" of that activation signal that persisted for several hours. This was evidenced by more rapid induction of activation markers and earlier commitment to proliferation upon subsequent stimulation, even when that secondary stimulation occurred hours later. Upregulation of the immediate early gene product c-fos, a component of the AP-1 transcription factor, was maximal by 1-2 hours of stimulation, and protein levels remained elevated for several hours after stimulus withdrawal. Moreover, phosphorylated forms of c-fos that are stable and transcriptionally active persisted for a least a day. Upon brief antigenic stimulation in vivo, we also observed a rapid upregulation of c-fos that could be boosted by subsequent stimulation. Accumulation of phosphorylated c-fos may therefore serve as a biochemical fingerprint of previous suboptimal stimulation, leaving the T cell poised to rapidly resume its activation program upon its next encounter with an antigen-bearing DC. PMID- 21552554 TI - MVPA is associated with lower weight gain in 8-10 year old children: a prospective study with 1 year follow-up. AB - BACKGROUND: Studies relating physical activity (PA) to weight gain in children have produced mixed results, although there is some evidence for stronger associations with more intense physical activities. The present study tested the hypothesis that weight gain over one year in 8-10 year olds would be more strongly predicted by moderate and vigorous physical activity (MVPA) than total physical activity (total PA) or sedentary behaviour. METHODOLOGY: Participants were 280 children taking part in the Physical Exercise and Appetite in Children Study (PEACHES). Weight status was assessed using body mass index (BMI), fat mass index (FMI), and waist circumference (WC) in school Year 4 (baseline; age 8.7 yrs) and Year 5 (follow-up; age 9.7 yrs). Physical activity was measured at baseline using the Actigraph GT1M accelerometer to assess total PA (mean accelerometers counts per minute), MVPA; >= 4000 counts per minute) and sedentary time (<100 counts per minute). PRINCIPAL FINDINGS: After adjustment for baseline BMI, SES, sex and ethnicity, MVPA was significantly associated with follow-up BMI (adjusted beta = -0.07; p = 0.002). This association was independent of total PA or sedentary time. Similar results were observed for FMI; again MVPA was significantly associated with follow up FMI (beta = -0.16; p = 0.001) independent of total PA or sedentary time. The pattern was similar for WC (beta = -0.07), but the association between MVPA and WC did not reach significance at p = 0.06. CONCLUSION: The results of this study strongly support promotion of MVPA in children. PMID- 21552555 TI - A genome-wide association study on obesity and obesity-related traits. AB - Large-scale genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI), but few studies focused on obesity as a binary trait. Here we report the results of a GWAS and candidate SNP genotyping study of obesity, including extremely obese cases and never overweight controls as well as families segregating extreme obesity and thinness. We first performed a GWAS on 520 cases (BMI>35 kg/m(2)) and 540 control subjects (BMI<25 kg/m(2)), on measures of obesity and obesity-related traits. We subsequently followed up obesity-associated signals by genotyping the top ~500 SNPs from GWAS in the combined sample of cases, controls and family members totaling 2,256 individuals. For the binary trait of obesity, we found 16 genome-wide significant signals within the FTO gene (strongest signal at rs17817449, P = 2.5 * 10(-12)). We next examined obesity-related quantitative traits (such as total body weight, waist circumference and waist to hip ratio), and detected genome-wide significant signals between waist to hip ratio and NRXN3 (rs11624704, P = 2.67 * 10(-9)), previously associated with body weight and fat distribution. Our study demonstrated how a relatively small sample ascertained through extreme phenotypes can detect genuine associations in a GWAS. PMID- 21552556 TI - In vivo analysis of inhibitory synaptic inputs and rebounds in deep cerebellar nuclear neurons. AB - Neuronal function depends on the properties of the synaptic inputs the neuron receive and on its intrinsic responsive properties. However, the conditions for synaptic integration and activation of intrinsic responses may to a large extent depend on the level of background synaptic input. In this respect, the deep cerebellar nuclear (DCN) neurons are of particular interest: they feature a massive background synaptic input and an intrinsic, postinhibitory rebound depolarization with profound effects on the synaptic integration. Using in vivo whole cell patch clamp recordings from DCN cells in the cat, we find that the background of Purkinje cell input provides a tonic inhibitory synaptic noise in the DCN cell. Under these conditions, individual Purkinje cells appear to have a near negligible influence on the DCN cell and clear-cut rebounds are difficult to induce. Peripheral input that drives the simple spike output of the afferent PCs to the DCN cell generates a relatively strong DCN cell inhibition, but do not induce rebounds. In contrast, synchronized climbing fiber activation, which leads to a synchronized input from a large number of Purkinje cells, can induce profound rebound responses. In light of what is known about climbing fiber activation under behaviour, the present findings suggest that DCN cell rebound responses may be an unusual event. Our results also suggest that cortical modulation of DCN cell output require a substantial co-modulation of a large proportion of the PCs that innervate the cell, which is a possible rationale for the existence of the cerebellar microcomplex. PMID- 21552557 TI - Rising from the sea: correlations between sulfated polysaccharides and salinity in plants. AB - High salinity soils inhibit crop production worldwide and represent a serious agricultural problem. To meet our ever-increasing demand for food, it is essential to understand and engineer salt-resistant crops. In this study, we evaluated the occurrence and function of sulfated polysaccharides in plants. Although ubiquitously present in marine algae, the presence of sulfated polysaccharides among the species tested was restricted to halophytes, suggesting a possible correlation with salt stress or resistance. To test this hypothesis, sulfated polysaccharides from plants artificially and naturally exposed to different salinities were analyzed. Our results revealed that the sulfated polysaccharide concentration, as well as the degree to which these compounds were sulfated in halophytic species, were positively correlated with salinity. We found that sulfated polysaccharides produced by Ruppia maritima Loisel disappeared when the plant was cultivated in the absence of salt. However, subjecting the glycophyte Oryza sativa Linnaeus to salt stress did not induce the biosynthesis of sulfated polysaccharides but increased the concentration of the carboxylated polysaccharides; this finding suggests that negatively charged cell wall polysaccharides might play a role in coping with salt stress. These data suggest that the presence of sulfated polysaccharides in plants is an adaptation to high salt environments, which may have been conserved during plant evolution from marine green algae. Our results address a practical biological concept; additionally, we suggest future strategies that may be beneficial when engineering salt-resistant crops. PMID- 21552558 TI - Plastid 16S rRNA gene diversity among eukaryotic picophytoplankton sorted by flow cytometry from the South Pacific Ocean. AB - The genetic diversity of photosynthetic picoeukaryotes was investigated in the South East Pacific Ocean. Genetic libraries of the plastid 16S rRNA gene were constructed on picoeukaryote populations sorted by flow cytometry, using two different primer sets, OXY107F/OXY1313R commonly used to amplify oxygenic organisms, and PLA491F/OXY1313R, biased towards plastids of marine algae. Surprisingly, the two sets revealed quite different photosynthetic picoeukaryote diversity patterns, which were moreover different from what we previously reported using the 18S rRNA nuclear gene as a marker. The first 16S primer set revealed many sequences related to Pelagophyceae and Dictyochophyceae, the second 16S primer set was heavily biased toward Prymnesiophyceae, while 18S sequences were dominated by Prasinophyceae, Chrysophyceae and Haptophyta. Primer mismatches with major algal lineages is probably one reason behind this discrepancy. However, other reasons, such as DNA accessibility or gene copy numbers, may be also critical. Based on plastid 16S rRNA gene sequences, the structure of photosynthetic picoeukaryotes varied along the BIOSOPE transect vertically and horizontally. In oligotrophic regions, Pelagophyceae, Chrysophyceae, and Prymnesiophyceae dominated. Pelagophyceae were prevalent at the DCM depth and Chrysophyceae at the surface. In mesotrophic regions Pelagophyceae were still important but Chlorophyta contribution increased. Phylogenetic analysis revealed a new clade of Prasinophyceae (clade 16S-IX), which seems to be restricted to hyper-oligotrophic stations. Our data suggest that a single gene marker, even as widely used as 18S rRNA, provides a biased view of eukaryotic communities and that the use of several markers is necessary to obtain a complete image. PMID- 21552559 TI - Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. AB - BACKGROUND: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival. METHODOLOGY/PRINCIPAL FINDINGS: Hormone-naive (n = 10) and CRPC bone metastases samples (n = 30) were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival. CONCLUSIONS/SIGNIFICANCE: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis. PMID- 21552560 TI - Effectiveness of protected areas in maintaining plant production. AB - Given the central importance of protected area systems in local, regional and global conservation strategies, it is vital that there is a good understanding of their effectiveness in maintaining ecological functioning. Here, we provide, to our knowledge, the first such global analysis, focusing on plant production, a "supporting" ecosystem function necessary for multiple other ecosystem services. We use data on the normalized difference vegetation index (NDVI) as a measure of variation in plant production in the core, boundary and surroundings of more than 1000 large protected areas over a 25 year period. Forested protected areas were higher (or similar), and those non-forested were lower (or similar), in NDVI than their surrounding areas, and these differences have been sustained. The differences from surrounding areas have increased for evergreen broadleaf forests and barren grounds, decreased for grasslands, and remained similar for deciduous forests, woodlands, and shrublands, reflecting different pressures on those surroundings. These results are consistent with protected areas being effective both in the representation and maintenance of plant production. However, widespread overall increases in NDVI during the study period suggest that plant production within the core of non-forested protected areas has become higher than it was in the surroundings of those areas in 1982, highlighting that whilst the distinctiveness of protected areas from their surroundings has persisted the nature of that difference has changed. PMID- 21552561 TI - How much remains undetected? Probability of molecular detection of human Plasmodia in the field. AB - BACKGROUND: In malaria endemic areas, most people are simultaneously infected with different parasite clones. Detection of individual clones is hampered when their densities fluctuate around the detection limit and, in case of P. falciparum, by sequestration during part of their life cycle. This has important implications for measures of levels of infection or for the outcome of clinical trials. This study aimed at measuring the detectability of individual P. falciparum and P. vivax parasite clones in consecutive samples of the same patient and at investigating the impact of sampling strategies on basic epidemiological measures such as multiplicity of infection (MOI). METHODS: Samples were obtained in a repeated cross-sectional field survey in 1 to 4.5 years old children from Papua New Guinea, who were followed up in 2-monthly intervals over 16 months. At each follow-up visit, two consecutive blood samples were collected from each child at intervals of 24 hours. Samples were genotyped for the polymorphic markers msp2 for P. falciparum and msp1F3 and MS16 for P. vivax. Observed prevalence and mean MOI estimated from single samples per host were compared to combined data from sampling twice within 24 h. FINDINGS AND CONCLUSION: Estimated detectability was high in our data set (0.79 [95% CI 0.76 0.82] for P. falciparum and, depending on the marker, 0.61 [0.58-0.63] or 0.73 [0.71-0.75] for P. vivax). When genotyping data from sequential samples, collected 24 hours apart, were combined, the increase in measured prevalence was moderate, 6 to 9% of all infections were missed on a single day. The effect on observed MOI was more pronounced, 18 to 31% of all individual clones were not detected in a single bleed. Repeated sampling revealed little difference between detectability of P. falciparum and P. vivax. PMID- 21552562 TI - Stage-specific pathways of Leishmania infantum chagasi entry and phagosome maturation in macrophages. AB - The life stages of Leishmania spp. include the infectious promastigote and the replicative intracellular amastigote. Each stage is phagocytosed by macrophages during the parasite life cycle. We previously showed that caveolae, a subset of cholesterol-rich membrane lipid rafts, facilitate uptake and intracellular survival of virulent promastigotes by macrophages, at least in part, by delaying parasitophorous vacuole (PV)-lysosome fusion. We hypothesized that amastigotes and promastigotes would differ in their route of macrophage entry and mechanism of PV maturation. Indeed, transient disruption of macrophage lipid rafts decreased the entry of promastigotes, but not amastigotes, into macrophages (P<0.001). Promastigote-containing PVs were positive for caveolin-1, and co localized transiently with EEA-1 and Rab5 at 5 minutes. Amastigote-generated PVs lacked caveolin-1 but retained Rab5 and EEA-1 for at least 30 minutes or 2 hours, respectively. Coinciding with their conversion into amastigotes, the number of promastigote PVs positive for LAMP-1 increased from 20% at 1 hour, to 46% by 24 hours, (P<0.001, Chi square). In contrast, more than 80% of amastigote-initiated PVs were LAMP-1+ at both 1 and 24 hours. Furthermore, lipid raft disruption increased LAMP-1 recruitment to promastigote, but not to amastigote-containing compartments. Overall, our data showed that promastigotes enter macrophages through cholesterol-rich domains like caveolae to delay fusion with lysosomes. In contrast, amastigotes enter through a non-caveolae pathway, and their PVs rapidly fuse with late endosomes but prolong their association with early endosome markers. These results suggest a model in which promastigotes and amastigotes use different mechanisms to enter macrophages, modulate the kinetics of phagosome maturation, and facilitate their intracellular survival. PMID- 21552563 TI - Intramyocardial transplantation of undifferentiated rat induced pluripotent stem cells causes tumorigenesis in the heart. AB - BACKGROUND: Induced pluripotent stem cells (iPSCs) are a novel candidate for use in cardiac stem cell therapy. However, their intrinsic tumorigenicity requires further investigation prior to use in a clinical setting. In this study we investigated whether undifferentiated iPSCs are tumorigenic after intramyocardial transplantation into immunocompetent allogeneic recipients. METHODOLOGY/PRINCIPAL FINDINGS: We transplanted 2 * 10(4), 2 * 10(5), or 2 * 10(6) cells from the established rat iPSC line M13 intramyocardially into intact or infarcted hearts of immunocompetent allogeneic rats. Transplant duration was 2, 4, or 6 weeks. Histological examination with hematoxylin-eosin staining confirmed that undifferentiated rat iPSCs could generate heterogeneous tumors in both intracardiac and extracardiac sites. Furthermore, tumor incidence was independent of cell dose, transplant duration, and the presence or absence of myocardial infarction. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that allogeneic iPSC transplantation in the heart will likely result in in situ tumorigenesis, and that cells leaked from the beating heart are a potential source of tumor spread, underscoring the importance of evaluating the safety of future iPSC therapy for cardiac disease. PMID- 21552564 TI - Nitrate paradigm does not hold up for sugarcane. AB - Modern agriculture is based on the notion that nitrate is the main source of nitrogen (N) for crops, but nitrate is also the most mobile form of N and easily lost from soil. Efficient acquisition of nitrate by crops is therefore a prerequisite for avoiding off-site N pollution. Sugarcane is considered the most suitable tropical crop for biofuel production, but surprisingly high N fertilizer applications in main producer countries raise doubt about the sustainability of production and are at odds with a carbon-based crop. Examining reasons for the inefficient use of N fertilizer, we hypothesized that sugarcane resembles other giant tropical grasses which inhibit the production of nitrate in soil and differ from related grain crops with a confirmed ability to use nitrate. The results of our study support the hypothesis that N-replete sugarcane and ancestral species in the Andropogoneae supertribe strongly prefer ammonium over nitrate. Sugarcane differs from grain crops, sorghum and maize, which acquired both N sources equally well, while giant grass, Erianthus, displayed an intermediate ability to use nitrate. We conclude that discrimination against nitrate and a low capacity to store nitrate in shoots prevents commercial sugarcane varieties from taking advantage of the high nitrate concentrations in fertilized soils in the first three months of the growing season, leaving nitrate vulnerable to loss. Our study addresses a major caveat of sugarcane production and affords a strong basis for improvement through breeding cultivars with enhanced capacity to use nitrate as well as through agronomic measures that reduce nitrification in soil. PMID- 21552565 TI - Is aboriginal food less allergenic? Comparing IgE-reactivity of eggs from modern and ancient chicken breeds in a cohort of allergic children. AB - BACKGROUND: Hen's egg allergy ranks among the most frequent primary food allergies in children. We aimed to investigate sensitization profiles of egg allergic patients and compare in vitro IgE reactivities of eggs from ancient chicken breeds (Araucana and Maran) with those from conventional laying hen hybrids. METHODOLOGY: Egg allergic children (n = 25) were subjected to skin prick test, double blind placebo controlled food challenge, and sensitization profiles to Gal d 1-5 were determined by allergen microarray. IgE binding and biological activity of eggs from different chicken breeds were investigated by immunoblot, ELISA, and mediator release assays. PRINCIPAL FINDINGS: We found that Gal d 1 and Gal d 2 are generally major egg allergens, whereas Gal d 3-5 displayed high sensitization prevalence only in patients reacting to both, egg white and yolk. It seems that the onset of egg allergy is mediated by egg white allergens expanding to yolk sensitization in later stages of disease. Of note, egg white/yolk weight ratios were reduced in eggs from Auraucana and Maran chicken. As determined in IgE immunoblots and mass analysis, eggs from ancient chicken breeds did not differ in their protein composition. Similar IgE-binding was observed for all egg white preparations, while an elevated allergenicity was detected in egg yolk from Araucana chicken. CONCLUSION/SIGNIFICANCE: Our results on allergenicity and biological activity do not confirm the common assumption that aboriginal food might be less allergenic. Comprehensive diagnosis of egg allergy should distinguish between reactivity to hen's egg white and yolk fractions to avoid unnecessary dietary restrictions to improve life quality of the allergic child and its family. PMID- 21552567 TI - The development of the Pacific Ocean Shelf Tracking project within the decade long Census of Marine Life. PMID- 21552566 TI - Variation in the FFAR1 gene modifies BMI, body composition and beta-cell function in overweight subjects: an exploratory analysis. AB - BACKGROUND: FFAR1 receptor is a long chain fatty acid G-protein coupled receptor which is expressed widely, but found in high density in the pancreas and central nervous system. It has been suggested that FFAR1 may play a role in insulin sensitivity, lipotoxicity and is associated with type 2 diabetes. Here we investigate the effect of three common SNPs of FFAR1 (rs2301151; rs16970264; rs1573611) on pancreatic function, BMI, body composition and plasma lipids. METHODOLOGY/PRINCIPAL FINDINGS: For this enquiry we used the baseline RISCK data, which provides a cohort of overweight subjects at increased cardiometabolic risk with detailed phenotyping. The key findings were SNPs of the FFAR1 gene region were associated with differences in body composition and lipids, and the effects of the 3 SNPs combined were cumulative on BMI, body composition and total cholesterol. The effects on BMI and body fat were predominantly mediated by rs1573611 (1.06 kg/m(2) higher (P = 0.009) BMI and 1.53% higher (P = 0.002) body fat per C allele). Differences in plasma lipids were also associated with the BMI increasing allele of rs2301151 including higher total cholesterol (0.2 mmol/L per G allele, P = 0.01) and with the variant A allele of rs16970264 associated with lower total (0.3 mmol/L, P = 0.02) and LDL (0.2 mmol/L, P<0.05) cholesterol, but also with lower HDL-cholesterol (0.09 mmol/L, P<0.05) although the difference was not apparent when controlling for multiple testing. There were no statistically significant effects of the three SNPs on insulin sensitivity or beta cell function. However accumulated risk allele showed a lower beta cell function on increasing plasma fatty acids with a carbon chain greater than six. CONCLUSIONS/SIGNIFICANCE: Differences in body composition and lipids associated with common SNPs in the FFAR1 gene were apparently not mediated by changes in insulin sensitivity or beta-cell function. PMID- 21552568 TI - A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration. AB - Age related macular degeneration (AMD) is the most common cause of blindness amongst the elderly. Approximately 10% of AMD patients suffer from an advanced form of AMD characterized by choroidal neovascularization (CNV). Recent evidence implicates a significant role for complement in the pathogenesis of AMD. Activation of complement terminates in the incorporation of the membrane attack complex (MAC) in biological membranes and subsequent cell lysis. Elevated levels of MAC have been documented on choroidal blood vessels and retinal pigment epithelium (RPE) of AMD patients. CD59 is a naturally occurring membrane bound inhibitor of MAC formation. Previously we have shown that membrane bound human CD59 delivered to the RPE cells of mice via an adenovirus vector can protect those cells from human complement mediated lysis ex vivo. However, application of those observations to choroidal blood vessels are limited because protection from MAC- mediated lysis was restricted only to the cells originally transduced by the vector. Here we demonstrate that subretinal delivery of an adenovirus vector expressing a transgene for a soluble non-membrane binding form of human CD59 can attenuate the formation of laser-induced choroidal neovascularization and murine MAC formation in mice even when the region of vector delivery is distal to the site of laser induced CNV. Furthermore, this same recombinant transgene delivered to the intravitreal space of mice by an adeno-associated virus vector (AAV) can also attenuate laser-induced CNV. To our knowledge, this is the first demonstration of a non-membrane targeting CD59 having biological potency in any animal model of disease in vivo. We propose that the above approaches warrant further exploration as potential approaches for alleviating complement mediated damage to ocular tissues in AMD. PMID- 21552569 TI - Acoustic trauma increases cochlear and hair cell uptake of gentamicin. AB - BACKGROUND: Exposure to intense sound or high doses of aminoglycoside antibiotics can increase hearing thresholds, induce cochlear dysfunction, disrupt hair cell morphology and promote hair cell death, leading to permanent hearing loss. When the two insults are combined, synergistic ototoxicity occurs, exacerbating cochlear vulnerability to sound exposure. The underlying mechanism of this synergism remains unknown. In this study, we tested the hypothesis that sound exposure enhances the intra-cochlear trafficking of aminoglycosides, such as gentamicin, leading to increased hair cell uptake of aminoglycosides and subsequent ototoxicity. METHODS: Juvenile C57Bl/6 mice were exposed to moderate or intense sound levels, while fluorescently-conjugated or native gentamicin was administered concurrently or following sound exposure. Drug uptake was then examined in cochlear tissues by confocal microscopy. RESULTS: Prolonged sound exposure that induced temporary threshold shifts increased gentamicin uptake by cochlear hair cells, and increased gentamicin permeation across the strial blood labyrinth barrier. Enhanced intra-cochlear trafficking and hair cell uptake of gentamicin also occurred when prolonged sound, and subsequent aminoglycoside exposure were temporally separated, confirming previous observations. Acute, concurrent sound exposure did not increase cochlear uptake of aminoglycosides. CONCLUSIONS: Prolonged, moderate sound exposures enhanced intra-cochlear aminoglycoside trafficking into the stria vascularis and hair cells. Changes in strial and/or hair cell physiology and integrity due to acoustic overstimulation could increase hair cell uptake of gentamicin, and may represent one mechanism of synergistic ototoxicity. PMID- 21552570 TI - Globular adiponectin, acting via AdipoR1/APPL1, protects H9c2 cells from hypoxia/reoxygenation-induced apoptosis. AB - Cardiomyocyte apoptosis is an important remodeling event contributing to heart failure and adiponectin may mediate cardioprotective effects at least in part via attenuating apoptosis. Here we used hypoxia-reoxygenation (H/R) induced apoptosis in H9c2 cells to examine the effect of adiponectin and cellular mechanisms of action. We first used TUNEL labeling in combination with laser scanning cytometry to demonstrate that adiponectin prevented H/R-induced DNA fragmentation. The anti apoptotic effect of adiponectin was also verified via attenuation of H/R-induced phosphatidylserine exposure using annexin V binding. H/R-induced apoptosis via the mitochondrial-mediated intrinsic pathway of apoptosis as assessed by cytochrome c release into cytosol and caspase-3 activation, both of which were attenuated by adiponectin. Mechanistically, we demonstrated that adiponectin enhanced anti-oxidative potential in these cells which led to attenuation of the increase in intracellular reactive oxygen species (ROS) caused by H/R. To further address the mechanism of adiponctins anti-apoptotic effects we used siRNA to efficiently knockdown adiponectin receptor (AdipoR1) expression and found that this attenuated the protective effects of adiponectin on ROS production and caspase 3 activity. Knockdown of APPL1, an important intracellular binding partner for AdipoR, also significantly reduced the ability of adiponectin to prevent H/R-induced ROS generation and caspase 3 activity. In summary, H/R induced ROS generation and activation of the intrinsic apoptotic pathway was prevented by adiponectin via AdipoR1/APPL1 signaling and increased anti-oxidant potential. PMID- 21552572 TI - Dendritic cells crosspresent antigens from live B16 cells more efficiently than from apoptotic cells and protect from melanoma in a therapeutic model. AB - Dendritic cells (DC) are able to elicit anti-tumoral CD8(+) T cell responses by cross-presenting exogenous antigens in association with major histocompatibility complex (MHC) class I molecules. Therefore they are crucial actors in cell-based cancer immunotherapy. Although apoptotic cells are usually considered to be the best source of antigens, live cells are also able to provide antigens for cross presentation by DC. We have recently shown that prophylactic immunotherapy by DC after capture of antigens from live B16 melanoma cells induced strong CD8(+) T cell responses and protection against a lethal tumor challenge in vivo in C57Bl/6 mice. Here, we showed that DC cross-presenting antigens from live B16 cells can also inhibit melanoma lung dissemination in a therapeutic protocol in mice. DC were first incubated with live tumor cells for antigen uptake and processing, then purified and irradiated for safety prior to injection. This treatment induced stronger tumor-specific CD8(+) T-cell responses than treatment by DC cross-presenting antigens from apoptotic cells. Apoptotic B16 cells induced more IL-10 secretion by DC than live B16 cells. They underwent strong native antigen degradation and led to the expression of fewer MHC class I/epitope complexes on the surface of DC than live cells. Therefore, the possibility to use live cells as sources of tumor antigens must be taken into account to improve the efficiency of cancer immunotherapy. PMID- 21552573 TI - Supramolecular architectures based on As(lone pair)...pi(aryl) interactions. AB - As(lone pair)...pi interactions provide stability to their crystal structures often leading to supramolecular chains and prevailing over As...X secondary contacts. The interaction (ca 8 kJ mol(-1)) arises from polarisation induced in the aryl ring by the As-lone pair plus the weak sharing of these electrons with the ring-C atoms. PMID- 21552571 TI - Dynamic diagnosis of familial prion diseases supports the beta2-alpha2 loop as a universal interference target. AB - BACKGROUND: Mutations in the cellular prion protein associated to familial prion disorders severely increase the likelihood of its misfolding into pathogenic conformers. Despite their postulation as incompatible elements with the native fold, these mutations rarely modify the native state structure. However they variably have impact on the thermodynamic stability and metabolism of PrP(C) and on the properties of PrP(Sc) aggregates. To investigate whether the pathogenic mutations affect the dynamic properties of the HuPrP(125-229) alpha-fold and find possible common patterns of effects that could help in prophylaxis we performed a dynamic diagnosis of ten point substitutions. METHODOLOGY/PRINCIPAL FINDINGS: Using all-atom molecular dynamics simulations and novel analytical tools we have explored the effect of D178N, V180I, T183A, T188K, E196K, F198S, E200K, R208H, V210I and E211Q mutations on the dynamics of HuPrP(125-228) alpha-fold. We have found that while preserving the native state, all mutations produce dynamic changes which perturb the coordination of the alpha2-alpha3 hairpin to the rest of the molecule and cause the reorganization of the patches for intermolecular recognition, as the disappearance of those for conversion inhibitors and the emergence of an interaction site at the beta2-alpha2 loop region. CONCLUSIONS/SIGNIFICANCE: Our results suggest that pathogenic mutations share a common pattern of dynamical alterations that converge to the conversion of the beta2-alpha2 loop into an interacting region that can be used as target for interference treatments in genetic diseases. PMID- 21552574 TI - Chromium chains as polydentate fluoride ligands for lanthanides. AB - Hexametallic chromium(III) chains can act as fluoride donor ligands to lanthanide ions giving {(Cr(6))Ln(x)}(n) complexes; preliminary spectroscopic studies are reported. PMID- 21552575 TI - Enhanced photocatalytic activity of bimodal mesoporous titania powders by C60 modification. AB - In this work, fullerene modified TiO(2) nanocomposites (denoted as C(60)/TiO(2)) with low C(60) loadings (0-1.5 wt.%) have been prepared by a simple hydrothermal method using tetrabutylorthotitanate (TBOT, Ti(OC(4)H(9))(4)) as the titanium precursor. The as-prepared C(60)/TiO(2) nanocomposites were characterized by X ray diffraction, transmission electron microscopy, UV-visible spectrophotometry, nitrogen adsorption, and X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy. The formation of hydroxyl radicals (OH) on the surface of UV-illuminated TiO(2) is probed by photoluminescence using terephthalic acid as a probe molecule. Our results have demonstrated that C(60) molecules can be dispersed as a monolayer onto bimodal mesoporous TiO(2)via covalent bonding. The photocatalytic oxidation rate of gas-phase acetone over C(60)/TiO(2) nanocomposites is greater than that over pure TiO(2), commercial Degussa P25 (P25) and C(60)-TiO(2) counterparts prepared by simple impregnating mixing. In particular, 0.5 wt.% C(60)/TiO(2) nanocomposites show the greatest photocatalytic activity with the rate constant k exceeding that of P25 by a factor of 3.3. Based on the results of the current study, we propose that C(60) molecules doped onto TiO(2) act as "electron acceptors" responsible for the efficient separation of photogenerated charge carriers and the enhancement of photocatalytic activity. The proposed mechanism for the observed photocatalytic performance of C(60)/TiO(2) nanocomposites is further corroborated by experiments on hydroxyl radical and transient photocurrent response. PMID- 21552576 TI - cis-Dithiolatonickel as metalloligand to dinitrosyl iron units: the di-metallic structure of Ni(MU-SR)[Fe(NO)2] and an unexpected, abbreviated metalloadamantyl cluster, Ni2(MU-SR)4[Fe(NO)2]3. AB - The reaction of Fe(CO)(2)(NO)(2) and Ni(N(2)S(2)) (N(2)S(2) = N,N'-Bis(2 mercaptoethyl)-1,4-diazacycloheptane) by a single CO replacement yields [Ni(N(2)S(2))]Fe(NO)(2)(CO), while an excess of Fe(CO)(2)(NO)(2) leads to triply bridging thiolate sulphurs in a cluster of core composition Ni(2)S(4)Fe(3), lacking one Fe(NO)(2) unit to complete the adamantane-like structure. This structural type was earlier identified in a Cu(I)Cl aggregate of M(II)(N(2)S(2)) (M(II) = Ni, Cu), in which complete M(II)(2)S(4)Cu(I)(4) core structures were obtained as the major, and, in the case of Cu(II)(N(2)S(2)), the incomplete Cu(II)(2)S(4)Cu(I)(3) as a minor, product. The full Ni(2)S(4)Fe(4) cluster has not yet been realized for Fe = Fe(NO)(2). Computational analysis of the NiFe heterobimetallic complex addresses structural issues including a ?Ni-S-Fe of 90 degrees in the bimetallic complex. PMID- 21552577 TI - One-dimensional uranium-organic coordination polymers: crystal and electronic structures of uranyl-diacetohydroxamate. AB - The structure of the uranyl-diacetohydroxamate compound, UO(2)(C(2)NO(2)H(4))(2), was elucidated using a combination of single crystal X-ray diffraction measurements and all-electron scalar relativistic density functional calculations. This polymeric compound crystallizes in the C2/c space group (IT No. 15; a = 12.8386(13) A, b = 7.5661(7) A, c = 8.9299(9) A, beta = 103.185(2) degrees ; Z = 4), with main-chain repeating units featuring a bidentate structure analogous to that frequently found for d-block as well as lanthanide metal ions. Density functional analysis reveals that this compound is a semiconductor, with a direct band gap of 1.1 eV. PMID- 21552578 TI - The interaction of CO with PdAg/Pd(111) surface alloys--a case study of ensemble effects on a bimetallic surface. AB - The interaction of CO with structurally well-defined PdAg/Pd(111) surface alloys was investigated by temperature-programmed desorption (TPD) and high-resolution electron energy loss spectroscopy (HREELS) to unravel and understand contributions from electronic strain, electronic ligand and geometric ensemble effects. TPD measurements indicate that CO adsorption is not possible on the Ag sites of the surface alloys (at 120 K) and that the CO binding strength on Pd sites decreases significantly with increasing Ag concentration. Comparison with previous scanning tunneling microscopy (STM) data on the distribution of Pd and Ag atoms in the surface alloy shows that this modification is mainly due to geometric ensemble effects, since Pd(3) ensembles, which are the preferred ensembles for CO adsorption on non-modified Pd(111), are no longer available on Ag-rich surfaces. Consequently, the preferred CO adsorption site changes with increasing Ag content from a Pd(3) trimer via a Pd(2) dimer to a Pd monomer, going along with a successive weakening of CO adsorption. Additionally, the CO adsorption properties of the surface alloys are also influenced by electronic ligand and strain effects, but on a lower scale. The results are discussed in comparison with previous findings on PdAg bulk alloys, supported PdAg catalysts and PdAu/Pd(111) model systems. PMID- 21552579 TI - Arrays of size and distance controlled platinum nanoparticles fabricated by a colloidal method. AB - Based on emulsion polymerization in the presence of a Pt complex, polystyrene (PS) particles were prepared exhibiting a well defined average diameter with narrow size-distribution. Furthermore, the colloids contain a controlled concentration of the Pt precursor complex. Optimized coating of Si substrates with such colloids leads to extended areas of hexagonally ordered close-packed PS particles. Subsequent application of plasma etching and annealing steps allows complete removal of the PS carriers and in parallel nucleation and growth of Pt nanoparticles (NPs) which are located at the original center of the PS colloids. In this way, hexagonally arranged spherical Pt NPs are obtained with controlled size and interparticle distances demonstrating variability and precision with so far unknown parameter scalability. This control is demonstrated by the fabrication of Pt NP arrays at a fixed particle distance of 185 nm while systematically varying the diameters between 8 and 15 nm. Further progress could be achieved by seeded emulsion polymerization. Here, Pt loaded PS colloids of 130 nm were used as seeds for a subsequent additional emulsion polymerization, systematically enlarging the diameter of the PS particles. Applying the plasma and annealing steps as above, in this way hexagonally ordered arrays of 9 nm Pt NPs could be obtained at distances up to 260 nm. To demonstrate their stability, such Pt particles were used as etching masks during reactive ion etching thereby transferring their hexagonal pattern into the Si substrate resulting in corresponding arrays of nanopillars. PMID- 21552580 TI - Synthesis of internal fluorinated alkenes via facile aryloxylation of substituted phenols with aryl trifluorovinyl ethers. AB - Nucleophilic addition-elimination of ortho- or para-substituted phenols to aryl trifluorovinyl ethers (TFVEs) in N,N-dimethylformamide was studied. Using sodium hydride as a base afforded vinyl substitution products R-Ar-O-CF=CF-O-Ar-R', where R or R' = H, Br, OMe, tert-Bu, or Ph. The vinyl substitution products produced mixtures of (Z)/(E)-isomers and this isomer ratio was influenced by substitution with more sterically encumbered phenol nucleophiles. Reactions using caesium carbonate afforded addition products R-Ar-O-CHFCF(2)-O-Ar-R' whereas upon dehydrofluorination using sodium hydride produced vinyl substitution products. The preparation of vinyl substituted and addition products proceeded in overall good isolated yields and were elucidated using (1)H and (19)F NMR, GC-MS, and X ray analysis. Vinyl substituted products were inert to UV light and chemical reactivity using common polymerization promoters. Thermal activation of the (Z)/(E)-fluoroolefin (-CF=CF-) was observed at an onset of 310 degrees C in nitrogen using differential scanning calorimetry (DSC) producing insoluble network material. The synthesis, characterization, and mechanism for stereoselectivity are discussed. PMID- 21552581 TI - Pipette-tip selective extraction of glycoproteins with lectin modified gold nano particles on a polymer monolithic phase. AB - The in situ preparation of ethylene dimethacrylate porous polymer monoliths within 20 MUL polypropylene pipette tips, bound via surface grafted methacrylate anchor sites, is reported. Gold nano-particles (AuNPs) were immobilised onto the monolith pore surface utilising azlactone chemistry and coverage verified using field emission scanning electron microscopy. Erythrina cristagalli lectin (ECL) was immobilised upon the attached AuNPs via a bio-functional linker. The ECL modified tip was successfully applied for the enrichment of galactosylated protein (desialylated transferrin) versus a non-galactosylated protein (ribonuclease B) due to the specificity of ECL. Reversed-phase capillary HPLC was used to validate the efficiency and selectivity of the developed micro-extraction phase which resulted in an increase in extraction recovery of ~95% due to the AuNP enhanced surface area. Further specificity of the ECL-modified tip was demonstrated with a complex mixture of non-glycosylated and glycosylated proteins with differing terminal sugar structures. Finally, the lectin affinity phase was applied to a galactosylated glycoproteins spiked Escherichia coli cell lysate to successfully demonstrate matrix tolerance. PMID- 21552582 TI - Asymmetric alkynylation of aldehydes with propiolates without high reagent loading and any additives. AB - The asymmetric alkynylation of aliphatic and aromatic aldehydes with propiolates was mediated by dialkylzinc and a novel prolinol catalyst without high reagent loading and any additives, such as Ti(Oi-Pr)(4), to give the corresponding gamma hydroxy-alpha,beta-acetylenic esters with high enantiomeric excess of up to 95%. PMID- 21552583 TI - The key role played by the Augusta basin (southern Italy) in the mercury contamination of the Mediterranean Sea. AB - The Augusta basin, located in SE Sicily (southern Italy), is a semi-enclosed marine area, labelled as a highly contaminated site. The release of mercury into the harbour seawater and its dispersion to the blue water, make the Augusta basin a potential source of anthropogenic pollution for the Mediterranean Sea. A mass balance was implemented to calculate the HgT budget in the Augusta basin. Results suggest that an average of ~0.073 kmol of HgT is released, by diffusion, on a yearly basis, from sediments to the seawater, with a consequent output of 0.162 kmol y(-1) to coastal and offshore waters; this makes the Augusta area an important contributor of mercury to the Mediterranean Sea. Owing to the geographical location of the Augusta basin, its outflowing shelf-waters are immediately intercepted by the surface Atlantic Ionian Stream (AIS) and mixed with the main gyres of the eastern Mediterranean Sea, thus representing a risk for the large-scale marine system. PMID- 21552584 TI - Forecasting of cyanobacterial density in Torrao reservoir using artificial neural networks. AB - The ability of general regression neural networks (GRNN) to forecast the density of cyanobacteria in the Torrao reservoir (Tamega river, Portugal), in a period of 15 days, based on three years of collected physical and chemical data, was assessed. Several models were developed and 176 were selected based on their correlation values for the verification series. A time lag of 11 was used, equivalent to one sample (periods of 15 days in the summer and 30 days in the winter). Several combinations of the series were used. Input and output data collected from three depths of the reservoir were applied (surface, euphotic zone limit and bottom). The model that presented a higher average correlation value presented the correlations 0.991; 0.843; 0.978 for training, verification and test series. This model had the three series independent in time: first test series, then verification series and, finally, training series. Only six input variables were considered significant to the performance of this model: ammonia, phosphates, dissolved oxygen, water temperature, pH and water evaporation, physical and chemical parameters referring to the three depths of the reservoir. These variables are common to the next four best models produced and, although these included other input variables, their performance was not better than the selected best model. PMID- 21552585 TI - Photonic properties of hybrid colloidal crystals fabricated by a rapid dip coating process. AB - The enhancement of the capillarity fabrication of well-ordered two-dimensional (2D) and three-dimensional (3D) opal photonic crystal is described herein. The quality enhancement and the reduction of the fabrication time are improved by using core@soft adhesive shell (Silica@PolyButylAcrylate) particles dispersed in an organic solvent with a high boiling point. The hybridization by an elastomeric corona polymer, grafted from the SiO(2) surface, has offered adhesive properties naturally tunable by changing the polymer state from a solvated to a dry one. Such properties involve drastic changes of the self-assembly behavior and qualities. Their use, as elementary building blocks, for colloidal crystal fabrication have required a high withdrawal rate (up to 4000 MUm s(-1)), i.e. involving a three order of magnitude reduction in time compared to a classic vertical deposition method (1 to 10 MUm s(-1)) and a good control/prediction of the coating thickness can be tuned by varying the withdrawal rate and the particle concentration. In addition, an analysis of the 2D synthetic iridescence of the hybrid photonic crystal was performed under white light, revealing the adhesive shell bridge influence on the dissipation energy of cracks linked to the crystal quality and the photonic properties. PMID- 21552586 TI - "Turn-on" fluorescent sensing with "reactive" probes. AB - Chemical probes are valuable tools for the investigation of biochemical processes, diagnosis of disease markers, detection of hazardous compounds, and other purposes. Therefore, the development of chemical probes continues to grow through various approaches with different disciplines and design strategies. Fluorescent probes have received much attention because they are sensitive and easy-to-operate, in general. To realize desired selectivity toward a given analyte, the recognition site of a fluorescent probe is designed in such a way to maximize the binding interactions, usually through weak molecular forces such as hydrogen bonding, toward the analyte over other competing ones. In addition to such a supramolecular approach, the development of fluorescent probes that sense analytes through chemical reactions has witnessed its usefulness for achieving high selectivity, in many cases, superior to that obtainable by the supramolecular approach. Creative incorporations of the reactive groups to latent fluorophores have provided novel chemical probes for various analytes. In this feature article, we overview the recent progress in the development of turn-on fluorescent probes that are operating through chemical reactions triggered by target analytes. Various chemical reactions have been implemented in the development of many reactive probes with very high selectivity and sensitivity toward target analytes. A major emphasis has been focused on the type of chemical reactions utilized, with the hope that further explorations can be made with new chemical reactions to develop reactive probes useful for various applications. PMID- 21552587 TI - Targeted synthesis of a 2D ordered porous organic framework for drug release. AB - A novel 2D porous organic framework based on the nucleophilic substitution of cyanuric chloride has been designed and synthesized successfully, which possesses an ordered structure, permanent porosity and drug release ability towards ibuprofen. PMID- 21552588 TI - Iron catalyzed highly regioselective dimerization of terminal aryl alkynes. AB - Iron can catalyze head-to-head dimerization of terminal aryl alkynes to give the corresponding (E) selective conjugated enynes in high yields. A variety of substituted aryl acetylenes underwent smooth dimerization using catalytic FeCl(3) and DMEDA in the presence of KO(t)Bu. PMID- 21552589 TI - PolyPEGA with predetermined molecular weights from enzyme-mediated radical polymerization in water. AB - The preparation of acrylic polymers with predetermined molecular weights using metalloenzymes as catalysts, ascorbic acid as reducing agent and alkyl halides as initiators is reported. The mechanism of polymerization resembles an ARGET ATRP process. PMID- 21552590 TI - Ultrafast irreversible phototautomerization of o-nitrobenzaldehyde. AB - o-Nitrobenzaldehyde is photolabile because of an irreversible phototautomerization, whereas comparable aromatic compounds function as photoprotectors because the tautomerization is reversible. In this experimental and theoretical study we track down the cause of this difference to the electronic changes that occur during the tautomerization. PMID- 21552591 TI - P3HT as hole transport material and assistant light absorber in CdS quantum dots sensitized solid-state solar cells. AB - Regioregular poly(3-hexylthiophene) (P3HT) was employed as a hole transport material and assistant light absorber for the fabrication of a CdS quantum dot sensitized solid-state solar cell, by which a power-conversion efficiency of 1.42% was achieved under an AM1.5 G (100 mW cm(-2)) condition. PMID- 21552592 TI - Solvent-modulated slow magnetic relaxation in a two-dimensional compound composed of cobalt(II) single-chain magnets. AB - A single-chain magnet consisting of Co(II) chains with (EO-N(3))(2) and (MU COO)(2)(MU-EO-N(3)) bridges reversibly transforms into an antiferromagnetic phase with metamagnetic character and modified slow magnetic relaxation upon dehydration. PMID- 21552593 TI - The role of intermolecular hydrogen bond on dielectric properties in hydrogen bonded material 5-bromo-9-hydroxyphenalenone: theoretical investigation. AB - Dielectric properties of the hydrogen-bonded material, 5-bromo-9 hydroxyphenalenone (C(13)H(7)O(2)Br; BrHPLN), are investigated theoretically by means of electronic structure calculations and Monte Carlo simulations. The density functional calculations of BrHPLN crystals have revealed that the polarization per one molecule can be about 1.7 times larger than that of the isolated monomer. It is also found that there exists significant electron density (0.01 e bohr(-3)) in an intermolecular C-H...O region, which, together with the interatomic distances of 2.39 A for H...O and 3.34 A for C...O, suggests the existence of intermolecular weak hydrogen bonding that may enhance the molecular polarization. The induced polarization effects in various intermolecular configurations are evaluated with the Fragment Molecular Orbital method. In addition to the pi-pi stacking interactions, two types of "in plane" intermolecular weak hydrogen-bonding configurations are found to affect the molecular dipole moment most significantly. These effects are efficiently included in a Monte Carlo simulation method in terms of "dipole corrections" as functions of both the intermolecular arrangements and the intramolecular proton configurations. The application to the dielectric phase transition of a BrHPLN crystal shows that the dipole corrections almost double the transition temperature, toward better agreement with experiments, and qualitatively affect the temperature dependence of the dielectric constant. Discussions are given to support that the results will remain adequate and consistent even after explicit inclusion of the quantum tunneling effects. PMID- 21552594 TI - An intramolecular charge transfer state of carbonyl carotenoids: implications for excited state dynamics of apo-carotenals and retinal. AB - Excited state dynamics of two apo-carotenals, retinal and 12'-apo-beta-carotenal, were studied by femtosecond transient absorption spectroscopy. We make use of previous knowledge gathered from studies of various carbonyl carotenoids and suggest that to consistently explain the excited-state dynamics of retinal in polar solvents, it is necessary to include an intermolecular charge transfer (ICT) state in the excited state manifold. Coupling of the ICT state to the A(g)( ) state, which occurs in polar solvents, shortens lifetime of the lowest excited state of 12'-apo-beta-carotenal from 180 ps in n-hexane to 7.1 ps in methanol. Comparison with a reference molecule lacking the conjugated carbonyl group, 12' apo-beta-carotene, demonstrates the importance of the carbonyl group; no polarity induced lifetime change is observed and 12'-apo-beta-carotene decays to the ground state in 220 ps regardless of solvent polarity. For retinal, we have confirmed the well-known three-state relaxation scheme in n-hexane. Population of the B(u)(+) state decays in <100 fs to the A(g)(-) state, which is quenched in 440 fs by a low-lying npi* state that decays with a 33 ps time constant to form the retinal triplet state. In methanol, however, the A(g)(-) state is coupled to the ICT state. This coupling prevents population of the npi* state, which explains the absence of retinal triplet formation in polar solvents. Instead, the coupled A(g)(-)/ICT state decays in 1.6 ps to the ground state. The A(g)(-)/ICT coupling is also evidenced by stimulated emission, which is a characteristic marker of the ICT state in carbonyl carotenoids. PMID- 21552595 TI - Structure, stoichiometry and transport properties of lithium copper nitride battery materials: combined NMR and powder neutron diffraction studies. AB - A combined NMR and neutron diffraction study has been carried out on three Li(3-x y)Cu(x)N materials with x=0.17, x=0.29 and x=0.36. Neutron diffraction indicates that the samples retain the P6/mmm space group of the parent Li(3)N with Cu located only on Li(1) sites. The lattice parameters vary smoothly with x in a similar fashion to Li(3-x-y)Ni(x)N, but the Li(2) vacancy concentration for the Cu-substituted materials is negligible. This structural model is confirmed by wideline (7)Li NMR spectra at 193 K which show three different local environments for the Li(1) site, resulting from the substitution of neighbouring Li atoms in the Li(1) layer by Cu. Since the Cu-substituted materials are only very weakly paramagnetic, variable temperature (7)Li wideline NMR spectra can be used to measure diffusion coefficients and activation energies. These indicate anisotropic Li(+) diffusion similar to the parent Li(3)N with transport confined to the [Li(2)N] plane at low temperature and exchange between Li(1) and Li(2) sites dominant at high temperature. For the intra-layer process the diffusion coefficients at room temperature are comparable to Li(3)N and Li(3-x-y) Ni(x)N, while E(a) decreases as x increases in contrast to the opposite trend in Ni substituted materials. For the inter-layer process E(a) decreases only slightly as x increases, but the diffusion coefficients at room temperature increase rapidly with x. PMID- 21552597 TI - A new tunable light-emitting and pi-stacked hexa-ethyleneglycol naphthalene bisimide oligomer: synthesis, photophysics and electrochemical properties. AB - An oligomer (3) containing flexible hydrophilic hexa(ethylene glycol) and hydrophobic naphthalene-bisimide chromophores has been synthesized by a one-step condensation reaction and its photophysical and electrochemical properties were investigated. 3 was characterized through the data from NMR, IR, UV-vis, GPC, DSC, TGA, elemental analysis and cyclic voltammetry. The average molecular weight (M(w)) of 3 was 4430 g mol(-1). Intrinsic viscosity was measured as 0.28 dL g(-1) in m-cresol at 25 degrees C. It has high thermal stability (T(d) = 325 degrees C). Interestingly, compound 3 shows excimer-like emission in all kinds of solvents. The band gap energy (E(g)), LUMO and HOMO energy values in nonpolar and polar protic solvents were 2.71 eV/3.12 eV, -3.69 eV/-3.88 eV and -6.40 eV/-7.00 eV for 3, respectively. The oligomer showed concentration and solvent dependent fluorescent color tunability. Remarkably, the fluorescent colors of the excimer emissions at 10(-6) M concentration in CHCl(3), DMF and MeOH are light yellow, light blue-yellow and strong blue, respectively, and become more intense at higher concentrations. The excimer emission color in CHCl(3) and DMF is fluorescent yellow and changed to green in MeOH at 10(-4) M concentration. 3 shows two reversible reduction steps at -1.103 and -1.457 V (vs. ferrocene/ferrocenium) in nonpolar solvent CH(2)Cl(2) and only one at -0.917 V in (50:50) CH(3)OH-CH(3)CN binary solvent mixture with higher reversibility. Strong blue-shifts of emission band were noted in protic solvents, which confirm the existence of a negative solvatochromism probably due to protonation. The strong solvent-dependent photophysical and electrochemical properties, including the large shift of excimer emission maximum reflecting self-assembly mediated through hydrogen bonding and pi-stacking interactions, make the oligomer a potential candidate for various photo-sensing applications. PMID- 21552596 TI - ZnO nanowire lasers. AB - The pathway towards the realization of optical solid-state lasers was gradual and slow. After Einstein's paper on absorption and stimulated emission of light in 1917 it took until 1960 for the first solid state laser device to see the light. Not much later, the first semiconductor laser was demonstrated and lasing in the near UV spectral range from ZnO was reported as early as 1966. The research on the optical properties of ZnO showed a remarkable revival since 1995 with the demonstration of room temperature lasing, which was further enhanced by the first report of lasing by a single nanowire in 2001. Since then, the research focussed increasingly on one-dimensional nanowires of ZnO. We start this review with a brief description of the opto-electronic properties of ZnO that are related to the wurtzite crystal structure. How these properties are modified by the nanowire geometry is discussed in the subsequent sections, in which we present the confined photon and/or polariton modes and how these can be investigated experimentally. Next, we review experimental studies of laser emission from single ZnO nanowires under different experimental conditions. We emphasize the special features resulting from the sub-wavelength dimensions by presenting our results on single ZnO nanowires lying on a substrate. At present, the mechanism of lasing in ZnO (nanowires) is the subject of a strong debate that is considered at the end of this review. PMID- 21552598 TI - Photophysical properties of alizarin and purpurin Al(III) complexes in solution and in solid state. AB - The present study was undertaken to investigate the photophysical properties of the organic-metal compounds which are the main components of madder lake, one of the most commonly used and widespread organic pigments in painted artworks, from both geographic and historic points of view. Alizarin- and purpurin-Al(III) complexes were studied in solution and as powders. In solution, the chelate stoichiometry, their absorption and emission properties and the efficiency of their excited electronic state deactivation pathways have been determined. The two organic-metal compounds show relevant differences in terms of spectral features consisting of multiple peak (structured) absorption and emission spectra for the purpurin derivative and single broad bands (structureless) for the Al(III)-alizarin chelate. For both the investigated molecules, the chelation process induces a relevant increase of the emission quantum yields and lifetimes. The main differences between photophysical properties of the two metal complexes concern emission quantum yield and lifetime, which are both higher for purpurin chelate compared to alizarine chelate. Furthermore, interesting differences between the two metal complexes concerning the relative relevance of inter- and intra-molecular interaction involved in the mechanism of the excitation energy dissipation have been also highlighted. The knowledge of the determined parameters allows better understanding of the spectral behaviour in the solid state, thus providing a solid reference for the non-invasive characterisation and identification of madder lake on original artworks through its absorption and emission features. PMID- 21552599 TI - P-type 3C-SiC nanowires and their optical and electrical transport properties. AB - We report for the first time the fabrication of p-type SiC nanowire field-effect transistors (FETs) using an individual Al-doped 3C-SiC nanowire with a single crystalline structure. The Raman spectroscopy of the as-grown p-type wire indicates that the linewidth and peak intensity of LO-phonon bands are sensitive to temperature variations. PMID- 21552600 TI - Synthesis of the B-seco limonoid scaffold. AB - The underlying stereochemically complex and densely functionalized scaffold of the B-seco limonoids was synthesized employing an Ireland-Claisen rearrangement as key transformation. PMID- 21552601 TI - Homo-DNA templated chemistry and its application to nucleic acid sensing. AB - We have investigated the homo-DNA templated Staudinger reduction of the profluorophore rhodamine azide and have applied this reaction to the detection of natural DNA with a hybrid homo-DNA/DNA molecular beacon. In this system the sensing and the reporting unit are bioorthogonal to each other which facilitates sequence design and increases fidelity. PMID- 21552602 TI - Temperature dependence of the Fricke dosimeter and spur expansion time in the low LET high-temperature radiolysis of water up to 350 degrees C: a Monte-Carlo simulation study. AB - Monte-Carlo simulations of the radiolysis of the ferrous sulfate (Fricke) dosimeter with low-linear energy transfer (LET) radiation (such as (60)Co gamma rays or fast electrons) have been performed as a function of temperature from 25 to 350 degrees C. The predicted yields of Fe(2+) oxidation are found to increase with increasing temperature up to ~100-150 degrees C, and then tend to remain essentially constant at higher temperatures, in very good agreement with experiment. By using a simple method based on the direct application of the stoichiometric relationship that exists between the ferric ion yields so obtained G(Fe(3+)) and the sum {3 [g(e(-)(aq) + H) + g(HO(2))] + g(OH) + 2 g(H(2)O(2))}, where g(e(-)(aq) + H), g(HO(2)), g(OH), and g(H(2)O(2)) are the primary radical and molecular yields of the radiolysis of deaerated 0.4 M H(2)SO(4) aqueous solutions, the lifetime (tau(s)) of the spur and its temperature dependence have been determined. In the spirit of the spur model, tau(s) is an important indicator for overlapping spurs, giving the time required for the changeover from nonhomogeneous spur kinetics to homogeneous kinetics in the bulk solution. The calculations show that tau(s) decreases by about an order of magnitude over the 25-350 degrees C temperature range, going from ~4.2 * 10(-7) s at 25 degrees C to ~5.7 * 10(-8) s at 350 degrees C. This decrease in tau(s) with increasing temperature mainly originates from the quicker diffusion of the individual species involved. Moreover, the observed dependence of G(Fe(3+)) on temperature largely reflects the influence of temperature upon the primary free-radical product yields of the radiolysis, especially the yield of H atoms. Above ~200-250 degrees C, the more and more pronounced intervention of the reaction of H atoms with water also contributes to the variation of G(Fe(3+)), which may decrease or increase slightly, depending on the choice made for the rate constant of this reaction. All calculations reported herein use the radiolysis database of Elliot (Atomic Energy of Canada Limited) and Bartels (University of Notre Dame) that contains all the best currently available information on the rate constants, reaction mechanisms, and g-values in the range 20 to 350 degrees C. PMID- 21552603 TI - Platinum-nanogaps for single-molecule electronics: room-temperature stability. AB - We present the formation of single-molecule devices based on nanometre-spaced platinum electrodes. The electrodes are fabricated using a self-breaking electromigration method which yields nanogaps with long-term stability at room temperature [Prins et al., APL, 2009, 94, 123108.]. The stability at room temperature allows for detailed comparison of the device electrical properties before and after deposition of the molecules. In this way, conductance as a result of direct tunneling between the electrodes can be distinguished from conductance through the molecule. After molecule deposition, some devices display transport in the strong coupling regime while others are in the weak-coupling Coulomb blockade regime. Gated transport is observed in the latter case. PMID- 21552604 TI - Covalent networks through on-surface chemistry in ultra-high vacuum: state-of-the art and recent developments. AB - The fabrication of large molecular devices, directly on surfaces in UHV conditions, by covalent coupling of smaller precursors has become in the past years an attractive solution for Molecular Electronics. This review presents the state-of-the-art and an analysis of the potential of this new field, from Ullmann type C-C coupling, cyclodehydrogenation, and reactions involving heteroelements to 2D polymerisation on insulating thin films. Mechanistic insights are also mentioned, giving preliminary explanations on the influence of the substrate and the 2D confinement. Potential perspectives for further developments are then evoked. PMID- 21552605 TI - Role of micro-structure and interfacial properties in the higher photocatalytic activity of TiO2-supported nanogold for methanol-assisted visible-light-induced splitting of water. AB - This paper deals with the textural, microstructural and interfacial properties of Au/TiO(2) nanocomposites, in relation to their photocatalytic activity for splitting of water. TiO(2) samples of two different morphologies were employed for dispersing different cocatalysts, such as: Au, Pt, Ag or Cu, for the sake of comparison. The samples were characterized using powder XRD, XPS, UV-visible, thermoluminescence, SEM, HRTEM and SAED techniques. Compared to other metal/TiO(2) photocatalysts, Au/TiO(2) with an optimum gold loading of 1 wt% was found to exhibit considerably higher activity for visible light induced production of H(2) from splitting water in the presence of methanol. Further, the sol-gel prepared TiO(2) (s.TiO(2)), having spherical grains of 10-15 nm size, displayed better photoactivity than a Degussa P25 catalyst. The electron microscopy investigations on s.TiO(2) revealed significant heterogeneity in grain morphology of individual TiO(2) particles, exposure of the lattice planes, metal dispersion, and the interfacial metal/TiO(2) contacts. The gold particles were found to be in a better dispersed state. O(2) TPD experiments revealed that the gold nanoparticles and Au/TiO(2) interfaces may serve as distinct binding sites for adsorbate molecules. At the same time, our thermoluminescence measurements provide an insight into Au-induced new defect states that may facilitate the semiconductor-to-metal charge transfer transition. In conclusion, the superior photocatalytic activity of Au/TiO(2) may relate to the grain morphology of TiO(2), dispersion of gold particles, and the peculiar architecture of metal/oxide heterojunctions; giving rise in turn to augmented adsorption of reactant molecules and their interaction with the photo-generated e(-)/h(+) pair. The role played by methanol as a sacrificial reagent in photocatalytic splitting of water is discussed. PMID- 21552606 TI - Molecular spintronics. AB - The electron spin made its debut in the device world only two decades ago but today our ability of detecting the spin state of a moving electron underpins the entire magnetic data storage industry. This technological revolution has been driven by a constant improvement in our understanding on how spins can be injected, manipulated and detected in the solid state, a field which is collectively named Spintronics. Recently a number of pioneering experiments and theoretical works suggest that organic materials can offer similar and perhaps superior performances in making spin-devices than the more conventional inorganic metals and semiconductors. Furthermore they can pave the way for radically new device concepts. This is Molecular Spintronics, a blossoming research area aimed at exploring how the unique properties of the organic world can marry the requirements of spin-devices. Importantly, after a first phase, where most of the research was focussed on exporting the concepts of inorganic spintronics to organic materials, the field has moved to a more mature age, where the exploitation of the unique properties of molecules has begun to emerge. Molecular spintronics now collects a diverse and interdisciplinary community ranging from device physicists to synthetic chemists to surface scientists. In this critical review, I will survey this fascinating, rapidly evolving, field with a particular eye on new directions and opportunities. The main differences and challenges with respect to standard spintronics will be discussed and so will be the potential cross-fertilization with other fields (177 references). PMID- 21552607 TI - Molecule-based magnets. PMID- 21552608 TI - Analysis and modeling of flow in rotating spiral microchannels: towards math aided design of microfluidic systems using centrifugal pumping. AB - This paper describes the experimental measurement and mathematical modeling of centrifugally-pumped flow in spiral microchannels. Here, the liquid is delivered by the rotation of a circular microchip as depicted before (X. Y. Peng, P. C. H. Li, H. Z. Yu, M. Parameswaran and W. L. Chou, Sens. Actuators, B, 2007, 128, 64 69). The spiral microchannel in it was specially designed to produce a constant centrifugal force component. From experimental measurements, it was found that the flow velocity inside the spiral microchannels was associated with the rotation speed only, but not with the length of the liquid column. The mathematical modeling of liquid flow was constructed based on solving the Navier Stokes equations of incompressible flow formulated in a new orthogonal curvilinear coordinate system aligned with the channel geometry. The governing equations were simplified under various assumptions, rendering a mathematically tractable physical model. In addition, a commercial computational fluid dynamics (CFD) program was used to simulate the flow in the spiral microchannel. The predicted liquid flow velocities from the mathematical model and the CFD program showed reasonable agreement with the experimental data. Under proper assumptions, the mathematical model gave a flexible and rather accurate analytical solution using much less computing power. The proposed study demonstrated the effectiveness of the spiral microchannel design in microfluidic applications using centrifugal force. With modifications, this study could be adapted to the simulation and modeling of other centrifugal-pumping microflow systems. PMID- 21552609 TI - Strategies for in vivo imaging of enzyme activity: an overview and recent advances. AB - Imaging of enzyme activity in living subjects promises many applications in both basic and translational researches from helping elucidate the enzyme function and mechanism in biology to better disease detection and monitoring, but the complexity and dynamics of enzymatic reactions in living systems present unique challenges for probe design. This critical review examines the approaches in recent literature to in vivo imaging of the activity of a variety of enzyme targets with an emphasis on the chemical perspective of probe design, structure and function. Strategies for designing enzyme-activated probes based on a variety of molecular scaffolds including small molecules, organic and inorganic nanoparticles, and genetically encoded proteins for commonly used molecular imaging modalities--whole body optical (fluorescence, bioluminescence) imaging, magnetic resonance imaging, and radionuclide-based tomographic imaging, are critically evaluated. Recent advances in combining multiple modalities to imaging enzyme activity in living subjects are also highlighted (255 references). PMID- 21552610 TI - New hexaphosphane ligands 1,3,5-C6H3{p-C6H4N(PX2)2}3 [X = Cl, F, C6H3OMe(C3H5)]: synthesis, derivatization and palladium(II) and platinum(II) complexes. AB - A novel dodecachlorohexaphosphane, 1,3,5-C(6)H(3)[p-C(6)H(4)N(PCl(2))(2)](3) (1) was synthesized by reacting 1,3,5-tris(4'-anilino)benzene with phosphorus trichloride. Fluorination of 1 with SbF(3) produces 1,3,5-C(6)H(3)[p C(6)H(4)N(PF(2))(2)](3) (2). The derivatization of chlorohexaphosphane with an aryloxy substituent and its palladium(II) and platinum(II) complexes are also described. PMID- 21552611 TI - Half metallicity in BC2)N nanoribbons: stability, electronic structures, and magnetism. AB - Nanoribbons are suggested to be among the most promising candidates being considered as building blocks in future electronics. In this study, we use density functional calculations to examine the structures and electronic properties of BC(2)N nanoribbons with bare zigzag-shaped edges (zz-BC(2)NNRs). Four different types of atomistic edge configurations are considered, including ribbons terminated with two C edges, B and N edges, B an C edges, and C and N edges. We find the existence of half-metallicity in the ground state of the zz BC(2)NNRs with two bare C edges and with bare C and N edges. The other two configurations of the zz-BC(2)NNRs can be either semiconducting or metallic, depending on the specific configuration. We also find that the stability of the zz-BC(2)NNRs are largely dependent on ribbon width. The zz-BC(2)NNRs become energetically more stable when the nanoribbon width exceeds 3.3 nm. It is interesting to find that half-metallic zz-BC(2)NNRs with a width of 0.7 nm are thermodynamically more stable than either metallic or semiconducting counterparts. Therefore, the possibility of synthesizing half-metallic zz BC(2)NNRs exists. PMID- 21552612 TI - Nanomaterials of high surface energy with exceptional properties in catalysis and energy storage. AB - The properties of nanomaterials for use in catalytic and energy storage applications strongly depends on the nature of their surfaces. Nanocrystals with high surface energy have an open surface structure and possess a high density of low-coordinated step and kink atoms. Possession of such features can lead to exceptional catalytic properties. The current barrier for widespread industrial use is found in the difficulty to synthesise nanocrystals with high-energy surfaces. In this critical review we present a review of the progress made for producing shape-controlled synthesis of nanomaterials of high surface energy using electrochemical and wet chemistry techniques. Important nanomaterials such as nanocrystal catalysts based on Pt, Pd, Au and Fe, metal oxides TiO(2) and SnO(2), as well as lithium Mn-rich metal oxides are covered. Emphasis of current applications in electrocatalysis, photocatalysis, gas sensor and lithium ion batteries are extensively discussed. Finally, a future synopsis about emerging applications is given (139 references). PMID- 21552613 TI - Photoemission study on the valence band of a beta-FeSi2 thin film using synchrotron radiation. AB - Resonant and constant-initial state photoemission spectroscopies using synchrotron radiation were applied to investigate the valence-band electronic structure of a semi-conducting beta-type iron-disilicide (beta-FeSi(2)) thin film. The results clearly indicated that the component elements, iron (Fe) and silicon (Si), contribute differently to the valence band features; the Fe 3d orbitals mainly concentrate in the top region of the valence band while the Si 3s and 3p orbitals spread over the wide region of the valence band. The beta-FeSi(2) thin film showed a typical p-type semi-conducting nature with a work function of 4.78 eV. The beta-FeSi(2) film showed the Fe M(1)VV Auger lines around the kinetic energy of 88 eV. It would be expected from these observations that there exist strong interactions between iron and silicon atoms in the beta-FeSi(2) film resulting in orbital mixing and band formation. PMID- 21552614 TI - Passive micromixer for luminol-peroxide chemiluminescence detection. AB - This paper reports a microchip with an integrated passive micromixer based on chaotic advection. The micromixer with staggered herringbone structures was used for luminol-peroxide chemiluminescence detection. The micromixer was examined to assess its suitability for chemiluminescence reaction. The relationship between the flow rate and the location of maximum chemiluminescence intensity was investigated. The light intensity was detected using an optical fiber attached along the mixing channel and a photon detector. A linear correlation between chemiluminescence intensity and the concentration of cobalt(ii) ions or hydrogen peroxide was observed. This microchip has a potential application in environmental monitoring for industries involved in heavy metals and in medical diagnostics. PMID- 21552615 TI - Novel rhenium(I) catalysts for the isomerization of propargylic alcohols into alpha,beta-unsaturated carbonyl compounds: an unprecedented recyclable catalytic system in ionic liquids. AB - Carbonyl rhenium(I) complexes are efficient catalysts for the regioselective isomerization of terminal propargylic alcohols into alpha,beta-unsaturated aldehydes or ketones which can be used as an unprecedented recyclable catalytic system (up to 10 consecutive runs) in the ionic liquid [BMIM][PF(6)]. PMID- 21552616 TI - Detection of three-base deletion by exciplex formation with perylene derivatives. AB - Here, we synthesized fluorescent DNA probes labeled with two perylene derivatives for the detection of a three-base deletion mutant. One such probe discriminated the three-base deletion mutant from the wild-type sequence by exciplex emission, and the deletion mutant was identifiable even by the naked eye. PMID- 21552617 TI - Synthesis of a new fluorescent small molecule probe and its use for in vivo lipid imaging. AB - A new small molecule probe for in vivo lipid imaging, LipidGreen (compound 5), was developed. LipidGreen stained lipid droplets in 3T3L1 cell lines and fat deposits in zebrafish without apparent toxicity up to 100 MUM. The utility of LipidGreen as a drug screening platform for fat regulation was also demonstrated in live zebrafish. PMID- 21552618 TI - Enhanced stability of blue-green light-emitting electrochemical cells based on a cationic iridium complex with 2-(1-phenyl-1H-pyrazol-3-yl)pyridine as the ancillary ligand. AB - A new cationic iridium complex has been developed with 2-(1-phenyl-1H-pyrazol-3 yl)pyridine as the ancillary ligand, which bears a pendant protective phenyl ring within the molecule; blue-green light-emitting electrochemical cells (LECs) based on the complex show dramatically enhanced stability compared to the LEC based on a similar complex without pendant phenyl rings. PMID- 21552619 TI - Supramolecular construction of vesicles based on core-substituted naphthalene diimide appended with triethyleneglycol motifs. AB - The self-assembly of core-substituted naphthalene diimides bearing triethylene glycol motifs leads to the formation of stable vesicles in DMSO and CHCl(3)/MeOH (6 : 4, v/v) solvents. The vesicles were evaluated by means of UV/vis and fluorescence spectroscopy, transmission electron microscopy, atomic force microscopy and dynamic light scattering. PMID- 21552620 TI - Uranyl sequestration: synthesis and structural characterization of uranyl complexes with a tetradentate methylterephthalamide ligand. AB - Uranyl complexes of a bis(methylterephthalamide) ligand (LH(4)) have been synthesized and characterized by X-ray crystallography. The structure is an unexpected [Me(4)N](8)[L(UO(2))](4) tetramer, formed via coordination of the two MeTAM units of L to two uranyl moieties. Addition of KOH to the tetramer gave the corresponding monomeric uranyl methoxide species [Me(4)N]K(2)[LUO(2)(OMe)]. PMID- 21552621 TI - Peptide coated gold nanoparticles that bind lanthanide ions. AB - Water soluble gold nanoparticles are coated with peptides bearing a dithiol surface active group for studies of lanthanide binding; characteristic red luminescence is observed upon europium binding to the nanoparticles. PMID- 21552622 TI - W-Band pulse EPR distance measurements in peptides using Gd(3+)-dipicolinic acid derivatives as spin labels. AB - We present high field DEER (double electron-electron resonance) distance measurements using Gd(3+) (S = 7/2) spin labels for probing peptides' conformations in solution. The motivation for using Gd(3+) spin labels as an alternative for the standard nitroxide spin labels is the sensitivity improvement they offer because of their very intense EPR signal at high magnetic fields. Gd(3+) was coordinated by dipicolinic acid derivative (4MMDPA) tags that were covalently attached to two cysteine thiol groups. Cysteines were introduced in positions 15 and 27 of the peptide melittin and then two types of spin labeled melittins were prepared, one labeled with two nitroxide spin labels and the other with two 4MMDPA-Gd(3+) labels. Both types were subjected to W-band (95 GHz, 3.5 T) DEER measurements. For the Gd(3+) labeled peptide we explored the effect of the solution molar ratio of Gd(3+) and the labeled peptide, the temperature, and the maximum dipolar evolution time T on the DEER modulation depth. We found that the optimization of the [Gd(3+)]/[Tag] ratio is crucial because excess Gd(3+) masked the DEER effect and too little Gd(3+) resulted in the formation of Gd(3+) tag(2) complexes, generating peptide dimers. In addition, we observed that the DEER modulation depth is sensitive to spectral diffusion processes even at Gd(3+) concentrations as low as 0.2 mM and therefore experimental conditions should be chosen to minimize it as it decreases the DEER effect. Finally, the distance between the two Gd(3+) ions, 3.4 nm, was found to be longer by 1.2 nm than the distance between the two nitroxides. The origin and implications of this difference are discussed. PMID- 21552623 TI - How to determine IR molar absorption coefficients of co-adsorbed species? Application to methanol adsorption for quantification of MgO basic sites. AB - Methanol adsorption on MgO samples with different morphologies is studied by infrared (IR) spectroscopy coupled to volumetry or thermogravimetry measurements to probe qualitatively and quantitatively the acid-base paired sites. The molar absorption coefficients of nu(OC) vibration of non-dissociated methanol, type I and type II methoxy species are determined by analyzing data obtained under specific adsorption conditions (epsilon(ND)=2.5 cm MUmol(-1); epsilon(I)=epsilon(II)=6.1 cm MUmol(-1)). Thanks to these results, the amounts of different adsorbed methanol species are evaluated. These various species are formed on surface sites presenting different topologies. Hence, the IR method is the only one allowing us to both discriminate and quantify the defects on the MgO surfaces, in terms of concentrations of convex and concave defective zones. This study reveals that sol-gel preparation leads to a MgO surface presenting a greater amount of concave defective zones than precipitated MgO. PMID- 21552624 TI - Metastable Se6 as a ligand for Ag+: from isolated molecular to polymeric 1D and 2D structures. AB - Attempts to prepare the hitherto unknown Se(6)(2+) cation by the reaction of elemental selenium and Ag[A] ([A](-) = [Sb(OTeF(5))(6)](-), [Al(OC(CF(3))(3))(4)](-)) in SO(2) led to the formation of [(OSO)Ag(Se(6))Ag(OSO)][Sb(OTeF(5))(6)](2)1 and [(OSO)(2)Ag(Se(6))Ag(OSO)(2)][Al(OC(CF(3))(3))(4)](2)2a. 1 could only be prepared by using bromine as co-oxidant, however, bulk 2b (2a with loss of SO(2)) was accessible from Ag[Al(OC(CF(3))(3))(4)] and grey Se in SO(2) (chem. analysis). The reactions of Ag[MF(6)] (M = As, Sb) and elemental selenium led to crystals of 1/infinity{[Ag(Se(6))](infinity)[Ag(2)(SbF(6))(3)](infinity)} 3 and {1/infinity[Ag(Se(6))Ag](infinity)}[AsF(6)](2)4. Pure bulk 4 was best prepared by the reaction of Se(4)[AsF(6)](2), silver metal and elemental selenium. Attempts to prepare bulk 1 and 3 were unsuccessful. 1-4 were characterized by single crystal X-ray structure determinations, 2b and 4 additionally by chemical analysis and 4 also by X-ray powder diffraction, FT-Raman and FT-IR spectroscopy. Application of the PRESTO III sequence allowed for the first time (109)Ag MAS NMR investigations of 4 as well as AgF, AgF(2), AgMF(6) and {1/infinity[Ag(I(2))](infinity)}[MF(6)] (M = As, Sb). Compounds 1 and 2a/b, with the very large counter ions, contain isolated [Ag(Se(6))Ag](2+) heterocubane units consisting of a Se(6) molecule bicapped by two silver cations (local D(3d) sym). 3 and 4, with the smaller anions, contain close packed stacked arrays of Se(6) rings with Ag(+) residing in octahedral holes. Each Ag(+) ion coordinates to three selenium atoms of each adjacent Se(6) ring. 4 contains [Ag(Se(6))(+)](infinity) stacks additionally linked by Ag(2)(+) into a two dimensional network. 3 features a remarkable 3-dimensional [Ag(2)(SbF(6))(3)](-) anion held together by strong Sb-FAg contacts between the component Ag(+) and [SbF(6)](-) ions. The hexagonal channels formed by the [Ag(2)(SbF(6))(3)](-) anions are filled by stacks of [Ag(Se(6))(+)](infinity) cations. Overall 1-4 are new members of the rare class of metal complexes of neutral main group elemental clusters, in which the main group element is positively polarized due to coordination to a metal ion. Notably, 1 to 4 include the commonly metastable Se(6) molecule as a ligand. The structure, bonding and thermodynamics of 1 to 4 were investigated with the help of quantum chemical calculations (PBE0/TZVPP and (RI-)MP2/TZVPP, in part including COSMO solvation) and Born-Fajans-Haber-cycle calculations. From an analysis of all the available data it appears that the formation of the usually metastable Se(6) molecule from grey selenium is thermodynamically driven by the coordination to the Ag(+) ions. PMID- 21552625 TI - Water-dispersible ultrathin Au nanowires prepared using a lamellar template of a long-chain amidoamine derivative. AB - Straight ultrathin Au nanowires (NWs) with diameters less than 2 nm were synthesized using the lamellar structure of C18AA in an organogel and its selective adsorption for specific gold surfaces. In addition, the potential to form a bilayer structure with interdigitated hydrocarbon chains enabled the production of water-dispersible Au NWs without morphological change. PMID- 21552626 TI - Ultrafast excited state dynamics of fucoxanthin: excitation energy dependent intramolecular charge transfer dynamics. AB - Carotenoids containing a carbonyl group in conjugation with their polyene backbone are naturally-occurring pigments in marine organisms and are essential to the photosynthetic light-harvesting function in aquatic algae. These carotenoids exhibit spectral characteristics attributed to an intramolecular charge transfer (ICT) state that arise in polar solvents due to the presence of the carbonyl group. Here, we report the spectroscopic properties of the carbonyl carotenoid fucoxanthin in polar (methanol) and nonpolar (cyclohexane) solvents studied by steady-state absorption and femtosecond pump-probe measurements. Transient absorption associated with the optically forbidden S(1) (2(1)A) state and/or the ICT state were observed following one-photon excitation to the optically allowed S(2) (1(1)B) state in methanol. The transient absorption measurements carried out in methanol showed that the ratio of the ICT-to-S(1) state formation increased with decreasing excitation energy. We also showed that the ICT character was clearly visible in the steady-state absorption in methanol based on a Franck-Condon analysis. The results suggest that two spectroscopic forms of fucoxanthin, blue and red, exist in the polar environment. PMID- 21552627 TI - Potent "clicked" MMP2 inhibitors: synthesis, molecular modeling and biological exploration. AB - A new series of MMP2 inhibitors is described, following a fragment-based drug design approach. One fragment containing an azide group and a well known hydroxamate Zinc Binding Group in a alpha-sulfone, alpha-tetrahydropyrane scaffold, has been synthesized. Water-LOGSY, STD and competition-STD experiments indicate that this fragment binds to the active site of the enzyme. A click chemistry reaction was used to connect the azide to lipophilic alkynes selected to interact selectively with the S1' subunit of MMP2, as shown by docking and molecular dynamic experiments of the designed compounds. The most potent compounds 18 and 19 displayed an IC(50) of 1.4 and 0.3 nM against MMP2 respectively, and showed negligible activity towards MMP1 and MMP7, two metalloproteinases which have a shallow S1' subsite. Compound 18 also showed a promising selectivity profile against some antitarget metalloproteinases, such as MMP8, and considerably less activity against MMP14 (IC(50) = 65 nM), and MMP9 (IC(50) = 98 nM), other MMPs characterized by having a deep S1' pocket and, therefore, more similar to MMP2. PMID- 21552629 TI - Predicting properties of new ionic liquids: density functional theory and experimental studies of tetra-alkylammonium salts of (thio)carboxylate anions, RCO2-, RCOS- and RCS2-. AB - Density functional theory calculations of alkyl-carboxylate anions and their sulfur substituted variants are presented here as an aid for the development of new ionic liquids. Electron transfer both within the anion, and between the anion and cation of an ion pair, are described using natural bond order analysis, using tetraethylammonium as a common cation. The overall stabilising effect of this electron transfer is quantified for the series of anions, and is found to correlate with clear trends in ion-pair binding energy. These and other electronic properties determine which compounds are synthesised, and experimental results validate the computational results. In combination with tetraethylammonium, a carboxylate with an unsaturated alkyl chain produces an ionic liquid at room temperature. However, computations suggest that sulfur substituted anions will produce a lower melting point and perhaps more fluid ionic liquid, but one which would be less stable against oxidation. PMID- 21552628 TI - Electrocatalytic detection of dopamine in the presence of ascorbic acid and uric acid at silicon carbide coated electrodes. AB - This communication demonstrates that the SiC coated glassy carbon electrode resolved the overlapping voltammetric responses of ascorbic acid (AA), dopamine (DA), and uric acid (UA), which could be used for selective determination of DA in the presence of AA and UA. PMID- 21552630 TI - A serendipitous phosphonocarboxylate complex of boron: when vessel becomes reagent. AB - Under certain conditions, the phosphonocarboxylate analogue (3) of the bisphosphonate drug minodronate (4) in contact with borosilicate glassware reversibly forms an isolable dimer complex of boron, as revealed by the X-ray crystallographic structure of the (R,R/S,S) complex and supported by NMR and HRMS data. PMID- 21552631 TI - Biochemistry of anionic calix[n]arenes. AB - This review treats the biological properties of the various anionic calix[n]arenes, both as soluble forms and in the colloidal state. The complexation of these molecules with amino-acids, peptides and proteins is discussed, as is their interaction with model membranes. The complexations with various Active Pharmaceutical Ingredients as complexes, for tamoxifen as solid state and colloidal structures, are treated in depth. Two sections deal with the direct biological action of the calix[n]arenes and their use as biosensors. A final section deals with the toxicity, in reality the lack of toxicity of the calix[n]arenes. PMID- 21552632 TI - Erbium-formate frameworks templated by diammonium cations: syntheses, structures, structural transition and magnetic properties. AB - Two structurally different Er-formate frameworks, one NaCl-like [dmenH(2)][Er(HCOO)(4)](2) (1) and the other pillared-layer type [tmenH(2)][Er(HCOO)(4)](2) (2), were obtained when templated by the corresponding protonated N,N'-dimethylethylenediamine (dmenH(2)) and N,N,N',N'-tetramethyl- ethylenediamine (tmenH(2)). The shape and size of the template cations dictate the different coordination geometries of erbium and consequently the framework topologies, though erbium adopts eight coordination in the two compounds. In the NaCl-like structure of 1, erbium is coordinated by eight anti-anti bridging formates in a square antiprism, while in the pillared-layer structure of 2, it is coordinated by six anti-anti bridging formates and one chelating formate in a pentagonal bipyramid. 2 exhibits a structural phase transition around -70 degrees C which is related to the disorder-order transition of the template cation. Both compounds behave as paramagnets between 2 and 300 K. However, they display field-dependent ac-susceptibilities with complicated field-induced magnetic relaxation processes, and the major slow ones probably results from spin lattice relaxation. PMID- 21552633 TI - Fugacity approach to evaluate the sediment-water diffusion of polycyclic aromatic hydrocarbons. AB - Diffusion is an important process for sediment-water exchange and plays a vital role in controlling water quality. Fugacity fraction (ff) was used to estimate the sediment-water diffusion of polycyclic aromatic hydrocarbons (PAHs) between seawater and surficial sediment. A total of 33 surface sediment and sea water samples were collected concurrently from the northeast coastal area in China and 25 PAHs were analyzed including the alkylated and chlorated PAHs. Fugacity fraction was calculated based on the PAH concentrations in water and sediment, octanol-water partition coefficient of PAHs, organic matter content in sediment, and density of sediment. The calculated results showed that ff increased with decreasing molecular weight of PAHs. The low molecular weight PAHs (2-3 rings) transferred from sediment to water and the sediment acted as a secondary source to the water. The medium molecular weight PAHs (4-5 rings) were close to the sediment-water equilibrium and the transfer tendency shifted between sediment and water. The high molecular weight PAHs (5-6 rings) transferred from water into sediment and the sediment acted as a sink. Soot carbon and the difference of PAH concentrations between sediment and water were found to be important factors affecting the sediment-water diffusion. This study provided new insight into the process of sediment-water diffusion, which has a great influence on the quality of water, especially in severely-polluted sediment areas. PMID- 21552634 TI - Kojic acid derivatives as powerful chelators for iron(III) and aluminium(III). AB - Proceeding from a ligand constituted by two units of kojic acid linked by a methylene group, which proved a very promising chelator for excess iron(III) and aluminium(III) pathologies, two new ligands have been designed and synthesized: one by adding a vanillin molecule in the linker and the second by adding an o vanillin molecule. Both these ligands, on the basis of complex formation studies presented here, show significant potential as therapeutic agents for iron and aluminium overload. Protonation constants of the pure ligands have been determined by potentiometry, and standard reaction heats by calorimetry. Hydrogen bonding plays an important role in the protonation reactions. The crystal structures of both ligands have furthermore been resolved. Complex formation equilibria for the iron complexes have been studied by combined potentiometry spectrophotometry and those of aluminium by potentiometry alone. All complexes were found to contain two metal ions. NMR diffusion measurements hardly applied to complex formation equilibria and the results of density functional theory (DFT) calculations were powerful tools in confirming the proposed reaction model and in evaluating the relative stabilities of the products. Further support was given by NMR chemical shift measurements and electrospray mass spectrometry. PMID- 21552635 TI - Evaluation of lot-to-lot repeatability and effect of assay media choice in the recombinant Factor C assay. AB - Measurement of environmental endotoxin exposures is complicated by variability encountered using current biological assay methods arising in part from lot-to lot variability of the Limulus-amebocyte lysate (LAL) reagents. Therefore, we investigated the lot-to-lot repeatability of commercially available recombinant Factor C (rFC) kits as an alternative to LAL. Specifically, we compared endotoxin estimates obtained from rFC assay of twenty indoor dust samples, using four different extraction and assay media, to endotoxin estimates previously obtained by Limulus amebocyte lysate (LAL) assay and amounts of 3-hydroxy fatty acids (3 OHFA) in lipopolysaccharide (LPS) using gas-chromatography mass spectroscopy (GC MS). We found that lot-to-lot variability of the rFC assay kits does not significantly alter endotoxin estimates in house dust samples when performed using three of the four assay media tested and that choice of assay media significantly altered endotoxin estimates obtained by rFC assay of house dust samples. Our findings demonstrate lot-to-lot reproducibility of rFC assay of environmental samples and suggest that use of rFC assay performed with Tris buffer or water as the extraction and assay medium for measurement of endotoxin in dust samples may be a suitable choice for developing a standardized methodology. PMID- 21552636 TI - Comparison of two dynamic measurement methods of odor and odorant emission rates from freshly dewatered biosolids. AB - Odor and odorant emission rates from freshly dewatered biosolids in a dewatering building of a Water Reclamation Plant (WRP) are measured using the EPA flux chamber and wind tunnel methods. Experimental results are compared statistically to test whether the two methods result in similar emission rates when experiments are performed under field conditions. To the best of our knowledge the literature is void of studies comparing the two methods indoors. In this paper the two methods are compared indoors where the wind velocity and air exchange rate are pertinent field conditions and can be measured. The difference between emission rates of odor and hydrogen sulfide measured with the two methods is not statistically significant (P values: 0.505 for odor, 0.130 for H(2)S). It is concluded that both methods can be used to estimate source emissions but selection of the most effective or efficient method depends on prevailing environmental conditions. The wind tunnel is appropriate for outdoor environments where wind effects on source emissions are more pronounced than indoors. The EPA flux chamber depends on the air exchange rate of the chamber, which simulates corresponding conditions of the indoor environment under investigation and is recommended for estimation of indoor pollution sources. PMID- 21552637 TI - Photophoretic assembly and migration of dielectric particles and Escherichia coli in liquids using a subwavelength diameter optical fiber. AB - We demonstrate a photophoretic assembly and migration of dielectric (SiO(2) and TiO(2)) particles and bacteria (Escherichia coli) in liquids by using a subwavelength diameter fiber. With a lightwave at 1.55 MUm launched into the fiber, the objects are radiated by the leaking light of the fiber to yield negative photophoretic forces which drive the objects to move toward the fiber, with an average assembling/migrating speed of 5-15 individuals per second (ind/s). The influences of laser-on duration, optical power, and size of particles on the photophoretic velocities are also investigated. PMID- 21552638 TI - NMR characterization of a Cu(I)-bound peptide model of copper metallochaperones: insights on the role of methionine. AB - The first NMR structure of a Cu(I)-bound metallochaperone model with the conserved sequence MT/HCXXC revealed that at pH ~3.0 and ~6.8 Cu(I) binds through one Cys and the Met rather than the two Cys residues, differently than at pH ~8.5. This suggests a possible role of Met in metal transport. PMID- 21552639 TI - Photocatalytic function of a polymer-supported B12 complex with a ruthenium trisbipyridine photosensitizer. AB - The hybrid polymer was synthesized by a radical polymerization of a B(12) derivative and a Ru complex having styrene moieties in each peripheral position, and the hybrid polymer showed photocatalytic activity for molecular transformation with visible light irradiation. PMID- 21552640 TI - Modeling of hyperbranched polyesters as hosts for the multifunctional bioactive agent Shikonin. AB - We employ fully atomistic molecular dynamics simulations to study in detail the mechanisms involved in the non-covalent association of the bioactive agent Shikonin with the commercially available hyperbranched polyesters (Boltorn(r)), in ethanol solutions. We examine effects of the (pseudo)generation of the hyperbranched polyester and mimic two different concentrations, under conditions corresponding to excess drug availability. The two mechanisms participating in the polymer/drug complexation are hydrogen bonding and spatial constriction of the drug molecules within the hyperbranched structure. Based on static, as well as on dynamic information obtained by the analysis performed, it is demonstrated that apart from the size of the polyester, factors like the degree of structural flexibility, the intrapolymer hydrogen bonding and the polymer concentration may affect decisively the polyester/shikonin associative behavior, as well as the behavior of the drug-molecules in the solution. The results from the present study offer a detailed picture of the relative importance of those parameters affecting the complexation, and may serve as a basis for the understanding of the behavior of more complex multi-polyester systems. PMID- 21552641 TI - Development of a high-performance anode for lithium ion batteries using novel ordered mesoporous tungsten oxide materials with high electrical conductivity. AB - An ordered mesoporous WO(3-X) with high electrical conductivity (m-WO(3-X)) was prepared and evaluated as an anode material for lithium ion batteries (LIBs). Ordered mesoporous tungsten trioxide (m-WO(3)) with an identical pore structure to that of m-WO(3-X) and bulk WO(3-X) (b-WO(3-X)) was prepared for the comparison purpose. An m-WO(3-X) electrode exhibited a high reversible capacity (748 mAh g( 1), 6.5 Li/W) and a high volumetric capacity (~1500 mAh cm(-3)), which is comparable to the Li metal itself (ca. 2000 mAh cm(-3)). Also, an improved rate capability and a good cyclability were observed in the m-WO(3-X) electrode when compared with m-WO(3) and b-WO(3-X) electrodes. From electrochemical impedance spectroscopy (EIS) analysis, the advanced anode performance of the m-WO(3-X) electrode was probably attributed to large ordered mesopores and a high electrical conductivity. Differential scanning calorimetry (DSC) result displayed that the safety of m-WO(3-X) was more improved than those of graphite and Si anode materials. PMID- 21552642 TI - A theoretical study on excited state double proton transfer reaction of a 7 azaindole dimer: an ab initio potential energy surface and its empirical valence bond model. AB - Double proton transfer (DPT) reaction of a 7-azaindole dimer in the first pipi* electronically excited state was studied theoretically. We investigated the reaction mechanism through constructing a full dimensional empirical valence bond potential energy function (PEF) based on potential energies evaluated by ab initio molecular orbital methods, and carrying out quantum dynamics calculations with the PEF. Potential energy surfaces of the DPT obtained at the multi reference perturbation level of theory favors a concerted DPT mechanism, although a stepwise channel is suggested to open for an excited initial vibrational state. Reduced two dimensional quantum dynamics calculations for a reaction surface Hamiltonian of DPT coordinates were performed. Time constants of the reaction were evaluated to be on the order of picoseconds, which is consistent with experiments. On the other hand, the computed kinetic isotope effect deviates from experimental evidence, suggesting the importance of intermolecular stretching motion, which is not explicit in the present calculations for the quantum effect. PMID- 21552643 TI - Highly depressed temperature-induced metal-insulator transition in synthetic monodisperse 10-nm V2O3 pseudocubes enclosed by {012} facets. AB - Monodisperse 10-nm V(2)O(3) pseudocubes enclosed by {012} facets were successfully synthesized for the first time via a novel and facile solvothermal method, offering the first opportunity to elucidate the effect of finite-size and facet on the temperature-induced reversible metal-insulator transition (MIT) behavior of V(2)O(3). Very excitingly, the transition temperature of these V(2)O(3) pseudocubes drastically depressed from 133 K to 36 K and their corresponding hysteresis width highly narrowed from 17 K to 5 K, compared to the MIT behaviors of other irregular V(2)O(3) particles with average sizes of 10 nm, 20 nm, 40 nm, 170 nm and 2 MUm. Notably, the size-related surface energy, grain boundary connectivity and volume expansion could be used to account for their strong size-dependent transition temperature and hysteresis width. Moreover, the improved grain boundary connectivity associated with well-defined {012} facets enabled these 10-nm V(2)O(3) pseudocubes to display a 10 times higher resistivity jump (at the order of 10(5)) and by nearly one-half smaller hysteresis width of 5 K than the irregular 10-nm V(2)O(3) particles with randomly exposed facets, directly evidencing the pronounced influence of facets on the MIT behavior. Briefly, the present work not only develops an effective strategy for synthesizing high-quality nanocrystals but also provides an excellent platform to investigate the size- and facet-dependent temperature-induced MIT behavior, enabling to design smart electrical switching nano-devices in the rapidly developing ultra-low temperature field. PMID- 21552644 TI - Continuous synthesis of monodispersed silver nanoparticles using a homogeneous heating microwave reactor system. AB - Continuous synthesis of silver nanoparticles based on a polyol process was conducted using a microwave-assisted flow reactor installed in a cylindrical resonance cavity. Silver nitrate (AgNO(3)) and poly(N-vinylpyrrolidone) (PVP) dissolved in ethylene glycol were used respectively as a silver metal precursor and as a capping agent of nanoparticles. Ethylene glycol worked as the solvent and simultaneously as the reductant. Silver nanoparticles of narrow size distributions were synthesized steadily for 5 h, maintaining almost constant yield (>93%) and quality. The reaction was achieved within 2.8 s of residence time, although nanoparticles were not formed under this flow rate by conventional heating. A narrower particle size distribution was realized by the increased flow rate of the reaction solution. Nanoparticles of 9.8 nm average size with a standard deviation of 0.9 nm were synthesized at the rate of 100 ml h(-l). PMID- 21552645 TI - Vitamin C restores blood pressure and vasodilator response during mental stress in obese children. AB - BACKGROUND: Peripheral vasodilation response plays an important role in the pathophysiology of obesity and heart disease. OBJECTIVE: To evaluate the chronic effect of vitamin C (VitC) supplementation on blood pressure and on vasodilation response to mental stress. METHODS: In a double-blind, randomized and prospective study we evaluated obese children with 8 to 12 years in 2 similar groups: 1) supplemented with 500 mg VitC (n = 11) and 2) placebo (n = 10) for 45 days. Eight age-matched lean control children were also studied. We evaluated: mean blood pressure (MBP), heart rate (HR) and forearm blood flow by venous occlusion plethismography. Forearm vascular conductance (FVC) was calculated by: (forearm blood flow/PAM) X100. RESULTS: On pre-intervention evaluations obese children showed higher MBP and lower FVC compared to lean control children. After intervention VitC diminished MBP at rest (81 +/- 2 vs 75 +/- 1 mmHg, p = 0.01), whereas placebo did not promote changes in MBP (p = 0.58). In addition, VitC promoted FVC increase at rest (3.40 +/- 0.5 vs 5.09 +/- 0.6 un, p = 0.04) and during the mental stress (3.92 +/- 0.5 vs 6.68 +/- 0.9 un, p = 0.03). Moreover, after VitC supplementation FVC levels were similar to the lean control children at rest (5.09 +/- 0.6 vs 5.82 +/- 0.4 un, p > 0.05) and during mental stress (6.68 +/- 0.9 vs 7.35 +/- 0.5 un, p > 0.05). CONCLUSION: VitC supplementation reduced the MBP and restored peripheral vasodilatation response during mental stress in obese children. PMID- 21552646 TI - Heart failure: comparison between six-minute walk test and cardiopulmonary test. AB - BACKGROUND: Chronic heart failure (HF) is a syndrome characterized by reduced cardiac output in relation to the metabolic needs of the organism, as well as metabolic and neurohormonal axis abnormalities. Symptoms such as fatigue and dyspnoea are notorious and stress tests are widely used to assess functional capacity, prognosis and effectiveness of therapeutic interventions in this syndrome. OBJECTIVE: To evaluate the reproducibility of the six-minute walk test (6MW) in patients with HF and correlate the magnitude of the variables reached at peak exercise of the 6MWT with a cardiopulmonary exercise test (CPET). METHODS: We studied 16 patients (12 men and 4 women) diagnosed with HF FC I-II (NYHA). The volunteers underwent two 6MWT (6MWT'1 and 6MWT'2) with 30-minute interval between them; then, they underwent a maximum CPET. RESULTS: All variables obtained in the two 6MWT' proved to be significant with high correlations: distance walked (DW) (r = 0.93, p < 0.0001), heart rate (HR) (r = 0.89, p < 0.0001), oxygen consumption (VO2) (r = 0.93, p < 0.0001) and scale of perceived exertion (r = 0.85, p < 0.0001). In turn, all variables analyzed in the 6MWT' showed significant and moderate correlations with the variables obtained from the CPET, namely: peak HR (r = 0.66; p = 0.005); VO2 (r = 0.57; p = 0.02) and VO2 in the CPET and DT in the 6MWT'2 (r = 0.70; p = 0.002). CONCLUSION: The 6MWT was reproducible in this group of patients with HF (NYHA - I-II) and correlated with the CPET. Therefore, it is a tool for reliable evaluation, and a suitable, safe and low-cost alternative for the prescription of aerobic exercise in patients with HF. PMID- 21552647 TI - Exercise-induced left bundle branch block: prevalence and prognosis. AB - BACKGROUND: Exercise-induced left bundle branch block (EI-LBBB) is an infrequent finding. Its prevalence and prognostic significance are not clear. OBJECTIVE: To evaluate, in a longitudinal study, the prevalence and prognostic significance of EI-LBBB in American war veterans. METHODS: We evaluated 9,623 patients submitted to an exercise test (ET) in treadmill between 1987 and 2007. The outcomes were compared between those with normal TE, the ones with EI-LBBB and the ones with down-sloping ST-segment. Mortality and causes of death were identified while blinded to the ET results. RESULTS: In this prospective cohort, 6,922 individuals had normal ET results (57.2 +/- 11.4 years), 1,739 had abnormal ST-segment depression (62.7 +/- 9.8 years), and 38 had EI-LBBB (65.2 +/- 11.9 years). The prevalence of EI-LBBB was 0.38%. After 8.8 years, there were 1,699 deaths due to all-cause mortality and 610 cardiovascular (CV) deaths; coronary artery disease and heart failure were more prevalent in patients with EI-LBBB. Patients with EI BCRE had a hazard ratio of 2.37 (p = 0.002) for all-cause mortality, but it was not significant when adjusted for age or when the CV death was the assessed outcome. CONCLUSION: EI-LBBB is a rare clinical finding. Individuals with BCRE-EI have higher all-cause mortality when compared to those with normal ET results. However, this fact is explained by the fact that these patients are significantly older and have more associated cardiovascular diseases. PMID- 21552648 TI - Swimming training attenuates contractile dysfunction in diabetic rat cardiomyocytes. AB - BACKGROUND: Experimental diabetes promotes contractile dysfunction in cardiomyocytes, but the effects of swimming in this disorder are not known. OBJECTIVE: To test the effects of a swimming training program (STP) on cardiomyocyte contractile dysfunction in rats with experimental diabetes. METHODS: Wistar rats (age: 30 days; mean body weight: 84.19 g) with diabetes induced by streptozotocin (60 mg/kg body weight; glucose > 300 mg/dl) were divided into sedentary diabetic rats (SD, n = 10) and exercised diabetic rats (ED, n = 13). Animals of same age and weight served as sedentary controls (SC, n = 10) and exercised controls (EC, n = 06). Animals and ED and EC underwent a STP (05 days/week, 90 min/day) for 08 weeks. Left ventricular (LV) myocytes were isolated and electrically stimulated at 3.0 Hz at room temperature (~ 25o C). RESULTS: Diabetes reduced contractile function in cardiomyocytes of animals compared to controls (i.e., lower amplitude of contraction, longer duration of contraction and relaxation). The STP attenuated the reduced amplitude of contraction (SC, 11 +/- 0.2% vs ED, 11.6 +/- 0.2%), time to peak contraction (SC, 319 +/- 5.8 ms vs ED, 333 +/- 4.8 ms) and time to 50.0% of relaxation (SC, 619 +/ 22.2 ms vs ED 698 +/- 18.6 ms) of cardiomyocytes of diabetic rats. Diabetes reduced the size of cardiomyocytes, however, the STP minimized the reduction of cell volume and width, without changing length. CONCLUSION: The swimming training program attenuated the contractile dysfunction of the LV myocytes of rats with experimental diabetes. PMID- 21552649 TI - Case 2/2011 - Young patient, male, with pleuritic chest pain, hypotension, profuse sweating, with ECG with no acute ischemic abnormalities and negative myocardial injury markers. PMID- 21552650 TI - Technical difficulty in stenting Supralimus in radial artery graft. AB - Woman, 67 years old, with unstable angina and history of myocardial revascularization: left internal thoracic artery to anterior descending artery and graft with radial artery (RA) to right coronary artery branches. Coronariography showed stenosis of 90% in the RA graft, treated with conventional stent. After two months, the patient developed unstable angina related to in stent restenosis, treated with sirolimus-eluting stent. In the follow-up, six months after implantation, the patient was asymptomatic and maintening the outcome of the implant. This case report demonstrates the technical difficulties of percutaneous intervention in RA grafts and treatment outcome of in-stent restenosis with sirolimus stent. PMID- 21552651 TI - Marantic endocarditis and adenocarcinoma of unknown primary site. AB - Nonbacterial thrombotic endocarditis (NBTE) is a disease characterized by deposition of thrombi and fibrin on normal or degenerated cardiac valves in the absence of microorganisms. This condition is more commonly seen in chronic inflammatory states, and is associated with higher incidence of thromboembolic events than infective endocarditis. We report the case of a 63-year old male patient with adenocarcinoma of unknown primary site and systemic embolism. PMID- 21552652 TI - Crossing coronary arteries. PMID- 21552653 TI - Optimized approach in cardiocerebral resuscitation. AB - Cardiocerebral Resuscitation (CCR) is a new approach to the resuscitation of patients with out-of-hospital cardiac arrest (OHCA). The first major component of CCR is continuous chest compressions (also referred to as chest compression-only CPR or "hands-only CPR") advocated as part of CCR for all bystanders who witness a sudden collapse of presumed cardiac origin. The second component of CCR is a new ACLS treatment algorithm for Emergency Medical Services. This algorithm emphasizes uninterrupted chest compressions regardless of other ongoing assignments as part of the rescue effort. A third component has recently been added to CCR, namely aggressive post-resuscitation care. Cardiocerebral resuscitation has increased bystander participation and has improved survival rates in a number of communities. Now is the time for other communities to re examine their own outcomes with cardiac arrest and consider joining those cities and communities that have doubled and even tripled their survival from OHCA. PMID- 21552654 TI - Cardiorespiratory test in healthy and cardiopathic children. PMID- 21552655 TI - Anomalous origin of the left main coronary artery: course determination by computed tomography. PMID- 21552656 TI - Regarding the modification of an old procedure (Vineberg) in the stem cell era - a new strategy? PMID- 21552657 TI - Influence of patellofemoral pain syndrome on plantar pressure in the foot rollover process during gait. AB - BACKGROUND: Patellofemoral Pain Syndrome is one of the most common knee disorders among physically active young women. Despite its high incidence, the multifactorial etiology of this disorder is not fully understood. OBJECTIVES: To investigate the influence of Patellofemoral Pain Syndrome on plantar pressure distribution during the foot rollover process (i.e., the initial heel contact, midstance and propulsion phases) of the gait. MATERIALS AND METHODS: Fifty-seven young adults, including 22 subjects with Patellofemoral Pain Syndrome (30 +/- 7 years, 165 +/- 9 cm, 63 +/- 12 kg) and 35 control subjects (29 +/- 7 years, 164 +/- 8 cm, 60 +/- 11 kg), volunteered for the study. The contact area and peak pressure were evaluated using the Pedar-X system (Novel, Germany) synchronized with ankle sagittal kinematics. RESULTS: Subjects with Patellofemoral Pain Syndrome showed a larger contact area over the medial (p = 0.004) and central (p = 0.002) rearfoot at the initial contact phase and a lower peak pressure over the medial forefoot (p = 0.033) during propulsion when compared with control subjects. CONCLUSIONS: Patellofemoral Pain Syndrome is related to a foot rollover pattern that is medially directed at the rearfoot during initial heel contact and laterally directed at the forefoot during propulsion. These detected alterations in the foot rollover process during gait may be used to develop clinical interventions using insoles, taping and therapeutic exercise to rehabilitate this dysfunction. PMID- 21552658 TI - Work-related injuries among physiotherapists in public hospitals: a Southeast Asian picture. AB - OBJECTIVES: A cross-sectional study was conducted to measure the prevalence of work-related injuries among physiotherapists in Malaysia and to explore the influence of factors such as gender, body mass index, years of work experience and clinical placement areas on the occurrence of work-related musculoskeletal disorders. METHODS: Self-administered questionnaires adapted from the Nordic Musculoskeletal Questionnaire were sent to 105 physiotherapists at three main public hospitals in Kuala Lumpur, Malaysia. The questionnaire had 12 items that covered demographic information, areas of musculoskeletal problems and physiotherapy techniques that could contribute to work-related musculoskeletal disorders. The data obtained were analyzed using the Statistical Package for Social Science version 14 software. RESULTS: The overall prevalence of work related injuries during the past 12 months was 71.6%. Female therapists reported a significantly higher prevalence of work-related musculoskeletal disorders than the male therapists (73.0%, p,0.001). Significant differences were observed between the proportion of therapists who had work-related musculoskeletal disorders and those who did not for the group with a body mass index (BMI) .25 (x2 = 9.0, p = 0.003) and the group with a BMI of 18-25 (x2 = 7.8, p = 0.006). Manual therapy (58.6%) and lifting/transfer tasks (41.3%) were the two physiotherapy techniques that most often contributed to work-related musculoskeletal disorders. CONCLUSION: Work-related injuries are significantly higher among the physiotherapists in Malaysia compared with many other countries. Female therapists reported a higher incidence of work-related musculoskeletal disorders in this study, and work-related musculoskeletal disorders were more common among therapists working in the pediatric specialty. This study contributes to the understanding of work-related disorders among physiotherapists from a southeast Asian perspective where the profession is in its development stage. PMID- 21552659 TI - Ocular findings in patients with systemic sclerosis. AB - OBJECTIVE: To evaluate the frequency and characteristics of ocular manifestations in outpatients with systemic sclerosis. METHODS: In this cross-sectional study, 45 patients with systemic sclerosis were enrolled. Data regarding demographics, disease duration and subtype, age at diagnosis, nailfold capillaroscopic pattern and autoantibody profile were collected, and a full ophthalmic examination was conducted. Parametric (Student's t-test) and nonparametric (Mann-Whitney U test) tests were used to compare continuous variables. Fisher's exact test was used to compare categorical data. P values < 0.05 were considered significant. RESULTS: Twenty-three subjects (51.1%) had eyelid skin changes; 22 (48.9%) had keratoconjunctivitis sicca, 19 (42.2%) had cataracts, 13 (28.9%) had retinal microvascular abnormalities and 6 (13.3%) had glaucoma. Eyelid skin changes were more frequent in patients with the diffuse subtype of systemic sclerosis and were associated with a younger age and an earlier age at diagnosis. Cataracts were presumed to be age-related and secondary to corticosteroid treatment. There was no association between demographic, clinical or serological data and keratoconjunctivitis sicca. The retinal microvascular abnormalities were indistinguishable from those related to systemic hypertension and were associated with an older age and a severe capillaroscopic pattern. CONCLUSIONS: Eyelid skin abnormalities and keratoconjunctivitis sicca were the most common ocular findings related to systemic sclerosis. Some demographic and clinical data were associated with some ophthalmic features and not with others, showing that the ocular manifestations of systemic sclerosis are characterized by heterogeneity and reflect the differences in the implicated pathophysiological mechanisms. PMID- 21552660 TI - Risk factors for early treatment discontinuation in patients with obsessive compulsive disorder. AB - INTRODUCTION: In obsessive-compulsive disorder, early treatment discontinuation can hamper the effectiveness of first-line treatments. OBJECTIVE: This study aimed to investigate the clinical correlates of early treatment discontinuation among obsessive-compulsive disorder patients. METHODS: A group of patients who stopped taking selective serotonin reuptake inhibitors (SSRIs) or stopped participating in cognitive behavioral therapy before completion of the first twelve weeks (total n = 41; n = 16 for cognitive behavioral therapy and n = 25 for SSRIs) were compared with a paired sample of compliant patients (n = 41). Demographic and clinical characteristics were obtained at baseline using structured clinical interviews. Chi-square and Mann-Whitney tests were used when indicated. Variables presenting a p value <0.15 for the difference between groups were selected for inclusion in a logistic regression analysis that used an interaction model with treatment dropout as the response variable. RESULTS: Agoraphobia was only present in one (2.4%) patient who completed the twelve-week therapy, whereas it was present in six (15.0%) patients who dropped out (p = 0.044). Social phobia was present in eight (19.5%) patients who completed the twelve-week therapy and eighteen (45%) patients who dropped out (p = 0.014). Generalized anxiety disorder was present in eight (19.5%) patients who completed the twelve-week therapy and twenty (50%) dropouts (p = 0.004), and somatization disorder was not present in any of the patients who completed the twelve-week therapy; however, it was present in six (15%) dropouts (p = 0.010). According to the logistic regression model, treatment modality (p = 0.05), agoraphobia, the Brown Assessment of Beliefs Scale scores (p = 0.03) and the Beck Anxiety Inventory (p = 0.02) scores were significantly associated with the probability of treatment discontinuation irrespective of interactions with other variables. DISCUSSION AND CONCLUSION: Early treatment discontinuation is a common phenomenon in obsessive-compulsive disorder patients from our therapeutic setting. Psychiatric comorbidities were associated with discontinuation rates of specific treatments. Future studies might use this information to improve management for increased compliance and treatment effectiveness. PMID- 21552661 TI - Incidence and recurrence of acute otitis media in Taiwan's pediatric population. AB - OBJECTIVE: To report the incidence and recurrence of acute otitis media (AOM) in Taiwan's pediatric population. METHODS: Information from children (aged <= 12 years) with a diagnosis of AOM was retrieved from the 2006 National Healthcare Insurance claims database. We calculated the cumulative incidence rate and the incidence density rate of recurrent AOM within one year after the initial diagnosis in 2006. We used a multivariate logistic regression model to assess the predictors for recurrence of AOM. RESULTS: The annual incidence rate of AOM was estimated to be 64.5 cases per 1,000 children. The overall one-year cumulative incidence rate of recurrence was 33.1%, and the incidence density rate was 33.5 cases per 100 person-years, with the highest figure (41.2 cases per 100 person years) noted for children aged 0-2 years. Recurrence was significantly associated with age, gender, place of treatment, and physician specialty. CONCLUSION: AOM remains a major threat to children's health in Taiwan. Male children and very young children require more aggressive preventive strategies to reduce the risk of recurrence. PMID- 21552662 TI - Neuromuscular electrical stimulation improves exercise tolerance in chronic obstructive pulmonary disease patients with better preserved fat-free mass. AB - BACKGROUND: High-frequency neuromuscular electrical stimulation increases exercise tolerance in patients with advanced chronic obstructive pulmonary disease (COPD patients). However, it is conceivable that its benefits are more prominent in patients with better-preserved peripheral muscle function and structure. OBJECTIVE: To investigate the effects of high-frequency neuromuscular electrical stimulation in COPD patients with better-preserved peripheral muscle function. DESIGN: Prospective and cross-over study. METHODS: Thirty COPD patients were randomly assigned to either home-based, high-frequency neuromuscular electrical stimulation or sham stimulation for six weeks. The training intensity was adjusted according to each subject's tolerance. Fat-free mass, isometric strength, six-minute walking distance and time to exercise intolerance (Tlim) were assessed. RESULTS: Thirteen (46.4%) patients responded to high-frequency neuromuscular electrical stimulation; that is, they had a post/pre Delta Tlim >10% after stimulation (unimproved after sham stimulation). Responders had a higher baseline fat-free mass and six-minute walking distance than their seventeen (53.6%) non-responding counterparts. Responders trained at higher stimulation intensities; their mean amplitude of stimulation during training was significantly related to their fat-free mass (r = 0.65; p<0.01). Logistic regression revealed that fat-free mass was the single independent predictor of Tlim improvement (odds ratio [95% CI] = 1.15 [1.04-1.26]; p<0.05). CONCLUSIONS: We conclude that high-frequency neuromuscular electrical stimulation improved the exercise capacity of COPD patients with better-preserved fat-free mass because they tolerated higher training stimulus levels. These data suggest that early training with high-frequency neuromuscular electrical stimulation before tissue wasting begins might enhance exercise tolerance in patients with less advanced COPD. PMID- 21552663 TI - Nutritional and metabolic status of HIV-positive patients with lipodystrophy during one year of follow-up. AB - OBJECTIVES: The aim of this prospective study was to compare changes in lipid metabolism and nutritional status after either 6 and 12 months of follow-up in subjects with lipodystrophy syndrome after traditional lifestyle therapy with or without fibric acid analogue intervention (bezafibrate and clofibrate). METHODS: Food intake, alterations in body composition and metabolic abnormalities were assessed in subjects with lipodystrophy syndrome at the beginning of the study. The nutritional status and metabolic alterations of the subjects were monitored, and the subjects received nutritional counseling each time they were seen. The subjects were monitored either two times over a period no longer than six months (Group A; n = 18) or three times over a period of at least 12 months (Group B; n = 35). All of the subjects underwent nutrition counseling that was based on behavior modification. The fibric acid analogue was only given to patients with serum triglyceride levels above 400 mg/dL. RESULTS: After six months of follow up, Group A showed no alterations in the experimental parameters. After twelve months, there was a decrease in serum triglyceride levels (410.4 +/- 235.5 vs. 307.7 +/- 150.5 mg/dL, p < 0.05) and an increase in both HDLc levels (37.9 +/- 36.6 vs. 44.9 +/- 27.9 mg/dL, p,0.05) and lean mass (79.9 +/- 7.8 vs. 80.3 +/- 9.9 %, p < 0.05) in Group B. CONCLUSION: After one year of follow-up (three sessions of nutritional and medical counseling), the metabolic parameters of the subjects with lipodystrophy improved after traditional lifestyle therapy with or without fibric acid analogue intervention. PMID- 21552664 TI - Wilson's disease in southern Brazil: a 40-year follow-up study. AB - BACKGROUND: Long-term data on the clinical follow-up and the treatment effectiveness of Wilson's disease are limited because of the low disease frequency. This study evaluated a retrospective cohort of Wilson's disease patients from southern Brazil during a 40-year follow-up period. METHODS: Thirty six Wilson's disease patients, diagnosed from 1971 to 2010, were retrospectively evaluated according to their clinical presentation, epidemiological and social features, response to therapy and outcome. RESULTS: Examining the patients' continental origins showed that 74.5% had a European ancestor. The mean age at the initial symptom presentation was 23.3 +/- 9.3 years, with a delay of 27.5 +/- 41.9 months until definitive diagnosis. At presentation, hepatic symptoms were predominant (38.9%), followed by mixed symptoms (hepatic and neuropsychiatric) (30.6%) and neuropsychiatric symptoms (25%). Kayser-Fleischer rings were identified in 55.6% of patients, with a higher frequency among those patients with neuropsychiatric symptoms (77.8%). Eighteen patients developed neuropsychiatric features, most commonly cerebellar syndrome. Neuroradiological imaging abnormalities were observed in 72.2% of these patients. Chronic liver disease was detected in 68% of the patients with hepatic symptoms. 94.2% of all the patients were treated with D-penicillamine for a mean time of 129.9 +/- 108.3 months. Other treatments included zinc salts, combined therapy and liver transplantation. After initiating therapy, 78.8% of the patients had a stable or improved outcome, and the overall survival rate was 90.1%. CONCLUSION: This study is the first retrospective description of a population of Wilson's disease patients of mainly European continental origin who live in southern Brazil. Wilson's disease is treatable if correctly diagnosed, and an adequate quality of life can be achieved, resulting in a long overall survival. PMID- 21552665 TI - What necessitates the conversion to open cholecystectomy? A retrospective analysis of 5164 consecutive laparoscopic operations. AB - OBJECTIVE: Laparoscopic cholecystectomy (LC) has become the gold standard for the surgical treatment of gallbladder disease, but conversion to open cholecystectomy is still inevitable in certain cases. Knowledge of the rate and impact of the underlying reasons for conversion could help surgeons during preoperative assessment and improve the informed consent of patients. We decided to review the rate and causes of conversion from laparoscopic to open cholecystectomy. METHOD: This study included all laparoscopic cholecystectomies due to gallstone disease undertaken from May 1999 to June 2010. The exclusion criteria were malignancy and/or existence of gallbladder polyps detected pathologically. Patient demographics, indications for cholecystectomy, concomitant diseases, and histories of previous abdominal surgery were collected. The rate of conversion to open cholecystectomy, the underlying reasons for conversion, and postoperative complications were also analyzed. RESULTS: Of 5382 patients for whom LC was attempted, 5164 were included this study. The overall rate of conversion to open cholecystectomy was 3.16% (163 patients). There were 84 male and 79 female patients; the mean age was 52.04 years (range: 26-85). The conversion rates in male and female patients were 5.6% and 2.2%, respectively (p < 0.001). The most common reasons for conversion were severe adhesions caused by tissue inflammation (97 patients) and fibrosis of Calot's triangle (12 patients). The overall postoperative morbidity rate was found to be 16.3% in patients who were converted to open surgery. CONCLUSION: Male gender was found to be the only statistically significant risk factor for conversion in our series. LC can be safely performed with a conversion rate of less than 5% in all patient groups. PMID- 21552666 TI - Leakage tests reduce the frequency of biliary fistulas following hydatid liver cyst surgery. AB - BACKGROUND AND AIM: Biliary fistulas are the most common morbidity (8.2-26%) following hydatid liver surgery. The aim of our study was to reduce the incidence of postoperative biliary fistulas after the suturing of cystobiliary communications by applying a bile leakage test. PATIENTS AND METHODS: A total of 133 hydatid liver cysts from 93 patients were divided into two groups, according to whether the test was performed. Tests were performed on 56 cysts from 34 patients, and the remaining 77 cysts from 59 patients were treated without the test. In both groups, all visible biliary orifices in the cysts were suture ligated, and drains were placed in all cysts. The visibility of the biliary orifices and postoperative biliary drainage through the drains were recorded. Patients in both groups were also compared with respect to the number of days living with the drains, the length of the hospital stay, and secondary interventions related to biliary complications. RESULTS: Biliary orifices were more visible in the tested cysts (13% vs. 48%; P <0.001). Fewer biliary complications occurred in the tested patients (8.8% vs. 27.7%, P = 0.033). The mean drain removal time (4.1 +/- 3.3 days vs. 6.8 +/- 8.9 days, P < 0.05) and the length of the hospital stay (6.7 +/- 2.7 days vs. 9.7 +/- 6.3 days, P,0.01) were shorter for the tested patients. None of the patients in the test group required postoperative Endoscopic retrograde cholangiopancreaticography (ERCP) or nasobiliary drainage (0.0% vs. 8.4%, P = 0.09). There were no long-term biliary complications for either group after three years of follow-up. CONCLUSIONS: Identification of biliary orifices with a bile leakage test and the suturing of cystobiliary communications significantly reduced postoperative biliary complications following hydatid liver surgery. PMID- 21552667 TI - Respiratory outcomes and atopy in school-age children who were preterm at birth, with and without bronchopulmonary dysplasia. AB - OBJECTIVE: To assess pulmonary function and the prevalence of atopy in school-age children who were very low birth weight as infants and to compare those who had bronchopulmonary dysplasia to those who did not. METHOD: We studied 85 (39 male and 46 female) at a mean age of 84 (range, 62 to 107) months who were very low birth weight infants. Bronchopulmonary dysplasia was defined as oxygen dependency at 36 weeks gestational age. We excluded 8 patients (4 for cerebral palsy and 4 for no collaboration). Detailed perinatal and clinical data were collected. Lung function was evaluated using conventional spirometry. Atopy (assessed by the allergy skin-prick test) was considered when at least one positive skin test occurred in a panel of the most common environmental allergens in the local region. Comparisons between the bronchopulmonary dysplasia and no bronchopulmonary dysplasia groups were performed using the Mann-Whitney, x2 and Fisher's exact tests. RESULTS: We compared the bronchopulmonary dysplasia (n = 13) and no bronchopulmonary dysplasia (n = 64) groups. Atopy was observed in 4 (30.8%) of the bronchopulmonary dysplasia patients and in 17 (26.6%) of the no bronchopulmonary dysplasia patients (p = 0.742). Two (15.4%) patients with bronchopulmonary dysplasia had a family history of atopy vs. 17 (26.6%) in the no bronchopulmonary dysplasia group (p = 0.5). Lung function tests showed airway obstruction in 2 (15.4%) of the bronchopulmonary dysplasia patients and in 10 (15.6%) of the no bronchopulmonary dysplasia patients (p = 1.0). Four (33.3%) of the bronchopulmonary dysplasia patients had small airway obstruction vs. 14 (22.2%) of the no bronchopulmonary dysplasia patients (p = 0.466). CONCLUSION: Our data showed no significant differences in lung function between bronchopulmonary dysplasia and no bronchopulmonary dysplasia patients at school age and no evidence of an association between atopy and bronchopulmonary dysplasia. PMID- 21552668 TI - Parathyroidectomy after kidney transplantation: short-and long-term impact on renal function. AB - INTRODUCTION: Kidney transplantation corrects endocrine imbalances. Nevertheless, these early favorable events are not always followed by rapid normalization of parathyroid hormone secretion. A possible deleterious effect of parathyroidectomy on kidney transplant function has been reported. This study aimed to compare acute and longterm renal changes after total parathyroidectomy with those occurring after general surgery. MATERIALS AND METHODS: This was a retrospective case-controlled study. Nineteen patients with persistent hyperparathyroidism underwent parathyroidectomy due to hypercalcemia. The control group included 19 patients undergoing various general and urological operations. RESULTS: In the parathyroidectomy group, a significant increase in serum creatinine from 1.58 to 2.29 mg/dl (P < 0.05) was noted within the first 5 days after parathyroidectomy. In the control group, a statistically insignificant increase in serum creatinine from 1.49 to 1.65 mg/dl occurred over the same time period. The long-term mean serum creatinine level was not statistically different from baseline either in the parathyroidectomy group (final follow-up creatinine = 1.91 mg/dL) or in the non-parathyroidectomy group (final follow-up creatinine = 1.72 mg/dL). CONCLUSION: Although renal function deteriorates in the acute period following parathyroidectomy, long-term stabilization occurs, with renal function similar to both preoperative function and to a control group of kidney-transplanted patients who underwent other general surgical operations by the final follow up. PMID- 21552669 TI - B-type natriuretic peptide as a predictor of anterior wall location in patients with non-ST-elevation myocardial infarction. AB - OBJECTIVE: Involvement of the left ventricular anterior wall in ST-elevation myocardial infarction has a worse prognosis compared with other regions. In non ST-elevation myocardial infarction, noninvasive methods of locating the ischemic myocardial territory have been limited. The objective of this report is therefore to determine what factors are predictive of the anterior location of the ischemic myocardial territory. METHODS: This study included 170 patients with non-ST elevation myocardial infarction. Clinical, echocardiographic, and laboratory characteristics, including B-type natriuretic peptide measured within 24 hours of hospitalization, and coronary angiographic features were analyzed. RESULTS: The mean age was 64.5 +/- 12.3 years, and 112 of the patients were male (66%). The median follow-up was 23 months. The territory involved, as determined from the angiogram, was divided into anterior [n = 80 (47%)] regions and inferior and lateral [n = 90 (53%)] regions. Multivariate analysis showed that B-type natriuretic peptide was the only independent predictor of an anterior wall infarct [OR = 3.70 (95% CI: 1.61 - 8.53); P = 0.002] in non-STelevation myocardial infarction patients. Multivariate analysis also showed that B-type natriuretic peptide was an independent predictor of in-hospital cardiac events during index admission [OR = 5.05 (95% CI: 1.49 - 17.12); P = 0.009] and of cardiac events occurring during follow-up [HR = 1.79 (95% CI: 1.05 - 3.04); P = 0.032]. CONCLUSIONS: B-type natriuretic peptide was the only factor independently associated with anterior wall involvement in non-ST-elevation myocardial infarction, and the peptide levels upon admission predicted in-hospital and subsequent cardiac events. PMID- 21552670 TI - Breast ultrasound diagnostic performance and outcomes for mass lesions using Breast Imaging Reporting and Data System category 0 mammogram. AB - PURPOSE: To evaluate the outcomes and diagnostic performance of ultrasonography after a Breast Imaging Reporting and Data System (Bi-RADS) category 0 mammogram. MATERIAL AND METHODS: This retrospective study reviewed 4,384 consecutive patients who underwent a screening mammography from January 2005 to July 2006; 391 of the 4,384 exams were classified as Bi-RADS category 0. After exclusions, 241 patients received subsequent sonogram. Ultrasonography was considered diagnostic when the Bi-RADS category was changed to 2, 4, or 5, and it was considered indeterminate (Bi-RADS 3) when the results indicated that the patients should return for a mammographic follow-up. The outcomes of these patients were assessed to evaluate the diagnostic performance of ultrasonography. RESULTS: The mean age of the patients was 53.3 years (ranging from 35 to 81). Of the 241 patients, ultrasonography was considered diagnostic in 146 (60.6%) patients and indeterminate in 95 (39.4%) patients. In the diagnostic group, 111 out of 146 patients (70.2%) had a sonogram result of Bi-RADS category 2 after a 2-year follow-up without evidence of malignancy. Furthermore, 35 out of 146 patients (29.8%) had a suspicious sonogram with a result of Bi-RADS category 4. After a tissue sampling procedure, 10 patients were confirmed to have breast cancer, and 25 had benign histopathological features without any evidence of malignancy after a 2-year follow-up. The sensitivity of ultrasonography was 100%, specificity was 89.1%, and overall accuracy was 89.6%. CONCLUSIONS: Based on the degree of resolution and its diagnostic performance, ultrasonography was determined to be an excellent method for the subsequent evaluation of Bi-RADS 0 mammograms. PMID- 21552671 TI - An analysis of 214 cases of rib fractures. AB - INTRODUCTION: Rib fractures are the most common type of injury associated with trauma to the thorax. In this study, we investigated whether morbidity and mortality rates increased in correlation with the number of fractured ribs. MATERIALS AND METHODS: Data from 214 patients with rib fractures who applied or were referred to our clinic between January 2007 and December 2008 were retrospectively evaluated. The patients were allocated into three groups according to the number of fractures: 1) patients with an isolated rib fracture (RF1) (n = 50, 23.4%), 2) patients with two rib fractures (RF2) (n = 53, 24.8%), and 3) patients with more than two rib fractures (RF3) (n = 111, 51.9%). The patients were evaluated and compared according to the number of rib fractures, mean age, associated chest injuries (hemothorax, pneumothorax, and/or pulmonary contusion), and co-existing injuries to other systems. FINDINGS: The mean age of the patients was 51.5 years. The distribution of associated chest injuries was 30% in group RF1, 24.6% in group RF2, and 75.6% in group RF3 (p<0.05). Co existing injuries to other systems were 24% in group RF1, 23.2% in group RF2, and 52.6% in group RF3 (p<0.05). Two patients (4%) in group RF1, 2 patients (3.8%) in group RF2, and 5 patients (4.5%) in group RF3 (total n = 9; 4.2%) died. CONCLUSION: Patients with any number of rib fractures should be carefully screened for co-existing injuries in other body systems and hospitalized to receive proper treatment. PMID- 21552672 TI - Cardiovascular and autonomic responses after exercise sessions with different intensities and durations. AB - BACKGROUND: Several studies have reported the phenomenon of post-exercise hypotension. However, the factors that cause this drop in blood pressure after a single exercise session are still unknown. OBJECTIVE: To investigate the effects of aerobic exercise on the acute blood pressure response and to investigate the indicators of autonomic activity after exercise. METHODS: Ten male subjects (aged 25 +/- 1 years) underwent four experimental exercise sessions and a control session on a cycle ergometer. The blood pressure and heart rate variability of each subject were measured at rest and at 60 min after the end of the sessions. RESULTS: Post-exercise hypotension was not observed in any experimental sessions (P > 0.05). The index of parasympathetic neural activity, the RMSSD, only remained lower than that during the pre-exercise session after the high-intensity session (Delta = -19 +/- 3.7 for 15-20 min post-exercise). In addition, this value varied significantly (P < 0.05) between the high- and low-intensity sessions (Delta = -30.7 +/- 4.0 for the high intensity session, and Delta = -9.9 +/- 2.5 for the low intensity session). CONCLUSION: The present study did not find a reduction in blood pressure after exercise in normotensive, physically active young adults. However, the measurements of the indicators of autonomic neural activity revealed that in exercise of greater intensity the parasympathetic recovery tends to be slower and that sympathetic withdrawal can apparently compensate for this delay in recovery. PMID- 21552673 TI - Cardiovascular responses to passive static flexibility exercises are influenced by the stretched muscle mass and the Valsalva maneuver. AB - BACKGROUND: The respiratory pattern is often modified or even blocked during flexibility exercises, but little is known about the cardiovascular response to concomitant stretching and the Valsalva maneuver (VM) in healthy subjects. OBJECTIVES: This study evaluated the heart rate (HR), systolic blood pressure (SBP), and rate-pressure product (RPP) during and after large and small muscle group flexibility exercises performed simultaneously with the VM. METHODS: Asymptomatic volunteers (N = 22) with the following characteristics were recruited: age, 22 +/- 3 years; weight, 73 +/- 6 kg; height, 175 +/- 5 cm; HR at rest, 66 +/- 9 BPM; and SBP at rest, 113 +/- 10 mmHg. They performed two exercises: four sets of passive static stretching for 30 s of the dorsi-flexion (DF) of the gastrocnemius and the hip flexion (HF) of the ischio-tibialis. The exercises were performed with (V+) or without (V-) the VM in a counterbalanced order. The SBP and HR were measured, and the RPP was calculated before the exercise session, at the end of each set, and during a 30-min post-exercise recovery period. RESULTS: The within-group comparisons showed that only the SBP and RPP increased throughout the sets (p < 0.05), but no post-exercise hypotension was detected. The between-group comparisons showed that greater SBP increases were related to the VM and to a larger stretched muscle mass. Differences for a given set were identified for the HR (the HFV+ and HFV- values were higher than the DFV+ and DFV- values by approximately 12 BPM), SBP (the HFV+ value was higher than the DFV+ and DFV- values by approximately 12 to 15 mmHg), and RPP (the HFV+ value was higher than the HFV- value by approximately 2000 mmHGxBPM, and the HFV+ value was higher than the DFV+ and DFV- values by approximately 4000 mmHGxBPM). CONCLUSION: Both the stretched muscle mass and the VM influence acute cardiovascular responses to multiple-set passive stretching exercise sessions. PMID- 21552674 TI - Angiogenesis in the progression of cutaneous squamous cell carcinoma: an immunohistochemical study of endothelial markers. AB - OBJECTIVE: To demonstrate the role of angiogenesis in the progression of cutaneous squamous cell carcinoma. INTRODUCTION: Angiogenesis is a pivotal phenomenon in carcinogenesis. Its time course in cutaneous squamous cell carcinoma has not yet been fully established. METHODS: We studied the vascular bed in 29 solar keratoses, 30 superficially invasive squamous cell carcinomas and 30 invasive squamous cell carcinomas. The Chalkley method was used to quantify the microvascular area by comparing panendothelial (CD34) with neoangiogenesis (CD105) immunohistochemical markers. The vascular bed from non-neoplastic adjacent skin was evaluated in 8 solar keratoses, 10 superficially invasive squamous cell carcinomas and 10 invasive squamous cell carcinomas. RESULTS: The microvascular area in CD105-stained specimens significantly increased in parallel with cutaneous squamous cell carcinoma progression. However, no differences between groups were found in CD34 sections. Solar keratosis, superficially invasive squamous cell carcinoma and invasive squamous cell carcinoma samples showed significant increases in microvascular area for both CD34- and CD105 stained specimens compared with the respective adjacent skin. DISCUSSION: The angiogenic switch occurs early in the development of cutaneous squamous cell carcinoma, and the rate of neovascularization is parallel to tumor progression. In contrast to panendothelial markers, CD105 use allows a dynamic evaluation of tumor angiogenesis. CONCLUSION: This study demonstrated the dependence of skin carcinogenesis on angiogenesis. PMID- 21552675 TI - Hypertonic saline and reduced peroxynitrite formation in experimental pancreatitis. AB - OBJECTIVES: In this study, we tested the hypothesis that hypertonic saline exerts anti-inflammatory effects by modulating hepatic oxidative stress in pancreatitis. INTRODUCTION: The incidence of hepatic injury is related to severe pancreatitis, and hypertonic saline reduces pancreatic injury and mortality in pancreatitis. METHODS: Wistar rats were divided into four groups: control (not subjected to treatment), untreated pancreatitis (NT, pancreatitis induced by a retrograde transduodenal infusion of 2.5% sodium taurocholate into the pancreatic duct with no further treatment administered), pancreatitis with normal saline (NS, pancreatitis induced as described above and followed by resuscitation with 0.9% NaCl), and pancreatitis with hypertonic saline (HS, pancreatitis induced as described above and followed by resuscitation with 7.5% NaCl). At 4, 12, and 24 h after pancreatitis induction, liver levels of inducible nitric oxide synthase (iNOS), heat-shock protein 70, nitrotyrosine (formation of peroxynitrite), nitrite/nitrate production, lipid peroxidation, and alanine aminotransferase (ALT) release were determined. RESULTS: Twelve hours after pancreatitis induction, animals in the HS group presented significantly lower iNOS expression (P<0.01 vs. NS), nitrite/nitrate levels (P<0.01 vs. NS), lipid peroxidation (P<0.05 vs. NT), and ALT release (P<0.01 vs. NS). Twenty-four hours after pancreatitis induction, nitrotyrosine expression was significantly lower in the HS group than in the NS group (P<0.05). DISCUSSION: The protective effect of hypertonic saline was related to the establishment of a superoxide-NO balance that was unfavorable to nitrotyrosine formation. CONCLUSIONS: Hypertonic saline decreases hepatic oxidative stress and thereby minimizes liver damage in pancreatitis. PMID- 21552676 TI - Effects of spironolactone in spontaneously hypertensive adult rats subjected to high salt intake. AB - OBJECTIVE: To evaluate the effect of spironolactone on ventricular stiffness in spontaneously hypertensive adult rats subjected to high salt intake. INTRODUCTION: High salt intake leads to cardiac hypertrophy, collagen accumulation and diastolic dysfunction. These effects are partially mediated by cardiac activation of the renin-angiotensin-aldosterone system. METHODS: Male spontaneously hypertensive rats (SHRs, 32 weeks) received drinking water (SHR), a 1% NaCl solution (SHR-Salt), or a 1% NaCl solution with a daily subcutaneous injection of spironolactone (80 mg.kg-1) (SHRSalt- S). Age-matched normotensive Wistar rats were used as a control. Eight weeks later, the animals were anesthetized and catheterized to evaluate left ventricular and arterial blood pressure. After cardiac arrest, a double-lumen catheter was inserted into the left ventricle through the aorta to obtain in situ left ventricular pressure volume curves. RESULTS: The blood pressures of all the SHR groups were similar to each other but were different from the normotensive controls (Wistar = 109 +/- 2; SHR = 118 +/- 2; SHR-Salt = 117 +/- 2; SHR-Salt-S = 116 +/- 2 mmHg; P < 0.05). The cardiac hypertrophy observed in the SHR was enhanced by salt overload and abated by spironolactone (Wistar = 2.90 +/- 0.06; SHR = 3.44 +/- 0.07; SHR-Salt = 3.68 +/- 0.07; SHR-Salt-S = 3.46 +/- 0.05 mg/g; P < 0.05). Myocardial relaxation, as evaluated by left ventricular dP/dt, was impaired by salt overload and improved by spironolactone (Wistar = -3698 +/- 92; SHR = -3729 +/- 125; SHR-Salt = -3342 +/- 80; SHR-Salt-S = -3647 +/- 104 mmHg/s; P < 0.05). Ventricular stiffness was not altered by salt overload, but spironolactone treatment reduced the ventricular stiffness to levels observed in the normotensive controls (Wistar = 1.40 +/- 0.04; SHR = 1.60 +/- 0.05; SHR-Salt = 1.67 +/- 0.12; SHR-Salt- S = 1.45 +/- 0.03 mmHg/ml; P < 0.05). CONCLUSION: Spironolactone reduces left ventricular hypertrophy secondary to high salt intake and ventricular stiffness in adult SHRs. PMID- 21552677 TI - An experimental model to study the effects of a senna extract on the blood constituent labeling and biodistribution of a radiopharmaceutical in rats. AB - Cassia angustifolia Vahl (senna) is a natural product that contains sennosides, which are active components that affect the intestinal tract and induce diarrhea. Authors have shown that senna produces DNA (deoxyribonucleic acid) lesions in Escherichia coli cultures and can act as an antifungal agent. Natural drugs can alter the labeling of blood constituents with technetium-99m (99mTc) and can affect the biodistribution of radiopharmaceuticals. In this work, we have evaluated the influence of a senna extract on the radiolabeling of blood constituents and on the biodistribution of the radiopharmaceutical sodium pertechnetate (Na99mTcO4)in Wistar rats. Twelve animals were treated with senna extract for 7 days. Blood samples were withdrawn from the animals and the radiolabeling procedure was carried out. The senna extract did not modify the radiolabeling of the blood constituents. A biodistributional assay was performed by administering Na99mTcO4 and determining its activity in different organs and in blood. The senna extract altered the biodistribution of Na99mTcO4 in the thyroid, liver, pancreas, lungs and blood. These results are associated with properties of the chemical substances present in the aqueous senna extract. Although these assays were performed in animals, our findings suggest that caution should be exercised when nuclear medicine examinations using Na99mTcO4 are conducted in patients who are using senna extract. PMID- 21552678 TI - Periosteum as a source of mesenchymal stem cells: the effects of TGF-beta3 on chondrogenesis. AB - INTRODUCTION: Numerous experimental efforts have been undertaken to induce the healing of lesions within articular cartilage by re-establishing competent repair tissue. Adult mesenchymal stem cells have attracted attention as a source of cells for cartilage tissue engineering. The purpose of this study was to investigate chondrogenesis employing periosteal mesenchymal cells. METHODS: Periosteum was harvested from patients who underwent orthopedic surgeries. Mesenchymal stem cells were characterized through flow cytometry using specific antibodies. The stem cells were divided into four groups. Two groups were stimulated with transforming growth factor beta3 (TGF-beta3), of which one group was cultivated in a monolayer culture and the other was cultured in a micromass culture. The remaining two groups were cultivated in monolayer or micromass cultures in the absence of TGF-beta3. Cell differentiation was verified through quantitative reverse transcription-polymerase chain reaction (RT-PCR) and using western blot analysis. RESULT: In the groups cultured without TGF-beta3, only the cells maintained in the micromass culture expressed type II collagen. Both the monolayer and the micromass groups that were stimulated with TGF-beta3 expressed type II collagen, which was observed in both quantitative RT-PCR and western blot analysis. The expression of type II collagen was significantly greater in the micromass system than in the monolayer system. CONCLUSION: The results of this study demonstrate that the interactions between the cells in the micromass culture system can regulate the proliferation and differentiation of periosteal mesenchymal cells during chondrogenesis and that this effect is enhanced by TGF beta3. PMID- 21552679 TI - Atypical mole syndrome and dysplastic nevi: identification of populations at risk for developing melanoma - review article. AB - Atypical Mole Syndrome is the most important phenotypic risk factor for developing cutaneous melanoma, a malignancy that accounts for about 80% of deaths from skin cancer. Because the diagnosis of melanoma at an early stage is of great prognostic relevance, the identification of Atypical Mole Syndrome carriers is essential, as well as the creation of recommended preventative measures that must be taken by these patients. PMID- 21552680 TI - Surgically-challenging chondrosarcomas of the chest wall: five-year follow-up at a single institution. PMID- 21552681 TI - Attention and memory of medical residents after a night on call: a cross sectional study. PMID- 21552682 TI - Central mechanisms in burning mouth syndrome involving the olfactory nerve: a preliminary study. PMID- 21552683 TI - Alopecia areata incognita. PMID- 21552684 TI - Psychological treatment for sleepwalking: two case reports. PMID- 21552686 TI - Editor's Note. PMID- 21552685 TI - Thiocolchicoside-induced liver injury. PMID- 21552687 TI - Taxa as types: Buffon, Cuvier and Lamarck. AB - From a Darwinian point of view, taxonomic groups are understood as historical entities that arise at an evolutionary moment and that can always disappear. But these groups were also understood by many naturalists as natural kinds; in other words, as permanent, ahistorical types. I will explore some of the forms that this typological thought took, showing that this typological perspective neither depends on theological beliefs, nor obeys the adoption of an ontology that might contradict natural science. Thus I shall analyze Buffon's understanding of species and the ways in which Cuvier and Lamarck understood the higher taxonomic orders. PMID- 21552688 TI - The tropics and the rise of the British Empire: Mungo Park's perspective on Africa in the late eighteenth century. AB - The young Scottish physician Mungo Park, aged 23, arrived in Africa in 1795 with a mission as specific as it was complex in those bygone days, namely to travel the entire length of the River Niger. In 1799, the story of this journey was published in a book that sold 1500 copies in the first month alone, with two further editions published that same year, as well as the translation of the work into French and German the following year. In this article, the narrative of Mungo Park is examined by taking due consideration of the relationship between the tropics, science and travel in the early days of British expansionism into the heart of Africa. PMID- 21552689 TI - John Banister: an Elizabethan surgeon in Brazil. AB - In Brazil's sixteenth-century history, very few references are made to health professionals. On the expedition of Edward Fenton, dispatched by the English Crown in 1582 to set up a trading post in Asia, was the famous barber-surgeon and physician John Banister. The naval squadron, diverted from its original route to repeat the feats of Sir Francis Drake, stopped over in Africa, crossed the Atlantic and anchored off the Santa Catarina coast in Brazil. In these waters, the expedition degenerated into piracy and returned unsuccessful to Europe. John Banister is considered the person who liberated English anatomy from mediaeval slavery, shedding upon it the light of the Renaissance. It was the first time that anyone of this importance in the area of health had visited these latitudes. PMID- 21552690 TI - [Fernand Braudel and the geo-history of civilizations]. AB - The article discusses the valuable role of geography in the study of civilizations entitled Grammaire des civilisations (A history of civilizations), by French historian Fernand Braudel. It also focuses on the epistemological role of the concept of geo-history in Braudel's thought. The article's underlying assumption is that geography has been crucial to comprehending history over large spans of time. PMID- 21552691 TI - [Brazilian geography congresses from 1909 to 1944]. AB - This analysis of the Brazilian geography congresses sponsored by the Geography Society of Rio de Janeiro between 1909 and 1944 identifies commonalities as well as differences over the years. Given how these scientific events focused on both the state of the art within the field as well as on its overall development, such an analysis serves as a good thermometer for measuring the social, economic, and political changes underway in Brazil. PMID- 21552692 TI - Popular strategies for identification and treatment of insanity in the first half of the twentieth century: an analysis of medical charts from the Uberaba Spiritist Asylum. AB - Through analysis of the medical charts from an institution for treatment of the insane run by an association of Kardecist spiritists, it is possible to identify the various perceptions and strategies for treatment and social control of insanity developed by different sectors of the Brazilian population in the first half of the twentieth century in the Brazilian countryside. The multidimensional aspect of the experience of insanity is stressed, as it is a sociocultural event capable of different analyses and interpretations by heterogeneous groups of social actors, who interpret it based on their own systems of meaning and understanding. PMID- 21552693 TI - [How to find a place in the world: exploring people's experiences recovering from serious mental disorders]. AB - This historical, conceptual, and cultural review of the concept of recovery within the realm of mental health discusses the last decade's research into the subjective experiences of people in the process of recovering from serious mental disorders and analyzes the differences between the notions of rehabilitation, integration, and recovery. After presenting a historical introduction, the article describes recovery experiences from three angles: identity and control over one's own life; personal and community relationships; and material resources, work, and other social activities. The concept of recovery entails new challenges and tensions that must be taken into account in the reform of mental health systems in Europe and the Americas. PMID- 21552694 TI - [The making of madness: counterculture and anti-psychiatry]. AB - The 1950s and especially the 1960s saw constant revisions of social values and customs, with young people's movements playing a major role, above all the so called counter-culture. The powers-that-be categorized the behavior and attitudes of the movement's followers as constituting madness. This making of madness gave rise to a stream of thought known as anti-psychiatry, which calls into question the very essence of psychiatry. The present article criticizes the psychiatric models of that era and draws links between counter-culture movements and anti psychiatry. PMID- 21552695 TI - [A critical analysis of research guidelines in Chinese medicine]. AB - The acculturation of Chinese medicine by the West since the 1970s has raised questions about the efficacy, validity, and potential of this form of medicine. Researchers in the field have agreed that studies on Chinese medicine present a methodological challenge. Research conducted in recent decades has focused basically on statistical clinical trials. This article offers a critical analysis of the problems encountered when applying to Chinese medicine the scientific methods common to biomedicine and also suggests new directions for such research guidelines. Relying primarily on the method of text analysis, the issue is approached by applying theoretical references from the social sciences to health. PMID- 21552696 TI - [Sociocultural aspects of vaccination in an indigenous region]. AB - The article analyzes interactions between the Baniwa, an indigenous group from the Alto Rio Negro region, and the multi-disciplinary healthcare teams that conduct vaccination there. Approaching from the perspectives of the anthropology of disease, studies of Rio Negro ethnology, and the theory of social representations, the study endeavors to comprehend indigenous interpretations of vaccination and the diseases these seek to prevent. Results show that biomedical ideas about vaccines are re-interpreted through Baniwa cosmology. It is concluded that the vigor of Baniwa thought encourages these indigenes to interpret biomedical action in accord with cultural features and that the clash between Baniwa outlooks and those of healthcare providers has negative repercussions on the vaccination process. PMID- 21552697 TI - [The Indian in Brazilian photography: incursions into image and medium]. AB - The article explores contradictions and convergences between a medium (photography) and the image of the Brazilian Indian from the perspective of the history of Brazilian photography. During the first of three distinct moments, the image of the Indian was of someone exotic, in contradiction with the modern meaning of photography under the Second Empire. During the second moment, in the first fifty years of the twentieth century, the boundaries between ethnography and Brazil as a nation were blurred, as exemplified by the Rondon Commission/Indian Protection Bureau's Research Section (Servico de Protecao ao Indio) and Brazil's modern photojournalism, as found in the magazine Cruzeiro. During the third moment, the expressions of an ethno-poetry present in the photographs of Claudia Andujar can be seen to blend medium and image as an ethnographic space in contemporary art. PMID- 21552698 TI - [Predictions are always deceptive: Joao Baptista de Lacerda and his white Brazil]. AB - The article presents and analyzes the talk given by scientist Joao Baptista de Lacerda at the First Universal Races Congress, held in London in 1911 and financed by England and other participating nations (France, Belgium, Italy, Persia, Turkey, Egypt, Japan, South Africa, Hungary, Russia, Haiti, Sierra Leone, and Brazil). Governmental and church authorities, professors, members of The Hague's Permanent Court of Arbitration and Second Conference, plus a representative of each invited country were in attendance. Brazil, the only Latin American nation invited, was seen as an example of the mixing of the races, and Lacerda argued that immigration policies would lead to the whitening of mestizos and the extinction of the "black race" in Brazil. The country thus occupied a unique position in the Americas, standing apart from the segregationist model of the United States and from South America's tyrannies. PMID- 21552699 TI - [The critique of a discourse: how could young people become protagonists?]. PMID- 21552700 TI - [The national question in Latin America: the rough road of comparative approaches]. PMID- 21552701 TI - [The dilemmas of an ethnography of racial classification within institutional frameworks]. PMID- 21552702 TI - [Emilio Goeldi and the Paraense Museum: in quest of an understanding of nature in the Amazon]. PMID- 21552703 TI - [Is there certainty in uncertainty?]. PMID- 21552704 TI - [Madness, Christian charity, and modernity in Arraial do Tijuco]. PMID- 21552705 TI - [Masculinity on the threshold of a new era]. PMID- 21552707 TI - Saliva and tongue coating pH before and after use of mouthwashes and relationship with parameters of halitosis. AB - OBJECTIVES: The aim of this work was to evaluate saliva and tongue coating pH in oral healthy patients with morning bad breath before and after use of different oral mouthrinses. MATERIAL AND METHODS: Saliva and tongue coating pH of 50 patients allocated in 5 groups were measured respectively by a digital pHmeter and color pH indicators, before, immediately after and 30 min after rinsing 5 different mouthrinses: cetilpiridine chloride associated with sodium chloride, triclosan, enzymatic solution, essential oil and distilled water. RESULTS: Only triclosan and essential oil increased salivary pH immediately after rising. The enzymatic solution decreased salivary and tongue coating pH immediately after rinsing. CONCLUSIONS: Salivary pH tended to be acidic while tongue coating pH tended to be alkaline, even after rising. Triclosan and essential oil mouthrinses increased salivary pH immediately after rinsing. Enzymatic solution decreased saliva and tongue coating pH immediately after rising. PMID- 21552708 TI - Flexural strength of fluorapatite-leucite and fluorapatite porcelains exposed to erosive agents in cyclic immersion. AB - OBJECTIVE: The aim of this study was to evaluate the flexural strength of two porcelain materials (IPS d.SIGN and IPS e.max Ceram) exposed to erosive agents. MATERIAL AND METHODS: One hundred and twenty bar-shaped specimens were made from each of fluorapatite-leucite porcelain (IPS d.SIGN) and fluorapatite porcelain (IPS e.max Ceram) and divided into 8 groups of 15 specimens each. Six groups were alternately immersed in the following storage agents for 30 min: deionized water (control), citrate buffer solution, pineapple juice, green mango juice, cola soft drink and 4% acetic acid. Then, they were immersed for 5 min in deionized water at 37oC. Seven cycles were completed, totalizing 245 min. A 7th group was continuously immersed in 4% acetic acid at 80oC for 16 h. The final, 8th, group was stored dry at 37oC for 245 min. Three-point bending tests were performed in a universal testing machine. The data were analyzed statistically by 2-way ANOVA, Tukey's HSD test and t-test at significance level of 0.05. RESULTS: The flexural strengths of all groups of each porcelain after exposure to erosive agents in cyclic immersion did not differ significantly (p>0.05). For both types of porcelain, dry storage at 37oC yielded the highest flexural strength, though without significant difference from the other groups (p>0.05). The flexural strengths of all groups of fluorapatite porcelains were significantly higher (p<0.05) than those of the fluorapatite-leucite porcelains. CONCLUSIONS: This study demonstrated that the erosive agents evaluated did not affect the flexural strength of the tested dental porcelains. PMID- 21552709 TI - Effect of green propolis addition to physical mechanical properties of glass ionomer cements. AB - OBJECTIVE: This study investigated the mechanical properties of glass ionomer cements (GICs) combined with propolis as a natural antimicrobial substance. MATERIAL AND METHODS: Typified green propolis, as an ethanolic extract (EEP) or in the lyophilized form (powder), was incorporated to specimens of Ketac Fil Plus, ChemFlex and Ketac Molar Easymix GICs. For each test, 8 specimens of each material were prepared. For water sorption and solubility tests, specimens were subjected to dehydration, hydration and redehydration cycles until a constant mass was obtained for each step. Measurements were recorded using a digital balance of 10-4 g precision. For the diametral tensile strength test, specimens were tested in a universal test machine at 0.5 mm/min crosshead speed after 24 h storage in deionized water. Data were evaluated by one-way ANOVA and Tukey's tests (p<0.05). RESULTS: The addition of propolis to GIC clearly increased water sorption compared to pure material. Solubility was material-dependent and was not clearly evident. For the diametral tensile strength test, association with propolis altered negatively only Chemflex. CONCLUSION: It may be concluded that incorporation of propolis to GICs alters some properties in a material-dependent condition. PMID- 21552710 TI - In vitro evaluation of the action of irrigating solutions associated with intracanal medications on Escherichia coli and its endotoxin in root canals. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of auxiliary chemical substances and intracanal medications on Escherichia coli and its endotoxin in root canals. MATERIAL AND METHODS: Teeth were contaminated with a suspension of E. coli for 14 days and divided into 3 groups according to the auxiliary chemical substance used: G1) 2.5% sodium hypochlorite (NaOCl); G2) 2% chlorhexidine gel (CLX); G3) pyrogen-free solution. After, these groups were subdivided according to the intracanal medication (ICM): A) Calcium hydroxide paste (Calen(r)), B) polymyxin B, and C) Calcium hydroxide paste+2% CLX gel. For the control group (G4), pyrogen-free saline solution was used without application of intracanal medication. Samples of the root canal content were collected immediately after biomechanical preparation (BMP), at 7 days after BMP, after 14 days of intracanal medication activity, and 7 days after removal of intracanal medication. The following aspects were evaluated for all collections: a) antimicrobial activity; b) quantification of endotoxin by the Limulus Amebocyte Lysate test (LAL). Results were analyzed by the Kruskal-Wallis and Dunn's tests at 5% significance level. RESULTS: The 2.5% NaOCl and CLX were able to eliminate E. coli from root canal lumen and reduced the amount of endotoxin compared to saline. CONCLUSIONS: It was concluded that 2.5% NaOCl and CLX were effective in eliminating E. coli. Only the studied intracanal medications were to reduce the amount of endotoxin present in the root canals, regardless of the irrigant used. PMID- 21552711 TI - Effect of nitric oxide inhibitor and donor substances on the inflammatory process caused by endodontic irrigants. AB - Nitric oxide (NO) has been considered a key molecule in inflammation. OBJECTIVE: The aim of this study was to evaluate the effect of treatment with L-NAME and sodium nitroprussiate, substances that inhibit and release NO, respectively, on tissue tolerance to endodontic irrigants. MATERIAL AND METHODS: The vital dye exudation method was used in a rat subcutaneous tissue model. Injections of 2% Evans blue were administered intravenously into the dorsal penial vein of 14 male rats (200-300 g). The NO inhibitor and donor substances were injected into the subcutaneous tissue in the dorsal region, forming two groups of animals: G1 was inoculated with L-NAME and G2 with sodium nitroprussiate. Both groups received injections of the test endodontic irrigants: acetic acid, 15% citric acid, 17% EDTA-T and saline (control). After 30 min, analysis of the extravasated dye was performed by light absorption spectrophotometry (620 nm). RESULTS: There was statistically significant difference (p<0.05) between groups 1 and 2 for all irrigants. L-NAME produced a less intense inflammatory reaction and nitroprussiate intensified this process. CONCLUSIONS: Independently of the administration of NO inhibitors and donors, EDTA-T produced the highest irritating potential in vital tissue among the tested irrigating solutions. PMID- 21552712 TI - Craniofacial characteristics of Caucasian and Afro-Caucasian Brazilian subjects with normal occlusion. AB - OBJECTIVE: The objective of this study was to compare the skeletal, dental and soft tissue characteristics of Caucasian and Afro-Caucasian Brazilian subjects with normal occlusion and to evaluate sexual dimorphism within the groups. MATERIAL AND METHODS: The sample comprised lateral cephalograms of untreated normal occlusion subjects, divided into 2 groups. Group 1 included 40 Caucasian subjects (20 of each sex), with a mean age of 13.02 years; group 2 included 40 Afro-Caucasian subjects (20 of each sex), with a mean age of 13.02 years. Groups 1 and 2 and males and females within each group were compared with t tests. RESULTS: Afro-Caucasian subjects presented greater maxillary protrusion, smaller upper anterior face height and lower posterior face height, larger upper posterior face height, greater maxillary and mandibular dentoalveolar protrusion as well as soft tissue protrusion than Caucasian subjects. The Afro-Caucasian female subjects had less mandibular protrusion and smaller total posterior facial height and upper posterior facial height than males. CONCLUSIONS: Brazilian Afro Caucasian subjects have greater dentoalveolar and soft tissue protrusion than Brazilian Caucasian subjects, with slight sexual dimorphism in some variables. PMID- 21552713 TI - HOXB5 expression in oral squamous cell carcinoma. AB - Human HOX genes encode transcription factors that act as master regulators of embryonic development. They are important in several processes such as cellular morphogenesis and differentiation. The HOXB5 gene in particular has been reported in some types of neoplasm, but not in oral cancer. OBJECTIVE: The present study investigated the expression of HOXB5 in oral squamous cell carcinoma (SCC) and in non-tumoral adjacent tissues, focusing on verifying its possible role as a broad tumor-associated gene and its association with histopathological and clinical (TNM) characteristics. MATERIAL AND METHODS: RT-PCR was performed to amplify HOXB5 mRNA in 15 OSCCs and adjacent non-tumoral epithelium. A possible association with TNM and histopathologic data was verified by the chi-square and post-hoc t-test. RESULTS: HOXB5 was amplified in 60% non-tumoral epithelium and in 93.3% carcinomas. No statistically significant differences were found regarding the HOXB5 mRNA expression and TNM or histological grade. CONCLUSION: HOXB5 is expressed in OSCCs and its role in cancer progression should be further investigated. PMID- 21552714 TI - Periodontal treatment during pregnancy decreases the rate of adverse pregnancy outcome: a controlled clinical trial. AB - OBJECTIVES: The aim of this study was to evaluate the effects of non-surgical treatment of periodontal disease during the second trimester of gestation on adverse pregnancy outcomes. MATERIAL AND METHODS: Pregnant patients during the 1st and 2nd trimesters at antenatal care in a Public Health Center were divided into 2 groups: NIG--"no intervention" (n=17) or IG--"intervention" (n=16). IG patients were submitted to a non-surgical periodontal treatment performed by a single periodontist consisting of scaling and root planning (SRP), professional prophylaxis (PROPH) and oral hygiene instruction (OHI). NIG received PROPH and OHI during pregnancy and were referred for treatment after delivery. Periodontal evaluation was performed by a single trained examiner, blinded to periodontal treatment, according to probing depth (PD), clinical attachment level (CAL), plaque index (PI) and sulcular bleeding index (SBI) at baseline and 35 gestational weeks-28 days post-partum. Primary adverse pregnancy outcomes were preterm birth (<37 weeks), low birth weight (<2.5 kg), late abortion (14-24 weeks) or abortion (<14 weeks). The results obtained were statistically evaluated according to OR, unpaired t test and paired t test at 5% significance level. RESULTS: No significant differences were observed between groups at baseline examination. Periodontal treatment resulted in stabilization of CAL and PI (p>0.05) at IG and worsening of all periodontal parameters at NIG (p<0.0001), except for PI. Significant differences in periodontal conditions of IG and NIG were observed at 2nd examination (p<0.001). The rate of adverse pregnancy outcomes was 47.05% in NIG and 6.25% in IG. Periodontal treatment during pregnancy was associated to a decreased risk of developing adverse pregnancy outcomes [OR=13.50; CI: 1.47-123.45; p=0.02]. CONCLUSIONS: Periodontal treatment during the second trimester of gestation contributes to decrease adverse pregnancy outcomes. PMID- 21552715 TI - Scanning electron microscopic study of Piper betle L. leaves extract effect against Streptococcus mutans ATCC 25175. AB - INTRODUCTION: Previous studies have shown that Piper betle L. leaves extract inhibits the adherence of Streptococcus mutans to glass surface, suggesting its potential role in controlling dental plaque development. OBJECTIVES: In this study, the effect of the Piper betle L. extract towards S. mutans (with/without sucrose) using scanning electron microscopy (SEM) and on partially purified cell associated glucosyltransferase activity were determined. MATERIAL AND METHODS: S. mutans were allowed to adhere to glass beads suspended in 6 different Brain Heart Infusion broths [without sucrose; with sucrose; without sucrose containing the extract (2 mg mL(-1) and 4 mg mL(-1)); with sucrose containing the extract (2 mg mL(-1) and 4 mg mL(-1))]. Positive control was 0.12% chlorhexidine. The glass beads were later processed for SEM viewing. Cell surface area and appearance and, cell population of S. mutans adhering to the glass beads were determined upon viewing using the SEM. The glucosyltransferase activity (with/without extract) was also determined. One- and two-way ANOVA were used accordingly. RESULTS: It was found that sucrose increased adherence and cell surface area of S. mutans (p<0.001). S. mutans adhering to 100 um2 glass surfaces (with/without sucrose) exhibited reduced cell surface area, fluffy extracellular appearance and cell population in the presence of the Piper betle L. leaves extract. It was also found that the extract inhibited glucosyltransferase activity and its inhibition at 2.5 mg mL(-1) corresponded to that of 0.12% chlorhexidine. At 4 mg mL(-1) of the extract, the glucosyltransferase activity was undetectable and despite that, bacterial cells still demonstrated adherence capacity. CONCLUSION: The SEM analysis confirmed the inhibitory effects of the Piper betle L. leaves extract towards cell adherence, cell growth and extracellular polysaccharide formation of S. mutans visually. In bacterial cell adherence, other factors besides glucosyltransferase are involved. PMID- 21552716 TI - In vitro dentin permeability after application of Gluma(r) desensitizer as aqueous solution or aqueous fumed silica dispersion. AB - OBJECTIVES: To assess and to compare the effects of Gluma(r) Desensitizer (GDL) with an experimental glutaraldehyde and HEMA containing fumed silica dispersion (GDG) on dentin permeability using a chemiluminous tracer penetration test. MATERIAL AND METHODS: Twenty disc-shaped dentin specimens were dissected from extracted human third molars. The dentin specimens were mounted in a split chamber device for determination of permeability under liquid pressure using a photochemical method. Ten specimens were randomly selected and allocated to the evaluation groups Gluma(r) Desensitizer as aqueous solution and glutaraldehyde/HEMA as fumed silica dispersion, respectively. Dentin disc permeability was determined at two pressure levels after removal of smear with EDTA, after albumin soaking, and after application of the desensitizing agents. Two desensitizer-treated and rinsed specimens of each group were examined by scanning electron microscopy (SEM) for surface remnants. RESULTS: Comparatively large standard deviations of the mean EDTA reference and albumin soaked samples permeability values reflected the differences of the dentin substrates. The mean chemiluminescence values of specimen treated with GDL and GDG, respectively, were significantly reduced after topical application of the desensitizing agents on albumin-soaked dentin. The effects of GDL and GDG on permeability were not significantly different. Treated specimens showed no surface remnants after rinsing. CONCLUSIONS: The experimental desensitizer gel formulation reduced dentin permeability as effectively as the original Gluma(r) Desensitizer solution. PMID- 21552717 TI - Difference in the color stability of direct and indirect resin composites. AB - Indirect resin composites are generally regarded to have better color stability than direct resin composites since they possess higher conversion degree. OBJECTIVE: The present study aimed at comparing the changes in color (DeltaE) and color coordinates (DeltaL, Deltaa and Deltab) of one direct (Estelite Sigma: 16 shades) and 2 indirect resin composites (BelleGlass NG: 16 shades; Sinfony: 26 shades) after thermocycling. MATERIAL AND METHODS: Resins were packed into a mold and light cured; post-curing was performed on indirect resins. Changes in color and color coordinates of 1-mm-thick specimens were determined after 5,000 cycles of thermocycling on a spectrophotometer. RESULTS: DeltaE values were in the range of 0.3 to 1.2 units for direct resins, and 0.3 to 1.5 units for indirect resins, which were clinically acceptable (DeltaE<3.3). Based on t-test, DeltaE values were not significantly different by the type of resins (p>0.05), while DeltaL, Deltaa and Deltab values were significantly different by the type of resins (p<0.05). For indirect resins, DeltaE values were influenced by the brand, shade group and shade designation based on three-way ANOVA (p<0.05). CONCLUSION: Direct and indirect resin composites showed similar color stability after 5,000 cycles of thermocycling; however, their changes in the color coordinates were different. PMID- 21552718 TI - Breastfeeding and non-nutritive sucking patterns related to the prevalence of anterior open bite in primary dentition. AB - OBJECTIVE: Nutritional, immunological and psychological benefits of exclusive breastfeeding for the first 6 months of life are unequivocally recognized. However, mothers should also be aware of the importance of breastfeeding for promoting adequate oral development. This study evaluated the association between breastfeeding and non-nutritive sucking patterns and the prevalence of anterior open bite in primary dentition. MATERIAL AND METHODS: Infant feeding and non nutritive sucking were investigated in a 3-6 year-old sample of 1,377 children, from Sao Paulo city, Brazil. Children were grouped according to breastfeeding duration: G1--non-breastfed, G2--shorter than 6 months, G3--interruption between 6 and 12 months, and G4--longer than 12 months. Three calibrated dentists performed clinical examinations and classified overbite into 3 categories: normal, anterior open bite and deep bite. Chi-square tests (p<0.05) with odds ratio (OR) calculation were used for intergroup comparisons. The impact of breastfeeding and non-nutritive sucking on the prevalence of anterior open bite was analyzed using binary logistic regression. RESULTS: The prevalence estimates of anterior open bite were: 31.9% (G1), 26.1% (G2), 22.1% (G3), and 6.2% (G4). G1 would have significantly more chances of having anterior open bite compared with G4; in the total sample (OR=7.1) and in the subgroup without history of non nutritive sucking (OR=9.3). Prolonging breastfeeding for 12 months was associated with a 3.7 times lower chance of having anterior open bite. In each year of persistence with non-nutritive sucking habits, the chance of developing this malocclusion increased in 2.38 times. CONCLUSIONS: Breastfeeding and non nutritive sucking durations demonstrated opposite effects on the prediction of anterior open bite. Non-breastfed children presented significantly greater chances of having anterior open bite compared with those who were breastfed for periods longer than 12 months, demonstrating the beneficial influence of breastfeeding on dental occlusion. PMID- 21552719 TI - Dental arch dimensions in the mixed dentition: a study of Brazilian children from 9 to 12 years of age. AB - OBJECTIVE: This study evaluated dental arch dimensional changes of Brazilian children. MATERIAL AND METHODS: Dental casts were taken from 66 children (29 males; 37 females) with normal occlusion selected among 1,687 students from public and private schools aged 9, 10, 11 and 12 years, according to the following criteria: Class I canine and molar relationships; well-aligned upper and lower dental arches; mixed dentition; good facial symmetry; no previous orthodontic treatment. Dental arch dimensions were taken by one examiner using the Korkhaus' compass and a digital pachymeter. ANOVA test was applied to compare the arch dimensions at the different ages and the t-test was used to compare the arch dimensions of male and female subjects. Arch forms were compared by means of chi-square tests. RESULTS: Only the maxillary anterior segment length showed a statistically significant increase from 10 to 12 years of age. Males had a significantly larger maxillary depth than females at the age range evaluated. The predominant dental arch form found was elliptical. CONCLUSIONS: In the studied age range, anterior maxillary length increased from 10 to 12 years of age, males had larger maxillary depth than females and the predominant arch form was elliptical. PMID- 21552720 TI - Facial and dental alterations according to the breathing pattern. AB - There is controversy in the literature about possible interaction of the respiratory mode with the facial and dental structures. OBJECTIVES: The aim of this study was to perform a longitudinal assessment of the changes in facial and dental structures in Angle's Class II, division 1 malocclusion individuals, divided according to the respiratory pattern (predominantly nasal or mouth), at two distinct moments of craniofacial development. MATERIAL AND METHODS: Pogonium and nose measurements were made on the lateral cephalometric tracings (LS'-Pog', LS'-B', B'-Pog', Pog'-PogTeg', Line NB, Pog-NB, N'-Prn, Prn-NPog, N-Prn-Sn, Prn Sn-LS). Dental measurements were made on the plaster models (distances between the tips of the canine cusps and the tips of mesial cusps of the first molars) of 40 individuals aged 10 to 14 years (moment 1) and 13 to 16 years (moment 2), 23 being nose breathers (NB) and 17 being predominantly mouth breathers (MB). RESULTS: The Student's-t test and two-way ANOVA with repeated measures were applied to indicate differences between the mean values of these variables according to the moments and/or respiratory mode. CONCLUSIONS: There were alterations in the facial measurements, without interference of the breathing pattern. However, the breathing pattern influenced dental alterations. PMID- 21552721 TI - Pleomorphic adenoma with extensive squamous metaplasia and keratin cyst formations in minor salivary gland: a case report. AB - Pleomorphic adenoma (PA), the most common salivary gland tumor, accounts for 54 to 65% of all salivary gland neoplasias and 80% of the benign salivary gland tumors. It most frequently affects the parotid gland, followed by the submandibular and the minor salivary glands. Microscopically, mucous, sebaceous, oncocytic and squamous metaplasia, sometimes with the formation of keratin pearls, may be present, but the latter rarely results in the formation of extensive keratin-filled cysts lined by squamous epithelium. Extensive squamous metaplasia can be mistaken for malignancy, including mucoepidermoid carcinoma and squamous cell carcinoma. Here, we present an unusual case of PA with extensive squamous metaplasia and keratin cyst formations in a minor salivary gland, and discuss its microscopic features, including the immunohistochemical characteristics, and differential diagnosis of this uncommon presentation. PMID- 21552725 TI - Orientation to mothers of children of the autistic spectrum about language and communication. AB - PURPOSE: To verify the results obtained by ten sessions of specific instruction about language and communication to mothers of children of the autistic spectrum. METHODS: Subjects were 26 mother-child dyads. The children attended language therapy in a specialized service. Five pre-planned instruction sessions and five accompanying sessions to small groups of mothers parallel to the children's language therapy were conducted. RESULTS: The focus directed to the child's communication allowed the identification of essential elements to the determination of successful interactive situation as joint attention, latency to answers and child's individual interests. The individualized analysis has shown that all subjects presented progress at least in one of the assessed areas. CONCLUSION: There was a positive impact of the systematic orientations to mothers about language and communication, conducted at the same time as language therapy (and not alternatively). The formal planning and recording were flexible enough to allow adjustments to group specific needs and demands. PMID- 21552726 TI - Comparison of the evolutional process of children with autism spectrum disorders in different language therapeutic interventions. AB - PURPOSE: To analyze and compare the extension and the speed of the evolutional process of children with Autism Spectrum Disorders in direct and indirect interventions as opposed to only indirect intervention. METHODS: The design of this study is a clinical trial. The sample was composed of 11 children diagnosed with Autism (n=6) and Asperger syndrome (n=5) by a multidisciplinary team, that attended specialized speech-language pathology therapy at the institution were the study was carried out. These children were randomly divided into two groups: Therapy Group (TG) - composed by six subjects receiving both direct and indirect intervention; and Orientation Group (OG) - constituted by five subjects receiving exclusively indirect intervention. It was used the Autism Behavior Checklist (ABC) to interview the mothers, and the Sample of Vocal Behavior (SVB), in three occasions: at the beginning of the intervention process (time 0), six months later (time 1) and 12 months later (time 2). RESULTS: It was observed greater speed and extension in the evolutional process of the TG Group, both in the analysis of the Autism Behavior Checklist (total and partial scores) and the Sample of Vocal Behavior, especially in the item Full Language. The performance of children with Asperger syndrome was considered more positive when compared to that of children with autism. There was greater evolution in younger children and with normal, mild, and moderate adaptive functioning. CONCLUSION: The tendency towards better performance of the children attending direct and indirect intervention showed that this association is fundamental in the therapeutic process of children with Autism Spectrum Disorders. PMID- 21552727 TI - Phonological remediation program in students with learning difficulties. AB - PURPOSE: To verify the effectiveness of a phonological remediation program in students with learning difficulties. METHODS: Forty students from 2nd to 4th grades, from both genders, ranging from eight years and one month to 12 years old, were divided into two groups: Group 1 (G1), composed by 20 students with learning disabilities; and Group 2 (G2), composed by 20 students without learning disabilities. The Cognitive-Linguistic Performance Test and the oral reading and comprehension were applied in pre-test and post-test situations in all students. After the pre-test, only the students from Group 1 were submitted to the phonological remediation program. RESULTS: After the phonological remediation program, Group 1 presented differences for reading abilities, auditory and visual processing, and processing speed, evidenced by superior performance in the post testing situation. CONCLUSION: The phonological remediation program was efficient to the development of cognitive-linguistic skills and reading and text comprehension of students with learning difficulties. PMID- 21552728 TI - Effects of reading fluency stimulation with emphasis on prosody. AB - PURPOSE: To characterize the reading ability of children with five years of education according to temporal standards, as well as to compare the reading fluency performance of these children before and after a reading program based on prosody standards. METHODS: Thirty two fourth-grade children participated in this study. They performed reading aloud and picture description tasks in order to verify reading rate, speech rate, text comprehension and the adequacy of prosody variation. Afterwards, it was carried out a reading stimulation program with emphasis on prosody, composed of five 15-minute sessions of reading tasks. At the end of the program, children were re-assessed, in order verify their performance after stimulation. RESULTS: Changes were observed in reading rate, number of words misread, and quality of prosody during the reading task. CONCLUSIONS: The reading program promoted positive changes in reading fluency measures. PMID- 21552729 TI - Immediate effect of sounded blowing exercise in the elderly voice. AB - PURPOSE: To observe the immediate effect of the sounded blowing exercise with semi-occluded vocal tract (SOVTE) in the voices of elderly subjects. METHODS: Thirty-three subjects with 65 years of age or older, with no voice or hearing disorder complaints, and with good self-perceived general health participated in the study. All participants filled in a vocal self-evaluation questionnaire. The sustained vowel /epsilon/ was recorded in three distinct moments: the first, denominated habitual (H), based on the subject's regular production; the second, usage (U), after one minute of continuous spontaneous conversation; the third, exercise (E), carried out after a one-minute execution of the SOVTE. After the exercise, the subjects self-evaluated the changes perceived in their voices. The recordings were edited and randomly paired, considering two moments of the same subject: H/U; H/E and U/E, for further perceptual examination of the better production by three specialized speech-language pathologists. RESULTS: There were no differences between H and U (p=0.199) and between U and E (p=0.773). However, the E production was considered better than the H production (p=0.004). In the vocal self-evaluation, most subjects (n=25, 75.8%) did not observe immediate effects in their voices after the exercise. CONCLUSION: The SOVTE produced positive immediate effects on the vocal quality of elderly subjects, observed only at the perceptual-auditory evaluation. PMID- 21552730 TI - From suspicion to intervention in deafness: characterization of this process in Campinas/SP. AB - PURPOSE: To identify and detail the current situation of diagnosis and assistance to deaf children in two cities belonging to the administrative region of Campinas (SP). METHODS: It was conducted a survey of 320 medical records of patients diagnosed with prelingual deafness in the period between 1996 and 2005, in two institutions located in the region of Campinas: a university clinic and a clinic specialized in the assistance to deaf individuals. RESULTS: Regarding the suspicion of hearing loss, the average age of the subjects was 1 year and 9 months. The mean age of children referred to medical or speech-language pathology service was 3 years and 6 months; the mean age for deafness diagnosis was 4 years and 3 months; the mean age for the beginning of clinical intervention was 6 years and 1 month; and the mean age for hearing aid adaptation was 7 years and 5 months. CONCLUSION: Suspicion of deafness, the first visit to a doctor, diagnosis, intervention and hearing aid adaptation were all delayed when compared to current recommended diagnostic standards and conditions of access to services. In addition, there was a significant delay between each stage, especially in the period between the suspicion of deafness and the beginning of clinical intervention. Although Campinas region is well developed in economic terms, offering a broad network of health assistance services, this network was little efficient regarding assistance to deafness. PMID- 21552731 TI - Effectiveness verification of an educational program about hearing protection for noise-exposed workers. AB - PURPOSE: To verify the effectiveness of an educational action in the form of training, emphasizing the importance of hearing protection for workers exposed to occupational noise. METHODS: The study included 78 male individuals. All participants answered a questionnaire before they were submitted to audiological evaluation. For the second application of the questionnaire, participants were randomly divided into two groups: Research Group, constituted by 44 subjects that received educational training before the second questionnaire application, and Control Group, comprising 34 individuals that answered the questionnaire before the educational training. Training was based on material with graphic images and text, in the form of conversation. The topics covered included: the importance of hearing, noise effects on health, importance of preventing hearing loss and using hearing protection, conservation and cleaning of hearing protectors, levels of noise in the workplace and noise attenuation provided by hearing protectors. The questionnaire contained 14 multiple choice questions that addressed the same themes explored in the educational training. RESULTS: There was a significant increase of correct responses in the second application of the questionnaire, only in the Research Group, in all comparisons. CONCLUSION: Educational action performed with workers exposed to occupational noise are effective, and the questionnaire is a stable and viable tool to evaluate the effectiveness of educational programs. PMID- 21552732 TI - Comparison of different protocols for vestibular rehabilitation in patients with peripheral vestibular disorders. AB - PURPOSE: To compare the therapeutic efficacy of two protocols for vestibular rehabilitation in several vestibular disordes. METHODS: Twenty patients with chronic peripheral disorders of both genders (prevalence of females, with 60% of the sample) and mean age of 55 years and 9 months participated in this study. Group 1 carried out exercices based on stimulation of vertical and horizontal vestibulocular reflex, and Group 2 carried out exercices based on a protocol of personalized vestibular rehabilitation. Data analysis considered the complaint manifested during anamnesis and the clinical evolution of the patient during the execution of the exercises. The results obtained from the application of the Dizziness Handicap Inventory questionnaire (DHI) and the dizziness visual analog scale (VAS), both before and after vestibular rehabilitation, were also considered in the analysis. RESULTS: Differences were found in the values obtained in VAS and DHI (physical and functional scales and total score), in both groups. However, the comparison of the groups after rehabilitation showed that Group 2 obtained better scores than Group 1, both in VAS and DHI (functional scale and total value). CONCLUSION: Vestibular rehabilitation allowed significant improvement in otoneurological clinical profile and in self-perception of dizziness, regardless the therapeutic method used. Personalized vestibular rehabilitation was more efficient than the vestibulocular reflex stimulation protocol in improving quality of life of individuals with chronic periferal disorders. PMID- 21552733 TI - Evaluation of participation restriction and cognitive processes in the elderly before and after the audiologic rehabilitation. AB - PURPOSE: To evaluate the restriction of participation in activities of daily living and cognitive processes in older adults, according to gender and age, before and after rehabilitation. METHODS: The study included 50 individuals, 23 females and 27 males. The elderly were divided into two groups: Group 1 to 24 individuals aged between 60 and 74 years (11 females and 13 males), Group 2 - 26 elderly aged above 75 years (12 of female and 14 male). The elderly were evaluated before one year after the adaptation of hearing aids through the HHIE test and MMSE. Bimonthly follow-ups were conducted a total of seven meetings, to ensure the effective use of the prosthesis. As for the statistical analysis were performed descriptive and statistical analysis. RESULTS: There was a reduction of the restriction of participation in social and emotional scales HHIE post intervention in both groups, individuals of both genders. The MMSE test results were better in the post-intervention, regardless of gender and age of the participant. CONCLUSION: There is little perception of the restrictions on participation in activities of daily living after rehabilitation. Moreover, the elderly of different ages and both genders decreased cognitive constraints refer after hearing aid fitting. PMID- 21552735 TI - Recreational strategies for the elimination of pacifier and finger sucking habits. AB - PURPOSE: To verify the efficacy of recreational strategies of awareness for spontaneous removal of finger sucking or pacifier habits in children. METHODS: Fifteen children (nine female and six male), with ages ranging from 4 to 8 years (mean age of 5.6 years) participated in the study. Recreational strategies were developed for the removal of oral habits. The program consisted of ten one-hour weekly sessions. At the end of each session, parents were oriented, solved questions, and reported their child's behaviors during the past week. RESULTS: Twelve children (80%) totally eliminated the suction habit after the program. No difference was found for the removal when data regarding finger and pacifier sucking were compared (p=0.34). CONCLUSION: The awareness strategies using recreational activities was effective to eliminate finger and pacifier habits in children. PMID- 21552734 TI - Characterization of the transition technique from enteral tube feeding to breastfeeding in preterm newborns. AB - PURPOSE: To verify the corrected gestational age when oral feeding (breast half full) and exclusive breastfeeding were initiated in preterm newborns submitted to the transition technique from enteral feeding directly to breastfeeding, and time spent (in days) under speech-language pathology intervention until discharge. METHODS: Study participants were 35 preterm infants (PTI) divided into two groups. Group 1 (G1) was composed by 22 PTI who did not present any important medical complications during hospitalization, and Group 2 (G2) comprised 13 PTI with a history of major medical complications. The following data were recorded: gestational age at birth, birth weight, weight and corrected gestational age during speech-language pathology evaluation, corrected gestational age when started oral feeding, number of days stimulated through the non-nutritive sucking (NNS) technique, corrected gestational age when oral feeding started and when they were discharged from speech-language pathology intervention, and total number of days under speech-language pathology intervention. RESULTS: No differences were found between the groups (G1 and G2) for any of the analyzed parameters. In general, oral feeding started with an average of 36 weeks corrected gestational age. Exclusive oral feeding occurred with an average of 36.6 weeks corrected gestational age. In average, speech-language pathology intervention lasted 12.3 days, and the NNS technique in "gloved finger" or "empty breast" lasted an average of 4.54 days. CONCLUSION: The technique allowed the PTI to be discharged in exclusive breastfeeding at a corrected gestational age corresponding to that of healthy term newborns. PMID- 21552736 TI - The treatment with rothics and generalization obtained in two models of phonological therapy. AB - This study had the aim to analyze both the phonological changes and the generalization obtained in the treatment with rothics in two models of phonological treatment. The sample consisted of four subjects diagnosed with phonological disorder, with ages between four and six years. All of them were assessed before and after the phonological therapy. Two groups were established for the treatment with rothics. One group was treated with ABAB - Withdrawal and Multiple Probes Model, and the other group with the Maximal Opposition Model. The phonological system and the occurrence of generalizations before and after the treatment were analyzed. It was found that none of the subjects acquired the rothics that were practiced in the treatment, however, the occurrence of generalization to untreated items was observed only in the subjects treated by the ABAB - Withdrawal and Multiple Probes model. The other types of generalization occurred in both models. The Maximal Opposition Model provided greatest changes in the phonological system of the subjects, which can have been favored by the other target-sound of the pair. PMID- 21552737 TI - Trajectory and outcomes of speech language therapy in the Prader-Willi syndrome (PWS): case report. AB - The aim of this study was to describe the trajectory and the outcomes of speech language therapy in Prader-Willi syndrome through a longitudinal study of the case of an 8 year-old boy, along four years of speech-language therapy follow-up. The therapy sessions were filmed and documental analysis of information from the child's records regarding anamnesis, evaluation and speech-language therapy reports and multidisciplinary evaluations were carried out. The child presented typical characteristics of Prader-Willi syndrome, such as obesity, hyperfagia, anxiety, behavioral problems and self aggression episodes. Speech-language pathology evaluation showed orofacial hypotony, sialorrhea, hypernasal voice, cognitive deficits, oral comprehension difficulties, communication using gestures and unintelligible isolated words. Initially, speech-language therapy had the aim to promote the language development emphasizing social interaction through recreational activities. With the evolution of the case, the main focus became the development of conversation and narrative abilities. It were observed improvements in attention, symbolic play, social contact and behavior. Moreover, there was an increase in vocabulary, and evolution in oral comprehension and the development of narrative abilities. Hence, speech-language pathology intervention in the case described was effective in different linguistic levels, regarding phonological, syntactic, lexical and pragmatic abilities. PMID- 21552738 TI - Modifications and evaluation of smell and taste functions in total laryngectomy: systematic review. AB - The aim of this study was to systematically review the alterations in smell and taste functions in individuals who underwent total laryngectomy, as well as to identify in the literature some aspects involved in the evaluation of these functions in this population. We performed a systematic review on the databases Medline, LILACS and SciELO, and this data search occurred in October/2010. The search used keywords and free terms, and retrieved 84 articles, 79 from Medline, via Pubmed, and five form LILACS and SciELO. Sixteen of these articles were selected. Most studies in this review attested decline in sensory of smell and taste functions in individuals who underwent total laryngectomy and, although there is consensus regarding the damage caused to these functions by the nasal airflow interruption, it is not yet possible to evidence details in the mechanisms and structures involved, especially regarding the modifications in the olfactory mucous. PMID- 21552739 TI - Quality indicators for integrated care of dysphagia in hospital settings. AB - This article proposes a panel of quality indicators for the management of swallowing rehabilitation (SR) therapy in a hospital setting. There were four stages in developing these indicators: identifying procedures to be managed; generating indicators and standardizing data collection; identifying the correlation among indicators; and formulating the panel of indicators. The following 12 quality indicators were developed: swallowing evaluation index; individual care index; speech-language pathologist (SLP) care index; number of assisted patients index; severity rate; swallowing diagnosis rate per hospital unit; swallowing rehabilitation demand index; time until first swallowing evaluation; SLP index per hospital bed; time until removal of feeding tube; time until reintroduction of oral feeding; and time until decannulation. The proposed indicators were designed to improve the management of dysphagia in a hospital setting. Measuring these indicators is essential to understanding the patient's needs and providing quality care. Managing care using these indicators will make it easier to track the patient's rehabilitation process, measure the effectiveness of new therapeutic processes and technologies, and evaluate the performance of hospital units relative to other providers in the area. The management of SR using quality indicators allows the effectiveness and efficiency of rehabilitation programs to be clearly evaluated. PMID- 21552740 TI - [Soil contamination by eggs of soil-transmitted helminths with zoonotic potential in the town of Fernandopolis, State of Sao Paulo, Brazil, between 2007 and 2008]. AB - INTRODUCTION: The concentration of dogs and cats in urban areas, associated with an ever-increasing wandering population of these animals, has an important epidemiological role in the soil contamination of public spaces and the spread of infections of several types of parasites. This study aimed to determine the frequency of soil-transmitted helminths with zoonotic potential in public squares and municipal primary schools in Fernandopolis, State of Sao Paulo, Brazil, conducted between 2007 and 2008. METHODS: All the squares (32) and schools (13) in the town were evaluated. Soil samples were tested using the Rugai method modified by Willis, Caldwell and Caldwell. RESULTS: A total of 225 soil samples were evaluated and 30.2% (68) were positive for helminths. In samples from public squares, 40% (64) contamination was observed; however, contamination in schools was only 6.1% (6). The parasites eggs identified were Toxocara spp. 79.3% (47), Trichuris spp. 13.8% (8) and Ancylostomatidae 6.9% (4). Variables related to the site, such as the number of dogs (OR 21.18, 10.81 - 41.51), fecal samples (OR 6.87, 3.51 - 13.47) and the use of fences (OR 0.1, 0.05 - 0.20), had an impact on soil contamination. CONCLUSIONS: In the contaminated samples, parasites with zoonotic potential were identified, including the etiologic agents of diseases like cutaneous and visceral larva migrans, a fact that poses a risk to health of the population that frequent such environments. PMID- 21552741 TI - Clinical and epidemiological profile of blood donors with positive serology for viral hepatitis in southern Brazil. AB - INTRODUCTION: Positive serological tests for hepatitis viruses B and C at blood banks are an important reason for blood deferral. Additionally, high residual risk for transfusing hepatitis-contaminated blood has been estimated in southern Brazil. This study aimed to identify risk factors for positive serological tests for viral hepatitis (VH) in blood donors (BD). METHODS: A case-control study included consecutive BD with positive serology for VH, between 2008 and 2009. Cases and controls (BD with negative serology for VH) were paired 1:1 by sex and donation date. Assessment of clinical and epidemiological characteristics related to viral hepatitis was conducted. RESULTS: Among 1,282 blood donors (641 cases and 641 controls), those with positive serology for viral hepatitis had higher mean age (p<0.001); higher proportion of replacement donation (p<0.001); first donation (p<0.001); and interviewer deferment (p=0.037), compared to controls. Furthermore, donors with positive tests were less regular donors (p<0.001), had less previous history of rejection (p=0.003) and showed lower hematocrit median before donation (p=0.019). Multivariate analysis demonstrated that age (OR=1.056, 95%CI 1.042-1.069, p<0.001), replacement donation (OR=1.545, 95%CI 1.171-2.038, p=0.002) and first donation (OR=9.931, 95%CI 7.486-13.173, p<0.001) were independently associated with positivity of serological tests for viral hepatitis. CONCLUSIONS: Specific characteristics of blood donors were associated with positive serology for viral hepatitis. These peculiarities should be taken into account when assessing candidates for blood donation. PMID- 21552742 TI - Schistosoma mansoni specimens first described by Piraja da Silva in Brazil (1908) re-examined by confocal laser scanning microscopy. AB - INTRODUCTION: Piraja da Silva made a seminal contribution to helminthology by demonstrating both schistosome eggs in feces of patients from the State of Bahia and the morphology of Schistosoma mansoni adult worms. METHODS: In this study, a microscopic investigation of the whole-mounts deposited at the Helminthological Collection of the Oswaldo Cruz Institute is presented. Confocal laser scanning microscopy was used as the main investigation technique. RESULTS: At the anterior end of the adult male, suckers with well-developed musculature and germinative cells inside the testicular lobes were observed, as well as spines located in the mid region of the male gynecophoric canal. Tegumental tubercles and transversal and longitudinal muscular bundles were observed at the dorsal surface. The female reproductive system presented a uterus lacking eggs and an elongated ovary with germinative cells. The vitellaria were restricted to the extreme posterior end of each female connected to a short vitelline duct. CONCLUSIONS: The results reported in this study demonstrate that the characteristic studied here are similar to those previously reported, using fresh worms. Moreover, this study also highlights the importance of deposits of specimens in helminthological collections, which further permit revisiting whole-mounts in such institutions. PMID- 21552743 TI - Breeding sites of Aedes aegypti in metropolitan vacant lots in Greater Vitoria, State of Espirito Santo, Brazil. AB - INTRODUCTION: This study aimed to evaluate the presence of Aedes aegypti in breeding sites located in vacant lots (VLs) and determine the effectiveness of VL cleaning to reduce insect foci. METHODS: Two types of VLs were sampled, the experimental VL, which was cleaned monthly, and the control VL, which was not cleaned. RESULTS: Monthly cleaning of VLs reduced the abundance of immature forms of A. aegypti. CONCLUSIONS: Strategies for combating this vector should include regular cleaning of VLs and educating the public regarding the risks of discarding waste in inappropriate areas. PMID- 21552744 TI - New report on the bionomics of Coquillettidia venezuelensis in temporary breeding sites (Diptera: Culicidae). AB - INTRODUCTION: Findings of immature forms of Coquillettidia venezuelensis in temporary breeding sites, without the presence of aquatic plants or other submerged plant tissue are reported. METHODS: A systematic scooping technique to collect specimens was used at the breeding site. RESULTS: Immature forms of Coquillettidia venezuelensis, Anopheles rangeli, An. evansae and Culex sp. were collected from areas of the hydroelectric power station of Sao Salvador, State of Goias. CONCLUSIONS This is a novel finding relating to the bioecology of Cq. venezuelensis, a species of medical interest that has been found naturally infected with arboviruses, including Oropouche and West Nile virus. PMID- 21552745 TI - [Dengue virus serotypes in children of Manaus, State of Amazonas, 2008]. AB - INTRODUCTION: Dengue is an arbovirus that continues to cause serious public health problems in tropical and sub-tropical regions of the planet. METHODS: In this study, blood samples from children were investigated by RT-PCR, aimed at identifying dengue virus serotypes in Manaus, AM, in 2008 in this infant population. RESULTS: DENV-3 was the only serotype identified. CONCLUSIONS: In this study, 83% of children examined were negative for dengue by RT-PCR, suggesting the occurrence of other febrile illnesses that need to be determined. PMID- 21552746 TI - [Overdose of yellow fever vaccine in the Southern region of Brazil]. AB - INTRODUCTION: Yellow fever is a preventable disease when using a safe, effective vaccine. METHODS: A prospective clinical follow-up of 49 people who received an overdose of the wrong vaccine against yellow fever during the 2009 outbreak in a rural area of the Vale do Rio Pardo, State of Rio Grande do Sul. RESULTS: During 45 days of clinical follow-up, only 1 (2.1%) case presented manifestations of a possible acute viscerotropism as an adverse postvaccination event. CONCLUSIONS: In the group of people monitored following an overdose of anti-yellow fever vaccine, observation confirmed almost total absence of adverse events. PMID- 21552747 TI - American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis resistant to meglumine antimoniate, but with good response to pentamidine: a case report. AB - This is a case report of a Brazilian soldier with cutaneous leishmaniasis. The lesion relapsed following two systemic treatments with meglumine antimoniate. The patient was treated with amphotericin B, which was interrupted due to poor tolerance. Following isolation of Leishmania sp., six intralesional infiltrations of meglumine antimoniate resulted in no response. Leishmania sp promastigotes were again isolated. The patient was submitted to intramuscular 4 mg/kg pentamidine. Parasites from the first and second biopsies were identified as Leishmania (Viannia) braziliensis; those isolated from the first biopsy were more sensitive to meglumine antimoniate in vitro than those isolated from the second biopsy. No relapse was observed. PMID- 21552748 TI - Rhinocerebral zygomycosis in a diabetic patient. AB - Rhinocerebral zygomycosis is the most frequent form of fungal infection caused by members of the Zygomycetes class. A fatal case of rhinocerebral zygomycosis caused by Rhizopus (oryzae) arrhizus with histopathological and mycological diagnosis is reported in a diabetic patient. PMID- 21552749 TI - [Pulmonary actinomycosis simulating Tobias-Pancoast tumor]. AB - Actinomycosis is a rare infection that may involve several organs. Thoracic involvement is uncommon (10-20%). This article describes the case of a 33 year old patient, HIV negative, complaining of burning pain in the left posterior chest radiating to the left upper arm and reduced strength and paresthesias. The CT scan showed a mass in close contact with the chest wall. Following a thoracotomy, observation verified a solid pulmonary lesion adhered to the left upper lobe, infiltrating the posterior thoracic wall and apex of the cavity with rich vascularization. An incisional biopsy of the lesion and microbiological study revealed actinomycosis. PMID- 21552750 TI - [Sylvatic dengue: should we be worried?]. PMID- 21552751 TI - Disseminated Mycobacterium abscessus infection in an AIDS patient. PMID- 21552753 TI - Prevalence of anemia and associated factors in children aged 6-59 months in Pernambuco, Northeastern Brazil. AB - OBJECTIVE: To estimate the prevalence of anemia and to identify its associated factors in children aged 6-59 months. METHODS: This was a cross-sectional study on data from the Third Health and Nutrition Survey of the State of Pernambuco, Northeastern Brazil, with a representative sample of 1,403 children from urban and rural areas. Anemia was diagnosed by means of hemoglobin assays. Multivariate analysis was performed though a hierarchical model, using robust-variance Poisson regression to estimate the prevalence ratio as a function of the following variables: biological factors, morbidity, child nutritional state, socioeconomic factors, housing, sanitation and maternal factors. RESULTS: The weighted prevalence of anemia was 32.8% overall: 31.5% in urban areas and 36.6% in rural areas. In urban areas, anemia was significantly associated with maternal education, consumer goods, number of children less than five years old in the home, drinking water treatment, maternal age, maternal anemia and the child's age. In rural areas, only maternal age and the child's age were significantly associated with anemia. CONCLUSIONS: The prevalence of anemia in children in Pernambuco was similar in urban and rural areas. The factors associated with anemia that are presented here should be taken into consideration in planning effective measures for its control. PMID- 21552754 TI - Health-related behavior and quality of life among the elderly: a population-based study. AB - OBJECTIVE: To assess the association between health-related behaviors and quality of life among the elderly. METHODS: A population-based cross-sectional study was carried out including 1,958 elderly living in four areas in the state of Sao Paulo, southeastern Brazil, 2001/2002. Quality of life was assessed using the Medical Outcomes Study SF-36-Item Short Form Health Survey instrument. This instrument's eight subscales and two components were the dependent variables. Independent variables were physical activity, weekly frequency of alcohol consumption and smoking. Multiple linear regression models were used to control for the effect of gender, age, schooling, work, area of residence and number of chronic conditions. RESULTS: Physical activity was positively associated with the eight SF-36 subscales. The stronger associations were found for role-physical (beta=11.9), physical functioning (beta=11.3) and physical component. Elderly individuals who consumed alcohol at least once a week showed a better quality of life than those did not consume alcohol. Compared to non-smokers, smokers had a poorer quality of life for the mental component (beta=-2.4). CONCLUSIONS: The study results showed that physical activity, moderate alcohol consumption and no smoking are positively associated with a better quality of life in the elderly. PMID- 21552755 TI - Disability pension from back pain among social security beneficiaries, Brazil. AB - OBJECTIVE: To describe disability pension from back pain. METHODS: Descriptive study based on data from the Brazilian Social Security Beneficiary Database and the Social Security Statistics Annual Report in 2007. The incidence rate of disability pension from back pain was estimated according to gender and age by Brazilian states. There were also estimated working days lost due to back pain disability by occupation. RESULTS: Idiopathic back pain was the most common cause of disability among social security pension and accidental retirement. Most pensioners were living in urban areas and were commercial workers. The rate of disability pension from back pain in Brazil was 29.96 per 100,000 beneficiaries. A higher rate was seen among males and older individuals. Rondonia showed the highest rate, four times as high as expected (RR= 4.05) followed by Bahia with a rate about twice as high as expected (RR=2.07). Commercial workers accounted for 96.9% of working days lost due to disability. CONCLUSIONS: Back pain was a major cause of disability in 2007 mostly among commercial workers showing great differences between the Brazilian states. PMID- 21552756 TI - Use of the International Classification of Diseases in the analysis of dental absenteeism. AB - OBJECTIVE: To compare the use of disease and injury classification codes in workplace absences requests due to dental causes. METHODS: The study analyzed 240 requests in a federal public agency between January 2008 and December 2009. The use of the International Classification of Diseases - 10th Revision (ICD-10) was compared to the Application of the International Classification of Diseases to Dentistry and Stomatology (ICD-DA). The degree of specificity was determined for the codifications on workplace justifications, as well as for codifications assigned by official dental experts in indirect inspections and expert examinations. RESULTS: Of the total number of dental certificates, 22.9% did not present the ICD, 7.1% used ICD-9, 3.3% used ICD-DA and 66.7% used ICD-10. The majority of codifications were concordant (55.1%), and greater specificity was found in codifications assigned after evaluation by official dental experts. CONCLUSIONS: The results indicate the need to improve use of ICD-10 among dentists and official dental experts .For analysis of work absenteeism, it is suggested the use of ICD-DA and the International Classification of Functioning, Disability and Health, which provide relevant data for monitoring absenteeism due to dental reasons. PMID- 21552757 TI - Mortality of motorcyclists in traffic accidents in the Brazilian Federal District from 1996 to 2007. AB - OBJECTIVE: To describe sociodemographic characteristics and analyze temporal trends in the mortality of motorcyclists injured in traffic accidents. METHODS: This was a time-series study with data from 580 motorcyclist deaths in the Brazilian Federal District from 1996 to 2007. The data were obtained from the Mortality Information System. Mortality rates specific for age and sex, the standardized rates (direct method), and the ratio of deaths per fleet (motorcycles) were calculated. The centralized moving average of the standardized mortality rate for men was calculated for a three-year period, and a linear regression model was constructed to study the evolution of mortality. The joinpoint method (inflection point) was used to calculate the annual increase in the standardized mortality rate. RESULTS: Most of the motorcyclists killed were male (94.3%), mixed skin color (71.0%), and between the ages of 20 and 39 years (73.8%). The standardized mortality rate for resident motorcyclists (men) was 1.9 to 7.2 deaths/100,000 men between 1996 and 2007. Between 1998 and 2007, the ratio of deaths per fleet increased from 2.0 deaths/10,000 motorcyclists to 10.0 deaths/10,000 motorcyclists among men. There was an estimated annual increase of 0.48 deaths/100,000 men (95%CI 0.31, 0.65; p <0.001). The percent increase of the annual standardized mortality rate for males was 36.2% in the period from 1998 2007 (95%CI 21.2%, 53.2%; p <0.05). CONCLUSIONS: The mortality rate resulting from motorcycle road accidents has increased dramatically. This increase is partially explained by the increase of the fleet of motorcycles. Individual characteristics of drivers, as well as local traffic conditions, need to be investigated for the planning of preventive policies. PMID- 21552758 TI - Femicides: female homicide in Brazil. AB - OBJECTIVE: To assess female homicide rates due to aggression according to sociodemographic and health indicators. METHODS: Ecological study on female homicides due to aggression in Brazil between 2003 and 2007. Information on 19,459 deaths were obtained form the Brazilian Mortality Database. Standardized female homicide rates due to aggression were correlated with 28 socioeconomic, demographic and health indicators, using Pearson's correlation test. Multiple linear regression was performed including variables with p < 0.20 and excluding those with multicollinearity. RESULTS: The standardized female homicide rate due to aggression was 4.1/100,000 during the study period. After adjustment, three variables remained significantly associated with female homicides: birth rate (p = 0.072), percentage of Evangelicals (p = 0.019) and male homicides due to aggression (p < 0.001). The model had a predictive power of 69% (r2 = 0.699). The Brazilian states of Espirito Santo, Pernambuco, Mato Grosso, Rio de Janeiro, Rondonia, Alagoas, Mato Grosso do Sul, Roraima e Amapa showed the highest rates during the study period. CONCLUSIONS: The female homicide rates due to aggression were high in Brazil and varied by region. The association with male homicides due to aggression stresses the importance of reducing structural violence to protect women against violence. PMID- 21552759 TI - The role of plausibility in the evaluation of scientific research. AB - The paper discusses the impact of plausibility (the a priori probability) on the results of scientific research, according to the approach proposed by Ioannidis, concerning the percentage of null hypotheses erroneously classified as "positive" (statistically significant). The question "what fraction of positive results are true-positives?", which is equivalent to the positive predictive value, is dependent on the combination of true and false hypotheses within a given area. For example, consider an area in which 90% of hypotheses are false and alpha = 0.05 and power = 0.8: for every 1,000 hypotheses, 45 (900 x 0.05) are false positives and 80 (100 x 0.8) are true-positives. Therefore, the probability of a positive result being a false-positive is 45/125. In addition, the reporting of negative results as if they were positive would contribute towards an increase in this fraction. Although this analysis is difficult to quantify, and these results are likely be overestimated, it has two implications: i) plausibility should be considered in the analysis of the ethical adequacy of a research proposal, and ii) mechanisms aimed at registering studies and protocols should be encouraged. PMID- 21552760 TI - Within-person variance for adjusting nutrient distribution in epidemiological studies. AB - The objective of the study was to present the within-person variance component for adjusting nutrient distribution in adults and elderly people. The data used were from a population-based survey with a representative sample (n = 511) of individuals aged 19 years and over in the municipality of Sao Paulo, Southeastern Brazil, conducted in 2007. The within-person variance component was obtained using the Iowa State University method. Differences in within-person variance components were observed for some nutrients according to gender. These values should be used to adjust nutrient intake distributions, because lack of adjustment may result in biased data analysis and interpretation. PMID- 21552761 TI - [Decentralization in the context of health research support]. PMID- 21552762 TI - [Relapse and drug resistance in leprosy]. PMID- 21552763 TI - Prediction on the seasonal behavior of hydrogen sulfide using a neural network model. AB - Models to predict seasonal hydrogen sulfide (H2S) concentrations were constructed using neural networks. To this end, two types of generalized regression neural networks and radial basis function networks are considered and optimized. The input data for H2S were collected from August 2005 to Fall 2006 from a huge industrial complex located in Ansan City, Korea. Three types of seasonal groupings were prepared and one optimized model is built for each dataset. These optimized models were then used for the analysis of the sensitivity and main effect of the parameters. H2S was noted to be very sensitive to rainfall during the spring and summer. In the autumn, its sensitivity showed a strong dependency on wind speed and pressure. Pressure was identified as the most influential parameter during the spring and summer. In the autumn, relative humidity overwhelmingly affected H2S. It was noted that H2S maintained an inverse relationship with a number of parameters (e.g., radiation, wind speed, or dew point temperature). In contrast, it exhibited a declining trend with a decrease in pressure. An increase in radiation was likely to decrease during spring and summer, but the opposite trend was predicted for the autumn. The overall results of this study thus suggest that the behavior of H2S can be accounted for by a diverse combination of meteorological parameters across seasons. PMID- 21552764 TI - Treatment of a textile effluent from dyeing with cochineal extracts using Trametes versicolor fungus. AB - Trametes versicolor (Tv) fungus can degrade synthetic dyes that contain azo groups, anthraquinone, triphenylmethane polymers, and heterocyclic groups. However, no references have been found related to the degradation of natural dyes, such as the carminic acid that is contained in the cochineal extract. Experiments to determine the decolorization of the effluent used in the cotton dyeing process with cochineal extract by means of Tv fungus were done. Treatments to determine decolorization in the presence or absence of Kirk's medium, glucose, and fungus, with an addition of 50% (v v-1) of nonsterilized effluent were performed. Physicochemical characterization was performed at the start and end of the treatment. Degradation kinetics were determined. A direct relationship was found between the dry weight of fungi, pH, and the decolorization system, with higher decolorization at lower pH levels (pH ~4.3). High decolorization (81% +/- 0.09; 88% +/- 0.17; and 99% +/- 0.04) for three of the eight treatments (Kirk's medium without glucose, Kirk's medium with glucose, and without medium with glucose, respectively) was found. Toxicity tests determined an increase in the initial effluent toxicity (7.33 TU) compared with the final treatment (47.73 TU) in a period of 11 days. For this system, a degradation sequence of the carminic acid structure present in the effluent by the Tv fungus is suggested, in which it is seen that metabolites still containing aromatic structures are generated. PMID- 21552765 TI - The moderating role of perceived social support on the relationship between physical functional impairment and depressive symptoms among Chinese nursing home elderly in Hong Kong. AB - With reference to the stress-buffering model, this study aimed to examine the moderating role of perceived social support (including institutional peer support and family support) on the relationship between physical functional impairment, as a source of stress, and depressive symptoms among Chinese nursing home elderly in Hong Kong. The study used a cross-sectional survey method and convenience sampling. The subjects were recruited from two private nursing homes. A total of 187 elderly (54 males and 133 females) participated in the survey. Interviews were conducted by experienced research assistants. The Geriatric Depression Scale was used to assess depressive symptoms of each participant. Pearson correlational analyses showed that females reported more depressive symptoms than their male counterparts, and a positive relationship was found between education level and depressive symptoms. Perceived institutional peer support was negatively correlated, while physical functional impairment was positively correlated with depressive symptoms. However, there was no significant correlation between perceived family support and depressive symptoms. Hierarchical regression analyses revealed that physical functional impairment and perceived institutional peer support were significant predictors of elderly depressive symptoms, while perceived family support was not a significant predictor, after statistically controlling for the influence of gender and education level. Perceived institutional peer support, but not perceived family support, was found to moderate the negative impact of physical functional impairment on elderly depressive symptoms. The theoretical and practical implications of this study were then discussed. PMID- 21552766 TI - Pseudosarcomatous fibromyxoid tumor of the prostate. AB - We present the case of a 61-year-old patient who was evaluated for benign infravesical obstruction due to a pseudosarcomatous fibromyxoid tumor of the prostate. This entity is rare and difficult to distinguish from a malignant lesion. A discussion of the pathological features and a review of the literature are given. PMID- 21552767 TI - Inverted nutcracker syndrome: a case of persistent hematuria and pain in the presence of a left-sided inferior vena cava. AB - Nutcracker syndrome is described as the symptomatic compression of left renal vein between the aorta and the superior mesenteric artery, resulting in outflow congestion of the left kidney. We present the case of a 51-year-old male with a left-sided inferior vena cava, resulting in compression of the right renal vein by the superior mesenteric artery. Secondary to this anatomic anomaly, the patient experienced a many-year history of flank pain and intermittent gross hematuria. We have termed this unusual anatomic finding and its associated symptoms as the "inverted nutcracker syndrome", and describe its successful management with nephrectomy and autotransplantation. PMID- 21552768 TI - Right diaphragm spontaneous rupture: a surgical approach. AB - We present a case of spontaneous rupture of the diaphragm, characterized by nonspecific symptoms. The rapid diagnosis and appropriate surgical approach led to a positive resolution of the pathology. PMID- 21552769 TI - Nephrotic syndrome and idiopathic membranous nephropathy associated with autosomal-dominant polycystic kidney disease. AB - We report the case of a 38-year-old male with autosomal-dominant polycystic kidney disease (ADPKD) and concomitant nephrotic syndrome secondary to membranous nephropathy (MN). A 3-month course of prednisone 60 mg daily and losartan 100 mg daily resulted in resistance. Treatment with chlorambucil 0.2 mg/kg daily, low dose prednisone, plus an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) for 6 weeks resulted in partial remission of his nephrotic syndrome for a duration of 10 months. After relapse of the nephrotic syndrome, a 13-month course of mycophenolate mofetil (MFM) 2 g daily and low-dose prednisone produced complete remission for 44 months. After a new relapse, a second 24-month course of MFM and low-dose prednisone produced partial to complete remission of proteinuria with preservation of renal function. Thirty six months after MFM withdrawal, complete remission of nephrotic-range proteinuria was maintained and renal function was preserved. This case supports the idea that renal biopsy is needed for ADPKD patients with nephrotic-range proteinuria in order to exclude coexisting glomerular disease and for appropriate treatment/prevention of renal function deterioration. To the best of our knowledge, this is the first reported case of nephrotic syndrome due to MN in a patient with ADPKD treated with MFM, with remission of proteinuria and preservation of renal function after more than 10 years. Findings in this patient also suggest that MFM might reduce cystic cell proliferation and fibrosis, preventing progressive renal scarring with preservation of renal function. PMID- 21552770 TI - Perils and pitfalls regarding differential diagnosis and treatment of primary cutaneous anaplastic large-cell lymphoma. AB - Primary cutaneous anaplastic large-cell lymphoma (PC-ALCL), belonging to the CD30+ T-cell lymphoproliferative disorders (PCLPDs), is a rare T-cell lymphoma, presenting on the skin and characterized by very good prognosis and response to treatment in the majority of cases. Nevertheless, PC-ALCL must be distinguished from secondary skin lesions in systemic ALCL, which confer a poor prognosis, and other CD30+ PCLPDs, reactive conditions, or borderline cases. Given their rarity and heterogeneity, these entities represent diagnostic and therapeutic challenges, thus requiring a multidisciplinary approach and expertise to ensure appropriate diagnosis and management. There are several perils and pitfalls that exist regarding the differential diagnosis, the possible progression, and the treatment of PC-ALCL. Careful staging, correlation of clinical findings with histopathology and immunopathology, and thorough follow-up are essential in order to achieve a correct diagnosis and proper treatment of the disease. PMID- 21552771 TI - Effect of lipoxin A4 on lipopolysaccharide-induced endothelial hyperpermeability. AB - Excessive oxidative stress, decreased antioxidant capacity, and enhanced cellular calcium levels are initial factors that cause endothelial cell (EC) hyperpermeability, which represents a crucial event in the pathogenesis of pre eclampsia. Lipoxin A4 (LXA4) strongly attenuated lipopolysaccharide (LPS)-induced hyperpermeability through maintaining the normal expression of VE-cadherin and a catenin. This effect was mainly mediated by a specific LXA4 receptor. LXA4 could also obviously inhibit LPS-induced elevation of the cellular calcium level and up regulation of the transient receptor potential protein family C 1, an important calcium channel in ECs. At the same time, LXA4 strongly blocked LPS-triggered reactive oxidative species production, while it promoted the expression of the NF E2 related factor 2 (Nrf2) protein. Our findings demonstrate that LXA4 could prevent the EC hyperpermeability induced by LPS in human umbilical vein endothelial cells (HUVECs), under which the possible mechanism is through Nrf2 as well as Ca2+-sensitive pathways. PMID- 21552772 TI - Eradication of HIV by transplantation of CCR5-deficient hematopoietic stem cells. AB - Today, 30 years after the onset of the HIV pandemic, although treatment strategies have considerably improved, there is still no cure for the disease. Recently, we described a successful hematopoietic stem cell transplantation in an HIV-1-infected patient, transferring donor-derived cells with a natural resistance against HIV infection. These hematopoietic stem cells engrafted, proliferated, and differentiated into mature myeloid and lymphoid cells. To date, the patient has not required any antiretroviral treatment, more than 4 years after allogeneic transplantation. In the analysis of peripheral blood cells and different tissue samples, including gut, liver, and brain, no viral load or proviral DNA could be detected. Our report raises the hope for further targeted treatment strategies against HIV and represents a successful personalized treatment with allogeneic stem cells carrying a beneficial gene. However, this case has ignited a controversy regarding the question of whether this patient has achieved complete eradication of HIV or not. Here we give an update on open questions, unsolved aspects, and clinical consequences concerning this unique case. PMID- 21552774 TI - Takotsubo cardiomyopathy: an uncommon cause of reversible heart failure. AB - Takotsubo cardiomyopathy is increasingly being diagnosed as a cause of acute coronary syndrome in postmenopausal women. It may also present as reversible acute left heart failure with an excellent prognosis for recovery. Although rare, it may be an underdiagnosed condition in the medical intensive care units among patients admitted with non-cardiac acute conditions. Therefore, intensivists must be aware of the possibility of this condition; this can help to avoid unnecessary costly investigations and provide an early, definite prognosis. PMID- 21552775 TI - Bilateral perisylvian infarct: a rare cause and a rare occurrence. AB - Foix-Chavany-Marie opercular syndrome is a severe form of pseudobulbar palsy occurring due to bilateral anterior opercular lesions. We report a case of a 51 year-old man with sudden onset of inability to speak and dysphagia, and a history of synovial sarcoma of the right hand. Detailed language evaluation was normal. The patient had right upper motor neuron facial paresis and absent gag reflex bilaterally. Magnetic resonance (MR) imaging revealed acute and subacute infarcts involving the bilateral insular cortex. Two-dimensional echocardiography and cardiac MR imaging showed a mobile mass in the left atrium attached to the interatrial septum, which was likely a myxoma. Chest radiograph and computed tomography imaging of the chest revealed multiple cannonball shadows that were suggestive of secondaries in the lung. The probable cause of the cerebral lesions was the mass lesion in the heart or metastatic lesions from the synovial sarcoma. The cardiac surgeon and surgical oncologist recommended palliative care. PMID- 21552776 TI - Subdural haematoma due to dural metastases from bronchogenic carcinoma in a previously well patient: an unusual cause of non-traumatic recurrent intracranial haematomata. AB - Subdural haematomata (SDH) are usually traumatic in aetiology. Non-traumatic instances of SDH are uncommon, and can rarely be due to metastases involving the dura. Computed tomography or magnetic resonance imaging can be misleading, as the underlying aetiology may be masked by the SDH, or the appearance can simulate meningiomas. A high index of suspicion for SDH is thus required. Under such circumstances, when no overt cause is identified, dural tissue should be sent for histological analysis and blood clot for cytology, even if the appearances are grossly normal at surgery. We present a rare case of a 42-year-old woman who was previously well, but presented with progressive weakness due to acute spontaneous SDH. She required repeated surgical evacuations for SDH and for subsequent recurrent extradural haematomata. After extensive investigations, the cause was identified to be secondary dural metastases from a primary lung carcinoma. PMID- 21552777 TI - Mediastinal parathyroid adenoma: diagnostic and management challenges. AB - Primary hyperparathyroidism due to ectopic parathyroid adenomas can pose diagnostic and management challenges, especially when imaging studies have localised the lesions to different sites. We report a case of symptomatic hypercalcaemia due to a mediastinal parathyroid adenoma. Ultrasonography identified a nodule posterior to the right thyroid gland. However, computed tomography and technetium-99m sestamibi scintigraphy revealed an ectopic parathyroid adenoma located in the anterior mediastinum. The adenoma was successfully removed through a median sternotomy. However, postoperatively, the patient developed prolonged symptomatic hypocalcaemia, possibly due to suppression of the normal parathyroid gland function, although the presence of concomitant hungry bone syndrome was possible. The histopathology of the mediastinal mass was consistent with a parathyroid adenoma. PMID- 21552778 TI - Aberrantly high glycated haemoglobin measurement due to the haemoglobin variant Hb Santa Juana. AB - Various laboratory and patient-related factors can result in falsely high or low glycated haemoglobin (HbA1c) measurements, and haemoglobin (Hb) variants that interfere with laboratory readings is an important cause of this. We report a case of a rare Hb variant, Hb Santa Juana, manifesting as a falsely high HbA1c in a 62-year-old patient with type 2 diabetes mellitus. The patient presented with high HbA1c values that persisted despite the intensification of anti-diabetic treatment. His home blood glucose levels were incongruently low compared to his HbA1c values. Further investigations revealed a family history of the variant Hb Santa Juana. This was confirmed in the patient when his blood was sent for DNA analysis. It is important for clinicians to be aware of the factors that can influence laboratory HbA1c measurements, as clinical decisions on treatment are often based on these measurements. PMID- 21552779 TI - Autoimmune pancreatitis presenting as a pancreatic mass mimicking malignancy. AB - Autoimmune pancreatitis is a rare cause of chronic pancreatitis and pancreatic mass. We describe a case of focal autoimmune pancreatitis in a 51-year-old man presenting with obstructive jaundice and pancreatic mass, mimicking malignancy. The immunological test was suggestive of autoimmune pancreatitis, and the patient responded well to a course of steroids, with complete resolution of the pancreatic mass. Autoimmune pancreatitis, therefore, must be kept in mind as a differential diagnosis of pancreatic mass. Recognition of this disease by its typical radiological and serological findings may help to avoid unnecessary surgical resection. PMID- 21552780 TI - Multiple indomethacin-induced colonic perforations in an adolescent. AB - Colonic perforation is an uncommon cause of acute abdomen in paediatric patients, and can present a diagnostic enigma as well as management challenge to the paediatric surgeon. An adolescent developed multiple colonic perforations following a short course of oral indomethacin, requiring emergency hemicolectomy. This is the youngest known case of enteral non-steroidal anti-inflammatory drug (NSAID)-mediated large bowel injury. We review current evidence on NSAID-related enteropathy, and postulate potentiating mechanisms that may have accounted for the unusually rapid clinical course of our patient. PMID- 21552781 TI - World Health Day 2011: combating antimicrobial resistance. PMID- 21552782 TI - Optimising the management of choroidal neovascularisation in Asian patients: consensus on treatment recommendations for anti-VEGF therapy. AB - In Asian countries, age-related macular degeneration (AMD), specifically wet AMD or choroidal neovascularisation (CNV), is an important cause of blindness and visual handicap. Vascular endothelial growth factors (VEGF) play an integral role in the development of CNV and thus provide an important therapeutic target. Current treatment paradigms for neovascular AMD recognise the place of photodynamic therapy (PDT) in the management of this condition. However, combination therapy targeting different pathways to produce a synergistic effect may result in improved visual outcomes and reduced duration of treatment. Anti VEGF therapy has greatly improved treatment outcomes in patients with CNV, and a growing body of evidence supports the role of these agents as monotherapy or in combination with PDT. In particular, anti-VEGF may be a first-line treatment option in certain types of subfoveal myopic CNV as well as for classic and occult juxtafoveal and subfoveal CNV. The implementation of evidence-based medicine into current clinical practice is paramount to improving patient care. The authors, who are also members of the Singapore Medical Retina Advisory Board, outline the consensus points and recommended treatment algorithms based on currently available knowledge to provide a structured management approach to the treatment of Asian patients with CNV. PMID- 21552783 TI - Palpitations and narrow-complex tachycardia. AB - A 56-year-old patient with a history of Parkinson's disease presented with palpitations and an apparently irregular narrow-complex tachycardia on electrocardiogram. The discrepancy in ventricular rate between the limb and precordial leads was the result of myopotentials from his tremors mimicking the QRS complexes in the limb leads. These myopotentials can be differentiated from true QRS complexes by the fact that they are usually variable in amplitude and occur at a frequency similar to that of limb tremors. PMID- 21552784 TI - Twenty years of familial adenomatosis polyposis syndromes in the Singapore Polyposis Registry: an analysis of outcomes. AB - INTRODUCTION: The Singapore Polyposis Registry (SPR) was established in 1989 at the Singapore General Hospital. This initiative was aimed at providing a central registry service to facilitate identification, surveillance and management of families and individuals at high risk of colorectal cancer. The aim of the present study was to provide a comprehensive review of all patients with familial adenomatous polyposis (FAP) syndrome in the SPR. METHODS: All patients diagnosed with FAP in 1989-2009 were analysed. Data was extracted from a prospectively collected database. RESULTS: 122 patients from 88 families were analysed. The median age of this cohort was 29 (range 10-68) years. 97 percent of the cases were FAP and 3 percent were attenuated FAP. 92 patients tested positive for adenomatous polyposis coli gene. 42 percent of patients were diagnosed with colorectal cancer, of which 78 percent were diagnosed at an advanced stage. 73 percent of patients underwent restorative proctocolectomy and 21 percent had total colectomy. The median age at operation was 30 years. At median follow-up of 98 months, ten-year overall survival was 75.6 percent (95 percent confidence interval 67.0-84.2) and the median age at death was 40 years. For cancer cases, the overall recurrence was 13.5 percent. Recurrence and disease-free survival were not significant for the type of surgery performed (p-value is 0.486). CONCLUSION: The SPR plays an important and integral part in counselling patients and families with FAP. Improved surveillance programmes may be required to detect the development of cancers in these patients at an earlier stage. PMID- 21552785 TI - Influence of Chinese cultural health beliefs among Malaysian Chinese in a suburban population: a survey. AB - INTRODUCTION: In a multiethnic nation, it is not uncommon for doctors to encounter patients of different cultural backgrounds. Often, patients' cultural beliefs influence their perception of health and illnesses, and their treatment option. Many Chinese cultural beliefs are influenced by the Taoist concept of yin yang balance. METHODS: We interviewed 50 Malaysian Chinese from the general public of a suburban population in order to unravel the impact of Chinese cultural health beliefs on their decision-making, and this was compared with the opinions of 50 Chinese medical students from second to final year. Convenience sampling was then applied. RESULTS: From the survey, 78 percent of the general public believed that 'too much heat' or 'too much coldness' in the body could cause diseases. Compared to the medical students, a significantly higher number of the respondents held such beliefs, including the beliefs that abdominal colic is due to excessive 'wind' in the abdomen, consuming certain food can dispel wind from the body, and the importance of observing taboos during the confinement period after delivery. The majority of respondents from both groups believed that it is acceptable to combine both traditional Chinese medicine and modern medicine. CONCLUSION: There is a discrepancy in the extent to which these beliefs influence the perception of health and illnesses among the general public and among medical students. Healthcare providers need to be aware of such beliefs and practices regarding traditional Chinese medicine among their Chinese patients. PMID- 21552786 TI - Transradial percutaneous coronary intervention in acute ST elevation myocardial infarction and high-risk patients: experience in a single centre without cardiothoracic surgical backup. AB - INTRODUCTION: Primary transradial percutaneous coronary intervention (TRI) is shown to be efficacious in stable patients with acute coronary syndrome. We aimed to evaluate the application of primary TRI for acute ST elevation myocardial infarction (STEMI), including among high-risk patients from our registry. METHODS: This was a single-centre case series comprising 138 patients who underwent primary TRI for STEMI between May 2007 and June 2008. TRI was attempted with a 6-Fr guiding catheter in all patients regardless of Killip class status. Outcome measures were success rates of primary TRI, door-to-balloon time, procedure duration and volume of contrast used. All patients were followed up for major adverse cardiac events in-hospital, at 30 days and six months. RESULTS: A total of 138 patients had primary TRI attempted for STEMI. Four patients failed primary TRI and required a femoral approach. The remaining 134 patients underwent primary TRI. The mean patient age was 56.4 years. Most patients with acute STEMI presented in Killip class I and II (91.8 percent). Only 8.2 percent were in Killip class III or IV on admission. 50 percent of patients presented with anterior STEMI. The median door-to-balloon time for this group was 92 (interquartile range [IQR] 77-121) minutes, with a median procedure time of 39 (IQR 29-51) minutes. The success rate of primary TRI was 97.1 percent. CONCLUSION: Success rate, procedural and radiation time for TRI are comparable to those achieved via the femoral approach. Primary TRI is therefore a feasible and effective approach for acute STEMI, even in high-risk patients. PMID- 21552787 TI - Impact of Ramadan fasting on intraocular pressure, visual acuity and refractive errors. AB - INTRODUCTION: Fasting evidently influences a variety of physiological parameters that can impact the ocular system. Among these modifications are alterations in insulin secretion, sympathetic activity, free fatty acids, lipid profile, melatonin, cortisol, electrolytes and catecholamines. In this study, we investigated the possible alterations in intraocular pressure (IOP), visual acuity and refractive errors during Ramadan fasting. METHODS: IOP, visual acuity and refractive errors of both eyes of volunteers were measured on the first and last days of Ramadan (once in the morning and evening). Body weight was measured so as to estimate the amount of dehydration. Data from the two examinations was analysed using one-way analysis of variance. A p-value of less than 0.05 was considered statistically significant. RESULTS: 58 healthy, fasting male volunteers with a mean age of 40.7 +/- 7.1 years participated in the study. Statistical analysis demonstrated no difference in IOP, visual acuity or refractive errors on the first and last days of Ramadan, or within a single day (from morning to evening). CONCLUSION: Our results reveal that Islamic Ramadan fasting does not profoundly affect physiological IOP, refractive error or visual acuity values in healthy volunteers. However, more detailed investigations using animal models should be designed to evaluate whether fasting has a pivotal influence on pathological conditions. PMID- 21552788 TI - Prolonged cough presenting with diagnostic difficulty: a study of aetiological and clinical outcomes. AB - INTRODUCTION: Prolonged cough is a common reason for referral to a respiratory physician. Some cases of prolonged cough can be a diagnostic challenge, especially when it is not accompanied by features that suggest common aetiologies. The current study examined this group of patients so as to ascertain the final aetiological and clinical outcomes. METHODS: We performed a chart review of cases that had been prospectively identified. The inclusion criteria were cough lasting more than three weeks, normal chest radiograph, non-smoking status, no history of angiotensin-converting enzyme inhibitor use, normal physical examination and absence of suggestive features of asthma, gastroesophageal reflux disease and postnasal drip syndrome. We classified the final diagnoses into three categories: likely diagnosis; possible diagnosis; and no diagnosis established, and traced the clinical outcomes. RESULTS: A total of 54 patients met the study criteria. The median duration of cough was 16 weeks (range four weeks to five years), while the median age of the patients was 38 (range 18-73) years. A likely diagnosis was reached in 23 patients and a possible diagnosis, in 12 patients. Gastroesophageal reflux disease and postnasal drip syndrome were the commonest diagnoses. There were no cases of asthma. The cough improved completely in 44 patients. Three cases were lost to follow-up before an outcome could be documented. CONCLUSION: In most of these cases, a diagnosis could be achieved. The cough improved in the majority of patients, including those in whom a diagnosis could not be made. PMID- 21552789 TI - Diagnostic value of renal resistive index for the assessment of renal colic. AB - INTRODUCTION: The aim of this study was to investigate the value of renal resistive index (RI) for the assessment of renal colic and to determine whether it is predictive of renal stone disease. METHODS: A total of 70 participants were included in the research study. Group 1 comprised 43 patients with acute unilateral ureteral obstruction due to a stone disease (G1), while Group 2 consisted of seven patients with flank pain without stone disease (G2) and the control group comprised 20 healthy individuals with two normal kidneys (G3). Urinalysis, abdominal plain film radiography, conventional ultrasonography (US) and colour Doppler US were performed in all three groups. RI was calculated for all patients using Doppler US. The RI values in G1 were then compared with those in G2 and the control group. RESULTS: There were statistically significant differences in the RI between the stone-positive group and stone-free groups (0.71 +/- 0.07 for G1; 0.69 +/- 0.06 for G2; 0.62 +/- 0.03 for G3, p-value < 0.05). CONCLUSION: RI measurement using Doppler US can be effectively used for the assessment of renal colic patients by non-invasive means. PMID- 21552790 TI - Analysis of isoproterenol-induced changes in gastrocnemius muscle and serum lactate dehydrogenase expression in mice. AB - INTRODUCTION: Beta-adrenergic agonists are highly abused by sportspeople for their muscle anabolic and lipolytic effects. Muscle growth effects are thought to result from beta-2 adrenoceptor activation. This study attempted to characterise muscle (gastrocnemius) tissue damage following the administration of isoproterenol. METHODS: Adult male Balb-C mice were treated with a single oral dose of isoproterenol (100 mg/kg body weight) for 4, 8, 20, 48 and 72 hours. Control mice received equal doses of saline. The animals were killed at the respective stages, followed by the collection of gastrocnemius and blood. Serum was then separated from blood. Histopathology and lactate dehydrogenase (LDH) assays were performed. RESULTS: Beta-adrenoceptor activation-induced histological changes began with structural aberrations, and ultimately resulted in myonecrosis and extensive degeneration within hours of the administration of isoproterenol. The effects of beta-agonist administration on muscle myofibre organisation were visible within four hours and became most prominent at 20 and 48 hours. Augmentation of more than 20 percent in muscle LDH activity was observed at 4, 8 and 72 hour stages, and was accompanied by a significant decline of 19 and 27 percent at 20 and 48 hour time points, respectively. Serum corroborated the above results. CONCLUSION: Isoproterenol treatment produced considerable histopathological changes, including myonecrosis in mice gastrocnemius, resulting in a leaky sarcolemma and the release of marker enzyme, LDH into the serum (more evident after 20 and 48 hours). This suggests that isoproterenol promotes the process of necrosis in mice gastrocnemius at the concentration employed, which raises a significant question regarding the use and abuse of beta-agonists. PMID- 21552791 TI - Oxidative and nitrosative stress in association with DNA damage in coronary heart disease. AB - INTRODUCTION: Oxidative and nitrosative stress caused by a disturbance in the homeostasis of pro-oxidants and antioxidants play a vital role in the pathogenesis of coronary heart disease (CHD). Enhanced formation of reactive oxygen species/reactive nitrogen species may also affect the oxidation/nitration of biomolecules such as lipids, proteins and DNA. The present study was undertaken to estimate oxidative and nitrosative stress, and to evaluate oxidative DNA damage. METHODS: The study population consisted of 120 patients with angiographically documented CHD and an equal number of age- and gender matched healthy controls. Lipid profiles were estimated using Glaxo kits. Estimation of plasma malondialdehyde (MDA), nitrite/nitrate and comet assay were carried out using previously published methods. RESULTS: Lipid profiles were significantly different in patients with coronary artery disease compared to the controls (p-value less than 0.01). The levels of MDA, nitrite/nitrate and DNA damage in the patients were significantly higher compared to the controls, and a strong correlation was found between the comet tail length and the MDA and nitrite/nitrate levels. Further analysis revealed that the influence of nitrite/nitrate was greater than that of MDA. CONCLUSION: Our results indicate that abnormal levels of lipid profiles, along with increased oxidative and nitrosative stress as well as somatic DNA damage, could be important pathogenic factors that act as additional prognostic predictors. They may also serve as potential targets for therapeutic strategies in CHD for early management and prevention of the disease. PMID- 21552792 TI - Prognostic factors for locoregional recurrence and survival in stage IIIC breast carcinoma: impact of adjuvant radiotherapy. AB - INTRODUCTION: The aims of the present study were to define the prognostic factors for locoregional recurrence (LRR) and survival in stage IIIC breast carcinoma as well as to examine the impact of adjuvant radiotherapy on the outcome of the disease. METHODS: The records of 586 consecutive patients with stage IIIC breast carcinoma who underwent modified radical mastectomy were evaluated, and the prognostic factors for LRR and survival were analysed. Survival curves were generated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard model. RESULTS: Five-year LRR and survival of stage IIIC breast carcinoma were 15 percent and 41.3 percent, respectively. Five year LRR was significantly lower and five-year survival was significantly higher for all patients as well as for T1-2 patients with one to three apical node involvements who were treated with adjuvant radiotherapy. In multivariate analysis, apical node involvement, age below 35 years, T4 tumour, grade 3, extracapsular extension and lymphovascular invasion decreased survival, whereas adjuvant tamoxifen and adjuvant radiotherapy (risk ratio [RR] 0.51, 95 percent confidence interval [CI] 0.39-0.67) increased survival. Adjuvant radiotherapy was the sole independent factor that was found to be significantly associated with decreased LRR (RR 0.25, 95 percent CI 0.16-0.38). CONCLUSION: Radiotherapy decreased LRR and increased survival significantly in all stage IIIC patients and in the subgroup of T1-2 patients with one to three apical node involvements. Thus, it should be considered in the treatment of stage IIIC breast carcinoma. PMID- 21552793 TI - The perils of medical tourism: NDM-1-positive Escherichia coli causing febrile neutropenia in a medical tourist. AB - NDM-1 is a new metallo-beta-lactamase that readily hydrolyses carbapenems, penicillins and cephalosporins. Its rising incidence has been reported in many countries around the world, with many cases linked to a possible origin from the Indian subcontinent. Due to the lack of effective antibiotic regimes to treat these infections, the increased prevalence of NDM-1 is alarming. We describe a case of NDM-1 infection in an immunocompromised foreign patient, and discuss its implications. PMID- 21552794 TI - Ministry of Health clinical practice guidelines: Chronic Hepatitis B Infection. AB - The Ministry of Health (MOH) publishes clinical practice guidelines on Chronic Hepatitis B Infection to provide doctors and patients in Singapore with evidence based guidance on managing important medical conditions. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Chronic Hepatitis B Infection, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website (http://www.moh.gov.sg/mohcorp/publications.aspx?id=26108). The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines. PMID- 21552796 TI - Comment on: Use of Ankaferd Blood Stopper for controlling actively bleeding fundal varices. PMID- 21552797 TI - Sciatic nerve division: anatomic support for clinical work. PMID- 21552798 TI - C-myc protein distribution - mammary adenocarcinomas of mtv/myc transgenic mice. AB - Transgenic mice have been used to demonstrate that the myc transgene, fused to the murine mammary tumor virus LTR promoter, leads to development of mammary tumors. To study the role of the Myc protein in these tumors, a sensitive immunohistochemical method was used to compare the Myc protein expression in mammary tumors and normal mammary gland from two independent MTV/myc transgenic lines. The highest levels of staining for Myc were found in the epithelial cell nuclei of mammary tumors and foci of mammary hyperplasia. Normal transgenic epithelium had only scattered foci of low intensity staining nuclei. The nuclei of transgenic mesenchyme and of non-transgenic mammary glands of control FVB mice did not contain detectable antigen. This work supports the hypothesis that the Myc protein can play a role in mammary tumorigenesis and suggests a correlation between high levels of Myc and the development of histopathology. PMID- 21552799 TI - The interaction between protein-kinase-C (pkc) and estrogens (review). AB - The interactions between protein kinase C (PKC) and the steroid hormone estradiol or its receptor (ER) are reviewed. Estradiol upregulates PKC both in vitro and in vivo in the ovary, the anterior pituitary and in mammary tissue of several mammalian species. The antiestrogen tamoxifen inhibits PKC. Activation of PKC leads to a marked decrease of ER protein and ERmRNA in human breast cancer cells and some other cell lines. Inhibition or down-regulation of PKC enhances ER binding. These results indicate that there are links between the PKC signal transduction pathway and the steroid receptor family. Further studies are needed to clarify the role of PKC isoforms in normal and cancerous tissues which are known to be influenced by estradiol. PMID- 21552800 TI - Injection of irradiated b16 melanoma genetically-modified to secrete IFN-alpha causes regression of an established tumor. AB - Highly aggressive murine B16 melanoma was engineered to secrete IFN-alpha constitutively. Cells expressing IFN-alpha were injected into syngeneic C57BL/6 mice and the mice were monitored for tumor development. Secretion of IFN-alpha by B16 melanoma cells completely abrogated their tumorigenicity in syngeneic mice. LFN-alpha-secreting cells also abrogated the tumorigenicity of IFN-gamma secreting and TNF-alpha-secreting cells when injected in combination whereas cells secreting either IFN-gamma or TNF-alpha grow progressively in mice when injected alone. Moreover, protected animals developed significant immunity against subsequent challenge with parental cells. Injection of parental cells and IFN-alpha-secreting cells together in a mixed tumor transplantation assay resulted in a significant reduction of tumorigenicity of the parental cells. Histopathological studies of the tissues from the injection site of the mice inoculated with a combination of parental and B16.IFN-alpha cells revealed the existence of a massive cellular infiltrate composed of lymphocytes and granulocytes at an early stage (7-11 days). In the later stages (22 days), no recognizable tumor tissue was detected. Injection of irradiated IFN-alpha secreting cells in the mice carrying an established tumor completely prevented tumor development in 80% of the treated mice when injection was performed on the same side as the tumors. Injection of irradiated IFN-alpha-secreting cells in the contralateral site showed much less effect on the established tumor. Systemic antitumor effects on the established tumor can be enhanced by using a combination of irradiated IFN-alpha and IFN-gamma secreting cells as a vaccinating inoculum. PMID- 21552801 TI - Genome scanning using endogenous LTR-like elements for rapid DNA-fingerprinting of breast-cancer and transformed human breast epithelial-cells. AB - In the present work genomic DNAs from nine primary breast cancers and transformed human breast epithelial cell lines obtained by treatment of MCF 10F, a spontaneously immortalized human breast epithelial cell line, with benzo(a)pyrene (BP) or 7,12 dimethyl benz(a)anthracene (DMBA), were used for genomic scanning. The treatment of MCF 10F with BP gave rise to different clones designated BP1 and BP1E, the latter being a tumorigenic cell line. Treatment with DMBA gave rise to D3 and D3-1 clones. The clones D3-1 and BP1 have been transfected with the plasmid pH06T1 containing the mutated c-Ha-ras oncogene resulting in the D3-1Tras and BP1T-ras cell lines, that are highly tumorigenic in SCID mice. Genomic DNA are separately hybridized to two different probes representing different families of human endogenous retrovirus like sequences (RTLV-H and HERV-K LTR). The technique of genomic scanning allows the mapping of each tumor or cell line and comparison with its counterpart obtained from the adjacent normal tissue of the same patient or with the untreated MCF 10F cells. DNA changes such as deletions, amplifications and/or rearrangements were detected in 5 of the tumor pairs studied. We have identified genomic alterations that involved amplification of a 10 kb band in the transformed cell lines. The cell lines D3-1Tras and BP1T-ras show, in addition, the presence of a second band of 4.5 kb in size. A third band of 500 bp size was found in clones D3-1 and BP1E that have a more aggressive behavior in vitro than their precursors D3 and BP1 cells respectively. In conclusion the present report indicates that genomic scanning detects DNA aberrations in primary primary tumors and in human breast epithelial cells transformed with chemical carcinogens and/or oncogene transfection that are not present in their normal counterpart. These results further indicate that detection of endogenous retrovirus elements may help in genome mapping and can be a useful tool for detecting genomic changes in the preliminary screening of DNA extracted from primary breast cancer and transformed cells. PMID- 21552802 TI - In-situ activated macrophages are involved in host-resistance to lymphoma metastasis by production of nitric-oxide. AB - We studied nitric oxide (NO) production, adenosine deaminase (ADA) and 5' nucleotidase (5-N) activity as a function of macrophage activation in the model of spontaneous metastasis of ESbL T lymphoma cells transduced with the lacZ gene. Liver and spleen macrophages were isolated and examined directly ex vivo without further experimental manipulation. Transient arrest of liver metastasis was accompanied by an increase of NO production and ADA activity and by a decrease of 5-N activity. An aggressive expansion of metastasis was correlated with a drop of NO production and ADA activity and with an increase of 5-N activity. To test the involvement of in situ activated Kupffer cells in an antimetastatic response, two immunotherapy protocols were used: i) active immunization with lymphoma cells and ii) adoptive transfer of antitumor immune spleen cells. Both treatments caused an upregulation of ADA activity and NO production in Kupffer cells, which correlated with host resistance against metastases. PMID- 21552803 TI - Regulation of the ribosomal-RNA gene-expression in fibroblasts isolated from different human or murine tissues. AB - Ag-NOR stainings of the fibroblastic cultures derived from skin, lung and kidney of mice and humans have shown differential regulation of rRNA gene expression. Ag NOR activities were found to be highest in the fibroblasts derived from the lung and the lowest in the skin-derived metaphases from both mice and humans and they were intermediate in the fibroblasts of kidney from both these species. Our observations indicate further that fibroblasts derived from different tissues are different not only in producing organ-specific growth factors but also in differential expression of ribosomal cistrons. This difference can also explain why orthotopic implantation of human tumor cells into nude mice is preferential compared with ectopic implantation in tumor take and metastasis. PMID- 21552804 TI - Retinoic Acid potently stimulates the production of granulocyte-colony stimulating factor in the human monocytic thp-1 cell-line. AB - Lipopolysaccharide (LPS) potently induces the production of several cytokines in THP-1 cells pretreated with phorbol 12-myristate 13-acetate (PMA). We report that all-trans retinoic acid (tRA) synergizes with LPS to enhance the production of granulocyte colony-stimulating factor (G-CSF) in PMA-treated cells, whereas the production of granulocyte-macrophage CSF, interleukin 1-beta (IL-1-beta), and tumor necrosis factor-alpha (TNF-alpha) is minimally affected by tRA. The interaction between LPS and tRA on G-CSF production is not due to IL-1-beta or TNF-alpha present in the culture medium during LPS and tRA treatment because neutralization of n-1-beta and TNF-alpha activity does not inhibit the synergy between LPS and tRA. However, exogenous IL-1-beta, but not TNF-alpha, also synergizes with tRA on G-CSF production, suggesting that LPS and IL-l-beta can independently interact with tRA to stimulate G-CSF production. PMID- 21552805 TI - Va-es-bj - an epithelioid sarcoma cell-line. AB - A tumor cell line was derived and established from a bone marrow aspirate of a 41 year-old male who presented with motor symptoms of cord compression and an epidural tumor with osseous, pulmonary and hepatic metastases. The epidural tumor was an epithelioid sarcoma staining positive for cytokeratin markers of epithelial differentiation AE-1 and AE-3. This cell line was composed of lowly refractile, multinucleated giant or mononuclear round or elongated cells with monopolar or bipolar short processes. When permitted to grow beyond confluence these cells clumped up and formed mounds progressing to free floating spheroids. The cells were characterized by chromosomal triploidy with marker chromosomes, rapid growth in nude mice and secretion of immunoreactive and biologically functional granulocyte macrophage colony stimulating factor. This epithelioid sarcoma cell line stained positive for AE-1, AE-3, vimentin, epithelial membrane antigen and was designated VA-ES-BJ. PMID- 21552806 TI - Multiple effects on drug-sensitivity, genome stability and malignant potential by combinations of h-ras, C-myc and mutant p53 gene overexpression. AB - Activation of specific oncogenes and inactivation of tumor suppressor genes play major roles in mechanisms leading to neoplastic transformation. The potential involvement of these genes in determining genome stability is an important issue. To examine the relationships between altered oncogene expression and the effects on genome stability, we have investigated the drug sensitivity properties of mouse 10T1/2 fibroblasts transfected with combinations of H-ras, c-myc and the proline 193 mutant form of p53. The relative colony forming efficiencies of these cells were investigated in the absence or presence of various concentrations of the chemotherapeutic agents, methotrexate, N-(phosphonacetyl)-L-aspartate (PALA) or hydroxyurea. The effects of altered oncogene expression were found to be drug and locus specific, and to lead to increased drug resistance (e.g. H-ras transfectants were significantly resistant to methotrexate or PALA), decreased drug resistance (e.g. H-ras/-myc transfectants were significantly less resistant to PALA or hydroxyurea than H-ras transfected cells), or to no significant change in drug sensitivity (e.g. H-ras transfected cells were not significantly different in sensitivity to hydroxyurea than non-transfected cells). Gene amplification was an important but not the only mechanism for drug resistance. Cells that were transfected with p53 (H-ras/p53 or H-ras/c-myc/p53) exhibited the greatest drug resistance properties with all three chemotherapeutic agents, in keeping with the important role of p53 in DNA repair and DNA amplification mechanisms. Although both H-ras/p53 and H-ras/c-myc/p53 groups exhibited very similar genome stability characteristics as determined by drug sensitivity results, they were significantly different in their abilities to produce transformed foci in vitro and lung metastases in vivo. The H-ras/c-myc/p53 transfected cells formed significantly higher numbers of transformed foci and exhibited a greater malignant potential. These results are consistent with observations that H-ras expression directly correlates with malignant potential, and that H-ras/c-myc/p53 transfected cells have higher H-ras expression than H ras/p53 transfected cells. Alterations in genomic integrity through changes in onocogene expression play important roles in mechanisms determining drug sensitivity; in addition to genome destabilization, other events are critically involved in regulating transformed and malignant characteristics. PMID- 21552807 TI - Phase-I tolerability study of 5-methyltetrahydrofolate in combination with a 4 hour infusion of 5-Fluorouracil in cancer-patients. AB - 5-methyltetrahydrofolate (MTHF) is a main serum metabolite of 5 formyltetrahydrofolate (folinic acid, FA), a standard agent for potentiation of the cytotoxic activity of 5-fluorouracil (5-FU). The clinical application of MTHF instead of FA as a precursor of the biologically active metabolite 5,10 methyltetrahydrofolate (mTHF) is based on favorable pharmacologic characteristics of MTHF described so far. In this phase I study 18 patients with advanced solid malignancies were treated with MTHF for 5 days at doses ranging from 100 to 500 mg/m(2)/day in combination with a fixed dose of 500 mg/m2/day 5-FU given as a 4 hour infusion. The treatment was repeated after 21 days. The toxicity observed was mainly gastrointestinal with loss of appetite, nausea and vomiting (up to WHO grade III), and less frequently stomatitis, decline of hemoglobin and hematuria (up to WHO grade II). The frequency and severity of side effects seen were not related to the dose of MTHF. Cumulative toxicity was not observed. The MTD was not reached up to an MTHF dose of 500 mg/m(2)/day. Objective remissions were not seen. The study was terminated on the basis of results showing comparable 5,10 methylenetetrahydrofolate (mTHF) tumor- and tissue levels after administration of MTHF or FA. PMID- 21552808 TI - The antiproliferative aspects of mortalin (review). AB - Cellular mortal and immortal phenotypes as defined by the limited and the infinite capacity of cells to divide are the characteristics of normal and cancerous cells in culture. Numerous strategies that have been employed to understand the mechanism(s) of normal as well as tumor cell growth have revealed that these are genetically controlled, however, the genes and the synchronized regulations remain largely undefined so far. The present report reviews the identification of mortalin, a novel member of murine hsp70 family of proteins, as a gene involved in pathways that determine divisional phenotype of cells in vitro. In the present study, the anti-proliferative activity of mortalin is demonstrated also in human skin fibroblasts (TIG-73PD) by microinjection of anti mortalin antibody. Furthermore, studies on the mortalin immunofluorescence patterns in SV40-immortalized pre-crisis and post-crisis human cells have revealed that the change in the intracellular distribution of mortalin is linked to the change in the divisional phenotype of cells. Thus, the studies to resolve the molecular basis of association of the cytosolically distributed form of mortalin with cellular mortal phenotype would be important in understanding of the mechanism(s) that determine replicative potential of cells in culture. PMID- 21552809 TI - Analysis of h-ras, k-ras and N-ras genes for expression, mutation and amplification in laryngeal tumors. AB - The levels of expression of the ras family genes, in 14 tumour specimens from squamous cell carcinomas of the larynx were analysed by reverse transcription polymerase chain reaction. The H-ras was overexpressed in 12 (86%) samples, K-ras in 11 (78%) and N-ras in 8 (57%) samples. All tumours exhibited overexpression of at least one member of the I-as family. In addition, each member of the ras family was activated independently from the rest of the ras family genes. The incidence of amplification in the ms family genes was also analysed by differential PCR: K-rns was found amplified in 14% (2/14), N-ras in 7% (1/14) and H-ras in none of the samples tested. Amplification data exhibited no association with the expressional levels of the ras genes. Furthermore, we investigated the incidence of codon 12 point mutations in the ras family genes but no mutation was found. The present study indicates that overexpression of the ras family genes is important for the development of the disease and it is not associated with the amplification status of the genes. In addition, the differential regulation among the members of the ms family might play a role in the development of laryngeal tumours. PMID- 21552810 TI - The anticancer agent pb-100 concentrates in the nucleus and nucleoli of human glioblastoma cells but does not enter normal astrocytes. AB - Selectivity of the anticancer agent PB-100 for malignant cells, already demonstrated using cell growth and viability evaluation, is now confirmed by microscopic observations. PB-100 is easily detected inside cells by its yellow color under visible light and by its blue fluorescence; it may be measured in isolated nuclei using its characteristic UV absorbance. After short treatment of human BCNU-resistant glioblastoma cells (U 251) and normal astrocyte controls (CRL 1656), PB-100 accumulates in the malignant cell nucleus, particularly concentrating in the multiple nucleoli and rapidly inducing glioblastoma cell death, whilst, in contrast, the anticancer agent does not even enter normal cells. We had already shown that PB-100 binds to DNA of cancer cells, but not to that of normal cells. In vitro tests described in this report indicate that PB 100 binds to purine bases, but not to pyrimidines, of various ribopolymers and its binding to purine rich nucleic acid stretches is inferred. PMID- 21552811 TI - Inverse expression of neurotrophins and neurotrophin receptors at the invasion front of human-melanoma brain metastases. AB - Neurotrophins (NT), such as nerve growth factor (NGF), stimulate the growth and differentiation of several neuronal subpopulations in a distinct yet overlapping manner. Brain-metastatic human melanoma cells overexpress p75(NTR), the low affinity neurotrophin receptor, and treatment of brain-metastatic cells with NGF stimulates extracellular matrix invasion and production of degradative enzymes in relation to the cellular expression of p75(NTR) Although human melanoma cells express high affinity neurotrophin receptors, such as TrkC (the putative receptor for NT-3), they do not express TrkA, the high-affinity NGF receptor. Using digoxigenin-labeled sense/antisense riboprobes against human p75(NTR) and NGF for in situ hybridization, we determined whether the expression of p75(NTR) and NGF mRNAs are related to brain metastasis of human melanoma. We detected p75(NTR) mRNA at the invasion front of human melanoma brain metastases, whereas p75(NTR) expression was not found in adjacent tissues. In contrast, human NGF mRNA levels were increased in tissues surrounding the melanoma lesions, supporting the notion that NGF and NT are important in determining melanoma brain-metastatic microenvironment. Using antibodies specific to p75(NTR), TrkC, NGF and related NT we found high but heterogeneous levels of p75(NTR) and TrkC expression in malignant melanomas metastatic to the brain. Lower levels of expression were found in primary melanomas or in metastatic melanomas to sites other than brain. Additionally, we found elevated levels of synthesis of NGF and NT-3 but not brain derived neurotrophic factor (BDNF) or NT-4/5 in the brain tissues surrounding melanoma lesions. These studies support a role for NT and their receptors in the progression of melanomas to the brain-metastatic phenotype. PMID- 21552812 TI - Interleukin-8 and granulocyte-macrophage colony-stimulating factor secretion in hematologic malignancies. AB - Interleukin-8 (LL-8) and granulocyte-macrophage colony-stimulating factor (GM CSF) are cytokines/hematopoietic growth factor and are important mediators of inflammation and immune resoponse producing pathophysiological changes in human disease. Levels of IL-8 and GM-CSF in circulation of various hematologic diseases are unknown. To demonstrate their importance in lymphoproliferative disorders, we have measured the circulating levels of these two cytokines from patients with chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). IL-8 and GM-CSF levels were determined by highly specific enzyme linked immunosorbent assays. IL-8 levels were elevated in most patients with B cell malignancies, B-cell CLL (B-CLL) and B-cell NHL (B-NHL) as well as in patients with HD. However, GM-CSF levels were higher in most patients with NHL (T NHL and B-NHL) and HD. IL-8 was undetectable in T-cell malignancies (T-CLL and T NHL), whereas GMCSF was undetectable from CLL (T-CLL and B-CLL). Of interest, IL 8 levels were correlated with white blood cell counts (WBC) in B-cell malignancies (B-CLL and B-NHL) but not in HD. These results suggest that both IL 8 and GMCSF may play an important role in pathophysiological changes in B-NHL and HD. IL-8 may be related with recruitment and activation of neutrophils, whereas, GM-CSF in proliferation and differentiation of hematopoietic progenitor cells and immune response in these malignancies. The clinical status of B-CLL patients in regards to WBC counts appeared to be associated with the serum levels of IL-8. PMID- 21552813 TI - Measurement of epithelial and stromal changes in vulvar carcinoma - a clinical, biochemical and immunohistochemical study. AB - We evaluated the clinical usefulness of the squamous cell carcinoma antigen (SCC) and CA 125, serum markers of epithelial cancer cells, in comparison with the serum concentration and tissue distribution of the aminoterminal propeptide of type III procollagen (PIIINP), a marker of connective tissue metabolism, in 31 patients with vulvar carcinoma. The SCC concentration was increased in 42%, that of CA 125 in 14% and that of PIIINP in 36% of the cases. The combination of SCC and PIIINP increased the detection rate to 57% and that of all three to 64%. None of the tumor markers correlated with the clinical stage of the disease. The initial values of the serum markers did not discriminate between different patterns of the clinical behavior of the disease. Six patients were followed with serial determinations of the markers. In each case at least one of the markers correlated with the clinical course of the disease. SCC did so in 5 cases, PIIINP in 3 cases and CA 125 in 2 cases. The mean concentrations of SCC and CA 125, but not that of PIIINP, were significantly lower during the periods of response to therapy than during the nonresponsive periods. Immunohistochemistry of PIIINP showed vulvar carcinoma to be associated with a distinct collagenous stroma. In the junctional area of the stroma around the malignant epithelium, the PIIINP positive fibers grew more sparse and irregular with decreasing differentiation of the tumor. The present data suggest that SCC, CA 125 and PIIINP are useful, especially SCC, in monitoring the clinical behaviour of the advanced vulvar cancer, less so in predicting its prognosis. PMID- 21552814 TI - Comparison of 4 proliferation markers and their significance for evaluation of tumor dignity in intracranial tumors. AB - The proliferation indices of immunohistochemically detected bromodeoxyuridine, Ki 67 antigen (antibodies Ki-67 and MIB 1), and proliferating cell nuclear antigen were determined manually and with computer assisted morphometry in 38 gliomas, 29 meningeomas, 9 metastases, and 16 other tumors. Comparing the markers among one another the highest correlation coefficient was found for bromodeoxyuridine and MIB 1 (0.9). The proliferation indices of all markers correlated significantly with the tumor grading. The highest correlation coefficient for proliferation index and grading (0.7) was calculated for the MIB 1 index determined in one high power field (0.0153 mm(2)) in the tissue area with the highest proliferative activity. Concerning applicability and correlation with tumor dignity MIB 1 was superior to the other three antibodies investigated. PMID- 21552815 TI - Autonomously replicating segment identified in the murine p53 gene contains p53 recognition sequence and bending region. AB - The mouse p53 gene, spreading over 16 kb, was divided into 10 segments of approximately 1,000 bp and subcloned into pUC19. The clones were transfected into mouse L cells together with an expression vector of the hygromycin B- or blasticidin S-resistance gene. The transfected cells were cultured in the drug containing medium to establish cell lines resistant to the drug. Among the established lines, a high percentage of the cells originally transfected with pp53(H-R), possessing the HindIII-EcoRI fragment located downstream from the last coding exon of the p53 gene, harbored plasmid DNAs in an episomal state. The plasmid DNAs recovered from the 53HR cell-lines, transfected with pp53(H-R), were indistinguishable in structure from the original plasmids used for transfection, as assayed by Southern blotting and back-transformation to bacteria. The plasmids in episome of the cells replicated once per cell cycle in S phase in concert with chromosomal DNA. In the HindIII-EcoRI fragment (i.e., the p53(H-R) fragment) which showed a highly efficient replication activity, there exists a putative sequence for p53 recognition near the HindIII site. A DNA bending region with the clusters of AT tracts also exists near the EcoRI site of the same p53(H-R) fragment. In a transient replication system, pp53(H-R) autonomously replicated in episome of transfected cells, while mutant plasmids lacking either the p53 recognition sequence or the bending region did not. The results suggest that the HindIII-EcoRI region downstream from the p53 gene contains an activity of cellular DNA replication and both the p53 recognition sequence and the bending region are necessary for the replication activity. PMID- 21552816 TI - Immunohistochemical detection of the laminin receptor polypeptide, a putative precursor of 67-kda-laminin receptor, in human lung-cancer. AB - Laminin receptor polypeptide was immunodetected in human lung cancer with a polyclonal antibody raised against a 20-mer peptide of the putative high-affinity laminin receptor of 67 kDa (Wewer et al: Cancer Res 47: 5691-5698, 1987). As a result, immunoreactivity was recognized specifically in cancer cells both in freshly-prepared cell samples and in paraffin-embedded tissue specimens. It was shown that immunodetection of the laminin receptor polypeptide with this antipeptide antibody could be applied to diagnostic use for lung cancer. The results also suggest that the laminin receptor polypeptide is not necessarily a membrane-associated protein and may function without further processing to the 67 kDa-laminin receptor. PMID- 21552817 TI - Relationship between tumor response and the ratio of nucleotide triphosphates to inorganic-phosphate in small-cell lung-cancer xenografts. AB - We examined whether grossly similar tumor responses, obtained by different therapies, induce similar patterns of change in the ratios of nucleotide triphosphate (NTP) to inorganic phosphate (P-i) in two human tumor lines, derived from the tumor of the same patient. The tumor responses were induced by doxorubicin 10 mg/kg i.p. or 5 Gy X-radiation in the human small cell lung cancer (SCLC) lines 54A and 54B, grown as xenografts in athymic nude mice. In vivo P-31 magnetic resonance spectroscopy of tumors was performed pretherapeutically, and on days 1, 4, 8, and 15 following therapy, in a 4.7 T magnet. Individual NTP/P-i ratios were calculated relative to the pretherapeutic values, and treated (n=28) versus controls (n=28) were compared. In both tumor lines, doxorubicin induced a significant drop in NTP/P-i at day 1. In 54A tumors 5 Gy induced a significant increase in NTP/P-i, whereas no difference between the NTP/P-i of irradiated and controls was found in 54B tumors. Thus three distinct NTP/P-i patterns were observed in tumors during response to therapy: (i) A decrease, (ii) an increase, and (iii) no change. Our findings indicate that changes in this ratio do not correlate independently with tumor response in the SCLC sublines 54A and 54B. PMID- 21552818 TI - Colon-cancer and dietary habits - a case-control study. AB - The importance of dietary factors in colon carcinogenesis was analyzed as part of a case-control study from Northern Sweden encompassing 312 cases and 623 controls. Data on 28 different food items, each divided into consumption before and after the age of 25, were collected by a food frequency questionnaire. Mantel Haenszel odds ratios (MH-ORs) were calculated for various food items and nutritients and are given in parentheses where A represents consumption before and B after the age of 25. Reduced MH-ORs were seen for daily cheese intake (A=0.64, B=0.41) and also for intake of crisp bread, boiled and fried fish although not significantly. A non-significantly decreased risk was seen for fibre rich food. When food items were grouped with regard to their content of certain nutrients, decreased risks were associated with food rich in selenium (A=0.74, B=0.82). Also food rich in vitamin C gave a reduced MH-OR but only for intake before the age of 25 (A=0.75, B=1.09). For daily consumption of 2 or more cups of tea a reduced MH-OR of 0.61 was seen. Frequent intake of smoked food gave increased MH-ORs for both age groups (A=1.52, B=1.36) whereas high fat intake was not identified as a risk factor for colon cancer. Intake of alcohol or coffee was not associated with colon cancer risk in this study. PMID- 21552819 TI - Modulation of urokinase-type plasminogen-activator expression by the wild-type and mutated p53 tumor-suppressor gene. AB - The urokinase-type plasminogen activator contributes to the invasive phenotype of tumor cells by facilitating extracellular matrix hydrolysis. However, the molecular mechanism(s) responsible for urokinase overexpression remains unclear. The current study was undertaken to determine the role of the p53 tumor suppressor gene in the regulation of urokinase expression. Transient cob transfection of a urokinase-producing cell line with a wildtype p53 expression vector and a CAT reporter driven by the urokinase promoter led to a dramatic reduction in CAT activity. Conversely, urokinase promoter activity was increased in cells transiently transfected with a p53 expression vector mutated at codon 175. To determine if the endogenous urokinase gene was modulated by p53, cells were stably transfected with a mutated p53-bearing expression vector. An increased level of urokinase mRNA was apparent in pooled mutant p53 overexpressing clones. These studies argue for a role of the p53 tumor suppressor gene in the regulation of urokinase expression. PMID- 21552820 TI - T-cell receptor v-Beta usage of tumor-infiltrating lymphocyte lines cloned from human breast-tumor and melanoma. AB - A total of forty-one tumor infiltrating T cell lines (TIL) were cloned, in the presence of interleukin-2, from nine breast tumor and five melanoma specimens with limiting dilution in a microculture system. Nineteen (46%) of the lines/clones reacted to autologous tumor targets. The T cell receptor (TcR) V beta gene usage was analyzed using polymerase chain reaction (PCR) technique and a set of oligonucleotide primers specific for 20 V beta families. T cell lines generated from paired peripheral blood lymphocytes (PBL) under similar condition were used as control. Our data revealed a limited heterogeneity in TcR V beta gene usage with a biased expression of V beta 6 in both breast tumor- and melanoma-derived TIL lines/clones. In contrast, a random pattern of TcR V beta usage was observed in 27 control T cell lines derived from PBL of patients with breast cancer and melanoma. The results lend support to oligoclonal expansion of TIL at tumor sites but fail to directly correlate the preferential expression of V beta 6 with the functional property of the TIL in recognition of tumor antigens. PMID- 21552821 TI - Nucleotide-sequence of a canine oral papillomavirus containing a long noncoding region. AB - The DNA genome of a canine oral papillomavirus (COPV) was completely sequenced and found to consist of 8607 base pairs, which were the longest of all known papillomaviruses (PVs). Its organization was similar to that of other PVs except that it lacked early gene 5 (E5) and possessed a unique long noncoding region (L NCR) between the end of the early genes and the beginning of the late genes. COPV also possessed a short noncoding region (S-NCR) which contained a putative upper regulatory region (URR), which is commonly found in PVs. The L-NCR did not show any similarity to known PV DNAs nor other DNA sequences in the GenBank database. Nucleotide sequence analysis of COPV showed that it was closely related to human papillomavirus type 1 (HPV 1) and animal PVs associated with cutaneous lesions in rabbit, European elk, deer and cow as we reported previously. PMID- 21552822 TI - Long-term survival in high-grade soft-tissue sarcoma - prognostic factors in synovial sarcoma. AB - One hundred and thirteen consecutive patients with synovial sarcoma of the extremity or trunk were studied retrospectively. Seventy-six patients had surgery of their primary tumor at our institution (37 elsewhere). Mean follow-up for survivors was 124 (13-302) months. Thirteen developed local recurrence and 62 pulmonary metastases. Increasing surgical margin, adjuvant radiotherapy, and center-based treatment correlated with better local control. Older age, large tumor size and proximal position on the limb correlated with more metastases. Overall 5- and 10-year survival was 68 and 56%, respectively. Age, size, metastasis, metastasis free period and center-based treatment were independently prognostic. PMID- 21552823 TI - Definition of the p53 binding-site on the tms1 protein. AB - Recently we described the cloning of the yeast tms1 gene by complementation of a lethal growth arrest caused by expression of a tumour mutant cDNA of p53 in fission yeast. The tms1 gene product was found to form stable complexes with p53 in yeast and in vitro using purified recombinant proteins the interaction was mapped to the C-terminal region of p53. Using a combination of a genetic and a synthetic approach we were able to establish the p53 binding site on the tms1 protein to the sequence YMITTED FCT (aa 116-125) in the vicinity of a well conserved cell division motif. PMID- 21552824 TI - Transforming growth-factor-Beta - a cytokine with multiple actions in oncology and potential clinical-applications (review). AB - The transforming growth factor beta s (TGF beta) represent a family of multifunctional cytokines that modulate growth and function of many cells including those with malignant transformation. The actions depend on the tissue involved, and on the presence of signaling TGF beta receptors. Both in vitro and in vivo studies indicate that TGF beta mediates not only tumor progression but also exerts strong suppressive effects on certain tumor cells. Besides direct TGF beta - cell interactions, the modulation of immunocompetent cells by TGF beta may influence tumor cell growth. Further studies on the beneficial TGF beta effects on tumors, and even on chemotherapy including adverse reactions are required to define the use of TGF beta or TGF beta modulating agents in cancer therapy. PMID- 21552825 TI - The combined use of the decision tree technique and the computer-assisted microscope analysis of feulgen-stained nuclei as an aid for astrocytic tumor aggressiveness characterization. AB - A systematic and thus objective method is proposed to characterize astrocytic tumor aggressiveness. This method relies upon the combined use of a specific decisional algorithm (the decision tree) and 23 parameters which include 15 morphonuclear parameters describing the geometric, densitometric, and textural features of a cell nucleus, and 8 parameters describing the various levels of nuclear DNA content. These 23 parameters were objectively quantified by means of the digital cell image analysis of Feulgen-stained nuclei. This methodology was used to investigate whether it could be applied as a diagnostic tool. The biological model chosen included 12 cell lines adapted to grow in vitro and stemming from 4 astrocytomas (weakly malignant astrocytic tumors) and 6 glioblastomas (highly malignant ones). The 2 additional cell lines were from two medulloblastomas (MED) (2 highly malignant primitive neuro-ectodermal tumors). The results demonstrate unambiguously that it is actually possible to distinguish between low-grade and high-grade tumors on the basis of these parameters, which describe their morphonuclear features and the amount of their nuclear content. However, a clear-cut distinction between these different types of tumors can only be attained when a specific technique is used. In the present case this was the decision tree technique. We were not able to distinguish between these various histopathological groups when we used conventional statistical methods including the one-way-variance analysis of data or the carrying out of the X(2) test. PMID- 21552826 TI - A phase-I clinical-trial of a protracted continuous-infusion of 5-Fluorouracil with oral folinic Acid in patients with unresectable adenocarcinoma of the colon or rectum. AB - Studies of the mechanism of action of 5-fluorouracil (5-FU) suggest that maximal inhibition of the target enzyme thymidylate synthase can be achieved with a protracted infusion of 5-FU and oral leucovorin. We report the results of a phase I study in which seven patients with advanced colorectal cancer were treated with a 30-day continuous infusion of 5-FU and a fixed 50 mg dose of oral folinic acid every 6 hours. The 5-FU dose started at 100 mg/m(2)/day with planned escalations of 50 mg/m(2)/day. The qualitative toxic effects observed included diarrhea, mucositis, and hand/foot syndrome. These toxic effects were manageable at 100 mg/m(2)/day, but became dose-limiting at 150 mg/m(2)/day with two of four patients unable to complete the planned 30-day infusion. No objective responses were observed, but minor activity was documented in two patients. We recommend a starting dose of 125 mg/m(2)/day for subsequent phase II trials of this regimen in patients with colorectal cancer. PMID- 21552827 TI - Immune cells and cytokines - their role in cancer-immunotherapy (review). AB - Conventional cancer therapies such as surgery, chemotherapy and/or radiotherapy, are not always successful in providing long-term survival for cancer patients. One of the major problems with conventional cancer therapies is their inability to eradicate residual/metastatic tumor cells that are resistant to therapy. Therefore, it is necessary to develop new methods for treating such cancer cells in order to improve the clinical outcome of these patients. Despite antitumor effector mechanisms working against cancer cells in the host's body, tumor-cell induced immunosuppression and or antigenic modulation by the tumor cells often help tumor cells escape host defense mechanisms. Therefore, one approach for treating residual cancer would be to enhance the host's own immunological/antitumor defense mechanisms. Immune cells that have a significant role in mediating antitumor responses include: T lymphocytes; natural killer (NK) cells; macrophages; and B lymphocytes. The ability of these immune cells to effectively destroy malignant cells is carefully governed by chemical mediators in the form of proteins otherwise known as cytokines. Many cytokines (interleukins, interferons, and tumor necrosis factor) have been shown to enhance in vitro and in vivo effector cell antitumor cytotoxic activities. Utilization of cytokines in conjunction with effector cells can also mediate significant antitumor responses in both animal models and cancer patients. One of the major problems associated with systemic treatment with cytokines is the development of dose limiting toxicities. Currently, attempts to reduce this problem include developing techniques to allow for the preferential release of cytokines in proximity to the tumor cell. In this regard, effector cells or tumor cells that have been genetically engineered to secrete cytokine(s) may be useful in localizing an immune response, preferably at the tumor site. Clinical trial using cytokine gene transfected cells for treating cancer are currently under investigation. With the availability of recombinant lymphokines and with our ability to genetically modify effector cells and tumor cells this hopefully will allow us to improve current therapeutic modalities for treating cancer. PMID- 21552828 TI - Antitumor-activity and distribution of Beta-d-lactosylisophosphoramide mustard - a potential cytostatic agent exploiting lectin mediated transport. AB - Affinity chromatography of the Walker carcinosarcoma 256 B tumor revealed a lactose-specific lectin of 24 kDa. In a chemotherapeutical experiment, B-D lactosylisophosphoramide mustard (corresponding lectin present in tumor tissue) proved to be significantly more active than B-D-maltosylisophosphoramide mustard (no corresponding lectin present), although both compounds differ only marginally in their sugar parts. Whole body autoradiography after application of C-14 labeled B-D-lactosylisophosphoramide mustard in tumor bearing rats shows an accumulation of radioactivity in kidneys, thymus, central nervous system and in the tumor. Binding between the isolated lectin and the lactose-conjugated drug is shown in vitro; its activation outside tumor cells is experimentally excluded. PMID- 21552829 TI - Rejection of parental meth-a tumor on concomitant inoculation of meth-a cells infected retrovirally with the interferon-gamma gene into (balb/cxc57bl/6)f-1 mice. AB - The IFN-gamma gene was introduced retrovirally into Meth A cells. IFN-gamma gene infected Meth A (K gamma) cells were highly antigenic and regressed in CB6F(1) mice. Concomitant immunization of CB6F(1), mice with IFN-gamma gene infected Meth A (K gamma) cells after inoculation of parental Meth A protected the mice from parental tumor growth. 1x10(6) infectant Meth A (K gamma) cells protected the mice from growth of 1x10(6) parental Meth A cells, but 2x10(6) infectant cells did not, suggesting that there was an optimal dose of infectant cells for rejection of the parental tumor. Specificity analysis revealed that growth of CMS13 tumor was slightly inhibited by Meth A (K gamma) cells but that of CMS5 was not inhibited. The findings are consistent to those obtained with parental Meth A cells and indicated that the relevant rejection antigen on Meth A (K gamma) cells was identical to the parental Meth A rejection antigen. PMID- 21552830 TI - Expression of activin and activin receptors in human prostatic-carcinoma cell line du145. AB - The purpose of this study was to determine whether DU145, a human prostate cancer cell line: (a) transcribes mRNAs coding for beta A- and beta B-subunits of activin, a member of transforming growth factor beta (TGF beta) superfamily, and activin receptors I, II, and IIB; and (b) produces activin proteins. The expression and localization of the mRNAs were elucidated by the reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization techniques. The production of activin was determined by immunocytochemistry. We have observed that messenger RNAs encoding activin beta A-, beta B-subunits, and activin receptors I, II, and IIB, but not that of the alpha-subunit of inhibin, were expressed, and activin proteins, but not inhibin, were produced, by DU145 cells. Furthermore, the RT-PCR products were confirmed by DNA sequencing. It is concluded that activins and their receptors are expressed in DU145 and activins may have autocrine functions in DU145 cells. PMID- 21552831 TI - Detection of DNA-adducts in normal and tumorous human prostate biopsies by p-32 postlabeling. AB - Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of male cancer deaths in the United States. Several risk factors have been identified for prostate cancer, including increased serum testosterone levels, dietary fat intake, and ethnicity. In attempts to detect DNA damage in prostate tissue, we examined in a pilot study 18 pairs (36 samples) of normal and tumorous tissue biopsies from patients ages 50-76 years. DNA was isolated from frozen tissue by solvent extractions with DNA yield ranging from 392-1925 mu g/g tissue (mean 849 +/- 339 mu g/g). Analysis of the DNA by the nuclease P1-mediated P-32-postlabeling assay revealed the presence of multiple adducts in all DNA samples, irrespective of whether the tissue was normal or tumorous. Adduct levels generally ranged from 1-34 (mean 8 +/- 8) per 10(9) nucleotides for normal tissue and 3-37 (mean 11 +/- 9) per 10(9) nucleotides for tumorous tissue. Our data suggest (i) accumulation of DNA adducts in both normal and tumorous tissues; (ii) chromatographic similarity of certain adducts; and (iii) on an average, somewhat higher adduct levels in tumorous than normal tissue. Due to the small sample size examined, it remains to be determined if these DNA adducts were related to any of the risk factors. PMID- 21552832 TI - Malignant transformation of hpv-immortalized human oral keratinocytes by chemical carcinogens. AB - We previously immortalized primary human oral keratinocytes by transfection with cloned human papillomavirus type 16 (HPV-16) DNA and established a cell line, human oral keratinocytes-16B (HOK-16B). This line contained intact HPV-16 DNA in an integrated form, expressed viral genes, and demonstrated an indefinite life span. However, the cells proliferated only in keratinocyte growth medium containing a low level of calcium and were not tumorigenic in nude mice. To develop an in vitro multistage model suitable for the study of human oral carcinogenesis and to investigate the molecular mechanisms of cell transformation, the HOK-16B cells were exposed to either benzo(a)pyrene [B(a)P] or 7,12-dimethylbenz(a)anthracene (DMBA). Two chemically transformed cell colonies, one from B(a)P exposure and the other from DMBA treatment, were isolated. These cell lines proliferated well in Dulbecco's minimum essential medium containing a physiological level of calcium, demonstrated anchorage independent growth, and developed tumors in nude mice. They contained integrated HPV-16 sequences and expressed higher levels of epidermal growth factor receptor (EGFR) and c-myc transcripts compared to the parental cells. Similar to their immortalized parental cells, the chemically transformed cells also contained lower levels of p53 protein and transforming growth factor-beta (TGF-beta) transcripts than normal human oral keratinocytes. These results indicate that malignant transformation of oral keratinocytes can be caused by a sequential combined effect of high-risk HPV and chemical carcinogens. It also demonstrates that overexpression of viral E6/E7, EGFR and c-myc messages, together with the down-regulation of TGF-beta mRNA and the inactivation of p53 gene, may be associated with the malignant conversion of HPV-immortalized cells. PMID- 21552833 TI - Multiple tumor-suppressor-1 gene and esophageal-carcinoma. AB - The multiple tumor suppressor 1 (MTS1) gene is homozygously deleted frequently in cell lines derived from a wide variety of tumors. We investigated the deletion of the MTS1 gene in esophageal cancer cell lines and primary esophageal squamous carcinomas using the polymerase chain reaction. Sixteen and 15 of 23 esophageal cancer cell lines showed homozygous deletion of MTS1 exon 1 and exon 2, respectively, while none of 21 primary esophageal carcinomas showed the deletion. An analysis of MTS1 gene mutations was carried out by direct DNA sequencing in 8 cell lines and 21 primary carcinomas showing no homozygous deletion. In contrast to previous reports of esophageal carcinoma, there were no mutations recognized in the region sequenced. Our study suggests that the inactivation of the MTS 1 gene may play an important role in esophageal carcinoma cell lines but may be less important in primary carcinomas of the human esophagus. PMID- 21552834 TI - Polymorphism of the hpv-16 e6 gene of cervical-carcinoma. AB - Polymorphism of the human papillomavirus type 16 (HPV-16) genome has been reported to occur within the noncoding regulatory long control region (LCR) and in the E7 and L1 genes. The current study focuses on the HPV-16 E6 oncogene which interacts with the antioncogenic regulator p53. Seventy-eight HPV-16-positive DNA samples derived from cervical carcinomas were screened for the presence of polymorphism in the HPV-16 E6 gene by polymerase chain reaction (PCR) linked single stranded conformational polymorphism (SSCP) analysis. Nine DNA samples had heterozygous mutations within the same region of the E6 gene 3' terminus; T to C transitions at HPV-16 position 511 (silent) and one of the nine also had a 513 mutation (Met to Thr). These mutations correlated with the clinical aggressiveness of the tumor, suggesting that the presence of these mutations may be due to genomic instability of advanced cervical carcinoma. PMID- 21552835 TI - Correlation between tps and cea in patients with colorectal-cancer. AB - Serum TPS and CEA levels were measured in 173 cancer patients with various disease stages. The patients were divided into 4 groups: preoperative group, 16 patients in whom TPS and CEA were measured pre- and postoperatively; group I, 66 newly diagnosed patients up to 40 days post surgery; group II, 86 patients whose blood was taken 40-365 days post surgery, and group III, 47 patients on long-term follow-up in whom blood was taken more than one year after surgery. The median preoperative TPS levels were significantly higher (p<0.01) than the postoperative levels. Patients with Dukes' D had significantly higher TPS (p<0.01) and CEA levels as compared to patients with Dukes' B or C. For both Dukes' B and C stages there was a significant increase in median TPS level between group I and II and III. There was no similar increase in median CEA level. Serial measurements in individual patients show a significant increase in TPS levels between groups I, II and III. In Dukes' D patients, individual TPS levels decreased in response to therapy. There was a significant correlation between TPS and CEA levels. These results suggest that TPS measurement is additive to CEA in follow-up of asymptomatic patients, and to monitor response to therapy in patients with metastatic disease. PMID- 21552836 TI - Dependency of the efficiency of transformation by simian-virus-40 on the proliferative state of cultured fibroblasts at the time of virus inoculation. AB - We previously demonstrated that the efficiency of cell transformation by simian virus 40 (SV40) is reduced when proliferating rat 3Y1 cells are inoculated with SV40 as compared with when density-arrested cells are inoculated. In this study, we characterized in more detail the cellular state at the time of virus inoculation that affects the susceptibility to SV40 transformation. When density arrested 3Y1 cells were stimulated to progress one round of cell cycle by refeeding with medium containing high serum, they began to reduce the susceptibility to SV40 transformation before entering S phase. After re-entry into the non-proliferative state, prolonged maintenance of cells in the non proliferative state was necessary for restoration of the susceptibility to SV40 transformation. Such dependency of the transformation efficiency on the cellular state at the time of SV40 inoculation paralleled with that of the expression of T antigen in nuclei, while virus adsorption and degradation of the DNA of the adsorbed virus was not dependent on the cellular state. We conclude that after inoculation of proliferating cells with SV40, an unidentified event between the virus adsorption and the accumulation of T antigen protein in nuclei is blocked and that this blockage causes the inhibition of the initiation of transformation. PMID- 21552837 TI - Cumulative gene and chromosome alterations associated with in-vitro neoplastic transformation of human cervical cells. AB - The development of cancer is a multistep process requiring cumulative genetic alterations. An in vit ro model utilizing human cervical cells and papillomaviruses (HPV) that mimics human cervical cancer has been developed. Chromosome and gene alterations associated with distinctive stages of neoplastic transformation were demonstrated with an exocervical cell line obtained after sequential transfection with recombinant HPV-16 DNA and v-Ha-ras oncogene. Acquisition of immortality after HPV-16 transfection was associated with aneuploidy, structural changes of chromosomes 8, 10, 17, 19, 20, and 21, as well as proto-oncogene alterations. HPV-16 DNA was localized to two sites on chromosome 21, with one site at 21q22.2-22.3 near the ets-2 proto-oncogene. Ets-2 as well as c-myc gene mRNA levels were elevated in HPV immortal cells compared to primary nontransfected exocervical strains. Although the HPV-immortalized cells had several features characteristic of malignant cells, they lacked tumorigenic potential. Tumorigenicity occurred after transfection with v-Ha-ras oncogene, which was found stably integrated on chromosome 12 at the telomeric band q24.3. The tumorigenic line had additional clonal chromosomal abnormalities; consisting of multiple deletions involving regions of chromosomes 1p/q, 3p, 9q, loss of one copy of chromosome 11, and a complex rearrangement of chromosomes 8 and 13 as shown by in situ suppression hybridization with whole chromosome probes. Loss of tumor suppressor genes on deleted regions may have contributed to the acquisition of tumorigenicity. The genetic changes observed in these cells parallel those found in cervical carcinomas, demonstrating the validity of the in vitro model for studying the multistep progression resulting in cervical carcinoma. PMID- 21552838 TI - Promoting activities of the C-9 oxidized metabolites of N-2-fluorenylacetamide in liver carcinogenesis in the rat. AB - The promoting potential of the C-9 oxidized metabolites of N-2-fluorenylacetamide (2-FAA) was examined and compared to that of the promoter 2-FAA in the two-stage hepatocarcinogensis system Male Sprague Dawley rats were initiated with a single intraperitoneal injection of diethylnitrosamine at 200 mg/kg of body weight (b.wt.). One, 2 and 5 weeks thereafter rats were given by gavage 5 doses per week of 2-FAA (0.05 mmol/kg of b.wt.), 9-hydroxy- or 9-oxo-2-FAA (0.05 and 0.1 mmol/kg of b.wt.) or the vehicle polyethylene glycol 400 (2 ml/kg of b.wt.). All rats underwent partial (70%) hepatectomy on day 3 after 5 initial doses. Following treatment with 2FAA, 9-hydroxy-or 9-oxo-2-FAA, the levels of gamma-glutamyl transpeptidase activity and placental glutathione S-transferase (GST-P) were increased in the livers proportional to the increased numbers of foci of GST-P positive hepatocytes. The activities of the C-9 oxidized compounds were dose dependent since treatment at 0.1 mmol/kg of b.wt. resulted in -2-fold greater effects than that at 0.05 mmol/kg of b.wt. The incidences of hepatocellular carcinoma increased with time after treatment and the relative order of potency was: 2-FAA>9-oxo-2-FAA>9-hydroxy-2-FAA. These data combined with our earlier evidence for preferential oxidations of 2-FAA at C-9 by hepatic microsomes of male Sprague Dawley rats support the significance of these metabolites as a promoting stimuli in liver carcinogenesis by 2-FAA. PMID- 21552839 TI - Differential-effects of viral and cellular oncogenes on the growth factor dependency of hematopoietic-cells. AB - The effects of different viral and cellular oncogenes on the cytokine-dependency of murine hematopoietic cell lines were compared. The myeloid FDC-P1 cell line was sensitive to abrogation of growth factor-dependency by the constitutive expression of viral oncogenes (v-abl, v-src, v-Ha-ras, and v-fms) and the activated cellular oncogene BCR-ABL and Delta Nraf. The Delta Nraf encoded serine threonine kinase was approximately 100-fold less efficient in relieving the factor-dependency of FDC-P1 cells than the other oncogenes examined. The synthesis of autocrine cytokines was not detected in the factor-independent FDC P1 lines, indicating that the oncogene-mediated transformation occurred by a non autocrine mechanism. A low frequency of cells were isolated after infection with the chronic retrovirus, murine leukemia virus and approximately 40% of these clones synthesized the autocrine lymphokine, granulocyte-macrophage colony stimulating factor. In contrast, only the v-abl and BCR-ABL oncogenes relieved the cytokine-dependency of the lymphoid FL5.12 cell line. In all the transformed cell lines, the rate of glucose transport was elevated above the basal level seen in uninfected cells indicating that this pivotal growth-regulated protein was associated with malignant transformation. In summary, these cell lines varied with respect to abrogation of growth factor-dependency as the myeloid FDC-P1 line was sensitive to transformation by all oncogenes examined whereas only the abl family members would relieve the cytokine-requirement of lymphoid FL5.12 cells. PMID- 21552840 TI - Recapitulation of a normal cellular growth program in early invasive breast cancer. AB - With a view to identifying markers reflecting not the evidence of, but the potential for, neoplastic progression of the breast we have compared the normal invasive mammary epithelial cell growth seen at puberty with invasive and non invasive carcinogenesis using the mouse as a model. We have analyzed cell proliferation, the expression of the metalloproteinase stromelysin-1 and of the extracellular matrix protein tenascin. Striking parallels were observed between pubertal growth and the development of invasive, metastasizing mouse mammary tumors. In particular, the myoepithelial to epithelial transition of proliferation and stromelysin-1 expression was a hallmark of both normal growth at puberty and the early development of aggressive tumors. Investigation of neoplastic lesions in the human breast indicated that the pubertal growth characteristics are recapitulated only in the development of ductal carcinomas and may define early stages of invasive and potentially malignant growth. PMID- 21552841 TI - Expression of p-glycoprotein in the normal colorectal epithelium and in colorectal-carcinoma. AB - Expression of P-glycoprotein (pgp) was analyzed by immunohistochemical staining with monoclonal antibody JSB-1 in 145 frozen specimens (67 were samples of normal colorectal mucosa from sites adjacent to the tumor, 66 were colorectal carcinomas, 5 colorectal polyps, 5 metastatic lymph nodes, and 2 samples of metastatic liver tumors) of 67 patients with colorectal carcinoma and polyps. All 72 specimens of normal colorectal mucosa and adenomatous polyps expressed pgp to various degrees. By contrast, 18 of 39 (46.2%) samples from cases of well differentiated adenocarcinoma were positive for pgp but only 3 of 21 (14.3%) samples from cases of moderately differentiated adenocarcinoma and none of the 4 samples from cases of poorly differentiated adenocarcinoma were positive for pgp. There was no correlation between the clinicopathological stage of colorectal carcinoma and the expression of pgp. These findings indicate that the expression of P-glycoprotein is closely related to the differentiation of cells. In normal colorectal epithelium, pgp was expressed normally and in well differentiated adenocarcinomas, pgp was still expressed. However, expression of pgp was no longer detectable in carcinomas with moderate or poor differentiation. PMID- 21552842 TI - Radiosensitization by Cisplatin treatment in Cisplatin-resistant and sensitive human ovarian-carcinoma cell-lines. AB - The responses of cisplatin resistant (A2780(cp)) and cisplatin sensitive (A2780) ovarian carcinoma cell lines to radiation, cisplatin and cisplatin plus radiation have been studied. The cisplatin resistant cell line showed cross resistance to radiation. When cells were exposed to 2 mu g/ml of cisplatin treatment for one hour radiosensitization was achieved. The degree of radiosensitization was treatment sequence dependent. Irradiation followed by cisplatin treatment resulted in synergistic interaction with dose modifying factors (DMFs) as high as 1.5 in the resistant line and 1.1 in the sensitive line. The reverse sequence resulted in antagonistic interaction with DMFs of 0.8 to 0.9 at the 10% survival level. At lower survival levels the interaction remained antagonistic for the resistant cell line. Increasing the cisplatin concentration to 4 mu g/ml did not increase the degree of cisplatin radiosensitization. Simultaneous treatment of irradiation during the middle of a one or two hour cisplatin treatment did not increase the degree of radiosensitization. The cisplatin resistant cell line had a much greater cisplatin radiosensitization effect than the sensitive parental cell line with maximum DMFs for the resistant cell line ranging from 0.9-1.5 and for the sensitive cell line from 0.8-1.1. These results indicate that cisplatin may be an effective radiosensitizer especially in cisplatin resistant cell lines. This effect may be related to the inhibition of repair of radiation damage which may be elevated as a mechanism of resistance in the resistant cell line. PMID- 21552843 TI - Overexpression of wild-type p53 overrides the mitogenic effect of ri-alpha subunit of protein-kinase-a in human breast cells. AB - Protein kinase A type I (PKAI) and its regulatory subunit RI alpha are overexpressed in cancer cells and are induced by mitogenic hormones and growth factors in nontransformed cells. RI alpha/PKAI are directly involved in the G1>S transition and cell proliferation of non-transformed human breast MCF-10A cells. Retroviral vector-mediated overexpression of RI alpha in these cells (MCF-10A RI alpha) confers the ability to grow in serum-free medium. p53 controls a G1 check point before transition to the S phase, playing a key role in the regulation of cell proliferation and in the preservation of DNA integrity. In this study we evaluated the interaction of p53 and RI alpha on cell cycle progression and cell proliferation of MCF-10A cells. Retroviral vector-mediated overexpression of wild type p53 in the MCF-10A neo and MCF-10A RI alpha cells determined a marked inhibition of RI alpha protein expression in MCF-10A-p53 cells and induced G0/G1 accumulation, cell gowth arrest and changes in cell morphology not due to apoptosis in both MCF-10A-p53 and MCF-10A RI alpha-p53 cells. On the other hand, in the MCF-10A RI alpha cells we observed an increased expression of the endogenous p53, although these cells were still able to proliferate. These results suggest that overexpression of wildtype p53 acts in a dominant fashion to abrogate the RI alpha induction of G1>S transition and cell proliferation. Moreover, overexpression of RI alpha leads to increased synthesis of endogenous p53 which, however, is unable to interfere with the RI alpha-dependent mitogenic signalling. PMID- 21552844 TI - Differential-effects of transforming growth-factor-Beta-1 on protein-levels of p21 waf and cdk-2 and on cdk-2 kinase-activity in human rd and ccl64 mink lung cells. AB - Currently, the cyclin-dependent kinase inhibitor p21 WAF-1 is considered to be a crucial downstream effector in the p53-specific pathway of negative growth control in mammalian cells. Wild-type p53, but not mutant forms of this protein, transactivate the WAF-1 gene. We show a correlation between growth-inhibition and induction of WAF-1 protein expression following transforming growth factor-beta 1 (TGF-beta 1) treatment of two human tumour cell lines devoid of wild-type p53 protein and in SV40-transformed WI38 fibroblasts. Inversely, TGF-beta 1 treatment of normal WI38 fibroblasts stimulates their growth and represses WAF-1 protein synthesis. As the mink lung epithelial CCL64 cell line is frequently used in TGF B studies we included it in this study: TGF-beta 1 growth-inhibition is accompanied by induction of WAF-1 synthesis concomitantly with a reduction of cdk2 synthesis and of its histone kinase activity. However in the human tumour line RD, TGF-beta 1 did not affect cdk-2 protein levels but did reduce its histone kinase activity. PMID- 21552845 TI - P53 and C-erbb-2 alterations in in-situ and invasive ductal breast carcinomas - a genetic and immunohistochemical analysis. AB - p53 mutations, c-erbB-2 amplifications and expression of the related proteins were evaluated in a panel of ductal breast carcinomas selected on the basis of their invasive component. The tumors comprised: 8 ductal carcinomas in situ (DCIS); 8 carcinomas with a minimal (less than 20%) invasive component, hereafter referred to as DCIC (<20%); 13 carcinomas with 20%-50% invasiveness, DCIC (20 50%), and 48 infiltrating carcinomas with more than 50% invasive component, DCIC (>50%). Tumors were further subdivided into large pleomorphic cell type or small regular cell type. A strong association was present between p53 gene mutations and p53 protein overexpression (p<0.001) as well as between amplification of the c-erbB-2 gene and expression of its protein product (p=0.006). p53 aberrations (gene mutation and/or protein overexpression) were observed in 1 (12%) of 8 DCIS, 1 (11%) of 9 DCIC (<20%), 3 (23%) of 13 DCIC (20%-50%), and 13 (28%) of 47 DCIC (>50%). Amplification and/or overexpression of c-erbB-2 were found in 30 (39%) of the 77 breast carcinomas analyzed and were more frequent in DCIC (<20%) and in DCIC (20%-50%) (56% and 46% respectively) than in DCIS or DCIC (>50%) (12% and 38% respectively). Irrespective of the presence of invasion, tumors with p53 or c erbB-2 alterations showed more frequently large cells with pleomorphic nuclei, (for p53, p=0.027; for c-erbB-2, p=0.014). Our data suggest that p53 and c-erbB-2 alerations may occur in the earliest recognized phase of breast cancer and may be important in the evolution of small cell to large cell mammary carcinoma during tumor progression. PMID- 21552846 TI - Prognostic implication of estramustine-binding protein in astrocytoma. AB - Estramustine-binding protein (EMBP) is a glycoprotein shown to be expressed in the cytoplasm of astrocytoma cells. Originally, it was found in rat prostatic tissue and described as a secretory protein. Its expression has been demonstrated to positively correlate with the degree of neoplastic transformation in astrocytoma tissue. EMBP has been proposed to be responsible for a specific and high affinity binding of estramustine in astrocytoma tumor tissue. In this study the expression of EMBP was evaluated by immunohistochemistry and radioimmunoassay in a series of astrocytoma of different grades. Staining intensity and the number of stained cells increased with the degree of malignancy. The levels of EMBP were 1.3-6.2 ng/g tumor tissue with higher levels in tumors of grade III to IV compared to grade I and II. It was found that a high expression of EMBP always implied a short survival of the patients. On the other hand, a low expression of EMBP did not always assure a favorable prognosis. It is proposed that EMBP might have a value to predict survival in patients with astrocytoma, especially if estramustine is to be included in the treatment schedule. However, further extended studies are needed before final conclusions can be made. PMID- 21552847 TI - Modulation of Cisplatin toxicity by glutathione. AB - Organ toxicity is the major limiting factor associated with chemotherapeutic treatment of malignancy. By raising the toxicity threshold of the organ to the detrimental effects of chemotherapeutic agents, larger and possibly curative doses may be administered without unacceptable side effects. Glutathione (GSH), a major nonprotein cellular thiol, participates in numerous cellular functions, including detoxification of chemotherapeutic agents. Previously, GSH was shown to protect against cisplatin-induced lethal toxicity. We find that in non-tumor bearing animals GSH injections (500 mg/kg body weight) prior to and after a single cisplatin injection (16 mg/kg) provided significant protection against the lethal effects of this drug (90% survival for GSH+cisplatin versus 35% for cisplatin alone). In addition, when GSH was given concurrently with the cisplatin, renal toxicity was markedly reduced as assessed by renal tubular dilation, tubular sloughing, and lumenal casts. When GSH was given with cisplatin no significant differences in the number of tumor cures was observed over cisplatin treatment alone; however, a small but statistically significant increase in tumor size was observed for cisplatin+GSH treated animals. Our results suggest that GSH may protect normal as well as malignant tissue and that further studies should be designed to determine a GSH dose and schedule regimen to be used with higher cisplatin dose schedules. PMID- 21552848 TI - Progressive elevation of ap-1 activity during preneoplastic-to-neoplastic progression as modeled in mouse jb6 cell variants. AB - The JB6 mouse epidermal cell system has been used extensively as an in vitro model for the study of tumor promotion and progression. The present study was directed to assessing the role of basal AP-1 activity in JB6 variants which represent preneoplastic to neoplastic progression and to addressing whether AP-1 activity is required for maintenance of the tumor phenotype. Constitutively higher AP-1 activity was found in tumorigenic JB6 RT101 cells than in later or earlier preneoplastic P+ or P- cells. Levels of c-jun mRNA and protein correlated with progression stage. Enhancement of AP-1 activity by TPA increased the formation of anchorage independent colonies by tumorigenic RT101 cells. Inhibition of AP-1 activity by retinoic acid or fluocinolone acetonide inhibited expression of tumor phenotype as measured by AI growth. These data together with our previous results suggest that in the JB6 model (i) basal levels of Jun and AP 1 appear to be important for preneoplastic-to-neoplastic progression; (ii) induced AP-1 appears to be required for further progression by tumor cells; (iii) constitutively elevated AP-I activity may be important for the expression of transformed phenotype; (iv) inhibition of AP-1 activity by RA or FA is not a general suppression of transcription but is gene-specific; and (v) even though both inhibition of AP-1 activity and activation of RARE-dependent or GRE dependent gene transcription correlate with inhibition of AI growth in RT101 cells by RA or FA, transactivation of RARE or GRE might better correlate with the inhibition of AI growth than the inhibition of AP-1 activity in RT101 cells. PMID- 21552849 TI - A report on the comparative response of sheep epidermal squamous-cell carcinoma to intraarterial versus intravenous Cisplatin infusion. AB - There is an apparent lack of randomised clinical trials demonstrating a therapeutic advantage for intra-arterial, versus systemic, cisplatin administration as cancer treatment. A spontaneous, head and neck epidermal squamous cell carcinoma in sheep was used to compare intra-arterial and equivalent dose intravenous cisplatin infusion. The objective response rate for intra-arterially infused lesions was 73%, with a mean tumour regression for all carcinomas of 70% +/- 6 (sem). In comparison, 27% of intravenously treated carcinomas showed an objective response, the mean volume reduction being 42% +/- 6 (sem). Statistical comparison of the number of objective response lesions was significantly in favour of intra-arterial cisplatin therapy (p<0.05), as was the difference in the mean tumour response for both groups (p<0.005). The experimental data suggest that further study of the clinical application of intra arterial induction cisplatin therapy is warranted. PMID- 21552850 TI - Characterization of a h-3 GnRH method for the measurement of GnRH binding-sites in human breast-cancer and breast-cancer cell-lines. AB - The peptide hormone, GnRH has been hypothesized to play a direct antitumoral role in certain kinds of breast cancer. This direct effect is considered to function via high affinity membrane receptors to GnRH that have been demonstrated in tumors. However, no routine assay for GnRH receptors exist limiting further research in elucidating the mechanisms of GnRH action during treatment and both the clinical usefulness of this measure and the development or refinement of GnRH treatments. Part of the problem has been that previously reported procedures require expensive, difficult (for routine clinical laboratories) iodination of specific GnRH analogs. The use of iodinated substrates present the additional problems of radioactive waste disposal and safety of laboratory personal. Further, the use of different analogs complicates the comparison of data between laboratories. We present an assay that utilizes tritiated natural GnRH in order to assay the native receptor binding and reduce both safety problems and cost of assay/waste disposal. The use of nitrocellulose filters treated overnight with 1% BSA resolved the problems of high blank values. Kinetic data demonstrate that this assay is sensitive, accurate and give results comparable with other methods. We also show that the membranes derived from the tumor and the cell cultures may be frozen at -80 degrees C for up to 90 days without affecting the results of the assay. PMID- 21552851 TI - Expression of p-glycoprotein in multidrug-resistant human leukemia k562 cells during erythroid-differentiation. AB - Expression of P-glycoprotein (P-gp), the multidrug resistance gene product, has previously been shown to be downregulated during differentiation of normal haematopoietic cells. In order to determine whether such a regulation also occurs in leukemic cells, we have investigated the relevance of differentiation levels to P-gp expression in multidrug-resistant leukemia K562R/7 cells and in parental drug-sensitive K562 cells. These leukemic cells were exposed to hemin and sodium butyrate, two known inducers of erythroid differentiation. Analysis of hemoglobin synthesizing cells indicated that hemin induced both K562R/7 and K562 cells to differentiate into erythroid cells while sodium butyrate led to hemoglobin synthesis in only K562 cells. Northern blotting and immunolabelling experiments revealed elevated levels of MDR1 mRNAs and P-gp in both untreated and hemin treated K562R/7 cells while P-gp expression was not detected in both uninduced and hemin-induced K562 cells. Flow cytometric analysis of cellular doxorubicin retention demonstrated that K562R/7 cells poorly accumulated the anticancer drug regarless their level of differentiation. These results therefore suggest that erythroid differentiation of leukemic drug-resistant K562R/7 cells in response to hemin treatment did not result in major alteration of P-gp expression and activity. PMID- 21552852 TI - Comparison of adherent lymphokine-activated killer (a-lak) cells generated by IL 2 and IL-7 - cellular modifications induced by IL-7. AB - At present, the clinical application of plastic-adherent-lymphokine-activated killer (A-LAK) cells shows limited success in the immunotherapy of patients with advanced cancer because of a low responder rate, severe side effects and failures in yielding sufficient numbers of cells for adoptive transfers. Since interleukin 7 (IL-7) is able to induce LAK activity independently of IL-2, we investigated the ability of IL-7 to improve the yield and the properties of A-LAK cells. A-LAK cells from 7 healthy donors generated in the presence of IL-2, IL-7 or combinations of IL-2 plus IL-7 (each 1000 U/ml) were compared with regard to plastic adherence, expansion rate, immunophenotype, cytokine secretion and cytotoxicity against malignant melanoma cells and non-malignant target cells. Our results demonstrate that A-LAK cells generated by a simultaneous stimulation of IL-2 plus IL-7 displayed a significantly higher expansion rate (10.7-fold vs. 9.0 fold), but showed no difference in the cytolytic activity compared to A-LAK cells generated by IL-2 alone. A-LAK cells generated by IL-7 alone demonstrated a low expansion rate (1.1-fold vs. 8.8-fold), and decreased in other properties like plastic adherence, CD56(+)/CD3(+) cell-ratio and cytolytic activity compared to A LAK cells generated by IL-2 alone. A-LAK cells generated by IL-7 or a sequential stimulation of IL-2 and IL-7, on the other hand, exhibited a more selective cytotoxicity for malignant melanoma cells compared to the non-malignant keratinocyte target cell line (HaCaT) and normal fibroblasts. A sequential replacement of LL-2 by IL-7 might help to reduce the severe side effects of IL-2. In vivo experiments are necessary to evaluate the potential value of IL-7 in adoptive immunotherapy. PMID- 21552853 TI - Infection of human papillomavirus (hpv) and epstein-barr-virus (ebv) and p53 overexpression in human gastric-carcinoma. AB - To clarify the role of human papillomavirus (HPV) and Epstein-Barr virus (EBV) infection in gastric carcinogenesis in relation to overexpression of mutated p53 anti-oncogene, we used PCR to amplify DNA sequences of these viruses and immunohistochemistry to detect p53 overexpression in formaline-fixed, paraffin embedded blocks including 12 normal gastric and 51 gastric carcinoma specimens. HPV and EBV DNA were found in 17% and 0% of normal gastric tissues and in 45% and 27% of gastric carcinoma specimens, respectively. p53 overexpression was shown in 37% of gastric carcinoma specimens only. HPV infection rate was significantly higher in stage I gastric carcinomas as compared with stage IV carcinomas (p<0.03). p53 overexpression was significantly increased in well-differentiated adenocarcinomas as compared with poorly differentiated carcinomas (p<0.01). The rates of both HPV infection and p53 overexpression were significantly higher in gastric carcinomas without vascular invasion than in those with the invasion (p<0.02). No correlation was found between p53 overexpression and/or the presence of viral DNA (HPV/EBV) in regard to the depth of invasion, lymph node involvement, distant metastasis, and the location of the tumors. Our results suggest that some of the gastric carcinomas are associated with HPV and/or EBV infection and p53 mutations, and that all of these may be involved in the early stage of this malignancy. There was no correlation between HPV and or EBV infection and overexpression of p53 in gastric carcinoma. PMID- 21552854 TI - The p53 tumor-suppressor gene is overexpressed but not mutated in human atherosclerotic tissue. AB - Excessive proliferation of smooth muscle cells (SMC) in the arterial intima is thought to be a major contributing factor to the development of atherosclerosis. One of the theories put forward to explain the aberrant growth is that genetic alterations similar to those observed in cancers also occur in the SMC. Since mutations in the p53 tumour suppressor gene and the c-Ki-ras oncogene are the most common genetic alterations observed in a wide variety of tumour types, we searched for evidence of mutation in human atherosclerotic tissue. DNA was extracted from atherosclerotic plaques and screened for p53 and c-Ki-ras gene mutations using polymerase chain reaction-single strand conformation polymorphism analysis. Tissue sections were also examined for overexpression of p53 protein using an immunohistochemical technique. The molecular analysis showed that wild type p53 and c-Ki-ms gene sequences were present in all 54 specimens examined. Overexpression of p53 protein was found in 61% of samples. Our results do not support the view that genetic alterations similar to those occurring in cancer contribute to the abnormal proliferation of SMC, although we caution that only two cancer-related genes were studied. Epigenetic changes to the gene products could play a role however, as evidenced by overexpression of p53 protein in many of the atherosclerotic specimens. PMID- 21552855 TI - Mutations of ras genes in human tumors (review). AB - Ras family genes (H-, K- and N-ras) are implicated in a wide range of human rumours. Mutations are a major activating mechanism for the ras family genes, mainly in codons 12, 13 and 61, resulting in their conversion from proto oncogenes to activated oncogenes. The detection of mutant ras alleles in human tumours has been performed by several investigators in a wide range of tissues. The aim of our review was to summarize the data obtained from these studies and to investigate whether the presence of mutant ras alleles was associated with particular clinical parameters. PMID- 21552856 TI - Telomeres and telomerase in human cancer (review). AB - Telomerase has recently come into the limelight as one of the most prevalent tumour markers, due to its nearly ubiquitous presence in malignant tissues and absence from most somatic tissues. The essential role of telomeres in unlimited cell proliferation and that of the enzyme in telomere maintenance have suggested that telomerase inhibitors may be effective in cancer therapy. We provide here a compendium and an evaluation of the available data relating to this hypothesis. PMID- 21552857 TI - Induction of apoptosis by retinoids in human cervical-carcinoma cell-lines. AB - Retinoids can inhibit the growth and modulate the differentiation of a variety of tumor cell types in vitro and in vivo. All-trans retinoic acid (ATRA) and N-(4 hydroxyphenyl)retinamide (4HPR) are currently being evaluated in clinical trials for their potential use in cancer chemoprevention and therapy. We compared the effects of these retinoids on 10 human cervical carcinoma cell lines. Four of the 10 cell lines showed dramatic morphological changes and the other 5 exhibited decreased cell density after treatment with 10 mu M 4HPR, whereas few changes were induced by 10 mu M ATRA. Cell rounding and detachment were also observed in four of the cell lines. An analysis of DNA from both detached and attached cells after retinoid treatment has demonstrated the formation of a DNA ladder after electrophoresis in agarose gels, which indicated that some of the cell lines had undergone apoptosis. Induction of DNA fragmentation by 4HPR but not by other retinoids (ATRA, 13-cis-RA, and 9-cis-RA) was further evidenced as early as 24 h after treatment by a quantitative assay based on the degradation of [H-3] thymidine-labeled DNA. Ln addition, morphological changes of nuclei associated with apoptosis such as chromatin condensation were observed by propidium iodide staining of the nuclei after 4HPR treatment. These results demonstrate that 4HPR causes apoptosis in several cervical carcinoma cell lines and that it is more potent in this effect than ATRA or other RA isomers. PMID- 21552858 TI - In-vivo and in-vitro analysis of retroviral vectors carrying the N-ras oncogene. AB - We have analyzed, in vivo and in vitro, the behavior of two retroviral vectors carrying the genomic or cDNA N-ras oncogene to study the role of N-ras in the initiation and development of thymic lymphomas. The vector bearing the genomic gene produced an array of transcripts originating from the LTR and the oncogene promoter. The majority of the transcripts initiated at the LTR did not carry the packaging signal producing low titer clones. The cDNA vector produced two transcripts correctly spliced and the titers obtained were as high as 10(6) pfu/ml. Bone marrow cell infection and grafting of lethally irradiated mice was performed. The integrated vector in blood cells was followed at different times, observing that the provirus can disappear and reappear in peripheral blood cells during the course of the experiment. This observation fits with the hypothesis of clonal contribution of small number of stem cells in the renewal of blood cells. No tumors were detected in the infected animals, probably due to low expression of the integrated provirus. These experiments provide information on the advantages and disadvantages of genomic versus cDNA constructs in retroviral vectors. PMID- 21552859 TI - Suppression and restoration of v-SRC expression in rsv transformed-cells after transfection with N-ras and its antagonist. AB - Previously, it was shown that hamster cells transformed by Rous Sarcoma Virus (RSV) exhibited a decreased expression of the RSV products (including the pp60 src oncogene) when these cells were supertransfected with the N-ras oncogene. To assess the responsibility of the activated N-ras in the modulation of the RSV viral products, a strategy based on two ras antagonists was used; i.e. i) a rap1A/K-rev1 expression vector known for its capacity to revert the K-ras induced transformed phenotype and ii) a plasmid containing antisense N-ras sequence. We present data showing only the plasmid construct containing the N-ras antisense sequense could inhibit expression or N-ras and, at the same time, restore the expression of v-src, up to a level comparable to that of the parental cells. Our results support the idea that some biological switches, triggered and activated through the N-ras oncogene pathway, might modulate the promoter activity of the RSV LTR. PMID- 21552860 TI - Tumor-necrosis-factor and DNA topoisomerase-ii inhibitors in human ovarian-cancer - potential role in chemotherapy. AB - Seven ovarian and one cervical human cancer cell lines were examined far their sensitivity or resistance to tumor necrosis factor, to three topoisomerase II inhibitors and to cisplatin. Only one line exhibited the multidrug-resistance phenotype and another one an 'atypical'-MDR phenotype. The combination of TNF and topoisomerase-II inhibitors produced enhanced cytotoxicity and overcame the MDR and the atypical resistance. No potentiation of cisplatin cytotoxicity was observed. These findings suggest that TNF enhances the activity of DNA topoisomerase II both in TNF resistant and sensitive cells. PMID- 21552861 TI - Increased expression of gelatinase-a and timp-2 in primary human glioblastomas. AB - The highly invasive growth of glioblastomas may be a consequence of an abnormal profile of proteinases and proteinase inhibitors involved in remodeling of the basement membrane and normal vasculature. We have detected a 1.5-3-fold increase in the transcription of gelatinase A and TIMP-2 (Tissue Inhibitor of Metalloproteinase) in glioblastomas as compared to the normal brain tissue. Increased expression of gelatinase A and TIMP-2 in these tumors was also evident by immunohistochemical analysis. Our data suggest that increased expression and perturbation of the balance between metalloproteinases and their inhibitors that are involved in extracellular matrix remodeling and angiogenesis may contribute to the invasive phenotype of glioblastomas. PMID- 21552862 TI - Difloxacin reverses multidrug-resistance in p388 adr cells via a mechanism independent of p-glycoprotein and without correcting drug transport or subcellular drug distribution. AB - In this study, we have examined in vitro chemosensitizing activity of difloxacin, a quinolone antimicrobial agent, in multidrug resistant murine leukemia P388/ADR cell line that overexpresses P-glycoprotein and exhibits decreased accumulation of anthracyclines and vincristine. Difloxacin, in a concentration-dependent manner, increased the sensitivity of P388/ADR cells to daunorubicin, adriamycin and vincristine without correcting the altered drug accumulation and subcellular distribution of daunorubicin. Furthermore, difloxacin had no significant effect on intracellular accumulation of rhodamine 123 dye, a substrate for P glycoprotein. In addition, difloxacin increased the sensitivity of drug sensitive parental P388 cells to vincristine. Taken together these data suggest that difloxacin reverses MDR by a mechanism independent of P-glycoprotein. The chemosensitizing effect of difloxacin was observed at clinically achievable plasma concentrations. These data suggest that difloxacin is an effective chemosensitizer of multidrug resistant tumor cells and is a potential candidate for clinical use to reverse MDR. PMID- 21552863 TI - Inhibin activin subunits and activin receptors in human breast cell-lines and lactating rat mammary-glands. AB - We have reported previously that a human breast cancer cell line, MCF-7, transcribes messenger RNAs coding inhibin/activin alpha-, beta A-, and beta B subunits and activin receptor II as well as produces inhibin and/or activin proteins, using immunocytochemistry, in situ hybridization, and the reverse transcription-polymerase chain reaction (RT-PCR) analysis. In the present study, we report that four additional cell lines derived from human breast cancers, T47D, HS-578, ZR-75-1, and MDA-MB 321 express mRNAs for alpha- and beta-subunits of inhibin/activin and activin receptors as well as stain positive with antisera specific for inhibin alpha- and inhibin/activin beta-subunits, respectively. We have also localized immunocytochemically inhibin and activin-A in rat lactating mammary glands and found mRNAs for activin receptors I, II, and IIB as well as follistatin, a binding protein for activin, in lactating rat mammary glands by RT PCR. These findings provide additional evidence that inhibin and activin may be involved in regulating the normal and abnormal cell growth of mammary glands. PMID- 21552864 TI - Cooperative inhibitory effect of n,n,n-trimethylsphingosine and sphingosine-1 phosphate, co-incorporated in liposomes, on b16 melanoma cell metastasis - cell membrane signaling as a target in cancer-therapy .4. AB - Two N-methylated derivatives of sphingosine (Sph), N,N-dimethyl-Sph (DMS) and N,N,N-trimethyl-Sph (TMS), have been shown to stereospecifically inhibit activity of protein kinase C and other kinases essential for active proliferation of tumor cells, as well as for activation of platelets and endothelial cells (ECs). DMS and TMS thereby inhibit tumor growth in vivo, and TMS inhibits in vivo metastatic potential of B16 melanoma cells. When TMS was administered in liposomes, its drug efficacy was increased and its undesirable side-effects were greatly reduced (Park YS, er al, Cancer Res 54: 2213, 1994). Sph-1-P, long known as the initial catabolite of Sph metabolism, has aroused considerable interest recently because of its inhibitory effect on cell motility (Sadahira Y, et al, Proc Natl Acad Sci USA 89: 9686, 1992). We now report that liposomes containing both TMS and Sph-1 P, in comparison to liposomes containing TMS or Sph-1-P alone, exert a much stronger inhibitory effect on B16 melanoma cell metastasis. This is ascribable to their inhibitory effect on tumor cell invasiveness through motility inhibition, in conjunction with the previously-observed inhibitory effect of TMS on activation of platelets and ECs. Furthermore, the liposomal formulation resulted in prolonged circulation time of both TMS and Sph-1-P in blood, and consequent higher concentration of these compounds in tumor tissues. PMID- 21552865 TI - Nonrandom secondary chromosome-aberrations in synovial sarcomas with t(x-18). AB - Thirty samples from 19 patients with synovial sarcoma were analyzed cytogenetically after short-term culturing. Thirteen samples were from primary tumors, 11 from local recurrences, and six from distant metastases. All samples showed the characteristic aberration t(X;18)(p11;q11) or variants thereof; 23 samples had additional numerical and/or structural changes. Including the present cases, chromosome aberrations have been reported in 74 synovial sarcomas, 50 of which have had secondary aberrations in addition to t(X;18). No secondary structural aberration was recurrent. The most common numerical changes were +7, +8, +12 (10 cases each), -3, +9, +21 (7 cases each), +2, -14, -17 (6 cases each), +4, -11, +15, and -22 (5 cases each). Unbalanced stuctural aberrations led to loss of 3p and 17p in six cases, each with loss of bands 3p21 and 17p13, respectively, in common. Most monosomies and trisomies seemed to occur at similar frequencies in primary, recurrent, and metastatic tumors. The only exceptions were +2, which was never seen in a primary tumor, and +8, which was never found in any metastatic lesion. PMID- 21552866 TI - IFN-gamma and b7 as costimulators of antitumor immune-responses. AB - We transfected the mouse IFN-gamma and/or the mouse B7 (T cell costimulatory molecule) cDNAs into B16 melanoma cells to study the effects of local constitutive expression of these molecules on the tumorigenicity and immunogenicity of this aggressive tumor. Cells expressing IFN-gamma (B16.IFN gamma), B7 (B16.B7), B7 and IFN-gamma (B16.IFN-gamma/B7), and parental cells were injected subcutaneously (s.c.) into syngeneic C57BL/6 mice to compare their in vivo growth. We report that IFN-gamma secretion significantly reduced the tumorigenicity of B16 cells. These effects were related to the direct action of secreted IFN-gamma since i) in vivo injection of antiserum to IFN-gamma accelerated tumor growth, ii) development of tumor correlated with loss of IFN gamma production, and iii) B16.IFN-gamma cells were tumorigenic in IFN-II receptor (IFN-gamma R) knockout mice, but not in parental mice. We propose that immune mechanisms are being activated by IFN-gamma since i) immune effector cells were recruited to the injection site, ii) expression of MHC class I and class II antigens was increased on cells secreting IFN-gamma and, iii) B16.IFN-gamma tumors appeared earlier in athymic mice than in immunocompetent mice. Since the in vivo growth of B16.IFN-gamma cells was not completely abolished, we studied the effect of co-expression of IFN-gamma and the T cell costimulatory molecule B7 on the tumorigenicity of B16 cells. We report that B16.IFN-gamma/B7 cells, which also express increased levels of MHC class I and class II molecules as compared to parental cells, had a dramatically suppressed tumorigenicity, while B16 cells expressing the B7 molecule only (B16.B7) were as tumorigenic as the parental cells. B16.IFN-gamma/B7 cells induced specific immune responses since all of the protected mice were able to reject challenges with parental cells. Results indicate that co-expression of two molecules which are involved in the activation of immune responses and in antigen presentation can influence the ability of the immune system to recognize and eliminate both transfected as well as parental tumor cell inocula and suggest that vaccines consisting of such cells may be used for the immunotherapy of cancer. PMID- 21552867 TI - Detection of k-ras mutations in nonsmall cell lung-carcinoma. AB - Forty-five non-small cell lung cancers (NSCLC) were examined for the presence of K-ras mutations in codon 12 using RFLP (restriction fragment length polymorphism) and ARMS (amplification refractory mutation system) assays. The RFLP analysis consisted of a PCR and subsequent digestion of the product with BstNI. Three adenocarcinomas and one adenosquamous carcinoma were shown to have mutations at codon 12. All of these samples were also examined using the ARMS assay for mutations at codon 12 and second base G to A transitions at codon 13 of the K-ras gene. The same four samples were confirmed to have a single base change in codon 12. No G to A transitions were found at codon 13. The four mutations were: one G to C transversion, one G to A transition and two G to T transversions. All mutations occurred at the second position of codon 12 as shown by the ARMS assay. Both of these techniques are rapid and reproducible for the identification of mutations in the K-ras gene and have potential for use in cancer diagnosis. PMID- 21552868 TI - The hsv-2 la-1 oncoprotein is a member of a novel family of serine threonine receptor kinases. AB - The large subunit of the herpes simplex virus type 2 ribonucleotide reductase (RR) (ICP10) is a chimera consisting of a serine/threonine (Ser/Thr) protein kinase (PK) domain preceded by a transmembrane (TM) segment at the amino terminus (LA-I oncoprotein) and the RR domain at the carboxy terminus. Human cells transformed by the LA-I oncogene constitutively express the oncoprotein on the cell surface and internalize it by the endocytic pathway as determined by immunogold staining and electron microscopy. The TM segment of the oncoprotein is required for cell surface localization, consistent with the interpretation that the oncoprotein is a growth factor receptor. Amino acid sequence alignment and comparative computer-assisted phylogenetic analyses of the LA-1 oncoprotein indicate that it is a member of the superfamily of growth factor receptor Ser/Thr kinases. However, many structural differences, including the presence of two SH3 binding motifs located within the PK catalytic domain suggest that the LA-I oncoprotein is a member of a novel subfamily. PMID- 21552869 TI - IFN-alpha therapy of renal-cell carcinoma - defect of lymphocyte sensitivity to mitogenic and activating cytokine signals in patients not-responding to therapy. AB - The present prospective study was designed to assess whether the renal cell carcinoma (RCC) patients treated with recombinant interferon alpha (IFN alpha), whose tumours respond (responders) and do not respond (non-responders) to IFN alpha therapy, differ with regard to in vitro sensitivity of peripheral blood lymphocytes (PBL) to interleukin 2 (IL-2), IFN alpha, and IFN gamma signals prior to therapy. Twenty-one patients with advanced RCC after nephrectomy, 15 responders and 6 non-responders, were entered into a protocol. The protocol involved isolation and freezing of PBL samples followed by IFN alpha treatment of patients, assessment of proliferative and activating PBL responses, and evaluation of the therapeutic results. Freezing of PBL samples allowed us to compare the in vitro reactivity of PBL from individual RCC patients, repeatedly and under standard conditions. Substantial differences in proliferative responses to the mitogenic IL-2 signal of PBL derived from IFN alpha responders and nonresponders were found. Whereas the IL-2-induced proliferative responses of PBL from normal blood donors and IFN alpha responders were comparable, the proliferative responses of PBL from IFN alpha non-responders were significantly decreased, suggesting an immune dysfunction in non-responders. Cultivation of PBL from RCC patients in medium supplemented with IFN alpha increased the lytic activity of PBL from IFN alpha responders directed against RCC targets; no such increase could be observed with non-RCC targets, with PBL from IFN alpha non responders, or with PBL from normal blood donors. Detection of phytohaemagglutinin (PHA)-stimulated IFN gamma secretion by PBL at the single cell level using enzyme-linked immunospot (ELISpot) assay revealed that the ability to produce IFN gamma was substantially decreased in IFN gamma non reponders, as compared to IFN alpha responders and to normal blood donors. PMID- 21552870 TI - Differential regulation by estrogen of C-fos in hamster-kidney and estrogen induced kidney tumor-cells - receptor mediation vs metabolic-activation. AB - Chronic administration of 17 beta-estradiol to male Syrian hamsters for at least six months induces estrogen-dependent kidney tumors, which express high levels of c-fos mRNA compared to surrounding renal or control tissues. We have investigated the cellular localization of c-Fos oncoprotein in these tissues and studied the estrogenic regulation of c-fos mRNA in kidney and in H-301 cells, a cell line derived from primary hamster kidney tumors. Immunocytochemical analyses showed that levels of c-Fos protein were high in estrogen-dependent tumors. To study the early events in this model, hamsters were treated with 17 beta-estradiol for only 15 days. At this time, well before the appearance of tumors, c-Fos protein was concentrated in interstitial capillaries, arteries, and podocytes of the glomerulus, but not in renal tubular epithelium, and this pattern was not appreciably changed from controls. To study the regulation of c-fos that led to the altered expression in tumor vs. kidney, total RNA was isolated from kidneys of Syrian hamsters 3-48 h after treatment with single injections of either 17 beta- or 17 alpha-estradiol, 17 alpha-ethinylestradiol, the steroidal antiestrogen ICI 182,780, or 17 beta-estradiol plus ICI 182,780. Similar studies were carried out on H-301 cells grown in D-MEM/F-12 medium and charcoal-stripped serum. The increases in c-fos mRNA levels in H-301 cells but not kidney were elicited by classical estrogen receptor-mediated processes. In H-301 cells, c-fos levels were increased four-fold over controls after 3 h of 17 beta-estradiol treatment and this induction was suppressed by antiestrogen treatment. In hamster kidneys, c-fos levels were increased about two-fold by 17 beta-estradiol, but this induction was not affected by antiestrogen treatment. In H-301 cells but not in hamster kidneys, 17 alpha-ethinylestradiol induced c-fos. 17 alpha-estradiol was more potent than 17 beta-estradiol in the induction of c-fos in hamster kidney but was a poor inducer in H-301 cells. These studies are consistent with regulation of c-fos expression in H-301 tumor cells by an estrogen receptor mediated mechanism. But in hamster kidney, c-fos expression does not appear to be regulated by receptor-mediated pathways. We propose that it may be induced by estrogen metabolites. PMID- 21552871 TI - Differential expression of Neu messenger-RNA and protein in hamster-kidney and estrogen-induced kidney tumors. AB - An inverse relationship between the expression of the neu oncogene and estrogen receptors has been observed in breast cancer patients. In this study, we examined neu expression in the estrogen-induced and -dependent hamster kidney tumors, in kidney and in controls to evaluate the usefulness of this animal model far studying the regulation of genes important in hormonal cancer. The expression of neu mRNA was analyzed by Northern analysis and Neu oncoprotein localization by immunocytochemistry. The Neu oncoprotein was detected in several segments of proximal and distal kidney tubules, the loops of Henle and the parietal epithelial cells of Bowman's capsule but not in the tumor. neu mRNA was expressed in renal tissue after estrogen treatment and in untreated controls, but not in kidney tumors. The absence of Neu oncoprotein and mRNA from those cell types that have previously been shown to overexpress estrogen receptors in response to estrogen, suggests that the estrogen receptor and neu genes are interdependent in this tumor system, which may thus be a useful animal model for studying the regulation of neu by estrogens. PMID- 21552872 TI - Adhesive function of newcastle-disease virus hemagglutinin in tumor-host interaction. AB - Infection of metastatic lymphoma cells (ESbL) by a low dose of a non-lytic strain of Newcastle disease virus (NDV) leads to viral replication followed by strong cell surface expression of viral antigens, especially hemagglutinin neuraminidase (HN). The expressed HN was functional and facilitated cell-cell interactions and cell attachment. This was shown for NDV infected tumor cells, lymphocytes, fibroblasts and endothelial cells. The interactions could be strongly inhibited by antibodies against the viral HN protein. Increased binding was also seen with HN c-DNA transfectants expressing the HN as the only viral protein. Viral infection did not influence proliferation and lysability of the infected tumor cells. Following intravenous injection of tumor cells, the number of hepatic metastases was significantly reduced when the cells had been pre-infected with NDV. This reduction of metastases correlated with an increased survival time of the animals. As potential mechanisms of these NDV effects we propose augmentation of cell-eel interactions and immune functions and reduction of invasive capacity of NDV infected, as compared to non-infected tumor cells. PMID- 21552873 TI - Nucleotide-metabolism and chromosome alterations in human-malignant melanoma xenografts. AB - The karyotypes of human melanomas exhibit multiple chromosome alterations. Recurrent deletions of 9p, 10q and 14q arms, which carry genes encoding for enzymes of purine metabolism, were also found in human gliomas, another neuroectodermal tumor previously studied for both cytogenetics and nucleotides metabolism. Postulating that this metabolism might also be modified in melanomas, the activities of eleven enzymes involved in catabolic and synthetic pathways of purine metabolism were measured, in addition to two enzymes of the pyrimidine synthesis. Assays were performed on six melanoma mestastases, five nodal and one cutaneous, after transplantation into nude mice. The purine metabolism was characterized by a more active catabolic than synthetic pathway, a possible imbalance between de novo and salvage pathways for adenylates synthesis, rather in favor of the de novo pathway, and a more active adenylate than guanylate synthesis. The skin metastasis exhibited quite different cytogenetic and metabolic patterns, when compared to the nodal metastases. Considering the relationships between cytogenetic and metabolic data, low activities of methylthioadenosine phosphorylase, adenosine kinase, adenosine monophosphate deaminase, nucleoside phosphorylase and 5'-nucleotidase were observed in melanomas, as well as frequent losses of 9p, 10q, Ip, 14q and 6q arms respectively carrying genes encoding for these enzymes, most of these rearrangements were confirmed by chromosome painting. The two enzymes exhibiting the highest activities were adenosine deaminase and adenylosuccinate lyase, encoded by genes mapped on chromosomes 20 and 22 respectively, frequently in excess in melanomas. Thus, for these tumors, the metabolic pattern roughly parallels the cytogenetic profile, even if the absence of case to case correlation suggests that gene dosage effect, if it occurs, is not the only parameter involved. The main enzymatic and cytogenetic difference between melanomas and gliomas, concerns both adenylosuccinate lyase activity and the balance of chromosome 22, high in melanomas and low in gliomas. PMID- 21552874 TI - Establishment of myeloid progenitor lines from primary cultures of murine bone marrow cells expressing a v-myb oncoprotein. AB - Infection of primary hematopoietic progenitors from post 5-fluorouracil-treated murine bone marrow with a novel replication-defective retroviral vector [murine stem cell virus-v-myb (MSCV-v-myb)] bearing a v-myb oncogene reproducibly gave rise to permanent myeloid cell lines that were dependent on either interleukin (LL)-3 or granulocyte-macrophage colony-stimulating factor (GM-CSF) for sustained growth in vitro. All of the v-Myb-transformed myeloid cells synthesized an apparently normal c-Myb protein in addition to the predicted v-Myb species, indicating that expression of c-Myb is not incompatible with transformation by v Myb. Cell lines derived in the presence of GM-CSF proliferated maximally in response to this factor but also responded well to IL-3 and macrophage-CSF (M CSF), and to a lesser extent to granulocyte-CSF (G-CSF) and Steel factor (SF). In contrast, v-Myb-transformed cell lines maintained in IL-3-supplemented medium were optimally stimulated by SF but, besides IL-3, did not respond to any of the other factors tested. Unlike the GM-CSF-dependent cell lines, these latter cell lines expressed the CD34 surface antigen that is present on a population of bone marrow cells with short- and long-term hematopoietic repopulating ability. To our knowledge, this is the first report documenting transformation of mammalian hematopoietic cells by v-Myb. The well-characterized murine hematopoietic system should prove valuable in further investigations aimed at elucidating the mechanisms by which ectopic v-Myb expression results in the immortalization of target cells belonging to varying stages of early myeloid development. PMID- 21552875 TI - Pkc-dependent and pkc-independent cellular effects induced by recombinant transforming growth-factor type-Beta-1. AB - TGF-beta 1 purified from human platelets induces colony formation of rat fibroblasts reversibly when administered together with EGF. TGF-beta 1 has been reported by us to lead to stable transformation of rat fibroblasts, to activate latent Epstein-Barr virus, to exhibit tumor promoting activity for murine fibroblasts, and to cause the release of apoptosis-inducing signals from normal cells which are directed specifically against transformed cells. The use of recombinant TGF-beta 1 in this study showed that all the effects measured were indeed due to TGF-beta 1. In order to get information on intracellular signal pathways induced by TGF-beta 1, specific inhibitors of protein kinase C (PKC) were applied. Induction of EBV antigens by TGF-beta 1 was dependent on the function of PKC, whereas induction of apoptosis in transformed cells by TGF-beta 1-treated normal cells was independent of the action of PKC. PMID- 21552876 TI - Autocrine growth-factor secretion after transformation of human cytokine dependent cells by viral and cellular oncogenes. AB - The effects of viral and cellular oncogenes on a human erythroleukemic cell line (TF-1) were investigated. The TF-1 cell line required granulocyte/macrophage colony stimulating factor (GM-CSF) for growth but this factor-dependency was abrogated by the constitutive expression of either viral (v-fms, v-Ha-ras and v src) or cellular oncogenes (BCR-ABL and Delta N-raf). Furthermore the overexpression of the human insulin-like growth factor-1 (IGF-1) receptor could substitute the dependency on GM-CSF with a requirement for either IGF-1 or insulin as a proliferative signal. An autocrine cytokine, (GM-CSF) was found in the supernatant of cells transformed by Delta N-raf (and to a lesser extent in cells infected with other oncogenes. The level of GM-CSF secreted by the Delta N raf transformants was sufficient to support the proliferation of the parental cell line. GM-CSF mRNA transcripts were detected in the Delta N-raf-infected but not in the parental cells. No structural alterations of the GMCSF locus were seen in these cells. Together these observations indicated that overexpression of a raf oncogene resulted in the expression of GM-CSF transcripts. The rates of glucose transport were elevated above basal levels by GMCSF and by oncogene expression indicating that this pivotal control point of metabolism correlated with mitogenesis and malignant transformation. These studies indicate the importance of raf in growth regulation as its deregulation can lead to autocrine synthesis of cytokines in certain hematopoietic cells. Furthermore these results suggest a synergy between oncogene and cytokine gene regulation leading to autocrine growth factor expression and tumor progression. PMID- 21552877 TI - Alterations of the apc gene in carcinoma cell-lines and precancerous lesions of the stomach. AB - Somatic mutations of the APC gene in eight cancer cell lines, twelve adenomas and sixteen intestinal metaplasias of the stomach were examined. The expression of the APC mRNA and protein in eight cancer cell lines was also investigated. PCR SSCP analysis detected mutations of the APC gene in 25% (2 out of 8) of cancer cell lines, 42% (5 out of 12) of gastric adenomas, 6% (1 out of 16) of intestinal metaplasia mucosae. Direct sequencing analysis confirmed nonsense mutations in one cancer cell line, one adenoma and one intestinal metaplasia mucosa resulted in truncation of the product, frameshift mutations in one adenoma and silent mutations in one cancer cell line and three adenomas. In addition, the KATO-III cell line, which was established from signet ring cell carcinoma, expressed very low level of APC mRNA and its APC protein could not be detected. On the other hand, the expression level of variant APC mRNA transcript which lacks exon 7 was relatively high in KATO-III. It is supposed that the variant APC mRNA transcript might contribute to the inactivation of the APC gene. These data overall provide strong evidence that changes in the APC gene play an important role in the early event of stomach carcinogenesis, especially in intestinal type gastric cancer. PMID- 21552878 TI - Effects of Cisplatin and mafosfamide on the interphase microtubular cytoskeleton of a human breast-cancer cell-line, mx-1, in-vitro - a fine-structure and antitubulin immunofluorescence study. AB - Modem therapy of solid tumors involves drugs such as cisplatin (CDDP) and mafosfamide (MAFO) that interact with the DNA. Hyperthermia facilitates the effectiveness of these drugs for the management of aggressive metastatic tumors. To evaluate the extent of cellular damage caused by anti-tumor drugs under hyperthermic conditions, we have examined the microtubular cytoskeleton in a human breast cancer line, MX-1, at two different temperatures: 37 and 42 degrees C. A mouse monoclonal antibody to beta-tubulin and a rabbit polyclonal antibody to gamma-tubulin were used in combination with indirect immunofluorescence. The former antibody stains the entire microtubular cytoskeleton, whereas the latter antibody detects microtubule-organizing centres. Untreated cells possessed a rich interphase cytoskeleton. The antibody against gamma-tubulin detected one to two distinct spots in mononucleate cells and a cluster of spots in multinucleate cells. Microtubules were usually not focused towards the gamma-tubulin-containing material. At 42 degrees C more cells were damaged when compared with cells treated at 37 degrees C. The drug effects were, however, highly variable. There were cells that appeared unaffected by a single treatment while other cells had almost completely lost their microtubules. Concomitantly, gamma-tubulin containing clumps had formed in the highly damaged cells. Electron microscopy of ultrathin sections revealed a range of structural changes of cytoplasmic components including mitochondrial defects after CDDP treatment. PMID- 21552879 TI - On the use of Syrian-hamster cell-cultures as targets for carcinogen-screening. AB - Syrian hamster embryo (SHE) cells have a reported culture lifespan limited to 30 to 40 population doublings (PDs). In contrast, we have observed continuous growth of two SHE cell lines without the hallmarks of cellular senescence. Two independent primary isolates (SHE-3, and SHE-15) have been grown for more than 160 PDs (SHE-3) and 50 PDs (SHE-15), respectively, with weekly subcultures and with no sign of senescence. During this study, we observed that SHE-3 cells ceased to multiply after about 30 PDs when grown in a nutritionally-inadequate serum-free medium, but resumed growth when switched to an adequate medium. The chromosomal profiles of both SHE cultures revealed a near diploid karyotype but not a completely normal karyotype, even at early passages with increasing chromosomal changes with continued culture. In addition, Syrian hamster chondrocytes were isolated, partially characterized, and their sensitivity to chemically-induced morphological transformation was compared to that of the standard Syrian hamster embryo (SHE) mixed cell culture. It appears that chondrocytes may be a suitable and more sensitive target for carcinogen-screening in vitro. PMID- 21552880 TI - Direct isolation of variably amplified cdnas from human tumor-cell lines. AB - Gene amplification is an important phenomenon in the pathogenetics of malignancy. A method is defined which allows the determination of gene amplification from any sample from which RNA can be obtained, and requires no a priori knowledge of the cytogenetic or genomic state of the tumor. This method allows the determination of various degrees of amplification, and is sensitive to lower degrees of increased copy number. Gene amplification from cell lines with known oncogene amplification of 13- and 7-fold could be detected. Hence, use of a simple modified subtractive hybridization technique can identify amplified cDNAs from tissue without detailed previous genomic knowledge of the samples. This methodology should prove useful in the assessment of disorders where copy number changes of expressed genes are present. PMID- 21552881 TI - Amphiregulin and cripto overexpression in breast-cancer - relationship with prognosis and clinical and molecular-variables. AB - The expression of amphiregulin (AR) and cripto (CR-1), two recently identified growth factor peptides, has been evaluated in 196 mammary carcinomas, 13 biopsies of normal breast and 17 benign breast lesions using immunohistochemical methods. Strong immunostaining with AR antibody indicating elevated protein expression was seen in more than 90% of cases of mammary carcinoma whereas with the CR-1 antibody strong staining was seen only in about 77% of cases. No significant relationship could be demonstrated between AR and CR-1 overexpression and traditional prognostic factors such as tumour grade, nodal status and steroid hormone receptor status. PMID- 21552882 TI - Tumorigenicity associated with chromosome 11p15 alterations in sv40-transformed human kidney-cells. AB - Chromosome 11p15 has been suggested to be a potential site for a second Wilms' tumour gene (a childhood nephroblastoma). Human foetal kidney cells and normal kidney cells from Wilms' tumour patients were transformed with SV40 derivative vectors. As some of the cell lines progressed to tumorigenicity, we observed that chromosome 11p13, site of the WT1 suppressor gene, did not show any allelic loss. However, RFLP analysis showed that chromosome 11p15 was affected by allelic losses on different genes in some cell lines but not necessarily prior to the appearance of tumorigenicity. We also observed that the most aggressive cell Line (SVCU/NK), derived from the normal kidney cells of a Wilms' tumour patient, showed increased expression of c-Ha-ras proto-oncogene at later passage and in the tumour tissue extracted from nude mice. Finally we report a lack of tumour suppression activity of one cell line SVT1B6/NK, when fused with the tumorigenic G401 cell line (the latter has been used in tumour suppression experiments as a Wilms' tumour cell line before being identified as a Rhabdoid tumour cell line). These experiments are consistent with the existence of a suppressor gene at chromosome 11p15. PMID- 21552883 TI - Prognostic-significance of chromosome 5q and 17p allelic deletion in colorectal adenocarcinomas. AB - Patient survival was analysed for 75 patients after surgery for primary colorectal adenocarcinoma with regards to allelic loss of chromosome 17p and chromosome 5q. Allelic loss of chromosome 17p occurred in 69% of patients and was not significantly associated with a poorer patient prognosis as assessed by log rank analysis of Kaplan-Meier survival plots (p = 0.161). Allelic loss of chromosome 5q occurred in 32% of patients and was significantly associated with a poorer patient prognosis as assessed by log rank analysis of Kaplan-Meier survival plots (p = 0.014). Analysis of the two variables by Cox regression analysis indicated that allelic loss of chromosome 5q was an independent variable for patient prognosis. Entry of Dukes' stage into the model resulted in a final model with Dukes' stage and allelic loss of chromosome 5q as independent significant variables in assessing patient survival. These results show that allelic loss of chromosome 5q, but not chromosome 17p provides additional prognostic information for assessing patient survival, over and above Dukes' stage. PMID- 21552884 TI - Rapid killing of urothelial carcinoma-cells by wild-type p53. AB - The effect of the tumor suppressor p53 on urothelial carcinoma cells was studied by transfecting six cell lines containing different mutations in the p53 gene with an expression construct for the wild-type protein. In all cell lines, the number of cell clones resistant to a neomycin analogue was strongly diminished when pCMVhup53 was cotransfected with the resistance plasmid pRSVneo as compared to cotransfection with either a plasmid vector, a p53 deletion and a mutant p53 expression vector. Cytochemical analysis showed that cells cotransfected with pCMVhup53 and an expression plasmid for beta-galactosidase disappeared during the second day after transfection. Thus, reexpression of wildtype p53 efficiently and rapidly kills urothelial carcinoma cells, independent of the different mutations in p53 they contain. PMID- 21552885 TI - Potentiation of the mitogenic effect of estrogen on the pituitary-gland by alcohol-consumption. AB - The effect of alcohol on estrogen-regulated lactotropic cell proliferation was examined in Fisher 344 rats. Alcohol was administered for 2 weeks using liquid diet containing 8.7% ethanol (v/v) and 37% ethanol-derived calories. The control group was pair-fed with an isocaloric diet minus the ethanol or adlib-fed with normal diet. Ethanol-treated rats showed mean blood ethanol concentrations between 60-90 mg/dl. Alcohol treatment did not effect the body growth rate, but increased the DNA synthesis in lactotropes and reduced the levels of lactotropic growth inhibitory transforming growth factor-beta 1 (TGF-beta 1) protein and mRNA in the pituitary. These results suggest that alcohol promotes estrogen-induced lactotropic proliferation, possibly by down regulating the inhibitory TGF-beta 1 control of lactotropic function. PMID- 21552886 TI - Partial characterization of a Cisplatin-resistant subline of murine rif-1 tumor cells. AB - We have developed a drug-resistant cell line (RIF/Ptr1) (R) from the murine radiation-induced fibrosarcoma (RIF-1) also designated Pts or (S). This subline has been characterized previously by an increased resistance to cisplatin (cis diamminedichloroplatinum(II) or CDDP), lowered intracellular CDDP concentrations, and elevated intracellular glutathione (GSH) levels (1.4-2.5-fold) but unaltered formation of CDDP-DNA interstrand cross-links. In this work, we have shown that RIF/Ptr1 cells were also resistant to carmustine (BCNU) and X-irradiation. Neither cell line had P-glycoprotein 170. The intrastrand CDDP-DNA adduct level was proportional to the concentration of intracellular CDDP. The oxygen consumption, ATP level, and glycolysis were similar in both cell lines. The cisplatin influx and efflux showed that the RIF/Ptr1 cells had lower drug influx and higher drug efflux compared to RIF-1. We conclude that the major difference between the cisplatin sensitive and cisplatin-resistant cells in this model is the regulation of cisplatin transport probably at the cell membrane level suggesting that a membrane active transport system other than P-glycoprotein 170 is involved. Whether glutathione is linked to the putative membrane transporter needs further investigation. PMID- 21552887 TI - Production of tgf-Beta and hgf receptor by a differentiated papillary thyroid carcinoma cell-line (B-cpap) - implication in malignancy. AB - The B-CPAP cell line was obtained from a human differentiated papillary thyroid carcinoma. Previous studies showed that the cells present thyroid characteristics such as thyroglobulin production, phenotypic alterations such as synthesis of human chorionic gonadotropin hormone (HCG), expression of neuron specific enolase (NSE) and protein S100, and also somatic mutations of p53 and K-rns oncogenes. The present data further characterize this cell line and show an overexpression of transforming growth factor (TGF beta 1) and c-met gene product i.e. the receptor for human growth factor (HGF). The relation between the phenotypic and somatic alterations in the process of malignancy are discussed. PMID- 21552888 TI - Juvenile granulosa-cell tumor of the ovary - interphase cytogenetics for chromosome-12 and chromosome-x and flow cytometric DNA-ploidy study. AB - We performed interphase in situ hybridization (ISH) for chromosomes 12 and X and now cytometric DNA analysis on seven juvenile granulosa cell tumors to verify this observation and correlate the results with clinicopathologic factors. Five cases were primary ovarian tumors and two were metastatic lesions. Our results show that four tumors exhibited polysomy 12 and four had monosomy X; only two tumors displayed concurrent aberrations of both chromosomes. Of the six tumors with interpretable flow cytometric histograms three showed DNA aneuploidy and three were DNA diploid. All three aneuploid tumors manifested polysomy 12. Of the three diploid DNA neoplasms two showed monosomy X and one displayed disomy for chromosomes 12 and X. No apparent correlation between numerical chromosomal abnormalities and the biological course was observed in this small cohort. Our results indicate that chromosomes 12 and X are frequently altered in these neoplasms and thus could be targeted for further molecular studies in order to identify genetic aberrations which might be associated with JGCT tumorigenesis. PMID- 21552889 TI - Differential-effects of omega-3 and omega-6 Fatty-acids on primary tumor-growth and metastasis. AB - The amount and type of dietary lipid can significantly influence spontaneous tumor development and tumor progression. To determine the effect of fish oil (rich in omega-3 polyunsaturated fatty acids) and corn oil (rich in omega-6 polyunsaturated fatty acids) on primary tumor growth, metastasis and carcass weight, 45 female Lewis/Wistar rats with subcutaneous mammary tumor implants (MAC 33) were randomized to 1 of 3 diets with 30% lipid consisting of: (i) corn oil alone, (ii) combined 50%:50% corn oil:fish oil, or (iii) fish oil alone. Primary tumor weight was significantly reduced in animals which were fed fish oil or corn oil alone compared to animals given combined corn oil:fish oil diet. Biochemical analysis (protein, DNA, RNA) of the primary revealed no difference between dietary groups. Cell cycle analysis of the primary tumor showed no difference in percent G(0)-G(1), S, G(2)-M or growth fraction (% S + G(2)-M) between dietary groups. In contrast, lung metastasis, was reduced in animals fed the combined corn oil:fish oil diet. Thus, dietary, lipid intake can significantly influence primary tumor growth and tumor metastasis. Differential effects of omega-3 and omega-6 polyunsaturated fatty acids occur on primary tumor growth and development of distant pulmonary metastases in this animal model. PMID- 21552890 TI - Nuclear morphometry for predicting cervical metastatic potential in laryngeal squamous-cell carcinoma. AB - Quantitative nuclear morphometry (QNM) provides a reliable, reproducible method for measuring the degree of nuclear pleomorphism, a qualitative parameter widely incorporated into histopathological grading schemes. Nuclear shape has successfully been shown to predict primary prostate adenocarcinoma metastatic potential. This investigation utilized QNM to measure the nuclear pleomorphism of 50 patients with primary laryngeal squamous cell carcinoma to determine whether this computer-assisted method could discriminate between those patients with and without cervical metastases. Nuclear cross-sectional area and nuclear roundness as determined by QNM could not discriminate between patients with and without cervical metastases, though significant alterations in nuclear morphology exist between normal laryngeal squamous epithelium and laryngeal squamous cell carcinoma. PMID- 21552891 TI - Histologic characteristics of residual renal-cell carcinoma following interferon alpha-based therapy - correlation with clinical-parameters. AB - To compare the histologic characteristics of residual renal cell carcinoma (RCC) following an interferon-alpha (IFN-alpha)-based therapy with clinical parameters, we examined 12 metastatic and 6 primary kidney tumors resected from 18 patients with advanced RCC. The histologic parameters including tumor necrosis, nuclear grade, inflammatory response and hemosiderin deposition were assessed. The immunophenotypes of tumorinfiltrating lymphocytes (TILs) were also characterized. The tumors of the 12 patients who had partial clinical response (responders) showed more tumor necrosis than the tumors of the 6 non-responders (patients with minor response or stable disease) (p = 0.0061). A tendency of longer overall survival was observed in the group with tumor necrosis compared to the group without necrosis. Predominance of T-cell TIL was demonstrated in all 9 responders compared to 3 non-responders (p = 0.053). Our findings suggest that tumor necrosis and a high percentage of T-cell TILs in residual RCC may be associated with favorable clinical response following IFN-alpha-based therapy. PMID- 21552892 TI - Inhibition of pkc and pka by chemopreventive organoselenium compounds. AB - Numerous efficacy studies in rodents revealed that 1,4-phenylenebis(methylene) selenocyanat (p-XSC) is a more effective chemopreventive organoselenium compound and less toxic than benzyl selenocyanate (BSC) or the inorganic compound Na2SeO3. To explore mechanisms which mediate chemopreventive activities of p-XSC we have tested its effect on protein kinase A and C using in vitro and cell culture systems. While p-XSC did completely inhibit PKC and PKA activity, BSC was less active and Na2SeO3 had no effect. Comparative EC,, revealed values of 0.1, 1 and > 10 mu M for p-XSC, BSC and Na2SeO3, respectively. p-XSC was also capable of inhibiting protein phosphorylation in cultures of primary human fibroblasts and altered morphology of rat fibroblast (R6) cells. When combined, sub-optimal doses of p-XSC and staurosporine yielded an additive effect on cell morphology. The ability of p-XSC and BSC to inhibit protein kinase A and C activities may in part account for the mechanism(s) by which these agents mediate their chemopreventive effects. PMID- 21552893 TI - Changes in glucose-transport associated with malignant transformation (review). AB - It has been known for many years that changes in glucose metabolism are associated with neoplasia and research on this phenomenon has focused on the enhancement of glucose transport by malignant transformation. Viral transformation of fibroblastic cells provided the first system in which this enhancement could be studied using non-metabolizable glucose analogs. Kinetic and immunological analyses demonstrated that this was due to an increase in the number of glucose carriers at the plasma membrane. In the last 10 years glucose transporter (GLUT) proteins have been characterized by molecular cloning allowing direct examination of the molecular mechanisms of induction of transporter expression. GLUT proteins are a family of at least six separate isoforms which are encoded by distinct genes and differ in tissue distribution and regulation. Two of these isoforms, GLUT1 and GLUT3, are responsible for the changes associated with malignant transformation. The processes involved in the disregulation of these isoforms in the transformation of cultured fibroblastic and hematopoietic cells are described. Analysis of clinical samples indicates that GLUT1 and GLUT3 are often overexpressed in malignant tissue where they may aid tumor growth. PMID- 21552894 TI - Anthracyclines - a review of general and special toxicity studies. AB - Preclinical safety assessment data on doxorubicin (DOXO), epirubicin (EPI), idarubicin (IDA) and methoxymorpholinodoxorubicin (MORPHO), from mouse, rat and dog studies are reviewed. These data are put into perspective allowing for extrapolations across species, doses and dose regimens with recommendations for proper human use. The compounds were administered intravenously or intraperitoneally in studies ranging from single dose to multiple dose studies of different durations. The compounds were given once, daily, weekly or cyclically. In the cyclic administration studies, DOXO, EPI, and IDA were given for 3 consecutive days a week for 6 or 13 weeks; MORPHO was given for 3 consecutive days a week every three weeks for a total of 9 cycles. The duration of the cyclic studies was from 6-26 weeks. Daily dose studies lasted from 4-26 weeks. In the single dose studies the recovery ranged from 4 weeks to one year; in the multiple dose studies from 4 to 8 weeks. A few special studies were also considered. In all studies reviewed, 2 different types of toxicity were observed. These toxicities occur also in man. The first is the acute toxicity, which is the consequence of cytotoxicity and expresses the exaggerated pharmacological activity of the compounds. The target sites in all 3 species and in man include the hemolymphopoietic system (HLPS), the gastrointestinal (GI) tract, skin and testes; all renewing cell types. The second type of toxicity is the chronic progressive toxicity. This toxicity is the expression and result of sustained disruption of cytoplasmic homeostasis and occurs in non-renewing cell types. The target sites include the heart (both animals and man), kidneys (rodents) and peripheral nervous system (PNS) (rodents). From single administration animal data, chronicity, site and magnitude of toxicities can be predicted in man. Despite strong mitogenic stimuli in the rat, there is no evidence that there is a potential for hemolympho- or hepatocarcinogenicity with these compounds. PMID- 21552895 TI - The hiv tat gene is a promoter of epidermal skin tumors. AB - Human immunodeficiency virus (HIV) infected patients have a very high incidence (>90%) of neoplastic and non-neoplastic skin disorders. The proliferative lesions frequently involve the epidermis and include squamous and basal cell carcinomas, and the papulosquamous diseases of seborrheic dermatitis and psoriasis. Although the role played by HIV in the development of these proliferative skin lesions is not clear, there are several lines of evidence suggesting that HIV may play a causative role. We show that transgenic mice carrying the HIV tat gene under the control of the viral LTR constitutively express the tnt gene in keratinocytes. When a single subthreshold dose of a carcinogen initiator is topically applied to these mice, tumor promoters are no longer required to induce the development of epidermal skin tumors, suggesting that Tat expression in keratinocytes is capable of substituting for phorbol ester tumor promoters in the two-step carcinogenesis skin cancer model. Together, Tat and phorbol ester have additive effects in promoting tumors in transgenic mice first initiated with carcinogens. We conclude that although Tat alone is insufficient to cause epidermal tumors, it functions as a tumor promoter and predisposes these mice to develop tumors following an initiating event. PMID- 21552896 TI - Synergism between the hbx gene and aflatoxin B-1 in the development of murine liver-cancer. AB - Infection by hepatitis B virus (HBV) and exposure to dietary aflatoxin B-1 (AFB(1)) have both been implicated by epidemiological studies to be important risk factors in the development of hepatocellular carcinoma (HCC). Our ability to derive transgenic mice which develop liver cancer as a consequence of the expression of a single gene from HBV, the HBx gene, provides an opportunity to use this animal model to test whether AFB(1) can induce p53 mutations, particularly at codon 249, which are frequently detected in HCC and, as a result, act synergistically with HBV to accelerate the manifestation of disease. While AFB(1) significantly shortened the latency of tumor development in the HBx transgenic mice, the tumors did not have p53 mutations. As in tumors from the untreated transgenic mice, the p53 tumor suppressor protein is found bound to the HBx protein and sequestered in the cytoplasmic compartment of the tumor cell. Despite the frequent involvement of ras mutations in mouse tumors, we also have not detected activation of the ms p21 protein in the tumors from the AFB(1) treated mice. We conclude that although AFB(1) can act as a co-factor with HBx to induce HCC in mice, its mode of action in vivo remains obscure. PMID- 21552897 TI - Detection and comparison of a 90-kd glycoprotein tumor-associated antigen specific immune-complexes with cea and ca15-3 in breast-cancer. AB - Serum samples selected randomly from 106 patients that had histopathologically proven breast cancer, and from 107 self-proclaimed and apparently healthy females were analyzed for the presence of a 90 kD subunit containing glycoprotein TAA specific immune complexes (IC) by a murine monoclonal antibody based ELISA. The incidence of the glycoprotein antigen specific IC in breast cancer patients was 63% (67/106), as indicated by the normalized ELISA value above 0.410 OD405nm. On the contrary, only 3 (2.8%) of 107 apparently healthy controls had positive ELISA value (p<0.05). Comparison of the glycoprotein TAA-specific IC results in breast cancer patients with evidence of disease with the results of CEA and CA15-3 revealed that the incidence of abnormal values was increased to 91%. Thus, use of the glycoprotein TAA specific-IC marker in conjunction with CEA and/or CA15-3 may prove to be more sensitive than when used alone for immunodiagnosis and immunoprognosis. PMID- 21552898 TI - New antagonists of bombesin gastrin-releasing Peptide with C-terminal leu-psi (ch2n)tac-nh2. AB - Several new pseudononapeptide bombesin/GRP analogs containing C-terminal Leu Psi(CH2N)Tac-NH2 with variations at the N-terminus, corresponding to position 6 of bombesin, have been synthesized in order to develop more potent Bn antagonists for the hormonal therapy of cancers. The biological activities of the new compounds were evaluated in vitro by investigating their ability to inhibit the binding of [I-125-Tyr(4)]Bn and to suppress the GRP(14-27)-stimulated DNA synthesis in quiescent Swiss 3T3 cells. All compounds investigated inhibited the binding of [I-125-Tyr(4)]Bn, suppressed the GRP(14-27)-induced proliferation of Swiss 3T3 cells in a dose-dependent manner and proved to act as Bn antagonists without agonistic activity. Two of the newly synthesized pseudononapeptides [Hca(6), Leu(13)Psi(CH2N)-Tac(14)]Bn(6-14) (RC-3940-II) and [D-Nal(6), Leu(13)Psi (CH2N)Tac(14)]Bn(6-14) (RC-3965-II) exhibited higher binding affinities to Swiss 3T3 cells than the Bn/GRP antagonist RC-3095 and the recently developed compound [D-Phe(6), Leu(13)Psi(CH2N) Tac(14)]Bn(6-14) (RC-3950-II). RC-3940-II caused 50% inhibition of the specific binding of [I-125-Tyr(4)]Bn to Swiss 3T3 cells at concentrations less than 1 pM and suppressed by 50% the GRP(14-27)-induced proliferation of Swiss 3T3 cells at doses one order of magnitude lower than RC 3095. This study demonstrates the importance of the nature of the N-terminus in addition to the C-terminal Leu Psi(CH2N)Tac-NH. The elimination of the free amino group in the aromatic residue in position 6 appears to increase the antagonistic activity. These findings suggest the merit of further investigations of this class of Bn/GRP antagonists for their antitumor activities in various cancers. PMID- 21552899 TI - The status of nf1-grd mutation and p53 expression in neuroblastoma. AB - The role of tumor suppressor genes in neuroblastoma is currently under intensive research. Recent reports seem to show that the NF1 gene plays a role in the pathogenesis of this tumor. In this study mutations at the gap related domain (GRD) of the NF1 gene were assesed in 29 neuroblastic tumors by means of the polymerase chain reaction (PCR) in combination with the single strand conformation polymorphism technique (SSCP). We have also analysed p53 expression in 16 of those neuroblastomas by means of immunohistochemistry with a monoclonal antibody that stains normal and mutant p53 protein. In no case could we detect either p53 expression or NF1 gene mutations. In light of these and previous results we can virtually exclude p53 from the pathogenesis of neuroblastoma, while NF1 should be further studied -out of its GRD-before concluding on its definite role in neuroblastoma initiation and/or progression. PMID- 21552900 TI - Messenger-rnas for activin and activin receptors are expressed in fetal bovine heart endothelial-cells. AB - Inhibin and activin, members of transforming growth factor beta (TGF beta) superfamily, have been localized immunohistochemically in fetal bovine heart endothelial cells (FBHE), suggesting that these cells produce inhibin/activin proteins. In addition, the mRNAs coding for alpha-, and beta A-subunits of inhibin/activin, and activin receptor II were expressed in these cells by in situ hybridization technique. It is concluded that inhibin/activin and activin receptor are expressed in FBHE and activin may have autocrine functions in these cells. PMID- 21552901 TI - Identification of primary chromosome-abnormalities in a patient with endometrial carcinoma - analyses of tumor-biopsy and lymphocyte-cultures. AB - The development of human cancer is generally considered to be the result of genetic mutations that cause a progressively more malignant phenotype. We propose that such genetic changes can be observed in a small number of lymphocytic metaphase plates. We have identified a specific chromosome marker formation in a primary endometrial adenocarcinoma obtained from a 74-year-old woman. After observing an isochromosome for 1q in the tumor cells, we predicted that in her lymphocytes this particular chromosome must show susceptibility to breakage. After 6 months, when lymphocytes were available from this patient, 4.0% of her metaphases exhibited chromatid breaks in the pericentromeric region of one homolog of chromosome 1, thus confirming our prediction. Since then, the primary endometrial tumor cell line has been passaged through nude mice and has become highly metastatic. Examination of tumors obtained from different organ sites of these mice has revealed that the same altered homolog 1 underwent various types of chromosome and chromatid aberrations, thereby confirming the presence of instability in this particular chromosome in this particular cancer. A detailed karyotypic evolution from normal lymphocyte cultures --> primary endometrial tumor --> highly metastatic endometrial tumor was therefore possible to construct. Our results further support the idea that peripheral blood lymphocytes can be used as the tissue for studying genetics of cancer predisposition. PMID- 21552902 TI - Therapy of desmoid tumors, fibromatosis, and related neoplasms. AB - Forty-seven patients with unresectable desmoid tumors and 32 patients with unresectable fibromatosis were treated with various anti-neoplastic agents including methotrexate, vinblastine, etoposide, actinomycin D, and fluorouracil. A combination of methotrexate with either vinblastine or etoposide was found to be effective in yielding long-term control to both groups of patients. Fluorouracil and actinomycin D were less effective. Other than a significant but slowly reversible peripheral neuropathy in 6 patients, therapy was well tolerated and no long-term hematologic, pulmonary, hepatic, or cardiac toxicity was noted in any patient. PMID- 21552903 TI - Combinations of tnp-470 or sr-4233 with antitumor alkylating-agents in emt-6 spheroids and monolayers. AB - EMT-6/Parent and EMT-6/CDDP and EMT-6/CTX in vivo alkylating agent resistant cells were grown as spheroids or as monolayers and their response to cis diamminedichloroplatinum(II) or 4-hydroperoxycyclophosphamide exposure for 1 h alone or in combination with TNP-470 or SR-4233 was determined. When grown as spheroids, each of the three cell lines were less responsive to cis diamminedichloroplatinum(II) and 4-hydroperoxycyclophosphamide exposure than when the cells were grown and drug-treated in monolayer. The hypoxic cell selective cytotoxic agent SR-4233 was additive in cytotoxicity with the antitumor alkylating agents in both the monolayer and spheroid cultures as determined by isobologram analysis. The antiangiogenic agent TNP-470 was synergistic in cytotoxicity in combination with cis-diammedichloroplatinum in each of the three cell lines when the cells were grown in monolayer and was additive in cytotoxicity with cis-diamminedichloroplatinum(II) when the cells were grown as spheroids. The combination of TNP-470 and 4-hydroperoxycyclophosphamide resulted in additive cytotoxicity toward both monolayer cultures and spheroids. Thus, co exposure with TNP-470 or SR-4233 increased the cytotoxicity of the antitumor alkylating agents in both the parental and drug resistant cells grown as monolayers or spheroids. PMID- 21552904 TI - Antibody-induced inhibition of growth of egfr overexpressing tumors occurs in the absence of receptor down-regulation. AB - Using two antibodies which bind to distinct epitopes on the extracellular domain of the EGF receptor (EGFR) we have developed a novel method for monitoring EGFR expression and the behaviour of monoclonal antibody (mAb) bound to the receptor. We have used this method to investigate the fate of the rat mAb ICR80 following binding to the EGF receptor on tumour cells. Antibody ICR80, which was raised against the external domain of the EGF receptor on a human brain tumour (A172) cell line and was employed in this study, has the following properties. It (a) blocks the binding of EGF, TGF alpha and HB-EGF to the EGFR, (b) prevents the EGF, TGF alpha and HB-EGF induced tyrosine phosphorylation of the EGFR, and (c) inhibits the growth in vitro of the head and neck tumour (HN5) cell line overexpressing the EGF receptor. Our results presented herein also show that EGF receptor blockade by antibody ICR80 is not accompanied by detectable loss of antibody from the cell surface or down-regulation of the receptor. On the basis of these results we conclude that the long-lasting blockade of the EGF receptor on tumour cells by antibody may be an important factor in preventing the binding of growth factors which are essential for their continued proliferation. PMID- 21552905 TI - Cytotoxicity of a novel indoloquinone eo9 in hypoxic non-small-cell lung-cancer cell-lines. AB - 3-Hydroxymethyl-5-aziridinyl-1-methyl-[1H-indole-4,7-dione]-prop-beta-en -alpha ol (EO9) is a bioreductive anticancer agent active for non-small cell lung cancer (NSCLC) and structurally related to mitomycin C (MMC). DT-diaphorase (DTD) is regarded as a two electron reductase that plays an important role in the biotransformation of MMC to antitumor metabolites. To evaluate the role of DTD as a bioactivator of EO9 in NSCLC cell lines under oxic and hypoxic conditions, we examined the inhibitory effect of dicumarol which was regarded as a selective inhibitor of DTD on the sensitivity to EO9 in vitro. In this study, we used an MMC-resistant NSCLC cell line (PC-9/MC4) which was established from a PC-9 cell line as a parent cell line by continuous exposure to MMC in our laboratory. We reported previously that the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9 with decreased DTD activity. The IC50 value of PC-9 against EO9 was significantly increased by co-incubation with dicumarol under oxic conditions. EO9 was more cytotoxic against PC-9/MC4 than against PC-9 cells and the enhancement was impaired by tempol under hypoxic conditions. These findings suggest a suppressive role of DTD against one-electron reduction pathway in the bioactivation of EO9 under hypoxic conditions and EO9 may be more active against oxygen-deficient solid tumors especially in MMC-resistant NSCLC cells with low levels of DTD activity. PMID- 21552906 TI - Rearrangement of esophageal-carcinoma cells and stromal fibroblasts in a multicellular spheroid. AB - Using a thermo-responsive polymer, a collagen-conjugated poly-N-isopropyl acrylamide (PNIPAAm) as a substratum, we developed hetero-multicellular spheroids (MCS) composed of esophageal squamous carcinoma cells (TE10) and esophageal fibroblasts isolated from esophageal carcinoma tissue. PNIPAAm is insoluble in water above the lower critical solution temperature (LCST; about 32 degrees C) and becomes reversibly solubilized below the LCST. Taking advantage of this conversion, we prepared three types of hetero-MCS as follows: F/T-multicellular spheroids made by seeding of TE10 onto a preprepared monolayer of fibroblasts; T/F-multicellular spheroids made by seeding of fibroblasts onto a preprepared monolayer of TE10; Mixed-multicellular spheroid made from a monolayer of mixed fibroblasts and TE10. Histolo,oical and immunohistochemical examinations revealed that fibroblasts and TE10 cells were intermingled in 5-day-old multicellular spheroids but were divided into three zones in 1- or 2 week-cultured spheroids: into an external zone composed almost entirely of TE10 cells that were positive for epithelial membrane antigen (EMA), an intermediate zone composed of fibroblasts that were positive for vimentin, and a necrotic zone showing variable evidence of cell injury. This distribution was observed in all three types of the spheroids described above. These findings indicate that TE10 cells are able to migrate and cover the surface to make organizing spheroid, thus mimicking in vivo structures. We conclude that the three-dimensional culture system using a thermo responsive polymer, which enables coculturing with different types of cells as a heteromilticellular spheroid, is a useful model to examine the interaction between carcinoma cells and their stroma cells as it occurs in vivo. PMID- 21552907 TI - Characterization of glioma-cells derived from human polyomavirus-induced brain tumors in hamsters. AB - Intracerebral injection of human polyomavirus, JCV, into neonatal hamsters causes tumors of,glial origin. HJC is an established cell Line derived from a JCV induced mixed hamster brain tumor with astrocytic and ependymal components. Flow cytometric and immunohistochemical analysis of HJC suggests that it is comprised of a mixed population of cells all of which contain the JCV early protein, T antigen, in the nuclei. Five individual clonal lines, called HJC-15a to HJC-15e, were isolated by limiting dilution and were found to exhibit distinct morphological characteristics with 25-30% variation in their sizes. It was evident that each clone has unique growth rates, doubling times, and cell cycle parameters with different G(1), S, and G(2) phase times. All clonal cells showed the presence of the JCV early protein in the nucleus. Of interest was the observation from immunoprecipitation and Western analysis indicating qualitative and quantitative differences in the T-antigen isoforms produced in these cells. Similar to the parental clone, HJC-15b produced two distinct forms of JCV T antigen isoforms, 88 kDa and 92 kDa proteins. In addition, HJC-15c was able to produce a 23-25 kDa protein which was recognized by anti-T-antigen antibody. The activity of cyclin-dependent kinases, in particular cdc2, was higher in HJC-15c than in the other cell lines. The data presented herein indicates that glioblastomas induced by viral T-antigen expression are composed of a multitude of distinct cells that possess a variety of different characteristics. PMID- 21552908 TI - Image cytometry for DNA analysis in endometrial carcinoma correlated with other prognostic parameters. AB - We evaluated by static cytometry DNA ploidy parameters in 30 stage I-IV endometrial carcinomas and correlated these data with standard clinical pathological features and disease-free period. We observed a direct correlation between either non-diploid DNA content and deeper myometrial invasion (p<0.02) or D.I.greater than or equal to 1.2 and M2-M3 tumors (p<0.009). The Kaplan Meier survival curves illustrate a more rapid relapse of disease associated with non diploidy, high 5cExR, high level of proliferation and D.I.greater than or equal to 1.2. while Cox regression model gave relative hazards for disease recurrence of 4, 6, 3.7 and 2.1 for non-diploidy, D.I.greater than or equal to 1.2, high 5cExR and high level of proliferation respectively. This prospective study confirmed the prognostic value of DNA Index, and its usefulness in clinical practice especially in stage I cases, otherwise characterised by favourable standard prognostic factors, is discussed. PMID- 21552909 TI - Urinary trypsin-inhibitor protects neutrophil chemotaxis in the inflammatory response. AB - The aim of this study was to assess the contribution of physiological protease inhibitors (urinary trypsin inhibitor [UTI] and alpha 1-antitrypsin [alpha 1AT]) to the inhibition of trypsin and human leukocyte elastase (HLE) activities, to examine whether UTI and UTI-trypsin complexes compete for binding of alpha 1AT HLE complexes to human neutrophils and promyeloid leukemia U937 cells, and to determine whether the modified ligands for the serpin-enzyme complex (SEC) receptor have neutrophil chemotactic activity. UTI is a strong inhibitor for trypsin and HLE and is relatively resistant to inactivation by trypsin,while the decline in inhibitor activity of alpha 1AT proceeds faster by trypsin. UTI protects the inactivation of alpha 1AT by trypsin. The SEC receptor mediates neutrophil chemotactic activity of alpha 1AT-HLE complexes. UTI and UTI-trypsin complexes failed to bind to the SEC receptor on neutrophils, and they did not inhibit alpha 1AT-HLE complexes-mediated neutrophil chemotactic activity. When alpha 1AT treated with trypsin was incubated with HLE, neutrophil chemotactic activity was inhibited. In the presence of UTI, however, UTI protected neutrophil chemotaxis mediated through SEC receptor. The present study suggests another working hypothesis that, besides the effects on anti-protease activity, UTI plays an important role in inhibition of inactivation/degradation of alpha 1AT by trypsin and in protection of neutrophil chemotaxis. PMID- 21552910 TI - Betacellulin, a member of the epidermal growth-factor family, is overexpressed in human pancreatic-cancer. AB - Human pancreatic ductal adenocarcinomas overexpress the epidermal growth factor (EGF) receptor. Betacellulin is a mitogenic polypeptide that binds and activates this receptor. To determine whether betacellulin has a role in human pancreatic cancer, we studied its expression in cultured human pancreatic cancer cell lines and in normal and cancerous pancreatic tissues. Five of 6 pancreatic cancer cell lines expressed the 3 kb betacellulin mRNA moiety, T3M4, MiaPaCa-2 and COLO-357 cells exhibiting the highest expression levels. EGF, heparin-binding EGF-like growth factor (HB-EGF), and basic fibroblast growth factor (bFGF) increased betacelullin mRNA levels. Only 2 of 15 normal samples and 1 of 10 cancer samples failed to exhibit the betacellulin transcript. Densitometric analysis of the autoradiographs revealed a 7.5-fold increase in betacellulin mRNA levels in the cancer tissues by comparison with the normal tissues. By in situ hybridization, the duct-like cancer cells exhibited many betacellulin mRNA in situ hybridization grains. These findings indicate that human pancreatic cancer cells express betacellulin in culture and in vivo, and suggest that this EGF-like ligand may participate in aberrant autocrine and paracrine activation of the EGF receptor in human pancreatic cancer. PMID- 21552911 TI - Changes in growth, po(2) and ph after exposure to oxamate - studies of 2 human tumor-cell lines growing as multicellular spheroids. AB - The basic metabolism and pO(2) and pH gradients in spheroids were characterized and, in some cases, changed by the addition of the pyruvate analogue oxamate. Two human tumour spheroid types, colon adenocarcinoma HT29 and malignant glioma U118MG, were applied as models. Microelectrode measurements in HT29 spheroids showed steep pO(2) gradients with large differences between surface and center, Delta pO(2), and low central pO(2) values. The HT29 spheroids had rather flat pH gradients. The U118MG spheroids had less steep pO(2) gradients but steeper pH gradients. Determinations of 1-C-14 and 2-C-14 pyruvate oxidation rates, for characterization of the oxidative glucose breakdown as well as of lactate dehydrogenase kinetics, showed consistent results with the microelectrode measurements in that there was high oxidative metabolism in the HT29 spheroids whereas the U118MG spheroids relied more on glycolysis. Western blot investigations of the LDH isoenzyme composition showed different isoenzyme patterns in the two spheroid types with a lack of LDH1 in U118MG spheroids. Addition of 40 mM of oxamate gave decreased 1-C-14- and 2-C-14-pyruvate oxidation rates in the HT29 cells and inhibition of LDH activity in the U118MG cells. Oxamate increased the central pO(2) values in HT29 spheroids and the central pH values in U118MG spheroids. One example of experimental therapy was applied and oxamate acted as a radiation sensitizer in the U118MG system and as a radioprotective substance in the HT29 system. This has to be analysed in more detail. PMID- 21552912 TI - Inhibition of tumor-cell invasion and gelatinase production in metastatic human gastric-carcinoma cells by retinoic Acid and bestatin. AB - We have selected a human variant gastric carcinoma cell line (MKN45H) with increased metastatic potential in nude mice to study the properties of metastatic cells, and investigated the effects of retinoic acid (RA), interferon-gamma and bestatin on invasion and gelatinase production by MKN45H cells. The MKN45H cells showed increased invasive phenotypes and greater secretion of gelatinases as compared to the parental cells. Treatment with RA and bestatin significantly decreased invasion through Matrigel and production of gelatinases by MKN45H cells. These results suggest that RA and bestatin may be useful for the inhibition of invasive potential of gastric carcinoma. PMID- 21552913 TI - Plasma pharmacokinetics of genistein in mice. AB - Genistein (GEN) has recently generated considerable interest as a potential agent for the prevention and treatment of cancer. The present investigation was undertaken to determine if the concentrations of drug shown to inhibit the growth of human tumor cell lines by 50% in vitro (IC50=2-27 mu g/ml) can be achieved and sustained systemically in mice. We found that GEN plasma levels decreased biexponetially from 64 mu g/ml to 0.55 mu g/ml during the initial 40 min after i.v. injection of a 52 mg/kg dose. Mean half-lives of the two initial disposition phases were 2.5+/-0.4 min and 7.1+/-1.1 min in mice treated with doses of 9-52 mg/kg. Plasma profiles of i.v. GEN exhibited a prominent secondary peak near 78 min followed by a terminal decay phase with a 39.5+/-16.8 min half-life. Although these features are suggestive of enterohepatic cycling, the mean apparent total plasma clearance of GEN (66.5+/-7.3 ml/min/kg) was nevertheless similar to hepatic blood flow. The systemic availability of GEN from a 180 mg/kg p.o. dose, which afforded 1.1 mu g/ml peak plasma concentration, was only 12%. Thus, bolus i.v. and p.o. administration of GEN failed to either achieve or adequately sustain plasma levels of the drug within the target range established by in vitro antitumor studies. Plasma levels resulting from i.p. injection of a 185 mg/kg dose were 5-times greater on average than achieved by the p.o. route. While the plasma concentration exceeded the IC50 values for the majority of human cancer cell lines responsive to GEN for only a short period of time, drug levels remained above 2 mu g/ml, the IC50 of the most sensitive cell lines, for 4 h. Extrapolation from the single dose study suggests that repetitive i.p. injection of at least 200 mg/kg GEN every 8 h will afford continuous systemic exposure to potentially cytostatic concentrations of the drug against these cell lines. This information should facilitate efforts to assess the effectiveness of GEN in appropriate in vivo tumor models. PMID- 21552914 TI - Is there a safe therapeutic window for delivery of chemotherapy prior to initiation of surgery and/or radiation-therapy for treatment of the primary tumor in children with rhabdomyosarcoma. AB - To avoid the delayed consequences of treatment with radiotherapy, an effort was made to determine if patients with rhabdomyosarcoma could be cured with chemotherapy as the sole form of treatment. Alternatively, if radiotherapy and/or surgery were required to reduce the severity and incidence of delayed sequelae, an effort was made to determine if there was an optimum safe period for delaying implementation of these definitive forms of treatment. In patients where primary (immediate) definitive non-mutilating surgical extirpation of tumor was not feasible, exclusive treatment with chemotherapy was implemented. If considered necessary or appropriate, delayed surgery and/or radiation therapy were employed in 3 circumstances: (i) to consolidate a partial response; (ii) failure to respond; (iii) recurrent disease. The outcome of the delays prior to the implementation of definitive therapy was analyzed as a function of local and systemic recurrence and cure. Fifty-two patients were evaluated. Seven underwent primary non-mutilating surgical extirpation of localized tumor followed by adjuvant chemotherapy. The remaining 45 were treated with primary chemotherapy and 44 responded. Actuarial survival curves of the delay in initiating definitive therapy in the 52 patients revealed that the optimum delay to attain the best survival was 5 months. In circumstances where definitive therapy was not electively introduced, recurrent disease during remission appeared between 7 and 14 months in 7 patients on continued treatment, and in one patient at 30 months, 8 months after discontinuation of chemotherapy. Based upon the 5-month delay an analysis of survival was performed: Definitive therapy was introduced in 14 patients within 5 months and 7 were cured. In the remaining 31 patients, definitive therapy was introduced between 5 and 30 months and 15 were cured. The five month delay is supported empirically by tumor doubling times. No patient was cured exclusively with chemotherapy. PMID- 21552915 TI - Mxt mammary-tumor treatment with a high-temperature radiofrequency ablation device. AB - A special catheter with a deploying needle was used to treat MXT mouse mammary tumors transplanted onto the flanks of B6D2F1 mice. The catheter was connected to a radiofrequency generator. Treatment was applied for five minutes, with central tumor temperatures reaching over 100 degrees C. Histopathological examination revealed extensive localized, reproducible and controlled necrosis of the tumors in animals sacrificed at days 5 and 15 after treatment. The effectiveness of this device against MXT tumor growth was enhanced when a combination of radiofrequency and intraperitoneal chemotherapy (9 injections of adriamycin, etoposide and cyclophosphamide) was administered. This study demonstrates the effectiveness and reproducibility of tumor destruction and the increase in effectiveness of chemotherapy effects by radiofrequency heating. PMID- 21552916 TI - Loss of heterozygosity at chromosome 6q correlates with tumor progression and patient survival. AB - Several chromosome regions exhibit loss of heterozygosity (LOH) in human breast carcinoma and are thought to carry tumor suppressor genes. We have analysed human breast tumors with 9 polymorphic microsatellite markers that are specific to chromosome 6q. The mapping of smallest region of overlap (SRO) indicated location of candidate suppressor genes at 6q23 and 6q27. Variations in estrogen receptor (ER) expression were independent of the number of copies of the corresponding gene. Tumors with and without LOH on chromosome 6q were tested for association with clinicopathological factors. A significant association was found between LOH at 6q and the following: high S-phase, aneuploidy, deletions at chromosomes 3p and 9p and lower survival rate. In a multivariate model LOH at 6q is an independent prognostic variable and patients having tumors with LOH have approximately twofold increase in relative risk of death. It can be concluded that the 6q deletions give additional prognostic information that might be useful in breast cancer treatment. PMID- 21552917 TI - Hepatocyte growth-factor and its receptor C-met regulate both cell-growth and invasion of human pancreatic-cancer. AB - Hepatocyte growth factor (HGF) has an important role not only in liver regeneration buy also in the development of cancer metastasis. It has been known that HGF and its receptor/c-MET are overexpressed in human pancreatic cancer in vivo, compared with the normal pancreas. To examine the propensity of pancreatic cancer to metastasize and its association with poor prognosis, we studied the effects of HGF and c-MET on pancreatic cancer cell growth and invasion in vitro. Dose-dependently, HGF promoted both the growth and invasiveness of pancreatic cancer cells that expressed c-MET; as a chemoattractant, the high gradient of HGF determined the direction of the invasiveness of the cells. No stimulant effect, however, was observed in cancer cells that did not express c-MET. These results suggest that HGF and c-MET may play important roles in human pancreatic cancer cell growth and invasion-metastatic potential. PMID- 21552918 TI - Modulation of proliferation and tumorigenic potential of cervical-carcinoma cells by the expression of sense and antisense p53. AB - Previous studies from our laboratory demonstrated that overexpression of wild type p53 suppresses the growth and alters the differentiation pattern of HPV immortalized keratinocytes (Woodworth et al: Cell Growth Differ 4: 367-376, 1993). In the present report we describe the use of sense and antisense p53 retroviral vectors to modulate the expression levels of the p53 tumor suppressor gene in cervical carcinoma cells. Representative cell lines (C-4 I, ME-180 and C 33 A) were selected for this study on the basis of their various expression levels of either wild-type or mutated p53, and also of their content of integrated human papillomavirus sequences. Our results show that p53 overexpression from the sense construct decreased the growth rate and tumorigenic potential of the HPV-negative C-4 I cell line, whereas it had no effect on the HPV-positive ME-180 and C-33 A cells. However, examination of the individual colonies early after transfection with sense constructs by light microscopy showed that overexpression of wild-type p53 in ME-180 induced significant morphological alterations resulting in cellular senescence. Nevertheless, the p53 overexpressing, ME-180-derived cell line established after selection did not exhibit any major changes compared to the parental cell line. In the case of C-33 A, the presence of high levels of mutant p53 prevented the exogenous wild-type p53 from causing any significant modulatory action on their proliferation or neoplastic phenotype. PMID- 21552919 TI - P53-independent induction of p21(waf1) pathway is preserved during tumor progression. AB - The p21(WAF1) gene encodes a cyclin-dependent kinase inhibitor and plays an important role in controlling the cell cycle. Its expression can be induced through wild-type p53-dependent or -independent pathways. Since the p53-dependent pathway is disrupted in more than 50% of human tumors, we wondered whether the p53-independent pathway is also altered during tumor progression. In the present study, we have determined p21(WAF1) induction by mitogenic stimuli, which is known to be a p53-independent process. p21(WAF1) is induced by mitogenic stimuli in all cell lines tested regardless of the status of p53, i.e. wild-type, wild type inactivated by SV40T or mutant, and the transformation of cells from immortal to tumorigenic and to metastatic. These results indicate that the p53 independent induction of p21(WAF1) pathway is preserved during tumor progression. PMID- 21552920 TI - Mutational state of p16/cdkn2 and vhl genes in squamous-cell carcinoma of the oral cavity. AB - Two new tumor-suppressor genes, the cyclin dependent kinase 4 inhibitor gene (p16/CDKN2) and the von Hippel-Lindau disease gene (VHL), have been cloned and mapped on chromosomes 9p and 3p respectively, where putative tumor-suppressor genes of the oral squamous-cell carcinoma (SCC) may be present. In order to elucidate whether abnormalities of these genes could contribute to the tumorigenesis of oral SCC, genomic DNAs from 62 tissue samples of tumors (32 primary SCCs and 30 pre-cancerous lesions) and from 7 oral SCC cell lines were examined by polymerase chain reaction-single strand conformation polymorphism analysis and direct DNA sequencing. Four of 7 (57%) cell lines contained nonsense mutations or missense mutations in the p16/CDKN2 gene and 2 of 32 (6%) primary oral SCCs had nonsense mutations. Particularly, 3 of 4 nonsense mutations detected in the present study were found in codon 80 (CGA-->TGA; Arg-->Stop), suggesting that codon 80 was a mutational hot spot of the p16/CDKN2 gene. No VHL gene mutation was found in any subject. These results suggest that mutation of the VHL gene is not a common factor in the development of human oral SCC. In contrast, the p16/CDKN2 gene may be correlated with the progression of a subtype of this cancer. PMID- 21552921 TI - Expression of cd34 and p-glycoprotein - prognostic-significance in primary myelodysplastic syndromes. AB - Expression of stem cell phenotype (CD34) and multidrug resistance (MDR) on blast cells of 49 untreated patients with primary myelodysplastic syndromes (MDS) was studied by means of the alkaline phosphatase antialkaline phosphatase technique (APAAP). In 29 patients (59%) CD34 and in 19 patients (39%) MDR positivity was found. Both immunocytological markers showed a strong positive correlation (p<0.0005) and MDR expression was only detectable in CD34 positive cases. When comparing CD34 and MDR expression with well established prognostic parameters, medullary bone marrow (BM) blast percentage was found to be the sole variable which correlated with expression of both cell surface markers. CD34 and MDR negative patients had a better prognosis although only the difference between CD34 positive and CD34 negative cases reached statistical significance. Regarding the prognostic value of immunocytological results and other clinical and hematological parameters medullary blast cell infiltration remained the strongest predictive variable for survival and AML transformation. In 6 patients sequential immunocytological analysis during progression of disease were performed. In contrast to stable CD34 expression a marked increase in MDR expression after AML development could be noted in 2 cases. PMID- 21552922 TI - The expression of stat91, ras-independent signal transducer and activator, in human gastric carcinomas. AB - Upon binding of interferon (IFN) and epidermal growth factor (EGF) to their cell surface receptors, tyrosine phosphorylation of latent cytoplasmic Stat91 (Ras independent signal transducer and activator of transcription, Stat1 alpha) protein is promptly induced and translocate from the cytoplasm to the nucleus to transduce the signal. The expression of mRNA for Stat91 was examined in 8 gastric carcinoma cell lines and 21 gastric carcinoma tissues as well as corresponding normal mucosa. Of the 8 gastric carcinoma cell lines, all expressed a 4.7 kb Stat91 mRNA and a 91 kD protein at various levels. In gastric carcinoma cell lines, the levels of Stat91 mRNA expression were compatible with those of Stat91 protein expression. In surgical cases, all the gastric carcinoma tissues and their adjacent non-neoplastic mucosa expressed Stat91 mRNA and protein. Interestingly, 14 (66%) out of 21 tumors expressed Stat91 mRNA at higher levels than their corresponding normal mucosas. Moreover, 6 (75%) of 8 tumor tissues expressed higher levels of Stat91 protein as compared with those of the corresponding normal gastric mucosa. No significant correlation was detected between the expression of Stat91 and clinicopathological feature of gastric carcinoma. These results suggest that the majority of gastric cancer in vivo harbour overexpression of Stat91 as a signal transducer in response to various cytokines or growth factors which may be implicated in the growth of gastric cancer. PMID- 21552923 TI - Do mucins promote tumor-cell metastasis. AB - Mucins are highly glycosylated proteins that are normally produced by epithelial cells to lubricate and protect the linings of the gastrointestinal, respiratory, and urogenital tracts. Recently, the oligosaccharides of mucins have been implicated in a number of events that contribute to tumor progression and metastasis. Mucin associated carbohydrates serve as receptors for pathogens, reduce homotypic cell-cell and cell-substratum interactions, and inhibit the cytotoxic actions of cells of the immune system. Tumor cells, and their mucinous products, impede the normal trafficking of inflammatory cells while, at the same time, they themselves may use similar mechanisms. These actions can occur at various stages during metastasis. PMID- 21552925 TI - Restoration of Cisplatin sensitivity by mild hyperthermia in radiation-induced Cisplatin-resistant mouse fibrosarcoma cells. AB - Moderate cisplatin resistance has been induced in murine fibrosarcoma cells SSK R3 by low-dose irradiation without associated changes in radiosensitivity. Resistance can be reverted selectively by stimulation of the cGMP-dependent transduction pathway with sodiumnitroprussid (SNP, 1). In the present study combined thermo-chemotherapy is demonstrated to overcome cisplatin resistance at mild hyperthermic temperature. Between 37 degrees C and 43 degrees C, heat alone has almost the same cytotoxic effect on SSK-R3 cells and the parental SSK cells. If cisplatin exposure is carried out at 40 degrees C for 1 hour, there is an increase in drug sensitization for both cell lines, but the thermal enhancement ratio (TER) is higher in the resistant cells. At 42 degrees C, the survival curves of the resistant SSK-R3 cells and the parental SSK cells almost coincide, resulting in thermal enhancement factors of 5.4 and 3.2, respectively, and restoration of the original cisplatin sensitivity in the SSK-R3 cells. Upon further rise of the exposure temperature to 43 degrees C, the cytotoxic effect of heat alone dominates in both cell lines. The radiosensitivity can be increased to the same extent in both cell lines after one hour exposure to 42 degrees C. SNP, which selectively reverses cisplatin resistance at 37 degrees C, does not exhibit additional differential cisplatin sensitization on SSK-R3 cells compared to the SSK cells at 42 degrees C. These results demonstrate a dominant role of mild, clinically relevant hyperthermic temperature to enhance cisplatin sensitivity and selectively revert cisplatin resistance in SSK-R3 cells. Possible mechanisms underlying this radiation-induced cisplatin resistance are discussed. PMID- 21552924 TI - Differential responses of human tumor-cells to polyunsaturated Fatty-acids - stimulation of proliferation of a colon-tumor cell-line by docosahexaenoic Acid. AB - The potential differential effects of polyunsaturated fatty acids (5-100 mu g/ml) on four human tumour cell lines of different origin and a human fibroblast cell line were investigated. Following 6 days exposure to the fatty acids, gamma linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, culture growth was almost completely abolished at the highest concentration used. At lower concentrations, the tumour cell lines exhibited a differential sensitivity to the inhibitory effects of the fatty acids on cell number (IC50, breast=lung>melanoma>colon). MRC-5 fibroblast cell numbers were significantly increased at low concentrations of gamma linolenate and eicosapentaenoate, but significantly reduced by docosahexaenoate. These effects on cell numbers were rapid in onset. Following only 2 days exposure to low concentrations of the fatty acids, cell numbers in the breast tumour cell line, MCF-7, were significantly reduced relative to controls. In contrast, the colon cell line, WiDR, was largely unaffected at this time, and in some cases, cell numbers were significantly increased. In the normal fibroblast cell line, cell numbers were significantly reduced by docosahexaenoate at concentrations greater than or equal to 20 mu g/ml. Following only 2 days exposure to PUFA, cell death in the breast cell cultures was maximally increased above controls by 20 mu g/ml of docosahexaenoate, whereas cell proliferation was unaffected at this concentration. In contrast, under these circumstances, cell proliferation in the colon cell cultures was significantly increased by this PUFA while there were only small increases in cell death. Our observations have highlighted the differential responses of human tumour cell lines to PUFAs and documented the stimulation of a colon cell line by certain PUFAs. PMID- 21552926 TI - The first intron of human h-ras is regulated by p53 - mediation of specific activation by a p53-binding element. AB - We conducted transient reporter gene expression assays to show that the wild-type but not the mutant-type p53 protein positively regulates the expression of the human H-ras gene. This activation of expression is mediated through a specific p53-binding DNA element located in the first intron of the H-ras gene. This element is similar to a previously identified p53-binding element. Without this element, wild-type p53 represses the H-ras promoter, as do several p53 mutants. The repression function is lost when the N-terminal 81 amino acids of the p53 protein are deleted, suggesting that the N-terminus is required for repression. Therefore, p53 seems to regulate the H-ras through both positive and negative mechanisms. PMID- 21552927 TI - Specific recognition of a transcriptional element within the human h-ras protooncogene by the p53 tumor-suppressor. AB - The nuclear phosphoprotein p53 is frequently inactivated in human cancer. Although it was previously classified as an oncoprotein, p53 has emerged as a tumor suppressor controlling cell cycle progression by regulating gene transcription. A major biochemical property of wild-type p53 is its ability to bind DNA in a sequence-specific manner. The human c-H-ras gene contains within its first intron sequences that partially match the p53 consensus binding site. We determined that these sequences represent a bona fide p53 element, since in vitro translated wild-type p53 recognized them with high affinity. Furthermore, wild-type p53 activated transcription from a reporter plasmid containing the c-H ras element as an enhancer. These findings suggest that p53 regulates cellular growth by coordinate transcription of genes that suppress and promote cellular proliferation. PMID- 21552928 TI - Binding of wild-type and mutant forms of p53 protein from human tumors to a specific DNA-sequence of the first intron of the h-ras oncogene. AB - p53 is the most frequent target for genetic alterations in a wide variety of human cancers. The product of the p53 tumor suppressor gene binds to DNA and activates transcription from promoters containing its consensus binding site. In the accompanying paper we have found that P53 tumor suppressor protein recognizes specifically a transcriptional element within the human H-ras protooncogene (Spandidos DA, et al, Int J Oncol 7: 1029-1034, 1995). We transfected Saos-2 cells, which are p53-null cells, with plasmids encoding for the wild type (wt) and for one 'hot spot' mutant (mt) of the p53 gene (H 273). Using the resulted nuclear extracts for gel retardation assays, we showed binding of both the wild type and the mutant form of p53 to the H-ras DNA. Furthermore, using nuclear extracts from head and neck tumors and from adjacent normal tissues in gel retardation assays, we found binding of both the wild-type and the p53 mutant in the same responsive element of the H-ras oncogene. These experimental results suggest a direct role of p53 in regulation of H-ras. Identification of cellular proto-oncogenes as mediators of the transcriptional effects of wild-type and mutant forms of p53 gene, will be a step towards a better understanding of the role of oncogenes and once-suppressor genes in tumor promotion. PMID- 21552929 TI - Molecular abnormalities of mdm-2 in human sarcomas. AB - MDM-2 is an oncoprotein that seems to function, at least in part, by interacting with the p53 protein and modulating its tumor-suppressing activity. The MDM-2 gene codes for p57, p74, p76, p85, and p90 proteins. Overexpression of only the p90 MDM-2 protein has been reported in sarcomas showing MDM-2 gene amplification. In addition, post-transcriptional mechanisms have been demonstrated to play a role in the expression of MDM-2 proteins. We investigated MDM-2 gene amplification, mRNA and protein levels in various cases of sarcomas. We found MDM 2 gene amplification in 12 (26%) of 46 cases of sarcoma: 11 of 13 cases of liposarcoma and 1 of 6 cases of malignant fibrous histiocytoma. The MDM-2 amplification correlated with the presence of elevated levels of mRNA and protein in the liposarcomas. In sarcomas other than liposarcomas, mRNA was overexpressed in 7 (30%) of 23 cases, without MDM-2 amplification. In 15 (62.5%) of 24 cases of sarcoma and in 1 case of lipoma the MDM-2 protein was overexpressed as shown by Western blot analysis. Interestingly, p57 not p90 was the most commonly overexpressed MDM-2 protein. These data indicate that the molecular abnormalities affecting MDM-2 expression in cases of sarcoma include transcriptional, post transcriptional, and gene dosage (amplification) mechanisms. Furthermore, our findings suggest that MDM-2 p57 protein may be as important as p90 in the pathogenesis of human sarcomas. PMID- 21552930 TI - Different dose regimens of the mouse monoclonal-antibody 17-1a for therapy of patients with metastatic colorectal-carcinoma. AB - Seventy-one patients with metastatic colorectal carcinoma(CRC) were treated with varying doses of the mouse monoclonal antibody (MAb) 17-1A. One patient achieved a partial remission (PR) (1%) with a survival duration of 114+ months. Further 10 patients showed a minor response (MR) or stable disease > 3 months (SD) (14%). In patients receiving a total dose of MAb17-1A < 2 g the overall response rate was 22% (10/45) (1 PR, 2 MR, 7 SD) while patients treated with a total dose > 2 g had a corresponding figure of 4% (1/26) (1 MR) (p < 0.05). Responding patients (n = 11) survived significantly longer than non-responding patients (n = 60) (median: 20 vs 10 months) (p < 0.0027). In the most intensive treatment group (total 12 g), 14 patients received 500 mg of MAb17-1A tiw for 8 weeks. The frequency and intensity of side-effects were mild and did not cause withdrawal or dose reduction of MAb17-1A, even in the 12 g dose schedule. Patients with a pretreatment ADCC (antibody dependent cellular cytotoxicity) activity above the median of all patients, survived significantly longer than those with a low value (p < 0.05). PMID- 21552931 TI - Preferential incorporation of 3'-azido-2',3'-dideoxythymidine (azt) in telomeric sequences of cho cells. AB - 3'-Azido-2',3'-dideoxythymidine (AZT), the thymidine analogue used against human immunodeficiency virus 1 (HIV-1), exhibits bone marrow and blood toxicity in humans, presumably as the result of genotoxic mechanisms induced by incorporation of AZT into eukaryotic DNA. Preferential incorporation of AZT into telomeric regions of DNA of Chinese hamster ovary (CHO) cells has been previously demonstrated by immunofluorescence using anti-AZT antibodies. We quantitatively compared the amount of [H-3]-AZT bound to telomeric and non-telomeric sequences of CHO cell DNA. DNA from cells exposed to [H-3]-AZT was digested by a mixture of restriction enzymes, frequent cutters in the overall genome, without restriction sites in the telomeric repeat. As a result, the telomeric fraction (TF): isolated by separation columns, comprised longer sequences (> 2 kb) than the non-telomeric fraction (NTF). Radioactivity associated with each fraction revealed a three fold increase in [H-3]-AZT incorporated in the TF compared with the NTF. No preferential telomeric binding was detected for [H-3]-thymidine (Tdr) or [H-3] 5'bromodeoxyuridine (BrdU) in similar experiments or in DNA of AZT-treated mouse primary fibroblasts, cells with large telomeric repeats that lack telomerase. When the chromosomal ends of high molecular weight [H-3]-AZT-DNA were digested with Pal 31, the radioactivity was double in the TF compared with the NTF. Therefore incorporation of AZT in CHO immortalized cells but not in primary fibroblasts (that lack telomerase) indirectly shows that AZT incorporation could be telomerase-mediated. PMID- 21552932 TI - Activin and activin receptors in a rat osteogenic-sarcoma cell-line, umr-106. AB - We have localized immunocytochemically activin-A-like reactivity in UMR-106 osteogenic cells with a characterized, specific antiserum against synthetic fragment of subunits of activin-A, a member of transforming growth factor B (TGFB) superfamily. No staining was seen when the activin BA-subunit antisera were replaced by immunoneutralized sera, antiserum dilution buffer, or normal rabbit serum. Using in situ hybridization and the reverse transcription polymerase chain reaction (RT-PCR), we have observed the expression of the BA subunit of activin and activin receptors II & IIB, DNA sequencing data show that the RT-PCR product corresponds to the predicted fragments of activin-A and activin receptors, respectively. In addition, exogenously administered activin inhibited cell growth in cultured UMR-106 cells. Our findings have shown that (a) activin-A was localized immunohistochemically to UMR-106 cells, (b) expression of activin-A and its receptors are detected by in situ hybridization and RT-PCR in UMR-106 cells, and (c) activin may have an inhibitory autocrine function in the proliferation of these cells. PMID- 21552933 TI - In-vivo effect of the combination of tnf and adriamycin against a human breast cell-line expressing the mdr-phenotype. AB - The combined effect of tumor necrosis factor alpha (TNF) and adriamycin (ADR) on tumor cell killing was investigated in vivo. The human breast adenocarcinoma ADR resistant MDA/ADR cells found to be resistant to in vitro TNF lysis and with an apparent index of resistance to ADR of 23 have been used. Treatment of MDA/ADR subcutaneous tumor bearing mice with PBS, TNF, ADR or the combination of TNF/ADR indicate that the combination of TNF and ADR treatment leads to a significant decrease in tumor growth while treatment with TNF was inactive and treatment with ADR was moderately active. Tumor cells were collected from mice treated with TNF/ADR combination and analysed by PCR for MnSOD and TNF ne expression. No induction of the expression of these genes, known to be involved in the regulation of TNF-induced cell killing, was noted following TNF/ADR combination treatment, suggesting that their products were not involved in the observed resistance. PMID- 21552934 TI - Dexniguldipine hydrochloride inhibits growth of human ht-29 colon-carcinoma cells and expression of protein-kinase-C-delta and protein-kinase-C-zeta. AB - Previous studies have implicated protein kinase C (PKC) in colon carcinogenesis, but a clear understanding of the role of PKC in colon cancer is lacking. The purpose of this study was to investigate the effects of dexniguldipine hydrochloride (DNIG) on the in vitro growth of HT-29 human colon carcinoma cells and the expression of PKC isoforms. DNIG is a selective inhibitor of PKC that binds specifically to the regulatory region and is also a potent antineoplastic drug with an ability to reverse multidrug resistance. DNIG (1.6-25 mu M) decreased the number of HT-29 cells in culture in a time- and dose-dependent manner with an EC(50) of 1.4 mu M on day 3. Predominant PKC isoforms expressed in HT-29 cells were identified as Delta and zeta by immunoblotting. The expression of PKC Delta and zeta was inhibited significantly by DNIG (0.16-1.25 mu M). These results suggest that the suppression of the growth of HT-29 colon carcinoma cells by DNIG involves the inhibition of the expression of PKC Delta and zeta. PMID- 21552935 TI - Induction of tumorigenicity by galectin-3 in a nontumorigenic human breast carcinoma cell-line. AB - The human galectin-3 is a galactoside-binding protein of 31 kDa which functions as a receptor for glycoproteins containing poly N-acetyllactosamine side chains and as a substrate for matrix metalloproteinases-2 and -9. We studied its expression by flow cytoflourimetry, Western, Northern and Southern analyses, in five cultured human breast carcinoma cell lines previously characterized as nontumorigenic, poorly metastatic or metastatic in nude mice. The expression of galectin-3 correlated with the reported tumorigenicity of the cells. The introduction of recombinant galectin-3 into the null expressing non-tumorigenic BT-549 cells resulted in the acquisition of anchorage-independent growth properties in all and tumorigenicity in 3/4 sense transfected cell clones. The data indicate a relationship between galectin-3 expression and malignancy of human breast carcinoma cell lines. PMID- 21552936 TI - Differential regulation of EGF production, EGF receptor-binding, and cellular growth by sodium-butyrate in hep3b and plc/prf/5 human hepatoma-cells. AB - Hep3B and PLC/PRF/5 human hepatoma cells express epidermal growth factor (ECF) mRNA and secret this polypeptide growth factor into the culture medium. The production of EGF was inhibited by sodium butyrate in a dose-dependent manner. EGF receptor numbers in both cell lines were increased after treatment with butyrate for 2 days, In addition, the binding affinity of EGF to its receptor was decreased in butyrate-treated PLC/PRF/5 cells while it did not change in Hep3B cells. EGF-stimulated cell growth in PLC/PRF/5 cells was attenuated by sodium butyrate whereas no significant inhibition df cell growth of Hep3B cells was found in the same condition. Our results suggest that EGF acts as an autocrine growth stimulator in human hepatoma cells and sodium butyrate can differentially regulate the responses of hepatoma cells to EGF by modulating the differentiation states of these cells. PMID- 21552937 TI - Steroid-hormone production and receptors in relation to ki-67, p53, s-phase fraction and ploidy in epithelial ovarian-tumors. AB - In this investigation, the in vitro production of progesterone and estradiol in ovarian tissues was studied for the first time in relation to the immunohistochemical expression of steroid hormone receptors, Ki-67, p53, DNA ploidy and S-phase fraction. Ovarian tissue from 44 women was examined. Steroid receptors were found more frequently in normal than in tumor ovaries. A substantial focal staining heterogeneity was demonstrated. Mucinous tumors were always progesterone receptor negative. Furthermore, the Ki-67 index was negatively correlated to the progesterone production of the tumor ovaries. Among the malignant tumors, all the high producers of progesterone expressing PR were low proliferating, diploid and p53-negative. PMID- 21552938 TI - Mutational analysis of the tumor-suppressor gene wt1 - detection of a novel homozygous point mutation in sporadic unilateral wilms-tumor. AB - The WT1 gene located on chromosome 11p13, has been identified as the first Wilms' tumor suppressor gene and has been implicated in the development of Wilms' tumor. About 10% of Wilms' tumors analyzed to date carry a mutation and only 6 different point mutations affecting the zinc finger region have been reported. We analyzed the zinc finger coding exons of 38 sporadic Wilms' tumor by SSCP and detected 2 point mutations. One homo/hemizygous mutation, already described in the literature, replaced an arginine in zinc finger II by a stop codon. The other mutation, a replacement of an arginine by a stop codon in zinc finger I, represents a novel mutation. PMID- 21552939 TI - A role for histamine in human-malignant glioma-cells. AB - Histaminergic neuron cells send fiber terminals to almost all parts of the brain, and the histamine receptors on astrocytes are the main targets of central histaminergic neurons. But no proof of the significance of histamine and its specific receptors on human malignant astrocytoma cells has been presented to date. Our results show that six malignant glioma cell lines used in this experiment secreted histamine into the culture medium and that the histamine stimulated their DNA synthesis in a dose-dependent manner. Moreover, histamine induced accumulation of inositol triphosphate (IP3) in all cell lines in either a time- or a dose-dependent manner, whereas cAMP accumulation was not induced by it in any of these cell lines, indicating that these cell lines express the H-1 receptors but not the H-2-receptors. In vivo, thus, malignant glioma may possibly produce histamine, which then would stimulate their neoplastic behavior mediated by the H-1-receptor. PMID- 21552940 TI - Interleukin-4 inhibits lak and initial phase til activity via interleukin-2 receptor. AB - In the present study, we analyzed the proliferation and cytotoxic activities of LAK cells and initial phase TILs by stimulation with IL-4. IL-4 obviously inhibited the DNA synthesis of LAK cells and initial phase TILs at the concentration of 250 pg/ml and 25 pg/ml, respectively. Furthermore, IL-4 (25 ng/ml for LAK cells, 25 pg/ml for initial phase TILs) suppressed the cytotoxic activities against K562, KATO-III, and autologous tumor cells. The discrepancy of the concentration between the proliferation and the cytotoxicicity by IL-4 suggested different pathways in terms of the generation of LAK cells. In order to clarify the inhibitory mechanism of IL-4, we measured the expression of IL-2 receptor. IL-2 receptor alpha chain was strongly down-regulated by IL-4. Thus, IL 4 modulates the activation of LAK cells and initial phase TILs via the IL-2 receptor alpha chain. PMID- 21552941 TI - Identification of genes overexpressed in the sqcc/y1 human buccal carcinoma cell line using the differential display method. AB - Although several oncogenes and tumor suppressor genes have been suggested to be of relevance for the development of oral cancer, it is likely that additional genes are involved in this complex process. Therefore, in an attempt to isolate such genes, the aim of this study was to investigate changes in gene expression in human buccal carcinoma cells as compared to normal buccal epithelial cells, and identify mRNA overexpressed in the carcinoma cell line. The method of differential display of mRNA was used to isolate differentially expressed genes (Liang P et al, Science 257:967-971, 1992). A key step of this method, a polymerase chain reaction amplification, was optimized in terms of choice of thermostable DNA polymerase, annealing temperature, molar ratios and concentrations of primers. The comparative analysis of expression in tumor and normal buccal epithelial cells led to the isolation of three different mRNAs overexpressed in human oral carcinoma cells, as confirmed by Northern blot analysis. Cloning and sequence analysis revealed that these genes, which were termed OTEX as in Oral Tumor EXpressed, included a novel, previously not characterized, human gene, OTEX-1. OTEX-2 was identical to the gene coding for the L26 ribosomal protein, a protein known to be overexpressed also in other tumor cell types. OTEX-3 showed a perfect match to a sequence isolated during the human genome sequencing project, with a hitherto unknown function. PMID- 21552942 TI - Adjuvant chemoendocrine therapy for early breast-cancer - is it worthwhile - (review). AB - The overview published in 1999 by the Early Breast Cancer Trialist' Cooperative Group demonstrated that systemic therapy after surgical removal of primary breast tumors prolongs both disease-free and overall survival of patients when compared with no systemic therapy, Specifically, both chemotherapy and ovarian ablation in patients aged less than 50 and tamoxifen in those aged 50 or more achieve a reduction of one-fifth to one-fourth in the annual odds of recurrence or death from any cause. The relative effect of different therapies is independent of the stage of the disease, while the absolute benefit depends not only upon the relative effect of treatment but also upon the baseline prognosis of patients. The overview did not report a direct estimation of the effect of combined chemoendocrine adjuvant therapy. Among the effects that may confound the evaluation of chemoendocrine adjuvant therapy are: (a) the possibility of biological interactions between drugs; (b) the presence on tumor cells of steroid hormone receptors; (c) the suppression of ovarian activity induced by chemotherapy in most premenopausal patients; (d) the scheduling of chemotherapy and endocrine therapy. Based on data of the overview, relevant questions are: (i) does the addition of endocrine therapy (tamoxifen dr ovarian ablation) to chemotherapy improve the outcome of premenopausal patients? (ii) does the addition of chemotherapy to tamoxifen improve the outcome of postmenopausal patients? We have reviewed single randomised trials in an attempt to answer these questions. In premenopausal patients, the addition of tamoxifen to chemotherapy probably induces only small advantages. The addition of ovarian ablation to chemotherapy could improve survival. The relationship between oophorectomy and receptor status has not been extensively studied; however, the addition of oophorectomy, like the addition of tamoxifen, to chemotherapy could be cost effective in cases of estrogen receptor-positive tumors. The effect of tamoxifen in association with ovarian ablation, after chemotherapy, has not yet been studied. In postmenopausal patients the addition of chemotherapy to tamoxifen is debated. The role of receptor status seems to be important in these patients. Most studies found that chemotherapy does not significantly increase the effect of tamoxifen in the subgroup of patients with receptor-positive tumors, while it does increase toxicity. On the contrary, the addition of chemotherapy to tamoxifen, in patients with receptor-negative tumors could significantly improve results. PMID- 21552943 TI - Pyrimidine nucleoside phosphorylase-activity and biological characteristics of breast-cancer. AB - We investigated whether Pyrimidine nucleoside phosphorylase (PyNPase) activity in breast cancer tissue correlated with biological characteristics of breast cancer. PyNPase activity, ER, PgR, EGFR, DNA ploidy pattern, PCNA positive cells and amplification of the c-erbB-2 gene were determined in specimens from 138 patients. PyNPase activity was significantly higher in ER negative than ER positive carcinomas (p<0.05), in PgR negative than PgR positive carcinomas (p<0.05) and significantly higher in tumors with c-erbB-2 gene amplification compared with tumors with no amplification (p<0.05). The results suggest that PyNPase activity in breast cancer tissue may be a new biological characteristic of breast cancer. PMID- 21552944 TI - Expression and structure of hox genes in wilms-tumor. AB - We have investigated the expression of all 38 human HOX genes in Wilms' tumour (WT) tissue, and the structure of the HOXA cluster (at chromosome 7p15) in a WT patient who has a novel constitutional chromosome translocation (t(1;7)(q42;p15)). No rearrangement of the HOXA genes was found in the translocation patient, but between 26 and 28 HOX genes were expressed in WT tissue. Thus, although it appears unlikely that HOX genes are mutated in WT, their extensive expression in WT indicates that HOX genes may well be important factors in the aberrant differentiation which leads to Wilms' tumour. PMID- 21552945 TI - Head and neck extranodal non-hodgkin-lymphoma - radiation-therapy and chemotherapy. AB - One hundred and seventy-five patients with extranodal non-Hodgkin lymphoma (NHL) treated between 1974 and 1993 in the Institute of Radiology and in the Department of Haematology of 'La Sapienza' University of Rome, have been examined. The sites involved were: Waldeyer's ring 96 patients (tonsils 84, nasopharinx 12), parotid 20, orbit 16, oral cavity 16, paranasal sinus 7, mandible 7, nasal fossal 3, minor salivary glands 3, larynx 3, conjunctive 2, lacrymal glands 1, thyroid 1. One hundred and forty-three patients had high and medium grade unfavourable histology; 68 patients were in stage I, 67 in II, 23 in III and 17 in IV. Fifteen patients were treated with radiotherapy alone and 86% obtained complete remission (CR). Chemotherapy alone was used in 90 cases and 87% C.R, was achieved; when chemotherapy in association with radiotherapy was used in 70 cases 85% obtained CR. The actuarial survival rate was 79% and recurrence-free survival in those patients who achieved complete remission 87%. Surviving and relapse-free patients were analysed in relation to main prognostic factors and therapy, and patterns of recurrence are reported. From the analysis of these cases we can learn how systemic therapy combined with the general conditions of patients and histology can control the disease. A minor relapse incidence with pharmacological therapy combined with a radiotherapic loco-regional treatment was also ascertained. PMID- 21552946 TI - Allele loss in human gastric carcinomas - relation to tumor progression and differentiation. AB - The sequence of genetic changes associated with the development of gastric carcinoma remains unclarified despite the numerous genetic and chromosomal abnormalities that have been implicated so far in this process. We investigated the frequency and pattern of allele loss in 68 gastric carcinomas, with the aim of identifying genetic changes putatively involved in the histologic differentiation and/or progression of gastric cancer. Allele loss was investigated using 12 RFLP and 11 microsatellite markers localized at 22 different loci from 9 autosomal chromosomes. Allele loss in at least one chromosome arm was detected in 41 out of the 68 cases (60%). A high ratio of allele loss was significantly associated with the masculine gender and aneuploidy. The chromosome arms most commonly affected were 3p (57%), 17p (44%), and 6q (32%). Alterations at these chromosome arms were also frequently found (greater than or equal to 40%) in the six less advanced gastric carcinomas of the series, thus suggesting that genetic changes involving these chromosomes are early events in gastric tumorigenesis. Genetic changes at 5q and 17p loci were only observed in gastric carcinomas of the intestinal and atypical (unclassified) types, thereby indicating a possible role of genes located at these chromosome arms in the differentiation of gastric carcinoma. PMID- 21552947 TI - In-vivo effect of somatostatin analog, lanreotide, and/or grp antagonist, bim 26226, on the growth of colon-cancer peritoneal carcinomatosis in the rat. AB - The effect of somatostatin analogue, lanreotide, and bombesin/GRP antagonist, BIM 26226, on the growth of colon cancer peritoneal carcinomatosis in the rat was studied. BDIX rats were i.p. injected with DHD/K12 rat colon cancer cells at day 0 and received from day 3 either lanreotide, BIM 26226, combination of treatments or peptide solvents. At sacrifice, an day 45, no significant difference between groups was observed for peritoneal tumor growth, hepatic metastases, ascite volume and labeling indices in normal colonic mucosa and tumoral tissues. Survival times were similar in other lanreotide-treated and control groups. However, BIM 26226 decreased plasma gastrin level, consistently with a physiological effect of this peptide. Ln all groups, somatostatin and bombesin receptors were found on mucosal and tumoral tissues. Interestingly, bombesin receptor number was higher in severe than in minor cancer stages, contrarily to that of somatostatin receptors. Moreover, an up-regulation of somatostatin and bombesin receptors was observed in BIM 26226- and lanreotide-treated group tumors, respectively, Despite the presence of these specific receptors, lanreotide and BIM 26226 were inactive on tumor growth in this model. PMID- 21552948 TI - A phase-ii study testing a combination chemotherapy with epirubicin and vindesine as 2nd line treatment for patients with advanced non-small-cell lung-cancer. AB - The European Lung Cancer Working Party conducted a phase II trial to determine the activity of a salvage regimen with high dose epirubicin (120 mg/m(2) on day 1) and vindesine (3 mg/m(2) on day 1) in patients with advanced non-small cell lung cancer failing to respond to first-line chemotherapy containing cisplatin and/or carboplatin. Courses were repeated every 3 weeks and evaluation of antitumoral response was performed after the 2 first courses. A total of 53 patients were registered, 4 were not eligible and 42 were evaluable for response. Two (5%) objective responses were documented. Although the regimen was very well tolerated, based oh the results it has to be considered inactive. PMID- 21552949 TI - Cross-sensitivity to x-radiation and type-I and type-ii DNA topoisomerase inhibitors in a range of human and rodent cell-lines. AB - We compared the relative X-radiation response of confluent (i.e. essentially non proliferating) cultures of three human tumor (U-87MG, Mel-3, HT-144), one human normal (AG1522) and two rodent normal (AA8, V3) cell lines to their relative sensitivities to a DNA topoisomerase (topo) II poison (etoposide) and to a topo I poison (camptothecin). The relative sensitivity of these cell lines to etoposide (for 8 h exposure at 37 degrees C) is extremely similar to their relative X radiation sensitivity, suggesting a direct correlation between X-radiation sensitivity and susceptibility to killing by topo II poison. The relative sensitivities of these cell lines to camptothecin (also 8 h, 37 degrees C exposure) also agree generally with their relative X-radiation sensitivities although the correlation is not as good as for etoposide. In addition, exponential phase (i.e, actively proliferating) cultures of the radiosensitive HT 144 cells are more susceptible to killing by both etoposide and camptothecin than the radioresistant Mel-3, confirming previously reported cross-sensitivities between X-radiation and topo poisons in actively proliferating cultures of other types of cell lines. Hence our results suggest that the previously reported cross sensitivity between topo II poisons and X-radiation in actively proliferating rodent cell lines is also observed in 'non-proliferating' rodent and human cell lines. Additionally, there is cross-sensitivity between topo I poisons and X radiation in both rodent and human cell lines as well. PMID- 21552950 TI - The role of a Drosophila replication related element in dras2 oncogene regulation. AB - The Drosophila ras2 and rop gene pair are governed by a common promoter. Characterisation of the Drosophila ras2/rop bidirectional promoter has revealed that a single major protein complex (M), composed of two subunits (factors A and B) interacts with two central promoter domains (regions A and B). To define the transcriptional control elements contained within region A (-58 to -39) we performed mutational analysis on several putative elements. This approach has revealed that the conserved TATA-like, SRE-like and GATA-like sequences do not interact with factor A and are not regulatory elements of this promoter. Nucleotides -56 to -49 bear perfect homology to the Drosophila DNA replication related element (DRE, TATCGATA) found in two genes involved in DNA replication and cell proliferation, the Drosophila proliferating cell nuclear antigen (PCNA) and DNA polymerase a. A CG pair (-53 and -52) has been pinpointed as cardinal for factor A binding. Factor A has been partially purified and identified as a 20 kDa polypeptide by photo-chemical crosslinking analysis. PMID- 21552951 TI - A novel 43 kd protein binds a conserved Mammalian caccc motif within the Drosophila ras2/rop bidirectional promoter. AB - The Drosophila ras2 promoter is an authentic bidirectional promoter governing the expression of both the Dras2 and rop genes by a single mechanism. Characterisation of the Dras2/rop promoter has revealed that a unitary complex (M) interacts with two promoter sub-domains (regions A and B). Two distinct transcription factors (factors A and B),which make up the major complex (M), bind regions A and B, respectively. We have analyzed the putative CACCC element and AP 1-Iike sequence contained within region B (-41 to -20) of the Dras2/rop promoter. It was found that AP-1 is not involved in Dras2 expression as is the case for the human Ha-ras1 gene. The entire CACCC motif (-34 to -21) shares 83% homology with the conserved mammalian element. Detailed mutational analysis has however revealed that the CACCC core sequence (-27 to -23) is vital for Dras2/rop recognition by factor B. The cytosine residues at positions -27, -25, -24 and -23 were observed to play a critical role in factor B recognition. Factor B has been purified as a 43 kD polypeptide as measured by SDS-PAGE and the relative mass was confirmed by photo-chemical crosslinking. Our findings are the first report of the conservation of the mammalian CACCC motif in Drosophila. PMID- 21552952 TI - Inhibition of dras2/rop expression in Xenopus oocytes by Drosophila nuclear extract. AB - Chloramphenicol acetyl transferase reporter plasmids driven by the Drosophila ras2/rop promoter were injected into Xenopus oocytes to study Dras2 and rop gene regulation by their bidirectional promoter. When injected without Drosophila nuclear extract, both Dras2 and rep were highly expressed. Dras2 and rop-CAT expression was very similar in Drosophila cells and Xenopus oocytes, suggesting the conservation of regulatory factors between the two species. When Drosophila nuclear extract was co-injected with Dras2 and rep promoter-CAT constructs, expression was inhibited. Inhibition decreased with elevation of plasmid concentration and was increased with an increase in nuclear extract concentration. Since specific DNA-protein interactions were diminished by the combination of oocyte and Drosophila nuclear extracts in gel retardation assays, a sequestering-type mechanism of repression has been proposed. PMID- 21552953 TI - N-(4-hydroxyphenyl)retinamide induces apoptosis in human leukemia hl-60 cells and mediates vimentin down-regulation. AB - N-(4-Hydroxyphenyl)retinamide (HPR) is a synthetic retinoid with anticancer properties and lower toxicity than all-trans retinoic acid (RA). We have studied the effects of HPR on apoptosis and differentiation in the human promyelocytic leukemia HL-60 cell line. In addition, we have tested the hypothesis that vimentin expression after HPR and RA, taken as indirect evidence of the mechanisms of action of the two retinoids, may be different. Quantitative evaluation of the percentage of apoptotic cells was carried out on a cell by cell basis by the flow cytometric DNA-content in situ-terminal-deoxynucleotydil transferase (TdT assay). HPR was found to clearly induce apoptosis, while RA: instead, induced differentiation without apoptosis. These data confirm previous observations. Vimentin protein content was evaluated by flow cytometry with use of monoclonal antibodies simultaneously with DNA content. We found that HPR treated apoptotic cells were characterized by negative vimentin expression, while the HPR treated non apoptotic cells had about the same level of vimentin as the RA treated cells. These latter findings suggest that HPR may induce a functional effect (apoptosis) by a mechanism of action different from that of RA. Further work is necessary to clarify this finding. PMID- 21552954 TI - In-vitro characterization of dihydrotestosterone-induced, epidermal growth factor induced and basic fibroblastic growth factor-induced modifications in the growth dynamics of the human prostate-cancer cell-line lncap, du145 and pc3. AB - The influence of dihydrotestosterone (DHT), the epithelial growth factor (EGF) and the basic fibroblast growth factor (bFGF) was investigated on LNCaP, DU145 and PC3 cell growth, which represents the ratio between cell gain (cell proliferation) and cell loss (cell death). In the present study, cell growth was assessed by means of the computer-assisted microscope analysis of Feulgen-stained nuclei combined with the mathematical Delaunay triangulation and Voronoi paving techniques, which enabled the cell colony patterns, i.e. their density and level of organisation, to be determined. The results from a previous study (Janssen et al, Prostate, in press) combined with those of the present one show that DHT was found to activate proliferation of the LNCaP model, as evidenced by increase in size of colonies, increase in number of cells within colonies, increase in cell colony density and, accordingly, decrease in mean segment length value (which is the distance between adjacent cell nuclei). Using the same criteria, DHT was found inhibitory on growth of DU145 cell line, and devoid of significant effect on PC3 cell line. Basic FGF was found to be a powerful stimulator of growth of PC3 cell Line and to induce a weaker stimulation of DU145 cell line. On LNCaP cell line, it increased the size of colonies without increase of the number of cells per colony. This feature can be explained by a decrease in cell colony density. With respect to the same colonies, the proliferation index (percentage of cells in the S+G2 phases of the cell cycle) was found similar to that of the controls. This suggests that the increase in the size of the colonies is due to a difference of spreading of the cells on their supports. EGF had no significant effect on LNCaP and PC3 models, and was decreasing cell density of DU145 colonies. PMID- 21552955 TI - Growth of human tumor-cell lines in immunodeficient scid and immune reconstituted human-pbl-scid mice - an improved in-vivo model for the study of human malignancy. AB - To assess the suitability of the SCID mouse as a relevant model of human malignant disease Various human cell lines were transferred to these animals and the ability of these cell lines to grow and develop in vivo carefully characterised. Tumour cells were injected at varying doses via the intraperitoneal, intravenous or subcutaneous routes and the growth pattern and metastasis evaluated by measuring survival time, by macroscopic observation of lesions and by performing histology on major organs and growing transplanted tumours. Using this approach a variety of human cell lines were observed to grow easily and rapidly in SCID mice without any histological evidence of immune rejection by the murine host. In particular, the growth of different human ovarian carcinoma cell lines was highly reproducible at the intraperitoneal site with the dissemination of disease from this site and the pathology of tumours similar to that found in human patients. Further experiments in chimeric human PBL-SCID mice created by the transfer of human lymphocytes to the immunodeficient host, showed that human ovarian tumours could still be established in reconstituted animals, although with a significant increase in survival time when compared with similarly challenged SCID hosts. The growth of human tumours in human-PBL-SCID mice provides a unique model for the study of the interaction of human lymphocytes with human tumours in vivo and for the development of tumour specific immunotherapies at present either unethical or impractical in human patients. PMID- 21552956 TI - Cancer cytogenetics and molecular-genetics - clinical implications (review). AB - Cancer genetics has become a burgeoning area of both cytogenetic and molecular genetic research and practical clinical application of the findings of such research in human cancer and leukemia. This review summarizes the specific types of chromosomal and associated molecular genetic alterations in leukemia and cancer. The primary objective is to acquaint physicians of various disciplines with the application of cytogenetics and molecular genetics as diagnostic, prognostic and therapeutic indices, as approaches to the evaluation of minimal residual disease and as guides for differentiation therapy and the molecular localization of oncogenes and tumor suppressor genes related to gene therapy in leukemias and cancers. PMID- 21552957 TI - An adenoviral vector expressing interleukin-4 modulates tumorigenicity and induces regression in a murine breast-cancer model. AB - Anti-tumor activity of a recombinant adenovirus expressing murine IL-4 (AdCAIL-4) was investigated in a murine model of mammary adenocarcinoma. Primary tumor cells derived from mammary adenocarcinomas induced in transgenic mice by the middle T antigen gene of polyomavirus were infected with AdCAIL-4 and injected into syngeneic non-tumor bearing recipients. Expression of IL-4 by AdCAIL-4 transduced tumor cells significantly prolonged survival of all animals and prevented tumor development in 61% of recipient mice. When tumor bearing animals were injected intra-tumorally with AdCAIL-4, all animals survived at least 8 to 10 weeks longer than controls, and 50% of treated animals underwent complete tumor regression. Both en: vivo and in vivo treatment with AdCAIL-4 resulted in infiltration by eosinophils in and around the tumor site. Animals which had undergone complete tumor regression were protected from a second challenge suggesting that immunotherapy with Ad vectors expressing cytokines may protect from metastatic disease. PMID- 21552958 TI - Epigenetic regulation of multidrug-resistance and metastasis-related genes in human lung adenocarcinoma cells growing in ectopic or orthotopic organs of nude mice. AB - We examined whether the organ microenvironment modulates the response of the human lung adenocarcinoma cell line DMS-4C to doxorubicin (DXR). DMS-4C cells were injected intrathoracically (orthotopic) and subcutaneously (ectopic) into nude mice. The mice were given intravenous (i.v.) injections of DXR (8 mg/kg) or saline (control) on days 50 and 58 after implantation, Tumors growing in the subcutis were more sensitive to DXR than tumors growing in the lung. Tumor cells established in culture from lung lesions were initially more resistant to DXR than cells established in culture from subcutaneous (s.c.) tumors. After 14 days in culture, all cells exhibited similar sensitivity to DXR. The expression level of several genes that regulate different steps of metastasis, basic fibroblast growth factor (angiogenesis), type IV collagenase (invasion), epidermal growth factor receptor (growth), and mdr1 (drug resistance), was examined by an in situ mRNA hybridization technique in DMS-4C lesions from the lung and subcutis. Higher mRNA expression for Mdr1, bFGF, and type IV collagenase was found in lung lesions than in s.c. tumors. These results demonstrate that the organ environment influences the expression of several metastasis-related genes in human lung adenocarcinoma cells. PMID- 21552959 TI - P53 mutations in egyptian bladder-cancer. AB - Cancer of the bladder is a frequent malignancy in Egypt and other developing countries in which bladder infection with the parasite Schistosoma haematobium is common. Several epidemiological, histopathological and clinical characteristics of cancer of the Bilharzial bladder suggest that it is distinct from bladder cancer seen in industrialized countries. Little is known, however, about molecular aberrations in Egyptian bladder cancer. We studied the status of p53 in a series of 25 cases of Egyptian bladder cancer using immunohistochemistry to detect the p53 protein and SSCP/sequencing to identify mutations in the p53 gene. Ten of 25 (40%) tumor samples showed a mutation by SSCP/sequencing. Mutations were seen in both the squamous and transitional cell variants. The presence of mutations was associated with advanced stage of disease. Immunohistochemistry had a sensitivity of 70%, and a Specificity of 85% for detecting p53 mutations. Our data show that p53 mutations are a common event in Egyptian bladder cancer, and may be an indicator of advanced disease. Immunohistochemistry is both sensitive and specific for detecting p53 mutations in this tumor, and may be used to assess the prognostic value of p53 mutations in this disease. PMID- 21552960 TI - Expression of mucinous ovarian-cancer antigen in hybrid-cells derived by fusing a malignantly transformed bloom-syndrome cell-line (bs-shi-4m ovc-mu) and mouse L cell-line. AB - The expression of mucinous ovarian cancer (OVC) antigen by hybrid cell lines derived by fusing a malignantly transformed Bloom syndrome (BS) cell line (BS-SHI 4M OVC-MU) and mouse L cells has been studied. Cell surfaces of 16 hybrids which grew 12-40 days post-fusion have been analysed by using a number of sera from mucinous OVC patients and indirect membrane immunofluorescence (IF). Three hybrids which appeared at a late stage (30-40 days in 24-well culture plates) were clearly positive in almost 100% of the hybrid cell population, while all of those which appeared earlier (in 12 days) were completely negative. Cytogenetic analysis showed that these three hybrids with positive mucinous OVC antigen contained human chromosome 22 or 22q-, though no metaphases from antigen negative population had 22 or 22q-. Therefore, we assign the gene for mucinous OVC antigen to the chromosome 22. Identification of chromosome 22 in hybrid cells was confirmed by the fluorescence in situ hybridization (FISH) analysis using chromosome 22 painting probe. PMID- 21552961 TI - Transcriptional switching model for the regulation of tumorigenesis and metastasis by the ha-ras oncogene - transcriptional changes in the ha-ras tumor suppressor gene lysyl oxidase. AB - A model system is described that allows an analysis of the molecular and biochemical changes associated with expression and suppression of the oncogenic and metastatic phenotype of cloned rat embryo fibroblast (CREF) cells. Ha-ras transformed CREF cells are morphologically transformed, anchorage-independent and both tumorigenic and metastatic in athymic nude mice and syngeneic Fischer rats. Co-expression of the Ha-ras oncogene and Krev-1 tumor suppressor gene in CREF cells results in suppression of in vitro transformation. In contrast, Ha-ras/Krev 1 transformed CREF cells retain, with greatly extended latency periods, both tumorigenic and metastatic capabilities in athymic nude mice. The present study investigates changes in the Ha-ms suppressor gene, rrg (lysyl oxidase), during expression and suppression of the oncogenic phenotype in CREF cells. Nontumorigenic CREF cells and CREF cells transformed by the Ha-ras and Krev-1 gene that express a suppression in in vitro transformation contain elevated levels of lysyl oxidase mRNA and protein. In contrast, Ha-ms and Ha-ras/Krev-1 nude mouse tumor- and nude mouse lung metastasis-derived CREF cells contain reduced levels of lysyl oxidase mRNA and protein. Nuclear run-on assays indicate that suppression of lysyl oxidase expression in transformed subclones of CREF cells correlates with a reduction in transcription of the lysyl oxidase gene. Taken together, the current studies support a transcriptional switching model in which lysyl oxidase expression correlates directly with suppression of the Ka-ms induced transformation phenotype and escape from oncogenic suppression correlates with a transcriptional silencing of the lysyl oxidase gene and decreased lysyl oxidase mRNA and protein. PMID- 21552962 TI - Influence of lobular development on breast epithelial-cell proliferation and steroid-hormone receptor content. AB - The development of the breast evolves through progressive formation of lobular structures. Lobules type 1 (Lob 1) are the most undifferentiated ones; they evolve to lobules type 2 (Lob 2), and those to type 3 (Lob 3), in response to mainly ovarian hormones. Although estradiol and progesterone act by binding to their specific receptors, their content in these structures and how they correlate with proliferative activity are not known. Normal breast tissues obtained from 40 reduction mammoplasties performed for cosmetic reasons in women free of mammary pathology were processed for light microscopy. Paraffin sections were immunoreacted with antibodies against estrogen receptor (ER), progesterone receptor (PgR), and proliferating cell nuclear antigen (PCNA). The number of cells positively labeled with each one of the three antibodies was quantitated in Lob 1, 2 and 3, and expressed as a percentage of the total number of cells. ER were positive in Lob 1 (21%) and Lob 2 (10%), but negative in Lob 3. PgR were positive in Lob 1 (66%) and 2 (68%), decreasing in Lob 3 (31%). The highest percentage of PCNA positive cells were found in Lob 1 (40%), decreasing in Lob 2 (33%) and Lob 3 (11%). These results indicate that the normal breast epithelium contains ER and PgR, but the former is at higher levels in Lob 1, which also expresses greater proliferative activity as demonstrated with PCNA. PMID- 21552963 TI - Role of p53 in mcf-10f cell immortalization and chemically-induced neoplastic transformation. AB - The present study was undertaken to determine the role of the tumor suppressor gene p53 in the transformation of the human breast epithelial cell (HBEC) line MCF-10F treated with chemical carcinogens in vitro. MCF-10F is a spontaneously immortalized diploid HBEC line, derived from a mortal cell strain designated MCF 10M. MCF-10F cells became neoplastically transformed by in vitro treatment with the chemical carcinogens 7,12-dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene (BP). DMBA and BP-treated cells gave rise to clones D3, D3-1, BP1 and BP1-E, respectively, all of which expressed colony formation in agar-methocel and high chemoinvasion index. BP1-E cells, derived from BP1, were tumorigenic in severe combined immunodeficient (SCID) mice. We designed this work utilizing this model in which isolated clones of cells express different stages of progression to neoplastic transformation for determining whether any specific phenotype was associated with alteration in the p53 tumor supressor gene. For this purpose, Southern blot, Northern blot, single-strand conformation polymorphism (SSCP) and DNA sequencing were used to detect mutations in the highly conserved exons 5-9 of the p53 gene. Whereas no changes were detected in any of the cells tested by Southern and Northern blot, SSCP analysis showed a conformational shift in exon 7 in the MCF-10F cell line, and in clones BP1, BP1-E, D3, and D3-1, derived from DMBA and BP treated cells, respectively. This shift was absent in MCF-10M cells, the mortal cells from which the MCF-10F immortal cells were derived, and in the placental DNA used as control. Sequence analysis using asymmetric PCR-amplified products of exon 7 and an antisense primer revealed an insertional mutation of thymine at codon 254 in MCF-10F cells and in transformed cells, but not in MCF 10M. These data indicate that the emergence of the immortalized phenotype was associated with a mutation of p53. DMBA- or BP-treatment did not induce additional changes in the p53 gene. The fact that the precursor of the immortalized MCF-10F did not present changes in p53, may indicate that the alteration of this tumor suppressor gene could be associated with the process of cell immortalization; this, in turn, might facilitate the neoplastic transformation of the cells by chemical carcinogens. PMID- 21552964 TI - Shared cytogenetic abnormalities in lung-tumors and corresponding peripheral blood lymphocytes. AB - We analyzed chromosomal alterations in primary lung tumours and peripheral blood lymphocytes (PBLs) from 10 lung cancer patients (nine with non-small cell lung carcinoma and one with small cell lung carcinoma) to determine whether there were shared chromosomal changes in the normal and diseased tissue of these cases. This study revealed that each paired sample had at least three chromosomes and two chromosomal regions in common for structural rearrangements. The chromosomes most frequently found structurally altered in paired analysis were 1 and 3 (60% each), 5 (50%), 6, 7, and 9 (40% each), and 14 (30%). Chromosome region 3p13-3p21 was structurally rearranged in both the normal and tumour tissues of three patients. Chromosome 3 was structurally rearranged in all ten tumours. The chromosome arms most commonly affected in the tumours were 3p (nine times), 9p and 5q (eight times each), Ip and 7q (six times each), 10q and 11q (five times each), 14q and 6q (four times each). The most frequently affected chromosomal regions in these tumours were (in decreasing order) 9p23-p24, 3p21-3p13, 5q11, 1p34, 7q22, and 11q13. Frequent polysomy of 7 and 12 and loss of D-group chromosomes were also observed in the tumours analyzed. Comparing the changes found only in tumours with those found in both PBLs and tumours was helpful in shedding some light on the probable sequence of genetic events leading to lung cancer. This investigation also offered compelling evidence that genomic instability at the chromosomal level in PBLs corresponds with the genetic changes observed in tumours indicating that PBL analysis can help identify the early chromosomal changes in lung cancer. PBL chromosomal analysis thus has a promising future in the genetic analysis of lung cancers. PMID- 21552966 TI - Prospective-study of stromelysin-3 expression in breast-cancer biopsies and disease-free survival. AB - Stromelysin-3 was estimated by Northern blot analysis in primary breast carcinomas. The patients were followed for an average of 47 months after initial surgery and the dates of recurrent carcinoma and of death, if applicable, were recorded. Stromelysin-3 expression in the primary tumour was found equally in patients with subsequent recurrent disease and in patients who remained disease free during the study period. There was no correlation between stromelysin-3 levels and disease-free survival. PMID- 21552965 TI - Generation of progenitor-cell precursors in long-term bone-marrow cultures after marrow purging with ether lipids. AB - Alkyl-lysophospholipid derivates (ALP) are currently being tested as bone marrow (BM) purging agents prior to autologous BM transplantation in different malignancies. We evaluated the toxicity of the ALP ET-18-OCH3 (ET-18; Edelfosine, 1-0-octadecyl-2-0-methyl-rac-glycero-3-phosphocholine) towards early hematopoietic precursors by testing progenitor regeneration of non-purged and ET 18-purged BM (75 mu g and 125 mu g ET-18/ml/2x10(7) BM cells) in autologous long term bone marrow cultures (LTBMC) from 3 different patients in complete remission. LTBMC feeder layers were irradiated with 875 rad for complete elimination of hematopoietic progenitors and recharged with cryopreserved purged and non-purged BM. In weekly intervals, adherent layer and supernatant LTBMC cells were completely removed and evaluated in colony forming unit (CFU)-assays. We have seen sufficient CFU-regeneration out of ET-18-purged BM up to 8 weeks of LTBMC (>40 CFU/flask). Total CFU-counts from LTBMC with purged BM were slightly reduced compared to non-purged control. High dose purging with 125 mu g ET-18/ml partly inhibited initial CFU-proliferation, but demonstrated elevated CFU-counts after 4 and 8 weeks of LTBMC compared to control. In conclusion, in our LTBMC series ET-18-purging yielded tolerable toxicity towards committed BM-progenitors, but no remarkable decline of early hematopoietic precursors regenerating CFU progenitors for up to 8 weeks of culture. PMID- 21552967 TI - Prevalence of p53 overexpression or mutations, but not k-ras mutations, in recurrent patients affected by colorectal-carcinoma. AB - In order to establish prognostic indicators of poor clinical evolution in colorectal cancer, we have studied p53 abnormalities and K-ras mutations in 65 patients affected by colorectal carcinoma who had undergone radical surgery. A single event of p53 protein overexpression or p53 mutation, but not K-ras mutation, was significantly prevalent in recurrent tumors. A double event of K ras mutation and p53 protein overexpression was prevalent in patients showing Dukes' stage C, but showed a lack of prevalence in patients who recurred. The presence of p53 protein overexpression does not assure an underlying mutation in colorectal carcinoma. PMID- 21552968 TI - Effects of lymphokine-activated killer-cells on melanoma nodules maintained in 3 dimensional culture. AB - Lymphokine activated killer (LAK) cells were cocultivated from 2 to 6 days with WM266 metastatic melanoma cells maintained as nodules in organotypic culture. The LAK cells in suspension were allowed to deposit freely on the nodule surface from where they could infiltrate spontaneously into the nodules. Immunohistochemical studies were done to localize the LAK cells as well as electron microscopical observations for effector/target membrane contacts. Proliferation of the nodules was tested and also that of the LAK cells after coculturing using tritiated thymidine incorporation into DNA. Cell death was determined by arrest of thymidine incorporation and total nodule disintegration. Infiltration rate of LAK cells into the nodules was low: after coculturing 5% of the nodule cells were LAK cells. Although close membrane contacts and cytoplasmic fusions between effector and target cells leading to tumor cell apoptosis were observed, this direct cytolytic process seemed to be too infrequent for the induction of total nodule disintegration at day 6. Therefore, the indirect pathway to cytolysis might be predominant implying, among other cytokines, soluble TNF. On the other hand, LAK cell proliferation diminished strongly after coculturing (down to 11%) but the cytotoxicity was significantly enhanced (18% higher) suggesting an enhancement of differentiation. This might account for the peculiar efficacy of LAK cells on melanomas in vivo and it would be of interest to study this phenomenon further. PMID- 21552969 TI - Increased expression of bcl-2 in drug-resistant squamous-cell lung carcinomas. AB - The aim of this investigation was to prove whether or not an association exists between Bcl-2 expression and in vitro resistance to doxorubicin in biopsies of 85 human squamous cell lung carcinomas. Additionally, the relationship of Bcl-2 expression with resistance related proteins (P-glycoprotein, glutathione S transferase-pi, catalase) was analyzed. Of the 85 carcinomas, 17 (20%) revealed Bcl-2 expression by immunohistochemistry. Seventeen of the tumors were classified as sensitive and 68 as resistant by an in vitro predictive test. All 17 Bcl-2 positive carcinomas were resistant to doxorubicin (p=0.018; chi(2)-test). A correlation was found between expression of Bcl-2 and expression of the resistance-related proteins P-glycoprotein and glutathione S-transferase-pi. The median survival time for patients with Bcl-2-negative carcinomas was two years and for Bcl-2-positive tumors over six years (log-rank test; p=0.08). Multivariate analysis (Cox regression model) revealed a borderline significant influence of Bcl-2 (p=0.07), whereas all other clinical factors (age, stage, metastasis) were of no significant influence on survival. PMID- 21552970 TI - Phenotypic characterization of androgen receptor-related proliferation in prostatic-carcinoma derived cell-cultures. AB - Our study reviews the central role of androgens for the development of androgen insensitive growth in prostatic carcinoma using an individual dynamic model which emulates aspects of proliferation control. Our aim is the identification of individually proliferating cells from prostate carcinoma. Short-term cultured cells (n=205) from radical prostatectomy specimens have been used as the major method to skew the correspondence between the androgen-receptor (AR), proliferation-markers (Ki-67, PCNA) and morphological landmarks (nucleoli, AgNOR). These techniques allowed the identification of distinct androgen insensitive, proliferating cell-clusters and in the future will allow the analysis of genotypic changes in identified proliferating cell clones. PMID- 21552971 TI - Differential carbohydrate expression in tumorigenic vs nontumorigenic prostate cell-lines. AB - Death from prostate cancer is most frequently a result of metastatic disease. A key step in the process of metastasis is the attachment of circulatory tumor cells to target organ endothelium. This process is thought to be mediated by lectins, a class of cell surface proteins that bind two or more carbohydrate groups. Using fluorescent microscopy and fluorescein isothiocyanate (FITC) conjugated lectins, the presence of various carbohydrates was examined in the following tumorigenic and non-tumorigenic cell lines: rat prostate epithelial (EPYP-2, EPYP-1), rat prostate endothelial (YPEN-2, YPEN-1, YPEN-2PV), Dunning rat prostate cancer cell lines (MLL, ML, AT6.3, AT.1, AT2.1, GP9F3), and three tumorigenic human prostate cell lines (LNCaP, PC3, PC3 bone). The lectin Triticum vulgaris (WGA) was found to readily bind the carbohydrates N-acetylglucosamine and sialic acid on the plasma membrane of tumorigenic cell lines. Interestingly, WGA bound carbohydrates located to the nucleus and cytoplasm in non-tumorigenic cell lines, indicating that N-acetylglucosamine and sialic acid residues are preferentially expressed on the cell membrane of prostate cancer cells. Lectin staining patterns in cell lines of varying metastatic potential revealed no significant difference between highly metastatic vs. low metastatic cell lines. Observations revealed an absence of N-acetylgalactosamine and L-fucose in all rat Dunning, epithelial and endothelial cell lines as well as all human prostate cancer cell lines except for the androgen insensitive human prostate cancer cell line PC3, in which L-fucose residues were detected in the nucleus and on the plasma membrane. PC3 bone cells, which metastasized selectively to bone, demonstrated the presence of galactose residues whereas PC3 cells did not, suggesting that preference for target organ endothelium may be influenced by the expression of carbohydrate residues. These data indicate that differential carbohydrate expression may play an important role in prostate cancer biology. PMID- 21552972 TI - Different subnuclear localization of wild-type and mutant p53 in human prostate cancer cells. AB - The growth suppressor protein p53 is abnormally expressed in a variety of different human tumor cells. We have analyzed the expression of p53 in cell cultures derived from tissues of radical prostatectomies and in the permanent prostate carcinoma cell line PC-3 using two different p53 specific monoclonal antibodies. With the wild-type specific monoclonal antibody PAb1620 we found p53 localized in nucleoli whereas only a few cells were positively stained in the nucleus with the mutant specific monoclonal antibody PAb240. Control experiments with p53 from SV80 cells which express wild-type p53 and HT29 cells expressing mutant p53 documented the specificity of the monoclonal antibodies. The specificity of the antibodies in recognizing indeed p53 was demonstrated further by immunoprecipitation analysis of p53 from the same cell cultures. Since p53 is usually localized to the nucleus our results may represent a specific feature of the wild-type phenotype of p53 in prostate carcinoma cells. The localization of p53 in nucleoli may be another mechanism of the inactivation of wild-type p53. PMID- 21552973 TI - The antiproliferative effect of luteolin against diethylstilbestrol-induced cell proliferation in the mammary-gland of rat. AB - We have shown previously that stilbene estrogen or estrone treatment increases proliferative activity and alters cell cycle. In the present study we present evidence that alterations of the proliferative activity and cell cycle kinetics in the epithelial cells of the mammary glands of Noble rats by stilbene estrogen can be significantly blocked by the coadministration with naturally occurring plant flavone, luteolin. Luteolin treatment alone does not have any effect on cell growth, cell proliferation, cell cycle or cell differentiation. Diethylstilbestrol (DES) treatment increased the average number of cells from 3,080 to 8,936 as compared to controls. The average number of cells observed in DES alone treated group was reduced to 3,845 by luteolin cotreatment. The co treatment with luteolin significantly reversed the effect of DES on the proliferative activity in all structures of mammary gland. An increase in both labeling index and growth fractions by DES exposure was also significantly reversed by co-treatment with luteolin. Cotreatment with luteolin plus DES led to a 64% decrease in the cells in G1 phase (p<0.05), whereas cells in S phase were reduced by 55% (p<0.05) as compared with DES alone. Similarly, the potential doubling time (T-pot) was significantly reduced from 50-55 h as observed in control group to 22-24 h by DES treatment. However. luteolin co-treatment protected the reduction of (T-pot) by DES by increasing the potential doubling time from 22-24 h to 33-38 h. Also, co-treatment with luteolin plus DES prevented the conversion of a small percentage of the gland to Lob 2 and Lob 3 compared to DES treated female rats. Antiproliferative action of luteolin suggests that it may have potential anticarcinogenic effects against estrogen-induced mammary carcinogenesis. PMID- 21552974 TI - Transformation of rat fibroblasts by tgf-Beta - restriction to a minor subpopulation, rather than a rare event. AB - TGF-beta has the ability to transform rat fibroblasts, but it also induces neigbouring normal cells to eliminate newly arizing transformed cells. Therefore, the transforming effect of TGF-beta can only be demonstrated when it is added to rat fibroblasts sparsely seeded in soft agar. Combination of monolayer and soft agar cultures revealed the unexpected result that transformation of rat fibroblasts by TGF-beta acts on a distinct subpopulation rather than reaching the total population. As a consequence, the comparison of transformed cells with the parental untransformed random cell population is not adequate to define alterations acquired during the transformation process. PMID- 21552975 TI - A study of Cisplatin-radiosensitization through inhibition of repair of sublethal radiation-damage in ovarian-carcinoma cells sensitive and resistant to Cisplatin. AB - Human ovarian carcinoma parental cells and cisplatin resistant variants were evaluated for the effect of cisplatin on radiosensitization and repair of sublethal radiation damage. The data showed that for 1 h cisplatin treatment (2 mu g/ml), radiosensitization was achieved only if the drug was given after irradiation. Cisplatin treatment was also able to inhibit repair of sublethal radiation damage (SLDR). The degree of inhibition was about the same in the resistant and the sensitive cell lines. In the parental line 4 mu g/ml cisplatin was required to inhibit SLDR while in the resistant line both 2 and 4 mu g/ml produced inhibition of SLDR and in the resistant cell line the degree of SLDR inhibition was greater for cisplatin after irradiation compared to cisplatin before irradiation. PMID- 21552976 TI - Reliability of smoking history in medical charts in relation to interview data. AB - We previously reported on a series of studies exploring relationships between cigarette smoking and mutations of tumor suppressor genes; the studies relying on medical charts for data on smoking. To assess the accuracy of these data we compared them with data obtained using a conventional epidemiologic interview. As part of an ongoing case-control study of tobacco-related cancers, a trained interviewer questioned 144 patients about their smoking habits using a structured interview instrument; the medical charts were then reviewed. Using the Spearman test to compare the data obtained from the two sources, the correlation coefficient was 0.85 for cigarettes per day; 0.88 for years of smoking and 0.95 for pack-years, suggesting that the data in the charts were reliable. The kappa coefficient was 0.96 for current smoking status, indicating a very strong agreement between the two sources of data. The sensitivity and specificity for chart review were 96.3% and 100% respectively, compared with the 'gold standard' of a structured interview. These results show that when patients cannot be interviewed, for example when performing retrospective studies using existing collections of archived tumors or other biologic materials, then data on smoking abstracted from medical charts may be a reliable substitute. PMID- 21552977 TI - Characterization of an altered DNA topoisomerase ii-alpha from a mitoxantrone resistant Mammalian-cell line hypersensitive to DNA cross-linking agents. AB - To further define the molecular basis for drug resistance to mitoxantrone, a Chinese hamster ovary cell line (MXN(4)) was selected in the presence of 25 nM mitoxantrone and fully characterized. This cell line is 20-fold resistant to mitoxantrone, cross-resistant to several other topoisomerase II poisons, and 2- to 3-fold collaterally sensitive to cisplatin, carboplatin and BCNU. Neither an alteration in cellular uptake of topoisomerase II inhibitor nor overexpression of P-glycoprotein contribute to the drug resistance of MXN(4) cells. Immunoblotting demonstrates equivalent amounts of topoisomerase II alpha and beta in the wild type and drug resistant cell lines, suggesting that a quantitative alteration in topoisomerase II is not the mechanism of resistance of MXN(4) cells. Mitoxantrone induced DNA double strand breaks measured in situ were attenuated 28-fold in the drug resistant cell line. Nuclear extracts of MXN(4) cells, as well as topoisomerase II alpha purified to homogeneity from these cells, were found to be markedly resistant to drug-induced covalent DNA: topoisomerase II complex formation. The catalytic activity of purified MXN(4) topoisomerase II was the same as wild-type activity. Thus, the resistance of MXN(4) cells to mitoxantrone involves the expression of a topoisomerase II alpha with altered DNA cleavage activity. The hypersensitivity of this cell line to platinum analogs is due to an apparent increased uptake of these drugs which results in augmented DNA interstrand crosslinking. PMID- 21552978 TI - Biochemical modulation of Doxorubicin using an isoprenoid derivative, N-1379 - plasma transmembrane potential as a target site. AB - A new isoprenoid derivative, N-1379, was evaluated as a modulating agent of doxorubicin (DOX)-induced anticancer efficacy. The level of plasma transmembrane potential, measured using DiOC6(3), correlated with cellular sensitivity to DOX in K562 myelogenous leukemia, SH101 stomach, and PH101 pancreatic cancer cells. Non-toxic N-1379 increased the cellular transmembrane potential and DOX efficacy for three cell lines. The modulation of membrane function was accompanied by increases of DOX accumulation and S/G(2)M phase population in these cells. Overexpression of a 170 kD plasma membrane glycoprotein (GP-170) was not observed in any cells examined. We suggest therefore that interaction between electronegative transmembrane potential and positive charge of DOX may be linked to intracellular DOX accumulation. N-1379 may augment DOX efficacy through its increasing effect on plasma membrane potential independently of GP-170 overexpression. PMID- 21552979 TI - On the relationship of ATP depletion to chemotherapeutically-induced tumor regression. AB - A positive correlation was found between increasing ATP depletion and enhanced tumor-regressing activity by combining PMA, a three drug combination (PALA, MMPR+6-AN), with FUra, or Adria, or FUra+Adria. For example, at 48 h post treatment, ATP was 68% of saline controls with a 10% tumor regression rate (PMA); ATP was 55% with a 60% regression rate (PMA+FUra); ATP was 54% with an 80% regression rate (PMA+Adria); and ATP was 30% with a;100% regression rate (PMA+FUra+Adria). The results give support to the suggestion that ATP depletion may be a significant factor in the production of chemotherapeutically-induced apoptosis. PMID- 21552980 TI - Effects related to indomethacin prolonged survival and decreased tumor-growth in a mouse-tumor model with cytokine dependent cancer cachexia. AB - Tumor-bearing mice with two different locally growing malignant tumors (epithelial like, MCG 101; malignant melanoma, K1735-M2) were used to evaluate the putative role of prostaglandins for survival and local tumor growth in experimental cancer. Daily systemic injections of indomethacin (1 mu g/g bw) were used to block prostaglandin production in normal and T-cell deficient tumor bearing nude mice. Tumor progression was determined by measurements of tumor weight, DNA-synthesis, cell cycle kinetics in vivo and in vitro (flow cytometry), tumor tissue concentrations of polyamines (putrescine, spermidine, spermine) and tumor tissue gene expression of growth regulating factors (IL-1 alpha, IL-6, TNF alpha, A,B-PDGF, EGF, VEGF, bFGF, TGF beta(3), angiogenin and transferrin receptor). Tumor tissue content of von Willebrandt factor VIII was estimated by immunohistochemistry. Indomethacin had no effect on survival, host nutritional state or local tumor growth in mice bearing the malignant melanoma with low PGE(2) production. In contrast, indomethacin prolonged survival, improved cachexia and decreased tumor growth in mice bearing the MCG 101 tumor with hundredfold higher prostaglandin tumor production, leading to elevated liver and muscle tissue as well as plasma concentrations of PGE(2). Indomethacin inhibited almost completely the high tumor PGE(2) production in MCG tumors, leading to prolonged potential doubling time for tumor growth in vivo, and a trend to decreased tumor tissue concentration of polyamines (spermidine). Indomethacin had no inhibitory effect on tumor cell proliferation in vitro, although PGE(2) production was decreased by 75%. The effect of indomethacin in vivo was independent of T-cells and was observed with similar magnitude irrespective of the number of MCG cells (10(4)-10(6)) implanted or the site of implantation (s.c., i.p., liver, lung, skeletal muscles). Tumor growth inhibition by indomethacin was not intrinsically transferable by tumor cells from indomethacin treated tumor-animals. Tumor expression of mRNA for several growth regulating factors were either increased (IL-6, TNF alpha, GM-CSF, TGF beta(3)) unchanged (EGF, VEGF, PDGF A,B, IL-1 alpha, transferrin receptor) or decreased (b-FGF and angiogenin) (p<0.05) by indomethacin treatment of MCG mice. Decreased tumor content of von Willebrandt factor VIII in combination with an attenuated tumor vasculature were associated with decreased tumor growth (p<0.05). Our results confirm that high tumor production of prostaglandins was related to reduced survival. Tumor prostaglandins probably promote local tumor growth by stimulation of tumor surrounding cells to produce growth factor(s) for tumor angiogenesis including tumor and matrix cell proliferation unrelated to immune cells. PMID- 21552981 TI - Treatment of malignant mesothelioma (review). AB - Malignant mesothelioma (MM) has a very variable natural history. Its known relationship to asbestos exposure is often difficult to establish in a particular patient in view of a long preceding latency period of up to 40+ years. Survival depends on several prognostic factors including histological type, stage, performance status, resectability, and response to radiation and chemotherapy (CT). The assessment of the therapeutic impact on survival is usually difficult due to the different treatment philosophies and selections of patients in various clinical trials. Combined modality treatment approaches seem to offer the best outcomes, with occasional long-term disease-free survivors. Unresectable MM presents a difficult therapeutic challenge. In patients treated with systemic CT the median survival time (MST) in the range of 6 to 12 months and the 2 year survival of <20% are typical. The MST in excess of 20 months and the 2 year survival in the range of 40% have been reported in a few multimodality therapy trials in patients with at least partially resectable MM. Despite some encouraging therapeutic results in selected patients, the overall response to treatment(s) remains unsatisfactory, and new treatments must be sought. PMID- 21552982 TI - Monoclonal-antibody pd-41 recognizes a prostate-cancer associated antigen whose expression increases in metastases and following hormonal-therapy. AB - Tissues of prostatic origin representing variable phenotypes were tested for reactivity to the prostate cancer specific mouse monoclonal antibody PD-41. Avidin biotin immunoperoxidase was applied on formalin-fixed, paraffin-embedded tissue sections of 15 benign prostatic hyperplasia (BPH), 23 prostatic intraepithelial neoplasia (PIN), 14 untreated primary adenocarcinoma, 35 diethylstilbestrol (DES) treated tumors, 50 lymph node and 11 bone metastases. Specimens were stratified according to the percentage of tumor cells expressing PD-41 antigen and degree of staining intensity, and correlated with PIN grade, Gleason score, flow cytometry (FCM) measured DNA ploidy, and reactivity to other antibodies. In PIN, 4 specimens (17.4%) showed reactivity in a significant number of cells while a few cells were reactive in most cases. PD-41 was significantly reactive (>5% of tumor cells) in 88% of nodal metastases and in 73% of bone metastases in contrast to 49% reactivity in primary tumors (p=0.0003). There was a tendency of increased antigen expression in hormonally treated primary tumors. In addition, involutional and metaplastic changes in hormonally treated cases were reactive in many instances. Semi-quantitative evaluation of PD-41 reactivity showed a statistically significant correlation with Gleason score in primary tumors (p=0.007) and in lymph node metastases (p=0.009). Moreover, the PD-41 antibody reacted in metastatic lesions that failed to express both prostatic acid phosphatase and prostate specific antigen. These data suggest that monoclonal antibody PD-41 merits further investigation to evaluate its potential diagnostic, prognostic and therapeutic role in prostate cancer. PMID- 21552983 TI - Whole-body hyperthermia increases plasma-levels of transforming growth-factor Beta. AB - The low bone marrow toxicity of high dose alkylating agents when given in combination with whole body hyperthermia (WBH) may be explained in part by the parallel induction of the granulocyte colony stimulating factor. Since transforming growth factor beta (TGF beta) is known to act synergistically with colony stimulating factors, we performed studies of TGF beta expression under WBH in 12 patients with histologically confirmed metastatic sarcoma. Each patient was given ifosfamide, carboplatin, and etoposide combined with WBH (41.8 degrees C, 1 h). Plasma specimens far determination of TGF beta levels were taken prior to WBH and at different time points after start of WBH. Immunoreactive TGF beta 1 and TGF beta 2 were measured by ELISA. Follow-up revealed a significant increase in TGF beta 1 and TGF beta 2 in 9 of 12 patients, starting 2 h after begin of WBH and peaking 10 h later. The mean value for TGF beta 1 prior to therapy was 3.3 ng/ml (range: 0.9-7.3 ng/ml), rising after 12 h to 5.3 ng/ml (range: 2.8-11,5 ng/ml) (p<0.05). The values for TGF beta 2 were 3.1 ng/ml (range: 1.9-4.1 ng/ml) and 3.9 ng/ml (range: 3.2-4.5 ng/ml) (p<0.05), respectively, Both TGF beta 1 and TGF beta 2 had to be activated in vitro by acidification, Initial TGF beta 1 and TGF beta 2 levels did not differ from those in healthy controls. Collectively, our data indicate enhanced TGF beta 1 and TGF beta 2 expression under WBH and support the thesis that TGF beta is a myeoloprotective factor because it stimulates granulopoiesis. The transient growth arrest of very early stem cells by TGF beta may be an additional factor contributing to the low myelotoxicity of alkylating agents when given under WBH. PMID- 21552984 TI - IL-2 receptor expression and ki-67 flow cytometric analysis in B-chronic lymphocytic-leukemia. AB - Chronic lymphocytic leukemia (CLL) is typically an indolent lympho-proliferative disorder. Its clinical course is notable for marked heterogeneity, but in a subset of patients, the disease pursues a relatively rapid clinical course. To identify patients that may have aggressive disease, the growth fraction as determined by Ki-67 proliferation marker, DNA and RNA content, and IL-2 receptor expression were determined in 46 patients with CLL by flow cytometry. Our results indicate a significant statistical correlation between Ki-67 positivity and IL-2 expression in B-CLL cells. No correlation between the proliferative activity or RNA content and IL-2 expression was found. Our data indicate that measurement of both IL-2 receptor and Ki-67 expression in B-CLL can identify a subset of patients with a high risk of rapid clinical progression. PMID- 21552985 TI - Characterization of the 14 kda fragment of human tumor-necrosis-factor-alpha. AB - We report the characterization of a 14 kDa degradation fragment from recombinant human tumour necrosis factor-alpha (TNF alpha) by N-terminal sequencing and mass spectrometry. A single site between the dibasic residues Arg(31)-Arg(32) of the mature recombinant 17 kDa protein has been identified as the target site that generates the 14 kDa fragment. The observation that a maximum of 33% degradation occurs suggests that only one monomer per TNF trimer is cleaved. E. coli proteases specific for dibasic residues are thought to be responsible for this cleavage. A strategy has been developed which completely inhibits proteolysis. This strategy has been used to reduce the 14 kDa degradation fragment obtained from approximately 33% of the total purified protein to zero. PMID- 21552987 TI - Characterizations of volatile organic compounds during high ozone episodes in Beijing, China. AB - Air samples were collected in Beijing from June through August 2008, and concentrations of volatile organic compounds (VOCs) in those samples are here discussed. This sampling was performed to increase understanding of the distributions of their compositions, illustrate the overall characteristics of different classes of VOCs, assess the ages of air masses, and apportion sources of VOCs using principal compound analysis/absolute principal component scores (PCA/APCS). During the sampling periods, the relative abundance of the four classes of VOCs as determined by the concentration-based method was different from that determined by the reactivity approach. Alkanes were found to be most abundant (44.3-50.1%) by the concentration-based method, but aromatic compounds were most abundant (38.2-44.5%) by the reactivity approach. Aromatics and alkenes contributed most (73-84%) to the ozone formation potential. Toluene was the most abundant compound (11.8-12.7%) during every sampling period. When the maximum incremental reactivity approach was used, propene, toluene, m,p-xylene, 1-butene, and 1,2,4-trimethylbenzene were the five most abundant compounds during two sampling periods. X/B, T/B, and E/B ratios in this study were lower than those found in other cities, possibly due to the aging of the air mass at this site. Four components were extracted from application of PCA to the data. It was found that the contribution of vehicle exhaust to total VOCs accounted for 53% of VOCs, while emissions due to the solvent use contributed 33% of the total VOCs. Industrial sources contributed 3% and biogenic sources contributed 11%. The results showed that vehicle exhausts (i.e., unburned vehicle emissions + vehicle internal engine combustion) were dominant in VOC emissions during the experimental period. The solvent use made the second most significant contribution to ambient VOCs. PMID- 21552986 TI - Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. AB - Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson's disease (PD), Crohn's disease and leprosy. As all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions. Here, we report that full-length Lrrk2 is a relatively common constituent of human peripheral blood mononuclear cells (PBMC) including affinity isolated, CD14(+) monocytes, CD19(+) B cells, and CD4(+) as well as CD8(+) T cells. Up to 26% of PBMC from healthy donors and up to 43% of CD14(+) monocytes were stained by anti-Lrrk2 antibodies using cell sorting. PBMC lysates contained full-length (>260 kDa) and higher molecular weight Lrrk2 species. The expression of LRRK2 in circulating leukocytes was confirmed by microscopy of human blood smears and in sections from normal midbrain and distal ileum. Lrrk2 reactivity was also detected in mesenteric lymph nodes and spleen (including in dendritic cells), but was absent in splenic mononuclear cells from lrrk2-null mice, as expected. In cultured bone marrow-derived macrophages from mice we made three observations: (i) a predominance of higher molecular weight lrrk2; (ii) the reduction of autophagy marker LC3-II in (R1441C)lrrk2-mutant cells (<31%); and (iii) a significant up-regulation of lrrk2 mRNA (>fourfold) and protein after exposure to several microbial structures including bacterial lipopolysaccharide and lentiviral particles. We conclude that Lrrk2 is a constituent of many cell types in the immune system. Following the recognition of microbial structures, stimulated macrophages respond with altered lrrk2 gene expression. In the same cells, lrrk2 appears to co-regulate autophagy. A pattern recognition receptor type function for LRRK2 could explain its locus' association with Crohn's disease and leprosy risk. We speculate that the role of Lrrk2 in immune cells may also be relevant to the susceptibility of developing PD or its progression. PMID- 21552988 TI - The efficacy of extended treatment with pegylated interferon plus ribavirin in patients with HCV genotype 1 and slow virologic response in Japan. AB - BACKGROUND: Which patients with hepatitis C virus (HCV) genotype 1 can benefit from extended treatment with pegylated interferon (Peg-IFN) plus ribavirin is unknown, although the overall sustained virologic response (SVR) rate has been shown to improve in patients with a late virologic response (LVR), defined as detectable serum HCV RNA at week 12 and undetectable at week 24. METHODS: Among 1163 chronic hepatitis C patients with genotype 1 treated with Peg-IFN plus ribavirin combination therapy, 213 patients with an LVR were examined in this study. In addition, we selected 81 patients of matched sex and age from each of the 48- and 72-week treatment groups, using the propensity score, to compare the efficacy of the two treatment durations. RESULTS: With 72-week treatment, the timing of HCV RNA disappearance and the hemoglobin level at baseline showed a strong correlation with the SVR on multivariate analysis. Earlier HCV RNA disappearance was associated with a better SVR rate, regardless of the ribavirin dose (HCV RNA disappearance at week 16, 74%; at week 20, 52%; and at week 24, 31%, p = 0.01). The SVR rate with 72-week treatment was higher than that with 48 week treatment, irrespective of age, sex, or the platelet value, and, especially in aged patients (>=65 years old), the SVR rate increased markedly with 72-week treatment (48 weeks, 25% vs. 72 weeks, 56%; p < 0.05). CONCLUSIONS: An earlier response predicts a higher SVR rate in patients with an LVR given 72-week treatment. Extended treatment with Peg-IFN plus ribavirin for patients with an LVR improved the treatment efficacy, even for aged patients. PMID- 21552989 TI - Biotechnological production of polyamines by bacteria: recent achievements and future perspectives. AB - In Bacteria, the pathways of polyamine biosynthesis start with the amino acids L lysine, L-ornithine, L-arginine, or L-aspartic acid. Some of these polyamines are of special interest due to their use in the production of engineering plastics (e.g., polyamides) or as curing agents in polymer applications. At present, the polyamines for industrial use are mainly synthesized on chemical routes. However, since a commercial market for polyamines as well as an industry for the fermentative production of amino acid exist, and since bacterial strains overproducing the polyamine precursors L-lysine, L-ornithine, and L-arginine are known, it was envisioned to engineer these amino acid-producing strains for polyamine production. Only recently, researchers have investigated the potential of amino acid-producing strains of Corynebacterium glutamicum and Escherichia coli for polyamine production. This mini-review illustrates the current knowledge of polyamine metabolism in Bacteria, including anabolism, catabolism, uptake, and excretion. The recent advances in engineering the industrial model bacteria C. glutamicum and E. coli for efficient production of the most promising polyamines, putrescine (1,4-diaminobutane), and cadaverine (1,5-diaminopentane), are discussed in more detail. PMID- 21552990 TI - The role of eosinophils and mast cells in intestinal functional disease. AB - Functional gastrointestinal disorders (FGIDs) are common and currently defined by a symptom-based classification with no discernable pathology. In functional dyspepsia (FD), the duodenum is now implicated as a key area where symptoms originate.This is attributed to immune activation with increasing evidence indicating a role for duodenal eosinophilia. In irritable bowel syndrome (IBS), mastocytosis has been documented throughout the small and large intestine. Eosinophils and mast cells are an important link between innate and adaptive immunity, and are important in allergic type TH2 inflammation. Eosinophils may give rise to symptoms due to release of preformed cytokine proteins, which trigger neural excitation, muscle spasm, and pain. The close relationship of mast cells to nerves in IBS may similarly give rise to symptoms. Genetic studies also support of the role of innate immunity in FGIDs. The data supporting a prime role for eosinophils and mast cells in subsets of FD and IBS has become credible, and these data should be used to implement advances in diagnosis and therapeutic trials. PMID- 21552992 TI - Dasatinib in previously treated metastatic colorectal cancer: a phase II trial of the University of Chicago Phase II Consortium. AB - BACKGROUND: Treatment options for metastatic colorectal cancer (CRC) are limited after a fluoropyrimidine, oxaliplatin and irinotecan; novel agents need to be explored in this setting. Dasatinib, an oral inhibitor of Src family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models. PATIENTS AND METHODS: We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic CRC patients. No more than 2 prior chemotherapy regimens were permitted, which must have contained a fluoropyrimidine, oxaliplatin and irinotecan. The primary endpoint was progression-free survival (PFS) at 4 months. The Simon two-stage design required that at least 5 of the first 19 patients be progression-free at 4 months to expand to a second stage. RESULTS: Nineteen patients enrolled at 9 centers. The study was terminated after the first stage due to lack of efficacy. There were no objective responses; 1 patient (5%) had stable disease for 7.3 months. The PFS rate at 4 months was 5.3% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Grade 3/4 toxicities included fatigue in 16% of patients, and anemia, anorexia, nausea/vomiting and dyspnea in 11%. CONCLUSION: Dasatinib is inactive as a single agent in previously treated metastatic CRC patients. PMID- 21552993 TI - Pathological staging of frontotemporal lobar degeneration. AB - We developed a staging scheme for assessing pathology in frontotemporal lobar degeneration (FTLD), which relates to atrophy and accounts for the large variability seen at postmortem (Broe et al. 2003;60:1005-11). Atrophy of the temporal lobe has the most linear relationship to disease stage. We review how this simple staging technique has been applied in clinical settings, where it is the best predictor of survival and discriminates semantic dementia and behavioural phenocopies. Patients with clinical presentations of motor neuron disease or progressive supranuclear palsy have significantly lower disease stages than other FTLD syndromes. We also review the pathologies relating to disease stage. There is no significant difference in the overall distribution of stages between the different pathological subtypes of FTLD, indicating a similar underlying disease process. The cellular variables relating independently to increasing disease stage are (1) increasing neuronal loss, astrocytosis and microvacuolation, and (2) increasing glial apoptosis. Of note, the degree of protein deposition does not relate to disease stage. PMID- 21552994 TI - In vitro toxicity evaluation of 25-nm anatase TiO2 nanoparticles in immortalized keratinocyte cells. AB - Titanium dioxide (TiO(2)) nanoparticles (NPs) are massively fabricated and widely used in daily life, and thus potential risk has been posed to human health. However, the mechanism of the interaction between TiO(2) NPs and cells is still unclear. In this study, the interaction of anatase TiO(2) NPs with HaCaT cells is studied in vitro with multi-techniques. The TiO(2) NPs not only insert into cells through endocytic pathway but also penetrate into the cell. The TiO(2) NPs could produce reactive oxygen species (ROS) after dispersion spontaneously. Furthermore, the interaction between TiO(2) NPs and cellular components might also generate ROS. The ROS generation could lead to cellular toxicity if the level of ROS production overwhelms the antioxidant defense. Cytoskeletal components, particularly the microfilaments and microtubules, cause modifications upon exposure to TiO(2) NPs. With all results, the toxicological effects of TiO(2) NPs on HaCaT cell can be simplified into six events. PMID- 21552995 TI - Behavioral and chemical investigations of contact kairomones released by the mud dauber wasp Trypoxylon politum, a host of the parasitoid Melittobia digitata. AB - Contact kairomones from the host mud dauber wasp Trypoxylon politum Say (Hymenoptera: Crabronidae) that mediate behavioral responses of its ectoparasitoid Melittobia digitata Dahms (Hymenoptera: Eulophidae) were investigated. Chemical residues from host by-products, the cocoon, and the meconium, induced arrestment behavior of macropterous female parasitoids, while those from the host stage attacked, i.e., the prepupa, did not. Melittobia digitata response to polar and apolar extracts of host by-products indicated kairomone(s) solubility mainly in hexane. GC and GC/MS analysis of cocoon and meconium apolar extracts revealed a mixture of linear carboxylic acids from C(6) to C(18), and both extracts contained almost identical compounds. When a reconstructed blend of host by-product carboxylic acids was tested, M. digitata females showed only a weak response, thus suggesting that other unidentified compounds present in small quantities also may be involved. Melittobia digitata's response to contact kairomones was innate and not affected by previous host exposure experience. Our results provide evidence of contact kairomone exploitation in the genus Melittobia. The ecological significance of these findings in the host selection process of M. digitata is discussed. PMID- 21552996 TI - Endoscopic third ventriculostomy for the treatment of osteopetrosis-related hydrocephalus: a case-based update. AB - BACKGROUND: Osteopetrosis is a heterogenous group of disorders characterised by a failure of normal bone maturation and abnormal bone sclerosis secondary to the failure of osteoclasts to resorb bone. The most serious consequences of this disorder affect the nervous system. Patients with infantile osteopetrosis (also called malignant osteopetrosis) can develop a gradual occlusion of, or narrowing of the skull foramina at the skull base, resulting in the compression of vital nerves and vessels. Hydrocephalus has been identified in these patients, particularly those with the autosomal recessive variety of osteopetrosis. Although the exact aetiology is uncertain, it is possible that venous outflow obstruction at the cranial foramina along with a reduced intracranial space for cerebrospinal fluid (CSF) to flow around the hemispheres could be contributing factors. There are few reports in the literature on the management of this unusual association, hydrocephalus secondary to osteopetrosis. The authors report one such case where this association has been successfully surgically treated with endoscopic third ventriculostomy as a form of CSF diversion. CASE REPORT: We successfully treated a 9-month-old girl with osteopetrosis and symptomatic hydrocephalus with an endoscopic third ventriculostomy (ETV). She later went on to have stem cell transplantation to treat the osteopetrosis. CONCLUSIONS: Most reports in the literature have identified ventriculoperitoneal (or other distal site) shunting as the treatment of choice for hydrocephalus in this setting. We would like to highlight that ETV is another effective and often very suitable method of CSF diversion in these patients. PMID- 21552997 TI - Decreased incidence of myelomeningocele at birth: effect of folic acid recommendations or prenatal diagnostics? AB - PURPOSE: In Denmark, prevention to reduce the spina bifida birth rate has focused on two areas: folic acid supplementation (1997) and changes in the national ultrasonography screening programme (2004). Myelomeningocele (MMC) is the most severe malformation among the spina bifidas. Taking into consideration the potential negative effect of high-dose folic acid consumption, we found a need to look into the effectiveness of these two strategies in our complete MMC population. METHODS: All spina bifida patients born in the western part of Denmark are differentiated into proper subgroups based on MR imaging, giving us a unique chance to study a true MMC population. The total number of the group of MMC children since 1983 is 121. One hundred and eight (89%) parents answered a questionnaire. RESULTS: Following the changes in the prenatal ultrasonography screening programme in 2004, a significant decline of 60% live birth MMC per year was noted, incidence rate ratio (IRR) = 40% (22-73%), p = 0.3%. We found no change in MMC birth rate after introduction of folic acid supplementation, IRR = 121% (81-181%), p = 36%. CONCLUSION: Our findings demonstrate no effect of folic acid recommendation due to lack of compliance among women of reproductive age in Denmark. However, we found an improved early detection rate of prenatal MMC by high-quality ultrasonography. Subsequent early termination of pregnancy has led to a significant reduction of birth rate of babies with MMC. PMID- 21552998 TI - Natural history and progression factors of unilateral moyamoya disease in pediatric patients. AB - PURPOSE: Thirty-four pediatric age patients with unilateral moyamoya disease (MMD) were reviewed to analyze the natural history and the predictive factors for progression to bilateral MMD. METHODS: Forty out of 259 MMD patients cared for between January 2000 and June 2008 in the Severance Hospital had unilateral lesion. These patients were followed for a mean of 32.3 months for their symptoms and imaging studies. Thirty-four out of 40 patients were included in this study. Magnetic resonance angiography (MRA) and magnetic resonance perfusion (MR perfusion) images were taken for all patients for initial diagnosis and repeated at 6 months from the initial diagnosis and then at yearly basis. Clinical manifestations, the results of imaging studies, outcome of the indirect revascularization procedure, and the progression of the lesion were reviewed in this study. RESULTS: Of these 34 patients, contralateral progression was identified in 20 patients (58.8%). Fourteen (70%) out of the 20 patients presented with anterior cerebral artery abnormalities at diagnosis progressed to bilateral disease as well as did 5 (83%) out of 6 patients with middle cerebral artery lesions at the initial examination. Among the 34 patients, six exhibited familial history of MMD and all of them progressed to bilateral disease (100%, p < 0.005). CONCLUSION: Careful and long-term follow-up would be essential to evaluate the hemodynamic status and progression to bilateral disease in unilateral MMD patients to make prompt decision for a surgical revascularization. PMID- 21552999 TI - Psoriatic arthritis in South and Central America. AB - Psoriasis and its related manifestations, including psoriatic arthritis, are prevalent disorders in the Western world, particularly among Caucasians. The study of these disorders in Latin America lags way behind the study of other more common rheumatic disorders, such as rheumatoid arthritis and systemic lupus erythematosus. From the scarce evidence available, however, it appears that the prevalence and incidence of psoriasis and psoriatic arthritis are lower than in other parts of the Western world and almost negligible among natives from the Andean region, although confirmatory epidemiologic studies are lacking. PMID- 21553000 TI - The perspective on psoriatic arthritis in Asia. AB - There is a wide variation in the prevalence, incidence, and clinical manifestation of psoriatic arthritis (PsA) across countries due to genetic and environmental factors. Data on PsA in Asia are limited and come from small cross sectional studies. The burden of PsA in Asia is high, including poor physical functioning, poor quality of life, and high socioeconomic cost. In addition, high rates of subclinical atherosclerosis and traditional cardiovascular risk factors among PsA patients in Asia have been demonstrated. Preliminary data suggest treatment with tumor necrosis factor blockers may reverse atherosclerosis in PsA. Several outcome measure instruments, including the Medical Outcomes Survey Short Form 36 and Health Assessment Questionnaire, have been validated for measuring PsA burden among the Chinese. A coordinated effort in Asia from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the Asia Pacific League of Associations for Rheumatology (APLAR) will help estimate disease burden and clinical behavior of PsA on that continent. PMID- 21553001 TI - Retrocyclins and their activity against HIV-1. AB - Primate theta-defensins are physically distinguished as the only known fully cyclic peptides of animal origin. Humans do not produce theta-defensin peptides due to a premature stop codon present in the signal sequence of all six theta defensin pseudogenes. Instead, since the putative coding regions of human theta defensin pseudogenes have remained remarkably intact, their corresponding peptides, called "retrocyclins", have been recreated using solid-phase synthetic approaches. Retrocyclins exhibit an exceptional therapeutic index both as inhibitors of HIV-1 entry and as bactericidal agents, which makes retrocyclins promising candidates for further development as topical microbicides to prevent sexually transmitted diseases. This review presents the evolution, antiretroviral mechanism of action, and potential clinical applications of retrocyclins to prevent sexual transmission of HIV-1. PMID- 21553002 TI - Antidepressants utilization among elderly in Lombardy from 2000 to 2007: dispensing trends and appropriateness. AB - PURPOSE: To investigate the prevalence and incidence of antidepressant (AD) use in the elderly during an 8-year period and to evaluate AD treatment appropriateness. METHODS: A population-based dispensation study on community dwelling elderly of a large area in Lombardy was performed. Data were drawn from the regional administrative database and from a general practice registry. For each year, prevalence of AD use (i.e., at least one recorded dispensation) and AD treatment (i.e., at least four recorded dispensations) was compared. RESULTS: The prevalence of AD use and treatment doubled and tripled, respectively. The greatest shift occurred between 2000 and 2002 and was entirely due to SSRIs. The most pronounced increase was seen in females who accounted for 72% of all dispensations. The increase in prevalence was not mirrored by incident use, which slightly decreased (OR: 0.98; 95% CI: 0.98-0.98). The proportion of those who received a minimally adequate AD treatment grew over the years (OR: 1.63; 95% CI: 1.59-1.68). The increase in prevalence of AD treatment was most pronounced among older age groups (ORs between 1.02 and 1.06 for age classes >=75 years relative to the 65-69 age class; P < 0.001) and was proportional to that of depressive disorders. CONCLUSIONS: A dramatic rise in dispensations was observed. The increasing prevalence of minimally adequately treated subjects and a possible decrease in untreated depression may reflect an improvement in the pharmacological treatment of depression. The increase in prevalence and not in the incidence of dispensations could be related to an inappropriate prolongation of treatment duration. PMID- 21553003 TI - Efficacy of Er:YAG laser in the treatment of chronic periodontitis: systematic review and meta-analysis. AB - Scaling root planing (SRP) has been proven efficacious as the traditional treatment approach for chronic periodontitis. However, important limitations such as difficult access in deep pockets, grooves, and furcations have led to the development of new therapeutic strategies. The erbium-doped:yttrium-aluminium garnet (Er:YAG) laser is one of the most promising laser types for periodontal therapy. Its efficacy in radicular debris removal and root smoothing has been proven in vitro. However, the clinical effectiveness of the Er:YAG laser remains controversial. The aim of the present systematic review was to systemically assess the scientific evidence for the effectiveness of Er:YAG laser compared to SRP in the treatment of chronic periodontitis. Electronic database searches of MEDLINE, Cochrane Controlled Clinical Trial Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, CINAHL, Science Direct, ISI Web of Science, and SCOPUS were performed, as well as hand-searching of relevant journals through December 23, 2010. Quality assessment was made according to the CONSORT guidelines. The systematic review was performed according to the QUOROM statement and Cochrane Collaboration recommendations. Meta-analyses of the clinical attachment level gain, probing depth reduction, and changes in gingival recession were performed using weighted mean differences for continuous data with 95% confidence intervals, nested in a random effect model. No statistically significant differences were found in any of the investigated clinical parameters among the five random controlled trials (RCTs) entered into the study, indicating that there was no evidence of effectiveness. However, significant heterogeneity, a high risk of bias in three of the five included studies, and methodological shortcomings indicate that the results should be considered with caution. Future long-term, well-designed RCTs are needed to assess the scientific evidence of Er:YAG laser efficacy as an alternative treatment strategy to SRP. PMID- 21553004 TI - Correlation of NM23-H1 cytoplasmic expression with metastatic stage in human prostate cancer tissue. AB - Nm23-H1 has been identified as a metastatic suppressor gene in murine melanoma cell lines. Several functions have been attributed to its activity in cancer, including a histidine kinase activity, DNA repair, and regulation of other proteins involved in metastatic formation. While in breast cancer, NM23-H1 overexpression indicates a benign status through impairing progression of disease, its function is opposite in other cancers; e.g., neuroblastoma. To further understand this dichotomy of function in cancer, we have analyzed its function in prostate cancer, in which the relationship between NM23-H1 expression and prognostic state is today controversial. In vitro, overexpression of NM23-H1 in PC3 cells inhibited their cell motility, while downregulation of NM23-H1 expression in these cells by RNA interference showed enhanced cell motility. Immunohistochemistry analysis performed on 346 prostate cancer tissue samples showed a relationship between high levels of NM23-H1 expression in the nuclei of these tumorigenic cells and elevated Gleason score, with high levels of NM23-H1 cytoplasmic staining related to metastatic stage. This retrospective survival study demonstrates that high levels of NM23-H1 expression in the cytoplasm determine recurrence of prostate-specific antigen levels only in those patients with metastatic disease. Our findings suggest a correlation between high levels of NM23-H1 protein in the cytoplasm of the cells and progression of prostate cancer to metastasis, thus definitively identifying NM23-H1 as a new negative prognostic marker in prostate cancer. PMID- 21553006 TI - The web-rhetoric of companies offering home-based personal health monitoring. AB - In this paper I investigate the web-rhetoric of companies offering home-based personal health monitoring to patients and elderly people. Two main rhetorical methods are found, namely a reference to practical benefits and a use of prestige words like "quality of life" and "independence". I interpret the practical benefits in terms of instrumental values and the prestige words in terms of final values. I also reconstruct the arguments on the websites in terms of six different types of argument. Finally, I articulate a general critique of the arguments, namely that the websites neglect the context of use of personal health monitoring technologies. Whether or not a technology is good depends on the use of the technology by a particular individual in a particular context. The technology is not good-or bad-in itself. I support this critique with a number of more specific arguments such as the risk for reduced personal contact. For some elderly people social contact with care providers is more valuable than the independent living made possible by remote monitoring, for others independence is more important. PMID- 21553005 TI - Neuroanatomical targets of reboxetine and bupropion as revealed by pharmacological magnetic resonance imaging. AB - RATIONALE: One of the key targets of psychopharmacology research is to determine the potential sites of action of antidepressants in order to characterise their underlying mechanism of action. OBJECTIVE: Using blood oxygenation level dependent (BOLD) pharmacological magnetic resonance imaging (phMRI), the neuroanatomical target-sites of reboxetine (a selective noradrenaline reuptake inhibitor) and bupropion (an antidepressant with stimulatory effects on dopamine and potentially on noradrenaline) were mapped. METHODS: Separate groups of rats were challenged acutely or chronically (daily injections for 14 days) with saline or psychoactive compounds and scanned. Subsequent statistical parametric mapping of the main effects of the drug was performed by identifying changes in the BOLD signal. RESULTS: Acute reboxetine challenge at a low dose (10 mg/kg i.p.) produced positive BOLD responses specifically in the hypothalamus, whereas a larger dose (30 mg/kg i.p.) produced activations in the hypothalamus, anterior hippocampus and prefrontal cortex. Chronic reboxetine (30 mg/kg i.p.) treatment induced increased BOLD responses in the posterior hippocampus and prefrontal cortex, while no significant contrast changes were observed in the hypothalamus and a significant decrease was apparent in the amygdala. In contrast, acute bupropion (15 and 30 mg/kg i.p.) challenge in both doses produced no significant contrast changes in the regions of interest. However, chronic bupropion treatment (30 mg/kg i.p.) produced robust increases in BOLD responses in the hippocampus, amygdala and prefrontal cortex. CONCLUSION: In summary, this study demonstrates that reboxetine and bupropion evoke a significant increase in BOLD functional activity in specific regions of the brain, including the hypothalamus, hippocampus, prefrontal cortex and amygdala. Furthermore, the study illustrates the potential value of pharmacological MRI in rodents to delineate pharmacologically induced changes in regional brain function. PMID- 21553007 TI - Mutations in BRAF correlate with poor survival of colorectal cancers in Chinese population. AB - PURPOSE: Mutations in KRAS and BRAF genes were associated with treatment failure from EGF receptor inhibitors in colorectal cancer (CRC) patients. However, whether these mutations were associated with survival in patients not treated with EGF receptor inhibitors remained controversial. Moreover, few data were available in Chinese. Therefore, we aimed to evaluate the impact of KRAS and BRAF mutations on the survival of Chinese CRC patients. METHODS: CRC patients who underwent surgery between October 2003 and April 2006 were included in this study. They were observed until June 30, 2010 or when death was ascertained by the National Death Registration System. Prospectively collected fresh frozen tumor tissues were used for detection of mutations at codons 12, 13, and 61 of the KRAS gene and exons 11 and 15 of BRAF gene by PCR amplification followed by direct sequencing. RESULTS: Among the 314 patients, KRAS and BRAF mutations were detected in 65 (20.7%) and 12 (3.8%) patients, respectively. KRAS mutations appeared to occur more frequently in females than males (p = 0.039) and in non smokers (p = 0.039). KRAS and BRAF mutations were significantly associated with the proximal location of cancer (p = 0.017 and 0.001, respectively). In the univariate analysis, KRAS and BRAF mutations were not associated with survival. However, BRAF mutations were associated with a significantly worse overall survival (hazard ratio = 3.91, 95% confidence interval 1.31 to 11.66, p = 0.014) in the multivariate Cox proportional hazard model after adjustment for all direct clincopathological variables. CONCLUSION: BRAF mutations, but not KRAS mutations, were associated with a worse outcome in Chinese CRC patients. PMID- 21553008 TI - Effects of subcutaneous drain for the prevention of incisional SSI in high-risk patients undergoing colorectal surgery. AB - INTRODUCTION: We have previously demonstrated that the risk of incisional surgical site infection (SSI) increases with obesity and that the most useful predictor of incisional SSI is the thickness of subcutaneous fat. Based on this finding, we have recently attempted a closure technique in surgery for the obese in which a subcutaneous drain is inserted for the prevention of incisional SSI. The aim of this study was to assess the utility of a subcutaneous drain for preventing incisional SSI in patients undergoing colorectal surgery who are at high risk for incisional SSI. MATERIALS AND METHODS: Seventy-nine patients who underwent colorectal resection with high risk for incisional SSI, including patients with obesity (thick subcutaneous fat tissue, >20 mm) and those undergoing emergency operations, were enrolled in this study. The clinical features of these cases with or without a subcutaneous drain were reviewed, and statistical analysis was performed. RESULTS: In these high-risk cases, the overall incidence of incisional SSI was 27.8%. The incidences of incisional SSI in these cases with or without a subcutaneous drain were 14.3% and 38.6%, respectively. Our results suggest that subcutaneous drains are effective for preventing incisional SSI in patients with thick subcutaneous fat in colorectal surgery. CONCLUSION: Therefore, incisional SSI surveillance for obese patients should be performed separately, which should lead to a further reduction in incisional SSIs. PMID- 21553009 TI - Complex rectal polyps: other treatment modalities required when offering a transanal endoscopic microsurgery service. AB - PURPOSE: Complex rectal polyps may present a clinical challenge. The study aim was to assess different treatment modalities required in the management of patients referred for transanal endoscopic microsurgery. METHODS: Patients referred with complex rectal polyps from 1998 to 2008 were entered prospectively to a colorectal database. These data was analyzed for referral pattern, histology, surgical procedures performed, and subsequent outcome. RESULTS: Of the 209 patients referred (101 female, 108 male, median age of 65 years, range of 24 89), 132 (63%) were deemed suitable for transanal endoscopic microsurgery. Seventeen patients required a second staged procedure; three patients required an anterior resection at time of index surgery. Seventeen patients referred for transanal endoscopic microsurgery went direct to anterior resection, 37 underwent snare polypectomy (SP), and 17 patients underwent transanal excision. Six patients had no surgery (three unfit for anesthesia and three had no residual lesions). Thus, 37% of the patients referred for transanal endoscopic microsurgery required a different treatment modality. CONCLUSIONS: Majority of patients referred to our unit with complex rectal polyps were suitable for transanal endoscopic microsurgery. However, this study highlights that in offering a transanal microsurgery service, one should be prepared for a diversity of pathology necessitating a range of management options. PMID- 21553010 TI - Platelet activation and function during eltrombopag treatment in immune thrombocytopenia. AB - We monitored platelet activation by means of P-selectin and platelet monocyte aggregates (PMA) and platelet function by whole blood multiple electrode aggregometry and platelet adhesion under high shear in chronic immune thrombocytopenia patients to define changes in platelet activation during treatment with eltrombopag. Overall, platelet activation and function normalized with increasing platelet counts. However, P-selectin, which was already elevated before treatment, and PMA increased further transiently during the first weeks. The increases in P-selectin and in PMA indicate ongoing platelet activation during the early period of treatment. PMID- 21553011 TI - Treatment of myelodysplastic syndromes with excess of blasts by bevacizumab is well tolerated and is associated with a decrease of VEGF plasma level. AB - Myelodysplastic syndromes (MDS) are associated with increased bone marrow vascularity and increased levels of various angiogenic factors including Vascular Endothelial Growth Factor (VEGF) which is implicated in the proliferation and survival of leukemic cells. Before the approval of hypomethylating agents in this indication, the GFM conducted a multicenter phase II trial testing the efficacy and tolerance of bevacizumab, a humanized monoclonal antibody against VEGF, in MDS with excess of marrow blasts and its impact on bone marrow angiogenesis. Twenty-one patients were enrolled (16 males and five females) with a median age of 70 years and 19 were evaluable for haematological response after treatment (5 mg/kg IV every 2 weeks for 12 weeks). WHO diagnosis at baseline was RAEB-1 (38%) and RAEB-2 (62%). Treatment was well tolerated and was associated with significant decrease of VEGF plasma level [median (low quartile-high quartile)] from 65.5 pg/ml [LQ (low-quartile)-HQ (high quartile), 35.3-87.3 to 30.4 pg/ml (LQ-HQ, 22.5-34.0 pg/ml)] (p < 0.01) and reduction of bone marrow angiogenesis from a median of 20 vessels/mm(3) (LQ-HQ, 16.5-33 vessels/mm(3)) to 15.5 vessels/mm(3) (LQ-HQ, 10-23.2 vessels/mm(3)) (p = 0.03). On the other hand, only one patient had a significant haematological response with achievement of RBC transfusion independence. Thus, although bevacizumab had a significant impact on VEGF levels and angiogenesis in our patients, very few responses were seen when this drug was used as single agent. Given its good tolerability profile, however, combination of bevacizumab with other drugs, especially hypomethylating agents, could be considered in MDS. PMID- 21553012 TI - Diagnosis of neuromyelitis optica (NMO) spectrum disorders: is MRI obsolete? AB - INTRODUCTION: Neuromyelitis optica (NMO) is a severe demyelinating disease that preferentially involves spinal cord and optic nerve. It is part of a spectrum of neurological conditions associated with antibodies to aquaporin-4 (AQP4). This study investigates the role of MRI where novel, more sensitive AQP4 antibody immunoassay techniques are being used. METHODS: Retrospective review of neuroimaging in 69 patients (25 antibody positive, 44 antibody negative), investigated in the context of suspected NMO or NMO spectrum disorder, was performed independently by two consultant neuroradiologists. RESULTS: Longitudinally extensive, central spinal cord lesions were more frequent in AQP4 positive patients (95.2% vs 35.5%, p < 0.0001; 85.7% vs 45.2%, p = 0.015). Multiple sclerosis diagnostic criteria were less frequently fulfilled on brain MRI in antibody positive patients (5.6% vs 33.3%, p = 0.035). Juxtacortical and corpus callosal lesions were also less common in this group (16.7% vs 46.7%, p = 0.063; 5.6% vs 46.7%, p = 0.0034). Hypothalamic and periependymal disease related to the aqueduct was not seen in antibody negative patients. T1 hypointensity was more common in cord lesions of antibody positive patients (75.0% vs 35.3%, p = 0.037). However, this characteristic did not discriminate antibody positive and negative longitudinally extensive cord lesions (73.3% vs 62.5%, p = 0.66). CONCLUSION: The NMO spectrum of diseases are among an increasing number of neurological conditions defined by serological tests. However, despite improved immunoassay techniques, MRI of the brain and spinal cord continues to be among the first-line investigations in these patients, providing valuable diagnostic information that will help guide patient management. PMID- 21553013 TI - Punctate white matter lesions in infants: new insights using susceptibility weighted imaging. AB - INTRODUCTION: Punctate white matter lesions (PWML) are recognized with magnetic resonance imaging (MRI) as hypersignal on T1-weighted imaging and hyposignal on T2-weighted imaging. Our aim was to assess how often a hemorrhagic component was present in PWML using susceptibility-weighted imaging (SWI). METHODS: Seventeen preterm (gestational age, 25-34 weeks) and seven full-term infants (age at MRI, 37-42 weeks) with PWML were included. Seven preterm infants had sequential MRIs. PWML were diagnosed with conventional MRI and compared with SWI, where signal loss is suggestive of hemorrhage. The pattern of associated brain lesions was taken into account, and the percentage of lesions with signal loss on SWI was calculated for each infant. RESULTS: A significantly higher percentage of signal loss on SWI (median, 93.9%) was found among infants with germinal matrix and intraventricular hemorrhage as the primary diagnosis (n = 8) compared to those with a primary diagnosis of white matter injury (n = 14; median, 14.2%; p < 0.01). In the infants with serial MRIs, a reduction in the number of PWML and/or signal loss on SWI was noted at term equivalent age. In the patient who died, cystic lesions, associated with hemorrhage and gliosis, were demonstrated on histology. CONCLUSIONS: SWI can distinguish hemorrhagic and non-hemorrhagic PWML. Signal loss on SWI was more common when PWML were associated with an intraventricular hemorrhage. Longitudinal imaging showed a decrease in the number of PWML over time, with some PWML no longer showing signal loss on SWI, suggesting early gliosis. PMID- 21553014 TI - Hybrid modeling of xanthan gum bioproduction in batch bioreactor. AB - This work is focused on hybrid modeling of xanthan gum bioproduction process by Xanthomonas campestris pv. mangiferaeindicae. Experiments were carried out to evaluate the effects of stirred speed and superficial gas velocity on the kinetics of cell growth, lactose consumption and xanthan gum production in a batch bioreactor using cheese whey as substrate. A hybrid model was employed to simulate the bio-process making use of an artificial neural network (ANN) as a kinetic parameter estimator for the phenomenological model. The hybrid modeling of the process provided a satisfactory fitting quality of the experimental data, since this approach makes possible the incorporation of the effects of operational variables on model parameters. The applicability of the validated model was investigated, using the model as a process simulator to evaluate the effects of initial cell and lactose concentration in the xanthan gum production. PMID- 21553015 TI - beta-Tubulin genotypes in six species of cyathostomins from anthelmintic-naive Przewalski and benzimidazole-resistant brood horses in Ukraine. AB - Resistance to benzimidazoles (BZ) in the gastrointestinal nematodes of livestock is characterised by the presence of specific polymorphisms in the beta-tubulin isotype 1 protein, a component of microtubules. The most prevalent polymorphism associated with resistance in nematodes infecting cattle, sheep, and goats is found at codon 200, with minor occurrences of polymorphisms at codons 167 and 198. In the cyathostomins that infect horses, however, a polymorphism at codon 167 appears to be more common than the codon 200 polymorphism. In the present study, a focussed analysis of PCR-amplified beta-tubulin fragments incorporating the above-mentioned three polymorphic sites in isotype 1 and 2 genes in worms of six species of cyathostomins, Cylicocyclus nassatus, Cylicocyclus ashworthi, Cyathostomum catinatum, Cylicostephanus goldi, Cylicostephanus longibursatus, and Coronocyclus coronatus, was performed. Worms were collected from two distinct horse populations, i.e. they were collected from Przewalski horses of the Askania Nova Biosphere Reserve that had never received any anthelmintic treatment and from brood horses of the Dubrovsky farm where benzimidazole resistance had become established. DNA was extracted and sequenced from three worms of each species and population as well as from pools of 50 male C. nassatus and C. catinatum from both populations. The vast majority of putatively BZ resistance-associated TAC alleles were found at codon 167, compared to codon 200. The former allele occurred in isotype 1 in all six species of the supposedly benzimidazole resistant cyathostomins from Dubrovsky horses. None of the polymorphisms associated with resistance was found in the corresponding isotype 2 codons nor at codon 198 in any of the six species of cyathostomins (neither single nor pooled worm DNA) from either of the two populations. These findings further support the predominant association of beta-tubulin isotype 1 and therein codon 167 with BZ resistance in cyathostomins. PMID- 21553016 TI - NKCC2 is activated in Milan hypertensive rats contributing to the maintenance of salt-sensitive hypertension. AB - The Milan hypertensive strain of rats (MHS) develops hypertension as a consequence of the increased tubular Na(+) reabsorption sustained by enhanced expression and activity of the renal tubular Na-K-ATPase. To verify whether the Na-K-2Cl cotransporter (NKCC2) is involved in the maintenance of hypertension in MHS rats, we have analysed the phosphorylation state and the activation of NKCC2 in Milan rats. Western blotting and immunofluorescence experiments were performed using specific antibodies against the regulatory phospho-threonines in the NKCC2 N terminus (R5 antibody). The phosphorylation levels of NKCC2 were significantly increased in the kidney of MHS rats. Moreover, the administration of furosemide in vivo decreased the blood pressure and increased the urine output and natriuresis in MHS rats demonstrating the actual involvement of NKCC2 activity in the pathogenesis of hypertension in this strain of rats. The up-regulation of NKCC2 activity is most probably mediated by a STE20/SPS1-related proline/alanine rich kinase (SPAK) phosphorylation at serine-325 since it was significantly increased in MHS rats. Interestingly, aldosterone treatment caused an increase in NKCC2 phosphorylation in NKCC2-expressing MDCK cells. In conclusion, we demonstrated an increase in the activity of NKCC2 along the TAL that significantly contributes to the increase in systemic blood pressure in MHS rats. The elevated plasma levels of aldosterone, found in MHS rats, may influence Na(+) balance through a SPAK-dependent regulation of NKCC2 accounting for the maintenance of the hypertensive state in MHS rats. PMID- 21553019 TI - Plasmacytoma presenting as hematuria. PMID- 21553018 TI - Development of POEMS syndrome after an initial manifestation of solitary plasmacytoma. AB - A 44-year-old male was admitted for numbness in the left arm. CT showed a tumor impacting on the spinal cord with an adjacent thoracic vertebral osteosclerotic lesion. The histopathology of the tumor showed diffuse proliferation of atypical plasma cells with expressed vascular endothelial growth factor (VEGF), which is a known etiological factor in POEMS syndrome. Though serum VEGF (sVEGF) level was elevated, a diagnosis of solitary plasmacytoma with an osteosclerotic lesion was made as the patient presented no polyneuropathy, organomegaly, endocrinopathy, or skin changes. The patient experienced muscle weakness of the lower limbs and skin pigmentation/hemangioma one year after irradiation of the osteosclerotic lesion. Laboratory tests revealed hypothyroidism, hyperglycemia, serum monoclonal gammopathy, further elevation of sVEGF, and increased atypical bone marrow plasma cells. CT imaging showed splenomegaly, and a nerve conduction test revealed demyelinating motor peripheral neuropathy. The patient was therefore diagnosed with POEMS syndrome. Plasmacytoma is very rare as an initial manifestation of POEMS syndrome. Patients presenting with plasmacytoma with an osteosclerotic lesion should be carefully observed and evaluated for the expression of sVEGF and development of POEMS syndrome, as most bone plasmacytomas in POEMS syndrome patients are reported to be osteosclerotic. This is to our knowledge the first case of osteosclerotic plasmacytoma that progressed to POEMS syndrome, with an increase of sVEGF. PMID- 21553017 TI - Unraveling the role of peptidyl-prolyl isomerases in neurodegeneration. AB - Immunophilins are a family of highly conserved proteins with a peptidyl-prolyl isomerase activity that binds immunosuppressive drugs such as FK506, cyclosporin A, and rapamycin. Immunophilins can be divided into two subfamilies, the cyclophilins, and the FK506 binding proteins (FKBPs). Next to the immunophilins, a third group of peptidyl-prolyl isomerases exist, the parvulins, which do not influence the immune system. The beneficial role of immunophilin ligands in neurodegenerative disease models has been known for more than a decade but remains largely unexplained in terms of molecular mechanisms. In this review, we summarize reported effects of parvulins, immunophilins, and their ligands in the context of neurodegeneration. We focus on the role of FKBP12 in Parkinson's disease and propose it as a novel drug target for therapy of Parkinson's disease. PMID- 21553020 TI - Inflammatory autoimmune neuropathy, presumably induced by bortezomib, in a patient suffering from multiple myeloma. AB - Bortezomib is a proteasome inhibitor demonstrating substantial activity in multiple myeloma. One of its key toxicities is peripheral neuropathy, which is reversible in most patients. The possibility that bortezomib might in rare cases induce severe neuropathies by auto-inflammatory mechanisms remains controversial. We report here the case of a 65-year-old female myeloma patient who was initially treated with bortezomib, doxorubicin, and dexamethasone (PAD). At the end of the second cycle of PAD, the patient presented with a rapid and severe onset of paresis of the left arm, accompanied by progressive sensory neuropathy and increasing neuropathic pain. After an extensive neurological work-up, including electrophysiological and laboratory evaluations as well as magnet resonance tomography imaging, we diagnosed an inflammatory autoimmune neuropathy, presumably induced by bortezomib, with accentuation of the left arm nerve plexus. We subsequently initiated regular treatment with polyvalent immunoglobulins, which gradually improved the neurological symptoms. In conclusion, the identification of an inflammatory autoimmune neuropathy, presumably associated with bortezomib, is a rare but important complication. An extensive neurological examination should be performed in patients who develop severe or unusual sensory or motor deficits under therapy with bortezomib, so as to differentiate autoimmune from toxic neuropathies, as therapeutic strategies differ for each. PMID- 21553021 TI - The sterol biosynthesis inhibitor molecule fenhexamid impacts the vegetative compatibility of Glomus clarum. AB - The vegetative compatibility of the arbuscular mycorrhizal fungus (AMF) Glomus clarum MUCL 46238 was evaluated after continuous exposure to fenhexamid, a sterol biosynthesis inhibitor (SBI). Three lineages of this AMF were cultured in vitro for five generations in association with Ri T-DNA transformed carrot roots in the presence of 0, 5 or 10 mg l(-1) of fenhexamid. Whatever the AMF generation, fenhexamid at 5 and 10 mg l(-1) had no significant impact on the number of spores produced. However, vegetative compatibility tests (VCT) conducted with spores from the three lineages, in the presence of 10 mg l(-1) of fenhexamid, impacted the anastomosis process. At this concentration, the morphology of the germ tubes was modified. In addition, nitrotetrazolium-trypan blue staining revealed that 10 mg l(-l) of fenhexamid significantly reduced the probability of fusion between the germ tubes regardless of the culture conditions (i.e. absence or presence of fenhexamid) preceding the VCT. Our results demonstrated that spore production was not affected by fenhexamid, while anastomosis between germ tubes was decreased. This suggested that high concentrations, accumulation or repeated application of this SBI fungicide may impact the community structure of AMF in soil. PMID- 21553022 TI - Lin-28 reactivation is required for let-7 repression and proliferation in human small cell lung cancer cells. AB - The let-7 family of microRNAs (miRNAs) are known to act as tumor suppressors and down-regulated in lung cancer. Recently, the RNA-binding protein Lin-28 was demonstrated to inhibit biogenesis of let-7 miRNAs by blocking both Drosha- and Dicer-mediated cleavage and accelerating decay of let-7 precursors. We selected NCI-H446 lung small cell lung cancer cell to determine whether it is broadly representative that Lin-28 can promote cell proliferation and affect cell cycle through negatively regulating let-7 biogenesis. Here, we showed that Lin-28 mRNA was up-regulated in NCI-H446 cell with a high c-Myc state. The result of real time RT-PCR further indicated that pri-let-7a-1/7g and mature let-7g were remarkably down-regulated. The expression of lin-28 was down-regulated while the mature let-7g transcript was up-regulated inversely. The MTT assay indicated that the proliferation of lung cancer cells with lin-28 inhibition was signally impaired. The cells with lin-28 knockdown revealed a higher proportion of cells at G1/G0 phase and less at S phase. The results presented here demonstrate that induction of Lin-28 could mediate repression of let-7 family members, promote cell cycle progression and suppress cell proliferation. PMID- 21553023 TI - CXCR4 positive cells from Lewis lung carcinoma cell line have cancer metastatic stem cell characteristics. AB - There is increasing evidence that cancer stem cells contribute to the initiation and propagation of many tumor. Therefore, to find out and identify the metastatic tumor stem-like cells in Lewis lung cancer cell line (LLC), the expression of CXCR4 was measured in LLC by flow cytometry and observed by laser scanning confocal microscope (LSCM). After the CXCR4(+) LLC cell was isolated from LLC by magnetic cell sorting, its properties were evaluated by their tumorigenic and metastatic potentials. CXCR4(+) cells were counted for 0.18% of the total number of LLC, and immunofluorescent staining cells were identified by LSCM. CXCR4(+) LLC suspension cultured in a serum-free medium, cell spheres expressed a high level of Sca-1. The chemotherapy sensitivity to cisplatin of CXCR4(+) LLC was lower than that of CXCR4(-) LLC. The expression of ABCG2 and IGF1R mRNA in CXCR4(+) LLC was higher than that in CXCR4(-) LLC (P < 0.01). Most of CXCR4(+) LLC cells were close to vascular endothelial cells, aberrant vasculature around it was forming. The expression of VEGF and MMP9 mRNA in CXCR4(+) LLC was higher than that in CXCR4(-) LLC (P < 0.05), the microvessel density (MVD) of CXCR4(+) subsets growing were higher than that of CXCR4(-) subsets growing tumor tissue (P < 0.01). The tumor size, volume, and metastatic foci in the lungs of CXCR4(+) LLC was significantly higher than that in CXCR4(-) LLC (P < 0.001). Similarly, elevated expression of MMP9 and VEGF was also positively associated with CXCR4(+) LLC. Our results demonstrated that CXCR4(+) cells from Lewis lung carcinoma cell line exhibit cancer metastatic stem cell characteristics. PMID- 21553024 TI - MiR-34a inhibits lymphatic metastasis potential of mouse hepatoma cells. AB - MicroRNAs are small non-coding RNAs that regulate the expression of other genes in a post-transcriptional manner. MiR-34a can induce apoptosis, cell cycle arrest, and senescence. However, its role in tumor progress remains to be fully elucidated. In the present study, the role of miR-34a in lymphatic metastasis was investigated using mouse hepatocarcinoma cell lines Hca-F and Hepa1-6. MicroRNA profiling and Hairpin-RT-PCR analysis showed that the expression level of miR-34a was higher in Hepa1-6 cells (of no metastatic ability) than that in Hca-F cells (of high metastatic ability). Ectopic expression of miR-34a can inhibit cell growth and cell invasion in Hepa1-6 and Hca-F cells. Moreover, miR-34a triggers G1 arrest and down-regulates CyclinD1 and CDK6 in Hepa1-6 cells. Furthermore, we proved that miR-34a decreased adhesion of Hca-F cells to regional lymph node in vitro, reduced lymph nodes-metastasized burden, and inhibited tumor lymph node metastases in vivo. All these results suggest that miR-34a plays multiple tumor suppressive roles in murine hepatocarcinoma, not only inhibiting cell growth by cell cycle arrest, but also repressing metastasis, and may serve as a novel therapeutic target for hepatocarcinoma. PMID- 21553027 TI - Surgical management of spheno-orbital meningiomas. PMID- 21553025 TI - Reduced dosage of the modifiers of epigenetic reprogramming Dnmt1, Dnmt3L, SmcHD1 and Foxo3a has no detectable effect on mouse telomere length in vivo. AB - Studies carried out in cultured cells have implicated modifiers of epigenetic reprogramming in the regulation of telomere length, reporting elongation in cells that were null for DNA methyltransferase DNA methyltransferase 1 (Dnmt1), both de novo DNA methyltransferases, Dnmt3a and Dnmt3b or various histone methyltransferases. To investigate this further, we assayed telomere length in whole embryos or adult tissue from mice carrying mutations in four different modifiers of epigenetic reprogramming: Dnmt1, DNA methyltransferase 3-like, structural maintenance of chromosomes hinge domain containing 1, and forkhead box O3a. Terminal restriction fragment analysis was used to compare telomere length in homozygous mutants, heterozygous mutants and wild-type littermates. Contrary to expectation, we did not detect overall lengthening in the mutants, raising questions about the role of epigenetic processes in telomere length in vivo. PMID- 21553028 TI - Mycotoxin detection in urine samples from patients with chronic kidney disease of uncertain etiology in Sri Lanka. AB - This was a screening study that aimed to determine the presence of nephrotoxic mycotoxins in urine samples from patients with chronic kidney disease of uncertain etiology in the North Central Province of Sri Lanka. The percentage detection of aflatoxins, ochratoxins and fumonisins in 31 patients were 61.29%, 93.5% and 19.4%, respectively. Geometric means of urinary aflatoxins and ochratoxins were 30.93 creatinine and 34.62 ng/g creatinine in chronic kidney disease of uncertain etiology stage 1-2 patients and 84.12 ng/g creatinine and 63.52 ng/g creatinine in unaffected relatives of patients. In chronic kidney disease of uncertain etiology stage 3-5 patients, geometric means of urinary aflatoxins and ochratoxins were 10.40 and 17.08 ng/g creatinine, respectively. Non-affected relatives of patients (n = 6) had comparable levels of these mycotoxins, but healthy Japanese individuals (n = 4) had lower levels than in Sri Lanka. The higher detection rate of urinary ochratoxins in Sri Lankans indicates that exposure is common in the region. PMID- 21553029 TI - Fate of chlortetracycline in Korean arable soil. AB - The widespread use of the pharmaceutical chlortetracycline to treat human and animal infectious diseases is raising concern in Korea regarding the potential development of antibiotic-resistant bacteria. This study investigated the fate of chlortetracycline in Korean arable soils, to assess its environmental impact. The estimated half-life of chlortetracycline was 26.70-27.17 days indoors and 18.63 30.16 days outdoors. The chlortetracycline epimers and metabolites, 4 epichlortetracycline and 4-epi-anydrochlotetracycline were determined using liquid chromatography tandem mass spectroscopy. The respective concentrations of 4-epi-anydrochlotetracycline and 4-epichlortetracycline were 1.91%-9.71% and 11.12%-23.92% of the total chlortetracycline residual concentration indoors and 2.96%-11.44% and 17.61%-40.73% outdoors. PMID- 21553030 TI - Mobility of veterinary drugs in soil with application of manure compost. AB - Sulfonamides and tetracyclines are pharmaceuticals widely used to treat human and animal diseases. They are of considerable concern in Korea because of the potential risk of residues in aquatic and terrestrial environments. This study investigated the mobility of veterinary drugs in the soil column with the application of manure compost to assess the risk of groundwater contamination by leaching in the Korean agricultural environment. The degree of sulfonamides and tetracyclines mobility, measured by the concentration of leachates from silty loam soil for 9 days, was observed being on the first day of this study, in the order sulfathiazole, sulfamethazine > sulfamethoxazole > chlortetracycline > oxytetracycline, and the sulfonamides concentrations were about ten times higher than the tetracyclines concentrations with continuous leaching. The results indicate that sulfonamides pose a high risk of ground and surface water contamination and tetracyclines have the potential to persist in soils with bioactive epimers. PMID- 21553031 TI - Assessment of multi-gate interceptors equipped with baffles in contaminated aquifers. AB - Funnel-and-gate structures with three gates, two funnels (collinear with gates), and two perpendicular flow-directing vanes (baffles) were assessed for capturing contaminated groundwater in a hypothetical unconfined aquifer. Simulated structures, anchored into an underlying aquiclude, were 35 m wide. One 5-m wide gate occupied the center, and two 3-m wide gates occupied the ends, of each structure. Both homogeneous and heterogeneous (with respect to hydraulic conductivity) aquifers were modeled, with baffles at various positions along funnels in alternative configurations. A contaminant transport model, accounting for advection and hydrodynamic dispersion, tested the capability of various structures for capturing contaminant plumes. Based upon modeling results: (1) structures with baffles performed up to 17% better (homogeneous case), but also up to 48% worse (heterogeneous case), than structures without them; (2) the most effective baffles generally occupied interior portions of funnels; and (3) small (1-m) shifts in the locations of baffles resulted in up to a 33% increase (homogeneous case) in remediation timeframe. PMID- 21553033 TI - Evaluation of Cu potential bioavailability changes upon coastal sediment resuspension: an example on how to improve the assessment of sediment dredging environmental risks. AB - PURPOSE: Metal bioavailability-based sediment quality analysis, inferred from geochemical partitioning data, may contribute to improve sediment management policies. This is important because decision-making processes should not give similar priorities to sediments offering contrasting environmental risks associated to metal bioavailability. However, current uses of Sediment Quality Guidelines (SQGs) as interpretive tools to support decisions about dredging related activities have not considered the changes in metal bioavailability upon sediment resuspension. METHODS: Sediments from a Cu-contaminated site in Guanabara Bay (Brazil) were submitted to 16-h resuspension experiments in estuarine water to assess the susceptibility of Cu mobilization to the dissolved phase and alteration in the solid phase partitioning between a potentially bioavailable (1 mol/l HCl-extractable) phase and concentrated HNO(3)-extractable phase. RESULTS: After sediment resuspensions, dissolved Cu levels became slightly lower (in a surface water-resuspension treatment) or slightly higher (in a bottom water-resuspension treatment). In both treatments, the 1 mol/l HCl-extractable solid phase concentrations changed from seven times lower to two times higher values than an SQG adopted in Brazilian legislation. This change was explained by a transition from concentrated HNO(3)-extractable phases to reactive HCl extractable phases upon resuspension. CONCLUSIONS: An evaluation of metal susceptibility to present geochemical partitioning changes, as can be inferred from HCl-extractable fraction analyses before and after resuspension experiments, is recommended as an additional criterion to assess environmental risks of sediment dredging in relation to resuspension-sensitive metals, such as Cu. PMID- 21553032 TI - Inhibition of renin-angiotensin system (RAS) reduces ventricular tachycardia risk by altering connexin43. AB - Renin-angiotensin system (RAS) activation is associated with arrhythmias. We investigated the effects of RAS inhibition in cardiac-specific angiotensin converting enzyme (ACE) overexpression (ACE 8/8) mice, which exhibit proclivity to ventricular tachycardia (VT) and sudden death because of reduced connexin43 (Cx43). ACE 8/8 mice were treated with an ACE inhibitor (captopril) or an angiotensin receptor type-1 blocker (losartan). Subsequently, electrophysiological studies were performed, and the hearts were extracted for Cx43 quantification using immunoblotting, immunohistochemistry, fluorescent dye spread method, and sodium current quantification using whole cell patch clamping. VT was induced in 12.5% of captopril-treated ACE 8/8 and in 28.6% of losartan treated mice compared to 87.5% of untreated mice (P < 0.01). Losartan and captopril treatment increased total Cx43 2.4-fold (P = 0.01) and the Cx43 phosphorylation ratio 2.3-fold (P = 0.005). Treatment was associated with a recovery of gap junctional conductance. Survival in treated mice improved to 0.78 at 10 weeks (95% confidence interval 0.64 to 0.92), compared to the expected survival of less than 0.50. In a model of RAS activation, arrhythmic risk was correlated with reduced Cx43 amount and phosphorylation. RAS inhibition resulted in increased total and phosphorylated Cx43, decreased VT inducibility, and improved survival. PMID- 21553034 TI - Levels and patterns of polycyclic aromatic hydrocarbons (PAHs) in soils after forest fires in South Korea. AB - INTRODUCTION: To investigate the influence of biomass burning on the levels of polycyclic aromatic hydrocarbons (PAHs) in soils, temporal trends and profiles of 16 US Environmental Protection Agency priority PAHs were studied in soil and ash samples collected 1, 5, and 9 months after forest fires in South Korea. RESULTS AND DISCUSSION: The levels of PAHs in the burnt soils 1 month after the forest fires (mean, 1,200 ng/g dry weight) were comparable with those of contaminated urban soils. However, 5 and 9 months after the forest fires, these levels decreased considerably to those of general forest soils (206 and 302 ng/g, respectively). The burnt soils and ash were characterized by higher levels of light PAHs with two to four rings, reflecting direct emissions from biomass burning. Five and 9 months after the forest fires, the presence of naphthalene decreased considerably, which indicates that light PAHs were rapidly volatilized or degraded from the burnt soils. CONCLUSION: The temporal trend and pattern of PAHs clearly suggests that soils in the forest-fire region can be contaminated by PAHs directly emitted from biomass burning. However, the fire-affected soils can return to the pre-fire conditions over time through the washout and wind dissipation of the ash with high content of PAHs as well as vaporization or degradation of light PAHs. PMID- 21553035 TI - Detection of human-induced environmental disturbances in a show cave. AB - PURPOSE: We investigated the effects of human-induced disruption in a subterranean stable environment containing valuable Palaeolithic paintings and engravings (Ardales Cave, Southern Spain) using a double analytical approach. METHODS: An environmental monitoring system was installed in the cave to record temperature, relative humidity, carbon dioxide (CO(2)) and radon ((222)Rn) concentrations in air. In the same stations, an aerobiological sampling was conducted to quantify the level of airborne microorganisms. RESULTS: The combination of different methods allowed us to detect the extent of human-induced changes, confirming that these can be very hazardous in certain cave areas that should be apparently outside the scope of human disturbances, either by their remoteness to the visitor entrance or by being briefly visited. CONCLUSIONS: The detection of evident anomalies in the environmental parameters and airborne microorganism concentration in the cave area housing the high density of paintings and engravings helps to control human disturbances and supports the direct application of this double approach for cave management purposes. PMID- 21553036 TI - Wet air oxidation and catalytic wet air oxidation for dyes degradation. AB - BACKGROUND, AIM, AND SCOPE: Textile industry produces wastewater which contributes to water pollution since it utilizes a lot of chemicals. Preliminary studies show that the wastewater from textile industries contains grease, wax, surfactant, and dyes. The objective of this study was to determine the treatment efficiency of the nickel catalysts supported on hydrotalcites in three-dye model compounds and two types of wastewater. MATERIALS AND METHODS: Hydrotalcites were employed to prepare supported nickel catalysts by wetness impregnation technique. Metal loadings from 1 to 10 wt% were tested. Catalysts were characterized by several techniques. They were tested in a catalytic wet air oxidation of three dyes and two wastewaters with different origins. RESULTS AND DISCUSSION: It could be observed that the higher the metal content, the lower the BET area, possibly due to sintering of Ni and the consequent blocking of the pores by the metal. In addition, metallic dispersion was also higher when the metal content was lower. Dye conversion was more than 95% for every catalyst showing no differences with the nickel content. A high degree of dye conversion was achieved. Wet air oxidation (WAO) and catalytic wet air oxidation (CWAO) processes have been proved to be extremely efficient in TOC removal for wastewaters. CONCLUSIONS: The CWAO process can be used to remove dyes from wastewater. Three different dyes were tested showing satisfactory results in all of them. TOC degradation and dye removal in the presence of the catalyst were effective. Also, the HTNi catalyst is very active for organic matter and toxicity removal in wastewaters. PMID- 21553037 TI - Caliceal diverticulum in pediatric patients: the spectrum of imaging findings. AB - BACKGROUND: Caliceal diverticulum (CD) is uncommon in children. As compared to adults, most children with CD are symptomatic. Common complications include stone formation and infection. Correct diagnosis of CD is important for guiding management. OBJECTIVE: To identify imaging findings at diagnosis and follow-up in pediatric patients with CD. MATERIALS AND METHODS: We identified all patients from 2003 to 2010 with a diagnosis of CD. We reviewed presenting symptoms, underlying diseases, complications, management, and all pertinent radiological examinations. RESULTS: Twenty-four patients (2.6 to 18.5 years old, 11 females) had CD. Urinary tract infection was the most common (n = 8) presentation. Diagnosis of CD was based on delayed post-contrast CT in 79% of patients with only one false-negative CT. Most patients (n = 20) had a single CD; others had either 2 CDs (n = 2) or multiple CDs (n = 2). CD diameter ranged from 1.0 to 18.3 cm and grew in five of nine patients who had follow-up studies. Seven patients developed stone in the CD. Fifteen patients (63%) underwent a surgical procedure. CONCLUSIONS: CD is commonly solitary, often grows with time and may mimic other diagnoses, including simple cyst, complex cyst and polycystic kidney disease. Delayed postcontrast CT is highly sensitive in diagnosing CD. PMID- 21553038 TI - Functional hepatobiliary MR imaging in children. AB - BACKGROUND: Clinical application efforts for the hepatocyte-specific MRI contrast agent gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) have mainly been directed toward detection and characterization of various hepatic masses in the adult population. OBJECTIVE: Here we report our initial experience with Gd-EOB-DTPA for evaluating congenital and acquired hepatobiliary pathologies in the pediatric population. MATERIALS AND METHODS: Twenty-one consecutive children receiving Gd-EOB-DTPA for functional hepatobiliary evaluation at our institution were retrospectively identified with IRB approval. The use of Gd-EOB-DTPA was classified in each case as definite, potential, or no clinical utility, focusing on the clinical value gained beyond traditional noncontrast fluid-sensitive MR cholangiopancreatography (FS-MRCP) and other imaging modalities. RESULTS: Definite added value of Gd-EOB-DTPA was found in 12 patients, with potential value in 4 patients, and no value in 5 patients. Benefit was seen in cases of iatrogenic and non-iatrogenic biliary strictures, perihepatic fluid collections for biliary leak, hepatobiliary dysfunction in the absence of hyperbilirubinemia, and in the functional exclusion of cystic duct occlusion that can be seen in acute cholecystitis. CONCLUSION: This is the first reported series of children with Gd-EOB-DTPA and this early work suggests potential pediatric applications. PMID- 21553039 TI - Paediatric radiology seen from Africa. Part II: recognising research advantages in a developing country. AB - Radiologists in developing countries cite numerous reasons for poor research output including heavier workloads, poor remuneration (resulting in "brain drain"), poor infrastructure, language barriers, lack of modern imaging equipment, and a disease spectrum that may be of little interest to journals and readers in the developed world. On the other hand, large populations of patients suffering from distinctive diseases, cost-effective healthcare systems, and a set up with highly centralised tertiary referral hospitals, may be seen as advantages to those willing to tap into this as a data source for research. The lack of resources may even stimulate cost-effective innovations relevant to the needs of poor communities. This paper challenges preconceived ideas and identifies advantages for radiologists in developing countries to producing good research and publications. It also cautions against "annexation of sites" by stakeholders from developed countries, and suggests simple solutions to maximise research output without a significant financial cost. PMID- 21553040 TI - Relationship between the clinical characteristics of osteomyelitis and the finding of extraosseous fat on MRI in pediatric patients. AB - BACKGROUND: MRI is frequently utilized to evaluate patients for osteomyelitis. The findings of intramedullary and extramedullary fat globules as well as extramedullary fat-fluid levels can help improve the specificity of MRI for this diagnosis. OBJECTIVE: To correlate these MRI findings with the clinical characteristics in children with osteomyelitis. MATERIALS AND METHODS: A retrospective electronic medical record search for pediatric patient charts from March 2004 to November 2009 that contained the word "osteomyelitis" in the "principal diagnosis" portion of the international classification of disease (ICD) billing code. Each electronic chart was reviewed. MRI examinations of selected children were reviewed by a pediatric radiologist, a general radiologist and a transitional year resident. RESULTS: A total of 10 patients/11 MRI studies were included. Five of the 11 had the MRI finding of extramedullary globular fat signal. There was a significantly increased likelihood of seeing this finding in children of pubertal or postpubertal age compared to those of prepubertal age (p < 0.05). CONCLUSION: This study provides evidence that the MRI finding of extramedullary fat globules in children with acute osteomyelitis is associated with the clinical characteristic of being within or above the age range for puberty. PMID- 21553041 TI - White hemithorax in children. AB - The aim of this pictorial review is to introduce the radiologist to the differential diagnosis of a white hemithorax in children, to provide significant information on the diagnostic work-up, and to promote radiation-free techniques whenever possible. There are many causes of white hemithorax in children and it can be due to a variety of chest disorders. In most cases, plain chest radiographs and ultrasound will suffice. However, additional information provided by, e.g., CT or MRI is sometimes required. PMID- 21553042 TI - Reinfection after two-stage revision for periprosthetic infection of total knee arthroplasty. AB - PURPOSE: Limited data exist regarding the long-term results or risk factors for failure after two-stage reimplantation for periprosthetic knee infection. The purpose of this retrospective review was to investigate infection-free implant survival and identify variables associated with reinfection after this procedure. Furthermore, a staging system was evaluated as a possible prognostic tool for patients undergoing two-stage reimplantation of infected total knee arthroplasty (TKA). METHODS: In this level II, retrospective prognostic study, 368 patients with infected TKA treated with a two-stage revision protocol at our institution between 1998 and 2006 were reviewed. Patients who developed recurrent infection and an equal number of patients randomly selected for the control group were analysed for risk factors associated with treatment failure. RESULTS: At the most recent follow-up, 58 (15.8%) patients had developed reinfection after the two stage reimplantation. The median time to reinfection was 1,303 days (3.6 years), with follow-up time ranging from six to 2,853 days (7.8 years). The strongest positive predictors of treatment failure included chronic lymphoedema [hazard ratio (HR) = 2.28, 95% confidence interval (CI) 1.16-4.48; p = 0.02),and revision between resection and definitive reimplantation (HR = 2.13, 95% CI 1.20-3.79; p = 0.01, whereas patients treated with intravenously administered Cefazolin had a significant reduction in recurrent infection rate (HR = 0.48, 95% CI 0.25-0.90; p = 0.02). CONCLUSIONS: Our findings should be of help in counselling patients regarding their prognosis when faced with two-stage exchange for infected TKA and provide a basis for future comparisons. PMID- 21553043 TI - Forty-five-degree or higher insertion angles are required to penetrate the opposite cortex in bicortical applications of Kirschner wires: an in vitro study on sheep bones. AB - PURPOSE: Slippage of the wires over the opposite cortex from the endosteal side is frequent and can lead to insufficient stability. This in vitro biomechanical study was planned to investigate the angle of wire insertion that leads to trans cortex perforation. METHODS: Long bones of sheep were cut longitudinally into two pieces and half bones were stabilised on a frame. Three orthopaedic surgeons performed the experiment using ten wires of four different diameters at two different drilling speeds. Each wire was introduced from the endosteal side at angles starting at 30 degrees in 5 degrees increments until perforation. When perforation was achieved, the angle was recorded. To determinate the critical angle of perforation, receiver operating characteristic (ROC) curve analyses was performed. Two-way factorial analysis of variance (ANOVA) and Kruskal-Wallis tests were used for statistical comparisons. RESULTS: Kirschner-wire insertion angles of >= 45 degrees provided perforation with a percentage of 83.9 %. Wire diameter, drilling speed and surgeon variables had no effect on perforation angles (p > 0.05). CONCLUSION: If preoperative evaluation of fractures to be fixed by K wires reveals the need for oblique wire insertion angle < 45 degrees , a standard trocar-tip K wire application would lead to slippage of the wire tip on the endosteal surface of the opposite cortex. According to this study, the operative plan should be changed if such obliquity of the K wire is mandatory during bicortical applications. PMID- 21553045 TI - Response to osmotic stress and temperature of the fungus Ustilago maydis. AB - Ustilago maydis is a fungal pathogen which is exposed during its life cycle to both abiotic and biotic stresses before and after the infection of maize. To cope with extreme environmental changes, microorganisms usually accumulate the disaccharide trehalose. We have investigated both the accumulation of trehalose and the activity of trehalase during the adaptation of U. maydis haploid cells to thermal, sorbitol, and NaCl stresses. Sorbitol and sodium chloride induced sustained accumulation of trehalose, while a transient increase was observed under heat stress. Sorbitol stressed cells showed higher trehalase activity compared with control cells and to those stressed by NaCl and high temperature. Addition of cycloheximide, a protein synthesis inhibitor, did not affect the trehalose accumulation during the first 15 min, but basal levels of trehalose were reached after the second period of 15 min. The proteomic analysis of the response of U. maydis to temperature, sorbitol, and salt stresses indicated a complex pattern which highlights the change of 18 proteins involved in carbohydrate and amino acid metabolism, protein folding, redox regulation, ion homeostasis, and stress response. We hypothesize that trehalose accumulation during sorbitol stress in U. maydis might be related to the adaptation of this organism during plant infection. PMID- 21553044 TI - Screening and treatment in developmental dysplasia of the hip-where do we go from here? AB - PURPOSE: Developmental dysplasia of the hip (DDH) is a leading cause of disability in childhood and early adult life. Clinical and sonographic screening programmes have been used to facilitate early detection but the effectiveness of both screening strategies is unproven. This article discusses the role for screening in DDH and provides an evidence-based review for early management of cases detected by such screening programmes. METHODS: We performed a literature review using the key words 'hip dysplasia,' 'screening,' 'ultrasound,' and 'treatment.' RESULTS: The screening method of choice and its effectiveness in DDH still needs to be established although it seems essential that screening tests are performed by trained and competent examiners. There is no level 1 evidence to advise on the role of abduction splinting in DDH although clinicians feel strongly that hip instability does improve with such a treatment regime. The definition of what constitutes a pathological dysplasia and when this requires treatment is also poorly understood. CONCLUSION: Further research needs to establish whether early splintage of clinically stable but sonographically dysplastic hips affects future risk of late-presenting dysplasia/dislocation and osteoarthritis. There is a need for high quality studies in the future if these questions are to be answered. PMID- 21553046 TI - Should we screen for hereditary hemochromatosis in healthy Lebanese: a pilot study. AB - Hereditary hemochromatosis (HHC) is a genetic disorder of iron metabolism characterized by abnormal accumulation of iron that may lead to organ damage and death. Diagnosis is usually based on various genetic and phenotypic criteria. The study goals were to perform mutation analysis for 18 different mutations associated with HHC in healthy Lebanese, determine their allele frequency, and compare iron-overload status in identified carriers versus those found to be wild type for mutations analyzed. 116 healthy adults (59 males and 57 females) underwent DNA testing for 18 different HHC mutations, and biochemical testing for percent transferrin saturation (%TS) and ferritin. C282Y mutation was not detected. Only H63D mutation (rs1799945) was found with an overall carrier frequency of 25.8% (24.1% heterozygous and 1.7% homozygous). %TS and ferritin differed significantly between genders. %TS and ferritin were significantly higher in males with H63D mutation when compared to males with wild-type (P=0.001, 0.019; respectively); but not in females. The proportion of subjects with increased %TS and serum ferritin was not statistically different between those with H63D mutation and the wild-type in either gender. In addition, none of the subjects had concurrent increase in %TS and ferritin. In conclusion, the H63D carrier frequency in healthy Lebanese is comparable to other populations in the region, and it does not result in significant biochemical iron overload. Moreover, in the absence of the C282Y mutation, genetic screening for HHC is not recommended according to this preliminary study in healthy Lebanese. PMID- 21553047 TI - Characterization of Malaysian Trichoderma isolates using random amplified microsatellites (RAMS). AB - Trichoderma species are commercially applied as biocontrol agents against numerous plant pathogenic fungi due to their production of antifungal metabolites, competition for nutrients and space, and mycoparasitism. However, currently the identification of Trichoderma species from throughout the world based on micro-morphological descriptions is tedious and prone to error. The correct identification of Trichoderma species is important as several traits are species-specific. The Random Amplified Microsatellites (RAMS) analysis done using five primers in this study showed different degrees of the genetic similarity among 42 isolates of this genus. The genetic similarity values were found to be in the range of 12.50-85.11% based on a total of 76 bands scored in the Trichoderma isolates. Of these 76 bands, 96.05% were polymorphic, 3.95% were monomorphic and 16% were exclusive bands. Two bands (250 bp and 200 bp) produced by primer LR-5 and one band (250 bp) by primer P1A were present in all the Trichoderma isolates collected from healthy and infected oil palm plantation soils. Cluster analysis based on UPGMA of the RAMS marker data showed that T. harzianum, T. virens and T. longibrachiatum isolates were grouped into different clades and lineages. In this study we found that although T. aureoviride isolates were morphologically different when compared to T. harzianum isolates, the UPGMA cluster analysis showed that the majority isolates of T. aureoviride (seven from nine) were closely related to the isolates of T. harzianum. PMID- 21553048 TI - Analysis of XPD genetic polymorphisms of esophageal squamous cell carcinoma in a population of Yili Prefecture, in Xinjiang, China. AB - To evaluate the association with genetic polymorphisms in Xeroderma pigmentosum complementation group D (XPD) gene of esophageal squamous cell carcinoma (ESCC) risk in a population of Yili Prefecture, in Xinjiang, China. A hospital-based case-control study was designed with 571 samples including 213 ESCC patients and 358 controls with age, gender and ethnicity-matched subjects (Kazakh, Uygur and Han ethnic). Genotypes were determined by PCR restriction fragment length polymorphism (PCR-RLFP) and confirmed by sequence. Relative risk associated with a particular genotype was estimated by calculating odds ratios (OR) along with 95% confidence intervals (CI). Significant ESCC risk was observed for XPD Lys751Gln (rs13181) frequency of presence C allele (OR: 1.409, 95% CI: 1.005 1.976) in the three ethnics. XPD Asp312Asn (rs1799793) of Han ethnic was associated with a borderline decrease of ESCC (OR: 0.362, 95% CI: 0.145-0.906), however, it was associated with ESCC risk in Uygur ethnic (OR: 2.403, 95% CI: 1.087-5.310). The results demonstrated an association between the XPD Lys751Gln (rs13181) for frequency of presence C allele and risk for ESCC in the three ethnics of Yili Prefecture, in Xinjiang, China. XPD Asp312Asn (rs1799793), which was associated with a borderline decrease of Han ethnic and risk of Uygur ethnic of ESCC, may play a different role in the three ethnics of ESCC. PMID- 21553049 TI - Inhibition of high glucose-induced VEGF and ICAM-1 expression in human retinal pigment epithelium cells by targeting ILK with small interference RNA. AB - The aim of this study was to investigate the change of Integrin-linked kinase (ILK) expression of human retinal pigment epithelium (RPE) cells in response to high glucose, and the effect of targeting ILK with small interference RNA (siRNA) on the high glucose-induced expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1). The ILK mRNA and protein expression in human RPE cells were analyzed with RT-PCR and western blot after exposure to 5.5, 30, 40, 50 mM glucose, or 5.5 mM glucose+45.5 mM mannitol for 48 h. The expression of VEGF and ICAM-1 was also determined. Cells were treated with ILK siRNA, to determine the effect of ILK on VEGF and ICAM-1 expression following treatment with high glucose. High concentrations of glucose significantly up regulated ILK mRNA and protein expression, and the ILK expression increased along with the glucose concentration. The changes of VEGF and ICAM-1 expression were similar to that of ILK expression. Knocking down ILK gene expression with siRNA inhibited the elevation of VEGF and ICAM-1 induced by high glucose treatment. These results suggested that ILK was involved in the response of RPE cells to high glucose and may therefore play a role in the pathogenesis of diabetic ophthalmology. PMID- 21553050 TI - CYP2E1 Rsa I/Pst I polymorphism contributes to oral cancer susceptibility: a meta analysis. AB - Previous data on association between CYP2E1 Rsa I/Pst I polymorphism and oral cancer risk were controversial. To investigate the association between CYP2E1 Rsa I/Pst I polymorphism and oral cancer risk. We performed a meta-analysis to assess the relationship between oral cancer and genotype with English language until June 2010. Twelve published case-control studies of 1259 patients with oral cancer and 2262 controls were acquired. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association in codominant and dominant models. Overall, the pooled ORs indicated a significant association between CYP2E1 Rsa I/Pst I polymorphism and oral cancer risk (for c1/c2 vs. c1/c1: OR=1.30, 95% CI=1.04-1.62, Pheterogeneity=0.57; for (c1/c2+c2/c2) vs. c1/c1: OR=1.32, 95% CI=1.07-1.64, Pheterogeneity=0.57, respectively). In subgroup analysis by race, the same significant risks were found among Asian (for c1/c2 vs. c1/c1: OR=1.41, 95% CI=1.05-1.91, Pheterogeneity=0.92; for (c1/c2+c2/c2) vs. c1/c1: OR=1.43, 95% CI=1.08-1.88, Pheterogeneity=0.97, respectively). In conclusion, this meta-analysis demonstrates that CYP2E1 Rsa I/Pst I c2 allele may be a biomarker for oral cancer, especially among Asian populations. PMID- 21553051 TI - Comparative study on factors influencing the codon and amino acid usage in Lactobacillus sakei 23K and 13 other lactobacilli. AB - In this study, major factors shaping codon and amino acid usage variation Lactobacillus sakei 23K were investigated. It included 13 other Lactobacillus species for a comparative analysis. The correspondence analysis (COA) showed that in 13 species the major trend of synonymous codon usage was highly correlated with gene expression level as assessed by the "Codon Adaptation Index" (CAI) values. In addition, Nc (effective number of codons) plot, SCUO (synonymous codon usage order) plot and correlation analyses showed that the base composition and mutational bias have dominant role in the codon usage variation. However, the translational selection for genes at higher expression level, where more frequent synonymous codons correspond to more abundant cognate transfer RNAs (tRNAs), was not found to be similar in all species. The study also showed that the amino acid usage in these species was significantly (P<0.01) influenced by hydrophobicity and aromaticity of proteins. Furthermore, 24 codons that were found to be optimally used by L. sakei and its comparative study with 13 Lactobacillus species might provide some useful information in their further study of molecular evolution and genetic engineering. PMID- 21553052 TI - Prevalence of H1299R polymorphism in the Factor V gene among the Taif-Saudi Arabia population using polymerase chain reaction-reverse hybridization technique. AB - Cardiovascular disease (CVD) remains a major health hazard worldwide. Single nucleotide polymorphisms (SNPs) represent a part of risk factors that contributes to cardiovascular disease. SNP in the coagulation factor V genes have been shown to play a role in the development of cardiovascular disease. Coagulation Factor V is an enzyme cofactor of the coagulation system and contributes to a normal haemostatic balance. The His1299Arg polymorphism in the Factor V gene has been identified and linked to hereditary thrombophilia. The aim of the present study is to determine the prevalence of HR2 haplotype and allele frequency of His1299Arg polymorphism in the Factor V gene among randomly selected healthy individuals from Taif population which belonging to western region of Saudi Arabia. Genotyping of this SNP was carried out via CVD StripAssay, which based on a polymerase chain reaction-reverse hybridization technique. Two hundred healthy unrelated individuals were included in the study. Seventeen out of the studied population (8.5%) had the HR2 haplotype; 14 (7%) were heterozygous (R1/R2), and three (1.5%) were homozygous (R2/R2), with an allelic frequency of 0.05. This is the first report for a Saudi Arabian population that estimates the prevalence of HR2 haplotype and its allele frequencies. In conclusion, the His1299Arg mutant was noticeable within population of western Saudi Arabia. Further larger studies are needed to (1) estimate the prevalence of this mutant among individuals belonging to different KSA locations (2) assess the relative contribution of this mutational event separately and in combination with other thrombophilic polymorphisms in the etiology of cardiovascular disease in KSA. PMID- 21553053 TI - The determination of relationship between "excision repair cross-complementing group 1" (ERCC1) gene T19007C and C8092A single nucleotide polymorphisms and clinicopathological parameters in non-small cell lung cancer. AB - DNA repair plays a key role in prevention of carcinogenesis and one of the most important DNA repair mechanisms is nucleotide excision repair (NER) pathway. This pathway includes a number of genes such as excision repair cross-complementing group 1 (ERCC1) gene which are responsible for the 5' incision of damaged DNA. A reduced DNA repair capacity associated with ERCC1 mRNA level has been observed in lung carcinogenesis. Two single nucleotide polymorphisms (SNPs) in ERCC1 gene, T19007C (rs11615) and C8092A (rs3212986), reportedly predict to affect the mRNA of ERCC1 in non-small cell lung cancer (NSCLC). To examine the role of two common SNPs in ERCC1 gene further, we conducted this study where 80 cases histopatologically diagnosed as NSCLC were genotyped. Genomic DNA was extracted from formalin-fixed, paraffin embedded tissues and two SNPs were analyzed using real-time PCR. The distributions of TT, TC, and CC genotypes of the T19007C SNP were 40, 44 and 16%, respectively. Significantly increased frequency of the patients carrying at least one 19007C allele was observed in early stage compared to advanced stage (P=0.002). And also, the frequency of TC and CC genotypes significantly increased in younger patients compared to older patients (P=0.035). Regarding C8092A SNP, the distribution of CC, CA, and AA genotypes was 38, 51 and 11%, respectively. There was no significant difference in the genotype distribution between C8092A SNP and clinicopathological parameters. This study indicated that harboring at least one 19007C allele may have protective effect in NSCLC. PMID- 21553054 TI - Expression of ERCC1 and its clinicopathological correlations in non-small cell lung cancer. AB - Excision Repair Cross-Complementing Group 1 (ERCC1) is an important DNA repair gene, playing critical role in nucleotide excision repair pathway and having a significant influence on genomic instability. Some studies support that ERCC1 might be a potential predictive and prognostic marker in non-small cell lung cancer (NSCLC). ERCC1 has also been shown to be a promising biomarker in NSCLC treated with a cisplatin-based regimen. Therefore, the determination of ERCC1 expression at DNA, mRNA and protein level in different stages of NSCLC is still an important topic in the cancer. Ninety-one formalin-fixed paraffin-embedded tumor samples histopathologically diagnosed as NSCLC were examined in this study. ERCC1 expression at protein level were scored by immunohistochemistry. The gene amplification and mRNA expression levels for ERCC1 were determined by real-time quantitative PCR. There was complete concordance among the three methods in 39 tumor samples (42.9%). A strong correlation was found between DNA amplification and mRNA expression (r=0.662) while there was no correlation between mRNA and protein assessment for ERCC1 expression (r=-0.013). ERCC1 expression at mRNA and DNA level (63.1 and 84.2%, respectively) in tumors at stage III was higher than at the other stages. In contrast, the protein expression at stage II and III (56.6 and 52.6%, respectively) of NSCLC was lower than that of tumors with stage I NSCLC. These results show that the mechanism by which ERCC1 expression might play a role in tumor behavior. This study was also confirmed that the appropriate validation and qualification in methods used for ERCC1 status were needed before its clinical application and implementation. PMID- 21553055 TI - CTLA-4 and TNF-alpha promoter-308 A/G polymorphisms and ANCA-associated vasculitis susceptibility: a meta-analysis. AB - The aim of this study was to explore whether the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) or tumor necrosis factor-alpha (TNF-alpha) polymorphisms contribute to anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) susceptibility. The authors conducted a meta-analysis on associations between polymorphisms of the 3' untranslated region (UTR) microsatellite at exon 3, exon 4 CT60 (A/G), exon 1 +49 (A/G), and promoter -318 (C/T) of CTLA-4, and TNF-alpha promoter-308 (A/G) and AAV susceptibility as determined using; (1) allelic contrast and (2) homozygote contrast, (3) recessive, and (4) dominant models. A total of 11 comparisons were considered in this meta-analysis. These studies encompassed 7 CTLA-4 studies and 4 TNF-alpha studies in 10 European populations and 1 Asian population. The (AT)n repeat polymorphisms of CTLA-4 were found to be significantly associated with AAV in European populations (OR of 86 vs. xx allele=0.402, 95% CI=0.184-0.875, P=0.022). The one study conducted on this polymorphism in Asians showed no significant association with AAV. Meta-analysis of the 86/86 (recessive effect), 86/86 and 86/xx (dominant effect), and 86/86 vs. xx/xx (homozygote contrast) of the (AT)n repeat revealed a significant association with AAV in Europeans. Both the CTLA-4 CT60 and +49 polymorphisms were found to be significantly associated with AAV in European populations, and allele and genotype-based analyses showed a significant association between the CTLA-4 CT60 and +49 polymorphisms with AAV in Europeans (OR of the A allele of CT60=0.769, 95% CI=0.619-0.017, P=0.035; OR of the T allele of +49=1.382, 95% CI=1.147-1.664, P=0.001, respectively). Meta-analysis of the CTLA-4 -318 polymorphism failed to identify any association with AAV. Furthermore, meta-analysis of the AA genotype, the AA and AG genotypes, and the A allele of TNF-alpha failed to reveal any association with Wegener's granulomatosis (WG). This meta-analysis demonstrates that the CTLA-4 polymorphisms confer susceptibility to AAV in Europeans. In contrast, no association was found between the TNF-alpha-308 polymorphism and susceptibility to WG in Europeans. PMID- 21553056 TI - Simvastatin augments the efficacy of therapeutic angiogenesis induced by bone marrow-derived mesenchymal stem cells in a murine model of hindlimb ischemia. AB - Many studies showed beneficial effects of either statin or bone marrow-derived mesenchymal stem cells (MSC) treatment in ischemic disease. In an attempt to further improve postischemic tissue repair, we investigated the effect of a local administration of MSC, in the presence or not of low-dose simvastatin, on angiogenesis and functional recovery in a mouse model of hindlimb ischemia. In vitro, the proliferation, migration, apoptosis, and tube formation of bone marrow MSC derived from transgenic mice expressing green fluorescent protein (GFP) were detected in the presence or not of 0.01 MUmol/l simvastatin, respectively. In vivo, immediately after hindlimb ischemia, the mice were divided into four groups, namely control, MSC, statin, and statin-MSC, and received a single local injection of MSC (2*10(6) cells) and/or a repeated gavages' administration of simvastatin (0.2 mg/kg) for 21 days. The blood flow was measured by laser Doppler imaging, the capillary density was detected by alkaline phosphatase staining and, the MSC differentiation was assessed by immunofluorescent staining at 21 days after the ischemia. In vitro, the MSC proliferation rate, migration ability and tube formation number were increased significantly in simvastatin group relative to control group. Whereas, the H2O2 induced-apoptosis was inhibited significantly in simvastatin group relative to control group. In vivo, hindlimb blood reperfusion was significantly improved (MSC 0.55+/-0.08, statin 0.57+/-0.05, vs. control 0.47+/-0.07, P<0.05) and capillary density was obviously higher at day 21 post-ischemia by Laser Doppler Imaging in the MSC group and the Statin group when compared with control group. The combined use of statin and MSC further improved revascularization (perfusion ratio of 0.70+/-0.09; P<0.001 verse other groups) and resulted in the highest capillary density (P<0.05 vs. all other groups). GFP labeled transplanted cells were more frequently observed in the Statin-MSC group than in the MSC group (6.8+/-0.5-3.1+/-0.7, P<0.05). Low-dose simvastatin could act in a synergistic way with MSC to potentiate the functional neovascularization in a mouse model of hind limb ischemia. PMID- 21553057 TI - Caudatin induces cell cycle arrest and caspase-dependent apoptosis in HepG2 cell. AB - In the present study, we investigate the anti-cancer activity and mechanism of caudatin, the C-21 steroidal glycosides, on human hepatoma cell line HepG2. The MTT assay and flow cytometry were used to evaluate HepG2 cell proliferation and cell cycle. Annexin-V/PI and DAPI staining were used to investigate cell apoptosis. Western blotting analysis was used to evaluate the expression levels of proteins. It is found that caudatin inhibits HepG2 cell growth and induces of G0/G1 phase arrest in a dose dependent manner, which is associated with a decreased in the expression of cyclinD1 and increased the levels of p21 and p53. HepG2 cells dealing with caudatin showed typical characteristics of apoptosis. Western blotting analysis indicated that the levels of Bcl-2 were down-regulated after caudatin treatment, whereas the expression of Bax was up-regulated. Furthermore, caudatin-induced apoptosis was accompanied by activation of caspase 3, -9, and poly(ADP-Ribose) Polymerase (PARP). Treatment with caudatin also induced phosphorylation of extracellular-signal regulating kinase (ERK) and c-Jun N-terminal kinase (JNK). These results demonstrate that caudatin inhibits cell proliferation via DNA synthesis reduction and induces caspase-dependent apoptosis in HepG2 cell. Activation of ERK and JNK may be involved in caudatin-induced hepatoma cell apoptosis. PMID- 21553058 TI - Can metal nanoparticles be a threat to microbial decomposers of plant litter in streams? AB - The extensive use of nanometal-based products increases the chance of their release into aquatic environments, raising the question whether they can pose a risk to aquatic biota and the associated ecological processes. Aquatic microbes, namely fungi and bacteria, play a key role in forested streams by decomposing plant litter from terrestrial vegetation. Here, we investigated the effects of nanocopper oxide and nanosilver on leaf litter decomposition by aquatic microbes, and the results were compared with the impacts of their ionic precursors. Alder leaves were immersed in a stream of Northwest Portugal to allow microbial colonization before being exposed in microcosms to increased nominal concentrations of nanometals (CuO, 100, 200 and 500 ppm; Ag, 100 and 300 ppm) and ionic metals (Cu(2+) in CuCl(2), 10, 20 and 30 ppm; Ag(+) in AgNO(3), 5 and 20 ppm) for 21 days. Results showed that rates of leaf decomposition decreased with exposure to nano- and ionic metals. Nano- and ionic metals inhibited bacterial biomass (from 68.6% to 96.5% of control) more than fungal biomass (from 28.5% to 82.9% of control). The exposure to increased concentrations of nano- and ionic metals decreased fungal sporulation rates from 91.0% to 99.4%. These effects were accompanied by shifts in the structure of fungal and bacterial communities based on DNA fingerprints and fungal spore morphology. The impacts of metal nanoparticles on leaf decomposition by aquatic microbes were less pronounced compared to their ionic forms, despite metal ions were applied at one order of magnitude lower concentrations. Overall, results indicate that the increased release of nanometals to the environment may affect aquatic microbial communities with impacts on organic matter decomposition in streams. PMID- 21553059 TI - Cytoarchitectonic study of the brain of a dwarf snakehead, Channa gachua (Ham.). I. The telencephalon. AB - Cytoarchitectonic pattern of the telencephalon of a dwarf snakehead, Channa gachua, is studied by serial transverse sections of the brain (Kluver and Barrera staining). On the anteriormost extremity of the telencephalon, olfactory bulbs terminate that are sessile. The olfactory bulbs comprise four concentric layers, which from outside toward the center are olfactory nerve layer, a glomerular layer, mitral cell layer, and internal cell layer. Large terminal nerve ganglion cells are prominently visible in the dorsomedial position where the bulbs terminate on the telencephalon. In all, 24 nuclei are identified in the telencephalon on ventral and dorsal areas and are named according to their position. Ventral telencephalon exhibits 11 nuclei. On the dorsal telencephalon, there are 13 nuclei. These again are named according to their position on dorsal, ventral, median, lateral, or posterior part. This study reported for the first time in this fish will be useful in tracing the neuronal system of Channa gachua and subsequent studies of the functional aspects of these nuclei in the regulation of reproductive cycle of this species. PMID- 21553060 TI - Seasonal changes in atrophy-associated proteins of the sonic muscle in the big snout croaker, Johnius macrorhynus (Pisces, Sciaenidae), identified by using a proteomic approach. AB - In most sciaenids, males possess sonic muscles and produce sound through the contraction of these muscles and amplification of the swim bladder. The sonic muscles in some fishes exhibit seasonal changes in size. For example, they are hypertrophic in the spawning season, and atrophic in the non-spawning months. The protein profiles of the sonic muscle, red muscle, and white muscle in the Johnius macrorhynus were shown by two-dimensional electrophoresis (2-DE) and were compared to reveal differential protein expressions. About 80 up-regulated protein spots in the sonic muscle, and 30 spots related to six contractile proteins (fast muscle myosin heavy chain, skeletal alpha actin, alpha actin cardiac, tropomyosin, myosin light chain 2, and myosin light chain 3), four energy metabolic enzymes (enolase, acyl-CoA synthetase, creatine kinase, and cytochrome P450 monooxygenase), and two miscellaneous proteins (DEAD box protein and cyclin H) were identified. Seasonal hypertrophy and atrophy of the sonic muscles related to the reproductive cycle were verified in male big-snout croaker. The contents of some proteins were significantly different in the muscles under these conditions. The levels of cytochrome P450 monooxygenase, fast muscle myosin heavy chain, DEAD box proteins, isocitrate dehydrogenase, and creatine kinase were up-regulated in the hypertrophic muscle, but the levels of alpha actin cardiac, myosin light 2, and myosin light 3 were lower than in the atrophic muscle. Potential reasons for these differences in protein expression related to physiological adaptation are discussed. PMID- 21553061 TI - Effects of a diet lacking HUFA on lipid and fatty acid content of intestine and gills of male gilthead seabream (Sparus aurata L.) broodstock at different stages of the reproductive cycle. AB - A feeding experiment was carried out to determine the effect of a diet lacking n 3 and n-6 highly unsaturated fatty acids (HUFA) on lipid and fatty acid content in intestine and gills of male gilthead seabream (Sparus aurata L.) broodstock at different stages of the reproductive cycle: November (pre-spermatogenesis), March (spermatogenesis), and June (post-spermatogenesis). For this purpose, gilthead seabream broodstock were fed either a control diet (C) or an n-3 and n-6 HUFA deficient diet (D). The results showed no changes in fatty acid content of polar lipids of intestine and gills from fish fed diet C at different stages of the reproductive cycle. However, significant changes were observed in the fatty acid content of neutral lipids in intestine but not in gills in this group. Thus, between November and March, saturates and n-3 HUFA decreased while monoenes increased. In June, the contents of these fatty acids had returned to their initial values (November). Moreover, in fish fed diet D, the fatty acid content of neutral lipid changed in both intestine and gills. In intestine NL, a decrease in saturates and n-3 HUFA and an increment in monoenes were observed from November to June. In gills, a decrease was also observed in n-3 HUFA from NL along the cycle. Nevertheless, n-6 HUFA content remained unchanged. These results show both tissue specificity in seasonal mobilization of fatty acids linked to reproductive processes and the influence of dietary fatty acids on body composition. PMID- 21553062 TI - Effect of rapid temperature change on resting routine metabolic rates of two benthic elasmobranchs. AB - In this study, flow-through respirometry was used to test the effect of acute temperature change on resting routine metabolic rates of two benthic elasmobranchs, Atlantic stingrays, Dasyatis sabina (n = 7) and whitespotted bamboo sharks, Chiloscyllium plagiosum (n = 7) kept under fluctuating temperature regime of 24-27 and 23-25 degrees C, respectively. Atlantic stingrays and whitespotted bamboo sharks showed a temperature sensitivity (Q(10)) of 2.10 (21 31 degrees C) and 2.08 (20-28 degrees C), respectively. Not surprisingly, oxygen consumption (MO(2)) increased in both species as temperature was raised. Acute increases in oxygen uptake may be useful during activities such as foraging, and some elasmobranchs may alter physiological processes by taking advantage of thermal variability in the environment. However, further investigation of different physiological processes is needed to better understand how temperature variation may affect behavioural choices of fishes. PMID- 21553063 TI - Platelets, oxidative stress and preservation of the vascular endothelium: is it a matter of fat? PMID- 21553065 TI - Primary hyperparathyroidism revealed by gluten-free diet in a woman with celiac disease. PMID- 21553066 TI - Condition of depressive symptoms among Japanese dental students. AB - The Zung Self-Rating Depression Scale (SDS) is generally used to screen for the presence of depression. The purpose of this study was to investigate scores on the SDS, Japanese version, in undergraduates at Tsurumi University School of Dental Medicine in Yokohama, Japan. A total of 2,197 dental students completed the SDS from 2006 through 2008. The investigation took place each year over a 3 week period from June to July. When investigating, the Institutional Review Board at Tsurumi University approved the study. Students could voluntarily agree or decline to participate in the study, and all responses were provided anonymously. SDS scores by sex, class year, and change over time were analyzed. The mean SDS score ranged from 43.7 +/- 8.5 to 44.8 +/- 9.0 between 2006 and 2008. Women were significantly more depressed than men in 2007 and 2008. The SDS scores of the same students were high continuously for 2 years. "Diurnal variation," "personal devaluation," and "confusion" had the highest scores of the 20 individual items of the SDS. Of the participating students, 31.4-37.2% were classified as being moderately to severely depressed. Logistic regression analysis was used to compute the odds ratio for SDS scores of <=47 versus >=48. The item "suicidal rumination" had the highest chance of being associated with depressive symptoms in all 3 years. Although this research was limited to a single department of dentistry, it appears that dental students experience various levels of depression. Providing mental healthcare options to these students may be helpful. PMID- 21553067 TI - Dental anomalies in the primary dentition and their repetition in the permanent dentition: a diagnostic performance study. AB - This study investigated the recurrence in the permanent dentition of dental anomalies of the primary dentition. A sample of 189 subjects (100 males, 89 females, mean age of 5 years and 7 months) with anomalies of primary teeth (tooth hypodontia, supernumerary teeth, geminated teeth, and fused teeth) was selected and re-analyzed at a mean age of 11 years and 2 months for the recurrence of the dental anomalies in the permanent dentition. As a control group, 271 subjects (123 males, 148 females) without dental anomalies in the primary dentition were selected. The recurrence in the permanent dentition of the dental anomalies in the primary dentition was evaluated by measures of diagnostic performance. The results showed high values for the repetition of hypodontia (positive likelihood ratio = 102.0); low score for the repetition of hyperdontia (positive likelihood ratio = 6.5); low positive likelihood ratio (9.1) for gemination of primary teeth resulting in supernumerary permanent teeth; high positive likelihood ratio (47.0) for fusion of primary teeth followed by missing permanent teeth. Dental anomalies in the primary dentition are associated with an increased likelihood of anomalies of the succedaneous permanent. PMID- 21553068 TI - Photomicrographic evaluation of the apical sealing capacity of three types of gutta-percha master cones: an in vitro study. AB - The purpose of this study was to compare the apical sealing capacity of three types of gutta-percha master cones of the same apical size and different tapers following root canal preparation with nickel-titanium ProTaper Universal rotary instruments and microstructural replication with System B and Obtura III. Thirty extracted human incisors having one single straight root canal (type I Weine) were instrumented with rotary ProTaper to an F3 (30/.09) and gauged to confirm a final apical size of #30. Teeth were divided into three groups (n = 10) to be obturated as follows: Group 1: master cone Meta 0.06 taper/AH Plus, Group 2: master cone fine-medium Autofit 0.08 taper/AH Plus, and Group 3: master cone ProTaper F3 0.09 taper/AH Plus. The chosen technique was the continuous wave of compaction (System B and Obtura III). Teeth were embedded in acrylic and incrementally reduced at 0.5 and 1.0 mm from the apical foramina in a grinding machine for metallographic samples. Sections were examined and digitally photographed under a metallographic optical microscope in normal and polarized light and the images were processed. The total cross-sectional area of the root canal, the gutta-percha/sealer/voids' areas were quantified for each sample and statistically compared using one-way ANOVA and Kruskal-Wallis tests. No statistically significant differences between groups were observed (P > 0.05); however, the mean percentage of the gutta-percha-filled area was slightly higher in Group 1 at both levels of observation. Despite different tapers, all the three types of cones provided a good sealing capacity in the last apical millimeter of the root canal, with good gutta-percha-sealer ratio and few or no voids. PMID- 21553069 TI - Nicorandil-induced tongue ulceration with or without fungal infection. AB - Oral ulceration is one of the common adverse effects of nicorandil in European countries. In Japan, however, only 9 cases of nicorandil-induced oral ulceration have been reported. Here, we report 3 cases of nicorandil-induced oral ulceration, one of which exhibited a unique clinical course associated with Candida infection. In this case, the initial discontinuation of nicorandil failed to ameliorate the lesion. However, the second discontinuation of the drug after the control of the Candida infection overlying the surface of the ulcer produced a favorable effect. This patient was diagnosed with nicorandil-induced tongue ulceration with Candida infection. PMID- 21553070 TI - Fluoride inhibits the response of bone cells to mechanical loading. AB - The response of bone cells to mechanical loading is mediated by the cytoskeleton. Since the bone anabolic agent fluoride disrupts the cytoskeleton, we investigated whether fluoride affects the response of bone cells to mechanical loading, and whether this is cytoskeleton mediated. The mechano-response of osteoblasts was assessed in vitro by measuring pulsating fluid flow-induced nitric oxide (NO) production. Osteocyte shape was determined in hamster mandibles in vivo as parameter of osteocyte mechanosensitivity. Pulsating fluid flow (0.7 +/- 0.3 Pa, 5 Hz) stimulated NO production by 8-fold within 5 min. NaF (10-50 MUM) inhibited pulsating fluid flow-stimulated NO production after 10 min, and decreased F-actin content by ~3-fold. Fluid flow-induced NO response was also inhibited after F actin disruption by cytochalasin B. NaF treatment resulted in more elongated, smaller osteocytes in interdental bone in vivo. Our results suggest that fluoride inhibits the mechano-response of bone cells, which might occur via cytoskeletal changes. Since decreased mechanosensitivity reduces bone mass, the reported anabolic effect of fluoride on bone mass in vivo is likely mediated by other factors than changed bone cell mechanosensitivity. PMID- 21553071 TI - Shear bond strength of rebonded brackets after removal of adhesives with Er,Cr:YSGG laser. AB - This study was conducted to examine the bond strength of rebonded orthodontic brackets after adhesive residuals on the surface of the bracket bases were removed by Er,Cr:YSGG lasers. Seventy-six brackets bonded to premolars with a self-etching primer adhesive system were equally divided into four groups after the first debonding with the bracket bases (Group 1) untreated, and treated by (Group 2) Er,Cr:YSGG laser, (Group 3) sandblaster, and (Group 4) Er,Cr:YSGG laser/sandblaster. The treated brackets were rebonded to the new premolars in the same manner as the first-stage experiment. The shear bond strengths were measured, with the bonding/debonding procedures repeated once after the first debonding, and the bracket/adhesive failure modes were evaluated after each debonding. The treated bracket base surfaces were observed under a scanning electron microscopy (SEM). The mean rebond strengths were significantly lower in group 1 than in other groups, and there were no significant differences between the other groups. The mean initial bond strength was significantly higher than the mean rebond strength in group 1 but there was no significant difference between the two in the other three groups. Failures at the bracket-adhesive interface occurred frequently at second debonding in group 1. Under the SEM, residual adhesive was removed from the bracket bases by Er,Cr:YSGG laser, while adhesive remnant was seen underneath the meshwork of the bracket bases and microroughness appeared on the meshwork after sandblasting. Er,Cr:YSGG laser certainly could serve the purpose of promoting the use of recycled orthodontic brackets. PMID- 21553072 TI - Dietary fish oil supplements increase tissue n-3 fatty acid composition and expression of delta-6 desaturase and elongase-2 in Jade Tiger hybrid abalone. AB - This study was conducted to investigate the effects of fish oil (FO) supplements on fatty acid composition and the expression of ?6 desaturase and elongase 2 genes in Jade Tiger abalone. Five test diets were formulated to contain 0.5, 1.0, 1.5, 2.0 and 2.5% of FO respectively, and the control diet was the normal commercial abalone diet with no additional FO supplement. The muscle, gonad and digestive glands (DG) of abalone fed with all of the five test diets showed significantly high levels of total n-3 polyunsaturated fatty acid (PUFA), eicosapentaenoic acid (EPA), docosapentaenoic acid n-3 (DPAn-3), and docosahexaenoic acid (DHA) than the control group. In all three types of tissue, abalone fed diet supplemented with 1.5% FO showed the highest level of these fatty acids (P < 0.05). For DPAn-3 the higher level was also found in muscle and gonad of abalone fed diet supplemented with 2% FO (P < 0.05). Elongase 2 expression was markedly higher in the muscle of abalone fed diet supplemented with 1.5% FO (P < 0.05), followed by the diet containing 2% FO supplement. For ?6 desaturase, significantly higher expression was observed in muscle of abalone fed with diet containing 0.5% FO supplement (P < 0.05). Supplementation with FO in the normal commercial diet can significantly improve long chain n-3 PUFA level in cultured abalone, with 1.5% being the most effective supplementation level. PMID- 21553073 TI - [Managing comorbidities of inflammatory rheumatic diseases]. AB - Patients with inflammatory rheumatic diseases often suffer from considerable comorbidities that can arise due to the chronic systemic inflammatory activity of the rheumatic disease itself, disorders of immune defense, or as a result of antirheumatic treatment; they can also occur independently. For example, almost 50% of patients with rheumatoid arthritis already exhibit two further chronic diseases at the time of initial manifestation. With regard to the elevated mortality observed in patients with rheumatism, particularly cardiovascular morbidity and increased predisposition to infections are of note. In addition, this article addresses further important possible concomitant diseases, i.e., osteoporosis and tumor diseases. A ground rule is to identify comorbidities and treat them just as diligently as the underlying rheumatic disease so that the patient with rheumatism should be accompanied by an interdisciplinary team of internists during each phase of the disease. Effective control of the systemic inflammatory activity may serve to reduce the risk of certain cardiovascular and neoplastic comorbidities. PMID- 21553074 TI - Generation of mice with a conditional Stat1 null allele. AB - Interferons (IFNs) are key cytokines in the innate immune response that also bridge the gap to adaptive immunity. Signaling upon stimulation by IFN type I, II and III is mediated by the Jak-Stat pathway. STAT1 is activated by all three IFN receptor complexes and absence of STAT1 from mice increases their susceptibility to pathogens. In addition, depending on the setting, STAT1 can act as tumor suppressor or oncogene. Here we report the generation and detailed functional characterization of a conditional Stat1 knockout mouse. We show the integrity of the conditional Stat1 locus and report successful in vivo deletion by means of a ubiquitous and a tissue-specific Cre recombinase. The conditional Stat1 null allele represents an important tool for identifying novel and cell-autonomous STAT1 functions in infection and cancer. PMID- 21553075 TI - Gene-environment interaction and the intergenerational transmission of parenting: testing the differential-susceptibility hypothesis. AB - The current study evaluated the differential-susceptibility hypothesis in explaining the intergenerational transmission of parenting, using data from the National Longitudinal Study of Adolescent Health (Add Health). Exposure to maternal parenting was measured prospectively when respondents were adolescents and parental stress was measured when they were parents themselves, some 14 years later, on average. Cumulative-genetic plasticity was measured by dominantly coding the presence of putative plasticity alleles from four genes: the 10R allele of DAT1, the A1 allele of DRD2, the 7R allele of DRD4, and the short allele of 5HTTLPR. Results showed that the more plasticity alleles individuals carried (range 0-4), the more that parenting experienced in adolescence predicted future parenting experience. Those respondents with the most plasticity alleles not only experienced the highest levels of parental stress when exposed to negative maternal parenting in adolescence but the lowest levels when exposed to positive maternal parenting in adolescence. These results indicate that differential susceptibility is operative in the case of the intergenerational transmission of parenting, which could explain why estimates of such transmission have proven so modest in studies which fail to consider GXE interactions. PMID- 21553076 TI - Left ventricular filling patterns in patients with previous myocardial infarction measured by conventional cine cardiac magnetic resonance. AB - To explore left ventricular filling patterns in patients with a history of previous myocardial infarction (MI) using time-volume curves obtained from conventional cine-cardiac magnetic resonance (CMR) examinations. Consecutive patients with a history of previous MI who were referred for CMR evaluation constituted the study population, and a consecutive cohort of sex and age-matched patients with a normal CMR constituted the control group. The following CMR diastolic parameters were evaluated: peak filling rate (PFR), time to PFR (tPFR), normalised PFR adjusted for diastolic volume at PFR (nPFR), and percent RR interval between end systole and PFR. Fifty patients were included, 25 with a history of previous MI and 25 control. The mean age was 59.6 +/- 13.9 years and 27 (54%) were male. Within the control group, age was significantly related to PFR (r = -0.53, p = 0.007), whereas among patients with previous MI age was not related to PFR (r = -0.16, p = 0.44). PFR (252.4 +/- 96.7 ml/s vs. 316.0 +/- 126.4 ml/s, p = 0.05) and nPFR (1.6 +/- 1.2 vs. 3.3 +/- 1.5, p < 0.001) were significantly lower in patients with previous MI, whereas no significant differences were detected regarding tPFR (143.0 +/- 67.5 ms vs. 176.2 +/- 83.9 ms, p = 0.13) and % RR to PFR (18.1 +/- 9.7% vs. 20.6 +/- 12.2%, p = 0.44). MI size was related to LV ejection fraction (r = -0.76, p < 0.001), PFR (r = -0.40, p = 0.004), nPFR (r = -0.52, p < 0.001) and left atrium area (r = 0.40, p = 0.004). Patients at the lowest PFR quartile (<200 ml/s) showed a larger MI size (Q1 26.5 +/- 25.5%, Q2 15.5 +/- 20.9%, Q3 6.3 +/- 12.4%, Q4 8.8 +/- 14.1%, p = 0.04). At multivariate analysis, MI size was the only independent predictor of the lowest PFR (p = 0.017). Infarct size has an impact on LV filling profiles, as assessed by conventional cine CMR without additional specific pulse sequences. PMID- 21553077 TI - Association between psoriasis and incident cancer: the Iowa's Women's Health Study. AB - INTRODUCTION: Studies have reported higher cancer risk in individuals with psoriasis, a chronic inflammatory autoimmune disease; however, adjustment for potential confounders was lacking. METHODS: We examined the association of psoriasis with cancer incidence in 32,910 women after age 65 in the IWHS cohort linked to Medicare. Psoriasis was defined as: 2+ psoriasis claims from any Medicare file during 1991-2004 or 1+ psoriasis claim from a dermatologist (n = 719). Severe psoriasis was defined as 4+ psoriasis claims from a dermatologist in any year (n = 121). Cox proportional hazards regression, with psoriasis as a time dependent variable was conducted to calculate hazard ratios (HR) and 95% confidence intervals (CI) of total (n = 6,488), breast (n = 2,066), lung (n = 742), and colon cancers (n = 947). RESULTS: With age-adjustment, psoriasis (yes vs. no) was associated with increased risk of lung 1.9 (95% CI: 1.2-3.0), colon 1.6 (95% CI: 1.1-2.5), and total cancer 1.2 (95% CI, 1.0-1.4). After further adjustment for smoking, body mass index, education, physical activity, and hormone therapy use, only the association for colon cancer remained statistically significant (HR = 1.6, 95% CI: 1.0-2.4) and was stronger for severe psoriasis. CONCLUSION: The observed association between psoriasis and colon cancer may reflect inflammatory or unidentified processes. PMID- 21553078 TI - Dietary carbohydrate, glycemic index, glycemic load, and risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. AB - OBJECTIVE: To evaluate the associations between dietary carbohydrate, glycemic index (GI), glycemic load (GL), and incident prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. METHODS: Between September 1993 and September 2000, 38,343 men were randomized to the screening arm of the trial at one of 10 PLCO centers. A food frequency questionnaire administered at baseline assessed usual dietary intake over the preceding 12 months. Prostate cancer was ascertained by medical follow-up of suspicious screening results and annual mailed questionnaires and confirmed with medical records. Cox proportional hazards regression was used to model the associations of carbohydrate, GI, and GL with prostate cancer risk. RESULTS: During follow-up (median = 9.2 years), 2,436 incident prostate cancers were identified among 30,482 eligible participants. Overall, there were no associations of baseline carbohydrate, GI, or GL with incident prostate cancer in minimally or fully adjusted models. There were no associations when the 228 advanced and 2,208 non-advanced cancers were analyzed separately. CONCLUSIONS: Dietary carbohydrate, GI, and GL were not associated with incident prostate cancer in PLCO. The narrow range of GI in this cohort may have limited our ability to detect associations, an issue that future studies should address. PMID- 21553079 TI - Jose Aboulker (1920-2009). PMID- 21553080 TI - Clinical features of spinal cord sarcoidosis: analysis of 17 neurosarcoidosis patients. AB - The diagnosis of neurosarcoidosis is often difficult; the imaging signs of spinal cord sarcoidosis sometimes mimic those of cervical spondylotic myelopathy, which is common in elderly persons. We examined the characteristics of spinal cord sarcoidosis in Japanese patients with neurosarcoidosis. This case series identified patients with neurosarcoidosis at four general hospitals and one university hospital from April 1998 to September 2010. All diagnoses were based on the diagnostic criteria proposed by Zajicek et al. Seventeen patients (nine men and eight women) were involved: six patients with spinal cord lesions accompanied by cervical spondylosis, five with cerebral lesions, three with cranial nerve lesions, two with meningitis, and one with nerve root lesions. Patients with spinal cord sarcoidosis had a higher onset age, longer duration from onset to diagnosis, reduced leukocytosis in the cerebrospinal fluid (CSF), and lower angiotensin-converting enzyme (ACE) levels in the CSF. The results of this study indicate that diagnosis of spinal cord sarcoidosis requires careful evaluation. PMID- 21553081 TI - Mixed results for GPi-DBS in the treatment of cranio-facial and cranio-cervical dystonia symptoms. AB - The aim of the study is to determine clinical outcomes in patients undergoing Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) for cranio-facial and cranio-cervical dystonia (Meige) symptoms. A total of 6 patients seen between 2002 and 2010 with cranio-facial and cranio-cervical dystonia symptoms were identified from the University of Florida Institutional Review Board approved database. Patients were videotaped using a standardized protocol, and tapes were randomized and blindly reviewed by a movement disorders neurologist. The Unified Dystonia Rating Scale improved 31.6 +/- 23.2% (range: 3.4-63.2%) at 6 months and 63.7 +/- 35.3% (range: 6.3-100%) at 12 months. The Burke-Fahn-Marsden Dystonia Rating Scale improved 45.3 +/- 29.5% (range: 4.7-75.0%) at 6 months and 61.8 +/- 30.9% (range: 16.6-100%) at 12 months. One patient significantly had a very large improvement with little evidence of residual dystonia. Blepharospasm improved in all patients, whereas speech and swallowing did not improve in this cohort. Two patients improved with unilateral GPi-DBS, although one required a contralateral DBS later in the disease course. Two patients were managed with low frequency stimulation (<100 Hz). Two patients had less than 20% benefit. GPi-DBS for cranio facial and cranio-cervical symptoms is an effective strategy to manage a subset of patients who remain unresponsive to optimized medical management. Unilateral stimulation may be an option for some patients, but it remains unclear whether response to single-sided stimulation will be sustainable. The mixed results of this GPi-DBS case series highlight the need for a careful re-examination of selection criteria, alternative brain targets, and possibly rescue leads for patients who are non-responders to the GPi target. PMID- 21553082 TI - Secondary infarction in single or in multiple vascular territories: two different entities following subarachnoid hemorrhage? AB - The pathogenesis of secondary infarctions (SI) after aneurysmal subarachnoid hemorrhage (SAH) is poorly understood. To assess whether SI in single (SSI) or multiple (MSI) vascular territories represent different disease entities, we compared clinical profiles of patients with these patterns of SI. CT/MRI examinations of 448 patients were reviewed for new infarctions within 28 days after SAH, and categorized into SSI or MSI. Only patients with adequate follow-up imaging excluding any new infarctions were included for analysis (269 patients). Procedure-related infarctions were excluded. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were calculated for patients with SSI or MSI versus patients without SI to analyze differences in demographic characteristics, vascular risk factors, disease-related characteristics and treatment modalities. Thirty-six patients had SSI, 53 MSI and 180 no SI. ORs in MSI-patients were >1.5 times higher compared with ORs in SSI-patients for multiple vascular risk factors [MSI:5.4 (2.3-13) versus SSI:1.2 (0.5-2.8)], poor clinical condition on admission [MSI:4.6 (2.4-8.9) versus SSI:2.4 (1.1-5.2)], initial loss of consciousness [MSI:2.6 (1.3-5.3) versus SSI:1.1 (0.5-2.3)] and large amounts of intraventricular blood [MSI:2.9 (1.4-5.8) versus SSI:1.5 (0.7-3.2)]. In multivariate analysis ORs remained higher in MSI for presence of multiple vascular risk factors [MSI:1.9 (1.2-2.9) versus SSI:1.1 (0.8-1.7)] and initial loss of consciousness [MSI:3.0 (1.0-8.9) versus SSI:1.6 (0.6-4.0)]. Our findings suggest that SSI and MSI after SAH are not distinct disease entities. MSI was related to the same characteristics as SSI but to a larger extent, specifically to the presence of multiple vascular risk factors, initial loss of consciousness, larger amounts of intraventricular blood, and poor clinical status on admission. PMID- 21553083 TI - Completeness and utility of interview data from proxy respondents in prenatal care research in rural China. AB - In household surveys, the use of data provided by relatives can increase response rates and generalisability of research findings. This study assessed the quality of data from relatives and the impact of the data source on the association between the use of prenatal care and pregnancy outcomes. Data for 3,673 new mothers and 293 proxy respondents were available from a house-hold survey in 2008 2009 in rural China. Analyses were performed using chi-square test, ANOVA, Kruskal-Wallis test, and logistic regression models. Differences in the studied variables were small, but proxy respondents were slightly more likely to have missing data than the new mothers. Differences and missing data were more common for the use of prenatal care and outcome variables (mode of delivery, place of delivery, birth weight, use of postnatal care, and gestational age at birth) than for the background characteristics of the participants. Husbands' reports were closer to the index reports than that of the other proxies. The associations between the exposures and outcomes were mostly similar between the proxy and index respondents. Relatives can be interviewed instead of women to study prenatal care without a substantial negative impact on study results. Studies using proxy respondents should stratify the analysis by type of respondents. PMID- 21553084 TI - A case of bacteremia caused by Hafnia paralvei. AB - The genus Hafnia, a member of the Enterobacteriaceae, is widespread in nature and rarely causes human infection. We describe a case of an 85-year-old Japanese man hospitalized consequent to suspected cholecystitis, in which Hafnia sp. was recovered from the blood culture concomitantly with Enterococcus faecalis. Sequencing of the 16S ribosomal RNA gene sequence and phenotyping with ID 32 E revealed that the recovered Hafnia sp. was considered to be Hafnia alvei genomosp. 2 (ATCC 29927), recently reclassified as Hafnia paralvei. The patient recovered uneventfully with antimicrobial therapies. PMID- 21553085 TI - Fitting and validating the genomic evaluation model to Polish Holstein-Friesian cattle. AB - The aim of the study was to fit the genomic evaluation model to Polish Holstein Friesian dairy cattle. A training data set for the estimation of additive effects of single nucleotide polymorphisms (SNPs) consisted of 1227 Polish Holstein Friesian bulls. Genotypes were obtained by the use of Illumina BovineSNP50 Genotyping BeadChip. Altogether 29 traits were considered: milk-, fat- and protein- yields, somatic cell score, four female fertility traits, and 21 traits describing conformation. The prediction of direct genomic values was based on a mixed model containing deregressed national proofs as a dependent variable and random SNP effects as independent variables. The correlations between direct genomic values and conventional estimated breeding values estimated for the whole data set were overall very high and varied between 0.98 for production traits and 0.78 for non return rates for cows. For the validation data set of 232 bulls the corresponding correlations were 0.38 for milk-, 0.37 for protein-, and 0.32 for fat yields, while the correlations between genomic enhanced breeding values and conventional estimated breeding values for the four traits were: 0.43, 0.44, 0.31, and 0.35. This model was able to pass the interbull validation criteria for genomic selection, which indicates that it is realistic to implement genomic selection in Polish Holstein-Friesian cattle. PMID- 21553086 TI - Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y DOTATATE and tandem 90Y/177Lu-DOTATATE: which is a better therapy option? AB - PURPOSE: Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues is a treatment option for patients with disseminated neuroendocrine tumours (NET). A combination treatment using the high-energy 90Y beta emitter for larger lesions and the lower energy 177Lu for smaller lesions has been postulated in the literature.The aim of the study was to evaluate combined 90Y/177Lu-DOTATATE therapy in comparison to 90Y-DOTATATE alone. METHODS: Fifty patients with disseminated NET were included in the study prospectively and divided into two groups: group A (n=25) was treated with 90Y-DOTATATE, whereas group B (n=25) received the 1:1 90Y/177Lu-DOTATATE. The administered activity was based on 3.7 GBq/m2 body surface area in three to five cycles, with amino acid infusion for nephroprotection. RESULTS: The median overall survival time in group A was 26.2 months while in group B median survival was not reached. Overall survival was significantly higher in group B (p=0.027). Median event-free survival time in group A was 21.4 months and in group B 29.4 months (p>0.1). At the 12-month follow-up, comparison of group A vs group B showed stable disease (SD) in 13 vs 16 patients, disease regression (RD) in 5 vs 3 patients and disease progression (PD) in 3 vs 4 patients; 4 and 2 patients died, respectively. The 24 month follow-up results were SD in nine vs ten patients, RD in one patient vs none and PD in four patients in both groups; three and four patients died, respectively. Side effects were rare and mild. CONCLUSION: The results indicate that therapy with tandem radioisotopes (90Y/177Lu-DOTATATE) provides longer overall survival than with a single radioisotope (90Y-DOTATATE) and the safety of both methods is comparable. PMID- 21553089 TI - Manifestation of lymphoma expansion following lymphatic drainage on 18F-FDG PET/CT. PMID- 21553087 TI - The potential use of 2-[18F]fluoro-2-deoxy-D-galactose as a PET/CT tracer for detection of hepatocellular carcinoma. AB - PURPOSE: The aim of the study was to evaluate the feasibility of using the hepatocyte-specific positron emission tomography (PET) tracer 2-[(18)F]fluoro-2 deoxy-D-galactose (FDGal) as a tracer for hepatocellular carcinoma (HCC). METHODS: In addition to standard clinical investigations, 39 patients with known HCC or suspected of having HCC underwent a partial-body FDGal PET/CT (from base of skull to mid-thigh). Diagnosis of HCC was based on internationally approved criteria. FDGal PET/CT images were analysed for areas with high (hot spots) or low (cold spots) tracer accumulation when compared to surrounding tissue. RESULTS: Seven patients did not have HCC and FDGal PET/CT was negative in each of them. Twenty-three patients had HCC and were included before treatment. FDGal PET/CT correctly identified 22 of these patients, which was comparable to contrast-enhanced CT. Interestingly, FDGal PET/CT was conclusive in 12 patients in whom conventional imaging techniques were inconclusive and required additional diagnostic investigations or close follow-up. Nine patients were included after treatment of HCC and in these patients FDGal PET/CT was able to distinguish between viable tumour tissue as hot spots and areas with low metabolic activity as cold spots. FDGal PET/CT detected extrahepatic disease in nine patients which was a novel finding in eight patients. CONCLUSION: FDGal PET/CT has great clinical potential as a PET tracer for detection of extra- but also intrahepatic HCC. In the present study, the specificity of FDGal PET/CT was 100%, which is very promising but needs to be confirmed in a larger, prospective study. PMID- 21553088 TI - Effect of amino acid infusion on potassium serum levels in neuroendocrine tumour patients treated with targeted radiopeptide therapy. AB - PURPOSE: Administration of positively charged amino acids has been introduced to reduce the nephrotoxicity of targeted radiopeptide therapy (TRT). However, the amino acid solution may have side effects, including hyperkalaemia. The aim of this study was to evaluate the frequency and the magnitude of hyperkalaemia in neuroendocrine tumour (NET) patients undergoing TRT. METHODS: Enrolled in the study were 31 patients with NET eligible for TRT with [(90)Y DOTA(0),Tyr(3)]octreotide ((90)Y-DOTATOC). Their mean age was 54 +/- 14 years. Of these 31 patients, 21 (67%) were referred for the first treatment cycle, while 10 (33%) were referred for a subsequent therapy cycle. Patients were treated with therapeutic doses of (90)Y-DOTATOC ranging from 7,030 to 35,520 MBq. To inhibit tubular reabsorption of (90)Y-DOTATOC, 1 l of physiological saline solution containing 25 g of arginine hydrochloride and 25 g of lysine hydrochloride was given over 4 h starting 1 h before (90)Y-DOTATOC injection. All patients underwent a standard biochemical blood analysis at baseline, and 4 h and 24 h after the beginning of the amino acid infusion. RESULTS: ANOVA repeated measures showed a significant overall effect on K(+) levels over time (F = 118.2, df = 2, P < 0.0001). Mean serum levels of K(+) were 4.00 +/- 0.33 mmol/l at baseline, 5.47 +/- 0.57 mmol/l at 4 h, and 4.38 +/- 0.63 mmol/l at 24 h after the beginning of the infusion. Post-hoc analysis showed that K(+) levels at 4 h were significantly (P < 0.05) higher than at baseline. K(+) levels at 24 h were significantly (P < 0.05) lower than at 4 h but they were still significantly (P < 0.05) higher than K(+) levels at baseline. On a subject-by-subject basis, none of the 31 patients had increased K(+) levels at baseline. At 4 h, 24 of the 31 patients (77%) had K(+) levels above the normal range, and 6 patients (19%) experienced severe hyperkalaemia (K(+) >= 6 mmol/l). All patients with increased K(+) levels were clinically asymptomatic. At 24 h, only 4 patients (13%) had increased K(+) serum levels. The magnitude of the increase in K(+) levels between baseline and 4 h was relatively homogeneous over the whole group (1.41 +/- 0.50 mmol/l) and it was not related (linear regression, P>0.05) to baseline K(+) levels. Intravenous administration of 40 mg furosemide 1 h after the beginning of the amino acid infusion did not have a significant effect on K(+) levels (P>0.05). No clinical characteristic was predictive for the increase in K(+) levels (chi-squared test, P > 0.05). CONCLUSION: Hyperkalaemia is a frequent, potentially life-threatening side effect of basic amino acid infusion during TRT. K(+) levels 4 h after the beginning of the infusion should be monitored in patients at risk of complications, such as those with heart disease and those with risk factors for nephrotoxicity. PMID- 21553090 TI - Comparison of dopamine turnover, dopamine influx constant and activity ratio of striatum and occipital brain with 18F-dopa brain PET in normal controls and patients with Parkinson's disease. AB - PURPOSE: The aim of the study was to estimate normal ranges and test-retest measures for various parameters characterising dopamine metabolism from a prolonged (18)F-dopa positron emission tomography (PET) measurement using a reference tissue model and compare their value for the detection of early Parkinson's disease (PD). METHODS: Healthy volunteers (n = 9) and patients (n = 36) in an early stage of PD underwent an (18)F-dopa PET measurement lasting 4 h. The influx rate constant k(occ) and the effective distribution volume ratio (EDVR, its inverse is an indicator for dopamine turnover) were estimated by a graphical approach using dynamic data in the striatum and, as a reference region, the occipital cortex. Furthermore, ratios of activity concentrations between striatum and occipital brain taken for three time intervals completed the data analysis. All parameters were determined both in eight small volumes of interest placed in the striatum as well as averaged for caudate nucleus and putamen. For the control group, reproducibility was checked in a second study 3 months later and ranges for normal values were derived from mean +/- 2 standard deviations. Receiver-operating characteristic (ROC) analyses were performed to assess the value of the parameters for diagnostic purposes. RESULTS: Patients with early stage PD and healthy volunteers could be separated by the values of the putamen, not the caudate nucleus. The normal ranges of the putamen were 0.0151-0.0216/min for the influx rate constant k(occ) and 2.02-3.00 for EDVR. For the various time intervals used the striato-occipital ratios yielded 2.24-3.06, 2.43-3.42 and 2.35 3.21, respectively. Patients were characterised by significantly lower values (p < 0.001) and significant differences between ipsi- and contralateral sides (p < 0.001) with regard to their clinical symptoms and a rostrocaudal gradient. EDVR as well as k(occ) for the putamen were able to effectively differentiate between groups (sensitivity >97%, specificity 100%). In contrast, striato-occipital ratios showed a sensitivity of about only 85%. CONCLUSION: For clinical applications, our data do not demonstrate any superiority of the EDVR determination compared to influx rate constant, while requiring long and tedious acquisition protocols. The normal range estimates do not represent absolute quantitative measures for dopamine metabolism but are specific for the chosen acquisition and processing procedures. PMID- 21553091 TI - Imaging of programmed cell death in arrhythmogenic right ventricle cardiomyopathy/dysplasia. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a myocardial disease that predominantly affects the right ventricle (RV). Its hallmark feature is fibrofatty replacement of the RV myocardium. Apoptosis in ARVC/D has been proposed as an important process that mediates the slow, ongoing loss of heart muscle cells which is followed by ventricular dysfunction. We aimed to establish whether cardiac apoptosis can be assessed noninvasively in patients with ARVC/D. METHODS: Six patients fulfilling the ARVC/D criteria were studied. Regional myocardial apoptosis was assessed with (99m)Tc-annexin V scintigraphy. RESULTS: Overall, the RV wall showed a higher (99m)Tc-annexin V signal than the left ventricular wall (p = 0.049) and the interventricular septum (p = 0.026). However, significantly increased uptake of (99m)Tc-annexin V in the RV was present in only three of the six ARVC/D patients (p = 0.001, compared to (99m)Tc annexin V uptake in the RV wall of the other three patients). CONCLUSION: Our results are suggestive of a chamber-specific apoptotic process. Although the role of apoptosis in ARVC/D is unsolved, the ability to assess apoptosis noninvasively may aid in the diagnostic course. In addition, the ability to detect apoptosis in vivo with (99m)Tc-annexin V scintigraphy might allow individual monitoring of disease progression and response to diverse treatments aimed at counteracting ARVC/D progression. PMID- 21553092 TI - Skeletal X-ray and dental methods in child victims of the Southeast Asian Tsunami.